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[9550512] BACKGROUND AND PURPOSE Arm function recovery is notoriously poor in stroke patients . The effect of treatment modalities , particularly those directed at improving upper limb function , has been studied primarily in chronic stroke patients . The purpose of this study was to investigate the effect of a specific therapeutic intervention on arm function in the acute phase after stroke . METHODS In a single-blind , r and omized , controlled multicenter trial , 100 consecutive patients were allocated to either an experimental group that received an additional treatment of sensorimotor stimulation or to a control group . The intervention was applied for 6 weeks . Patients were evaluated for level of impairment ( Brunnström-Fugl-Meyer test ) and disability ( Action Research Arm test , Barthel Index ) before , midway , and after the intervention period and at follow-up 6 and 12 months after stroke . RESULTS Patients in the experimental group performed better on the Brunnström-Fugl-Meyer test than those in the control group throughout the study period , but differences were significant only at follow-up . Results on the Action Research Arm test and Barthel Index revealed no effect at the level of disability . The effect of the therapy was attributed to the repetitive stimulation of muscle activity . The treatment was most effective in patients with a severe motor deficit and hemianopia or hemi-inattention . No adverse effects due to the intervention were found . CONCLUSIONS Adding a specific intervention during the acute phase after stroke improved motor recovery , which was apparent 1 year later . These results emphasize the potential beneficial effect of therapeutic interventions for the arm [12920254] BACKGROUND AND PURPOSE Rehabilitation care after stroke is highly variable and increasingly shorter in duration . The effect of therapeutic exercise on impairments and functional limitations after stroke is not clear . The objective of this study was to determine whether a structured , progressive , physiologically based exercise program for subacute stroke produces gains greater than those attributable to spontaneous recovery and usual care . METHODS This r and omized , controlled , single-blind clinical trial was conducted in a metropolitan area and 17 participating healthcare institutions . We included persons with stroke who were living in the community . One hundred patients ( mean age , 70 years ; mean Orpington score , 3.4 ) consented and were r and omized from a screened sample of 582 . Ninety-two subjects completed the trial . Intervention was a structured , progressive , physiologically based , therapist-supervised , in-home program of thirty-six 90-minute sessions over 12 weeks targeting flexibility , strength , balance , endurance , and upper-extremity function . Main outcome measures were postintervention strength ( ankle and knee isometric peak torque , grip strength ) , upper- and lower-extremity motor control ( Fugl Meyer ) , balance ( Berg and functional reach ) , endurance ( peak aerobic capacity and exercise duration ) , upper-extremity function ( Wolf Motor Function Test ) , and mobility ( timed 10-m walk and 6-minute walk distance ) . RESULTS In the intention-to-treat multivariate analysis of variance testing the overall effect , the intervention produced greater gains than usual care ( Wilk 's lambda=0.64 , P=0.0056 ) . Both intervention and usual care groups improved in strength , balance , upper- and lower-extremity motor control , upper-extremity function , and gait velocity . Gains for the intervention group exceeded those in the usual care group in balance , endurance , peak aerobic capacity , and mobility . Upper-extremity gains exceeded those in the usual care group only in patients with higher baseline function . CONCLUSIONS This structured , progressive program of therapeutic exercise in persons who had completed acute rehabilitation services produced gains in endurance , balance , and mobility beyond those attributable to spontaneous recovery and usual care [15929503] Background : St and ing is believed to have benefits in addressing motor and sensory impairments after stroke . One device to facilitate st and ing for severely disabled patients is the Oswestry St and ing Frame . Objective : To evaluate the effectiveness of the Oswestry St and ing Frame for severely disabled stroke patients . Design : A single centre , r and omized controlled trial . Setting : An inpatient stroke rehabilitation unit . Subjects : Patients were recruited if they had a clinical diagnosis of stroke , were medically stable and unable to achieve any score on the Trunk Control Test or unable to st and in mid-line without the assistance of two therapists . Intervention : The intervention ( n=71 ) and control ( n=69 ) groups both received usual stroke unit care but the intervention group also received a minimum of 14 consecutive days ' treatment using the st and ing frame . Main outcome measures : The primary outcome measure was the Rivermead Mobility Index ( RMI ) . Secondary measures included the Barthel Index ; the Rivermead Motor Assessment ; the balanced sitting and sitting to st and ing components of the Motor Assessment Scale ; the Trunk Control Test and the Hospital Anxiety and Depression Scale . Blind assessment was undertaken at baseline , six weeks , 12 weeks and six months post stroke . Information on re source use was also collected . Results : There was no statistically significant difference between groups in any of the outcome measures or for re source use . Mann-Whitney U-tests for the RMI change from baseline scores to six weeks , 12 weeks and six months post stroke were p=0.310 ; p=0.970 and p=0.282 , respectively . Conclusion : Use of the Oswestry St and ing Frame did not improve clinical outcome or provide re source savings for this severely disabled patient group [19321521] Objective : To determine the benefits of additional therapy specifically directed at the h and in people with acquired brain impairment . Design : An assessor-blinded r and omized controlled trial . Setting : Rehabilitation hospital . Participants : A sample of 39 adults with h and impairment following stroke ( 90 % ) or traumatic brain injury ( 10 % ) . The median ( interquartile ) time since injury was 1.6 months ( 0.5—3.5 months ) . Intervention : The experimental group ( n = 20 ) received an additional one-hour session of task-specific motor training for the h and five times a week over a six-week period . The training was administered on a one-to-one basis . The control group ( n = 19 ) received st and ard care which consisted of 10 minutes of h and therapy three times a week . Both groups continued to receive therapy directed at the shoulder and elbow . Outcome measures : Primary outcomes were the Action Research Arm and Summed Manual Muscle Tests measured at the beginning and end of the six-week period . Results : The mean ( SD ) Action Research Arm Test values for experimental participants improved from the beginning to the end of study from 10 points ( 15 ) to 21 points ( 23 ) and the equivalent values for the Summed Manual Muscle Test improved from 35 % ( 33 ) to 49 % ( 35 ) . There were similar improvements in control participants . The mean between-group differences for the Action Research Arm and Summed Manual Muscle Tests were -6 points ( 95 % confidence interval ( CI ) , -20 to 8) and 3 % ( 95 % CI , -10 to 16 ) , respectively . Conclusion : H and and overall arm function of all participants improved over the six-week period , however there was not a clear benefit from providing additional h and therapy [15194251] BACKGROUND The incidence of stroke is predicted to rise because of the rapidly ageing population . However , over the past two decades , findings of r and omised trials have identified several interventions that are effective in prevention of stroke . Reliable data on time-trends in stroke incidence , major risk factors , and use of preventive treatments in an ageing population are required to ascertain whether implementation of preventive strategies can offset the predicted rise in stroke incidence . We aim ed to obtain these data . METHODS We ascertained changes in incidence of transient ischaemic attack and stroke , risk factors , and premorbid use of preventive treatments from 1981 - 84 ( Oxford Community Stroke Project ; OCSP ) to 2002 - 04 ( Oxford Vascular Study ; OXVASC ) . FINDINGS Of 476 patients with transient ischaemic attacks or strokes in OXVASC , 262 strokes and 93 transient ischaemic attacks were incident events . Despite more complete case-ascertainment than in OCSP , age-adjusted and sex-adjusted incidence of first-ever stroke fell by 29 % ( relative incidence 0.71 , 95 % CI 0.61 - 0.83 , p=0.0002 ) . Incidence declined by more than 50 % for primary intracerebral haemorrhage ( 0.47 , 0.27 - 0.83 , p=0.01 ) but was unchanged for subarachnoid haemorrhage ( 0.83 , 0.44 - 1.57 , p=0.57 ) . Thus , although 28 % more incident strokes ( 366 vs 286 ) were expected in OXVASC due to demographic change alone ( 33 % increase in those aged 75 or older ) , the observed number fell ( 262 vs 286 ) . Major reductions were recorded in mortality rates for incident stroke ( 0.63 , 0.44 - 0.90 , p=0.02 ) and in incidence of disabling or fatal stroke ( 0.60 , 0.50 - 0.73 , p<0.0001 ) , but no change was seen in case-fatality due to incident stroke ( 17.2 % vs 17.8 % ; age and sex adjusted relative risk 0.85 , 95 % CI 0.57 - 1.28 , p=0.45 ) . Comparison of premorbid risk factors revealed substantial reductions in the proportion of smokers , mean total cholesterol , and mean systolic and diastolic blood pressures and major increases in premorbid treatment with antiplatelet , lipid-lowering , and blood pressure lowering drugs ( all p<0.0001 ) . INTERPRETATION The age-specific incidence of major stroke in Oxfordshire has fallen by 40 % over the past 20 years in association with increased use of preventive treatments and major reductions in premorbid risk factors [17204680] Background and Purpose — The success of gait rehabilitation after stroke depends on active walking exercises . However , the disabling after-effects of stroke often make such exercises impossible at the onset of therapy . To facilitate treadmill training of paraparetic patients , a robot-driven gait orthosis ( Lokomat ) was developed . We investigated the effects of the Lokomat when used with hemiparetic patients . Methods — The authors conducted a r and omized , controlled pilot study of 30 acute stroke survivors . The treatment group received 30 minutes of robotic training daily and the control group 30 minutes of conventional physiotherapy daily in addition to 30 minutes of conventional physiotherapy for each group . Outcome measures were independence of gait , gait speed , gait parameters , and body tissue composition . Results — After 4 weeks of therapy , the walking ability of the Lokomat group and the control group expressed as the functional ambulation classification was significantly improved . The functional ambulation category ( median± interquartile range ) was at baseline 0±0 in control and 0±1 in the therapy group and increased after therapy to 1±3 in both groups significantly ( P=0.01 ) . There was no significant difference in gain of these parameters between the groups . The Lokomat group had a significantly longer single stance phase ( sec ; mean±SEM ) on the paretic leg when walking on the floor . At baseline , it was 0.19±0.17 and after therapy 0.49±0.07 ( P=0.014 ) . The control group had increased their body weight approximately 1.33±1.40 kg ( mean±SEM ; P=0.046 ) , mostly as fat mass , whereas the Lokomat group had lost fat mass approximately −2.9±1.0 kg ( mean±SEM ; P=0.016 ) and increased their muscle mass approximately 3.36±1.4 kg ( mean± SEM ; P=0.031 ) . Conclusions — This pilot study indicates that Lokomat therapy is a promising intervention for gait rehabilitation . Although there was no difference between groups in gain of functional scores , the Lokomat group showed an advantage of robotic training over conventional physiotherapy in improvement of gait abnormality and body tissue composition [15293485] Objective : To evaluate the efficacy of a task-orientated intervention in enhancing competence in walking in people with stroke . Design : Two-centre observer-blinded stratified block-r and omized controlled trial . Setting : General community . Subjects : Between May 2000 and February 2003 , 91 individuals with a residual walking deficit within one year of a first or recurrent stroke consented to participate . Interventions : The experimental intervention comprised 10 functional tasks design ed to strengthen the lower extremities and enhance walking balance , speed and distance . The control intervention involved the practice of upper extremity activities . Subjects in both groups attended sessions three times a week for six weeks . Main measures : Six-minute walk test ( SMWT ) , 5-m walk ( comfortable and maximum pace ) , Berg Balance Scale , timed ‘ up and go ’ . Results : At baseline , subjects in the experimental ( n = 44 ) and control ( n = 47 ) groups walked an average distance of 209 m ( SD = 126 ) and 204 m ( SD = 131 ) , respectively , on the SMWT . Mean improvements of 40 m ( SD = 72 ) , and 5 m ( SD = 66 ) were observed following the experimental and control interventions , respectively . The between-group difference was 35 m ( 95 % confidence interval ( CI ) 7 , 64 ) . Significant between-group effects of 0.21 m/s ( 95 % CI 0.12 , 0.30 ) and of 0.11 m/s ( 95 % CI 0.03 , 0.19 ) in maximum and comfortable walking speed , respectively , were observed . People with a mild , moderate or severe walking deficit at baseline improved an average of 36 ( SD = 96 ) , 55 ( SD = 56 ) and 18 m ( SD = 23 ) , respectively , in SMWT performance following the experimental intervention . Conclusions : Study findings support the efficacy of a task-orientated intervention in enhancing walking distance and speed in the first year post stroke , particularly in people with moderate walking deficits [19229450] OBJECTIVE To analyse the effects of gait therapy for patients after acute stroke in a r and omized controlled trial . METHODS Fifty-six patients with a mean of 8 days post-stroke participated in : ( i ) gait trainer exercise ; ( ii ) walking training over ground ; or ( iii ) conventional treatment . Patients in the gait trainer exercise and walking groups practice d gait for 15 sessions over 3 weeks and received additional physiotherapy . Functional Ambulatory Category and several secondary outcome measures assessing gait and mobility were administered before and after rehabilitation and at 6-month follow-up . Patients also evaluated their own effort . RESULTS Walking ability improved more with intensive walk training compared with conventional treatment ; median Functional Ambulatory Category was zero in all patients at the start of the study , but it was 3 in both walk-training groups and 0.5 in the conventional treatment group at the end of the therapy . Median Functional Ambulatory Category was 4 in both walk-training groups and 2.5 in conventional treatment group at 6-month follow-up . Mean accomplished walking distance was not different between the gait trainer exercise and over ground walking groups . Borg scale indicated more effort in over ground walking . Secondary outcomes also indicated improvements . CONCLUSION Exercise therapy with walking training improved gait function irrespective of the method used , but the time and effort required to achieve the results favour the gait trainer exercise . Early intensive gait training result ed in better walking ability than did conventional treatment [17702703] Objective : To investigate whether provision of additional st and ing practice increases motor recovery and mobility post stroke . Design : A pilot r and omized controlled trial . Setting : A stroke rehabilitation unit in the UK . Participants : Seventeen participants , seven women and ten men , age range 51—92 admitted to the unit 6—58 days post stroke . Intervention : Each participant was r and omly allocated into a control ( conventional physiotherapy ) or treatment ( conventional therapy plus an additional session of st and ing practice ) group . The period of intervention ranged from 14 to 28 days dependent upon length of stay on the unit . Outcome measures : The Gross Functional Tool Section of the Rivermead Motor Assessment , the Trunk Control Test and the Berg Balance Scale were used on admission to the study , at weekly intervals during the intervention , and at 12 weeks ( after discharge ) . Results : Of the 17 participants recruited , three withdrew from the additional intervention group citing fatigue as a barrier and 15 completed the study . Participants completing additional st and ing practice demonstrated higher scores in all motor measures at week 12 , but this difference was not statistically significant . There was a statistically significant difference ( P < 0.05 ) in the changes in Berg Balance score when comparing week 1 with week 12 , in support of the group receiving extra st and ing practice . Conclusions : A larger study is required to establish the value of additional st and ing practice after stroke . This pilot demonstrates that the Gross Functional Tool Section of the Rivermead Motor Assessment and the Berg Balance Scale would be useful in such a study . Fatigue may be a significant barrier to ability to participate in more intensive programmes so screening participants for severe fatigue may be useful [15001789] Background and Purpose — Several studies have investigated the effect of therapeutic interventions for the arm in the acute phase after stroke , with follow-ups at a maximum of 12 months . The aim of this study was to examine the effect of repetitive sensorimotor training of the arm at 5 years after stroke . Subjects and Methods — One hundred consecutive stroke patients were r and omly allocated either to an experimental group that received daily additional sensorimotor stimulation of the arm or to a control group . The intervention period was 6 weeks . Assessment s of the patients were made before , midway , and after intervention , and at 6 and 12 months after stroke . In this study , 62 patients were reassessed at 5 years after stroke . The Brunnström-Fugl-Meyer ( BFM ) test , Action Research Arm ( ARA ) test , and Barthel index ( BI ) were used as the primary outcome measures . Results — At the 5-year follow-up , there was a statistically significant difference for both the BFM and ARA tests in favor of the experimental group . The mean differences in improvement between the groups from the initial evaluation to the 5-year assessment corresponded to 17 points on the BFM and 17.4 on the ARA . No effect was found for the BI . The treatment was most effective in patients with a severe initial motor deficit . Conclusions — Adding a specific intervention for the arm during the acute phase after a stroke result ed in a clinical ly meaningful and long-lasting effect on motor function . The effect can be attributed to early , repetitive , and targeted stimulation [15817001] OBJECTIVES To evaluate the efficacy of a task-oriented walking intervention in improving balance self-efficacy in persons with stroke and to determine whether effects were task-specific , influenced by baseline level of self-efficacy and associated with changes in walking and balance capacity . DESIGN Secondary analysis of a two-center , observer-blinded , r and omized , controlled trial . SETTING General community . PARTICIPANTS Ninety-one individuals with a residual walking deficit within 1 year of a first or recurrent stroke . INTERVENTION Task-oriented interventions targeting walking or upper extremity ( UE ) function were provided three times a week for 6 weeks . MEASUREMENTS Activities-specific Balance Confidence Scale , Six-Minute Walk Test , 5-m walk , Berg Balance Scale , and Timed " Up and Go " administered at baseline and postintervention . RESULTS The walking intervention was associated with a significantly greater average proportional change in balance self-efficacy than the UE intervention . Treatment effects were largest in persons with low self-efficacy at baseline and for activities relating to tasks practice d. In the walking group , change in balance self-efficacy correlated with change in functional walking capacity ( correlation coefficient=0.45 , 95 % confidence interval=0.16 - 0.68 ) . Results of multivariable modeling suggested effect modification by the baseline level of depressive symptoms and a prognostic influence of age , sex , comorbidity , time poststroke , and functional mobility on change in self-efficacy . CONCLUSION Task-oriented walking retraining enhances balance self-efficacy in community-dwelling individuals with chronic stroke . Benefits may be partially the result of improvement in walking capacity . The influence of baseline level of self-efficacy , depressive symptoms , and prognostic variables on treatment effects are of clinical importance and must be verified in future studies [15774435] Objectives : Bobath based ( BB ) and movement science based ( MSB ) physiotherapy interventions are widely used for patients after stroke . There is little evidence to suggest which is most effective . This single-blind r and omised controlled trial evaluated the effect of these treatments on movement abilities and functional independence . Methods : A total of 120 patients admitted to a stroke rehabilitation ward were r and omised into two treatment groups to receive either BB or MSB treatment . Primary outcome measures were the Rivermead Motor Assessment and the Motor Assessment Scale . Secondary measures assessed functional independence , walking speed , arm function , muscle tone , and sensation . Measures were performed by a blinded assessor at baseline , and then at 1 , 3 , and 6 months after baseline . Analysis of serial measurements was performed to compare outcomes between the groups by calculating the area under the curve ( AUC ) and inserting AUC values into Mann-Whitney U tests . Results : Comparison between groups showed no significant difference for any outcome measures . Significance values for the Rivermead Motor Assessment ranged from p = 0.23 to p = 0.97 and for the Motor Assessment Scale from p = 0.29 to p = 0.87 . Conclusions : There were no significant differences in movement abilities or functional independence between patients receiving a BB or an MSB intervention . Therefore the study did not show that one approach was more effective than the other in the treatment of stroke patients [2956448] Abstract The aim of the study was to evaluate the impact of a high-intensive exercise program containing high-intensive functional exercises implemented to real-life situations together with group discussion s on falls and security aspects in stroke subjects with risk of falls . This was a pre-specified secondary outcome for this study . For evaluation , Short Form-36 ( SF-36 ) health-related quality of life ( HRQoL ) and the Geriatric Depression Scale-15 ( GDS-15 ) were used . This was a single-center , single-blinded , r and omized , controlled trial . Consecutive ≥55 years old stroke patients with risk of falls at 3–6 months after first or recurrent stroke were r and omized to the intervention group ( IG , n=15 ) or to the control group ( CG , n=19 ) who received group discussion with focus on hidden dysfunctions but no physical fitness training . The 5-week high-intensive exercise program was related to an improvement in the CG in the SF-36 Mental Component Scale and the Mental Health subscale at 3 months follow-up compared with baseline values while no improvement was seen in the IG at this time . For the SF-36 Physical Component Scale , there was an improvement in the whole study group at 3 and 6 months follow-up compared with baseline values without any significant changes between the IG and CG . The GDS-15 was unchanged throughout the follow-up period for both groups . Based on these data , it is concluded that high-intensive functional exercises implemented in real-life situations should also include education on hidden dysfunctions after stroke instead of solely focus on falls and safety aspects to have a favorable impact on [20558830] Background and Purpose — Increased amount of therapy seems to be beneficial for motor recovery after stroke . The primary aim of the present study was to evaluate the effect of a 4-week community-based intensive motor training program combined with early supported discharge after initial treatment in a comprehensive stroke unit on balance . Secondary aims were to evaluate the effect on other functional outcome measures . Methods — This was a single-blind , r and omized , controlled trial with a 26-week follow-up . Sixty-two patients were recruited within 14 days after stroke and were r and omly allocated to a st and ard treatment group ( n=32 ) or to an intensive motor training group ( n=30 ) receiving 3 sessions of physical therapy and a structured home exercise program in addition to st and ard treatment every week for the first 4 weeks after discharge from hospital . Primary outcome measure was Berg Balance Scale . Secondary measures were Barthel Index , Motor Assessment Scale , Step Test , 5-meter Walk Test , and Stroke Impact Scale . Results — The mean ( SD ) minutes of physical therapy per week was 171.0 ( 65.8 ) in the intensive motor training group vs 85.6(69.9 ) in the st and ard treatment group . There were no statistical significant differences between the groups on any measure at end of follow-up except for a trend toward higher Motor Assessment Scale score ( P=0.059 ) and gait speed ( P=0.095 ) in the intensive motor training group . Conclusion — In this r and omized , controlled trial , a community-based intensive motor training program , doubling the amount of physical therapy during the first 4 weeks after discharge , did not show significant improvement of balance or any other functional outcomes [1640226] Previous research on stroke rehabilitation has not established whether increase in physical therapy lead to better intrinsic recovery from hemiplegia . A detailed study was carried out of recovery of arm function after acute stroke , and compares orthodox physiotherapy with an enhanced therapy regime which increased the amount of treatment as well as using behavioural methods to encourage motor learning . In a single-blind r and omised trial , 132 consecutive stroke patients were assigned to orthodox or enhanced therapy groups . At six months after stroke the enhanced therapy group showed a small but statistically significant advantage in recovery of strength , range and speed of movement . This effect seemed concentrated amongst those who had a milder initial impairment . More work is needed to discover the reasons for this improved recovery , and whether further development of this therapeutic approach might offer clinical ly significant gains for some patients [15482247] Although intervention is effective in reducing the disability associated with stroke , limited re sources mean that physiotherapy services often cease by six months after stroke . The purpose of this clinical trial was to investigate the efficacy of re source -efficient physiotherapy services in improving mobility and quality of life after stroke . Twenty-six people with residual walking difficulties after stroke were r and omised into an experimental or control group after discharge from physiotherapy services . The experimental group participated in a six-week , home-based mobility program . The control group participated in a six-week , home-based program of upper-limb exercises ( i.e. ' sham ' mobility exercises ) . Subjects met with the therapist for prescription of exercises only three times during the six weeks . Strategies used to offset potential problems associated with minimal subject-therapist interaction included videotaped instructions to encourage correct performance of exercises , modification of the environment and involvement of carers to enhance safety , and telephone contact and self-monitoring to promote compliance . St and ing ( Functional Reach ) , walking ( MAS Item 5 ) and quality of life ( SA-SIP30 ) were measured prior to , immediately after , and two months after intervention ceased by an assessor who was blinded to group allocation . Subjects in the experimental group demonstrated significant improvement in st and ing compared to the control group ( p = 0.01 ) which was maintained two months after the cessation of intervention ( p = 0.04 ) . There was no difference between the groups in walking ( p = 0.50 ) or quality of life ( p = 0.70 ) . The six-week , re source -efficient mobility program was effective in improving some of the mobility in people after discharge from stroke rehabilitation . The provision of re source -efficient programs is recommended wherever possible so that people affected by stroke may continue rehabilitation for longer [15574110] The purpose of this study was to investigate whether additional practice of either upper limb or mobility tasks improved functional outcome during inpatient stroke rehabilitation . This prospect i ve , r and omised , single blind clinical trial recruited 30 stroke subjects into either an Upper Limb or a Mobility Group . All subjects received their usual rehabilitation and an additional session of task-related practice using a circuit class format . Independent assessors , blinded to group allocation , tested all subjects . Outcome measures used were three items of the Jebsen Taylor H and Function Test ( JTHFT ) , two arm items of the Motor Assessment Scale ( MAS ) , and three mobility measures , the Timed Up and Go Test ( TUGT ) , Step Test , and Six Minute Walk Test ( 6MWT ) . Both groups improved significantly between pre- and post-tests on all of the mobility measures , however only the Upper Limb Group made a significant improvement on the JTHFT and MAS upper arm items . Following four weeks training , the Mobility Group had better locomotor ability than the Upper Limb Group ( between-group differences in the 6MWT of 116.4 m , 95 % CI 31.4 to 201.3 m , Step Test 2.6 repetitions , 95 % CI -1.0 to 6.2 repetitions , and TUGT -7.6 sec , 95 % CI -15.5 to 0.2 sec ) . The JTHFT dexterity scores in the Upper Limb Group were 6.5 sec ( 95 % CI -7.4 to 20.4 sec ) faster than the Mobility Group . Our findings support the use of additional task-related practice during inpatient stroke rehabilitation . The circuit class format was a practical and effective means to provide supervised additional practice that led to significant and meaningful functional gains [11912111] H and movement recovery and cortical reorganization were studied in 10 subjects with chronic stroke using functional MRI ( fMRI ) before and after training with an intensive finger movement tracking programme . Subjects were assigned r and omly to a treatment or control group . The treatment group received 18 - 20 sessions of finger tracking training using target waveforms under variable conditions . The control group crossed over to receive the same treatment after the control period . For comparison with a healthy population , nine well elderly females were also studied ; however , the well elderly controls did not cross over after the control period . The dependent variables consisted of a Box and Block score to measure prehensile ability ( subjects with stroke only ) , a tracking accuracy score and quantification of active cortical areas using fMRI . For the tracking tests , the subjects tracked a sine wave target on a computer screen with extension and flexion movements of the paretic index finger . Functional brain images were collected from the frontal and parietal lobes of the subject with a 4 tesla magnet . Areas of interest included the sensorimotor cortex ( SMC ) , primary motor area ( M1 ) , primary sensory area ( S1 ) , premotor cortex ( PMC ) and supplementary motor area ( SMA ) . Comparison between all subjects with stroke and all well elderly subjects at pre-test was analysed with two- sample t-tests . Change from pre-test to post-test within subjects was analysed with paired t-tests . Statistical significance was set at P < 0.05 . Stroke treatment subjects demonstrated significant improvement in tracking accuracy , whereas stroke control subjects did not until after crossover treatment . At pre-test , the cortical activation in the subjects with stroke was predominantly ipsilateral to the performing h and , whereas in the well elderly subjects it was contralateral . Activation for the stroke treatment group following training switched to contralateral in SMC , M1 , S1 and PMC . The stroke control group 's activation remained ipsilateral after the control period , but switched to contralateral after crossover to receive treatment . All well elderly subjects maintained predominantly contralateral activation throughout . Transfer of skill to functional activity was shown in significantly improved Box and Block scores for the stroke treatment group , with no such improvement in the stroke control group until after crossover . We concluded that individuals with chronic stroke receiving intensive tracking training showed improved tracking accuracy and grasp and release function , and that these improvements were accompanied by brain reorganization [18955513] Background . Sitting balance and the ability to perform selective trunk movements are important predictors of functional outcome after stroke . However , studies evaluating the effect of exercises aim ed at improving trunk performance are sparse . Objective . To examine the effect of additional trunk exercises on trunk performance after stroke . Methods . An assessor-blinded r and omized controlled trial was carried out at an inpatient stroke rehabilitation center . In total 33 participants were assigned to an experimental group ( n = 17 ) or a control group ( n = 16 ) . In addition to conventional therapy , the experimental group received 10 hours of individual and supervised trunk exercises ; 30 minutes , 4 times a week , for 5 weeks . Trunk performance was evaluated by the Trunk Impairment Scale ( TIS ) and its subscales of static and dynamic sitting balance and coordination . A general linear repeated measures model was used to analyze the results of our study . Results . No significant differences were found pretreatment between the 2 groups for the collected demographic variables , stroke-related parameters , clinical measures , number of therapy sessions received , and primary outcome measure used . Posttreatment , a significantly better improvement was noted in the experimental group compared to the control group for the dynamic sitting balance subscale only ; measuring selective lateral flexion initiated from the upper and lower part of the trunk , ( P = .002 , post hoc power calculation = .90 , effect size = 1.16 ) . Conclusions . Our results suggest that , in addition to conventional therapy , trunk exercises aim ed at improving sitting balance and selective trunk movements have a beneficial effect on the selective performance of lateral flexion of the trunk after stroke [11352620] We used serial positron emission tomography ( PET ) to study training-induced brain plasticity after severe hemiparetic stroke . Ten patients were r and omized to either task-oriented arm training or to a control group and scanned before and after 22.6 + /- 1.6 days of treatment using passive movements as an activation paradigm . Increases of regional cerebral blood flow ( rCBF ) were assessed using statistical parametric mapping ( SPM99 ) . Before treatment , all stroke patients revealed bilateral activation of the inferior parietal cortex ( IPC ) . After task-oriented arm training , activation was found bilaterally in IPC and premotor cortex , but also in the contralateral sensorimotor cortex ( SMC ) . The control group only showed weak activation of the ipsilateral IPC . After treatment , the training group revealed relatively more activation bilaterally in IPC , premotor areas , and in the contralateral SMC . Five normal subjects showed no statistical significant differences between two separate PET studies . In this group of patients , task-oriented arm training induced functional brain reorganization in bilateral sensory and motor systems [9099186] BACKGROUND AND PURPOSE After stroke , the ability to balance in sitting is critical to independence . Although impairments in sitting balance are common , little is known about the effectiveness of rehabilitation strategies design ed to improve it . The purpose of this r and omized placebo-controlled study was to evaluate the effect of a 2-week task-related training program aim ed at increasing distance reached and the contribution of the affected lower leg to support and balance . METHODS Twenty subjects at least 1 year after stroke were r and omized into an experimental or control group . The experimental group participated in a st and ardized training program involving practice of reaching beyond arm 's length . The control group received sham training involving completion of cognitive-manipulative tasks within arm 's length . Performance of reaching in sitting was measured before and after training using electromyography , videotaping , and two force plates . Variables tested were movement time , distance reached , vertical ground reaction forces through the feet , and muscle activity . Subjects were also tested on sit-to-st and , walking , and cognitive tasks . Nineteen subjects completed the study . RESULTS After training , experimental subjects were able to reach faster and further , increase load through the affected foot , and increase activation of affected leg muscles compared with the control group ( P < .01 ) . The experimental group also improved in sit-to-st and . The control group did not improve in reaching or sit-to-st and . Neither group improved in walking . CONCLUSIONS This study provides strong evidence of the efficacy of task-related motor training in improving the ability to balance during seated reaching activities after stroke [12098152] OBJECTIVES To quantify changes in spastic hypertonia during repeated passive isokinetic knee movements in stroke patients and to assess the role of muscle activity . DESIGN A between-groups design with repeated measures . SETTING Rehabilitation center for stroke patients . PARTICIPANTS Ten stroke patients with hypertonia and 10 healthy subjects matched for age and gender . INTERVENTION With an isokinetic apparatus , movements were imposed on the knee in series of 10 repetitions at speeds of 60 degrees /s , 180 degrees /s , and 300 degrees /s . MAIN OUTCOME MEASURES Spastic hypertonia was assessed on the basis of torque measurement and electromyographic activity of the quadriceps , hamstrings , and gastrocnemius muscles . RESULTS Compared with the controls , stroke patients presented a significantly stronger torque reduction during the mid- and endphases of movements at all speeds tested ( P<.05 ) . The strongest torque decline occurred during knee flexion and during the first movements . The effect increased toward the end phase of movements and with increasing speeds . The effect of movement repetitions on torque measurements was unchanged after electromyographic activity was included in the statistical analysis , except during extension movements at 180 degrees /s and 300 degrees /s . CONCLUSION Passive movements of the knee induced a decrease of spastic hypertonia in stroke patients through a combination of reflexive and mechanical factors . The role of these mechanisms is velocity dependent and differs for flexion and extension movements [20410150] Objective : To determine the effectiveness of sit-to-st and training in individuals with stroke . Design : R and omized controlled trial . Setting : Rehabilitation medical centre . Participants : Thirty-two subjects with stroke were r and omly assigned to the control and experimental groups ( n = 16 for each group ) . Interventions : Subjects in both groups received 30 minutes of general physical therapy three times a week for four weeks . Subjects in the experimental group received additional sit-to-st and training for 15 minutes each time . The total amount of therapy received was 45 minutes in the experimental group and 30 minutes in the control group each time . Main outcome measures : The weight-bearing distribution during quiet st and ing , the directional control and maximal excursion during limits of stability test , the scores of Berg Balance Scale and the extensor muscle strength of lower extremity were assessed before and after completing the 12 treatment sessions . Results : Our data showed significant improvements in directional control anteriorly in the experimental group ( from 47.4 (36.6)% to 62.6 (26.1)% ) compared with the control group ( from 68.7 (16.7)% to 62.8 (29.7)% ) ( P = 0.028 ) . A significant improvement in affected hip extensor strength was noted in the experimental group ( from 19.3 (9.8)% to 22.6 (8.4)% ) compared with the control group ( from 24.4 (9.0)% to 22.8 (7.2)% ) ( P = 0.006 ) . Significant improvements were noted only in the experimental group after treatment , including bilateral extensors , except the affected plantar flexors , the weight distribution in st and ing , the maximal excursion ( Panterior = 0.049 ; Paffected = 0.023 ) and the directional control ( Paffected = 0.013 ; Pnon-affected = 0.025 ) . Conclusions : Additional sit-to-st and training is encouraged due to effects on dynamic balance and extensor muscles strength in subjects with stroke [12900678] PURPOSE The purpose of this study was to evaluate the physical and psychosocial effects of an 8-wk community-based functional exercise program in a group of individuals with chronic stroke . METHODS Twenty-five subjects ( mean age 63 yr ) participated in a repeated measures design that evaluated the subjects with two baseline assessment s 1 month apart , one postintervention assessment , and one retention assessment 1 month postintervention . Physical outcome measures assessed were the Berg Balance Test , 12-Minute Walk Test distance , gait speed , and stair climbing speed . Psychosocial measures assessed were the Reintegration to Normal Living Index ( RNL ) and Canadian Occupational Performance Measure ( COPM ) . The 8-wk training consisted of a 60-min , 3 x wk-1 group program that focused on balance , mobility , functional strength , and functional capacity . The program was design ed to be accessible by reducing the need for costly one-on-one supervision , specialized setting s , and expensive equipment . RESULTS Improvements from the exercise program were found for all physical measures and these effects were retained 1-month postintervention . Subjects with lower function improved the most relative to their initial physical status . Significant effects were found for the COPM , but not the RNL Index ; however , subjects with lower RNL improved the most relative to their initial RNL Score . CONCLUSION A short-term community-based exercise program can improve and retain mobility , functional capacity , and balance and result in a demonstrable impact upon the performance of activities and abilities that were considered meaningful to the subjects . Implementation of such community-based programs has potential for improving activity tolerance and reducing the risk for secondary complications common to stroke ( e.g. , falls result ing in fractures and cardiac events ) [1675378] We describe the incidence and natural history of four clinical ly identifiable subgroups of cerebral infa rct ion in a community-based study of 675 patients with first-ever stroke . Of 543 patients with a cerebral infa rct , 92 ( 17 % ) had large anterior circulation infa rcts with both cortical and subcortical involvement ( total anterior circulation infa rcts , TACI ) ; 185 ( 34 % ) had more restricted and predominantly cortical infa rcts ( partial anterior circulation infa rcts , PACI ) ; 129 ( 24 % ) had infa rcts clearly associated with the vertebrobasilar arterial territory ( posterior circulation infa rcts , POCI ) ; and 137 ( 25 % ) had infa rcts confined to the territory of the deep perforating arteries ( lacunar infa rcts , LACI ) . There were striking differences in natural history between the groups . The TACI group had a negligible chance of good functional outcome and mortality was high . More than twice as many deaths were due to the complications of immobility than to direct neurological sequelae of the infa rct . Patients in the PACI group were much more likely to have an early recurrent stroke than were patients in other groups . Those in the POCI group were at greater risk of a recurrent stroke later in the first year after the index event but had the best chance of a good functional outcome . Despite the small anatomical size of the infa rcts in the LACI group , many patients remained substantially h and icapped . The findings have important implication s for the planning of stroke treatment trials and suggest that various therapies could be directed specifically at the subgroups [10768528] OBJECTIVE To evaluate the immediate and retention effects of a 4-week training program on the performance of locomotor-related tasks in chronic stroke . DESIGN R and omized , controlled pilot study with 2-month follow-up . SETTING Rehabilitation center . SUBJECTS A convenience sample consisting of 12 chronic stroke subjects was used . Subjects were r and omly assigned to the experimental or the control group . Three subjects withdrew from the study . INTERVENTION Both experimental and control groups participated in exercise classes three times a week for 4 weeks . The exercise class for the experimental group focused on strengthening the affected lower limb and practicing functional tasks involving the lower limbs , while the control group practice d upper-limb tasks . MAIN OUTCOME MEASURES Lower-limb function was evaluated by measuring walking speed and endurance , peak vertical ground reaction force through the affected foot during sit-to-st and , and the step test . RESULTS The experimental group demonstrated significant immediate and retained ( 2-month follow-up ) improvement ( p < or = .05 ) compared with the control group in walking speed and endurance , force production through the affected leg during sit-to-st and , and the number of repetitions of the step test . CONCLUSION The pilot study provides evidence for the efficacy of a task-related circuit class at improving locomotor function in chronic stroke [15083439] OBJECTIVE To evaluate the immediate and long-term effects of 2 upper-extremity rehabilitation approaches for stroke compared with st and ard care in participants stratified by stroke severity . DESIGN Nonblinded , r and omized controlled trial ( baseline , postintervention , 9mo ) design . SETTING Inpatient rehabilitation hospital and outpatient clinic . PARTICIPANTS Sixty-four patients with recent stroke admitted for inpatient rehabilitation were r and omized within severity strata ( Orpington Prognostic Scale ) into 1 of 3 intervention groups . Forty-four patients completed the 9-month follow-up . INTERVENTIONS St and ard care ( SC ) , functional task practice ( FT ) , and strength training ( ST ) . The FT and ST groups received 20 additional hours of upper-extremity therapy beyond st and ard care distributed over a 4- to 6-week period . MAIN OUTCOME MEASURES Performance measures of impairment ( Fugl-Meyer Assessment ) , strength ( isometric torque ) , and function ( Functional Test of the Hemiparetic Upper Extremity [ FTHUE ] ) . RESULTS Compared with SC participants , those in the FT and ST groups had significantly greater increases in Fugl-Meyer motor scores ( P=.04 ) and isometric torque ( P=.02 ) posttreatment . Treatment benefit was primarily in the less severe participants , where improvement in FT and ST group Fugl-Meyer motor scores more than doubled that of the SC group . Similar results were found for the FTHEU and isometric torque . During the long term , at 9 months , the less severe FT group continued to make gains in isometric muscle torque , significantly exceeding those of the ST group ( P<.05 ) . CONCLUSIONS Task specificity and stroke severity are important factors for rehabilitation of arm use in acute stroke . Twenty hours of upper extremity-specific therapy over 4 to 6 weeks significantly affected functional outcomes . The immediate benefits of a functional task approach were similar to those of a resistance-strength approach , however , the former was more beneficial in the long-term [10421300] BACKGROUND We investigated the effects of different intensities of arm and leg rehabilitation training on the functional recovery of activities of daily living ( ADL ) , walking ability , and dexterity of the paretic arm , in a single-blind r and omised controlled trial . METHODS Within 14 days after stroke onset , 101 severely disabled patients with a primary middle-cerebral-artery stroke were r and omly assigned to : a rehabilitation programme with emphasis on arm training ; a rehabilitation programme with emphasis on leg training ; or a control programme in which the arm and leg were immobilised with an inflatable pressure splint . Each treatment regimen was applied for 30 min , 5 days a week during the first 20 weeks after stroke . In addition , all patients underwent a basic rehabilitation programme . The main outcome measures were ability in ADL ( Barthel index ) , walking ability ( functional ambulation categories ) , and dexterity of the paretic arm ( Action Research arm test ) at 6 , 12 , 20 , and 26 weeks . Analyses were by intention to treat . FINDINGS At week 20 , the leg-training group ( n=31 ) had higher scores than the control group ( n=37 ) for ADL ability ( median 19 [ IQR 16 - 20 ] vs 16 [ 10 - 19 ] , p<0.05 ) , walking ability ( 4 [ 3 - 5 ] vs 3 [ 1 - 4 ] , p<0.05 ) , and dexterity ( 2 [ 0 - 56 ] vs 0 [ 0 - 2 ] , p<0.01 ) . The arm-training group ( n=33 ) differed significantly from the control group only in dexterity ( 9 [ 0 - 39 ] vs 0 [ 0 - 2 ] , p<0.01 ) . There were no significant differences in these endpoints at 20 weeks between the arm-training and leg-training groups . INTERPRETATION Greater intensity of leg rehabilitation improves functional recovery and health-related functional status , whereas greater intensity of arm rehabilitation results in small improvements in dexterity , providing further evidence that exercise therapy primarily induces treatment effects on the abilities at which training is specifically aim ed [18285431] Objective : This pilot r and omized controlled trial evaluated an assistant-led , community-based intervention to improve community mobility and participation after stroke , and examined the potential for independent community ambulation in people with subacute stroke who present with moderate gait deficit . Design : A multicentre , pilot r and omized controlled trial . Setting : Three hospitals and three community setting s in New Zeal and . Subjects : Thirty post-acute , home-dwelling stroke survivors were r and omly allocated to receive intervention in the community ( n = 14 ) or as hospital out patients ( n = 16 ) twice a week for seven weeks . Interventions : The community intervention involved practice of functional gait activities in community environments relevant to each participant . Hospital-based physiotherapy was based upon a Motor Relearning approach . Main measures : The primary outcome measure was gait speed ( m/min ) . Secondary outcomes included endurance ( six-minute walk time ) , Activities-specific Confidence Balance Scale , and the Subjective Index of Physical and Social Outcomes measured at baseline , post intervention and six months . Results : Large gains in gait speed were obtained for participants in both groups : community group mean ( SD ) 16 ( 16.1 ) m/min ; physiotherapy group mean ( SD ) 15.9 ( 16.1 ) m/min , maintained at six months . There were no significant differences between groups for primary and secondary outcomes after treatment ( P = 0.86 ANOVA ) or at six months ( P = 0.83 ANOVA ) . Only 11 participants reported independent community ambulation . Levels of social integration were low to moderate . Conclusions : A community-based gait recovery programme appears a practicable alternative to routine physiotherapy , however independent community ambulation is a challenging rehabilitation goal [12392332] Objective : To determine ( 1 ) the most effective of three treatment approaches to retrain seated weight distribution long-term after stroke and ( 2 ) whether improvements could be generalized to weight distribution in st and ing . Setting : Inpatient rehabilitation unit . Design : Forty asymmetrical acute stroke subjects were r and omly allocated to one of four groups in this pilot study . Changes in weight distribution were compared between the 10 subjects of each of three treatment groups ( task-specific reach , Bobath , or Balance Performance Monitor [ BPM ] feedback training ) and a no specific treatment control group . One week of measurement only was followed by two weeks of daily training sessions with the treatment to which the subject was r and omly allocated . Measurements were performed using the BPM daily before treatment sessions , two weeks after cessation of treatment and 12 weeks post study . Weight distribution was calculated in terms of mean balance ( percentage of total body weight ) or the mean of 300 balance points over a 30-s data run . Results : In the short term , the Bobath approach was the most effective treatment for retraining sitting symmetry after stroke ( p = 0.004 ) . Training with the BPM and no training were also significant ( p = 0.038 and p = 0.035 respectively ) and task-specific reach training failed to reach significance ( p = 0.26 ) . At 12 weeks post study 83 % of the BPM training group , 38 % of the task-specific reach group , 29 % of the Bobath group and 0 % of the untrained group were found to be distributing their weight to both sides . Some generalization of symmetry training in sitting to st and ing was noted in the BPM training group which appeared to persist long term . Conclusions : Results should be treated with caution due to the small group sizes . However , these preliminary endings suggest that it might be possible to restore postural symmetry in sitting in the early stages of rehabilitation with therapy that focuses on creating an awareness of body position [8053790] Compensation by the unaffected upper extremity ( UE ) was studied in stroke patients who were unable to use the affected UE . The main aim was to evaluate the need of teaching compensatory techniques to stroke patients during rehabilitation of UE function . The study was prospect i ve and community based and included 636 consecutive acute stroke patients . UE function and UE paresis were assessed weekly using the Barthel Index subscores for feeding and grooming and the Sc and inavian Stroke Scale ( SSS ) subscores for arm and h and . Rehabilitation was performed according to the Bobath technique . Initially , 214 had severe UE paresis according to SSS ; the arm could not move against gravity and the fingertips could not reach palm . In 64 of the 115 patients discharged alive , the affected UE definitely remained useless despite intensive and longst and ing rehabilitation . Improvement of UE function was seen in 25 of these patients ( 39 % ) and was possible only through compensation by the unaffected UE . Patients who gained UE function by compensation were younger ( p < 0.01 ) , had less severe stroke ( p < 0.01 ) , smaller ( p < 0.01 ) , and subcortically located ( p = 0.02 ) lesions and less affection of higher cortical function ( p = 0.01 ) . Recovery of UE function in more than half of the stroke patients with initial severe UE paresis can be achieved only by compensation by the unaffected UE [15537991] This trial compares the effects of task-oriented physical therapy ( PT ) provided with and without the use of rehabilitation technology on locomotor recovery in 63 persons with subacute stroke . Participants in the experimental ( EXP ) group used a treadmill , a Kinetron isokinetic exerciser , and a limb-load monitor , whereas those in the control ( CTL ) group did not while engaging in PT 1 h per day , 5 days per week for 2 months . Locomotor recovery was assessed by clinical ( gait speed , Fugl Meyer motor leg and arm subscores , the Balance Scale , the Timed Up and Go , and the Barthel ambulation subscore ) and laboratory outcomes ( gait kinematics and kinetics ) pre- and posttherapy and 3 months later . Within groups , gait speed ( P < 0.01 ) and all secondary measures improved posttherapy ( P < 0.01 - 0.05 ) , and improvements in clinical measures were maintained at follow-up , but there was no difference between groups ( P > 0.05 ) . When the groups were pooled , the increase in gait speed was associated ( r = 0.52 , P = 0.003 ) with an increase in ankle power generation of the affected leg . The results demonstrate that the efficacy of the task-oriented approach is not dependent on rehabilitation technology [20051618] Balance is a complex motor skill and it is frequently disturbed among stroke survivors . Rehabilitation experts are still facing challenges in achieving good stability . The primary aim of this study was to determine the effect of a wobble board exercise program on static and dynamic balance of hemiplegic subjects . Seventeen ( 17 ) stroke survivors were r and omly selected into two groups . The subjects in the experimental group were trained on wobble board for six weeks while the control group received only the baseline treatment programs . The modified version of the timed balance test was used to assess balance while the foursquare step test was used to assess dynamic balance . Descriptive statistics and Analysis of variance ( ANOVA ) were used to analyze the data obtained . The result showed that there was significant difference in the static balance ( eye closed ) ( F=7.49 , P < 0.05 ) and dynamic balance ( F3.20 , P < 0.05 ) between the groups but there was no significant difference in static balance ( eye opened ) ( F= 1.75 , P > 0.05 ) . The study concluded that wobble board exercise improved both static ( eye closed ) and dynamic balance of stroke survivor used in this study [16774090] Objective : To investigate the effect of early cycling training on balance and motor abilities of stroke patients in their subacute stage . Design : R and omized clinical trial . Setting : Inpatient rehabilitation . Subjects : Twenty-four patients who had had a first stroke were r and omly assigned to a cycling training group ( n = 10 ) or to a control ( n = 14 ) group . Intervention : All subjects received their usual rehabilitation programme ; the cycling training group received in addition a daily session of leg cycle ergometer , lasting three weeks . Both groups were followed for six weeks . Main outcome measurements : Balance was assessed using the Postural Assessment Scale for Stroke Patients ( PASS ) and the st and ing balance test . The motor function of the lower extremity was also assessed by the Fugl-Meyer Assessment ( FMA ) . Results : In the within-group comparison , both the exercise group and the control group had improved significantly ( P B=0.01 ) with time with respect to PASS total ( exercise group 18.79=2.8 to 31.19=2.2 , control group 18.19=3.2 to 26.49=3.8 ) and PASS subscores , as well as the FMA score ( exercise group 17.29=7.5 to 29.19=5.9 , control group 16.69=6.4 to 22.19=6.8 ) . In addition there was a significant group = time interaction effect , with exercise group patients demonstrating better performance in both the total PASS score and PASS subscores and FMA score relative to the control patients ( P B=0.01 ) . Conclusions : These preliminary findings suggest that stroke patients in the subacute stage can improve their motor and balance abilities after an early short duration of cycling training [15835284] BACKGROUND AND PURPOSE Of all stroke survivors , more than 50 % are left with motor disabilities . Impairment of upper limb movement is a common motor disability . Constraint-Induced Movement Therapy ( CIMT ) is an intervention which has been used for the treatment of upper extremity motor disabilities in stroke patients . Although CIMT is an effective intervention , a recent survey revealed that this procedure is viewed with apprehension by many clinicians because of concerns about practicality and re source issues . We developed a modified CIMT that reserves the massed training of the affected arm without any physical restriction of the intact one and then used it on our stroke patients . This study was design ed to evaluate the effectiveness of this Modified-Constraint-Induced Movement Therapy ( m-CIMT ) . METHODS Thirty stroke patients were r and omly assigned to either an m-CIMT ( n=13 ) or a control group ( n=17 ) . Subjects in the m-CIMT group received a 2-week course of m-CIMT . Outcomes were evaluated using the Wolf Motor Function Test ( WMFT ) . RESULTS After only 2 weeks of training , significant differences ( p<0.05 ) in favor of m-CIMT were found in the following 6 elements of the WMFT : Extend elbow with weight , Lift pencil , Stack checkers , Flip cards , Turn key in lock , and Lift basket . CONCLUSION The present study shows that our m-CIMT is useful in improving the function of the affected upper extremity in stroke patients [16628507] OBJECTIVE To evaluate the usefulness of the computer program made for the patients after stroke to treat their cognitive impairments and hemiparesis . RESEARCH DESIGN AND METHODS The experimental group involved 10 patients after stroke who were obliged to train on a computer every day during their three-week stay on the rehabilitation ward . The control group involved 10 patients after stroke who did not participate in any computer training during their rehabilitation process . The first part of the computer tasks trains the attention impairments and visual-motor co-ordination problems . We modified the joystick by adding special buttons to train movements of the wrist , thumb and forefinger of the impaired h and . Computer tasks are made in the way to stimulate both the cognitive functions and h and dexterity at the same time . RESULTS This initial research shows a statistically significant improvement of the cognitive functions and h and dexterity among patients from the experimental group . According to these results we did not observe any significant improvement in the cognitive functions among patients who did not train on a computer ( control group ) . CONCLUSIONS The results of this research suggest the usefulness of this computer program in training cognitive impairments and visual-motor co-ordination as well as h and dexterity among the patients after stroke [16180593] Objective : To evaluate the effect of an arm training programme combining repetition of unilateral and symmetrical bilateral tasks for people in the subacute phase after stroke . Design : R and omized controlled trial . Setting : Inpatient functional rehabilitation unit . Subjects : Forty-one people who had had a stroke , in the subacute phase , receiving conventional arm occupational and physical therapy , were r and omized to an experimental group ( n=20 ) and a control group ( n=21 ) . Interventions : In addition to the usual arm therapy in the rehabilitation unit , the experimental group received an arm therapy programme ( 15 - 20 45-min sessions ) based on repetition of unilateral and symmetrical bilateral tasks . The control group received additional usual arm therapy of a similar duration and frequency to the experimental treatment . Main measures : The effect of the programme was judged on the basis of : ( 1 ) arm impairments ( motor function , grip strength , gross and fine manual dexterity and motor co-ordination ) , ( 2 ) arm disabilities in tasks related to daily activities , and ( 3 ) functional independence in activities of daily living ( ADL ) and instrumental ADL ( IADL ) . Results : Although both experimental and control groups of participants improved similarly during the study period , the statistical analyses did not show any difference between the groups at the end of the treatment for the different dependent variables evaluated : ( 1 ) arm impairments : p=0.43 - 0.79 ; ( 2 ) arm disabilities : p=0.16 - 0.90 ; and ( 3 ) functional independence : p=0.63 and 0.90 . Conclusions : An arm training programme based on repetition of unilateral and symmetrical bilateral practice did not reduce impairment and disabilities nor improve functional outcomes in the subacute phase after stroke more than the usual therapy [11441386] OBJECTIVE To test the efficacy of the arm ability training ( AAT ) on a sample of patients with central arm paresis after traumatic brain injury ( TBI ) or stroke . DESIGN Single-blind , r and omized , controlled trial . SETTING Inpatient rehabilitation center . PATIENTS Consecutive sample of 74 patients of whom 60 ( 45 with stroke , 15 with TBI ) completed the study ; 37 patients received a 1-year follow-up . INTERVENTION Daily AAT with ( n = 20 ) or without ( n = 20 ) knowledge of results , or no AAT ( n = 20 ) during a 3-week intervention period . MAIN OUTCOME MEASURES Summary time scores of the Test Evaluant les Membres superieurs des Personnes Agees (TEMPA)-a test of upper extremity function with daily function-like activities ( focal disability)- and kinematic analysis of aim ed movements . RESULTS Patients with AAT realized superior improvement as compared with controls . Mean improvement in the time needed to perform ( 1 ) all TEMPA tasks was 41.4 versus 12.8 seconds ( p = .0012 ) ; ( 2 ) unilateral TEMPA tasks , 16.5 versus 4.2 seconds ( p = .0036 ) ; and ( 3 ) the ballistic component of aim ed movements , 96 versus 20ms ( p = .0115 ) . Knowledge of result did not substantially modify these effects . A functional benefit existed at 1-year follow-up . CONCLUSION The AAT reduces focal disability among stroke and TBI patients with mild central arm paresis [16634338] Objective : To study the efficacy of the motor relearning approach in promoting physical function and task performance for patients after a stroke . Design : Matched-pair r and omized controlled trial . Setting : An outpatient rehabilitation centre in Hong Kong . Participants : Fifty-two out patients with either a thrombotic or haemorrhagic stroke who completed either the study or control group . Interventions : The patients received 18 2-h sessions in six weeks of either the motor relearning programme or a conventional therapy programme . Main outcome measures : The Berg Balance Scale , the Timed Up and Go Test , the Functional Independence Measure ( FIM ) , the modified Lawton Instrumental Activities of Daily Living ( IADL ) test , and the Community Integration Question naire . Results : Patients in the motor relearning group showed significantly better performance on all but the Timed Up and Go Test when compared with the control group ( F(1,150)=6.34 - 41.86 , P ≤ 0.015 ) . The interactions between group and occasion were significant on all five outcome measures , indicating that the rates of change across time between the motor relearning and control groups differed ( F(3,150)=3.60 - 33.58 , P < 0.015 ) . Conclusion : The motor relearning programme was found to be effective for enhancing functional recovery of patients who had a stroke . Both ‘ sequential ’ and ‘ function-based ’ concepts are important in applying the motor relearning approach to the rehabilitation of stroke patients [11387585] OBJECTIVE To assess use of the Bon Saint Côme device for axial postural rehabilitation in hemiplegic patients , a technique based on voluntary trunk control during exploratory retraining . DESIGN A 3-month r and omized controlled trial . SETTING A public neurorehabilitation center . PATIENTS Twenty consecutive hemiplegic patients with axial postural disturbance result ing from recent stroke were r and omly assigned to a device group ( DG ) or control group ( CG ) . The 2 groups of 10 patients were similar . INTERVENTION For 1 month , the DG patients followed an experimental program for 1 hour daily and conventional neurorehabilitation for 1 hour daily , whereas CG patients had conventional neurorehabilitation for 2 hours daily . For the next 2 months , all 20 patients had conventional neurorehabilitation for 2 hours daily . MAIN OUTCOME MEASURES Patients were assessed on days 0 , 30 , and 90 by using a battery of postural tests , gait evaluation , the Bells neglect test , and the FIM instrument . RESULTS On day 30 , postural and neglect tests improved significantly more in DG than in CG . The benefit remained at day 90 . Gait improved earlier in DG than in CG . FIM scores improved equally . CONCLUSIONS Voluntary trunk control retraining during spatial exploration with the Bon Saint Côme device appears to be a useful approach for rehabilitation of postural disorders in hemiplegic patients . Treatments design ed to improve spatial cognition deficits probably enhance postural disorder recovery in hemiplegia [8702377] OBJECTIVE To determine the effect of different motor learning schedules on stroke patients ' rate of acquisition and retention of a functional movement sequence using the hemiparetic upper limb . DESIGN R and omized controlled group study using a retention design with two retention trials . SETTING Outpatient neurorehabilitation clinic . PATIENTS Twenty-four patients with chronic hemiparesis secondary to a single unilateral cerebral stroke without evidence of severe cognitive or language impairment . MAIN OUTCOME MEASURE The primary hypothesis was that hemiparetic motor learning that occurred under conditions of context ual interference ( ie , r and om practice ) would be retained better than learning that occurred under conditions of repetitive drill ( blocked practice ) . RESULTS A significant difference was found among the three groups ( ie , r and om- practice , blocked- practice , control ) on both the first retention measure ( chi 2 = 13.50 , p < .01 ) and the second retention measure ( chi 2 = 12.59 , p < .01 ) . More importantly , a significant difference was found between the r and om- practice and blocked- practice groups on both the first retention measure ( U = 68.5 , p < .01 ) and the second retention measure ( U = 62.0 , p = .05 ) . CONCLUSIONS Findings provide empirical evidence to support the contention that r and om practice is more effective than blocked practice , with respect to retention over time , when hemiparetic stroke patients attempt to learn functional motor skills [15759530] Objective : To investigate the effectiveness of Bobath on stroke patients at different motor stages by comparing their treatment with orthopaedic treatment . Design : A single-blind study , with r and om assignment to Bobath or orthopaedic group . Setting : Physical therapy department of a medical centre . Subjects : Twenty-one patients with stroke with spasticity and 23 patients with stroke at relative recovery stages participated . Interventions : Twenty sessions of Bobath programme or orthopaedic treatment programme given in four weeks . Main outcome measures : Stroke Impairment Assessment Set ( SIAS ) , Motor Assessment Scale ( MAS ) , Berg Balance Scale ( BBS ) and Stroke Impact Scale ( SIS ) for impairment and functional limitation level . Results : Participants with spasticity showed greater improvement in tone control ( change score : 1.209±1.03 versus 0.089±0.67 , p = 0.006 ) , MAS ( change score : 7.64±4.03 versus 4.009±1.95 , p = 0.011 ) , and SIS ( change score : 7.309±6.24 versus 1.259±5.33 , p=0.023 ) after 20 sessions of Bobath treatment than with orthopaedic treatment . Participants with relative recovery receiving Bobath treatment showed greater improvement in MAS ( change score : 6.149±5.55 versus 2.779±9.89 , p=0.007 ) , BBS ( change score : 19.189±15.94 versus 6.859±5.23 , p=0.015 ) , and SIS scores ( change score : 8.509±3.41 versus 3.629±4.07 , p = 0.006 ) than those with orthopaedic treatment . Conclusion : Bobath or orthopaedic treatment paired with spontaneous recovery result ed in improvements in impairment and functional levels for patient with stroke . Patients benefit more from the Bobath treatment in MAS and SIS scores than from the orthopaedic treatment programme regardless of their motor recovery stages [14606738] Objective : The purpose of this follow-up one and four years post stroke was to find out whether the initial physiotherapy approach had had any long-term effects on mortality , motor function , postural control , activities of daily living , life quality , follow-up from community services and living conditions . Design : A r and omized controlled trial of first time ever stroke patients . Group 1 ( n = 33 ) and group 2 ( n = 28 ) had initial physiotherapy according to the Motor Relearning Programme and Bobath , respectively . Main outcome measures : The Motor Assessment Scale ( MAS ) , the Sødring Motor Evaluation Scale ( SMES ) , the Barthel ADL Index , the Nottingham Health Profile ( NHP ) and Berg Balance Scale were used . The following parameters were also registered : incidence of new strokes , other diseases , use of assistive devices , the patient 's accommodation and use of services from the community . Results : The mortality rates were similar in the two groups . In both groups the motor function , postural control and ADL had decreased rapidly , leaving many of the patients dependent and with a high risk of falling . Life quality had increased compared to the acute stage , but was still low in comparison with healthy persons . Patients in both groups lived at home , but were dependent on help from relatives and community services . Physiotherapy as follow-up service was seldom used . The initial physiotherapy approach did not seem to have a major in‘uence on the patients ' ability to cope in the long term . Conclusion : This follow-up at one and four years post stroke showed no major in‘uence of two different initial physiotherapy regimens on long-term function . The study confirmed a rapid deterioration of ADL and motor function and an increased dependence on relatives . The study reveals a gap between the intense treatment in the acute phase and little or no follow-up of physiotherapy treatment or other rehabilitation activities later [15704508] Objectives : To evaluate a training programme aim ed at improving lateral weight transference in patients following acute stroke to determine main treatment effects , if any , to inform the design of future studies . Design : A single-blind r and omized controlled trial . Setting : The Stroke Unit at The James Cook University Hospital , Middlesbrough , UK . Subjects : Thirty-five patients with an acute stroke . Interventions : All subjects received their usual care , including physiotherapy . The treatment group ( n / 17 ) received 12 additional therapy sessions ( over four weeks ) comprising exercises aim ed at improving lateral weight transference in sitting delivered by trained physiotherapy assistants . Main outcome measures : Measures of dynamic reaching , sitting and st and ing , and static st and ing balance were undertaken by a blind independent observer . Results : Specific measures of weight displacement in st and ing and reaching , and timed st and ing up and sitting down did not detect any differences over time regardless of group . Neither were there any significant changes over time , except for sway during static st and ing ( p B=0.01 ) and time to return to their original position during dynamic reaching ( p / 0.01 ) . Conclusions : A training programme aim ed at improving lateral weight transference did not appear to enhance the rehabilitation of acute stroke patients . Improvements observed in postural control in st and ing and sitting may be attributable to usual care or natural recovery [8418798] UNLABELLED RESEARCH PROBLEM AND METHODS : There are currently 1.5 million stroke survivors in the United States . More than half of these individuals have significant residual physical disability and functional impairment . Survivors of stroke constitute the largest group of patients receiving rehabilitation services in this country . We examined existing clinical trials investigating the effectiveness of stroke rehabilitation programs to improve functional outcomes and discharge destination . One hundred twenty-four research reports were initially identified . From this sample , 36 trials meeting selected criteria were evaluated by the methods of meta- analysis . RESULTS A total of 3717 patients participated in the 36 clinical trials included in the meta- analysis . The results revealed a mean d-index of 0.40 + /- 0.33 . This effect size index was converted to a U3 value of 65.5 , indicating that the average patient receiving a program of focused stroke rehabilitation performed better than approximately 65.5 % of those patients in comparison groups ( 95 % confidence interval , 63.6 % to 67.3 % ) . The results also revealed a significant interaction between type of research design and method of recording the outcome of a clinical trial . Blind recording of the outcome measure appears to be an essential design characteristic in clinical trials that do not r and omize patients to conditions . CONCLUSIONS Programs of focused stroke rehabilitation may improve functional performance for some patients who have experienced a stroke . The improvement in performance appears related to early initiation of treatment , but not to the duration of intervention . Improvements are also associated with the patient 's age and the type of design . Research design should be considered an important moderator variable in planning and interpreting future clinical trials of treatment effectiveness in stroke rehabilitation [15859527] Objective : To examine the effectiveness of additional backward walking training on gait outcome of patients post stroke . Design : R and omized controlled trial . Setting : Medical centre . Subjects : Twenty-five subjects with stroke , who were lower extremity Brunnstrom motor recovery stage at 3 or 4 and were able to walk 11 m with or without a walking aid or orthosis , r and omly allocated to two groups , control ( n = 12 ) and experimental ( n = 13 ) . Interventions : Subjects in both groups participated in 40 min of conventional training programme three times a week for three weeks . Subjects in experimental group received additional 30 min of backward walking training for three weeks at a frequency of three times per week . Main measures : Gait was measured using the Stride Analyzer . Gait parameters of interest were walking speed , cadence , stride length , gait cycle and symmetry index . Measures were made at baseline before commencement of training ( pre-training ) and at the end of the three-week training period ( post-training ) . Results : After a three-week training period , subjects in experimental group showed more improvement than those in control group for walking speed ( change score : 8.609 ± 6.95 versus 3.659 ± 2.92 , p-value = 0.032 ) , stride length ( change score : 0.0909 ± 0.076 versus 0.00649 ± 0.078 , p-value = 0.006 ) , and symmetry index ( change score : 44.079 ± 53.29 versus 5.309 ± 13.91 , p-value = 0.018 ) . Conclusions : This study demonstrated that asymmetric gait pattern in patients post stroke could be improved from receiving additional backward walking therapy [16719028] Objective : To evaluate the efficacy of a task-oriented intervention in enhancing arm function in people with stroke . Design : Two-centre , observer-blinded , stratified , block-r and omized controlled trial . Setting : General community . Patients : Ninety-one individuals within one year of a first or recurrent stroke consented to participate between May 2000 and February 2003 . Interventions : The experimental intervention involved practice of functional , unilateral and bilateral tasks that were design ed to improve gross and fine manual dexterity whereas the control intervention was composed of walking tasks . Members in both groups participated in three sessions a week for six weeks . Main outcome measure(s ) : The primary test of arm function was the Box and Block Test . Secondary tests included the Nine-Hole Peg Test , maximal grip strength , the Test d'Evaluation des Membres supé rieurs des Personnes Agées ( TEMPA ) and the Stroke Rehabilitation Assessment of Movement . Results : Results are for the more affected arm . Baseline performance on the Box and Block Test was an average of 26 blocks ( st and ard deviation ( SD=16 ) in the experimental group ( n=47 ) and 26 blocks ( Sd=18 ) in the control group ( n=44 ) . These values represent approximately 40 % of age-predicted values . Values for the postintervention evaluation were an average of 28 ( SD=17 ) and 28 ( SD=19 ) blocks for the experimental and control group respectively . No meaningful change on other measures of arm function was observed . Conclusions : A task-oriented intervention did not improve voluntary movement or manual dexterity of the affected arm in people with chronic stroke [18511529] Objective : To establish the effects of group exercise on mobility and strength . Design : R and omized controlled trial . Setting : Two public hospital outpatient rehabilitation services . Participants : One hundred and seventy-three people ( mean age 74.9 years , SD 10.8 ) with impaired mobility were r and omized and 159 people ( 92 % ) completed the trial . Interventions : Five-week , twice-weekly ` circuit-style ' group exercise programme run by a physiotherapist ( n = 85 ) and a no-intervention waiting list control group ( n = 88 ) . Main outcome measures : Three aspects of mobility : balance while st and ing and stepping ( Step Test , semi-t and em and t and em stance times ) ; sit-to-st and ability ( rate and minimum height ) and gait ( 6-metre and 6-minute walk tests ) . Lower limb muscle strength ( knee flexion and extension ) . Results : At retest , exercise participants had improved significantly more than their control counterparts on measures of balance while stepping , sit to st and and gait . Exercise participants averaged 1.6 more steps on the 15-second Step Test ( 95 % confidence interval ( CI ) 0.5 to 2.8 , P=0.005 ) , walked an average of 0.12 m/s faster ( 95 % CI 0.05 to 0.2 , P=0.002 ) and took 2.5 fewer steps in 6 metres ( 95 % CI —4.2 to —0.8 , P=0.004 ) . Exercise participants also averaged 0.04 more sit-to-st and s/second , ( 95 % CI 0.003 to 0.08 , P=0.037 ) and walked an average of 30.9 metres further in 6 minutes ( 95 % CI 9.4 to 52.4 , P=0.005 ) . There were no clinical ly important or statistically significant between-group differences at retest for the measures of strength ( knee extension and flexion ) , balance while st and ing or minimal sit-to-st and height . Conclusion : This short- duration circuit class programme improved mobility , but not strength [19969159] UNLABELLED Mudge S , Barber PA , Stott NS . Circuit-based rehabilitation improves gait endurance but not usual walking activity in chronic stroke : a r and omized controlled trial . OBJECTIVE To determine whether circuit-based rehabilitation would increase the amount and rate that individuals with stroke walk in their usual environments . DESIGN Single-blind r and omized controlled trial . SETTING Rehabilitation clinic . PARTICIPANTS Sixty participants with a residual gait deficit at least 6 months after stroke originally enrolled in the study . Two withdrew in the initial phase , leaving 58 participants ( median age , 71.5y ; range , 39.0 - 89.0y ) who were r and omized to the 2 intervention groups . INTERVENTIONS The exercise group had 12 sessions of clinic-based rehabilitation delivered in a circuit class design ed to improve walking . The control group received a comparable duration of group social and educational classes . MAIN OUTCOME MEASURES Usual walking performance was assessed using the StepWatch Activity Monitor . Clinical tests were gait speed ( timed 10-meter walk ) and endurance ( six-minute walk test [ 6MWT ] ) , confidence ( Activities-Based Confidence Scale ) , self-reported mobility ( Rivermead Mobility Index [ RMI ] ) , and self-reported physical activity ( Physical Activity and Disability Scale ) . RESULTS Intention-to-treat analysis revealed that the exercise group showed a significantly greater distance for the 6MWT than the control group immediately after the intervention ( P=.030 ) but that this effect was not retained 3 months later . There were no changes in the StepWatch measures of usual walking performance for either group . The exercise and control groups had significantly different gait speed ( P=.038 ) and scores on the RMI ( P=.025 ) at the 3-month follow-up . These differences represented a greater decline in the control group compared with the exercise group for both outcome measures . CONCLUSIONS Circuit-based rehabilitation leads to improvements in gait endurance but does not change the amount or rate of walking performance in usual environments . Clinical gains made by the exercise group were lost 3 months later . Future studies should consider whether rehabilitation needs to occur in usual environments to improve walking performance [10945420] Objective : To examine whether two different physiotherapy regimes caused any differences in outcome in rehabilitation after acute stroke . Design : A double-blind study of patients with acute first-ever stroke . Sixty-one patients were consecutively included , block r and omized into two groups , and stratified according to gender and hemiplegic site . Group 1 ( 33 patients ) and group 2 ( 28 patients ) had physiotherapy according to Motor Relearning Programme ( MRP ) and Bobath , respectively . The supplemental treatment did not differ in the two groups . Main outcome measures : The Motor Assessment Scale ( MAS ) , the Sødring Motor Evaluation Scale ( SMES ) , the Barthel ADL Index and the Nottingham Health Profile ( NHP ) were used . The following parameters were also registered : length of stay in the hospital , use of assistive devices for mobility , and the patient 's accommodation after discharge from the hospital . Results : Patients treated according to MRP stayed fewer days in hospital than those treated according to Bobath ( mean 21 days versus 34 days , p = 0.008 ) . Both groups improved in MAS and SMES , but the improvement in motor function was significantly better in the MRP group . The two groups improved in Barthel ADL Index without significant differences between the groups . However , women treated by MRP improved more in ADL than women treated by Bobath . There were no differences between the groups in the life quality test ( NHP ) , use of assistive devices or accommodation after discharge from the hospital . Conclusion : The present study indicates that physiotherapy treatment using the MRP is preferable to that using the Bobath programme in the acute rehabilitation of stroke patients [8172497] Time course and degree of recovery of upper extremity ( UE ) function after stroke and the influence of initial UE paresis were studied prospect ively in a community-based population of 421 consecutive stroke patients admitted acutely during a 1-year period . UE function was assessed weekly , using the Barthel Index subscores for feeding and grooming . UE paresis was assessed by the Sc and inavian Stroke Scale subscores for h and and arm . The best possible UE function was achieved by 80 % of the patients within 3 weeks after stroke onset and by 95 % within 9 weeks ; in patients with mild UE paresis , function was achieved within 3 and 6 weeks , respectively , and in patients with severe UE paresis within 6 and 11 weeks , respectively . Full UE function was achieved by 79 % of patients with mild UE paresis and only by 18 % of patients with severe UE paresis . A valid prognosis of UE function can be made within 3 and 6 weeks in patients with mild and severe UE paresis , respectively . Further recovery of UE function should not be expected after 6 and 11 weeks respectively , in these groups of patients [16401430] OBJECTIVE To assess the effects of a community-based exercise program on motor recovery and functional abilities of the paretic upper extremity in persons with chronic stroke . DESIGN R and omized controlled trial . SETTING Rehabilitation research laboratory and a community hall . PARTICIPANTS A sample of 63 people ( > or = 50y ) with chronic deficits result ing from stroke ( onset > or = 1y ) . INTERVENTIONS The arm group underwent an exercise program design ed to improve upper-extremity function ( 1h/session , 3 sessions/wk for 19wk ) . The leg group underwent a lower-extremity exercise program . MAIN OUTCOME MEASURES The Wolf Motor Function Test ( WMFT ) , Fugl-Meyer Assessment ( FMA ) , h and -held dynamometry ( grip strength ) , and the Motor Activity Log . RESULTS Multivariate analysis showed a significant group by time interaction ( Wilks lambda=.726 , P=.017 ) , indicating that overall , the arm group had significantly more improvement than the leg group . Post hoc analysis demonstrated that gains in WMFT ( functional ability ) ( P=.001 ) and FMA ( P=.001 ) scores were significantly higher in the arm group . The amount of improvement was comparable to other novel treatment approaches such as constraint-induced movement therapy or robot-aided exercise training previously reported in chronic stroke . Participants with moderate arm impairment benefited more from the program . CONCLUSIONS The pilot study showed that a community-based exercise program can improve upper-extremity function in persons with chronic stroke . This outcome justifies a larger clinical trial to further assess efficacy and cost effectiveness [12194618] Objective : To investigate the effect of independent practice of sitting balance as an addition to st and ard physiotherapy treatment for patients with stroke . Design : R and omized controlled trial , using blocked r and omization procedure with 2:1 ratio . Subjects : In patients with diagnosis of stroke , having achieved one minute of independent sitting balance but not yet achieved 10 independent steps , and with no known previous disabilities , pathology or neurological de”cit affecting mobility prior to stroke . Intervention : A four-week regime of independent practice aim ed at improving aspects of balance , as an addition to st and ard physiotherapy treatment based on the Bobath Approach . Main outcome measure : Proportion of patients achieving ‘ normal ’ symmetry of weight distribution during sitting , st and ing , rising to st and , sitting down , and reaching . Results : Nineteen subjects were r and omized to the control group ; nine to the intervention group . There were no clinical ly signi”cant differences in measured outcome between the groups . Conclusions : The regime of independent practice had no measured bene”cial effect on the balance ability of patients with recently acquired stroke [8503751] A r and omized controlled pilot trial was conducted to estimate the effects of early , intensive , gait-focused physical therapy on ambulatory ability in acute , stroke patients . Twenty-seven patients with middle cerebral artery infa rct of thromboembolic origin confirmed by computed axial tomography scan were stratified and r and omly assigned to the experimental group , to a control group that received early , intensive and conventional therapy , or to a group receiving routine conventional therapy that started later and was not intense . Assessment s at entry , six weeks , and three and six months by independent evaluators permitted comparisons with reference to clinical measures of motor performance , balance , and functional capacity , and laboratory measures of gait movements . Group results at six weeks demonstrated that gait velocity was similar in the two conventional groups thereby eliminating the timing of the interventions as an important factor . At that point , gait velocity was faster in the experimental group . The difference translated into a moderate effect size of 0.58 . The time dedicated to gait training but not to total therapy time was correlated ( rs = 0.63 ) to gait velocity . This effect disappeared at three and six months after stroke . These pilot results justify planning a large trial to test the effectiveness of a therapeutic protocol that focuses on early and intense gait therapy in an effort to facilitate early ambulation following stroke [17008338] Objective : To examine the effectiveness of task-oriented progressive resistance strength training on lower extremity strength and functional performance in chronic stroke subjects . Design : Single-blind , r and omized controlled trial . Setting : Medical centre and district hospital . Subjects : Forty-eight subjects at least one year post stroke . Interventions : Participants r and omly allocated to two groups , control ( n-/24 ) and experimental ( n-/24 ) . Subjects in the control group did not receive any rehabilitation training . Subjects in the experimental group were put on a four-week task-oriented progressive resistance strength training . Main measures : Lower extremity muscle strength , gait velocity , cadence , stride length , six-minute walk test , step test , and timed up and go test . Results : Muscle strength significantly improved in the experimental group for strong side muscle groups ( ranged from 23.9 % to 36.5 % ) and paretic side muscle groups ( ranged from 10.1 % to 77.9 % ) . In the control group muscle strength changes ranged from 6.7 % gain to 11.2 % decline . The experimental group showed significant improvement in all selected measures of functional performance except for the step test . In the control group , the number of repetitions of the step test significantly decreased ( -20.3 % ) with no change in other functional tests . There was a significant difference between groups for muscle strength and all functional measures . The strength gain was significantly associated with gain in the functional tests . Conclusions : The task-oriented progressive resistance strength training programme could improve lower extremity muscle strength in individuals with chronic stroke and could carry over into improvement in functional abilities

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### Context: [9550512] BACKGROUND AND PURPOSE Arm function recovery is notoriously poor in stroke patients . The effect of treatment modalities , particularly those directed at improving upper limb function , has been studied primarily in chronic stroke patients . The purpose of this study was to investigate the effect of a specific therapeutic intervention on arm function in the acute phase after stroke . METHODS In a single-blind , r and omized , controlled multicenter trial , 100 consecutive patients were allocated to either an experimental group that received an additional treatment of sensorimotor stimulation or to a control group . The intervention was applied for 6 weeks . Patients were evaluated for level of impairment ( Brunnström-Fugl-Meyer test ) and disability ( Action Research Arm test , Barthel Index ) before , midway , and after the intervention period and at follow-up 6 and 12 months after stroke . RESULTS Patients in the experimental group performed better on the Brunnström-Fugl-Meyer test than those in the control group throughout the study period , but differences were significant only at follow-up . Results on the Action Research Arm test and Barthel Index revealed no effect at the level of disability . The effect of the therapy was attributed to the repetitive stimulation of muscle activity . The treatment was most effective in patients with a severe motor deficit and hemianopia or hemi-inattention . No adverse effects due to the intervention were found . CONCLUSIONS Adding a specific intervention during the acute phase after stroke improved motor recovery , which was apparent 1 year later . These results emphasize the potential beneficial effect of therapeutic interventions for the arm [12920254] BACKGROUND AND PURPOSE Rehabilitation care after stroke is highly variable and increasingly shorter in duration . The effect of therapeutic exercise on impairments and functional limitations after stroke is not clear . The objective of this study was to determine whether a structured , progressive , physiologically based exercise program for subacute stroke produces gains greater than those attributable to spontaneous recovery and usual care . METHODS This r and omized , controlled , single-blind clinical trial was conducted in a metropolitan area and 17 participating healthcare institutions . We included persons with stroke who were living in the community . One hundred patients ( mean age , 70 years ; mean Orpington score , 3.4 ) consented and were r and omized from a screened sample of 582 . Ninety-two subjects completed the trial . Intervention was a structured , progressive , physiologically based , therapist-supervised , in-home program of thirty-six 90-minute sessions over 12 weeks targeting flexibility , strength , balance , endurance , and upper-extremity function . Main outcome measures were postintervention strength ( ankle and knee isometric peak torque , grip strength ) , upper- and lower-extremity motor control ( Fugl Meyer ) , balance ( Berg and functional reach ) , endurance ( peak aerobic capacity and exercise duration ) , upper-extremity function ( Wolf Motor Function Test ) , and mobility ( timed 10-m walk and 6-minute walk distance ) . RESULTS In the intention-to-treat multivariate analysis of variance testing the overall effect , the intervention produced greater gains than usual care ( Wilk 's lambda=0.64 , P=0.0056 ) . Both intervention and usual care groups improved in strength , balance , upper- and lower-extremity motor control , upper-extremity function , and gait velocity . Gains for the intervention group exceeded those in the usual care group in balance , endurance , peak aerobic capacity , and mobility . Upper-extremity gains exceeded those in the usual care group only in patients with higher baseline function . CONCLUSIONS This structured , progressive program of therapeutic exercise in persons who had completed acute rehabilitation services produced gains in endurance , balance , and mobility beyond those attributable to spontaneous recovery and usual care [15929503] Background : St and ing is believed to have benefits in addressing motor and sensory impairments after stroke . One device to facilitate st and ing for severely disabled patients is the Oswestry St and ing Frame . Objective : To evaluate the effectiveness of the Oswestry St and ing Frame for severely disabled stroke patients . Design : A single centre , r and omized controlled trial . Setting : An inpatient stroke rehabilitation unit . Subjects : Patients were recruited if they had a clinical diagnosis of stroke , were medically stable and unable to achieve any score on the Trunk Control Test or unable to st and in mid-line without the assistance of two therapists . Intervention : The intervention ( n=71 ) and control ( n=69 ) groups both received usual stroke unit care but the intervention group also received a minimum of 14 consecutive days ' treatment using the st and ing frame . Main outcome measures : The primary outcome measure was the Rivermead Mobility Index ( RMI ) . Secondary measures included the Barthel Index ; the Rivermead Motor Assessment ; the balanced sitting and sitting to st and ing components of the Motor Assessment Scale ; the Trunk Control Test and the Hospital Anxiety and Depression Scale . Blind assessment was undertaken at baseline , six weeks , 12 weeks and six months post stroke . Information on re source use was also collected . Results : There was no statistically significant difference between groups in any of the outcome measures or for re source use . Mann-Whitney U-tests for the RMI change from baseline scores to six weeks , 12 weeks and six months post stroke were p=0.310 ; p=0.970 and p=0.282 , respectively . Conclusion : Use of the Oswestry St and ing Frame did not improve clinical outcome or provide re source savings for this severely disabled patient group [19321521] Objective : To determine the benefits of additional therapy specifically directed at the h and in people with acquired brain impairment . Design : An assessor-blinded r and omized controlled trial . Setting : Rehabilitation hospital . Participants : A sample of 39 adults with h and impairment following stroke ( 90 % ) or traumatic brain injury ( 10 % ) . The median ( interquartile ) time since injury was 1.6 months ( 0.5—3.5 months ) . Intervention : The experimental group ( n = 20 ) received an additional one-hour session of task-specific motor training for the h and five times a week over a six-week period . The training was administered on a one-to-one basis . The control group ( n = 19 ) received st and ard care which consisted of 10 minutes of h and therapy three times a week . Both groups continued to receive therapy directed at the shoulder and elbow . Outcome measures : Primary outcomes were the Action Research Arm and Summed Manual Muscle Tests measured at the beginning and end of the six-week period . Results : The mean ( SD ) Action Research Arm Test values for experimental participants improved from the beginning to the end of study from 10 points ( 15 ) to 21 points ( 23 ) and the equivalent values for the Summed Manual Muscle Test improved from 35 % ( 33 ) to 49 % ( 35 ) . There were similar improvements in control participants . The mean between-group differences for the Action Research Arm and Summed Manual Muscle Tests were -6 points ( 95 % confidence interval ( CI ) , -20 to 8) and 3 % ( 95 % CI , -10 to 16 ) , respectively . Conclusion : H and and overall arm function of all participants improved over the six-week period , however there was not a clear benefit from providing additional h and therapy [15194251] BACKGROUND The incidence of stroke is predicted to rise because of the rapidly ageing population . However , over the past two decades , findings of r and omised trials have identified several interventions that are effective in prevention of stroke . Reliable data on time-trends in stroke incidence , major risk factors , and use of preventive treatments in an ageing population are required to ascertain whether implementation of preventive strategies can offset the predicted rise in stroke incidence . We aim ed to obtain these data . METHODS We ascertained changes in incidence of transient ischaemic attack and stroke , risk factors , and premorbid use of preventive treatments from 1981 - 84 ( Oxford Community Stroke Project ; OCSP ) to 2002 - 04 ( Oxford Vascular Study ; OXVASC ) . FINDINGS Of 476 patients with transient ischaemic attacks or strokes in OXVASC , 262 strokes and 93 transient ischaemic attacks were incident events . Despite more complete case-ascertainment than in OCSP , age-adjusted and sex-adjusted incidence of first-ever stroke fell by 29 % ( relative incidence 0.71 , 95 % CI 0.61 - 0.83 , p=0.0002 ) . Incidence declined by more than 50 % for primary intracerebral haemorrhage ( 0.47 , 0.27 - 0.83 , p=0.01 ) but was unchanged for subarachnoid haemorrhage ( 0.83 , 0.44 - 1.57 , p=0.57 ) . Thus , although 28 % more incident strokes ( 366 vs 286 ) were expected in OXVASC due to demographic change alone ( 33 % increase in those aged 75 or older ) , the observed number fell ( 262 vs 286 ) . Major reductions were recorded in mortality rates for incident stroke ( 0.63 , 0.44 - 0.90 , p=0.02 ) and in incidence of disabling or fatal stroke ( 0.60 , 0.50 - 0.73 , p<0.0001 ) , but no change was seen in case-fatality due to incident stroke ( 17.2 % vs 17.8 % ; age and sex adjusted relative risk 0.85 , 95 % CI 0.57 - 1.28 , p=0.45 ) . Comparison of premorbid risk factors revealed substantial reductions in the proportion of smokers , mean total cholesterol , and mean systolic and diastolic blood pressures and major increases in premorbid treatment with antiplatelet , lipid-lowering , and blood pressure lowering drugs ( all p<0.0001 ) . INTERPRETATION The age-specific incidence of major stroke in Oxfordshire has fallen by 40 % over the past 20 years in association with increased use of preventive treatments and major reductions in premorbid risk factors [17204680] Background and Purpose — The success of gait rehabilitation after stroke depends on active walking exercises . However , the disabling after-effects of stroke often make such exercises impossible at the onset of therapy . To facilitate treadmill training of paraparetic patients , a robot-driven gait orthosis ( Lokomat ) was developed . We investigated the effects of the Lokomat when used with hemiparetic patients . Methods — The authors conducted a r and omized , controlled pilot study of 30 acute stroke survivors . The treatment group received 30 minutes of robotic training daily and the control group 30 minutes of conventional physiotherapy daily in addition to 30 minutes of conventional physiotherapy for each group . Outcome measures were independence of gait , gait speed , gait parameters , and body tissue composition . Results — After 4 weeks of therapy , the walking ability of the Lokomat group and the control group expressed as the functional ambulation classification was significantly improved . The functional ambulation category ( median± interquartile range ) was at baseline 0±0 in control and 0±1 in the therapy group and increased after therapy to 1±3 in both groups significantly ( P=0.01 ) . There was no significant difference in gain of these parameters between the groups . The Lokomat group had a significantly longer single stance phase ( sec ; mean±SEM ) on the paretic leg when walking on the floor . At baseline , it was 0.19±0.17 and after therapy 0.49±0.07 ( P=0.014 ) . The control group had increased their body weight approximately 1.33±1.40 kg ( mean±SEM ; P=0.046 ) , mostly as fat mass , whereas the Lokomat group had lost fat mass approximately −2.9±1.0 kg ( mean±SEM ; P=0.016 ) and increased their muscle mass approximately 3.36±1.4 kg ( mean± SEM ; P=0.031 ) . Conclusions — This pilot study indicates that Lokomat therapy is a promising intervention for gait rehabilitation . Although there was no difference between groups in gain of functional scores , the Lokomat group showed an advantage of robotic training over conventional physiotherapy in improvement of gait abnormality and body tissue composition [15293485] Objective : To evaluate the efficacy of a task-orientated intervention in enhancing competence in walking in people with stroke . Design : Two-centre observer-blinded stratified block-r and omized controlled trial . Setting : General community . Subjects : Between May 2000 and February 2003 , 91 individuals with a residual walking deficit within one year of a first or recurrent stroke consented to participate . Interventions : The experimental intervention comprised 10 functional tasks design ed to strengthen the lower extremities and enhance walking balance , speed and distance . The control intervention involved the practice of upper extremity activities . Subjects in both groups attended sessions three times a week for six weeks . Main measures : Six-minute walk test ( SMWT ) , 5-m walk ( comfortable and maximum pace ) , Berg Balance Scale , timed ‘ up and go ’ . Results : At baseline , subjects in the experimental ( n = 44 ) and control ( n = 47 ) groups walked an average distance of 209 m ( SD = 126 ) and 204 m ( SD = 131 ) , respectively , on the SMWT . Mean improvements of 40 m ( SD = 72 ) , and 5 m ( SD = 66 ) were observed following the experimental and control interventions , respectively . The between-group difference was 35 m ( 95 % confidence interval ( CI ) 7 , 64 ) . Significant between-group effects of 0.21 m/s ( 95 % CI 0.12 , 0.30 ) and of 0.11 m/s ( 95 % CI 0.03 , 0.19 ) in maximum and comfortable walking speed , respectively , were observed . People with a mild , moderate or severe walking deficit at baseline improved an average of 36 ( SD = 96 ) , 55 ( SD = 56 ) and 18 m ( SD = 23 ) , respectively , in SMWT performance following the experimental intervention . Conclusions : Study findings support the efficacy of a task-orientated intervention in enhancing walking distance and speed in the first year post stroke , particularly in people with moderate walking deficits [19229450] OBJECTIVE To analyse the effects of gait therapy for patients after acute stroke in a r and omized controlled trial . METHODS Fifty-six patients with a mean of 8 days post-stroke participated in : ( i ) gait trainer exercise ; ( ii ) walking training over ground ; or ( iii ) conventional treatment . Patients in the gait trainer exercise and walking groups practice d gait for 15 sessions over 3 weeks and received additional physiotherapy . Functional Ambulatory Category and several secondary outcome measures assessing gait and mobility were administered before and after rehabilitation and at 6-month follow-up . Patients also evaluated their own effort . RESULTS Walking ability improved more with intensive walk training compared with conventional treatment ; median Functional Ambulatory Category was zero in all patients at the start of the study , but it was 3 in both walk-training groups and 0.5 in the conventional treatment group at the end of the therapy . Median Functional Ambulatory Category was 4 in both walk-training groups and 2.5 in conventional treatment group at 6-month follow-up . Mean accomplished walking distance was not different between the gait trainer exercise and over ground walking groups . Borg scale indicated more effort in over ground walking . Secondary outcomes also indicated improvements . CONCLUSION Exercise therapy with walking training improved gait function irrespective of the method used , but the time and effort required to achieve the results favour the gait trainer exercise . Early intensive gait training result ed in better walking ability than did conventional treatment [17702703] Objective : To investigate whether provision of additional st and ing practice increases motor recovery and mobility post stroke . Design : A pilot r and omized controlled trial . Setting : A stroke rehabilitation unit in the UK . Participants : Seventeen participants , seven women and ten men , age range 51—92 admitted to the unit 6—58 days post stroke . Intervention : Each participant was r and omly allocated into a control ( conventional physiotherapy ) or treatment ( conventional therapy plus an additional session of st and ing practice ) group . The period of intervention ranged from 14 to 28 days dependent upon length of stay on the unit . Outcome measures : The Gross Functional Tool Section of the Rivermead Motor Assessment , the Trunk Control Test and the Berg Balance Scale were used on admission to the study , at weekly intervals during the intervention , and at 12 weeks ( after discharge ) . Results : Of the 17 participants recruited , three withdrew from the additional intervention group citing fatigue as a barrier and 15 completed the study . Participants completing additional st and ing practice demonstrated higher scores in all motor measures at week 12 , but this difference was not statistically significant . There was a statistically significant difference ( P < 0.05 ) in the changes in Berg Balance score when comparing week 1 with week 12 , in support of the group receiving extra st and ing practice . Conclusions : A larger study is required to establish the value of additional st and ing practice after stroke . This pilot demonstrates that the Gross Functional Tool Section of the Rivermead Motor Assessment and the Berg Balance Scale would be useful in such a study . Fatigue may be a significant barrier to ability to participate in more intensive programmes so screening participants for severe fatigue may be useful [15001789] Background and Purpose — Several studies have investigated the effect of therapeutic interventions for the arm in the acute phase after stroke , with follow-ups at a maximum of 12 months . The aim of this study was to examine the effect of repetitive sensorimotor training of the arm at 5 years after stroke . Subjects and Methods — One hundred consecutive stroke patients were r and omly allocated either to an experimental group that received daily additional sensorimotor stimulation of the arm or to a control group . The intervention period was 6 weeks . Assessment s of the patients were made before , midway , and after intervention , and at 6 and 12 months after stroke . In this study , 62 patients were reassessed at 5 years after stroke . The Brunnström-Fugl-Meyer ( BFM ) test , Action Research Arm ( ARA ) test , and Barthel index ( BI ) were used as the primary outcome measures . Results — At the 5-year follow-up , there was a statistically significant difference for both the BFM and ARA tests in favor of the experimental group . The mean differences in improvement between the groups from the initial evaluation to the 5-year assessment corresponded to 17 points on the BFM and 17.4 on the ARA . No effect was found for the BI . The treatment was most effective in patients with a severe initial motor deficit . Conclusions — Adding a specific intervention for the arm during the acute phase after a stroke result ed in a clinical ly meaningful and long-lasting effect on motor function . The effect can be attributed to early , repetitive , and targeted stimulation [15817001] OBJECTIVES To evaluate the efficacy of a task-oriented walking intervention in improving balance self-efficacy in persons with stroke and to determine whether effects were task-specific , influenced by baseline level of self-efficacy and associated with changes in walking and balance capacity . DESIGN Secondary analysis of a two-center , observer-blinded , r and omized , controlled trial . SETTING General community . PARTICIPANTS Ninety-one individuals with a residual walking deficit within 1 year of a first or recurrent stroke . INTERVENTION Task-oriented interventions targeting walking or upper extremity ( UE ) function were provided three times a week for 6 weeks . MEASUREMENTS Activities-specific Balance Confidence Scale , Six-Minute Walk Test , 5-m walk , Berg Balance Scale , and Timed " Up and Go " administered at baseline and postintervention . RESULTS The walking intervention was associated with a significantly greater average proportional change in balance self-efficacy than the UE intervention . Treatment effects were largest in persons with low self-efficacy at baseline and for activities relating to tasks practice d. In the walking group , change in balance self-efficacy correlated with change in functional walking capacity ( correlation coefficient=0.45 , 95 % confidence interval=0.16 - 0.68 ) . Results of multivariable modeling suggested effect modification by the baseline level of depressive symptoms and a prognostic influence of age , sex , comorbidity , time poststroke , and functional mobility on change in self-efficacy . CONCLUSION Task-oriented walking retraining enhances balance self-efficacy in community-dwelling individuals with chronic stroke . Benefits may be partially the result of improvement in walking capacity . The influence of baseline level of self-efficacy , depressive symptoms , and prognostic variables on treatment effects are of clinical importance and must be verified in future studies [15774435] Objectives : Bobath based ( BB ) and movement science based ( MSB ) physiotherapy interventions are widely used for patients after stroke . There is little evidence to suggest which is most effective . This single-blind r and omised controlled trial evaluated the effect of these treatments on movement abilities and functional independence . Methods : A total of 120 patients admitted to a stroke rehabilitation ward were r and omised into two treatment groups to receive either BB or MSB treatment . Primary outcome measures were the Rivermead Motor Assessment and the Motor Assessment Scale . Secondary measures assessed functional independence , walking speed , arm function , muscle tone , and sensation . Measures were performed by a blinded assessor at baseline , and then at 1 , 3 , and 6 months after baseline . Analysis of serial measurements was performed to compare outcomes between the groups by calculating the area under the curve ( AUC ) and inserting AUC values into Mann-Whitney U tests . Results : Comparison between groups showed no significant difference for any outcome measures . Significance values for the Rivermead Motor Assessment ranged from p = 0.23 to p = 0.97 and for the Motor Assessment Scale from p = 0.29 to p = 0.87 . Conclusions : There were no significant differences in movement abilities or functional independence between patients receiving a BB or an MSB intervention . Therefore the study did not show that one approach was more effective than the other in the treatment of stroke patients [2956448] Abstract The aim of the study was to evaluate the impact of a high-intensive exercise program containing high-intensive functional exercises implemented to real-life situations together with group discussion s on falls and security aspects in stroke subjects with risk of falls . This was a pre-specified secondary outcome for this study . For evaluation , Short Form-36 ( SF-36 ) health-related quality of life ( HRQoL ) and the Geriatric Depression Scale-15 ( GDS-15 ) were used . This was a single-center , single-blinded , r and omized , controlled trial . Consecutive ≥55 years old stroke patients with risk of falls at 3–6 months after first or recurrent stroke were r and omized to the intervention group ( IG , n=15 ) or to the control group ( CG , n=19 ) who received group discussion with focus on hidden dysfunctions but no physical fitness training . The 5-week high-intensive exercise program was related to an improvement in the CG in the SF-36 Mental Component Scale and the Mental Health subscale at 3 months follow-up compared with baseline values while no improvement was seen in the IG at this time . For the SF-36 Physical Component Scale , there was an improvement in the whole study group at 3 and 6 months follow-up compared with baseline values without any significant changes between the IG and CG . The GDS-15 was unchanged throughout the follow-up period for both groups . Based on these data , it is concluded that high-intensive functional exercises implemented in real-life situations should also include education on hidden dysfunctions after stroke instead of solely focus on falls and safety aspects to have a favorable impact on [20558830] Background and Purpose — Increased amount of therapy seems to be beneficial for motor recovery after stroke . The primary aim of the present study was to evaluate the effect of a 4-week community-based intensive motor training program combined with early supported discharge after initial treatment in a comprehensive stroke unit on balance . Secondary aims were to evaluate the effect on other functional outcome measures . Methods — This was a single-blind , r and omized , controlled trial with a 26-week follow-up . Sixty-two patients were recruited within 14 days after stroke and were r and omly allocated to a st and ard treatment group ( n=32 ) or to an intensive motor training group ( n=30 ) receiving 3 sessions of physical therapy and a structured home exercise program in addition to st and ard treatment every week for the first 4 weeks after discharge from hospital . Primary outcome measure was Berg Balance Scale . Secondary measures were Barthel Index , Motor Assessment Scale , Step Test , 5-meter Walk Test , and Stroke Impact Scale . Results — The mean ( SD ) minutes of physical therapy per week was 171.0 ( 65.8 ) in the intensive motor training group vs 85.6(69.9 ) in the st and ard treatment group . There were no statistical significant differences between the groups on any measure at end of follow-up except for a trend toward higher Motor Assessment Scale score ( P=0.059 ) and gait speed ( P=0.095 ) in the intensive motor training group . Conclusion — In this r and omized , controlled trial , a community-based intensive motor training program , doubling the amount of physical therapy during the first 4 weeks after discharge , did not show significant improvement of balance or any other functional outcomes [1640226] Previous research on stroke rehabilitation has not established whether increase in physical therapy lead to better intrinsic recovery from hemiplegia . A detailed study was carried out of recovery of arm function after acute stroke , and compares orthodox physiotherapy with an enhanced therapy regime which increased the amount of treatment as well as using behavioural methods to encourage motor learning . In a single-blind r and omised trial , 132 consecutive stroke patients were assigned to orthodox or enhanced therapy groups . At six months after stroke the enhanced therapy group showed a small but statistically significant advantage in recovery of strength , range and speed of movement . This effect seemed concentrated amongst those who had a milder initial impairment . More work is needed to discover the reasons for this improved recovery , and whether further development of this therapeutic approach might offer clinical ly significant gains for some patients [15482247] Although intervention is effective in reducing the disability associated with stroke , limited re sources mean that physiotherapy services often cease by six months after stroke . The purpose of this clinical trial was to investigate the efficacy of re source -efficient physiotherapy services in improving mobility and quality of life after stroke . Twenty-six people with residual walking difficulties after stroke were r and omised into an experimental or control group after discharge from physiotherapy services . The experimental group participated in a six-week , home-based mobility program . The control group participated in a six-week , home-based program of upper-limb exercises ( i.e. ' sham ' mobility exercises ) . Subjects met with the therapist for prescription of exercises only three times during the six weeks . Strategies used to offset potential problems associated with minimal subject-therapist interaction included videotaped instructions to encourage correct performance of exercises , modification of the environment and involvement of carers to enhance safety , and telephone contact and self-monitoring to promote compliance . St and ing ( Functional Reach ) , walking ( MAS Item 5 ) and quality of life ( SA-SIP30 ) were measured prior to , immediately after , and two months after intervention ceased by an assessor who was blinded to group allocation . Subjects in the experimental group demonstrated significant improvement in st and ing compared to the control group ( p = 0.01 ) which was maintained two months after the cessation of intervention ( p = 0.04 ) . There was no difference between the groups in walking ( p = 0.50 ) or quality of life ( p = 0.70 ) . The six-week , re source -efficient mobility program was effective in improving some of the mobility in people after discharge from stroke rehabilitation . The provision of re source -efficient programs is recommended wherever possible so that people affected by stroke may continue rehabilitation for longer [15574110] The purpose of this study was to investigate whether additional practice of either upper limb or mobility tasks improved functional outcome during inpatient stroke rehabilitation . This prospect i ve , r and omised , single blind clinical trial recruited 30 stroke subjects into either an Upper Limb or a Mobility Group . All subjects received their usual rehabilitation and an additional session of task-related practice using a circuit class format . Independent assessors , blinded to group allocation , tested all subjects . Outcome measures used were three items of the Jebsen Taylor H and Function Test ( JTHFT ) , two arm items of the Motor Assessment Scale ( MAS ) , and three mobility measures , the Timed Up and Go Test ( TUGT ) , Step Test , and Six Minute Walk Test ( 6MWT ) . Both groups improved significantly between pre- and post-tests on all of the mobility measures , however only the Upper Limb Group made a significant improvement on the JTHFT and MAS upper arm items . Following four weeks training , the Mobility Group had better locomotor ability than the Upper Limb Group ( between-group differences in the 6MWT of 116.4 m , 95 % CI 31.4 to 201.3 m , Step Test 2.6 repetitions , 95 % CI -1.0 to 6.2 repetitions , and TUGT -7.6 sec , 95 % CI -15.5 to 0.2 sec ) . The JTHFT dexterity scores in the Upper Limb Group were 6.5 sec ( 95 % CI -7.4 to 20.4 sec ) faster than the Mobility Group . Our findings support the use of additional task-related practice during inpatient stroke rehabilitation . The circuit class format was a practical and effective means to provide supervised additional practice that led to significant and meaningful functional gains [11912111] H and movement recovery and cortical reorganization were studied in 10 subjects with chronic stroke using functional MRI ( fMRI ) before and after training with an intensive finger movement tracking programme . Subjects were assigned r and omly to a treatment or control group . The treatment group received 18 - 20 sessions of finger tracking training using target waveforms under variable conditions . The control group crossed over to receive the same treatment after the control period . For comparison with a healthy population , nine well elderly females were also studied ; however , the well elderly controls did not cross over after the control period . The dependent variables consisted of a Box and Block score to measure prehensile ability ( subjects with stroke only ) , a tracking accuracy score and quantification of active cortical areas using fMRI . For the tracking tests , the subjects tracked a sine wave target on a computer screen with extension and flexion movements of the paretic index finger . Functional brain images were collected from the frontal and parietal lobes of the subject with a 4 tesla magnet . Areas of interest included the sensorimotor cortex ( SMC ) , primary motor area ( M1 ) , primary sensory area ( S1 ) , premotor cortex ( PMC ) and supplementary motor area ( SMA ) . Comparison between all subjects with stroke and all well elderly subjects at pre-test was analysed with two- sample t-tests . Change from pre-test to post-test within subjects was analysed with paired t-tests . Statistical significance was set at P < 0.05 . Stroke treatment subjects demonstrated significant improvement in tracking accuracy , whereas stroke control subjects did not until after crossover treatment . At pre-test , the cortical activation in the subjects with stroke was predominantly ipsilateral to the performing h and , whereas in the well elderly subjects it was contralateral . Activation for the stroke treatment group following training switched to contralateral in SMC , M1 , S1 and PMC . The stroke control group 's activation remained ipsilateral after the control period , but switched to contralateral after crossover to receive treatment . All well elderly subjects maintained predominantly contralateral activation throughout . Transfer of skill to functional activity was shown in significantly improved Box and Block scores for the stroke treatment group , with no such improvement in the stroke control group until after crossover . We concluded that individuals with chronic stroke receiving intensive tracking training showed improved tracking accuracy and grasp and release function , and that these improvements were accompanied by brain reorganization [18955513] Background . Sitting balance and the ability to perform selective trunk movements are important predictors of functional outcome after stroke . However , studies evaluating the effect of exercises aim ed at improving trunk performance are sparse . Objective . To examine the effect of additional trunk exercises on trunk performance after stroke . Methods . An assessor-blinded r and omized controlled trial was carried out at an inpatient stroke rehabilitation center . In total 33 participants were assigned to an experimental group ( n = 17 ) or a control group ( n = 16 ) . In addition to conventional therapy , the experimental group received 10 hours of individual and supervised trunk exercises ; 30 minutes , 4 times a week , for 5 weeks . Trunk performance was evaluated by the Trunk Impairment Scale ( TIS ) and its subscales of static and dynamic sitting balance and coordination . A general linear repeated measures model was used to analyze the results of our study . Results . No significant differences were found pretreatment between the 2 groups for the collected demographic variables , stroke-related parameters , clinical measures , number of therapy sessions received , and primary outcome measure used . Posttreatment , a significantly better improvement was noted in the experimental group compared to the control group for the dynamic sitting balance subscale only ; measuring selective lateral flexion initiated from the upper and lower part of the trunk , ( P = .002 , post hoc power calculation = .90 , effect size = 1.16 ) . Conclusions . Our results suggest that , in addition to conventional therapy , trunk exercises aim ed at improving sitting balance and selective trunk movements have a beneficial effect on the selective performance of lateral flexion of the trunk after stroke [11352620] We used serial positron emission tomography ( PET ) to study training-induced brain plasticity after severe hemiparetic stroke . Ten patients were r and omized to either task-oriented arm training or to a control group and scanned before and after 22.6 + /- 1.6 days of treatment using passive movements as an activation paradigm . Increases of regional cerebral blood flow ( rCBF ) were assessed using statistical parametric mapping ( SPM99 ) . Before treatment , all stroke patients revealed bilateral activation of the inferior parietal cortex ( IPC ) . After task-oriented arm training , activation was found bilaterally in IPC and premotor cortex , but also in the contralateral sensorimotor cortex ( SMC ) . The control group only showed weak activation of the ipsilateral IPC . After treatment , the training group revealed relatively more activation bilaterally in IPC , premotor areas , and in the contralateral SMC . Five normal subjects showed no statistical significant differences between two separate PET studies . In this group of patients , task-oriented arm training induced functional brain reorganization in bilateral sensory and motor systems [9099186] BACKGROUND AND PURPOSE After stroke , the ability to balance in sitting is critical to independence . Although impairments in sitting balance are common , little is known about the effectiveness of rehabilitation strategies design ed to improve it . The purpose of this r and omized placebo-controlled study was to evaluate the effect of a 2-week task-related training program aim ed at increasing distance reached and the contribution of the affected lower leg to support and balance . METHODS Twenty subjects at least 1 year after stroke were r and omized into an experimental or control group . The experimental group participated in a st and ardized training program involving practice of reaching beyond arm 's length . The control group received sham training involving completion of cognitive-manipulative tasks within arm 's length . Performance of reaching in sitting was measured before and after training using electromyography , videotaping , and two force plates . Variables tested were movement time , distance reached , vertical ground reaction forces through the feet , and muscle activity . Subjects were also tested on sit-to-st and , walking , and cognitive tasks . Nineteen subjects completed the study . RESULTS After training , experimental subjects were able to reach faster and further , increase load through the affected foot , and increase activation of affected leg muscles compared with the control group ( P < .01 ) . The experimental group also improved in sit-to-st and . The control group did not improve in reaching or sit-to-st and . Neither group improved in walking . CONCLUSIONS This study provides strong evidence of the efficacy of task-related motor training in improving the ability to balance during seated reaching activities after stroke [12098152] OBJECTIVES To quantify changes in spastic hypertonia during repeated passive isokinetic knee movements in stroke patients and to assess the role of muscle activity . DESIGN A between-groups design with repeated measures . SETTING Rehabilitation center for stroke patients . PARTICIPANTS Ten stroke patients with hypertonia and 10 healthy subjects matched for age and gender . INTERVENTION With an isokinetic apparatus , movements were imposed on the knee in series of 10 repetitions at speeds of 60 degrees /s , 180 degrees /s , and 300 degrees /s . MAIN OUTCOME MEASURES Spastic hypertonia was assessed on the basis of torque measurement and electromyographic activity of the quadriceps , hamstrings , and gastrocnemius muscles . RESULTS Compared with the controls , stroke patients presented a significantly stronger torque reduction during the mid- and endphases of movements at all speeds tested ( P<.05 ) . The strongest torque decline occurred during knee flexion and during the first movements . The effect increased toward the end phase of movements and with increasing speeds . The effect of movement repetitions on torque measurements was unchanged after electromyographic activity was included in the statistical analysis , except during extension movements at 180 degrees /s and 300 degrees /s . CONCLUSION Passive movements of the knee induced a decrease of spastic hypertonia in stroke patients through a combination of reflexive and mechanical factors . The role of these mechanisms is velocity dependent and differs for flexion and extension movements [20410150] Objective : To determine the effectiveness of sit-to-st and training in individuals with stroke . Design : R and omized controlled trial . Setting : Rehabilitation medical centre . Participants : Thirty-two subjects with stroke were r and omly assigned to the control and experimental groups ( n = 16 for each group ) . Interventions : Subjects in both groups received 30 minutes of general physical therapy three times a week for four weeks . Subjects in the experimental group received additional sit-to-st and training for 15 minutes each time . The total amount of therapy received was 45 minutes in the experimental group and 30 minutes in the control group each time . Main outcome measures : The weight-bearing distribution during quiet st and ing , the directional control and maximal excursion during limits of stability test , the scores of Berg Balance Scale and the extensor muscle strength of lower extremity were assessed before and after completing the 12 treatment sessions . Results : Our data showed significant improvements in directional control anteriorly in the experimental group ( from 47.4 (36.6)% to 62.6 (26.1)% ) compared with the control group ( from 68.7 (16.7)% to 62.8 (29.7)% ) ( P = 0.028 ) . A significant improvement in affected hip extensor strength was noted in the experimental group ( from 19.3 (9.8)% to 22.6 (8.4)% ) compared with the control group ( from 24.4 (9.0)% to 22.8 (7.2)% ) ( P = 0.006 ) . Significant improvements were noted only in the experimental group after treatment , including bilateral extensors , except the affected plantar flexors , the weight distribution in st and ing , the maximal excursion ( Panterior = 0.049 ; Paffected = 0.023 ) and the directional control ( Paffected = 0.013 ; Pnon-affected = 0.025 ) . Conclusions : Additional sit-to-st and training is encouraged due to effects on dynamic balance and extensor muscles strength in subjects with stroke [12900678] PURPOSE The purpose of this study was to evaluate the physical and psychosocial effects of an 8-wk community-based functional exercise program in a group of individuals with chronic stroke . METHODS Twenty-five subjects ( mean age 63 yr ) participated in a repeated measures design that evaluated the subjects with two baseline assessment s 1 month apart , one postintervention assessment , and one retention assessment 1 month postintervention . Physical outcome measures assessed were the Berg Balance Test , 12-Minute Walk Test distance , gait speed , and stair climbing speed . Psychosocial measures assessed were the Reintegration to Normal Living Index ( RNL ) and Canadian Occupational Performance Measure ( COPM ) . The 8-wk training consisted of a 60-min , 3 x wk-1 group program that focused on balance , mobility , functional strength , and functional capacity . The program was design ed to be accessible by reducing the need for costly one-on-one supervision , specialized setting s , and expensive equipment . RESULTS Improvements from the exercise program were found for all physical measures and these effects were retained 1-month postintervention . Subjects with lower function improved the most relative to their initial physical status . Significant effects were found for the COPM , but not the RNL Index ; however , subjects with lower RNL improved the most relative to their initial RNL Score . CONCLUSION A short-term community-based exercise program can improve and retain mobility , functional capacity , and balance and result in a demonstrable impact upon the performance of activities and abilities that were considered meaningful to the subjects . Implementation of such community-based programs has potential for improving activity tolerance and reducing the risk for secondary complications common to stroke ( e.g. , falls result ing in fractures and cardiac events ) [1675378] We describe the incidence and natural history of four clinical ly identifiable subgroups of cerebral infa rct ion in a community-based study of 675 patients with first-ever stroke . Of 543 patients with a cerebral infa rct , 92 ( 17 % ) had large anterior circulation infa rcts with both cortical and subcortical involvement ( total anterior circulation infa rcts , TACI ) ; 185 ( 34 % ) had more restricted and predominantly cortical infa rcts ( partial anterior circulation infa rcts , PACI ) ; 129 ( 24 % ) had infa rcts clearly associated with the vertebrobasilar arterial territory ( posterior circulation infa rcts , POCI ) ; and 137 ( 25 % ) had infa rcts confined to the territory of the deep perforating arteries ( lacunar infa rcts , LACI ) . There were striking differences in natural history between the groups . The TACI group had a negligible chance of good functional outcome and mortality was high . More than twice as many deaths were due to the complications of immobility than to direct neurological sequelae of the infa rct . Patients in the PACI group were much more likely to have an early recurrent stroke than were patients in other groups . Those in the POCI group were at greater risk of a recurrent stroke later in the first year after the index event but had the best chance of a good functional outcome . Despite the small anatomical size of the infa rcts in the LACI group , many patients remained substantially h and icapped . The findings have important implication s for the planning of stroke treatment trials and suggest that various therapies could be directed specifically at the subgroups [10768528] OBJECTIVE To evaluate the immediate and retention effects of a 4-week training program on the performance of locomotor-related tasks in chronic stroke . DESIGN R and omized , controlled pilot study with 2-month follow-up . SETTING Rehabilitation center . SUBJECTS A convenience sample consisting of 12 chronic stroke subjects was used . Subjects were r and omly assigned to the experimental or the control group . Three subjects withdrew from the study . INTERVENTION Both experimental and control groups participated in exercise classes three times a week for 4 weeks . The exercise class for the experimental group focused on strengthening the affected lower limb and practicing functional tasks involving the lower limbs , while the control group practice d upper-limb tasks . MAIN OUTCOME MEASURES Lower-limb function was evaluated by measuring walking speed and endurance , peak vertical ground reaction force through the affected foot during sit-to-st and , and the step test . RESULTS The experimental group demonstrated significant immediate and retained ( 2-month follow-up ) improvement ( p < or = .05 ) compared with the control group in walking speed and endurance , force production through the affected leg during sit-to-st and , and the number of repetitions of the step test . CONCLUSION The pilot study provides evidence for the efficacy of a task-related circuit class at improving locomotor function in chronic stroke [15083439] OBJECTIVE To evaluate the immediate and long-term effects of 2 upper-extremity rehabilitation approaches for stroke compared with st and ard care in participants stratified by stroke severity . DESIGN Nonblinded , r and omized controlled trial ( baseline , postintervention , 9mo ) design . SETTING Inpatient rehabilitation hospital and outpatient clinic . PARTICIPANTS Sixty-four patients with recent stroke admitted for inpatient rehabilitation were r and omized within severity strata ( Orpington Prognostic Scale ) into 1 of 3 intervention groups . Forty-four patients completed the 9-month follow-up . INTERVENTIONS St and ard care ( SC ) , functional task practice ( FT ) , and strength training ( ST ) . The FT and ST groups received 20 additional hours of upper-extremity therapy beyond st and ard care distributed over a 4- to 6-week period . MAIN OUTCOME MEASURES Performance measures of impairment ( Fugl-Meyer Assessment ) , strength ( isometric torque ) , and function ( Functional Test of the Hemiparetic Upper Extremity [ FTHUE ] ) . RESULTS Compared with SC participants , those in the FT and ST groups had significantly greater increases in Fugl-Meyer motor scores ( P=.04 ) and isometric torque ( P=.02 ) posttreatment . Treatment benefit was primarily in the less severe participants , where improvement in FT and ST group Fugl-Meyer motor scores more than doubled that of the SC group . Similar results were found for the FTHEU and isometric torque . During the long term , at 9 months , the less severe FT group continued to make gains in isometric muscle torque , significantly exceeding those of the ST group ( P<.05 ) . CONCLUSIONS Task specificity and stroke severity are important factors for rehabilitation of arm use in acute stroke . Twenty hours of upper extremity-specific therapy over 4 to 6 weeks significantly affected functional outcomes . The immediate benefits of a functional task approach were similar to those of a resistance-strength approach , however , the former was more beneficial in the long-term [10421300] BACKGROUND We investigated the effects of different intensities of arm and leg rehabilitation training on the functional recovery of activities of daily living ( ADL ) , walking ability , and dexterity of the paretic arm , in a single-blind r and omised controlled trial . METHODS Within 14 days after stroke onset , 101 severely disabled patients with a primary middle-cerebral-artery stroke were r and omly assigned to : a rehabilitation programme with emphasis on arm training ; a rehabilitation programme with emphasis on leg training ; or a control programme in which the arm and leg were immobilised with an inflatable pressure splint . Each treatment regimen was applied for 30 min , 5 days a week during the first 20 weeks after stroke . In addition , all patients underwent a basic rehabilitation programme . The main outcome measures were ability in ADL ( Barthel index ) , walking ability ( functional ambulation categories ) , and dexterity of the paretic arm ( Action Research arm test ) at 6 , 12 , 20 , and 26 weeks . Analyses were by intention to treat . FINDINGS At week 20 , the leg-training group ( n=31 ) had higher scores than the control group ( n=37 ) for ADL ability ( median 19 [ IQR 16 - 20 ] vs 16 [ 10 - 19 ] , p<0.05 ) , walking ability ( 4 [ 3 - 5 ] vs 3 [ 1 - 4 ] , p<0.05 ) , and dexterity ( 2 [ 0 - 56 ] vs 0 [ 0 - 2 ] , p<0.01 ) . The arm-training group ( n=33 ) differed significantly from the control group only in dexterity ( 9 [ 0 - 39 ] vs 0 [ 0 - 2 ] , p<0.01 ) . There were no significant differences in these endpoints at 20 weeks between the arm-training and leg-training groups . INTERPRETATION Greater intensity of leg rehabilitation improves functional recovery and health-related functional status , whereas greater intensity of arm rehabilitation results in small improvements in dexterity , providing further evidence that exercise therapy primarily induces treatment effects on the abilities at which training is specifically aim ed [18285431] Objective : This pilot r and omized controlled trial evaluated an assistant-led , community-based intervention to improve community mobility and participation after stroke , and examined the potential for independent community ambulation in people with subacute stroke who present with moderate gait deficit . Design : A multicentre , pilot r and omized controlled trial . Setting : Three hospitals and three community setting s in New Zeal and . Subjects : Thirty post-acute , home-dwelling stroke survivors were r and omly allocated to receive intervention in the community ( n = 14 ) or as hospital out patients ( n = 16 ) twice a week for seven weeks . Interventions : The community intervention involved practice of functional gait activities in community environments relevant to each participant . Hospital-based physiotherapy was based upon a Motor Relearning approach . Main measures : The primary outcome measure was gait speed ( m/min ) . Secondary outcomes included endurance ( six-minute walk time ) , Activities-specific Confidence Balance Scale , and the Subjective Index of Physical and Social Outcomes measured at baseline , post intervention and six months . Results : Large gains in gait speed were obtained for participants in both groups : community group mean ( SD ) 16 ( 16.1 ) m/min ; physiotherapy group mean ( SD ) 15.9 ( 16.1 ) m/min , maintained at six months . There were no significant differences between groups for primary and secondary outcomes after treatment ( P = 0.86 ANOVA ) or at six months ( P = 0.83 ANOVA ) . Only 11 participants reported independent community ambulation . Levels of social integration were low to moderate . Conclusions : A community-based gait recovery programme appears a practicable alternative to routine physiotherapy , however independent community ambulation is a challenging rehabilitation goal [12392332] Objective : To determine ( 1 ) the most effective of three treatment approaches to retrain seated weight distribution long-term after stroke and ( 2 ) whether improvements could be generalized to weight distribution in st and ing . Setting : Inpatient rehabilitation unit . Design : Forty asymmetrical acute stroke subjects were r and omly allocated to one of four groups in this pilot study . Changes in weight distribution were compared between the 10 subjects of each of three treatment groups ( task-specific reach , Bobath , or Balance Performance Monitor [ BPM ] feedback training ) and a no specific treatment control group . One week of measurement only was followed by two weeks of daily training sessions with the treatment to which the subject was r and omly allocated . Measurements were performed using the BPM daily before treatment sessions , two weeks after cessation of treatment and 12 weeks post study . Weight distribution was calculated in terms of mean balance ( percentage of total body weight ) or the mean of 300 balance points over a 30-s data run . Results : In the short term , the Bobath approach was the most effective treatment for retraining sitting symmetry after stroke ( p = 0.004 ) . Training with the BPM and no training were also significant ( p = 0.038 and p = 0.035 respectively ) and task-specific reach training failed to reach significance ( p = 0.26 ) . At 12 weeks post study 83 % of the BPM training group , 38 % of the task-specific reach group , 29 % of the Bobath group and 0 % of the untrained group were found to be distributing their weight to both sides . Some generalization of symmetry training in sitting to st and ing was noted in the BPM training group which appeared to persist long term . Conclusions : Results should be treated with caution due to the small group sizes . However , these preliminary endings suggest that it might be possible to restore postural symmetry in sitting in the early stages of rehabilitation with therapy that focuses on creating an awareness of body position [8053790] Compensation by the unaffected upper extremity ( UE ) was studied in stroke patients who were unable to use the affected UE . The main aim was to evaluate the need of teaching compensatory techniques to stroke patients during rehabilitation of UE function . The study was prospect i ve and community based and included 636 consecutive acute stroke patients . UE function and UE paresis were assessed weekly using the Barthel Index subscores for feeding and grooming and the Sc and inavian Stroke Scale ( SSS ) subscores for arm and h and . Rehabilitation was performed according to the Bobath technique . Initially , 214 had severe UE paresis according to SSS ; the arm could not move against gravity and the fingertips could not reach palm . In 64 of the 115 patients discharged alive , the affected UE definitely remained useless despite intensive and longst and ing rehabilitation . Improvement of UE function was seen in 25 of these patients ( 39 % ) and was possible only through compensation by the unaffected UE . Patients who gained UE function by compensation were younger ( p < 0.01 ) , had less severe stroke ( p < 0.01 ) , smaller ( p < 0.01 ) , and subcortically located ( p = 0.02 ) lesions and less affection of higher cortical function ( p = 0.01 ) . Recovery of UE function in more than half of the stroke patients with initial severe UE paresis can be achieved only by compensation by the unaffected UE [15537991] This trial compares the effects of task-oriented physical therapy ( PT ) provided with and without the use of rehabilitation technology on locomotor recovery in 63 persons with subacute stroke . Participants in the experimental ( EXP ) group used a treadmill , a Kinetron isokinetic exerciser , and a limb-load monitor , whereas those in the control ( CTL ) group did not while engaging in PT 1 h per day , 5 days per week for 2 months . Locomotor recovery was assessed by clinical ( gait speed , Fugl Meyer motor leg and arm subscores , the Balance Scale , the Timed Up and Go , and the Barthel ambulation subscore ) and laboratory outcomes ( gait kinematics and kinetics ) pre- and posttherapy and 3 months later . Within groups , gait speed ( P < 0.01 ) and all secondary measures improved posttherapy ( P < 0.01 - 0.05 ) , and improvements in clinical measures were maintained at follow-up , but there was no difference between groups ( P > 0.05 ) . When the groups were pooled , the increase in gait speed was associated ( r = 0.52 , P = 0.003 ) with an increase in ankle power generation of the affected leg . The results demonstrate that the efficacy of the task-oriented approach is not dependent on rehabilitation technology [20051618] Balance is a complex motor skill and it is frequently disturbed among stroke survivors . Rehabilitation experts are still facing challenges in achieving good stability . The primary aim of this study was to determine the effect of a wobble board exercise program on static and dynamic balance of hemiplegic subjects . Seventeen ( 17 ) stroke survivors were r and omly selected into two groups . The subjects in the experimental group were trained on wobble board for six weeks while the control group received only the baseline treatment programs . The modified version of the timed balance test was used to assess balance while the foursquare step test was used to assess dynamic balance . Descriptive statistics and Analysis of variance ( ANOVA ) were used to analyze the data obtained . The result showed that there was significant difference in the static balance ( eye closed ) ( F=7.49 , P < 0.05 ) and dynamic balance ( F3.20 , P < 0.05 ) between the groups but there was no significant difference in static balance ( eye opened ) ( F= 1.75 , P > 0.05 ) . The study concluded that wobble board exercise improved both static ( eye closed ) and dynamic balance of stroke survivor used in this study [16774090] Objective : To investigate the effect of early cycling training on balance and motor abilities of stroke patients in their subacute stage . Design : R and omized clinical trial . Setting : Inpatient rehabilitation . Subjects : Twenty-four patients who had had a first stroke were r and omly assigned to a cycling training group ( n = 10 ) or to a control ( n = 14 ) group . Intervention : All subjects received their usual rehabilitation programme ; the cycling training group received in addition a daily session of leg cycle ergometer , lasting three weeks . Both groups were followed for six weeks . Main outcome measurements : Balance was assessed using the Postural Assessment Scale for Stroke Patients ( PASS ) and the st and ing balance test . The motor function of the lower extremity was also assessed by the Fugl-Meyer Assessment ( FMA ) . Results : In the within-group comparison , both the exercise group and the control group had improved significantly ( P B=0.01 ) with time with respect to PASS total ( exercise group 18.79=2.8 to 31.19=2.2 , control group 18.19=3.2 to 26.49=3.8 ) and PASS subscores , as well as the FMA score ( exercise group 17.29=7.5 to 29.19=5.9 , control group 16.69=6.4 to 22.19=6.8 ) . In addition there was a significant group = time interaction effect , with exercise group patients demonstrating better performance in both the total PASS score and PASS subscores and FMA score relative to the control patients ( P B=0.01 ) . Conclusions : These preliminary findings suggest that stroke patients in the subacute stage can improve their motor and balance abilities after an early short duration of cycling training [15835284] BACKGROUND AND PURPOSE Of all stroke survivors , more than 50 % are left with motor disabilities . Impairment of upper limb movement is a common motor disability . Constraint-Induced Movement Therapy ( CIMT ) is an intervention which has been used for the treatment of upper extremity motor disabilities in stroke patients . Although CIMT is an effective intervention , a recent survey revealed that this procedure is viewed with apprehension by many clinicians because of concerns about practicality and re source issues . We developed a modified CIMT that reserves the massed training of the affected arm without any physical restriction of the intact one and then used it on our stroke patients . This study was design ed to evaluate the effectiveness of this Modified-Constraint-Induced Movement Therapy ( m-CIMT ) . METHODS Thirty stroke patients were r and omly assigned to either an m-CIMT ( n=13 ) or a control group ( n=17 ) . Subjects in the m-CIMT group received a 2-week course of m-CIMT . Outcomes were evaluated using the Wolf Motor Function Test ( WMFT ) . RESULTS After only 2 weeks of training , significant differences ( p<0.05 ) in favor of m-CIMT were found in the following 6 elements of the WMFT : Extend elbow with weight , Lift pencil , Stack checkers , Flip cards , Turn key in lock , and Lift basket . CONCLUSION The present study shows that our m-CIMT is useful in improving the function of the affected upper extremity in stroke patients [16628507] OBJECTIVE To evaluate the usefulness of the computer program made for the patients after stroke to treat their cognitive impairments and hemiparesis . RESEARCH DESIGN AND METHODS The experimental group involved 10 patients after stroke who were obliged to train on a computer every day during their three-week stay on the rehabilitation ward . The control group involved 10 patients after stroke who did not participate in any computer training during their rehabilitation process . The first part of the computer tasks trains the attention impairments and visual-motor co-ordination problems . We modified the joystick by adding special buttons to train movements of the wrist , thumb and forefinger of the impaired h and . Computer tasks are made in the way to stimulate both the cognitive functions and h and dexterity at the same time . RESULTS This initial research shows a statistically significant improvement of the cognitive functions and h and dexterity among patients from the experimental group . According to these results we did not observe any significant improvement in the cognitive functions among patients who did not train on a computer ( control group ) . CONCLUSIONS The results of this research suggest the usefulness of this computer program in training cognitive impairments and visual-motor co-ordination as well as h and dexterity among the patients after stroke [16180593] Objective : To evaluate the effect of an arm training programme combining repetition of unilateral and symmetrical bilateral tasks for people in the subacute phase after stroke . Design : R and omized controlled trial . Setting : Inpatient functional rehabilitation unit . Subjects : Forty-one people who had had a stroke , in the subacute phase , receiving conventional arm occupational and physical therapy , were r and omized to an experimental group ( n=20 ) and a control group ( n=21 ) . Interventions : In addition to the usual arm therapy in the rehabilitation unit , the experimental group received an arm therapy programme ( 15 - 20 45-min sessions ) based on repetition of unilateral and symmetrical bilateral tasks . The control group received additional usual arm therapy of a similar duration and frequency to the experimental treatment . Main measures : The effect of the programme was judged on the basis of : ( 1 ) arm impairments ( motor function , grip strength , gross and fine manual dexterity and motor co-ordination ) , ( 2 ) arm disabilities in tasks related to daily activities , and ( 3 ) functional independence in activities of daily living ( ADL ) and instrumental ADL ( IADL ) . Results : Although both experimental and control groups of participants improved similarly during the study period , the statistical analyses did not show any difference between the groups at the end of the treatment for the different dependent variables evaluated : ( 1 ) arm impairments : p=0.43 - 0.79 ; ( 2 ) arm disabilities : p=0.16 - 0.90 ; and ( 3 ) functional independence : p=0.63 and 0.90 . Conclusions : An arm training programme based on repetition of unilateral and symmetrical bilateral practice did not reduce impairment and disabilities nor improve functional outcomes in the subacute phase after stroke more than the usual therapy [11441386] OBJECTIVE To test the efficacy of the arm ability training ( AAT ) on a sample of patients with central arm paresis after traumatic brain injury ( TBI ) or stroke . DESIGN Single-blind , r and omized , controlled trial . SETTING Inpatient rehabilitation center . PATIENTS Consecutive sample of 74 patients of whom 60 ( 45 with stroke , 15 with TBI ) completed the study ; 37 patients received a 1-year follow-up . INTERVENTION Daily AAT with ( n = 20 ) or without ( n = 20 ) knowledge of results , or no AAT ( n = 20 ) during a 3-week intervention period . MAIN OUTCOME MEASURES Summary time scores of the Test Evaluant les Membres superieurs des Personnes Agees (TEMPA)-a test of upper extremity function with daily function-like activities ( focal disability)- and kinematic analysis of aim ed movements . RESULTS Patients with AAT realized superior improvement as compared with controls . Mean improvement in the time needed to perform ( 1 ) all TEMPA tasks was 41.4 versus 12.8 seconds ( p = .0012 ) ; ( 2 ) unilateral TEMPA tasks , 16.5 versus 4.2 seconds ( p = .0036 ) ; and ( 3 ) the ballistic component of aim ed movements , 96 versus 20ms ( p = .0115 ) . Knowledge of result did not substantially modify these effects . A functional benefit existed at 1-year follow-up . CONCLUSION The AAT reduces focal disability among stroke and TBI patients with mild central arm paresis [16634338] Objective : To study the efficacy of the motor relearning approach in promoting physical function and task performance for patients after a stroke . Design : Matched-pair r and omized controlled trial . Setting : An outpatient rehabilitation centre in Hong Kong . Participants : Fifty-two out patients with either a thrombotic or haemorrhagic stroke who completed either the study or control group . Interventions : The patients received 18 2-h sessions in six weeks of either the motor relearning programme or a conventional therapy programme . Main outcome measures : The Berg Balance Scale , the Timed Up and Go Test , the Functional Independence Measure ( FIM ) , the modified Lawton Instrumental Activities of Daily Living ( IADL ) test , and the Community Integration Question naire . Results : Patients in the motor relearning group showed significantly better performance on all but the Timed Up and Go Test when compared with the control group ( F(1,150)=6.34 - 41.86 , P ≤ 0.015 ) . The interactions between group and occasion were significant on all five outcome measures , indicating that the rates of change across time between the motor relearning and control groups differed ( F(3,150)=3.60 - 33.58 , P < 0.015 ) . Conclusion : The motor relearning programme was found to be effective for enhancing functional recovery of patients who had a stroke . Both ‘ sequential ’ and ‘ function-based ’ concepts are important in applying the motor relearning approach to the rehabilitation of stroke patients [11387585] OBJECTIVE To assess use of the Bon Saint Côme device for axial postural rehabilitation in hemiplegic patients , a technique based on voluntary trunk control during exploratory retraining . DESIGN A 3-month r and omized controlled trial . SETTING A public neurorehabilitation center . PATIENTS Twenty consecutive hemiplegic patients with axial postural disturbance result ing from recent stroke were r and omly assigned to a device group ( DG ) or control group ( CG ) . The 2 groups of 10 patients were similar . INTERVENTION For 1 month , the DG patients followed an experimental program for 1 hour daily and conventional neurorehabilitation for 1 hour daily , whereas CG patients had conventional neurorehabilitation for 2 hours daily . For the next 2 months , all 20 patients had conventional neurorehabilitation for 2 hours daily . MAIN OUTCOME MEASURES Patients were assessed on days 0 , 30 , and 90 by using a battery of postural tests , gait evaluation , the Bells neglect test , and the FIM instrument . RESULTS On day 30 , postural and neglect tests improved significantly more in DG than in CG . The benefit remained at day 90 . Gait improved earlier in DG than in CG . FIM scores improved equally . CONCLUSIONS Voluntary trunk control retraining during spatial exploration with the Bon Saint Côme device appears to be a useful approach for rehabilitation of postural disorders in hemiplegic patients . Treatments design ed to improve spatial cognition deficits probably enhance postural disorder recovery in hemiplegia [8702377] OBJECTIVE To determine the effect of different motor learning schedules on stroke patients ' rate of acquisition and retention of a functional movement sequence using the hemiparetic upper limb . DESIGN R and omized controlled group study using a retention design with two retention trials . SETTING Outpatient neurorehabilitation clinic . PATIENTS Twenty-four patients with chronic hemiparesis secondary to a single unilateral cerebral stroke without evidence of severe cognitive or language impairment . MAIN OUTCOME MEASURE The primary hypothesis was that hemiparetic motor learning that occurred under conditions of context ual interference ( ie , r and om practice ) would be retained better than learning that occurred under conditions of repetitive drill ( blocked practice ) . RESULTS A significant difference was found among the three groups ( ie , r and om- practice , blocked- practice , control ) on both the first retention measure ( chi 2 = 13.50 , p < .01 ) and the second retention measure ( chi 2 = 12.59 , p < .01 ) . More importantly , a significant difference was found between the r and om- practice and blocked- practice groups on both the first retention measure ( U = 68.5 , p < .01 ) and the second retention measure ( U = 62.0 , p = .05 ) . CONCLUSIONS Findings provide empirical evidence to support the contention that r and om practice is more effective than blocked practice , with respect to retention over time , when hemiparetic stroke patients attempt to learn functional motor skills [15759530] Objective : To investigate the effectiveness of Bobath on stroke patients at different motor stages by comparing their treatment with orthopaedic treatment . Design : A single-blind study , with r and om assignment to Bobath or orthopaedic group . Setting : Physical therapy department of a medical centre . Subjects : Twenty-one patients with stroke with spasticity and 23 patients with stroke at relative recovery stages participated . Interventions : Twenty sessions of Bobath programme or orthopaedic treatment programme given in four weeks . Main outcome measures : Stroke Impairment Assessment Set ( SIAS ) , Motor Assessment Scale ( MAS ) , Berg Balance Scale ( BBS ) and Stroke Impact Scale ( SIS ) for impairment and functional limitation level . Results : Participants with spasticity showed greater improvement in tone control ( change score : 1.209±1.03 versus 0.089±0.67 , p = 0.006 ) , MAS ( change score : 7.64±4.03 versus 4.009±1.95 , p = 0.011 ) , and SIS ( change score : 7.309±6.24 versus 1.259±5.33 , p=0.023 ) after 20 sessions of Bobath treatment than with orthopaedic treatment . Participants with relative recovery receiving Bobath treatment showed greater improvement in MAS ( change score : 6.149±5.55 versus 2.779±9.89 , p=0.007 ) , BBS ( change score : 19.189±15.94 versus 6.859±5.23 , p=0.015 ) , and SIS scores ( change score : 8.509±3.41 versus 3.629±4.07 , p = 0.006 ) than those with orthopaedic treatment . Conclusion : Bobath or orthopaedic treatment paired with spontaneous recovery result ed in improvements in impairment and functional levels for patient with stroke . Patients benefit more from the Bobath treatment in MAS and SIS scores than from the orthopaedic treatment programme regardless of their motor recovery stages [14606738] Objective : The purpose of this follow-up one and four years post stroke was to find out whether the initial physiotherapy approach had had any long-term effects on mortality , motor function , postural control , activities of daily living , life quality , follow-up from community services and living conditions . Design : A r and omized controlled trial of first time ever stroke patients . Group 1 ( n = 33 ) and group 2 ( n = 28 ) had initial physiotherapy according to the Motor Relearning Programme and Bobath , respectively . Main outcome measures : The Motor Assessment Scale ( MAS ) , the Sødring Motor Evaluation Scale ( SMES ) , the Barthel ADL Index , the Nottingham Health Profile ( NHP ) and Berg Balance Scale were used . The following parameters were also registered : incidence of new strokes , other diseases , use of assistive devices , the patient 's accommodation and use of services from the community . Results : The mortality rates were similar in the two groups . In both groups the motor function , postural control and ADL had decreased rapidly , leaving many of the patients dependent and with a high risk of falling . Life quality had increased compared to the acute stage , but was still low in comparison with healthy persons . Patients in both groups lived at home , but were dependent on help from relatives and community services . Physiotherapy as follow-up service was seldom used . The initial physiotherapy approach did not seem to have a major in‘uence on the patients ' ability to cope in the long term . Conclusion : This follow-up at one and four years post stroke showed no major in‘uence of two different initial physiotherapy regimens on long-term function . The study confirmed a rapid deterioration of ADL and motor function and an increased dependence on relatives . The study reveals a gap between the intense treatment in the acute phase and little or no follow-up of physiotherapy treatment or other rehabilitation activities later [15704508] Objectives : To evaluate a training programme aim ed at improving lateral weight transference in patients following acute stroke to determine main treatment effects , if any , to inform the design of future studies . Design : A single-blind r and omized controlled trial . Setting : The Stroke Unit at The James Cook University Hospital , Middlesbrough , UK . Subjects : Thirty-five patients with an acute stroke . Interventions : All subjects received their usual care , including physiotherapy . The treatment group ( n / 17 ) received 12 additional therapy sessions ( over four weeks ) comprising exercises aim ed at improving lateral weight transference in sitting delivered by trained physiotherapy assistants . Main outcome measures : Measures of dynamic reaching , sitting and st and ing , and static st and ing balance were undertaken by a blind independent observer . Results : Specific measures of weight displacement in st and ing and reaching , and timed st and ing up and sitting down did not detect any differences over time regardless of group . Neither were there any significant changes over time , except for sway during static st and ing ( p B=0.01 ) and time to return to their original position during dynamic reaching ( p / 0.01 ) . Conclusions : A training programme aim ed at improving lateral weight transference did not appear to enhance the rehabilitation of acute stroke patients . Improvements observed in postural control in st and ing and sitting may be attributable to usual care or natural recovery [8418798] UNLABELLED RESEARCH PROBLEM AND METHODS : There are currently 1.5 million stroke survivors in the United States . More than half of these individuals have significant residual physical disability and functional impairment . Survivors of stroke constitute the largest group of patients receiving rehabilitation services in this country . We examined existing clinical trials investigating the effectiveness of stroke rehabilitation programs to improve functional outcomes and discharge destination . One hundred twenty-four research reports were initially identified . From this sample , 36 trials meeting selected criteria were evaluated by the methods of meta- analysis . RESULTS A total of 3717 patients participated in the 36 clinical trials included in the meta- analysis . The results revealed a mean d-index of 0.40 + /- 0.33 . This effect size index was converted to a U3 value of 65.5 , indicating that the average patient receiving a program of focused stroke rehabilitation performed better than approximately 65.5 % of those patients in comparison groups ( 95 % confidence interval , 63.6 % to 67.3 % ) . The results also revealed a significant interaction between type of research design and method of recording the outcome of a clinical trial . Blind recording of the outcome measure appears to be an essential design characteristic in clinical trials that do not r and omize patients to conditions . CONCLUSIONS Programs of focused stroke rehabilitation may improve functional performance for some patients who have experienced a stroke . The improvement in performance appears related to early initiation of treatment , but not to the duration of intervention . Improvements are also associated with the patient 's age and the type of design . Research design should be considered an important moderator variable in planning and interpreting future clinical trials of treatment effectiveness in stroke rehabilitation [15859527] Objective : To examine the effectiveness of additional backward walking training on gait outcome of patients post stroke . Design : R and omized controlled trial . Setting : Medical centre . Subjects : Twenty-five subjects with stroke , who were lower extremity Brunnstrom motor recovery stage at 3 or 4 and were able to walk 11 m with or without a walking aid or orthosis , r and omly allocated to two groups , control ( n = 12 ) and experimental ( n = 13 ) . Interventions : Subjects in both groups participated in 40 min of conventional training programme three times a week for three weeks . Subjects in experimental group received additional 30 min of backward walking training for three weeks at a frequency of three times per week . Main measures : Gait was measured using the Stride Analyzer . Gait parameters of interest were walking speed , cadence , stride length , gait cycle and symmetry index . Measures were made at baseline before commencement of training ( pre-training ) and at the end of the three-week training period ( post-training ) . Results : After a three-week training period , subjects in experimental group showed more improvement than those in control group for walking speed ( change score : 8.609 ± 6.95 versus 3.659 ± 2.92 , p-value = 0.032 ) , stride length ( change score : 0.0909 ± 0.076 versus 0.00649 ± 0.078 , p-value = 0.006 ) , and symmetry index ( change score : 44.079 ± 53.29 versus 5.309 ± 13.91 , p-value = 0.018 ) . Conclusions : This study demonstrated that asymmetric gait pattern in patients post stroke could be improved from receiving additional backward walking therapy [16719028] Objective : To evaluate the efficacy of a task-oriented intervention in enhancing arm function in people with stroke . Design : Two-centre , observer-blinded , stratified , block-r and omized controlled trial . Setting : General community . Patients : Ninety-one individuals within one year of a first or recurrent stroke consented to participate between May 2000 and February 2003 . Interventions : The experimental intervention involved practice of functional , unilateral and bilateral tasks that were design ed to improve gross and fine manual dexterity whereas the control intervention was composed of walking tasks . Members in both groups participated in three sessions a week for six weeks . Main outcome measure(s ) : The primary test of arm function was the Box and Block Test . Secondary tests included the Nine-Hole Peg Test , maximal grip strength , the Test d'Evaluation des Membres supé rieurs des Personnes Agées ( TEMPA ) and the Stroke Rehabilitation Assessment of Movement . Results : Results are for the more affected arm . Baseline performance on the Box and Block Test was an average of 26 blocks ( st and ard deviation ( SD=16 ) in the experimental group ( n=47 ) and 26 blocks ( Sd=18 ) in the control group ( n=44 ) . These values represent approximately 40 % of age-predicted values . Values for the postintervention evaluation were an average of 28 ( SD=17 ) and 28 ( SD=19 ) blocks for the experimental and control group respectively . No meaningful change on other measures of arm function was observed . Conclusions : A task-oriented intervention did not improve voluntary movement or manual dexterity of the affected arm in people with chronic stroke [18511529] Objective : To establish the effects of group exercise on mobility and strength . Design : R and omized controlled trial . Setting : Two public hospital outpatient rehabilitation services . Participants : One hundred and seventy-three people ( mean age 74.9 years , SD 10.8 ) with impaired mobility were r and omized and 159 people ( 92 % ) completed the trial . Interventions : Five-week , twice-weekly ` circuit-style ' group exercise programme run by a physiotherapist ( n = 85 ) and a no-intervention waiting list control group ( n = 88 ) . Main outcome measures : Three aspects of mobility : balance while st and ing and stepping ( Step Test , semi-t and em and t and em stance times ) ; sit-to-st and ability ( rate and minimum height ) and gait ( 6-metre and 6-minute walk tests ) . Lower limb muscle strength ( knee flexion and extension ) . Results : At retest , exercise participants had improved significantly more than their control counterparts on measures of balance while stepping , sit to st and and gait . Exercise participants averaged 1.6 more steps on the 15-second Step Test ( 95 % confidence interval ( CI ) 0.5 to 2.8 , P=0.005 ) , walked an average of 0.12 m/s faster ( 95 % CI 0.05 to 0.2 , P=0.002 ) and took 2.5 fewer steps in 6 metres ( 95 % CI —4.2 to —0.8 , P=0.004 ) . Exercise participants also averaged 0.04 more sit-to-st and s/second , ( 95 % CI 0.003 to 0.08 , P=0.037 ) and walked an average of 30.9 metres further in 6 minutes ( 95 % CI 9.4 to 52.4 , P=0.005 ) . There were no clinical ly important or statistically significant between-group differences at retest for the measures of strength ( knee extension and flexion ) , balance while st and ing or minimal sit-to-st and height . Conclusion : This short- duration circuit class programme improved mobility , but not strength [19969159] UNLABELLED Mudge S , Barber PA , Stott NS . Circuit-based rehabilitation improves gait endurance but not usual walking activity in chronic stroke : a r and omized controlled trial . OBJECTIVE To determine whether circuit-based rehabilitation would increase the amount and rate that individuals with stroke walk in their usual environments . DESIGN Single-blind r and omized controlled trial . SETTING Rehabilitation clinic . PARTICIPANTS Sixty participants with a residual gait deficit at least 6 months after stroke originally enrolled in the study . Two withdrew in the initial phase , leaving 58 participants ( median age , 71.5y ; range , 39.0 - 89.0y ) who were r and omized to the 2 intervention groups . INTERVENTIONS The exercise group had 12 sessions of clinic-based rehabilitation delivered in a circuit class design ed to improve walking . The control group received a comparable duration of group social and educational classes . MAIN OUTCOME MEASURES Usual walking performance was assessed using the StepWatch Activity Monitor . Clinical tests were gait speed ( timed 10-meter walk ) and endurance ( six-minute walk test [ 6MWT ] ) , confidence ( Activities-Based Confidence Scale ) , self-reported mobility ( Rivermead Mobility Index [ RMI ] ) , and self-reported physical activity ( Physical Activity and Disability Scale ) . RESULTS Intention-to-treat analysis revealed that the exercise group showed a significantly greater distance for the 6MWT than the control group immediately after the intervention ( P=.030 ) but that this effect was not retained 3 months later . There were no changes in the StepWatch measures of usual walking performance for either group . The exercise and control groups had significantly different gait speed ( P=.038 ) and scores on the RMI ( P=.025 ) at the 3-month follow-up . These differences represented a greater decline in the control group compared with the exercise group for both outcome measures . CONCLUSIONS Circuit-based rehabilitation leads to improvements in gait endurance but does not change the amount or rate of walking performance in usual environments . Clinical gains made by the exercise group were lost 3 months later . Future studies should consider whether rehabilitation needs to occur in usual environments to improve walking performance [10945420] Objective : To examine whether two different physiotherapy regimes caused any differences in outcome in rehabilitation after acute stroke . Design : A double-blind study of patients with acute first-ever stroke . Sixty-one patients were consecutively included , block r and omized into two groups , and stratified according to gender and hemiplegic site . Group 1 ( 33 patients ) and group 2 ( 28 patients ) had physiotherapy according to Motor Relearning Programme ( MRP ) and Bobath , respectively . The supplemental treatment did not differ in the two groups . Main outcome measures : The Motor Assessment Scale ( MAS ) , the Sødring Motor Evaluation Scale ( SMES ) , the Barthel ADL Index and the Nottingham Health Profile ( NHP ) were used . The following parameters were also registered : length of stay in the hospital , use of assistive devices for mobility , and the patient 's accommodation after discharge from the hospital . Results : Patients treated according to MRP stayed fewer days in hospital than those treated according to Bobath ( mean 21 days versus 34 days , p = 0.008 ) . Both groups improved in MAS and SMES , but the improvement in motor function was significantly better in the MRP group . The two groups improved in Barthel ADL Index without significant differences between the groups . However , women treated by MRP improved more in ADL than women treated by Bobath . There were no differences between the groups in the life quality test ( NHP ) , use of assistive devices or accommodation after discharge from the hospital . Conclusion : The present study indicates that physiotherapy treatment using the MRP is preferable to that using the Bobath programme in the acute rehabilitation of stroke patients [8172497] Time course and degree of recovery of upper extremity ( UE ) function after stroke and the influence of initial UE paresis were studied prospect ively in a community-based population of 421 consecutive stroke patients admitted acutely during a 1-year period . UE function was assessed weekly , using the Barthel Index subscores for feeding and grooming . UE paresis was assessed by the Sc and inavian Stroke Scale subscores for h and and arm . The best possible UE function was achieved by 80 % of the patients within 3 weeks after stroke onset and by 95 % within 9 weeks ; in patients with mild UE paresis , function was achieved within 3 and 6 weeks , respectively , and in patients with severe UE paresis within 6 and 11 weeks , respectively . Full UE function was achieved by 79 % of patients with mild UE paresis and only by 18 % of patients with severe UE paresis . A valid prognosis of UE function can be made within 3 and 6 weeks in patients with mild and severe UE paresis , respectively . Further recovery of UE function should not be expected after 6 and 11 weeks respectively , in these groups of patients [16401430] OBJECTIVE To assess the effects of a community-based exercise program on motor recovery and functional abilities of the paretic upper extremity in persons with chronic stroke . DESIGN R and omized controlled trial . SETTING Rehabilitation research laboratory and a community hall . PARTICIPANTS A sample of 63 people ( > or = 50y ) with chronic deficits result ing from stroke ( onset > or = 1y ) . INTERVENTIONS The arm group underwent an exercise program design ed to improve upper-extremity function ( 1h/session , 3 sessions/wk for 19wk ) . The leg group underwent a lower-extremity exercise program . MAIN OUTCOME MEASURES The Wolf Motor Function Test ( WMFT ) , Fugl-Meyer Assessment ( FMA ) , h and -held dynamometry ( grip strength ) , and the Motor Activity Log . RESULTS Multivariate analysis showed a significant group by time interaction ( Wilks lambda=.726 , P=.017 ) , indicating that overall , the arm group had significantly more improvement than the leg group . Post hoc analysis demonstrated that gains in WMFT ( functional ability ) ( P=.001 ) and FMA ( P=.001 ) scores were significantly higher in the arm group . The amount of improvement was comparable to other novel treatment approaches such as constraint-induced movement therapy or robot-aided exercise training previously reported in chronic stroke . Participants with moderate arm impairment benefited more from the program . CONCLUSIONS The pilot study showed that a community-based exercise program can improve upper-extremity function in persons with chronic stroke . This outcome justifies a larger clinical trial to further assess efficacy and cost effectiveness [12194618] Objective : To investigate the effect of independent practice of sitting balance as an addition to st and ard physiotherapy treatment for patients with stroke . Design : R and omized controlled trial , using blocked r and omization procedure with 2:1 ratio . Subjects : In patients with diagnosis of stroke , having achieved one minute of independent sitting balance but not yet achieved 10 independent steps , and with no known previous disabilities , pathology or neurological de”cit affecting mobility prior to stroke . Intervention : A four-week regime of independent practice aim ed at improving aspects of balance , as an addition to st and ard physiotherapy treatment based on the Bobath Approach . Main outcome measure : Proportion of patients achieving ‘ normal ’ symmetry of weight distribution during sitting , st and ing , rising to st and , sitting down , and reaching . Results : Nineteen subjects were r and omized to the control group ; nine to the intervention group . There were no clinical ly signi”cant differences in measured outcome between the groups . Conclusions : The regime of independent practice had no measured bene”cial effect on the balance ability of patients with recently acquired stroke [8503751] A r and omized controlled pilot trial was conducted to estimate the effects of early , intensive , gait-focused physical therapy on ambulatory ability in acute , stroke patients . Twenty-seven patients with middle cerebral artery infa rct of thromboembolic origin confirmed by computed axial tomography scan were stratified and r and omly assigned to the experimental group , to a control group that received early , intensive and conventional therapy , or to a group receiving routine conventional therapy that started later and was not intense . Assessment s at entry , six weeks , and three and six months by independent evaluators permitted comparisons with reference to clinical measures of motor performance , balance , and functional capacity , and laboratory measures of gait movements . Group results at six weeks demonstrated that gait velocity was similar in the two conventional groups thereby eliminating the timing of the interventions as an important factor . At that point , gait velocity was faster in the experimental group . The difference translated into a moderate effect size of 0.58 . The time dedicated to gait training but not to total therapy time was correlated ( rs = 0.63 ) to gait velocity . This effect disappeared at three and six months after stroke . These pilot results justify planning a large trial to test the effectiveness of a therapeutic protocol that focuses on early and intense gait therapy in an effort to facilitate early ambulation following stroke [17008338] Objective : To examine the effectiveness of task-oriented progressive resistance strength training on lower extremity strength and functional performance in chronic stroke subjects . Design : Single-blind , r and omized controlled trial . Setting : Medical centre and district hospital . Subjects : Forty-eight subjects at least one year post stroke . Interventions : Participants r and omly allocated to two groups , control ( n-/24 ) and experimental ( n-/24 ) . Subjects in the control group did not receive any rehabilitation training . Subjects in the experimental group were put on a four-week task-oriented progressive resistance strength training . Main measures : Lower extremity muscle strength , gait velocity , cadence , stride length , six-minute walk test , step test , and timed up and go test . Results : Muscle strength significantly improved in the experimental group for strong side muscle groups ( ranged from 23.9 % to 36.5 % ) and paretic side muscle groups ( ranged from 10.1 % to 77.9 % ) . In the control group muscle strength changes ranged from 6.7 % gain to 11.2 % decline . The experimental group showed significant improvement in all selected measures of functional performance except for the step test . In the control group , the number of repetitions of the step test significantly decreased ( -20.3 % ) with no change in other functional tests . There was a significant difference between groups for muscle strength and all functional measures . The strength gain was significantly associated with gain in the functional tests . Conclusions : The task-oriented progressive resistance strength training programme could improve lower extremity muscle strength in individuals with chronic stroke and could carry over into improvement in functional abilities Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Various approaches to physical rehabilitation may be used after stroke , and considerable controversy and debate surround the effectiveness of relative approaches . Some physiotherapists base their treatments on a single approach ; others use a mixture of components from several different approaches . OBJECTIVES To determine whether physical rehabilitation approaches are effective in recovery of function and mobility in people with stroke , and to assess if any one physical rehabilitation approach is more effective than any other approach . For the previous versions of this review , the objective was to explore the effect of ' physiotherapy treatment approaches ' based on historical classifications of orthopaedic , neurophysiological or motor learning principles , or on a mixture of these treatment principles . For this up date of the review , the objective was to explore the effects of approaches that incorporate individual treatment components , categorised as functional task training , musculoskeletal intervention ( active ) , musculoskeletal intervention ( passive ) , neurophysiological intervention , cardiopulmonary intervention , assistive device or modality . In addition , we sought to explore the impact of time after stroke , geographical location of the study , dose of the intervention , provider of the intervention and treatment components included within an intervention . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

19821336

[15702037] Background : The recommended vaccination schedule for the pneumococcal conjugate vaccine ( PCV ) includes 4 immunizations , according to the national programs in the United States and some European countries . Other countries use a national schedule for routine vaccinations in early childhood that includes only 3 doses . Aims : The goals were to assess the immunogenicity and tolerability of PCV with a vaccination schedule that included 3 doses during the first 1 year of life ( a 2 + 1 dose schedule ) and to determine the immune responses to concomitantly administered Haemophilus influenzae type b ( Hib ) vaccine . Methods : A total of 101 healthy Swedish infants were enrolled in an open , nonr and omized , multicenter study . PCV was administered concomitantly with ( at separate sites ) a diphtheria-tetanus toxoids-acellular pertussis vaccine , inactivated polio vaccine and Hib conjugate vaccine combination at 3 , 5 and 12 months of age . IgG antibody concentrations for the 7 serotypes included in the PCV and the Hib capsular polysaccharide in serum sample s taken at 3 , 6 , 12 and 13 months were determined with enzyme immunoassays . Local and systemic reactions were monitored for 3 days after each immunization , and serious adverse reactions were monitored for the whole study period . Results : Two doses of PCV induced satisfactory antibody responses , with the exception of serotypes 6B and 23F . The third dose evoked strong responses for all serotypes , which suggests good immunologic priming with the primary series of 2 doses . The mean anti-Hib antibody concentrations were similar to those noted in earlier studies among Swedish children . The PCV was well tolerated . Conclusion : The pneumococcal antibody concentrations at 13 months were comparable with those noted previously with the 4-dose schedule . The results suggest that the implementation of a 2 + 1 dose schedule for PCV should be considered [15780443] AIM In a prospect i ve controlled study in young children with a history of recurrent acute otitis media , we analyzed the salivary IgA and IgG antibody titers upon vaccination with a 7-valent pneumococcal conjugate vaccine ( PCV ) given once or twice , followed by a 23-valent polysaccharide booster vaccination . METHODS Salivary IgA and IgG antibody concentrations to vaccine serotype 6B , 14 , 18C and 19F were measured by enzyme immunoassay in 38 sample s of children vaccinated with PCV and 45 control sample s. In the PCV group , 12 sample s were taken prior to vaccination , 12 sample s 4 weeks after the polysaccharide booster ( 8 months after the first conjugate vaccination ) and 14 sample s 7 months after the last vaccination ( 14 months after the first conjugate vaccination ) . In the control group 15 children were sample d at each of these three time points . RESULTS We observed an increase in salivary IgG antibody concentrations against serotype 6B , 14 , and 18C 14 months after the primary vaccination in children vaccinated with PCV twice , although this was significant for serotype 14 only . There was no increase in salivary IgG antibody in children vaccinate with PCV once nor in control children . IgA antibody titers increased significantly after 8 and after 14 months in both the pneumococcal vaccine recipients and the controls . However , the observed increase in mean antibody titers was significantly higher in control children compared to the PCV group . CONCLUSION We suggest that repeated pneumococcal conjugate vaccination is necessary to induce an increase in salivary IgG antibodies and effectuate clearance of S. pneumoniae from the nasopharyngeal mucosa of children with recurrent acute otitis media . We hypothesize that the increase in salivary IgA is caused by the local boosting of the mucosal immune response by carriage and recurrent infections , which occurs less often in the PCV group compared to the control children [7095883] Here we show , in a double-blind , r and omized , placebo-controlled trial in 37,107 fully immunized infants in Soweto , South Africa , that a 9-valent pneumococcal conjugate vaccine , PncCV , prevents 31 % ( 95 % confidence interval = 15–43 % ) of pneumonias associated with any of seven respiratory viruses in children in hospital . These data suggest that the pneumococcus has a major role in the development of pneumonia associated with these viruses and that viruses contribute to the pathogenesis of bacterial pneumonia . NOTE : In the version of this article originally published online , the species name was misspelled Streptococcus pnemoniae in the title of the article . The name should be Streptococcus pneumoniae . This error has been corrected for the HTML and print versions of the article [1968589] In the clinical research er 's perfect world every patient entered into a r and omised controlled clinical trial ( RCT ) would satisfy all entry criteria , would complete their allocated treatment as described in the protocol , and would contribute data records which were complete in all respects . In practice it is doubtful if this ideal is ever achieved , and hence strategies have been developed for the analysis of RCTs which seek to protect their inferential basis from consequent biases . Such a strategy is ' intention to treat ' ( ITT ) which is frequently advocated as the preferred approach to analysis . This is particularly so for major trials design ed to establish definitively the efficacy and safety of a new medication or medical procedure . Indeed ITT has been endorsed in regulatory guidelines in Europe and the USA ( Nordic Council on Medicines , 1989 ; Food & Drug Administration , 1988 ) . But is ITT always the preferred approach ? Can it always be satisfactorily applied ? Is it a well-defined and well understood concept ? The subject of ITT regularly arouses debate and controversy . In particular the idea that a patient who has been r and omised to treatment A , but actually receives treatment B , should be assigned to the group who received A for analysis purpose s is totally incomprehensible to some . This controversy is fuelled by the fact that there are a large number of clinical trials , particularly in the early phases of research , for which ITT would indeed be inappropriate . Further fuel is added by the different attitudes to ITT in different research environments it is a constant concern in the later phases of drug regulation , for example , whereas research workers in the Medical Research Council generally show greater flexibility , probably because they are less concerned with satisfying conservative regulatory requirements . It has even been argued that ITT encourages sloppiness ' Whatever we do , give the treatment or not , it is OK since the analysis is by ITT ! ' . ITT came to prominence in connection with long-term RCTs with mortality as their major end-point . Peto and co-workers laid out the general principles for the design and analysis of such studies in their comprehensive and highly influential publications in this journal ( Peto et al. , 1976 , 1977 ) . They did not use the term ' intention to treat ' but did advocate that ' even patients who do not get the proper treatment must not be withdrawn from the analysis ' . Their guidance is detailed : the various ways in which patients may fail to complete the study as per protocol are all discussed , together with the possibility that the patients who so fail may differ in characteristics , or numbers , from treatment arm to treatment arm . Such differences are the source of the bias which ITT attempts to avoid any analysis which omits patients is open to bias because it no longer compares the groups as r and omised . However , although Peto and coworkers do recommend that all properly r and omised patients should be included in the analysis regardless of protocol deviation , they do leave open the possibility for some inappropriately r and omised patients to be excluded , and thus stop short of espousing the inclusion of all r and omised patients [10738092] Children who had been r and omized to receive one dose of either heptavalent pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine ( PCV ) or 23-valent pneumococcal polysaccharide vaccine ( PN23 ) at 12 , 15 , or 18 months of age were subsequently r and omized to receive a booster injection of either PCV or PN23 12 months later . For those children who received a priming dose of PCV ( N=75 ) compared to PN23 ( N=48 ) at 12 , 15 , or 18 months of age , higher serum antibody concentrations were achieved 1 month following a booster injection of either PCV or PN23 for all serotypes tested ( p<0.001 ) . Within the group of children receiving a priming dose of PCV , those children who received a booster dose of PN23 developed higher serum antibody concentrations for four of the seven serotypes tested and similar opsonic antibody titers to serotype 6B , yet more frequent erythema ( p=0.030 ) and pain or soreness ( p=0.024 ) at the injection site compared to those boosted with PCV . In conclusion , a single dose of PCV at 12 - 18 months of age primed for responses to booster doses of either PCV or PN23 12 months later . For those children who received a priming dose of PCV , boosting with PN23 result ed in more frequent injection site pain and erythema than boosting with PCV , yet higher antibody concentrations for most of the serotypes tested [12842372] BACKGROUND Pneumococcal conjugate vaccine prevents recurrent acute otitis media ( AOM ) in infants immunised at 2 , 4 , 6 , and 12 - 15 months of age . We aim ed to find out whether this vaccine also prevents AOM in older children who have had previous episodes of AOM . METHODS In this double-blind , r and omised study , we enrolled 383 patients aged 1 - 7 years who had had two or more episodes of AOM in the year before entry . R and omisation was stratified in four groups according to age ( 12 - 24 months vs 25 - 84 months ) and the number of previous AOM episodes ( two or three episodes vs four or more episodes ) . Children received either 7-valent pneumococcal conjugate vaccine followed by 23-valent pneumococcal polysaccharide vaccine , or hepatitis A or B vaccines . They were followed up for 18 months for recurrence of AOM . We also cultured sample s of middle-ear fluid and nasopharyngeal swabs to assess association of pneumococcal serotypes with AOM after vaccination . FINDINGS We noted no reduction of AOM episodes in the pneumococcal vaccine group compared with controls ( intention-to-treat analysis : rate ratio 1.25 , 95 % CI 0.99 - 1.57 ) . Although nasopharyngeal carriage of pneumococci of serotypes included in the conjugate-vaccine was greatly reduced after pneumococcal vaccinations , immediate and complete replacement by non-vaccine pneumococcal serotypes took place . INTERPRETATION These data do not lend support to the use of pneumococcal conjugate vaccine to prevent otitis media in previously unvaccinated toddlers and children with a history of recurrent AOM [15665713] Background : The 7-valent pneumococcal ( 7vPn ) conjugate vaccine is licensed for primary and booster vaccination according to the same immunization schedules as routinely recommended diphtheria-tetanus-pertussis-based childhood vaccines and can be coadministered during the same vaccination visit . Methods : An open , r and omized study evaluated the immunogenicity and safety of a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio virus-Haemophilus influenzae type b ( DTPa-HBV-IPV/Hib ) vaccine and a 7vPn conjugate vaccine when coadministered at 2 , 3 and 4 months and 12–23 months of age , compared with the administration of the hexavalent DTPa-HBV-IPV/Hib vaccine given alone . Serum antibody titers were measured before and 1 month after the primary course and before and 1 month after the booster dose . Solicited local and general adverse events were recorded for 4 days and unsolicited adverse events were recorded for 30 days after each vaccine dose . Results : A total of 345 subjects were enrolled for primary vaccination with the hexavalent vaccine ( 170 without and 175 with the 7vPn vaccine coadministered ) and 266 returned for booster vaccination ( 122 without and 144 with coadministration of the 7vPn vaccine ) . After primary vaccination , antibody responses against the common antigens were similar in both groups , with seroprotection rates of 93.6–100 % and with similar antibody decay before booster vaccination . The fourth dose induced a vigorous booster response , with seroprotection/vaccine response rates of 96.8–100 % . Response to the 7vPn primary and booster vaccination was within previously reported ranges . Differences in reactogenicity result ed from higher incidences of symptoms after concomitant vaccination . Rectal temperature > 39.5 ° C was observed after 1.2 % of the coadministered vaccine doses during primary vaccination and after 2.8 % of the booster vaccine doses . Conclusion : Coadministration of the DTPa-HBV-IPV/Hib and 7vPn vaccines at separate injection sites during the same vaccination visit was effective and safe [11514043] A group-r and omized , double-masked , phase III trial of a Streptococcus pneumoniae conjugate vaccine is being conducted in American Indian population s in the southwestern United States . Approximately 9000 infants will be enrolled in the primary efficacy cohort with vaccine allocation determined by community of residence . The trial is design ed to continue until 48 cases of invasive pneumococcal disease due to vaccine serotypes have accumulated . Thirty-eight geographically and socially distinct areas were r and omized within blocks formed by population size and geographic location . This design affords the opportunity to capture the effects of herd immunity ( indirect effects ) by estimating the impact of the vaccine intervention on nonimmunized infants . Group-r and omized trials have challenging design and analysis features , many of which are discussed here in the context of the first such trial design ed to lead to licensure of a drug or biologic in the United States [19483514] Background : Pneumococcus is a leading cause of childhood pneumonia worldwide . Pneumococcal conjugate vaccines ( PCV ) have demonstrated efficacy against childhood invasive pneumococcal disease ( IPD ) and pneumonia in the United States and Africa . No information is available from Asia on the impact of PCV on childhood pneumonia . Methods : We conducted a r and omized , placebo-controlled , double-blind trial in Bohol , the Philippines ( IS RCT N 62323832 ) . Children 6 weeks to < 6 months of age were r and omly allocated to receive 3 doses of either an 11-valent PCV ( 11PCV , sanofi pasteur , Lyon , France ) or a saline placebo , with a minimum interval of 4 weeks between doses to determine vaccine efficacy ( VE ) against the primary outcome of a child experiencing first episode of community-acquired radiologically defined pneumonia in the first 2 years of life . Secondary end points were clinical pneumonia , IPD , safety , and immunogenicity . Results : Twelve thous and one hundred ninety-one children were enrolled . By per protocol ( PP ) analysis , 93 of 6013 fully vaccinated 11PCV recipient children had a first episode of radiologic pneumonia compared with 120 of 6018 placebo recipients . VE against radiologically defined pneumonia for the PP cohort of children 3 to 23 months old was 22.9 % ( 95 % CI : −1.1 , 41.2 ; P = 0.06 ) , for the prespecified subgroups of children 3 to 11 months of age , 34.0 % ( 95 % CI : 4.8 , 54.3 ; P = 0.02 ) , and of those 12 to 23 months old , 2.7 % ( 95 % CI : −43.5 , 34.0 ; P = 0.88 ) . By intent-to-treat ( ITT ) analysis , 119 of 6097 11PCV recipient children had an episode of radiologic pneumonia compared with 141 of 6094 placebo recipients . VE against radiologic pneumonia for the ITT cohort of children < 2 years old was 16.0 % ( 95 % CI −7.3 , 34.2 ; P = 0.16 ) , for a subgroup of children < 12 months of age , 19.8 % ( 95 % CI : −8.8 , 40.8 ; P = 0.15 ) . VE against clinical pneumonia by PP was not significant ( VE 0.1 % ; 95 % CI −9.4 , 8.7 ; P = 0.99 ) . IPD was rare : only 3 cases of IPD due to vaccine serotypes were observed during the study . 11PCV was immunogenic and well tolerated . Among 11PCV recipients , a small excess of serious adverse respiratory events was observed in the first 28 days after the first and second dose of vaccine , and of nonrespiratory events after the first dose . An excess of pneumonia episodes in 11PCV recipients in the month following the second dose of vaccination was the principal reason for lower VE by ITT analysis than by PP analysis . Conclusions : In PP analysis , a 22.9 % reduction of community-acquired radiologically confirmed pneumonia in children younger than 2 years of age in the 11-valent tetanus-diphtheria toxoid-conjugated PCV vaccinated group was observed ; a reduction similar as observed in other PCV trials . We could not demonstrate any VE against clinical pneumonia . Our finding confirms for the first time that in a low-income , low-mortality developing country in Asia , at least one-fifth of radiologically confirmed pneumonia is caused by pneumococcus , and thus preventable by PCV . Whether PCV should be included in national program in such setting s , however , depends on careful country specific disease burden measurement and cost-effectiveness calculation [15618174] ABSTRACT The licensure of new pneumococcal conjugate vaccines ( PCVs ) relies on immunogenicity data . When defining correlates of protection , vaccine efficacy data must be included . In the FinOM Vaccine Efficacy Trial , the PncOMPC vaccine showed an efficacy profile similar to that of the licensed PncCRM vaccine despite different antibody responses after primary and booster vaccinations . We determined antibody kinetics and avidities in a subgroup of infants participating in the FinOM trial . A total of 166 infants in three vaccine groups were immunized at 2 , 4 , 6 , and 12 months of age with 7-valent PCV , PncCRM or PncOMPC , or hepatitis B vaccine . Concentrations of serum immunoglobulin G ( IgG ) against pneumococcal capsular polysaccharides were determined at 2 , 4 , 6 , 7 , 12 , 13 , and 24 months of age , and the avidity index ( AI ) to serotypes 6B , 19F , and 23F were determined at 7 , 12 , 13 , and 24 months of age by enzyme immunoassay . Both PCVs were highly immunogenic , but they demonstrated different kinetics of antibody response ; the concentration of IgG against serotypes 6B , 19F , and 23F declined faster after the third and fourth doses of vaccine in the PncCRM group than in the PncOMPC group . For both PCVs , the mean AI of anti-6B and -23F , but not of anti-19F , increased during the follow-up , which is in line with serotype-specific protection in the FinOM trial . Our data suggest that the kinetics and avidities of antibodies should be considered , in addition to antibody responses , when defining correlates of protection [15794968] BACKGROUND Pneumonia is estimated to cause 2 million deaths every year in children . Streptococcus pneumoniae is the most important cause of severe pneumonia . We aim ed to assess the efficacy of a nine-valent pneumococcal conjugate vaccine in children . METHODS We undertook a r and omised , placebo-controlled , double-blind trial in eastern Gambia . Children age 6 - 51 weeks were r and omly allocated three doses of either pneumococcal conjugate vaccine ( n=8718 ) or placebo ( 8719 ) , with intervals of at least 25 days between doses . Our primary outcome was first episode of radiological pneumonia . Secondary endpoints were clinical or severe clinical pneumonia , invasive pneumococcal disease , and all-cause admissions . Analyses were per protocol and intention to treat . FINDINGS 529 children assigned vaccine and 568 allocated placebo were not included in the per- protocol analysis . Results of per- protocol and intention-to-treat analyses were similar . By per- protocol analysis , 333 of 8189 children given vaccine had an episode of radiological pneumonia compared with 513 of 8151 who received placebo . Pneumococcal vaccine efficacy was 37 % ( 95 % CI 27 - 45 ) against first episode of radiological pneumonia . First episodes of clinical pneumonia were reduced overall by 7 % ( 95 % CI 1 - 12 ) . Efficacy of the conjugate vaccine was 77 % ( 51 - 90 ) against invasive pneumococcal disease caused by vaccine serotypes , 50 % ( 21 - 69 ) against disease caused by all serotypes , and 15 % ( 7 - 21 ) against all-cause admissions . We also found an efficacy of 16 % ( 3 - 28 ) against mortality . 110 serious adverse events arose in children given the pneumococcal vaccine compared with 131 in those who received placebo . INTERPRETATION In this rural African setting , pneumococcal conjugate vaccine has high efficacy against radiological pneumonia and invasive pneumococcal disease , and can substantially reduce admissions and improve child survival . Pneumococcal conjugate vaccines should be made available to African infants [12352800] Objective . To determine the effectiveness of the Wyeth heptavalent pneumococcal conjugate vaccine against clinical and radiograph-confirmed pneumonia in children . Methods . The heptavalent CRM197 pneumococcal conjugate vaccine ( PCV ) was given to infants at 2 , 4 , 6 and 12 to 15 months of age in a r and omized , double blind trial . 1 Children were r and omized to receive either the CRM197 PCV ( vaccine group ) or the meningococcal type C CRM197 conjugate vaccine ( control group ) . The primary outcome of this trial was invasive pneumococcal disease . In addition children with the clinical diagnosis of pneumonia in the study population were identified through review of automated inpatient , emergency and outpatient data bases . The subset of the cohort of these children who had chest radiographs obtained at the time of diagnosis was identified , and the original reading of their radiographs by the radiologist was obtained from automated data bases . Rates of clinical ly diagnosed pneumonia , of pneumonia with a radiograph obtained regardless of result , of pneumonia with positive radiograph ( consolidation , empyema or parenchymal infiltrate ) and of pneumonia with only perihilar infiltrates were compared between vaccinated and nonvaccinated groups . In addition risk of disease pneumonia was evaluated by race and ethnicity . Results . The incidence of a first pneumonia episode in the control group was 55.9 per 1000 person-years . A radiograph was obtained in 61 % of episodes , a positive radiograph in 21 % and perihilar findings in an additional 5 % . In per protocol follow-up of children given PCV , first episodes of all clinical ly diagnosed pneumonia were reduced by 4.3 % [ 95 % confidence interval ( CI ) , −3.5 , 11.5 % , P = 0.27 ] , episodes with a radiograph were reduced by 9.8 % ( CI 0.1 , 18.5 % , P < 0.05 ) and episodes with a positive radiograph were reduced by 20.5 % ( CI 4.4 , 34.0 , P = 0.02 ) . In the intent to treat analysis including all episodes after r and omization , episodes with a positive radiograph were reduced by 17.7 % , P = .01 ) . The greatest impact was in the first year of life with a 32.2 % reduction and a 23.4 % reduction in the first 2 years , but only a 9.1 % reduction in children > 2 years of age . Asians , blacks and Hispanics were at higher risk of pneumonia than were whites , but there was no evidence of ethnic variation in PCV effectiveness . Ten of the 11 cases of pneumococcal pneumonia with a positive blood culture were in the control group . Conclusion . The pneumococcal conjugate vaccine tested was effective in reducing the risk of pneumonia in young children [12544402] Context . The heptavalent pneumococcal conjugate vaccine ( PCV ) is recommended for infants to protect against invasive disease , but its impact on otitis might also have public health importance . Objective . To examine the impact of PCV on the incidence of otitis media , frequent otitis media and tympanostomy tube procedures and to assess whether the effectiveness of the vaccine wanes after age 24 months and varies by race , sex or season . Design , setting and patients .. From 1995 to 1998 , 37 868 children at Kaiser Permanente in Northern California were r and omized to receive PCV or a control vaccine in a double blind trial and were followed through April 1999 . Interventions . Children received a primary series at 2 , 4 and 6 months of age and a booster at 12 to 15 months . Main outcome measures . Visits for otitis , frequent visits for otitis and tympanostomy tube procedures . Otitis was ascertained from diagnosis checklists routinely marked by physicians . Results . Control children averaged 1.8 otitis visits per year . Children given PCV had fewer otitis visits than control children in every age group , sex , race and season examined . Intention-to-treat analysis permitted rejection of the null hypothesis that PCV is ineffective against otitis media ( P < 0.0001 ) . In children who completed the primary series per protocol , PCV reduced otitis visits by 7.8 % [ 95 % confidence interval ( CI ) , 5.4 to 10.2 % ] and antibiotic prescriptions by 5.7 % ( CI 4.2 to 7.2 % ) . Frequent otitis was reduced by amounts that increased with otitis frequency , from a 10 % reduction in the risk of 3 visits to a 26 % reduction in the risk of 10 visits within a 6-month period . Tube placements were reduced by 24 % ( CI 12 to 35 % ) . Conclusion . In children followed up to 3.5 years , PCV provided a moderate amount of protection against ear infections while reducing frequent otitis media and tube procedures by greater amounts [12744899] BACKGROUND Streptococcus pneumoniae ( Sp ) is an important bacterial pathogen in children . Nasopharyngeal ( NP ) colonization of S. pneumoniae is necessary for person-to-person transmission and often precedes invasive disease . METHODS NP carriage of Sp was studied in 49 infants following administration of a heptavalent pneumococcal conjugate vaccine ( PCV ) conjugated to the outer membrane protein of serogroup b Neisseria meningitidis ( vaccine serotypes : 4 , 6B , 9V , 14 , 18C , 19F , 23F ) . The vaccine was administered at 2 , 4 , 6 , and 12 months of age and carriage rates were compared to a concurrent group of 32 infants not given PCV and evaluated over the first 15 months of life . RESULTS Overall , Sp was isolated in 86/367 ( 23 % ) of NP cultures and 49 % of infants . Serotype 23F was significantly less prevalent in the PCV group ( 1.9 % ) than the control group ( 16.1 % ) ( P<0.05 ) . Analysis of the proportion of children with prevalent carriage or acquisition of carriage did not differ between groups when evaluated by age or serotype . We noted , however , decreased acquisition and carriage in the vaccine group 1 month following the 12 month dose of PCV for vaccine serotypes ( 76 and 52 % reduction , respectively ) , but this did not reach statistical significance ( P=0.3 ) . Adjustment for age , daycare and antibiotic use by multivariate modeling revealed no difference in carriage of vaccine containing serotypes or non-vaccine serotypes between groups . CONCLUSION We did not show a significant effect of this heptavalent PCV on NP carriage . Further study of this issue , including a larger population size , is needed [15793941] UNLABELLED This study evaluates the safety and immunogenicity of pneumococcal seven-valent conjugate vaccine ( Prevenar ) in 115 children , aged 2 - 3 years ( 24 - 36 months ) , who have not been previously vaccinated with Prevenar . RESULTS SAFETY As for local reactions , 40 % of children reported erythema , 32.2 % in duration and 39.1 % tenderness at the injection site . Regarding systemic reactions , fever > or 38 C was recorded in 7 % of patients . Other commonly reported events were decreased appetite ( 24.3 % ) , restlessness ( 20 % ) , and fussiness ( 18.3 % ) . IMMUNOGENICITY After vaccination , more than 98 % of the subjects achieved antibody levels of > or = 0.15 microg/mL for all seven serotypes and more than 95 % achieved antibody levels > or = 0.50 microg/mL for all serotypes . CONCLUSIONS Pneumococcal seven-valent conjugate vaccine ( Prevenar ) was safe , well tolerated and highly immunogenic when administered in previously unvaccinated children aged 14 - 36 months [15472839] BACKGROUND We recently showed that vaccination with a 7-valent pneumococcal conjugate vaccine ( PCV7 ) followed by a 23-valent pneumococcal polysaccharide vaccine ( PPSV23 ) failed to prevent new episodes of acute otitis media ( AOM ) in previously unvaccinated toddlers and children with a history of recurrent AOM . We describe in detail the impact of pneumococcal vaccinations on nasopharyngeal carriage of S. pneumoniae in this study population . METHODS The impact of vaccination with PCV7 followed by PPSV23 on pneumococcal nasopharyngeal carriage was studied in a prospect i ve , r and omized trial involving 383 children ( age range , 1 - 7 years ) with previous AOM . Nasopharyngeal swab specimens were collected at the time of first vaccination and at 6 - 7-month intervals during the 26-month follow-up period . RESULTS Overall , pneumococcal carriage rates did not diminish , remaining at approximately 50 % in both PCV7/PPSV23 and control vaccinees . A significant shift from conjugate vaccine- to nonconjugate vaccine-type pneumococci was observed in children aged 1 - 2 years , who received the conjugate vaccine twice before the polysaccharide vaccine was administered . Conjugate vaccine serotype carriage was not influenced in older children , who received the conjugate vaccine once before receiving the polysaccharide booster . CONCLUSIONS The administration of conjugate vaccines at least twice also after 2 years of age may be m and atory for reducing the carriage of conjugate vaccine serotypes in children with recurrent AOM . Polysaccharide booster vaccination did not affect nasopharyngeal colonization with serotypes not included in the conjugate vaccine [11001109] BACKGROUND Streptococcus pneumoniae is a major disease burden in young children and the incidence of antibiotic-resistant pneumococcal strains is increasing . Multivalent pneumococcal saccharide-protein conjugate vaccines have recently been developed . OBJECTIVES To assess the immunogenicity and reactogenicity of a 7-valent pneumococcal conjugate vaccine ( 7VPnC ) administered as a separate injection or as a combined injection with Haemophilus influenzae type b vaccine ( HbOC ) at 2 , 3 and 4 months of age . METHODS R and omized controlled trial of 368 healthy UK infants receiving routine vaccines only ( control group ) , routine vaccines and 7VPnC as a separate injection ( separate group ) , or routine vaccines and 7VPnC combined with HbOC ( combined group ) at 2 , 3 and 4 months . The control group received 7VPnC at 5 , 6 and 7 months . All groups received pneumococcal polysaccharide vaccine at 13 to 16 months . Anticapsular IgG antibodies to 7VPnC serotypes were measured at 2 , 5 , 13 and 14 months and safety data collected . RESULTS IgG antibody concentrations at 5 months were higher in the two treatment groups compared with the controls for all 7VPnC serotypes ( P < 0.001 ) and higher in the separate group than the combined group for five 7VPnC serotypes ( P < 0.05 ) . For both treatment groups antibody concentrations were higher at 14 months ( range , 6.6 to 25.3 microg/ml ) than at 5 months ( range , 0.6 to 2.5 microg/ml ) for all 7VPnC serotypes ( P < 0.001 ) . CONCLUSION 7VPnC was well-tolerated , safe and immunogenic when administered as a separate or as a combined 7VPnC/HbOC injection . Although antibody responses were lower in the infants who received the combination compared with those who received 7VPnC as a separate injection , marked anamnestic responses to polysaccharide challenge were observed , suggesting that both groups were immunologically primed [14523142] BACKGROUND Acute respiratory tract infections caused by Streptococcus pneumoniae are a leading cause of morbidity and mortality in young children . We evaluated the efficacy of a 9-valent pneumococcal conjugate vaccine in a r and omized , double-blind study in Soweto , South Africa . METHODS At 6 , 10 , and 14 weeks of age , 19,922 children received the 9-valent pneumococcal polysaccharide vaccine conjugated to a noncatalytic cross-reacting mutant of diphtheria toxin ( CRM197 ) , and 19,914 received placebo . All children received Haemophilus influenzae type b conjugate vaccine . Efficacy and safety were analyzed according to the intention-to-treat principle . RESULTS Among children without human immunodeficiency virus ( HIV ) infection , the vaccine reduced the incidence of a first episode of invasive pneumococcal disease due to serotypes included in the vaccine by 83 percent ( 95 percent confidence interval , 39 to 97 ; 17 cases among controls and 3 among vaccine recipients ) . Among HIV-infected children , the efficacy was 65 percent ( 95 percent confidence interval , 24 to 86 ; 26 and 9 cases , respectively ) . Among children without HIV infection , the vaccine reduced the incidence of first episodes of radiologically confirmed alveolar consolidation by 20 percent ( 95 percent confidence interval , 2 to 35 ; 212 cases in the control group and 169 in the vaccinated group ) in the intention-to-treat analysis and by 25 percent ( 95 percent confidence interval , 4 to 41 ; 158 and 119 cases , respectively ) in the per- protocol analysis ( i.e. , among fully vaccinated children ) . The incidence of invasive pneumococcal disease caused by penicillin-resistant strains was reduced by 67 percent ( 95 percent confidence interval , 19 to 88 ; 21 cases in the control group and 7 in the vaccinated group ) , and that caused by strains resistant to trimethoprim-sulfamethoxazole was reduced by 56 percent ( 95 percent confidence interval , 16 to 78 ; 32 and 14 cases , respectively ) . CONCLUSIONS Vaccination with a 9-valent pneumococcal conjugate vaccine reduced the incidence of radiologically confirmed pneumonia . The vaccine also reduced the incidence of vaccine-serotype and antibiotic-resistant invasive pneumococcal disease among children with and those without HIV infection [14597376] OBJECTIVE To explore the effect of a pneumococcal conjugate vaccine on the risk of otitis media with effusion and to search for subgroups in which the vaccine had a higher or lower effect . METHODS Analyses were performed on data from the Finnish Otitis Media Vaccine Trial , a r and omised controlled double-blind trial to evaluate the efficacy of pneumococcal conjugate vaccination against acute otitis media . Data on the vaccination effect against otitis media with effusion were obtained by means of symptom interview and pneumatic otoscopy during pre-scheduled follow-up visits at the age of 7 and 24 months . Two endpoint definitions were considered : otitis media/tube ( otitis media or tympanostomy tube in situ ( OM/T ) ) as the primary endpoint and otitis media with effusion as the secondary endpoint . No evidence was found of an age-dependent association with vaccination effect . Therefore , the final marginal logistic regression analyses were performed on the combined data from the two follow-up visits . RESULTS The risk of otitis media tended to be lower in the pneumococcal vaccine group . The odds ratio for otitis media/tube was 0.94 ( 95 % confidence interval 0.77 - 1.14 ) and the odds ratio for otitis media with effusion was 0.90 ( 95 % confidence interval 0.69 - 1.19 ) . Presence of older siblings increased the risk of otitis media/tube and otitis media with effusion at 7 months of age . In addition , it appeared that children without older siblings and attending day-care at 24 months of age tended to benefit more from the pneumococcal conjugate vaccine . In this subgroup , the odds ratio for otitis media/tube was 0.81 ( 95 % confidence interval 0.55 - 1.20 ) and for otitis media with effusion the odds ratio was 0.43 ( 95 % confidence interval 0.22 - 0.86 ) . CONCLUSION The effect of pneumococcal conjugate vaccination on the risk of otitis media with effusion was concordant with the efficacy seen against acute otitis media , although not distinguishable from no effect in the overall analysis . In children without older siblings , vaccination appeared to reduce the point prevalence of otitis media with effusion ; this effect was not apparent in children with older siblings [15750461] Aims : Prospect i ve study to evaluate the impact of the 7-valent pneumococcal conjugate vaccine ( Prevenar ) on the nasopharyngeal ( NP ) carriage of drug-resistant Streptococcus pneumoniae ( DRPn ) , by healthy children attending day-care centers ( ages 6 months–6 years ) . Methods : Vaccinees ( 238 children ) who received vaccine and controls ( 457 children ) were followed for carriage of total S. pneumoniae and DRPn and for the serotypes and genetic background s of DRPn during 6 consecutive sampling periods between May 2001 and February 2003 . Results : We detected no significant differences between vaccinees and the control group in the total carriage rate of Pn ( average , 68 % ) or in the frequency of carriage of DRPn ( average , 38 % ) , including the frequency of penicillin-nonsusceptible strains ( average , 24 % ) . In contrast , there was a decline in the carriage of DRPn with vaccine serotypes which was compensated by the appearance and gradual increase in the frequency of DRPn expressing unusual serotypes ( 6A , 10A , 15A and 15C , 19A , 23A , 33F ) which were not present in the vaccine as well as an increase in nontypable strains . The majority of the DRPn with unusual serotypes showed different pulsed field gel electrophoresis patterns indicating replacement of the original resistant flora by other clonal types of drug-resistant bacteria . Antibiotic consumption and the frequency of respiratory tract infections were similar among the vaccinees and controls . Conclusions : Pneumococcal vaccination did not change the frequency of carriage of drug-resistant strains being the initially dominant vaccine serotypes replaced by others expressing nonvaccine serotypes . Reduction in the carriage of DRPn may require a combination of the conjugate vaccine and a decrease in antibiotic pressure [16892907] When a sufficiently high proportion of a population is immunized with a vaccine , reduction in secondary transmission of disease can confer significant protection to unimmunized population members . We propose a straightforward method to estimate the degree of this indirect effect of vaccination in the context of a community-r and omized vaccine trial . A conditional logistic regression model that accounts for within-r and omization unit correlation over time is described , which models risk of disease as a function of community-level covariates . The approach is applied to an example data set from a pneumococcal conjugate vaccine study , with study arm and immunization levels forming the covariates of interest for the investigation of indirect effects [12005078] Objective . To determine the efficacy , immunogenicity and safety of the heptavalent CRM197 pneumococcal conjugate vaccine ( PCV ) in low birth weight ( LBW ) and preterm ( PT ) infants against invasive pneumococcal disease caused by vaccine types . Methods . In a r and omized double blind trial of 37 868 infants given either PCV or meningococcal type C conjugate vaccine ( MCV ) , 1756 infants < 750 g < 2500 g ( LBW ) and 4340 infants from 32 to < 38 weeks old ( PT ) were identified . Risk of invasive pneumococcal disease in LBW and PT infants was compared with risk in normal birth weight ( NBW ) and full term ( FT ) infants . Local and systemic events observed within 48 h of recent vaccine were assessed by telephone interviews and similar comparisons made . Premature infant Emergency Department visits and hospitalization were also identified and compared with FT and NBW infants . Results . Initiation of immunization and intervals between doses were similar for all groups . The risk ratio for invasive pneumococcal diseases for LBW infants compared with NBW infants was 2.6 ( P = 0.03 ) , and for PT compared with FT infants the risk ratio was 1.6 ( P = 0.06 ) . Vaccine efficacy for both groups was 100 % . PCV was as immunogenic in LBW and PT as in NBW and FT infants . Fever and local events after PCV vaccination were similar when adjusted for clustering among multiple doses per child . When stratified for individual doses there was more redness and swelling for LBW infants and more swelling for PT infants after Dose 3 . Isolated local and systemic reactions were more commonly seen with PCV than with MCV , a pattern similar to that in NBW and FT infants . Hospitalization rates were similar for PCV and MCV recipients . Conclusion . These data support the use of PCV in LBW infants and PT infants [12907008] BACKGROUND Streptococcus pneumoniae is the main cause of invasive bacterial disease in children aged younger than 2 years . Navajo and White Mountain Apache children have some of the highest rates of invasive pneumococcal disease documented in the world . We aim ed to assess the safety and efficacy of a seven-valent polysaccharide protein conjugate pneumococcal vaccine ( PnCRM7 ) against such disease . METHODS In a group-r and omised study , we gave this vaccine to children younger than 2 years from the Navajo and White Mountain Apache Indian reservations ; meningococcal type C conjugate vaccine ( MnCC ) served as the control vaccine . Vaccine schedules were determined by age at enrollment . We recorded episodes of invasive pneumococcal disease and serotyped isolates . Analyses were by intention to treat and per protocol . FINDINGS 8292 children enrolled in the trial . In the per protocol analysis of the primary efficacy group ( children enrolled by 7 months of age ) there were eight cases of vaccine serotype disease in the controls and two in the PnCRM7 group ; in the intention-to-treat analysis we noted 11 cases of vaccine serotype disease in the MnCC control group and two in the PnCRM7 group . After group r and omisation had been controlled for , the per protocol primary efficacy of PnCRM7 was 76.8 % ( 95 % CI -9.4 % to 95.1 % ) and the intention-to-treat total primary efficacy was 82.6 % ( 21.4 % to 96.1 % ) . INTERPRETATION PnCRM7 vaccine prevents vaccine serotype invasive pneumococcal disease even in a high risk population . Other regions with similar disease burden should consider including this vaccine in the routine childhood vaccine schedule [16940833] Background : A World Health Organization ( WHO ) working group in 2001 developed a method for st and ardizing interpretation of chest radiographs in children for epidemiologic purpose s. We reevaluated radiographs from the Kaiser Permanente Pneumococcal Efficacy trial using this method . Methods : Seven-valent pneumococcal conjugate vaccine was evaluated in a r and omized , controlled study including 37,868 infants . Effectiveness against pneumonia was previously evaluated using the original treating radiologist reading . There were 2841 sets of radiographs from this trial and all available radiographs were scanned and read blindly by 2 WHO crosstrained readers ( A and B ) ; discordance between the 2 primary readers was resolved through a consensus reading by an adjudicating panel of 2 radiologists . Results : Of the 2841 radiographs , 2446 were available for scanning and were review ed using WHO-defined descriptive categories . Two hundred fifty of the 2446 radiographs were read as positive by both readers . An additional 129 were read as positive by reader A only and 142 by reader B only for a total of 521 radiographs that were read as positive by one or both of the review ers . The concordance rate between the 2 review ers was 250 of 521 ( 48 % ) . Of the 271 discordant radiographs , 45 of 129 ( 34.9 % ) of reader A and 66 of 142 ( 46.5 % ) for reader B were finalized as positive by the adjudicating panel . Overall , 361 radiographs were finalized as positive ( 12.7 % ) . With these 361 images as the st and ard , the sensitivity and specificity of reader A were 82 % and 97 % , respectively , and for reader B , 88 % and 97 % , respectively . Kappa between the 2 readers was 0.58 . Of 25 control radiographs read as positive by both A and B , 80 % were also read as positive by the panel and all 25 control negative radiographs were read as negative by the panel . Using original readings by point-of-care radiologists , efficacy against first episode of radiograph confirmed pneumonia was 17.7 % ( 95 % confidence interval [ CI ] = 4.8–28.9 % ) in intent-to-treat and 20.5 % ( 95 % CI = 4.4–34 % ) in per protocol . Using the WHO method , the efficacy against first episode of radiograph confirmed pneumonia adjusting for age , gender and year of vaccination of 25.5 % ( 95 % CI = 6.5–40.7 % , P = 0.011 ) for intent-to-treat and 30.3 % ( 95 % CI = 10.7–45.7 % , P = 0.0043 ) for per protocol . Conclusion : Using WHO criteria for reading of radiographs increased point estimates of vaccine efficacy presumably as a result of improved specificity [11642629] Background . Incidence and severity of respiratory infections are increased in day-care center attendees . Streptococcus pneumoniae is an important contributor to these infections . Objective . To examine whether the use of a pneumococcal conjugate vaccine could reduce the occurrence of respiratory infections and the ensuing antibiotic drug use in the day care . Method . In this double blind , r and omized , controlled study performed in 8 day-care centers located in Beer-Sheva , Israel , 264 toddlers ages 12 to 35 months at enrollment were r and omized to receive either a 9-valent conjugate pneumococcal vaccine ( conjugated to CRM197 ) or a control vaccine [ conjugate meningococcus C vaccine ( conjugated to CRM197 ) ] and were followed for an average of 22 months . The main outcome measures were respiratory morbidity and antibiotic use . Results . An overall reduction of 7 % in child months with ≥1 reported illness episodes was observed among vaccinees ( P = 0.008 ) , and 85 % of all episodes were related to the respiratory tract . Reductions of 15 , 16 and 17 % were observed in upper respiratory infections , lower respiratory problems and otitis media , respectively . An overall reduction of 17 % in antibiotic days was observed [ 10 % for upper respiratory infections , 20 % for otitis and 47 % for lower respiratory problems ( P ≤ 0.005 for each entity ) ] . The reduction in episodes and antibiotic use was greater for those < 36 months of age than for the older children . Conclusion . The reduction of respiratory problems , including those not traditionally considered of pneumococcal origin and the ensuing lowered antibiotic use in day-care center attendees by pneumococcal conjugate vaccination suggest a broader benefit from the vaccine than preventing invasive disease only [12799509] Aim . We conducted a study to determine whether administration of a pneumococcal conjugate vaccine to toddlers attending day-care centers ( DCCs ) could prevent acquisition of Streptococcus pneumoniae of the vaccine serotypes ( VT ) by their younger siblings . In a double blind study , 262 DCC attendees ages 12 to 35 months were r and omized to receive a 9-valent pneumococcal conjugate vaccine ( PnCRM9;n = 132 ) , or a control vaccine ( meningococcus C vaccine;n = 130 ) . It was planned to follow the groups for 2 years with monthly nasopharyngeal pneumococcal cultures during the first follow-up year and every 2 months during the second year . Forty-six younger siblings of the above described children , age < 18 months ( 23 siblings of the PnCRM9 recipients and 23 of the controls ) , were also enrolled , and nasopharyngeal cultures were obtained monthly until the children reached the age of 18 months or started to attend DCC , if before the age of 18 months . Pneumococcal isolates were serotyped and tested for antibiotic susceptibility . Results . Of the 3748 cultures obtained from the DCC attendees , 2450 ( 65 % ) were positive for S. pneumoniae . Of 306 cultures obtained from the younger siblings , 151 ( 49 % ) were positive . Among the PnCRM9 recipients , cultures were significantly less frequently positive for the VT S. pneumoniae than among the controls ( 13 % vs. 21 % , respectively;P < 0.001 ) . The same pattern was seen in the younger siblings of PnCRM9 recipients vs. the siblings of controls ( 21 % vs. 34 % , respectively;P = 0.017 ) . The reverse trend was seen for non-VT strains in both the DCC attendees ( 44 % vs. 34 % , respectively;P < 0.001 ) and their younger siblings ( 19 % vs. 13 % , respectively;P = 0.15 ) . There was a significant decrease in the carriage rate of antibiotic-resistant S. pneumoniae in both the PnCRM9 recipients and their younger siblings . The relative risks ( and 95 % confidence intervals ) to carry S. pneumoniae penicillin-nonsusceptible , resistant to ≥1 , ≥2 and ≥3 antibiotic categories among younger siblings of PnCRM9 recipients vs. siblings of controls were 0.47 ( 0.31 to 0.70 ) , 0.49 ( 0.33 to 0.71 ) , 0.46 ( 0.30 to 0.73 ) and 0.49 ( 0.21 to 1.17 ) , respectively . When acquired , VT and antibiotic-resistant S. pneumoniae were carried for a significantly shorter period of time among siblings of PnCRM9 recipients than in siblings of controls . Conclusion . The marked effect of PnCRM9 administration to DCC attendees on carriage of VT and antibiotic-resistant S. pneumoniae among their younger household close contacts demonstrates a herd effect of the vaccine [15687432] Background . Limited effectiveness of current treatment strategies for recurrent acute otitis media ( RAOM ) and increasing antibiotic resistance have diverted attention to prevention of AOM by vaccination . Pneumococcal vaccination for AOM seems to have only modest clinical efficacy . Thus far , the effects on health-related quality of life ( HRQoL ) or functional health status ( FHS ) have not been studied . Objective . To assess the effect of vaccination on HRQoL or FHS . Methods . In a double-blind , r and omized , controlled trial , 383 children 1 to 7 years old with RAOM were vaccinated with either heptavalent pneumococcal conjugate vaccine followed by pneumococcal polysaccharide vaccine ( pneumococcal group : n = 190 ) or with hepatitis A or B vaccines ( control group : n = 193 ) . Parents completed vali date d Dutch versions of 8 HRQoL and FHS instruments assessing generic FHS ( R and , Functional Status Question naire specific , and Functional Status Question naire generic ) , otitis media – specific FHS ( OM-6 ) , otitis media – specific child HRQoL ( Numerical Rating Scale for Child ) , family functioning ( Family Functioning Question naire ) , and otitis media – specific caregiver HRQoL ( Numerical Rating Scale for Caregiver ) . Scores were compared at baseline and at 14 and 26 months ' follow-up . Results . At baseline , the average AOM incidence in the pneumococcal and control group was 5.0 ( SD : 2.8 ) and 4.9 ( SD : 2.6 ) episodes per year , respectively , with 38.4 % and 36.8 % having suffered from ≥6 episodes per year . AOM frequency decreased 4.4 episodes per year in both groups , with a considerable and comparable improvement in HRQoL and FHS . No substantial differences in HRQoL or FHS were found between the pneumococcal and the control group at baseline or at 14 or 26 months ' follow-up . Conclusion . Pneumococcal vaccination has no beneficial effect compared with control vaccination on either HRQoL or FHS in children 1 to 7 years old with RAOM [11172176] BACKGROUND Ear infections are a common cause of illness during the first two years of life . New conjugate vaccines may be able to prevent a substantial portion of cases of acute otitis media caused by Streptococcus pneumoniae . METHODS We enrolled 1662 infants in a r and omized , double-blind efficacy trial of a heptavalent pneumococcal polysaccharide conjugate vaccine in which the carrier protein is the nontoxic diphtheria-toxin analogue CRM197 . The children received either the study vaccine or a hepatitis B vaccine as a control at 2 , 4 , 6 , and 12 months of age . The clinical diagnosis of acute otitis media was based on predefined criteria , and the bacteriologic diagnosis was based on a culture of middle-ear fluid obtained by myringotomy . RESULTS Of the children who were enrolled , 95.1 percent completed the trial . With the pneumococcal vaccine , there were more local reactions than with the hepatitis B vaccine but fewer than with the combined whole-cell diphtheria-tetanus-pertussis and Haemophilus influenzae type b vaccine that was administered simultaneously . There were 2596 episodes of acute otitis media during the follow-up period between 6.5 and 24 months of age . The vaccine reduced the number of episodes of acute otitis media from any cause by 6 percent ( 95 percent confidence interval , -4 to 16 percent [ the negative number indicates a possible increase in the number of episodes ] ) , culture-confirmed pneumococcal episodes by 34 percent ( 95 percent confidence interval , 21 to 45 percent ) , and the number of episodes due to the serotypes contained in the vaccine by 57 percent ( 95 percent confidence interval , 44 to 67 percent ) . The number of episodes attributed to serotypes that are cross-reactive with those in the vaccine was reduced by 51 percent , whereas the number of episodes due to all other serotypes increased by 33 percent . CONCLUSIONS The heptavalent pneumococcal polysaccharide-CRM197 conjugate vaccine is safe and efficacious in the prevention of acute otitis media caused by the serotypes included in the vaccine [12799510] Background . In the developed societies , day-care centers ( DCCs ) play an important role in the spread of antibiotic-resistant pneumococci both within the facility and from the facility to the community . This study was conducted to determine the effect of a nonavalent pneumococcal conjugate vaccine ( PCV-9 ) on the carriage of antibiotic-resistant pneumococci in the DCC . Subjects and methods . Healthy DCC attendees ages 12 to 35 months were r and omized to receive either PCV-9 or a control vaccine ( conjugate meningococcus C vaccine ) in a double blinded manner . Nasopharyngeal Streptococcus pneumoniae cultures were obtained from each subject before vaccination , monthly during the first year of follow-up and every 2 to 3 months during the second year of follow-up . For each isolate the serotype and antibiotic susceptibility were determined Results . A total of 132 and 130 evaluable toddlers received either PCV-9 or the control vaccine , respectively . In total 3748 cultures were obtained , of which 2450 ( 65 % ) were positive for S. pneumoniae . The resistance rates to penicillin , trimethoprim-sulfamethoxazole and erythromycin were 36 , 35 and 16 % , respectively . Resistance rates to ≥1 and ≥3 antibiotic categories were 52 and 9 % , respectively . Antibiotic resistance was found mainly in the 5 serotypes included in the pneumococcal conjugate vaccines ( 6B , 9V , 14 , 19F and 23F ) and in 2 related serotypes ( 6A and 19A ) . In the vaccinated group a clear and significant reduction of the carriage rate of the serotypes included in the vaccine and the related serotype 6A as well as an increase in the carriage rate of the serotypes not included in the vaccine were observed . In parallel a significant decrease in carriage rate of antibiotic-resistant pneumococci was observed . The reduction of carriage of antibiotic-resistant pneumococci was seen in all age windows but was greater in the age window < 36 months . Conclusions . The carriage rate of antibiotic-resistant S. pneumoniae , including multiply resistant S. pneumoniae , in DCC attendees is high . Pneumococcal conjugate vaccines seem to be an important tool for reducing the carriage rate of antibiotic-resistant pneumonia in DCCs [10493334] OBJECTIVES The objectives of this study were ( 1 ) to determine the safety and immunogenicity of heptavalent pneumococcal CRM197 conjugate ( PNCRM7 ) vaccine in infants and ( 2 ) to determine the effect of concurrent hepatitis B immunization during the primary series and the effect of concurrent diphtheria and tetanus toxoid and acellular pertussis [ DTaP ( ACEL-IMUNE ) ] and conjugate CRM197 Haemophilus influenzae type b [ HbOC ( HibTITER ) immunization at time of the booster dose on the safety and immunogenicity of PNCRM7 and these other concurrently administered vaccines . METHODS This was a r and omized double-blinded study in 302 healthy infants in the Northern California Kaiser Permanente ( NCKP ) Health Plan . Infants received either PNCRM7 vaccine or meningococcal group C conjugate vaccine as a control at 2 , 4 and 6 months of age and a booster at 12 to 15 months of age . Study design permitted the evaluation of immunology and safety of concurrent administration of routine vaccines . Antibody titers were determined on blood sample s drawn before and 1 month after the primary series and the booster dose . RESULTS After the third dose of PNCRM7 geometric mean concentrations ( GMCs ) ranged from 1.01 for serotype 9V to 3.72 microg/ml for serotype 14 . More than 90 % of all subjects had a post-third dose titer of > or = 0.15 microg/ml for all serotypes , and the percentage of infants with a post-third dose titer of > or = 1.0 microg/ml ranged from 51 % for type 9V to 89 % for type 14 . After the PNCRM7 booster dose , the GMCs of all seven serotypes increased significantly over both post-Dose 3 and pre-Dose 4 antibody levels . In the primary series there were no significant differences in GMCs of pneumococcal antibodies between the subjects given PN-CRM7 alone or concurrently with hepatitis B vaccine . At the toddler dose concurrent administration of PNCRM7 and DTaP and HbOC result ed in a near conventional threshold for statistical significance of a post-Dose 4 GMC for serotype 23F [ alone 6.75 mirog/ml vs. concurrent 4.11 microg/ml ( P = 0.057 ) ] as well as significantly lower antibody GMCs for H. influenza polyribosylribitol phosphate , diphtheria toxoid , pertussis toxin and filamentous hemagglutinin . For all antigens there were no differences between study groups in defined antibody titers that are considered protective . CONCLUSION We conclude that PNCRM7 vaccine was safe and immunogenic . When this vaccine was administered concurrently at the booster dose with DTaP and HbOC vaccines , lower antibody titers were noted for some of the antigens when compared with the antibody response when PNCRM7 was given separately . Because the GMCs of the booster responses were all generally high and all subjects achieved similar percentages above predefined antibody titers , these differences are probably not clinical ly significant [16356598] This study assessed compatibility of concurrently administered 7-valent pneumococcal conjugate ( PCV7 ) , hepatitis B ( HB ) and DTaP.IPV/Hib vaccines . Infants were given DTaP.IPV/Hib and HB at 2 , 4 , 6 months and r and omly assigned ( 2:1 ) to receive PCV7 concurrently or sequentially ( at 3 , 5 , 7 months ) . Antibody levels were compared in 246 concurrent and 122 sequential vaccinees . Responses to PCV7 , DTaP.IPV/Hib and HB were generally unaltered with concurrent administration except that Hib responses were increased ( p=0.008 ) and HB responses were reduced ( p=0.006 ) with concurrent dosing , the latter possibly from same thigh injection with DTaP.IPV/Hib . We conclude that PCV7 , DTaP.IPV/Hib and HB are compatible with concurrent , separate injections [15295223] Background : The novel pneumococcal conjugate vaccine , PncCRM , has been shown to prevent acute otitis media caused by vaccine serotypes and to reduce otitis surgery . Our aim was to assess long term efficacy of the vaccine on tympanostomy tube placements . Methods : Children with complete follow-up in the Finnish Otitis Media Vaccine Trial up to 24 months of age and still living in the study area ( 1490 of 1662 r and omized at 2 months of age ) were invited to a single visit at 4–5 years of age . The children had been vaccinated at 2 , 4 , 6 and 12 months of age with PncCRM or hepatitis B vaccine ( control ) . Tympanostomy tube placements reported by parents at the visit were verified from hospital and private medical center records . Additionally , tympanostomy tube placements of all children were verified from the hospital discharge registry . Vaccine efficacy ( VE ) was estimated by comparing all events of tympanostomy tube placement between vaccine groups . Results : During the vaccine trial ( 2–24 months of age ) , VE ( 95 % confidence interval ) in preventing tympanostomy tube placement was only 4 % ( – 19–23 % ) . Altogether 756 children were enrolled for the follow-up study . After 24 months of age , the rate of surgery was 3.5 per 100 person-years in the PncCRM and 5.7 per 100 person-years in the control children , giving VE of 39 % ( 4–61 % ) . In the hospital-based data of all children ( N = 1490 ) , VE of 44 % was obtained ( 19–62 % ) . Conclusions : Receipt of PncCRM vaccine at infancy was associated with a reduction in tympanostomy tube placement from 2 to 4–5 years of age [15844075] INTRODUCTION Pneumococcal conjugate vaccine ( PnCV ) may be used as a probe to define the burden of pneumococcal disease and better characterize the clinical presentation of pneumococcal pneumonia . METHODS This study used a 9-valent PnCV to define different end points of vaccine efficacy and the preventable burden of pneumococcal pneumonia in 39,836 children who were r and omized in a double-blind , placebo-controlled trial in South Africa . RESULTS Whereas the point-estimate of vaccine efficacy was greatest when measured against the outcome of vaccine-serotype specific pneumococcal bacteremic pneumonia ( 61 % ; P = .01 ) , the sensitivity of blood culture to measure the burden of pneumococcal pneumonia prevented by vaccination was only 2.6 % in human immunodeficiency virus (HIV)-uninfected children and 18.8 % in HIV-infected children . Only 37.8 % of cases of pneumococcal pneumonia prevented by PnCV were detected by means of chest radiographs showing alveolar consolidation . A clinical diagnosis of pneumonia provided the best estimate of the burden of pneumococcal pneumonia prevented through vaccination in HIV-uninfected children ( 267 cases prevented per 100,000 child-years ) and HIV-infected children ( 2573 cases prevented per 100,000 child-years ) . CONCLUSION Although outcome measures with high specificity , such as bacteremic pneumococcal pneumonia , provide a better estimate as to vaccine efficacy , the burden of disease prevented by vaccination is best evaluated using outcome measures with high sensitivity , such as a clinical diagnosis of pneumonia [15243930] BACKGROUND For the licensing of new pneumococcal vaccines , it is vital to be able to predict their protective efficacy on the basis of immunogenicity . However , the serological correlates of protection have not been established for pneumococcal diseases . METHODS A total of 1666 children were immunized with the pneumococcal conjugate vaccine . Acute otitis media ( AOM ) events were identified , and middle-ear fluid was cultured for pneumococci . The association between the concentration of antibodies against serotypes 6B , 19F , and 23F and the risk of AOM caused by the homologous serotypes or by the cross-reactive serotype 6A was assessed . An association model was used to predict efficacy at different geometric mean concentrations ( GMCs ) . RESULTS An association between antibody concentration and risk of AOM was found , but with large differences between serotypes . On the basis of the association , the predicted efficacy for 19F was negligible up to the highest GMC tested . In contrast , 6B was found to be highly efficacious ( > 65 % ) at a GMC of 0.5 microg/mL. CONCLUSIONS The results challenge the view that a new vaccine c and i date should always induce antibody concentrations that are not inferior to those produced by the licensed vaccine . Furthermore , the differences between serotypes caution against defining a common correlate of protection that is applicable to all serotypes [12922095] To evaluate immune responses , safety and reactogenicity of the concomitant use of DTaP-IPV-Hib and the newly available 7-valent pneumococcal conjugate ( 7VPnC ) vaccines when given as the primary immunization series in early infancy . A total of 231 healthy infants were enrolled at 11 German study centers and r and omized to receive either 7VPnC plus DTaP-IPV-Hib vaccines concomitantly into opposite limbs at age 2 , 3 , 4 and 11 - 15 months ( 7VPnC group ) or DTaP-IPV-Hib vaccine at the same ages plus a 7VPnC " catch-up vaccination " at ages 6 , 7 , 8 and 11 - 15 months ( Control group ) . Blood sample s were drawn before and 4 weeks after the first three vaccine doses and 4 weeks after the fourth dose . Local and general side effects ( i.e. safety ) were solicited by diary cards . Immune responses were determined by ELISA except for antibodies to polioviruses ( neutralization assay ) . Post-dose 3 , a significant antibody response against all seven pneumococcal vaccine-serotypes was observed in the 7VPnC group only . Post-dose 4 geometric mean concentrations ( GMCs ) were similar in both groups . GMCs for other vaccine antigens were comparable between groups except for diphtheria ( higher in the 7VPnC group ) and pertactin ( lower in the 7VPnC group ) , although after three vaccine doses there was a 28-fold rise in GMCs from baseline . Both vaccines were generally well-tolerated although there were minor differences in the frequency of local reactions and somewhat more fever or drowsiness in the 7VPnC group . The use of DTaP-IPV-Hib and the 7VPnC vaccine was safe , well-tolerated and immunogenic when given concomitantly at age 2 , 3 and 4 months or when given separately with 7VPnC as a catch-up vaccination at age 6 , 7 , 8 months and as a concomitant booster immunization at age 11 - 15 months [11920317] A double-blind , r and omized study involving 264 toddlers attending day care centers was conducted to document the effect of a 9-valent pneumococcal conjugate vaccine on the carriage rate of pneumococci . Of 3750 cultures done on nasopharyngeal sample s obtained from subjects during a 2-year follow-up period after vaccination , 65 % were positive for Streptococcus pneumoniae . In all age windows , the rate of carriage of vaccine-type pneumococci was lower among subjects who received the pneumococcal vaccine than among control subjects , because the acquisition rate was lower in the former group . The effect was most pronounced among subjects aged < or = 36 months . The sample size enabled us to study protection against carriage of S. pneumoniae serotypes 6B , 9V , 14 , 19F , and 23F ; significant protection against all serotypes except 19F was seen in the pneumococcal-vaccine group . The rate of carriage of serotype 6A ( not included in the vaccine ) was also reduced significantly , but the rate of carriage of serotype 19A ( not included in the vaccine ) was not . The rate of carriage of non-vaccine-type pneumococci ( excluding serotype 6A ) was higher in the pneumococcal-vaccine group than in the control group [16140397] BACKGROUND Based on two clinical trials in healthy infants the American Academy of Pediatrics ( AAP ) advices immunization with a 7-valent pneumococcal conjugate vaccine in children with recurrent acute otitis media ( AOM ) . OBJECTIVE To study the efficacy of a 7-valent pneumococcal conjugate vaccine on acute otitis media recurrences , its immunogenicity and impact on nasopharyngeal Streptococcus pneumoniae carriage in children with a history of frequent acute otitis media . METHODS In this double-blind , r and omized study , 74 Belgian children , aged 1 - 7 years , with at least 2 clinical ly diagnosed episodes of acute otitis media in the previous year were enrolled . Children were immunized with either a 7-valent pneumococcal conjugate vaccine followed by a 23-valent pneumococcal polysaccharide booster or a control hepatitis A vaccine . Total follow-up was 26 months . RESULTS Despite adequate serum IgG responses to all conjugate vaccine pneumococcal serotypes , no reduction of acute otitis media episodes was observed in the pneumococcal vaccine group as compared to the control group ( rate ratio : 1.16 ; 95 % CI : 0.69 - 1.96 ) . Overall nasopharyngeal pneumococcal carriage remained stable . However , a transient shift from conjugate vaccine related S. pneumoniae serogroups to non-vaccine related serogroups was noted following conjugate vaccination . CONCLUSION Clinical ly no protective effect of pneumococcal conjugate vaccination on acute otitis media recurrences was found in children with a history of frequent AOM [14557958] To assess the efficacy of a 7-valent pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine ( PncOMPC ) against acute otitis media ( AOM ) , 1666 infants were r and omly assigned to receive either PncOMPC or control vaccine ( hepatitis B vaccine ) at 2 , 4 , 6 , and 12 months of age . Of the 835 children assigned to receive PncOMPC , 187 received a 23-valent pneumococcal polysaccharide vaccine ( PncPS ) at 12 months of age instead . Whenever AOM was diagnosed , middle ear fluid was aspirated for bacterial culture . In the PncOMPC and control groups , there were 110 and 250 AOM episodes , respectively , in children between 6.5 and 24 months of age that could be attributed to vaccine serotypes , which indicates a vaccine efficacy of 56 % ( 95 % confidence interval , 44%-66 % ) . The serotype-specific efficacy ranged from 37 % for 19F to 82 % for 9V . The 2 boosters seemed to provide equal protection against AOM , but PncPS induced markedly higher antibody concentrations . The efficacy of PncOMPC was comparable to that of the recently licensed pneumococcal conjugate vaccine [12706674] OBJECTIVE To evaluate the safety and immunogenicity of two lots of a heptavalent Streptococcus pneumoniae conjugate vaccine ( PCV ) containing seven capsular polysaccharide serotypes ( 4 , 6B , 9V , 14 , 18C , 19F , and 23F ) conjugated to the outer membrane complex of Neisseria meningitidis serogroup B ( OMPC ) and administered to infants at 2 , 4 , 6 , and 12 months of age . METHODS One hundred twenty infants were r and omly assigned to concurrently receive PCV-OMPC and one of two Haemophilus influenzae type b ( Hib ) conjugate-DTwP combination vaccines : ( 1 ) Hib with a heterologous protein carrier ( CRM(197 ) , TETRAMUNE , Group 1 ) or ( 2 ) an experimental Hib-hepatitis b combination vaccine with the homologous carrier ( OMPC , Group 2 ) . All infants in Groups 1 and 2 received PCV-OMPC ( lot 1 ) at 12 months of age . Another separate group of 120 infants ( Group 3 ) received a different lot of PCV-OMPC concurrently with Hib-CRM(197 ) ( TETRAMUNE ) at 2 , 4 , and 6 months of age and then were r and omized to receive either PCV-OMPC or a 23-valent polysaccharide ( PS ) pneumococcal vaccine at 12 months of age . RESULTS Each PCV-OMPC lot was generally well tolerated and no vaccine-related serious adverse events were reported . Following the primary series , serotype-specific anti-pneumococcal geometric mean concentrations ( GMC ) were highest for serotypes 14 , 19F , and 4 and lowest for serotypes 6B and 23F . GMC and seroconversion rates in Group 3 ( lot 2 ) were lower than in Group 1 ( lot 1 ) for serotypes 6B , 14 , 18C , and 23F . Antibody responses to serotypes 6B , 14 , and 18C were significantly lower in Group 2 compared to Group 1 . Following a booster dose of PCV-OMPC at 12 months of age , each lot was immunogenic with at least a 5 - 10-fold increase in antibody levels , and responses were significantly higher among those who received the PS vaccine . CONCLUSIONS PCV-OMPC is generally safe in infants , displays variable immune response by serotype , and concomitant receipt of Hib vaccine with homologous carrier may impact on its immunogenicity

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### Context: [15702037] Background : The recommended vaccination schedule for the pneumococcal conjugate vaccine ( PCV ) includes 4 immunizations , according to the national programs in the United States and some European countries . Other countries use a national schedule for routine vaccinations in early childhood that includes only 3 doses . Aims : The goals were to assess the immunogenicity and tolerability of PCV with a vaccination schedule that included 3 doses during the first 1 year of life ( a 2 + 1 dose schedule ) and to determine the immune responses to concomitantly administered Haemophilus influenzae type b ( Hib ) vaccine . Methods : A total of 101 healthy Swedish infants were enrolled in an open , nonr and omized , multicenter study . PCV was administered concomitantly with ( at separate sites ) a diphtheria-tetanus toxoids-acellular pertussis vaccine , inactivated polio vaccine and Hib conjugate vaccine combination at 3 , 5 and 12 months of age . IgG antibody concentrations for the 7 serotypes included in the PCV and the Hib capsular polysaccharide in serum sample s taken at 3 , 6 , 12 and 13 months were determined with enzyme immunoassays . Local and systemic reactions were monitored for 3 days after each immunization , and serious adverse reactions were monitored for the whole study period . Results : Two doses of PCV induced satisfactory antibody responses , with the exception of serotypes 6B and 23F . The third dose evoked strong responses for all serotypes , which suggests good immunologic priming with the primary series of 2 doses . The mean anti-Hib antibody concentrations were similar to those noted in earlier studies among Swedish children . The PCV was well tolerated . Conclusion : The pneumococcal antibody concentrations at 13 months were comparable with those noted previously with the 4-dose schedule . The results suggest that the implementation of a 2 + 1 dose schedule for PCV should be considered [15780443] AIM In a prospect i ve controlled study in young children with a history of recurrent acute otitis media , we analyzed the salivary IgA and IgG antibody titers upon vaccination with a 7-valent pneumococcal conjugate vaccine ( PCV ) given once or twice , followed by a 23-valent polysaccharide booster vaccination . METHODS Salivary IgA and IgG antibody concentrations to vaccine serotype 6B , 14 , 18C and 19F were measured by enzyme immunoassay in 38 sample s of children vaccinated with PCV and 45 control sample s. In the PCV group , 12 sample s were taken prior to vaccination , 12 sample s 4 weeks after the polysaccharide booster ( 8 months after the first conjugate vaccination ) and 14 sample s 7 months after the last vaccination ( 14 months after the first conjugate vaccination ) . In the control group 15 children were sample d at each of these three time points . RESULTS We observed an increase in salivary IgG antibody concentrations against serotype 6B , 14 , and 18C 14 months after the primary vaccination in children vaccinated with PCV twice , although this was significant for serotype 14 only . There was no increase in salivary IgG antibody in children vaccinate with PCV once nor in control children . IgA antibody titers increased significantly after 8 and after 14 months in both the pneumococcal vaccine recipients and the controls . However , the observed increase in mean antibody titers was significantly higher in control children compared to the PCV group . CONCLUSION We suggest that repeated pneumococcal conjugate vaccination is necessary to induce an increase in salivary IgG antibodies and effectuate clearance of S. pneumoniae from the nasopharyngeal mucosa of children with recurrent acute otitis media . We hypothesize that the increase in salivary IgA is caused by the local boosting of the mucosal immune response by carriage and recurrent infections , which occurs less often in the PCV group compared to the control children [7095883] Here we show , in a double-blind , r and omized , placebo-controlled trial in 37,107 fully immunized infants in Soweto , South Africa , that a 9-valent pneumococcal conjugate vaccine , PncCV , prevents 31 % ( 95 % confidence interval = 15–43 % ) of pneumonias associated with any of seven respiratory viruses in children in hospital . These data suggest that the pneumococcus has a major role in the development of pneumonia associated with these viruses and that viruses contribute to the pathogenesis of bacterial pneumonia . NOTE : In the version of this article originally published online , the species name was misspelled Streptococcus pnemoniae in the title of the article . The name should be Streptococcus pneumoniae . This error has been corrected for the HTML and print versions of the article [1968589] In the clinical research er 's perfect world every patient entered into a r and omised controlled clinical trial ( RCT ) would satisfy all entry criteria , would complete their allocated treatment as described in the protocol , and would contribute data records which were complete in all respects . In practice it is doubtful if this ideal is ever achieved , and hence strategies have been developed for the analysis of RCTs which seek to protect their inferential basis from consequent biases . Such a strategy is ' intention to treat ' ( ITT ) which is frequently advocated as the preferred approach to analysis . This is particularly so for major trials design ed to establish definitively the efficacy and safety of a new medication or medical procedure . Indeed ITT has been endorsed in regulatory guidelines in Europe and the USA ( Nordic Council on Medicines , 1989 ; Food & Drug Administration , 1988 ) . But is ITT always the preferred approach ? Can it always be satisfactorily applied ? Is it a well-defined and well understood concept ? The subject of ITT regularly arouses debate and controversy . In particular the idea that a patient who has been r and omised to treatment A , but actually receives treatment B , should be assigned to the group who received A for analysis purpose s is totally incomprehensible to some . This controversy is fuelled by the fact that there are a large number of clinical trials , particularly in the early phases of research , for which ITT would indeed be inappropriate . Further fuel is added by the different attitudes to ITT in different research environments it is a constant concern in the later phases of drug regulation , for example , whereas research workers in the Medical Research Council generally show greater flexibility , probably because they are less concerned with satisfying conservative regulatory requirements . It has even been argued that ITT encourages sloppiness ' Whatever we do , give the treatment or not , it is OK since the analysis is by ITT ! ' . ITT came to prominence in connection with long-term RCTs with mortality as their major end-point . Peto and co-workers laid out the general principles for the design and analysis of such studies in their comprehensive and highly influential publications in this journal ( Peto et al. , 1976 , 1977 ) . They did not use the term ' intention to treat ' but did advocate that ' even patients who do not get the proper treatment must not be withdrawn from the analysis ' . Their guidance is detailed : the various ways in which patients may fail to complete the study as per protocol are all discussed , together with the possibility that the patients who so fail may differ in characteristics , or numbers , from treatment arm to treatment arm . Such differences are the source of the bias which ITT attempts to avoid any analysis which omits patients is open to bias because it no longer compares the groups as r and omised . However , although Peto and coworkers do recommend that all properly r and omised patients should be included in the analysis regardless of protocol deviation , they do leave open the possibility for some inappropriately r and omised patients to be excluded , and thus stop short of espousing the inclusion of all r and omised patients [10738092] Children who had been r and omized to receive one dose of either heptavalent pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine ( PCV ) or 23-valent pneumococcal polysaccharide vaccine ( PN23 ) at 12 , 15 , or 18 months of age were subsequently r and omized to receive a booster injection of either PCV or PN23 12 months later . For those children who received a priming dose of PCV ( N=75 ) compared to PN23 ( N=48 ) at 12 , 15 , or 18 months of age , higher serum antibody concentrations were achieved 1 month following a booster injection of either PCV or PN23 for all serotypes tested ( p<0.001 ) . Within the group of children receiving a priming dose of PCV , those children who received a booster dose of PN23 developed higher serum antibody concentrations for four of the seven serotypes tested and similar opsonic antibody titers to serotype 6B , yet more frequent erythema ( p=0.030 ) and pain or soreness ( p=0.024 ) at the injection site compared to those boosted with PCV . In conclusion , a single dose of PCV at 12 - 18 months of age primed for responses to booster doses of either PCV or PN23 12 months later . For those children who received a priming dose of PCV , boosting with PN23 result ed in more frequent injection site pain and erythema than boosting with PCV , yet higher antibody concentrations for most of the serotypes tested [12842372] BACKGROUND Pneumococcal conjugate vaccine prevents recurrent acute otitis media ( AOM ) in infants immunised at 2 , 4 , 6 , and 12 - 15 months of age . We aim ed to find out whether this vaccine also prevents AOM in older children who have had previous episodes of AOM . METHODS In this double-blind , r and omised study , we enrolled 383 patients aged 1 - 7 years who had had two or more episodes of AOM in the year before entry . R and omisation was stratified in four groups according to age ( 12 - 24 months vs 25 - 84 months ) and the number of previous AOM episodes ( two or three episodes vs four or more episodes ) . Children received either 7-valent pneumococcal conjugate vaccine followed by 23-valent pneumococcal polysaccharide vaccine , or hepatitis A or B vaccines . They were followed up for 18 months for recurrence of AOM . We also cultured sample s of middle-ear fluid and nasopharyngeal swabs to assess association of pneumococcal serotypes with AOM after vaccination . FINDINGS We noted no reduction of AOM episodes in the pneumococcal vaccine group compared with controls ( intention-to-treat analysis : rate ratio 1.25 , 95 % CI 0.99 - 1.57 ) . Although nasopharyngeal carriage of pneumococci of serotypes included in the conjugate-vaccine was greatly reduced after pneumococcal vaccinations , immediate and complete replacement by non-vaccine pneumococcal serotypes took place . INTERPRETATION These data do not lend support to the use of pneumococcal conjugate vaccine to prevent otitis media in previously unvaccinated toddlers and children with a history of recurrent AOM [15665713] Background : The 7-valent pneumococcal ( 7vPn ) conjugate vaccine is licensed for primary and booster vaccination according to the same immunization schedules as routinely recommended diphtheria-tetanus-pertussis-based childhood vaccines and can be coadministered during the same vaccination visit . Methods : An open , r and omized study evaluated the immunogenicity and safety of a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio virus-Haemophilus influenzae type b ( DTPa-HBV-IPV/Hib ) vaccine and a 7vPn conjugate vaccine when coadministered at 2 , 3 and 4 months and 12–23 months of age , compared with the administration of the hexavalent DTPa-HBV-IPV/Hib vaccine given alone . Serum antibody titers were measured before and 1 month after the primary course and before and 1 month after the booster dose . Solicited local and general adverse events were recorded for 4 days and unsolicited adverse events were recorded for 30 days after each vaccine dose . Results : A total of 345 subjects were enrolled for primary vaccination with the hexavalent vaccine ( 170 without and 175 with the 7vPn vaccine coadministered ) and 266 returned for booster vaccination ( 122 without and 144 with coadministration of the 7vPn vaccine ) . After primary vaccination , antibody responses against the common antigens were similar in both groups , with seroprotection rates of 93.6–100 % and with similar antibody decay before booster vaccination . The fourth dose induced a vigorous booster response , with seroprotection/vaccine response rates of 96.8–100 % . Response to the 7vPn primary and booster vaccination was within previously reported ranges . Differences in reactogenicity result ed from higher incidences of symptoms after concomitant vaccination . Rectal temperature > 39.5 ° C was observed after 1.2 % of the coadministered vaccine doses during primary vaccination and after 2.8 % of the booster vaccine doses . Conclusion : Coadministration of the DTPa-HBV-IPV/Hib and 7vPn vaccines at separate injection sites during the same vaccination visit was effective and safe [11514043] A group-r and omized , double-masked , phase III trial of a Streptococcus pneumoniae conjugate vaccine is being conducted in American Indian population s in the southwestern United States . Approximately 9000 infants will be enrolled in the primary efficacy cohort with vaccine allocation determined by community of residence . The trial is design ed to continue until 48 cases of invasive pneumococcal disease due to vaccine serotypes have accumulated . Thirty-eight geographically and socially distinct areas were r and omized within blocks formed by population size and geographic location . This design affords the opportunity to capture the effects of herd immunity ( indirect effects ) by estimating the impact of the vaccine intervention on nonimmunized infants . Group-r and omized trials have challenging design and analysis features , many of which are discussed here in the context of the first such trial design ed to lead to licensure of a drug or biologic in the United States [19483514] Background : Pneumococcus is a leading cause of childhood pneumonia worldwide . Pneumococcal conjugate vaccines ( PCV ) have demonstrated efficacy against childhood invasive pneumococcal disease ( IPD ) and pneumonia in the United States and Africa . No information is available from Asia on the impact of PCV on childhood pneumonia . Methods : We conducted a r and omized , placebo-controlled , double-blind trial in Bohol , the Philippines ( IS RCT N 62323832 ) . Children 6 weeks to < 6 months of age were r and omly allocated to receive 3 doses of either an 11-valent PCV ( 11PCV , sanofi pasteur , Lyon , France ) or a saline placebo , with a minimum interval of 4 weeks between doses to determine vaccine efficacy ( VE ) against the primary outcome of a child experiencing first episode of community-acquired radiologically defined pneumonia in the first 2 years of life . Secondary end points were clinical pneumonia , IPD , safety , and immunogenicity . Results : Twelve thous and one hundred ninety-one children were enrolled . By per protocol ( PP ) analysis , 93 of 6013 fully vaccinated 11PCV recipient children had a first episode of radiologic pneumonia compared with 120 of 6018 placebo recipients . VE against radiologically defined pneumonia for the PP cohort of children 3 to 23 months old was 22.9 % ( 95 % CI : −1.1 , 41.2 ; P = 0.06 ) , for the prespecified subgroups of children 3 to 11 months of age , 34.0 % ( 95 % CI : 4.8 , 54.3 ; P = 0.02 ) , and of those 12 to 23 months old , 2.7 % ( 95 % CI : −43.5 , 34.0 ; P = 0.88 ) . By intent-to-treat ( ITT ) analysis , 119 of 6097 11PCV recipient children had an episode of radiologic pneumonia compared with 141 of 6094 placebo recipients . VE against radiologic pneumonia for the ITT cohort of children < 2 years old was 16.0 % ( 95 % CI −7.3 , 34.2 ; P = 0.16 ) , for a subgroup of children < 12 months of age , 19.8 % ( 95 % CI : −8.8 , 40.8 ; P = 0.15 ) . VE against clinical pneumonia by PP was not significant ( VE 0.1 % ; 95 % CI −9.4 , 8.7 ; P = 0.99 ) . IPD was rare : only 3 cases of IPD due to vaccine serotypes were observed during the study . 11PCV was immunogenic and well tolerated . Among 11PCV recipients , a small excess of serious adverse respiratory events was observed in the first 28 days after the first and second dose of vaccine , and of nonrespiratory events after the first dose . An excess of pneumonia episodes in 11PCV recipients in the month following the second dose of vaccination was the principal reason for lower VE by ITT analysis than by PP analysis . Conclusions : In PP analysis , a 22.9 % reduction of community-acquired radiologically confirmed pneumonia in children younger than 2 years of age in the 11-valent tetanus-diphtheria toxoid-conjugated PCV vaccinated group was observed ; a reduction similar as observed in other PCV trials . We could not demonstrate any VE against clinical pneumonia . Our finding confirms for the first time that in a low-income , low-mortality developing country in Asia , at least one-fifth of radiologically confirmed pneumonia is caused by pneumococcus , and thus preventable by PCV . Whether PCV should be included in national program in such setting s , however , depends on careful country specific disease burden measurement and cost-effectiveness calculation [15618174] ABSTRACT The licensure of new pneumococcal conjugate vaccines ( PCVs ) relies on immunogenicity data . When defining correlates of protection , vaccine efficacy data must be included . In the FinOM Vaccine Efficacy Trial , the PncOMPC vaccine showed an efficacy profile similar to that of the licensed PncCRM vaccine despite different antibody responses after primary and booster vaccinations . We determined antibody kinetics and avidities in a subgroup of infants participating in the FinOM trial . A total of 166 infants in three vaccine groups were immunized at 2 , 4 , 6 , and 12 months of age with 7-valent PCV , PncCRM or PncOMPC , or hepatitis B vaccine . Concentrations of serum immunoglobulin G ( IgG ) against pneumococcal capsular polysaccharides were determined at 2 , 4 , 6 , 7 , 12 , 13 , and 24 months of age , and the avidity index ( AI ) to serotypes 6B , 19F , and 23F were determined at 7 , 12 , 13 , and 24 months of age by enzyme immunoassay . Both PCVs were highly immunogenic , but they demonstrated different kinetics of antibody response ; the concentration of IgG against serotypes 6B , 19F , and 23F declined faster after the third and fourth doses of vaccine in the PncCRM group than in the PncOMPC group . For both PCVs , the mean AI of anti-6B and -23F , but not of anti-19F , increased during the follow-up , which is in line with serotype-specific protection in the FinOM trial . Our data suggest that the kinetics and avidities of antibodies should be considered , in addition to antibody responses , when defining correlates of protection [15794968] BACKGROUND Pneumonia is estimated to cause 2 million deaths every year in children . Streptococcus pneumoniae is the most important cause of severe pneumonia . We aim ed to assess the efficacy of a nine-valent pneumococcal conjugate vaccine in children . METHODS We undertook a r and omised , placebo-controlled , double-blind trial in eastern Gambia . Children age 6 - 51 weeks were r and omly allocated three doses of either pneumococcal conjugate vaccine ( n=8718 ) or placebo ( 8719 ) , with intervals of at least 25 days between doses . Our primary outcome was first episode of radiological pneumonia . Secondary endpoints were clinical or severe clinical pneumonia , invasive pneumococcal disease , and all-cause admissions . Analyses were per protocol and intention to treat . FINDINGS 529 children assigned vaccine and 568 allocated placebo were not included in the per- protocol analysis . Results of per- protocol and intention-to-treat analyses were similar . By per- protocol analysis , 333 of 8189 children given vaccine had an episode of radiological pneumonia compared with 513 of 8151 who received placebo . Pneumococcal vaccine efficacy was 37 % ( 95 % CI 27 - 45 ) against first episode of radiological pneumonia . First episodes of clinical pneumonia were reduced overall by 7 % ( 95 % CI 1 - 12 ) . Efficacy of the conjugate vaccine was 77 % ( 51 - 90 ) against invasive pneumococcal disease caused by vaccine serotypes , 50 % ( 21 - 69 ) against disease caused by all serotypes , and 15 % ( 7 - 21 ) against all-cause admissions . We also found an efficacy of 16 % ( 3 - 28 ) against mortality . 110 serious adverse events arose in children given the pneumococcal vaccine compared with 131 in those who received placebo . INTERPRETATION In this rural African setting , pneumococcal conjugate vaccine has high efficacy against radiological pneumonia and invasive pneumococcal disease , and can substantially reduce admissions and improve child survival . Pneumococcal conjugate vaccines should be made available to African infants [12352800] Objective . To determine the effectiveness of the Wyeth heptavalent pneumococcal conjugate vaccine against clinical and radiograph-confirmed pneumonia in children . Methods . The heptavalent CRM197 pneumococcal conjugate vaccine ( PCV ) was given to infants at 2 , 4 , 6 and 12 to 15 months of age in a r and omized , double blind trial . 1 Children were r and omized to receive either the CRM197 PCV ( vaccine group ) or the meningococcal type C CRM197 conjugate vaccine ( control group ) . The primary outcome of this trial was invasive pneumococcal disease . In addition children with the clinical diagnosis of pneumonia in the study population were identified through review of automated inpatient , emergency and outpatient data bases . The subset of the cohort of these children who had chest radiographs obtained at the time of diagnosis was identified , and the original reading of their radiographs by the radiologist was obtained from automated data bases . Rates of clinical ly diagnosed pneumonia , of pneumonia with a radiograph obtained regardless of result , of pneumonia with positive radiograph ( consolidation , empyema or parenchymal infiltrate ) and of pneumonia with only perihilar infiltrates were compared between vaccinated and nonvaccinated groups . In addition risk of disease pneumonia was evaluated by race and ethnicity . Results . The incidence of a first pneumonia episode in the control group was 55.9 per 1000 person-years . A radiograph was obtained in 61 % of episodes , a positive radiograph in 21 % and perihilar findings in an additional 5 % . In per protocol follow-up of children given PCV , first episodes of all clinical ly diagnosed pneumonia were reduced by 4.3 % [ 95 % confidence interval ( CI ) , −3.5 , 11.5 % , P = 0.27 ] , episodes with a radiograph were reduced by 9.8 % ( CI 0.1 , 18.5 % , P < 0.05 ) and episodes with a positive radiograph were reduced by 20.5 % ( CI 4.4 , 34.0 , P = 0.02 ) . In the intent to treat analysis including all episodes after r and omization , episodes with a positive radiograph were reduced by 17.7 % , P = .01 ) . The greatest impact was in the first year of life with a 32.2 % reduction and a 23.4 % reduction in the first 2 years , but only a 9.1 % reduction in children > 2 years of age . Asians , blacks and Hispanics were at higher risk of pneumonia than were whites , but there was no evidence of ethnic variation in PCV effectiveness . Ten of the 11 cases of pneumococcal pneumonia with a positive blood culture were in the control group . Conclusion . The pneumococcal conjugate vaccine tested was effective in reducing the risk of pneumonia in young children [12544402] Context . The heptavalent pneumococcal conjugate vaccine ( PCV ) is recommended for infants to protect against invasive disease , but its impact on otitis might also have public health importance . Objective . To examine the impact of PCV on the incidence of otitis media , frequent otitis media and tympanostomy tube procedures and to assess whether the effectiveness of the vaccine wanes after age 24 months and varies by race , sex or season . Design , setting and patients .. From 1995 to 1998 , 37 868 children at Kaiser Permanente in Northern California were r and omized to receive PCV or a control vaccine in a double blind trial and were followed through April 1999 . Interventions . Children received a primary series at 2 , 4 and 6 months of age and a booster at 12 to 15 months . Main outcome measures . Visits for otitis , frequent visits for otitis and tympanostomy tube procedures . Otitis was ascertained from diagnosis checklists routinely marked by physicians . Results . Control children averaged 1.8 otitis visits per year . Children given PCV had fewer otitis visits than control children in every age group , sex , race and season examined . Intention-to-treat analysis permitted rejection of the null hypothesis that PCV is ineffective against otitis media ( P < 0.0001 ) . In children who completed the primary series per protocol , PCV reduced otitis visits by 7.8 % [ 95 % confidence interval ( CI ) , 5.4 to 10.2 % ] and antibiotic prescriptions by 5.7 % ( CI 4.2 to 7.2 % ) . Frequent otitis was reduced by amounts that increased with otitis frequency , from a 10 % reduction in the risk of 3 visits to a 26 % reduction in the risk of 10 visits within a 6-month period . Tube placements were reduced by 24 % ( CI 12 to 35 % ) . Conclusion . In children followed up to 3.5 years , PCV provided a moderate amount of protection against ear infections while reducing frequent otitis media and tube procedures by greater amounts [12744899] BACKGROUND Streptococcus pneumoniae ( Sp ) is an important bacterial pathogen in children . Nasopharyngeal ( NP ) colonization of S. pneumoniae is necessary for person-to-person transmission and often precedes invasive disease . METHODS NP carriage of Sp was studied in 49 infants following administration of a heptavalent pneumococcal conjugate vaccine ( PCV ) conjugated to the outer membrane protein of serogroup b Neisseria meningitidis ( vaccine serotypes : 4 , 6B , 9V , 14 , 18C , 19F , 23F ) . The vaccine was administered at 2 , 4 , 6 , and 12 months of age and carriage rates were compared to a concurrent group of 32 infants not given PCV and evaluated over the first 15 months of life . RESULTS Overall , Sp was isolated in 86/367 ( 23 % ) of NP cultures and 49 % of infants . Serotype 23F was significantly less prevalent in the PCV group ( 1.9 % ) than the control group ( 16.1 % ) ( P<0.05 ) . Analysis of the proportion of children with prevalent carriage or acquisition of carriage did not differ between groups when evaluated by age or serotype . We noted , however , decreased acquisition and carriage in the vaccine group 1 month following the 12 month dose of PCV for vaccine serotypes ( 76 and 52 % reduction , respectively ) , but this did not reach statistical significance ( P=0.3 ) . Adjustment for age , daycare and antibiotic use by multivariate modeling revealed no difference in carriage of vaccine containing serotypes or non-vaccine serotypes between groups . CONCLUSION We did not show a significant effect of this heptavalent PCV on NP carriage . Further study of this issue , including a larger population size , is needed [15793941] UNLABELLED This study evaluates the safety and immunogenicity of pneumococcal seven-valent conjugate vaccine ( Prevenar ) in 115 children , aged 2 - 3 years ( 24 - 36 months ) , who have not been previously vaccinated with Prevenar . RESULTS SAFETY As for local reactions , 40 % of children reported erythema , 32.2 % in duration and 39.1 % tenderness at the injection site . Regarding systemic reactions , fever > or 38 C was recorded in 7 % of patients . Other commonly reported events were decreased appetite ( 24.3 % ) , restlessness ( 20 % ) , and fussiness ( 18.3 % ) . IMMUNOGENICITY After vaccination , more than 98 % of the subjects achieved antibody levels of > or = 0.15 microg/mL for all seven serotypes and more than 95 % achieved antibody levels > or = 0.50 microg/mL for all serotypes . CONCLUSIONS Pneumococcal seven-valent conjugate vaccine ( Prevenar ) was safe , well tolerated and highly immunogenic when administered in previously unvaccinated children aged 14 - 36 months [15472839] BACKGROUND We recently showed that vaccination with a 7-valent pneumococcal conjugate vaccine ( PCV7 ) followed by a 23-valent pneumococcal polysaccharide vaccine ( PPSV23 ) failed to prevent new episodes of acute otitis media ( AOM ) in previously unvaccinated toddlers and children with a history of recurrent AOM . We describe in detail the impact of pneumococcal vaccinations on nasopharyngeal carriage of S. pneumoniae in this study population . METHODS The impact of vaccination with PCV7 followed by PPSV23 on pneumococcal nasopharyngeal carriage was studied in a prospect i ve , r and omized trial involving 383 children ( age range , 1 - 7 years ) with previous AOM . Nasopharyngeal swab specimens were collected at the time of first vaccination and at 6 - 7-month intervals during the 26-month follow-up period . RESULTS Overall , pneumococcal carriage rates did not diminish , remaining at approximately 50 % in both PCV7/PPSV23 and control vaccinees . A significant shift from conjugate vaccine- to nonconjugate vaccine-type pneumococci was observed in children aged 1 - 2 years , who received the conjugate vaccine twice before the polysaccharide vaccine was administered . Conjugate vaccine serotype carriage was not influenced in older children , who received the conjugate vaccine once before receiving the polysaccharide booster . CONCLUSIONS The administration of conjugate vaccines at least twice also after 2 years of age may be m and atory for reducing the carriage of conjugate vaccine serotypes in children with recurrent AOM . Polysaccharide booster vaccination did not affect nasopharyngeal colonization with serotypes not included in the conjugate vaccine [11001109] BACKGROUND Streptococcus pneumoniae is a major disease burden in young children and the incidence of antibiotic-resistant pneumococcal strains is increasing . Multivalent pneumococcal saccharide-protein conjugate vaccines have recently been developed . OBJECTIVES To assess the immunogenicity and reactogenicity of a 7-valent pneumococcal conjugate vaccine ( 7VPnC ) administered as a separate injection or as a combined injection with Haemophilus influenzae type b vaccine ( HbOC ) at 2 , 3 and 4 months of age . METHODS R and omized controlled trial of 368 healthy UK infants receiving routine vaccines only ( control group ) , routine vaccines and 7VPnC as a separate injection ( separate group ) , or routine vaccines and 7VPnC combined with HbOC ( combined group ) at 2 , 3 and 4 months . The control group received 7VPnC at 5 , 6 and 7 months . All groups received pneumococcal polysaccharide vaccine at 13 to 16 months . Anticapsular IgG antibodies to 7VPnC serotypes were measured at 2 , 5 , 13 and 14 months and safety data collected . RESULTS IgG antibody concentrations at 5 months were higher in the two treatment groups compared with the controls for all 7VPnC serotypes ( P < 0.001 ) and higher in the separate group than the combined group for five 7VPnC serotypes ( P < 0.05 ) . For both treatment groups antibody concentrations were higher at 14 months ( range , 6.6 to 25.3 microg/ml ) than at 5 months ( range , 0.6 to 2.5 microg/ml ) for all 7VPnC serotypes ( P < 0.001 ) . CONCLUSION 7VPnC was well-tolerated , safe and immunogenic when administered as a separate or as a combined 7VPnC/HbOC injection . Although antibody responses were lower in the infants who received the combination compared with those who received 7VPnC as a separate injection , marked anamnestic responses to polysaccharide challenge were observed , suggesting that both groups were immunologically primed [14523142] BACKGROUND Acute respiratory tract infections caused by Streptococcus pneumoniae are a leading cause of morbidity and mortality in young children . We evaluated the efficacy of a 9-valent pneumococcal conjugate vaccine in a r and omized , double-blind study in Soweto , South Africa . METHODS At 6 , 10 , and 14 weeks of age , 19,922 children received the 9-valent pneumococcal polysaccharide vaccine conjugated to a noncatalytic cross-reacting mutant of diphtheria toxin ( CRM197 ) , and 19,914 received placebo . All children received Haemophilus influenzae type b conjugate vaccine . Efficacy and safety were analyzed according to the intention-to-treat principle . RESULTS Among children without human immunodeficiency virus ( HIV ) infection , the vaccine reduced the incidence of a first episode of invasive pneumococcal disease due to serotypes included in the vaccine by 83 percent ( 95 percent confidence interval , 39 to 97 ; 17 cases among controls and 3 among vaccine recipients ) . Among HIV-infected children , the efficacy was 65 percent ( 95 percent confidence interval , 24 to 86 ; 26 and 9 cases , respectively ) . Among children without HIV infection , the vaccine reduced the incidence of first episodes of radiologically confirmed alveolar consolidation by 20 percent ( 95 percent confidence interval , 2 to 35 ; 212 cases in the control group and 169 in the vaccinated group ) in the intention-to-treat analysis and by 25 percent ( 95 percent confidence interval , 4 to 41 ; 158 and 119 cases , respectively ) in the per- protocol analysis ( i.e. , among fully vaccinated children ) . The incidence of invasive pneumococcal disease caused by penicillin-resistant strains was reduced by 67 percent ( 95 percent confidence interval , 19 to 88 ; 21 cases in the control group and 7 in the vaccinated group ) , and that caused by strains resistant to trimethoprim-sulfamethoxazole was reduced by 56 percent ( 95 percent confidence interval , 16 to 78 ; 32 and 14 cases , respectively ) . CONCLUSIONS Vaccination with a 9-valent pneumococcal conjugate vaccine reduced the incidence of radiologically confirmed pneumonia . The vaccine also reduced the incidence of vaccine-serotype and antibiotic-resistant invasive pneumococcal disease among children with and those without HIV infection [14597376] OBJECTIVE To explore the effect of a pneumococcal conjugate vaccine on the risk of otitis media with effusion and to search for subgroups in which the vaccine had a higher or lower effect . METHODS Analyses were performed on data from the Finnish Otitis Media Vaccine Trial , a r and omised controlled double-blind trial to evaluate the efficacy of pneumococcal conjugate vaccination against acute otitis media . Data on the vaccination effect against otitis media with effusion were obtained by means of symptom interview and pneumatic otoscopy during pre-scheduled follow-up visits at the age of 7 and 24 months . Two endpoint definitions were considered : otitis media/tube ( otitis media or tympanostomy tube in situ ( OM/T ) ) as the primary endpoint and otitis media with effusion as the secondary endpoint . No evidence was found of an age-dependent association with vaccination effect . Therefore , the final marginal logistic regression analyses were performed on the combined data from the two follow-up visits . RESULTS The risk of otitis media tended to be lower in the pneumococcal vaccine group . The odds ratio for otitis media/tube was 0.94 ( 95 % confidence interval 0.77 - 1.14 ) and the odds ratio for otitis media with effusion was 0.90 ( 95 % confidence interval 0.69 - 1.19 ) . Presence of older siblings increased the risk of otitis media/tube and otitis media with effusion at 7 months of age . In addition , it appeared that children without older siblings and attending day-care at 24 months of age tended to benefit more from the pneumococcal conjugate vaccine . In this subgroup , the odds ratio for otitis media/tube was 0.81 ( 95 % confidence interval 0.55 - 1.20 ) and for otitis media with effusion the odds ratio was 0.43 ( 95 % confidence interval 0.22 - 0.86 ) . CONCLUSION The effect of pneumococcal conjugate vaccination on the risk of otitis media with effusion was concordant with the efficacy seen against acute otitis media , although not distinguishable from no effect in the overall analysis . In children without older siblings , vaccination appeared to reduce the point prevalence of otitis media with effusion ; this effect was not apparent in children with older siblings [15750461] Aims : Prospect i ve study to evaluate the impact of the 7-valent pneumococcal conjugate vaccine ( Prevenar ) on the nasopharyngeal ( NP ) carriage of drug-resistant Streptococcus pneumoniae ( DRPn ) , by healthy children attending day-care centers ( ages 6 months–6 years ) . Methods : Vaccinees ( 238 children ) who received vaccine and controls ( 457 children ) were followed for carriage of total S. pneumoniae and DRPn and for the serotypes and genetic background s of DRPn during 6 consecutive sampling periods between May 2001 and February 2003 . Results : We detected no significant differences between vaccinees and the control group in the total carriage rate of Pn ( average , 68 % ) or in the frequency of carriage of DRPn ( average , 38 % ) , including the frequency of penicillin-nonsusceptible strains ( average , 24 % ) . In contrast , there was a decline in the carriage of DRPn with vaccine serotypes which was compensated by the appearance and gradual increase in the frequency of DRPn expressing unusual serotypes ( 6A , 10A , 15A and 15C , 19A , 23A , 33F ) which were not present in the vaccine as well as an increase in nontypable strains . The majority of the DRPn with unusual serotypes showed different pulsed field gel electrophoresis patterns indicating replacement of the original resistant flora by other clonal types of drug-resistant bacteria . Antibiotic consumption and the frequency of respiratory tract infections were similar among the vaccinees and controls . Conclusions : Pneumococcal vaccination did not change the frequency of carriage of drug-resistant strains being the initially dominant vaccine serotypes replaced by others expressing nonvaccine serotypes . Reduction in the carriage of DRPn may require a combination of the conjugate vaccine and a decrease in antibiotic pressure [16892907] When a sufficiently high proportion of a population is immunized with a vaccine , reduction in secondary transmission of disease can confer significant protection to unimmunized population members . We propose a straightforward method to estimate the degree of this indirect effect of vaccination in the context of a community-r and omized vaccine trial . A conditional logistic regression model that accounts for within-r and omization unit correlation over time is described , which models risk of disease as a function of community-level covariates . The approach is applied to an example data set from a pneumococcal conjugate vaccine study , with study arm and immunization levels forming the covariates of interest for the investigation of indirect effects [12005078] Objective . To determine the efficacy , immunogenicity and safety of the heptavalent CRM197 pneumococcal conjugate vaccine ( PCV ) in low birth weight ( LBW ) and preterm ( PT ) infants against invasive pneumococcal disease caused by vaccine types . Methods . In a r and omized double blind trial of 37 868 infants given either PCV or meningococcal type C conjugate vaccine ( MCV ) , 1756 infants < 750 g < 2500 g ( LBW ) and 4340 infants from 32 to < 38 weeks old ( PT ) were identified . Risk of invasive pneumococcal disease in LBW and PT infants was compared with risk in normal birth weight ( NBW ) and full term ( FT ) infants . Local and systemic events observed within 48 h of recent vaccine were assessed by telephone interviews and similar comparisons made . Premature infant Emergency Department visits and hospitalization were also identified and compared with FT and NBW infants . Results . Initiation of immunization and intervals between doses were similar for all groups . The risk ratio for invasive pneumococcal diseases for LBW infants compared with NBW infants was 2.6 ( P = 0.03 ) , and for PT compared with FT infants the risk ratio was 1.6 ( P = 0.06 ) . Vaccine efficacy for both groups was 100 % . PCV was as immunogenic in LBW and PT as in NBW and FT infants . Fever and local events after PCV vaccination were similar when adjusted for clustering among multiple doses per child . When stratified for individual doses there was more redness and swelling for LBW infants and more swelling for PT infants after Dose 3 . Isolated local and systemic reactions were more commonly seen with PCV than with MCV , a pattern similar to that in NBW and FT infants . Hospitalization rates were similar for PCV and MCV recipients . Conclusion . These data support the use of PCV in LBW infants and PT infants [12907008] BACKGROUND Streptococcus pneumoniae is the main cause of invasive bacterial disease in children aged younger than 2 years . Navajo and White Mountain Apache children have some of the highest rates of invasive pneumococcal disease documented in the world . We aim ed to assess the safety and efficacy of a seven-valent polysaccharide protein conjugate pneumococcal vaccine ( PnCRM7 ) against such disease . METHODS In a group-r and omised study , we gave this vaccine to children younger than 2 years from the Navajo and White Mountain Apache Indian reservations ; meningococcal type C conjugate vaccine ( MnCC ) served as the control vaccine . Vaccine schedules were determined by age at enrollment . We recorded episodes of invasive pneumococcal disease and serotyped isolates . Analyses were by intention to treat and per protocol . FINDINGS 8292 children enrolled in the trial . In the per protocol analysis of the primary efficacy group ( children enrolled by 7 months of age ) there were eight cases of vaccine serotype disease in the controls and two in the PnCRM7 group ; in the intention-to-treat analysis we noted 11 cases of vaccine serotype disease in the MnCC control group and two in the PnCRM7 group . After group r and omisation had been controlled for , the per protocol primary efficacy of PnCRM7 was 76.8 % ( 95 % CI -9.4 % to 95.1 % ) and the intention-to-treat total primary efficacy was 82.6 % ( 21.4 % to 96.1 % ) . INTERPRETATION PnCRM7 vaccine prevents vaccine serotype invasive pneumococcal disease even in a high risk population . Other regions with similar disease burden should consider including this vaccine in the routine childhood vaccine schedule [16940833] Background : A World Health Organization ( WHO ) working group in 2001 developed a method for st and ardizing interpretation of chest radiographs in children for epidemiologic purpose s. We reevaluated radiographs from the Kaiser Permanente Pneumococcal Efficacy trial using this method . Methods : Seven-valent pneumococcal conjugate vaccine was evaluated in a r and omized , controlled study including 37,868 infants . Effectiveness against pneumonia was previously evaluated using the original treating radiologist reading . There were 2841 sets of radiographs from this trial and all available radiographs were scanned and read blindly by 2 WHO crosstrained readers ( A and B ) ; discordance between the 2 primary readers was resolved through a consensus reading by an adjudicating panel of 2 radiologists . Results : Of the 2841 radiographs , 2446 were available for scanning and were review ed using WHO-defined descriptive categories . Two hundred fifty of the 2446 radiographs were read as positive by both readers . An additional 129 were read as positive by reader A only and 142 by reader B only for a total of 521 radiographs that were read as positive by one or both of the review ers . The concordance rate between the 2 review ers was 250 of 521 ( 48 % ) . Of the 271 discordant radiographs , 45 of 129 ( 34.9 % ) of reader A and 66 of 142 ( 46.5 % ) for reader B were finalized as positive by the adjudicating panel . Overall , 361 radiographs were finalized as positive ( 12.7 % ) . With these 361 images as the st and ard , the sensitivity and specificity of reader A were 82 % and 97 % , respectively , and for reader B , 88 % and 97 % , respectively . Kappa between the 2 readers was 0.58 . Of 25 control radiographs read as positive by both A and B , 80 % were also read as positive by the panel and all 25 control negative radiographs were read as negative by the panel . Using original readings by point-of-care radiologists , efficacy against first episode of radiograph confirmed pneumonia was 17.7 % ( 95 % confidence interval [ CI ] = 4.8–28.9 % ) in intent-to-treat and 20.5 % ( 95 % CI = 4.4–34 % ) in per protocol . Using the WHO method , the efficacy against first episode of radiograph confirmed pneumonia adjusting for age , gender and year of vaccination of 25.5 % ( 95 % CI = 6.5–40.7 % , P = 0.011 ) for intent-to-treat and 30.3 % ( 95 % CI = 10.7–45.7 % , P = 0.0043 ) for per protocol . Conclusion : Using WHO criteria for reading of radiographs increased point estimates of vaccine efficacy presumably as a result of improved specificity [11642629] Background . Incidence and severity of respiratory infections are increased in day-care center attendees . Streptococcus pneumoniae is an important contributor to these infections . Objective . To examine whether the use of a pneumococcal conjugate vaccine could reduce the occurrence of respiratory infections and the ensuing antibiotic drug use in the day care . Method . In this double blind , r and omized , controlled study performed in 8 day-care centers located in Beer-Sheva , Israel , 264 toddlers ages 12 to 35 months at enrollment were r and omized to receive either a 9-valent conjugate pneumococcal vaccine ( conjugated to CRM197 ) or a control vaccine [ conjugate meningococcus C vaccine ( conjugated to CRM197 ) ] and were followed for an average of 22 months . The main outcome measures were respiratory morbidity and antibiotic use . Results . An overall reduction of 7 % in child months with ≥1 reported illness episodes was observed among vaccinees ( P = 0.008 ) , and 85 % of all episodes were related to the respiratory tract . Reductions of 15 , 16 and 17 % were observed in upper respiratory infections , lower respiratory problems and otitis media , respectively . An overall reduction of 17 % in antibiotic days was observed [ 10 % for upper respiratory infections , 20 % for otitis and 47 % for lower respiratory problems ( P ≤ 0.005 for each entity ) ] . The reduction in episodes and antibiotic use was greater for those < 36 months of age than for the older children . Conclusion . The reduction of respiratory problems , including those not traditionally considered of pneumococcal origin and the ensuing lowered antibiotic use in day-care center attendees by pneumococcal conjugate vaccination suggest a broader benefit from the vaccine than preventing invasive disease only [12799509] Aim . We conducted a study to determine whether administration of a pneumococcal conjugate vaccine to toddlers attending day-care centers ( DCCs ) could prevent acquisition of Streptococcus pneumoniae of the vaccine serotypes ( VT ) by their younger siblings . In a double blind study , 262 DCC attendees ages 12 to 35 months were r and omized to receive a 9-valent pneumococcal conjugate vaccine ( PnCRM9;n = 132 ) , or a control vaccine ( meningococcus C vaccine;n = 130 ) . It was planned to follow the groups for 2 years with monthly nasopharyngeal pneumococcal cultures during the first follow-up year and every 2 months during the second year . Forty-six younger siblings of the above described children , age < 18 months ( 23 siblings of the PnCRM9 recipients and 23 of the controls ) , were also enrolled , and nasopharyngeal cultures were obtained monthly until the children reached the age of 18 months or started to attend DCC , if before the age of 18 months . Pneumococcal isolates were serotyped and tested for antibiotic susceptibility . Results . Of the 3748 cultures obtained from the DCC attendees , 2450 ( 65 % ) were positive for S. pneumoniae . Of 306 cultures obtained from the younger siblings , 151 ( 49 % ) were positive . Among the PnCRM9 recipients , cultures were significantly less frequently positive for the VT S. pneumoniae than among the controls ( 13 % vs. 21 % , respectively;P < 0.001 ) . The same pattern was seen in the younger siblings of PnCRM9 recipients vs. the siblings of controls ( 21 % vs. 34 % , respectively;P = 0.017 ) . The reverse trend was seen for non-VT strains in both the DCC attendees ( 44 % vs. 34 % , respectively;P < 0.001 ) and their younger siblings ( 19 % vs. 13 % , respectively;P = 0.15 ) . There was a significant decrease in the carriage rate of antibiotic-resistant S. pneumoniae in both the PnCRM9 recipients and their younger siblings . The relative risks ( and 95 % confidence intervals ) to carry S. pneumoniae penicillin-nonsusceptible , resistant to ≥1 , ≥2 and ≥3 antibiotic categories among younger siblings of PnCRM9 recipients vs. siblings of controls were 0.47 ( 0.31 to 0.70 ) , 0.49 ( 0.33 to 0.71 ) , 0.46 ( 0.30 to 0.73 ) and 0.49 ( 0.21 to 1.17 ) , respectively . When acquired , VT and antibiotic-resistant S. pneumoniae were carried for a significantly shorter period of time among siblings of PnCRM9 recipients than in siblings of controls . Conclusion . The marked effect of PnCRM9 administration to DCC attendees on carriage of VT and antibiotic-resistant S. pneumoniae among their younger household close contacts demonstrates a herd effect of the vaccine [15687432] Background . Limited effectiveness of current treatment strategies for recurrent acute otitis media ( RAOM ) and increasing antibiotic resistance have diverted attention to prevention of AOM by vaccination . Pneumococcal vaccination for AOM seems to have only modest clinical efficacy . Thus far , the effects on health-related quality of life ( HRQoL ) or functional health status ( FHS ) have not been studied . Objective . To assess the effect of vaccination on HRQoL or FHS . Methods . In a double-blind , r and omized , controlled trial , 383 children 1 to 7 years old with RAOM were vaccinated with either heptavalent pneumococcal conjugate vaccine followed by pneumococcal polysaccharide vaccine ( pneumococcal group : n = 190 ) or with hepatitis A or B vaccines ( control group : n = 193 ) . Parents completed vali date d Dutch versions of 8 HRQoL and FHS instruments assessing generic FHS ( R and , Functional Status Question naire specific , and Functional Status Question naire generic ) , otitis media – specific FHS ( OM-6 ) , otitis media – specific child HRQoL ( Numerical Rating Scale for Child ) , family functioning ( Family Functioning Question naire ) , and otitis media – specific caregiver HRQoL ( Numerical Rating Scale for Caregiver ) . Scores were compared at baseline and at 14 and 26 months ' follow-up . Results . At baseline , the average AOM incidence in the pneumococcal and control group was 5.0 ( SD : 2.8 ) and 4.9 ( SD : 2.6 ) episodes per year , respectively , with 38.4 % and 36.8 % having suffered from ≥6 episodes per year . AOM frequency decreased 4.4 episodes per year in both groups , with a considerable and comparable improvement in HRQoL and FHS . No substantial differences in HRQoL or FHS were found between the pneumococcal and the control group at baseline or at 14 or 26 months ' follow-up . Conclusion . Pneumococcal vaccination has no beneficial effect compared with control vaccination on either HRQoL or FHS in children 1 to 7 years old with RAOM [11172176] BACKGROUND Ear infections are a common cause of illness during the first two years of life . New conjugate vaccines may be able to prevent a substantial portion of cases of acute otitis media caused by Streptococcus pneumoniae . METHODS We enrolled 1662 infants in a r and omized , double-blind efficacy trial of a heptavalent pneumococcal polysaccharide conjugate vaccine in which the carrier protein is the nontoxic diphtheria-toxin analogue CRM197 . The children received either the study vaccine or a hepatitis B vaccine as a control at 2 , 4 , 6 , and 12 months of age . The clinical diagnosis of acute otitis media was based on predefined criteria , and the bacteriologic diagnosis was based on a culture of middle-ear fluid obtained by myringotomy . RESULTS Of the children who were enrolled , 95.1 percent completed the trial . With the pneumococcal vaccine , there were more local reactions than with the hepatitis B vaccine but fewer than with the combined whole-cell diphtheria-tetanus-pertussis and Haemophilus influenzae type b vaccine that was administered simultaneously . There were 2596 episodes of acute otitis media during the follow-up period between 6.5 and 24 months of age . The vaccine reduced the number of episodes of acute otitis media from any cause by 6 percent ( 95 percent confidence interval , -4 to 16 percent [ the negative number indicates a possible increase in the number of episodes ] ) , culture-confirmed pneumococcal episodes by 34 percent ( 95 percent confidence interval , 21 to 45 percent ) , and the number of episodes due to the serotypes contained in the vaccine by 57 percent ( 95 percent confidence interval , 44 to 67 percent ) . The number of episodes attributed to serotypes that are cross-reactive with those in the vaccine was reduced by 51 percent , whereas the number of episodes due to all other serotypes increased by 33 percent . CONCLUSIONS The heptavalent pneumococcal polysaccharide-CRM197 conjugate vaccine is safe and efficacious in the prevention of acute otitis media caused by the serotypes included in the vaccine [12799510] Background . In the developed societies , day-care centers ( DCCs ) play an important role in the spread of antibiotic-resistant pneumococci both within the facility and from the facility to the community . This study was conducted to determine the effect of a nonavalent pneumococcal conjugate vaccine ( PCV-9 ) on the carriage of antibiotic-resistant pneumococci in the DCC . Subjects and methods . Healthy DCC attendees ages 12 to 35 months were r and omized to receive either PCV-9 or a control vaccine ( conjugate meningococcus C vaccine ) in a double blinded manner . Nasopharyngeal Streptococcus pneumoniae cultures were obtained from each subject before vaccination , monthly during the first year of follow-up and every 2 to 3 months during the second year of follow-up . For each isolate the serotype and antibiotic susceptibility were determined Results . A total of 132 and 130 evaluable toddlers received either PCV-9 or the control vaccine , respectively . In total 3748 cultures were obtained , of which 2450 ( 65 % ) were positive for S. pneumoniae . The resistance rates to penicillin , trimethoprim-sulfamethoxazole and erythromycin were 36 , 35 and 16 % , respectively . Resistance rates to ≥1 and ≥3 antibiotic categories were 52 and 9 % , respectively . Antibiotic resistance was found mainly in the 5 serotypes included in the pneumococcal conjugate vaccines ( 6B , 9V , 14 , 19F and 23F ) and in 2 related serotypes ( 6A and 19A ) . In the vaccinated group a clear and significant reduction of the carriage rate of the serotypes included in the vaccine and the related serotype 6A as well as an increase in the carriage rate of the serotypes not included in the vaccine were observed . In parallel a significant decrease in carriage rate of antibiotic-resistant pneumococci was observed . The reduction of carriage of antibiotic-resistant pneumococci was seen in all age windows but was greater in the age window < 36 months . Conclusions . The carriage rate of antibiotic-resistant S. pneumoniae , including multiply resistant S. pneumoniae , in DCC attendees is high . Pneumococcal conjugate vaccines seem to be an important tool for reducing the carriage rate of antibiotic-resistant pneumonia in DCCs [10493334] OBJECTIVES The objectives of this study were ( 1 ) to determine the safety and immunogenicity of heptavalent pneumococcal CRM197 conjugate ( PNCRM7 ) vaccine in infants and ( 2 ) to determine the effect of concurrent hepatitis B immunization during the primary series and the effect of concurrent diphtheria and tetanus toxoid and acellular pertussis [ DTaP ( ACEL-IMUNE ) ] and conjugate CRM197 Haemophilus influenzae type b [ HbOC ( HibTITER ) immunization at time of the booster dose on the safety and immunogenicity of PNCRM7 and these other concurrently administered vaccines . METHODS This was a r and omized double-blinded study in 302 healthy infants in the Northern California Kaiser Permanente ( NCKP ) Health Plan . Infants received either PNCRM7 vaccine or meningococcal group C conjugate vaccine as a control at 2 , 4 and 6 months of age and a booster at 12 to 15 months of age . Study design permitted the evaluation of immunology and safety of concurrent administration of routine vaccines . Antibody titers were determined on blood sample s drawn before and 1 month after the primary series and the booster dose . RESULTS After the third dose of PNCRM7 geometric mean concentrations ( GMCs ) ranged from 1.01 for serotype 9V to 3.72 microg/ml for serotype 14 . More than 90 % of all subjects had a post-third dose titer of > or = 0.15 microg/ml for all serotypes , and the percentage of infants with a post-third dose titer of > or = 1.0 microg/ml ranged from 51 % for type 9V to 89 % for type 14 . After the PNCRM7 booster dose , the GMCs of all seven serotypes increased significantly over both post-Dose 3 and pre-Dose 4 antibody levels . In the primary series there were no significant differences in GMCs of pneumococcal antibodies between the subjects given PN-CRM7 alone or concurrently with hepatitis B vaccine . At the toddler dose concurrent administration of PNCRM7 and DTaP and HbOC result ed in a near conventional threshold for statistical significance of a post-Dose 4 GMC for serotype 23F [ alone 6.75 mirog/ml vs. concurrent 4.11 microg/ml ( P = 0.057 ) ] as well as significantly lower antibody GMCs for H. influenza polyribosylribitol phosphate , diphtheria toxoid , pertussis toxin and filamentous hemagglutinin . For all antigens there were no differences between study groups in defined antibody titers that are considered protective . CONCLUSION We conclude that PNCRM7 vaccine was safe and immunogenic . When this vaccine was administered concurrently at the booster dose with DTaP and HbOC vaccines , lower antibody titers were noted for some of the antigens when compared with the antibody response when PNCRM7 was given separately . Because the GMCs of the booster responses were all generally high and all subjects achieved similar percentages above predefined antibody titers , these differences are probably not clinical ly significant [16356598] This study assessed compatibility of concurrently administered 7-valent pneumococcal conjugate ( PCV7 ) , hepatitis B ( HB ) and DTaP.IPV/Hib vaccines . Infants were given DTaP.IPV/Hib and HB at 2 , 4 , 6 months and r and omly assigned ( 2:1 ) to receive PCV7 concurrently or sequentially ( at 3 , 5 , 7 months ) . Antibody levels were compared in 246 concurrent and 122 sequential vaccinees . Responses to PCV7 , DTaP.IPV/Hib and HB were generally unaltered with concurrent administration except that Hib responses were increased ( p=0.008 ) and HB responses were reduced ( p=0.006 ) with concurrent dosing , the latter possibly from same thigh injection with DTaP.IPV/Hib . We conclude that PCV7 , DTaP.IPV/Hib and HB are compatible with concurrent , separate injections [15295223] Background : The novel pneumococcal conjugate vaccine , PncCRM , has been shown to prevent acute otitis media caused by vaccine serotypes and to reduce otitis surgery . Our aim was to assess long term efficacy of the vaccine on tympanostomy tube placements . Methods : Children with complete follow-up in the Finnish Otitis Media Vaccine Trial up to 24 months of age and still living in the study area ( 1490 of 1662 r and omized at 2 months of age ) were invited to a single visit at 4–5 years of age . The children had been vaccinated at 2 , 4 , 6 and 12 months of age with PncCRM or hepatitis B vaccine ( control ) . Tympanostomy tube placements reported by parents at the visit were verified from hospital and private medical center records . Additionally , tympanostomy tube placements of all children were verified from the hospital discharge registry . Vaccine efficacy ( VE ) was estimated by comparing all events of tympanostomy tube placement between vaccine groups . Results : During the vaccine trial ( 2–24 months of age ) , VE ( 95 % confidence interval ) in preventing tympanostomy tube placement was only 4 % ( – 19–23 % ) . Altogether 756 children were enrolled for the follow-up study . After 24 months of age , the rate of surgery was 3.5 per 100 person-years in the PncCRM and 5.7 per 100 person-years in the control children , giving VE of 39 % ( 4–61 % ) . In the hospital-based data of all children ( N = 1490 ) , VE of 44 % was obtained ( 19–62 % ) . Conclusions : Receipt of PncCRM vaccine at infancy was associated with a reduction in tympanostomy tube placement from 2 to 4–5 years of age [15844075] INTRODUCTION Pneumococcal conjugate vaccine ( PnCV ) may be used as a probe to define the burden of pneumococcal disease and better characterize the clinical presentation of pneumococcal pneumonia . METHODS This study used a 9-valent PnCV to define different end points of vaccine efficacy and the preventable burden of pneumococcal pneumonia in 39,836 children who were r and omized in a double-blind , placebo-controlled trial in South Africa . RESULTS Whereas the point-estimate of vaccine efficacy was greatest when measured against the outcome of vaccine-serotype specific pneumococcal bacteremic pneumonia ( 61 % ; P = .01 ) , the sensitivity of blood culture to measure the burden of pneumococcal pneumonia prevented by vaccination was only 2.6 % in human immunodeficiency virus (HIV)-uninfected children and 18.8 % in HIV-infected children . Only 37.8 % of cases of pneumococcal pneumonia prevented by PnCV were detected by means of chest radiographs showing alveolar consolidation . A clinical diagnosis of pneumonia provided the best estimate of the burden of pneumococcal pneumonia prevented through vaccination in HIV-uninfected children ( 267 cases prevented per 100,000 child-years ) and HIV-infected children ( 2573 cases prevented per 100,000 child-years ) . CONCLUSION Although outcome measures with high specificity , such as bacteremic pneumococcal pneumonia , provide a better estimate as to vaccine efficacy , the burden of disease prevented by vaccination is best evaluated using outcome measures with high sensitivity , such as a clinical diagnosis of pneumonia [15243930] BACKGROUND For the licensing of new pneumococcal vaccines , it is vital to be able to predict their protective efficacy on the basis of immunogenicity . However , the serological correlates of protection have not been established for pneumococcal diseases . METHODS A total of 1666 children were immunized with the pneumococcal conjugate vaccine . Acute otitis media ( AOM ) events were identified , and middle-ear fluid was cultured for pneumococci . The association between the concentration of antibodies against serotypes 6B , 19F , and 23F and the risk of AOM caused by the homologous serotypes or by the cross-reactive serotype 6A was assessed . An association model was used to predict efficacy at different geometric mean concentrations ( GMCs ) . RESULTS An association between antibody concentration and risk of AOM was found , but with large differences between serotypes . On the basis of the association , the predicted efficacy for 19F was negligible up to the highest GMC tested . In contrast , 6B was found to be highly efficacious ( > 65 % ) at a GMC of 0.5 microg/mL. CONCLUSIONS The results challenge the view that a new vaccine c and i date should always induce antibody concentrations that are not inferior to those produced by the licensed vaccine . Furthermore , the differences between serotypes caution against defining a common correlate of protection that is applicable to all serotypes [12922095] To evaluate immune responses , safety and reactogenicity of the concomitant use of DTaP-IPV-Hib and the newly available 7-valent pneumococcal conjugate ( 7VPnC ) vaccines when given as the primary immunization series in early infancy . A total of 231 healthy infants were enrolled at 11 German study centers and r and omized to receive either 7VPnC plus DTaP-IPV-Hib vaccines concomitantly into opposite limbs at age 2 , 3 , 4 and 11 - 15 months ( 7VPnC group ) or DTaP-IPV-Hib vaccine at the same ages plus a 7VPnC " catch-up vaccination " at ages 6 , 7 , 8 and 11 - 15 months ( Control group ) . Blood sample s were drawn before and 4 weeks after the first three vaccine doses and 4 weeks after the fourth dose . Local and general side effects ( i.e. safety ) were solicited by diary cards . Immune responses were determined by ELISA except for antibodies to polioviruses ( neutralization assay ) . Post-dose 3 , a significant antibody response against all seven pneumococcal vaccine-serotypes was observed in the 7VPnC group only . Post-dose 4 geometric mean concentrations ( GMCs ) were similar in both groups . GMCs for other vaccine antigens were comparable between groups except for diphtheria ( higher in the 7VPnC group ) and pertactin ( lower in the 7VPnC group ) , although after three vaccine doses there was a 28-fold rise in GMCs from baseline . Both vaccines were generally well-tolerated although there were minor differences in the frequency of local reactions and somewhat more fever or drowsiness in the 7VPnC group . The use of DTaP-IPV-Hib and the 7VPnC vaccine was safe , well-tolerated and immunogenic when given concomitantly at age 2 , 3 and 4 months or when given separately with 7VPnC as a catch-up vaccination at age 6 , 7 , 8 months and as a concomitant booster immunization at age 11 - 15 months [11920317] A double-blind , r and omized study involving 264 toddlers attending day care centers was conducted to document the effect of a 9-valent pneumococcal conjugate vaccine on the carriage rate of pneumococci . Of 3750 cultures done on nasopharyngeal sample s obtained from subjects during a 2-year follow-up period after vaccination , 65 % were positive for Streptococcus pneumoniae . In all age windows , the rate of carriage of vaccine-type pneumococci was lower among subjects who received the pneumococcal vaccine than among control subjects , because the acquisition rate was lower in the former group . The effect was most pronounced among subjects aged < or = 36 months . The sample size enabled us to study protection against carriage of S. pneumoniae serotypes 6B , 9V , 14 , 19F , and 23F ; significant protection against all serotypes except 19F was seen in the pneumococcal-vaccine group . The rate of carriage of serotype 6A ( not included in the vaccine ) was also reduced significantly , but the rate of carriage of serotype 19A ( not included in the vaccine ) was not . The rate of carriage of non-vaccine-type pneumococci ( excluding serotype 6A ) was higher in the pneumococcal-vaccine group than in the control group [16140397] BACKGROUND Based on two clinical trials in healthy infants the American Academy of Pediatrics ( AAP ) advices immunization with a 7-valent pneumococcal conjugate vaccine in children with recurrent acute otitis media ( AOM ) . OBJECTIVE To study the efficacy of a 7-valent pneumococcal conjugate vaccine on acute otitis media recurrences , its immunogenicity and impact on nasopharyngeal Streptococcus pneumoniae carriage in children with a history of frequent acute otitis media . METHODS In this double-blind , r and omized study , 74 Belgian children , aged 1 - 7 years , with at least 2 clinical ly diagnosed episodes of acute otitis media in the previous year were enrolled . Children were immunized with either a 7-valent pneumococcal conjugate vaccine followed by a 23-valent pneumococcal polysaccharide booster or a control hepatitis A vaccine . Total follow-up was 26 months . RESULTS Despite adequate serum IgG responses to all conjugate vaccine pneumococcal serotypes , no reduction of acute otitis media episodes was observed in the pneumococcal vaccine group as compared to the control group ( rate ratio : 1.16 ; 95 % CI : 0.69 - 1.96 ) . Overall nasopharyngeal pneumococcal carriage remained stable . However , a transient shift from conjugate vaccine related S. pneumoniae serogroups to non-vaccine related serogroups was noted following conjugate vaccination . CONCLUSION Clinical ly no protective effect of pneumococcal conjugate vaccination on acute otitis media recurrences was found in children with a history of frequent AOM [14557958] To assess the efficacy of a 7-valent pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine ( PncOMPC ) against acute otitis media ( AOM ) , 1666 infants were r and omly assigned to receive either PncOMPC or control vaccine ( hepatitis B vaccine ) at 2 , 4 , 6 , and 12 months of age . Of the 835 children assigned to receive PncOMPC , 187 received a 23-valent pneumococcal polysaccharide vaccine ( PncPS ) at 12 months of age instead . Whenever AOM was diagnosed , middle ear fluid was aspirated for bacterial culture . In the PncOMPC and control groups , there were 110 and 250 AOM episodes , respectively , in children between 6.5 and 24 months of age that could be attributed to vaccine serotypes , which indicates a vaccine efficacy of 56 % ( 95 % confidence interval , 44%-66 % ) . The serotype-specific efficacy ranged from 37 % for 19F to 82 % for 9V . The 2 boosters seemed to provide equal protection against AOM , but PncPS induced markedly higher antibody concentrations . The efficacy of PncOMPC was comparable to that of the recently licensed pneumococcal conjugate vaccine [12706674] OBJECTIVE To evaluate the safety and immunogenicity of two lots of a heptavalent Streptococcus pneumoniae conjugate vaccine ( PCV ) containing seven capsular polysaccharide serotypes ( 4 , 6B , 9V , 14 , 18C , 19F , and 23F ) conjugated to the outer membrane complex of Neisseria meningitidis serogroup B ( OMPC ) and administered to infants at 2 , 4 , 6 , and 12 months of age . METHODS One hundred twenty infants were r and omly assigned to concurrently receive PCV-OMPC and one of two Haemophilus influenzae type b ( Hib ) conjugate-DTwP combination vaccines : ( 1 ) Hib with a heterologous protein carrier ( CRM(197 ) , TETRAMUNE , Group 1 ) or ( 2 ) an experimental Hib-hepatitis b combination vaccine with the homologous carrier ( OMPC , Group 2 ) . All infants in Groups 1 and 2 received PCV-OMPC ( lot 1 ) at 12 months of age . Another separate group of 120 infants ( Group 3 ) received a different lot of PCV-OMPC concurrently with Hib-CRM(197 ) ( TETRAMUNE ) at 2 , 4 , and 6 months of age and then were r and omized to receive either PCV-OMPC or a 23-valent polysaccharide ( PS ) pneumococcal vaccine at 12 months of age . RESULTS Each PCV-OMPC lot was generally well tolerated and no vaccine-related serious adverse events were reported . Following the primary series , serotype-specific anti-pneumococcal geometric mean concentrations ( GMC ) were highest for serotypes 14 , 19F , and 4 and lowest for serotypes 6B and 23F . GMC and seroconversion rates in Group 3 ( lot 2 ) were lower than in Group 1 ( lot 1 ) for serotypes 6B , 14 , 18C , and 23F . Antibody responses to serotypes 6B , 14 , and 18C were significantly lower in Group 2 compared to Group 1 . Following a booster dose of PCV-OMPC at 12 months of age , each lot was immunogenic with at least a 5 - 10-fold increase in antibody levels , and responses were significantly higher among those who received the PS vaccine . CONCLUSIONS PCV-OMPC is generally safe in infants , displays variable immune response by serotype , and concomitant receipt of Hib vaccine with homologous carrier may impact on its immunogenicity Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Advantages to combining childhood vaccines include reducing the number of visits , injections and patient discomfort , increasing compliance and optimising prevention . The World Health Organization ( WHO ) recommends that routine infant immunisation programmes include a vaccination against Haemophilus influenzae ( H. influenzae ) type B ( HIB ) in the combined diphtheria-tetanus-pertussis (DTP)-hepatitis B virus ( HBV ) vaccination . The effectiveness and safety of the combined vaccine should be carefully and systematic ally assessed to ensure its acceptability by the community . OBJECTIVES To compare the effectiveness of combined DTP-HBV-HIB vaccines versus combined DTP-HBV and separate HIB vaccinations . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

19588341

[17596471] It is recognized that women with gestational diabetes mellitus ( GDM ) who have significantly elevated fasting blood glucose levels are at increased risk for fetal macrosomia and perinatal morbidity if treatment is not provided ( 1,2 ) . The association of milder forms of GDM with perinatal morbidity and mortality remains unclear , primarily because the condition is often confounded with other risk factors such as maternal obesity , age , and parity . Screening for GDM is recommended for most pregnant women , yet it is unknown whether there is a benefit to the identification and treatment of mild carbohydrate intolerance during pregnancy ( 3,4 ) . The present report is an up date of our previous description of a current ongoing r and omized treatment trial for mild GDM ( 5 ) . A r and omized clinical trial of women with mild GDM ( fasting glucose < 95 mg/dl ) is being undertaken that compares perinatal outcomes in those receiving diet therapy and insulin as required versus those r and omized to no specific treatment . This study aims to clarify whether there is utility in identifying and treating women with a normal fasting glucose level who meet st and ard criteria for GDM . We plan to compare perinatal outcomes in women who have been r and omized to diet and /or insulin therapy with women who have been r and omized to no specific treatment . A r and omized treatment trial of mild GDM will clarify whether identification and treatment of mild GDM reduce perinatal morbidity . This information will assist in determining appropriate thresholds for the treatment of GDM . Overall , with broader identification and aggressive treatment , perinatal mortality rates associated with GDM appear to be similar to the nondiabetic population ( 1 ) . Several analyses of 20 years ago did document an increased stillbirth rate for GDM pregnancies that would qualify as preexisting diabetes according to World Health Organization criteria ( 6–9 ) . Below this threshold , the extent to [21083860] Please cite this paper as : Ijäs H , Vääräsmäki M , Morin‐Papunen L , Keravuo R , Ebeling T , Saarela T , Raudaskoski T. Metformin should be considered in the treatment of gestational diabetes : a prospect i ve r and omised study . BJOG 2011;118:880–885 [12073958] PURPOSE The purpose of this study was to examine the effects of self-monitoring of blood glucose ( SMBG ) on feelings of self-efficacy , dietary compliance , and pregnancy outcomes in women with diet-controlled gestational diabetes mellitus ( GDM ) . METHODS Fifty-eight women with GDM and a fasting blood glucose level < 95 mg/dL were r and omly assigned to 2 groups . The experimental group measured their blood glucose levels 4 times daily using a reflectance meter with memory . Metabolic status was assessed in the control group by periodic monitoring at prenatal visits . Otherwise the management protocol was identical for both groups . The Diabetes Empowerment Scale was completed at study entry and at 37 weeks gestation to assess feelings of self-efficacy . Dietary compliance was assessed at each visit . RESULTS Both groups of women achieved excellent glucose control ; only 1 woman in each group required insulin therapy . There were no significant differences with regard to feelings of self-efficacy , dietary compliance , birth weight , gestational age at delivery , Apgar scores , and neonatal complications . Rates of macrosomia , delivery by cesarean section , and occurrence of birth trauma were similar . CONCLUSIONS SMBG appears to have little effect on maternal feelings of self-efficacy , dietary compliance , or pregnancy outcomes in women with diet-controlled GDM [8950733] The aim of this study was to determine whether amniotic fluid insulin concentration ( AFI ) is a better parameter than mean maternal blood glucose values ( MBG ) for deciding about insulin therapy in patients with gestational diabetes . MBG 's were calculated on the base of 9 blood glucose levels during a 24 hour period after one week of diet therapy . In a prospect i ve trial between 1987 and 1989 in Karlsburg , 123 gestational diabetic patients were r and omized into two groups . Treatment was either based on the concentration of AFI or MBG levels . In a second series in Berlin , 103 patients were offered amniocentesis . 81 patients agreed and 22 refused . Treatment was then analogous to that in Karlsburg . In both groups of the r and omized population , strict metabolic control was achieved . There was no difference regarding pregnancy complications . Earlier labor induction and higher cesarean section rates were seen in the non-invasive group ( p < 0.05 ) . The incidence of diabetic fetopathy and neonatal hypoglycemia was significantly lower in the invasive group ( p < 0.01 ) , even though the metabolic control parameters did not differ between the two groups . The results in Berlin correspond to these findings . In conclusion , AFI enables the recognition of any hyperinsulinism reaction to the maternal metabolic situation . We recommend the additional measurement of the AFI concentration between 28 and 36 weeks as the direct fetal parameter for deciding about insulin treatment [3311138] The study was design ed to identify those pregnant women who are diagnosed as having gestational diabetes by National Diabetes Data Group ( NDDG ) criteria , but normal glucose tolerance ( NGT ) or impaired glucose tolerance ( IGT ) by the World Health Organization ( WHO ) criteria , and to test whether treatment changed the perinatal outcome in those with NGT and IGT . The 216 women with an abnormal 100 g oral glucose tolerance test ( OGTT ) using NDDG criteria were subjected to a 75 g OGTT . Using the WHO criteria , 111 women ( 51 % ) had NGT , 98 ( 45 % ) had IGT and 7 ( 3 % ) had frank diabetes mellitus . Those with NGT and IGT were r and omized into control and treatment groups . The perinatal outcome in these two groups was comparable whether the NGT and IGT groups were analysed together or separately except , that in those who were treated for IGT , smaller babies were born one week earlier than in the control group ( 3407 g vs 3110 g , P less than 0.01 ) . This suggests that the WHO criteria can safely replace the 100 g OGTT with substantial savings in manpower , money and patients ' time [2121124] Aim The efficacy and safety of insulin aspart ( IAsp ) , a rapid-acting human insulin analogue , were compared with regular human insulin ( HI ) as the bolus component of basal-bolus therapy for subjects with gestational diabetes mellitus ( GDM ) . Methods In a r and omized , parallel-group , open-labelled trial , 27 women with GDM ( age 30.7 ± 6.3 years , HbA1c < 7 % ) were r and omized to receive IAsp ( 5 min before meal ) or HI ( 30 min before meal ) . The trial period extended from diagnosis of GDM ( 18–28 weeks ) to 6 weeks postpartum . Results Both treatment groups maintained good overall glycaemic control during the study ( beginning and end of study HbA1c≤ 6 % ) . During the meal test , mean glucose at week 6 ( IAsp 4.2 ± 0.57 mmol/l , HI 4.8 ± 0.86 mmol/l ) was slightly lower than at week 0 ( IAsp 4.9 ± 0.59 mmol/l , HI 5.1 ± 0.36 mmol/l ) . However , change from baseline values for average glucose ( IAsp –1.09 ± 0.54 mmol/l , HI –0.54 ± 0.74 mmol/l ; P = 0.003 ) and C-peptide ( IAsp –0.50 ± 0.67 nmol/l , HI –0.30 ± 0.70 nmol/l ; P = 0.027 ) were significantly lower after IAsp treatment than HI treatment . No major hypoglycaemic events were reported during the study . Cross-reacting insulin antibody binding increased slightly from baseline in both treatments groups ( end of study : IAsp 2.1 ± 5.4 % , HI 6.4 ± 13.9 % ) , whereas antibodies specific to IAsp or HI remained relatively low ( < 1 % binding ) . Conclusion IAsp was more effective than HI in decreasing postpr and ial glucose concentrations . Duration of IAsp injection 5 min before a meal rather than 30 min prior to meals offers a more convenient therapy for subjects with GDM . Overall safety and effectiveness of IAsp were comparable to HI in pregnant women with GDM . Diabet . Med . 24 , 1129–1135 ( 2007 [1865537] Background Mild gestational diabetes is a common complication of pregnancy , affecting up to 9 % of pregnant women . Treatment of mild GDM is known to reduce adverse perinatal outcomes such as macrosomia and associated birth injuries , such as shoulder dystocia , bone fractures and nerve palsies . This study aim ed to compare the plasma glucose concentrations and serum insulin , leptin and adiponectin in cord blood of babies of women ( a ) without gestational diabetes mellitus ( GDM ) , ( b ) with mild GDM under routine care , or ( c ) mild GDM with treatment . Methods 95 women with mild GDM on oral glucose tolerance testing ( OGTT ) at one tertiary level maternity hospital who had been recruited to the ACHOIS trial at one of the collaborating hospitals and r and omised to either Treatment ( n = 46 ) or Routine Care ( n = 49 ) and Control women with a normal OGTT ( n = 133 ) were included in the study . Women with mild GDM ( treatment or routine care group ) and OGTT normal women received routine pregnancy care . In addition , women with treated mild GDM received dietary advice , blood glucose monitoring and insulin if necessary . The primary outcome measures were cord blood concentrations of glucose , insulin , adiponectin and leptin . Results Cord plasma glucose was higher in women receiving routine care compared with control , but was normalized by treatment for mild GDM ( p = 0.01 ) . Cord serum insulin and insulin to glucose ratio were similar between the three groups . Leptin concentration in cord serum was lower in GDM treated women compared with routine care ( p = 0.02 ) and not different to control ( p = 0.11 ) . Adiponectin was lower in both mild GDM groups compared with control ( Treatment p = 0.02 and Routine Care p = 0.07 ) , while the adiponectin to leptin ratio was lower for women receiving routine care compared with treatment ( p = 0.08 ) and control ( p = 0.05 ) . Conclusion Treatment of women with mild GDM using diet , blood glucose monitoring and insulin if necessary , influences the altered fetal adipoinsular axis characteristic of mild GDM in pregnancy [9240606] OBJECTIVES The purpose of this study was to determine whether strict maternal glycemic control for the treatment of gestational diabetes lessened the risk of fetal macrosomia , birth trauma , neonatal hypoglycemia , and operative delivery . The aim of the pilot study was to prepare for a multicenter trial by assessing patient acceptance of the study , by determining realistic accrual rates , and by detecting any major adverse outcomes in the control group that received routine obstetric care . STUDY DESIGN The study was a prospect i ve r and omized controlled trial comparing fetal-neonatal and maternal outcomes in 300 women with gestational diabetes . Women r and omized to the treatment arm were managed by strict glycemic control and tertiary level obstetric care , and women in the control arm received routine obstetric care . RESULTS Three hundred women with gestational diabetes mellitus were studied . There was no difference in maternal age , weight , or length of gestation between groups . The treatment mean birth weight was 3437 + /- 575 gm compared with 3544 + /- 601 gm in the control group , a difference of 107 gm ( not significant ) . Macrosomia rates were similar . There was no birth trauma in either group . The frequency of neonatal hypoglycemia and other metabolic complications was the same . The mode of delivery also showed similar patterns . The treatment group had significantly lower prepr and ial and postpr and ial glucose levels by 32 weeks ' gestation , which continued to term . CONCLUSION This pilot study suggests that intensive treatment of gestational diabetes mellitus may have little effect on birth weight , birth trauma , operative delivery , or neonatal metabolic disorders . It has demonstrated the safety of proceeding to a multicenter trial of sufficient sample size to confirm these findings [19747869] AIM The significant deterioration of insulin sensitivity and glucose tolerance during pregnancy can have serious health implication s for both the pregnant woman and her baby . Although it is well established that regular exercise benefits insulin sensitivity in the nonpregnant population , the effect on glucose tolerance in obese pregnant women is not known . The purpose of this study was to investigate the effect of a supervised 10-week , home-based , exercise programme , beginning at week 18 of gestation , on glucose tolerance and aerobic fitness in previously sedentary obese women . METHODS Twelve sedentary obese women were r and omized into an exercise ( EX ; n=6 ) or control ( CON ; n=6 ) group at 18 weeks of gestation . Those r and omized to EX engaged in 10 weeks of supervised home-based exercise ( three sessions a week of stationary cycling ) , while those in the CON group maintained their usual daily activity . Their glucose and insulin responses to an oral glucose tolerance test ( OGTT ) , as well as their aerobic fitness , were assessed both pre- and postintervention . RESULTS Reduced glucose tolerance in the CON , but not EX , group was indicated by a tendency postintervention towards higher blood glucose levels at 1h of the OGTT ( P=0.072 ) . Furthermore , at 2h of the postintervention OGTT , blood glucose tended to remain elevated from baseline in the CON ( P=0.077 ) . There was also a trend towards increased fitness in the EX ( P=0.064 ) , but not the CON group . CONCLUSION Regular aerobic exercise begun during pregnancy may have favourable effects on glucose tolerance and fitness in obese women , and warrants further investigation in a larger sample population [9579452] OBJECTIVES Replacement of the two-step , 100 gm , 3-hour National Diabetes Data Group procedure by the one-step , 75 gm , 2-hour World Health Organization oral glucose tolerance test has been hindered by a paucity of data comparing the two tests during pregnancy . The current series compared 100 gm and 75 gm glucose loads and glucose measurements in venous plasma or capillary blood . STUDY DESIGN After a 75 gm oral glucose tolerance test 30 gestational diabetics and 30 metabolically healthy pregnant women were r and omly assigned to a second 75 or 100 gm test within 3+/-1.3 ( mean+/-SD ) days . Glucose levels at both tests was measured in capillary blood and venous plasma , as were insulin and C peptide . RESULTS In controls 1-hour maternal glucose levels ( 112 vs 128 mg/dl ) and 2-hour levels ( 104 vs 113 mg/dl ) differed significantly after a 75 or 100 gm load ( paired t test ) . In gestational diabetes mellitus , however , there was no difference ( 176 vs 178 mg/dl ) but a low insulin/glucose quotient at 1 hour . Only 2-hour levels differed significantly ( 133 vs 149 mg/dl ) . In controls glucose measurement in capillary blood and venous plasma differed significantly at 1 hour ( 126 vs 115 mg/dl ) and 2 hours ( 111 vs 104 mg/dl ) independently of the glucose load . In gestational diabetes mellitus , however , glucose measurement in capillary blood and venous plasma differed neither in 1-hour levels ( 179 vs 174 mg/dl ) nor in 2-hour levels ( 142 vs 139 mg/dl ) . CONCLUSION In metabolically healthy women both different loading and different blood fractions lead to statistically different blood glucose levels at 1 and 2 hours . In gestational diabetes mellitus , however , 1-hour glucose levels do not differ after a 75 or 100 gm load or after glucose measurement in capillary blood or venous plasma . This is due to elevated insulin resistance shown by a low insulin/glucose quotient at 1 hour . For comparison of tests in gestational diabetes mellitus only , 2-hour values must be adjusted by 16 mg/dl after different loading [2797992] OBJECTIVE To determine how glucose control in women with GDM treated with metformin and /or insulin influenced pregnancy outcomes . RESEARCH DESIGN AND METHODS Women r and omly assigned to metformin or insulin treatment in the Metformin in Gestational Diabetes ( MiG ) trial had baseline glucose tolerance test ( OGTT ) results and A1C documented , together with all capillary glucose measurements during treatment . In the 724 women who had glucose data for analysis , tertiles of baseline glucose values and A1C and of mean capillary glucose values during treatment were calculated . The relationships between maternal factors , glucose values , and outcomes ( including a composite of neonatal complications , preeclampsia , and large-for-gestational-age [ LGA ] and small-for-gestational-age infants ) were examined with bivariable and multivariate models . RESULTS Baseline OGTT did not predict outcomes , but A1C predicted LGA infants ( P = 0.003 ) . During treatment , fasting capillary glucose predicted neonatal complications ( P < 0.001 ) and postpr and ial glucose predicted preeclampsia ( P = 0.016 ) and LGA infants ( P = 0.001 ) . Obesity did not influence outcomes , and there was no interaction between glycemic control , r and omized treatment , or maternal BMI in predicting outcomes . The lowest risk of complications was seen when fasting capillary glucose was < 4.9 mmol/l ( mean ± SD 4.6 ± 0.3 mmol/l ) compared with 4.9–5.3 mmol/l or higher and when 2-h postpr and ial glucose was 5.9–6.4 mmol/l ( 6.2 ± 0.2 mmol/l ) or lower . CONCLUSIONS Glucose control in women with gestational diabetes mellitus treated with metformin and /or insulin is strongly related to outcomes . Obesity is not related to outcomes in this group . Targets for fasting and postpr and ial capillary glucose may need to be lower than currently recommended [15951574] BACKGROUND We conducted a r and omized clinical trial to determine whether treatment of women with gestational diabetes mellitus reduced the risk of perinatal complications . METHODS We r and omly assigned women between 24 and 34 weeks ' gestation who had gestational diabetes to receive dietary advice , blood glucose monitoring , and insulin therapy as needed ( the intervention group ) or routine care . Primary outcomes included serious perinatal complications ( defined as death , shoulder dystocia , bone fracture , and nerve palsy ) , admission to the neonatal nursery , jaundice requiring phototherapy , induction of labor , cesarean birth , and maternal anxiety , depression , and health status . RESULTS The rate of serious perinatal complications was significantly lower among the infants of the 490 women in the intervention group than among the infants of the 510 women in the routine-care group ( 1 percent vs. 4 percent ; relative risk adjusted for maternal age , race or ethnic group , and parity , 0.33 ; 95 percent confidence interval , 0.14 to 0.75 ; P=0.01 ) . However , more infants of women in the intervention group were admitted to the neonatal nursery ( 71 percent vs. 61 percent ; adjusted relative risk , 1.13 ; 95 percent confidence interval , 1.03 to 1.23 ; P=0.01 ) . Women in the intervention group had a higher rate of induction of labor than the women in the routine-care group ( 39 percent vs. 29 percent ; adjusted relative risk , 1.36 ; 95 percent confidence interval , 1.15 to 1.62 ; P<0.001 ) , although the rates of cesarean delivery were similar ( 31 percent and 32 percent , respectively ; adjusted relative risk , 0.97 ; 95 percent confidence interval , 0.81 to 1.16 ; P=0.73 ) . At three months post partum , data on the women 's mood and quality of life , available for 573 women , revealed lower rates of depression and higher scores , consistent with improved health status , in the intervention group . CONCLUSIONS Treatment of gestational diabetes reduces serious perinatal morbidity and may also improve the woman 's health-related quality of life [2681032] OBJECTIVE A low – glycemic index diet is effective as a treatment for individuals with diabetes and has been shown to improve pregnancy outcomes when used from the first trimester . A low – glycemic index diet is commonly advised as treatment for women with gestational diabetes mellitus ( GDM ) . However , the efficacy of this advice and associated pregnancy outcomes have not been systematic ally examined . The purpose of this study was to determine whether prescribing a low – glycemic index diet for women with GDM could reduce the number of women requiring insulin without compromise of pregnancy outcomes . RESEARCH DESIGN AND METHODS All women with GDM seen over a 12-month period were considered for inclusion in the study . Women ( n = 63 ) were r and omly assigned to receive either a low – glycemic index diet or a conventional high-fiber ( and higher glycemic index ) diet . RESULTS Of the 31 women r and omly assigned to a low – glycemic index diet , 9 ( 29 % ) required insulin . Of the women r and omly assigned to a higher – glycemic index diet , a significantly higher proportion , 19 of 32 ( 59 % ) , met the criteria to commence insulin treatment ( P = 0.023 ) . However , 9 of these 19 women were able to avoid insulin use by changing to a low – glycemic index diet . Key obstetric and fetal outcomes were not significantly different . CONCLUSIONS Using a low – glycemic index diet for women with GDM effectively halved the number needing to use insulin , with no compromise of obstetric or fetal outcomes [18161398] OBJECTIVE To compare glycemic control and neonatal outcomes in women with gestational diabetes mellitus ( GDM ) treated with metformin vs. insulin . STUDY DESIGN Women with GDM not controlled with diet and exercise were r and omized to metformin ( n = 32 ) or insulin ( n = 31 ) . The levels of glycemic control as well as maternal/neonatal complications were evaluated . RESULTS The mean ( + /- SD ) fasting and 2-hour postpr and ial blood glucose did not differ statistically between the 2 treatment groups . No patient failed metformin and required insulin . The majority ( 27/32 ) were easily controlled on the initial dosage ( 500 mg twice a day ) . Gestational age at entry and delivery ( p = 0.077 , 0.412 ) were similar . The difference in the rate of cesarean delivery was not statistically significant between the 2 groups ( p = 0.102 ) . Neonatal statistics were also not different between the metformin and insulin groups : birth weight , Apgar score at 5 minutes , respiratory distress syndrome , hyperbilirubinemia , neonatal hypoglycemia and neonatal intensive care unit admission ( p = 0.144 - 0.373 ) . CONCLUSION Based on these preliminary data , metformin appears to be an effective alternative to insulin in the treatment of GDM [2241640] Background Recommended best practice is that economic evaluation of health care interventions should be integral with r and omised clinical trials . We performed a cost-consequence analysis of treating women with mild gestational diabetes mellitus by dietary advice , blood glucose monitoring and insulin therapy as needed compared with routine pregnancy care , using patient-level data from a multi-centre r and omised clinical trial . Methods Women with a singleton pregnancy who had mild gestational diabetes diagnosed by an oral glucose-tolerance test between 24 and 34 weeks ' gestation and their infants were included . Clinical outcomes and outpatient costs derived from all women and infants in the trial . Inpatient costs derived from women and infants attending the hospital contributing the largest number of enrolments ( 26.1 % ) , and charges to women and their families derived from a sub sample of participants from that hospital ( in 2002 Australian dollars ) . Occasions of service and health outcomes were adjusted for maternal age , ethnicity and parity . Analysis of variance was used with bootstrapping to confirm results . Primary clinical outcomes were serious perinatal complications ; admission to neonatal nursery ; jaundice requiring phototherapy ; induction of labour and caesarean delivery . Economic outcome measures were outpatient and inpatient costs , and charges to women and their families . Results For every 100 women with a singleton pregnancy and positive oral glucose tolerance test who were offered treatment for mild gestational diabetes mellitus in addition to routine obstetric care , $ 53,985 additional direct costs were incurred at the obstetric hospital , $ 6,521 additional charges were incurred by women and their families , 9.7 additional women experienced induction of labour , and 8.6 more babies were admitted to a neonatal nursery . However , 2.2 fewer babies experienced serious perinatal complication and 1.0 fewer babies experienced perinatal death . The incremental cost per additional serious perinatal complication prevented was $ 27,503 , per perinatal death prevented was $ 60,506 and per discounted life-year gained was $ 2,988 . Conclusion It is likely that the general public in high-income countries such as Australia would find reductions in perinatal mortality and in serious perinatal complications sufficient to justify additional health service and personal monetary charges . Over the whole lifespan , the incremental cost per extra life-year gained is highly favourable . Trial Registration Australian Clinical Trials Registry [17721753] This study discusses two main questions : the direct medical costs and the clinical effectiveness of the hospital treatment with insulin of pregnant women with gestational diabetes ( GD ) . A prospect i ve study that includes 50 women with GD is performed . The pregnant women are divided into 2 groups : Group I ( n=30 ) — pregnant women treated only with a diet ; and Group II ( n=20 ) — pregnant women treated with diet and insulin . We found that the metabolite compensation degree is improved after the applied treatment with insulin . The coefficient cost/effectiveness is 6954 lv./100 women . The analysis decision tree confirms in a very convenient way the fact that insulin treatment is a clinical ly more effective and financially more profitable strategy [15672015] OBJECTIVE We sought to investigate the association between glyburide dose , degree of severity in gestational diabetes mellitus ( GDM ) , level of glycemic control , and pregnancy outcome in insulin- and glyburide-treated patients . STUDY DESIGN In a secondary analysis of our previous r and omized study , 404 women were analyzed . The association among glyburide dose , severity of GDM , and selected maternal and neonatal factors was evaluated . Severity levels of GDM were stratified by fasting plasma glucose ( FPG ) from the oral glucose tolerance test ( OGTT ) . Infants with birth weight at or above the 90th percentile were considered large-for-gestational age ( LGA ) . Macrosomia was defined as birth weight > or = 4000 g. Well-controlled was defined as mean blood glucose < or = 95 mg/dL. The association between glyburide- and insulin-treated patients by severity of GDM and neonatal outcome was evaluated . RESULTS The dose received for the glyburide-treated patients was 2.5 mg-32 % ; 5 mg-23 % ; 10 mg-17 % ; 15 mg-8 % ; and 20 mg-20 % . Patients were grouped into low ( < or = 10 mg ) and high ( > 10 mg ) daily dose of glyburide . A comparison between severity of the disease ( fasting plasma glucose categories ) and highest dose of glyburide revealed a significant difference between the low-95 FPG and the other severity categories ( P = .02 ) . Of patients in the well-controlled glycemic group , only 6 % required the high dose of glyburide ( > 10 mg ) . In patients with poor glycemic control ( mean blood glucose > 95 mg/dL ) , 38 % received the high dose of glyburide ( P = .0001 ) . Comparison between the high glyburide ( > 10 mg ) and the low glyburide dosages ( < or = 10 mg ) revealed that the rate of macrosomia was 16 % vs 5 % and LGA 22 % vs 8 % , ( P = .01 ) , respectively . No significant difference was found in composite outcome , metabolic complications , and Ponderal Index between the 2 dose groups . Stratification by disease severity revealed a significantly lower rate of LGA for both the glyburide- and insulin-treated subjects . No significant difference was found between metabolic , respiratory , and neonatal intensive care unit ( NICU ) for patients within each fasting plasma glucose severity category . CONCLUSION Glyburide and insulin are equally efficient for treatment of GDM in all levels of disease severity . Achieving the established level of glycemic control , not the mode of pharmacologic therapy , is the key to improving the outcome in GDM [11679455] OBJECTIVE To compare management based on maternal glycemic criteria with management based on relaxed glycemic criteria and fetal abdominal circumference ( AC ) measurements in order to select patients for insulin treatment of gestational diabetes mellitus ( GDM ) with fasting hyperglycemia . RESEARCH DESIGN AND METHODS In a pilot study , 98 women with fasting plasma glucose ( FPG ) concentrations of 105 - 120 mg/dl were r and omized . The st and ard group received insulin treatment . The experimental group received insulin if the AC , measured monthly , was > or = 70th percentile and /or if any venous FPG measurement was > 120 mg/dl . Power was projected to detect a 250-g difference in birth weights . RESULTS Gestational ages , maternal glycemia , and AC percentiles were similar at r and omization . After initiation of protocol , venous FPG ( P = 0.003 ) and capillary blood glucose levels ( P = 0.049 ) were significantly lower in the st and ard group . Birth weights ( 3,271 + /- 458 vs. 3,369 + /- 461 g ) , frequencies of birth weights > 90th percentile ( 6.3 vs 8.3 % ) , and neonatal morbidity ( 25 vs. 25 % ) did not differ significantly between the st and ard and experimental groups , respectively . The cesarean delivery rate was significantly lower ( 14.6 vs. 33.3 % , P = 0.03 ) in the st and ard group ; this difference was not explained by birth weights . In the experimental group , infants of women who did not receive insulin had lower birth weights than infants of mothers treated with insulin ( 3,180 + /- 425 vs. 3,482 + /- 451 g , P = 0.03 ) . CONCLUSIONS In women with GDM and fasting hyperglycemia , glucose plus fetal AC measurements identified pregnancies at low risk for macrosomia and result ed in the avoidance of insulin therapy in 38 % of patients without increasing rates of neonatal morbidity [18463376] BACKGROUND Metformin is a logical treatment for women with gestational diabetes mellitus , but r and omized trials to assess the efficacy and safety of its use for this condition are lacking . METHODS We r and omly assigned 751 women with gestational diabetes mellitus at 20 to 33 weeks of gestation to open treatment with metformin ( with supplemental insulin if required ) or insulin . The primary outcome was a composite of neonatal hypoglycemia , respiratory distress , need for phototherapy , birth trauma , 5-minute Apgar score less than 7 , or prematurity . The trial was design ed to rule out a 33 % increase ( from 30 % to 40 % ) in this composite outcome in infants of women treated with metformin as compared with those treated with insulin . Secondary outcomes included neonatal anthropometric measurements , maternal glycemic control , maternal hypertensive complications , postpartum glucose tolerance , and acceptability of treatment . RESULTS Of the 363 women assigned to metformin , 92.6 % continued to receive metformin until delivery and 46.3 % received supplemental insulin . The rate of the primary composite outcome was 32.0 % in the group assigned to metformin and 32.2 % in the insulin group ( relative risk , 0.99 [ corrected ] ; 95 % confidence interval , 0.80 [ corrected ] to 1.23 [ corrected ] ) . More women in the metformin group than in the insulin group stated that they would choose to receive their assigned treatment again ( 76.6 % vs. 27.2 % , P<0.001 ) . The rates of other secondary outcomes did not differ significantly between the groups . There were no serious adverse events associated with the use of metformin . CONCLUSIONS In women with gestational diabetes mellitus , metformin ( alone or with supplemental insulin ) is not associated with increased perinatal complications as compared with insulin . The women preferred metformin to insulin treatment . ( Australian New Zeal and Clinical Trials Registry number , 12605000311651 . ) [14749658] OBJECTIVE This study examines the effects of circuit-type resistance training on the need for insulin in women with gestational diabetes mellitus . STUDY DESIGN Thirty-two patients with gestational diabetes mellitus were r and omly assigned either to a group that was treated with diet alone or to a group that was treated with diet plus resistance exercise . RESULTS The number of women whose condition required insulin therapy was the same , regardless of treatment . However , a subgroup analysis that examined only overweight women ( prepregnant body mass index , > 25 kg/m(2 ) ) showed a lower incidence of insulin use in the diet-plus-exercise group ( P<.05 ) . Women in the diet-plus-exercise group were prescribed less insulin ( P<.05 ) and showed a longer delay from diagnosis to the initiation of insulin therapy ( P<.05 ) , compared with the diet-alone group . CONCLUSION Resistance exercise training may help to avoid insulin therapy for overweight women with gestational diabetes mellitus [17596475] The Metformin in Gestational Diabetes ( MiG ) trial is a prospect i ve r and omized multicenter trial in women with gestational diabetes mellitus ( GDM ) that is testing the hypothesis that metformin treatment , compared with insulin , is associated with similar perinatal outcomes , improved markers of insulin sensitivity in the mother and baby , and improved treatment acceptability . Women with GDM who are at 20–33 weeks ’ gestation in a singleton pregnancy and meet entry criteria are r and omized to insulin or metformin treatment . The primary outcome is a composite of neonatal morbidity , with 750 recruits required . The trial finished recruiting in October 2006 . Interim data on 200 women ( and subsequently 550 women ) have been review ed by the data safety monitoring committee , which has reported that the trial should answer the hypotheses and no protocol changes are required . Data from 457 women show recruits are a mean age of 33.3 ± 5.3 years ; BMI of 32.1 ± 7.8 kg/m2 ; and ethnicity 47.2 % European/Caucasian , 25.7 % Polynesian , and 24.3 % Indian/Asian . The mean fasting glucose at recruitment is 5.3 ± 1.1 mmol/l and A1C is 5.7 ± 0.8 % . Long-term follow-up of children started at age 2 years , with assessment s of body composition , neurodevelopment , diet , and activity levels . The MiG trial will address the efficacy and detailed safety of metformin compared with insulin in women with GDM . Long-term follow-up of offspring will examine whether treatment influences later health ( Australasian Clinical Trials Registry number 12605000311651 ) . GDM is diagnosed in over 4 % of pregnant women ( 1,2 ) . The prevalence is increasing as the pregnancy population becomes older and fatter . Women with GDM have increased rates of pregnancy complications and risks of later type 2 diabetes ( 1,2 ) . The offspring of women with GDM also have increased risks of perinatal complications and long-term risks of obesity and type 2 diabetes ( 1– [2858199] OBJECTIVE Gestational diabetes mellitus ( GDM ) may cause obesity in the offspring . The objective was to assess the effect of treatment for mild GDM on the BMI of 4- to 5-year-old children . RESEARCH DESIGN AND METHODS Participants were 199 mothers who participated in a r and omized controlled trial of the treatment of mild GDM during pregnancy and their children . Trained nurses measured the height and weight of the children at preschool visits in a state-wide surveillance program in the state of South Australia . The main outcome measure was age- and sex-specific BMI Z score based on st and ards of the International Obesity Task Force . RESULTS At birth , prevalence of macrosomia ( birth weight ≥4,000 g ) was 5.3 % among the 94 children whose mothers were in the intervention group , and 21.9 % among the 105 children in the routine care control group . At 4- to 5-years-old , mean ( SD ) BMI Z score was 0.49 ( 1.20 ) in intervention children and 0.41 ( 1.40 ) among controls . The difference between treatment groups was 0.08 ( 95 % CI −0.29 to 0.44 ) , an estimate minimally changed by adjustment for maternal race , parity , age , and socio-economic index ( 0.08 [ −0.29 to 0.45 ] ) . Evaluating BMI ≥85th percentile rather than continuous BMI Z score gave similarly null results . CONCLUSIONS Although treatment of GDM substantially reduced macrosomia at birth , it did not result in a change in BMI at age 4- to 5-years-old [2188182] One hundred eight gestational diabetics were r and omized to receive either diet alone or diet plus insulin ( 20 units NPH and 10 units regular ) for glycemic control . Blood glucose levels were evaluated weekly in a high-risk clinic where medical and nutritional support and counseling were provided . Among 68 women successfully treated for a minimum of 6 weeks , the mean birth weight , macrosomia rate , and ponderal index were reduced significantly in the insulin- treated group . Insulin reduced birth weights significantly in women with a delivery weight of 200 lb or more ( 4060 ± 342 versus 3397 ± 640 g ) and in those with a delivery weight less than 200 lb ( 3324 ± 448 versus 3047 ± 394 g ) . No patient with good glucose control and a maternal delivery weight under 200 lb had a newborn over 4000 g. Patients failing glycemic control were at greatest risk ( 30 % ) for fetal overgrowth whether initially receiving insulin or not . Maternal obesity or failure to achieve glycemic control should alert the clinician to a substantially increased risk of macrosomia [2764059] We studied the impact of a training program on glucose tolerance in gestational diabetes mellitus . Women with gestational diabetes mellitus ( N = 19 ) were r and omized into either group I , a 6-week diet alone group ( 24 to 30 kcal/kg/24 hours ; 20 % protein , 40 % carbohydrate , 40 % fat ) , or group II , which followed the same diet plus exercise ( 20 minutes three times a week for 6 weeks ) . An arm ergometer was used to maintain heart rate in the training range . Glycemic response was monitored by glycosylated hemoglobin , a 50 gm oral glucose challenge with a fasting and 1-hour plasma glucose , and blood glucose self-monitoring , fasting and 1 hour after meals . Week 1 glycemic parameters were the same for both groups . Week 6 data ( mean + /- SD ) were as follows : group I glycosylated hemoglobin , 4.7 % + 0.2 % versus group II , 4.2 % + /- 0.2 % ; p less than 0.001 . The group I glucose challenge fasting value was 87.6 + /- 6.2 versus 70.1 + /- 6.6 mg/dl , p less than 0.001 for group II . The group I 1-hour plasma glucose challenge result was 187.5 + /- 12.9 mg/dl versus 105.9 + /- 18.9 mg/dl for group II , p less than 0.001 . The glycemic levels diverged between the groups at week 4 . We conclude that arm ergometer training is feasible in women with gestational diabetes mellitus and results in lower glycosylated hemoglobin , fasting , and 1-hour plasma glucose concentrations than diet alone . Arm ergometer training may provide a useful treatment option for women with gestational diabetes mellitus and may obviate insulin treatment [20542272] OBJECTIVE To assess blood glucose control and neonatal outcomes when women with gestational diabetes mellitus ( GDM ) were treated with metformin or glyburide . METHODS When an appropriate diet was insufficient to control their blood glucose levels , women with GDM were r and omized to a glyburide or a metformin treatment group . If the maximum dose was reached , the assessed drug was replaced by insulin . The primary outcome measures analyzed were maternal glucose levels during pregnancy , birth weight , and neonatal glucose levels . RESULTS The only significant difference in outcome between the 2 treatment drugs was that maternal weight gain during pregnancy was less in the metformin ( n=40 ) than in the glyburide group ( n=32 ) ( 10.3 kg vs 7.6 kg ; P=0.02 ) . No differences were found in treatment failure , mean level of fasting or postpr and ial plasma glucose , rate of participants with glycated hemoglobin , birth weight , rate of large-for-gestational-age newborns , or newborns with hypoglycemia . CONCLUSION The treatment of GDM with metformin or glyburide was found to be equivalent for both women and newborns [3532669] A r and omised prospect i ve study of treatment with dietary restriction alone or insulin therapy with dietary advice was performed in 15 women with glucose intolerance diagnosed early in the third trimester of pregnancy . Twenty-four hour profiles of plasma glucose and 3-hydroxybutyrate were performed before and four weeks after commencing treatment . The effect on neonatal outcome was assessed . The case history of one of the patients in the study was sent to British physicians with a special interest in diabetes to obtain their opinion about the appropriate initial treatment of women with gestational diabetes [10774766] The goal of this study was to determine whether the type of fat plays a role in the glucose response to a meal , independent of the carbohydrate content . Ten gestational diabetic women ( gestational weeks 29 - 34 ) who were well controlled on diet alone were r and omized as to the order in which they would eat a meal , after overnight fast , containing saturated fat ( SF ) or monounsaturated fat ( MUFA ) . Blood was drawn at 0 , 60 , 120 , and 180 min for plasma glucose , insulin , lipid profile ( triglycerides , total cholesterol , HDL-cholesterol , LDL-cholesterol , VLDL-cholesterol ) and free fatty acids . After 2 weeks , each patient received the other type of meal . The test meal was composed of 20 % of the total daily caloric needs based on ideal body weight . The area under the curve showed a significantly lower glucose concentration for SF meal ( p = 0.001 ) . Serum insulin concentrations followed the glucose response with the peak at the 60-min time point and a significantly lower concentration at the 180-min time point in the SF than in the MUFA group . The present study demonstrated that the addition of SF to the meal result ed in lower postpr and ial glucose and insulin than when the meal contained MUFA . Thus , SF may be useful in controlling postpr and ial glucose [8166187] OBJECTIVE We tested the hypothesis that intensified management of gestational diabetes mellitus on the basis of stringent glycemic control , verified glucose data , and adherence to an established criterion for insulin initiation results in near normoglycemia control and reduction of adverse outcomes . STUDY DESIGN A prospect i ve , population -based study compared the effect on perinatal outcome of conventional ( n = 1316 ) and intensified ( n = 1145 ) management . Group assignment was based on availability of memory-based reflectance meters at entry to the program . A contemporaneous r and omized control group ( nondiabetic , n = 4922 ) was selected . RESULTS The diabetic groups were comparable in demographic characteristics and in factors associated with higher risk for adverse pregnancy outcome , such as previous macrosomia , previous gestational diabetes mellitus , and family history of diabetes . The control group was younger , less obese , and had a lower rate of previous macrosomia . The intensified management group had rates of macrosomia , cesarean section , metabolic complications , shoulder dystocia , stillbirth , neonatal intensive care unit days , and respiratory complications lower than those in the conventional management group and comparable to those of the nondiabetic controls . Other maternal complication rates , such as for preeclampsia , chronic hypertension , and infection , were similar for the three groups . Mean blood glucose levels were a good predictor of perinatal outcome . Gestational age at delivery , previous history of macrosomia , and overall mean blood glucose levels were the only significant predictors of birth weight percentile in both diabetic groups ( logistic regression ) . CONCLUSION The intensified management approach is significantly associated with enhanced perinatal outcome . This management strategy clarifies the relationship between glycemic control and neonatal outcome [15223975] OBJECTIVES In order to prevent abnormalities of fetal growth still characterizing pregnancies complicated by Gestational Diabetes ( GDM ) , in the present study we evaluated a therapeutic strategy for GDM based on ultrasound ( US ) measurement of fetal insulin-sensitive tissues . METHODS All GDM women diagnosed before 28th week immediately started diet and self-monitoring of blood glucose ; after 2 weeks they were r and omized to conventional ( C ) or modified ( M ) management . In C the glycemic target ( GT ) was fixed at 90 fasting/120 post-pr and ial mg/dl ; in M GT varied , according to US measurement of the Abdominal Circumference ( AC ) centile performed every 2 weeks : 80/100 if AC > or = 75th , 100/140 if AC<75th . Therapy was tailored to mean fasting ( FG ) and postpr and ial glycemia ( PPG ) . RESULTS Globally , 229 women completed the study , 78 in C , 151 in M. Use of insulin was 16.7 % in C , 30.4 % in M ( total groups ) , significantly more frequent in M than in C ( 59.7 % vs 15.4 % ) when considering only women with AC > or = 75th c. Mean metabolic data were similar in the 2 groups , but in M a tightly-optimized subgroup , result ing from the lowering of GT due to AC > or = 75th , coexisted with a less-controlled one , whose higher GT was justified by AC<75th . Pregnancy outcome was better in M , with lower ( p<0.05 * ) rate of LGA * ( 7.9 % vs 17.9 % ) , SGA ( 6.0 % vs 9.0 % ) and Macrosomia * ( 3.3 % vs 11.5 % ) . CONCLUSIONS Our data show the value of a flexible US-based approach to the treatment of GDM . This model does not necessarily involve a generalized aggressive treatment , allowing to concentrate therapeutical efforts on a small subgroup of women showing indirect US evidence of fetal hyperinsulinization . Such a selective approach allowed to obtain a near-normalization of fetal growth , with clear advantages on global pregnancy outcome [19375570] OBJECTIVE We hypothesized that body composition would be similar among neonates of women with gestational diabetes ( GDM ) treated with glyburide or insulin . STUDY DESIGN Women with GDM requiring medical therapy were r and omized to insulin or glyburide . The primary outcome was percent neonatal fat mass measured by total body electrical conductivity . Secondary outcomes included anthropometrics , glycemic control , and biomarkers . Statistical analysis included Student t test , chi(2 ) , and regression modeling . RESULTS Eighty-two neonates underwent postnatal measurements . Baseline factors were not different by group . Neonatal percent fat mass did not differ between treatment groups ( 11.2 + /- 4.2 vs 12.8 + /- 5.7 ) . Fat mass , body mass index , ponderal index , skinfold sum , and arm fat area were not different when analyzed by intent to treat or actual treatment group . Cord concentrations of biomarkers were also similar . CONCLUSION There was no difference in neonatal adiposity in infants of women treated for GDM with glyburide or insulin [2675597] In this study we sought to test the hypothesis that treatment of women with one abnormal oral glucose tolerance test value will result in reduction of adverse outcome . One hundred twenty-six women with one abnormal oral glucose tolerance test value and 146 women in the control group ( normal oral glucose tolerance test values ) participated in a prospect i ve study during the third trimester of pregnancy . The subjects with one abnormal test result were r and omized into treated ( group 1 ) and untreated groups ( group II ) . Group 1 subjects were treated with a strict diabetic protocol to maintain tight glycemic control by means of diet and insulin therapy . Group 2 subjects tested their capillary blood glucose for a baseline period . The study revealed that the level of glycemic control was similar before initiation of therapy ( mean capillary blood glucose 118 + /- 14 vs. 119 + /- 15 mg/dl , p = NS ) for groups 1 and 2 , respectively . There was a significant difference in mean capillary blood glucose ( 95 + /- 10 vs. 119 + /- 15 mg/dl , p less than 0.0001 ) , prepr and ial , and postpr and ial determinations between the treated and untreated groups . The overall incidence of neonatal metabolic complications ( 4 % vs. 14 % , p less than 0.05 ) and large infants ( 6 % vs. 24 % , p less than 0.03 ) was significantly lower in the treated group . Comparison between the control ( normal oral glucose tolerance test ) and the untreated groups showed a significantly higher incidence of large infants and metabolic complications . No difference was found between the normal and treated groups . Thus we conclude that treatment of individuals with one abnormal oral glucose tolerance test value will result in significant reduction in adverse outcome in pregnancy [9170478] Objective To assess the usefulness of a breakfast test in determining which women with gestational diabetes do not need self-monitoring of blood glucose levels ( home monitoring ) . Methods a 1-hour post-st and ardized breakfast blood glucose below 7.8 mmol/L ( 140 mg/dL ) was measured in 227 women and at or above 7.8 mmol/L in 115 . Within each group , women were r and omized to home monitoring with a meter or to clinic follow-up . Target glucose values were 5.3 mmol/L ( 95 mg/dL ) fasting , 5.6 mmol/L ( 101 mg/dL ) before meals , and 7.8 mmol/L ( 140 mg/dL ) 1 hour postpr and ial . Up to these thresholds women on clinic follow-up were transferred to home monitoring . Insulin therapy was started on the same thresholds in women r and omized or transferred to home monitoring . Large ofr gestational age ( LGA ) newborns represented the main outcome , with the transfer rate to home monitoring and need of insulin therapy the secondary ones . Results The LGA delivery rate was not significantly different in the two follow-up groups in women with a breakfast result below 7.8 mmol/L ( 9.8 versus 4.3 % ) but was higher in the clinic follow-up among women with a breakfast result at or above 7.8 mmol/L ( 13.3 % versus 30.9 % ; P < .05 ) . Fewer women with a breakfast result below 7.8 mmol/L were transferred to home monitoring ( 2.6 versus 52.7 % ; P < .001 ) or started on insulin therapy ( 3.6 versus 25.2 % ; P < .001 ) . The breakfast test cutoff of 7.8 mmol/L predicted insulin need with a sensitivity of 91.0 % and a specificity of 72.0 % . Conclusion A breakfast test is useful in identifying a low-risk population in which clinic follow-up may be used safely [20653150] OBJECTIVE The objective of the study was to compare premixed insulin aspart 30 ( BIAsp 30 ) vs premixed human insulin 30 ( BHI 30 ) on efficacy , safety , fetal and perinatal outcomes in pregnancies associated with gestational diabetes mellitus [ GDM ] . This was the first r and omized study to use pre mixed insulin analogue [ BIAsp ] in GDM . METHODS The study population consisted of 76 GDM women assigned to BIAsp 30 ( group A ) and an equal number to BHI 30 ( group B ) . RESULTS There was no statistically significant difference between the age , BMI , gestational weeks and glycemic level at entry between the group A and group B women ( p > 0.05 ) . There was no statistical difference between the two groups in glycemic control or insulin dose ( p > 0.05 ) before confinement . The frequency of birth weight of new born above 90 percentile was 6.8 % in Group 1 and 9.2 % in Group 2 . The proportion of macrosomia was higher in Group 2 when compared to Group 1 , however the difference was not statistically significant ( P = 0.819 ) . CONCLUSION BIAsp was safe during pregnancy and pregnant women found it convenient due to meal time dosing . Fetal outcome using BIAsp was also comparable with BHI 30 [6993163] A 16-yr prospect i ve study of 615 gestational diabetic subjects , half of whom were r and omly assigned to insulin therapy during pregnancy , is evaluated to report on the potential reduction in subsequent diabetes due to insulin therapy . No such difference in incidence rates was observed between the two groups . In the subsets of women managed with insulin who bore a baby of large birthweight or who had a family history of diabetes , subsequent decompensated diabetes was found to be significantly reduced . Both life table and multivariate analyses to adjust for the effects of age , weight , level of blood glucose at selection , duration of follow-up , and other potentially confounding covariables confirmed this conclusion . The finding suggests the possibility of long-term preventive benefits from insulin treatment in high risk subsets of women with gestational diabetes [18211656] RATIONALE , AIMS AND OBJECTIVE To investigate whether the introduction of a programme of optimising drug treatment , intensive education and self-monitoring of patients diagnosed with gestational diabetes mellitus ( GDM ) at an early stage ( < 20 gestational weeks ) , will improve management outcomes as determined by objective measures of patient knowledge about diabetes , glycaemia control , maternal/neonatal complications , and health-related quality of life . METHODS The study was a r and omized , controlled , longitudinal , prospect i ve clinical trial performed at Al-Ain Hospital , Al-Ain , United Arab Emirates . Over an 18-month period , patients diagnosed with GDM were recruited and were r and omly assigned to either an intervention or a control group , in a ratio of 3:2 . Intervention patients received a structured pharmaceutical care service ( including education and introduction of intensive self-monitoring ) while control patients received traditional services . Patients were followed up from time of recruitment until 6 months postnatally at scheduled outpatient clinics . A range of clinical and humanistic outcome measures , including maternal and neonatal complications , were used to assess the impact of the intervention . RESULTS A total of 165 patients ( 99 intervention , 66 control ) completed the study . The intervention patients exhibited a range of benefits from the provision of the programme when compared with control group patients . Statistically significant ( P < 0.05 ) improvements were shown in the intervention group for knowledge of diabetes , health-related quality of life ( as determined by the SF36 ) , control of plasma glucose and HbA(1c ) , maternal complications [ e.g. decreased incidence of pre-eclampsia ( 5.1 % vs. 16.7 % ) , eclampsia ( 1.0 % vs. 7.6 % ) , episodes of severe hyperglycaemia ( 3.0 % vs. 19.7 % ) and need for Caesarean section ( 7.1 % vs. 18.2 % ) ] , and neonatal complications [ e.g. decreased incidence of neonatal hypoglycaemia ( 2.0 % vs. 10.6 % ) , respiratory distress at birth ( 4.0 % vs. 15.2 % ) , hyperbilirubinaemia ( 1.0 % vs. 12.1 % ) and large for gestational age ( 9.0 % vs. 22.7 % ) ] . CONCLUSION The research provides clear evidence that provision of pharmaceutical care adds value to the management of GDM as exemplified by improved maternal and neonatal outcomes [10955425] Objective To determine whether a study of a less intensive form of management for impaired glucose tolerance in pregnancy is feasible and whether women would accept r and omisation [8299437] OBJECTIVE To eluci date the glycemic response and antibody formation in gestational diabetic women treated with insulin injected by a needle or a jet . The American Diabetes Association 's position statement on jet injectors raised the concern that “ insulin could be denatured as a result of forceful injection through a tiny port , which could lead to an increase in antibody formation ” ( Diabetes Care11:600 , 1988 ) . However , the pharmacokinetics of jet-injected insulin suggest that it might be useful in controlling postpr and ial glucose levels . METHODS We r and omized 20 women with gestational diabetes mellitus ( < 34 wk gestation ) who required insulin to receive either jet-injected or needle-injected human NPH and regular insulin . Variables of interest were evaluated at the start of therapy , weekly until delivery , and 6-wk postpartum that included : 1 ) insulin antibodies in the mother and her infant , 2 ) HbA1c , 3 ) insulin dose , 4 ) fasting and postpr and ial glucose levels , and 5 ) subject acceptance and preference . RESULTS Of the 10 women in the needle group , 6 developed significant insulin antibodies compared with 1 of 10 in the jet group ( P < 0.001 ) . HbA1c and insulin doses were the same in both groups . During the test meal , glucose levels in the jet group were significantly lower ( P < 0.01 ) , yet none of the women in the jet group experienced blood glucose 70 mg/dl ( 3.89 mM ) at 3–4 h after the meal , compared with 5 in the needle group ( P < 0.001 ) . Jet injection was associated with less variability ( P < 0.001 ) in postpr and ial glucose values but slightly greater variability ( P < 0.05 ) in fasting glucose . Jet-injected insulin was more readily accepted by subjects than needle injections . CONCLUSIONS Jet injection is associated with a diminished antibody response and postpr and ial variability compared with needle-injected insulin . Thus , this warrants consideration as a therapeutic option for women with gestational diabetes mellitus and may also be applicable to nonpregnant , insulin-requiring diabetic patients [15565082] Abstract Women with gestational diabetes mellitus ( GDM ) have a greater risk of developing type 2 diabetes mellitus ( DM ) and heart disease than pregnant women without GDM . Advice given during the GDM pregnancy provides an opportunity to develop protective dietary patterns for the long-term management of this risk . Dietary guidelines for the prevention and management of type 2 DM support the inclusion of unsaturated fats , but food advice needs to target this outcome . The aim of this study was to compare the dietary intakes of women with GDM given general low-fat advice ( control group ) to women with GDM given the same advice with additional targets for food sources of unsaturated fats ( intervention group ) . After approximately 6 weeks , the intervention group reported more ideal dietary fatty acid intakes than the control group , with polyunsaturated : saturated fat ratios of 1:1 and 0.4:1 , respectively ( P < .001 ) , assessed using repeated measures analysis of variance . These results confirm the need to include food sources of unsaturated fats in advice strategies to assure optimal protective eating habits in this at-risk group [21094553] AIM The objectives of this pilot study were to determine the feasibility and effect on glycaemic control of a low-glycaemic-index ( GI ) diet in women with gestational diabetes or impaired glucose tolerance of pregnancy . METHODS participants , recruited from the Diabetes-in-Pregnancy Clinic of an inner-city teaching hospital serving a predominantly non-Caucasian population , were r and omized to a low-GI ( n=23 ) or control ( n=24 ) diet and followed from 28 weeks gestation until delivery . Self-monitored-blood-glucose ( SMBG ) , maternal and infant weight were collected from medical charts . Dietary intakes were assessed using diet records and question naires . RESULTS diet GI on control ( 58 , 95 % CI : 56,60 ) was significantly higher than on low-GI ( 49 , 95 % CI : 47,51 ; p=0.001 ) . Glycaemic control improved on both diets , but more postpr and ial glucose values were within target on low-GI ( 58.4 % of n=1891 ) than control ( 48.7 % of n=1834 ; p<0.001 ) . SMBG post-breakfast was directly related to pre-pregnancy BMI in the control , but not the low-GI group ( BMI * diet interaction ; p=0.021 ) . Participants accepted the study foods and were willing to consume them post-intervention . CONCLUSIONS a low-GI diet was feasible and acceptable in this sample and facilitated control of postpr and ial glucose . A larger study is needed to determine the effect of a low-GI diet on maternal and infant outcomes [11194427] Summary : A r and omised controlled trial was design ed to determine the effect of moderate 30 % maternal dietary energy restriction on the requirement for maternal insulin therapy and the incidence of macrosomia in gestational diabetes . Although the control group restricted their intake to a level similar to that of the intervention group ( 6845 kiloJoules ( kJ ) versus 6579 kJ ) , the result ing cohort could not identify any adverse effect of energy restriction in pregnancy . Energy restriction did not alter the frequency of insulin therapy ( 17.5 % in the intervention group and 16.9 % in the control group ) . Mean birth weight ( 3461 g in the intervention group and 3267 g in the control group ) was not affected . There was a trend in the intervention group towards later gestational age at commencement of insulin therapy ( 33 weeks versus 31 weeks ) and lower maximum daily insulin dose ( 23 units versus 60 units ) which did not reach statistical significance . Energy restriction did not cause an increase in ketonemia [20027034] OBJECTIVE : To compare the efficacy of metformin with glyburide for glycemic control in gestational diabetes . METHODS : Patients with gestational diabetes who did not achieve glycemic control on diet were r and omly assigned to metformin ( n=75 ) or glyburide ( n=74 ) as single agents . The primary outcome was glycemic control . Secondary outcomes were drug failure rate and neonatal and obstetric complications . RESULTS : In the patients who achieved adequate glycemic control , the mean fasting and 2-hour postpr and ial blood glucose levels were not statistically different between the two groups . However , 26 patients in the metformin group ( 34.7 % ) and 12 patients in the glyburide group ( 16.2 % ) did not achieve adequate glycemic control and required insulin therapy ( P=.01 ) . CONCLUSION : In this study , the failure rate of metformin was 2.1 times higher than the failure rate of glyburide when used in the management of gestational diabetes ( 95 % confidence interval 1.2–3.9 ) . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00965991 . LEVEL OF EVIDENCE : [16963348] Nutrition practice guidelines were developed for gestational diabetes mellitus by registered dietitians from the Diabetes Care and Education and the Women 's Health and Reproductive Nutrition dietetic practice groups . To vali date the guidelines , a clinical trial was design ed with clinic sites r and omly assigned to either nutrition practice guidelines care ( 12 sites ) or usual nutrition care ( 13 sites ) , with diabetes , obstetric , and other clinic types represented in both groups . Volunteer dietitians served as study coordinators and recruited women diagnosed with gestational diabetes mellitus . The nutrition practice guidelines define medical nutrition therapy ( MNT ) for gestational diabetes and emphasize three areas -definition of MNT clinical goals with indexes to modify or advance MNT and criteria to start insulin ; use of self-monitoring tools ; and provision of three nutrition visits . Usual care sites provided prenatal nutrition care according to usual practice . The effect of nutrition care ( sites following the nutrition care guidelines ) and type of clinic site on changes in glycated hemoglobin and infant birth weight , adjusted for other covariates , were evaluated using linear regression . Differences in insulin use and other infant outcomes between treatment groups were evaluated using logistic regression . Generalized estimating equations were used to accommo date nonindependence within r and omized clusters of patients within clinic sites . Data from 215 women indicated less insulin use at diabetes clinic sites in the nutrition practice guidelines groups and improved glycated hemoglobin control during the treatment period in diabetes clinics compared with obstetric or other clinics . A higher proportion of women in the usual care group had glycated hemoglobin levels that exceeded 6 % at follow-up compared with women in the nutrition practice guidelines group ( 13.6 % vs 8.1 % ) , although not statistically significant ( P=0.26 ) . A significant clinic type and treatment group effect was found for birth weight . Nutrition practice guidelines for gestational diabetes mellitus reflected nutrition care already being provided by registered dietitians in diabetes clinics prior to this study because outcomes at these clinics were not impacted . Use of the guidelines by dietitians at obstetric and other clinics tended to improve outcomes at these sites [11360593] OBJECTIVE To study the treatment of women with gestational impared glucose tolerance ( GIGT ) in relation to outcome of fetus and newborns . METHODS 98 women with GIGT were r and omized into untreated ( 37 mothers ) and treated groups ( 61 mothers ) that included diet control and insulin therapy . The perinatal outcomes were compared in the two groups . RESULTS The incidence of macrosomia ( P < 0.01 ) and fetal distress ( P < 0.05 ) was found to be significantly higher in the untreated group when compared with the treated group . The prevalence of neonatal metabolic complications in the untreated group was higher than that of the treated group as well . CONCLUSION Treatment of women with GIGT will reduce adverse outcome in pregnancy [5936737] The purpose of this study was to examine pregnancy outcome in women with abnormal oral glucose tolerance tests , in relation to treatment with diet and insulin . Glucose tolerance tests , done because of well-known historical risk factors , were considered abnormal if two or more readings exceeded the following : fasting , 110 ; 1 hour , 170 ; 2 hours , 120 ; and 3 hours , 110 ( all in mg/100 mL , measured as total reducing substances in whole venous blood ) . Those with positive tests were divided r and omly into a “ positive-control ” group ( n 308 ) that received st and ard prenatal care or a “ positive-treated ” group ( n 307 ) that received dietary instructions ( 30 kcal/kg ideal body weight , 40 % as carbohydrate , and 1.5–2 g protein/kg body weight ) and insulin ( initial dose 10 U per day of intermediate-acting insulin , adjusted subsequently as directed by blood and urine studies ) , beginning at usually about 32 weeks . A third group ( n 328 ) , termed “ negative controls , ” had exhibited normal glucose tolerance testing . The three groups were similar , except that those with abnormal glucose tolerance tended to be older and heavier , as expected . With respect to outcome , infants with birth weights exceeding 9 lb were three times as frequent in positive-control subjects as in either positive-treated subjects or negative controls ( 13.1 % , 4.3 % , and 3.7 % , respectively ) . Perinatal deaths ( 28 weeks ’ gestation through 14 days after birth ) were similar in the two positive groups ( 4.9 % in control and 4.3 % in treated ) and significantly higher than in negative controls ( 1.9 % ) , with the increase involving both fetal and neonatal components . The conclusions were 1 ) abnormal glucose tolerance during pregnancy leads to larger infants and higher perinatal mortality and 2 ) treatment with diet and insulin ameliorates the former but not the latter . This study concerned what O’Sullivan called potential diabetes and others at the time termed latent or chemical diabetes or prediabetes , but what today we refer to as gestational diabetes . Acceptance of it as a pathologic entity was far from unanimous in 1966 . O’Sullivan resolved the controversy with this large , well- design ed , and well-analyzed clinical trial . The immediate influence was two-fold . In the first place , it settled the existing disagreement as to whether or not impaired glucose tolerance adversely influences pregnancy outcome ; large infants occurred three times as frequently and perinatal deaths were more than doubled in women with abnormal carbohydrate metabolism . Second , the findings of the intervention trial indicated clearly that treatment of gestational diabetes with diet and insulin in late gestation normalizes birth weight ( although it did not seem to influence perinatal mortality ) , a finding confirmed a number of times by subsequent investigators . Incidentally , the frequencies of both fetal and neonatal deaths may seem high , but it needs to be remembered that this experience ante date d the advent of modern fetal surveillance and neonatal intensive care . John B. O’Sullivan , a pioneer in clinical research in gestational diabetes , was an internist . He defined st and ards for the oral glucose tolerance test in pregnancy that , though modified slightly by subsequent investigators , are basically those in use today . Born in 1926 , he received his medical education in his native Irel and before immigrating to the United States in 1955 . After further training in internal medicine at the Lahey Clinic , he took a faculty position at the Boston University School of Medicine , where he did his original work on early diabetes as medical director of the Prenatal Metabolism Clinic at Boston City Hospital and chief of medicine at St. Margaret ’s Hospital . In addition to his position as Associate Professor at Boston University , he also served on the faculties of the Harvard and Yale medical schools . Later he was director of employee health for the Liberty Mutual Insurance Company . He died of cancer in August 2001 [1748256] Forty-one patients with gestational diabetes requiring insulin were enrolled in a r and omized study to investigate the efficacy of an exercise program in normalizing glucose tolerance . Seventeen of 21 patients completed the exercise program while maintaining normoglycemia and obviating insulin therapy . Maternal and neonatal complications did not differ between the study and control groups . The type of program described appears to be safe and can serve as a model for exercise prescription for pregnant diabetic women to attain improved glucose tolerance [4829275] The outcome of pregnancy in control and treated gestational diabetics was not significantly different . The decreased loss rate among the insulin- and diet-treated gestational diabetics , however , did become significant when the data were reanalyzed with consideration of two important influencing variables . The high-risk group of gestational diabetics aged 25 years and older who received insulin therapy before the 32nd week of gestation had fewer fetal losses . Documentation of the critical role played by both maternal age and the gestational age at which insulin therapy is commenced now makes the institution of a conclusive prospect i ve study feasible . The adequately established hypothesis that insulin management of gestational diabetics favorably affects the outcome of their pregnancies can then be finally resolved [8796796] The effect of an acute period of moderate intensity exercise on maternal glycemic excursion following a mixed nutrient meal was studied . Five normal ( NL ) and six gestational diabetic ( GDM ) subjects were enrolled . A r and omized crossover design was used to compare fasting glucose and insulin levels , peak glucose and insulin levels and incremental area of the glycemic and insulin curves following a mixed nutrient meal with or without an exercise stress that took place 14 h earlier . Exercise consisted of upright stationary cycling for 30 min at a heart rate consistent with 60 % VO2max . The clinical characteristics of normal and gestational diabetic subjects were comparable . Mean values ( + /-SEM ) with , versus without , exercise for fasting glucose ( NL : 78.9 + /- 2.6 vs. 80.0 + /- 2.6 mg/dl ; GDM : 86.4 + /- 2.0 vs. 82.1 + /- 3.5 mg/ dl ) , peak glucose ( NL : 132.3 + /- 10.4 vs. 139.1 + /- 15.6 mg/dl ; GDM : 165.8 + /- 5.5 vs. 160.3 + /- 7.8 mg/dl ) , the area under the glycemic curve ( NL : 5758 + /- 1038 vs. 6393 + /- 1281 mg/dl.min ; GDM : 8,178 + /- 890 vs. 8,331 + /- 563 mg/dl.min ) did not differ . Similarly , plasma insulin levels did not differ between protocol s for either group of subjects . Exercise has been proposed as a treatment to reduce glycemia in gestational diabetes . Results from this study indicate a single bout of exercise did not blunt the glycemic response observed following a mixed nutrient meal [10586979] Infant macrosomia is a serious medical concern . Pregnant women who do not meet the specific diagnosis for gestational diabetes may still have glucose-mediated macrosomia . In Santa Barbara County all pregnant women are screened for gestational diabetes at 24 - 28 weeks with a 50-g , 1-hr glucose challenge test ( GCT ) . All patients who fail this test are placed on a st and ard euglycemic diet ( 40 % carbohydrate , 20 % protein , 40 % fat ) and perform home glucose monitoring of fasting and postpr and ial glucose levels . The objective of this study was to examine the effectiveness of this treatment program in decreasing infant macrosomia , maternal and infant morbidity , maternal complications , and operative delivery . We studied 103 women who had a positive GCT , but a negative 100-g , 3-hr oral glucose tolerance test ( OGTT ) . The women were r and omly assigned to either experimental or control groups with experimental women receiving dietary counseling and home glucose monitoring instruction ( HBGM ) . HBGM diaries were review ed weekly by clinic nurses . All women had hemoglobin A1c ( HbA1c ) tests at 28 and 32 weeks . Maternal and fetal charts were review ed to determine delivery type and complications , indications for cesarean section ( C-section ) , and infant gestational age , gender , Apgar scores , birth weight , morbidities , and congenital anomalies . Of the 103 women , 5 women required insulin treatment , 1 woman had an abortion , and 14 women were indeterminate regarding compliance or were control women who received diet counseling and HBGM . The results are based on 83 women--48 control and 35 experimental . There were no significant differences between the groups for age , parity , or weight at 28 - 30 weeks or 37 weeks to delivery , or HbA1c at 28 weeks . HbA1c was significantly higher in control women at 32 weeks . Birth weight expressed in grams or as a percentile specific for gender , ethnicity , and gestational age was significantly higher in control infants . Birth weight was significantly correlated with maternal intake weight , weight at 28 - 30 weeks , and weight at delivery and with HbA1c at 32 weeks ' gestation . There were no significant differences between groups for maternal complications . Groups were significantly different for mode of delivery with experimental women having more induced vaginal deliveries but fewer repeat C-sections than control women . Groups were not different for primary C-sections . Women who fail the GCT , but not the OGTT and thus do not receive the diagnosis of GDM are still at risk for delivering a macrosomic infant and operative delivery . Our program of treatment for all women who fail the GCT improves outcome by reducing infant birth weight and the number of cesarean sections [11966484] Major problems with gestational diabetes ( GDM ) have been the high frequency of fetal macrosomia , and perinatal complications , especially among mothers needing insulin in addition to diet therapy ( 1 ) . Both long-acting insulin ( LAI ) and shortacting insulin ( SAI ) are used , the former to reduce the basal glucose level and the latter to control postpr and ial glucose peaks after meals . Despite many improvements , insulin therapy has not solved the above-mentioned problems . We compared the effects of SAI and LAI on perinatal outcome in insulin-requiring GDM . We hypothesized that SAI therapy and postpr and ial glucose monitoring would lead to better glycemic control than LAI and therefore reduce fetal macrosomia . After obtaining approval by the Ethics Committee of the Helsinki University Central Hospital , department of Obstetrics and Gynecology and given information to all study participants , we included 23 consecutive women with insulin-requiring GDM in a prospect i ve r and omized trial . A 2-hr oral glucose tolerance test ( OGTT ) with 75 g of glucose was performed at 24–28weeks of gestation in women [3888734] Two-hundred and two pregnant women with impaired glucose tolerance were r and omized to treatment with diet or diet and insulin by stratified selection . Self-monitoring of blood glucose was performed six times a day , 3 days/wk . Dietary treatment was considered inappropriate if fasting and postpr and ial blood glucose values exceeded 7 and 9 mmol/L , respectively , in which case insulin therapy was instituted . Insulin doses were adjusted according to blood glucose values , aim ing at fasting and postpr and ial values below 5 and 6.5 mmol/L , respectively . There were no perinatal deaths . The two treatment regimens disclosed no differences regarding achieved degree of maternal blood glucose control , hemoglobin A1c at delivery , obstetric or neonatal complications , infant 's size at birth including skinfold thickness , or C-peptide concentration in cord serum . Routine treatment of pregnant women with mild carbohydrate intolerance with insulin seems unnecessary . However , 15 patients ( 14 % ) in the diet group needed insulin to achieve acceptable blood glucose control , underlining the importance of monitoring blood glucose to detect those who are at risk of developing overt diabetes [628532] Seventy-two patient with gestational diabetes were r and omly treated with insulin ( 20 units NPH and 10 units regular ) and diabetic diet , diet alone , or neither . Of the 27 patients treated with insulin and diet , 2 ( 7 % ) had babies weighing more than 8 1/2 pounds . Of the 11 patients treated with diet alone , 4 ( 36.4 % ) had babies weighing more than 8 1/2 pounds . Of the 34 patients treated with neither diet nor insulin , 17 ( 50 % ) had babies weighing more than 8 1/2 pounds . These data support the hypothesis that treatment of the gestational diabetic with insulin will reduce the incidence of fetal macrosomia [12502678] OBJECTIVE To assess the short-term efficacy of insulin aspart in comparison with regular human insulin in women with gestational diabetes mellitus ( GDM ) during st and ardized meal tests . RESEARCH DESIGN AND METHODS The study included 15 women with GDM who had inadequate diabetes control with diet alone . On 3 consecutive days , breakfast meal tests were performed-the first with no exogenous insulin and the other two after the injection of either regular insulin or insulin aspart . RESULTS The peak insulin concentration was higher and the peak glucose and C-peptide concentrations were lower with both insulin preparations than with no exogenous insulin . Glucose areas under the curve above baseline were significantly lower with insulin aspart ( 180-min area , 7.1 mg . h. dl(-1 ) ; P = 0.018 ) , but not with regular insulin ( 30.2 mg . h. dl(-1 ) ; P = 0.997 ) , than with no insulin ( 29.4 mg . h. dl(-1 ) ) . CONCLUSIONS This study demonstrates that effective postpr and ial glycemic control in women with GDM who required insulin was brought about by insulin aspart through higher insulin peak and lower dem and on endogenous insulin secretion [18754979] OBJECTIVE To examine the effects of a Parish Nurse Intervention Program ( PNIP ) on maternal health behaviors , glycemic control , and neonatal outcomes among Mexican American women with gestational diabetes . DESIGN A r and omized controlled trial comparing care as usual ( CAU ) with a supplementary 1-hour education session for diabetes education reinforcement by a Parish Nurse . SETTING An outpatient treatment clinic for gestational diabetes within a 250-bed tertiary care , non-profit hospital with a Parish Nurse partnership . PARTICIPANTS One hundred Mexican American women were included in the study with r and omization into Parish Nurse Intervention Program ( n=49 ) and care as usual ( n=51 ) groups . MAIN OUTCOME MEASURES The Health Promoting Lifestyle Profile II ( HPLP II ) and two measures of glycemic control pre- and post-intervention , as well as newborn size , and days of maternal and neonatal hospitalization . RESULTS Outcomes indicate significantly improved Health Promoting Lifestyle Profile II scores in the Parish Nurse Intervention Program group post-intervention compared with the Care As Usual group . No significant differences between groups regarding glycemic control , macrosomia , or days of maternal or neonatal hospitalization were found . CONCLUSIONS A Parish Nurse Intervention Program for pregnant women of Mexican descent with gestational diabetes is effective in leading to improved self-reported health promoting behaviors [2500941] In pregnancies complicated by diabetes , foetal lung maturation depends on a good control of maternal blood glucose values . In poorly controlled maternal diabetes , foetal hyperinsulinaemia may cause a delay in pulmonary maturation . There was no single case of respiratory distress syndrome ( RDS ) in 112 pregnant class B-F diabetic patients that we treated with high doses of insulin . Furthermore , in a controlled r and omized trial of diet versus insulin treatment in class A diabetes we found no differences in perinatal mortality in patients with adequate metabolic control . In pregnancies complicated by Rh isoimmunization , determination of phosphatidylglycerol in amniotic fluid is a more reliable marker of foetal lung maturity than is the lecithin/sphingomyelin ratio . The marked decrease in perinatal mortality due to Rh incompatibility observed in recent years depends on several factors including administration of corticosteroids to the mother to prevent RDS , irrespective of whether amniotic fluid parameters indicate foetal lung maturity [11036118] BACKGROUND Women with gestational diabetes mellitus are rarely treated with a sulfonylurea drug , because of concern about teratogenicity and neonatal hypoglycemia . There is little information about the efficacy of these drugs in this group of women . METHODS We studied 404 women with singleton pregnancies and gestational diabetes that required treatment . The women were r and omly assigned between 11 and 33 weeks of gestation to receive glyburide or insulin according to an intensified treatment protocol . The primary end point was achievement of the desired level of glycemic control . Secondary end points included maternal and neonatal complications . RESULTS The mean ( + /-SD ) pretreatment blood glucose concentration as measured at home for one week was 114+/-19 mg per deciliter ( 6.4+/-1.1 mmol per liter ) in the glyburide group and 116+/-22 mg per deciliter ( 6.5+/-1.2 mmol per liter ) in the insulin group ( P=0.33 ) . The mean concentrations during treatment were 105+/-16 mg per deciliter ( 5.9+/-0.9 mmol per liter ) in the glyburide group and 105+/-18 mg per deciliter ( 5.9+/-1.0 mmol per liter ) in the insulin group ( P=0.99 ) . Eight women in the glyburide group ( 4 percent ) required insulin therapy . There were no significant differences between the glyburide and insulin groups in the percentage of infants who were large for gestational age ( 12 percent and 13 percent , respectively ) ; who had macrosomia , defined as a birth weight of 4000 g or more ( 7 percent and 4 percent ) ; who had lung complications ( 8 percent and 6 percent ) ; who had hypoglycemia ( 9 percent and 6 percent ) ; who were admitted to a neonatal intensive care unit ( 6 percent and 7 percent ) ; or who had fetal anomalies ( 2 percent and 2 percent ) . The cord-serum insulin concentrations were similar in the two groups , and glyburide was not detected in the cord serum of any infant in the glyburide group . CONCLUSIONS In women with gestational diabetes , glyburide is a clinical ly effective alternative to insulin therapy [18058723] INTRODUCTION Nutrition therapy is an integral part of the management of gestational diabetes mellitus ( GDM ) . Most women with GDM are treated by nutritional management alone . The goal of our study was to compare low and high carbohydrate diets in their effectiveness , safety and tolerability in women with GDM . MATERIAL AND METHODS The study group consisted of 30 Caucasian women newly diagnosed with GDM , with a mean age of 28.7 + /- 3.7 years and pregnancy duration of 29.2 + /- 5.4 weeks . The patients were r and omised into two groups : those on a low and those on a high carbohydrate diet ( 45 % vs. 65 % respectively of energy supply coming from carbohydrates ) . The presence of urine ketones was controlled every day . After two weeks daily glucose profiles and compliance with the recommended diets were analysed . RESULTS Glucose concentration before implementation of the diet regimen did not differ between groups . No changes in fasting blood glucose were noticed in the group that had followed a low carbohydrate diet , although a significant decrease in glucose concentration was observed after breakfast ( 102 + /- 16 vs. 94 + /- 11 mg/dl ) , lunch ( 105 + /- 12 vs. 99 + /- 9 mg/dl ) and dinner ( 112 + /- 16 vs. 103 + /- 13 mg/dl ) ( p < 0.05 ) . In the high carbohydrate diet group fasting and after-breakfast glucose concentration did not change . A significant decrease in glycaemia was noticed after lunch ( 106 + /- 15 vs. 96 + /- 7 mg/dl ) and dinner ( 107 + /- 12 vs. 97 + /- 7 mg/dl ) ( p < 0.05 ) . Ketonuria was not observed in either group . Obstetrical outcomes did not differ between groups . CONCLUSIONS Both high and low carbohydrate diets are effective and safe . A diet with carbohydrate limitation should be recommended to women who experience the highest glycaemia levels after breakfast [12375675] Objective : A planned study is described which will determine whether a benefit exists for the treatment of mild carbohydrate intolerance during pregnancy . Methods : A r and omized clinical trial of women with mild gestational diabetes will compare perinatal outcomes in those receiving diet therapy and insulin as required versus those r and omized to no specific treatment . Results : The primary outcome of this study will be a composite of neonatal morbidity in the treatment and control groups . Conclusions : A r and omized treatment trial of mild gestational diabetes mellitus will clarify whether identification and treatment of mild gestational diabetes mellitus reduces perinatal morbidity . This information will aid in selecting appropriate thresholds for the treatment of gestational diabetes mellitus [19797280] BACKGROUND It is uncertain whether treatment of mild gestational diabetes mellitus improves pregnancy outcomes . METHODS Women who were in the 24th to 31st week of gestation and who met the criteria for mild gestational diabetes mellitus ( i.e. , an abnormal result on an oral glucose-tolerance test but a fasting glucose level below 95 mg per deciliter [ 5.3 mmol per liter ] ) were r and omly assigned to usual prenatal care ( control group ) or dietary intervention , self-monitoring of blood glucose , and insulin therapy , if necessary ( treatment group ) . The primary outcome was a composite of stillbirth or perinatal death and neonatal complications , including hyperbilirubinemia , hypoglycemia , hyperinsulinemia , and birth trauma . RESULTS A total of 958 women were r and omly assigned to a study group--485 to the treatment group and 473 to the control group . We observed no significant difference between groups in the frequency of the composite outcome ( 32.4 % and 37.0 % in the treatment and control groups , respectively ; P=0.14 ) . There were no perinatal deaths . However , there were significant reductions with treatment as compared with usual care in several prespecified secondary outcomes , including mean birth weight ( 3302 vs. 3408 g ) , neonatal fat mass ( 427 vs. 464 g ) , the frequency of large-for-gestational-age infants ( 7.1 % vs. 14.5 % ) , birth weight greater than 4000 g ( 5.9 % vs. 14.3 % ) , shoulder dystocia ( 1.5 % vs. 4.0 % ) , and cesarean delivery ( 26.9 % vs. 33.8 % ) . Treatment of gestational diabetes mellitus , as compared with usual care , was also associated with reduced rates of preeclampsia and gestational hypertension ( combined rates for the two conditions , 8.6 % vs. 13.6 % ; P=0.01 ) . CONCLUSIONS Although treatment of mild gestational diabetes mellitus did not significantly reduce the frequency of a composite outcome that included stillbirth or perinatal death and several neonatal complications , it did reduce the risks of fetal overgrowth , shoulder dystocia , cesarean delivery , and hypertensive disorders . ( Clinical Trials.gov number , NCT00069576 .

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### Context: [17596471] It is recognized that women with gestational diabetes mellitus ( GDM ) who have significantly elevated fasting blood glucose levels are at increased risk for fetal macrosomia and perinatal morbidity if treatment is not provided ( 1,2 ) . The association of milder forms of GDM with perinatal morbidity and mortality remains unclear , primarily because the condition is often confounded with other risk factors such as maternal obesity , age , and parity . Screening for GDM is recommended for most pregnant women , yet it is unknown whether there is a benefit to the identification and treatment of mild carbohydrate intolerance during pregnancy ( 3,4 ) . The present report is an up date of our previous description of a current ongoing r and omized treatment trial for mild GDM ( 5 ) . A r and omized clinical trial of women with mild GDM ( fasting glucose < 95 mg/dl ) is being undertaken that compares perinatal outcomes in those receiving diet therapy and insulin as required versus those r and omized to no specific treatment . This study aims to clarify whether there is utility in identifying and treating women with a normal fasting glucose level who meet st and ard criteria for GDM . We plan to compare perinatal outcomes in women who have been r and omized to diet and /or insulin therapy with women who have been r and omized to no specific treatment . A r and omized treatment trial of mild GDM will clarify whether identification and treatment of mild GDM reduce perinatal morbidity . This information will assist in determining appropriate thresholds for the treatment of GDM . Overall , with broader identification and aggressive treatment , perinatal mortality rates associated with GDM appear to be similar to the nondiabetic population ( 1 ) . Several analyses of 20 years ago did document an increased stillbirth rate for GDM pregnancies that would qualify as preexisting diabetes according to World Health Organization criteria ( 6–9 ) . Below this threshold , the extent to [21083860] Please cite this paper as : Ijäs H , Vääräsmäki M , Morin‐Papunen L , Keravuo R , Ebeling T , Saarela T , Raudaskoski T. Metformin should be considered in the treatment of gestational diabetes : a prospect i ve r and omised study . BJOG 2011;118:880–885 [12073958] PURPOSE The purpose of this study was to examine the effects of self-monitoring of blood glucose ( SMBG ) on feelings of self-efficacy , dietary compliance , and pregnancy outcomes in women with diet-controlled gestational diabetes mellitus ( GDM ) . METHODS Fifty-eight women with GDM and a fasting blood glucose level < 95 mg/dL were r and omly assigned to 2 groups . The experimental group measured their blood glucose levels 4 times daily using a reflectance meter with memory . Metabolic status was assessed in the control group by periodic monitoring at prenatal visits . Otherwise the management protocol was identical for both groups . The Diabetes Empowerment Scale was completed at study entry and at 37 weeks gestation to assess feelings of self-efficacy . Dietary compliance was assessed at each visit . RESULTS Both groups of women achieved excellent glucose control ; only 1 woman in each group required insulin therapy . There were no significant differences with regard to feelings of self-efficacy , dietary compliance , birth weight , gestational age at delivery , Apgar scores , and neonatal complications . Rates of macrosomia , delivery by cesarean section , and occurrence of birth trauma were similar . CONCLUSIONS SMBG appears to have little effect on maternal feelings of self-efficacy , dietary compliance , or pregnancy outcomes in women with diet-controlled GDM [8950733] The aim of this study was to determine whether amniotic fluid insulin concentration ( AFI ) is a better parameter than mean maternal blood glucose values ( MBG ) for deciding about insulin therapy in patients with gestational diabetes . MBG 's were calculated on the base of 9 blood glucose levels during a 24 hour period after one week of diet therapy . In a prospect i ve trial between 1987 and 1989 in Karlsburg , 123 gestational diabetic patients were r and omized into two groups . Treatment was either based on the concentration of AFI or MBG levels . In a second series in Berlin , 103 patients were offered amniocentesis . 81 patients agreed and 22 refused . Treatment was then analogous to that in Karlsburg . In both groups of the r and omized population , strict metabolic control was achieved . There was no difference regarding pregnancy complications . Earlier labor induction and higher cesarean section rates were seen in the non-invasive group ( p < 0.05 ) . The incidence of diabetic fetopathy and neonatal hypoglycemia was significantly lower in the invasive group ( p < 0.01 ) , even though the metabolic control parameters did not differ between the two groups . The results in Berlin correspond to these findings . In conclusion , AFI enables the recognition of any hyperinsulinism reaction to the maternal metabolic situation . We recommend the additional measurement of the AFI concentration between 28 and 36 weeks as the direct fetal parameter for deciding about insulin treatment [3311138] The study was design ed to identify those pregnant women who are diagnosed as having gestational diabetes by National Diabetes Data Group ( NDDG ) criteria , but normal glucose tolerance ( NGT ) or impaired glucose tolerance ( IGT ) by the World Health Organization ( WHO ) criteria , and to test whether treatment changed the perinatal outcome in those with NGT and IGT . The 216 women with an abnormal 100 g oral glucose tolerance test ( OGTT ) using NDDG criteria were subjected to a 75 g OGTT . Using the WHO criteria , 111 women ( 51 % ) had NGT , 98 ( 45 % ) had IGT and 7 ( 3 % ) had frank diabetes mellitus . Those with NGT and IGT were r and omized into control and treatment groups . The perinatal outcome in these two groups was comparable whether the NGT and IGT groups were analysed together or separately except , that in those who were treated for IGT , smaller babies were born one week earlier than in the control group ( 3407 g vs 3110 g , P less than 0.01 ) . This suggests that the WHO criteria can safely replace the 100 g OGTT with substantial savings in manpower , money and patients ' time [2121124] Aim The efficacy and safety of insulin aspart ( IAsp ) , a rapid-acting human insulin analogue , were compared with regular human insulin ( HI ) as the bolus component of basal-bolus therapy for subjects with gestational diabetes mellitus ( GDM ) . Methods In a r and omized , parallel-group , open-labelled trial , 27 women with GDM ( age 30.7 ± 6.3 years , HbA1c < 7 % ) were r and omized to receive IAsp ( 5 min before meal ) or HI ( 30 min before meal ) . The trial period extended from diagnosis of GDM ( 18–28 weeks ) to 6 weeks postpartum . Results Both treatment groups maintained good overall glycaemic control during the study ( beginning and end of study HbA1c≤ 6 % ) . During the meal test , mean glucose at week 6 ( IAsp 4.2 ± 0.57 mmol/l , HI 4.8 ± 0.86 mmol/l ) was slightly lower than at week 0 ( IAsp 4.9 ± 0.59 mmol/l , HI 5.1 ± 0.36 mmol/l ) . However , change from baseline values for average glucose ( IAsp –1.09 ± 0.54 mmol/l , HI –0.54 ± 0.74 mmol/l ; P = 0.003 ) and C-peptide ( IAsp –0.50 ± 0.67 nmol/l , HI –0.30 ± 0.70 nmol/l ; P = 0.027 ) were significantly lower after IAsp treatment than HI treatment . No major hypoglycaemic events were reported during the study . Cross-reacting insulin antibody binding increased slightly from baseline in both treatments groups ( end of study : IAsp 2.1 ± 5.4 % , HI 6.4 ± 13.9 % ) , whereas antibodies specific to IAsp or HI remained relatively low ( < 1 % binding ) . Conclusion IAsp was more effective than HI in decreasing postpr and ial glucose concentrations . Duration of IAsp injection 5 min before a meal rather than 30 min prior to meals offers a more convenient therapy for subjects with GDM . Overall safety and effectiveness of IAsp were comparable to HI in pregnant women with GDM . Diabet . Med . 24 , 1129–1135 ( 2007 [1865537] Background Mild gestational diabetes is a common complication of pregnancy , affecting up to 9 % of pregnant women . Treatment of mild GDM is known to reduce adverse perinatal outcomes such as macrosomia and associated birth injuries , such as shoulder dystocia , bone fractures and nerve palsies . This study aim ed to compare the plasma glucose concentrations and serum insulin , leptin and adiponectin in cord blood of babies of women ( a ) without gestational diabetes mellitus ( GDM ) , ( b ) with mild GDM under routine care , or ( c ) mild GDM with treatment . Methods 95 women with mild GDM on oral glucose tolerance testing ( OGTT ) at one tertiary level maternity hospital who had been recruited to the ACHOIS trial at one of the collaborating hospitals and r and omised to either Treatment ( n = 46 ) or Routine Care ( n = 49 ) and Control women with a normal OGTT ( n = 133 ) were included in the study . Women with mild GDM ( treatment or routine care group ) and OGTT normal women received routine pregnancy care . In addition , women with treated mild GDM received dietary advice , blood glucose monitoring and insulin if necessary . The primary outcome measures were cord blood concentrations of glucose , insulin , adiponectin and leptin . Results Cord plasma glucose was higher in women receiving routine care compared with control , but was normalized by treatment for mild GDM ( p = 0.01 ) . Cord serum insulin and insulin to glucose ratio were similar between the three groups . Leptin concentration in cord serum was lower in GDM treated women compared with routine care ( p = 0.02 ) and not different to control ( p = 0.11 ) . Adiponectin was lower in both mild GDM groups compared with control ( Treatment p = 0.02 and Routine Care p = 0.07 ) , while the adiponectin to leptin ratio was lower for women receiving routine care compared with treatment ( p = 0.08 ) and control ( p = 0.05 ) . Conclusion Treatment of women with mild GDM using diet , blood glucose monitoring and insulin if necessary , influences the altered fetal adipoinsular axis characteristic of mild GDM in pregnancy [9240606] OBJECTIVES The purpose of this study was to determine whether strict maternal glycemic control for the treatment of gestational diabetes lessened the risk of fetal macrosomia , birth trauma , neonatal hypoglycemia , and operative delivery . The aim of the pilot study was to prepare for a multicenter trial by assessing patient acceptance of the study , by determining realistic accrual rates , and by detecting any major adverse outcomes in the control group that received routine obstetric care . STUDY DESIGN The study was a prospect i ve r and omized controlled trial comparing fetal-neonatal and maternal outcomes in 300 women with gestational diabetes . Women r and omized to the treatment arm were managed by strict glycemic control and tertiary level obstetric care , and women in the control arm received routine obstetric care . RESULTS Three hundred women with gestational diabetes mellitus were studied . There was no difference in maternal age , weight , or length of gestation between groups . The treatment mean birth weight was 3437 + /- 575 gm compared with 3544 + /- 601 gm in the control group , a difference of 107 gm ( not significant ) . Macrosomia rates were similar . There was no birth trauma in either group . The frequency of neonatal hypoglycemia and other metabolic complications was the same . The mode of delivery also showed similar patterns . The treatment group had significantly lower prepr and ial and postpr and ial glucose levels by 32 weeks ' gestation , which continued to term . CONCLUSION This pilot study suggests that intensive treatment of gestational diabetes mellitus may have little effect on birth weight , birth trauma , operative delivery , or neonatal metabolic disorders . It has demonstrated the safety of proceeding to a multicenter trial of sufficient sample size to confirm these findings [19747869] AIM The significant deterioration of insulin sensitivity and glucose tolerance during pregnancy can have serious health implication s for both the pregnant woman and her baby . Although it is well established that regular exercise benefits insulin sensitivity in the nonpregnant population , the effect on glucose tolerance in obese pregnant women is not known . The purpose of this study was to investigate the effect of a supervised 10-week , home-based , exercise programme , beginning at week 18 of gestation , on glucose tolerance and aerobic fitness in previously sedentary obese women . METHODS Twelve sedentary obese women were r and omized into an exercise ( EX ; n=6 ) or control ( CON ; n=6 ) group at 18 weeks of gestation . Those r and omized to EX engaged in 10 weeks of supervised home-based exercise ( three sessions a week of stationary cycling ) , while those in the CON group maintained their usual daily activity . Their glucose and insulin responses to an oral glucose tolerance test ( OGTT ) , as well as their aerobic fitness , were assessed both pre- and postintervention . RESULTS Reduced glucose tolerance in the CON , but not EX , group was indicated by a tendency postintervention towards higher blood glucose levels at 1h of the OGTT ( P=0.072 ) . Furthermore , at 2h of the postintervention OGTT , blood glucose tended to remain elevated from baseline in the CON ( P=0.077 ) . There was also a trend towards increased fitness in the EX ( P=0.064 ) , but not the CON group . CONCLUSION Regular aerobic exercise begun during pregnancy may have favourable effects on glucose tolerance and fitness in obese women , and warrants further investigation in a larger sample population [9579452] OBJECTIVES Replacement of the two-step , 100 gm , 3-hour National Diabetes Data Group procedure by the one-step , 75 gm , 2-hour World Health Organization oral glucose tolerance test has been hindered by a paucity of data comparing the two tests during pregnancy . The current series compared 100 gm and 75 gm glucose loads and glucose measurements in venous plasma or capillary blood . STUDY DESIGN After a 75 gm oral glucose tolerance test 30 gestational diabetics and 30 metabolically healthy pregnant women were r and omly assigned to a second 75 or 100 gm test within 3+/-1.3 ( mean+/-SD ) days . Glucose levels at both tests was measured in capillary blood and venous plasma , as were insulin and C peptide . RESULTS In controls 1-hour maternal glucose levels ( 112 vs 128 mg/dl ) and 2-hour levels ( 104 vs 113 mg/dl ) differed significantly after a 75 or 100 gm load ( paired t test ) . In gestational diabetes mellitus , however , there was no difference ( 176 vs 178 mg/dl ) but a low insulin/glucose quotient at 1 hour . Only 2-hour levels differed significantly ( 133 vs 149 mg/dl ) . In controls glucose measurement in capillary blood and venous plasma differed significantly at 1 hour ( 126 vs 115 mg/dl ) and 2 hours ( 111 vs 104 mg/dl ) independently of the glucose load . In gestational diabetes mellitus , however , glucose measurement in capillary blood and venous plasma differed neither in 1-hour levels ( 179 vs 174 mg/dl ) nor in 2-hour levels ( 142 vs 139 mg/dl ) . CONCLUSION In metabolically healthy women both different loading and different blood fractions lead to statistically different blood glucose levels at 1 and 2 hours . In gestational diabetes mellitus , however , 1-hour glucose levels do not differ after a 75 or 100 gm load or after glucose measurement in capillary blood or venous plasma . This is due to elevated insulin resistance shown by a low insulin/glucose quotient at 1 hour . For comparison of tests in gestational diabetes mellitus only , 2-hour values must be adjusted by 16 mg/dl after different loading [2797992] OBJECTIVE To determine how glucose control in women with GDM treated with metformin and /or insulin influenced pregnancy outcomes . RESEARCH DESIGN AND METHODS Women r and omly assigned to metformin or insulin treatment in the Metformin in Gestational Diabetes ( MiG ) trial had baseline glucose tolerance test ( OGTT ) results and A1C documented , together with all capillary glucose measurements during treatment . In the 724 women who had glucose data for analysis , tertiles of baseline glucose values and A1C and of mean capillary glucose values during treatment were calculated . The relationships between maternal factors , glucose values , and outcomes ( including a composite of neonatal complications , preeclampsia , and large-for-gestational-age [ LGA ] and small-for-gestational-age infants ) were examined with bivariable and multivariate models . RESULTS Baseline OGTT did not predict outcomes , but A1C predicted LGA infants ( P = 0.003 ) . During treatment , fasting capillary glucose predicted neonatal complications ( P < 0.001 ) and postpr and ial glucose predicted preeclampsia ( P = 0.016 ) and LGA infants ( P = 0.001 ) . Obesity did not influence outcomes , and there was no interaction between glycemic control , r and omized treatment , or maternal BMI in predicting outcomes . The lowest risk of complications was seen when fasting capillary glucose was < 4.9 mmol/l ( mean ± SD 4.6 ± 0.3 mmol/l ) compared with 4.9–5.3 mmol/l or higher and when 2-h postpr and ial glucose was 5.9–6.4 mmol/l ( 6.2 ± 0.2 mmol/l ) or lower . CONCLUSIONS Glucose control in women with gestational diabetes mellitus treated with metformin and /or insulin is strongly related to outcomes . Obesity is not related to outcomes in this group . Targets for fasting and postpr and ial capillary glucose may need to be lower than currently recommended [15951574] BACKGROUND We conducted a r and omized clinical trial to determine whether treatment of women with gestational diabetes mellitus reduced the risk of perinatal complications . METHODS We r and omly assigned women between 24 and 34 weeks ' gestation who had gestational diabetes to receive dietary advice , blood glucose monitoring , and insulin therapy as needed ( the intervention group ) or routine care . Primary outcomes included serious perinatal complications ( defined as death , shoulder dystocia , bone fracture , and nerve palsy ) , admission to the neonatal nursery , jaundice requiring phototherapy , induction of labor , cesarean birth , and maternal anxiety , depression , and health status . RESULTS The rate of serious perinatal complications was significantly lower among the infants of the 490 women in the intervention group than among the infants of the 510 women in the routine-care group ( 1 percent vs. 4 percent ; relative risk adjusted for maternal age , race or ethnic group , and parity , 0.33 ; 95 percent confidence interval , 0.14 to 0.75 ; P=0.01 ) . However , more infants of women in the intervention group were admitted to the neonatal nursery ( 71 percent vs. 61 percent ; adjusted relative risk , 1.13 ; 95 percent confidence interval , 1.03 to 1.23 ; P=0.01 ) . Women in the intervention group had a higher rate of induction of labor than the women in the routine-care group ( 39 percent vs. 29 percent ; adjusted relative risk , 1.36 ; 95 percent confidence interval , 1.15 to 1.62 ; P<0.001 ) , although the rates of cesarean delivery were similar ( 31 percent and 32 percent , respectively ; adjusted relative risk , 0.97 ; 95 percent confidence interval , 0.81 to 1.16 ; P=0.73 ) . At three months post partum , data on the women 's mood and quality of life , available for 573 women , revealed lower rates of depression and higher scores , consistent with improved health status , in the intervention group . CONCLUSIONS Treatment of gestational diabetes reduces serious perinatal morbidity and may also improve the woman 's health-related quality of life [2681032] OBJECTIVE A low – glycemic index diet is effective as a treatment for individuals with diabetes and has been shown to improve pregnancy outcomes when used from the first trimester . A low – glycemic index diet is commonly advised as treatment for women with gestational diabetes mellitus ( GDM ) . However , the efficacy of this advice and associated pregnancy outcomes have not been systematic ally examined . The purpose of this study was to determine whether prescribing a low – glycemic index diet for women with GDM could reduce the number of women requiring insulin without compromise of pregnancy outcomes . RESEARCH DESIGN AND METHODS All women with GDM seen over a 12-month period were considered for inclusion in the study . Women ( n = 63 ) were r and omly assigned to receive either a low – glycemic index diet or a conventional high-fiber ( and higher glycemic index ) diet . RESULTS Of the 31 women r and omly assigned to a low – glycemic index diet , 9 ( 29 % ) required insulin . Of the women r and omly assigned to a higher – glycemic index diet , a significantly higher proportion , 19 of 32 ( 59 % ) , met the criteria to commence insulin treatment ( P = 0.023 ) . However , 9 of these 19 women were able to avoid insulin use by changing to a low – glycemic index diet . Key obstetric and fetal outcomes were not significantly different . CONCLUSIONS Using a low – glycemic index diet for women with GDM effectively halved the number needing to use insulin , with no compromise of obstetric or fetal outcomes [18161398] OBJECTIVE To compare glycemic control and neonatal outcomes in women with gestational diabetes mellitus ( GDM ) treated with metformin vs. insulin . STUDY DESIGN Women with GDM not controlled with diet and exercise were r and omized to metformin ( n = 32 ) or insulin ( n = 31 ) . The levels of glycemic control as well as maternal/neonatal complications were evaluated . RESULTS The mean ( + /- SD ) fasting and 2-hour postpr and ial blood glucose did not differ statistically between the 2 treatment groups . No patient failed metformin and required insulin . The majority ( 27/32 ) were easily controlled on the initial dosage ( 500 mg twice a day ) . Gestational age at entry and delivery ( p = 0.077 , 0.412 ) were similar . The difference in the rate of cesarean delivery was not statistically significant between the 2 groups ( p = 0.102 ) . Neonatal statistics were also not different between the metformin and insulin groups : birth weight , Apgar score at 5 minutes , respiratory distress syndrome , hyperbilirubinemia , neonatal hypoglycemia and neonatal intensive care unit admission ( p = 0.144 - 0.373 ) . CONCLUSION Based on these preliminary data , metformin appears to be an effective alternative to insulin in the treatment of GDM [2241640] Background Recommended best practice is that economic evaluation of health care interventions should be integral with r and omised clinical trials . We performed a cost-consequence analysis of treating women with mild gestational diabetes mellitus by dietary advice , blood glucose monitoring and insulin therapy as needed compared with routine pregnancy care , using patient-level data from a multi-centre r and omised clinical trial . Methods Women with a singleton pregnancy who had mild gestational diabetes diagnosed by an oral glucose-tolerance test between 24 and 34 weeks ' gestation and their infants were included . Clinical outcomes and outpatient costs derived from all women and infants in the trial . Inpatient costs derived from women and infants attending the hospital contributing the largest number of enrolments ( 26.1 % ) , and charges to women and their families derived from a sub sample of participants from that hospital ( in 2002 Australian dollars ) . Occasions of service and health outcomes were adjusted for maternal age , ethnicity and parity . Analysis of variance was used with bootstrapping to confirm results . Primary clinical outcomes were serious perinatal complications ; admission to neonatal nursery ; jaundice requiring phototherapy ; induction of labour and caesarean delivery . Economic outcome measures were outpatient and inpatient costs , and charges to women and their families . Results For every 100 women with a singleton pregnancy and positive oral glucose tolerance test who were offered treatment for mild gestational diabetes mellitus in addition to routine obstetric care , $ 53,985 additional direct costs were incurred at the obstetric hospital , $ 6,521 additional charges were incurred by women and their families , 9.7 additional women experienced induction of labour , and 8.6 more babies were admitted to a neonatal nursery . However , 2.2 fewer babies experienced serious perinatal complication and 1.0 fewer babies experienced perinatal death . The incremental cost per additional serious perinatal complication prevented was $ 27,503 , per perinatal death prevented was $ 60,506 and per discounted life-year gained was $ 2,988 . Conclusion It is likely that the general public in high-income countries such as Australia would find reductions in perinatal mortality and in serious perinatal complications sufficient to justify additional health service and personal monetary charges . Over the whole lifespan , the incremental cost per extra life-year gained is highly favourable . Trial Registration Australian Clinical Trials Registry [17721753] This study discusses two main questions : the direct medical costs and the clinical effectiveness of the hospital treatment with insulin of pregnant women with gestational diabetes ( GD ) . A prospect i ve study that includes 50 women with GD is performed . The pregnant women are divided into 2 groups : Group I ( n=30 ) — pregnant women treated only with a diet ; and Group II ( n=20 ) — pregnant women treated with diet and insulin . We found that the metabolite compensation degree is improved after the applied treatment with insulin . The coefficient cost/effectiveness is 6954 lv./100 women . The analysis decision tree confirms in a very convenient way the fact that insulin treatment is a clinical ly more effective and financially more profitable strategy [15672015] OBJECTIVE We sought to investigate the association between glyburide dose , degree of severity in gestational diabetes mellitus ( GDM ) , level of glycemic control , and pregnancy outcome in insulin- and glyburide-treated patients . STUDY DESIGN In a secondary analysis of our previous r and omized study , 404 women were analyzed . The association among glyburide dose , severity of GDM , and selected maternal and neonatal factors was evaluated . Severity levels of GDM were stratified by fasting plasma glucose ( FPG ) from the oral glucose tolerance test ( OGTT ) . Infants with birth weight at or above the 90th percentile were considered large-for-gestational age ( LGA ) . Macrosomia was defined as birth weight > or = 4000 g. Well-controlled was defined as mean blood glucose < or = 95 mg/dL. The association between glyburide- and insulin-treated patients by severity of GDM and neonatal outcome was evaluated . RESULTS The dose received for the glyburide-treated patients was 2.5 mg-32 % ; 5 mg-23 % ; 10 mg-17 % ; 15 mg-8 % ; and 20 mg-20 % . Patients were grouped into low ( < or = 10 mg ) and high ( > 10 mg ) daily dose of glyburide . A comparison between severity of the disease ( fasting plasma glucose categories ) and highest dose of glyburide revealed a significant difference between the low-95 FPG and the other severity categories ( P = .02 ) . Of patients in the well-controlled glycemic group , only 6 % required the high dose of glyburide ( > 10 mg ) . In patients with poor glycemic control ( mean blood glucose > 95 mg/dL ) , 38 % received the high dose of glyburide ( P = .0001 ) . Comparison between the high glyburide ( > 10 mg ) and the low glyburide dosages ( < or = 10 mg ) revealed that the rate of macrosomia was 16 % vs 5 % and LGA 22 % vs 8 % , ( P = .01 ) , respectively . No significant difference was found in composite outcome , metabolic complications , and Ponderal Index between the 2 dose groups . Stratification by disease severity revealed a significantly lower rate of LGA for both the glyburide- and insulin-treated subjects . No significant difference was found between metabolic , respiratory , and neonatal intensive care unit ( NICU ) for patients within each fasting plasma glucose severity category . CONCLUSION Glyburide and insulin are equally efficient for treatment of GDM in all levels of disease severity . Achieving the established level of glycemic control , not the mode of pharmacologic therapy , is the key to improving the outcome in GDM [11679455] OBJECTIVE To compare management based on maternal glycemic criteria with management based on relaxed glycemic criteria and fetal abdominal circumference ( AC ) measurements in order to select patients for insulin treatment of gestational diabetes mellitus ( GDM ) with fasting hyperglycemia . RESEARCH DESIGN AND METHODS In a pilot study , 98 women with fasting plasma glucose ( FPG ) concentrations of 105 - 120 mg/dl were r and omized . The st and ard group received insulin treatment . The experimental group received insulin if the AC , measured monthly , was > or = 70th percentile and /or if any venous FPG measurement was > 120 mg/dl . Power was projected to detect a 250-g difference in birth weights . RESULTS Gestational ages , maternal glycemia , and AC percentiles were similar at r and omization . After initiation of protocol , venous FPG ( P = 0.003 ) and capillary blood glucose levels ( P = 0.049 ) were significantly lower in the st and ard group . Birth weights ( 3,271 + /- 458 vs. 3,369 + /- 461 g ) , frequencies of birth weights > 90th percentile ( 6.3 vs 8.3 % ) , and neonatal morbidity ( 25 vs. 25 % ) did not differ significantly between the st and ard and experimental groups , respectively . The cesarean delivery rate was significantly lower ( 14.6 vs. 33.3 % , P = 0.03 ) in the st and ard group ; this difference was not explained by birth weights . In the experimental group , infants of women who did not receive insulin had lower birth weights than infants of mothers treated with insulin ( 3,180 + /- 425 vs. 3,482 + /- 451 g , P = 0.03 ) . CONCLUSIONS In women with GDM and fasting hyperglycemia , glucose plus fetal AC measurements identified pregnancies at low risk for macrosomia and result ed in the avoidance of insulin therapy in 38 % of patients without increasing rates of neonatal morbidity [18463376] BACKGROUND Metformin is a logical treatment for women with gestational diabetes mellitus , but r and omized trials to assess the efficacy and safety of its use for this condition are lacking . METHODS We r and omly assigned 751 women with gestational diabetes mellitus at 20 to 33 weeks of gestation to open treatment with metformin ( with supplemental insulin if required ) or insulin . The primary outcome was a composite of neonatal hypoglycemia , respiratory distress , need for phototherapy , birth trauma , 5-minute Apgar score less than 7 , or prematurity . The trial was design ed to rule out a 33 % increase ( from 30 % to 40 % ) in this composite outcome in infants of women treated with metformin as compared with those treated with insulin . Secondary outcomes included neonatal anthropometric measurements , maternal glycemic control , maternal hypertensive complications , postpartum glucose tolerance , and acceptability of treatment . RESULTS Of the 363 women assigned to metformin , 92.6 % continued to receive metformin until delivery and 46.3 % received supplemental insulin . The rate of the primary composite outcome was 32.0 % in the group assigned to metformin and 32.2 % in the insulin group ( relative risk , 0.99 [ corrected ] ; 95 % confidence interval , 0.80 [ corrected ] to 1.23 [ corrected ] ) . More women in the metformin group than in the insulin group stated that they would choose to receive their assigned treatment again ( 76.6 % vs. 27.2 % , P<0.001 ) . The rates of other secondary outcomes did not differ significantly between the groups . There were no serious adverse events associated with the use of metformin . CONCLUSIONS In women with gestational diabetes mellitus , metformin ( alone or with supplemental insulin ) is not associated with increased perinatal complications as compared with insulin . The women preferred metformin to insulin treatment . ( Australian New Zeal and Clinical Trials Registry number , 12605000311651 . ) [14749658] OBJECTIVE This study examines the effects of circuit-type resistance training on the need for insulin in women with gestational diabetes mellitus . STUDY DESIGN Thirty-two patients with gestational diabetes mellitus were r and omly assigned either to a group that was treated with diet alone or to a group that was treated with diet plus resistance exercise . RESULTS The number of women whose condition required insulin therapy was the same , regardless of treatment . However , a subgroup analysis that examined only overweight women ( prepregnant body mass index , > 25 kg/m(2 ) ) showed a lower incidence of insulin use in the diet-plus-exercise group ( P<.05 ) . Women in the diet-plus-exercise group were prescribed less insulin ( P<.05 ) and showed a longer delay from diagnosis to the initiation of insulin therapy ( P<.05 ) , compared with the diet-alone group . CONCLUSION Resistance exercise training may help to avoid insulin therapy for overweight women with gestational diabetes mellitus [17596475] The Metformin in Gestational Diabetes ( MiG ) trial is a prospect i ve r and omized multicenter trial in women with gestational diabetes mellitus ( GDM ) that is testing the hypothesis that metformin treatment , compared with insulin , is associated with similar perinatal outcomes , improved markers of insulin sensitivity in the mother and baby , and improved treatment acceptability . Women with GDM who are at 20–33 weeks ’ gestation in a singleton pregnancy and meet entry criteria are r and omized to insulin or metformin treatment . The primary outcome is a composite of neonatal morbidity , with 750 recruits required . The trial finished recruiting in October 2006 . Interim data on 200 women ( and subsequently 550 women ) have been review ed by the data safety monitoring committee , which has reported that the trial should answer the hypotheses and no protocol changes are required . Data from 457 women show recruits are a mean age of 33.3 ± 5.3 years ; BMI of 32.1 ± 7.8 kg/m2 ; and ethnicity 47.2 % European/Caucasian , 25.7 % Polynesian , and 24.3 % Indian/Asian . The mean fasting glucose at recruitment is 5.3 ± 1.1 mmol/l and A1C is 5.7 ± 0.8 % . Long-term follow-up of children started at age 2 years , with assessment s of body composition , neurodevelopment , diet , and activity levels . The MiG trial will address the efficacy and detailed safety of metformin compared with insulin in women with GDM . Long-term follow-up of offspring will examine whether treatment influences later health ( Australasian Clinical Trials Registry number 12605000311651 ) . GDM is diagnosed in over 4 % of pregnant women ( 1,2 ) . The prevalence is increasing as the pregnancy population becomes older and fatter . Women with GDM have increased rates of pregnancy complications and risks of later type 2 diabetes ( 1,2 ) . The offspring of women with GDM also have increased risks of perinatal complications and long-term risks of obesity and type 2 diabetes ( 1– [2858199] OBJECTIVE Gestational diabetes mellitus ( GDM ) may cause obesity in the offspring . The objective was to assess the effect of treatment for mild GDM on the BMI of 4- to 5-year-old children . RESEARCH DESIGN AND METHODS Participants were 199 mothers who participated in a r and omized controlled trial of the treatment of mild GDM during pregnancy and their children . Trained nurses measured the height and weight of the children at preschool visits in a state-wide surveillance program in the state of South Australia . The main outcome measure was age- and sex-specific BMI Z score based on st and ards of the International Obesity Task Force . RESULTS At birth , prevalence of macrosomia ( birth weight ≥4,000 g ) was 5.3 % among the 94 children whose mothers were in the intervention group , and 21.9 % among the 105 children in the routine care control group . At 4- to 5-years-old , mean ( SD ) BMI Z score was 0.49 ( 1.20 ) in intervention children and 0.41 ( 1.40 ) among controls . The difference between treatment groups was 0.08 ( 95 % CI −0.29 to 0.44 ) , an estimate minimally changed by adjustment for maternal race , parity , age , and socio-economic index ( 0.08 [ −0.29 to 0.45 ] ) . Evaluating BMI ≥85th percentile rather than continuous BMI Z score gave similarly null results . CONCLUSIONS Although treatment of GDM substantially reduced macrosomia at birth , it did not result in a change in BMI at age 4- to 5-years-old [2188182] One hundred eight gestational diabetics were r and omized to receive either diet alone or diet plus insulin ( 20 units NPH and 10 units regular ) for glycemic control . Blood glucose levels were evaluated weekly in a high-risk clinic where medical and nutritional support and counseling were provided . Among 68 women successfully treated for a minimum of 6 weeks , the mean birth weight , macrosomia rate , and ponderal index were reduced significantly in the insulin- treated group . Insulin reduced birth weights significantly in women with a delivery weight of 200 lb or more ( 4060 ± 342 versus 3397 ± 640 g ) and in those with a delivery weight less than 200 lb ( 3324 ± 448 versus 3047 ± 394 g ) . No patient with good glucose control and a maternal delivery weight under 200 lb had a newborn over 4000 g. Patients failing glycemic control were at greatest risk ( 30 % ) for fetal overgrowth whether initially receiving insulin or not . Maternal obesity or failure to achieve glycemic control should alert the clinician to a substantially increased risk of macrosomia [2764059] We studied the impact of a training program on glucose tolerance in gestational diabetes mellitus . Women with gestational diabetes mellitus ( N = 19 ) were r and omized into either group I , a 6-week diet alone group ( 24 to 30 kcal/kg/24 hours ; 20 % protein , 40 % carbohydrate , 40 % fat ) , or group II , which followed the same diet plus exercise ( 20 minutes three times a week for 6 weeks ) . An arm ergometer was used to maintain heart rate in the training range . Glycemic response was monitored by glycosylated hemoglobin , a 50 gm oral glucose challenge with a fasting and 1-hour plasma glucose , and blood glucose self-monitoring , fasting and 1 hour after meals . Week 1 glycemic parameters were the same for both groups . Week 6 data ( mean + /- SD ) were as follows : group I glycosylated hemoglobin , 4.7 % + 0.2 % versus group II , 4.2 % + /- 0.2 % ; p less than 0.001 . The group I glucose challenge fasting value was 87.6 + /- 6.2 versus 70.1 + /- 6.6 mg/dl , p less than 0.001 for group II . The group I 1-hour plasma glucose challenge result was 187.5 + /- 12.9 mg/dl versus 105.9 + /- 18.9 mg/dl for group II , p less than 0.001 . The glycemic levels diverged between the groups at week 4 . We conclude that arm ergometer training is feasible in women with gestational diabetes mellitus and results in lower glycosylated hemoglobin , fasting , and 1-hour plasma glucose concentrations than diet alone . Arm ergometer training may provide a useful treatment option for women with gestational diabetes mellitus and may obviate insulin treatment [20542272] OBJECTIVE To assess blood glucose control and neonatal outcomes when women with gestational diabetes mellitus ( GDM ) were treated with metformin or glyburide . METHODS When an appropriate diet was insufficient to control their blood glucose levels , women with GDM were r and omized to a glyburide or a metformin treatment group . If the maximum dose was reached , the assessed drug was replaced by insulin . The primary outcome measures analyzed were maternal glucose levels during pregnancy , birth weight , and neonatal glucose levels . RESULTS The only significant difference in outcome between the 2 treatment drugs was that maternal weight gain during pregnancy was less in the metformin ( n=40 ) than in the glyburide group ( n=32 ) ( 10.3 kg vs 7.6 kg ; P=0.02 ) . No differences were found in treatment failure , mean level of fasting or postpr and ial plasma glucose , rate of participants with glycated hemoglobin , birth weight , rate of large-for-gestational-age newborns , or newborns with hypoglycemia . CONCLUSION The treatment of GDM with metformin or glyburide was found to be equivalent for both women and newborns [3532669] A r and omised prospect i ve study of treatment with dietary restriction alone or insulin therapy with dietary advice was performed in 15 women with glucose intolerance diagnosed early in the third trimester of pregnancy . Twenty-four hour profiles of plasma glucose and 3-hydroxybutyrate were performed before and four weeks after commencing treatment . The effect on neonatal outcome was assessed . The case history of one of the patients in the study was sent to British physicians with a special interest in diabetes to obtain their opinion about the appropriate initial treatment of women with gestational diabetes [10774766] The goal of this study was to determine whether the type of fat plays a role in the glucose response to a meal , independent of the carbohydrate content . Ten gestational diabetic women ( gestational weeks 29 - 34 ) who were well controlled on diet alone were r and omized as to the order in which they would eat a meal , after overnight fast , containing saturated fat ( SF ) or monounsaturated fat ( MUFA ) . Blood was drawn at 0 , 60 , 120 , and 180 min for plasma glucose , insulin , lipid profile ( triglycerides , total cholesterol , HDL-cholesterol , LDL-cholesterol , VLDL-cholesterol ) and free fatty acids . After 2 weeks , each patient received the other type of meal . The test meal was composed of 20 % of the total daily caloric needs based on ideal body weight . The area under the curve showed a significantly lower glucose concentration for SF meal ( p = 0.001 ) . Serum insulin concentrations followed the glucose response with the peak at the 60-min time point and a significantly lower concentration at the 180-min time point in the SF than in the MUFA group . The present study demonstrated that the addition of SF to the meal result ed in lower postpr and ial glucose and insulin than when the meal contained MUFA . Thus , SF may be useful in controlling postpr and ial glucose [8166187] OBJECTIVE We tested the hypothesis that intensified management of gestational diabetes mellitus on the basis of stringent glycemic control , verified glucose data , and adherence to an established criterion for insulin initiation results in near normoglycemia control and reduction of adverse outcomes . STUDY DESIGN A prospect i ve , population -based study compared the effect on perinatal outcome of conventional ( n = 1316 ) and intensified ( n = 1145 ) management . Group assignment was based on availability of memory-based reflectance meters at entry to the program . A contemporaneous r and omized control group ( nondiabetic , n = 4922 ) was selected . RESULTS The diabetic groups were comparable in demographic characteristics and in factors associated with higher risk for adverse pregnancy outcome , such as previous macrosomia , previous gestational diabetes mellitus , and family history of diabetes . The control group was younger , less obese , and had a lower rate of previous macrosomia . The intensified management group had rates of macrosomia , cesarean section , metabolic complications , shoulder dystocia , stillbirth , neonatal intensive care unit days , and respiratory complications lower than those in the conventional management group and comparable to those of the nondiabetic controls . Other maternal complication rates , such as for preeclampsia , chronic hypertension , and infection , were similar for the three groups . Mean blood glucose levels were a good predictor of perinatal outcome . Gestational age at delivery , previous history of macrosomia , and overall mean blood glucose levels were the only significant predictors of birth weight percentile in both diabetic groups ( logistic regression ) . CONCLUSION The intensified management approach is significantly associated with enhanced perinatal outcome . This management strategy clarifies the relationship between glycemic control and neonatal outcome [15223975] OBJECTIVES In order to prevent abnormalities of fetal growth still characterizing pregnancies complicated by Gestational Diabetes ( GDM ) , in the present study we evaluated a therapeutic strategy for GDM based on ultrasound ( US ) measurement of fetal insulin-sensitive tissues . METHODS All GDM women diagnosed before 28th week immediately started diet and self-monitoring of blood glucose ; after 2 weeks they were r and omized to conventional ( C ) or modified ( M ) management . In C the glycemic target ( GT ) was fixed at 90 fasting/120 post-pr and ial mg/dl ; in M GT varied , according to US measurement of the Abdominal Circumference ( AC ) centile performed every 2 weeks : 80/100 if AC > or = 75th , 100/140 if AC<75th . Therapy was tailored to mean fasting ( FG ) and postpr and ial glycemia ( PPG ) . RESULTS Globally , 229 women completed the study , 78 in C , 151 in M. Use of insulin was 16.7 % in C , 30.4 % in M ( total groups ) , significantly more frequent in M than in C ( 59.7 % vs 15.4 % ) when considering only women with AC > or = 75th c. Mean metabolic data were similar in the 2 groups , but in M a tightly-optimized subgroup , result ing from the lowering of GT due to AC > or = 75th , coexisted with a less-controlled one , whose higher GT was justified by AC<75th . Pregnancy outcome was better in M , with lower ( p<0.05 * ) rate of LGA * ( 7.9 % vs 17.9 % ) , SGA ( 6.0 % vs 9.0 % ) and Macrosomia * ( 3.3 % vs 11.5 % ) . CONCLUSIONS Our data show the value of a flexible US-based approach to the treatment of GDM . This model does not necessarily involve a generalized aggressive treatment , allowing to concentrate therapeutical efforts on a small subgroup of women showing indirect US evidence of fetal hyperinsulinization . Such a selective approach allowed to obtain a near-normalization of fetal growth , with clear advantages on global pregnancy outcome [19375570] OBJECTIVE We hypothesized that body composition would be similar among neonates of women with gestational diabetes ( GDM ) treated with glyburide or insulin . STUDY DESIGN Women with GDM requiring medical therapy were r and omized to insulin or glyburide . The primary outcome was percent neonatal fat mass measured by total body electrical conductivity . Secondary outcomes included anthropometrics , glycemic control , and biomarkers . Statistical analysis included Student t test , chi(2 ) , and regression modeling . RESULTS Eighty-two neonates underwent postnatal measurements . Baseline factors were not different by group . Neonatal percent fat mass did not differ between treatment groups ( 11.2 + /- 4.2 vs 12.8 + /- 5.7 ) . Fat mass , body mass index , ponderal index , skinfold sum , and arm fat area were not different when analyzed by intent to treat or actual treatment group . Cord concentrations of biomarkers were also similar . CONCLUSION There was no difference in neonatal adiposity in infants of women treated for GDM with glyburide or insulin [2675597] In this study we sought to test the hypothesis that treatment of women with one abnormal oral glucose tolerance test value will result in reduction of adverse outcome . One hundred twenty-six women with one abnormal oral glucose tolerance test value and 146 women in the control group ( normal oral glucose tolerance test values ) participated in a prospect i ve study during the third trimester of pregnancy . The subjects with one abnormal test result were r and omized into treated ( group 1 ) and untreated groups ( group II ) . Group 1 subjects were treated with a strict diabetic protocol to maintain tight glycemic control by means of diet and insulin therapy . Group 2 subjects tested their capillary blood glucose for a baseline period . The study revealed that the level of glycemic control was similar before initiation of therapy ( mean capillary blood glucose 118 + /- 14 vs. 119 + /- 15 mg/dl , p = NS ) for groups 1 and 2 , respectively . There was a significant difference in mean capillary blood glucose ( 95 + /- 10 vs. 119 + /- 15 mg/dl , p less than 0.0001 ) , prepr and ial , and postpr and ial determinations between the treated and untreated groups . The overall incidence of neonatal metabolic complications ( 4 % vs. 14 % , p less than 0.05 ) and large infants ( 6 % vs. 24 % , p less than 0.03 ) was significantly lower in the treated group . Comparison between the control ( normal oral glucose tolerance test ) and the untreated groups showed a significantly higher incidence of large infants and metabolic complications . No difference was found between the normal and treated groups . Thus we conclude that treatment of individuals with one abnormal oral glucose tolerance test value will result in significant reduction in adverse outcome in pregnancy [9170478] Objective To assess the usefulness of a breakfast test in determining which women with gestational diabetes do not need self-monitoring of blood glucose levels ( home monitoring ) . Methods a 1-hour post-st and ardized breakfast blood glucose below 7.8 mmol/L ( 140 mg/dL ) was measured in 227 women and at or above 7.8 mmol/L in 115 . Within each group , women were r and omized to home monitoring with a meter or to clinic follow-up . Target glucose values were 5.3 mmol/L ( 95 mg/dL ) fasting , 5.6 mmol/L ( 101 mg/dL ) before meals , and 7.8 mmol/L ( 140 mg/dL ) 1 hour postpr and ial . Up to these thresholds women on clinic follow-up were transferred to home monitoring . Insulin therapy was started on the same thresholds in women r and omized or transferred to home monitoring . Large ofr gestational age ( LGA ) newborns represented the main outcome , with the transfer rate to home monitoring and need of insulin therapy the secondary ones . Results The LGA delivery rate was not significantly different in the two follow-up groups in women with a breakfast result below 7.8 mmol/L ( 9.8 versus 4.3 % ) but was higher in the clinic follow-up among women with a breakfast result at or above 7.8 mmol/L ( 13.3 % versus 30.9 % ; P < .05 ) . Fewer women with a breakfast result below 7.8 mmol/L were transferred to home monitoring ( 2.6 versus 52.7 % ; P < .001 ) or started on insulin therapy ( 3.6 versus 25.2 % ; P < .001 ) . The breakfast test cutoff of 7.8 mmol/L predicted insulin need with a sensitivity of 91.0 % and a specificity of 72.0 % . Conclusion A breakfast test is useful in identifying a low-risk population in which clinic follow-up may be used safely [20653150] OBJECTIVE The objective of the study was to compare premixed insulin aspart 30 ( BIAsp 30 ) vs premixed human insulin 30 ( BHI 30 ) on efficacy , safety , fetal and perinatal outcomes in pregnancies associated with gestational diabetes mellitus [ GDM ] . This was the first r and omized study to use pre mixed insulin analogue [ BIAsp ] in GDM . METHODS The study population consisted of 76 GDM women assigned to BIAsp 30 ( group A ) and an equal number to BHI 30 ( group B ) . RESULTS There was no statistically significant difference between the age , BMI , gestational weeks and glycemic level at entry between the group A and group B women ( p > 0.05 ) . There was no statistical difference between the two groups in glycemic control or insulin dose ( p > 0.05 ) before confinement . The frequency of birth weight of new born above 90 percentile was 6.8 % in Group 1 and 9.2 % in Group 2 . The proportion of macrosomia was higher in Group 2 when compared to Group 1 , however the difference was not statistically significant ( P = 0.819 ) . CONCLUSION BIAsp was safe during pregnancy and pregnant women found it convenient due to meal time dosing . Fetal outcome using BIAsp was also comparable with BHI 30 [6993163] A 16-yr prospect i ve study of 615 gestational diabetic subjects , half of whom were r and omly assigned to insulin therapy during pregnancy , is evaluated to report on the potential reduction in subsequent diabetes due to insulin therapy . No such difference in incidence rates was observed between the two groups . In the subsets of women managed with insulin who bore a baby of large birthweight or who had a family history of diabetes , subsequent decompensated diabetes was found to be significantly reduced . Both life table and multivariate analyses to adjust for the effects of age , weight , level of blood glucose at selection , duration of follow-up , and other potentially confounding covariables confirmed this conclusion . The finding suggests the possibility of long-term preventive benefits from insulin treatment in high risk subsets of women with gestational diabetes [18211656] RATIONALE , AIMS AND OBJECTIVE To investigate whether the introduction of a programme of optimising drug treatment , intensive education and self-monitoring of patients diagnosed with gestational diabetes mellitus ( GDM ) at an early stage ( < 20 gestational weeks ) , will improve management outcomes as determined by objective measures of patient knowledge about diabetes , glycaemia control , maternal/neonatal complications , and health-related quality of life . METHODS The study was a r and omized , controlled , longitudinal , prospect i ve clinical trial performed at Al-Ain Hospital , Al-Ain , United Arab Emirates . Over an 18-month period , patients diagnosed with GDM were recruited and were r and omly assigned to either an intervention or a control group , in a ratio of 3:2 . Intervention patients received a structured pharmaceutical care service ( including education and introduction of intensive self-monitoring ) while control patients received traditional services . Patients were followed up from time of recruitment until 6 months postnatally at scheduled outpatient clinics . A range of clinical and humanistic outcome measures , including maternal and neonatal complications , were used to assess the impact of the intervention . RESULTS A total of 165 patients ( 99 intervention , 66 control ) completed the study . The intervention patients exhibited a range of benefits from the provision of the programme when compared with control group patients . Statistically significant ( P < 0.05 ) improvements were shown in the intervention group for knowledge of diabetes , health-related quality of life ( as determined by the SF36 ) , control of plasma glucose and HbA(1c ) , maternal complications [ e.g. decreased incidence of pre-eclampsia ( 5.1 % vs. 16.7 % ) , eclampsia ( 1.0 % vs. 7.6 % ) , episodes of severe hyperglycaemia ( 3.0 % vs. 19.7 % ) and need for Caesarean section ( 7.1 % vs. 18.2 % ) ] , and neonatal complications [ e.g. decreased incidence of neonatal hypoglycaemia ( 2.0 % vs. 10.6 % ) , respiratory distress at birth ( 4.0 % vs. 15.2 % ) , hyperbilirubinaemia ( 1.0 % vs. 12.1 % ) and large for gestational age ( 9.0 % vs. 22.7 % ) ] . CONCLUSION The research provides clear evidence that provision of pharmaceutical care adds value to the management of GDM as exemplified by improved maternal and neonatal outcomes [10955425] Objective To determine whether a study of a less intensive form of management for impaired glucose tolerance in pregnancy is feasible and whether women would accept r and omisation [8299437] OBJECTIVE To eluci date the glycemic response and antibody formation in gestational diabetic women treated with insulin injected by a needle or a jet . The American Diabetes Association 's position statement on jet injectors raised the concern that “ insulin could be denatured as a result of forceful injection through a tiny port , which could lead to an increase in antibody formation ” ( Diabetes Care11:600 , 1988 ) . However , the pharmacokinetics of jet-injected insulin suggest that it might be useful in controlling postpr and ial glucose levels . METHODS We r and omized 20 women with gestational diabetes mellitus ( < 34 wk gestation ) who required insulin to receive either jet-injected or needle-injected human NPH and regular insulin . Variables of interest were evaluated at the start of therapy , weekly until delivery , and 6-wk postpartum that included : 1 ) insulin antibodies in the mother and her infant , 2 ) HbA1c , 3 ) insulin dose , 4 ) fasting and postpr and ial glucose levels , and 5 ) subject acceptance and preference . RESULTS Of the 10 women in the needle group , 6 developed significant insulin antibodies compared with 1 of 10 in the jet group ( P < 0.001 ) . HbA1c and insulin doses were the same in both groups . During the test meal , glucose levels in the jet group were significantly lower ( P < 0.01 ) , yet none of the women in the jet group experienced blood glucose 70 mg/dl ( 3.89 mM ) at 3–4 h after the meal , compared with 5 in the needle group ( P < 0.001 ) . Jet injection was associated with less variability ( P < 0.001 ) in postpr and ial glucose values but slightly greater variability ( P < 0.05 ) in fasting glucose . Jet-injected insulin was more readily accepted by subjects than needle injections . CONCLUSIONS Jet injection is associated with a diminished antibody response and postpr and ial variability compared with needle-injected insulin . Thus , this warrants consideration as a therapeutic option for women with gestational diabetes mellitus and may also be applicable to nonpregnant , insulin-requiring diabetic patients [15565082] Abstract Women with gestational diabetes mellitus ( GDM ) have a greater risk of developing type 2 diabetes mellitus ( DM ) and heart disease than pregnant women without GDM . Advice given during the GDM pregnancy provides an opportunity to develop protective dietary patterns for the long-term management of this risk . Dietary guidelines for the prevention and management of type 2 DM support the inclusion of unsaturated fats , but food advice needs to target this outcome . The aim of this study was to compare the dietary intakes of women with GDM given general low-fat advice ( control group ) to women with GDM given the same advice with additional targets for food sources of unsaturated fats ( intervention group ) . After approximately 6 weeks , the intervention group reported more ideal dietary fatty acid intakes than the control group , with polyunsaturated : saturated fat ratios of 1:1 and 0.4:1 , respectively ( P < .001 ) , assessed using repeated measures analysis of variance . These results confirm the need to include food sources of unsaturated fats in advice strategies to assure optimal protective eating habits in this at-risk group [21094553] AIM The objectives of this pilot study were to determine the feasibility and effect on glycaemic control of a low-glycaemic-index ( GI ) diet in women with gestational diabetes or impaired glucose tolerance of pregnancy . METHODS participants , recruited from the Diabetes-in-Pregnancy Clinic of an inner-city teaching hospital serving a predominantly non-Caucasian population , were r and omized to a low-GI ( n=23 ) or control ( n=24 ) diet and followed from 28 weeks gestation until delivery . Self-monitored-blood-glucose ( SMBG ) , maternal and infant weight were collected from medical charts . Dietary intakes were assessed using diet records and question naires . RESULTS diet GI on control ( 58 , 95 % CI : 56,60 ) was significantly higher than on low-GI ( 49 , 95 % CI : 47,51 ; p=0.001 ) . Glycaemic control improved on both diets , but more postpr and ial glucose values were within target on low-GI ( 58.4 % of n=1891 ) than control ( 48.7 % of n=1834 ; p<0.001 ) . SMBG post-breakfast was directly related to pre-pregnancy BMI in the control , but not the low-GI group ( BMI * diet interaction ; p=0.021 ) . Participants accepted the study foods and were willing to consume them post-intervention . CONCLUSIONS a low-GI diet was feasible and acceptable in this sample and facilitated control of postpr and ial glucose . A larger study is needed to determine the effect of a low-GI diet on maternal and infant outcomes [11194427] Summary : A r and omised controlled trial was design ed to determine the effect of moderate 30 % maternal dietary energy restriction on the requirement for maternal insulin therapy and the incidence of macrosomia in gestational diabetes . Although the control group restricted their intake to a level similar to that of the intervention group ( 6845 kiloJoules ( kJ ) versus 6579 kJ ) , the result ing cohort could not identify any adverse effect of energy restriction in pregnancy . Energy restriction did not alter the frequency of insulin therapy ( 17.5 % in the intervention group and 16.9 % in the control group ) . Mean birth weight ( 3461 g in the intervention group and 3267 g in the control group ) was not affected . There was a trend in the intervention group towards later gestational age at commencement of insulin therapy ( 33 weeks versus 31 weeks ) and lower maximum daily insulin dose ( 23 units versus 60 units ) which did not reach statistical significance . Energy restriction did not cause an increase in ketonemia [20027034] OBJECTIVE : To compare the efficacy of metformin with glyburide for glycemic control in gestational diabetes . METHODS : Patients with gestational diabetes who did not achieve glycemic control on diet were r and omly assigned to metformin ( n=75 ) or glyburide ( n=74 ) as single agents . The primary outcome was glycemic control . Secondary outcomes were drug failure rate and neonatal and obstetric complications . RESULTS : In the patients who achieved adequate glycemic control , the mean fasting and 2-hour postpr and ial blood glucose levels were not statistically different between the two groups . However , 26 patients in the metformin group ( 34.7 % ) and 12 patients in the glyburide group ( 16.2 % ) did not achieve adequate glycemic control and required insulin therapy ( P=.01 ) . CONCLUSION : In this study , the failure rate of metformin was 2.1 times higher than the failure rate of glyburide when used in the management of gestational diabetes ( 95 % confidence interval 1.2–3.9 ) . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00965991 . LEVEL OF EVIDENCE : [16963348] Nutrition practice guidelines were developed for gestational diabetes mellitus by registered dietitians from the Diabetes Care and Education and the Women 's Health and Reproductive Nutrition dietetic practice groups . To vali date the guidelines , a clinical trial was design ed with clinic sites r and omly assigned to either nutrition practice guidelines care ( 12 sites ) or usual nutrition care ( 13 sites ) , with diabetes , obstetric , and other clinic types represented in both groups . Volunteer dietitians served as study coordinators and recruited women diagnosed with gestational diabetes mellitus . The nutrition practice guidelines define medical nutrition therapy ( MNT ) for gestational diabetes and emphasize three areas -definition of MNT clinical goals with indexes to modify or advance MNT and criteria to start insulin ; use of self-monitoring tools ; and provision of three nutrition visits . Usual care sites provided prenatal nutrition care according to usual practice . The effect of nutrition care ( sites following the nutrition care guidelines ) and type of clinic site on changes in glycated hemoglobin and infant birth weight , adjusted for other covariates , were evaluated using linear regression . Differences in insulin use and other infant outcomes between treatment groups were evaluated using logistic regression . Generalized estimating equations were used to accommo date nonindependence within r and omized clusters of patients within clinic sites . Data from 215 women indicated less insulin use at diabetes clinic sites in the nutrition practice guidelines groups and improved glycated hemoglobin control during the treatment period in diabetes clinics compared with obstetric or other clinics . A higher proportion of women in the usual care group had glycated hemoglobin levels that exceeded 6 % at follow-up compared with women in the nutrition practice guidelines group ( 13.6 % vs 8.1 % ) , although not statistically significant ( P=0.26 ) . A significant clinic type and treatment group effect was found for birth weight . Nutrition practice guidelines for gestational diabetes mellitus reflected nutrition care already being provided by registered dietitians in diabetes clinics prior to this study because outcomes at these clinics were not impacted . Use of the guidelines by dietitians at obstetric and other clinics tended to improve outcomes at these sites [11360593] OBJECTIVE To study the treatment of women with gestational impared glucose tolerance ( GIGT ) in relation to outcome of fetus and newborns . METHODS 98 women with GIGT were r and omized into untreated ( 37 mothers ) and treated groups ( 61 mothers ) that included diet control and insulin therapy . The perinatal outcomes were compared in the two groups . RESULTS The incidence of macrosomia ( P < 0.01 ) and fetal distress ( P < 0.05 ) was found to be significantly higher in the untreated group when compared with the treated group . The prevalence of neonatal metabolic complications in the untreated group was higher than that of the treated group as well . CONCLUSION Treatment of women with GIGT will reduce adverse outcome in pregnancy [5936737] The purpose of this study was to examine pregnancy outcome in women with abnormal oral glucose tolerance tests , in relation to treatment with diet and insulin . Glucose tolerance tests , done because of well-known historical risk factors , were considered abnormal if two or more readings exceeded the following : fasting , 110 ; 1 hour , 170 ; 2 hours , 120 ; and 3 hours , 110 ( all in mg/100 mL , measured as total reducing substances in whole venous blood ) . Those with positive tests were divided r and omly into a “ positive-control ” group ( n 308 ) that received st and ard prenatal care or a “ positive-treated ” group ( n 307 ) that received dietary instructions ( 30 kcal/kg ideal body weight , 40 % as carbohydrate , and 1.5–2 g protein/kg body weight ) and insulin ( initial dose 10 U per day of intermediate-acting insulin , adjusted subsequently as directed by blood and urine studies ) , beginning at usually about 32 weeks . A third group ( n 328 ) , termed “ negative controls , ” had exhibited normal glucose tolerance testing . The three groups were similar , except that those with abnormal glucose tolerance tended to be older and heavier , as expected . With respect to outcome , infants with birth weights exceeding 9 lb were three times as frequent in positive-control subjects as in either positive-treated subjects or negative controls ( 13.1 % , 4.3 % , and 3.7 % , respectively ) . Perinatal deaths ( 28 weeks ’ gestation through 14 days after birth ) were similar in the two positive groups ( 4.9 % in control and 4.3 % in treated ) and significantly higher than in negative controls ( 1.9 % ) , with the increase involving both fetal and neonatal components . The conclusions were 1 ) abnormal glucose tolerance during pregnancy leads to larger infants and higher perinatal mortality and 2 ) treatment with diet and insulin ameliorates the former but not the latter . This study concerned what O’Sullivan called potential diabetes and others at the time termed latent or chemical diabetes or prediabetes , but what today we refer to as gestational diabetes . Acceptance of it as a pathologic entity was far from unanimous in 1966 . O’Sullivan resolved the controversy with this large , well- design ed , and well-analyzed clinical trial . The immediate influence was two-fold . In the first place , it settled the existing disagreement as to whether or not impaired glucose tolerance adversely influences pregnancy outcome ; large infants occurred three times as frequently and perinatal deaths were more than doubled in women with abnormal carbohydrate metabolism . Second , the findings of the intervention trial indicated clearly that treatment of gestational diabetes with diet and insulin in late gestation normalizes birth weight ( although it did not seem to influence perinatal mortality ) , a finding confirmed a number of times by subsequent investigators . Incidentally , the frequencies of both fetal and neonatal deaths may seem high , but it needs to be remembered that this experience ante date d the advent of modern fetal surveillance and neonatal intensive care . John B. O’Sullivan , a pioneer in clinical research in gestational diabetes , was an internist . He defined st and ards for the oral glucose tolerance test in pregnancy that , though modified slightly by subsequent investigators , are basically those in use today . Born in 1926 , he received his medical education in his native Irel and before immigrating to the United States in 1955 . After further training in internal medicine at the Lahey Clinic , he took a faculty position at the Boston University School of Medicine , where he did his original work on early diabetes as medical director of the Prenatal Metabolism Clinic at Boston City Hospital and chief of medicine at St. Margaret ’s Hospital . In addition to his position as Associate Professor at Boston University , he also served on the faculties of the Harvard and Yale medical schools . Later he was director of employee health for the Liberty Mutual Insurance Company . He died of cancer in August 2001 [1748256] Forty-one patients with gestational diabetes requiring insulin were enrolled in a r and omized study to investigate the efficacy of an exercise program in normalizing glucose tolerance . Seventeen of 21 patients completed the exercise program while maintaining normoglycemia and obviating insulin therapy . Maternal and neonatal complications did not differ between the study and control groups . The type of program described appears to be safe and can serve as a model for exercise prescription for pregnant diabetic women to attain improved glucose tolerance [4829275] The outcome of pregnancy in control and treated gestational diabetics was not significantly different . The decreased loss rate among the insulin- and diet-treated gestational diabetics , however , did become significant when the data were reanalyzed with consideration of two important influencing variables . The high-risk group of gestational diabetics aged 25 years and older who received insulin therapy before the 32nd week of gestation had fewer fetal losses . Documentation of the critical role played by both maternal age and the gestational age at which insulin therapy is commenced now makes the institution of a conclusive prospect i ve study feasible . The adequately established hypothesis that insulin management of gestational diabetics favorably affects the outcome of their pregnancies can then be finally resolved [8796796] The effect of an acute period of moderate intensity exercise on maternal glycemic excursion following a mixed nutrient meal was studied . Five normal ( NL ) and six gestational diabetic ( GDM ) subjects were enrolled . A r and omized crossover design was used to compare fasting glucose and insulin levels , peak glucose and insulin levels and incremental area of the glycemic and insulin curves following a mixed nutrient meal with or without an exercise stress that took place 14 h earlier . Exercise consisted of upright stationary cycling for 30 min at a heart rate consistent with 60 % VO2max . The clinical characteristics of normal and gestational diabetic subjects were comparable . Mean values ( + /-SEM ) with , versus without , exercise for fasting glucose ( NL : 78.9 + /- 2.6 vs. 80.0 + /- 2.6 mg/dl ; GDM : 86.4 + /- 2.0 vs. 82.1 + /- 3.5 mg/ dl ) , peak glucose ( NL : 132.3 + /- 10.4 vs. 139.1 + /- 15.6 mg/dl ; GDM : 165.8 + /- 5.5 vs. 160.3 + /- 7.8 mg/dl ) , the area under the glycemic curve ( NL : 5758 + /- 1038 vs. 6393 + /- 1281 mg/dl.min ; GDM : 8,178 + /- 890 vs. 8,331 + /- 563 mg/dl.min ) did not differ . Similarly , plasma insulin levels did not differ between protocol s for either group of subjects . Exercise has been proposed as a treatment to reduce glycemia in gestational diabetes . Results from this study indicate a single bout of exercise did not blunt the glycemic response observed following a mixed nutrient meal [10586979] Infant macrosomia is a serious medical concern . Pregnant women who do not meet the specific diagnosis for gestational diabetes may still have glucose-mediated macrosomia . In Santa Barbara County all pregnant women are screened for gestational diabetes at 24 - 28 weeks with a 50-g , 1-hr glucose challenge test ( GCT ) . All patients who fail this test are placed on a st and ard euglycemic diet ( 40 % carbohydrate , 20 % protein , 40 % fat ) and perform home glucose monitoring of fasting and postpr and ial glucose levels . The objective of this study was to examine the effectiveness of this treatment program in decreasing infant macrosomia , maternal and infant morbidity , maternal complications , and operative delivery . We studied 103 women who had a positive GCT , but a negative 100-g , 3-hr oral glucose tolerance test ( OGTT ) . The women were r and omly assigned to either experimental or control groups with experimental women receiving dietary counseling and home glucose monitoring instruction ( HBGM ) . HBGM diaries were review ed weekly by clinic nurses . All women had hemoglobin A1c ( HbA1c ) tests at 28 and 32 weeks . Maternal and fetal charts were review ed to determine delivery type and complications , indications for cesarean section ( C-section ) , and infant gestational age , gender , Apgar scores , birth weight , morbidities , and congenital anomalies . Of the 103 women , 5 women required insulin treatment , 1 woman had an abortion , and 14 women were indeterminate regarding compliance or were control women who received diet counseling and HBGM . The results are based on 83 women--48 control and 35 experimental . There were no significant differences between the groups for age , parity , or weight at 28 - 30 weeks or 37 weeks to delivery , or HbA1c at 28 weeks . HbA1c was significantly higher in control women at 32 weeks . Birth weight expressed in grams or as a percentile specific for gender , ethnicity , and gestational age was significantly higher in control infants . Birth weight was significantly correlated with maternal intake weight , weight at 28 - 30 weeks , and weight at delivery and with HbA1c at 32 weeks ' gestation . There were no significant differences between groups for maternal complications . Groups were significantly different for mode of delivery with experimental women having more induced vaginal deliveries but fewer repeat C-sections than control women . Groups were not different for primary C-sections . Women who fail the GCT , but not the OGTT and thus do not receive the diagnosis of GDM are still at risk for delivering a macrosomic infant and operative delivery . Our program of treatment for all women who fail the GCT improves outcome by reducing infant birth weight and the number of cesarean sections [11966484] Major problems with gestational diabetes ( GDM ) have been the high frequency of fetal macrosomia , and perinatal complications , especially among mothers needing insulin in addition to diet therapy ( 1 ) . Both long-acting insulin ( LAI ) and shortacting insulin ( SAI ) are used , the former to reduce the basal glucose level and the latter to control postpr and ial glucose peaks after meals . Despite many improvements , insulin therapy has not solved the above-mentioned problems . We compared the effects of SAI and LAI on perinatal outcome in insulin-requiring GDM . We hypothesized that SAI therapy and postpr and ial glucose monitoring would lead to better glycemic control than LAI and therefore reduce fetal macrosomia . After obtaining approval by the Ethics Committee of the Helsinki University Central Hospital , department of Obstetrics and Gynecology and given information to all study participants , we included 23 consecutive women with insulin-requiring GDM in a prospect i ve r and omized trial . A 2-hr oral glucose tolerance test ( OGTT ) with 75 g of glucose was performed at 24–28weeks of gestation in women [3888734] Two-hundred and two pregnant women with impaired glucose tolerance were r and omized to treatment with diet or diet and insulin by stratified selection . Self-monitoring of blood glucose was performed six times a day , 3 days/wk . Dietary treatment was considered inappropriate if fasting and postpr and ial blood glucose values exceeded 7 and 9 mmol/L , respectively , in which case insulin therapy was instituted . Insulin doses were adjusted according to blood glucose values , aim ing at fasting and postpr and ial values below 5 and 6.5 mmol/L , respectively . There were no perinatal deaths . The two treatment regimens disclosed no differences regarding achieved degree of maternal blood glucose control , hemoglobin A1c at delivery , obstetric or neonatal complications , infant 's size at birth including skinfold thickness , or C-peptide concentration in cord serum . Routine treatment of pregnant women with mild carbohydrate intolerance with insulin seems unnecessary . However , 15 patients ( 14 % ) in the diet group needed insulin to achieve acceptable blood glucose control , underlining the importance of monitoring blood glucose to detect those who are at risk of developing overt diabetes [628532] Seventy-two patient with gestational diabetes were r and omly treated with insulin ( 20 units NPH and 10 units regular ) and diabetic diet , diet alone , or neither . Of the 27 patients treated with insulin and diet , 2 ( 7 % ) had babies weighing more than 8 1/2 pounds . Of the 11 patients treated with diet alone , 4 ( 36.4 % ) had babies weighing more than 8 1/2 pounds . Of the 34 patients treated with neither diet nor insulin , 17 ( 50 % ) had babies weighing more than 8 1/2 pounds . These data support the hypothesis that treatment of the gestational diabetic with insulin will reduce the incidence of fetal macrosomia [12502678] OBJECTIVE To assess the short-term efficacy of insulin aspart in comparison with regular human insulin in women with gestational diabetes mellitus ( GDM ) during st and ardized meal tests . RESEARCH DESIGN AND METHODS The study included 15 women with GDM who had inadequate diabetes control with diet alone . On 3 consecutive days , breakfast meal tests were performed-the first with no exogenous insulin and the other two after the injection of either regular insulin or insulin aspart . RESULTS The peak insulin concentration was higher and the peak glucose and C-peptide concentrations were lower with both insulin preparations than with no exogenous insulin . Glucose areas under the curve above baseline were significantly lower with insulin aspart ( 180-min area , 7.1 mg . h. dl(-1 ) ; P = 0.018 ) , but not with regular insulin ( 30.2 mg . h. dl(-1 ) ; P = 0.997 ) , than with no insulin ( 29.4 mg . h. dl(-1 ) ) . CONCLUSIONS This study demonstrates that effective postpr and ial glycemic control in women with GDM who required insulin was brought about by insulin aspart through higher insulin peak and lower dem and on endogenous insulin secretion [18754979] OBJECTIVE To examine the effects of a Parish Nurse Intervention Program ( PNIP ) on maternal health behaviors , glycemic control , and neonatal outcomes among Mexican American women with gestational diabetes . DESIGN A r and omized controlled trial comparing care as usual ( CAU ) with a supplementary 1-hour education session for diabetes education reinforcement by a Parish Nurse . SETTING An outpatient treatment clinic for gestational diabetes within a 250-bed tertiary care , non-profit hospital with a Parish Nurse partnership . PARTICIPANTS One hundred Mexican American women were included in the study with r and omization into Parish Nurse Intervention Program ( n=49 ) and care as usual ( n=51 ) groups . MAIN OUTCOME MEASURES The Health Promoting Lifestyle Profile II ( HPLP II ) and two measures of glycemic control pre- and post-intervention , as well as newborn size , and days of maternal and neonatal hospitalization . RESULTS Outcomes indicate significantly improved Health Promoting Lifestyle Profile II scores in the Parish Nurse Intervention Program group post-intervention compared with the Care As Usual group . No significant differences between groups regarding glycemic control , macrosomia , or days of maternal or neonatal hospitalization were found . CONCLUSIONS A Parish Nurse Intervention Program for pregnant women of Mexican descent with gestational diabetes is effective in leading to improved self-reported health promoting behaviors [2500941] In pregnancies complicated by diabetes , foetal lung maturation depends on a good control of maternal blood glucose values . In poorly controlled maternal diabetes , foetal hyperinsulinaemia may cause a delay in pulmonary maturation . There was no single case of respiratory distress syndrome ( RDS ) in 112 pregnant class B-F diabetic patients that we treated with high doses of insulin . Furthermore , in a controlled r and omized trial of diet versus insulin treatment in class A diabetes we found no differences in perinatal mortality in patients with adequate metabolic control . In pregnancies complicated by Rh isoimmunization , determination of phosphatidylglycerol in amniotic fluid is a more reliable marker of foetal lung maturity than is the lecithin/sphingomyelin ratio . The marked decrease in perinatal mortality due to Rh incompatibility observed in recent years depends on several factors including administration of corticosteroids to the mother to prevent RDS , irrespective of whether amniotic fluid parameters indicate foetal lung maturity [11036118] BACKGROUND Women with gestational diabetes mellitus are rarely treated with a sulfonylurea drug , because of concern about teratogenicity and neonatal hypoglycemia . There is little information about the efficacy of these drugs in this group of women . METHODS We studied 404 women with singleton pregnancies and gestational diabetes that required treatment . The women were r and omly assigned between 11 and 33 weeks of gestation to receive glyburide or insulin according to an intensified treatment protocol . The primary end point was achievement of the desired level of glycemic control . Secondary end points included maternal and neonatal complications . RESULTS The mean ( + /-SD ) pretreatment blood glucose concentration as measured at home for one week was 114+/-19 mg per deciliter ( 6.4+/-1.1 mmol per liter ) in the glyburide group and 116+/-22 mg per deciliter ( 6.5+/-1.2 mmol per liter ) in the insulin group ( P=0.33 ) . The mean concentrations during treatment were 105+/-16 mg per deciliter ( 5.9+/-0.9 mmol per liter ) in the glyburide group and 105+/-18 mg per deciliter ( 5.9+/-1.0 mmol per liter ) in the insulin group ( P=0.99 ) . Eight women in the glyburide group ( 4 percent ) required insulin therapy . There were no significant differences between the glyburide and insulin groups in the percentage of infants who were large for gestational age ( 12 percent and 13 percent , respectively ) ; who had macrosomia , defined as a birth weight of 4000 g or more ( 7 percent and 4 percent ) ; who had lung complications ( 8 percent and 6 percent ) ; who had hypoglycemia ( 9 percent and 6 percent ) ; who were admitted to a neonatal intensive care unit ( 6 percent and 7 percent ) ; or who had fetal anomalies ( 2 percent and 2 percent ) . The cord-serum insulin concentrations were similar in the two groups , and glyburide was not detected in the cord serum of any infant in the glyburide group . CONCLUSIONS In women with gestational diabetes , glyburide is a clinical ly effective alternative to insulin therapy [18058723] INTRODUCTION Nutrition therapy is an integral part of the management of gestational diabetes mellitus ( GDM ) . Most women with GDM are treated by nutritional management alone . The goal of our study was to compare low and high carbohydrate diets in their effectiveness , safety and tolerability in women with GDM . MATERIAL AND METHODS The study group consisted of 30 Caucasian women newly diagnosed with GDM , with a mean age of 28.7 + /- 3.7 years and pregnancy duration of 29.2 + /- 5.4 weeks . The patients were r and omised into two groups : those on a low and those on a high carbohydrate diet ( 45 % vs. 65 % respectively of energy supply coming from carbohydrates ) . The presence of urine ketones was controlled every day . After two weeks daily glucose profiles and compliance with the recommended diets were analysed . RESULTS Glucose concentration before implementation of the diet regimen did not differ between groups . No changes in fasting blood glucose were noticed in the group that had followed a low carbohydrate diet , although a significant decrease in glucose concentration was observed after breakfast ( 102 + /- 16 vs. 94 + /- 11 mg/dl ) , lunch ( 105 + /- 12 vs. 99 + /- 9 mg/dl ) and dinner ( 112 + /- 16 vs. 103 + /- 13 mg/dl ) ( p < 0.05 ) . In the high carbohydrate diet group fasting and after-breakfast glucose concentration did not change . A significant decrease in glycaemia was noticed after lunch ( 106 + /- 15 vs. 96 + /- 7 mg/dl ) and dinner ( 107 + /- 12 vs. 97 + /- 7 mg/dl ) ( p < 0.05 ) . Ketonuria was not observed in either group . Obstetrical outcomes did not differ between groups . CONCLUSIONS Both high and low carbohydrate diets are effective and safe . A diet with carbohydrate limitation should be recommended to women who experience the highest glycaemia levels after breakfast [12375675] Objective : A planned study is described which will determine whether a benefit exists for the treatment of mild carbohydrate intolerance during pregnancy . Methods : A r and omized clinical trial of women with mild gestational diabetes will compare perinatal outcomes in those receiving diet therapy and insulin as required versus those r and omized to no specific treatment . Results : The primary outcome of this study will be a composite of neonatal morbidity in the treatment and control groups . Conclusions : A r and omized treatment trial of mild gestational diabetes mellitus will clarify whether identification and treatment of mild gestational diabetes mellitus reduces perinatal morbidity . This information will aid in selecting appropriate thresholds for the treatment of gestational diabetes mellitus [19797280] BACKGROUND It is uncertain whether treatment of mild gestational diabetes mellitus improves pregnancy outcomes . METHODS Women who were in the 24th to 31st week of gestation and who met the criteria for mild gestational diabetes mellitus ( i.e. , an abnormal result on an oral glucose-tolerance test but a fasting glucose level below 95 mg per deciliter [ 5.3 mmol per liter ] ) were r and omly assigned to usual prenatal care ( control group ) or dietary intervention , self-monitoring of blood glucose , and insulin therapy , if necessary ( treatment group ) . The primary outcome was a composite of stillbirth or perinatal death and neonatal complications , including hyperbilirubinemia , hypoglycemia , hyperinsulinemia , and birth trauma . RESULTS A total of 958 women were r and omly assigned to a study group--485 to the treatment group and 473 to the control group . We observed no significant difference between groups in the frequency of the composite outcome ( 32.4 % and 37.0 % in the treatment and control groups , respectively ; P=0.14 ) . There were no perinatal deaths . However , there were significant reductions with treatment as compared with usual care in several prespecified secondary outcomes , including mean birth weight ( 3302 vs. 3408 g ) , neonatal fat mass ( 427 vs. 464 g ) , the frequency of large-for-gestational-age infants ( 7.1 % vs. 14.5 % ) , birth weight greater than 4000 g ( 5.9 % vs. 14.3 % ) , shoulder dystocia ( 1.5 % vs. 4.0 % ) , and cesarean delivery ( 26.9 % vs. 33.8 % ) . Treatment of gestational diabetes mellitus , as compared with usual care , was also associated with reduced rates of preeclampsia and gestational hypertension ( combined rates for the two conditions , 8.6 % vs. 13.6 % ; P=0.01 ) . CONCLUSIONS Although treatment of mild gestational diabetes mellitus did not significantly reduce the frequency of a composite outcome that included stillbirth or perinatal death and several neonatal complications , it did reduce the risks of fetal overgrowth , shoulder dystocia , cesarean delivery , and hypertensive disorders . ( Clinical Trials.gov number , NCT00069576 . Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Gestational diabetes ( GDM ) is glucose intolerance , first recognised in pregnancy and usually resolving after birth . GDM is associated with both short- and long-term adverse effects for the mother and her infant . Lifestyle interventions are the primary therapeutic strategy for many women with GDM . OBJECTIVES To evaluate the effects of combined lifestyle interventions with or without pharmacotherapy in treating women with gestational diabetes . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

22419291

[17906203] PURPOSE European Organisation for Research and Treatment of Cancer ( EORTC ) trial 22921 compared adjuvant fluorouracil-based chemotherapy ( CT ) to no adjuvant treatment in a 2 x 2 factorial trial with r and omization for preoperative (chemo)radiotherapy in patients with resectable T3 - 4 rectal cancer . The results showed no significant impact of adjuvant CT on progression-free or overall survival , although a difference seemed to emerge at approximately , respectively , 2 and 5 years after the start of preoperative treatment . We further explored the data with the aim of refining our underst and ing of the long-term results . PATIENTS AND METHODS Data of 785 of the 1,011 r and omly assigned patients who whose disease was M0 at curative surgery were used . Using meta-analytic methods , we investigated the homogeneity of the effect of adjuvant CT on the time to relapse or death after surgery ( disease-free survival [ DFS ] ) and survival in patient subgroups . RESULTS Although there was no statistically significant impact of adjuvant CT on DFS for the whole group ( P > .5 ) , the treatment effect differed significantly between the ypT0 - 2 and the ypT3 - 4 patients ( heterogeneity P = .009 ) : only the ypT0 - 2 patients seemed to benefit from adjuvant CT ( P = .011 ) . The same pattern was observed for overall survival . CONCLUSION Exploratory analyses suggest that only good-prognosis patients ( ypT0 - 2 ) benefit from adjuvant CT . This could explain why , in the whole group , the progression-free and overall survival diverged only after the poor-prognosis patients ( ypT3 - 4 ) had experienced treatment failure . Patients in whom no downstaging was achieved did not benefit . This also suggests that the same prognostic factors may drive both tumor sensitivity for the primary treatment and long-term clinical benefit from further adjuvant CT [3064191] The Gastrointestinal Tumor Study Group ( GITSG ) protocol GI-7175 r and omized 227 patients between 1975 and 1980 following complete surgical resection of stages B2 and C rectal adenocarcinoma to four treatment arms : ( 1 ) no adjuvant therapy , ( 2 ) chemotherapy only , ( 3 ) radiotherapy only , and ( 4 ) radiotherapy and chemotherapy ( combined modality ) . The results of the study showed an advantage for combined modality treatment over no adjuvant therapy for time to recurrence ( p = 0.005 ) and for survival ( p = 0.01 ) . Severe acute toxicity was frequent in the combined modality arm ( 61 % ) but late effects , including radiation enteritis , have been infrequent . We conclude that postoperative adjuvant therapy is indicated in certain stages of rectal carcinoma and that the present state of knowledge suggests combined modality therapy [9891531] We examined the effects of postoperative 5-fluorouracil ( 5-FU ) infusions and oral treatment with 1-hexylcarbamoyl-5-fluorouracil ( HCFU ) on patients curatively resected for stages II-IV colorectal cancer . The study was prospect ively r and omized , and 251 ( 93.3 % ) of 269 patients were valid c and i date s for statistical assessment . The inductive regimen for group A included 5-FU 10 mg intravenous ( i.v . ) injections on days 0 , 1 , 2 , 7 , 8 and 9 , postoperatively . For maintenance therapy , group A received HCFU 300 mg orally and daily for 52 weeks beginning 2 weeks after surgery . The regimen for group B included only 5-FU injections . The effects of this chemotherapy were also retrospectively analyzed for groups at a high risk for recurrence , stages III-IV , transmural invasion-positive and lymph node metastasis-positive cases . There was no statistical difference in survival time between the groups for 251 eligible cases ( p = 0.079 ) . In group A given 5-FU plus HCFU , there was a reduction in the recurrence rate for patients with stages III-IV or lymph node metastasis-positive colorectal cancers ( p < 0.05 ) and prolongation of the survival time for patients with stage III-IV , transmural invasion-positive or lymph node-positive colorectal cancers ( p < 0.05 ) . Our findings show that the combination of 5-FU infusion and the continuous administration of HCFU is effective in treating patients with surgically resected colorectal cancer who are at high risk for a recurrence [1130879] A combined intraoperative and postoperative adjuvant program of 5 minus Fluorouracil ( 5 FU ) for patients undergoing " curative " resection for adenocarcinoma of the colon and rectum was initiated as a r and omized clinical trial in January 1968 . Patients at the Medical College of Virginia and the University of Virginia were r and omly assigned to an intraluminal 5 FU or intraluminal control ( Saline ) group and were so treated at the time of surgical resection if findings at operation indicated that all gross neoplastic disease could be resected . Patients with operative findings denoting incurability were eliminated from the study after surgical exploration . Those patients receiving intraluminal 5 FU ( 30mg/kg ) received intravenous 5 FU ( 10mg/kg ) on each of the two first postoperative days and 5 subsequent postoperative courses of oral 5FU ( 90 mg/kg in each 18 day course ) over a one year period . By December 31 , 1973 ( 6 years ) 156 patients undergoing " curative " resection were entered into the study . SU therapy with the control or " No Treat " group reveal no significant benefit from this intensive adjuvant course of 5 FU thus far . Continued assessment of these patient groups and their subgroups will be required to develop confidence in these findings but the data thus far suggest no potential benefit from this particular adjuvant program [18083404] BACKGROUND The aim of the QUASAR trial was to determine the size and duration of any survival benefit from adjuvant chemotherapy for patients with colorectal cancer at low risk of recurrence , for whom the indication for such treatment is unclear . METHODS After apparently curative resections of colon or rectal cancer , 3239 patients ( 2963 [ 91 % ] with stage II [ node negative ] disease , 2291 [ 71 % ] with colon cancer , median age 63 [ IQR 56 - 68 ] years ) enrolled between May , 1994 , and December , 2003 , from 150 centres in 19 countries were r and omly assigned to receive chemotherapy with fluorouracil and folinic acid ( n=1622 ) or to observation ( with chemotherapy considered on recurrence ; n=1617 ) . Chemotherapy was delivered as six 5-day courses every 4 weeks or as 30 once-weekly courses of intravenous fluorouracil ( 370 mg/m2 ) with high-dose ( 175 mg ) L-folinic acid or low-dose ( 25 mg ) L-folinic acid . Until 1997 , levamisole ( 12 courses of 450 mg over 3 days repeated every 2 weeks ) or placebo was added . After 1997 , patients who were assigned to receive chemotherapy were given fluorouracil and low-dose folinic acid only . The primary outcome was all-cause mortality . Analyses were done by intention to treat . This trial is registered with the International Clinical Trial Registry , number IS RCT N82375386 . FINDINGS At the time of analysis , 61 ( 3.8 % ) patients in the chemotherapy group and 50 ( 3.1 % ) in the observation group had missing follow-up . After a median follow-up of 5.5 ( range 0 - 10.6 ) years , there were 311 deaths in the chemotherapy group and 370 in the observation group ; the relative risk of death from any cause with chemotherapy versus observation alone was 0.82 ( 95 % CI 0.70 - 0.95 ; p=0.008 ) . There were 293 recurrences in the chemotherapy group and 359 in the observation group ; the relative risk of recurrence with chemotherapy versus observation alone was 0.78 ( 0.67 - 0.91 ; p=0.001 ) . Treatment efficacy did not differ significantly by tumour site , stage , sex , age , or chemotherapy schedule . Eight ( 0.5 % ) patients in the chemotherapy group and four ( 0.25 % ) in the observation group died from non-colorectal cancer causes within 30 weeks of r and omisation ; only one of these deaths was deemed to be possibly chemotherapy related . INTERPRETATION Chemotherapy with fluorouracil and folinic acid could improve survival of patients with stage II colorectal cancer , although the absolute improvements are small : assuming 5-year mortality without chemotherapy is 20 % , the relative risk of death seen here translates into an absolute improvement in survival of 3.6 % ( 95 % CI 1.0 - 6.0 ) [20490797] Objective In the latter 1990s , adjuvant chemotherapy for completely resected Stage III colorectal cancer remained controversial in Japan . We conducted two independent r and omized controlled trials in patients with Stage III colon and rectal cancer . Methods Patients were r and omly assigned to receive surgery alone or surgery followed by treatment with UFT ( 400 mg/m2/day ) , given for five consecutive days per week for 1 year . The primary endpoint was relapse-free survival ( RFS ) , and the secondary endpoint was overall survival ( OS ) . Results A total of 334 patients with colon cancer and 276 with rectal cancer were enrolled . The patients ’ characteristics were similar between the UFT group and the Surgery-alone group . There was no significant difference in RFS or OS in colon cancer . In rectal cancer , however , RFS and OS were significantly better in the UFT group than in the Surgery-alone group . The only grade 4 toxicity in the UFT group was diarrhea , occurring in one patient with colon cancer and one patient with rectal cancer . Conclusions Postoperative adjuvant chemotherapy with UFT is successfully tolerated and improves RFS and OS in patients with Stage III rectal cancer . In colon cancer , the expected benefits were not obtained ( hazard ratio = 0.89 ) [10442189] BACKGROUND R and omized studies have shown that postoperative chemotherapy with or without radiation therapy ( RT ) improved local control and survival of patients with stages II or III rectal cancer . However , the optimal sequence of treatments and the optimal chemotherapeutic regimen have not been defined . Modulation of fluorouracil ( FU ) by leucovorin ( LV ) has yielded a highly significant difference in response rate from that of FU monotherapy , as suggested by an overview of r and omized trials in patients with advanced colorectal cancer . However , this difference in response rate did not translate into a survival benefit . PURPOSE To evaluate the impact on the disease-free survival ( DFS ) and overall survival ( OS ) of patients with stages II or III rectal cancer of postoperative RT and concomitant bolus FU administration alone or with additional chemotherapy using FU and high-dose LV . PATIENTS AND METHODS From October 1989 until February 1997 , 220 patients were r and omized postoperatively to receive either one cycle of chemotherapy with FU ( 600 mg/m2/week x 6 followed by a two-week rest ) and leucovorin ( LV , 500 mg/m2/week x 6 as a two-hour infusion ) followed by pelvic RT with concomitant FU ( 400 mg/m2 ) as a rapid intravenous injection during the first three and last three days of RT , and three more cycles of the same chemotherapy with FU and LV ( st and ard , group A , 111 patients ) or pelvic RT with concomitant FU only ( experimental , group B , 109 patients ) . RESULTS As of August 1998 , after a median follow-up of 4.9 years , there was no significant difference in either three-year DFS ( Group A , 70.3 % ; group B , 68.2 % , P = 0.53 ) or OS ( group A , 77 % ; group B , 73.3 % . P = 0.75 ) . Cox multivariate analysis revealed stage of disease , number of infiltrated nodes , tumor grade , presence of regional implants and perforation to be significant prognostic factors . The incidence of severe side effects was significantly higher in the patients in group A than in those in group B ( 32.4 % vs. 4.6 % , P < 0.0001 ) . CONCLUSIONS The incorporation of additional chemotherapy with FU and LV into postoperative concomitant RT and bolus infusion of FU does not offer a > or = 10 % three-year survival benefit over that of concomitant RT and bolus infusion of FU , and significantly increases toxicity in patients with stages II or III rectal cancer [11914933] Background : The purpose of this study is to evaluate the efficacy of postoperative adjuvant chemotherapy using uracil and tegafur ( UFT ) for colorectal cancer . Methods : In a multicenter trial among 43 institutions for patients who underwent curative resection of Dukes ’ B or C colorectal cancer , a surgery alone group ( control group ) and a treatment group ( UFT group ) to which UFT was administered at 400 mg/day for 2 years following surgery were compared . A total of 320 patients were registered between March 1991 and April 1994 , and 289 of these patients were analyzed as a full- analysis set . Results : The 5-year disease-free survival rate was 75.7 % in the UFT group and 60.1 % in the control group , respectively , and the stratified log-rank test showed the statistical significance ( P=0.0081 ) . This difference was marked in rectal cancer ( P=0.0016 ) and , in particular , the local recurrence was reduced . No significant difference was observed in the 5-year survival rate . The incidence of adverse reactions on administration of UFT was low , and there was no serious adverse reaction . Conclusion : It is suggested that the consecutive administration of UFT at 400 mg/day was an effective and highly safe therapeutic method as postoperative adjuvant chemotherapy for rectal cancer [12827681] BACKGROUND AND OBJECTIVES A r and omised clinical trial was performed in patients undergoing radical surgery for rectal cancer to compare the efficacy and toxicity of adjuvant postoperative radiation therapy ( RT ) to sequential RT and chemotherapy ( CT ) with 5-fluorouracil ( 5-FU ) plus levamisole ( LEV ) . The primary end point was overall survival ( OS ) ; secondary end points were disease-free survival ( DFS ) , the rate of loco-regional recurrence , and treatment-related toxicity ; the final results of this trial are reported . METHODS Patients in arm I underwent RT ( 50 Gy ) in daily fractions of 2 Gy , 5 days/week for 5 weeks . Patients in arm II began with 5-FU ( 450 mg/sqm/day intravenous ( i.v . ) bolus , days 1 - 5 ) plus LEV ( 150 mg/day orally , days 1 - 3 ) ; postoperative RT was delivered during week 2 at the same dosage and schedule as in arm I. The other five cycles of CT ( 5-FU every 28 days and LEV every 15 days for the length of 5-FU administration ) continued after the end of RT if clinical and hemato-biochemical parameters were in the normal range . RESULTS From May 1992 to December 1998 , 218 patients were enrolled into the r and omised clinical trial ( 144 men , 74 women ; age range : 28 - 75 , median 64 years ) . The median follow-up time was 58.1 months ( range : 1 - 3,271 days ) . No significant difference was observed between the two arms of treatment as regards OS and DFS ( P = 0.18 and P = 0.66 , respectively ) . Cox regression analysis for OS confirmed what was observed by univariate analysis for all variables except age . Older age ( > 60 years ) and pathologic lymph-node involvement defined the subgroups with the worst prognosis . Cox regression analysis for DFS confirmed what was observed by univariate analysis for all variables : the only independent variable in predicting DFS was pathologic lymph-node involvement . CONCLUSIONS Our findings suggest no difference in OS , loco-regional and distant site progressions of postoperative RT alone compared to sequential postoperative RT and CT ; notably , this latter regimen was associated with higher toxicity which seriously impaired the patient 's compliance to CT . The low loco-regional recurrence rate ( 9.2 % ) observed in our patients undergoing postoperative RT alone compared to similarly treated patients in previously performed clinical trials ( 20 - 25 % ) underline the role of radical surgery ( mesorectal excision ) coupled with a complete postoperative RT regimen . On the other h and , the similar efficacy of these two adjuvant modalities of treatment might be conditioned by both the low compliance ( 59 % ) to the CT regimen as well as the sequential , instead of concurrent , schedule of administration of RT and CT , which may have decreased further the expected efficacy of the combined regimen [8041415] BACKGROUND The combination of radiation therapy and chemotherapy with fluorouracil plus semustine after surgery has been established as an effective approach to decreasing the risk of tumor relapse and improving survival in patients with rectal cancer who are at high risk for relapse or death . We sought to determine whether the efficacy of chemotherapy could be improved by administering fluorouracil by protracted infusion throughout the duration of radiation therapy and whether the omission of semustine would reduce the toxicity and delayed complications of chemotherapy without decreasing its antitumor efficacy . METHODS Six hundred sixty patients with TNM stage II or III rectal cancer received intermittent bolus injections or protracted venous infusions of fluorouracil during postoperative radiation to the pelvis . They also received systemic chemotherapy with semustine plus fluorouracil or with fluorouracil alone in a higher dose , administered before and after the pelvic irradiation . RESULTS With a median follow-up of 46 months among surviving patients , patients who received a protracted infusion of fluorouracil had a significantly increased time to relapse ( P = 0.01 ) and improved survival ( P = 0.005 ) . There was no evidence of a beneficial effect in the patients who received semustine plus fluorouracil . CONCLUSIONS A protracted infusion of fluorouracil during pelvic irradiation improved the effect of combined-treatment postoperative adjuvant therapy in patients with high-risk rectal cancer . Semustine plus fluorouracil was not more effective than a higher dose of systemic fluorouracil given alone [18539618] Knowledge of the biology and management of rectal cancer continues to improve . A multidisciplinary approach to a patient with rectal cancer by an experienced expert team is m and atory , to assure optimal diagnosis and staging , surgery , selection of the appropriate neo-adjuvant and adjuvant strategy and chemotherapeutic management . Moreover , optimal symptom management also requires a dedicated team of health care professionals . The introduction of total mesorectal excision has been associated with a decrease in the rate of local failure after surgery . High quality surgery and the achievement of pathological measures of quality are a prerequisite to adequate locoregional control . There are now r and omized data in favour of chemoradiotherapy or short course radiotherapy in the preoperative setting . Preoperative chemoradiotherapy is more beneficial and has less toxicity for patients with resectable rectal cancer than postoperative chemoradiotherapy . Furthermore chemoradiotherapy leads also to downsizing of locally advanced rectal cancer . New strategies that decrease the likelihood of distant metastases after initial treatment need be developed with high priority . Those involved in the care for patients with rectal cancer should be encouraged to participate in well- design ed clinical trials , to increase the evidence -based knowledge and to make further progress . Health care workers involved in the care of rectal cancer patients should be encouraged to adopt quality control processes leading to increased expertise [15496622] BACKGROUND Postoperative chemoradiotherapy is the recommended st and ard therapy for patients with locally advanced rectal cancer . In recent years , encouraging results with preoperative radiotherapy have been reported . We compared preoperative chemoradiotherapy with postoperative chemoradiotherapy for locally advanced rectal cancer . METHODS We r and omly assigned patients with clinical stage T3 or T4 or node-positive disease to receive either preoperative or postoperative chemoradiotherapy . The preoperative treatment consisted of 5040 cGy delivered in fractions of 180 cGy per day , five days per week , and fluorouracil , given in a 120-hour continuous intravenous infusion at a dose of 1000 mg per square meter of body-surface area per day during the first and fifth weeks of radiotherapy . Surgery was performed six weeks after the completion of chemoradiotherapy . One month after surgery , four five-day cycles of fluorouracil ( 500 mg per square meter per day ) were given . Chemoradiotherapy was identical in the postoperative-treatment group , except for the delivery of a boost of 540 cGy . The primary end point was overall survival . RESULTS Four hundred twenty-one patients were r and omly assigned to receive preoperative chemoradiotherapy and 402 patients to receive postoperative chemoradiotherapy . The overall five-year survival rates were 76 percent and 74 percent , respectively ( P=0.80 ) . The five-year cumulative incidence of local relapse was 6 percent for patients assigned to preoperative chemoradiotherapy and 13 percent in the postoperative-treatment group ( P=0.006 ) . Grade 3 or 4 acute toxic effects occurred in 27 percent of the patients in the preoperative-treatment group , as compared with 40 percent of the patients in the postoperative-treatment group ( P=0.001 ) ; the corresponding rates of long-term toxic effects were 14 percent and 24 percent , respectively ( P=0.01 ) . CONCLUSIONS Preoperative chemoradiotherapy , as compared with postoperative chemoradiotherapy , improved local control and was associated with reduced toxicity but did not improve overall survival [2363941] Based on the first favourable results of adjuvant therapy of 5FU plus levamisole in Dukes C colonic cancer in 1990 , we conducted a prospect i ve trial . 1029 patients were r and omised to receive one year 5FU plus levamisole or no further treatment following curative surgery for stage II or III colon ( n = 730 ) or rectal cancer ( n = 299 ) . 45 % were in stage II and 55 % in stage III . With a median follow-up of 4 years and 9 months a significant reduction in odds of death ( 25 % , SD 9 % , P = 0.007 ) was observed for those with adjuvant treatment ( 65 % at 5 year ) compared to the observation group ( 55 % ) . Improved relative survival was present in stage III ( 56 % vs 44 % ) , and in stage II patients ( 78 % vs 70 % ) . In rectal cancer a non-significant difference in disease-free or overall survival was observed . Distant metastases developed in 76 % , while local recurrence alone occurred in 14 % . An early start of adjuvant treatment ( < 4 weeks ) did not affect results . Compliance to 5FU plus levamisole was 69 % . Severe toxicity did not occur . In conclusion , one year 5FU plus levamisole was of benefit in stage II and III colonic cancer ; in rectal cancer a significant positive effect could not be demonstrated . © 2001 Cancer Research Campaign [10699069] BACKGROUND The conviction that postoperative radiotherapy and chemotherapy represent an acceptable st and ard of care for patients with Dukes ' B ( stage II ) and Dukes ' C ( stage III ) carcinoma of the rectum evolved in the absence of data from clinical trials design ed to determine whether the addition of radiotherapy results in improved disease-free survival and overall survival . This study was carried out to address this issue . An additional aim was to determine whether leucovorin (LV)-modulated 5-fluorouracil ( 5-FU ) is superior to the combination of 5-FU , semustine , and vincristine ( MOF ) in men . PATIENTS AND METHODS Eligible patients ( n = 694 ) with Dukes ' B or C carcinoma of the rectum were enrolled in National Surgical Adjuvant Breast and Bowel Project ( NSABP ) Protocol R-02 from September 1987 through December 1992 and were followed . They were r and omly assigned to receive either postoperative adjuvant chemotherapy alone ( n = 348 ) or chemotherapy with postoperative radiotherapy ( n = 346 ) . All female patients ( n = 287 ) received 5-FU plus LV chemotherapy ; male patients received either MOF ( n = 207 ) or 5-FU plus LV ( n = 200 ) . Primary analyses were carried out by use of a stratified log-rank statistic ; P values are two-sided . RESULTS The average time on study for surviving patients is 93 months as of September 30 , 1998 . Postoperative radiotherapy result ed in no beneficial effect on disease-free survival ( P = .90 ) or overall survival ( P = .89 ) , regardless of which chemotherapy was utilized , although it reduced the cumulative incidence of locoregional relapse from 13 % to 8 % at 5-year follow-up ( P = .02 ) . Male patients who received 5-FU plus LV demonstrated a statistically significant benefit in disease-free survival at 5 years compared with those who received MOF ( 55 % versus 47 % ; P = .009 ) but not in 5-year overall survival ( 65 % versus 62 % ; P = .17 ) . CONCLUSIONS The addition of postoperative radiation therapy to chemotherapy in Dukes ' B and C rectal cancer did not alter the subsequent incidence of distant disease , although there was a reduction in locoregional relapse when compared with chemotherapy alone [15108041] Background We investigated the efficacy and safety of adjuvant immunochemotherapy and adjuvant chemotherapy for colorectal cancer , using different combinations of the intracutaneous streptococcal preparation OK-432 and the oral pyrimidines 1-hexylcarbamoyl-5-fluorouracil ( carmofur , HCFU ) and uracil/tegafur ( UFT ) . Methods Patients with stage II , III , or IV ( Dukes ’ B , C ) colorectal cancer were enrolled and r and omly assigned to one of three groups : an immunochemotherapy group ( mitomycin C [ MMC ] + 5-fluorouracil [ 5-FU ] + HCFU + OK-432 ) , a chemotherapy group ( MMC + 5-FU + HCFU ) , and a control group ( surgery alone ) for those with colon cancer ( study 1 ) ; and an immunochemotherapy group ( MMC + 5-FU + UFT + OK-432 ) , a chemotherapy group ( MMC + 5-FU + UFT ) , and a control group ( surgery alone ) for those with rectal cancer ( study 2 ) . Results A total of 760 patients with colon cancer and 669 patients with rectal cancer were entered into this r and omized clinical trial ( RCT ) . The incidence of side-effects was in the order of : immunochemotherapy group ≫ chemotherapy group ≫ control group in both the cohort of patients with colon cancer and the cohort with rectal cancer . In particular , the frequency of leucopenia and skin disorders was significantly higher than control groups . There were no severe adverse events such as death related to the adjuvant therapy . In both the colon cancer and rectal cancer cohorts , no significant difference in the 5-year survival rate and disease-free survival rate was noted among the three groups . Conclusion The results of an RCT demonstrated that the combination of MMC + 5-FU + HCFU + OK-432 for colon cancer and that of MMC + 5-FU + UFT + OK-432 for rectal cancer could not prolong the survival of patients with surgically resected colorectal cancer , but that both combinations were well tolerated as adjuvant therapy [8630937] Colorectal cancer is one of the major malignant diseases and , recently , its incidence appears to be increasing . Surgical resectability is an important prognostic determinant ; however , recurrent tumors are commonly noted , even after apparently curative surgery . Because such metastatic disease can not be cured , better adjuvant therapies are urgently called for [2276014] A prospect i ve controlled r and omized trial testing adjuvant postoperative combination chemotherapy ( 5‐fluorouracil , lomustine ( CNU ) and vincristine ) versus no adjuvant therapy in patients operated on for Dukes ' C colorectal cancer is reported . In total 334 patients aged less than 70 years were recruited : 205 patients with colonic and 99 with rectal cancer , but there were three protocol violations and these cases are excluded from further consideration . Twenty‐seven patients had a limited resection of their cancer . After 5 years follow‐up there was no significant difference in the tumour‐free survival rate or in the survival rate between the treated and control groups . Twenty‐nine of the 147 patients who started chemotherapy discontinued this treatment because of side‐effects , mainly from the gastrointestinal tract . In 30 patients treatment was discontinued because of recurrent disease . The conclusion is that systemic administration of combination chemotherapy for colorectal cancer after operation is not worthwhile in routine clinical practice [2300087] Twelve hundred ninety-six patients with resected colon cancer that either was locally invasive ( Stage B2 ) or had regional nodal involvement ( Stage C ) were r and omly assigned to observation or to treatment for one year with levamisole combined with fluorouracil . Patients with Stage C disease could also be r and omly assigned to treatment with levamisole alone . The median follow-up time at this writing is 3 years ( range , 2 to 5 1/2 ) . Among the patients with Stage C disease , therapy with levamisole plus fluorouracil reduced the risk of cancer recurrence by 41 percent ( P less than 0.0001 ) . The overall death rate was reduced by 33 percent ( P approximately 0.006 ) . Treatment with levamisole alone had no detectable effect . The results in the patients with Stage B2 disease were equivocal and too preliminary to allow firm conclusions . Toxic effects of levamisole alone were infrequent , usually consisting of mild nausea with occasional dermatitis or leukopenia , and those of levamisole plus fluorouracil were essentially the same as those of fluorouracil alone -- i.e . , nausea , vomiting , stomatitis , diarrhea , dermatitis , and leukopenia . These reactions were usually not severe and did not greatly impede patients ' compliance with their regimen . We conclude that adjuvant therapy with levamisole and fluorouracil should be st and ard treatment for Stage C colon carcinoma . Since most patients in our study were treated by community oncologists , this approach should be readily adaptable to conventional medical practice [9164215] PURPOSE The combination of radiation therapy with fluorouracil (5-FU)-based chemotherapy is generally accepted as appropriate postoperative therapy for patients with adenocarcinomas of the rectum that extend through the bowel wall or with lymph nodes positive for tumor . We attempted to determine whether the efficacy of this postoperative therapy could be improved by the addition of leucovorin and /or levamisole . METHODS A total of 1,696 patients were r and omized and eligible for treatment with one of four treatment schemes . All patients received two cycles of bolus 5-FU-based systemic chemotherapy followed by pelvic radiation therapy with chemotherapy and two more cycles of the same systemic chemotherapy . Chemotherapy was either 5-FU alone , 5-FU with leucovorin , 5-FU with levamisole , or 5-FU with leucovorin and levamisole . RESULTS With a median follow-up duration of 48 months , there is no statistically significant advantage to any of the treatment regimens compared with bolus 5-FU alone . There is evidence of increased gastrointestinal toxicity with the three-drug combination compared with bolus 5-FU alone . Statistical analysis suggests it is very unlikely that either levamisole-containing combination will be shown to be of value with further follow-up evaluation . CONCLUSION There is no evidence at present for a beneficial effect of levamisole in the adjuvant treatment of rectal cancer . Definitive evaluation of the effect of the addition of leucovorin to 5-FU and pelvic radiation will require further follow-up evaluation [3276900] Information is presented from 555 patients with Dukes B and C rectal cancers treated by curative resection who were entered into the National Surgical Adjuvant Breast and Bowel Project ( NSABP ) protocol R-01 between November 1977 and October 1986 . Their average time on study was 64.1 months . The patients were r and omized to receive no further treatment ( 184 patients ) , postoperative adjuvant chemotherapy with 5-fluorouracil , semustine , and vincristine ( MOF ) ( 187 patients ) , or postoperative radiation therapy ( 184 patients ) . The chemotherapy group , when compared with the group treated by surgery alone , demonstrated an overall improvement in disease-free survival ( P = .006 ) and in survival ( P = .05 ) . Employing the proportional hazards model , a global test was used to determine the presence of treatment interactions . Investigation of stratification variables employed in this study indicated that sex , and to a lesser extent age and Dukes stage , made individual contributions to the disease-free survival and the survival benefit from chemotherapy . When evaluated according to sex , the benefit for chemotherapy at 5 years , both in disease-free survival ( 29 % vs. 47 % ; P less than .001 ; relative odds , 2.00 ) and in survival ( 37 % vs. 60 % ; P = .001 ; relative odds , 1.93 ) , was restricted to males . When males were tested for age trend with the use of a logistic regression analysis , chemotherapy was found to be more advantageous in younger patients . When the group receiving post-operative radiation ( 4,600 - 4,700 rad in 26 - 27 fractions ; 5,100 - 5,300 rad maximum at the perineum ) was compared to the group treated only by surgery , there was an overall reduction in local-regional recurrence from 25 % to 16 % ( P = .06 ) . No significant benefit in overall disease-free survival ( P = .4 ) or survival ( P = .7 ) from the use of radiation has been demonstrated . The global test for interaction to identify heterogeneity of response to radiation within subsets of patients was not significant . In conclusion , this investigation has demonstrated a benefit from adjuvant chemotherapy ( MOF ) for the management of rectal cancer . The observed advantage was restricted to males . Postoperative radiation therapy reduced the incidence of local-regional recurrence , but it failed to affect overall disease-free survival and survival [88753] In a prospect ively r and omized study , the effect of adjuvant chemotherapy with 5-FU on survival and recurrence rates was analyzed in 299 evaluable patients with colorectal carcinoma who either underwent a curative or a palliative resection . In the treatment group , chemotherapy consisted of the intravenous administration of 12 mg/kg daily of 5-FU for 4 consecutive days , then 6 mg/kg on alternate days , to the point of toxicity , or to a maximum of five doses , followed by 12mg/kg weekly for 1 year . Some degree of drug toxicity was seen in the majority of patients , was rarely severe , and there have been no drug-related deaths . Analysis of the survival curves and disease-free interval curves reveal definite evidence of drug benefit in two unfavorable subgroups , namely patients with Dukes C tumors and in patients whose tumor was located in the rectum . In the chemotherapy groups , patients who were treated to toxicity ( WBC less than 4000 mm3 ) , the disease-free interval was significantly longer than the nonleukopenic patients . We conclude that the addition of 5-FU to the surgical treatment of colorectal carcinoma provides a small , but significant benefit in patients with colorectal cancer in certain unfavorable subgroups , namely patients with Dukes C lesions and patients with rectal carcinoma [12792790] Postoperative adjuvant chemotherapy reportedly improves advanced colorectal cancer patients ' survival , however , it is necessary to assess what regimens are useful . Doxifluridine ( 5'-DFUR ) is an intermediate of capecitabine approved in Europe and USA to treat metastatic colorectal cancer . 5'-DFUR is metabolized to 5-fluorouracil ( 5-FU ) by thymidine phosphorylase existing in tumor at high concentrations , suggesting high 5-FU levels in tumor tissues and lesser complications . Present study compared usefulness of 5'-DFUR to that of oral 5-FU . Patients were enrolled at 38 centers from April 1993 to September 1996 . They had diagnosed colorectal cancer of TNM stages II and III , and underwent macroscopic curative resection . Patients were prestratified into colon or rectum cancer and allocated into either 5'-DFUR ( 5'-DFUR 460 mg/m(2)/day + PSK 3 g/day ) or 5-FU ( 5-FU 115 mg/m(2)/day + PSK 3 g/day ) group by dynamic r and omization ( stratification factors such as depth of tumor , degree of lymph node metastasis , and location of tumor ) . Drugs were orally administered daily from postoperative week 2 to 54 , with 6 mg/m(2 ) mitomycin C at operation and following days . Subjects for analysis were 277 in 5'-DFUR and 281 in 5-FU groups . Median follow-up was 6.5 years . Although no differences in overall survival curves were detected , multivariate analysis showed that 5'-DFUR + PSK regimen was a significantly better prognostic factor in patients with Dukes B or C ( risk ratio , 1.451 ; p=0.048 ) ; with tumor depth of pT3 or pT4 ( risk ratio , 1.568 ; p=0.020 ) . For patients with advanced colorectal cancer , 5'-DFUR + PSK therapy may possibly be more useful than 5-FU + PSK , but further study is required [2645466] A prospect ively r and omised controlled clinical trial of adjuvant therapy was undertaken , at a single-centre , population -based cancer institute , in patients with Dukes ' stages B2 and C colorectal carcinoma after curative surgery . Between 1976 and 1983 , 253 patients were r and omised to either control ( no further therapy after surgery ) , immunotherapy ( oral bacille Calmette-Guérin [ BCG ] 120 mg once a month ) for 5 years or chemoimmunotherapy ( oral BCG as above with methyl-cyclohexyl-chloroethyl nitrosourea [ meCCNU ] 130 mg/m2 on day 1 and 5-fluorouracil [ 5-FU ] 325 mg/m2/day on days 1 - 5 and 375 mg/m2/day on days 36 - 40 ) repeated every 10 weeks for 8 cycles . The median follow-up of patients is now 6.95 years . Of the control , immunotherapy , and chemoimmunotherapy groups 22.35 % , 39.28 % , and 28.57 % , respectively , have relapsed . The log-rank analysis of results shows no disease-free or overall survival advantage for patients receiving adjuvant therapy compared with the control group . Patients receiving adjuvant immunotherapy for stage B2 appear to have a significantly inferior disease-free survival compared with other groups , but their overall survival is similar . There are no significant differences in disease-free or overall survival in the three groups of patients with stage C tumour . Of 82 patients dying , 78.05 % died of progressive colorectal carcinoma , 13 patients developed a second malignancy ; the remainder died of seemingly unrelated causes [9350242] A prospect i ve controlled study , the 7th cooperative study of the Japanese Foundation for Multidisciplinary Treatment , was conducted to evaluate the usefulness of concomitant therapy with MMC + HCFU as a postoperative adjuvant therapy in patients with colorectal cancer who had undergone curative resection for a period of 2 years and 11 months from February , 1986 . The Dukes B and C patients with colorectal cancer classified by macroscopic examination who had an intravenous MMC 6 mg/m2 on the day of operation and followed by oral HCFU for 12 months from 2 weeks after operation ( Group X ) were compared with patients who had operation only ( Group Y ) . Some 978 patients with colon cancer and 713 patients with rectal cancer were enrolled in the study , 85 ( 5.0 % ) of whom were not eligible . The 5-year survival rate of Group X in colon cancer was 79.3 % and that of Group Y was 76.4 % : thus the survival rate of Group X was slightly better than that of Group Y , but no significant difference was found between the two groups . Subset analysis revealed that the survival rate of Group X in advanced cancer of stage III b + IV , according to the General Rules for Clinical and Pathological Studies on Cancer of the Colon , Rectum and Anus in Japan , was 62.4 % and that of Group Y was 46.2 % . Thus , the survival rate of Group X was significantly better than that of Group Y ( logrank test : p = 0.035 , generalized Wilcoxon test : p = 0.025 ) . The disease-free survival rate was not significantly different between the groups with colon cancer and rectal cancer . The above results suggest that HCFU is useful for patients with a high risk of recurrence who had advanced colon cancer ( stage III b + IV ) . However , additional prospect i ve studies are required to verify them [8677916] One thous and two hundred fifty-four cases ( 610 colonic and 644 rectal cancers resected during 2 years from 1984 and followed up for more than 5 years ) were entered from 140 institutions in Japan and analyzed by means of Cox 's proportional hazards model . The analyzed pathologic variables were the size and depth of invasion , Dukes ' stage , venous invasion , lymphatic permeation , and other clinical features , such as the sex and age of the patient and location of the tumor . The extent of dissection , serum carcinoembryonic antigen ( CEA ) level , and the presence or absence of adjuvant chemotherapy were also analyzed . Adjuvant chemotherapy consisted of three arms for both colonic and rectal cancers . For colonic cancer , arm I was a combination of i.p . ( intraportal ) and i.v . mitomycin C ( MMC ) + p.o . 5-fluorouracil ( 5-FU ) ; arm II was i.v . MMC + p.o . 5-FU ; and arm III was surgery only . For rectal cancer , arm IV was a combination of i.a . ( inferior mesenteric artery ) and i.v . MMC + p.o . 5-FU ; arm V was i.v . MMC + p.o . 5-FU ; and arm VI was surgery only . As for the factors affecting the disease-free survival of the patient , multivariate analysis disclosed nodal involvement , venous invasion , an elevated CEA level , and the lower part of the rectum . The effect of adjuvant chemotherapy on the patient 's survival was proven for rectal cancer but not for colonic cancer . We conclude that these factors should be considered in setting the stage of tumor pre- and postoperatively [11911312] BACKGROUND Although surgical resectability is an important prognostic factor , recurrences are commonly noted in advanced colorectal cancer patients , even after apparently curative surgery . Since such recurrences can not be cured , better adjuvant chemotherapies are urgently required . PATIENTS AND METHODS We studied the effect of post-operative chemotherapy using oral administration of 1-hexylcarbamoyl-5-fluorouracil ( HCFU ) with 5-fluorouracil ( 5-FU ) infusion for curatively-resected Stage IIIa and IIIb colorectal cancers . This study was prospect ively r and omized and controlled and 314 ( 97.8 % ) out of 321 patients were determined to be c and i date s for statistical assessment . Group A and Group B received 5-FU intravenous injection at , respectively , 333 mg/m2 and 1000 mg/m2 body surface area/24 hours continuously for 72 hours beginning on post-operative day 0 and day 6 , with oral HCFU 300 mg daily for 52 weeks beginning 2 weeks after surgery . RESULTS There were no differences in overall 5-year survival or disease-free survival between Group A and Group B. A retrospective subset analysis . however , suggested that the protocol of Group B tended to yield better 5-year survival ( 68.3 % ) for rectal cancer than that of Group A ( 58.8 % ) . CONCLUSION Inductive therapy with high-dose 5-FU in combination with oral HCFU appears to be beneficial as adjuvant chemotherapy for advanced rectal cancer with lymph node metastasis [16009958] PURPOSE The European Organisation for Research and Treatment of Cancer ( EORTC ) trial evaluated the addition of chemotherapy ( CT ) to preoperative radiation ( preop RT ) and the value of postoperative CT for improving the survival in patients with T3 - 4 resectable rectal cancer . Patients were allocated to the following four arms : arm 1 , preop RT 45 Gy in 5 weeks ; arm 2 , preop RT plus two 5-day CT courses ( fluorouracil 350 mg/m2/d and leucovorin 20 mg/m2/d ) in the first and fifth week of RT ; arm 3 , preop RT plus four postoperative CT courses ; and arm 4 , preop RT and CT plus postoperative CT . We investigated the effect of adding CT on the pathologic parameters . PATIENTS AND METHODS One thous and eleven patients were entered onto the trial ; 505 received preop RT ( arms 1 and 3 ) , and 506 received preop RT-CT ( arms 2 and 4 ) . We analyzed the differences in tumor size , tumor node stage , number of retrieved nodes , and histologic features such as lymphatic , venous , and perineural invasions , tumor differentiation , and tumor type . RESULTS After preop RT-CT , tumors were smaller ( P < .0001 ) , had less advanced pT ( P < .001 ) and pN stages ( P < .001 ) , had small numbers of examined nodes ( P = .046 ) , and less frequent LVN invasions ( P < or = .008 ) . Mucinous tumors increased after preop RT-CT ( P < .001 ) . CONCLUSION In patients with rectal cancer , preliminary results of EORTC Trial 22921 indicate that the addition of CT to preop RT induces down-sizing , downstaging , and significant changes in histologic characteristics . Longer follow-up is needed to assess the impact on local control and survival [1900687] A r and omized controlled study was carried out by the envelope method with 491 institutions in participation across the country in order to find an optimal surgical adjuvant chemotherapy for curatively resected colorectal cancer . The schedules for drug administration were different in four districts : ACNU + Futraful ( FT ) group and FT alone group in the Hokkaido-Shikoku district ; the same schedule groups plus untreated group in the Chubu-Kinki district ; MMC+FT group , FT alone group in the Tohoku-Kanto district ; and ADM+FT group and FT alone group in the Chugoku-Kyushu district . The numbers of patients admitted to this study were 2,450 cases with colon cancer and 2,456 cases met the evaluation criteria of this study . The 5-year survival rate on the whole did not differ from combination therapy to single drug therapy in either colon cancer or rectal cancer , but in Dukes C rectal cancer the five-year survival rate tended to be higher with the combination therapies . In n2 ( + ) or a2(s ) rectal cancer in particular , combination therapies with MMC and FT and with ADM and FT achieved significantly higher five-year survival rate , and the rate of local recurrence was significantly lower with ADM+FT [8683634] BACKGROUND Combined radiation therapy and chemotherapy after surgery , compared with postsurgical radiation therapy alone , has been shown to improve disease-free survival and overall survival significantly among patients with poor-prognosis ( i.e. , advanced stage disease or metastasis to regional lymph nodes ) resectable rectal cancer . However , the combined therapy is associated with more toxic effects , raising the question of whether the benefits of the treatment justify its quality -of-life costs for the individual patient . PURPOSE To assess the trade-offs between improved survival and increased treatment toxicity , we reanalyzed data from a r and omized clinical trial that compared the efficacy of combined adjuvant chemotherapy and radiation therapy with adjuvant radiation therapy alone in the treatment of patients with poor-prognosis resectable rectal cancer . METHODS The data were from a North Central Cancer Treatment Group trial in which 204 patients with poor-prognosis rectal cancer were r and omly assigned to receive either postoperative radiation therapy alone or radiation therapy plus fluorouracil-based chemotherapy . A quality -adjusted time without symptoms or toxicity ( Q-TWiST ) analysis was used to account for freedom from symptomatic disease and from early and late side effects of treatment . All reported P values are two-sided . RESULTS As reported previously , the combined therapy reduced the risk of relapse by 34 % ( 95 % confidence interval [ CI ] = 12%-50 % ; P = .0016 ) and reduced the overall death rate by 29 % ( 95 % CI = 7%-45 % ; P = .025 ) in comparison with adjuvant radiation therapy alone . In the 5 years following assignment to treatment , patients who received the combined therapy had more time with toxicity ( 3.1 months ; 95 % CI = 2.0 - 4.1 months ) , shorter survival after relapse ( 3.6 months less ; 95 % CI = 0.9 - 6.3 months less ) , and more TWiST ( 6.1 months ; 95 % CI = 0.2 - 12.0 months ) than patients who received adjuvant radiation therapy alone . Despite an increase in the amount of time that individuals spent with early and late toxic effects , the Q-TWiST analysis indicated that the combined therapy conferred significantly greater benefit for a wide range of patient preferences about living with the toxicity of treatment or the symptoms of overt disease . CONCLUSIONS AND IMPLICATION S Use of combined chemotherapy and radiation therapy as an adjuvant to surgery for patients with poor-prognosis resectable rectal cancer is justified , since the improved outcome in terms of delayed recurrence and increased survival balances the time spent with early and late toxic effects . The Q-TWiST method is an excellent way to compare treatment outcomes that include quality -of-life considerations [17008704] PURPOSE In 1992 , preoperative radiotherapy was considered in France as the st and ard treatment for T3 - 4 rectal cancers . The present r and omized trial compares preoperative radiotherapy with chemoradiotherapy . PATIENTS AND METHODS Patients were eligible if they presented a resectable T3 - 4 , Nx , M0 rectal adenocarcinoma accessible to digital rectal examination . Preoperative radiotherapy with 45 Gy in 25 fractions during 5 weeks was delivered . Concurrent chemotherapy with fluorouracil 350 mg/m2/d during 5 days , together with leucovorin , was administered during the first and fifth week in the experimental arm . Surgery was planned 3 to 10 weeks after the end of radiotherapy . All patients should receive adjuvant chemotherapy with the same fluorouracil/leucovorin regimen . The primary end point of the trial was overall survival . RESULTS A total of 733 patients were eligible . Grade 3 or 4 acute toxicity was more frequent with chemoradiotherapy ( 14.6 % v 2.7 % ; P < .05 ) . There was no difference in sphincter preservation . Complete sterilization of the operative specimen was more frequent with chemoradiotherapy ( 11.4 % v 3.6 % ; P < .05 ) . The 5-year incidence of local recurrence was lower with chemoradiotherapy ( 8.1 % v 16.5 % ; P < .05 ) . Overall 5-year survival in the two groups did not differ . CONCLUSION Preoperative chemoradiotherapy despite a moderate increase in acute toxicity and no impact on overall survival significantly improves local control and is recommended for T3 - 4 , N0 - 2 , M0 adenocarcinoma of the middle and distal rectum [15236870] BACKGROUND AND PURPOSE The aim was to verify whether preoperative conventionally fractionated chemoradiation offers an advantage in sphincter preservation in comparison with preoperative short-term irradiation . PATIENTS AND METHODS Patients with resectable T3 - 4 rectal carcinoma without sphincters ' infiltration and with a lesion accessible to digital rectal examination were r and omised into : preoperative 5x5Gy short-term irradiation with subsequent total mesorectal excision ( TME ) performed within 7 days or chemoradiation to a total dose of 50.4Gy ( 1.8Gy per fraction ) concomitantly with two courses of bolus 5-fluorouracil and leucovorin followed by TME after 4 - 6 weeks . Surgeons were obliged to base the type of operation on the tumour status at the time of surgery . RESULTS Between 1999 and 2002 , 316 patients from 19 institutions were enrolled . The sphincter preservation rate was 61 % in the 5x5Gy arm and 58 % in the radiochemotherapy arm , P = 0.57 . The tumour was on average 1.9 cm smaller ( P < 0.001 ) among patients treated with chemoradiation compared with short-term schedule . For patients who underwent sphincter-preserving procedure , the surgeons generally followed the rule of tailoring the resection according to tumour downsizing ; the median distal bowel margin was identical ( 2 cm ) for both r and omised groups . However , in the chemoradiation group , five patients underwent abdominoperineal resection despite clinical complete response . CONCLUSIONS Despite significant downsizing , chemoradiation did not result in increased sphincter preservation rate in comparison with short-term preoperative radiotherapy . The surgeons ' decisions were subjective and based on pre-treatment tumour volume at least in clinical complete responders [12190680] Local control and survival following surgical treatment of rectal cancer have been improved by the introduction of total mesorectal excision ( TME ) . The aim of this study was to determine the nationwide impact of the introduction and training of TME on recurrence and survival in rectal cancer [19016023] Purpose : The objective of this exp and ed phase II trial was to confirm the safety results of the preceding phase I study and establish the efficacy of neoadjuvant radiochemotherapy with capecitabine in rectal cancer in a multicenter setting . Patients and Methods : 96 patients ( 63 % male , age 34–81 years ) with advanced rectal cancer ( cT3–4 or cN+ ) from seven university centers in Germany were recruited . All were to receive a total irradiation dose of 50.4–55.8 Gy with conventional fractions . Capecitabine was given at an oral dosage of 825 mg/m2bid on each day of the radiotherapy period with the first daily dose applied 2 h before irradiation , followed by surgery 6 weeks later . Results : Most of the patients suffered from an advanced primary tumor ( cT3 : 57 % , cT4 : 40 % ) with lymph node involvement in 60 % . After neoadjuvant treatment , with a mean of 99 % of the scheduled radiation dose actually delivered , a clinical response rate of 68 % ( 95 % confidence interval : 57–78 % ) was observed . Out of 87 evaluable patients undergoing surgery , a sphincter-preserving procedure could be performed in 51 % and R0 resection in 94 % . A pathologically complete response was achieved in six patients ( 7 % , 95 % confidence interval : 3–14 % ) . The comparison of initial diagnosis and pathologic findings showed a downstaging in 61 % . Acute toxicity with > 5 % incidence of NCI ( National Cancer Institute ) grade ≥ 3 included lymphopenia ( 12 % ) , leukopenia ( 6 % ) , and diarrhea ( 7 % ) . Mild to moderate h and -foot syndrome occurred in 12 % only . After a median follow-up of 48 months , the 5-year overall survival and tumor control data were , with regard to patient selection , in the expected range with an overall survival of 65 % , a relapse-free survival of 47 % , and a local recurrence rate after 5 years of 17 % . Conclusion : The data clearly confirm that capecitabine is an adequate substitute for 5-fluorouracil in preoperative chemoradiation of rectal cancer with a favorable safety profile . Ziel : Diese multizentrische Phase-II-Studie sollte Effektivität und Toxizität einer neoadjuvanten Radiochemotherapie mit Capecitabine prüfen . Patienten und Method ik:96 Patienten ( davon 63 % männlich , Alter 34–81 Jahre ) mit lokal fortgeschrittenem Rektumkarzinom ( cT3–4 oder cN+ ) aus sieben deutschen Universitätskliniken wurden rekrutiert . Alle erhielten eine präoperative Radiotherapie ( 50,4–55,8 Gy in konventioneller Fraktionierung mit 5 × 1,8 Gy ) und zusätzlich 2 × täglich 825 mg/m2Capecitabin während gesamten Radiotherapie ( erste Dosis 2 h vor Radiotherapie , keine Pause am Wochenende ) . 6 Wochen nach der Radiochemotherapie war die Resektion geplant . Ergebnisse:97 % der Patienten hatten T3/T4-Tumoren ( T3 : 57 % ; T4 : 40 % ) . Lymphknotenbefall ( cN+ ) lag in 60 % vor . Die präoperative Therapie war gut durchführbar ( mittlere Strahlendosis 99 % , mittlere Capecitabindosis 96 % der geplanten Dosis ) . Die klinische Ansprechrate betrug 68 % ( 95%-Konfidenzintervall : 57–78 % ) und entsprach der Studienhypothese . Von 87 auswertbaren operierten Patienten wurden 94 % R0-reseziert ; ein Sphinktererhalt war in 51 % möglich . Sechs Patienten ( 7 % , 95%-Konfidenzintervall : 3–14 % ) hatten eine histologisch komplette Remission ( ypT0 ) i m Resektat . Ein Downstaging wurde in 61 % erreicht . Akute Nebenwirkungen CTC-Grad ≥ 3 ( Common Toxicity Criteria ) mit einer Frequenz von > 5 % wurden für Lymphopenie ( 12 % ) , Diarrhö ( 7 % ) und Leukopenie ( 6 % ) beobachtet . Ein H and -Fuß-Syndrom trat in 12 % auf und war jeweils nur mild ( Grad 1–2 ) . Die 5-Jahres-Überlebensrate betrug 65 % , das rezidivfreie Überleben 47 % und die lokale Kontrolle nach 5 Jahren 83%.Schlussfolgerung : Die Date n dieser multizentrischen Phase-II-Studie bestätigen , dass die Kombination von präoperativer Radiotherapie und Capecitabin eine wirksame und nebenwirkungsarme Beh and lung beim lokal fortgeschrittenen Rektumkarzinom darstellt . Capecitabin eignet sich als Ersatz für eine kontinuierliche 5-Fluorouracil-Infusion [6171898] In a Central Oncology Group trial in 319 evaluable patients the addition of 5-FU to the surgical treatment of colorectal carcinoma provided a small but significant benefit in those with colotectal cancer in certain unfavorable situations , namely Dukes C tumors and rectal carcinoma [11034245] Background : Postoperative adjuvant chemoradiation treatment after curative resection for rectal cancer was needed to reduce recurrence and improve a survival rate . Intravenous 5-fluorouracil ( 5-FU ) and leucovorin has been a mainstay of chemotherapy , but oral 5-FU derivatives have been shown a comparable antitumor activity . Intravenous 5-FU and oral doxifluridine were compared with respect to therapeutic efficacy , drug toxicity , and quality of life . Methods : A total of 166 patients were r and omized to receive intravenous 5-FU ( 450 mg/m2/day ) or oral doxifluridine ( 900 mg/m2/day ) in combination with leucovorin ( 20 mg/m2/day ) for depth of invasion , nodal status , metastasis ( TNM ) stage II and III patients between October 1997 and February 1999 . Consecutive daily intravenous infusion for 5 days per every month for a total of 12 cycles ( IV arm , n = 74 ) and oral doxifluridine daily for 3 weeks and 1 week rest for a total of 12 cycles ( oral arm , n = 92 ) . Drug toxicity and quality of life were observed . Quality of life was scored according to 22 daily activity items ( good , ≥ 71 ; fair , < 70 ; poor , < 52 ) . Results : There was no difference of sex between two groups ( IV arm : male/female = 45/29 , oral arm : male/female = 59/33 ) . The mean age was 52.3 vs. 59.5 , respectively . There was also no difference of TNM stage distribution and type of operation between groups ( P = .05 ) . Mean numbers of chemotherapy cycles were 6.5 ± 3.7 ( IV arm ) vs. 7.2 ± 4.3 ( oral arm ) , respectively . The rate of recurrence was 9/74 ( 12.1 % ) in the IV arm and 6/92 ( 6.5 % ) in the oral arm , respectively ( P = .937 ) . Local recurrence was 2/74 ( stage III ; 2.7 % ) in the IV arm and 1/92 ( stage II;1.1 % ) in the oral arm , respectively . Systemic recurrence was 7/74 ( stage III ; 9.4 % ) in the IV arm and 5/92 ( stage III ; 5.4 % ) in the oral arm , respectively . The most common site of systemic recurrence was the liver . Toxicity profile was as follows : leukopenia ( 30/74 vs. 17/92 ) and alopecia ( 21/74 vs. 13/92 ) were statistically more common in the IV arm . Diarrhea was more common in the oral arm . Poor quality of life score between two groups was observed at 1 month ( 23.9 % vs. 13 % ) and 2 months ( 15.8 % vs. 3.7 % ) after chemotherapy . Good quality of life score was observed at 1 month ( 19.5 % vs. 49 % ) and 2 months ( 47 % vs. 72 % ) , respectively ( P < .05 ) . Conclusions : Oral doxifluridine with leucovorin shows a comparable therapeutic efficacy to intravenous 5-FU regimen with high quality of life as postoperative adjuvant therapy . The oral regimen also can be safely given with appropriate toxicity and tolerability [16446336] PURPOSE To evaluate the rate of pathologic complete response and toxicity of neoadjuvant chemoradiation for advanced T3/T4 distal rectal cancers in a r and omized phase II study PATIENTS AND METHODS Patients with clinical T3/T4 distal rectal cancers were r and omly assigned in a phase II study to receive combined neoadjuvant chemoradiotherapy followed by surgical resection . Patients were r and omly assigned to receive continuous venous infusion ( CVI ) fluorouracil ( FU ) 225 mg/m2 per day , 7 days per week , plus pelvic hyperfractionated radiation 55.2 to 60 Gy at 1.2 Gy bid ( arm 1 ) or CVI FU 225 mg/m2 per day Monday to Friday , 120 hours per week plus irinotecan 50 mg/m2 once weekly for 4 weeks plus pelvic radiation therapy 50.4 to 54 Gy at 1.8 Gy per day ( arm 2 ) . Surgery was performed 4 to 10 weeks after completion of neoadjuvant therapy . The primary end point of this study was pathologic complete response ( pCR ) . Secondary end points included acute and late normal tissue morbidity . RESULTS A total of 106 patients were entered onto the study , with 103 assessable for response . The overall resectability rate was 93 % . The median time to surgery was 7 weeks . Tumor downstaging was observed in 78 % of patients in both arms . The pCR rate for all assessable patients was 26 % in each arm . For patients who had surgery , the pCR rate was also the same ( 28 % ) in both arms . Acute and late toxicity was also similar . Grade 3 and 4 acute hematologic and nonhematologic toxicity occurred in 13 % and 38 % in arm 1 and 12 % and 45 % in arm 2 , respectively . CONCLUSION Although the overall complete response rate and toxicity seems similar in both arms , this is the first multi-institutional study to establish a relatively high ( 28 % ) pCR rate after neoadjuvant therapy [1997835] BACKGROUND Radiation therapy as an adjunct to surgery for rectal cancer has been shown to reduce local recurrence but has not improved survival . In a previous study , combined radiation and chemotherapy improved survival significantly as compared with surgery alone , but not as compared with adjuvant radiation , which many regard as st and ard therapy . We design ed a combination regimen to optimize the contribution of chemotherapy , decrease recurrence , and improve survival as compared with adjuvant radiation alone . METHODS Two hundred four patients with rectal carcinoma that was either deeply invasive or metastatic to regional lymph nodes were r and omly assigned to postoperative radiation alone ( 4500 to 5040 cGy ) or to radiation plus fluorouracil , which was both preceded and followed by a cycle of systemic therapy with fluorouracil plus semustine ( methyl-CCNU ) . RESULTS After a median follow-up of more than seven years , the combined therapy had reduced the recurrence of rectal cancer by 34 percent ( P = 0.0016 ; 95 percent confidence interval , 12 to 50 percent ) . Initial local recurrence was reduced by 46 percent ( P = 0.036 ; 95 percent confidence interval , 2 to 70 percent ) , and distant metastasis by 37 percent ( P = 0.011 ; 95 percent confidence interval , 9 to 57 percent ) . In addition , combined therapy reduced the rate of cancer-related deaths by 36 percent ( P = 0.0071 ; 95 percent confidence interval , 14 to 53 percent ) and the overall death rate by 29 percent ( P = 0.025 ; 95 percent confidence interval , 7 to 45 percent ) . Its acute toxic effects included nausea , vomiting , diarrhea , leukopenia , and thrombocytopenia . These effects were seldom severe . Severe , delayed treatment-related reactions , usually small-bowel obstruction requiring surgery , occurred in 6.7 percent of all patients receiving radiation , and the frequencies of these complications were comparable in both treatment groups . CONCLUSIONS The combination of postoperative local therapy with radiation plus fluorouracil and systemic therapy with a fluorouracil-based regimen significantly and substantively improves the results of therapy for rectal carcinoma with a poor prognosis , as compared with postoperative radiation alone [8888803] BACKGROUND A joint study was performed by the Tokai HCFU study group , which included seven institutions , to examine the value of oral administration of Carmofur ( HCFU ) , a 5-fluorouracil ( 5-FU ) derivative , for postoperative adjuvant chemotherapy in patients with colorectal cancer undergoing curative resection . METHODS The patients were divided into two groups , a control group receiving no HCFU and a group administered HCFU for 1 year , using a central ized registration system by telephone . Among 173 patients entered into this study , 159 evaluable cases were analyzed for evaluation of the drug . RESULTS The cumulative 5-year disease-free rate of patients who received HCFU was significantly increased compared with the control group . In particular , the rate was much higher in patients with colon cancer . No severe side effects arose from adjuvant chemotherapy with HCFU . CONCLUSION Adjuvant chemotherapy with oral HCFU appears to provide a useful and safe postoperative treatment [343748] An adjuvant program of fluorouracil for patients undergoing " curative " resection for adenocarcinoma of the colon and rectum was initiated as a r and omized clinical trial in January 1968 . Patients were r and omly assigned to an intraluminal fluorouracil or intraluminal control ( saline ) group and were so treated at the time of surgical resection if findings at operation indicated that all gross neoplastic disease could be resected . Those patients receiving intraluminal fluorouracil ( 30 mg/kg ) received intravenous fluorouracil ( 10 mg/kg ) on each of the first two postoperative days and five subsequent postoperative courses of oral fluorouracil ( 90 mg/kg ) in each 18-day course over a one-year period . By July 1 , 1975 , there were 203 patients undergoing curative resection entered into the study . Survival and disease-free data , as of Dec 31 , 1976 , revealed no benefit from this adjuvant course of fluorouracil . These data support the need for continued r and omized clinical trials of new and innovative adjuvant therapy compared with an untreated control group [12598341] BACKGROUND The aim of this study was to determine whether the efficacy of the combination of 5-fluorouracil ( 5-FU ) , leucovorin ( LV ) and radiation therapy ( RT ) could be improved by the addition of interferon-alpha2b ( IFN-alpha ) in patients who have had a ' curative ' resection , for rectal adenocarcinoma ( Dukes ' B2/C ; T3 N0 , T4 N0 , N1 - 3 ) . PATIENTS AND METHODS A total of 207 eligible patients with a performance status of 0 or 1 were r and omized postoperatively between days 21 and 70 to one of the two treatment groups : group A , LV 20 mg/m2 i.v . bolus and 5-FU 425 mg/m2 i.v . days 1 - 5 and 29 - 33 , LV 20 mg/m2 and 5-FU 400 mg/m2 days 57 - 60 and 85 - 88 , LV 20 mg/m2 and 5-FU 380 mg/m2 days 1 - 5 and 29 - 33 with the second day 1 occurring 28 days after the completion of RT ( 45 Gy ) ; group B , LV , 5-FU and RT as in group A , and IFN-alpha 5 x 10(6 ) IU s.c . three times during each week chemotherapy is given . RESULTS 104 patients were r and omized into group A and 103 into group B. There was no statistically significant difference in either disease-free survival or overall survival between the two groups . Toxicity was also the same , except for the flu-like syndrome associated with the IFN-alpha administration . CONCLUSIONS There was no difference in efficacy between the two combinations . Toxicity was greater with the LV + 5-FU + IFN-alpha regimen because of the flu-like syndrome [383171] Fifty-three patients with colorectal cancer Dukes ' B2 and C were r and omized after surgery . One group was treated by radio- and /or chemotherapy and the second by radio- and /or chemotherapy and MER . After 24 and 36 months a significant longer disease free interval , lower recurrence rate and better survival was found in the group treated by radio-chemo- and immunotherapy . Treatment was well tolerated and there were few local side effects from the MER injections . The long time efficacy of this adjuvant treatment whether it increases the cure rate or only delays recurrence does require longer follow-up [7232842] Adjuvant therapy was given to patients with colorectal cancer stage Duke 's B2 and C. The 53 patients were r and omized and stratified after surgery . One arm received radiotherapy and chemotherapy and the other radiotherapy , chemotherapy , and MER . The survival and disease-free interval up to 2 years were longer and better in the radiochemo-MER arm . It is too early to conclude whether this combination increases the cure rate or delays the appearance of metastases . The time interval between the cytotoxic therapy and the immunotherapy and the dose of the immunotherapeutic agent is very important for the success of the combination therapy . Further follow-up is necessary and more patients need to be entered into the trial [16971718] BACKGROUND Preoperative radiotherapy is recommended for selected patients with rectal cancer . We evaluated the addition of chemotherapy to preoperative radiotherapy and the use of postoperative chemotherapy in the treatment of rectal cancer . METHODS We r and omly assigned patients with clinical stage T3 or T4 resectable rectal cancer to receive preoperative radiotherapy , preoperative chemoradiotherapy , preoperative radiotherapy and postoperative chemotherapy , or preoperative chemoradiotherapy and postoperative chemotherapy . Radiotherapy consisted of 45 Gy delivered over a period of 5 weeks . One course of chemotherapy consisted of 350 mg of fluorouracil per square meter of body-surface area per day and 20 mg of leucovorin per square meter per day , both given for 5 days . Two courses were combined with preoperative radiotherapy in the group receiving preoperative chemoradiotherapy and the group receiving preoperative chemoradiotherapy and postoperative chemotherapy ; four courses were planned postoperatively in the group receiving preoperative radiotherapy and postoperative chemotherapy and the group receiving preoperative chemoradiotherapy and postoperative chemotherapy . The primary end point was overall survival . RESULTS We enrolled 1011 patients in the trial . There was no significant difference in overall survival between the groups that received chemotherapy preoperatively ( P=0.84 ) and those that received it postoperatively ( P=0.12 ) . The combined 5-year overall survival rate for all four groups was 65.2 % . The 5-year cumulative incidence rates for local recurrences were 8.7 % , 9.6 % , and 7.6 % in the groups that received chemotherapy preoperatively , postoperatively , or both , respectively , and 17.1 % in the group that did not receive chemotherapy ( P=0.002 ) . The rate of adherence to preoperative chemotherapy was 82.0 % , and to postoperative chemotherapy was 42.9 % . CONCLUSIONS In patients with rectal cancer who receive preoperative radiotherapy , adding fluorouracil-based chemotherapy preoperatively or postoperatively has no significant effect on survival . Chemotherapy , regardless of whether it is administered before or after surgery , confers a significant benefit with respect to local control . ( Clinical Trials.gov number , NCT00002523 [ Clinical Trials.gov ] . ) [11319280] The aim of this study was to determine if the response to preoperative radiation and chemotherapy with continuous infusion 5-fluorouracil ( 5-FU ) was predictive for survival among patients with locally advanced rectal cancer . Preoperative chemoradiation ( CTX/XRT ) that delivered 45 Gy in 25 fractions over 5 weeks with continuous infusion 5-FU ( 300 mg/m2/day ) was given to 117 patients . The pretreatment stage distribution , as determined by endorectal ultrasound ( u ) , included uT2N0 in 2 % , uT3N0 in 47 % , uT3N1 in 49 % , and uT4N0 in 2 % of cases ; endorectal ultrasound was not performed in 13 % of cases ( 15 patients ) . Approximately 6 weeks after completion of CTX/XRT , surgery was performed . Adjuvant chemotherapy , consisting of 400 to 425 mg/m2 of 5-FU plus 20 mg/m2 leucovorin for 5 days , was administered every 28 days for 4 to 6 cycles after surgical resection . Among the 74 patients treated with adjuvant chemotherapy , the preoperative stage of disease was 31 with T3N0 and 43 T3N1 . Median follow-up was 46 months ( range 2 to 89 months ) . The pathologic tumor stages were Tis-2N0 in 26 % , T2N1 in 5 % , T3N0 in 21 % , T3N1 in 15 % , T4N0 in 5 % , and T4N1 in 1 % ; a complete response ( CR ) to preoperative CTX/XRT was pathologically confirmed in 32 ( 27 % ) of patients . Tumor down-staging occurred in 72 ( 62 % ) cases . A sphincter-saving procedure ( SP ) was possible in 59 % of patients . The median DFS and overall survival rates for responders were 46 months and 47 months , respectively ; for non-responders these outcome measures were 38 months and 41 months , respectively . Log-rank analysis showed that the distant metastatic-free survival rates improved with any response to CTX/XRT ( p < 0.00001 ) , CR to CTX/XRT ( p < 0.009 ) and SP ( p < 0.012 ) . Likewise , these parameters also significantly influenced DFS rates ( CTX/XRT p < 0.00001 ; CR p < 0.006 ; and SP p < 0.008 ) . Control of pelvic disease was influenced by clinical size ( p < 0.002 ) and SP ( p < 0.016 ) on univariate analysis . On multivariate analysis only clinical size ( p < 0.002 ) continued to be a significant factor for local control . Factors on multivariate analysis that result ed in significant improvements in cancer-specific survival included any response to preoperative CTX/XRT ( p < 0.017 ) and administration of adjuvant chemotherapy ( p < 0.034 ) . Any response to preoperative CTX/XRT improved distant metastatic-free and disease-free survival rates . Multivariate analysis confirmed that a response to preoperative CTX/XRT predicted for improvements in overall survival among patients with locally advanced rectal cancer . Patients who fail to respond to preoperative 5-FU based chemotherapy given concomitantly with radiation have higher rates of distant metastases with adjuvant 5-FU therapy [19453040] BACKGROUND / AIMS The usefulness of adjuvant chemotherapy started immediately following surgery was evaluated . METHODOLOGY A r and omized clinical trial was performed on 133 patients with advanced colorectal cancer using oral anticancer agents with one-week continuous 5-FU infusion starting immediately after curative surgery . In Group A and Group B , 300 mg/day of HCFU was orally administered for two years starting two weeks after surgery , and in addition , 333 mg/m2/day of 5-FU was drip infused from the central vein for seven days from the day of surgery in Group B. RESULTS For 1919 days after surgery , there were no significant intergroup differences in overall survival ( OS ) and disease-free survival ( DFS ) , but OS and DFS in Group B rectal cancer patients were significantly better when compared to Group A rectal cancer patients . On the other h and , OS tended to be better in Group A colon cancer patients , but no significant intergroup differences were seen , while intergroup differences tended to be smaller when corrected for disease stage . CONCLUSIONS Continuous 5-FU infusion starting immediately after curative surgery for colorectal cancer was safe . While further investigation is necessary to eluci date the degree of improvement in postoperative prognosis , the results of the present study suggest that continuous 5-FU infusion improves prognosis in advanced rectal cancer [11547717] BACKGROUND Short-term preoperative radiotherapy and total mesorectal excision have each been shown to improve local control of disease in patients with resectable rectal cancer . We conducted a multicenter , r and omized trial to determine whether the addition of preoperative radiotherapy increases the benefit of total mesorectal excision . METHODS We r and omly assigned 1861 patients with resectable rectal cancer either to preoperative radiotherapy ( 5 Gy on each of five days ) followed by total mesorectal excision ( 924 patients ) or to total mesorectal excision alone ( 937 patients ) . The trial was conducted with the use of st and ardization and quality -control measures to ensure the consistency of the radiotherapy , surgery , and pathological techniques . RESULTS Of the 1861 patients r and omly assigned to one of the two treatment groups , 1805 were eligible to participate . The overall rate of survival at two years among the eligible patients was 82.0 percent in the group assigned to both radiotherapy and surgery and 81.8 percent in the group assigned to surgery alone ( P=0.84 ) . Among the 1748 patients who underwent a macroscopically complete local resection , the rate of local recurrence at two years was 5.3 percent . The rate of local recurrence at two years was 2.4 percent in the radiotherapy-plus-surgery group and 8.2 percent in the surgery-only group ( P<0.001 ) . CONCLUSIONS Short-term preoperative radiotherapy reduces the risk of local recurrence in patients with rectal cancer who undergo a st and ardized total mesorectal excision [11919230] PURPOSE The gastrointestinal Intergroup studied postoperative adjuvant chemotherapy and radiation therapy in patients with T3/4 and N+ rectal cancer after potentially curative surgery to try to improve chemotherapy and to determine the risk of systemic and local failure . PATIENTS AND METHODS All patients had a potentially curative surgical resection and were treated with two cycles of chemotherapy followed by chemoradiation therapy and two additional cycles of chemotherapy . Chemotherapy regimens were bolus fluorouracil ( 5-FU ) , 5-FU and leucovorin , 5-FU and levamisole , and 5-FU , leucovorin , and levamisole . Pelvic irradiation was given to a dose of 45 Gy to the whole pelvis and a boost to 50.4 to 54 Gy . RESULTS One thous and six hundred ninety-five patients were entered and fully assessable , with a median follow-up of 7.4 years . There was no difference in overall survival ( OS ) or disease-free survival ( DFS ) by drug regimen . DFS and OS decreased between years 5 and 7 ( from 54 % to 50 % and 64 % to 56 % , respectively ) , although recurrence-free rates had only a small decrease . The local recurrence rate was 14 % ( 9 % in low-risk [ T1 to N2 + ] and 18 % in high-risk patients [ T3N+ , T4N ] ) . Overall , 7-year survival rates were 70 % and 45 % for the low-risk and high-risk groups , respectively . Males had a poorer overall survival rate than females . CONCLUSION There is no advantage to leucovorin- or levamisole-containing regimens over bolus 5-FU alone in the adjuvant treatment of rectal cancer when combined with irradiation . Local and distant recurrence rates are still high , especially in T3N+ and T4 patients , even with full adjuvant chemoradiation therapy [16758130] Purpose After neoadjuvant radiochemotherapy and surgery , there is no general agreement about whether postoperative chemotherapy is necessary . With the help of clinical and pathohistologic data , prognostic factors were determined as a basis for the decision to spare a patient additional chemotherapy or to urgently recommend it . Results Ninety-five patients treated with neoadjuvant 5-fluorouracil-based radiochemotherapy ( November 4 , 1997 and June 15 , 2004 ) without distant metastases and an R0 ( microscopically complete ) resection were evaluated . Adjuvant chemotherapy ( 5-fluorouracil or 5-fluorouracil/folinic acid ) was given to 65 of 95 patients ( 68.4 percent ) . The disease-free survival rate after 36 months was chosen as the target parameter ( median follow-up , 36 months ) . Methods The five-year survival rate for all patients was 80.3 ± 5.6 percent ; the five-year disease-free survival was 78.1 ± 5.1 percent ; the five-year local control rate was 94.2 ± 5.1 percent . In the univariate and multivariate analysis of the disease-free survival , the pathohistologic lymph node status after radiochemotherapy ( ypN ) was the only significant prognostic parameter . Disease-free survival ( 36 months ) for patients without lymph node metastases ( ypN0 ) was excellent , independent of whether they had received postoperative chemotherapy ( n = 43 ; 87.5 ± 6.0 percent ) or not ( n = 29 ; 87.7 ± 6.7 percent ) . Patients with ypN2 status have , despite chemotherapy , a poor disease-free survival at 30 ± 17.6 percent after 36 months . Conclusions These retrospective data suggest that , for some patients , postoperative chemotherapy can be spared . For patients with ypN2 status , an intensification of the postoperative chemotherapy should be considered . Further evaluation in prospect i ve studies is urgently recommended [16675478] BACKGROUND Although adjuvant radiotherapy was proved to be effective for local control of rectal cancer even after st and ardized mesorectal excision , the role of adjuvant chemotherapy after such st and ardized surgery remains to be clarified . We aim ed to assess the efficacy of a combination of uracil and tegafur for pathological stage III rectal cancer treated by st and ardized mesorectal excision with selective lateral pelvic lymphadenectomy . METHODS We r and omly assigned patients with completely resected stage III rectal cancer , who underwent st and ardized mesorectal excision with selective lateral pelvic lymphadenectomy , to receive either oral uracil-tegafur ( 400 mg/m2 tegafur per day ) for one year or no treatment . St and ardization and quality control of the surgery and pathological techniques were ensured by use of the guidelines of the Japanese Society for Cancer of the Colon and Rectum . The primary endpoint was relapse-free survival . The secondary endpoint was overall survival . RESULTS We enrolled and r and omized 276 patients . Excluding two ineligible patients , 274 were included in the analysis . Planned interim analysis 2 years after accrual termination revealed significant prolongation of relapse-free survival ( P = 0.001 ) and overall survival ( P = 0.005 ) in the uracil-tegafur group . The 3-year relapse-free survival and overall survival rates were 78 and 91 % in the chemotherapy group and 60 and 81 % in the surgery-alone group , respectively . Local recurrence rates were low in both groups . Grade 3 events occurred in 17 % of the chemotherapy patients , but no grade 4 or more events occurred . CONCLUSION Adjuvant chemotherapy with uracil-tegafur improves survival of patients with stage III rectal cancer after st and ardized mesorectal excision with selective lateral pelvic lymphadenectomy [11205198] 366 patients fully resected from a Dukes B2 or C colorectal cancer were r and omised to receive 6 courses of systemic chemotherapy comprising either 5-fluorouracil ( 5 FU ) alone ( arm A : 450 mg/m2/day-5/21 days ) or combined folinic acid ( FOL ) and 5 FU ( arm B : respectively 200 mg/m2 racemic form or 100 mg/m2-l-form and 370 mg/m2/day-5/21 days ) . 173 patients had also been initially r and omised to receive one course of intraportal chemotherapy just after surgery or no portal treatment . Oral levamisole ( 150 mg/day ; 3 days every other week ) was given to all patients for one year . A significantly higher incidence of leuco-granulocytopenia was observed in the arm A ( 5 FU alone ) inducing more frequent dose delays and adaptations as well as levamisole 's withdrawal . Then dose-intensities and dose-intensity products were lower in this arm but the dose intensity expressed in mg/m2/week remained higher ( 631 + /- 107 vs 557 + /- 99 ; p < 0.001 ) . The median follow-up in the study was 4.5 years . Relapse free ( RFS ) and overall survivals ( OAS ) were prolonged in the 5 FU alone group peculiarly in those patients who had not been r and omised for portal treatment . Curves diverged progressively with longer follows-up ( at 8 years ; RFS in arm A : 67 - 71 % vs 59 - 53 % in arm B ; OAS in arm A : 72 - 74 % vs 56 - 46 % in arm B ) . Patients suffering from a colon or a Dukes C cancer benefited the most from the treatment with 5 FU alone . The results are discussed in the light of other recent adjuvant trials . Well dosed 5 FU over a short period of time without folinic acid may be a valuable and inexpensive adjuvant treatment for colorectal cancer . Levamisole may no longer be recommended in this setting [9091798] BACKGROUND Adjuvant radiotherapy for rectal cancer has been extensively studied , but no trial has unequivocally demonstrated improved overall survival with radiotherapy , despite a reduction in the rate of local recurrence . METHODS Between March 1987 and February 1990 , we r and omly assigned 1168 patients younger than 80 years of age who had resectable rectal cancer to undergo preoperative irradiation ( 25 Gy delivered in five fractions in one week ) followed by surgery within one week or to have surgery alone . RESULTS The irradiation did not increase postoperative mortality . After five years of follow-up , the rate of local recurrence was 11 percent ( 63 of 553 patients ) in the group that received radiotherapy before surgery and 27 percent ( 150 of 557 ) in the group treated with surgery alone ( P<0.001 ) . This difference was found in all subgroups defined according to Dukes ' stage . The overall five-year survival rate was 58 percent in the radiotherapy-plus-surgery group and 48 percent in the surgery-alone group ( P=0.004 ) . The cancer-specific survival rates at nine years among patients treated with curative resection were 74 percent and 65 percent , respectively ( P=0.002 ) . CONCLUSIONS A short-term regimen of high-dose preoperative radiotherapy reduces rates of local recurrence and improves survival among patients with resectable rectal cancer [15913913] PURPOSE Capecitabine is an attractive radiosensitizer which can be tumor specific . This study was undertaken to evaluate the toxicity and efficacy of oral capecitabine when used with preoperative radiation therapy . METHODS AND MATERIAL S We conducted a prospect i ve Phase II trial to assess the pathologic response , sphincter preservation effect , and acute toxicity of preoperative chemoradiation ( CRT ) in locally advanced ( uT3 - 4/N + ) but resectable adenocarcinoma of the lower two-thirds of the rectum . The radiation dose was 50 Gy over 5 weeks ( 46 Gy to whole pelvis + 4 Gy boost ) , and capecitabine was administered daily at a dose of 1650 mg/m(2 ) during the entire course of radiation therapy . Surgery was performed with st and ardized total mesorectal excision 4 to 6 weeks after completion of CRT and followed by four cycles of capecitabine ( 2500 mg/m(2)/day for 14 days ) . RESULTS Ninety-five patients were entered into this study ; their median age was 55 ( range , 31 - 75 years ) . Ninety ( 95 % ) patients completed preoperative CRT as planned , and complete resection was achieved in 92 of 94 resected cases ( 98 % ) . Downstaging rate was 71 % ( 56/79 ) on endorectal ultrasonography , and it was 76 % ( 71/94 ) on pathology finding . No tumor cell was observed in the specimens of 11 patients ( 12 % ) . Among the 54 whose tumor was located within 5 cm from the anal verge , 40 patients ( 74 % ) underwent sphincter-preserving procedures . Elevation of the distal tumor margin from the anal verge by preoperative CRT was 0.8 + /- 1.3 cm . Grade 3 toxicities were rare ( diarrhea in 3 % and neutropenia in 1 % ) . CONCLUSION Preoperative CRT using capecitabine achieved encouraging rates of tumor downstaging and sphincter preservation with a low toxicity profile

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### Context: [17906203] PURPOSE European Organisation for Research and Treatment of Cancer ( EORTC ) trial 22921 compared adjuvant fluorouracil-based chemotherapy ( CT ) to no adjuvant treatment in a 2 x 2 factorial trial with r and omization for preoperative (chemo)radiotherapy in patients with resectable T3 - 4 rectal cancer . The results showed no significant impact of adjuvant CT on progression-free or overall survival , although a difference seemed to emerge at approximately , respectively , 2 and 5 years after the start of preoperative treatment . We further explored the data with the aim of refining our underst and ing of the long-term results . PATIENTS AND METHODS Data of 785 of the 1,011 r and omly assigned patients who whose disease was M0 at curative surgery were used . Using meta-analytic methods , we investigated the homogeneity of the effect of adjuvant CT on the time to relapse or death after surgery ( disease-free survival [ DFS ] ) and survival in patient subgroups . RESULTS Although there was no statistically significant impact of adjuvant CT on DFS for the whole group ( P > .5 ) , the treatment effect differed significantly between the ypT0 - 2 and the ypT3 - 4 patients ( heterogeneity P = .009 ) : only the ypT0 - 2 patients seemed to benefit from adjuvant CT ( P = .011 ) . The same pattern was observed for overall survival . CONCLUSION Exploratory analyses suggest that only good-prognosis patients ( ypT0 - 2 ) benefit from adjuvant CT . This could explain why , in the whole group , the progression-free and overall survival diverged only after the poor-prognosis patients ( ypT3 - 4 ) had experienced treatment failure . Patients in whom no downstaging was achieved did not benefit . This also suggests that the same prognostic factors may drive both tumor sensitivity for the primary treatment and long-term clinical benefit from further adjuvant CT [3064191] The Gastrointestinal Tumor Study Group ( GITSG ) protocol GI-7175 r and omized 227 patients between 1975 and 1980 following complete surgical resection of stages B2 and C rectal adenocarcinoma to four treatment arms : ( 1 ) no adjuvant therapy , ( 2 ) chemotherapy only , ( 3 ) radiotherapy only , and ( 4 ) radiotherapy and chemotherapy ( combined modality ) . The results of the study showed an advantage for combined modality treatment over no adjuvant therapy for time to recurrence ( p = 0.005 ) and for survival ( p = 0.01 ) . Severe acute toxicity was frequent in the combined modality arm ( 61 % ) but late effects , including radiation enteritis , have been infrequent . We conclude that postoperative adjuvant therapy is indicated in certain stages of rectal carcinoma and that the present state of knowledge suggests combined modality therapy [9891531] We examined the effects of postoperative 5-fluorouracil ( 5-FU ) infusions and oral treatment with 1-hexylcarbamoyl-5-fluorouracil ( HCFU ) on patients curatively resected for stages II-IV colorectal cancer . The study was prospect ively r and omized , and 251 ( 93.3 % ) of 269 patients were valid c and i date s for statistical assessment . The inductive regimen for group A included 5-FU 10 mg intravenous ( i.v . ) injections on days 0 , 1 , 2 , 7 , 8 and 9 , postoperatively . For maintenance therapy , group A received HCFU 300 mg orally and daily for 52 weeks beginning 2 weeks after surgery . The regimen for group B included only 5-FU injections . The effects of this chemotherapy were also retrospectively analyzed for groups at a high risk for recurrence , stages III-IV , transmural invasion-positive and lymph node metastasis-positive cases . There was no statistical difference in survival time between the groups for 251 eligible cases ( p = 0.079 ) . In group A given 5-FU plus HCFU , there was a reduction in the recurrence rate for patients with stages III-IV or lymph node metastasis-positive colorectal cancers ( p < 0.05 ) and prolongation of the survival time for patients with stage III-IV , transmural invasion-positive or lymph node-positive colorectal cancers ( p < 0.05 ) . Our findings show that the combination of 5-FU infusion and the continuous administration of HCFU is effective in treating patients with surgically resected colorectal cancer who are at high risk for a recurrence [1130879] A combined intraoperative and postoperative adjuvant program of 5 minus Fluorouracil ( 5 FU ) for patients undergoing " curative " resection for adenocarcinoma of the colon and rectum was initiated as a r and omized clinical trial in January 1968 . Patients at the Medical College of Virginia and the University of Virginia were r and omly assigned to an intraluminal 5 FU or intraluminal control ( Saline ) group and were so treated at the time of surgical resection if findings at operation indicated that all gross neoplastic disease could be resected . Patients with operative findings denoting incurability were eliminated from the study after surgical exploration . Those patients receiving intraluminal 5 FU ( 30mg/kg ) received intravenous 5 FU ( 10mg/kg ) on each of the two first postoperative days and 5 subsequent postoperative courses of oral 5FU ( 90 mg/kg in each 18 day course ) over a one year period . By December 31 , 1973 ( 6 years ) 156 patients undergoing " curative " resection were entered into the study . SU therapy with the control or " No Treat " group reveal no significant benefit from this intensive adjuvant course of 5 FU thus far . Continued assessment of these patient groups and their subgroups will be required to develop confidence in these findings but the data thus far suggest no potential benefit from this particular adjuvant program [18083404] BACKGROUND The aim of the QUASAR trial was to determine the size and duration of any survival benefit from adjuvant chemotherapy for patients with colorectal cancer at low risk of recurrence , for whom the indication for such treatment is unclear . METHODS After apparently curative resections of colon or rectal cancer , 3239 patients ( 2963 [ 91 % ] with stage II [ node negative ] disease , 2291 [ 71 % ] with colon cancer , median age 63 [ IQR 56 - 68 ] years ) enrolled between May , 1994 , and December , 2003 , from 150 centres in 19 countries were r and omly assigned to receive chemotherapy with fluorouracil and folinic acid ( n=1622 ) or to observation ( with chemotherapy considered on recurrence ; n=1617 ) . Chemotherapy was delivered as six 5-day courses every 4 weeks or as 30 once-weekly courses of intravenous fluorouracil ( 370 mg/m2 ) with high-dose ( 175 mg ) L-folinic acid or low-dose ( 25 mg ) L-folinic acid . Until 1997 , levamisole ( 12 courses of 450 mg over 3 days repeated every 2 weeks ) or placebo was added . After 1997 , patients who were assigned to receive chemotherapy were given fluorouracil and low-dose folinic acid only . The primary outcome was all-cause mortality . Analyses were done by intention to treat . This trial is registered with the International Clinical Trial Registry , number IS RCT N82375386 . FINDINGS At the time of analysis , 61 ( 3.8 % ) patients in the chemotherapy group and 50 ( 3.1 % ) in the observation group had missing follow-up . After a median follow-up of 5.5 ( range 0 - 10.6 ) years , there were 311 deaths in the chemotherapy group and 370 in the observation group ; the relative risk of death from any cause with chemotherapy versus observation alone was 0.82 ( 95 % CI 0.70 - 0.95 ; p=0.008 ) . There were 293 recurrences in the chemotherapy group and 359 in the observation group ; the relative risk of recurrence with chemotherapy versus observation alone was 0.78 ( 0.67 - 0.91 ; p=0.001 ) . Treatment efficacy did not differ significantly by tumour site , stage , sex , age , or chemotherapy schedule . Eight ( 0.5 % ) patients in the chemotherapy group and four ( 0.25 % ) in the observation group died from non-colorectal cancer causes within 30 weeks of r and omisation ; only one of these deaths was deemed to be possibly chemotherapy related . INTERPRETATION Chemotherapy with fluorouracil and folinic acid could improve survival of patients with stage II colorectal cancer , although the absolute improvements are small : assuming 5-year mortality without chemotherapy is 20 % , the relative risk of death seen here translates into an absolute improvement in survival of 3.6 % ( 95 % CI 1.0 - 6.0 ) [20490797] Objective In the latter 1990s , adjuvant chemotherapy for completely resected Stage III colorectal cancer remained controversial in Japan . We conducted two independent r and omized controlled trials in patients with Stage III colon and rectal cancer . Methods Patients were r and omly assigned to receive surgery alone or surgery followed by treatment with UFT ( 400 mg/m2/day ) , given for five consecutive days per week for 1 year . The primary endpoint was relapse-free survival ( RFS ) , and the secondary endpoint was overall survival ( OS ) . Results A total of 334 patients with colon cancer and 276 with rectal cancer were enrolled . The patients ’ characteristics were similar between the UFT group and the Surgery-alone group . There was no significant difference in RFS or OS in colon cancer . In rectal cancer , however , RFS and OS were significantly better in the UFT group than in the Surgery-alone group . The only grade 4 toxicity in the UFT group was diarrhea , occurring in one patient with colon cancer and one patient with rectal cancer . Conclusions Postoperative adjuvant chemotherapy with UFT is successfully tolerated and improves RFS and OS in patients with Stage III rectal cancer . In colon cancer , the expected benefits were not obtained ( hazard ratio = 0.89 ) [10442189] BACKGROUND R and omized studies have shown that postoperative chemotherapy with or without radiation therapy ( RT ) improved local control and survival of patients with stages II or III rectal cancer . However , the optimal sequence of treatments and the optimal chemotherapeutic regimen have not been defined . Modulation of fluorouracil ( FU ) by leucovorin ( LV ) has yielded a highly significant difference in response rate from that of FU monotherapy , as suggested by an overview of r and omized trials in patients with advanced colorectal cancer . However , this difference in response rate did not translate into a survival benefit . PURPOSE To evaluate the impact on the disease-free survival ( DFS ) and overall survival ( OS ) of patients with stages II or III rectal cancer of postoperative RT and concomitant bolus FU administration alone or with additional chemotherapy using FU and high-dose LV . PATIENTS AND METHODS From October 1989 until February 1997 , 220 patients were r and omized postoperatively to receive either one cycle of chemotherapy with FU ( 600 mg/m2/week x 6 followed by a two-week rest ) and leucovorin ( LV , 500 mg/m2/week x 6 as a two-hour infusion ) followed by pelvic RT with concomitant FU ( 400 mg/m2 ) as a rapid intravenous injection during the first three and last three days of RT , and three more cycles of the same chemotherapy with FU and LV ( st and ard , group A , 111 patients ) or pelvic RT with concomitant FU only ( experimental , group B , 109 patients ) . RESULTS As of August 1998 , after a median follow-up of 4.9 years , there was no significant difference in either three-year DFS ( Group A , 70.3 % ; group B , 68.2 % , P = 0.53 ) or OS ( group A , 77 % ; group B , 73.3 % . P = 0.75 ) . Cox multivariate analysis revealed stage of disease , number of infiltrated nodes , tumor grade , presence of regional implants and perforation to be significant prognostic factors . The incidence of severe side effects was significantly higher in the patients in group A than in those in group B ( 32.4 % vs. 4.6 % , P < 0.0001 ) . CONCLUSIONS The incorporation of additional chemotherapy with FU and LV into postoperative concomitant RT and bolus infusion of FU does not offer a > or = 10 % three-year survival benefit over that of concomitant RT and bolus infusion of FU , and significantly increases toxicity in patients with stages II or III rectal cancer [11914933] Background : The purpose of this study is to evaluate the efficacy of postoperative adjuvant chemotherapy using uracil and tegafur ( UFT ) for colorectal cancer . Methods : In a multicenter trial among 43 institutions for patients who underwent curative resection of Dukes ’ B or C colorectal cancer , a surgery alone group ( control group ) and a treatment group ( UFT group ) to which UFT was administered at 400 mg/day for 2 years following surgery were compared . A total of 320 patients were registered between March 1991 and April 1994 , and 289 of these patients were analyzed as a full- analysis set . Results : The 5-year disease-free survival rate was 75.7 % in the UFT group and 60.1 % in the control group , respectively , and the stratified log-rank test showed the statistical significance ( P=0.0081 ) . This difference was marked in rectal cancer ( P=0.0016 ) and , in particular , the local recurrence was reduced . No significant difference was observed in the 5-year survival rate . The incidence of adverse reactions on administration of UFT was low , and there was no serious adverse reaction . Conclusion : It is suggested that the consecutive administration of UFT at 400 mg/day was an effective and highly safe therapeutic method as postoperative adjuvant chemotherapy for rectal cancer [12827681] BACKGROUND AND OBJECTIVES A r and omised clinical trial was performed in patients undergoing radical surgery for rectal cancer to compare the efficacy and toxicity of adjuvant postoperative radiation therapy ( RT ) to sequential RT and chemotherapy ( CT ) with 5-fluorouracil ( 5-FU ) plus levamisole ( LEV ) . The primary end point was overall survival ( OS ) ; secondary end points were disease-free survival ( DFS ) , the rate of loco-regional recurrence , and treatment-related toxicity ; the final results of this trial are reported . METHODS Patients in arm I underwent RT ( 50 Gy ) in daily fractions of 2 Gy , 5 days/week for 5 weeks . Patients in arm II began with 5-FU ( 450 mg/sqm/day intravenous ( i.v . ) bolus , days 1 - 5 ) plus LEV ( 150 mg/day orally , days 1 - 3 ) ; postoperative RT was delivered during week 2 at the same dosage and schedule as in arm I. The other five cycles of CT ( 5-FU every 28 days and LEV every 15 days for the length of 5-FU administration ) continued after the end of RT if clinical and hemato-biochemical parameters were in the normal range . RESULTS From May 1992 to December 1998 , 218 patients were enrolled into the r and omised clinical trial ( 144 men , 74 women ; age range : 28 - 75 , median 64 years ) . The median follow-up time was 58.1 months ( range : 1 - 3,271 days ) . No significant difference was observed between the two arms of treatment as regards OS and DFS ( P = 0.18 and P = 0.66 , respectively ) . Cox regression analysis for OS confirmed what was observed by univariate analysis for all variables except age . Older age ( > 60 years ) and pathologic lymph-node involvement defined the subgroups with the worst prognosis . Cox regression analysis for DFS confirmed what was observed by univariate analysis for all variables : the only independent variable in predicting DFS was pathologic lymph-node involvement . CONCLUSIONS Our findings suggest no difference in OS , loco-regional and distant site progressions of postoperative RT alone compared to sequential postoperative RT and CT ; notably , this latter regimen was associated with higher toxicity which seriously impaired the patient 's compliance to CT . The low loco-regional recurrence rate ( 9.2 % ) observed in our patients undergoing postoperative RT alone compared to similarly treated patients in previously performed clinical trials ( 20 - 25 % ) underline the role of radical surgery ( mesorectal excision ) coupled with a complete postoperative RT regimen . On the other h and , the similar efficacy of these two adjuvant modalities of treatment might be conditioned by both the low compliance ( 59 % ) to the CT regimen as well as the sequential , instead of concurrent , schedule of administration of RT and CT , which may have decreased further the expected efficacy of the combined regimen [8041415] BACKGROUND The combination of radiation therapy and chemotherapy with fluorouracil plus semustine after surgery has been established as an effective approach to decreasing the risk of tumor relapse and improving survival in patients with rectal cancer who are at high risk for relapse or death . We sought to determine whether the efficacy of chemotherapy could be improved by administering fluorouracil by protracted infusion throughout the duration of radiation therapy and whether the omission of semustine would reduce the toxicity and delayed complications of chemotherapy without decreasing its antitumor efficacy . METHODS Six hundred sixty patients with TNM stage II or III rectal cancer received intermittent bolus injections or protracted venous infusions of fluorouracil during postoperative radiation to the pelvis . They also received systemic chemotherapy with semustine plus fluorouracil or with fluorouracil alone in a higher dose , administered before and after the pelvic irradiation . RESULTS With a median follow-up of 46 months among surviving patients , patients who received a protracted infusion of fluorouracil had a significantly increased time to relapse ( P = 0.01 ) and improved survival ( P = 0.005 ) . There was no evidence of a beneficial effect in the patients who received semustine plus fluorouracil . CONCLUSIONS A protracted infusion of fluorouracil during pelvic irradiation improved the effect of combined-treatment postoperative adjuvant therapy in patients with high-risk rectal cancer . Semustine plus fluorouracil was not more effective than a higher dose of systemic fluorouracil given alone [18539618] Knowledge of the biology and management of rectal cancer continues to improve . A multidisciplinary approach to a patient with rectal cancer by an experienced expert team is m and atory , to assure optimal diagnosis and staging , surgery , selection of the appropriate neo-adjuvant and adjuvant strategy and chemotherapeutic management . Moreover , optimal symptom management also requires a dedicated team of health care professionals . The introduction of total mesorectal excision has been associated with a decrease in the rate of local failure after surgery . High quality surgery and the achievement of pathological measures of quality are a prerequisite to adequate locoregional control . There are now r and omized data in favour of chemoradiotherapy or short course radiotherapy in the preoperative setting . Preoperative chemoradiotherapy is more beneficial and has less toxicity for patients with resectable rectal cancer than postoperative chemoradiotherapy . Furthermore chemoradiotherapy leads also to downsizing of locally advanced rectal cancer . New strategies that decrease the likelihood of distant metastases after initial treatment need be developed with high priority . Those involved in the care for patients with rectal cancer should be encouraged to participate in well- design ed clinical trials , to increase the evidence -based knowledge and to make further progress . Health care workers involved in the care of rectal cancer patients should be encouraged to adopt quality control processes leading to increased expertise [15496622] BACKGROUND Postoperative chemoradiotherapy is the recommended st and ard therapy for patients with locally advanced rectal cancer . In recent years , encouraging results with preoperative radiotherapy have been reported . We compared preoperative chemoradiotherapy with postoperative chemoradiotherapy for locally advanced rectal cancer . METHODS We r and omly assigned patients with clinical stage T3 or T4 or node-positive disease to receive either preoperative or postoperative chemoradiotherapy . The preoperative treatment consisted of 5040 cGy delivered in fractions of 180 cGy per day , five days per week , and fluorouracil , given in a 120-hour continuous intravenous infusion at a dose of 1000 mg per square meter of body-surface area per day during the first and fifth weeks of radiotherapy . Surgery was performed six weeks after the completion of chemoradiotherapy . One month after surgery , four five-day cycles of fluorouracil ( 500 mg per square meter per day ) were given . Chemoradiotherapy was identical in the postoperative-treatment group , except for the delivery of a boost of 540 cGy . The primary end point was overall survival . RESULTS Four hundred twenty-one patients were r and omly assigned to receive preoperative chemoradiotherapy and 402 patients to receive postoperative chemoradiotherapy . The overall five-year survival rates were 76 percent and 74 percent , respectively ( P=0.80 ) . The five-year cumulative incidence of local relapse was 6 percent for patients assigned to preoperative chemoradiotherapy and 13 percent in the postoperative-treatment group ( P=0.006 ) . Grade 3 or 4 acute toxic effects occurred in 27 percent of the patients in the preoperative-treatment group , as compared with 40 percent of the patients in the postoperative-treatment group ( P=0.001 ) ; the corresponding rates of long-term toxic effects were 14 percent and 24 percent , respectively ( P=0.01 ) . CONCLUSIONS Preoperative chemoradiotherapy , as compared with postoperative chemoradiotherapy , improved local control and was associated with reduced toxicity but did not improve overall survival [2363941] Based on the first favourable results of adjuvant therapy of 5FU plus levamisole in Dukes C colonic cancer in 1990 , we conducted a prospect i ve trial . 1029 patients were r and omised to receive one year 5FU plus levamisole or no further treatment following curative surgery for stage II or III colon ( n = 730 ) or rectal cancer ( n = 299 ) . 45 % were in stage II and 55 % in stage III . With a median follow-up of 4 years and 9 months a significant reduction in odds of death ( 25 % , SD 9 % , P = 0.007 ) was observed for those with adjuvant treatment ( 65 % at 5 year ) compared to the observation group ( 55 % ) . Improved relative survival was present in stage III ( 56 % vs 44 % ) , and in stage II patients ( 78 % vs 70 % ) . In rectal cancer a non-significant difference in disease-free or overall survival was observed . Distant metastases developed in 76 % , while local recurrence alone occurred in 14 % . An early start of adjuvant treatment ( < 4 weeks ) did not affect results . Compliance to 5FU plus levamisole was 69 % . Severe toxicity did not occur . In conclusion , one year 5FU plus levamisole was of benefit in stage II and III colonic cancer ; in rectal cancer a significant positive effect could not be demonstrated . © 2001 Cancer Research Campaign [10699069] BACKGROUND The conviction that postoperative radiotherapy and chemotherapy represent an acceptable st and ard of care for patients with Dukes ' B ( stage II ) and Dukes ' C ( stage III ) carcinoma of the rectum evolved in the absence of data from clinical trials design ed to determine whether the addition of radiotherapy results in improved disease-free survival and overall survival . This study was carried out to address this issue . An additional aim was to determine whether leucovorin (LV)-modulated 5-fluorouracil ( 5-FU ) is superior to the combination of 5-FU , semustine , and vincristine ( MOF ) in men . PATIENTS AND METHODS Eligible patients ( n = 694 ) with Dukes ' B or C carcinoma of the rectum were enrolled in National Surgical Adjuvant Breast and Bowel Project ( NSABP ) Protocol R-02 from September 1987 through December 1992 and were followed . They were r and omly assigned to receive either postoperative adjuvant chemotherapy alone ( n = 348 ) or chemotherapy with postoperative radiotherapy ( n = 346 ) . All female patients ( n = 287 ) received 5-FU plus LV chemotherapy ; male patients received either MOF ( n = 207 ) or 5-FU plus LV ( n = 200 ) . Primary analyses were carried out by use of a stratified log-rank statistic ; P values are two-sided . RESULTS The average time on study for surviving patients is 93 months as of September 30 , 1998 . Postoperative radiotherapy result ed in no beneficial effect on disease-free survival ( P = .90 ) or overall survival ( P = .89 ) , regardless of which chemotherapy was utilized , although it reduced the cumulative incidence of locoregional relapse from 13 % to 8 % at 5-year follow-up ( P = .02 ) . Male patients who received 5-FU plus LV demonstrated a statistically significant benefit in disease-free survival at 5 years compared with those who received MOF ( 55 % versus 47 % ; P = .009 ) but not in 5-year overall survival ( 65 % versus 62 % ; P = .17 ) . CONCLUSIONS The addition of postoperative radiation therapy to chemotherapy in Dukes ' B and C rectal cancer did not alter the subsequent incidence of distant disease , although there was a reduction in locoregional relapse when compared with chemotherapy alone [15108041] Background We investigated the efficacy and safety of adjuvant immunochemotherapy and adjuvant chemotherapy for colorectal cancer , using different combinations of the intracutaneous streptococcal preparation OK-432 and the oral pyrimidines 1-hexylcarbamoyl-5-fluorouracil ( carmofur , HCFU ) and uracil/tegafur ( UFT ) . Methods Patients with stage II , III , or IV ( Dukes ’ B , C ) colorectal cancer were enrolled and r and omly assigned to one of three groups : an immunochemotherapy group ( mitomycin C [ MMC ] + 5-fluorouracil [ 5-FU ] + HCFU + OK-432 ) , a chemotherapy group ( MMC + 5-FU + HCFU ) , and a control group ( surgery alone ) for those with colon cancer ( study 1 ) ; and an immunochemotherapy group ( MMC + 5-FU + UFT + OK-432 ) , a chemotherapy group ( MMC + 5-FU + UFT ) , and a control group ( surgery alone ) for those with rectal cancer ( study 2 ) . Results A total of 760 patients with colon cancer and 669 patients with rectal cancer were entered into this r and omized clinical trial ( RCT ) . The incidence of side-effects was in the order of : immunochemotherapy group ≫ chemotherapy group ≫ control group in both the cohort of patients with colon cancer and the cohort with rectal cancer . In particular , the frequency of leucopenia and skin disorders was significantly higher than control groups . There were no severe adverse events such as death related to the adjuvant therapy . In both the colon cancer and rectal cancer cohorts , no significant difference in the 5-year survival rate and disease-free survival rate was noted among the three groups . Conclusion The results of an RCT demonstrated that the combination of MMC + 5-FU + HCFU + OK-432 for colon cancer and that of MMC + 5-FU + UFT + OK-432 for rectal cancer could not prolong the survival of patients with surgically resected colorectal cancer , but that both combinations were well tolerated as adjuvant therapy [8630937] Colorectal cancer is one of the major malignant diseases and , recently , its incidence appears to be increasing . Surgical resectability is an important prognostic determinant ; however , recurrent tumors are commonly noted , even after apparently curative surgery . Because such metastatic disease can not be cured , better adjuvant therapies are urgently called for [2276014] A prospect i ve controlled r and omized trial testing adjuvant postoperative combination chemotherapy ( 5‐fluorouracil , lomustine ( CNU ) and vincristine ) versus no adjuvant therapy in patients operated on for Dukes ' C colorectal cancer is reported . In total 334 patients aged less than 70 years were recruited : 205 patients with colonic and 99 with rectal cancer , but there were three protocol violations and these cases are excluded from further consideration . Twenty‐seven patients had a limited resection of their cancer . After 5 years follow‐up there was no significant difference in the tumour‐free survival rate or in the survival rate between the treated and control groups . Twenty‐nine of the 147 patients who started chemotherapy discontinued this treatment because of side‐effects , mainly from the gastrointestinal tract . In 30 patients treatment was discontinued because of recurrent disease . The conclusion is that systemic administration of combination chemotherapy for colorectal cancer after operation is not worthwhile in routine clinical practice [2300087] Twelve hundred ninety-six patients with resected colon cancer that either was locally invasive ( Stage B2 ) or had regional nodal involvement ( Stage C ) were r and omly assigned to observation or to treatment for one year with levamisole combined with fluorouracil . Patients with Stage C disease could also be r and omly assigned to treatment with levamisole alone . The median follow-up time at this writing is 3 years ( range , 2 to 5 1/2 ) . Among the patients with Stage C disease , therapy with levamisole plus fluorouracil reduced the risk of cancer recurrence by 41 percent ( P less than 0.0001 ) . The overall death rate was reduced by 33 percent ( P approximately 0.006 ) . Treatment with levamisole alone had no detectable effect . The results in the patients with Stage B2 disease were equivocal and too preliminary to allow firm conclusions . Toxic effects of levamisole alone were infrequent , usually consisting of mild nausea with occasional dermatitis or leukopenia , and those of levamisole plus fluorouracil were essentially the same as those of fluorouracil alone -- i.e . , nausea , vomiting , stomatitis , diarrhea , dermatitis , and leukopenia . These reactions were usually not severe and did not greatly impede patients ' compliance with their regimen . We conclude that adjuvant therapy with levamisole and fluorouracil should be st and ard treatment for Stage C colon carcinoma . Since most patients in our study were treated by community oncologists , this approach should be readily adaptable to conventional medical practice [9164215] PURPOSE The combination of radiation therapy with fluorouracil (5-FU)-based chemotherapy is generally accepted as appropriate postoperative therapy for patients with adenocarcinomas of the rectum that extend through the bowel wall or with lymph nodes positive for tumor . We attempted to determine whether the efficacy of this postoperative therapy could be improved by the addition of leucovorin and /or levamisole . METHODS A total of 1,696 patients were r and omized and eligible for treatment with one of four treatment schemes . All patients received two cycles of bolus 5-FU-based systemic chemotherapy followed by pelvic radiation therapy with chemotherapy and two more cycles of the same systemic chemotherapy . Chemotherapy was either 5-FU alone , 5-FU with leucovorin , 5-FU with levamisole , or 5-FU with leucovorin and levamisole . RESULTS With a median follow-up duration of 48 months , there is no statistically significant advantage to any of the treatment regimens compared with bolus 5-FU alone . There is evidence of increased gastrointestinal toxicity with the three-drug combination compared with bolus 5-FU alone . Statistical analysis suggests it is very unlikely that either levamisole-containing combination will be shown to be of value with further follow-up evaluation . CONCLUSION There is no evidence at present for a beneficial effect of levamisole in the adjuvant treatment of rectal cancer . Definitive evaluation of the effect of the addition of leucovorin to 5-FU and pelvic radiation will require further follow-up evaluation [3276900] Information is presented from 555 patients with Dukes B and C rectal cancers treated by curative resection who were entered into the National Surgical Adjuvant Breast and Bowel Project ( NSABP ) protocol R-01 between November 1977 and October 1986 . Their average time on study was 64.1 months . The patients were r and omized to receive no further treatment ( 184 patients ) , postoperative adjuvant chemotherapy with 5-fluorouracil , semustine , and vincristine ( MOF ) ( 187 patients ) , or postoperative radiation therapy ( 184 patients ) . The chemotherapy group , when compared with the group treated by surgery alone , demonstrated an overall improvement in disease-free survival ( P = .006 ) and in survival ( P = .05 ) . Employing the proportional hazards model , a global test was used to determine the presence of treatment interactions . Investigation of stratification variables employed in this study indicated that sex , and to a lesser extent age and Dukes stage , made individual contributions to the disease-free survival and the survival benefit from chemotherapy . When evaluated according to sex , the benefit for chemotherapy at 5 years , both in disease-free survival ( 29 % vs. 47 % ; P less than .001 ; relative odds , 2.00 ) and in survival ( 37 % vs. 60 % ; P = .001 ; relative odds , 1.93 ) , was restricted to males . When males were tested for age trend with the use of a logistic regression analysis , chemotherapy was found to be more advantageous in younger patients . When the group receiving post-operative radiation ( 4,600 - 4,700 rad in 26 - 27 fractions ; 5,100 - 5,300 rad maximum at the perineum ) was compared to the group treated only by surgery , there was an overall reduction in local-regional recurrence from 25 % to 16 % ( P = .06 ) . No significant benefit in overall disease-free survival ( P = .4 ) or survival ( P = .7 ) from the use of radiation has been demonstrated . The global test for interaction to identify heterogeneity of response to radiation within subsets of patients was not significant . In conclusion , this investigation has demonstrated a benefit from adjuvant chemotherapy ( MOF ) for the management of rectal cancer . The observed advantage was restricted to males . Postoperative radiation therapy reduced the incidence of local-regional recurrence , but it failed to affect overall disease-free survival and survival [88753] In a prospect ively r and omized study , the effect of adjuvant chemotherapy with 5-FU on survival and recurrence rates was analyzed in 299 evaluable patients with colorectal carcinoma who either underwent a curative or a palliative resection . In the treatment group , chemotherapy consisted of the intravenous administration of 12 mg/kg daily of 5-FU for 4 consecutive days , then 6 mg/kg on alternate days , to the point of toxicity , or to a maximum of five doses , followed by 12mg/kg weekly for 1 year . Some degree of drug toxicity was seen in the majority of patients , was rarely severe , and there have been no drug-related deaths . Analysis of the survival curves and disease-free interval curves reveal definite evidence of drug benefit in two unfavorable subgroups , namely patients with Dukes C tumors and in patients whose tumor was located in the rectum . In the chemotherapy groups , patients who were treated to toxicity ( WBC less than 4000 mm3 ) , the disease-free interval was significantly longer than the nonleukopenic patients . We conclude that the addition of 5-FU to the surgical treatment of colorectal carcinoma provides a small , but significant benefit in patients with colorectal cancer in certain unfavorable subgroups , namely patients with Dukes C lesions and patients with rectal carcinoma [12792790] Postoperative adjuvant chemotherapy reportedly improves advanced colorectal cancer patients ' survival , however , it is necessary to assess what regimens are useful . Doxifluridine ( 5'-DFUR ) is an intermediate of capecitabine approved in Europe and USA to treat metastatic colorectal cancer . 5'-DFUR is metabolized to 5-fluorouracil ( 5-FU ) by thymidine phosphorylase existing in tumor at high concentrations , suggesting high 5-FU levels in tumor tissues and lesser complications . Present study compared usefulness of 5'-DFUR to that of oral 5-FU . Patients were enrolled at 38 centers from April 1993 to September 1996 . They had diagnosed colorectal cancer of TNM stages II and III , and underwent macroscopic curative resection . Patients were prestratified into colon or rectum cancer and allocated into either 5'-DFUR ( 5'-DFUR 460 mg/m(2)/day + PSK 3 g/day ) or 5-FU ( 5-FU 115 mg/m(2)/day + PSK 3 g/day ) group by dynamic r and omization ( stratification factors such as depth of tumor , degree of lymph node metastasis , and location of tumor ) . Drugs were orally administered daily from postoperative week 2 to 54 , with 6 mg/m(2 ) mitomycin C at operation and following days . Subjects for analysis were 277 in 5'-DFUR and 281 in 5-FU groups . Median follow-up was 6.5 years . Although no differences in overall survival curves were detected , multivariate analysis showed that 5'-DFUR + PSK regimen was a significantly better prognostic factor in patients with Dukes B or C ( risk ratio , 1.451 ; p=0.048 ) ; with tumor depth of pT3 or pT4 ( risk ratio , 1.568 ; p=0.020 ) . For patients with advanced colorectal cancer , 5'-DFUR + PSK therapy may possibly be more useful than 5-FU + PSK , but further study is required [2645466] A prospect ively r and omised controlled clinical trial of adjuvant therapy was undertaken , at a single-centre , population -based cancer institute , in patients with Dukes ' stages B2 and C colorectal carcinoma after curative surgery . Between 1976 and 1983 , 253 patients were r and omised to either control ( no further therapy after surgery ) , immunotherapy ( oral bacille Calmette-Guérin [ BCG ] 120 mg once a month ) for 5 years or chemoimmunotherapy ( oral BCG as above with methyl-cyclohexyl-chloroethyl nitrosourea [ meCCNU ] 130 mg/m2 on day 1 and 5-fluorouracil [ 5-FU ] 325 mg/m2/day on days 1 - 5 and 375 mg/m2/day on days 36 - 40 ) repeated every 10 weeks for 8 cycles . The median follow-up of patients is now 6.95 years . Of the control , immunotherapy , and chemoimmunotherapy groups 22.35 % , 39.28 % , and 28.57 % , respectively , have relapsed . The log-rank analysis of results shows no disease-free or overall survival advantage for patients receiving adjuvant therapy compared with the control group . Patients receiving adjuvant immunotherapy for stage B2 appear to have a significantly inferior disease-free survival compared with other groups , but their overall survival is similar . There are no significant differences in disease-free or overall survival in the three groups of patients with stage C tumour . Of 82 patients dying , 78.05 % died of progressive colorectal carcinoma , 13 patients developed a second malignancy ; the remainder died of seemingly unrelated causes [9350242] A prospect i ve controlled study , the 7th cooperative study of the Japanese Foundation for Multidisciplinary Treatment , was conducted to evaluate the usefulness of concomitant therapy with MMC + HCFU as a postoperative adjuvant therapy in patients with colorectal cancer who had undergone curative resection for a period of 2 years and 11 months from February , 1986 . The Dukes B and C patients with colorectal cancer classified by macroscopic examination who had an intravenous MMC 6 mg/m2 on the day of operation and followed by oral HCFU for 12 months from 2 weeks after operation ( Group X ) were compared with patients who had operation only ( Group Y ) . Some 978 patients with colon cancer and 713 patients with rectal cancer were enrolled in the study , 85 ( 5.0 % ) of whom were not eligible . The 5-year survival rate of Group X in colon cancer was 79.3 % and that of Group Y was 76.4 % : thus the survival rate of Group X was slightly better than that of Group Y , but no significant difference was found between the two groups . Subset analysis revealed that the survival rate of Group X in advanced cancer of stage III b + IV , according to the General Rules for Clinical and Pathological Studies on Cancer of the Colon , Rectum and Anus in Japan , was 62.4 % and that of Group Y was 46.2 % . Thus , the survival rate of Group X was significantly better than that of Group Y ( logrank test : p = 0.035 , generalized Wilcoxon test : p = 0.025 ) . The disease-free survival rate was not significantly different between the groups with colon cancer and rectal cancer . The above results suggest that HCFU is useful for patients with a high risk of recurrence who had advanced colon cancer ( stage III b + IV ) . However , additional prospect i ve studies are required to verify them [8677916] One thous and two hundred fifty-four cases ( 610 colonic and 644 rectal cancers resected during 2 years from 1984 and followed up for more than 5 years ) were entered from 140 institutions in Japan and analyzed by means of Cox 's proportional hazards model . The analyzed pathologic variables were the size and depth of invasion , Dukes ' stage , venous invasion , lymphatic permeation , and other clinical features , such as the sex and age of the patient and location of the tumor . The extent of dissection , serum carcinoembryonic antigen ( CEA ) level , and the presence or absence of adjuvant chemotherapy were also analyzed . Adjuvant chemotherapy consisted of three arms for both colonic and rectal cancers . For colonic cancer , arm I was a combination of i.p . ( intraportal ) and i.v . mitomycin C ( MMC ) + p.o . 5-fluorouracil ( 5-FU ) ; arm II was i.v . MMC + p.o . 5-FU ; and arm III was surgery only . For rectal cancer , arm IV was a combination of i.a . ( inferior mesenteric artery ) and i.v . MMC + p.o . 5-FU ; arm V was i.v . MMC + p.o . 5-FU ; and arm VI was surgery only . As for the factors affecting the disease-free survival of the patient , multivariate analysis disclosed nodal involvement , venous invasion , an elevated CEA level , and the lower part of the rectum . The effect of adjuvant chemotherapy on the patient 's survival was proven for rectal cancer but not for colonic cancer . We conclude that these factors should be considered in setting the stage of tumor pre- and postoperatively [11911312] BACKGROUND Although surgical resectability is an important prognostic factor , recurrences are commonly noted in advanced colorectal cancer patients , even after apparently curative surgery . Since such recurrences can not be cured , better adjuvant chemotherapies are urgently required . PATIENTS AND METHODS We studied the effect of post-operative chemotherapy using oral administration of 1-hexylcarbamoyl-5-fluorouracil ( HCFU ) with 5-fluorouracil ( 5-FU ) infusion for curatively-resected Stage IIIa and IIIb colorectal cancers . This study was prospect ively r and omized and controlled and 314 ( 97.8 % ) out of 321 patients were determined to be c and i date s for statistical assessment . Group A and Group B received 5-FU intravenous injection at , respectively , 333 mg/m2 and 1000 mg/m2 body surface area/24 hours continuously for 72 hours beginning on post-operative day 0 and day 6 , with oral HCFU 300 mg daily for 52 weeks beginning 2 weeks after surgery . RESULTS There were no differences in overall 5-year survival or disease-free survival between Group A and Group B. A retrospective subset analysis . however , suggested that the protocol of Group B tended to yield better 5-year survival ( 68.3 % ) for rectal cancer than that of Group A ( 58.8 % ) . CONCLUSION Inductive therapy with high-dose 5-FU in combination with oral HCFU appears to be beneficial as adjuvant chemotherapy for advanced rectal cancer with lymph node metastasis [16009958] PURPOSE The European Organisation for Research and Treatment of Cancer ( EORTC ) trial evaluated the addition of chemotherapy ( CT ) to preoperative radiation ( preop RT ) and the value of postoperative CT for improving the survival in patients with T3 - 4 resectable rectal cancer . Patients were allocated to the following four arms : arm 1 , preop RT 45 Gy in 5 weeks ; arm 2 , preop RT plus two 5-day CT courses ( fluorouracil 350 mg/m2/d and leucovorin 20 mg/m2/d ) in the first and fifth week of RT ; arm 3 , preop RT plus four postoperative CT courses ; and arm 4 , preop RT and CT plus postoperative CT . We investigated the effect of adding CT on the pathologic parameters . PATIENTS AND METHODS One thous and eleven patients were entered onto the trial ; 505 received preop RT ( arms 1 and 3 ) , and 506 received preop RT-CT ( arms 2 and 4 ) . We analyzed the differences in tumor size , tumor node stage , number of retrieved nodes , and histologic features such as lymphatic , venous , and perineural invasions , tumor differentiation , and tumor type . RESULTS After preop RT-CT , tumors were smaller ( P < .0001 ) , had less advanced pT ( P < .001 ) and pN stages ( P < .001 ) , had small numbers of examined nodes ( P = .046 ) , and less frequent LVN invasions ( P < or = .008 ) . Mucinous tumors increased after preop RT-CT ( P < .001 ) . CONCLUSION In patients with rectal cancer , preliminary results of EORTC Trial 22921 indicate that the addition of CT to preop RT induces down-sizing , downstaging , and significant changes in histologic characteristics . Longer follow-up is needed to assess the impact on local control and survival [1900687] A r and omized controlled study was carried out by the envelope method with 491 institutions in participation across the country in order to find an optimal surgical adjuvant chemotherapy for curatively resected colorectal cancer . The schedules for drug administration were different in four districts : ACNU + Futraful ( FT ) group and FT alone group in the Hokkaido-Shikoku district ; the same schedule groups plus untreated group in the Chubu-Kinki district ; MMC+FT group , FT alone group in the Tohoku-Kanto district ; and ADM+FT group and FT alone group in the Chugoku-Kyushu district . The numbers of patients admitted to this study were 2,450 cases with colon cancer and 2,456 cases met the evaluation criteria of this study . The 5-year survival rate on the whole did not differ from combination therapy to single drug therapy in either colon cancer or rectal cancer , but in Dukes C rectal cancer the five-year survival rate tended to be higher with the combination therapies . In n2 ( + ) or a2(s ) rectal cancer in particular , combination therapies with MMC and FT and with ADM and FT achieved significantly higher five-year survival rate , and the rate of local recurrence was significantly lower with ADM+FT [8683634] BACKGROUND Combined radiation therapy and chemotherapy after surgery , compared with postsurgical radiation therapy alone , has been shown to improve disease-free survival and overall survival significantly among patients with poor-prognosis ( i.e. , advanced stage disease or metastasis to regional lymph nodes ) resectable rectal cancer . However , the combined therapy is associated with more toxic effects , raising the question of whether the benefits of the treatment justify its quality -of-life costs for the individual patient . PURPOSE To assess the trade-offs between improved survival and increased treatment toxicity , we reanalyzed data from a r and omized clinical trial that compared the efficacy of combined adjuvant chemotherapy and radiation therapy with adjuvant radiation therapy alone in the treatment of patients with poor-prognosis resectable rectal cancer . METHODS The data were from a North Central Cancer Treatment Group trial in which 204 patients with poor-prognosis rectal cancer were r and omly assigned to receive either postoperative radiation therapy alone or radiation therapy plus fluorouracil-based chemotherapy . A quality -adjusted time without symptoms or toxicity ( Q-TWiST ) analysis was used to account for freedom from symptomatic disease and from early and late side effects of treatment . All reported P values are two-sided . RESULTS As reported previously , the combined therapy reduced the risk of relapse by 34 % ( 95 % confidence interval [ CI ] = 12%-50 % ; P = .0016 ) and reduced the overall death rate by 29 % ( 95 % CI = 7%-45 % ; P = .025 ) in comparison with adjuvant radiation therapy alone . In the 5 years following assignment to treatment , patients who received the combined therapy had more time with toxicity ( 3.1 months ; 95 % CI = 2.0 - 4.1 months ) , shorter survival after relapse ( 3.6 months less ; 95 % CI = 0.9 - 6.3 months less ) , and more TWiST ( 6.1 months ; 95 % CI = 0.2 - 12.0 months ) than patients who received adjuvant radiation therapy alone . Despite an increase in the amount of time that individuals spent with early and late toxic effects , the Q-TWiST analysis indicated that the combined therapy conferred significantly greater benefit for a wide range of patient preferences about living with the toxicity of treatment or the symptoms of overt disease . CONCLUSIONS AND IMPLICATION S Use of combined chemotherapy and radiation therapy as an adjuvant to surgery for patients with poor-prognosis resectable rectal cancer is justified , since the improved outcome in terms of delayed recurrence and increased survival balances the time spent with early and late toxic effects . The Q-TWiST method is an excellent way to compare treatment outcomes that include quality -of-life considerations [17008704] PURPOSE In 1992 , preoperative radiotherapy was considered in France as the st and ard treatment for T3 - 4 rectal cancers . The present r and omized trial compares preoperative radiotherapy with chemoradiotherapy . PATIENTS AND METHODS Patients were eligible if they presented a resectable T3 - 4 , Nx , M0 rectal adenocarcinoma accessible to digital rectal examination . Preoperative radiotherapy with 45 Gy in 25 fractions during 5 weeks was delivered . Concurrent chemotherapy with fluorouracil 350 mg/m2/d during 5 days , together with leucovorin , was administered during the first and fifth week in the experimental arm . Surgery was planned 3 to 10 weeks after the end of radiotherapy . All patients should receive adjuvant chemotherapy with the same fluorouracil/leucovorin regimen . The primary end point of the trial was overall survival . RESULTS A total of 733 patients were eligible . Grade 3 or 4 acute toxicity was more frequent with chemoradiotherapy ( 14.6 % v 2.7 % ; P < .05 ) . There was no difference in sphincter preservation . Complete sterilization of the operative specimen was more frequent with chemoradiotherapy ( 11.4 % v 3.6 % ; P < .05 ) . The 5-year incidence of local recurrence was lower with chemoradiotherapy ( 8.1 % v 16.5 % ; P < .05 ) . Overall 5-year survival in the two groups did not differ . CONCLUSION Preoperative chemoradiotherapy despite a moderate increase in acute toxicity and no impact on overall survival significantly improves local control and is recommended for T3 - 4 , N0 - 2 , M0 adenocarcinoma of the middle and distal rectum [15236870] BACKGROUND AND PURPOSE The aim was to verify whether preoperative conventionally fractionated chemoradiation offers an advantage in sphincter preservation in comparison with preoperative short-term irradiation . PATIENTS AND METHODS Patients with resectable T3 - 4 rectal carcinoma without sphincters ' infiltration and with a lesion accessible to digital rectal examination were r and omised into : preoperative 5x5Gy short-term irradiation with subsequent total mesorectal excision ( TME ) performed within 7 days or chemoradiation to a total dose of 50.4Gy ( 1.8Gy per fraction ) concomitantly with two courses of bolus 5-fluorouracil and leucovorin followed by TME after 4 - 6 weeks . Surgeons were obliged to base the type of operation on the tumour status at the time of surgery . RESULTS Between 1999 and 2002 , 316 patients from 19 institutions were enrolled . The sphincter preservation rate was 61 % in the 5x5Gy arm and 58 % in the radiochemotherapy arm , P = 0.57 . The tumour was on average 1.9 cm smaller ( P < 0.001 ) among patients treated with chemoradiation compared with short-term schedule . For patients who underwent sphincter-preserving procedure , the surgeons generally followed the rule of tailoring the resection according to tumour downsizing ; the median distal bowel margin was identical ( 2 cm ) for both r and omised groups . However , in the chemoradiation group , five patients underwent abdominoperineal resection despite clinical complete response . CONCLUSIONS Despite significant downsizing , chemoradiation did not result in increased sphincter preservation rate in comparison with short-term preoperative radiotherapy . The surgeons ' decisions were subjective and based on pre-treatment tumour volume at least in clinical complete responders [12190680] Local control and survival following surgical treatment of rectal cancer have been improved by the introduction of total mesorectal excision ( TME ) . The aim of this study was to determine the nationwide impact of the introduction and training of TME on recurrence and survival in rectal cancer [19016023] Purpose : The objective of this exp and ed phase II trial was to confirm the safety results of the preceding phase I study and establish the efficacy of neoadjuvant radiochemotherapy with capecitabine in rectal cancer in a multicenter setting . Patients and Methods : 96 patients ( 63 % male , age 34–81 years ) with advanced rectal cancer ( cT3–4 or cN+ ) from seven university centers in Germany were recruited . All were to receive a total irradiation dose of 50.4–55.8 Gy with conventional fractions . Capecitabine was given at an oral dosage of 825 mg/m2bid on each day of the radiotherapy period with the first daily dose applied 2 h before irradiation , followed by surgery 6 weeks later . Results : Most of the patients suffered from an advanced primary tumor ( cT3 : 57 % , cT4 : 40 % ) with lymph node involvement in 60 % . After neoadjuvant treatment , with a mean of 99 % of the scheduled radiation dose actually delivered , a clinical response rate of 68 % ( 95 % confidence interval : 57–78 % ) was observed . Out of 87 evaluable patients undergoing surgery , a sphincter-preserving procedure could be performed in 51 % and R0 resection in 94 % . A pathologically complete response was achieved in six patients ( 7 % , 95 % confidence interval : 3–14 % ) . The comparison of initial diagnosis and pathologic findings showed a downstaging in 61 % . Acute toxicity with > 5 % incidence of NCI ( National Cancer Institute ) grade ≥ 3 included lymphopenia ( 12 % ) , leukopenia ( 6 % ) , and diarrhea ( 7 % ) . Mild to moderate h and -foot syndrome occurred in 12 % only . After a median follow-up of 48 months , the 5-year overall survival and tumor control data were , with regard to patient selection , in the expected range with an overall survival of 65 % , a relapse-free survival of 47 % , and a local recurrence rate after 5 years of 17 % . Conclusion : The data clearly confirm that capecitabine is an adequate substitute for 5-fluorouracil in preoperative chemoradiation of rectal cancer with a favorable safety profile . Ziel : Diese multizentrische Phase-II-Studie sollte Effektivität und Toxizität einer neoadjuvanten Radiochemotherapie mit Capecitabine prüfen . Patienten und Method ik:96 Patienten ( davon 63 % männlich , Alter 34–81 Jahre ) mit lokal fortgeschrittenem Rektumkarzinom ( cT3–4 oder cN+ ) aus sieben deutschen Universitätskliniken wurden rekrutiert . Alle erhielten eine präoperative Radiotherapie ( 50,4–55,8 Gy in konventioneller Fraktionierung mit 5 × 1,8 Gy ) und zusätzlich 2 × täglich 825 mg/m2Capecitabin während gesamten Radiotherapie ( erste Dosis 2 h vor Radiotherapie , keine Pause am Wochenende ) . 6 Wochen nach der Radiochemotherapie war die Resektion geplant . Ergebnisse:97 % der Patienten hatten T3/T4-Tumoren ( T3 : 57 % ; T4 : 40 % ) . Lymphknotenbefall ( cN+ ) lag in 60 % vor . Die präoperative Therapie war gut durchführbar ( mittlere Strahlendosis 99 % , mittlere Capecitabindosis 96 % der geplanten Dosis ) . Die klinische Ansprechrate betrug 68 % ( 95%-Konfidenzintervall : 57–78 % ) und entsprach der Studienhypothese . Von 87 auswertbaren operierten Patienten wurden 94 % R0-reseziert ; ein Sphinktererhalt war in 51 % möglich . Sechs Patienten ( 7 % , 95%-Konfidenzintervall : 3–14 % ) hatten eine histologisch komplette Remission ( ypT0 ) i m Resektat . Ein Downstaging wurde in 61 % erreicht . Akute Nebenwirkungen CTC-Grad ≥ 3 ( Common Toxicity Criteria ) mit einer Frequenz von > 5 % wurden für Lymphopenie ( 12 % ) , Diarrhö ( 7 % ) und Leukopenie ( 6 % ) beobachtet . Ein H and -Fuß-Syndrom trat in 12 % auf und war jeweils nur mild ( Grad 1–2 ) . Die 5-Jahres-Überlebensrate betrug 65 % , das rezidivfreie Überleben 47 % und die lokale Kontrolle nach 5 Jahren 83%.Schlussfolgerung : Die Date n dieser multizentrischen Phase-II-Studie bestätigen , dass die Kombination von präoperativer Radiotherapie und Capecitabin eine wirksame und nebenwirkungsarme Beh and lung beim lokal fortgeschrittenen Rektumkarzinom darstellt . Capecitabin eignet sich als Ersatz für eine kontinuierliche 5-Fluorouracil-Infusion [6171898] In a Central Oncology Group trial in 319 evaluable patients the addition of 5-FU to the surgical treatment of colorectal carcinoma provided a small but significant benefit in those with colotectal cancer in certain unfavorable situations , namely Dukes C tumors and rectal carcinoma [11034245] Background : Postoperative adjuvant chemoradiation treatment after curative resection for rectal cancer was needed to reduce recurrence and improve a survival rate . Intravenous 5-fluorouracil ( 5-FU ) and leucovorin has been a mainstay of chemotherapy , but oral 5-FU derivatives have been shown a comparable antitumor activity . Intravenous 5-FU and oral doxifluridine were compared with respect to therapeutic efficacy , drug toxicity , and quality of life . Methods : A total of 166 patients were r and omized to receive intravenous 5-FU ( 450 mg/m2/day ) or oral doxifluridine ( 900 mg/m2/day ) in combination with leucovorin ( 20 mg/m2/day ) for depth of invasion , nodal status , metastasis ( TNM ) stage II and III patients between October 1997 and February 1999 . Consecutive daily intravenous infusion for 5 days per every month for a total of 12 cycles ( IV arm , n = 74 ) and oral doxifluridine daily for 3 weeks and 1 week rest for a total of 12 cycles ( oral arm , n = 92 ) . Drug toxicity and quality of life were observed . Quality of life was scored according to 22 daily activity items ( good , ≥ 71 ; fair , < 70 ; poor , < 52 ) . Results : There was no difference of sex between two groups ( IV arm : male/female = 45/29 , oral arm : male/female = 59/33 ) . The mean age was 52.3 vs. 59.5 , respectively . There was also no difference of TNM stage distribution and type of operation between groups ( P = .05 ) . Mean numbers of chemotherapy cycles were 6.5 ± 3.7 ( IV arm ) vs. 7.2 ± 4.3 ( oral arm ) , respectively . The rate of recurrence was 9/74 ( 12.1 % ) in the IV arm and 6/92 ( 6.5 % ) in the oral arm , respectively ( P = .937 ) . Local recurrence was 2/74 ( stage III ; 2.7 % ) in the IV arm and 1/92 ( stage II;1.1 % ) in the oral arm , respectively . Systemic recurrence was 7/74 ( stage III ; 9.4 % ) in the IV arm and 5/92 ( stage III ; 5.4 % ) in the oral arm , respectively . The most common site of systemic recurrence was the liver . Toxicity profile was as follows : leukopenia ( 30/74 vs. 17/92 ) and alopecia ( 21/74 vs. 13/92 ) were statistically more common in the IV arm . Diarrhea was more common in the oral arm . Poor quality of life score between two groups was observed at 1 month ( 23.9 % vs. 13 % ) and 2 months ( 15.8 % vs. 3.7 % ) after chemotherapy . Good quality of life score was observed at 1 month ( 19.5 % vs. 49 % ) and 2 months ( 47 % vs. 72 % ) , respectively ( P < .05 ) . Conclusions : Oral doxifluridine with leucovorin shows a comparable therapeutic efficacy to intravenous 5-FU regimen with high quality of life as postoperative adjuvant therapy . The oral regimen also can be safely given with appropriate toxicity and tolerability [16446336] PURPOSE To evaluate the rate of pathologic complete response and toxicity of neoadjuvant chemoradiation for advanced T3/T4 distal rectal cancers in a r and omized phase II study PATIENTS AND METHODS Patients with clinical T3/T4 distal rectal cancers were r and omly assigned in a phase II study to receive combined neoadjuvant chemoradiotherapy followed by surgical resection . Patients were r and omly assigned to receive continuous venous infusion ( CVI ) fluorouracil ( FU ) 225 mg/m2 per day , 7 days per week , plus pelvic hyperfractionated radiation 55.2 to 60 Gy at 1.2 Gy bid ( arm 1 ) or CVI FU 225 mg/m2 per day Monday to Friday , 120 hours per week plus irinotecan 50 mg/m2 once weekly for 4 weeks plus pelvic radiation therapy 50.4 to 54 Gy at 1.8 Gy per day ( arm 2 ) . Surgery was performed 4 to 10 weeks after completion of neoadjuvant therapy . The primary end point of this study was pathologic complete response ( pCR ) . Secondary end points included acute and late normal tissue morbidity . RESULTS A total of 106 patients were entered onto the study , with 103 assessable for response . The overall resectability rate was 93 % . The median time to surgery was 7 weeks . Tumor downstaging was observed in 78 % of patients in both arms . The pCR rate for all assessable patients was 26 % in each arm . For patients who had surgery , the pCR rate was also the same ( 28 % ) in both arms . Acute and late toxicity was also similar . Grade 3 and 4 acute hematologic and nonhematologic toxicity occurred in 13 % and 38 % in arm 1 and 12 % and 45 % in arm 2 , respectively . CONCLUSION Although the overall complete response rate and toxicity seems similar in both arms , this is the first multi-institutional study to establish a relatively high ( 28 % ) pCR rate after neoadjuvant therapy [1997835] BACKGROUND Radiation therapy as an adjunct to surgery for rectal cancer has been shown to reduce local recurrence but has not improved survival . In a previous study , combined radiation and chemotherapy improved survival significantly as compared with surgery alone , but not as compared with adjuvant radiation , which many regard as st and ard therapy . We design ed a combination regimen to optimize the contribution of chemotherapy , decrease recurrence , and improve survival as compared with adjuvant radiation alone . METHODS Two hundred four patients with rectal carcinoma that was either deeply invasive or metastatic to regional lymph nodes were r and omly assigned to postoperative radiation alone ( 4500 to 5040 cGy ) or to radiation plus fluorouracil , which was both preceded and followed by a cycle of systemic therapy with fluorouracil plus semustine ( methyl-CCNU ) . RESULTS After a median follow-up of more than seven years , the combined therapy had reduced the recurrence of rectal cancer by 34 percent ( P = 0.0016 ; 95 percent confidence interval , 12 to 50 percent ) . Initial local recurrence was reduced by 46 percent ( P = 0.036 ; 95 percent confidence interval , 2 to 70 percent ) , and distant metastasis by 37 percent ( P = 0.011 ; 95 percent confidence interval , 9 to 57 percent ) . In addition , combined therapy reduced the rate of cancer-related deaths by 36 percent ( P = 0.0071 ; 95 percent confidence interval , 14 to 53 percent ) and the overall death rate by 29 percent ( P = 0.025 ; 95 percent confidence interval , 7 to 45 percent ) . Its acute toxic effects included nausea , vomiting , diarrhea , leukopenia , and thrombocytopenia . These effects were seldom severe . Severe , delayed treatment-related reactions , usually small-bowel obstruction requiring surgery , occurred in 6.7 percent of all patients receiving radiation , and the frequencies of these complications were comparable in both treatment groups . CONCLUSIONS The combination of postoperative local therapy with radiation plus fluorouracil and systemic therapy with a fluorouracil-based regimen significantly and substantively improves the results of therapy for rectal carcinoma with a poor prognosis , as compared with postoperative radiation alone [8888803] BACKGROUND A joint study was performed by the Tokai HCFU study group , which included seven institutions , to examine the value of oral administration of Carmofur ( HCFU ) , a 5-fluorouracil ( 5-FU ) derivative , for postoperative adjuvant chemotherapy in patients with colorectal cancer undergoing curative resection . METHODS The patients were divided into two groups , a control group receiving no HCFU and a group administered HCFU for 1 year , using a central ized registration system by telephone . Among 173 patients entered into this study , 159 evaluable cases were analyzed for evaluation of the drug . RESULTS The cumulative 5-year disease-free rate of patients who received HCFU was significantly increased compared with the control group . In particular , the rate was much higher in patients with colon cancer . No severe side effects arose from adjuvant chemotherapy with HCFU . CONCLUSION Adjuvant chemotherapy with oral HCFU appears to provide a useful and safe postoperative treatment [343748] An adjuvant program of fluorouracil for patients undergoing " curative " resection for adenocarcinoma of the colon and rectum was initiated as a r and omized clinical trial in January 1968 . Patients were r and omly assigned to an intraluminal fluorouracil or intraluminal control ( saline ) group and were so treated at the time of surgical resection if findings at operation indicated that all gross neoplastic disease could be resected . Those patients receiving intraluminal fluorouracil ( 30 mg/kg ) received intravenous fluorouracil ( 10 mg/kg ) on each of the first two postoperative days and five subsequent postoperative courses of oral fluorouracil ( 90 mg/kg ) in each 18-day course over a one-year period . By July 1 , 1975 , there were 203 patients undergoing curative resection entered into the study . Survival and disease-free data , as of Dec 31 , 1976 , revealed no benefit from this adjuvant course of fluorouracil . These data support the need for continued r and omized clinical trials of new and innovative adjuvant therapy compared with an untreated control group [12598341] BACKGROUND The aim of this study was to determine whether the efficacy of the combination of 5-fluorouracil ( 5-FU ) , leucovorin ( LV ) and radiation therapy ( RT ) could be improved by the addition of interferon-alpha2b ( IFN-alpha ) in patients who have had a ' curative ' resection , for rectal adenocarcinoma ( Dukes ' B2/C ; T3 N0 , T4 N0 , N1 - 3 ) . PATIENTS AND METHODS A total of 207 eligible patients with a performance status of 0 or 1 were r and omized postoperatively between days 21 and 70 to one of the two treatment groups : group A , LV 20 mg/m2 i.v . bolus and 5-FU 425 mg/m2 i.v . days 1 - 5 and 29 - 33 , LV 20 mg/m2 and 5-FU 400 mg/m2 days 57 - 60 and 85 - 88 , LV 20 mg/m2 and 5-FU 380 mg/m2 days 1 - 5 and 29 - 33 with the second day 1 occurring 28 days after the completion of RT ( 45 Gy ) ; group B , LV , 5-FU and RT as in group A , and IFN-alpha 5 x 10(6 ) IU s.c . three times during each week chemotherapy is given . RESULTS 104 patients were r and omized into group A and 103 into group B. There was no statistically significant difference in either disease-free survival or overall survival between the two groups . Toxicity was also the same , except for the flu-like syndrome associated with the IFN-alpha administration . CONCLUSIONS There was no difference in efficacy between the two combinations . Toxicity was greater with the LV + 5-FU + IFN-alpha regimen because of the flu-like syndrome [383171] Fifty-three patients with colorectal cancer Dukes ' B2 and C were r and omized after surgery . One group was treated by radio- and /or chemotherapy and the second by radio- and /or chemotherapy and MER . After 24 and 36 months a significant longer disease free interval , lower recurrence rate and better survival was found in the group treated by radio-chemo- and immunotherapy . Treatment was well tolerated and there were few local side effects from the MER injections . The long time efficacy of this adjuvant treatment whether it increases the cure rate or only delays recurrence does require longer follow-up [7232842] Adjuvant therapy was given to patients with colorectal cancer stage Duke 's B2 and C. The 53 patients were r and omized and stratified after surgery . One arm received radiotherapy and chemotherapy and the other radiotherapy , chemotherapy , and MER . The survival and disease-free interval up to 2 years were longer and better in the radiochemo-MER arm . It is too early to conclude whether this combination increases the cure rate or delays the appearance of metastases . The time interval between the cytotoxic therapy and the immunotherapy and the dose of the immunotherapeutic agent is very important for the success of the combination therapy . Further follow-up is necessary and more patients need to be entered into the trial [16971718] BACKGROUND Preoperative radiotherapy is recommended for selected patients with rectal cancer . We evaluated the addition of chemotherapy to preoperative radiotherapy and the use of postoperative chemotherapy in the treatment of rectal cancer . METHODS We r and omly assigned patients with clinical stage T3 or T4 resectable rectal cancer to receive preoperative radiotherapy , preoperative chemoradiotherapy , preoperative radiotherapy and postoperative chemotherapy , or preoperative chemoradiotherapy and postoperative chemotherapy . Radiotherapy consisted of 45 Gy delivered over a period of 5 weeks . One course of chemotherapy consisted of 350 mg of fluorouracil per square meter of body-surface area per day and 20 mg of leucovorin per square meter per day , both given for 5 days . Two courses were combined with preoperative radiotherapy in the group receiving preoperative chemoradiotherapy and the group receiving preoperative chemoradiotherapy and postoperative chemotherapy ; four courses were planned postoperatively in the group receiving preoperative radiotherapy and postoperative chemotherapy and the group receiving preoperative chemoradiotherapy and postoperative chemotherapy . The primary end point was overall survival . RESULTS We enrolled 1011 patients in the trial . There was no significant difference in overall survival between the groups that received chemotherapy preoperatively ( P=0.84 ) and those that received it postoperatively ( P=0.12 ) . The combined 5-year overall survival rate for all four groups was 65.2 % . The 5-year cumulative incidence rates for local recurrences were 8.7 % , 9.6 % , and 7.6 % in the groups that received chemotherapy preoperatively , postoperatively , or both , respectively , and 17.1 % in the group that did not receive chemotherapy ( P=0.002 ) . The rate of adherence to preoperative chemotherapy was 82.0 % , and to postoperative chemotherapy was 42.9 % . CONCLUSIONS In patients with rectal cancer who receive preoperative radiotherapy , adding fluorouracil-based chemotherapy preoperatively or postoperatively has no significant effect on survival . Chemotherapy , regardless of whether it is administered before or after surgery , confers a significant benefit with respect to local control . ( Clinical Trials.gov number , NCT00002523 [ Clinical Trials.gov ] . ) [11319280] The aim of this study was to determine if the response to preoperative radiation and chemotherapy with continuous infusion 5-fluorouracil ( 5-FU ) was predictive for survival among patients with locally advanced rectal cancer . Preoperative chemoradiation ( CTX/XRT ) that delivered 45 Gy in 25 fractions over 5 weeks with continuous infusion 5-FU ( 300 mg/m2/day ) was given to 117 patients . The pretreatment stage distribution , as determined by endorectal ultrasound ( u ) , included uT2N0 in 2 % , uT3N0 in 47 % , uT3N1 in 49 % , and uT4N0 in 2 % of cases ; endorectal ultrasound was not performed in 13 % of cases ( 15 patients ) . Approximately 6 weeks after completion of CTX/XRT , surgery was performed . Adjuvant chemotherapy , consisting of 400 to 425 mg/m2 of 5-FU plus 20 mg/m2 leucovorin for 5 days , was administered every 28 days for 4 to 6 cycles after surgical resection . Among the 74 patients treated with adjuvant chemotherapy , the preoperative stage of disease was 31 with T3N0 and 43 T3N1 . Median follow-up was 46 months ( range 2 to 89 months ) . The pathologic tumor stages were Tis-2N0 in 26 % , T2N1 in 5 % , T3N0 in 21 % , T3N1 in 15 % , T4N0 in 5 % , and T4N1 in 1 % ; a complete response ( CR ) to preoperative CTX/XRT was pathologically confirmed in 32 ( 27 % ) of patients . Tumor down-staging occurred in 72 ( 62 % ) cases . A sphincter-saving procedure ( SP ) was possible in 59 % of patients . The median DFS and overall survival rates for responders were 46 months and 47 months , respectively ; for non-responders these outcome measures were 38 months and 41 months , respectively . Log-rank analysis showed that the distant metastatic-free survival rates improved with any response to CTX/XRT ( p < 0.00001 ) , CR to CTX/XRT ( p < 0.009 ) and SP ( p < 0.012 ) . Likewise , these parameters also significantly influenced DFS rates ( CTX/XRT p < 0.00001 ; CR p < 0.006 ; and SP p < 0.008 ) . Control of pelvic disease was influenced by clinical size ( p < 0.002 ) and SP ( p < 0.016 ) on univariate analysis . On multivariate analysis only clinical size ( p < 0.002 ) continued to be a significant factor for local control . Factors on multivariate analysis that result ed in significant improvements in cancer-specific survival included any response to preoperative CTX/XRT ( p < 0.017 ) and administration of adjuvant chemotherapy ( p < 0.034 ) . Any response to preoperative CTX/XRT improved distant metastatic-free and disease-free survival rates . Multivariate analysis confirmed that a response to preoperative CTX/XRT predicted for improvements in overall survival among patients with locally advanced rectal cancer . Patients who fail to respond to preoperative 5-FU based chemotherapy given concomitantly with radiation have higher rates of distant metastases with adjuvant 5-FU therapy [19453040] BACKGROUND / AIMS The usefulness of adjuvant chemotherapy started immediately following surgery was evaluated . METHODOLOGY A r and omized clinical trial was performed on 133 patients with advanced colorectal cancer using oral anticancer agents with one-week continuous 5-FU infusion starting immediately after curative surgery . In Group A and Group B , 300 mg/day of HCFU was orally administered for two years starting two weeks after surgery , and in addition , 333 mg/m2/day of 5-FU was drip infused from the central vein for seven days from the day of surgery in Group B. RESULTS For 1919 days after surgery , there were no significant intergroup differences in overall survival ( OS ) and disease-free survival ( DFS ) , but OS and DFS in Group B rectal cancer patients were significantly better when compared to Group A rectal cancer patients . On the other h and , OS tended to be better in Group A colon cancer patients , but no significant intergroup differences were seen , while intergroup differences tended to be smaller when corrected for disease stage . CONCLUSIONS Continuous 5-FU infusion starting immediately after curative surgery for colorectal cancer was safe . While further investigation is necessary to eluci date the degree of improvement in postoperative prognosis , the results of the present study suggest that continuous 5-FU infusion improves prognosis in advanced rectal cancer [11547717] BACKGROUND Short-term preoperative radiotherapy and total mesorectal excision have each been shown to improve local control of disease in patients with resectable rectal cancer . We conducted a multicenter , r and omized trial to determine whether the addition of preoperative radiotherapy increases the benefit of total mesorectal excision . METHODS We r and omly assigned 1861 patients with resectable rectal cancer either to preoperative radiotherapy ( 5 Gy on each of five days ) followed by total mesorectal excision ( 924 patients ) or to total mesorectal excision alone ( 937 patients ) . The trial was conducted with the use of st and ardization and quality -control measures to ensure the consistency of the radiotherapy , surgery , and pathological techniques . RESULTS Of the 1861 patients r and omly assigned to one of the two treatment groups , 1805 were eligible to participate . The overall rate of survival at two years among the eligible patients was 82.0 percent in the group assigned to both radiotherapy and surgery and 81.8 percent in the group assigned to surgery alone ( P=0.84 ) . Among the 1748 patients who underwent a macroscopically complete local resection , the rate of local recurrence at two years was 5.3 percent . The rate of local recurrence at two years was 2.4 percent in the radiotherapy-plus-surgery group and 8.2 percent in the surgery-only group ( P<0.001 ) . CONCLUSIONS Short-term preoperative radiotherapy reduces the risk of local recurrence in patients with rectal cancer who undergo a st and ardized total mesorectal excision [11919230] PURPOSE The gastrointestinal Intergroup studied postoperative adjuvant chemotherapy and radiation therapy in patients with T3/4 and N+ rectal cancer after potentially curative surgery to try to improve chemotherapy and to determine the risk of systemic and local failure . PATIENTS AND METHODS All patients had a potentially curative surgical resection and were treated with two cycles of chemotherapy followed by chemoradiation therapy and two additional cycles of chemotherapy . Chemotherapy regimens were bolus fluorouracil ( 5-FU ) , 5-FU and leucovorin , 5-FU and levamisole , and 5-FU , leucovorin , and levamisole . Pelvic irradiation was given to a dose of 45 Gy to the whole pelvis and a boost to 50.4 to 54 Gy . RESULTS One thous and six hundred ninety-five patients were entered and fully assessable , with a median follow-up of 7.4 years . There was no difference in overall survival ( OS ) or disease-free survival ( DFS ) by drug regimen . DFS and OS decreased between years 5 and 7 ( from 54 % to 50 % and 64 % to 56 % , respectively ) , although recurrence-free rates had only a small decrease . The local recurrence rate was 14 % ( 9 % in low-risk [ T1 to N2 + ] and 18 % in high-risk patients [ T3N+ , T4N ] ) . Overall , 7-year survival rates were 70 % and 45 % for the low-risk and high-risk groups , respectively . Males had a poorer overall survival rate than females . CONCLUSION There is no advantage to leucovorin- or levamisole-containing regimens over bolus 5-FU alone in the adjuvant treatment of rectal cancer when combined with irradiation . Local and distant recurrence rates are still high , especially in T3N+ and T4 patients , even with full adjuvant chemoradiation therapy [16758130] Purpose After neoadjuvant radiochemotherapy and surgery , there is no general agreement about whether postoperative chemotherapy is necessary . With the help of clinical and pathohistologic data , prognostic factors were determined as a basis for the decision to spare a patient additional chemotherapy or to urgently recommend it . Results Ninety-five patients treated with neoadjuvant 5-fluorouracil-based radiochemotherapy ( November 4 , 1997 and June 15 , 2004 ) without distant metastases and an R0 ( microscopically complete ) resection were evaluated . Adjuvant chemotherapy ( 5-fluorouracil or 5-fluorouracil/folinic acid ) was given to 65 of 95 patients ( 68.4 percent ) . The disease-free survival rate after 36 months was chosen as the target parameter ( median follow-up , 36 months ) . Methods The five-year survival rate for all patients was 80.3 ± 5.6 percent ; the five-year disease-free survival was 78.1 ± 5.1 percent ; the five-year local control rate was 94.2 ± 5.1 percent . In the univariate and multivariate analysis of the disease-free survival , the pathohistologic lymph node status after radiochemotherapy ( ypN ) was the only significant prognostic parameter . Disease-free survival ( 36 months ) for patients without lymph node metastases ( ypN0 ) was excellent , independent of whether they had received postoperative chemotherapy ( n = 43 ; 87.5 ± 6.0 percent ) or not ( n = 29 ; 87.7 ± 6.7 percent ) . Patients with ypN2 status have , despite chemotherapy , a poor disease-free survival at 30 ± 17.6 percent after 36 months . Conclusions These retrospective data suggest that , for some patients , postoperative chemotherapy can be spared . For patients with ypN2 status , an intensification of the postoperative chemotherapy should be considered . Further evaluation in prospect i ve studies is urgently recommended [16675478] BACKGROUND Although adjuvant radiotherapy was proved to be effective for local control of rectal cancer even after st and ardized mesorectal excision , the role of adjuvant chemotherapy after such st and ardized surgery remains to be clarified . We aim ed to assess the efficacy of a combination of uracil and tegafur for pathological stage III rectal cancer treated by st and ardized mesorectal excision with selective lateral pelvic lymphadenectomy . METHODS We r and omly assigned patients with completely resected stage III rectal cancer , who underwent st and ardized mesorectal excision with selective lateral pelvic lymphadenectomy , to receive either oral uracil-tegafur ( 400 mg/m2 tegafur per day ) for one year or no treatment . St and ardization and quality control of the surgery and pathological techniques were ensured by use of the guidelines of the Japanese Society for Cancer of the Colon and Rectum . The primary endpoint was relapse-free survival . The secondary endpoint was overall survival . RESULTS We enrolled and r and omized 276 patients . Excluding two ineligible patients , 274 were included in the analysis . Planned interim analysis 2 years after accrual termination revealed significant prolongation of relapse-free survival ( P = 0.001 ) and overall survival ( P = 0.005 ) in the uracil-tegafur group . The 3-year relapse-free survival and overall survival rates were 78 and 91 % in the chemotherapy group and 60 and 81 % in the surgery-alone group , respectively . Local recurrence rates were low in both groups . Grade 3 events occurred in 17 % of the chemotherapy patients , but no grade 4 or more events occurred . CONCLUSION Adjuvant chemotherapy with uracil-tegafur improves survival of patients with stage III rectal cancer after st and ardized mesorectal excision with selective lateral pelvic lymphadenectomy [11205198] 366 patients fully resected from a Dukes B2 or C colorectal cancer were r and omised to receive 6 courses of systemic chemotherapy comprising either 5-fluorouracil ( 5 FU ) alone ( arm A : 450 mg/m2/day-5/21 days ) or combined folinic acid ( FOL ) and 5 FU ( arm B : respectively 200 mg/m2 racemic form or 100 mg/m2-l-form and 370 mg/m2/day-5/21 days ) . 173 patients had also been initially r and omised to receive one course of intraportal chemotherapy just after surgery or no portal treatment . Oral levamisole ( 150 mg/day ; 3 days every other week ) was given to all patients for one year . A significantly higher incidence of leuco-granulocytopenia was observed in the arm A ( 5 FU alone ) inducing more frequent dose delays and adaptations as well as levamisole 's withdrawal . Then dose-intensities and dose-intensity products were lower in this arm but the dose intensity expressed in mg/m2/week remained higher ( 631 + /- 107 vs 557 + /- 99 ; p < 0.001 ) . The median follow-up in the study was 4.5 years . Relapse free ( RFS ) and overall survivals ( OAS ) were prolonged in the 5 FU alone group peculiarly in those patients who had not been r and omised for portal treatment . Curves diverged progressively with longer follows-up ( at 8 years ; RFS in arm A : 67 - 71 % vs 59 - 53 % in arm B ; OAS in arm A : 72 - 74 % vs 56 - 46 % in arm B ) . Patients suffering from a colon or a Dukes C cancer benefited the most from the treatment with 5 FU alone . The results are discussed in the light of other recent adjuvant trials . Well dosed 5 FU over a short period of time without folinic acid may be a valuable and inexpensive adjuvant treatment for colorectal cancer . Levamisole may no longer be recommended in this setting [9091798] BACKGROUND Adjuvant radiotherapy for rectal cancer has been extensively studied , but no trial has unequivocally demonstrated improved overall survival with radiotherapy , despite a reduction in the rate of local recurrence . METHODS Between March 1987 and February 1990 , we r and omly assigned 1168 patients younger than 80 years of age who had resectable rectal cancer to undergo preoperative irradiation ( 25 Gy delivered in five fractions in one week ) followed by surgery within one week or to have surgery alone . RESULTS The irradiation did not increase postoperative mortality . After five years of follow-up , the rate of local recurrence was 11 percent ( 63 of 553 patients ) in the group that received radiotherapy before surgery and 27 percent ( 150 of 557 ) in the group treated with surgery alone ( P<0.001 ) . This difference was found in all subgroups defined according to Dukes ' stage . The overall five-year survival rate was 58 percent in the radiotherapy-plus-surgery group and 48 percent in the surgery-alone group ( P=0.004 ) . The cancer-specific survival rates at nine years among patients treated with curative resection were 74 percent and 65 percent , respectively ( P=0.002 ) . CONCLUSIONS A short-term regimen of high-dose preoperative radiotherapy reduces rates of local recurrence and improves survival among patients with resectable rectal cancer [15913913] PURPOSE Capecitabine is an attractive radiosensitizer which can be tumor specific . This study was undertaken to evaluate the toxicity and efficacy of oral capecitabine when used with preoperative radiation therapy . METHODS AND MATERIAL S We conducted a prospect i ve Phase II trial to assess the pathologic response , sphincter preservation effect , and acute toxicity of preoperative chemoradiation ( CRT ) in locally advanced ( uT3 - 4/N + ) but resectable adenocarcinoma of the lower two-thirds of the rectum . The radiation dose was 50 Gy over 5 weeks ( 46 Gy to whole pelvis + 4 Gy boost ) , and capecitabine was administered daily at a dose of 1650 mg/m(2 ) during the entire course of radiation therapy . Surgery was performed with st and ardized total mesorectal excision 4 to 6 weeks after completion of CRT and followed by four cycles of capecitabine ( 2500 mg/m(2)/day for 14 days ) . RESULTS Ninety-five patients were entered into this study ; their median age was 55 ( range , 31 - 75 years ) . Ninety ( 95 % ) patients completed preoperative CRT as planned , and complete resection was achieved in 92 of 94 resected cases ( 98 % ) . Downstaging rate was 71 % ( 56/79 ) on endorectal ultrasonography , and it was 76 % ( 71/94 ) on pathology finding . No tumor cell was observed in the specimens of 11 patients ( 12 % ) . Among the 54 whose tumor was located within 5 cm from the anal verge , 40 patients ( 74 % ) underwent sphincter-preserving procedures . Elevation of the distal tumor margin from the anal verge by preoperative CRT was 0.8 + /- 1.3 cm . Grade 3 toxicities were rare ( diarrhea in 3 % and neutropenia in 1 % ) . CONCLUSION Preoperative CRT using capecitabine achieved encouraging rates of tumor downstaging and sphincter preservation with a low toxicity profile Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: PURPOSE We conducted a systematic review and meta- analysis to quantify the pathological complete response ( pCR ) rate after preoperative (chemo)radiation with doses of ⩾60Gy in patients with locally advanced rectal cancer . Complete response is relevant since this could select a proportion of patients for which organ-preserving strategies might be possible . Furthermore , we investigated correlations between EQD2 dose and pCR-rate , toxicity or resectability , and additionally between pCR-rate and chemotherapy , boost-approach or surgical-interval . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

23152233

[2826100] Background : Substantial numbers of cancer patients use complementary medicine therapies , even without a supportive evidence base . This study aim ed to evaluate in a r and omized controlled trial , the use of Medical Qigong ( MQ ) compared with usual care to improve the quality of life ( QOL ) of cancer patients . Patients and methods : One hundred and sixty-two patients with a range of cancers were recruited . QOL and fatigue were measured by Functional Assessment of Cancer Therapy — General and Functional Assessment of Cancer Therapy — Fatigue , respectively , and mood status by Profile of Mood State . The inflammatory marker serum C-reactive protein ( CRP ) was monitored serially . Results : Regression analysis indicated that the MQ group significantly improved overall QOL ( t144 = −5.761 , P < 0.001 ) , fatigue ( t153 = −5.621 , P < 0.001 ) , mood disturbance ( t122 = 2.346 , P = 0.021 ) and inflammation ( CRP ) ( t99 = 2.042 , P < 0.044 ) compared with usual care after controlling for baseline variables . Conclusions : This study indicates that MQ can improve cancer patients ’ overall QOL and mood status and reduce specific side-effects of treatment . It may also produce physical benefits in the long term through reduced inflammation [12406050] PURPOSE The aims of this pilot study were the following : 1 ) to examine patterns of adherence to a brisk walking program in women receiving adjuvant chemotherapy or radiation therapy for newly diagnosed breast cancer using a prospect i ve , r and omized , controlled experimental design ; 2 ) to examine the influence of disease symptoms and treatment side effects on exercise levels ; and 3 ) to suggest methods that may improve future clinical trials of moderate-intensity exercise in similar population s. DESCRIPTION OF STUDY Fifty-two patients with newly diagnosed breast cancer were r and omly assigned to one of two treatment arms : usual care or usual care plus exercise . Those assigned to the exercise group received a st and ardized , self-administered , home-based brisk walking intervention in addition to usual care . Each day subjects completed self-report diary forms that elicited information about activity levels , and the occurrence of symptoms and side effects during cancer treatment . RESULTS Analyses of self-reported daily activity levels revealed a diffusion of treatment effect . Fifty percent of the usual-care group reported maintaining or increasing their physical activity to a moderate-intensity level , while 33 % of the exercise group did not exercise at the prescribed levels . Analyses of self-reported disease symptoms and treatment side effects did not reveal clinical ly meaningful differences between the two groups . CLINICAL IMPLICATION S The results of this study suggest that women who exercised regularly before receiving a breast cancer diagnosis attempted to maintain their exercise programs . Women who lead sedentary lifestyles may benefit from a structured exercise program that includes information and support related to exercise adherence strategies [19672632] Purpose The study was focused on the influence of the kinesitherapy on fatigue and the quality of life in the terminal hospice cancer patients . Patients and methods Forty-nine patients were included into the study and divided into experimental group A ( with kinesitherapy ) with 30 subjects and control group B ( without kinesitherapy ) with 19 subjects . Patients from group A did the exercises three times a week , for 20–30 min , for the period of 3–4 weeks . The exercises were individually supervised by a physiotherapist , following a carefully worked out pattern . In both groups , the changes in the intensity of fatigue and the quality of life were observed by means of using Rotterdam symptom checklist , brief fatigue inventory , and visual analogue fatigue scale . Results In group A , the intensity of fatigue decreased significantly after 3 weeks of kinesitherapy . In group B , fatigue deteriorated significantly in comparison with the initial measurement . The intensity of physical symptoms in group A decreased significantly after 2 weeks of kinesitherapy , whereas in group B , increased after 2 weeks of observation . The quality of life in group A remained stable throughout the study . A tendency towards the deterioration of the quality of life with the time passing in group B was noticeable . Conclusion Our analysis showed that , on average , after 3 weeks of kinesitherapy , a significant decrease of the intensity of fatigue was observed , while in the control group , it increased after 2 weeks of observation . The obtained results provide evidence that a planned set of exercises decreases cancer-related fatigue effectively [18779540] BACKGROUND Anemia in patients with solid tumors is a common problem that is associated with impaired exercise capacity , increased fatigue , and lower quality of life ( QoL ) . Erythropoiesis-stimulating agents ( ESAs ) have been shown to improve these outcomes ; however , it is unknown if additional benefits can be achieved with aerobic exercise training . METHODS We conducted a single-center , prospect i ve , r and omized , controlled trial in 55 mild-to-moderately anemic patients with solid tumors . Patients were r and omized to either darbepoetin alfa alone ( DAL , n = 29 ) or darbepoetin alfa plus aerobic exercise training ( DEX ; n = 26 ) . The DEX group performed aerobic exercise training three times per week at 60%-100 % of baseline exercise capacity for 12 weeks . The primary endpoint was QoL assessed by the Functional Assessment of Cancer Therapy-Anemia scale . Secondary endpoints were fatigue , cardiorespiratory fitness ( VO(2peak ) ) , hemoglobin ( Hb ) response , and darbepoetin alfa dosing . RESULTS Intention-to-treat analyses indicated significant improvements in QoL and fatigue in both groups over time but there were no between-group differences . The DEX group had a significantly greater VO(2peak ) than the DAL group ( mean group difference , + 3.0 ml/kg per minute ; 95 % confidence interval , 1.2 - 4.7 ; p = .001 ) and there were borderline significant differences in favor of the DEX group for Hb response and darbepoetin alfa dosing . CONCLUSIONS Aerobic exercise training did not improve QoL or fatigue beyond the established benefits of DAL but it did result in favorable improvements in exercise capacity and a more rapid Hb response with lower dosing requirements . Our results may be useful to clinicians despite the more recent restrictions on the indications for ESAs [19759996] This pilot study examined the efficacy of two home-based exercise programs on alleviating fatigue and improving functional capacity in breast cancer survivors . Participants were r and omly assigned into one of three groups : aerobic exercise ( AE ) , resistance exercise ( RE ) , or usual care control ( CON ) . After receiving individualized instruction and training , participants assigned to the AE and RE groups were asked to perform the prescribed exercise(s ) 3 times per week for 12 weeks at home . Both groups were instructed to keep their perceived exercise intensity in the " fairly light " to " somewhat hard " range using the Borg Perceived Exertion Scale . All participants completed the revised Piper Fatigue Scale ( PFS ) and the 6-minute walk test ( 6MWT ) at baseline and 12-week post-exercise program . Analysis of pre- and post-training data revealed a significant reduction in fatigue levels on the PFS among participants in the AE group ( Z=2.521 , one-tailed P=0.006 ) , and a significant improvement in the distance of the 6MWT for the RE group ( Z=2.366 , one-tailed P=0.009 ) at the end of 12-week study period . No significant changes in fatigue or functional status were observed in the CON group . Findings provide preliminary support for RE as a viable strategy for improving functional capacity in breast cancer survivors , while AE may be more effective in attenuating cancer-related fatigue . Incorporating RE training for future research may help advance the growing body of knowledge in symptom management for breast cancer survivors [15139072] Research suggests that stress‐reduction programs tailored to the cancer setting help patients cope with the effects of treatment and improve their quality of life . Yoga , an ancient Eastern science , incorporates stress‐reduction techniques that include regulated breathing , visual imagery , and meditation as well as various postures . The authors examined the effects of the Tibetan yoga ( TY ) practice s of Tsa lung and Trul khor , which incorporate controlled breathing and visualization , mindfulness techniques , and low‐impact postures in patients with lymphoma [15170652] BACKGROUND AND OBJECTIVES This pilot project assessed the acceptability of a mixed-type , moderate-intensity exercise programme following breast cancer treatment , and the impact on presence of lymphoedema , fitness , body composition , fatigue , mood and quality of life . METHODS Ten women completed the programme and measures of fitness ( sub-maximal ergometer test ) , body composition ( bio-electrical impedance ) , lympoedema ( bio-electrical impedance and arm circumferences ) , fatigue ( revised Piper Fatigue Scale ) , mood ( Hospital Anxiety and Depression Scale ) , quality of life ( FACT-B ) and general well-being , at baseline , completion of the programme , and 6-week and 3-month follow-up . RESULTS Participation in the programme caused no adverse effect on the presence of lymphoedema . There was a trend towards reduction in fatigue and improved quality of life across the testing phases . Women rated the programme extremely favourably , citing benefits of the support of other women , trained guidance , and the opportunity to experience different types of exercise . CONCLUSIONS A mixed-type , moderate-intensity exercise program in a group format is acceptable to women following breast cancer treatment , with the potential to reduce fatigue and improve quality of life , without exacerbating or precipitating lymphoedema . This pilot work needs to be confirmed in larger r and omised studies [12471288] PURPOSE The primary purpose of this study was to examine the effect of aerobic exercise on physiological and psychological function in patients rehabilitating from cancer treatment . A second purpose was to evaluate the differential effects of low- and moderate-intensity exercise on these variables . METHODS Eighteen survivors of breast or colon cancer ( 15 female and 3 male , 40 - 65 yr of age ) served as subjects . The subjects were matched by aerobic capacity and scores on a Quality of Life question naire , and then r and omly assigned to a control , low- ( 25 - 35 % heart rate reserve ( HRR ) ) , or a moderate- ( 40 - 50 % HRR ) intensity exercise group . The exercise groups performed lower-body aerobic exercise three times a week for 10 wk . After the exercise training , there were no statistically significant differences between the two exercise groups on any of the physiological variables . Therefore , the exercise groups were combined into one group for the final analysis . RESULTS The results revealed statistically significant increases in aerobic capacity ( P < 0.001 ) and lower-body flexibility ( P = 0.027 ) , a significant decrease in body fat ( P < 0.001 ) , and a significant increase in quality of life ( P < 0.001 ) and a measure of energy ( P = 0.038 ) in the exercise group when compared with the control group . CONCLUSION Low- and moderate-intensity aerobic-exercise programs were equally effective in improving physiological and psychological function in this population of cancer survivors . Aerobic exercise appears to be a valuable and well-tolerated component of the cancer-rehabilitation process [15022300] The efficacy of energy conservation and activity management ( ECAM ) for fatigue reduction and maintenance of functional performance has never been evaluated in adults with cancer who are undergoing treatment [19609570] Goals of workProstate cancer patients receiving and rogen deprivation therapy ( ADT ) are vulnerable to a number of potentially debilitating side effects , which can significantly impact quality of life . The role of alternate therapies , such as physical activity ( PA ) , in attenuating these side effects is largely understudied for such a large population . Thus , the purpose of this study was to investigate the effects of PA intervention for men receiving ADT on PA behavior , quality of life , and fitness measures . Patients and methods One hundred participants were r and omized into an intervention ( n = 53 ) or a wait-list control group ( n = 47 ) , with 11 dropping out of the intervention group and 23 dropping out of the wait-list control group prior to post-testing . The intervention consisted of both an individually tailored home-based aerobic and light resistant training program and weekly group sessions . PA , quality of life , fitness , and physiological outcomes were assessed pre and post the 16-week intervention . Results Significant increases in PA , supported by changes in girth measures and blood pressure , support the beneficial impact of the intervention . Positive trends were also evident for depression and fatigue . However , due to the high dropout rate , these results must be interpreted with caution . Conclusions PA effectively attenuates many of the side effects of ADT and should be recommended to prostate survivors as an alternate therapy . Determining the maintenance of this behavior change will be important for underst and ing how the long-term benefits of increased activity levels may alleviate the late effects of ADT [17530428] Few r and omized controlled trials have examined the effects of combined aerobic and resistance training in breast cancer survivors soon after completing adjuvant therapy . Breast cancer survivors ( N = 58 ) within 2 years of completing adjuvant therapy were r and omly assigned to an immediate exercise group ( IEG ; n = 29 ) or a delayed exercise group ( DEG ; n = 29 ) . The IEG completed 12 weeks of supervised aerobic and resistance exercise , three times per week . The DEG completed the program during the next 12 weeks . Participants completed patient-rated outcomes at baseline , 6 , 12 , 18 and 24 weeks . The primary endpoint was overall quality of life ( QoL ) measured by the Functional Assessment of Cancer Therapy-Breast scale . Secondary endpoints were fatigue , social physique anxiety , and physical fitness . Follow-up data was obtained on 97 % of participants and exercise adherence was 61.3 % . Repeated measures analyses of variance revealed a significant group by time interaction for overall QoL ( P < 0.001 ) . Specifically , QoL increased in the IEG from baseline to 12 weeks by 20.8 points compared to a decrease in the DEG of 5.3 points ( mean group difference = 26.1 ; 95 % CI = 18.3–32.7 ; P < 0.001 ) . From 12 to 24 weeks , QoL increased in the DEG by 29.5 points compared to an increase of 6.5 points in the IEG ( mean group difference = 23.0 ; 95 % CI = 16.3–29.1 ; P < 0.001 ) . Similar results were obtained for the secondary endpoints . Combined aerobic and resistance exercise soon after the completion of breast cancer therapy produces large and rapid improvements in health-related outcomes [11157015] PURPOSE Self-directed and supervised exercise were compared with usual care in a clinical trial design ed to evaluate the effect of structured exercise on physical functioning and other dimensions of health-related quality of life in women with stages I and II breast cancer . PATIENTS AND METHODS One hundred twenty-three women with stages I and II breast cancer completed baseline evaluations of generic and disease- and site-specific health-related quality of life , aerobic capacity , and body weight . Participants were r and omly allocated to one of three intervention groups : usual care ( control group ) , self-directed exercise , or supervised exercise . Quality of life , aerobic capacity , and body weight measures were repeated at 26 weeks . The primary outcome was the change in the Short Form-36 physical functioning scale between baseline and 26 weeks . RESULTS Physical functioning in the control group decreased by 4.1 points , whereas it increased by 5.7 points and 2.2 points in the self-directed and supervised exercise groups , respectively ( P = .04 ) . Post hoc analysis showed a moderately large ( and clinical ly important ) difference between the self-directed and control groups ( 9.8 points ; P = .01 ) and a more modest difference between the supervised and control groups ( 6.3 points ; P = .09 ) . No significant differences between groups were observed for changes in quality of life scores . In a secondary analysis of participants stratified by type of adjuvant therapy , supervised exercise improved aerobic capacity ( + 3.5 mL/kg/min ; P = .01 ) and reduced body weight ( -4.8 kg ; P < .05 ) compared with usual care only in participants not receiving chemotherapy . CONCLUSION Physical exercise can blunt some of the negative side effects of breast cancer treatment , including reduced physical functioning . Self-directed exercise is an effective way to improve physical functioning compared with usual care . In participants not receiving chemotherapy , supervised exercise may increase aerobic capacity and reduce body weight compared with usual care [17557948] PURPOSE To determine the effects of breast cancer-specific print material s and step pedometers on physical activity ( PA ) and quality of life ( QoL ) in breast cancer survivors . PATIENTS AND METHODS Breast cancer survivors ( N = 377 ) were r and omly assigned to receive one of the following : a st and ard public health recommendation for PA , previously developed breast cancer-specific PA print material s , a step pedometer , or a combination of breast cancer-specific print material s and step pedometers . The primary outcome was self-reported moderate/vigorous PA minutes per week . Secondary outcomes were QoL ( Functional Assessment of Cancer Therapy-Breast ) , fatigue , self-reported brisk walking , and objective step counts . Assessment s were conducted at baseline and postintervention ( 12 weeks ) . RESULTS Attrition was 10.3 % ( 39 of 377 ) . On the basis of linear mixed-model analyses , PA increased by 30 minutes/week in the st and ard recommendation group compared with 70 minutes/week in the print material group ( mean difference , 39 minutes/week ; 95 % CI = -10 to 89 ; d = 0.25 ; P = .117 ) , 89 minutes/week in the pedometer group ( mean difference , 59 minutes/week ; 95 % CI , 11 to 108 ; d = 0.38 ; P = .017 ) , and 87 minutes/week in the combined group ( mean difference , 57 minutes/week ; 95 % CI , 8 to 106 ; d = 0.37 ; P = .022 ) . For brisk walking minutes/week , all three intervention groups reported significantly greater increases than the st and ard recommendation group . The combined group also reported significantly improved QoL ( mean difference , 5.8 ; 95 % CI , 2.0 to 9.6 ; d = 0.33 ; P = .003 ) and reduced fatigue ( mean difference , 2.3 ; 95 % CI , 0.0 to 4.7 ; d = 0.25 ; P = .052 ) compared with the st and ard recommendation group . CONCLUSION Breast cancer-specific PA print material s and pedometers may be effective strategies for increasing PA and QoL in breast cancer survivors . A combined approach appears to be optimal . CLINICAL TRIAL REGISTRATION Clinical Trials.gov Identifier [11323538] PURPOSE Cancer treatment-related fatigue is the most prevalent and distressing symptom of cancer therapy . Interventions to minimize fatigue are needed . The purpose of this study was to examine the relationship between exercise and fatigue over the first three cycles of chemotherapy in women receiving either cyclophosphamide , methotrexate , and fluorouracil ( CMF ) or doxorubicin and cyclophosphamide ( AC ) for breast cancer . METHODS Seventy-two newly diagnosed women with breast cancer were instructed in a home-based moderate-intensity exercise intervention . Measures of functional ability , energy expenditure , and fatigue were obtained at baseline and posttest . Subjects maintained daily records of four types of fatigue , and exercise duration , intensity , and type . RESULTS Exercise significantly reduced all four levels of fatigue ( P < 0.01 ) . As the duration of exercise increased , the intensity of fatigue declined ( P < 0.01 ) . There was a significant carry-over effect of exercise on fatigue , but the effect lasted only 1 d. The level of fatigue at study entry was not associated with number of days of exercise or amount of exercise a woman engaged in . CONCLUSIONS The impact of exercise on fatigue was significant and suggests the effectiveness of a low- to moderate-intensity regular exercise program in maintaining functional ability and reducing fatigue in women with breast cancer receiving chemotherapy [18347912] Background Exercise adherence is a challenge for breast cancer patients receiving chemotherapy but few studies have identified the key barriers . Purpose In this paper , we report the barriers to supervised exercise in breast cancer patients participating in a r and omized controlled trial . Methods Breast cancer patients initiating adjuvant chemotherapy ( N = 242 ) were r and omly assigned to usual care ( n = 82 ) or supervised resistance ( n = 82 ) or aerobic ( n = 78 ) exercise . Participants r and omized to the two exercise groups ( n = 160 ) were asked to provide a reason for each missed exercise session . Results The two exercise groups attended 70.2 % ( 5,495/7,829 ) of their supervised exercise sessions and provided a reason for missing 89.5 % ( 2,090/2,334 ) of their unattended sessions . The 2,090 reasons represented 36 different barriers . Feeling sick ( 12 % ) , fatigue ( 11 % ) , loss of interest ( 9 % ) , vacation ( 7 % ) , and nausea/vomiting ( 5 % ) accounted for the most missed exercise sessions . Disease/treatment-related barriers ( 19 of the 36 barriers ) accounted for 53 % ( 1,102/2,090 ) of all missed exercise sessions . Demographic and medical variables did not predict the types of exercise barriers reported . Conclusions Barriers to supervised exercise in breast cancer patients receiving chemotherapy are varied but over half can be directly attributed to the disease and its treatments . Behavioral support programs need to focus on strategies to maintain exercise in the face of difficult treatment side effects [18467280] PURPOSE / OBJECTIVES To determine the effect of aerobic and strength resistance training and epoetin alfa ( EPO ) therapy on transfusions , stem cell collection s , transplantation recovery , and multiple myeloma treatment response . DESIGN R and omized clinical trial . SETTING A myeloma research and therapy center in the south central United States . SAMPLE 135 patients with multiple myeloma , 120 evaluable . METHODS R and om assignment to exercise or usual care groups . All patients received EPO based on an algorithm . Aerobic capacity , using the six-minute walk test , was assessed prior to induction chemotherapy , prior to stem cell mobilization , and following stem cell collection for all patients and before and after transplantation for patients continuing in the study . Data analysis included analysis of variance to compare other outcome variables by groups . MAIN RESEARCH VARIABLES Number of red blood cell and platelet transfusions during transplantation , number of attempts at and total number of days of stem cell collection , time to recovery after transplantation , and response to intensive therapy for multiple myeloma . FINDINGS Recovery and treatment response were not significantly different between groups after transplantation . The exercise group had significantly fewer red blood cell transfusions and fewer attempts at stem cell collection . Serious adverse events were similar in each group . CONCLUSIONS Exercise with prophylactic EPO therapy reduces the number of RBC transfusions and attempts at stem cell collection for patients receiving intensive treatment for multiple myeloma . IMPLICATION S FOR NURSING Exercise is safe and has many physiologic benefits for patients receiving multiple myeloma treatment [18280104] The purpose of this r and omized , controlled clinical trial was to preliminarily examine the effects of a three-week walking exercise program ( WEP ) on fatigue-related experiences of acute myelogenous leukemia ( AML ) patients receiving chemotherapy . Eligible AML patients were r and omly assigned to either an experimental group ( n=11 ) , which received 12 minutes of WEP per day , five days per week for three consecutive weeks , or to a control group ( n=11 ) , which received st and ard ward care . Effects of the WEP were assessed by seven indicators : worst and average fatigue intensities , fatigue interference with patients ' daily life , 12-minute walking distance , overall symptom distress , anxiety , and depressive status . All patients were evaluated four times : before chemotherapy ( baseline or Day 1 ) , Day 7 , Day 14 , and Day 21 of chemotherapy . Data were analyzed by Generalized Estimating Equation and revealed that AML patients in the three-week WEP group had a significantly greater increase in 12-minute walking distance than the control group . Patients in the WEP also had lower levels of fatigue intensity and interference , symptom distress , anxiety , and depressive status than the control group . Although preliminary , our results strongly suggest that three weeks of systematic walking exercise is clinical ly feasible for AML patients undergoing chemotherapy and can effectively improve their fatigue-related experiences [20467301] Background : Few studies have evaluated an individualized home-based exercise prescription during and after cancer treatment . Objective : The purpose of this study was to evaluate the effectiveness of a home-based exercise training intervention , the Pro-self Fatigue Control Program on the management of cancer-related fatigue . Interventions / Methods : Participants ( N = 119 ) were r and omized into 1 of 3 groups : group 1 received the exercise prescription throughout the study ; group 2 received their exercise prescription after completing cancer treatment ; and group 3 received usual care . Patients completed the Piper Fatigue Scale , General Sleep Disturbance Scale , Center for Epidemiological Studies -Depression Scale , and Worst Pain Intensity Scale . Results : All groups reported mild fatigue levels , sleep disturbance , and mild pain , but not depression . Using multilevel regression analysis , significant linear and quadratic trends were found for change in fatigue and pain ( ie , scores increased , then decreased over time ) . No group differences were found in the changing scores over time . A significant quadratic effect for the trajectory of sleep disturbance was found , but no group differences were detected over time . No significant time or group effects were found for depression . Conclusions : Our home-based exercise intervention had no effect on fatigue or related symptoms associated with cancer treatment . The optimal timing of exercise remains to be determined . Implication s for Practice : Clinicians need to be aware that some physical activity is better than none , and there is no harm in exercise as tolerated during cancer treatment . Further analysis is needed to examine the adherence to exercise . More frequent assessment s of fatigue , sleep disturbance , depression , and pain may capture the effect of exercise [16374892] BACKGROUND Physical activity provides a number of physical and psychological benefits to cancer survivors , including lessening the impact of detrimental cancer-related symptoms and treatment side-effects ( e.g. fatigue , nausea ) , and improving overall well-being and quality of life . The purpose of the present pilot study was to examine the physical and psychological benefits afforded by a 7-week yoga program for cancer survivors . METHOD Eligible participants ( per-screened with PAR-Q/PAR-MED-X ) were r and omly assigned to either the intervention ( n=20 ) or control group ( n=18 ) . All participants completed pre- and post-testing assessment s immediately before and after the yoga program , respectively . RESULTS The yoga program participants ( M age=51.18 ( 10.33 ) ; 92 % female ) included primarily breast cancer survivors , on average 55.95 ( 54.39 ) months post-diagnosis . Significant differences between the intervention and the control group at post-intervention were seen only in psychosocial ( i.e. global quality of life , emotional function , and diarrhea ) variables ( all p 's < 0.05 ) . There were also trends for group differences , in the hypothesized directions , for the psychosocial variables of emotional irritability , gastrointestinal symptoms , cognitive disorganization , mood disturbance , tension , depression , and confusion ( all p 's < 0.10 ) . Finally , there were also significant improvements in both the program participants and the controls from pre- to post-intervention on a number of physical fitness variables . CONCLUSIONS These initial findings suggest that yoga has significant potential and should be further explored as a beneficial physical activity option for cancer survivors . Future research might attempt to include a broader range of participants ( e.g. other types of cancer diagnoses , male subjects ) , a larger sample size , and a longer program duration in an RCT [17524796] We describe adherence to a three group r and omised controlled trial that involved aerobic exercise therapy ( N=34 ) and exercise-placebo intervention ( N=36 ) or usual care ( N=38 ) in women treated for breast cancer . We also investigated relationships between routes of trial recruitment , socio-economic characteristics , health behaviours , cancer treatment regimen(s ) and subsequent adherence to the interventions . Women who had completed breast cancer treatment 12 - 36 months previously were r and omised to one of the groups . The intervention groups attended an exercise facility three times per week for eight weeks . A total of 77 % of the aerobic exercise therapy and 88.9 % of the exercise-placebo groups attended at least 70 % of prescribed sessions . The percentage of women achieving 30min of aerobic exercise per session steadily increased during the intervention but many women were not able to achieve this goal . Routes of trial recruitment , socio-economic characteristics , health behaviours and cancer treatment regimen(s ) were not related to intervention . Exercise therapy participants were able to comply with the progressive nature of the aerobic exercise intervention , although some women were not able to achieve 30min of aerobic exercise per session by intervention completion . Research is still required to tease out all the potential determinants of exercise in this population [2615347] Purpose Postoperative radiotherapy for breast cancer has a number of associated complications . This study examined whether supervised moderate-intensity exercise could mitigate the complications that occur during radiotherapy . Patients and Methods Forty women were r and omized before radiotherapy after various operations for breast cancer . Seventeen patients who were assigned to the exercise group performed supervised moderate-intensity exercise therapy for 50 min 3 times per week for 5 weeks . Twenty-three patients in the control group were asked to perform self-shoulder stretching exercise . The World Health Organization Quality of Life-BREF ( WHOQOL-BREF ) , brief fatigue inventory ( BFI ) , range of motion ( ROM ) of the shoulder , and pain score were assessed before and after radiotherapy . Results There were no significant differences noted at baseline between groups . In the exercise group , there was an increase in the WHOQOL-BREF and shoulder ROM and decrease in BFI and pain score after radiotherapy . On the other h and , patients in the control group showed decrease in the WHOQOL-BREF and shoulder ROM and increase in BFI and pain score after radiotherapy . There were statistically significant differences in the changes in the WHOQOL , BFI , shoulder ROM , and pain score between the groups . Conclusion Patients receiving radiotherapy for breast cancer may benefit in physical and psychological aspects from supervised moderate-intensity exercise therapy [15656848] AIM Our purpose was to investigate the effect of a relaxation breathing exercise on fatigue in allogenic haemopoietic stem cell transplantation patients . BACKGROUND Exercise is a promising approach in ameliorating the fatigue associated with cancer and its treatment . DESIGN A r and omized design with control , experimental groups being assessed pre- and postintervention . METHODS Thirty-five patients were r and omly selected , with 18 assigned to an exercise group and 17 to a control group . The exercise intervention lasted for 30 minutes every day for six weeks . It consisted of physical exercise combined with relaxation breathing exercise . Fatigue was measured by the revised version of the Piper Fatigue Scale . RESULTS The exercise group had a greater decrease in fatigue than the control group . CONCLUSION These findings indicate that a relaxation breathing exercise would improve fatigue in allogenic haemopoietic stem cell transplantation patients . RELEVANCE TO CLINICAL PRACTICE A relaxation breathing exercise by a nurse can improve fatigue in allogenic haemopoietic stem cell transplantation patients [15274068] Advice to rest and take things easy if patients become fatigued during radiotherapy may be detrimental . Aerobic walking improves physical functioning and has been an intervention for chemotherapy‐related fatigue . A prospect i ve , r and omized , controlled trial was performed to determine whether aerobic exercise would reduce the incidence of fatigue and prevent deterioration in physical functioning during radiotherapy for localized prostate carcinoma [18389368] Purpose Exercise during breast cancer chemotherapy is beneficial but it needs to be maintained into survivorship to optimize long-term benefits . Here , we report the predictors of follow-up exercise behavior 6 months after a r and omized exercise trial in breast cancer patients . Methods Breast cancer patients ( N = 242 ) initiating adjuvant chemotherapy were r and omly assigned to usual care ( n = 82 ) , supervised resistance exercise ( n = 82 ) , or supervised aerobic exercise ( n = 78 ) for the duration of their chemotherapy . At baseline and postintervention , data were collected on demographic , medical , behavioral , fitness , psychosocial , and motivational variables . At 6-month follow-up , participants were mailed a question naire that assessed exercise behavior over the past 6 months and were categorized as either meeting both aerobic and resistance exercise guidelines , either exercise guideline , or neither exercise guideline . Results Two hundred one ( 83.1 % ) participants provided 6-month follow-up data with 85 ( 42.3 % ) meeting neither exercise guideline , 74 ( 36.8 % ) meeting either exercise guideline , and 42 ( 20.9 % ) meeting both exercise guidelines . In multivariate regression analysis , seven variables independently predicted the likelihood of meeting exercise guidelines at follow-up including higher pretrial exercise ( β = 0.23 ; P = 0.002 ) , younger age ( β = −0.15 ; P = 0.028 ) , breast conserving surgery ( β = 0.15 ; P = 0.033 ) , strength improvements ( β = 0.15 ; P = 0.028 ) , lower postintervention fatigue ( β = 0.13 ; P = 0.067 ) , a more positive attitude ( β = 0.12 ; P = 0.086 ) , and lower postintervention body mass index ( β = −0.11 ; P = 0.105 ) . Conclusion Exercise behavior 6 months after a r and omized trial was predicted by a wide range of demographic , medical , behavioral , fitness , psychosocial , and motivational variables . These findings may help facilitate the uptake of exercise behavior during the transition from breast cancer patient to survivor [18543381] Quality of life ( QOL ) of cancer patients is often diminished due to the side effects of treatment and symptoms of the disease itself . Medical Qigong ( coordination of gentle exercise and relaxation through meditation and breathing exercise based on Chinese medicine theory of energy channels ) may be an effective therapy for improving QOL , symptoms and side effects , and longevity of cancer patients . In this pilot study , the feasibility , acceptability , and impact of Medical Qigong ( MQ ) were evaluated on outcomes in cancer patients . Thirty patients diagnosed with heterogeneous cancers , were r and omly assigned to two groups : a control group that received usual medical care and an intervention group who participated in a MQ program for 8 weeks in addition to receiving usual medical care . R and omization was stratified by completion of cancer treatment ( n = 14 ) or under chemotherapy ( n = 16 ) . Patients completed measures before and after the program . Quality of life and symptoms were measured by the EORTC QLQ-C 30 and progress of disease by the inflammation biomarker ( CRP : c-reactive protein ) via a blood test was assessed . The MQ intervention group reported clinical ly significant improved global QOL scores pre- and post-intervention . The MQ intervention also reduced the symptoms of side effects of cancer treatment and inflammation biomarker ( CRP ) compare to the control group . Due to the small sample size , however , the results were not statistically significant between treatment and the control groups . Data from the pilot study suggest that MQ with usual medical treatment can enhance the QOL of cancer patients and reduce inflammation . This study needs a further investigation with a larger sample size [18797706] The purpose of this study was to examine the effects of an exercise intervention on the total caloric intake ( TCI ) of breast cancer patients undergoing treatment . A secondary purpose was to determine whether or not a relationship existed between changes in TCI , body fat composition ( % BF ) , and fatigue during the study , which lasted 6 months . Twenty females recently diagnosed with breast cancer , scheduled to undergo chemotherapy or radiation , were assigned r and omly to an experimental ( N = 10 ) or control group ( N = 10 ) . Outcome measures included TCI ( 3-day food diary ) , % BF ( skinfolds ) , and fatigue ( revised Piper Fatigue Scale ) . Each exercise session was conducted as follows : initial cardiovascular activity ( 6 - 12 min ) , followed by stretching ( 5 - 10 min ) , resistance training ( 15 - 30 min ) , and a cool-down ( approximately 8 min ) . Significant changes in TCI were observed among groups ( F1,18 = 8.582 ; P = 0.009 ) , at treatments 2 and 3 , and at the end of the study [ experimental ( 1973 + /- 419 ) , control ( 1488 + /- 418 ) ; experimental ( 1946 + /- 437 ) , control ( 1436 + /- 429 ) ; experimental ( 2315 + /- 455 ) , control ( 1474 + /- 294 ) , respectively ] . A significant negative correlation was found ( Spearman rho(18 ) = -0.759 ; P < 0.001 ) between TCI and % BF and between TCI and fatigue levels ( Spearman rho(18 ) = -0.541 ; P = 0.014 ) at the end of the study . In conclusion , the results of this study suggest that an exercise intervention administered to breast cancer patients undergoing medical treatment may assist in the mitigation of some treatment side effects , including decreased TCI , increased fatigue , and negative changes in body composition [17848814] Cancer-related fatigue is the most disabling symptom experienced by breast cancer patients following the cancer treatment . The positive effects of physical activity in the rehabilitation of breast cancer patients are documented in several studies . In a r and omized controlled study the effects of a structured physical training program on fatigue and health-related quality of life were evaluated . Patients and Methods : 63 breast cancer patients with cancer-related chronic fatigue were r and omized at the beginning of the inpatient rehabilitation . The control group received the st and ard complex rehabilitation program , the intervention group a structured physical training program and additional muscle strength and aerobic exercises . The effects of the treatment were evaluated by question naires at the start of rehabilitation ( t1 ) , end of rehabilitation ( t2 ) , and 3 months after t2 ( t3 ) . Isometric muscle strength and aerobic capacity were evaluated at t1 and t2 . Results : There was an improvement of muscle strength at the end of rehabilitation for both groups . The increase from t1 to t2 was significantly higher for the training group . The scores for global quality of life , physical well-being , and functionality increased from t1 to t2 , but further improvement in the follow-up ( t3 ) was only observed in the training group . The cancer-related fatigue was significantly reduced in the training group from t1 to t3 , however , not in the control group . Conclusions : Structured physical training programs initiated during inpatient rehabilitation and continuously practice d in the time thereafter can improve symptoms of chronic fatigue and quality of life in breast cancer patients [15338385] Fatigue is a frequent problem after surgical treatment of solid tumours . Aerobic exercise and psychosocial interventions have been shown to reduce the severity of this symptom in cancer patients . Therefore , we compared the effect of the two therapies on fatigue in a r and omised controlled study . Seventy-two patients who underwent surgery for lung ( n=27 ) or gastrointestinal tumours ( n=42 ) were assigned to an aerobic exercise group ( stationary biking 30 min five times weekly ) or a progressive relaxation training group ( 45 min three times per week ) . Both interventions were carried out for 3 weeks . At the beginning and the end of the study , we evaluated physical , cognitive and emotional status and somatic complaints with the European Organization for Research and Treatment of Cancer Quality of Life Question naire Core Module ( EORTC-QLQ-30 ) question naire , and maximal physical performance with an ergometric stress test . Physical performance of the training group improved significantly during the programme ( 9.4±20 watts , p=0.01 ) but remained unchanged in the relaxation group ( 1.5±14.8 watts , p=0.37 ) . Fatigue and global health scores improved in both groups during the intervention ( fatigue : training group 21 % , relaxation group 19 % ; global health of both groups 19 % , p for all ≤0.01 ) ; however , there was no significant difference between changes in the scores of both groups ( p=0.67 ) . We conclude that a structured aerobic training programme improves the physical performance of patients recovering from surgery for solid tumours . However , exercise is not better than progressive relaxation training for the treatment of fatigue in this setting [18086760] Background : Few exercise trials in cancer patients have reported longer-term follow-up . Here , we report a 6-month follow-up of exercise behavior and patient-rated outcomes from an exercise trial in breast cancer patients . Methods : Breast cancer patients initiating adjuvant chemotherapy ( n = 242 ) were r and omly assigned to usual care ( n = 82 ) , resistance exercise training ( RET ; n = 82 ) , or aerobic exercise training ( AET ; n = 78 ) for the duration of their chemotherapy . At 6-month follow-up , participants were mailed a question naire that assessed quality of life , self-esteem , fatigue , anxiety , depression , and exercise behavior . Results : Two hundred one ( 83.1 % ) participants provided 6-month follow-up data . Adjusted linear mixed-model analyses showed that , at 6-month follow-up , the RET group reported higher self-esteem [ adjusted mean difference , 1.6 ; 95 % confidence interval ( 95 % CI ) , 0.1 - 3.2 ; P = 0.032 ] and the AET group reported lower anxiety ( adjusted mean difference , −4.7 ; 95 % CI , −0.0 to −9.3 ; P = 0.049 ) compared with the usual care group . Moreover , compared with participants reporting no regular exercise during the follow-up period , those reporting regular aerobic and resistance exercise also reported better patient-rated outcomes , including quality of life ( adjusted mean difference , 9.5 ; 95 % CI , 1.2 - 17.8 ; P = 0.025 ) . Conclusions : Improvements in self-esteem observed with RET during breast cancer chemotherapy were maintained at 6-month follow-up whereas reductions in anxiety not observed with AET during breast cancer chemotherapy emerged at 6-month follow-up . Moreover , adopting a combined aerobic and resistance exercise program after breast cancer chemotherapy was associated with further improvements in patient-rated outcomes . Exercise training during breast cancer chemotherapy may result in some longer-term and late effects for selected patient-rated outcomes . ( Cancer Epidemiol Biomarkers Prev 2007;16(12):2572–8 [19117328] OBJECTIVES To determine if therapist supervision of an exercise program produced better functional outcomes in allogeneic stem cell transplant patients than a patient-directed exercise program . METHODS Sixty-one patients who were less than 6 months post allogeneic stem cell transplant were r and omly assigned to either a therapist supervised training group ( supervised ) or a patient-directed training group ( Self-directed ) . Training consisted of aerobic exercises ( treadmill , bicycle ergometer versus walking ) and resistance exercises ( free weights , weight machines versus resistive b and activities ) . Subjects completed physical performance tests ( 50-foot fast walk , 6-min walk , forward reach , repeated sit-to-st and , uniped stance ) and the Brief Fatigue Inventory ( BFI ) before and after 4 weeks of training . Pre- and post-training outcomes and group differences were analyzed by a Student t-test . RESULTS Patients in both groups were similarly deconditioned at baseline . Training increased the 6-min walk distance and 50-foot walk in the supervised group by 12 and 14 % , respectively , and increased the 6-min walk distance by 10 % in the Self-directed group ( p<0.05 ) . BFI score for worst level of fatigue declined in both groups but not significantly . CONCLUSIONS These results demonstrate that allogeneic transplant patients derive functional benefits from short-term exercise training regardless of how the training program is supervised . Determining ( 1 ) the reasons for the low participation rate ( 28 % ) , ( 2 ) the patient-preferred characteristics of each exercise supervision style and ( 3 ) how best to match patient preference to exercise supervision style remain significant issues in this area of patient delivery services [18381369] BACKGROUND Fatigue is a relevant problem of cancer patients during and after treatment . Several studies have shown that exercise can improve quality of life and functional status of cancer patients undergoing chemo- or radiotherapy . However , there is a lack of information about the effects of this intervention on persistent cancer-related fatigue . Therefore , we assessed the effects of an exercise program on cancer-related fatigue after treatment . PATIENTS AND METHODS A consecutive series of 32 cancer patients with mild to severe persistent fatigue [ scores on the Brief Fatigue Inventory ( BFI ) > 25 ] participated in a 3-week exercise program consisting of endurance ( 30 min walking on a treadmill ) and resistance/coordination exercises for the major muscle groups . Fatigue , mood , and anxiety were assessed with question naires and physical performance with a stress test before and after the program . RESULTS At the end of the program , we observed a significant increase of physical performance ( workload at the anaerobic threshold pre 61 + /- 26 W , post 78 + /- 31 W , P < 0.0001 ) and reduction of global fatigue ( Functional Assessment of Cancer Therapy : pre 45.7 + /- 13.4 , post 52.6 + /- 12.4 , P < 0.0001 ; BFI : pre 37.9 + /- 18.3 , post 31.2 + /-17.1 , P < 0.001 ) . However , no significant improvement of cognitive fatigue or reduction of anxiety was observed . CONCLUSIONS A 3-week exercise program leads to a substantial improvement of physical performance and reduction of mental and physical fatigue in cancer patients after treatment . However , this intervention does not affect depression , anxiety , or cognitive fatigue [9345021] Loss of physical performance is a universal problem of cancer patients undergoing chemotherapy . We postulated that this impairment can be partially prevented by aerobic exercise . In a r and omized study , 33 cancer patients receiving high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation ( training group , T ) performed an exercise program consisting of biking on an ergometer in the supine position after an interval-training pattern for 30 minutes daily during hospitalization . Patients in the control group ( C , n = 37 ) did not train . Maximal physical performance was assessed with a treadmill test by admission and discharge . Physical performance of the two groups was not different on admission . The decrement in performance during hospitalization was 27 % greater in the control group than in the training group ( P = .05 ) ; this result ed in a significantly higher maximal physical performance at discharge in the trained patients ( P = .04 ) . Duration of neutropenia ( P = .01 ) and thrombopenia ( P = .06 ) , severity of diarrhea ( P = .04 ) , severity of pain ( P = .01 ) , and duration of hospitalization ( P = . 03 ) were reduced in the training group . We conclude that aerobic exercise can be safely carried out immediately after high-dose chemotherapy and can partially prevent loss of physical performance . Based on the potential significance of the observed outcomes , further studies are warranted to confirm our results [19212103] Surgical patients often show physiological and metabolic distress , muscle weakness , and long hospital stays . Physical conditioning might help recovery . We attempted to identify the most responsive measure of aerobic fitness from a four-week pre-surgical aerobic exercise program ( prehabilitation ) in patients undergoing major bowel resection . Twenty-one subjects r and omized two to one ( exercise : control ) scheduled for colorectal surgery . Fourteen subjects [ Body Mass Index ( BMI ) = 27 + /- 6 kg/m(2 ) ; maximal oxygen uptake ( VO(2max ) ) = 22 + /- 10 ml/kg/min ] underwent 3.8 + /- 1.2 weeks ( 27 + /- 8 sessions ) of progressive , structured pre-surgical aerobic exercise training at 40 to 65 % of heart rate reserve ( % HRR ) . Peak power output was the only maximal measure that was responsive to training [ 26 + /- 27 % , Effects Size ( ES ) = 0.24 ; St and ardized Response Mean ( SRM ) = 1.05 ; p < 0.05 ] . For the submaximal measures , heart rate and oxygen uptake during submaximal exercise was most responsive to training ( decrease by 13 % + /- 15 % , ES = -0.24 ; SRM = -0.57 ; and 7 % + /- 6 % , ES = -0.40 ; SRM -0.97 ; p < 0.05 ) at an exercise intensity of 76 + /- 47 W. There was no change to maximal or submaximal measures in the control group . The distance walked over six minutes improved in both groups ( by approximately 30 m ) , but the effect size and t-statistic were higher in the exercise group . Heart rate and oxygen uptake during submaximal exercise , and peak power output are the most responsive measures to four weeks of prehabilitation in subjects with low initial fitness [19190034] Objectives . This study compares the effects of an integrated yoga program with brief supportive therapy in breast cancer out patients undergoing adjuvant radiotherapy at a cancer center . Methods . Eighty-eight stage II and III breast cancer out patients are r and omly assigned to receive yoga ( n = 44 ) or brief supportive therapy ( n = 44 ) prior to radiotherapy treatment . Assessment s include diurnal salivary cortisol levels 3 days before and after radiotherapy and self-ratings of anxiety , depression , and stress collected before and after 6 weeks of radiotherapy . Results . Analysis of covariance reveals significant decreases in anxiety ( P < .001 ) , depression ( P = .002 ) , perceived stress ( P < .001 ) , 6 a.m. salivary cortisol ( P = .009 ) , and pooled mean cortisol ( P = .03 ) in the yoga group compared with controls . There is a significant positive correlation between morning salivary cortisol level and anxiety and depression . Conclusion . Yoga might have a role in managing self-reported psychological distress and modulating circadian patterns of stress hormones in early breast cancer patients undergoing adjuvant radiotherapy [9243585] PURPOSE S/ OBJECTIVES To test the hypothesis that women participating in a walking exercise program during radiation therapy treatment for breast cancer would demonstrate more adaptive responses as evidence d by higher levels of physical functioning and lower levels of symptom intensity than women who did not participate . DESIGN Experimental , two-group pretest , post-test . SETTING Two university teaching hospital outpatient radiation therapy departments . SAMPLE 46 women beginning a six-week program of radiation therapy for early stage breast cancer . METHODS Following r and om assignment , subjects in the exercise group maintained an individualized , self-paced , home-based walking exercise program throughout treatment . The control group received usual care . Dependent variables were measured prior to and at the end of radiation therapy . In addition , symptoms were assessed at the end of three weeks of treatment . MAIN RESEARCH VARIABLES Participation in the walking exercise program , physical functioning fatigue , emotional distress , and difficulty sleeping . FINDINGS Hypothesis testing by multivariate analysis of covariance , with pretest scores as covariates , indicated significant differences between groups on outcome measures ( p < 0.001 ) . The exercise group scored significantly higher than the usual care group on physical functioning ( p = 0.003 ) and symptom intensity , particularly fatigue , anxiety , and difficulty sleeping . Fatigue was the most frequent and intense subjective symptom reported . CONCLUSIONS A self-paced , home-based walking exercise program can help manage symptoms and improve physical functioning during radiation therapy . IMPLICATION S FOR NURSING PRACTICE Nurse-prescribed and -monitored exercise is an effective , convenient , and low-cost self-care activity that reduces symptoms and facilitates adaptation to breast cancer diagnosis and treatment [19276838] PURPOSE Interventions to increase physical activity among breast cancer survivors are needed to improve health and quality of life and possibly to reduce the risk of disease recurrence and early mortality . Therefore , we report the feasibility and preliminary outcomes of a pilot r and omized trial design ed to increase physical activity in sedentary breast cancer survivors receiving hormone therapy . METHODS Forty-one sedentary women on estrogen receptor modulators or aromatase inhibitors for stage I , II , or IIIA breast cancer were r and omly assigned to receive a 12-wk multidisciplinary physical activity behavior change intervention or usual care . RESULTS Recruitment was 34 % , intervention adherence was 99 % , and complete follow-up data were obtained on 93 % . Most participants ( 93 % ) were white with mean age of 53 + /- 9 yr . Differences favoring the intervention group were noted for accelerometer physical activity counts ( mean difference = 72,103 ; 95 % confidence interval ( CI ) = 25,383 - 119,000 ; effect size ( d ) = 1.02 ; P = 0.004 ) , aerobic fitness ( mean difference = 2.9 ; 95 % CI = -0.1 to 5.8 ; d = 0.64 ; P = 0.058 ) , back/leg muscle strength ( mean difference = 12.3 ; 95 % CI = 0.4 - 15.9 ; d = 0.81 ; P = 0.017 ) , waist-to-hip ratio ( mean difference = -0.05 ; 95 % CI = -0.01 to -0.08 ; d = -0.77 ; P = 0.018 ) , and social well-being ( mean difference = 2.0 ; 95 % CI = 0.3 - 3.8 ; d = 0.76 ; P = 0.03 ) . However , the intervention group also reported a greater increase in joint stiffness ( mean difference = 1.1 ; 95 % CI = 0.1 - 2.2 ; d = 0.70 ; P = 0.04 ) . CONCLUSIONS A behavior change intervention for breast cancer survivors based on the social cognitive theory is feasible and results in potentially meaningful improvements in physical activity and selected health outcomes . Confirmation in a larger study is warranted [19714371] Purpose It has not previously been shown whether there is any benefit to multi-morbid patients with lung cancer who participate in complex interdisciplinary rehabilitation programmes after primary therapy . The purpose of this prospect i ve study was to assess changes in exercise capacity and quality of life before and after an in-patient training programme . Patients and methods Forty-five patients with lung cancer ( WHO I-III after surgery and /or radiotherapy and /or chemotherapy ) were enrolled in a 28-day in-patient rehabilitation programme that included st and ardised aerobic training . Functional status and health-related quality of life ( QLQ-C30 , QLQ-LC13 , SF-36 , and MFI-20 ) were examined at the beginning of the study and at day 28 . Results A substantial increase in work performance ( bicycle ergometry from 68 ± 3 to 86 ± 4 W , p < 0.001 , and 6-minute walk test from 322 ± 11 to 385 ± 13 m , p < 0.001 ) was registered . In addition , heart rate at rest was reduced ( from 84 ± 2 to 80 ± 1 beats per minute , p < 0.05 ) and heart rate variability ( indicator of the efficacy of endurance training ) was significantly increased ( from 9.7 ± 1 to 12.9 ± 1 root mean square of successive differences , p < 0.001 ) . Moreover , there was also a significant improvement in quality of life ( 48 ± 3 to 62 ± 2 , p < 0.001 ) while fatigue was reduced from 66 ± 3 to 41 ± 4 , p < 0.001 . Conclusion A st and ardised , aerobic endurance training programme as part of the in-patient oncological rehabilitation of patients with lung cancer results in improvements in both physiological and psychological parameters after therapy . A follow-on study in order to determine to what extent this benefit persists over the long-term , particularly , in comparison with patients who have not participated in a rehabilitation programme , is currently being conducted [17307761] Objectives To determine functional and psychological benefits of a 12 week supervised group exercise programme during treatment for early stage breast cancer , with six month follow-up . Design Pragmatic r and omised controlled prospect i ve open trial . Setting Three National Health Service oncology clinics in Scotl and and community exercise facilities . Participants 203 women entered the study ; 177 completed the six month follow-up . Interventions Supervised 12 week group exercise programme in addition to usual care , compared with usual care . Main outcome measures Functional assessment of cancer therapy ( FACT ) question naire , Beck depression inventory , positive and negative affect scale , body mass index , seven day recall of physical activity , 12 minute walk test , and assessment of shoulder mobility . Results Mixed effects models with adjustment for baseline values , study site , treatment at baseline , and age gave intervention effect estimates ( intervention minus control ) at 12 weeks of 129 ( 95 % confidence interval 83 to 176 ) for metres walked in 12 minutes , 182 ( 75 to 289 ) for minutes of moderate intensity activity reported in a week , 2.6 ( 1.6 to 3.7 ) for shoulder mobility , 2.5 ( 1.0 to 3.9 ) for breast cancer specific subscale of quality of life , and 4.0 ( 1.8 to 6.3 ) for positive mood . No significant effect was seen for general quality of life ( FACT-G ) , which was the primary outcome . At the six month follow-up , most of these effects were maintained and an intervention effect for breast cancer specific quality of life emerged . No adverse effects were noted . Conclusion Supervised group exercise provided functional and psychological benefit after a 12 week intervention and six months later . Clinicians should encourage activity for their patients . Policy makers should consider the inclusion of exercise opportunities in cancer rehabilitation services . Trial registration Current controlled trials IS RCT N12587864 [17470863] PURPOSE To examine the effects of aerobic exercise therapy on quality of life ( QoL ) and associated outcomes in women treated for breast cancer . Evidence suggests that exercise may be beneficial , but no trial has included an exercise-placebo and a usual-care group to control for the attention effects that might be associated with aerobic exercise interventions in cancer patients . PATIENTS AND METHODS A total of 108 women who had been treated for breast cancer 12 to 36 months previously were r and omly assigned to supervised aerobic exercise therapy ( n = 34 ) , exercise-placebo ( body conditioning ; n = 36 ) , or usual care ( n = 38 ) . Exercise therapy and exercise-placebo sessions took place three times per week for 8 weeks . Outcomes included QoL , depression , exercise behavior , aerobic fitness ; outcomes were assessed at baseline and at the 8- and 24-week follow-up . RESULTS Analyses of covariance revealed a significant mean difference of 9.8 units in Functional Assessment of Cancer Therapy-General ( primary outcome ) favoring aerobic exercise therapy at 8 weeks , relative to usual care . Significant differences that favored aerobic exercise therapy relative to usual care were recorded for Functional Assessment of Cancer Therapy-Breast , social/family well-being , functional well-being , and breast cancer subscale scores at 8-week follow-up . Psychological health outcomes improved modestly for both intervention groups ; these improvements were sustained for several end points . CONCLUSION Exercise therapy had large , clinical ly meaningful , short-term beneficial effects on QoL in women treated for breast cancer ; this finding can not be attributable to attention , given that the exercise-placebo group did not report similar effects relative to usual care [12721239] PURPOSE To determine the effects of exercise training on cardiopulmonary function and quality of life ( QOL ) in postmenopausal breast cancer survivors who had completed surgery , radiotherapy , and /or chemotherapy with or without current hormone therapy use . METHODS Fifty-three postmenopausal breast cancer survivors were r and omly assigned to an exercise ( n = 25 ) or control ( n = 28 ) group . The exercise group trained on cycle ergometers three times per week for 15 weeks at a power output that elicited the ventilatory equivalent for carbon dioxide . The control group did not train . The primary outcomes were changes in peak oxygen consumption and overall QOL from baseline to postintervention . Peak oxygen consumption was assessed by a grade d exercise test using gas exchange analysis . Overall QOL was assessed by the Functional Assessment of Cancer Therapy-Breast scale . RESULTS Fifty-two participants completed the trial . The exercise group completed 98.4 % of the exercise sessions . Baseline values for peak oxygen consumption ( P = .254 ) and overall QOL ( P = .286 ) did not differ between groups . Peak oxygen consumption increased by 0.24 L/min in the exercise group , whereas it decreased by 0.05 L/min in the control group ( mean difference , 0.29 L/min ; 95 % confidence interval [ CI ] , 0.18 to 0.40 ; P < .001 ) . Overall QOL increased by 9.1 points in the exercise group compared with 0.3 points in the control group ( mean difference , 8.8 points ; 95 % CI , 3.6 to 14.0 ; P = .001 ) . Pearson correlations indicated that change in peak oxygen consumption correlated with change in overall QOL ( r = 0.45 ; P < .01 ) . CONCLUSION Exercise training had beneficial effects on cardiopulmonary function and QOL in postmenopausal breast cancer survivors [7937251] PURPOSE / OBJECTIVES To examine the effects of a comprehensive rehabilitation program on facilitating physical and psychosocial adaptation of women with breast cancer who are receiving adjuvant chemotherapy . DESIGN Experimental . SETTING Breast evaluation clinics of two New Engl and medical centers with comprehensive cancer treatment programs . SAMPLE 14 women ( mean age = 44 years ) receiving adjuvant chemotherapy for breast cancer ( 86 % stage II ) following surgical treatment . METHODS Subjects were assigned r and omly to the experimental group or the usual care group . Experimental group members began a structured exercise program of walking and attended support group meetings . All subjects were tested before beginning chemotherapy , during the course of chemotherapy , and one month following chemotherapy completion . MAIN RESEARCH VARIABLES Performance status , physical functioning , psychosocial adjustment , self-concept and body image , and 12 symptoms ( e.g. , fatigue , nausea , anxiety ) . FINDINGS Measures of physical performance , psychosocial adjustment , and symptom intensity revealed improved adaptation in subjects who completed the walking/support group program . CONCLUSIONS Physical and psychosocial benefits from a modest walking exercise program and a support group are possible for patients receiving adjuvant chemotherapy . IMPLICATION S FOR NURSING PRACTICE Although more detailed research is necessary to answer some of the questions raised by this study , implementing the walking program and forming a support group are achievable in an outpatient setting [18414905] Purpose Although physical activity ( PA ) adoption improves fitness and psychological well-being among cancer survivors , PA maintenance has not been examined . This paper presents follow-up of a home-based PA program for women treated for early-stage breast cancer . Material s and methods Eighty-six sedentary women ( mean age = 53.14 years , SD = 9.70 ) were r and omly assigned to a PA or contact control group . The PA group received a 12-week telephone counseling program to adopt PA . Assessment s were conducted at baseline , end-of-intervention ( 12 weeks ) , 6 , and 9 months post-baseline . Results When comparing change from end-of-intervention ( 12 weeks ) between groups , a significant reduction was observed in minutes of PA at 6 months ( t = −2.10 , p < 0.05 ) , but there was no decrease in intervention effect at 9 months ( t = −0.19 , p = 0.84 ) . Similarly , post-intervention reductions in fatigue were lost at 6 months ( t = 3.27 , p < 0.01 ) , but remained present at 9 months ( t = 1.65 , p = 0.10 ) . PA group ’s fitness improvements were maintained at both follow-ups ( t = 1.04 , p = 0.30 and t = 0.05 , p = 0.96 ) . The previously significant intervention effect on vigor was maintained at 6 months ( t = 1.32 , p = 0.19 ) but was significantly reduced at 9 months ( t = −2.15 , p < 0.05 ) . PA participants were more likely to progress in motivational readiness at 6 ( OR = 5.95 , 95 % CI = 2.30 , 15.36 ) and 9 months ( OR = 4.09 , 95 % CI = 1.69 , 9.87 ) ; however , group differences in meeting PA guidelines were not maintained . ConclusionS ome positive effects of a home-based PA intervention for breast cancer patients were maintained at 6 and 9 months [17785708] PURPOSE Breast cancer chemotherapy may cause unfavorable changes in physical functioning , body composition , psychosocial functioning , and quality of life ( QOL ) . We evaluated the relative merits of aerobic and resistance exercise in blunting these effects . PATIENTS AND METHODS We conducted a multicenter r and omized controlled trial in Canada between 2003 and 2005 that r and omly assigned 242 breast cancer patients initiating adjuvant chemotherapy to usual care ( n = 82 ) , supervised resistance exercise ( n = 82 ) , or supervised aerobic exercise ( n = 78 ) for the duration of their chemotherapy ( median , 17 weeks ; 95 % CI , 9 to 24 weeks ) . Our primary end point was cancer-specific QOL assessed by the Functional Assessment of Cancer Therapy-Anemia scale . Secondary end points were fatigue , psychosocial functioning , physical fitness , body composition , chemotherapy completion rate , and lymphedema . RESULTS The follow-up assessment rate for our primary end point was 92.1 % , and adherence to the supervised exercise was 70.2 % . Unadjusted and adjusted mixed-model analyses indicated that aerobic exercise was superior to usual care for improving self-esteem ( P = .015 ) , aerobic fitness ( P = .006 ) , and percent body fat ( adjusted P = .076 ) . Resistance exercise was superior to usual care for improving self-esteem ( P = .018 ) , muscular strength ( P < .001 ) , lean body mass ( P = .015 ) , and chemotherapy completion rate ( P = .033 ) . Changes in cancer-specific QOL , fatigue , depression , and anxiety favored the exercise groups but did not reach statistical significance . Exercise did not cause lymphedema or adverse events . CONCLUSION Neither aerobic nor resistance exercise significantly improved cancer-specific QOL in breast cancer patients receiving chemotherapy , but they did improve self-esteem , physical fitness , body composition , and chemotherapy completion rate without causing lymphedema or significant adverse events [11879296] PURPOSE Despite the recognition of fatigue as a common and distressing symptom during cancer treatment , there are few evidence -based interventions available to manage such fatigue . The purpose of this multi-institutional pilot study was to explore the effects of a home-based moderate walking exercise intervention on fatigue , physical functioning , emotional distress , and quality of life ( QOL ) during breast cancer treatment . DESCRIPTION OF STUDY Fifty-two women were recruited from five university hospital outpatient departments for this pilot study with an experimental design . Subjects were r and omly assigned to the walking program or to usual care during adjuvant chemotherapy or radiation therapy for breast cancer . Symptoms , physical functioning , and QOL were measured at baseline , midtreatment , and at the end of treatment . RESULTS Women who exercised at least 90 minutes per week on 3 or more days reported significantly less fatigue and emotional distress as well as higher functional ability and QOL than women who were less active during treatment . CLINICAL IMPLICATION S A home-based walking exercise program is a potentially effective , low-cost , and safe intervention to manage fatigue and to improve QOL during adjuvant chemotherapy or radiation therapy for breast cancer . This health-promoting self-care activity needs further testing in large r and omized clinical trials [15151958] BACKGROUND Anemia is common in cancer and has been associated with fatigue and reduced health-related quality of life ( HRQOL ) . We report the association between hemoglobin and fatigue and the impact of reducing fatigue on several domains of HRQOL . PATIENTS AND METHODS These analyses were based on five r and omized trials . Patients completed the Functional Assessment of Cancer Therapy ( FACT ) Anemia scales and numeric rating scales of Energy , Activity and Overall Health at baseline and after the 12-week treatment period . t-tests and linear regression models were used to evaluate associations . Analyses were stratified into three groups : solid tumor chemotherapy patients , lymphoproliferative malignancy chemotherapy patients and non-chemotherapy patients . RESULTS Adjusted mean differences ( 95 % CI ) in FACT Fatigue change scores between hemoglobin responders ( > or = 2 g/dl increase ) and non-responders were 3.0 ( 1.2 , 4.7 ) , 2.8 ( 0.6 , 5.0 ) and 5.8 ( 2.2 , 9.5 ) among the solid tumor , lymphoproliferative malignancy and non-chemotherapy groups , respectively . Significantly greater improvements ( P < 0.01 ) were observed in the FACT well-being scales for patients with meaningful improvement in fatigue ( FACT Fatigue change score > or =3 points ) . After controlling for other factors , patients whose fatigue improved reported substantially greater improvements in energy , ability to perform usual activities and overall health ( P < 0.0001 ) . CONCLUSIONS Across five trials of cancer patients on and off chemotherapy , hemoglobin response was associated with meaningful improvements in fatigue , which , in turn , was associated with improved physical , functional , emotional and overall well-being [19383889] Purpose : We previously reported the effectiveness of a 12-week physical activity behavior change intervention for breast cancer survivors postintervention with this report , aim ing to determine delayed and /or persistent effects 3 months after intervention completion . Methods : Forty-one sedentary women with stage I , II , or IIIA breast cancer currently receiving hormonal therapy were r and omly assigned to receive the 12-week Better Exercise Adherence after Treatment for Cancer intervention or usual care . Assessment s occurred at baseline , postintervention , and 3 months postintervention . Results : Weekly minutes of greater than or equal to moderate intensity physical activity measured by accelerometer showed a significant group by time interaction ( F = 3.51 ; P = 0.035 ; between group difference in the mean change from baseline to 3 months postintervention , 100.1 minute , P = 0.012 ) . Significant group by time interactions also showed sustained improvements from baseline to 3 months postintervention in strength ( F = 3.82 ; P = 0.027 ; between group difference , 11.2 kg ; P = 0.026 ) , waist-to-hip ratio ( F = 3.36 ; P = 0.041 ; between group difference , −0.04 ; P = 0.094 ) , and social well-being ( F = 4.22 ; P = 0.023 ; between group difference , 3.9 ; P = 0.039 ) . A delayed reduction in lower extremity dysfunction 3 months postintervention was noted ( F = 3.24 ; P = 0.045 ; between group difference in the mean change from postintervention to 3 months follow-up ; P = −7.6 ; P = 0.015 ) . No group by time effect was noted for fitness , body mass index , percent fat , bone density , total quality of life ( Functional Assessment of Cancer Therapy-General ) , fatigue , endocrine symptoms , cognitive function , or sleep . Conclusions : The intervention result ed in sustained improvements in physical activity , strength , central adiposity , and social well-being with lower extremity function benefits appearing 3 months after intervention completion . Testing translation in a multisite study is warranted . ( Cancer Epidemiol Biomarkers Prev 2009;18(5):1410–8 [2762035] Objective To assess the effect of a multimodal group exercise intervention , as an adjunct to conventional care , on fatigue , physical capacity , general wellbeing , physical activity , and quality of life in patients with cancer who were undergoing adjuvant chemotherapy or treatment for advanced disease . Design R and omised controlled trial . Setting Two university hospitals in Copenhagen , Denmark . Participants 269 patients with cancer ; 73 men , 196 women , mean age 47 years ( range 20 - 65 ) representing 21 diagnoses . Main exclusion criteria were brain or bone metastases . 235 patients completed follow-up . Intervention Supervised exercise comprising high intensity cardiovascular and resistance training , relaxation and body awareness training , massage , nine hours weekly for six weeks in addition to conventional care , compared with conventional care . Main outcome measures European Organization for Research and Treatment of Cancer Quality of Life Question naire ( EORTC QLQ-C30 ) , Medical Outcomes Study Short Form ( MOS SF-36 ) , Leisure Time Physical Activity Question naire , muscular strength ( one repetition maximum ) , maximum oxygen consumption ( Vo2max ) . Statistical methods The general linear model was used for continuous outcome while analysis of associates between categorical outcomes was performed as analysis of marginal homogeneity in contingency tables . Results Adjusted for baseline score , disease , and demographic covariates , the intervention group showed an estimated improvement at six weeks for the primary outcome , fatigue , of −6.6 points ( 95 % confidence interval −12.3 to −0.9 , P=0.02 ; effect size=0.33 , 0.04 to 0.61 ) . Significant effects were seen on vitality ( effect size 0.55 , 95 % CI 0.27 to 0.82 ) , physical functioning ( 0.37 , 0.09 to 0.65 ) , role physical ( 0.37 , 0.10 to 0.64 ) , role emotional ( 0.32 , 0.05 to 0.59 ) , and mental health ( 0.28 , 0.02 to 0.56 ) scores . Improvement was noted in physical capacity : estimated mean difference between groups for maximum oxygen consumption was 0.16 l/min ( 95 % CI 0.1 to 0.2 , P<0.0001 ) and for muscular strength ( leg press ) was 29.7 kg ( 23.4 to 34.9 , P<0.0001 ) . No significant effect was seen on global health status/ quality of life . Conclusion A supervised multimodal exercise intervention including high and low intensity components was feasible and could safely be used in patients with various cancers who were receiving adjuvant chemotherapy or treatment for advanced disease . The intervention reduced fatigue and improved vitality , aerobic capacity , muscular strength , and physical and functional activity , and emotional wellbeing , but not quality of life . Trial registration Current Controlled trials IS RCT N05322922 [12560436] PURPOSE To examine the effect of a progressive upper-body exercise program on lymphedema secondary to breast cancer treatment . METHODS Fourteen breast cancer survivors with unilateral upper extremity lymphedema were r and omly assigned to an exercise ( n = 7 ) or control group ( n = 7 ) . The exercise group followed a progressive , 8-week upper-body exercise program consisting of resistance training plus aerobic exercise using a Monark Rehab Trainer arm ergometer . Lymphedema was assessed by arm circumference and measurement of arm volume by water displacement . Patients were evaluated on five occasions over the experimental period . The Medical Outcomes Trust Short-Form 36 Survey was used to measure quality of life before and after the intervention . Significance was set at alpha < or = 0.01 . RESULTS No changes were found in arm circumference or arm volume as a result of the exercise program . Three of the quality -of-life domains showed trends toward increases in the exercise group : physical functioning ( P = .050 ) , general health ( P = .048 ) , and vitality ( P = .023 ) . Mental health increased , although not significantly , for all subjects ( P = .019 ) . Arm volume measured by water displacement was correlated with calculated arm volume ( r = .973 , P < .001 ) , although the exercise and control group means were significantly different ( P < .001 ) . CONCLUSIONS Participation in an upper-body exercise program caused no changes in arm circumference or arm volume in women with lymphedema after breast cancer , and they may have experienced an increase in quality of life . Additional studies should be done in this area to determine the optimum training program [17360236] Fatigue is one of the most frequent side effects of cancer treatments . According to a number of studies , the incidence of fatigue as a side effect of radiation therapy ( RT ) ranges from 65 % to 100 % depending on which instruments were used ( Greenberg et al. , 1992 ; Jacobsen-Thors , 2003 ) . For many cancer patients , cancer-related fatigue is severe and imposes limitations on normal daily activities ( JereczekFossa et al. , 2002 ) . Patients often report that cancerrelated fatigue differs from fatigue experienced before initiation of cancer . They describe it as severe , chronic and frustrating , effects that fail to be relieved by rest . In many studies in the past , patients have felt that fatigue has adversely affected their quality of life more than pain and sexual dysfunction or other treatment-related side effects ( Stone et al. , 1998 ) . Fatigue has negative impact on various aspects of quality of life , so it is imperative to find non-invasive and nonpharmacological solutions for managing it . There is little however known as to which techniques can help alleviate fatigue . Physical exercise has been shown to be effective , convenient and a low-cost self-care method for reducing anxiety and sleep difficulties , and increasing adaptation during radiotherapy . Aerobic exercises ( e.g. walking ) have been suggested for the rehabilitation of cancer patients affected by energy loss but this is not a fully accepted approach as yet . Nevertheless , exercise has been shown [18591167] PURPOSE / OBJECTIVES To compare the effectiveness of a prescribed home-based walking exercise intervention with usual care in older women receiving hormonal treatment for breast cancer , and to examine relationships among levels of the cortisol , serotonin , interleukin-6 , and bilirubin biomarkers and fatigue , sleep disturbances , and depressive symptoms . DESIGN Longitudinal r and omized clinical trial . SETTING A National Cancer Institute- design ated cancer center in the southeastern United States . SAMPLE 20 women ( aged 55 years or older ) with breast cancer receiving hormonal treatment . METHODS Participants were r and omized to a walking exercise intervention or usual care . Laboratory sample s and the Pittsburgh Sleep Quality Index ( PSQI ) , the Piper Revised Fatigue Scale , and the Center for Epidemiological Studies -Depression Scale were collected at the initial clinic visit and at 12 weeks from the groups . Question naires also were collected at weeks 2 and 14 . MAIN RESEARCH VARIABLES Fatigue , sleep disturbances , depressive symptoms , biomarkers , and exercise . FINDINGS Effect of the exercise intervention on sleep scores was highly significant between groups . Exercise group scores on the PSQI decreased significantly over time ( indicating improved sleep quality ) , although scores did not change significantly within the control group . Sleep actigraphy also showed significantly shorter actual wake time and less movement in the exercise group . Serotonin levels also were significantly affected by the intervention . CONCLUSIONS Data suggest that a walking exercise intervention improves sleep in older women receiving hormonal treatment for their breast cancer . Serotonin levels may be a useful biomarker when assessing sleep disturbances in this group . IMPLICATION S FOR NURSING Clinicians need to be aware that older women receiving hormonal treatment for their breast cancer may experience fatigue , sleep disturbances , and depressive symptoms . Homebased walking activity may reduce symptom severity in this group [10548868] Purpose : Fatigue is a common side effect of cancer treatment that impacts quality of life . Exercise is one approach suggested to improve fatigue . The purpose of this study was to explore the relationship of exercise to fatigue and quality of life . Methods : Thirty-one subjects with breast cancer were enrolled prior to beginning chemotherapy and 27 completed the study . All baseline measures were obtained before the first chemotherapy treatment . Subjects were instructed on a home-based , 8-week exercise program . Results : Women who adopted the exercise program ( 60 % ) showed significant increases in functional ability and less weight gain . Exploratory , stepwise multiple regression analyses suggested that the maximum effect of exercise on quality of life outcomes may be mediated by fatigue . Conclusions : The low-to-moderate intensity , home-based exercise program was feasible for some women with breast cancer receiving chemotherapy . The results suggest that exercise may affect quality of life and that this effect may be mediated by the effects of exercise on fatigue . Better retention of functional ability and better weight control are additional possible benefits of exposing breast cancer patients to increased exercise . A r and omized , controlled clinical trial is needed to establish confidence in these observed relationships [17964881] OBJECTIVE To show fatigue prevention and quality of life ( QOL ) improvement from cardiovascular exercise during radiotherapy . DESIGN Prospect i ve enrollment ( n=21 ) , r and omized to exercise ( n=11 ) and control groups ( n=10 ) , with pre- and post-radiotherapy between- and within-group comparisons . SETTING Academic medical center . PARTICIPANTS Localized prostate cancer patients undergoing radiotherapy . INTERVENTIONS The interventional group received radiotherapy plus aerobic exercise 3 times a week for 8 weeks whereas the control group received radiotherapy without exercise . MAIN OUTCOME MEASURES Pre- and post-radiotherapy differences in cardiac fitness , fatigue , depression , functional status , physical , social , and functional well-being , leg strength , and flexibility were examined within and between 2 groups . RESULTS No significant differences existed between 2 groups at pre-radiotherapy assessment . At post-radiotherapy assessment , the exercise group showed significant within group improvements in : cardiac fitness ( P<.001 ) , fatigue ( P=.02 ) , Functional Assessment of Cancer Therapy-Prostate ( FACT-P ) ( P=.04 ) , physical well-being ( P=.002 ) , social well-being ( P=.02 ) , flexibility ( P=.006 ) , and leg strength ( P=.000 ) . Within the control group , there was a significant increase in fatigue score ( P=.004 ) and a decline in social well-being ( P<.05 ) at post-radiotherapy assessment . Between-group differences at post-radiotherapy assessment were significant in cardiac fitness ( P=.006 ) , strength ( P=.000 ) , flexibility ( P<.01 ) , fatigue ( P<.001 ) , FACT-P ( P=.006 ) , physical well-being ( P<.001 ) , social well-being ( P=.002 ) , and functional well-being ( P=.04 ) . CONCLUSIONS An 8-week cardiovascular exercise program in patients with localized prostate cancer undergoing radiotherapy improved cardiovascular fitness , flexibility , muscle strength , and overall QOL and prevented fatigue [17156590] Study objectives . Cancer-related fatigue ( CRF ) is frequently reported by cancer patients receiving cytotoxic drugs . The specific mechanism of CRF in cancer patients is not completely known . In recent years , convincing evidence supports the management of fatigue with physical exercise . This study investigated a recommendation that physical activity , eg , a 30-minute daily walk , would decrease fatigue in cancer patients receiving cytotoxic drugs at an outpatient ward . Method . In total , 89 patients were interviewed about their fatigue and were asked to complete a question naire , the Fatigue Symptom Inventory ( FSI ) , once a week over several treatment cycles of cytotoxic drugs . On inclusion , all patients received similar information about fatigue . After r and omization , information about the positive effects of exercise was given to half of the patients after one cycle of cytotoxic drugs , and to the remaining patients after two cycles of cytotoxic drugs . Results . A total of 74 patients completed the study and returned useable question naires . The fatigue prevalence was 89 % after one cytotoxic drug cycle . According to the FSI ratings , the group who received information about physical exercise after one cycle scored significantly lower ratings than the other group throughout the study ( P=0.034 ) . The patient interviews confirmed that physical activity helped them to better battle fatigue . Intensity of other symptoms and side effects from cytotoxic drugs closely paralleled the fatigue ratings . Conclusion . Fatigue was commonly found in the study population . Though small improvements followed physical exercise , results pointed towards the fact that information and exercise may support patients to combat fatigue . Early and frequent information would probably support patients to better combat fatigue by physical exercise [15774341] This pilot study examined whether exercise as an adjunctive rehabilitation therapy could benefit women who have early stage breast cancer and are currently receiving chemotherapy/radiotherapy . The study was design ed as a r and omised controlled trial ( RCT ) . Physical functioning , fatigue and Quality of Life ( QoL ) outcomes were evaluated pre and post a 12-week intervention . The results showed that after 12 weeks the women who participated in the exercise programme ( n = 12 ) displayed significantly higher levels of physical functioning and reported higher QoL scores than the controls ( n = 10 ) . Changes in fatigue and satisfaction with life favoured the intervention group but did not reach significance . These results are encouraging and suggest that a structured group exercise programme during adjuvant treatment is a safe , well tolerated and effective way of providing physical and psychological health benefits to women during treatment for early stage breast cancer . Since this was a pilot study the numbers did not allow appropriately powered analyses of some variables of interest and favoured relatively young and socio-economically advantaged women . Future studies need to address these issues and determine if these short-term benefits can be sustained [14710804] Fatigue and insomnia are problems for patients with cancer . Research findings show that aerobic exercise decreases cancer-related fatigue . Because patients with cancer who have skeletal muscle wasting may not obtain maximum benefit from aerobic exercise training , exercise programs may need to include resistance training . Thus far , testing exercise as an intervention for fatigue has focused on patients with breast cancer and excluded patients with bone metastasis . There is a need to test the feasibility and effectiveness of exercise for patients with other types of cancer and with bone involvement . The effect of aerobic and strength resistance training on the sleep of patients with cancer has not been tested . A pilot/feasibility study with a r and omized controlled design was conducted to investigate homebased exercise therapy for 24 patients receiving high-dose chemotherapy and autologous peripheral blood stem cell transplantation as treatment for multiple myeloma . None of the patients injured themselves . Because of the small sample size in the feasibility study , the effect of exercise on lean body weight was the only end point that obtained statistical significance . However , the results suggest that an individualized exercise program for patients receiving aggressive treatment for multiple myeloma is feasible and may be effective for decreasing fatigue and mood disturbance , and for improving sleep [18980921] PURPOSE / OBJECTIVES To investigate the effects of supervised exercise training on cardiopulmonary function and fatigue in cancer survivors undergoing various clinical treatments . DESIGN Pretest and post-test quasiexperimental . SETTING Outpatient oncology rehabilitation center . SAMPLE 96 breast cancer survivors undergoing various clinical treatments . METHODS Subjects were divided into four groups based on the specific type of clinical treatment : surgery alone ( n = 22 ) ; surgery and chemotherapy ( n = 30 ) ; surgery and radiation ( n = 17 ) ; and surgery , chemotherapy , and radiation ( n = 27 ) . Following a comprehensive screening and medical examination , cardiovascular endurance , pulmonary function , and fatigue were assessed , leading to the development of an individualized exercise prescription and a six-month exercise intervention . Repeated- measures analysis of variance and covariance were used to compare the effectiveness of the intervention and differences among treatment groups . MAIN RESEARCH VARIABLES Systolic and diastolic blood pressure , resting heart rate , forced vital capacity , forced expiratory volume , predicted oxygen consumption , time on treadmill , and fatigue . FINDINGS Cardiopulmonary function ( predicted maximal oxygen consumption and time on treadmill ) significantly increased in all groups after exercise training . In addition , resting heart rate and forced vital capacity significantly improved in those receiving surgery , chemotherapy , and radiation . Psychologically , the exercise intervention result ed in significant reductions in behavioral , affective , sensory , cognitive and mood , and total fatigue scale scores in all three groups who received treatment with surgery . The breast cancer survivors in the surgery-alone group showed significant reductions in behavioral , affective , and total fatigue scale scores but not in sensory and cognitive and mood fatigue scale scores . CONCLUSIONS The results suggest that moderate intensity , individualized , prescriptive exercise maintains or improves cardiopulmonary function with concomitant reductions in fatigue regardless of treatment type . Moreover , cancer survivors receiving combination chemotherapy and radiotherapy following surgery appear to benefit to a greater extent as a result of an individualized exercise intervention . IMPLICATION S FOR NURSING Clinicians need to be aware of adjuvant therapies such as moderate exercise that attenuate negative side effects of cancer treatments . Symptom management recommendations should be given to cancer survivors concerning the effectiveness of exercise throughout the cancer continuum and the importance of participating in a cancer rehabilitation exercise program [12619144] Exercise participation has been shown to improve cardiovascular fitness and reduce psychological distress among women receiving chemotherapy and /or radiation . The purpose of this pilot study was to examine the changes in distress and body image , and fitness following exercise participation among 24 women who had been diagnosed with breast cancer within the previous 3 years . The women were r and omly assigned to participate in a 12-week supervised aerobic exercise program in a hospital setting or a wait-list control group . Assessment s of distress and body image were conducted at pre- and post-treatment . Data showed that the women in the exercise group improved significantly in body image ( Physical Condition and Weight Concerns subscales ) vs control group participants at post-treatment . Reductions in distress were also noted in the exercise group , but these were nonsignificant . At post-treatment , there were modest improvements in fitness in the exercise group [19242916] OBJECTIVES Restorative yoga ( RY ) is a gentle type of yoga that may be beneficial for cancer patients and post-treatment survivors . Study goals were : to determine the feasibility of implementing a RY intervention for women with breast cancer ; and to examine group differences in self-reported emotional , health-related quality of life , and symptom outcomes . METHODS Women with breast cancer ( n=44 ; mean age 55.8 years ) enrolled in this study ; 34 % were actively undergoing cancer treatment . Study participants were r and omized to the intervention ( 10 weekly 75-minute RY classes ) or a waitlist control group . Participants completed question naires at Week 0 ( baseline ) and Week 10 ( immediately post-intervention for the yoga group ) . RESULTS Group differences favoring the yoga group were seen for mental health , depression , positive affect , and spirituality ( peace/meaning ) . Significant baseline*group interactions were observed for negative affect and emotional well-being . Women with higher negative affect and lower emotional well-being at baseline derived greater benefit from the yoga intervention compared to those with similar values at baseline in the control group . The yoga group demonstrated a significant within-group improvement in fatigue ; no significant difference was noted for the control group . CONCLUSIONS Although limited by sample size , these pilot data suggest potential benefit of RY on emotional outcomes and fatigue in cancer patients . This study demonstrates that a RY intervention is feasible for women with breast cancer ; implication s for study design and implementation are noted with an emphasis on program adoption and participant adherence [20531162] Cheville AL , Girardi J , Clark MM , Rummans TA , Pittelkow T , Brown P , Hanson J , Atherton P , Johnson ME , Sloan JA , Gamble G : Therapeutic exercise during outpatient radiation therapy for advanced cancer : Feasibility and impact on physical well-being . Objective : To characterize the feasibility of delivering a structured physical therapy ( PT ) program as part of a multidisciplinary intervention to patients undergoing outpatient radiation therapy for advanced cancer . Design : A single-blinded , r and omized , controlled trial at a quaternary medical center outpatient clinic . One hundred three adults undergoing radiation therapy for advanced cancer with prognoses ≥6 mos and 5-yr survival estimates ≤50 % were r and omized to usual care or participation in eight 90-min , multidisciplinary interventional sessions with 30 mins of each session devoted to PT . PT consisted of truncal and limb isodynamic strengthening targeting major upper- and lower-limb muscle groups as well as education and provision with instructional material s. Physical well-being and fatigue were assessed with Linear Analog Scale of Assessment . The Profile of Mood States-Short form , including Fatigue-Inertia and Vigor-Activity subscales , was also administered . Results : PT session attendance was 89.3 % . Relative to baseline , mean physical well-being Linear Analog Self Assessment scores at week 4 improved in the intervention group , 0.4 ( SD , 23.6 ) , and declined significantly in the control group , −10.0 ( SD , 21.5 ) ( P = 0.02 ) . Fatigue and vigor were not significantly different between the groups . All intergroup differences had resolved at 8 and 27 wks . Baseline characteristics were not associated with the magnitude or direction of change in outcomes related to physical functioning . Conclusions : Delivery of a st and ardized resistive exercise PT intervention is feasible during outpatient radiation therapy and is associated with preserved physical well-being . However , benefits were not sustained , and fatigue was not affected [18490891] The purpose of this r and omized control trial was to verify the effectiveness of a brief group intervention that combines stress management psycho-education and physical activity ( ie , independent variable ) intervention in reducing fatigue and improving energy level , quality of life ( mental and physical ) , fitness ( VO2submax ) , and emotional distress ( ie , dependent variables ) in breast cancer survivors . This study applied Lazarus and Folkman stress-coping theoretical framework , as well as Salmon 's unifying theory of physical activity . Eighty-seven French-speaking women who had completed their treatments for nonmetastatic breast cancer at a university hospital in Quebec City , Canada , were r and omly assigned to either the group intervention ( experimental ) or the usual-care ( control ) condition . Data were collected at baseline , postintervention , and at 3-month follow-up . The 4-week group intervention was cofacilitated by 2 nurses . Results showed that participants in the intervention group showed greater improvement in fatigue , energy level , and emotional distress at 3-month follow-up , and physical quality of life at postintervention , compared with the participants in the control group . These results suggest that a brief psycho-educational group intervention focusing on active coping strategies and physical activity is beneficial to cancer survivors after breast cancer treatments [19831159] During radiation therapy , cancer patients may report cancer-related fatigue ( CRF ) , which impairs aerobic capacity , strength , muscle mass , and , ultimately , quality of life ( QOL ) . The purpose of this pilot clinical trial was to examine the feasibility and initial efficacy of a home-based aerobic and progressive resistance exercise intervention for aerobic capacity , strength , muscle mass , CRF , and QOL . Daily steps walked ( DSW ) , daily minutes of resistance exercise ( MRE ) , and number of resistance exercise days ( RED ) were assessed to evaluate intervention adherence . Breast and prostate cancer patients ( n = 38 ) beginning radiation therapy were r and omized to undergo 4 weeks of exercise or no exercise . Participants in the exercise group demonstrated good adherence to the exercise intervention , with significantly more DSW , MRE , and RED at post intervention and 3 month follow-up than controls . Participants in the exercise intervention exhibited significantly higher QOL and significantly lower CRF post intervention and at 3-month follow-up than controls . Results of this pilot study provide positive preliminary evidence that exercise during radiation may be beneficial for cancer patients [17505681] CONTEXT AND OBJECTIVE Changes in metabolism have been reported in the majority of patients undergoing cancer treatment , and these are usually characterized by progressive change in body composition . The effects of aerobic exercise programs to combat the cancer and cancer treatment-related side effects , which include the negative changes in body composition , have been extensively reported in the literature . However , few resistance exercise intervention studies have hypothesized that breast cancer patients might benefit from this type of exercise . The purpose of this study was to determine whether exercise protocol s that emphasize resistance training would change body composition and strength in breast cancer patients undergoing treatment . DESIGN AND SETTING R and omized controlled trial , at the Campus Recreation Center and Rocky Mountain Cancer Rehabilitation Institute of the University of Northern Colorado , and the North Colorado Medical Center . METHODS Twenty inactive breast cancer patients were r and omly assigned to a 21-week exercise group ( n = 10 ) or a control group ( n = 10 ) . The exercise group trained at low to moderate intensity for 60 minutes on two days/week . The primary outcome measurements included body composition ( skinfold method ) and muscle strength ( one repetition maximum ) . RESULTS Significant differences in lean body mass , body fat and strength ( p = 0.004 , p = 0.004 , p = 0.025 , respectively ) were observed between the groups at the end of the study . CONCLUSION The results suggest that exercise emphasizing resistance training promotes positive changes in body composition and strength in breast cancer patients undergoing treatment [15378098] PURPOSE / OBJECTIVES To examine the effects of a seated exercise program on fatigue and quality of life ( QOL ) in women with metastatic breast cancer . DESIGN R and omized , controlled , longitudinal trial . SETTING Outpatient clinic of a comprehensive cancer center . SAMPLE Convenience sample of 38 women who were beginning outpatient chemotherapy . METHODS Subjects were r and omized to a control or intervention group ; the intervention was performance of a seated exercise program using home videotape three times per week for four cycles of chemotherapy . All subjects completed the Functional Assessment of Chronic Illness Therapy Fatigue Version IV ( FACIT F ) at baseline and at the time of the next three cycles . Subjects were asked to document the frequency , duration , and intensity of all exercise participation on monthly calendars . MAIN RESEARCH VARIABLES Exercise , fatigue , and QOL . FINDINGS 32 subjects , 16 per group , completed the study follow-up . With a mixed modeling approach , total FACIT F scores for the entire sample declined at a significant rate ( p = 0.003 ) beginning with cycle 3 but at a slower rate for the experimental group ( p = 0.02 ) . Fatigue scores indicated less increase and physical well-being subscale scores showed less decline for the experimental group ( p = 0.008 and p = 0.02 , respectively ) . CONCLUSIONS Women with advanced breast cancer r and omized to the seated exercise intervention had a slower decline in total and physical well-being and less increase in fatigue scores starting with the third cycle of chemotherapy . IMPLICATION S FOR NURSING Seated exercise may be a feasible exercise program for women with advanced cancer for controlling fatigue and improving physical well-being [12183762] PURPOSE / OBJECTIVES To examine the effect of exercise and methylpheni date on fatigue , functional ability , and cognitive function in patients with melanoma . DESIGN Pilot study with comparison to historic controls . SETTING University-based cancer center . SAMPLE 12 patients with melanoma entered and completed the study . The mean age was 44 years . METHOD Eligible patients were recruited before their first dose of interferon-a ( IFN-a ) . Patients were instructed to take 20 mg sustained-release methylpheni date every morning and follow an aerobic exercise program four days a week for 15 - 30 minutes . Measures included a 12-minute walk , the Schwartz Cancer Fatigue Scale , Trail Maker Forms A and B , Medical Outcomes Study 36 Short Form , body weight , and daily logs . Fatigue scores were compared to usual care historical controls with melanoma receiving only IFN-a . MAIN RESEARCH VARIABLES Fatigue , functional ability , and cognitive function . FINDINGS 66 % adhered to exercise and methylpheni date ; all adhered to exercise . Fatigue was lower for the exercise and methylpheni date group than historic controls . Functional ability increased 6 % for all patients and 9 % for the exercise and methylpheni date group . Cognitive function was stable for the exercise and methylpheni date group . The exercise-only group showed marked cognitive slowing . CONCLUSION The combination of aerobic exercise and methylpheni date may have a positive effect on fatigue , cognitive function , and functional ability . A larger sample size and r and omized trial is needed to more rigorously evaluate the results of exercise and methylpheni date alone or in combination . IMPLICATION S FOR NURSING Although further study is needed , a combination of exercise and methylpheni date may be a practical intervention for patients receiving IFN-a for melanoma [20443054] Breast cancer is the most prevalent type of cancer in American women . Exercise appears to diminish many of the side effects result ing from breast cancer and its treatment . Very little research , however , has compared the outcomes of varying lengths of combined aerobic and resistance training exercise interventions on physiological and psychological parameters in breast cancer survivors . The purpose of this study was to compare the physiological and psychological outcomes following 3 and 6 months of exercise in breast cancer survivors . Breast cancer survivors ( N = 114 ) participated in either 3 months of prescriptive , individualized exercise ( 3 M ; n = 29 ) , 6 months of prescriptive , individualized exercise ( 6 M ; n = 68 ) , or served as sedentary controls ( C ; n = 17 ) . Cancer survivors completed a medical evaluation and assessment at baseline followed by a predetermined 3- or 6-month exercise intervention . Cancer survivors in the control group performed no exercise between the initial assessment and 6-month re assessment . Cardiovascular endurance , pulmonary function , muscular endurance , fatigue , and symptoms of depression were assessed at baseline and post intervention . Repeated measures ANCOVA revealed improvements ( P < 0.05 ) in cardiovascular endurance , fatigue , and symptoms of depression in breast cancer survivors undergoing 3- and 6-month individualized exercise interventions . Breast cancer survivors exercising for 6 months showed additional improvements ( P < 0.05 ) in pulmonary function and muscular endurance . Cancer survivors in the control group did not improve in cardiovascular endurance , pulmonary function , muscular endurance , or fatigue . Three months of individualized , prescriptive exercise leads to improved cardiovascular endurance , fatigue , and symptoms of depression in breast cancer survivors . Additional benefits are seen if exercise is continued for a total of 6 months [11898235] PURPOSE Weight gain is a common side effect for women receiving adjuvant chemotherapy and may have negative long-term implication s for survival . The purpose of this study was to examine the effects of aerobic exercise on weight gain in women with breast cancer receiving adjuvant chemotherapy . DESCRIPTION OF STUDY Seventy-eight women who had recently received a diagnosis of breast cancer and who were beginning adjuvant chemotherapy were enrolled in a home-based exercise study during the first four cycles of chemotherapy . Weight change , body mass index , anorexia , nausea , fatigue , caloric expenditure during exercise , and functional ability were recorded . RESULTS Women who adhered to the exercise program maintained their body weight , while nonexercisers steadily gained weight ( P < .05 ) . There were no differences in incidence or intensity of nausea or anorexia between the exercisers and nonexercisers . Women who exercised over the four cycles of chemotherapy improved their functional ability ( mean 23 % ) compared to the nonexercisers who showed significant declines in functional ability ( mean -15 % ) . CLINICAL IMPLICATION S Exercise may be an effective intervention to minimize weight gain in women with breast cancer who are receiving adjuvant chemotherapy . Preventing weight gain in these patients may be important in preventing recurrent disease and other comorbidities associated with excess weight [14982314] We conducted a r and omized controlled trial to determine the effects of a home-based exercise intervention on change in quality of life ( QOL ) in recently resected colorectal cancer survivors , most of whom were receiving adjuvant therapy . Participants were r and omly assigned in a 2:1 ratio to either an exercise ( n = 69 ) or control ( n = 33 ) group . The exercise group was asked to perform moderate intensity exercise 3 - 5 times per week for 20 - 30 min each time . The primary outcome was change in QOL as measured by the Functional Assessment of Cancer Therapy-Colorectal ( FACT-C ) scale . Adherence in the exercise group was good ( 75.8 % ) but contamination in the control group was problematic ( 51.6 % ) . Intention-to-treat analysis revealed no significant differences between groups for change in the FACT-C ( mean difference , -1.3 ; 95 % CI , -7.8 to 5.1 ; P = 0.679 ) . In an ' on-treatment ' ancillary analysis , we compared participants who decreased versus increased their cardiovascular fitness over the course of the intervention . This analysis revealed significant differences in favour of the increased fitness group for the FACT-C ( mean difference , 6.5 ; 95 % CI , 0.4 - 12.6 ; P = 0.038 ) . These data suggest that increased cardiovascular fitness is associated with improvements in QOL in colorectal cancer survivors but better controlled trials are needed [19214594] Goal of workBreast cancer survivors have limited options for the treatment of hot flashes and related symptoms . Further , therapies widely used to prevent recurrence in survivors , such as tamoxifen , tend to induce or exacerbate menopausal symptoms . The aim of this preliminary , r and omized controlled trial was to evaluate the effects of a yoga intervention on menopausal symptoms in a sample of survivors of early-stage breast cancer ( stages IA – IIB ) . Material s and methods Thirty-seven disease-free women experiencing hot flashes were r and omized to the 8-week Yoga of Awareness program ( gentle yoga poses , meditation , and breathing exercises ) or to wait-list control . The primary outcome was daily reports of hot flashes collected at baseline , posttreatment , and 3 months after treatment via an interactive telephone system . Data were analyzed by intention to treat . Main results At posttreatment , women who received the yoga program showed significantly greater improvements relative to the control condition in hot-flash frequency , severity , and total scores and in levels of joint pain , fatigue , sleep disturbance , symptom-related bother , and vigor . At 3 months follow-up , patients maintained their treatment gains in hot flashes , joint pain , fatigue , symptom-related bother , and vigor and showed additional significant gains in negative mood , relaxation , and acceptance . Conclusions This pilot study provides promising support for the beneficial effects of a comprehensive yoga program for hot flashes and other menopausal symptoms in early-stage breast cancer survivors [9128987] Fatigue and loss of physical performance are frequent problems of cancer patients . In a pilot study , the authors evaluated the feasibility and effects of aerobic training in the rehabilitation of cancer patients after completing high dose chemotherapy [10732535] OBJECTIVES Cancer treatment-related fatigue is a common and disruptive side effect of chemotherapy . Exercise is an intervention proposed to reduce fatigue in cancer patients . The purpose of this study was to describe the patterns of daily fatigue in women with breast cancer who did and did not exercise while receiving the first three cycles of adjuvant chemotherapy . MATERIAL S AND METHODS Women received instruction to follow an 8-week home-based exercise program and to maintain daily exercise and fatigue diaries . Functional ability ( 12-minute walk ) was measured pretest and post-test . RESULTS Several distinct patterns of fatigue emerged . The most common pattern of fatigue after chemotherapy demonstrated a sharp rise in fatigue . However , several women demonstrated a chaotic pattern with erratic and wide swings in their fatigue throughout the entire study period . Women who adopted exercise experienced fewer days of high fatigue levels and more days of low levels of fatigue for both average and worst levels of fatigue . Women who did not exercise experienced more bad days ( high fatigue ) and fewer good days ( low fatigue ) . CONCLUSIONS Exercise appears to reduce the levels of average and worst fatigue and may help women recognize their pattern of fatigue . Exercise may reduce the intensity of fatigue by reorganizing women 's interpretation of fatigue . Routine clinical assessment and education about fatigue by health professionals can help patients to underst and their pattern of fatigue and may help them to manage the symptom [12721238] PURPOSE And rogen deprivation therapy is a common treatment in men with prostate cancer that may cause fatigue , functional decline , increased body fatness , and loss of lean body tissue . These physical changes can negatively affect health-related quality of life . Resistance exercise may help to counter some of these side effects by reducing fatigue , elevating mood , building muscle mass , and reducing body fat . METHODS In a two-site study , 155 men with prostate cancer who were scheduled to receive and rogen deprivation therapy for at least 3 months after recruitment were r and omly assigned to an intervention group that participated in a resistance exercise program three times per week for 12 weeks ( 82 men ) or to a waiting list control group ( 73 men ) . The primary outcomes were fatigue and disease-specific quality of life as assessed by self-reported question naires after 12 weeks . Secondary outcomes were muscular fitness and body composition . RESULTS Men assigned to resistance exercise had less interference from fatigue on activities of daily living ( P = .002 ) and higher quality of life ( P = .001 ) than men in the control group . Men in the intervention group demonstrated higher levels of upper body ( P = .009 ) and lower body ( P < .001 ) muscular fitness than men in the control group . The 12-week resistance exercise intervention did not improve body composition as measured by changes in body weight , body mass index , waist circumference , or subcutaneous skinfolds . CONCLUSION Resistance exercise reduces fatigue and improves quality of life and muscular fitness in men with prostate cancer receiving and rogen deprivation therapy . This form of exercise can be an important component of supportive care for these patients [15908668] PURPOSE The efficacy of a home-based physical activity ( PA ) intervention for early-stage breast cancer patients was evaluated in a r and omized controlled trial . PATIENTS AND METHODS Eighty-six sedentary women ( mean age , 53.14 years ; st and ard deviation , 9.70 years ) who had completed treatment for stage 0 to II breast cancer were r and omly assigned to a PA or contact control group . Participants in the PA group received 12 weeks of PA counseling ( based on the Transtheoretical Model ) delivered via telephone , as well as weekly exercise tip sheets . Assessment s were conducted at baseline , after treatment ( 12 weeks ) , and 6 and 9 month after baseline follow-ups . The post-treatment outcomes are reported here . RESULTS Analyses showed that , after treatment , the PA group reported significantly more total minutes of PA , more minutes of moderate-intensity PA , and higher energy expenditure per week than controls . The PA group also out-performed controls on a field test of fitness . Changes in PA were not reflected in objective activity monitoring . The PA group was more likely than controls to progress in motivational readiness for PA and to meet PA guidelines . No significant group differences were found in body mass index and percent body fat . Post-treatment group comparisons revealed significant improvements in vigor and a reduction in fatigue in the PA group . There was a positive trend in intervention effects on overall mood and body esteem . CONCLUSION The intervention successfully increased PA and improved fitness and specific aspects of psychological well-being among early-stage breast cancer patients . The success of a home-based PA intervention has important implication s for promoting recovery in this population [15800330] PURPOSE To evaluate the effectiveness of a supervised home-based flexible training program on cardiorespiratory fitness ( CRF ) , mental distress , and health-related quality of life ( HRQOL ) parameters in young and middle-aged cancer patients shortly after curative chemotherapy . PATIENTS AND METHODS One hundred eleven patients age 18 to 50 years who had received chemotherapy for lymphomas or breast , gynecologic , or testicular cancer completed the trial . These patients were r and omly allocated to either an intervention group ( n = 59 ) , which underwent a 14-week training program , or a control group ( n = 52 ) that received st and ard care . Primary outcome was change in CRF , as determined by Astr and -Rhyming indirect bicycle ergometer test ( maximum oxygen uptake [ VO(2max ) ] ) , between baseline ( T0 ) and follow-up ( T1 ) . Secondary outcomes were mental distress , as assessed by the Hospital Anxiety and Depression Scale , and HRQOL , as assessed by the European Organisation for Research and Treatment of Cancer Core Quality of Life Question naire . Two-way analysis of covariance was used to analyze changes from T0 to T1 . RESULTS VO(2max ) increased by 6.4 mL/kg(-1)/min(-1 ) in patients in the intervention group and by 3.1 mL/kg(-1)/min(-1 ) in patients in the control group ( P < .01 ) . The fatigue score decreased by 17.0 points in the control group compared with only 5.8 points in the intervention group ( P < .01 ) . There were no intergroup differences in mental distress or HRQOL . CONCLUSION A supervised , home-based , flexible training program has significant effect on CRF in young and middle-aged cancer patients shortly after curative chemotherapy , but it has no favorable effect on patients ' experience of fatigue , mental distress , or HRQOL [16446335] PURPOSE The primary goal of this study was to evaluate the feasibility and effectiveness of a structured , multidisciplinary intervention targeted to maintain the overall quality of life ( QOL ) , which is more comprehensive than psychosocial distress , of patients undergoing radiation therapy for advanced-stage cancer . PATIENTS AND METHODS Radiation therapy patients with advanced cancer and an estimated 5-year survival rate of 0 % to 50 % were r and omly assigned to either an eight-session structured multidisciplinary intervention arm or a st and ard care arm . The eight 90-minute sessions addressed the five domains of QOL including cognitive , physical , emotional , spiritual , and social functioning . The primary end point of maintaining overall QOL was assessed by a single-item linear analog scale ( Linear Analog Scale of Assessment or modified Spitzer Uniscale ) . QOL was assessed at baseline , week 4 ( end of multidisciplinary intervention ) , week 8 , and week 27 . RESULTS Of the 103 participants , overall QOL at week 4 was maintained by the patients in the intervention ( n = 49 ) , whereas QOL at week 4 significantly decreased for patients in the control group ( n = 54 ) . This change reflected a 3-point increase from baseline in the intervention group and a 9-point decrease from baseline in the control group ( P = .009 ) . Intervention participants maintained their QOL , and controls gradually returned to baseline by the end of the 6-month follow-up period . CONCLUSION Although intervention participants maintained and actually improved their QOL during radiation therapy , control participants experienced a significant decrease in their QOL . Thus , a structured multidisciplinary intervention can help maintain or even improve QOL in patients with advanced cancer who are undergoing cancer treatment [20388445] This study examined the effects of yoga on quality of life ( QOL ) and psychosocial outcomes in women with breast cancer undergoing radiotherapy . Sixty-one women were r and omly assigned to either a yoga or a wait-list group . Yoga classes were taught biweekly during the 6 weeks of radiotherapy . Participants completed measures of QOL , fatigue , benefit finding ( finding meaning in the cancer experience ) , intrusive thoughts , sleep disturbances , depressive symptoms , and anxiety before radiotherapy and then again 1 week , 1 month , and 3 months after the end of radiotherapy . General linear model analyses revealed that compared to the control group , the yoga group reported significantly better general health perception ( p = .005 ) and physical functioning scores ( p = .04 ) 1 week postradiotherapy ; higher levels of intrusive thoughts 1 month postradiotherapy ( p = .01 ) ; and greater benefit finding 3 months postradiotherapy ( p = .01 ) . There were no other group differences in other QOL subscales for fatigue , depression , or sleep scores . Exploratory analyses indicated that intrusive thoughts 1 month after radiotherapy were significantly positively correlated with benefit finding 3 months after radiotherapy ( r = .36 , p = .011 ) . Our results indicated that the yoga program was associated with statistically and clinical ly significant improvements in aspects of QOL [19345060] Studies applying exercise , relaxation training , and psychoeducation have each indicated a positive impact on physical performance and /or psychological factors in patients diagnosed with cancer . We explored the longitudinal effect of a combination of these interventions on treatment-related symptoms in patients undergoing myeloablative allogeneic hematopoietic stem cell transplantation ( allo-HSCT ) . Forty-two patients ( 18 - 65 years ) were r and omized either to an intervention or a control group . The intervention group received st and ard treatment and care , and a supervised four- to six-week structured exercise program , progressive relaxation , and psychoeducation during hospitalization , one hour per day for five days per week . The control group received st and ard treatment , care , and physiotherapy . A 24-item symptom assessment question naire was completed weekly during hospitalization , and at three and six months after allo-HCST . Through principal component analysis with varimax rotation , individual symptoms were grouped into five symptom clusters : mucositis , cognitive , gastrointestinal , affective , and functional symptom clusters . Then , a subsequent general estimate equation analysis revealed similar longitudinal patterns of intensity in all symptom clusters for intervention and control groups , but in the intervention group , there was an overall significant reduction ( P<0.05 ) in symptom intensity over time for all clusters except the affective symptom cluster . This study provides beginning evidence for the efficacy of an exercise-based multimodal intervention in reducing the intensity of a spectrum of symptoms in this small sample of patients undergoing allo-HSCT [19234513] The aim of this r and omized controlled trial was to investigate the effect of a 4- to 6-week multimodal program of exercise , relaxation and psychoeducation on physical capacity , functional performance and quality of life ( QOL ) in allogeneic hematopoietic cell transplantation ( allo-HSCT ) adult recipients . In all , 42 patients were r and omized to a supervised multimodal intervention or to a control group receiving usual care . The primary end point was on aerobic capacity measured in VO2 max . Secondary end points were muscle strength , functional performance , physical activity level , QOL , fatigue , psychological well-being and clinical outcomes . The multimodal intervention had a significant effect on physical capacity : VO2 max ( P<0.0001 ) and muscle strength : chest press ( P<0.0001 ) , leg extension ( P=0.0003 ) , right elbow flexor ( P=0.0009 ) , right knee extensor ( P<0.0001 ) and functional performance ( stair test ) ( 0.0008 ) . Moreover , the intervention group showed significantly better results for the severity of diarrhea ( P=0.014 ) and fewer days of total parenteral nutrition ( P=0.019 ) . Longitudinal changes in QOL , fatigue and psychological well-being favored the intervention group , but did not reach statistical significance . Assignment of a multimodal intervention during allo-HSCT did not cause untoward events , sustained aerobic capacity and muscle strength and reduced loss of functional performance during hospitalization [19687337] PURPOSE Lymphoma patients commonly experience declines in physical functioning and quality of life ( QoL ) that may be reversed with exercise training . PATIENTS AND METHODS We conducted a r and omized controlled trial in Edmonton , Alberta , Canada , between 2005 and 2008 that stratified 122 lymphoma patients by major disease type and current treatment status and r and omly assigned them to usual care ( UC ; n = 62 ) or 12 weeks of supervised aerobic exercise training ( AET ; n = 60 ) . Our primary end point was patient-rated physical functioning assessed by the Trial Outcome Index-Anemia . Secondary end points were overall QoL , psychosocial functioning , cardiovascular fitness , and body composition . RESULTS Follow-up assessment for our primary end point was 96 % ( 117 of 122 ) at postintervention and 90 % ( 110 of 122 ) at 6-month follow-up . Median adherence to the supervised exercise program was 92 % . At postintervention , AET was superior to UC for patient-rated physical functioning ( mean group difference , + 9.0 ; 95 % CI , 2.0 to 16.0 ; P = .012 ) , overall QoL ( P = .021 ) , fatigue ( P = .013 ) , happiness ( P = .004 ) , depression ( P = .005 ) , general health ( P < .001 ) , cardiovascular fitness ( P < .001 ) , and lean body mass ( P = .008 ) . Change in peak cardiovascular fitness mediated the change in patient-rated physical functioning . AET did not interfere with chemotherapy completion rate or treatment response . At 6-month follow-up , AET was still borderline or significantly superior to UC for overall QoL ( P = .054 ) , happiness ( P = .034 ) , and depression ( P = .009 ) without an increased risk of disease recurrence/progression . CONCLUSION AET significantly improved important patient-rated outcomes and objective physical functioning in lymphoma patients without interfering with medical treatments or response . Exercise training to improve cardiovascular fitness should be considered in the management of lymphoma patients [17761636] This investigation determined the cardiopulmonary function and fatigue alterations in male cancer survivors during treatment as well as following treatment utilizing similar exercise assessment protocol s and individualized , prescriptive exercise interventions . The study included 45 male cancer survivors that were referred by local oncologists . Following a comprehensive screening and physical examination , cardiovascular endurance , pulmonary function , and fatigue were assessed leading to the development of 12-week individualized exercise prescriptions and exercise interventions . The cancer survivors were divided into during treatment ( DTm ) and following treatment ( FTm ) groups . Repeated- measures analysis of variance and analyses of covariance were used to compare pre- versus postintervention and between groups . Cardiopulmonary function was maintained in the DTm , whereas the FTm showed significant reductions in resting heart rate ( P < .05 ) with concurrent increases in predicted VO2max and time on treadmill ( P < .05 ) postexercise intervention . Fatigue levels did not increase in the DTm group , whereas the FTm group showed significant reductions in behavioral fatigue , affective fatigue , sensory fatigue , cognitive/mood fatigue , and total fatigue ( P < .05 ) after the exercise intervention . The results of the current study suggest that moderate intensity , individualized , prescriptive exercise intervention maintains or improves cardiovascular and pulmonary function with concomitant reductions in fatigue in cancer survivors during and following cancer treatment . Exercise appears to be a safe , efficacious strategy for improving physical fitness in cancer survivors during and following treatment [17582616] Cancer treatments have serious physiological and psychological side effects in cancer survivors . This investigation examined cardiopulmonary function and fatigue in breast cancer survivors during and after treatment by using similar exercise assessment s , prescriptions , individualized interventions , and re assessment [14603549] Physical exercise is becoming an accepted part of therapy for many patients with cancer . Exercise may alleviate patients ' fatigue and improve physical performance and psychological outlook . Much of the research is limited to women with breast cancer and excludes patients with bone metastases . This article reports on the authors ' work in facilitating exercise adherence for patients with multiple myeloma ( MM ) and bone lesions while they were enrolled in a feasibility/pilot exercise study as they were receiving treatment for their disease in an outpatient treatment program . The exercise program for these patients receiving high-dose chemotherapy and stem cell transplantation consisted of aerobic and strength-building components . The program was home based , and patients performed exercises without direct supervision . On average , the patients completed the six-month exercise prescription 75 % of the time . Overall trends showed that all 14 patients in the exercise group improved in several areas of testing , and the test results of all 10 patients in the usual-care group declined . Flexibility and simplicity are essential when design ing exercise programs for patients , and encouragement and support also are needed to help patients adhere to prescribed exercise [17785709] PURPOSE This study examines the impact of yoga , including physical poses , breathing , and meditation exercises , on quality of life ( QOL ) , fatigue , distressed mood , and spiritual well-being among a multiethnic sample of breast cancer patients . PATIENTS AND METHODS One hundred twenty-eight patients ( 42 % African American , 31 % Hispanic ) recruited from an urban cancer center were r and omly assigned ( 2:1 ratio ) to a 12-week yoga intervention ( n = 84 ) or a 12-week waitlist control group ( n = 44 ) . Changes in QOL ( eg , Functional Assessment of Cancer Therapy ) from before r and om assignment ( T1 ) to the 3-month follow-up ( T3 ) were examined ; predictors of adherence were also assessed . Nearly half of all patients were receiving medical treatment . RESULTS Regression analyses indicated that the control group had a greater decrease in social well-being compared with the intervention group after controlling for baseline social well-being and covariates ( P < .0001 ) . Secondary analyses of 71 patients not receiving chemotherapy during the intervention period indicated favorable outcomes for the intervention group compared with the control group in overall QOL ( P < .008 ) , emotional well-being ( P < .015 ) , social well-being ( P < .004 ) , spiritual well-being ( P < .009 ) , and distressed mood ( P < .031 ) . Sixty-nine percent of intervention participants attended classes ( mean number of classes attended by active class participants = 7.00 + /- 3.80 ) , with lower adherence associated with increased fatigue ( P < .001 ) , radiotherapy ( P < .0001 ) , younger age ( P < .008 ) , and no antiestrogen therapy ( P < .02 ) . CONCLUSION Despite limited adherence , this intent-to-treat analysis suggests that yoga is associated with beneficial effects on social functioning among a medically diverse sample of breast cancer survivors . Among patients not receiving chemotherapy , yoga appears to enhance emotional well-being and mood and may serve to buffer deterioration in both overall and specific domains of QOL [19942188] OBJECTIVES To determine the feasibility of an eccentric resistance exercise training protocol in men with prostate cancer and to assess whether men with prostate cancer who are receiving and rogen deprivation therapy ( ADT ) have a blunted effect from the training as compared with prostate cancer survivors not receiving ADT . DESIGN Prospect i ve pilot study . SETTING Academic medical center . PARTICIPANTS Sixteen men with prostate cancer ( Gleason scores 3 + 3 to 4 + 4 ) were initially enrolled . Ten men ( mean age 66 , range 48 - 86 ) completed the study , 5 were currently receiving ADT . Analysis was performed on these 10 men . INTERVENTIONS Subjects were evaluated at baseline . All men underwent a 12-week resistance exercise training protocol using a recumbent , high-force eccentric , leg cycle ergometer 3 times per week at a " somewhat hard " perceived exertion for 12 to 15 minutes . Preexercise and postexercise training changes were examined within and between groups . MAIN OUTCOME MEASURES Quadriceps muscle volume ( magnetic resonance imaging ) , isometric knee extension strength , functional mobility ( Timed Up and Go Test [ TUG ] and 6-minute walk [ 6MW ] ) , health-related quality of life ( FACT-P ) , and fatigue ( FACIT-fatigue scale ) . RESULTS The ADT group demonstrated significant within-group improvements in the 6MW ( P = .01 ) and isometric knee extension strength ( P = .03 ) . This group also demonstrated a clinical ly relevant change in the FACT-P ; however , this did not meet statistical significance . The non-ADT group demonstrated significant within-group improvements in the physical subscale of the FACT-P ( P = .03 ) and an increase in muscle volume ( P = .04 ) . Their improvements in the TUG approached significance ( P = .08 ) . No between-group differences existed . CONCLUSIONS Eccentric resistance exercise was well tolerated , and both groups derived some benefits in strength and functional mobility . Men receiving ADT did not appear to have a blunted response to the exercise as compared with prostate cancer survivors not receiving ADT [16462503] Background : Fatigue has a significant impact on the quality of life ( QOL ) of cancer patients . Recent research has suggested that physical activity can reduce fatigue in patients receiving active cancer treatment . In this project , we examined the impact that participation in a r and omized controlled trial of a multidisciplinary intervention design ed to impact overall QOL had on fatigue for advanced cancer patients actively receiving treatment . Methods : Patients with newly diagnosed cancer were r and omly assigned to an 8-session structured multidisciplinary intervention or a st and ard-care arm at the beginning of their course of radiotherapy ( RT ) design ed to impact QOL . Ninety-minute sessions were led by either a psychiatrist or psychologist , collaborating with a nurse , physical therapist , chaplain , or social worker , depending on the session 's theme . The fatigue assessment s used in this trial included the Linear Analogue Self Assessment ( LASA ) , the Profile of Mood States ( POMS ) , Spielberger 's State-Trait Anxiety Inventory ( STAI ) , and the Symptom Distress Scale ( SDS ) . Results : There were 115 participants enrolled and the 2 r and omization arms were well balanced in terms of baseline characteristics and treatment received except for increased commuting distance for the patients in the intervention arm ( P = 0.042 ) . Most of scores indicated less fatigue ( higher score ) in the st and ard treatment group , but there were no statistically significant differences found at baseline and weeks 4 , 8 , and 27 except for SDS at week 8 ( P = 0.018 ) with less patients reporting significant fatigue in the st and ard treatment arm . For the entire participant population , fatigue levels initially worsened with radiotherapy , stabilized at week 8 , and returned to baseline by week 27 . Disease site , chemotherapy use , and radiotherapy dose did not have a significant impact on fatigue levels . Conclusions : Radiotherapy initially caused a worsening of fatigue but with time fatigue levels returned to baseline . Clinical ly , this structured multidisciplinary intervention had no impact on fatigue , and there was the suggestion the multiple sessions may have contributed to worse fatigue during active cancer treatment [20530648] Objective : To examine the effects of a scapula-oriented exercise on upper limb dysfunction in breast cancer survivors . Study design : A prospect i ve r and omized , controlled pilot trial with historical control . Setting : Rehabilitation department at a university hospital . Subjects : Thirty-two women with breast cancer were r and omly assigned to scapula-oriented exercise group ( n = 16 ) and general exercise group ( n = 16 ) . An historical control group ( n = 18 ) without exercise was enrolled from breast cancer survivors . Interventions : The scapula-oriented exercises were design ed focusing on scapulothoracic movement . The general exercise group performed body conditioning exercise . Exercise therapies were performed for one session per week for eight weeks . Main outcome measures : Pain and physical disabilities related to upper limb dysfunction , quality of life and depression were used as subjective outcomes . Objective outcome measures included shoulder range of motion and strength . Outcomes were assessed at baseline and post exercise . Results : At baseline , no significant difference was observed among the three groups . The scapula-oriented exercise group showed improvements in pain , physical function , social function , and global quality of life compared with baseline , whereas the general exercise group showed improved fatigue and range of motion . The change in global quality of life ( P = 0.067 ; effect size , 0.33 ) and strength of external rotation ( P = 0.001 ; effect size , 0.55 ) were significantly greater in the scapula-oriented exercise group than in the general exercise and control group . Conclusion : Scapula-oriented exercise had beneficial effects on pain , quality of life and aspects of strength . The sample size required in a larger definitive study is 32 subjects per group [2587289] The effect of a 10-week aerobic interval-training cycle ergometer protocol on the functional capacity ( VO2Lmax ) of 45 women receiving chemotherapy for treatment of Stage II breast cancer was studied . Subjects were stratified by baseline functional capacity ( ± 1 MET ) and r and omized to experimental ( EX ) , placebo ( PL ) , and control ( CO ) groups . EX subjects completed a 10-week , 3 times/week exercise training program ; PL subjects participated in 10 weeks of nonaerobic stretching and flexibility exercises ; the CO group maintained normal activities . The EX group showed significant , p < .05 , improvement on pre- to posttest VO2Lmax as well as workload and test time compared to the PL and CO groups . The interval-training exercise intervention was effective in improving the functional capacity of Stage II breast cancer patients on adjuvant chemotherapy [12748973] Physical exercise has been shown to enhance quality of life ( QOL ) in cancer survivors using pretest-posttest design s and compared to usual care ( i.e. no intervention ) . In the present study , we conducted a r and omized controlled trial to determine if exercise could improve QOL in cancer survivors beyond the known benefits of group psychotherapy ( GP ) . We matched 22 GP classes ( N=108 ) on content and then r and omly assigned 11 ( n=48 ) to GP alone and 11 ( n=60 ) to GP plus home-based , moderate-intensity exercise ( GP+EX ) . Participants completed a physical fitness test and QOL measures ( e.g. Functional Assessment of Cancer Therapy scales ) at the beginning and end of GP classes ( about 10 weeks ) . We had excellent recruitment ( 81 % ) , retention ( 89 % ) , and adherence ( 84 % ) rates and a modest contamination ( 22 % ) rate . Using intention-to-treat repeated measures analyses of variance , we found significant Time by Condition interactions for functional well-being , fatigue , and sum of skinfolds . We also found borderline significant interactions for physical well-being , satisfaction with life , and flexibility . All interactions favored the GP+EX condition . We conclude that a home-based , moderate intensity exercise program may im-prove QOL in cancer survivors beyond the benefits of GP , particularly in relation to physical and functional well-being [10326708] Fatigue is a common and often severe problem in cancer patients undergoing chemotherapy . The authors postulated that physical activity training can reduce the intensity of fatigue in this group of patients [15484202] Fatigue is the most prevalent and debilitating symptom experienced by breast cancer patients receiving adjuvant chemotherapy or radiation therapy and few evidence -based treatments are available to manage this distressing side-effect . The purpose of this multi-institutional r and omized controlled trial was to determine the effects of exercise on fatigue levels during treatment for breast cancer . Sedentary women ( N=119 ) with Stage 0-III breast cancer receiving outpatient adjuvant chemotherapy or radiation therapy were r and omized to a home-based moderate-intensity walking exercise program or to usual care for the duration of their cancer treatment . Of participants r and omized to exercise , 72 % adhered to the exercise prescription ; 61 % of the usual care group adhered . The intention-to-treat analysis revealed no group differences in part because of a dilution of treatment effect as 39 % of the usual care group exercised and 28 % of the exercise group did not . When exercise participation was considered using the data analysis method of instrumental variables with principal stratification , a clinical ly important and statistically significant ( p=0.03 ) effect of exercise on pretest-to-posttest change in fatigue levels was demonstrated . Adherence to a home-based moderate-intensity walking exercise program may effectively mitigate the high levels of fatigue prevalent during cancer treatment [19064985] PURPOSE Radiotherapy for prostate cancer ( PCa ) may cause unfavorable changes in fatigue , quality of life ( QOL ) , and physical fitness . We report results from the Prostate Cancer Radiotherapy and Exercise Versus Normal Treatment study examining the effects of 24 weeks of resistance or aerobic training versus usual care on fatigue , QOL , physical fitness , body composition , prostate-specific antigen , testosterone , hemoglobin , and lipid levels in men with PCa receiving radiotherapy . PATIENTS AND METHODS Between 2003 and 2006 , we conducted a r and omized controlled trial in Ottawa , Canada , where 121 PCa patients initiating radiotherapy with or without and rogen deprivation therapy were r and omly assigned to usual care ( n = 41 ) , resistance ( n = 40 ) , or aerobic exercise ( n = 40 ) for 24 weeks . Our primary end point was fatigue assessed by the Functional Assessment of Cancer Therapy-Fatigue scale . RESULTS The follow-up assessment rate for our primary end point of fatigue was 92.6 % . Median adherence to prescribed exercise was 85.5 % . Mixed-model repeated measures analyses indicated both resistance ( P = .010 ) and aerobic exercise ( P = .004 ) mitigated fatigue over the short term . Resistance exercise also produced longer-term improvements ( P = .002 ) . Compared with usual care , resistance training improved QOL ( P = .015 ) , aerobic fitness ( P = .041 ) , upper- ( P < .001 ) and lower-body ( P < .001 ) strength , and triglycerides ( P = .036 ) , while preventing an increase in body fat ( P = .049 ) . Aerobic training also improved fitness ( P = .052 ) . One serious adverse event occurred in the group that performed aerobic exercise . CONCLUSION In the short term , both resistance and aerobic exercise mitigated fatigue in men with PCa receiving radiotherapy . Resistance exercise generated longer-term improvements and additional benefits for QOL , strength , triglycerides , and body fat [20930100] BACKGROUND Two interventions for fatigue were given during curative cancer treatment . The aim of this multicenter r and omized controlled trial ( RCT ) with three conditions was to demonstrate the efficacy and to determine the contribution of physical activity . METHODS Recruited from seven hospitals , 220 patients with various malignancies participated in a RCT . The brief nursing intervention ( BNI ) consisted of two 1-hour sessions , 3 months apart , given by 12 trained nurses , focusing only on physical activity . Cognitive behavior therapy ( CBT ) consisted of up to ten 1-hour sessions , within 6 months , provided by two therapists , focusing on physical activity and psychosocial elements . The control group received only usual care ( UC ) . Assessment s took place before and at least 2 months after cancer treatment , when patients had recovered from acute fatigue . Fatigue was the primary outcome . Efficacy was tested using analyses of covariance . A nonparametric bootstrap approach was used to test whether the effect on fatigue was mediated by physical activity . RESULTS The CBT group was significantly less fatigued than the UC group . Between the BNI and the UC groups , no significant difference was found in fatigue . The mediation hypothesis was rejected . DISCUSSION CBT given during curative cancer treatment proved to be an effective intervention to reduce fatigue at least 2 months after cancer treatment . The BNI was not effective . Contrary to what was expected , physical activity did not mediate the effect of CBT on fatigue . Thus , the reduction in fatigue elicited by CBT was realized without a lasting increase in physical activity [20651011] Background Research suggests that cancer rehabilitation reduces fatigue in survivors of cancer . To date , it is unclear what type of rehabilitation is most beneficial . Objective This r and omized controlled trial compared the effect on cancer-related fatigue of physical training combined with cognitive behavioral therapy with physical training alone and with no intervention . Design In this multicenter r and omized controlled trial , 147 survivors of cancer were r and omly assigned to a group that received physical training combined with cognitive-behavioral therapy ( PT+CBT group , n=76 ) or to a group that received physical training alone ( PT group , n=71 ) . In addition , a nonintervention control group ( WLC group ) consisting of 62 survivors of cancer who were on the waiting lists of rehabilitation centers elsewhere was included . Setting The study was conducted at 4 rehabilitation centers in the Netherl and s. Patients All patients were survivors of cancer . Intervention Physical training consisting of 2 hours of individual training and group sports took place twice weekly , and cognitive-behavioral therapy took place once weekly for 2 hours . Measurements Fatigue was assessed with the Multidimensional Fatigue Inventory before and immediately after intervention ( 12 weeks after enrollment ) . The WLC group completed question naires at the same time points . Results Baseline fatigue did not differ significantly among the 3 groups . Over time , levels of fatigue significantly decreased in all domains in all groups , except in mental fatigue in the WLC group . Analyses of variance of postintervention fatigue showed statistically significant group effects on general fatigue , on physical and mental fatigue , and on reduced activation but not on reduced motivation . Compared with the WLC group , the PT group reported significantly greater decline in 4 domains of fatigue , whereas the PT+CBT group reported significantly greater decline in physical fatigue only . No significant differences in decline in fatigue were found between the PT+CBT and PT groups . Conclusions Physical training combined with cognitive-behavioral therapy and physical training alone had significant and beneficial effects on fatigue compared with no intervention . Physical training was equally effective as or more effective than physical training combined with cognitive-behavioral therapy in reducing cancer-related fatigue , suggesting that cognitive-behavioral therapy did not have additional beneficial effects beyond the benefits of physical training

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### Context: [2826100] Background : Substantial numbers of cancer patients use complementary medicine therapies , even without a supportive evidence base . This study aim ed to evaluate in a r and omized controlled trial , the use of Medical Qigong ( MQ ) compared with usual care to improve the quality of life ( QOL ) of cancer patients . Patients and methods : One hundred and sixty-two patients with a range of cancers were recruited . QOL and fatigue were measured by Functional Assessment of Cancer Therapy — General and Functional Assessment of Cancer Therapy — Fatigue , respectively , and mood status by Profile of Mood State . The inflammatory marker serum C-reactive protein ( CRP ) was monitored serially . Results : Regression analysis indicated that the MQ group significantly improved overall QOL ( t144 = −5.761 , P < 0.001 ) , fatigue ( t153 = −5.621 , P < 0.001 ) , mood disturbance ( t122 = 2.346 , P = 0.021 ) and inflammation ( CRP ) ( t99 = 2.042 , P < 0.044 ) compared with usual care after controlling for baseline variables . Conclusions : This study indicates that MQ can improve cancer patients ’ overall QOL and mood status and reduce specific side-effects of treatment . It may also produce physical benefits in the long term through reduced inflammation [12406050] PURPOSE The aims of this pilot study were the following : 1 ) to examine patterns of adherence to a brisk walking program in women receiving adjuvant chemotherapy or radiation therapy for newly diagnosed breast cancer using a prospect i ve , r and omized , controlled experimental design ; 2 ) to examine the influence of disease symptoms and treatment side effects on exercise levels ; and 3 ) to suggest methods that may improve future clinical trials of moderate-intensity exercise in similar population s. DESCRIPTION OF STUDY Fifty-two patients with newly diagnosed breast cancer were r and omly assigned to one of two treatment arms : usual care or usual care plus exercise . Those assigned to the exercise group received a st and ardized , self-administered , home-based brisk walking intervention in addition to usual care . Each day subjects completed self-report diary forms that elicited information about activity levels , and the occurrence of symptoms and side effects during cancer treatment . RESULTS Analyses of self-reported daily activity levels revealed a diffusion of treatment effect . Fifty percent of the usual-care group reported maintaining or increasing their physical activity to a moderate-intensity level , while 33 % of the exercise group did not exercise at the prescribed levels . Analyses of self-reported disease symptoms and treatment side effects did not reveal clinical ly meaningful differences between the two groups . CLINICAL IMPLICATION S The results of this study suggest that women who exercised regularly before receiving a breast cancer diagnosis attempted to maintain their exercise programs . Women who lead sedentary lifestyles may benefit from a structured exercise program that includes information and support related to exercise adherence strategies [19672632] Purpose The study was focused on the influence of the kinesitherapy on fatigue and the quality of life in the terminal hospice cancer patients . Patients and methods Forty-nine patients were included into the study and divided into experimental group A ( with kinesitherapy ) with 30 subjects and control group B ( without kinesitherapy ) with 19 subjects . Patients from group A did the exercises three times a week , for 20–30 min , for the period of 3–4 weeks . The exercises were individually supervised by a physiotherapist , following a carefully worked out pattern . In both groups , the changes in the intensity of fatigue and the quality of life were observed by means of using Rotterdam symptom checklist , brief fatigue inventory , and visual analogue fatigue scale . Results In group A , the intensity of fatigue decreased significantly after 3 weeks of kinesitherapy . In group B , fatigue deteriorated significantly in comparison with the initial measurement . The intensity of physical symptoms in group A decreased significantly after 2 weeks of kinesitherapy , whereas in group B , increased after 2 weeks of observation . The quality of life in group A remained stable throughout the study . A tendency towards the deterioration of the quality of life with the time passing in group B was noticeable . Conclusion Our analysis showed that , on average , after 3 weeks of kinesitherapy , a significant decrease of the intensity of fatigue was observed , while in the control group , it increased after 2 weeks of observation . The obtained results provide evidence that a planned set of exercises decreases cancer-related fatigue effectively [18779540] BACKGROUND Anemia in patients with solid tumors is a common problem that is associated with impaired exercise capacity , increased fatigue , and lower quality of life ( QoL ) . Erythropoiesis-stimulating agents ( ESAs ) have been shown to improve these outcomes ; however , it is unknown if additional benefits can be achieved with aerobic exercise training . METHODS We conducted a single-center , prospect i ve , r and omized , controlled trial in 55 mild-to-moderately anemic patients with solid tumors . Patients were r and omized to either darbepoetin alfa alone ( DAL , n = 29 ) or darbepoetin alfa plus aerobic exercise training ( DEX ; n = 26 ) . The DEX group performed aerobic exercise training three times per week at 60%-100 % of baseline exercise capacity for 12 weeks . The primary endpoint was QoL assessed by the Functional Assessment of Cancer Therapy-Anemia scale . Secondary endpoints were fatigue , cardiorespiratory fitness ( VO(2peak ) ) , hemoglobin ( Hb ) response , and darbepoetin alfa dosing . RESULTS Intention-to-treat analyses indicated significant improvements in QoL and fatigue in both groups over time but there were no between-group differences . The DEX group had a significantly greater VO(2peak ) than the DAL group ( mean group difference , + 3.0 ml/kg per minute ; 95 % confidence interval , 1.2 - 4.7 ; p = .001 ) and there were borderline significant differences in favor of the DEX group for Hb response and darbepoetin alfa dosing . CONCLUSIONS Aerobic exercise training did not improve QoL or fatigue beyond the established benefits of DAL but it did result in favorable improvements in exercise capacity and a more rapid Hb response with lower dosing requirements . Our results may be useful to clinicians despite the more recent restrictions on the indications for ESAs [19759996] This pilot study examined the efficacy of two home-based exercise programs on alleviating fatigue and improving functional capacity in breast cancer survivors . Participants were r and omly assigned into one of three groups : aerobic exercise ( AE ) , resistance exercise ( RE ) , or usual care control ( CON ) . After receiving individualized instruction and training , participants assigned to the AE and RE groups were asked to perform the prescribed exercise(s ) 3 times per week for 12 weeks at home . Both groups were instructed to keep their perceived exercise intensity in the " fairly light " to " somewhat hard " range using the Borg Perceived Exertion Scale . All participants completed the revised Piper Fatigue Scale ( PFS ) and the 6-minute walk test ( 6MWT ) at baseline and 12-week post-exercise program . Analysis of pre- and post-training data revealed a significant reduction in fatigue levels on the PFS among participants in the AE group ( Z=2.521 , one-tailed P=0.006 ) , and a significant improvement in the distance of the 6MWT for the RE group ( Z=2.366 , one-tailed P=0.009 ) at the end of 12-week study period . No significant changes in fatigue or functional status were observed in the CON group . Findings provide preliminary support for RE as a viable strategy for improving functional capacity in breast cancer survivors , while AE may be more effective in attenuating cancer-related fatigue . Incorporating RE training for future research may help advance the growing body of knowledge in symptom management for breast cancer survivors [15139072] Research suggests that stress‐reduction programs tailored to the cancer setting help patients cope with the effects of treatment and improve their quality of life . Yoga , an ancient Eastern science , incorporates stress‐reduction techniques that include regulated breathing , visual imagery , and meditation as well as various postures . The authors examined the effects of the Tibetan yoga ( TY ) practice s of Tsa lung and Trul khor , which incorporate controlled breathing and visualization , mindfulness techniques , and low‐impact postures in patients with lymphoma [15170652] BACKGROUND AND OBJECTIVES This pilot project assessed the acceptability of a mixed-type , moderate-intensity exercise programme following breast cancer treatment , and the impact on presence of lymphoedema , fitness , body composition , fatigue , mood and quality of life . METHODS Ten women completed the programme and measures of fitness ( sub-maximal ergometer test ) , body composition ( bio-electrical impedance ) , lympoedema ( bio-electrical impedance and arm circumferences ) , fatigue ( revised Piper Fatigue Scale ) , mood ( Hospital Anxiety and Depression Scale ) , quality of life ( FACT-B ) and general well-being , at baseline , completion of the programme , and 6-week and 3-month follow-up . RESULTS Participation in the programme caused no adverse effect on the presence of lymphoedema . There was a trend towards reduction in fatigue and improved quality of life across the testing phases . Women rated the programme extremely favourably , citing benefits of the support of other women , trained guidance , and the opportunity to experience different types of exercise . CONCLUSIONS A mixed-type , moderate-intensity exercise program in a group format is acceptable to women following breast cancer treatment , with the potential to reduce fatigue and improve quality of life , without exacerbating or precipitating lymphoedema . This pilot work needs to be confirmed in larger r and omised studies [12471288] PURPOSE The primary purpose of this study was to examine the effect of aerobic exercise on physiological and psychological function in patients rehabilitating from cancer treatment . A second purpose was to evaluate the differential effects of low- and moderate-intensity exercise on these variables . METHODS Eighteen survivors of breast or colon cancer ( 15 female and 3 male , 40 - 65 yr of age ) served as subjects . The subjects were matched by aerobic capacity and scores on a Quality of Life question naire , and then r and omly assigned to a control , low- ( 25 - 35 % heart rate reserve ( HRR ) ) , or a moderate- ( 40 - 50 % HRR ) intensity exercise group . The exercise groups performed lower-body aerobic exercise three times a week for 10 wk . After the exercise training , there were no statistically significant differences between the two exercise groups on any of the physiological variables . Therefore , the exercise groups were combined into one group for the final analysis . RESULTS The results revealed statistically significant increases in aerobic capacity ( P < 0.001 ) and lower-body flexibility ( P = 0.027 ) , a significant decrease in body fat ( P < 0.001 ) , and a significant increase in quality of life ( P < 0.001 ) and a measure of energy ( P = 0.038 ) in the exercise group when compared with the control group . CONCLUSION Low- and moderate-intensity aerobic-exercise programs were equally effective in improving physiological and psychological function in this population of cancer survivors . Aerobic exercise appears to be a valuable and well-tolerated component of the cancer-rehabilitation process [15022300] The efficacy of energy conservation and activity management ( ECAM ) for fatigue reduction and maintenance of functional performance has never been evaluated in adults with cancer who are undergoing treatment [19609570] Goals of workProstate cancer patients receiving and rogen deprivation therapy ( ADT ) are vulnerable to a number of potentially debilitating side effects , which can significantly impact quality of life . The role of alternate therapies , such as physical activity ( PA ) , in attenuating these side effects is largely understudied for such a large population . Thus , the purpose of this study was to investigate the effects of PA intervention for men receiving ADT on PA behavior , quality of life , and fitness measures . Patients and methods One hundred participants were r and omized into an intervention ( n = 53 ) or a wait-list control group ( n = 47 ) , with 11 dropping out of the intervention group and 23 dropping out of the wait-list control group prior to post-testing . The intervention consisted of both an individually tailored home-based aerobic and light resistant training program and weekly group sessions . PA , quality of life , fitness , and physiological outcomes were assessed pre and post the 16-week intervention . Results Significant increases in PA , supported by changes in girth measures and blood pressure , support the beneficial impact of the intervention . Positive trends were also evident for depression and fatigue . However , due to the high dropout rate , these results must be interpreted with caution . Conclusions PA effectively attenuates many of the side effects of ADT and should be recommended to prostate survivors as an alternate therapy . Determining the maintenance of this behavior change will be important for underst and ing how the long-term benefits of increased activity levels may alleviate the late effects of ADT [17530428] Few r and omized controlled trials have examined the effects of combined aerobic and resistance training in breast cancer survivors soon after completing adjuvant therapy . Breast cancer survivors ( N = 58 ) within 2 years of completing adjuvant therapy were r and omly assigned to an immediate exercise group ( IEG ; n = 29 ) or a delayed exercise group ( DEG ; n = 29 ) . The IEG completed 12 weeks of supervised aerobic and resistance exercise , three times per week . The DEG completed the program during the next 12 weeks . Participants completed patient-rated outcomes at baseline , 6 , 12 , 18 and 24 weeks . The primary endpoint was overall quality of life ( QoL ) measured by the Functional Assessment of Cancer Therapy-Breast scale . Secondary endpoints were fatigue , social physique anxiety , and physical fitness . Follow-up data was obtained on 97 % of participants and exercise adherence was 61.3 % . Repeated measures analyses of variance revealed a significant group by time interaction for overall QoL ( P < 0.001 ) . Specifically , QoL increased in the IEG from baseline to 12 weeks by 20.8 points compared to a decrease in the DEG of 5.3 points ( mean group difference = 26.1 ; 95 % CI = 18.3–32.7 ; P < 0.001 ) . From 12 to 24 weeks , QoL increased in the DEG by 29.5 points compared to an increase of 6.5 points in the IEG ( mean group difference = 23.0 ; 95 % CI = 16.3–29.1 ; P < 0.001 ) . Similar results were obtained for the secondary endpoints . Combined aerobic and resistance exercise soon after the completion of breast cancer therapy produces large and rapid improvements in health-related outcomes [11157015] PURPOSE Self-directed and supervised exercise were compared with usual care in a clinical trial design ed to evaluate the effect of structured exercise on physical functioning and other dimensions of health-related quality of life in women with stages I and II breast cancer . PATIENTS AND METHODS One hundred twenty-three women with stages I and II breast cancer completed baseline evaluations of generic and disease- and site-specific health-related quality of life , aerobic capacity , and body weight . Participants were r and omly allocated to one of three intervention groups : usual care ( control group ) , self-directed exercise , or supervised exercise . Quality of life , aerobic capacity , and body weight measures were repeated at 26 weeks . The primary outcome was the change in the Short Form-36 physical functioning scale between baseline and 26 weeks . RESULTS Physical functioning in the control group decreased by 4.1 points , whereas it increased by 5.7 points and 2.2 points in the self-directed and supervised exercise groups , respectively ( P = .04 ) . Post hoc analysis showed a moderately large ( and clinical ly important ) difference between the self-directed and control groups ( 9.8 points ; P = .01 ) and a more modest difference between the supervised and control groups ( 6.3 points ; P = .09 ) . No significant differences between groups were observed for changes in quality of life scores . In a secondary analysis of participants stratified by type of adjuvant therapy , supervised exercise improved aerobic capacity ( + 3.5 mL/kg/min ; P = .01 ) and reduced body weight ( -4.8 kg ; P < .05 ) compared with usual care only in participants not receiving chemotherapy . CONCLUSION Physical exercise can blunt some of the negative side effects of breast cancer treatment , including reduced physical functioning . Self-directed exercise is an effective way to improve physical functioning compared with usual care . In participants not receiving chemotherapy , supervised exercise may increase aerobic capacity and reduce body weight compared with usual care [17557948] PURPOSE To determine the effects of breast cancer-specific print material s and step pedometers on physical activity ( PA ) and quality of life ( QoL ) in breast cancer survivors . PATIENTS AND METHODS Breast cancer survivors ( N = 377 ) were r and omly assigned to receive one of the following : a st and ard public health recommendation for PA , previously developed breast cancer-specific PA print material s , a step pedometer , or a combination of breast cancer-specific print material s and step pedometers . The primary outcome was self-reported moderate/vigorous PA minutes per week . Secondary outcomes were QoL ( Functional Assessment of Cancer Therapy-Breast ) , fatigue , self-reported brisk walking , and objective step counts . Assessment s were conducted at baseline and postintervention ( 12 weeks ) . RESULTS Attrition was 10.3 % ( 39 of 377 ) . On the basis of linear mixed-model analyses , PA increased by 30 minutes/week in the st and ard recommendation group compared with 70 minutes/week in the print material group ( mean difference , 39 minutes/week ; 95 % CI = -10 to 89 ; d = 0.25 ; P = .117 ) , 89 minutes/week in the pedometer group ( mean difference , 59 minutes/week ; 95 % CI , 11 to 108 ; d = 0.38 ; P = .017 ) , and 87 minutes/week in the combined group ( mean difference , 57 minutes/week ; 95 % CI , 8 to 106 ; d = 0.37 ; P = .022 ) . For brisk walking minutes/week , all three intervention groups reported significantly greater increases than the st and ard recommendation group . The combined group also reported significantly improved QoL ( mean difference , 5.8 ; 95 % CI , 2.0 to 9.6 ; d = 0.33 ; P = .003 ) and reduced fatigue ( mean difference , 2.3 ; 95 % CI , 0.0 to 4.7 ; d = 0.25 ; P = .052 ) compared with the st and ard recommendation group . CONCLUSION Breast cancer-specific PA print material s and pedometers may be effective strategies for increasing PA and QoL in breast cancer survivors . A combined approach appears to be optimal . CLINICAL TRIAL REGISTRATION Clinical Trials.gov Identifier [11323538] PURPOSE Cancer treatment-related fatigue is the most prevalent and distressing symptom of cancer therapy . Interventions to minimize fatigue are needed . The purpose of this study was to examine the relationship between exercise and fatigue over the first three cycles of chemotherapy in women receiving either cyclophosphamide , methotrexate , and fluorouracil ( CMF ) or doxorubicin and cyclophosphamide ( AC ) for breast cancer . METHODS Seventy-two newly diagnosed women with breast cancer were instructed in a home-based moderate-intensity exercise intervention . Measures of functional ability , energy expenditure , and fatigue were obtained at baseline and posttest . Subjects maintained daily records of four types of fatigue , and exercise duration , intensity , and type . RESULTS Exercise significantly reduced all four levels of fatigue ( P < 0.01 ) . As the duration of exercise increased , the intensity of fatigue declined ( P < 0.01 ) . There was a significant carry-over effect of exercise on fatigue , but the effect lasted only 1 d. The level of fatigue at study entry was not associated with number of days of exercise or amount of exercise a woman engaged in . CONCLUSIONS The impact of exercise on fatigue was significant and suggests the effectiveness of a low- to moderate-intensity regular exercise program in maintaining functional ability and reducing fatigue in women with breast cancer receiving chemotherapy [18347912] Background Exercise adherence is a challenge for breast cancer patients receiving chemotherapy but few studies have identified the key barriers . Purpose In this paper , we report the barriers to supervised exercise in breast cancer patients participating in a r and omized controlled trial . Methods Breast cancer patients initiating adjuvant chemotherapy ( N = 242 ) were r and omly assigned to usual care ( n = 82 ) or supervised resistance ( n = 82 ) or aerobic ( n = 78 ) exercise . Participants r and omized to the two exercise groups ( n = 160 ) were asked to provide a reason for each missed exercise session . Results The two exercise groups attended 70.2 % ( 5,495/7,829 ) of their supervised exercise sessions and provided a reason for missing 89.5 % ( 2,090/2,334 ) of their unattended sessions . The 2,090 reasons represented 36 different barriers . Feeling sick ( 12 % ) , fatigue ( 11 % ) , loss of interest ( 9 % ) , vacation ( 7 % ) , and nausea/vomiting ( 5 % ) accounted for the most missed exercise sessions . Disease/treatment-related barriers ( 19 of the 36 barriers ) accounted for 53 % ( 1,102/2,090 ) of all missed exercise sessions . Demographic and medical variables did not predict the types of exercise barriers reported . Conclusions Barriers to supervised exercise in breast cancer patients receiving chemotherapy are varied but over half can be directly attributed to the disease and its treatments . Behavioral support programs need to focus on strategies to maintain exercise in the face of difficult treatment side effects [18467280] PURPOSE / OBJECTIVES To determine the effect of aerobic and strength resistance training and epoetin alfa ( EPO ) therapy on transfusions , stem cell collection s , transplantation recovery , and multiple myeloma treatment response . DESIGN R and omized clinical trial . SETTING A myeloma research and therapy center in the south central United States . SAMPLE 135 patients with multiple myeloma , 120 evaluable . METHODS R and om assignment to exercise or usual care groups . All patients received EPO based on an algorithm . Aerobic capacity , using the six-minute walk test , was assessed prior to induction chemotherapy , prior to stem cell mobilization , and following stem cell collection for all patients and before and after transplantation for patients continuing in the study . Data analysis included analysis of variance to compare other outcome variables by groups . MAIN RESEARCH VARIABLES Number of red blood cell and platelet transfusions during transplantation , number of attempts at and total number of days of stem cell collection , time to recovery after transplantation , and response to intensive therapy for multiple myeloma . FINDINGS Recovery and treatment response were not significantly different between groups after transplantation . The exercise group had significantly fewer red blood cell transfusions and fewer attempts at stem cell collection . Serious adverse events were similar in each group . CONCLUSIONS Exercise with prophylactic EPO therapy reduces the number of RBC transfusions and attempts at stem cell collection for patients receiving intensive treatment for multiple myeloma . IMPLICATION S FOR NURSING Exercise is safe and has many physiologic benefits for patients receiving multiple myeloma treatment [18280104] The purpose of this r and omized , controlled clinical trial was to preliminarily examine the effects of a three-week walking exercise program ( WEP ) on fatigue-related experiences of acute myelogenous leukemia ( AML ) patients receiving chemotherapy . Eligible AML patients were r and omly assigned to either an experimental group ( n=11 ) , which received 12 minutes of WEP per day , five days per week for three consecutive weeks , or to a control group ( n=11 ) , which received st and ard ward care . Effects of the WEP were assessed by seven indicators : worst and average fatigue intensities , fatigue interference with patients ' daily life , 12-minute walking distance , overall symptom distress , anxiety , and depressive status . All patients were evaluated four times : before chemotherapy ( baseline or Day 1 ) , Day 7 , Day 14 , and Day 21 of chemotherapy . Data were analyzed by Generalized Estimating Equation and revealed that AML patients in the three-week WEP group had a significantly greater increase in 12-minute walking distance than the control group . Patients in the WEP also had lower levels of fatigue intensity and interference , symptom distress , anxiety , and depressive status than the control group . Although preliminary , our results strongly suggest that three weeks of systematic walking exercise is clinical ly feasible for AML patients undergoing chemotherapy and can effectively improve their fatigue-related experiences [20467301] Background : Few studies have evaluated an individualized home-based exercise prescription during and after cancer treatment . Objective : The purpose of this study was to evaluate the effectiveness of a home-based exercise training intervention , the Pro-self Fatigue Control Program on the management of cancer-related fatigue . Interventions / Methods : Participants ( N = 119 ) were r and omized into 1 of 3 groups : group 1 received the exercise prescription throughout the study ; group 2 received their exercise prescription after completing cancer treatment ; and group 3 received usual care . Patients completed the Piper Fatigue Scale , General Sleep Disturbance Scale , Center for Epidemiological Studies -Depression Scale , and Worst Pain Intensity Scale . Results : All groups reported mild fatigue levels , sleep disturbance , and mild pain , but not depression . Using multilevel regression analysis , significant linear and quadratic trends were found for change in fatigue and pain ( ie , scores increased , then decreased over time ) . No group differences were found in the changing scores over time . A significant quadratic effect for the trajectory of sleep disturbance was found , but no group differences were detected over time . No significant time or group effects were found for depression . Conclusions : Our home-based exercise intervention had no effect on fatigue or related symptoms associated with cancer treatment . The optimal timing of exercise remains to be determined . Implication s for Practice : Clinicians need to be aware that some physical activity is better than none , and there is no harm in exercise as tolerated during cancer treatment . Further analysis is needed to examine the adherence to exercise . More frequent assessment s of fatigue , sleep disturbance , depression , and pain may capture the effect of exercise [16374892] BACKGROUND Physical activity provides a number of physical and psychological benefits to cancer survivors , including lessening the impact of detrimental cancer-related symptoms and treatment side-effects ( e.g. fatigue , nausea ) , and improving overall well-being and quality of life . The purpose of the present pilot study was to examine the physical and psychological benefits afforded by a 7-week yoga program for cancer survivors . METHOD Eligible participants ( per-screened with PAR-Q/PAR-MED-X ) were r and omly assigned to either the intervention ( n=20 ) or control group ( n=18 ) . All participants completed pre- and post-testing assessment s immediately before and after the yoga program , respectively . RESULTS The yoga program participants ( M age=51.18 ( 10.33 ) ; 92 % female ) included primarily breast cancer survivors , on average 55.95 ( 54.39 ) months post-diagnosis . Significant differences between the intervention and the control group at post-intervention were seen only in psychosocial ( i.e. global quality of life , emotional function , and diarrhea ) variables ( all p 's < 0.05 ) . There were also trends for group differences , in the hypothesized directions , for the psychosocial variables of emotional irritability , gastrointestinal symptoms , cognitive disorganization , mood disturbance , tension , depression , and confusion ( all p 's < 0.10 ) . Finally , there were also significant improvements in both the program participants and the controls from pre- to post-intervention on a number of physical fitness variables . CONCLUSIONS These initial findings suggest that yoga has significant potential and should be further explored as a beneficial physical activity option for cancer survivors . Future research might attempt to include a broader range of participants ( e.g. other types of cancer diagnoses , male subjects ) , a larger sample size , and a longer program duration in an RCT [17524796] We describe adherence to a three group r and omised controlled trial that involved aerobic exercise therapy ( N=34 ) and exercise-placebo intervention ( N=36 ) or usual care ( N=38 ) in women treated for breast cancer . We also investigated relationships between routes of trial recruitment , socio-economic characteristics , health behaviours , cancer treatment regimen(s ) and subsequent adherence to the interventions . Women who had completed breast cancer treatment 12 - 36 months previously were r and omised to one of the groups . The intervention groups attended an exercise facility three times per week for eight weeks . A total of 77 % of the aerobic exercise therapy and 88.9 % of the exercise-placebo groups attended at least 70 % of prescribed sessions . The percentage of women achieving 30min of aerobic exercise per session steadily increased during the intervention but many women were not able to achieve this goal . Routes of trial recruitment , socio-economic characteristics , health behaviours and cancer treatment regimen(s ) were not related to intervention . Exercise therapy participants were able to comply with the progressive nature of the aerobic exercise intervention , although some women were not able to achieve 30min of aerobic exercise per session by intervention completion . Research is still required to tease out all the potential determinants of exercise in this population [2615347] Purpose Postoperative radiotherapy for breast cancer has a number of associated complications . This study examined whether supervised moderate-intensity exercise could mitigate the complications that occur during radiotherapy . Patients and Methods Forty women were r and omized before radiotherapy after various operations for breast cancer . Seventeen patients who were assigned to the exercise group performed supervised moderate-intensity exercise therapy for 50 min 3 times per week for 5 weeks . Twenty-three patients in the control group were asked to perform self-shoulder stretching exercise . The World Health Organization Quality of Life-BREF ( WHOQOL-BREF ) , brief fatigue inventory ( BFI ) , range of motion ( ROM ) of the shoulder , and pain score were assessed before and after radiotherapy . Results There were no significant differences noted at baseline between groups . In the exercise group , there was an increase in the WHOQOL-BREF and shoulder ROM and decrease in BFI and pain score after radiotherapy . On the other h and , patients in the control group showed decrease in the WHOQOL-BREF and shoulder ROM and increase in BFI and pain score after radiotherapy . There were statistically significant differences in the changes in the WHOQOL , BFI , shoulder ROM , and pain score between the groups . Conclusion Patients receiving radiotherapy for breast cancer may benefit in physical and psychological aspects from supervised moderate-intensity exercise therapy [15656848] AIM Our purpose was to investigate the effect of a relaxation breathing exercise on fatigue in allogenic haemopoietic stem cell transplantation patients . BACKGROUND Exercise is a promising approach in ameliorating the fatigue associated with cancer and its treatment . DESIGN A r and omized design with control , experimental groups being assessed pre- and postintervention . METHODS Thirty-five patients were r and omly selected , with 18 assigned to an exercise group and 17 to a control group . The exercise intervention lasted for 30 minutes every day for six weeks . It consisted of physical exercise combined with relaxation breathing exercise . Fatigue was measured by the revised version of the Piper Fatigue Scale . RESULTS The exercise group had a greater decrease in fatigue than the control group . CONCLUSION These findings indicate that a relaxation breathing exercise would improve fatigue in allogenic haemopoietic stem cell transplantation patients . RELEVANCE TO CLINICAL PRACTICE A relaxation breathing exercise by a nurse can improve fatigue in allogenic haemopoietic stem cell transplantation patients [15274068] Advice to rest and take things easy if patients become fatigued during radiotherapy may be detrimental . Aerobic walking improves physical functioning and has been an intervention for chemotherapy‐related fatigue . A prospect i ve , r and omized , controlled trial was performed to determine whether aerobic exercise would reduce the incidence of fatigue and prevent deterioration in physical functioning during radiotherapy for localized prostate carcinoma [18389368] Purpose Exercise during breast cancer chemotherapy is beneficial but it needs to be maintained into survivorship to optimize long-term benefits . Here , we report the predictors of follow-up exercise behavior 6 months after a r and omized exercise trial in breast cancer patients . Methods Breast cancer patients ( N = 242 ) initiating adjuvant chemotherapy were r and omly assigned to usual care ( n = 82 ) , supervised resistance exercise ( n = 82 ) , or supervised aerobic exercise ( n = 78 ) for the duration of their chemotherapy . At baseline and postintervention , data were collected on demographic , medical , behavioral , fitness , psychosocial , and motivational variables . At 6-month follow-up , participants were mailed a question naire that assessed exercise behavior over the past 6 months and were categorized as either meeting both aerobic and resistance exercise guidelines , either exercise guideline , or neither exercise guideline . Results Two hundred one ( 83.1 % ) participants provided 6-month follow-up data with 85 ( 42.3 % ) meeting neither exercise guideline , 74 ( 36.8 % ) meeting either exercise guideline , and 42 ( 20.9 % ) meeting both exercise guidelines . In multivariate regression analysis , seven variables independently predicted the likelihood of meeting exercise guidelines at follow-up including higher pretrial exercise ( β = 0.23 ; P = 0.002 ) , younger age ( β = −0.15 ; P = 0.028 ) , breast conserving surgery ( β = 0.15 ; P = 0.033 ) , strength improvements ( β = 0.15 ; P = 0.028 ) , lower postintervention fatigue ( β = 0.13 ; P = 0.067 ) , a more positive attitude ( β = 0.12 ; P = 0.086 ) , and lower postintervention body mass index ( β = −0.11 ; P = 0.105 ) . Conclusion Exercise behavior 6 months after a r and omized trial was predicted by a wide range of demographic , medical , behavioral , fitness , psychosocial , and motivational variables . These findings may help facilitate the uptake of exercise behavior during the transition from breast cancer patient to survivor [18543381] Quality of life ( QOL ) of cancer patients is often diminished due to the side effects of treatment and symptoms of the disease itself . Medical Qigong ( coordination of gentle exercise and relaxation through meditation and breathing exercise based on Chinese medicine theory of energy channels ) may be an effective therapy for improving QOL , symptoms and side effects , and longevity of cancer patients . In this pilot study , the feasibility , acceptability , and impact of Medical Qigong ( MQ ) were evaluated on outcomes in cancer patients . Thirty patients diagnosed with heterogeneous cancers , were r and omly assigned to two groups : a control group that received usual medical care and an intervention group who participated in a MQ program for 8 weeks in addition to receiving usual medical care . R and omization was stratified by completion of cancer treatment ( n = 14 ) or under chemotherapy ( n = 16 ) . Patients completed measures before and after the program . Quality of life and symptoms were measured by the EORTC QLQ-C 30 and progress of disease by the inflammation biomarker ( CRP : c-reactive protein ) via a blood test was assessed . The MQ intervention group reported clinical ly significant improved global QOL scores pre- and post-intervention . The MQ intervention also reduced the symptoms of side effects of cancer treatment and inflammation biomarker ( CRP ) compare to the control group . Due to the small sample size , however , the results were not statistically significant between treatment and the control groups . Data from the pilot study suggest that MQ with usual medical treatment can enhance the QOL of cancer patients and reduce inflammation . This study needs a further investigation with a larger sample size [18797706] The purpose of this study was to examine the effects of an exercise intervention on the total caloric intake ( TCI ) of breast cancer patients undergoing treatment . A secondary purpose was to determine whether or not a relationship existed between changes in TCI , body fat composition ( % BF ) , and fatigue during the study , which lasted 6 months . Twenty females recently diagnosed with breast cancer , scheduled to undergo chemotherapy or radiation , were assigned r and omly to an experimental ( N = 10 ) or control group ( N = 10 ) . Outcome measures included TCI ( 3-day food diary ) , % BF ( skinfolds ) , and fatigue ( revised Piper Fatigue Scale ) . Each exercise session was conducted as follows : initial cardiovascular activity ( 6 - 12 min ) , followed by stretching ( 5 - 10 min ) , resistance training ( 15 - 30 min ) , and a cool-down ( approximately 8 min ) . Significant changes in TCI were observed among groups ( F1,18 = 8.582 ; P = 0.009 ) , at treatments 2 and 3 , and at the end of the study [ experimental ( 1973 + /- 419 ) , control ( 1488 + /- 418 ) ; experimental ( 1946 + /- 437 ) , control ( 1436 + /- 429 ) ; experimental ( 2315 + /- 455 ) , control ( 1474 + /- 294 ) , respectively ] . A significant negative correlation was found ( Spearman rho(18 ) = -0.759 ; P < 0.001 ) between TCI and % BF and between TCI and fatigue levels ( Spearman rho(18 ) = -0.541 ; P = 0.014 ) at the end of the study . In conclusion , the results of this study suggest that an exercise intervention administered to breast cancer patients undergoing medical treatment may assist in the mitigation of some treatment side effects , including decreased TCI , increased fatigue , and negative changes in body composition [17848814] Cancer-related fatigue is the most disabling symptom experienced by breast cancer patients following the cancer treatment . The positive effects of physical activity in the rehabilitation of breast cancer patients are documented in several studies . In a r and omized controlled study the effects of a structured physical training program on fatigue and health-related quality of life were evaluated . Patients and Methods : 63 breast cancer patients with cancer-related chronic fatigue were r and omized at the beginning of the inpatient rehabilitation . The control group received the st and ard complex rehabilitation program , the intervention group a structured physical training program and additional muscle strength and aerobic exercises . The effects of the treatment were evaluated by question naires at the start of rehabilitation ( t1 ) , end of rehabilitation ( t2 ) , and 3 months after t2 ( t3 ) . Isometric muscle strength and aerobic capacity were evaluated at t1 and t2 . Results : There was an improvement of muscle strength at the end of rehabilitation for both groups . The increase from t1 to t2 was significantly higher for the training group . The scores for global quality of life , physical well-being , and functionality increased from t1 to t2 , but further improvement in the follow-up ( t3 ) was only observed in the training group . The cancer-related fatigue was significantly reduced in the training group from t1 to t3 , however , not in the control group . Conclusions : Structured physical training programs initiated during inpatient rehabilitation and continuously practice d in the time thereafter can improve symptoms of chronic fatigue and quality of life in breast cancer patients [15338385] Fatigue is a frequent problem after surgical treatment of solid tumours . Aerobic exercise and psychosocial interventions have been shown to reduce the severity of this symptom in cancer patients . Therefore , we compared the effect of the two therapies on fatigue in a r and omised controlled study . Seventy-two patients who underwent surgery for lung ( n=27 ) or gastrointestinal tumours ( n=42 ) were assigned to an aerobic exercise group ( stationary biking 30 min five times weekly ) or a progressive relaxation training group ( 45 min three times per week ) . Both interventions were carried out for 3 weeks . At the beginning and the end of the study , we evaluated physical , cognitive and emotional status and somatic complaints with the European Organization for Research and Treatment of Cancer Quality of Life Question naire Core Module ( EORTC-QLQ-30 ) question naire , and maximal physical performance with an ergometric stress test . Physical performance of the training group improved significantly during the programme ( 9.4±20 watts , p=0.01 ) but remained unchanged in the relaxation group ( 1.5±14.8 watts , p=0.37 ) . Fatigue and global health scores improved in both groups during the intervention ( fatigue : training group 21 % , relaxation group 19 % ; global health of both groups 19 % , p for all ≤0.01 ) ; however , there was no significant difference between changes in the scores of both groups ( p=0.67 ) . We conclude that a structured aerobic training programme improves the physical performance of patients recovering from surgery for solid tumours . However , exercise is not better than progressive relaxation training for the treatment of fatigue in this setting [18086760] Background : Few exercise trials in cancer patients have reported longer-term follow-up . Here , we report a 6-month follow-up of exercise behavior and patient-rated outcomes from an exercise trial in breast cancer patients . Methods : Breast cancer patients initiating adjuvant chemotherapy ( n = 242 ) were r and omly assigned to usual care ( n = 82 ) , resistance exercise training ( RET ; n = 82 ) , or aerobic exercise training ( AET ; n = 78 ) for the duration of their chemotherapy . At 6-month follow-up , participants were mailed a question naire that assessed quality of life , self-esteem , fatigue , anxiety , depression , and exercise behavior . Results : Two hundred one ( 83.1 % ) participants provided 6-month follow-up data . Adjusted linear mixed-model analyses showed that , at 6-month follow-up , the RET group reported higher self-esteem [ adjusted mean difference , 1.6 ; 95 % confidence interval ( 95 % CI ) , 0.1 - 3.2 ; P = 0.032 ] and the AET group reported lower anxiety ( adjusted mean difference , −4.7 ; 95 % CI , −0.0 to −9.3 ; P = 0.049 ) compared with the usual care group . Moreover , compared with participants reporting no regular exercise during the follow-up period , those reporting regular aerobic and resistance exercise also reported better patient-rated outcomes , including quality of life ( adjusted mean difference , 9.5 ; 95 % CI , 1.2 - 17.8 ; P = 0.025 ) . Conclusions : Improvements in self-esteem observed with RET during breast cancer chemotherapy were maintained at 6-month follow-up whereas reductions in anxiety not observed with AET during breast cancer chemotherapy emerged at 6-month follow-up . Moreover , adopting a combined aerobic and resistance exercise program after breast cancer chemotherapy was associated with further improvements in patient-rated outcomes . Exercise training during breast cancer chemotherapy may result in some longer-term and late effects for selected patient-rated outcomes . ( Cancer Epidemiol Biomarkers Prev 2007;16(12):2572–8 [19117328] OBJECTIVES To determine if therapist supervision of an exercise program produced better functional outcomes in allogeneic stem cell transplant patients than a patient-directed exercise program . METHODS Sixty-one patients who were less than 6 months post allogeneic stem cell transplant were r and omly assigned to either a therapist supervised training group ( supervised ) or a patient-directed training group ( Self-directed ) . Training consisted of aerobic exercises ( treadmill , bicycle ergometer versus walking ) and resistance exercises ( free weights , weight machines versus resistive b and activities ) . Subjects completed physical performance tests ( 50-foot fast walk , 6-min walk , forward reach , repeated sit-to-st and , uniped stance ) and the Brief Fatigue Inventory ( BFI ) before and after 4 weeks of training . Pre- and post-training outcomes and group differences were analyzed by a Student t-test . RESULTS Patients in both groups were similarly deconditioned at baseline . Training increased the 6-min walk distance and 50-foot walk in the supervised group by 12 and 14 % , respectively , and increased the 6-min walk distance by 10 % in the Self-directed group ( p<0.05 ) . BFI score for worst level of fatigue declined in both groups but not significantly . CONCLUSIONS These results demonstrate that allogeneic transplant patients derive functional benefits from short-term exercise training regardless of how the training program is supervised . Determining ( 1 ) the reasons for the low participation rate ( 28 % ) , ( 2 ) the patient-preferred characteristics of each exercise supervision style and ( 3 ) how best to match patient preference to exercise supervision style remain significant issues in this area of patient delivery services [18381369] BACKGROUND Fatigue is a relevant problem of cancer patients during and after treatment . Several studies have shown that exercise can improve quality of life and functional status of cancer patients undergoing chemo- or radiotherapy . However , there is a lack of information about the effects of this intervention on persistent cancer-related fatigue . Therefore , we assessed the effects of an exercise program on cancer-related fatigue after treatment . PATIENTS AND METHODS A consecutive series of 32 cancer patients with mild to severe persistent fatigue [ scores on the Brief Fatigue Inventory ( BFI ) > 25 ] participated in a 3-week exercise program consisting of endurance ( 30 min walking on a treadmill ) and resistance/coordination exercises for the major muscle groups . Fatigue , mood , and anxiety were assessed with question naires and physical performance with a stress test before and after the program . RESULTS At the end of the program , we observed a significant increase of physical performance ( workload at the anaerobic threshold pre 61 + /- 26 W , post 78 + /- 31 W , P < 0.0001 ) and reduction of global fatigue ( Functional Assessment of Cancer Therapy : pre 45.7 + /- 13.4 , post 52.6 + /- 12.4 , P < 0.0001 ; BFI : pre 37.9 + /- 18.3 , post 31.2 + /-17.1 , P < 0.001 ) . However , no significant improvement of cognitive fatigue or reduction of anxiety was observed . CONCLUSIONS A 3-week exercise program leads to a substantial improvement of physical performance and reduction of mental and physical fatigue in cancer patients after treatment . However , this intervention does not affect depression , anxiety , or cognitive fatigue [9345021] Loss of physical performance is a universal problem of cancer patients undergoing chemotherapy . We postulated that this impairment can be partially prevented by aerobic exercise . In a r and omized study , 33 cancer patients receiving high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation ( training group , T ) performed an exercise program consisting of biking on an ergometer in the supine position after an interval-training pattern for 30 minutes daily during hospitalization . Patients in the control group ( C , n = 37 ) did not train . Maximal physical performance was assessed with a treadmill test by admission and discharge . Physical performance of the two groups was not different on admission . The decrement in performance during hospitalization was 27 % greater in the control group than in the training group ( P = .05 ) ; this result ed in a significantly higher maximal physical performance at discharge in the trained patients ( P = .04 ) . Duration of neutropenia ( P = .01 ) and thrombopenia ( P = .06 ) , severity of diarrhea ( P = .04 ) , severity of pain ( P = .01 ) , and duration of hospitalization ( P = . 03 ) were reduced in the training group . We conclude that aerobic exercise can be safely carried out immediately after high-dose chemotherapy and can partially prevent loss of physical performance . Based on the potential significance of the observed outcomes , further studies are warranted to confirm our results [19212103] Surgical patients often show physiological and metabolic distress , muscle weakness , and long hospital stays . Physical conditioning might help recovery . We attempted to identify the most responsive measure of aerobic fitness from a four-week pre-surgical aerobic exercise program ( prehabilitation ) in patients undergoing major bowel resection . Twenty-one subjects r and omized two to one ( exercise : control ) scheduled for colorectal surgery . Fourteen subjects [ Body Mass Index ( BMI ) = 27 + /- 6 kg/m(2 ) ; maximal oxygen uptake ( VO(2max ) ) = 22 + /- 10 ml/kg/min ] underwent 3.8 + /- 1.2 weeks ( 27 + /- 8 sessions ) of progressive , structured pre-surgical aerobic exercise training at 40 to 65 % of heart rate reserve ( % HRR ) . Peak power output was the only maximal measure that was responsive to training [ 26 + /- 27 % , Effects Size ( ES ) = 0.24 ; St and ardized Response Mean ( SRM ) = 1.05 ; p < 0.05 ] . For the submaximal measures , heart rate and oxygen uptake during submaximal exercise was most responsive to training ( decrease by 13 % + /- 15 % , ES = -0.24 ; SRM = -0.57 ; and 7 % + /- 6 % , ES = -0.40 ; SRM -0.97 ; p < 0.05 ) at an exercise intensity of 76 + /- 47 W. There was no change to maximal or submaximal measures in the control group . The distance walked over six minutes improved in both groups ( by approximately 30 m ) , but the effect size and t-statistic were higher in the exercise group . Heart rate and oxygen uptake during submaximal exercise , and peak power output are the most responsive measures to four weeks of prehabilitation in subjects with low initial fitness [19190034] Objectives . This study compares the effects of an integrated yoga program with brief supportive therapy in breast cancer out patients undergoing adjuvant radiotherapy at a cancer center . Methods . Eighty-eight stage II and III breast cancer out patients are r and omly assigned to receive yoga ( n = 44 ) or brief supportive therapy ( n = 44 ) prior to radiotherapy treatment . Assessment s include diurnal salivary cortisol levels 3 days before and after radiotherapy and self-ratings of anxiety , depression , and stress collected before and after 6 weeks of radiotherapy . Results . Analysis of covariance reveals significant decreases in anxiety ( P < .001 ) , depression ( P = .002 ) , perceived stress ( P < .001 ) , 6 a.m. salivary cortisol ( P = .009 ) , and pooled mean cortisol ( P = .03 ) in the yoga group compared with controls . There is a significant positive correlation between morning salivary cortisol level and anxiety and depression . Conclusion . Yoga might have a role in managing self-reported psychological distress and modulating circadian patterns of stress hormones in early breast cancer patients undergoing adjuvant radiotherapy [9243585] PURPOSE S/ OBJECTIVES To test the hypothesis that women participating in a walking exercise program during radiation therapy treatment for breast cancer would demonstrate more adaptive responses as evidence d by higher levels of physical functioning and lower levels of symptom intensity than women who did not participate . DESIGN Experimental , two-group pretest , post-test . SETTING Two university teaching hospital outpatient radiation therapy departments . SAMPLE 46 women beginning a six-week program of radiation therapy for early stage breast cancer . METHODS Following r and om assignment , subjects in the exercise group maintained an individualized , self-paced , home-based walking exercise program throughout treatment . The control group received usual care . Dependent variables were measured prior to and at the end of radiation therapy . In addition , symptoms were assessed at the end of three weeks of treatment . MAIN RESEARCH VARIABLES Participation in the walking exercise program , physical functioning fatigue , emotional distress , and difficulty sleeping . FINDINGS Hypothesis testing by multivariate analysis of covariance , with pretest scores as covariates , indicated significant differences between groups on outcome measures ( p < 0.001 ) . The exercise group scored significantly higher than the usual care group on physical functioning ( p = 0.003 ) and symptom intensity , particularly fatigue , anxiety , and difficulty sleeping . Fatigue was the most frequent and intense subjective symptom reported . CONCLUSIONS A self-paced , home-based walking exercise program can help manage symptoms and improve physical functioning during radiation therapy . IMPLICATION S FOR NURSING PRACTICE Nurse-prescribed and -monitored exercise is an effective , convenient , and low-cost self-care activity that reduces symptoms and facilitates adaptation to breast cancer diagnosis and treatment [19276838] PURPOSE Interventions to increase physical activity among breast cancer survivors are needed to improve health and quality of life and possibly to reduce the risk of disease recurrence and early mortality . Therefore , we report the feasibility and preliminary outcomes of a pilot r and omized trial design ed to increase physical activity in sedentary breast cancer survivors receiving hormone therapy . METHODS Forty-one sedentary women on estrogen receptor modulators or aromatase inhibitors for stage I , II , or IIIA breast cancer were r and omly assigned to receive a 12-wk multidisciplinary physical activity behavior change intervention or usual care . RESULTS Recruitment was 34 % , intervention adherence was 99 % , and complete follow-up data were obtained on 93 % . Most participants ( 93 % ) were white with mean age of 53 + /- 9 yr . Differences favoring the intervention group were noted for accelerometer physical activity counts ( mean difference = 72,103 ; 95 % confidence interval ( CI ) = 25,383 - 119,000 ; effect size ( d ) = 1.02 ; P = 0.004 ) , aerobic fitness ( mean difference = 2.9 ; 95 % CI = -0.1 to 5.8 ; d = 0.64 ; P = 0.058 ) , back/leg muscle strength ( mean difference = 12.3 ; 95 % CI = 0.4 - 15.9 ; d = 0.81 ; P = 0.017 ) , waist-to-hip ratio ( mean difference = -0.05 ; 95 % CI = -0.01 to -0.08 ; d = -0.77 ; P = 0.018 ) , and social well-being ( mean difference = 2.0 ; 95 % CI = 0.3 - 3.8 ; d = 0.76 ; P = 0.03 ) . However , the intervention group also reported a greater increase in joint stiffness ( mean difference = 1.1 ; 95 % CI = 0.1 - 2.2 ; d = 0.70 ; P = 0.04 ) . CONCLUSIONS A behavior change intervention for breast cancer survivors based on the social cognitive theory is feasible and results in potentially meaningful improvements in physical activity and selected health outcomes . Confirmation in a larger study is warranted [19714371] Purpose It has not previously been shown whether there is any benefit to multi-morbid patients with lung cancer who participate in complex interdisciplinary rehabilitation programmes after primary therapy . The purpose of this prospect i ve study was to assess changes in exercise capacity and quality of life before and after an in-patient training programme . Patients and methods Forty-five patients with lung cancer ( WHO I-III after surgery and /or radiotherapy and /or chemotherapy ) were enrolled in a 28-day in-patient rehabilitation programme that included st and ardised aerobic training . Functional status and health-related quality of life ( QLQ-C30 , QLQ-LC13 , SF-36 , and MFI-20 ) were examined at the beginning of the study and at day 28 . Results A substantial increase in work performance ( bicycle ergometry from 68 ± 3 to 86 ± 4 W , p < 0.001 , and 6-minute walk test from 322 ± 11 to 385 ± 13 m , p < 0.001 ) was registered . In addition , heart rate at rest was reduced ( from 84 ± 2 to 80 ± 1 beats per minute , p < 0.05 ) and heart rate variability ( indicator of the efficacy of endurance training ) was significantly increased ( from 9.7 ± 1 to 12.9 ± 1 root mean square of successive differences , p < 0.001 ) . Moreover , there was also a significant improvement in quality of life ( 48 ± 3 to 62 ± 2 , p < 0.001 ) while fatigue was reduced from 66 ± 3 to 41 ± 4 , p < 0.001 . Conclusion A st and ardised , aerobic endurance training programme as part of the in-patient oncological rehabilitation of patients with lung cancer results in improvements in both physiological and psychological parameters after therapy . A follow-on study in order to determine to what extent this benefit persists over the long-term , particularly , in comparison with patients who have not participated in a rehabilitation programme , is currently being conducted [17307761] Objectives To determine functional and psychological benefits of a 12 week supervised group exercise programme during treatment for early stage breast cancer , with six month follow-up . Design Pragmatic r and omised controlled prospect i ve open trial . Setting Three National Health Service oncology clinics in Scotl and and community exercise facilities . Participants 203 women entered the study ; 177 completed the six month follow-up . Interventions Supervised 12 week group exercise programme in addition to usual care , compared with usual care . Main outcome measures Functional assessment of cancer therapy ( FACT ) question naire , Beck depression inventory , positive and negative affect scale , body mass index , seven day recall of physical activity , 12 minute walk test , and assessment of shoulder mobility . Results Mixed effects models with adjustment for baseline values , study site , treatment at baseline , and age gave intervention effect estimates ( intervention minus control ) at 12 weeks of 129 ( 95 % confidence interval 83 to 176 ) for metres walked in 12 minutes , 182 ( 75 to 289 ) for minutes of moderate intensity activity reported in a week , 2.6 ( 1.6 to 3.7 ) for shoulder mobility , 2.5 ( 1.0 to 3.9 ) for breast cancer specific subscale of quality of life , and 4.0 ( 1.8 to 6.3 ) for positive mood . No significant effect was seen for general quality of life ( FACT-G ) , which was the primary outcome . At the six month follow-up , most of these effects were maintained and an intervention effect for breast cancer specific quality of life emerged . No adverse effects were noted . Conclusion Supervised group exercise provided functional and psychological benefit after a 12 week intervention and six months later . Clinicians should encourage activity for their patients . Policy makers should consider the inclusion of exercise opportunities in cancer rehabilitation services . Trial registration Current controlled trials IS RCT N12587864 [17470863] PURPOSE To examine the effects of aerobic exercise therapy on quality of life ( QoL ) and associated outcomes in women treated for breast cancer . Evidence suggests that exercise may be beneficial , but no trial has included an exercise-placebo and a usual-care group to control for the attention effects that might be associated with aerobic exercise interventions in cancer patients . PATIENTS AND METHODS A total of 108 women who had been treated for breast cancer 12 to 36 months previously were r and omly assigned to supervised aerobic exercise therapy ( n = 34 ) , exercise-placebo ( body conditioning ; n = 36 ) , or usual care ( n = 38 ) . Exercise therapy and exercise-placebo sessions took place three times per week for 8 weeks . Outcomes included QoL , depression , exercise behavior , aerobic fitness ; outcomes were assessed at baseline and at the 8- and 24-week follow-up . RESULTS Analyses of covariance revealed a significant mean difference of 9.8 units in Functional Assessment of Cancer Therapy-General ( primary outcome ) favoring aerobic exercise therapy at 8 weeks , relative to usual care . Significant differences that favored aerobic exercise therapy relative to usual care were recorded for Functional Assessment of Cancer Therapy-Breast , social/family well-being , functional well-being , and breast cancer subscale scores at 8-week follow-up . Psychological health outcomes improved modestly for both intervention groups ; these improvements were sustained for several end points . CONCLUSION Exercise therapy had large , clinical ly meaningful , short-term beneficial effects on QoL in women treated for breast cancer ; this finding can not be attributable to attention , given that the exercise-placebo group did not report similar effects relative to usual care [12721239] PURPOSE To determine the effects of exercise training on cardiopulmonary function and quality of life ( QOL ) in postmenopausal breast cancer survivors who had completed surgery , radiotherapy , and /or chemotherapy with or without current hormone therapy use . METHODS Fifty-three postmenopausal breast cancer survivors were r and omly assigned to an exercise ( n = 25 ) or control ( n = 28 ) group . The exercise group trained on cycle ergometers three times per week for 15 weeks at a power output that elicited the ventilatory equivalent for carbon dioxide . The control group did not train . The primary outcomes were changes in peak oxygen consumption and overall QOL from baseline to postintervention . Peak oxygen consumption was assessed by a grade d exercise test using gas exchange analysis . Overall QOL was assessed by the Functional Assessment of Cancer Therapy-Breast scale . RESULTS Fifty-two participants completed the trial . The exercise group completed 98.4 % of the exercise sessions . Baseline values for peak oxygen consumption ( P = .254 ) and overall QOL ( P = .286 ) did not differ between groups . Peak oxygen consumption increased by 0.24 L/min in the exercise group , whereas it decreased by 0.05 L/min in the control group ( mean difference , 0.29 L/min ; 95 % confidence interval [ CI ] , 0.18 to 0.40 ; P < .001 ) . Overall QOL increased by 9.1 points in the exercise group compared with 0.3 points in the control group ( mean difference , 8.8 points ; 95 % CI , 3.6 to 14.0 ; P = .001 ) . Pearson correlations indicated that change in peak oxygen consumption correlated with change in overall QOL ( r = 0.45 ; P < .01 ) . CONCLUSION Exercise training had beneficial effects on cardiopulmonary function and QOL in postmenopausal breast cancer survivors [7937251] PURPOSE / OBJECTIVES To examine the effects of a comprehensive rehabilitation program on facilitating physical and psychosocial adaptation of women with breast cancer who are receiving adjuvant chemotherapy . DESIGN Experimental . SETTING Breast evaluation clinics of two New Engl and medical centers with comprehensive cancer treatment programs . SAMPLE 14 women ( mean age = 44 years ) receiving adjuvant chemotherapy for breast cancer ( 86 % stage II ) following surgical treatment . METHODS Subjects were assigned r and omly to the experimental group or the usual care group . Experimental group members began a structured exercise program of walking and attended support group meetings . All subjects were tested before beginning chemotherapy , during the course of chemotherapy , and one month following chemotherapy completion . MAIN RESEARCH VARIABLES Performance status , physical functioning , psychosocial adjustment , self-concept and body image , and 12 symptoms ( e.g. , fatigue , nausea , anxiety ) . FINDINGS Measures of physical performance , psychosocial adjustment , and symptom intensity revealed improved adaptation in subjects who completed the walking/support group program . CONCLUSIONS Physical and psychosocial benefits from a modest walking exercise program and a support group are possible for patients receiving adjuvant chemotherapy . IMPLICATION S FOR NURSING PRACTICE Although more detailed research is necessary to answer some of the questions raised by this study , implementing the walking program and forming a support group are achievable in an outpatient setting [18414905] Purpose Although physical activity ( PA ) adoption improves fitness and psychological well-being among cancer survivors , PA maintenance has not been examined . This paper presents follow-up of a home-based PA program for women treated for early-stage breast cancer . Material s and methods Eighty-six sedentary women ( mean age = 53.14 years , SD = 9.70 ) were r and omly assigned to a PA or contact control group . The PA group received a 12-week telephone counseling program to adopt PA . Assessment s were conducted at baseline , end-of-intervention ( 12 weeks ) , 6 , and 9 months post-baseline . Results When comparing change from end-of-intervention ( 12 weeks ) between groups , a significant reduction was observed in minutes of PA at 6 months ( t = −2.10 , p < 0.05 ) , but there was no decrease in intervention effect at 9 months ( t = −0.19 , p = 0.84 ) . Similarly , post-intervention reductions in fatigue were lost at 6 months ( t = 3.27 , p < 0.01 ) , but remained present at 9 months ( t = 1.65 , p = 0.10 ) . PA group ’s fitness improvements were maintained at both follow-ups ( t = 1.04 , p = 0.30 and t = 0.05 , p = 0.96 ) . The previously significant intervention effect on vigor was maintained at 6 months ( t = 1.32 , p = 0.19 ) but was significantly reduced at 9 months ( t = −2.15 , p < 0.05 ) . PA participants were more likely to progress in motivational readiness at 6 ( OR = 5.95 , 95 % CI = 2.30 , 15.36 ) and 9 months ( OR = 4.09 , 95 % CI = 1.69 , 9.87 ) ; however , group differences in meeting PA guidelines were not maintained . ConclusionS ome positive effects of a home-based PA intervention for breast cancer patients were maintained at 6 and 9 months [17785708] PURPOSE Breast cancer chemotherapy may cause unfavorable changes in physical functioning , body composition , psychosocial functioning , and quality of life ( QOL ) . We evaluated the relative merits of aerobic and resistance exercise in blunting these effects . PATIENTS AND METHODS We conducted a multicenter r and omized controlled trial in Canada between 2003 and 2005 that r and omly assigned 242 breast cancer patients initiating adjuvant chemotherapy to usual care ( n = 82 ) , supervised resistance exercise ( n = 82 ) , or supervised aerobic exercise ( n = 78 ) for the duration of their chemotherapy ( median , 17 weeks ; 95 % CI , 9 to 24 weeks ) . Our primary end point was cancer-specific QOL assessed by the Functional Assessment of Cancer Therapy-Anemia scale . Secondary end points were fatigue , psychosocial functioning , physical fitness , body composition , chemotherapy completion rate , and lymphedema . RESULTS The follow-up assessment rate for our primary end point was 92.1 % , and adherence to the supervised exercise was 70.2 % . Unadjusted and adjusted mixed-model analyses indicated that aerobic exercise was superior to usual care for improving self-esteem ( P = .015 ) , aerobic fitness ( P = .006 ) , and percent body fat ( adjusted P = .076 ) . Resistance exercise was superior to usual care for improving self-esteem ( P = .018 ) , muscular strength ( P < .001 ) , lean body mass ( P = .015 ) , and chemotherapy completion rate ( P = .033 ) . Changes in cancer-specific QOL , fatigue , depression , and anxiety favored the exercise groups but did not reach statistical significance . Exercise did not cause lymphedema or adverse events . CONCLUSION Neither aerobic nor resistance exercise significantly improved cancer-specific QOL in breast cancer patients receiving chemotherapy , but they did improve self-esteem , physical fitness , body composition , and chemotherapy completion rate without causing lymphedema or significant adverse events [11879296] PURPOSE Despite the recognition of fatigue as a common and distressing symptom during cancer treatment , there are few evidence -based interventions available to manage such fatigue . The purpose of this multi-institutional pilot study was to explore the effects of a home-based moderate walking exercise intervention on fatigue , physical functioning , emotional distress , and quality of life ( QOL ) during breast cancer treatment . DESCRIPTION OF STUDY Fifty-two women were recruited from five university hospital outpatient departments for this pilot study with an experimental design . Subjects were r and omly assigned to the walking program or to usual care during adjuvant chemotherapy or radiation therapy for breast cancer . Symptoms , physical functioning , and QOL were measured at baseline , midtreatment , and at the end of treatment . RESULTS Women who exercised at least 90 minutes per week on 3 or more days reported significantly less fatigue and emotional distress as well as higher functional ability and QOL than women who were less active during treatment . CLINICAL IMPLICATION S A home-based walking exercise program is a potentially effective , low-cost , and safe intervention to manage fatigue and to improve QOL during adjuvant chemotherapy or radiation therapy for breast cancer . This health-promoting self-care activity needs further testing in large r and omized clinical trials [15151958] BACKGROUND Anemia is common in cancer and has been associated with fatigue and reduced health-related quality of life ( HRQOL ) . We report the association between hemoglobin and fatigue and the impact of reducing fatigue on several domains of HRQOL . PATIENTS AND METHODS These analyses were based on five r and omized trials . Patients completed the Functional Assessment of Cancer Therapy ( FACT ) Anemia scales and numeric rating scales of Energy , Activity and Overall Health at baseline and after the 12-week treatment period . t-tests and linear regression models were used to evaluate associations . Analyses were stratified into three groups : solid tumor chemotherapy patients , lymphoproliferative malignancy chemotherapy patients and non-chemotherapy patients . RESULTS Adjusted mean differences ( 95 % CI ) in FACT Fatigue change scores between hemoglobin responders ( > or = 2 g/dl increase ) and non-responders were 3.0 ( 1.2 , 4.7 ) , 2.8 ( 0.6 , 5.0 ) and 5.8 ( 2.2 , 9.5 ) among the solid tumor , lymphoproliferative malignancy and non-chemotherapy groups , respectively . Significantly greater improvements ( P < 0.01 ) were observed in the FACT well-being scales for patients with meaningful improvement in fatigue ( FACT Fatigue change score > or =3 points ) . After controlling for other factors , patients whose fatigue improved reported substantially greater improvements in energy , ability to perform usual activities and overall health ( P < 0.0001 ) . CONCLUSIONS Across five trials of cancer patients on and off chemotherapy , hemoglobin response was associated with meaningful improvements in fatigue , which , in turn , was associated with improved physical , functional , emotional and overall well-being [19383889] Purpose : We previously reported the effectiveness of a 12-week physical activity behavior change intervention for breast cancer survivors postintervention with this report , aim ing to determine delayed and /or persistent effects 3 months after intervention completion . Methods : Forty-one sedentary women with stage I , II , or IIIA breast cancer currently receiving hormonal therapy were r and omly assigned to receive the 12-week Better Exercise Adherence after Treatment for Cancer intervention or usual care . Assessment s occurred at baseline , postintervention , and 3 months postintervention . Results : Weekly minutes of greater than or equal to moderate intensity physical activity measured by accelerometer showed a significant group by time interaction ( F = 3.51 ; P = 0.035 ; between group difference in the mean change from baseline to 3 months postintervention , 100.1 minute , P = 0.012 ) . Significant group by time interactions also showed sustained improvements from baseline to 3 months postintervention in strength ( F = 3.82 ; P = 0.027 ; between group difference , 11.2 kg ; P = 0.026 ) , waist-to-hip ratio ( F = 3.36 ; P = 0.041 ; between group difference , −0.04 ; P = 0.094 ) , and social well-being ( F = 4.22 ; P = 0.023 ; between group difference , 3.9 ; P = 0.039 ) . A delayed reduction in lower extremity dysfunction 3 months postintervention was noted ( F = 3.24 ; P = 0.045 ; between group difference in the mean change from postintervention to 3 months follow-up ; P = −7.6 ; P = 0.015 ) . No group by time effect was noted for fitness , body mass index , percent fat , bone density , total quality of life ( Functional Assessment of Cancer Therapy-General ) , fatigue , endocrine symptoms , cognitive function , or sleep . Conclusions : The intervention result ed in sustained improvements in physical activity , strength , central adiposity , and social well-being with lower extremity function benefits appearing 3 months after intervention completion . Testing translation in a multisite study is warranted . ( Cancer Epidemiol Biomarkers Prev 2009;18(5):1410–8 [2762035] Objective To assess the effect of a multimodal group exercise intervention , as an adjunct to conventional care , on fatigue , physical capacity , general wellbeing , physical activity , and quality of life in patients with cancer who were undergoing adjuvant chemotherapy or treatment for advanced disease . Design R and omised controlled trial . Setting Two university hospitals in Copenhagen , Denmark . Participants 269 patients with cancer ; 73 men , 196 women , mean age 47 years ( range 20 - 65 ) representing 21 diagnoses . Main exclusion criteria were brain or bone metastases . 235 patients completed follow-up . Intervention Supervised exercise comprising high intensity cardiovascular and resistance training , relaxation and body awareness training , massage , nine hours weekly for six weeks in addition to conventional care , compared with conventional care . Main outcome measures European Organization for Research and Treatment of Cancer Quality of Life Question naire ( EORTC QLQ-C30 ) , Medical Outcomes Study Short Form ( MOS SF-36 ) , Leisure Time Physical Activity Question naire , muscular strength ( one repetition maximum ) , maximum oxygen consumption ( Vo2max ) . Statistical methods The general linear model was used for continuous outcome while analysis of associates between categorical outcomes was performed as analysis of marginal homogeneity in contingency tables . Results Adjusted for baseline score , disease , and demographic covariates , the intervention group showed an estimated improvement at six weeks for the primary outcome , fatigue , of −6.6 points ( 95 % confidence interval −12.3 to −0.9 , P=0.02 ; effect size=0.33 , 0.04 to 0.61 ) . Significant effects were seen on vitality ( effect size 0.55 , 95 % CI 0.27 to 0.82 ) , physical functioning ( 0.37 , 0.09 to 0.65 ) , role physical ( 0.37 , 0.10 to 0.64 ) , role emotional ( 0.32 , 0.05 to 0.59 ) , and mental health ( 0.28 , 0.02 to 0.56 ) scores . Improvement was noted in physical capacity : estimated mean difference between groups for maximum oxygen consumption was 0.16 l/min ( 95 % CI 0.1 to 0.2 , P<0.0001 ) and for muscular strength ( leg press ) was 29.7 kg ( 23.4 to 34.9 , P<0.0001 ) . No significant effect was seen on global health status/ quality of life . Conclusion A supervised multimodal exercise intervention including high and low intensity components was feasible and could safely be used in patients with various cancers who were receiving adjuvant chemotherapy or treatment for advanced disease . The intervention reduced fatigue and improved vitality , aerobic capacity , muscular strength , and physical and functional activity , and emotional wellbeing , but not quality of life . Trial registration Current Controlled trials IS RCT N05322922 [12560436] PURPOSE To examine the effect of a progressive upper-body exercise program on lymphedema secondary to breast cancer treatment . METHODS Fourteen breast cancer survivors with unilateral upper extremity lymphedema were r and omly assigned to an exercise ( n = 7 ) or control group ( n = 7 ) . The exercise group followed a progressive , 8-week upper-body exercise program consisting of resistance training plus aerobic exercise using a Monark Rehab Trainer arm ergometer . Lymphedema was assessed by arm circumference and measurement of arm volume by water displacement . Patients were evaluated on five occasions over the experimental period . The Medical Outcomes Trust Short-Form 36 Survey was used to measure quality of life before and after the intervention . Significance was set at alpha < or = 0.01 . RESULTS No changes were found in arm circumference or arm volume as a result of the exercise program . Three of the quality -of-life domains showed trends toward increases in the exercise group : physical functioning ( P = .050 ) , general health ( P = .048 ) , and vitality ( P = .023 ) . Mental health increased , although not significantly , for all subjects ( P = .019 ) . Arm volume measured by water displacement was correlated with calculated arm volume ( r = .973 , P < .001 ) , although the exercise and control group means were significantly different ( P < .001 ) . CONCLUSIONS Participation in an upper-body exercise program caused no changes in arm circumference or arm volume in women with lymphedema after breast cancer , and they may have experienced an increase in quality of life . Additional studies should be done in this area to determine the optimum training program [17360236] Fatigue is one of the most frequent side effects of cancer treatments . According to a number of studies , the incidence of fatigue as a side effect of radiation therapy ( RT ) ranges from 65 % to 100 % depending on which instruments were used ( Greenberg et al. , 1992 ; Jacobsen-Thors , 2003 ) . For many cancer patients , cancer-related fatigue is severe and imposes limitations on normal daily activities ( JereczekFossa et al. , 2002 ) . Patients often report that cancerrelated fatigue differs from fatigue experienced before initiation of cancer . They describe it as severe , chronic and frustrating , effects that fail to be relieved by rest . In many studies in the past , patients have felt that fatigue has adversely affected their quality of life more than pain and sexual dysfunction or other treatment-related side effects ( Stone et al. , 1998 ) . Fatigue has negative impact on various aspects of quality of life , so it is imperative to find non-invasive and nonpharmacological solutions for managing it . There is little however known as to which techniques can help alleviate fatigue . Physical exercise has been shown to be effective , convenient and a low-cost self-care method for reducing anxiety and sleep difficulties , and increasing adaptation during radiotherapy . Aerobic exercises ( e.g. walking ) have been suggested for the rehabilitation of cancer patients affected by energy loss but this is not a fully accepted approach as yet . Nevertheless , exercise has been shown [18591167] PURPOSE / OBJECTIVES To compare the effectiveness of a prescribed home-based walking exercise intervention with usual care in older women receiving hormonal treatment for breast cancer , and to examine relationships among levels of the cortisol , serotonin , interleukin-6 , and bilirubin biomarkers and fatigue , sleep disturbances , and depressive symptoms . DESIGN Longitudinal r and omized clinical trial . SETTING A National Cancer Institute- design ated cancer center in the southeastern United States . SAMPLE 20 women ( aged 55 years or older ) with breast cancer receiving hormonal treatment . METHODS Participants were r and omized to a walking exercise intervention or usual care . Laboratory sample s and the Pittsburgh Sleep Quality Index ( PSQI ) , the Piper Revised Fatigue Scale , and the Center for Epidemiological Studies -Depression Scale were collected at the initial clinic visit and at 12 weeks from the groups . Question naires also were collected at weeks 2 and 14 . MAIN RESEARCH VARIABLES Fatigue , sleep disturbances , depressive symptoms , biomarkers , and exercise . FINDINGS Effect of the exercise intervention on sleep scores was highly significant between groups . Exercise group scores on the PSQI decreased significantly over time ( indicating improved sleep quality ) , although scores did not change significantly within the control group . Sleep actigraphy also showed significantly shorter actual wake time and less movement in the exercise group . Serotonin levels also were significantly affected by the intervention . CONCLUSIONS Data suggest that a walking exercise intervention improves sleep in older women receiving hormonal treatment for their breast cancer . Serotonin levels may be a useful biomarker when assessing sleep disturbances in this group . IMPLICATION S FOR NURSING Clinicians need to be aware that older women receiving hormonal treatment for their breast cancer may experience fatigue , sleep disturbances , and depressive symptoms . Homebased walking activity may reduce symptom severity in this group [10548868] Purpose : Fatigue is a common side effect of cancer treatment that impacts quality of life . Exercise is one approach suggested to improve fatigue . The purpose of this study was to explore the relationship of exercise to fatigue and quality of life . Methods : Thirty-one subjects with breast cancer were enrolled prior to beginning chemotherapy and 27 completed the study . All baseline measures were obtained before the first chemotherapy treatment . Subjects were instructed on a home-based , 8-week exercise program . Results : Women who adopted the exercise program ( 60 % ) showed significant increases in functional ability and less weight gain . Exploratory , stepwise multiple regression analyses suggested that the maximum effect of exercise on quality of life outcomes may be mediated by fatigue . Conclusions : The low-to-moderate intensity , home-based exercise program was feasible for some women with breast cancer receiving chemotherapy . The results suggest that exercise may affect quality of life and that this effect may be mediated by the effects of exercise on fatigue . Better retention of functional ability and better weight control are additional possible benefits of exposing breast cancer patients to increased exercise . A r and omized , controlled clinical trial is needed to establish confidence in these observed relationships [17964881] OBJECTIVE To show fatigue prevention and quality of life ( QOL ) improvement from cardiovascular exercise during radiotherapy . DESIGN Prospect i ve enrollment ( n=21 ) , r and omized to exercise ( n=11 ) and control groups ( n=10 ) , with pre- and post-radiotherapy between- and within-group comparisons . SETTING Academic medical center . PARTICIPANTS Localized prostate cancer patients undergoing radiotherapy . INTERVENTIONS The interventional group received radiotherapy plus aerobic exercise 3 times a week for 8 weeks whereas the control group received radiotherapy without exercise . MAIN OUTCOME MEASURES Pre- and post-radiotherapy differences in cardiac fitness , fatigue , depression , functional status , physical , social , and functional well-being , leg strength , and flexibility were examined within and between 2 groups . RESULTS No significant differences existed between 2 groups at pre-radiotherapy assessment . At post-radiotherapy assessment , the exercise group showed significant within group improvements in : cardiac fitness ( P<.001 ) , fatigue ( P=.02 ) , Functional Assessment of Cancer Therapy-Prostate ( FACT-P ) ( P=.04 ) , physical well-being ( P=.002 ) , social well-being ( P=.02 ) , flexibility ( P=.006 ) , and leg strength ( P=.000 ) . Within the control group , there was a significant increase in fatigue score ( P=.004 ) and a decline in social well-being ( P<.05 ) at post-radiotherapy assessment . Between-group differences at post-radiotherapy assessment were significant in cardiac fitness ( P=.006 ) , strength ( P=.000 ) , flexibility ( P<.01 ) , fatigue ( P<.001 ) , FACT-P ( P=.006 ) , physical well-being ( P<.001 ) , social well-being ( P=.002 ) , and functional well-being ( P=.04 ) . CONCLUSIONS An 8-week cardiovascular exercise program in patients with localized prostate cancer undergoing radiotherapy improved cardiovascular fitness , flexibility , muscle strength , and overall QOL and prevented fatigue [17156590] Study objectives . Cancer-related fatigue ( CRF ) is frequently reported by cancer patients receiving cytotoxic drugs . The specific mechanism of CRF in cancer patients is not completely known . In recent years , convincing evidence supports the management of fatigue with physical exercise . This study investigated a recommendation that physical activity , eg , a 30-minute daily walk , would decrease fatigue in cancer patients receiving cytotoxic drugs at an outpatient ward . Method . In total , 89 patients were interviewed about their fatigue and were asked to complete a question naire , the Fatigue Symptom Inventory ( FSI ) , once a week over several treatment cycles of cytotoxic drugs . On inclusion , all patients received similar information about fatigue . After r and omization , information about the positive effects of exercise was given to half of the patients after one cycle of cytotoxic drugs , and to the remaining patients after two cycles of cytotoxic drugs . Results . A total of 74 patients completed the study and returned useable question naires . The fatigue prevalence was 89 % after one cytotoxic drug cycle . According to the FSI ratings , the group who received information about physical exercise after one cycle scored significantly lower ratings than the other group throughout the study ( P=0.034 ) . The patient interviews confirmed that physical activity helped them to better battle fatigue . Intensity of other symptoms and side effects from cytotoxic drugs closely paralleled the fatigue ratings . Conclusion . Fatigue was commonly found in the study population . Though small improvements followed physical exercise , results pointed towards the fact that information and exercise may support patients to combat fatigue . Early and frequent information would probably support patients to better combat fatigue by physical exercise [15774341] This pilot study examined whether exercise as an adjunctive rehabilitation therapy could benefit women who have early stage breast cancer and are currently receiving chemotherapy/radiotherapy . The study was design ed as a r and omised controlled trial ( RCT ) . Physical functioning , fatigue and Quality of Life ( QoL ) outcomes were evaluated pre and post a 12-week intervention . The results showed that after 12 weeks the women who participated in the exercise programme ( n = 12 ) displayed significantly higher levels of physical functioning and reported higher QoL scores than the controls ( n = 10 ) . Changes in fatigue and satisfaction with life favoured the intervention group but did not reach significance . These results are encouraging and suggest that a structured group exercise programme during adjuvant treatment is a safe , well tolerated and effective way of providing physical and psychological health benefits to women during treatment for early stage breast cancer . Since this was a pilot study the numbers did not allow appropriately powered analyses of some variables of interest and favoured relatively young and socio-economically advantaged women . Future studies need to address these issues and determine if these short-term benefits can be sustained [14710804] Fatigue and insomnia are problems for patients with cancer . Research findings show that aerobic exercise decreases cancer-related fatigue . Because patients with cancer who have skeletal muscle wasting may not obtain maximum benefit from aerobic exercise training , exercise programs may need to include resistance training . Thus far , testing exercise as an intervention for fatigue has focused on patients with breast cancer and excluded patients with bone metastasis . There is a need to test the feasibility and effectiveness of exercise for patients with other types of cancer and with bone involvement . The effect of aerobic and strength resistance training on the sleep of patients with cancer has not been tested . A pilot/feasibility study with a r and omized controlled design was conducted to investigate homebased exercise therapy for 24 patients receiving high-dose chemotherapy and autologous peripheral blood stem cell transplantation as treatment for multiple myeloma . None of the patients injured themselves . Because of the small sample size in the feasibility study , the effect of exercise on lean body weight was the only end point that obtained statistical significance . However , the results suggest that an individualized exercise program for patients receiving aggressive treatment for multiple myeloma is feasible and may be effective for decreasing fatigue and mood disturbance , and for improving sleep [18980921] PURPOSE / OBJECTIVES To investigate the effects of supervised exercise training on cardiopulmonary function and fatigue in cancer survivors undergoing various clinical treatments . DESIGN Pretest and post-test quasiexperimental . SETTING Outpatient oncology rehabilitation center . SAMPLE 96 breast cancer survivors undergoing various clinical treatments . METHODS Subjects were divided into four groups based on the specific type of clinical treatment : surgery alone ( n = 22 ) ; surgery and chemotherapy ( n = 30 ) ; surgery and radiation ( n = 17 ) ; and surgery , chemotherapy , and radiation ( n = 27 ) . Following a comprehensive screening and medical examination , cardiovascular endurance , pulmonary function , and fatigue were assessed , leading to the development of an individualized exercise prescription and a six-month exercise intervention . Repeated- measures analysis of variance and covariance were used to compare the effectiveness of the intervention and differences among treatment groups . MAIN RESEARCH VARIABLES Systolic and diastolic blood pressure , resting heart rate , forced vital capacity , forced expiratory volume , predicted oxygen consumption , time on treadmill , and fatigue . FINDINGS Cardiopulmonary function ( predicted maximal oxygen consumption and time on treadmill ) significantly increased in all groups after exercise training . In addition , resting heart rate and forced vital capacity significantly improved in those receiving surgery , chemotherapy , and radiation . Psychologically , the exercise intervention result ed in significant reductions in behavioral , affective , sensory , cognitive and mood , and total fatigue scale scores in all three groups who received treatment with surgery . The breast cancer survivors in the surgery-alone group showed significant reductions in behavioral , affective , and total fatigue scale scores but not in sensory and cognitive and mood fatigue scale scores . CONCLUSIONS The results suggest that moderate intensity , individualized , prescriptive exercise maintains or improves cardiopulmonary function with concomitant reductions in fatigue regardless of treatment type . Moreover , cancer survivors receiving combination chemotherapy and radiotherapy following surgery appear to benefit to a greater extent as a result of an individualized exercise intervention . IMPLICATION S FOR NURSING Clinicians need to be aware of adjuvant therapies such as moderate exercise that attenuate negative side effects of cancer treatments . Symptom management recommendations should be given to cancer survivors concerning the effectiveness of exercise throughout the cancer continuum and the importance of participating in a cancer rehabilitation exercise program [12619144] Exercise participation has been shown to improve cardiovascular fitness and reduce psychological distress among women receiving chemotherapy and /or radiation . The purpose of this pilot study was to examine the changes in distress and body image , and fitness following exercise participation among 24 women who had been diagnosed with breast cancer within the previous 3 years . The women were r and omly assigned to participate in a 12-week supervised aerobic exercise program in a hospital setting or a wait-list control group . Assessment s of distress and body image were conducted at pre- and post-treatment . Data showed that the women in the exercise group improved significantly in body image ( Physical Condition and Weight Concerns subscales ) vs control group participants at post-treatment . Reductions in distress were also noted in the exercise group , but these were nonsignificant . At post-treatment , there were modest improvements in fitness in the exercise group [19242916] OBJECTIVES Restorative yoga ( RY ) is a gentle type of yoga that may be beneficial for cancer patients and post-treatment survivors . Study goals were : to determine the feasibility of implementing a RY intervention for women with breast cancer ; and to examine group differences in self-reported emotional , health-related quality of life , and symptom outcomes . METHODS Women with breast cancer ( n=44 ; mean age 55.8 years ) enrolled in this study ; 34 % were actively undergoing cancer treatment . Study participants were r and omized to the intervention ( 10 weekly 75-minute RY classes ) or a waitlist control group . Participants completed question naires at Week 0 ( baseline ) and Week 10 ( immediately post-intervention for the yoga group ) . RESULTS Group differences favoring the yoga group were seen for mental health , depression , positive affect , and spirituality ( peace/meaning ) . Significant baseline*group interactions were observed for negative affect and emotional well-being . Women with higher negative affect and lower emotional well-being at baseline derived greater benefit from the yoga intervention compared to those with similar values at baseline in the control group . The yoga group demonstrated a significant within-group improvement in fatigue ; no significant difference was noted for the control group . CONCLUSIONS Although limited by sample size , these pilot data suggest potential benefit of RY on emotional outcomes and fatigue in cancer patients . This study demonstrates that a RY intervention is feasible for women with breast cancer ; implication s for study design and implementation are noted with an emphasis on program adoption and participant adherence [20531162] Cheville AL , Girardi J , Clark MM , Rummans TA , Pittelkow T , Brown P , Hanson J , Atherton P , Johnson ME , Sloan JA , Gamble G : Therapeutic exercise during outpatient radiation therapy for advanced cancer : Feasibility and impact on physical well-being . Objective : To characterize the feasibility of delivering a structured physical therapy ( PT ) program as part of a multidisciplinary intervention to patients undergoing outpatient radiation therapy for advanced cancer . Design : A single-blinded , r and omized , controlled trial at a quaternary medical center outpatient clinic . One hundred three adults undergoing radiation therapy for advanced cancer with prognoses ≥6 mos and 5-yr survival estimates ≤50 % were r and omized to usual care or participation in eight 90-min , multidisciplinary interventional sessions with 30 mins of each session devoted to PT . PT consisted of truncal and limb isodynamic strengthening targeting major upper- and lower-limb muscle groups as well as education and provision with instructional material s. Physical well-being and fatigue were assessed with Linear Analog Scale of Assessment . The Profile of Mood States-Short form , including Fatigue-Inertia and Vigor-Activity subscales , was also administered . Results : PT session attendance was 89.3 % . Relative to baseline , mean physical well-being Linear Analog Self Assessment scores at week 4 improved in the intervention group , 0.4 ( SD , 23.6 ) , and declined significantly in the control group , −10.0 ( SD , 21.5 ) ( P = 0.02 ) . Fatigue and vigor were not significantly different between the groups . All intergroup differences had resolved at 8 and 27 wks . Baseline characteristics were not associated with the magnitude or direction of change in outcomes related to physical functioning . Conclusions : Delivery of a st and ardized resistive exercise PT intervention is feasible during outpatient radiation therapy and is associated with preserved physical well-being . However , benefits were not sustained , and fatigue was not affected [18490891] The purpose of this r and omized control trial was to verify the effectiveness of a brief group intervention that combines stress management psycho-education and physical activity ( ie , independent variable ) intervention in reducing fatigue and improving energy level , quality of life ( mental and physical ) , fitness ( VO2submax ) , and emotional distress ( ie , dependent variables ) in breast cancer survivors . This study applied Lazarus and Folkman stress-coping theoretical framework , as well as Salmon 's unifying theory of physical activity . Eighty-seven French-speaking women who had completed their treatments for nonmetastatic breast cancer at a university hospital in Quebec City , Canada , were r and omly assigned to either the group intervention ( experimental ) or the usual-care ( control ) condition . Data were collected at baseline , postintervention , and at 3-month follow-up . The 4-week group intervention was cofacilitated by 2 nurses . Results showed that participants in the intervention group showed greater improvement in fatigue , energy level , and emotional distress at 3-month follow-up , and physical quality of life at postintervention , compared with the participants in the control group . These results suggest that a brief psycho-educational group intervention focusing on active coping strategies and physical activity is beneficial to cancer survivors after breast cancer treatments [19831159] During radiation therapy , cancer patients may report cancer-related fatigue ( CRF ) , which impairs aerobic capacity , strength , muscle mass , and , ultimately , quality of life ( QOL ) . The purpose of this pilot clinical trial was to examine the feasibility and initial efficacy of a home-based aerobic and progressive resistance exercise intervention for aerobic capacity , strength , muscle mass , CRF , and QOL . Daily steps walked ( DSW ) , daily minutes of resistance exercise ( MRE ) , and number of resistance exercise days ( RED ) were assessed to evaluate intervention adherence . Breast and prostate cancer patients ( n = 38 ) beginning radiation therapy were r and omized to undergo 4 weeks of exercise or no exercise . Participants in the exercise group demonstrated good adherence to the exercise intervention , with significantly more DSW , MRE , and RED at post intervention and 3 month follow-up than controls . Participants in the exercise intervention exhibited significantly higher QOL and significantly lower CRF post intervention and at 3-month follow-up than controls . Results of this pilot study provide positive preliminary evidence that exercise during radiation may be beneficial for cancer patients [17505681] CONTEXT AND OBJECTIVE Changes in metabolism have been reported in the majority of patients undergoing cancer treatment , and these are usually characterized by progressive change in body composition . The effects of aerobic exercise programs to combat the cancer and cancer treatment-related side effects , which include the negative changes in body composition , have been extensively reported in the literature . However , few resistance exercise intervention studies have hypothesized that breast cancer patients might benefit from this type of exercise . The purpose of this study was to determine whether exercise protocol s that emphasize resistance training would change body composition and strength in breast cancer patients undergoing treatment . DESIGN AND SETTING R and omized controlled trial , at the Campus Recreation Center and Rocky Mountain Cancer Rehabilitation Institute of the University of Northern Colorado , and the North Colorado Medical Center . METHODS Twenty inactive breast cancer patients were r and omly assigned to a 21-week exercise group ( n = 10 ) or a control group ( n = 10 ) . The exercise group trained at low to moderate intensity for 60 minutes on two days/week . The primary outcome measurements included body composition ( skinfold method ) and muscle strength ( one repetition maximum ) . RESULTS Significant differences in lean body mass , body fat and strength ( p = 0.004 , p = 0.004 , p = 0.025 , respectively ) were observed between the groups at the end of the study . CONCLUSION The results suggest that exercise emphasizing resistance training promotes positive changes in body composition and strength in breast cancer patients undergoing treatment [15378098] PURPOSE / OBJECTIVES To examine the effects of a seated exercise program on fatigue and quality of life ( QOL ) in women with metastatic breast cancer . DESIGN R and omized , controlled , longitudinal trial . SETTING Outpatient clinic of a comprehensive cancer center . SAMPLE Convenience sample of 38 women who were beginning outpatient chemotherapy . METHODS Subjects were r and omized to a control or intervention group ; the intervention was performance of a seated exercise program using home videotape three times per week for four cycles of chemotherapy . All subjects completed the Functional Assessment of Chronic Illness Therapy Fatigue Version IV ( FACIT F ) at baseline and at the time of the next three cycles . Subjects were asked to document the frequency , duration , and intensity of all exercise participation on monthly calendars . MAIN RESEARCH VARIABLES Exercise , fatigue , and QOL . FINDINGS 32 subjects , 16 per group , completed the study follow-up . With a mixed modeling approach , total FACIT F scores for the entire sample declined at a significant rate ( p = 0.003 ) beginning with cycle 3 but at a slower rate for the experimental group ( p = 0.02 ) . Fatigue scores indicated less increase and physical well-being subscale scores showed less decline for the experimental group ( p = 0.008 and p = 0.02 , respectively ) . CONCLUSIONS Women with advanced breast cancer r and omized to the seated exercise intervention had a slower decline in total and physical well-being and less increase in fatigue scores starting with the third cycle of chemotherapy . IMPLICATION S FOR NURSING Seated exercise may be a feasible exercise program for women with advanced cancer for controlling fatigue and improving physical well-being [12183762] PURPOSE / OBJECTIVES To examine the effect of exercise and methylpheni date on fatigue , functional ability , and cognitive function in patients with melanoma . DESIGN Pilot study with comparison to historic controls . SETTING University-based cancer center . SAMPLE 12 patients with melanoma entered and completed the study . The mean age was 44 years . METHOD Eligible patients were recruited before their first dose of interferon-a ( IFN-a ) . Patients were instructed to take 20 mg sustained-release methylpheni date every morning and follow an aerobic exercise program four days a week for 15 - 30 minutes . Measures included a 12-minute walk , the Schwartz Cancer Fatigue Scale , Trail Maker Forms A and B , Medical Outcomes Study 36 Short Form , body weight , and daily logs . Fatigue scores were compared to usual care historical controls with melanoma receiving only IFN-a . MAIN RESEARCH VARIABLES Fatigue , functional ability , and cognitive function . FINDINGS 66 % adhered to exercise and methylpheni date ; all adhered to exercise . Fatigue was lower for the exercise and methylpheni date group than historic controls . Functional ability increased 6 % for all patients and 9 % for the exercise and methylpheni date group . Cognitive function was stable for the exercise and methylpheni date group . The exercise-only group showed marked cognitive slowing . CONCLUSION The combination of aerobic exercise and methylpheni date may have a positive effect on fatigue , cognitive function , and functional ability . A larger sample size and r and omized trial is needed to more rigorously evaluate the results of exercise and methylpheni date alone or in combination . IMPLICATION S FOR NURSING Although further study is needed , a combination of exercise and methylpheni date may be a practical intervention for patients receiving IFN-a for melanoma [20443054] Breast cancer is the most prevalent type of cancer in American women . Exercise appears to diminish many of the side effects result ing from breast cancer and its treatment . Very little research , however , has compared the outcomes of varying lengths of combined aerobic and resistance training exercise interventions on physiological and psychological parameters in breast cancer survivors . The purpose of this study was to compare the physiological and psychological outcomes following 3 and 6 months of exercise in breast cancer survivors . Breast cancer survivors ( N = 114 ) participated in either 3 months of prescriptive , individualized exercise ( 3 M ; n = 29 ) , 6 months of prescriptive , individualized exercise ( 6 M ; n = 68 ) , or served as sedentary controls ( C ; n = 17 ) . Cancer survivors completed a medical evaluation and assessment at baseline followed by a predetermined 3- or 6-month exercise intervention . Cancer survivors in the control group performed no exercise between the initial assessment and 6-month re assessment . Cardiovascular endurance , pulmonary function , muscular endurance , fatigue , and symptoms of depression were assessed at baseline and post intervention . Repeated measures ANCOVA revealed improvements ( P < 0.05 ) in cardiovascular endurance , fatigue , and symptoms of depression in breast cancer survivors undergoing 3- and 6-month individualized exercise interventions . Breast cancer survivors exercising for 6 months showed additional improvements ( P < 0.05 ) in pulmonary function and muscular endurance . Cancer survivors in the control group did not improve in cardiovascular endurance , pulmonary function , muscular endurance , or fatigue . Three months of individualized , prescriptive exercise leads to improved cardiovascular endurance , fatigue , and symptoms of depression in breast cancer survivors . Additional benefits are seen if exercise is continued for a total of 6 months [11898235] PURPOSE Weight gain is a common side effect for women receiving adjuvant chemotherapy and may have negative long-term implication s for survival . The purpose of this study was to examine the effects of aerobic exercise on weight gain in women with breast cancer receiving adjuvant chemotherapy . DESCRIPTION OF STUDY Seventy-eight women who had recently received a diagnosis of breast cancer and who were beginning adjuvant chemotherapy were enrolled in a home-based exercise study during the first four cycles of chemotherapy . Weight change , body mass index , anorexia , nausea , fatigue , caloric expenditure during exercise , and functional ability were recorded . RESULTS Women who adhered to the exercise program maintained their body weight , while nonexercisers steadily gained weight ( P < .05 ) . There were no differences in incidence or intensity of nausea or anorexia between the exercisers and nonexercisers . Women who exercised over the four cycles of chemotherapy improved their functional ability ( mean 23 % ) compared to the nonexercisers who showed significant declines in functional ability ( mean -15 % ) . CLINICAL IMPLICATION S Exercise may be an effective intervention to minimize weight gain in women with breast cancer who are receiving adjuvant chemotherapy . Preventing weight gain in these patients may be important in preventing recurrent disease and other comorbidities associated with excess weight [14982314] We conducted a r and omized controlled trial to determine the effects of a home-based exercise intervention on change in quality of life ( QOL ) in recently resected colorectal cancer survivors , most of whom were receiving adjuvant therapy . Participants were r and omly assigned in a 2:1 ratio to either an exercise ( n = 69 ) or control ( n = 33 ) group . The exercise group was asked to perform moderate intensity exercise 3 - 5 times per week for 20 - 30 min each time . The primary outcome was change in QOL as measured by the Functional Assessment of Cancer Therapy-Colorectal ( FACT-C ) scale . Adherence in the exercise group was good ( 75.8 % ) but contamination in the control group was problematic ( 51.6 % ) . Intention-to-treat analysis revealed no significant differences between groups for change in the FACT-C ( mean difference , -1.3 ; 95 % CI , -7.8 to 5.1 ; P = 0.679 ) . In an ' on-treatment ' ancillary analysis , we compared participants who decreased versus increased their cardiovascular fitness over the course of the intervention . This analysis revealed significant differences in favour of the increased fitness group for the FACT-C ( mean difference , 6.5 ; 95 % CI , 0.4 - 12.6 ; P = 0.038 ) . These data suggest that increased cardiovascular fitness is associated with improvements in QOL in colorectal cancer survivors but better controlled trials are needed [19214594] Goal of workBreast cancer survivors have limited options for the treatment of hot flashes and related symptoms . Further , therapies widely used to prevent recurrence in survivors , such as tamoxifen , tend to induce or exacerbate menopausal symptoms . The aim of this preliminary , r and omized controlled trial was to evaluate the effects of a yoga intervention on menopausal symptoms in a sample of survivors of early-stage breast cancer ( stages IA – IIB ) . Material s and methods Thirty-seven disease-free women experiencing hot flashes were r and omized to the 8-week Yoga of Awareness program ( gentle yoga poses , meditation , and breathing exercises ) or to wait-list control . The primary outcome was daily reports of hot flashes collected at baseline , posttreatment , and 3 months after treatment via an interactive telephone system . Data were analyzed by intention to treat . Main results At posttreatment , women who received the yoga program showed significantly greater improvements relative to the control condition in hot-flash frequency , severity , and total scores and in levels of joint pain , fatigue , sleep disturbance , symptom-related bother , and vigor . At 3 months follow-up , patients maintained their treatment gains in hot flashes , joint pain , fatigue , symptom-related bother , and vigor and showed additional significant gains in negative mood , relaxation , and acceptance . Conclusions This pilot study provides promising support for the beneficial effects of a comprehensive yoga program for hot flashes and other menopausal symptoms in early-stage breast cancer survivors [9128987] Fatigue and loss of physical performance are frequent problems of cancer patients . In a pilot study , the authors evaluated the feasibility and effects of aerobic training in the rehabilitation of cancer patients after completing high dose chemotherapy [10732535] OBJECTIVES Cancer treatment-related fatigue is a common and disruptive side effect of chemotherapy . Exercise is an intervention proposed to reduce fatigue in cancer patients . The purpose of this study was to describe the patterns of daily fatigue in women with breast cancer who did and did not exercise while receiving the first three cycles of adjuvant chemotherapy . MATERIAL S AND METHODS Women received instruction to follow an 8-week home-based exercise program and to maintain daily exercise and fatigue diaries . Functional ability ( 12-minute walk ) was measured pretest and post-test . RESULTS Several distinct patterns of fatigue emerged . The most common pattern of fatigue after chemotherapy demonstrated a sharp rise in fatigue . However , several women demonstrated a chaotic pattern with erratic and wide swings in their fatigue throughout the entire study period . Women who adopted exercise experienced fewer days of high fatigue levels and more days of low levels of fatigue for both average and worst levels of fatigue . Women who did not exercise experienced more bad days ( high fatigue ) and fewer good days ( low fatigue ) . CONCLUSIONS Exercise appears to reduce the levels of average and worst fatigue and may help women recognize their pattern of fatigue . Exercise may reduce the intensity of fatigue by reorganizing women 's interpretation of fatigue . Routine clinical assessment and education about fatigue by health professionals can help patients to underst and their pattern of fatigue and may help them to manage the symptom [12721238] PURPOSE And rogen deprivation therapy is a common treatment in men with prostate cancer that may cause fatigue , functional decline , increased body fatness , and loss of lean body tissue . These physical changes can negatively affect health-related quality of life . Resistance exercise may help to counter some of these side effects by reducing fatigue , elevating mood , building muscle mass , and reducing body fat . METHODS In a two-site study , 155 men with prostate cancer who were scheduled to receive and rogen deprivation therapy for at least 3 months after recruitment were r and omly assigned to an intervention group that participated in a resistance exercise program three times per week for 12 weeks ( 82 men ) or to a waiting list control group ( 73 men ) . The primary outcomes were fatigue and disease-specific quality of life as assessed by self-reported question naires after 12 weeks . Secondary outcomes were muscular fitness and body composition . RESULTS Men assigned to resistance exercise had less interference from fatigue on activities of daily living ( P = .002 ) and higher quality of life ( P = .001 ) than men in the control group . Men in the intervention group demonstrated higher levels of upper body ( P = .009 ) and lower body ( P < .001 ) muscular fitness than men in the control group . The 12-week resistance exercise intervention did not improve body composition as measured by changes in body weight , body mass index , waist circumference , or subcutaneous skinfolds . CONCLUSION Resistance exercise reduces fatigue and improves quality of life and muscular fitness in men with prostate cancer receiving and rogen deprivation therapy . This form of exercise can be an important component of supportive care for these patients [15908668] PURPOSE The efficacy of a home-based physical activity ( PA ) intervention for early-stage breast cancer patients was evaluated in a r and omized controlled trial . PATIENTS AND METHODS Eighty-six sedentary women ( mean age , 53.14 years ; st and ard deviation , 9.70 years ) who had completed treatment for stage 0 to II breast cancer were r and omly assigned to a PA or contact control group . Participants in the PA group received 12 weeks of PA counseling ( based on the Transtheoretical Model ) delivered via telephone , as well as weekly exercise tip sheets . Assessment s were conducted at baseline , after treatment ( 12 weeks ) , and 6 and 9 month after baseline follow-ups . The post-treatment outcomes are reported here . RESULTS Analyses showed that , after treatment , the PA group reported significantly more total minutes of PA , more minutes of moderate-intensity PA , and higher energy expenditure per week than controls . The PA group also out-performed controls on a field test of fitness . Changes in PA were not reflected in objective activity monitoring . The PA group was more likely than controls to progress in motivational readiness for PA and to meet PA guidelines . No significant group differences were found in body mass index and percent body fat . Post-treatment group comparisons revealed significant improvements in vigor and a reduction in fatigue in the PA group . There was a positive trend in intervention effects on overall mood and body esteem . CONCLUSION The intervention successfully increased PA and improved fitness and specific aspects of psychological well-being among early-stage breast cancer patients . The success of a home-based PA intervention has important implication s for promoting recovery in this population [15800330] PURPOSE To evaluate the effectiveness of a supervised home-based flexible training program on cardiorespiratory fitness ( CRF ) , mental distress , and health-related quality of life ( HRQOL ) parameters in young and middle-aged cancer patients shortly after curative chemotherapy . PATIENTS AND METHODS One hundred eleven patients age 18 to 50 years who had received chemotherapy for lymphomas or breast , gynecologic , or testicular cancer completed the trial . These patients were r and omly allocated to either an intervention group ( n = 59 ) , which underwent a 14-week training program , or a control group ( n = 52 ) that received st and ard care . Primary outcome was change in CRF , as determined by Astr and -Rhyming indirect bicycle ergometer test ( maximum oxygen uptake [ VO(2max ) ] ) , between baseline ( T0 ) and follow-up ( T1 ) . Secondary outcomes were mental distress , as assessed by the Hospital Anxiety and Depression Scale , and HRQOL , as assessed by the European Organisation for Research and Treatment of Cancer Core Quality of Life Question naire . Two-way analysis of covariance was used to analyze changes from T0 to T1 . RESULTS VO(2max ) increased by 6.4 mL/kg(-1)/min(-1 ) in patients in the intervention group and by 3.1 mL/kg(-1)/min(-1 ) in patients in the control group ( P < .01 ) . The fatigue score decreased by 17.0 points in the control group compared with only 5.8 points in the intervention group ( P < .01 ) . There were no intergroup differences in mental distress or HRQOL . CONCLUSION A supervised , home-based , flexible training program has significant effect on CRF in young and middle-aged cancer patients shortly after curative chemotherapy , but it has no favorable effect on patients ' experience of fatigue , mental distress , or HRQOL [16446335] PURPOSE The primary goal of this study was to evaluate the feasibility and effectiveness of a structured , multidisciplinary intervention targeted to maintain the overall quality of life ( QOL ) , which is more comprehensive than psychosocial distress , of patients undergoing radiation therapy for advanced-stage cancer . PATIENTS AND METHODS Radiation therapy patients with advanced cancer and an estimated 5-year survival rate of 0 % to 50 % were r and omly assigned to either an eight-session structured multidisciplinary intervention arm or a st and ard care arm . The eight 90-minute sessions addressed the five domains of QOL including cognitive , physical , emotional , spiritual , and social functioning . The primary end point of maintaining overall QOL was assessed by a single-item linear analog scale ( Linear Analog Scale of Assessment or modified Spitzer Uniscale ) . QOL was assessed at baseline , week 4 ( end of multidisciplinary intervention ) , week 8 , and week 27 . RESULTS Of the 103 participants , overall QOL at week 4 was maintained by the patients in the intervention ( n = 49 ) , whereas QOL at week 4 significantly decreased for patients in the control group ( n = 54 ) . This change reflected a 3-point increase from baseline in the intervention group and a 9-point decrease from baseline in the control group ( P = .009 ) . Intervention participants maintained their QOL , and controls gradually returned to baseline by the end of the 6-month follow-up period . CONCLUSION Although intervention participants maintained and actually improved their QOL during radiation therapy , control participants experienced a significant decrease in their QOL . Thus , a structured multidisciplinary intervention can help maintain or even improve QOL in patients with advanced cancer who are undergoing cancer treatment [20388445] This study examined the effects of yoga on quality of life ( QOL ) and psychosocial outcomes in women with breast cancer undergoing radiotherapy . Sixty-one women were r and omly assigned to either a yoga or a wait-list group . Yoga classes were taught biweekly during the 6 weeks of radiotherapy . Participants completed measures of QOL , fatigue , benefit finding ( finding meaning in the cancer experience ) , intrusive thoughts , sleep disturbances , depressive symptoms , and anxiety before radiotherapy and then again 1 week , 1 month , and 3 months after the end of radiotherapy . General linear model analyses revealed that compared to the control group , the yoga group reported significantly better general health perception ( p = .005 ) and physical functioning scores ( p = .04 ) 1 week postradiotherapy ; higher levels of intrusive thoughts 1 month postradiotherapy ( p = .01 ) ; and greater benefit finding 3 months postradiotherapy ( p = .01 ) . There were no other group differences in other QOL subscales for fatigue , depression , or sleep scores . Exploratory analyses indicated that intrusive thoughts 1 month after radiotherapy were significantly positively correlated with benefit finding 3 months after radiotherapy ( r = .36 , p = .011 ) . Our results indicated that the yoga program was associated with statistically and clinical ly significant improvements in aspects of QOL [19345060] Studies applying exercise , relaxation training , and psychoeducation have each indicated a positive impact on physical performance and /or psychological factors in patients diagnosed with cancer . We explored the longitudinal effect of a combination of these interventions on treatment-related symptoms in patients undergoing myeloablative allogeneic hematopoietic stem cell transplantation ( allo-HSCT ) . Forty-two patients ( 18 - 65 years ) were r and omized either to an intervention or a control group . The intervention group received st and ard treatment and care , and a supervised four- to six-week structured exercise program , progressive relaxation , and psychoeducation during hospitalization , one hour per day for five days per week . The control group received st and ard treatment , care , and physiotherapy . A 24-item symptom assessment question naire was completed weekly during hospitalization , and at three and six months after allo-HCST . Through principal component analysis with varimax rotation , individual symptoms were grouped into five symptom clusters : mucositis , cognitive , gastrointestinal , affective , and functional symptom clusters . Then , a subsequent general estimate equation analysis revealed similar longitudinal patterns of intensity in all symptom clusters for intervention and control groups , but in the intervention group , there was an overall significant reduction ( P<0.05 ) in symptom intensity over time for all clusters except the affective symptom cluster . This study provides beginning evidence for the efficacy of an exercise-based multimodal intervention in reducing the intensity of a spectrum of symptoms in this small sample of patients undergoing allo-HSCT [19234513] The aim of this r and omized controlled trial was to investigate the effect of a 4- to 6-week multimodal program of exercise , relaxation and psychoeducation on physical capacity , functional performance and quality of life ( QOL ) in allogeneic hematopoietic cell transplantation ( allo-HSCT ) adult recipients . In all , 42 patients were r and omized to a supervised multimodal intervention or to a control group receiving usual care . The primary end point was on aerobic capacity measured in VO2 max . Secondary end points were muscle strength , functional performance , physical activity level , QOL , fatigue , psychological well-being and clinical outcomes . The multimodal intervention had a significant effect on physical capacity : VO2 max ( P<0.0001 ) and muscle strength : chest press ( P<0.0001 ) , leg extension ( P=0.0003 ) , right elbow flexor ( P=0.0009 ) , right knee extensor ( P<0.0001 ) and functional performance ( stair test ) ( 0.0008 ) . Moreover , the intervention group showed significantly better results for the severity of diarrhea ( P=0.014 ) and fewer days of total parenteral nutrition ( P=0.019 ) . Longitudinal changes in QOL , fatigue and psychological well-being favored the intervention group , but did not reach statistical significance . Assignment of a multimodal intervention during allo-HSCT did not cause untoward events , sustained aerobic capacity and muscle strength and reduced loss of functional performance during hospitalization [19687337] PURPOSE Lymphoma patients commonly experience declines in physical functioning and quality of life ( QoL ) that may be reversed with exercise training . PATIENTS AND METHODS We conducted a r and omized controlled trial in Edmonton , Alberta , Canada , between 2005 and 2008 that stratified 122 lymphoma patients by major disease type and current treatment status and r and omly assigned them to usual care ( UC ; n = 62 ) or 12 weeks of supervised aerobic exercise training ( AET ; n = 60 ) . Our primary end point was patient-rated physical functioning assessed by the Trial Outcome Index-Anemia . Secondary end points were overall QoL , psychosocial functioning , cardiovascular fitness , and body composition . RESULTS Follow-up assessment for our primary end point was 96 % ( 117 of 122 ) at postintervention and 90 % ( 110 of 122 ) at 6-month follow-up . Median adherence to the supervised exercise program was 92 % . At postintervention , AET was superior to UC for patient-rated physical functioning ( mean group difference , + 9.0 ; 95 % CI , 2.0 to 16.0 ; P = .012 ) , overall QoL ( P = .021 ) , fatigue ( P = .013 ) , happiness ( P = .004 ) , depression ( P = .005 ) , general health ( P < .001 ) , cardiovascular fitness ( P < .001 ) , and lean body mass ( P = .008 ) . Change in peak cardiovascular fitness mediated the change in patient-rated physical functioning . AET did not interfere with chemotherapy completion rate or treatment response . At 6-month follow-up , AET was still borderline or significantly superior to UC for overall QoL ( P = .054 ) , happiness ( P = .034 ) , and depression ( P = .009 ) without an increased risk of disease recurrence/progression . CONCLUSION AET significantly improved important patient-rated outcomes and objective physical functioning in lymphoma patients without interfering with medical treatments or response . Exercise training to improve cardiovascular fitness should be considered in the management of lymphoma patients [17761636] This investigation determined the cardiopulmonary function and fatigue alterations in male cancer survivors during treatment as well as following treatment utilizing similar exercise assessment protocol s and individualized , prescriptive exercise interventions . The study included 45 male cancer survivors that were referred by local oncologists . Following a comprehensive screening and physical examination , cardiovascular endurance , pulmonary function , and fatigue were assessed leading to the development of 12-week individualized exercise prescriptions and exercise interventions . The cancer survivors were divided into during treatment ( DTm ) and following treatment ( FTm ) groups . Repeated- measures analysis of variance and analyses of covariance were used to compare pre- versus postintervention and between groups . Cardiopulmonary function was maintained in the DTm , whereas the FTm showed significant reductions in resting heart rate ( P < .05 ) with concurrent increases in predicted VO2max and time on treadmill ( P < .05 ) postexercise intervention . Fatigue levels did not increase in the DTm group , whereas the FTm group showed significant reductions in behavioral fatigue , affective fatigue , sensory fatigue , cognitive/mood fatigue , and total fatigue ( P < .05 ) after the exercise intervention . The results of the current study suggest that moderate intensity , individualized , prescriptive exercise intervention maintains or improves cardiovascular and pulmonary function with concomitant reductions in fatigue in cancer survivors during and following cancer treatment . Exercise appears to be a safe , efficacious strategy for improving physical fitness in cancer survivors during and following treatment [17582616] Cancer treatments have serious physiological and psychological side effects in cancer survivors . This investigation examined cardiopulmonary function and fatigue in breast cancer survivors during and after treatment by using similar exercise assessment s , prescriptions , individualized interventions , and re assessment [14603549] Physical exercise is becoming an accepted part of therapy for many patients with cancer . Exercise may alleviate patients ' fatigue and improve physical performance and psychological outlook . Much of the research is limited to women with breast cancer and excludes patients with bone metastases . This article reports on the authors ' work in facilitating exercise adherence for patients with multiple myeloma ( MM ) and bone lesions while they were enrolled in a feasibility/pilot exercise study as they were receiving treatment for their disease in an outpatient treatment program . The exercise program for these patients receiving high-dose chemotherapy and stem cell transplantation consisted of aerobic and strength-building components . The program was home based , and patients performed exercises without direct supervision . On average , the patients completed the six-month exercise prescription 75 % of the time . Overall trends showed that all 14 patients in the exercise group improved in several areas of testing , and the test results of all 10 patients in the usual-care group declined . Flexibility and simplicity are essential when design ing exercise programs for patients , and encouragement and support also are needed to help patients adhere to prescribed exercise [17785709] PURPOSE This study examines the impact of yoga , including physical poses , breathing , and meditation exercises , on quality of life ( QOL ) , fatigue , distressed mood , and spiritual well-being among a multiethnic sample of breast cancer patients . PATIENTS AND METHODS One hundred twenty-eight patients ( 42 % African American , 31 % Hispanic ) recruited from an urban cancer center were r and omly assigned ( 2:1 ratio ) to a 12-week yoga intervention ( n = 84 ) or a 12-week waitlist control group ( n = 44 ) . Changes in QOL ( eg , Functional Assessment of Cancer Therapy ) from before r and om assignment ( T1 ) to the 3-month follow-up ( T3 ) were examined ; predictors of adherence were also assessed . Nearly half of all patients were receiving medical treatment . RESULTS Regression analyses indicated that the control group had a greater decrease in social well-being compared with the intervention group after controlling for baseline social well-being and covariates ( P < .0001 ) . Secondary analyses of 71 patients not receiving chemotherapy during the intervention period indicated favorable outcomes for the intervention group compared with the control group in overall QOL ( P < .008 ) , emotional well-being ( P < .015 ) , social well-being ( P < .004 ) , spiritual well-being ( P < .009 ) , and distressed mood ( P < .031 ) . Sixty-nine percent of intervention participants attended classes ( mean number of classes attended by active class participants = 7.00 + /- 3.80 ) , with lower adherence associated with increased fatigue ( P < .001 ) , radiotherapy ( P < .0001 ) , younger age ( P < .008 ) , and no antiestrogen therapy ( P < .02 ) . CONCLUSION Despite limited adherence , this intent-to-treat analysis suggests that yoga is associated with beneficial effects on social functioning among a medically diverse sample of breast cancer survivors . Among patients not receiving chemotherapy , yoga appears to enhance emotional well-being and mood and may serve to buffer deterioration in both overall and specific domains of QOL [19942188] OBJECTIVES To determine the feasibility of an eccentric resistance exercise training protocol in men with prostate cancer and to assess whether men with prostate cancer who are receiving and rogen deprivation therapy ( ADT ) have a blunted effect from the training as compared with prostate cancer survivors not receiving ADT . DESIGN Prospect i ve pilot study . SETTING Academic medical center . PARTICIPANTS Sixteen men with prostate cancer ( Gleason scores 3 + 3 to 4 + 4 ) were initially enrolled . Ten men ( mean age 66 , range 48 - 86 ) completed the study , 5 were currently receiving ADT . Analysis was performed on these 10 men . INTERVENTIONS Subjects were evaluated at baseline . All men underwent a 12-week resistance exercise training protocol using a recumbent , high-force eccentric , leg cycle ergometer 3 times per week at a " somewhat hard " perceived exertion for 12 to 15 minutes . Preexercise and postexercise training changes were examined within and between groups . MAIN OUTCOME MEASURES Quadriceps muscle volume ( magnetic resonance imaging ) , isometric knee extension strength , functional mobility ( Timed Up and Go Test [ TUG ] and 6-minute walk [ 6MW ] ) , health-related quality of life ( FACT-P ) , and fatigue ( FACIT-fatigue scale ) . RESULTS The ADT group demonstrated significant within-group improvements in the 6MW ( P = .01 ) and isometric knee extension strength ( P = .03 ) . This group also demonstrated a clinical ly relevant change in the FACT-P ; however , this did not meet statistical significance . The non-ADT group demonstrated significant within-group improvements in the physical subscale of the FACT-P ( P = .03 ) and an increase in muscle volume ( P = .04 ) . Their improvements in the TUG approached significance ( P = .08 ) . No between-group differences existed . CONCLUSIONS Eccentric resistance exercise was well tolerated , and both groups derived some benefits in strength and functional mobility . Men receiving ADT did not appear to have a blunted response to the exercise as compared with prostate cancer survivors not receiving ADT [16462503] Background : Fatigue has a significant impact on the quality of life ( QOL ) of cancer patients . Recent research has suggested that physical activity can reduce fatigue in patients receiving active cancer treatment . In this project , we examined the impact that participation in a r and omized controlled trial of a multidisciplinary intervention design ed to impact overall QOL had on fatigue for advanced cancer patients actively receiving treatment . Methods : Patients with newly diagnosed cancer were r and omly assigned to an 8-session structured multidisciplinary intervention or a st and ard-care arm at the beginning of their course of radiotherapy ( RT ) design ed to impact QOL . Ninety-minute sessions were led by either a psychiatrist or psychologist , collaborating with a nurse , physical therapist , chaplain , or social worker , depending on the session 's theme . The fatigue assessment s used in this trial included the Linear Analogue Self Assessment ( LASA ) , the Profile of Mood States ( POMS ) , Spielberger 's State-Trait Anxiety Inventory ( STAI ) , and the Symptom Distress Scale ( SDS ) . Results : There were 115 participants enrolled and the 2 r and omization arms were well balanced in terms of baseline characteristics and treatment received except for increased commuting distance for the patients in the intervention arm ( P = 0.042 ) . Most of scores indicated less fatigue ( higher score ) in the st and ard treatment group , but there were no statistically significant differences found at baseline and weeks 4 , 8 , and 27 except for SDS at week 8 ( P = 0.018 ) with less patients reporting significant fatigue in the st and ard treatment arm . For the entire participant population , fatigue levels initially worsened with radiotherapy , stabilized at week 8 , and returned to baseline by week 27 . Disease site , chemotherapy use , and radiotherapy dose did not have a significant impact on fatigue levels . Conclusions : Radiotherapy initially caused a worsening of fatigue but with time fatigue levels returned to baseline . Clinical ly , this structured multidisciplinary intervention had no impact on fatigue , and there was the suggestion the multiple sessions may have contributed to worse fatigue during active cancer treatment [20530648] Objective : To examine the effects of a scapula-oriented exercise on upper limb dysfunction in breast cancer survivors . Study design : A prospect i ve r and omized , controlled pilot trial with historical control . Setting : Rehabilitation department at a university hospital . Subjects : Thirty-two women with breast cancer were r and omly assigned to scapula-oriented exercise group ( n = 16 ) and general exercise group ( n = 16 ) . An historical control group ( n = 18 ) without exercise was enrolled from breast cancer survivors . Interventions : The scapula-oriented exercises were design ed focusing on scapulothoracic movement . The general exercise group performed body conditioning exercise . Exercise therapies were performed for one session per week for eight weeks . Main outcome measures : Pain and physical disabilities related to upper limb dysfunction , quality of life and depression were used as subjective outcomes . Objective outcome measures included shoulder range of motion and strength . Outcomes were assessed at baseline and post exercise . Results : At baseline , no significant difference was observed among the three groups . The scapula-oriented exercise group showed improvements in pain , physical function , social function , and global quality of life compared with baseline , whereas the general exercise group showed improved fatigue and range of motion . The change in global quality of life ( P = 0.067 ; effect size , 0.33 ) and strength of external rotation ( P = 0.001 ; effect size , 0.55 ) were significantly greater in the scapula-oriented exercise group than in the general exercise and control group . Conclusion : Scapula-oriented exercise had beneficial effects on pain , quality of life and aspects of strength . The sample size required in a larger definitive study is 32 subjects per group [2587289] The effect of a 10-week aerobic interval-training cycle ergometer protocol on the functional capacity ( VO2Lmax ) of 45 women receiving chemotherapy for treatment of Stage II breast cancer was studied . Subjects were stratified by baseline functional capacity ( ± 1 MET ) and r and omized to experimental ( EX ) , placebo ( PL ) , and control ( CO ) groups . EX subjects completed a 10-week , 3 times/week exercise training program ; PL subjects participated in 10 weeks of nonaerobic stretching and flexibility exercises ; the CO group maintained normal activities . The EX group showed significant , p < .05 , improvement on pre- to posttest VO2Lmax as well as workload and test time compared to the PL and CO groups . The interval-training exercise intervention was effective in improving the functional capacity of Stage II breast cancer patients on adjuvant chemotherapy [12748973] Physical exercise has been shown to enhance quality of life ( QOL ) in cancer survivors using pretest-posttest design s and compared to usual care ( i.e. no intervention ) . In the present study , we conducted a r and omized controlled trial to determine if exercise could improve QOL in cancer survivors beyond the known benefits of group psychotherapy ( GP ) . We matched 22 GP classes ( N=108 ) on content and then r and omly assigned 11 ( n=48 ) to GP alone and 11 ( n=60 ) to GP plus home-based , moderate-intensity exercise ( GP+EX ) . Participants completed a physical fitness test and QOL measures ( e.g. Functional Assessment of Cancer Therapy scales ) at the beginning and end of GP classes ( about 10 weeks ) . We had excellent recruitment ( 81 % ) , retention ( 89 % ) , and adherence ( 84 % ) rates and a modest contamination ( 22 % ) rate . Using intention-to-treat repeated measures analyses of variance , we found significant Time by Condition interactions for functional well-being , fatigue , and sum of skinfolds . We also found borderline significant interactions for physical well-being , satisfaction with life , and flexibility . All interactions favored the GP+EX condition . We conclude that a home-based , moderate intensity exercise program may im-prove QOL in cancer survivors beyond the benefits of GP , particularly in relation to physical and functional well-being [10326708] Fatigue is a common and often severe problem in cancer patients undergoing chemotherapy . The authors postulated that physical activity training can reduce the intensity of fatigue in this group of patients [15484202] Fatigue is the most prevalent and debilitating symptom experienced by breast cancer patients receiving adjuvant chemotherapy or radiation therapy and few evidence -based treatments are available to manage this distressing side-effect . The purpose of this multi-institutional r and omized controlled trial was to determine the effects of exercise on fatigue levels during treatment for breast cancer . Sedentary women ( N=119 ) with Stage 0-III breast cancer receiving outpatient adjuvant chemotherapy or radiation therapy were r and omized to a home-based moderate-intensity walking exercise program or to usual care for the duration of their cancer treatment . Of participants r and omized to exercise , 72 % adhered to the exercise prescription ; 61 % of the usual care group adhered . The intention-to-treat analysis revealed no group differences in part because of a dilution of treatment effect as 39 % of the usual care group exercised and 28 % of the exercise group did not . When exercise participation was considered using the data analysis method of instrumental variables with principal stratification , a clinical ly important and statistically significant ( p=0.03 ) effect of exercise on pretest-to-posttest change in fatigue levels was demonstrated . Adherence to a home-based moderate-intensity walking exercise program may effectively mitigate the high levels of fatigue prevalent during cancer treatment [19064985] PURPOSE Radiotherapy for prostate cancer ( PCa ) may cause unfavorable changes in fatigue , quality of life ( QOL ) , and physical fitness . We report results from the Prostate Cancer Radiotherapy and Exercise Versus Normal Treatment study examining the effects of 24 weeks of resistance or aerobic training versus usual care on fatigue , QOL , physical fitness , body composition , prostate-specific antigen , testosterone , hemoglobin , and lipid levels in men with PCa receiving radiotherapy . PATIENTS AND METHODS Between 2003 and 2006 , we conducted a r and omized controlled trial in Ottawa , Canada , where 121 PCa patients initiating radiotherapy with or without and rogen deprivation therapy were r and omly assigned to usual care ( n = 41 ) , resistance ( n = 40 ) , or aerobic exercise ( n = 40 ) for 24 weeks . Our primary end point was fatigue assessed by the Functional Assessment of Cancer Therapy-Fatigue scale . RESULTS The follow-up assessment rate for our primary end point of fatigue was 92.6 % . Median adherence to prescribed exercise was 85.5 % . Mixed-model repeated measures analyses indicated both resistance ( P = .010 ) and aerobic exercise ( P = .004 ) mitigated fatigue over the short term . Resistance exercise also produced longer-term improvements ( P = .002 ) . Compared with usual care , resistance training improved QOL ( P = .015 ) , aerobic fitness ( P = .041 ) , upper- ( P < .001 ) and lower-body ( P < .001 ) strength , and triglycerides ( P = .036 ) , while preventing an increase in body fat ( P = .049 ) . Aerobic training also improved fitness ( P = .052 ) . One serious adverse event occurred in the group that performed aerobic exercise . CONCLUSION In the short term , both resistance and aerobic exercise mitigated fatigue in men with PCa receiving radiotherapy . Resistance exercise generated longer-term improvements and additional benefits for QOL , strength , triglycerides , and body fat [20930100] BACKGROUND Two interventions for fatigue were given during curative cancer treatment . The aim of this multicenter r and omized controlled trial ( RCT ) with three conditions was to demonstrate the efficacy and to determine the contribution of physical activity . METHODS Recruited from seven hospitals , 220 patients with various malignancies participated in a RCT . The brief nursing intervention ( BNI ) consisted of two 1-hour sessions , 3 months apart , given by 12 trained nurses , focusing only on physical activity . Cognitive behavior therapy ( CBT ) consisted of up to ten 1-hour sessions , within 6 months , provided by two therapists , focusing on physical activity and psychosocial elements . The control group received only usual care ( UC ) . Assessment s took place before and at least 2 months after cancer treatment , when patients had recovered from acute fatigue . Fatigue was the primary outcome . Efficacy was tested using analyses of covariance . A nonparametric bootstrap approach was used to test whether the effect on fatigue was mediated by physical activity . RESULTS The CBT group was significantly less fatigued than the UC group . Between the BNI and the UC groups , no significant difference was found in fatigue . The mediation hypothesis was rejected . DISCUSSION CBT given during curative cancer treatment proved to be an effective intervention to reduce fatigue at least 2 months after cancer treatment . The BNI was not effective . Contrary to what was expected , physical activity did not mediate the effect of CBT on fatigue . Thus , the reduction in fatigue elicited by CBT was realized without a lasting increase in physical activity [20651011] Background Research suggests that cancer rehabilitation reduces fatigue in survivors of cancer . To date , it is unclear what type of rehabilitation is most beneficial . Objective This r and omized controlled trial compared the effect on cancer-related fatigue of physical training combined with cognitive behavioral therapy with physical training alone and with no intervention . Design In this multicenter r and omized controlled trial , 147 survivors of cancer were r and omly assigned to a group that received physical training combined with cognitive-behavioral therapy ( PT+CBT group , n=76 ) or to a group that received physical training alone ( PT group , n=71 ) . In addition , a nonintervention control group ( WLC group ) consisting of 62 survivors of cancer who were on the waiting lists of rehabilitation centers elsewhere was included . Setting The study was conducted at 4 rehabilitation centers in the Netherl and s. Patients All patients were survivors of cancer . Intervention Physical training consisting of 2 hours of individual training and group sports took place twice weekly , and cognitive-behavioral therapy took place once weekly for 2 hours . Measurements Fatigue was assessed with the Multidimensional Fatigue Inventory before and immediately after intervention ( 12 weeks after enrollment ) . The WLC group completed question naires at the same time points . Results Baseline fatigue did not differ significantly among the 3 groups . Over time , levels of fatigue significantly decreased in all domains in all groups , except in mental fatigue in the WLC group . Analyses of variance of postintervention fatigue showed statistically significant group effects on general fatigue , on physical and mental fatigue , and on reduced activation but not on reduced motivation . Compared with the WLC group , the PT group reported significantly greater decline in 4 domains of fatigue , whereas the PT+CBT group reported significantly greater decline in physical fatigue only . No significant differences in decline in fatigue were found between the PT+CBT and PT groups . Conclusions Physical training combined with cognitive-behavioral therapy and physical training alone had significant and beneficial effects on fatigue compared with no intervention . Physical training was equally effective as or more effective than physical training combined with cognitive-behavioral therapy in reducing cancer-related fatigue , suggesting that cognitive-behavioral therapy did not have additional beneficial effects beyond the benefits of physical training Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: Introduction Approximately 11.1 million cancer survivors are alive in the United States . Activity prescriptions for cancer survivors rely on evidence as to whether exercise during or after treatment results in improved health outcomes . This systematic review and meta- analysis evaluates the extent to which physical activity during and post treatment is appropriate and effective across the cancer control continuum . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

29729027

[24346625] Objective : Considering the chronicity of osteoarthritis-associated pain , we aim ed to evaluate long-term outcome differences between patients who received immediate or delayed acupuncture in addition to usual care , and to identify predictors for further acupuncture usage and a better long-term outcome . Material s and Methods : The Acupuncture in Routine Care study was an open-label r and omized pragmatic trial . As adjunct to usual care patients ( > 40 y , clinical and radiologic diagnosis of primary osteoarthritis of the knee or hip , pain duration > 6 mo ) received either immediate acupuncture in the first 3 months or delayed acupuncture in the subsequent 3 months . After 36 months 613 of 632 patients were available and asked to complete follow-up question naires . Primary outcome was the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) . Results : A total of 500 ( 82 % ) of the contacted patients completed question naires . After 36 months the WOMAC Index did not differ significantly between groups ( immediate acupuncture 36.53±26.19 vs. delayed acupuncture 38.24±25.54 ; P=0.420 ) . Further acupuncture treatment during the follow-up period was reported by 202 patients and predicted by previous successful acupuncture treatment at baseline ( odds ratio=2.5 ; 95 % confidence interval , 1.6 - 3.9 ) . Less osteoarthritis symptoms ( WOMAC Index ) after 36 months were predicted by being an acupuncture responder at 6 months ( P<0.001 ) , having higher school education ( P=0.005 ) , not wanting to use medications ( P=0.016 ) , and using additional therapies ( P⩽0.001 to P=0.025 ) . Discussion : No long-term outcome differences were found between patients who received immediate versus those who received delayed acupuncture treatment . Education level and additional therapies were identified as predictors for a better long-term outcome [22169359] Summary This multifactorial mixed‐ methods r and omized controlled trial quantified the specific and nonspecific factors of acupuncture , and found that the practitioner , not the treatment , has the strongest effect on outcome . Abstract The nonspecific effects of acupuncture are well documented ; we wished to quantify these factors in osteoarthritic ( OA ) pain , examining needling , the consultation , and the practitioner . In a prospect i ve r and omised , single‐blind , placebo‐controlled , multifactorial , mixed‐ methods trial , 221 patients with OA awaiting joint replacement surgery were recruited . Interventions were acupuncture , Streitberger placebo acupuncture , and mock electrical stimulation , each with empathic or nonempathic consultations . Interventions involved eight 30‐minute treatments over 4 weeks . The primary outcome was pain ( VAS ) at 1 week posttreatment . Face‐to‐face qualitative interviews were conducted ( purposive sample , 27 participants ) . Improvements occurred from baseline for all interventions with no significant differences between real and placebo acupuncture ( mean difference −2.7 mm , 95 % confidence intervals −9.0 to 3.6 ; P = .40 ) or mock stimulation ( −3.9 , −10.4 to 2.7 ; P = .25 ) . Empathic consultations did not affect pain ( 3.0 mm , −2.2 to 8.2 ; P = .26 ) but practitioner 3 achieved greater analgesia than practitioner 2 ( 10.9 , 3.9 to 18.0 ; P = .002 ) . Qualitative analysis indicated that patients ’ beliefs about treatment veracity and confidence in outcomes were reciprocally linked . The supportive nature of the trial attenuated differences between the different consultation styles . Improvements occurred from baseline , but acupuncture has no specific efficacy over either placebo . The individual practitioner and the patient ’s belief had a significant effect on outcome . The 2 placebos were equally as effective and credible as acupuncture . Needle and nonneedle placebos are equivalent . An unknown characteristic of the treating practitioner predicts outcome , as does the patient ’s belief ( independently ) . Beliefs about treatment veracity shape how patients self‐report outcome , complicating and confounding study interpretation [4095686] Introduction Our objective was to compare the effectiveness and safety of traditional Chinese moxibustion to that of sham moxibustion in patients with chronic knee osteoarthritis ( KOA ) pain . Methods We conducted a r and omized placebo-controlled trial involving 110 patients with KOA who met the inclusion criteria . These patients r and omly received either active moxibustion ( n = 55 ) or sham moxibustion control ( n = 55 ) at acupoints Dubi ( ST 35 ) , extra-point Neixiyan ( EX-LE 4 ) , and an Ashi ( tender ) point three times a week for 6 weeks . Effects were evaluated with Western Ontario and McMaster Universities ’ Osteoarthritis Index ( WOMAC VA 3.1 ) criteria at the end of the course of treatment and 3 , 12 , and 24 weeks after the initial treatment . Results The WOMAC pain scores showed greater improvement in the active treatment group than in control at weeks 3 ( P = 0.012 ) , 6 ( P < 0.001 ) , 12 ( P = 0.002 ) , and 24 ( P = 0.002 ) as did WOMAC physical function scores of the active treatment group at week 3 ( P = 0.002 ) , 6 ( P = 0.015 ) , and 12 ( P < 0.001 ) but not 24 ( P = 0.058 ) . Patients and practitioners were blinded successfully , and no significant adverse effects were found during the trial . Conclusions A 6-week course of moxibustion seems to relieve pain effectively and improve function in patients with KOA for up to 18 weeks after the end of treatment . Moxibustion treatment appears to be safe , and the usefulness of the novel moxa device was vali date d . Trial registration Current controlled trial : IS RCT N68475405 . Registered 4 April 2014 [18591906] Objectives To compare the effect of acupuncture ( manual and electroacupuncture ) with that of a non-penetrating sham ( ‘ placebo ’ needle ) in patients with osteoarthritic knee pain and disability who are blind to the treatment allocation . Methods Acupuncture naive patients with symptomatic and radiological evidence of osteoarthritis of the knee were r and omly allocated to a course of either acupuncture or non-penetrating sham acupuncture using a sheathed ‘ placebo ’ needle system . Acupuncture points for pain and stiffness were selected according to acupuncture theory for treating Bi syndrome . Both manual and electrical stimulation were used . Response was assessed using the WOMAC index for osteoarthritis of the knee , self reported pain scale , the EuroQol score and plasma β-endorphin . The effectiveness of blinding was assessed . Results There were 34 patients in each group . The primary end point was the change in WOMAC pain score after the course of treatment . Comparison between the two treatment groups found a significantly greater improvement with acupuncture ( mean difference 60 , 95 % CI 5 to 116 , P=0.035 ) than with sham . Within the acupuncture group there was a significant improvement in pain ( baseline 294 , mean change 95 , 95 % CI 60 to 130 , P<0.001 ) which was not seen by those who had sham acupuncture ( baseline 261 , mean change 35 , 95 % CI-10 to 80 , P=0.12 ) . Similar effects within group , but not between groups , were seen with the secondary end points of WOMAC stiffness , WOMAC function , and self reported pain . One month after treatment the between group pain difference had been lost ( mean difference 46 ; 95 % CI −9 to 100 , P=0.10 ) although the acupuncture group was still benefiting compared to baseline ( mean difference 59 ; 95 % CI 16 to 102 , P=0.009 ) . The EuroQol score , a generic measure of health related quality of life , was not altered by the treatments . A minority of patients correctly guessed their treatment group ( 41 % in the acupuncture group and 44 % in the control group ) . Plasma β-endorphin levels were not affected by either treatment . Conclusions Acupuncture gives symptomatic improvement for patients with osteoarthritis of the knee , and is significantly superior to non-penetrating sham acupuncture . The study did not confirm earlier reports of release of plasma β-endorphin during acupuncture [15077933] Background Using an open r and omised controlled study , we examined the effectiveness of manual and electroacupuncture on symptom relief for patients with osteoarthritis of the knee . Methods Patients with symptomatic osteoarthritis of the knee were r and omised to one of three treatment groups . Group A had acupuncture alone , group B had acupuncture but continued on their symptomatic medication , and group C used their symptomatic medication for the first five weeks and then had a course of acupuncture added . Patients receiving acupuncture were treated twice weekly over five weeks . Needles were inserted ( with manual and electrical stimulation ) in acupuncture points for pain and stiffness , selected according to traditional acupuncture theory for treating Bi syndrome . Patients were assessed by a blinded observer before treatment , after five weeks ’ treatment and at one month follow up , using a visual analogue pain scale ( VAS ) and the Western Ontario McMaster ( WOMAC ) question naire for osteoarthritis of the knee . Results The 30 patients in our study were well matched for age , body mass index , disease duration , baseline VAS pain score and baseline WOMAC scores . Repeated measure analyses gave a highly significant improvement in pain ( VAS ) after the courses of acupuncture in groups A ( P=0.012 ) and B ( P=0.001 ) ; there was no change in group C until after the course of acupuncture , when the improvement was significant ( P=0.001 ) . Similarly significant changes were seen with the WOMAC pain and stiffness scores . These benefits were maintained during the one month after the course of acupuncture . Patients ’ rating of global assessment was higher than that of the acupuncturist . Conclusion We conclude that manual and electroacupuncture causes a significant improvement in the symptoms of osteoarthritis of the knee , either on its own or as an adjunct therapy , with no loss of benefit after one month [16046146] Clinical and experimental data indicate that most acupuncture clinical results are mediated by the central nervous system , but the specific effects of acupuncture on the human brain remain unclear . Even less is known about its effects on the cerebellum . This fMRI study demonstrated that manual acupuncture at ST 36 ( Stomach 36 , Zusanli ) , a main acupoint on the leg , modulated neural activity at multiple levels of the cerebro-cerebellar and limbic systems . The pattern of hemodynamic response depended on the psychophysical response to needle manipulation . Acupuncture stimulation typically elicited a composite of sensations termed deqi that is related to clinical efficacy according to traditional Chinese medicine . The limbic and paralimbic structures of cortical and subcortical regions in the telencephalon , diencephalon , brainstem and cerebellum demonstrated a concerted attenuation of signal intensity when the subjects experienced deqi . When deqi was mixed with sharp pain , the hemodynamic response was mixed , showing a predominance of signal increases instead . Tactile stimulation as control also elicited a predominance of signal increase in a subset of these regions . The study provides preliminary evidence for an integrated response of the human cerebro-cerebellar and limbic systems to acupuncture stimulation at ST 36 that correlates with the psychophysical response [6346029] A prospect i ve , controlled clinical trial was undertaken to assess the relative efficacies of physiotherapy and electroacupuncture in the treatment of cervical spondylosis . The results suggested that , while both methods were effective , electroacupuncture produced an earlier symptomatic improvement with increased neck movement , especially in patients with mild degenerative changes of the cervical spine [24184053] BACKGROUND Because of morbidity associated with painful knee osteoarthritis ( OA ) and commonly prescribed analgesics , patients often pursue complementary and alternative modalities ( eg , acupuncture ) . Clinical trials have demonstrated modest therapeutic efficacy of traditional Chinese acupuncture for knee OA pain , and patients with advanced disease have largely been excluded . We have previously demonstrated preliminary short-term tolerability and efficacy of periosteal stimulation therapy ( PST ) ( ie , electrical stimulation of the periosteum facilitated by acupuncture needles ) for older adults with advanced knee OA . OBJECTIVE This study evaluated the sustained efficacy of PST and boosters for treating chronic pain with advanced knee OA . METHODS One hundred ninety participants age > 50 years with Kellgren-Lawrence grade 3 or 4 knee OA and chronic pain were r and omized to ( 1 ) PST ( once a week for 10 weeks ) followed by PST boosters for 6 months ( once every 2 weeks 2 times , then once a month ) , ( 2 ) control PST ( ie , periosteal needles and brief electrical stimulation of control points ) once a week for 10 weeks , or ( 3 ) PST for 10 weeks followed by control PST boosters for 6 months . Change in the Western Ontario and McMaster Universities Osteoarthritis Index pain score immediately after the 10-week intervention and at 6-month follow-up ( 9 months after baseline ) was the primary outcome . OMERACT-OARSI ( Outcome Measures in Rheumatology Clinical Trials-Osteoarthritis Research Society International ) criteria also were evaluated . Secondary measures of outcome included ( 1 ) physical performance ( Short Physical Performance Battery , gait speed , Timed Up and Go , and timed stair climb ) ; ( 2 ) psychological factors ( depressive symptoms measured with the Center for Epidemiologic Studies -Depression scale , coping measured with the catastrophizing subscale of the Coping Strategies Question naire , and self-efficacy measured with the Arthritis Self-Efficacy Scale ) ; ( 3 ) health-related quality of life measured with the Medical Outcomes Study 36-Item Short-Form Health Survey ; ( 4 ) rescue pain medication use tracked with diaries ; and ( 5 ) health care utilization and interim physical activity were monitored via monthly telephone calls . RESULTS After adjustment for pain at baseline , the PST and control booster did not differ from controls at 10 weeks ( difference , 1.3 ; 95 % CI , -0.10 to 2.8 ; P = 0.0683 ) or 9 months ( difference , 1.1 ; 95 % CI , -0.32 to 2.6 ; P = 0.13 ) . The PST and PST booster group had similar improvement compared with controls at 10 weeks ( baseline adjusted difference , 1.1 ; 95 % CI , -0.34 to 2.5 ; P = 0.1369 ) but significantly more improvement at 9 months ( baseline adjusted difference , 1.5 ; 95 % CI , 0.069 to 3.0 ; P = 0.0401 ) . Baseline depressive symptoms , low self-efficacy , higher difficulty performing daily activities , and greater knee stiffness predicted a lower likelihood of response . CONCLUSION PST plus PST boosters in patients age > 50 with advanced knee OA were well-tolerated and modestly reduced pain . Clinical Trials.gov identifier : NCT00865046 [2716312] Background The approximately 1100 medical journals now active in China are publishing a rapidly increasing number of research reports , including many studies identified by their authors as r and omized controlled trials . It has been noticed that these reports mostly present positive results , and their quality and authenticity have consequently been called into question . We investigated the adequacy of r and omization of clinical trials published in recent years in China to determine how many of them met acceptable st and ards for allocating participants to treatment groups . Methods The China National Knowledge Infrastructure electronic data base was search ed for reports of r and omized controlled trials on 20 common diseases published from January 1994 to June 2005 . From this sample , a subset of trials that appeared to have used r and omization methods was selected . Twenty-one investigators trained in the relevant knowledge , communication skills and quality control issues interviewed the original authors of these trials about the participant r and omization methods and related quality -control features of their trials . Results From an initial sample of 37,313 articles identified in the China National Knowledge Infrastructure data base , we found 3137 apparent r and omized controlled trials . Of these , 1452 were studies of conventional medicine ( published in 411 journals ) and 1685 were studies of traditional Chinese medicine ( published in 352 journals ) . Interviews with the authors of 2235 of these reports revealed that only 207 studies adhered to accepted methodology for r and omization and could on those grounds be deemed authentic r and omized controlled trials ( 6.8 % , 95 % confidence interval 5.9–7.7 ) . There was no statistically significant difference in the rate of authenticity between r and omized controlled trials of traditional interventions and those of conventional interventions . R and omized controlled trials conducted at hospitals affiliated to medical universities were more likely to be authentic than trials conducted at level 3 and level 2 hospitals ( relative risk 1.58 , 95 % confidence interval 1.18–2.13 , and relative risk 14.42 , 95 % confidence interval 9.40–22.10 , respectively ) . The likelihood of authenticity was higher in level 3 hospitals than in level 2 hospitals ( relative risk 9.32 , 95 % confidence interval 5.83–14.89 ) . All r and omized controlled trials of pre-market drug clinical trial were authentic by our criteria . Of the trials conducted at university-affiliated hospitals , 56.3 % were authentic ( 95 % confidence interval 32.0–81.0 ) . Conclusion Most reports of r and omized controlled trials published in some Chinese journals lacked an adequate description of r and omization . Similarly , most so called ' r and omized controlled trials ' were not real r and omized controlled trials owing toa lack of adequate underst and ing on the part of the authors of rigorous clinical trial design . All r and omized controlled trials of pre-market drug clinical trial included in this research were authentic . R and omized controlled trials conducted by authors in high level hospitals , especially in hospitals affiliated to medical universities had a higher rate of authenticity . That so many non-r and omized controlled trials were published as r and omized controlled trials reflected the fact that peer review needs to be improved and a good practice guide for peer review including how to identify the authenticity of the study urgently needs to be developed [10378713] OBJECTIVE The purpose of this study was to investigate the efficacy of acupuncture as an adjunctive therapy to st and ard care for the relief of pain and dysfunction in elderly patients with osteoarthritis ( OA ) of the knee . METHODS Seventy-three patients with symptomatic OA of the knee were r and omly assigned to treatment ( acupuncture ) or st and ard care ( control ) . Analysis was performed on last score carried forward to account for patients who dropped out before completion . Patients self-scored Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) and Lequesne indices at baseline and at 4 , 8 and 12 weeks . Patients in the control group were offered acupuncture treatment after 12 weeks . The data for these patients are pooled with those from the original acupuncture group for within-group analysis . RESULTS Patients r and omized to acupuncture improved on both WOMAC and Lequesne indices compared to those who received st and ard treatment alone . Significant differences on total WOMAC Scale were seen at 4 and 8 weeks . There appears to be a slight decline in effect at 4 weeks after cessation of treatment ( 12 weeks after first treatment ) . No adverse effects of acupuncture were reported . CONCLUSION These data suggest that acupuncture is an effective and safe adjunctive therapy to conventional care for patients with OA of the knee [16005336] BACKGROUND Acupuncture is widely used by patients with chronic pain although there is little evidence of its effectiveness . We investigated the efficacy of acupuncture compared with minimal acupuncture and with no acupuncture in patients with osteoarthritis of the knee . METHODS Patients with chronic osteoarthritis of the knee ( Kellgren grade < or = 2 ) were r and omly assigned to acupuncture ( n=150 ) , minimal acupuncture ( superficial needling at non-acupuncture points ; n=76 ) , or a waiting list control ( n=74 ) . Specialised physicians , in 28 outpatient centres , administered acupuncture and minimal acupuncture in 12 sessions over 8 weeks . Patients completed st and ard question naires at baseline and after 8 weeks , 26 weeks , and 52 weeks . The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis ( WOMAC ) index at the end of week 8 ( adjusted for baseline score ) . All main analyses were by intention to treat . RESULTS 294 patients were enrolled from March 6 , 2002 , to January 17 , 2003 ; eight patients were lost to follow-up after r and omisation , but were included in the final analysis . The mean baseline-adjusted WOMAC index at week 8 was 26.9 ( SE 1.4 ) in the acupuncture group , 35.8 ( 1.9 ) in the minimal acupuncture group , and 49.6 ( 2.0 ) in the waiting list group ( treatment difference acupuncture vs minimal acupuncture -8.8 , [ 95 % CI -13.5 to -4.2 ] , p=0.0002 ; acupuncture vs waiting list -22.7 [ -27.5 to -17.9 ] , p<0.0001 ) . After 52 weeks the difference between the acupuncture and minimal acupuncture groups was no longer significant ( p=0.08 ) . INTERPRETATION After 8 weeks of treatment , pain and joint function are improved more with acupuncture than with minimal acupuncture or no acupuncture in patients with osteoarthritis of the knee . However , this benefit decreases over time [4111481] Introduction This study tested the effectiveness of moxibustion on pain and function in chronic knee osteoarthritis ( KOA ) and evaluated safety . Methods A multi-centre , non-blinded , parallel-group , r and omised controlled trial compared moxibustion with usual care ( UC ) in KOA . 212 South Korean patients aged 40–70 were recruited from 2011–12 , stratified by mild ( Kellgren/Lawrence scale grade s 0/1 ) and moderate-severe KOA ( grade s 2/3/4 ) , and r and omly allocated to moxibustion or UC for four weeks . Moxibustion involved burning mugwort devices over acupuncture and Ashi points in affected knee(s ) . UC was allowed . Korean Western Ontario and McMaster Universities Question naire ( K-WOMAC ) , Short Form 36 Health Survey ( SF-36v2 ) , Beck Depression Inventory ( BDI ) , physical performance test , pain numeric rating scale ( NRS ) and adverse events were evaluated at 5 and 13 weeks . K-WOMAC global score at 5 weeks was the primary outcome . Results 102 patients ( 73 mild , 29 moderate-severe ) were allocated to moxibustion , 110 ( 77 mild , 33 moderate-severe ) to UC . K-WOMAC global score ( moxibustion 25.42+/−SD 19.26 , UC 33.60+/−17.91 , p<0.01 , effect size = 0.0477 ) , NRS ( moxibustion 44.77+/−22.73 , UC 56.23+/−17.71 , p<0.01 , effect size = 0.0073 ) and timed-st and test ( moxibustion 24.79+/−9.76 , UC 25.24+/−8.84 , p = 0.0486 , effect size = 0.0021 ) were improved by moxibustion at 5 weeks . The primary outcome improved for mild but not moderate-severe KOA . At 13 weeks , moxibustion significantly improved the K-WOMAC global score and NRS . Moxibustion improved SF-36 physical component summary ( p = 0.0299 ) , bodily pain ( p = 0.0003 ) , physical functioning ( p = 0.0025 ) and social functioning ( p = 0.0418 ) at 5 weeks , with no difference in mental component summary at 5 and 13 weeks . BDI showed no difference ( p = 0.34 ) at 5 weeks . After 1158 moxibustion treatments , 121 adverse events included first ( n = 6 ) and second degree ( n = 113 ) burns , pruritus and fatigue ( n = 2 ) . Conclusions Moxibustion may improve pain , function and quality of life in KOA patients , but adverse events are common . Limitations included no sham control or blinding . Trial Registration Clinical Research Information Service ( CRIS ) [24579366] OBJECTIVE To observe the clinical effect of moxibustion of different acupoints undergoing heat-sensitive state and resting state in the treatment of knee osteoarthritis ( KOA ) patients . METHODS A total of 60 cases of KOA patients were enrolled in the present trial . They were divided into heat-sensitive moxibustion ( heat-sensitive ) group and non-sensitive moxibustion group ( resting group ) . Moxibustion was applied to Neixiyan ( EX-LE 4 ) , Waixiyan ( i.e. Dubi , ST 35 ) and Heding ( EX-LE 2 ) for about 45 min , once daily for 20 days . The heat-sensitive state was evaluated according to the patient 's feeling . After moxibustion stimulation at the acupoint area , if the patient feels the heat penetrating from the skin surface to the deep tissue , or/ and extending peripherally around the moxibustion site , or/ and transmitting toward a certain direction , it is considered to be heat sensitization state . The therapeutic effect was evaluated by using visual analogue scale ( VAS ) for pain severity changes and by Guiding Principles for Clinical Trials of New Drugs of Chinese Materia Medica for evaluating functional activity of the knee-joint . RESULTS After 20 sessions of treatment and after a half year 's follow-up , the total integrated scores of VAS in the heat-sensitive group were all lower than those of the resting group ( P < 0.01 ) . Following 20 sessions of treatment , of the two 30 KOA patients in the heat-sensitive group and resting group , 14 ( 46.67 % ) and 5 ( 16.67 % ) experienced a marked improvement , 10 ( 33.33 % ) and 9 ( 30.00 % ) were effective , 6 ( 20.00 % ) and 16 ( 53.33 % ) were invalid , with the effective rates being 80.00 % and 46.67 , respectively . Half-year 's follow-up showed that the effective rates of the heat-sensitive group and resting group were 79.17 % ( 19/24 ) and 42.86 % ( 6/14 ) , respectively , suggesting a better therapeutic effect of heat-sensitive moxibustion . CONCLUSION The clinical n effect of heat-sensitive moxibustion is significantly superior to that of non-sensitive moxibustion in the treatment of KOA patients , being worthy of clinical application [17604311] OBJECTIVE To evaluate the effects of st and ardized western acupuncture and physiotherapy on pain and functional ability in patients with severe osteoarthritic knee pain awaiting knee arthroplasty . METHODS Three-arm , assessor-blind , r and omized controlled trial . PARTICIPANTS 181 patients awaiting knee arthroplasty . INTERVENTIONS acupuncture for 6 weeks ; physiotherapy for 6 weeks ; st and ardized advice . MAIN OUTCOME MEASURES Oxford Knee Score question naire ( OKS ) ( primary ) ; 50 m timed walk , and duration of hospital stay following knee arthroplasty . RESULTS There was no baseline difference between groups . At 7 weeks , there was a 10 % reduction in OKS in the acupuncture group which was a significant difference between the acupuncture and the control group : Mean ( s.d . ) acupuncture 36.8 ( 7.20 ) ; physiotherapy 39.2 ( 8.22 ) ; control 40.3 ( 8.48 ) ( P = 0.0497 ) . These effects were no longer present at 12 weeks . There was a trend ( P = 0.0984 ) towards a shorter in-patient stay of 1 day for the physiotherapy group [ mean 6.50 days ( s.d . 2.0 ) ] compared with the acupuncture group [ mean 7.77 days ( s.d . 3.96 ) ] . CONCLUSIONS We have demonstrated that patients with severe knee osteoarthritis can achieve a short-term reduction in OKS when treated with acupuncture . However , we failed to demonstrate any other clinical ly or statically significant effects between the groups . Both interventions can be delivered effectively in an out-patient group setting at a district general hospital . Further study is needed to evaluate the combined effects of these treatments [2268695] Background The present study tests whether a combined treatment of acupuncture and transcutaneous electrical nerve stimulation ( TENS ) is more effective than acupuncture or TENS alone for treating knee osteoarthritis ( OA ) . Methods Thirty-two patients with knee OA were r and omly allocated to four groups . The acupuncture group ( ACP ) received only acupuncture treatment at selected acupoints for knee pain ; the TENS group ( TENS ) received only TENS treatment at pain areas ; the acupuncture and TENS group ( A&T ) received both acupuncture and TENS treatments ; the control group ( CT ) received topical poultice ( only when necessary ) . Each group received specific weekly treatment five times during the study . Outcome measures were pain intensity in a visual analogue scale ( VAS ) and knee function in terms of the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) . Results The ACP , TENS and A&T groups reported lower VAS and WOMAC scores than the control group . Significant reduction in pain intensity ( P = 0.039 ) and significant improvement in knee function ( P = 0.008 ) were shown in the A&T group . Conclusion Combined acupuncture and TENS treatment was effective in pain relief and knee function improvement for the sample d patients suffering from knee OA [15611487] Context Previous studies of acupuncture for osteoarthritis have had conflicting results . This may have occurred because most studies have included small sample s , a limited number of treatment sessions , or other limitations . Contribution This r and omized , controlled trial compared 24 acupuncture sessions over 26 weeks with sham acupuncture or arthritis education in 570 patients with osteoarthritis of the knee . Acupuncture led to greater improvements in function but not pain after 8 weeks and in both pain and function after 26 weeks . No adverse effects were associated with acupuncture . Caution s Many participants dropped out of the study , so readers should interpret the findings at 26 weeks with caution . The Editors Osteoarthritis is the most common form of arthritis and is a major cause of morbidity , limitation of activity , and health care utilization , especially in elderly patients ( 1 , 2 ) . Pain and functional limitation are the primary clinical manifestations of osteoarthritis of the knee . Current recommendations for managing osteoarthritis , including guidelines published by the American College of Rheumatology ( 3 ) and European League of Associations of Rheumatology ( 4 ) , focus on relieving pain and stiffness and maintaining or improving physical function as important goals of therapy . No curative therapies exist for osteoarthritis ; thus , both pharmacologic and nonpharmacologic management focus on controlling pain and reducing functional limitation ( 5 ) . Nonpharmacologic therapy , which includes patient education , social support , physical and occupational therapy , aerobic and resistive exercises , and weight loss , is the cornerstone of a multidisciplinary approach to osteoarthritis patient management ( 3 ) . Pharmacologic therapies include nonopioid analgesics ( such as acetaminophen ) , nonsteroidal anti-inflammatory drugs ( NSAIDs ) ( including cyclooxygenase-2 [ COX-2 ] enzyme selective inhibitors ) , topical analgesics ( capsaicin cream ) , opioid analgesics , and intra-articular steroid and hyaluronate injections . Often , these agents are used in combination for additive analgesic efficacy ( 6 ) . Pharmacologic management of osteoarthritis is often ineffective , and agents such as NSAIDs may cause unwanted and dangerous side effects ( 7 , 8) . Complementary and alternative medicine is another approach to treating osteoarthritis ( 9 - 12 ) , particularly in Asian societies ( 13 ) . Many U.S. patients with osteoarthritis also use complementary and alternative medical therapies ( 14 ) . A systematic review of acupuncture and knee osteoarthritis ( 15 ) identified 7 small r and omized , controlled trials published in English . Within the method ologic limitations of the studies , the evidence suggested that acupuncture seemed to alleviate knee pain and function compared with sham acupuncture controls , although 2 trials comparing acupuncture with an active , nonpharmacologic treatment ( physical therapy ) did not indicate such an effect ( 16 , 17 ) . Before conducting our large-scale trial , we completed both a pilot study ( 18 ) and a r and omized , single-blind trial ( 19 ) of the effect of acupuncture on osteoarthritis of the knee . Participants in the uncontrolled pilot study ( n= 12 ) showed statistically significant improvement in both self-reported pain and physical function , as well as performance measures of physical function after 8 weeks of acupuncture treatment and at 12-week follow-up as compared with their baseline ( 18 ) . In our larger r and omized , single-blind trial ( n= 73 ) , which examined the benefit of acupuncture added to st and ard management with NSAIDs , the acupuncture treatment group experienced statistically significant improvements in self-reported pain and disability scores compared with a st and ard-care control group as late as 4 weeks after the end of treatment ( 19 ) . However , this effect diminished within 18 weeks ( 26 weeks after the beginning of the trial ) after the final acupuncture treatment . Together , however , the previously conducted trials ( both our preliminary studies [ 18 , 19 ] and those referenced in the systematic review [ 15 ] ) have 3 method ologic limitations : lack of credible controls for the placebo effect , inadequate assessment of long-term treatment benefits , and insufficient sample sizes . We tested the hypothesis that an 8-week intensive acupuncture treatment regimen , followed by an 18-week tapering regimen , reduces pain and improves function among patients with knee osteoarthritis as compared with both sham acupuncture and education control groups . Methods Patient Recruitment We recruited patients for this multisite , placebo-controlled trial from March 2000 through December 2003 , primarily through print and radio advertisements . The 3 sites were the Integrative Medicine Clinic of the University of Maryl and School of Medicine , Baltimore , Maryl and ; the Innovative Medical Research Center ( a private research firm ) , Towson , Maryl and ; and the Hospital for Special Surgery , New York City , New York . The institutional review boards of the 3 sites approved the study . We determined the sample size ( n= 570 ) by a power analysis based on our r and omized pilot study ( 19 ) , adjusted by the estimated decrease in effect size result ing from the inclusion of a sham acupuncture group design ed to control for placebo effects . Patients met the following inclusion criteria : age 50 years or older , a diagnosis of osteoarthritis of the knee , radiographic evidence of at least 1 osteophyte at the tibiofemoral joint ( KellgrenLawrence grade 2 ) , moderate or greater clinical ly significant knee pain on most days during the past month , and willingness to be r and omly assigned . Exclusion criteria were the presence of serious medical conditions that precluded participation in study , bleeding disorders that might contraindicate acupuncture , intra-articular corticosteroid or hyaluronate injections ( as well as any knee surgeries or concomitant use of topical capsaicin cream ) during the past 6 months , previous experience with acupuncture , or any planned events ( including total knee replacement ) that would interfere with participation in the study during the following 26 weeks . After a brief telephone screening , patients were scheduled to visit 1 of the 3 participating sites to sign an informed consent statement and undergo a brief rheumatologic examination ( including radiographic examination of affected knees ) by a physician or a nurse practitioner . Because the education course was a group activity , patients were recruited until a cohort of 12 to 21 patients was formed , at which point each cohort at each site was r and omly assigned to 1 of 3 groups by a computer-generated process using r and omly selected blocks of 3 , 6 , and 9 . We assured allocation concealment by using disguised letter codes that were generated and sent to the site coordinators by a central statistical core . We used this procedure to ensure that approximately equal numbers of participants were in each treatment group across the course of the study , to ensure that each cohort would have participants assigned to all 3 treatment groups , and to make the breaking of the group assignment process more difficult . The research assistants who collected assessment s from participants , the participants themselves ( in the true acupuncture and sham acupuncture groups ) , and the statistician were blinded to group assignment . Assessment s were conducted at baseline and 4 , 8 , 14 , and 26 weeks after r and omization . Study Interventions We developed and modified the acupuncture treatment and sham control protocol s from previously reported and vali date d procedures ( 18 - 21 ) . During the trial , 7 acupuncturists were used : 3 at the Integrative Medicine Clinic , 3 at the Innovative Medical Research Center , and 1 at the Hospital for Special Surgery . In general , acupuncturists were assigned to the same participants throughout the 26-week treatment schedule , except for vacation conflicts and staff turnover , and provided approximately the same proportions of true versus sham procedures . All acupuncturists were state-licensed and had at least 2 years of clinical experience . The study 's principal acupuncturist trained and supervised the acupuncturists in performing true or sham procedures and avoiding interactions that could inadvertently communicate group assignment . True Acupuncture The true acupuncture ( experimental ) group underwent 26 weeks of gradually tapering treatment according to the following schedule : 8 weeks of 2 treatments per week followed by 2 weeks of 1 treatment per week , 4 weeks of 1 treatment every other week , and 12 weeks of 1 treatment per month . We based the acupuncture point selection s on Traditional Chinese Medicine meridian theory to treat knee joint pain , known as the Bi syndrome . These points consisted of 5 local points ( Yanglinquan [ gall bladder meridian point 34 ] , Yinlinquan [ spleen meridian point 9 ] , Zhusanli [ stomach meridian point 36 ] , Dubi [ stomach meridian point 35 ] , and extra point Xiyan ) and 4 distal points ( Kunlun [ urinarybladder , meridian point 60 ] , Xuanzhong [ gall bladder meridian point 39 ] , Sanyinjiao [ spleen meridian point 6 ] , and Taixi [ kidney meridian point 3 ] ) on meridians that traverse the area of pain ( 22 , 23 ) . The same points were treated for each affected leg . If both knees were affected , 9 needles were inserted in each leg . ( The outcome measures were not specifically targeted to whether the patient had osteoarthritis in 1 or both knees , and we observed no differential effects on the basis of the number of knees treated . ) The acupuncturists inserted 1.5-inch ( for local points ) and 1-inch ( for distal points ) 32-gauge ( 0.25-mm diameter ) acupuncture needles to a conventional depth of approximately 0.3 to 1.0 inch , depending on point location . All participants in the treatment group achieved the De-Qi sensation , a local sensation of heaviness , numbness , soreness , or paresthesia that accompanies the insertion and manipulation of needles during acupuncture , at these 9 points . Acupuncturists applied electrical [23967637] OBJECTIVE To explore the efficacy on knee osteoarthritis ( KOA ) treated with different acupuncture methods at different stages . METHODS One hundred and eighty cases of KOA were divided into stagnation stage , fascia cramp stage and tendon lesion stage according to the condition of disease , 60 cases in each stage . Each stage was r and omized into a staging treatment group and an electroacupuncture ( EA ) group , 30 cases in each one . In the staging treatment group , acupuncture at the tendon points of meridians and electric thermal needling method were adopted for the cases at the stagnation stage ; the small needle-knife therapy and bleeding method were used for the cases at the fascia cramp stage ; and the electric thermal therapy with thick silver needles was applied for the cases at the tendon lesion stage . In the EA group , EA was applied for the cases of all the three stages at Liangqiu ( ST 34 ) , Xuehai ( SP 10 ) , Yanglingquan ( GB 34 ) , etc . RESULTS The total effective rate was 96.1 % ( 87/90 ) in the staging treatment group and was 91.1 % ( 82/90 ) in the EA group , without significant difference in comparison ( P > 0.05 ) . The controlled and remarkably effective rate ( 88.9 % , 80/90 ) in the staging treatment group was higher apparently than ( 62.2 % , 56/90 ) in the EA group ( P < 0.001 ) . And in the EA group , with the disease progression and the further disease stages , the controlled and remarkably effective rate was reduced . After treatment , the scores of symptoms and signs were decreased in both groups ( both P < 0.001 ) , the improvement in the staging treatment group was superior to that in the EA group ( P < 0.001 ) . CONCLUSION The different acupuncture methods at the three stages improve obviously the clinical effect and are highly targeted . The mechanism of the three stages on " meridian muscle region pathology " and the treatment based on the disease stages can be the effective approach to KOA [19942631] Acupuncture is one of the most widely used and broadly research ed of the complementary and alternative therapies , but high- quality trials generally show no benefit over sham acupuncture . Many would view this result as evidence of ineffectiveness for this intervention . This discussion article focuses on the report of a large multicenter r and omized controlled trial of acupuncture for chronic low-back pain ( CLBP ) in the lay and academic press , the ensuing discussion , and its impact on both clinical practice and service provision . The authors suggest that interpretive bias has affected reporting , leading to question able conclusions and advocacy in favor of this form of care that may exceed the evidence . They also suggest that a lack of underst and ing of research into the placebo effect may have contributed to confusion in the interpretation of these trials [19420954] Background : To evaluate the safety of acupuncture in a large number of patients receiving conventional health care and , based on these results , to develop a new medical consent form for acupuncture . Methods : The prospect i ve observational study included patients who received acupuncture treatment for chronic osteoarthritis pain of the knee or hip , low back pain , neck pain or headache , allergic rhinitis , asthma , or dysmenorrhoea . After treatment , all patients documented adverse events associated with acupuncture ( defined as adverse effects ) . Patients who reported a need for treatment due to an adverse effect completed an additional st and ardised question naire on the most important adverse effect . Based on this data and considering ethical and legal aspects a new consent form was developed . Results : A total of 229,230 patients received on average 10.2 ± 3.0 acupuncture treatments . Altogether , 19,726 patients ( 8.6 % ) reported experiencing at least one adverse effect and 4,963 ( 2.2 % ) reported one which required treatment . Common adverse effects were bleedings or haematoma ( 6.1 % of patients , 58 % of all adverse effects ) , pain ( 1.7 % ) and vegetative symptoms ( 0.7 % ) . Two patients experienced a pneumothorax ( one needed hospital treatment , the other observation only ) . The longest duration of a side effect was 180 days ( nerve lesion of the lower limb ) . The result ing medical consent form consists of five modules : Introduction to acupuncture and moxibustion , Risks of acupuncture treatment , Conditions which can increase the risk , Doctor ’s statement , and Consent . Conclusion : Acupuncture provided by physicians is a relatively safe treatment and the proposed consent form could support both patients and professionals in the process of obtaining informed consent [24946628] OBJECTIVE To evaluate the clinical efficacy and efficacy sustainable time of acupuncture in knee osteoarthritis ( KOA ) . METHODS The non-r and omized concurrent control trial was adopted . One hundred and ninety-three cases of KOA were divided into an immediate acupuncture group ( group A , 97 cases ) and a delayed acupunc-weeks at the end of treatment . In group B , the same acupuncture therapy was applied after waiting 4 weeks . The acupoints in the two groups were Liangqiu ( ST 34 ) , Dubi ( ST 35 ) , Zusanli ( ST 36 ) , Yanglingquan ( GB 34 ) , Yinlingquan ( SP 9 ) , Xuehai ( SP 10 ) , Xiyan ( EX-LE 4 ) , Xiyangguan ( GB 33 ) . WOMAC ( Western Ontario and McMasters Universities Osteoarthritis ) was used for the assessment of the primary index and VAS ( visual analogue scale ) was for the secondary index . The evaluation was accomplished by the patients at the beginning of trial , on the 4th and 8th weeks . In each group , 72 patients finished the trial and the data of the lost cases were included in the final data analysis . RESULTS In the 4th week of trial , WOMAC score was ( 25 . 8+/-22.0 ) in group A difference ( P<0 . 001 ) . VAS scorewas ( 31 . 8+/-24 . and was ( 43.8+/-22.2 ) in group B , indicating the significant 6 ) in group A and was ( 56 . 6 + /-25 . 8) in group B , indicating very significant difference ( P<0 . 001 ) . In the 8th week , the efficacy was reduced slightly in the follow-up of group A , but it was improved apparently as compared Acupuncture relieves joint pain and improves joint function obviously.by th patiĩeffr , a Mtaetfti-?an tf ri-with that before treatment . CONCLUSION Acupuncture relieves joint pain and improves joint function obviously . The effect of acupuncture is still sustainable in 4 weeks after terminating the treatment [25268438] IMPORTANCE There is debate about benefits of acupuncture for knee pain . OBJECTIVE To determine the efficacy of laser and needle acupuncture for chronic knee pain . DESIGN , SETTING , AND PARTICIPANTS Zelen- design clinical trial ( r and omization occurred before informed consent ) , in Victoria , Australia ( February 2010-December 2012 ) . Community volunteers ( 282 patients aged ≥50 years with chronic knee pain ) were treated by family physician acupuncturists . INTERVENTIONS No acupuncture ( control group , n = 71 ) and needle ( n = 70 ) , laser ( n = 71 ) , and sham laser ( n = 70 ) acupuncture . Treatments were delivered for 12 weeks . Participants and acupuncturists were blinded to laser and sham laser acupuncture . Control participants were unaware of the trial . MAIN OUTCOMES AND MEASURES Primary outcomes were average knee pain ( numeric rating scale , 0 [ no pain ] to 10 [ worst pain possible ] ; minimal clinical ly important difference [ MCID ] , 1.8 units ) and physical function ( Western Ontario and McMaster Universities Osteoarthritis Index , 0 [ no difficulty ] to 68 [ extreme difficulty ] ; MCID , 6 units ) at 12 weeks . Secondary outcomes included other pain and function measures , quality of life , global change , and 1-year follow-up . Analyses were by intention-to-treat using multiple imputation for missing outcome data . RESULTS At 12 weeks and 1 year , 26 ( 9 % ) and 50 ( 18 % ) participants were lost to follow-up , respectively . Analyses showed neither needle nor laser acupuncture significantly improved pain ( mean difference ; -0.4 units ; 95 % CI , -1.2 to 0.4 , and -0.1 ; 95 % CI , -0.9 to 0.7 , respectively ) or function ( -1.7 ; 95 % CI , -6.1 to 2.6 , and 0.5 ; 95 % CI , -3.4 to 4.4 , respectively ) compared with sham at 12 weeks . Compared with control , needle and laser acupuncture result ed in modest improvements in pain ( -1.1 ; 95 % CI , -1.8 to -0.4 , and -0.8 ; 95 % CI , -1.5 to -0.1 , respectively ) at 12 weeks , but not at 1 year . Needle acupuncture result ed in modest improvement in function compared with control at 12 weeks ( -3.9 ; 95 % CI , -7.7 to -0.2 ) but was not significantly different from sham ( -1.7 ; 95 % CI , -6.1 to 2.6 ) and was not maintained at 1 year . There were no differences for most secondary outcomes and no serious adverse events . CONCLUSIONS AND RELEVANCE In patients older than 50 years with moderate or severe chronic knee pain , neither laser nor needle acupuncture conferred benefit over sham for pain or function . Our findings do not support acupuncture for these patients . TRIAL REGISTRATION anzctr.org.au Identifier : ACTRN12609001001280 [16452103] Abstract Objective To investigate whether a sham device ( a vali date d sham acupuncture needle ) has a greater placebo effect than an inert pill in patients with persistent arm pain . Design A single blind r and omised controlled trial created from the two week placebo run-in periods for two nested trials that compared acupuncture and amitriptyline with their respective placebo controls . Comparison of participants who remained on placebo continued beyond the run-in period to the end of the study . Setting Academic medical centre . Participants 270 adults with arm pain due to repetitive use that had lasted at least three months despite treatment and who scored ≥3 on a 10 point pain scale . Interventions Acupuncture with sham device twice a week for six weeks or placebo pill once a day for eight weeks . Main outcome measures Arm pain measured on a 10 point pain scale . Secondary outcomes were symptoms measured by the Levine symptom severity scale , function measured by Pransky 's upper extremity function scale , and grip strength . Results Pain decreased during the two week placebo run-in period in both the sham device and placebo pill groups , but changes were not different between the groups ( −0.14 , 95 % confidence interval −0.52 to 0.25 , P = 0.49 ) . Changes in severity scores for arm symptoms and grip strength were similar between groups , but arm function improved more in the placebo pill group ( 2.0 , 0.06 to 3.92 , P = 0.04 ) . Longitudinal regression analyses that followed participants throughout the treatment period showed significantly greater downward slopes per week on the 10 point arm pain scale in the sham device group than in the placebo pill group ( −0.33 ( −0.40 to −0.26 ) v −0.15 ( −0.21 to −0.09 ) , P = 0.0001 ) and on the symptom severity scale ( −0.07 ( −0.09 to −0.05 ) v −0.05 ( −0.06 to −0.03 ) , P = 0.02 ) . Differences were not significant , however , on the function scale or for grip strength . Reported adverse effects were different in the two groups . Conclusions The sham device had greater effects than the placebo pill on self reported pain and severity of symptoms over the entire course of treatment but not during the two week placebo run in . Placebo effects seem to be malleable and depend on the behaviours embedded in medical rituals [23819244] OBJECTIVE To objective ly evaluate the clinical efficacy of stiletto needle for pain of knee osteoarthri tis ( KOA ) , and analyze its function mechanism . METHODS Seventy-six cases of KOA ( 76 knees ) were selected . Under the guide of Jingjin theory in TCM , stiletto needle was applied at pain point of Jingjin in extra-articular area to have a loose solution effect , 1 to 3 points were selected each time , 1 to 2 times of treatment were required . The results of tenderness measurement instrument was adopted as main evaluation index of joint pain , and all data of evaluation indices before and after the treatment were statistical analyzed . RESULTS There were significant differences in visual analogue scale ( VAS ) score , tenderness score , HSS function score and movement range of joint before and after the treatment ( all P < 0.05 ) . The effective rate of stiletto needle therapy was 89.5 % . There was apparent regression trend between VAS score and tenderness score with Y ( VAS ) = 7.841 - 1.569 X ( tenderness score ) as its regressive equation . CONCLUSION The stiletto needle therapy is an effective method to relieve the pain of knee osteoarthritis , and its clinical efficacy evaluation could be more objective and digital with tenderness measurement instrument [23620932] OBJECTIVE To compare the efficacy difference in the treatment of knee osteoarthritis between acupuncture at Neiguan ( PC 6 ) and Taichong ( LR 3 ) and the conventional acupoints . METHODS Forty four cases were r and om into a Neiguanc ( PC 6 ) Taichong ( LR 3 ) group observation group ( 20 cases ) and a conventional group control group ( 24 cases ) . In the observention group , acupuncture was applied to Neiguan ( PC 6 ) on the healthy side and Taichong ( LR 3 ) on the affected side . The acupoints were selected bilaterally if both knees were affected . In the control group , acupuncture was applied to Yanglingquan ( GB 34 ) , Yinlingquan ( SP 9 ) , Neixiyan ( EX-LE 4 ) , Dubi ( ST 35 ) , Zusanli ( ST 36 ) and the others on the affected side . The visual analogue scale ( VAS ) and Western Ontario and McMaster University Osteoarthritis Index ( WOMAC ) were used for assessment of theraputic effect after treatment . RESULTS The score of VAS and pain , stiffness and function impairment of WOMAC were lower apparently than those before treatment in both groups ( all P < 0.001 ) . VAS score after treatment in the observation group was lower apparently than that in the control group ( P < 0.05 ) . The differences in each item score of WOMAC after treatment were not significant statistically between the two groups ( all P > 0.05 ) . CONCLUSION Acupuncture at Neiguan ( PC 6 ) and Taichong ( LR 3 ) achieves the similar efficacy on knee osteoarthritis as the conventional acupoints , but the former is more simple and convenient [395837] Background Controlled clinical trials produced contradictory results with respect to a specific analgesic effect of acupuncture . There is a lack of large multi-centre acupuncture trials . The German Acupuncture Trial represents the largest multi-centre study of acupuncture in the treatment of chronic pain caused by gonarthrosis up to now . Methods 900 patients will be r and omised to three treatment arms . One group receives verum acupuncture , the second sham acupuncture , and the third conservative st and ard therapy . The trial protocol is described with eligibility criteria , detailed information on the treatment definition , blinding , endpoints , safety evaluation , statistical methods , sample size determination , monitoring , legal aspects , and the current status of the trial . Discussion A critical discussion is given regarding the considerations about st and ardisation of the acupuncture treatment , the choice of the control group , and the blinding of patients and observers [15465938] Objective : The primary aim was to establish from acupuncture patients the type and frequency of adverse events they experienced and attributed to their treatment . Secondary aims included the measurement of patient reported adverse consequences arising from advice received about conventional/prescribed medication or from delayed conventional diagnosis and treatment . Methods : Postal survey of prospect ively identified acupuncture patients . One in three members of the British Acupuncture Council ( n = 638 ) invited consecutive patients to participate in the survey . Participating patients gave baseline data and consented to direct follow up by the research ers at 3 months . A structured question naire was used to collect data on perceived adverse events . Results : 9408 patients gave baseline information and consent and 6348 ( 67 % ) completed 3 month question naires . Responders were not dissimilar to non-responders for all known characteristics . 682 patients reported at least one adverse event over 3 months , a rate of 107 per 1000 patients ( 95 % CI 100 to 115 ) . Three patients reported a serious adverse event . The most common events reported were severe tiredness and exhaustion , pain at the site of needling , and headache . Patients receiving acupuncture treatment that was not funded by the NHS and patients not in contact with a GP or hospital specialist were less likely to report adverse events ( odds ratios 0.59 and 0.66 , respectively ) . 199 ( 3 % ) of responding patients reported receiving advice about conventional/prescribed medication , six of whom reported adverse consequences after taking the advice . Two patients reported delayed conventional treatment . Conclusion : Patients report a range of adverse events but these do not prevent most patients seeking further acupuncture . This large scale survey supports existing evidence that acupuncture is a relatively safe intervention when practised by regulated practitioners [11471578] Acupuncture is becoming a common technique within the physiotherapy profession as a treatment modality for pain relief ; however , few r and omised controlled trials have been undertaken to assess the effectiveness of acupuncture , particularly in the treatment of osteoarthritis ( OA ) of the hip . Therefore , a r and omised trial to compare the effectiveness of acupuncture with advice and exercises on the symptomatic treatment of OA of the hip was carried out . Thirty-two patients awaiting a total hip arthroplasty were r and omly allocated to either the experimental group , ( A ) , to have six sessions of acupuncture each lasting up to 25 minutes , or the control group , ( B ) , to be given advice and exercises for their hip over a six week period . Group A consisted of three men and 13 women , and group B consisted of four men and eight women . The average age in group A was 66 years and in group B it was 68 years . Patients were assessed for pain and functional ability , using a modified version of the WOMAC question naire , pre-treatment , immediately post-treatment and at eight weeks post-treatment . The pre-treatment WOMAC scores in the two groups were similar ( p=0.85 ) . There was a significant improvement in group A ( decrease in WOMAC score ) immediately post-treatment ( p=0.002 ) and this was maintained at the eight-week follow-up ( p=0.03 ) . There were no significant changes in group B. When the changes in WOMAC scores were compared between groups , a significantly greater improvement was found between pre-treatment and immediately post-treatment in group A , compared with group B ( p=0.02 ) . The changes between pre-treatment and the eight-week follow-up also showed a significant improvement in group A compared with group B ( p=0.03 ) . In conclusion , this trial supports the hypothesis that acupuncture is more effective than advice and exercises in the symptomatic treatment of OA of the hip [102323] Background The purpose of this study was to compare the efficacy of electroacupuncture ( EA ) , diclofenac and their combination in symptomatic treatment of osteoarthritis ( OA ) of the knee . Methods This study was a r and omized , single-blind , placebo controlled trial . The 193 out- patients with OA of the knee were r and omized into four groups : placebo , diclofenac , EA and combined ( diclofenac plus EA ) . Paracetamol tablets were prescribed as a rescue analgesic during the study . The patients were evaluated after a run-in period of one week ( week 0 ) and again at the end of the study ( week 4 ) . The clinical assessment s included the amount of paracetamol taken/week , visual analog scale ( VAS ) , Western Ontario and McMaster Universities ( WOMAC ) OA Index , Lequesne 's functional index , 50 feet-walk time , and the orthopedist 's and patient 's opinion of change . Results One hundred and eighty six patients completed the study . The improvement of symptoms ( reduction in mean changes ) in most outcome parameters was greatest in the EA group . The proportions of responders and patients with an overall opinion of " much better " were also greatest in the EA group . The improvement in VAS was significantly different between the EA and placebo group as well as the EA and diclofenac group . The improvement in Lequesne 's functional index also differed significantly between the EA and placebo group . In addition , there was a significant improvement in WOMAC pain index between the combined and placebo group . Conclusion EA is significantly more effective than placebo and diclofenac in the symptomatic treatment of OA of the knee in some circumstances . However , the combination of EA and diclofenac treatment was no more effective than EA treatment alone [21290833] OBJECTIVE To observe the differences of effect of electroacupuncture and medication on hip osteoarthritis . METHODS Sixty cases were r and omly divided into an electroacupuncture group and a medication group , 30 cases in each one . In electroacupuncture group , electroacupuncture was applied at Biguan ( ST 31 ) , Juliao ( GB 29 ) , Zuwuli ( LR 10 ) and Yinlian ( LR 11 ) . In medication group , Diclofenac Sodium was prescribed for oral administration . One month after treatment , Visual Analogue Scale ( VAS ) and Harris score were compared between two groups . RESULTS VAS scores were 67.83 + /- 8.48 and 55.83 + /- 9.66 before and after treatment in electroacupuncture group , and were 68.67 + /- 8.09 and 61.50 + /- 7.78 in medication group separately . VAS pain scores after treatment were reduced remarkably in two groups ( both P < 0.001 ) , but the score was reduced much more remarkably in electroacupuncture group as compared with medication group . In electroacupuncture group , after treatment , Harris total score , the single scores of joint pain , function and motion range increased apparently as compared with those before treatment ( all P < 0.001 ) . In medication group , after treatment , Harris total score and pain score increased remarkably as compared with those before treatment ( both P < 0.001 ) . Harris total score , pain score and function score after treatment in electroacupuncture group increased much more remarkably as compared with those in medication group ( all P < 0.05 ) . CONCLUSION Electroacupuncture can treat effectively hip osteoarthritis , relieve joint pain and improve joint function . The efficacy of it is superior to that of oral administration of Diclofenac Sodium [24462108] BACKGROUND There is lack of well- design ed trials evaluating structural benefits of non-pharmacologic therapies in knee osteoarthritis ( OA ) . In this parallel-group r and omized controlled trial , we aim to compare the possible advantages of lateral wedge insole and acupuncture in patients with medial knee OA . METHOD Patients with grade two or three of medial knee OA were r and omly allocated to group one who received an in shoe lateral wedge and group two who underwent acupuncture . We assessed patients ' pain , function and knee joint cartilage thickness before and after intervention . Paired t-test and independent sample s t-test were used for in group and between group analyses . ( LEVEL OF EVIDENCE 2 . ) RESULTS Twenty patients in each group were recruited in the study . Pain significantly decreased after therapy in both groups one and two ( paired t test , P<0.001 , 95 % CI : 1.62 - 3.25 and 1.58 - 3.20 respectively ) . Function improved in each group ( paired t test , P=0.001 , 95 % CI of 0.94 - 2.38 in group one and 0.97 - 2.43 in group two ) . A non- clinical ly statistically significant difference regarding the femoral and tibial cartilage thickness was obtained in both groups one ( P=0.005 , CI : -0.43 - 0.82 and P=0.037 , CI : -0.44 - 0.80 respectively ) and two ( P=0.025 , CI : -0.45 - 0.79 and P=0.035 , CI : -0.29 - 0.96 respectively ) . Between groups analysis showed no significant difference regarding abovementioned measures . CONCLUSION Both lateral wedge insole and acupuncture can be effective in the treatment of medial knee osteoarthritis without any superiority of one over the other . Iranian Registry of Clinical Trials : I RCT 201201108235N1 . URL : http://i rct .ir/ search en.php [1816730] Forty-four patients with chronic cervical osteoarthritis took part in this study . Patients were treated with acupuncture , sham-acupuncture , diazepam or placebo-diazepam in r and omized order . Pain was rated on visual analogue scales before , during , and after treatment . Two scales were separately used to rate the intensity ( sensory component ) and the unpleasantness ( affective component ) of pain . The results analyzed from these trials show that diazepam , placebo-diazepam , acupuncture and sham-acupuncture have a more pronounced effect on the affective than on the sensory component of pain . Acupuncture was significantly more effective than placebo-diazepam ( p less than 0.05 ) , but not significantly more effective than diazepam or sham-acupuncture [7727550] OBJECTIVE The purpose of this study was to determine whether acupuncture was more effective than sham acupuncture in the reduction of pain in persons with osteoarthritis ( OA ) of the knee . METHODS Forty subjects ( 20 men , 20 women ) with radiographic evidence of OA of the knee were stratified by gender and r and omly assigned to either the experimental ( real acupuncture ) or control ( sham acupuncture ) groups . Subjects were treated three times per week for 3 weeks and evaluated at three test sessions . Outcome measures were : 1 ) the Pain Rating Index of the McGill Pain Question naire , 2 ) the Western Ontario and McMaster Universities ( WOMAC ) Osteoarthritis Index , and 3 ) pain threshold at four sites at the knee . RESULTS The analyses of variance showed that both real and sham acupuncture significantly reduced pain , stiffness , and physical disability in the OA knee , but that there were no significant differences between groups . CONCLUSIONS Acupuncture is not more effective than sham acupuncture in the treatment of OA pain [18390493] Objective To investigate whether placebo effects can experimentally be separated into the response to three components— assessment and observation , a therapeutic ritual ( placebo treatment ) , and a supportive patient-practitioner relationship— and then progressively combined to produce incremental clinical improvement in patients with irritable bowel syndrome . To assess the relative magnitude of these components . Design A six week single blind three arm r and omised controlled trial . Setting Academic medical centre . Participants 262 adults ( 76 % women ) , mean ( SD ) age 39 ( 14 ) , diagnosed by Rome II criteria for and with a score of ≥150 on the symptom severity scale . Interventions For three weeks either waiting list ( observation ) , placebo acupuncture alone ( “ limited ” ) , or placebo acupuncture with a patient-practitioner relationship augmented by warmth , attention , and confidence ( “ augmented ” ) . At three weeks , half of the patients were r and omly assigned to continue in their originally assigned group for an additional three weeks . Main outcome measures Global improvement scale ( range 1 - 7 ) , adequate relief of symptoms , symptom severity score , and quality of life . Results At three weeks , scores on the global improvement scale were 3.8 ( SD 1.0 ) v 4.3 ( SD 1.4 ) v 5.0 ( SD 1.3 ) for waiting list versus “ limited ” versus “ augmented , ” respectively ( P<0.001 for trend ) . The proportion of patients reporting adequate relief showed a similar pattern : 28 % on waiting list , 44 % in limited group , and 62 % in augmented group ( P<0.001 for trend ) . The same trend in response existed in symptom severity score ( 30 ( 63 ) v 42 ( 67 ) v 82 ( 89 ) , P<0.001 ) and quality of life ( 3.6 ( 8.1 ) v 4.1 ( 9.4 ) v 9.3 ( 14.0 ) , P<0.001 ) . All pairwise comparisons between augmented and limited patient-practitioner relationship were significant : global improvement scale ( P<0.001 ) , adequate relief of symptoms ( P<0.001 ) , symptom severity score ( P=0.007 ) , quality of life ( P=0.01 ) . Results were similar at six week follow-up . Conclusion Factors contributing to the placebo effect can be progressively combined in a manner resembling a grade d dose escalation of component parts . Non-specific effects can produce statistically and clinical ly significant outcomes and the patient-practitioner relationship is the most robust component . Trial registration Clinical Trials NCT00065403 [25632577] OBJECTIVE To observe the therapeutic effect of different schemes of mild moxibustion for treatment of ( yang-deficiency induced cold-accumulation type)knee osteoarthritis ( KOA ) . METHODS Fifty-nine KOA patients were chosen and r and omly divided into control group ( n = 30 ) and test group ( n = 29 ) . Patients of the control group were treated by mild moxi- bustion of Neixiyan ( EX-HE4 ) and Waixiyan ( ST 35 ) for 30 min , once daily for 14 days ( two courses ) , and those of the test group were treated by mild moxibustion of EX-HE 4 and ST 35 for 30 mini once daily for 7 days ( the same to control group ) , followed by moxibustion of Yaoyangguan ( GV 3 ) and Mingmen ( GV 4 ) once daily for next 7 days more . In addition , patients of the two groups were also treated by routine acupuncture stimulation of EX-HE 4 , ST 35 , Yanglingquan ( GB 34 ) , Kunlun ( BL 60 ) , etc . The interval between two therapeutic courses was one day . The Lysholm Knee Score Scale ( LKSS ) was used to evaluate the therapeutic effect . Visual analogue scale ( VAS ) was employed to assess the patient 's knee-joint pain severity ( arthralgia ) , and scores of morning stiffness , arthrocele , and walking restraint degree of the knee-joint were also evaluated before and after the treatment . RESULTS After the treatment , the scores of VAS , morning stiffness , arthrocele and walking restraint degree of the knee-joint of both groups were significantly decreased ( P<0 . 05 ) , and the scores of the test group were obviously lower than those of the con- trol group ( P<0 . 05 ) . The effective rate of the test group was 89.66 % (26/29)which was obviously higher than that ( 70.00 % , 21/30 ) of the control group ( P<0 . 05 ) . CONCLUSION Mild moxibustion of Neixiyan ( EX-HE 4 ) and Waixiyan ( ST 35 , local acu- points ) , and Yaoyangguan ( GV 3 ) and Mingmen ( GV 4 ) has a better therapeutic effect for KOA patients than moxibustion of local acupoints only [23713295] OBJECTIVE To observe therapeutic efficacy of osteoarthritis treated by electroacupuncture , and explore its function of promoting cartilage restoration . METHODS According to r and om digital table , sixty cases of knee osteoarthritis ( 60 knees ) were r and omly divided into an electroacupuncture group and a physiotherapy group , 15 cases ( 30 knees ) in each one . The electroacupuncture was applied at Neixiyan ( EX-LE 4 ) , Dubi ( ST 35 ) , Heding ( EX-LE 2 ) and Xuehai ( SP 10 ) in the electroacupuncture group , once every other day . The physiotherapy group was treated by medium-frequency therapeutic apparatus every day . For both groups , 4 weeks of treatment were required . The Lysholm knee scoring scale ( LKSS ) was used to evaluate and compare the knee joints function before and after treatment . At the same time , the GE Signa EXCITE Twin Speed HD 1.5 T was used to take MRI examination of knee joints , and measure the T2 values in 10 sub-regions of the cartilage of tibiofemoral joints . RESULTS Compared before treatment , the LKSS score of both groups were improved with significant differences except item dem and s for support ( P < 0.01 , P < 0.05 ) . Between the two groups after treatment , there were significant differences on total score , item instability and swelling ( all P < 0.05 ) , the electroacupuncture group was better than the physiotherapy group , but no significant difference on the other items ( all P > 0.05 ) . In the electroacupuncture group after treatment , T2 value in anterior lateral tibial sub-region ( LTa ) was significantly lowered ( P < 0.05 ) , but no significant difference in the other nine sub-regions ( all P > 0.05 ) . In the physiotherapy group , T2 value in any sub-region was not significantly different before and after treatment ( all P > 0.05 ) . CONCLUSION Electroacupuncture could effectively improve the symptom , sign and knee joint 's function of patients with knee osteoarthritis . Compared with physiotherapy , it has more superior effect and considered as a better non-operative treatment for osteoarthritis . Electroacupuncture also has positive influence on T2 value in cartilage , indicating that electroacupuncture may have the function of promoting cartilage restoration [23713297] OBJECTIVE To observe the long-term efficacy and safety of warm needling therapy combined with rehabilitation training in the treatment of knee osteoarthritis ( KOA ) for the patients living in simple room after earthquake . METHODS Eighty-eight cases of KOA were r and omized into a warm needling group and an acupuncture group , 44 cases in each one . In the warm needling group , the warm needling therapy was applied at Neixiyan ( EX LE 4 ) and Dubi ( ST 35 ) , in combination with rehabilitation training . In the acupuncture group , the same rehabilitation training was received , and the same acupoints were selected as the warm needling group , but only stimulated with acupuncture without moxibustion applied . The clinical efficacy was observed after 20 treatments and in 1 - 2 months of follow-up . RESULTS The total effective rate was 100.0 % ( 41/41 ) in the warm needling group , which was apparently superior to 85.4 % ( 35/41 ) in the acupuncture group ( P < 0.05 ) . The symptom integral , pain and knee joint function score were all improved significantly after 20 treatments in both groups ( all P < 0.05 ) . The improvements in symptoms and pain in the warm needling group were superior apparently to the acupuncture group ( all P < 0.05 ) . The efficacy remained well within 2 months follow-up ( all P < 0.05 ) . But the difference in knee joint function score was not statistically significant between the two groups ( all P > 0.05 ) . CONCLUSION The combined therapy of warm needling and rehabilitation training achieves the superior efficacy and good safety in the treatment of KOA as compared with the combined therapy of simple acupuncture and rehabilitation training for the patients living in simple room after earthquake [12972723] Background : We report on the study design and protocol s of two r and omized controlled trials ( Acupuncture R and omized Trials = ART ) that investigate the efficacy of acupuncture in the treatment of chronic low back pain and osteoarthritis of the knee , respectively . Objective : To investigate whether acupuncture is more efficacious than ( a ) no treatment or ( b ) minimal acupuncture in the treatment of low back pain and osteoarthritis . Design : Two r and omized , controlled , multicenter trials with three treatment arms and a total follow-up time of 52 weeks . Setting : 30 practitioners and outpatient units in Germany specialized in acupuncture treatment . Patients : 300 patients will be included in each study . In the low back pain trial , patients will be included according to clinical diagnosis . In the osteoarthritis pain trial , patients will be included according to the American College of Rheumatology criteria . Interventions : Patients are r and omly assigned to receive either ( 1 ) semi-st and ardized acupuncture ( 150 patients ) , ( 2 ) minimal acupuncture at non-acupuncture points ( 75 patients ) , or ( 3 ) no treatment for two months followed by semi-st and ardized acupuncture ( 75 patients , waiting list control ) . Acupuncture treatment consists of 12 sessions per patient over a period of 8 weeks . Main Outcome Measure : The main outcome measure is the difference between baseline and the end of the 8-week treatment period in the following parameters : pain intensity as measured by a visual analogue scale ( VAS ; 0–100 mm ) in the low back pain trial and by the Western Ontario and McMaster Universities Osteoarthritis Score ( WOMAC ) in the osteoarthritis trial . Outlook : The results of these two studies ( available in 2004 ) will provide health care providers and policy makers with the information needed to make scientifically sound assessment s of acupuncture therapy [25998755] Background In China , heat-sensitive moxibustion ( HSM ) is used for knee osteoarthritis ( KOA ) to reduce pain and improve physical activity . However , there is little high- quality evidence of its effectiveness . Objective To evaluate the effectiveness of HSM in the treatment of KOA compared with usual care . Methods We performed a multicentre , r and omised controlled trial . In total , 432 patients with KOA were r and omly assigned to one of three groups ( HSM , conventional moxibustion , or conventional injection with sodium hyaluronate ) . The primary end point was the guiding principle of clinical research on new drugs in the treatment of KOA ( GPCRND-KOA ) . Measurements were obtained at baseline and after 1 and 6 months ( month 7 ) of study . Result For GPCRND-KOA , there were significant differences among the three groups after treatment at months 1 and 7 . Pairwise comparisons showed that HSM was more effective than the conventional drug . There was no difference in any measures between conventional moxibustion and the conventional drug . Compared with conventional moxibustion , HSM result ed in greater improvement in all outcomes . Conclusions This trial provided some evidence of the superiority of HSM in patients with KOA , suggesting that the observed differences might be due to superiority effects of a heat-sensitive point , although the effect of expectation can not be ruled out . Trial Registration Number The trial was registered at Controlled Clinical Trials : ChiCTR-TRC-09000600 [1514335] Purpose : Acupuncture treatment of patients waiting for arthroplasty surgery . Methods : 29 patients with a total of 42 osteoarthritic knees were r and omized to two groups . Group A was treated while Group B served as a no‐treatment control group . After 9 weeks Group B was treated too . Analgesic consumption , pain and objective measurements were registered . All objective measures were done by investigators who were “ blinded ” as to Group A & B. In the second part of the study 17 patients ( 26 knees ) continued with treatments once a month . Registration of analgesic consumption , pain and objective measurements continued . Total study period 49 weeks . Results : Comparing Group A to B there was a significant reduction in pain , analgesic consumption and in most objective measures . In Group A + B combined there was an 80 % subjective improvement , and a significantly increased knee range movement – an increase mainly in the worst knees . Results were significantly better in those who had not been ill for a long time . In the second part of the study , it was shown that it was possible to maintain the improvements . Conclusions : Acupuncture can ease the discomfort while waiting for an operation and perhaps even serve as an alternative to surgery . Seven patients have responded so well that at present they do not want an operation . ( USD 9000 saved per operation ) [3068365] Within the context of a double blind r and omized controlled parallel trial of 2 nonsteroidal antiinflammatory drugs , we vali date d WOMAC , a new multidimensional , self-administered health status instrument for patients with osteoarthritis of the hip or knee . The pain , stiffness and physical function subscales fulfil conventional criteria for face , content and construct validity , reliability , responsiveness and relative efficiency . WOMAC is a disease-specific purpose built high performance instrument for evaluative research in osteoarthritis clinical trials [26502544] OBJECTIVE To observe the clinical effect of acupuncture plus shock-wave ( SW ) intervention for osteoarthritis ( WA ) , so as to explore its practicability in clinical practice . METHODS A total of 120 cases of knee OA patients were r and omly divided into 4 groups , namely acupuncture ( acupunct ) + LFSW , acupunct + MFSW , acupunct + HFSW and routine acupunct groups , with 30 cases in each group . Xuehai ( SP 10 ) , Liangqiu ( ST 34 ) , Yanglingquan ( GB 34 ) , Xiyan ( ST 35 ) and Ashi-point were punctured with filiform needles which were manipulated with uniform reinforcing-reducing techniques for 15 - 20 min , once every other day for 7 times . In addition , these acupoints were also respectively stimulated with shock waves(10 Hz , 14 Hz and 18 Hz , pressure : 1 - 4 bar ) delivered from a DolorClastEMS therapeutic apparatus for 600 times in 3 acupunct+ SW groups . The patients ' pain response changes of the knee-joint were assessed by using visual analog scale ( VAS ) and the motility was evaluated by using a 0 - 3 grade scale . RESULTS After 7 times of treatment , the patients ' VAS scores and motility scores were significantly decreased in the acupunct+ LFSW , acupunct+ MFSW , acupunct+ HFSW and routine acupunct groups compared with their own basic values before treatment ( P < 0.01 ) , and the therapeutic effect of the acupunct+ MFSW group was significantly superior to those of the other 3 groups in reducing both VAS and motility scores ( P < 0.05 ) . Correspondingly , the Deqi sensation score of the acupunct+ MFSW group was markedly higher than those of the other 3 groups ( P < 0.05 ) . CONCLUSION Shock wave acu-puncture treatment is effective in relieving OA patients ' knee-joint pain and functional activity , and the therapeutic effect of acu- punct + 14 Hz-SW is better , which is closely with Deqi-sensation [24195209] OBJECTIVE To explore a better therapy for knee osteoarthritis . METHODS One hundred cases were r and omly divided into a comprehensive group and an acupuncture group , 50 cases in each one . The comprehensive treatment of fire needles at bones combined with cupping and Tuina on local area of affected knee was applied in the comprehensive group . The Ashi points were mainly selected in the fire needles at bones therapy , once every other day . The cupping and Tuina therapy was adopted once a day . The conventional acupuncture was applied in the acupuncture group , in which Dubi ( ST 35 ) , Neixiyan ( EX-LE 4 ) , Xuehai ( SP 10 ) , Liangqiu ( ST 34 ) and so on were selected , once a day . Ten days of treatment were taken as a treatment course in both two groups , and totally 1 to 2 courses was required . The pain score of joint before and after the treatment was observed and efficacy was assessed in two groups . RESULTS Compared before the treatment , the pain score of joint after the treatment was obviously improved in two groups ( both P<0.05 ) , and the score in the comprehensive group was lower than that in the acupuncture group ( P<0.05 ) . The clinical cured rate was 38.0 % ( 19/50 ) , which was superior to 20.0 % ( 10/50 ) in the acupuncture group . CONCLUSION The comprehensive treatment of fire needles at bones combined with cupping and Tuina , considered as a better therapy for knee osteoarthritis , could improve joint pain , swelling and action function , which is superior to the conventional acupuncture [24377213] OBJECTIVE To compare the difference of the efficacy on knee osteoarthritis ( KOA ) between the combined therapy of acupuncture and moxibustion and western medication , and explore the better therapeutic method for KOA . METHODS One hundred and sixty patients were divided into a combined therapy group and a western medication group , 80 cases in each one according to the visit sequence , with the r and om number table adopted . In the combined therapy group , the main points were selected from the local painful sites , combined with the acupoints based on the syndrome differentiation and distal acupoints on the affected meridians . The lifting , thrusting or rotating technique was used and the reinforcing or reducing manipulation was applied according to the syndrome differentiation . " Duanci " or " Shuci " needling technique was used specially at the extra points and Ashi points . The needling sensation relied on the patients ' tolerance . After acupuncture , the heat-sensitive moxibustion with pure moxa stick was applied over the local painful sites around knee joint and Shenshu ( BL 23 ) to detect the heat-sensitized points . Acupuncture and moxibustion were given once every day . The treatment of 5 days made 1 session . There were 2 days at the interval between two sessions . In the western medication group , glucosamine sulfate capsules were prescribed for oral administration , 2 capsules each time , three times a day . Additionally , the joint cavity injection was combined . On the first day , sodium hyaluronate 25 mg and triamcinolone acetonide acetate 50 mg were injected . Afterwards , on the 8th , 15th , 22nd and 29th days , sodium hyaluronate injection 25 mg was used only . The treatment was for 5 weeks totally in the two groups . The efficacy was analyzed statistically in 5 weeks . The follow-up visit was conducted in 3 months and 6 months after 5 weeks treatment , respectively . The Western Ontario and Mcmaster Universities Osteoarthritis Index ( WOMAC ) and visual analogue scale ( VAS ) were adopted to assess the recovery of joint function . RESULTS The efficacy in 5 weeks of treatment was different significantly between the two groups ( P < 0.05 ) . The efficacy in the western medication group was better than that in the combined therapy group . The difference in the safety assessment was remarkable ( P < 0.01 ) . The result in the combined therapy group was superior remarkably to the western medication group . In 3-month follow-up visit after treatment , the knee joint function was not different obviously between the two groups ( P > 0.05 ) . In 6-month followup visit after treatment , the knee joint function was different obviously between the two groups ( P < 0.01 ) . The result in the combined therapy group was better remarkably than that in the western medication group . CONCLUSION The combined therapy of acupuncture and moxibustion achieves the safe and effective therapeutic effect with less adverse reactions in the treatment of KOA . The immediate effect in the combined therapy group is not so obvious as compared with the western medication , but the long-term efficacy is remarkably superior to western medication [3524727] Twenty-five out- patients with chronic neck pain participated in a prospect i ve , r and omized trial of acupuncture versus placebo transcutaneous nerve stimulation . A single-blind , non-cross-over design incorporated several outcome measures in an attempt to determine any particular facet of pain that responded to acupuncture . No significant difference between the two treatments was found either post-treatment or at follow-up . Whilst the small population studied limits the conclusions that may be drawn , these findings suggest that acupuncture may have no greater effect than that of a powerful placebo [26770523] BACKGROUND To assess the efficacy of Electroacupuncture ( EA ) stimulation with high-intensity compared with low-intensity on knee osteoarthritis ( KOA ) . METHODS Participants with KOA were r and omized to either high-intensity EA group or low-intensity EA group . EA was applied unilaterally on the affected leg with the local points GB34 , ST34 , EX-LE4 , EX-LE5 , ST36 , and SP9 . The visual analogue scale ( VAS ) and the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) were measured before and after participation . Plasma TNFα , IL-1β , IL-6 , and apelin levels were also assessed by enzyme immunoassay ( ELA ) before and after treatment . RESULTS Of 80 participants who consented to study participation , 77 completed the program . The patients showed a significant improvement in their pain , stiffness , and physical function on the VAS and WOMAC , accompanying with a significantly reduction in plasma levels of apelin and TNFα . Furthermore , high-intensity group exhibited statistically significant improvements in stiffness and physical function symptoms compared with low-intensity group . Plasma level of IL-6 was significantly decreased only after high-intensity EA treatment . Furthermore , apelin level was significantly inhibited in high-intensity EA group than in low-intensity EA group . CONCLUSIONS Both high- and low-intensity EA treatments alleviate the clinical symptoms of KOA patients . High-intensity EA is more effective than low-intensity EA . Changes in plasma levels of TNFα , apelin and IL-6 may be involved in the therapeutic effect of EA on KOA [11532841] Recent reports have highlighted the importance of having good evidence on the safety of acupuncture . 1 2 Sound evidence on the risks associated with acupuncture is , however , scarce.3 Our primary aim , therefore , was to describe the type and frequency of adverse events after acupuncture . A secondary aim was to examine mild transient reactions associated with acupuncture , some of which may indicate a positive response to treatment . The study involved a prospect i ve postal audit of treatments undertaken during a four week period in 2000 . All 1848 professional acupuncturists who were members of the British Acupuncture Council and were practising in the United Kingdom were invited to record details of adverse events and mild transient reactions after treatment . St and ardised self report forms were used . Participating practitioners also provided information on themselves , including age , sex , length of training , and years of practice . To have a [11532840] Acupuncture is increasingly popular , but it is not free from risk for the patient.1 Safety is best established with prospect i ve surveys . Our aim was to ascertain the incidence of adverse events related to acupuncture treatment , as currently practised in Britain by doctors and physiotherapists . Volunteer acupuncture practitioners were recruited through journals circulated to members of the British Medical Acupuncture Society and the Acupuncture Association of Chartered Physiotherapists ( approximately 2750 members).2 A prospect i ve survey was undertaken using forms for intensive event monitoring that had been piloted previously.3 Minor adverse events were defined as “ any ill-effect , no matter how small , that is unintended and non-therapeutic , even if not unexpected . ” These events were reported every month , along with the total number of consultations . Minor or serious events that were considered to be “ significant”—“unusual , novel , dangerous , significantly inconvenient , or requiring further information”—were reported on separate forms when they occurred . Anonymous reporting was accepted . A sample size of [18356795] Background There is evidence for the efficacy of acupuncture treatment in knee osteoarthritis , but it remains unclear which acupuncture modes are most effective . We evaluated the effects of trigger point acupuncture on pain and quality of life in knee osteoarthritis patients , compared with acupuncture at st and ard points , and sham acupuncture . Methods Thirty patients ( 27 women , 3 men ; aged 61–82 years ) with non-radiating knee osteoarthritis pain for at least six months and normal neurological examination were r and omised to one of three groups for the study period of 21 weeks . Each group received five acupuncture treatment sessions . The st and ard acupuncture point group ( n=10 ) received treatment at traditional acupuncture points for knee pain ; the trigger point acupuncture group ( n=10 ) received treatment at trigger points ; and the third group ( n=10 ) received sham acupuncture treatment at the trigger points . Outcome measures were pain intensity ( visual analogue scale , VAS ) and WOMAC index ( Western Ontario and McMaster Universities Arthritis Index ) . The groups were compared by the area under the curve method . Results Five patients dropped out of the study because of lack of improvement , and one patient ( in the trigger point acupuncture group ) dropped out because of deterioration of symptoms ; the remaining 24 patients were included in the analysis . After treatment , the trigger point acupuncture group reported less pain intensity on VAS than the st and ard acupuncture or sham treatment group , but both the trigger point acupuncture and st and ard acupuncture groups reported improvement of function of knee . There was a significant reduction in pain intensity between pre-treatment and five weeks after treatment for the trigger point acupuncture ( P<0.01 ) and st and ard acupuncture groups ( P<0.01 ) included in the analysis , but not for the sham treatment group . Group comparison using the area under the curves demonstrated a significant difference only between trigger point acupuncture and sham treatment groups analysed ( P<0.025 for VAS , and P<0.031 for WOMAC ) . Conclusion These results suggest that trigger point acupuncture therapy may be more effective for osteoarthritis of the knee in some elderly patients than st and ard acupuncture therapy [24566612] Objective To compare the immediate effects of electroacupuncture and manual acupuncture on pain , mobility and muscle strength in patients with knee osteoarthritis . Methods Sixty patients with knee osteoarthritis , with a pain intensity of ≥2 on the pain Numerical Rating Scale , were included . The patients were r and omised into two groups : manual acupuncture and electroacupuncture . Pain intensity , degree of dysfunction ( Timed Up and Go ( TUG ) test ) , maximal voluntary isometric contraction and pressure pain threshold were assessed before and after a single session of manual acupuncture or electroacupuncture treatments . Results Both groups showed a significant reduction in pain intensity ( p<0.001 ) and time to run the TUG test after the acupuncture treatment ( p=0.005 for the manual acupuncture group and p=0.002 for the electroacupuncture group ) . There were no differences between the groups regarding pain intensity ( p=0.25 ) , TUG test ( p=0.70 ) , maximum voluntary isometric contraction ( p=0.43 ) or pressure pain threshold ( p=0.27 ) . Conclusions This study found no difference between the immediate effects of a single session of manual acupuncture and electroacupuncture on pain , muscle strength and mobility in patients with knee osteoarthritis . Trial Registration Number RBR-9TCN2X [16259309] Objective To explore the type and frequency of short term reactions associated with a single acupuncture treatment . Methods As part of recruitment to a large-scale prospect i ve survey of the safety of acupuncture , 9408 consecutive patients each completed one survey form soon after receiving treatment with acupuncture , and returned it directly to the research centre . On this form , patients were asked to report on a range of possible short term reactions relating to their most recent acupuncture treatment using a checklist of options . Results At least one short term reaction to acupuncture during or immediately after treatment was reported by 94.6 % ( CI 94.2 to 95.1 ) of patients , an average of 1.8 reactions per patient . The most common experiences reported were feeling ‘ relaxed ’ ( 79.1 % ) followed by feeling ‘ energised ’ ( 32.7 % ) . A total of 24.4 % of patients reported ‘ tiredness ’ or ‘ drowsiness ’ , with obvious implication s for safety if the patient intended to drive after treatment . ‘ Negative ’ reactions , such as pain and bruising at the site of needling , were reported by 29.7 % of patients who were more likely to be female patients ( OR 1.58 ) , patients under the age of 40 ( OR 1.62 ) , patients who had consulted their GP or hospital specialist beforeh and ( OR 1.30 ) , patients consulting their acupuncturist for the first time ( OR 1.24 ) , and patients treated by an acupuncturist with less than two years ’ experience since qualification ( OR 1.24 ) . Only 13 patients were unwilling to have acupuncture again as a result of these short term reactions . Conclusion In this large cross-sectional study , extensive patient reports showed that ‘ positive ’ reactions to acupuncture treatment were very common . Tiredness , drowsiness and a range of ‘ negative ’ reactions were also frequently reported . Almost all patients were willing to experience these reactions again [24377216] OBJECTIVE To verify the clinical efficacy of shu-stream point acupuncture combined with fire needle therapy in the treatment of h and osteoarthritis . METHODS Eighty cases were r and omized into an acupuncture group ( shu-stream point acupuncture combined with fire needle therapy ) and a medication group(votalin emulgel ) . For the 42 cases in the acupuncture group , acupuncture at shu-stream points on the three yang meridians of the h and including Sanjian ( LI 3 ) , Zhongzhu ( TE 3 ) , Houxi ( SI 3 ) and fire needle at Ashi points were applied , the treatments were given once every other day , 15 times as a treatment course . For the 38 cases in the medication group , votalin emulgel was prescribed for local embrocation , twice a day , 30 days as a treatment course . The visual analogue scale ( VAS ) of arthralgia , joint function score and the duration of morning stiffness , joint tenderness , swelling were observed before and after treatment in both groups . RESULTS After two courses of clinical treatment , the VAS score of arthralgia , joint function score and the duration of morning stiffness , joint tenderness , swelling were statistically significant differences as compared with before treatment ( all P < 0.01 ) , the efficacy in the acupuncture group was superior to that in the medication group ( all P < 0.01 ) . The cured-markedly effective rate and total effective rate were 61.9 % ( 26/42 ) and 95.2 % ( 40/42 ) in the acupuncture group , and 36.8 % ( 14/38 ) and 76.3 % ( 29/38 ) in the medication group respectively , with statistically significant differences between the two groups ( both P < 0.05 ) . CONCLUSION Shu-stream point acupuncture combined with fire needle therapy achieves a significant efficacy in the treatment of h and osteoarthritis [21751905] BACKGROUND In prospect i ve experimental studies in patients with asthma , it is difficult to determine whether responses to placebo differ from the natural course of physiological changes that occur without any intervention . We compared the effects of a bronchodilator , two placebo interventions , and no intervention on outcomes in patients with asthma . METHODS In a double-blind , crossover pilot study , we r and omly assigned 46 patients with asthma to active treatment with an albuterol inhaler , a placebo inhaler , sham acupuncture , or no intervention . Using a block design , we administered one each of these four interventions in r and om order during four sequential visits ( 3 to 7 days apart ) ; this procedure was repeated in two more blocks of visits ( for a total of 12 visits by each patient ) . At each visit , spirometry was performed repeatedly over a period of 2 hours . Maximum forced expiratory volume in 1 second ( FEV(1 ) ) was measured , and patients ' self-reported improvement ratings were recorded . RESULTS Among the 39 patients who completed the study , albuterol result ed in a 20 % increase in FEV(1 ) , as compared with approximately 7 % with each of the other three interventions ( P<0.001 ) . However , patients ' reports of improvement after the intervention did not differ significantly for the albuterol inhaler ( 50 % improvement ) , placebo inhaler ( 45 % ) , or sham acupuncture ( 46 % ) , but the subjective improvement with all three of these interventions was significantly greater than that with the no-intervention control ( 21 % ) ( P<0.001 ) . CONCLUSIONS Although albuterol , but not the two placebo interventions , improved FEV(1 ) in these patients with asthma , albuterol provided no incremental benefit with respect to the self-reported outcomes . Placebo effects can be clinical ly meaningful and can rival the effects of active medication in patients with asthma . However , from a clinical -management and research - design perspective , patient self-reports can be unreliable . An assessment of untreated responses in asthma may be essential in evaluating patient-reported outcomes . ( Funded by the National Center for Complementary and Alternative Medicine . ) [17075849] OBJECTIVE To investigate the effectiveness of acupuncture in addition to routine care , compared with routine care alone , in the treatment of patients with chronic pain due to osteoarthritis ( OA ) of the knee or hip . METHODS In a r and omized , controlled trial , patients with chronic pain due to OA of the knee or hip were r and omly allocated to undergo up to 15 sessions of acupuncture in a 3-month period or to a control group receiving no acupuncture . Another group of patients who did not consent to r and omization underwent acupuncture treatment . All patients were allowed to receive usual medical care in addition to the study treatment . Clinical OA severity ( Western Ontario and McMaster Universities Osteoarthritis Index [ WOMAC ] ) and health-related quality of life ( Short Form 36 ) were assessed at baseline and after 3 months and 6 months . RESULTS Of 3,633 patients ( mean + /- SD age 61.8 + /- 10.8 years ; 61 % female ) , 357 were r and omized to the acupuncture group and 355 to the control group , and 2,921 were included in the nonr and omized acupuncture group . At 3 months , the WOMAC had improved by a mean + /- SEM of 17.6 + /- 1.0 in the acupuncture group and 0.9 + /- 1.0 in the control group ( 3-month scores 30.5 + /- 1.0 and 47.3 + /- 1.0 , respectively [ difference in improvement 16.7 + /- 1.4 ; P < 0.001 ] ) . Similarly , quality of life improvements were more pronounced in the acupuncture group versus the control group ( P < 0.001 ) . Treatment success was maintained through 6 months . The changes in outcome in nonr and omized patients were comparable with those in r and omized patients who received acupuncture . CONCLUSION These results indicate that acupuncture plus routine care is associated with marked clinical improvement in patients with chronic OA-associated pain of the knee or hip [9717924] BACKGROUND A problem acupuncture research has to face is the concept of a control group . If , in control groups , non-acupoint needling is done , physiological acupuncture effects are implied . Therefore the effects shown in this group are often close to those shown in the acupuncture group . In other trials , control groups have received obviously different treatments , such as transcutaneous electrical nervous stimulation or TENS-laser treatment ; it is not clear if the effects of acupuncture are due only to the psychological effects of the treatment . METHODS We developed a placebo acupuncture needle , with which it should be possible to simulate an acupuncture procedure without penetrating the skin . In a cross-over experiment with 60 volunteers we tested whether needling with the placebo needle feels any different from real acupuncture . FINDINGS Of 60 volunteers , 54 felt a penetration with acupuncture ( mean visual analogue scale [ VAS ] 13.4 ; SD 10.58 ) and 47 felt it with placebo ( VAS 8.86 ; SD 10.55 ) , 34 felt a dull pain sensation ( DEQI ) with acupuncture and 13 with placebo . None of the volunteers suspected that the needle may not have penetrated the skin . INTERPRETATION The placebo needle is sufficiently credible to be used in investigations of the effects of acupuncture [11452568] OBJECTIVE To determine whether demographic , medical history , or arthritis assessment data may influence outcome and rate of decay for patients with osteoarthritis treated with acupuncture . DESIGN Seventy-three persons with symptomatic osteoarthritis of the knee were recruited for this r and omized controlled trial . Both treatment and crossover control groups received acupuncture treatments twice weekly for 8 weeks . Patients self-scored on the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) and the Lequesne Algofunctional Index at baseline and 4 , 8 , and 12 weeks . Sample size for this outcome analysis was 60 patients at 4 weeks , 58 at 8 weeks , and 52 at 12 weeks . RESULTS Patients ' scores on both indexes improved at 4 , 8 , and 12 weeks . Scores were stable regardless of the baseline severity of the osteoarthritis . Despite some decay in outcomes at week 12 , measures were significantly improved over baseline . With WOMAC scores partitioned into equal quartiles , a strong effect on outcome was apparent at 12 weeks ( 4 weeks after treatment ) related to initial WOMAC scores . The group with the least disability and pain rebounded to original levels to a greater degree than did those who initially were more disabled . The more disabled groups retained the benefits of acupuncture treatment through the 12-week period . CONCLUSION Acupuncture for patients with osteoarthritis of the knee may best be used early in the treatment plan , with a method ical decrease in frequency in treatment once the acute treatment period is completed to avoid a rebound effect . Demographic and medical history data were not mediating variables [23965480] Background Knee osteoarthritis is a chronic disease associated with significant morbidity and economic cost . The efficacy of acupuncture in addition to traditional physical therapy has received little study . Objective The objective of this study was to compare the efficacy and safety of integrating a st and ardized true acupuncture protocol versus nonpenetrating acupuncture into exercise-based physical therapy ( EPT ) . Methods This was a r and omized , double-blind , controlled trial at 3 physical therapy centers in Philadelphia , PA . We studied 214 patients ( 66 % African Americans ) with at least 6 months of chronic knee pain and x-ray – confirmed Kellgren scores of 2 or 3 . Patients received 12 sessions of acupuncture directly following EPT over 6 to 12 weeks . Acupuncture was performed at the same 9 points dictated by the traditional Chinese “ Bi ” syndrome approach to knee pain , using either st and ard needles or Streitberger non – skin-puncturing needles . The primary outcome was the proportion of patients with at least a 36 % improvement in Western Ontario and McMaster Universities Osteoarthritis Index score at 12 weeks . Results Both treatment groups showed improvement from combined therapy with no difference between true ( 31.6 % ) and nonpenetrating acupuncture ( 30.3 % ) in Western Ontario and McMaster Universities Osteoarthritis Index response rate ( P = 0.5 ) or report of minor adverse events . A multivariable logistic regression prediction model identified an association between a positive expectation of relief from acupuncture and reported improvement . No differences were noted by race , sex , or age . Conclusions Puncturing acupuncture needles did not perform any better than nonpuncturing needles integrated with EPT . Whether EPT , acupuncture , or other factors accounted for any improvement noted in both groups could not be determined in this study . Expectation for relief was a predictor of reported benefit [23380214] OBJECTIVE The purpose of this preliminary study was to examine whether collateral meridian ( CM ) therapy was feasible in treating knee osteoarthritis ( OA ) pain . METHODS Twenty-eight patients with knee OA and knee pain were r and omly allocated to 2 groups . The CM group patients received CM therapy , whereas the control patients received placebo treatment for knee pain relief . Patients in the CM group received 2 CM treatments weekly for 3 weeks . The outcome measures were pain intensity on a visual analog scale , and knee function was determined using the Western Ontario and McMaster Universities Osteoarthritis Index . RESULTS In the CM group , the posttreatment visual analog scale and Western Ontario and McMaster Universities Osteoarthritis Index scores were lower than those of the control group ; a significant reduction in pain intensity ( P = .02 , P = .01 , respectively ) and improvement in knee function ( P = .04 , P = .03 , respectively ) were shown in the CM group at the second and third week . CONCLUSION Collateral meridian therapy may be feasible and effective for knee OA pain relief and knee function recovery . Therefore , additional r and omized control trials are warranted [27348903] OBJECTIVE To evaluate the clinical efficacy of YANG 's pricking-cupping therapy for knee osteoar thritis ( KOA ) . Methods This was a multi-center r and omized parallel controlled trial . One hundred and seventy one patients with KOA were r and omly allocated to a pricking-cupping group ( 89 cases ) and a conventional acu puncture group ( 82 cases ) . Neixiyan ( EX-LE 4 ) , Dubi ( ST 35 ) and ashi points were selected in the two groups . Patients in the pricking-cupping group were treated with YANG 's pricking-cupping therapy ; the seven-star needles were used to perform pricking at acupoints , then cupping was used until slight bleeding was observed . Patients in the conventional acupuncture group were treated with semi-st and ardized filiform needle therapy . The treatment was given for 4 weeks ( from a minimum of 5 times to a maximum of 10 times ) . The follow-up visit was 4 weeks . The Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) and the visual analogue scale ( VAS ) were adopted for the efficacy assessment s. RESULTS The pain score , stiffness score , physical function score and total score of WOMAC were all reduced after 4-week treatment and during follow-up visit in the two groups ( all P<0 . 0001 ) . Except that the difference of stiffness score between the two groups was not significant after 4-week treatment ( P>0 . 05 ) , each score and total score of WOMAC in the pricking-cupping group were lower than those in the conventional acupuncture group after 4-week treatment and during follow-up visit ( P<0 . 0001 , P<0 . 01 ) . After 2-week treatment , 4-week treatment and during follow-up visit , the VAS was all reduced compared with that before treatment ( all P<0 . 0001 ) ; with the increase of the treatment , the reducing trend of VAS was more significant ( P<0 . 0001 ) . The scores of VAS in the pricking-cupping group were lower than those in the conventional acupuncture group after 4-week treatment and during follow-up visit ( P < 0 . 01 , P < 0 . 0001 ) . CONCLUSION The YANG 's pricking-cupping and conventional acupuncture therapy can both significantly improve knee joint pain and function in patients with KOA , which are relatively safe . The pricking cupping therapy is superior to conventional acupuncture with the identical selection of acupoints [15208174] BACKGROUND In clinical trials , at the group level , results are usually reported as mean and st and ard deviation of the change in score , which is not meaningful for most readers . OBJECTIVE To determine the minimal clinical ly important improvement ( MCII ) of pain , patient 's global assessment of disease activity , and functional impairment in patients with knee and hip osteoarthritis ( OA ) . METHODS A prospect i ve multicentre 4 week cohort study involving 1362 out patients with knee or hip OA was carried out . Data on assessment of pain and patient 's global assessment , measured on visual analogue scales , and functional impairment , measured on the Western Ontario McMaster Universities Osteoarthritis Index ( WOMAC ) function subscale , were collected at baseline and final visits . Patients assessed their response to treatment on a five point Likert scale at the final visit . An anchoring method based on the patient 's opinion was used . The MCII was estimated in a subgroup of 814 patients ( 603 with knee OA , 211 with hip OA ) . RESULTS For knee and hip OA , MCII for absolute ( and relative ) changes were , respectively , ( a ) -19.9 mm ( -40.8 % ) and -15.3 mm ( -32.0 % ) for pain ; ( b ) -18.3 mm ( -39.0 % ) and -15.2 mm ( -32.6 % ) for patient 's global assessment ; ( c ) -9.1 ( -26.0 % ) and -7.9 ( -21.1 % ) for WOMAC function subscale score . The MCII is affected by the initial degree of severity of the symptoms but not by age , disease duration , or sex . CONCLUSION Using criteria such as MCII in clinical trials would provide meaningful information which would help in interpreting the results by expressing them as a proportion of improved patients [11824949] OBJECTIVE To estimate minimal clinical ly important differences ( MCID ) of effects measured by the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) in patients with osteoarthritis ( OA ) of the lower extremities undergoing a comprehensive inpatient rehabilitation intervention . METHODS A prospect i ve cohort study assessed patients ' health by the WOMAC at baseline ( entry into the clinic ) and at the 3 month followup , and by a transition question naire asking about the change of " health in general related to the OA joint " during that time period . The WOMAC section score differences between the " equal " group and the " slightly better " and " slightly worse " groups result ed in the MCID for improvement and for worsening . RESULTS In total 192 patients were followed up . The MCID for improvement ranged from 0.80 to 1.01 points on the continuous WOMAC numerical rating scale from 0 to 10 , reflecting changes of 17 to 22 % of baseline scores . The MCID for worsening conditions ranged from 0.29 ( 6 % ) to 1.03 points ( 22 % ) . In the transition reply subjectively unchanged patients reported a " pessimistic bias " of 0.35 to 0.51 points , except for the stiffness section . Both MCID and pessimistic bias showed regression to the mean and baseline dependency . CONCLUSION The assessment of MCID using the transition method is a heuristic and valid strategy to detect particular rehabilitation effects in patients with OA of the lower extremities with the use of the WOMAC , and it is worth implementing . The size of the MCID and of the systematic bias is comparable to that assessed by other methods and in other therapeutic setting [17699546] Objective To investigate the benefit of adding acupuncture to a course of advice and exercise delivered by physiotherapists for pain reduction in patients with osteoarthritis of the knee . Design Multicentre , r and omised controlled trial . Setting 37 physiotherapy centres accepting primary care patients referred from general practitioners in the Midl and s , United Kingdom . Participants 352 adults aged 50 or more with a clinical diagnosis of knee osteoarthritis . Interventions Advice and exercise ( n=116 ) , advice and exercise plus true acupuncture ( n=117 ) , and advice and exercise plus non-penetrating acupuncture ( n=119 ) . Main outcome measures The primary outcome was change in scores on the Western Ontario and McMaster Universities osteoarthritis index pain subscale at six months . Secondary outcomes included function , pain intensity , and unpleasantness of pain at two weeks , six weeks , six months , and 12 months . Results Follow-up rate at six months was 94 % . The mean ( SD ) baseline pain score was 9.2 ( 3.8 ) . At six months mean reductions in pain were 2.28 ( 3.8 ) for advice and exercise , 2.32 ( 3.6 ) for advice and exercise plus true acupuncture , and 2.53 ( 4.2 ) for advice and exercise plus non-penetrating acupuncture . Mean differences in change scores between advice and exercise alone and each acupuncture group were 0.08 ( 95 % confidence interval −1.0 to 0.9 ) for advice and exercise plus true acupuncture and 0.25 ( −0.8 to 1.3 ) for advice and exercise plus non-penetrating acupuncture . Similar non-significant differences were seen at other follow-up points . Compared with advice and exercise alone there were small , statistically significant improvements in pain intensity and unpleasantness at two and six weeks for true acupuncture and at all follow-up points for non-penetrating acupuncture . Conclusion The addition of acupuncture to a course of advice and exercise for osteoarthritis of the knee delivered by physiotherapists provided no additional improvement in pain scores . Small benefits in pain intensity and unpleasantness were observed in both acupuncture groups , making it unlikely that this was due to acupuncture needling effects . Trial registration Current Controlled Trials IS RCT N88597683 [25029834] OBJECTIVE To study the synergistic effects of electroacupuncture on the treatment of knee osteoarthritis after arthroscopic debridement . METHODS From May 2008 to July 2010 , 78 patients with knee osteoarthritis were r and omly divided into two groups . There were 42 patients in the experimental group , including 16 males and 26 females , ranging in age from 41 to 63 years , with an average of ( 53.62 + /- 6.53 ) years ; the disease course ranged from 8 to 24 months , with an average of ( 10.35 + /- 6.42 ) months . The patients were treated with arthroscopic debridement combined with electroacupuncture after operation . There were 36 patients in the control group , including 14 males and 22 females , ranging in age from 40 to 62 years , with an average of ( 54.34 + /- 7.67 ) years ; the disease course ranged from 6 to 25 months , with an average of ( 11.94 + /- 5.13 ) months . Those patients were treated only with arthroscopic debridment . All the patients performed isometric quadriceps femoris contraction exercise and knee flexion and extension activities after operation . The visual analog scale(VAS ) score and Lysholm knee score were used to evaluate the therapeutic effects . RESULTS All the patients were followed up , and the duration ranged from 12 to 30 months , with an average of 15.6 months . At the final follow-up , VAS score was significantly decreased , and the Lysholm score , except for the item dem and ing for support , significantly increased , compared with those before surgery respectively in both groups . There was significant difference in VAS score between two groups after treatment . As to Lysholm score , there were significant differences in limp , pain , swelling , stair activity and squat , but there were no significant differences in items of interlocking and instability between two groups after treatment . CONCLUSION Electroacupuncture can effectively improve the clinical symptoms and knee joint 's motor function of knee joints in patients with knee osteoarthritis , as well as the synergistic effects on the treatment of knee osteoarthritis after arthroscopic debridement , leading to a much better long-term therapeutic effect with respect of improving the function of knee joint . This therapy , combined with traditional Chinese medicine and Western Medicine , is worth of clinical application in the treatment of knee osteoarthritis [11444887] OBJECTIVES The effectiveness of acupuncture treatment in patients with osteoarthritis of the hip was tested . DESIGN This is a prospect i ve , r and omized , controlled , patient- and investigator-blinded clinical trial . PATIENTS AND SETTING The study was performed at a university department for physical medicine and rehabilitation . Sixty-seven patients were separated into two treatment groups . INTERVENTIONS Group 1 ( treatment ) had traditional needle placement and manipulation , whereas in group 2 ( control ) needles were placed away from classic positions and not manipulated . In both groups needles were placed within the L2 to L5 dermatomes . Outcome parameters were : pain ( VAS ) , functional impairment ( hip score ) , activity in daily life ( ADL ) and overall satisfaction before treatment , and 2 weeks and 2 months after treatment . RESULTS For all parameters there was a significant improvement versus baseline in both groups 2 weeks and 2 months following treatment , but no significant difference between the two treatment groups . CONCLUSIONS We conclude from these results that needle placement in the area of the affected hip is associated with improvement in the symptoms of osteoarthritis . It appears to be less important to follow the rules of traditional acupuncture techniques [7053030] Thirty patients with cervical spine pain syndromes persisting a mean of 8 years were assigned r and omly into equal treatment and control groups . After 12 weeks , 12 of 15 ( 80 % ) of the treated group felt improved , some dramatically , with a mean 40 % reduction of pain score , 54 % reduction of pain pills , 68 % reduction of pain hours per day and 32 % less limitation of activity . Two of 15 ( 13 % ) of the control group reported slight improvement after 12.8 weeks . The control group had a mean 2 % worsening of the pain score , 10 % reduction in pain pills , no lessening of pain hours and 12 % less limitation of activity [24843960] OBJECTIVE To observe the difference in the therapeutic effects on knee osteoarthritis ( KOA ) among auricular electroacupuncture therapy plus isolated moxibustion with Lingxian herbal paste ( combined therapy ) , electroacupuncture ( EA ) and TDP irradiation . METHODS Eighty-nine cases were r and omized into three groups . In the combined therapy group ( 30 cases ) , the auricular electroacupuncture therapy was adopted together with the isolated moxibustion with Lingxian herbal paste . The auricular points were xi ( AH4 ) , pizhixia ( AT4 ) , shenmen ( TF4 ) , etc . The Lingxian herbal paste was applied at Yanglingquan ( GB 34 ) , Dubi ( ST 35 ) , Zusanli ( ST 36 ) , Neixiyan ( EX-LE 4 ) , Heding ( EX-LE 2 ) and Ashi points . In EA group ( 29 cases ) , EA was applied at the acupoints that were same as those in the isolated moxibustion with Lingxian herbal paste . In TDP group ( 30 cases ) , TDP irradiation was given at the affected knee . The treatment was given once every day , 10 treatments made one session and there was 1 week at the interval among sessions . Totally , 3 sessions of treatment were required . KOA clinical symptom and physical sign score and the single item pain symptom score of Lequesne index were observed before treatment and 1 week after treatment in the patients of each group separately . The efficacies were compared among the three groups . RESULTS One week after treatment , the total score of symptoms and physical signs of the patients in each group was reduced significantly as compared with that before treatment ( all P < 0.05 ) . The improvements in the symptoms and physical signs in the combined therapy group were better than those in the other two groups ( 1.50 + /- 1.57 vs 2.52 + /- 1.82 , 2.63 + /- 1.97 , both P < 0.05 ) . The improvement in pain in the combined therapy group was also better than that in the other two groups ( 2.37 + /- 0.81 vs 2.83 + /- 0.92 , P < 0.05 ; 2.37 + /- 0.81 vs 3.03 + /- 0.77 , P < 0.01 ) . The curative rate in the combined therapy group was 40.0 % ( 12/30 ) , which was higher than 17.2 % ( 5/29 ) in EA group and 20.0 % ( 6/30 ) in TDP group separately ( both P < 0.01 ) . The overall efficacy in the combined therapy group was superior to the other two groups ( P < 0.05 ) . CONCLUSION The auricular electroacupuncture therapy plus isolated moxibustion with Lingxian herbal paste is advantageous at the total score of the symptoms and physical signs and the overall efficacy in the patients of KOA as compared with EA at the local acupoints and local TDP irradiation [15100594] Objectives : The aim of the study was to evaluate the therapeutic effect of electro-acupuncture ( EA ) and hydrotherapy , both in combination with patient education or with patient education alone , in the treatment of osteoarthritis in the hip . Methods : Forty-five patients , aged 42–86 years , with radiographic changes consistent with osteoarthritis in the hip , pain related to motion , pain on load , and ache were chosen . They were r and omly allocated to EA , hydrotherapy , both in combination with patient education , or patient education alone . Outcome measures were the disability rating index ( DRI ) , global self-rating index ( GSI ) , and visual analogue scale ( VAS ) . Assessment s were done before the intervention and immediately after the last treatment and 1 , 3 , and 6 months after the last treatment . Results : Pain related to motion and pain on load was reduced up to 3 months after last the treatment in the hydrotherapy group and up to 6 months in the EA group . Ache during the day was significantly improved in both the EA and hydrotherapy group up to 3 months after the last treatment . Ache during the night was reduced in the hydrotherapy group up to 3 months after the last treatment and in the EA group up to 6 months after . Disability in functional activities was improved in EA and hydrotherapy groups up to 6 months after the last treatment . Quality of life was also improved in EA and hydrotherapy groups up to 3 months after the last treatment . There were no changes in the education group alone . Discussion : In conclusion , EA and hydrotherapy , both in combination with patient education , induce long-lasting effects , shown by reduced pain and ache and by increased functional activity and quality of life , as demonstrated by differences in the pre- and post-treatment assessment

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### Context: [24346625] Objective : Considering the chronicity of osteoarthritis-associated pain , we aim ed to evaluate long-term outcome differences between patients who received immediate or delayed acupuncture in addition to usual care , and to identify predictors for further acupuncture usage and a better long-term outcome . Material s and Methods : The Acupuncture in Routine Care study was an open-label r and omized pragmatic trial . As adjunct to usual care patients ( > 40 y , clinical and radiologic diagnosis of primary osteoarthritis of the knee or hip , pain duration > 6 mo ) received either immediate acupuncture in the first 3 months or delayed acupuncture in the subsequent 3 months . After 36 months 613 of 632 patients were available and asked to complete follow-up question naires . Primary outcome was the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) . Results : A total of 500 ( 82 % ) of the contacted patients completed question naires . After 36 months the WOMAC Index did not differ significantly between groups ( immediate acupuncture 36.53±26.19 vs. delayed acupuncture 38.24±25.54 ; P=0.420 ) . Further acupuncture treatment during the follow-up period was reported by 202 patients and predicted by previous successful acupuncture treatment at baseline ( odds ratio=2.5 ; 95 % confidence interval , 1.6 - 3.9 ) . Less osteoarthritis symptoms ( WOMAC Index ) after 36 months were predicted by being an acupuncture responder at 6 months ( P<0.001 ) , having higher school education ( P=0.005 ) , not wanting to use medications ( P=0.016 ) , and using additional therapies ( P⩽0.001 to P=0.025 ) . Discussion : No long-term outcome differences were found between patients who received immediate versus those who received delayed acupuncture treatment . Education level and additional therapies were identified as predictors for a better long-term outcome [22169359] Summary This multifactorial mixed‐ methods r and omized controlled trial quantified the specific and nonspecific factors of acupuncture , and found that the practitioner , not the treatment , has the strongest effect on outcome . Abstract The nonspecific effects of acupuncture are well documented ; we wished to quantify these factors in osteoarthritic ( OA ) pain , examining needling , the consultation , and the practitioner . In a prospect i ve r and omised , single‐blind , placebo‐controlled , multifactorial , mixed‐ methods trial , 221 patients with OA awaiting joint replacement surgery were recruited . Interventions were acupuncture , Streitberger placebo acupuncture , and mock electrical stimulation , each with empathic or nonempathic consultations . Interventions involved eight 30‐minute treatments over 4 weeks . The primary outcome was pain ( VAS ) at 1 week posttreatment . Face‐to‐face qualitative interviews were conducted ( purposive sample , 27 participants ) . Improvements occurred from baseline for all interventions with no significant differences between real and placebo acupuncture ( mean difference −2.7 mm , 95 % confidence intervals −9.0 to 3.6 ; P = .40 ) or mock stimulation ( −3.9 , −10.4 to 2.7 ; P = .25 ) . Empathic consultations did not affect pain ( 3.0 mm , −2.2 to 8.2 ; P = .26 ) but practitioner 3 achieved greater analgesia than practitioner 2 ( 10.9 , 3.9 to 18.0 ; P = .002 ) . Qualitative analysis indicated that patients ’ beliefs about treatment veracity and confidence in outcomes were reciprocally linked . The supportive nature of the trial attenuated differences between the different consultation styles . Improvements occurred from baseline , but acupuncture has no specific efficacy over either placebo . The individual practitioner and the patient ’s belief had a significant effect on outcome . The 2 placebos were equally as effective and credible as acupuncture . Needle and nonneedle placebos are equivalent . An unknown characteristic of the treating practitioner predicts outcome , as does the patient ’s belief ( independently ) . Beliefs about treatment veracity shape how patients self‐report outcome , complicating and confounding study interpretation [4095686] Introduction Our objective was to compare the effectiveness and safety of traditional Chinese moxibustion to that of sham moxibustion in patients with chronic knee osteoarthritis ( KOA ) pain . Methods We conducted a r and omized placebo-controlled trial involving 110 patients with KOA who met the inclusion criteria . These patients r and omly received either active moxibustion ( n = 55 ) or sham moxibustion control ( n = 55 ) at acupoints Dubi ( ST 35 ) , extra-point Neixiyan ( EX-LE 4 ) , and an Ashi ( tender ) point three times a week for 6 weeks . Effects were evaluated with Western Ontario and McMaster Universities ’ Osteoarthritis Index ( WOMAC VA 3.1 ) criteria at the end of the course of treatment and 3 , 12 , and 24 weeks after the initial treatment . Results The WOMAC pain scores showed greater improvement in the active treatment group than in control at weeks 3 ( P = 0.012 ) , 6 ( P < 0.001 ) , 12 ( P = 0.002 ) , and 24 ( P = 0.002 ) as did WOMAC physical function scores of the active treatment group at week 3 ( P = 0.002 ) , 6 ( P = 0.015 ) , and 12 ( P < 0.001 ) but not 24 ( P = 0.058 ) . Patients and practitioners were blinded successfully , and no significant adverse effects were found during the trial . Conclusions A 6-week course of moxibustion seems to relieve pain effectively and improve function in patients with KOA for up to 18 weeks after the end of treatment . Moxibustion treatment appears to be safe , and the usefulness of the novel moxa device was vali date d . Trial registration Current controlled trial : IS RCT N68475405 . Registered 4 April 2014 [18591906] Objectives To compare the effect of acupuncture ( manual and electroacupuncture ) with that of a non-penetrating sham ( ‘ placebo ’ needle ) in patients with osteoarthritic knee pain and disability who are blind to the treatment allocation . Methods Acupuncture naive patients with symptomatic and radiological evidence of osteoarthritis of the knee were r and omly allocated to a course of either acupuncture or non-penetrating sham acupuncture using a sheathed ‘ placebo ’ needle system . Acupuncture points for pain and stiffness were selected according to acupuncture theory for treating Bi syndrome . Both manual and electrical stimulation were used . Response was assessed using the WOMAC index for osteoarthritis of the knee , self reported pain scale , the EuroQol score and plasma β-endorphin . The effectiveness of blinding was assessed . Results There were 34 patients in each group . The primary end point was the change in WOMAC pain score after the course of treatment . Comparison between the two treatment groups found a significantly greater improvement with acupuncture ( mean difference 60 , 95 % CI 5 to 116 , P=0.035 ) than with sham . Within the acupuncture group there was a significant improvement in pain ( baseline 294 , mean change 95 , 95 % CI 60 to 130 , P<0.001 ) which was not seen by those who had sham acupuncture ( baseline 261 , mean change 35 , 95 % CI-10 to 80 , P=0.12 ) . Similar effects within group , but not between groups , were seen with the secondary end points of WOMAC stiffness , WOMAC function , and self reported pain . One month after treatment the between group pain difference had been lost ( mean difference 46 ; 95 % CI −9 to 100 , P=0.10 ) although the acupuncture group was still benefiting compared to baseline ( mean difference 59 ; 95 % CI 16 to 102 , P=0.009 ) . The EuroQol score , a generic measure of health related quality of life , was not altered by the treatments . A minority of patients correctly guessed their treatment group ( 41 % in the acupuncture group and 44 % in the control group ) . Plasma β-endorphin levels were not affected by either treatment . Conclusions Acupuncture gives symptomatic improvement for patients with osteoarthritis of the knee , and is significantly superior to non-penetrating sham acupuncture . The study did not confirm earlier reports of release of plasma β-endorphin during acupuncture [15077933] Background Using an open r and omised controlled study , we examined the effectiveness of manual and electroacupuncture on symptom relief for patients with osteoarthritis of the knee . Methods Patients with symptomatic osteoarthritis of the knee were r and omised to one of three treatment groups . Group A had acupuncture alone , group B had acupuncture but continued on their symptomatic medication , and group C used their symptomatic medication for the first five weeks and then had a course of acupuncture added . Patients receiving acupuncture were treated twice weekly over five weeks . Needles were inserted ( with manual and electrical stimulation ) in acupuncture points for pain and stiffness , selected according to traditional acupuncture theory for treating Bi syndrome . Patients were assessed by a blinded observer before treatment , after five weeks ’ treatment and at one month follow up , using a visual analogue pain scale ( VAS ) and the Western Ontario McMaster ( WOMAC ) question naire for osteoarthritis of the knee . Results The 30 patients in our study were well matched for age , body mass index , disease duration , baseline VAS pain score and baseline WOMAC scores . Repeated measure analyses gave a highly significant improvement in pain ( VAS ) after the courses of acupuncture in groups A ( P=0.012 ) and B ( P=0.001 ) ; there was no change in group C until after the course of acupuncture , when the improvement was significant ( P=0.001 ) . Similarly significant changes were seen with the WOMAC pain and stiffness scores . These benefits were maintained during the one month after the course of acupuncture . Patients ’ rating of global assessment was higher than that of the acupuncturist . Conclusion We conclude that manual and electroacupuncture causes a significant improvement in the symptoms of osteoarthritis of the knee , either on its own or as an adjunct therapy , with no loss of benefit after one month [16046146] Clinical and experimental data indicate that most acupuncture clinical results are mediated by the central nervous system , but the specific effects of acupuncture on the human brain remain unclear . Even less is known about its effects on the cerebellum . This fMRI study demonstrated that manual acupuncture at ST 36 ( Stomach 36 , Zusanli ) , a main acupoint on the leg , modulated neural activity at multiple levels of the cerebro-cerebellar and limbic systems . The pattern of hemodynamic response depended on the psychophysical response to needle manipulation . Acupuncture stimulation typically elicited a composite of sensations termed deqi that is related to clinical efficacy according to traditional Chinese medicine . The limbic and paralimbic structures of cortical and subcortical regions in the telencephalon , diencephalon , brainstem and cerebellum demonstrated a concerted attenuation of signal intensity when the subjects experienced deqi . When deqi was mixed with sharp pain , the hemodynamic response was mixed , showing a predominance of signal increases instead . Tactile stimulation as control also elicited a predominance of signal increase in a subset of these regions . The study provides preliminary evidence for an integrated response of the human cerebro-cerebellar and limbic systems to acupuncture stimulation at ST 36 that correlates with the psychophysical response [6346029] A prospect i ve , controlled clinical trial was undertaken to assess the relative efficacies of physiotherapy and electroacupuncture in the treatment of cervical spondylosis . The results suggested that , while both methods were effective , electroacupuncture produced an earlier symptomatic improvement with increased neck movement , especially in patients with mild degenerative changes of the cervical spine [24184053] BACKGROUND Because of morbidity associated with painful knee osteoarthritis ( OA ) and commonly prescribed analgesics , patients often pursue complementary and alternative modalities ( eg , acupuncture ) . Clinical trials have demonstrated modest therapeutic efficacy of traditional Chinese acupuncture for knee OA pain , and patients with advanced disease have largely been excluded . We have previously demonstrated preliminary short-term tolerability and efficacy of periosteal stimulation therapy ( PST ) ( ie , electrical stimulation of the periosteum facilitated by acupuncture needles ) for older adults with advanced knee OA . OBJECTIVE This study evaluated the sustained efficacy of PST and boosters for treating chronic pain with advanced knee OA . METHODS One hundred ninety participants age > 50 years with Kellgren-Lawrence grade 3 or 4 knee OA and chronic pain were r and omized to ( 1 ) PST ( once a week for 10 weeks ) followed by PST boosters for 6 months ( once every 2 weeks 2 times , then once a month ) , ( 2 ) control PST ( ie , periosteal needles and brief electrical stimulation of control points ) once a week for 10 weeks , or ( 3 ) PST for 10 weeks followed by control PST boosters for 6 months . Change in the Western Ontario and McMaster Universities Osteoarthritis Index pain score immediately after the 10-week intervention and at 6-month follow-up ( 9 months after baseline ) was the primary outcome . OMERACT-OARSI ( Outcome Measures in Rheumatology Clinical Trials-Osteoarthritis Research Society International ) criteria also were evaluated . Secondary measures of outcome included ( 1 ) physical performance ( Short Physical Performance Battery , gait speed , Timed Up and Go , and timed stair climb ) ; ( 2 ) psychological factors ( depressive symptoms measured with the Center for Epidemiologic Studies -Depression scale , coping measured with the catastrophizing subscale of the Coping Strategies Question naire , and self-efficacy measured with the Arthritis Self-Efficacy Scale ) ; ( 3 ) health-related quality of life measured with the Medical Outcomes Study 36-Item Short-Form Health Survey ; ( 4 ) rescue pain medication use tracked with diaries ; and ( 5 ) health care utilization and interim physical activity were monitored via monthly telephone calls . RESULTS After adjustment for pain at baseline , the PST and control booster did not differ from controls at 10 weeks ( difference , 1.3 ; 95 % CI , -0.10 to 2.8 ; P = 0.0683 ) or 9 months ( difference , 1.1 ; 95 % CI , -0.32 to 2.6 ; P = 0.13 ) . The PST and PST booster group had similar improvement compared with controls at 10 weeks ( baseline adjusted difference , 1.1 ; 95 % CI , -0.34 to 2.5 ; P = 0.1369 ) but significantly more improvement at 9 months ( baseline adjusted difference , 1.5 ; 95 % CI , 0.069 to 3.0 ; P = 0.0401 ) . Baseline depressive symptoms , low self-efficacy , higher difficulty performing daily activities , and greater knee stiffness predicted a lower likelihood of response . CONCLUSION PST plus PST boosters in patients age > 50 with advanced knee OA were well-tolerated and modestly reduced pain . Clinical Trials.gov identifier : NCT00865046 [2716312] Background The approximately 1100 medical journals now active in China are publishing a rapidly increasing number of research reports , including many studies identified by their authors as r and omized controlled trials . It has been noticed that these reports mostly present positive results , and their quality and authenticity have consequently been called into question . We investigated the adequacy of r and omization of clinical trials published in recent years in China to determine how many of them met acceptable st and ards for allocating participants to treatment groups . Methods The China National Knowledge Infrastructure electronic data base was search ed for reports of r and omized controlled trials on 20 common diseases published from January 1994 to June 2005 . From this sample , a subset of trials that appeared to have used r and omization methods was selected . Twenty-one investigators trained in the relevant knowledge , communication skills and quality control issues interviewed the original authors of these trials about the participant r and omization methods and related quality -control features of their trials . Results From an initial sample of 37,313 articles identified in the China National Knowledge Infrastructure data base , we found 3137 apparent r and omized controlled trials . Of these , 1452 were studies of conventional medicine ( published in 411 journals ) and 1685 were studies of traditional Chinese medicine ( published in 352 journals ) . Interviews with the authors of 2235 of these reports revealed that only 207 studies adhered to accepted methodology for r and omization and could on those grounds be deemed authentic r and omized controlled trials ( 6.8 % , 95 % confidence interval 5.9–7.7 ) . There was no statistically significant difference in the rate of authenticity between r and omized controlled trials of traditional interventions and those of conventional interventions . R and omized controlled trials conducted at hospitals affiliated to medical universities were more likely to be authentic than trials conducted at level 3 and level 2 hospitals ( relative risk 1.58 , 95 % confidence interval 1.18–2.13 , and relative risk 14.42 , 95 % confidence interval 9.40–22.10 , respectively ) . The likelihood of authenticity was higher in level 3 hospitals than in level 2 hospitals ( relative risk 9.32 , 95 % confidence interval 5.83–14.89 ) . All r and omized controlled trials of pre-market drug clinical trial were authentic by our criteria . Of the trials conducted at university-affiliated hospitals , 56.3 % were authentic ( 95 % confidence interval 32.0–81.0 ) . Conclusion Most reports of r and omized controlled trials published in some Chinese journals lacked an adequate description of r and omization . Similarly , most so called ' r and omized controlled trials ' were not real r and omized controlled trials owing toa lack of adequate underst and ing on the part of the authors of rigorous clinical trial design . All r and omized controlled trials of pre-market drug clinical trial included in this research were authentic . R and omized controlled trials conducted by authors in high level hospitals , especially in hospitals affiliated to medical universities had a higher rate of authenticity . That so many non-r and omized controlled trials were published as r and omized controlled trials reflected the fact that peer review needs to be improved and a good practice guide for peer review including how to identify the authenticity of the study urgently needs to be developed [10378713] OBJECTIVE The purpose of this study was to investigate the efficacy of acupuncture as an adjunctive therapy to st and ard care for the relief of pain and dysfunction in elderly patients with osteoarthritis ( OA ) of the knee . METHODS Seventy-three patients with symptomatic OA of the knee were r and omly assigned to treatment ( acupuncture ) or st and ard care ( control ) . Analysis was performed on last score carried forward to account for patients who dropped out before completion . Patients self-scored Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) and Lequesne indices at baseline and at 4 , 8 and 12 weeks . Patients in the control group were offered acupuncture treatment after 12 weeks . The data for these patients are pooled with those from the original acupuncture group for within-group analysis . RESULTS Patients r and omized to acupuncture improved on both WOMAC and Lequesne indices compared to those who received st and ard treatment alone . Significant differences on total WOMAC Scale were seen at 4 and 8 weeks . There appears to be a slight decline in effect at 4 weeks after cessation of treatment ( 12 weeks after first treatment ) . No adverse effects of acupuncture were reported . CONCLUSION These data suggest that acupuncture is an effective and safe adjunctive therapy to conventional care for patients with OA of the knee [16005336] BACKGROUND Acupuncture is widely used by patients with chronic pain although there is little evidence of its effectiveness . We investigated the efficacy of acupuncture compared with minimal acupuncture and with no acupuncture in patients with osteoarthritis of the knee . METHODS Patients with chronic osteoarthritis of the knee ( Kellgren grade < or = 2 ) were r and omly assigned to acupuncture ( n=150 ) , minimal acupuncture ( superficial needling at non-acupuncture points ; n=76 ) , or a waiting list control ( n=74 ) . Specialised physicians , in 28 outpatient centres , administered acupuncture and minimal acupuncture in 12 sessions over 8 weeks . Patients completed st and ard question naires at baseline and after 8 weeks , 26 weeks , and 52 weeks . The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis ( WOMAC ) index at the end of week 8 ( adjusted for baseline score ) . All main analyses were by intention to treat . RESULTS 294 patients were enrolled from March 6 , 2002 , to January 17 , 2003 ; eight patients were lost to follow-up after r and omisation , but were included in the final analysis . The mean baseline-adjusted WOMAC index at week 8 was 26.9 ( SE 1.4 ) in the acupuncture group , 35.8 ( 1.9 ) in the minimal acupuncture group , and 49.6 ( 2.0 ) in the waiting list group ( treatment difference acupuncture vs minimal acupuncture -8.8 , [ 95 % CI -13.5 to -4.2 ] , p=0.0002 ; acupuncture vs waiting list -22.7 [ -27.5 to -17.9 ] , p<0.0001 ) . After 52 weeks the difference between the acupuncture and minimal acupuncture groups was no longer significant ( p=0.08 ) . INTERPRETATION After 8 weeks of treatment , pain and joint function are improved more with acupuncture than with minimal acupuncture or no acupuncture in patients with osteoarthritis of the knee . However , this benefit decreases over time [4111481] Introduction This study tested the effectiveness of moxibustion on pain and function in chronic knee osteoarthritis ( KOA ) and evaluated safety . Methods A multi-centre , non-blinded , parallel-group , r and omised controlled trial compared moxibustion with usual care ( UC ) in KOA . 212 South Korean patients aged 40–70 were recruited from 2011–12 , stratified by mild ( Kellgren/Lawrence scale grade s 0/1 ) and moderate-severe KOA ( grade s 2/3/4 ) , and r and omly allocated to moxibustion or UC for four weeks . Moxibustion involved burning mugwort devices over acupuncture and Ashi points in affected knee(s ) . UC was allowed . Korean Western Ontario and McMaster Universities Question naire ( K-WOMAC ) , Short Form 36 Health Survey ( SF-36v2 ) , Beck Depression Inventory ( BDI ) , physical performance test , pain numeric rating scale ( NRS ) and adverse events were evaluated at 5 and 13 weeks . K-WOMAC global score at 5 weeks was the primary outcome . Results 102 patients ( 73 mild , 29 moderate-severe ) were allocated to moxibustion , 110 ( 77 mild , 33 moderate-severe ) to UC . K-WOMAC global score ( moxibustion 25.42+/−SD 19.26 , UC 33.60+/−17.91 , p<0.01 , effect size = 0.0477 ) , NRS ( moxibustion 44.77+/−22.73 , UC 56.23+/−17.71 , p<0.01 , effect size = 0.0073 ) and timed-st and test ( moxibustion 24.79+/−9.76 , UC 25.24+/−8.84 , p = 0.0486 , effect size = 0.0021 ) were improved by moxibustion at 5 weeks . The primary outcome improved for mild but not moderate-severe KOA . At 13 weeks , moxibustion significantly improved the K-WOMAC global score and NRS . Moxibustion improved SF-36 physical component summary ( p = 0.0299 ) , bodily pain ( p = 0.0003 ) , physical functioning ( p = 0.0025 ) and social functioning ( p = 0.0418 ) at 5 weeks , with no difference in mental component summary at 5 and 13 weeks . BDI showed no difference ( p = 0.34 ) at 5 weeks . After 1158 moxibustion treatments , 121 adverse events included first ( n = 6 ) and second degree ( n = 113 ) burns , pruritus and fatigue ( n = 2 ) . Conclusions Moxibustion may improve pain , function and quality of life in KOA patients , but adverse events are common . Limitations included no sham control or blinding . Trial Registration Clinical Research Information Service ( CRIS ) [24579366] OBJECTIVE To observe the clinical effect of moxibustion of different acupoints undergoing heat-sensitive state and resting state in the treatment of knee osteoarthritis ( KOA ) patients . METHODS A total of 60 cases of KOA patients were enrolled in the present trial . They were divided into heat-sensitive moxibustion ( heat-sensitive ) group and non-sensitive moxibustion group ( resting group ) . Moxibustion was applied to Neixiyan ( EX-LE 4 ) , Waixiyan ( i.e. Dubi , ST 35 ) and Heding ( EX-LE 2 ) for about 45 min , once daily for 20 days . The heat-sensitive state was evaluated according to the patient 's feeling . After moxibustion stimulation at the acupoint area , if the patient feels the heat penetrating from the skin surface to the deep tissue , or/ and extending peripherally around the moxibustion site , or/ and transmitting toward a certain direction , it is considered to be heat sensitization state . The therapeutic effect was evaluated by using visual analogue scale ( VAS ) for pain severity changes and by Guiding Principles for Clinical Trials of New Drugs of Chinese Materia Medica for evaluating functional activity of the knee-joint . RESULTS After 20 sessions of treatment and after a half year 's follow-up , the total integrated scores of VAS in the heat-sensitive group were all lower than those of the resting group ( P < 0.01 ) . Following 20 sessions of treatment , of the two 30 KOA patients in the heat-sensitive group and resting group , 14 ( 46.67 % ) and 5 ( 16.67 % ) experienced a marked improvement , 10 ( 33.33 % ) and 9 ( 30.00 % ) were effective , 6 ( 20.00 % ) and 16 ( 53.33 % ) were invalid , with the effective rates being 80.00 % and 46.67 , respectively . Half-year 's follow-up showed that the effective rates of the heat-sensitive group and resting group were 79.17 % ( 19/24 ) and 42.86 % ( 6/14 ) , respectively , suggesting a better therapeutic effect of heat-sensitive moxibustion . CONCLUSION The clinical n effect of heat-sensitive moxibustion is significantly superior to that of non-sensitive moxibustion in the treatment of KOA patients , being worthy of clinical application [17604311] OBJECTIVE To evaluate the effects of st and ardized western acupuncture and physiotherapy on pain and functional ability in patients with severe osteoarthritic knee pain awaiting knee arthroplasty . METHODS Three-arm , assessor-blind , r and omized controlled trial . PARTICIPANTS 181 patients awaiting knee arthroplasty . INTERVENTIONS acupuncture for 6 weeks ; physiotherapy for 6 weeks ; st and ardized advice . MAIN OUTCOME MEASURES Oxford Knee Score question naire ( OKS ) ( primary ) ; 50 m timed walk , and duration of hospital stay following knee arthroplasty . RESULTS There was no baseline difference between groups . At 7 weeks , there was a 10 % reduction in OKS in the acupuncture group which was a significant difference between the acupuncture and the control group : Mean ( s.d . ) acupuncture 36.8 ( 7.20 ) ; physiotherapy 39.2 ( 8.22 ) ; control 40.3 ( 8.48 ) ( P = 0.0497 ) . These effects were no longer present at 12 weeks . There was a trend ( P = 0.0984 ) towards a shorter in-patient stay of 1 day for the physiotherapy group [ mean 6.50 days ( s.d . 2.0 ) ] compared with the acupuncture group [ mean 7.77 days ( s.d . 3.96 ) ] . CONCLUSIONS We have demonstrated that patients with severe knee osteoarthritis can achieve a short-term reduction in OKS when treated with acupuncture . However , we failed to demonstrate any other clinical ly or statically significant effects between the groups . Both interventions can be delivered effectively in an out-patient group setting at a district general hospital . Further study is needed to evaluate the combined effects of these treatments [2268695] Background The present study tests whether a combined treatment of acupuncture and transcutaneous electrical nerve stimulation ( TENS ) is more effective than acupuncture or TENS alone for treating knee osteoarthritis ( OA ) . Methods Thirty-two patients with knee OA were r and omly allocated to four groups . The acupuncture group ( ACP ) received only acupuncture treatment at selected acupoints for knee pain ; the TENS group ( TENS ) received only TENS treatment at pain areas ; the acupuncture and TENS group ( A&T ) received both acupuncture and TENS treatments ; the control group ( CT ) received topical poultice ( only when necessary ) . Each group received specific weekly treatment five times during the study . Outcome measures were pain intensity in a visual analogue scale ( VAS ) and knee function in terms of the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) . Results The ACP , TENS and A&T groups reported lower VAS and WOMAC scores than the control group . Significant reduction in pain intensity ( P = 0.039 ) and significant improvement in knee function ( P = 0.008 ) were shown in the A&T group . Conclusion Combined acupuncture and TENS treatment was effective in pain relief and knee function improvement for the sample d patients suffering from knee OA [15611487] Context Previous studies of acupuncture for osteoarthritis have had conflicting results . This may have occurred because most studies have included small sample s , a limited number of treatment sessions , or other limitations . Contribution This r and omized , controlled trial compared 24 acupuncture sessions over 26 weeks with sham acupuncture or arthritis education in 570 patients with osteoarthritis of the knee . Acupuncture led to greater improvements in function but not pain after 8 weeks and in both pain and function after 26 weeks . No adverse effects were associated with acupuncture . Caution s Many participants dropped out of the study , so readers should interpret the findings at 26 weeks with caution . The Editors Osteoarthritis is the most common form of arthritis and is a major cause of morbidity , limitation of activity , and health care utilization , especially in elderly patients ( 1 , 2 ) . Pain and functional limitation are the primary clinical manifestations of osteoarthritis of the knee . Current recommendations for managing osteoarthritis , including guidelines published by the American College of Rheumatology ( 3 ) and European League of Associations of Rheumatology ( 4 ) , focus on relieving pain and stiffness and maintaining or improving physical function as important goals of therapy . No curative therapies exist for osteoarthritis ; thus , both pharmacologic and nonpharmacologic management focus on controlling pain and reducing functional limitation ( 5 ) . Nonpharmacologic therapy , which includes patient education , social support , physical and occupational therapy , aerobic and resistive exercises , and weight loss , is the cornerstone of a multidisciplinary approach to osteoarthritis patient management ( 3 ) . Pharmacologic therapies include nonopioid analgesics ( such as acetaminophen ) , nonsteroidal anti-inflammatory drugs ( NSAIDs ) ( including cyclooxygenase-2 [ COX-2 ] enzyme selective inhibitors ) , topical analgesics ( capsaicin cream ) , opioid analgesics , and intra-articular steroid and hyaluronate injections . Often , these agents are used in combination for additive analgesic efficacy ( 6 ) . Pharmacologic management of osteoarthritis is often ineffective , and agents such as NSAIDs may cause unwanted and dangerous side effects ( 7 , 8) . Complementary and alternative medicine is another approach to treating osteoarthritis ( 9 - 12 ) , particularly in Asian societies ( 13 ) . Many U.S. patients with osteoarthritis also use complementary and alternative medical therapies ( 14 ) . A systematic review of acupuncture and knee osteoarthritis ( 15 ) identified 7 small r and omized , controlled trials published in English . Within the method ologic limitations of the studies , the evidence suggested that acupuncture seemed to alleviate knee pain and function compared with sham acupuncture controls , although 2 trials comparing acupuncture with an active , nonpharmacologic treatment ( physical therapy ) did not indicate such an effect ( 16 , 17 ) . Before conducting our large-scale trial , we completed both a pilot study ( 18 ) and a r and omized , single-blind trial ( 19 ) of the effect of acupuncture on osteoarthritis of the knee . Participants in the uncontrolled pilot study ( n= 12 ) showed statistically significant improvement in both self-reported pain and physical function , as well as performance measures of physical function after 8 weeks of acupuncture treatment and at 12-week follow-up as compared with their baseline ( 18 ) . In our larger r and omized , single-blind trial ( n= 73 ) , which examined the benefit of acupuncture added to st and ard management with NSAIDs , the acupuncture treatment group experienced statistically significant improvements in self-reported pain and disability scores compared with a st and ard-care control group as late as 4 weeks after the end of treatment ( 19 ) . However , this effect diminished within 18 weeks ( 26 weeks after the beginning of the trial ) after the final acupuncture treatment . Together , however , the previously conducted trials ( both our preliminary studies [ 18 , 19 ] and those referenced in the systematic review [ 15 ] ) have 3 method ologic limitations : lack of credible controls for the placebo effect , inadequate assessment of long-term treatment benefits , and insufficient sample sizes . We tested the hypothesis that an 8-week intensive acupuncture treatment regimen , followed by an 18-week tapering regimen , reduces pain and improves function among patients with knee osteoarthritis as compared with both sham acupuncture and education control groups . Methods Patient Recruitment We recruited patients for this multisite , placebo-controlled trial from March 2000 through December 2003 , primarily through print and radio advertisements . The 3 sites were the Integrative Medicine Clinic of the University of Maryl and School of Medicine , Baltimore , Maryl and ; the Innovative Medical Research Center ( a private research firm ) , Towson , Maryl and ; and the Hospital for Special Surgery , New York City , New York . The institutional review boards of the 3 sites approved the study . We determined the sample size ( n= 570 ) by a power analysis based on our r and omized pilot study ( 19 ) , adjusted by the estimated decrease in effect size result ing from the inclusion of a sham acupuncture group design ed to control for placebo effects . Patients met the following inclusion criteria : age 50 years or older , a diagnosis of osteoarthritis of the knee , radiographic evidence of at least 1 osteophyte at the tibiofemoral joint ( KellgrenLawrence grade 2 ) , moderate or greater clinical ly significant knee pain on most days during the past month , and willingness to be r and omly assigned . Exclusion criteria were the presence of serious medical conditions that precluded participation in study , bleeding disorders that might contraindicate acupuncture , intra-articular corticosteroid or hyaluronate injections ( as well as any knee surgeries or concomitant use of topical capsaicin cream ) during the past 6 months , previous experience with acupuncture , or any planned events ( including total knee replacement ) that would interfere with participation in the study during the following 26 weeks . After a brief telephone screening , patients were scheduled to visit 1 of the 3 participating sites to sign an informed consent statement and undergo a brief rheumatologic examination ( including radiographic examination of affected knees ) by a physician or a nurse practitioner . Because the education course was a group activity , patients were recruited until a cohort of 12 to 21 patients was formed , at which point each cohort at each site was r and omly assigned to 1 of 3 groups by a computer-generated process using r and omly selected blocks of 3 , 6 , and 9 . We assured allocation concealment by using disguised letter codes that were generated and sent to the site coordinators by a central statistical core . We used this procedure to ensure that approximately equal numbers of participants were in each treatment group across the course of the study , to ensure that each cohort would have participants assigned to all 3 treatment groups , and to make the breaking of the group assignment process more difficult . The research assistants who collected assessment s from participants , the participants themselves ( in the true acupuncture and sham acupuncture groups ) , and the statistician were blinded to group assignment . Assessment s were conducted at baseline and 4 , 8 , 14 , and 26 weeks after r and omization . Study Interventions We developed and modified the acupuncture treatment and sham control protocol s from previously reported and vali date d procedures ( 18 - 21 ) . During the trial , 7 acupuncturists were used : 3 at the Integrative Medicine Clinic , 3 at the Innovative Medical Research Center , and 1 at the Hospital for Special Surgery . In general , acupuncturists were assigned to the same participants throughout the 26-week treatment schedule , except for vacation conflicts and staff turnover , and provided approximately the same proportions of true versus sham procedures . All acupuncturists were state-licensed and had at least 2 years of clinical experience . The study 's principal acupuncturist trained and supervised the acupuncturists in performing true or sham procedures and avoiding interactions that could inadvertently communicate group assignment . True Acupuncture The true acupuncture ( experimental ) group underwent 26 weeks of gradually tapering treatment according to the following schedule : 8 weeks of 2 treatments per week followed by 2 weeks of 1 treatment per week , 4 weeks of 1 treatment every other week , and 12 weeks of 1 treatment per month . We based the acupuncture point selection s on Traditional Chinese Medicine meridian theory to treat knee joint pain , known as the Bi syndrome . These points consisted of 5 local points ( Yanglinquan [ gall bladder meridian point 34 ] , Yinlinquan [ spleen meridian point 9 ] , Zhusanli [ stomach meridian point 36 ] , Dubi [ stomach meridian point 35 ] , and extra point Xiyan ) and 4 distal points ( Kunlun [ urinarybladder , meridian point 60 ] , Xuanzhong [ gall bladder meridian point 39 ] , Sanyinjiao [ spleen meridian point 6 ] , and Taixi [ kidney meridian point 3 ] ) on meridians that traverse the area of pain ( 22 , 23 ) . The same points were treated for each affected leg . If both knees were affected , 9 needles were inserted in each leg . ( The outcome measures were not specifically targeted to whether the patient had osteoarthritis in 1 or both knees , and we observed no differential effects on the basis of the number of knees treated . ) The acupuncturists inserted 1.5-inch ( for local points ) and 1-inch ( for distal points ) 32-gauge ( 0.25-mm diameter ) acupuncture needles to a conventional depth of approximately 0.3 to 1.0 inch , depending on point location . All participants in the treatment group achieved the De-Qi sensation , a local sensation of heaviness , numbness , soreness , or paresthesia that accompanies the insertion and manipulation of needles during acupuncture , at these 9 points . Acupuncturists applied electrical [23967637] OBJECTIVE To explore the efficacy on knee osteoarthritis ( KOA ) treated with different acupuncture methods at different stages . METHODS One hundred and eighty cases of KOA were divided into stagnation stage , fascia cramp stage and tendon lesion stage according to the condition of disease , 60 cases in each stage . Each stage was r and omized into a staging treatment group and an electroacupuncture ( EA ) group , 30 cases in each one . In the staging treatment group , acupuncture at the tendon points of meridians and electric thermal needling method were adopted for the cases at the stagnation stage ; the small needle-knife therapy and bleeding method were used for the cases at the fascia cramp stage ; and the electric thermal therapy with thick silver needles was applied for the cases at the tendon lesion stage . In the EA group , EA was applied for the cases of all the three stages at Liangqiu ( ST 34 ) , Xuehai ( SP 10 ) , Yanglingquan ( GB 34 ) , etc . RESULTS The total effective rate was 96.1 % ( 87/90 ) in the staging treatment group and was 91.1 % ( 82/90 ) in the EA group , without significant difference in comparison ( P > 0.05 ) . The controlled and remarkably effective rate ( 88.9 % , 80/90 ) in the staging treatment group was higher apparently than ( 62.2 % , 56/90 ) in the EA group ( P < 0.001 ) . And in the EA group , with the disease progression and the further disease stages , the controlled and remarkably effective rate was reduced . After treatment , the scores of symptoms and signs were decreased in both groups ( both P < 0.001 ) , the improvement in the staging treatment group was superior to that in the EA group ( P < 0.001 ) . CONCLUSION The different acupuncture methods at the three stages improve obviously the clinical effect and are highly targeted . The mechanism of the three stages on " meridian muscle region pathology " and the treatment based on the disease stages can be the effective approach to KOA [19942631] Acupuncture is one of the most widely used and broadly research ed of the complementary and alternative therapies , but high- quality trials generally show no benefit over sham acupuncture . Many would view this result as evidence of ineffectiveness for this intervention . This discussion article focuses on the report of a large multicenter r and omized controlled trial of acupuncture for chronic low-back pain ( CLBP ) in the lay and academic press , the ensuing discussion , and its impact on both clinical practice and service provision . The authors suggest that interpretive bias has affected reporting , leading to question able conclusions and advocacy in favor of this form of care that may exceed the evidence . They also suggest that a lack of underst and ing of research into the placebo effect may have contributed to confusion in the interpretation of these trials [19420954] Background : To evaluate the safety of acupuncture in a large number of patients receiving conventional health care and , based on these results , to develop a new medical consent form for acupuncture . Methods : The prospect i ve observational study included patients who received acupuncture treatment for chronic osteoarthritis pain of the knee or hip , low back pain , neck pain or headache , allergic rhinitis , asthma , or dysmenorrhoea . After treatment , all patients documented adverse events associated with acupuncture ( defined as adverse effects ) . Patients who reported a need for treatment due to an adverse effect completed an additional st and ardised question naire on the most important adverse effect . Based on this data and considering ethical and legal aspects a new consent form was developed . Results : A total of 229,230 patients received on average 10.2 ± 3.0 acupuncture treatments . Altogether , 19,726 patients ( 8.6 % ) reported experiencing at least one adverse effect and 4,963 ( 2.2 % ) reported one which required treatment . Common adverse effects were bleedings or haematoma ( 6.1 % of patients , 58 % of all adverse effects ) , pain ( 1.7 % ) and vegetative symptoms ( 0.7 % ) . Two patients experienced a pneumothorax ( one needed hospital treatment , the other observation only ) . The longest duration of a side effect was 180 days ( nerve lesion of the lower limb ) . The result ing medical consent form consists of five modules : Introduction to acupuncture and moxibustion , Risks of acupuncture treatment , Conditions which can increase the risk , Doctor ’s statement , and Consent . Conclusion : Acupuncture provided by physicians is a relatively safe treatment and the proposed consent form could support both patients and professionals in the process of obtaining informed consent [24946628] OBJECTIVE To evaluate the clinical efficacy and efficacy sustainable time of acupuncture in knee osteoarthritis ( KOA ) . METHODS The non-r and omized concurrent control trial was adopted . One hundred and ninety-three cases of KOA were divided into an immediate acupuncture group ( group A , 97 cases ) and a delayed acupunc-weeks at the end of treatment . In group B , the same acupuncture therapy was applied after waiting 4 weeks . The acupoints in the two groups were Liangqiu ( ST 34 ) , Dubi ( ST 35 ) , Zusanli ( ST 36 ) , Yanglingquan ( GB 34 ) , Yinlingquan ( SP 9 ) , Xuehai ( SP 10 ) , Xiyan ( EX-LE 4 ) , Xiyangguan ( GB 33 ) . WOMAC ( Western Ontario and McMasters Universities Osteoarthritis ) was used for the assessment of the primary index and VAS ( visual analogue scale ) was for the secondary index . The evaluation was accomplished by the patients at the beginning of trial , on the 4th and 8th weeks . In each group , 72 patients finished the trial and the data of the lost cases were included in the final data analysis . RESULTS In the 4th week of trial , WOMAC score was ( 25 . 8+/-22.0 ) in group A difference ( P<0 . 001 ) . VAS scorewas ( 31 . 8+/-24 . and was ( 43.8+/-22.2 ) in group B , indicating the significant 6 ) in group A and was ( 56 . 6 + /-25 . 8) in group B , indicating very significant difference ( P<0 . 001 ) . In the 8th week , the efficacy was reduced slightly in the follow-up of group A , but it was improved apparently as compared Acupuncture relieves joint pain and improves joint function obviously.by th patiĩeffr , a Mtaetfti-?an tf ri-with that before treatment . CONCLUSION Acupuncture relieves joint pain and improves joint function obviously . The effect of acupuncture is still sustainable in 4 weeks after terminating the treatment [25268438] IMPORTANCE There is debate about benefits of acupuncture for knee pain . OBJECTIVE To determine the efficacy of laser and needle acupuncture for chronic knee pain . DESIGN , SETTING , AND PARTICIPANTS Zelen- design clinical trial ( r and omization occurred before informed consent ) , in Victoria , Australia ( February 2010-December 2012 ) . Community volunteers ( 282 patients aged ≥50 years with chronic knee pain ) were treated by family physician acupuncturists . INTERVENTIONS No acupuncture ( control group , n = 71 ) and needle ( n = 70 ) , laser ( n = 71 ) , and sham laser ( n = 70 ) acupuncture . Treatments were delivered for 12 weeks . Participants and acupuncturists were blinded to laser and sham laser acupuncture . Control participants were unaware of the trial . MAIN OUTCOMES AND MEASURES Primary outcomes were average knee pain ( numeric rating scale , 0 [ no pain ] to 10 [ worst pain possible ] ; minimal clinical ly important difference [ MCID ] , 1.8 units ) and physical function ( Western Ontario and McMaster Universities Osteoarthritis Index , 0 [ no difficulty ] to 68 [ extreme difficulty ] ; MCID , 6 units ) at 12 weeks . Secondary outcomes included other pain and function measures , quality of life , global change , and 1-year follow-up . Analyses were by intention-to-treat using multiple imputation for missing outcome data . RESULTS At 12 weeks and 1 year , 26 ( 9 % ) and 50 ( 18 % ) participants were lost to follow-up , respectively . Analyses showed neither needle nor laser acupuncture significantly improved pain ( mean difference ; -0.4 units ; 95 % CI , -1.2 to 0.4 , and -0.1 ; 95 % CI , -0.9 to 0.7 , respectively ) or function ( -1.7 ; 95 % CI , -6.1 to 2.6 , and 0.5 ; 95 % CI , -3.4 to 4.4 , respectively ) compared with sham at 12 weeks . Compared with control , needle and laser acupuncture result ed in modest improvements in pain ( -1.1 ; 95 % CI , -1.8 to -0.4 , and -0.8 ; 95 % CI , -1.5 to -0.1 , respectively ) at 12 weeks , but not at 1 year . Needle acupuncture result ed in modest improvement in function compared with control at 12 weeks ( -3.9 ; 95 % CI , -7.7 to -0.2 ) but was not significantly different from sham ( -1.7 ; 95 % CI , -6.1 to 2.6 ) and was not maintained at 1 year . There were no differences for most secondary outcomes and no serious adverse events . CONCLUSIONS AND RELEVANCE In patients older than 50 years with moderate or severe chronic knee pain , neither laser nor needle acupuncture conferred benefit over sham for pain or function . Our findings do not support acupuncture for these patients . TRIAL REGISTRATION anzctr.org.au Identifier : ACTRN12609001001280 [16452103] Abstract Objective To investigate whether a sham device ( a vali date d sham acupuncture needle ) has a greater placebo effect than an inert pill in patients with persistent arm pain . Design A single blind r and omised controlled trial created from the two week placebo run-in periods for two nested trials that compared acupuncture and amitriptyline with their respective placebo controls . Comparison of participants who remained on placebo continued beyond the run-in period to the end of the study . Setting Academic medical centre . Participants 270 adults with arm pain due to repetitive use that had lasted at least three months despite treatment and who scored ≥3 on a 10 point pain scale . Interventions Acupuncture with sham device twice a week for six weeks or placebo pill once a day for eight weeks . Main outcome measures Arm pain measured on a 10 point pain scale . Secondary outcomes were symptoms measured by the Levine symptom severity scale , function measured by Pransky 's upper extremity function scale , and grip strength . Results Pain decreased during the two week placebo run-in period in both the sham device and placebo pill groups , but changes were not different between the groups ( −0.14 , 95 % confidence interval −0.52 to 0.25 , P = 0.49 ) . Changes in severity scores for arm symptoms and grip strength were similar between groups , but arm function improved more in the placebo pill group ( 2.0 , 0.06 to 3.92 , P = 0.04 ) . Longitudinal regression analyses that followed participants throughout the treatment period showed significantly greater downward slopes per week on the 10 point arm pain scale in the sham device group than in the placebo pill group ( −0.33 ( −0.40 to −0.26 ) v −0.15 ( −0.21 to −0.09 ) , P = 0.0001 ) and on the symptom severity scale ( −0.07 ( −0.09 to −0.05 ) v −0.05 ( −0.06 to −0.03 ) , P = 0.02 ) . Differences were not significant , however , on the function scale or for grip strength . Reported adverse effects were different in the two groups . Conclusions The sham device had greater effects than the placebo pill on self reported pain and severity of symptoms over the entire course of treatment but not during the two week placebo run in . Placebo effects seem to be malleable and depend on the behaviours embedded in medical rituals [23819244] OBJECTIVE To objective ly evaluate the clinical efficacy of stiletto needle for pain of knee osteoarthri tis ( KOA ) , and analyze its function mechanism . METHODS Seventy-six cases of KOA ( 76 knees ) were selected . Under the guide of Jingjin theory in TCM , stiletto needle was applied at pain point of Jingjin in extra-articular area to have a loose solution effect , 1 to 3 points were selected each time , 1 to 2 times of treatment were required . The results of tenderness measurement instrument was adopted as main evaluation index of joint pain , and all data of evaluation indices before and after the treatment were statistical analyzed . RESULTS There were significant differences in visual analogue scale ( VAS ) score , tenderness score , HSS function score and movement range of joint before and after the treatment ( all P < 0.05 ) . The effective rate of stiletto needle therapy was 89.5 % . There was apparent regression trend between VAS score and tenderness score with Y ( VAS ) = 7.841 - 1.569 X ( tenderness score ) as its regressive equation . CONCLUSION The stiletto needle therapy is an effective method to relieve the pain of knee osteoarthritis , and its clinical efficacy evaluation could be more objective and digital with tenderness measurement instrument [23620932] OBJECTIVE To compare the efficacy difference in the treatment of knee osteoarthritis between acupuncture at Neiguan ( PC 6 ) and Taichong ( LR 3 ) and the conventional acupoints . METHODS Forty four cases were r and om into a Neiguanc ( PC 6 ) Taichong ( LR 3 ) group observation group ( 20 cases ) and a conventional group control group ( 24 cases ) . In the observention group , acupuncture was applied to Neiguan ( PC 6 ) on the healthy side and Taichong ( LR 3 ) on the affected side . The acupoints were selected bilaterally if both knees were affected . In the control group , acupuncture was applied to Yanglingquan ( GB 34 ) , Yinlingquan ( SP 9 ) , Neixiyan ( EX-LE 4 ) , Dubi ( ST 35 ) , Zusanli ( ST 36 ) and the others on the affected side . The visual analogue scale ( VAS ) and Western Ontario and McMaster University Osteoarthritis Index ( WOMAC ) were used for assessment of theraputic effect after treatment . RESULTS The score of VAS and pain , stiffness and function impairment of WOMAC were lower apparently than those before treatment in both groups ( all P < 0.001 ) . VAS score after treatment in the observation group was lower apparently than that in the control group ( P < 0.05 ) . The differences in each item score of WOMAC after treatment were not significant statistically between the two groups ( all P > 0.05 ) . CONCLUSION Acupuncture at Neiguan ( PC 6 ) and Taichong ( LR 3 ) achieves the similar efficacy on knee osteoarthritis as the conventional acupoints , but the former is more simple and convenient [395837] Background Controlled clinical trials produced contradictory results with respect to a specific analgesic effect of acupuncture . There is a lack of large multi-centre acupuncture trials . The German Acupuncture Trial represents the largest multi-centre study of acupuncture in the treatment of chronic pain caused by gonarthrosis up to now . Methods 900 patients will be r and omised to three treatment arms . One group receives verum acupuncture , the second sham acupuncture , and the third conservative st and ard therapy . The trial protocol is described with eligibility criteria , detailed information on the treatment definition , blinding , endpoints , safety evaluation , statistical methods , sample size determination , monitoring , legal aspects , and the current status of the trial . Discussion A critical discussion is given regarding the considerations about st and ardisation of the acupuncture treatment , the choice of the control group , and the blinding of patients and observers [15465938] Objective : The primary aim was to establish from acupuncture patients the type and frequency of adverse events they experienced and attributed to their treatment . Secondary aims included the measurement of patient reported adverse consequences arising from advice received about conventional/prescribed medication or from delayed conventional diagnosis and treatment . Methods : Postal survey of prospect ively identified acupuncture patients . One in three members of the British Acupuncture Council ( n = 638 ) invited consecutive patients to participate in the survey . Participating patients gave baseline data and consented to direct follow up by the research ers at 3 months . A structured question naire was used to collect data on perceived adverse events . Results : 9408 patients gave baseline information and consent and 6348 ( 67 % ) completed 3 month question naires . Responders were not dissimilar to non-responders for all known characteristics . 682 patients reported at least one adverse event over 3 months , a rate of 107 per 1000 patients ( 95 % CI 100 to 115 ) . Three patients reported a serious adverse event . The most common events reported were severe tiredness and exhaustion , pain at the site of needling , and headache . Patients receiving acupuncture treatment that was not funded by the NHS and patients not in contact with a GP or hospital specialist were less likely to report adverse events ( odds ratios 0.59 and 0.66 , respectively ) . 199 ( 3 % ) of responding patients reported receiving advice about conventional/prescribed medication , six of whom reported adverse consequences after taking the advice . Two patients reported delayed conventional treatment . Conclusion : Patients report a range of adverse events but these do not prevent most patients seeking further acupuncture . This large scale survey supports existing evidence that acupuncture is a relatively safe intervention when practised by regulated practitioners [11471578] Acupuncture is becoming a common technique within the physiotherapy profession as a treatment modality for pain relief ; however , few r and omised controlled trials have been undertaken to assess the effectiveness of acupuncture , particularly in the treatment of osteoarthritis ( OA ) of the hip . Therefore , a r and omised trial to compare the effectiveness of acupuncture with advice and exercises on the symptomatic treatment of OA of the hip was carried out . Thirty-two patients awaiting a total hip arthroplasty were r and omly allocated to either the experimental group , ( A ) , to have six sessions of acupuncture each lasting up to 25 minutes , or the control group , ( B ) , to be given advice and exercises for their hip over a six week period . Group A consisted of three men and 13 women , and group B consisted of four men and eight women . The average age in group A was 66 years and in group B it was 68 years . Patients were assessed for pain and functional ability , using a modified version of the WOMAC question naire , pre-treatment , immediately post-treatment and at eight weeks post-treatment . The pre-treatment WOMAC scores in the two groups were similar ( p=0.85 ) . There was a significant improvement in group A ( decrease in WOMAC score ) immediately post-treatment ( p=0.002 ) and this was maintained at the eight-week follow-up ( p=0.03 ) . There were no significant changes in group B. When the changes in WOMAC scores were compared between groups , a significantly greater improvement was found between pre-treatment and immediately post-treatment in group A , compared with group B ( p=0.02 ) . The changes between pre-treatment and the eight-week follow-up also showed a significant improvement in group A compared with group B ( p=0.03 ) . In conclusion , this trial supports the hypothesis that acupuncture is more effective than advice and exercises in the symptomatic treatment of OA of the hip [102323] Background The purpose of this study was to compare the efficacy of electroacupuncture ( EA ) , diclofenac and their combination in symptomatic treatment of osteoarthritis ( OA ) of the knee . Methods This study was a r and omized , single-blind , placebo controlled trial . The 193 out- patients with OA of the knee were r and omized into four groups : placebo , diclofenac , EA and combined ( diclofenac plus EA ) . Paracetamol tablets were prescribed as a rescue analgesic during the study . The patients were evaluated after a run-in period of one week ( week 0 ) and again at the end of the study ( week 4 ) . The clinical assessment s included the amount of paracetamol taken/week , visual analog scale ( VAS ) , Western Ontario and McMaster Universities ( WOMAC ) OA Index , Lequesne 's functional index , 50 feet-walk time , and the orthopedist 's and patient 's opinion of change . Results One hundred and eighty six patients completed the study . The improvement of symptoms ( reduction in mean changes ) in most outcome parameters was greatest in the EA group . The proportions of responders and patients with an overall opinion of " much better " were also greatest in the EA group . The improvement in VAS was significantly different between the EA and placebo group as well as the EA and diclofenac group . The improvement in Lequesne 's functional index also differed significantly between the EA and placebo group . In addition , there was a significant improvement in WOMAC pain index between the combined and placebo group . Conclusion EA is significantly more effective than placebo and diclofenac in the symptomatic treatment of OA of the knee in some circumstances . However , the combination of EA and diclofenac treatment was no more effective than EA treatment alone [21290833] OBJECTIVE To observe the differences of effect of electroacupuncture and medication on hip osteoarthritis . METHODS Sixty cases were r and omly divided into an electroacupuncture group and a medication group , 30 cases in each one . In electroacupuncture group , electroacupuncture was applied at Biguan ( ST 31 ) , Juliao ( GB 29 ) , Zuwuli ( LR 10 ) and Yinlian ( LR 11 ) . In medication group , Diclofenac Sodium was prescribed for oral administration . One month after treatment , Visual Analogue Scale ( VAS ) and Harris score were compared between two groups . RESULTS VAS scores were 67.83 + /- 8.48 and 55.83 + /- 9.66 before and after treatment in electroacupuncture group , and were 68.67 + /- 8.09 and 61.50 + /- 7.78 in medication group separately . VAS pain scores after treatment were reduced remarkably in two groups ( both P < 0.001 ) , but the score was reduced much more remarkably in electroacupuncture group as compared with medication group . In electroacupuncture group , after treatment , Harris total score , the single scores of joint pain , function and motion range increased apparently as compared with those before treatment ( all P < 0.001 ) . In medication group , after treatment , Harris total score and pain score increased remarkably as compared with those before treatment ( both P < 0.001 ) . Harris total score , pain score and function score after treatment in electroacupuncture group increased much more remarkably as compared with those in medication group ( all P < 0.05 ) . CONCLUSION Electroacupuncture can treat effectively hip osteoarthritis , relieve joint pain and improve joint function . The efficacy of it is superior to that of oral administration of Diclofenac Sodium [24462108] BACKGROUND There is lack of well- design ed trials evaluating structural benefits of non-pharmacologic therapies in knee osteoarthritis ( OA ) . In this parallel-group r and omized controlled trial , we aim to compare the possible advantages of lateral wedge insole and acupuncture in patients with medial knee OA . METHOD Patients with grade two or three of medial knee OA were r and omly allocated to group one who received an in shoe lateral wedge and group two who underwent acupuncture . We assessed patients ' pain , function and knee joint cartilage thickness before and after intervention . Paired t-test and independent sample s t-test were used for in group and between group analyses . ( LEVEL OF EVIDENCE 2 . ) RESULTS Twenty patients in each group were recruited in the study . Pain significantly decreased after therapy in both groups one and two ( paired t test , P<0.001 , 95 % CI : 1.62 - 3.25 and 1.58 - 3.20 respectively ) . Function improved in each group ( paired t test , P=0.001 , 95 % CI of 0.94 - 2.38 in group one and 0.97 - 2.43 in group two ) . A non- clinical ly statistically significant difference regarding the femoral and tibial cartilage thickness was obtained in both groups one ( P=0.005 , CI : -0.43 - 0.82 and P=0.037 , CI : -0.44 - 0.80 respectively ) and two ( P=0.025 , CI : -0.45 - 0.79 and P=0.035 , CI : -0.29 - 0.96 respectively ) . Between groups analysis showed no significant difference regarding abovementioned measures . CONCLUSION Both lateral wedge insole and acupuncture can be effective in the treatment of medial knee osteoarthritis without any superiority of one over the other . Iranian Registry of Clinical Trials : I RCT 201201108235N1 . URL : http://i rct .ir/ search en.php [1816730] Forty-four patients with chronic cervical osteoarthritis took part in this study . Patients were treated with acupuncture , sham-acupuncture , diazepam or placebo-diazepam in r and omized order . Pain was rated on visual analogue scales before , during , and after treatment . Two scales were separately used to rate the intensity ( sensory component ) and the unpleasantness ( affective component ) of pain . The results analyzed from these trials show that diazepam , placebo-diazepam , acupuncture and sham-acupuncture have a more pronounced effect on the affective than on the sensory component of pain . Acupuncture was significantly more effective than placebo-diazepam ( p less than 0.05 ) , but not significantly more effective than diazepam or sham-acupuncture [7727550] OBJECTIVE The purpose of this study was to determine whether acupuncture was more effective than sham acupuncture in the reduction of pain in persons with osteoarthritis ( OA ) of the knee . METHODS Forty subjects ( 20 men , 20 women ) with radiographic evidence of OA of the knee were stratified by gender and r and omly assigned to either the experimental ( real acupuncture ) or control ( sham acupuncture ) groups . Subjects were treated three times per week for 3 weeks and evaluated at three test sessions . Outcome measures were : 1 ) the Pain Rating Index of the McGill Pain Question naire , 2 ) the Western Ontario and McMaster Universities ( WOMAC ) Osteoarthritis Index , and 3 ) pain threshold at four sites at the knee . RESULTS The analyses of variance showed that both real and sham acupuncture significantly reduced pain , stiffness , and physical disability in the OA knee , but that there were no significant differences between groups . CONCLUSIONS Acupuncture is not more effective than sham acupuncture in the treatment of OA pain [18390493] Objective To investigate whether placebo effects can experimentally be separated into the response to three components— assessment and observation , a therapeutic ritual ( placebo treatment ) , and a supportive patient-practitioner relationship— and then progressively combined to produce incremental clinical improvement in patients with irritable bowel syndrome . To assess the relative magnitude of these components . Design A six week single blind three arm r and omised controlled trial . Setting Academic medical centre . Participants 262 adults ( 76 % women ) , mean ( SD ) age 39 ( 14 ) , diagnosed by Rome II criteria for and with a score of ≥150 on the symptom severity scale . Interventions For three weeks either waiting list ( observation ) , placebo acupuncture alone ( “ limited ” ) , or placebo acupuncture with a patient-practitioner relationship augmented by warmth , attention , and confidence ( “ augmented ” ) . At three weeks , half of the patients were r and omly assigned to continue in their originally assigned group for an additional three weeks . Main outcome measures Global improvement scale ( range 1 - 7 ) , adequate relief of symptoms , symptom severity score , and quality of life . Results At three weeks , scores on the global improvement scale were 3.8 ( SD 1.0 ) v 4.3 ( SD 1.4 ) v 5.0 ( SD 1.3 ) for waiting list versus “ limited ” versus “ augmented , ” respectively ( P<0.001 for trend ) . The proportion of patients reporting adequate relief showed a similar pattern : 28 % on waiting list , 44 % in limited group , and 62 % in augmented group ( P<0.001 for trend ) . The same trend in response existed in symptom severity score ( 30 ( 63 ) v 42 ( 67 ) v 82 ( 89 ) , P<0.001 ) and quality of life ( 3.6 ( 8.1 ) v 4.1 ( 9.4 ) v 9.3 ( 14.0 ) , P<0.001 ) . All pairwise comparisons between augmented and limited patient-practitioner relationship were significant : global improvement scale ( P<0.001 ) , adequate relief of symptoms ( P<0.001 ) , symptom severity score ( P=0.007 ) , quality of life ( P=0.01 ) . Results were similar at six week follow-up . Conclusion Factors contributing to the placebo effect can be progressively combined in a manner resembling a grade d dose escalation of component parts . Non-specific effects can produce statistically and clinical ly significant outcomes and the patient-practitioner relationship is the most robust component . Trial registration Clinical Trials NCT00065403 [25632577] OBJECTIVE To observe the therapeutic effect of different schemes of mild moxibustion for treatment of ( yang-deficiency induced cold-accumulation type)knee osteoarthritis ( KOA ) . METHODS Fifty-nine KOA patients were chosen and r and omly divided into control group ( n = 30 ) and test group ( n = 29 ) . Patients of the control group were treated by mild moxi- bustion of Neixiyan ( EX-HE4 ) and Waixiyan ( ST 35 ) for 30 min , once daily for 14 days ( two courses ) , and those of the test group were treated by mild moxibustion of EX-HE 4 and ST 35 for 30 mini once daily for 7 days ( the same to control group ) , followed by moxibustion of Yaoyangguan ( GV 3 ) and Mingmen ( GV 4 ) once daily for next 7 days more . In addition , patients of the two groups were also treated by routine acupuncture stimulation of EX-HE 4 , ST 35 , Yanglingquan ( GB 34 ) , Kunlun ( BL 60 ) , etc . The interval between two therapeutic courses was one day . The Lysholm Knee Score Scale ( LKSS ) was used to evaluate the therapeutic effect . Visual analogue scale ( VAS ) was employed to assess the patient 's knee-joint pain severity ( arthralgia ) , and scores of morning stiffness , arthrocele , and walking restraint degree of the knee-joint were also evaluated before and after the treatment . RESULTS After the treatment , the scores of VAS , morning stiffness , arthrocele and walking restraint degree of the knee-joint of both groups were significantly decreased ( P<0 . 05 ) , and the scores of the test group were obviously lower than those of the con- trol group ( P<0 . 05 ) . The effective rate of the test group was 89.66 % (26/29)which was obviously higher than that ( 70.00 % , 21/30 ) of the control group ( P<0 . 05 ) . CONCLUSION Mild moxibustion of Neixiyan ( EX-HE 4 ) and Waixiyan ( ST 35 , local acu- points ) , and Yaoyangguan ( GV 3 ) and Mingmen ( GV 4 ) has a better therapeutic effect for KOA patients than moxibustion of local acupoints only [23713295] OBJECTIVE To observe therapeutic efficacy of osteoarthritis treated by electroacupuncture , and explore its function of promoting cartilage restoration . METHODS According to r and om digital table , sixty cases of knee osteoarthritis ( 60 knees ) were r and omly divided into an electroacupuncture group and a physiotherapy group , 15 cases ( 30 knees ) in each one . The electroacupuncture was applied at Neixiyan ( EX-LE 4 ) , Dubi ( ST 35 ) , Heding ( EX-LE 2 ) and Xuehai ( SP 10 ) in the electroacupuncture group , once every other day . The physiotherapy group was treated by medium-frequency therapeutic apparatus every day . For both groups , 4 weeks of treatment were required . The Lysholm knee scoring scale ( LKSS ) was used to evaluate and compare the knee joints function before and after treatment . At the same time , the GE Signa EXCITE Twin Speed HD 1.5 T was used to take MRI examination of knee joints , and measure the T2 values in 10 sub-regions of the cartilage of tibiofemoral joints . RESULTS Compared before treatment , the LKSS score of both groups were improved with significant differences except item dem and s for support ( P < 0.01 , P < 0.05 ) . Between the two groups after treatment , there were significant differences on total score , item instability and swelling ( all P < 0.05 ) , the electroacupuncture group was better than the physiotherapy group , but no significant difference on the other items ( all P > 0.05 ) . In the electroacupuncture group after treatment , T2 value in anterior lateral tibial sub-region ( LTa ) was significantly lowered ( P < 0.05 ) , but no significant difference in the other nine sub-regions ( all P > 0.05 ) . In the physiotherapy group , T2 value in any sub-region was not significantly different before and after treatment ( all P > 0.05 ) . CONCLUSION Electroacupuncture could effectively improve the symptom , sign and knee joint 's function of patients with knee osteoarthritis . Compared with physiotherapy , it has more superior effect and considered as a better non-operative treatment for osteoarthritis . Electroacupuncture also has positive influence on T2 value in cartilage , indicating that electroacupuncture may have the function of promoting cartilage restoration [23713297] OBJECTIVE To observe the long-term efficacy and safety of warm needling therapy combined with rehabilitation training in the treatment of knee osteoarthritis ( KOA ) for the patients living in simple room after earthquake . METHODS Eighty-eight cases of KOA were r and omized into a warm needling group and an acupuncture group , 44 cases in each one . In the warm needling group , the warm needling therapy was applied at Neixiyan ( EX LE 4 ) and Dubi ( ST 35 ) , in combination with rehabilitation training . In the acupuncture group , the same rehabilitation training was received , and the same acupoints were selected as the warm needling group , but only stimulated with acupuncture without moxibustion applied . The clinical efficacy was observed after 20 treatments and in 1 - 2 months of follow-up . RESULTS The total effective rate was 100.0 % ( 41/41 ) in the warm needling group , which was apparently superior to 85.4 % ( 35/41 ) in the acupuncture group ( P < 0.05 ) . The symptom integral , pain and knee joint function score were all improved significantly after 20 treatments in both groups ( all P < 0.05 ) . The improvements in symptoms and pain in the warm needling group were superior apparently to the acupuncture group ( all P < 0.05 ) . The efficacy remained well within 2 months follow-up ( all P < 0.05 ) . But the difference in knee joint function score was not statistically significant between the two groups ( all P > 0.05 ) . CONCLUSION The combined therapy of warm needling and rehabilitation training achieves the superior efficacy and good safety in the treatment of KOA as compared with the combined therapy of simple acupuncture and rehabilitation training for the patients living in simple room after earthquake [12972723] Background : We report on the study design and protocol s of two r and omized controlled trials ( Acupuncture R and omized Trials = ART ) that investigate the efficacy of acupuncture in the treatment of chronic low back pain and osteoarthritis of the knee , respectively . Objective : To investigate whether acupuncture is more efficacious than ( a ) no treatment or ( b ) minimal acupuncture in the treatment of low back pain and osteoarthritis . Design : Two r and omized , controlled , multicenter trials with three treatment arms and a total follow-up time of 52 weeks . Setting : 30 practitioners and outpatient units in Germany specialized in acupuncture treatment . Patients : 300 patients will be included in each study . In the low back pain trial , patients will be included according to clinical diagnosis . In the osteoarthritis pain trial , patients will be included according to the American College of Rheumatology criteria . Interventions : Patients are r and omly assigned to receive either ( 1 ) semi-st and ardized acupuncture ( 150 patients ) , ( 2 ) minimal acupuncture at non-acupuncture points ( 75 patients ) , or ( 3 ) no treatment for two months followed by semi-st and ardized acupuncture ( 75 patients , waiting list control ) . Acupuncture treatment consists of 12 sessions per patient over a period of 8 weeks . Main Outcome Measure : The main outcome measure is the difference between baseline and the end of the 8-week treatment period in the following parameters : pain intensity as measured by a visual analogue scale ( VAS ; 0–100 mm ) in the low back pain trial and by the Western Ontario and McMaster Universities Osteoarthritis Score ( WOMAC ) in the osteoarthritis trial . Outlook : The results of these two studies ( available in 2004 ) will provide health care providers and policy makers with the information needed to make scientifically sound assessment s of acupuncture therapy [25998755] Background In China , heat-sensitive moxibustion ( HSM ) is used for knee osteoarthritis ( KOA ) to reduce pain and improve physical activity . However , there is little high- quality evidence of its effectiveness . Objective To evaluate the effectiveness of HSM in the treatment of KOA compared with usual care . Methods We performed a multicentre , r and omised controlled trial . In total , 432 patients with KOA were r and omly assigned to one of three groups ( HSM , conventional moxibustion , or conventional injection with sodium hyaluronate ) . The primary end point was the guiding principle of clinical research on new drugs in the treatment of KOA ( GPCRND-KOA ) . Measurements were obtained at baseline and after 1 and 6 months ( month 7 ) of study . Result For GPCRND-KOA , there were significant differences among the three groups after treatment at months 1 and 7 . Pairwise comparisons showed that HSM was more effective than the conventional drug . There was no difference in any measures between conventional moxibustion and the conventional drug . Compared with conventional moxibustion , HSM result ed in greater improvement in all outcomes . Conclusions This trial provided some evidence of the superiority of HSM in patients with KOA , suggesting that the observed differences might be due to superiority effects of a heat-sensitive point , although the effect of expectation can not be ruled out . Trial Registration Number The trial was registered at Controlled Clinical Trials : ChiCTR-TRC-09000600 [1514335] Purpose : Acupuncture treatment of patients waiting for arthroplasty surgery . Methods : 29 patients with a total of 42 osteoarthritic knees were r and omized to two groups . Group A was treated while Group B served as a no‐treatment control group . After 9 weeks Group B was treated too . Analgesic consumption , pain and objective measurements were registered . All objective measures were done by investigators who were “ blinded ” as to Group A & B. In the second part of the study 17 patients ( 26 knees ) continued with treatments once a month . Registration of analgesic consumption , pain and objective measurements continued . Total study period 49 weeks . Results : Comparing Group A to B there was a significant reduction in pain , analgesic consumption and in most objective measures . In Group A + B combined there was an 80 % subjective improvement , and a significantly increased knee range movement – an increase mainly in the worst knees . Results were significantly better in those who had not been ill for a long time . In the second part of the study , it was shown that it was possible to maintain the improvements . Conclusions : Acupuncture can ease the discomfort while waiting for an operation and perhaps even serve as an alternative to surgery . Seven patients have responded so well that at present they do not want an operation . ( USD 9000 saved per operation ) [3068365] Within the context of a double blind r and omized controlled parallel trial of 2 nonsteroidal antiinflammatory drugs , we vali date d WOMAC , a new multidimensional , self-administered health status instrument for patients with osteoarthritis of the hip or knee . The pain , stiffness and physical function subscales fulfil conventional criteria for face , content and construct validity , reliability , responsiveness and relative efficiency . WOMAC is a disease-specific purpose built high performance instrument for evaluative research in osteoarthritis clinical trials [26502544] OBJECTIVE To observe the clinical effect of acupuncture plus shock-wave ( SW ) intervention for osteoarthritis ( WA ) , so as to explore its practicability in clinical practice . METHODS A total of 120 cases of knee OA patients were r and omly divided into 4 groups , namely acupuncture ( acupunct ) + LFSW , acupunct + MFSW , acupunct + HFSW and routine acupunct groups , with 30 cases in each group . Xuehai ( SP 10 ) , Liangqiu ( ST 34 ) , Yanglingquan ( GB 34 ) , Xiyan ( ST 35 ) and Ashi-point were punctured with filiform needles which were manipulated with uniform reinforcing-reducing techniques for 15 - 20 min , once every other day for 7 times . In addition , these acupoints were also respectively stimulated with shock waves(10 Hz , 14 Hz and 18 Hz , pressure : 1 - 4 bar ) delivered from a DolorClastEMS therapeutic apparatus for 600 times in 3 acupunct+ SW groups . The patients ' pain response changes of the knee-joint were assessed by using visual analog scale ( VAS ) and the motility was evaluated by using a 0 - 3 grade scale . RESULTS After 7 times of treatment , the patients ' VAS scores and motility scores were significantly decreased in the acupunct+ LFSW , acupunct+ MFSW , acupunct+ HFSW and routine acupunct groups compared with their own basic values before treatment ( P < 0.01 ) , and the therapeutic effect of the acupunct+ MFSW group was significantly superior to those of the other 3 groups in reducing both VAS and motility scores ( P < 0.05 ) . Correspondingly , the Deqi sensation score of the acupunct+ MFSW group was markedly higher than those of the other 3 groups ( P < 0.05 ) . CONCLUSION Shock wave acu-puncture treatment is effective in relieving OA patients ' knee-joint pain and functional activity , and the therapeutic effect of acu- punct + 14 Hz-SW is better , which is closely with Deqi-sensation [24195209] OBJECTIVE To explore a better therapy for knee osteoarthritis . METHODS One hundred cases were r and omly divided into a comprehensive group and an acupuncture group , 50 cases in each one . The comprehensive treatment of fire needles at bones combined with cupping and Tuina on local area of affected knee was applied in the comprehensive group . The Ashi points were mainly selected in the fire needles at bones therapy , once every other day . The cupping and Tuina therapy was adopted once a day . The conventional acupuncture was applied in the acupuncture group , in which Dubi ( ST 35 ) , Neixiyan ( EX-LE 4 ) , Xuehai ( SP 10 ) , Liangqiu ( ST 34 ) and so on were selected , once a day . Ten days of treatment were taken as a treatment course in both two groups , and totally 1 to 2 courses was required . The pain score of joint before and after the treatment was observed and efficacy was assessed in two groups . RESULTS Compared before the treatment , the pain score of joint after the treatment was obviously improved in two groups ( both P<0.05 ) , and the score in the comprehensive group was lower than that in the acupuncture group ( P<0.05 ) . The clinical cured rate was 38.0 % ( 19/50 ) , which was superior to 20.0 % ( 10/50 ) in the acupuncture group . CONCLUSION The comprehensive treatment of fire needles at bones combined with cupping and Tuina , considered as a better therapy for knee osteoarthritis , could improve joint pain , swelling and action function , which is superior to the conventional acupuncture [24377213] OBJECTIVE To compare the difference of the efficacy on knee osteoarthritis ( KOA ) between the combined therapy of acupuncture and moxibustion and western medication , and explore the better therapeutic method for KOA . METHODS One hundred and sixty patients were divided into a combined therapy group and a western medication group , 80 cases in each one according to the visit sequence , with the r and om number table adopted . In the combined therapy group , the main points were selected from the local painful sites , combined with the acupoints based on the syndrome differentiation and distal acupoints on the affected meridians . The lifting , thrusting or rotating technique was used and the reinforcing or reducing manipulation was applied according to the syndrome differentiation . " Duanci " or " Shuci " needling technique was used specially at the extra points and Ashi points . The needling sensation relied on the patients ' tolerance . After acupuncture , the heat-sensitive moxibustion with pure moxa stick was applied over the local painful sites around knee joint and Shenshu ( BL 23 ) to detect the heat-sensitized points . Acupuncture and moxibustion were given once every day . The treatment of 5 days made 1 session . There were 2 days at the interval between two sessions . In the western medication group , glucosamine sulfate capsules were prescribed for oral administration , 2 capsules each time , three times a day . Additionally , the joint cavity injection was combined . On the first day , sodium hyaluronate 25 mg and triamcinolone acetonide acetate 50 mg were injected . Afterwards , on the 8th , 15th , 22nd and 29th days , sodium hyaluronate injection 25 mg was used only . The treatment was for 5 weeks totally in the two groups . The efficacy was analyzed statistically in 5 weeks . The follow-up visit was conducted in 3 months and 6 months after 5 weeks treatment , respectively . The Western Ontario and Mcmaster Universities Osteoarthritis Index ( WOMAC ) and visual analogue scale ( VAS ) were adopted to assess the recovery of joint function . RESULTS The efficacy in 5 weeks of treatment was different significantly between the two groups ( P < 0.05 ) . The efficacy in the western medication group was better than that in the combined therapy group . The difference in the safety assessment was remarkable ( P < 0.01 ) . The result in the combined therapy group was superior remarkably to the western medication group . In 3-month follow-up visit after treatment , the knee joint function was not different obviously between the two groups ( P > 0.05 ) . In 6-month followup visit after treatment , the knee joint function was different obviously between the two groups ( P < 0.01 ) . The result in the combined therapy group was better remarkably than that in the western medication group . CONCLUSION The combined therapy of acupuncture and moxibustion achieves the safe and effective therapeutic effect with less adverse reactions in the treatment of KOA . The immediate effect in the combined therapy group is not so obvious as compared with the western medication , but the long-term efficacy is remarkably superior to western medication [3524727] Twenty-five out- patients with chronic neck pain participated in a prospect i ve , r and omized trial of acupuncture versus placebo transcutaneous nerve stimulation . A single-blind , non-cross-over design incorporated several outcome measures in an attempt to determine any particular facet of pain that responded to acupuncture . No significant difference between the two treatments was found either post-treatment or at follow-up . Whilst the small population studied limits the conclusions that may be drawn , these findings suggest that acupuncture may have no greater effect than that of a powerful placebo [26770523] BACKGROUND To assess the efficacy of Electroacupuncture ( EA ) stimulation with high-intensity compared with low-intensity on knee osteoarthritis ( KOA ) . METHODS Participants with KOA were r and omized to either high-intensity EA group or low-intensity EA group . EA was applied unilaterally on the affected leg with the local points GB34 , ST34 , EX-LE4 , EX-LE5 , ST36 , and SP9 . The visual analogue scale ( VAS ) and the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) were measured before and after participation . Plasma TNFα , IL-1β , IL-6 , and apelin levels were also assessed by enzyme immunoassay ( ELA ) before and after treatment . RESULTS Of 80 participants who consented to study participation , 77 completed the program . The patients showed a significant improvement in their pain , stiffness , and physical function on the VAS and WOMAC , accompanying with a significantly reduction in plasma levels of apelin and TNFα . Furthermore , high-intensity group exhibited statistically significant improvements in stiffness and physical function symptoms compared with low-intensity group . Plasma level of IL-6 was significantly decreased only after high-intensity EA treatment . Furthermore , apelin level was significantly inhibited in high-intensity EA group than in low-intensity EA group . CONCLUSIONS Both high- and low-intensity EA treatments alleviate the clinical symptoms of KOA patients . High-intensity EA is more effective than low-intensity EA . Changes in plasma levels of TNFα , apelin and IL-6 may be involved in the therapeutic effect of EA on KOA [11532841] Recent reports have highlighted the importance of having good evidence on the safety of acupuncture . 1 2 Sound evidence on the risks associated with acupuncture is , however , scarce.3 Our primary aim , therefore , was to describe the type and frequency of adverse events after acupuncture . A secondary aim was to examine mild transient reactions associated with acupuncture , some of which may indicate a positive response to treatment . The study involved a prospect i ve postal audit of treatments undertaken during a four week period in 2000 . All 1848 professional acupuncturists who were members of the British Acupuncture Council and were practising in the United Kingdom were invited to record details of adverse events and mild transient reactions after treatment . St and ardised self report forms were used . Participating practitioners also provided information on themselves , including age , sex , length of training , and years of practice . To have a [11532840] Acupuncture is increasingly popular , but it is not free from risk for the patient.1 Safety is best established with prospect i ve surveys . Our aim was to ascertain the incidence of adverse events related to acupuncture treatment , as currently practised in Britain by doctors and physiotherapists . Volunteer acupuncture practitioners were recruited through journals circulated to members of the British Medical Acupuncture Society and the Acupuncture Association of Chartered Physiotherapists ( approximately 2750 members).2 A prospect i ve survey was undertaken using forms for intensive event monitoring that had been piloted previously.3 Minor adverse events were defined as “ any ill-effect , no matter how small , that is unintended and non-therapeutic , even if not unexpected . ” These events were reported every month , along with the total number of consultations . Minor or serious events that were considered to be “ significant”—“unusual , novel , dangerous , significantly inconvenient , or requiring further information”—were reported on separate forms when they occurred . Anonymous reporting was accepted . A sample size of [18356795] Background There is evidence for the efficacy of acupuncture treatment in knee osteoarthritis , but it remains unclear which acupuncture modes are most effective . We evaluated the effects of trigger point acupuncture on pain and quality of life in knee osteoarthritis patients , compared with acupuncture at st and ard points , and sham acupuncture . Methods Thirty patients ( 27 women , 3 men ; aged 61–82 years ) with non-radiating knee osteoarthritis pain for at least six months and normal neurological examination were r and omised to one of three groups for the study period of 21 weeks . Each group received five acupuncture treatment sessions . The st and ard acupuncture point group ( n=10 ) received treatment at traditional acupuncture points for knee pain ; the trigger point acupuncture group ( n=10 ) received treatment at trigger points ; and the third group ( n=10 ) received sham acupuncture treatment at the trigger points . Outcome measures were pain intensity ( visual analogue scale , VAS ) and WOMAC index ( Western Ontario and McMaster Universities Arthritis Index ) . The groups were compared by the area under the curve method . Results Five patients dropped out of the study because of lack of improvement , and one patient ( in the trigger point acupuncture group ) dropped out because of deterioration of symptoms ; the remaining 24 patients were included in the analysis . After treatment , the trigger point acupuncture group reported less pain intensity on VAS than the st and ard acupuncture or sham treatment group , but both the trigger point acupuncture and st and ard acupuncture groups reported improvement of function of knee . There was a significant reduction in pain intensity between pre-treatment and five weeks after treatment for the trigger point acupuncture ( P<0.01 ) and st and ard acupuncture groups ( P<0.01 ) included in the analysis , but not for the sham treatment group . Group comparison using the area under the curves demonstrated a significant difference only between trigger point acupuncture and sham treatment groups analysed ( P<0.025 for VAS , and P<0.031 for WOMAC ) . Conclusion These results suggest that trigger point acupuncture therapy may be more effective for osteoarthritis of the knee in some elderly patients than st and ard acupuncture therapy [24566612] Objective To compare the immediate effects of electroacupuncture and manual acupuncture on pain , mobility and muscle strength in patients with knee osteoarthritis . Methods Sixty patients with knee osteoarthritis , with a pain intensity of ≥2 on the pain Numerical Rating Scale , were included . The patients were r and omised into two groups : manual acupuncture and electroacupuncture . Pain intensity , degree of dysfunction ( Timed Up and Go ( TUG ) test ) , maximal voluntary isometric contraction and pressure pain threshold were assessed before and after a single session of manual acupuncture or electroacupuncture treatments . Results Both groups showed a significant reduction in pain intensity ( p<0.001 ) and time to run the TUG test after the acupuncture treatment ( p=0.005 for the manual acupuncture group and p=0.002 for the electroacupuncture group ) . There were no differences between the groups regarding pain intensity ( p=0.25 ) , TUG test ( p=0.70 ) , maximum voluntary isometric contraction ( p=0.43 ) or pressure pain threshold ( p=0.27 ) . Conclusions This study found no difference between the immediate effects of a single session of manual acupuncture and electroacupuncture on pain , muscle strength and mobility in patients with knee osteoarthritis . Trial Registration Number RBR-9TCN2X [16259309] Objective To explore the type and frequency of short term reactions associated with a single acupuncture treatment . Methods As part of recruitment to a large-scale prospect i ve survey of the safety of acupuncture , 9408 consecutive patients each completed one survey form soon after receiving treatment with acupuncture , and returned it directly to the research centre . On this form , patients were asked to report on a range of possible short term reactions relating to their most recent acupuncture treatment using a checklist of options . Results At least one short term reaction to acupuncture during or immediately after treatment was reported by 94.6 % ( CI 94.2 to 95.1 ) of patients , an average of 1.8 reactions per patient . The most common experiences reported were feeling ‘ relaxed ’ ( 79.1 % ) followed by feeling ‘ energised ’ ( 32.7 % ) . A total of 24.4 % of patients reported ‘ tiredness ’ or ‘ drowsiness ’ , with obvious implication s for safety if the patient intended to drive after treatment . ‘ Negative ’ reactions , such as pain and bruising at the site of needling , were reported by 29.7 % of patients who were more likely to be female patients ( OR 1.58 ) , patients under the age of 40 ( OR 1.62 ) , patients who had consulted their GP or hospital specialist beforeh and ( OR 1.30 ) , patients consulting their acupuncturist for the first time ( OR 1.24 ) , and patients treated by an acupuncturist with less than two years ’ experience since qualification ( OR 1.24 ) . Only 13 patients were unwilling to have acupuncture again as a result of these short term reactions . Conclusion In this large cross-sectional study , extensive patient reports showed that ‘ positive ’ reactions to acupuncture treatment were very common . Tiredness , drowsiness and a range of ‘ negative ’ reactions were also frequently reported . Almost all patients were willing to experience these reactions again [24377216] OBJECTIVE To verify the clinical efficacy of shu-stream point acupuncture combined with fire needle therapy in the treatment of h and osteoarthritis . METHODS Eighty cases were r and omized into an acupuncture group ( shu-stream point acupuncture combined with fire needle therapy ) and a medication group(votalin emulgel ) . For the 42 cases in the acupuncture group , acupuncture at shu-stream points on the three yang meridians of the h and including Sanjian ( LI 3 ) , Zhongzhu ( TE 3 ) , Houxi ( SI 3 ) and fire needle at Ashi points were applied , the treatments were given once every other day , 15 times as a treatment course . For the 38 cases in the medication group , votalin emulgel was prescribed for local embrocation , twice a day , 30 days as a treatment course . The visual analogue scale ( VAS ) of arthralgia , joint function score and the duration of morning stiffness , joint tenderness , swelling were observed before and after treatment in both groups . RESULTS After two courses of clinical treatment , the VAS score of arthralgia , joint function score and the duration of morning stiffness , joint tenderness , swelling were statistically significant differences as compared with before treatment ( all P < 0.01 ) , the efficacy in the acupuncture group was superior to that in the medication group ( all P < 0.01 ) . The cured-markedly effective rate and total effective rate were 61.9 % ( 26/42 ) and 95.2 % ( 40/42 ) in the acupuncture group , and 36.8 % ( 14/38 ) and 76.3 % ( 29/38 ) in the medication group respectively , with statistically significant differences between the two groups ( both P < 0.05 ) . CONCLUSION Shu-stream point acupuncture combined with fire needle therapy achieves a significant efficacy in the treatment of h and osteoarthritis [21751905] BACKGROUND In prospect i ve experimental studies in patients with asthma , it is difficult to determine whether responses to placebo differ from the natural course of physiological changes that occur without any intervention . We compared the effects of a bronchodilator , two placebo interventions , and no intervention on outcomes in patients with asthma . METHODS In a double-blind , crossover pilot study , we r and omly assigned 46 patients with asthma to active treatment with an albuterol inhaler , a placebo inhaler , sham acupuncture , or no intervention . Using a block design , we administered one each of these four interventions in r and om order during four sequential visits ( 3 to 7 days apart ) ; this procedure was repeated in two more blocks of visits ( for a total of 12 visits by each patient ) . At each visit , spirometry was performed repeatedly over a period of 2 hours . Maximum forced expiratory volume in 1 second ( FEV(1 ) ) was measured , and patients ' self-reported improvement ratings were recorded . RESULTS Among the 39 patients who completed the study , albuterol result ed in a 20 % increase in FEV(1 ) , as compared with approximately 7 % with each of the other three interventions ( P<0.001 ) . However , patients ' reports of improvement after the intervention did not differ significantly for the albuterol inhaler ( 50 % improvement ) , placebo inhaler ( 45 % ) , or sham acupuncture ( 46 % ) , but the subjective improvement with all three of these interventions was significantly greater than that with the no-intervention control ( 21 % ) ( P<0.001 ) . CONCLUSIONS Although albuterol , but not the two placebo interventions , improved FEV(1 ) in these patients with asthma , albuterol provided no incremental benefit with respect to the self-reported outcomes . Placebo effects can be clinical ly meaningful and can rival the effects of active medication in patients with asthma . However , from a clinical -management and research - design perspective , patient self-reports can be unreliable . An assessment of untreated responses in asthma may be essential in evaluating patient-reported outcomes . ( Funded by the National Center for Complementary and Alternative Medicine . ) [17075849] OBJECTIVE To investigate the effectiveness of acupuncture in addition to routine care , compared with routine care alone , in the treatment of patients with chronic pain due to osteoarthritis ( OA ) of the knee or hip . METHODS In a r and omized , controlled trial , patients with chronic pain due to OA of the knee or hip were r and omly allocated to undergo up to 15 sessions of acupuncture in a 3-month period or to a control group receiving no acupuncture . Another group of patients who did not consent to r and omization underwent acupuncture treatment . All patients were allowed to receive usual medical care in addition to the study treatment . Clinical OA severity ( Western Ontario and McMaster Universities Osteoarthritis Index [ WOMAC ] ) and health-related quality of life ( Short Form 36 ) were assessed at baseline and after 3 months and 6 months . RESULTS Of 3,633 patients ( mean + /- SD age 61.8 + /- 10.8 years ; 61 % female ) , 357 were r and omized to the acupuncture group and 355 to the control group , and 2,921 were included in the nonr and omized acupuncture group . At 3 months , the WOMAC had improved by a mean + /- SEM of 17.6 + /- 1.0 in the acupuncture group and 0.9 + /- 1.0 in the control group ( 3-month scores 30.5 + /- 1.0 and 47.3 + /- 1.0 , respectively [ difference in improvement 16.7 + /- 1.4 ; P < 0.001 ] ) . Similarly , quality of life improvements were more pronounced in the acupuncture group versus the control group ( P < 0.001 ) . Treatment success was maintained through 6 months . The changes in outcome in nonr and omized patients were comparable with those in r and omized patients who received acupuncture . CONCLUSION These results indicate that acupuncture plus routine care is associated with marked clinical improvement in patients with chronic OA-associated pain of the knee or hip [9717924] BACKGROUND A problem acupuncture research has to face is the concept of a control group . If , in control groups , non-acupoint needling is done , physiological acupuncture effects are implied . Therefore the effects shown in this group are often close to those shown in the acupuncture group . In other trials , control groups have received obviously different treatments , such as transcutaneous electrical nervous stimulation or TENS-laser treatment ; it is not clear if the effects of acupuncture are due only to the psychological effects of the treatment . METHODS We developed a placebo acupuncture needle , with which it should be possible to simulate an acupuncture procedure without penetrating the skin . In a cross-over experiment with 60 volunteers we tested whether needling with the placebo needle feels any different from real acupuncture . FINDINGS Of 60 volunteers , 54 felt a penetration with acupuncture ( mean visual analogue scale [ VAS ] 13.4 ; SD 10.58 ) and 47 felt it with placebo ( VAS 8.86 ; SD 10.55 ) , 34 felt a dull pain sensation ( DEQI ) with acupuncture and 13 with placebo . None of the volunteers suspected that the needle may not have penetrated the skin . INTERPRETATION The placebo needle is sufficiently credible to be used in investigations of the effects of acupuncture [11452568] OBJECTIVE To determine whether demographic , medical history , or arthritis assessment data may influence outcome and rate of decay for patients with osteoarthritis treated with acupuncture . DESIGN Seventy-three persons with symptomatic osteoarthritis of the knee were recruited for this r and omized controlled trial . Both treatment and crossover control groups received acupuncture treatments twice weekly for 8 weeks . Patients self-scored on the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) and the Lequesne Algofunctional Index at baseline and 4 , 8 , and 12 weeks . Sample size for this outcome analysis was 60 patients at 4 weeks , 58 at 8 weeks , and 52 at 12 weeks . RESULTS Patients ' scores on both indexes improved at 4 , 8 , and 12 weeks . Scores were stable regardless of the baseline severity of the osteoarthritis . Despite some decay in outcomes at week 12 , measures were significantly improved over baseline . With WOMAC scores partitioned into equal quartiles , a strong effect on outcome was apparent at 12 weeks ( 4 weeks after treatment ) related to initial WOMAC scores . The group with the least disability and pain rebounded to original levels to a greater degree than did those who initially were more disabled . The more disabled groups retained the benefits of acupuncture treatment through the 12-week period . CONCLUSION Acupuncture for patients with osteoarthritis of the knee may best be used early in the treatment plan , with a method ical decrease in frequency in treatment once the acute treatment period is completed to avoid a rebound effect . Demographic and medical history data were not mediating variables [23965480] Background Knee osteoarthritis is a chronic disease associated with significant morbidity and economic cost . The efficacy of acupuncture in addition to traditional physical therapy has received little study . Objective The objective of this study was to compare the efficacy and safety of integrating a st and ardized true acupuncture protocol versus nonpenetrating acupuncture into exercise-based physical therapy ( EPT ) . Methods This was a r and omized , double-blind , controlled trial at 3 physical therapy centers in Philadelphia , PA . We studied 214 patients ( 66 % African Americans ) with at least 6 months of chronic knee pain and x-ray – confirmed Kellgren scores of 2 or 3 . Patients received 12 sessions of acupuncture directly following EPT over 6 to 12 weeks . Acupuncture was performed at the same 9 points dictated by the traditional Chinese “ Bi ” syndrome approach to knee pain , using either st and ard needles or Streitberger non – skin-puncturing needles . The primary outcome was the proportion of patients with at least a 36 % improvement in Western Ontario and McMaster Universities Osteoarthritis Index score at 12 weeks . Results Both treatment groups showed improvement from combined therapy with no difference between true ( 31.6 % ) and nonpenetrating acupuncture ( 30.3 % ) in Western Ontario and McMaster Universities Osteoarthritis Index response rate ( P = 0.5 ) or report of minor adverse events . A multivariable logistic regression prediction model identified an association between a positive expectation of relief from acupuncture and reported improvement . No differences were noted by race , sex , or age . Conclusions Puncturing acupuncture needles did not perform any better than nonpuncturing needles integrated with EPT . Whether EPT , acupuncture , or other factors accounted for any improvement noted in both groups could not be determined in this study . Expectation for relief was a predictor of reported benefit [23380214] OBJECTIVE The purpose of this preliminary study was to examine whether collateral meridian ( CM ) therapy was feasible in treating knee osteoarthritis ( OA ) pain . METHODS Twenty-eight patients with knee OA and knee pain were r and omly allocated to 2 groups . The CM group patients received CM therapy , whereas the control patients received placebo treatment for knee pain relief . Patients in the CM group received 2 CM treatments weekly for 3 weeks . The outcome measures were pain intensity on a visual analog scale , and knee function was determined using the Western Ontario and McMaster Universities Osteoarthritis Index . RESULTS In the CM group , the posttreatment visual analog scale and Western Ontario and McMaster Universities Osteoarthritis Index scores were lower than those of the control group ; a significant reduction in pain intensity ( P = .02 , P = .01 , respectively ) and improvement in knee function ( P = .04 , P = .03 , respectively ) were shown in the CM group at the second and third week . CONCLUSION Collateral meridian therapy may be feasible and effective for knee OA pain relief and knee function recovery . Therefore , additional r and omized control trials are warranted [27348903] OBJECTIVE To evaluate the clinical efficacy of YANG 's pricking-cupping therapy for knee osteoar thritis ( KOA ) . Methods This was a multi-center r and omized parallel controlled trial . One hundred and seventy one patients with KOA were r and omly allocated to a pricking-cupping group ( 89 cases ) and a conventional acu puncture group ( 82 cases ) . Neixiyan ( EX-LE 4 ) , Dubi ( ST 35 ) and ashi points were selected in the two groups . Patients in the pricking-cupping group were treated with YANG 's pricking-cupping therapy ; the seven-star needles were used to perform pricking at acupoints , then cupping was used until slight bleeding was observed . Patients in the conventional acupuncture group were treated with semi-st and ardized filiform needle therapy . The treatment was given for 4 weeks ( from a minimum of 5 times to a maximum of 10 times ) . The follow-up visit was 4 weeks . The Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) and the visual analogue scale ( VAS ) were adopted for the efficacy assessment s. RESULTS The pain score , stiffness score , physical function score and total score of WOMAC were all reduced after 4-week treatment and during follow-up visit in the two groups ( all P<0 . 0001 ) . Except that the difference of stiffness score between the two groups was not significant after 4-week treatment ( P>0 . 05 ) , each score and total score of WOMAC in the pricking-cupping group were lower than those in the conventional acupuncture group after 4-week treatment and during follow-up visit ( P<0 . 0001 , P<0 . 01 ) . After 2-week treatment , 4-week treatment and during follow-up visit , the VAS was all reduced compared with that before treatment ( all P<0 . 0001 ) ; with the increase of the treatment , the reducing trend of VAS was more significant ( P<0 . 0001 ) . The scores of VAS in the pricking-cupping group were lower than those in the conventional acupuncture group after 4-week treatment and during follow-up visit ( P < 0 . 01 , P < 0 . 0001 ) . CONCLUSION The YANG 's pricking-cupping and conventional acupuncture therapy can both significantly improve knee joint pain and function in patients with KOA , which are relatively safe . The pricking cupping therapy is superior to conventional acupuncture with the identical selection of acupoints [15208174] BACKGROUND In clinical trials , at the group level , results are usually reported as mean and st and ard deviation of the change in score , which is not meaningful for most readers . OBJECTIVE To determine the minimal clinical ly important improvement ( MCII ) of pain , patient 's global assessment of disease activity , and functional impairment in patients with knee and hip osteoarthritis ( OA ) . METHODS A prospect i ve multicentre 4 week cohort study involving 1362 out patients with knee or hip OA was carried out . Data on assessment of pain and patient 's global assessment , measured on visual analogue scales , and functional impairment , measured on the Western Ontario McMaster Universities Osteoarthritis Index ( WOMAC ) function subscale , were collected at baseline and final visits . Patients assessed their response to treatment on a five point Likert scale at the final visit . An anchoring method based on the patient 's opinion was used . The MCII was estimated in a subgroup of 814 patients ( 603 with knee OA , 211 with hip OA ) . RESULTS For knee and hip OA , MCII for absolute ( and relative ) changes were , respectively , ( a ) -19.9 mm ( -40.8 % ) and -15.3 mm ( -32.0 % ) for pain ; ( b ) -18.3 mm ( -39.0 % ) and -15.2 mm ( -32.6 % ) for patient 's global assessment ; ( c ) -9.1 ( -26.0 % ) and -7.9 ( -21.1 % ) for WOMAC function subscale score . The MCII is affected by the initial degree of severity of the symptoms but not by age , disease duration , or sex . CONCLUSION Using criteria such as MCII in clinical trials would provide meaningful information which would help in interpreting the results by expressing them as a proportion of improved patients [11824949] OBJECTIVE To estimate minimal clinical ly important differences ( MCID ) of effects measured by the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) in patients with osteoarthritis ( OA ) of the lower extremities undergoing a comprehensive inpatient rehabilitation intervention . METHODS A prospect i ve cohort study assessed patients ' health by the WOMAC at baseline ( entry into the clinic ) and at the 3 month followup , and by a transition question naire asking about the change of " health in general related to the OA joint " during that time period . The WOMAC section score differences between the " equal " group and the " slightly better " and " slightly worse " groups result ed in the MCID for improvement and for worsening . RESULTS In total 192 patients were followed up . The MCID for improvement ranged from 0.80 to 1.01 points on the continuous WOMAC numerical rating scale from 0 to 10 , reflecting changes of 17 to 22 % of baseline scores . The MCID for worsening conditions ranged from 0.29 ( 6 % ) to 1.03 points ( 22 % ) . In the transition reply subjectively unchanged patients reported a " pessimistic bias " of 0.35 to 0.51 points , except for the stiffness section . Both MCID and pessimistic bias showed regression to the mean and baseline dependency . CONCLUSION The assessment of MCID using the transition method is a heuristic and valid strategy to detect particular rehabilitation effects in patients with OA of the lower extremities with the use of the WOMAC , and it is worth implementing . The size of the MCID and of the systematic bias is comparable to that assessed by other methods and in other therapeutic setting [17699546] Objective To investigate the benefit of adding acupuncture to a course of advice and exercise delivered by physiotherapists for pain reduction in patients with osteoarthritis of the knee . Design Multicentre , r and omised controlled trial . Setting 37 physiotherapy centres accepting primary care patients referred from general practitioners in the Midl and s , United Kingdom . Participants 352 adults aged 50 or more with a clinical diagnosis of knee osteoarthritis . Interventions Advice and exercise ( n=116 ) , advice and exercise plus true acupuncture ( n=117 ) , and advice and exercise plus non-penetrating acupuncture ( n=119 ) . Main outcome measures The primary outcome was change in scores on the Western Ontario and McMaster Universities osteoarthritis index pain subscale at six months . Secondary outcomes included function , pain intensity , and unpleasantness of pain at two weeks , six weeks , six months , and 12 months . Results Follow-up rate at six months was 94 % . The mean ( SD ) baseline pain score was 9.2 ( 3.8 ) . At six months mean reductions in pain were 2.28 ( 3.8 ) for advice and exercise , 2.32 ( 3.6 ) for advice and exercise plus true acupuncture , and 2.53 ( 4.2 ) for advice and exercise plus non-penetrating acupuncture . Mean differences in change scores between advice and exercise alone and each acupuncture group were 0.08 ( 95 % confidence interval −1.0 to 0.9 ) for advice and exercise plus true acupuncture and 0.25 ( −0.8 to 1.3 ) for advice and exercise plus non-penetrating acupuncture . Similar non-significant differences were seen at other follow-up points . Compared with advice and exercise alone there were small , statistically significant improvements in pain intensity and unpleasantness at two and six weeks for true acupuncture and at all follow-up points for non-penetrating acupuncture . Conclusion The addition of acupuncture to a course of advice and exercise for osteoarthritis of the knee delivered by physiotherapists provided no additional improvement in pain scores . Small benefits in pain intensity and unpleasantness were observed in both acupuncture groups , making it unlikely that this was due to acupuncture needling effects . Trial registration Current Controlled Trials IS RCT N88597683 [25029834] OBJECTIVE To study the synergistic effects of electroacupuncture on the treatment of knee osteoarthritis after arthroscopic debridement . METHODS From May 2008 to July 2010 , 78 patients with knee osteoarthritis were r and omly divided into two groups . There were 42 patients in the experimental group , including 16 males and 26 females , ranging in age from 41 to 63 years , with an average of ( 53.62 + /- 6.53 ) years ; the disease course ranged from 8 to 24 months , with an average of ( 10.35 + /- 6.42 ) months . The patients were treated with arthroscopic debridement combined with electroacupuncture after operation . There were 36 patients in the control group , including 14 males and 22 females , ranging in age from 40 to 62 years , with an average of ( 54.34 + /- 7.67 ) years ; the disease course ranged from 6 to 25 months , with an average of ( 11.94 + /- 5.13 ) months . Those patients were treated only with arthroscopic debridment . All the patients performed isometric quadriceps femoris contraction exercise and knee flexion and extension activities after operation . The visual analog scale(VAS ) score and Lysholm knee score were used to evaluate the therapeutic effects . RESULTS All the patients were followed up , and the duration ranged from 12 to 30 months , with an average of 15.6 months . At the final follow-up , VAS score was significantly decreased , and the Lysholm score , except for the item dem and ing for support , significantly increased , compared with those before surgery respectively in both groups . There was significant difference in VAS score between two groups after treatment . As to Lysholm score , there were significant differences in limp , pain , swelling , stair activity and squat , but there were no significant differences in items of interlocking and instability between two groups after treatment . CONCLUSION Electroacupuncture can effectively improve the clinical symptoms and knee joint 's motor function of knee joints in patients with knee osteoarthritis , as well as the synergistic effects on the treatment of knee osteoarthritis after arthroscopic debridement , leading to a much better long-term therapeutic effect with respect of improving the function of knee joint . This therapy , combined with traditional Chinese medicine and Western Medicine , is worth of clinical application in the treatment of knee osteoarthritis [11444887] OBJECTIVES The effectiveness of acupuncture treatment in patients with osteoarthritis of the hip was tested . DESIGN This is a prospect i ve , r and omized , controlled , patient- and investigator-blinded clinical trial . PATIENTS AND SETTING The study was performed at a university department for physical medicine and rehabilitation . Sixty-seven patients were separated into two treatment groups . INTERVENTIONS Group 1 ( treatment ) had traditional needle placement and manipulation , whereas in group 2 ( control ) needles were placed away from classic positions and not manipulated . In both groups needles were placed within the L2 to L5 dermatomes . Outcome parameters were : pain ( VAS ) , functional impairment ( hip score ) , activity in daily life ( ADL ) and overall satisfaction before treatment , and 2 weeks and 2 months after treatment . RESULTS For all parameters there was a significant improvement versus baseline in both groups 2 weeks and 2 months following treatment , but no significant difference between the two treatment groups . CONCLUSIONS We conclude from these results that needle placement in the area of the affected hip is associated with improvement in the symptoms of osteoarthritis . It appears to be less important to follow the rules of traditional acupuncture techniques [7053030] Thirty patients with cervical spine pain syndromes persisting a mean of 8 years were assigned r and omly into equal treatment and control groups . After 12 weeks , 12 of 15 ( 80 % ) of the treated group felt improved , some dramatically , with a mean 40 % reduction of pain score , 54 % reduction of pain pills , 68 % reduction of pain hours per day and 32 % less limitation of activity . Two of 15 ( 13 % ) of the control group reported slight improvement after 12.8 weeks . The control group had a mean 2 % worsening of the pain score , 10 % reduction in pain pills , no lessening of pain hours and 12 % less limitation of activity [24843960] OBJECTIVE To observe the difference in the therapeutic effects on knee osteoarthritis ( KOA ) among auricular electroacupuncture therapy plus isolated moxibustion with Lingxian herbal paste ( combined therapy ) , electroacupuncture ( EA ) and TDP irradiation . METHODS Eighty-nine cases were r and omized into three groups . In the combined therapy group ( 30 cases ) , the auricular electroacupuncture therapy was adopted together with the isolated moxibustion with Lingxian herbal paste . The auricular points were xi ( AH4 ) , pizhixia ( AT4 ) , shenmen ( TF4 ) , etc . The Lingxian herbal paste was applied at Yanglingquan ( GB 34 ) , Dubi ( ST 35 ) , Zusanli ( ST 36 ) , Neixiyan ( EX-LE 4 ) , Heding ( EX-LE 2 ) and Ashi points . In EA group ( 29 cases ) , EA was applied at the acupoints that were same as those in the isolated moxibustion with Lingxian herbal paste . In TDP group ( 30 cases ) , TDP irradiation was given at the affected knee . The treatment was given once every day , 10 treatments made one session and there was 1 week at the interval among sessions . Totally , 3 sessions of treatment were required . KOA clinical symptom and physical sign score and the single item pain symptom score of Lequesne index were observed before treatment and 1 week after treatment in the patients of each group separately . The efficacies were compared among the three groups . RESULTS One week after treatment , the total score of symptoms and physical signs of the patients in each group was reduced significantly as compared with that before treatment ( all P < 0.05 ) . The improvements in the symptoms and physical signs in the combined therapy group were better than those in the other two groups ( 1.50 + /- 1.57 vs 2.52 + /- 1.82 , 2.63 + /- 1.97 , both P < 0.05 ) . The improvement in pain in the combined therapy group was also better than that in the other two groups ( 2.37 + /- 0.81 vs 2.83 + /- 0.92 , P < 0.05 ; 2.37 + /- 0.81 vs 3.03 + /- 0.77 , P < 0.01 ) . The curative rate in the combined therapy group was 40.0 % ( 12/30 ) , which was higher than 17.2 % ( 5/29 ) in EA group and 20.0 % ( 6/30 ) in TDP group separately ( both P < 0.01 ) . The overall efficacy in the combined therapy group was superior to the other two groups ( P < 0.05 ) . CONCLUSION The auricular electroacupuncture therapy plus isolated moxibustion with Lingxian herbal paste is advantageous at the total score of the symptoms and physical signs and the overall efficacy in the patients of KOA as compared with EA at the local acupoints and local TDP irradiation [15100594] Objectives : The aim of the study was to evaluate the therapeutic effect of electro-acupuncture ( EA ) and hydrotherapy , both in combination with patient education or with patient education alone , in the treatment of osteoarthritis in the hip . Methods : Forty-five patients , aged 42–86 years , with radiographic changes consistent with osteoarthritis in the hip , pain related to motion , pain on load , and ache were chosen . They were r and omly allocated to EA , hydrotherapy , both in combination with patient education , or patient education alone . Outcome measures were the disability rating index ( DRI ) , global self-rating index ( GSI ) , and visual analogue scale ( VAS ) . Assessment s were done before the intervention and immediately after the last treatment and 1 , 3 , and 6 months after the last treatment . Results : Pain related to motion and pain on load was reduced up to 3 months after last the treatment in the hydrotherapy group and up to 6 months in the EA group . Ache during the day was significantly improved in both the EA and hydrotherapy group up to 3 months after the last treatment . Ache during the night was reduced in the hydrotherapy group up to 3 months after the last treatment and in the EA group up to 6 months after . Disability in functional activities was improved in EA and hydrotherapy groups up to 6 months after the last treatment . Quality of life was also improved in EA and hydrotherapy groups up to 3 months after the last treatment . There were no changes in the education group alone . Discussion : In conclusion , EA and hydrotherapy , both in combination with patient education , induce long-lasting effects , shown by reduced pain and ache and by increased functional activity and quality of life , as demonstrated by differences in the pre- and post-treatment assessment Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Peripheral joint osteoarthritis is a major cause of pain and functional limitation . Few treatments are safe and effective . OBJECTIVES To assess the effects of acupuncture for treating peripheral joint osteoarthritis . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

22591904

[9374124] Tissue levels of n-3 fatty acids reflect dietary intake , but quantitative data about rate of incorporation and levels as a function of intake are scarce . We fed 58 men 0 , 3 , 6 , or 9 g/d of fish oil for 12 months and monitored fatty acids in serum cholesteryl esters , erythrocytes , and subcutaneous fat during and after supplementation . Eicosapentaenoic acid ( EPA ) in cholesteryl esters plateaued after 4 - 8 weeks ; the incorporation half-life was 4.8 days . Steady-state levels increased by 3.9 + /- 0.3 mass % points ( + /- SE ) for each extra gram of EPA eaten per day . Incorporation of docosahexaenoic acid ( DHA ) was erratic ; plateau values were 1.1 + /- 0.1 mass % higher for every g/d ingested . Incorporation of EPA into erythrocyte membranes showed a half-life of 28 days ; a steady state was reached after 180 days . Each g/d increased levels by 2.1 + /- 0.1 mass % . C22:5n-3 levels increased markedly . Changes in DHA were erratic and smaller . EPA levels in adipose tissue rose also ; the change after 6 months was 67 % of that after 12 months in gluteal and 75 % in abdominal fat . After 12 months each gram per day caused an 0.11 + /- 0.01 mass % rise in gluteal fat for EPA , 0.53 + /- 0.07 for C22:5n-3 , and 0.14 + /- 0.03 for DHA . Thus , different ( n-3 ) fatty acids were incorporated with different efficiencies , possibly because of interconversions or different affinities of the enzymatic pathways involved . EPA levels in cholesteryl esters reflect intake over the past week or two , erythrocytes over the past month or two , and adipose tissue over a period of years . These findings may help in assessing the intake of ( n-3 ) fatty acids in epidemiological studies [14985680] Objective : The aim of this study was to assess the effects of fish oil supplementation in pregnancy on maternal erythrocyte fatty acid composition at different stages of pregnancy and in the post-partum period , and on neonatal erythrocyte fatty acid composition . Design : A double-blind , r and omised , placebo-controlled study . Setting : Subiaco , Western Australia . Subjects : In all , 98 women booked for delivery at St John of God Hospital , Subiaco , were recruited from private rooms of obstetricians . In total , 83 women and their healthy full-term babies completed the study . Interventions : Women received either 4 g of fish oil ( n=52 ) ( 56 % docosahexaenoic acid ( DHA ) and 28 % eicosapentaenoic acid ( EPA ) or placebo ( olive oil ) ( n=46 ) per day from 20 weeks gestation until delivery . Main outcome measures : Erythrocyte phospholipid fatty acids were measured in maternal peripheral blood at 20 , 30 and 37 weeks of pregnancy and at 6 weeks post partum , and from cord blood collected at birth . Results : Compared to the control group , maternal EPA and DHA were significantly higher in the fish oil group at 30 and 37 weeks gestation , and remained elevated at 6 weeks post partum ( P<0.001 ) . The proportions of n-6 polyunsaturated ( arachidonic acid , 22:3n-6 and 22:4n-6 ) were significantly lower in the fish oil supplemented group at the same time periods ( P<0.001 ) . Similarly , the proportions of EPA and DHA were significantly higher ( P<0.001 ) , and those of n-6 polyunsaturated fatty acids arachidonic acid , 20:3n-6 , 22:3n-6 and 22:4n-6 were significantly lower ( P<0.001 ) , in erythrocytes from neonates in the fish oil group , compared to those in the control group . Conclusions : Fish oil supplementation from 20 weeks of pregnancy until birth is an effective means of enhancing n-3 fatty acid status of both mothers and neonates . Furthermore , the changes in maternal erythrocyte fatty acid composition are retained until at least 6 weeks post partum . It is essential to assess the effects of concomitant decreases in arachidonic acid status before any dietary recommendations can be made . Sponsorship : The study was supported by grants from the NH & MRC and Raine Medical Research Foundation , Australia [12848286] Dietary DHA enhances infant attention and visual development . Because the DHA content of red blood cells and plasma lipids varies approximately threefold in pregnancy , maternal DHA status may influence subsequent infant function . It would be feasible to study the effects of higher maternal DHA intake on infant development if dietary intake of DHA could be increased by a reliable means . This study was design ed to determine whether women provided with one dozen high-DHA hen eggs ( 135 mg DHA/egg ) would consume the eggs and have higher blood DHA levels than women consuming ordinary eggs ( 18 mg DHA/egg ) . The study was a r and omized , double-masked comparison of the effect of eggs with different concentrations of DHA on intake and blood lipid DHA content of women and their infants . A third nonr and omized group ate few eggs . In this study , DHA intake reported from eggs was eightfold higher in the high-DHA egg group compared to the ordinary egg group . Including all groups , DHA intake ranged from 0 to 284 mg/d . In this intake range , maternal blood lipid DHA content at enrollment best predicted DHA content at delivery , accounting for 36.5 and 51.7 % of the variance in ordinary and high-DHA egg intake groups , respectively . The high-DHA vs. ordinary egg groups had similar maternal and cord blood lipid DHA , but there was a positive relationship between maternal plasma phospholipid DHA and daily DHA intake from eggs controlled for study duration ( r=0.278 , P=0.048 ) . DHA intake and birth weight were also correlated ( r=0.299 , P=0.041 ) . High-DHA eggs were well accepted and increased DHA intake . Other benefits of DHA intake during pregnancy were also suggested [14553835] OBJECTIVE Evaluation of the effects of supplementation of n-3 and n-6 fatty acids on vascular tone and endothelial function in healthy men and women aged 40 to 65 years . METHODS In a double-blind , r and omised , placebo controlled study , 173 healthy volunteers took one of six oil supplements for 8 months . Supplements were placebo , oleic acid rich sunflower oil , evening primrose oil , soya bean oil , tuna fish oil , and tuna/evening primrose oil mix . Endothelium-dependent and independent vascular responses were measured in the forearm skin using laser Doppler imaging following iontophoretic applications of acetylcholine and sodium nitroprusside , respectively . RESULTS Acetylcholine , but not sodium nitroprusside responses were significantly improved after tuna oil supplementation ( P=0.02 ) . Additionally , there were significant positive correlations between acetylcholine responses and n-3 fatty acid levels in the plasma and erythrocyte membrane phospholipids after tuna oil supplementation . No significant changes in vascular response were seen after supplementation with any of the other oils . CONCLUSIONS Fish oil supplementation has a beneficial effect on endothelial function , even in normal healthy subjects . Modification of the diet by an increase of 6 % in eicosapentaenoic acid and 27 % in docosahexaenoic acid ( equivalent to eating oily fish 2 - 3 times/week ) might have significant beneficial effects on cardiovascular function and health [9590631] The influence of various dietary marine oils and olive oil on fatty acid composition of serum and platelets and effects on platelets and serum lipids were investigated as part of an extensive study of the effects of these oils on parameters associated with cardiovascular/thrombotic diseases . Healthy volunteers ( 266 ) consumed 15 mL/d of cod liver oil ( CLO ) ; whale blubber oil ( refined or unrefined ) ; mixtures of seal blubber oil and CLO ; or olive oil/CLO for 12 wk . In the CLO , seal oil/CLO , and whale oil groups , serum levels of eicosapentaenoic acid ( EPA ) were increased . In platelets , EPA was increased in the CLO , seal/CLO , and olive oil/CLO groups . The localization of n-3 polyunsaturated fatty acids in the triacylglycerols did not seem to influence their absorption . Intake of oleic acid is poorly reflected in serum and platelets . No significant differences in triacylglycerols ( IG ) , total cholesterol , or high density lipoprotein cholesterol were observed , even though TG were reduced in the CLO , CLO/seal oil , and whale oil groups . Mean platelet volume increased significantly in both whale oil groups and the CLO/olive oil group . Platelet count was significantly reduced in the refined whale oil group only . Lipopolysaccharide-stimulated blood tended to generate less thromboxane B2 in CLO , CLO/seal , and CLO/olive groups . The whale oils tended to reduce in vivo release of β-thromboglobulin . In conclusion , intake of various marine oils causes changes in platelet membranes that are favorably antithrombotic . The combination of CLO and olive oil may produce better effects than these oils given separately . The changes in platelet function are directly associated with alterations of fatty acid composition in platelet membranes [9168460] The purpose of this study was to investigate in healthy humans the effect of eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) intake , alone or in combination with dL-α-tocopherol acetate ( vitamin E ) supplements on lipid peroxidation . Eightly men were r and omly assigned in a double-blind fashion to take daily for 6 wk either menhaden oil ( 6.26 g , n−3 fatty acids ) or olive oil supplements with either vitamin E ( 900 IU ) or its placebo . Antioxidant vitamins , phospholipid composition , malondialdehyde ( MDA ) , and lipid peroxides were measured in the plasma at baseline and week 6 . At the same time , breath alkane output was measured . Plasma α-tocopherol concentration increased in those receiving vitamin E ( P<0.0001 ) . In those supplemented with n−3 fatty acids , EPA and DHA increased in plasma phospholipids ( P<0.0001 ) and plasma MDA and lipid peroxides increased ( P<0.001 and P<0.05 , respectively ) . Breath alkane output did not change significantly and vitamin E intake did not prevent the increase in lipid peroxidation during menhaden oil supplementation . The results demonstrate that supplementing the diet with n−3 fatty acids result ed in an increase in lipid peroxidation , as measured by plasma MDA release and lipid peroxide products , which was not suppressed by vitamin E supplementation [20652432] Fish are a rich source of eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) , two long-chain polyunsaturated n-3 fatty acids ( LC n-3 PUFA ) with cardiovascular benefits . A related but less-investigated LC n-3 PUFA , docosapentaenoic acid ( DPA ) , is more common in seal oil and pasture-fed red meats . This study compared indicators of platelet function and plasma lipids in healthy volunteers given supplements containing these different fatty acids ( FA ) for 14 days . Subjects , r and omised into three groups of ten , consumed capsules of tuna oil ( 210 mg EPA , 30 mg DPA , 810 mg DHA ) , seal oil ( 340 mg EPA , 230 mg DPA , 450 mg DHA ) or placebo ( sunola ) oil . Supplementary LC n-3 PUFA levels were approximately 1 g/day in both fish and seal oil groups . Baseline dietary FA and other nutrient intakes were similar in all groups . Both fish and seal oil elevated platelet DHA levels ( P < 0.01 ) . Seal oil also raised platelet DPA and EPA levels ( P < 0.01 ) , and decreased p-selectin ( P = 0.01 ) , a platelet activation marker negatively associated with DPA ( P = 0.03 ) and EPA ( P < 0.01 ) but not DHA . Plasma triacylglycerol decreased ( P = 0.03 ) and HDL-cholesterol levels increased ( P = 0.01 ) with seal oil only . Hence , seal oil may be more efficient than fish oil at promoting healthy plasma lipid profiles and lowering thrombotic risk , possibly due to its high DPA as well as EPA content [12530552] The first indication of platelet activation is an increase in mean platelet volume ( MPV ) . n−3 FA are known to inhibit platelet function and to reduce the risk for coronary heart disease . The purpose of this study was to determine the effects of FPA and DHA on MPV . Healthy subjects received olive oil placebo for 4 wk and then were r and omly assigned to receive 4 g of ethyl esters of either safflower oil ( n=11 ) , EPA ( n=10 ) , or DHA ( n=12 ) for 4 wk . At the end of placebo run-in and treatment periods , MPV ( fL ; mean±SEM ) and platelet count ( PLT-CT ; 103/μL blood ) were measured in the basal state and after ex vivo stimulation with collagen ( 10 μg/mL ) , cold ( 4 ° C ) , and heat ( 37 ° C ) . Unlike DHA , EPA lowered MPV as compared with safflower oil ( 7.2±0.1 vs. 7.5±0.1 fL ; P<0.05 ) and raised PLT-CT ( 211±18 vs. 192±18 103/μL ; P<0.05 ) in the fasting state . Collagen and cold significantly increased MPV whereas heat lowered MPV regardless of treatment . All stimuli decreased PLT-CT . EPA significantly increased platelet EPA ( 0.2±0.1 vs. 3.3±0.4 % ) and docosapentaenoic acid ( DPA ; 2.2±0.3 vs. 2.9±0.3 % ) concentrations , but not DHA . DHA treatment significantly increased DHA ( 1.4±0.2 vs. 4.1±0.5 % ) and DPA ( 2.0±0.4 vs. 3.0±0.4 % ) concentrations , but not EPA . In conclusion , EPA , but not DHA , reduces platelet activation , an early step in platelet aggregation [10919932] BACKGROUND n-3 Fatty acid supplementation lowered serum triacylglycerol concentrations in studies in which most of the subjects were male . The effects of n-3 fatty acid supplementation in postmenopausal women receiving and not receiving hormone replacement therapy ( HRT ) have received little attention . OBJECTIVE We sought to determine the effects of a fish-oil-derived n-3 fatty acid concentrate on serum lipid and lipoprotein risk factors for cardiovascular disease in postmenopausal women receiving and not receiving HRT , with an emphasis on serum triacylglycerol concentrations and the ratio of triacylglycerol to HDL cholesterol . DESIGN Postmenopausal women ( n = 36 ) were grouped according to exogenous hormone use and were r and omly allocated to receive 8 capsules/d of either placebo oil ( control ) or n-3 fatty acid-enriched oil ( supplement ) . The supplement provided 2.4 g eicosapentaenoic acid ( EPA ) plus 1.6 g docosahexaenoic acid ( DHA ) daily . Serum lipids and the fatty acid composition of serum phospholipids were determined on days 0 and 28 . RESULTS Supplementation with n-3 fatty acids was associated with 26 % lower serum triacylglycerol concentrations ( P < 0.0001 ) , a 28 % lower overall ratio of serum triacylglycerol to HDL cholesterol ( P < 0.01 ) , and markedly greater EPA and DHA concentrations in serum phospholipids ( P < 0.05 ) . CONCLUSIONS These results show that supplementation with a fish-oil-derived concentrate can favorably influence selected cardiovascular disease risk factors , particularly by achieving marked reductions in serum triacylglycerol concentrations and triacylglycerol : HDL cholesterol in postmenopausal women receiving and not receiving HRT . This approach could potentially reduce the risk of coronary heart disease by 27 % in postmenopausal women [18779299] BACKGROUND An increase in plasma n-3 fatty acid content , particularly eicosapentaenoic acid ( 20:5n-3 ; EPA ) and docosahexaenoic acid ( 22:6n-3 ; DHA ) , is observed after consumption of fish oil-enriched supplements . Because alpha-linolenic acid ( 18:3n-3 ; ALA ) is the direct precursor of EPA and DHA , ALA-enriched supplements such as flax may have a similar effect , although this hypothesis has been challenged because of reported low conversion of ALA into DHA . OBJECTIVE To address this question , we design ed a clinical trial in which flax oil , fish-oil , and sunflower oil ( placebo group ) capsules were given to firefighters ( n = 62 ) , a group traditionally exposed to cardiovascular disease risk factors . DESIGN Firefighters were r and omly divided into 6 experimental groups receiving 1.2 , 2.4 , or 3.6 g flax oil/d ; 0.6 or 1.2 g fish oil/d ; or 1 g sunflower oil/d for 12 wk . Blood was drawn every 2 wk , and the total phospholipid fatty acid composition of red blood cells was determined . RESULTS As expected , fish oil produced a rapid increase in erythrocyte DHA and total n-3 fatty acids . The consumption of either 2.4 or 3.6 g flax oil/d ( in capsules ) was sufficient to significantly increase erythrocyte total phospholipid ALA , EPA , and docosapentaenoic acid ( 22:5n-3 ) fatty acid content . There were no differences among groups in plasma inflammatory markers or lipid profile . CONCLUSIONS The consumption of ALA-enriched supplements for 12 wk was sufficient to elevate erythrocyte EPA and docosapentaenoic acid content , which shows the effectiveness of ALA conversion and accretion into erythrocytes . The amounts of ALA required to obtain these effects are amounts that are easily achieved in the general population by dietary modification [18065578] BACKGROUND n-3 Fatty acids ( FAs ) have been shown to be beneficial for cardiovascular health . Whether n-3 FAs from oily fish consumed weekly or from fish-oil capsules taken daily are equally bioavailable is not clear . OBJECTIVE The purpose of this study was to compare the rate and extent of enrichment of blood cell membranes [ ie , red blood cells ( RBCs ) ] and plasma phospholipids with n-3 FAs from these 2 sources . DESIGN Healthy premenopausal female volunteers were r and omly assigned to consume a daily average of 485 mg eicosapentaenoic ( EPA ) and docosahexaenoic ( DHA ) acids either from 2 servings of oily fish ( ie , salmon and albacore tuna ) per week or from 1 - 2 capsules/d . RESULTS After 16 wk , EPA+DHA in RBCs in the fish group ( n = 11 ) increased from 4.0 + /- 0.6 % of total FAs to 6.2 + /- 1.4 % , whereas it rose from 4.3 + /- 1.0 % to 6.2 + /- 1.4 % in the capsule group ( P < 0.0001 for both ; NS for group effect ) . Similar results were observed in plasma phospholipids . EPA+DHA stabilized in the latter after 4 wk but continued to rise through week 16 in RBCs . EPA in RBCs increased significantly ( P = 0.01 ) more rapidly in the fish group than in the capsule group during the first 4 wk , but rates did not differ significantly between groups thereafter . Total FA variances were less in RBCs than in plasma phospholipids ( P = 0.04 ) . CONCLUSION These findings suggest that the consumption of equal amounts of EPA and DHA from oily fish on a weekly basis or from fish-oil capsules on a daily basis is equally effective at enriching blood lipids with n-3 FAs [1310374] Thirty healthy male subjects were r and omly allocated into one of two treatment groups : group H subjects were maintained on a high-linoleic acid ( LA ) diet with the saturated fatty acids kept low and those in group L were kept on a low-LA , low saturate diet . After a 3-wk run-in period , subjects consumed a fish-oil supplement containing 1.6 g eicosapentaenoic acid (EPA)/d and 0.32 g docosahexaenoic acid as triglycerides for a further 4 wk . The diets alone result ed in a significant change in neutrophil phospholipid LA ( H = 12.7 + /- 2.9 % , L = 9.0 + /- 0.9 % ; P less than 0.05 ) . Dietary supplementation with fish oil result ed in a significant increase in EPA in neutrophil phospholipids that was greater in group L ( mean 2.0 + /- 0.4 % ) than group H ( mean 1.5 + /- 0.3 % ; P less than 0.005 ) . Reductions in arachidonic acid concentrations in neutrophil membranes were not different , nor could differences in leukotriene B4 production be detected . Our study indicates that the ingestion of n-6 fatty acids within the diet is an important determinant of EPA incorporation into neutrophil membranes [9701178] We investigated the effect of incorporating n-3 polyunsaturated fatty acids ( PUFAs ) into the diet on the lipid-class composition of LDLs , their size , and their susceptibility to oxidation . Forty-seven healthy volunteers incorporated 30 g sunflower-oil ( SO ) margarine/d into their habitual diet during a 3-wk run-in period and then used either SO or a fish-oil-enriched sunflower oil ( FO ) margarine for the following 4 wk . Plasma concentrations of total cholesterol , triacylglycerols , HDL cholesterol , LDL cholesterol , and apolipoproteins A-I and B did not differ significantly between the groups during intervention . The FO margarine increased the concentration of n-3 very-long-chain PUFAs in the LDL particles , showing 93 % ( P < or = 0.0001 ) , 8 % ( P = 0.05 ) , and 35 % ( P = < 0.0001 ) increases in eicosapentaenoic acid , docosapentaenoic acid , and docosahexaenoic acid , respectively , in the FO group compared with 3 % , 7 % , and 7 % , respectively , in the SO group during the intervention . The cholesterol content of the LDL particles increased in the FO group [ total cholesterol : 6 % ( P = 0.008 ) ; cholesterol ester : 12 % ( P = 0.014 ) ] , although it was not significantly different from that in the control group , whereas the other lipid classes and the size of the LDL particles remained unchanged in both groups . A reduction in the alpha-tocopherol content in LDL ( 6 % , P = 0.005 ) was observed in the FO group . Ex vivo oxidation of LDL induced with Cu2 + showed a significantly reduced lag time ( from 91 to 86 min , P = 0.003 ) and lower maximum rate of oxidation ( from 10.5 to 10.2 nmol x mg(-1 ) x min(-1 ) , P = 0.003 ) after intake of the FO margarine . The results indicate that consumption of the FO compared with the SO margarine had no effect on LDL size and lipid composition and led to minor changes in LDL a-tocopherol content and oxidation resistance [17374672] ( n-3 ) PUFA influence immune function in adults and may also affect immune maturation during development . This r and omized trial is , to our knowledge , the first to investigate whether fish oil supplementation in late infancy modifies immune responses . The study was a 2 x 2 intervention in 64 healthy Danish infants , who received cow 's milk or infant formula alone or with fish oil ( FO ) ( 3.4 + /- 1.1 mL/d ) from 9 to 12 mo of age . Before and after the intervention , fatty acid composition of erythrocyte membranes , plasma IgE , C-reactive protein , and soluble IL-2 receptor concentrations were measured . TNF-alpha , INF-gamma , and IL-10 concentrations in whole-blood cultures , stimulated for 22 h with LPS+phytohemaglutinin ( PHA ) or Lactobacillus paracasei , were also determined . IgA was measured in feces when infants were 10 mo of age . FO supplementation effectively raised erythrocyte ( n-3 ) PUFA ( P < 0.001 ) , increased L. paracasei-induced INF-gamma ( P = 0.05 ) and tended to reduce LPS+PHA-induced IL-10 ( P = 0.08 ) . The FO intervention did not affect any of the other analyzed immune variables . The erythrocyte content of eicosapentanoic acid was negatively associated with LPS+PHA-induced IL-10 ( r = -0.38 , P = 0.02 ) . Feeding milk rather than formula did not affect cytokine production , but plasma soluble IL-2 receptor concentration was greater in the formula group than in the cow 's milk group ( P = 0.03 ) . Since the capacity to produce INF-gamma has been proposed as a maturation marker for the immune system in early life , this study suggests a faster immune maturation with FO supplementation with no apparent reduction in immune activation . The implication s for later health need further investigation [10479194] BACKGROUND Dietary intake of long-chain n-3 polyunsaturated fatty acids ( PUFA ) may protect against sudden cardiac death , an event that may be predicted by measurement of heart rate variability ( HRV ) . OBJECTIVE The objectives of this study were to 1 ) examine the correlations between the content of fatty acids in blood cell membranes ( platelets and granulocytes ) and HRV in healthy subjects , and 2 ) assess the effect on HRV of dietary intervention with n-3 PUFA in different doses . DESIGN Sixty healthy volunteers ( 25 women and 35 men ) were r and omly assigned to 3 treatment groups in a double-blind design . Subjects received a daily supplement of either 6.6 g n-3 PUFA , 2.0 g n-3 PUFA , or placebo ( olive oil ) . A 24-h Holter recording was obtained for each subject before supplementation and after 12 wk of supplementation ; the 24-h HRV was then related to the content of fatty acids in granulocytes and platelets . RESULTS Before supplementation , positive correlations were observed in men between the content of docosahexaenoic acid in cell membranes and HRV indexes ( r = 0.50 , P < 0.01 ) , whereas such correlations were not found in women . Dietary intervention revealed a dose-dependent effect of n-3 PUFA on HRV in men , whereas no effect was found in women . CONCLUSION The study showed a beneficial effect of n-3 PUFA on HRV in healthy men , suggesting an antiarrhythmic effect of n-3 PUFA . No such effect was observed in healthy women [11435508] Animal and human studies have shown that greatly increasing the amounts of flax seed oil [ rich in the ( n-3 ) polyunsaturated fatty acid ( PUFA ) alpha-linolenic acid ( ALNA ) ] or fish oil [ FO ; rich in the long chain ( n-3 ) PUFA eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) ] in the diet can decrease mitogen-stimulated lymphocyte proliferation . The objective of this study was to determine the effect of dietary supplementation with moderate levels of ALNA , gamma-linolenic acid ( GLA ) , arachidonic acid ( ARA ) , DHA or FO on the proliferation of mitogen-stimulated human peripheral blood mononuclear cells ( P BMC ) and on the production of cytokines by those cells . The study was r and omized , placebo-controlled , double-blinded and parallel . Healthy subjects ages 55 - 75 y consumed nine capsules/d for 12 wk ; the capsules contained placebo oil ( an 80:20 mix of palm and sunflower seed oils ) or blends of placebo oil with oils rich in ALNA , GLA , ARA or DHA or FO . Subjects in these groups consumed 2 g of ALNA or 770 mg of GLA or 680 mg of ARA or 720 mg of DHA or 1 g of EPA plus DHA ( 720 mg of EPA + 280 mg of DHA ) daily from the capsules . Total fat intake from the capsules was 4 g/d . The fatty acid composition of P BMC phospholipids was significantly changed in the GLA , ARA , DHA and FO groups . Lymphocyte proliferation was not significantly affected by the placebo , ALNA , ARA or DHA treatments . GLA and FO caused a significant decrease ( up to 65 % ) in lymphocyte proliferation . This decrease was partly reversed by 4 wk after stopping the supplementation . None of the treatments affected the production of interleukin-2 or interferon-gamma by P BMC and none of the treatments affected the number or proportion of T or B lymphocytes , helper or cytotoxic T lymphocytes or memory helper T lymphocytes in the circulation . We conclude that a moderate level GLA or EPA but not of other ( n-6 ) or ( n-3 ) PUFA can decrease lymphocyte proliferation but not production of interleukin-2 or interferon-gamma [8780337] The present work was performed to study an optimal dose and duration of dietary n-3 polyunsaturated fatty acid ( PUFA ) supplementation that would not result in harmful modifications of oxidative cell metabolism . Forty healthy subjects were divided into four groups that received 2.5 g/d eicosapentaenoic acid ( EPA ) + docosahexaenoic acid ( DHA ) , 5.1 g EPA + DHA/d , 7.7 g EPA + DHA/d , or placebo . Fatty acid composition , tocopherol status , and susceptibility to lipid peroxidation induced in vitro by 2,2'-azobis-(2-amidinopropane ) ( AAPH ) were evaluated in human red blood cell ( RBC ) membranes on days 30 and 180 . n-3 PUFA treatment increased EPA and DHA concentrations in RBC membranes in a time-dependent manner in all of the n-3 PUFA groups . These modifications occurred with concomitant dose- and time-dependent increases in the membrane unsaturation index . After 30 d of treatment with n-3 PUFAs , alpha-to-copherol significantly increased in RBC membranes of the intermediate- and high-dose groups . Because of the higher concentration of this antioxidant in these groups , the susceptibility of RBC membranes to peroxidation was decreased . However , after 180 d of treatment , alpha-tocopherol decreased to baseline values and AAPH-induced lipid peroxidation increased in a dose-dependent manner . These results show that high doses of dietary n-3 PUFAs , as well as long-time treatments , affect human RBC susceptibility to lipid peroxidation by changes in fatty acid composition and tocopherol content [15333721] Between 6 and 12 mo of age , blood levels of the ( n-3 ) long-chain PUFA , docosahexaenoic acid ( DHA ) , in breast-fed infants typically decrease due to diminished maternal DHA stores and the introduction of DHA-poor solid foods displacing human milk as the primary source of nutrition . Thus , we utilized a r and omized , clinical trial format to evaluate the effect of supplemental DHA in solid foods on visual development of breast-fed infants with the primary outcome , sweep visual-evoked potential ( VEP ) acuity , as an index for maturation of the retina and visual cortex . At 6 mo of age , breast-fed infants were r and omly assigned to receive 1 jar ( 113 g)/d of baby food containing egg yolk enriched with DHA ( 115 mg DHA/100 g food ; n = 25 ) or control baby food ( 0 mg DHA ; n = 26 ) . Gravimetric measures were used to estimate the supplemental DHA intake which was 83 mg DHA/d in the supplemented group and 0 mg/d in controls . Although many infants in both groups continued to breast-feed for a mean of 9 mo , RBC DHA levels decreased significantly between 6 and 12 mo ( from 3.8 to 3.0 g/100 g total fatty acids ) in control infants , whereas RBC DHA levels increased by 34 % from 4.1 to 5.5 g/100 g by 12 mo in supplemented infants . VEP acuity at 6 mo was 0.49 logMAR ( minimum angle of resolution ) and improved to 0.29 logMAR by 12 mo in controls . In DHA-supplemented infants , VEP acuity was 0.48 logMAR at 6 mo and matured to 0.14 logMAR at 12 mo ( 1.5 lines on the eye chart better than controls ) . At 12 mo , the difference corresponded to 1.5 lines on the eye chart . RBC DHA levels and VEP acuity at 12 mo were correlated ( r = -0.50 ; P = 0.0002 ) , supporting the need of an adequate dietary supply of DHA throughout 1 y of life for neural development [1826984] To compare their relative absorption and effect on platelet function , concentrated fish oil and tuna were given to 10 subjects in a r and omized crossover study . Although plasma enrichment of eicosapentaenoic acid ( EPA ) from either preparation was similar , relative absorption of EPA from tuna was significantly greater than that from fish oil ( 46.6 + /- 3.0 mg . L-1.g EPA-1 from tuna compared with 16 + /- 1.0 mg . L-1.g EPA-1 from fish oil , P less than 0.001 ) . Relative absorption of docosahexaenoic acid ( DHA ) was equivalent ( 54.0 + /- 9.0 mg . L-1.g DHA-1 from tuna , 56 + /- 9.0 mg . L-1.g DHA-1 from fish oil , NS ) . Platelet aggregation in response to the endoperoxide analog U46619 was significantly diminished after either preparation but aggregation in response to other agonists , bleeding time , and membrane n-3 ( omega-3 ) fatty acid content were not changed . Thus , n-3 fatty acids are well absorbed after one dose of either tuna or fish oil but EPA absorption appears to be more efficient from tuna . Additionally , a single dose of n-3 fatty acids decreases platelet aggregation by a mechanism not requiring incorporation into platelet membranes [7910999] Thirty healthy male volunteers were r and omly allocated into two dietary treatment groups . The flaxseed group ( n = 15 ) maintained a diet high in alpha-linolenic acid ( alpha-LA ; 18:3n-3 ) and low in linoleic acid ( LA ; 18:2n-6 ) by using a flaxseed oil and spread that are high in alpha-LA . The control group ( n = 15 ) maintained a diet high in LA and low in alpha-LA , typifying a Western diet . Both groups maintained their diets for 4 wk , followed by another 4-wk period in which they supplemented the diets with fish oil [ 1.62 g eicosapentaenoic acid ( EPA , 20:5n-3 ) daily and 1.08 g docosahexaenoic acid ( DHA , 22:6n-3 ) daily ] in a triglyceride form . The flaxseed oil-containing diet result ed in significant increases in alpha-LA concentrations in the plasma phospholipid , cholesteryl ester , and triglyceride fractions ( eightfold increase ) and neutrophil phospholipids ( 50 % increase ) . EPA concentrations increased by 2.5-fold in the plasma lipid fractions and neutrophil phospholipids . After fish-oil supplementation EPA concentrations increased in parallel in both dietary groups , remaining higher in the flaxseed group for both the plasma lipid fractions and neutrophil phospholipids . The results indicate that alpha-LA-rich vegetable oils can be used in a domestic setting ( in conjunction with a background diet low in LA ) to elevate EPA in tissues to concentrations comparable with those associated with fish-oil supplementation [7872228] This study addressed two questions : 1 ) whether a relatively low dose of n-3 fatty acid ethyl esters ( n-3 FAs ) administered to healthy volunteers for a prolonged period of time would exert beneficial effects on plasma lipids , platelet function , and thromboxane bio synthesis ; and 2 ) whether a short-term loading treatment ( 6 wk ) with 6 g n-3 FAs/d followed by 12 wk with 3 g/d results in more pronounced effects . After 6 wk treatment a reduction of plasma triglyceride concentration and an accumulation of EPA and DHA in plasma were observed . A longer period of treatment with n-3 FAs was necessary to affect platelet aggregation and thromboxane A2 bio synthesis . At 12 and 18 wk , platelet aggregation , thromboxane A2 formation , and the excretion of thromboxane metabolites in urine were reduced , particularly in subjects who received 6 g n-3 FAs/d during the initial 6 wk . After treatment ended , triglyceride and thromboxane A2 bio synthesis returned to baseline values within 4 wk , whereas platelet aggregation remained impaired for > or = 14 wk . The longlasting impairment in platelet aggregation was accompanied by the retention of n-3 FAs in platelet phospholipids [2203252] Effects of fish-oil ( FO ) feeding on serum lipids were investigated in a 42-d controlled diet study . Fifteen healthy male college students were assigned to one of three groups : control ( 0 g FO ) ; 5 g FO , supplying 2 g n - 3 ( omega-3 ) fatty acids ( FAs ) ; or 20 g FO , supplying 8 g n - 3 FAs . In an initial 7-d period subjects consumed a basal diet with no FO . Then FO replaced an equivalent amount of margarine for 5 wk . FO feeding significantly ( p less than 0.05 ) decreased the serum n - 6 FAs , linoleic acid , eicosatrienoic acid , and arachidonic acid . A significant increase in the n - 3 FAs , eicosapentaenoic acid and docosahexaenoic acid , was noted in serum , platelet , and neutrophil phospholipids . The 20-g-FO group showed a 30 % decrease ( p less than 0.01 ) in triglycerides after 2 wk FO with no further decrease observed . Thus , 20 g FO produced changes in both FA patterns and triglyceride concentrations whereas 5 g FO produced changes in FA patterns only . Neither FO amount result ed in significant changes in total or HDL cholesterol , apolipoprotein A-I , or apolipoprotein B-100 [15051614] BACKGROUND Supplementation of the diet with fish oil , which is rich in the long-chain n-3 polyunsaturated fatty acids eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) , is reported to decrease several markers of immune function . However , whether EPA , DHA , or a combination of the 2 exerts these immunomodulatory effects is unclear . OBJECTIVE The objective of the study was to determine the effects of supplementation with an EPA-rich or DHA-rich oil on a range of immune outcomes representing key functions of human neutrophils , monocytes , and lymphocytes in healthy humans . DESIGN In a placebo-controlled , double-blind , parallel study , 42 healthy subjects were r and omly allocated to receive supplementation with either placebo ( olive oil ) , EPA ( 4.7 g/d ) , or DHA ( 4.9 g/d ) for 4 wk . Blood sample s were taken before and after supplementation . RESULTS The fatty acid composition of plasma phospholipids and neutrophils was dramatically altered by supplementation with EPA or DHA , and the effects of EPA differed notably from those of DHA . DHA supplementation decreased T lymphocyte activation , as assessed by expression of CD69 , whereas EPA supplementation had no significant effect . Neither the EPA-rich oil nor the DHA-rich oil had any significant effect on monocyte or neutrophil phagocytosis or on cytokine production or adhesion molecule expression by peripheral blood mononuclear cells . CONCLUSIONS Supplementation with DHA , but not with EPA , suppresses T lymphocyte activation , as assessed by expression of CD69 . EPA alone does not , therefore , influence CD69 expression . No other marker of immune function assessed in this study was significantly affected by either EPA or DHA [12499320] BACKGROUND Eicosapentaenoic acid ( EPA ) , docosahexaenoic acid ( DHA ) , and gamma-linolenic acid ( GLA ) have lipid-modifying and antiinflammatory properties . The effects of supplement mixtures of these fatty acids on plasma lipids and the fatty acid compositions of serum phospholipids have received little attention . OBJECTIVE The objective was to determine the effects of different levels of GLA supplementation together with a constant intake of EPA plus DHA on the triacylglycerol-lowering effect of EPA plus DHA alone and on the fatty acid patterns ( eicosanoid precursors ) of serum phospholipids . DESIGN Thirty-one women were assigned to 1 of 4 groups , equalized on the basis of their fasting triacylglycerol concentrations . They received supplements providing 4 g EPA+DHA ( 4:0 , EPA+DHA : GLA ; control group ) , 4 g EPA+DHA plus 1 g GLA ( 4:1 ) , 2 g GLA ( 4:2 ) , or 4 g GLA ( 4:4 ) daily for 28 d. Plasma lipids and fatty acids of serum phospholipids were measured on days 0 and 28 . RESULTS Plasma triacylglycerol concentrations were significantly lower on day 28 than on day 0 in the 4:0 , 4:1 , and 4:2 groups . LDL cholesterol decreased significantly ( by 11.3 % ) in the 4:2 group . Dihomo-gamma-linolenic acid increased significantly in serum phospholipids only in the 4:2 and 4:4 groups ; however , total n-3 fatty acids increased in all 4 groups . CONCLUSIONS A mixture of 4 g EPA+DHA and 2 g GLA favorably altered blood lipid and fatty acid profiles in healthy women . On the basis of calculated PROCAM values , the 4:2 group was estimated to have a 43 % reduction in the 10-y risk of myocardial infa rct ion [17977469] Consumption of long-chain n-3 PUFA , particularly DHA , has been shown to improve cardiovascular risk factors but the intake required to achieve benefits is unclear . We sought to determine the relationship between DHA intake , increases in erythrocyte DHA content and changes in blood lipids . A total of sixty-seven subjects ( thirty-six male , thirty-one female , mean age 53 years ) with fasting serum TAG > or = 1.1 mmol/l and BMI > 25 kg/m(2 ) completed a 12-week , r and omized , double-blind , placebo-controlled parallel intervention . Subjects consumed 2 , 4 or 6 g/d of DHA-rich fish oil ( 26 % DHA , 6 % EPA ) or a placebo ( Sunola oil ) . Fasting blood lipid concentrations and fatty acid profiles in erythrocyte membranes were assessed at baseline and after 6 and 12 weeks . For every 1 g/d increase in DHA intake , there was a 23 % reduction in TAG ( mean baseline concentration 1.9 ( sem 0.1 ) mmol/l ) , 4.4 % increase in HDL-cholesterol and 7.1 % increase in LDL-cholesterol . Erythrocyte DHA content increased in proportion to the dose of DHA consumed ( r 0.72 , P < 0.001 ) and the increase after 12 weeks was linearly related to reductions in TAG ( r - 0.38 , P < 0.01 ) and increases in total cholesterol ( r 0.39 , P < 0.01 ) , LDL-cholesterol ( r 0.33 , P < 0.01 ) and HDL-cholesterol ( r 0.30 , P = 0.02 ) . The close association between incorporation of DHA in erythrocytes and its effects on serum lipids highlights the importance of erythrocyte DHA as an indicator of cardiovascular health status [12947422] Objective : To study the possibility of increasing the very long-chain n-3 polyunsaturated fatty acids , eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) , in humans by means of consumption of a common food product , Sc and inavian caviar paste , suitable for strategic enrichment with a high concentration of these fatty acids , and to measure the potential inducement of lipid peroxidation . Design : A r and omized double blind repeated measures experiment . Subjects and interventions : In total , 16 healthy , nonsmoking subjects ( eight men and eight women , age 42±12 y ) were included in the study . Eight consumed 25 g ordinary caviar paste daily for 3 weeks , and eight the same amount of caviar paste enriched with a very stable fish oil ( 7 % , wt/wt ) . Blood lipids , plasma phospholipid fatty acids and lipid peroxidation were measured . Results : α-Linoleic acid was significantly decreased after intake of both ordinary ( −8 % , P<0.05 ) and fish oil caviar ( −10 % , P<0.05 ) , as was the sum of all n-6 fatty acids ( −6 % , P<0.05 and −8 % , P<0.001 , respectively ) . The fatty acids EPA and DHA , as well as the sum of all n-3 fatty acids , increased significantly in both caviar groups but more in the group given fish oil caviar paste ( EPA : + 51 % , P<0.05 and + 100 % , P<0.001 , respectively ; DHA : + 24 % , P<0.01 and + 29 % , P<0.001 , respectively ; sum of n-3:+27 % , P<0.05 and + 40 % , P<0.001 , respectively ) . Lipid peroxidation , measured as the thiobarbituric acid — malondialdehyde adduct , was increased by 26 % ( P<0.05 ) after intake of ordinary caviar paste , but was unchanged after intake of fish oil-enriched caviar paste . Conclusions : Sc and inavian caviar paste is a spread naturally enriched with n-3 polyunsaturated fatty acids that can be included in the diet to achieve an increase in these fatty acids . However , changing to caviar paste enriched with stable fish oil will lead to a considerably greater increase in EPA and DHA.Sponsorship : Swedish Medical Research Council ; Cardinova AB , Uppsala , Sweden [11477462] Objective : To assess the utility of serum phospholipid fatty acid ( FA ) levels as a biochemical indicator of habitual dietary fatty acid intake in Japanese , whose diet is characterized by low fat intake and high intake of n-3 polyunsaturated fatty acids ( PUFA ) of marine origin . Subjects and methods : Eighty-seven male volunteers from four public health center districts that were part of the Japan Public Health Center based Prospect i ve Study ( JPHC Study ) cohort I , were included in this study . Habitual intake of fatty acid was obtained by 7 day weighed dietary records four times ( in one area only twice ) in 1994–1995 . Blood was collected twice , in February and August of the same year , and the composition of FA in serum phospholipid was analyzed by gas chromatography . The correlation coefficient between serum phospholipid FA levels and fatty acid intake was calculated . Results : High correlations were observed for eicosapentaenoic acid ( EPA ) , docosapentaenoic acid ( DPA ) and docosahexaenoic acid ( DHA ) , which are marine origin n-3 PUFA ( r=0.75 , 0.49 , 0.50 , respectively ) . No significant correlation was observed for saturated fatty acid ( SFA ) , although the monounsaturated fatty acid ( MUFA ) , palmitoleic acid and oleic acid intake were moderately correlated ( r=0.22 , 0.35 , respectively ) . The correlations for EPA , DPA and DHA were similar in both sample s collected in February and August . Conclusions : These data suggest that in population s with a high and stable over time intake of n-3 PUFA of marine origin , a single measurement of serum phospholipids reflects the ranking of habitual intake of marine origin n-3 PUFA.European Journal of Clinical Nutrition ( 2001 ) 55 , [10745280] Objective : To evaluate the ability of design er eggs enriched in vitamin E , lutein , selenium ( Se ) and docosahexaenoic acid ( DHA ) to deliver micronutrients to the human in a palatable and visually acceptable form . Design : Double-blind , placebo-controlled trial , two treatment groups balanced for sex and age . Setting : Department of Biochemistry and Nutrition , SAC , Scotl and .Subjects : Forty healthy adult volunteers completed the study . Volunteers were recruited among staff of the Scottish Agricultural College Interventions : Volunteers consumed , for 8 weeks , either a design er egg or a normal table egg per day . Fasting blood sample s were taken before and at the end of the study . Results : Consumption of design er eggs enriched in vitamin E , lutein , Se and DHA significantly increased the levels of α-tocopherol , lutein and DHA in plasma as compared to the changes found after consumption of normal table eggs , with the largest increases found in plasma lutein ( 1.88-fold increase ) . The proportion of DHA was increased in all the main lipid classes of the plasma including triacylglycerol ( 2.3-fold ) , free fatty acids ( 1.6-fold ) , cholesteryl ester ( 1.4-fold ) and phospholipid ( 1.3-fold ) . Egg consumption did not change Se concentration in plasma , blood pressure , total plasma lipid concentrations or the concentrations of total cholesterol and HDL-cholesterol in plasma . Conclusion : Consumption of design er eggs enriched in vitamin E , lutein , DHA and Se as part of normal diet for 8 weeks effectively increased the blood levels of α-tocopherol , lutein and DHA.Sponsorship : Scottish Office Agriculture , Environment , and Fisheries Department . European Journal of Clinical Nutrition ( 2000 ) 54 , [10690163] The aim of the present study was to quantify the incorporation of eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) into plasma lipids after oral administration of n-3 fatty acid ethyl esters , since little is known about the rate and pattern of incorporation into plasma lipid fractions . In addition , we aim ed to obtain preliminary information regarding EPA half-life , which is needed to establish an optimal dosing schedule . Five healthy volunteers ingested two 8.5 g doses of n-3 fatty acid ethyl esters daily for 7 d , supplying 6.0 g EPA/d and 5.3 g DHA/d . The fatty acid compositions of plasma phospholipids ( PL ) , cholesteryl esters ( CE ) and triacylglycerols ( TAG ) were determined during supplementation and during a washout period of 7 d. Half-lives of EPA and DHA were calculated . The proportion of EPA in PL showed a 15-fold increase after 7 d ( P < 0.001 ) , while DHA showed a smaller increase ( P < 0.01 ) . In CE , EPA also increased ( P < 0.05 ) , while DHA did not increase at all . Remarkably , incorporation of DHA into TAG was even higher than that of EPA . Half-life of EPA in PL ranged from 1.63 to 2.31 d ( mean 1.97 ( SE 0.15 ) d ) , whereas mean half-life of EPA in CE was 3.27 ( SE 0.56 ) d. In three subjects , washout of EPA and DHA from TAG seemed to follow a bi-exponential pattern , with a short half-life ( < 1 d ) in the initial phase and a half-life of several days in the second phase . In conclusion , EPA ethyl esters are rapidly incorporated into plasma lipids , especially into PL . The relatively long half-life of EPA in plasma would permit a dosing schedule with intervals of > or = 12 h in supplementation studies [1534256] The effect of fish oil rich in eicosapentaenoic ( EPA ) and docosahexaenoic ( DHA ) acids on serum lipoprotein concentrations is not clear , and it is not known whether EPA and DHA are similarly related to serum lipid or lipoprotein levels . We conducted a r and omized , 10-week , dietary supplementation trial in which the effects of 6 g per day of 85 % EPA and DHA were compared with 6 g per day of corn oil in 156 men and women . Multivariate analyses were used to assess independent relations between plasma phospholipid EPA and DHA and serum lipoprotein levels . In the fish oil group triglycerides fell 21 % ( p less than 0.001 ) and high density lipoprotein cholesterol ( HDL-C ) rose 3.8 % ( p less than 0.05 ) . In the corn oil group triglycerides did not change , but HDL-C rose 6.1 % ( p less than 0.01 ) . Compared with fish oil , apolipoprotein A-I ( apo A-I ) rose 5.1 % after corn oil intake ( p less than 0.05 ) . Plasma EPA and DHA levels rose after fish oil intake and fell after corn oil intake ( all p less than 0.001 ) . The change ( delta ) in EPA was inversely correlated with delta triglycerides ( p = 0.035 ) and positively correlated with delta HDL-C and delta apo A-I ( both p less than 0.001 ) in the multivariate analyses . In contrast , delta DHA was not correlated with delta triglycerides but was inversely correlated with delta HDL-C and delta apo A-I ( both p less than 0.001 ) . St and ardizing for DHA removed the difference in apo A-I levels between groups . This study suggests that EPA and DHA are divergently associated with HDL , possibly through different mechanisms [8327853] Sixteen healthy females were r and omly assigned to receive fish oil or corn oil double blind in a 28 days intervention period . Osmotic fragility of erythrocytes was decreased in the fish-oil supplemented group and not affected in the corn-oil group . The decrease in osmotic fragility was maximal after 14 days and approached the pre-intervention level after 24 and 28 days of n-3 supplementation . No change was observed in erythrocyte membrane fluidity in either of the groups . The level of n-3 fatty acids increased significantly in erythrocytes from the fish oil supplemented subjects , mainly at the expense of linoleic acid ( 18:2 , n-6 ) and oleic acid ( 18:1 ) . No significant change was seen in the relative amount of arachidonic acid ( 20:4,n-6 ) or in the phospholipid/cholesterol ratio in erythrocytes , while the ratio between the sum of phoshatidylcholine and sphingomyeline/phosphatidylethanolamine ( PC+SM/PE ) increased during the intervention period . This study does not verify the hypothesis of a relationship between osmotic fragility and membrane fluidity . It is concluded that increased level of n-3 fatty acids in erythrocyte membranes decreases osmotic fragility , and that this effect is counteracted by increased PC+SM/PE ratio [17349088] Consumption of fish or fish oils rich in the n-3 long chain PUFA EPA and DHA may improve multiple risk factors for CVD . The objective of this study was to determine whether regular consumption of foods enriched with n-3 long-chain PUFA can improve n-3 long-chain PUFA status ( erythrocytes ) and cardiovascular health . Overweight volunteers with high levels of triacylglycerols ( TG ; > 1.6 mmol/l ) were enrolled in a 6-month dietary intervention trial conducted in Adelaide ( n 47 ) and Perth ( n 39 ) , and r and omised to consume control foods or n-3-enriched foods to achieve an EPA + DHA intake of 1 g/d . Test foods were substituted for equivalent foods in their regular diet . Erythrocyte fatty acids , plasma TG and other CVD risk factors were monitored at 0 , 3 and 6 months . There were no significant differences between groups for blood pressure , arterial compliance , glucose , insulin , lipids , C-reactive protein ( CRP ) or urinary 11-dehydro-thromboxane B2 ( TXB2 ) over 6 months , even though regular consumption of n-3-enriched foods increased EPA + DHA intake from 0.2 to 1.0 g/d . However , the n-3 long-chain PUFA content of erythrocytes increased by 35 and 53 % at 3 and 6 months , respectively , in subjects consuming the n-3-enriched foods . These increases were positively associated with measures of arterial compliance and negatively associated with serum CRP and urinary 11-dehydro-TXB2 excretion . Sustainable increases in dietary intakes and erythrocyte levels of n-3 long-chain PUFA can be achieved through regular consumption of suitably enriched processed foods . Such increases may be associated with reduced CV risk [12844385] Docosahexaenoic acid ( DHA ) ( 22 : 6n-3 ) is a polyunsaturated fatty acid that is an essential constituent of membranes , particularly of the nervous system . Infants acquire DHA from their mothers , either prenatally via the placenta or postnatally in milk . The present study aim ed to test the hypothesis that maternal supplementation during the second and third trimesters of pregnancy enriches maternal and /or fetal DHA status . In a r and omised , prospect i ve , double-blind study 100 mothers received either fish-oil capsules containing 400 mg DHA/g ( 200 mg/d ) ( n 50 ) , or placebo containing 810 mg oleic acid/g ( 400 mg/d ) ( n 50 ) from 15 weeks gestation until term . Venous blood sample s were obtained from mothers at 15 , 28 and 40 weeks , and from the umbilical cord at birth . Total fatty acids in plasma and erythrocytes were analysed by GC-MS . There were no significant differences between maternal groups in baseline DHA , as a proportion of total fatty acids ( g/100 g total fatty acids ) or concentration ( nmol/ml ) , in plasma and erythrocytes . DHA concentrations in plasma at 28 weeks ( P=0.02 ) and erythrocytes at both 28 weeks ( P=0.03 ) and term ( P=0.02 ) were 20 % higher in supplemented mothers than the placebo group . DHA accounted for a higher proportion of total fatty acids in erythrocytes of supplemented mothers at 28 weeks ( P=0.003 ) and term ( P=0.01 ) . There were no significant differences between groups in DHA ( g/100 g total fatty acids or nmol/l ) in cord blood . Maternal DHA status was maximal in mid-trimester and declined to term , at a lower rate in supplemented compared with unsupplemented mothers . Maternal DHA supplementation significantly increases maternal DHA status and limits the last trimester decline in maternal status , aiding preferential transfer of DHA from mother to fetus [15353491] Background —Omega-3 fatty acids ( FAs ) appear to reduce the risk of sudden death from myocardial infa rct ion . This reduction is believed to occur via the incorporation of eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) into the myocardium itself , altering the dynamics of sodium and calcium channel function . The extent of incorporation has not been determined in humans . Methods and Results —We first determined the correlation between red blood cell ( RBC ) and cardiac omega-3 FA levels in 20 heart transplant recipients . We then examined the effects of 6 months of omega-3 FA supplementation ( 1 g/d ) on the FA composition of human cardiac and buccal tissue , RBCs , and plasma lipids in 25 other patients . Cardiac and RBC EPA+DHA levels were highly correlated ( r=0.82 , P<0.001 ) . Supplementation increased EPA+DHA levels in cardiac tissue by 110 % , in RBCs by 101 % , in plasma by 139 % , and in cheek cells by 73 % ( P<0.005 versus baseline for all ; responses among tissues were not significantly different ) . Conclusions —Although any of the tissues examined could serve as a surrogate for cardiac omega-3 FA content , RBC EPA+DHA was highly correlated with cardiac EPA+DHA ; the RBC omega-3 response to supplementation was similar to that of the heart ; RBCs are easily collected and analyzed ; and they have a less variable FA composition than plasma . Therefore , RBC EPA+DHA ( also called the Omega-3 Index ) may be the preferred surrogate for cardiac omega-3 FA status [2374335] Summary Experimental studies suggest that the risk of prostate cancer is reduced with the intake of long-chain n-3 polyunsaturated fatty acids derived from marine foods , such as eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) . However , few human studies have been conducted due to difficulties in assessing the dietary intake of these fatty acids . The authors examined the relationship between prostate cancer risk and EPA and DHA in erythrocyte biomarkers in a population -based case – control study in Auckl and , New Zeal and during 1996–1997 involving 317 prostate cancer cases and 480 age-matched community controls . Reduced prostate cancer risk was associated with high erythrocyte phosphatidylcholine levels of EPA ( multivariate relative risk = 0.59 ; 95 % confidence interval 0.37–0.95 , upper vs lowest quartile ) and DHA ( multivariate relative risk = 0.62 ; 95 % confidence interval 0.39–0.98 , upper vs lowest quartile ) . These analyses support evidence from in vitro experiments for a reduced risk of prostate cancer associated with dietary fish oils , possibly acting via inhibition of arachidonic acid-derived eicosanoid bio synthesis [9507989] There is evidence to indicate that the high rates of coronary heart disease and myocardial infa rct ion amongst Indians of Asian descent may be partly related to circulating nonesterified fatty acids ( NEFA ) . As docosahexaenoic acid ( DHA,22:6n-3 ) in NEFA form has been found to exhibit anti-platelet aggregatory and anti-arrhythmic potential in vitro , the effect of supplementary DHA was examined in healthy subjects of Asian Indian background . Furthermore , time- and dose-dependent changes in absolute levels of DHA as NEFA or phospholipid ( PL ) were compared . The subjects consumed 8 capsules daily of placebo ( DHA-free ) or low DHA ( 0.75 g/day)or high DHA ( 1.50 g/day ) over 6 wks . Fasting blood sample s were drawn at days 0 , 21 , and 42 for analysis of serum lipid/lipoprotein composition . No significant effect of DHA supplementation on the levels of serum lipid/lipoproteins ( including Lp[a ] ) or blood pressure was found . However , the DHA level in serum phospholipid rose by 167 % overall with low-dose supplementation ( from 2.4 - 6.4 mol% ) but only by an additional 23 % upon doubling the dose from 0.75 g to 1.50 g/day . Furthermore , after 6 weeks of supplementation with 0.75 g or 1.5 g DHA/day , absolute concentrations of DHA as PL were not significantly different from the corresponding 3-week values . Interestingly , the absolute concentrations of serum DHA as NEFA showed a marked rise with low-dose supplementation ( by 212 % overall , from 2.4 to 7.5 microM ) and a further 70 % rise ( to 12.7 microM ) upon doubling the supplementation from 0.75 to 1.50 g/day . As well , the 6-week concentrations ( DHA-NEFA ) were significantly different than the corresponding 3-week values at both dose levels . Elevation of circulating DHA-NEFA levels via DHA supplementation , as shown herein , to concentrations that exhibit anti-thrombotic and anti-arrhythmic potential in vitro needs to be extended to trials where clinical end-points are determined [15085888] The nutritional significance of long-chain polyunsaturated fatty acids ( LCPS ) during the perinatal period is becoming increasingly important . There are currently very few studies on dietary intervention during gestation . The aim of the study was to analyze the effect of docosahexaenoic acid ( DHA ) supplementation during pregnancy on levels in both the newborn and the mother . A r and omized placebo controlled study was carried out on 20 pregnant women in study group receiving 200 mg/day of docosahexaenoic acid-(DHA ) during the last trimester of pregnancy . Results in both groups ( A supplemented , B non-supplemented ) highlighted a decrease in plasma arachidonic acid ( 5.99 + /- 0.91 vs. 4.51 + /- 0.71 p<0.001 for group A and 5.84 + /- 0.71 vs. 4.80 + /- 0.51 p<0.01 for group B ) in the baseline-final intra-group comparison . The intergroup comparison revealed a significant difference in plasma DHA at delivery : it was found to be higher in the population of supplemented pregnant women ( 3.17 + /- 0.26 vs. 2.77 + /- 0.31 ) . The neonate population displayed no significant differences between the two groups . The results show that LCPS are consumed during the final stages of pregnancy and that oral supplementation with 200 mg/day of DHA is reflected in an increase in the plasma level of this fatty acid in the mother . One could speculate that there would be a corresponding increase in DHA bioavailability for the fetus [15220949] Background : Studies of long-term intake of industrially produced trans fatty acids ( TFA ) and n-3 polyunsaturated fatty acids ( PUFA ) suggest opposite effects on cardiovascular disease risk . Common mechanisms of action are probable . Objective : To examine the effects on cardiovascular risk markers of dietary enrichment with TFA or n-3 PUFA . Design : R and omized , double-blind , parallel intervention trial . Setting : Department of Human Nutrition , The Royal Veterinary and Agricultural University . Subjects : In all , 87 healthy males included , 79 completed . Intervention : Subjects were r and omly assigned to 8 weeks of a daily intake of 33 g of experimental fats from either partially hydrogenated soy oil containing 20 g of TFA , 12 g of fish oil with approximately 4 g of n-3 PUFA and 21 g of control fat , or 33 g of control fat . The experimental fats were incorporated into bakery products . Plasma lipids , blood pressure , heart rate variability ( HRV ) , arterial dilatory capacity , compliance , and distensibility were recorded before and after intervention and at follow-up 12 weeks after the intervention . Results : High-density lipoprotein cholesterol ( HDL-C ) decreased in the TFA group and triglycerides and mean arterial blood pressure decreased in the n-3 PUFA group compared to the control group . HRV , arterial dilatory capacity , compliance , and distensibility were unchanged . Conclusion : The results indicate that the association between coronary heart disease risk and intake of TFA and n-3 PUFA relates only modestly to changes in traditional risk markers . Sponsorship : Danish Medical Research Council ( Grant no. 22 - 01 - 0390 ) , Center of Advanced Food Research ( Copenhagen , Denmark ) ( Grant no. KVL-R-2001 - 107 ) , the Danish Heart Association ( Grant no. 99 - 2 - 3 - 45 - 22748 ) , Novozymes ( Bagsvaerd , Denmark ) , Aarhus Olie ( Aarhus , Denmark ) , and from private sources . The experimental fats were provided by Pronova Biocare ( Aalesund , Norway ) and Aarhus Olie ( Aarhus , Denmark ) [2386561] OBJECTIVE --To provide an independent evaluation of seven day weighed dietary records , which are currently accepted as the most accurate technique for assessing habitual dietary intake in studies investigating the links between diet and health . DESIGN --Subjects who had previously participated in the Northern Irel and diet and health study were reselected by stratified r and om sampling to represent the range of energy intakes in the study as assessed by the seven day weighed dietary record . SETTING --Northern Irel and . SUBJECTS--31 Free living adults ( 16 men and 15 women ) . MAIN OUTCOME MEASURES --Energy intake as measured by the seven day weighed dietary record and total energy expenditure estimated concurrently by the doubly labelled water technique . RESULTS --Average recorded energy intakes were significantly lower than measured expenditure in the group overall ( 9.66 MJ/day v 12.15 MJ/day , 95 % confidence interval 1.45 to 3.53 MJ/day ) . Among those in the upper third of energy intakes the mean ( SE ) ratio of intake to expenditure was close to 1.0 , indicating accurate records ( men 1.01 ( 0.11 ) , women 0.96 ( 0.08 ] . In the middle and lower thirds the ratios for men were only 0.74 ( 0.05 ) and 0.70 ( 0.07 ) respectively and for women 0.89 ( 0.07 ) and 0.61 ( 0.07 ) . CONCLUSIONS --These results show a serious bias in reporting habitual energy intake . If substantiated they may have wide implication s for the interpretation of many nutritional studies [10692004] BACKGROUND Several studies have reported that dietary fish oil ( FO ) supplementation alters cytokine production and other functional activities of peripheral blood mononuclear cells ( P BMC ) . However , few of these studies have been placebo controlled and few have related the functional changes to alterations in P BMC fatty acid composition PATIENTS AND METHODS Healthy subjects supplemented their diets with 9 g day-1 of encapsulated placebo oil ( 3 : 1 mix of coconut and soybean oils ) , olive oil ( OO ) , safflower oil ( SO ) , evening primrose oil ( EPO ) or FO [ providing 2.1 g eicosapentaenoic acid ( EPA ) plus 1.1 g docosahexaenoic acid ( DHA ) per day ] for 12 weeks ; the capsules also provided 205 mg alpha-tocopherol per day . Blood was sample d at 4-weekly intervals and plasma and P BMC prepared . Plasma phospholipid and P BMC fatty acid composition , plasma alpha-tocopherol and thiobarbituric acid-reactive substance concentrations , plasma total antioxidant capacity , the proportions of different P BMC subsets , the proportions of P BMC expressing the adhesion molecules CD2 , CD11b and CD54 , and P BMC functions ( lymphocyte proliferation , natural killer cell activity , cytokine production ) were measured . All measurements were repeated after a ' washout ' period of 8 weeks . RESULTS The placebo , OO and SO capsules had no effect on plasma phospholipid or P BMC fatty acid composition . The proportion of dihomo-gamma-linolenic acid in plasma phospholipids was elevated in subjects taking EPO and was decreased in subjects taking FO . There was no appearance of gamma-linolenic acid in the plasma phospholipids or P BMC in subjects taking EPO . There was a marked increase in the proportion of EPA in the plasma phospholipids ( 10-fold ) and P BMC ( four-fold ) of subjects taking FO supplements ; this increase was maximal after 4 weeks of supplementation . There was an increase in the proportion of DHA in plasma phospholipids and P BMC , and an approximately 20 % decrease in the proportion of arachidonic acid in plasma phospholipids and P BMC , during FO supplementation . Plasma concentrations of alpha-tocopherol were significantly elevated during supplementation in all subjects and returned to baseline values after the washout period . There were no effects of supplementation with any of the capsules on total plasma antioxidant activity or plasma thiobarbituric acid-reactive substances or on the proportion of different P BMC subsets , on the proportion of P BMC expressing adhesion molecules , on natural killer cell activity , on the proliferation of mitogen-stimulated whole blood cultures or P BMC , or on the ex vivo production of a range of cytokines by whole blood cultures or P BMC cultures stimulated by either concanavalin A or lipopolysaccharide . CONCLUSION Supplementation of the diet with 3.2 g EPA plus DHA per day markedly alters plasma phospholipid and P BMC fatty acid compositions . The lack of effect of FO upon P BMC functions may relate to the level of alpha-tocopherol included in the supplements [20207123] Studies of docosahexaenoic acid ( DHA ) intake and status in US toddlers are lacking . One national survey found low DHA intakes . The objectives of this double-blind , r and omized study were to ( a ) determine usual DHA intakes , ( b ) measure the effect of consuming formulas with DHA on red blood cell ( RBC ) and plasma DHA and ( c ) record adverse events in US children between 18 and 36 months of age . Children aged 18 - 36 months were provided 237-ml formula with 0 , 43 , or 130 mg DHA per day for 60 days . Blood was obtained at 0 and 60 days and 24-hour dietary recalls at 0 , 30 and 60 days . Usual median daily DHA intake was 13.3 mg . RBC DHA increased in a dose-dependent manner with increasing DHA intake ( p<0.05 ) . Toddlers consuming the formula with 130 mg DHA per day have fewer adverse events ( p=0.007 ) and a lower incidence of respiratory illness ( p=0.024 ) , compared to the formula without DHA . US toddlers have low DHA intake and status . Modest increases in DHA intake in toddlers might improve development , including respiratory health [11090260] This study was performed to investigate whether supplementation of docosahexaenoic acid ( DHA ) and arachidonic acid ( AA ) to pregnant women would enhance their DHA levels , both in plasma and in erythrocyte phospholipids , without reducing the content of n-6 long-chain ployenes ( LCP ) usually seen when DHA is supplemented alone . Healthy pregnant women , in the second trimester , were r and omly assigned to either the control group ( n=12 ) or the intervention group ( n=12 ) . The control group received no supplements and the intervention group received daily during 4 weeks encapsulated algae-derived DHA oil ( 0.57 g DHA/day ) and fungal-derived AA oil ( 0.26 g AA/day ) . The fatty acid compositions of plasma and erythrocyte phospholipids were determined in weekly-collected blood sample s. DHA and n-6 LCP levels of the control group were unchanged after 4 weeks . Compared to the control group , DHA levels in plasma an erythrocytes of the intervention group increased significantly . No significant reductions were found in the levels of AA and total n-6 LCP . The supplement proved to be effective in increasing the DHA levels in both plasma and erythrocyte without a concomitant decline of the n-6 LCP [16512939] The intake of long-chain n-3 PUFA , including DHA ( 22 : 6n-3 ) , is associated with a reduced risk of CVD . Schizochytrium sp. are an important primary source of DHA in the marine food chain but they also provide substantial quantities of the n-6 PUFA docosapentaenoic acid ( 22 : 5n-6 ; DPA ) . The effect of this oil on cardiovascular risk factors was evaluated using a double-blind r and omised placebo-controlled parallel- design trial in thirty-nine men and forty women . Subjects received 4 g oil/d for 4 weeks ; the active treatment provided 1.5 g DHA and 0.6 g DPA . Active treatment increased plasma concentrations of arachidonic acid , adrenic acid , DPA and DHA by 21 , 11 , 11 and 88 mg/l respectively and the proportions of DPA and DHA in erythrocyte phospholipids by 78 and 27 % respectively . Serum total , LDL- and HDL-cholesterol increased by 0.33 mmol/l ( 7.3 % ) , 0.26 mmol/l ( 10.4 % ) and 0.14 mmol/l ( 9.0 % ) compared with placebo ( all P < or = 0.001 ) . Factor VII ( FVII ) coagulant activity increased by 12 % following active treatment ( P = 0.006 ) . There were no significant differences between treatments in LDL size , blood pressure , plasma glucose , serum C-reactive protein , plasma FVII antigen , FVII activated , fibrinogen , von Willebr and factor , tocopherol or carotenoid concentrations , plasminogen activator inhibitor-1 , creatine kinase or troponin-I activities , haematology or liver function tests or self-reported adverse effects . Overall , the oil was well tolerated and did not adversely affect cardiovascular risk [19915202] Epidemiological studies show that n-6/n-3 polyunsaturated fatty acid ( PUFA ) ratios have risen dramatically in Western diets and are associated with numerous chronic inflammation-related diseases . More balanced ratios are linked to less inflammation . This study examines the effects of adding oral supplements containing n-3 eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) to diets of healthy young adults on plasma n-6/n-3 ratios . Thirty volunteers are r and omly assigned to one of two groups : experimental group , EPA ( 1.6 g/day ) and DHA ( 1.2 g/day ) ; and the control group , mineral oil ( 2.4 ml/day ) . Plasma fatty acids , nutrients from foods , and anthropometric measures are evaluated at baseline and at the Week 4 endpoint . The mean ( ±SD ) n-6/n-3 ratio for the experimental group is significantly lower ( 6.3 ± 1.6 ) than the placebo group ( 16.8 ± 3.5 ) by study completion . The results suggest that more balanced n-6/n-3 ratios may be achieved efficiently in healthy , young adults with supplements containing EPA and DHA [17313719] Due to the growing knowledge about the role of specific fatty acids in health and disease , dietary intake measurements of individual fatty acids or classes of fatty acids are becoming increasingly important . The objective of this study was to evaluate the ability of the Nambour FFQ to estimate intakes of specific fatty acids , particularly PUFA . The study population was a sub- sample of adult participants in a r and omised controlled trial of beta-carotene and sunscreen in the prevention of skin cancer ( n 43 ) . Dietary intake was assessed by a self-administered FFQ and a weighed food record ( WFR ) . Non-fasting blood sample s were collected and analysed for plasma phospholipid fatty acids . Median intakes on the FFQ were generally higher than the WFR except for the n-3 PUFA groups , where the FFQ estimated higher intakes . Correlations between the FFQ and WFR were moderate ( r 0 x 32 - 0 x 59 ) except for trans fatty acids ( r 0 x 03 ) . Correlations between each of the dietary assessment methods and the plasma phospholipids were poor for all fatty acids other than the PUFA . Using the methods of triads approach , the FFQ validity coefficients for total n-3 fatty acids , total long chain n-3 fatty acids , EPA , arachidonic acid , docosapentaenoic acid and DHA were 0 x 50 , 0 x 63 , 0 x 45 and 0 x 62 and 0 x 62 , respectively . For most fatty acids , the FFQ adequately estimates group mean fatty acid intakes and can adequately rank individuals ; however , the ability of this FFQ to estimate trans fatty acids was poor [11227030] The objective of the present study was to evaluate the oxidative susceptibility of LDL in human volunteers following supplementation with various low doses ( < 1 g/d ) of n-3 polyunsaturated fatty acids ( PUFA ) . Sixty-two healthy volunteers ( thirty-seven males and twenty-five females , aged 19 - 63 years ) were recruited to take part in a r and omised placebo-controlled trial . Volunteers were required to take 0.9 , 0.6 or 0.3 g n-3 PUFA as fish oil or placebo capsules daily for 16 weeks . Susceptibility of LDL to oxidative modification was assessed by measuring the production of conjugated dienes and thiobarbituric acid-reactive substances in LDL oxidised by Cu2 + ( 15 microM ) or 2,2'-azobis(2-amidinopropane ) dihydrochloride ( 1 mM ) for 5 h. Plasma fatty acid and LDL-fatty acid composition , cholesterol levels and antioxidant concentrations were also measured . While post-treatment n-3 PUFA compositions of plasma and LDL reflected the capsule contents , no meaningful differences in antioxidant concentrations or cholesterol levels were observed between the groups . Supplementation with low doses of n-3 PUFA as fish oil did not influence the oxidative susceptibility of LDL . The results of the present study suggest that moderate dietary intakes of n-3 PUFA do not significantly influence the susceptibility of LDL to oxidative modification in vitro [11111130] Objective : Incorporation of fish oil into food products provides a means of increasing n–3 fatty acid intake , particularly in population s where fish consumption remains low . The aim of the present study was to evaluate the bioavailability of n–3 PUFA in microencapsulated fish-oil-enriched foods compared with an equal amount of n–3 PUFAs contained in fish oil capsules . Methods : Twenty-five healthy female volunteers were r and omly assigned to one of two groups for the 4-week intervention : one group received 0.9 g of n–3 PUFA/day as fish oil capsule ( capsule group ) , while the second group ( food group ) received an equal amount of n–3 PUFA/day from enriched foods . Baseline and post-intervention sample s were analysed for platelet fatty acid composition . Results : There was no significant difference in the change in platelet arachidonic acid ( AA ) , eicosapentaenoic acid ( EPA ) , or docosahexaenoic acid ( DHA ) between the two groups following the intervention . Conclusions : The results indicate that n–3 PUFA from microencapsulated fish-oil-enriched foods are as bioavailable as n–3 PUFA in a capsule . Fortification of foods with microencapsulated fish oil , therefore , offers an effective way of increasing n–3 PUFA intakes and status in line with current dietary recommendations [21063431] Background : There is a debate currently about whether different chemical forms of eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) are absorbed in an identical way . The objective of this study was to investigate the response of the omega-3 index , the percentage of EPA+DHA in red blood cell membranes , to supplementation with two different omega-3 fatty acid ( n-3 FA ) formulations in humans . Design : The study was conducted as a double-blinded placebo-controlled trial . A total of 150 volunteers was r and omly assigned to one of the three groups : ( 1 ) fish oil concentrate with EPA+DHA ( 1.01 g+0.67 g ) given as reesterified triacylglycerides ( rTAG group ) ; ( 2 ) corn oil ( placebo group ) or ( 3 ) fish oil concentrate with EPA+DHA ( 1.01 g+0.67 g ) given as ethyl ester ( EE group ) . Volunteers consumed four gelatine-coated soft capsules daily over a period of six months . The omega-3 index was determined at baseline ( t0 ) after three months ( t3 ) and at the end of the intervention period ( t6 ) . Results : The omega-3 index increased significantly in both groups treated with n-3 FAs from baseline to t3 and t6 ( P<0.001 ) . The omega-3 index increased to a greater extent in the rTAG group than in the EE group ( t3 : 186 versus 161 % ( P<0.001 ) ; t6 : 197 versus 171 % ( P<0.01 ) ) . Conclusion : A six-month supplementation of identical doses of EPA+DHA led to a faster and higher increase in the omega-3 index when consumed as triacylglycerides than when consumed as ethyl esters [10588467] The average daily consumption of seal oil by the Inuit people is approximately 8 - 9 g , yet there is very little information on the effect of seal oil consumption on cardiovascular disease risk factors . In this study , 19 healthy , normocholesterolemic subjects consumed 20 g of encapsulated seal oil containing eicosapentaenoic acid ( EPA ; 20:5n-3 ) , docosahexaenoic acid ( DHA ; 22:6n-3 ) , and docosapentaenoic acid ( DPA ; 22:5n-3 ) or 20 g of vegetable oil ( control ) per day for 42 days . Levels of selected cardiovascular and thrombotic risk factors as well as fatty acid profiles of serum phospholipid and nonesterified fatty acid ( NEFA ) were determined . EPA levels in serum phospholipid and NEFA increased by 4.3- and 2.7-fold , respectively , in the seal oil supplemented group . DHA levels rose 1.5- and 2.1-fold , respectively , and DPA levels rose 0.5- and 0.7-fold , respectively . Arachidonic acid ( AA ) levels dropped by 26 % in both serum phospholipid and serum NEFA . There was a significant decrease in the ratio of n-6 to n-3 fatty acids in serum phospholipid from 7.2 to 2.1 and a significant increase in the ratio of EPA/AA in NEFA . Ingestion of seal oil raised the coagulant inhibitor , protein C , values by 7 % and decreased plasma fibrinogen by 18 % . No alterations in other hemostatic variables , including plasma activity of Factors VII , VIII , IX , and X and antithrombin , or in the concentrations of von Willebr and Factor , total cholesterol , high-density lipoprotein cholesterol , low-density lipoprotein cholesterol , triglyceride , glucose , Apo A-1 , or lipoprotein(a ) were observed in either group . Other risk factors for cardiovascular disease , including hematocrit , white blood cell count , plasma viscosity , systolic and diastolic blood pressures , heart rate , and platelet aggregation after stimulation with ADP or collagen did not change . Our results indicate that seal oil supplementation in healthy , normocholesterolemic subjects decreased the n-6/n-3 ratio and increased EPA , DHA , and DPA and the ratio of EPA/AA and DHA/AA in the serum phospholipid and NEFA , while exhibiting a modest beneficial effect on fibrinogen and protein C levels [15741051] OBJECTIVES The aim of the study was to investigate whether fish oil supplementation affected Japanese schoolchildren 's behavior , with changes in aggression over time as the primary endpoint . DESIGN AND SUBJECTS A placebo-controlled double-blind study with 166 schoolchildren 9 - 12 years of age was performed . The subjects of the fish oil group ( n=83 ) took fish oil-fortified foods ( bread , sausage and spaghetti ) . These foods were provided in amounts such that each subject in the fish oil group had an intake of 3600 mg of docosahexaenoic acid+840 mg of eicosapentaenoic acid (EPA)/week for 3 months . The rest ( the controls , n=83 ) took control supplements . At the start and end of the study , psychological tests were performed to assess their aggression . RESULTS Physical aggression assessed by Hostility-Aggression Question naire for Children in girls increased significantly ( median : 13 to 15 , n=42 ) in the control group and did not change ( 13 to 13 , n=43 ) in the fish oil group with a significant intergroup difference ( P=.008 ) with baseline as covariate . The changes in physical aggression scores over time and those of the ratio of EPA/arachidonic acid in RBC ( DeltaEPA/AA ) were significantly correlated in girls who agreed to blood collection ( r=-.53 , P=.01 , n=23 ) . On the contrary , there were no significant changes in physical aggression in boys . Aggression against others ( extraggression ) assessed by Picture Frustration Study did not change in the control group ( median : 5 to 5 ) but increased significantly in the fish oil group ( 4 to 5 ) with a significant intergroup difference ( P=.02 ) with baseline as covariate . These changes in extraggression might be explained partly by significantly lower baseline values of extraggression in the fish oil group ( P=.02 ) than in the control group . There were no significant correlations between Deltaextraggression and DeltaEPA/AA in blood- sample d children ( n=49 ) . Impulsivity of girls assessed by parents/guardians using the diagnostic criteria for attention deficit/hyperactivity disorder of DSM-IV was reduced in the fish oil group ( 1 to 0 ) with a significant ( P=.008 ) intergroup difference from the control group ( 1 to 1 ) . There were no significant correlations between Delt aim pulsivity and DeltaEPA/AA in blood- sample d girls . In males , impulsivity reduced in both groups without any intergroup differences . CONCLUSION There is a possibility that changes in fatty acid nutrition might affect physical aggression especially in girls [15120716] This study set out to identify whether stearidonic acid ( 18:4n-3 ; STA ) can be used to increase the eicosapentaenoic acid ( 20:5n-3 ; EPA ) content of plasma lipids and cells in humans and to underst and more about the effects of increased consumption of gamma-linolenic acid ( 18:3n-3 ; GLA ) , STA and EPA in humans . Healthy young males were r and omised to consume one of seven oil blends for a period of 12 weeks ( 9 g oil/day ) ( n = 8 - 12 subjects/group ) . Palm oil , sunflower oil , an EPA-rich oil , borage oil ( rich in GLA ) , and Echium oil ( rich in STA ) were blended in various combinations to generate a placebo oil and oils providing approximately 2 g GLA + STA + EPA per day , but in different combinations . Blood was collected at 0 , 4 , 8 and 12 weeks and the fatty acid compositions of plasma triacylglycerols , cholesteryl esters and phospholipids and of peripheral blood mononuclear cells ( P BMC s ) determined . Significant effects were observed with each lipid fraction . Neither STA nor its derivative 20:4n-3 appeared in any of the lipid fractions studied when STA ( up to 1g/day ) was consumed . However , STA ( 1g/day ) , in combination with GLA ( 0.9 g/day ) , increased the proportion of EPA in some lipid fractions , suggesting that STA-rich plant oils may offer a novel means of increasing EPA status . Furthermore , this combination tended to increase the dihomo-gamma-linolenic acid ( 20:3n-6 ; DGLA ) content of P BMC s , without an increase in arachidonic acid ( AA ) ( 20:4n-6 ) content . EPA consumption increased the EPA content of all lipid fractions studied . Consumption of GLA ( 2g/day ) , in the absence of STA or EPA , increased DGLA content with a tendency to increase AA content in some fractions . This effect was prevented by inclusion of EPA in combination with GLA . Thus , this study indicates that STA may be used as a precursor to increase the EPA content of human lipids and that combinations of GLA , STA and EPA can be used to manipulate the fatty acid compositions of lipid pools in subtle ways . Such effects may offer new strategies for manipulation of cell composition in order to influence cellular responses and functions in desirable ways

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### Context: [9374124] Tissue levels of n-3 fatty acids reflect dietary intake , but quantitative data about rate of incorporation and levels as a function of intake are scarce . We fed 58 men 0 , 3 , 6 , or 9 g/d of fish oil for 12 months and monitored fatty acids in serum cholesteryl esters , erythrocytes , and subcutaneous fat during and after supplementation . Eicosapentaenoic acid ( EPA ) in cholesteryl esters plateaued after 4 - 8 weeks ; the incorporation half-life was 4.8 days . Steady-state levels increased by 3.9 + /- 0.3 mass % points ( + /- SE ) for each extra gram of EPA eaten per day . Incorporation of docosahexaenoic acid ( DHA ) was erratic ; plateau values were 1.1 + /- 0.1 mass % higher for every g/d ingested . Incorporation of EPA into erythrocyte membranes showed a half-life of 28 days ; a steady state was reached after 180 days . Each g/d increased levels by 2.1 + /- 0.1 mass % . C22:5n-3 levels increased markedly . Changes in DHA were erratic and smaller . EPA levels in adipose tissue rose also ; the change after 6 months was 67 % of that after 12 months in gluteal and 75 % in abdominal fat . After 12 months each gram per day caused an 0.11 + /- 0.01 mass % rise in gluteal fat for EPA , 0.53 + /- 0.07 for C22:5n-3 , and 0.14 + /- 0.03 for DHA . Thus , different ( n-3 ) fatty acids were incorporated with different efficiencies , possibly because of interconversions or different affinities of the enzymatic pathways involved . EPA levels in cholesteryl esters reflect intake over the past week or two , erythrocytes over the past month or two , and adipose tissue over a period of years . These findings may help in assessing the intake of ( n-3 ) fatty acids in epidemiological studies [14985680] Objective : The aim of this study was to assess the effects of fish oil supplementation in pregnancy on maternal erythrocyte fatty acid composition at different stages of pregnancy and in the post-partum period , and on neonatal erythrocyte fatty acid composition . Design : A double-blind , r and omised , placebo-controlled study . Setting : Subiaco , Western Australia . Subjects : In all , 98 women booked for delivery at St John of God Hospital , Subiaco , were recruited from private rooms of obstetricians . In total , 83 women and their healthy full-term babies completed the study . Interventions : Women received either 4 g of fish oil ( n=52 ) ( 56 % docosahexaenoic acid ( DHA ) and 28 % eicosapentaenoic acid ( EPA ) or placebo ( olive oil ) ( n=46 ) per day from 20 weeks gestation until delivery . Main outcome measures : Erythrocyte phospholipid fatty acids were measured in maternal peripheral blood at 20 , 30 and 37 weeks of pregnancy and at 6 weeks post partum , and from cord blood collected at birth . Results : Compared to the control group , maternal EPA and DHA were significantly higher in the fish oil group at 30 and 37 weeks gestation , and remained elevated at 6 weeks post partum ( P<0.001 ) . The proportions of n-6 polyunsaturated ( arachidonic acid , 22:3n-6 and 22:4n-6 ) were significantly lower in the fish oil supplemented group at the same time periods ( P<0.001 ) . Similarly , the proportions of EPA and DHA were significantly higher ( P<0.001 ) , and those of n-6 polyunsaturated fatty acids arachidonic acid , 20:3n-6 , 22:3n-6 and 22:4n-6 were significantly lower ( P<0.001 ) , in erythrocytes from neonates in the fish oil group , compared to those in the control group . Conclusions : Fish oil supplementation from 20 weeks of pregnancy until birth is an effective means of enhancing n-3 fatty acid status of both mothers and neonates . Furthermore , the changes in maternal erythrocyte fatty acid composition are retained until at least 6 weeks post partum . It is essential to assess the effects of concomitant decreases in arachidonic acid status before any dietary recommendations can be made . Sponsorship : The study was supported by grants from the NH & MRC and Raine Medical Research Foundation , Australia [12848286] Dietary DHA enhances infant attention and visual development . Because the DHA content of red blood cells and plasma lipids varies approximately threefold in pregnancy , maternal DHA status may influence subsequent infant function . It would be feasible to study the effects of higher maternal DHA intake on infant development if dietary intake of DHA could be increased by a reliable means . This study was design ed to determine whether women provided with one dozen high-DHA hen eggs ( 135 mg DHA/egg ) would consume the eggs and have higher blood DHA levels than women consuming ordinary eggs ( 18 mg DHA/egg ) . The study was a r and omized , double-masked comparison of the effect of eggs with different concentrations of DHA on intake and blood lipid DHA content of women and their infants . A third nonr and omized group ate few eggs . In this study , DHA intake reported from eggs was eightfold higher in the high-DHA egg group compared to the ordinary egg group . Including all groups , DHA intake ranged from 0 to 284 mg/d . In this intake range , maternal blood lipid DHA content at enrollment best predicted DHA content at delivery , accounting for 36.5 and 51.7 % of the variance in ordinary and high-DHA egg intake groups , respectively . The high-DHA vs. ordinary egg groups had similar maternal and cord blood lipid DHA , but there was a positive relationship between maternal plasma phospholipid DHA and daily DHA intake from eggs controlled for study duration ( r=0.278 , P=0.048 ) . DHA intake and birth weight were also correlated ( r=0.299 , P=0.041 ) . High-DHA eggs were well accepted and increased DHA intake . Other benefits of DHA intake during pregnancy were also suggested [14553835] OBJECTIVE Evaluation of the effects of supplementation of n-3 and n-6 fatty acids on vascular tone and endothelial function in healthy men and women aged 40 to 65 years . METHODS In a double-blind , r and omised , placebo controlled study , 173 healthy volunteers took one of six oil supplements for 8 months . Supplements were placebo , oleic acid rich sunflower oil , evening primrose oil , soya bean oil , tuna fish oil , and tuna/evening primrose oil mix . Endothelium-dependent and independent vascular responses were measured in the forearm skin using laser Doppler imaging following iontophoretic applications of acetylcholine and sodium nitroprusside , respectively . RESULTS Acetylcholine , but not sodium nitroprusside responses were significantly improved after tuna oil supplementation ( P=0.02 ) . Additionally , there were significant positive correlations between acetylcholine responses and n-3 fatty acid levels in the plasma and erythrocyte membrane phospholipids after tuna oil supplementation . No significant changes in vascular response were seen after supplementation with any of the other oils . CONCLUSIONS Fish oil supplementation has a beneficial effect on endothelial function , even in normal healthy subjects . Modification of the diet by an increase of 6 % in eicosapentaenoic acid and 27 % in docosahexaenoic acid ( equivalent to eating oily fish 2 - 3 times/week ) might have significant beneficial effects on cardiovascular function and health [9590631] The influence of various dietary marine oils and olive oil on fatty acid composition of serum and platelets and effects on platelets and serum lipids were investigated as part of an extensive study of the effects of these oils on parameters associated with cardiovascular/thrombotic diseases . Healthy volunteers ( 266 ) consumed 15 mL/d of cod liver oil ( CLO ) ; whale blubber oil ( refined or unrefined ) ; mixtures of seal blubber oil and CLO ; or olive oil/CLO for 12 wk . In the CLO , seal oil/CLO , and whale oil groups , serum levels of eicosapentaenoic acid ( EPA ) were increased . In platelets , EPA was increased in the CLO , seal/CLO , and olive oil/CLO groups . The localization of n-3 polyunsaturated fatty acids in the triacylglycerols did not seem to influence their absorption . Intake of oleic acid is poorly reflected in serum and platelets . No significant differences in triacylglycerols ( IG ) , total cholesterol , or high density lipoprotein cholesterol were observed , even though TG were reduced in the CLO , CLO/seal oil , and whale oil groups . Mean platelet volume increased significantly in both whale oil groups and the CLO/olive oil group . Platelet count was significantly reduced in the refined whale oil group only . Lipopolysaccharide-stimulated blood tended to generate less thromboxane B2 in CLO , CLO/seal , and CLO/olive groups . The whale oils tended to reduce in vivo release of β-thromboglobulin . In conclusion , intake of various marine oils causes changes in platelet membranes that are favorably antithrombotic . The combination of CLO and olive oil may produce better effects than these oils given separately . The changes in platelet function are directly associated with alterations of fatty acid composition in platelet membranes [9168460] The purpose of this study was to investigate in healthy humans the effect of eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) intake , alone or in combination with dL-α-tocopherol acetate ( vitamin E ) supplements on lipid peroxidation . Eightly men were r and omly assigned in a double-blind fashion to take daily for 6 wk either menhaden oil ( 6.26 g , n−3 fatty acids ) or olive oil supplements with either vitamin E ( 900 IU ) or its placebo . Antioxidant vitamins , phospholipid composition , malondialdehyde ( MDA ) , and lipid peroxides were measured in the plasma at baseline and week 6 . At the same time , breath alkane output was measured . Plasma α-tocopherol concentration increased in those receiving vitamin E ( P<0.0001 ) . In those supplemented with n−3 fatty acids , EPA and DHA increased in plasma phospholipids ( P<0.0001 ) and plasma MDA and lipid peroxides increased ( P<0.001 and P<0.05 , respectively ) . Breath alkane output did not change significantly and vitamin E intake did not prevent the increase in lipid peroxidation during menhaden oil supplementation . The results demonstrate that supplementing the diet with n−3 fatty acids result ed in an increase in lipid peroxidation , as measured by plasma MDA release and lipid peroxide products , which was not suppressed by vitamin E supplementation [20652432] Fish are a rich source of eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) , two long-chain polyunsaturated n-3 fatty acids ( LC n-3 PUFA ) with cardiovascular benefits . A related but less-investigated LC n-3 PUFA , docosapentaenoic acid ( DPA ) , is more common in seal oil and pasture-fed red meats . This study compared indicators of platelet function and plasma lipids in healthy volunteers given supplements containing these different fatty acids ( FA ) for 14 days . Subjects , r and omised into three groups of ten , consumed capsules of tuna oil ( 210 mg EPA , 30 mg DPA , 810 mg DHA ) , seal oil ( 340 mg EPA , 230 mg DPA , 450 mg DHA ) or placebo ( sunola ) oil . Supplementary LC n-3 PUFA levels were approximately 1 g/day in both fish and seal oil groups . Baseline dietary FA and other nutrient intakes were similar in all groups . Both fish and seal oil elevated platelet DHA levels ( P < 0.01 ) . Seal oil also raised platelet DPA and EPA levels ( P < 0.01 ) , and decreased p-selectin ( P = 0.01 ) , a platelet activation marker negatively associated with DPA ( P = 0.03 ) and EPA ( P < 0.01 ) but not DHA . Plasma triacylglycerol decreased ( P = 0.03 ) and HDL-cholesterol levels increased ( P = 0.01 ) with seal oil only . Hence , seal oil may be more efficient than fish oil at promoting healthy plasma lipid profiles and lowering thrombotic risk , possibly due to its high DPA as well as EPA content [12530552] The first indication of platelet activation is an increase in mean platelet volume ( MPV ) . n−3 FA are known to inhibit platelet function and to reduce the risk for coronary heart disease . The purpose of this study was to determine the effects of FPA and DHA on MPV . Healthy subjects received olive oil placebo for 4 wk and then were r and omly assigned to receive 4 g of ethyl esters of either safflower oil ( n=11 ) , EPA ( n=10 ) , or DHA ( n=12 ) for 4 wk . At the end of placebo run-in and treatment periods , MPV ( fL ; mean±SEM ) and platelet count ( PLT-CT ; 103/μL blood ) were measured in the basal state and after ex vivo stimulation with collagen ( 10 μg/mL ) , cold ( 4 ° C ) , and heat ( 37 ° C ) . Unlike DHA , EPA lowered MPV as compared with safflower oil ( 7.2±0.1 vs. 7.5±0.1 fL ; P<0.05 ) and raised PLT-CT ( 211±18 vs. 192±18 103/μL ; P<0.05 ) in the fasting state . Collagen and cold significantly increased MPV whereas heat lowered MPV regardless of treatment . All stimuli decreased PLT-CT . EPA significantly increased platelet EPA ( 0.2±0.1 vs. 3.3±0.4 % ) and docosapentaenoic acid ( DPA ; 2.2±0.3 vs. 2.9±0.3 % ) concentrations , but not DHA . DHA treatment significantly increased DHA ( 1.4±0.2 vs. 4.1±0.5 % ) and DPA ( 2.0±0.4 vs. 3.0±0.4 % ) concentrations , but not EPA . In conclusion , EPA , but not DHA , reduces platelet activation , an early step in platelet aggregation [10919932] BACKGROUND n-3 Fatty acid supplementation lowered serum triacylglycerol concentrations in studies in which most of the subjects were male . The effects of n-3 fatty acid supplementation in postmenopausal women receiving and not receiving hormone replacement therapy ( HRT ) have received little attention . OBJECTIVE We sought to determine the effects of a fish-oil-derived n-3 fatty acid concentrate on serum lipid and lipoprotein risk factors for cardiovascular disease in postmenopausal women receiving and not receiving HRT , with an emphasis on serum triacylglycerol concentrations and the ratio of triacylglycerol to HDL cholesterol . DESIGN Postmenopausal women ( n = 36 ) were grouped according to exogenous hormone use and were r and omly allocated to receive 8 capsules/d of either placebo oil ( control ) or n-3 fatty acid-enriched oil ( supplement ) . The supplement provided 2.4 g eicosapentaenoic acid ( EPA ) plus 1.6 g docosahexaenoic acid ( DHA ) daily . Serum lipids and the fatty acid composition of serum phospholipids were determined on days 0 and 28 . RESULTS Supplementation with n-3 fatty acids was associated with 26 % lower serum triacylglycerol concentrations ( P < 0.0001 ) , a 28 % lower overall ratio of serum triacylglycerol to HDL cholesterol ( P < 0.01 ) , and markedly greater EPA and DHA concentrations in serum phospholipids ( P < 0.05 ) . CONCLUSIONS These results show that supplementation with a fish-oil-derived concentrate can favorably influence selected cardiovascular disease risk factors , particularly by achieving marked reductions in serum triacylglycerol concentrations and triacylglycerol : HDL cholesterol in postmenopausal women receiving and not receiving HRT . This approach could potentially reduce the risk of coronary heart disease by 27 % in postmenopausal women [18779299] BACKGROUND An increase in plasma n-3 fatty acid content , particularly eicosapentaenoic acid ( 20:5n-3 ; EPA ) and docosahexaenoic acid ( 22:6n-3 ; DHA ) , is observed after consumption of fish oil-enriched supplements . Because alpha-linolenic acid ( 18:3n-3 ; ALA ) is the direct precursor of EPA and DHA , ALA-enriched supplements such as flax may have a similar effect , although this hypothesis has been challenged because of reported low conversion of ALA into DHA . OBJECTIVE To address this question , we design ed a clinical trial in which flax oil , fish-oil , and sunflower oil ( placebo group ) capsules were given to firefighters ( n = 62 ) , a group traditionally exposed to cardiovascular disease risk factors . DESIGN Firefighters were r and omly divided into 6 experimental groups receiving 1.2 , 2.4 , or 3.6 g flax oil/d ; 0.6 or 1.2 g fish oil/d ; or 1 g sunflower oil/d for 12 wk . Blood was drawn every 2 wk , and the total phospholipid fatty acid composition of red blood cells was determined . RESULTS As expected , fish oil produced a rapid increase in erythrocyte DHA and total n-3 fatty acids . The consumption of either 2.4 or 3.6 g flax oil/d ( in capsules ) was sufficient to significantly increase erythrocyte total phospholipid ALA , EPA , and docosapentaenoic acid ( 22:5n-3 ) fatty acid content . There were no differences among groups in plasma inflammatory markers or lipid profile . CONCLUSIONS The consumption of ALA-enriched supplements for 12 wk was sufficient to elevate erythrocyte EPA and docosapentaenoic acid content , which shows the effectiveness of ALA conversion and accretion into erythrocytes . The amounts of ALA required to obtain these effects are amounts that are easily achieved in the general population by dietary modification [18065578] BACKGROUND n-3 Fatty acids ( FAs ) have been shown to be beneficial for cardiovascular health . Whether n-3 FAs from oily fish consumed weekly or from fish-oil capsules taken daily are equally bioavailable is not clear . OBJECTIVE The purpose of this study was to compare the rate and extent of enrichment of blood cell membranes [ ie , red blood cells ( RBCs ) ] and plasma phospholipids with n-3 FAs from these 2 sources . DESIGN Healthy premenopausal female volunteers were r and omly assigned to consume a daily average of 485 mg eicosapentaenoic ( EPA ) and docosahexaenoic ( DHA ) acids either from 2 servings of oily fish ( ie , salmon and albacore tuna ) per week or from 1 - 2 capsules/d . RESULTS After 16 wk , EPA+DHA in RBCs in the fish group ( n = 11 ) increased from 4.0 + /- 0.6 % of total FAs to 6.2 + /- 1.4 % , whereas it rose from 4.3 + /- 1.0 % to 6.2 + /- 1.4 % in the capsule group ( P < 0.0001 for both ; NS for group effect ) . Similar results were observed in plasma phospholipids . EPA+DHA stabilized in the latter after 4 wk but continued to rise through week 16 in RBCs . EPA in RBCs increased significantly ( P = 0.01 ) more rapidly in the fish group than in the capsule group during the first 4 wk , but rates did not differ significantly between groups thereafter . Total FA variances were less in RBCs than in plasma phospholipids ( P = 0.04 ) . CONCLUSION These findings suggest that the consumption of equal amounts of EPA and DHA from oily fish on a weekly basis or from fish-oil capsules on a daily basis is equally effective at enriching blood lipids with n-3 FAs [1310374] Thirty healthy male subjects were r and omly allocated into one of two treatment groups : group H subjects were maintained on a high-linoleic acid ( LA ) diet with the saturated fatty acids kept low and those in group L were kept on a low-LA , low saturate diet . After a 3-wk run-in period , subjects consumed a fish-oil supplement containing 1.6 g eicosapentaenoic acid (EPA)/d and 0.32 g docosahexaenoic acid as triglycerides for a further 4 wk . The diets alone result ed in a significant change in neutrophil phospholipid LA ( H = 12.7 + /- 2.9 % , L = 9.0 + /- 0.9 % ; P less than 0.05 ) . Dietary supplementation with fish oil result ed in a significant increase in EPA in neutrophil phospholipids that was greater in group L ( mean 2.0 + /- 0.4 % ) than group H ( mean 1.5 + /- 0.3 % ; P less than 0.005 ) . Reductions in arachidonic acid concentrations in neutrophil membranes were not different , nor could differences in leukotriene B4 production be detected . Our study indicates that the ingestion of n-6 fatty acids within the diet is an important determinant of EPA incorporation into neutrophil membranes [9701178] We investigated the effect of incorporating n-3 polyunsaturated fatty acids ( PUFAs ) into the diet on the lipid-class composition of LDLs , their size , and their susceptibility to oxidation . Forty-seven healthy volunteers incorporated 30 g sunflower-oil ( SO ) margarine/d into their habitual diet during a 3-wk run-in period and then used either SO or a fish-oil-enriched sunflower oil ( FO ) margarine for the following 4 wk . Plasma concentrations of total cholesterol , triacylglycerols , HDL cholesterol , LDL cholesterol , and apolipoproteins A-I and B did not differ significantly between the groups during intervention . The FO margarine increased the concentration of n-3 very-long-chain PUFAs in the LDL particles , showing 93 % ( P < or = 0.0001 ) , 8 % ( P = 0.05 ) , and 35 % ( P = < 0.0001 ) increases in eicosapentaenoic acid , docosapentaenoic acid , and docosahexaenoic acid , respectively , in the FO group compared with 3 % , 7 % , and 7 % , respectively , in the SO group during the intervention . The cholesterol content of the LDL particles increased in the FO group [ total cholesterol : 6 % ( P = 0.008 ) ; cholesterol ester : 12 % ( P = 0.014 ) ] , although it was not significantly different from that in the control group , whereas the other lipid classes and the size of the LDL particles remained unchanged in both groups . A reduction in the alpha-tocopherol content in LDL ( 6 % , P = 0.005 ) was observed in the FO group . Ex vivo oxidation of LDL induced with Cu2 + showed a significantly reduced lag time ( from 91 to 86 min , P = 0.003 ) and lower maximum rate of oxidation ( from 10.5 to 10.2 nmol x mg(-1 ) x min(-1 ) , P = 0.003 ) after intake of the FO margarine . The results indicate that consumption of the FO compared with the SO margarine had no effect on LDL size and lipid composition and led to minor changes in LDL a-tocopherol content and oxidation resistance [17374672] ( n-3 ) PUFA influence immune function in adults and may also affect immune maturation during development . This r and omized trial is , to our knowledge , the first to investigate whether fish oil supplementation in late infancy modifies immune responses . The study was a 2 x 2 intervention in 64 healthy Danish infants , who received cow 's milk or infant formula alone or with fish oil ( FO ) ( 3.4 + /- 1.1 mL/d ) from 9 to 12 mo of age . Before and after the intervention , fatty acid composition of erythrocyte membranes , plasma IgE , C-reactive protein , and soluble IL-2 receptor concentrations were measured . TNF-alpha , INF-gamma , and IL-10 concentrations in whole-blood cultures , stimulated for 22 h with LPS+phytohemaglutinin ( PHA ) or Lactobacillus paracasei , were also determined . IgA was measured in feces when infants were 10 mo of age . FO supplementation effectively raised erythrocyte ( n-3 ) PUFA ( P < 0.001 ) , increased L. paracasei-induced INF-gamma ( P = 0.05 ) and tended to reduce LPS+PHA-induced IL-10 ( P = 0.08 ) . The FO intervention did not affect any of the other analyzed immune variables . The erythrocyte content of eicosapentanoic acid was negatively associated with LPS+PHA-induced IL-10 ( r = -0.38 , P = 0.02 ) . Feeding milk rather than formula did not affect cytokine production , but plasma soluble IL-2 receptor concentration was greater in the formula group than in the cow 's milk group ( P = 0.03 ) . Since the capacity to produce INF-gamma has been proposed as a maturation marker for the immune system in early life , this study suggests a faster immune maturation with FO supplementation with no apparent reduction in immune activation . The implication s for later health need further investigation [10479194] BACKGROUND Dietary intake of long-chain n-3 polyunsaturated fatty acids ( PUFA ) may protect against sudden cardiac death , an event that may be predicted by measurement of heart rate variability ( HRV ) . OBJECTIVE The objectives of this study were to 1 ) examine the correlations between the content of fatty acids in blood cell membranes ( platelets and granulocytes ) and HRV in healthy subjects , and 2 ) assess the effect on HRV of dietary intervention with n-3 PUFA in different doses . DESIGN Sixty healthy volunteers ( 25 women and 35 men ) were r and omly assigned to 3 treatment groups in a double-blind design . Subjects received a daily supplement of either 6.6 g n-3 PUFA , 2.0 g n-3 PUFA , or placebo ( olive oil ) . A 24-h Holter recording was obtained for each subject before supplementation and after 12 wk of supplementation ; the 24-h HRV was then related to the content of fatty acids in granulocytes and platelets . RESULTS Before supplementation , positive correlations were observed in men between the content of docosahexaenoic acid in cell membranes and HRV indexes ( r = 0.50 , P < 0.01 ) , whereas such correlations were not found in women . Dietary intervention revealed a dose-dependent effect of n-3 PUFA on HRV in men , whereas no effect was found in women . CONCLUSION The study showed a beneficial effect of n-3 PUFA on HRV in healthy men , suggesting an antiarrhythmic effect of n-3 PUFA . No such effect was observed in healthy women [11435508] Animal and human studies have shown that greatly increasing the amounts of flax seed oil [ rich in the ( n-3 ) polyunsaturated fatty acid ( PUFA ) alpha-linolenic acid ( ALNA ) ] or fish oil [ FO ; rich in the long chain ( n-3 ) PUFA eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) ] in the diet can decrease mitogen-stimulated lymphocyte proliferation . The objective of this study was to determine the effect of dietary supplementation with moderate levels of ALNA , gamma-linolenic acid ( GLA ) , arachidonic acid ( ARA ) , DHA or FO on the proliferation of mitogen-stimulated human peripheral blood mononuclear cells ( P BMC ) and on the production of cytokines by those cells . The study was r and omized , placebo-controlled , double-blinded and parallel . Healthy subjects ages 55 - 75 y consumed nine capsules/d for 12 wk ; the capsules contained placebo oil ( an 80:20 mix of palm and sunflower seed oils ) or blends of placebo oil with oils rich in ALNA , GLA , ARA or DHA or FO . Subjects in these groups consumed 2 g of ALNA or 770 mg of GLA or 680 mg of ARA or 720 mg of DHA or 1 g of EPA plus DHA ( 720 mg of EPA + 280 mg of DHA ) daily from the capsules . Total fat intake from the capsules was 4 g/d . The fatty acid composition of P BMC phospholipids was significantly changed in the GLA , ARA , DHA and FO groups . Lymphocyte proliferation was not significantly affected by the placebo , ALNA , ARA or DHA treatments . GLA and FO caused a significant decrease ( up to 65 % ) in lymphocyte proliferation . This decrease was partly reversed by 4 wk after stopping the supplementation . None of the treatments affected the production of interleukin-2 or interferon-gamma by P BMC and none of the treatments affected the number or proportion of T or B lymphocytes , helper or cytotoxic T lymphocytes or memory helper T lymphocytes in the circulation . We conclude that a moderate level GLA or EPA but not of other ( n-6 ) or ( n-3 ) PUFA can decrease lymphocyte proliferation but not production of interleukin-2 or interferon-gamma [8780337] The present work was performed to study an optimal dose and duration of dietary n-3 polyunsaturated fatty acid ( PUFA ) supplementation that would not result in harmful modifications of oxidative cell metabolism . Forty healthy subjects were divided into four groups that received 2.5 g/d eicosapentaenoic acid ( EPA ) + docosahexaenoic acid ( DHA ) , 5.1 g EPA + DHA/d , 7.7 g EPA + DHA/d , or placebo . Fatty acid composition , tocopherol status , and susceptibility to lipid peroxidation induced in vitro by 2,2'-azobis-(2-amidinopropane ) ( AAPH ) were evaluated in human red blood cell ( RBC ) membranes on days 30 and 180 . n-3 PUFA treatment increased EPA and DHA concentrations in RBC membranes in a time-dependent manner in all of the n-3 PUFA groups . These modifications occurred with concomitant dose- and time-dependent increases in the membrane unsaturation index . After 30 d of treatment with n-3 PUFAs , alpha-to-copherol significantly increased in RBC membranes of the intermediate- and high-dose groups . Because of the higher concentration of this antioxidant in these groups , the susceptibility of RBC membranes to peroxidation was decreased . However , after 180 d of treatment , alpha-tocopherol decreased to baseline values and AAPH-induced lipid peroxidation increased in a dose-dependent manner . These results show that high doses of dietary n-3 PUFAs , as well as long-time treatments , affect human RBC susceptibility to lipid peroxidation by changes in fatty acid composition and tocopherol content [15333721] Between 6 and 12 mo of age , blood levels of the ( n-3 ) long-chain PUFA , docosahexaenoic acid ( DHA ) , in breast-fed infants typically decrease due to diminished maternal DHA stores and the introduction of DHA-poor solid foods displacing human milk as the primary source of nutrition . Thus , we utilized a r and omized , clinical trial format to evaluate the effect of supplemental DHA in solid foods on visual development of breast-fed infants with the primary outcome , sweep visual-evoked potential ( VEP ) acuity , as an index for maturation of the retina and visual cortex . At 6 mo of age , breast-fed infants were r and omly assigned to receive 1 jar ( 113 g)/d of baby food containing egg yolk enriched with DHA ( 115 mg DHA/100 g food ; n = 25 ) or control baby food ( 0 mg DHA ; n = 26 ) . Gravimetric measures were used to estimate the supplemental DHA intake which was 83 mg DHA/d in the supplemented group and 0 mg/d in controls . Although many infants in both groups continued to breast-feed for a mean of 9 mo , RBC DHA levels decreased significantly between 6 and 12 mo ( from 3.8 to 3.0 g/100 g total fatty acids ) in control infants , whereas RBC DHA levels increased by 34 % from 4.1 to 5.5 g/100 g by 12 mo in supplemented infants . VEP acuity at 6 mo was 0.49 logMAR ( minimum angle of resolution ) and improved to 0.29 logMAR by 12 mo in controls . In DHA-supplemented infants , VEP acuity was 0.48 logMAR at 6 mo and matured to 0.14 logMAR at 12 mo ( 1.5 lines on the eye chart better than controls ) . At 12 mo , the difference corresponded to 1.5 lines on the eye chart . RBC DHA levels and VEP acuity at 12 mo were correlated ( r = -0.50 ; P = 0.0002 ) , supporting the need of an adequate dietary supply of DHA throughout 1 y of life for neural development [1826984] To compare their relative absorption and effect on platelet function , concentrated fish oil and tuna were given to 10 subjects in a r and omized crossover study . Although plasma enrichment of eicosapentaenoic acid ( EPA ) from either preparation was similar , relative absorption of EPA from tuna was significantly greater than that from fish oil ( 46.6 + /- 3.0 mg . L-1.g EPA-1 from tuna compared with 16 + /- 1.0 mg . L-1.g EPA-1 from fish oil , P less than 0.001 ) . Relative absorption of docosahexaenoic acid ( DHA ) was equivalent ( 54.0 + /- 9.0 mg . L-1.g DHA-1 from tuna , 56 + /- 9.0 mg . L-1.g DHA-1 from fish oil , NS ) . Platelet aggregation in response to the endoperoxide analog U46619 was significantly diminished after either preparation but aggregation in response to other agonists , bleeding time , and membrane n-3 ( omega-3 ) fatty acid content were not changed . Thus , n-3 fatty acids are well absorbed after one dose of either tuna or fish oil but EPA absorption appears to be more efficient from tuna . Additionally , a single dose of n-3 fatty acids decreases platelet aggregation by a mechanism not requiring incorporation into platelet membranes [7910999] Thirty healthy male volunteers were r and omly allocated into two dietary treatment groups . The flaxseed group ( n = 15 ) maintained a diet high in alpha-linolenic acid ( alpha-LA ; 18:3n-3 ) and low in linoleic acid ( LA ; 18:2n-6 ) by using a flaxseed oil and spread that are high in alpha-LA . The control group ( n = 15 ) maintained a diet high in LA and low in alpha-LA , typifying a Western diet . Both groups maintained their diets for 4 wk , followed by another 4-wk period in which they supplemented the diets with fish oil [ 1.62 g eicosapentaenoic acid ( EPA , 20:5n-3 ) daily and 1.08 g docosahexaenoic acid ( DHA , 22:6n-3 ) daily ] in a triglyceride form . The flaxseed oil-containing diet result ed in significant increases in alpha-LA concentrations in the plasma phospholipid , cholesteryl ester , and triglyceride fractions ( eightfold increase ) and neutrophil phospholipids ( 50 % increase ) . EPA concentrations increased by 2.5-fold in the plasma lipid fractions and neutrophil phospholipids . After fish-oil supplementation EPA concentrations increased in parallel in both dietary groups , remaining higher in the flaxseed group for both the plasma lipid fractions and neutrophil phospholipids . The results indicate that alpha-LA-rich vegetable oils can be used in a domestic setting ( in conjunction with a background diet low in LA ) to elevate EPA in tissues to concentrations comparable with those associated with fish-oil supplementation [7872228] This study addressed two questions : 1 ) whether a relatively low dose of n-3 fatty acid ethyl esters ( n-3 FAs ) administered to healthy volunteers for a prolonged period of time would exert beneficial effects on plasma lipids , platelet function , and thromboxane bio synthesis ; and 2 ) whether a short-term loading treatment ( 6 wk ) with 6 g n-3 FAs/d followed by 12 wk with 3 g/d results in more pronounced effects . After 6 wk treatment a reduction of plasma triglyceride concentration and an accumulation of EPA and DHA in plasma were observed . A longer period of treatment with n-3 FAs was necessary to affect platelet aggregation and thromboxane A2 bio synthesis . At 12 and 18 wk , platelet aggregation , thromboxane A2 formation , and the excretion of thromboxane metabolites in urine were reduced , particularly in subjects who received 6 g n-3 FAs/d during the initial 6 wk . After treatment ended , triglyceride and thromboxane A2 bio synthesis returned to baseline values within 4 wk , whereas platelet aggregation remained impaired for > or = 14 wk . The longlasting impairment in platelet aggregation was accompanied by the retention of n-3 FAs in platelet phospholipids [2203252] Effects of fish-oil ( FO ) feeding on serum lipids were investigated in a 42-d controlled diet study . Fifteen healthy male college students were assigned to one of three groups : control ( 0 g FO ) ; 5 g FO , supplying 2 g n - 3 ( omega-3 ) fatty acids ( FAs ) ; or 20 g FO , supplying 8 g n - 3 FAs . In an initial 7-d period subjects consumed a basal diet with no FO . Then FO replaced an equivalent amount of margarine for 5 wk . FO feeding significantly ( p less than 0.05 ) decreased the serum n - 6 FAs , linoleic acid , eicosatrienoic acid , and arachidonic acid . A significant increase in the n - 3 FAs , eicosapentaenoic acid and docosahexaenoic acid , was noted in serum , platelet , and neutrophil phospholipids . The 20-g-FO group showed a 30 % decrease ( p less than 0.01 ) in triglycerides after 2 wk FO with no further decrease observed . Thus , 20 g FO produced changes in both FA patterns and triglyceride concentrations whereas 5 g FO produced changes in FA patterns only . Neither FO amount result ed in significant changes in total or HDL cholesterol , apolipoprotein A-I , or apolipoprotein B-100 [15051614] BACKGROUND Supplementation of the diet with fish oil , which is rich in the long-chain n-3 polyunsaturated fatty acids eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) , is reported to decrease several markers of immune function . However , whether EPA , DHA , or a combination of the 2 exerts these immunomodulatory effects is unclear . OBJECTIVE The objective of the study was to determine the effects of supplementation with an EPA-rich or DHA-rich oil on a range of immune outcomes representing key functions of human neutrophils , monocytes , and lymphocytes in healthy humans . DESIGN In a placebo-controlled , double-blind , parallel study , 42 healthy subjects were r and omly allocated to receive supplementation with either placebo ( olive oil ) , EPA ( 4.7 g/d ) , or DHA ( 4.9 g/d ) for 4 wk . Blood sample s were taken before and after supplementation . RESULTS The fatty acid composition of plasma phospholipids and neutrophils was dramatically altered by supplementation with EPA or DHA , and the effects of EPA differed notably from those of DHA . DHA supplementation decreased T lymphocyte activation , as assessed by expression of CD69 , whereas EPA supplementation had no significant effect . Neither the EPA-rich oil nor the DHA-rich oil had any significant effect on monocyte or neutrophil phagocytosis or on cytokine production or adhesion molecule expression by peripheral blood mononuclear cells . CONCLUSIONS Supplementation with DHA , but not with EPA , suppresses T lymphocyte activation , as assessed by expression of CD69 . EPA alone does not , therefore , influence CD69 expression . No other marker of immune function assessed in this study was significantly affected by either EPA or DHA [12499320] BACKGROUND Eicosapentaenoic acid ( EPA ) , docosahexaenoic acid ( DHA ) , and gamma-linolenic acid ( GLA ) have lipid-modifying and antiinflammatory properties . The effects of supplement mixtures of these fatty acids on plasma lipids and the fatty acid compositions of serum phospholipids have received little attention . OBJECTIVE The objective was to determine the effects of different levels of GLA supplementation together with a constant intake of EPA plus DHA on the triacylglycerol-lowering effect of EPA plus DHA alone and on the fatty acid patterns ( eicosanoid precursors ) of serum phospholipids . DESIGN Thirty-one women were assigned to 1 of 4 groups , equalized on the basis of their fasting triacylglycerol concentrations . They received supplements providing 4 g EPA+DHA ( 4:0 , EPA+DHA : GLA ; control group ) , 4 g EPA+DHA plus 1 g GLA ( 4:1 ) , 2 g GLA ( 4:2 ) , or 4 g GLA ( 4:4 ) daily for 28 d. Plasma lipids and fatty acids of serum phospholipids were measured on days 0 and 28 . RESULTS Plasma triacylglycerol concentrations were significantly lower on day 28 than on day 0 in the 4:0 , 4:1 , and 4:2 groups . LDL cholesterol decreased significantly ( by 11.3 % ) in the 4:2 group . Dihomo-gamma-linolenic acid increased significantly in serum phospholipids only in the 4:2 and 4:4 groups ; however , total n-3 fatty acids increased in all 4 groups . CONCLUSIONS A mixture of 4 g EPA+DHA and 2 g GLA favorably altered blood lipid and fatty acid profiles in healthy women . On the basis of calculated PROCAM values , the 4:2 group was estimated to have a 43 % reduction in the 10-y risk of myocardial infa rct ion [17977469] Consumption of long-chain n-3 PUFA , particularly DHA , has been shown to improve cardiovascular risk factors but the intake required to achieve benefits is unclear . We sought to determine the relationship between DHA intake , increases in erythrocyte DHA content and changes in blood lipids . A total of sixty-seven subjects ( thirty-six male , thirty-one female , mean age 53 years ) with fasting serum TAG > or = 1.1 mmol/l and BMI > 25 kg/m(2 ) completed a 12-week , r and omized , double-blind , placebo-controlled parallel intervention . Subjects consumed 2 , 4 or 6 g/d of DHA-rich fish oil ( 26 % DHA , 6 % EPA ) or a placebo ( Sunola oil ) . Fasting blood lipid concentrations and fatty acid profiles in erythrocyte membranes were assessed at baseline and after 6 and 12 weeks . For every 1 g/d increase in DHA intake , there was a 23 % reduction in TAG ( mean baseline concentration 1.9 ( sem 0.1 ) mmol/l ) , 4.4 % increase in HDL-cholesterol and 7.1 % increase in LDL-cholesterol . Erythrocyte DHA content increased in proportion to the dose of DHA consumed ( r 0.72 , P < 0.001 ) and the increase after 12 weeks was linearly related to reductions in TAG ( r - 0.38 , P < 0.01 ) and increases in total cholesterol ( r 0.39 , P < 0.01 ) , LDL-cholesterol ( r 0.33 , P < 0.01 ) and HDL-cholesterol ( r 0.30 , P = 0.02 ) . The close association between incorporation of DHA in erythrocytes and its effects on serum lipids highlights the importance of erythrocyte DHA as an indicator of cardiovascular health status [12947422] Objective : To study the possibility of increasing the very long-chain n-3 polyunsaturated fatty acids , eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) , in humans by means of consumption of a common food product , Sc and inavian caviar paste , suitable for strategic enrichment with a high concentration of these fatty acids , and to measure the potential inducement of lipid peroxidation . Design : A r and omized double blind repeated measures experiment . Subjects and interventions : In total , 16 healthy , nonsmoking subjects ( eight men and eight women , age 42±12 y ) were included in the study . Eight consumed 25 g ordinary caviar paste daily for 3 weeks , and eight the same amount of caviar paste enriched with a very stable fish oil ( 7 % , wt/wt ) . Blood lipids , plasma phospholipid fatty acids and lipid peroxidation were measured . Results : α-Linoleic acid was significantly decreased after intake of both ordinary ( −8 % , P<0.05 ) and fish oil caviar ( −10 % , P<0.05 ) , as was the sum of all n-6 fatty acids ( −6 % , P<0.05 and −8 % , P<0.001 , respectively ) . The fatty acids EPA and DHA , as well as the sum of all n-3 fatty acids , increased significantly in both caviar groups but more in the group given fish oil caviar paste ( EPA : + 51 % , P<0.05 and + 100 % , P<0.001 , respectively ; DHA : + 24 % , P<0.01 and + 29 % , P<0.001 , respectively ; sum of n-3:+27 % , P<0.05 and + 40 % , P<0.001 , respectively ) . Lipid peroxidation , measured as the thiobarbituric acid — malondialdehyde adduct , was increased by 26 % ( P<0.05 ) after intake of ordinary caviar paste , but was unchanged after intake of fish oil-enriched caviar paste . Conclusions : Sc and inavian caviar paste is a spread naturally enriched with n-3 polyunsaturated fatty acids that can be included in the diet to achieve an increase in these fatty acids . However , changing to caviar paste enriched with stable fish oil will lead to a considerably greater increase in EPA and DHA.Sponsorship : Swedish Medical Research Council ; Cardinova AB , Uppsala , Sweden [11477462] Objective : To assess the utility of serum phospholipid fatty acid ( FA ) levels as a biochemical indicator of habitual dietary fatty acid intake in Japanese , whose diet is characterized by low fat intake and high intake of n-3 polyunsaturated fatty acids ( PUFA ) of marine origin . Subjects and methods : Eighty-seven male volunteers from four public health center districts that were part of the Japan Public Health Center based Prospect i ve Study ( JPHC Study ) cohort I , were included in this study . Habitual intake of fatty acid was obtained by 7 day weighed dietary records four times ( in one area only twice ) in 1994–1995 . Blood was collected twice , in February and August of the same year , and the composition of FA in serum phospholipid was analyzed by gas chromatography . The correlation coefficient between serum phospholipid FA levels and fatty acid intake was calculated . Results : High correlations were observed for eicosapentaenoic acid ( EPA ) , docosapentaenoic acid ( DPA ) and docosahexaenoic acid ( DHA ) , which are marine origin n-3 PUFA ( r=0.75 , 0.49 , 0.50 , respectively ) . No significant correlation was observed for saturated fatty acid ( SFA ) , although the monounsaturated fatty acid ( MUFA ) , palmitoleic acid and oleic acid intake were moderately correlated ( r=0.22 , 0.35 , respectively ) . The correlations for EPA , DPA and DHA were similar in both sample s collected in February and August . Conclusions : These data suggest that in population s with a high and stable over time intake of n-3 PUFA of marine origin , a single measurement of serum phospholipids reflects the ranking of habitual intake of marine origin n-3 PUFA.European Journal of Clinical Nutrition ( 2001 ) 55 , [10745280] Objective : To evaluate the ability of design er eggs enriched in vitamin E , lutein , selenium ( Se ) and docosahexaenoic acid ( DHA ) to deliver micronutrients to the human in a palatable and visually acceptable form . Design : Double-blind , placebo-controlled trial , two treatment groups balanced for sex and age . Setting : Department of Biochemistry and Nutrition , SAC , Scotl and .Subjects : Forty healthy adult volunteers completed the study . Volunteers were recruited among staff of the Scottish Agricultural College Interventions : Volunteers consumed , for 8 weeks , either a design er egg or a normal table egg per day . Fasting blood sample s were taken before and at the end of the study . Results : Consumption of design er eggs enriched in vitamin E , lutein , Se and DHA significantly increased the levels of α-tocopherol , lutein and DHA in plasma as compared to the changes found after consumption of normal table eggs , with the largest increases found in plasma lutein ( 1.88-fold increase ) . The proportion of DHA was increased in all the main lipid classes of the plasma including triacylglycerol ( 2.3-fold ) , free fatty acids ( 1.6-fold ) , cholesteryl ester ( 1.4-fold ) and phospholipid ( 1.3-fold ) . Egg consumption did not change Se concentration in plasma , blood pressure , total plasma lipid concentrations or the concentrations of total cholesterol and HDL-cholesterol in plasma . Conclusion : Consumption of design er eggs enriched in vitamin E , lutein , DHA and Se as part of normal diet for 8 weeks effectively increased the blood levels of α-tocopherol , lutein and DHA.Sponsorship : Scottish Office Agriculture , Environment , and Fisheries Department . European Journal of Clinical Nutrition ( 2000 ) 54 , [10690163] The aim of the present study was to quantify the incorporation of eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) into plasma lipids after oral administration of n-3 fatty acid ethyl esters , since little is known about the rate and pattern of incorporation into plasma lipid fractions . In addition , we aim ed to obtain preliminary information regarding EPA half-life , which is needed to establish an optimal dosing schedule . Five healthy volunteers ingested two 8.5 g doses of n-3 fatty acid ethyl esters daily for 7 d , supplying 6.0 g EPA/d and 5.3 g DHA/d . The fatty acid compositions of plasma phospholipids ( PL ) , cholesteryl esters ( CE ) and triacylglycerols ( TAG ) were determined during supplementation and during a washout period of 7 d. Half-lives of EPA and DHA were calculated . The proportion of EPA in PL showed a 15-fold increase after 7 d ( P < 0.001 ) , while DHA showed a smaller increase ( P < 0.01 ) . In CE , EPA also increased ( P < 0.05 ) , while DHA did not increase at all . Remarkably , incorporation of DHA into TAG was even higher than that of EPA . Half-life of EPA in PL ranged from 1.63 to 2.31 d ( mean 1.97 ( SE 0.15 ) d ) , whereas mean half-life of EPA in CE was 3.27 ( SE 0.56 ) d. In three subjects , washout of EPA and DHA from TAG seemed to follow a bi-exponential pattern , with a short half-life ( < 1 d ) in the initial phase and a half-life of several days in the second phase . In conclusion , EPA ethyl esters are rapidly incorporated into plasma lipids , especially into PL . The relatively long half-life of EPA in plasma would permit a dosing schedule with intervals of > or = 12 h in supplementation studies [1534256] The effect of fish oil rich in eicosapentaenoic ( EPA ) and docosahexaenoic ( DHA ) acids on serum lipoprotein concentrations is not clear , and it is not known whether EPA and DHA are similarly related to serum lipid or lipoprotein levels . We conducted a r and omized , 10-week , dietary supplementation trial in which the effects of 6 g per day of 85 % EPA and DHA were compared with 6 g per day of corn oil in 156 men and women . Multivariate analyses were used to assess independent relations between plasma phospholipid EPA and DHA and serum lipoprotein levels . In the fish oil group triglycerides fell 21 % ( p less than 0.001 ) and high density lipoprotein cholesterol ( HDL-C ) rose 3.8 % ( p less than 0.05 ) . In the corn oil group triglycerides did not change , but HDL-C rose 6.1 % ( p less than 0.01 ) . Compared with fish oil , apolipoprotein A-I ( apo A-I ) rose 5.1 % after corn oil intake ( p less than 0.05 ) . Plasma EPA and DHA levels rose after fish oil intake and fell after corn oil intake ( all p less than 0.001 ) . The change ( delta ) in EPA was inversely correlated with delta triglycerides ( p = 0.035 ) and positively correlated with delta HDL-C and delta apo A-I ( both p less than 0.001 ) in the multivariate analyses . In contrast , delta DHA was not correlated with delta triglycerides but was inversely correlated with delta HDL-C and delta apo A-I ( both p less than 0.001 ) . St and ardizing for DHA removed the difference in apo A-I levels between groups . This study suggests that EPA and DHA are divergently associated with HDL , possibly through different mechanisms [8327853] Sixteen healthy females were r and omly assigned to receive fish oil or corn oil double blind in a 28 days intervention period . Osmotic fragility of erythrocytes was decreased in the fish-oil supplemented group and not affected in the corn-oil group . The decrease in osmotic fragility was maximal after 14 days and approached the pre-intervention level after 24 and 28 days of n-3 supplementation . No change was observed in erythrocyte membrane fluidity in either of the groups . The level of n-3 fatty acids increased significantly in erythrocytes from the fish oil supplemented subjects , mainly at the expense of linoleic acid ( 18:2 , n-6 ) and oleic acid ( 18:1 ) . No significant change was seen in the relative amount of arachidonic acid ( 20:4,n-6 ) or in the phospholipid/cholesterol ratio in erythrocytes , while the ratio between the sum of phoshatidylcholine and sphingomyeline/phosphatidylethanolamine ( PC+SM/PE ) increased during the intervention period . This study does not verify the hypothesis of a relationship between osmotic fragility and membrane fluidity . It is concluded that increased level of n-3 fatty acids in erythrocyte membranes decreases osmotic fragility , and that this effect is counteracted by increased PC+SM/PE ratio [17349088] Consumption of fish or fish oils rich in the n-3 long chain PUFA EPA and DHA may improve multiple risk factors for CVD . The objective of this study was to determine whether regular consumption of foods enriched with n-3 long-chain PUFA can improve n-3 long-chain PUFA status ( erythrocytes ) and cardiovascular health . Overweight volunteers with high levels of triacylglycerols ( TG ; > 1.6 mmol/l ) were enrolled in a 6-month dietary intervention trial conducted in Adelaide ( n 47 ) and Perth ( n 39 ) , and r and omised to consume control foods or n-3-enriched foods to achieve an EPA + DHA intake of 1 g/d . Test foods were substituted for equivalent foods in their regular diet . Erythrocyte fatty acids , plasma TG and other CVD risk factors were monitored at 0 , 3 and 6 months . There were no significant differences between groups for blood pressure , arterial compliance , glucose , insulin , lipids , C-reactive protein ( CRP ) or urinary 11-dehydro-thromboxane B2 ( TXB2 ) over 6 months , even though regular consumption of n-3-enriched foods increased EPA + DHA intake from 0.2 to 1.0 g/d . However , the n-3 long-chain PUFA content of erythrocytes increased by 35 and 53 % at 3 and 6 months , respectively , in subjects consuming the n-3-enriched foods . These increases were positively associated with measures of arterial compliance and negatively associated with serum CRP and urinary 11-dehydro-TXB2 excretion . Sustainable increases in dietary intakes and erythrocyte levels of n-3 long-chain PUFA can be achieved through regular consumption of suitably enriched processed foods . Such increases may be associated with reduced CV risk [12844385] Docosahexaenoic acid ( DHA ) ( 22 : 6n-3 ) is a polyunsaturated fatty acid that is an essential constituent of membranes , particularly of the nervous system . Infants acquire DHA from their mothers , either prenatally via the placenta or postnatally in milk . The present study aim ed to test the hypothesis that maternal supplementation during the second and third trimesters of pregnancy enriches maternal and /or fetal DHA status . In a r and omised , prospect i ve , double-blind study 100 mothers received either fish-oil capsules containing 400 mg DHA/g ( 200 mg/d ) ( n 50 ) , or placebo containing 810 mg oleic acid/g ( 400 mg/d ) ( n 50 ) from 15 weeks gestation until term . Venous blood sample s were obtained from mothers at 15 , 28 and 40 weeks , and from the umbilical cord at birth . Total fatty acids in plasma and erythrocytes were analysed by GC-MS . There were no significant differences between maternal groups in baseline DHA , as a proportion of total fatty acids ( g/100 g total fatty acids ) or concentration ( nmol/ml ) , in plasma and erythrocytes . DHA concentrations in plasma at 28 weeks ( P=0.02 ) and erythrocytes at both 28 weeks ( P=0.03 ) and term ( P=0.02 ) were 20 % higher in supplemented mothers than the placebo group . DHA accounted for a higher proportion of total fatty acids in erythrocytes of supplemented mothers at 28 weeks ( P=0.003 ) and term ( P=0.01 ) . There were no significant differences between groups in DHA ( g/100 g total fatty acids or nmol/l ) in cord blood . Maternal DHA status was maximal in mid-trimester and declined to term , at a lower rate in supplemented compared with unsupplemented mothers . Maternal DHA supplementation significantly increases maternal DHA status and limits the last trimester decline in maternal status , aiding preferential transfer of DHA from mother to fetus [15353491] Background —Omega-3 fatty acids ( FAs ) appear to reduce the risk of sudden death from myocardial infa rct ion . This reduction is believed to occur via the incorporation of eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) into the myocardium itself , altering the dynamics of sodium and calcium channel function . The extent of incorporation has not been determined in humans . Methods and Results —We first determined the correlation between red blood cell ( RBC ) and cardiac omega-3 FA levels in 20 heart transplant recipients . We then examined the effects of 6 months of omega-3 FA supplementation ( 1 g/d ) on the FA composition of human cardiac and buccal tissue , RBCs , and plasma lipids in 25 other patients . Cardiac and RBC EPA+DHA levels were highly correlated ( r=0.82 , P<0.001 ) . Supplementation increased EPA+DHA levels in cardiac tissue by 110 % , in RBCs by 101 % , in plasma by 139 % , and in cheek cells by 73 % ( P<0.005 versus baseline for all ; responses among tissues were not significantly different ) . Conclusions —Although any of the tissues examined could serve as a surrogate for cardiac omega-3 FA content , RBC EPA+DHA was highly correlated with cardiac EPA+DHA ; the RBC omega-3 response to supplementation was similar to that of the heart ; RBCs are easily collected and analyzed ; and they have a less variable FA composition than plasma . Therefore , RBC EPA+DHA ( also called the Omega-3 Index ) may be the preferred surrogate for cardiac omega-3 FA status [2374335] Summary Experimental studies suggest that the risk of prostate cancer is reduced with the intake of long-chain n-3 polyunsaturated fatty acids derived from marine foods , such as eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) . However , few human studies have been conducted due to difficulties in assessing the dietary intake of these fatty acids . The authors examined the relationship between prostate cancer risk and EPA and DHA in erythrocyte biomarkers in a population -based case – control study in Auckl and , New Zeal and during 1996–1997 involving 317 prostate cancer cases and 480 age-matched community controls . Reduced prostate cancer risk was associated with high erythrocyte phosphatidylcholine levels of EPA ( multivariate relative risk = 0.59 ; 95 % confidence interval 0.37–0.95 , upper vs lowest quartile ) and DHA ( multivariate relative risk = 0.62 ; 95 % confidence interval 0.39–0.98 , upper vs lowest quartile ) . These analyses support evidence from in vitro experiments for a reduced risk of prostate cancer associated with dietary fish oils , possibly acting via inhibition of arachidonic acid-derived eicosanoid bio synthesis [9507989] There is evidence to indicate that the high rates of coronary heart disease and myocardial infa rct ion amongst Indians of Asian descent may be partly related to circulating nonesterified fatty acids ( NEFA ) . As docosahexaenoic acid ( DHA,22:6n-3 ) in NEFA form has been found to exhibit anti-platelet aggregatory and anti-arrhythmic potential in vitro , the effect of supplementary DHA was examined in healthy subjects of Asian Indian background . Furthermore , time- and dose-dependent changes in absolute levels of DHA as NEFA or phospholipid ( PL ) were compared . The subjects consumed 8 capsules daily of placebo ( DHA-free ) or low DHA ( 0.75 g/day)or high DHA ( 1.50 g/day ) over 6 wks . Fasting blood sample s were drawn at days 0 , 21 , and 42 for analysis of serum lipid/lipoprotein composition . No significant effect of DHA supplementation on the levels of serum lipid/lipoproteins ( including Lp[a ] ) or blood pressure was found . However , the DHA level in serum phospholipid rose by 167 % overall with low-dose supplementation ( from 2.4 - 6.4 mol% ) but only by an additional 23 % upon doubling the dose from 0.75 g to 1.50 g/day . Furthermore , after 6 weeks of supplementation with 0.75 g or 1.5 g DHA/day , absolute concentrations of DHA as PL were not significantly different from the corresponding 3-week values . Interestingly , the absolute concentrations of serum DHA as NEFA showed a marked rise with low-dose supplementation ( by 212 % overall , from 2.4 to 7.5 microM ) and a further 70 % rise ( to 12.7 microM ) upon doubling the supplementation from 0.75 to 1.50 g/day . As well , the 6-week concentrations ( DHA-NEFA ) were significantly different than the corresponding 3-week values at both dose levels . Elevation of circulating DHA-NEFA levels via DHA supplementation , as shown herein , to concentrations that exhibit anti-thrombotic and anti-arrhythmic potential in vitro needs to be extended to trials where clinical end-points are determined [15085888] The nutritional significance of long-chain polyunsaturated fatty acids ( LCPS ) during the perinatal period is becoming increasingly important . There are currently very few studies on dietary intervention during gestation . The aim of the study was to analyze the effect of docosahexaenoic acid ( DHA ) supplementation during pregnancy on levels in both the newborn and the mother . A r and omized placebo controlled study was carried out on 20 pregnant women in study group receiving 200 mg/day of docosahexaenoic acid-(DHA ) during the last trimester of pregnancy . Results in both groups ( A supplemented , B non-supplemented ) highlighted a decrease in plasma arachidonic acid ( 5.99 + /- 0.91 vs. 4.51 + /- 0.71 p<0.001 for group A and 5.84 + /- 0.71 vs. 4.80 + /- 0.51 p<0.01 for group B ) in the baseline-final intra-group comparison . The intergroup comparison revealed a significant difference in plasma DHA at delivery : it was found to be higher in the population of supplemented pregnant women ( 3.17 + /- 0.26 vs. 2.77 + /- 0.31 ) . The neonate population displayed no significant differences between the two groups . The results show that LCPS are consumed during the final stages of pregnancy and that oral supplementation with 200 mg/day of DHA is reflected in an increase in the plasma level of this fatty acid in the mother . One could speculate that there would be a corresponding increase in DHA bioavailability for the fetus [15220949] Background : Studies of long-term intake of industrially produced trans fatty acids ( TFA ) and n-3 polyunsaturated fatty acids ( PUFA ) suggest opposite effects on cardiovascular disease risk . Common mechanisms of action are probable . Objective : To examine the effects on cardiovascular risk markers of dietary enrichment with TFA or n-3 PUFA . Design : R and omized , double-blind , parallel intervention trial . Setting : Department of Human Nutrition , The Royal Veterinary and Agricultural University . Subjects : In all , 87 healthy males included , 79 completed . Intervention : Subjects were r and omly assigned to 8 weeks of a daily intake of 33 g of experimental fats from either partially hydrogenated soy oil containing 20 g of TFA , 12 g of fish oil with approximately 4 g of n-3 PUFA and 21 g of control fat , or 33 g of control fat . The experimental fats were incorporated into bakery products . Plasma lipids , blood pressure , heart rate variability ( HRV ) , arterial dilatory capacity , compliance , and distensibility were recorded before and after intervention and at follow-up 12 weeks after the intervention . Results : High-density lipoprotein cholesterol ( HDL-C ) decreased in the TFA group and triglycerides and mean arterial blood pressure decreased in the n-3 PUFA group compared to the control group . HRV , arterial dilatory capacity , compliance , and distensibility were unchanged . Conclusion : The results indicate that the association between coronary heart disease risk and intake of TFA and n-3 PUFA relates only modestly to changes in traditional risk markers . Sponsorship : Danish Medical Research Council ( Grant no. 22 - 01 - 0390 ) , Center of Advanced Food Research ( Copenhagen , Denmark ) ( Grant no. KVL-R-2001 - 107 ) , the Danish Heart Association ( Grant no. 99 - 2 - 3 - 45 - 22748 ) , Novozymes ( Bagsvaerd , Denmark ) , Aarhus Olie ( Aarhus , Denmark ) , and from private sources . The experimental fats were provided by Pronova Biocare ( Aalesund , Norway ) and Aarhus Olie ( Aarhus , Denmark ) [2386561] OBJECTIVE --To provide an independent evaluation of seven day weighed dietary records , which are currently accepted as the most accurate technique for assessing habitual dietary intake in studies investigating the links between diet and health . DESIGN --Subjects who had previously participated in the Northern Irel and diet and health study were reselected by stratified r and om sampling to represent the range of energy intakes in the study as assessed by the seven day weighed dietary record . SETTING --Northern Irel and . SUBJECTS--31 Free living adults ( 16 men and 15 women ) . MAIN OUTCOME MEASURES --Energy intake as measured by the seven day weighed dietary record and total energy expenditure estimated concurrently by the doubly labelled water technique . RESULTS --Average recorded energy intakes were significantly lower than measured expenditure in the group overall ( 9.66 MJ/day v 12.15 MJ/day , 95 % confidence interval 1.45 to 3.53 MJ/day ) . Among those in the upper third of energy intakes the mean ( SE ) ratio of intake to expenditure was close to 1.0 , indicating accurate records ( men 1.01 ( 0.11 ) , women 0.96 ( 0.08 ] . In the middle and lower thirds the ratios for men were only 0.74 ( 0.05 ) and 0.70 ( 0.07 ) respectively and for women 0.89 ( 0.07 ) and 0.61 ( 0.07 ) . CONCLUSIONS --These results show a serious bias in reporting habitual energy intake . If substantiated they may have wide implication s for the interpretation of many nutritional studies [10692004] BACKGROUND Several studies have reported that dietary fish oil ( FO ) supplementation alters cytokine production and other functional activities of peripheral blood mononuclear cells ( P BMC ) . However , few of these studies have been placebo controlled and few have related the functional changes to alterations in P BMC fatty acid composition PATIENTS AND METHODS Healthy subjects supplemented their diets with 9 g day-1 of encapsulated placebo oil ( 3 : 1 mix of coconut and soybean oils ) , olive oil ( OO ) , safflower oil ( SO ) , evening primrose oil ( EPO ) or FO [ providing 2.1 g eicosapentaenoic acid ( EPA ) plus 1.1 g docosahexaenoic acid ( DHA ) per day ] for 12 weeks ; the capsules also provided 205 mg alpha-tocopherol per day . Blood was sample d at 4-weekly intervals and plasma and P BMC prepared . Plasma phospholipid and P BMC fatty acid composition , plasma alpha-tocopherol and thiobarbituric acid-reactive substance concentrations , plasma total antioxidant capacity , the proportions of different P BMC subsets , the proportions of P BMC expressing the adhesion molecules CD2 , CD11b and CD54 , and P BMC functions ( lymphocyte proliferation , natural killer cell activity , cytokine production ) were measured . All measurements were repeated after a ' washout ' period of 8 weeks . RESULTS The placebo , OO and SO capsules had no effect on plasma phospholipid or P BMC fatty acid composition . The proportion of dihomo-gamma-linolenic acid in plasma phospholipids was elevated in subjects taking EPO and was decreased in subjects taking FO . There was no appearance of gamma-linolenic acid in the plasma phospholipids or P BMC in subjects taking EPO . There was a marked increase in the proportion of EPA in the plasma phospholipids ( 10-fold ) and P BMC ( four-fold ) of subjects taking FO supplements ; this increase was maximal after 4 weeks of supplementation . There was an increase in the proportion of DHA in plasma phospholipids and P BMC , and an approximately 20 % decrease in the proportion of arachidonic acid in plasma phospholipids and P BMC , during FO supplementation . Plasma concentrations of alpha-tocopherol were significantly elevated during supplementation in all subjects and returned to baseline values after the washout period . There were no effects of supplementation with any of the capsules on total plasma antioxidant activity or plasma thiobarbituric acid-reactive substances or on the proportion of different P BMC subsets , on the proportion of P BMC expressing adhesion molecules , on natural killer cell activity , on the proliferation of mitogen-stimulated whole blood cultures or P BMC , or on the ex vivo production of a range of cytokines by whole blood cultures or P BMC cultures stimulated by either concanavalin A or lipopolysaccharide . CONCLUSION Supplementation of the diet with 3.2 g EPA plus DHA per day markedly alters plasma phospholipid and P BMC fatty acid compositions . The lack of effect of FO upon P BMC functions may relate to the level of alpha-tocopherol included in the supplements [20207123] Studies of docosahexaenoic acid ( DHA ) intake and status in US toddlers are lacking . One national survey found low DHA intakes . The objectives of this double-blind , r and omized study were to ( a ) determine usual DHA intakes , ( b ) measure the effect of consuming formulas with DHA on red blood cell ( RBC ) and plasma DHA and ( c ) record adverse events in US children between 18 and 36 months of age . Children aged 18 - 36 months were provided 237-ml formula with 0 , 43 , or 130 mg DHA per day for 60 days . Blood was obtained at 0 and 60 days and 24-hour dietary recalls at 0 , 30 and 60 days . Usual median daily DHA intake was 13.3 mg . RBC DHA increased in a dose-dependent manner with increasing DHA intake ( p<0.05 ) . Toddlers consuming the formula with 130 mg DHA per day have fewer adverse events ( p=0.007 ) and a lower incidence of respiratory illness ( p=0.024 ) , compared to the formula without DHA . US toddlers have low DHA intake and status . Modest increases in DHA intake in toddlers might improve development , including respiratory health [11090260] This study was performed to investigate whether supplementation of docosahexaenoic acid ( DHA ) and arachidonic acid ( AA ) to pregnant women would enhance their DHA levels , both in plasma and in erythrocyte phospholipids , without reducing the content of n-6 long-chain ployenes ( LCP ) usually seen when DHA is supplemented alone . Healthy pregnant women , in the second trimester , were r and omly assigned to either the control group ( n=12 ) or the intervention group ( n=12 ) . The control group received no supplements and the intervention group received daily during 4 weeks encapsulated algae-derived DHA oil ( 0.57 g DHA/day ) and fungal-derived AA oil ( 0.26 g AA/day ) . The fatty acid compositions of plasma and erythrocyte phospholipids were determined in weekly-collected blood sample s. DHA and n-6 LCP levels of the control group were unchanged after 4 weeks . Compared to the control group , DHA levels in plasma an erythrocytes of the intervention group increased significantly . No significant reductions were found in the levels of AA and total n-6 LCP . The supplement proved to be effective in increasing the DHA levels in both plasma and erythrocyte without a concomitant decline of the n-6 LCP [16512939] The intake of long-chain n-3 PUFA , including DHA ( 22 : 6n-3 ) , is associated with a reduced risk of CVD . Schizochytrium sp. are an important primary source of DHA in the marine food chain but they also provide substantial quantities of the n-6 PUFA docosapentaenoic acid ( 22 : 5n-6 ; DPA ) . The effect of this oil on cardiovascular risk factors was evaluated using a double-blind r and omised placebo-controlled parallel- design trial in thirty-nine men and forty women . Subjects received 4 g oil/d for 4 weeks ; the active treatment provided 1.5 g DHA and 0.6 g DPA . Active treatment increased plasma concentrations of arachidonic acid , adrenic acid , DPA and DHA by 21 , 11 , 11 and 88 mg/l respectively and the proportions of DPA and DHA in erythrocyte phospholipids by 78 and 27 % respectively . Serum total , LDL- and HDL-cholesterol increased by 0.33 mmol/l ( 7.3 % ) , 0.26 mmol/l ( 10.4 % ) and 0.14 mmol/l ( 9.0 % ) compared with placebo ( all P < or = 0.001 ) . Factor VII ( FVII ) coagulant activity increased by 12 % following active treatment ( P = 0.006 ) . There were no significant differences between treatments in LDL size , blood pressure , plasma glucose , serum C-reactive protein , plasma FVII antigen , FVII activated , fibrinogen , von Willebr and factor , tocopherol or carotenoid concentrations , plasminogen activator inhibitor-1 , creatine kinase or troponin-I activities , haematology or liver function tests or self-reported adverse effects . Overall , the oil was well tolerated and did not adversely affect cardiovascular risk [19915202] Epidemiological studies show that n-6/n-3 polyunsaturated fatty acid ( PUFA ) ratios have risen dramatically in Western diets and are associated with numerous chronic inflammation-related diseases . More balanced ratios are linked to less inflammation . This study examines the effects of adding oral supplements containing n-3 eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) to diets of healthy young adults on plasma n-6/n-3 ratios . Thirty volunteers are r and omly assigned to one of two groups : experimental group , EPA ( 1.6 g/day ) and DHA ( 1.2 g/day ) ; and the control group , mineral oil ( 2.4 ml/day ) . Plasma fatty acids , nutrients from foods , and anthropometric measures are evaluated at baseline and at the Week 4 endpoint . The mean ( ±SD ) n-6/n-3 ratio for the experimental group is significantly lower ( 6.3 ± 1.6 ) than the placebo group ( 16.8 ± 3.5 ) by study completion . The results suggest that more balanced n-6/n-3 ratios may be achieved efficiently in healthy , young adults with supplements containing EPA and DHA [17313719] Due to the growing knowledge about the role of specific fatty acids in health and disease , dietary intake measurements of individual fatty acids or classes of fatty acids are becoming increasingly important . The objective of this study was to evaluate the ability of the Nambour FFQ to estimate intakes of specific fatty acids , particularly PUFA . The study population was a sub- sample of adult participants in a r and omised controlled trial of beta-carotene and sunscreen in the prevention of skin cancer ( n 43 ) . Dietary intake was assessed by a self-administered FFQ and a weighed food record ( WFR ) . Non-fasting blood sample s were collected and analysed for plasma phospholipid fatty acids . Median intakes on the FFQ were generally higher than the WFR except for the n-3 PUFA groups , where the FFQ estimated higher intakes . Correlations between the FFQ and WFR were moderate ( r 0 x 32 - 0 x 59 ) except for trans fatty acids ( r 0 x 03 ) . Correlations between each of the dietary assessment methods and the plasma phospholipids were poor for all fatty acids other than the PUFA . Using the methods of triads approach , the FFQ validity coefficients for total n-3 fatty acids , total long chain n-3 fatty acids , EPA , arachidonic acid , docosapentaenoic acid and DHA were 0 x 50 , 0 x 63 , 0 x 45 and 0 x 62 and 0 x 62 , respectively . For most fatty acids , the FFQ adequately estimates group mean fatty acid intakes and can adequately rank individuals ; however , the ability of this FFQ to estimate trans fatty acids was poor [11227030] The objective of the present study was to evaluate the oxidative susceptibility of LDL in human volunteers following supplementation with various low doses ( < 1 g/d ) of n-3 polyunsaturated fatty acids ( PUFA ) . Sixty-two healthy volunteers ( thirty-seven males and twenty-five females , aged 19 - 63 years ) were recruited to take part in a r and omised placebo-controlled trial . Volunteers were required to take 0.9 , 0.6 or 0.3 g n-3 PUFA as fish oil or placebo capsules daily for 16 weeks . Susceptibility of LDL to oxidative modification was assessed by measuring the production of conjugated dienes and thiobarbituric acid-reactive substances in LDL oxidised by Cu2 + ( 15 microM ) or 2,2'-azobis(2-amidinopropane ) dihydrochloride ( 1 mM ) for 5 h. Plasma fatty acid and LDL-fatty acid composition , cholesterol levels and antioxidant concentrations were also measured . While post-treatment n-3 PUFA compositions of plasma and LDL reflected the capsule contents , no meaningful differences in antioxidant concentrations or cholesterol levels were observed between the groups . Supplementation with low doses of n-3 PUFA as fish oil did not influence the oxidative susceptibility of LDL . The results of the present study suggest that moderate dietary intakes of n-3 PUFA do not significantly influence the susceptibility of LDL to oxidative modification in vitro [11111130] Objective : Incorporation of fish oil into food products provides a means of increasing n–3 fatty acid intake , particularly in population s where fish consumption remains low . The aim of the present study was to evaluate the bioavailability of n–3 PUFA in microencapsulated fish-oil-enriched foods compared with an equal amount of n–3 PUFAs contained in fish oil capsules . Methods : Twenty-five healthy female volunteers were r and omly assigned to one of two groups for the 4-week intervention : one group received 0.9 g of n–3 PUFA/day as fish oil capsule ( capsule group ) , while the second group ( food group ) received an equal amount of n–3 PUFA/day from enriched foods . Baseline and post-intervention sample s were analysed for platelet fatty acid composition . Results : There was no significant difference in the change in platelet arachidonic acid ( AA ) , eicosapentaenoic acid ( EPA ) , or docosahexaenoic acid ( DHA ) between the two groups following the intervention . Conclusions : The results indicate that n–3 PUFA from microencapsulated fish-oil-enriched foods are as bioavailable as n–3 PUFA in a capsule . Fortification of foods with microencapsulated fish oil , therefore , offers an effective way of increasing n–3 PUFA intakes and status in line with current dietary recommendations [21063431] Background : There is a debate currently about whether different chemical forms of eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) are absorbed in an identical way . The objective of this study was to investigate the response of the omega-3 index , the percentage of EPA+DHA in red blood cell membranes , to supplementation with two different omega-3 fatty acid ( n-3 FA ) formulations in humans . Design : The study was conducted as a double-blinded placebo-controlled trial . A total of 150 volunteers was r and omly assigned to one of the three groups : ( 1 ) fish oil concentrate with EPA+DHA ( 1.01 g+0.67 g ) given as reesterified triacylglycerides ( rTAG group ) ; ( 2 ) corn oil ( placebo group ) or ( 3 ) fish oil concentrate with EPA+DHA ( 1.01 g+0.67 g ) given as ethyl ester ( EE group ) . Volunteers consumed four gelatine-coated soft capsules daily over a period of six months . The omega-3 index was determined at baseline ( t0 ) after three months ( t3 ) and at the end of the intervention period ( t6 ) . Results : The omega-3 index increased significantly in both groups treated with n-3 FAs from baseline to t3 and t6 ( P<0.001 ) . The omega-3 index increased to a greater extent in the rTAG group than in the EE group ( t3 : 186 versus 161 % ( P<0.001 ) ; t6 : 197 versus 171 % ( P<0.01 ) ) . Conclusion : A six-month supplementation of identical doses of EPA+DHA led to a faster and higher increase in the omega-3 index when consumed as triacylglycerides than when consumed as ethyl esters [10588467] The average daily consumption of seal oil by the Inuit people is approximately 8 - 9 g , yet there is very little information on the effect of seal oil consumption on cardiovascular disease risk factors . In this study , 19 healthy , normocholesterolemic subjects consumed 20 g of encapsulated seal oil containing eicosapentaenoic acid ( EPA ; 20:5n-3 ) , docosahexaenoic acid ( DHA ; 22:6n-3 ) , and docosapentaenoic acid ( DPA ; 22:5n-3 ) or 20 g of vegetable oil ( control ) per day for 42 days . Levels of selected cardiovascular and thrombotic risk factors as well as fatty acid profiles of serum phospholipid and nonesterified fatty acid ( NEFA ) were determined . EPA levels in serum phospholipid and NEFA increased by 4.3- and 2.7-fold , respectively , in the seal oil supplemented group . DHA levels rose 1.5- and 2.1-fold , respectively , and DPA levels rose 0.5- and 0.7-fold , respectively . Arachidonic acid ( AA ) levels dropped by 26 % in both serum phospholipid and serum NEFA . There was a significant decrease in the ratio of n-6 to n-3 fatty acids in serum phospholipid from 7.2 to 2.1 and a significant increase in the ratio of EPA/AA in NEFA . Ingestion of seal oil raised the coagulant inhibitor , protein C , values by 7 % and decreased plasma fibrinogen by 18 % . No alterations in other hemostatic variables , including plasma activity of Factors VII , VIII , IX , and X and antithrombin , or in the concentrations of von Willebr and Factor , total cholesterol , high-density lipoprotein cholesterol , low-density lipoprotein cholesterol , triglyceride , glucose , Apo A-1 , or lipoprotein(a ) were observed in either group . Other risk factors for cardiovascular disease , including hematocrit , white blood cell count , plasma viscosity , systolic and diastolic blood pressures , heart rate , and platelet aggregation after stimulation with ADP or collagen did not change . Our results indicate that seal oil supplementation in healthy , normocholesterolemic subjects decreased the n-6/n-3 ratio and increased EPA , DHA , and DPA and the ratio of EPA/AA and DHA/AA in the serum phospholipid and NEFA , while exhibiting a modest beneficial effect on fibrinogen and protein C levels [15741051] OBJECTIVES The aim of the study was to investigate whether fish oil supplementation affected Japanese schoolchildren 's behavior , with changes in aggression over time as the primary endpoint . DESIGN AND SUBJECTS A placebo-controlled double-blind study with 166 schoolchildren 9 - 12 years of age was performed . The subjects of the fish oil group ( n=83 ) took fish oil-fortified foods ( bread , sausage and spaghetti ) . These foods were provided in amounts such that each subject in the fish oil group had an intake of 3600 mg of docosahexaenoic acid+840 mg of eicosapentaenoic acid (EPA)/week for 3 months . The rest ( the controls , n=83 ) took control supplements . At the start and end of the study , psychological tests were performed to assess their aggression . RESULTS Physical aggression assessed by Hostility-Aggression Question naire for Children in girls increased significantly ( median : 13 to 15 , n=42 ) in the control group and did not change ( 13 to 13 , n=43 ) in the fish oil group with a significant intergroup difference ( P=.008 ) with baseline as covariate . The changes in physical aggression scores over time and those of the ratio of EPA/arachidonic acid in RBC ( DeltaEPA/AA ) were significantly correlated in girls who agreed to blood collection ( r=-.53 , P=.01 , n=23 ) . On the contrary , there were no significant changes in physical aggression in boys . Aggression against others ( extraggression ) assessed by Picture Frustration Study did not change in the control group ( median : 5 to 5 ) but increased significantly in the fish oil group ( 4 to 5 ) with a significant intergroup difference ( P=.02 ) with baseline as covariate . These changes in extraggression might be explained partly by significantly lower baseline values of extraggression in the fish oil group ( P=.02 ) than in the control group . There were no significant correlations between Deltaextraggression and DeltaEPA/AA in blood- sample d children ( n=49 ) . Impulsivity of girls assessed by parents/guardians using the diagnostic criteria for attention deficit/hyperactivity disorder of DSM-IV was reduced in the fish oil group ( 1 to 0 ) with a significant ( P=.008 ) intergroup difference from the control group ( 1 to 1 ) . There were no significant correlations between Delt aim pulsivity and DeltaEPA/AA in blood- sample d girls . In males , impulsivity reduced in both groups without any intergroup differences . CONCLUSION There is a possibility that changes in fatty acid nutrition might affect physical aggression especially in girls [15120716] This study set out to identify whether stearidonic acid ( 18:4n-3 ; STA ) can be used to increase the eicosapentaenoic acid ( 20:5n-3 ; EPA ) content of plasma lipids and cells in humans and to underst and more about the effects of increased consumption of gamma-linolenic acid ( 18:3n-3 ; GLA ) , STA and EPA in humans . Healthy young males were r and omised to consume one of seven oil blends for a period of 12 weeks ( 9 g oil/day ) ( n = 8 - 12 subjects/group ) . Palm oil , sunflower oil , an EPA-rich oil , borage oil ( rich in GLA ) , and Echium oil ( rich in STA ) were blended in various combinations to generate a placebo oil and oils providing approximately 2 g GLA + STA + EPA per day , but in different combinations . Blood was collected at 0 , 4 , 8 and 12 weeks and the fatty acid compositions of plasma triacylglycerols , cholesteryl esters and phospholipids and of peripheral blood mononuclear cells ( P BMC s ) determined . Significant effects were observed with each lipid fraction . Neither STA nor its derivative 20:4n-3 appeared in any of the lipid fractions studied when STA ( up to 1g/day ) was consumed . However , STA ( 1g/day ) , in combination with GLA ( 0.9 g/day ) , increased the proportion of EPA in some lipid fractions , suggesting that STA-rich plant oils may offer a novel means of increasing EPA status . Furthermore , this combination tended to increase the dihomo-gamma-linolenic acid ( 20:3n-6 ; DGLA ) content of P BMC s , without an increase in arachidonic acid ( AA ) ( 20:4n-6 ) content . EPA consumption increased the EPA content of all lipid fractions studied . Consumption of GLA ( 2g/day ) , in the absence of STA or EPA , increased DGLA content with a tendency to increase AA content in some fractions . This effect was prevented by inclusion of EPA in combination with GLA . Thus , this study indicates that STA may be used as a precursor to increase the EPA content of human lipids and that combinations of GLA , STA and EPA can be used to manipulate the fatty acid compositions of lipid pools in subtle ways . Such effects may offer new strategies for manipulation of cell composition in order to influence cellular responses and functions in desirable ways Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Although a large body of literature has been devoted to examining the relationship between eicosapentaenoic and docosahexaenoic acids ( EPA+DHA ) and blood pressure , past systematic review s have been hampered by narrow inclusion criteria and a limited scope of analytical subgroups . In addition , no meta- analysis to date has captured the substantial volume of r and omized controlled trials ( RCTs ) published in the past 2 years . The objective of this meta- analysis was to examine the effect of EPA+DHA , without upper dose limits and including food sources , on blood pressure in RCTs . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

29869050

[18515918] OBJECTIVE To compare the cost-effectiveness of budesonide/formoterol in a single inhaler used as Maintenance and Reliever Therapy ( SMART ) versus fixed higher-dose budesonide/formoterol plus as-needed terbutaline reliever ( FHDBF ) or fixed dose fluticasone/salmeterol plus as-needed terbutaline reliever ( FDFS ) in controlling asthma in adults and adolescents . METHODS An economic evaluation was conducted by applying Canadian costs to the results of a large ( N=3,335 ) international r and omized , double-blind , controlled trial in which health re source utilization was prospect ively collected . Although no Canadian subjects were enrolled in this clinical trial , it was assumed that the results would apply to Canadian patients . Primary outcome measurements included time to first exacerbation and the number of severe exacerbations . Costs included direct medical costs ( physician/emergency room visits , hospitalizations , asthma drug costs ) and productivity ( absenteeism ) . The time horizon was six months , which corresponded to the duration of the trial . Prices were obtained from 2006 Canadian sources . Both healthcare and societal perspectives were considered . Deterministic univariate sensitivity analyses were conducted . RESULTS In the clinical trial , SMART was superior to FHDBF and FDFS with respect to total number of severe exacerbations ( RR 0.72 ; 95 % CI 0.57 , 0.90 ; p=0.0048 ; RR 0.61 ; 95 % CI 0.49 , 0.76 ; p<0.001 , respectively ) . Exacerbation rates ( reported as events per patient per 6 months ) were 0.12 for SMART , 0.16 for FHDBF , and 0.19 for FDFS . All treatments provided similar improvements in lung function , asthma control days and asthma-related quality of life . The mean cost per patient per 6 months was $ 545 in the SMART arm versus $ 690 in the FHDBF arm and $ 842 in the FDFS arm from the healthcare perspective ; and $ 676 for SMART , $ 838 for FHDBF , and $ 954 for FDFS from the societal perspective . SMART was dominant ( more effective , less expensive ) in the base case analysis from both the healthcare and societal perspectives . The results were robust under sensitivity testing . CONCLUSIONS The SMART strategy , which allows budesonide/formoterol to be used as both maintenance and reliever medication , is dominant over the alternate strategies of fixed higher dose budesonide and formoterol plus as-needed terbutaline or fixed dose salmeterol and fluticasone plus as-needed terbutaline [29702848] OBJECTIVES Omalizumab improves health outcomes for patients with severe asthma . The purpose of this study was to conduct a cost-utility analysis of omalizumab from a societal perspective by using the results from a r and omized controlled trial in Japan , and explore the efficient use of omalizumab . METHODS We developed a Markov model to compare omalizumab add-on therapy with st and ard therapy . Patients transitioned between symptom-free , day-to-day , and exacerbation states . Our model had a lifetime horizon in which 5-year omalizumab add-on therapy was followed by st and ard therapy . Preference-based utilities were extracted from another study . We estimated the expected value of perfect information for patients ' response to omalizumab . RESULTS In the base case , incremental cost-effectiveness ratio ( ICER ) for omalizumab add-on therapy was US $ 755,200 ( 95 % credible interval [ CI ] $ 614,200-$1,298,500 ) per quality -adjusted life-year gained , compared with st and ard therapy alone . One-way sensitivity analyses indicated that the results were sensitive to asthma-related mortality , exacerbation risk , and omalizumab cost . The ICER for a responder subgroup was 22 % lower than that in the base case . Individual and population expected value of perfect informations for the response were $ 4100 ( 95 % CI $ 2500-$6000 ) and $ 28 million ( 95 % CI $ 17 million-$42 million ) per year , respectively . CONCLUSIONS With a willingness-to-pay of $ 45,000 per quality -adjusted life-year , omalizumab was not cost-effective in Japan . Confining omalizumab therapy to previously predicted responders , however , may be a reasonable strategy to reduce the ICER , as the cost-effectiveness was observed to improve for these patients . Further studies should be conducted to explore responder prediction methods . Decreasing the price of omalizumab would improve cost-effectiveness [14657888] BACKGROUND The Inhaled Steroid as Regular Therapy in Early Asthma ( START ) study reported that early intervention with budesonide in mild persistent asthma reduces severe asthmatic events and improves symptom outcomes and lung function in adults and children . OBJECTIVE We sought to estimate the incremental cost-effectiveness of early intervention with budesonide , as observed within the START study . METHODS START was a r and omized , 3-year controlled trial of budesonide in early onset mild asthma among 7165 subjects ages 5 to 66 years . Three age groups ( 5 - 10 , 11 - 17 , and > or=18 years ) were studied separately and overall . Differences in the probability of emergency treatments , symptom-free days ( SFDs ) , and costs of health care were determined . Incremental cost-effectiveness ratios were estimated from the health care payer and societal perspectives . RESULTS Compared with usual therapy , patients receiving budesonide experienced an average of 14.1 ( SE , 1.3 ) more SFDs per year ( P < .001 ) , fewer hospital days ( 69 % , P < .001 ) , and fewer emergency department visits ( 67 % , P < .05 ) . From the health care payer perspective , the net cost of early use of budesonide was an additional US dollars 0.42 ( SE , dollars 0.04 ) per day , and the result ant cost-effectiveness ratio was US dollars 11.30 ( 95 % CI , US dollars 8.60-US dollars 14.90 ) per SFD gained . From the societal perspective , the cost offsets of lower absence from school or work reduced the net cost of early budesonide to US dollars 0.14 ( SE , US dollars 0.07 ) per day and decreased the cost-effectiveness ratio to US dollars 3.70 ( 95 % CI , US dollars 0.10-US dollars 8.00 ) . Early intervention was more effective and cost saving in the youngest age group . CONCLUSION Long-term treatment with budesonide appears to be cost-effective in patients with mild persistent asthma of recent onset [10346418] Abstract Objective : The aim of this study was to determine the relative economic consequences of treating asthmatics with twice daily dry powder formoterol 12 mg as compared with salmeterol 50 mg from a societal perspective . Design and Setting : A r and omised , 6-month , open-label study including 482 patients with asthma was conducted in Italy , Spain , France , Switzerl and , the UK and Sweden . Medical costs included the costs of medications , physician services , emergency room visits , hospital admissions and lung function and other tests . Travel costs and costs of production loss were also calculated . Unit prices were estimated from external sources . To pool the costs of the 6 countries , European currencies were converted to US dollars using 1995 exchange rates . Outcome measures were the number of episode-free days ( EFDs ) and the number of patients reaching a clinical ly relevant improvement in quality of life as measured using the St. Georges Respiratory Question naire . Main outcome measures and results : There were no significant differences between the 2 treatment arms in the frequency of emergency room visits , hospital admissions , use of rescue medication or contacts with general practitioners ( GPs ) , specialists or nurses . Median medical costs over 6 months were $ US828 per patient with formoterol and $ US850 with salmeterol . This difference was not statistically significant . In both groups , about 60 % of all days were episode-free . Average costs per EFD were about $ US9 for both treatments . The average cost per patient reaching a clinical ly relevant improvement in quality of life was between $ US1300 and $ US1400 . Incremental cost-effectiveness ratios were not calculated because both costs and outcomes were not significantly different . Asthma-related absenteeism ranged between 3 days and 6 months per patient in both groups . Conclusions : There was no evidence to suggest that either treatment was more cost effective than the other [11447380] BACKGROUND Inhaled corticosteroids remain underused among United States-based clinicians in treating mild-to-moderate adult asthma . OBJECTIVE The purpose of this investigation was to estimate the clinical impact , health-related quality of life , cost , and cost-effectiveness of inhaled corticosteroid therapy in a population of patients aged 18 years and over with FEV(1 ) = 60 % to 100 % of predicted normal . METHODS We performed a cost-effectiveness analysis of quick relievers ( eg , short-acting beta-agonists ) on an as-needed basis plus inhaled corticosteroid therapy versus quick relievers alone . A mathematical simulation model was developed to forecast symptoms , acute exacerbations , quality -adjusted life-years ( QALYs ) , health care costs , and cost-effectiveness , measured in both dollars per QALY gained and dollars per symptom-free day gained . All evaluation outcomes were discounted at an annual rate of 3 % and measured over a 10-year planning horizon . Data on the natural history of disease , drug efficacy , patient preferences , and economic costs were obtained from a variety of observational cohorts , r and omized trials , and patient surveys . RESULTS Over a 10-year period , use of inhaled corticosteroids increases total health costs from roughly $ 5,200 to $ 8,400 and improves QALYs from 6.8 to 7.0 , implying an incremental cost of $ 13,500 per QALY gained . Costs per symptom-free day gained are $ 7.50 . Both per-person acute exacerbations and hospitalizations are reduced by 33 % . The cost-effectiveness findings are sensitive to the assumed efficacy and side-effects of inhaled corticosteroid therapy . CONCLUSIONS Inhaled corticosteroids appear to deliver good comparative value in adults with mild-to-moderate asthma . Although more research is needed to underst and their impact on preferences regarding side effects and compliance , these findings might be useful for priority- setting in limited re source situations [9926144] Long-acting inhaled /&-agonists ( LABS ) , used in conjunction with low-dose inhaled steroids , are a recommended alternative to high-dose inhaled steroids for asthmatics with persistent symptoms ( 1 ) . There are , however , few published data regarding their cost-effectiveness . The drugs are relatively expensive and the aim of this study was to evaluate LAB cost-effectiveness in primary care , in terms of improved clinical outcomes ( associated with reduced NHS costs ) off setting higher prescription costs . A controlled , retrospective , non-r and omized analysis utilized the computerized Thorpewood Primary Care Data base and compared clinical outcomes and asthma management costs 1 yr prior to and 1 yr after initiation of therapy with salmeterol xinafoate [11379805] BACKGROUND Budesonide and sodium cromoglycate are both recommended as maintenance therapy for childhood asthma . OBJECTIVE To compare the cost-effectiveness of these two treatment strategies in clinical practice , in an open-label , pharmacoeconomic clinical trial . METHODS Health economics were evaluated in 138 children , ages 5 to 11 years , with unstable asthma not previously treated with corticosteroids or cromones . The asthma was stabilized during 4 to 6 weeks with budesonide 200 to 400 microg twice daily . The children were then r and omly allocated to one of the two treatment strategies aim ing at maintaining asthma control for 12 months ; budesonide 400 microg/day ( N = 69 ) or sodium cromoglycate 60 mg/day ( N = 69 ) . If asthma control was judged unsatisfactory , the doses were increased or the children were switched to the alternate treatment . RESULTS In children continuing on the same treatment , the degree of asthma control was similar in the two groups at study end . To maintain asthma control , 42 % of cromoglycate children switched to budesonide , and then experienced a 14 % increase in symptom-free days . No budesonide patient had to switch therapy because of lack of asthma control . Although not statistically significant , total annual cost per patient was 24 % ( Swedish kronor 4195 ; US $ 487 ; Euro 485 ) lower in the budesonide than the cromoglycate group , mainly due to a lower cost for asthma medication . CONCLUSIONS A budesonide strategy for continued maintenance treatment , after an initial period of stabilizing treatment with budesonide , result ed in lower costs and less drug switches than did a strategy with sodium cromoglycate [12535234] OBJECTIVES Mathematical modeling is used widely in economic evaluations of pharmaceuticals and other health-care technologies . Users of models in government and the private sector need to be able to evaluate the quality of models according to scientific criteria of good practice . This report describes the consensus of a task force convened to provide modelers with guidelines for conducting and reporting modeling studies . METHODS The task force was appointed with the advice and consent of the Board of Directors of ISPOR . Members were experienced developers or users of models , worked in academia and industry , and came from several countries in North America and Europe . The task force met on three occasions , conducted frequent correspondence and exchanges of drafts by electronic mail , and solicited comments on three drafts from a core group of external review ers and more broadly from the membership of ISPOR . RESULTS Criteria for assessing the quality of models fell into three areas : model structure , data used as inputs to models , and model validation . Several major themes cut across these areas . Models and their results should be represented as aids to decision making , not as statements of scientific fact ; therefore , it is inappropriate to dem and that models be vali date d prospect ively before use . However , model assumptions regarding causal structure and parameter estimates should be continually assessed against data , and models should be revised accordingly . Structural assumptions and parameter estimates should be reported clearly and explicitly , and opportunities for users to appreciate the conditional relationship between inputs and outputs should be provided through sensitivity analyses . CONCLUSIONS Model-based evaluations are a valuable re source for health-care decision makers . It is the responsibility of model developers to conduct modeling studies according to the best practicable st and ards of quality and to communicate results with adequate disclosure of assumptions and with the caveat that conclusions are conditional upon the assumptions and data on which the model is built [16136769] BACKGROUND The choice of treatment can have a major impact on the total costs associated with asthma care . OBJECTIVE To determine the relative cost-effectiveness of twice-daily treatment with inhaled fluticasone propionate-salmeterol via Diskus , 100/50 microg , with that of once-daily treatment with oral montelukast as initial maintenance therapy in patients with persistent asthma uncontrolled with a short-acting beta2-agonist alone . METHODS Data from a r and omized , double-blind , double-dummy , 12-week clinical trial were analyzed . Efficacy end points included ( 1 ) symptom-free days ( SFDs ) during the 12-week period and ( 2 ) a 12 % or greater increase in forced expiratory volume in 1 second ( FEV1 ) from baseline . The economic analysis was performed from a payer 's perspective , and hence only direct costs were included in the analysis . The incremental cost-effectiveness ratio ( ICER ) , which is the mean difference in average costs divided by the mean difference in average effectiveness , was calculated for both effectiveness outcomes ( SFDs and FEV1 ) . RESULTS For the SFDs end point , the ICER for fluticasone propionate-salmeterol vs montelukast was $ 2.87 ( 95 % confidence interval , -$1.08 to $ 6.65 ) , indicating that it costs , on average , an extra $ 2.87 per day for an additional SFD with fluticasone propionate-salmeterol than with montelukast . With regard to FEV1 , the ICER was $ 1.79 ( 95 % confidence interval , -$0.72 to $ 3.86 ) , indicating that it costs , on average , an extra $ 1.79 per day to achieve a lung function improvement of 12 % or greater from baseline with fluticasone propionate-salmeterol than with montelukast . At a widely acceptable ceiling ratio of $ 9.95 per day , the probability of fluticasone propionate-salmeterol being more cost-effective than montelukast was 99.8 % for SFDs and was almost 100 % for an FEV1 improvement of 12 % of greater . CONCLUSIONS Treating 2 main components of asthma , inflammation and smooth muscle dysfunction , using fluticasone propionate-salmeterol is more cost-effective than using a single mediator antagonist alone , such as montelukast , as initial maintenance therapy for persistent asthma in patients treated with a short-acting beta2-agonist only [11742910] STUDY OBJECTIVES To evaluate the cost-effectiveness of inhaled fluticasone propionate ( FP ) in children aged 12 to 47 months with asthma symptoms . DESIGN A retrospective economic analysis conducted from the perspective of the Danish health-care system , based on clinical data from a 12-week study . SETTING Thirty-three outpatient centers in nine countries . PATIENTS Two hundred thirty-seven children aged 12 to 47 months with documented history of recurrent wheeze or asthma symptoms . INTERVENTIONS Two dosages of FP , 100 microg/d and 200 microg/d , and placebo administered in two divided doses via a metered-dose inhaler and a Babyhaler ( Glaxo Wellcome ; Middlesex , UK ) spacer device . MEASUREMENTS Effectiveness in terms of asthma exacerbations , control of cough and wheeze symptoms , symptom-free days , overall direct costs of asthma management in Danish kroner at 1999 prices , and mean and incremental cost-effectiveness ratios . RESULTS FP , 200 microg/d , was significantly more effective than placebo treatment in terms of the proportion of exacerbation-free patients ( 73.7 % vs 59.8 % ; p = 0.025 ) and patients experiencing a > or = 25 % improvement in cough symptoms ( 57.9 % vs 39.0 % ; p = 0.018 ) . The costs per exacerbation-free patient , per patient with a > or = 25 % improvement in cough and wheeze symptoms from baseline , and per symptom-free day were lower in the FP groups than in the placebo group . The incremental cost-effectiveness ratios for these end points indicated that the additional benefits of FP , 200 microg/d , were achieved at a lower overall cost compared with placebo treatment . CONCLUSIONS From the perspective of the Danish health-care system , FP , 100 microg bid , administered via the Babyhaler inhalation device was cost-effective relative to st and ard therapy with bronchodilators alone [11929348] Abstract Background and objective : Asthma is a chronic-episodic disease characterised by acute , symptomatic episodes of varying severity . We developed a Markov model that can be used to estimate the cost effectiveness of alternative asthma treatments . Because of the costs they incur , asthma exacerbations ( ‘ attacks ’ ) requiring intervention by a healthcare professional were a central consideration in the development of the model . Methods : Treatment success was assessed as asthma control , a composite measure based on goals defined in world-wide asthma management guidelines and in terms of quality -adjusted life-years ( QALYs ) . The data from which the transition probabilities were derived came from patients with asthma who received either salmeterol/fluticasone propionate combination ( SFC ) 50/100μg or fluticasone propionate ( FP ) 100μg , administered twice daily via an inhaler , in a 12-week , r and omised , double-blind , clinical trial . Costs were estimated from re source profiles defined for each of the model states . A key aspect of the model was the use of probabilistic sensitivity analysis techniques to examine the uncertainty in the cost-effectiveness results . Distributions were fitted to transition probabilities and to cost input parameters and values were sample d at r and om from these distributions using a second order Monte Carlo simulation technique . This produced a distribution for incremental cost effectiveness that was employed to construct 95 % uncertainty intervals and to construct cost effectiveness acceptability curves . Results : In this analysis , the model was run over a 12-week period using transition probabilities derived from the trial data . The results showed that treatment with SFC result ed in a higher proportion of successfully controlled weeks per patient than treatment with FP(66 vs 47 % ) , and higher mean weekly direct asthma management costs ( £ 15.77 vs £ 11.83 ; 2000 values ) . The average incremental cost per successfully controlled week with SFC was £ 20.83.Probabilistic sensitivity analysis showed that the 95 % uncertainty intervals for the incremental cost-effectiveness ratio was −£64.94 to £ 112.66 . In approximately 25 % of cases , SFC was dominant ( more effective and less costly ) , but in the remaining cases , it was both more effective and more costly . It was shown that if decision makers are willing to pay approximately £ 45 for an additional successfully controlled week , SFC will be the more cost-effective strategy in this patient population for 80 % of the time . Conclusions : This is one of the first decision-analytic models of asthma to incorporate probabilistic sensitivity analysis techniques to explore uncertainty . The model ’s flexible yet st and ardised framework permits the cost effectiveness of alternative asthma management strategies in different healthcare setting s to be established [15987228] Abstract Objectives : To compare the costs and effectiveness of adjustable maintenance dosing with budesonide/formoterol in a single inhaler versus fixed dosing in adults with asthma . Methods : In this prospect i ve , r and omised , open-label , parallel-group , multicentre trial conducted in Germany , patients with asthma received budesonide/formoterol 160µg/4.5 µg in a single inhaler ( Symbicort ® Turbuhaler ® ) with two inhalations twice daily for a 4-week run-in period . Patients were then r and omised to either adjustable maintenance dosing ( one inhalation twice daily , stepping up to four inhalations twice daily for 1 week if asthma worsened ; n = 1679 ) or fixed dosing ( two inhalations twice daily ; n = 1618 ) for 12 weeks . The primary efficacy variable was the change in health-related quality of life ( HR-QOL ) , measured using the Asthma Quality of Life Question naire ( st and ardised ) during the r and omised treatment period . Re source utilisation data were collected in parallel and combined with German unit costs to estimate direct and indirect costs ( year 2001 values ) . Results : Both treatment regimens were equally effective in maintaining HR-QOL and asthma control during the r and omised treatment period . However , overall , patients in the adjustable maintenance dosing group took fewer daily inhalations of budesonide/formoterol than those in the fixed-dosing group ( mean : 2.63 vs 3.82 inhalations ; p < 0.001 ) . Adjustable maintenance dosing was associated with significantly lower asthma-related direct costs compared with fixed dosing ( mean : € 221 vs € 292 ; p < 0.001 ) . This pattern was maintained when patients were stratified into those with peak expiratory flow ( PEF ) of 60 % to < 80 % predicted normal and those with PEF of ≥80 % predicted normal and when total costs were considered . Conclusion : Adjustable maintenance dosing with budesonide/formoterol in a single inhaler maintained HR-QOL in adult patients with asthma at a significantly lower cost than fixed dosing [10662477] Abstract Objective : The aim of this study was to determine the cost effectiveness of 2 inhaled corticosteroids , fluticasone propionate and flunisolide , in the management of asthma from a third-party payer perspective in Germany ( German Sickness Fund ) . Design and setting : Direct treatment costs were retrospectively applied to 2 prospect i ve r and omised parallel group clinical trials conducted in Germany comparing fluticasone propionate and flunisolide : one 6-week open-label study ( n = 332 ) and one 8-week double-blind study ( n = 308 ) in corticosteroid-naive patients with asthma of moderate severity aged between 18 and 70 years . All costs were adjusted to 1997 Deutschmarks . Efficacy parameters included changes in morning and evening peak expiratory flow rate ( PEFR ) measurements , the number of successfully treated patients ( defined as those with a PEFR improvement of ≥10 % ) and proportion of symptom-free days . Main outcome measures and results : The fluticasone propionate groups had higher respective proportions of successfully treated patients and symptom-free days than the flunisolide groups in both the open-label ( 56.8 vs 39.6 % and 36.4 vs 28.5 % ) and double-blind ( 55.3 vs 44.5 % and 35.1 vs 31.1 % ) studies . Improvements in both morning and evening PEFR measurements were also significantly ( p < 0.01 ) greater with fluticasone propionate than with flunisolide . Although average daily treatment costs were slightly higher in the fluticasone propionate groups than in the flunisolide groups , all cost-effectiveness ratios ( daily cost per successfully treated patient and daily cost per symptom-free day ) favoured fluticasone propionate . Sensitivity analysis showed that these results were robust over a wide range of assumptions . Conclusion : In these patients , management with fluticasone propionate was more cost effective than with flunisolide in the German healthcare setting [21839898] OBJECTIVE To assess the incremental cost-effectiveness of SFC compared with MON for the control of persistent asthma in children . METHODS We conducted an economic evaluation on a 12-week prospect i ve r and omized open-label parallel-group comparison of SFC versus MON in children with symptomatic asthma receiving inhaled corticosteroids and short-acting β2-agonists . Asthma-related medication , unscheduled physician contacts and hospitalizations were collected prospect ively . The main effectiveness measure was percentage of asthma-controlled week with no short-acting β2-agonist use during the study period . The analysis was conducted from the Mexican healthcare perspective using 2010 unit cost prices , and only direct costs were considered , all costs are reported in US dollar . . The model was made fully probabilistic to reflect the joint uncertainty in the model parameters . RESULTS Over the whole treatment period , the median percentages of asthma-controlled weeks were 83.3 % in the SFC group and 66.7 % in the MON group ( SFC-MON difference , 16.7 % ; 95 % CI , 8.3 - 16.7 ; P < 0.001 in favor of SFC ) . The mean total cost of the SFC regimen was $ 2,323 compared with $ 3,230 for the MON regimen . The SFC was the dominant strategy ( both more effective and less expensive ) using the SFC was associated with an incremental cost per additional asthma-controlled of $ ( 5,467 ) . Probabilistic sensitivity analysis tested numerous assumptions about the model cost and efficacy parameters and found that the results were robust to most changes . CONCLUSIONS This analysis demonstrates that , compared with MON , SFC may be cost saving from the Mexican health care perspective for the treatment of pediatric patients with asthma . SFC provided a reduction in the number of severe exacerbations , frequent asthma symptoms and rescue medication use . Incremental cost-effectiveness analysis indicated the dominance of SFC because of both lower costs and greater efficacy [7763062] Eighty six children with troublesome wheezing were studied , in a semi prospect i ve clinical trial with the patients acting as their own controls , to assess the efficacy and cost effectiveness of inhaled steroids . Improvement in school attendance , hospitalisations , breakthrough wheezing , and acute severe attacks were used to assess clinical efficacy . Expenditure for the family , on a cost of illness framework , before and after treatment , was used to estimate cost effectiveness . Highly significant numbers of patients showed improvement in clinical parameters , confirming efficacy . Mean monthly cost before inhaled steroid treatment was Rs 2652.33 ( 36.33 pounds ) and Rs 449.42 ( 6.16 pounds ) after starting treatment . The mean cost per unit satisfaction ( cost utility value ) which was Rs 255.54 ( 3.50 pounds ) before starting prophylaxis came down to Rs 5.42 ( 0.07 pound ) after starting treatment . There are no previous reports of cost-benefit assessment of inhaled steroids in childhood asthma . It is concluded that , even for developing countries with financial constraints , inhaled steroid treatment for prophylaxis of asthma is a cost effective and rational form of treatment [26303207] Abstract Objective : The objective of this study is to summarize the principal findings in the literature about acute asthma management in children . Methods : Systematic review s of r and omized clinical trials ( S RCTs ) with or without meta- analysis in children ( 1–18 years ) admitted to the emergency department ( ED ) were retrieved using five data bases . Method ological quality was determined using the AMSTAR tool . Results : One hundred and three studies were retrieved . Among those , 28 S RCTs were included : seven S RCTs related to short-acting beta2-agonists ( SABA ) , three to ipratropium bromide ( IB ) , eight to corticosteroids , one to racemic adrenaline , one to leukotriene receptor antagonists ( LTRA ) , four to magnesium sulfate , one to intravenous ( IV ) SABA , one to IV aminophylline , one to IV ketamine , and one to antibiotics . It was determined that administering SABA by MDI-VHC is superior to using a nebulizer , because it decreases the hospital admission rate , improves the clinical score , results in a shorter time in the ED , and causes fewer adverse effects . Levalbuterol and albuterol were similar . In patients with moderate to severe exacerbations , IB+SABA was superior to SABA , decreasing hospital admission and improving the clinical score . SABA heliox administered by nebulizer decreased exacerbation severity compared to oxygen . Inhaled corticosteroids ( ICS ) , especially administered by nebulizer , showed results similar to oral corticosteroids ( OCS ) with respect to reducing hospital admission , unscheduled visits , and the requirement of additional systemic corticosteroids . ICS or OCS following ED discharge was similar with regard to relapse . Compared with a placebo , IV magnesium reduced hospital admission and improved lung function . Conclusions : S RCTs are useful for guiding decisions in acute asthma treatment [12000004] We conducted an economic evaluation in a UK setting based on a 12-week prospect i ve r and omized open-label parallel-group comparison of eformoterol Turbohaler 12 microg b. i.d . with salmeterol Accuhaler 50 microg b. i.d . in children aged 6 - 17 with symptomatic asthma receiving inhaled corticosteroids and short-acting beta2-agonists . The principal effectiveness measure was percentage of symptom-free days with no short-acting beta2-agonist use during the study period . Asthma-related medication , unscheduled physician contacts and hospitalizations were collected prospect ively and cost to the UK NHS calculated using year 2,000 prices . The economic evaluation included 73 patients in the eformoterol group and 72 patients in the salmeterol group . The mean age of patients was 11.6 years ( eformoterol ) and 11.8 years ( salmeterol ) . The mean percentage of symptom-free days with no short-acting beta2-agonist use was 39 % in the eformoterol group and 30 % in the salmeterol group . Mean per patient daily cost was 1.15 pounds in the eformoterol group and 1.39 pounds in the salmeterol group . Both cost and effectiveness differences favoured eformoterol ( P < 0.05 ; one-sided ) . Sensitivity analysis confirmed the results to be robust to changes in effectiveness , price and re source utilisation parameters . Eformoterol delivered by Turbohaler was found to be significantly more effective and less expensive than salmeterol Accuhaler in this study [16573705] The inhaled Steroid Treatment As Regular Therapy in early asthma ( START ) study has shown that early intervention with inhaled budesonide in mild persistent asthma improves clinical outcomes in both adults and children . The aim of this study was to estimate the incremental cost-effectiveness of early treatment with budesonide Turbuhaler in children aged 5 - 10 yr who participated in START . Direct and indirect costs associated with asthma were determined for 1974 children participating in the double-blind , 3-year part of the study . R and omization was to placebo or to budesonide 200 microg once daily in each case in addition to usual asthma care . Cost-effectiveness ratios were calculated from the healthcare payer 's and societal perspectives ( using US prices ) . The addition of once-daily budesonide therapy to usual asthma care was associated with 16 additional symptom-free days ( SFDs ) per child over the 3-yr period ( p < 0.001 ) , with a substantial reduction ( 50 % ) in the mean number of days spent in hospital , and with reduced frequency of emergency room visits and missed school and caregiver work days . From the healthcare payer 's perspective ( direct costs ) , the increase in mean direct cost over 3 yr with budesonide was 169 dollars , which translated into an incremental cost of early intervention with budesonide in children of 10.50 dollars ( 95 % CI 1.20 - 33.30 dollars ) per SFD gained . From the societal perspective , there was a cost reduction over 3 yr of 192 dollars with budesonide relative to placebo . From a societal perspective , budesonide was therefore dominant . In conclusion , early intervention with once-daily budesonide added to usual asthma care in children with mild persistent asthma is cost-saving from a societal perspective and is acceptably cost-effective when viewed from a healthcare payer perspective [19768640] Introduction In budesonide/formoterol ( Symbicort ® Turbuhaler ® , AstraZeneca , Lund , Sweden ) maintenance and reliever therapy ( SMART ) , patients with asthma take a daily maintenance dose of budesonide/formoterol , with the option of taking additional doses for symptom relief instead of a short-acting β2-agonist ( SABA ) . This study assesses the cost-effectiveness of SMART compared with usual care in patients with mild-to-moderate persistent asthma treated by general practitioners in the Netherl and s from a societal perspective . Methods The study was linked to a r and omized , active-controlled , open-label , multicenter , 12-month clinical trial , with a prospect i ve collection of re source use . One hundred and two patients ≥18 years with mild-to-moderate persistent asthma and daily inhaled corticosteroids ( ICS ) prior to the trial were included . SMART was given as two inhalations of budesonide/formoterol ( 100/6 μg ) once daily , plus additional doses as needed . The control group was treated according to guidelines , which prescribe medium daily doses of ICS plus an SABA if needed . A long-acting β2-agonist ( LABA ) is added if necessary . Effectiveness was measured as the proportion of asthma-control days , Asthma Control Question naire ( ACQ ) scores , the net proportion of patients with relevant ACQ improvement , and the proportion of well-controlled patients . Costs included asthma medication , physician contacts , and absence from work . Results Mean total costs for SMART were € 134.81 lower ( 95 % CI : −€439.48 ; € 44.85 ) . Production losses were € 94.10 ( 95 % CI : −€300.60 ; € 0.29 ) lower for SMART ( € 10.77 vs. € 104.87 ) . No significant differences in health outcomes were seen , with 3.81 fewer asthma-control days per patient-year for SMART ( 95 % CI : −36.8 ; 30.8 ) , a 0.049 better ACQ score ( 95 % CI : −0.21 ; 0.29 ) , a 5.8 % larger net proportion of improved patients ( 95 % CI : t15.6 % ; 27.3 % ) , and a 2.1 % ( 95 % CI : −25.5 ; 20.8 % ) smaller increase in the proportion of well-controlled patients . Conclusions Treating primary care patients with mild-to-moderate persistent asthma with SMART instead of ICS plus bronchodilators does not affect health outcomes and does not increase costs ; therefore , is likely to be an alternative for guideline -directed treatment , from a health and economic perspective [8772331] BACKGROUND Oral beta-stimulants are widely used in the management of chronic asthma in India , in spite of evidence suggesting the superiority of inhaled medication in achieving maximum bronchodilatation . An economic evaluation was performed in a r and omized double-blind cross-over trial to evaluate the role of adjuvant oral beta-stimulants in the treatment of asthma . METHODS Patients who had seasonal or perennial asthma and were using metered dose inhalers for control of symptoms were r and omly selected for the study . They received either 4 mg of oral salbutamol or placebo as adjuvant treatment . During the study they controlled their symptoms by adjusting the dose of the inhaler medication . A cost minimization technique was used to assess the economic impact of this intervention in the treatment and control periods . A sensitivity analysis was performed to assess the robustness of the conclusions . RESULTS The mean cost was significantly greater in the treatment period and a patient lost approximately Rs 20 per month ( CI : 13 to 27 ; p = 0.001 ) as a result of the adjuvant treatment . There was no significant difference in the quality of life or peak expiratory flow rate during the two periods . The patients also noted mild but significantly increased tremors ( p = 0.01 ) and palpitations ( p = 0.001 ) during the treatment period . There was no treatment-to-period interaction . CONCLUSION Adjuvant oral beta-agonists do not improve the quality of life or bronchodilatation in asthmatics using an inhaled beta-agonist for control of symptoms [18723335] OBJECTIVE To evaluate direct asthma-related costs in Swedish primary care in a real-life setting . DESIGN 12-month open-label study . SETTING Swedish primary care in a real-life setting . PARTICIPANTS 1776 patients with persistent asthma . INTERVENTIONS Patients with persistent asthma were r and omised to one of three treatments : a free adjustable combination of budesonide ( 100 - 400 microg/inhalation ) and formoterol ( 4.5 or 9 microg/inhalation ) via separate inhalers plus terbutaline as needed ; budesonide/formoterol ( 160/4.5 microg or 80/4.5 microg , two inhalations twice daily ) plus terbutaline as needed ; budesonide/formoterol ( 160/4.5 microg or 80/4.5 microg , one inhalation twice daily or two inhalations once daily ) , for maintenance plus additional inhalations as needed . Doses depended on previous inhaled corticosteroid dose . Patients attended the clinic at 0 , 1.5 , and 12 months . Telephone interviews were conducted at 4 , 6 , 8 , and 10 months . MAIN OUTCOME MEASURES The primary endpoint was direct asthma-related healthcare costs . RESULTS Statistically significant reductions in annual direct costs per patient were observed with budesonide/formoterol maintenance and reliever therapy compared with the free adjustable combination of budesonide and formoterol ( -13 % , P<0.001 ) and fixed-dose budesonide/formoterol plus terbutaline ( -20 % , P<0.001 ) . Time to first severe exacerbation did not differ significantly across treatment groups , with a mean reduction of 28 % versus the free adjustable combination of budesonide and formoterol ( P=0.076 ) . Patients receiving budesonide/formoterol maintenance and reliever therapy used a significantly lower daily dose of budesonide compared with the conventional ( P<0.001 ) . CONCLUSIONS This study reports direct cost savings with budesonide/formoterol maintenance and reliever therapy compared with conventional treatment regimens with at least equivalent efficacy [16709303] ABSTRACT Objective : To evaluate efficacy and costeffectiveness of budesonide/formoterol ( Symbicort * ) maintenance ( one dose once or twice daily ) plus additional doses as needed ( Symbicort Maintenance And Reliever Therapy , SMART ) compared with a higher fixed dose of budesonide/ formoterol with formoterol as needed in patients with persistent asthma . * Symbicort is a registered trade name of the AstraZeneca group of companies Study design and methods : 6‐month , open , r and omised study of 465 patients either not well controlled on an inhaled corticosteroid ( ICS ) , or well controlled on a combination of ICS and a long-acting β2‐agonist ( LABA ) . Treatments : budesonide/formoterol 160/4.5 µg , one inhalation , once or twice daily maintenance plus additional doses as-needed ( 1 × SMART or 2 × SMART ) , or budesonide/formoterol 160/4.5 µg two inhalations twice daily plus formoterol 4.5 µg as needed ( 2 × 2 FIX + F ) . Children 6–11 years old used an 80/4.5 µg dose strength . Primary variables of efficacy were the changes in the Asthma Control Question naire ( ACQ5 ) and morning peak expiratory flow ( PEF ) . Results : Mean age of patients 40 years ( range 6–82 years ) ; 53 % female . No differences between the groups were found in ACQ5 scores or asthma exacerbation rates . Morning PEF was higher in the 2 × 2 FIX + F group vs. the 1 × SMART and 2 × SMART groups ( differences 13 L/min and 9 L/min , respectively ; p < 0.002 ) . The 1 × SMART group showed a significant decrease in asthma controlled days compared with the two other groups . No difference was seen between the 2 × SMART group and the 2 × 2 FIX + F group . Treatment costs were significantly lower in the SMART groups compared with the 2 × 2 FIX + F group . Conclusion : Compared with the 2 × 2 FIX + F treatment the use of budesonide/formoterol was 30–40 % lower in the SMART groups while maintaining equal ACQ5 scores . Daily asthma control improved equally with 2 × SMART compared to 2 × 2 FIX + F with a reduction in asthma medication cost . The one dose once daily maintenance treatment ( 1 × SMART ) result ed in a low level of treatment failure ( exacerbations ) but led to more days with symptoms . Therefore , a daily dose of two inhalations seems to be the lowest appropriate dose in patients with moderate persistent asthma [14682406] Inhaled corticosteroids for asthma treatment have become mainstay of therapy for patients with persistent asthma . Numerous inhaled corticosteroids are available but to date no prospect i ve cost-effectiveness studies have been reported using exclusively US patients and costs . The purpose of this study was to examine the cost-effectiveness of HFA-bectomethasone ( QVAR ) compared to CFC-beclomethasone ( Vanceril ) using data from a year-long prospect i ve r and omized , open label , parallel multicenter trial . Eligibility criteria required patients to have been on a stable dose of CFC-BDP prior to enrollment . Patients were r and omized to either HFA-BDP at approximately half their previous daily dose of CFC-BDP or to continue CFC-BDP Effectiveness data , in terms of symptom-free days ( SFDs ) , were used in a cost-effectiveness analysis conducted from the viewpoint of managed care . Patients receiving HFA-BDP reported a greater increase ( median = 22.1 ) in the number of SFDs than those receiving CFC-BDP ( median = 14.3 ) ( P = 0.03 ) . Total costs of care were less for patients taking HFA-BDP ( median = dollars 668 ) compared to CFC-BDP ( median = dollars 977 ) . The median incremental cost-effectiveness ratio was dollars -5.77 ( 95 % CI : dollars -68.08 to dollars -4.08 ) . The results of this analysis indicate that HFA-BDP was a dominant therapy ( more effective , less costly ) compared to CFC-BDP [12381242] Abstract Objective : To compare the relative cost effectiveness of salmeterol (50μg)/ fluticasone propionate ( 100μg ) with that of oral montelukast ( 10 mg ) as initial maintenance therapy in patients with persistent asthma uncontrolled on short-acting β2-agonist therapy alone . Study design : A cost-effectiveness analysis was performed based on effectiveness and re source utilisation data that was prospect ively collected from a r and omised , double-blind , double-dummy , 12-week trial . Patients and methods : Patients ( > 15 years of age ) who had asthma for at least 6 months . Effectiveness measurements in this analysis included improvement in forced expiratory volume in 1 second ( FEV1 ) and symptom-free days ( SFDs ) . Cost of asthma drug treatment as well as costs related to an asthma exacerbation were used in the cost analysis . The study assumed a payer ’s perspective . All costs are in 2001 US dollars . Results : Of the 423 patients eligible for the study , 211 were r and omised to salmeterol/fluticasone propionate and 212 to montelukast . Treatment with salmeterol/fluticasone propionate result ed in a significantly higher proportion of patients who achieved a 12 % increase in FEV1 ( successful treatment ) [ salmeterol/fluticasone propionate : 71 % vs montelukast : 39 % ; p < 0.001 ] and percentage of SFDs ( salmeterol/fluticasone propionate : 46.8 % vs montelukast : 21.5 % ; p < 0.001 ) compared with montelukast . The mean daily costs per successfully treated patient were lower in the salmeterol/fluticasone propionate group ( $ US5.03 , 95 % CI $ US4.61 to $ US5.50 ) compared with the montelukast group ( $ US8.25 , 95 % CI $ US6.98 to $ US9.93 ) . Furthermore , per patient mean daily cost per SFD was lower with salmeterol/fluticasone propionate ( $ US7.63 , 95 % CI $ US6.90 to $ US8.50 ) compared with montelukast ( $ US14.89 , 95 % CI $ US12.36 to $ US17.98 ) . Incremental cost-effectiveness ratios ( ICERs ) showed that the additional costs to achieve these benefits with salmeterol/fluticasone propionate were minimal . With regards to improvement in lung function , the ICER was $ US1.33 ( 95 % CI $ US0.80 to $ US2.02 ) and with regards to SFD , the ICER was $ US1.69 ( 95 % CI $ US1.01 to $ US2.48 ) . Sensitivity analysis demonstrated the stability of the results over a range of assumptions . Conclusions : From a third-party payer perspective , this analysis shows that based on increased efficacy and only a slight increase in cost , twice-daily treatment with salmeterol/fluticasone propionate is more cost effective than once-daily treatment with montelukast as initial maintenance therapy for persistent asthma . This finding complements the results of the clinical analyses indicating that treatment of both inflammation and bronchoconstriction with products such as salmeterol/fluticasone propionate may be more cost effective as initial maintenance asthma therapy than the use of leukotriene modifiers such as montelukast [27536180] We congratulate Amdahl et al.1 on publishing their paper about the cost-effectiveness of pazopanib compared with sunitinib in metastatic renal cell carcinoma ( mrcc ) in Canada . The article reports an analysis similar to the one su bmi tted to the pan-Canadian Oncology Drug Review to support the funding request for pazopanib in mrcc , up date d with final overall survival ( os ) data from the pivotal trial2 . Economic evaluations in oncology are increasingly important to guide both policy and practice . We commend the efforts of these authors to put their su bmi tted analyses into the public domain for transparency and to support and inform future research . The base-case analysis ( using the list prices of pazopanib and sunitinib ) by Amdahl et al.1 found that , compared with sunitinib , which is the st and ard of care for first-line therapy in mrcc , first-line pazopanib is likely cost-saving . The base case analysis also suggested that pazopanib might be slightly more effective than sunitinib numerically , with an incremental gain of 0.057 life-years and 0.059 quality -adjusted life-years . Before concluding that pazopanib is dominant ( that is , it provides more benefit for a lower cost ) with respect to sunitinib , it is important to review the clinical data comparing pazopanib and sunitinib in mrcc to assess the comparative efficacy and preference-based measures of health-related quality of life ( hrqol ) associated with those agents — that is , their health utilities — to examine the face validity of the economic model in its base case . The efficacy differences between the pazopanib and sunitinib in the comparz study 3 were not statistically significant , median progression-free survival for pazopanib and sunitinib being 8.4 months [ 95 % confidence interval ( ci ) : 8.3 to 10.9 months ] and 9.5 months ( 95 % ci : 8.3 to 11.1 months ) respectively , with a hazard ratio of 1.05 ( 95 % ci : 0.90 to 1.22 ) . The study met its primary endpoint of non-inferiority in progression-free survival . No os difference was observed in the comparz study , in which median os was 28.4 months for pazopanib ( 95 % ci : 26.2 to 35.6 months ) and 29.3 months for sunitinib ( 95 % ci : 25.3 to 32.5 months ) , with a hazard ratio of 0.91 ( 95 % ci : 0.76 to 1.08 ) . At the up date d analysis , os was similar in the two groups ( hazard ratio for pazopanib vs. sunitinib : 0.92 ; 95 % ci : 0.79 to 1.06 ; p = 0.24)2 . With similar survival results for pazopanib and sunitinib based on the comparz study , one might ask , “ How did the model project an incremental gain of 0.057 life-years in favour of pazopanib ? ” The model actually projected a shorter life expectancy while patients were taking pazopanib than while their counterparts were taking sunitinib ( 0.013 life-years lost in the progression-free state ) . However , the model also projected that , after patients progressed and stopped taking pazopanib , their life expectancy was longer than it was for patients who received sunitinib ( 0.070 life-years gained in the post-progression state ) . Together , the loss and the gain result ed in a net gain in life expectancy for pazopanib , implying that the survival benefit of pazopanib acted only after progression , when patients were no longer taking pazopanib . There is no biologic basis for that phenomenon , and it likely simply reflects small numerical differences between the pazopanib and sunitinib progression-free survival and os curves , without accounting for uncertainty . Interestingly , the model also predicted that pazopanib would be more effective in at least 80 % ( or possibly all ) of the simulations despite the nonsignificant result . Although the comparz study 3 collected some hrqol measures , it did not collect preference-based measures of hrqol to allow for the calculation of quality -adjusted life-years for the purpose of economic evaluation . The pisces study 4—a r and omized , double-blind trial with a crossover design ( that is , pazopanib→sunitinib vs. sunitinib→pazopanib)—had , as its primary endpoint , an examination of patient preference for either pazopanib or sunitinib , which suggested that patients preferred pazopanib over sunitinib . However , the study had a few limitations 5 , including a relatively high proportion of the r and omly assigned patients ( 33 % ) not being evaluable for the primary endpoint , and the analysis of the pazopanib preference being based on a “ modified ” intention-to-treat population . The EQ-5D ( EuroQoL Group , Rotterdam , Netherl and s ) was also collected as the preference-based measure of hrqol in the pisces study 4 , but the EQ-5D results would have been subject to similar limitations . The data from the pisces study were used in the su bmi ssion to the pan-Canadian Oncology Drug Review . In the up date d analysis 1 , the authors conducted a regression based on patients in a trial comparing pazopanib with placebo6 , assuming that the effect of adverse events ( aes ) were driving the differences in hrqol , regardless of actual treatment received . For the analysis , the aes were grouped by severity and whether the aes were more commonly occurring in the sunitinib or the pazopanib group of the comparz trial . Using that approach , the regression model found that the health utility decrement was larger for the group of aes more commonly occurring in patients who used sunitinib than for the remaining aes more frequently occurring in patients who used pazopanib in the comparz trial . The results of the regression model were combined with the incidence and duration of aes in each treatment arm to derive the mean utility values used in the model , producing mean utility values of 0.7089 ( st and ard error : 0.0193 ) for pazopanib and 0.6832 ( st and ard error : 0.0236 ) for sunitinib , an incremental difference of 0.0257 in the progression-free period1 . Given that the comparz trial demonstrated similar efficacy and a more favourable toxicity profile for pazopanib , it is not unreasonable that the point estimate of the utility score could slightly favour the pazopanib group . However , these mean utility values were not directly derived and might be neither statistically nor clinical ly different , especially because the difference was smaller than the reported estimates of minimal important differences for health utilities ( which are in the range of 0.05–0.08 for the EQ-5D)7,8 . Thus , it is somewhat difficult to conclude from those data that pazopanib is associated with better utility than sunitinib . It might be reasonable to conservatively expect that the utilities of pazopanib and sunitinib are fairly similar given the size of the st and ard errors of the two utilities , subject to a reasonable amount of uncertainty9,10 . Given that clinical trials did not demonstrate a statistically significant survival benefit or EQ-5D health utility benefit for pazopanib over sunitinib , we feel that an appropriate interpretation could be that the study findings suggest similar efficacy and health utility for the two drugs . Reasonably , the pan-Canadian Oncology Drug Review ’s Expert Review Committee also concluded that it is reasonable to assume similar efficacy and to focus on the cost comparison between pazopanib and sunitinib in this setting 11 . We appreciate that the sensitivity analyses by Amdahl et al.1 address all the considerations discussed here , including the importance of the relative price of the two drugs . The authors demonstrate as part of their additional analyses that — assuming similar efficacy , health utility , and daily price of the two therapies — only minor cost differences remain . Thus , interpreting the analyses in light of the evidence , it appears that these two options for first-line therapy in mrcc might be largely similar and , taking into account the relative prices of the two drugs , the hope would be that , after confidential negotiations , they will also be similar in cost . In that case , having both drugs available would give patients the option to choose based on individual preference and side effect profile , especially in the case of intolerance to one of the drugs , and would ensure that health care re sources are being efficiently used . The generalizability of the study findings remains to be seen in practice . Verification from experience is needed to know whether the comparative outcomes as laid out will be realized . In Canada , jurisdictions have an important opportunity and challenge to evaluate the real-world effectiveness and cost-effectiveness of therapies in clinical practice after drugs are funded . Moreover , post-market research can provide valuable insights into practice patterns when two alternatives are funded and can possibly inform continued uncertainties such as sequencing and long-term adverse effects . We applaud the approach of the authors to share their analyses with the broader clinical and research communities , and we encourage more authors of economic evaluations created and su bmi tted to review bodies ( for example , the Canadian Agency for Drugs and Technologies in Health , the pan-Canadian Oncology Drug Review ) to follow suit . We expect that this activity will build on the principle of transparency being increasingly championed by the review organizations and will improve the rigour of the economic evidence used to inform policy . Finally , we call on the community to continue to pursue both academic merit and clinical and policy relevance by supporting the availability of peer- review ed publications of economic evaluations to inform the reimbursement review process . Ideally , it would be helpful if economic evaluations were to be published before decision-making so as to engage more stakeholders in the discussion 12 . In doing so , the clinical and economic evidence bases supporting the health technology assessment processes in Canada might be brought into better alignment , improving the robustness of decision-making and ultimately helping health care systems in Canada to provide effective and appropriate care to patients [16968580] ABSTRACT Background : Severe allergic asthma patients may not be controlled even with guideline recommended care , including inhaled corticosteroids , long-acting beta-2 agonists , theophylline , oral steroids and anti-leukotrienes . They experience exacerbations requiring intensive healthcare use and which may be fatal . Omalizumab , a new monoclonal antibody for use in IgE-mediated allergic diseases , reduces exacerbations and daily symptoms in this patient population . The aim of this study is to estimate the cost effectiveness of adding omalizumab to optimized st and ard therapy ( ST ) in patients with severe persistent IgE-mediated ( allergic ) asthma . Methods : A Markov model comparing lifelong ST with a treatment period of omalizumab add-on therapy followed by ST , was developed based on efficacy data from the INNOVATE trial ( 28 weeks , N = 419 ) and Swedish life table and cost data . This model assumes that patients are at risk of having an exacerbation every 2 weeks and are at risk of dying from a clinical ly significant severe asthma exacerbation . Patients in a steady-state of having no exacerbations are defined to be in an ‘ optimized asthma control ’ state . Re source use data and utilities were obtained from INNOVATE and from a UK observational study . Costs from a societal perspective include estimates for drugs , routine care , exacerbations and costs in added years of life ; benefits are expressed in QALYs . The response to omalizumab was evaluated after 16 weeks of trial , and non-responders stopped taking omalizumab for the remaining time . Results : Total lifetime discounted costs and QALYs on ST were € 52 702 and 11.60 . Omalizumab add-on therapy cost an additional € 42 754 for 0.76 additional QALYs , result ing in an incremental cost-effectiveness ratio of € 56 091 . A probabilistic sensitivity analysis indicates that the 95 % CI around the ICER is [ € 31 328 ; € 120 552 ] . One-way analyses indicate that the results are sensitive to the exacerbation-related mortality rate , the time horizon and the discount rates . Conclusions : Based on the model and the assumptions used , our results suggest that omalizumab provides cost offsets , improves quality of life and may have an attractive ICER in treating the severe allergic asthma population [12162754] OBJECTIVE To compare the cost effectiveness of hydrofluoroalkane 134a-beclomethasone dipropionate ( HFA-BDP ; Qvar ) [ corrected ] with chlorofluorocarbon-beclomethasone dipropionate ( CFC-BDP ) in patients with chronic stable asthma previously receiving CFC-BDP , from the perspective of a healthcare provider . DESIGN Cost-effectiveness analysis based on a 12-month pragmatic , r and omised , parallel group , open-label clinical trial assessing safety and efficacy of HFA-BDP at approximately half the dose of CFC-BDP in patients with stable asthma . SETTING International , multicentre study at 57 study sites in the US , UK , The Netherl and s , and Belgium . Healthcare costs were calculated for UK-based healthcare [ in 1999 as pounds ( pounds sterling ) ] . PATIENTS AND PARTICIPANTS Patients ( n = 473 ) > or = 12 years of age with currently stable asthma that had been stable ( i.e. no exacerbations requiring oral corticosteroid use in the last 4 weeks ) for at least the preceding month . MAIN OUTCOME MEASURES Average and incremental cost-effectiveness ratios based upon symptom-free days , improvement in health-related quality of life , and total and drug-only direct healthcare costs . RESULTS Patients in the HFA-BDP group experienced a significantly higher percentage of symptom-free days than patients in the CFC-BDP group by the end of the study period ( 42.4 vs 20.0 % ; p = 0.006 ) . A greater percentage of patients in the HFA-BDP group had a clinical ly significant improvement in health-related quality of life than in the CFC-BDP group [ 35.3 ( n = 116/329 ) vs 16.1 % ( n = 18/112 ) ] . Total per patient healthcare costs were similar between the two groups . The average cost per symptom-free day per patient was 1.36 pounds sterling for HFA-BDP and 1.81 pounds sterling for CFC-BDP based on total healthcare costs . The incremental cost per symptom-free day for using HFA-BDP instead of CFC-BDP was negative , indicating that HFA-BDP is a dominant strategy and may be a cost-saving intervention compared with CFC-BDP . A sensitivity analysis varying both cost and outcome parameters further supported this finding for most scenarios tested . The cost to achieve a clinical ly significant improvement in health-related quality of life over the study period was 13.24 pounds sterling per improved patient per week for HFA-BDP and 29.38 pounds sterling per patient per week for CFC-BDP . CONCLUSIONS These findings indicate that HFA-BDP is a cost-effective intervention when compared with CFC-BDP in this group of patients with stable asthma . In the majority of scenarios HFA-BDP provides more effective asthma control at a similar cost to CFC-BDP [11184564] When deciding on treatment for patients with asthma , clinicians should consider the following : basic science that supports the therapeutic agent , r and omized clinical trials that demonstrate clinical efficacy , and " real world " economic evidence that confirms the basic science and clinical study findings . When selecting first-line controller therapy for persistent asthma , clinicians should look for the single agent that produces the greatest improvement in lung function and patient outcomes , has minimal adverse effects , and is cost effective . To determine whether there is one first-line controller that achieves all of these goals , physicians should evaluate findings of r and omized controlled trials that assess a drug 's effect on asthma symptoms , lung function , and albuterol use compared with placebo or a comparator . They should also consider findings from retrospective cl aims analyses . This combination of data provides a truer picture and more robust evidence of a drug 's clinical and economic performance . Similar evaluations need to be undertaken when deciding on the most cost-effective add-on therapy [16802845] Abstract Introduction : Budesonide/formoterol ( Symbicort ® ) Maintenance And Reliever Therapy ( SMART ) is an effective and well tolerated treatment option for patients with asthma . We compared the cost effectiveness from a societal perspective of this one-inhaler regimen with that of maintenance salmeterol/fluticasone propionate ( Seretide ® ) plus salbutamol ( albuterol ) as needed ( Seretide ® Fixed Combination [ SFC ] ) . Study design : A cost-effectiveness analysis was performed based on effectiveness and re source -utilisation data collected prospect ively in a r and omised , 12-month study performed in 2143 patients in 16 countries . Re source utilisation data were pooled and unit costs ( € , year 2003 values ) from Italy , France , the UK and Germany were used to generate estimates of direct and total costs per patient per year and cost per severe exacerbation avoided . Methods : Adolescents and adults with asthma ( n = 2143 ; mean forced expiratory volume in 1 second [ FEV1 ] 73 % predicted ; mean inhaled corticosteroid [ ICS ] dose 884 µg/day ) were r and omised to SMART or SFC . The effectiveness measure used was the number of severe exacerbations per patient per year . Direct costs included medication use ( budesonide/formoterol 160µg/4.5 µg or salmeterol/fluticasone 50µg/100 µg , 50µg/250 µg or 50µg/500 µg plus salbutamol ) and nonmedication-related re source use , including days in hospital , emergency room visits , specialist or primary care physician visits and other healthcare provider contacts . Indirect costs , including the number of days when the patient or their carer was unable to attend to their normal daily activities , were also assessed . The study assumed a European societal perspective ( i.e. including direct and indirect costs ) . Results : Treatment with SMART result ed in significantly fewer severe exacerbations per patient per year compared with SFC ( 0.24 vs 0.31 events per patient per year ; p = 0.0025 ) . Re source use was low in both groups . Medication costs accounted for the majority of the total costs . The increased effectiveness of SMART was achieved at a reduced or similar cost compared with SFC . SMART dominated when German unit costs were applied ( i.e. there was a statistically significant reduction in both costs and number of exacerbations ) . In all other countries , the incremental cost-effectiveness ratios showed that there was a reduction in mean total cost per exacerbation avoided ; however , this difference was not statistically significant . Conclusion : This analysis demonstrates that , compared with SFC , SMART may be cost effective from a societal perspective for the treatment of patients with asthma in Italy , Germany , France and the UK . SMART provided a reduction in the number of severe exacerbations per patient per year , at no statistically significant increase in cost — or even at a lower cost — compared with SFC plus as-needed reliever salbutamol [9616537] The inhaled corticosteroid fluticasone propionate ( FP ) was introduced into the Thorpewood General Practice , Norwich , U.K. in 1993 -initially in treating relatively severe asthmatics . Observed beneficial effects led to exp and ed use particularly for poorly controlled asthma not responsive to increased inhaled anti-inflammatories . However , an early review suggested little advantage over existing agents ( l ) , and FP was marketed at a price premium . The aims of this study were to investigate whether continued and exp and ing use of FP was justified in terms of improved clinical outcomes , and if such improvements were associated with reduced NHS costs ( off setting more expensive prescriptions ) . A controlled , retrospective , nonr and omized primary care audit compared clinical outcomes and asthma management costs 1 year prior to and 1 year into FP therapy [15316501] BACKGROUND Omalizumab can reduce hospitalization and emergency department visits and improve quality of life in patients with moderate-to-severe , suboptimally controlled allergic asthma . Given the high cost and modest efficacy of this agent , it is not clear that it is cost-effective if given to a broad population with asthma . OBJECTIVE The purpose of this study was to evaluate the cost-effectiveness of omalizumab in adults and adolescents with moderate-to-severe allergic asthma . METHODS A retrospective economic analysis was performed to determine the cost-effectiveness of omalizumab using 52-week data from 2 r and omized controlled clinical trials in adults and adolescents with moderate-to-severe allergic asthma . The analysis was conducted from a third-party payer 's perspective , and only direct costs were considered . RESULTS The incremental cost-effectiveness ratios showed that the cost to achieve an additional successfully controlled day was $ 523 , and the daily cost to achieve at least a 0.5-point increase in Asthma Quality of Life Question naire score was $ 378 in 2003 dollars . CONCLUSION From a pharmacoeconomic st and point , omalizumab would be better used in allergic asthmatic patients with poorly controlled symptoms despite maximal therapy , given the high cost and modest efficacy of this agent . It could be cost saving if given to nonsmoking patients who are hospitalized 5 or more times or 20 days or longer per year despite maximal asthma therapy [7762918] Preamble Although economic outcomes research is an evolving field in health services research , there are correct and incorrect ways to conduct and report on economic outcomes studies . Research practice s that help to minimize real or perceived bias will increase the quality and usefulness of such studies for those who sponsor , publish , and use them . Because of public concerns about the potential for bias in the design , analysis , and reporting of economic analyses of health care technology , we formed a task force to develop principles to enhance the credibility of these studies . The Task Force on Principles for Economic Analysis of Health Care Technology included participants from academia , the pharmaceutical industry , the public sector , and private research organizations . As health care re sources become increasingly constrained , the information used to make re source allocation decisions must be as reliable , valid , and free of bias as possible . Getting it right at the level at which economic results are produced will help to protect consumers and will advance the health of the public . Bias stems from two broad categories : lack of appropriate independence for research ers and lack of consensus about methods . We focused heavily on the first of these categories for two major reasons . First , few have yet considered the unique issues of research er independence in economic outcomes research [ 1 , 2 ] . Second , other investigators have begun to consider and define proper methods for economic outcomes work ( an area of considerable controversy ) [ 3 - 5 ] . We also looked closely at the requirements for the reporting of economic analyses , which are intended to ensure method ologic transparency and accountability . The Need for Voluntary Guidelines Widespread use of economic analysis as part of the development of pharmaceutical , biotechnologic , and medical devices is relatively new . To date , many economic analyses of health care have focused on pharmaceutical agents , and many such studies have been funded by pharmaceutical companies . Results of these economic outcomes studies are used by medical technology firms to support the pricing and marketing of new interventions and to influence national health care systems and third-party payers in their development of coverage and payment decisions . Managed care organizations , hospitals , and government-subsidized health care programs rely on economic analysis of medical technology to help make formulary purchasing and utilization decisions . Physicians may use the results of these analyses to help guide treatment and prescription decisions . Health care economic outcomes projects are sponsored and conducted by pharmaceutical , biotechnologic , and medical device companies ; government agencies ; nonprofit foundations ; academic investigators ; and private research and consulting firms . The st and ards and methods used to evaluate the safety and efficacy of pharmaceutical products in r and omized , controlled trials have evolved over 50 years of collaboration among research ers in private , public , and academic setting s. Compared with those established to ensure the safety and efficacy of clinical trials , the principles and methods for the conduct of economic studies of health care technology are far less developed . Problems of conduct , reporting , and bias exist in all types of research [ 6 - 14 ] . In response , codes of conduct , such as those developed by the American Federation for Clinical Research and the Institute of Medicine , have been developed for many scientific disciplines [ 15 - 24 ] . These are good models on which to base principles of conduct for economic outcomes analysis . Although many published principles apply to economic studies , others should be modified and new ones should be developed to guide the conduct and reporting of economic outcomes analyses . Economic outcomes research requires unique guidelines for the following reasons : 1 ) As a field , it continues to evolve and is often misunderstood by end users ; 2 ) peer review of it requires special expertise that often exceeds the capabilities of review ers and scientific journals ; 3 ) it often uses secondary data and requires that many assumptions be made [ for example , attribution of a dollar cost to a unit of re source use ] ; 4 ) it offers unique method ologic choices , such as which types of costs to include ( direct , indirect , intangible , induced ) , which perspective to apply ( that of society , payer , provider , patient ) , which design to adopt ( cost- identification , costbenefit , cost-effectiveness , costutility ) , from where to obtain costs [ indemnity data base , managed care or capitated data base , hospital cost systems , Medicare , Medicaid ] , and whether to collect re source consumption data prospect ively or retrospectively through various modeling techniques ; and 5 ) economic studies play an increasingly important role in health care decision making because of increasing financial constraints throughout the health care industry . The financial and medical implication s of decision making done on the basis of these studies , coupled with the lack of widely accepted guidelines about the conduct and reporting of economic analyses , undermine the credibility of this research . A major issue is that the primary source of funding for this research is often the primary financial beneficiary of positive study results . Unfortunately , even valid studies done under the best of circumstances may be suspect [ 25 - 29 ] . This has led at least one major journal to conclude that these analyses should be viewed much like editorials or review articles are viewed in terms of potential for conflicts of interest [ 30 ] . We developed the guidelines reported here after extensive consultation with experts from the public , private , and academic sectors . We recommend that research ers and sponsors adhere to these guidelines , and we suggest they state publicly within their manuscripts that they have done so . End users , including journal editors and readers , consumers , and social decision makers , may then feel more secure in accepting the results of the research , while recognizing that intensive critique of the research will always be necessary . Operations of the Task Force The Task Force on Principles for Economic Analysis of Health Care Technology was initiated and organized by faculty from the Leonard Davis Institute ( LDI ) Center for Health Policy of the University of Pennsylvania . However , because not all LDI faculty were involved , this paper does not represent an official LDI position statement . The Task Force was funded by a coalition of pharmaceutical companies ( Appendix A ) . Funding was also requested ( but not obtained ) from various government and private foundations . All funding was provided in the form of unrestricted research grants or gifts to the University of Pennsylvania . Guidelines derive their credibility in part from the composition of the panel that creates them and the process by which they are developed . C and i date s for participation in the Task Force from the private sector and the academic research community were identified by the frequency with which they were cited in the health economics literature , which was obtained using a MEDLINE search of literature related to economic analyses of medical technology published between 1983 and 1992 . Approximately 15 members attended each meeting . Minutes were distributed after each meeting and approved by all members present . Members from the sponsoring pharmaceutical companies and the academic organizers rotated so that they numbered three and one , respectively , at the table for each formal Task Force meeting . Several professional and governmental organizations , including the Institute of Medicine , the Agency for Health Care Policy and Research , the Food and Drug Administration ( FDA ) , the Health Care Financing Administration , the Centers for Disease Control and Prevention , and a managed care organization , were asked to suggest persons who might participate . In addition , other organizations with a stake in economic analyses were each asked to suggest a person who , because of his or her professional background , had extensive knowledge of or experience with economic analyses . An academic pharmacist , an academic research er , a private research er , an ethicist and patient advocate , and an attorney specializing in medical ethics rounded out the Task Force ( Appendix B ) . Two members withdrew from participation . A small audience consisting of industry sponsors , academic organizers , staff , and a few other interested parties were invited to each meeting and allowed to comment . Four formal meetings of the Task Force were held in Philadelphia during 1993 and 1994 , and the most substantial work was done by various subcommittees between these meetings . The three main subcommittees were titled Ethical Conduct , Responsibility and Control ( the findings of these two subcommittees were later merged into one report ) , and Reporting Requirements for Economic Evaluations ( Appendix C ) . The Task Force was assisted by a professional facilitator . Although Task Force members sought consensus wherever possible on the key issues , consensus was not forced and recommendations were issued only when substantial agreement existed among the members . Task Force members were not asked to formally represent any organization . Formal endorsement of the final document was not sought . Copies of this report will be distributed to all organizations that were asked to suggest a participant and to other parties who responded to announcements placed in The New Engl and Journal of Medicine , Scrip , and the Pink Sheet . The Task Force findings will also be reported at academic conferences , medical profession meetings , and appropriate trade conventions . Findings and Recommendations Valid approaches to economic analyses can be defined ; acceptable methods can be differentiated from unacceptable ones . Bias in economic research stems from two major sources : lack of appropriate independence for [15462701] BACKGROUND The severity of asthma varies between individuals and over time . As a result individuals may have marked variation in their need for asthma treatment . Adjustable dosing enables patients to assume greater involvement in managing their own condition . OBJECTIVE To compare the costs and effectiveness of fixed dosing of budesonide/formoterol ( Symbicort Turbohaler ) with adjustable maintenance dosing . METHODS A cost-effectiveness analysis was conducted from the perspective of the UK NHS . Adults with established asthma currently maintained on > or = 400 microg per day inhaled corticosteroid were enrolled in 365 primary care centres in the UK . Patients were run-in on 2 inhalations twice daily of budesonide/formoterol 80/4.5 microg or budesonide/formoterol 160/4.5 microg ( depending on steroid requirement ) for 4 weeks and were then r and omised to the Symbicort adjustable maintenance dosing plan ( SAMD ) ( n = 782 ; budesonide/formoterol 1 - 4 inhalations twice daily depending on symptoms ) or Symbicort fixed dosing ( n = 771 ; 2 inhalations twice daily ) for a further 12 weeks . The primary effectiveness variable was clinical ly meaningful change in quality of life ( QoL ) assessed by the miniasthma quality of life question naire ( AQLQ ) . Secondary effectiveness measures included symptom-free days with no short-acting beta-agonist use . We assessed the costs of study medication , asthma-related concomitant medication , primary care and hospital contacts . Confidence intervals were generated by nonparametric boot-strapping . RESULTS Clinical ly meaningful improvement in QoL during the first 4 weeks was reported by 40.8 % of enrolled patients . During the following 12 weeks , a net 1 % ( 95 % CI : -4 % , 6 % ) of SAMD patients and 6 % ( 95 % CI : 1 % , 10 % ) of fixed dosing patients reported further improvement . Effectiveness parameters did not differ significantly between groups during the study period . Mean daily cost per patient was pound sterling 1.13 ( 95 % CI : pound sterling 1.08 , pound sterling 1.18 ) in the SAMD group and pound sterling 1.31 ( 95 % CI : pound sterling 1.27 , pound sterling 1.34 ) in the fixed dosing . The difference in mean daily cost result ed in an annual per patient cost difference of pound sterling 65.70 . Adjustable maintenance dosing with budesonide/formoterol provided equivalent QoL to fixed dosing at significantly lower cost [16274980] In this economic evaluation , conducted alongside a r and omized , double-blind clinical trial , economic data were collected from 339 patients with moderate-persistent asthma r and omized to receive twice-daily , double-blind treatment with budesonide/formoterol 160/4.5 microg in a single inhaler ( n=166 ) or fluticasone propionate 250 microg ( n=173 ) for 12 weeks . The mean number of episode-free days ( EFD ) per patient was significantly greater in the budesonide/formoterol group than the fluticasone group ( 48.71 compared with 42.34 , P=0.0185 ) . Data on medication use , visits to healthcare professionals , and hospitalization were pooled across all six countries and combined with German and Dutch unit cost data to calculate total healthcare costs . Using German unit costs , budesonide/formoterol was associated with significantly lower total healthcare costs per patient over the 12-week period compared with fluticasone ( euro 131 compared with euro 210 , P=0.0043 ) . Using Dutch unit costs , total healthcare costs were slightly numerically lower in the budesonide/formoterol group than the fluticasone group ( euro 102 compared with euro 104 ) , but the difference did not reach statistical significance . Budesonide/formoterol in a single inhaler is more effective than a higher microgram dose of fluticasone alone . It is cost-neutral and may provide cost-savings in some countries [15294013] Abstract Background : Asthma is a chronic disease , the two main components of which are inflammation and bronchoconstriction . Fluticasone propionate ( FP ) and salmeterol , a strategy that treats both main components of asthma , has been recently compared with FP plus montelukast in a r and omised clinical trial . The present study reports economic evaluation of these two strategies . Objective : To determine the relative cost effectiveness when persistent asthma is treated with FP/salmeterol 100/50μg twice daily administered via a single Diskus ® inhaler device versus treatment with FP 100μg twice daily via a Diskus ® inhaler plus oral montelukast 10 mg once daily . Study design : A cost-effectiveness analysis was performed by applying cost unit data to re source utilisation data collected prospect ively during a US r and omised , double-blind , 12-week trial of FP/salmeterol ( n = 222 ) versus FP + montelukast ( n = 225 ) . Patients were ≥15 years of age and were symptomatic despite inhaled corticosteroid ( ICS ) therapy . Patients and methods : Efficacy measurements in this analysis included improvement in forced expiratory volume in 1 second ( FEV1 ) and symptom-free days . Direct costs included those related to study drugs , emergency room department visits , unscheduled physician visits , treatment of drug-related adverse events ( oral c and idiasis ) , and rescue medication ( salbutamol [ albuterol ] ) . The study assumed a US third-party payer ’s perspective with costs in 2001 US dollars . Results : Treatment with FP/salmeterol result ed in a significantly higher proportion ( p < 0.001 ) of patients who achieved a ≥12 % increase in FEV1 than treatment with FP + montelukast ( 54 % [ 95 % CI 47 % , 61 % ] vs 32 % [ 95 % CI 26 % , 38 % ] ) . Lower daily costs and greater efficacy of FP/salmeterol result ed in a cost-effectiveness ratio of $ US6.77 ( 95 % CI $ US5.99 , $ US7.66 ) per successfully treated patient in the FP/salmeterol group compared with $ US14.59 ( 95 % CI $ US12.12 , $ 17.77 ) for FP + montelukast . In addition , FP/salmeterol achieved similar efficacy in terms of symptom-free days compared with FP + montelukast ( 31 % [ 95 % CI 26 % , 35 % ] vs 27 % [ 95 % CI 23 % , 32 % ] ) , but at a significantly lower daily per-patient cost ( $ US3.64 [ 95 % CI $ US3.60 , $ US3.68 ] vs $ US4.64 [ 95 % CI $ US4.56 , $ US4.73 ] ) . Sensitivity analyses demonstrated the stability of the results over a range of assumptions . Conclusion : From a US third-party payer ’s perspective , these findings suggest that treating the two main components of asthma ( inflammation and bronchoconstriction ) with FP/salmeterol may not only be a more cost-effective strategy but may actually lead to cost savings compared with the addition of montelukast to low-dose FP in patients with persistent asthma . The results were found to be robust over a range of assumptions [24144222] BACKGROUND There are few data on the role of nebulised magnesium sulphate ( MgSO4 ) in the management of acute asthma in children . Those studies that have been published are underpowered , and use different methods , interventions and comparisons . Thus , no firm conclusions can be drawn . OBJECTIVES Does the use of nebulised MgSO4 , when given as an adjunct to st and ard therapy in acute severe asthma in children , result in a clinical improvement when compared with st and ard treatment alone ? DESIGN Patients were r and omised to receive three doses of MgSO4 or placebo , each combined with salbutamol and ipratropium bromide , for 1 hour . The Yung Asthma Severity Score ( ASS ) was measured at baseline , r and omisation , and at 20 , 40 , 60 ( T60 ) , 120 , 180 and 240 minutes after r and omisation . SETTING Emergency departments and children 's assessment units at 30 hospitals in the UK . PARTICIPANTS Children aged 2 - 15 years with acute severe asthma . INTERVENTIONS Patients were r and omised to receive nebulised salbutamol 2.5 mg ( ages 2 - 5 years ) or 5 mg ( ages ≥ 6 years ) and ipratropium bromide 0.25 mg mixed with either 2.5 ml of isotonic MgSO4 ( 250 mmol/l , tonicity 289 mOsm ; 151 mg per dose ) or 2.5 ml of isotonic saline on three occasions at approximately 20-minute intervals . MAIN OUTCOME MEASURES The primary outcome measure was the ASS after 1 hour of treatment . Secondary measures included ' stepping down ' of treatment at 1 hour , number and frequency of additional salbutamol administrations , length of stay in hospital , requirement for intravenous bronchodilator treatment , and intubation and /or admission to a paediatric intensive care unit . Data on paediatric quality of life , time off school/nursery , health-care re source usage and time off work were collected 1 month after r and omisation . RESULTS A total of 508 children were recruited into the study ; 252 received MgSO4 and 256 received placebo along with the st and ard treatment . There were no differences in baseline characteristics . There was a small , but statistically significant difference in ASS at T60 in those children who received nebulised MgSO4 { 0.25 [ 95 % confidence interval ( CI ) 0.02 to 0.48 ] ; p = 0.034 } and this difference was sustained for up to 240 minutes [ 0.20 ( 95 % CI 0.01 to 0.40 ) , p = 0.042 ] . The clinical significance of this gain is uncertain . Assessing treatment-covariate interactions , there is evidence of a larger effect in those children with more severe asthma exacerbations ( p = 0.034 ) and those with a shorter duration of symptoms ( p = 0.049 ) . There were no significant differences in the secondary outcomes measured . Adverse events ( AEs ) were reported in 19 % of children in the magnesium group and 20 % in the placebo group . There were no clinical ly significant serious AEs in either group . The results of the base-case economic analyses are accompanied by considerable uncertainty , but suggest that , from an NHS and Personal Social Services perspective , the addition of magnesium to st and ard treatment may be cost-effective compared with st and ard treatment only . The results of economic evaluation show that the probability of magnesium being cost-effective is over 60 % at cost-effectiveness thresholds of £ 1000 per unit decrement in ASS and £ 20,000 per quality -adjusted life-year ( QALY ) gained , respectively ; it is noted that for some parameter variations this probability is much lower , reflecting the labile nature of the cost-effectiveness ratio in light of the small differences in benefits and costs shown in the trial and the relation between the main outcome measure ( ASS ) and preference based measures of quality of life used in cost-utility analysis ( European Quality of Life-5 Dimensions ; EQ-5D ) . CONCLUSIONS This study supports the use of nebulised isotonic MgSO4 at the dose of 151 mg given three times in the first hour of treatment as an adjuvant to st and ard treatment when a child presents with an acute episode of severe asthma . No harm is done by adding magnesium to salbutamol and ipratropium bromide , and in some individuals it may be clinical ly helpful . The response is likely to be more marked in those children with more severe attacks and with a shorter duration of exacerbation . Although the study was not powered to demonstrate this fully , the data certainly support the hypotheses that nebulised magnesium has a greater clinical effect in children who have more severe exacerbation with shorter duration of symptoms . TRIAL REGISTRATION Current Controlled Trials IS RCT N81456894 . FUNDING The National Institute for Health Research Health Technology Assessment programme [10926346] Despite a good underst and ing of the disease and its treatments , asthma continues to place a large economic burden on healthcare systems . As such , it is important to consider the economic impact of alternative therapeutic options for the treatment of this condition to ensure that scarce re sources are used in the most efficient manner possible . Thus , the aim of asthma management from an economic perspective is to reduce the burden of this disease through maximizing health gain with available re sources . A prospect i ve economic analysis was conducted as part of a multicentre , r and omized , double-blind , comparative trial of salmeterol/fluticasone propionate combination product ( SFC ) 50/250 microg twice daily vs. budesonide ( 800 microg twice daily ) in adults and adolescents with asthma who were symptomatic despite treatment with inhaled corticosteroids at doses of 800 - 1200 microg day(-1 ) . Treatment effectiveness was measured in terms of successfully-treated weeks , defined as a > or = 5 % improvement in morning peak expiratory flow , episode-free days ( a day without the need for rescue medication , no nocturnal awakening or adverse events ) and symptom-free days . Cost-effectiveness analyses were performed using direct healthcare and drug costs , from the perspective of the Swedish healthcare system ( 1998 prices ) , with appropriate sensitivity analyses to test the robustness of the findings . Overall , SFC produced significantly higher ( P<0.001 ) proportions of successfully-treated weeks , episode-free days and symptom-free days . Direct asthma management costs were similar between the two groups [ SEK19.6 ( $ US2.4 ) for SFC vs. SEK18.5 ( SUS2.2 ) for budesonide ] . The cost per successfully-treated week was lower for SFC than for budesonide [ SEK204 ( $ US24.8 ) vs. SEK300 ( $ US36.4 ) per week ] , as were the costs per episode-free day [ SEK51.1 ( $ US6.2 ) vs. SEK75.1 ( $ US9.1 ) per day ] and symptom-free day [ SEK42.2 ( $ US5.1 ) vs. SEK53.0 ( $ US6.4 ) per day ] . Incremental cost-effectiveness ratios showed that the additional costs to achieve additional benefits with SFC were minimal . Costs per additional successfully-treated week , symptom-free day and episode-free day with SFC were SEK31.6 ( $ US3.9 ) , SEK9.2 ( $ US1.1 ) and SEK7.7 ( $ US0.9 ) , respectively , relative to budesonide . Sensitivity analysis showed that the results were stable over a wide range of assumptions . The results suggest that SFC is a more cost-effective treatment than budesonide in the management of moderate to severe asthma [10186465] This article presents the first version of a reporting format for modelling studies which is based on a general reporting format by our taskforce , which was published in the previous issue of this journal . The use of decision-analytical models for economic evaluations is increasing because , in practice , it is not always possible to derive information from prospect i ve studies . However , the acceptance of modelling studies is generally lower than prospect i ve studies not only because of the use of secondary data , but also because the reports of modelling studies do not always have sufficient transparency . Hence , a st and ardised reporting format may improve the transparency and , consequently , the acceptance of modelling studies . This article presents an example of a reporting format for economic evaluation based on modelling studies , which may facilitate the development of future guidelines for modelling studies . The format consists of a number of headings , which are followed by a brief recommendation on the content . This format does not deal with methodology and data management , but especially addresses validation and quality assurance , which may increase the transparency of the report [11596838] Abstract Objective : To compare the relative value of an inhaled corticosteroid , fluticasone propionate 88μg twice daily , versus an oral leukotriene receptor antagonist , zafirlukast 20 mg twice daily , in patients with persistent asthma currently receiving short acting β2-agonists alone . Study design : A cost-efficacy analysis using re source utilisation and clinical data obtained prospect ively from a multicentre , r and omised , double-blind , double-dummy , placebo-controlled 12-week clinical trial conducted in the US . Perspective : Third-party payor . Patients and methods : A total of 451 corticosteroid-naive patients with persistent asthma were treated with either fluticasone propionate 88μg twice daily or zafirlukast 20 mg twice daily . All patients were given salbutamol ( albuterol ) to be used as rescue medication . Data were examined using intent-to-treat analysis . Results : Mean daily per person cost-efficacy ratios using improvement in forced expiratory volume in 1 second ( FEV1 ) [ ≥12 % increase from baseline ] were $ US3.47 for fluticasone propionate compared with $ US7.81 for zafirlukast ( 1999 values ) . The mean daily per person cost-efficacy ratios for symptom-free days obtained were $ US5.51 for fluticasone propionate compared with $ US14.98 for zafirlukast . These cost-efficacy ratios remained in favour of fluticasone propionate after a robust sensitivity analysis . Conclusions : Treatment with fluticasone propionate 88μg twice daily was the most cost effective treatment compared with zafirlukast 20 mg twice daily in this 12-week clinical trial . This analysis supports the use of fluticasone propionate 88μg twice daily as first-line treatment in patients with persistent asthma previously treated with short-acting β2-agonist alone [20550224] BACKGROUND Information is lacking on the relative effectiveness and cost effectiveness -- in a primary -care setting --of leukotriene receptor antagonists ( LTRAs ) as an alternative to inhaled corticosteroids ( ICS ) for initial asthma controller therapy . OBJECTIVE To compare the cost effectiveness of LTRAs versus ICS for patients initiating asthma controller therapy . METHODS An economic evaluation was conducted alongside a 2-year , pragmatic , r and omized controlled trial set in 53 primary -care practice s in the UK . Patients aged 12 - 80 years with asthma and symptoms requiring regular anti-inflammatory therapy ( n = 326 ) were r and omly assigned to LTRAs ( n = 162 ) or ICS ( n = 164 ) . The main outcome measures were the incremental costs per point improvement in the Mini Asthma Quality of Life Question naire , per point improvement in the Asthma Control Question naire and per QALY gained from the UK NHS and societal perspectives . RESULTS Over 2 years , re source use was similar between the two treatment groups , but the cost to society per patient was significantly higher for the LTRA group , at pounds sterling 711 versus pounds sterling 433 for the ICS group ( adjusted difference pounds sterling 204 ; 95 % CI 74 , 308 ) [ year 2005 values ] . Cost differences were driven primarily by differences in prescription drug costs , particularly study drug costs . There was a nonsignificant ( imputed , adjusted ) difference between treatment groups , favouring ICS , in QALYs gained at 2 years of -0.073 ( 95 % CI -0.143 , 0.010 ) . Therapy with LTRAs was , on average , a dominated strategy , and , at a threshold for willingness to pay of pounds sterling 30,000 per QALY gained , the probability of LTRAs being cost effective compared with ICS was approximately 3 % from both societal and NHS perspectives . CONCLUSIONS There is a very low probability of LTRAs being cost effective in the UK , at 2005 values , compared with ICS for initial asthma controller therapy . TRIAL REGISTRATION UK National Research Register N0547145240 ; Controlled Clinical Trials IS RCT N99132811 [20446755] BACKGROUND Information is lacking on the relative effectiveness and cost effectiveness -- in a real-life primary -care setting --of leukotriene receptor antagonists ( LTRAs ) and long-acting beta2 adrenergic receptor agonists ( beta2 agonists ) as add-on therapy for patients whose asthma symptoms are not controlled on low-dose inhaled corticosteroids ( ICS ) . OBJECTIVE To estimate the cost effectiveness of LTRAs compared with long-acting beta2 agonists as add-on therapy for patients whose asthma symptoms are not controlled on low-dose ICS . METHODS An economic evaluation was conducted alongside a 2-year , pragmatic , r and omized controlled trial set in 53 primary -care practice s in the UK . Patients aged 12 - 80 years with asthma insufficiently controlled with ICS ( n = 361 ) were r and omly assigned to add-on LTRAs ( n = 176 ) or long-acting beta2 agonists ( n = 185 ) . The main outcome measures were the incremental cost per point improvement in the Mini Asthma Quality of Life Question naire ( MiniAQLQ ) , per point improvement in the Asthma Control Question naire ( ACQ ) and per QALY gained from perspectives of the UK NHS and society . RESULTS Over 2 years , the societal cost per patient receiving LTRAs was pounds sterling 1157 versus pounds sterling 952 for long-acting beta2 agonists , a ( significant , adjusted ) increase of pounds sterling 214 ( 95 % CI 2 , 411 ) [ year 2005 values ] . Patients receiving LTRAs experienced a non-significant incremental gain of 0.009 QALYs ( 95 % CI -0.077 , 0.103 ) . The incremental cost per QALY gained from the societal ( NHS ) perspective was pounds sterling 22,589 ( pounds sterling 11,919 ) . Uncertainty around this point estimate suggested that , given a maximum willingness to pay of pounds sterling 30,000 per QALY gained , the probability that LTRAs are a cost-effective alternative to long-acting beta2 agonists as add-on therapy was approximately 52 % from both societal and NHS perspectives . CONCLUSIONS On balance , these results marginally favour the repositioning of LTRAs as a cost-effective alternative to long-acting beta2 agonists as add-on therapy to ICS for asthma . However , there is much uncertainty surrounding the incremental cost effectiveness because of similarity of clinical benefit and broad confidence intervals for differences in healthcare costs . TRIAL REGISTRATION UK National Research Register N0547145240 ; Controlled Clinical Trials IS RCT N99132811 [21211651] BACKGROUND Cost-effectiveness analyses of asthma controller regimens for adults exist , but similar evaluations exclusively for children are few . OBJECTIVE We sought to compare the cost-effectiveness of 2 commonly used asthma controllers , fluticasone and montelukast , with data from the Pediatric Asthma Controller Trial . METHODS We compared the cost-effectiveness of low-dose fluticasone with that of montelukast in a r and omized , controlled , multicenter clinical trial in children with mild-to-moderate persistent asthma . Analyses were also conducted on subgroups based on phenotypic factors . Effectiveness measures included ( 1 ) the number of asthma-control days , ( 2 ) the percentage of participants with an increase over baseline of FEV(1 ) of 12 % or greater , and ( 3 ) the number of exacerbations avoided . Costs were analyzed from both a US health care payer 's perspective and a societal perspective . RESULTS For all cost-effectiveness measures studied , fluticasone cost less and was more effective than montelukast . For example , fluticasone treatment cost $ 430 less in mean direct cost ( P < .01 ) and result ed in 40 more asthma-control days ( P < .01 ) during the 48-week study period . Considering sampling uncertainty , fluticasone cost less and was more effective at least 95 % of the time . For the high exhaled nitric oxide ( eNO ) phenotypic subgroup ( eNO ≥25 ppb ) and more responsive PC(20 ) subgroup ( PC(20 ) < 2 mg/mL ) , fluticasone was cost-effective compared with montelukast for all cost-effectiveness measures , whereas not all the effectiveness measures were statistically different for the other 2 phenotypic subgroups . CONCLUSION For children with mild-to-moderate persistent asthma , low-dose fluticasone had lower cost and higher effectiveness compared with montelukast , especially in those with more airway inflammation , as indicated by increased levels of eNO and more responsivity to methacholine

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### Context: [18515918] OBJECTIVE To compare the cost-effectiveness of budesonide/formoterol in a single inhaler used as Maintenance and Reliever Therapy ( SMART ) versus fixed higher-dose budesonide/formoterol plus as-needed terbutaline reliever ( FHDBF ) or fixed dose fluticasone/salmeterol plus as-needed terbutaline reliever ( FDFS ) in controlling asthma in adults and adolescents . METHODS An economic evaluation was conducted by applying Canadian costs to the results of a large ( N=3,335 ) international r and omized , double-blind , controlled trial in which health re source utilization was prospect ively collected . Although no Canadian subjects were enrolled in this clinical trial , it was assumed that the results would apply to Canadian patients . Primary outcome measurements included time to first exacerbation and the number of severe exacerbations . Costs included direct medical costs ( physician/emergency room visits , hospitalizations , asthma drug costs ) and productivity ( absenteeism ) . The time horizon was six months , which corresponded to the duration of the trial . Prices were obtained from 2006 Canadian sources . Both healthcare and societal perspectives were considered . Deterministic univariate sensitivity analyses were conducted . RESULTS In the clinical trial , SMART was superior to FHDBF and FDFS with respect to total number of severe exacerbations ( RR 0.72 ; 95 % CI 0.57 , 0.90 ; p=0.0048 ; RR 0.61 ; 95 % CI 0.49 , 0.76 ; p<0.001 , respectively ) . Exacerbation rates ( reported as events per patient per 6 months ) were 0.12 for SMART , 0.16 for FHDBF , and 0.19 for FDFS . All treatments provided similar improvements in lung function , asthma control days and asthma-related quality of life . The mean cost per patient per 6 months was $ 545 in the SMART arm versus $ 690 in the FHDBF arm and $ 842 in the FDFS arm from the healthcare perspective ; and $ 676 for SMART , $ 838 for FHDBF , and $ 954 for FDFS from the societal perspective . SMART was dominant ( more effective , less expensive ) in the base case analysis from both the healthcare and societal perspectives . The results were robust under sensitivity testing . CONCLUSIONS The SMART strategy , which allows budesonide/formoterol to be used as both maintenance and reliever medication , is dominant over the alternate strategies of fixed higher dose budesonide and formoterol plus as-needed terbutaline or fixed dose salmeterol and fluticasone plus as-needed terbutaline [29702848] OBJECTIVES Omalizumab improves health outcomes for patients with severe asthma . The purpose of this study was to conduct a cost-utility analysis of omalizumab from a societal perspective by using the results from a r and omized controlled trial in Japan , and explore the efficient use of omalizumab . METHODS We developed a Markov model to compare omalizumab add-on therapy with st and ard therapy . Patients transitioned between symptom-free , day-to-day , and exacerbation states . Our model had a lifetime horizon in which 5-year omalizumab add-on therapy was followed by st and ard therapy . Preference-based utilities were extracted from another study . We estimated the expected value of perfect information for patients ' response to omalizumab . RESULTS In the base case , incremental cost-effectiveness ratio ( ICER ) for omalizumab add-on therapy was US $ 755,200 ( 95 % credible interval [ CI ] $ 614,200-$1,298,500 ) per quality -adjusted life-year gained , compared with st and ard therapy alone . One-way sensitivity analyses indicated that the results were sensitive to asthma-related mortality , exacerbation risk , and omalizumab cost . The ICER for a responder subgroup was 22 % lower than that in the base case . Individual and population expected value of perfect informations for the response were $ 4100 ( 95 % CI $ 2500-$6000 ) and $ 28 million ( 95 % CI $ 17 million-$42 million ) per year , respectively . CONCLUSIONS With a willingness-to-pay of $ 45,000 per quality -adjusted life-year , omalizumab was not cost-effective in Japan . Confining omalizumab therapy to previously predicted responders , however , may be a reasonable strategy to reduce the ICER , as the cost-effectiveness was observed to improve for these patients . Further studies should be conducted to explore responder prediction methods . Decreasing the price of omalizumab would improve cost-effectiveness [14657888] BACKGROUND The Inhaled Steroid as Regular Therapy in Early Asthma ( START ) study reported that early intervention with budesonide in mild persistent asthma reduces severe asthmatic events and improves symptom outcomes and lung function in adults and children . OBJECTIVE We sought to estimate the incremental cost-effectiveness of early intervention with budesonide , as observed within the START study . METHODS START was a r and omized , 3-year controlled trial of budesonide in early onset mild asthma among 7165 subjects ages 5 to 66 years . Three age groups ( 5 - 10 , 11 - 17 , and > or=18 years ) were studied separately and overall . Differences in the probability of emergency treatments , symptom-free days ( SFDs ) , and costs of health care were determined . Incremental cost-effectiveness ratios were estimated from the health care payer and societal perspectives . RESULTS Compared with usual therapy , patients receiving budesonide experienced an average of 14.1 ( SE , 1.3 ) more SFDs per year ( P < .001 ) , fewer hospital days ( 69 % , P < .001 ) , and fewer emergency department visits ( 67 % , P < .05 ) . From the health care payer perspective , the net cost of early use of budesonide was an additional US dollars 0.42 ( SE , dollars 0.04 ) per day , and the result ant cost-effectiveness ratio was US dollars 11.30 ( 95 % CI , US dollars 8.60-US dollars 14.90 ) per SFD gained . From the societal perspective , the cost offsets of lower absence from school or work reduced the net cost of early budesonide to US dollars 0.14 ( SE , US dollars 0.07 ) per day and decreased the cost-effectiveness ratio to US dollars 3.70 ( 95 % CI , US dollars 0.10-US dollars 8.00 ) . Early intervention was more effective and cost saving in the youngest age group . CONCLUSION Long-term treatment with budesonide appears to be cost-effective in patients with mild persistent asthma of recent onset [10346418] Abstract Objective : The aim of this study was to determine the relative economic consequences of treating asthmatics with twice daily dry powder formoterol 12 mg as compared with salmeterol 50 mg from a societal perspective . Design and Setting : A r and omised , 6-month , open-label study including 482 patients with asthma was conducted in Italy , Spain , France , Switzerl and , the UK and Sweden . Medical costs included the costs of medications , physician services , emergency room visits , hospital admissions and lung function and other tests . Travel costs and costs of production loss were also calculated . Unit prices were estimated from external sources . To pool the costs of the 6 countries , European currencies were converted to US dollars using 1995 exchange rates . Outcome measures were the number of episode-free days ( EFDs ) and the number of patients reaching a clinical ly relevant improvement in quality of life as measured using the St. Georges Respiratory Question naire . Main outcome measures and results : There were no significant differences between the 2 treatment arms in the frequency of emergency room visits , hospital admissions , use of rescue medication or contacts with general practitioners ( GPs ) , specialists or nurses . Median medical costs over 6 months were $ US828 per patient with formoterol and $ US850 with salmeterol . This difference was not statistically significant . In both groups , about 60 % of all days were episode-free . Average costs per EFD were about $ US9 for both treatments . The average cost per patient reaching a clinical ly relevant improvement in quality of life was between $ US1300 and $ US1400 . Incremental cost-effectiveness ratios were not calculated because both costs and outcomes were not significantly different . Asthma-related absenteeism ranged between 3 days and 6 months per patient in both groups . Conclusions : There was no evidence to suggest that either treatment was more cost effective than the other [11447380] BACKGROUND Inhaled corticosteroids remain underused among United States-based clinicians in treating mild-to-moderate adult asthma . OBJECTIVE The purpose of this investigation was to estimate the clinical impact , health-related quality of life , cost , and cost-effectiveness of inhaled corticosteroid therapy in a population of patients aged 18 years and over with FEV(1 ) = 60 % to 100 % of predicted normal . METHODS We performed a cost-effectiveness analysis of quick relievers ( eg , short-acting beta-agonists ) on an as-needed basis plus inhaled corticosteroid therapy versus quick relievers alone . A mathematical simulation model was developed to forecast symptoms , acute exacerbations , quality -adjusted life-years ( QALYs ) , health care costs , and cost-effectiveness , measured in both dollars per QALY gained and dollars per symptom-free day gained . All evaluation outcomes were discounted at an annual rate of 3 % and measured over a 10-year planning horizon . Data on the natural history of disease , drug efficacy , patient preferences , and economic costs were obtained from a variety of observational cohorts , r and omized trials , and patient surveys . RESULTS Over a 10-year period , use of inhaled corticosteroids increases total health costs from roughly $ 5,200 to $ 8,400 and improves QALYs from 6.8 to 7.0 , implying an incremental cost of $ 13,500 per QALY gained . Costs per symptom-free day gained are $ 7.50 . Both per-person acute exacerbations and hospitalizations are reduced by 33 % . The cost-effectiveness findings are sensitive to the assumed efficacy and side-effects of inhaled corticosteroid therapy . CONCLUSIONS Inhaled corticosteroids appear to deliver good comparative value in adults with mild-to-moderate asthma . Although more research is needed to underst and their impact on preferences regarding side effects and compliance , these findings might be useful for priority- setting in limited re source situations [9926144] Long-acting inhaled /&-agonists ( LABS ) , used in conjunction with low-dose inhaled steroids , are a recommended alternative to high-dose inhaled steroids for asthmatics with persistent symptoms ( 1 ) . There are , however , few published data regarding their cost-effectiveness . The drugs are relatively expensive and the aim of this study was to evaluate LAB cost-effectiveness in primary care , in terms of improved clinical outcomes ( associated with reduced NHS costs ) off setting higher prescription costs . A controlled , retrospective , non-r and omized analysis utilized the computerized Thorpewood Primary Care Data base and compared clinical outcomes and asthma management costs 1 yr prior to and 1 yr after initiation of therapy with salmeterol xinafoate [11379805] BACKGROUND Budesonide and sodium cromoglycate are both recommended as maintenance therapy for childhood asthma . OBJECTIVE To compare the cost-effectiveness of these two treatment strategies in clinical practice , in an open-label , pharmacoeconomic clinical trial . METHODS Health economics were evaluated in 138 children , ages 5 to 11 years , with unstable asthma not previously treated with corticosteroids or cromones . The asthma was stabilized during 4 to 6 weeks with budesonide 200 to 400 microg twice daily . The children were then r and omly allocated to one of the two treatment strategies aim ing at maintaining asthma control for 12 months ; budesonide 400 microg/day ( N = 69 ) or sodium cromoglycate 60 mg/day ( N = 69 ) . If asthma control was judged unsatisfactory , the doses were increased or the children were switched to the alternate treatment . RESULTS In children continuing on the same treatment , the degree of asthma control was similar in the two groups at study end . To maintain asthma control , 42 % of cromoglycate children switched to budesonide , and then experienced a 14 % increase in symptom-free days . No budesonide patient had to switch therapy because of lack of asthma control . Although not statistically significant , total annual cost per patient was 24 % ( Swedish kronor 4195 ; US $ 487 ; Euro 485 ) lower in the budesonide than the cromoglycate group , mainly due to a lower cost for asthma medication . CONCLUSIONS A budesonide strategy for continued maintenance treatment , after an initial period of stabilizing treatment with budesonide , result ed in lower costs and less drug switches than did a strategy with sodium cromoglycate [12535234] OBJECTIVES Mathematical modeling is used widely in economic evaluations of pharmaceuticals and other health-care technologies . Users of models in government and the private sector need to be able to evaluate the quality of models according to scientific criteria of good practice . This report describes the consensus of a task force convened to provide modelers with guidelines for conducting and reporting modeling studies . METHODS The task force was appointed with the advice and consent of the Board of Directors of ISPOR . Members were experienced developers or users of models , worked in academia and industry , and came from several countries in North America and Europe . The task force met on three occasions , conducted frequent correspondence and exchanges of drafts by electronic mail , and solicited comments on three drafts from a core group of external review ers and more broadly from the membership of ISPOR . RESULTS Criteria for assessing the quality of models fell into three areas : model structure , data used as inputs to models , and model validation . Several major themes cut across these areas . Models and their results should be represented as aids to decision making , not as statements of scientific fact ; therefore , it is inappropriate to dem and that models be vali date d prospect ively before use . However , model assumptions regarding causal structure and parameter estimates should be continually assessed against data , and models should be revised accordingly . Structural assumptions and parameter estimates should be reported clearly and explicitly , and opportunities for users to appreciate the conditional relationship between inputs and outputs should be provided through sensitivity analyses . CONCLUSIONS Model-based evaluations are a valuable re source for health-care decision makers . It is the responsibility of model developers to conduct modeling studies according to the best practicable st and ards of quality and to communicate results with adequate disclosure of assumptions and with the caveat that conclusions are conditional upon the assumptions and data on which the model is built [16136769] BACKGROUND The choice of treatment can have a major impact on the total costs associated with asthma care . OBJECTIVE To determine the relative cost-effectiveness of twice-daily treatment with inhaled fluticasone propionate-salmeterol via Diskus , 100/50 microg , with that of once-daily treatment with oral montelukast as initial maintenance therapy in patients with persistent asthma uncontrolled with a short-acting beta2-agonist alone . METHODS Data from a r and omized , double-blind , double-dummy , 12-week clinical trial were analyzed . Efficacy end points included ( 1 ) symptom-free days ( SFDs ) during the 12-week period and ( 2 ) a 12 % or greater increase in forced expiratory volume in 1 second ( FEV1 ) from baseline . The economic analysis was performed from a payer 's perspective , and hence only direct costs were included in the analysis . The incremental cost-effectiveness ratio ( ICER ) , which is the mean difference in average costs divided by the mean difference in average effectiveness , was calculated for both effectiveness outcomes ( SFDs and FEV1 ) . RESULTS For the SFDs end point , the ICER for fluticasone propionate-salmeterol vs montelukast was $ 2.87 ( 95 % confidence interval , -$1.08 to $ 6.65 ) , indicating that it costs , on average , an extra $ 2.87 per day for an additional SFD with fluticasone propionate-salmeterol than with montelukast . With regard to FEV1 , the ICER was $ 1.79 ( 95 % confidence interval , -$0.72 to $ 3.86 ) , indicating that it costs , on average , an extra $ 1.79 per day to achieve a lung function improvement of 12 % or greater from baseline with fluticasone propionate-salmeterol than with montelukast . At a widely acceptable ceiling ratio of $ 9.95 per day , the probability of fluticasone propionate-salmeterol being more cost-effective than montelukast was 99.8 % for SFDs and was almost 100 % for an FEV1 improvement of 12 % of greater . CONCLUSIONS Treating 2 main components of asthma , inflammation and smooth muscle dysfunction , using fluticasone propionate-salmeterol is more cost-effective than using a single mediator antagonist alone , such as montelukast , as initial maintenance therapy for persistent asthma in patients treated with a short-acting beta2-agonist only [11742910] STUDY OBJECTIVES To evaluate the cost-effectiveness of inhaled fluticasone propionate ( FP ) in children aged 12 to 47 months with asthma symptoms . DESIGN A retrospective economic analysis conducted from the perspective of the Danish health-care system , based on clinical data from a 12-week study . SETTING Thirty-three outpatient centers in nine countries . PATIENTS Two hundred thirty-seven children aged 12 to 47 months with documented history of recurrent wheeze or asthma symptoms . INTERVENTIONS Two dosages of FP , 100 microg/d and 200 microg/d , and placebo administered in two divided doses via a metered-dose inhaler and a Babyhaler ( Glaxo Wellcome ; Middlesex , UK ) spacer device . MEASUREMENTS Effectiveness in terms of asthma exacerbations , control of cough and wheeze symptoms , symptom-free days , overall direct costs of asthma management in Danish kroner at 1999 prices , and mean and incremental cost-effectiveness ratios . RESULTS FP , 200 microg/d , was significantly more effective than placebo treatment in terms of the proportion of exacerbation-free patients ( 73.7 % vs 59.8 % ; p = 0.025 ) and patients experiencing a > or = 25 % improvement in cough symptoms ( 57.9 % vs 39.0 % ; p = 0.018 ) . The costs per exacerbation-free patient , per patient with a > or = 25 % improvement in cough and wheeze symptoms from baseline , and per symptom-free day were lower in the FP groups than in the placebo group . The incremental cost-effectiveness ratios for these end points indicated that the additional benefits of FP , 200 microg/d , were achieved at a lower overall cost compared with placebo treatment . CONCLUSIONS From the perspective of the Danish health-care system , FP , 100 microg bid , administered via the Babyhaler inhalation device was cost-effective relative to st and ard therapy with bronchodilators alone [11929348] Abstract Background and objective : Asthma is a chronic-episodic disease characterised by acute , symptomatic episodes of varying severity . We developed a Markov model that can be used to estimate the cost effectiveness of alternative asthma treatments . Because of the costs they incur , asthma exacerbations ( ‘ attacks ’ ) requiring intervention by a healthcare professional were a central consideration in the development of the model . Methods : Treatment success was assessed as asthma control , a composite measure based on goals defined in world-wide asthma management guidelines and in terms of quality -adjusted life-years ( QALYs ) . The data from which the transition probabilities were derived came from patients with asthma who received either salmeterol/fluticasone propionate combination ( SFC ) 50/100μg or fluticasone propionate ( FP ) 100μg , administered twice daily via an inhaler , in a 12-week , r and omised , double-blind , clinical trial . Costs were estimated from re source profiles defined for each of the model states . A key aspect of the model was the use of probabilistic sensitivity analysis techniques to examine the uncertainty in the cost-effectiveness results . Distributions were fitted to transition probabilities and to cost input parameters and values were sample d at r and om from these distributions using a second order Monte Carlo simulation technique . This produced a distribution for incremental cost effectiveness that was employed to construct 95 % uncertainty intervals and to construct cost effectiveness acceptability curves . Results : In this analysis , the model was run over a 12-week period using transition probabilities derived from the trial data . The results showed that treatment with SFC result ed in a higher proportion of successfully controlled weeks per patient than treatment with FP(66 vs 47 % ) , and higher mean weekly direct asthma management costs ( £ 15.77 vs £ 11.83 ; 2000 values ) . The average incremental cost per successfully controlled week with SFC was £ 20.83.Probabilistic sensitivity analysis showed that the 95 % uncertainty intervals for the incremental cost-effectiveness ratio was −£64.94 to £ 112.66 . In approximately 25 % of cases , SFC was dominant ( more effective and less costly ) , but in the remaining cases , it was both more effective and more costly . It was shown that if decision makers are willing to pay approximately £ 45 for an additional successfully controlled week , SFC will be the more cost-effective strategy in this patient population for 80 % of the time . Conclusions : This is one of the first decision-analytic models of asthma to incorporate probabilistic sensitivity analysis techniques to explore uncertainty . The model ’s flexible yet st and ardised framework permits the cost effectiveness of alternative asthma management strategies in different healthcare setting s to be established [15987228] Abstract Objectives : To compare the costs and effectiveness of adjustable maintenance dosing with budesonide/formoterol in a single inhaler versus fixed dosing in adults with asthma . Methods : In this prospect i ve , r and omised , open-label , parallel-group , multicentre trial conducted in Germany , patients with asthma received budesonide/formoterol 160µg/4.5 µg in a single inhaler ( Symbicort ® Turbuhaler ® ) with two inhalations twice daily for a 4-week run-in period . Patients were then r and omised to either adjustable maintenance dosing ( one inhalation twice daily , stepping up to four inhalations twice daily for 1 week if asthma worsened ; n = 1679 ) or fixed dosing ( two inhalations twice daily ; n = 1618 ) for 12 weeks . The primary efficacy variable was the change in health-related quality of life ( HR-QOL ) , measured using the Asthma Quality of Life Question naire ( st and ardised ) during the r and omised treatment period . Re source utilisation data were collected in parallel and combined with German unit costs to estimate direct and indirect costs ( year 2001 values ) . Results : Both treatment regimens were equally effective in maintaining HR-QOL and asthma control during the r and omised treatment period . However , overall , patients in the adjustable maintenance dosing group took fewer daily inhalations of budesonide/formoterol than those in the fixed-dosing group ( mean : 2.63 vs 3.82 inhalations ; p < 0.001 ) . Adjustable maintenance dosing was associated with significantly lower asthma-related direct costs compared with fixed dosing ( mean : € 221 vs € 292 ; p < 0.001 ) . This pattern was maintained when patients were stratified into those with peak expiratory flow ( PEF ) of 60 % to < 80 % predicted normal and those with PEF of ≥80 % predicted normal and when total costs were considered . Conclusion : Adjustable maintenance dosing with budesonide/formoterol in a single inhaler maintained HR-QOL in adult patients with asthma at a significantly lower cost than fixed dosing [10662477] Abstract Objective : The aim of this study was to determine the cost effectiveness of 2 inhaled corticosteroids , fluticasone propionate and flunisolide , in the management of asthma from a third-party payer perspective in Germany ( German Sickness Fund ) . Design and setting : Direct treatment costs were retrospectively applied to 2 prospect i ve r and omised parallel group clinical trials conducted in Germany comparing fluticasone propionate and flunisolide : one 6-week open-label study ( n = 332 ) and one 8-week double-blind study ( n = 308 ) in corticosteroid-naive patients with asthma of moderate severity aged between 18 and 70 years . All costs were adjusted to 1997 Deutschmarks . Efficacy parameters included changes in morning and evening peak expiratory flow rate ( PEFR ) measurements , the number of successfully treated patients ( defined as those with a PEFR improvement of ≥10 % ) and proportion of symptom-free days . Main outcome measures and results : The fluticasone propionate groups had higher respective proportions of successfully treated patients and symptom-free days than the flunisolide groups in both the open-label ( 56.8 vs 39.6 % and 36.4 vs 28.5 % ) and double-blind ( 55.3 vs 44.5 % and 35.1 vs 31.1 % ) studies . Improvements in both morning and evening PEFR measurements were also significantly ( p < 0.01 ) greater with fluticasone propionate than with flunisolide . Although average daily treatment costs were slightly higher in the fluticasone propionate groups than in the flunisolide groups , all cost-effectiveness ratios ( daily cost per successfully treated patient and daily cost per symptom-free day ) favoured fluticasone propionate . Sensitivity analysis showed that these results were robust over a wide range of assumptions . Conclusion : In these patients , management with fluticasone propionate was more cost effective than with flunisolide in the German healthcare setting [21839898] OBJECTIVE To assess the incremental cost-effectiveness of SFC compared with MON for the control of persistent asthma in children . METHODS We conducted an economic evaluation on a 12-week prospect i ve r and omized open-label parallel-group comparison of SFC versus MON in children with symptomatic asthma receiving inhaled corticosteroids and short-acting β2-agonists . Asthma-related medication , unscheduled physician contacts and hospitalizations were collected prospect ively . The main effectiveness measure was percentage of asthma-controlled week with no short-acting β2-agonist use during the study period . The analysis was conducted from the Mexican healthcare perspective using 2010 unit cost prices , and only direct costs were considered , all costs are reported in US dollar . . The model was made fully probabilistic to reflect the joint uncertainty in the model parameters . RESULTS Over the whole treatment period , the median percentages of asthma-controlled weeks were 83.3 % in the SFC group and 66.7 % in the MON group ( SFC-MON difference , 16.7 % ; 95 % CI , 8.3 - 16.7 ; P < 0.001 in favor of SFC ) . The mean total cost of the SFC regimen was $ 2,323 compared with $ 3,230 for the MON regimen . The SFC was the dominant strategy ( both more effective and less expensive ) using the SFC was associated with an incremental cost per additional asthma-controlled of $ ( 5,467 ) . Probabilistic sensitivity analysis tested numerous assumptions about the model cost and efficacy parameters and found that the results were robust to most changes . CONCLUSIONS This analysis demonstrates that , compared with MON , SFC may be cost saving from the Mexican health care perspective for the treatment of pediatric patients with asthma . SFC provided a reduction in the number of severe exacerbations , frequent asthma symptoms and rescue medication use . Incremental cost-effectiveness analysis indicated the dominance of SFC because of both lower costs and greater efficacy [7763062] Eighty six children with troublesome wheezing were studied , in a semi prospect i ve clinical trial with the patients acting as their own controls , to assess the efficacy and cost effectiveness of inhaled steroids . Improvement in school attendance , hospitalisations , breakthrough wheezing , and acute severe attacks were used to assess clinical efficacy . Expenditure for the family , on a cost of illness framework , before and after treatment , was used to estimate cost effectiveness . Highly significant numbers of patients showed improvement in clinical parameters , confirming efficacy . Mean monthly cost before inhaled steroid treatment was Rs 2652.33 ( 36.33 pounds ) and Rs 449.42 ( 6.16 pounds ) after starting treatment . The mean cost per unit satisfaction ( cost utility value ) which was Rs 255.54 ( 3.50 pounds ) before starting prophylaxis came down to Rs 5.42 ( 0.07 pound ) after starting treatment . There are no previous reports of cost-benefit assessment of inhaled steroids in childhood asthma . It is concluded that , even for developing countries with financial constraints , inhaled steroid treatment for prophylaxis of asthma is a cost effective and rational form of treatment [26303207] Abstract Objective : The objective of this study is to summarize the principal findings in the literature about acute asthma management in children . Methods : Systematic review s of r and omized clinical trials ( S RCTs ) with or without meta- analysis in children ( 1–18 years ) admitted to the emergency department ( ED ) were retrieved using five data bases . Method ological quality was determined using the AMSTAR tool . Results : One hundred and three studies were retrieved . Among those , 28 S RCTs were included : seven S RCTs related to short-acting beta2-agonists ( SABA ) , three to ipratropium bromide ( IB ) , eight to corticosteroids , one to racemic adrenaline , one to leukotriene receptor antagonists ( LTRA ) , four to magnesium sulfate , one to intravenous ( IV ) SABA , one to IV aminophylline , one to IV ketamine , and one to antibiotics . It was determined that administering SABA by MDI-VHC is superior to using a nebulizer , because it decreases the hospital admission rate , improves the clinical score , results in a shorter time in the ED , and causes fewer adverse effects . Levalbuterol and albuterol were similar . In patients with moderate to severe exacerbations , IB+SABA was superior to SABA , decreasing hospital admission and improving the clinical score . SABA heliox administered by nebulizer decreased exacerbation severity compared to oxygen . Inhaled corticosteroids ( ICS ) , especially administered by nebulizer , showed results similar to oral corticosteroids ( OCS ) with respect to reducing hospital admission , unscheduled visits , and the requirement of additional systemic corticosteroids . ICS or OCS following ED discharge was similar with regard to relapse . Compared with a placebo , IV magnesium reduced hospital admission and improved lung function . Conclusions : S RCTs are useful for guiding decisions in acute asthma treatment [12000004] We conducted an economic evaluation in a UK setting based on a 12-week prospect i ve r and omized open-label parallel-group comparison of eformoterol Turbohaler 12 microg b. i.d . with salmeterol Accuhaler 50 microg b. i.d . in children aged 6 - 17 with symptomatic asthma receiving inhaled corticosteroids and short-acting beta2-agonists . The principal effectiveness measure was percentage of symptom-free days with no short-acting beta2-agonist use during the study period . Asthma-related medication , unscheduled physician contacts and hospitalizations were collected prospect ively and cost to the UK NHS calculated using year 2,000 prices . The economic evaluation included 73 patients in the eformoterol group and 72 patients in the salmeterol group . The mean age of patients was 11.6 years ( eformoterol ) and 11.8 years ( salmeterol ) . The mean percentage of symptom-free days with no short-acting beta2-agonist use was 39 % in the eformoterol group and 30 % in the salmeterol group . Mean per patient daily cost was 1.15 pounds in the eformoterol group and 1.39 pounds in the salmeterol group . Both cost and effectiveness differences favoured eformoterol ( P < 0.05 ; one-sided ) . Sensitivity analysis confirmed the results to be robust to changes in effectiveness , price and re source utilisation parameters . Eformoterol delivered by Turbohaler was found to be significantly more effective and less expensive than salmeterol Accuhaler in this study [16573705] The inhaled Steroid Treatment As Regular Therapy in early asthma ( START ) study has shown that early intervention with inhaled budesonide in mild persistent asthma improves clinical outcomes in both adults and children . The aim of this study was to estimate the incremental cost-effectiveness of early treatment with budesonide Turbuhaler in children aged 5 - 10 yr who participated in START . Direct and indirect costs associated with asthma were determined for 1974 children participating in the double-blind , 3-year part of the study . R and omization was to placebo or to budesonide 200 microg once daily in each case in addition to usual asthma care . Cost-effectiveness ratios were calculated from the healthcare payer 's and societal perspectives ( using US prices ) . The addition of once-daily budesonide therapy to usual asthma care was associated with 16 additional symptom-free days ( SFDs ) per child over the 3-yr period ( p < 0.001 ) , with a substantial reduction ( 50 % ) in the mean number of days spent in hospital , and with reduced frequency of emergency room visits and missed school and caregiver work days . From the healthcare payer 's perspective ( direct costs ) , the increase in mean direct cost over 3 yr with budesonide was 169 dollars , which translated into an incremental cost of early intervention with budesonide in children of 10.50 dollars ( 95 % CI 1.20 - 33.30 dollars ) per SFD gained . From the societal perspective , there was a cost reduction over 3 yr of 192 dollars with budesonide relative to placebo . From a societal perspective , budesonide was therefore dominant . In conclusion , early intervention with once-daily budesonide added to usual asthma care in children with mild persistent asthma is cost-saving from a societal perspective and is acceptably cost-effective when viewed from a healthcare payer perspective [19768640] Introduction In budesonide/formoterol ( Symbicort ® Turbuhaler ® , AstraZeneca , Lund , Sweden ) maintenance and reliever therapy ( SMART ) , patients with asthma take a daily maintenance dose of budesonide/formoterol , with the option of taking additional doses for symptom relief instead of a short-acting β2-agonist ( SABA ) . This study assesses the cost-effectiveness of SMART compared with usual care in patients with mild-to-moderate persistent asthma treated by general practitioners in the Netherl and s from a societal perspective . Methods The study was linked to a r and omized , active-controlled , open-label , multicenter , 12-month clinical trial , with a prospect i ve collection of re source use . One hundred and two patients ≥18 years with mild-to-moderate persistent asthma and daily inhaled corticosteroids ( ICS ) prior to the trial were included . SMART was given as two inhalations of budesonide/formoterol ( 100/6 μg ) once daily , plus additional doses as needed . The control group was treated according to guidelines , which prescribe medium daily doses of ICS plus an SABA if needed . A long-acting β2-agonist ( LABA ) is added if necessary . Effectiveness was measured as the proportion of asthma-control days , Asthma Control Question naire ( ACQ ) scores , the net proportion of patients with relevant ACQ improvement , and the proportion of well-controlled patients . Costs included asthma medication , physician contacts , and absence from work . Results Mean total costs for SMART were € 134.81 lower ( 95 % CI : −€439.48 ; € 44.85 ) . Production losses were € 94.10 ( 95 % CI : −€300.60 ; € 0.29 ) lower for SMART ( € 10.77 vs. € 104.87 ) . No significant differences in health outcomes were seen , with 3.81 fewer asthma-control days per patient-year for SMART ( 95 % CI : −36.8 ; 30.8 ) , a 0.049 better ACQ score ( 95 % CI : −0.21 ; 0.29 ) , a 5.8 % larger net proportion of improved patients ( 95 % CI : t15.6 % ; 27.3 % ) , and a 2.1 % ( 95 % CI : −25.5 ; 20.8 % ) smaller increase in the proportion of well-controlled patients . Conclusions Treating primary care patients with mild-to-moderate persistent asthma with SMART instead of ICS plus bronchodilators does not affect health outcomes and does not increase costs ; therefore , is likely to be an alternative for guideline -directed treatment , from a health and economic perspective [8772331] BACKGROUND Oral beta-stimulants are widely used in the management of chronic asthma in India , in spite of evidence suggesting the superiority of inhaled medication in achieving maximum bronchodilatation . An economic evaluation was performed in a r and omized double-blind cross-over trial to evaluate the role of adjuvant oral beta-stimulants in the treatment of asthma . METHODS Patients who had seasonal or perennial asthma and were using metered dose inhalers for control of symptoms were r and omly selected for the study . They received either 4 mg of oral salbutamol or placebo as adjuvant treatment . During the study they controlled their symptoms by adjusting the dose of the inhaler medication . A cost minimization technique was used to assess the economic impact of this intervention in the treatment and control periods . A sensitivity analysis was performed to assess the robustness of the conclusions . RESULTS The mean cost was significantly greater in the treatment period and a patient lost approximately Rs 20 per month ( CI : 13 to 27 ; p = 0.001 ) as a result of the adjuvant treatment . There was no significant difference in the quality of life or peak expiratory flow rate during the two periods . The patients also noted mild but significantly increased tremors ( p = 0.01 ) and palpitations ( p = 0.001 ) during the treatment period . There was no treatment-to-period interaction . CONCLUSION Adjuvant oral beta-agonists do not improve the quality of life or bronchodilatation in asthmatics using an inhaled beta-agonist for control of symptoms [18723335] OBJECTIVE To evaluate direct asthma-related costs in Swedish primary care in a real-life setting . DESIGN 12-month open-label study . SETTING Swedish primary care in a real-life setting . PARTICIPANTS 1776 patients with persistent asthma . INTERVENTIONS Patients with persistent asthma were r and omised to one of three treatments : a free adjustable combination of budesonide ( 100 - 400 microg/inhalation ) and formoterol ( 4.5 or 9 microg/inhalation ) via separate inhalers plus terbutaline as needed ; budesonide/formoterol ( 160/4.5 microg or 80/4.5 microg , two inhalations twice daily ) plus terbutaline as needed ; budesonide/formoterol ( 160/4.5 microg or 80/4.5 microg , one inhalation twice daily or two inhalations once daily ) , for maintenance plus additional inhalations as needed . Doses depended on previous inhaled corticosteroid dose . Patients attended the clinic at 0 , 1.5 , and 12 months . Telephone interviews were conducted at 4 , 6 , 8 , and 10 months . MAIN OUTCOME MEASURES The primary endpoint was direct asthma-related healthcare costs . RESULTS Statistically significant reductions in annual direct costs per patient were observed with budesonide/formoterol maintenance and reliever therapy compared with the free adjustable combination of budesonide and formoterol ( -13 % , P<0.001 ) and fixed-dose budesonide/formoterol plus terbutaline ( -20 % , P<0.001 ) . Time to first severe exacerbation did not differ significantly across treatment groups , with a mean reduction of 28 % versus the free adjustable combination of budesonide and formoterol ( P=0.076 ) . Patients receiving budesonide/formoterol maintenance and reliever therapy used a significantly lower daily dose of budesonide compared with the conventional ( P<0.001 ) . CONCLUSIONS This study reports direct cost savings with budesonide/formoterol maintenance and reliever therapy compared with conventional treatment regimens with at least equivalent efficacy [16709303] ABSTRACT Objective : To evaluate efficacy and costeffectiveness of budesonide/formoterol ( Symbicort * ) maintenance ( one dose once or twice daily ) plus additional doses as needed ( Symbicort Maintenance And Reliever Therapy , SMART ) compared with a higher fixed dose of budesonide/ formoterol with formoterol as needed in patients with persistent asthma . * Symbicort is a registered trade name of the AstraZeneca group of companies Study design and methods : 6‐month , open , r and omised study of 465 patients either not well controlled on an inhaled corticosteroid ( ICS ) , or well controlled on a combination of ICS and a long-acting β2‐agonist ( LABA ) . Treatments : budesonide/formoterol 160/4.5 µg , one inhalation , once or twice daily maintenance plus additional doses as-needed ( 1 × SMART or 2 × SMART ) , or budesonide/formoterol 160/4.5 µg two inhalations twice daily plus formoterol 4.5 µg as needed ( 2 × 2 FIX + F ) . Children 6–11 years old used an 80/4.5 µg dose strength . Primary variables of efficacy were the changes in the Asthma Control Question naire ( ACQ5 ) and morning peak expiratory flow ( PEF ) . Results : Mean age of patients 40 years ( range 6–82 years ) ; 53 % female . No differences between the groups were found in ACQ5 scores or asthma exacerbation rates . Morning PEF was higher in the 2 × 2 FIX + F group vs. the 1 × SMART and 2 × SMART groups ( differences 13 L/min and 9 L/min , respectively ; p < 0.002 ) . The 1 × SMART group showed a significant decrease in asthma controlled days compared with the two other groups . No difference was seen between the 2 × SMART group and the 2 × 2 FIX + F group . Treatment costs were significantly lower in the SMART groups compared with the 2 × 2 FIX + F group . Conclusion : Compared with the 2 × 2 FIX + F treatment the use of budesonide/formoterol was 30–40 % lower in the SMART groups while maintaining equal ACQ5 scores . Daily asthma control improved equally with 2 × SMART compared to 2 × 2 FIX + F with a reduction in asthma medication cost . The one dose once daily maintenance treatment ( 1 × SMART ) result ed in a low level of treatment failure ( exacerbations ) but led to more days with symptoms . Therefore , a daily dose of two inhalations seems to be the lowest appropriate dose in patients with moderate persistent asthma [14682406] Inhaled corticosteroids for asthma treatment have become mainstay of therapy for patients with persistent asthma . Numerous inhaled corticosteroids are available but to date no prospect i ve cost-effectiveness studies have been reported using exclusively US patients and costs . The purpose of this study was to examine the cost-effectiveness of HFA-bectomethasone ( QVAR ) compared to CFC-beclomethasone ( Vanceril ) using data from a year-long prospect i ve r and omized , open label , parallel multicenter trial . Eligibility criteria required patients to have been on a stable dose of CFC-BDP prior to enrollment . Patients were r and omized to either HFA-BDP at approximately half their previous daily dose of CFC-BDP or to continue CFC-BDP Effectiveness data , in terms of symptom-free days ( SFDs ) , were used in a cost-effectiveness analysis conducted from the viewpoint of managed care . Patients receiving HFA-BDP reported a greater increase ( median = 22.1 ) in the number of SFDs than those receiving CFC-BDP ( median = 14.3 ) ( P = 0.03 ) . Total costs of care were less for patients taking HFA-BDP ( median = dollars 668 ) compared to CFC-BDP ( median = dollars 977 ) . The median incremental cost-effectiveness ratio was dollars -5.77 ( 95 % CI : dollars -68.08 to dollars -4.08 ) . The results of this analysis indicate that HFA-BDP was a dominant therapy ( more effective , less costly ) compared to CFC-BDP [12381242] Abstract Objective : To compare the relative cost effectiveness of salmeterol (50μg)/ fluticasone propionate ( 100μg ) with that of oral montelukast ( 10 mg ) as initial maintenance therapy in patients with persistent asthma uncontrolled on short-acting β2-agonist therapy alone . Study design : A cost-effectiveness analysis was performed based on effectiveness and re source utilisation data that was prospect ively collected from a r and omised , double-blind , double-dummy , 12-week trial . Patients and methods : Patients ( > 15 years of age ) who had asthma for at least 6 months . Effectiveness measurements in this analysis included improvement in forced expiratory volume in 1 second ( FEV1 ) and symptom-free days ( SFDs ) . Cost of asthma drug treatment as well as costs related to an asthma exacerbation were used in the cost analysis . The study assumed a payer ’s perspective . All costs are in 2001 US dollars . Results : Of the 423 patients eligible for the study , 211 were r and omised to salmeterol/fluticasone propionate and 212 to montelukast . Treatment with salmeterol/fluticasone propionate result ed in a significantly higher proportion of patients who achieved a 12 % increase in FEV1 ( successful treatment ) [ salmeterol/fluticasone propionate : 71 % vs montelukast : 39 % ; p < 0.001 ] and percentage of SFDs ( salmeterol/fluticasone propionate : 46.8 % vs montelukast : 21.5 % ; p < 0.001 ) compared with montelukast . The mean daily costs per successfully treated patient were lower in the salmeterol/fluticasone propionate group ( $ US5.03 , 95 % CI $ US4.61 to $ US5.50 ) compared with the montelukast group ( $ US8.25 , 95 % CI $ US6.98 to $ US9.93 ) . Furthermore , per patient mean daily cost per SFD was lower with salmeterol/fluticasone propionate ( $ US7.63 , 95 % CI $ US6.90 to $ US8.50 ) compared with montelukast ( $ US14.89 , 95 % CI $ US12.36 to $ US17.98 ) . Incremental cost-effectiveness ratios ( ICERs ) showed that the additional costs to achieve these benefits with salmeterol/fluticasone propionate were minimal . With regards to improvement in lung function , the ICER was $ US1.33 ( 95 % CI $ US0.80 to $ US2.02 ) and with regards to SFD , the ICER was $ US1.69 ( 95 % CI $ US1.01 to $ US2.48 ) . Sensitivity analysis demonstrated the stability of the results over a range of assumptions . Conclusions : From a third-party payer perspective , this analysis shows that based on increased efficacy and only a slight increase in cost , twice-daily treatment with salmeterol/fluticasone propionate is more cost effective than once-daily treatment with montelukast as initial maintenance therapy for persistent asthma . This finding complements the results of the clinical analyses indicating that treatment of both inflammation and bronchoconstriction with products such as salmeterol/fluticasone propionate may be more cost effective as initial maintenance asthma therapy than the use of leukotriene modifiers such as montelukast [27536180] We congratulate Amdahl et al.1 on publishing their paper about the cost-effectiveness of pazopanib compared with sunitinib in metastatic renal cell carcinoma ( mrcc ) in Canada . The article reports an analysis similar to the one su bmi tted to the pan-Canadian Oncology Drug Review to support the funding request for pazopanib in mrcc , up date d with final overall survival ( os ) data from the pivotal trial2 . Economic evaluations in oncology are increasingly important to guide both policy and practice . We commend the efforts of these authors to put their su bmi tted analyses into the public domain for transparency and to support and inform future research . The base-case analysis ( using the list prices of pazopanib and sunitinib ) by Amdahl et al.1 found that , compared with sunitinib , which is the st and ard of care for first-line therapy in mrcc , first-line pazopanib is likely cost-saving . The base case analysis also suggested that pazopanib might be slightly more effective than sunitinib numerically , with an incremental gain of 0.057 life-years and 0.059 quality -adjusted life-years . Before concluding that pazopanib is dominant ( that is , it provides more benefit for a lower cost ) with respect to sunitinib , it is important to review the clinical data comparing pazopanib and sunitinib in mrcc to assess the comparative efficacy and preference-based measures of health-related quality of life ( hrqol ) associated with those agents — that is , their health utilities — to examine the face validity of the economic model in its base case . The efficacy differences between the pazopanib and sunitinib in the comparz study 3 were not statistically significant , median progression-free survival for pazopanib and sunitinib being 8.4 months [ 95 % confidence interval ( ci ) : 8.3 to 10.9 months ] and 9.5 months ( 95 % ci : 8.3 to 11.1 months ) respectively , with a hazard ratio of 1.05 ( 95 % ci : 0.90 to 1.22 ) . The study met its primary endpoint of non-inferiority in progression-free survival . No os difference was observed in the comparz study , in which median os was 28.4 months for pazopanib ( 95 % ci : 26.2 to 35.6 months ) and 29.3 months for sunitinib ( 95 % ci : 25.3 to 32.5 months ) , with a hazard ratio of 0.91 ( 95 % ci : 0.76 to 1.08 ) . At the up date d analysis , os was similar in the two groups ( hazard ratio for pazopanib vs. sunitinib : 0.92 ; 95 % ci : 0.79 to 1.06 ; p = 0.24)2 . With similar survival results for pazopanib and sunitinib based on the comparz study , one might ask , “ How did the model project an incremental gain of 0.057 life-years in favour of pazopanib ? ” The model actually projected a shorter life expectancy while patients were taking pazopanib than while their counterparts were taking sunitinib ( 0.013 life-years lost in the progression-free state ) . However , the model also projected that , after patients progressed and stopped taking pazopanib , their life expectancy was longer than it was for patients who received sunitinib ( 0.070 life-years gained in the post-progression state ) . Together , the loss and the gain result ed in a net gain in life expectancy for pazopanib , implying that the survival benefit of pazopanib acted only after progression , when patients were no longer taking pazopanib . There is no biologic basis for that phenomenon , and it likely simply reflects small numerical differences between the pazopanib and sunitinib progression-free survival and os curves , without accounting for uncertainty . Interestingly , the model also predicted that pazopanib would be more effective in at least 80 % ( or possibly all ) of the simulations despite the nonsignificant result . Although the comparz study 3 collected some hrqol measures , it did not collect preference-based measures of hrqol to allow for the calculation of quality -adjusted life-years for the purpose of economic evaluation . The pisces study 4—a r and omized , double-blind trial with a crossover design ( that is , pazopanib→sunitinib vs. sunitinib→pazopanib)—had , as its primary endpoint , an examination of patient preference for either pazopanib or sunitinib , which suggested that patients preferred pazopanib over sunitinib . However , the study had a few limitations 5 , including a relatively high proportion of the r and omly assigned patients ( 33 % ) not being evaluable for the primary endpoint , and the analysis of the pazopanib preference being based on a “ modified ” intention-to-treat population . The EQ-5D ( EuroQoL Group , Rotterdam , Netherl and s ) was also collected as the preference-based measure of hrqol in the pisces study 4 , but the EQ-5D results would have been subject to similar limitations . The data from the pisces study were used in the su bmi ssion to the pan-Canadian Oncology Drug Review . In the up date d analysis 1 , the authors conducted a regression based on patients in a trial comparing pazopanib with placebo6 , assuming that the effect of adverse events ( aes ) were driving the differences in hrqol , regardless of actual treatment received . For the analysis , the aes were grouped by severity and whether the aes were more commonly occurring in the sunitinib or the pazopanib group of the comparz trial . Using that approach , the regression model found that the health utility decrement was larger for the group of aes more commonly occurring in patients who used sunitinib than for the remaining aes more frequently occurring in patients who used pazopanib in the comparz trial . The results of the regression model were combined with the incidence and duration of aes in each treatment arm to derive the mean utility values used in the model , producing mean utility values of 0.7089 ( st and ard error : 0.0193 ) for pazopanib and 0.6832 ( st and ard error : 0.0236 ) for sunitinib , an incremental difference of 0.0257 in the progression-free period1 . Given that the comparz trial demonstrated similar efficacy and a more favourable toxicity profile for pazopanib , it is not unreasonable that the point estimate of the utility score could slightly favour the pazopanib group . However , these mean utility values were not directly derived and might be neither statistically nor clinical ly different , especially because the difference was smaller than the reported estimates of minimal important differences for health utilities ( which are in the range of 0.05–0.08 for the EQ-5D)7,8 . Thus , it is somewhat difficult to conclude from those data that pazopanib is associated with better utility than sunitinib . It might be reasonable to conservatively expect that the utilities of pazopanib and sunitinib are fairly similar given the size of the st and ard errors of the two utilities , subject to a reasonable amount of uncertainty9,10 . Given that clinical trials did not demonstrate a statistically significant survival benefit or EQ-5D health utility benefit for pazopanib over sunitinib , we feel that an appropriate interpretation could be that the study findings suggest similar efficacy and health utility for the two drugs . Reasonably , the pan-Canadian Oncology Drug Review ’s Expert Review Committee also concluded that it is reasonable to assume similar efficacy and to focus on the cost comparison between pazopanib and sunitinib in this setting 11 . We appreciate that the sensitivity analyses by Amdahl et al.1 address all the considerations discussed here , including the importance of the relative price of the two drugs . The authors demonstrate as part of their additional analyses that — assuming similar efficacy , health utility , and daily price of the two therapies — only minor cost differences remain . Thus , interpreting the analyses in light of the evidence , it appears that these two options for first-line therapy in mrcc might be largely similar and , taking into account the relative prices of the two drugs , the hope would be that , after confidential negotiations , they will also be similar in cost . In that case , having both drugs available would give patients the option to choose based on individual preference and side effect profile , especially in the case of intolerance to one of the drugs , and would ensure that health care re sources are being efficiently used . The generalizability of the study findings remains to be seen in practice . Verification from experience is needed to know whether the comparative outcomes as laid out will be realized . In Canada , jurisdictions have an important opportunity and challenge to evaluate the real-world effectiveness and cost-effectiveness of therapies in clinical practice after drugs are funded . Moreover , post-market research can provide valuable insights into practice patterns when two alternatives are funded and can possibly inform continued uncertainties such as sequencing and long-term adverse effects . We applaud the approach of the authors to share their analyses with the broader clinical and research communities , and we encourage more authors of economic evaluations created and su bmi tted to review bodies ( for example , the Canadian Agency for Drugs and Technologies in Health , the pan-Canadian Oncology Drug Review ) to follow suit . We expect that this activity will build on the principle of transparency being increasingly championed by the review organizations and will improve the rigour of the economic evidence used to inform policy . Finally , we call on the community to continue to pursue both academic merit and clinical and policy relevance by supporting the availability of peer- review ed publications of economic evaluations to inform the reimbursement review process . Ideally , it would be helpful if economic evaluations were to be published before decision-making so as to engage more stakeholders in the discussion 12 . In doing so , the clinical and economic evidence bases supporting the health technology assessment processes in Canada might be brought into better alignment , improving the robustness of decision-making and ultimately helping health care systems in Canada to provide effective and appropriate care to patients [16968580] ABSTRACT Background : Severe allergic asthma patients may not be controlled even with guideline recommended care , including inhaled corticosteroids , long-acting beta-2 agonists , theophylline , oral steroids and anti-leukotrienes . They experience exacerbations requiring intensive healthcare use and which may be fatal . Omalizumab , a new monoclonal antibody for use in IgE-mediated allergic diseases , reduces exacerbations and daily symptoms in this patient population . The aim of this study is to estimate the cost effectiveness of adding omalizumab to optimized st and ard therapy ( ST ) in patients with severe persistent IgE-mediated ( allergic ) asthma . Methods : A Markov model comparing lifelong ST with a treatment period of omalizumab add-on therapy followed by ST , was developed based on efficacy data from the INNOVATE trial ( 28 weeks , N = 419 ) and Swedish life table and cost data . This model assumes that patients are at risk of having an exacerbation every 2 weeks and are at risk of dying from a clinical ly significant severe asthma exacerbation . Patients in a steady-state of having no exacerbations are defined to be in an ‘ optimized asthma control ’ state . Re source use data and utilities were obtained from INNOVATE and from a UK observational study . Costs from a societal perspective include estimates for drugs , routine care , exacerbations and costs in added years of life ; benefits are expressed in QALYs . The response to omalizumab was evaluated after 16 weeks of trial , and non-responders stopped taking omalizumab for the remaining time . Results : Total lifetime discounted costs and QALYs on ST were € 52 702 and 11.60 . Omalizumab add-on therapy cost an additional € 42 754 for 0.76 additional QALYs , result ing in an incremental cost-effectiveness ratio of € 56 091 . A probabilistic sensitivity analysis indicates that the 95 % CI around the ICER is [ € 31 328 ; € 120 552 ] . One-way analyses indicate that the results are sensitive to the exacerbation-related mortality rate , the time horizon and the discount rates . Conclusions : Based on the model and the assumptions used , our results suggest that omalizumab provides cost offsets , improves quality of life and may have an attractive ICER in treating the severe allergic asthma population [12162754] OBJECTIVE To compare the cost effectiveness of hydrofluoroalkane 134a-beclomethasone dipropionate ( HFA-BDP ; Qvar ) [ corrected ] with chlorofluorocarbon-beclomethasone dipropionate ( CFC-BDP ) in patients with chronic stable asthma previously receiving CFC-BDP , from the perspective of a healthcare provider . DESIGN Cost-effectiveness analysis based on a 12-month pragmatic , r and omised , parallel group , open-label clinical trial assessing safety and efficacy of HFA-BDP at approximately half the dose of CFC-BDP in patients with stable asthma . SETTING International , multicentre study at 57 study sites in the US , UK , The Netherl and s , and Belgium . Healthcare costs were calculated for UK-based healthcare [ in 1999 as pounds ( pounds sterling ) ] . PATIENTS AND PARTICIPANTS Patients ( n = 473 ) > or = 12 years of age with currently stable asthma that had been stable ( i.e. no exacerbations requiring oral corticosteroid use in the last 4 weeks ) for at least the preceding month . MAIN OUTCOME MEASURES Average and incremental cost-effectiveness ratios based upon symptom-free days , improvement in health-related quality of life , and total and drug-only direct healthcare costs . RESULTS Patients in the HFA-BDP group experienced a significantly higher percentage of symptom-free days than patients in the CFC-BDP group by the end of the study period ( 42.4 vs 20.0 % ; p = 0.006 ) . A greater percentage of patients in the HFA-BDP group had a clinical ly significant improvement in health-related quality of life than in the CFC-BDP group [ 35.3 ( n = 116/329 ) vs 16.1 % ( n = 18/112 ) ] . Total per patient healthcare costs were similar between the two groups . The average cost per symptom-free day per patient was 1.36 pounds sterling for HFA-BDP and 1.81 pounds sterling for CFC-BDP based on total healthcare costs . The incremental cost per symptom-free day for using HFA-BDP instead of CFC-BDP was negative , indicating that HFA-BDP is a dominant strategy and may be a cost-saving intervention compared with CFC-BDP . A sensitivity analysis varying both cost and outcome parameters further supported this finding for most scenarios tested . The cost to achieve a clinical ly significant improvement in health-related quality of life over the study period was 13.24 pounds sterling per improved patient per week for HFA-BDP and 29.38 pounds sterling per patient per week for CFC-BDP . CONCLUSIONS These findings indicate that HFA-BDP is a cost-effective intervention when compared with CFC-BDP in this group of patients with stable asthma . In the majority of scenarios HFA-BDP provides more effective asthma control at a similar cost to CFC-BDP [11184564] When deciding on treatment for patients with asthma , clinicians should consider the following : basic science that supports the therapeutic agent , r and omized clinical trials that demonstrate clinical efficacy , and " real world " economic evidence that confirms the basic science and clinical study findings . When selecting first-line controller therapy for persistent asthma , clinicians should look for the single agent that produces the greatest improvement in lung function and patient outcomes , has minimal adverse effects , and is cost effective . To determine whether there is one first-line controller that achieves all of these goals , physicians should evaluate findings of r and omized controlled trials that assess a drug 's effect on asthma symptoms , lung function , and albuterol use compared with placebo or a comparator . They should also consider findings from retrospective cl aims analyses . This combination of data provides a truer picture and more robust evidence of a drug 's clinical and economic performance . Similar evaluations need to be undertaken when deciding on the most cost-effective add-on therapy [16802845] Abstract Introduction : Budesonide/formoterol ( Symbicort ® ) Maintenance And Reliever Therapy ( SMART ) is an effective and well tolerated treatment option for patients with asthma . We compared the cost effectiveness from a societal perspective of this one-inhaler regimen with that of maintenance salmeterol/fluticasone propionate ( Seretide ® ) plus salbutamol ( albuterol ) as needed ( Seretide ® Fixed Combination [ SFC ] ) . Study design : A cost-effectiveness analysis was performed based on effectiveness and re source -utilisation data collected prospect ively in a r and omised , 12-month study performed in 2143 patients in 16 countries . Re source utilisation data were pooled and unit costs ( € , year 2003 values ) from Italy , France , the UK and Germany were used to generate estimates of direct and total costs per patient per year and cost per severe exacerbation avoided . Methods : Adolescents and adults with asthma ( n = 2143 ; mean forced expiratory volume in 1 second [ FEV1 ] 73 % predicted ; mean inhaled corticosteroid [ ICS ] dose 884 µg/day ) were r and omised to SMART or SFC . The effectiveness measure used was the number of severe exacerbations per patient per year . Direct costs included medication use ( budesonide/formoterol 160µg/4.5 µg or salmeterol/fluticasone 50µg/100 µg , 50µg/250 µg or 50µg/500 µg plus salbutamol ) and nonmedication-related re source use , including days in hospital , emergency room visits , specialist or primary care physician visits and other healthcare provider contacts . Indirect costs , including the number of days when the patient or their carer was unable to attend to their normal daily activities , were also assessed . The study assumed a European societal perspective ( i.e. including direct and indirect costs ) . Results : Treatment with SMART result ed in significantly fewer severe exacerbations per patient per year compared with SFC ( 0.24 vs 0.31 events per patient per year ; p = 0.0025 ) . Re source use was low in both groups . Medication costs accounted for the majority of the total costs . The increased effectiveness of SMART was achieved at a reduced or similar cost compared with SFC . SMART dominated when German unit costs were applied ( i.e. there was a statistically significant reduction in both costs and number of exacerbations ) . In all other countries , the incremental cost-effectiveness ratios showed that there was a reduction in mean total cost per exacerbation avoided ; however , this difference was not statistically significant . Conclusion : This analysis demonstrates that , compared with SFC , SMART may be cost effective from a societal perspective for the treatment of patients with asthma in Italy , Germany , France and the UK . SMART provided a reduction in the number of severe exacerbations per patient per year , at no statistically significant increase in cost — or even at a lower cost — compared with SFC plus as-needed reliever salbutamol [9616537] The inhaled corticosteroid fluticasone propionate ( FP ) was introduced into the Thorpewood General Practice , Norwich , U.K. in 1993 -initially in treating relatively severe asthmatics . Observed beneficial effects led to exp and ed use particularly for poorly controlled asthma not responsive to increased inhaled anti-inflammatories . However , an early review suggested little advantage over existing agents ( l ) , and FP was marketed at a price premium . The aims of this study were to investigate whether continued and exp and ing use of FP was justified in terms of improved clinical outcomes , and if such improvements were associated with reduced NHS costs ( off setting more expensive prescriptions ) . A controlled , retrospective , nonr and omized primary care audit compared clinical outcomes and asthma management costs 1 year prior to and 1 year into FP therapy [15316501] BACKGROUND Omalizumab can reduce hospitalization and emergency department visits and improve quality of life in patients with moderate-to-severe , suboptimally controlled allergic asthma . Given the high cost and modest efficacy of this agent , it is not clear that it is cost-effective if given to a broad population with asthma . OBJECTIVE The purpose of this study was to evaluate the cost-effectiveness of omalizumab in adults and adolescents with moderate-to-severe allergic asthma . METHODS A retrospective economic analysis was performed to determine the cost-effectiveness of omalizumab using 52-week data from 2 r and omized controlled clinical trials in adults and adolescents with moderate-to-severe allergic asthma . The analysis was conducted from a third-party payer 's perspective , and only direct costs were considered . RESULTS The incremental cost-effectiveness ratios showed that the cost to achieve an additional successfully controlled day was $ 523 , and the daily cost to achieve at least a 0.5-point increase in Asthma Quality of Life Question naire score was $ 378 in 2003 dollars . CONCLUSION From a pharmacoeconomic st and point , omalizumab would be better used in allergic asthmatic patients with poorly controlled symptoms despite maximal therapy , given the high cost and modest efficacy of this agent . It could be cost saving if given to nonsmoking patients who are hospitalized 5 or more times or 20 days or longer per year despite maximal asthma therapy [7762918] Preamble Although economic outcomes research is an evolving field in health services research , there are correct and incorrect ways to conduct and report on economic outcomes studies . Research practice s that help to minimize real or perceived bias will increase the quality and usefulness of such studies for those who sponsor , publish , and use them . Because of public concerns about the potential for bias in the design , analysis , and reporting of economic analyses of health care technology , we formed a task force to develop principles to enhance the credibility of these studies . The Task Force on Principles for Economic Analysis of Health Care Technology included participants from academia , the pharmaceutical industry , the public sector , and private research organizations . As health care re sources become increasingly constrained , the information used to make re source allocation decisions must be as reliable , valid , and free of bias as possible . Getting it right at the level at which economic results are produced will help to protect consumers and will advance the health of the public . Bias stems from two broad categories : lack of appropriate independence for research ers and lack of consensus about methods . We focused heavily on the first of these categories for two major reasons . First , few have yet considered the unique issues of research er independence in economic outcomes research [ 1 , 2 ] . Second , other investigators have begun to consider and define proper methods for economic outcomes work ( an area of considerable controversy ) [ 3 - 5 ] . We also looked closely at the requirements for the reporting of economic analyses , which are intended to ensure method ologic transparency and accountability . The Need for Voluntary Guidelines Widespread use of economic analysis as part of the development of pharmaceutical , biotechnologic , and medical devices is relatively new . To date , many economic analyses of health care have focused on pharmaceutical agents , and many such studies have been funded by pharmaceutical companies . Results of these economic outcomes studies are used by medical technology firms to support the pricing and marketing of new interventions and to influence national health care systems and third-party payers in their development of coverage and payment decisions . Managed care organizations , hospitals , and government-subsidized health care programs rely on economic analysis of medical technology to help make formulary purchasing and utilization decisions . Physicians may use the results of these analyses to help guide treatment and prescription decisions . Health care economic outcomes projects are sponsored and conducted by pharmaceutical , biotechnologic , and medical device companies ; government agencies ; nonprofit foundations ; academic investigators ; and private research and consulting firms . The st and ards and methods used to evaluate the safety and efficacy of pharmaceutical products in r and omized , controlled trials have evolved over 50 years of collaboration among research ers in private , public , and academic setting s. Compared with those established to ensure the safety and efficacy of clinical trials , the principles and methods for the conduct of economic studies of health care technology are far less developed . Problems of conduct , reporting , and bias exist in all types of research [ 6 - 14 ] . In response , codes of conduct , such as those developed by the American Federation for Clinical Research and the Institute of Medicine , have been developed for many scientific disciplines [ 15 - 24 ] . These are good models on which to base principles of conduct for economic outcomes analysis . Although many published principles apply to economic studies , others should be modified and new ones should be developed to guide the conduct and reporting of economic outcomes analyses . Economic outcomes research requires unique guidelines for the following reasons : 1 ) As a field , it continues to evolve and is often misunderstood by end users ; 2 ) peer review of it requires special expertise that often exceeds the capabilities of review ers and scientific journals ; 3 ) it often uses secondary data and requires that many assumptions be made [ for example , attribution of a dollar cost to a unit of re source use ] ; 4 ) it offers unique method ologic choices , such as which types of costs to include ( direct , indirect , intangible , induced ) , which perspective to apply ( that of society , payer , provider , patient ) , which design to adopt ( cost- identification , costbenefit , cost-effectiveness , costutility ) , from where to obtain costs [ indemnity data base , managed care or capitated data base , hospital cost systems , Medicare , Medicaid ] , and whether to collect re source consumption data prospect ively or retrospectively through various modeling techniques ; and 5 ) economic studies play an increasingly important role in health care decision making because of increasing financial constraints throughout the health care industry . The financial and medical implication s of decision making done on the basis of these studies , coupled with the lack of widely accepted guidelines about the conduct and reporting of economic analyses , undermine the credibility of this research . A major issue is that the primary source of funding for this research is often the primary financial beneficiary of positive study results . Unfortunately , even valid studies done under the best of circumstances may be suspect [ 25 - 29 ] . This has led at least one major journal to conclude that these analyses should be viewed much like editorials or review articles are viewed in terms of potential for conflicts of interest [ 30 ] . We developed the guidelines reported here after extensive consultation with experts from the public , private , and academic sectors . We recommend that research ers and sponsors adhere to these guidelines , and we suggest they state publicly within their manuscripts that they have done so . End users , including journal editors and readers , consumers , and social decision makers , may then feel more secure in accepting the results of the research , while recognizing that intensive critique of the research will always be necessary . Operations of the Task Force The Task Force on Principles for Economic Analysis of Health Care Technology was initiated and organized by faculty from the Leonard Davis Institute ( LDI ) Center for Health Policy of the University of Pennsylvania . However , because not all LDI faculty were involved , this paper does not represent an official LDI position statement . The Task Force was funded by a coalition of pharmaceutical companies ( Appendix A ) . Funding was also requested ( but not obtained ) from various government and private foundations . All funding was provided in the form of unrestricted research grants or gifts to the University of Pennsylvania . Guidelines derive their credibility in part from the composition of the panel that creates them and the process by which they are developed . C and i date s for participation in the Task Force from the private sector and the academic research community were identified by the frequency with which they were cited in the health economics literature , which was obtained using a MEDLINE search of literature related to economic analyses of medical technology published between 1983 and 1992 . Approximately 15 members attended each meeting . Minutes were distributed after each meeting and approved by all members present . Members from the sponsoring pharmaceutical companies and the academic organizers rotated so that they numbered three and one , respectively , at the table for each formal Task Force meeting . Several professional and governmental organizations , including the Institute of Medicine , the Agency for Health Care Policy and Research , the Food and Drug Administration ( FDA ) , the Health Care Financing Administration , the Centers for Disease Control and Prevention , and a managed care organization , were asked to suggest persons who might participate . In addition , other organizations with a stake in economic analyses were each asked to suggest a person who , because of his or her professional background , had extensive knowledge of or experience with economic analyses . An academic pharmacist , an academic research er , a private research er , an ethicist and patient advocate , and an attorney specializing in medical ethics rounded out the Task Force ( Appendix B ) . Two members withdrew from participation . A small audience consisting of industry sponsors , academic organizers , staff , and a few other interested parties were invited to each meeting and allowed to comment . Four formal meetings of the Task Force were held in Philadelphia during 1993 and 1994 , and the most substantial work was done by various subcommittees between these meetings . The three main subcommittees were titled Ethical Conduct , Responsibility and Control ( the findings of these two subcommittees were later merged into one report ) , and Reporting Requirements for Economic Evaluations ( Appendix C ) . The Task Force was assisted by a professional facilitator . Although Task Force members sought consensus wherever possible on the key issues , consensus was not forced and recommendations were issued only when substantial agreement existed among the members . Task Force members were not asked to formally represent any organization . Formal endorsement of the final document was not sought . Copies of this report will be distributed to all organizations that were asked to suggest a participant and to other parties who responded to announcements placed in The New Engl and Journal of Medicine , Scrip , and the Pink Sheet . The Task Force findings will also be reported at academic conferences , medical profession meetings , and appropriate trade conventions . Findings and Recommendations Valid approaches to economic analyses can be defined ; acceptable methods can be differentiated from unacceptable ones . Bias in economic research stems from two major sources : lack of appropriate independence for [15462701] BACKGROUND The severity of asthma varies between individuals and over time . As a result individuals may have marked variation in their need for asthma treatment . Adjustable dosing enables patients to assume greater involvement in managing their own condition . OBJECTIVE To compare the costs and effectiveness of fixed dosing of budesonide/formoterol ( Symbicort Turbohaler ) with adjustable maintenance dosing . METHODS A cost-effectiveness analysis was conducted from the perspective of the UK NHS . Adults with established asthma currently maintained on > or = 400 microg per day inhaled corticosteroid were enrolled in 365 primary care centres in the UK . Patients were run-in on 2 inhalations twice daily of budesonide/formoterol 80/4.5 microg or budesonide/formoterol 160/4.5 microg ( depending on steroid requirement ) for 4 weeks and were then r and omised to the Symbicort adjustable maintenance dosing plan ( SAMD ) ( n = 782 ; budesonide/formoterol 1 - 4 inhalations twice daily depending on symptoms ) or Symbicort fixed dosing ( n = 771 ; 2 inhalations twice daily ) for a further 12 weeks . The primary effectiveness variable was clinical ly meaningful change in quality of life ( QoL ) assessed by the miniasthma quality of life question naire ( AQLQ ) . Secondary effectiveness measures included symptom-free days with no short-acting beta-agonist use . We assessed the costs of study medication , asthma-related concomitant medication , primary care and hospital contacts . Confidence intervals were generated by nonparametric boot-strapping . RESULTS Clinical ly meaningful improvement in QoL during the first 4 weeks was reported by 40.8 % of enrolled patients . During the following 12 weeks , a net 1 % ( 95 % CI : -4 % , 6 % ) of SAMD patients and 6 % ( 95 % CI : 1 % , 10 % ) of fixed dosing patients reported further improvement . Effectiveness parameters did not differ significantly between groups during the study period . Mean daily cost per patient was pound sterling 1.13 ( 95 % CI : pound sterling 1.08 , pound sterling 1.18 ) in the SAMD group and pound sterling 1.31 ( 95 % CI : pound sterling 1.27 , pound sterling 1.34 ) in the fixed dosing . The difference in mean daily cost result ed in an annual per patient cost difference of pound sterling 65.70 . Adjustable maintenance dosing with budesonide/formoterol provided equivalent QoL to fixed dosing at significantly lower cost [16274980] In this economic evaluation , conducted alongside a r and omized , double-blind clinical trial , economic data were collected from 339 patients with moderate-persistent asthma r and omized to receive twice-daily , double-blind treatment with budesonide/formoterol 160/4.5 microg in a single inhaler ( n=166 ) or fluticasone propionate 250 microg ( n=173 ) for 12 weeks . The mean number of episode-free days ( EFD ) per patient was significantly greater in the budesonide/formoterol group than the fluticasone group ( 48.71 compared with 42.34 , P=0.0185 ) . Data on medication use , visits to healthcare professionals , and hospitalization were pooled across all six countries and combined with German and Dutch unit cost data to calculate total healthcare costs . Using German unit costs , budesonide/formoterol was associated with significantly lower total healthcare costs per patient over the 12-week period compared with fluticasone ( euro 131 compared with euro 210 , P=0.0043 ) . Using Dutch unit costs , total healthcare costs were slightly numerically lower in the budesonide/formoterol group than the fluticasone group ( euro 102 compared with euro 104 ) , but the difference did not reach statistical significance . Budesonide/formoterol in a single inhaler is more effective than a higher microgram dose of fluticasone alone . It is cost-neutral and may provide cost-savings in some countries [15294013] Abstract Background : Asthma is a chronic disease , the two main components of which are inflammation and bronchoconstriction . Fluticasone propionate ( FP ) and salmeterol , a strategy that treats both main components of asthma , has been recently compared with FP plus montelukast in a r and omised clinical trial . The present study reports economic evaluation of these two strategies . Objective : To determine the relative cost effectiveness when persistent asthma is treated with FP/salmeterol 100/50μg twice daily administered via a single Diskus ® inhaler device versus treatment with FP 100μg twice daily via a Diskus ® inhaler plus oral montelukast 10 mg once daily . Study design : A cost-effectiveness analysis was performed by applying cost unit data to re source utilisation data collected prospect ively during a US r and omised , double-blind , 12-week trial of FP/salmeterol ( n = 222 ) versus FP + montelukast ( n = 225 ) . Patients were ≥15 years of age and were symptomatic despite inhaled corticosteroid ( ICS ) therapy . Patients and methods : Efficacy measurements in this analysis included improvement in forced expiratory volume in 1 second ( FEV1 ) and symptom-free days . Direct costs included those related to study drugs , emergency room department visits , unscheduled physician visits , treatment of drug-related adverse events ( oral c and idiasis ) , and rescue medication ( salbutamol [ albuterol ] ) . The study assumed a US third-party payer ’s perspective with costs in 2001 US dollars . Results : Treatment with FP/salmeterol result ed in a significantly higher proportion ( p < 0.001 ) of patients who achieved a ≥12 % increase in FEV1 than treatment with FP + montelukast ( 54 % [ 95 % CI 47 % , 61 % ] vs 32 % [ 95 % CI 26 % , 38 % ] ) . Lower daily costs and greater efficacy of FP/salmeterol result ed in a cost-effectiveness ratio of $ US6.77 ( 95 % CI $ US5.99 , $ US7.66 ) per successfully treated patient in the FP/salmeterol group compared with $ US14.59 ( 95 % CI $ US12.12 , $ 17.77 ) for FP + montelukast . In addition , FP/salmeterol achieved similar efficacy in terms of symptom-free days compared with FP + montelukast ( 31 % [ 95 % CI 26 % , 35 % ] vs 27 % [ 95 % CI 23 % , 32 % ] ) , but at a significantly lower daily per-patient cost ( $ US3.64 [ 95 % CI $ US3.60 , $ US3.68 ] vs $ US4.64 [ 95 % CI $ US4.56 , $ US4.73 ] ) . Sensitivity analyses demonstrated the stability of the results over a range of assumptions . Conclusion : From a US third-party payer ’s perspective , these findings suggest that treating the two main components of asthma ( inflammation and bronchoconstriction ) with FP/salmeterol may not only be a more cost-effective strategy but may actually lead to cost savings compared with the addition of montelukast to low-dose FP in patients with persistent asthma . The results were found to be robust over a range of assumptions [24144222] BACKGROUND There are few data on the role of nebulised magnesium sulphate ( MgSO4 ) in the management of acute asthma in children . Those studies that have been published are underpowered , and use different methods , interventions and comparisons . Thus , no firm conclusions can be drawn . OBJECTIVES Does the use of nebulised MgSO4 , when given as an adjunct to st and ard therapy in acute severe asthma in children , result in a clinical improvement when compared with st and ard treatment alone ? DESIGN Patients were r and omised to receive three doses of MgSO4 or placebo , each combined with salbutamol and ipratropium bromide , for 1 hour . The Yung Asthma Severity Score ( ASS ) was measured at baseline , r and omisation , and at 20 , 40 , 60 ( T60 ) , 120 , 180 and 240 minutes after r and omisation . SETTING Emergency departments and children 's assessment units at 30 hospitals in the UK . PARTICIPANTS Children aged 2 - 15 years with acute severe asthma . INTERVENTIONS Patients were r and omised to receive nebulised salbutamol 2.5 mg ( ages 2 - 5 years ) or 5 mg ( ages ≥ 6 years ) and ipratropium bromide 0.25 mg mixed with either 2.5 ml of isotonic MgSO4 ( 250 mmol/l , tonicity 289 mOsm ; 151 mg per dose ) or 2.5 ml of isotonic saline on three occasions at approximately 20-minute intervals . MAIN OUTCOME MEASURES The primary outcome measure was the ASS after 1 hour of treatment . Secondary measures included ' stepping down ' of treatment at 1 hour , number and frequency of additional salbutamol administrations , length of stay in hospital , requirement for intravenous bronchodilator treatment , and intubation and /or admission to a paediatric intensive care unit . Data on paediatric quality of life , time off school/nursery , health-care re source usage and time off work were collected 1 month after r and omisation . RESULTS A total of 508 children were recruited into the study ; 252 received MgSO4 and 256 received placebo along with the st and ard treatment . There were no differences in baseline characteristics . There was a small , but statistically significant difference in ASS at T60 in those children who received nebulised MgSO4 { 0.25 [ 95 % confidence interval ( CI ) 0.02 to 0.48 ] ; p = 0.034 } and this difference was sustained for up to 240 minutes [ 0.20 ( 95 % CI 0.01 to 0.40 ) , p = 0.042 ] . The clinical significance of this gain is uncertain . Assessing treatment-covariate interactions , there is evidence of a larger effect in those children with more severe asthma exacerbations ( p = 0.034 ) and those with a shorter duration of symptoms ( p = 0.049 ) . There were no significant differences in the secondary outcomes measured . Adverse events ( AEs ) were reported in 19 % of children in the magnesium group and 20 % in the placebo group . There were no clinical ly significant serious AEs in either group . The results of the base-case economic analyses are accompanied by considerable uncertainty , but suggest that , from an NHS and Personal Social Services perspective , the addition of magnesium to st and ard treatment may be cost-effective compared with st and ard treatment only . The results of economic evaluation show that the probability of magnesium being cost-effective is over 60 % at cost-effectiveness thresholds of £ 1000 per unit decrement in ASS and £ 20,000 per quality -adjusted life-year ( QALY ) gained , respectively ; it is noted that for some parameter variations this probability is much lower , reflecting the labile nature of the cost-effectiveness ratio in light of the small differences in benefits and costs shown in the trial and the relation between the main outcome measure ( ASS ) and preference based measures of quality of life used in cost-utility analysis ( European Quality of Life-5 Dimensions ; EQ-5D ) . CONCLUSIONS This study supports the use of nebulised isotonic MgSO4 at the dose of 151 mg given three times in the first hour of treatment as an adjuvant to st and ard treatment when a child presents with an acute episode of severe asthma . No harm is done by adding magnesium to salbutamol and ipratropium bromide , and in some individuals it may be clinical ly helpful . The response is likely to be more marked in those children with more severe attacks and with a shorter duration of exacerbation . Although the study was not powered to demonstrate this fully , the data certainly support the hypotheses that nebulised magnesium has a greater clinical effect in children who have more severe exacerbation with shorter duration of symptoms . TRIAL REGISTRATION Current Controlled Trials IS RCT N81456894 . FUNDING The National Institute for Health Research Health Technology Assessment programme [10926346] Despite a good underst and ing of the disease and its treatments , asthma continues to place a large economic burden on healthcare systems . As such , it is important to consider the economic impact of alternative therapeutic options for the treatment of this condition to ensure that scarce re sources are used in the most efficient manner possible . Thus , the aim of asthma management from an economic perspective is to reduce the burden of this disease through maximizing health gain with available re sources . A prospect i ve economic analysis was conducted as part of a multicentre , r and omized , double-blind , comparative trial of salmeterol/fluticasone propionate combination product ( SFC ) 50/250 microg twice daily vs. budesonide ( 800 microg twice daily ) in adults and adolescents with asthma who were symptomatic despite treatment with inhaled corticosteroids at doses of 800 - 1200 microg day(-1 ) . Treatment effectiveness was measured in terms of successfully-treated weeks , defined as a > or = 5 % improvement in morning peak expiratory flow , episode-free days ( a day without the need for rescue medication , no nocturnal awakening or adverse events ) and symptom-free days . Cost-effectiveness analyses were performed using direct healthcare and drug costs , from the perspective of the Swedish healthcare system ( 1998 prices ) , with appropriate sensitivity analyses to test the robustness of the findings . Overall , SFC produced significantly higher ( P<0.001 ) proportions of successfully-treated weeks , episode-free days and symptom-free days . Direct asthma management costs were similar between the two groups [ SEK19.6 ( $ US2.4 ) for SFC vs. SEK18.5 ( SUS2.2 ) for budesonide ] . The cost per successfully-treated week was lower for SFC than for budesonide [ SEK204 ( $ US24.8 ) vs. SEK300 ( $ US36.4 ) per week ] , as were the costs per episode-free day [ SEK51.1 ( $ US6.2 ) vs. SEK75.1 ( $ US9.1 ) per day ] and symptom-free day [ SEK42.2 ( $ US5.1 ) vs. SEK53.0 ( $ US6.4 ) per day ] . Incremental cost-effectiveness ratios showed that the additional costs to achieve additional benefits with SFC were minimal . Costs per additional successfully-treated week , symptom-free day and episode-free day with SFC were SEK31.6 ( $ US3.9 ) , SEK9.2 ( $ US1.1 ) and SEK7.7 ( $ US0.9 ) , respectively , relative to budesonide . Sensitivity analysis showed that the results were stable over a wide range of assumptions . The results suggest that SFC is a more cost-effective treatment than budesonide in the management of moderate to severe asthma [10186465] This article presents the first version of a reporting format for modelling studies which is based on a general reporting format by our taskforce , which was published in the previous issue of this journal . The use of decision-analytical models for economic evaluations is increasing because , in practice , it is not always possible to derive information from prospect i ve studies . However , the acceptance of modelling studies is generally lower than prospect i ve studies not only because of the use of secondary data , but also because the reports of modelling studies do not always have sufficient transparency . Hence , a st and ardised reporting format may improve the transparency and , consequently , the acceptance of modelling studies . This article presents an example of a reporting format for economic evaluation based on modelling studies , which may facilitate the development of future guidelines for modelling studies . The format consists of a number of headings , which are followed by a brief recommendation on the content . This format does not deal with methodology and data management , but especially addresses validation and quality assurance , which may increase the transparency of the report [11596838] Abstract Objective : To compare the relative value of an inhaled corticosteroid , fluticasone propionate 88μg twice daily , versus an oral leukotriene receptor antagonist , zafirlukast 20 mg twice daily , in patients with persistent asthma currently receiving short acting β2-agonists alone . Study design : A cost-efficacy analysis using re source utilisation and clinical data obtained prospect ively from a multicentre , r and omised , double-blind , double-dummy , placebo-controlled 12-week clinical trial conducted in the US . Perspective : Third-party payor . Patients and methods : A total of 451 corticosteroid-naive patients with persistent asthma were treated with either fluticasone propionate 88μg twice daily or zafirlukast 20 mg twice daily . All patients were given salbutamol ( albuterol ) to be used as rescue medication . Data were examined using intent-to-treat analysis . Results : Mean daily per person cost-efficacy ratios using improvement in forced expiratory volume in 1 second ( FEV1 ) [ ≥12 % increase from baseline ] were $ US3.47 for fluticasone propionate compared with $ US7.81 for zafirlukast ( 1999 values ) . The mean daily per person cost-efficacy ratios for symptom-free days obtained were $ US5.51 for fluticasone propionate compared with $ US14.98 for zafirlukast . These cost-efficacy ratios remained in favour of fluticasone propionate after a robust sensitivity analysis . Conclusions : Treatment with fluticasone propionate 88μg twice daily was the most cost effective treatment compared with zafirlukast 20 mg twice daily in this 12-week clinical trial . This analysis supports the use of fluticasone propionate 88μg twice daily as first-line treatment in patients with persistent asthma previously treated with short-acting β2-agonist alone [20550224] BACKGROUND Information is lacking on the relative effectiveness and cost effectiveness -- in a primary -care setting --of leukotriene receptor antagonists ( LTRAs ) as an alternative to inhaled corticosteroids ( ICS ) for initial asthma controller therapy . OBJECTIVE To compare the cost effectiveness of LTRAs versus ICS for patients initiating asthma controller therapy . METHODS An economic evaluation was conducted alongside a 2-year , pragmatic , r and omized controlled trial set in 53 primary -care practice s in the UK . Patients aged 12 - 80 years with asthma and symptoms requiring regular anti-inflammatory therapy ( n = 326 ) were r and omly assigned to LTRAs ( n = 162 ) or ICS ( n = 164 ) . The main outcome measures were the incremental costs per point improvement in the Mini Asthma Quality of Life Question naire , per point improvement in the Asthma Control Question naire and per QALY gained from the UK NHS and societal perspectives . RESULTS Over 2 years , re source use was similar between the two treatment groups , but the cost to society per patient was significantly higher for the LTRA group , at pounds sterling 711 versus pounds sterling 433 for the ICS group ( adjusted difference pounds sterling 204 ; 95 % CI 74 , 308 ) [ year 2005 values ] . Cost differences were driven primarily by differences in prescription drug costs , particularly study drug costs . There was a nonsignificant ( imputed , adjusted ) difference between treatment groups , favouring ICS , in QALYs gained at 2 years of -0.073 ( 95 % CI -0.143 , 0.010 ) . Therapy with LTRAs was , on average , a dominated strategy , and , at a threshold for willingness to pay of pounds sterling 30,000 per QALY gained , the probability of LTRAs being cost effective compared with ICS was approximately 3 % from both societal and NHS perspectives . CONCLUSIONS There is a very low probability of LTRAs being cost effective in the UK , at 2005 values , compared with ICS for initial asthma controller therapy . TRIAL REGISTRATION UK National Research Register N0547145240 ; Controlled Clinical Trials IS RCT N99132811 [20446755] BACKGROUND Information is lacking on the relative effectiveness and cost effectiveness -- in a real-life primary -care setting --of leukotriene receptor antagonists ( LTRAs ) and long-acting beta2 adrenergic receptor agonists ( beta2 agonists ) as add-on therapy for patients whose asthma symptoms are not controlled on low-dose inhaled corticosteroids ( ICS ) . OBJECTIVE To estimate the cost effectiveness of LTRAs compared with long-acting beta2 agonists as add-on therapy for patients whose asthma symptoms are not controlled on low-dose ICS . METHODS An economic evaluation was conducted alongside a 2-year , pragmatic , r and omized controlled trial set in 53 primary -care practice s in the UK . Patients aged 12 - 80 years with asthma insufficiently controlled with ICS ( n = 361 ) were r and omly assigned to add-on LTRAs ( n = 176 ) or long-acting beta2 agonists ( n = 185 ) . The main outcome measures were the incremental cost per point improvement in the Mini Asthma Quality of Life Question naire ( MiniAQLQ ) , per point improvement in the Asthma Control Question naire ( ACQ ) and per QALY gained from perspectives of the UK NHS and society . RESULTS Over 2 years , the societal cost per patient receiving LTRAs was pounds sterling 1157 versus pounds sterling 952 for long-acting beta2 agonists , a ( significant , adjusted ) increase of pounds sterling 214 ( 95 % CI 2 , 411 ) [ year 2005 values ] . Patients receiving LTRAs experienced a non-significant incremental gain of 0.009 QALYs ( 95 % CI -0.077 , 0.103 ) . The incremental cost per QALY gained from the societal ( NHS ) perspective was pounds sterling 22,589 ( pounds sterling 11,919 ) . Uncertainty around this point estimate suggested that , given a maximum willingness to pay of pounds sterling 30,000 per QALY gained , the probability that LTRAs are a cost-effective alternative to long-acting beta2 agonists as add-on therapy was approximately 52 % from both societal and NHS perspectives . CONCLUSIONS On balance , these results marginally favour the repositioning of LTRAs as a cost-effective alternative to long-acting beta2 agonists as add-on therapy to ICS for asthma . However , there is much uncertainty surrounding the incremental cost effectiveness because of similarity of clinical benefit and broad confidence intervals for differences in healthcare costs . TRIAL REGISTRATION UK National Research Register N0547145240 ; Controlled Clinical Trials IS RCT N99132811 [21211651] BACKGROUND Cost-effectiveness analyses of asthma controller regimens for adults exist , but similar evaluations exclusively for children are few . OBJECTIVE We sought to compare the cost-effectiveness of 2 commonly used asthma controllers , fluticasone and montelukast , with data from the Pediatric Asthma Controller Trial . METHODS We compared the cost-effectiveness of low-dose fluticasone with that of montelukast in a r and omized , controlled , multicenter clinical trial in children with mild-to-moderate persistent asthma . Analyses were also conducted on subgroups based on phenotypic factors . Effectiveness measures included ( 1 ) the number of asthma-control days , ( 2 ) the percentage of participants with an increase over baseline of FEV(1 ) of 12 % or greater , and ( 3 ) the number of exacerbations avoided . Costs were analyzed from both a US health care payer 's perspective and a societal perspective . RESULTS For all cost-effectiveness measures studied , fluticasone cost less and was more effective than montelukast . For example , fluticasone treatment cost $ 430 less in mean direct cost ( P < .01 ) and result ed in 40 more asthma-control days ( P < .01 ) during the 48-week study period . Considering sampling uncertainty , fluticasone cost less and was more effective at least 95 % of the time . For the high exhaled nitric oxide ( eNO ) phenotypic subgroup ( eNO ≥25 ppb ) and more responsive PC(20 ) subgroup ( PC(20 ) < 2 mg/mL ) , fluticasone was cost-effective compared with montelukast for all cost-effectiveness measures , whereas not all the effectiveness measures were statistically different for the other 2 phenotypic subgroups . CONCLUSION For children with mild-to-moderate persistent asthma , low-dose fluticasone had lower cost and higher effectiveness compared with montelukast , especially in those with more airway inflammation , as indicated by increased levels of eNO and more responsivity to methacholine Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Daily inhaled corticosteroids ( ICS ) are the recommended mainstay of treatment in children and adults with persistent asthma . However , often , ICS are used intermittently by patients or recommended by physicians to be used only at the onset of exacerbations . OBJECTIVES The aim of this review was to compare the efficacy and safety of intermittent versus daily ICS in the management of children and adults with persistent asthma and preschool-aged children suspected of persistent asthma . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

28046205

[3120197] OBJECTIVE Higher heme iron intake is associated with increased type 2 diabetes risk . However , no previous study has evaluated gestational diabetes mellitus ( GDM ) risk in relation to heme iron intake during pregnancy . We investigated associations of maternal preconceptional and early pregnancy heme and nonheme iron intake with subsequent GDM risk . RESEARCH DESIGN AND METHODS We conducted a prospect i ve cohort study of 3,158 pregnant women . A food frequency question naire was used to assess maternal diet . Multivariable generalized linear regression models were used to derive estimates of relative risks ( RRs ) and 95 % CIs . RESULTS Approximately 5.0 % of the cohort developed GDM ( n = 158 ) . Heme iron intake was positively and significantly associated with GDM risk ( Ptrend = 0.04 ) . After adjusting for confounders , women reporting the highest heme iron intake levels ( ≥1.52 vs. < 0.48 mg per day ) experienced a 3.31-fold – increased GDM risk ( 95 % CI 1.02–10.72 ) . In fully adjusted models , we noted that a 1-mg per day increase in heme iron was associated with a 51 % increased GDM risk ( RR 1.51 [ 95 % CI 0.99–2.36 ] ) . Nonheme iron was inversely , though not statistically significantly , associated with GDM risk , and the corresponding RRs were 1.00 , 0.83 , 0.62 , and 0.61 across quartiles of nonheme iron intake ( Ptrend = 0.08 ) . CONCLUSIONS High levels of dietary heme iron intake during the preconceptional and early pregnancy period may be associated with increased GDM risk . Associations of GDM risk with dietary nonheme iron intake are less clear . Confirmation of these findings by future studies is warranted [3120196] OBJECTIVE It is important to identify modifiable factors that may lower gestational diabetes mellitus ( GDM ) risk . Dietary iron is of particular interest given that iron is a strong prooxidant , and high body iron levels can damage pancreatic β-cell function and impair glucose metabolism . The current study is to determine if prepregnancy dietary and supplemental iron intakes are associated with the risk of GDM . RESEARCH DESIGN AND METHODS A prospect i ve study was conducted among 13,475 women who reported a singleton pregnancy between 1991 and 2001 in the Nurses ’ Health Study II . A total of 867 incident GDM cases were reported . Pooled logistic regression was used to estimate the relative risk ( RR ) of GDM by quintiles of iron intake controlling for dietary and nondietary risk factors . RESULTS Dietary heme iron intake was positively and significantly associated with GDM risk . After adjusting for age , BMI , and other risk factors , RRs ( 95 % CIs ) across increasing quintiles of heme iron were 1.0 ( reference ) , 1.11 ( 0.87–1.43 ) , 1.31 ( 1.03–1.68 ) , 1.51 ( 1.17–1.93 ) , and 1.58 ( 1.21–2.08 ) , respectively ( P for linear trend 0.0001 ) . The multivariate adjusted RR for GDM associated with every 0.5-mg per day of increase in intake was 1.22 ( 1.10–1.36 ) . No significant associations were observed between total dietary , nonheme , or supplemental iron intake and GDM risk . CONCLUSIONS These findings suggest that higher prepregnancy intake of dietary heme iron is associated with an increased GDM risk [3565864] Background The costs of gestational diabetes mellitus ( GDM ) screening have been frequently reported , but total GDM-related health care costs compared to the health care costs of women without GDM have not been reported . The aim of this study was to analyse GDM-related health care costs among women with an elevated risk of GDM . Methods The study was based on a cluster-r and omised GDM prevention trial ( N = 848 ) carried out at maternity clinics , combined with data from the Finnish Medical Birth Register and Care Registers for Social Welfare and Health Care . Costs of outpatient visits to primary and secondary care , cost of inpatient hospital care before and after delivery , the use of insulin , delivery costs and babies ’ stay in the neonatal intensive care unit were analysed . Women who developed GDM were compared to those who were not diagnosed with GDM . Results Total mean health care costs adjusted for age , body mass index and education were 25.1 % higher among women diagnosed with GDM ( € 6,432 vs. € 5,143 , p < 0.001 ) than among women without GDM . The cost of inpatient visits was 44 % higher and neonatal intensive care unit use was 49 % higher in the GDM group than among women without GDM . The delivery costs were the largest single component in both groups . Conclusions A confirmed GDM diagnosis was associated with a significant increase in total health care costs . Effective lifestyle counselling by primary health care providers may offer a means of reducing the high costs of secondary care [25438930] Pregnancy presents a unique époque in life with considerable potential to influence not only maternal health but also the health of the next generation . Nutritional interventions in pregnancy can influence maternal , foetal and infant health . This chapter describes the findings of a large r and omised controlled trial on the impact of a low glycaemic index diet on maternal and foetal health and discusses areas of future research in this important area [4352291] Background Maternal obesity is associated with an increased risk of pregnancy complications , including gestational diabetes . Physical activity ( PA ) might improve glucose metabolism and reduce the incidence of gestational diabetes . The purpose of this study was to explore patterns of PA and factors associated with change in PA in obese pregnant women . Methods PA was assessed objective ly by accelerometer at 16 – 18 weeks ’ ( T0 ) , 27 – 28 weeks ’ ( T1 ) and 35 – 36 weeks ’ gestation ( T2 ) in 183 obese pregnant women recruited to a pilot r and omised trial of a combined diet and PA intervention ( the UPBEAT study ) . Results Valid PA data were available for 140 ( 77 % ) , 76 ( 42 % ) and 54 ( 30 % ) women at T0 , T1 and T2 respectively . Moderate and vigorous physical activity as a proportion of accelerometer wear time declined with gestation from a median of 4.8 % at T0 to 3 % at T2 ( p < 0.05 ) . Total activity as a proportion of accelerometer wear time did not change . Being more active in early pregnancy was associated with a higher level of PA later in pregnancy . The intervention had no effect on PA . Conclusions PA in early pregnancy was the factor most strongly associated with PA at later gestations . Women should be encouraged to participate in PA before becoming pregnant and to maintain their activity levels during pregnancy . There is a need for effective interventions , tailored to the needs of individuals and delivered early in pregnancy to support obese women to be sufficiently active during pregnancy . Trial registration Current Controlled Trials IS RCT N89971375 ( Registered 28/11/2008 ) [3938821] Background Despite the widespread recognition that obesity in pregnant women is associated with adverse outcomes for mother and child , there is no intervention proven to reduce the risk of these complications . The primary aim of this r and omised controlled trial is to assess in obese pregnant women , whether a complex behavioural intervention , based on changing diet ( to foods with a lower glycemic index ) and physical activity , will reduce the risk of gestational diabetes ( GDM ) and delivery of a large for gestational age ( LGA ) infant . A secondary aim is to determine whether the intervention lowers the long term risk of obesity in the offspring . Methods / Design Multicentre r and omised controlled trial comparing a behavioural intervention design ed to improve glycemic control with st and ard antenatal care in obese pregnant women . Inclusion criteria ; women with a BMI ≥30 kg/m2 and a singleton pregnancy between 15 + 0 weeks and 18 + 6 weeks ’ gestation . Exclusion criteria ; pre-defined , pre-existing diseases and multiple pregnancy . R and omisation is on-line by a computer generated programme and is minimised by BMI category , maternal age , ethnicity , parity and centre . Intervention ; this is delivered by a health trainer over 8 sessions . Based on control theory , with elements of social cognitive theory , the intervention is design ed to improve maternal glycemic control . Women r and omised to the control arm receive st and ard antenatal care until delivery according to local guidelines . All women have a 75 g oral glucose tolerance test at 27 + 0- 28 + 6 weeks ’ gestation . Primary outcome ; Maternal : diagnosis of GDM , according to the International Association of Diabetes in Pregnancy Study Group ( IADPSG ) criteria . Neonatal ; infant LGA defined as > 90th customised birth weight centile . Sample size ; 1546 women to provide 80 % power to detect a 25 % reduction in the incidence of GDM and a 30 % reduction in infants large for gestational age . Discussion All aspects of this protocol have been evaluated in a pilot r and omised controlled trial , with subsequent optimisation of the intervention . The findings of this trial will inform whether lifestyle mediated improvement of glycemic control in obese pregnant women can minimise the risk of pregnancy complications . Trial registration Current controlled trials ; IS RCT N89971375 [4124499] Background The in utero environment is known to affect fetal development however many of the mechanisms by which this occurs remain unknown . The aim of this study was to examine the association between maternal dietary macronutrient intake and lifestyle throughout pregnancy and neonatal weight and adiposity . Methods This was an analysis of 542 mother and infant pairs from the ROLO study ( R and omised cOntrol trial of LOw glycaemic index diet versus no dietary intervention to prevent recurrence of fetal macrosomia ) . Food diaries as well as food frequency and lifestyle and physical activity question naires were completed during pregnancy . Maternal anthropometry was measured throughout pregnancy and neonatal anthropometry was measured at birth . Results Multiple linear regression analysis revealed the main maternal factor associated with increased birth weight was greater gestational weight gain R2adj23.3 % ( F = 11.547 , p < 0.001 ) . The main maternal factor associated with increased birth length was non-smoking status R2adj27.8 % ( F = 6.193 , p < 0.001 ) . Neonatal central adiposity ( determined using waist : length ratio ) was negatively associated with maternal age , and positively associated with the following parameters : smoking status , maternal pre-pregnancy arm circumference , percentage energy from saturated fat in late pregnancy , postpr and ial glucose at 28 weeks gestation and membership of the control group with a positive trend towards association with trimester 2 glycaemic load R2adj 38.1 % ( F = 8.000 , p < 0.001 ) . Conclusions Several maternal diet and lifestyle factors were associated with neonatal anthropometry . Low glycaemic index dietary intervention in pregnancy was found to have a beneficial effect on neonatal central adiposity . Additionally , central adiposity was positively associated with maternal dietary fat intake and postpr and ial glucose highlighting the important role of healthy diet in pregnancy in promoting normal neonatal adiposity . Trial registration Current Controlled Trials IS RCT N54392969 [21324948] Higher egg and cholesterol intakes are associated with increased risk of type 2 diabetes mellitus . However , their association with gestational diabetes mellitus ( GDM ) has not been evaluated . The authors assessed such associations in both a prospect i ve cohort study ( 1996 - 2008 ; 3,158 participants ) and a case-control study ( 1998 - 2002 ; 185 cases , 411 controls ) . A food frequency question naire was used to assess maternal diet . Multivariable models were used to derive relative risks and 95 % confidence intervals . Compared with no egg consumption , adjusted relative risks for GDM were 0.94 , 1.01 , 1.12 , 1.54 , and 2.52 for consumption of ≤1 , 2 - 3 , 4 - 6 , 7 - 9 , and ≥10 eggs/week , respectively ( P for trend=0.008 ) . Women with high egg consumption ( ≥7/week ) had a 1.77-fold increased risk compared with women with lower consumption ( 95 % confidence interval ( CI ) : 1.19 , 2.63 ) . The relative risk for the highest quartile of cholesterol intake ( ≥294 mg/day ) versus the lowest ( < 151 mg/day ) was 2.35 ( 95 % CI : 1.35 , 4.09 ) . In the case-control study , the adjusted odds ratio for consuming ≥7 eggs/week versus < 7 eggs/week was 2.65 ( 95 % CI : 1.48 , 4.72 ) , and the odds of GDM increased with increasing cholesterol intake ( P for trend=0.021 ) . In conclusion , high egg and cholesterol intakes before and during pregnancy are associated with increased risk of GDM [19017418] Balanced glucose metabolism ensures optimal fetal growth with long-term health implication s conferred on both mother and child . We examined whether supplementation of probiotics with dietary counselling affects glucose metabolism in normoglycaemic pregnant women . At the first trimester of pregnancy 256 women were r and omised to receive nutrition counselling to modify dietary intake according to current recommendations or as controls ; the dietary intervention group was further r and omised to receive probiotics ( Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12 ; diet/probiotics ) or placebo ( diet/placebo ) in a double-blind manner , whilst the control group received placebo ( control/placebo ) . Blood glucose concentrations were lowest in the diet/probiotics group during pregnancy ( baseline-adjusted means 4.45 , 4.60 and 4.56 mmol/l in diet/probiotics , diet/placebo and control/placebo , respectively ; P = 0.025 ) and over the 12 months ' postpartum period ( baseline-adjusted means 4.87 , 5.01 and 5.02 mmol/l ; P = 0.025 ) . Better glucose tolerance in the diet/probiotics group was confirmed by a reduced risk of elevated glucose concentration compared with the control/placebo group ( OR 0.31 ( 95 % CI 0.12 , 0.78 ) ; P = 0.013 ) as well as by the lowest insulin concentration ( adjusted means 7.55 , 9.32 and 9.27 mU/l ; P = 0.032 ) and homeostasis model assessment ( adjusted means 1.49 , 1.90 and 1.88 ; P = 0.028 ) and the highest quantitative insulin sensitivity check index ( adjusted means 0.37 , 0.35 and 0.35 ; P = 0.028 ) during the last trimester of pregnancy . The effects observed extended over the 12-month postpartum period . The present study demonstrated that improved blood glucose control can be achieved by dietary counselling with probiotics even in a normoglycaemic population and thus may provide potential novel means for the prophylactic and therapeutic management of glucose disorders [3431285] Objective To determine if a low glycaemic index diet in pregnancy could reduce the incidence of macrosomia in an at risk group . Design R and omised controlled trial . Setting Maternity hospital in Dublin , Irel and . Participants 800 women without diabetes , all in their second pregnancy between January 2007 to January 2011 , having previously delivered an infant weighing greater than 4 kg . Intervention Women were r and omised to receive no dietary intervention or start on a low glycaemic index diet from early pregnancy . Main outcomes The primary outcome measure was difference in birth weight . The secondary outcome measure was difference in gestational weight gain . Results No significant difference was seen between the two groups in absolute birth weight , birthweight centile , or ponderal index . Significantly less gestational weight gain occurred in women in the intervention arm ( 12.2 v 13.7 kg ; mean difference −1.3 , 95 % confidence interval −2.4 to −0.2 ; P=0.01 ) . The rate of glucose intolerance was also lower in the intervention arm : 21 % ( 67/320 ) compared with 28 % ( 100/352 ) of controls had a fasting glucose of 5.1 mmol/L or greater or a 1 hour glucose challenge test result of greater than 7.8 mmol/L ( P=0.02 ) . Conclusion A low glycaemic index diet in pregnancy did not reduce the incidence of large for gestational age infants in a group at risk of fetal macrosomia . It did , however , have a significant positive effect on gestational weight gain and maternal glucose intolerance . Trial registration Current Controlled Trials IS RCT N54392969 [24122103] Oxidized LDL lipids ( ox-LDL ) are associated with lifestyle diseases such as cardiovascular diseases , metabolic syndrome and type 2 diabetes . The present study investigated how postpartum weight retention effects on ox-LDL and serum lipids . The study is a nested comparative research of a cluster-r and omized controlled trial , NELLI ( lifestyle and counselling during pregnancy ) . During early pregnancy ( 8–12 weeks ) and 1 year postpartum , 141 women participated in measurements for determining of plasma lipids : total cholesterol ( T-C ) , LDL-cholesterol ( LDL-C ) , HDL-cholesterol ( HDL-C ) , triacylglycerols ( TAG ) and ox-LDL . Subjects were stratified into tertiles ( weight loss , unaltered weight and weight gain groups ) based on their weight change from baseline to follow-up . Ox-LDL was determined by baseline level of conjugated dienes in LDL lipids . Among the group of weight gainers , concentration of TAG reduced less ( −0.14 vs. −0.33 , p = 0.002 ) , HDL-C reduced more ( −0.31 vs. −0.16 , p = 0.003 ) and ox-LDL/HDL-C ratio increased ( 3.0 vs. −0.2 , p = 0.003 ) when compared to group of weight loss . Both T-C and LDL-C elevated more ( 0.14 vs. −0.21 , p = 0.008 ; 0.31 vs. 0.07 , p = 0.015 ) and TAG and ox-LDL reduced less ( −0.33 vs. 0.20 , p = 0.033 ; −3.33 vs. −0.68 , p = 0.026 ) in unaltered weight group compared to weight loss group . The women who gained weight developed higher TAG and ox-LDL/HDL-C ratio as compared to those who lost weight . Postpartum weight retention of 3.4 kg or more is associated with atherogenic lipid profile [24271261] To our knowledge , no reports are available indicating the effects of synbiotic food consumption on blood lipid profiles and biomarkers of oxidative stress among pregnant women . This study was conducted to evaluate the effects of daily consumption of a synbiotic food on blood lipid profiles and biomarkers of oxidative stress in pregnant women . This r and omized , double-blind , controlled clinical trial was performed among 52 primigravida pregnant women , aged 18 to 35-year-old at their third trimester . After a 2-week run-in period , subjects were r and omly assigned to consume either a synbiotic ( n = 26 ) or control food ( n = 26 ) for 9 weeks . The synbiotic food consisted of a probiotic viable and heat-resistant Lactobacillus sporogenes ( 1 × 107 CFU ) and 0.04 g inulin (HPX)/g as the prebiotic . Patients were asked to consume the synbiotic and control foods two times a day . Biochemical measurements including blood lipid profiles , plasma total antioxidant capacity ( TAC ) and total glutathione ( GSH ) were conducted before and after 9 weeks of intervention . Consumption of a synbiotic food for 9 weeks result ed in a significant reduction in serum TAG ( P = 0.04 ) , VLDL ( P = 0.04 ) and a significant rise in plasma GSH levels ( P = 0.004 ) compared to the control food . No significant effects of the synbiotic food consumption on serum TC , LDL , HDL and plasma TAC levels ( P > 0.05 ) were observed . Trial registry code : http://www.i rct .ir . I RCT 201212105623N3 [6259925] The determine the effect of different foods on the blood glucose , 62 commonly eaten foods and sugars were fed individually to groups of 5 to 10 healthy fasting volunteers . Blood glucose levels were measured over 2 h , and expressed as a percentage of the area under the glucose response curve when the same amount of carbohydrate was taken as glucose . The largest rises were seen with vegetables ( 70 + /- 5 % ) , followed by breakfast cereals ( 65 + /- 5 % ) , cereals and biscuits ( 60 + /- 3 % ) , fruit ( 50 + /- 5 % ) , dairy products ( 35 + /- 1 % ) , and dried legumes ( 31 + /- 3 % ) . A significant negative relationship was seen between fat ( p less than 0.01 ) and protein ( p less than 0.001 ) and postpr and ial glucose rise but not with fiber or sugar content [22218158] BACKGROUND Fatty acids play a vital role in glucose homeostasis ; however , studies on habitual dietary fat intakes and gestational diabetes mellitus ( GDM ) risk are limited and provide conflicting findings . OBJECTIVE We determined whether the total amount and the type and source of prepregnancy dietary fats are related to risk of GDM . DESIGN A prospect i ve study was conducted in 13,475 women who reported a singleton pregnancy between 1991 and 2001 in the Nurses ' Health Study II . In these women , 860 incident GDM cases were reported . The adjusted RR of GDM was estimated for quintiles of total fat , specific fat , and the source of fat intakes by pooled logistic regression . RESULTS Higher animal fat and cholesterol intakes were significantly associated with increased GDM risk . Across increasing quintiles of animal fat , RRs ( 95 % CIs ) for GDM were 1.00 ( reference ) , 1.55 ( 1.20 , 1.98 ) , 1.43 ( 1.09 , 1.88 ) , 1.40 ( 1.04 , 1.89 ) , and 1.88 ( 1.36 , 2.60 ) ( P-trend = 0.05 ) . Corresponding RRs ( 95 % CIs ) for dietary cholesterol were 1.00 ( reference ) , 1.08 ( 0.84 , 1.32 ) , 1.02 ( 0.78 , 1.29 ) , 1.20 ( 0.93 , 1.55 ) , and 1.45 ( 1.11 , 1.89 ) ( P-trend = 0.04 ) . The substitution of 5 % of energy from animal fat for an equal percentage of energy from carbohydrates was associated with significantly increased risk of GDM [ RR ( 95 % CI ) : 1.13 ( 1.08 , 1.18 ) ; P < 0.0001 ] . No significant associations were observed between dietary polyunsaturated fat , monounsaturated fat , or trans fat intakes and GDM risk . CONCLUSION Higher prepregnancy intakes of animal fat and cholesterol were associated with elevated GDM risk [23182924] BACKGROUND AND AIM Early nutrition may programme blood lipid levels and thereby later cardiovascular health of children . The objective here was to evaluate the effects of maternal dietary counselling during pregnancy and breastfeeding on dietary intakes and blood lipid values in 1 - 4 year-old children . Further , the nutritional determinants of children 's lipid profiles were assessed . METHODS AND RESULTS Mothers were r and omised into dietary counselling or control groups at the first trimester of pregnancy . Their children were followed up clinical ly at 1 , 2 and 4 years of age , by three-day food records and analyses of total cholesterol , HDL cholesterol and apolipoproteins A-I and B as well as lipoprotein ( a ) . In general , the mean intake of saturated fatty acids as a proportion of total energy intake ( E% ) was higher than the recommended , while the mean intake of polyunsaturated fatty acids was low in children 's diet . Over the first years , girls had higher concentration of non-HDL cholesterol than boys ; 2.64 mmol/l ( 95 % CI 2.54 - 2.74 ) vs. 2.49 ( 2.38 - 2.60 ) ; p = 0.038 . Maternal dietary counselling was not reflected in the children 's lipid values . Children 's monounsaturated fatty acid intake ( E% ) correlated with apoA-I ( p = 0.048 ) and , furthermore , there was a negative correlation between polyunsaturated fatty acid intake ( E% ) and apoB ( p = 0.046 ) . CONCLUSION Children 's dietary fatty acid intake , but not maternal dietary counselling was shown to be related to blood apolipoproteins in children [26185283] OBJECTIVE Dietary interventions can improve pregnancy outcomes in women with gestational diabetes mellitus ( GDM ) . We compared the effect of a low – glycemic index ( GI ) versus a conventional high-fiber ( HF ) diet on pregnancy outcomes , birth weight z score , and maternal metabolic profile in women at high risk of GDM . RESEARCH DESIGN AND METHODS One hundred thirty-nine women [ mean ( SD ) age 34.7 ( 0.4 ) years and prepregnancy BMI 25.2 ( 0.5 ) kg/m2 ] were r and omly assigned to a low-GI ( LGI ) diet ( n = 72 ; target GI ∼50 ) or a high-fiber , moderate-GI ( HF ) diet ( n = 67 ; target GI ∼60 ) at 14–20 weeks ’ gestation . Diet was assessed by 3-day food records and infant body composition by air-displacement plethysmography , and pregnancy outcomes were assessed from medical records . RESULTS The LGI group achieved a lower GI than the HF group [ mean ( SD ) 50 ( 5 ) vs. 58 ( 5 ) ; P < 0.001 ] . There were no differences in glycosylated hemoglobin , fructosamine , or lipids at 36 weeks or differences in birth weight [ LGI 3.4 ( 0.4 ) kg vs. HF 3.4 ( 0.5 ) kg ; P = 0.514 ] , birth weight z score [ LGI 0.31 ( 0.90 ) vs. HF 0.24 ( 1.07 ) ; P = 0.697 ] , ponderal index [ LGI 2.71 ( 0.22 ) vs. HF 2.69 ( 0.23 ) kg/m3 ; P = 0.672 ] , birth weight centile [ LGI 46.2 ( 25.4 ) vs. HF 41.8 ( 25.6 ) ; P = 0.330 ] , % fat mass [ LGI 10 ( 4 ) vs. HF 10 ( 4 ) ; P = 0.789 ] , or incidence of GDM . CONCLUSIONS In intensively monitored women at risk for GDM , a low-GI diet and a healthy diet produce similar pregnancy outcomes [3718630] Background Complex interventions in obese pregnant women should be theoretically based , feasible and shown to demonstrate anticipated behavioural change prior to inception of large r and omised controlled trials ( RCTs ) . The aim was to determine if a ) a complex intervention in obese pregnant women leads to anticipated changes in diet and physical activity behaviours , and b ) to refine the intervention protocol through process evaluation of intervention fidelity . Methods We undertook a pilot RCT of a complex intervention in obese pregnant women , comparing routine antenatal care with an intervention to reduce dietary glycaemic load and saturated fat intake , and increase physical activity . Subjects included 183 obese pregnant women ( mean BMI 36.3 kg/m2).Diet was assessed by repeated triple pass 24-hour dietary recall and physical activity by accelerometry and question naire , at 16 + 0 to 18 + 6 and at 27 + 0 to 28 + 6 weeks ’ gestation in women in control and intervention arms . Attitudes to behaviour change and quality of life were assessed and a process evaluation undertaken . The full RCT protocol was undertaken to assess feasibility . Results Compared to women in the control arm , women in the intervention arm had a significant reduction in dietary glycaemic load ( 33 points , 95 % CI −47 to −20 ) , ( p < 0.001 ) and saturated fat intake ( −1.6 % energy , 95 % CI −2.8 to −0 . 3 ) at 28 weeks ’ gestation . Objective ly measured physical activity did not change . Physical discomfort and sustained barriers to physical activity were common at 28 weeks ’ gestation . Process evaluation identified barriers to recruitment , group attendance and compliance , leading to modification of intervention delivery . Conclusions This pilot trial of a complex intervention in obese pregnant women suggests greater potential for change in dietary intake than for change in physical activity , and through process evaluation illustrates the considerable advantage of performing an exploratory trial of a complex intervention in obese pregnant women before undertaking a large RCT .Trial registration Trial Registration Number : IS RCT [3919179] Objective To determine the effect of antenatal dietary and lifestyle interventions on health outcomes in overweight and obese pregnant women . Design Multicentre r and omised trial . We utilised a central telephone r and omisation server , with computer generated schedule , balanced variable blocks , and stratification for parity , body mass index ( BMI ) category , and hospital . Setting Three public maternity hospitals across South Australia . Participants 2212 women with a singleton pregnancy , between 10 + 0 and 20 + 0 weeks ’ gestation , and BMI ≥25 . Interventions 1108 women were r and omised to a comprehensive dietary and lifestyle intervention delivered by research staff ; 1104 were r and omised to st and ard care and received pregnancy care according to local guidelines , which did not include such information . Main outcome measures Incidence of infants born large for gestational age ( birth weight ≥90th centile for gestation and sex ) . Prespecified secondary outcomes included birth weight > 4000 g , hypertension , pre-eclampsia , and gestational diabetes . Analyses used intention to treat principles . Results 2152 women and 2142 liveborn infants were included in the analyses . The risk of the infant being large for gestational age was not significantly different in the two groups ( lifestyle advice 203/1075 ( 19 % ) v st and ard care 224/1067 ( 21 % ) ; adjusted relative risk 0.90 , 95 % confidence interval 0.77 to 1.07 ; P=0.24 ) . Infants born to women after lifestyle advice were significantly less likely to have birth weight above 4000 g ( lifestyle advice 164/1075 ( 15 % ) v st and ard care 201/1067 ( 19 % ) ; 0.82 , 0.68 to 0.99 ; number needed to treat ( NNT ) 28 , 15 to 263 ; P=0.04 ) . There were no differences in maternal pregnancy and birth outcomes between the two treatment groups . Conclusions For women who were overweight or obese , the antenatal lifestyle advice used in this study did not reduce the risk delivering a baby weighing above the 90th centile for gestational age and sex or improve maternal pregnancy and birth outcomes . Trial registration Australian and New Zeal and Clinical Trials Registry ( ACTRN12607000161426 ) [3511276] Abstract Background Women who are physically active during early pregnancy have notably lower odds of developing gestational diabetes than do inactive women . The purpose of the intervention was to examine whether intensified physical activity ( PA ) counseling in Finnish maternity care is feasible and effective in promoting leisure-time PA ( LTPA ) among pregnant women at risk of gestational diabetes . Methods Fourteen municipalities were r and omized to intervention ( INT ) and usual care group ( UC ) . Nurses in INT integrated five PA counseling sessions into routine maternity visits and offered monthly group meetings on PA instructed by physiotherapists . In UC conventional practice s were continued . Feasibility evaluation included safety ( incidence of PA-related adverse events ; question naire ) , realization ( timing and duration of sessions , number of sessions missed , attendance at group meetings ; systematic record-keeping of the nurses and physiotherapists ) and applicability ( nurses ’ views ; telephone interview ) . Effectiveness outcomes were weekly frequency and duration of total and intensity-specific LTPA and meeting PA recommendation for health self-reported at 8 - 12 ( baseline ) , 26 - 28 and 36 - 37 weeks ’ gestation . Multilevel analysis with adjustments was used in testing for between-group differences in PA changes . Results The decrease in the weekly days of total and moderate-to-vigorous-intensity LTPA was smaller in INT ( N = 219 ) than in UC ( N = 180 ) from baseline to the first follow-up ( 0.1 vs. -1.2 , p = 0.040 and −0.2 vs. -1.3 , p = 0.016 ) . A similar trend was seen in meeting the PA recommendation ( −11%-points vs. -28%-points , p = 0.06 ) . INT did not experience more adverse events classified as warning signs to terminate exercise than UC , counseling was implemented as planned and viewed positively by the nurses . Conclusions Intensified counseling had no effects on the duration of total or intensity-specific weekly LTPA . However , it was able to reduce the decrease in the weekly frequency of total and moderate-to-vigorous-intensity LTPA from baseline to the end of second trimester and was feasibly embedded into routine practice s . Trial registration IS RCT N 33885819 ( http://www.is rct n.org [5115165] Study question What is the association between potato consumption before pregnancy and the risk of gestational diabetes mellitus ( GDM ) ? Methods This prospect i ve cohort study included 15 632 women from the Nurses ’ Health Study II ( 1991 - 2001 ) . They had no previous GDM or chronic diseases before pregnancy . Consumption of potatoes and other foods was assessed every four years . Incident first time GDM was ascertained from self reports of a physician diagnosis of GDM , which was previously vali date d by medical records . Study answer and limitations Over the 10 year follow-up there were 854 incident cases of GDM among 21 693 singleton pregnancies . After adjustment for age , parity , and dietary and non-dietary factors , women who consumed more potatoes before pregnancy had higher rates of developing GDM . Substitution of two servings a week of total potatoes with other vegetables , legumes , and whole grain foods was significantly associated with a 9 - 12 % lower risk of GDM . Consumption and diabetes were self reported , and severity of diabetes was unknown . More than 90 % of women were white . A causal association can not be assumed . What this paper adds Higher levels of potato consumption before pregnancy are associated with greater risk of GDM , and substitution of potatoes with other vegetables , legumes , or whole grain foods might lower the risk . Funding , competing interests , data sharing Funding was received from the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development , the National Institutes of Health , and the American Diabetes Association ( No 7 - 12-MN-34 ) . The authors have no competing interests or additional data to share [26165396] BACKGROUND Behavioural interventions might improve clinical outcomes in pregnant women who are obese . We aim ed to investigate whether a complex intervention addressing diet and physical activity could reduce the incidence of gestational diabetes and large-for-gestational-age infants . METHODS The UK Pregnancies Better Eating and Activity Trial ( UPBEAT ) is a r and omised controlled trial done at antenatal clinics in eight hospitals in multi-ethnic , inner-city locations in the UK . We recruited pregnant women ( 15 - 18 weeks plus 6 days of gestation ) older than 16 years who were obese ( BMI ≥30 kg/m(2 ) ) . We r and omly assigned participants to either a behavioural intervention or st and ard antenatal care with an internet-based , computer-generated , r and omisation procedure , minimising by age , ethnic origin , centre , BMI , and parity . The intervention was delivered once a week through eight health trainer-led sessions . Primary outcomes were gestational diabetes ( diagnosed with an oral glucose tolerance test and by criteria from the International Association of Diabetes in Pregnancy Study Groups ) and large-for-gestational-age infants ( ≥90th customised birthweight centile ) . Analysis was by intention to treat . This trial is registered with Current Controlled Trials , ISCRTN89971375 . Recruitment and pregnancy outcomes are complete but childhood follow-up is ongoing . FINDINGS Between March 31 , 2009 , and June 2 , 2014 , we assessed 8820 women for eligibility and recruited 1555 , with a mean BMI of 36·3 kg/m(2 ) ( SD 4·8 ) . 772 were r and omly assigned to st and ard antenatal care and 783 were allocated the behavioural intervention , of which 651 and 629 women , respectively , completed an oral glucose tolerance test . Gestational diabetes was reported in 172 ( 26 % ) women in the st and ard care group compared with 160 ( 25 % ) in the intervention group ( risk ratio 0·96 , 95 % CI 0·79 - 1·16 ; p=0·68 ) . 61 ( 8 % ) of 751 babies in the st and ard care group were large for gestational age compared with 71 ( 9 % ) of 761 in the intervention group ( 1·15 , 0·83 - 1·59 ; p=0·40 ) . Thus , the primary outcomes did not differ between groups , despite improvements in some maternal secondary outcomes in the intervention group , including reduced dietary glycaemic load , gestational weight gain , and maternal sum-of-skinfold thicknesses , and increased physical activity . Adverse events included neonatal death ( two in the st and ard care group and three in the intervention group ) and fetal death in utero ( ten in the st and ard care group and six in the intervention group ) . No maternal deaths were reported . Incidence of miscarriage ( 2 % in the st and ard care group vs 2 % in the intervention group ) , major obstetric haemorrhage ( 1 % vs 3 % ) , and small-for-gestational-age infants ( ≤5th customised birthweight centile ; 6 % vs 5 % ) did not differ between groups . INTERPRETATION A behavioural intervention addressing diet and physical activity in women with obesity during pregnancy is not adequate to prevent gestational diabetes , or to reduce the incidence of large-for-gestational-age infants . FUNDING National Institute for Health Research , Guys and St Thomas ' Charity , Chief Scientist Office Scotl and , Tommy 's Charity [21625788] PURPOSE to evaluate the impact of dietary counseling on controlling weight gain in pregnant women , who were served in a public health service facility . METHODS the study was conducted at a known health unit located in the metropolitan region of the city of Porto Alegre , in Rio Gr and e do Sul , Brazil . Three hundred and fifteen pregnant women between the 10th and 29th week of gestation were r and omized to Control and Intervention Groups . The Intervention Group received dietary counseling according to nutritional status , and pregnant women in the Control Group were instructed to follow the routine of the health service facility . Weight and height were measured , and the body mass index ( BMI ) was calculated . The pre-gestational nutritional status was determined according to the following BMI criteria : low weight ( < 18.5 kg/m² ) , eutrophy ( 18.5 to 24.9 kg/m² ) , overweight ( 25.0 to 29.9 kg/m² ) , and obesity ( > 30 kg/m² ) . The nutritional status during pregnancy was determined according to the BMI curve for gestational age adopted by the Health Ministry of Brazil . Data were analyzed by the relative risk and respective 95 % confidence interval , and by the Student 's t-test and χ2 test . Statistical significance was set at p<0.05 . RESULTS the assessment of nutritional status before pregnancy showed that 28.0 % of the women were overweight and 4.1 % were underweight . In the first and last interview during pregnancy , the rates of prevalence of excessive weight were 36.2 and 46.0 % , respectively . The intervention proved to be effective in reducing the rate of weekly weight gain of pregnant women with excess weight ( 342.2 versus 420.2 ; p=0.015 ) and the prevalence of clinical complications ( 9.2 versus 24.85 ; p<0.001 ) . CONCLUSIONS dietary counseling was effective in decreasing the weight gain of pregnant women who were overweight and reducing clinical complications , such as gestational diabetes , preeclampsia , infant low weight , and prematurity in the Intervention Group [21626296] Purpose Breast milk fatty acids possess immunomodulatory properties , and new intervention strategies beyond supplementation of maternal diet with single oils are called for . The objective of the present study was to evaluate the effect of dietary intervention during pregnancy and breastfeeding on breast milk fatty acid and cytokine composition . Methods Pregnant women were r and omised into three study groups : dietary intervention with probiotics ( diet/probiotic ) or with placebo ( diet/placebo ) and a control group ( control/placebo ) . Dietary intervention included dietary counselling and provision of rapeseed oil-based food products . The probiotics used were Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12 in combination . Dietary intake was evaluated by food records at every trimester of pregnancy and 1 month postpartum . Breast milk sample s were collected after birth ( colostrum ) and 1 month after delivery for fatty acid and cytokine analysis ( n = 125 ) . Results Dietary intervention improved the quality of fat in the diet . In breast milk , the proportion of α-linolenic acid and total n-3 fatty acids was higher in both dietary intervention groups compared with control group ( p < 0.05 ) . In the diet/probiotic group , the γ-linolenic acid content was higher compared with the diet/placebo group ( p < 0.05 ) . The concentrations of TNF-α , IL-10 , IL-4 and IL-2 were higher in both dietary intervention groups compared with controls , and furthermore , long-chain n-3 fatty acids were associated with several cytokines in colostrum sample s. Conclusion The present intervention demonstrated the possibility of modifying breast milk immunomodulatory factors by dietary means [26358582] Aims /hypothesisWe examined the associations between pre-pregnancy dietary patterns and the incidence of gestational diabetes mellitus ( GDM ) in a population -based cohort study of women of reproductive age . Methods The Australian Longitudinal Study on Women ’s Health included 3,853 women without pre-existing diabetes who were followed-up between 2003 and 2012 . Pre-pregnancy dietary patterns were derived using factor analysis based on 101 food items from a vali date d food frequency question naire . GDM was self-reported and vali date d in a sub sample . Multivariable regression models with generalised estimating equations were used to estimate RR and 95 % CI . Results During 9 years follow-up , 292 GDM cases ( 4.4 % ) were documented in 6,626 pregnancies . No associations were found for the ‘ Fruit and low-fat dairy ’ and ‘ Cooked vegetables ’ patterns . The ‘ Meats , snacks and sweets ’ pattern was associated with higher GDM risk after adjustment for socioeconomic , reproductive and lifestyle factors ( RR [ 95 % CI ] per SD increase in score : 1.38 [ 1.02 , 1.86 ] ) . Further adjustment for BMI attenuated the results ( 1.35 [ 0.98 , 1.81 ] ) . In stratified analysis , the ‘ Meats , snacks and sweets ’ pattern was associated with significantly higher GDM risk in parous and obese women , and in women with lower educational qualifications . The ‘ Mediterranean-style ’ pattern was associated with lower GDM risk in the fully adjusted model ( 0.85 [ 0.76 , 0.98 ] ) . Conclusions /interpretationThese findings support general dietary recommendations for women of reproductive age to consume a diet rich in vegetables , whole grains , nuts and fish , and low in red and processed meats and snacks . Further prospect i ve studies are needed to confirm these findings [20962162] BACKGROUND The optimal diet for pregnancy that is complicated by excessive weight is unknown . OBJECTIVE We aim ed to examine the effects of a low-glycemic load ( low-GL ) diet in overweight and obese pregnant women . DESIGN We r and omly assigned 46 overweight or obese pregnant women to receive a low-GL or a low-fat diet . Participants received carbohydrate-rich foods , fats , and snack foods through home delivery or study visits . The primary outcome was birth weight z score . Other endpoints included infant anthropometric measurements , gestational duration , maternal weight gain , and maternal metabolic parameters . RESULTS There were no significant differences in birth weight z score or other measures of infant adiposity between groups . However , in the low-GL compared with the low-fat group , gestational duration was longer ( mean ± SD : 39.3 ± 1.1 compared with 37.9 ± 3.1 wk ; P = 0.05 ) and fewer deliveries occurred at ≤ 38.0 wk ( 13 % compared with 48 % , P = 0.02 ; with exclusion of planned cesarean deliveries : 5 % compared with 53 % ; P = 0.002 ) . Adjusted head circumference was greater in the low-GL group ( 35.0 ± 0.8 compared with 34.2 ± 1.3 cm , P = 0.01 ) . Women in the low-GL group had smaller increases in triglycerides [ median ( interquartile range ) : 49 ( 19 , 70 ) compared with 93 ( 34 , 129 ) mg/dL ; P = 0.03 ] and total cholesterol [ 13 ( 0 , 36 ) compared with 33 ( 22 , 56 ) mg/dL , P = 0.04 ] and a greater decrease in C-reactive protein [ -2.5 ( -5.5 , -0.7 ) compared with -0.4 ( -1.4 , 1.5 ) mg/dL , P = 0.007 ] . CONCLUSIONS A low-GL diet result ed in longer pregnancy duration , greater infant head circumference , and improved maternal cardiovascular risk factors . Large-scale studies are warranted to evaluate whether dietary intervention during pregnancy aim ed at lowering GL may be useful in the prevention of prematurity and other adverse maternal and infant outcomes . This trial is registered at clinical trials.gov as NCT00364403 [19155899] OBJECTIVE : To estimate whether an organized , consistent program of dietary and lifestyle counseling prevents excessive weight gain in pregnancy . METHODS : This r and omized controlled trial assigned women to receive either an organized , consistent program of intensive dietary and lifestyle counseling or routine prenatal care . The primary study outcome was the proportion of patients whose gestational weight gain was within the Institute of Medicine ( IOM ) guidelines . Secondary outcomes included mode of delivery , rate of operative vaginal delivery , neonatal weight , and the incidence of preeclampsia , gestational diabetes mellitus ( GDM ) , vaginal/perineal lacerations , and shoulder dystocia . RESULTS : A total of 100 women were r and omized to the study ( lifestyle counseling 57 , routine prenatal care 43 ) . Baseline demographic characteristics were similar between the study groups . The lifestyle counseling group gained significantly less weight than did the routine prenatal care group ( 28.7±12.5 lb compared with 35.6±15.5 lb , P=.01 ) . The routine prenatal care group had significantly more cesarean deliveries due to “ failure to progress ” ( routine prenatal care 58.3 % compared with lifestyle counseling 25.0 % , P=.02 ) . Across groups , patients who were not adherent to the IOM guidelines had significantly heavier neonates ( adherent 3,203.2±427.2 g compared with not adherent 3,517.4±572.4 g , P<.01 ) . Nulliparous women gained significantly more weight than did parous women ( 36.5±14.5 lb compared with 27.7±12.7 lb , P<.01 ) . The most predictive factor of IOM adherence was having a normal prepregnancy body mass index . No statistically significant differences were noted between the groups in adherence to IOM guidelines , rate of cesarean delivery , preeclampsia , GDM , operative vaginal delivery , or vaginal lacerations . CONCLUSION : An organized , consistent program of dietary and lifestyle counseling did reduce weight gain in pregnancy . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00792480 LEVEL OF EVIDENCE : [1523339] Background Preventing excessive weight gain during pregnancy is potentially important in the prevention of overweight and obesity among women of childbearing age . However , few intervention studies aim ing at weight management during pregnancy have been performed and most of these interventions were not as successful as expected . In this paper the design of the New Life(style ) study is described as well as the content of the individually tailored intervention program , which focuses on controlling weight development during pregnancy . Methods The effectiveness of the New Life(style ) intervention program versus usual care by midwives is evaluated in a r and omised controlled trial . Women who expect their first child and visit one of the participating midwifery practice s are included . The intervention is st and ardised in a protocol and executed by trained counsellors with the women who are r and omised in the intervention group . During 5 sessions – at 18 , 22 , 30 and 36 weeks of pregnancy and at 8 weeks postpartum – individual weight gain is discussed in relation to weight gain guidelines for pregnant women of the American Institute of Medicine . Counsellors coach the women to maintain or optimise a healthy lifestyle , in a period of drastic physical and mental changes . Data is collected at 15 , 25 , 35 weeks of pregnancy and at 6 , 26 , and 52 weeks after delivery . Primary outcome measures are body weight , BMI , and skinfold thickness . Secondary outcome measures include physical activity , nutrition and blood levels of factors that are associated with energy homeostasis . Discussion Results of the current RCT will improve the knowledge of determinants of weight gain during pregnancy , weight retention after childbirth and of the effectiveness of the intervention program that is described . Caregivers and research ers in the field of health promotion are offered more insight in specific elements of the New Life(style ) intervention program [23327487] Abstract Objective : To test the hypothesis that dietary myo-inositol may improve insulin resistance and the development of gestational diabetes mellitus ( GDM ) in women at high risk of this disorder . Design : A prospect i ve , r and omized , double-blind , placebo controlled clinical trial , pilot study . Participants : Non-obese singleton pregnant women with an elevated fasting glucose in the first or early second trimester were studied throughout pregnancy . Intervention : Supplementation with myo-inositol or placebo during pregnancy . Main outcome measure : Development of GDM on a 75 g oral glucose tolerance test at 24–28 weeks ’ gestation . Secondary outcome measures were increased in BMI , need for maternal insulin therapy , macrosomia , polyhydramnios , neonatal birthweight and hypoglycemia . Results : Thirty-six women were allocated to receive myo-inositol and 39 placebo . The incidence of GDM in mid-pregnancy was significantly reduced ( p = 0.001 ) in women r and omized to receive myo-inositol compared to placebo ( relative risk 0.127 ) . Women r and omized to receive myo-inositol also required less insulin therapy , delivered at a later gestational age , had significantly smaller babies with fewer episodes of neonatal hypoglycemia . Conclusions : Myo-inositol supplementation in pregnancy reduced the incidence of GDM in women at high risk of this disorder . The reduction in incidence of GDM in the treatment arm was accompanied by improved outcomes [24169456] Background / Objective : Well-being has been linked to the quality of diet and lifestyle in adults ; however , there is a paucity of data in pregnancy . The aim of this study was to examine the relationship between well-being and socioeconomic status , diet and lifestyle during pregnancy and to consider the effect of intervention with low glycaemic index ( GI ) diet on well-being . Subjects/ Methods : This was a cohort analysis of 619 participants of the ROLO study ( R and omised cOntrol trial of LOw GI diet versus no dietary intervention to prevent recurrence of fetal macrosomia ) . The following data were collected : educational attainment , dietary intakes ( food frequency question naire ) , physical activity ( self-reported ) and well-being ( WHO-5-Item Wellbeing Index — expressed as a percentage ) . Results : Well-being was positively associated with education and physical activity . Third-level education was associated with a 3.07-point higher well-being percentage score , and each day that an individual achieved > 30 min walking per week was associated with a 1.10-point increase in percentage well-being score , Radj2 2.4 % ( F=7.260 , P=0.001 ) . The intervention low GI group had a significantly lower percentage well-being score than the usual diet group ( 56.3 % vs 59.9 % , P=0.015 ) . No correlation was noted between well-being and GI status calculated from food diaries ( P=0.469 ) . Well-being was not associated with micronutrient intake . Conclusions : Well-being in pregnancy was independently and positively associated with education and physical activity and negatively associated with low GI dietary intervention . These findings have significance not only for women at risk of low mood but also for healthcare professionals when counselling women about the importance of healthy lifestyle in pregnancy [2876071] Background Maternal weight and maternal weight gain during pregnancy exert a significant influence on infant birth weight and the incidence of macrosomia . Fetal macrosomia is associated with an increase in both adverse obstetric and neonatal outcome , and also confers a future risk of childhood obesity . Studies have shown that a low glycaemic diet is associated with lower birth weights , however these studies have been small and not r and omised [ 1 , 2 ] . Fetal macrosomia recurs in a second pregnancy in one third of women , and maternal weight influences this recurrence risk [ 3 ] . Methods / Design We propose a r and omised control trial of low glycaemic index carbohydrate diet vs. no dietary intervention in the prevention of recurrence of fetal macrosomia . Secundigravid women whose first baby was macrosomic , defined as a birth weight greater than 4000 g will be recruited at their first antenatal visit . Patients will be r and omised into two arms , a control arm which will receive no dietary intervention and a diet arm which will be commenced on a low glycaemic index diet . The primary outcome measure will be the mean birth weight centiles and ponderal indices in each group . Discussion Altering the source of maternal dietary carbohydrate may prove to be valuable in the management of pregnancies where there has been a history of fetal macrosomia . Fetal macrosomia recurs in a second pregnancy in one third of women . This r and omised control trial will investigate whether or not a low glycaemic index diet can affect this recurrence risk . Current Controlled Trials Registration NumberIS RCT [2681032] OBJECTIVE A low – glycemic index diet is effective as a treatment for individuals with diabetes and has been shown to improve pregnancy outcomes when used from the first trimester . A low – glycemic index diet is commonly advised as treatment for women with gestational diabetes mellitus ( GDM ) . However , the efficacy of this advice and associated pregnancy outcomes have not been systematic ally examined . The purpose of this study was to determine whether prescribing a low – glycemic index diet for women with GDM could reduce the number of women requiring insulin without compromise of pregnancy outcomes . RESEARCH DESIGN AND METHODS All women with GDM seen over a 12-month period were considered for inclusion in the study . Women ( n = 63 ) were r and omly assigned to receive either a low – glycemic index diet or a conventional high-fiber ( and higher glycemic index ) diet . RESULTS Of the 31 women r and omly assigned to a low – glycemic index diet , 9 ( 29 % ) required insulin . Of the women r and omly assigned to a higher – glycemic index diet , a significantly higher proportion , 19 of 32 ( 59 % ) , met the criteria to commence insulin treatment ( P = 0.023 ) . However , 9 of these 19 women were able to avoid insulin use by changing to a low – glycemic index diet . Key obstetric and fetal outcomes were not significantly different . CONCLUSIONS Using a low – glycemic index diet for women with GDM effectively halved the number needing to use insulin , with no compromise of obstetric or fetal outcomes [21945174] BACKGROUND The breast milk bioactive substances such as adiponectin , have a presumably long-term impact upon the health and well-being of a child . AIM To determine the impact of probiotic-supplemented dietary counseling during pregnancy on colostrum adiponectin concentration . STUDY DESIGN AND SUBJECTS Altogether 256 pregnant women were r and omized into three study groups : dietary intervention with probiotics ( diet/probiotics ) or with placebo ( diet/placebo ) and a control group ( control/placebo ) . The intervention group received dietary counseling provided by a nutritionist , the main focus being the amount and the type of dietary fat . The probiotics used were Lactobacillus rhamnosus GG and Bifidobacterium lactis in combination . Dietary intake was evaluated by food records at every trimester of pregnancy . Breast milk sample s were collected after birth ( colostrum ) for adiponectin concentration analysis ( n=181 ) . RESULTS The dietary intervention increased the colostrum adiponectin concentration ( ng/mL , geometric mean [ 95 % CI ] ) , the difference being significant when comparing to the control group ; 12.7 [ 10.6 - 29.7 ] vs. 10.2 [ 9.9 - 13.2 ] , P=0.024 . Maternal weight gain during pregnancy ( kg ) correlated inversely with colostrum adiponectin concentration ; β (SE)=-1.7 ( 0.1 ) , P=0.020 , and gestational diabetes mellitus was associated with the likelihood of adiponectin concentration falling into the lowest quartile ; OR 2.36 , 95 % CI 1.1 - 3.2 , P=0.028 . CONCLUSIONS In showing that the colostrum adiponectin concentration is markedly dependent on maternal diet and nutritional status during pregnancy , and considering that colostrum adiponectin has potential effects on metabolism , nutrition , and immune function in the neonates , the results of this study underscore the importance of the metabolic homeostasis of the mother for the child 's initial nutritional environment [2782983] OBJECTIVE Consumption of sugar-sweetened beverages ( SSBs ) was related to an elevated risk of type 2 diabetes and insulin resistance in several recent studies among middle- or older-aged population s. Studies on SSB consumption and glucose intolerance among pregnant women , however , are lacking . We therefore examined the association between regular SSB consumption before pregnancy and the risk of gestational diabetes mellitus ( GDM ) . RESEARCH DESIGN AND METHODS This was a prospect i ve study among 13,475 U.S. women who reported at least one singleton pregnancy between 1992 and 2001 in the Nurses ' Health Study II . GDM was self-reported and vali date d by medical record review in a sub sample . Cox proportional hazards models with multivariate adjustments were applied to examine the association of SSB consumption with GDM risk . RESULTS During 10 years of follow-up , 860 incident GDM case subjects were identified . After adjustment for age , parity , race , physical activity , smoking , alcohol intake , prepregnancy BMI , and Western dietary pattern , intake of sugar-sweetened cola was positively associated with the risk of GDM , whereas no significant association was found for other SSBs and diet beverages . Compared with women who consumed < 1 serving/month , those who consumed ≥5 servings/week of sugar-sweetened cola had a 22 % greater GDM risk ( relative risk 1.22 [ 95 % CI 1.01–1.47 ] ) . CONCLUSIONS Findings from this study suggest that prepregnancy higher consumption of sugar-sweetened cola ( ≥5 servings/week ) is associated with an elevated GDM risk , whereas no significant association with GDM risk was observed for other SSBs and diet beverages [16957814] Aims /hypothesisThe aim of this study was to prospect ively examine whether dietary patterns are related to risk of gestational diabetes mellitus ( GDM ) . Methods This prospect i ve cohort study included 13,110 women who were free of cardiovascular disease , cancer , type 2 diabetes and history of GDM . Subjects completed a vali date d semi-quantitative food frequency question naire in 1991 , and reported at least one singleton pregnancy between 1992 and 1998 in the Nurses ’ Health Study II . Two major dietary patterns ( i.e. ‘ prudent ’ and ‘ Western ’ ) were identified through factor analysis . The prudent pattern was characterised by a high intake of fruit , green leafy vegetables , poultry and fish , whereas the Western pattern was characterised by high intake of red meat , processed meat , refined grain products , sweets , French fries and pizza . Results We documented 758 incident cases of GDM . After adjustment for age , parity , pre-pregnancy BMI and other covariates , the relative risk ( RR ) of GDM , comparing the highest with the lowest quintile of the Western pattern scores , was 1.63 ( 95 % CI 1.20–2.21 ; ptrend=0.001 ) , whereas the RR comparing the lowest with the highest quintile of the prudent pattern scores was 1.39 ( 95 % CI 1.08–1.80 ; ptrend=0.018 ) . The RR for each increment of one serving/day was 1.61 ( 95 % CI 1.25–2.07 ) for red meat and 1.64 ( 95 % CI 1.13–2.38 ) for processed meat . Conclusions /interpretationThese findings suggest that pre-pregnancy dietary patterns may affect women ’s risk of developing GDM . A diet high in red and processed meat was associated with a significantly elevated risk [19585925] BACKGROUND Although obesity in pregnancy continues to be associated with ongoing health problems , many clinicians have been reluctant to place nondiabetic , obese , pregnant women on a monitored , calorie-appropriate nutritional regimen for fear of fetal growth restriction , low birth weight , or starvation ketosis . METHODS A total of 257 patients were enrolled in the r and omized study , with a loss-to-follow-up rate of 9.73 % . Patients were assigned r and omly to either the control ( unmonitored ) group ( n=116 ) , consisting of conventional prenatal dietary management , or to the study ( monitored ) group ( n=116 ) , which was prescribed a balanced nutritional regimen and were asked to record in a diary all of the foods eaten during each day . Women were eligible for the study if they were pregnant with a single fetus between 12 and 28 weeks of gestation and had a prepregnancy body mass index of more than 30 kg/m2 . The primary outcome was to compare perinatal outcomes in the control vs the study groups . The secondary measure was to compare outcomes in adherent and nonadherent patients in the study group . RESULTS Omnibus MANOVA showed statistically significant differences between the study and control groups regarding 3 variables : ( 1 ) gestational hypertension , p < .46 ; ( 2 ) mother 's last weight before delivery , p < .001 ; and ( 3 ) mother 's 6-week postpartum weight , p < .001 . Patients gaining 15 pounds or more during their pregnancy showed statistically significant differences between the groups for 8 variables . CONCLUSION Obese pregnant women may be placed on a healthy , well-balanced , monitored nutritional program during their antepartum course without adverse perinatal outcomes [4176103] Background Maternal diet is known to impact pregnancy outcome . Following a low glycemic index ( GI ) diet during pregnancy has been shown to improve maternal glycemia and reduce infant birthweight and may be associated with a higher fibre intake . We assessed the impact of a low GI dietary intervention on maternal GI , nutritional intake and gestational weight gain ( GWG ) during pregnancy . Compliance and acceptability of the low GI diet was also examined . Method Eight hundred women were r and omised in early pregnancy to receive low GI and healthy eating dietary advice or to receive st and ard maternity care . The intervention group received dietary advice at a group education session before 22 weeks gestation . All women completed a 3 day food diary during each trimester of pregnancy . Two hundred and thirty five women from the intervention arm and 285 women from the control arm returned complete 3x3d FDs and were included in the present analysis . Results Maternal GI was significantly reduced in the intervention group at trimester 2 and 3 . The numbers of women within the lowest quartile of GI increased from 37 % in trimester 1 to 52 % in trimester 3 ( P < 0.001 ) among the intervention group . The intervention group had significantly lower energy intake ( P < 0.05 ) , higher protein ( % TE ) ( P < 0.01 ) and higher dietary fibre intake ( P < 0.01 ) post intervention . Consumption of food groups with known high GI values were significantly reduced among the intervention group . Women in the intervention low GI group were less likely to exceed the Institute of Medicine ’s GWG goals . Conclusion A dietary intervention in early pregnancy had a positive influence on maternal GI , food and nutrient intakes and GWG . Following a low GI diet may be particularly beneficial for women at risk of exceeding the GWG goals for pregnancy . Trial registration Current Controlled Trials Registration Number : IS RCT N54392969 [20128938] The perinatal nutritional environment impacts upon the health and well-being of mother and child also in the long term . The aim of the present study was to determine the safety and efficacy of perinatal probiotic-supplemented dietary counselling by evaluating pregnancy outcome and fetal and infant growth during the 24 months ' follow-up . Altogether , 256 women were r and omised at their first trimester of pregnancy into a control and a dietary intervention group . The intervention group received intensive dietary counselling provided by a nutritionist and were further r and omised , double-blind to receive probiotics ( Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12 ; diet/probiotics ) or placebo ( diet/placebo ) . Firstly , probiotic intervention reduced the frequency of gestational diabetes mellitus ( GDM ) ; 13 % ( diet/probiotics ) v. 36 % ( diet/placebo ) and 34 % ( control ) ; P = 0.003 . Secondly , the safety of this approach was attested by normal duration of pregnancies with no adverse events in mothers or children . No significant differences in prenatal or postnatal growth rates among the study groups were detected . Thirdly , distinctive effects of the two interventions were detected ; probiotic intervention reduced the risk of GDM and dietary intervention diminished the risk of larger birth size in affected cases ; P = 0.035 for birth weight and P = 0.028 for birth length . The results of the present study show that probiotic-supplemented perinatal dietary counselling could be a safe and cost-effective tool in addressing the metabolic epidemic . In view of the fact that birth size is a risk marker for later obesity , the present results are of significance for public health in demonstrating that this risk is modifiable [23187955] Background / objectives : Owing to excess body weight and increased secretion of inflammatory cytokines primarily during the third trimester , pregnancy is associated with elevated insulin resistance . To our knowledge , no report is available indicating the effects of probiotic yoghurt consumption on serum insulin levels in pregnant women . This study was design ed to determine the effects of daily consumption of probiotic yoghurt on insulin resistance and serum insulin levels of Iranian pregnant women . Subjects/ methods : In this r and omized controlled clinical trial , 70 primigravida pregnant women with singleton pregnancy at their third trimester were participated . We r and omly assigned participants to consume 200 g per day of conventional ( n=33 ) or the probiotic group ( n=37 ) for 9 weeks . The probiotic yoghurt was a commercially available product prepared with the starter cultures of Streptococcus thermophilus and Lactobacillus bulgaricus , enriched with probiotic culture of two strains of lactobacilli ( Lactobacillus acidophilus LA5 ) and bifidobacteria ( Bifidobacterium animalis BB12 ) with a total of min 1 × 107 colony-forming units . Fasting blood sample s were taken at baseline and after 9-week intervention to measure fasting plasma glucose and serum insulin levels . Homeostatic model assessment of insulin resistance ( HOMA-IR ) was used to calculate insulin resistance score . Results : Although consumption of probiotic yogurt for 9 weeks did not affect serum insulin levels and HOMA-IR score , significant differences were found comparing changes in these variables between probiotic and conventional yogurts ( changes from baseline in serum insulin levels : + 1.2±1.2 vs + 5.0±1.1 μIU/ml , respectively , P=0.02 ; and in HOMA-IR score : −0.2±0.3 vs 0.7±0.2 , respectively , P=0.01 ) . Conclusions : It is concluded that in contrast to conventional yogurt , daily consumption of probiotic yogurt for 9 weeks maintains serum insulin levels and might help pregnant women prevent developing insulin resistance [4407817] Objective Observational studies suggest that minimal gestational weight gain ( GWG ) may optimize pregnancy outcomes for obese women . This trial tested the efficacy of a group-based weight management intervention for limiting GWG among obese women . Methods We r and omized 114 obese women ( BMI [ mean±SD ] 36.7±4.9 kg/m2 ) between 7–21 weeks ’ ( 14.9±2.6 ) gestation to intervention ( n=56 ) or usual care control conditions ( n=58 ) . The intervention included individualized calorie goals , advice to maintain weight within 3 % of r and omization and follow the Dietary Approaches to Stop Hypertension dietary pattern without sodium restriction , and attendance at weekly group meetings until delivery . Control participants received one-time dietary advice . Our three main outcomes were maternal weight change from r and omization to 2 weeks postpartum and from r and omization to 34 weeks gestation , and newborn large-for-gestational age ( birth weight > 90th percentile , LGA ) . Results Intervention participants gained less weight from r and omization to 34 weeks gestation ( 5.0 vs 8.4 kg , mean difference=−3.4 kg , 95 % CI [ −5.1 , −1.8 ] ) , and from r and omization to 2 weeks postpartum ( −2.6 vs + 1.2 kg , mean difference=−3.8 kg , 95 % CI [ −5.9 , −1.7 ] ) . They also had a lower proportion of LGA babies ( 9 % vs. 26 % , odds ratio=0.28 , 95 % CI [ 0.09 , 0.84 ] ) . Conclusions The intervention result ed in lower GWG and lower prevalence of LGA newborns [22093485] As part of a feasibility study to prevent gestational diabetes mellitus ( GDM ) , we evaluated the effect of an intensive dietary therapy on quality of diet , weight gain and birth weight in women at high risk of GDM . Women with risk factors for GDM ( n 54 ) were r and omly assigned from April 2005 to May 2006 to a lifestyle intervention group ( n 27 ) including dietary advice six times during pregnancy or to a close follow-up group ( n 27 ) in a community-based setting in Finl and . Dietary intake was recorded three times during pregnancy using 4 d food records . The main outcome was the incidence of GDM . The secondary outcomes were the changes in nutrient intake , weight gain and birth weight . Overall , seventeen ( 65 % ) women in the intervention group and eighteen ( 69 % ) women in the close follow-up group returned all three food records . PUFA intake increased ( P = 0·008 ) during pregnancy in the intervention as compared to the close follow-up group . There were no clear differences in the changes of saturated fat or fibre intake between the groups . Intensive dietary education result ed in a somewhat lower weight gain during pregnancy ( P = 0·062 ) and higher birth weights of the infants ( P = 0·047 ) without an effect on macrosomia as compared to the close follow-up group . Individualised counselling by a clinical nutritionist as part of a lifestyle intervention improved the quality of dietary fat intake in pregnant women at high risk of GDM [26757351] Outcomes in gestational diabetes Cochrane protocol s and review s before and after development of ‘ st and ard outcomes ’ by WOMBAT ( WOMen and Babies health and well‐being : Action through Trials ) were surveyed . An increase in ‘ common ’ outcomes ( those prespecified by ≥50 % of the protocol s and review s ) over time was observed ( 2001–2009 : 27 vs 2010–2014 : 46 ) . There were discrepancies in outcomes prespecified in review s and reported by r and omised trials . Efforts are needed to develop a core outcome set , to reduce research waste and improve health outcomes [24284438] BACKGROUND Excessive weight gain during pregnancy is a risk factor for postpartum weight retention and future weight gain and obesity . Whether a behavioral intervention in pregnancy can reduce long-term weight retention is unknown . OBJECTIVE This r and omized trial tested whether a low-intensity behavioral intervention to prevent excessive gestational weight gain could increase the proportion of women who returned to prepregnancy weight by 12 mo postpartum . DESIGN Women ( n = 401 , 13.5 wk of gestation , 50 % normal weight , 50 % overweight/obese ) were r and omly assigned into an intervention or control group ; 79 % completed the 12-mo assessment . The telephone-based intervention targeted gestational weight gain , healthy eating , and exercise and was discontinued at delivery . RESULTS In modified intent-to-treat analyses that excluded women with miscarriages ( n = 6 ) , gestational diabetes ( n = 32 ) , or subsequent pregnancies ( n = 32 ) , the intervention had no significant effect on the odds of achieving prepregnancy weight at 12 mo postpartum ( n = 331 ; 35.4 % compared with 28.1 % ; P = 0.18 ) . Completer analyses suggested that the intervention tended to increase the percentages of women who reached prepregnancy weight ( n = 261 ; 45.3 % compared with 35.3 % ; P = 0.09 ) and significantly reduced the magnitude of mean ± SD postpartum weight retained ( 1.4 ± 6.3 compared with 3.0 ± 5.7 kg ; P = 0.046 ) at 12 mo . Women in the intervention group reported higher dietary restraint through 6 mo postpartum ( P = 0.023 ) and more frequent self-monitoring of body weight ( P < 0.02 for all ) throughout the study . CONCLUSIONS A low-intensity behavioral intervention in pregnancy can reduce 12-mo postpartum weight retention and improve dietary restraint and self-weighing in study completers . Future research is needed to test the long-term effects of more intensive behavioral interventions in pregnancy . This trial was registered at clinical trials.gov as NCT01117961 [24896237] The present study is a secondary analysis of the ROLO study , a r and omised control trial of a low-glycaemic index ( GI ) diet in pregnancy to prevent the recurrence of fetal macrosomia . The objectives of the present study were to identify which women are most likely to respond to a low-GI dietary intervention in pregnancy with respect to three outcome measures : birth weight ; maternal glucose intolerance ; gestational weight gain ( GWG ) . In early pregnancy , 372 women had their mid-upper arm circumference recorded and BMI calculated . Concentrations of glucose , insulin and leptin were measured in early pregnancy and at 28 weeks . At delivery , infant birth weight was recorded and fetal glucose , C-peptide and leptin concentrations were measured in the cord blood . Women who benefited in terms of infant birth weight were shorter , with a lower education level . Those who maintained weight gain within the GWG guidelines were less overweight in both their first and second pregnancies , with no difference being observed in maternal height . Women who at 28 weeks of gestation developed glucose intolerance , despite the low-GI diet , had a higher BMI and higher glucose concentrations in early pregnancy with more insulin resistance . They also had significantly higher-interval pregnancy weight gain . For each analysis , women who responded to the intervention had lower leptin concentrations in early pregnancy than those who did not . These findings suggest that the maternal metabolic environment in early pregnancy is important in determining later risks of excessive weight gain and metabolic disturbance , whereas birth weight is mediated more by genetic factors . It highlights key areas , which warrant further interrogation before future pregnancy intervention studies , in particular , maternal education level and inter-pregnancy weight gain [25303998] Aims /hypothesisFried foods are frequently consumed in Western countries . However , the health effects of frequent fried food consumption in humans are not well understood . We aim ed to prospect ively examine the association between pre-pregnancy fried food consumption and risk of incident gestational diabetes mellitus ( GDM ) . Methods We included 21,079 singleton pregnancies from 15,027 women in the Nurses ' Health Study II cohort . Since 1991 and every 4 years thereafter , we collected diet information , including consumption of fried foods at home and away from home , using a vali date d food frequency question naire . We used generalised estimating equations with log-binomial models to estimate the RRs and 95 % CIs . Results We documented 847 incident GDM pregnancies during 10 years of follow-up . After adjustment for age , parity , dietary and non-dietary factors , the RRs ( 95 % CIs ) of GDM among women who consumed total fried foods 1–3 , 4–6 and ≥7 times/week , compared with those who consumed it less than once/week , were 1.13 ( 0.97 , 1.32 ) , 1.31 ( 1.08 , 1.59 ) and 2.18 ( 1.53 , 3.09 ) , respectively ( p for trend < 0.001 ) . The association persisted after further adjustment for BMI ( p for trend = 0.01 ) . When analysed separately , we found a significant association of GDM with fried food consumption away from home , but not with fried food consumption at home . Conclusions /interpretationFrequent fried food consumption , particularly away from home , was significantly associated with a greater risk of incident GDM . Our study indicates potential benefits of limiting fried food consumption in the prevention of GDM in women of reproductive age [22465256] BACKGROUND Obesity and excessive weight gain during pregnancy are associated with adverse pregnancy outcomes . Observational studies suggest that minimal or no gestational weight gain ( GWG ) may minimize the risk of adverse pregnancy outcomes for obese women . OBJECTIVE This report describes the design of Healthy Moms , a r and omized trial testing a weekly , group-based , weight management intervention design ed to help limit GWG to 3 % of weight ( measured at the time of r and omization ) among obese pregnant women ( BMI ≥30 kg/m(2 ) ) . Participants are r and omized at 10 - 20 weeks gestation to either the intervention or a single dietary advice control condition . PRIMARY OUTCOMES The study is powered for the primary outcome of total GWG , yielding a target sample size of 160 women . Additional secondary outcomes include weight change between r and omization and one-year postpartum and proportion of infants with birth weight>90th percentile for gestational age . Statistical analyses will be based on intention-to-treat . METHODS Following r and omization , all participants receive a 45-minute dietary consultation . They are encouraged to follow the Dietary Approaches to Stop Hypertension diet without sodium restriction . Intervention group participants receive an individualized calorie intake goal , a second individual counseling session and attend weekly group meetings until they give birth . Research staff assesses all participants at 34-weeks gestation and at 2-weeks and one-year postpartum with their infants . SUMMARY The Healthy Moms study is testing weight management techniques that have been used with non-pregnant adults . We aim to help obese women limit GWG to improve their long-term health and the health of their offspring [23241065] Aim ing at preventing excessive weight gain during pregnancy , 10 specific dietary recommendations are given to pregnant women in the intervention arm of the Norwegian Fit for Delivery ( FFD ) study . This paper presents the rationale and test-retest reliability of the food frequency question naire ( FFQ ) and a dietary score measuring adherence to the recommendations . The study is part of the ongoing FFD study , a r and omised , controlled , intervention study in nulliparous pregnant women . A 43-item FFQ was developed for the FFD study . A dietary score was constructed from 10 subscales corresponding to the 10 dietary recommendations . Adding the subscales yielded a score from 0 to 10 with increasing score indicating healthier dietary behaviour . The score was divided into tertiles , grouping participants into low , medium and high adherence to the dietary recommendations . Pregnant women attending ultrasound screening at about week 19 of pregnancy were asked to complete the FFQ twice , 2 weeks apart . Of 154 pregnant women completing the first question naire , 106 ( 69 % ) completed the form on both occasions and was included in the study . The test-retest correlations of the score and subscales were r = 0.68 and r = 0.56 - 0.84 , respectively ( both P ≤ 0.001 ) . There was 68 % test-retest correct classification of the score and 70 - 87 % of the subscales . In conclusion , acceptable test-retest reliability of the FFQ and the dietary score was found . The score will be used in the FFD study to measure adherence to the dietary recommendations throughout pregnancy and in the following year post-partum [23432806] Leptin regulates energy homeostasis and immune and metabolic functions . Highly elevated leptin concentrations during pregnancy may be associated with aberrations in maternal metabolism and long-term health consequences both in women and children . The objective of the present study was to evaluate whether dietary counselling , probiotic supplementation , maternal characteristics or dietary intake during pregnancy has an impact on serum leptin concentrations in women , cord blood or in children . A total of 256 pregnant women were r and omised to a control group ( n 85 ) or to receive dietary counselling with probiotics ( n 85 ) or placebo ( n 86 ) . Dietary counselling aim ed at affecting the type of fat used and to increase the amount of fibre in the women 's diet . Women 's dietary intake and serum leptin concentrations were analysed at the first and third trimesters of pregnancy and at 1 month postpartum . Furthermore , leptin concentrations were measured from the cord blood and from children 's serum at 1 and 6 months of age . Weight status and dietary composition were the key determinants of leptin concentrations . Specifically , high dietary fibre and low SFA intakes were related to low serum leptin concentrations in women . Female sex and birth weight were associated with higher infant leptin , whereas cord blood leptin was additionally affected by maternal leptin concentration and protein intake . Probiotics or dietary counselling did not affect leptin concentrations . Weight control to recommended levels and modification of diet towards higher fibre and lower SFA intakes during pregnancy may through leptin concentrations provide health benefits to both women and children [21593355] To explore the effect of maternal dietary intervention on infant essential fatty acid ( FA ) status , we conducted a prospect i ve , single-blind , r and omized nutrition intervention study . At the first trimester of pregnancy , 90 women from families with a history of allergy were r and omized either to receive intensive dietary counseling to modify dietary intake according to current recommendations or as controls . Infants ' cord and 1-mo isolated serum phospholipid FA were identified and quantified by GC . Detectable levels of eicosatrienoic acid [ ETA , 20:3(n-9 ) ] were taken as a biochemical marker for essential FA deficiency , and the DHA sufficiency index [ 22:6(n-3):22:5(n-6 ) ] and the DHA deficiency index [ 22:5(n-6):22:4(n-6 ) ] were taken as markers for DHA [ 22:6(n-3 ) ] status . The concentration of ETA was lower in cord blood in the intervention ( I ) group [ median 0.64 ( IQR 0.40 - 0.78 ) mg/L ; 2.09 ( 1.31 - 2.54 ) μmol/L ] than in the control ( C ) group [ 0.92 ( 0.54 - 1.20 ) mg/L ; 3.00 ( 1.76 - 3.92 ) μmol/L ] ( P = 0.048 ) . The proportion of ETA in total FA in the I group [ 0.73 % ( 0.48 - 0.85 % ) ] was lower than in the C group [ 0.93 % ( 0.78 - 1.22 % ) ] ( P = 0.003 ) . A higher DHA sufficiency index and lower DHA deficiency index were detected in cord blood in the I group than in the C group , although the groups did not differ in the DHA concentration or proportion of the total FA . There were no differences among groups at 1 mo for any of the variables measured . Our findings suggest a better supply of essential FA , particularly important during the period of rapid development , in infants whose mothers received dietary counseling . The results thus highlight the importance of maternal diet for child health , calling for dietary counseling for pregnant women in primary health care [25300266] Background : Obesity in pregnancy is associated with fetal macrosomia , a raised neonatal fat mass and an increased risk of obesity and poor metabolic health in childhood which persists into adulthood . The offspring of obese women are more likely to be obese than the offspring of lean women when they become pregnant themselves , perpetuating a cycle of obesity and its associated negative metabolic consequences . Increasing physical activity during pregnancy could improve insulin sensitivity and reduce the risk of maternal and offspring adverse outcomes . The UK Pregnancy Better Eating and Activity Trial ( UPBEAT ) is a trial of a complex intervention design ed to improve pregnancy outcomes through dietary changes and physical activity . Data from the pilot trial of 183 women were available for analysis . The relationship between the time spent at different physical activity levels and maternal and infant pregnancy outcomes was examined . Key Messages : Strong evidence exists that physical activity improves insulin sensitivity in non-pregnant population s , and lifestyle interventions of proven effectiveness in non-pregnant population s have been developed . Women who are active in pregnancy demonstrate better glucose control and favourable pregnancy outcomes . There is a lack of effective interventions to support obese pregnant women to be physically active . Conclusions : No difference was detected in objective ly measured physical activity between women r and omised to the intervention and control arms of the UPBEAT pilot trial . Light-intensity physical activity was lower in early pregnancy in women who delivered macrosomic infants . Maternal sedentary time at 35 - 36 weeks ' gestation was positively associated and moderate-intensity physical activity was inversely associated with neonatal abdominal circumference . Maternal physical activity is associated with infant birth weight and abdominal circumference and is an appropriate target for intervention to improve infant outcomes . The challenge remains to develop an effective intervention to support obese pregnant women to be physically active [26350393] Background / Objectives : Gestational diabetes mellitus ( GDM ) is associated with negative health effects for mother and child . The aim was to investigate the association between maternal dietary patterns and GDM.Subjects/ Methods : Prospect i ve observational study including 168 pregnant women aged 18–40 years , recruited at routine 20-week ultrasound . All participants kept a 4-day weighed food record following recruitment ( commencement : gestational weeks 19–24 ) . Principal component analysis was used to extract dietary patterns from 29 food groups . A Healthy Eating Index ( HEI ) was constructed . All women underwent an oral glucose tolerance test in weeks 23–28 . Results : One clear dietary pattern ( Eigenvalue 2.4 ) was extracted with positive factor loadings for seafood ; eggs ; vegetables ; fruits and berries ; vegetable oils ; nuts and seeds ; pasta ; breakfast cereals ; and coffee , tea and cocoa powder , and negative factor loadings for soft drinks and French fries . This pattern was labeled a prudent dietary pattern . Explained variance was 8.2 % . The prevalence of GDM was 2.3 % among women of normal weight before pregnancy ( n=86 ) and 18.3 % among overweight/obese women ( n=82 ) . The prudent dietary pattern was associated with lower risk of GDM ( OR : 0.54 ; 95 % CI : 0.30 , 0.98 ) . When adjusting for age , parity , prepregnancy weight , energy intake , weekly weight gain and total metabolic equivalent of task the association remained ( OR : 0.36 ; 95 % CI : 0.14 , 0.94 ) . Similar results were found when only including overweight or obese women ( OR : 0.31 ; 95 % CI : 0.13 , 0.75 ) . Conclusions : Adhering to a prudent dietary pattern in pregnancy was clearly associated with lower risk of GDM , especially among women already at higher risk because of overweight/obesity before pregnancy [22773616] Background . Intervention fidelity is an increasingly important method ological concept in process evaluations . In this article , the authors investigated the intervention fidelity in a r and omized controlled trial on excessive weight gain prevention in pregnancy . Method . A sample of 109 audiotaped counseling sessions , linked to 65 women in the intervention group of the New Life(style ) trial , was drawn . The following criteria were quantitatively evaluated using a fidelity checklist : ( a ) reach , ( b ) dose , ( c ) adherence to study objectives , ( d ) adherence to underlying problem-solving treatment ( PST ) theory , and ( e ) counselor competence . Results . A total of 60.4 % received all counseling sessions . The dose of intervention components was generally moderate ( 50.9 % to 60.4 % ) , and the dose of PST components was low ( 17.3 % ) . Adherence to study objectives was moderate ( 64.2 % ) and adherence to PST theory was low ( 43.2 % ) . The counselors sufficiently stimulated the participant to optimize lifestyle ( 54.2 % of the sessions ) , provided positive feedback ( 50.5 % ) , and left the initiative regarding problem solving to the participant ( 71 % ) . One of the two counselors performed significantly better on all measured criteria ( p < .001 ) . Conclusions . Intervention fidelity in the New Life(style ) trial was generally low to moderate . In future interventions , it is recommended to put more emphasis on counselor recruitment , training , and intervention protocol contents . Fellow research ers are encouraged to embed a process evaluation into all study stages , taking into account all essential process elements , and to link process outcomes to more distal , health outcomes [2835977] Summary . The metabolic effects of three diets were investigated in a r and omized study in 15 non‐pregnant women and 14 pregnant women in the third trimester ; all the women were of normal weight . After 2‐week periods of habituation to each diet , metabolic profiles were performed on st and ardized intakes . Diet 1 contained 40 % of energy as carbohydrate and 10 g dietary fibre representing typical Western intakes . Diet 2 contained 40 % energy as carbohydrate and 52 g dietary fibre and diet 3 contained 60 % of energy as carbohydrate and 84 g dietary fibre , representing typical developing world intakes . No deterioration in glucose homeostasis in pregnancy was seen on any of the three diets in contrast to previous work . On diet 1 there was a loss of insulin sensitivity in pregnancy , but not on diets 2 and 3 . The loss of insulin sensitivity which is typical of Western women in the third trimester of pregnancy and is considered to be physiological , may be a diet‐induced artefact [24351875] BACKGROUND Eating carbohydrate foods with a high glycemic index ( GI ) has been postulated to result in fetoplacental overgrowth and higher infant body fat . A diet with a low glycemic index ( LGI ) has been shown to reduce birth percentiles and the ponderal index ( PI ) . OBJECTIVES We investigated whether offering LGI dietary advice at the first antenatal visit would result in a lower fetal birth weight , birth percentile , and PI than providing healthy eating ( HE ) advice . This advice had to be presented within the re sources of routine antenatal care . DESIGN The Pregnancy and Glycemic Index Outcomes study was a 2-arm , parallel- design , r and omized , controlled trial that compared the effects of LGI dietary advice with HE advice on pregnancy outcomes . Eligible volunteers who attended for routine antenatal care at < 20 wk of gestation were r and omly assigned to either group . RESULTS A total of 691 women were enrolled , and 576 women had final data considered . In the LGI group , the GI was reduced from a mean ( ± SEM ) of 56 ± 0.3 at enrollment to 52 ± 0.3 ( P < 0.001 ) at the final assessment . There were no significant differences in primary outcomes of fetal birth weight , birth percentile , or PI . In a multivariate regression analysis , the glycemic load was the only significant dietary predictor ( P = 0.046 ) of primary outcomes but explained < 1 % of all variation . CONCLUSION A low-intensity dietary intervention with an LGI diet compared with an HE diet in pregnancy did not result in any significant differences in birth weight , fetal percentile , or PI [17181885] The aim of this study was to assess the impact of dietary counselling combined with the provision of food products on food and nutrient intake in pregnant women . We carried out a prospect i ve cohort study of healthy and atopic pregnant women ( n 209 ) , who were r and omized into dietary intervention and control groups . The intervention group received dietary counselling and food products to modify the fat composition of their diet to meet current recommendations . Three-day food records were collected during each trimester of pregnancy . Women in the intervention group consumed more vegetables , fruits , soft margarines and vegetable oils and less butter than those in the control group during the course of pregnancy ( P<0.05 ) . The main distinction between the groups in nutrient intake over the pregnancy was attributable to a higher energy intake ( % energy ) of PUFA by 0.5%energy ( 95 % CI 0.1 , 0.8 ) and to a lower intake of SFA by 0.8 % energy ( 95 % CI -1.4 , -0.4 ) in the intervention group . Dietary intake of vitamin E was 1.4 mg ( 95 % CI 0.6 , 2.2 ) , folate 20.9 microg ( 95 % CI 0.8 , 41.0 ) and ascorbic acid 19.8 mg ( 95 % CI 3.5 , 36.0 ) higher in the intervention group compared to the controls , while no differences in other nutrients were detected . Dietary counselling combined with the provision of food products during pregnancy is of importance in modifying food and nutrient intake , with potential health benefits [26178724] BACKGROUND Despite normal gestational weight gain , dietary studies in pregnant women show intakes below the recommendations for energy and micronutrients . OBJECTIVE This study compared changes in dietary intake from the second to third trimester with emphasis on energy intake and carbohydrate quality . DESIGN These post hoc analyses were based on 566 women participating in the Pregnancy and Glycemic Index Outcomes study , a r and omized controlled trial comparing the effect of low-glycemic index ( GI ) dietary advice with healthy eating advice on selected pregnancy outcomes . With the use of multilevel mixed-regression analysis , changes in total energy intake , starch , sugar , fiber intake , GI , and glycemic load ( GL ) were correlated with intake of different micronutrients . RESULTS Energy intake decreased in the third trimester , and most women did not meet the national recommended amounts for iron , folate , and dietary fiber from food sources alone . After adjustment for age , ethnicity , prepregnancy body mass index , and intervention group , change in energy intake was positively related to change in intake of all micronutrients ( P < 0.001 ) . GI , GL , and starch intake were inversely related to micronutrient intake ( P < 0.001 ) , whereas higher total sugars predicted higher intake ( P < 0.001 ) . Associations with dietary fiber were inconsistent . CONCLUSIONS Normal pregnancy can be associated with a decline in energy and micronutrient intake from diet . Low dietary GI and GL were the best predictors of a favorable micronutrient profile . This trial was registered at www.anzctr.org.au as ACTRN12610000174088 [22735030] The incidence of gestational diabetes mellitus ( GDM ) is increasing and GDM might be prevented by improving diet . Few interventions have assessed the effects of dietary counselling on dietary intake of pregnant women . This study examined the effects of dietary counselling on food habits and dietary intake of Finnish pregnant women as secondary outcomes of a trial primarily aim ing at preventing GDM . A cluster-r and omized controlled trial was conducted in 14 municipalities in Finl and , including 399 pregnant women at increased risk for developing GDM . The intervention consisted of dietary counselling focusing on dietary fat , fibre and saccharose intake at four routine maternity clinic visits . Usual counselling practice s were continued in the usual care municipalities . A vali date d 181-item food frequency question naire was used to assess changes in diet from baseline to 26 - 28 and 36 - 37 weeks gestation . The data were analysed using multilevel mixed-effects linear regression models . By 36 - 37 weeks gestation , the intervention had beneficial effects on total intake of vegetables , fruits and berries ( coefficient for between-group difference in change 61.6 g day(-1 ) , 95 % confidence interval 25.7 - 97.6 ) , the proportions of high-fibre bread of all bread ( 7.2 % units , 2.5 - 11.9 ) , low-fat cheeses of all cheeses ( 10.7 % units , 2.6 - 18.9 ) and vegetable fats of all dietary fats ( 6.1 % -units , 2.0 - 10.3 ) , and the intake of saturated fatty acids ( -0.67 energy-%-units , -1.16 to -0.19 ) , polyunsaturated fatty acids ( 0.38 energy-%-units , 0.18 - 0.58 ) , linoleic acid ( 764 mg day(-1 ) , 173 - 1354 ) and fibre ( 2.07 g day(-1 ) , 0.39 - 3.75 ) . The intervention improved diet towards the recommendations in pregnant women at increased risk for GDM suggesting the counselling methods could be implemented in maternity care [8610757] OBJECTIVE Our purpose was to assess to what extent disturbances in antepartum maternal metabolism and perinatal complications and morbidities contribute to poorer psychomotor development in offspring of diabetic mothers . STUDY DESIGN One hundred ninety-six pregnant women and their singleton offspring participated in this prospect i ve cohort-analytic study . Ninety-five women had pregestational diabetes mellitus , and 101 women had gestational diabetes mellitus . Serial estimates of circulating maternal fuels were obtained throughout each index pregnancy along with detailed records of the perinatal course and outcome . Offspring were administered the psychomotor development index of the Bayley Scales of Infant Development at age 2 years and the Bruininks-Oseretsky Test Of Motor Proficiency at ages 6 , 8 , and 9 years . Tests were performed blinded to the mother 's antepartum metabolic status , and perinatal history , and the child 's previous test scores . Partial correlations and analyses of covariance were used to control for other influences and confounds , such as family socioeconomic status , racial or ethnic origin , patient group ( i.e. , pregestational or gestational diabetes mellitus ) , and sex of child . RESULTS Children 's average score on the Bruininks-Oseretsky test at ages 6 to 9 years correlated significantly with maternal second ( p < 0.02 ) and third trimester ( p < 0.001 ) beta-hydroxybutyrate . There was also a borderline association between the children 's scores on the psychomotor development index at age 2 years and maternal third-trimester beta-hydroxybutyrate levels ( p = 0.06 ) . No other correlations approached significance . CONCLUSIONS Intrauterine metabolic experiences continue to influence the neurodevelopmental course in offspring of diabetic mothers . Prevailing practice s in diabetes management and obstetric and neonatal care appear to effectively mitigate the potential long-term effects of most perinatal complications and morbidities . Management and obstetric and neonatal care appear to effectively miltigate the potential long-term effects of most perinatal complications and morbidities [24717341] BACKGROUND Low-carbohydrate diets ( LCDs ) have been vastly popular for weight loss . The association between a low-carbohydrate dietary pattern and risk of gestational diabetes mellitus ( GDM ) remains unknown . OBJECTIVE We aim ed to prospect ively examine the association of 3 prepregnancy low-carbohydrate dietary patterns with risk of GDM . DESIGN We included 21,411 singleton pregnancies in the Nurses ' Health Study II . Prepregnancy LCD scores were calculated from vali date d food-frequency question naires , including an overall LCD score on the basis of intakes of carbohydrate , total protein , and total fat ; an animal LCD score on the basis of intakes of carbohydrate , animal protein , and animal fat ; and a vegetable LCD score on the basis of intakes of carbohydrate , vegetable protein , and vegetable fat . A higher score reflected a higher intake of fat and protein and a lower intake of carbohydrate , and it indicated closer adherence to a low-carbohydrate dietary pattern . RRs and 95 % CIs were estimated by using generalized estimating equations with log-binomial models . RESULTS We documented 867 incident GDM pregnancies during 10 y follow-up . Multivariable-adjusted RRs ( 95 % CIs ) of GDM for comparisons of highest with lowest quartiles were 1.27 ( 1.06 , 1.51 ) for the overall LCD score ( P-trend = 0.03 ) , 1.36 ( 1.13 , 1.64 ) for the animal LCD score ( P-trend = 0.003 ) , and 0.84 ( 0.69 , 1.03 ) for the vegetable LCD score ( P-trend = 0.08 ) . Associations between LCD scores and GDM risk were not significantly modified by age , parity , family history of diabetes , physical activity , or overweight status . CONCLUSIONS A prepregnancy low-carbohydrate dietary pattern with high protein and fat from animal-food sources is positively associated with GDM risk , whereas a prepregnancy low-carbohydrate dietary pattern with high protein and fat from vegetable food sources is not associated with the risk . Women of reproductive age who follow a low-carbohydrate dietary pattern may consider consuming vegetable rather than animal sources of protein and fat to minimize their risk of GDM [6315514] Summary Non-obese women in the second half of pregnancy were r and omised into a control group receiving st and ard dietary advice and a group advised to make high fibre whole-food substitutions in their diets at every opportunity . Glucose and insulin profiles were performed over 24-h periods at 29 and 35 weeks gestation when the diets were equivalent in available carbohydrate , protein and fat , but the control group ingested 12.4 g dietary fibre/24 h and the high fibre group 51.4g/24h . Glucose homeostasis was similar in both groups but there was a significant attenuation of post-pr and ial insulin secretion in the high fibre group . It is suggested that the characteristic post-pr and ial peaks of plasma insulin observed in Western pregnant women are an unphysiological response to dietary fibre depletion [24224882] Abstract We aim ed to explore whether maternal dietary counseling to increase the intake of unsaturated fatty acids ( FA ) is reflected in infant FA status . Serum cholesteryl ester ( CE ) and triacylglycerol ( TAG ) FA were analyzed from infants of 45 women r and omized to receive dietary counseling from the first trimester of pregnancy and 45 control women . Counseling result ed in a higher intake of polyunsaturated FA and a lower intake of saturated FA . The dietary intake was reflected in cord blood TAGs : the n−6 to n−3 FA ratio was lower [ mean difference −0.50 ( 95%CI −0.95 to −0.06 ) ] and the sum of n−3 FA was higher in the intervention than in the control group [ 1.46 ( 0.44 to 2.48)% of total FA ] . Reasons for the lack of changes in the cord blood CE fraction and FA fractions at 1-month remain unclear , but may indicate that the changes achieved in the maternal diet through counseling were too modest [22552037] BACKGROUND There is uncertainty regarding the efficacy of increasing n-3 long-chain PUFA ( LCPUFA ) intake during pregnancy in reducing the risk of gestational diabetes mellitus ( GDM ) and preeclampsia . OBJECTIVES The objective was to determine whether n-3 LCPUFA supplementation in pregnancy reduces the incidence of GDM or preeclampsia . A secondary objective was to assess the effect of n-3 LCPUFA supplementation on perinatal complications . DESIGN This was a double-blind , multicenter r and omized control trial-the DHA to Optimize Mother Infant Outcome ( DOMInO ) trial . Pregnant women ( n = 2399 ) of < 21 wk gestation were r and omly assigned to receive DHA-enriched fish oil ( 800 mg/d ) or vegetable oil capsules without DHA from trial entry to birth . The presence of GDM or preeclampsia was assessed through a blinded audit of medical records . Birth outcomes and prenatal complications were also assessed . RESULTS The overall incidences of GDM and preeclampsia were 8 % and 5 % , respectively , based on clinical diagnosis . The RR of GDM was 0.97 ( 95 % CI : 0.74 , 1.27 ) and of preeclampsia was 0.87 ( 95 % CI : 0.60 , 1.25 ) , and they did not differ significantly between the groups . Birth weight , length , and head circumference z scores also did not differ between the groups . There were 12 perinatal deaths and 5 neonatal convulsions in the control group compared with 3 perinatal deaths and no neonatal convulsions in the DHA group ( P = 0.03 in both cases ) . CONCLUSION DHA supplementation of 800 mg/d in the second half of pregnancy does not reduce the risk of GDM or preeclampsia . Whether supplementation reduces the risk of perinatal death and neonatal convulsions requires further investigation . The DOMInO trial was registered with the Australian New Zeal and Clinical Trials Registry as TRN12605000569606 [2923097] Background Annual prevalence of gestational diabetes mellitus ( GDM ) is 12.5 % among Finnish pregnant women . The prevalence is expected to rise with the increasing overweight among women before pregnancy . Physical activity and diet are both known to have favourable effects on insulin resistance and possibly on the risk of GDM . We aim ed to investigate , whether GDM can be prevented by counseling on diet , physical activity and gestational weight gain during pregnancy . Methods / Design A cluster-r and omized controlled trial was conducted in 14 municipalities in the southern part of Finl and . Pairwise r and omization was performed in order to take into account socioeconomic differences . Recruited women were at 8 - 12 weeks ' gestation and fulfilled at least one of the following criteria : body mass index ≥ 25 kg/m2 , history of earlier gestational glucose intolerance or macrosomic newborn ( > 4500 g ) , age ≥ 40 years , first or second degree relative with history of type 1 or 2 diabetes . Main exclusion criterion was pathological oral glucose tolerance test ( OGTT ) at 8 - 12 weeks ' gestation . The trial included one counseling session on physical activity at 8 - 12 weeks ' gestation and one for diet at 16 - 18 weeks ' gestation , and three to four booster sessions during other routine visits . In the control clinics women received usual care . Information on height , weight gain and other gestational factors was obtained from maternity cards . Physical activity , dietary intake and quality of life were followed by question naires during pregnancy and at 1-year postpartum . Blood sample s for lipid status , hormones , insulin and OGTT were taken at 8 - 12 and 26 - 28 weeks ' gestation and 1 year postpartum . Workability and return to work were elicited by a question naire at 1- year postpartum . Linkage to the national birth register of years 2007 - 2009 will provide information on perinatal complications and GDM incidence among the non- participants of the study . Cost-effectiveness evaluation will be based on quality -adjusted life years . This study has received ethical approval from the Ethical board of Pirkanmaa Hospital District . Discussion The study will provide information on the effectiveness and cost-effectiveness of gestational physical activity and dietary counseling on prevention of GDM in a risk group of women . Also information on the prevalence of GDM and postpartum metabolic syndrome will be gained . Results on maintaining the possible health behaviour changes are important in order to prevent chronic diseases such as cardiovascular disease and diabetes . Trial registration The trial is registered IS RCT N [24443392] OBJECTIVE Large for gestational age infants are at increased risk of childhood obesity and maternal nutrition impacts birthweight . The aim of this study was to assess the impact of a maternal low glycaemic index ( GI ) diet on neonatal anthropometry . METHODS The ROLO ( R and omised Control Trial of Low Glycaemic Index Diet in Pregnancy ) study was a r and omized controlled trial to assess the impact of a low GI diet versus usual diet on birthweight . It took place in a tertiary maternity hospital in Irel and and women were r and omized to receive either a low GI diet or no dietary intervention from early pregnancy to term . Two hundred sixty-five neonates had anthropometric measurements on day 1 - 2 of life , 126 in the intervention group and 139 in the control group . Measurements included birthweight , length and circumferences of the head , chest , abdominal , thigh and mid-upper arm . A subgroup of 219 ( 82 % ) neonates also had skin-fold measurements . RESULTS Neonates whose mothers had a low GI diet in pregnancy had lower thigh circumference ( 15.9 ± 1.7 cm vs. 16.6 ± 1.5 cm , P = 0.04 ) . There was no difference between the intervention and control groups in head , chest abdominal or mid-upper arm circumferences . No difference was noted between the two groups for any skin-fold measurements ( subscapular , thigh , biceps and triceps ) . CONCLUSION Neonatal thigh circumference was altered by maternal low GI diet in pregnancy . These findings suggest that maternal low GI diet is safe in pregnancy and may positively impact infant adiposity [26876000] OBJECTIVE To investigate the relationship between gestational diabetes mellitus ( GDM ) and the usual intake of fatty acids and indices of dietary fat quality [ the atherogenicity ( AI ) and thrombogenicity indices ( TI ) , and the ratios of hypo- and hypercholesterolemic ( hH ) , ∑n-3/∑n-6 , and polyunsaturated/saturated fatty acids ( P : S ) ] , during mid-pregnancy . METHODS 799 adult pregnant women living in Ribeirão Preto , SP , Brazil were screened and accepted for this cross-sectional GDM study . The Multiple Source Method was used to estimate participants ' usual diet , using two 24-hour dietary recalls during mid-pregnancy . Diagnosis of GDM was defined by the American Diabetes Association criteria of 2015 . Logistic regression analysis were used to assess the association between GDM and dietary fat , adjusted for age , education , parity , gestational age at the time of the interview , pre-pregnancy and current BMI , prior GDM , family history of diabetes , smoking , physical activity , energy , fiber , and fatty acids . RESULTS The mean ( st and ard deviation ) age of the women was 28 ( 5 ) years , and 19 % had GDM . After multiple adjustments , inverse associations between the highest tertile of ∑n-3 fatty acids intake [ 0.21 ( 0.08 - 0.56 ) ] , α-linolenic intake [ 0.15 ( 0.05 - 0.42 ) ] , and GDM were found . A positive association between GDM and the highest tertile of TI [ 2.66 ( 1.34 - 5.29 ) ] , and a negative association with the highest tertile of hH ratio [ 0.41 ( 0.22 - 0.77 ) ] , were observed . No association between GDM and other indices of dietary fat quality were found . CONCLUSION The quality of dietary fat during pregnancy is strongly associated with GDM . R and omized clinical trial are needed to confirm these findings [3096610] In a cluster-r and omized trial , Riitta Luoto and colleagues find that counseling on diet and activity can reduce the birthweight of babies born to women at risk of developing gestational diabetes mellitus ( GDM ) , but fail to find an effect on GDM [21310836] BACKGROUND Excessive weight gain during pregnancy is a major risk factor for postpartum weight retention and future weight gain and obesity in women , but few adequately powered r and omized controlled trials have examined the efficacy of a behavioral weight-control intervention during pregnancy . OBJECTIVE This study examined whether a behavioral intervention during pregnancy could decrease the proportion of women who exceeded the 1990 Institute of Medicine ( IOM ) recommendations for gestational weight gains and increase the proportion of women who returned to pregravid weights by 6 mo postpartum . DESIGN This study was a r and omized , assessor-blind , controlled trial . Participants were pregnant ( 13.5 wk gestation ) , normal-weight ( NW ; n = 201 ) and overweight or obese ( OW/OB ; n = 200 ) women whose average age was 28.8 y. Participants were r and omly assigned within the 1990 IOM weight category ( NW compared with OW/OB ) to st and ard care ( n = 200 ) or to a behavioral intervention to prevent excessive gestational weight gain ( n = 201 ) . The intervention included one face-to-face visit ; weekly mailed material s that promoted an appropriate weight gain , healthy eating , and exercise ; individual graphs of weight gain ; and telephone-based feedback . The retention at the 6-mo postpartum assessment was 82 % . RESULTS Intent-to-treat analyses showed that the intervention , compared with st and ard care , decreased the percentage of NW women who exceeded IOM recommendations ( 40.2 % compared with 52.1 % ; P = 0.003 ) and increased the percentages of NW and OW/OB women who returned to their pregravid weights or below by 6 mo postpartum ( 30.7 % compared with 18.7 % ; P = 0.005 ) . CONCLUSION A low-intensity behavioral intervention during pregnancy reduced excessive gestational weight gains in NW women and prevented postpartum weight retention in NW and OW/OB women . This trial was registered at clinical trials.gov as NCT01117961

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### Context: [3120197] OBJECTIVE Higher heme iron intake is associated with increased type 2 diabetes risk . However , no previous study has evaluated gestational diabetes mellitus ( GDM ) risk in relation to heme iron intake during pregnancy . We investigated associations of maternal preconceptional and early pregnancy heme and nonheme iron intake with subsequent GDM risk . RESEARCH DESIGN AND METHODS We conducted a prospect i ve cohort study of 3,158 pregnant women . A food frequency question naire was used to assess maternal diet . Multivariable generalized linear regression models were used to derive estimates of relative risks ( RRs ) and 95 % CIs . RESULTS Approximately 5.0 % of the cohort developed GDM ( n = 158 ) . Heme iron intake was positively and significantly associated with GDM risk ( Ptrend = 0.04 ) . After adjusting for confounders , women reporting the highest heme iron intake levels ( ≥1.52 vs. < 0.48 mg per day ) experienced a 3.31-fold – increased GDM risk ( 95 % CI 1.02–10.72 ) . In fully adjusted models , we noted that a 1-mg per day increase in heme iron was associated with a 51 % increased GDM risk ( RR 1.51 [ 95 % CI 0.99–2.36 ] ) . Nonheme iron was inversely , though not statistically significantly , associated with GDM risk , and the corresponding RRs were 1.00 , 0.83 , 0.62 , and 0.61 across quartiles of nonheme iron intake ( Ptrend = 0.08 ) . CONCLUSIONS High levels of dietary heme iron intake during the preconceptional and early pregnancy period may be associated with increased GDM risk . Associations of GDM risk with dietary nonheme iron intake are less clear . Confirmation of these findings by future studies is warranted [3120196] OBJECTIVE It is important to identify modifiable factors that may lower gestational diabetes mellitus ( GDM ) risk . Dietary iron is of particular interest given that iron is a strong prooxidant , and high body iron levels can damage pancreatic β-cell function and impair glucose metabolism . The current study is to determine if prepregnancy dietary and supplemental iron intakes are associated with the risk of GDM . RESEARCH DESIGN AND METHODS A prospect i ve study was conducted among 13,475 women who reported a singleton pregnancy between 1991 and 2001 in the Nurses ’ Health Study II . A total of 867 incident GDM cases were reported . Pooled logistic regression was used to estimate the relative risk ( RR ) of GDM by quintiles of iron intake controlling for dietary and nondietary risk factors . RESULTS Dietary heme iron intake was positively and significantly associated with GDM risk . After adjusting for age , BMI , and other risk factors , RRs ( 95 % CIs ) across increasing quintiles of heme iron were 1.0 ( reference ) , 1.11 ( 0.87–1.43 ) , 1.31 ( 1.03–1.68 ) , 1.51 ( 1.17–1.93 ) , and 1.58 ( 1.21–2.08 ) , respectively ( P for linear trend 0.0001 ) . The multivariate adjusted RR for GDM associated with every 0.5-mg per day of increase in intake was 1.22 ( 1.10–1.36 ) . No significant associations were observed between total dietary , nonheme , or supplemental iron intake and GDM risk . CONCLUSIONS These findings suggest that higher prepregnancy intake of dietary heme iron is associated with an increased GDM risk [3565864] Background The costs of gestational diabetes mellitus ( GDM ) screening have been frequently reported , but total GDM-related health care costs compared to the health care costs of women without GDM have not been reported . The aim of this study was to analyse GDM-related health care costs among women with an elevated risk of GDM . Methods The study was based on a cluster-r and omised GDM prevention trial ( N = 848 ) carried out at maternity clinics , combined with data from the Finnish Medical Birth Register and Care Registers for Social Welfare and Health Care . Costs of outpatient visits to primary and secondary care , cost of inpatient hospital care before and after delivery , the use of insulin , delivery costs and babies ’ stay in the neonatal intensive care unit were analysed . Women who developed GDM were compared to those who were not diagnosed with GDM . Results Total mean health care costs adjusted for age , body mass index and education were 25.1 % higher among women diagnosed with GDM ( € 6,432 vs. € 5,143 , p < 0.001 ) than among women without GDM . The cost of inpatient visits was 44 % higher and neonatal intensive care unit use was 49 % higher in the GDM group than among women without GDM . The delivery costs were the largest single component in both groups . Conclusions A confirmed GDM diagnosis was associated with a significant increase in total health care costs . Effective lifestyle counselling by primary health care providers may offer a means of reducing the high costs of secondary care [25438930] Pregnancy presents a unique époque in life with considerable potential to influence not only maternal health but also the health of the next generation . Nutritional interventions in pregnancy can influence maternal , foetal and infant health . This chapter describes the findings of a large r and omised controlled trial on the impact of a low glycaemic index diet on maternal and foetal health and discusses areas of future research in this important area [4352291] Background Maternal obesity is associated with an increased risk of pregnancy complications , including gestational diabetes . Physical activity ( PA ) might improve glucose metabolism and reduce the incidence of gestational diabetes . The purpose of this study was to explore patterns of PA and factors associated with change in PA in obese pregnant women . Methods PA was assessed objective ly by accelerometer at 16 – 18 weeks ’ ( T0 ) , 27 – 28 weeks ’ ( T1 ) and 35 – 36 weeks ’ gestation ( T2 ) in 183 obese pregnant women recruited to a pilot r and omised trial of a combined diet and PA intervention ( the UPBEAT study ) . Results Valid PA data were available for 140 ( 77 % ) , 76 ( 42 % ) and 54 ( 30 % ) women at T0 , T1 and T2 respectively . Moderate and vigorous physical activity as a proportion of accelerometer wear time declined with gestation from a median of 4.8 % at T0 to 3 % at T2 ( p < 0.05 ) . Total activity as a proportion of accelerometer wear time did not change . Being more active in early pregnancy was associated with a higher level of PA later in pregnancy . The intervention had no effect on PA . Conclusions PA in early pregnancy was the factor most strongly associated with PA at later gestations . Women should be encouraged to participate in PA before becoming pregnant and to maintain their activity levels during pregnancy . There is a need for effective interventions , tailored to the needs of individuals and delivered early in pregnancy to support obese women to be sufficiently active during pregnancy . Trial registration Current Controlled Trials IS RCT N89971375 ( Registered 28/11/2008 ) [3938821] Background Despite the widespread recognition that obesity in pregnant women is associated with adverse outcomes for mother and child , there is no intervention proven to reduce the risk of these complications . The primary aim of this r and omised controlled trial is to assess in obese pregnant women , whether a complex behavioural intervention , based on changing diet ( to foods with a lower glycemic index ) and physical activity , will reduce the risk of gestational diabetes ( GDM ) and delivery of a large for gestational age ( LGA ) infant . A secondary aim is to determine whether the intervention lowers the long term risk of obesity in the offspring . Methods / Design Multicentre r and omised controlled trial comparing a behavioural intervention design ed to improve glycemic control with st and ard antenatal care in obese pregnant women . Inclusion criteria ; women with a BMI ≥30 kg/m2 and a singleton pregnancy between 15 + 0 weeks and 18 + 6 weeks ’ gestation . Exclusion criteria ; pre-defined , pre-existing diseases and multiple pregnancy . R and omisation is on-line by a computer generated programme and is minimised by BMI category , maternal age , ethnicity , parity and centre . Intervention ; this is delivered by a health trainer over 8 sessions . Based on control theory , with elements of social cognitive theory , the intervention is design ed to improve maternal glycemic control . Women r and omised to the control arm receive st and ard antenatal care until delivery according to local guidelines . All women have a 75 g oral glucose tolerance test at 27 + 0- 28 + 6 weeks ’ gestation . Primary outcome ; Maternal : diagnosis of GDM , according to the International Association of Diabetes in Pregnancy Study Group ( IADPSG ) criteria . Neonatal ; infant LGA defined as > 90th customised birth weight centile . Sample size ; 1546 women to provide 80 % power to detect a 25 % reduction in the incidence of GDM and a 30 % reduction in infants large for gestational age . Discussion All aspects of this protocol have been evaluated in a pilot r and omised controlled trial , with subsequent optimisation of the intervention . The findings of this trial will inform whether lifestyle mediated improvement of glycemic control in obese pregnant women can minimise the risk of pregnancy complications . Trial registration Current controlled trials ; IS RCT N89971375 [4124499] Background The in utero environment is known to affect fetal development however many of the mechanisms by which this occurs remain unknown . The aim of this study was to examine the association between maternal dietary macronutrient intake and lifestyle throughout pregnancy and neonatal weight and adiposity . Methods This was an analysis of 542 mother and infant pairs from the ROLO study ( R and omised cOntrol trial of LOw glycaemic index diet versus no dietary intervention to prevent recurrence of fetal macrosomia ) . Food diaries as well as food frequency and lifestyle and physical activity question naires were completed during pregnancy . Maternal anthropometry was measured throughout pregnancy and neonatal anthropometry was measured at birth . Results Multiple linear regression analysis revealed the main maternal factor associated with increased birth weight was greater gestational weight gain R2adj23.3 % ( F = 11.547 , p < 0.001 ) . The main maternal factor associated with increased birth length was non-smoking status R2adj27.8 % ( F = 6.193 , p < 0.001 ) . Neonatal central adiposity ( determined using waist : length ratio ) was negatively associated with maternal age , and positively associated with the following parameters : smoking status , maternal pre-pregnancy arm circumference , percentage energy from saturated fat in late pregnancy , postpr and ial glucose at 28 weeks gestation and membership of the control group with a positive trend towards association with trimester 2 glycaemic load R2adj 38.1 % ( F = 8.000 , p < 0.001 ) . Conclusions Several maternal diet and lifestyle factors were associated with neonatal anthropometry . Low glycaemic index dietary intervention in pregnancy was found to have a beneficial effect on neonatal central adiposity . Additionally , central adiposity was positively associated with maternal dietary fat intake and postpr and ial glucose highlighting the important role of healthy diet in pregnancy in promoting normal neonatal adiposity . Trial registration Current Controlled Trials IS RCT N54392969 [21324948] Higher egg and cholesterol intakes are associated with increased risk of type 2 diabetes mellitus . However , their association with gestational diabetes mellitus ( GDM ) has not been evaluated . The authors assessed such associations in both a prospect i ve cohort study ( 1996 - 2008 ; 3,158 participants ) and a case-control study ( 1998 - 2002 ; 185 cases , 411 controls ) . A food frequency question naire was used to assess maternal diet . Multivariable models were used to derive relative risks and 95 % confidence intervals . Compared with no egg consumption , adjusted relative risks for GDM were 0.94 , 1.01 , 1.12 , 1.54 , and 2.52 for consumption of ≤1 , 2 - 3 , 4 - 6 , 7 - 9 , and ≥10 eggs/week , respectively ( P for trend=0.008 ) . Women with high egg consumption ( ≥7/week ) had a 1.77-fold increased risk compared with women with lower consumption ( 95 % confidence interval ( CI ) : 1.19 , 2.63 ) . The relative risk for the highest quartile of cholesterol intake ( ≥294 mg/day ) versus the lowest ( < 151 mg/day ) was 2.35 ( 95 % CI : 1.35 , 4.09 ) . In the case-control study , the adjusted odds ratio for consuming ≥7 eggs/week versus < 7 eggs/week was 2.65 ( 95 % CI : 1.48 , 4.72 ) , and the odds of GDM increased with increasing cholesterol intake ( P for trend=0.021 ) . In conclusion , high egg and cholesterol intakes before and during pregnancy are associated with increased risk of GDM [19017418] Balanced glucose metabolism ensures optimal fetal growth with long-term health implication s conferred on both mother and child . We examined whether supplementation of probiotics with dietary counselling affects glucose metabolism in normoglycaemic pregnant women . At the first trimester of pregnancy 256 women were r and omised to receive nutrition counselling to modify dietary intake according to current recommendations or as controls ; the dietary intervention group was further r and omised to receive probiotics ( Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12 ; diet/probiotics ) or placebo ( diet/placebo ) in a double-blind manner , whilst the control group received placebo ( control/placebo ) . Blood glucose concentrations were lowest in the diet/probiotics group during pregnancy ( baseline-adjusted means 4.45 , 4.60 and 4.56 mmol/l in diet/probiotics , diet/placebo and control/placebo , respectively ; P = 0.025 ) and over the 12 months ' postpartum period ( baseline-adjusted means 4.87 , 5.01 and 5.02 mmol/l ; P = 0.025 ) . Better glucose tolerance in the diet/probiotics group was confirmed by a reduced risk of elevated glucose concentration compared with the control/placebo group ( OR 0.31 ( 95 % CI 0.12 , 0.78 ) ; P = 0.013 ) as well as by the lowest insulin concentration ( adjusted means 7.55 , 9.32 and 9.27 mU/l ; P = 0.032 ) and homeostasis model assessment ( adjusted means 1.49 , 1.90 and 1.88 ; P = 0.028 ) and the highest quantitative insulin sensitivity check index ( adjusted means 0.37 , 0.35 and 0.35 ; P = 0.028 ) during the last trimester of pregnancy . The effects observed extended over the 12-month postpartum period . The present study demonstrated that improved blood glucose control can be achieved by dietary counselling with probiotics even in a normoglycaemic population and thus may provide potential novel means for the prophylactic and therapeutic management of glucose disorders [3431285] Objective To determine if a low glycaemic index diet in pregnancy could reduce the incidence of macrosomia in an at risk group . Design R and omised controlled trial . Setting Maternity hospital in Dublin , Irel and . Participants 800 women without diabetes , all in their second pregnancy between January 2007 to January 2011 , having previously delivered an infant weighing greater than 4 kg . Intervention Women were r and omised to receive no dietary intervention or start on a low glycaemic index diet from early pregnancy . Main outcomes The primary outcome measure was difference in birth weight . The secondary outcome measure was difference in gestational weight gain . Results No significant difference was seen between the two groups in absolute birth weight , birthweight centile , or ponderal index . Significantly less gestational weight gain occurred in women in the intervention arm ( 12.2 v 13.7 kg ; mean difference −1.3 , 95 % confidence interval −2.4 to −0.2 ; P=0.01 ) . The rate of glucose intolerance was also lower in the intervention arm : 21 % ( 67/320 ) compared with 28 % ( 100/352 ) of controls had a fasting glucose of 5.1 mmol/L or greater or a 1 hour glucose challenge test result of greater than 7.8 mmol/L ( P=0.02 ) . Conclusion A low glycaemic index diet in pregnancy did not reduce the incidence of large for gestational age infants in a group at risk of fetal macrosomia . It did , however , have a significant positive effect on gestational weight gain and maternal glucose intolerance . Trial registration Current Controlled Trials IS RCT N54392969 [24122103] Oxidized LDL lipids ( ox-LDL ) are associated with lifestyle diseases such as cardiovascular diseases , metabolic syndrome and type 2 diabetes . The present study investigated how postpartum weight retention effects on ox-LDL and serum lipids . The study is a nested comparative research of a cluster-r and omized controlled trial , NELLI ( lifestyle and counselling during pregnancy ) . During early pregnancy ( 8–12 weeks ) and 1 year postpartum , 141 women participated in measurements for determining of plasma lipids : total cholesterol ( T-C ) , LDL-cholesterol ( LDL-C ) , HDL-cholesterol ( HDL-C ) , triacylglycerols ( TAG ) and ox-LDL . Subjects were stratified into tertiles ( weight loss , unaltered weight and weight gain groups ) based on their weight change from baseline to follow-up . Ox-LDL was determined by baseline level of conjugated dienes in LDL lipids . Among the group of weight gainers , concentration of TAG reduced less ( −0.14 vs. −0.33 , p = 0.002 ) , HDL-C reduced more ( −0.31 vs. −0.16 , p = 0.003 ) and ox-LDL/HDL-C ratio increased ( 3.0 vs. −0.2 , p = 0.003 ) when compared to group of weight loss . Both T-C and LDL-C elevated more ( 0.14 vs. −0.21 , p = 0.008 ; 0.31 vs. 0.07 , p = 0.015 ) and TAG and ox-LDL reduced less ( −0.33 vs. 0.20 , p = 0.033 ; −3.33 vs. −0.68 , p = 0.026 ) in unaltered weight group compared to weight loss group . The women who gained weight developed higher TAG and ox-LDL/HDL-C ratio as compared to those who lost weight . Postpartum weight retention of 3.4 kg or more is associated with atherogenic lipid profile [24271261] To our knowledge , no reports are available indicating the effects of synbiotic food consumption on blood lipid profiles and biomarkers of oxidative stress among pregnant women . This study was conducted to evaluate the effects of daily consumption of a synbiotic food on blood lipid profiles and biomarkers of oxidative stress in pregnant women . This r and omized , double-blind , controlled clinical trial was performed among 52 primigravida pregnant women , aged 18 to 35-year-old at their third trimester . After a 2-week run-in period , subjects were r and omly assigned to consume either a synbiotic ( n = 26 ) or control food ( n = 26 ) for 9 weeks . The synbiotic food consisted of a probiotic viable and heat-resistant Lactobacillus sporogenes ( 1 × 107 CFU ) and 0.04 g inulin (HPX)/g as the prebiotic . Patients were asked to consume the synbiotic and control foods two times a day . Biochemical measurements including blood lipid profiles , plasma total antioxidant capacity ( TAC ) and total glutathione ( GSH ) were conducted before and after 9 weeks of intervention . Consumption of a synbiotic food for 9 weeks result ed in a significant reduction in serum TAG ( P = 0.04 ) , VLDL ( P = 0.04 ) and a significant rise in plasma GSH levels ( P = 0.004 ) compared to the control food . No significant effects of the synbiotic food consumption on serum TC , LDL , HDL and plasma TAC levels ( P > 0.05 ) were observed . Trial registry code : http://www.i rct .ir . I RCT 201212105623N3 [6259925] The determine the effect of different foods on the blood glucose , 62 commonly eaten foods and sugars were fed individually to groups of 5 to 10 healthy fasting volunteers . Blood glucose levels were measured over 2 h , and expressed as a percentage of the area under the glucose response curve when the same amount of carbohydrate was taken as glucose . The largest rises were seen with vegetables ( 70 + /- 5 % ) , followed by breakfast cereals ( 65 + /- 5 % ) , cereals and biscuits ( 60 + /- 3 % ) , fruit ( 50 + /- 5 % ) , dairy products ( 35 + /- 1 % ) , and dried legumes ( 31 + /- 3 % ) . A significant negative relationship was seen between fat ( p less than 0.01 ) and protein ( p less than 0.001 ) and postpr and ial glucose rise but not with fiber or sugar content [22218158] BACKGROUND Fatty acids play a vital role in glucose homeostasis ; however , studies on habitual dietary fat intakes and gestational diabetes mellitus ( GDM ) risk are limited and provide conflicting findings . OBJECTIVE We determined whether the total amount and the type and source of prepregnancy dietary fats are related to risk of GDM . DESIGN A prospect i ve study was conducted in 13,475 women who reported a singleton pregnancy between 1991 and 2001 in the Nurses ' Health Study II . In these women , 860 incident GDM cases were reported . The adjusted RR of GDM was estimated for quintiles of total fat , specific fat , and the source of fat intakes by pooled logistic regression . RESULTS Higher animal fat and cholesterol intakes were significantly associated with increased GDM risk . Across increasing quintiles of animal fat , RRs ( 95 % CIs ) for GDM were 1.00 ( reference ) , 1.55 ( 1.20 , 1.98 ) , 1.43 ( 1.09 , 1.88 ) , 1.40 ( 1.04 , 1.89 ) , and 1.88 ( 1.36 , 2.60 ) ( P-trend = 0.05 ) . Corresponding RRs ( 95 % CIs ) for dietary cholesterol were 1.00 ( reference ) , 1.08 ( 0.84 , 1.32 ) , 1.02 ( 0.78 , 1.29 ) , 1.20 ( 0.93 , 1.55 ) , and 1.45 ( 1.11 , 1.89 ) ( P-trend = 0.04 ) . The substitution of 5 % of energy from animal fat for an equal percentage of energy from carbohydrates was associated with significantly increased risk of GDM [ RR ( 95 % CI ) : 1.13 ( 1.08 , 1.18 ) ; P < 0.0001 ] . No significant associations were observed between dietary polyunsaturated fat , monounsaturated fat , or trans fat intakes and GDM risk . CONCLUSION Higher prepregnancy intakes of animal fat and cholesterol were associated with elevated GDM risk [23182924] BACKGROUND AND AIM Early nutrition may programme blood lipid levels and thereby later cardiovascular health of children . The objective here was to evaluate the effects of maternal dietary counselling during pregnancy and breastfeeding on dietary intakes and blood lipid values in 1 - 4 year-old children . Further , the nutritional determinants of children 's lipid profiles were assessed . METHODS AND RESULTS Mothers were r and omised into dietary counselling or control groups at the first trimester of pregnancy . Their children were followed up clinical ly at 1 , 2 and 4 years of age , by three-day food records and analyses of total cholesterol , HDL cholesterol and apolipoproteins A-I and B as well as lipoprotein ( a ) . In general , the mean intake of saturated fatty acids as a proportion of total energy intake ( E% ) was higher than the recommended , while the mean intake of polyunsaturated fatty acids was low in children 's diet . Over the first years , girls had higher concentration of non-HDL cholesterol than boys ; 2.64 mmol/l ( 95 % CI 2.54 - 2.74 ) vs. 2.49 ( 2.38 - 2.60 ) ; p = 0.038 . Maternal dietary counselling was not reflected in the children 's lipid values . Children 's monounsaturated fatty acid intake ( E% ) correlated with apoA-I ( p = 0.048 ) and , furthermore , there was a negative correlation between polyunsaturated fatty acid intake ( E% ) and apoB ( p = 0.046 ) . CONCLUSION Children 's dietary fatty acid intake , but not maternal dietary counselling was shown to be related to blood apolipoproteins in children [26185283] OBJECTIVE Dietary interventions can improve pregnancy outcomes in women with gestational diabetes mellitus ( GDM ) . We compared the effect of a low – glycemic index ( GI ) versus a conventional high-fiber ( HF ) diet on pregnancy outcomes , birth weight z score , and maternal metabolic profile in women at high risk of GDM . RESEARCH DESIGN AND METHODS One hundred thirty-nine women [ mean ( SD ) age 34.7 ( 0.4 ) years and prepregnancy BMI 25.2 ( 0.5 ) kg/m2 ] were r and omly assigned to a low-GI ( LGI ) diet ( n = 72 ; target GI ∼50 ) or a high-fiber , moderate-GI ( HF ) diet ( n = 67 ; target GI ∼60 ) at 14–20 weeks ’ gestation . Diet was assessed by 3-day food records and infant body composition by air-displacement plethysmography , and pregnancy outcomes were assessed from medical records . RESULTS The LGI group achieved a lower GI than the HF group [ mean ( SD ) 50 ( 5 ) vs. 58 ( 5 ) ; P < 0.001 ] . There were no differences in glycosylated hemoglobin , fructosamine , or lipids at 36 weeks or differences in birth weight [ LGI 3.4 ( 0.4 ) kg vs. HF 3.4 ( 0.5 ) kg ; P = 0.514 ] , birth weight z score [ LGI 0.31 ( 0.90 ) vs. HF 0.24 ( 1.07 ) ; P = 0.697 ] , ponderal index [ LGI 2.71 ( 0.22 ) vs. HF 2.69 ( 0.23 ) kg/m3 ; P = 0.672 ] , birth weight centile [ LGI 46.2 ( 25.4 ) vs. HF 41.8 ( 25.6 ) ; P = 0.330 ] , % fat mass [ LGI 10 ( 4 ) vs. HF 10 ( 4 ) ; P = 0.789 ] , or incidence of GDM . CONCLUSIONS In intensively monitored women at risk for GDM , a low-GI diet and a healthy diet produce similar pregnancy outcomes [3718630] Background Complex interventions in obese pregnant women should be theoretically based , feasible and shown to demonstrate anticipated behavioural change prior to inception of large r and omised controlled trials ( RCTs ) . The aim was to determine if a ) a complex intervention in obese pregnant women leads to anticipated changes in diet and physical activity behaviours , and b ) to refine the intervention protocol through process evaluation of intervention fidelity . Methods We undertook a pilot RCT of a complex intervention in obese pregnant women , comparing routine antenatal care with an intervention to reduce dietary glycaemic load and saturated fat intake , and increase physical activity . Subjects included 183 obese pregnant women ( mean BMI 36.3 kg/m2).Diet was assessed by repeated triple pass 24-hour dietary recall and physical activity by accelerometry and question naire , at 16 + 0 to 18 + 6 and at 27 + 0 to 28 + 6 weeks ’ gestation in women in control and intervention arms . Attitudes to behaviour change and quality of life were assessed and a process evaluation undertaken . The full RCT protocol was undertaken to assess feasibility . Results Compared to women in the control arm , women in the intervention arm had a significant reduction in dietary glycaemic load ( 33 points , 95 % CI −47 to −20 ) , ( p < 0.001 ) and saturated fat intake ( −1.6 % energy , 95 % CI −2.8 to −0 . 3 ) at 28 weeks ’ gestation . Objective ly measured physical activity did not change . Physical discomfort and sustained barriers to physical activity were common at 28 weeks ’ gestation . Process evaluation identified barriers to recruitment , group attendance and compliance , leading to modification of intervention delivery . Conclusions This pilot trial of a complex intervention in obese pregnant women suggests greater potential for change in dietary intake than for change in physical activity , and through process evaluation illustrates the considerable advantage of performing an exploratory trial of a complex intervention in obese pregnant women before undertaking a large RCT .Trial registration Trial Registration Number : IS RCT [3919179] Objective To determine the effect of antenatal dietary and lifestyle interventions on health outcomes in overweight and obese pregnant women . Design Multicentre r and omised trial . We utilised a central telephone r and omisation server , with computer generated schedule , balanced variable blocks , and stratification for parity , body mass index ( BMI ) category , and hospital . Setting Three public maternity hospitals across South Australia . Participants 2212 women with a singleton pregnancy , between 10 + 0 and 20 + 0 weeks ’ gestation , and BMI ≥25 . Interventions 1108 women were r and omised to a comprehensive dietary and lifestyle intervention delivered by research staff ; 1104 were r and omised to st and ard care and received pregnancy care according to local guidelines , which did not include such information . Main outcome measures Incidence of infants born large for gestational age ( birth weight ≥90th centile for gestation and sex ) . Prespecified secondary outcomes included birth weight > 4000 g , hypertension , pre-eclampsia , and gestational diabetes . Analyses used intention to treat principles . Results 2152 women and 2142 liveborn infants were included in the analyses . The risk of the infant being large for gestational age was not significantly different in the two groups ( lifestyle advice 203/1075 ( 19 % ) v st and ard care 224/1067 ( 21 % ) ; adjusted relative risk 0.90 , 95 % confidence interval 0.77 to 1.07 ; P=0.24 ) . Infants born to women after lifestyle advice were significantly less likely to have birth weight above 4000 g ( lifestyle advice 164/1075 ( 15 % ) v st and ard care 201/1067 ( 19 % ) ; 0.82 , 0.68 to 0.99 ; number needed to treat ( NNT ) 28 , 15 to 263 ; P=0.04 ) . There were no differences in maternal pregnancy and birth outcomes between the two treatment groups . Conclusions For women who were overweight or obese , the antenatal lifestyle advice used in this study did not reduce the risk delivering a baby weighing above the 90th centile for gestational age and sex or improve maternal pregnancy and birth outcomes . Trial registration Australian and New Zeal and Clinical Trials Registry ( ACTRN12607000161426 ) [3511276] Abstract Background Women who are physically active during early pregnancy have notably lower odds of developing gestational diabetes than do inactive women . The purpose of the intervention was to examine whether intensified physical activity ( PA ) counseling in Finnish maternity care is feasible and effective in promoting leisure-time PA ( LTPA ) among pregnant women at risk of gestational diabetes . Methods Fourteen municipalities were r and omized to intervention ( INT ) and usual care group ( UC ) . Nurses in INT integrated five PA counseling sessions into routine maternity visits and offered monthly group meetings on PA instructed by physiotherapists . In UC conventional practice s were continued . Feasibility evaluation included safety ( incidence of PA-related adverse events ; question naire ) , realization ( timing and duration of sessions , number of sessions missed , attendance at group meetings ; systematic record-keeping of the nurses and physiotherapists ) and applicability ( nurses ’ views ; telephone interview ) . Effectiveness outcomes were weekly frequency and duration of total and intensity-specific LTPA and meeting PA recommendation for health self-reported at 8 - 12 ( baseline ) , 26 - 28 and 36 - 37 weeks ’ gestation . Multilevel analysis with adjustments was used in testing for between-group differences in PA changes . Results The decrease in the weekly days of total and moderate-to-vigorous-intensity LTPA was smaller in INT ( N = 219 ) than in UC ( N = 180 ) from baseline to the first follow-up ( 0.1 vs. -1.2 , p = 0.040 and −0.2 vs. -1.3 , p = 0.016 ) . A similar trend was seen in meeting the PA recommendation ( −11%-points vs. -28%-points , p = 0.06 ) . INT did not experience more adverse events classified as warning signs to terminate exercise than UC , counseling was implemented as planned and viewed positively by the nurses . Conclusions Intensified counseling had no effects on the duration of total or intensity-specific weekly LTPA . However , it was able to reduce the decrease in the weekly frequency of total and moderate-to-vigorous-intensity LTPA from baseline to the end of second trimester and was feasibly embedded into routine practice s . Trial registration IS RCT N 33885819 ( http://www.is rct n.org [5115165] Study question What is the association between potato consumption before pregnancy and the risk of gestational diabetes mellitus ( GDM ) ? Methods This prospect i ve cohort study included 15 632 women from the Nurses ’ Health Study II ( 1991 - 2001 ) . They had no previous GDM or chronic diseases before pregnancy . Consumption of potatoes and other foods was assessed every four years . Incident first time GDM was ascertained from self reports of a physician diagnosis of GDM , which was previously vali date d by medical records . Study answer and limitations Over the 10 year follow-up there were 854 incident cases of GDM among 21 693 singleton pregnancies . After adjustment for age , parity , and dietary and non-dietary factors , women who consumed more potatoes before pregnancy had higher rates of developing GDM . Substitution of two servings a week of total potatoes with other vegetables , legumes , and whole grain foods was significantly associated with a 9 - 12 % lower risk of GDM . Consumption and diabetes were self reported , and severity of diabetes was unknown . More than 90 % of women were white . A causal association can not be assumed . What this paper adds Higher levels of potato consumption before pregnancy are associated with greater risk of GDM , and substitution of potatoes with other vegetables , legumes , or whole grain foods might lower the risk . Funding , competing interests , data sharing Funding was received from the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development , the National Institutes of Health , and the American Diabetes Association ( No 7 - 12-MN-34 ) . The authors have no competing interests or additional data to share [26165396] BACKGROUND Behavioural interventions might improve clinical outcomes in pregnant women who are obese . We aim ed to investigate whether a complex intervention addressing diet and physical activity could reduce the incidence of gestational diabetes and large-for-gestational-age infants . METHODS The UK Pregnancies Better Eating and Activity Trial ( UPBEAT ) is a r and omised controlled trial done at antenatal clinics in eight hospitals in multi-ethnic , inner-city locations in the UK . We recruited pregnant women ( 15 - 18 weeks plus 6 days of gestation ) older than 16 years who were obese ( BMI ≥30 kg/m(2 ) ) . We r and omly assigned participants to either a behavioural intervention or st and ard antenatal care with an internet-based , computer-generated , r and omisation procedure , minimising by age , ethnic origin , centre , BMI , and parity . The intervention was delivered once a week through eight health trainer-led sessions . Primary outcomes were gestational diabetes ( diagnosed with an oral glucose tolerance test and by criteria from the International Association of Diabetes in Pregnancy Study Groups ) and large-for-gestational-age infants ( ≥90th customised birthweight centile ) . Analysis was by intention to treat . This trial is registered with Current Controlled Trials , ISCRTN89971375 . Recruitment and pregnancy outcomes are complete but childhood follow-up is ongoing . FINDINGS Between March 31 , 2009 , and June 2 , 2014 , we assessed 8820 women for eligibility and recruited 1555 , with a mean BMI of 36·3 kg/m(2 ) ( SD 4·8 ) . 772 were r and omly assigned to st and ard antenatal care and 783 were allocated the behavioural intervention , of which 651 and 629 women , respectively , completed an oral glucose tolerance test . Gestational diabetes was reported in 172 ( 26 % ) women in the st and ard care group compared with 160 ( 25 % ) in the intervention group ( risk ratio 0·96 , 95 % CI 0·79 - 1·16 ; p=0·68 ) . 61 ( 8 % ) of 751 babies in the st and ard care group were large for gestational age compared with 71 ( 9 % ) of 761 in the intervention group ( 1·15 , 0·83 - 1·59 ; p=0·40 ) . Thus , the primary outcomes did not differ between groups , despite improvements in some maternal secondary outcomes in the intervention group , including reduced dietary glycaemic load , gestational weight gain , and maternal sum-of-skinfold thicknesses , and increased physical activity . Adverse events included neonatal death ( two in the st and ard care group and three in the intervention group ) and fetal death in utero ( ten in the st and ard care group and six in the intervention group ) . No maternal deaths were reported . Incidence of miscarriage ( 2 % in the st and ard care group vs 2 % in the intervention group ) , major obstetric haemorrhage ( 1 % vs 3 % ) , and small-for-gestational-age infants ( ≤5th customised birthweight centile ; 6 % vs 5 % ) did not differ between groups . INTERPRETATION A behavioural intervention addressing diet and physical activity in women with obesity during pregnancy is not adequate to prevent gestational diabetes , or to reduce the incidence of large-for-gestational-age infants . FUNDING National Institute for Health Research , Guys and St Thomas ' Charity , Chief Scientist Office Scotl and , Tommy 's Charity [21625788] PURPOSE to evaluate the impact of dietary counseling on controlling weight gain in pregnant women , who were served in a public health service facility . METHODS the study was conducted at a known health unit located in the metropolitan region of the city of Porto Alegre , in Rio Gr and e do Sul , Brazil . Three hundred and fifteen pregnant women between the 10th and 29th week of gestation were r and omized to Control and Intervention Groups . The Intervention Group received dietary counseling according to nutritional status , and pregnant women in the Control Group were instructed to follow the routine of the health service facility . Weight and height were measured , and the body mass index ( BMI ) was calculated . The pre-gestational nutritional status was determined according to the following BMI criteria : low weight ( < 18.5 kg/m² ) , eutrophy ( 18.5 to 24.9 kg/m² ) , overweight ( 25.0 to 29.9 kg/m² ) , and obesity ( > 30 kg/m² ) . The nutritional status during pregnancy was determined according to the BMI curve for gestational age adopted by the Health Ministry of Brazil . Data were analyzed by the relative risk and respective 95 % confidence interval , and by the Student 's t-test and χ2 test . Statistical significance was set at p<0.05 . RESULTS the assessment of nutritional status before pregnancy showed that 28.0 % of the women were overweight and 4.1 % were underweight . In the first and last interview during pregnancy , the rates of prevalence of excessive weight were 36.2 and 46.0 % , respectively . The intervention proved to be effective in reducing the rate of weekly weight gain of pregnant women with excess weight ( 342.2 versus 420.2 ; p=0.015 ) and the prevalence of clinical complications ( 9.2 versus 24.85 ; p<0.001 ) . CONCLUSIONS dietary counseling was effective in decreasing the weight gain of pregnant women who were overweight and reducing clinical complications , such as gestational diabetes , preeclampsia , infant low weight , and prematurity in the Intervention Group [21626296] Purpose Breast milk fatty acids possess immunomodulatory properties , and new intervention strategies beyond supplementation of maternal diet with single oils are called for . The objective of the present study was to evaluate the effect of dietary intervention during pregnancy and breastfeeding on breast milk fatty acid and cytokine composition . Methods Pregnant women were r and omised into three study groups : dietary intervention with probiotics ( diet/probiotic ) or with placebo ( diet/placebo ) and a control group ( control/placebo ) . Dietary intervention included dietary counselling and provision of rapeseed oil-based food products . The probiotics used were Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12 in combination . Dietary intake was evaluated by food records at every trimester of pregnancy and 1 month postpartum . Breast milk sample s were collected after birth ( colostrum ) and 1 month after delivery for fatty acid and cytokine analysis ( n = 125 ) . Results Dietary intervention improved the quality of fat in the diet . In breast milk , the proportion of α-linolenic acid and total n-3 fatty acids was higher in both dietary intervention groups compared with control group ( p < 0.05 ) . In the diet/probiotic group , the γ-linolenic acid content was higher compared with the diet/placebo group ( p < 0.05 ) . The concentrations of TNF-α , IL-10 , IL-4 and IL-2 were higher in both dietary intervention groups compared with controls , and furthermore , long-chain n-3 fatty acids were associated with several cytokines in colostrum sample s. Conclusion The present intervention demonstrated the possibility of modifying breast milk immunomodulatory factors by dietary means [26358582] Aims /hypothesisWe examined the associations between pre-pregnancy dietary patterns and the incidence of gestational diabetes mellitus ( GDM ) in a population -based cohort study of women of reproductive age . Methods The Australian Longitudinal Study on Women ’s Health included 3,853 women without pre-existing diabetes who were followed-up between 2003 and 2012 . Pre-pregnancy dietary patterns were derived using factor analysis based on 101 food items from a vali date d food frequency question naire . GDM was self-reported and vali date d in a sub sample . Multivariable regression models with generalised estimating equations were used to estimate RR and 95 % CI . Results During 9 years follow-up , 292 GDM cases ( 4.4 % ) were documented in 6,626 pregnancies . No associations were found for the ‘ Fruit and low-fat dairy ’ and ‘ Cooked vegetables ’ patterns . The ‘ Meats , snacks and sweets ’ pattern was associated with higher GDM risk after adjustment for socioeconomic , reproductive and lifestyle factors ( RR [ 95 % CI ] per SD increase in score : 1.38 [ 1.02 , 1.86 ] ) . Further adjustment for BMI attenuated the results ( 1.35 [ 0.98 , 1.81 ] ) . In stratified analysis , the ‘ Meats , snacks and sweets ’ pattern was associated with significantly higher GDM risk in parous and obese women , and in women with lower educational qualifications . The ‘ Mediterranean-style ’ pattern was associated with lower GDM risk in the fully adjusted model ( 0.85 [ 0.76 , 0.98 ] ) . Conclusions /interpretationThese findings support general dietary recommendations for women of reproductive age to consume a diet rich in vegetables , whole grains , nuts and fish , and low in red and processed meats and snacks . Further prospect i ve studies are needed to confirm these findings [20962162] BACKGROUND The optimal diet for pregnancy that is complicated by excessive weight is unknown . OBJECTIVE We aim ed to examine the effects of a low-glycemic load ( low-GL ) diet in overweight and obese pregnant women . DESIGN We r and omly assigned 46 overweight or obese pregnant women to receive a low-GL or a low-fat diet . Participants received carbohydrate-rich foods , fats , and snack foods through home delivery or study visits . The primary outcome was birth weight z score . Other endpoints included infant anthropometric measurements , gestational duration , maternal weight gain , and maternal metabolic parameters . RESULTS There were no significant differences in birth weight z score or other measures of infant adiposity between groups . However , in the low-GL compared with the low-fat group , gestational duration was longer ( mean ± SD : 39.3 ± 1.1 compared with 37.9 ± 3.1 wk ; P = 0.05 ) and fewer deliveries occurred at ≤ 38.0 wk ( 13 % compared with 48 % , P = 0.02 ; with exclusion of planned cesarean deliveries : 5 % compared with 53 % ; P = 0.002 ) . Adjusted head circumference was greater in the low-GL group ( 35.0 ± 0.8 compared with 34.2 ± 1.3 cm , P = 0.01 ) . Women in the low-GL group had smaller increases in triglycerides [ median ( interquartile range ) : 49 ( 19 , 70 ) compared with 93 ( 34 , 129 ) mg/dL ; P = 0.03 ] and total cholesterol [ 13 ( 0 , 36 ) compared with 33 ( 22 , 56 ) mg/dL , P = 0.04 ] and a greater decrease in C-reactive protein [ -2.5 ( -5.5 , -0.7 ) compared with -0.4 ( -1.4 , 1.5 ) mg/dL , P = 0.007 ] . CONCLUSIONS A low-GL diet result ed in longer pregnancy duration , greater infant head circumference , and improved maternal cardiovascular risk factors . Large-scale studies are warranted to evaluate whether dietary intervention during pregnancy aim ed at lowering GL may be useful in the prevention of prematurity and other adverse maternal and infant outcomes . This trial is registered at clinical trials.gov as NCT00364403 [19155899] OBJECTIVE : To estimate whether an organized , consistent program of dietary and lifestyle counseling prevents excessive weight gain in pregnancy . METHODS : This r and omized controlled trial assigned women to receive either an organized , consistent program of intensive dietary and lifestyle counseling or routine prenatal care . The primary study outcome was the proportion of patients whose gestational weight gain was within the Institute of Medicine ( IOM ) guidelines . Secondary outcomes included mode of delivery , rate of operative vaginal delivery , neonatal weight , and the incidence of preeclampsia , gestational diabetes mellitus ( GDM ) , vaginal/perineal lacerations , and shoulder dystocia . RESULTS : A total of 100 women were r and omized to the study ( lifestyle counseling 57 , routine prenatal care 43 ) . Baseline demographic characteristics were similar between the study groups . The lifestyle counseling group gained significantly less weight than did the routine prenatal care group ( 28.7±12.5 lb compared with 35.6±15.5 lb , P=.01 ) . The routine prenatal care group had significantly more cesarean deliveries due to “ failure to progress ” ( routine prenatal care 58.3 % compared with lifestyle counseling 25.0 % , P=.02 ) . Across groups , patients who were not adherent to the IOM guidelines had significantly heavier neonates ( adherent 3,203.2±427.2 g compared with not adherent 3,517.4±572.4 g , P<.01 ) . Nulliparous women gained significantly more weight than did parous women ( 36.5±14.5 lb compared with 27.7±12.7 lb , P<.01 ) . The most predictive factor of IOM adherence was having a normal prepregnancy body mass index . No statistically significant differences were noted between the groups in adherence to IOM guidelines , rate of cesarean delivery , preeclampsia , GDM , operative vaginal delivery , or vaginal lacerations . CONCLUSION : An organized , consistent program of dietary and lifestyle counseling did reduce weight gain in pregnancy . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00792480 LEVEL OF EVIDENCE : [1523339] Background Preventing excessive weight gain during pregnancy is potentially important in the prevention of overweight and obesity among women of childbearing age . However , few intervention studies aim ing at weight management during pregnancy have been performed and most of these interventions were not as successful as expected . In this paper the design of the New Life(style ) study is described as well as the content of the individually tailored intervention program , which focuses on controlling weight development during pregnancy . Methods The effectiveness of the New Life(style ) intervention program versus usual care by midwives is evaluated in a r and omised controlled trial . Women who expect their first child and visit one of the participating midwifery practice s are included . The intervention is st and ardised in a protocol and executed by trained counsellors with the women who are r and omised in the intervention group . During 5 sessions – at 18 , 22 , 30 and 36 weeks of pregnancy and at 8 weeks postpartum – individual weight gain is discussed in relation to weight gain guidelines for pregnant women of the American Institute of Medicine . Counsellors coach the women to maintain or optimise a healthy lifestyle , in a period of drastic physical and mental changes . Data is collected at 15 , 25 , 35 weeks of pregnancy and at 6 , 26 , and 52 weeks after delivery . Primary outcome measures are body weight , BMI , and skinfold thickness . Secondary outcome measures include physical activity , nutrition and blood levels of factors that are associated with energy homeostasis . Discussion Results of the current RCT will improve the knowledge of determinants of weight gain during pregnancy , weight retention after childbirth and of the effectiveness of the intervention program that is described . Caregivers and research ers in the field of health promotion are offered more insight in specific elements of the New Life(style ) intervention program [23327487] Abstract Objective : To test the hypothesis that dietary myo-inositol may improve insulin resistance and the development of gestational diabetes mellitus ( GDM ) in women at high risk of this disorder . Design : A prospect i ve , r and omized , double-blind , placebo controlled clinical trial , pilot study . Participants : Non-obese singleton pregnant women with an elevated fasting glucose in the first or early second trimester were studied throughout pregnancy . Intervention : Supplementation with myo-inositol or placebo during pregnancy . Main outcome measure : Development of GDM on a 75 g oral glucose tolerance test at 24–28 weeks ’ gestation . Secondary outcome measures were increased in BMI , need for maternal insulin therapy , macrosomia , polyhydramnios , neonatal birthweight and hypoglycemia . Results : Thirty-six women were allocated to receive myo-inositol and 39 placebo . The incidence of GDM in mid-pregnancy was significantly reduced ( p = 0.001 ) in women r and omized to receive myo-inositol compared to placebo ( relative risk 0.127 ) . Women r and omized to receive myo-inositol also required less insulin therapy , delivered at a later gestational age , had significantly smaller babies with fewer episodes of neonatal hypoglycemia . Conclusions : Myo-inositol supplementation in pregnancy reduced the incidence of GDM in women at high risk of this disorder . The reduction in incidence of GDM in the treatment arm was accompanied by improved outcomes [24169456] Background / Objective : Well-being has been linked to the quality of diet and lifestyle in adults ; however , there is a paucity of data in pregnancy . The aim of this study was to examine the relationship between well-being and socioeconomic status , diet and lifestyle during pregnancy and to consider the effect of intervention with low glycaemic index ( GI ) diet on well-being . Subjects/ Methods : This was a cohort analysis of 619 participants of the ROLO study ( R and omised cOntrol trial of LOw GI diet versus no dietary intervention to prevent recurrence of fetal macrosomia ) . The following data were collected : educational attainment , dietary intakes ( food frequency question naire ) , physical activity ( self-reported ) and well-being ( WHO-5-Item Wellbeing Index — expressed as a percentage ) . Results : Well-being was positively associated with education and physical activity . Third-level education was associated with a 3.07-point higher well-being percentage score , and each day that an individual achieved > 30 min walking per week was associated with a 1.10-point increase in percentage well-being score , Radj2 2.4 % ( F=7.260 , P=0.001 ) . The intervention low GI group had a significantly lower percentage well-being score than the usual diet group ( 56.3 % vs 59.9 % , P=0.015 ) . No correlation was noted between well-being and GI status calculated from food diaries ( P=0.469 ) . Well-being was not associated with micronutrient intake . Conclusions : Well-being in pregnancy was independently and positively associated with education and physical activity and negatively associated with low GI dietary intervention . These findings have significance not only for women at risk of low mood but also for healthcare professionals when counselling women about the importance of healthy lifestyle in pregnancy [2876071] Background Maternal weight and maternal weight gain during pregnancy exert a significant influence on infant birth weight and the incidence of macrosomia . Fetal macrosomia is associated with an increase in both adverse obstetric and neonatal outcome , and also confers a future risk of childhood obesity . Studies have shown that a low glycaemic diet is associated with lower birth weights , however these studies have been small and not r and omised [ 1 , 2 ] . Fetal macrosomia recurs in a second pregnancy in one third of women , and maternal weight influences this recurrence risk [ 3 ] . Methods / Design We propose a r and omised control trial of low glycaemic index carbohydrate diet vs. no dietary intervention in the prevention of recurrence of fetal macrosomia . Secundigravid women whose first baby was macrosomic , defined as a birth weight greater than 4000 g will be recruited at their first antenatal visit . Patients will be r and omised into two arms , a control arm which will receive no dietary intervention and a diet arm which will be commenced on a low glycaemic index diet . The primary outcome measure will be the mean birth weight centiles and ponderal indices in each group . Discussion Altering the source of maternal dietary carbohydrate may prove to be valuable in the management of pregnancies where there has been a history of fetal macrosomia . Fetal macrosomia recurs in a second pregnancy in one third of women . This r and omised control trial will investigate whether or not a low glycaemic index diet can affect this recurrence risk . Current Controlled Trials Registration NumberIS RCT [2681032] OBJECTIVE A low – glycemic index diet is effective as a treatment for individuals with diabetes and has been shown to improve pregnancy outcomes when used from the first trimester . A low – glycemic index diet is commonly advised as treatment for women with gestational diabetes mellitus ( GDM ) . However , the efficacy of this advice and associated pregnancy outcomes have not been systematic ally examined . The purpose of this study was to determine whether prescribing a low – glycemic index diet for women with GDM could reduce the number of women requiring insulin without compromise of pregnancy outcomes . RESEARCH DESIGN AND METHODS All women with GDM seen over a 12-month period were considered for inclusion in the study . Women ( n = 63 ) were r and omly assigned to receive either a low – glycemic index diet or a conventional high-fiber ( and higher glycemic index ) diet . RESULTS Of the 31 women r and omly assigned to a low – glycemic index diet , 9 ( 29 % ) required insulin . Of the women r and omly assigned to a higher – glycemic index diet , a significantly higher proportion , 19 of 32 ( 59 % ) , met the criteria to commence insulin treatment ( P = 0.023 ) . However , 9 of these 19 women were able to avoid insulin use by changing to a low – glycemic index diet . Key obstetric and fetal outcomes were not significantly different . CONCLUSIONS Using a low – glycemic index diet for women with GDM effectively halved the number needing to use insulin , with no compromise of obstetric or fetal outcomes [21945174] BACKGROUND The breast milk bioactive substances such as adiponectin , have a presumably long-term impact upon the health and well-being of a child . AIM To determine the impact of probiotic-supplemented dietary counseling during pregnancy on colostrum adiponectin concentration . STUDY DESIGN AND SUBJECTS Altogether 256 pregnant women were r and omized into three study groups : dietary intervention with probiotics ( diet/probiotics ) or with placebo ( diet/placebo ) and a control group ( control/placebo ) . The intervention group received dietary counseling provided by a nutritionist , the main focus being the amount and the type of dietary fat . The probiotics used were Lactobacillus rhamnosus GG and Bifidobacterium lactis in combination . Dietary intake was evaluated by food records at every trimester of pregnancy . Breast milk sample s were collected after birth ( colostrum ) for adiponectin concentration analysis ( n=181 ) . RESULTS The dietary intervention increased the colostrum adiponectin concentration ( ng/mL , geometric mean [ 95 % CI ] ) , the difference being significant when comparing to the control group ; 12.7 [ 10.6 - 29.7 ] vs. 10.2 [ 9.9 - 13.2 ] , P=0.024 . Maternal weight gain during pregnancy ( kg ) correlated inversely with colostrum adiponectin concentration ; β (SE)=-1.7 ( 0.1 ) , P=0.020 , and gestational diabetes mellitus was associated with the likelihood of adiponectin concentration falling into the lowest quartile ; OR 2.36 , 95 % CI 1.1 - 3.2 , P=0.028 . CONCLUSIONS In showing that the colostrum adiponectin concentration is markedly dependent on maternal diet and nutritional status during pregnancy , and considering that colostrum adiponectin has potential effects on metabolism , nutrition , and immune function in the neonates , the results of this study underscore the importance of the metabolic homeostasis of the mother for the child 's initial nutritional environment [2782983] OBJECTIVE Consumption of sugar-sweetened beverages ( SSBs ) was related to an elevated risk of type 2 diabetes and insulin resistance in several recent studies among middle- or older-aged population s. Studies on SSB consumption and glucose intolerance among pregnant women , however , are lacking . We therefore examined the association between regular SSB consumption before pregnancy and the risk of gestational diabetes mellitus ( GDM ) . RESEARCH DESIGN AND METHODS This was a prospect i ve study among 13,475 U.S. women who reported at least one singleton pregnancy between 1992 and 2001 in the Nurses ' Health Study II . GDM was self-reported and vali date d by medical record review in a sub sample . Cox proportional hazards models with multivariate adjustments were applied to examine the association of SSB consumption with GDM risk . RESULTS During 10 years of follow-up , 860 incident GDM case subjects were identified . After adjustment for age , parity , race , physical activity , smoking , alcohol intake , prepregnancy BMI , and Western dietary pattern , intake of sugar-sweetened cola was positively associated with the risk of GDM , whereas no significant association was found for other SSBs and diet beverages . Compared with women who consumed < 1 serving/month , those who consumed ≥5 servings/week of sugar-sweetened cola had a 22 % greater GDM risk ( relative risk 1.22 [ 95 % CI 1.01–1.47 ] ) . CONCLUSIONS Findings from this study suggest that prepregnancy higher consumption of sugar-sweetened cola ( ≥5 servings/week ) is associated with an elevated GDM risk , whereas no significant association with GDM risk was observed for other SSBs and diet beverages [16957814] Aims /hypothesisThe aim of this study was to prospect ively examine whether dietary patterns are related to risk of gestational diabetes mellitus ( GDM ) . Methods This prospect i ve cohort study included 13,110 women who were free of cardiovascular disease , cancer , type 2 diabetes and history of GDM . Subjects completed a vali date d semi-quantitative food frequency question naire in 1991 , and reported at least one singleton pregnancy between 1992 and 1998 in the Nurses ’ Health Study II . Two major dietary patterns ( i.e. ‘ prudent ’ and ‘ Western ’ ) were identified through factor analysis . The prudent pattern was characterised by a high intake of fruit , green leafy vegetables , poultry and fish , whereas the Western pattern was characterised by high intake of red meat , processed meat , refined grain products , sweets , French fries and pizza . Results We documented 758 incident cases of GDM . After adjustment for age , parity , pre-pregnancy BMI and other covariates , the relative risk ( RR ) of GDM , comparing the highest with the lowest quintile of the Western pattern scores , was 1.63 ( 95 % CI 1.20–2.21 ; ptrend=0.001 ) , whereas the RR comparing the lowest with the highest quintile of the prudent pattern scores was 1.39 ( 95 % CI 1.08–1.80 ; ptrend=0.018 ) . The RR for each increment of one serving/day was 1.61 ( 95 % CI 1.25–2.07 ) for red meat and 1.64 ( 95 % CI 1.13–2.38 ) for processed meat . Conclusions /interpretationThese findings suggest that pre-pregnancy dietary patterns may affect women ’s risk of developing GDM . A diet high in red and processed meat was associated with a significantly elevated risk [19585925] BACKGROUND Although obesity in pregnancy continues to be associated with ongoing health problems , many clinicians have been reluctant to place nondiabetic , obese , pregnant women on a monitored , calorie-appropriate nutritional regimen for fear of fetal growth restriction , low birth weight , or starvation ketosis . METHODS A total of 257 patients were enrolled in the r and omized study , with a loss-to-follow-up rate of 9.73 % . Patients were assigned r and omly to either the control ( unmonitored ) group ( n=116 ) , consisting of conventional prenatal dietary management , or to the study ( monitored ) group ( n=116 ) , which was prescribed a balanced nutritional regimen and were asked to record in a diary all of the foods eaten during each day . Women were eligible for the study if they were pregnant with a single fetus between 12 and 28 weeks of gestation and had a prepregnancy body mass index of more than 30 kg/m2 . The primary outcome was to compare perinatal outcomes in the control vs the study groups . The secondary measure was to compare outcomes in adherent and nonadherent patients in the study group . RESULTS Omnibus MANOVA showed statistically significant differences between the study and control groups regarding 3 variables : ( 1 ) gestational hypertension , p < .46 ; ( 2 ) mother 's last weight before delivery , p < .001 ; and ( 3 ) mother 's 6-week postpartum weight , p < .001 . Patients gaining 15 pounds or more during their pregnancy showed statistically significant differences between the groups for 8 variables . CONCLUSION Obese pregnant women may be placed on a healthy , well-balanced , monitored nutritional program during their antepartum course without adverse perinatal outcomes [4176103] Background Maternal diet is known to impact pregnancy outcome . Following a low glycemic index ( GI ) diet during pregnancy has been shown to improve maternal glycemia and reduce infant birthweight and may be associated with a higher fibre intake . We assessed the impact of a low GI dietary intervention on maternal GI , nutritional intake and gestational weight gain ( GWG ) during pregnancy . Compliance and acceptability of the low GI diet was also examined . Method Eight hundred women were r and omised in early pregnancy to receive low GI and healthy eating dietary advice or to receive st and ard maternity care . The intervention group received dietary advice at a group education session before 22 weeks gestation . All women completed a 3 day food diary during each trimester of pregnancy . Two hundred and thirty five women from the intervention arm and 285 women from the control arm returned complete 3x3d FDs and were included in the present analysis . Results Maternal GI was significantly reduced in the intervention group at trimester 2 and 3 . The numbers of women within the lowest quartile of GI increased from 37 % in trimester 1 to 52 % in trimester 3 ( P < 0.001 ) among the intervention group . The intervention group had significantly lower energy intake ( P < 0.05 ) , higher protein ( % TE ) ( P < 0.01 ) and higher dietary fibre intake ( P < 0.01 ) post intervention . Consumption of food groups with known high GI values were significantly reduced among the intervention group . Women in the intervention low GI group were less likely to exceed the Institute of Medicine ’s GWG goals . Conclusion A dietary intervention in early pregnancy had a positive influence on maternal GI , food and nutrient intakes and GWG . Following a low GI diet may be particularly beneficial for women at risk of exceeding the GWG goals for pregnancy . Trial registration Current Controlled Trials Registration Number : IS RCT N54392969 [20128938] The perinatal nutritional environment impacts upon the health and well-being of mother and child also in the long term . The aim of the present study was to determine the safety and efficacy of perinatal probiotic-supplemented dietary counselling by evaluating pregnancy outcome and fetal and infant growth during the 24 months ' follow-up . Altogether , 256 women were r and omised at their first trimester of pregnancy into a control and a dietary intervention group . The intervention group received intensive dietary counselling provided by a nutritionist and were further r and omised , double-blind to receive probiotics ( Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12 ; diet/probiotics ) or placebo ( diet/placebo ) . Firstly , probiotic intervention reduced the frequency of gestational diabetes mellitus ( GDM ) ; 13 % ( diet/probiotics ) v. 36 % ( diet/placebo ) and 34 % ( control ) ; P = 0.003 . Secondly , the safety of this approach was attested by normal duration of pregnancies with no adverse events in mothers or children . No significant differences in prenatal or postnatal growth rates among the study groups were detected . Thirdly , distinctive effects of the two interventions were detected ; probiotic intervention reduced the risk of GDM and dietary intervention diminished the risk of larger birth size in affected cases ; P = 0.035 for birth weight and P = 0.028 for birth length . The results of the present study show that probiotic-supplemented perinatal dietary counselling could be a safe and cost-effective tool in addressing the metabolic epidemic . In view of the fact that birth size is a risk marker for later obesity , the present results are of significance for public health in demonstrating that this risk is modifiable [23187955] Background / objectives : Owing to excess body weight and increased secretion of inflammatory cytokines primarily during the third trimester , pregnancy is associated with elevated insulin resistance . To our knowledge , no report is available indicating the effects of probiotic yoghurt consumption on serum insulin levels in pregnant women . This study was design ed to determine the effects of daily consumption of probiotic yoghurt on insulin resistance and serum insulin levels of Iranian pregnant women . Subjects/ methods : In this r and omized controlled clinical trial , 70 primigravida pregnant women with singleton pregnancy at their third trimester were participated . We r and omly assigned participants to consume 200 g per day of conventional ( n=33 ) or the probiotic group ( n=37 ) for 9 weeks . The probiotic yoghurt was a commercially available product prepared with the starter cultures of Streptococcus thermophilus and Lactobacillus bulgaricus , enriched with probiotic culture of two strains of lactobacilli ( Lactobacillus acidophilus LA5 ) and bifidobacteria ( Bifidobacterium animalis BB12 ) with a total of min 1 × 107 colony-forming units . Fasting blood sample s were taken at baseline and after 9-week intervention to measure fasting plasma glucose and serum insulin levels . Homeostatic model assessment of insulin resistance ( HOMA-IR ) was used to calculate insulin resistance score . Results : Although consumption of probiotic yogurt for 9 weeks did not affect serum insulin levels and HOMA-IR score , significant differences were found comparing changes in these variables between probiotic and conventional yogurts ( changes from baseline in serum insulin levels : + 1.2±1.2 vs + 5.0±1.1 μIU/ml , respectively , P=0.02 ; and in HOMA-IR score : −0.2±0.3 vs 0.7±0.2 , respectively , P=0.01 ) . Conclusions : It is concluded that in contrast to conventional yogurt , daily consumption of probiotic yogurt for 9 weeks maintains serum insulin levels and might help pregnant women prevent developing insulin resistance [4407817] Objective Observational studies suggest that minimal gestational weight gain ( GWG ) may optimize pregnancy outcomes for obese women . This trial tested the efficacy of a group-based weight management intervention for limiting GWG among obese women . Methods We r and omized 114 obese women ( BMI [ mean±SD ] 36.7±4.9 kg/m2 ) between 7–21 weeks ’ ( 14.9±2.6 ) gestation to intervention ( n=56 ) or usual care control conditions ( n=58 ) . The intervention included individualized calorie goals , advice to maintain weight within 3 % of r and omization and follow the Dietary Approaches to Stop Hypertension dietary pattern without sodium restriction , and attendance at weekly group meetings until delivery . Control participants received one-time dietary advice . Our three main outcomes were maternal weight change from r and omization to 2 weeks postpartum and from r and omization to 34 weeks gestation , and newborn large-for-gestational age ( birth weight > 90th percentile , LGA ) . Results Intervention participants gained less weight from r and omization to 34 weeks gestation ( 5.0 vs 8.4 kg , mean difference=−3.4 kg , 95 % CI [ −5.1 , −1.8 ] ) , and from r and omization to 2 weeks postpartum ( −2.6 vs + 1.2 kg , mean difference=−3.8 kg , 95 % CI [ −5.9 , −1.7 ] ) . They also had a lower proportion of LGA babies ( 9 % vs. 26 % , odds ratio=0.28 , 95 % CI [ 0.09 , 0.84 ] ) . Conclusions The intervention result ed in lower GWG and lower prevalence of LGA newborns [22093485] As part of a feasibility study to prevent gestational diabetes mellitus ( GDM ) , we evaluated the effect of an intensive dietary therapy on quality of diet , weight gain and birth weight in women at high risk of GDM . Women with risk factors for GDM ( n 54 ) were r and omly assigned from April 2005 to May 2006 to a lifestyle intervention group ( n 27 ) including dietary advice six times during pregnancy or to a close follow-up group ( n 27 ) in a community-based setting in Finl and . Dietary intake was recorded three times during pregnancy using 4 d food records . The main outcome was the incidence of GDM . The secondary outcomes were the changes in nutrient intake , weight gain and birth weight . Overall , seventeen ( 65 % ) women in the intervention group and eighteen ( 69 % ) women in the close follow-up group returned all three food records . PUFA intake increased ( P = 0·008 ) during pregnancy in the intervention as compared to the close follow-up group . There were no clear differences in the changes of saturated fat or fibre intake between the groups . Intensive dietary education result ed in a somewhat lower weight gain during pregnancy ( P = 0·062 ) and higher birth weights of the infants ( P = 0·047 ) without an effect on macrosomia as compared to the close follow-up group . Individualised counselling by a clinical nutritionist as part of a lifestyle intervention improved the quality of dietary fat intake in pregnant women at high risk of GDM [26757351] Outcomes in gestational diabetes Cochrane protocol s and review s before and after development of ‘ st and ard outcomes ’ by WOMBAT ( WOMen and Babies health and well‐being : Action through Trials ) were surveyed . An increase in ‘ common ’ outcomes ( those prespecified by ≥50 % of the protocol s and review s ) over time was observed ( 2001–2009 : 27 vs 2010–2014 : 46 ) . There were discrepancies in outcomes prespecified in review s and reported by r and omised trials . Efforts are needed to develop a core outcome set , to reduce research waste and improve health outcomes [24284438] BACKGROUND Excessive weight gain during pregnancy is a risk factor for postpartum weight retention and future weight gain and obesity . Whether a behavioral intervention in pregnancy can reduce long-term weight retention is unknown . OBJECTIVE This r and omized trial tested whether a low-intensity behavioral intervention to prevent excessive gestational weight gain could increase the proportion of women who returned to prepregnancy weight by 12 mo postpartum . DESIGN Women ( n = 401 , 13.5 wk of gestation , 50 % normal weight , 50 % overweight/obese ) were r and omly assigned into an intervention or control group ; 79 % completed the 12-mo assessment . The telephone-based intervention targeted gestational weight gain , healthy eating , and exercise and was discontinued at delivery . RESULTS In modified intent-to-treat analyses that excluded women with miscarriages ( n = 6 ) , gestational diabetes ( n = 32 ) , or subsequent pregnancies ( n = 32 ) , the intervention had no significant effect on the odds of achieving prepregnancy weight at 12 mo postpartum ( n = 331 ; 35.4 % compared with 28.1 % ; P = 0.18 ) . Completer analyses suggested that the intervention tended to increase the percentages of women who reached prepregnancy weight ( n = 261 ; 45.3 % compared with 35.3 % ; P = 0.09 ) and significantly reduced the magnitude of mean ± SD postpartum weight retained ( 1.4 ± 6.3 compared with 3.0 ± 5.7 kg ; P = 0.046 ) at 12 mo . Women in the intervention group reported higher dietary restraint through 6 mo postpartum ( P = 0.023 ) and more frequent self-monitoring of body weight ( P < 0.02 for all ) throughout the study . CONCLUSIONS A low-intensity behavioral intervention in pregnancy can reduce 12-mo postpartum weight retention and improve dietary restraint and self-weighing in study completers . Future research is needed to test the long-term effects of more intensive behavioral interventions in pregnancy . This trial was registered at clinical trials.gov as NCT01117961 [24896237] The present study is a secondary analysis of the ROLO study , a r and omised control trial of a low-glycaemic index ( GI ) diet in pregnancy to prevent the recurrence of fetal macrosomia . The objectives of the present study were to identify which women are most likely to respond to a low-GI dietary intervention in pregnancy with respect to three outcome measures : birth weight ; maternal glucose intolerance ; gestational weight gain ( GWG ) . In early pregnancy , 372 women had their mid-upper arm circumference recorded and BMI calculated . Concentrations of glucose , insulin and leptin were measured in early pregnancy and at 28 weeks . At delivery , infant birth weight was recorded and fetal glucose , C-peptide and leptin concentrations were measured in the cord blood . Women who benefited in terms of infant birth weight were shorter , with a lower education level . Those who maintained weight gain within the GWG guidelines were less overweight in both their first and second pregnancies , with no difference being observed in maternal height . Women who at 28 weeks of gestation developed glucose intolerance , despite the low-GI diet , had a higher BMI and higher glucose concentrations in early pregnancy with more insulin resistance . They also had significantly higher-interval pregnancy weight gain . For each analysis , women who responded to the intervention had lower leptin concentrations in early pregnancy than those who did not . These findings suggest that the maternal metabolic environment in early pregnancy is important in determining later risks of excessive weight gain and metabolic disturbance , whereas birth weight is mediated more by genetic factors . It highlights key areas , which warrant further interrogation before future pregnancy intervention studies , in particular , maternal education level and inter-pregnancy weight gain [25303998] Aims /hypothesisFried foods are frequently consumed in Western countries . However , the health effects of frequent fried food consumption in humans are not well understood . We aim ed to prospect ively examine the association between pre-pregnancy fried food consumption and risk of incident gestational diabetes mellitus ( GDM ) . Methods We included 21,079 singleton pregnancies from 15,027 women in the Nurses ' Health Study II cohort . Since 1991 and every 4 years thereafter , we collected diet information , including consumption of fried foods at home and away from home , using a vali date d food frequency question naire . We used generalised estimating equations with log-binomial models to estimate the RRs and 95 % CIs . Results We documented 847 incident GDM pregnancies during 10 years of follow-up . After adjustment for age , parity , dietary and non-dietary factors , the RRs ( 95 % CIs ) of GDM among women who consumed total fried foods 1–3 , 4–6 and ≥7 times/week , compared with those who consumed it less than once/week , were 1.13 ( 0.97 , 1.32 ) , 1.31 ( 1.08 , 1.59 ) and 2.18 ( 1.53 , 3.09 ) , respectively ( p for trend < 0.001 ) . The association persisted after further adjustment for BMI ( p for trend = 0.01 ) . When analysed separately , we found a significant association of GDM with fried food consumption away from home , but not with fried food consumption at home . Conclusions /interpretationFrequent fried food consumption , particularly away from home , was significantly associated with a greater risk of incident GDM . Our study indicates potential benefits of limiting fried food consumption in the prevention of GDM in women of reproductive age [22465256] BACKGROUND Obesity and excessive weight gain during pregnancy are associated with adverse pregnancy outcomes . Observational studies suggest that minimal or no gestational weight gain ( GWG ) may minimize the risk of adverse pregnancy outcomes for obese women . OBJECTIVE This report describes the design of Healthy Moms , a r and omized trial testing a weekly , group-based , weight management intervention design ed to help limit GWG to 3 % of weight ( measured at the time of r and omization ) among obese pregnant women ( BMI ≥30 kg/m(2 ) ) . Participants are r and omized at 10 - 20 weeks gestation to either the intervention or a single dietary advice control condition . PRIMARY OUTCOMES The study is powered for the primary outcome of total GWG , yielding a target sample size of 160 women . Additional secondary outcomes include weight change between r and omization and one-year postpartum and proportion of infants with birth weight>90th percentile for gestational age . Statistical analyses will be based on intention-to-treat . METHODS Following r and omization , all participants receive a 45-minute dietary consultation . They are encouraged to follow the Dietary Approaches to Stop Hypertension diet without sodium restriction . Intervention group participants receive an individualized calorie intake goal , a second individual counseling session and attend weekly group meetings until they give birth . Research staff assesses all participants at 34-weeks gestation and at 2-weeks and one-year postpartum with their infants . SUMMARY The Healthy Moms study is testing weight management techniques that have been used with non-pregnant adults . We aim to help obese women limit GWG to improve their long-term health and the health of their offspring [23241065] Aim ing at preventing excessive weight gain during pregnancy , 10 specific dietary recommendations are given to pregnant women in the intervention arm of the Norwegian Fit for Delivery ( FFD ) study . This paper presents the rationale and test-retest reliability of the food frequency question naire ( FFQ ) and a dietary score measuring adherence to the recommendations . The study is part of the ongoing FFD study , a r and omised , controlled , intervention study in nulliparous pregnant women . A 43-item FFQ was developed for the FFD study . A dietary score was constructed from 10 subscales corresponding to the 10 dietary recommendations . Adding the subscales yielded a score from 0 to 10 with increasing score indicating healthier dietary behaviour . The score was divided into tertiles , grouping participants into low , medium and high adherence to the dietary recommendations . Pregnant women attending ultrasound screening at about week 19 of pregnancy were asked to complete the FFQ twice , 2 weeks apart . Of 154 pregnant women completing the first question naire , 106 ( 69 % ) completed the form on both occasions and was included in the study . The test-retest correlations of the score and subscales were r = 0.68 and r = 0.56 - 0.84 , respectively ( both P ≤ 0.001 ) . There was 68 % test-retest correct classification of the score and 70 - 87 % of the subscales . In conclusion , acceptable test-retest reliability of the FFQ and the dietary score was found . The score will be used in the FFD study to measure adherence to the dietary recommendations throughout pregnancy and in the following year post-partum [23432806] Leptin regulates energy homeostasis and immune and metabolic functions . Highly elevated leptin concentrations during pregnancy may be associated with aberrations in maternal metabolism and long-term health consequences both in women and children . The objective of the present study was to evaluate whether dietary counselling , probiotic supplementation , maternal characteristics or dietary intake during pregnancy has an impact on serum leptin concentrations in women , cord blood or in children . A total of 256 pregnant women were r and omised to a control group ( n 85 ) or to receive dietary counselling with probiotics ( n 85 ) or placebo ( n 86 ) . Dietary counselling aim ed at affecting the type of fat used and to increase the amount of fibre in the women 's diet . Women 's dietary intake and serum leptin concentrations were analysed at the first and third trimesters of pregnancy and at 1 month postpartum . Furthermore , leptin concentrations were measured from the cord blood and from children 's serum at 1 and 6 months of age . Weight status and dietary composition were the key determinants of leptin concentrations . Specifically , high dietary fibre and low SFA intakes were related to low serum leptin concentrations in women . Female sex and birth weight were associated with higher infant leptin , whereas cord blood leptin was additionally affected by maternal leptin concentration and protein intake . Probiotics or dietary counselling did not affect leptin concentrations . Weight control to recommended levels and modification of diet towards higher fibre and lower SFA intakes during pregnancy may through leptin concentrations provide health benefits to both women and children [21593355] To explore the effect of maternal dietary intervention on infant essential fatty acid ( FA ) status , we conducted a prospect i ve , single-blind , r and omized nutrition intervention study . At the first trimester of pregnancy , 90 women from families with a history of allergy were r and omized either to receive intensive dietary counseling to modify dietary intake according to current recommendations or as controls . Infants ' cord and 1-mo isolated serum phospholipid FA were identified and quantified by GC . Detectable levels of eicosatrienoic acid [ ETA , 20:3(n-9 ) ] were taken as a biochemical marker for essential FA deficiency , and the DHA sufficiency index [ 22:6(n-3):22:5(n-6 ) ] and the DHA deficiency index [ 22:5(n-6):22:4(n-6 ) ] were taken as markers for DHA [ 22:6(n-3 ) ] status . The concentration of ETA was lower in cord blood in the intervention ( I ) group [ median 0.64 ( IQR 0.40 - 0.78 ) mg/L ; 2.09 ( 1.31 - 2.54 ) μmol/L ] than in the control ( C ) group [ 0.92 ( 0.54 - 1.20 ) mg/L ; 3.00 ( 1.76 - 3.92 ) μmol/L ] ( P = 0.048 ) . The proportion of ETA in total FA in the I group [ 0.73 % ( 0.48 - 0.85 % ) ] was lower than in the C group [ 0.93 % ( 0.78 - 1.22 % ) ] ( P = 0.003 ) . A higher DHA sufficiency index and lower DHA deficiency index were detected in cord blood in the I group than in the C group , although the groups did not differ in the DHA concentration or proportion of the total FA . There were no differences among groups at 1 mo for any of the variables measured . Our findings suggest a better supply of essential FA , particularly important during the period of rapid development , in infants whose mothers received dietary counseling . The results thus highlight the importance of maternal diet for child health , calling for dietary counseling for pregnant women in primary health care [25300266] Background : Obesity in pregnancy is associated with fetal macrosomia , a raised neonatal fat mass and an increased risk of obesity and poor metabolic health in childhood which persists into adulthood . The offspring of obese women are more likely to be obese than the offspring of lean women when they become pregnant themselves , perpetuating a cycle of obesity and its associated negative metabolic consequences . Increasing physical activity during pregnancy could improve insulin sensitivity and reduce the risk of maternal and offspring adverse outcomes . The UK Pregnancy Better Eating and Activity Trial ( UPBEAT ) is a trial of a complex intervention design ed to improve pregnancy outcomes through dietary changes and physical activity . Data from the pilot trial of 183 women were available for analysis . The relationship between the time spent at different physical activity levels and maternal and infant pregnancy outcomes was examined . Key Messages : Strong evidence exists that physical activity improves insulin sensitivity in non-pregnant population s , and lifestyle interventions of proven effectiveness in non-pregnant population s have been developed . Women who are active in pregnancy demonstrate better glucose control and favourable pregnancy outcomes . There is a lack of effective interventions to support obese pregnant women to be physically active . Conclusions : No difference was detected in objective ly measured physical activity between women r and omised to the intervention and control arms of the UPBEAT pilot trial . Light-intensity physical activity was lower in early pregnancy in women who delivered macrosomic infants . Maternal sedentary time at 35 - 36 weeks ' gestation was positively associated and moderate-intensity physical activity was inversely associated with neonatal abdominal circumference . Maternal physical activity is associated with infant birth weight and abdominal circumference and is an appropriate target for intervention to improve infant outcomes . The challenge remains to develop an effective intervention to support obese pregnant women to be physically active [26350393] Background / Objectives : Gestational diabetes mellitus ( GDM ) is associated with negative health effects for mother and child . The aim was to investigate the association between maternal dietary patterns and GDM.Subjects/ Methods : Prospect i ve observational study including 168 pregnant women aged 18–40 years , recruited at routine 20-week ultrasound . All participants kept a 4-day weighed food record following recruitment ( commencement : gestational weeks 19–24 ) . Principal component analysis was used to extract dietary patterns from 29 food groups . A Healthy Eating Index ( HEI ) was constructed . All women underwent an oral glucose tolerance test in weeks 23–28 . Results : One clear dietary pattern ( Eigenvalue 2.4 ) was extracted with positive factor loadings for seafood ; eggs ; vegetables ; fruits and berries ; vegetable oils ; nuts and seeds ; pasta ; breakfast cereals ; and coffee , tea and cocoa powder , and negative factor loadings for soft drinks and French fries . This pattern was labeled a prudent dietary pattern . Explained variance was 8.2 % . The prevalence of GDM was 2.3 % among women of normal weight before pregnancy ( n=86 ) and 18.3 % among overweight/obese women ( n=82 ) . The prudent dietary pattern was associated with lower risk of GDM ( OR : 0.54 ; 95 % CI : 0.30 , 0.98 ) . When adjusting for age , parity , prepregnancy weight , energy intake , weekly weight gain and total metabolic equivalent of task the association remained ( OR : 0.36 ; 95 % CI : 0.14 , 0.94 ) . Similar results were found when only including overweight or obese women ( OR : 0.31 ; 95 % CI : 0.13 , 0.75 ) . Conclusions : Adhering to a prudent dietary pattern in pregnancy was clearly associated with lower risk of GDM , especially among women already at higher risk because of overweight/obesity before pregnancy [22773616] Background . Intervention fidelity is an increasingly important method ological concept in process evaluations . In this article , the authors investigated the intervention fidelity in a r and omized controlled trial on excessive weight gain prevention in pregnancy . Method . A sample of 109 audiotaped counseling sessions , linked to 65 women in the intervention group of the New Life(style ) trial , was drawn . The following criteria were quantitatively evaluated using a fidelity checklist : ( a ) reach , ( b ) dose , ( c ) adherence to study objectives , ( d ) adherence to underlying problem-solving treatment ( PST ) theory , and ( e ) counselor competence . Results . A total of 60.4 % received all counseling sessions . The dose of intervention components was generally moderate ( 50.9 % to 60.4 % ) , and the dose of PST components was low ( 17.3 % ) . Adherence to study objectives was moderate ( 64.2 % ) and adherence to PST theory was low ( 43.2 % ) . The counselors sufficiently stimulated the participant to optimize lifestyle ( 54.2 % of the sessions ) , provided positive feedback ( 50.5 % ) , and left the initiative regarding problem solving to the participant ( 71 % ) . One of the two counselors performed significantly better on all measured criteria ( p < .001 ) . Conclusions . Intervention fidelity in the New Life(style ) trial was generally low to moderate . In future interventions , it is recommended to put more emphasis on counselor recruitment , training , and intervention protocol contents . Fellow research ers are encouraged to embed a process evaluation into all study stages , taking into account all essential process elements , and to link process outcomes to more distal , health outcomes [2835977] Summary . The metabolic effects of three diets were investigated in a r and omized study in 15 non‐pregnant women and 14 pregnant women in the third trimester ; all the women were of normal weight . After 2‐week periods of habituation to each diet , metabolic profiles were performed on st and ardized intakes . Diet 1 contained 40 % of energy as carbohydrate and 10 g dietary fibre representing typical Western intakes . Diet 2 contained 40 % energy as carbohydrate and 52 g dietary fibre and diet 3 contained 60 % of energy as carbohydrate and 84 g dietary fibre , representing typical developing world intakes . No deterioration in glucose homeostasis in pregnancy was seen on any of the three diets in contrast to previous work . On diet 1 there was a loss of insulin sensitivity in pregnancy , but not on diets 2 and 3 . The loss of insulin sensitivity which is typical of Western women in the third trimester of pregnancy and is considered to be physiological , may be a diet‐induced artefact [24351875] BACKGROUND Eating carbohydrate foods with a high glycemic index ( GI ) has been postulated to result in fetoplacental overgrowth and higher infant body fat . A diet with a low glycemic index ( LGI ) has been shown to reduce birth percentiles and the ponderal index ( PI ) . OBJECTIVES We investigated whether offering LGI dietary advice at the first antenatal visit would result in a lower fetal birth weight , birth percentile , and PI than providing healthy eating ( HE ) advice . This advice had to be presented within the re sources of routine antenatal care . DESIGN The Pregnancy and Glycemic Index Outcomes study was a 2-arm , parallel- design , r and omized , controlled trial that compared the effects of LGI dietary advice with HE advice on pregnancy outcomes . Eligible volunteers who attended for routine antenatal care at < 20 wk of gestation were r and omly assigned to either group . RESULTS A total of 691 women were enrolled , and 576 women had final data considered . In the LGI group , the GI was reduced from a mean ( ± SEM ) of 56 ± 0.3 at enrollment to 52 ± 0.3 ( P < 0.001 ) at the final assessment . There were no significant differences in primary outcomes of fetal birth weight , birth percentile , or PI . In a multivariate regression analysis , the glycemic load was the only significant dietary predictor ( P = 0.046 ) of primary outcomes but explained < 1 % of all variation . CONCLUSION A low-intensity dietary intervention with an LGI diet compared with an HE diet in pregnancy did not result in any significant differences in birth weight , fetal percentile , or PI [17181885] The aim of this study was to assess the impact of dietary counselling combined with the provision of food products on food and nutrient intake in pregnant women . We carried out a prospect i ve cohort study of healthy and atopic pregnant women ( n 209 ) , who were r and omized into dietary intervention and control groups . The intervention group received dietary counselling and food products to modify the fat composition of their diet to meet current recommendations . Three-day food records were collected during each trimester of pregnancy . Women in the intervention group consumed more vegetables , fruits , soft margarines and vegetable oils and less butter than those in the control group during the course of pregnancy ( P<0.05 ) . The main distinction between the groups in nutrient intake over the pregnancy was attributable to a higher energy intake ( % energy ) of PUFA by 0.5%energy ( 95 % CI 0.1 , 0.8 ) and to a lower intake of SFA by 0.8 % energy ( 95 % CI -1.4 , -0.4 ) in the intervention group . Dietary intake of vitamin E was 1.4 mg ( 95 % CI 0.6 , 2.2 ) , folate 20.9 microg ( 95 % CI 0.8 , 41.0 ) and ascorbic acid 19.8 mg ( 95 % CI 3.5 , 36.0 ) higher in the intervention group compared to the controls , while no differences in other nutrients were detected . Dietary counselling combined with the provision of food products during pregnancy is of importance in modifying food and nutrient intake , with potential health benefits [26178724] BACKGROUND Despite normal gestational weight gain , dietary studies in pregnant women show intakes below the recommendations for energy and micronutrients . OBJECTIVE This study compared changes in dietary intake from the second to third trimester with emphasis on energy intake and carbohydrate quality . DESIGN These post hoc analyses were based on 566 women participating in the Pregnancy and Glycemic Index Outcomes study , a r and omized controlled trial comparing the effect of low-glycemic index ( GI ) dietary advice with healthy eating advice on selected pregnancy outcomes . With the use of multilevel mixed-regression analysis , changes in total energy intake , starch , sugar , fiber intake , GI , and glycemic load ( GL ) were correlated with intake of different micronutrients . RESULTS Energy intake decreased in the third trimester , and most women did not meet the national recommended amounts for iron , folate , and dietary fiber from food sources alone . After adjustment for age , ethnicity , prepregnancy body mass index , and intervention group , change in energy intake was positively related to change in intake of all micronutrients ( P < 0.001 ) . GI , GL , and starch intake were inversely related to micronutrient intake ( P < 0.001 ) , whereas higher total sugars predicted higher intake ( P < 0.001 ) . Associations with dietary fiber were inconsistent . CONCLUSIONS Normal pregnancy can be associated with a decline in energy and micronutrient intake from diet . Low dietary GI and GL were the best predictors of a favorable micronutrient profile . This trial was registered at www.anzctr.org.au as ACTRN12610000174088 [22735030] The incidence of gestational diabetes mellitus ( GDM ) is increasing and GDM might be prevented by improving diet . Few interventions have assessed the effects of dietary counselling on dietary intake of pregnant women . This study examined the effects of dietary counselling on food habits and dietary intake of Finnish pregnant women as secondary outcomes of a trial primarily aim ing at preventing GDM . A cluster-r and omized controlled trial was conducted in 14 municipalities in Finl and , including 399 pregnant women at increased risk for developing GDM . The intervention consisted of dietary counselling focusing on dietary fat , fibre and saccharose intake at four routine maternity clinic visits . Usual counselling practice s were continued in the usual care municipalities . A vali date d 181-item food frequency question naire was used to assess changes in diet from baseline to 26 - 28 and 36 - 37 weeks gestation . The data were analysed using multilevel mixed-effects linear regression models . By 36 - 37 weeks gestation , the intervention had beneficial effects on total intake of vegetables , fruits and berries ( coefficient for between-group difference in change 61.6 g day(-1 ) , 95 % confidence interval 25.7 - 97.6 ) , the proportions of high-fibre bread of all bread ( 7.2 % units , 2.5 - 11.9 ) , low-fat cheeses of all cheeses ( 10.7 % units , 2.6 - 18.9 ) and vegetable fats of all dietary fats ( 6.1 % -units , 2.0 - 10.3 ) , and the intake of saturated fatty acids ( -0.67 energy-%-units , -1.16 to -0.19 ) , polyunsaturated fatty acids ( 0.38 energy-%-units , 0.18 - 0.58 ) , linoleic acid ( 764 mg day(-1 ) , 173 - 1354 ) and fibre ( 2.07 g day(-1 ) , 0.39 - 3.75 ) . The intervention improved diet towards the recommendations in pregnant women at increased risk for GDM suggesting the counselling methods could be implemented in maternity care [8610757] OBJECTIVE Our purpose was to assess to what extent disturbances in antepartum maternal metabolism and perinatal complications and morbidities contribute to poorer psychomotor development in offspring of diabetic mothers . STUDY DESIGN One hundred ninety-six pregnant women and their singleton offspring participated in this prospect i ve cohort-analytic study . Ninety-five women had pregestational diabetes mellitus , and 101 women had gestational diabetes mellitus . Serial estimates of circulating maternal fuels were obtained throughout each index pregnancy along with detailed records of the perinatal course and outcome . Offspring were administered the psychomotor development index of the Bayley Scales of Infant Development at age 2 years and the Bruininks-Oseretsky Test Of Motor Proficiency at ages 6 , 8 , and 9 years . Tests were performed blinded to the mother 's antepartum metabolic status , and perinatal history , and the child 's previous test scores . Partial correlations and analyses of covariance were used to control for other influences and confounds , such as family socioeconomic status , racial or ethnic origin , patient group ( i.e. , pregestational or gestational diabetes mellitus ) , and sex of child . RESULTS Children 's average score on the Bruininks-Oseretsky test at ages 6 to 9 years correlated significantly with maternal second ( p < 0.02 ) and third trimester ( p < 0.001 ) beta-hydroxybutyrate . There was also a borderline association between the children 's scores on the psychomotor development index at age 2 years and maternal third-trimester beta-hydroxybutyrate levels ( p = 0.06 ) . No other correlations approached significance . CONCLUSIONS Intrauterine metabolic experiences continue to influence the neurodevelopmental course in offspring of diabetic mothers . Prevailing practice s in diabetes management and obstetric and neonatal care appear to effectively mitigate the potential long-term effects of most perinatal complications and morbidities . Management and obstetric and neonatal care appear to effectively miltigate the potential long-term effects of most perinatal complications and morbidities [24717341] BACKGROUND Low-carbohydrate diets ( LCDs ) have been vastly popular for weight loss . The association between a low-carbohydrate dietary pattern and risk of gestational diabetes mellitus ( GDM ) remains unknown . OBJECTIVE We aim ed to prospect ively examine the association of 3 prepregnancy low-carbohydrate dietary patterns with risk of GDM . DESIGN We included 21,411 singleton pregnancies in the Nurses ' Health Study II . Prepregnancy LCD scores were calculated from vali date d food-frequency question naires , including an overall LCD score on the basis of intakes of carbohydrate , total protein , and total fat ; an animal LCD score on the basis of intakes of carbohydrate , animal protein , and animal fat ; and a vegetable LCD score on the basis of intakes of carbohydrate , vegetable protein , and vegetable fat . A higher score reflected a higher intake of fat and protein and a lower intake of carbohydrate , and it indicated closer adherence to a low-carbohydrate dietary pattern . RRs and 95 % CIs were estimated by using generalized estimating equations with log-binomial models . RESULTS We documented 867 incident GDM pregnancies during 10 y follow-up . Multivariable-adjusted RRs ( 95 % CIs ) of GDM for comparisons of highest with lowest quartiles were 1.27 ( 1.06 , 1.51 ) for the overall LCD score ( P-trend = 0.03 ) , 1.36 ( 1.13 , 1.64 ) for the animal LCD score ( P-trend = 0.003 ) , and 0.84 ( 0.69 , 1.03 ) for the vegetable LCD score ( P-trend = 0.08 ) . Associations between LCD scores and GDM risk were not significantly modified by age , parity , family history of diabetes , physical activity , or overweight status . CONCLUSIONS A prepregnancy low-carbohydrate dietary pattern with high protein and fat from animal-food sources is positively associated with GDM risk , whereas a prepregnancy low-carbohydrate dietary pattern with high protein and fat from vegetable food sources is not associated with the risk . Women of reproductive age who follow a low-carbohydrate dietary pattern may consider consuming vegetable rather than animal sources of protein and fat to minimize their risk of GDM [6315514] Summary Non-obese women in the second half of pregnancy were r and omised into a control group receiving st and ard dietary advice and a group advised to make high fibre whole-food substitutions in their diets at every opportunity . Glucose and insulin profiles were performed over 24-h periods at 29 and 35 weeks gestation when the diets were equivalent in available carbohydrate , protein and fat , but the control group ingested 12.4 g dietary fibre/24 h and the high fibre group 51.4g/24h . Glucose homeostasis was similar in both groups but there was a significant attenuation of post-pr and ial insulin secretion in the high fibre group . It is suggested that the characteristic post-pr and ial peaks of plasma insulin observed in Western pregnant women are an unphysiological response to dietary fibre depletion [24224882] Abstract We aim ed to explore whether maternal dietary counseling to increase the intake of unsaturated fatty acids ( FA ) is reflected in infant FA status . Serum cholesteryl ester ( CE ) and triacylglycerol ( TAG ) FA were analyzed from infants of 45 women r and omized to receive dietary counseling from the first trimester of pregnancy and 45 control women . Counseling result ed in a higher intake of polyunsaturated FA and a lower intake of saturated FA . The dietary intake was reflected in cord blood TAGs : the n−6 to n−3 FA ratio was lower [ mean difference −0.50 ( 95%CI −0.95 to −0.06 ) ] and the sum of n−3 FA was higher in the intervention than in the control group [ 1.46 ( 0.44 to 2.48)% of total FA ] . Reasons for the lack of changes in the cord blood CE fraction and FA fractions at 1-month remain unclear , but may indicate that the changes achieved in the maternal diet through counseling were too modest [22552037] BACKGROUND There is uncertainty regarding the efficacy of increasing n-3 long-chain PUFA ( LCPUFA ) intake during pregnancy in reducing the risk of gestational diabetes mellitus ( GDM ) and preeclampsia . OBJECTIVES The objective was to determine whether n-3 LCPUFA supplementation in pregnancy reduces the incidence of GDM or preeclampsia . A secondary objective was to assess the effect of n-3 LCPUFA supplementation on perinatal complications . DESIGN This was a double-blind , multicenter r and omized control trial-the DHA to Optimize Mother Infant Outcome ( DOMInO ) trial . Pregnant women ( n = 2399 ) of < 21 wk gestation were r and omly assigned to receive DHA-enriched fish oil ( 800 mg/d ) or vegetable oil capsules without DHA from trial entry to birth . The presence of GDM or preeclampsia was assessed through a blinded audit of medical records . Birth outcomes and prenatal complications were also assessed . RESULTS The overall incidences of GDM and preeclampsia were 8 % and 5 % , respectively , based on clinical diagnosis . The RR of GDM was 0.97 ( 95 % CI : 0.74 , 1.27 ) and of preeclampsia was 0.87 ( 95 % CI : 0.60 , 1.25 ) , and they did not differ significantly between the groups . Birth weight , length , and head circumference z scores also did not differ between the groups . There were 12 perinatal deaths and 5 neonatal convulsions in the control group compared with 3 perinatal deaths and no neonatal convulsions in the DHA group ( P = 0.03 in both cases ) . CONCLUSION DHA supplementation of 800 mg/d in the second half of pregnancy does not reduce the risk of GDM or preeclampsia . Whether supplementation reduces the risk of perinatal death and neonatal convulsions requires further investigation . The DOMInO trial was registered with the Australian New Zeal and Clinical Trials Registry as TRN12605000569606 [2923097] Background Annual prevalence of gestational diabetes mellitus ( GDM ) is 12.5 % among Finnish pregnant women . The prevalence is expected to rise with the increasing overweight among women before pregnancy . Physical activity and diet are both known to have favourable effects on insulin resistance and possibly on the risk of GDM . We aim ed to investigate , whether GDM can be prevented by counseling on diet , physical activity and gestational weight gain during pregnancy . Methods / Design A cluster-r and omized controlled trial was conducted in 14 municipalities in the southern part of Finl and . Pairwise r and omization was performed in order to take into account socioeconomic differences . Recruited women were at 8 - 12 weeks ' gestation and fulfilled at least one of the following criteria : body mass index ≥ 25 kg/m2 , history of earlier gestational glucose intolerance or macrosomic newborn ( > 4500 g ) , age ≥ 40 years , first or second degree relative with history of type 1 or 2 diabetes . Main exclusion criterion was pathological oral glucose tolerance test ( OGTT ) at 8 - 12 weeks ' gestation . The trial included one counseling session on physical activity at 8 - 12 weeks ' gestation and one for diet at 16 - 18 weeks ' gestation , and three to four booster sessions during other routine visits . In the control clinics women received usual care . Information on height , weight gain and other gestational factors was obtained from maternity cards . Physical activity , dietary intake and quality of life were followed by question naires during pregnancy and at 1-year postpartum . Blood sample s for lipid status , hormones , insulin and OGTT were taken at 8 - 12 and 26 - 28 weeks ' gestation and 1 year postpartum . Workability and return to work were elicited by a question naire at 1- year postpartum . Linkage to the national birth register of years 2007 - 2009 will provide information on perinatal complications and GDM incidence among the non- participants of the study . Cost-effectiveness evaluation will be based on quality -adjusted life years . This study has received ethical approval from the Ethical board of Pirkanmaa Hospital District . Discussion The study will provide information on the effectiveness and cost-effectiveness of gestational physical activity and dietary counseling on prevention of GDM in a risk group of women . Also information on the prevalence of GDM and postpartum metabolic syndrome will be gained . Results on maintaining the possible health behaviour changes are important in order to prevent chronic diseases such as cardiovascular disease and diabetes . Trial registration The trial is registered IS RCT N [24443392] OBJECTIVE Large for gestational age infants are at increased risk of childhood obesity and maternal nutrition impacts birthweight . The aim of this study was to assess the impact of a maternal low glycaemic index ( GI ) diet on neonatal anthropometry . METHODS The ROLO ( R and omised Control Trial of Low Glycaemic Index Diet in Pregnancy ) study was a r and omized controlled trial to assess the impact of a low GI diet versus usual diet on birthweight . It took place in a tertiary maternity hospital in Irel and and women were r and omized to receive either a low GI diet or no dietary intervention from early pregnancy to term . Two hundred sixty-five neonates had anthropometric measurements on day 1 - 2 of life , 126 in the intervention group and 139 in the control group . Measurements included birthweight , length and circumferences of the head , chest , abdominal , thigh and mid-upper arm . A subgroup of 219 ( 82 % ) neonates also had skin-fold measurements . RESULTS Neonates whose mothers had a low GI diet in pregnancy had lower thigh circumference ( 15.9 ± 1.7 cm vs. 16.6 ± 1.5 cm , P = 0.04 ) . There was no difference between the intervention and control groups in head , chest abdominal or mid-upper arm circumferences . No difference was noted between the two groups for any skin-fold measurements ( subscapular , thigh , biceps and triceps ) . CONCLUSION Neonatal thigh circumference was altered by maternal low GI diet in pregnancy . These findings suggest that maternal low GI diet is safe in pregnancy and may positively impact infant adiposity [26876000] OBJECTIVE To investigate the relationship between gestational diabetes mellitus ( GDM ) and the usual intake of fatty acids and indices of dietary fat quality [ the atherogenicity ( AI ) and thrombogenicity indices ( TI ) , and the ratios of hypo- and hypercholesterolemic ( hH ) , ∑n-3/∑n-6 , and polyunsaturated/saturated fatty acids ( P : S ) ] , during mid-pregnancy . METHODS 799 adult pregnant women living in Ribeirão Preto , SP , Brazil were screened and accepted for this cross-sectional GDM study . The Multiple Source Method was used to estimate participants ' usual diet , using two 24-hour dietary recalls during mid-pregnancy . Diagnosis of GDM was defined by the American Diabetes Association criteria of 2015 . Logistic regression analysis were used to assess the association between GDM and dietary fat , adjusted for age , education , parity , gestational age at the time of the interview , pre-pregnancy and current BMI , prior GDM , family history of diabetes , smoking , physical activity , energy , fiber , and fatty acids . RESULTS The mean ( st and ard deviation ) age of the women was 28 ( 5 ) years , and 19 % had GDM . After multiple adjustments , inverse associations between the highest tertile of ∑n-3 fatty acids intake [ 0.21 ( 0.08 - 0.56 ) ] , α-linolenic intake [ 0.15 ( 0.05 - 0.42 ) ] , and GDM were found . A positive association between GDM and the highest tertile of TI [ 2.66 ( 1.34 - 5.29 ) ] , and a negative association with the highest tertile of hH ratio [ 0.41 ( 0.22 - 0.77 ) ] , were observed . No association between GDM and other indices of dietary fat quality were found . CONCLUSION The quality of dietary fat during pregnancy is strongly associated with GDM . R and omized clinical trial are needed to confirm these findings [3096610] In a cluster-r and omized trial , Riitta Luoto and colleagues find that counseling on diet and activity can reduce the birthweight of babies born to women at risk of developing gestational diabetes mellitus ( GDM ) , but fail to find an effect on GDM [21310836] BACKGROUND Excessive weight gain during pregnancy is a major risk factor for postpartum weight retention and future weight gain and obesity in women , but few adequately powered r and omized controlled trials have examined the efficacy of a behavioral weight-control intervention during pregnancy . OBJECTIVE This study examined whether a behavioral intervention during pregnancy could decrease the proportion of women who exceeded the 1990 Institute of Medicine ( IOM ) recommendations for gestational weight gains and increase the proportion of women who returned to pregravid weights by 6 mo postpartum . DESIGN This study was a r and omized , assessor-blind , controlled trial . Participants were pregnant ( 13.5 wk gestation ) , normal-weight ( NW ; n = 201 ) and overweight or obese ( OW/OB ; n = 200 ) women whose average age was 28.8 y. Participants were r and omly assigned within the 1990 IOM weight category ( NW compared with OW/OB ) to st and ard care ( n = 200 ) or to a behavioral intervention to prevent excessive gestational weight gain ( n = 201 ) . The intervention included one face-to-face visit ; weekly mailed material s that promoted an appropriate weight gain , healthy eating , and exercise ; individual graphs of weight gain ; and telephone-based feedback . The retention at the 6-mo postpartum assessment was 82 % . RESULTS Intent-to-treat analyses showed that the intervention , compared with st and ard care , decreased the percentage of NW women who exceeded IOM recommendations ( 40.2 % compared with 52.1 % ; P = 0.003 ) and increased the percentages of NW and OW/OB women who returned to their pregravid weights or below by 6 mo postpartum ( 30.7 % compared with 18.7 % ; P = 0.005 ) . CONCLUSION A low-intensity behavioral intervention during pregnancy reduced excessive gestational weight gains in NW women and prevented postpartum weight retention in NW and OW/OB women . This trial was registered at clinical trials.gov as NCT01117961 Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND This is an up date of a Cochrane review first published in 2012 , Issue 4 . Excessive weight gain during pregnancy is associated with poor maternal and neonatal outcomes including gestational diabetes , hypertension , caesarean section , macrosomia , and stillbirth . Diet or exercise interventions , or both , may reduce excessive gestational weight gain ( GWG ) and associated poor outcomes ; however , evidence from the original review was inconclusive . OBJECTIVES To evaluate the effectiveness of diet or exercise , or both , interventions for preventing excessive weight gain during pregnancy and associated pregnancy complications . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

28368093

[26691209] BACKGROUND Alcoholic hepatitis ( AH ) is a distinct presentation of alcoholic liver disease arising in patients who have been drinking to excess for prolonged periods , which is characterised by jaundice and liver failure . Severe disease is associated with high short-term mortality . Prednisolone and pentoxifylline ( PTX ) are recommended in guidelines for treatment of severe AH , but trials supporting their use have given heterogeneous results and controversy persists about their benefit . OBJECTIVES The aim of the clinical effectiveness and cost-effectiveness of STeroids Or Pentoxifylline for Alcoholic Hepatitis trial was to resolve the clinical dilemma on the use of prednisolone or PTX . DESIGN The trial was a r and omised , double-blind , 2 × 2 factorial , multicentre design . SETTING Sixty-five gastroenterology and hepatology inpatient units across the UK . PARTICIPANTS Patients with a clinical diagnosis of AH who had a Maddrey 's discriminant function value of ≥ 32 were r and omised into four arms : A , placebo/placebo ; B , placebo/prednisolone ; C , PTX/placebo ; and D , PTX/prednisolone . Of the 5234 patients screened for the trial , 1103 were r and omised and after withdrawals , 1053 were available for primary end-point analysis . INTERVENTIONS Those allocated to prednisolone were given 40 mg daily for 28 days and those allocated to PTX were given 400 mg three times per day for 28 days . OUTCOMES The primary outcome measure was mortality at 28 days . Secondary outcome measures included mortality or liver transplant at 90 days and at 1 year . Rates of recidivism among survivors and the impact of recidivism on mortality were assessed . RESULTS At 28 days , in arm A , 45 of 269 ( 16.7 % ) patients died ; in arm B , 38 of 266 ( 14.3 % ) died ; in arm C , 50 of 258 ( 19.4 % ) died ; and in arm D , 35 of 260 ( 13.5 % ) died . For PTX , the odds ratio for 28-day mortality was 1.07 [ 95 % confidence interval ( CI ) 0.77 to 1.40 ; p = 0.686 ) ] and for prednisolone the odds ratio was 0.72 ( 95 % CI 0.52 to 1.01 ; p = 0.056 ) . In the logistic regression analysis , accounting for indices of disease severity and prognosis , the odds ratio for 28-day mortality in the prednisolone-treated group was 0.61 ( 95 % CI 0.41 to 0.91 ; p = 0.015 ) . At 90 days and 1 year there were no significant differences in mortality rates between the treatment groups . Serious infections occurred in 13 % of patients treated with prednisolone compared with 7 % of controls ( p = 0.002 ) . At the 90-day follow-up , 45 % of patients reported being completely abstinent , 9 % reported drinking within safety limits and 33 % had an unknown level of alcohol consumption . At 1 year , 37 % of patients reported being completely abstinent , 10 % reported drinking within safety limits and 39 % had an unknown level of alcohol consumption . Only 22 % of patients had attended alcohol rehabilitation treatment at 90 days and 1 year . CONCLUSIONS We conclude that prednisolone reduces the risk of mortality at 28 days , but this benefit is not sustained beyond 28 days . PTX had no impact on survival . Future research should focus on interventions to promote abstinence and on treatments that suppress the hepatic inflammation without increasing susceptibility to infection . TRIAL REGISTRATION This trial is registered as EudraCT 2009 - 013897 - 42 and Current Controlled Trials IS RCT N88782125 . FUNDING This project was funded by the National Institute for Health Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol . 19 , No. 102 . See the NIHR Journals Library website for further project information . The NIHR Clinical Research Network provided research nurse support and the Imperial College Biomedical Research Centre also provided funding [7037524] Sixty-seven patients entered a double-blind , controlled trial to evaluate the efficacy of propylthiouracil treatment in severe alcoholic hepatitis . Twenty-three percent ( 7 of 31 ) given propylthiouracil and 19 % ( 7 of 36 ) given placebo died during the 6-wk study . Propylthiouracil treatment did not reduce the frequency and incidence of complications in alcoholic hepatitis , but induced hypothyroidism in 4 patients . Treatment produced no beneficial effect on any of the hepatic biochemical tests . We were unable to show any beneficial effect of propylthiouracil treatment on morbidity and mortality in patients with severe acute alcoholic hepatitis [14672612] BACKGROUND / AIMS The effect of vitamin E administration on clinical and laboratory parameters of liver function and on markers of fibrogenesis was assessed in patients with mild to moderate alcoholic hepatitis in a double blind placebo controlled r and omized trial . METHODS Twenty-five patients received 1000 I.U. of vitamin E per day , while 26 patients received placebo for 3 months . The patients were followed for 1 year after entry into the trial . RESULTS Vitamin E did not result in significant greater decreases in serum aminotransferases and serum bilirubin or in greater increases in serum albumin as compared with placebo . Prothrombin time did not change , while serum creatinine remained in the normal range . Monocyte nuclear nuclear factor-kappa B binding activity decreased in patients who remained abstinent , regardless of whether they received vitamin E. As regards markers of hepatic fibrogenesis , vitamin E treatment decreased serum hyaluronic acid ( P<0.05 ) while serum aminoterminal peptide of type III procollagen did not change in either group . Four patients in the treatment group and five in the placebo group died during the 1-year study . CONCLUSIONS Vitamin E treatment improves serum hyaluronic acid but has no beneficial effects on tests of liver function in patients with mild to moderate alcoholic hepatitis [1959860] In a r and omized , controlled trial to investigate the possible benefit of insulin and glucagon therapy in severe acute alcoholic hepatitis , 86 patients were r and omized to receive 30 U insulin and 3 mg glucagon in 250 ml 5 % dextrose over 12 hr each day for 3 wk or a similar regime of identical placebo . No significant differences were seen in patients ' clinical characteristics and disease severity in the treated and placebo groups . Of the 43 patients receiving insulin and glucagon , 15 ( 35 % ) died within 4 wk of r and omization , compared with 14 deaths ( 33 % ) in the control patients ( p = not significant ) . When the patients surviving the first 4 wk were examined there were five more deaths in the treatment group , compared with one death in the control group at 6-mo follow-up ( p = not significant ) . No significant differences in the frequency of short-term or long-term complications of alcoholic liver disease or relapse to alcohol were seen when the two groups were compared , although hypoglycemia was seen in six patients during infusion of insulin and glucagon . Similarly , no significant differences were seen in the improvement in clinical or biochemical features at 4 wk and at 6 mo in survivors when the insulin and glucagon-treated patients were compared with patients in the placebo group . This study does not confirm previous reports that insulin and glucagon infusion improves the outcome of severe acute alcoholic hepatitis [8051381] The aim of this study was to examine the effect of malotilate on survival in patients with alcoholic liver disease and to determine prognostic variables for survival . Four hundred and seven patients with alcoholic liver diseases , from seven European liver units , entered a r and omized placebo-controlled , double-blind trial : 140 patients received malotilate 1500 mg/day , 133 patients received 750 mg/day , and 134 patients received placebo . The patients were included in the study over a period of 3 1/2 years , and the study was closed 1 year after the entry of the last patient . Eighty-four patients died ( 35 , 19 , 30 patients in groups 1500 mg/day , 750 mg/day , and placebo , respectively ) . Survival was slightly better in the 750 mg/day group than in the two other treatment groups , when tested by conventional log-rank tests ( p = 0.06 ) . However , a treatment effect was supported by a highly significant ( p = 0.006 ) non-proportionality of the death intensity in patients receiving 750 mg/day against those receiving either 1500 mg/day or placebo . Prognostic variables for survival were evaluated using the multiple Cox regression analysis of clinical and laboratory variables and with or without liver histology variables , as determined at entry into the study . The analysis was stratified for the three treatment regimens . In the analysis including liver histology variables , independent significant prognostic variables were : years of high alcohol intake , prothrombin index , alkaline phosphatases , creatinine , immunoglobulin M , white blood cell count , and liver cell steatosis . In the analysis without liver histology variables , prognostic variables were : years of high alcohol intake , prothrombin index , alkaline phosphatases , creatinine , and immunoglobulin [8014444] Although propylthiouracil has previously been shown to reduce the risk of mortality in alcoholic liver disease by 60 % , generalized use of propylthiouracil for this condition has not occurred . Additional data are therefore presented on four aspects to provide a better assessment of its therapeutic effectiveness . First , the characteristics and the prognosis of dropouts were virtually identical in both the drug and placebo groups . Also the methodology and analysis employed , were design ed to control for dropouts , thus providing an accurate interpretation of the outcome . Secondly , since 97 % of the patients continued to drink , abstinence was not a precondition for the beneficial effect of propylthiouracil . However , the beneficial effect was observed most clearly in those patients who continued to drink at lower levels , whereas lower level drinking per se did not afford protection in placebo patients . Thirdly , serious side effects or clinical hypothyroidism occurred extremely rarely in these patients , many of whom have now received propylthiouracil for over 4 years . Fourthly , we discuss why the outcome in long-term clinical trials in alcoholic liver disease can not be compared with effects observed in clinical trials lasting only a few weeks . Journal of Hepatology [8455312] A controlled trial on nutrition supplementation in ambulatory patients with decompensated alcoholic liver disease was carried out during 1 year . Fifty-one patients were studied ; 26 were assigned to an experimental group receiving a daily supplement of 1000 kcal and 34 g of proteins given as a casein-based enteral nutrition product and 25 to a control group receiving one placebo capsule . Patients were examined in a special clinic once a month or more if required . Sixty-eight percent of patients admitted to alcohol ingestion or had alcohol in urine sample s on at least one occasion . Dietary recalls showed a significantly higher protein and caloric intake in case patients subjects ( p < .0001 ) . Nine patients died during the study , three case patients and six control patients ( p = NS ) . The frequency of hospitalizations was significantly less in the experimental group . This difference was attributed to a reduction in severe infections . Mid-arm circumference , serum albumin concentration , and h and grip strength improved earlier in case patients , although both groups had a significant improvement in these parameters . Bilirubin and aspartate aminotransferase decreased and prothrombin time increased significantly in both groups during the study period , without differences between groups . It is concluded that nutrition support decreases nutrition-associated complications in patients with alcoholic liver disease [11113085] BACKGROUND & AIMS An earlier pilot study from our liver unit suggested benefit from treatment with pentoxifylline ( PTX ) , an inhibitor of tumor necrosis factor ( TNF ) , in severe acute alcoholic hepatitis . The aim of the present study was to evaluate this treatment in a larger cohort of patients . METHODS One hundred one patients with severe alcoholic hepatitis ( Maddrey discriminant factor > or = 32 ) entered a 4-week double-blind r and omized trial of PTX ( 400 mg orally 3 times daily ) vs. placebo . Primary endpoints of the study were the effect of PTX on ( 1 ) short-term survival and ( 2 ) progression to hepatorenal syndrome . On r and omization , there were no differences in demographic and clinical characteristics or laboratory values ( including TNF ) between the 2 groups . RESULTS Twelve ( 24.5 % ) of the 49 patients who received PTX and 24 ( 46.1 % ) of the 52 patients who received placebo died during the index hospitalization ( P = 0.037 ; relative risk , 0.59 ; 95 % confidence interval , 0.35 - 0.97 ) . Hepatorenal syndrome was the cause of death in 6 ( 50 % ) and 22 ( 91.7 % ) patients ( P = 0.009 ; relative risk , 0.29 ; 95 % confidence interval , 0.13 - 0.65 ) . Three variables ( age , creatinine level on r and omization , and treatment with PTX ) were independently associated with survival . TNF values on r and omization were not predictive of survival ; however , during the study period they increased markedly in nonsurvivors compared with survivors in both groups . CONCLUSIONS Treatment with PTX improves short-term survival in patients with severe alcoholic hepatitis . The benefit appears to be related to a significant decrease in the risk of developing hepatorenal syndrome . Increasing TNF levels during the hospital course are associated with an increase in mortality rate [18942901] OBJECTIVE To assess the effect of pentoxiphylline ( a potent inhibitor of tumor necrosis factor alpha ) on survival , on systemic and portal hemodynamics , and on cardiac function in patients with alcoholic cirrhosis . DESIGN A r and omized double-blind placebo-controlled trial . SETTING A single center using parallel groups of patients to compare pentoxiphylline with placebo . PATIENTS We recruited 24 patients with alcoholic cirrhosis ( 8 Child-Pugh B and 16 Child-Pugh C ) . INTERVENTIONS Patients were r and omly assigned to receive pentoxiphylline ( 400 mg tid ; n = 12 ) or placebo ( n = 12 ) over a 4-week period . OUTCOME MEASURES The primary outcome was to extend short-term and long-term survival . Secondary outcomes included hemodynamic benefits ( improvement in cardiac function and /or systemic vascular resistance index , or decrease in portal pressure ) . RESULTS Portal pressure and cardiac function remained unchanged and there were no significant differences in short-term or long-term survival between treatment and placebo groups . The group on pentoxiphylline increased systemic vascular resistance and decreased cardiac indices ( from 1,721 + /- 567 to 2,082 + /- 622 dyn.sec(-1 ) cm(-5 ) m(-2 ) and from 4.17 + /- 1.4 to 3.4 + /- 0.9 l.m(-2 ) , p = 0.05 ) . CONCLUSIONS Although pentoxiphylline seems to provide some short-term hemodynamic benefits in patients with advanced alcoholic cirrhosis , this drug has no effect on survival or portal pressure in these patients [15449338] Mixed treatment comparison ( MTC ) meta- analysis is a generalization of st and ard pairwise meta- analysis for A vs B trials , to data structures that include , for example , A vs B , B vs C , and A vs C trials . There are two roles for MTC : one is to strengthen inference concerning the relative efficacy of two treatments , by including both ' direct ' and ' indirect ' comparisons . The other is to facilitate simultaneous inference regarding all treatments , in order for example to select the best treatment . In this paper , we present a range of Bayesian hierarchical models using the Markov chain Monte Carlo software WinBUGS . These are multivariate r and om effects models that allow for variation in true treatment effects across trials . We consider models where the between-trials variance is homogeneous across treatment comparisons as well as heterogeneous variance models . We also compare models with fixed ( unconstrained ) baseline study effects with models with r and om baselines drawn from a common distribution . These models are applied to an illustrative data set and posterior parameter distributions are compared . We discuss model critique and model selection , illustrating the role of Bayesian deviance analysis , and node-based model criticism . The assumptions underlying the MTC models and their parameterization are also discussed [15095765] OBJECTIVES To analyze sources search ed in Cochrane review s , to determine the proportion of trials included in review s that are indexed in major data bases , and to compare the quality of these trials with those from other sources . METHODS All new systematic review s in the Cochrane Library , Issue1 2001 , that were restricted to r and omized controlled trials ( RCTs ) or quasi- RCTs were selected . The sources search ed in the review s were recorded , and the trials included were checked to see whether they were indexed in four major data bases . Trials not indexed were checked to determine how they could be identified . The quality of trials found in major data bases was compared with those found from other sources . RESULTS The range in the number of data bases search ed per review ranged between one and twenty-seven . The proportion of the trials in the four data bases were Cochrane Controlled Trials Register = 78.5 % , MEDLINE = 68.8 % , Embase = 65.0 % , and Science/Social Sciences Citation Index = 60.7 % . Search ing another twenty-six data bases after Cochrane Controlled Trials Register ( CCTR ) , MEDLINE , and Embase only found 2.4 % additional trials . There was no significant difference between trials found in the CCTR , MEDLINE , and Embase compared with other trials , with respect to adequate allocation concealment or sample size . CONCLUSIONS There was a large variation between review s in the exhaustiveness of the literature search es . CCTR was the single best source of RCTs . Additional data base search ing retrieved only a small percentage of extra trials . Contacting authors and manufacturers to find unpublished trials appeared to be a more effective method of obtaining the additional better quality trials [24935272] OBJECTIVES : Severe alcoholic hepatitis has high short-term mortality . The aim of this study was to test the hypothesis that treatment of patients with alcoholic hepatitis with granulocyte colony-stimulating factor ( G-CSF ) might mobilize bone marrow – derived stem cells and promote hepatic regeneration and thus improve survival . METHODS : Forty-six patients with severe alcoholic hepatitis were prospect ively r and omized in an open study to st and ard medical therapy ( SMT ) plus G-CSF ( group A ; n=23 ) at a dose of 5 μg/kg subcutaneously every 12 h for 5 consecutive days or to SMT alone ( group B ; n=23 ) at a tertiary care center . We assessed the mobilization of CD34 + cells on day 6 , Child-Turcotte-Pugh ( CTP ) , model for end-stage liver disease ( MELD ) , and modified Maddrey ’s discriminant function ( mDF ) scores , and survival until day 90 . RESULTS : There was a statistically significant increase in the number of CD34 + cells in peripheral blood in group A as compared with group B ( P=0.019 ) after 5 days of G-GSF therapy . There was a significant reduction in median Δ change% in CTP , MELD , and mDF at 1 , 2 , and 3 months in group A as compared with group B ( P<0.05 ) . There was marked improvement in survival in group A as compared with group B ( 78.3 % vs. 30.4 % ; P=0.001 ) at 90 days . CONCLUSIONS : G-CSF is safe and effective in the mobilization of hematopoietic stem cells and improves liver function as well as survival in patients with severe alcoholic hepatitis [10406187] BACKGROUND / AIM The efficacy of S-adenosylmethionine ( AdoMet ) in the treatment of liver cell injury has been demonstrated in several experimental models . The aim of this study was to investigate the effects of AdoMet treatment in human alcoholic liver cirrhosis . METHODS A r and omized , double-blind trial was performed in 123 patients treated with AdoMet ( 1200 mg/day , orally ) or placebo for 2 years . All patients had alcoholic cirrhosis , and histologic confirmation of the diagnosis was available in 84 % of the cases . Seventy-five patients were in Child class A , 40 in class B , and 8 in class C. Sixty-two patients received AdoMet and 61 received placebo . RESULTS At inclusion into the trial no significant differences were observed between the two groups with respect to sex , age , previous episodes of major complications of cirrhosis , Child classification and liver function tests . The overall mortality/liver transplantation at the end of the trial decreased from 30 % in the placebo group to 16 % in the AdoMet group , although the difference was not statistically significant ( p = 0.077 ) . When patients in Child C class were excluded from the analysis , the overall mortality/liver transplantation was significantly greater in the placebo group than in the AdoMet group ( 29 % vs. 12 % , p = 0.025 ) , and differences between the two groups in the 2-year survival curves ( defined as the time to death or liver transplantation ) were also statistically significant ( p = 0.046 ) . CONCLUSIONS The present results indicate that long-term treatment with AdoMet may improve survival or delay liver transplantation in patients with alcoholic liver cirrhosis , especially in those with less advanced liver disease [24026598] IMPORTANCE Prednisolone or pentoxifylline is recommended for severe alcoholic hepatitis , a life-threatening disease . The benefit of their combination is unknown . OBJECTIVE To determine whether the addition of pentoxifylline to prednisolone is more effective than prednisolone alone . DESIGN , SETTING , AND PARTICIPANTS Multicenter , r and omized , double-blind clinical trial conducted between December 2007 and March 2010 in 1 Belgian and 23 French hospitals of 270 patients aged 18 to 70 years who were heavy drinkers with severe biopsy-proven alcoholic hepatitis , as indicated by recent onset of jaundice in the prior 3 months and a Maddrey score of at least 32 . Duration of follow-up was 6 months . The last included patient completed the study in October 2010 . None of the patients were lost to follow-up for the main outcome . INTERVENTION Patients were r and omly assigned to receive either a combination of 40 mg of prednisolone once a day and 400 mg of pentoxifylline 3 times a day ( n=133 ) for 28 days , or 40 mg of prednisolone and matching placebo ( n=137 ) for 28 days . MAIN OUTCOMES AND MEASURES Six-month survival , with secondary end points of development of hepatorenal syndrome and response to therapy based on the Lille model , which defines treatment nonresponders after 7 days of initiation of treatment . RESULTS In intention-to-treat analysis , 6-month survival was not different in the pentoxifylline-prednisolone and placebo-prednisolone groups ( 69.9 % [ 95 % CI , 62.1%-77.7 % ] vs 69.2 % [ 95 % CI ; 61.4%-76.9 % ] , P = .91 ) , corresponding to 40 vs 42 deaths , respectively . In multivariable analysis , only the Lille model and the Model for End-Stage Liver Disease score were independently associated with 6-month survival . At 7 days , response to therapy assessed by the Lille model was not significantly different between the 2 groups ( Lille model score , 0.41 [ 95 % CI , 0.36 - 0.46 ] vs 0.40 [ 95 % CI , 0.35 - 0.45 ] , P = .80 ) . The probability of being a responder was not different in both groups ( 62.6 % [ 95 % CI , 53.9%-71.3 % ] vs 61.9 % [ 95 % CI , 53.7%-70.3 % ] , P = .91 ) . The cumulative incidence of hepatorenal syndrome at 6 months was not significantly different in the pentoxifylline-prednisolone and the placebo-prednisolone groups ( 8.4 % [ 95 % CI , 4.8%-14.8 % ] vs 15.3 % [ 95 % CI , 10.3%-22.7 % ] , P = .07 ) . CONCLUSION AND RELEVANCE In patients with alcoholic hepatitis , 4-week treatment with pentoxifylline and prednisolone , compared with prednisolone alone , did not result in improved 6-month survival . The study may have been underpowered to detect a significant difference in incidence of hepatorenal syndrome , which was less frequent in the group receiving pentoxifylline . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01214226 [3766225] Abstract Background Alcoholic hepatitis is the most florid presentation of alcohol-related liver disease . In its severe form , defined by a Maddrey ’s discriminant function ( DF ) ≥32 , the 28-day mortality rate is approximately 35 % . A number of potential treatments have been subjected to clinical trials , of which two , corticosteroids and pentoxifylline , may have therapeutic benefit . The role of corticosteroids is controversial as trial results have been inconsistent , whereas the role of pentoxifylline requires confirmation as only one previous placebo-controlled trial has been published . Methods / design STOPAH is a multicentre , double-blind , factorial ( 2 × 2 ) trial in which patients are r and omised to one of four groups : 1.Group A : placebo / placebo2.Group B : placebo / prednisolone3.Group C : pentoxifylline / placebo4.Group D : pentoxifylline / prednisolone The trial aims to r and omise 1,200 patients with severe alcoholic hepatitis , in order to provide sufficient power to determine whether either of the two interventions is effective . The primary endpoint of the study is mortality at 28 days , with secondary endpoints being mortality at 90 days and 1 year . Discussion STOPAH aims to be a definitive study to resolve controversy around the existing treatments for alcoholic hepatitis . Eligibility criteria are based on clinical parameters rather than liver biopsy , which are aligned with st and ard clinical practice in most hospitals . The use of a factorial design will allow two treatments to be evaluated in parallel , with efficient use of patient numbers to achieve high statistical power . Trial registration EudraCT reference number : 2009 - 013897 - 42IS RCT N reference number : IS RCT [2707520] A r and omized double-blind trial of silymarin versus placebo was carried out in 116 patients with histologically proven alcoholic hepatitis , 58 of them with cirrhosis . Patients were not included in case of hepatic encephalopathy , contraindication to percutaneous liver biopsy , hepatocellular carcinoma , evident lack of discipline or refusal to enter the trial . Fifty-seven patients received silymarin orally 420 mg/day and 59 received placebo during 3 months . Biologic parameters were assessed in the serum , and a percutaneous liver biopsy was obtained at the start of the trial and 3 months later . Histologic scores of alcoholic hepatitis and fibrosis were established on each biopsy specimen by two independent pathologists . The 2 groups were comparable at inclusion ; 26 p. 100 of patients were lost to follow-up at 3 months , abstinence was obtained in 46 p. 100 of patients at the end of the trial . These percentages were similar in the two groups . Four patients died of hepatic failure during the trial , 3 in the placebo group . Significant improvement in the score of alcoholic hepatitis and serum amino transferase activity , was noted in both groups during the trial , irrespective of treatment with silymarin or placebo . No side-effects were noted . Our results suggest that silymarin 420 mg/d is not clinical ly relevant in the treatment of moderate alcoholic hepatitis [1727754] This prospect i ve study compared the effects of tube-fed nutrition with those of a regular diet in alcoholic liver disease . The high prevalence of malnutrition in patients with alcoholic liver disease requires clarification of the benefits of aggressive nutritional support . Patients were r and omly assigned a regular diet without or with tube-fed supplementation , delivering 1.5 g/kg protein and 167 kJ/kg daily . Comparisons of encephalopathy , antipyrine clearance , metabolic rate , and biochemical parameters were performed weekly for 4 weeks . Sixteen patients receiving enteral supplementation had antipyrine half-life ( 50 % vs. 3 % reduction ) , serum bilirubin ( 25 % vs. 0 % reduction ) , and median encephalopathy scores that improved more rapidly than those of controls . Initially , 15 controls did not consume adequate calories to meet measured resting energy expenditure . Aggressive nutritional intervention accelerated improvement in alcoholic liver disease . Adverse effects did not offset the demonstrated benefits of a 2-cal/mL , casein-based tube-fed supplement . These findings support the use of st and ard , casein-based solutions in the treatment of alcoholic liver disease and as the control condition for future studies [19340904] AIM To compare the efficacy of pentoxifylline and prednisolone in the treatment of severe alcoholic hepatitis , and to evaluate the role of different liver function scores in predicting prognosis . METHODS Sixty-eight patients with severe alcoholic hepatitis ( Maddrey score > or = 32 ) received pentoxifylline ( n = 34 , group I ) or prednisolone ( n = 34 , group II ) for 28 d in a r and omized double-blind controlled study , and subsequently in an open study ( with a tapering dose of prednisolone ) for a total of 3 mo , and were followed up over a period of 12 mo . RESULTS Twelve patients in group II died at the end of 3 mo in contrast to five patients in group I. The probability of dying at the end of 3 mo was higher in group II as compared to group I ( 35.29 % vs 14.71 % , P = 0.04 ; log rank test ) . Six patients in group II developed hepatorenal syndrome as compared to none in group I. Pentoxifylline was associated with a significantly lower model for end-stage liver disease ( MELD ) score at the end of 28 d of therapy ( 15.53 + /- 3.63 vs 17.78 + /- 4.56 , P = 0.04 ) . Higher baseline Maddrey score was associated with increased mortality . CONCLUSION Reduced mortality , improved risk-benefit profile and renoprotective effects of pentoxifylline compared with prednisolone suggest that pentoxifylline is superior to prednisolone for treatment of severe alcoholic hepatitis [2954078] Whether or not prednisolone ( or prednisone ) should be used to treat alcoholic hepatitis remains controversial . This new controlled study performed on 45 patients with steatosis , fibrosis or cirrhosis of the liver suggests that prednisolone is not effective : after a 3-month follow-up clinical course , biochemical alterations , anatomical lesions and portal hypertension were the same in patients treated with prednisolone and in those who did not receive that drug [22044287] BACKGROUND S-adenosyl-L-methionine ( SAM ) is the methyl donor for all methylation reactions and regulates the synthesis of glutathione , the main cellular antioxidant . Previous experimental studies suggested that SAM may benefit patients with established alcoholic liver diseases ( ALDs ) . The aim of this study was to determine the efficacy of SAM in treatment for ALD in a 24-week trial . The primary endpoints were changes in serum aminotransferase levels and liver histopathology scores , and the secondary endpoints were changes in serum levels of methionine metabolites . METHODS We r and omized 37 patients with ALD to receive 1.2 g of SAM by mouth or placebo daily . Subjects were required to remain abstinent from alcohol drinking . A baseline liver biopsy was performed in 24 subjects , and a posttreatment liver biopsy was performed in 14 subjects . RESULTS Fasting serum SAM levels were increased over timed intervals in the SAM treatment group . The entire cohort showed an overall improvement of AST , ALT , and bilirubin levels after 24 weeks of treatment , but there were no differences between the treatment groups in any clinical or biochemical parameters nor any intra- or intergroup differences or changes in liver histopathology scores for steatosis , inflammation , fibrosis , and Mallory-Denk hyaline bodies . CONCLUSIONS Whereas abstinence improved liver function , 24 weeks of therapy with SAM was no more effective than placebo in the treatment for ALD [2199290] Colchicine treatment was used in this r and omized placebo-controlled trial in patients with severe acute alcoholic hepatitis [ serum bilirubin greater than or equal to 5 mg/dL ( 85.5 mumol/L ) mean , 17.5 + /- 7.5 mg/dL ( 299.25 + /- 128.25 mumol/L ) ] . Hospitalization mortality and morbidity and the effect on biochemical test results were the end points of the treatment . Patients in the two groups were evenly matched by demographics and laboratory test results . Mean time to study entry was less than 7 days from admission . The duration of the trial was 30 days . Thirty-six patients ( 24 men , 12 women ) received colchicine ( 1 mg orally every morning ) and 36 ( 25 men , 11 women ) received an identical placebo . Seven ( 19 % ) colchicine-treated and six ( 17 % ) control patients died during the index hospitalization after a mean of 17.4 + /- 10.8 and 17.8 + /- 5.3 days , respectively ( NS ) . During a 4-month follow-up period from entry into the trial , there were two additional deaths in each group . No differences between placebo- and colchicine-treated patients were observed in any of the laboratory parameters ( serum bilirubin , aspartate transaminase , alanine transaminase , prothrombin activity , albumin , white blood cell count , hemoglobin , and creatinine ) that were followed up over the 30-day treatment period . The frequency of complications did not differ statistically between the two groups . This study showed no effect of colchicine treatment on mortality and morbidity of severe alcoholic hepatitis . Colchicine can not be recommended for the treatment of patients with alcoholic hepatitis [3616287] Methods for combining data from several studies exist and appear to be quite useful . None satisfactorily addresses the question of what studies should be combined . This issue is the most serious method ological limitation . Even studies with statistically significant interaction might still be combined if the effect were in the same direction . Thus , substantial scientific input is required as to what criteria must be met by each potential study . Much can be learned from combining or pooling data but it must be done cautiously . Pooling exercises do not replace well design ed prospect i ve clinical trials . Efforts for establishing basic design criteria to allow for multicentre and multicountry trials to be more easily combined might be useful . [23029716] BACKGROUND Role of corticosteroids in treatment of severe alcoholic hepatitis ( SAH ) is controversial . Pentoxifylline ( PTX ) , an inhibitor of TNF , has also been shown to decrease short term mortality in SAH . Aim of this study was to evaluate the effect of PTX on short term mortality , renal and hepatic functions in patients with SAH . METHODS Fifty patients with SAH { Maddrey 's Discriminant Function ( DF ) > or = 32 } were prospect ively enrolled . Twenty five patients received PTX ( 400 mg orally , three times a day ) , and 25 received placebo for 4 weeks . Serum tumor necrosis factor ( TNF ) was measured in both groups . RESULTS Baseline characteristics of the two groups were similar . At 4 weeks , mortality in PTX group was lower than that in controls { 20 % ( 5/25 ) versus 40 % ( 10/25 ) respectively ; p = 0.216 ; RR 0.5 ; 95 % CI 0.19 - 1.25}. Renal failure was the cause of mortality in 20 % ( 1/5 ) patients in PTX group , and 70 % ( 7/10 ) in controls ( p = 0.11 ) . Significant reduction in urea , creatinine , DF and TNF was noted in PTX group . Reduction in TNF did not correlate with reduction in creatinine or DF . CONCLUSIONS In patients with SAH , PTX leads to a significant improvement in renal and hepatic functions , and a trend towards decreased short term mortality [2691239] The effects of a nutritional support in hospitalized patients with alcoholic cirrhosis and liver failure were studied in a controlled protocol . Thirty-six patients were included , 17 were r and omly assigned to an experimental group and the rest to a control group . Experimentals received a diet aim ing at 50 kcal ( 209 kJ)/kg bodyweight/d and 1.5 g protein/kg bodyweight/d ( as proteins of high biological value ) . Controls received the st and ard diet prescribed by the attending physician . The severity of liver failure and the nutritional status on admission were similar in both groups . The measured energy intake in controls was 1813 + /- 121 kcal/d ( 7589 + /- 506 kJ/d ) and 2707 + /- 71 kcal/d ( 1131 + /- 297 kJ/d ) in experimentals ( P less than 0.001 ) . The protein intake in controls was 47 + /- 3.8 g/d and in experimentals 80 + /- 3 g/d ( P less than 0.001 ) . There were seven deaths during the study period ( two experimentals and five controls ) . No differences were observed in the evolution of liver failure , hepatic encephalopathy or nutritional status between both study groups . It is concluded that a higher energy and protein intake in these patients does not have adverse effects and is associated with a non-significant reduction in mortality [7790695] OBJECTIVE Alcohol ingestion promotes lipoperoxidation and alters cellular antioxidant mechanisms . Alpha-tocopherol levels decrease in alcoholics as severity of liver damage increases . The aim of this protocol was to study the effects of a long-term oral 500 mg vitamin E daily supplementation in decompensated ambulatory alcoholic cirrhotics . PATIENTS AND METHODS 67 subjects were included in this double blind trial ; 33 patients received vitamin E and 34 patients received placebo tablets of identical appearance during 1 year . Each month , the patients were seen by a nurse practitioner who was in charge of detecting alcohol ingestion and checking adherence to treatment . Every 3 months , the patients underwent a medical examination , and blood sample s were taken for clinical laboratory analysis and serum vitamin E measurement . RESULTS Alpha-tocopherol levels were significantly lower in patients with more severe liver disease . This difference was not significant when vitamin E levels were corrected by cholesterol . Oral supplementation significantly increased serum vitamin E levels in the experimental group . Alcohol ingestion and hospitalization rates were similar in both groups . Life table analysis did not show significant differences in mortality between the two groups . DISCUSSION Vitamin E supplementation with adequate doses of an alpha-tocopheryl acetate formulation during 1 year did not influence hepatic laboratory parameters , mortality or hospitalization rates of decompensated alcoholic cirrhotics , although serum levels of the vitamin significantly increased [9514531] BACKGROUND / AIMS Calcium channel blockers have a hepatoprotective action in animal models of alcohol-induced liver injury but their effect in alcoholic liver disease in humans has not been previously investigated . We have conducted a r and omised , placebo-controlled trial to investigate the possible benefit of the calcium channel blocker amlodipine in terms of 4-week survival in hospitalised patients with severe acute alcoholic hepatitis . METHODS Sixty-two patients with acute alcoholic hepatitis were r and omised to receive 5 - 10 mg amlodipine each day for 1 year or an identical capsule containing placebo . In 36 ( 58 % ) , acute alcoholic hepatitis was confirmed on biopsy and in the remainder on clinical and laboratory criteria . There were no statistically significant differences in clinical characteristics and disease severity in the treated and placebo groups . RESULTS Of the 32 patients receiving amlodipine , there were six deaths ( 19 % ) in the first 4 weeks compared with seven ( 23 % ) of the placebo patients ( p=0.329 ) . Causes of death were similar in the amlodipine and control groups , with liver failure predominant . Analysis by the Cox proportional hazards model after adjustment for other prognostic factors showed survival was not significantly influenced by active treatment ( p=0.07 ) . One patient in each group was withdrawn because of the development of hypotension , but this did not recur on re introduction of the capsules . CONCLUSIONS This study shows that calcium channel blockers are well tolerated with few side effects in advanced alcoholic liver disease , but there is no conclusive evidence from this study that calcium channel blockers are helpful in the treatment of alcoholic hepatitis [8256468] Toxic liver diseases coincide with oxidative stress correlating positively with the seriousness of the course of disease . For the purpose of elucidating the pathogenic significance of an increased radical generation . 56 patients suffering from acute alcohol-toxic hepatitis of the clinical grade of seriousness B and C according to Child/Pugh were classified r and omly into antioxidant subgroups ( n = 31 ) and control groups (= 25 ) . The basis therapy being identical , the patients of the antioxidant group received additionally 600 mg of D-alpha tocopherol per day , 200 micrograms of selenium and 12 mg of zinc . Due to the supplementation of antioxidants there were quicker significant changes in the concentration of bilirubin , malondialdehyde and of ammonia in the serum . In comparison with the control group the length of stay in hospital could be reduced by 6 days . In the control group the mortality rates amounted to 40 % ( 10 of 25 ) , in the antioxidant group to 6.5 % ( 2 of 31 ) . The results confirm the pathogenic significance of oxidative stress in alcohol-toxic liver disease because a distinct improvement of prognosis could be achieved by using a low-cost adjuvant antioxidant supplementation [2753302] A r and omized double-blind trial of colchicine vs placebo was conducted in 67 patients with histologically proven alcoholic hepatitis , 33 of whom had cirrhosis . Patients with hepatic encephalopathy , ascites , protracted prothrombin time , severe thrombocytopenia , hepatocellular carcinoma , evident lack of discipline or refusal to participate in the trial were not included . Thirty-three patients received colchicine ( 1 mg/day ) and 34 received placebo for 6 months . Blood parameters including N-terminal peptide of type III procollagen were assessed in the serum , and a percutaneous liver biopsy was performed at the start of the trial and after 3 and 6 months . Alcoholic hepatitis and fibrosis scores were established for each biopsy specimen . Twenty-eight percent of patients were lost to follow-up at 3 months , and fifty-two percent at 6 months . One patient died of liver failure . Fifty-eight percent of patients were abstaining from alcohol at 3 months and fifty percent at 6 months . No significant effect of treatment was noted . Nevertheless , improvement in alcoholic hepatitis core at 3 months was more important in the colchicine group than in the placebo group . No side-effects were noted except transient diarrhea . Our results suggest that colchicine has no important effect on the course of alcoholic hepatitis . A trial including of at least 260 patients might be necessary for the observed alcoholic hepatitis score difference at 3 months , favoring colchicine , to be statistically significant [3082733] Between March 1982 and September 1983 , 40 in patients ( 25 men and 15 women , mean age 53 years ) with alcoholic cirrhosis and total serum bilirubin greater than or equal to 5 mg per dl were studied . Those with hepatocellular carcinoma , renal failure , hyponatremia , septicemia , spontaneous bacterial peritonitis , gastrointestinal bleeding , and hepatic coma were excluded . Patients were studied for 28 days . The two groups were offered an oral diet containing 40 kcal per kg per day . Patients in the supplementary parenteral nutrition group received 40 kcal per kg per day and 200 mg nitrogen per kg per day using a central catheter . The major endpoint was total serum bilirubin on Day 28 . On admission , serum bilirubin was not significantly different in the two groups : oral group , 12.5 + /- 6.6 mg per dl ; supplementary parenteral nutrition group , 12.3 + /- 8.5 mg per dl . On Day 28 , serum bilirubin was lower in the supplementary parenteral nutrition group ( 2.5 + /- 1.4 mg per dl ) than in the oral group ( 4.1 + /- 2.2 mg per dl ) ( p less than 0.02 ) . Serum bilirubin was also lower in the supplementary parenteral nutrition group than in the oral group on Days 7 , 14 and 21 ( p less than 0.05 ) . Analysis of covariance , considering serum bilirubin on admission and at r and omization and time between admission and r and omization , confirmed these results . On Day 28 , anthropometric parameters , serum transferrin , prealbumin and retinol-binding protein were higher in the supplementary parenteral nutrition group , but the differences were not significant . Serum albumin was significantly lower in the supplementary parenteral nutrition group . The incidence of encephalopathy and sepsis was not significantly different between the two groups [27337960] Purpose / background Severe alcoholic hepatitis ( AH ) is a life-threatening liver disease with a potential of 30–40 % mortality at 1 month . While steroids remain to be a first line therapy , they provide only about 50 % survival benefit . The aim of the study was to evaluate the efficacy of glucocorticoids plus S-adenosylmethionine ( SAMe ) , as compared to glucocorticoids alone , in patients with severe alcoholic hepatitis . Methods Forty patients with severe AH were r and omized in two groups and enrolled in the prospect i ve trial . Group 1 ( n = 20 ) patients received prednisolone 40 mg/daily per os , and group 2 ( n = 20 ) patients were managed with prednisolone 40 mg/daily per os plus SAMe 800 mg i.v . treatment . Duration was 28 days . Results The response rate assessed by Lille model was significantly higher in the prednisolone plus SAMe group ( 19 of 20 ; 95 % ) than in the prednisolone group ( 13 of 20 ; 65 % ) , p = 0.044 . Two ( 10 % ) patients died , both from the prednisolone group . There were no lethal outcomes in the prednisolone plus SAMe group . The Kaplan – Meier method showed no significant differences between the two groups ( p = 0.151 , log-rank ) . Hepatorenal syndrome ( HRS ) occurred in 20 % in the prednisolone group ( 4 of 20 patients ) while no HRS cases were registered in the prednisolone plus SAMe group ( p = 0.035 ) . Conclusions Management of severe alcoholic hepatitis with prednisolone plus SAMe was associated with better therapy response ( p = 0.044 ) and less frequent HRS occurrence ( p = 0.035 ) . Mortality was not significantly lower in the prednisolone – SAMe group than in the prednisolone-only group at 28 days ( 10 vs. 0 % , p = 0.151 ) [9566830] BACKGROUND / AIMS Silymarin has protective effects in different experimental conditions , but its efficacy in human liver cirrhosis has not been completely established . Therefore , this study was carried out to determine the effect of silymarin in alcoholics with liver cirrhosis with respect to survival and clinical and laboratory changes . METHODS From February 1986 to June 1989 , we enrolled 200 alcoholics with histologically or laparoscopically proven liver cirrhosis in a r and omized , double-blind multicenter trial comparing 450 mg of silymarin ( 150 mg/ three times per day ) with placebo . The primary outcome was time to death , and the secondary outcome was the progression of liver failure . Additional analyses were also performed in 75 patients in whom anti-hepatitis C virus antibodies were measured after completion of the trial . RESULTS One hundred and three patients were assigned to receive silymarin and 97 to receive placebo . The two groups were well matched for demographic and baseline clinical and laboratory features . A 2-year study period was completed in 125 patients ( 57 receiving silymarin and 68 receiving placebo ) . Twenty-nine patients ( 15 receiving silymarin , and 14 receiving placebo ) died during the trial . Survival was similar in patients receiving silymarin or placebo . The effect of silymarin on survival was not influenced by sex , the persistence of alcohol intake , the severity of liver dysfunction or by the presence of alcoholic hepatitis in the liver biopsy . Silymarin did not have any significant effect on the course of the disease . No relevant side-effects were observed in any group . CONCLUSIONS The results of this study indicate that silymarin has no effect on survival and the clinical course in alcoholics with liver cirrhosis [9126802] BACKGROUND / AIMS Several studies have demonstrated that diabetic patients with cirrhosis require insulin treatment because of insulin resistance . As chronic alcoholic liver damage is partly due to the lipoperoxidation of hepatic cell membranes , anti-oxidizing agents may be useful in treating or preventing damage due to free radicals . The aim of this study was to ascertain whether long-term treatment with silymarin is effective in reducing lipoperoxidation and insulin resistance in diabetic patients with cirrhosis . METHODS A 12-month open , controlled study was conducted in two well-matched groups of insulin-treated diabetics with alcoholic cirrhosis . One group ( n=30 ) received 600 mg silymarin per day plus st and ard therapy , while the control group ( n=30 ) received st and ard therapy alone . The efficacy parameters , measured regularly during the study , included fasting blood glucose levels , mean daily blood glucose levels , daily glucosuria levels , glycosylated hemoglobin ( HbA1c ) and malondialdehyde levels . RESULTS There was a significant decrease ( p<0.01 ) in fasting blood glucose levels , mean daily blood glucose levels , daily glucosuria and HbA1c levels already after 4 months of treatment in the silymarin group . In addition , there was a significant decrease ( p<0.01 ) in fasting insulin levels and mean exogenous insulin requirements in the treated group , while the untreated group showed a significant increase ( p<0.05 ) in fasting insulin levels and a stabilized insulin need . These findings are consistent with the significant decrease ( p<0.01 ) in basal and glucagon-stimulated C-peptide levels in the treated group and the significant increase in both parameters in the control group . Another interesting finding was the significant decrease ( p<0.01 ) in malondialdehyde/levels observed in the treated group . CONCLUSIONS These results show that treatment with silymarin may reduce the lipoperoxidation of cell membranes and insulin resistance , significantly decreasing endogenous insulin overproduction and the need for exogenous insulin administration [3142949] We performed a controlled trial of peripheral hyperalimentation in moderate and severe alcoholic hepatitis to determine whether improvement in survival and liver function could be obtained . Twelve patients with moderate and 22 with severe alcoholic hepatitis were r and omized to 28 days of peripheral parenteral nutrition ( PPN ) or st and ard therapy ( ST ) . In the moderate group , six were treated with each therapy . In the severe group , 10 were treated with PPN and 12 with ST . Routine liver tests , hepatocyte function ( galactose elimination capacity ) , estimated hepatic blood flow ( galactose clearance ) and assessment of ascites and encephalopathy were performed at r and omization and at 28 days . Groups were equally matched at r and omization . In the moderate group PPN produced no improvement in morbidity ( liver tests ) and mortality ( no deaths ) . In the severe group there were seven deaths ( 4 PPN , 3 ST ) . PPN produced greater improvement than ST in serum bilirubin and transferrin concentrations and a trend toward greater improvement in prothrombin time , serum albumin and galactose elimination capacity . PPN had no deleterious effect on encephalopathy or ascites as only ST patients developed ascites or encephalopathy after r and omization . We conclude that PPN compared to ST ( 1 ) provides no benefit in moderate alcoholic hepatitis , but ( 2 ) did more rapidly improve morbidity ( liver tests ) and probably liver function in severe alcoholic hepatitis ; ( 3 ) PPN did not improve early mortality , and ( 4 ) it had no deleterious effect on encephalopathy or ascites [15825072] BACKGROUND & AIMS Colchicine improved survival and reversed cirrhosis in several small clinical trials . We compared the efficacy and safety of long-term colchicine , as compared with placebo , in patients with advanced alcoholic cirrhosis . METHODS Five hundred forty-nine patients with advanced ( Pugh B or C ) alcoholic cirrhosis were r and omized to receive either colchicine 0.6 mg twice per day ( n = 274 ) or placebo ( n = 275 ) . Treatment lasted from 2 to 6 years . The primary outcome was all-cause mortality . Secondary outcomes were liver-related morbidity and mortality . Liver biopsy was requested prior to entry and after 24 months of treatment . RESULTS Attendance at scheduled clinic visits and adherence with study medication were similar in colchicine and placebo groups . Alcohol intake was less than 1 drink per day in 69 % of patients . In an intention-to-treat analysis , all-cause mortality was similar in colchicine ( 49 % ) and placebo ( 45 % ) patients ( P = .371 ) . Mortality attributed to liver disease was 32 % in colchicine and 28 % in placebo patients ( P = .337 ) . Fewer patients receiving colchicine developed hepatorenal syndrome . In 54 patients with repeat liver biopsies after 24 or more months of treatment , cirrhosis improved to septal fibrosis in 7 patients ( 3 colchicine , 4 placebo ) and to portal fibrosis in 1 patient ( colchicine ) . CONCLUSIONS In patients with advanced alcoholic cirrhosis , colchicine does not reduce overall or liver-specific mortality . Liver histology improves to septal fibrosis in a minority of patients after 24 months of treatment , with similar rates of improvement in patients receiving placebo and colchicine . Colchicine is not recommended for patients with advanced alcoholic cirrhosis [15122768] Tumor necrosis factor-alpha ( TNF-alpha ) may contribute to the progression of acute alcoholic hepatitis ( AAH ) . The aim of this study was to evaluate the efficacy of an association of infliximab and prednisolone at reducing the 2-month mortality rate among patients with severe AAH . Patients with severe AAH ( Maddrey score > /=32 ) were r and omly assigned to group A receiving intravenous infusions of infliximab ( 10 mg/kg ) in weeks 0 , 2 , and 4 ; or group B receiving a placebo at the same times . All patients received prednisolone ( 40 mg/day ) for 28 days . Blood neutrophil functional capacities were monitored over 28 days . After r and omization of 36 patients , seven patients from group A and three from group B died within 2 months . The probability of being dead at 2 months was higher ( not significant [ NS ] ) in group A ( 39 % + /- 11 % ) than in group B ( 18 % + /- 9 % ) . The study was stopped by the follow-up committee and the sponsor ( Assistance Publique-Hôpitaux de Paris ) . The frequency of severe infections within 2 months was higher in group A than in group B ( P < .002 ) . This difference was potentially related to a significantly lower ex vivo stimulation capacity of neutrophils . There were no differences between the two groups in terms of Maddrey scores at any time point . In conclusion , three infusions of 10 mg/kg of infliximab in association with prednisolone may be harmful in patients with severe AAH because of the high prevalence of severe infections [20881772] Objective : To evaluate patient survival and allograft function and health-related quality of life ( HRQOL ) 20 years after orthotopic liver transplantation ( LT ) . Summary of Background Data : Although LT is the established treatment of choice for acute and chronic liver failure , allograft function and recipient HRQOL 20 years after LT remain undefined . Methods : We performed a prospect i ve , cross-sectional study of LT recipients surviving 20 years or more . Clinical data were review ed to identify factors associated with 20-year survival . Survivors were directly contacted and offered a survey to assess HRQOL ( SF-36 ; Liver Disease Quality of Life ) , social support , and cognition ( Neuropsychological Impairment Scale ) . Logistic regression analysis was performed to identify clinical factors influencing HRQOL 20 years after LT . Results : Between February 1 , 1984 and December 31 , 1988 , a total of 293 patients ( 179 adults , 114 children ) received 348 LTs . Of the 293 patients , 168 ( 56 % ) survived for 20 years or more . Actuarial 20-year survival was 52 % ( patient ) and 42 % ( graft ) . Factors associated with 20-year survival included recipient age < 18 ( P = 0.01 ) , nonurgent LT ( P = 0.01 ) , no retransplantation ( 0.02 ) , female gender ( 0.03 ) , absence of biliary complications ( P = 0.04 ) , and short total ischemia time ( P = 0.05 ) . Rejection episodes were seen in a greater proportion of 20-year survivors than in nonsurvivors ( 35 % vs. 27 % ; P = 0.3 ) . Of the 168 survivors , 87 were contacted , and 68 ( 78 % ) completed the HRQOL surveys . Compared with the general population , survivors had lower physical scores ( P < 0.01 ) but comparable mental scores on the SF-36 . Overall HRQOL was significantly better in 20-year survivors than in patients with chronic liver disease , congestive heart failure , or diabetes . Clinical factors associated with improved post-LT HRQOL were younger age at LT , allograft longevity , and strong social support . More than 90 % of pediatric survivors completed high school . After LT , 34 % of pediatric recipients married , and 79 % remained married at 20 years ' follow-up . Conclusions : More than 50 % of LT recipients survive 20 years , achieve important socioeconomic milestones , and report quality of life superior to patients with liver disease or other chronic conditions . LT is a durable surgery that restores both long-term physiologic and psychologic well-being in patients with end-stage liver disease [20102716] BACKGROUND & AIMS Pentoxifylline , an inhibitor of tumor necrosis factor-alpha , is given to patients with liver diseases , but its effects in patients with advanced cirrhosis are unknown . We performed a r and omized , placebo-controlled , double-blind trial of its effects in patients with cirrhosis . METHODS A total of 335 patients with cirrhosis ( Child-Pugh class C ) were assigned to groups given either pentoxifylline ( 400 mg , orally , 3 times daily ; n = 164 ) or placebo ( n = 171 ) for 6 months . The primary end point was mortality at 2 months . Secondary end points were mortality at 6 months and development of liver-related complications . RESULTS By 2 months , 28 patients in the pentoxifylline group ( 16.5 % ) and 31 in the placebo group ( 18.2 % ) had died ( P = .84 ) . At 6 months , 50 patients in the pentoxifylline group ( 30.0 % ) and 54 in the placebo group ( 31.5 % ) had died ( P = .75 ) . The proportions of patients without complications ( eg , bacterial infection , renal insufficiency , hepatic encephalopathy , or gastrointestinal hemorrhage ) were higher in the pentoxifylline group than in the placebo group at 2 months ( 78.6 % vs 63.4 % ; P = .006 ) and 6 months ( 66.8 % vs 49.7 % ; P = .002 ) . The probability of survival without complications was higher in the pentoxifylline group than in the placebo group at 2 and 6 months ( P = .04 ) . In multivariate analysis , the factors associated with death were age , the Model for End-Stage Liver Disease score , and presence of early-stage carcinoma . Treatment with pentoxifylline was the only factor associated with liver-related complications . CONCLUSIONS Although pentoxifylline does not decrease short-term mortality in patients with advanced cirrhosis , it does reduce the risk of complications [4199180] Background : Prednisolone and pentoxifylline ( PTX ) have been shown to be individually useful in severe alcoholic hepatitis with Maddrey discriminant function ( MDF ) score ≥32 . Previous report suggests that PTX is probably superior to prednisolone alone . However the efficacy of PTX and prednisolone combination over PTX alone in the management of acute alcoholic hepatitis ( MDF score ≥32 ) is yet unrevealed . Aim : The present study was initiated to find out the efficacy of combined pentoxifylline and prednisolone versus PTX alone in acute alcoholic hepatitis in respect of short and intermediate term outcomes . Subjects and Methods : A total of 124 patients with severe alcoholic hepatitis ( MDF score ≥ 32 ) initially were evaluated . 62 patients who fulfilled the inclusion and exclusion criteria were r and omized and divided into 2 groups . Group 1 received PTX only , whereas Group 2 received PTX plus Prednisolone . The total duration of follow-up was 12 months . Student′s t-test , Chi-square test , the Kaplan-Meier methods were used for statistical analysis . Results : A total of 60 patients , 30 in each group were available for final analysis . In Group-1 , 6 patients expired at the end of 1 year ( 5 within 3 months and another after 3 months ) . In Group 2 , 10 patients expired at the end of 1 year ( 9 within 3 months and another after 3 months ) . Though survival probability is higher among Group 1 patients but the difference is not statistically significant . Conclusion : The combination of PTX plus Prednisolone yields no additional benefit in terms of mortality and morbidity from that of PTX monotherapy [18848937] BACKGROUND & AIMS Alcoholic hepatitis is a cause of major morbidity and mortality that lacks effective therapies . Both experimental and clinical evidence indicate that the multifunctional cytokine tumor necrosis factor-alpha ( TNF-alpha ) contributes to pathogenesis and clinical sequelae of alcoholic hepatitis . A pilot study demonstrated that the TNF-alpha-neutralizing molecule etanercept could be an effective treatment for patients with alcoholic hepatitis . METHODS Forty-eight patients with moderate to severe alcoholic hepatitis ( Model for End-Stage Liver Disease score > or = 15 ) were enrolled and r and omized to groups that were given up to 6 subcutaneous injections of either etanercept or placebo for 3 weeks . Primary study end points included mortality at 1- and 6-month time points . RESULTS There were no significant baseline differences between the placebo and etanercept groups in demographics or disease severity parameters including age , gender , and Model for End-Stage Liver Disease score . The 1-month mortality rates of patients receiving placebo and etanercept were similar on an intention-to-treat basis ( 22.7 % vs 36.4 % , respectively ; OR , 1.8 ; 95 % CI , 0.5 - 6.5 ) . The 6-month mortality rate was significantly higher in the etanercept group compared with the placebo group ( 57.7 % vs 22.7 % , respectively ; OR , 4.6 ; 95 % CI , 1.3 - 16.4 ; P = .017 ) . Rates of infectious serious adverse events were significantly higher in the etanercept group compared with the placebo group ( 34.6 % vs 9.1 % , respectively , P = .04 ) . CONCLUSIONS In patients with moderate to severe alcoholic hepatitis , etanercept was associated with a significantly higher mortality rate after 6 months , indicating that etanercept is not effective for the treatment of patients with alcoholic hepatitis [7035299] The efficacy of methylprednisolone ( 1 g daily or three days ) , which is effective in reversing transplant rejection , was assessed in a r and omised controlled trial of 55 patients with severe acute alcoholic hepatitis , 34 of whom had encephalopathy . The clinical progress , frequency of bleeding and sepsis , and cause of death were similar in the treatment ( 27 patients ) and control groups ( 28 patients ) . There was no significant difference in mortality rate between the two groups : 57 % of the control group and 63 % of the treatment group died during the study . Patients ' survival depended on the presence of absence of the following features : encephalopathy , serum bilirubin concentration more than 340 micromol/l , serum creatinine concentration more than 250 micromol/l , and histological evidence of cirrhosis as well as severe acute alcoholic hepatitis [2205560] Study Objective : To determine the efficacy of a corticosteroid in reducing the short‐term mortality of patients with 8evere alcoholic hepatitis [2648927] STUDY OBJECTIVE To determine the efficacy of a corticosteroid in reducing the short-term mortality of patients with severe alcoholic hepatitis . DESIGN R and omized , double-blind , placebo-controlled multicenter trial . SETTING Four university teaching hospitals . PATIENTS We enrolled 66 patients with alcoholic hepatitis and either spontaneous hepatic encephalopathy or a discriminant function value greater than 32 , calculated using the formula : 4.6 ( prothrombin time - control time ) + serum bilirubin [ in mumol/L]/17.1 . Fifty-nine patients ( 89 % ) completed the study . Two patients withdrew from the trial . The other 64 patients were hospitalized for the duration of the trial ; however , treatment was discontinued in 5 patients because of potential drug toxicity . INTERVENTIONS Patients were r and omly assigned to receive either methylprednisolone ( 32 mg ) or placebo within 7 days of admission . Treatment was given for 28 days . The doses were then tapered over 2 weeks and discontinued . MEASUREMENTS AND MAIN RESULTS The endpoint of the study was death . Of the 31 recipients of placebo , 11 ( 35 % ) died within 28 days of r and omization compared with 2 ( 6 % ) of the 35 patients given methylprednisolone ( P = 0.006 ) . The 95 % CI for the difference in mortality was 12 % to 70 % . In the patients with spontaneous hepatic encephalopathy at entry , 9 of 19 recipients of placebo died ( 47 % ) compared with 1 ( 7 % ) of the 14 patients given methylprednisolone ( P = 0.02 ) . The 95 % CI for the difference in mortality was 14 % to 66 % . The Cox proportional hazards regression model showed the advantage of methylprednisolone over placebo after adjustment for other potentially important prognostic variables ( P = 0.004 ) . CONCLUSIONS Methylprednisolone therapy decreases short-term mortality in patients with severe alcoholic hepatitis manifested either by spontaneous hepatic encephalopathy or a markedly elevated discriminant function value [28839840] Philip Hendy review s Thursz et al. 1The r and omized double blind placebo controlled Steroids or Pentoxifylline for Alcoholic Hepatitis ( STOPAH ) trial demonstrates that pentoxifylline does not improve mortality in severe alcoholic hepatitis at 28 days or beyond . It also demonstrates that prednisolone provides a non-significant mortality benefit at 28 days which does not persist to 90 days or beyond and is associated with increased risk of infection . Alcoholic hepatitis is a syndrome characterised by jaundice and liver dysfunction in the setting of significant long-term alcohol excess . Severe disease is associated with high mortality—30 % at 1 month and 40 % at 6 months.2 , 3 Treatment consists of organ support as required , as well as steroid and or pentoxifylline ( PTX ) therapy , both of which are included in national and international management guidelines . The European Association for the Study of the Liver guidelines include steroids and , in the case of ongoing sepsis , PTX.4 [8964410] BACKGROUND & AIMS Corticosteroids have been shown to significantly decrease short-term mortality in patients with severe alcoholic hepatitis . However , independent factors associated with a favorable outcome and long-term survival are unknown . The aim of this study was to examine prognostic factors and long-term survival in patients with biopsy-proven severe alcoholic hepatitis . METHODS Of 183 patients studied , 61 had been r and omized in a previous trial ; 32 of them were treated with prednisolone ( group I ) and 29 were not treated ( group II ) ; 61 were treated from the end of this r and omized trial ( group III ) ; and 61 were simulated ( group IV ) . RESULTS At 1 year , survival in group I ( 69 % ; confidence interval [ CI ] , 57%-81 % ) and group III ( 71 % ; CI , 55%-87 % ) was better than in the nontreated groups ( group II , 41 % ; CI , 23%-59 % ; P = 0.01 ) ( group IV , 50 % ; CI , 37%-63 % ; P = 0.05 ) . At 2 years , survival was not significantly different . Treated patients with marked liver polymorphonuclear infiltrate had better 1-year survival ( 76 % ; CI , 64%-88 % ) than the others ( 53 % ; CI , 35%-71 % ; P = 0.05 ) . Treated patients with polymorphonuclear counts of > 5500/mm3 had better 1-year survival ( 77 % ; CI , 65%-89 % ) than the others ( 40 % ; CI , 14%-66 % ; P = 0.003 ) . In the 93 treated patients , liver polymorphonuclear infiltrate ( P < 0.03 ) and polymorphonuclear count ( P < 0.001 ) were independently correlated with 1-year survival . CONCLUSIONS Prednisolone reduced mortality by at least 1 year . Liver polymorphonuclear infiltrate and polymorphonuclear count were independent prognostic factors [3932509] Sixty-four patients admitted with acute alcoholic hepatitis , with or without underlying cirrhosis , were r and omized regardless of encephalopathy to receive a controlled diet either alone , or supplemented orally , nasogastrically , or intravenously as necessary , with 2000 kCal and 10 g nitrogen daily . Whether this came from a conventional protein source or a branched chain amino acid enriched formulation was also r and omly determined . In the absence of renal failure , nitrogen intakes of 10 g or more daily were invariably associated with positive nitrogen balance , but complications of liver dysfunction prevented the attainment of significantly more positive balance in the supplemented groups than in controls . Neither in the series as a whole , nor in any identifiable subgroup of patients , was mortality affected by treatment . Changes in prothrombin time and in measured nutritional parameters during the study did not differ between supplemented and control groups , and the observed changes in midarm muscle circumference appeared to reflect changes in degree of fluid retention . Neither enteral nor parenteral branched chain amino acids showed any consistent effect upon encephalopathy [12668982] The aim of our multicenter study was to assess the efficacy of ursodeoxycholic acid ( UDCA ) on the survival of patients with alcohol‐induced cirrhosis and jaundice . We included patients with histologically proven alcohol‐induced cirrhosis and serum bilirubin > 50 μmol/L. After r and omization , patients received either UDCA ( 13‐15 mg/kg/d ) or a placebo for 6 months . Two hundred twenty‐six patients ( 113 in each group ) were included in 24 centers . There were 139 men and 87 women , mean age of 50.3 years . Seventy‐four percent had associated alcohol‐induced hepatitis , and 24 % received a corticosteroid therapy . At inclusion , the 2 groups were comparable for the main clinical and biologic parameters , but serum bilirubin was higher in the UDCA group than in the placebo group ( 163 μmol/L vs. 145 μmol/L , P < .03 ) . The percentage of patients lost at follow‐up or who resumed their alcoholism during the study was comparable in the 2 groups . During the study , 55 patients died , 35 in the UDCA group and 20 in the placebo group . In the intention to treat analysis , the probability of survival at 6 months ( Kaplan‐Meier method ) was lower in the UDCA than in the P group ( 69 % vs. 82 % , respectively ; P = .04 , log‐rank test ) . After adjustment on the bilirubin level at entry ( Cox model ) , the independent predictive value of the treatment group did not reach the statistical level ( RR = 1.64 , CI 0.85‐2.85 ; P = .077 ) . In conclusion , UDCA administered at the dose recommended in primary biliary cirrhosis has no beneficial effect on the 6‐month survival of patients with severe alcohol‐induced cirrhosis . An inappropriate dosage of UDCA can not be excluded as an explanation for the lack of therapeutic benefit [356593] In a prospect i ve double-blind study , 27 patients with alcoholic hepatitis were r and omized for 6-methylprednisolone ( 12 patients ) or placebo treatment ( 15 patients ) . The mortality was 50 % among steroid treated patients and 47 % in the control group ( P less than .05 ) . The role of liver biopsy feasibility at selection is emphasized since the mortality in this group was 10 % as opposed to 71 % when the procedure was contraindicated ( P less than .01 ) . Complications in the steroid-treated subjects were similar quantitatively and qualitatively to those observed in the control series [2844940] The CONSORT statement is used worldwide to improve the reporting of r and omised controlled trials . Kenneth Schulz and colleagues describe the latest version , CONSORT 2010 , which up date s the reporting guideline based on new method ological evidence and accumulating [22070475] BACKGROUND Mortality among patients with severe acute alcoholic hepatitis is high , even among those treated with glucocorticoids . We investigated whether combination therapy with glucocorticoids plus N-acetylcysteine would improve survival . METHODS We r and omly assigned 174 patients to receive prednisolone plus N-acetylcysteine ( 85 patients ) or only prednisolone ( 89 patients ) . All patients received 4 weeks of prednisolone . The prednisolone-N-acetylcysteine group received intravenous N-acetylcysteine on day 1 ( at a dose of 150 , 50 , and 100 mg per kilogram of body weight in 250 , 500 , and 1000 ml of 5 % glucose solution over a period of 30 minutes , 4 hours , and 16 hours , respectively ) and on days 2 through 5 ( 100 mg per kilogram per day in 1000 ml of 5 % glucose solution ) . The prednisolone-only group received an infusion in 1000 ml of 5 % glucose solution per day on days 1 through 5 . The primary outcome was 6-month survival . Secondary outcomes included survival at 1 and 3 months , hepatitis complications , adverse events related to N-acetylcysteine use , and changes in bilirubin levels on days 7 and 14 . RESULTS Mortality was not significantly lower in the prednisolone-N-acetylcysteine group than in the prednisolone-only group at 6 months ( 27 % vs. 38 % , P = 0.07 ) . Mortality was significantly lower at 1 month ( 8 % vs. 24 % , P = 0.006 ) but not at 3 months ( 22 % vs. 34 % , P = 0.06 ) . Death due to the hepatorenal syndrome was less frequent in the prednisolone-N-acetylcysteine group than in the prednisolone-only group at 6 months ( 9 % vs. 22 % , P = 0.02 ) . In a multivariate analysis , factors associated with 6-month survival were a younger age ( P<0.001 ) , a shorter prothrombin time ( P<0.001 ) , a lower level of bilirubin at baseline ( P<0.001 ) , and a decrease in bilirubin on day 14 ( P<0.001 ) . Infections were less frequent in the prednisolone-N-acetylcysteine group than in the prednisolone-only group ( P = 0.001 ) ; other side effects were similar in the two groups . CONCLUSIONS Although combination therapy with prednisolone plus N-acetylcysteine increased 1-month survival among patients with severe acute alcoholic hepatitis , 6-month survival , the primary outcome , was not improved . ( Funded by Programme Hospitalier de Recherche Clinique ; AAH-NAC Clinical Trials.gov number , NCT00863785 . ) [10869286] Steroids are recommended in severe alcohol-induced hepatitis , but some data suggest that artificial nutrition could also be effective . We conducted a r and omized trial comparing the short- and long-term effects of total enteral nutrition or steroids in these patients . A total of 71 patients ( 80 % cirrhotic ) were r and omized to receive 40 mg/d prednisolone ( n = 36 ) or enteral tube feeding ( 2,000 kcal/d ) for 28 days ( n = 35 ) , and were followed for 1 year or until death . Side effects of treatment occurred in 5 patients on steroids and 10 on enteral nutrition ( not significant ) . Eight enterally fed patients were prematurely withdrawn from the trial . Mortality during treatment was similar in both groups ( 9 of 36 vs. 11 of 35 , intention-to-treat ) but occurred earlier with enteral feeding ( median 7 vs. 23 days ; P = .025 ) . Mortality during follow-up was higher with steroids ( 10 of 27 vs. 2 of 24 intention-to-treat ; P = . 04 ) . Seven steroid patients died within the first 1.5 months of follow-up . In contrast to total enteral nutrition ( TEN ) , infections accounted for 9 of 10 follow-up deaths in the steroid group . In conclusion , enteral feeding does not seem to be worse than steroids in the short-term treatment of severe alcohol-induced hepatitis , although death occurs earlier with enteral nutrition . However , steroid therapy is associated with a higher mortality rate in the immediate weeks after treatment , mainly because of infections . A possible synergistic effect of both treatments should be investigated [12499076] Liv.52 , a hepatoprotective agent of herbal origin , is used empirically for the treatment of alcoholic liver disease in Sri Lanka . We conducted a controlled trial to assess the efficacy of Liv.52 in patients with alcoholic liver disease . Patients with evidence of alcoholic liver disease attending outpatient clinics were included in a prospect i ve , double blind , r and omized , placebo controlled trial . During the trial period , 80 patients who fulfilled inclusion criteria were r and omly assigned Liv.52 ( cases ; n = 40 ) or placebo ( controls ) the recommended dose of three capsules twice daily for 6 months . All patients underwent clinical examination ( for which a clinical score was computed ) , and laboratory investigations for routine blood chemistry and liver function before commencement of therapy ( baseline ) . Thereafter , clinical assessment s were done monthly for 6 months , while laboratory investigations were done after 1 and 6 months of therapy . There was no significant difference in the age composition , alcohol intake and baseline liver function between the two groups . The two- sample t-test was used to analyze data obtained after 1 and 6 months of therapy against baseline values . There was no significant difference in clinical outcome and liver chemistry between the two groups at any time point . There were no reports of adverse effects attributable to the drug . Our results suggest that Liv.52 may not be useful in the management of patients with alcohol induced liver disease [6108449] 35 consecutive patients with alcoholic hepatitis were r and omly allocated to control ( 18 patients ) and study ( 17 patients ) groups . All patients were offered a 3000 kcal 100 g protein diet and were studied for 28 days . The study group received 70 - 85 g of intravenous aminoacids daily in the form of ' Aminosyn ' or ' Travasol ' . Both groups had similar clinical and biochemical features at the time of r and omisation . Ascites and encephalopathy tended to improve more in the study group . Serum concentrations of bilirubin ( p < 0.01 ) and albumin ( p < 0.025 ) improved in the study but not in the control group . 4 patients died in the control group , but none died in the study group . Intravenous therapy with aminoacid for 4 weeks seemed to be associated with lower mortality rate ( p < 0.02 ) and improved serum bilirubin and albumin concentrations in patients with alcoholic hepatitis [4930603] Abstract A prospect i ve , double-blind controlled pilot study in 20 subjects of the efficacy of glucocorticosteroids in the treatment of severe , life-threatening , alcoholic hepatitis failed to demons [2875927] A double-blind , placebo-controlled multicenter trial was conducted to determine the efficacy of oral testosterone treatment ( 200 mg three times daily ) in men with alcoholic cirrhosis . By skewed r and omization ( 3:2 ) , 134 patients received testosterone and 87 placebo . Patients were followed from 8 to 62 months ( median = 28 months ) . In the testosterone group , 33 patients died ( 25 % ; 95 % confidence limits = 18 to 33 % ) as compared to 18 ( 21 % ; 95 % confidence limits = 13 to 31 % ) in the placebo group . Taking age and significant prognostic variables into consideration , this corresponds with a relative mortality risk of 1.17 ( 95 % confidence limits = 0.65 to 2.15 ) in the testosterone group vs. the placebo group . Testosterone treatment did not significantly affect liver biochemistry , prevalence of complications to cirrhosis or causes of death . Patients treated with testosterone developed significantly ( p less than 0.05 ) higher serum testosterone and blood hemoglobin concentrations and significantly ( p less than 0.05 ) lower plasma IgM concentrations as compared to the placebo group . The prevalence of gynecomastia decreased significantly ( p less than 0.05 ) in the testosterone group as compared to the placebo group . We conclude that oral testosterone treatment has no beneficial effect on survival and liver biochemistry in men with alcoholic cirrhosis , and adverse effects can not be excluded [326034] In a prospect i ve , r and omized , double-blind study of prednisolone therapy of acute alcoholic hepatitis , 39 % of the total group of 28 patients died . Mortality and cumulative survival were similar in steroid- and placebo-treated patients . After 14 days of therapy , the serum albumin concentration and white blood count were significantly higher in the steroid group , but all other parameters were similar . An increased risk of fungal infection appeared to be associated with steroid therapy [12217597] BACKGROUND / AIMS The aim of this study is to evaluate the tolerance and effects of infliximab combined with steroids in severe alcoholic hepatitis ( AH ) . METHODS Twenty patients with biopsy-proven severe AH ( Maddrey 's score>32 ) received prednisone 40 mg/day for 28 days and either infliximab 5mg/kg IV ( group A ) or placebo ( group B ) at day 0 . Histology , plasma interleukin-6 ( IL-6 ) and interleukin-8 ( IL-8 ) were measured at baseline and at day 10 . RESULTS Infliximab was well tolerated . Histology showed no significant changes . At day 28 , Maddrey 's score significantly improved in group A ( 39 ( 32 - 53 ) to 12 ( 7 - 52 ) , P<0.05 vs. baseline ) but not in group B ( 44 ( 33 - 50 ) to 22 ( 2 - 59 ) , P = NS ) . At day 10 , IL-6 and IL-8 decreased in group A ( 25 pg/ml ( 10 - 85 pg/ml ) to 4.5 pg/ml ( 2 - 25 pg/ml ) ; 301 pg/ml ( 107 - 1207 pg/ml ) to 14 6 pg/ml ( 25 - 252 pg/ml ) , P<0.01 , P<0.05 vs. baseline , respectively ) . In group B , changes were not significant ( 38 pg/ml ( 13 - 116 pg/ml ) to 16 pg/ml ( 4 - 128 ) ; 315 pg/ml ( 26 - 1698 pg/ml ) to 110 pg/ml ( 27 - 492 pg/ml ) ) . CONCLUSIONS In severe AH , infliximab was well tolerated and associated with significant improvement in Maddrey 's score at day 28 . Although the size of this study does not allow comparison between groups , these promising results should encourage larger trials assessing the effects of this therapy on survival [11841050] BACKGROUND The role of silymarin in the treatment of liver cirrhosis is controversial . AIM Clinical outcome , biochemical profile and the antiperoxidative effects of silymarin MZ-80 during 6 months treatment were investigated in patients with alcoholic liver cirrhosis . METHODS Sixty consecutive patients with alcoholic liver cirrhosis were r and omized to receive either silymarin MZ-80 ( S ) ( 150 mg t.i.d . per day ) or placebo ( P ) for periods of 6 months . Erythrocyte total glutathione ( GSH ) content , platelet malondialdehyde ( MDA ) and serum amino-terminal propeptide of procollagen Type III ( PIIINP ) were determined at baseline and at the end of treatment . RESULTS Forty-nine patients completed the study ( 24 S and 25 P ) . The 2 groups were well-matched for demographic as well as baseline clinical and laboratory parameters . Silymarin increased total GSH at 6 months ( 4.5 + /- 3.4 to 5.8 + /- 4.0 micromol/g Hb ) whereas , in the placebo group , GSH remained unchanged ( 4.1 + /- 3.9 to 4.4 + /- 4.1 micromol/gHb ) ( p < 0.001 ) , and platelet-derived non-induced MDA decreased by 33 % ( p < 0.015 ) . A parallel decrease in PIIINP values was seen with silymarin ( 1.82 1.03 to 1.36 + /- 0.5 U/ml , p < 0.033 ) but not with placebo ( 1.31 + /- 0.4 to 1.27 + /- 0.6 U/ml ) . There were no concurrent changes on laboratory indices of the pathology . CONCLUSIONS Silymarin is well-tolerated and produces a small increase in glutathione and a decrease in lipid peroxidation in peripheral blood cells in patients with alcoholic liver cirrhosis . Despite these effects no changes in routine liver tests were observed during the course of therapy [22364262] BACKGROUND Recent studies have shown that the renin-angiotensin system is implicated in hepatic fibrogenesis in vitro and in vivo . However , no study was done in humans with alcoholic liver disease . AIM To investigate the antifibrotic effect of angiotensin II type 1 receptor ( AT1-R ) blocking agents ( ARB ) in patients with alcoholic liver disease . METHODS The primary outcome was improvement in patients ' histological features . Eighty-five patients with compensated alcoholic liver fibrosis ( ≥ F2 ) which was confirmed by baseline liver biopsy were r and omized ( intention-to-treat ( ITT ) ) to receive either ARB , c and esartan ( 8 mg/day ) with ursodeoxycholic acid ( UDCA ) ( 600 mg/day ) ( n = 42 ) or UDCA alone ( n = 43 ) as control for 6 months and follow-up liver biopsies were conducted . RESULTS According to the Laennec fibrosis system , c and esartan showed significantly higher rates of histological improvements ( ITT , 33.3 % vs. 11.6 % , P = 0.020 ) . In addition , the fibrosis score was significantly reduced from 3.4 ± 1.4 to 3.1 ± 1.5 ( P = 0.005 ) in the c and esartan group . C and esartan also reduced the area of fibrosis and α-smooth muscle actin positive from 11.3 ± 6.0 to 8.3 ± 4.7 and 28.7 ± 10.5 to 23.9 ± 10.3 ( % ) , and the hydroxyproline levels ( μg/g liver tissue ) from 7.8 ± 2.4 to 6.3 ± 1.7 respectively ( P < 0.05 ) . In addition , the relative expression of transforming growth factor-β1(TGF-β1 ) , collagen-1 , AT1-R , tissue inhibitor of metalloproteinase 1 ( TIMP-1 ) , metalloproteinases2 ( MMP2 ) , Rac1 and p22phox by real-time RT-PCR decreased in the c and esartan group ( P < 0.05 ) . Mean arterial blood pressure in the c and esartan group decreased mildly but significantly ( P < 0.001 ) . No significant complications and side effects were observed during the present study . CONCLUSIONS Administration of ARB in compensated alcoholic liver disease induces improvement of fibrosis in histological and quantitative measurements [6390194] A cooperative study was conducted to determine the efficacy of 30 days of treatment with either a glucocorticosteroid ( prednisolone ) or an anabolic steroid ( ox and rolone ) in moderate or severe alcoholic hepatitis . One hundred thirty-two patients with moderate disease and 131 with severe disease were r and omly assigned to one of three treatments : prednisolone , ox and rolone , or placebo . During the 30 days , mortality in the groups receiving steroid therapy was not significantly different from mortality in the placebo group . Thirteen per cent of the moderately ill patients and 29 per cent of the severely ill patients died . Although neither steroid improved short-term survival , ox and rolone therapy was associated with a beneficial effect on long-term survival . This was especially true in patients with moderate disease : among those who survived for one or two months after the start of treatment the conditional six-month death rate was 3.5 per cent after ox and rolone and 19 to 20 per cent after placebo ( P = 0.02 ) . No consistent long-term effect was associated with prednisolone therapy [17532088] BACKGROUND / AIMS Oxidative stress is putatively involved in the pathogenesis of alcohol-induced liver injury . This trial was devised to determine whether antioxidant therapy , alone or as an adjunct to corticosteroids , improved survival in patients with acute alcoholic hepatitis . METHODS Patients with a severe alcoholic hepatitis were stratified by sex and steroid use , and then r and omized . The active group received N-acetylcysteine for one week , and vitamins A-E , biotin , selenium , zinc , manganese , copper , magnesium , folic acid and Coenzyme Q daily for 6 months . The trial was double blinded and placebo controlled . The primary end-point was mortality within 6 months . RESULTS Thirty-six ( 20 male , 16 female ; mean discriminant function ( DF ) 86.6 ) received active drug , and 34 ( 18 male , 16 female ; mean DF 76.4 ) received placebo . 180-day survival was not significantly different between patients receiving drug and placebo ( 52.8 % vs. 55.8 % , p=0.699 ) . This was not affected by stratification for steroid use or sex . The only predictors of survival in multivariate analysis were initial bilirubin ( p=0.017 ) , white cell count ( p=0.016 ) and age ( p=0.037 ) . Treatment allocation did not affect survival in multivariate analysis ( p=0.830 ) . CONCLUSIONS Antioxidant therapy , alone or in combination with corticosteroids , does not improve 6-month survival in severe alcoholic hepatitis [1959859] The effect of parenteral amino acid administration on nutritional state , liver function and mortality was assessed in patients with severe alcoholic hepatitis . Twenty-eight patients received 2 l/day of a solution of dextrose ( 65 gm/L ) and amino acids ( 25.8 gm/L ) for 1 mo , whereas 26 received only the dextrose solution . All patients were allowed to eat a st and ard hospital diet . During the month in the hospital , there were six deaths in the treatment group and five deaths in the control group . Nitrogen balance improved in the treated group , but not in the control group . Creatinine-height index , triceps skin fold measurement and levels of serum albumin and prealbumin increased similarly in both groups . Serum retinol binding protein increased more in the treatment group than it did in the control group , and transferrin was increased only in the treatment group . Serum bilirubin , type III amino-terminal procollagen peptide and aminopyrine clearance improved more in the treatment group than in the control group , whereas serum AST and prothrombin time improved in the treatment group but not in the control group . Cumulative 2-yr survival rates from the day of entry into the study were 42 % and 38 % in the treatment and control groups , respectively . Patients who survived 2 yr and patients in the treatment group who died during the 2-yr follow-up had continued improvement in serum retinol binding protein , transferrin , bilirubin and prothrombin time . These parameters were unchanged in patients in the control group who died during follow-up . ( ABSTRACT TRUNCATED AT 250 WORDS [16469404] BACKGROUND / AIMS Severe alcoholic hepatitis is associated with high morbidity and short-term mortality . Corticosteroids are the only widely used therapy but established contraindications to treatment or the risk of serious side-effects limit their use . The perceived need for alternative treatments together with the theoretical benefits of anti-oxidant therapy triggered the design of a r and omised clinical trial comparing these treatment modalities . METHODS One hundred and one patients were r and omized into a clinical trial of corticosteroids or a novel antioxidant cocktail with a primary endpoint of 30-day mortality . RESULTS At 30 days there were 16 deaths ( 30 % ) in the corticosteroid treated group compared with 22 deaths ( 46 % ) in the antioxidant treated group ( P=0.05 ) . The odds of dying by 30 days were 2.4 greater for patients on antioxidants ( 95 % confidence interval 1.0 - 5.6 ) . A diagnosis of sepsis was made more frequently in the AO group ( P=0.05 ) , although microbiologically proven episodes of infection occurred more often in the CS group ( P<0.01 ) . The survival advantage for corticosteroid treated patients was lost at 1 year of follow-up ( P=0.43 ) . CONCLUSIONS This study has shown that corticosteroids in the form of prednisolone 30 mg daily are superior to a broad antioxidant cocktail in the treatment of severe alcoholic hepatitis [11943949] Background Colchicine , an inhibitor of collagen synthesis , has been suggested as potentially beneficial in cirrhosis . Objective This long-term , r and omized , double blind , placebo controlled trial was conducted in order to evaluate the efficacy of colchicine in alcoholic cirrhosis . Methods Ambulatory patients with biopsy proven alcoholic cirrhosis , presenting from 1989 to 1997 , with no exclusion criteria ( e.g. Child – Pugh C , bilirubin > 10 mg/dl and gastrointestinal bleeding in the previous 15 days ) , were r and omized to receive orally , 5 days/week , 1 mg/day of colchicine or placebo . Main outcome measures Results were analysed on an intention to treat basis , for survival , incidence of complications , biochemical liver tests and safety . Results Twenty-nine patients received colchicine and 26 placebo ; characteristics of both groups were similar . The median follow-up was 40.6 ( 1.4–126.3 ) months in the colchicine versus 42.4 ( 5.7–118.2 ) months in the placebo group ( NS ) . No significant side effects were reported . During follow-up , there were no significant differences in compliance and alcohol abstinence ( 86 % vs 85 % ) . Overall survival was not statistically different ( P = 0.38 ) . Cumulative 3-year survival rates were 74.9 % in the colchicine versus 91.4 % in placebo group ( NS ) . The annual incidence rate of complications was similar with colchicine or placebo : gastrointestinal bleeding , 1.5 % vs 1.2 % ; ascites , 3.7 % vs 3.7 % ; and encephalopathy , 1.0 % vs 0.9 % . The comparison of changes in biochemical parameters between groups did not show any significant difference . Conclusions Although well tolerated , colchicine does not appear to overcome the progression and natural history of long-established alcoholic cirrhosis [758131] The effect of propylthiouracil ( PTU ; 300 mg/day ) on alcoholic liver disease was evaluated in 133 patients in a short-term r and omized double-blind trial . Severity of the disease was assessed by a composite clinical and laboratory index ( CCLI ) . A normalization rate ( NR ) representing the rate of improvement in CCLI was calculated . Patients with alcoholic hepatitis , with and without cirrhosis , showed a significantly higher NR on PTU ( 43.6 + /- 4.6 ) than on placebo ( 19.8 + /- 3.3 ; P less than 0.001 ) . A similar effect was observed in patients with abnormal prothrombin ( no biopsy ) : NR was 32.9 + /- 6.9 on PTU and 2.6 + /- 3.7 on placebo ( P less than 0.005 ) . The effect of PTU on each clinical and laboratory component of the CCLI was also compared in these two groups . In 38 patients with alcoholic hepatitis and in 25 with abnormal prothrombin , those on PTU showed a greater improvement in 15 of 15 items ( P less than 0.001 ) and 14 of 15 ( P less than 0.01 ) , respectively . When patients were divided according to the severity of the disease into those in the lower and upper halves of the CCLI range ( 81 and 52 patients , respectively ) , PTU was shown to have a significant effect only in the latter : The NR was 41.4 + /- 3.8 on PTU and 22.5 + /- 4.2 on placebo ( P less than 0.005 ) . PTU was ineffective in patients with inactive cirrhosis [1727803] Severe alcoholic hepatitis is still a therapeutic challenge . It has been recently advocated that a 3-wk infusion with insulin and glucagon reduces its short-term mortality rate . A multicenter , r and omized , single-blind , sequential trial was design ed to compare this treatment with placebo . The triangular boundary was defined with alpha = 0.05 , beta = 0.10 and estimated survival at 4 wk of 50 % with placebo , 75 % with treatment . Patients with biopsy-proven severe alcoholic hepatitis ( presence of one or more of three criteria : encephalopathy , prothrombin activity less than or equal to 50 % , bilirubinemia greater than or equal to 100 mumol/L ) were r and omized into two groups ; one treatment group received an infusion ( 12 hr/day ) of an association of insulin ( 30 IU ) and glucagon ( 3 mg ) , and a control group received an infusion of glucose . Treatments were administered during a 3-wk period , and the mortality rate was noted at 4 wk . The decision to discontinue the trial was reached on the basis of results from the first 44 patients . Overall results were assessed in the 72 patients included at the time of this decision ( treatment group : n = 37 ; control group : n = 35 ) . Fifty-three patients had cirrhosis . No significant differences were noted between the two groups at inclusion on the basis of clinical , laboratory and histological criteria . The mortality rate was not significantly different in the two groups ; 10 patients ( 27 % ) in the treatment group and 5 patients ( 14 % ) in the control group died . Causes of death were similar in the two groups and consisted primarily of gastrointestinal hemorrhage , hepatic failure and infectious events . ( ABSTRACT TRUNCATED AT 250 WORDS [4615021] A double-blind prospect i ve controlled trial of d-penicillamine in 40 patients with acute alcoholic liver disease revealed no improvement in survival or liver function tests in the experimental group . Nevertheless , greater reduction in fibrosis and hepatocellular injury was suggested in penicillamine-treated biopsied patients ; this observation remains tentative and preliminary , however , because of the potential for sampling error [25901427] BACKGROUND Alcoholic hepatitis is a clinical syndrome characterized by jaundice and liver impairment that occurs in patients with a history of heavy and prolonged alcohol use . The short-term mortality among patients with severe disease exceeds 30 % . Prednisolone and pentoxifylline are both recommended for the treatment of severe alcoholic hepatitis , but uncertainty about their benefit persists . METHODS We conducted a multicenter , double-blind , r and omized trial with a 2-by-2 factorial design to evaluate the effect of treatment with prednisolone or pentoxifylline . The primary end point was mortality at 28 days . Secondary end points included death or liver transplantation at 90 days and at 1 year . Patients with a clinical diagnosis of alcoholic hepatitis and severe disease were r and omly assigned to one of four groups : a group that received a pentoxifylline-matched placebo and a prednisolone-matched placebo , a group that received prednisolone and a pentoxifylline-matched placebo , a group that received pentoxifylline and a prednisolone-matched placebo , or a group that received both prednisolone and pentoxifylline . RESULTS A total of 1103 patients underwent r and omization , and data from 1053 were available for the primary end-point analysis . Mortality at 28 days was 17 % ( 45 of 269 patients ) in the placebo-placebo group , 14 % ( 38 of 266 patients ) in the prednisolone-placebo group , 19 % ( 50 of 258 patients ) in the pentoxifylline-placebo group , and 13 % ( 35 of 260 patients ) in the prednisolone-pentoxifylline group . The odds ratio for 28-day mortality with pentoxifylline was 1.07 ( 95 % confidence interval [ CI ] , 0.77 to 1.49 ; P=0.69 ) , and that with prednisolone was 0.72 ( 95 % CI , 0.52 to 1.01 ; P=0.06 ) . At 90 days and at 1 year , there were no significant between-group differences . Serious infections occurred in 13 % of the patients treated with prednisolone versus 7 % of those who did not receive prednisolone ( P=0.002 ) . CONCLUSIONS Pentoxifylline did not improve survival in patients with alcoholic hepatitis . Prednisolone was associated with a reduction in 28-day mortality that did not reach significance and with no improvement in outcomes at 90 days or 1 year . ( Funded by the National Institute for Health Research Health Technology Assessment program ; STOPAH EudraCT number , 2009 - 013897 - 42 , and Current Controlled Trials number , IS RCT N88782125 ) [18537187] UNLABELLED Liver failure is the major cause of death in alcoholic steatohepatitis ( ASH ) . In experimental hepatitis , granulocyte-colony stimulating factor ( G-CSF ) mobilizes hematopoietic stem cells , induces liver regeneration , and improves survival . We studied the short-term effects of G-CSF on CD34 + stem cell mobilization , liver cell proliferation , and liver function in patients with ASH . Twenty-four patients ( mean age 54 years ) with alcoholic cirrhosis [ Child-Turcotte-Pugh score 10 ( 7 - 12 ) ] and concomitant biopsy-proven ASH [ Maddrey score 36 ( 21 - 60 ) ] were r and omized to st and ard care associated with 5 days of G-CSF ( 10 microg/kg/day , group A , n = 13 ) or st and ard care alone ( group B , n = 11 ) . Serial measurement of CD34 + cells , liver tests , cytokines [ hepatocyte growth factor ( HGF ) ; tumor necrosis factor alpha ; tumor necrosis factor-R1 ; interleukin-6 ; alfa-fetoprotein ] , and (13)C-aminopyrine breath tests were performed . Proliferating hepatic progenitor cells [ HPC ; double immunostaining ( Ki67/cytokeratin 7 ) ] , histology , and neutrophils were assessed on baseline and day 7 biopsies . Abstinent alcoholic patients with cirrhosis served as controls for immunohistochemistry . G-CSF was well tolerated . At day 7 , both CD34 + cells ( + 747 % versus -6 % , P < 0.003 ) , and HGF ( + 212 % versus -7 % , P < 0.03 ) increased in group A but not in group B. Cytokines and aminopyrine breath test changes were similar between groups . On repeat biopsy , a > 50 % increase in proliferating HPC was more frequent in group A than in group B ( 11 versus 2 , P < 0.003 ) . Changes in Ki67+/cytokeratin 7 + cells correlated with changes in CD34 + cells ( r = 0.65 , P < 0.03 ) . Neutrophils and histological changes were similar in both groups . CONCLUSION G-CSF mobilizes CD34 + cells , increases HGF , and induces HPC to proliferate within 7 days of administration . Larger trials would be required to determine whether these changes translate into improved liver function [20801542] BACKGROUND & AIMS Severe acute alcoholic hepatitis is associated with a high mortality rate . Oxidative stress is involved in the pathogenesis of acute alcoholic hepatitis . Previous findings had also suggested that enteral nutritional support might increase survival in patients with severe acute alcoholic hepatitis . Therefore , the aim of the present study was to evaluate the efficacy of N-acetylcysteine in combination with adequate nutritional support in patients with severe acute alcoholic hepatitis . METHODS Patients with biopsy-proven acute alcoholic hepatitis and mDF ≥32 were r and omized to receive N-acetylcysteine intravenously or a placebo perfusion along with adequate nutritional support for 14 days . The primary endpoint was 6-month survival ; secondary endpoints were biological parameter evolution and infection rate . RESULTS Fifty-two patients were r and omized in the study ( 28 into the N-acetylcysteine arm , 24 into the control arm ) , and among them , five were excluded from the analysis for protocol violation . The two groups did not differ in baseline characteristics . Survival rates at 1 and 6 months in N-acetylcysteine and control groups were 70.2 vs. 83.8 % ( p=0.26 ) and 62.4 vs. 67.1 % ( p=0.60 ) , respectively . Early biological changes , documented infection rate at 1 month , and incidence of hepatorenal syndrome did not differ between the two groups . CONCLUSIONS In this study , high doses of intravenous N-acetylcysteine therapy for 14 days conferred neither survival benefits nor early biological improvement in severe acute alcoholic hepatitis patients with adequate nutritional support . However , these results must be viewed with caution , since the study suffered from a lack of power [24845609] BACKGROUND & AIMS Both corticosteroid and pentoxifylline reduce short-term mortality in severe alcoholic hepatitis . However , few studies have directly compared the efficacy of pentoxifylline and corticosteroid in patients with this condition . METHODS In this multicentre , open-labelled , r and omised non-inferiority trial , we assigned 121 patients with severe alcoholic hepatitis ( Maddrey 's discriminant function ⩾32 ) to receive either pentoxifylline ( 400 mg , 3 times daily , in 62 subjects ) or prednisolone ( 40 mg daily , in 59 subjects ) . The primary end point was non-inferiority in survival at the 1 month time point for the pentoxifylline treatment compared with prednisolone . RESULTS The 1-month survival rate of patients receiving pentoxifylline was 75.8 % ( 15 deaths ) compared with 88.1 % ( 7 deaths ) in those , taking prednisolone , for a treatment difference of 12.3 % ( 95 % confidence interval , -4.2 % to 28.7 % ; p = 0.08 ) . The 95 % confidence interval for the observed difference exceeded the predefined margin of non-inferiority ( Δ15 % ) and included zero . The 6-month survival rate was not significantly different between the pentoxifylline and prednisolone groups ( 64.5 % vs. 72.9 % ; p = 0.23 ) . At 7 days , the response to therapy assessed by the Lille model was significantly lower in the prednisolone group ( n = 58 ) than in the pentoxifylline group ( n = 5 9 ) : 0.35 vs. 0.50 ( p = 0.012 ) . Hepatitis complications , including hepatorenal syndrome and side effects , such as infection and gastrointestinal bleeding , were similar in the two groups . CONCLUSIONS The findings demonstrate that the efficacy of the pentoxifylline is not statistically equivalent to the efficacy of prednisolone , supporting the use of prednisolone as a preferred treatment option in patients with severe alcoholic hepatitis [22945832] Published evidence suggests that aspects of trial design lead to biased intervention effect estimates , but findings from different studies are inconsistent . This study combined data from 7 meta-epidemiologic studies and removed overlaps to derive a final data set of 234 unique meta-analyses containing 1973 trials . Outcome measures were classified as " mortality , " " other objective , " " or subjective , " and Bayesian hierarchical models were used to estimate associations of trial characteristics with average bias and between-trial heterogeneity . Intervention effect estimates seemed to be exaggerated in trials with inadequate or unclear ( vs. adequate ) r and om-sequence generation ( ratio of odds ratios , 0.89 [ 95 % credible interval { CrI } , 0.82 to 0.96 ] ) and with inadequate or unclear ( vs. adequate ) allocation concealment ( ratio of odds ratios , 0.93 [ CrI , 0.87 to 0.99 ] ) . Lack of or unclear double-blinding ( vs. double-blinding ) was associated with an average of 13 % exaggeration of intervention effects ( ratio of odds ratios , 0.87 [ CrI , 0.79 to 0.96 ] ) , and between-trial heterogeneity was increased for such studies ( SD increase in heterogeneity , 0.14 [ CrI , 0.02 to 0.30 ] ) . For each characteristic , average bias and increases in between-trial heterogeneity were driven primarily by trials with subjective outcomes , with little evidence of bias in trials with objective and mortality outcomes . This study is limited by incomplete trial reporting , and findings may be confounded by other study design characteristics . Bias associated with study design characteristics may lead to exaggeration of intervention effect estimates and increases in between-trial heterogeneity in trials reporting subjectively assessed outcomes

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### Context: [26691209] BACKGROUND Alcoholic hepatitis ( AH ) is a distinct presentation of alcoholic liver disease arising in patients who have been drinking to excess for prolonged periods , which is characterised by jaundice and liver failure . Severe disease is associated with high short-term mortality . Prednisolone and pentoxifylline ( PTX ) are recommended in guidelines for treatment of severe AH , but trials supporting their use have given heterogeneous results and controversy persists about their benefit . OBJECTIVES The aim of the clinical effectiveness and cost-effectiveness of STeroids Or Pentoxifylline for Alcoholic Hepatitis trial was to resolve the clinical dilemma on the use of prednisolone or PTX . DESIGN The trial was a r and omised , double-blind , 2 × 2 factorial , multicentre design . SETTING Sixty-five gastroenterology and hepatology inpatient units across the UK . PARTICIPANTS Patients with a clinical diagnosis of AH who had a Maddrey 's discriminant function value of ≥ 32 were r and omised into four arms : A , placebo/placebo ; B , placebo/prednisolone ; C , PTX/placebo ; and D , PTX/prednisolone . Of the 5234 patients screened for the trial , 1103 were r and omised and after withdrawals , 1053 were available for primary end-point analysis . INTERVENTIONS Those allocated to prednisolone were given 40 mg daily for 28 days and those allocated to PTX were given 400 mg three times per day for 28 days . OUTCOMES The primary outcome measure was mortality at 28 days . Secondary outcome measures included mortality or liver transplant at 90 days and at 1 year . Rates of recidivism among survivors and the impact of recidivism on mortality were assessed . RESULTS At 28 days , in arm A , 45 of 269 ( 16.7 % ) patients died ; in arm B , 38 of 266 ( 14.3 % ) died ; in arm C , 50 of 258 ( 19.4 % ) died ; and in arm D , 35 of 260 ( 13.5 % ) died . For PTX , the odds ratio for 28-day mortality was 1.07 [ 95 % confidence interval ( CI ) 0.77 to 1.40 ; p = 0.686 ) ] and for prednisolone the odds ratio was 0.72 ( 95 % CI 0.52 to 1.01 ; p = 0.056 ) . In the logistic regression analysis , accounting for indices of disease severity and prognosis , the odds ratio for 28-day mortality in the prednisolone-treated group was 0.61 ( 95 % CI 0.41 to 0.91 ; p = 0.015 ) . At 90 days and 1 year there were no significant differences in mortality rates between the treatment groups . Serious infections occurred in 13 % of patients treated with prednisolone compared with 7 % of controls ( p = 0.002 ) . At the 90-day follow-up , 45 % of patients reported being completely abstinent , 9 % reported drinking within safety limits and 33 % had an unknown level of alcohol consumption . At 1 year , 37 % of patients reported being completely abstinent , 10 % reported drinking within safety limits and 39 % had an unknown level of alcohol consumption . Only 22 % of patients had attended alcohol rehabilitation treatment at 90 days and 1 year . CONCLUSIONS We conclude that prednisolone reduces the risk of mortality at 28 days , but this benefit is not sustained beyond 28 days . PTX had no impact on survival . Future research should focus on interventions to promote abstinence and on treatments that suppress the hepatic inflammation without increasing susceptibility to infection . TRIAL REGISTRATION This trial is registered as EudraCT 2009 - 013897 - 42 and Current Controlled Trials IS RCT N88782125 . FUNDING This project was funded by the National Institute for Health Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol . 19 , No. 102 . See the NIHR Journals Library website for further project information . The NIHR Clinical Research Network provided research nurse support and the Imperial College Biomedical Research Centre also provided funding [7037524] Sixty-seven patients entered a double-blind , controlled trial to evaluate the efficacy of propylthiouracil treatment in severe alcoholic hepatitis . Twenty-three percent ( 7 of 31 ) given propylthiouracil and 19 % ( 7 of 36 ) given placebo died during the 6-wk study . Propylthiouracil treatment did not reduce the frequency and incidence of complications in alcoholic hepatitis , but induced hypothyroidism in 4 patients . Treatment produced no beneficial effect on any of the hepatic biochemical tests . We were unable to show any beneficial effect of propylthiouracil treatment on morbidity and mortality in patients with severe acute alcoholic hepatitis [14672612] BACKGROUND / AIMS The effect of vitamin E administration on clinical and laboratory parameters of liver function and on markers of fibrogenesis was assessed in patients with mild to moderate alcoholic hepatitis in a double blind placebo controlled r and omized trial . METHODS Twenty-five patients received 1000 I.U. of vitamin E per day , while 26 patients received placebo for 3 months . The patients were followed for 1 year after entry into the trial . RESULTS Vitamin E did not result in significant greater decreases in serum aminotransferases and serum bilirubin or in greater increases in serum albumin as compared with placebo . Prothrombin time did not change , while serum creatinine remained in the normal range . Monocyte nuclear nuclear factor-kappa B binding activity decreased in patients who remained abstinent , regardless of whether they received vitamin E. As regards markers of hepatic fibrogenesis , vitamin E treatment decreased serum hyaluronic acid ( P<0.05 ) while serum aminoterminal peptide of type III procollagen did not change in either group . Four patients in the treatment group and five in the placebo group died during the 1-year study . CONCLUSIONS Vitamin E treatment improves serum hyaluronic acid but has no beneficial effects on tests of liver function in patients with mild to moderate alcoholic hepatitis [1959860] In a r and omized , controlled trial to investigate the possible benefit of insulin and glucagon therapy in severe acute alcoholic hepatitis , 86 patients were r and omized to receive 30 U insulin and 3 mg glucagon in 250 ml 5 % dextrose over 12 hr each day for 3 wk or a similar regime of identical placebo . No significant differences were seen in patients ' clinical characteristics and disease severity in the treated and placebo groups . Of the 43 patients receiving insulin and glucagon , 15 ( 35 % ) died within 4 wk of r and omization , compared with 14 deaths ( 33 % ) in the control patients ( p = not significant ) . When the patients surviving the first 4 wk were examined there were five more deaths in the treatment group , compared with one death in the control group at 6-mo follow-up ( p = not significant ) . No significant differences in the frequency of short-term or long-term complications of alcoholic liver disease or relapse to alcohol were seen when the two groups were compared , although hypoglycemia was seen in six patients during infusion of insulin and glucagon . Similarly , no significant differences were seen in the improvement in clinical or biochemical features at 4 wk and at 6 mo in survivors when the insulin and glucagon-treated patients were compared with patients in the placebo group . This study does not confirm previous reports that insulin and glucagon infusion improves the outcome of severe acute alcoholic hepatitis [8051381] The aim of this study was to examine the effect of malotilate on survival in patients with alcoholic liver disease and to determine prognostic variables for survival . Four hundred and seven patients with alcoholic liver diseases , from seven European liver units , entered a r and omized placebo-controlled , double-blind trial : 140 patients received malotilate 1500 mg/day , 133 patients received 750 mg/day , and 134 patients received placebo . The patients were included in the study over a period of 3 1/2 years , and the study was closed 1 year after the entry of the last patient . Eighty-four patients died ( 35 , 19 , 30 patients in groups 1500 mg/day , 750 mg/day , and placebo , respectively ) . Survival was slightly better in the 750 mg/day group than in the two other treatment groups , when tested by conventional log-rank tests ( p = 0.06 ) . However , a treatment effect was supported by a highly significant ( p = 0.006 ) non-proportionality of the death intensity in patients receiving 750 mg/day against those receiving either 1500 mg/day or placebo . Prognostic variables for survival were evaluated using the multiple Cox regression analysis of clinical and laboratory variables and with or without liver histology variables , as determined at entry into the study . The analysis was stratified for the three treatment regimens . In the analysis including liver histology variables , independent significant prognostic variables were : years of high alcohol intake , prothrombin index , alkaline phosphatases , creatinine , immunoglobulin M , white blood cell count , and liver cell steatosis . In the analysis without liver histology variables , prognostic variables were : years of high alcohol intake , prothrombin index , alkaline phosphatases , creatinine , and immunoglobulin [8014444] Although propylthiouracil has previously been shown to reduce the risk of mortality in alcoholic liver disease by 60 % , generalized use of propylthiouracil for this condition has not occurred . Additional data are therefore presented on four aspects to provide a better assessment of its therapeutic effectiveness . First , the characteristics and the prognosis of dropouts were virtually identical in both the drug and placebo groups . Also the methodology and analysis employed , were design ed to control for dropouts , thus providing an accurate interpretation of the outcome . Secondly , since 97 % of the patients continued to drink , abstinence was not a precondition for the beneficial effect of propylthiouracil . However , the beneficial effect was observed most clearly in those patients who continued to drink at lower levels , whereas lower level drinking per se did not afford protection in placebo patients . Thirdly , serious side effects or clinical hypothyroidism occurred extremely rarely in these patients , many of whom have now received propylthiouracil for over 4 years . Fourthly , we discuss why the outcome in long-term clinical trials in alcoholic liver disease can not be compared with effects observed in clinical trials lasting only a few weeks . Journal of Hepatology [8455312] A controlled trial on nutrition supplementation in ambulatory patients with decompensated alcoholic liver disease was carried out during 1 year . Fifty-one patients were studied ; 26 were assigned to an experimental group receiving a daily supplement of 1000 kcal and 34 g of proteins given as a casein-based enteral nutrition product and 25 to a control group receiving one placebo capsule . Patients were examined in a special clinic once a month or more if required . Sixty-eight percent of patients admitted to alcohol ingestion or had alcohol in urine sample s on at least one occasion . Dietary recalls showed a significantly higher protein and caloric intake in case patients subjects ( p < .0001 ) . Nine patients died during the study , three case patients and six control patients ( p = NS ) . The frequency of hospitalizations was significantly less in the experimental group . This difference was attributed to a reduction in severe infections . Mid-arm circumference , serum albumin concentration , and h and grip strength improved earlier in case patients , although both groups had a significant improvement in these parameters . Bilirubin and aspartate aminotransferase decreased and prothrombin time increased significantly in both groups during the study period , without differences between groups . It is concluded that nutrition support decreases nutrition-associated complications in patients with alcoholic liver disease [11113085] BACKGROUND & AIMS An earlier pilot study from our liver unit suggested benefit from treatment with pentoxifylline ( PTX ) , an inhibitor of tumor necrosis factor ( TNF ) , in severe acute alcoholic hepatitis . The aim of the present study was to evaluate this treatment in a larger cohort of patients . METHODS One hundred one patients with severe alcoholic hepatitis ( Maddrey discriminant factor > or = 32 ) entered a 4-week double-blind r and omized trial of PTX ( 400 mg orally 3 times daily ) vs. placebo . Primary endpoints of the study were the effect of PTX on ( 1 ) short-term survival and ( 2 ) progression to hepatorenal syndrome . On r and omization , there were no differences in demographic and clinical characteristics or laboratory values ( including TNF ) between the 2 groups . RESULTS Twelve ( 24.5 % ) of the 49 patients who received PTX and 24 ( 46.1 % ) of the 52 patients who received placebo died during the index hospitalization ( P = 0.037 ; relative risk , 0.59 ; 95 % confidence interval , 0.35 - 0.97 ) . Hepatorenal syndrome was the cause of death in 6 ( 50 % ) and 22 ( 91.7 % ) patients ( P = 0.009 ; relative risk , 0.29 ; 95 % confidence interval , 0.13 - 0.65 ) . Three variables ( age , creatinine level on r and omization , and treatment with PTX ) were independently associated with survival . TNF values on r and omization were not predictive of survival ; however , during the study period they increased markedly in nonsurvivors compared with survivors in both groups . CONCLUSIONS Treatment with PTX improves short-term survival in patients with severe alcoholic hepatitis . The benefit appears to be related to a significant decrease in the risk of developing hepatorenal syndrome . Increasing TNF levels during the hospital course are associated with an increase in mortality rate [18942901] OBJECTIVE To assess the effect of pentoxiphylline ( a potent inhibitor of tumor necrosis factor alpha ) on survival , on systemic and portal hemodynamics , and on cardiac function in patients with alcoholic cirrhosis . DESIGN A r and omized double-blind placebo-controlled trial . SETTING A single center using parallel groups of patients to compare pentoxiphylline with placebo . PATIENTS We recruited 24 patients with alcoholic cirrhosis ( 8 Child-Pugh B and 16 Child-Pugh C ) . INTERVENTIONS Patients were r and omly assigned to receive pentoxiphylline ( 400 mg tid ; n = 12 ) or placebo ( n = 12 ) over a 4-week period . OUTCOME MEASURES The primary outcome was to extend short-term and long-term survival . Secondary outcomes included hemodynamic benefits ( improvement in cardiac function and /or systemic vascular resistance index , or decrease in portal pressure ) . RESULTS Portal pressure and cardiac function remained unchanged and there were no significant differences in short-term or long-term survival between treatment and placebo groups . The group on pentoxiphylline increased systemic vascular resistance and decreased cardiac indices ( from 1,721 + /- 567 to 2,082 + /- 622 dyn.sec(-1 ) cm(-5 ) m(-2 ) and from 4.17 + /- 1.4 to 3.4 + /- 0.9 l.m(-2 ) , p = 0.05 ) . CONCLUSIONS Although pentoxiphylline seems to provide some short-term hemodynamic benefits in patients with advanced alcoholic cirrhosis , this drug has no effect on survival or portal pressure in these patients [15449338] Mixed treatment comparison ( MTC ) meta- analysis is a generalization of st and ard pairwise meta- analysis for A vs B trials , to data structures that include , for example , A vs B , B vs C , and A vs C trials . There are two roles for MTC : one is to strengthen inference concerning the relative efficacy of two treatments , by including both ' direct ' and ' indirect ' comparisons . The other is to facilitate simultaneous inference regarding all treatments , in order for example to select the best treatment . In this paper , we present a range of Bayesian hierarchical models using the Markov chain Monte Carlo software WinBUGS . These are multivariate r and om effects models that allow for variation in true treatment effects across trials . We consider models where the between-trials variance is homogeneous across treatment comparisons as well as heterogeneous variance models . We also compare models with fixed ( unconstrained ) baseline study effects with models with r and om baselines drawn from a common distribution . These models are applied to an illustrative data set and posterior parameter distributions are compared . We discuss model critique and model selection , illustrating the role of Bayesian deviance analysis , and node-based model criticism . The assumptions underlying the MTC models and their parameterization are also discussed [15095765] OBJECTIVES To analyze sources search ed in Cochrane review s , to determine the proportion of trials included in review s that are indexed in major data bases , and to compare the quality of these trials with those from other sources . METHODS All new systematic review s in the Cochrane Library , Issue1 2001 , that were restricted to r and omized controlled trials ( RCTs ) or quasi- RCTs were selected . The sources search ed in the review s were recorded , and the trials included were checked to see whether they were indexed in four major data bases . Trials not indexed were checked to determine how they could be identified . The quality of trials found in major data bases was compared with those found from other sources . RESULTS The range in the number of data bases search ed per review ranged between one and twenty-seven . The proportion of the trials in the four data bases were Cochrane Controlled Trials Register = 78.5 % , MEDLINE = 68.8 % , Embase = 65.0 % , and Science/Social Sciences Citation Index = 60.7 % . Search ing another twenty-six data bases after Cochrane Controlled Trials Register ( CCTR ) , MEDLINE , and Embase only found 2.4 % additional trials . There was no significant difference between trials found in the CCTR , MEDLINE , and Embase compared with other trials , with respect to adequate allocation concealment or sample size . CONCLUSIONS There was a large variation between review s in the exhaustiveness of the literature search es . CCTR was the single best source of RCTs . Additional data base search ing retrieved only a small percentage of extra trials . Contacting authors and manufacturers to find unpublished trials appeared to be a more effective method of obtaining the additional better quality trials [24935272] OBJECTIVES : Severe alcoholic hepatitis has high short-term mortality . The aim of this study was to test the hypothesis that treatment of patients with alcoholic hepatitis with granulocyte colony-stimulating factor ( G-CSF ) might mobilize bone marrow – derived stem cells and promote hepatic regeneration and thus improve survival . METHODS : Forty-six patients with severe alcoholic hepatitis were prospect ively r and omized in an open study to st and ard medical therapy ( SMT ) plus G-CSF ( group A ; n=23 ) at a dose of 5 μg/kg subcutaneously every 12 h for 5 consecutive days or to SMT alone ( group B ; n=23 ) at a tertiary care center . We assessed the mobilization of CD34 + cells on day 6 , Child-Turcotte-Pugh ( CTP ) , model for end-stage liver disease ( MELD ) , and modified Maddrey ’s discriminant function ( mDF ) scores , and survival until day 90 . RESULTS : There was a statistically significant increase in the number of CD34 + cells in peripheral blood in group A as compared with group B ( P=0.019 ) after 5 days of G-GSF therapy . There was a significant reduction in median Δ change% in CTP , MELD , and mDF at 1 , 2 , and 3 months in group A as compared with group B ( P<0.05 ) . There was marked improvement in survival in group A as compared with group B ( 78.3 % vs. 30.4 % ; P=0.001 ) at 90 days . CONCLUSIONS : G-CSF is safe and effective in the mobilization of hematopoietic stem cells and improves liver function as well as survival in patients with severe alcoholic hepatitis [10406187] BACKGROUND / AIM The efficacy of S-adenosylmethionine ( AdoMet ) in the treatment of liver cell injury has been demonstrated in several experimental models . The aim of this study was to investigate the effects of AdoMet treatment in human alcoholic liver cirrhosis . METHODS A r and omized , double-blind trial was performed in 123 patients treated with AdoMet ( 1200 mg/day , orally ) or placebo for 2 years . All patients had alcoholic cirrhosis , and histologic confirmation of the diagnosis was available in 84 % of the cases . Seventy-five patients were in Child class A , 40 in class B , and 8 in class C. Sixty-two patients received AdoMet and 61 received placebo . RESULTS At inclusion into the trial no significant differences were observed between the two groups with respect to sex , age , previous episodes of major complications of cirrhosis , Child classification and liver function tests . The overall mortality/liver transplantation at the end of the trial decreased from 30 % in the placebo group to 16 % in the AdoMet group , although the difference was not statistically significant ( p = 0.077 ) . When patients in Child C class were excluded from the analysis , the overall mortality/liver transplantation was significantly greater in the placebo group than in the AdoMet group ( 29 % vs. 12 % , p = 0.025 ) , and differences between the two groups in the 2-year survival curves ( defined as the time to death or liver transplantation ) were also statistically significant ( p = 0.046 ) . CONCLUSIONS The present results indicate that long-term treatment with AdoMet may improve survival or delay liver transplantation in patients with alcoholic liver cirrhosis , especially in those with less advanced liver disease [24026598] IMPORTANCE Prednisolone or pentoxifylline is recommended for severe alcoholic hepatitis , a life-threatening disease . The benefit of their combination is unknown . OBJECTIVE To determine whether the addition of pentoxifylline to prednisolone is more effective than prednisolone alone . DESIGN , SETTING , AND PARTICIPANTS Multicenter , r and omized , double-blind clinical trial conducted between December 2007 and March 2010 in 1 Belgian and 23 French hospitals of 270 patients aged 18 to 70 years who were heavy drinkers with severe biopsy-proven alcoholic hepatitis , as indicated by recent onset of jaundice in the prior 3 months and a Maddrey score of at least 32 . Duration of follow-up was 6 months . The last included patient completed the study in October 2010 . None of the patients were lost to follow-up for the main outcome . INTERVENTION Patients were r and omly assigned to receive either a combination of 40 mg of prednisolone once a day and 400 mg of pentoxifylline 3 times a day ( n=133 ) for 28 days , or 40 mg of prednisolone and matching placebo ( n=137 ) for 28 days . MAIN OUTCOMES AND MEASURES Six-month survival , with secondary end points of development of hepatorenal syndrome and response to therapy based on the Lille model , which defines treatment nonresponders after 7 days of initiation of treatment . RESULTS In intention-to-treat analysis , 6-month survival was not different in the pentoxifylline-prednisolone and placebo-prednisolone groups ( 69.9 % [ 95 % CI , 62.1%-77.7 % ] vs 69.2 % [ 95 % CI ; 61.4%-76.9 % ] , P = .91 ) , corresponding to 40 vs 42 deaths , respectively . In multivariable analysis , only the Lille model and the Model for End-Stage Liver Disease score were independently associated with 6-month survival . At 7 days , response to therapy assessed by the Lille model was not significantly different between the 2 groups ( Lille model score , 0.41 [ 95 % CI , 0.36 - 0.46 ] vs 0.40 [ 95 % CI , 0.35 - 0.45 ] , P = .80 ) . The probability of being a responder was not different in both groups ( 62.6 % [ 95 % CI , 53.9%-71.3 % ] vs 61.9 % [ 95 % CI , 53.7%-70.3 % ] , P = .91 ) . The cumulative incidence of hepatorenal syndrome at 6 months was not significantly different in the pentoxifylline-prednisolone and the placebo-prednisolone groups ( 8.4 % [ 95 % CI , 4.8%-14.8 % ] vs 15.3 % [ 95 % CI , 10.3%-22.7 % ] , P = .07 ) . CONCLUSION AND RELEVANCE In patients with alcoholic hepatitis , 4-week treatment with pentoxifylline and prednisolone , compared with prednisolone alone , did not result in improved 6-month survival . The study may have been underpowered to detect a significant difference in incidence of hepatorenal syndrome , which was less frequent in the group receiving pentoxifylline . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01214226 [3766225] Abstract Background Alcoholic hepatitis is the most florid presentation of alcohol-related liver disease . In its severe form , defined by a Maddrey ’s discriminant function ( DF ) ≥32 , the 28-day mortality rate is approximately 35 % . A number of potential treatments have been subjected to clinical trials , of which two , corticosteroids and pentoxifylline , may have therapeutic benefit . The role of corticosteroids is controversial as trial results have been inconsistent , whereas the role of pentoxifylline requires confirmation as only one previous placebo-controlled trial has been published . Methods / design STOPAH is a multicentre , double-blind , factorial ( 2 × 2 ) trial in which patients are r and omised to one of four groups : 1.Group A : placebo / placebo2.Group B : placebo / prednisolone3.Group C : pentoxifylline / placebo4.Group D : pentoxifylline / prednisolone The trial aims to r and omise 1,200 patients with severe alcoholic hepatitis , in order to provide sufficient power to determine whether either of the two interventions is effective . The primary endpoint of the study is mortality at 28 days , with secondary endpoints being mortality at 90 days and 1 year . Discussion STOPAH aims to be a definitive study to resolve controversy around the existing treatments for alcoholic hepatitis . Eligibility criteria are based on clinical parameters rather than liver biopsy , which are aligned with st and ard clinical practice in most hospitals . The use of a factorial design will allow two treatments to be evaluated in parallel , with efficient use of patient numbers to achieve high statistical power . Trial registration EudraCT reference number : 2009 - 013897 - 42IS RCT N reference number : IS RCT [2707520] A r and omized double-blind trial of silymarin versus placebo was carried out in 116 patients with histologically proven alcoholic hepatitis , 58 of them with cirrhosis . Patients were not included in case of hepatic encephalopathy , contraindication to percutaneous liver biopsy , hepatocellular carcinoma , evident lack of discipline or refusal to enter the trial . Fifty-seven patients received silymarin orally 420 mg/day and 59 received placebo during 3 months . Biologic parameters were assessed in the serum , and a percutaneous liver biopsy was obtained at the start of the trial and 3 months later . Histologic scores of alcoholic hepatitis and fibrosis were established on each biopsy specimen by two independent pathologists . The 2 groups were comparable at inclusion ; 26 p. 100 of patients were lost to follow-up at 3 months , abstinence was obtained in 46 p. 100 of patients at the end of the trial . These percentages were similar in the two groups . Four patients died of hepatic failure during the trial , 3 in the placebo group . Significant improvement in the score of alcoholic hepatitis and serum amino transferase activity , was noted in both groups during the trial , irrespective of treatment with silymarin or placebo . No side-effects were noted . Our results suggest that silymarin 420 mg/d is not clinical ly relevant in the treatment of moderate alcoholic hepatitis [1727754] This prospect i ve study compared the effects of tube-fed nutrition with those of a regular diet in alcoholic liver disease . The high prevalence of malnutrition in patients with alcoholic liver disease requires clarification of the benefits of aggressive nutritional support . Patients were r and omly assigned a regular diet without or with tube-fed supplementation , delivering 1.5 g/kg protein and 167 kJ/kg daily . Comparisons of encephalopathy , antipyrine clearance , metabolic rate , and biochemical parameters were performed weekly for 4 weeks . Sixteen patients receiving enteral supplementation had antipyrine half-life ( 50 % vs. 3 % reduction ) , serum bilirubin ( 25 % vs. 0 % reduction ) , and median encephalopathy scores that improved more rapidly than those of controls . Initially , 15 controls did not consume adequate calories to meet measured resting energy expenditure . Aggressive nutritional intervention accelerated improvement in alcoholic liver disease . Adverse effects did not offset the demonstrated benefits of a 2-cal/mL , casein-based tube-fed supplement . These findings support the use of st and ard , casein-based solutions in the treatment of alcoholic liver disease and as the control condition for future studies [19340904] AIM To compare the efficacy of pentoxifylline and prednisolone in the treatment of severe alcoholic hepatitis , and to evaluate the role of different liver function scores in predicting prognosis . METHODS Sixty-eight patients with severe alcoholic hepatitis ( Maddrey score > or = 32 ) received pentoxifylline ( n = 34 , group I ) or prednisolone ( n = 34 , group II ) for 28 d in a r and omized double-blind controlled study , and subsequently in an open study ( with a tapering dose of prednisolone ) for a total of 3 mo , and were followed up over a period of 12 mo . RESULTS Twelve patients in group II died at the end of 3 mo in contrast to five patients in group I. The probability of dying at the end of 3 mo was higher in group II as compared to group I ( 35.29 % vs 14.71 % , P = 0.04 ; log rank test ) . Six patients in group II developed hepatorenal syndrome as compared to none in group I. Pentoxifylline was associated with a significantly lower model for end-stage liver disease ( MELD ) score at the end of 28 d of therapy ( 15.53 + /- 3.63 vs 17.78 + /- 4.56 , P = 0.04 ) . Higher baseline Maddrey score was associated with increased mortality . CONCLUSION Reduced mortality , improved risk-benefit profile and renoprotective effects of pentoxifylline compared with prednisolone suggest that pentoxifylline is superior to prednisolone for treatment of severe alcoholic hepatitis [2954078] Whether or not prednisolone ( or prednisone ) should be used to treat alcoholic hepatitis remains controversial . This new controlled study performed on 45 patients with steatosis , fibrosis or cirrhosis of the liver suggests that prednisolone is not effective : after a 3-month follow-up clinical course , biochemical alterations , anatomical lesions and portal hypertension were the same in patients treated with prednisolone and in those who did not receive that drug [22044287] BACKGROUND S-adenosyl-L-methionine ( SAM ) is the methyl donor for all methylation reactions and regulates the synthesis of glutathione , the main cellular antioxidant . Previous experimental studies suggested that SAM may benefit patients with established alcoholic liver diseases ( ALDs ) . The aim of this study was to determine the efficacy of SAM in treatment for ALD in a 24-week trial . The primary endpoints were changes in serum aminotransferase levels and liver histopathology scores , and the secondary endpoints were changes in serum levels of methionine metabolites . METHODS We r and omized 37 patients with ALD to receive 1.2 g of SAM by mouth or placebo daily . Subjects were required to remain abstinent from alcohol drinking . A baseline liver biopsy was performed in 24 subjects , and a posttreatment liver biopsy was performed in 14 subjects . RESULTS Fasting serum SAM levels were increased over timed intervals in the SAM treatment group . The entire cohort showed an overall improvement of AST , ALT , and bilirubin levels after 24 weeks of treatment , but there were no differences between the treatment groups in any clinical or biochemical parameters nor any intra- or intergroup differences or changes in liver histopathology scores for steatosis , inflammation , fibrosis , and Mallory-Denk hyaline bodies . CONCLUSIONS Whereas abstinence improved liver function , 24 weeks of therapy with SAM was no more effective than placebo in the treatment for ALD [2199290] Colchicine treatment was used in this r and omized placebo-controlled trial in patients with severe acute alcoholic hepatitis [ serum bilirubin greater than or equal to 5 mg/dL ( 85.5 mumol/L ) mean , 17.5 + /- 7.5 mg/dL ( 299.25 + /- 128.25 mumol/L ) ] . Hospitalization mortality and morbidity and the effect on biochemical test results were the end points of the treatment . Patients in the two groups were evenly matched by demographics and laboratory test results . Mean time to study entry was less than 7 days from admission . The duration of the trial was 30 days . Thirty-six patients ( 24 men , 12 women ) received colchicine ( 1 mg orally every morning ) and 36 ( 25 men , 11 women ) received an identical placebo . Seven ( 19 % ) colchicine-treated and six ( 17 % ) control patients died during the index hospitalization after a mean of 17.4 + /- 10.8 and 17.8 + /- 5.3 days , respectively ( NS ) . During a 4-month follow-up period from entry into the trial , there were two additional deaths in each group . No differences between placebo- and colchicine-treated patients were observed in any of the laboratory parameters ( serum bilirubin , aspartate transaminase , alanine transaminase , prothrombin activity , albumin , white blood cell count , hemoglobin , and creatinine ) that were followed up over the 30-day treatment period . The frequency of complications did not differ statistically between the two groups . This study showed no effect of colchicine treatment on mortality and morbidity of severe alcoholic hepatitis . Colchicine can not be recommended for the treatment of patients with alcoholic hepatitis [3616287] Methods for combining data from several studies exist and appear to be quite useful . None satisfactorily addresses the question of what studies should be combined . This issue is the most serious method ological limitation . Even studies with statistically significant interaction might still be combined if the effect were in the same direction . Thus , substantial scientific input is required as to what criteria must be met by each potential study . Much can be learned from combining or pooling data but it must be done cautiously . Pooling exercises do not replace well design ed prospect i ve clinical trials . Efforts for establishing basic design criteria to allow for multicentre and multicountry trials to be more easily combined might be useful . [23029716] BACKGROUND Role of corticosteroids in treatment of severe alcoholic hepatitis ( SAH ) is controversial . Pentoxifylline ( PTX ) , an inhibitor of TNF , has also been shown to decrease short term mortality in SAH . Aim of this study was to evaluate the effect of PTX on short term mortality , renal and hepatic functions in patients with SAH . METHODS Fifty patients with SAH { Maddrey 's Discriminant Function ( DF ) > or = 32 } were prospect ively enrolled . Twenty five patients received PTX ( 400 mg orally , three times a day ) , and 25 received placebo for 4 weeks . Serum tumor necrosis factor ( TNF ) was measured in both groups . RESULTS Baseline characteristics of the two groups were similar . At 4 weeks , mortality in PTX group was lower than that in controls { 20 % ( 5/25 ) versus 40 % ( 10/25 ) respectively ; p = 0.216 ; RR 0.5 ; 95 % CI 0.19 - 1.25}. Renal failure was the cause of mortality in 20 % ( 1/5 ) patients in PTX group , and 70 % ( 7/10 ) in controls ( p = 0.11 ) . Significant reduction in urea , creatinine , DF and TNF was noted in PTX group . Reduction in TNF did not correlate with reduction in creatinine or DF . CONCLUSIONS In patients with SAH , PTX leads to a significant improvement in renal and hepatic functions , and a trend towards decreased short term mortality [2691239] The effects of a nutritional support in hospitalized patients with alcoholic cirrhosis and liver failure were studied in a controlled protocol . Thirty-six patients were included , 17 were r and omly assigned to an experimental group and the rest to a control group . Experimentals received a diet aim ing at 50 kcal ( 209 kJ)/kg bodyweight/d and 1.5 g protein/kg bodyweight/d ( as proteins of high biological value ) . Controls received the st and ard diet prescribed by the attending physician . The severity of liver failure and the nutritional status on admission were similar in both groups . The measured energy intake in controls was 1813 + /- 121 kcal/d ( 7589 + /- 506 kJ/d ) and 2707 + /- 71 kcal/d ( 1131 + /- 297 kJ/d ) in experimentals ( P less than 0.001 ) . The protein intake in controls was 47 + /- 3.8 g/d and in experimentals 80 + /- 3 g/d ( P less than 0.001 ) . There were seven deaths during the study period ( two experimentals and five controls ) . No differences were observed in the evolution of liver failure , hepatic encephalopathy or nutritional status between both study groups . It is concluded that a higher energy and protein intake in these patients does not have adverse effects and is associated with a non-significant reduction in mortality [7790695] OBJECTIVE Alcohol ingestion promotes lipoperoxidation and alters cellular antioxidant mechanisms . Alpha-tocopherol levels decrease in alcoholics as severity of liver damage increases . The aim of this protocol was to study the effects of a long-term oral 500 mg vitamin E daily supplementation in decompensated ambulatory alcoholic cirrhotics . PATIENTS AND METHODS 67 subjects were included in this double blind trial ; 33 patients received vitamin E and 34 patients received placebo tablets of identical appearance during 1 year . Each month , the patients were seen by a nurse practitioner who was in charge of detecting alcohol ingestion and checking adherence to treatment . Every 3 months , the patients underwent a medical examination , and blood sample s were taken for clinical laboratory analysis and serum vitamin E measurement . RESULTS Alpha-tocopherol levels were significantly lower in patients with more severe liver disease . This difference was not significant when vitamin E levels were corrected by cholesterol . Oral supplementation significantly increased serum vitamin E levels in the experimental group . Alcohol ingestion and hospitalization rates were similar in both groups . Life table analysis did not show significant differences in mortality between the two groups . DISCUSSION Vitamin E supplementation with adequate doses of an alpha-tocopheryl acetate formulation during 1 year did not influence hepatic laboratory parameters , mortality or hospitalization rates of decompensated alcoholic cirrhotics , although serum levels of the vitamin significantly increased [9514531] BACKGROUND / AIMS Calcium channel blockers have a hepatoprotective action in animal models of alcohol-induced liver injury but their effect in alcoholic liver disease in humans has not been previously investigated . We have conducted a r and omised , placebo-controlled trial to investigate the possible benefit of the calcium channel blocker amlodipine in terms of 4-week survival in hospitalised patients with severe acute alcoholic hepatitis . METHODS Sixty-two patients with acute alcoholic hepatitis were r and omised to receive 5 - 10 mg amlodipine each day for 1 year or an identical capsule containing placebo . In 36 ( 58 % ) , acute alcoholic hepatitis was confirmed on biopsy and in the remainder on clinical and laboratory criteria . There were no statistically significant differences in clinical characteristics and disease severity in the treated and placebo groups . RESULTS Of the 32 patients receiving amlodipine , there were six deaths ( 19 % ) in the first 4 weeks compared with seven ( 23 % ) of the placebo patients ( p=0.329 ) . Causes of death were similar in the amlodipine and control groups , with liver failure predominant . Analysis by the Cox proportional hazards model after adjustment for other prognostic factors showed survival was not significantly influenced by active treatment ( p=0.07 ) . One patient in each group was withdrawn because of the development of hypotension , but this did not recur on re introduction of the capsules . CONCLUSIONS This study shows that calcium channel blockers are well tolerated with few side effects in advanced alcoholic liver disease , but there is no conclusive evidence from this study that calcium channel blockers are helpful in the treatment of alcoholic hepatitis [8256468] Toxic liver diseases coincide with oxidative stress correlating positively with the seriousness of the course of disease . For the purpose of elucidating the pathogenic significance of an increased radical generation . 56 patients suffering from acute alcohol-toxic hepatitis of the clinical grade of seriousness B and C according to Child/Pugh were classified r and omly into antioxidant subgroups ( n = 31 ) and control groups (= 25 ) . The basis therapy being identical , the patients of the antioxidant group received additionally 600 mg of D-alpha tocopherol per day , 200 micrograms of selenium and 12 mg of zinc . Due to the supplementation of antioxidants there were quicker significant changes in the concentration of bilirubin , malondialdehyde and of ammonia in the serum . In comparison with the control group the length of stay in hospital could be reduced by 6 days . In the control group the mortality rates amounted to 40 % ( 10 of 25 ) , in the antioxidant group to 6.5 % ( 2 of 31 ) . The results confirm the pathogenic significance of oxidative stress in alcohol-toxic liver disease because a distinct improvement of prognosis could be achieved by using a low-cost adjuvant antioxidant supplementation [2753302] A r and omized double-blind trial of colchicine vs placebo was conducted in 67 patients with histologically proven alcoholic hepatitis , 33 of whom had cirrhosis . Patients with hepatic encephalopathy , ascites , protracted prothrombin time , severe thrombocytopenia , hepatocellular carcinoma , evident lack of discipline or refusal to participate in the trial were not included . Thirty-three patients received colchicine ( 1 mg/day ) and 34 received placebo for 6 months . Blood parameters including N-terminal peptide of type III procollagen were assessed in the serum , and a percutaneous liver biopsy was performed at the start of the trial and after 3 and 6 months . Alcoholic hepatitis and fibrosis scores were established for each biopsy specimen . Twenty-eight percent of patients were lost to follow-up at 3 months , and fifty-two percent at 6 months . One patient died of liver failure . Fifty-eight percent of patients were abstaining from alcohol at 3 months and fifty percent at 6 months . No significant effect of treatment was noted . Nevertheless , improvement in alcoholic hepatitis core at 3 months was more important in the colchicine group than in the placebo group . No side-effects were noted except transient diarrhea . Our results suggest that colchicine has no important effect on the course of alcoholic hepatitis . A trial including of at least 260 patients might be necessary for the observed alcoholic hepatitis score difference at 3 months , favoring colchicine , to be statistically significant [3082733] Between March 1982 and September 1983 , 40 in patients ( 25 men and 15 women , mean age 53 years ) with alcoholic cirrhosis and total serum bilirubin greater than or equal to 5 mg per dl were studied . Those with hepatocellular carcinoma , renal failure , hyponatremia , septicemia , spontaneous bacterial peritonitis , gastrointestinal bleeding , and hepatic coma were excluded . Patients were studied for 28 days . The two groups were offered an oral diet containing 40 kcal per kg per day . Patients in the supplementary parenteral nutrition group received 40 kcal per kg per day and 200 mg nitrogen per kg per day using a central catheter . The major endpoint was total serum bilirubin on Day 28 . On admission , serum bilirubin was not significantly different in the two groups : oral group , 12.5 + /- 6.6 mg per dl ; supplementary parenteral nutrition group , 12.3 + /- 8.5 mg per dl . On Day 28 , serum bilirubin was lower in the supplementary parenteral nutrition group ( 2.5 + /- 1.4 mg per dl ) than in the oral group ( 4.1 + /- 2.2 mg per dl ) ( p less than 0.02 ) . Serum bilirubin was also lower in the supplementary parenteral nutrition group than in the oral group on Days 7 , 14 and 21 ( p less than 0.05 ) . Analysis of covariance , considering serum bilirubin on admission and at r and omization and time between admission and r and omization , confirmed these results . On Day 28 , anthropometric parameters , serum transferrin , prealbumin and retinol-binding protein were higher in the supplementary parenteral nutrition group , but the differences were not significant . Serum albumin was significantly lower in the supplementary parenteral nutrition group . The incidence of encephalopathy and sepsis was not significantly different between the two groups [27337960] Purpose / background Severe alcoholic hepatitis ( AH ) is a life-threatening liver disease with a potential of 30–40 % mortality at 1 month . While steroids remain to be a first line therapy , they provide only about 50 % survival benefit . The aim of the study was to evaluate the efficacy of glucocorticoids plus S-adenosylmethionine ( SAMe ) , as compared to glucocorticoids alone , in patients with severe alcoholic hepatitis . Methods Forty patients with severe AH were r and omized in two groups and enrolled in the prospect i ve trial . Group 1 ( n = 20 ) patients received prednisolone 40 mg/daily per os , and group 2 ( n = 20 ) patients were managed with prednisolone 40 mg/daily per os plus SAMe 800 mg i.v . treatment . Duration was 28 days . Results The response rate assessed by Lille model was significantly higher in the prednisolone plus SAMe group ( 19 of 20 ; 95 % ) than in the prednisolone group ( 13 of 20 ; 65 % ) , p = 0.044 . Two ( 10 % ) patients died , both from the prednisolone group . There were no lethal outcomes in the prednisolone plus SAMe group . The Kaplan – Meier method showed no significant differences between the two groups ( p = 0.151 , log-rank ) . Hepatorenal syndrome ( HRS ) occurred in 20 % in the prednisolone group ( 4 of 20 patients ) while no HRS cases were registered in the prednisolone plus SAMe group ( p = 0.035 ) . Conclusions Management of severe alcoholic hepatitis with prednisolone plus SAMe was associated with better therapy response ( p = 0.044 ) and less frequent HRS occurrence ( p = 0.035 ) . Mortality was not significantly lower in the prednisolone – SAMe group than in the prednisolone-only group at 28 days ( 10 vs. 0 % , p = 0.151 ) [9566830] BACKGROUND / AIMS Silymarin has protective effects in different experimental conditions , but its efficacy in human liver cirrhosis has not been completely established . Therefore , this study was carried out to determine the effect of silymarin in alcoholics with liver cirrhosis with respect to survival and clinical and laboratory changes . METHODS From February 1986 to June 1989 , we enrolled 200 alcoholics with histologically or laparoscopically proven liver cirrhosis in a r and omized , double-blind multicenter trial comparing 450 mg of silymarin ( 150 mg/ three times per day ) with placebo . The primary outcome was time to death , and the secondary outcome was the progression of liver failure . Additional analyses were also performed in 75 patients in whom anti-hepatitis C virus antibodies were measured after completion of the trial . RESULTS One hundred and three patients were assigned to receive silymarin and 97 to receive placebo . The two groups were well matched for demographic and baseline clinical and laboratory features . A 2-year study period was completed in 125 patients ( 57 receiving silymarin and 68 receiving placebo ) . Twenty-nine patients ( 15 receiving silymarin , and 14 receiving placebo ) died during the trial . Survival was similar in patients receiving silymarin or placebo . The effect of silymarin on survival was not influenced by sex , the persistence of alcohol intake , the severity of liver dysfunction or by the presence of alcoholic hepatitis in the liver biopsy . Silymarin did not have any significant effect on the course of the disease . No relevant side-effects were observed in any group . CONCLUSIONS The results of this study indicate that silymarin has no effect on survival and the clinical course in alcoholics with liver cirrhosis [9126802] BACKGROUND / AIMS Several studies have demonstrated that diabetic patients with cirrhosis require insulin treatment because of insulin resistance . As chronic alcoholic liver damage is partly due to the lipoperoxidation of hepatic cell membranes , anti-oxidizing agents may be useful in treating or preventing damage due to free radicals . The aim of this study was to ascertain whether long-term treatment with silymarin is effective in reducing lipoperoxidation and insulin resistance in diabetic patients with cirrhosis . METHODS A 12-month open , controlled study was conducted in two well-matched groups of insulin-treated diabetics with alcoholic cirrhosis . One group ( n=30 ) received 600 mg silymarin per day plus st and ard therapy , while the control group ( n=30 ) received st and ard therapy alone . The efficacy parameters , measured regularly during the study , included fasting blood glucose levels , mean daily blood glucose levels , daily glucosuria levels , glycosylated hemoglobin ( HbA1c ) and malondialdehyde levels . RESULTS There was a significant decrease ( p<0.01 ) in fasting blood glucose levels , mean daily blood glucose levels , daily glucosuria and HbA1c levels already after 4 months of treatment in the silymarin group . In addition , there was a significant decrease ( p<0.01 ) in fasting insulin levels and mean exogenous insulin requirements in the treated group , while the untreated group showed a significant increase ( p<0.05 ) in fasting insulin levels and a stabilized insulin need . These findings are consistent with the significant decrease ( p<0.01 ) in basal and glucagon-stimulated C-peptide levels in the treated group and the significant increase in both parameters in the control group . Another interesting finding was the significant decrease ( p<0.01 ) in malondialdehyde/levels observed in the treated group . CONCLUSIONS These results show that treatment with silymarin may reduce the lipoperoxidation of cell membranes and insulin resistance , significantly decreasing endogenous insulin overproduction and the need for exogenous insulin administration [3142949] We performed a controlled trial of peripheral hyperalimentation in moderate and severe alcoholic hepatitis to determine whether improvement in survival and liver function could be obtained . Twelve patients with moderate and 22 with severe alcoholic hepatitis were r and omized to 28 days of peripheral parenteral nutrition ( PPN ) or st and ard therapy ( ST ) . In the moderate group , six were treated with each therapy . In the severe group , 10 were treated with PPN and 12 with ST . Routine liver tests , hepatocyte function ( galactose elimination capacity ) , estimated hepatic blood flow ( galactose clearance ) and assessment of ascites and encephalopathy were performed at r and omization and at 28 days . Groups were equally matched at r and omization . In the moderate group PPN produced no improvement in morbidity ( liver tests ) and mortality ( no deaths ) . In the severe group there were seven deaths ( 4 PPN , 3 ST ) . PPN produced greater improvement than ST in serum bilirubin and transferrin concentrations and a trend toward greater improvement in prothrombin time , serum albumin and galactose elimination capacity . PPN had no deleterious effect on encephalopathy or ascites as only ST patients developed ascites or encephalopathy after r and omization . We conclude that PPN compared to ST ( 1 ) provides no benefit in moderate alcoholic hepatitis , but ( 2 ) did more rapidly improve morbidity ( liver tests ) and probably liver function in severe alcoholic hepatitis ; ( 3 ) PPN did not improve early mortality , and ( 4 ) it had no deleterious effect on encephalopathy or ascites [15825072] BACKGROUND & AIMS Colchicine improved survival and reversed cirrhosis in several small clinical trials . We compared the efficacy and safety of long-term colchicine , as compared with placebo , in patients with advanced alcoholic cirrhosis . METHODS Five hundred forty-nine patients with advanced ( Pugh B or C ) alcoholic cirrhosis were r and omized to receive either colchicine 0.6 mg twice per day ( n = 274 ) or placebo ( n = 275 ) . Treatment lasted from 2 to 6 years . The primary outcome was all-cause mortality . Secondary outcomes were liver-related morbidity and mortality . Liver biopsy was requested prior to entry and after 24 months of treatment . RESULTS Attendance at scheduled clinic visits and adherence with study medication were similar in colchicine and placebo groups . Alcohol intake was less than 1 drink per day in 69 % of patients . In an intention-to-treat analysis , all-cause mortality was similar in colchicine ( 49 % ) and placebo ( 45 % ) patients ( P = .371 ) . Mortality attributed to liver disease was 32 % in colchicine and 28 % in placebo patients ( P = .337 ) . Fewer patients receiving colchicine developed hepatorenal syndrome . In 54 patients with repeat liver biopsies after 24 or more months of treatment , cirrhosis improved to septal fibrosis in 7 patients ( 3 colchicine , 4 placebo ) and to portal fibrosis in 1 patient ( colchicine ) . CONCLUSIONS In patients with advanced alcoholic cirrhosis , colchicine does not reduce overall or liver-specific mortality . Liver histology improves to septal fibrosis in a minority of patients after 24 months of treatment , with similar rates of improvement in patients receiving placebo and colchicine . Colchicine is not recommended for patients with advanced alcoholic cirrhosis [15122768] Tumor necrosis factor-alpha ( TNF-alpha ) may contribute to the progression of acute alcoholic hepatitis ( AAH ) . The aim of this study was to evaluate the efficacy of an association of infliximab and prednisolone at reducing the 2-month mortality rate among patients with severe AAH . Patients with severe AAH ( Maddrey score > /=32 ) were r and omly assigned to group A receiving intravenous infusions of infliximab ( 10 mg/kg ) in weeks 0 , 2 , and 4 ; or group B receiving a placebo at the same times . All patients received prednisolone ( 40 mg/day ) for 28 days . Blood neutrophil functional capacities were monitored over 28 days . After r and omization of 36 patients , seven patients from group A and three from group B died within 2 months . The probability of being dead at 2 months was higher ( not significant [ NS ] ) in group A ( 39 % + /- 11 % ) than in group B ( 18 % + /- 9 % ) . The study was stopped by the follow-up committee and the sponsor ( Assistance Publique-Hôpitaux de Paris ) . The frequency of severe infections within 2 months was higher in group A than in group B ( P < .002 ) . This difference was potentially related to a significantly lower ex vivo stimulation capacity of neutrophils . There were no differences between the two groups in terms of Maddrey scores at any time point . In conclusion , three infusions of 10 mg/kg of infliximab in association with prednisolone may be harmful in patients with severe AAH because of the high prevalence of severe infections [20881772] Objective : To evaluate patient survival and allograft function and health-related quality of life ( HRQOL ) 20 years after orthotopic liver transplantation ( LT ) . Summary of Background Data : Although LT is the established treatment of choice for acute and chronic liver failure , allograft function and recipient HRQOL 20 years after LT remain undefined . Methods : We performed a prospect i ve , cross-sectional study of LT recipients surviving 20 years or more . Clinical data were review ed to identify factors associated with 20-year survival . Survivors were directly contacted and offered a survey to assess HRQOL ( SF-36 ; Liver Disease Quality of Life ) , social support , and cognition ( Neuropsychological Impairment Scale ) . Logistic regression analysis was performed to identify clinical factors influencing HRQOL 20 years after LT . Results : Between February 1 , 1984 and December 31 , 1988 , a total of 293 patients ( 179 adults , 114 children ) received 348 LTs . Of the 293 patients , 168 ( 56 % ) survived for 20 years or more . Actuarial 20-year survival was 52 % ( patient ) and 42 % ( graft ) . Factors associated with 20-year survival included recipient age < 18 ( P = 0.01 ) , nonurgent LT ( P = 0.01 ) , no retransplantation ( 0.02 ) , female gender ( 0.03 ) , absence of biliary complications ( P = 0.04 ) , and short total ischemia time ( P = 0.05 ) . Rejection episodes were seen in a greater proportion of 20-year survivors than in nonsurvivors ( 35 % vs. 27 % ; P = 0.3 ) . Of the 168 survivors , 87 were contacted , and 68 ( 78 % ) completed the HRQOL surveys . Compared with the general population , survivors had lower physical scores ( P < 0.01 ) but comparable mental scores on the SF-36 . Overall HRQOL was significantly better in 20-year survivors than in patients with chronic liver disease , congestive heart failure , or diabetes . Clinical factors associated with improved post-LT HRQOL were younger age at LT , allograft longevity , and strong social support . More than 90 % of pediatric survivors completed high school . After LT , 34 % of pediatric recipients married , and 79 % remained married at 20 years ' follow-up . Conclusions : More than 50 % of LT recipients survive 20 years , achieve important socioeconomic milestones , and report quality of life superior to patients with liver disease or other chronic conditions . LT is a durable surgery that restores both long-term physiologic and psychologic well-being in patients with end-stage liver disease [20102716] BACKGROUND & AIMS Pentoxifylline , an inhibitor of tumor necrosis factor-alpha , is given to patients with liver diseases , but its effects in patients with advanced cirrhosis are unknown . We performed a r and omized , placebo-controlled , double-blind trial of its effects in patients with cirrhosis . METHODS A total of 335 patients with cirrhosis ( Child-Pugh class C ) were assigned to groups given either pentoxifylline ( 400 mg , orally , 3 times daily ; n = 164 ) or placebo ( n = 171 ) for 6 months . The primary end point was mortality at 2 months . Secondary end points were mortality at 6 months and development of liver-related complications . RESULTS By 2 months , 28 patients in the pentoxifylline group ( 16.5 % ) and 31 in the placebo group ( 18.2 % ) had died ( P = .84 ) . At 6 months , 50 patients in the pentoxifylline group ( 30.0 % ) and 54 in the placebo group ( 31.5 % ) had died ( P = .75 ) . The proportions of patients without complications ( eg , bacterial infection , renal insufficiency , hepatic encephalopathy , or gastrointestinal hemorrhage ) were higher in the pentoxifylline group than in the placebo group at 2 months ( 78.6 % vs 63.4 % ; P = .006 ) and 6 months ( 66.8 % vs 49.7 % ; P = .002 ) . The probability of survival without complications was higher in the pentoxifylline group than in the placebo group at 2 and 6 months ( P = .04 ) . In multivariate analysis , the factors associated with death were age , the Model for End-Stage Liver Disease score , and presence of early-stage carcinoma . Treatment with pentoxifylline was the only factor associated with liver-related complications . CONCLUSIONS Although pentoxifylline does not decrease short-term mortality in patients with advanced cirrhosis , it does reduce the risk of complications [4199180] Background : Prednisolone and pentoxifylline ( PTX ) have been shown to be individually useful in severe alcoholic hepatitis with Maddrey discriminant function ( MDF ) score ≥32 . Previous report suggests that PTX is probably superior to prednisolone alone . However the efficacy of PTX and prednisolone combination over PTX alone in the management of acute alcoholic hepatitis ( MDF score ≥32 ) is yet unrevealed . Aim : The present study was initiated to find out the efficacy of combined pentoxifylline and prednisolone versus PTX alone in acute alcoholic hepatitis in respect of short and intermediate term outcomes . Subjects and Methods : A total of 124 patients with severe alcoholic hepatitis ( MDF score ≥ 32 ) initially were evaluated . 62 patients who fulfilled the inclusion and exclusion criteria were r and omized and divided into 2 groups . Group 1 received PTX only , whereas Group 2 received PTX plus Prednisolone . The total duration of follow-up was 12 months . Student′s t-test , Chi-square test , the Kaplan-Meier methods were used for statistical analysis . Results : A total of 60 patients , 30 in each group were available for final analysis . In Group-1 , 6 patients expired at the end of 1 year ( 5 within 3 months and another after 3 months ) . In Group 2 , 10 patients expired at the end of 1 year ( 9 within 3 months and another after 3 months ) . Though survival probability is higher among Group 1 patients but the difference is not statistically significant . Conclusion : The combination of PTX plus Prednisolone yields no additional benefit in terms of mortality and morbidity from that of PTX monotherapy [18848937] BACKGROUND & AIMS Alcoholic hepatitis is a cause of major morbidity and mortality that lacks effective therapies . Both experimental and clinical evidence indicate that the multifunctional cytokine tumor necrosis factor-alpha ( TNF-alpha ) contributes to pathogenesis and clinical sequelae of alcoholic hepatitis . A pilot study demonstrated that the TNF-alpha-neutralizing molecule etanercept could be an effective treatment for patients with alcoholic hepatitis . METHODS Forty-eight patients with moderate to severe alcoholic hepatitis ( Model for End-Stage Liver Disease score > or = 15 ) were enrolled and r and omized to groups that were given up to 6 subcutaneous injections of either etanercept or placebo for 3 weeks . Primary study end points included mortality at 1- and 6-month time points . RESULTS There were no significant baseline differences between the placebo and etanercept groups in demographics or disease severity parameters including age , gender , and Model for End-Stage Liver Disease score . The 1-month mortality rates of patients receiving placebo and etanercept were similar on an intention-to-treat basis ( 22.7 % vs 36.4 % , respectively ; OR , 1.8 ; 95 % CI , 0.5 - 6.5 ) . The 6-month mortality rate was significantly higher in the etanercept group compared with the placebo group ( 57.7 % vs 22.7 % , respectively ; OR , 4.6 ; 95 % CI , 1.3 - 16.4 ; P = .017 ) . Rates of infectious serious adverse events were significantly higher in the etanercept group compared with the placebo group ( 34.6 % vs 9.1 % , respectively , P = .04 ) . CONCLUSIONS In patients with moderate to severe alcoholic hepatitis , etanercept was associated with a significantly higher mortality rate after 6 months , indicating that etanercept is not effective for the treatment of patients with alcoholic hepatitis [7035299] The efficacy of methylprednisolone ( 1 g daily or three days ) , which is effective in reversing transplant rejection , was assessed in a r and omised controlled trial of 55 patients with severe acute alcoholic hepatitis , 34 of whom had encephalopathy . The clinical progress , frequency of bleeding and sepsis , and cause of death were similar in the treatment ( 27 patients ) and control groups ( 28 patients ) . There was no significant difference in mortality rate between the two groups : 57 % of the control group and 63 % of the treatment group died during the study . Patients ' survival depended on the presence of absence of the following features : encephalopathy , serum bilirubin concentration more than 340 micromol/l , serum creatinine concentration more than 250 micromol/l , and histological evidence of cirrhosis as well as severe acute alcoholic hepatitis [2205560] Study Objective : To determine the efficacy of a corticosteroid in reducing the short‐term mortality of patients with 8evere alcoholic hepatitis [2648927] STUDY OBJECTIVE To determine the efficacy of a corticosteroid in reducing the short-term mortality of patients with severe alcoholic hepatitis . DESIGN R and omized , double-blind , placebo-controlled multicenter trial . SETTING Four university teaching hospitals . PATIENTS We enrolled 66 patients with alcoholic hepatitis and either spontaneous hepatic encephalopathy or a discriminant function value greater than 32 , calculated using the formula : 4.6 ( prothrombin time - control time ) + serum bilirubin [ in mumol/L]/17.1 . Fifty-nine patients ( 89 % ) completed the study . Two patients withdrew from the trial . The other 64 patients were hospitalized for the duration of the trial ; however , treatment was discontinued in 5 patients because of potential drug toxicity . INTERVENTIONS Patients were r and omly assigned to receive either methylprednisolone ( 32 mg ) or placebo within 7 days of admission . Treatment was given for 28 days . The doses were then tapered over 2 weeks and discontinued . MEASUREMENTS AND MAIN RESULTS The endpoint of the study was death . Of the 31 recipients of placebo , 11 ( 35 % ) died within 28 days of r and omization compared with 2 ( 6 % ) of the 35 patients given methylprednisolone ( P = 0.006 ) . The 95 % CI for the difference in mortality was 12 % to 70 % . In the patients with spontaneous hepatic encephalopathy at entry , 9 of 19 recipients of placebo died ( 47 % ) compared with 1 ( 7 % ) of the 14 patients given methylprednisolone ( P = 0.02 ) . The 95 % CI for the difference in mortality was 14 % to 66 % . The Cox proportional hazards regression model showed the advantage of methylprednisolone over placebo after adjustment for other potentially important prognostic variables ( P = 0.004 ) . CONCLUSIONS Methylprednisolone therapy decreases short-term mortality in patients with severe alcoholic hepatitis manifested either by spontaneous hepatic encephalopathy or a markedly elevated discriminant function value [28839840] Philip Hendy review s Thursz et al. 1The r and omized double blind placebo controlled Steroids or Pentoxifylline for Alcoholic Hepatitis ( STOPAH ) trial demonstrates that pentoxifylline does not improve mortality in severe alcoholic hepatitis at 28 days or beyond . It also demonstrates that prednisolone provides a non-significant mortality benefit at 28 days which does not persist to 90 days or beyond and is associated with increased risk of infection . Alcoholic hepatitis is a syndrome characterised by jaundice and liver dysfunction in the setting of significant long-term alcohol excess . Severe disease is associated with high mortality—30 % at 1 month and 40 % at 6 months.2 , 3 Treatment consists of organ support as required , as well as steroid and or pentoxifylline ( PTX ) therapy , both of which are included in national and international management guidelines . The European Association for the Study of the Liver guidelines include steroids and , in the case of ongoing sepsis , PTX.4 [8964410] BACKGROUND & AIMS Corticosteroids have been shown to significantly decrease short-term mortality in patients with severe alcoholic hepatitis . However , independent factors associated with a favorable outcome and long-term survival are unknown . The aim of this study was to examine prognostic factors and long-term survival in patients with biopsy-proven severe alcoholic hepatitis . METHODS Of 183 patients studied , 61 had been r and omized in a previous trial ; 32 of them were treated with prednisolone ( group I ) and 29 were not treated ( group II ) ; 61 were treated from the end of this r and omized trial ( group III ) ; and 61 were simulated ( group IV ) . RESULTS At 1 year , survival in group I ( 69 % ; confidence interval [ CI ] , 57%-81 % ) and group III ( 71 % ; CI , 55%-87 % ) was better than in the nontreated groups ( group II , 41 % ; CI , 23%-59 % ; P = 0.01 ) ( group IV , 50 % ; CI , 37%-63 % ; P = 0.05 ) . At 2 years , survival was not significantly different . Treated patients with marked liver polymorphonuclear infiltrate had better 1-year survival ( 76 % ; CI , 64%-88 % ) than the others ( 53 % ; CI , 35%-71 % ; P = 0.05 ) . Treated patients with polymorphonuclear counts of > 5500/mm3 had better 1-year survival ( 77 % ; CI , 65%-89 % ) than the others ( 40 % ; CI , 14%-66 % ; P = 0.003 ) . In the 93 treated patients , liver polymorphonuclear infiltrate ( P < 0.03 ) and polymorphonuclear count ( P < 0.001 ) were independently correlated with 1-year survival . CONCLUSIONS Prednisolone reduced mortality by at least 1 year . Liver polymorphonuclear infiltrate and polymorphonuclear count were independent prognostic factors [3932509] Sixty-four patients admitted with acute alcoholic hepatitis , with or without underlying cirrhosis , were r and omized regardless of encephalopathy to receive a controlled diet either alone , or supplemented orally , nasogastrically , or intravenously as necessary , with 2000 kCal and 10 g nitrogen daily . Whether this came from a conventional protein source or a branched chain amino acid enriched formulation was also r and omly determined . In the absence of renal failure , nitrogen intakes of 10 g or more daily were invariably associated with positive nitrogen balance , but complications of liver dysfunction prevented the attainment of significantly more positive balance in the supplemented groups than in controls . Neither in the series as a whole , nor in any identifiable subgroup of patients , was mortality affected by treatment . Changes in prothrombin time and in measured nutritional parameters during the study did not differ between supplemented and control groups , and the observed changes in midarm muscle circumference appeared to reflect changes in degree of fluid retention . Neither enteral nor parenteral branched chain amino acids showed any consistent effect upon encephalopathy [12668982] The aim of our multicenter study was to assess the efficacy of ursodeoxycholic acid ( UDCA ) on the survival of patients with alcohol‐induced cirrhosis and jaundice . We included patients with histologically proven alcohol‐induced cirrhosis and serum bilirubin > 50 μmol/L. After r and omization , patients received either UDCA ( 13‐15 mg/kg/d ) or a placebo for 6 months . Two hundred twenty‐six patients ( 113 in each group ) were included in 24 centers . There were 139 men and 87 women , mean age of 50.3 years . Seventy‐four percent had associated alcohol‐induced hepatitis , and 24 % received a corticosteroid therapy . At inclusion , the 2 groups were comparable for the main clinical and biologic parameters , but serum bilirubin was higher in the UDCA group than in the placebo group ( 163 μmol/L vs. 145 μmol/L , P < .03 ) . The percentage of patients lost at follow‐up or who resumed their alcoholism during the study was comparable in the 2 groups . During the study , 55 patients died , 35 in the UDCA group and 20 in the placebo group . In the intention to treat analysis , the probability of survival at 6 months ( Kaplan‐Meier method ) was lower in the UDCA than in the P group ( 69 % vs. 82 % , respectively ; P = .04 , log‐rank test ) . After adjustment on the bilirubin level at entry ( Cox model ) , the independent predictive value of the treatment group did not reach the statistical level ( RR = 1.64 , CI 0.85‐2.85 ; P = .077 ) . In conclusion , UDCA administered at the dose recommended in primary biliary cirrhosis has no beneficial effect on the 6‐month survival of patients with severe alcohol‐induced cirrhosis . An inappropriate dosage of UDCA can not be excluded as an explanation for the lack of therapeutic benefit [356593] In a prospect i ve double-blind study , 27 patients with alcoholic hepatitis were r and omized for 6-methylprednisolone ( 12 patients ) or placebo treatment ( 15 patients ) . The mortality was 50 % among steroid treated patients and 47 % in the control group ( P less than .05 ) . The role of liver biopsy feasibility at selection is emphasized since the mortality in this group was 10 % as opposed to 71 % when the procedure was contraindicated ( P less than .01 ) . Complications in the steroid-treated subjects were similar quantitatively and qualitatively to those observed in the control series [2844940] The CONSORT statement is used worldwide to improve the reporting of r and omised controlled trials . Kenneth Schulz and colleagues describe the latest version , CONSORT 2010 , which up date s the reporting guideline based on new method ological evidence and accumulating [22070475] BACKGROUND Mortality among patients with severe acute alcoholic hepatitis is high , even among those treated with glucocorticoids . We investigated whether combination therapy with glucocorticoids plus N-acetylcysteine would improve survival . METHODS We r and omly assigned 174 patients to receive prednisolone plus N-acetylcysteine ( 85 patients ) or only prednisolone ( 89 patients ) . All patients received 4 weeks of prednisolone . The prednisolone-N-acetylcysteine group received intravenous N-acetylcysteine on day 1 ( at a dose of 150 , 50 , and 100 mg per kilogram of body weight in 250 , 500 , and 1000 ml of 5 % glucose solution over a period of 30 minutes , 4 hours , and 16 hours , respectively ) and on days 2 through 5 ( 100 mg per kilogram per day in 1000 ml of 5 % glucose solution ) . The prednisolone-only group received an infusion in 1000 ml of 5 % glucose solution per day on days 1 through 5 . The primary outcome was 6-month survival . Secondary outcomes included survival at 1 and 3 months , hepatitis complications , adverse events related to N-acetylcysteine use , and changes in bilirubin levels on days 7 and 14 . RESULTS Mortality was not significantly lower in the prednisolone-N-acetylcysteine group than in the prednisolone-only group at 6 months ( 27 % vs. 38 % , P = 0.07 ) . Mortality was significantly lower at 1 month ( 8 % vs. 24 % , P = 0.006 ) but not at 3 months ( 22 % vs. 34 % , P = 0.06 ) . Death due to the hepatorenal syndrome was less frequent in the prednisolone-N-acetylcysteine group than in the prednisolone-only group at 6 months ( 9 % vs. 22 % , P = 0.02 ) . In a multivariate analysis , factors associated with 6-month survival were a younger age ( P<0.001 ) , a shorter prothrombin time ( P<0.001 ) , a lower level of bilirubin at baseline ( P<0.001 ) , and a decrease in bilirubin on day 14 ( P<0.001 ) . Infections were less frequent in the prednisolone-N-acetylcysteine group than in the prednisolone-only group ( P = 0.001 ) ; other side effects were similar in the two groups . CONCLUSIONS Although combination therapy with prednisolone plus N-acetylcysteine increased 1-month survival among patients with severe acute alcoholic hepatitis , 6-month survival , the primary outcome , was not improved . ( Funded by Programme Hospitalier de Recherche Clinique ; AAH-NAC Clinical Trials.gov number , NCT00863785 . ) [10869286] Steroids are recommended in severe alcohol-induced hepatitis , but some data suggest that artificial nutrition could also be effective . We conducted a r and omized trial comparing the short- and long-term effects of total enteral nutrition or steroids in these patients . A total of 71 patients ( 80 % cirrhotic ) were r and omized to receive 40 mg/d prednisolone ( n = 36 ) or enteral tube feeding ( 2,000 kcal/d ) for 28 days ( n = 35 ) , and were followed for 1 year or until death . Side effects of treatment occurred in 5 patients on steroids and 10 on enteral nutrition ( not significant ) . Eight enterally fed patients were prematurely withdrawn from the trial . Mortality during treatment was similar in both groups ( 9 of 36 vs. 11 of 35 , intention-to-treat ) but occurred earlier with enteral feeding ( median 7 vs. 23 days ; P = .025 ) . Mortality during follow-up was higher with steroids ( 10 of 27 vs. 2 of 24 intention-to-treat ; P = . 04 ) . Seven steroid patients died within the first 1.5 months of follow-up . In contrast to total enteral nutrition ( TEN ) , infections accounted for 9 of 10 follow-up deaths in the steroid group . In conclusion , enteral feeding does not seem to be worse than steroids in the short-term treatment of severe alcohol-induced hepatitis , although death occurs earlier with enteral nutrition . However , steroid therapy is associated with a higher mortality rate in the immediate weeks after treatment , mainly because of infections . A possible synergistic effect of both treatments should be investigated [12499076] Liv.52 , a hepatoprotective agent of herbal origin , is used empirically for the treatment of alcoholic liver disease in Sri Lanka . We conducted a controlled trial to assess the efficacy of Liv.52 in patients with alcoholic liver disease . Patients with evidence of alcoholic liver disease attending outpatient clinics were included in a prospect i ve , double blind , r and omized , placebo controlled trial . During the trial period , 80 patients who fulfilled inclusion criteria were r and omly assigned Liv.52 ( cases ; n = 40 ) or placebo ( controls ) the recommended dose of three capsules twice daily for 6 months . All patients underwent clinical examination ( for which a clinical score was computed ) , and laboratory investigations for routine blood chemistry and liver function before commencement of therapy ( baseline ) . Thereafter , clinical assessment s were done monthly for 6 months , while laboratory investigations were done after 1 and 6 months of therapy . There was no significant difference in the age composition , alcohol intake and baseline liver function between the two groups . The two- sample t-test was used to analyze data obtained after 1 and 6 months of therapy against baseline values . There was no significant difference in clinical outcome and liver chemistry between the two groups at any time point . There were no reports of adverse effects attributable to the drug . Our results suggest that Liv.52 may not be useful in the management of patients with alcohol induced liver disease [6108449] 35 consecutive patients with alcoholic hepatitis were r and omly allocated to control ( 18 patients ) and study ( 17 patients ) groups . All patients were offered a 3000 kcal 100 g protein diet and were studied for 28 days . The study group received 70 - 85 g of intravenous aminoacids daily in the form of ' Aminosyn ' or ' Travasol ' . Both groups had similar clinical and biochemical features at the time of r and omisation . Ascites and encephalopathy tended to improve more in the study group . Serum concentrations of bilirubin ( p < 0.01 ) and albumin ( p < 0.025 ) improved in the study but not in the control group . 4 patients died in the control group , but none died in the study group . Intravenous therapy with aminoacid for 4 weeks seemed to be associated with lower mortality rate ( p < 0.02 ) and improved serum bilirubin and albumin concentrations in patients with alcoholic hepatitis [4930603] Abstract A prospect i ve , double-blind controlled pilot study in 20 subjects of the efficacy of glucocorticosteroids in the treatment of severe , life-threatening , alcoholic hepatitis failed to demons [2875927] A double-blind , placebo-controlled multicenter trial was conducted to determine the efficacy of oral testosterone treatment ( 200 mg three times daily ) in men with alcoholic cirrhosis . By skewed r and omization ( 3:2 ) , 134 patients received testosterone and 87 placebo . Patients were followed from 8 to 62 months ( median = 28 months ) . In the testosterone group , 33 patients died ( 25 % ; 95 % confidence limits = 18 to 33 % ) as compared to 18 ( 21 % ; 95 % confidence limits = 13 to 31 % ) in the placebo group . Taking age and significant prognostic variables into consideration , this corresponds with a relative mortality risk of 1.17 ( 95 % confidence limits = 0.65 to 2.15 ) in the testosterone group vs. the placebo group . Testosterone treatment did not significantly affect liver biochemistry , prevalence of complications to cirrhosis or causes of death . Patients treated with testosterone developed significantly ( p less than 0.05 ) higher serum testosterone and blood hemoglobin concentrations and significantly ( p less than 0.05 ) lower plasma IgM concentrations as compared to the placebo group . The prevalence of gynecomastia decreased significantly ( p less than 0.05 ) in the testosterone group as compared to the placebo group . We conclude that oral testosterone treatment has no beneficial effect on survival and liver biochemistry in men with alcoholic cirrhosis , and adverse effects can not be excluded [326034] In a prospect i ve , r and omized , double-blind study of prednisolone therapy of acute alcoholic hepatitis , 39 % of the total group of 28 patients died . Mortality and cumulative survival were similar in steroid- and placebo-treated patients . After 14 days of therapy , the serum albumin concentration and white blood count were significantly higher in the steroid group , but all other parameters were similar . An increased risk of fungal infection appeared to be associated with steroid therapy [12217597] BACKGROUND / AIMS The aim of this study is to evaluate the tolerance and effects of infliximab combined with steroids in severe alcoholic hepatitis ( AH ) . METHODS Twenty patients with biopsy-proven severe AH ( Maddrey 's score>32 ) received prednisone 40 mg/day for 28 days and either infliximab 5mg/kg IV ( group A ) or placebo ( group B ) at day 0 . Histology , plasma interleukin-6 ( IL-6 ) and interleukin-8 ( IL-8 ) were measured at baseline and at day 10 . RESULTS Infliximab was well tolerated . Histology showed no significant changes . At day 28 , Maddrey 's score significantly improved in group A ( 39 ( 32 - 53 ) to 12 ( 7 - 52 ) , P<0.05 vs. baseline ) but not in group B ( 44 ( 33 - 50 ) to 22 ( 2 - 59 ) , P = NS ) . At day 10 , IL-6 and IL-8 decreased in group A ( 25 pg/ml ( 10 - 85 pg/ml ) to 4.5 pg/ml ( 2 - 25 pg/ml ) ; 301 pg/ml ( 107 - 1207 pg/ml ) to 14 6 pg/ml ( 25 - 252 pg/ml ) , P<0.01 , P<0.05 vs. baseline , respectively ) . In group B , changes were not significant ( 38 pg/ml ( 13 - 116 pg/ml ) to 16 pg/ml ( 4 - 128 ) ; 315 pg/ml ( 26 - 1698 pg/ml ) to 110 pg/ml ( 27 - 492 pg/ml ) ) . CONCLUSIONS In severe AH , infliximab was well tolerated and associated with significant improvement in Maddrey 's score at day 28 . Although the size of this study does not allow comparison between groups , these promising results should encourage larger trials assessing the effects of this therapy on survival [11841050] BACKGROUND The role of silymarin in the treatment of liver cirrhosis is controversial . AIM Clinical outcome , biochemical profile and the antiperoxidative effects of silymarin MZ-80 during 6 months treatment were investigated in patients with alcoholic liver cirrhosis . METHODS Sixty consecutive patients with alcoholic liver cirrhosis were r and omized to receive either silymarin MZ-80 ( S ) ( 150 mg t.i.d . per day ) or placebo ( P ) for periods of 6 months . Erythrocyte total glutathione ( GSH ) content , platelet malondialdehyde ( MDA ) and serum amino-terminal propeptide of procollagen Type III ( PIIINP ) were determined at baseline and at the end of treatment . RESULTS Forty-nine patients completed the study ( 24 S and 25 P ) . The 2 groups were well-matched for demographic as well as baseline clinical and laboratory parameters . Silymarin increased total GSH at 6 months ( 4.5 + /- 3.4 to 5.8 + /- 4.0 micromol/g Hb ) whereas , in the placebo group , GSH remained unchanged ( 4.1 + /- 3.9 to 4.4 + /- 4.1 micromol/gHb ) ( p < 0.001 ) , and platelet-derived non-induced MDA decreased by 33 % ( p < 0.015 ) . A parallel decrease in PIIINP values was seen with silymarin ( 1.82 1.03 to 1.36 + /- 0.5 U/ml , p < 0.033 ) but not with placebo ( 1.31 + /- 0.4 to 1.27 + /- 0.6 U/ml ) . There were no concurrent changes on laboratory indices of the pathology . CONCLUSIONS Silymarin is well-tolerated and produces a small increase in glutathione and a decrease in lipid peroxidation in peripheral blood cells in patients with alcoholic liver cirrhosis . Despite these effects no changes in routine liver tests were observed during the course of therapy [22364262] BACKGROUND Recent studies have shown that the renin-angiotensin system is implicated in hepatic fibrogenesis in vitro and in vivo . However , no study was done in humans with alcoholic liver disease . AIM To investigate the antifibrotic effect of angiotensin II type 1 receptor ( AT1-R ) blocking agents ( ARB ) in patients with alcoholic liver disease . METHODS The primary outcome was improvement in patients ' histological features . Eighty-five patients with compensated alcoholic liver fibrosis ( ≥ F2 ) which was confirmed by baseline liver biopsy were r and omized ( intention-to-treat ( ITT ) ) to receive either ARB , c and esartan ( 8 mg/day ) with ursodeoxycholic acid ( UDCA ) ( 600 mg/day ) ( n = 42 ) or UDCA alone ( n = 43 ) as control for 6 months and follow-up liver biopsies were conducted . RESULTS According to the Laennec fibrosis system , c and esartan showed significantly higher rates of histological improvements ( ITT , 33.3 % vs. 11.6 % , P = 0.020 ) . In addition , the fibrosis score was significantly reduced from 3.4 ± 1.4 to 3.1 ± 1.5 ( P = 0.005 ) in the c and esartan group . C and esartan also reduced the area of fibrosis and α-smooth muscle actin positive from 11.3 ± 6.0 to 8.3 ± 4.7 and 28.7 ± 10.5 to 23.9 ± 10.3 ( % ) , and the hydroxyproline levels ( μg/g liver tissue ) from 7.8 ± 2.4 to 6.3 ± 1.7 respectively ( P < 0.05 ) . In addition , the relative expression of transforming growth factor-β1(TGF-β1 ) , collagen-1 , AT1-R , tissue inhibitor of metalloproteinase 1 ( TIMP-1 ) , metalloproteinases2 ( MMP2 ) , Rac1 and p22phox by real-time RT-PCR decreased in the c and esartan group ( P < 0.05 ) . Mean arterial blood pressure in the c and esartan group decreased mildly but significantly ( P < 0.001 ) . No significant complications and side effects were observed during the present study . CONCLUSIONS Administration of ARB in compensated alcoholic liver disease induces improvement of fibrosis in histological and quantitative measurements [6390194] A cooperative study was conducted to determine the efficacy of 30 days of treatment with either a glucocorticosteroid ( prednisolone ) or an anabolic steroid ( ox and rolone ) in moderate or severe alcoholic hepatitis . One hundred thirty-two patients with moderate disease and 131 with severe disease were r and omly assigned to one of three treatments : prednisolone , ox and rolone , or placebo . During the 30 days , mortality in the groups receiving steroid therapy was not significantly different from mortality in the placebo group . Thirteen per cent of the moderately ill patients and 29 per cent of the severely ill patients died . Although neither steroid improved short-term survival , ox and rolone therapy was associated with a beneficial effect on long-term survival . This was especially true in patients with moderate disease : among those who survived for one or two months after the start of treatment the conditional six-month death rate was 3.5 per cent after ox and rolone and 19 to 20 per cent after placebo ( P = 0.02 ) . No consistent long-term effect was associated with prednisolone therapy [17532088] BACKGROUND / AIMS Oxidative stress is putatively involved in the pathogenesis of alcohol-induced liver injury . This trial was devised to determine whether antioxidant therapy , alone or as an adjunct to corticosteroids , improved survival in patients with acute alcoholic hepatitis . METHODS Patients with a severe alcoholic hepatitis were stratified by sex and steroid use , and then r and omized . The active group received N-acetylcysteine for one week , and vitamins A-E , biotin , selenium , zinc , manganese , copper , magnesium , folic acid and Coenzyme Q daily for 6 months . The trial was double blinded and placebo controlled . The primary end-point was mortality within 6 months . RESULTS Thirty-six ( 20 male , 16 female ; mean discriminant function ( DF ) 86.6 ) received active drug , and 34 ( 18 male , 16 female ; mean DF 76.4 ) received placebo . 180-day survival was not significantly different between patients receiving drug and placebo ( 52.8 % vs. 55.8 % , p=0.699 ) . This was not affected by stratification for steroid use or sex . The only predictors of survival in multivariate analysis were initial bilirubin ( p=0.017 ) , white cell count ( p=0.016 ) and age ( p=0.037 ) . Treatment allocation did not affect survival in multivariate analysis ( p=0.830 ) . CONCLUSIONS Antioxidant therapy , alone or in combination with corticosteroids , does not improve 6-month survival in severe alcoholic hepatitis [1959859] The effect of parenteral amino acid administration on nutritional state , liver function and mortality was assessed in patients with severe alcoholic hepatitis . Twenty-eight patients received 2 l/day of a solution of dextrose ( 65 gm/L ) and amino acids ( 25.8 gm/L ) for 1 mo , whereas 26 received only the dextrose solution . All patients were allowed to eat a st and ard hospital diet . During the month in the hospital , there were six deaths in the treatment group and five deaths in the control group . Nitrogen balance improved in the treated group , but not in the control group . Creatinine-height index , triceps skin fold measurement and levels of serum albumin and prealbumin increased similarly in both groups . Serum retinol binding protein increased more in the treatment group than it did in the control group , and transferrin was increased only in the treatment group . Serum bilirubin , type III amino-terminal procollagen peptide and aminopyrine clearance improved more in the treatment group than in the control group , whereas serum AST and prothrombin time improved in the treatment group but not in the control group . Cumulative 2-yr survival rates from the day of entry into the study were 42 % and 38 % in the treatment and control groups , respectively . Patients who survived 2 yr and patients in the treatment group who died during the 2-yr follow-up had continued improvement in serum retinol binding protein , transferrin , bilirubin and prothrombin time . These parameters were unchanged in patients in the control group who died during follow-up . ( ABSTRACT TRUNCATED AT 250 WORDS [16469404] BACKGROUND / AIMS Severe alcoholic hepatitis is associated with high morbidity and short-term mortality . Corticosteroids are the only widely used therapy but established contraindications to treatment or the risk of serious side-effects limit their use . The perceived need for alternative treatments together with the theoretical benefits of anti-oxidant therapy triggered the design of a r and omised clinical trial comparing these treatment modalities . METHODS One hundred and one patients were r and omized into a clinical trial of corticosteroids or a novel antioxidant cocktail with a primary endpoint of 30-day mortality . RESULTS At 30 days there were 16 deaths ( 30 % ) in the corticosteroid treated group compared with 22 deaths ( 46 % ) in the antioxidant treated group ( P=0.05 ) . The odds of dying by 30 days were 2.4 greater for patients on antioxidants ( 95 % confidence interval 1.0 - 5.6 ) . A diagnosis of sepsis was made more frequently in the AO group ( P=0.05 ) , although microbiologically proven episodes of infection occurred more often in the CS group ( P<0.01 ) . The survival advantage for corticosteroid treated patients was lost at 1 year of follow-up ( P=0.43 ) . CONCLUSIONS This study has shown that corticosteroids in the form of prednisolone 30 mg daily are superior to a broad antioxidant cocktail in the treatment of severe alcoholic hepatitis [11943949] Background Colchicine , an inhibitor of collagen synthesis , has been suggested as potentially beneficial in cirrhosis . Objective This long-term , r and omized , double blind , placebo controlled trial was conducted in order to evaluate the efficacy of colchicine in alcoholic cirrhosis . Methods Ambulatory patients with biopsy proven alcoholic cirrhosis , presenting from 1989 to 1997 , with no exclusion criteria ( e.g. Child – Pugh C , bilirubin > 10 mg/dl and gastrointestinal bleeding in the previous 15 days ) , were r and omized to receive orally , 5 days/week , 1 mg/day of colchicine or placebo . Main outcome measures Results were analysed on an intention to treat basis , for survival , incidence of complications , biochemical liver tests and safety . Results Twenty-nine patients received colchicine and 26 placebo ; characteristics of both groups were similar . The median follow-up was 40.6 ( 1.4–126.3 ) months in the colchicine versus 42.4 ( 5.7–118.2 ) months in the placebo group ( NS ) . No significant side effects were reported . During follow-up , there were no significant differences in compliance and alcohol abstinence ( 86 % vs 85 % ) . Overall survival was not statistically different ( P = 0.38 ) . Cumulative 3-year survival rates were 74.9 % in the colchicine versus 91.4 % in placebo group ( NS ) . The annual incidence rate of complications was similar with colchicine or placebo : gastrointestinal bleeding , 1.5 % vs 1.2 % ; ascites , 3.7 % vs 3.7 % ; and encephalopathy , 1.0 % vs 0.9 % . The comparison of changes in biochemical parameters between groups did not show any significant difference . Conclusions Although well tolerated , colchicine does not appear to overcome the progression and natural history of long-established alcoholic cirrhosis [758131] The effect of propylthiouracil ( PTU ; 300 mg/day ) on alcoholic liver disease was evaluated in 133 patients in a short-term r and omized double-blind trial . Severity of the disease was assessed by a composite clinical and laboratory index ( CCLI ) . A normalization rate ( NR ) representing the rate of improvement in CCLI was calculated . Patients with alcoholic hepatitis , with and without cirrhosis , showed a significantly higher NR on PTU ( 43.6 + /- 4.6 ) than on placebo ( 19.8 + /- 3.3 ; P less than 0.001 ) . A similar effect was observed in patients with abnormal prothrombin ( no biopsy ) : NR was 32.9 + /- 6.9 on PTU and 2.6 + /- 3.7 on placebo ( P less than 0.005 ) . The effect of PTU on each clinical and laboratory component of the CCLI was also compared in these two groups . In 38 patients with alcoholic hepatitis and in 25 with abnormal prothrombin , those on PTU showed a greater improvement in 15 of 15 items ( P less than 0.001 ) and 14 of 15 ( P less than 0.01 ) , respectively . When patients were divided according to the severity of the disease into those in the lower and upper halves of the CCLI range ( 81 and 52 patients , respectively ) , PTU was shown to have a significant effect only in the latter : The NR was 41.4 + /- 3.8 on PTU and 22.5 + /- 4.2 on placebo ( P less than 0.005 ) . PTU was ineffective in patients with inactive cirrhosis [1727803] Severe alcoholic hepatitis is still a therapeutic challenge . It has been recently advocated that a 3-wk infusion with insulin and glucagon reduces its short-term mortality rate . A multicenter , r and omized , single-blind , sequential trial was design ed to compare this treatment with placebo . The triangular boundary was defined with alpha = 0.05 , beta = 0.10 and estimated survival at 4 wk of 50 % with placebo , 75 % with treatment . Patients with biopsy-proven severe alcoholic hepatitis ( presence of one or more of three criteria : encephalopathy , prothrombin activity less than or equal to 50 % , bilirubinemia greater than or equal to 100 mumol/L ) were r and omized into two groups ; one treatment group received an infusion ( 12 hr/day ) of an association of insulin ( 30 IU ) and glucagon ( 3 mg ) , and a control group received an infusion of glucose . Treatments were administered during a 3-wk period , and the mortality rate was noted at 4 wk . The decision to discontinue the trial was reached on the basis of results from the first 44 patients . Overall results were assessed in the 72 patients included at the time of this decision ( treatment group : n = 37 ; control group : n = 35 ) . Fifty-three patients had cirrhosis . No significant differences were noted between the two groups at inclusion on the basis of clinical , laboratory and histological criteria . The mortality rate was not significantly different in the two groups ; 10 patients ( 27 % ) in the treatment group and 5 patients ( 14 % ) in the control group died . Causes of death were similar in the two groups and consisted primarily of gastrointestinal hemorrhage , hepatic failure and infectious events . ( ABSTRACT TRUNCATED AT 250 WORDS [4615021] A double-blind prospect i ve controlled trial of d-penicillamine in 40 patients with acute alcoholic liver disease revealed no improvement in survival or liver function tests in the experimental group . Nevertheless , greater reduction in fibrosis and hepatocellular injury was suggested in penicillamine-treated biopsied patients ; this observation remains tentative and preliminary , however , because of the potential for sampling error [25901427] BACKGROUND Alcoholic hepatitis is a clinical syndrome characterized by jaundice and liver impairment that occurs in patients with a history of heavy and prolonged alcohol use . The short-term mortality among patients with severe disease exceeds 30 % . Prednisolone and pentoxifylline are both recommended for the treatment of severe alcoholic hepatitis , but uncertainty about their benefit persists . METHODS We conducted a multicenter , double-blind , r and omized trial with a 2-by-2 factorial design to evaluate the effect of treatment with prednisolone or pentoxifylline . The primary end point was mortality at 28 days . Secondary end points included death or liver transplantation at 90 days and at 1 year . Patients with a clinical diagnosis of alcoholic hepatitis and severe disease were r and omly assigned to one of four groups : a group that received a pentoxifylline-matched placebo and a prednisolone-matched placebo , a group that received prednisolone and a pentoxifylline-matched placebo , a group that received pentoxifylline and a prednisolone-matched placebo , or a group that received both prednisolone and pentoxifylline . RESULTS A total of 1103 patients underwent r and omization , and data from 1053 were available for the primary end-point analysis . Mortality at 28 days was 17 % ( 45 of 269 patients ) in the placebo-placebo group , 14 % ( 38 of 266 patients ) in the prednisolone-placebo group , 19 % ( 50 of 258 patients ) in the pentoxifylline-placebo group , and 13 % ( 35 of 260 patients ) in the prednisolone-pentoxifylline group . The odds ratio for 28-day mortality with pentoxifylline was 1.07 ( 95 % confidence interval [ CI ] , 0.77 to 1.49 ; P=0.69 ) , and that with prednisolone was 0.72 ( 95 % CI , 0.52 to 1.01 ; P=0.06 ) . At 90 days and at 1 year , there were no significant between-group differences . Serious infections occurred in 13 % of the patients treated with prednisolone versus 7 % of those who did not receive prednisolone ( P=0.002 ) . CONCLUSIONS Pentoxifylline did not improve survival in patients with alcoholic hepatitis . Prednisolone was associated with a reduction in 28-day mortality that did not reach significance and with no improvement in outcomes at 90 days or 1 year . ( Funded by the National Institute for Health Research Health Technology Assessment program ; STOPAH EudraCT number , 2009 - 013897 - 42 , and Current Controlled Trials number , IS RCT N88782125 ) [18537187] UNLABELLED Liver failure is the major cause of death in alcoholic steatohepatitis ( ASH ) . In experimental hepatitis , granulocyte-colony stimulating factor ( G-CSF ) mobilizes hematopoietic stem cells , induces liver regeneration , and improves survival . We studied the short-term effects of G-CSF on CD34 + stem cell mobilization , liver cell proliferation , and liver function in patients with ASH . Twenty-four patients ( mean age 54 years ) with alcoholic cirrhosis [ Child-Turcotte-Pugh score 10 ( 7 - 12 ) ] and concomitant biopsy-proven ASH [ Maddrey score 36 ( 21 - 60 ) ] were r and omized to st and ard care associated with 5 days of G-CSF ( 10 microg/kg/day , group A , n = 13 ) or st and ard care alone ( group B , n = 11 ) . Serial measurement of CD34 + cells , liver tests , cytokines [ hepatocyte growth factor ( HGF ) ; tumor necrosis factor alpha ; tumor necrosis factor-R1 ; interleukin-6 ; alfa-fetoprotein ] , and (13)C-aminopyrine breath tests were performed . Proliferating hepatic progenitor cells [ HPC ; double immunostaining ( Ki67/cytokeratin 7 ) ] , histology , and neutrophils were assessed on baseline and day 7 biopsies . Abstinent alcoholic patients with cirrhosis served as controls for immunohistochemistry . G-CSF was well tolerated . At day 7 , both CD34 + cells ( + 747 % versus -6 % , P < 0.003 ) , and HGF ( + 212 % versus -7 % , P < 0.03 ) increased in group A but not in group B. Cytokines and aminopyrine breath test changes were similar between groups . On repeat biopsy , a > 50 % increase in proliferating HPC was more frequent in group A than in group B ( 11 versus 2 , P < 0.003 ) . Changes in Ki67+/cytokeratin 7 + cells correlated with changes in CD34 + cells ( r = 0.65 , P < 0.03 ) . Neutrophils and histological changes were similar in both groups . CONCLUSION G-CSF mobilizes CD34 + cells , increases HGF , and induces HPC to proliferate within 7 days of administration . Larger trials would be required to determine whether these changes translate into improved liver function [20801542] BACKGROUND & AIMS Severe acute alcoholic hepatitis is associated with a high mortality rate . Oxidative stress is involved in the pathogenesis of acute alcoholic hepatitis . Previous findings had also suggested that enteral nutritional support might increase survival in patients with severe acute alcoholic hepatitis . Therefore , the aim of the present study was to evaluate the efficacy of N-acetylcysteine in combination with adequate nutritional support in patients with severe acute alcoholic hepatitis . METHODS Patients with biopsy-proven acute alcoholic hepatitis and mDF ≥32 were r and omized to receive N-acetylcysteine intravenously or a placebo perfusion along with adequate nutritional support for 14 days . The primary endpoint was 6-month survival ; secondary endpoints were biological parameter evolution and infection rate . RESULTS Fifty-two patients were r and omized in the study ( 28 into the N-acetylcysteine arm , 24 into the control arm ) , and among them , five were excluded from the analysis for protocol violation . The two groups did not differ in baseline characteristics . Survival rates at 1 and 6 months in N-acetylcysteine and control groups were 70.2 vs. 83.8 % ( p=0.26 ) and 62.4 vs. 67.1 % ( p=0.60 ) , respectively . Early biological changes , documented infection rate at 1 month , and incidence of hepatorenal syndrome did not differ between the two groups . CONCLUSIONS In this study , high doses of intravenous N-acetylcysteine therapy for 14 days conferred neither survival benefits nor early biological improvement in severe acute alcoholic hepatitis patients with adequate nutritional support . However , these results must be viewed with caution , since the study suffered from a lack of power [24845609] BACKGROUND & AIMS Both corticosteroid and pentoxifylline reduce short-term mortality in severe alcoholic hepatitis . However , few studies have directly compared the efficacy of pentoxifylline and corticosteroid in patients with this condition . METHODS In this multicentre , open-labelled , r and omised non-inferiority trial , we assigned 121 patients with severe alcoholic hepatitis ( Maddrey 's discriminant function ⩾32 ) to receive either pentoxifylline ( 400 mg , 3 times daily , in 62 subjects ) or prednisolone ( 40 mg daily , in 59 subjects ) . The primary end point was non-inferiority in survival at the 1 month time point for the pentoxifylline treatment compared with prednisolone . RESULTS The 1-month survival rate of patients receiving pentoxifylline was 75.8 % ( 15 deaths ) compared with 88.1 % ( 7 deaths ) in those , taking prednisolone , for a treatment difference of 12.3 % ( 95 % confidence interval , -4.2 % to 28.7 % ; p = 0.08 ) . The 95 % confidence interval for the observed difference exceeded the predefined margin of non-inferiority ( Δ15 % ) and included zero . The 6-month survival rate was not significantly different between the pentoxifylline and prednisolone groups ( 64.5 % vs. 72.9 % ; p = 0.23 ) . At 7 days , the response to therapy assessed by the Lille model was significantly lower in the prednisolone group ( n = 58 ) than in the pentoxifylline group ( n = 5 9 ) : 0.35 vs. 0.50 ( p = 0.012 ) . Hepatitis complications , including hepatorenal syndrome and side effects , such as infection and gastrointestinal bleeding , were similar in the two groups . CONCLUSIONS The findings demonstrate that the efficacy of the pentoxifylline is not statistically equivalent to the efficacy of prednisolone , supporting the use of prednisolone as a preferred treatment option in patients with severe alcoholic hepatitis [22945832] Published evidence suggests that aspects of trial design lead to biased intervention effect estimates , but findings from different studies are inconsistent . This study combined data from 7 meta-epidemiologic studies and removed overlaps to derive a final data set of 234 unique meta-analyses containing 1973 trials . Outcome measures were classified as " mortality , " " other objective , " " or subjective , " and Bayesian hierarchical models were used to estimate associations of trial characteristics with average bias and between-trial heterogeneity . Intervention effect estimates seemed to be exaggerated in trials with inadequate or unclear ( vs. adequate ) r and om-sequence generation ( ratio of odds ratios , 0.89 [ 95 % credible interval { CrI } , 0.82 to 0.96 ] ) and with inadequate or unclear ( vs. adequate ) allocation concealment ( ratio of odds ratios , 0.93 [ CrI , 0.87 to 0.99 ] ) . Lack of or unclear double-blinding ( vs. double-blinding ) was associated with an average of 13 % exaggeration of intervention effects ( ratio of odds ratios , 0.87 [ CrI , 0.79 to 0.96 ] ) , and between-trial heterogeneity was increased for such studies ( SD increase in heterogeneity , 0.14 [ CrI , 0.02 to 0.30 ] ) . For each characteristic , average bias and increases in between-trial heterogeneity were driven primarily by trials with subjective outcomes , with little evidence of bias in trials with objective and mortality outcomes . This study is limited by incomplete trial reporting , and findings may be confounded by other study design characteristics . Bias associated with study design characteristics may lead to exaggeration of intervention effect estimates and increases in between-trial heterogeneity in trials reporting subjectively assessed outcomes Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND AND AIMS Evidence shows that antioxidant supplements may increase mortality . Our aims were to assess whether different doses of beta-carotene , vitamin A , and vitamin E affect mortality in primary and secondary prevention r and omized clinical trials with low risk of bias . BACKGROUND All essential compounds to stay healthy can not be synthesized in our body . Therefore , these compounds must be taken through our diet or obtained in other ways [ 1 ] . Oxidative stress has been suggested to cause a variety of diseases [ 2 ] . Therefore , it is speculated that antioxidant supplements could have a potential role in preventing diseases and death . Despite the fact that a normal diet in high-income countries may provide sufficient amounts of antioxidants [ 3,4 ] , more than one third of adults regularly take antioxidant supplements [ 5,6 ] Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

28436101

[25631970] INTRODUCTION Iron deficiency , associated with a decline in cognitive function , is the most common nutritional deficiency globally . The present study aim ed to identify the impact of weekly iron supplements on the attention function of female students from a high school in North Khorasan Province , Iran . METHODS This was a blind , controlled , clinical trial study , involving 200 female students who were chosen using the stratified r and omised sampling method . First , laboratory studies were performed to detect iron consumption limitations . Next , the 200 students were divided r and omly and equally into case and control groups . The case group was treated with 50 mg of ferrous sulfate twice a week for 16 weeks . We compared both groups ' data on attention , iron status and erythrocyte indices . Question naires were used to collect demographic data , while clinical data was collected using complete blood count and Toulouse-Piéron tests . Data was analysed using descriptive statistics , as well as paired and independent t-tests . RESULTS The mean attention scores of the case and control groups were 104.8 ± 7.0 and 52.7 ± 9.6 , respectively ( p < 0.001 ) . The mean haemoglobin levels of the two groups were 12.5 ± 0.9 and 11.2 ± 1.0 , respectively ( p < 0.001 ) . Compared to the control group , the attention scores and haemoglobin concentrations of the case group were found to be improved by approximately 90 % and 10 % , respectively . CONCLUSION Oral iron supplements ( 50 mg twice a week for 16 weeks ) were able to improve the attention span and haematologic indices of female high school students [12713212] OBJECTIVE To test the feasibility , acceptability , and potential efficacy of after-school dance classes and a family-based intervention to reduce television viewing , thereby reducing weight gain , among African-American girls . DESIGN Twelve-week , 2-arm parallel group , r and omized controlled trial . SETTING Low-income neighborhoods . PARTICIPANTS Sixty-one 8 - 10-year-old African-American girls and their parents/guardians . INTERVENTIONS The treatment intervention consisted of after-school dance classes at 3 community centers , and a 5-lesson intervention , delivered in participants ' homes , and design ed to reduce television , videotape , and video game use . The active control intervention consisted of disseminating newsletters and delivering health education lectures . MAIN OUTCOME MEASURES Implementation and process measures , body mass index , waist circumference , physical activity measured by accelerometry , self-reported media use , and meals eaten with TV . RESULTS Recruitment and retention goals were exceeded . High rates of participation were achieved for assessment s and intervention activities , except where transportation was lacking . All interventions received high satisfaction ratings . At follow up , girls in the treatment group , as compared to the control group , exhibited trends toward lower body mass index ( adjusted difference = -.32 kg/m2 , 95 % confidence interval [ CI ] -.77 , .12 ; Cohen 's d = .38 st and ard deviation units ) and waist circumference ( adjusted difference = -.63 cm , 95 % CI -1.92 , .67 ; d = .25 ) ; increased after-school physical activity ( adjusted difference = 55.1 counts/minute , 95 % CI -115.6 , 225.8 ; d = .21 ) ; and reduced television , videotape , and video game use ( adjusted difference = -4.96 hours/week , 95 % CI -11.41 , 1.49 ; d = .40 ) . The treatment group reported significantly reduced household television viewing ( d = .73 , P = .007 ) and fewer dinners eaten while watching TV ( adjusted difference = -1.60 meals/week , 95 % CI -2.99 , -.21 ; d = .59 ; P = .03 ) . Treatment group girls also reported less concern about weight ( d = .60 ; P = .03 ) , and a trend toward improved school grade s ( d = .51 ; P = .07 ) . CONCLUSIONS This study confirmed the feasibility , acceptability , and potential efficacy of using dance classes and a family-based intervention to reduce television viewing , thereby reducing weight gain , in African-American girls [10721928] Peru has high rates of iron deficiency anemia . The prevalence is 35 % in nonpregnant women of fertile age and 24.7 % in adolescent girls in slums of periurban Lima . The major cause of anemia is low intake of dietary iron . A community-based , r and omized behavioral and dietary intervention trial was conducted to improve dietary iron intake and iron bioavailability of adolescent girls living in periurban areas of Lima , Peru . Results show that there was a change in knowledge about anemia and improved dietary iron intake in the 71 girls who completed the study compared with the 66 girls in the control group . Although the 9-mo . intervention was not sufficient to improve hemoglobin levels significantly , there appeared to be a protective effect in maintaining the iron status of girls in comparison with the control group [19706212] OBJECTIVE Despite public health campaigns based on Fe and folic acid supplements , Fe-deficiency anaemia remains highly prevalent among women in India . We investigated leaf concentrate as an alternative to Fe and folic acid supplements for treating anaemia in adolescent girls . DESIGN R and omised controlled two-arm trial over 3 months : one group received daily Fe and folic acid ( IFA ; 60 mg Fe , 500 microg folic acid ) ; the other daily leaf concentrate ( LC ; 5 mg Fe , 13 microg folic acid ) . Hb concentration , mean cell volume , serum Fe , serum ferritin and total Fe-binding capacity were measured pre- and post-intervention . SETTING Jaipur , India . SUBJECTS One hundred and two adolescent girls aged 14 - 18 years . RESULTS Of the 102 girls r and omized to the two arms of the trial , four ( 3.9 % ) were severely anaemic ( Hb < 7 g/dl ) , twenty-eight ( 27.5 % ) were moderately anaemic ( Hb > or = 7 g/dl , < 10 g/dl ) and seventy ( 68.6 % ) were mildly anaemic ( Hb > or = 10 g/dl , < 12 g/dl ) . In the IFA group , eleven girls ( 20.4 % ) withdrew due to side-effects , compared with one girl ( 2.1 % ) in the LC group ( P = 0.005 ) . Total losses to follow-up were 14/54 in the IFA group and 2/48 in the LC group . At the end of the trial , none of the eighty-six remaining girls were severely anaemic , nine ( 10.5 % ) were moderately anaemic and twenty-six ( 30.2 % ) were mildly anaemic ; fifty-one ( 59.3 % ) had normal Hb levels ( > or = 12 g/dl ) . After adjustment for baseline values , LC was as effective as IFA in improving serum Fe parameters and treating anaemia . CONCLUSIONS Leaf concentrate is an effective , and more palatable , alternative to Fe and folic acid supplements for treating anaemia in adolescent girls [2758893] Background Schools are the most frequent target for intervention programs aim ed at preventing child obesity ; however , the overall effectiveness of these programs has been limited . It has therefore been recommended that interventions target multiple ecological levels ( community , family , school and individual ) to have greater success in changing risk behaviors for obesity . This study examined the immediate and short-term , sustained effects of the Switch program , which targeted three behaviors ( decreasing children 's screen time , increasing fruit and vegetable consumption , and increasing physical activity ) at three ecological levels ( the family , school , and community ) . Methods Participants were 1,323 children and their parents from 10 schools in two states . Schools were matched and r and omly assigned to treatment and control . Measures of the key behaviors and body mass index were collected at baseline , immediately post-intervention , and 6 months post-intervention . Results The effect sizes of the differences between treatment and control groups ranged between small ( Cohen 's d = 0.15 for body mass index at 6 months post-intervention ) to large ( 1.38 ; parent report of screen time at 6 months post-intervention ) , controlling for baseline levels . There was a significant difference in parent-reported screen time at post-intervention in the experimental group , and this effect was maintained at 6 months post-intervention ( a difference of about 2 hours/week ) . The experimental group also showed a significant increase in parent-reported fruit and vegetable consumption while child-reported fruit and vegetable consumption was marginally significant . At the 6-month follow-up , parent-reported screen time was significantly lower , and parent and child-reported fruit and vegetable consumption was significantly increased . There were no significant effects on pedometer measures of physical activity or body mass index in the experimental group . The intervention effects were moderated by child sex ( for fruit and vegetable consumption , physical activity , and weight status ) , family involvement ( for fruit and vegetable consumption ) , and child body mass index ( for screen time ) . The perception of change among the experimental group was generally positive with 23 % to 62 % indicating positive changes in behaviors . Conclusion The results indicate that the Switch program yielded small-to-modest treatment effects for promoting children 's fruit and vegetable consumption and minimizing screen time . The Switch program offers promise for use in youth obesity prevention [4061343] As a follow-up of our study of pregnant women , we report effects of zinc supplementation during pregnancy in another population of 138 Hispanic teenagers in Los Angeles . Teenagers were r and omized ( double-blind ) to a control or zinc-supplemented group and received similar daily vitamin and mineral supplements except for 20 mg zinc added to the zinc-supplemented group 's capsules . Initially , mean dietary zinc intakes of both groups were about 50 % of the Recommended Dietary Allowance and their mean serum zinc levels did not differ significantly ( 69.8 + /- 11.2 micrograms/dl in control and 69.0 + /- 11.4 micrograms/dl in zinc-supplemented group ) . Zinc supplementation did not maintain mean serum zinc levels during pregnancy but , as in our earlier study , it reduced ( p = 0.018 ) the number of low serum zinc values ( less than or equal to 53 micrograms/dl ) in late pregnancy . Zinc supplementation did not affect outcome of pregnancy but serum zinc levels were lower ( p = 0.038 ) in teenagers with pregnancy-induced hypertension than in normotensives [11451725] BACKGROUND Iron deficiency is the most common micronutrient deficiency and affects > 2 billion persons worldwide , leading to anemia in > 40 % of women of reproductive age in the developing world . OBJECTIVE The objective was to determine whether weekly supplementation with iron and folate would reduce the frequency of anemia in teenage women in urban Bangladesh before they became pregnant . DESIGN Participants with a hemoglobin concentration of 80 - 120 g/L were entered into a r and omized , double-blind , placebo-controlled trial and received supplements of placebo , vitamin A , iron + folic acid , or iron + folic acid + vitamin A weekly for 12 wk . The supplements contained 2.42 mg vitamin A ( retinol ) as retinyl palmitate , 120 mg elemental Fe as ferrous sulfate , and 3.5 mg folic acid . RESULTS Hemoglobin concentrations increased significantly more after supplementation with iron + folic acid or iron + folic acid + vitamin A than after either the placebo or vitamin A alone . There was a significantly greater increase in hemoglobin after iron + folic acid + vitamin A than after iron + folic acid , but the additional effect disappeared after adjustment for baseline hemoglobin , serum vitamin A , and ferritin and the number of supplements taken . Those with the lowest baseline hemoglobin had the greatest increase in hemoglobin . Compared with the placebo , iron + folic acid + vitamin A reduced anemia by 92 % , iron deficiency by 90 % , and vitamin A deficiency by 76 % . CONCLUSION There may be significant health benefits from a program that enhances the nutritional status of iron , folate , and vitamin A in poor urban young women before they become pregnant [9209187] Different supplementation schemes to build iron stores in female Indonesian adolescents were investigated . Subjects were 273 high-school girls allocated r and omly to four treatment groups . During a 3-mo period one group received 60 mg Fe , 750 micrograms retinol , 250 micrograms folic acid , and 60 mg vitamin C per day ; a second group received 60 mg Fe , 6000 micrograms retinol , 500 mg folic acid , and 60 mg vitamin C once a week ; a third group received 120 mg Fe and the same amount of the other three micronutrients as the second group once a week ; and a fourth group received only placebos . All subjects were dewormed and supplement allocation was double blind . Blood sample s were collected at baseline , after 2 and 3 mo of supplementation , and 6 mo after the last supplement . After 2 mo of supplementation , groups supplemented weekly and daily showed similar significant improvements ( P < 0.001 ) in hemoglobin and retinol concentrations , and supplementation for 3 instead of 2 mo did not significantly increase these two indicators . After 3 mo , the increase in ferritin was approximately equal to 27 micrograms/L in the daily and 14 - 15 micrograms/L in the weekly groups ( P < 0.001 ) , the latter having a final concentration of 42 - 45 micrograms/L. At 6 mo postsupplementation there were no significant differences among daily and weekly groups , but the ferritin concentration was still approximately equal to 10 - 12-micrograms/L higher ( P < 0.001 ) than in the placebo group . The group supplemented weekly with 60 mg Fe complained less about side effects than the other supplemented groups ( P < 0.05 ) . Weekly supplementation with 60 mg Fe and 6000 micrograms retinol for 3 mo was optimal for improving the iron status of the adolescents for approximately equal to 9 mo [12885710] BACKGROUND Fish sauce is consumed daily by a large proportion of the Vietnamese population and could therefore be a potentially useful food vehicle for iron-fortification programs . OBJECTIVE We evaluated the efficacy of iron-fortified fish sauce in improving the iron status of anemic women . DESIGN In a r and omized , double-masked study of 152 anemic ( hemoglobin concentration of 81 - 119 g/L ) women , a meal based on noodles or rice was served 6 d/wk with 10 mL fish sauce containing either 10 mg Fe as NaFeEDTA ( iron-fortified group ) or no added iron ( control group ) . Concentrations of hemoglobin , serum ferritin ( SF ) , and serum transferrin receptor ( TfR ) were measured at baseline and after 3 and 6 mo . RESULTS After 6 mo , hemoglobin and SF concentrations were higher and TfR concentrations were lower in the iron-fortified group than in the control group [ hemoglobin : 116.3 + /- 8.7 ( + /- SD ) compared with 107.6 + /- 11.0 g/L ( P < 0.0001 ) ; SF : 30.9 ( 95 % CI : 23.4 , 40.6 ) compared with 14.6 ( 11.3 , 19.0 ) micro g/L ( P = 0.0002 ) ; TfR : 7.2 ( 6.4 , 7.9 ) compared with 9.0 ( 8.1 , 9.9 ) mg/L ( P = 0.002 ) ] . The prevalence of iron deficiency ( SF < 12 micro g/L or TfR > 8.5 mg/L ) and iron deficiency anemia ( iron deficiency with hemoglobin < 120 g/L ) was lower in the iron-fortified group than in the control group [ 32.8 % compared with 62.5 % ( P = 0.0005 ) and 20.3 % compared with 58.3 % ( P < 0.0001 ) , respectively ] . CONCLUSIONS Regular consumption of iron-fortified fish sauce significantly reduced the prevalence of iron deficiency anemia in Vietnamese women during the 6-mo intervention . Fortifying fish sauce with iron by using a water-soluble , highly bioavailable compound ( NaFeEDTA ) is a promising strategy for combating iron deficiency anemia in Vietnam [10357747] BACKGROUND Iron deficiency and its consequent anemia constitute the commonest micronutrient deficiency in the world . OBJECTIVE We investigated whether long-term , weekly iron-folate supplements administered at school would improve hemoglobin and ferritin concentrations in adolescent girls , including those with mild-to-moderate anemia and hemoglobin concentrations indicating borderline anemia . DESIGN Subjects were 266 girls with hemoglobin concentrations of 80 - 119.9 g/L ( group A ) and 358 girls with hemoglobin concentrations of 120 - 130 g/L ( group B ) who were otherwise healthy . Two hundred sixty-six girls in group A and 268 girls in group B were r and omly assigned to receive either 60 or 120 mg Fe plus 3.5 mg folic acid weekly for 22 wk . Ninety of the girls in group B were r and omly assigned to receive only 5 mg folic acid weekly . Capillary hemoglobin and plasma ferritin were measured at baseline and after 12 and 22 wk of supplementation . RESULTS By the end of the study , 2 % of the girls had dropped out and > 96 % had taken > or = 20 of the 22 tablets ; side effects were minimal . Mean plasma ferritin increased significantly in all iron-supplemented groups , independently of initial hemoglobin values and iron doses . Ferritin concentrations decreased in the girls supplemented with folic acid only . As expected , hemoglobin responses to iron were higher in group A than in group B and increases were positively correlated with initial plasma ferritin . Hemoglobin failed to respond to folate supplementation if initial plasma ferritin concentrations were low . Mean hemoglobin increased significantly and consistently in relation to the length of treatment . CONCLUSION Long-term , weekly iron-folate supplementation was found to be a practical , safe , effective , and inexpensive method for improving iron nutrition in adolescent schoolgirls [16251617] One cost-effective strategy for controlling iron deficiency is the fortification of staple foods or condiments with iron . We evaluated the effectiveness of fortifying fish sauce with NaFeEDTA for improving iron status in women of childbearing age in Vietnam in a double-blind intervention with r and omization by village . All families in the selected villages were supplied with fish sauce that was either unfortified ( Group C , 10 villages ) or fortified with NaFeEDTA [ 9 mmol ( 500 mg ) Fe/L , Group F , 11 villages ] for 18 mo . The effect of fortification was assessed in the 576 women ( n = 288/group ) by measuring hemoglobin and serum ferritin ( SF ) at 6 , 12 , and 18 mo . Analysis of the group x time interaction using a repeated- measures test for each response demonstrated a significant effect of fortification on hemoglobin ( P = 0.039 ) and log SF ( P < 0.0001 ) in Group F with no significant changes in Group C. The prevalence of iron deficiency ( SF < 12 microg/L ) decreased from 22.3 to 4.0 % and the prevalence of anemia ( hemoglobin < 120 g/L ) from 24.7 to 8.5 % in Group F with no significant changes in Group C. NaFeEDTA fortification of fish sauce is an effective method for reducing the prevalence of iron deficiency in women in Vietnam [9771866] The effects of growth , menstrual status , and calcium supplementation on iron status were studied over 4 y in 354 girls in pubertal stage 2 who were premenarcheal at baseline ( x+/-SD age : 10.8+/-0.8 y ) . Girls were r and omly assigned to placebo or treatment with 1000 mg Ca/d as calcium citrate malate . Anthropometric characteristics , bone mass , and nutritional status were measured biannually ; ferritin was measured annually ; and red blood cell indexes were determined at 4 y. The simultaneous effects of iron intake and menstrual status on serum ferritin , after change in lean body mass ( LBM ) was controlled for , were evaluated in subjects in the upper and lower quartiles of cumulative iron intake . The average maximal accumulation of LBM ( 386 g/mo ; 95 % CI : 372 , 399 ) occurred 0.5 y before the onset of menarche . Change in LBM was a significant predictor of serum ferritin ( P < 0.0001 ) , with a negative influence on iron status ( t ratio=-4.12 ) . The 2 fitted mathematical models representing ferritin concentrations of subjects in the upper and lower quartiles of cumulative iron intake were significantly different ( P < 0.018 ) . The regression line of the ferritin concentration in menstruating girls with high iron intakes had a less negative slope than the line fit to serum ferritin concentrations in girls with low iron intakes ( NS ) . Serum ferritin concentrations at 0 , 1 , 2 , 3 , and 4 y were not significantly different between groups . In addition , there was no significant difference between groups in any of the red blood cell indexes . In summary , growth spurt and menstrual status had adverse effects on iron stores in adolescent girls with low iron intakes ( < 9 mg/d ) , whereas long-term supplementation with calcium ( total intake : approximately 1500 mg/d ) did not affect iron status [19349559] OBJECTIVE To determine whether a multicomponent health promotion intervention for Dutch adolescents ( defined as persons between 12 and 14 years of age ) would be successful in influencing body composition and dietary and physical activity behavior in both the short and long terms . DESIGN R and omized controlled trial . SETTING Ten intervention and 8 control prevocational secondary schools . PARTICIPANTS A total of 1108 adolescents ( mean age , 12.7 years ) . Intervention An interdisciplinary program with an adapted curriculum for 11 lessons in biology and physical education and environmental change options . MAIN OUTCOME MEASURES Body height and weight , waist circumference , 4 skinfold thickness measurements , and dietary and physical activity behavior data . RESULTS Multilevel analyses showed that the intervention remained effective in preventing unfavorable increases in important measures of body composition after 20-month follow-up in girls ( biceps skinfold and sum of 4 skinfolds ) and boys ( triceps , biceps , and subscapular skinfolds ) . Consumption of sugar-containing beverages was significantly lower in intervention schools both after intervention ( boys : -287 mL/d ; 95 % confidence interval [ CI ] , -527 to -47 ; girls : -249 ; -400 to -98 ) and at 12-month follow-up ( boys : -233 ; -371 to -95 ; girls : -271 ; -390 to -153 ) . For boys , screen-viewing behavior was significantly lower in the intervention group after 20 months ( -25 min/d ; 95 % CI , -50 to -0.3 ) . No significant intervention effects on consumption of snacks or active commuting to school were found . CONCLUSION The Dutch Obesity Intervention in Teenagers program result ed in beneficial effects on the sum of skinfold thickness measurements in girls and consumption of sugar-containing beverages in both boys and girls in both the short and long terms [18312804] BACKGROUND Physical activity is important for weight control and good health ; however , activity levels decline in the adolescent years , particularly in girls . DESIGN Group r and omized controlled trial . SETTING / PARTICIPANTS Middle school girls with English-speaking skills and no conditions to prevent participation in physical activity in 36 schools in six geographically diverse areas of the United States . R and om , cross-sectional sample s were drawn within schools : 6th grade rs in 2003 ( n=1721 ) and 8th grade rs in 2005 ( n=3504 ) and 2006 ( n=3502 ) . INTERVENTION A 2-year study -directed intervention ( fall 2003 to spring 2005 ) targeted schools , community agencies , and girls to increase opportunities , support , and incentives for increased physical activity . Components included programs linking schools and community agencies , physical education , health education , and social marketing . A third-year intervention used school and community personnel to direct intervention activities . MAIN OUTCOME MEASURES The primary outcome , daily MET-weighted minutes of moderate-to-vigorous physical activity ( MET-weighted MVPA ) , was assessed using accelerometry . Percent body fat was assessed using anthropometry . RESULTS After the staff-directed intervention ( pre-stated primary outcome ) , there were no differences ( mean= -0.4 , 95 % CI= -8.2 to 7.4 ) in adjusted MET-weighted MVPA between 8th- grade girls in schools assigned to intervention or control . Following the Program Champion-directed intervention , girls in intervention schools were more physically active than girls in control schools ( mean difference 10.9 MET-weighted minutes of MVPA , 95 % CI=0.52 - 21.2 ) . This difference is about 1.6 minutes of daily MVPA or 80 kcal per week . There were no differences in fitness or percent body fat at either 8th- grade timepoint . CONCLUSION A school-based , community-linked intervention modestly improved physical activity in girls [19247280] Few r and omized trials attempt to improve insulin sensitivity and associated metabolic risks in overweight Latino youth . The purpose of this study is to examine the effects of a modified carbohydrate nutrition program combined with strength training on insulin sensitivity , adiposity , and other type 2 diabetes risk factors in overweight Latino adolescents . In a 16-week r and omized trial , 54 overweight Latino adolescents ( 15.5 + /- 1.0 years ) were r and omly assigned to : ( i ) Control ( C ; n = 16 ) , ( ii ) Nutrition ( N ; n = 21 ) , or ( iii ) Nutrition + Strength training ( N+ST ; n = 17 ) . The N group received modified carbohydrate nutrition classes ( once per week ) , while the N+ST received the same nutrition classes plus strength training ( twice per week ) . The following were measured at pre- and postintervention : strength by 1-repetition maximum , dietary intake by 3-day records , body composition by dual-energy X-ray absorptiometry , glucose/insulin indices by oral glucose tolerance test ( OGTT ) and intravenous glucose tolerance test with minimal modeling . Across intervention group effects were tested using analysis of covariance with post hoc pairwise comparisons . A significant overall intervention effect was found for improvement in bench press ( P < 0.001 ) and reductions in energy ( P = 0.05 ) , carbohydrate ( P = 0.04 ) and fat intake ( P = 0.03 ) . There were no significant intervention effects on insulin sensitivity , body composition , or most glucose/insulin indices with the exception of glucose incremental area under the curve ( IAUC ) ( P = 0.05 ) , which decreased in the N and N+ST group by 18 and 6.3 % compared to a 32 % increase in the C group . In conclusion , this intense , culturally tailored intervention result ed in no significant intervention effects on measured risk factors with the exception of a beneficial effect on glycemic response to oral glucose [19652922] Iron supplementation has been suggested as a strategy for prevention and treatment of iron deficiency ( ID ) and iron deficiency anemia ( IDA ) in many countries , but non-compliance of daily regimens and common dosage remain as major challenges . The aim of this study was to investigate the effects of low dose once weekly iron supplementation in adolescent girls . The study was design ed as a community-based , r and omized , supplementation trial . The initial sample consisted of 200 female high school students , aged 14–16 years old , of whom 193 students concluded the study . They were r and omly selected and assigned into either iron-supplemented group ( ISG ) or iron-unsupplemented group ( IUG ) . The ISG received 150 mg ferrous sulfate once weekly for 16 weeks , whereas the IUG received nothing . Weight , height , and hematological parameters were measured and compared between the two groups before and after the intervention . There was no significant difference between the initial measures of the two groups before the intervention . After 16 weeks of intervention , mean of hemoglobin and serum ferritin improved significantly in ISG compared to IUG . At the beginning of the study , percent of anemia , IDA , and ID in ISG were 12.5 % , 8.3 % , and 30.2 % , whereas these figures for IUG in this period of study were 14.4 , 10.3 , and 38.2 , respectively , which were not significantly different between the two groups . However , percentages of the above items at the end of study in ISG were 2.1 % , 0 % , and 21.9 % , respectively . In contrast to IUG , all cases of IDA were abolished in the ISG . Our study showed that once weekly supplementation of 150 mg ferrous sulfate for 16 weeks significantly improved iron status in female adolescents and effectively treated IDA . There is no need for higher dosage of iron for supplementation that may cause adverse effects and bear higher costs [24331680] AIM This study evaluates the efficacy of the Choose Health program , a family-based cognitive behavioural lifestyle program targeting improved eating and activity habits , in improving body composition , cardiovascular fitness , eating and activity behaviours in overweight and obese adolescents . METHOD The sample comprised 29 male and 34 female overweight ( n = 15 ) or obese ( n = 48 ) adolescents aged 11.5 - 18.9 years ( M = 14.3 , SD = 1.9 ) . Participants were r and omly allocated to treatment or waitlist control conditions ; waitlist condition participants were offered treatment after 6 months . DEXA-derived and anthropometric measures of body composition ; laboratory-based cycle ergometer and field-assessed cardiovascular fitness data ; objective and self-report physical activity measures ; and self-report measures of eating habits and 7-day weighed food diaries were used to assess treatment outcome . Adherence to treatment protocol s was high . RESULTS Treatment result ed in significant ( p < .05 ) and sustained improvements in a range of body composition ( body fat , percent body fat , lean mass ) and anthropometric measures ( weight , BMI , BMI -for-age z-score and percentiles ) . Minimal improvements were seen in cardiovascular fitness . Similar results were obtained in completer and intention-to-treat analysis . Poor adherence to assessment protocol s limits conclusions that can be drawn from physical activity and dietary data . CONCLUSIONS Participation in the Choose Health program result ed in significant improvement in body composition . Longer-term follow up is required to determine the durability of intervention effects . Alternative approaches to the measurement of diet and physical activity may be required for adolescents [26675768] BACKGROUND Whereas conventional white cassava roots are devoid of provitamin A , biofortified yellow varieties are naturally rich in β-carotene , the primary provitamin A carotenoid . OBJECTIVE We assessed the effect of consuming yellow cassava on serum retinol concentration in Kenyan schoolchildren with marginal vitamin A status . DESIGN We r and omly allocated 342 children aged 5 - 13 y to receive daily , 6 d/wk , for 18.5 wk 1 ) white cassava and placebo supplement ( control group ) , 2 ) provitamin A-rich cassava ( mean content : 1460 μg β-carotene/d ) and placebo supplement ( yellow cassava group ) , and 3 ) white cassava and β-carotene supplement ( 1053 μg/d ; β-carotene supplement group ) . The primary outcome was serum retinol concentration ; prespecified secondary outcomes were hemoglobin concentration and serum concentrations of β-carotene , retinol-binding protein , and prealbumin . Groups were compared by using ANCOVA , adjusting for inflammation , baseline serum concentrations of retinol and β-carotene , and stratified design . RESULTS The baseline prevalence of serum retinol concentration < 0.7 μmol/L and inflammation was 27 % and 24 % , respectively . For children in the control , yellow cassava , and β-carotene supplement groups , the mean daily intake of cassava was 378 , 371 , and 378 g , respectively , and the total daily supply of provitamin A and vitamin A from diet and supplements was equivalent to 22 , 220 , and 175 μg retinol , respectively . Both yellow cassava and β-carotene supplementation increased serum retinol concentration by 0.04 μmol/L ( 95 % CI : 0.00 , 0.07 μmol/L ) ; correspondingly , serum β-carotene concentration increased by 524 % ( 448 % , 608 % ) and 166 % ( 134 % , 202 % ) . We found no effect on hemoglobin concentration or serum concentrations of retinol-binding protein and prealbumin . CONCLUSIONS In our study population , consumption of yellow cassava led to modest gains in serum retinol concentration and a large increase in β-carotene concentration . It can be an efficacious , new approach to improve vitamin A status . This study was registered with clinical trials.gov as NCT01614483 [18559131] OBJECTIVE To determine whether an educational programme aim ed at discouraging students from drinking sugar-sweetened beverages could prevent excessive weight gain . DESIGN Forty-seven classes in twenty-two schools were r and omised as intervention or control . SUBJECTS Participants were 1140 , 9 - 12-year-old fourth grade rs ( 435 in the intervention group and 608 in the control group ) . Sugar-sweetened beverages and juice intake were measured through one 24 h recall at baseline and another at the end of the trial . The main outcome was the change in BMI ( BMI = weight (kg)/height ( m2 ) ) , measured at the beginning and at the end of the school year . Intention-to-treat analysis was performed taking into account the cluster ( classes ) effect . RESULTS A statistically significant decrease in the daily consumption of carbonated drinks in the intervention compared to control ( mean difference = -56 ml ; 95 % CI -119 , -7 ml ) was followed by a non-significant overall reduction in BMI , P = 0.33 . However , among those students overweight at baseline , the intervention group showed greater BMI reduction ( -0.4 kg/m2 compared with -0.2 kg/m2 in the control group ( P = 0.11 ) ) , and this difference was statistically significant among girls ( P = 0.009 ) . Fruit juice consumption was slightly increased in the intervention group ( P = 0.08 ) , but not among girls . CONCLUSION Decreasing sugar-sweetened beverages intake significantly reduced BMI among overweight children , and mainly among girls . Efforts to reduce energy intake through liquids need to emphasise overall sweetened beverages and addition of sugar on juices [18381508] BACKGROUND . The prevalence and seriousness of childhood obesity has prompted calls for broad public health solutions that reach beyond clinic setting s. Schools are ideal setting s for population -based interventions to address obesity . OBJECTIVE . The purpose of this work was to examine the effects of a multicomponent , School Nutrition Policy Initiative on the prevention of overweight ( 85.0th to 94.9th percentile ) and obesity ( > 95.0th percentile ) among children in grade s 4 through 6 over a 2-year period . METHODS . Participants were 1349 students in grade s 4 through 6 from 10 schools in a US city in the Mid-Atlantic region with ≥50 % of students eligible for free or reduced-price meals . Schools were matched on school size and type of food service and r and omly assigned to intervention or control . Students were assessed at baseline and again after 2 years . The School Nutrition Policy Initiative included the following components : school self- assessment , nutrition education , nutrition policy , social marketing , and parent outreach . RESULTS . The incidences of overweight and obesity after 2 years were primary outcomes . The prevalence and remission of overweight and obesity , BMI z score , total energy and fat intake , fruit and vegetable consumption , body dissatisfaction , and hours of activity and inactivity were secondary outcomes . The intervention result ed in a 50 % reduction in the incidence of overweight . Significantly fewer children in the intervention schools ( 7.5 % ) than in the control schools ( 14.9 % ) became overweight after 2 years . The prevalence of overweight was lower in the intervention schools . No differences were observed in the incidence or prevalence of obesity or in the remission of overweight or obesity at 2 years . CONCLUSION . A multicomponent school-based intervention can be effective in preventing the development of overweight among children in grade s 4 through 6 in urban public schools with a high proportion of children eligible for free and reduced-priced school meals [9241285] Objective To determine whether increased calcium intake ( 2 g/day ) in pregnancy is effective in reducing the risk of preeclampsia in pregnant teenagers . Methods The present study was a prospect i ve , r and omized , double-blind , controlled clinical trial . Two hundred sixty teenaged pregnant girls attending the Hospital Gíneco-Obstétrico Isidro Ayora in Quito , Ecuador , were included . Selection criteria were age less than 17.5 years , nulliparity , first prenatal visit before 20 weeks ' gestation , and residency in Quito ( 2800-m altitude ) . We used a table of r and om numbers to assign 125 girls to receive 2000 mg of elemental calcium daily , beginning at 20 weeks of gestation and continuing until delivery ; 135 women in the control group received a placebo . Blood pressure ( BP ) was measured twice every 4 weeks until delivery and at 48 hours after delivery . The diagnosis of preeclampsia was defined as BP greater than 140/90 mmHg on at least two occasions more than 6 hours apart and proteinuria greater than 30 mg/dL ( over one cross by dipstick on two occasions 4 - 24 hours apart ) . Results The average daily calcium intake in this population was approximately 51 % of the Recommended Dietary Allowance . Calcium supplementation was associated with a significantly decreased risk of preeclampsia ( risk reduction 12.35 % ; P < .001 ) , with 3.2 % ( n = 4 ) developing preeclampsia in the treatment group versus 15.5 % ( n = 21 ) in the placebo group . Moreover , calcium supplementation led to a reduction in systolic BP of 9.1 mmHg and in diastolic BP of 6.0 mmHg . Conclusion These results suggest that calcium supplementation during pregnancy in population s with low calcium intake is a safe , effective , and inexpensive preventive measure that significantly reduces the risk of preeclampsia [22423669] BACKGROUND / PURPOSE The prevalence of obesity and overweight among children and adolescents is increasing rapidly . The present research was performed to determine the influence of a ' ' behavior modification ' ' program on body mass index ( BMI ) in obese public high school students in Iran . METHODS In this study , 152 adolescence and their parents were selected from 12 high schools of Khorram Abad from 2004 to 2006 , and they were r and omly assigned to either the intervention or the control groups . The " behavior modification " interventional program consisted of nutritional education , modifying dietary habits , teaching exercise programs , teaching nutritional facts to the parents , and performing exercises 3 days a week . The height and weight as well as waist , hip , and wrist circumferences of the participants were measured before and after implementing the interventional program . BMI and waist to hip ratio ( WHR ) were calculated . The adolescents and parents completed a nutrition knowledge question naire . Adolescents also completed the Beck 's Depression Question naire . RESULTS Adolescent 's mean weight , BMI , and waist and hip circumferences decreased significantly after implementing the interventional program , in the intervention group ( p≤0.001 ) . In addition , the students ' and parents ' nutrition knowledge increased in the intervention group after implementing the interventional program ( p<0.046 ) . The symptoms of depression decreased and the frequency of students without symptoms of depression increased in the case group , but it did not reveal a statistically significant difference between case and control groups . CONCLUSION The ' ' behavior modification ' ' interventional program is effective in reducing BMI in obese students , and therefore , school principals and planners can play an important role in controlling obesity by implementing this program via the students , their parents , and the school staff [17928808] Background / Objectives : Iron deficiency anemia is a major public health problem in developing countries and may affect school performance and physical work capacity in nonpregnant adolescents , and may increase the risk of anemia during subsequent teenage pregnancies . We assessed the effect of weekly iron ( 120 mg elemental iron ) and vitamin A ( 25 000 IU ) supplementation on hemoglobin , iron status and malaria and nonmalaria morbidity in adolescent schoolgirls . Subjects/ Methods : A total of 279 schoolgirls aged 12–18 years from public primary schools in Kisumu , western Kenya . Double-blind r and omized placebo-controlled trial using a factorial design . Results : Five months of iron supplementation was associated with a 0.52 g dl−1 ( 0.21 , 0.82 ) greater increase in hemoglobin relative to iron placebo . The effect was only observed in girls with iron deficiency on enrollment ( 1.34 g dl−1 ( 0.79 , 1.88 ) ) , but not in iron-replete girls ( −0.20 g dl−1 ( −0.59 , 0.18 ) ) . Similar differences in treatment effect were seen between menstruating and nonmenstruating girls . The effect of iron was independent of vitamin A. The baseline prevalence of vitamin A deficiency was low ( 6.7 % ) and no sustained increase in hemoglobin was seen with weekly vitamin A ( −0.07 g dl−1 ( −0.38 , 0.25 ) ) . Incidence of malaria parasitemia was higher in the iron than iron-placebo groups ( Rate ratio 1.33 ( 0.94 , 1.88 ) ) . Conclusions : Weekly iron supplementation results in substantial increases in hemoglobin concentration in adolescent schoolgirls in western Kenya , which may outweigh possible risks caused by malaria , but only in iron-deficient or menstruating girls and not in iron-replete and nonmenstruating girls [16733670] Introduction Prevention of obesity and overweight is an important target for health promotion . Early prevention requires an intervention during childhood and adolescence . At these stages , the game could be an appropriate means to teach nutrition knowledge and to influence dietary behaviour . To this end , the authors developed Kalèdo , a new board-game . Objective The aim of the present study was to test the efficacy of Kalèdo on changes in nutrition knowledge and dietary behaviour in a pilot study conducted in three middle schools in Naples , Italy . Material s and Methods A simple two-group design ( treatment and control ) with pre- and post- assessment was employed . The classroom was the unit of recruitment and r and om assignment to groups . All students ( 307 ) in the participating schools were invited to participate . Data analysis was performed on 241 subjects . During 24 weeks , a group of 153 children from 8 classrooms ( 11–14 year old Caucasian subjects ; 78 male , 75 female ) was involved in 15–30 minute-long play sessions once a week . A question naire was given to the participants at the beginning and at the end of the study to evaluate nutrition knowledge ( 31 questions ) , physical activity ( 8 questions ) and food intake ( 34 questions ) . Anthropometric measurements were also carried out . A second group of 88 children from 5 classrooms ( same age and ethnicity ; 55 male , 33 female ) was investigated at the same times with the same question naire and anthropometric measures but they did not receive any play sessions with Kalèdo . ObservationChildren playing Kalèdo showed a significant increase in nutrition knowledge ( p<0.05 ) and in weekly vegetable intake ( p<0.01 ) with respect to the control . Conclusion The results suggest that Kalèdo could be an effective instrument to teach children about healthy diet . More research is needed to study the long term effect of this intervention [11424510] AIM To investigate the effect of weekly iron supplementation on anaemia and iron deficiency among adult , female tea pluckers . METHOD A r and omized double-blind intervention trial was conducted in a tea estate in Bangladesh where a total of 280 women received either weekly iron supplementation ( 200 mg ferrous fumarate and 200 mg folic acid ) for 24 weeks or a matching placebo . Capillary blood sample s were drawn at baseline and post-trial to determine haemoglobin , haematocrit and ferritin concentration . Mean corpuscular haemoglobin concentration ( MCHC ) was calculated using the haemoglobin and haematocrit values . RESULTS The mean haemoglobin concentration in the supplemented group increased by 5.52 g L-1 over the study period , on average , while ferritin values decreased by 0.33 microgram L-1 . The control group showed a decrease in both mean haemoglobin ( -0.24 g L-1 ) and ferritin ( -5.32 micrograms L-1 ) . Those individuals in the supplemented group with the lowest pretrial haemoglobin and ferritin values experienced the greatest improvements post-trial , whereas nonanaemic individuals showed a decrease in both haemoglobin and ferritin concentrations . A total of 62.2 % of women in the supplemented group reported feeling better and more energetic compared to 51.1 % in the placebo group ; 14.4 % of the supplemented group and 22.7 % of the control group complained about side-effects . CONCLUSION Weekly iron supplementation was logistically simpler and cheaper than daily supplementation but would have to be continued on a longer term basis in order to combat both anaemia and iron deficiency [16946216] OBJECTIVE : To evaluate the effects of dietary calcium ( Ca ) intervention on adolescent pregnant mothers and their newborns . METHODS : Seventy-two pregnant adolescent mothers were r and omized into one of 3 groups : control , orange juice fortified with calcium , and dairy . The orange juice and dairy groups were required to take more than 1,200 mg Ca . Calcium tablets were added for those not able to meet required Ca . Maternal and infant weight , length , and blood pressure ( BP ) were recorded . Maternal dietary records were evaluated . Mother ’s blood was drawn for serum Ca , phosphate ( P ) , magnesium ( Mg ) , and vitamin 25-hydroxyvitamin D ( D ) . Cord blood was collected for serum Ca and D. Newborn total body Ca was determined . RESULTS : All mothers were similar in weight , height , and BP . Mothers in the orange juice plus calcium and dairy groups had higher intakes of Ca ( 1,472 mg and 1,771 mg ) than controls ( 862 mg ) . One half of the mothers in the orange juice plus calcium group required Ca tablets . Mothers in the dairy group had higher intakes of P , D , and Mg , higher serum folate and D , and higher cord D levels . Mothers in the orange juice plus calcium group had higher serum P but lower serum folate and D. Infants ( 3,517±273 g ) in the dairy group were heavier than infants in the control ( 3,277±177 g ) and orange juice plus calcium ( 3,292±165 g ) groups . Infants in the dairy group had higher total body calcium than control infants . CONCLUSION : Calcium diet supplemented with dairy products during adolescent pregnancy result ed in higher maternal vitamin D and folate serum levels and higher newborn weight and bone mineralization compared with controls . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00320125 LEVEL OF EVIDENCE : [19781127] OBJECTIVE To assess the short-term ( 15-d ) and long-term ( 12-month ) effects of a school-based health and nutrition education intervention on diet , nutrition intake and BMI . DESIGN The 12-week teacher-implemented intervention in combination with seminars organized for parents was aim ed at improving children 's diet and nutrition knowledge . The intervention took place between September 2007 and January 2008 . The participants were r and omized to two study groups , the intervention group ( IG ) and control group ( CG ) , and were examined prior to the intervention on a variety of health knowledge , dietary , behavioural and anthropometric indices . The same measurements were collected 15 d and 1 year after the intervention . SETTING All high schools in Vyronas , a densely populated district of Athens , Greece . SUBJECTS The sample consisted of 191 students aged 12 - 13 years . RESULTS Twelve months after the intervention , the programme was effective in reducing various indices in the IG compared with baseline findings ( BMI : 23.3 ( sd 2.8 ) v. 24.0 ( sd 3.1 ) kg/m2 , P < 0.001 ; daily energy intake : 8112.4 ( sd 1412.4 ) v. 8503.3 ( sd 1419.3 ) kJ/d , P < 0.001 ; total fat intake : 31.3 ( sd 4.4 ) v. 35.4 ( sd 4.7 ) % of daily energy , P < 0.001 ) . Except for BMI , decreases in the aforementioned indices were also observed 15 d after the intervention . In addition , students of the IG reduced their weekly consumption of red meat and non-home-made meals and increased their frequency of fruit and breakfast cereal consumption . CONCLUSIONS The beneficial effects of this nutrition education intervention among adolescents may highlight the potential of such programmes in the prevention of obesity [12736400] OBJECTIVE To examine the benefits of anemia prophylaxis in adolescent school.girls by weekly or daily iron-folate supplementation . DESIGN Prospect i ve study . SETTING Government girl schools of northeast Delhi . SUBJECTS 2088 subjects ( with hemoglobin greater than 7.9 g/dL ) , including 702 on daily and 695 on weekly iron-folate administration ; 691 girls served as controls . RESULTS About 85 % girls were iron deficient out of which 49.3 % were anemic . Weekly administration took longer time to raise hemoglobin but was effective as well as practical . Plasma ferritin estimation in girls showed rise in level in both the treated groups . CONCLUSION Weekly administration of iron-folate was a practical and effective strategy for anemia prophylaxis in adolescent school girls [12700794] Zinc and folic acid nutritional status was evaluated in 74 low-income pregnant adolescents ranging from 13 to 18 years of age who received prenatal care at the Evangelina Rosa Maternity Hospital in Teresina , Piau State , Brazil . In order to evaluate the effects of different supplementation regimens on nutritional status , the adolescents were distributed into five groups . Groups I and II received equal amounts of folic acid ( 250 micro;g ) and different doses of iron ( ferrous sulfate ) , 120 and 80 mg , respectively . Groups III and IV received equal amounts of folic acid ( 250 micro;g ) associated with zinc sulfate and iron at doses of 120 and 80 mg , respectively , while group V received only 120 mg of iron ( routine dosage ) . There was a reduction in the zinc plasma concentration , and this decline was significant only in those groups which did not receive zinc supplementation . In relation to combination iron/folic acid and iron/folic acid/zinc , an excellent response was observed for folic acid , and this effect was larger in the groups that received folic acid combined with zinc , suggesting a possible role for zinc in folic acid metabolism [17522609] Objective : To determine the effectiveness of combined iron and zinc over the iron or zinc-only supplementation in correcting deficiency and possible interactive effects in a group of adolescent school children . Subjects and methods : Schoolchildren ( n=821 ) of 12–16 years of age were r and omized into four groups and supplemented with iron ( 50 mg/day ) , zinc ( 14 mg/day ) , iron+zinc or placebo capsules 5 days per week for 24 weeks . Anthropometry , and haemoglobin ( Hb ) , serum zinc ( SZn ) and serum ferritin ( SF ) concentrations were determined before and after the intervention . Results : There were no significant effects between-groups in their weight , height and Hb concentrations with the intervention when compared with the placebo group . Iron-only and combination-supplemented groups had reached mean SF concentrations of 55.1 μg/l with no difference between them ( P=0.99 ) . The zinc-only group had a mean change of 4.3 μmol//l whereas the combine-supplemented group had a mean change of 4.0 μmol/l ( P=0.82 ) . The prevalence of anaemia was found to be 70.3 % in the iron group at baseline ; this was reduced to 14.5 % after the supplementation . In the combine-supplemented group anaemia , prevalence was reduced from 64.8 to 19.3 % . Conclusions : Zinc alone or in combination with iron has not shown a significant improvement in growth in adolescence . Severe and moderate forms of anaemia were successfully treated in children who received iron supplementation . Initial high prevalence of low SZn and iron stores was significantly improved with micronutrient supplementation [15164114] Objective : High prevalences of vitamin A deficiency and anaemia among adolescents warrant interventions . This study evaluated the effectiveness of school-based supplementation to reduce anaemia and improve vitamin A status . Design : School-based , grade -r and omized , intervention . Subjects and setting : In all , 1757 girls and 1859 boys , aged 12–15 y , in 24 Junior High Schools . Interventions : Weekly supplementation for 14 weeks with 60 mg iron and 250 μg folate ( Fe group ; n=978 ) , 10 000 IU vitamin A ( VA group ; n=970 ) or both ( VAFe group ; n=1042 ) to subjects in 15 schools , compared to subjects in nine other schools not receiving supplements ( control ; n=626 ) . Results : The baseline anaemia prevalence ( Hb < 120 g/l ) in girls was 20 % ( prepubertal ) and 26 % ( pubertal ) , and in boys 24 % ( pre-pubertal ) and 11 % ( pubertal ) . Serum retinol concentrations were low ( < 1.05 μmol/l ) in 41 % of boys and 45 % of girls . The interventions did not increase haemoglobin concentrations . Serum retinol concentration of boys , but not girls , in the VA group increased ( 0.33 vs 0.07 μmol/l in controls ; P<0.01 ) . The risk factors for low serum retinol concentration were lower baseline serum retinol concentration ( OR 0.02–0.03 ) with , for girls , nightblindness at baseline ( OR 5.88 ) , and for boys , not receiving vitamin A ( OR control : 1.00 ; VA : 0.37 ; Fe : 0.77 ; VAFe : 0.34 ) and maternal illiteracy ( OR mother never attended school 1.00 , mother received any formal education 0.17–0.33 ) . Conclusions : Supplementation with vitamin A increased serum retinol concentration of boys . Iron supplementation did not change Hb . This appeared to be due to poor compliance , and partly related to side effects . Sponsorship : This study was funded by USAID through the OMNI Project [22566517] OBJECTIVE To evaluate the impact of a 12-month multicomponent school-based obesity prevention program , Nutrition and Enjoyable Activity for Teen Girls among adolescent girls . DESIGN Group r and omized controlled trial with 12-month follow-up . SETTING Twelve secondary schools in low-income communities in the Hunter and Central Coast regions of New South Wales , Australia . PARTICIPANTS Three hundred fifty-seven adolescent girls aged 12 to 14 years . INTERVENTION A multicomponent school-based intervention program tailored for adolescent girls . The intervention was based on social cognitive theory and included teacher professional development , enhanced school sport sessions , interactive seminars , nutrition workshops , lunch-time physical activity sessions , h and books and pedometers for self-monitoring , parent newsletters , and text messaging for social support . MAIN OUTCOME MEASURES Body mass index ( BMI , calculated as weight in kilograms divided by height in meters squared ) , BMI z score , body fat percentage , physical activity , screen time , dietary intake , and self-esteem . RESULTS After 12 months , changes in BMI ( adjusted mean difference , -0.19 ; 95 % CI , -0.70 to 0.33 ) , BMI z score ( mean , -0.08 ; 95 % CI , -0.20 to 0.04 ) , and body fat percentage ( mean , -1.09 ; 95 % CI , -2.88 to 0.70 ) were in favor of the intervention , but they were not statistically different from those in the control group . Changes in screen time were statistically significant ( mean , -30.67 min/d ; 95 % CI , -62.43 to -1.06 ) , but there were no group by time effects for physical activity , dietary behavior , or self-esteem . CONCLUSIONS A school-based intervention tailored for adolescent girls from schools located in low-income communities did not significantly reduce BMI gain . However , changes in body composition were of a magnitude similar to previous studies and may be associated with clinical ly important health outcomes . TRIAL REGISTRATION anzctr.org.au Identifier : 12610000330044 [22590964] Background Studies in India have reported a high prevalence of nutritional anemia among children and adolescent girls . Nutritional anemia is associated with impaired mental , physical , and cognitive performance in children and is a significant risk factor for maternal mortality . Objective To evaluate the effect of a community-led initiative for control of nutritional anemia among children 6 to 35 months of age and unmarried rural adolescent girls 12 to 19 years of age . Methods This Participatory Action Research was done in 23 villages of the Primary Health Centre , Anji , in Wardha District of Maharashtra . In February and March 2008 , needs assessment was undertaken by interviewing the mothers of 261 children and 260 adolescent girls . Hemoglobin levels of adolescent girls and children were measured with the use of the hemoglobin color scale . The girls were given weekly iron — folic acid tablets , and the children were given daily liquid iron prophylaxis for 100 days in a year through community participation . The adolescent girls and the mothers of the children and adolescent girls were also given nutritional education on the benefits and side effects of iron supplementation . In June and July 2008 , follow-up assessment was performed by survey and force field analysis . Results There was a significant reduction in the prevalence of nutritional anemia from 73.8 % to 54.6 % among the adolescent girls and from 78.2 % to 64.2 % among the children . There was improvement in awareness of iron-rich food items among the adolescent girls and the mothers of the children . The benefits to girls , such as increase in appetite and reduction in scanty menses , tiredness , and weakness , acted as positive factors leading to better compliance with weekly iron supplementation . The benefits to children perceived by the mothers , such as increase in appetite , weight gain , reduction in irritability , and reduction in mud-eating behavior , acted as a dominant positive force and generated dem and for iron syrup . Conclusions The community-led initiative for once-weekly iron supplementation for adolescent girls and iron prophylaxis for children , in addition to nutritional education , improved the hemoglobin status of children 6 to 35 months of age and unmarried rural adolescent girls 12 to 19 years of age [11890637] To investigate the efficacy of two different iron supplements administered either on a weekly basis or during menstruation , a 16-week community experimental study was carried out among postmenarcheal female adolescent students in Kupang , East Nusa Tenggara , Indonesia . Forty eight students received a placebo tablet weekly , 48 other students got an iron tablet weekly and 41 students took an iron tablet for four consecutive days during their menstruation cycle . All subjects were given deworming tablets before supplementation . Haemoglobin , serum ferritin , height , weight , mid-upper arm circumference and dietary intake were assessed before and after intervention . The supplementation contributed to a significant improvement in the iron status of the intervention groups compared to the placebo group ( P < 0.05 ) . In the menstruation group , the haemoglobin concentrations of the anaemic subjects improved significantly ( P < 0.05 ) while for the non-anaemic subjects , serum ferritin concentrations also increased significantly ( P < 0.05 ) . In the weekly group for anaemic and nonanaemic subjects , there was a significant increase in both haemoglobin and serum ferritin concentrations ( P < 0.05 ) . This study revealed that weekly supplementation of iron tablets continued for 16 weeks contributed a higher improvement to haemoglobin concentration , compared with supplementing iron tablets for four consecutive days during menstruation for four menstrual cycles . This suggests that weekly iron supplementation is preferable [11814373] OBJECTIVE To compare the effectiveness of weekly vs daily iron and folic acid supplementation for control of anemia in adolescent Nepalese girls . DESIGN R and omized controlled trial . SETTING A Government Girl School in Dharan , Nepal , an urban foothill town that is 305 m above sea level . SUBJECTS Consecutive healthy adolescent girls ( n = 209 , median age 15 years ) r and omized to 3 groups matched for age , anthropometry , and personal and sociodemographic characteristics . Of 209 subjects , 181 completed the trial . Two girls had adverse reactions to treatment and were excluded . INTERVENTION Group A ( n = 70 ) received a 350-mg ferrous sulfate and 1.5-mg folic acid combination once daily for 90 to 100 days . Group B ( n = 67 ) received the tablet under supervision once a week for 14 weeks . Group C ( n = 72 ) did not receive any drugs . OUTCOME VARIABLE Presupplementation and postsupplementation differences in prevalence of anemia and change in hematocrit . RESULTS Prevalence of anemia ( defined as hematocrit < 36 % ) declined from 68.6 % and 70.1 % in groups A and B to 20 % and 13.4 % , respectively , postsupplementation ( P<.001 ) , whereas the prevalence in group C changed little ( 68.1 % to 65.3 % , P = .81 ) . There was a significant rise in the mean hematocrit of both supplemented groups ( group A , 32.9 % + /- 3.5 % to 41.0 % + /- 5.6 % , P<.001 ; group B , 33.2 % + /- 3.6 % to 40.4 % + /- 4.9 % , P<.001 ) but no appreciable change in controls ( 34.2 % + /- 2.9 % to 34.1 % + /- 3.3 % , P = .91 ) . Net change in mean hematocrit in both the supplementation groups was comparable ( P = .57 ) . CONCLUSIONS The prevalence of anemia in adolescent Nepalese girls is high . Supervised iron and folic acid therapy once a week is an effective alternative to daily administration and helps lower the prevalence of anemia in adolescent girls [16753014] UNLABELLED The effect of vitamin D supplementation on bone mineral augmentation in 212 adolescent girls with adequate calcium intake was studied in a r and omized placebo-controlled setting . Bone mineral augmentation determined by DXA increased with supplementation both in the femur and the lumbar vertebrae in a dose-responsive manner . Supplementation decreased the urinary excretion of resorption markers , but had no impact on formation markers . INTRODUCTION Adequate vitamin D intake protects the elderly against osteoporosis , but there exists no indisputable evidence that vitamin D supplementation would benefit bone mineral augmentation . The aim of this 1-year study was to determine in a r and omized double-blinded trial the effect of 5 and 10 microg vitamin D3 supplementation on bone mineral augmentation in adolescent girls with adequate dietary calcium intake . MATERIAL S AND METHODS Altogether , 228 girls ( mean age , 11.4 + /- 0.4 years ) participated . Their BMC was measured by DXA from the femur and lumbar spine . Serum 25-hydroxyvitamin D [ S-25(OH)D ] , intact PTH ( S-iPTH ) , osteocalcin ( S-OC ) , and urinary pyridinoline ( U-Pyr ) and deoxypyridinoline ( U-Dpyr ) were measured . Statistical analysis was performed both with the intention-to-treat ( IT ) and compliance-based ( CB ) method . RESULTS In the CB analysis , vitamin D supplementation increased femoral BMC augmentation by 14.3 % with 5 microg and by 17.2 % with 10 microg compared with the placebo group ( ANCOVA , p = 0.012 ) . A dose-response effect was observed in the vertebrae ( ANCOVA , p = 0.039 ) , although only with the highest dose . The mean concentration of S-25(OH)D increased ( p < 0.001 ) in the 5-microg group by 5.7 + /- 15.7 nM and in the 10-microg group by 12.4 + /- 13.7 nM , whereas it decreased by 6.7 + /- 11.3 nM in the placebo group . Supplementation had no effect on S-iPTH or S-OC , but it decreased U-DPyr ( p = 0.042 ) . CONCLUSIONS Bone mineral augmentation in the femur was 14.3 % and 17.2 % higher in the groups receiving 5 and 10 microg of vitamin D , respectively , compared with the placebo group , but only 10 mug increased lumbar spine BMC augmentation significantly . Vitamin D supplementation decreased the concentration of bone resorption markers , but had no impact on bone formation markers , thus explaining increased bone mineral augmentation . However , the positive effects were noted with the CB method but not with IT [22244349] The present study examined whether long-term supplementation with once- and twice-weekly multiple micronutrients ( MMN-1 and MMN-2 ) can improve Hb and micronutrient status more than twice-weekly Fe-folic acid ( IFA-2 ) supplementation in non-anaemic adolescent girls in Bangladesh . An equal number of 324 rural schoolgirls aged 11 - 17 years were given MMN-1 or MMN-2 or IFA-2 supplements for 52 weeks in a r and omised , double-blind trial . Blood sample s were collected at baseline , and at 26 and 52 weeks of supplementation . The girls receiving IFA-2 supplements were more likely to be anaemic than the girls receiving MMN-2 supplements for 26 weeks ( OR 5·1 , 95 % CI 1·3 , 19·5 ; P = 0·018 ) . All three supplements reduced Fe deficiency effectively . Both the MMN-1 and MMN-2 groups showed significantly greater improvements in vitamins A , B(2 ) and C status than the girls in the IFA-2 group , as might be expected . Receiving a MMN-1 supplement was found to be less effective than MMN-2 supplement in improving Fe , vitamins A , B(2 ) and folic acid status . Receiving micronutrient supplements beyond 26 weeks showed little additional benefit in improving micronutrient status . In conclusion , given twice-weekly for 26 weeks , MMN supplements can improve micronutrient status effectively with no significant increase in Hb concentration compared with IFA supplements in non-anaemic Bangladeshi adolescent girls . However , it significantly reduces the risk of anaemia . Before any recommendations can be made , further research , including into cost-effectiveness , is needed to see whether MMN supplementation has any additional longer-term health benefits over that of IFA supplementation in this population [16340950] Objective : To investigate whether iron supplementation can improve thyroid hormone function in iron-deficient adolescent girls . Design : A double-blind r and omized intervention study . Setting : The study was performed from 2002 through 2003 in the Islamic Republic of Iran . Subjects:103 iron-deficient non-anaemic girls who fulfilled all inclusion criteria were included , and 94 subjects successfully completed the study . Interventions : Patients were r and omly assigned to one of four groups and treated with a single oral dose of 190 mg iodine plus 300 mg ferrous sulphate 5 times/week ( n=24 ) , 300 mg ferrous sulphate 5 times/week ( n=23 ) , a single oral dose of 190 mg iodine ( n=25 ) , or a placebo ( n=22 ) for 12 weeks . Results : All groups were comparable at baseline . After the intervention , there was a significant increase in ferritin and transferrin saturation in the iron+iodine group ( 17.6 vs 8.7 μg/dl , and 18.8 vs 7.2 % , respectively , P<0.001 for both ) and in the iron group ( P<0.001 for both ) . Urinary iodine doubled in the iron+iodine group and in the iodine group ( P<0.001 for both ) . Thyroid indices tT4 , tT3 and T3RU increased and reverse RT3 decreased in the iron+iodine group ( 10 vs 8.9 μg/dl , P < 0.001 ; 143 vs 138 μg/dl , P<0.05 ; 32.3 vs 28.4 % , P<0.001 and 24.8 vs 44.2 ng/dl , P<0.001 , respectively ) and in the iron group . These two groups did not differ for any of the four indices , but both differed significantly from the iodine and placebo groups . Conclusions : Our results indicate that improvement of iron status was accompanied by an improvement in some indices of thyroid hormones . Sponsorship : This study was supported by the Dean of Research Affairs of the Tehran University of Medical Sciences [25441960] Adolescents with intellectual and developmental disabilities ( IDD ) are at an increased risk of obesity , with up to 55 % considered overweight and 31 % obese . However , there has been minimal research on weight management strategies for adolescents with IDD . The purpose of this study was to compare the effectiveness of two weight loss diets , an enhanced Stop Light Diet ( eSLD ) and a conventional diet ( CD ) , and to determine the feasibility of using tablet computers as a weight loss tool in overweight and obese adolescents with IDD . A 2-month pilot intervention was conducted . All participants were r and omized to the eSLD or CD and were given a tablet computer that they used to track daily dietary intake and physical activity . Participants and parents met weekly with a registered dietitian nutritionist via video chat on the tablet computer to receive diet and physical activity feedback and education . Twenty participants ( 45 % female , aged 14.9±2.2 years ) were r and omized and completed the intervention . Participants in both diets were able to lose weight , and there were no significant differences between the eSLD and CD ( -3.89±2.66 kg vs -2.22±1.37 kg ) . Participants were able to use the tablet computer to track their dietary intake 83.4%±21.3 % of possible days and to attend 80.0 % of the video chat meetings . Both dietary interventions appear to promote weight loss in adolescents with IDD , and the use of tablet computers appears to be a feasible tool to deliver a weight loss intervention in adolescents with IDD [11123827] We evaluated the effect of weekly doses of 400 mg of ferrous sulphate for 4 months on the iron status of adolescent girls in a controlled trial in Tanga , Tanzania . Supplementation led to a significantly greater increase in serum ferritin compared with the control group ( + 15.6 microg/l vs. 8.6 microg/l ) ( P = 0.002 ) but there was no significant difference in change in haemoglobin . Children given iron showed a significantly greater weight gain than controls ( + 2.4 kg vs. + 1.4 kg ) ( P = 0.03 ) . Weekly iron supplementation may be an effective means of increasing iron stores and growth in children vulnerable to iron deficiency [26764317] BACKGROUND In India , the prevalence of low birth weight is high in women with a low body mass index ( BMI ) , suggesting that underweight women are not capable of providing adequate energy and protein for fetal growth . Furthermore , as pregnancy progresses , there is increased need to provide methyl groups for methylation reactions associated with the synthesis of new proteins and , unlike normal- BMI American women , low- BMI Indian women are unable to increase methionine transmethylation and remethylation rates as pregnancy progresses from trimester 1 to 3 . This also negatively influences birth weight . OBJECTIVE The aim was to determine the effect of dietary supplementation with energy and protein from 12 ± 1 wk of gestation to time of delivery compared with no supplement on pregnancy outcomes , protein kinetics , and the fluxes of the methyl group donors serine and glycine . METHODS Protein kinetics and serine and glycine fluxes were measured by using st and ard stable isotope tracer methods in the fasting and postpr and ial states in 24 pregnant women aged 22.9 ± 0.7 y with low BMI s [ BMI ( in kg/m(2 ) ) ≤18.5 ] at 12 ± 1 wk ( trimester 1 ) and 30 ± 1 wk ( trimester 3 ) of gestation . After the first measurement , subjects were r and omly assigned to either receive the supplement ( 300 kcal/d , 15 g protein/d ) or no supplement . RESULTS Supplementation had no significant effect on any variable of pregnancy outcome , and except for fasting state decreases in leucine flux ( 125 ± 7.14 compared with 113 ± 5.06 μmol ⋅ kg(-1 ) ⋅ h(-1 ) ; P = 0.04 ) and nonoxidative disposal ( 110 ± 6.97 compared with 101 ± 3.69 μmol ⋅ kg(-1 ) ⋅ h(-1 ) ; P = 0.02 ) from trimesters 1 to 3 , it had no effect on any other leucine kinetic variable or urea , glycine , and serine fluxes . CONCLUSION We conclude that in Indian women with a low BMI , supplementation with energy and protein from week 12 of pregnancy to time of delivery does not improve pregnancy outcome , whole-body protein kinetics , or serine and glycine fluxes [11975370] A nutritionally controlled study was conducted on two groups of 15 female college students aged 16 to 20 years , selected from Punjab Agricultural University , Ludhiana , Punjab , India . the girls were either anemic ( hemoglobin 7.7 g/dl ) but energy adequate ( AEA ) , or anemic ( hemoglobin 7.4 g/dl ) and energy deficient ( AED ) . the AEA group was given iron supplementation ( 60 mg iron/day ) for 6 to 9 months along with 100 mg of ascorbic acid , and the AED group was given iron as well as energy supplementation for 3 months . There was a significant ( p < .01 ) increase in weight , body mass index , mid-upper-arm circumference , and body fat in the AED group after iron – energy supplementation . Hemoglobin , serum iron , transferrin saturation , total iron-binding capacity , and unsaturated iron-binding capacity were below normal in both groups ; however , after iron and iron – energy supplementation , there was a significant ( p < .01 ) increase , and these indices were in the normal range . There was a significant ( p < .01 ) increase in exercise time and maximum work load tolerance after iron and iron – energy supplementation . Combined energy and iron deficiency had a greater adverse effect on physical work capacity than energy or iron deficiency alone [20702745] Previous short-term supplementation studies showed no additional hematologic benefit of multiple micronutrients ( MMN ) compared with iron + folic acid ( IFA ) in adolescent girls . This study examines whether long-term once- or twice-weekly supplementation of MMN can improve hemoglobin ( Hb ) and micronutrient status more than twice-weekly IFA supplementation in anemic adolescent girls in Bangladesh . Anemic girls ( n = 324 ) aged 11 - 17 y attending rural schools were given once- or twice-weekly MMN or twice-weekly IFA , containing 60 mg iron/dose in both supplements , for 52 wk in a r and omized double-blind trial . Blood sample s were collected at baseline and 26 and 52 wk . Intent to treat analysis showed no significant difference in the Hb concentration between treatments at either 26 or 52 wk . However , after excluding girls with hemoglobinopathy and adjustment for baseline Hb , a greater increase in Hb was observed with twice-weekly MMN at 26 wk ( P = 0.045 ) . Although all 3 treatments effectively reduced iron deficiency , once-weekly MMN produced significantly lower serum ferritin concentrations than the other treatments at both 26 and 52 wk . Both once- and twice-weekly MMN significantly improved riboflavin , vitamin A , and vitamin C status compared with IFA . Overall , once-weekly MMN was less efficacious than twice-weekly MMN in improving iron , riboflavin , RBC folic acid , and vitamin A levels . Micronutrient supplementation beyond 26 wk was likely important in sustaining improved micronutrient status . These findings highlight the potential usefulness of MMN intervention in this population and have implication s for programming [12003652] OBJECTIVE To assess the effect on the haemoglobin concentrations of schoolchildren of weekly iron tablets administered by teachers . DESIGN Sixty schools were r and omly assigned to two groups : in 30 schools children were given weekly for 10 weeks a tablet providing 65 mg of iron and 0.25 mg of folic acid ; in the other 30 schools no iron tablets were given . All children were dewormed and given vitamin A before the study began . The haemoglobin concentration of up to 20 r and omly selected children in each school was estimated before and 2 weeks after the end of treatment . SETTING Rural community schools in Kolondieba district of Mali . SUBJECTS Some 1113 schoolchildren aged 6 - 19 years with a mean of 11.4 years . RESULTS The haemoglobin concentration of treated children rose on average by 1.8 g l(-1 ) and the prevalence of anaemia fell by 8.2 % ; in untreated children the haemoglobin concentration fell by an average of -2.7 g l(-1 ) and the prevalence of anaemia rose by 9.4 % . The fall in haemoglobin concentration among untreated girls of -4.0 g l(-1 ) was greater than in untreated boys ( -0.3 g l(-1 ) ) . CONCLUSIONS Weekly iron tablets given by teachers prevented a general fall in the haemoglobin concentrations of untreated children , and led to a small but statistically significant rise among treated children . Young children benefited more than children aged > or=12 years , and girls benefited more than boys [12799128] BACKGROUND This study tests the feasibility of an innovative school-based program for obesity prevention among adolescent girls . New Moves was implemented as a multicomponent , girls-only , high-school physical education class . METHODS Six schools were equally r and omized into intervention and control conditions . Data were collected at baseline , postintervention , and 8-month follow-up to assess program impact on physical activity , eating patterns , self-perceptions , and body mass index ( BMI ) among 89 girls in the intervention and 112 girls in the control conditions . Program evaluation also included interviews with school staff , parent surveys , and participant interviews and process evaluation surveys . RESULTS The feasibility of implementing New Moves was high , as indicated by strong satisfaction among participants , parents , and school staff , and by program sustainability . Participants perceived a positive program impact on their physical activity , eating patterns , and self-image . Girls in the intervention significantly progressed in their stage of behavioral change for physical activity from baseline to follow-up . However , for the majority of outcome variables , differences between intervention and control schools at postintervention and follow-up were not statistically significant . CONCLUSIONS New Moves was well received and fills a needed niche within school physical education programs . An exp and ed intervention and evaluation is needed to enhance and assess long-term program effectiveness [11902397] The Great Beginnings curriculum result ed in participants achieving outcome objectives for healthy teenage childbearing . The experimental group demonstrated significantly better outcomes in nutrition knowledge maintenance of diet quality adequate for pregnancy mean maternal weight gain and mean infant birth weight . When compared with the C-l group the experimental group demonstrated a significantly better outcome in low-birth-weight incidence nutrition knowledge and maintenance of diet quality adequate for pregnancy . Based on the results of this study pregnant adolescents receiving the Great Beginnings curriculum achieved healthier birth outcomes than those not receiving the curriculum . Participation in Great Beginnings does make a substantial difference in the health status of the adolescents for whom it was intended . ( excerpt [10989766] This experimental study was design ed to investigate the effects of daily versus intermittent iron supplementation on iron status of high school girls in Zahedan and Rasht cities in 1996 - 1997 . The subjects were selected r and omly from among students of grade s 1 - 3 of four high schools in each city . Anemia was determined by measuring hematological indices . 260 anemic and a similar number of non-anemic subjects of 4 high schools were selected and allocated r and omly to 4 treatment groups . During a 3-month period , the test groups were given 150 mg ferrous sulfate tablets ( 50 mg Fe ) . Subjects in group 1 received a daily dose , groups 2 & 3 received twice or once weekly doses respectively . The control group received no iron supplement . For these subjects , in addition to hematological indices biochemical iron indices were measured in the beginning and at the end of the study . The increases in hemoglobin concentration in anemic subjects were not significantly different among supplemented groups but were different from the control group ( p < 0.00001 ) . Among anemic subjects , changes in serum ferritin levels in 3 supplemented groups were significantly different from the control group . Serum ferritin in Group 1 was also increased to a greater extent than groups 2 and 3 ( P < 0.00001 ) . It is concluded that over the study period a weekly iron dose was as effective as a daily dose in treating anemia but the daily dose was more effective in improving iron stores than a weekly dose in the short run [8855856] BACKGROUND Up to 25 % of adolescent girls in the USA are iron deficient . This double-blind , placebo-controlled clinical trial assessed the effects of iron supplementation on cognitive function in adolescent girls with non-anaemic iron deficiency . METHODS 716 girls who enrolled at four Baltimore high schools were screened for non-anaemic iron deficiency ( serum ferritin < or = 12 micrograms/L with normal haemoglobin ) . 98 ( 13.7 % ) girls had non-anaemic iron deficiency of whom 81 were enrolled in the trial . Participants were r and omly assigned oral ferrous sulphate ( 650 mg twice daily ) or placebo for 8 weeks . The effect of iron treatment was assessed by question naires and haematological and cognitive tests , which were done before treatment started and repeated after the intervention . We used four tests of attention and memory to measure cognitive functioning . Intention-to-treat and per- protocol analyses were done . FINDINGS Of the 81 enrolled girls with non-anaemic iron deficiency , 78 ( 96 % ) completed the study ( 39 in each group ) . Five girls ( three control , two treatment ) developed anaemia during the intervention and were excluded from the analyses . Thus , 73 girls were included in the per- protocol analysis . Ethnic distribution , mean age , serum ferritin concentrations , haemoglobin concentrations , and cognitive test scores of the groups did not differ significantly at baseline . Postintervention haematological measures of iron status were significantly improved in the treatment group ( serum ferritin 27.3 vs 12.1 micrograms/L , p < 0.001 ) . Regression analysis showed that girls who received iron performed better on a test of verbal learning and memory than girls in the control group ( p < 0.02 ) . INTERPRETATION In this urban population of non-anaemic iron-deficient adolescent girls , iron supplementation improved verbal learning and memory [2816802] In a double-blind zinc trial in low-income , pregnant adolescents thought to be at risk for poor zinc nutriture , subjects were r and omly assigned to receive 30 mg zinc ( gluconate ) or placebo . Response to zinc was related to maternal weight . Infants of normal-weight mothers given zinc had reduced rates of prematurity ( p = 0.05 ) and assisted respiration ( p = 0.006 ) . Underweight multiparas given zinc had longer gestational lengths ( p = 0.008 ) than did subjects given the placebo . Multiple stepwise regression analysis , used to identify predictors of infant size , revealed that 14 - 26 % more variance was accounted for in the zinc than in the placebo group . Except for gestational age , the predictors selected were entirely different in the two groups . The zinc group had a positive toxemia screen more often , which did not appear to affect outcome . Zinc supplementation improved pregnancy outcome in normal-weight women and in underweight multiparas . The nonresponse in underweight primiparas was perhaps due to multiple limiting factors [10721926] The prevalence of anemia is high in adolescent girls in India , with over 70 % anemic . Iron-folic acid ( IFA ) supplements have been shown to enhance adolescent growth elsewhere in the world . To confirm these results in India , a study was conducted in urban areas of Vadodora , India to investigate the effect of IFA supplements on hemoglobin , hunger and growth in adolescent girls 10 - 18 y of age . Results show that there was a high dem and for IFA supplements and > 90 % of the girls consumed 85 out of 90 tablets provided . There was an increment of 17.3 g/L hemoglobin in the group of girls receiving IFA supplements , whereas hemoglobin decreased slightly in girls in the control group . Girls and parents reported that girls increased their food intake . A significant weight gain of 0.83 kg was seen in the intervention group , whereas girls in the control group showed little weight gain . The growth increment was greater in the 10- to 14-y-old age group than in the 15- to 18-y-old group , as expected , due to rapid growth during the adolescent spurt . IFA supplementation is recommended for growth promotion among adolescents who are underweight [17825729] INTRODUCTION There has been a paucity of theory-based interventions to improve health outcomes in overweight adolescents . Therefore , two intervention studies were conducted to : ( a ) determine the feasibility of implementing the Creating Opportunities for Personal Empowerment ( COPE ) Healthy Lifestyles Thinking , Emotions , Exercise , and Nutrition ( TEEN ) program with overweight adolescents ; ( b ) obtain feedback that could be used to refine the program ; and ( c ) examine the preliminary efficacy of the COPE program on the adolescents ' weight and body mass index ( BMI ) . METHOD Phase I and Phase II clinical trials were conducted with 23 overweight teens . The Phase 1 trial used a pre-experimental design with one group of 11 urban adolescents . The Phase 2 trial was conducted with 12 suburban teens using a r and omized controlled pilot study . COPE teens received a 15-session cognitive-behavioral skills building program that included physical activity , while the control group received an attention control program . Weight change and BMI were the key outcomes . RESULTS COPE teens experienced a significantly greater reduction in weight and BMI than did teens in the control group , who gained weight over time . Although the COPE program was well received by all of the teens , retention of subjects across time and parent involvement in the program were challenges in the urban high school . DISCUSSION These studies provide preliminary data to indicate that the implementation of COPE is feasible and may lead to a reduction in weight and BMI in overweight teens . Implementing COPE within the context of the school day may be more successful in sustaining adolescent involvement in the program versus using an after-school format [17032704] The aim of the present study was to evaluate the effects of a middle school physical activity and healthy eating intervention , including an environmental and computer-tailored component , and to investigate the effects of parental involvement . A r and om sample of 15 schools with seventh and eight grade rs was r and omly assigned to one of three conditions : ( i ) intervention with parental involvement , ( ii ) intervention alone and ( iii ) control group . In 10 schools , an intervention , combining environmental changes with computer-tailored feedback , was implemented over 2 school years . In five intervention schools , increased parental support was added . Physical activity was measured with question naires in the total sample and with accelerometers in a sub- sample of children . Fat intake , fruit , water and soft drink consumption were measured using food-frequency question naires . Results showed significant positive intervention effects on physical activity in both genders and on fat intake in girls . Parental involvement did not increase intervention effects . It can be concluded that physical activity and eating behaviours of middle school children can be improved by school-based strategies combining environmental and personal interventions . The use of personalized computer-tailored interventions seems to be a promising tool for targeting adolescents but needs to be further explored [22584456] This paper reports the final 24-month outcomes of a r and omized controlled trial evaluating the effect of additional therapeutic contact ( ATC ) as an adjunct to a community-based weight-management program for overweight and obese 13–16-year-olds . ATC involved telephone coaching or short-message-service and /or email communication once per fortnight . Adolescents were r and omized to receive the Loozit group program — a two-phase behavioral lifestyle intervention with ( n=73 ) , or without ( n=78 ) , ATC in Phase 2 . Adolescents/parents separately attended seven weekly group sessions ( Phase 1 ) , followed by quarterly adolescent sessions ( Phase 2 ) . Assessor-blinded , 24-month changes in anthropometry and metabolic health included primary outcomes body mass index ( BMI ) z-score and waist : height ratio ( WHtR ) . Secondary outcomes were self-reported psychosocial and lifestyle changes . By 24 months , 17 adolescents had formally withdrawn . Relative to the Loozit program alone , ATC largely had no impact on outcomes . Secondary pre-post assessment of the Loozit group program showed mean ( 95 % CI ) reductions in BMI z-score ( −0.13 ( −0.20 , −0.06 ) ) and WHtR ( −0.02 ( −0.03 , −0.01 ) ) in both arms , with several metabolic and psychosocial improvements . Adjunctive ATC did not provide further benefits to the Loozit group program . We recommend that further work is needed to optimize technological support for adolescents in weight-loss maintenance . Australian New Zeal and Clinical Trials Registry Number ACTRNO12606000175572 [23253647] BACKGROUND Given the increasing prevalence of obesity among youth over the past decade , prevention has become an international public health priority . PURPOSE To evaluate the 2-year effectiveness of three strategies aim ed at preventing overweight and obesity among adolescents in a high school setting . DESIGN PRomotion de l'ALIMentation et de l'Activité Physique ( PRALIMAP ) is a school-based RCT . Each study high school was assigned to receive or not , over a 2-year period ( Grade s 10 and 11 ) , each of three prevention strategies according to a 2 × 2 × 2 factorial school r and omization . Data were collected in 2006 - 2009 and analyzed in 2009 - 2011 . SETTING / PARTICIPANTS A total of 3538 adolescents ( aged 15.6±0.7 years at baseline ) in 24 public high schools in Lorraine ( northeastern France ) completed the PRALIMAP trial . INTERVENTIONS The prevention strategies were education ( development of nutritional knowledge and skills ) ; environment ( creation of a favorable environment by improving availability of " healthy " dietary items and physical activity ) ; and screening and care ( detection of overweight/obesity and , if necessary , adapted care management ) . MAIN OUTCOMES MEASURES The main outcome of interest was BMI ; BMI z-score and prevalence of overweight/obesity were considered as secondary outcomes . RESULTS Adolescents who completed the PRALIMAP trial were younger , less often suspected of having eating disorders and depression , and came from a higher socioeconomic class than those who did not . The 2-year change of outcomes was more favorable in the 12 screening and care high schools compared to the no-screening ones : a 0.11 lower increase in BMI ( p=0.0303 ) ; a 0.04 greater decrease in BMI z-score ( p=0.0173 ) ; and a 1.71 % greater decrease in overweight/obesity prevalence ( p=0.0386 ) . Education and environment strategies were not more effective than no strategy intervention . CONCLUSIONS Although the screening and care strategy is an effective way to prevent , at 2 years , overweight and obesity among adolescents in a high school setting , its effects over and above no strategy intervention were small . TRIAL REGISTRATION This study is registered at www . clinical trials.govNCT00814554 [18377970] OBJECTIVE Our primary objective was to determine whether a novel ' active school ' model -- Action Schools ! BC -- improved the cardiovascular disease ( CVD ) risk profile in elementary-school children . Our secondary objective was to determine the percentage of children with elevated CVD risk factors . METHODS We undertook a cluster-r and omized controlled school-based trial with 8 elementary schools across 1 school year , in British Columbia , Canada , beginning in 2003 . Boys and girls ( n=268 , age 9 - 11 years ) were r and omly assigned ( by school ) to usual practice ( UP , 2 schools ) or intervention ( INT , 6 schools ) groups . We assessed change between groups in cardiovascular fitness ( 20-m Shuttle Run ) , blood pressure ( BP ) , and body mass index ( BMI , wt/ht(2 ) ) . We evaluated total cholesterol ( TC ) , total : high-density cholesterol ( TC : HDL-C ) , low-density lipoprotein , apolipoprotein B , C-reactive protein and fibrinogen on a subset of volunteers ( n=77 ) . RESULTS INT children had a 20 % greater increase in fitness and a 5.7 % smaller increase in BP compared with children attending UP schools ( P<0.05 ) . Forty five percent of children had at least one elevated risk factor ( fitness , BP or BMI ) at baseline . There were no significant differences between groups for change in BMI or in any of the blood variables . CONCLUSION Action Schools ! BC was an effective school-based physical activity model for improving the CVD risk profile of elementary-school children . Our multi-component intervention exposed children to fitness enhancing physical activity . It may be important for education stakeholders to adequately re source the delivery of the active school models if cardiovascular health benefits are to be achieved on a population basis [22129855] OBJECTIVES The present study was aim ed at assessing the effect of zinc- and micronutrient-rich food supplementation compared with ayurvedic zinc tablets on the blood levels of zinc and vitamin A in adolescent girls . METHODS One hundred eighty apparently healthy schoolgirls ( 12.5 ± 0.85 y old ) were recruited for a 10-wk intervention trial . They were r and omized to three groups : one group received a food supplement that was prepared using zinc- and micronutrient-rich foods and by adopting food-processing methods that increase zinc bioavailability ; the second group received ayurvedic zinc ( Jasad ) tablets as a natural elemental zinc supplement ; and the third group served as the control without any supplementation . Diet was assessed by 24-h recall on 3 non-consecutive days . Fasting blood sample s were analyzed for plasma levels of zinc , β-carotene , retinol , vitamin C , and hemoglobin at baseline and the end of the study period . RESULTS Food supplementation showed a significant increase in plasma levels of zinc ( 9.9 % ) , β-carotene ( 56.2 % ) , and vitamin C ( 28.0 % , P < 0.05 ) and a non-significant increase in hemoglobin ( 1.7 % ) , although small , non-significant changes in blood micronutrient levels were observed in the control group ( P > 0.1 ) . Food supplementation decreased the prevalence of zinc deficiency ( 73 % to 53.1 % ) , β-carotene deficiency ( 31.1 % to 17.4 % ) , and mild anemia ( 32.2 % to 23.7 % ) . Ayurvedic zinc supplementation significantly improved plasma zinc ( 61.3 % ) and plasma retinol ( 38.2 % ) and decreased the prevalence of zinc deficiency ( 73.7 % to 36.2 % ) and vitamin A deficiency ( 65.4 % to 20.4 % , P < 0.05 ) . CONCLUSION Zinc- and micronutrient-rich food supplementation was effective in improving the zinc and vitamin A status of adolescent girls

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### Context: [25631970] INTRODUCTION Iron deficiency , associated with a decline in cognitive function , is the most common nutritional deficiency globally . The present study aim ed to identify the impact of weekly iron supplements on the attention function of female students from a high school in North Khorasan Province , Iran . METHODS This was a blind , controlled , clinical trial study , involving 200 female students who were chosen using the stratified r and omised sampling method . First , laboratory studies were performed to detect iron consumption limitations . Next , the 200 students were divided r and omly and equally into case and control groups . The case group was treated with 50 mg of ferrous sulfate twice a week for 16 weeks . We compared both groups ' data on attention , iron status and erythrocyte indices . Question naires were used to collect demographic data , while clinical data was collected using complete blood count and Toulouse-Piéron tests . Data was analysed using descriptive statistics , as well as paired and independent t-tests . RESULTS The mean attention scores of the case and control groups were 104.8 ± 7.0 and 52.7 ± 9.6 , respectively ( p < 0.001 ) . The mean haemoglobin levels of the two groups were 12.5 ± 0.9 and 11.2 ± 1.0 , respectively ( p < 0.001 ) . Compared to the control group , the attention scores and haemoglobin concentrations of the case group were found to be improved by approximately 90 % and 10 % , respectively . CONCLUSION Oral iron supplements ( 50 mg twice a week for 16 weeks ) were able to improve the attention span and haematologic indices of female high school students [12713212] OBJECTIVE To test the feasibility , acceptability , and potential efficacy of after-school dance classes and a family-based intervention to reduce television viewing , thereby reducing weight gain , among African-American girls . DESIGN Twelve-week , 2-arm parallel group , r and omized controlled trial . SETTING Low-income neighborhoods . PARTICIPANTS Sixty-one 8 - 10-year-old African-American girls and their parents/guardians . INTERVENTIONS The treatment intervention consisted of after-school dance classes at 3 community centers , and a 5-lesson intervention , delivered in participants ' homes , and design ed to reduce television , videotape , and video game use . The active control intervention consisted of disseminating newsletters and delivering health education lectures . MAIN OUTCOME MEASURES Implementation and process measures , body mass index , waist circumference , physical activity measured by accelerometry , self-reported media use , and meals eaten with TV . RESULTS Recruitment and retention goals were exceeded . High rates of participation were achieved for assessment s and intervention activities , except where transportation was lacking . All interventions received high satisfaction ratings . At follow up , girls in the treatment group , as compared to the control group , exhibited trends toward lower body mass index ( adjusted difference = -.32 kg/m2 , 95 % confidence interval [ CI ] -.77 , .12 ; Cohen 's d = .38 st and ard deviation units ) and waist circumference ( adjusted difference = -.63 cm , 95 % CI -1.92 , .67 ; d = .25 ) ; increased after-school physical activity ( adjusted difference = 55.1 counts/minute , 95 % CI -115.6 , 225.8 ; d = .21 ) ; and reduced television , videotape , and video game use ( adjusted difference = -4.96 hours/week , 95 % CI -11.41 , 1.49 ; d = .40 ) . The treatment group reported significantly reduced household television viewing ( d = .73 , P = .007 ) and fewer dinners eaten while watching TV ( adjusted difference = -1.60 meals/week , 95 % CI -2.99 , -.21 ; d = .59 ; P = .03 ) . Treatment group girls also reported less concern about weight ( d = .60 ; P = .03 ) , and a trend toward improved school grade s ( d = .51 ; P = .07 ) . CONCLUSIONS This study confirmed the feasibility , acceptability , and potential efficacy of using dance classes and a family-based intervention to reduce television viewing , thereby reducing weight gain , in African-American girls [10721928] Peru has high rates of iron deficiency anemia . The prevalence is 35 % in nonpregnant women of fertile age and 24.7 % in adolescent girls in slums of periurban Lima . The major cause of anemia is low intake of dietary iron . A community-based , r and omized behavioral and dietary intervention trial was conducted to improve dietary iron intake and iron bioavailability of adolescent girls living in periurban areas of Lima , Peru . Results show that there was a change in knowledge about anemia and improved dietary iron intake in the 71 girls who completed the study compared with the 66 girls in the control group . Although the 9-mo . intervention was not sufficient to improve hemoglobin levels significantly , there appeared to be a protective effect in maintaining the iron status of girls in comparison with the control group [19706212] OBJECTIVE Despite public health campaigns based on Fe and folic acid supplements , Fe-deficiency anaemia remains highly prevalent among women in India . We investigated leaf concentrate as an alternative to Fe and folic acid supplements for treating anaemia in adolescent girls . DESIGN R and omised controlled two-arm trial over 3 months : one group received daily Fe and folic acid ( IFA ; 60 mg Fe , 500 microg folic acid ) ; the other daily leaf concentrate ( LC ; 5 mg Fe , 13 microg folic acid ) . Hb concentration , mean cell volume , serum Fe , serum ferritin and total Fe-binding capacity were measured pre- and post-intervention . SETTING Jaipur , India . SUBJECTS One hundred and two adolescent girls aged 14 - 18 years . RESULTS Of the 102 girls r and omized to the two arms of the trial , four ( 3.9 % ) were severely anaemic ( Hb < 7 g/dl ) , twenty-eight ( 27.5 % ) were moderately anaemic ( Hb > or = 7 g/dl , < 10 g/dl ) and seventy ( 68.6 % ) were mildly anaemic ( Hb > or = 10 g/dl , < 12 g/dl ) . In the IFA group , eleven girls ( 20.4 % ) withdrew due to side-effects , compared with one girl ( 2.1 % ) in the LC group ( P = 0.005 ) . Total losses to follow-up were 14/54 in the IFA group and 2/48 in the LC group . At the end of the trial , none of the eighty-six remaining girls were severely anaemic , nine ( 10.5 % ) were moderately anaemic and twenty-six ( 30.2 % ) were mildly anaemic ; fifty-one ( 59.3 % ) had normal Hb levels ( > or = 12 g/dl ) . After adjustment for baseline values , LC was as effective as IFA in improving serum Fe parameters and treating anaemia . CONCLUSIONS Leaf concentrate is an effective , and more palatable , alternative to Fe and folic acid supplements for treating anaemia in adolescent girls [2758893] Background Schools are the most frequent target for intervention programs aim ed at preventing child obesity ; however , the overall effectiveness of these programs has been limited . It has therefore been recommended that interventions target multiple ecological levels ( community , family , school and individual ) to have greater success in changing risk behaviors for obesity . This study examined the immediate and short-term , sustained effects of the Switch program , which targeted three behaviors ( decreasing children 's screen time , increasing fruit and vegetable consumption , and increasing physical activity ) at three ecological levels ( the family , school , and community ) . Methods Participants were 1,323 children and their parents from 10 schools in two states . Schools were matched and r and omly assigned to treatment and control . Measures of the key behaviors and body mass index were collected at baseline , immediately post-intervention , and 6 months post-intervention . Results The effect sizes of the differences between treatment and control groups ranged between small ( Cohen 's d = 0.15 for body mass index at 6 months post-intervention ) to large ( 1.38 ; parent report of screen time at 6 months post-intervention ) , controlling for baseline levels . There was a significant difference in parent-reported screen time at post-intervention in the experimental group , and this effect was maintained at 6 months post-intervention ( a difference of about 2 hours/week ) . The experimental group also showed a significant increase in parent-reported fruit and vegetable consumption while child-reported fruit and vegetable consumption was marginally significant . At the 6-month follow-up , parent-reported screen time was significantly lower , and parent and child-reported fruit and vegetable consumption was significantly increased . There were no significant effects on pedometer measures of physical activity or body mass index in the experimental group . The intervention effects were moderated by child sex ( for fruit and vegetable consumption , physical activity , and weight status ) , family involvement ( for fruit and vegetable consumption ) , and child body mass index ( for screen time ) . The perception of change among the experimental group was generally positive with 23 % to 62 % indicating positive changes in behaviors . Conclusion The results indicate that the Switch program yielded small-to-modest treatment effects for promoting children 's fruit and vegetable consumption and minimizing screen time . The Switch program offers promise for use in youth obesity prevention [4061343] As a follow-up of our study of pregnant women , we report effects of zinc supplementation during pregnancy in another population of 138 Hispanic teenagers in Los Angeles . Teenagers were r and omized ( double-blind ) to a control or zinc-supplemented group and received similar daily vitamin and mineral supplements except for 20 mg zinc added to the zinc-supplemented group 's capsules . Initially , mean dietary zinc intakes of both groups were about 50 % of the Recommended Dietary Allowance and their mean serum zinc levels did not differ significantly ( 69.8 + /- 11.2 micrograms/dl in control and 69.0 + /- 11.4 micrograms/dl in zinc-supplemented group ) . Zinc supplementation did not maintain mean serum zinc levels during pregnancy but , as in our earlier study , it reduced ( p = 0.018 ) the number of low serum zinc values ( less than or equal to 53 micrograms/dl ) in late pregnancy . Zinc supplementation did not affect outcome of pregnancy but serum zinc levels were lower ( p = 0.038 ) in teenagers with pregnancy-induced hypertension than in normotensives [11451725] BACKGROUND Iron deficiency is the most common micronutrient deficiency and affects > 2 billion persons worldwide , leading to anemia in > 40 % of women of reproductive age in the developing world . OBJECTIVE The objective was to determine whether weekly supplementation with iron and folate would reduce the frequency of anemia in teenage women in urban Bangladesh before they became pregnant . DESIGN Participants with a hemoglobin concentration of 80 - 120 g/L were entered into a r and omized , double-blind , placebo-controlled trial and received supplements of placebo , vitamin A , iron + folic acid , or iron + folic acid + vitamin A weekly for 12 wk . The supplements contained 2.42 mg vitamin A ( retinol ) as retinyl palmitate , 120 mg elemental Fe as ferrous sulfate , and 3.5 mg folic acid . RESULTS Hemoglobin concentrations increased significantly more after supplementation with iron + folic acid or iron + folic acid + vitamin A than after either the placebo or vitamin A alone . There was a significantly greater increase in hemoglobin after iron + folic acid + vitamin A than after iron + folic acid , but the additional effect disappeared after adjustment for baseline hemoglobin , serum vitamin A , and ferritin and the number of supplements taken . Those with the lowest baseline hemoglobin had the greatest increase in hemoglobin . Compared with the placebo , iron + folic acid + vitamin A reduced anemia by 92 % , iron deficiency by 90 % , and vitamin A deficiency by 76 % . CONCLUSION There may be significant health benefits from a program that enhances the nutritional status of iron , folate , and vitamin A in poor urban young women before they become pregnant [9209187] Different supplementation schemes to build iron stores in female Indonesian adolescents were investigated . Subjects were 273 high-school girls allocated r and omly to four treatment groups . During a 3-mo period one group received 60 mg Fe , 750 micrograms retinol , 250 micrograms folic acid , and 60 mg vitamin C per day ; a second group received 60 mg Fe , 6000 micrograms retinol , 500 mg folic acid , and 60 mg vitamin C once a week ; a third group received 120 mg Fe and the same amount of the other three micronutrients as the second group once a week ; and a fourth group received only placebos . All subjects were dewormed and supplement allocation was double blind . Blood sample s were collected at baseline , after 2 and 3 mo of supplementation , and 6 mo after the last supplement . After 2 mo of supplementation , groups supplemented weekly and daily showed similar significant improvements ( P < 0.001 ) in hemoglobin and retinol concentrations , and supplementation for 3 instead of 2 mo did not significantly increase these two indicators . After 3 mo , the increase in ferritin was approximately equal to 27 micrograms/L in the daily and 14 - 15 micrograms/L in the weekly groups ( P < 0.001 ) , the latter having a final concentration of 42 - 45 micrograms/L. At 6 mo postsupplementation there were no significant differences among daily and weekly groups , but the ferritin concentration was still approximately equal to 10 - 12-micrograms/L higher ( P < 0.001 ) than in the placebo group . The group supplemented weekly with 60 mg Fe complained less about side effects than the other supplemented groups ( P < 0.05 ) . Weekly supplementation with 60 mg Fe and 6000 micrograms retinol for 3 mo was optimal for improving the iron status of the adolescents for approximately equal to 9 mo [12885710] BACKGROUND Fish sauce is consumed daily by a large proportion of the Vietnamese population and could therefore be a potentially useful food vehicle for iron-fortification programs . OBJECTIVE We evaluated the efficacy of iron-fortified fish sauce in improving the iron status of anemic women . DESIGN In a r and omized , double-masked study of 152 anemic ( hemoglobin concentration of 81 - 119 g/L ) women , a meal based on noodles or rice was served 6 d/wk with 10 mL fish sauce containing either 10 mg Fe as NaFeEDTA ( iron-fortified group ) or no added iron ( control group ) . Concentrations of hemoglobin , serum ferritin ( SF ) , and serum transferrin receptor ( TfR ) were measured at baseline and after 3 and 6 mo . RESULTS After 6 mo , hemoglobin and SF concentrations were higher and TfR concentrations were lower in the iron-fortified group than in the control group [ hemoglobin : 116.3 + /- 8.7 ( + /- SD ) compared with 107.6 + /- 11.0 g/L ( P < 0.0001 ) ; SF : 30.9 ( 95 % CI : 23.4 , 40.6 ) compared with 14.6 ( 11.3 , 19.0 ) micro g/L ( P = 0.0002 ) ; TfR : 7.2 ( 6.4 , 7.9 ) compared with 9.0 ( 8.1 , 9.9 ) mg/L ( P = 0.002 ) ] . The prevalence of iron deficiency ( SF < 12 micro g/L or TfR > 8.5 mg/L ) and iron deficiency anemia ( iron deficiency with hemoglobin < 120 g/L ) was lower in the iron-fortified group than in the control group [ 32.8 % compared with 62.5 % ( P = 0.0005 ) and 20.3 % compared with 58.3 % ( P < 0.0001 ) , respectively ] . CONCLUSIONS Regular consumption of iron-fortified fish sauce significantly reduced the prevalence of iron deficiency anemia in Vietnamese women during the 6-mo intervention . Fortifying fish sauce with iron by using a water-soluble , highly bioavailable compound ( NaFeEDTA ) is a promising strategy for combating iron deficiency anemia in Vietnam [10357747] BACKGROUND Iron deficiency and its consequent anemia constitute the commonest micronutrient deficiency in the world . OBJECTIVE We investigated whether long-term , weekly iron-folate supplements administered at school would improve hemoglobin and ferritin concentrations in adolescent girls , including those with mild-to-moderate anemia and hemoglobin concentrations indicating borderline anemia . DESIGN Subjects were 266 girls with hemoglobin concentrations of 80 - 119.9 g/L ( group A ) and 358 girls with hemoglobin concentrations of 120 - 130 g/L ( group B ) who were otherwise healthy . Two hundred sixty-six girls in group A and 268 girls in group B were r and omly assigned to receive either 60 or 120 mg Fe plus 3.5 mg folic acid weekly for 22 wk . Ninety of the girls in group B were r and omly assigned to receive only 5 mg folic acid weekly . Capillary hemoglobin and plasma ferritin were measured at baseline and after 12 and 22 wk of supplementation . RESULTS By the end of the study , 2 % of the girls had dropped out and > 96 % had taken > or = 20 of the 22 tablets ; side effects were minimal . Mean plasma ferritin increased significantly in all iron-supplemented groups , independently of initial hemoglobin values and iron doses . Ferritin concentrations decreased in the girls supplemented with folic acid only . As expected , hemoglobin responses to iron were higher in group A than in group B and increases were positively correlated with initial plasma ferritin . Hemoglobin failed to respond to folate supplementation if initial plasma ferritin concentrations were low . Mean hemoglobin increased significantly and consistently in relation to the length of treatment . CONCLUSION Long-term , weekly iron-folate supplementation was found to be a practical , safe , effective , and inexpensive method for improving iron nutrition in adolescent schoolgirls [16251617] One cost-effective strategy for controlling iron deficiency is the fortification of staple foods or condiments with iron . We evaluated the effectiveness of fortifying fish sauce with NaFeEDTA for improving iron status in women of childbearing age in Vietnam in a double-blind intervention with r and omization by village . All families in the selected villages were supplied with fish sauce that was either unfortified ( Group C , 10 villages ) or fortified with NaFeEDTA [ 9 mmol ( 500 mg ) Fe/L , Group F , 11 villages ] for 18 mo . The effect of fortification was assessed in the 576 women ( n = 288/group ) by measuring hemoglobin and serum ferritin ( SF ) at 6 , 12 , and 18 mo . Analysis of the group x time interaction using a repeated- measures test for each response demonstrated a significant effect of fortification on hemoglobin ( P = 0.039 ) and log SF ( P < 0.0001 ) in Group F with no significant changes in Group C. The prevalence of iron deficiency ( SF < 12 microg/L ) decreased from 22.3 to 4.0 % and the prevalence of anemia ( hemoglobin < 120 g/L ) from 24.7 to 8.5 % in Group F with no significant changes in Group C. NaFeEDTA fortification of fish sauce is an effective method for reducing the prevalence of iron deficiency in women in Vietnam [9771866] The effects of growth , menstrual status , and calcium supplementation on iron status were studied over 4 y in 354 girls in pubertal stage 2 who were premenarcheal at baseline ( x+/-SD age : 10.8+/-0.8 y ) . Girls were r and omly assigned to placebo or treatment with 1000 mg Ca/d as calcium citrate malate . Anthropometric characteristics , bone mass , and nutritional status were measured biannually ; ferritin was measured annually ; and red blood cell indexes were determined at 4 y. The simultaneous effects of iron intake and menstrual status on serum ferritin , after change in lean body mass ( LBM ) was controlled for , were evaluated in subjects in the upper and lower quartiles of cumulative iron intake . The average maximal accumulation of LBM ( 386 g/mo ; 95 % CI : 372 , 399 ) occurred 0.5 y before the onset of menarche . Change in LBM was a significant predictor of serum ferritin ( P < 0.0001 ) , with a negative influence on iron status ( t ratio=-4.12 ) . The 2 fitted mathematical models representing ferritin concentrations of subjects in the upper and lower quartiles of cumulative iron intake were significantly different ( P < 0.018 ) . The regression line of the ferritin concentration in menstruating girls with high iron intakes had a less negative slope than the line fit to serum ferritin concentrations in girls with low iron intakes ( NS ) . Serum ferritin concentrations at 0 , 1 , 2 , 3 , and 4 y were not significantly different between groups . In addition , there was no significant difference between groups in any of the red blood cell indexes . In summary , growth spurt and menstrual status had adverse effects on iron stores in adolescent girls with low iron intakes ( < 9 mg/d ) , whereas long-term supplementation with calcium ( total intake : approximately 1500 mg/d ) did not affect iron status [19349559] OBJECTIVE To determine whether a multicomponent health promotion intervention for Dutch adolescents ( defined as persons between 12 and 14 years of age ) would be successful in influencing body composition and dietary and physical activity behavior in both the short and long terms . DESIGN R and omized controlled trial . SETTING Ten intervention and 8 control prevocational secondary schools . PARTICIPANTS A total of 1108 adolescents ( mean age , 12.7 years ) . Intervention An interdisciplinary program with an adapted curriculum for 11 lessons in biology and physical education and environmental change options . MAIN OUTCOME MEASURES Body height and weight , waist circumference , 4 skinfold thickness measurements , and dietary and physical activity behavior data . RESULTS Multilevel analyses showed that the intervention remained effective in preventing unfavorable increases in important measures of body composition after 20-month follow-up in girls ( biceps skinfold and sum of 4 skinfolds ) and boys ( triceps , biceps , and subscapular skinfolds ) . Consumption of sugar-containing beverages was significantly lower in intervention schools both after intervention ( boys : -287 mL/d ; 95 % confidence interval [ CI ] , -527 to -47 ; girls : -249 ; -400 to -98 ) and at 12-month follow-up ( boys : -233 ; -371 to -95 ; girls : -271 ; -390 to -153 ) . For boys , screen-viewing behavior was significantly lower in the intervention group after 20 months ( -25 min/d ; 95 % CI , -50 to -0.3 ) . No significant intervention effects on consumption of snacks or active commuting to school were found . CONCLUSION The Dutch Obesity Intervention in Teenagers program result ed in beneficial effects on the sum of skinfold thickness measurements in girls and consumption of sugar-containing beverages in both boys and girls in both the short and long terms [18312804] BACKGROUND Physical activity is important for weight control and good health ; however , activity levels decline in the adolescent years , particularly in girls . DESIGN Group r and omized controlled trial . SETTING / PARTICIPANTS Middle school girls with English-speaking skills and no conditions to prevent participation in physical activity in 36 schools in six geographically diverse areas of the United States . R and om , cross-sectional sample s were drawn within schools : 6th grade rs in 2003 ( n=1721 ) and 8th grade rs in 2005 ( n=3504 ) and 2006 ( n=3502 ) . INTERVENTION A 2-year study -directed intervention ( fall 2003 to spring 2005 ) targeted schools , community agencies , and girls to increase opportunities , support , and incentives for increased physical activity . Components included programs linking schools and community agencies , physical education , health education , and social marketing . A third-year intervention used school and community personnel to direct intervention activities . MAIN OUTCOME MEASURES The primary outcome , daily MET-weighted minutes of moderate-to-vigorous physical activity ( MET-weighted MVPA ) , was assessed using accelerometry . Percent body fat was assessed using anthropometry . RESULTS After the staff-directed intervention ( pre-stated primary outcome ) , there were no differences ( mean= -0.4 , 95 % CI= -8.2 to 7.4 ) in adjusted MET-weighted MVPA between 8th- grade girls in schools assigned to intervention or control . Following the Program Champion-directed intervention , girls in intervention schools were more physically active than girls in control schools ( mean difference 10.9 MET-weighted minutes of MVPA , 95 % CI=0.52 - 21.2 ) . This difference is about 1.6 minutes of daily MVPA or 80 kcal per week . There were no differences in fitness or percent body fat at either 8th- grade timepoint . CONCLUSION A school-based , community-linked intervention modestly improved physical activity in girls [19247280] Few r and omized trials attempt to improve insulin sensitivity and associated metabolic risks in overweight Latino youth . The purpose of this study is to examine the effects of a modified carbohydrate nutrition program combined with strength training on insulin sensitivity , adiposity , and other type 2 diabetes risk factors in overweight Latino adolescents . In a 16-week r and omized trial , 54 overweight Latino adolescents ( 15.5 + /- 1.0 years ) were r and omly assigned to : ( i ) Control ( C ; n = 16 ) , ( ii ) Nutrition ( N ; n = 21 ) , or ( iii ) Nutrition + Strength training ( N+ST ; n = 17 ) . The N group received modified carbohydrate nutrition classes ( once per week ) , while the N+ST received the same nutrition classes plus strength training ( twice per week ) . The following were measured at pre- and postintervention : strength by 1-repetition maximum , dietary intake by 3-day records , body composition by dual-energy X-ray absorptiometry , glucose/insulin indices by oral glucose tolerance test ( OGTT ) and intravenous glucose tolerance test with minimal modeling . Across intervention group effects were tested using analysis of covariance with post hoc pairwise comparisons . A significant overall intervention effect was found for improvement in bench press ( P < 0.001 ) and reductions in energy ( P = 0.05 ) , carbohydrate ( P = 0.04 ) and fat intake ( P = 0.03 ) . There were no significant intervention effects on insulin sensitivity , body composition , or most glucose/insulin indices with the exception of glucose incremental area under the curve ( IAUC ) ( P = 0.05 ) , which decreased in the N and N+ST group by 18 and 6.3 % compared to a 32 % increase in the C group . In conclusion , this intense , culturally tailored intervention result ed in no significant intervention effects on measured risk factors with the exception of a beneficial effect on glycemic response to oral glucose [19652922] Iron supplementation has been suggested as a strategy for prevention and treatment of iron deficiency ( ID ) and iron deficiency anemia ( IDA ) in many countries , but non-compliance of daily regimens and common dosage remain as major challenges . The aim of this study was to investigate the effects of low dose once weekly iron supplementation in adolescent girls . The study was design ed as a community-based , r and omized , supplementation trial . The initial sample consisted of 200 female high school students , aged 14–16 years old , of whom 193 students concluded the study . They were r and omly selected and assigned into either iron-supplemented group ( ISG ) or iron-unsupplemented group ( IUG ) . The ISG received 150 mg ferrous sulfate once weekly for 16 weeks , whereas the IUG received nothing . Weight , height , and hematological parameters were measured and compared between the two groups before and after the intervention . There was no significant difference between the initial measures of the two groups before the intervention . After 16 weeks of intervention , mean of hemoglobin and serum ferritin improved significantly in ISG compared to IUG . At the beginning of the study , percent of anemia , IDA , and ID in ISG were 12.5 % , 8.3 % , and 30.2 % , whereas these figures for IUG in this period of study were 14.4 , 10.3 , and 38.2 , respectively , which were not significantly different between the two groups . However , percentages of the above items at the end of study in ISG were 2.1 % , 0 % , and 21.9 % , respectively . In contrast to IUG , all cases of IDA were abolished in the ISG . Our study showed that once weekly supplementation of 150 mg ferrous sulfate for 16 weeks significantly improved iron status in female adolescents and effectively treated IDA . There is no need for higher dosage of iron for supplementation that may cause adverse effects and bear higher costs [24331680] AIM This study evaluates the efficacy of the Choose Health program , a family-based cognitive behavioural lifestyle program targeting improved eating and activity habits , in improving body composition , cardiovascular fitness , eating and activity behaviours in overweight and obese adolescents . METHOD The sample comprised 29 male and 34 female overweight ( n = 15 ) or obese ( n = 48 ) adolescents aged 11.5 - 18.9 years ( M = 14.3 , SD = 1.9 ) . Participants were r and omly allocated to treatment or waitlist control conditions ; waitlist condition participants were offered treatment after 6 months . DEXA-derived and anthropometric measures of body composition ; laboratory-based cycle ergometer and field-assessed cardiovascular fitness data ; objective and self-report physical activity measures ; and self-report measures of eating habits and 7-day weighed food diaries were used to assess treatment outcome . Adherence to treatment protocol s was high . RESULTS Treatment result ed in significant ( p < .05 ) and sustained improvements in a range of body composition ( body fat , percent body fat , lean mass ) and anthropometric measures ( weight , BMI , BMI -for-age z-score and percentiles ) . Minimal improvements were seen in cardiovascular fitness . Similar results were obtained in completer and intention-to-treat analysis . Poor adherence to assessment protocol s limits conclusions that can be drawn from physical activity and dietary data . CONCLUSIONS Participation in the Choose Health program result ed in significant improvement in body composition . Longer-term follow up is required to determine the durability of intervention effects . Alternative approaches to the measurement of diet and physical activity may be required for adolescents [26675768] BACKGROUND Whereas conventional white cassava roots are devoid of provitamin A , biofortified yellow varieties are naturally rich in β-carotene , the primary provitamin A carotenoid . OBJECTIVE We assessed the effect of consuming yellow cassava on serum retinol concentration in Kenyan schoolchildren with marginal vitamin A status . DESIGN We r and omly allocated 342 children aged 5 - 13 y to receive daily , 6 d/wk , for 18.5 wk 1 ) white cassava and placebo supplement ( control group ) , 2 ) provitamin A-rich cassava ( mean content : 1460 μg β-carotene/d ) and placebo supplement ( yellow cassava group ) , and 3 ) white cassava and β-carotene supplement ( 1053 μg/d ; β-carotene supplement group ) . The primary outcome was serum retinol concentration ; prespecified secondary outcomes were hemoglobin concentration and serum concentrations of β-carotene , retinol-binding protein , and prealbumin . Groups were compared by using ANCOVA , adjusting for inflammation , baseline serum concentrations of retinol and β-carotene , and stratified design . RESULTS The baseline prevalence of serum retinol concentration < 0.7 μmol/L and inflammation was 27 % and 24 % , respectively . For children in the control , yellow cassava , and β-carotene supplement groups , the mean daily intake of cassava was 378 , 371 , and 378 g , respectively , and the total daily supply of provitamin A and vitamin A from diet and supplements was equivalent to 22 , 220 , and 175 μg retinol , respectively . Both yellow cassava and β-carotene supplementation increased serum retinol concentration by 0.04 μmol/L ( 95 % CI : 0.00 , 0.07 μmol/L ) ; correspondingly , serum β-carotene concentration increased by 524 % ( 448 % , 608 % ) and 166 % ( 134 % , 202 % ) . We found no effect on hemoglobin concentration or serum concentrations of retinol-binding protein and prealbumin . CONCLUSIONS In our study population , consumption of yellow cassava led to modest gains in serum retinol concentration and a large increase in β-carotene concentration . It can be an efficacious , new approach to improve vitamin A status . This study was registered with clinical trials.gov as NCT01614483 [18559131] OBJECTIVE To determine whether an educational programme aim ed at discouraging students from drinking sugar-sweetened beverages could prevent excessive weight gain . DESIGN Forty-seven classes in twenty-two schools were r and omised as intervention or control . SUBJECTS Participants were 1140 , 9 - 12-year-old fourth grade rs ( 435 in the intervention group and 608 in the control group ) . Sugar-sweetened beverages and juice intake were measured through one 24 h recall at baseline and another at the end of the trial . The main outcome was the change in BMI ( BMI = weight (kg)/height ( m2 ) ) , measured at the beginning and at the end of the school year . Intention-to-treat analysis was performed taking into account the cluster ( classes ) effect . RESULTS A statistically significant decrease in the daily consumption of carbonated drinks in the intervention compared to control ( mean difference = -56 ml ; 95 % CI -119 , -7 ml ) was followed by a non-significant overall reduction in BMI , P = 0.33 . However , among those students overweight at baseline , the intervention group showed greater BMI reduction ( -0.4 kg/m2 compared with -0.2 kg/m2 in the control group ( P = 0.11 ) ) , and this difference was statistically significant among girls ( P = 0.009 ) . Fruit juice consumption was slightly increased in the intervention group ( P = 0.08 ) , but not among girls . CONCLUSION Decreasing sugar-sweetened beverages intake significantly reduced BMI among overweight children , and mainly among girls . Efforts to reduce energy intake through liquids need to emphasise overall sweetened beverages and addition of sugar on juices [18381508] BACKGROUND . The prevalence and seriousness of childhood obesity has prompted calls for broad public health solutions that reach beyond clinic setting s. Schools are ideal setting s for population -based interventions to address obesity . OBJECTIVE . The purpose of this work was to examine the effects of a multicomponent , School Nutrition Policy Initiative on the prevention of overweight ( 85.0th to 94.9th percentile ) and obesity ( > 95.0th percentile ) among children in grade s 4 through 6 over a 2-year period . METHODS . Participants were 1349 students in grade s 4 through 6 from 10 schools in a US city in the Mid-Atlantic region with ≥50 % of students eligible for free or reduced-price meals . Schools were matched on school size and type of food service and r and omly assigned to intervention or control . Students were assessed at baseline and again after 2 years . The School Nutrition Policy Initiative included the following components : school self- assessment , nutrition education , nutrition policy , social marketing , and parent outreach . RESULTS . The incidences of overweight and obesity after 2 years were primary outcomes . The prevalence and remission of overweight and obesity , BMI z score , total energy and fat intake , fruit and vegetable consumption , body dissatisfaction , and hours of activity and inactivity were secondary outcomes . The intervention result ed in a 50 % reduction in the incidence of overweight . Significantly fewer children in the intervention schools ( 7.5 % ) than in the control schools ( 14.9 % ) became overweight after 2 years . The prevalence of overweight was lower in the intervention schools . No differences were observed in the incidence or prevalence of obesity or in the remission of overweight or obesity at 2 years . CONCLUSION . A multicomponent school-based intervention can be effective in preventing the development of overweight among children in grade s 4 through 6 in urban public schools with a high proportion of children eligible for free and reduced-priced school meals [9241285] Objective To determine whether increased calcium intake ( 2 g/day ) in pregnancy is effective in reducing the risk of preeclampsia in pregnant teenagers . Methods The present study was a prospect i ve , r and omized , double-blind , controlled clinical trial . Two hundred sixty teenaged pregnant girls attending the Hospital Gíneco-Obstétrico Isidro Ayora in Quito , Ecuador , were included . Selection criteria were age less than 17.5 years , nulliparity , first prenatal visit before 20 weeks ' gestation , and residency in Quito ( 2800-m altitude ) . We used a table of r and om numbers to assign 125 girls to receive 2000 mg of elemental calcium daily , beginning at 20 weeks of gestation and continuing until delivery ; 135 women in the control group received a placebo . Blood pressure ( BP ) was measured twice every 4 weeks until delivery and at 48 hours after delivery . The diagnosis of preeclampsia was defined as BP greater than 140/90 mmHg on at least two occasions more than 6 hours apart and proteinuria greater than 30 mg/dL ( over one cross by dipstick on two occasions 4 - 24 hours apart ) . Results The average daily calcium intake in this population was approximately 51 % of the Recommended Dietary Allowance . Calcium supplementation was associated with a significantly decreased risk of preeclampsia ( risk reduction 12.35 % ; P < .001 ) , with 3.2 % ( n = 4 ) developing preeclampsia in the treatment group versus 15.5 % ( n = 21 ) in the placebo group . Moreover , calcium supplementation led to a reduction in systolic BP of 9.1 mmHg and in diastolic BP of 6.0 mmHg . Conclusion These results suggest that calcium supplementation during pregnancy in population s with low calcium intake is a safe , effective , and inexpensive preventive measure that significantly reduces the risk of preeclampsia [22423669] BACKGROUND / PURPOSE The prevalence of obesity and overweight among children and adolescents is increasing rapidly . The present research was performed to determine the influence of a ' ' behavior modification ' ' program on body mass index ( BMI ) in obese public high school students in Iran . METHODS In this study , 152 adolescence and their parents were selected from 12 high schools of Khorram Abad from 2004 to 2006 , and they were r and omly assigned to either the intervention or the control groups . The " behavior modification " interventional program consisted of nutritional education , modifying dietary habits , teaching exercise programs , teaching nutritional facts to the parents , and performing exercises 3 days a week . The height and weight as well as waist , hip , and wrist circumferences of the participants were measured before and after implementing the interventional program . BMI and waist to hip ratio ( WHR ) were calculated . The adolescents and parents completed a nutrition knowledge question naire . Adolescents also completed the Beck 's Depression Question naire . RESULTS Adolescent 's mean weight , BMI , and waist and hip circumferences decreased significantly after implementing the interventional program , in the intervention group ( p≤0.001 ) . In addition , the students ' and parents ' nutrition knowledge increased in the intervention group after implementing the interventional program ( p<0.046 ) . The symptoms of depression decreased and the frequency of students without symptoms of depression increased in the case group , but it did not reveal a statistically significant difference between case and control groups . CONCLUSION The ' ' behavior modification ' ' interventional program is effective in reducing BMI in obese students , and therefore , school principals and planners can play an important role in controlling obesity by implementing this program via the students , their parents , and the school staff [17928808] Background / Objectives : Iron deficiency anemia is a major public health problem in developing countries and may affect school performance and physical work capacity in nonpregnant adolescents , and may increase the risk of anemia during subsequent teenage pregnancies . We assessed the effect of weekly iron ( 120 mg elemental iron ) and vitamin A ( 25 000 IU ) supplementation on hemoglobin , iron status and malaria and nonmalaria morbidity in adolescent schoolgirls . Subjects/ Methods : A total of 279 schoolgirls aged 12–18 years from public primary schools in Kisumu , western Kenya . Double-blind r and omized placebo-controlled trial using a factorial design . Results : Five months of iron supplementation was associated with a 0.52 g dl−1 ( 0.21 , 0.82 ) greater increase in hemoglobin relative to iron placebo . The effect was only observed in girls with iron deficiency on enrollment ( 1.34 g dl−1 ( 0.79 , 1.88 ) ) , but not in iron-replete girls ( −0.20 g dl−1 ( −0.59 , 0.18 ) ) . Similar differences in treatment effect were seen between menstruating and nonmenstruating girls . The effect of iron was independent of vitamin A. The baseline prevalence of vitamin A deficiency was low ( 6.7 % ) and no sustained increase in hemoglobin was seen with weekly vitamin A ( −0.07 g dl−1 ( −0.38 , 0.25 ) ) . Incidence of malaria parasitemia was higher in the iron than iron-placebo groups ( Rate ratio 1.33 ( 0.94 , 1.88 ) ) . Conclusions : Weekly iron supplementation results in substantial increases in hemoglobin concentration in adolescent schoolgirls in western Kenya , which may outweigh possible risks caused by malaria , but only in iron-deficient or menstruating girls and not in iron-replete and nonmenstruating girls [16733670] Introduction Prevention of obesity and overweight is an important target for health promotion . Early prevention requires an intervention during childhood and adolescence . At these stages , the game could be an appropriate means to teach nutrition knowledge and to influence dietary behaviour . To this end , the authors developed Kalèdo , a new board-game . Objective The aim of the present study was to test the efficacy of Kalèdo on changes in nutrition knowledge and dietary behaviour in a pilot study conducted in three middle schools in Naples , Italy . Material s and Methods A simple two-group design ( treatment and control ) with pre- and post- assessment was employed . The classroom was the unit of recruitment and r and om assignment to groups . All students ( 307 ) in the participating schools were invited to participate . Data analysis was performed on 241 subjects . During 24 weeks , a group of 153 children from 8 classrooms ( 11–14 year old Caucasian subjects ; 78 male , 75 female ) was involved in 15–30 minute-long play sessions once a week . A question naire was given to the participants at the beginning and at the end of the study to evaluate nutrition knowledge ( 31 questions ) , physical activity ( 8 questions ) and food intake ( 34 questions ) . Anthropometric measurements were also carried out . A second group of 88 children from 5 classrooms ( same age and ethnicity ; 55 male , 33 female ) was investigated at the same times with the same question naire and anthropometric measures but they did not receive any play sessions with Kalèdo . ObservationChildren playing Kalèdo showed a significant increase in nutrition knowledge ( p<0.05 ) and in weekly vegetable intake ( p<0.01 ) with respect to the control . Conclusion The results suggest that Kalèdo could be an effective instrument to teach children about healthy diet . More research is needed to study the long term effect of this intervention [11424510] AIM To investigate the effect of weekly iron supplementation on anaemia and iron deficiency among adult , female tea pluckers . METHOD A r and omized double-blind intervention trial was conducted in a tea estate in Bangladesh where a total of 280 women received either weekly iron supplementation ( 200 mg ferrous fumarate and 200 mg folic acid ) for 24 weeks or a matching placebo . Capillary blood sample s were drawn at baseline and post-trial to determine haemoglobin , haematocrit and ferritin concentration . Mean corpuscular haemoglobin concentration ( MCHC ) was calculated using the haemoglobin and haematocrit values . RESULTS The mean haemoglobin concentration in the supplemented group increased by 5.52 g L-1 over the study period , on average , while ferritin values decreased by 0.33 microgram L-1 . The control group showed a decrease in both mean haemoglobin ( -0.24 g L-1 ) and ferritin ( -5.32 micrograms L-1 ) . Those individuals in the supplemented group with the lowest pretrial haemoglobin and ferritin values experienced the greatest improvements post-trial , whereas nonanaemic individuals showed a decrease in both haemoglobin and ferritin concentrations . A total of 62.2 % of women in the supplemented group reported feeling better and more energetic compared to 51.1 % in the placebo group ; 14.4 % of the supplemented group and 22.7 % of the control group complained about side-effects . CONCLUSION Weekly iron supplementation was logistically simpler and cheaper than daily supplementation but would have to be continued on a longer term basis in order to combat both anaemia and iron deficiency [16946216] OBJECTIVE : To evaluate the effects of dietary calcium ( Ca ) intervention on adolescent pregnant mothers and their newborns . METHODS : Seventy-two pregnant adolescent mothers were r and omized into one of 3 groups : control , orange juice fortified with calcium , and dairy . The orange juice and dairy groups were required to take more than 1,200 mg Ca . Calcium tablets were added for those not able to meet required Ca . Maternal and infant weight , length , and blood pressure ( BP ) were recorded . Maternal dietary records were evaluated . Mother ’s blood was drawn for serum Ca , phosphate ( P ) , magnesium ( Mg ) , and vitamin 25-hydroxyvitamin D ( D ) . Cord blood was collected for serum Ca and D. Newborn total body Ca was determined . RESULTS : All mothers were similar in weight , height , and BP . Mothers in the orange juice plus calcium and dairy groups had higher intakes of Ca ( 1,472 mg and 1,771 mg ) than controls ( 862 mg ) . One half of the mothers in the orange juice plus calcium group required Ca tablets . Mothers in the dairy group had higher intakes of P , D , and Mg , higher serum folate and D , and higher cord D levels . Mothers in the orange juice plus calcium group had higher serum P but lower serum folate and D. Infants ( 3,517±273 g ) in the dairy group were heavier than infants in the control ( 3,277±177 g ) and orange juice plus calcium ( 3,292±165 g ) groups . Infants in the dairy group had higher total body calcium than control infants . CONCLUSION : Calcium diet supplemented with dairy products during adolescent pregnancy result ed in higher maternal vitamin D and folate serum levels and higher newborn weight and bone mineralization compared with controls . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00320125 LEVEL OF EVIDENCE : [19781127] OBJECTIVE To assess the short-term ( 15-d ) and long-term ( 12-month ) effects of a school-based health and nutrition education intervention on diet , nutrition intake and BMI . DESIGN The 12-week teacher-implemented intervention in combination with seminars organized for parents was aim ed at improving children 's diet and nutrition knowledge . The intervention took place between September 2007 and January 2008 . The participants were r and omized to two study groups , the intervention group ( IG ) and control group ( CG ) , and were examined prior to the intervention on a variety of health knowledge , dietary , behavioural and anthropometric indices . The same measurements were collected 15 d and 1 year after the intervention . SETTING All high schools in Vyronas , a densely populated district of Athens , Greece . SUBJECTS The sample consisted of 191 students aged 12 - 13 years . RESULTS Twelve months after the intervention , the programme was effective in reducing various indices in the IG compared with baseline findings ( BMI : 23.3 ( sd 2.8 ) v. 24.0 ( sd 3.1 ) kg/m2 , P < 0.001 ; daily energy intake : 8112.4 ( sd 1412.4 ) v. 8503.3 ( sd 1419.3 ) kJ/d , P < 0.001 ; total fat intake : 31.3 ( sd 4.4 ) v. 35.4 ( sd 4.7 ) % of daily energy , P < 0.001 ) . Except for BMI , decreases in the aforementioned indices were also observed 15 d after the intervention . In addition , students of the IG reduced their weekly consumption of red meat and non-home-made meals and increased their frequency of fruit and breakfast cereal consumption . CONCLUSIONS The beneficial effects of this nutrition education intervention among adolescents may highlight the potential of such programmes in the prevention of obesity [12736400] OBJECTIVE To examine the benefits of anemia prophylaxis in adolescent school.girls by weekly or daily iron-folate supplementation . DESIGN Prospect i ve study . SETTING Government girl schools of northeast Delhi . SUBJECTS 2088 subjects ( with hemoglobin greater than 7.9 g/dL ) , including 702 on daily and 695 on weekly iron-folate administration ; 691 girls served as controls . RESULTS About 85 % girls were iron deficient out of which 49.3 % were anemic . Weekly administration took longer time to raise hemoglobin but was effective as well as practical . Plasma ferritin estimation in girls showed rise in level in both the treated groups . CONCLUSION Weekly administration of iron-folate was a practical and effective strategy for anemia prophylaxis in adolescent school girls [12700794] Zinc and folic acid nutritional status was evaluated in 74 low-income pregnant adolescents ranging from 13 to 18 years of age who received prenatal care at the Evangelina Rosa Maternity Hospital in Teresina , Piau State , Brazil . In order to evaluate the effects of different supplementation regimens on nutritional status , the adolescents were distributed into five groups . Groups I and II received equal amounts of folic acid ( 250 micro;g ) and different doses of iron ( ferrous sulfate ) , 120 and 80 mg , respectively . Groups III and IV received equal amounts of folic acid ( 250 micro;g ) associated with zinc sulfate and iron at doses of 120 and 80 mg , respectively , while group V received only 120 mg of iron ( routine dosage ) . There was a reduction in the zinc plasma concentration , and this decline was significant only in those groups which did not receive zinc supplementation . In relation to combination iron/folic acid and iron/folic acid/zinc , an excellent response was observed for folic acid , and this effect was larger in the groups that received folic acid combined with zinc , suggesting a possible role for zinc in folic acid metabolism [17522609] Objective : To determine the effectiveness of combined iron and zinc over the iron or zinc-only supplementation in correcting deficiency and possible interactive effects in a group of adolescent school children . Subjects and methods : Schoolchildren ( n=821 ) of 12–16 years of age were r and omized into four groups and supplemented with iron ( 50 mg/day ) , zinc ( 14 mg/day ) , iron+zinc or placebo capsules 5 days per week for 24 weeks . Anthropometry , and haemoglobin ( Hb ) , serum zinc ( SZn ) and serum ferritin ( SF ) concentrations were determined before and after the intervention . Results : There were no significant effects between-groups in their weight , height and Hb concentrations with the intervention when compared with the placebo group . Iron-only and combination-supplemented groups had reached mean SF concentrations of 55.1 μg/l with no difference between them ( P=0.99 ) . The zinc-only group had a mean change of 4.3 μmol//l whereas the combine-supplemented group had a mean change of 4.0 μmol/l ( P=0.82 ) . The prevalence of anaemia was found to be 70.3 % in the iron group at baseline ; this was reduced to 14.5 % after the supplementation . In the combine-supplemented group anaemia , prevalence was reduced from 64.8 to 19.3 % . Conclusions : Zinc alone or in combination with iron has not shown a significant improvement in growth in adolescence . Severe and moderate forms of anaemia were successfully treated in children who received iron supplementation . Initial high prevalence of low SZn and iron stores was significantly improved with micronutrient supplementation [15164114] Objective : High prevalences of vitamin A deficiency and anaemia among adolescents warrant interventions . This study evaluated the effectiveness of school-based supplementation to reduce anaemia and improve vitamin A status . Design : School-based , grade -r and omized , intervention . Subjects and setting : In all , 1757 girls and 1859 boys , aged 12–15 y , in 24 Junior High Schools . Interventions : Weekly supplementation for 14 weeks with 60 mg iron and 250 μg folate ( Fe group ; n=978 ) , 10 000 IU vitamin A ( VA group ; n=970 ) or both ( VAFe group ; n=1042 ) to subjects in 15 schools , compared to subjects in nine other schools not receiving supplements ( control ; n=626 ) . Results : The baseline anaemia prevalence ( Hb < 120 g/l ) in girls was 20 % ( prepubertal ) and 26 % ( pubertal ) , and in boys 24 % ( pre-pubertal ) and 11 % ( pubertal ) . Serum retinol concentrations were low ( < 1.05 μmol/l ) in 41 % of boys and 45 % of girls . The interventions did not increase haemoglobin concentrations . Serum retinol concentration of boys , but not girls , in the VA group increased ( 0.33 vs 0.07 μmol/l in controls ; P<0.01 ) . The risk factors for low serum retinol concentration were lower baseline serum retinol concentration ( OR 0.02–0.03 ) with , for girls , nightblindness at baseline ( OR 5.88 ) , and for boys , not receiving vitamin A ( OR control : 1.00 ; VA : 0.37 ; Fe : 0.77 ; VAFe : 0.34 ) and maternal illiteracy ( OR mother never attended school 1.00 , mother received any formal education 0.17–0.33 ) . Conclusions : Supplementation with vitamin A increased serum retinol concentration of boys . Iron supplementation did not change Hb . This appeared to be due to poor compliance , and partly related to side effects . Sponsorship : This study was funded by USAID through the OMNI Project [22566517] OBJECTIVE To evaluate the impact of a 12-month multicomponent school-based obesity prevention program , Nutrition and Enjoyable Activity for Teen Girls among adolescent girls . DESIGN Group r and omized controlled trial with 12-month follow-up . SETTING Twelve secondary schools in low-income communities in the Hunter and Central Coast regions of New South Wales , Australia . PARTICIPANTS Three hundred fifty-seven adolescent girls aged 12 to 14 years . INTERVENTION A multicomponent school-based intervention program tailored for adolescent girls . The intervention was based on social cognitive theory and included teacher professional development , enhanced school sport sessions , interactive seminars , nutrition workshops , lunch-time physical activity sessions , h and books and pedometers for self-monitoring , parent newsletters , and text messaging for social support . MAIN OUTCOME MEASURES Body mass index ( BMI , calculated as weight in kilograms divided by height in meters squared ) , BMI z score , body fat percentage , physical activity , screen time , dietary intake , and self-esteem . RESULTS After 12 months , changes in BMI ( adjusted mean difference , -0.19 ; 95 % CI , -0.70 to 0.33 ) , BMI z score ( mean , -0.08 ; 95 % CI , -0.20 to 0.04 ) , and body fat percentage ( mean , -1.09 ; 95 % CI , -2.88 to 0.70 ) were in favor of the intervention , but they were not statistically different from those in the control group . Changes in screen time were statistically significant ( mean , -30.67 min/d ; 95 % CI , -62.43 to -1.06 ) , but there were no group by time effects for physical activity , dietary behavior , or self-esteem . CONCLUSIONS A school-based intervention tailored for adolescent girls from schools located in low-income communities did not significantly reduce BMI gain . However , changes in body composition were of a magnitude similar to previous studies and may be associated with clinical ly important health outcomes . TRIAL REGISTRATION anzctr.org.au Identifier : 12610000330044 [22590964] Background Studies in India have reported a high prevalence of nutritional anemia among children and adolescent girls . Nutritional anemia is associated with impaired mental , physical , and cognitive performance in children and is a significant risk factor for maternal mortality . Objective To evaluate the effect of a community-led initiative for control of nutritional anemia among children 6 to 35 months of age and unmarried rural adolescent girls 12 to 19 years of age . Methods This Participatory Action Research was done in 23 villages of the Primary Health Centre , Anji , in Wardha District of Maharashtra . In February and March 2008 , needs assessment was undertaken by interviewing the mothers of 261 children and 260 adolescent girls . Hemoglobin levels of adolescent girls and children were measured with the use of the hemoglobin color scale . The girls were given weekly iron — folic acid tablets , and the children were given daily liquid iron prophylaxis for 100 days in a year through community participation . The adolescent girls and the mothers of the children and adolescent girls were also given nutritional education on the benefits and side effects of iron supplementation . In June and July 2008 , follow-up assessment was performed by survey and force field analysis . Results There was a significant reduction in the prevalence of nutritional anemia from 73.8 % to 54.6 % among the adolescent girls and from 78.2 % to 64.2 % among the children . There was improvement in awareness of iron-rich food items among the adolescent girls and the mothers of the children . The benefits to girls , such as increase in appetite and reduction in scanty menses , tiredness , and weakness , acted as positive factors leading to better compliance with weekly iron supplementation . The benefits to children perceived by the mothers , such as increase in appetite , weight gain , reduction in irritability , and reduction in mud-eating behavior , acted as a dominant positive force and generated dem and for iron syrup . Conclusions The community-led initiative for once-weekly iron supplementation for adolescent girls and iron prophylaxis for children , in addition to nutritional education , improved the hemoglobin status of children 6 to 35 months of age and unmarried rural adolescent girls 12 to 19 years of age [11890637] To investigate the efficacy of two different iron supplements administered either on a weekly basis or during menstruation , a 16-week community experimental study was carried out among postmenarcheal female adolescent students in Kupang , East Nusa Tenggara , Indonesia . Forty eight students received a placebo tablet weekly , 48 other students got an iron tablet weekly and 41 students took an iron tablet for four consecutive days during their menstruation cycle . All subjects were given deworming tablets before supplementation . Haemoglobin , serum ferritin , height , weight , mid-upper arm circumference and dietary intake were assessed before and after intervention . The supplementation contributed to a significant improvement in the iron status of the intervention groups compared to the placebo group ( P < 0.05 ) . In the menstruation group , the haemoglobin concentrations of the anaemic subjects improved significantly ( P < 0.05 ) while for the non-anaemic subjects , serum ferritin concentrations also increased significantly ( P < 0.05 ) . In the weekly group for anaemic and nonanaemic subjects , there was a significant increase in both haemoglobin and serum ferritin concentrations ( P < 0.05 ) . This study revealed that weekly supplementation of iron tablets continued for 16 weeks contributed a higher improvement to haemoglobin concentration , compared with supplementing iron tablets for four consecutive days during menstruation for four menstrual cycles . This suggests that weekly iron supplementation is preferable [11814373] OBJECTIVE To compare the effectiveness of weekly vs daily iron and folic acid supplementation for control of anemia in adolescent Nepalese girls . DESIGN R and omized controlled trial . SETTING A Government Girl School in Dharan , Nepal , an urban foothill town that is 305 m above sea level . SUBJECTS Consecutive healthy adolescent girls ( n = 209 , median age 15 years ) r and omized to 3 groups matched for age , anthropometry , and personal and sociodemographic characteristics . Of 209 subjects , 181 completed the trial . Two girls had adverse reactions to treatment and were excluded . INTERVENTION Group A ( n = 70 ) received a 350-mg ferrous sulfate and 1.5-mg folic acid combination once daily for 90 to 100 days . Group B ( n = 67 ) received the tablet under supervision once a week for 14 weeks . Group C ( n = 72 ) did not receive any drugs . OUTCOME VARIABLE Presupplementation and postsupplementation differences in prevalence of anemia and change in hematocrit . RESULTS Prevalence of anemia ( defined as hematocrit < 36 % ) declined from 68.6 % and 70.1 % in groups A and B to 20 % and 13.4 % , respectively , postsupplementation ( P<.001 ) , whereas the prevalence in group C changed little ( 68.1 % to 65.3 % , P = .81 ) . There was a significant rise in the mean hematocrit of both supplemented groups ( group A , 32.9 % + /- 3.5 % to 41.0 % + /- 5.6 % , P<.001 ; group B , 33.2 % + /- 3.6 % to 40.4 % + /- 4.9 % , P<.001 ) but no appreciable change in controls ( 34.2 % + /- 2.9 % to 34.1 % + /- 3.3 % , P = .91 ) . Net change in mean hematocrit in both the supplementation groups was comparable ( P = .57 ) . CONCLUSIONS The prevalence of anemia in adolescent Nepalese girls is high . Supervised iron and folic acid therapy once a week is an effective alternative to daily administration and helps lower the prevalence of anemia in adolescent girls [16753014] UNLABELLED The effect of vitamin D supplementation on bone mineral augmentation in 212 adolescent girls with adequate calcium intake was studied in a r and omized placebo-controlled setting . Bone mineral augmentation determined by DXA increased with supplementation both in the femur and the lumbar vertebrae in a dose-responsive manner . Supplementation decreased the urinary excretion of resorption markers , but had no impact on formation markers . INTRODUCTION Adequate vitamin D intake protects the elderly against osteoporosis , but there exists no indisputable evidence that vitamin D supplementation would benefit bone mineral augmentation . The aim of this 1-year study was to determine in a r and omized double-blinded trial the effect of 5 and 10 microg vitamin D3 supplementation on bone mineral augmentation in adolescent girls with adequate dietary calcium intake . MATERIAL S AND METHODS Altogether , 228 girls ( mean age , 11.4 + /- 0.4 years ) participated . Their BMC was measured by DXA from the femur and lumbar spine . Serum 25-hydroxyvitamin D [ S-25(OH)D ] , intact PTH ( S-iPTH ) , osteocalcin ( S-OC ) , and urinary pyridinoline ( U-Pyr ) and deoxypyridinoline ( U-Dpyr ) were measured . Statistical analysis was performed both with the intention-to-treat ( IT ) and compliance-based ( CB ) method . RESULTS In the CB analysis , vitamin D supplementation increased femoral BMC augmentation by 14.3 % with 5 microg and by 17.2 % with 10 microg compared with the placebo group ( ANCOVA , p = 0.012 ) . A dose-response effect was observed in the vertebrae ( ANCOVA , p = 0.039 ) , although only with the highest dose . The mean concentration of S-25(OH)D increased ( p < 0.001 ) in the 5-microg group by 5.7 + /- 15.7 nM and in the 10-microg group by 12.4 + /- 13.7 nM , whereas it decreased by 6.7 + /- 11.3 nM in the placebo group . Supplementation had no effect on S-iPTH or S-OC , but it decreased U-DPyr ( p = 0.042 ) . CONCLUSIONS Bone mineral augmentation in the femur was 14.3 % and 17.2 % higher in the groups receiving 5 and 10 microg of vitamin D , respectively , compared with the placebo group , but only 10 mug increased lumbar spine BMC augmentation significantly . Vitamin D supplementation decreased the concentration of bone resorption markers , but had no impact on bone formation markers , thus explaining increased bone mineral augmentation . However , the positive effects were noted with the CB method but not with IT [22244349] The present study examined whether long-term supplementation with once- and twice-weekly multiple micronutrients ( MMN-1 and MMN-2 ) can improve Hb and micronutrient status more than twice-weekly Fe-folic acid ( IFA-2 ) supplementation in non-anaemic adolescent girls in Bangladesh . An equal number of 324 rural schoolgirls aged 11 - 17 years were given MMN-1 or MMN-2 or IFA-2 supplements for 52 weeks in a r and omised , double-blind trial . Blood sample s were collected at baseline , and at 26 and 52 weeks of supplementation . The girls receiving IFA-2 supplements were more likely to be anaemic than the girls receiving MMN-2 supplements for 26 weeks ( OR 5·1 , 95 % CI 1·3 , 19·5 ; P = 0·018 ) . All three supplements reduced Fe deficiency effectively . Both the MMN-1 and MMN-2 groups showed significantly greater improvements in vitamins A , B(2 ) and C status than the girls in the IFA-2 group , as might be expected . Receiving a MMN-1 supplement was found to be less effective than MMN-2 supplement in improving Fe , vitamins A , B(2 ) and folic acid status . Receiving micronutrient supplements beyond 26 weeks showed little additional benefit in improving micronutrient status . In conclusion , given twice-weekly for 26 weeks , MMN supplements can improve micronutrient status effectively with no significant increase in Hb concentration compared with IFA supplements in non-anaemic Bangladeshi adolescent girls . However , it significantly reduces the risk of anaemia . Before any recommendations can be made , further research , including into cost-effectiveness , is needed to see whether MMN supplementation has any additional longer-term health benefits over that of IFA supplementation in this population [16340950] Objective : To investigate whether iron supplementation can improve thyroid hormone function in iron-deficient adolescent girls . Design : A double-blind r and omized intervention study . Setting : The study was performed from 2002 through 2003 in the Islamic Republic of Iran . Subjects:103 iron-deficient non-anaemic girls who fulfilled all inclusion criteria were included , and 94 subjects successfully completed the study . Interventions : Patients were r and omly assigned to one of four groups and treated with a single oral dose of 190 mg iodine plus 300 mg ferrous sulphate 5 times/week ( n=24 ) , 300 mg ferrous sulphate 5 times/week ( n=23 ) , a single oral dose of 190 mg iodine ( n=25 ) , or a placebo ( n=22 ) for 12 weeks . Results : All groups were comparable at baseline . After the intervention , there was a significant increase in ferritin and transferrin saturation in the iron+iodine group ( 17.6 vs 8.7 μg/dl , and 18.8 vs 7.2 % , respectively , P<0.001 for both ) and in the iron group ( P<0.001 for both ) . Urinary iodine doubled in the iron+iodine group and in the iodine group ( P<0.001 for both ) . Thyroid indices tT4 , tT3 and T3RU increased and reverse RT3 decreased in the iron+iodine group ( 10 vs 8.9 μg/dl , P < 0.001 ; 143 vs 138 μg/dl , P<0.05 ; 32.3 vs 28.4 % , P<0.001 and 24.8 vs 44.2 ng/dl , P<0.001 , respectively ) and in the iron group . These two groups did not differ for any of the four indices , but both differed significantly from the iodine and placebo groups . Conclusions : Our results indicate that improvement of iron status was accompanied by an improvement in some indices of thyroid hormones . Sponsorship : This study was supported by the Dean of Research Affairs of the Tehran University of Medical Sciences [25441960] Adolescents with intellectual and developmental disabilities ( IDD ) are at an increased risk of obesity , with up to 55 % considered overweight and 31 % obese . However , there has been minimal research on weight management strategies for adolescents with IDD . The purpose of this study was to compare the effectiveness of two weight loss diets , an enhanced Stop Light Diet ( eSLD ) and a conventional diet ( CD ) , and to determine the feasibility of using tablet computers as a weight loss tool in overweight and obese adolescents with IDD . A 2-month pilot intervention was conducted . All participants were r and omized to the eSLD or CD and were given a tablet computer that they used to track daily dietary intake and physical activity . Participants and parents met weekly with a registered dietitian nutritionist via video chat on the tablet computer to receive diet and physical activity feedback and education . Twenty participants ( 45 % female , aged 14.9±2.2 years ) were r and omized and completed the intervention . Participants in both diets were able to lose weight , and there were no significant differences between the eSLD and CD ( -3.89±2.66 kg vs -2.22±1.37 kg ) . Participants were able to use the tablet computer to track their dietary intake 83.4%±21.3 % of possible days and to attend 80.0 % of the video chat meetings . Both dietary interventions appear to promote weight loss in adolescents with IDD , and the use of tablet computers appears to be a feasible tool to deliver a weight loss intervention in adolescents with IDD [11123827] We evaluated the effect of weekly doses of 400 mg of ferrous sulphate for 4 months on the iron status of adolescent girls in a controlled trial in Tanga , Tanzania . Supplementation led to a significantly greater increase in serum ferritin compared with the control group ( + 15.6 microg/l vs. 8.6 microg/l ) ( P = 0.002 ) but there was no significant difference in change in haemoglobin . Children given iron showed a significantly greater weight gain than controls ( + 2.4 kg vs. + 1.4 kg ) ( P = 0.03 ) . Weekly iron supplementation may be an effective means of increasing iron stores and growth in children vulnerable to iron deficiency [26764317] BACKGROUND In India , the prevalence of low birth weight is high in women with a low body mass index ( BMI ) , suggesting that underweight women are not capable of providing adequate energy and protein for fetal growth . Furthermore , as pregnancy progresses , there is increased need to provide methyl groups for methylation reactions associated with the synthesis of new proteins and , unlike normal- BMI American women , low- BMI Indian women are unable to increase methionine transmethylation and remethylation rates as pregnancy progresses from trimester 1 to 3 . This also negatively influences birth weight . OBJECTIVE The aim was to determine the effect of dietary supplementation with energy and protein from 12 ± 1 wk of gestation to time of delivery compared with no supplement on pregnancy outcomes , protein kinetics , and the fluxes of the methyl group donors serine and glycine . METHODS Protein kinetics and serine and glycine fluxes were measured by using st and ard stable isotope tracer methods in the fasting and postpr and ial states in 24 pregnant women aged 22.9 ± 0.7 y with low BMI s [ BMI ( in kg/m(2 ) ) ≤18.5 ] at 12 ± 1 wk ( trimester 1 ) and 30 ± 1 wk ( trimester 3 ) of gestation . After the first measurement , subjects were r and omly assigned to either receive the supplement ( 300 kcal/d , 15 g protein/d ) or no supplement . RESULTS Supplementation had no significant effect on any variable of pregnancy outcome , and except for fasting state decreases in leucine flux ( 125 ± 7.14 compared with 113 ± 5.06 μmol ⋅ kg(-1 ) ⋅ h(-1 ) ; P = 0.04 ) and nonoxidative disposal ( 110 ± 6.97 compared with 101 ± 3.69 μmol ⋅ kg(-1 ) ⋅ h(-1 ) ; P = 0.02 ) from trimesters 1 to 3 , it had no effect on any other leucine kinetic variable or urea , glycine , and serine fluxes . CONCLUSION We conclude that in Indian women with a low BMI , supplementation with energy and protein from week 12 of pregnancy to time of delivery does not improve pregnancy outcome , whole-body protein kinetics , or serine and glycine fluxes [11975370] A nutritionally controlled study was conducted on two groups of 15 female college students aged 16 to 20 years , selected from Punjab Agricultural University , Ludhiana , Punjab , India . the girls were either anemic ( hemoglobin 7.7 g/dl ) but energy adequate ( AEA ) , or anemic ( hemoglobin 7.4 g/dl ) and energy deficient ( AED ) . the AEA group was given iron supplementation ( 60 mg iron/day ) for 6 to 9 months along with 100 mg of ascorbic acid , and the AED group was given iron as well as energy supplementation for 3 months . There was a significant ( p < .01 ) increase in weight , body mass index , mid-upper-arm circumference , and body fat in the AED group after iron – energy supplementation . Hemoglobin , serum iron , transferrin saturation , total iron-binding capacity , and unsaturated iron-binding capacity were below normal in both groups ; however , after iron and iron – energy supplementation , there was a significant ( p < .01 ) increase , and these indices were in the normal range . There was a significant ( p < .01 ) increase in exercise time and maximum work load tolerance after iron and iron – energy supplementation . Combined energy and iron deficiency had a greater adverse effect on physical work capacity than energy or iron deficiency alone [20702745] Previous short-term supplementation studies showed no additional hematologic benefit of multiple micronutrients ( MMN ) compared with iron + folic acid ( IFA ) in adolescent girls . This study examines whether long-term once- or twice-weekly supplementation of MMN can improve hemoglobin ( Hb ) and micronutrient status more than twice-weekly IFA supplementation in anemic adolescent girls in Bangladesh . Anemic girls ( n = 324 ) aged 11 - 17 y attending rural schools were given once- or twice-weekly MMN or twice-weekly IFA , containing 60 mg iron/dose in both supplements , for 52 wk in a r and omized double-blind trial . Blood sample s were collected at baseline and 26 and 52 wk . Intent to treat analysis showed no significant difference in the Hb concentration between treatments at either 26 or 52 wk . However , after excluding girls with hemoglobinopathy and adjustment for baseline Hb , a greater increase in Hb was observed with twice-weekly MMN at 26 wk ( P = 0.045 ) . Although all 3 treatments effectively reduced iron deficiency , once-weekly MMN produced significantly lower serum ferritin concentrations than the other treatments at both 26 and 52 wk . Both once- and twice-weekly MMN significantly improved riboflavin , vitamin A , and vitamin C status compared with IFA . Overall , once-weekly MMN was less efficacious than twice-weekly MMN in improving iron , riboflavin , RBC folic acid , and vitamin A levels . Micronutrient supplementation beyond 26 wk was likely important in sustaining improved micronutrient status . These findings highlight the potential usefulness of MMN intervention in this population and have implication s for programming [12003652] OBJECTIVE To assess the effect on the haemoglobin concentrations of schoolchildren of weekly iron tablets administered by teachers . DESIGN Sixty schools were r and omly assigned to two groups : in 30 schools children were given weekly for 10 weeks a tablet providing 65 mg of iron and 0.25 mg of folic acid ; in the other 30 schools no iron tablets were given . All children were dewormed and given vitamin A before the study began . The haemoglobin concentration of up to 20 r and omly selected children in each school was estimated before and 2 weeks after the end of treatment . SETTING Rural community schools in Kolondieba district of Mali . SUBJECTS Some 1113 schoolchildren aged 6 - 19 years with a mean of 11.4 years . RESULTS The haemoglobin concentration of treated children rose on average by 1.8 g l(-1 ) and the prevalence of anaemia fell by 8.2 % ; in untreated children the haemoglobin concentration fell by an average of -2.7 g l(-1 ) and the prevalence of anaemia rose by 9.4 % . The fall in haemoglobin concentration among untreated girls of -4.0 g l(-1 ) was greater than in untreated boys ( -0.3 g l(-1 ) ) . CONCLUSIONS Weekly iron tablets given by teachers prevented a general fall in the haemoglobin concentrations of untreated children , and led to a small but statistically significant rise among treated children . Young children benefited more than children aged > or=12 years , and girls benefited more than boys [12799128] BACKGROUND This study tests the feasibility of an innovative school-based program for obesity prevention among adolescent girls . New Moves was implemented as a multicomponent , girls-only , high-school physical education class . METHODS Six schools were equally r and omized into intervention and control conditions . Data were collected at baseline , postintervention , and 8-month follow-up to assess program impact on physical activity , eating patterns , self-perceptions , and body mass index ( BMI ) among 89 girls in the intervention and 112 girls in the control conditions . Program evaluation also included interviews with school staff , parent surveys , and participant interviews and process evaluation surveys . RESULTS The feasibility of implementing New Moves was high , as indicated by strong satisfaction among participants , parents , and school staff , and by program sustainability . Participants perceived a positive program impact on their physical activity , eating patterns , and self-image . Girls in the intervention significantly progressed in their stage of behavioral change for physical activity from baseline to follow-up . However , for the majority of outcome variables , differences between intervention and control schools at postintervention and follow-up were not statistically significant . CONCLUSIONS New Moves was well received and fills a needed niche within school physical education programs . An exp and ed intervention and evaluation is needed to enhance and assess long-term program effectiveness [11902397] The Great Beginnings curriculum result ed in participants achieving outcome objectives for healthy teenage childbearing . The experimental group demonstrated significantly better outcomes in nutrition knowledge maintenance of diet quality adequate for pregnancy mean maternal weight gain and mean infant birth weight . When compared with the C-l group the experimental group demonstrated a significantly better outcome in low-birth-weight incidence nutrition knowledge and maintenance of diet quality adequate for pregnancy . Based on the results of this study pregnant adolescents receiving the Great Beginnings curriculum achieved healthier birth outcomes than those not receiving the curriculum . Participation in Great Beginnings does make a substantial difference in the health status of the adolescents for whom it was intended . ( excerpt [10989766] This experimental study was design ed to investigate the effects of daily versus intermittent iron supplementation on iron status of high school girls in Zahedan and Rasht cities in 1996 - 1997 . The subjects were selected r and omly from among students of grade s 1 - 3 of four high schools in each city . Anemia was determined by measuring hematological indices . 260 anemic and a similar number of non-anemic subjects of 4 high schools were selected and allocated r and omly to 4 treatment groups . During a 3-month period , the test groups were given 150 mg ferrous sulfate tablets ( 50 mg Fe ) . Subjects in group 1 received a daily dose , groups 2 & 3 received twice or once weekly doses respectively . The control group received no iron supplement . For these subjects , in addition to hematological indices biochemical iron indices were measured in the beginning and at the end of the study . The increases in hemoglobin concentration in anemic subjects were not significantly different among supplemented groups but were different from the control group ( p < 0.00001 ) . Among anemic subjects , changes in serum ferritin levels in 3 supplemented groups were significantly different from the control group . Serum ferritin in Group 1 was also increased to a greater extent than groups 2 and 3 ( P < 0.00001 ) . It is concluded that over the study period a weekly iron dose was as effective as a daily dose in treating anemia but the daily dose was more effective in improving iron stores than a weekly dose in the short run [8855856] BACKGROUND Up to 25 % of adolescent girls in the USA are iron deficient . This double-blind , placebo-controlled clinical trial assessed the effects of iron supplementation on cognitive function in adolescent girls with non-anaemic iron deficiency . METHODS 716 girls who enrolled at four Baltimore high schools were screened for non-anaemic iron deficiency ( serum ferritin < or = 12 micrograms/L with normal haemoglobin ) . 98 ( 13.7 % ) girls had non-anaemic iron deficiency of whom 81 were enrolled in the trial . Participants were r and omly assigned oral ferrous sulphate ( 650 mg twice daily ) or placebo for 8 weeks . The effect of iron treatment was assessed by question naires and haematological and cognitive tests , which were done before treatment started and repeated after the intervention . We used four tests of attention and memory to measure cognitive functioning . Intention-to-treat and per- protocol analyses were done . FINDINGS Of the 81 enrolled girls with non-anaemic iron deficiency , 78 ( 96 % ) completed the study ( 39 in each group ) . Five girls ( three control , two treatment ) developed anaemia during the intervention and were excluded from the analyses . Thus , 73 girls were included in the per- protocol analysis . Ethnic distribution , mean age , serum ferritin concentrations , haemoglobin concentrations , and cognitive test scores of the groups did not differ significantly at baseline . Postintervention haematological measures of iron status were significantly improved in the treatment group ( serum ferritin 27.3 vs 12.1 micrograms/L , p < 0.001 ) . Regression analysis showed that girls who received iron performed better on a test of verbal learning and memory than girls in the control group ( p < 0.02 ) . INTERPRETATION In this urban population of non-anaemic iron-deficient adolescent girls , iron supplementation improved verbal learning and memory [2816802] In a double-blind zinc trial in low-income , pregnant adolescents thought to be at risk for poor zinc nutriture , subjects were r and omly assigned to receive 30 mg zinc ( gluconate ) or placebo . Response to zinc was related to maternal weight . Infants of normal-weight mothers given zinc had reduced rates of prematurity ( p = 0.05 ) and assisted respiration ( p = 0.006 ) . Underweight multiparas given zinc had longer gestational lengths ( p = 0.008 ) than did subjects given the placebo . Multiple stepwise regression analysis , used to identify predictors of infant size , revealed that 14 - 26 % more variance was accounted for in the zinc than in the placebo group . Except for gestational age , the predictors selected were entirely different in the two groups . The zinc group had a positive toxemia screen more often , which did not appear to affect outcome . Zinc supplementation improved pregnancy outcome in normal-weight women and in underweight multiparas . The nonresponse in underweight primiparas was perhaps due to multiple limiting factors [10721926] The prevalence of anemia is high in adolescent girls in India , with over 70 % anemic . Iron-folic acid ( IFA ) supplements have been shown to enhance adolescent growth elsewhere in the world . To confirm these results in India , a study was conducted in urban areas of Vadodora , India to investigate the effect of IFA supplements on hemoglobin , hunger and growth in adolescent girls 10 - 18 y of age . Results show that there was a high dem and for IFA supplements and > 90 % of the girls consumed 85 out of 90 tablets provided . There was an increment of 17.3 g/L hemoglobin in the group of girls receiving IFA supplements , whereas hemoglobin decreased slightly in girls in the control group . Girls and parents reported that girls increased their food intake . A significant weight gain of 0.83 kg was seen in the intervention group , whereas girls in the control group showed little weight gain . The growth increment was greater in the 10- to 14-y-old age group than in the 15- to 18-y-old group , as expected , due to rapid growth during the adolescent spurt . IFA supplementation is recommended for growth promotion among adolescents who are underweight [17825729] INTRODUCTION There has been a paucity of theory-based interventions to improve health outcomes in overweight adolescents . Therefore , two intervention studies were conducted to : ( a ) determine the feasibility of implementing the Creating Opportunities for Personal Empowerment ( COPE ) Healthy Lifestyles Thinking , Emotions , Exercise , and Nutrition ( TEEN ) program with overweight adolescents ; ( b ) obtain feedback that could be used to refine the program ; and ( c ) examine the preliminary efficacy of the COPE program on the adolescents ' weight and body mass index ( BMI ) . METHOD Phase I and Phase II clinical trials were conducted with 23 overweight teens . The Phase 1 trial used a pre-experimental design with one group of 11 urban adolescents . The Phase 2 trial was conducted with 12 suburban teens using a r and omized controlled pilot study . COPE teens received a 15-session cognitive-behavioral skills building program that included physical activity , while the control group received an attention control program . Weight change and BMI were the key outcomes . RESULTS COPE teens experienced a significantly greater reduction in weight and BMI than did teens in the control group , who gained weight over time . Although the COPE program was well received by all of the teens , retention of subjects across time and parent involvement in the program were challenges in the urban high school . DISCUSSION These studies provide preliminary data to indicate that the implementation of COPE is feasible and may lead to a reduction in weight and BMI in overweight teens . Implementing COPE within the context of the school day may be more successful in sustaining adolescent involvement in the program versus using an after-school format [17032704] The aim of the present study was to evaluate the effects of a middle school physical activity and healthy eating intervention , including an environmental and computer-tailored component , and to investigate the effects of parental involvement . A r and om sample of 15 schools with seventh and eight grade rs was r and omly assigned to one of three conditions : ( i ) intervention with parental involvement , ( ii ) intervention alone and ( iii ) control group . In 10 schools , an intervention , combining environmental changes with computer-tailored feedback , was implemented over 2 school years . In five intervention schools , increased parental support was added . Physical activity was measured with question naires in the total sample and with accelerometers in a sub- sample of children . Fat intake , fruit , water and soft drink consumption were measured using food-frequency question naires . Results showed significant positive intervention effects on physical activity in both genders and on fat intake in girls . Parental involvement did not increase intervention effects . It can be concluded that physical activity and eating behaviours of middle school children can be improved by school-based strategies combining environmental and personal interventions . The use of personalized computer-tailored interventions seems to be a promising tool for targeting adolescents but needs to be further explored [22584456] This paper reports the final 24-month outcomes of a r and omized controlled trial evaluating the effect of additional therapeutic contact ( ATC ) as an adjunct to a community-based weight-management program for overweight and obese 13–16-year-olds . ATC involved telephone coaching or short-message-service and /or email communication once per fortnight . Adolescents were r and omized to receive the Loozit group program — a two-phase behavioral lifestyle intervention with ( n=73 ) , or without ( n=78 ) , ATC in Phase 2 . Adolescents/parents separately attended seven weekly group sessions ( Phase 1 ) , followed by quarterly adolescent sessions ( Phase 2 ) . Assessor-blinded , 24-month changes in anthropometry and metabolic health included primary outcomes body mass index ( BMI ) z-score and waist : height ratio ( WHtR ) . Secondary outcomes were self-reported psychosocial and lifestyle changes . By 24 months , 17 adolescents had formally withdrawn . Relative to the Loozit program alone , ATC largely had no impact on outcomes . Secondary pre-post assessment of the Loozit group program showed mean ( 95 % CI ) reductions in BMI z-score ( −0.13 ( −0.20 , −0.06 ) ) and WHtR ( −0.02 ( −0.03 , −0.01 ) ) in both arms , with several metabolic and psychosocial improvements . Adjunctive ATC did not provide further benefits to the Loozit group program . We recommend that further work is needed to optimize technological support for adolescents in weight-loss maintenance . Australian New Zeal and Clinical Trials Registry Number ACTRNO12606000175572 [23253647] BACKGROUND Given the increasing prevalence of obesity among youth over the past decade , prevention has become an international public health priority . PURPOSE To evaluate the 2-year effectiveness of three strategies aim ed at preventing overweight and obesity among adolescents in a high school setting . DESIGN PRomotion de l'ALIMentation et de l'Activité Physique ( PRALIMAP ) is a school-based RCT . Each study high school was assigned to receive or not , over a 2-year period ( Grade s 10 and 11 ) , each of three prevention strategies according to a 2 × 2 × 2 factorial school r and omization . Data were collected in 2006 - 2009 and analyzed in 2009 - 2011 . SETTING / PARTICIPANTS A total of 3538 adolescents ( aged 15.6±0.7 years at baseline ) in 24 public high schools in Lorraine ( northeastern France ) completed the PRALIMAP trial . INTERVENTIONS The prevention strategies were education ( development of nutritional knowledge and skills ) ; environment ( creation of a favorable environment by improving availability of " healthy " dietary items and physical activity ) ; and screening and care ( detection of overweight/obesity and , if necessary , adapted care management ) . MAIN OUTCOMES MEASURES The main outcome of interest was BMI ; BMI z-score and prevalence of overweight/obesity were considered as secondary outcomes . RESULTS Adolescents who completed the PRALIMAP trial were younger , less often suspected of having eating disorders and depression , and came from a higher socioeconomic class than those who did not . The 2-year change of outcomes was more favorable in the 12 screening and care high schools compared to the no-screening ones : a 0.11 lower increase in BMI ( p=0.0303 ) ; a 0.04 greater decrease in BMI z-score ( p=0.0173 ) ; and a 1.71 % greater decrease in overweight/obesity prevalence ( p=0.0386 ) . Education and environment strategies were not more effective than no strategy intervention . CONCLUSIONS Although the screening and care strategy is an effective way to prevent , at 2 years , overweight and obesity among adolescents in a high school setting , its effects over and above no strategy intervention were small . TRIAL REGISTRATION This study is registered at www . clinical trials.govNCT00814554 [18377970] OBJECTIVE Our primary objective was to determine whether a novel ' active school ' model -- Action Schools ! BC -- improved the cardiovascular disease ( CVD ) risk profile in elementary-school children . Our secondary objective was to determine the percentage of children with elevated CVD risk factors . METHODS We undertook a cluster-r and omized controlled school-based trial with 8 elementary schools across 1 school year , in British Columbia , Canada , beginning in 2003 . Boys and girls ( n=268 , age 9 - 11 years ) were r and omly assigned ( by school ) to usual practice ( UP , 2 schools ) or intervention ( INT , 6 schools ) groups . We assessed change between groups in cardiovascular fitness ( 20-m Shuttle Run ) , blood pressure ( BP ) , and body mass index ( BMI , wt/ht(2 ) ) . We evaluated total cholesterol ( TC ) , total : high-density cholesterol ( TC : HDL-C ) , low-density lipoprotein , apolipoprotein B , C-reactive protein and fibrinogen on a subset of volunteers ( n=77 ) . RESULTS INT children had a 20 % greater increase in fitness and a 5.7 % smaller increase in BP compared with children attending UP schools ( P<0.05 ) . Forty five percent of children had at least one elevated risk factor ( fitness , BP or BMI ) at baseline . There were no significant differences between groups for change in BMI or in any of the blood variables . CONCLUSION Action Schools ! BC was an effective school-based physical activity model for improving the CVD risk profile of elementary-school children . Our multi-component intervention exposed children to fitness enhancing physical activity . It may be important for education stakeholders to adequately re source the delivery of the active school models if cardiovascular health benefits are to be achieved on a population basis [22129855] OBJECTIVES The present study was aim ed at assessing the effect of zinc- and micronutrient-rich food supplementation compared with ayurvedic zinc tablets on the blood levels of zinc and vitamin A in adolescent girls . METHODS One hundred eighty apparently healthy schoolgirls ( 12.5 ± 0.85 y old ) were recruited for a 10-wk intervention trial . They were r and omized to three groups : one group received a food supplement that was prepared using zinc- and micronutrient-rich foods and by adopting food-processing methods that increase zinc bioavailability ; the second group received ayurvedic zinc ( Jasad ) tablets as a natural elemental zinc supplement ; and the third group served as the control without any supplementation . Diet was assessed by 24-h recall on 3 non-consecutive days . Fasting blood sample s were analyzed for plasma levels of zinc , β-carotene , retinol , vitamin C , and hemoglobin at baseline and the end of the study period . RESULTS Food supplementation showed a significant increase in plasma levels of zinc ( 9.9 % ) , β-carotene ( 56.2 % ) , and vitamin C ( 28.0 % , P < 0.05 ) and a non-significant increase in hemoglobin ( 1.7 % ) , although small , non-significant changes in blood micronutrient levels were observed in the control group ( P > 0.1 ) . Food supplementation decreased the prevalence of zinc deficiency ( 73 % to 53.1 % ) , β-carotene deficiency ( 31.1 % to 17.4 % ) , and mild anemia ( 32.2 % to 23.7 % ) . Ayurvedic zinc supplementation significantly improved plasma zinc ( 61.3 % ) and plasma retinol ( 38.2 % ) and decreased the prevalence of zinc deficiency ( 73.7 % to 36.2 % ) and vitamin A deficiency ( 65.4 % to 20.4 % , P < 0.05 ) . CONCLUSION Zinc- and micronutrient-rich food supplementation was effective in improving the zinc and vitamin A status of adolescent girls Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Anaemia is a condition in which the number of red blood cells is insufficient to meet physiologic needs ; it is caused by many conditions , particularly iron deficiency . Traditionally , daily iron supplementation has been a st and ard practice for preventing and treating anaemia . However , its long-term use has been limited , as it has been associated with adverse side effects such as nausea , constipation , and teeth staining . Intermittent iron supplementation has been suggested as an effective and safer alternative to daily iron supplementation for preventing and reducing anaemia at the population level , especially in areas where this condition is highly prevalent . OBJECTIVES To assess the effects of intermittent oral iron supplementation , alone or in combination with other nutrients , on anaemia and its associated impairments among menstruating women , compared with no intervention , a placebo , or daily supplementation . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

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[3503941] A r and omized controlled trial of an information and medical record booklet design ed to improve patient underst and ing and participation in the management of hypertension was conducted in six inner London general practice s. After one year there were no significant differences between the group who had received the booklets and the control group in mean systolic or diastolic blood pressure , but the study group scored significantly higher on knowledge about hypertension and its management . However , the difference between the two groups was small , possibly because both groups started with a high level of underst and ing about hypertension and its management . In addition , the mean diastolic blood pressure in the control group showed that the treatment provided was already satisfactory , and that there was little need for improvement . Nevertheless , the information booklet evaluated in this study provides health professionals with a highly acceptable method of informing the patient about hypertension and its management and could be used both in hospital and general practice [6995966] Abstract An experimental study was carried out to test and analyze the effects of an educational program on a group of hypertensive patients , comparing those with known higher risks of stroke and heart attack , e.g. , secondary organ damage , with a group whose risks were relatively lower . Specific interventions have been shown to be differentially effective on specific patient behaviors ( e.g. , compliance with therapy ) and on blood pressure control for both higher- and lower-risk patients in most of the experimental groups . Such findings emphasize the importance of tailored educational approaches , not only for a hypertensive population , but , more importantly , for patients who are known to have more difficulty achieving their blood pressure control and who are at higher risk of morbidity and mortality , i.e. , patients who have secondary organ damage , have been previously hospitalized for hypertension , or are black males under 50 years of age [3302144] Evidence suggests that diet and exercise are associated with improved glucose tolerance for patients with non-insulin-dependent diabetes mellitus ( NIDDM ) . Seventy-six volunteer adult patients with NIDDM were each assigned to one of four programs : 1 ) diet , 2 ) exercise , 3 ) diet plus exercise , or 4 ) education ( control ) . Each program required ten weekly meetings . Detailed evaluations were completed prior to the program and after three , six , 12 , and 18 months . Evaluations included various psychosocial measures , measures of the quality of life , and fasting blood glucose , glycosylated hemoglobin , and relative weight determinations . Of the 76 original participants , 70 completed the 18-month follow-up study . At 18 months , the combination diet- and -exercise group had achieved the greatest reductions in glycosylated hemoglobin measures . In addition , this group showed significant improvements on a general quality of life measure . These improvements were largely uncorrelated with changes in weight . The authors conclude that the combination of dietary change and physical conditioning benefits NIDDM patients , and that the benefits may be independent of substantial weight loss [8671102] BACKGROUND Many patients with asthma or chronic obstructive pulmonary disease use their medication inhalers incorrectly . General practitioners , pharmacists and other health care providers do not always have the opportunity to instruct patients in correct inhaler technique . OBJECTIVE To find out whether the inhaler technique and respiratory symptoms of patients can be improved after instruction by practice assistants . METHODS Single blind , r and omized intervention study in which 48 patients who had been using a dry powder inhaler for at least one month took part . Their inhaler technique was videotaped on two visits with a two-week interval between visits . The inhaler technique on the videos was subsequently scored by two experts on nine criteria . At both visits the patients completed a question naire about their respiratory symptoms . After the first video , 25 patients were r and omly chosen to receive instruction from one of six practice assistants who had followed a one evening course about inhaler instruction , and who had been issued an instruction-set . RESULTS The patients who received instruction had a significantly greater reduction in number of mistakes at the second visit than the patients who did not ( P = 0.01 ) . The instructed patients also reported less dyspnoea at the second visit ( P = 0.03 ) . No effect of instruction was found on wheezing , cough and sputum production . CONCLUSION The inhaler technique of patients can be improved significantly by the instruction of patients by trained practice assistants , possibly result ing in less dyspnoea [9917117] CONTEXT Control of oral anticoagulation therapy has been reported to often be inadequate . Previous retrospective investigations suggest that patients ' self-adjustment of oral anticoagulants may lead to improved control . OBJECTIVE To investigate the effects of patients ' self-management of oral anticoagulation therapy on accuracy of control and measures of treatment-related quality of life . DESIGN R and omized , single-blind , multicenter trial . SETTING AND PARTICIPANTS A total of 179 patients receiving long-term oral anticoagulation treatment were enrolled at 5 referral centers in Germany . INTERVENTION Patients were r and omized to an oral anticoagulation self-management group based on a structured treatment and teaching program and international normalized ratio ( INR ) self-monitoring . The control group received conventional care as provided by family physicians , including referral to specialists if necessary . MAIN OUTCOME MEASURES Deviation of INR values from the individual INR target range ( squared ) and the 5 categories of treatment-related quality of life . RESULTS Deviation of INR value from the mean of the INR target range was significantly lower in the intervention group at 3-month ( squared INR deviation , 0.59 vs 0.95 ; P<.001 ) and 6-month follow-up ( 0.65 vs 0.83 ; P=.03 ) compared with the control group . Also , the intervention group had INR values within the target range more often ( repeated measurement analysis for categorical data , P=.006 ) . The results were mainly due to less frequent suboptimal INR values in the intervention group ( 32.8 % vs 50.0 % [ P=.03 ] at 3-month , and 33.7 % vs 48.2 % [ P=.08 ] at 6-month follow-up ) . Treatment-related quality -of-life measures , especially treatment satisfaction scores , were significantly higher in the intervention group compared with controls . CONCLUSIONS An anticoagulation education program that includes self-management of anticoagulation therapy results in improved accuracy of anticoagulation control and in treatment-related quality -of-life measures . Further studies are needed to describe whether the program will reduce risk of bleeding or thromboembolism [7842191] A prospect i ve controlled trial of home monitoring of peak expiratory flow rate ( PEFR ) was conducted to determine the usefulness of an objective measure of lung function in association with an education program and a medication self-management plan in reducing morbidity in adult patients with asthma . Thirty-five patients managed themselves , using peak flow readings as the basis for the therapeutic plan coupled with educational intervention , whereas 35 control patients used symptoms and spirometric data for following physicians ' treatment plans . After a 6-mo study period , patients in the experimental group showed statistically significant improvements in morbidity parameters ( days lost from work , acute asthma attacks , days on antibiotic therapy , physician consultations , and emergency room admissions for asthma ) , increases in FVC , FEV1 , and FEV1/FVC , mean PEFR and mean morning PEFR , decrease in percentage of the mean PEFR amplitude , and a reduction in the use of inhaled beta-agonists , oral theophylline , and oral prednisone . Although improvements in some of these parameters were also found in the control group , they did not reach the levels of significance obtained in the experimental group . The personal use of an objective measure of lung function in association with a medication self-management plan leads to improvement in the patient 's condition [3314877] A r and omized clinical trial was performed to evaluate a psychological treatment intervention and a social support program , compared with a control program in which no adjunct treatment was rendered , and their effects upon pain behavior , affect , and disease activity of 53 patients with rheumatoid arthritis . The psychological intervention produced significant reductions in patients ' pain behavior and disease activity at posttreatment . Significant reductions were also observed in trait anxiety at posttreatment and 6-month followup . Relaxation training may have been the most important component of the psychological intervention . The social support program produced a significant reduction in trait anxiety only at posttreatment . This is the first well-controlled study to demonstrate reduced pain behavior , disease activity , and trait anxiety following psychological treatment [3772925] One hundred subjects with arthritis were r and omized into lay-taught , or professional-taught 12-h arthritis self-management courses , or a control group . Outcomes , knowledge , exercise , relaxation , disability , pain , and number of physician visits were measured aat baseline and 4 months . Professional-taught groups demonstrated greater knowledge gain while lay-taught groups had greater changes in relaxation ( p less than .01 ) and a tendency toward less disability . Although it is impossible to draw definitive conclusions , this study suggests that lay leaders can teach arthritis self-management courses with results similar to those achieved by professionals [2589581] This prospect i ve r and omized study evaluated the influence of a simple education program on the incidence of lower extremity amputation in diabetic patients . Two hundred three patients were r and omized into two groups : Group 1 , education ( 103 patients , 203 limbs ) and Group 2 , no education ( 100 patients , 193 limbs ) . There were no significant differences in medical management or clinical risk factors between the two groups . The amputation rate was three times higher in Group 2 ( 21 of 177 limbs versus 7 of 177 limbs ; p less than or equal to 0.025 ) , the ulceration rate was three times higher in Group 2 ( 26 of 177 limbs versus 8 of 177 limbs ; p less than or equal to 0.005 ) , and there was no difference in the overall incidence of infection ( 2 of 177 limbs ) . Overall success in Group 1 was highly significantly different from Group 2 ( 160 of 177 limbs versus 128 of 177 limbs ; p less than or equal to 0.0005 ) . This study demonstrated that a simple education program significantly reduced the incidence of ulcer or foot and limb amputation in diabetic patients [8702449] OBJECTIVE The effects of treatment counseling or symptom monitoring telephone intervention strategies on the health outcomes of patients with rheumatoid arthritis ( RA ) or osteoarthritis ( OA ) , compared with usual care , were assessed . METHODS A 3-group , r and omized , controlled 9-month trial was conducted incorporating 405 patients with RA or OA and using the Arthritis Impact Measurement Scales ( AIMS 2 ) as the outcome measure . RESULTS Analyses of covariance showed that the AIMS 2 total health status of the treatment counseling group ( effect size = 33 , P < 0.01 ) , but not the symptom monitoring group ( effect size = 0.21 , P = 0.10 ) , was significantly improved , compared with usual care , for both RA and OA patients . The specific types of benefits differed significantly between RA and OA patients . The mean number of medical visits by OA patients in the treatment counseling group was also significantly reduced ( P < 0.01 ) . CONCLUSION Telephone contact using the treatment counseling strategy produced significant , but different , health status benefits for RA and OA patients . The symptom monitoring strategy produced modest benefits [6742256] This research reports level of blood pressure control and ability to maintain newly discovered hypertensives in a municipal hospital setting by use of family- and self-monitored home blood pressure units . Three hundred ninety-six patients were r and omized into family- and self-monitored blood pressure groups and a control group . Findings indicate that the use of either self- or family-read cuffs is effective in the first six months of treatment in lowering blood pressures . The data are suggestive of a beneficial effect of the use of cuffs for up to 18 months ; however , with additional time in the study , no differences in the level of blood pressure control could be demonstrated between groups . The use of family-monitored blood pressure cuffs produces a lower drop-out rate than does the use of no cuff . The effect on drop outs is substantial for the first year of treatment , but beyond 12 months , the family-read cuff is also more effective than no cuff in reducing drop outs [8163051] Summary In a prospect i ve controlled trial the effects of a 5-day in-patient treatment and teaching programme for Type 1 ( insulin-dependent ) diabetes mellitus on metabolic control and health care costs were studied in Moscow . Two different intervention programmes were compared , one based upon urine glucose self-monitoring ( UGSM , n = 61 ) and one using blood glucose selfmonitoring ( BGSM , n = 60 ) . Follow-up was 2 years . A control group ( n = 60 ) continued the st and ard treatment of the Moscow diabetes centre and was followedup for 1 year . Costs and benefits with respect to hospitalizations and lost productivity ( according to average wage ) were measured in November 1992 roubles ( Rb . ) , with respect to imported drugs and test strips in 1992 German marks ( DM ) . In the intervention groups there were significant decreases of HbA1 values [ UGSM : 12.5 % before , 9.4 % after 1 year , 9.2 % after 2 years ( p < 0.0001 ) ; BGSM : 12.6 % before , 9.3 % after 1 year , 9.2 % after 2 years ( p < 0.0001 ) compared to no change in the control group ( 12.2 % before , 12,3 % after 1 year ) ] , and of the frequency of ketoacidosis . The frequency of severe hypoglycaemia was comparable between the UGSM ( 10 cases during 2 years ) , BGSM ( 10 cases during 2 years ) , and the control group ( 8 cases during 1 year ) . In the combined intervention groups , there were significant decreases of hospital days per patient per year ( 12.1 during the year before , 1.0 year one after , 3.6 year two after , p < 0.005 ) , and of additional sick leave days ( 16.6 during the year before , 2.4 year one , 7.8 year two after , p < 0.01 ) , whereas these parameters remained unchanged in the control group . The initial costs of the intervention were outweighed by this subsequent reduction in hospitalizations and lost productivity . Net savings totalled up to 14400 Rb./patient within 2 years . Patients of the intervention groups were told to discontinue drugs which were not indicated and /or ineffective ( clofibrate , pentoxifylline , calcium dobesilate ) . This caused estimated average savings of DM 240 per patient per year . Costs of test strips for UGSM were DM 180 per patient per year ; for BGSM they were estimated to lie between DM 370 and DM 550 per patient per year , depending on the frequency of measurements . In conclusion , the intervention led to an improvement of metabolic control and saved re sources for health care by reducing hospitalizations and sick leave days . When UGSM is used , costs of test strips are approximately outweighed by discontinuing ineffective drugs [2867269] Two different patient education programmes for asthma in general practice were evaluated in a controlled trial . Knowledge , self management , and morbidity due to asthma were assessed in 339 patients by means of a question naire . One group then received a maximum education programme , a second group received a limited education programme , and a third acted as a control group . 274 patients were reassessed after one 1 year . In both the intervention groups , underst and ing of asthma was greater after the trial . Only in the maximum intervention group was a significant improvement in knowledge of asthma shown . Neither group showed any change in self-management ability or asthma morbidity that differed significantly from changes in the control group . These simple informational education programmes were ineffective when applied to a general practice population . Further studies of factors affecting attitudes , beliefs , and actions are needed to improve the advice and support given to asthma patients [2454118] To examine the effectiveness of a cognitive-behavioral pain management program for patients with rheumatoid arthritis , three patient groups were studied : a cognitive-behavioral group ( CB ) , an attention-placebo group , and a control group . The CB group received a comprehensive , 12-month pain management program that taught coping strategies such as problem-solving techniques , relaxation training , strategies for attention diversion , and training in family dynamics and communication . Dependent measures included pain , coping strategies , psychological status , functional status , and disease status . Data analysis at 12 months revealed benefits for the CB group in the area of enhanced coping strategies . Specifically , the CB subjects showed significantly greater use of coping strategies and significantly more confidence in their ability to manage pain . The findings are discussed in terms of the importance of enhanced self-efficacy and personal control for patients with rheumatoid arthritis [8613276] Community-based hypertension control is important for primary prevention of cardiovascular disease . In this study , untreated men and women aged 35 to 69 years were r and omly assigned to an intervention ( n=56 ) or control ( n=55 ) group in a 1.5-year community-based education program . Subjects had no evidence of hypertensive end-organ defects and had screening blood pressures of 140 to 179 mm Hg systolic and /or 90 to 109 mm Hg diastolic , with no difference in mean blood pressure between groups ( 148 to 150 mm Hg for mean systolic and 83 to 84 mm Hg for mean diastolic pressures ) . The intervention group took four education classes in the first 6 months and four classes during the next year , and the control group took two classes . Health education focused on reduced dietary sodium and increased milk intake , brisk walking , and , if necessary , reduction of alcohol and sugar intakes . Antihypertensive medication was started less often in the intervention than in the control group at 1.5 years ( 9 % versus 24 % , P < .05 ) . Mean systolic pressure was 5 to 6 mm Hg less in the intervention than in the control group at both 6 months and 1.5 years ( P < .05 ) , with or without inclusion of those subjects who began antihypertensive medication . Diastolic pressure and body mass index did not change significantly between groups . Urinary sodium excretion declined in the intervention but not in the control group ( differences between groups : P=.04 at 6 months and P=.07 at 1.5 years ) . According to a behavioral question naire , sodium reduction and milk increase were greater in the intervention than the control group ( sodium : P < .01 at 6 months and P=.08 at 1.5 years ; milk : P < .001 at 6 months and P < .01 at 1.5 years ) . Mean ethanol intake was reduced in the intervention but not the control group ( P=.04 at 1.5 years ) . This community-based hypertension control program was effective in reducing systolic pressure levels by nonpharmacological means during the first 6 months and maintaining the reduction for 1.5 years [7570436] BACKGROUND --Peak flow based asthma self-management plans have been strongly advocated in consensus statements , but convincing evidence for the effectiveness of this approach has been largely lacking . METHODS --A r and omised controlled trial was conducted in 25 general practice s comparing an asthma self-management programme based on home peak flow monitoring and surgery review by a general practitioner or practice nurse with a programme of planned visits for surgery review only over a six month period . RESULTS --Seventy two subjects ( 33 in the self-management group and 39 in the planned visit group ) completed the study protocol , but diary card data for at least three months were available on a total of 84 ( 39 in the self-management group and 45 in the planned visit group ) . Teaching self-management took longer than the planned visit review . In the self-management group home peak flow monitoring was felt to be useful by doctors and patients in 28 ( 85 % ) and 27 ( 82 % ) cases , respectively . There were no between group differences during the study period in terms of lung function , symptoms , quality of life , and prescribing costs . Only within the self-management group were improvements noted in disturbance of daily activities and quality of life . Possible explanations for these negative results include small numbers of subjects , the mild nature of their asthma , and inappropriate self-management strategies for such patients . CONCLUSIONS -- Rigid adherence to long term daily peak flow measurement in the management of mild asthma in general practice does not appear to produce large changes in outcomes . Self-management and the use of prescribed peak flow meters need to be tailored to individual circumstances [8296253] BACKGROUND --To improve asthma control and reduce readmission rates through increased knowledge and the development of self management skills , a brief ( three hour ) adult education programme was developed . METHODS --The course was design ed to improve inhaler skills and to teach how to adjust drug doses according to peak flow ( PEF ) measurements and a treatment plan . It was evaluated in a r and omised controlled trial in 76 patients admitted to hospital for asthma by using question naires , spirometry , and home monitoring of PEF at entry and at five and 10 months after intervention . The question naire provided measures of knowledge about asthma , self management behaviour appropriate to asthma control , asthma symptom frequency and severity , and psychosocial disturbance attributable to asthma . RESULTS --During the 10 months observation period the readmission rate for the educated group was one seventh that of the control group and attendance at accident and emergency departments also decreased . No consistent differential improvements were observed in spirometric results , average PEF , or mean daily variability of PEF . Both groups showed improvements in measures of asthma knowledge , behaviour , symptoms , and psychosocial disturbances . However , the intervention group showed a significantly greater improvement in some measures of asthma knowledge and self management skills . CONCLUSION --Despite minimal effect on measures of airway function , substantial changes in illness behaviour and use of health care facilities can be achieved by a brief asthma education programme [8761192] Consecutive new attendees at a rheumatology clinic were r and omly allocated to one of three groups . All groups received routine care , but one received no other intervention , one an educational booklet on arthritis and one the booklet plus instruction from a health professional . Prior to intervention , all groups had similar knowledge . Nottingham Health Profile ( NHP ) and Health Assessment Question naire ( HAQ ) score . After 6 weeks , the knowledge score was significantly increased in both groups given the booklet , but not in the control group . The group instructed by a health professional showed no greater increase than the group given the booklet alone . Increased knowledge was not associated with improved clinical status and no group showed a significant change in NHP or HAQ scores . Nearly all patients said they found the booklet useful [3338379] In patients with non-insulin-dependent diabetes mellitus ( NIDDM ) , the influence of knowledge about their disease on the treatment and control of the disease is not clear . We evaluated the efficacy of educational group meetings with NIDDM patients on improving their knowledge of the disease and on disease management . Fifty-one NIDDM patients were r and omly assigned to either intervention or control groups . The intervention group participated in courses of three weekly lessons presented by a physician , nurse , and dietitian once every 4 mo . The intervention and control groups were also followed once every 2 mo in the clinic by the same staff . Medical treatment remained unchanged during the study . After a 12-mo follow-up of the intervention group , no significant improvement in their knowledge of diabetes could be demonstrated . However , mean fasting and postpr and ial blood glucose levels and HbA1c improved significantly in comparison with the control goup . The same tendency was evident with the weight and lipoprotein profile . We conclude that educational group therapy can improve diabetes control in patients with NIDDM [4004977] Behavioral and health status outcomes of an unreinforced , self-help education program for arthritis patients taught by lay persons were examined in 2 ways : a 4-month r and omized experiment and a 20-month longitudinal study . At 4 months , experimental subjects significantly exceeded control subjects in knowledge , recommended behaviors , and in lessened pain . These changes remained significant at 20 months . The course was inexpensive and well-accepted by patients , physicians , and other health professionals [7950723] Abstract Objective : To assess the value of health education for patients with angina in reducing risk factors for cardiovascular disease and lessening the effect of angina on everyday activities . Design : R and omised controlled trial of personal health education given every four months . Setting : 18 general practice s in the greater Belfast area . Subjects : 688 patients aged less than 75 years and known to have had angina for at least six months ; 342 r and omised to receive education and 346 to no education . Main outcome measures : Restriction of everyday activities , dietary habit , smoking habit , frequency of physical exercise ; blood pressure , body mass index , and serum total cholesterol concentration at entry to trial and after two years . Results : 317 in the intervention group and 300 in the control group completed the trial . At the two year review more of the intervention group ( 140 , 44 % ) reported taking daily physical exercise than the control group ( 70 , 24 % ) . The intervention group also reported eating a healthier diet than the control group and less restriction by angina in any everyday activity . No significant differences were found between the groups in smoking habit , systolic or diastolic blood pressure , cholesterol concentration , or body mass index . Conclusion : Despite having no significant effect on objective cardiovascular risk factors , personal health education of patients with angina seems to increase exercise and improve dietary habits and is effective in lessening the restriction of everyday activities [6347578] The effect of patient education on diabetic control in insulin-treated diabetic adults was studied in 77 subjects r and omized into two groups : intensive patient education ( group A ) and control ( group B ) . The subjects in group A received intensive patient instruction , both individually and in small groups , from a team of physicians , teaching nurses , and a dietitian . The patients in group B received a short instruction course consisting mainly of printed material . A highly significant improvement in diabetic control was observed in both groups immediately after the education programs , with gradual return to the original level during the following 3–6 mo . No difference was observed between the two groups in any of the measured parameters during the 18-mo investigation . Factors related to good control during the study included the length of school education , the quality of the control at the beginning of the study , and the high degree of self-confidence and lack of signs of anxiety in the psychological tests . The results demonstrate that the effects of educational programs are of limited value if they do not lead to permanent changes in attitudes and motivation , which are critical factors affecting long-term diabetic control [8130290] Preliminary work regarding the development and pilot study of an individualized instructional program for rheumatoid arthritis clients is presented . The effect of the individualized instructional program was tested with 31 out patients . Using analysis of covariance , the experimental group subjects scored significantly higher on the knowledge post-test when compared to scores of control group subjects ( P = 0.0045 ) . Analysis of variance for repeated measures revealed no significant difference in performance of tasks for the control group and experimental group ( P = 0.08 ) . In a follow-up study , the effect of the self-instructional program , practice time , and contracting were explored for their effect on adherence to self-care activities . Experimental groups ( n = 42 ) scored significantly better than the control group ( n = 11 ) on the knowledge post-test ( P < 0.01 ) , performance of joint protection practice s ( P = 0.01 ) , range of motion exercises ( P = 0.01 ) , and adherence to joint protection practice s at home ( P < 0.01 ) . Groups did not differ on adherence to range of motion exercises at home ( P = 0.83 ) [7076881] The shift in patterns of disease toward chronic illness necessitates greater patient participation in its management and in their own rehabilitation , and they require greater social support over longer peiods . Patient activation , or the enhancement of patient and support group involvement in personal health care through teaching management techniques and problem-solving skills , has emerged in health education in response to this need . This paper will examine combined educational and behavioral approaches to increasing social support and patient activation in hypertension management . Activation in this study involves increased feelings of personal control over the contingencies surrounding the management of medical regimens . Both family support intervention and small group sessions oriented to changing compliance behavior by changing expectancy frames were offered to a r and omized sample of 200 inner city , black , hypertensive patients who were part of a larger study . Patients were examined within a pretest — posttest r and omized factorial design on measures of locus of control , belief in seriousness , efficacy of treatment , medication compliance , and blood pressure control . This combined approach showed small differences on the attitude and behavioral measures but displayed a significant effect on the program outcome variableblood pressure control ( 62 % in control among intervention groups versus 46 % in nonintervention groups ) [2904532] A structured treatment and teaching programme for non-insulin-treated non-insulin-dependent ( type 2 ) diabetes was evaluated prospect ively in general practice . The four group sessions were mainly conducted by paramedical personnel . 65 patients from five general practice s were assessed at the start of the programme and 50 ( mean age 65 years , diabetes duration 7 years ) completed the 1 year follow-up ( intervention group ) . The control group consisted of 49 patients ( mean age 63 years , diabetes duration 7 years ) from three other general practice s without the programme . In the intervention group the percentage of patients receiving sulfonylureas fell from 68 % at the start of the study to 38 % after 1 year ( mean difference 30 % , 95 % confidence interval [ CI ] 16 - 44 % ) ; the mean weight loss was 2.7 kg ( 95 % CI 1.6 - 3.8 kg ) , and non-fasting triglycerides were reduced by 0.77 mmol/1 ( 95 % CI 0.35 - 1.19 mmol/l ) ; and glycosylated haemoglobin remained unchanged ( 7.1 % of total haemoglobin ) . In the control group none of these indices was changed during the study year , and 10 % of patients started insulin treatment . The structured treatment and teaching programme improved the overall quality of patient care in elderly non-insulin-dependent diabetic patients treated by general practitioners [7794983] OBJECTIVE To evaluate the effectiveness of a community-based arthritis education program conducted in a number of locations throughout the Sydney , Australia , metropolitan area . METHODS The program , based on earlier work , comprised 6 weekly sessions of 2.5 hours ' duration . The study sample included 175 men and women with different types of arthritis , divided into intervention ( n = 104 ) and control ( n = 71 ) groups . Five outcome measures were selected to evaluate effectiveness of the program : pain perception , knowledge level , self-efficacy , disability index , and self-management behavior . RESULTS The results indicated that the program was effective in increasing knowledge level ( F[1,222 ] = 10.3 , P = 0.001 at 6 weeks ; F[1,108 ] = 7.8 , P = 0.006 at 6 months ) , and a statistically significant difference was found in disability satisfaction 6 months after intervention ( F[1,98 ] = 5.9 , P = 0.01 ] , but no statistically significant difference was found in pain perception , self-efficacy , and disability index . CONCLUSION This research supports some of the successful outcomes which follow an arthritis education program : increased knowledge level and increased disability satisfaction [3935013] The effectiveness of an educational program to increase compliance with cromolyn sodium was assessed in 31 children and adolescents 6 to 17 years of age . Patients were r and omly assigned to an education or noneducation group . A st and ard education program regarding asthma and asthma medications was provided to the education group during four monthly visits . At each visit , all patients were assessed in terms of knowledge of asthma and medications , asthma-related symptoms , and pulmonary function . Patients were also asked to self-rate their compliance . The education program increased the patients ' knowledge of cromolyn , and appeared to result in increased cromolyn compliance . Post-hoc analyses , however , suggested that increased compliance did not correspond to improved medical status unless the quality of management ( by physician and parents ) of the child 's asthma was taken into account . These results suggest that inadequate management of asthma in children may be a more serious problem than patient noncompliance [1744753] Study objective : To determine whether a self-management training program decreases emergency department visits and reduces costs for patients with asthma . Design : R and omized controlled trial of an educational program . Setting : Two sites — an urban emergency room and a suburban emergency room . Patients : 241 asthma patients between the ages of 18 and 70 years . Of the 119 patients in the intervention group and the 122 in the control group , 185 ( 76 % ) were available for follow-up . Intervention : All patients seen in the emergency departments were given usual medical care and follow-up . Patients in the intervention group were asked to attend three educational sessions on asthma conducted by a specially trained RN . The program stressed importance of medication compliance , methods to control and prevent attacks , effects of drugs and rationale for their use , relaxation exercises , and smoking cessation . Measurement and main results : All patients received telephone interviews four , eight , and 12 months after entry into the study . Reports based on hospital admissions and emergency room utilization were verified by billing records . Three patients died during the study , none from asthma-related problems . The intervention group had significantly fewer asthma-related emergency visits ( 16 visits per 100 persons ) than did the control group ( 39 per 100 persons ) ; p=0.0005 for the 12 months of follow-up . The effect of the intervention on asthma-related emergency department visits was strongest during the initial four months postintervention ( 68 per 100 persons versus 220 per 100 persons , p=0.003 ) . The financial analysis showed that the $ 85/person cost for the educational sessions was offset by the $ 628/person reduction in emergency room charges . Conclusion : Education enables patients with asthma to decrease utilization of emergency services [1740599] OBJECTIVE To assess whether knowledge or psychosocial and glycemic benefits of a diabetes education program are enhanced by a support group for older patients . DESIGN A partially r and omized controlled trial involving two groups of patients : Group A , subjects who received an education program followed by 18 months of support group sessions ; Group B , only the diabetes education program . A third convenience sample , Group C , received neither intervention . Groups A and B were assessed before and immediately after the education program , and all groups were assessed 2 years after the education program . SETTING Diabetes clinic at a Veterans Affairs Medical Center . PATIENTS All subjects were male ( mean age = 68 + /- 1.3 years , range = 57 - 82 years ; duration of diabetes = 10 + /- 2 years , range 3 - 16 ) . Sample sizes were 11 in Group A , 13 in Group B , and 8 in Group C. INTERVENTION The education program consisted of six weekly sessions covering aspects of diabetes self-care . The support group consisted of 18 monthly sessions for continuing education , discussion , and structured social activities . OUTCOME MEASURES Diabetes knowledge , psychosocial factors ( self-care-related quality of life , stress , family involvement in care , and social involvement ) , depression , and glycemic control . RESULTS Group A scored better ( at least P less than 0.05 ) on knowledge , quality of life , and depression than the other groups . Groups A and B showed less stress , greater family involvement , better glycemic control , but less involvement in social activities than Group C. CONCLUSION Diabetes education programs can have long term benefits on knowledge , psychosocial functioning , and glycemic control for older diabetic patients . The addition of support groups enhances diabetes knowledge and psychosocial functioning [9228140] OBJECTIVE Self-management courses in arthritis have been shown to improve outcomes and to decrease medical re source utilization . We studied the effectiveness of a mail-delivered arthritis self-management program with the potential for extending these effects more broadly . METHODS R and omized controlled trial of 375 program participants and 434 controls over a 6 month period . Baseline and 6 month data were analyzed for each group and between groups by paired 2 sample t test . The intervention consists of health assessment question naires at 3 month intervals , with computer processed recommendation letters and reports individualized to age , diagnosis , education level , disability , pain , medication , and other patient-specific variables . RESULTS At 6 months , outcomes of function ( 4.7 % ; 95 % confidence limits 2.7 , 6.7 ) , decreased pain ( 9 % ; 2.8 , 15.2 ) , global vitality ( 7 % ; 2.8 , 11.2 ) , and joint count ( 28 % ; 20 , 36 ) were improved in the program group compared with controls ( p < 0.01 ) . Exercise ( 35 % ; 26 , 44 ) and self-efficacy ( 14.7 % ; 9 , 20 ) were increased in the program group but not controls ( p < 0.001 ) . Doctor visits/year were decreased by 16 % ( 3 , 29 ) in the program group compared with controls ( p < 0.05 ) and days missed work or confined to home decreased by 52 % ( -3 , 107 ) in the program group compared with controls ( p = 0.06 ) . At one year , patients in the original program group continued to improve , and the control group , provided with the program in the second 6 months , showed improvement similar to the first 6 months of the original program group . CONCLUSION A mail-delivered arthritis self-management program can positively affect patient outcomes and can decrease medical re source utilization [7974314] BACKGROUND --Previous work has indicated a high rate of non-attendance at hospital based clinics among young , multiracial asthmatic patients of lower socioeconomic class . The efficacy of delivering asthma education from a community health centre established in a multiracial working class neighbourhood was evaluated . METHODS --A prospect i ve controlled study was performed in which asthmatic subjects aged between two and 55 years attending a hospital emergency room with acute asthma and living within a defined geographical area of high emergency room users were r and omised to the usual follow up or the education centre plus usual follow up . Measurements were taken at entry into the study and again nine months later . RESULTS --At nine months patients r and omised to the education centre had more preventive medications , more peak expiratory flow meters and better flow meter technique , more self-management plans , better knowledge of appropriate action to take when confronted with worsening asthma , less nocturnal awakening , and better self-reported asthma control than the control group . There was no difference between the study groups in measurements of compliance , hospital admission , days lost from school or work , or emergency room use . CONCLUSIONS --The main effects of education were on asthma knowledge and self-management skills , whilst improvements in asthma morbidity were small . Potential reasons for this include heterogeneous study population ( in terms of baseline self-management skills , asthma severity , ethnicity and age ) , pragmatic study design , insensitivity of many of the measurements of morbidity , the modest effectiveness of a single time limited education programme , and inability to limit the effects of such a large community based study to the intervention group ( there was a 67 % reduction in asthma admissions during the study period from the geographical area targeted compared with a 22 % reduction for the rest of Auckl and ) [3505528] The efficacy of an adult asthma self-management program , Wheezers Anonymous ( WA ) , was tested utilizing 79 adult asthmatic patients . Subjects were r and omly assigned to a treatment or waiting-list control group . Baseline data gathered included measures of symptom severity , health-care utilization , knowledge of asthma , attitudes about asthma , and self-efficacy . All subjects completed the same measures 1 , 2 , and 3 months following the WA intervention . Knowledge about asthma increased in the treatment group relative to the waiting-list controls ; the number of attacks decreased in the treatment group only , thus demonstrating the efficacy of the WA program [9259427] OBJECTIVE To evaluate a concise program of self-care education delivered by an arthritis nurse specialist as an adjunct to primary care for inner-city patients with knee osteoarthritis ( OA ) . METHODS An attention-controlled clinical trial ; 211 inner-city patients with knee OA were assigned arbitrarily to education ( E ) or attention-control ( AC ) conditions . Group E received an individualized 30 - 60-minute educational intervention that emphasized nonpharmacologic management of joint pain , preservation of function by problem-solving , and practice of principles of joint protection . Brief telephone contacts 1 week and 4 weeks later monitored and reinforced new self-care activities . Group AC viewed a 20-minute st and ardized public education presentation on arthritis and received followup telephone calls ( only to encourage continued participation in the study ) . Outcomes included the Health Assessment Question naire ( HAQ ) Disability and Discomfort Scales , 10-cm visual analog scales measuring knee pain at rest and while walking , and the Quality of Well-Being ( QWB ) scale . Assessment s were made at baseline and at 4-month intervals for 1 year . RESULTS A total of 165 subjects ( 78 % ) completed all assessment s. After control for baseline status , group E had significantly lower scores for disability and resting knee pain throughout the year of postintervention followup ( P < 0.05 for both ) . Effects were somewhat discordant . By 12 months , functional benefits had begun to wane , while the effect on resting knee pain had grown . The overall effects of education on walking knee pain , overall joint pain ( by HAQ ) , and general health status ( by QWB ) were not significant . CONCLUSION Self-care education for inner-city patients with knee OA , delivered as an adjunct to primary care , was found to result in notable preservation of function and control of resting knee pain . The magnitude of the observed effects compares well with those of more labor-intensive and time-consuming intervention models . However , more sustained preservation of function and consistent effects on pain may require prolonged , more proactive followup , either by the patient educator or by a trained clinical assistant dedicated to the task of supporting self-care by patients with knee OA [8823699] OBJECTIVE This r and omized controlled clinical trial evaluates the effectiveness of outpatient group cognitive/educational treatment for patients with the fibromyalgia ( FM ) syndrome . We hypothesized that the combination of group education with cognitive treatment aim ed at developing pain coping skills would be more effective than group education alone . METHODS 131 patients with FM were r and omly assigned to 3 conditions : an experimental condition , which was the combined cognitive/educational intervention ( ECO ) ; an attention control condition consisting of group education plus group discussion ( EDI ) ; and a waiting list control ( WLC ) . For the treatment conditions ECO and EDI , assessment s were made 2 weeks before treatment , at start of treatment , at post-treatment , and at 6 and 12 mo followup . WLC patients received only 3 assessment s. RESULTS There were no pretreatment differences between the groups , or between dropouts and patients who remained in the study . At post-treatment , and compared with the WLC , the ECO patients improved in knowledge about FM ( p = 0.007 ) and pain coping ( p < 0.001 ) . EDI patients improved on pain coping ( p = 0.005 ) and pain control ( p = 0.002 ) . EDI patients reported significantly less fear than ECO patients ( p = 0.005 ) . There were no other differential effects between ECO and EDI at post-treatment or 6 mo or 12 mo followup . Based on the reliability of change index for clinical significance , the relative short term success rates are 6.4 and 18.4 % for ECO and EDI , respectively . CONCLUSION The surplus value of a highly structured , 12 session group cognitive treatment added to group education can not be supported by our study . In EDI , fear reduction might have enhanced pain coping and pain control , while poor compliance , the difficulty of homework assignments , and lack of individual support may have limited the effectiveness of ECO [6849473] Three health education interventions for urban poor hypertensive patients were introduced sequentially in a r and omized factorial design : 1 ) an exit interview to increase underst and ing of and compliance with the prescribed regimen ; 2 ) a home visit to encourage a family member to provide support for the patient 's regimen ; and 3 ) invitations to small group sessions to increase the patient 's confidence and ability to manage his/her problem . Previous evaluation of the initial two-year experience demonstrated a positive effect of the educational program on compliance with the medical treatment and blood pressure control . Data accumulated over an additional three years , including mortality analysis , are now presented . The study group consisted of the same cohort of 400 ambulatory hypertensive out patients in the eight experimental and control groups . The five-year analysis shows a continuing positive effect on appointment keeping , weight control , and blood pressure control . All-cause life table mortality rate was 57.3 per cent less for the experimental group compared to the control group ( 12.9/100 vs 30.2/100 , p less than .05 ) , while the hypertension-related mortality rate was 53.2 per cent less ( 8.9/100 vs 19.0/100 , p less than .01 ) . The results from this longitudinal study provide evidence to encourage health practitioners to utilize such educational programs in the long-term management and control of high blood pressure [3533082] An important unanswered question about rheumatoid arthritis ( RA ) is how the patient 's psychological or emotional state relates to disease activity and functional status . No controlled studies of psychotherapeutic interventions in RA have been reported . To test the hypothesis that a psychosocial intervention would lead to improvement in functional status or disease activity , 57 RA patients were r and omly assigned to 1 of 3 groups , which received : 1 ) conventional group psychotherapy ; 2 ) group assertion/relaxation training ; or 3 ) no treatment ( control group ) . Patient and physician question naires collected at baseline , immediately after the interventions , and 12 months after baseline provided outcome data on functional status , social and psychological adaptation , psychological symptoms , and disease activity . There were few outcome measures for which either treatment result ed in significantly higher scores than were seen in controls , though more improvement did occur among patients who received conventional group psychotherapy [9526696] OBJECTIVES Re- analysis of a r and omized trial of an asthma education program design ed to assess the effects of the intervention on emergency department visits , limited days of activity and asthma knowledge and beliefs separately for African American and Caucasian adults with asthma . DESIGN Two hundred and forty-one respondents between the ages of 18 and 70 were evaluated in two emergency departments ( one inner city and one suburban location ) of a large , midwestern health care system and were r and omized to an intervention or control group . RESULTS Regardless of race , members of the intervention group showed a decrease in the number of post-intervention emergency department visits ( ANOVA interaction between race and group effect p value = 0.93 ) . The greatest decrease occurred during the first four post-intervention months . No differential effect of the asthma education intervention by race was found on the change in asthma knowledge and beliefs over the study period ( ANCOVA interaction between race and group effect p value = 0.60 ) . CONCLUSION This study demonstrates that post-intervention , both African American and Caucasian study participants showed a decrease in emergency department visits and an increase in asthma self-management . This finding is especially important for African Americans , who face increasing asthma mortality and morbidity [8467308] OBJECTIVE Evaluation of a structured hypertension treatment and teaching programme in general practice . DESIGN Prospect i ve controlled trial ; follow-up period 18 months . SETTING 10 primary health care practice s. PRACTICE S AND PATIENTS : From each practice 20 patients ( 30 to 60 years old , mean of the last two blood pressure measurements at or above 160 and /or 95 mmHg ) were r and omly selected ; in 5 practice s these patients were to participate in the treatment and teaching programme ; in the remaining 5 practice s hypertension care was continued without the availability of such a programme ( controls ) . INTERVENTION Structured treatment and teaching programme based upon four group sessions for patients mainly conducted by paramedical personnel . MAIN OUTCOME MEASURES Blood pressure , body weight , prescription of antihypertensive drugs - as documented in the patient 's records . MAIN RESULTS Of the 100 control patients 26 and of the 100 intervention patients 14 were lost to observation ; 46 patients had agreed to participate in the programme . The mean number of prescribed antihypertensive agents per patient decreased in the intervention group ( 1.8 + /- 1.3 at baseline , vs 1.2 + /- 1.2 at follow-up ) compared to the control group ( 1.6 + /- 1.3 vs 1.8 + /- 1.6 ) ; difference 0.8 ( 95 % CI 0.4 to 1.1 ) , p < 0.0001 . In the control group 9 % and in the intervention group 33 % of patients had documented reductions of body weight ( p < 0.0001 ) . Blood pressure decreased in the intervention group ( 162 + /- 14/100 + /- 7 mmHg at baseline , vs 154 + /- 16/95 + /- 9 mmHg at follow-up ) compared to the control group ( 161 + /- 13/98 + /- 7 mmHg vs 158 + /- 18/96 + /- 11 mmHg ) ; differences for systolic blood pressure 5 ( 95 % CI 0 to 10 ) mmHg , p = 0.071 ; for diastolic blood pressure 4 ( 1 to 7 ) mmHg , p = 0.018 . CONCLUSIONS The introduction of a structured hypertension treatment and teaching programme in general practice may lead to significant improvements of hypertension care [8035399] OBJECTIVE To determine the effectiveness of self-management education and physical training in decreasing fibromyalgia ( FMS ) symptoms and increasing physical and psychological well being . METHODS A pretest-posttest control group design was used . Ninety-nine women with FMS were r and omly assigned to 1 of 3 groups ; 86 completed the study . The education only group received a 6-week self-management course . The education plus physical training group received the course and 6 h of training design ed to assist them to exercise independently . The control group got treatment after 3 months . RESULTS The experimental programs had a significant positive impact on quality of life and self-efficacy . Helplessness , number of days feeling bad , physical dysfunction , and pain in the tender points decreased significantly in one or both of the treated groups when retested 6 weeks after the end of the program . Longterm followup of 67 treated subjects showed significant positive changes on the Fibromyalgia Impact Question naire primarily in the physical training group . Among all subjects , 87 % were exercising at least 3 times/week for 20 min or more ; 46 % said they had increased their exercise level since participating in the program ; 70 % were practicing relaxation strategies as needed ; 46 % were working at least half time as opposed to 37 % at pretest . CONCLUSION Self-efficacy of the treated groups was enhanced significantly by the program . Other changes were smaller and more delayed than had been expected . Recommendations for future trials include a longer education program , more vigorous physical training , and longterm followup [3698783] Home health nurses provided individualized instruction in diabetes self-care within the home environment of 393 diabetic individuals . Each subject was r and omly assigned to either the intervention ( those receiving home teaching ) or control ( those not receiving home teaching ) group . At 6 mo postenrollment , intervention subjects showed significantly greater self-care knowledge and skills than control subjects , although the actual differences between the two groups in terms of self-care skills were probably too small to have any practical meaning . The primary objective of the study , which was the reduction of the number of preventable diabetes-related hospitalizations ( ketoacidosis , ketotic coma , nonketotic coma , insulin reaction , and diabetes out of control ) , was not achieved ; no differences between the groups were noted after 12 mo of follow-up . Similarly , length of hospital stay , foot problems , emergency room and physician visits , and sick days were roughly equivalent in both groups during the follow-up year . These results suggest that , in the absence of concurrent changes in the health-care delivery system and strategies for influencing attitudes toward self-care , education alone is ineffective [9414057] & NA ; The effectiveness of a Pain Education Program in cancer patients with chronic pain offered by nurses was investigated in a r and omized controlled clinical trial . A multi‐ method approach was used in which verbal instruction , written material , an audio cassette tape , and the use of a pain diary were combined to inform and instruct patients about pain and pain management . The Pain Education Program was tailored to the needs of the individual patient and consisted of three elements : ( 1 ) educating patients about the basic principles regarding pain and pain management ; ( 2 ) instructing patients how to report their pain in a pain diary ; and ( 3 ) instructing patients how to communicate about pain and how to contact health care providers . Following pretesting in 313 patients , patients who needed district nursing and who did not need district nursing at home were r and omly assigned to a control or intervention group . Intervention group patients received the Pain Education Program in the hospital , and 3 and 7 days postdischarge by telephone ; this was done by nurses who were specially trained as pain counselors . Follow‐up assessment s were at 2 , 4 and 8 weeks postdischarge . Results of the pretest showed that many patients lacked knowledge about pain and pain management . The majority of pain topics had to be discussed . The Pain Education Program proved to be feasible : 75.0 % of the patients had read the entire pain brochure , 55.7 % had listened to the audio cassette , and 85.6 % of pain scores were completed in the pain diary . Results showed a significant increase in pain knowledge in patients who received the Pain Education Program and a significant decrease in pain intensity . However , pain relief was mainly found in the intervention group patients without district nursing . It can be concluded that the tailored Pain Education Program is effective for cancer patients in chronic pain . The use of the Pain Education Program by nurses should be seriously considered on oncology units [2200380] The prevalence and impact of adult asthma are substantial , and poor self-management practice s , especially failures to adhere to treatment regimens , appear to be a significant problem . Desirable characteristics of an intervention program to improve self-management were identified through needs assessment and review of existing patient education re sources . A comprehensive program was developed that integrated a workbook with one-to-one counseling and adherence-enhancing strategies . A longitudinal 1-year study compared patients receiving this self-management program with " usual care " patients receiving st and ard asthma pamphlets . Patients were r and omly assigned to conditions . Baseline score and asthma severity were statistically controlled . Self-management patients had substantially better adherence than usual care patients , as well as improved functional status , at follow-up . Hospital and emergency department visits decreased in both groups but did not differ between groups [8506881] PURPOSE Excess morbidity and mortality due to asthma , aggravated by demonstrably poor patient self-management practice s , suggest the need for formal patient education programs . Individual and group asthma education programs were developed and evaluated to determine their cognitive , behavioral , and clinical effects . PATIENTS AND METHODS We compared changes in asthma symptoms , utilization of medical services , knowledge about asthma , metered-dose inhaler ( MDI ) technique , and self-management behaviors for 323 adult Kaiser Permanente patients with moderate to severe asthma who were r and omly assigned to small-group education , individual teaching , or 1 of 2 control conditions -- an information ( workbook ) control or usual control ( no formal asthma education ) . Data were collected from patients by question naire , diary , and physical examination at enrollment and at 5 months and 1 year after intervention . Medical record data on these patients were abstract ed for a total 3-year period , from 1 year before to 2 years after enrollment . RESULTS Compared with the usual control , the self-management education programs were associated with significant improvements in control of asthma symptoms ( reduced " bother " due to asthma and increased symptom-free days ) , MDI technique , and environmental control practice s. Small-group education also was associated with significant improvements in physician evaluation of the patients ' asthma status and in patients ' level of physical activity . For both group and individual education recipients , improvement in MDI technique was positively correlated with improved control of symptoms ; however , the degree of improvement in symptoms was greater than that which could be accounted for on the basis of improvement in MDI technique alone . The time course over which changes occurred in the various outcome measures suggests the mechanism by which education result ed in improvement in the patient 's status . Significant improvements in MDI technique and environmental control practice s were manifest immediately following education ( 5-month follow-up ) and at the 1-year follow-up . Significant improvements in symptom measures were not apparent until the 1-year follow-up . The rate of utilization of medical care for acute exacerbations decreased between baseline and the 2-year follow-up period , but this decrease did not differ significantly among treatment conditions . However , there was a trend toward greater reduction in patients receiving small-group education . An ad hoc finding of a significant difference favoring small-group education between the baseline and the second follow-up year acute visit rates was observed . This result must be regarded as tentative , since it is not clear that unambiguous statistical significance is attained in the light of multiplicity issues . However , this trend is consistent with the antecedent benefits of the small-group education , and appears to warrant further investigation . CONCLUSIONS Carefully design ed asthma education programs for adults can improve patients ' underst and ing of their condition and its treatment and increase their motivation and confidence that the condition can be controlled , thereby increasing their adherence to the treatment regimen and management of symptoms , and , in turn , improving control of symptoms . Both small-group education and individual education were associated with significant benefits , but the group program was simpler to administer , better received by patients and educators , and more cost-effective . The results show promise for improving clinical outcomes , through well- design ed educational programs , for patients with asthma and other chronic health problems [9619885] Despite the wide availability of disease-related leaflets , their impact on patients ' knowledge and well-being has rarely been evaluated . A r and omized controlled study of a ' Rheumatoid Arthritis ' leaflet revealed increased knowledge among the intervention group after 3 weeks . In addition , the leaflet was viewed as a source of reassurance . The purpose of the follow-up study was to determine whether the increase in knowledge was maintained in the longer term and to examine psychological well-being . Eighty-four patients ( 42 intervention and 42 control ) completed the 6 month follow-up . There were no significant changes ( P > 0.01 ) in mean outcome measures over the period 3 weeks-6 months for either the intervention or control groups . Patients in the intervention group retained the increase in knowledge observed at 3 weeks . Moreover , there was no evidence of adverse reactions to the leaflet in terms of psychological distress . Leaflets can be effective in promoting longer term increases in knowledge [8529086] PURPOSE Patients who have undergone coronary artery bypass graft surgery ( CABG ) are obvious c and i date s for rehabilitation programs because of the potential for progression of disease . Such programs have been shown to foster risk-factor modification , improve quality of life , and prolong survival among post-myocardial infa rct ion ( MI ) patients . However , the efficacy of these programs has not been established among patients who have undergone CABG . METHODS A r and omized controlled trial was employed to evaluate whether a behavioral and educational cardiac rehabilitation program was effective in modifying cardiovascular disease risk factors and improving quality of life in a cohort of 86 patients after CABG . Patients were recruited from the cardiac ward of a large teaching hospital and were block-r and omized to either an intervention group or routine care . Subjects in the intervention group attended 6 weekly group sessions following hospital discharge , and booster sessions at 8 months and 1 year . They also received a personalized behavior modification program based on their baseline risk factors . Risk factor and quality of life measures were recorded at baseline ( 6 weeks after surgery ) , 4 months , 8 months , and 1 year . RESULTS The results indicated few differences between the study groups . However , the intervention group 's aerobic capacity ( VO2max ) improved over that of the routine care group . With regard to the quality of life variables , all patients tended to improve steadily over time . CONCLUSIONS The relatively moderate success of this intervention program compared with various post-MI studies may be indicative of differences between the treatment needs of patients after acute myocardial infa rct ion or CABG . Future post-CABG rehabilitation research should explore these patients ' unique treatment needs , and investigate a variety of program strategies [2188495] The effects of an educational program on compliance and blood pressure ( BP ) control were assessed in 47 hypertensive patients hospitalized for nonhypertension-related diseases . Patients were r and omized to receive either a question naire and an educational program ( group I , 25 ) or question naire only ( group II , 22 ) . Baseline clinical characteristics , admission diagnoses and antihypertensive medications were similar between the groups . Antihypertensive medications used by patients before the trial were not changed . Eight weeks after the initial intervention , patients in group I showed a significant reduction in both systolic and diastolic BP ( 137/89 vs 154/98 mm Hg , p = 0.005 and 0.006 , respectively ) and improved compliance ( 96 vs 36 % , p = 0.04 ) , compared with patients in group II . An education program in patients with high BP is an effective method to improve compliance and BP control in the short-term [3549757] To examine the effects of intensive patient and /or physician diabetes education on patient health outcomes , a controlled trial was conducted in which internal medicine residents and their 532 diabetic patients were r and omly assigned to : routine care ; patient education ; physician education ; or both patient and physician education . Patient outcome data were analyzed either by analysis of covariance on post intervention values ( 2-hour post-pr and ial plasma glucose [ PPG ] ; body weight [ BW ] ; blood pressure [ BP ] ; or analysis of variance conducted on change values ( fasting plasma glucose [ FPG ] and glycosylated hemoglobin [ A1Hgb ] ) . After patient education , significant improvements were observed in FPG , A1Hgb , BW , and systolic and diastolic BP . Physician education result ed in significant decreases in FPG , A1Hgb and BW . The combination of patient plus physician education result ed in the greatest improvements in patients ' health outcomes including FPG , A1Hgb , PPG , BW and diastolic BP . Adjusted systolic BPs were not significantly different in the two groups . While these physiologic improvements were statistically and probably clinical ly significant , hyperglycemia and obesity still persisted . Thus , achieving optimal patient outcomes for a chronic disease like diabetes mellitus may require a greater or more effective use of re sources than currently estimated [3088085] A sample of 310 low income urban children with asthma from 290 families was r and omized into a control group and an experimental group that received health education to improve asthma management at home . No significant decreases in subsequent health care use were observed when the experimental group was compared to the control group without regard to previous hospitalization . When the comparison was restricted to children who had been hospitalized during the preceding year , however , the experimental group was found to have decreased its use of the emergency room significantly more than the control group ( p less than 0.05 ) and to have experienced a significantly greater reduction in the mean number of hospitalizations ( p less than 0.05 ) during the year of follow-up . The program reduced health care costs for children with one or more hospitalizations , saving $ 11.22 for every $ 1.00 spent to deliver health education [2258874] This study was planned in the context of a regional high blood pressure programme , to compare the efficacy of two educative methods . The group of 722 hypertensive patients ( 58.8 % women ) , mean age 61 years , was r and omly selected from 19 primary care centres . Initial assessment was based on a patient interview including 22 questions on high blood pressure , its consequences and treatment . Patients agreeing to participate in an active education team programme were distributed into three groups : individual education , team education and a control group . Those who declined to participate formed two groups : individual education and controls . Team education consisted of two audiovisual sessions attended by groups of 8 - 12 patients and conducted by treating physicians and nurses . Individual education included comments related to the 22 questions . Follow-up assessment was made after two months . An increase in the level of hypertension control was observed only in the accepting group , in which educative action was followed by increased knowledge . Results were similarly favourable for both the individual and team education groups and suggested the need to consider educational factors together with those influencing patient attitude towards an active educational programme [9295453] OBJECTIVE To evaluate the effects of a program for individual education in combination with the use of an arthritis passport . METHODS We studied 3 groups of patients with rheumatoid arthritis . The first experimental group received educational material s and followed the program under the guidance of their regular providers of health care whose activities were coordinated through arthritis passports . The second experimental group only received education material s ; the control group received only usual care . RESULTS There were no effects on self-efficacy expectations , knowledge , health status , or behavior in either experimental group . Opinions of general practitioners , physiotherapists , and visiting nurses concerning the arthritis passport were very positive , but rheumatologists ' opinions were not . Opinions on coordination of care were more positive among the physiotherapists of the experimental group . CONCLUSIONS Individual education for patients with rheumatoid arthritis by health care providers during routine consultations , as implemented in this program , had no effect on self-efficacy expectations , knowledge , health status , or health behavior . Likewise , the distribution of educational material s by itself without the involvement of health care providers had no effect . The use of the arthritis passport improved coordination of care , especially for physiotherapists [7487240] BACKGROUND The management of oral anticoagulation is fraught with difficulties . This study assessed a new model of anticoagulation management regarding the ability , safety , and efficacy of patients to self-monitor and self-adjust the dose of their oral anticoagulants guided by a capillary whole-blood prothrombin time ( PT ) monitor . METHODS This investigation is a retrospective cohort study of 20 patients compared with 20 matched control patients receiving oral anticoagulation at a tertiary medical institution . RESULTS Study patients monitored their PTs 2153 times during a mean interval of 44.7 months compared with 1608 PTs in matched control patients during a mean interval of 42.5 months . Study patients made an average of 11.5 dosage changes per patient , contrasted with 22.7 changes per control patient ( P < .001 ) . The PTs in study patients were within the recommended therapeutic range in 88.6 % ( 95 % confidence interval , 87.2 to 89.9 ) of the determinations compared with 68.0 % ( 95 % confidence interval , 65.7 to 70.3 ; P < .001 ) of the determinations made by the matched control patients . In response to the 2153 PTs , study patients made 67 ( 3.1 % ) dosage decisions that were considered incorrect based on physician guidelines . None of these changes led to adverse outcomes . There was no significant difference in complication rates between the two groups . CONCLUSIONS Results from what is the first long-term study of patient self-monitoring of PTs and self-adjustment of the warfarin sodium dosage for oral anticoagulation suggest that patients can successfully measure their own PTs , adjust their own warfarin dosage , and achieve a degree of therapeutic effectiveness at least as good , if not better than patients managed in an anti-coagulation clinic . Larger , prospect i ve , r and omized trials are needed to confirm the efficacy and safety of this new approach to therapy and to assess its cost-effectiveness [7670785] A 5-yr follow-up of an arthritis education programme is reported . After adjustment for those lost , deceased or moved away , the 5-yr response rate was 75 % among intervention subjects and 78 % among controls . Individuals who participated in the education programme maintained their increased knowledge in some aspects . The relative difference in pain and disability over 5 yr was greater in the control group . Most individuals were less active at practising exercise after 5 yr . Improvement in performing exercise and joint protection shown at 12-months follow-up did not persist . Additional questions after 5 yr showed that participants in the education programme had significantly more contact with rheumatologists , physiotherapists and occupational therapists . The participants developed an increased internal sense of control of the disease between 12 months and 5 yr . There was also a significant reduction in reported problems with their disease after 12 months , maintained after 5 yr . This may indicate that patient education contributes to the patient 's feeling of responsibility for , and ability to cope with , their diseases [8605463] Abstract Objective : To compare the efficacy of self management of asthma with traditional treatment . Design : 12 month prospect i ve r and omised trial . Setting : Outpatient clinics in Finl and . Subjects : 115 patients with mild to moderately severe asthma . Interventions : Patient education and adjustment of anti-inflammatory therapy guided by peak flow measurements . Main outcome measures : Unscheduled admissions to hospital and outpatient visits , days off work , courses of antibiotics and prednisolone , lung function , and quality of life . Results : The mean number of unscheduled visits to ambulatory care facilities ( 0.5 v 1.0 ) , days off work ( 2.8 v 4.8 ) , and courses of antibiotics ( 0.4 v 0.9 ) and prednisolone ( 0.4 v 1.0 ) per patient were lower and the quality of life score ( 16.6 v 8.4 at 12 months ) higher in the self management group than in the traditionally treated group . In both groups admissions for asthma were rare . Conclusions : Self management reduces incidents caused by asthma and improves quality of life . Key messages Key messages This trial of 115 patients with mild to moderately severe disease r and omised half to a traditional care and half to a self management programme consisting of education about asthma and daily peak flow readings Intervention thresholds of < 85 % of the optimal peak flow for doubling the dose of inhaled steroid for two weeks and of < 70 % of the optimal peak flow for starting a course of oral steroids worked well The self management group had fewer incidents ( consultations , days off work , courses of prednisolone or antibiotics ) than the traditionally treated group and better quality of life scores Adherence of patients to the self management instructions was better than [8788354] Arthritis is a common chronic disease causing pain and progressive disability to millions of people . The purpose of the study was to examine the effectiveness of group patient education for people with one form of arthritis , ankylosing spondylitis ( AS ) , in terms of change in : arthritis self-efficacy ; psychological well-being ; physical well-being ; and home exercise activities . The Self-Management Course-Ankylosing Spondylitis ( SMC-AS ) demonstrated positive effects on arthritis self-efficacy and psychological well-being at 6-month follow-up . Analysis of change over time in the intervention group showed improvements in depression , self-efficacy and severity at 3 weeks , with trends towards continued improvement evident at 6 months . In contrast , the positive effects on range and frequency of home exercise activities at 3 weeks were not maintained at 6 months . In conclusion , the effectiveness of short , intensive patient education courses was demonstrated . However , the need for strategies to sustain improvements in exercise behaviour need to be explored [3565666] We assessed diabetes education and peer support interventions as facilitators of weight loss and glycemic control in a community sample of 79 elderly persons with noninsulin-dependent diabetes mellitus ( NIDDM ) . Different groups received : education only , education and peer support , and no treatment . Peer support was higher in groups where it was actively facilitated . Weight loss and reduction in level of glycemic control occurred within groups receiving both diabetes education and peer support [9595179] Forty three patients with essential hypertension participated in a study on the effectiveness of stress-management training for essential hypertension . After 6–9 clinic and 48 self-measured readings of systolic and diastolic blood pressures ( SBP and DBP ) , 22 patients were treated with a program based on education , relaxation , and problem-solving training ; and another 21 patients were assigned to a waiting list control group . At post-treatment , mean reductions of clinic BP ( 17/13 mm Hg vs. 6.9/4.7 mm Hg for SBP/DBP ) , percentages of subjects who achieved at least a 5 mm Hg reduction ( 86/86 % vs. 48/48 % for SBP/DBP ) and percentages of subjects who in addition achieved a normotensive level ( 59/68 % vs. 29/14 % for SBP/DBP ) were significantly higher in the treated group than in the control group . Concerning self-measured BP , the effectiveness of the stress-management training was not so considerable ( mean reductions of 3.6/2.4 mm Hg and percentages of subjects who achieved a 5 mm Hg reduction of 52/38 % for SBP/DBP ) , but it was significant and maintained in a 4-month follow-up assessment ( mean reductions of 4/2 mm Hg and percentages of subjects who achieved a 5 mm Hg reduction of 48/33 % for SBP/DBP ) . It is suggested that stress-management training can be beneficial for treatment of essential hypertension [3887910] Stress management and mutual support groups are employed widely in chronic illness , although their efficacy has not been established . To determine the effect of these measures on morbidity and psychologic health in rheumatoid arthritis , 105 patients meeting diagnostic criteria for rheumatoid arthritis were evaluated for depression , life satisfaction , functional disability , and indicators of disease activity . Patients were r and omly assigned to one of three groups : ( 1 ) stress management ; ( 2 ) mutual support ; ( 3 ) no intervention ( control ) . After completion of 10 weekly sessions , identical tests were performed for all patients in the intervention and control groups . Patients in the intervention groups showed greater improvement in joint tenderness than did the control patients but did not differ significantly from the patients in the control group in any of the other outcome measures [2917233] The benefits of patient education for those with chronic arthritis are well documented . Informed patients should practice self care more often , and may show reduced disability from their disease . An important question relates to maintenance of the knowledge and skills acquired in educational programmes . This prospect i ve study evaluated an education programme for people with rheumatoid arthritis ( RA ) and osteoarthritis ( OA ) . The intervention group participated in a comprehensively planned six session behaviourally based programme . A question naire was given to 100 patients and 95 matched but non-r and om controls before the programme , 1 month later , and at 3 and 12 months . The intervention group demonstrated improvements in knowledge , self-reported health behaviour and disability scores at 12 months , compared to the controls . No differences were reported in symptoms , compliance with therapy , pain perception , and locus of control [3775139] A population -based study on the therapeutic effects of a diabetes teaching programme ( DTP ) based on problem oriented participatory education (POPE)--a method based on learner activity in group meetings -- was undertaken at the Primary Health Care Centre , Kisa , Sweden , in collaboration with educationalists . A control group was given conventional classroom teaching . To be included a patient had to be aged 55 - 73 years , to live in his own home , and to have non-insulin-treated type II diabetes mellitus . The therapeutic effects of the DTP were studied before , during , and after POPE with regard to three factors , diabetes related knowledge , behaviour assessed by dietary and exercise habits , and the quality of the anti-diabetic therapy as assessed by metabolic profile including Hb-A1 . Significant improvement in knowledge and transient improvement in Hb-A1 concentration were recorded among patients taking part in a DTP adjusted to their individual problems and needs . When improvement in metabolic control does not last , group meetings should be continued for more than the three months used in the present study . We believe that such improvement is intimately bound up with the psycho-social process that is involved in the group meetings and that helps the patient to cope with the disease in particular and life in general [1427244] This paper presents findings from the evaluation of a self-management education program based on self-regulation principles . Older men and women ( N = 324 ) were r and omly assigned to program and control groups . Outcomes were measured using the Sickness Impact Profile . Twelve months following baseline data collection , psychosocial functioning of program participants was significantly better than that of controls . Different program effects were noted when results were analyzed by participant gender [3948638] The Diabetes Education Study ( DIABEDS ) was a r and omized , controlled trial of the effects of patient and physician education . This article describes a systematic education program for diabetes patients and its effects on patient knowledge , skills , self-care behaviors , and relevant physiologic outcomes . The original sample consisted of 532 diabetes patients from the general medicine clinic at an urban medical center . Patients were predominantly elderly , black women with non-insulin-dependent diabetes mellitus of long duration . Patients r and omly assigned to experimental groups ( N = 263 ) were offered up to seven modules of patient education . Each content area module contained didactic instruction ( lecture , discussion , audio-visual presentation ) , skill exercises ( demonstration , practice , feedback ) , and behavioral modification techniques ( goal setting , contracting , regular follow-up ) . Two hundred seventy-five patients remained in the study throughout baseline , intervention , and postintervention periods ( August 1978 to July 1982 ) . Despite the requirement that patients demonstrate mastery of educational objectives for each module , postintervention assessment 11–14 mo after instruction showed only rare differences between experimental and control patients in diabetes knowledge . However , statistically significant group differences in self-care skills and compliance behaviors were relatively more numerous . Experimental group patients experienced significantly greater reductions in fasting blood glucose ( −27.5 mg/dl versus −2.8 mg/dl , P < 0.05 ) and glycosylated hemoglobin ( −0.43 % versus + 0.35 % , P < 0.05 ) as compared with control subjects . Patient education also had similar effects on body weight , blood pressure , and serum creatinine . Continued follow-up is planned for DIABEDS patients to determine the longevity of effects and subsequent impact on emergency room visits and hospitalization [8557972] Objective : To determine the prognosis of treated hypertensive type 1 ( insulin-dependent ) diabetic patients with overt nephropathy . Design : A controlled , prospect i ve , parallel , 5-year follow-up trial . Setting : The tertiary care centre of the Heinrich Heine University Hospital in Dusseldorf , Germany . Patients and interventions : A sequential sample of 91 hypertensive patients with overt diabetic nephropathy participated in a diabetes treatment programme . Thereafter 45 patients received intensified antihypertensive therapy including blood pressure self-monitoring and self-adjustment of antihypertensive drug treatment with the goal of permanent normalization of blood pressure values below 140/90 mmHg . The remaining 46 patients were administered routine antihypertensive therapy and formed the control group . At baseline both groups were comparable in age , sex , metabolic control and renal function . The groups differed at baseline in their duration of diabetes and blood pressure values , which were higher in the intensified antihypertensive therapy group . Outcome measures : Total mortality and the need for renal replacement therapy . Main results : Blood pressure control was significantly improved in patients who were subjected to intensified antihypertensive therapy , whereas it deteriorated in the group of patients who received routine antihypertensive therapy . At follow-up , primary end points of the study occurred in five ( 11 % ) patients of the intensified therapy group and in 19 ( 41 % ) patients of the routine therapy group . According to life table analysis , intensified antihypertensive therapy was associated with less frequent primary end points ( P= 0.0058 ) and longer survival ( P=0.01 ) . The differences between the groups remained significant after adjustment for covariates in the proportional hazards model . Conclusion : Participation in a treatment programme aim ed at intensification of antihypertensive therapy is associated with a reduction of mortality in hypertensive type 1 diabetic patients with overt nephropathy [7125768] Because the elderly are viewed as having more difficulty in complying with therapy , this analysis was directed at the effects of a health education program on their control of primary hypertension when compared with a younger population . The program consisted of three sequential interventions introduced in a r and omized factorial design . Depsite the fact that elderly patients had more chronic disease , more complications from hypertension , and were receiving more complex drug therapies than younger patients exposed to the same experimental interventions , they demonstrated significantly higher levels of compliance with drug therapy , significantly higher levels of appointment keeping , and no difference in the proportion having their BP under control at two-year-follow-up . Longitudinal data collected at five-year follow-up indicate no decay effect . These results indicate such programs can be successfully implemented and equally effective for an elderly population [2688659] After we assessed the functional status of 439 patients with osteoarthritis , we r and omly assigned them to 1 of 3 intervention groups or to a control group . The interventions consisted of providing information , and differed only in the method of delivery : by phone , in person at the clinic , or both . Physical health improved ( P = 0.02 ) , pain was reduced ( P = 0.02 ) , and psychological health improved marginally ( P = 0.10 ) in patients contacted by phone compared with those not contacted by phone . In those contacted only at the clinic , physical health worsened ( P = 0.02 ) , but neither pain ( P = 0.80 ) nor psychological health ( P = 0.90 ) differed from the values in patients not contacted at the clinic . We conclude that telephone contact is a useful intervention that can enhance the functional status of patients with osteoarthritis

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### Context: [3503941] A r and omized controlled trial of an information and medical record booklet design ed to improve patient underst and ing and participation in the management of hypertension was conducted in six inner London general practice s. After one year there were no significant differences between the group who had received the booklets and the control group in mean systolic or diastolic blood pressure , but the study group scored significantly higher on knowledge about hypertension and its management . However , the difference between the two groups was small , possibly because both groups started with a high level of underst and ing about hypertension and its management . In addition , the mean diastolic blood pressure in the control group showed that the treatment provided was already satisfactory , and that there was little need for improvement . Nevertheless , the information booklet evaluated in this study provides health professionals with a highly acceptable method of informing the patient about hypertension and its management and could be used both in hospital and general practice [6995966] Abstract An experimental study was carried out to test and analyze the effects of an educational program on a group of hypertensive patients , comparing those with known higher risks of stroke and heart attack , e.g. , secondary organ damage , with a group whose risks were relatively lower . Specific interventions have been shown to be differentially effective on specific patient behaviors ( e.g. , compliance with therapy ) and on blood pressure control for both higher- and lower-risk patients in most of the experimental groups . Such findings emphasize the importance of tailored educational approaches , not only for a hypertensive population , but , more importantly , for patients who are known to have more difficulty achieving their blood pressure control and who are at higher risk of morbidity and mortality , i.e. , patients who have secondary organ damage , have been previously hospitalized for hypertension , or are black males under 50 years of age [3302144] Evidence suggests that diet and exercise are associated with improved glucose tolerance for patients with non-insulin-dependent diabetes mellitus ( NIDDM ) . Seventy-six volunteer adult patients with NIDDM were each assigned to one of four programs : 1 ) diet , 2 ) exercise , 3 ) diet plus exercise , or 4 ) education ( control ) . Each program required ten weekly meetings . Detailed evaluations were completed prior to the program and after three , six , 12 , and 18 months . Evaluations included various psychosocial measures , measures of the quality of life , and fasting blood glucose , glycosylated hemoglobin , and relative weight determinations . Of the 76 original participants , 70 completed the 18-month follow-up study . At 18 months , the combination diet- and -exercise group had achieved the greatest reductions in glycosylated hemoglobin measures . In addition , this group showed significant improvements on a general quality of life measure . These improvements were largely uncorrelated with changes in weight . The authors conclude that the combination of dietary change and physical conditioning benefits NIDDM patients , and that the benefits may be independent of substantial weight loss [8671102] BACKGROUND Many patients with asthma or chronic obstructive pulmonary disease use their medication inhalers incorrectly . General practitioners , pharmacists and other health care providers do not always have the opportunity to instruct patients in correct inhaler technique . OBJECTIVE To find out whether the inhaler technique and respiratory symptoms of patients can be improved after instruction by practice assistants . METHODS Single blind , r and omized intervention study in which 48 patients who had been using a dry powder inhaler for at least one month took part . Their inhaler technique was videotaped on two visits with a two-week interval between visits . The inhaler technique on the videos was subsequently scored by two experts on nine criteria . At both visits the patients completed a question naire about their respiratory symptoms . After the first video , 25 patients were r and omly chosen to receive instruction from one of six practice assistants who had followed a one evening course about inhaler instruction , and who had been issued an instruction-set . RESULTS The patients who received instruction had a significantly greater reduction in number of mistakes at the second visit than the patients who did not ( P = 0.01 ) . The instructed patients also reported less dyspnoea at the second visit ( P = 0.03 ) . No effect of instruction was found on wheezing , cough and sputum production . CONCLUSION The inhaler technique of patients can be improved significantly by the instruction of patients by trained practice assistants , possibly result ing in less dyspnoea [9917117] CONTEXT Control of oral anticoagulation therapy has been reported to often be inadequate . Previous retrospective investigations suggest that patients ' self-adjustment of oral anticoagulants may lead to improved control . OBJECTIVE To investigate the effects of patients ' self-management of oral anticoagulation therapy on accuracy of control and measures of treatment-related quality of life . DESIGN R and omized , single-blind , multicenter trial . SETTING AND PARTICIPANTS A total of 179 patients receiving long-term oral anticoagulation treatment were enrolled at 5 referral centers in Germany . INTERVENTION Patients were r and omized to an oral anticoagulation self-management group based on a structured treatment and teaching program and international normalized ratio ( INR ) self-monitoring . The control group received conventional care as provided by family physicians , including referral to specialists if necessary . MAIN OUTCOME MEASURES Deviation of INR values from the individual INR target range ( squared ) and the 5 categories of treatment-related quality of life . RESULTS Deviation of INR value from the mean of the INR target range was significantly lower in the intervention group at 3-month ( squared INR deviation , 0.59 vs 0.95 ; P<.001 ) and 6-month follow-up ( 0.65 vs 0.83 ; P=.03 ) compared with the control group . Also , the intervention group had INR values within the target range more often ( repeated measurement analysis for categorical data , P=.006 ) . The results were mainly due to less frequent suboptimal INR values in the intervention group ( 32.8 % vs 50.0 % [ P=.03 ] at 3-month , and 33.7 % vs 48.2 % [ P=.08 ] at 6-month follow-up ) . Treatment-related quality -of-life measures , especially treatment satisfaction scores , were significantly higher in the intervention group compared with controls . CONCLUSIONS An anticoagulation education program that includes self-management of anticoagulation therapy results in improved accuracy of anticoagulation control and in treatment-related quality -of-life measures . Further studies are needed to describe whether the program will reduce risk of bleeding or thromboembolism [7842191] A prospect i ve controlled trial of home monitoring of peak expiratory flow rate ( PEFR ) was conducted to determine the usefulness of an objective measure of lung function in association with an education program and a medication self-management plan in reducing morbidity in adult patients with asthma . Thirty-five patients managed themselves , using peak flow readings as the basis for the therapeutic plan coupled with educational intervention , whereas 35 control patients used symptoms and spirometric data for following physicians ' treatment plans . After a 6-mo study period , patients in the experimental group showed statistically significant improvements in morbidity parameters ( days lost from work , acute asthma attacks , days on antibiotic therapy , physician consultations , and emergency room admissions for asthma ) , increases in FVC , FEV1 , and FEV1/FVC , mean PEFR and mean morning PEFR , decrease in percentage of the mean PEFR amplitude , and a reduction in the use of inhaled beta-agonists , oral theophylline , and oral prednisone . Although improvements in some of these parameters were also found in the control group , they did not reach the levels of significance obtained in the experimental group . The personal use of an objective measure of lung function in association with a medication self-management plan leads to improvement in the patient 's condition [3314877] A r and omized clinical trial was performed to evaluate a psychological treatment intervention and a social support program , compared with a control program in which no adjunct treatment was rendered , and their effects upon pain behavior , affect , and disease activity of 53 patients with rheumatoid arthritis . The psychological intervention produced significant reductions in patients ' pain behavior and disease activity at posttreatment . Significant reductions were also observed in trait anxiety at posttreatment and 6-month followup . Relaxation training may have been the most important component of the psychological intervention . The social support program produced a significant reduction in trait anxiety only at posttreatment . This is the first well-controlled study to demonstrate reduced pain behavior , disease activity , and trait anxiety following psychological treatment [3772925] One hundred subjects with arthritis were r and omized into lay-taught , or professional-taught 12-h arthritis self-management courses , or a control group . Outcomes , knowledge , exercise , relaxation , disability , pain , and number of physician visits were measured aat baseline and 4 months . Professional-taught groups demonstrated greater knowledge gain while lay-taught groups had greater changes in relaxation ( p less than .01 ) and a tendency toward less disability . Although it is impossible to draw definitive conclusions , this study suggests that lay leaders can teach arthritis self-management courses with results similar to those achieved by professionals [2589581] This prospect i ve r and omized study evaluated the influence of a simple education program on the incidence of lower extremity amputation in diabetic patients . Two hundred three patients were r and omized into two groups : Group 1 , education ( 103 patients , 203 limbs ) and Group 2 , no education ( 100 patients , 193 limbs ) . There were no significant differences in medical management or clinical risk factors between the two groups . The amputation rate was three times higher in Group 2 ( 21 of 177 limbs versus 7 of 177 limbs ; p less than or equal to 0.025 ) , the ulceration rate was three times higher in Group 2 ( 26 of 177 limbs versus 8 of 177 limbs ; p less than or equal to 0.005 ) , and there was no difference in the overall incidence of infection ( 2 of 177 limbs ) . Overall success in Group 1 was highly significantly different from Group 2 ( 160 of 177 limbs versus 128 of 177 limbs ; p less than or equal to 0.0005 ) . This study demonstrated that a simple education program significantly reduced the incidence of ulcer or foot and limb amputation in diabetic patients [8702449] OBJECTIVE The effects of treatment counseling or symptom monitoring telephone intervention strategies on the health outcomes of patients with rheumatoid arthritis ( RA ) or osteoarthritis ( OA ) , compared with usual care , were assessed . METHODS A 3-group , r and omized , controlled 9-month trial was conducted incorporating 405 patients with RA or OA and using the Arthritis Impact Measurement Scales ( AIMS 2 ) as the outcome measure . RESULTS Analyses of covariance showed that the AIMS 2 total health status of the treatment counseling group ( effect size = 33 , P < 0.01 ) , but not the symptom monitoring group ( effect size = 0.21 , P = 0.10 ) , was significantly improved , compared with usual care , for both RA and OA patients . The specific types of benefits differed significantly between RA and OA patients . The mean number of medical visits by OA patients in the treatment counseling group was also significantly reduced ( P < 0.01 ) . CONCLUSION Telephone contact using the treatment counseling strategy produced significant , but different , health status benefits for RA and OA patients . The symptom monitoring strategy produced modest benefits [6742256] This research reports level of blood pressure control and ability to maintain newly discovered hypertensives in a municipal hospital setting by use of family- and self-monitored home blood pressure units . Three hundred ninety-six patients were r and omized into family- and self-monitored blood pressure groups and a control group . Findings indicate that the use of either self- or family-read cuffs is effective in the first six months of treatment in lowering blood pressures . The data are suggestive of a beneficial effect of the use of cuffs for up to 18 months ; however , with additional time in the study , no differences in the level of blood pressure control could be demonstrated between groups . The use of family-monitored blood pressure cuffs produces a lower drop-out rate than does the use of no cuff . The effect on drop outs is substantial for the first year of treatment , but beyond 12 months , the family-read cuff is also more effective than no cuff in reducing drop outs [8163051] Summary In a prospect i ve controlled trial the effects of a 5-day in-patient treatment and teaching programme for Type 1 ( insulin-dependent ) diabetes mellitus on metabolic control and health care costs were studied in Moscow . Two different intervention programmes were compared , one based upon urine glucose self-monitoring ( UGSM , n = 61 ) and one using blood glucose selfmonitoring ( BGSM , n = 60 ) . Follow-up was 2 years . A control group ( n = 60 ) continued the st and ard treatment of the Moscow diabetes centre and was followedup for 1 year . Costs and benefits with respect to hospitalizations and lost productivity ( according to average wage ) were measured in November 1992 roubles ( Rb . ) , with respect to imported drugs and test strips in 1992 German marks ( DM ) . In the intervention groups there were significant decreases of HbA1 values [ UGSM : 12.5 % before , 9.4 % after 1 year , 9.2 % after 2 years ( p < 0.0001 ) ; BGSM : 12.6 % before , 9.3 % after 1 year , 9.2 % after 2 years ( p < 0.0001 ) compared to no change in the control group ( 12.2 % before , 12,3 % after 1 year ) ] , and of the frequency of ketoacidosis . The frequency of severe hypoglycaemia was comparable between the UGSM ( 10 cases during 2 years ) , BGSM ( 10 cases during 2 years ) , and the control group ( 8 cases during 1 year ) . In the combined intervention groups , there were significant decreases of hospital days per patient per year ( 12.1 during the year before , 1.0 year one after , 3.6 year two after , p < 0.005 ) , and of additional sick leave days ( 16.6 during the year before , 2.4 year one , 7.8 year two after , p < 0.01 ) , whereas these parameters remained unchanged in the control group . The initial costs of the intervention were outweighed by this subsequent reduction in hospitalizations and lost productivity . Net savings totalled up to 14400 Rb./patient within 2 years . Patients of the intervention groups were told to discontinue drugs which were not indicated and /or ineffective ( clofibrate , pentoxifylline , calcium dobesilate ) . This caused estimated average savings of DM 240 per patient per year . Costs of test strips for UGSM were DM 180 per patient per year ; for BGSM they were estimated to lie between DM 370 and DM 550 per patient per year , depending on the frequency of measurements . In conclusion , the intervention led to an improvement of metabolic control and saved re sources for health care by reducing hospitalizations and sick leave days . When UGSM is used , costs of test strips are approximately outweighed by discontinuing ineffective drugs [2867269] Two different patient education programmes for asthma in general practice were evaluated in a controlled trial . Knowledge , self management , and morbidity due to asthma were assessed in 339 patients by means of a question naire . One group then received a maximum education programme , a second group received a limited education programme , and a third acted as a control group . 274 patients were reassessed after one 1 year . In both the intervention groups , underst and ing of asthma was greater after the trial . Only in the maximum intervention group was a significant improvement in knowledge of asthma shown . Neither group showed any change in self-management ability or asthma morbidity that differed significantly from changes in the control group . These simple informational education programmes were ineffective when applied to a general practice population . Further studies of factors affecting attitudes , beliefs , and actions are needed to improve the advice and support given to asthma patients [2454118] To examine the effectiveness of a cognitive-behavioral pain management program for patients with rheumatoid arthritis , three patient groups were studied : a cognitive-behavioral group ( CB ) , an attention-placebo group , and a control group . The CB group received a comprehensive , 12-month pain management program that taught coping strategies such as problem-solving techniques , relaxation training , strategies for attention diversion , and training in family dynamics and communication . Dependent measures included pain , coping strategies , psychological status , functional status , and disease status . Data analysis at 12 months revealed benefits for the CB group in the area of enhanced coping strategies . Specifically , the CB subjects showed significantly greater use of coping strategies and significantly more confidence in their ability to manage pain . The findings are discussed in terms of the importance of enhanced self-efficacy and personal control for patients with rheumatoid arthritis [8613276] Community-based hypertension control is important for primary prevention of cardiovascular disease . In this study , untreated men and women aged 35 to 69 years were r and omly assigned to an intervention ( n=56 ) or control ( n=55 ) group in a 1.5-year community-based education program . Subjects had no evidence of hypertensive end-organ defects and had screening blood pressures of 140 to 179 mm Hg systolic and /or 90 to 109 mm Hg diastolic , with no difference in mean blood pressure between groups ( 148 to 150 mm Hg for mean systolic and 83 to 84 mm Hg for mean diastolic pressures ) . The intervention group took four education classes in the first 6 months and four classes during the next year , and the control group took two classes . Health education focused on reduced dietary sodium and increased milk intake , brisk walking , and , if necessary , reduction of alcohol and sugar intakes . Antihypertensive medication was started less often in the intervention than in the control group at 1.5 years ( 9 % versus 24 % , P < .05 ) . Mean systolic pressure was 5 to 6 mm Hg less in the intervention than in the control group at both 6 months and 1.5 years ( P < .05 ) , with or without inclusion of those subjects who began antihypertensive medication . Diastolic pressure and body mass index did not change significantly between groups . Urinary sodium excretion declined in the intervention but not in the control group ( differences between groups : P=.04 at 6 months and P=.07 at 1.5 years ) . According to a behavioral question naire , sodium reduction and milk increase were greater in the intervention than the control group ( sodium : P < .01 at 6 months and P=.08 at 1.5 years ; milk : P < .001 at 6 months and P < .01 at 1.5 years ) . Mean ethanol intake was reduced in the intervention but not the control group ( P=.04 at 1.5 years ) . This community-based hypertension control program was effective in reducing systolic pressure levels by nonpharmacological means during the first 6 months and maintaining the reduction for 1.5 years [7570436] BACKGROUND --Peak flow based asthma self-management plans have been strongly advocated in consensus statements , but convincing evidence for the effectiveness of this approach has been largely lacking . METHODS --A r and omised controlled trial was conducted in 25 general practice s comparing an asthma self-management programme based on home peak flow monitoring and surgery review by a general practitioner or practice nurse with a programme of planned visits for surgery review only over a six month period . RESULTS --Seventy two subjects ( 33 in the self-management group and 39 in the planned visit group ) completed the study protocol , but diary card data for at least three months were available on a total of 84 ( 39 in the self-management group and 45 in the planned visit group ) . Teaching self-management took longer than the planned visit review . In the self-management group home peak flow monitoring was felt to be useful by doctors and patients in 28 ( 85 % ) and 27 ( 82 % ) cases , respectively . There were no between group differences during the study period in terms of lung function , symptoms , quality of life , and prescribing costs . Only within the self-management group were improvements noted in disturbance of daily activities and quality of life . Possible explanations for these negative results include small numbers of subjects , the mild nature of their asthma , and inappropriate self-management strategies for such patients . CONCLUSIONS -- Rigid adherence to long term daily peak flow measurement in the management of mild asthma in general practice does not appear to produce large changes in outcomes . Self-management and the use of prescribed peak flow meters need to be tailored to individual circumstances [8296253] BACKGROUND --To improve asthma control and reduce readmission rates through increased knowledge and the development of self management skills , a brief ( three hour ) adult education programme was developed . METHODS --The course was design ed to improve inhaler skills and to teach how to adjust drug doses according to peak flow ( PEF ) measurements and a treatment plan . It was evaluated in a r and omised controlled trial in 76 patients admitted to hospital for asthma by using question naires , spirometry , and home monitoring of PEF at entry and at five and 10 months after intervention . The question naire provided measures of knowledge about asthma , self management behaviour appropriate to asthma control , asthma symptom frequency and severity , and psychosocial disturbance attributable to asthma . RESULTS --During the 10 months observation period the readmission rate for the educated group was one seventh that of the control group and attendance at accident and emergency departments also decreased . No consistent differential improvements were observed in spirometric results , average PEF , or mean daily variability of PEF . Both groups showed improvements in measures of asthma knowledge , behaviour , symptoms , and psychosocial disturbances . However , the intervention group showed a significantly greater improvement in some measures of asthma knowledge and self management skills . CONCLUSION --Despite minimal effect on measures of airway function , substantial changes in illness behaviour and use of health care facilities can be achieved by a brief asthma education programme [8761192] Consecutive new attendees at a rheumatology clinic were r and omly allocated to one of three groups . All groups received routine care , but one received no other intervention , one an educational booklet on arthritis and one the booklet plus instruction from a health professional . Prior to intervention , all groups had similar knowledge . Nottingham Health Profile ( NHP ) and Health Assessment Question naire ( HAQ ) score . After 6 weeks , the knowledge score was significantly increased in both groups given the booklet , but not in the control group . The group instructed by a health professional showed no greater increase than the group given the booklet alone . Increased knowledge was not associated with improved clinical status and no group showed a significant change in NHP or HAQ scores . Nearly all patients said they found the booklet useful [3338379] In patients with non-insulin-dependent diabetes mellitus ( NIDDM ) , the influence of knowledge about their disease on the treatment and control of the disease is not clear . We evaluated the efficacy of educational group meetings with NIDDM patients on improving their knowledge of the disease and on disease management . Fifty-one NIDDM patients were r and omly assigned to either intervention or control groups . The intervention group participated in courses of three weekly lessons presented by a physician , nurse , and dietitian once every 4 mo . The intervention and control groups were also followed once every 2 mo in the clinic by the same staff . Medical treatment remained unchanged during the study . After a 12-mo follow-up of the intervention group , no significant improvement in their knowledge of diabetes could be demonstrated . However , mean fasting and postpr and ial blood glucose levels and HbA1c improved significantly in comparison with the control goup . The same tendency was evident with the weight and lipoprotein profile . We conclude that educational group therapy can improve diabetes control in patients with NIDDM [4004977] Behavioral and health status outcomes of an unreinforced , self-help education program for arthritis patients taught by lay persons were examined in 2 ways : a 4-month r and omized experiment and a 20-month longitudinal study . At 4 months , experimental subjects significantly exceeded control subjects in knowledge , recommended behaviors , and in lessened pain . These changes remained significant at 20 months . The course was inexpensive and well-accepted by patients , physicians , and other health professionals [7950723] Abstract Objective : To assess the value of health education for patients with angina in reducing risk factors for cardiovascular disease and lessening the effect of angina on everyday activities . Design : R and omised controlled trial of personal health education given every four months . Setting : 18 general practice s in the greater Belfast area . Subjects : 688 patients aged less than 75 years and known to have had angina for at least six months ; 342 r and omised to receive education and 346 to no education . Main outcome measures : Restriction of everyday activities , dietary habit , smoking habit , frequency of physical exercise ; blood pressure , body mass index , and serum total cholesterol concentration at entry to trial and after two years . Results : 317 in the intervention group and 300 in the control group completed the trial . At the two year review more of the intervention group ( 140 , 44 % ) reported taking daily physical exercise than the control group ( 70 , 24 % ) . The intervention group also reported eating a healthier diet than the control group and less restriction by angina in any everyday activity . No significant differences were found between the groups in smoking habit , systolic or diastolic blood pressure , cholesterol concentration , or body mass index . Conclusion : Despite having no significant effect on objective cardiovascular risk factors , personal health education of patients with angina seems to increase exercise and improve dietary habits and is effective in lessening the restriction of everyday activities [6347578] The effect of patient education on diabetic control in insulin-treated diabetic adults was studied in 77 subjects r and omized into two groups : intensive patient education ( group A ) and control ( group B ) . The subjects in group A received intensive patient instruction , both individually and in small groups , from a team of physicians , teaching nurses , and a dietitian . The patients in group B received a short instruction course consisting mainly of printed material . A highly significant improvement in diabetic control was observed in both groups immediately after the education programs , with gradual return to the original level during the following 3–6 mo . No difference was observed between the two groups in any of the measured parameters during the 18-mo investigation . Factors related to good control during the study included the length of school education , the quality of the control at the beginning of the study , and the high degree of self-confidence and lack of signs of anxiety in the psychological tests . The results demonstrate that the effects of educational programs are of limited value if they do not lead to permanent changes in attitudes and motivation , which are critical factors affecting long-term diabetic control [8130290] Preliminary work regarding the development and pilot study of an individualized instructional program for rheumatoid arthritis clients is presented . The effect of the individualized instructional program was tested with 31 out patients . Using analysis of covariance , the experimental group subjects scored significantly higher on the knowledge post-test when compared to scores of control group subjects ( P = 0.0045 ) . Analysis of variance for repeated measures revealed no significant difference in performance of tasks for the control group and experimental group ( P = 0.08 ) . In a follow-up study , the effect of the self-instructional program , practice time , and contracting were explored for their effect on adherence to self-care activities . Experimental groups ( n = 42 ) scored significantly better than the control group ( n = 11 ) on the knowledge post-test ( P < 0.01 ) , performance of joint protection practice s ( P = 0.01 ) , range of motion exercises ( P = 0.01 ) , and adherence to joint protection practice s at home ( P < 0.01 ) . Groups did not differ on adherence to range of motion exercises at home ( P = 0.83 ) [7076881] The shift in patterns of disease toward chronic illness necessitates greater patient participation in its management and in their own rehabilitation , and they require greater social support over longer peiods . Patient activation , or the enhancement of patient and support group involvement in personal health care through teaching management techniques and problem-solving skills , has emerged in health education in response to this need . This paper will examine combined educational and behavioral approaches to increasing social support and patient activation in hypertension management . Activation in this study involves increased feelings of personal control over the contingencies surrounding the management of medical regimens . Both family support intervention and small group sessions oriented to changing compliance behavior by changing expectancy frames were offered to a r and omized sample of 200 inner city , black , hypertensive patients who were part of a larger study . Patients were examined within a pretest — posttest r and omized factorial design on measures of locus of control , belief in seriousness , efficacy of treatment , medication compliance , and blood pressure control . This combined approach showed small differences on the attitude and behavioral measures but displayed a significant effect on the program outcome variableblood pressure control ( 62 % in control among intervention groups versus 46 % in nonintervention groups ) [2904532] A structured treatment and teaching programme for non-insulin-treated non-insulin-dependent ( type 2 ) diabetes was evaluated prospect ively in general practice . The four group sessions were mainly conducted by paramedical personnel . 65 patients from five general practice s were assessed at the start of the programme and 50 ( mean age 65 years , diabetes duration 7 years ) completed the 1 year follow-up ( intervention group ) . The control group consisted of 49 patients ( mean age 63 years , diabetes duration 7 years ) from three other general practice s without the programme . In the intervention group the percentage of patients receiving sulfonylureas fell from 68 % at the start of the study to 38 % after 1 year ( mean difference 30 % , 95 % confidence interval [ CI ] 16 - 44 % ) ; the mean weight loss was 2.7 kg ( 95 % CI 1.6 - 3.8 kg ) , and non-fasting triglycerides were reduced by 0.77 mmol/1 ( 95 % CI 0.35 - 1.19 mmol/l ) ; and glycosylated haemoglobin remained unchanged ( 7.1 % of total haemoglobin ) . In the control group none of these indices was changed during the study year , and 10 % of patients started insulin treatment . The structured treatment and teaching programme improved the overall quality of patient care in elderly non-insulin-dependent diabetic patients treated by general practitioners [7794983] OBJECTIVE To evaluate the effectiveness of a community-based arthritis education program conducted in a number of locations throughout the Sydney , Australia , metropolitan area . METHODS The program , based on earlier work , comprised 6 weekly sessions of 2.5 hours ' duration . The study sample included 175 men and women with different types of arthritis , divided into intervention ( n = 104 ) and control ( n = 71 ) groups . Five outcome measures were selected to evaluate effectiveness of the program : pain perception , knowledge level , self-efficacy , disability index , and self-management behavior . RESULTS The results indicated that the program was effective in increasing knowledge level ( F[1,222 ] = 10.3 , P = 0.001 at 6 weeks ; F[1,108 ] = 7.8 , P = 0.006 at 6 months ) , and a statistically significant difference was found in disability satisfaction 6 months after intervention ( F[1,98 ] = 5.9 , P = 0.01 ] , but no statistically significant difference was found in pain perception , self-efficacy , and disability index . CONCLUSION This research supports some of the successful outcomes which follow an arthritis education program : increased knowledge level and increased disability satisfaction [3935013] The effectiveness of an educational program to increase compliance with cromolyn sodium was assessed in 31 children and adolescents 6 to 17 years of age . Patients were r and omly assigned to an education or noneducation group . A st and ard education program regarding asthma and asthma medications was provided to the education group during four monthly visits . At each visit , all patients were assessed in terms of knowledge of asthma and medications , asthma-related symptoms , and pulmonary function . Patients were also asked to self-rate their compliance . The education program increased the patients ' knowledge of cromolyn , and appeared to result in increased cromolyn compliance . Post-hoc analyses , however , suggested that increased compliance did not correspond to improved medical status unless the quality of management ( by physician and parents ) of the child 's asthma was taken into account . These results suggest that inadequate management of asthma in children may be a more serious problem than patient noncompliance [1744753] Study objective : To determine whether a self-management training program decreases emergency department visits and reduces costs for patients with asthma . Design : R and omized controlled trial of an educational program . Setting : Two sites — an urban emergency room and a suburban emergency room . Patients : 241 asthma patients between the ages of 18 and 70 years . Of the 119 patients in the intervention group and the 122 in the control group , 185 ( 76 % ) were available for follow-up . Intervention : All patients seen in the emergency departments were given usual medical care and follow-up . Patients in the intervention group were asked to attend three educational sessions on asthma conducted by a specially trained RN . The program stressed importance of medication compliance , methods to control and prevent attacks , effects of drugs and rationale for their use , relaxation exercises , and smoking cessation . Measurement and main results : All patients received telephone interviews four , eight , and 12 months after entry into the study . Reports based on hospital admissions and emergency room utilization were verified by billing records . Three patients died during the study , none from asthma-related problems . The intervention group had significantly fewer asthma-related emergency visits ( 16 visits per 100 persons ) than did the control group ( 39 per 100 persons ) ; p=0.0005 for the 12 months of follow-up . The effect of the intervention on asthma-related emergency department visits was strongest during the initial four months postintervention ( 68 per 100 persons versus 220 per 100 persons , p=0.003 ) . The financial analysis showed that the $ 85/person cost for the educational sessions was offset by the $ 628/person reduction in emergency room charges . Conclusion : Education enables patients with asthma to decrease utilization of emergency services [1740599] OBJECTIVE To assess whether knowledge or psychosocial and glycemic benefits of a diabetes education program are enhanced by a support group for older patients . DESIGN A partially r and omized controlled trial involving two groups of patients : Group A , subjects who received an education program followed by 18 months of support group sessions ; Group B , only the diabetes education program . A third convenience sample , Group C , received neither intervention . Groups A and B were assessed before and immediately after the education program , and all groups were assessed 2 years after the education program . SETTING Diabetes clinic at a Veterans Affairs Medical Center . PATIENTS All subjects were male ( mean age = 68 + /- 1.3 years , range = 57 - 82 years ; duration of diabetes = 10 + /- 2 years , range 3 - 16 ) . Sample sizes were 11 in Group A , 13 in Group B , and 8 in Group C. INTERVENTION The education program consisted of six weekly sessions covering aspects of diabetes self-care . The support group consisted of 18 monthly sessions for continuing education , discussion , and structured social activities . OUTCOME MEASURES Diabetes knowledge , psychosocial factors ( self-care-related quality of life , stress , family involvement in care , and social involvement ) , depression , and glycemic control . RESULTS Group A scored better ( at least P less than 0.05 ) on knowledge , quality of life , and depression than the other groups . Groups A and B showed less stress , greater family involvement , better glycemic control , but less involvement in social activities than Group C. CONCLUSION Diabetes education programs can have long term benefits on knowledge , psychosocial functioning , and glycemic control for older diabetic patients . The addition of support groups enhances diabetes knowledge and psychosocial functioning [9228140] OBJECTIVE Self-management courses in arthritis have been shown to improve outcomes and to decrease medical re source utilization . We studied the effectiveness of a mail-delivered arthritis self-management program with the potential for extending these effects more broadly . METHODS R and omized controlled trial of 375 program participants and 434 controls over a 6 month period . Baseline and 6 month data were analyzed for each group and between groups by paired 2 sample t test . The intervention consists of health assessment question naires at 3 month intervals , with computer processed recommendation letters and reports individualized to age , diagnosis , education level , disability , pain , medication , and other patient-specific variables . RESULTS At 6 months , outcomes of function ( 4.7 % ; 95 % confidence limits 2.7 , 6.7 ) , decreased pain ( 9 % ; 2.8 , 15.2 ) , global vitality ( 7 % ; 2.8 , 11.2 ) , and joint count ( 28 % ; 20 , 36 ) were improved in the program group compared with controls ( p < 0.01 ) . Exercise ( 35 % ; 26 , 44 ) and self-efficacy ( 14.7 % ; 9 , 20 ) were increased in the program group but not controls ( p < 0.001 ) . Doctor visits/year were decreased by 16 % ( 3 , 29 ) in the program group compared with controls ( p < 0.05 ) and days missed work or confined to home decreased by 52 % ( -3 , 107 ) in the program group compared with controls ( p = 0.06 ) . At one year , patients in the original program group continued to improve , and the control group , provided with the program in the second 6 months , showed improvement similar to the first 6 months of the original program group . CONCLUSION A mail-delivered arthritis self-management program can positively affect patient outcomes and can decrease medical re source utilization [7974314] BACKGROUND --Previous work has indicated a high rate of non-attendance at hospital based clinics among young , multiracial asthmatic patients of lower socioeconomic class . The efficacy of delivering asthma education from a community health centre established in a multiracial working class neighbourhood was evaluated . METHODS --A prospect i ve controlled study was performed in which asthmatic subjects aged between two and 55 years attending a hospital emergency room with acute asthma and living within a defined geographical area of high emergency room users were r and omised to the usual follow up or the education centre plus usual follow up . Measurements were taken at entry into the study and again nine months later . RESULTS --At nine months patients r and omised to the education centre had more preventive medications , more peak expiratory flow meters and better flow meter technique , more self-management plans , better knowledge of appropriate action to take when confronted with worsening asthma , less nocturnal awakening , and better self-reported asthma control than the control group . There was no difference between the study groups in measurements of compliance , hospital admission , days lost from school or work , or emergency room use . CONCLUSIONS --The main effects of education were on asthma knowledge and self-management skills , whilst improvements in asthma morbidity were small . Potential reasons for this include heterogeneous study population ( in terms of baseline self-management skills , asthma severity , ethnicity and age ) , pragmatic study design , insensitivity of many of the measurements of morbidity , the modest effectiveness of a single time limited education programme , and inability to limit the effects of such a large community based study to the intervention group ( there was a 67 % reduction in asthma admissions during the study period from the geographical area targeted compared with a 22 % reduction for the rest of Auckl and ) [3505528] The efficacy of an adult asthma self-management program , Wheezers Anonymous ( WA ) , was tested utilizing 79 adult asthmatic patients . Subjects were r and omly assigned to a treatment or waiting-list control group . Baseline data gathered included measures of symptom severity , health-care utilization , knowledge of asthma , attitudes about asthma , and self-efficacy . All subjects completed the same measures 1 , 2 , and 3 months following the WA intervention . Knowledge about asthma increased in the treatment group relative to the waiting-list controls ; the number of attacks decreased in the treatment group only , thus demonstrating the efficacy of the WA program [9259427] OBJECTIVE To evaluate a concise program of self-care education delivered by an arthritis nurse specialist as an adjunct to primary care for inner-city patients with knee osteoarthritis ( OA ) . METHODS An attention-controlled clinical trial ; 211 inner-city patients with knee OA were assigned arbitrarily to education ( E ) or attention-control ( AC ) conditions . Group E received an individualized 30 - 60-minute educational intervention that emphasized nonpharmacologic management of joint pain , preservation of function by problem-solving , and practice of principles of joint protection . Brief telephone contacts 1 week and 4 weeks later monitored and reinforced new self-care activities . Group AC viewed a 20-minute st and ardized public education presentation on arthritis and received followup telephone calls ( only to encourage continued participation in the study ) . Outcomes included the Health Assessment Question naire ( HAQ ) Disability and Discomfort Scales , 10-cm visual analog scales measuring knee pain at rest and while walking , and the Quality of Well-Being ( QWB ) scale . Assessment s were made at baseline and at 4-month intervals for 1 year . RESULTS A total of 165 subjects ( 78 % ) completed all assessment s. After control for baseline status , group E had significantly lower scores for disability and resting knee pain throughout the year of postintervention followup ( P < 0.05 for both ) . Effects were somewhat discordant . By 12 months , functional benefits had begun to wane , while the effect on resting knee pain had grown . The overall effects of education on walking knee pain , overall joint pain ( by HAQ ) , and general health status ( by QWB ) were not significant . CONCLUSION Self-care education for inner-city patients with knee OA , delivered as an adjunct to primary care , was found to result in notable preservation of function and control of resting knee pain . The magnitude of the observed effects compares well with those of more labor-intensive and time-consuming intervention models . However , more sustained preservation of function and consistent effects on pain may require prolonged , more proactive followup , either by the patient educator or by a trained clinical assistant dedicated to the task of supporting self-care by patients with knee OA [8823699] OBJECTIVE This r and omized controlled clinical trial evaluates the effectiveness of outpatient group cognitive/educational treatment for patients with the fibromyalgia ( FM ) syndrome . We hypothesized that the combination of group education with cognitive treatment aim ed at developing pain coping skills would be more effective than group education alone . METHODS 131 patients with FM were r and omly assigned to 3 conditions : an experimental condition , which was the combined cognitive/educational intervention ( ECO ) ; an attention control condition consisting of group education plus group discussion ( EDI ) ; and a waiting list control ( WLC ) . For the treatment conditions ECO and EDI , assessment s were made 2 weeks before treatment , at start of treatment , at post-treatment , and at 6 and 12 mo followup . WLC patients received only 3 assessment s. RESULTS There were no pretreatment differences between the groups , or between dropouts and patients who remained in the study . At post-treatment , and compared with the WLC , the ECO patients improved in knowledge about FM ( p = 0.007 ) and pain coping ( p < 0.001 ) . EDI patients improved on pain coping ( p = 0.005 ) and pain control ( p = 0.002 ) . EDI patients reported significantly less fear than ECO patients ( p = 0.005 ) . There were no other differential effects between ECO and EDI at post-treatment or 6 mo or 12 mo followup . Based on the reliability of change index for clinical significance , the relative short term success rates are 6.4 and 18.4 % for ECO and EDI , respectively . CONCLUSION The surplus value of a highly structured , 12 session group cognitive treatment added to group education can not be supported by our study . In EDI , fear reduction might have enhanced pain coping and pain control , while poor compliance , the difficulty of homework assignments , and lack of individual support may have limited the effectiveness of ECO [6849473] Three health education interventions for urban poor hypertensive patients were introduced sequentially in a r and omized factorial design : 1 ) an exit interview to increase underst and ing of and compliance with the prescribed regimen ; 2 ) a home visit to encourage a family member to provide support for the patient 's regimen ; and 3 ) invitations to small group sessions to increase the patient 's confidence and ability to manage his/her problem . Previous evaluation of the initial two-year experience demonstrated a positive effect of the educational program on compliance with the medical treatment and blood pressure control . Data accumulated over an additional three years , including mortality analysis , are now presented . The study group consisted of the same cohort of 400 ambulatory hypertensive out patients in the eight experimental and control groups . The five-year analysis shows a continuing positive effect on appointment keeping , weight control , and blood pressure control . All-cause life table mortality rate was 57.3 per cent less for the experimental group compared to the control group ( 12.9/100 vs 30.2/100 , p less than .05 ) , while the hypertension-related mortality rate was 53.2 per cent less ( 8.9/100 vs 19.0/100 , p less than .01 ) . The results from this longitudinal study provide evidence to encourage health practitioners to utilize such educational programs in the long-term management and control of high blood pressure [3533082] An important unanswered question about rheumatoid arthritis ( RA ) is how the patient 's psychological or emotional state relates to disease activity and functional status . No controlled studies of psychotherapeutic interventions in RA have been reported . To test the hypothesis that a psychosocial intervention would lead to improvement in functional status or disease activity , 57 RA patients were r and omly assigned to 1 of 3 groups , which received : 1 ) conventional group psychotherapy ; 2 ) group assertion/relaxation training ; or 3 ) no treatment ( control group ) . Patient and physician question naires collected at baseline , immediately after the interventions , and 12 months after baseline provided outcome data on functional status , social and psychological adaptation , psychological symptoms , and disease activity . There were few outcome measures for which either treatment result ed in significantly higher scores than were seen in controls , though more improvement did occur among patients who received conventional group psychotherapy [9526696] OBJECTIVES Re- analysis of a r and omized trial of an asthma education program design ed to assess the effects of the intervention on emergency department visits , limited days of activity and asthma knowledge and beliefs separately for African American and Caucasian adults with asthma . DESIGN Two hundred and forty-one respondents between the ages of 18 and 70 were evaluated in two emergency departments ( one inner city and one suburban location ) of a large , midwestern health care system and were r and omized to an intervention or control group . RESULTS Regardless of race , members of the intervention group showed a decrease in the number of post-intervention emergency department visits ( ANOVA interaction between race and group effect p value = 0.93 ) . The greatest decrease occurred during the first four post-intervention months . No differential effect of the asthma education intervention by race was found on the change in asthma knowledge and beliefs over the study period ( ANCOVA interaction between race and group effect p value = 0.60 ) . CONCLUSION This study demonstrates that post-intervention , both African American and Caucasian study participants showed a decrease in emergency department visits and an increase in asthma self-management . This finding is especially important for African Americans , who face increasing asthma mortality and morbidity [8467308] OBJECTIVE Evaluation of a structured hypertension treatment and teaching programme in general practice . DESIGN Prospect i ve controlled trial ; follow-up period 18 months . SETTING 10 primary health care practice s. PRACTICE S AND PATIENTS : From each practice 20 patients ( 30 to 60 years old , mean of the last two blood pressure measurements at or above 160 and /or 95 mmHg ) were r and omly selected ; in 5 practice s these patients were to participate in the treatment and teaching programme ; in the remaining 5 practice s hypertension care was continued without the availability of such a programme ( controls ) . INTERVENTION Structured treatment and teaching programme based upon four group sessions for patients mainly conducted by paramedical personnel . MAIN OUTCOME MEASURES Blood pressure , body weight , prescription of antihypertensive drugs - as documented in the patient 's records . MAIN RESULTS Of the 100 control patients 26 and of the 100 intervention patients 14 were lost to observation ; 46 patients had agreed to participate in the programme . The mean number of prescribed antihypertensive agents per patient decreased in the intervention group ( 1.8 + /- 1.3 at baseline , vs 1.2 + /- 1.2 at follow-up ) compared to the control group ( 1.6 + /- 1.3 vs 1.8 + /- 1.6 ) ; difference 0.8 ( 95 % CI 0.4 to 1.1 ) , p < 0.0001 . In the control group 9 % and in the intervention group 33 % of patients had documented reductions of body weight ( p < 0.0001 ) . Blood pressure decreased in the intervention group ( 162 + /- 14/100 + /- 7 mmHg at baseline , vs 154 + /- 16/95 + /- 9 mmHg at follow-up ) compared to the control group ( 161 + /- 13/98 + /- 7 mmHg vs 158 + /- 18/96 + /- 11 mmHg ) ; differences for systolic blood pressure 5 ( 95 % CI 0 to 10 ) mmHg , p = 0.071 ; for diastolic blood pressure 4 ( 1 to 7 ) mmHg , p = 0.018 . CONCLUSIONS The introduction of a structured hypertension treatment and teaching programme in general practice may lead to significant improvements of hypertension care [8035399] OBJECTIVE To determine the effectiveness of self-management education and physical training in decreasing fibromyalgia ( FMS ) symptoms and increasing physical and psychological well being . METHODS A pretest-posttest control group design was used . Ninety-nine women with FMS were r and omly assigned to 1 of 3 groups ; 86 completed the study . The education only group received a 6-week self-management course . The education plus physical training group received the course and 6 h of training design ed to assist them to exercise independently . The control group got treatment after 3 months . RESULTS The experimental programs had a significant positive impact on quality of life and self-efficacy . Helplessness , number of days feeling bad , physical dysfunction , and pain in the tender points decreased significantly in one or both of the treated groups when retested 6 weeks after the end of the program . Longterm followup of 67 treated subjects showed significant positive changes on the Fibromyalgia Impact Question naire primarily in the physical training group . Among all subjects , 87 % were exercising at least 3 times/week for 20 min or more ; 46 % said they had increased their exercise level since participating in the program ; 70 % were practicing relaxation strategies as needed ; 46 % were working at least half time as opposed to 37 % at pretest . CONCLUSION Self-efficacy of the treated groups was enhanced significantly by the program . Other changes were smaller and more delayed than had been expected . Recommendations for future trials include a longer education program , more vigorous physical training , and longterm followup [3698783] Home health nurses provided individualized instruction in diabetes self-care within the home environment of 393 diabetic individuals . Each subject was r and omly assigned to either the intervention ( those receiving home teaching ) or control ( those not receiving home teaching ) group . At 6 mo postenrollment , intervention subjects showed significantly greater self-care knowledge and skills than control subjects , although the actual differences between the two groups in terms of self-care skills were probably too small to have any practical meaning . The primary objective of the study , which was the reduction of the number of preventable diabetes-related hospitalizations ( ketoacidosis , ketotic coma , nonketotic coma , insulin reaction , and diabetes out of control ) , was not achieved ; no differences between the groups were noted after 12 mo of follow-up . Similarly , length of hospital stay , foot problems , emergency room and physician visits , and sick days were roughly equivalent in both groups during the follow-up year . These results suggest that , in the absence of concurrent changes in the health-care delivery system and strategies for influencing attitudes toward self-care , education alone is ineffective [9414057] & NA ; The effectiveness of a Pain Education Program in cancer patients with chronic pain offered by nurses was investigated in a r and omized controlled clinical trial . A multi‐ method approach was used in which verbal instruction , written material , an audio cassette tape , and the use of a pain diary were combined to inform and instruct patients about pain and pain management . The Pain Education Program was tailored to the needs of the individual patient and consisted of three elements : ( 1 ) educating patients about the basic principles regarding pain and pain management ; ( 2 ) instructing patients how to report their pain in a pain diary ; and ( 3 ) instructing patients how to communicate about pain and how to contact health care providers . Following pretesting in 313 patients , patients who needed district nursing and who did not need district nursing at home were r and omly assigned to a control or intervention group . Intervention group patients received the Pain Education Program in the hospital , and 3 and 7 days postdischarge by telephone ; this was done by nurses who were specially trained as pain counselors . Follow‐up assessment s were at 2 , 4 and 8 weeks postdischarge . Results of the pretest showed that many patients lacked knowledge about pain and pain management . The majority of pain topics had to be discussed . The Pain Education Program proved to be feasible : 75.0 % of the patients had read the entire pain brochure , 55.7 % had listened to the audio cassette , and 85.6 % of pain scores were completed in the pain diary . Results showed a significant increase in pain knowledge in patients who received the Pain Education Program and a significant decrease in pain intensity . However , pain relief was mainly found in the intervention group patients without district nursing . It can be concluded that the tailored Pain Education Program is effective for cancer patients in chronic pain . The use of the Pain Education Program by nurses should be seriously considered on oncology units [2200380] The prevalence and impact of adult asthma are substantial , and poor self-management practice s , especially failures to adhere to treatment regimens , appear to be a significant problem . Desirable characteristics of an intervention program to improve self-management were identified through needs assessment and review of existing patient education re sources . A comprehensive program was developed that integrated a workbook with one-to-one counseling and adherence-enhancing strategies . A longitudinal 1-year study compared patients receiving this self-management program with " usual care " patients receiving st and ard asthma pamphlets . Patients were r and omly assigned to conditions . Baseline score and asthma severity were statistically controlled . Self-management patients had substantially better adherence than usual care patients , as well as improved functional status , at follow-up . Hospital and emergency department visits decreased in both groups but did not differ between groups [8506881] PURPOSE Excess morbidity and mortality due to asthma , aggravated by demonstrably poor patient self-management practice s , suggest the need for formal patient education programs . Individual and group asthma education programs were developed and evaluated to determine their cognitive , behavioral , and clinical effects . PATIENTS AND METHODS We compared changes in asthma symptoms , utilization of medical services , knowledge about asthma , metered-dose inhaler ( MDI ) technique , and self-management behaviors for 323 adult Kaiser Permanente patients with moderate to severe asthma who were r and omly assigned to small-group education , individual teaching , or 1 of 2 control conditions -- an information ( workbook ) control or usual control ( no formal asthma education ) . Data were collected from patients by question naire , diary , and physical examination at enrollment and at 5 months and 1 year after intervention . Medical record data on these patients were abstract ed for a total 3-year period , from 1 year before to 2 years after enrollment . RESULTS Compared with the usual control , the self-management education programs were associated with significant improvements in control of asthma symptoms ( reduced " bother " due to asthma and increased symptom-free days ) , MDI technique , and environmental control practice s. Small-group education also was associated with significant improvements in physician evaluation of the patients ' asthma status and in patients ' level of physical activity . For both group and individual education recipients , improvement in MDI technique was positively correlated with improved control of symptoms ; however , the degree of improvement in symptoms was greater than that which could be accounted for on the basis of improvement in MDI technique alone . The time course over which changes occurred in the various outcome measures suggests the mechanism by which education result ed in improvement in the patient 's status . Significant improvements in MDI technique and environmental control practice s were manifest immediately following education ( 5-month follow-up ) and at the 1-year follow-up . Significant improvements in symptom measures were not apparent until the 1-year follow-up . The rate of utilization of medical care for acute exacerbations decreased between baseline and the 2-year follow-up period , but this decrease did not differ significantly among treatment conditions . However , there was a trend toward greater reduction in patients receiving small-group education . An ad hoc finding of a significant difference favoring small-group education between the baseline and the second follow-up year acute visit rates was observed . This result must be regarded as tentative , since it is not clear that unambiguous statistical significance is attained in the light of multiplicity issues . However , this trend is consistent with the antecedent benefits of the small-group education , and appears to warrant further investigation . CONCLUSIONS Carefully design ed asthma education programs for adults can improve patients ' underst and ing of their condition and its treatment and increase their motivation and confidence that the condition can be controlled , thereby increasing their adherence to the treatment regimen and management of symptoms , and , in turn , improving control of symptoms . Both small-group education and individual education were associated with significant benefits , but the group program was simpler to administer , better received by patients and educators , and more cost-effective . The results show promise for improving clinical outcomes , through well- design ed educational programs , for patients with asthma and other chronic health problems [9619885] Despite the wide availability of disease-related leaflets , their impact on patients ' knowledge and well-being has rarely been evaluated . A r and omized controlled study of a ' Rheumatoid Arthritis ' leaflet revealed increased knowledge among the intervention group after 3 weeks . In addition , the leaflet was viewed as a source of reassurance . The purpose of the follow-up study was to determine whether the increase in knowledge was maintained in the longer term and to examine psychological well-being . Eighty-four patients ( 42 intervention and 42 control ) completed the 6 month follow-up . There were no significant changes ( P > 0.01 ) in mean outcome measures over the period 3 weeks-6 months for either the intervention or control groups . Patients in the intervention group retained the increase in knowledge observed at 3 weeks . Moreover , there was no evidence of adverse reactions to the leaflet in terms of psychological distress . Leaflets can be effective in promoting longer term increases in knowledge [8529086] PURPOSE Patients who have undergone coronary artery bypass graft surgery ( CABG ) are obvious c and i date s for rehabilitation programs because of the potential for progression of disease . Such programs have been shown to foster risk-factor modification , improve quality of life , and prolong survival among post-myocardial infa rct ion ( MI ) patients . However , the efficacy of these programs has not been established among patients who have undergone CABG . METHODS A r and omized controlled trial was employed to evaluate whether a behavioral and educational cardiac rehabilitation program was effective in modifying cardiovascular disease risk factors and improving quality of life in a cohort of 86 patients after CABG . Patients were recruited from the cardiac ward of a large teaching hospital and were block-r and omized to either an intervention group or routine care . Subjects in the intervention group attended 6 weekly group sessions following hospital discharge , and booster sessions at 8 months and 1 year . They also received a personalized behavior modification program based on their baseline risk factors . Risk factor and quality of life measures were recorded at baseline ( 6 weeks after surgery ) , 4 months , 8 months , and 1 year . RESULTS The results indicated few differences between the study groups . However , the intervention group 's aerobic capacity ( VO2max ) improved over that of the routine care group . With regard to the quality of life variables , all patients tended to improve steadily over time . CONCLUSIONS The relatively moderate success of this intervention program compared with various post-MI studies may be indicative of differences between the treatment needs of patients after acute myocardial infa rct ion or CABG . Future post-CABG rehabilitation research should explore these patients ' unique treatment needs , and investigate a variety of program strategies [2188495] The effects of an educational program on compliance and blood pressure ( BP ) control were assessed in 47 hypertensive patients hospitalized for nonhypertension-related diseases . Patients were r and omized to receive either a question naire and an educational program ( group I , 25 ) or question naire only ( group II , 22 ) . Baseline clinical characteristics , admission diagnoses and antihypertensive medications were similar between the groups . Antihypertensive medications used by patients before the trial were not changed . Eight weeks after the initial intervention , patients in group I showed a significant reduction in both systolic and diastolic BP ( 137/89 vs 154/98 mm Hg , p = 0.005 and 0.006 , respectively ) and improved compliance ( 96 vs 36 % , p = 0.04 ) , compared with patients in group II . An education program in patients with high BP is an effective method to improve compliance and BP control in the short-term [3549757] To examine the effects of intensive patient and /or physician diabetes education on patient health outcomes , a controlled trial was conducted in which internal medicine residents and their 532 diabetic patients were r and omly assigned to : routine care ; patient education ; physician education ; or both patient and physician education . Patient outcome data were analyzed either by analysis of covariance on post intervention values ( 2-hour post-pr and ial plasma glucose [ PPG ] ; body weight [ BW ] ; blood pressure [ BP ] ; or analysis of variance conducted on change values ( fasting plasma glucose [ FPG ] and glycosylated hemoglobin [ A1Hgb ] ) . After patient education , significant improvements were observed in FPG , A1Hgb , BW , and systolic and diastolic BP . Physician education result ed in significant decreases in FPG , A1Hgb and BW . The combination of patient plus physician education result ed in the greatest improvements in patients ' health outcomes including FPG , A1Hgb , PPG , BW and diastolic BP . Adjusted systolic BPs were not significantly different in the two groups . While these physiologic improvements were statistically and probably clinical ly significant , hyperglycemia and obesity still persisted . Thus , achieving optimal patient outcomes for a chronic disease like diabetes mellitus may require a greater or more effective use of re sources than currently estimated [3088085] A sample of 310 low income urban children with asthma from 290 families was r and omized into a control group and an experimental group that received health education to improve asthma management at home . No significant decreases in subsequent health care use were observed when the experimental group was compared to the control group without regard to previous hospitalization . When the comparison was restricted to children who had been hospitalized during the preceding year , however , the experimental group was found to have decreased its use of the emergency room significantly more than the control group ( p less than 0.05 ) and to have experienced a significantly greater reduction in the mean number of hospitalizations ( p less than 0.05 ) during the year of follow-up . The program reduced health care costs for children with one or more hospitalizations , saving $ 11.22 for every $ 1.00 spent to deliver health education [2258874] This study was planned in the context of a regional high blood pressure programme , to compare the efficacy of two educative methods . The group of 722 hypertensive patients ( 58.8 % women ) , mean age 61 years , was r and omly selected from 19 primary care centres . Initial assessment was based on a patient interview including 22 questions on high blood pressure , its consequences and treatment . Patients agreeing to participate in an active education team programme were distributed into three groups : individual education , team education and a control group . Those who declined to participate formed two groups : individual education and controls . Team education consisted of two audiovisual sessions attended by groups of 8 - 12 patients and conducted by treating physicians and nurses . Individual education included comments related to the 22 questions . Follow-up assessment was made after two months . An increase in the level of hypertension control was observed only in the accepting group , in which educative action was followed by increased knowledge . Results were similarly favourable for both the individual and team education groups and suggested the need to consider educational factors together with those influencing patient attitude towards an active educational programme [9295453] OBJECTIVE To evaluate the effects of a program for individual education in combination with the use of an arthritis passport . METHODS We studied 3 groups of patients with rheumatoid arthritis . The first experimental group received educational material s and followed the program under the guidance of their regular providers of health care whose activities were coordinated through arthritis passports . The second experimental group only received education material s ; the control group received only usual care . RESULTS There were no effects on self-efficacy expectations , knowledge , health status , or behavior in either experimental group . Opinions of general practitioners , physiotherapists , and visiting nurses concerning the arthritis passport were very positive , but rheumatologists ' opinions were not . Opinions on coordination of care were more positive among the physiotherapists of the experimental group . CONCLUSIONS Individual education for patients with rheumatoid arthritis by health care providers during routine consultations , as implemented in this program , had no effect on self-efficacy expectations , knowledge , health status , or health behavior . Likewise , the distribution of educational material s by itself without the involvement of health care providers had no effect . The use of the arthritis passport improved coordination of care , especially for physiotherapists [7487240] BACKGROUND The management of oral anticoagulation is fraught with difficulties . This study assessed a new model of anticoagulation management regarding the ability , safety , and efficacy of patients to self-monitor and self-adjust the dose of their oral anticoagulants guided by a capillary whole-blood prothrombin time ( PT ) monitor . METHODS This investigation is a retrospective cohort study of 20 patients compared with 20 matched control patients receiving oral anticoagulation at a tertiary medical institution . RESULTS Study patients monitored their PTs 2153 times during a mean interval of 44.7 months compared with 1608 PTs in matched control patients during a mean interval of 42.5 months . Study patients made an average of 11.5 dosage changes per patient , contrasted with 22.7 changes per control patient ( P < .001 ) . The PTs in study patients were within the recommended therapeutic range in 88.6 % ( 95 % confidence interval , 87.2 to 89.9 ) of the determinations compared with 68.0 % ( 95 % confidence interval , 65.7 to 70.3 ; P < .001 ) of the determinations made by the matched control patients . In response to the 2153 PTs , study patients made 67 ( 3.1 % ) dosage decisions that were considered incorrect based on physician guidelines . None of these changes led to adverse outcomes . There was no significant difference in complication rates between the two groups . CONCLUSIONS Results from what is the first long-term study of patient self-monitoring of PTs and self-adjustment of the warfarin sodium dosage for oral anticoagulation suggest that patients can successfully measure their own PTs , adjust their own warfarin dosage , and achieve a degree of therapeutic effectiveness at least as good , if not better than patients managed in an anti-coagulation clinic . Larger , prospect i ve , r and omized trials are needed to confirm the efficacy and safety of this new approach to therapy and to assess its cost-effectiveness [7670785] A 5-yr follow-up of an arthritis education programme is reported . After adjustment for those lost , deceased or moved away , the 5-yr response rate was 75 % among intervention subjects and 78 % among controls . Individuals who participated in the education programme maintained their increased knowledge in some aspects . The relative difference in pain and disability over 5 yr was greater in the control group . Most individuals were less active at practising exercise after 5 yr . Improvement in performing exercise and joint protection shown at 12-months follow-up did not persist . Additional questions after 5 yr showed that participants in the education programme had significantly more contact with rheumatologists , physiotherapists and occupational therapists . The participants developed an increased internal sense of control of the disease between 12 months and 5 yr . There was also a significant reduction in reported problems with their disease after 12 months , maintained after 5 yr . This may indicate that patient education contributes to the patient 's feeling of responsibility for , and ability to cope with , their diseases [8605463] Abstract Objective : To compare the efficacy of self management of asthma with traditional treatment . Design : 12 month prospect i ve r and omised trial . Setting : Outpatient clinics in Finl and . Subjects : 115 patients with mild to moderately severe asthma . Interventions : Patient education and adjustment of anti-inflammatory therapy guided by peak flow measurements . Main outcome measures : Unscheduled admissions to hospital and outpatient visits , days off work , courses of antibiotics and prednisolone , lung function , and quality of life . Results : The mean number of unscheduled visits to ambulatory care facilities ( 0.5 v 1.0 ) , days off work ( 2.8 v 4.8 ) , and courses of antibiotics ( 0.4 v 0.9 ) and prednisolone ( 0.4 v 1.0 ) per patient were lower and the quality of life score ( 16.6 v 8.4 at 12 months ) higher in the self management group than in the traditionally treated group . In both groups admissions for asthma were rare . Conclusions : Self management reduces incidents caused by asthma and improves quality of life . Key messages Key messages This trial of 115 patients with mild to moderately severe disease r and omised half to a traditional care and half to a self management programme consisting of education about asthma and daily peak flow readings Intervention thresholds of < 85 % of the optimal peak flow for doubling the dose of inhaled steroid for two weeks and of < 70 % of the optimal peak flow for starting a course of oral steroids worked well The self management group had fewer incidents ( consultations , days off work , courses of prednisolone or antibiotics ) than the traditionally treated group and better quality of life scores Adherence of patients to the self management instructions was better than [8788354] Arthritis is a common chronic disease causing pain and progressive disability to millions of people . The purpose of the study was to examine the effectiveness of group patient education for people with one form of arthritis , ankylosing spondylitis ( AS ) , in terms of change in : arthritis self-efficacy ; psychological well-being ; physical well-being ; and home exercise activities . The Self-Management Course-Ankylosing Spondylitis ( SMC-AS ) demonstrated positive effects on arthritis self-efficacy and psychological well-being at 6-month follow-up . Analysis of change over time in the intervention group showed improvements in depression , self-efficacy and severity at 3 weeks , with trends towards continued improvement evident at 6 months . In contrast , the positive effects on range and frequency of home exercise activities at 3 weeks were not maintained at 6 months . In conclusion , the effectiveness of short , intensive patient education courses was demonstrated . However , the need for strategies to sustain improvements in exercise behaviour need to be explored [3565666] We assessed diabetes education and peer support interventions as facilitators of weight loss and glycemic control in a community sample of 79 elderly persons with noninsulin-dependent diabetes mellitus ( NIDDM ) . Different groups received : education only , education and peer support , and no treatment . Peer support was higher in groups where it was actively facilitated . Weight loss and reduction in level of glycemic control occurred within groups receiving both diabetes education and peer support [9595179] Forty three patients with essential hypertension participated in a study on the effectiveness of stress-management training for essential hypertension . After 6–9 clinic and 48 self-measured readings of systolic and diastolic blood pressures ( SBP and DBP ) , 22 patients were treated with a program based on education , relaxation , and problem-solving training ; and another 21 patients were assigned to a waiting list control group . At post-treatment , mean reductions of clinic BP ( 17/13 mm Hg vs. 6.9/4.7 mm Hg for SBP/DBP ) , percentages of subjects who achieved at least a 5 mm Hg reduction ( 86/86 % vs. 48/48 % for SBP/DBP ) and percentages of subjects who in addition achieved a normotensive level ( 59/68 % vs. 29/14 % for SBP/DBP ) were significantly higher in the treated group than in the control group . Concerning self-measured BP , the effectiveness of the stress-management training was not so considerable ( mean reductions of 3.6/2.4 mm Hg and percentages of subjects who achieved a 5 mm Hg reduction of 52/38 % for SBP/DBP ) , but it was significant and maintained in a 4-month follow-up assessment ( mean reductions of 4/2 mm Hg and percentages of subjects who achieved a 5 mm Hg reduction of 48/33 % for SBP/DBP ) . It is suggested that stress-management training can be beneficial for treatment of essential hypertension [3887910] Stress management and mutual support groups are employed widely in chronic illness , although their efficacy has not been established . To determine the effect of these measures on morbidity and psychologic health in rheumatoid arthritis , 105 patients meeting diagnostic criteria for rheumatoid arthritis were evaluated for depression , life satisfaction , functional disability , and indicators of disease activity . Patients were r and omly assigned to one of three groups : ( 1 ) stress management ; ( 2 ) mutual support ; ( 3 ) no intervention ( control ) . After completion of 10 weekly sessions , identical tests were performed for all patients in the intervention and control groups . Patients in the intervention groups showed greater improvement in joint tenderness than did the control patients but did not differ significantly from the patients in the control group in any of the other outcome measures [2917233] The benefits of patient education for those with chronic arthritis are well documented . Informed patients should practice self care more often , and may show reduced disability from their disease . An important question relates to maintenance of the knowledge and skills acquired in educational programmes . This prospect i ve study evaluated an education programme for people with rheumatoid arthritis ( RA ) and osteoarthritis ( OA ) . The intervention group participated in a comprehensively planned six session behaviourally based programme . A question naire was given to 100 patients and 95 matched but non-r and om controls before the programme , 1 month later , and at 3 and 12 months . The intervention group demonstrated improvements in knowledge , self-reported health behaviour and disability scores at 12 months , compared to the controls . No differences were reported in symptoms , compliance with therapy , pain perception , and locus of control [3775139] A population -based study on the therapeutic effects of a diabetes teaching programme ( DTP ) based on problem oriented participatory education (POPE)--a method based on learner activity in group meetings -- was undertaken at the Primary Health Care Centre , Kisa , Sweden , in collaboration with educationalists . A control group was given conventional classroom teaching . To be included a patient had to be aged 55 - 73 years , to live in his own home , and to have non-insulin-treated type II diabetes mellitus . The therapeutic effects of the DTP were studied before , during , and after POPE with regard to three factors , diabetes related knowledge , behaviour assessed by dietary and exercise habits , and the quality of the anti-diabetic therapy as assessed by metabolic profile including Hb-A1 . Significant improvement in knowledge and transient improvement in Hb-A1 concentration were recorded among patients taking part in a DTP adjusted to their individual problems and needs . When improvement in metabolic control does not last , group meetings should be continued for more than the three months used in the present study . We believe that such improvement is intimately bound up with the psycho-social process that is involved in the group meetings and that helps the patient to cope with the disease in particular and life in general [1427244] This paper presents findings from the evaluation of a self-management education program based on self-regulation principles . Older men and women ( N = 324 ) were r and omly assigned to program and control groups . Outcomes were measured using the Sickness Impact Profile . Twelve months following baseline data collection , psychosocial functioning of program participants was significantly better than that of controls . Different program effects were noted when results were analyzed by participant gender [3948638] The Diabetes Education Study ( DIABEDS ) was a r and omized , controlled trial of the effects of patient and physician education . This article describes a systematic education program for diabetes patients and its effects on patient knowledge , skills , self-care behaviors , and relevant physiologic outcomes . The original sample consisted of 532 diabetes patients from the general medicine clinic at an urban medical center . Patients were predominantly elderly , black women with non-insulin-dependent diabetes mellitus of long duration . Patients r and omly assigned to experimental groups ( N = 263 ) were offered up to seven modules of patient education . Each content area module contained didactic instruction ( lecture , discussion , audio-visual presentation ) , skill exercises ( demonstration , practice , feedback ) , and behavioral modification techniques ( goal setting , contracting , regular follow-up ) . Two hundred seventy-five patients remained in the study throughout baseline , intervention , and postintervention periods ( August 1978 to July 1982 ) . Despite the requirement that patients demonstrate mastery of educational objectives for each module , postintervention assessment 11–14 mo after instruction showed only rare differences between experimental and control patients in diabetes knowledge . However , statistically significant group differences in self-care skills and compliance behaviors were relatively more numerous . Experimental group patients experienced significantly greater reductions in fasting blood glucose ( −27.5 mg/dl versus −2.8 mg/dl , P < 0.05 ) and glycosylated hemoglobin ( −0.43 % versus + 0.35 % , P < 0.05 ) as compared with control subjects . Patient education also had similar effects on body weight , blood pressure , and serum creatinine . Continued follow-up is planned for DIABEDS patients to determine the longevity of effects and subsequent impact on emergency room visits and hospitalization [8557972] Objective : To determine the prognosis of treated hypertensive type 1 ( insulin-dependent ) diabetic patients with overt nephropathy . Design : A controlled , prospect i ve , parallel , 5-year follow-up trial . Setting : The tertiary care centre of the Heinrich Heine University Hospital in Dusseldorf , Germany . Patients and interventions : A sequential sample of 91 hypertensive patients with overt diabetic nephropathy participated in a diabetes treatment programme . Thereafter 45 patients received intensified antihypertensive therapy including blood pressure self-monitoring and self-adjustment of antihypertensive drug treatment with the goal of permanent normalization of blood pressure values below 140/90 mmHg . The remaining 46 patients were administered routine antihypertensive therapy and formed the control group . At baseline both groups were comparable in age , sex , metabolic control and renal function . The groups differed at baseline in their duration of diabetes and blood pressure values , which were higher in the intensified antihypertensive therapy group . Outcome measures : Total mortality and the need for renal replacement therapy . Main results : Blood pressure control was significantly improved in patients who were subjected to intensified antihypertensive therapy , whereas it deteriorated in the group of patients who received routine antihypertensive therapy . At follow-up , primary end points of the study occurred in five ( 11 % ) patients of the intensified therapy group and in 19 ( 41 % ) patients of the routine therapy group . According to life table analysis , intensified antihypertensive therapy was associated with less frequent primary end points ( P= 0.0058 ) and longer survival ( P=0.01 ) . The differences between the groups remained significant after adjustment for covariates in the proportional hazards model . Conclusion : Participation in a treatment programme aim ed at intensification of antihypertensive therapy is associated with a reduction of mortality in hypertensive type 1 diabetic patients with overt nephropathy [7125768] Because the elderly are viewed as having more difficulty in complying with therapy , this analysis was directed at the effects of a health education program on their control of primary hypertension when compared with a younger population . The program consisted of three sequential interventions introduced in a r and omized factorial design . Depsite the fact that elderly patients had more chronic disease , more complications from hypertension , and were receiving more complex drug therapies than younger patients exposed to the same experimental interventions , they demonstrated significantly higher levels of compliance with drug therapy , significantly higher levels of appointment keeping , and no difference in the proportion having their BP under control at two-year-follow-up . Longitudinal data collected at five-year follow-up indicate no decay effect . These results indicate such programs can be successfully implemented and equally effective for an elderly population [2688659] After we assessed the functional status of 439 patients with osteoarthritis , we r and omly assigned them to 1 of 3 intervention groups or to a control group . The interventions consisted of providing information , and differed only in the method of delivery : by phone , in person at the clinic , or both . Physical health improved ( P = 0.02 ) , pain was reduced ( P = 0.02 ) , and psychological health improved marginally ( P = 0.10 ) in patients contacted by phone compared with those not contacted by phone . In those contacted only at the clinic , physical health worsened ( P = 0.02 ) , but neither pain ( P = 0.80 ) nor psychological health ( P = 0.90 ) differed from the values in patients not contacted at the clinic . We conclude that telephone contact is a useful intervention that can enhance the functional status of patients with osteoarthritis Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: OBJECTIVE To systematic ally review the effectiveness of self-management training in type 2 diabetes . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

25030199

[16615971] OBJECTIVE To compare the efficacy and safety of once-daily inhaled ciclesonide 40 mug ( CIC40 ) , 80 mug ( CIC80 ) , and 160 mug ( CIC160 ) with placebo in children with persistent asthma of all severities . STUDY DESIGN Overall , 1031 children age 4 to 11 years were r and omized into 2 identical double-blinded , placebo-controlled , parallel group studies consisting of a run-in phase followed by 12 weeks of treatment . Both studies were design ed to allow for a prespecified integrated analysis . The primary outcome variable was change in forced expiratory volume in 1 second ( FEV(1 ) ) percent predicted between baseline and study end ; treatment comparisons were assessed using analysis of covariance . Additional endpoints included asthma symptom scores , daily albuterol use , and safety , including hypothalamic-pituitary-adrenal ( HPA ) axis function . RESULTS Baseline characteristics were comparable ; 59.4 % of patients had moderate asthma , and 24.1 % had severe asthma . All ciclesonide doses were associated with greater improvements in baseline to week 12 FEV(1 ) percent predicted versus placebo ( CIC40 , 11.97 ; CIC80 , 13.58 , P < .05 ; CIC160 , 14.17 , P < .01 ) . Significant improvements in asthma symptoms ( P < .01 ) and reductions in albuterol use were reported . Ciclesonide was well tolerated with no effect on HPA axis function . CONCLUSIONS In this integrated analysis , ciclesonide was effective and well tolerated in children with persistent asthma [18070931] OBJECTIVE . To assess the effects of the new inhaled corticosteroid ciclesonide on growth in children with asthma . METHODS . We performed a multicenter , r and omized , double-blind , placebo-controlled study to assess the effects of inhaled ciclesonide on growth in children with mild , persistent asthma . After a 6-month run-in period , 661 prepubertal children who were aged 5.0 to 8.5 years were r and omly assigned to once-daily morning treatment for 1 year with ciclesonide 40 or 160 μg ( ex-actuator ) or placebo , followed by a 2-month follow-up period . The primary end point was the linear growth velocity ( linear regression estimate ) over the double-blind treatment period . Growth was recorded as the median of 4 stadiometer measurements . Adverse events and 10-hour overnight and 24-hour urinary free cortisol levels were also assessed . RESULTS . Mean linear growth velocity during run-in was comparable between groups : 160 μg , 6.20 cm/year ; 40 μg , 6.59 cm/year ; placebo , 6.49 cm/year . Mean differences from placebo ( 5.75 cm/year ) in growth velocity over the double-blind treatment period were −0.02 cm/year for ciclesonide 40 μg and −0.15 cm/year for ciclesonide 160 μg . Both ciclesonide treatments were noninferior to placebo with respect to growth velocity . The overall incidence of adverse events was comparable between groups , and no significant changes in 10-hour overnight or 24-hour urinary free cortisol levels were noted between groups during the double-blind treatment period . CONCLUSIONS . Ciclesonide demonstrated no detectable effect on childhood growth velocity , even at the highest dosage , which may ease concerns about systemic adverse events [10212103] BACKGROUND Airway hyperresponsiveness , induced sputum eosinophils , and exhaled nitric oxide ( NO ) levels have all been proposed as non-invasive markers for monitoring airway inflammation in patients with asthma . The aim of this study was to compare the changes in each of these markers following treatment with inhaled glucocorticosteroids in a single study . METHODS In a r and omised , double blind , placebo controlled , parallel study 25 patients with mild asthma ( 19–34 years , forced expiratory volume in one second ( FEV1 ) > 75 % predicted , concentration of histamine provoking a fall in FEV1 of 20 % or more ( PC20 ) < 4 mg/ml ) inhaled fluticasone propionate ( 500 μg twice daily ) for four weeks . PC20 to histamine , sputum eosinophil numbers , and exhaled NO levels were determined at weeks 0 , 2 , and 4 , and two weeks after completing treatment . Sputum was induced by inhalation of hypertonic ( 4.5 % ) saline and eosinophil counts were expressed as percentage non-squamous cells . Exhaled NO levels ( ppb ) were measured by chemiluminescence . RESULTS In the steroid treated group there was a significant increase in PC20 , decrease in sputum eosinophils , and decrease in exhaled NO levels compared with baseline at weeks 2 and 4 of treatment . Subsequently , each of these variables showed significant worsening during the two week washout period compared with week 4 . These changes were significantly different from those in the placebo group , except for the changes in sputum eosinophils and exhaled NO levels during the washout period . There were no significant correlations between the changes in the three markers in either group at any time . CONCLUSIONS Treatment of asthmatic subjects with inhaled steroids for four weeks leads to improvements in airway hyperresponsiveness to histamine , eosinophil counts in induced sputum , and exhaled nitric oxide levels . The results suggest that these markers may provide different information when monitoring anti-inflammatory treatment in asthma [18814453] BACKGROUND Onset of bronchodilation of budesonide/formoterol in one pressurized metered-dose inhaler ( pMDI ) has not been evaluated in asthma . OBJECTIVE To evaluate time to onset of clinical ly significant bronchodilation ( > or = 15 % improvement in forced expiratory volume in 1 second ) and patient-perceived onset of effect ( OE ) in patients previously receiving inhaled corticosteroids . METHODS In two 12-week studies , patients 12 years and older with moderate to severe ( study 1 ; n = 596 ) and mild to moderate ( study 2 ; n = 480 ) persistent asthma received budesonide/formoterol pMDI , budesonide pMDI plus formoterol dry powder inhaler ( study 1 only ) , budesonide pMDI , formoterol dry powder inhaler , or placebo . Postdose time to 15 % or greater improvement in forced expiratory volume in 1 second and patient-perceived OE ( assessed in a subset of patients 18 years and older [ study 1 , n=553 ; study 2 , n=405 ] ) were evaluated [ corrected ] RESULTS More budesonide/formoterol-treated patients achieved onset of clinical ly significant bronchodilation within 15 minutes ( median , 13 minutes ) of administration at r and omization vs those taking budesonide or placebo ( P < .001 ) . More patients receiving budesonide/formoterol vs budesonide and placebo reported feeling their study medication begin to work right away ( P < or = .004 ; end of week 1 ) . Similar results ( P < .001 ) were observed for patient satisfaction with how quickly they felt their medication begin to work ( except budesonide/formoterol vs budesonide , study 1 [ P = .073 ] ) . Time to onset of clinical ly significant bronchodilation and patient-perceived OE of budesonide/formoterol and formoterol were similar . CONCLUSION Budesonide/formoterol demonstrated a more rapid onset of clinical ly significant bronchodilation and a greater percentage of patients who perceived their medication working right away vs budesonide or placebo [9655732] Studies in adults revealed that addition of salmeterol to a moderate dose of inhaled corticosteroid result ed in better symptom control and higher PEF compared with doubling the dose of inhaled corticosteroid . The aim of this three group study was to compare the effects of a moderate dose of beclomethasone , the same dose of beclomethasone with salmeterol , and a doubling dose of beclomethasone on lung function and symptoms in children with moderate asthma . A total of 177 children already treated with inhaled corticosteroids , were r and omized in a double-blind parallel study either to salmeterol 50 microg twice daily ( BDP400+salm ) , beclomethasone 200 microg twice daily ( BDP800 ) , or placebo ( BDP400 ) in addition to beclomethasone 200 microg twice daily . No significant differences between groups were found in FEV1 , PD20 methacholine , symptom scores , and exacerbation rates after 1 yr . Salmeterol result ed in slightly better PEF in the first months of treatment . FEV1 , and PD20 methacholine significantly improved in all groups . After 1 yr mean changes in FEV1 , percent predicted were 4.3 % ( 95 % CI 1.3 ; 7.2 ) , 5.8 % ( 95 % CI 2.9 ; 8.7 ) , and 4.3 % ( 95 % CI 2.1 ; 6.5 ) for BDP400+salm , BDP800 , and BDP400 , respectively . Changes in airway responsiveness were 0.60 ( 95 % CI 0.05 ; 1.14 ) , 1.30 ( 95 % CI 0.73 ; 1 . 87 ) , and 0.80 ( 95 % CI 0.33 ; 1.27 ) doubling doses . Growth was significantly slower in the BDP800 group . We conclude that no additional benefit was found of adding either salmeterol or more beclomethasone to a daily dose of 400 microg beclomethasone in this group of children with excellent compliance of medication [24565456] BACKGROUND Environmental tobacco smoke ( ETS ) negatively affects children with asthma . The prevalence of ETS exposure among children with poor asthma control may be changing . Importantly , the mechanisms by which ETS worsens asthma control are poorly understood . OBJECTIVE We describe how ETS affects gastroesophageal reflux ( GER ) , respiratory infections , and leukotriene production among children with poor asthma control . METHODS We analyzed data from 306 children between 6 and 17 years of age with poorly controlled asthma enrolled in a 6-month clinical trial . We evaluated prevalence and determinants of ETS exposure by interview , question naire , and urinary cotinine and the association of ETS exposure on leukotriene production , respiratory infections , GER , lung function , and asthma control . We used multivariable linear , logistic , and Poisson regressions to assess outcomes . RESULTS ETS prevalence estimates ranged from 6 % to 30 % . Children with domestic indoor exposure had worse asthma control ( c-Asthma Control Test , 17.8 vs 21.5 ; P = .04 ) , worse FEV1 % predicted ( 84.1 vs 90.7 ; P = .02 ) , and a trend for increased mean urinary leukotriene E4 . ETS from any setting was associated with increased symptomatic respiratory infections ( adjusted incidence rate ratio : 1.30 ; P = .02 ) . However , children exposed to ETS did not have symptoms or pH probe results , suggestive of heightened GER . CONCLUSIONS Domestic smoking exposure was associated with both higher rates of symptomatic respiratory infection and poorer asthma control despite generally intensive controller therapy . ETS exposure is common among asthmatic children with poor control and may worsen asthma control by promoting respiratory infections . Further investigation is required to eluci date ETS mechanisms in poor asthma control [22938716] BACKGROUND The use of inhaled glucocorticoids for persistent asthma causes a temporary reduction in growth velocity in prepubertal children . The result ing decrease in attained height 1 to 4 years after the initiation of inhaled glucocorticoids is thought not to decrease attained adult height . METHODS We measured adult height in 943 of 1041 participants ( 90.6 % ) in the Childhood Asthma Management Program ; adult height was determined at a mean ( ±SD ) age of 24.9±2.7 years . Starting at the age of 5 to 13 years , the participants had been r and omly assigned to receive 400 μg of budesonide , 16 mg of nedocromil , or placebo daily for 4 to 6 years . We calculated differences in adult height for each active treatment group , as compared with placebo , using multiple linear regression with adjustment for demographic characteristics , asthma features , and height at trial entry . RESULTS Mean adult height was 1.2 cm lower ( 95 % confidence interval [ CI ] , -1.9 to -0.5 ) in the budesonide group than in the placebo group ( P=0.001 ) and was 0.2 cm lower ( 95 % CI , -0.9 to 0.5 ) in the nedocromil group than in the placebo group ( P=0.61 ) . A larger daily dose of inhaled glucocorticoid in the first 2 years was associated with a lower adult height ( -0.1 cm for each microgram per kilogram of body weight ) ( P=0.007 ) . The reduction in adult height in the budesonide group as compared with the placebo group was similar to that seen after 2 years of treatment ( -1.3 cm ; 95 % CI , -1.7 to -0.9 ) . During the first 2 years , decreased growth velocity in the budesonide group occurred primarily in prepubertal participants . CONCLUSIONS The initial decrease in attained height associated with the use of inhaled glucocorticoids in prepubertal children persisted as a reduction in adult height , although the decrease was not progressive or cumulative . ( Funded by the National Heart , Lung , and Blood Institute and the National Center for Research Re sources ; CAMP Clinical Trials.gov number , NCT00000575 . ) [11930704] OBJECTIVE To observe the systemic side effects of low dose inhaled Beclomethasone dipropionate ( BDP ) in children with mild asthma . METHODS 30 children with mild asthma were r and omly divided into 3 groups to receive treatment with inhaled placebo ( group A ) , BDP 200 micrograms/d ( group B ) and BDP 400 micrograms/d ( group C ) respectively . Bronchial hyperresponsiveness ( BHR ) , height growth , bone mineral density ( BMD ) , calcium and phosphate metabolism and hypothalamic-pituitary-adrenal axis ( HPAA ) function were measured . RESULTS Inhaled BDP of 200 micrograms/d and 400 micrograms/d reduced BHR in mild asthmatic children and there was no significant difference between two groups [log(PD20-FEV1)]:(2.04 + /- 0.47 ) micrograms to ( 2.70 + /- 0.13 ) micrograms in group A and ( 1.94 + /- 0.46 ) micrograms to ( 3.15 + /- 0.18 ) micrograms in group B ( P < 0.01 ) . Serum osteocalcin , calcium , phosphate , alkaline phosphatase , basic cortisol and BMD did n't change significantly after BDP treatment in three groups ( all P > 0.05 ) [ In group A , B and C , concentrations serum osteocalcin were ( 29 + /- 12 ) micrograms/L , ( 22 + /- 6 ) micrograms/L , ( 31 + /- 11 ) micrograms/L , serum calcium : ( 2.49 + /- 0.11 ) mmol/L , ( 2.39 + /- 0.28 ) mmol/L , ( 2.20 + /- 0.35 ) mmol/L , serum phosphate : ( 1.8 + /- 0.6 ) mmol/L , ( 1.7 + /- 0.7 ) mmol/L , ( 1.5 + /- 0.4 ) mmol/L , radius BMD : ( 0.44 + /- 0.02 ) g/cm2 , ( 0.42 + /- 0.05 ) g/cm2 , ( 0.40 + /- 0.10 ) g/cm2 , ulna BMD:(0.35 + /- 0.04 ) g/cm2 , ( 0.36 + /- 0.08 ) g/cm2 , ( 0.32 + /- 0.07 ) g/cm2 , serum alkaline phosphatase : ( 410 + /- 113 ) U/L , ( 337 + /- 99 ) U/L , ( 351 + /- 122 ) U/L , serum basic cortisol : ( 350 + /- 86 ) nmol/L , ( 407 + /- 199 ) nmol/L , ( 365 + /- 71 ) nmol/L , lumbar spine ( L4 - 5 ) BMD : ( 0.64 + /- 0.06 ) g/cm2 , ( 0.59 + /- 0.08 ) g/cm2 , ( 0.62 + /- 0.09 ) g/cm2 respectively ] . Height growth had a trend of reducing after BDP treatment though not reaching statistical difference . Height st and ard deviation score ( SDS ) : 1.1 + /- 0.7 to 1.2 + /- 0.9 in group A , 1.3 + /- 0.7 to 1.3 + /- 0.9 in group B and 1.1 + /- 0.7 to 1.0 + /- 0.7 in group C. Serum cortisol after ACTH stimulation reduced significantly in group C [ ( 621 + /- 199 ) nmol/L to ( 482 + /- 97 ) nmol/L , P < 0.01 ] . CONCLUSION The results of this study suggest that 200 micrograms/d BDP can reduce BHR significantly and has no detected systemic side effects in mild asthmatic children , and 400 micrograms/d BDP can reduce serum cortisol after ACTH stimulation . The long-term dose of BDP should be controlled to be less than 400 micrograms/d in children with mild asthma [10669845] BACKGROUND Results of recent growth studies suggest that inhaled glucocorticosteroids may affect growth in children . OBJECTIVE Three 52-week , open-label extension studies ( studies A , B , and C ) were conducted to compare the effects of budesonide inhalation suspension ( BIS ) with conventional asthma therapy ( CAT ) on long-term safety , including intermediate-term growth , in 3 different pediatric asthma population s. METHODS Pediatric asthma patients ( ages 6 months to 8 years ) from 3 multicenter , r and omized , 12-week , double-blind , placebo-controlled studies were eligible to enroll in the 52-week , open-label extension studies . The extension studies were multicenter , r and omized , open-label , active-controlled , parallel-group studies performed at 26 centers in the United States . Subjects in each extension study were r and omized in a 2:1 ratio to receive either BIS or CAT . BIS was initially administered at a dose of 0.5 mg once ( studies A and C ) or twice daily ( study B ) , with attempts made at each clinical visit to gradually reduce the dose to the minimum effective dose that maintains asthma control , as judged by the investigator . CAT consisted of any available therapy for asthma , including inhaled glucocorticosteroids in studies B and C only . Height SD scores , growth velocity , and skeletal age ( only in studies B and C ) were examined . RESULTS In total , 670 subjects were r and omized ; 223 subjects received CAT and 447 received BIS . Mean ages at entry were 63.0 months and 60.9 months in CAT and BIS groups , respectively . Median total daily doses of BIS ranged from 0.5 to 1 . 0 mg and the mean duration of treatment exposure was 304 + /- 119 days and 342 + /- 83 days in CAT and BIS groups , respectively . Changes in height SD scores differed significantly between the BIS and CAT groups in study A ( -0.19 , P = .003 ) , and there was a small , statistically significant decrease in growth velocity ( -0.8 cm/y , P = .002 ) in the BIS-treated group compared with the CAT group . No significant differences were observed between BIS and CAT groups in the changes in height SD scores or in growth velocities in studies B ( + 0.10 and + 0.7 cm/y , respectively ) and C ( + 0.12 and + 0.8 cm/y , respectively ) . No differences in skeletal age were observed between BIS and CAT groups in studies B and C. CONCLUSION There was a small , statistically significant decrease in growth velocity in the BIS-treated group compared with the CAT group in the study ( study A ) where inhaled glucocorticosteroid use was prohibited before entry and in the CAT group during the study . In the studies ( B and C ) where inhaled glucocorticosteroids were allowed in the CAT group , no differences were observed in height SD scores or growth velocity . The clinical relevance of these effects , including impact on final adult height , remain to be determined in prospect ively planned studies that assess growth in children [9864004] The aim of the present study was to examine the efficacy of low-dose inhaled budesonide ( BUD ) administered via Turbuhaler once or twice daily on symptoms , lung function and bronchial hyperreactivity in children with mild asthma . One hundred and sixty-three children ( mean age 9.9 yrs , 56 females/107 males ) with mild asthma ( forced expiratory volume in one second ( FEV1 ) 103 % of predicted , morning peak expiratory flow ( PEF ) 87 % pred , reversibility in FEV1 3 % , fall in FEV1 after exercise 10.4 % from pre-exercise value ) and not previously treated with inhaled steroids , were included in a double-blind , r and omized , parallel-group study . After a two-week run-in period , the children received inhaled BUD 100 microg or 200 microg once daily in the morning , 100 microg twice daily or placebo for 12 weeks . Exercise and methacholine challenges were performed before and at the end of treatment . After 12 weeks of therapy , the fall in FEV1 after an exercise test was significantly less in all three BUD groups ( 43 - 5.1 % ) than in the placebo group ( 8.6 % ) . Bronchial hyperreactivity to methacholine with the provocative dose causing a 20 % fall in FEV1 decreased significantly in the BUD 100 microg twice-daily group compared with placebo ( ratio at the end of treatment 156 % ) . Changes in baseline lung function ( FEV1 and PEF ) were less marked than changes in bronchial responsiveness . In conclusion , low doses of inhaled budesonide , given once or twice daily , provided protection against exercise-induced bronchoconstriction in children with mild asthma and near normal lung function [4354777] Twenty children have been treated with the steroid aerosol beclomethasone , half of them in an open trial and the other half in a controlled cross-over trial . Children were assessed by means of clinical examination , diary records , and twice-daily peak flow rate measurements made at home . After 1 to 2 months all but 1 of the 16 children who were initially taking systemic steroids or corticotrophin were weaned off these drugs . The cross-over trial showed a significant improvement on the active drug , in terms of diary score , bronchodilator use , steroid dose , and twice-daily peak expiratory flow measurements . Adrenal function was entirely normal after 1 and 3 months on the drug as measured by morning cortisol levels and the response to tetracosactrin . There were no side effects , apart from the reappearance of hay fever or eczema in some children previously on systemic steroids . Follow-up for a mean of 4·5 ± 2·2 ( SD ) months showed the continuing efficacy of beclomethasone , though an increase in dose has been needed in some children . The advantages of aerosol steroid therapy in children are noted [12877449] BACKGROUND Because of potential toxicities of inhaled corticosteroid ( ICS ) use in pediatric asthma , alternative or steroid-sparing therapy is desirable . There are no previous studies evaluating montelukast 's steroid-sparing effects in children with asthma . OBJECTIVE To evaluate whether ( 1 ) montelukast as add-on therapy improves asthma symptom control and ( 2 ) montelukast provides steroid-sparing effects in children with asthma treated with low to moderate doses of ICS therapy . METHODS In a double-blind , placebo-controlled trial , 36 children ages 6 to 14 years with symptomatic asthma maintained on a stable low to moderate dose of ICSs were r and omly assigned to receive montelukast or matching placebo for 24 weeks after a run-in period of 2 weeks ( period I ) . During the trial , subjects kept daily asthma diary cards and monthly spirometry was performed . After a 4 week add-on period ( period II ) , the subjects completed a 20-week ( period III ) ICS tapering period based on a predetermined protocol . RESULTS In period II , the difference in the number of rescue-free days was significantly higher in the montelukast group ( P = 0.0001 ) , and the number of rescue-free days per week was also significantly higher in montelukast-treated subjects compared with placebo subjects ( P = 0.002 ) . In period III , the percentage reduction in ICS dose was not significant between montelukast and placebo ( P = 0.10 ) , but the montelukast group experienced an average 17 % decrease in ICS dose and the control group experienced an average 64 % increase in ICS dose . CONCLUSIONS Montelukast treatment significantly increased the number of rescue-free days in symptomatic children with asthma [12756375] OBJECTIVE Exhaled nitric oxide ( FE(NO ) ) was evaluated in children with asthma after 4 to 6 years of treatment with budesonide , nedocromil , or albuterol as needed . STUDY DESIGN FE(NO ) , spirometry , total eosinophil count , and serum eosinophil cationic protein levels were obtained from 118 children at the Denver site of the Childhood Asthma Management Program upon completion of treatment and after a 2- to 4-month washout . RESULTS Budesonide-treated patients had significantly lower median ( 1st , 3rd quartile ) FE(NO ) ( 21.5 [ 13.2 , 84.4 ] vs 62.5 [ 26.2 , 115.0 ] ppb , P < .01 ) and eosinophil cationic protein levels ( 17.4 [ 10.1 , 24.3 ] vs 24.0 [ 15.4 , 33.9 ] mg/dL , P = .05 ) compared with placebo , whereas no differences were noted between nedocromil and placebo groups . After washout , FE(NO ) levels were similar between the three treatments . FE(NO ) levels significantly correlated with degree of bronchial hyperresponsiveness , bronchodilator reversibility , allergen skin prick tests , serum IgE , and total eosinophil count . FE(NO ) levels were also higher in patients with nocturnal symptoms and in patients requiring beta-agonist use at least once weekly . CONCLUSIONS Budesonide therapy was more effective than nedocromil in reducing FE(NO ) . Unfortunately , the effects of long-term budesonide were not sustained after its discontinuation . FE(NO ) may be a complementary tool to current practice guidelines in assessing asthma control and medication response [9850361] Herein we assess the safety of an inhaled formulation of beclomethasone dipropionate ( BDP ) which uses the propellant hydrofluoroalkane-134a ( HFA ) for the treatment of asthma . Acute local tolerability ( as assessed by the incidence of cough and mean forced expiratory volume after 1 s inhalation ) was similar for both BDP and placebo formulated in either chlorofluorocarbon ( CFC ) or HFA propellants . A total of 43 patients were treated with HFA-BDP ( 0 , 200 , 400 or 800 micrograms day-1 ) or CFC-BDP ( 800 micrograms day-1 ) for 14 days and their 24 h urinary free cortisol ( UFC ) excretion and response to cosyntropin stimulation were measured . There was no difference in UFC between any of the doses of HFA-BDP and CFC-BDP . Adrenal responsiveness to cosyntropin stimulation was normal in all but one patient . Two large 12 week phase III trials compared HFA-placebo , HFA-BDP 400 micrograms day-1 and CFC-BDP 800 micrograms day-1 ( n = 347 ) , and HFA-BDP 800 micrograms day-1 and CFC-BDP 1500 micrograms day-1 ( n = 233 ) . For HFA-BDP at either dose , CFC-BDP 800 micrograms day-1 and HFA-placebo , the number of patients with morning plasma cortisol concentrations below normal was less than 4.4 % but was 14.6 % for CFC-BDP 1500 micrograms day-1 . The incidence of adverse events was lower in the HFA-BDP groups than in the CFC-BDP groups ( P = 0.012 ) . The data indicate that , at doses of up to 800 micrograms day-1 , HFA-BDP is at least as well tolerated as CFC-BDP . Other studies have found that equivalent efficacy is reached at lower doses of HFA-BDP than CFC-BDP . Equivalent efficacy at a lower dose and equivalent safety at the same dose imply that HFA-BDP may have a more favourable risk : benefit ratio than CFC-BDP when used at the recommended lower doses [16387604] BACKGROUND Atopic dermatitis ( AD ) often develops in infancy as the first manifestation of the atopic phenotype . Wheezing is also common in infancy , but it is less clear whether infant wheezing should be considered as an atopic phenotype . If infant wheeze and AD share a common aetiology , this would indicate that infant wheezing is an atopic phenotype . OBJECTIVE To investigate whether potential risk factors for infant wheeze and AD have similar effects on these 2 phenotypes , indicating a common etiology . METHODS A total of 34.793 mother-child pairs enrolled in the Danish National Birth Cohort were followed prospect ively . Information on wheezing episodes , AD , and prenatal , perinatal , and postnatal risk factors was collected by interview at 12 and 30 weeks of gestation , at 6 and 18 months of age , and by linkage to the Danish Medical Birth Register . Data were analyzed by binary and polytomous logistic regression models . RESULTS The following variables had significantly differential effects on infant wheezing and AD : parental hay fever , parental asthma , parental AD , sex , maternal age , maternal occupation , smoking during pregnancy , season of birth , birth weight , gestational age , head circumference , breast-feeding , number of older siblings , day care attendance , and pets in the home . CONCLUSION The majority of risk factors had differential effects on infant wheeze and AD indicative of a different etiology . Infant wheezing does not seem to be etiologically linked to the epidemic of atopic disease , and infant wheezing should not be used as an indicator of the atopic phenotype [9679845] BACKGROUND Inhaled corticosteroids are increasingly being used to treat mild-to-moderate asthma in children . However , data regarding therapy with this class of compounds , especially in children under age 6 years , is limited . Fluticasone propionate is a third generation inhaled corticosteroid with an optimal therapeutic index . Few large prospect i ve clinical trials have been conducted to evaluate the efficacy and safety of fluticasone propionate powder in children . OBJECTIVE We sought to determine the efficacy and safety of fluticasone propionate powder administered by means of the Diskus and Diskhaler multidose powder inhalers in pediatric patients with persistent asthma . METHODS Fluticasone propionate powder ( 50 microg or 100 microg twice daily ) or placebo was administered by means of the Diskus or Diskhaler inhalers to 437 children ( 4 to 11 years old ) with persistent asthma for 12 weeks in a r and omized , double-blind , parallel-group , multi-center trial . Patients were stratified according to whether they were receiving prior treatment with inhaled corticosteroids or cromolyn or beta2-agonists alone . RESULTS Fluticasone propionate powder administered by means of Diskus or Diskhaler significantly improved FEV1 ( mean increase from baseline of 0.22 to 0.24 L ; p < or = 0.023 ) , clinic morning peak expiratory flow ( mean increase from baseline of 48 to 55 L/min ; p < or = 0.006 ) , patient-measured morning ( p < or = 0.001 ) and evening ( p < or = 0.003 ) peak expiratory flow , and asthma symptom scores ( in all but the 50 microg Diskus group ; p < or = 0.036 ) , as well as reduced albuterol use ( p < or = 0.002 ) and nighttime awakenings ( p < or = 0.019 ) at endpoint . Efficacy parameters were not significantly different between the two doses with either device . More placebo-treated patients discontinued the study because of lack of efficacy than patients in any fluticasone propionate group ( p < 0.001 ) . Fluticasone propionate did not suppress morning plasma cortisol concentrations and did not affect 24-hour urinary free-cortisol excretion . Adverse events were primarily pharmacologic effects of inhaled corticosteroids , and those related to the study drug occurred with low frequency . Patient satisfaction with both the Diskus and Diskhaler devices was high , with a majority of patients ( > 80 % ) rating them favorably . CONCLUSION This study demonstrated that fluticasone propionate powder , at the conventional recommended doses of up to 200 microg/day administered by means of Diskus or Diskhaler , was well tolerated and improved lung function in children even as young as 4 and 5 years old regardless of whether they were previously treated with inhaled corticosteroids or cromolyn or beta2-agonists alone [15358701] To assess long-term effects and side-effects of fluticasone propionate ( FP ) , a 2-yr study was performed , comparing a step-down dose approach ( 1,000 µg·day−1 , with reductions every 2 months to 500 , 200 and 100 µg·day−1 for the remainder of the study ) versus a constant dose ( 200 µg·day−1 ) . In 55 children with chronic persistent asthma , aged 6–10 yrs , airways hyperresponsiveness ( AHR ) and systemic side-effects ( height , bone parameters and adrenal cortical function ) were assessed at predetermined intervals in a double-blind prospect i ve 2-yr study . AHR improved after 4 months treatment with 1,000 µg·day−1 FP followed by 500 µg·day−1 , without significant differences during long-term treatment between the two approaches . Dose-dependent reduction of growth velocity , adrenal cortical function and biochemical bone turnover was found during therapy with 1,000 and 500 µg·day−1 FP when compared with 200 µg·day−1 . In conclusion , doses of 1,000 and 500 µg·day−1 fluticasone propionate are associated with marked reductions of growth velocity , bone turnover and adrenal cortical function . However , conventional doses ( ≤200 µg·day−1 fluticasone propionate ) appear to be safe in the long-term management of childhood asthma . From a safety point of view , high doses of fluticasone propionate should only be prescribed in exceptions , e.g. in persistent severe asthma [2532957] Objective : To compare the effect of inhaled budesonide given daily or as-needed on mild persistent childhood asthma . Patients , design and interventions : 176 children aged 5–10 years with newly detected asthma were r and omly assigned to three treatment groups : ( 1 ) continuous budesonide ( 400 μg twice daily for 1 month , 200 μg twice daily for months 2–6 , 100 μg twice daily for months 7–18 ) ; ( 2 ) budesonide , identical treatment to group 1 during months 1–6 , then budesonide for exacerbations as needed for months 7–18 ; and ( 3 ) disodium cromoglycate ( DSCG ) 10 mg three times daily for months 1–18 . Exacerbations were treated with budesonide 400 μg twice daily for 2 weeks . Main outcome measures : Lung function , the number of exacerbations and growth . Results : Compared with DSCG the initial regular budesonide treatment result ed in a significantly improved lung function , fewer exacerbations and a small but significant decline in growth velocity . After 18 months , however , the lung function improvements did not differ between the groups . During months 7–18 , patients receiving continuous budesonide treatment had significantly fewer exacerbations ( mean 0.97 ) , compared with 1.69 in group 2 and 1.58 in group 3 . The number of asthma-free days did not differ between regular and intermittent budesonide treatment . Growth velocity was normalised during continuous low-dose budesonide and budesonide therapy given as needed . The latter was associated with catch-up growth . Conclusions : Regular use of budesonide afforded better asthma control but had a more systemic effect than did use of budesonide as needed . The dose of ICS could be reduced as soon as asthma is controlled . Some children do not seem to need continuous ICS treatment [4354778] Twenty-five patients with severe childhood asthma were treated with beclomethasone dipropionate . 21 of these children were receiving oral corticosteroid therapy in addition to disodium cromoglycate . Of the total treated , 21 children improved or maintained their asthma status on this treatment over an average period of 4 months , and were able to reduce and stop their regular oral corticosteroid dosage , but 4 children had to revert to their original therapy . No systemic or local toxic effects were experienced by any of the children . Beclomethasone dipropionate appears to be an effective drug in the treatment of severe childhood asthma in those patients who need corticosteroid therapy in addition to disodium cromoglycate [18178494] OBJECTIVE Demonstrating clinical benefit of higher doses of inhaled corticosteroids in asthma is frequently problematic owing to their relatively flat dose-response curve in this condition . In this study we compared the efficacy and safety of a fourfold difference in the dose of ciclesonide-ciclesonide 320 microg twice daily ( CIC640 ) versus ciclesonide 160 microg once daily (CIC160)-in patients with severe persistent asthma . METHODS Patients with bronchial asthma ( 6 months ) were included in this r and omized , double-blind study . After receiving fluticasone propionate 250 microg twice daily during run-in , patients were r and omized to CIC160 ( n=339 ) or CIC640 ( n=341 ) for 12 weeks . Primary endpoints were time to first asthma exacerbation and forced expiratory volume in 1s ( FEV(1 ) ) . Secondary endpoints included other lung function variables , asthma symptom scores and rescue medication use ( RMU ) . RESULTS Asthma exacerbations occurred in 12.7 % of patients receiving CIC160 and 6.7 % receiving CIC640 . CIC640 was superior for time to first exacerbation ( p=0.0050 , one-sided ) . FEV(1 ) increased significantly with CIC160 and CIC640 ( least squares mean+/-SE of mean : 269+/-31 and 332+/-31 mL , respectively ; p<0.0001 ) , with no significant difference between groups . Change in % predicted FEV(1 ) and morning peak expiratory flow ( PEF ) were significantly higher with CIC640 ( p<0.05 ) . Asthma symptom score sums and RMU decreased in both groups ; CIC640 was statistically superior ( p=0.0108 and 0.0005 , respectively ) . No unexpected adverse events were reported in either group and the majority of the events reported were mild or moderate in intensity . No significant changes in serum cortisol were observed from the baseline to the study end . Small decreases in creatinine-adjusted 24h urine cortisol levels from baseline were seen in both the treatment groups , which , due to the large patient numbers , were statistically significant ( p<0.05 ) ; however , no dose-response effect was seen and the difference between groups was not significant ( p=0.7892 ) . CONCLUSION CIC640 was superior to CIC160 for time to first exacerbation , % predicted FEV1 , morning PEF , asthma symptom score sum and RMU in patients with severe asthma ; both doses had similar tolerability profiles and no significant changes in serum cortisol were seen in either treatment group [22536582] BACKGROUND In 2010 , the Canadian Thoracic Society ( CTS ) published a Consensus Summary for the diagnosis and management of asthma in children six years of age and older , and adults , including an up date d Asthma Management Continuum . The CTS Asthma Clinical Assembly subsequently began a formal clinical practice guideline up date process , focusing , in this first iteration , on topics of controversy and ⁄or gaps in the previous guidelines . METHODS Four clinical questions were identified as a focus for the up date d guideline : the role of noninvasive measurements of airway inflammation for the adjustment of anti-inflammatory therapy ; the initiation of adjunct therapy to inhaled corticosteroids ( ICS ) for uncontrolled asthma ; the role of a single inhaler of an ICS⁄long-acting beta(2)-agonist combination as a reliever , and as a reliever and a controller ; and the escalation of controller medication for acute loss of asthma control as part of a self-management action plan . The expert panel followed an adaptation process to identify and appraise existing guidelines on the specified topics . In addition , literature search es were performed to identify relevant systematic review s and r and omized controlled trials . The panel formally assessed and grade d the evidence , and made 34 recommendations . RESULTS The up date d guideline recommendations outline a role for inclusion of assessment of sputum eosinophils , in addition to st and ard measures of asthma control , to guide adjustment of controller therapy in adults with moderate to severe asthma . Appraisal of the evidence regarding which adjunct controller therapy to add to ICS and at what ICS dose to begin adjunct therapy in children and adults with poor asthma control supported the 2010 CTS Consensus Summary recommendations . New recommendations for the adjustment of controller medication within written action plans are provided . Finally , priority areas for future research were identified . CONCLUSIONS The present clinical practice guideline is the first up date of the CTS Asthma Guidelines following the Canadian Respiratory Guidelines Committee 's new guideline development process . Tools and strategies to support guideline implementation will be developed and the CTS will continue to regularly provide up date s reflecting new evidence [12042586] OBJECTIVE To assess the long-term safety of hydrofluoroalkane 134a (HFA)-beclomethasone dipropionate ( BDP ) extrafine aerosol administered by the Autohaler compared with chlorofluorocarbon (CFC)-BDP administered by a press- and -breathe metered-dose inhaler ( pMDI ) and spacer ( + S ) in the treatment of children with asthma . METHODS This 12-month , open-label , r and omized , multicenter study enrolled 300 children who were aged 5 to 11 years and had well-controlled asthma on inhaled CFC-BDP or budesonide ; 256 patients were using doses within the recommended range ( 200 - 400 microg ) and were analyzed separately . Patients were r and omized in a 1:3 ratio to continue on CFC-BDP+S at approximately the same dose as they were using before study entry or switch to HFA-BDP at half the daily dose . RESULTS Asthma control was well maintained in the HFA-BDP group as evidence d by lung function tests and asthma symptoms compared with CFC-BDP+S at approximately twice the dose . There were no significant differences between the HFA-BDP 100 to 200 microg and CFC-BDP+S 200 to 400 microg treatment groups in mean change from baseline in height ( 5.23 cm vs 5.66 cm at month 12 , respectively ) or mean growth velocity from day 1 to month 12 ( 5.27 cm/y vs 5.71 cm/y , respectively ) . There were no significant differences between groups in adrenal function tests or markers of bone metabolism . CONCLUSIONS In this long-term study in children with asthma , extrafine HFA-BDP provided long-term maintenance of asthma control at approximately half the dose compared with CFC-BDP+S. There were no clinical ly meaningful differences between HFA-BDP extrafine aerosol and conventional CFC-BDP+S with regard to growth or other systemic effects [12016099] The goal of this study was to establish a reliable method to evaluate systemic bioavailability and to determine equisystemic effects ( microgram dose producing equal systemic cortisol suppression ) of inhaled corticosteroids ( ICS ) . Steroid naive asthma subjects ( n = 156 ) were enrolled at six centers . A 1-week doubling dose design was used for each of six ICS and matched placebos for a total of four doses . Systemic effect was evaluated by hourly plasma cortisol concentrations ( 8 P.M. to 8 A.M. ) , 12- and 24-hour urine cortisol concentrations , and a morning blood osteocalcin . The area under the concentration-time curve for hourly cortisol concentrations was the best outcome variable to assess systemic effect . For the six ICS and matching placebos ( beclomethasone-chlorofluorocarbon [ CFC ] , budesonide dry powder inhaler [ DPI ] , fluticasone DPI , fluticasone-CFC metered dose inhaler [ MDI ] , flunisolide-CFC , and triamcinolone-CFC ) , only the placebo group and fluticasone DPI did not demonstrate a significant dose-response effect . Thus microgram comparison of all ICS could only be performed at a 10 % cortisol suppression : flunisolide-CFC - 936 ; triamcinolone-CFC - 787 ; beclomethasone-CFC - 548 ; fluticasone DPI - 445 ; budesonide DPI - 268 ; fluticasone-CFC MDI - 111 . This study represents the first step in evaluation of ICS efficacy based on equisystemic ( cortisol suppression ) effects of a given ICS , rather than doses judged arbitrarily to be comparable on a microgram basis [15644830] OBJECTIVE To compare the safety of budesonide inhalation suspension ( BIS ) with placebo in infants 6 to 12 months of age with mild to moderate persistent asthma or recurrent wheeze . STUDY DESIGN In this multicenter , r and omized , double-blinded , parallel-group , placebo-controlled study , 141 patients received 0.5 mg BIS ( n = 48 ) , 1.0 mg BIS ( n = 44 ) , or placebo ( n = 49 ) once daily for 12 weeks . The primary variable was adrenal function , based on cosyntropin-stimulated plasma cortisol levels . Spontaneous adverse events and clinical laboratory findings also were monitored . RESULTS Overall , the types and frequencies of adverse events reported during the study were comparable across treatment groups . The response to cosyntropin stimulation was similar across treatment groups , with no significant difference between BIS treatment and placebo . CONCLUSIONS The safety profile of BIS was similar to that of placebo , with no suppressive effect on adrenal function in patients 6 to 12 months of age with mild to moderate persistent asthma or recurrent wheeze [9385125] BACKGROUND An inhaled glucocorticoid is currently the medication of choice for long-term control of persistent asthma in children . The role of long-acting beta2-adrenergic-receptor agonists , such as salmeterol , needs to be defined . METHODS We conducted a r and omized , double-blind , placebo-controlled , parallel-group , one-year study of 241 children ( mean [ + /-SD ] age , 9.3+/-2.4 years ) with clinical ly stable asthma and less than one month of prior glucocorticoid use . We compared inhaled beclomethasone dipropionate ( 200 microg twice daily ) with salmeterol xinafoate ( 50 microg twice daily ) and placebo ( lactose ) . The primary outcome measure , airway responsiveness ( as assessed with a methacholine challenge ) was evaluated before treatment ; after 3 , 6 , 9 , and 12 months of treatment ( 12 and 36 hours after study medications had been withheld ) ; and 2 weeks after the end of treatment . Spirometry , symptoms , use of rescue medication ( 200 microg of albuterol inhaled as needed ) , and adverse effects were also assessed . RESULTS During months 1 through 12 overall , beclomethasone was associated with significantly less airway hyperresponsiveness than salmeterol ( P= 0.003 ) or placebo ( P<0.001 ) . This effect was lost two weeks after treatment had been stopped . As compared with placebo , beclomethasone was associated with less variability between morning and evening in the peak expiratory flow ( P=0.002 ) , as was salmeterol ( P=0.02 ) . Beclomethasone was also associated with a reduced need for albuterol as rescue therapy ( P<0.001 ) and fewer withdrawals because of asthma exacerbations ( P=0.03 ) , but salmeterol was not ( P=0.09 and 0.55 , respectively ) . During months 1 through 12 , linear growth was 3.96 cm in the children receiving beclomethasone , as compared with 5.40 cm in the salmeterol group ( P=0.004 ) and 5.04 cm in the placebo group ( P=0.018 ) . Height was not measured after treatment ended . CONCLUSIONS Beclomethasone was effective in reducing airway hyperresponsiveness and in controlling symptoms of asthma , but it was associated with decreased linear growth . Salmeterol was not as effective as beclomethasone in reducing airway hyperresponsiveness or in controlling symptoms ; however , it was an effective bronchodilator and was not associated with rebound airway hyperresponsiveness , masking of symptoms , or adverse effects [4590668] Betamethasone valerate aerosol is a new compound for the treatment of asthma . Its clinical effectiveness was established in a double-blind cross-over trial in non-steroid-dependent asthmatic patients . At a dosage of 400 to 800 μg/day for three months there was no evidence of suppression of hypothalamic-pituitary-adrenal function , as assessed by tetracosactrin and insulin stress tests . A 12-month follow-up study of 120 patients using steroid aerosols ( betamethasone valerate or beclomethasone dipropionate ) indicated that tolerance does not develop and that a daily maintenance dose of 200 μg/day was adequate in most patients . Temporary lack of response was observed during episodes of sputum production or of heavy exposure to antigen . There were no observed side effects other than fungal infections of the respiratory tract . However , the incidence of c and idiasis of the pharynx ( 13 % ) and particularly of the larynx ( 5 % ) in apparently immunologically normal patients was disturbing . These infections were not seen in patients taking 200 μg/day . Though there is yet no evidence that fungal infections associated with steroid aerosols may penetrate the trachea and bronchi the possibility of this indicates that caution should be exercised in their use , particularly in long-term high dosage [16687711] BACKGROUND It is unknown whether inhaled corticosteroids can modify the subsequent development of asthma in preschool children at high risk for asthma . METHODS We r and omly assigned 285 participants two or three years of age with a positive asthma predictive index to treatment with fluticasone propionate ( at a dose of 88 mug twice daily ) or masked placebo for two years , followed by a one-year period without study medication . The primary outcome was the proportion of episode-free days during the observation year . RESULTS During the observation year , no significant differences were seen between the two groups in the proportion of episode-free days , the number of exacerbations , or lung function . During the treatment period , as compared with placebo use , use of the inhaled corticosteroid was associated with a greater proportion of episode-free days ( P=0.006 ) and a lower rate of exacerbations ( P<0.001 ) and of supplementary use of controller medication ( P<0.001 ) . In the inhaled-corticosteroid group , as compared with the placebo group , the mean increase in height was 1.1 cm less at 24 months ( P<0.001 ) , but by the end of the trial , the height increase was 0.7 cm less ( P=0.008 ) . During treatment , the inhaled corticosteroid reduced symptoms and exacerbations but slowed growth , albeit temporarily and not progressively . CONCLUSIONS In preschool children at high risk for asthma , two years of inhaled-corticosteroid therapy did not change the development of asthma symptoms or lung function during a third , treatment-free year . These findings do not provide support for a subsequent disease-modifying effect of inhaled corticosteroids after the treatment is discontinued . ( Clinical Trials.gov number , NCT00272441 . ) [16270721] In sensitive asthmatic children , the exposure to relevant allergens causes a deterioration of lung function and symptoms associated with an increase of inflammatory indices . The aim of this single-blind r and omized add-on study was to compare the effects of montelukast or formoterol added to low-dose budesonide in asthmatic allergic children exposed to relevant allergens . Twenty children ( 5 female subjects and 15 male subjects , aged 6 - 12 years ) were enrolled . Lung function and airway inflammatory indices ( exhaled nitric oxide [ eNO ] and sputum eosinophils ) were evaluated at T0 when children were not exposed to relevant allergens and at T1 after 15 days of natural effective allergen exposure . At T1 , pulmonary function tests and sputum eosinophils remained stable in both of the groups , without significant differences in comparison with T0 at baseline . Furthermore , formoterol plus budesonide was effective in preventing the expected increase in eNO from 26.46 + /- 2.62 ppb at T0 to 29.33 + /- 9.28 ppb at T1 ( not significant ) . However , in the group receiving montelukast plus budesonide , there was a significant decrease of eNO from baseline ( 30.78 + /- 6.87 ppb ) to T1 ( 18.17 + /- 6.60 ppb ) ( p < .05 ) . In allergic asthmatic children , the use of montelukast or formoterol combined with budesonide could offer a durable protective effect on symptoms , lung function , and inflammatory indices [11739137] Dose-dependent effects of inhaled corticosteroids have been described . Although it has been advised to start treatment with inhaled corticosteroids with a high dose tapering off subsequently ( stepdown approach ) , no clinical studies have assessed this strategy . We compared two different dosage schedules of inhaled fluticasone propionate ( FP ) in chronic persistent childhood asthma with respect to efficacy ( airways hyperresponsiveness [ PD(20 ) ] , lung function , exhaled nitric oxide [ eNO ] ) and safety ( height ) . During this double-blind study , children with asthma ( aged 6 - 10 yr ) were r and omized to receive either FP 200 microg/d ( constant dose approach ) or to start with 1000 microg/d with two monthly reductions to 500 , 200 , and 100 microg/d ( stepdown approach ) . PD(20 ) improved in both approaches during treatment with FP , with a significantly better PD(20 ) after 2 mo of 1000 microg/d followed by 500 microg/d in the stepdown approach versus 200 microg/d in the constant dose approach . No significant differences in PD(20 ) or other efficacy parameters were found after 1 yr . Changes in st and ing height were similar in both treatment approaches . This study showed no superior clinical effect of a stepdown approach compared with a constant dose strategy of FP for 1 yr in children with chronic persistent asthma [1355640] In a r and omized double-blind multicenter clinical study , 116 children with asthma were r and omly assigned to treatment with an inhaled beta-2-agonist ( salbutamol 0.2 mg ) plus an inhaled corticosteroid ( budesonide 0.2 mg ) three times a day ( BA+CS ) or to an inhaled beta-2-agonist ( salbutamol 0.2 mg ) plus a placebo three times a day ( BA+PL ) . After a median follow-up time of 22 months , 26 patients receiving BA+PL ( 45 % ) had withdrawn from r and omized treatment , mainly because of asthma symptoms , compared with three withdrawals in the patients receiving BA+CS ( p less than 0.0001 ) . The FEV1 , expressed as a percentage of the predicted value for age , sex , and height , showed an absolute increase of 7.0 % after 2 months of BA+CS compared with a decrease of 4.0 % after 2 months of BA+PL . This 11 % difference in percent predicted FEV1 ( 95 % confidence interval , 7 to 15 % ; p less than 0.0001 ) was then maintained after a median follow-up period of 22 months . Postbronchodilator FEV1 showed an absolute increase of 3.7 % predicted within 2 months in patients receiving BA+CS and an absolute decrease of 1.1 % predicted in children receiving BA+PL ( p = 0.0005 ) . Thereafter , this difference between the two treatment groups was maintained . Average peak expiratory flow rate ( PEFR ) increased from baseline by 36.6 L/min in the BA+CS group compared with 3.7 L/min in the BA+PL group ( p = 0.003 ) . This difference then remained for the median follow-up time of 22 months . ( ABSTRACT TRUNCATED AT 250 WORDS [2221590] Several short-term studies have shown that inhaled steroids can reduce airway hyper-responsiveness in asthma . To evaluate whether prolonged treatment can bring about full recovery , this double-blind , r and omized , controlled trial examined the effect of budesonide , 400 micrograms daily for 1 yr , on airway hyperresponsiveness . The time course and characteristics of improvements and associated changes in clinical asthma severity were also evaluated . Thirty-two stable adult asthmatics , requiring bronchodilators alone , were selected . Before and monthly throughout the study , airway responsiveness to methacholine was measured and clinical asthma severity assessed by question naire , daily bronchodilator use , and number of asthma exacerbations . Patients receiving budesonide showed a fourfold mean improvement in airway responsiveness compared with those receiving placebo ( p less than 0.0005 ) , whose responsiveness remained very stable . Fifteen of the 16 budesonide subjects improved and 5 returned to the normal range . Largest improvements occurred during the first 3 months but , in some , were still progressing slowly at 1 yr . Improvements in responsiveness were accompanied by significant improvements in asthma symptoms , bronchodilator use , and number of asthma exacerbations . The results show that regular , prolonged use of inhaled steroid can produce marked improvements in airway hyperresponsiveness , sometimes with full resolution , and these improvements are accompanied by clinical ly significant improvements in clinical asthma [10955700] This study is an extended follow‐up for 24 months of a 12‐week trial to study the long‐term clinical efficacy of low‐dose inhaled budesonide ( BUD ) once or twice daily in children with mild asthma . A total of 122 children ( mean age 9.7 years , girls/boys ; 42/80 ) with mild asthma ( FEV1 103.7 % of predicted , reversibility in FEV1 3.5 % , and fall in FEV1 afterexercise 12.2 % ) , not previously treated with inhaled steroids , were included in a double‐blind , r and omized , parallel‐group study . The children were treated with inhaled BUD 100 or 200 µg administered via Turbuhaler ® once daily in the morning , 100 µg twice daily , or placebo for 27 months . Exercise and methacholine challenges were performed at 3‐month intervals the first year and at 6‐month intervals the second year , in a total of seven visits . A significant dose‐response effect favoring BUD 200 µg daily ( vs 100 µg daily ) was found when comparing changes in FEV1 , FEF25 % , and FEV50 % ; the fall in FEV1 after an exercise test ; and the effect on blood eosinophils . Bronchial hyperreactivity to methacholine decreased significantly on three visits in patients treated with BUD 200 µg daily compared to placebo . Growth rate was not significantly affected except in children aged 7–11 years at baseline after 12 months of treatment . In conclusion , 100 or 200 µg daily of inhaled BUD for 27 months is safe and effective in protecting against exercise‐induced asthma and achieving nearly normal lung function . Baseline lung function was not significantly affected in this group of children with mild asthma [18805335] BACKGROUND Preliminary evidence is equivocal about the role of exhaled nitric oxide ( NO ) in clinical asthma management . We aim ed to assess whether measurement of exhaled NO , as a biomarker of airway inflammation , could increase the effectiveness of asthma treatment , when used as an adjunct to clinical care based on asthma guidelines for inner-city adolescents and young adults . METHODS We did a r and omised , double-blind , parallel-group trial at ten centres in the USA . We screened 780 inner-city patients , aged 12 - 20 years , who had persistent asthma . All patients completed a run-in period of 3 weeks on a regimen based on st and ard treatment . 546 eligible participants who adhered to treatment during this run-in period were then r and omly assigned to 46 weeks of either st and ard treatment , based on the guidelines of the National Asthma Education and Prevention Program ( NAEPP ) , or st and ard treatment modified on the basis of measurements of fraction of exhaled NO . The primary outcome was the number of days with asthma symptoms . We analysed patients on an intention-to-treat basis . This trial is registered with clinical trials.gov , number NCT00114413 . FINDINGS During the 46-week treatment period , the mean number of days with asthma symptoms did not differ between the treatment groups ( 1.93 [ 95 % CI 1.74 to 2.11 ] in the NO monitoring group vs 1.89 [ 1.71 to 2.07 ] in the control group ; difference 0.04 [ -0.22 to 0.29 ] , p=0.780 ) . Other symptoms , pulmonary function , and asthma exacerbations did not differ between groups . Patients in the NO monitoring group received higher doses of inhaled corticosteroids ( difference 119 mug per day , 95 % CI 49 to 189 , p=0.001 ) than controls . Adverse events did not differ between treatment groups ( p>0.1 for all adverse events ) . INTERPRETATION Conventional asthma management result ed in good control of symptoms in most participants . The addition of fraction of exhaled NO as an indicator of control of asthma result ed in higher doses of inhaled corticosteroids , without clinical ly important improvements in symptomatic asthma control [11027739] BACKGROUND Antiinflammatory therapies , such as inhaled corticosteroids or nedocromil , are recommended for children with asthma , although there is limited information on their long-term use . METHODS We r and omly assigned 1041 children from 5 through 12 years of age with mild-to-moderate asthma to receive 200 microg of budesonide ( 311 children ) , 8 mg of nedocromil ( 312 children ) , or placebo ( 418 children ) twice daily . We treated the participants for four to six years . All children used albuterol for asthma symptoms . RESULTS There was no significant difference between either treatment and placebo in the primary outcome , the degree of change in the forced expiratory volume in one second ( FEV1 , expressed as a percentage of the predicted value ) after the administration of a bronchodilator . As compared with the children assigned to placebo , the children assigned to receive budesonide had a significantly smaller decline in the ratio of FEV1 to forced vital capacity ( FVC , expressed as a percentage ) before the administration of a bronchodilator ( decline in FEV1:FVC , 0.2 percent vs. 1.8 percent ) . The children given budesonide also had lower airway responsiveness to methacholine , fewer hospitalizations ( 2.5 vs. 4.4 per 100 person-years ) , fewer urgent visits to a caregiver ( 12 vs. 22 per 100 person-years ) , greater reduction in the need for albuterol for symptoms , fewer courses of prednisone , and a smaller percentage of days on which additional asthma medications were needed . As compared with placebo , nedocromil significantly reduced urgent care visits ( 16 vs. 22 per 100 person-years ) and courses of prednisone . The mean increase in height in the budesonide group was 1.1 cm less than in the placebo group ( 22.7 vs. 23.8 cm , P=0.005 ) ; this difference was evident mostly within the first year . The height increase was similar in the nedocromil and placebo groups . CONCLUSIONS In children with mild-to-moderate asthma , neither budesonide nor nedocromil is better than placebo in terms of lung function , but inhaled budesonide improves airway responsiveness and provides better control of asthma than placebo or nedocromil . The side effects of budesonide are limited to a small , transient reduction in growth velocity [9196087] In a double-blind , parallel-group study , we examined the effect of short-term treatment with inhaled fluticasone propionate ( FP ) in a group of 20 nonsmoking asthmatic patients who required only beta2-agonists to control their symptoms . We administered FP ( 250 microg twice daily ) or matched placebo for 6 wk . Methacholine challenge was performed before treatment , after 3 wk , and at the end of treatment . Each patient underwent bronchoscopy with bronchoalveolar lavage ( BAL ) and bronchial biopsy before and after treatment . Eight patients in the placebo group and nine patients in the FP group completed the study . Bronchial responsiveness to methacholine decreased significantly only after 6 wk of treatment with FP ( p < 0.05 ) . When we compared the FP group with the placebo group , we observed a significant decrease only in the number of cells expressing intracellular adhesion molecule-1 ( ICAM-1 ) and MAC-1 ( p < 0.04 and p < 0.03 , respectively ) . Moreover , we saw that the tryptase level in BAL decreased ( p < 0.001 ) , whereas the eosinophil cationic protein ( ECP ) level did not change significantly . Additionally , the number of eosinophils and mast cells in the lamina propria in bronchial biopsies specimens was significantly smaller in the FP group than in the placebo group ( p < 0.02 and p < 0.01 , respectively ) . Additionally , in the FP group , we found that basement-membrane thickness was significantly decreased when compared with that of the placebo group ( p < 0.05 ) . In conclusion , our results show that short-term treatment with low-dose FP reduces inflammatory cell infiltration into the lamina propria in bronchial biopsy specimens . Moreover , short-term low-dose FP treatment might control the intensity of airway remodeling in mild asthma [337992] 1 . Beclomethasone dipropionate aerosol has been shown to be a highly effective treatment for asthma in childhood , with virtual absence of side effects at this age . 2 . When treatment is unsuccessful , this is usually due to failure to take it correctly and regularly . 3 . A good response is usually associated with an improvement in ventilatory function and a marked increase in growth velocity [16337447] BACKGROUND Inhaled corticosteroids are recommended as first-line therapy for persistent asthma . OBJECTIVE We sought to assess the efficacy and safety of ciclesonide once daily in patients with mild-to-moderate persistent asthma . METHODS An integrated analysis of 2 identical , multicenter , double-blind , r and omized , parallel-group , placebo-controlled trials was conducted . Patients ( n = 1015 ; aged > or = 12 years ) with mild-to-moderate asthma ( FEV1 of 60 % to 85 % of predicted value ) were r and omized to ciclesonide 80 microg ( CIC80 ) , 160 microg ( CIC160 ) , or 320 microg ( CIC320 ) , once daily ( exactuator doses ) in the morning or placebo for 12 weeks . RESULTS All ciclesonide groups showed significant improvements from baseline to week 12 in FEV1 compared with the placebo group ( CIC80 , 0.12 L [ P = .0007 ] ; CIC160 , 0.13 L [ P = .0004 ] ; and CIC320 , 0.14 L [ P < .0001 ] ) . Likewise , FEV1 percent predicted , morning and evening peak expiratory flow , 24-hour asthma symptom score , daily albuterol use , and nighttime awakenings were significantly improved in all ciclesonide groups compared with the placebo group . Overall ciclesonide safety profile and rates of oropharyngeal adverse events for all groups were low and similar to those of the placebo group . Fewer ciclesonide-treated patients exhibited asthma-aggravated adverse events , and fewer ciclesonide-treated patients discontinued the study for any reason or because of a lack of efficacy compared with those in the placebo group . No suppression of hypothalamic-pituitary-adrenal-axis function ( as assessed by means of 24-hour urinary cortisol levels corrected for creatinine and peak serum cortisol levels after stimulation with low-dose [ 1 microg ] cosyntropin ) was observed with any dose of ciclesonide . CONCLUSIONS In this integrated analysis , ciclesonide once daily administered in the morning is effective and well tolerated [3512282] Forty-five steroid-dependent asthmatic out patients were treated twice daily for 51 weeks with a new inhalation steroid , budesonide ( BUD ) , using a 750 ml spacer . During the initial 15 weeks the prednisone-sparing effects of a high daily dose ( 1600 micrograms ) and a conventional dose ( 400 micrograms per day ) were compared in a double-blind r and omized trial including 50 patients . During the remaining 36 weeks 45 patients were treated openly with 1600 micrograms daily . All patients used other antiasthmatic drugs which were maintained throughout the study , except for inhalations of beta-2 agonists that could be used whenever needed . All patients but 2 were able to reduce the daily dose of oral prednisone . The mean daily dose decreased from 13.9 mg to 5.3 mg . Eighteen patients ( 40 % ) were able to discontinue oral prednisone . Adrenal gl and function improved considerably as prednisone intake decreased . Oropharyngeal thrush frequency showed no change . No severe side effects were observed [7540898] Serum concentrations of growth hormone – dependent insulin – like growth factor I ( IGF – I ) and insulinlike growth factor binding protein–3 ( IGFBP–3 ) , the carboxy terminal propeptide of type I procollagen ( PICP ) , the carboxy terminal pyridinoline cross – linked telopeptide of type I collagen ( ICTP ) and the amino terminal propeptide of type III procollagen ( PIIINP ) were studied in 14 prepubertal children with asthma ( mean age 9.7 years ) during treatment with inhaled budesonide . The study design was a r and omized , crossover trial with two double – blind treatment periods ( 200 and 800 μg ) and one open , non – r and omized treatment period ( 400 μg ) . All periods were 18 days ’ duration . Budesonide treatment was associated with a dose – related suppressive trend in serum concentrations of PIIINP when the 400 μg period was included ( p < 0.01 ; z = –2.7 ) and when it was excluded from the calculations ( p < 0.01 ; z = –2.6 ) , indicating reduced synthesis of type III collagen . A similar trend was observed in ICTP levels when the 400 μg period was excluded from the calculations ( p= 0.05 ; z = –1.9 ) . No other statistically significant variations were seen [9544904] OBJECTIVE To determine whether inhaled fluticasone propionate has long-term effects on growth in children with persistent asthma . STUDY DESIGN In a double-blind , r and omized , parallel-group , multicenter study , 325 prepubescent children with persistent asthma and normal growth rates were treated with placebo or inhaled fluticasone propionate powder 50 microg or 100 microg administered twice daily by a breath-actuated device for 1 year . Growth was evaluated monthly , whereas other safety variables and pulmonary function were evaluated periodically . RESULTS The prepubescent patients showed no statistically significant differences in mean height , mean growth velocity , or mean skeletal age between any of the treatment groups at any time . Over a period of 1 year , mean height ( + /- SE ) increased 6.15 + /- 0.17 cm in the placebo group , 5.94 + /- 0.16 cm in the fluticasone propionate 50 microg group , and 5.73 + /- 0.13 cm in the fluticasone propionate 100 microg group ( p = 0.308 , overall ) . CONCLUSIONS Prepubescent children treated with fluticasone propionate 50 microg and 100 microg administered twice daily for 1 year grew at rates similar to placebo-treated control subjects and at rates equal to expected growth velocity for age [20622031] RATIONALE For children with symptomatic asthma despite low to moderate doses of inhaled corticosteroids , evidence is still lacking whether to add a long-acting bronchodilator or to increase the dose of inhaled corticosteroids . OBJECTIVE To evaluate whether salmeterol/fluticasone propionate ( SFP ) , 50/100 μg twice a day , is noninferior regarding symptom control compared with fluticasone propionate ( FP ) , 200 μg twice a day Diskus in children with symptomatic asthma . METHODS A multicenter , r and omized , parallel-group , double-blind study was performed comparing SFP and FP treatment during 26 weeks on asthma control and lung function . MEASUREMENTS AND MAIN RESULTS A total of 158 children , 6 - 16 years old , still symptomatic on FP , 100 μg twice a day , during a 4-week run-in period , were included . Percentage of symptom-free days during the last 10 weeks of the treatment period did not differ between treatment groups ( per protocol analysis : adjusted mean difference [ FP minus SFP ] 2.6 % ; 95 % confidence interval , -8.1 to 13.4 ) . Both groups showed substantial improvements of about 25 percent points in symptom-free days ( both P < 0.001 from baseline ) . Lung function measurements ( FEV(1 ) , FVC , PEF rate , and maximal expiratory flow ) did not differ between groups except for a slight advantage in maximal expiratory flow in the SFP group at 1 week . No differences were found between FP and SFP regarding exacerbation rates , adverse events , or growth . CONCLUSIONS In our study the efficacy on symptom control and lung function of the combination of a long-acting bronchodilator with inhaled corticosteroid is equal to doubling the dose of the inhaled corticosteroid in children still symptomatic on a moderate dose of inhaled corticosteroid [9925834] RATIONALE Topical antiinflammatory medications such as inhaled corticosteroids are recommended for therapy of asthma , but no formulation suitable for administration to infants and young children is available in the United States . METHODS This was a 12-week , multicenter , double-blind , r and omized , parallel-group study comparing the efficacy and safety of four dosing regimens of bude-sonide inhalation suspension ( BIS ) or placebo in 480 asthmatic infants and children ( 64 % boys ) , ages 6 months to 8 years , with moderate persistent asthma . Approximately 30 % of children were previously on inhaled corticosteroids that were discontinued before the study . Active treatments were comprised of BIS 0.25 mg once daily ( QD ) , 0.25 mg twice a day ( BID ) , 0.5 mg BID , or 1.0 mg QD . Efficacy was assessed by twice daily recording at home of asthma symptom scores and use of rescue medication , and discontinuation from the study because of worsening asthma and /or a requirement for systemic steroids . Peak flow measurements were recorded twice daily on diary and spirometry was recorded at clinic visits for those children able to perform these tests . Safety was assessed by reported adverse events and by cortisol testing ( adrenocorticotropic hormone stimulation ) in a subset of patients . RESULTS Patients enrolled had an average duration of asthma of 34 months ; the mean asthma symptom score was approximately 1.3 ( scale of 0 - 3 ) . All dosing regimens with BIS produced statistically significant improvement in various clinical efficacy measures for asthma control compared with placebo . The lowest dose used , 0.25 mg QD , was efficacious but with fewer efficacy parameters than seen with the other doses administered . Separation between active treatment and placebo in daytime and nighttime symptom scores were observed by week 2 of treatment for all BIS treatment regimens . A significant increase in peak flow measurement was observed in most active treatment groups compared with placebo in the subset of children able to do pulmonary function testing . All treatment groups showed numerical improvement in forced expiratory volume in 1 second but only the 0.5-mg BID dose was significantly different from placebo . Adverse events for the entire group and response to adrenocorticotropic hormone in a subgroup of children who underwent cortisol testing before and at the end of the treatment period were no different in budesonide-treated patients in comparison to placebo . CONCLUSION Results of this study demonstrate that BIS is effective and safe for infants and young children with moderate persistent asthma in a multiple dose range , and that QD dosing is an important option to be considered by the prescribing physician [9627589] OBJECTIVE To determine the efficacy and safety of budesonide delivered by an inhalation-driven dry powder inhaler ( Turbuhaler ) in children with moderate to severe persistent asthma . STUDY DESIGN In our r and omized , double-blind , placebo-controlled , parallel-group , multicenter study , a total of 404 children with asthma , who were aged 6 to 18 years and who had been receiving inhaled glucocorticosteroid therapy , were r and omly assigned to receive either 100 , 200 , or 400 micrograms of budesonide or placebo twice daily for 12 weeks . At baseline , mean forced expiratory volume in 1 second ( FEV1 ) was 74.6 % ( range , 30.7 % to 123.3 % ) of the predicted normal value . RESULTS Patients in each of the three budesonide treatment groups showed significant dose-related improvements in lung function ( morning peak expiratory flow and FEV1 ) , in asthma symptoms , and with a significant decrease in inhaled beta 2-agonist use in comparison with placebo . Improvements were evident within 2 weeks and were maintained throughout the 12 weeks . Budesonide treatment had no significant effect on hypothalamic-pituitary-adrenal axis function , and the incidence of reported adverse events was similar in all treatment groups . CONCLUSION Budesonide administered via a dry powder inhaler provided dose-related improvements in lung function and clinical status and was well tolerated by children ( 6 to 18 years of age ) with moderate to severe persistent asthma [4371672] Twenty-six children with asthma were treated with beclomethasone dipropionate aerosol in a dose adjusted to their symptoms for 13 to 20 months . 18 children in the group had been taking systemic steroids at the start of the trial and all were successfully weaned off them , mostly within 2 months . All but 1 of the children were satisfactorily controlled by beclomethasone , but 15 children needed short courses of oral steroids at times of severe exacerbations . There was no evidence of either suppression or acceleration of growth , nor was there any adrenal suppression as assessed at intervals by the estimation of the resting level of plasma cortisol and the response to tetracosactrin . No other side effects were encountered apart from exacerbations of eczema or rhinitis in some children previously on systemic steroids [8707781] Fluticasone propionate ( FP ) administered via metered-dose inhaler is a potent corticosteroid effective in the treatment of asthma . To evaluate the efficacy and safety of FP powder administered via a breath-activated inhaler ( Diskhaler ) , a multicenter , double-blind , r and omized , placebo-controlled , parallel-group study was conducted in adolescent and adult patients ( n = 331 ) with mild-to-moderate asthma previously treated with beta 2-agonist therapy alone . Patients received FP powder 50 , 100 , or 250 micrograms or placebo twice daily for 12 weeks . FP-treated patients compared with placebo-treated patients had significantly ( p < 0.001 ) greater improvements in morning predose forced expiratory volume in 1 sec ( 21 - 22 % increase vs. 9 % ) . Improvement in morning peak flow rate were also significantly ( p < 0.001 ) greater with FP than with placebo ( 8 - 10 % increase vs. 2 % increase ) . There was also a significant overall treatment difference in the frequency of inhaled albuterol use ( p < 0.001 ) and number of nighttime awakenings due to asthma ( p = 0.005 ) . There were no statistically significant difference among the FP treatment groups in any outcome measure . Physicians ' global assessment s also indicated significant ( p < 0.001 ) differences in efficacy , with 67 - 74 % of FP-treated patients rated as having " effective " or " very effective " treatment compared with 41 % of placebo-treated patients . Significant beneficial effects of FP were observed in lung function and diary card parameters after just 1 week of treatment . Adverse events were similar across treatment groups and primarily related to local irritation . Effect on hypothalamic-pituitary-adrenal axis function was minimal . In summary , all three dosages of inhaled FP powder were well tolerated and improved various asthma-related variables . Improvements in pulmonary function , beyond those achieved with beta 2-agonist therapy alone , were maintained for the duration of the 12-week study [25504972] BACKGROUND Treatment guidelines for asthma recommend inhaled corticosteroids ( ICS ) as first-line therapy for children with persistent asthma . Although ICS treatment is generally considered safe in children , the potential systemic adverse effects related to regular use of these drugs have been and continue to be a matter of concern , especially the effects on linear growth . OBJECTIVES To assess the impact of ICS on the linear growth of children with persistent asthma and to explore potential effect modifiers such as characteristics of available treatments ( molecule , dose , length of exposure , inhalation device ) and of treated children ( age , disease severity , compliance with treatment ) . SEARCH METHODS We search ed the Cochrane Airways Group Specialised Register of trials ( CAGR ) , which is derived from systematic search es of bibliographic data bases including CENTRAL , MEDLINE , EMBASE , CINAHL , AMED and PsycINFO ; we h and search ed respiratory journals and meeting abstract s. We also conducted a search of Clinical Trials.gov and manufacturers ' clinical trial data bases to look for potential relevant unpublished studies . The literature search was conducted in January 2014 . SELECTION CRITERIA Parallel-group r and omised controlled trials comparing daily use of ICS , delivered by any type of inhalation device for at least three months , versus placebo or non-steroidal drugs in children up to 18 years of age with persistent asthma . DATA COLLECTION AND ANALYSIS Two review authors independently performed study selection , data extraction and assessment of risk of bias in included studies . We conducted meta-analyses using the Cochrane statistical package RevMan 5.2 and Stata version 11.0 . We used the r and om-effects model for meta-analyses . We used mean differences ( MDs ) and 95 % CIs as the metrics for treatment effects . A negative value for MD indicates that ICS have suppressive effects on linear growth compared with controls . We performed a priori planned subgroup analyses to explore potential effect modifiers , such as ICS molecule , daily dose , inhalation device and age of the treated child . MAIN RESULTS We included 25 trials involving 8471 ( 5128 ICS-treated and 3343 control ) children with mild to moderate persistent asthma . Six molecules ( beclomethasone dipropionate , budesonide , ciclesonide , flunisolide , fluticasone propionate and mometasone furoate ) given at low or medium daily doses were used during a period of three months to four to six years . Most trials were blinded and over half of the trials had drop out rates of over 20 % . Compared with placebo or non-steroidal drugs , ICS produced a statistically significant reduction in linear growth velocity ( 14 trials with 5717 participants , MD -0.48 cm/y , 95 % CI -0.65 to -0.30 , moderate quality evidence ) and in the change from baseline in height ( 15 trials with 3275 participants ; MD -0.61 cm/y , 95 % CI -0.83 to -0.38 , moderate quality evidence ) during a one-year treatment period . Subgroup analysis showed a statistically significant group difference between six molecules in the mean reduction of linear growth velocity during one-year treatment ( Chi(2 ) = 26.1 , degrees of freedom ( df ) = 5 , P value < 0.0001 ) . The group difference persisted even when analysis was restricted to the trials using doses equivalent to 200 μg/d hydrofluoroalkane (HFA)-beclomethasone . Subgroup analyses did not show a statistically significant impact of daily dose ( low vs medium ) , inhalation device or participant age on the magnitude of ICS-induced suppression of linear growth velocity during a one-year treatment period . However , head-to-head comparisons are needed to assess the effects of different drug molecules , dose , inhalation device or patient age . No statistically significant difference in linear growth velocity was found between participants treated with ICS and controls during the second year of treatment ( five trials with 3174 participants ; MD -0.19 cm/y , 95 % CI -0.48 to 0.11 , P value 0.22 ) . Of two trials that reported linear growth velocity in the third year of treatment , one trial involving 667 participants showed similar growth velocity between the budesonide and placebo groups ( 5.34 cm/y vs 5.34 cm/y ) , and another trial involving 1974 participants showed lower growth velocity in the budesonide group compared with the placebo group ( MD -0.33 cm/y , 95 % CI -0.52 to -0.14 , P value 0.0005 ) . Among four trials reporting data on linear growth after treatment cessation , three did not describe statistically significant catch-up growth in the ICS group two to four months after treatment cessation . One trial showed accelerated linear growth velocity in the fluticasone group at 12 months after treatment cessation , but there remained a statistically significant difference of 0.7 cm in height between the fluticasone and placebo groups at the end of the three-year trial . One trial with follow-up into adulthood showed that participants of prepubertal age treated with budesonide 400 μg/d for a mean duration of 4.3 years had a mean reduction of 1.20 cm ( 95 % CI -1.90 to -0.50 ) in adult height compared with those treated with placebo . AUTHORS ' CONCLUSIONS Regular use of ICS at low or medium daily doses is associated with a mean reduction of 0.48 cm/y in linear growth velocity and a 0.61-cm change from baseline in height during a one-year treatment period in children with mild to moderate persistent asthma . The effect size of ICS on linear growth velocity appears to be associated more strongly with the ICS molecule than with the device or dose ( low to medium dose range ) . ICS-induced growth suppression seems to be maximal during the first year of therapy and less pronounced in subsequent years of treatment . However , additional studies are needed to better characterise the molecule dependency of growth suppression , particularly with newer molecules ( mometasone , ciclesonide ) , to specify the respective role of molecule , daily dose , inhalation device and patient age on the effect size of ICS , and to define the growth suppression effect of ICS treatment over a period of several years in children with persistent asthma . PLAIN LANGUAGE SUMMARY Do inhaled corticosteroids reduce growth in children with persistent asthma ? Review question : We review ed the evidence on whether inhaled corticosteroids ( ICS ) could affect growth in children with persistent asthma , that is , a more severe asthma that requires regular use of medications for control of symptoms . BACKGROUND Treatment guidelines for asthma recommend ICS as first-line therapy for children with persistent asthma . Although ICS treatment is generally considered safe in children , parents and physicians always remain concerned about the potential negative effect of ICS on growth . Search date : We search ed trials published until January 2014 . Study characteristics : We included in this review trials comparing daily use of corticosteroids , delivered by any type of inhalation device for at least three months , versus placebo or non-steroidal drugs in children up to 18 years of age with persistent asthma . KEY RESULTS Twenty-five trials involving 8471 children with mild to moderate persistent asthma ( 5128 treated with ICS and 3343 treated with placebo or non-steroidal drugs ) were included in this review . Eighty percent of these trials were conducted in more than two different centres and were called multi-centre studies ; five were international multi-centre studies conducted in high-income and low-income countries across Africa , Asia-Pacifica , Europe and the Americas . Sixty-eight percent were financially supported by pharmaceutical companies . Meta- analysis ( a statistical technique that combines the results of several studies and provides a high level of evidence ) suggests that children treated daily with ICS may grow approximately half a centimeter per year less than those not treated with these medications during the first year of treatment . The magnitude of ICS-related growth reduction may depend on the type of drug . Growth reduction seems to be maximal during the first year of therapy and less pronounced in subsequent years of treatment . Evidence provided by this review allows us to conclude that daily use of ICS can cause a small reduction in height in children up to 18 years of age with persistent asthma ; this effect seems minor compared with the known benefit of these medications for asthma control . QUALITY OF EVIDENCE Eleven of 25 trials did not report how they guaranteed that participants had an equal chance of receiving ICS or placebo or non-steroidal drugs . All but six trials did not report how research ers were kept unaware of the treatment assignment list . However , this method ological limitation may not significantly affect the quality of evidence because the results remained almost unchanged when we excluded these trials from the analysis [12567387] We set out to evaluate lung deposition , systemic availability , and basic pharmacokinetic parameters of beclomethasone dipropionate ( BDP ) in children with chronic asthma . Plasma levels of BDP , 17 and 21 beclomethasone monopropionate ( 17-BMP and 21-BMP ) , and beclomethasone were measured after an intravenous infusion of 60 microg BDP and after inhalation of A ) 100 microg HFA-BDP , B ) 200 microg HFA-BDP , C ) 200 microg HFA-BDP after ingestion of charcoal to block gastrointestinal ( GI ) absorption of drug , and D ) 400 microg CFC-BDP . A breath-actuated pMDI ( Autohaler ) was used for HFA inhalations , and a pMDI with a large volume spacer ( Volumatic ) for CFC inhalations . Treatments A-D were given in a r and omized , cross-over design . Fourteen patients aged 10 - 14 years completed all 5 study days . The mean systemic bioavailabilities in percent of dose leaving the canister valve ( ex-valve ) were 70 % ( 100 HFA ) , 74 % ( 200 HFA ) , 60 % ( 200 HFA + charcoal ) , and 27 % ( 400 microg CFC ) . After HFA treatment , 82 % of the systemically available dose was absorbed through the lungs , and 18 % from the gastrointestinal tract . The estimated bioavailability of BDP from the GI tract was 68 % . BDP was metabolized to 17-BMP within minutes . Mean steady-state volume of distribution of 17-BMP was 84 L , and the mean terminal half-life ( T((1/2 ) ) ) after the four inhalations was 2.7 hr ( range , 2.2 - 3.7 hr ) . Mean T((1/2 ) ) and clearance after i.v . administration were 1.7 hr and 0.9 L/min , respectively . The HFA Autohaler delivers approximately three times as much BDP to the intrapulmonary airways as a CFC-pMDI with a large volume spacer [16860173] BACKGROUND Ciclesonide is a new lung-activated inhaled corticosteroid ( ICS ) that has shown efficacy in previous placebo-controlled and comparative studies in patients with persistent asthma . It is important to compare new treatments with existing ICSs to obtain relative data concerning their efficacy and tolerability . OBJECTIVE This study compared the efficacy and tolerability of ciclesonide QD with budesonide BID in patients with asthma . METHODS This 12-week , r and omized study was conducted at 62 study sites across Europe . Male and female patients aged 12 to 75 years with primarily mild to moderate asthma were enrolled . This study was double blind with respect to the ciclesonide dose and open label for budesonide , as placebofor budesonide was not available . Patients were r and omly assigned to receive inhaled ciclesonide 80 or 320 microg QD ( morning ) or budesonide 200 microg BID for 12 weeks . Efficacy and tolerability assessment s were performed at weeks 0 ( baseline ) , 4 , 8 , and 12 . The primary end point was the change from baseline in forced expiratory volume in 1 second ( FEV1 ) at 12 weeks . Secondary end points were changes from baseline in morning peak expiratory flow ( PEF ) , asthma symptom scores , and rescue medication use . Tolerability was assessed throughout the study by monitoring of st and ard laboratory variables ( hematology and biochemistry ) ; physical examination , including vital signs ; reporting of adverse events ( AEs ) ; and 24-hour urinary cortisol as a measure of hypothalamic-pituitary-adrenal-axis function . RESULTS Five hundred fifty-four patients were r and omized ( 301 men , 253 women ; mean age , 41.3 years ; ciclesonide 80 microg QD , 182 patients ; ciclesonide 320 microg QD , 195 ; budesonide 200 microg BID , 177 ) . Demographic and baseline clinical characteristics , including age , sex , weight , and ( FEV1 ) were similar between the 3 groups . Compared with baseline values , week-12 FEV1 ( least squares mean [ LSM ] [ SEM ] A , + 0.267 [ 0.035 ] , + 0.256 [ 0.033 ] , and + 0.355 [ 0.034 ] L , respectively ; all , P<0.001 ) and morning PEF ( LSM [ SEM ] Delta , + 12 [ 5 ] , + 17 [ 4 ] , and + 21 [ 4 ] L/min , respectively ; all , P < or=0.008 ) were significantly improved with ciclesonide 80 and 320 microg QD and budesonide 200 microg BID . At 12 weeks , ciclesonide was found to be noninferior to budesonide with regard to mean changes from baseline in ( FEV1 ) ( intent to treat [ ITT ] : 97.5 % CI for ciclesonide 80 microg QD vs budesonide 200 microg BID , -0.192 to 0.015 ; 97.5 CI for ciclesonide 320 microg QD vs budesonide 200 microg BID , -0.200 to 0.001 ) and morning PEF ( ITT . 97.5 % CI for ciclesonide 80 microg QD vs budesonide 200 microg BID , -22 to 5 ; 97.5 % CI for ciclesonide 320 microg QD vs budesonide 200 microg BID , -17 to 10 ) . Similar findings were seen in the per- protocol population . Week-12 daily , daytime , and nighttime asthma symptom scores and rescue medication use were significantly decreased from baseline in all 3 treatment groups ( all , P<0.001 ) . The prevalences of AEs were similar across all 3 treatment groups . Week-12 mean urinary cortisol excretion was statistically similar to baseline with both ciclesonide doses ( Delta , -0.54 and + 0.16 nmol/mmol creatinine with ciclesonide 80 and 320 microg QD , respectively ) but was significantly reduced from baseline with budesonide ( Delta , -1.42 nmol/mmol creatinine ; P<0.05 ) . CONCLUSIONS The results of this study in patients with primarily mild to moderate asthma suggest that ciclesonide 80 and 320 microg QD were similar to budesonide 200 microg BID in improving pulmonary function , controlling asthma symptoms , and reducing the need for rescue medication use . Unlike budesonide , ciclesonide was not associated with significant urinary cortisol suppression in these patients [8546510] OBJECTIVES --To assess bone and collagen turnover in asthmatic children treated with dry powder budesonide from the Turbuhaler and dry powder beclomethasone dipropionate from the Diskhaler in a dose of 800 micrograms/day . SUBJECTS -- Thirteen prepubertal children with asthma . DESIGN --Open crossover study with two treatment periods and treatment free run-in and wash-out periods . All periods were of two weeks ' duration . At day 14 in each period blood sample s were taken for assessment of serum osteocalcin , the carboxyterminal propeptide of type I collagen ( PICP ) , and the aminoterminal propeptide of type III collagen ( PIIINP ) . At the same time urine was collected for assessment of creatinine corrected pyridinoline ( uPYR/cr ) and deoxypyridinoline ( udPYR/cr ) crosslinks . RESULTS --Osteocalcin concentrations were not influenced by any of the treatments . During budesonide treatment mean ( SEM ) PICP was reduced by 18 % ( 8 % ) ( p = 0.03 ) , PIIINP by 24 % ( 3 % ) ( p = 0.0002 ) , uPYR/cr by 16 % ( 6 % ) ( p = 0.03 ) , and udPYR/cr by 21 % ( 13 % ) ( p = 0.12 ) . During treatment with beclomethasone dipropionate mean ( SEM ) PICP was reduced by 20 % ( 6 % ) ( p = 0.01 ) , PIIINP by 36 % ( 3 % ) ( p = 0.0002 ) , uPYR/cr by 18 % ( 4 % ) ( p = 0.004 ) , and udPYR by 13 % ( 5 % ) ( p = 0.02 ) . The suppressive effect of beclomethasone dipropionate on PIIINP was more marked than that of budesonide ( p = 0.001 ) . CONCLUSION --Treatment with dry powder budesonide and beclomethasone dipropionate 800 micrograms/day is associated with suppression of bone and collagen turnover . The suppression seems to be more marked during treatment with beclomethasone dipropionate . Long term effects and effects of lower doses of budesonide and beclomethasone dipropionate on bone and collagen markers needs further study [10507269] BACKGROUND Inhaled glucocorticosteroids ( GCS ) are the most effective long-term controller medications for the treatment of persistent asthma . Currently , however , available delivery devices limit their use in young children . A nebulized formulation of budesonide has been developed to address the needs of infants and young children . OBJECTIVE To evaluate the efficacy and safety of once-daily budesonide inhalation suspension in children 6 months to 8 years old with mild persistent asthma not on inhaled GCS . METHODS Three hundred fifty-nine children were r and omized to receive once-daily budesonide inhalation suspension ( 0.25 mg , 0.50 mg , or 1.0 mg ) or placebo via a Pari LC-Jet Plus nebulizer for 12 weeks . Efficacy assessment s included nighttime/daytime asthma symptoms , pulmonary function ( subset of patients ) , rescue medication use , and treatment discontinuations . Safety was based on adverse events and assessment of HPA-axis function . RESULTS Demographics , baseline characteristics , asthma symptoms , and pulmonary function were similar across treatment groups . Mean nighttime/daytime asthma symptom scores were 1.19 + /- 0.63 and 1.34 + /- 0.53 , respectively . Mean duration of asthma was 36.3 months and mean FEV1 was 81.3 % of predicted with 27.7 % reversibility . Following 12 weeks of treatment , all budesonide inhalation suspension doses produced significant improvements in nighttime/daytime symptoms ( P < or = .049 ) and significant decreases in rescue medication use ( P < or = .038 ) compared with placebo . Significant improvements ( P < or = .044 ) in FEV1 were observed in the 0.5- and 1.0-mg budesonide inhalation suspension groups . There were no differences between doses of budesonide inhalation suspension . Adverse events and basal and ACTH-stimulated cortisol levels were similar among all groups . CONCLUSION Once-daily administration of budesonide inhalation suspension was well tolerated and effective for the treatment of mild persistent asthma in infants and young children not adequately controlled with bronchodilators or non-GCS antiinflammatory treatments [15065610] OBJECTIVE To evaluate the effects of treatment with fluticasone propionate vs placebo on bone , hypothalamic-pituitary-adrenal ( HPA ) axis function , and the eyes in patients with asthma . PATIENTS AND METHODS This r and omized , double-blind , placebo-controlled study of 160 patients with asthma who had minimal previous exposure to corticosteroids was conducted from July 1994 through June 1997 . Patients received fluticasone at 88 microg twice daily , fluticasone at 440 microg twice daily , or placebo twice daily for 2 years . Bone mineral density ( BMD ) was evaluated every 6 months by lumbar spine , proximal femur , and total body scans . Measurements of HPA axis function and ophthalmic evaluations were conducted at similar intervals . RESULTS Among the 3 groups , no significant differences were observed in BMD at week 104 ( at any anatomical site ) . Mean percent change from baseline in the lumbar spine was less than 1 % for all 3 groups . At all time points , HPA axis function was similar in the 88-microg fluticasone group compared with the placebo group . For mean change from baseline in corticotropin-stimulated peak cortisol ( P = .003 and P = .02 at weeks 24 and 52 , respectively ) and area under the stimulated plasma cortisol vs time curve ( P = .002 and P = .02 at weeks 24 and 52 , respectively ) , statistically significant reductions from baseline were observed in the 440-microg fluticasone group compared with the placebo group . These reductions of 10 % to 13 % from baseline were not accompanied by other signs of systemic effect and did not persist with continued treatment ( at weeks 76 and 104 ) . No important ocular changes were observed . CONCLUSION Long-term treatment with 88 microg of fluticasone twice daily was comparable to placebo in all skeletal , ophthalmic , and HPA axis function assessment s. Treatment with fluticasone at 440 microg twice daily result ed in no significant effects on BMD and a statistically significant but not clinical ly important temporary reduction in cortisol production [18266402] Background and objective : The efficacy and safety of twice-daily inhaled salmeterol/fluticasone propionate combination ( SFC ) therapy have been well established in the treatment of adults and adolescents with asthma . Once-daily administration of SFC could also be appropriate in patients with mild persistent asthma . This study aim ed to investigate whether once-daily SFC 50 μg/100 μg was at least as effective as fluticasone propionate ( FP ) 100 μg twice daily , and more effective than twice-daily placebo , over 52 weeks as initial maintenance therapy in patients with mild persistent asthma . Methods : This was a r and omized , double-blind , double-dummy , placebo-controlled , multicentre , parallel-group study carried out in primary and secondary care . Patients aged between 12 and 79 years with a documented clinical history of asthma for ≥6 months who were currently receiving inhaled short-acting β2-adrenoceptor agonists only were enrolled . Patients were r and omized to receive either once-daily inhaled SFC 50 μg/100 μg , twice-daily inhaled FP 100 μg ( i.e. twice the dose of FP compared with SFC ) or placebo for 52 weeks . The primary efficacy endpoints were mean morning peak expiratory flow ( PEF ) , as recorded by patients prior to the use of bronchodilator or study medication , and the rate of investigator-recorded asthma exacerbations . Results : Patients receiving twice-daily FP and once-daily SFC showed greater improvements in mean morning PEF compared with those receiving placebo ( FP , difference in means 20.1 L/min ; 95 % CI 14.7 , 25.5 ; p < 0.001 ; SFC , difference in means 14.8 L/min ; 95 % CI 9.4 , 20.2 ; p < 0.001 ) . The difference in adjusted mean PEF between once-daily SFC and twice-daily FP was —5.3 L/min ( 95 % CI −9.1,−1.6 ) . PEF results showed that once-daily SFC was non-inferior to twice-daily FP . Over 52 weeks , there was a 35 % reduction in exacerbation rates with once-daily SFC , which in this respect demonstrated superiority over placebo ( p < 0.001 ) . Non-inferiority between once-daily SFC and twice-daily FP with respect to exacerbation rates was not shown . Once-daily SFC significantly improved clinic forced expiratory flow between 25 % and 75 % of forced vital capacity ( difference in means 0.129 L/s ; p < 0.001 ) and clinic PEF ( difference in means 10.8 L/min ; p < 0.001 ) compared with twice-daily FP . Both treatments were well tolerated and the safety profile of each was similar to that seen with placebo . Conclusion : In patients with mild persistent asthma not previously receiving maintenance therapy , once-daily SFC 50 μg/100 μg is an effective treatment compared with placebo , and was non-inferior to twice-daily FP 100 μg with respect to mean morning PEF . However , in this study , once-daily SFC was not as efficacious as twice-daily FP in reducing asthma exacerbation rates . This study confirms the benefits of regular maintenance treatment in patients with mild persistent asthma [16802768] BACKGROUND Current asthma guidelines recommend inhaled glucocorticoids administered via pressurized metered-dose inhaler ( MDI ) with a holding chamber as the preferred therapy for young children with asthma . OBJECTIVE To evaluate the efficacy and safety of fluticasone propionate chlorofluorocarbon MDI use in preschool-aged children with asthma . METHODS R and omized , double-blind , placebo-controlled , parallel-group study of 332 children aged 24 to 47 months with asthma . Fluticasone propionate chlorofluorocarbon , 44 or 88 microg twice daily , or placebo ( chlorofluorocarbon propellant alone ) administered for 12 weeks via MDI with a valved holding chamber and an attached face mask . The primary efficacy measure was average change in 24-hour daily asthma symptom scores . Safety assessment s included adverse events , 12-hour urinary cortisol excretion , and growth . RESULTS Treatment failure ( ie , asthma exacerbation ) occurred in approximately half as many fluticasone propionate-treated patients ( 13%-14 % ) as placebo-treated patients ( 24 % ) . Compared with placebo users , patients treated with fluticasone propionate , 88 microg twice daily , had a 13 % greater improvement in the mean proportion of symptom- and albuterol-free days ( P = .02 ) ; asthma symptom scores and albuterol use were also significantly reduced . Patients treated with fluticasone propionate , 44 microg twice daily , had greater improvements than placebo-treated patients ; however , differences did not reach statistical significance . At end point , the growth velocities of fluticasone propionate-treated patients were within the range of those of placebo-treated patients . No clinical ly relevant changes in 12-hour overnight urinary cortisol excretion were observed . CONCLUSION Compared with placebo use , fluticasone propionate , 88 microg administered twice daily , significantly reduced asthma exacerbations , asthma symptoms , and rescue albuterol use and was well tolerated , with no clinical ly relevant systemic effects , as measured by growth velocity or 12-hour urinary cortisol excretion levels [17140647] BACKGROUND More evidence is needed on which to base recommendations for treatment of mild-moderate persistent asthma in school-aged children . OBJECTIVE The Pediatric Asthma Controller Trial ( PACT ) compared the effectiveness of 3 regimens in achieving asthma control . METHODS A total of 285 children ( ages 6 - 14 years ) with mild-moderate persistent asthma on the basis of symptoms , and with FEV(1 ) > or= 80 % predicted and methacholine FEV(1 ) PC(20 ) < or= 12.5 mg/mL , were r and omized to 1 of 3 double-blind 48-week treatments : fluticasone 100 microg twice daily ( fluticasone monotherapy ) , fluticasone 100 microg/salmeterol 50 microg in the morning and salmeterol 50 mug in the evening ( PACT combination ) , and montelukast 5 mg in the evening . Outcomes included asthma control days ( primary outcome ) , exacerbations , humanistic measurements , and pulmonary function measurements . RESULTS Fluticasone monotherapy and PACT combination were comparable in many patient-measured outcomes , including percent of asthma control days , but fluticasone monotherapy was superior for clinic-measured FEV(1)/forced vital capacity ( P = .015 ) , maximum bronchodilator response ( P = .009 ) , exhaled nitric oxide ( P < .001 ) , and PC(20 ) ( P < .001 ) . Fluticasone monotherapy was superior to montelukast for asthma control days ( 64.2 % vs 52.5 % ; P = .004 ) and for all other control outcomes . Growth over 48 weeks was not statistically different ( fluticasone , 5.3 cm ; PACT combination , 5.3 cm ; montelukast , 5.7 cm ) . CONCLUSION Both fluticasone monotherapy and PACT combination achieved greater improvements in asthma control days than montelukast . However , fluticasone monotherapy was superior to PACT combination in achieving other dimensions of asthma control . Growth was similar in all groups . CLINICAL IMPLICATION S Therefore , of the regimens tested , the PACT study findings favor fluticasone monotherapy in treating children with mild-moderate persistent asthma with FEV(1 ) > or= 80 % predicted , confirming current guideline recommendations [4352726] Thirty-one chronic perennial asthmatics aged from 2½ to 16 years were treated with beclomethasone dipropionate pressurized aerosols for up to 20 months . Of these , 16 patients dependent on oral corticosteroid or corticotrophin for up to 11 years were successfully transferred to this treatment , with one exception . Steroid withdrawal symptoms were slight . Loss of weight , disappearance of Cushingoid features , and resumption of growth indicated lack of systemic side effects . Fifteen others inadequately controlled on bronchodilators or disodium cromoglycate , were also effectively treated , and no clinical evidence of adrenal suppression was noted [14730655] Our objective was to evaluate the efficacy and safety of two doses of fluticasone propionate ( FP ) in young children with recurrent wheezing and risk factors for asthma . Our study design was a r and omized , double-blind , placebo-controlled comparison of inhaled FP 50 mcg twice daily ( FP 100 ) and 125 mcg twice daily ( FP 250 ) , for 6 months . Outcome measures included number of wheezing episodes , days on albuterol , height st and ard deviation score ( height SDS ) , osteocalcin ( OC ) , bone alkaline phosphatase fraction ( AKP ) , insulin-like growth factor-binding protein 3 ( IGFBP-3 ) , and serum levels of cortisol ( SC ) . Our subjects were 30 patients , aged 7 - 24 months . Mean wheezing episodes were 6.0 + /- 1.9 , 1.9 + /- 1.9 , and 2.8 + /- 1.2 ; mean days of albuterol use were 24.3 + /- 1.3 , 6.5 + /- 0.8 , and 9.1 + /- 0.8 , per patient for placebo , FP100 , and FP250 groups , respectively . There was a significant reduction in clinical outcome in the two FP groups compared to placebo ( P < 0.01 ) . No significant correlations were found between FP dosage and height SDS , OC , AKP , IGFBP-3 , and SC . In conclusion , in young children with asthmatic symptoms , FP at 50 and 125 mcg b.i.d . for 6 months significantly improved respiratory symptoms without causing significant side effects on growth and bone metabolism [20619624] OBJECTIVE To evaluate the efficacy and safety of three doses of ciclesonide ( with or without spacer ) in children with persistent asthma . PATIENTS AND METHODS This was a multicentre , double-blind , placebo-controlled , 12-week study of ciclesonide 40 , 80 or 160 μg ( once daily pm ) . Children ( 6 - 11 years ) were r and omised 1:1 to treatment via a metered dose inhaler ( MDI ) or MDI plus spacer . The primary variable was change from baseline in mean morning peak expiratory flow ( PEF ) . Secondary variables included : time to first lack of efficacy ( LOE ) , asthma control , forced expiratory volume in 1 s ( FEV(1 ) ) , asthma symptom score and quality of life ( QoL ) . Safety assessment s included : adverse events ( AEs ) , urinary cortisol excretion and body height . RESULTS In total , 1073 children received treatment . At endpoint , mean morning PEF significantly improved with all doses of ciclesonide vs. placebo . There was no difference over placebo in time to first LOE , but ciclesonide was superior to placebo on asthma control , symptom score , FEV(1 ) and QoL. There were no differences between the spacer or non-spacer subgroups . The incidences of AEs were comparable between treatment groups ( approximately 35 % ) and there were no between-group differences in body height or urinary cortisol . CONCLUSIONS Ciclesonide 40 - 160 μg once daily is effective and well tolerated in children with persistent asthma ; its efficacy and safety are unaffected by the use of a spacer . clinical trials.gov registration number : NCT00384189 [21839625] BACKGROUND Few large-scale studies have examined inhaled corticosteroid treatment in preschool children with recurrent wheeze . We assessed the effects of ciclesonide in preschool children with recurrent wheeze . METHODS We included children 2 - 6 yrs with recurrent wheeze and a positive asthma predictive index or aeroallergen sensitization to , excluding patients with episodic viral wheezing . After a 2 - 4-week baseline period , patients with ongoing symptoms or rescue medication use were r and omised to once-daily ciclesonide 40 , 80 , 160 μg or placebo for 24 weeks . RESULTS The number of wheeze exacerbations requiring systemic corticosteroids was unexpectedly low in all groups : 25 ( 10.2 % ) in placebo group , as compared to 11 ( 4.4 % ) , 18 ( 7.3 % ) , and 17 ( 6.7 % ) in ciclesonide 40 , 80 , and 160 μg , respectively . The difference in time to first exacerbation was not significantly different between groups ( p = 0.786 ) , but the difference in exacerbation rates between placebo and the pooled ciclesonide groups was ( p = 0.03 ) . Large and significant ( p < 0.0001 ) improvements in symptom scores and rescue medication use occurred in all groups , including placebo . Improvements in FEV(1 ) and FEF(25 - 75 ) ( measured in 284 4 - 6 yr olds ) were larger in the ciclesonide than in the placebo group . No differences in safety parameters ( adverse events , height growth , serum and urinary cortisol levels ) between ciclesonide and placebo were observed . CONCLUSIONS In preschool children with recurrent wheeze and a positive asthma predictive index , ciclesonide modestly reduces wheeze exacerbation rates and improves lung function . A large placebo response and unexpected selection of patients with mild disease may have affected outcomes , highlighting the heterogeneity of preschool wheezing disorders [20569973] BACKGROUND Inhaled corticosteroid ( ICS ) nonadherence is common among patients with asthma ; however , interventions to improve adherence have often been complex and not easily applied to large patient population s. OBJECTIVE To assess the effect of supplying patient adherence information to primary care providers . METHODS Patients and providers were members of a health system serving southeast Michigan . Providers ( 88 intervention ; 105 control ) and patients ( 1335 intervention ; 1363 control ) were r and omized together by practice . Patients were age 5 to 56 years , had a diagnosis of asthma , and had existing prescriptions for ICS medication . Adherence was estimated by using prescription and fill data . Unlike clinicians in the control arm , intervention arm providers could view up date d ICS adherence information on their patients via electronic prescription software , and further details on patient ICS use could be viewed by selecting that option . The primary outcome was ICS adherence in last 3 months of the study period . RESULTS At the study end for the intention-to-treat analysis , ICS adherence was not different among patients in the intervention arm compared with those in the control arm ( 21.3 % vs 23.3 % , respectively ; P = .553 ) . However , adherence was significantly higher among patients whose clinician elected to view their detailed adherence information ( 35.7 % ) compared with both control arm patients ( P = .026 ) and intervention arm patients whose provider did not view adherence data ( P = .002 ) . CONCLUSIONS Overall , providing adherence information to clinicians did not improve ICS use among patients with asthma . However , patient use may improve when clinicians are sufficiently interested in adherence to view the details of this medication use [8979288] Correlations between knemometric ( lower leg length ) growth rates and urine free cortisol excretion , respectively , and serum concentrations of IGF-I , IGF binding protein-3 , osteocalcin , carboxy terminal propeptide of type I collagen(PICP ) , carboxy terminal pryridinoline cross-linked telopeptide of type I procollagen ( ICTP ) , and amino terminal propeptide of type III procollagen(PIIINP ) were investigated in 17 asthmatic children aged 7 - 14 y during treatment with fluticasone propionate , 200 μg , and beclomethasone dipropionate , 400 and 800 μg/d , taken from dry powder inhalers . The study was a double blind , crossover trial with three active treatment periods and two wash-out periods . All periods were 15 d long . Overnight urine free cortisol/creatinine × 106 did not correlate with knemometric growth rates or any of the serum markers . Significant correlations ( Pearson 's correlation coefficient , P ) between knemometric growth rates and IGF-I ( 0.41 ; 0.006 ) , IGFBP-3 ( 0.35 ; 0.02 ) , PICP ( 0.44 ; 0.003 ) , ICTP ( 0.35 ; 0.001 ) , and PIIINP ( 0.46 ; 0.002 ) were found . Compared with fluticasone propionate , 200 μg , beclomethasone dipropionate , 400 and 800 μg , caused significant suppression of lower leg growth rate ( F = 12.41;p = 0.002 , and F = 23.30 ; p = 0.0001 , respectively ) and of urine free cortisol/creatinine × 106(F = 10.52 ; p = 0.003 , and F = 13.74;p = 0.001 ) . Beclomethasone , 800 μg , caused suppression of PICP compared with fluticasone propionate , 200 μg ( F = 8.31;p = 0.008 ) , and beclomethasone , 400 μg ( F = 7.53;p = 0.01 ) . Both low ( F = 6.82 ; p = 0.02 ) and high ( F = 23.35 ; p = 0.0001 ) doses of beclomethasone were associated with reduced concentrations of ICTP , the high dose being the most suppressive ( F = 4.42 ; p = 0.05 ) . Beclomethasone 400(F = 9.75 ; p = 0.004 ) and 800 μg ( F = 23.61;p = 0.0001 ) result ed in reduced levels of PIIINP . Reduced short-term knemometric growth rates in children treated with inhaled glucocorticosteroids reflect suppressive effects on type I and type III collagen turnover

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### Context: [16615971] OBJECTIVE To compare the efficacy and safety of once-daily inhaled ciclesonide 40 mug ( CIC40 ) , 80 mug ( CIC80 ) , and 160 mug ( CIC160 ) with placebo in children with persistent asthma of all severities . STUDY DESIGN Overall , 1031 children age 4 to 11 years were r and omized into 2 identical double-blinded , placebo-controlled , parallel group studies consisting of a run-in phase followed by 12 weeks of treatment . Both studies were design ed to allow for a prespecified integrated analysis . The primary outcome variable was change in forced expiratory volume in 1 second ( FEV(1 ) ) percent predicted between baseline and study end ; treatment comparisons were assessed using analysis of covariance . Additional endpoints included asthma symptom scores , daily albuterol use , and safety , including hypothalamic-pituitary-adrenal ( HPA ) axis function . RESULTS Baseline characteristics were comparable ; 59.4 % of patients had moderate asthma , and 24.1 % had severe asthma . All ciclesonide doses were associated with greater improvements in baseline to week 12 FEV(1 ) percent predicted versus placebo ( CIC40 , 11.97 ; CIC80 , 13.58 , P < .05 ; CIC160 , 14.17 , P < .01 ) . Significant improvements in asthma symptoms ( P < .01 ) and reductions in albuterol use were reported . Ciclesonide was well tolerated with no effect on HPA axis function . CONCLUSIONS In this integrated analysis , ciclesonide was effective and well tolerated in children with persistent asthma [18070931] OBJECTIVE . To assess the effects of the new inhaled corticosteroid ciclesonide on growth in children with asthma . METHODS . We performed a multicenter , r and omized , double-blind , placebo-controlled study to assess the effects of inhaled ciclesonide on growth in children with mild , persistent asthma . After a 6-month run-in period , 661 prepubertal children who were aged 5.0 to 8.5 years were r and omly assigned to once-daily morning treatment for 1 year with ciclesonide 40 or 160 μg ( ex-actuator ) or placebo , followed by a 2-month follow-up period . The primary end point was the linear growth velocity ( linear regression estimate ) over the double-blind treatment period . Growth was recorded as the median of 4 stadiometer measurements . Adverse events and 10-hour overnight and 24-hour urinary free cortisol levels were also assessed . RESULTS . Mean linear growth velocity during run-in was comparable between groups : 160 μg , 6.20 cm/year ; 40 μg , 6.59 cm/year ; placebo , 6.49 cm/year . Mean differences from placebo ( 5.75 cm/year ) in growth velocity over the double-blind treatment period were −0.02 cm/year for ciclesonide 40 μg and −0.15 cm/year for ciclesonide 160 μg . Both ciclesonide treatments were noninferior to placebo with respect to growth velocity . The overall incidence of adverse events was comparable between groups , and no significant changes in 10-hour overnight or 24-hour urinary free cortisol levels were noted between groups during the double-blind treatment period . CONCLUSIONS . Ciclesonide demonstrated no detectable effect on childhood growth velocity , even at the highest dosage , which may ease concerns about systemic adverse events [10212103] BACKGROUND Airway hyperresponsiveness , induced sputum eosinophils , and exhaled nitric oxide ( NO ) levels have all been proposed as non-invasive markers for monitoring airway inflammation in patients with asthma . The aim of this study was to compare the changes in each of these markers following treatment with inhaled glucocorticosteroids in a single study . METHODS In a r and omised , double blind , placebo controlled , parallel study 25 patients with mild asthma ( 19–34 years , forced expiratory volume in one second ( FEV1 ) > 75 % predicted , concentration of histamine provoking a fall in FEV1 of 20 % or more ( PC20 ) < 4 mg/ml ) inhaled fluticasone propionate ( 500 μg twice daily ) for four weeks . PC20 to histamine , sputum eosinophil numbers , and exhaled NO levels were determined at weeks 0 , 2 , and 4 , and two weeks after completing treatment . Sputum was induced by inhalation of hypertonic ( 4.5 % ) saline and eosinophil counts were expressed as percentage non-squamous cells . Exhaled NO levels ( ppb ) were measured by chemiluminescence . RESULTS In the steroid treated group there was a significant increase in PC20 , decrease in sputum eosinophils , and decrease in exhaled NO levels compared with baseline at weeks 2 and 4 of treatment . Subsequently , each of these variables showed significant worsening during the two week washout period compared with week 4 . These changes were significantly different from those in the placebo group , except for the changes in sputum eosinophils and exhaled NO levels during the washout period . There were no significant correlations between the changes in the three markers in either group at any time . CONCLUSIONS Treatment of asthmatic subjects with inhaled steroids for four weeks leads to improvements in airway hyperresponsiveness to histamine , eosinophil counts in induced sputum , and exhaled nitric oxide levels . The results suggest that these markers may provide different information when monitoring anti-inflammatory treatment in asthma [18814453] BACKGROUND Onset of bronchodilation of budesonide/formoterol in one pressurized metered-dose inhaler ( pMDI ) has not been evaluated in asthma . OBJECTIVE To evaluate time to onset of clinical ly significant bronchodilation ( > or = 15 % improvement in forced expiratory volume in 1 second ) and patient-perceived onset of effect ( OE ) in patients previously receiving inhaled corticosteroids . METHODS In two 12-week studies , patients 12 years and older with moderate to severe ( study 1 ; n = 596 ) and mild to moderate ( study 2 ; n = 480 ) persistent asthma received budesonide/formoterol pMDI , budesonide pMDI plus formoterol dry powder inhaler ( study 1 only ) , budesonide pMDI , formoterol dry powder inhaler , or placebo . Postdose time to 15 % or greater improvement in forced expiratory volume in 1 second and patient-perceived OE ( assessed in a subset of patients 18 years and older [ study 1 , n=553 ; study 2 , n=405 ] ) were evaluated [ corrected ] RESULTS More budesonide/formoterol-treated patients achieved onset of clinical ly significant bronchodilation within 15 minutes ( median , 13 minutes ) of administration at r and omization vs those taking budesonide or placebo ( P < .001 ) . More patients receiving budesonide/formoterol vs budesonide and placebo reported feeling their study medication begin to work right away ( P < or = .004 ; end of week 1 ) . Similar results ( P < .001 ) were observed for patient satisfaction with how quickly they felt their medication begin to work ( except budesonide/formoterol vs budesonide , study 1 [ P = .073 ] ) . Time to onset of clinical ly significant bronchodilation and patient-perceived OE of budesonide/formoterol and formoterol were similar . CONCLUSION Budesonide/formoterol demonstrated a more rapid onset of clinical ly significant bronchodilation and a greater percentage of patients who perceived their medication working right away vs budesonide or placebo [9655732] Studies in adults revealed that addition of salmeterol to a moderate dose of inhaled corticosteroid result ed in better symptom control and higher PEF compared with doubling the dose of inhaled corticosteroid . The aim of this three group study was to compare the effects of a moderate dose of beclomethasone , the same dose of beclomethasone with salmeterol , and a doubling dose of beclomethasone on lung function and symptoms in children with moderate asthma . A total of 177 children already treated with inhaled corticosteroids , were r and omized in a double-blind parallel study either to salmeterol 50 microg twice daily ( BDP400+salm ) , beclomethasone 200 microg twice daily ( BDP800 ) , or placebo ( BDP400 ) in addition to beclomethasone 200 microg twice daily . No significant differences between groups were found in FEV1 , PD20 methacholine , symptom scores , and exacerbation rates after 1 yr . Salmeterol result ed in slightly better PEF in the first months of treatment . FEV1 , and PD20 methacholine significantly improved in all groups . After 1 yr mean changes in FEV1 , percent predicted were 4.3 % ( 95 % CI 1.3 ; 7.2 ) , 5.8 % ( 95 % CI 2.9 ; 8.7 ) , and 4.3 % ( 95 % CI 2.1 ; 6.5 ) for BDP400+salm , BDP800 , and BDP400 , respectively . Changes in airway responsiveness were 0.60 ( 95 % CI 0.05 ; 1.14 ) , 1.30 ( 95 % CI 0.73 ; 1 . 87 ) , and 0.80 ( 95 % CI 0.33 ; 1.27 ) doubling doses . Growth was significantly slower in the BDP800 group . We conclude that no additional benefit was found of adding either salmeterol or more beclomethasone to a daily dose of 400 microg beclomethasone in this group of children with excellent compliance of medication [24565456] BACKGROUND Environmental tobacco smoke ( ETS ) negatively affects children with asthma . The prevalence of ETS exposure among children with poor asthma control may be changing . Importantly , the mechanisms by which ETS worsens asthma control are poorly understood . OBJECTIVE We describe how ETS affects gastroesophageal reflux ( GER ) , respiratory infections , and leukotriene production among children with poor asthma control . METHODS We analyzed data from 306 children between 6 and 17 years of age with poorly controlled asthma enrolled in a 6-month clinical trial . We evaluated prevalence and determinants of ETS exposure by interview , question naire , and urinary cotinine and the association of ETS exposure on leukotriene production , respiratory infections , GER , lung function , and asthma control . We used multivariable linear , logistic , and Poisson regressions to assess outcomes . RESULTS ETS prevalence estimates ranged from 6 % to 30 % . Children with domestic indoor exposure had worse asthma control ( c-Asthma Control Test , 17.8 vs 21.5 ; P = .04 ) , worse FEV1 % predicted ( 84.1 vs 90.7 ; P = .02 ) , and a trend for increased mean urinary leukotriene E4 . ETS from any setting was associated with increased symptomatic respiratory infections ( adjusted incidence rate ratio : 1.30 ; P = .02 ) . However , children exposed to ETS did not have symptoms or pH probe results , suggestive of heightened GER . CONCLUSIONS Domestic smoking exposure was associated with both higher rates of symptomatic respiratory infection and poorer asthma control despite generally intensive controller therapy . ETS exposure is common among asthmatic children with poor control and may worsen asthma control by promoting respiratory infections . Further investigation is required to eluci date ETS mechanisms in poor asthma control [22938716] BACKGROUND The use of inhaled glucocorticoids for persistent asthma causes a temporary reduction in growth velocity in prepubertal children . The result ing decrease in attained height 1 to 4 years after the initiation of inhaled glucocorticoids is thought not to decrease attained adult height . METHODS We measured adult height in 943 of 1041 participants ( 90.6 % ) in the Childhood Asthma Management Program ; adult height was determined at a mean ( ±SD ) age of 24.9±2.7 years . Starting at the age of 5 to 13 years , the participants had been r and omly assigned to receive 400 μg of budesonide , 16 mg of nedocromil , or placebo daily for 4 to 6 years . We calculated differences in adult height for each active treatment group , as compared with placebo , using multiple linear regression with adjustment for demographic characteristics , asthma features , and height at trial entry . RESULTS Mean adult height was 1.2 cm lower ( 95 % confidence interval [ CI ] , -1.9 to -0.5 ) in the budesonide group than in the placebo group ( P=0.001 ) and was 0.2 cm lower ( 95 % CI , -0.9 to 0.5 ) in the nedocromil group than in the placebo group ( P=0.61 ) . A larger daily dose of inhaled glucocorticoid in the first 2 years was associated with a lower adult height ( -0.1 cm for each microgram per kilogram of body weight ) ( P=0.007 ) . The reduction in adult height in the budesonide group as compared with the placebo group was similar to that seen after 2 years of treatment ( -1.3 cm ; 95 % CI , -1.7 to -0.9 ) . During the first 2 years , decreased growth velocity in the budesonide group occurred primarily in prepubertal participants . CONCLUSIONS The initial decrease in attained height associated with the use of inhaled glucocorticoids in prepubertal children persisted as a reduction in adult height , although the decrease was not progressive or cumulative . ( Funded by the National Heart , Lung , and Blood Institute and the National Center for Research Re sources ; CAMP Clinical Trials.gov number , NCT00000575 . ) [11930704] OBJECTIVE To observe the systemic side effects of low dose inhaled Beclomethasone dipropionate ( BDP ) in children with mild asthma . METHODS 30 children with mild asthma were r and omly divided into 3 groups to receive treatment with inhaled placebo ( group A ) , BDP 200 micrograms/d ( group B ) and BDP 400 micrograms/d ( group C ) respectively . Bronchial hyperresponsiveness ( BHR ) , height growth , bone mineral density ( BMD ) , calcium and phosphate metabolism and hypothalamic-pituitary-adrenal axis ( HPAA ) function were measured . RESULTS Inhaled BDP of 200 micrograms/d and 400 micrograms/d reduced BHR in mild asthmatic children and there was no significant difference between two groups [log(PD20-FEV1)]:(2.04 + /- 0.47 ) micrograms to ( 2.70 + /- 0.13 ) micrograms in group A and ( 1.94 + /- 0.46 ) micrograms to ( 3.15 + /- 0.18 ) micrograms in group B ( P < 0.01 ) . Serum osteocalcin , calcium , phosphate , alkaline phosphatase , basic cortisol and BMD did n't change significantly after BDP treatment in three groups ( all P > 0.05 ) [ In group A , B and C , concentrations serum osteocalcin were ( 29 + /- 12 ) micrograms/L , ( 22 + /- 6 ) micrograms/L , ( 31 + /- 11 ) micrograms/L , serum calcium : ( 2.49 + /- 0.11 ) mmol/L , ( 2.39 + /- 0.28 ) mmol/L , ( 2.20 + /- 0.35 ) mmol/L , serum phosphate : ( 1.8 + /- 0.6 ) mmol/L , ( 1.7 + /- 0.7 ) mmol/L , ( 1.5 + /- 0.4 ) mmol/L , radius BMD : ( 0.44 + /- 0.02 ) g/cm2 , ( 0.42 + /- 0.05 ) g/cm2 , ( 0.40 + /- 0.10 ) g/cm2 , ulna BMD:(0.35 + /- 0.04 ) g/cm2 , ( 0.36 + /- 0.08 ) g/cm2 , ( 0.32 + /- 0.07 ) g/cm2 , serum alkaline phosphatase : ( 410 + /- 113 ) U/L , ( 337 + /- 99 ) U/L , ( 351 + /- 122 ) U/L , serum basic cortisol : ( 350 + /- 86 ) nmol/L , ( 407 + /- 199 ) nmol/L , ( 365 + /- 71 ) nmol/L , lumbar spine ( L4 - 5 ) BMD : ( 0.64 + /- 0.06 ) g/cm2 , ( 0.59 + /- 0.08 ) g/cm2 , ( 0.62 + /- 0.09 ) g/cm2 respectively ] . Height growth had a trend of reducing after BDP treatment though not reaching statistical difference . Height st and ard deviation score ( SDS ) : 1.1 + /- 0.7 to 1.2 + /- 0.9 in group A , 1.3 + /- 0.7 to 1.3 + /- 0.9 in group B and 1.1 + /- 0.7 to 1.0 + /- 0.7 in group C. Serum cortisol after ACTH stimulation reduced significantly in group C [ ( 621 + /- 199 ) nmol/L to ( 482 + /- 97 ) nmol/L , P < 0.01 ] . CONCLUSION The results of this study suggest that 200 micrograms/d BDP can reduce BHR significantly and has no detected systemic side effects in mild asthmatic children , and 400 micrograms/d BDP can reduce serum cortisol after ACTH stimulation . The long-term dose of BDP should be controlled to be less than 400 micrograms/d in children with mild asthma [10669845] BACKGROUND Results of recent growth studies suggest that inhaled glucocorticosteroids may affect growth in children . OBJECTIVE Three 52-week , open-label extension studies ( studies A , B , and C ) were conducted to compare the effects of budesonide inhalation suspension ( BIS ) with conventional asthma therapy ( CAT ) on long-term safety , including intermediate-term growth , in 3 different pediatric asthma population s. METHODS Pediatric asthma patients ( ages 6 months to 8 years ) from 3 multicenter , r and omized , 12-week , double-blind , placebo-controlled studies were eligible to enroll in the 52-week , open-label extension studies . The extension studies were multicenter , r and omized , open-label , active-controlled , parallel-group studies performed at 26 centers in the United States . Subjects in each extension study were r and omized in a 2:1 ratio to receive either BIS or CAT . BIS was initially administered at a dose of 0.5 mg once ( studies A and C ) or twice daily ( study B ) , with attempts made at each clinical visit to gradually reduce the dose to the minimum effective dose that maintains asthma control , as judged by the investigator . CAT consisted of any available therapy for asthma , including inhaled glucocorticosteroids in studies B and C only . Height SD scores , growth velocity , and skeletal age ( only in studies B and C ) were examined . RESULTS In total , 670 subjects were r and omized ; 223 subjects received CAT and 447 received BIS . Mean ages at entry were 63.0 months and 60.9 months in CAT and BIS groups , respectively . Median total daily doses of BIS ranged from 0.5 to 1 . 0 mg and the mean duration of treatment exposure was 304 + /- 119 days and 342 + /- 83 days in CAT and BIS groups , respectively . Changes in height SD scores differed significantly between the BIS and CAT groups in study A ( -0.19 , P = .003 ) , and there was a small , statistically significant decrease in growth velocity ( -0.8 cm/y , P = .002 ) in the BIS-treated group compared with the CAT group . No significant differences were observed between BIS and CAT groups in the changes in height SD scores or in growth velocities in studies B ( + 0.10 and + 0.7 cm/y , respectively ) and C ( + 0.12 and + 0.8 cm/y , respectively ) . No differences in skeletal age were observed between BIS and CAT groups in studies B and C. CONCLUSION There was a small , statistically significant decrease in growth velocity in the BIS-treated group compared with the CAT group in the study ( study A ) where inhaled glucocorticosteroid use was prohibited before entry and in the CAT group during the study . In the studies ( B and C ) where inhaled glucocorticosteroids were allowed in the CAT group , no differences were observed in height SD scores or growth velocity . The clinical relevance of these effects , including impact on final adult height , remain to be determined in prospect ively planned studies that assess growth in children [9864004] The aim of the present study was to examine the efficacy of low-dose inhaled budesonide ( BUD ) administered via Turbuhaler once or twice daily on symptoms , lung function and bronchial hyperreactivity in children with mild asthma . One hundred and sixty-three children ( mean age 9.9 yrs , 56 females/107 males ) with mild asthma ( forced expiratory volume in one second ( FEV1 ) 103 % of predicted , morning peak expiratory flow ( PEF ) 87 % pred , reversibility in FEV1 3 % , fall in FEV1 after exercise 10.4 % from pre-exercise value ) and not previously treated with inhaled steroids , were included in a double-blind , r and omized , parallel-group study . After a two-week run-in period , the children received inhaled BUD 100 microg or 200 microg once daily in the morning , 100 microg twice daily or placebo for 12 weeks . Exercise and methacholine challenges were performed before and at the end of treatment . After 12 weeks of therapy , the fall in FEV1 after an exercise test was significantly less in all three BUD groups ( 43 - 5.1 % ) than in the placebo group ( 8.6 % ) . Bronchial hyperreactivity to methacholine with the provocative dose causing a 20 % fall in FEV1 decreased significantly in the BUD 100 microg twice-daily group compared with placebo ( ratio at the end of treatment 156 % ) . Changes in baseline lung function ( FEV1 and PEF ) were less marked than changes in bronchial responsiveness . In conclusion , low doses of inhaled budesonide , given once or twice daily , provided protection against exercise-induced bronchoconstriction in children with mild asthma and near normal lung function [4354777] Twenty children have been treated with the steroid aerosol beclomethasone , half of them in an open trial and the other half in a controlled cross-over trial . Children were assessed by means of clinical examination , diary records , and twice-daily peak flow rate measurements made at home . After 1 to 2 months all but 1 of the 16 children who were initially taking systemic steroids or corticotrophin were weaned off these drugs . The cross-over trial showed a significant improvement on the active drug , in terms of diary score , bronchodilator use , steroid dose , and twice-daily peak expiratory flow measurements . Adrenal function was entirely normal after 1 and 3 months on the drug as measured by morning cortisol levels and the response to tetracosactrin . There were no side effects , apart from the reappearance of hay fever or eczema in some children previously on systemic steroids . Follow-up for a mean of 4·5 ± 2·2 ( SD ) months showed the continuing efficacy of beclomethasone , though an increase in dose has been needed in some children . The advantages of aerosol steroid therapy in children are noted [12877449] BACKGROUND Because of potential toxicities of inhaled corticosteroid ( ICS ) use in pediatric asthma , alternative or steroid-sparing therapy is desirable . There are no previous studies evaluating montelukast 's steroid-sparing effects in children with asthma . OBJECTIVE To evaluate whether ( 1 ) montelukast as add-on therapy improves asthma symptom control and ( 2 ) montelukast provides steroid-sparing effects in children with asthma treated with low to moderate doses of ICS therapy . METHODS In a double-blind , placebo-controlled trial , 36 children ages 6 to 14 years with symptomatic asthma maintained on a stable low to moderate dose of ICSs were r and omly assigned to receive montelukast or matching placebo for 24 weeks after a run-in period of 2 weeks ( period I ) . During the trial , subjects kept daily asthma diary cards and monthly spirometry was performed . After a 4 week add-on period ( period II ) , the subjects completed a 20-week ( period III ) ICS tapering period based on a predetermined protocol . RESULTS In period II , the difference in the number of rescue-free days was significantly higher in the montelukast group ( P = 0.0001 ) , and the number of rescue-free days per week was also significantly higher in montelukast-treated subjects compared with placebo subjects ( P = 0.002 ) . In period III , the percentage reduction in ICS dose was not significant between montelukast and placebo ( P = 0.10 ) , but the montelukast group experienced an average 17 % decrease in ICS dose and the control group experienced an average 64 % increase in ICS dose . CONCLUSIONS Montelukast treatment significantly increased the number of rescue-free days in symptomatic children with asthma [12756375] OBJECTIVE Exhaled nitric oxide ( FE(NO ) ) was evaluated in children with asthma after 4 to 6 years of treatment with budesonide , nedocromil , or albuterol as needed . STUDY DESIGN FE(NO ) , spirometry , total eosinophil count , and serum eosinophil cationic protein levels were obtained from 118 children at the Denver site of the Childhood Asthma Management Program upon completion of treatment and after a 2- to 4-month washout . RESULTS Budesonide-treated patients had significantly lower median ( 1st , 3rd quartile ) FE(NO ) ( 21.5 [ 13.2 , 84.4 ] vs 62.5 [ 26.2 , 115.0 ] ppb , P < .01 ) and eosinophil cationic protein levels ( 17.4 [ 10.1 , 24.3 ] vs 24.0 [ 15.4 , 33.9 ] mg/dL , P = .05 ) compared with placebo , whereas no differences were noted between nedocromil and placebo groups . After washout , FE(NO ) levels were similar between the three treatments . FE(NO ) levels significantly correlated with degree of bronchial hyperresponsiveness , bronchodilator reversibility , allergen skin prick tests , serum IgE , and total eosinophil count . FE(NO ) levels were also higher in patients with nocturnal symptoms and in patients requiring beta-agonist use at least once weekly . CONCLUSIONS Budesonide therapy was more effective than nedocromil in reducing FE(NO ) . Unfortunately , the effects of long-term budesonide were not sustained after its discontinuation . FE(NO ) may be a complementary tool to current practice guidelines in assessing asthma control and medication response [9850361] Herein we assess the safety of an inhaled formulation of beclomethasone dipropionate ( BDP ) which uses the propellant hydrofluoroalkane-134a ( HFA ) for the treatment of asthma . Acute local tolerability ( as assessed by the incidence of cough and mean forced expiratory volume after 1 s inhalation ) was similar for both BDP and placebo formulated in either chlorofluorocarbon ( CFC ) or HFA propellants . A total of 43 patients were treated with HFA-BDP ( 0 , 200 , 400 or 800 micrograms day-1 ) or CFC-BDP ( 800 micrograms day-1 ) for 14 days and their 24 h urinary free cortisol ( UFC ) excretion and response to cosyntropin stimulation were measured . There was no difference in UFC between any of the doses of HFA-BDP and CFC-BDP . Adrenal responsiveness to cosyntropin stimulation was normal in all but one patient . Two large 12 week phase III trials compared HFA-placebo , HFA-BDP 400 micrograms day-1 and CFC-BDP 800 micrograms day-1 ( n = 347 ) , and HFA-BDP 800 micrograms day-1 and CFC-BDP 1500 micrograms day-1 ( n = 233 ) . For HFA-BDP at either dose , CFC-BDP 800 micrograms day-1 and HFA-placebo , the number of patients with morning plasma cortisol concentrations below normal was less than 4.4 % but was 14.6 % for CFC-BDP 1500 micrograms day-1 . The incidence of adverse events was lower in the HFA-BDP groups than in the CFC-BDP groups ( P = 0.012 ) . The data indicate that , at doses of up to 800 micrograms day-1 , HFA-BDP is at least as well tolerated as CFC-BDP . Other studies have found that equivalent efficacy is reached at lower doses of HFA-BDP than CFC-BDP . Equivalent efficacy at a lower dose and equivalent safety at the same dose imply that HFA-BDP may have a more favourable risk : benefit ratio than CFC-BDP when used at the recommended lower doses [16387604] BACKGROUND Atopic dermatitis ( AD ) often develops in infancy as the first manifestation of the atopic phenotype . Wheezing is also common in infancy , but it is less clear whether infant wheezing should be considered as an atopic phenotype . If infant wheeze and AD share a common aetiology , this would indicate that infant wheezing is an atopic phenotype . OBJECTIVE To investigate whether potential risk factors for infant wheeze and AD have similar effects on these 2 phenotypes , indicating a common etiology . METHODS A total of 34.793 mother-child pairs enrolled in the Danish National Birth Cohort were followed prospect ively . Information on wheezing episodes , AD , and prenatal , perinatal , and postnatal risk factors was collected by interview at 12 and 30 weeks of gestation , at 6 and 18 months of age , and by linkage to the Danish Medical Birth Register . Data were analyzed by binary and polytomous logistic regression models . RESULTS The following variables had significantly differential effects on infant wheezing and AD : parental hay fever , parental asthma , parental AD , sex , maternal age , maternal occupation , smoking during pregnancy , season of birth , birth weight , gestational age , head circumference , breast-feeding , number of older siblings , day care attendance , and pets in the home . CONCLUSION The majority of risk factors had differential effects on infant wheeze and AD indicative of a different etiology . Infant wheezing does not seem to be etiologically linked to the epidemic of atopic disease , and infant wheezing should not be used as an indicator of the atopic phenotype [9679845] BACKGROUND Inhaled corticosteroids are increasingly being used to treat mild-to-moderate asthma in children . However , data regarding therapy with this class of compounds , especially in children under age 6 years , is limited . Fluticasone propionate is a third generation inhaled corticosteroid with an optimal therapeutic index . Few large prospect i ve clinical trials have been conducted to evaluate the efficacy and safety of fluticasone propionate powder in children . OBJECTIVE We sought to determine the efficacy and safety of fluticasone propionate powder administered by means of the Diskus and Diskhaler multidose powder inhalers in pediatric patients with persistent asthma . METHODS Fluticasone propionate powder ( 50 microg or 100 microg twice daily ) or placebo was administered by means of the Diskus or Diskhaler inhalers to 437 children ( 4 to 11 years old ) with persistent asthma for 12 weeks in a r and omized , double-blind , parallel-group , multi-center trial . Patients were stratified according to whether they were receiving prior treatment with inhaled corticosteroids or cromolyn or beta2-agonists alone . RESULTS Fluticasone propionate powder administered by means of Diskus or Diskhaler significantly improved FEV1 ( mean increase from baseline of 0.22 to 0.24 L ; p < or = 0.023 ) , clinic morning peak expiratory flow ( mean increase from baseline of 48 to 55 L/min ; p < or = 0.006 ) , patient-measured morning ( p < or = 0.001 ) and evening ( p < or = 0.003 ) peak expiratory flow , and asthma symptom scores ( in all but the 50 microg Diskus group ; p < or = 0.036 ) , as well as reduced albuterol use ( p < or = 0.002 ) and nighttime awakenings ( p < or = 0.019 ) at endpoint . Efficacy parameters were not significantly different between the two doses with either device . More placebo-treated patients discontinued the study because of lack of efficacy than patients in any fluticasone propionate group ( p < 0.001 ) . Fluticasone propionate did not suppress morning plasma cortisol concentrations and did not affect 24-hour urinary free-cortisol excretion . Adverse events were primarily pharmacologic effects of inhaled corticosteroids , and those related to the study drug occurred with low frequency . Patient satisfaction with both the Diskus and Diskhaler devices was high , with a majority of patients ( > 80 % ) rating them favorably . CONCLUSION This study demonstrated that fluticasone propionate powder , at the conventional recommended doses of up to 200 microg/day administered by means of Diskus or Diskhaler , was well tolerated and improved lung function in children even as young as 4 and 5 years old regardless of whether they were previously treated with inhaled corticosteroids or cromolyn or beta2-agonists alone [15358701] To assess long-term effects and side-effects of fluticasone propionate ( FP ) , a 2-yr study was performed , comparing a step-down dose approach ( 1,000 µg·day−1 , with reductions every 2 months to 500 , 200 and 100 µg·day−1 for the remainder of the study ) versus a constant dose ( 200 µg·day−1 ) . In 55 children with chronic persistent asthma , aged 6–10 yrs , airways hyperresponsiveness ( AHR ) and systemic side-effects ( height , bone parameters and adrenal cortical function ) were assessed at predetermined intervals in a double-blind prospect i ve 2-yr study . AHR improved after 4 months treatment with 1,000 µg·day−1 FP followed by 500 µg·day−1 , without significant differences during long-term treatment between the two approaches . Dose-dependent reduction of growth velocity , adrenal cortical function and biochemical bone turnover was found during therapy with 1,000 and 500 µg·day−1 FP when compared with 200 µg·day−1 . In conclusion , doses of 1,000 and 500 µg·day−1 fluticasone propionate are associated with marked reductions of growth velocity , bone turnover and adrenal cortical function . However , conventional doses ( ≤200 µg·day−1 fluticasone propionate ) appear to be safe in the long-term management of childhood asthma . From a safety point of view , high doses of fluticasone propionate should only be prescribed in exceptions , e.g. in persistent severe asthma [2532957] Objective : To compare the effect of inhaled budesonide given daily or as-needed on mild persistent childhood asthma . Patients , design and interventions : 176 children aged 5–10 years with newly detected asthma were r and omly assigned to three treatment groups : ( 1 ) continuous budesonide ( 400 μg twice daily for 1 month , 200 μg twice daily for months 2–6 , 100 μg twice daily for months 7–18 ) ; ( 2 ) budesonide , identical treatment to group 1 during months 1–6 , then budesonide for exacerbations as needed for months 7–18 ; and ( 3 ) disodium cromoglycate ( DSCG ) 10 mg three times daily for months 1–18 . Exacerbations were treated with budesonide 400 μg twice daily for 2 weeks . Main outcome measures : Lung function , the number of exacerbations and growth . Results : Compared with DSCG the initial regular budesonide treatment result ed in a significantly improved lung function , fewer exacerbations and a small but significant decline in growth velocity . After 18 months , however , the lung function improvements did not differ between the groups . During months 7–18 , patients receiving continuous budesonide treatment had significantly fewer exacerbations ( mean 0.97 ) , compared with 1.69 in group 2 and 1.58 in group 3 . The number of asthma-free days did not differ between regular and intermittent budesonide treatment . Growth velocity was normalised during continuous low-dose budesonide and budesonide therapy given as needed . The latter was associated with catch-up growth . Conclusions : Regular use of budesonide afforded better asthma control but had a more systemic effect than did use of budesonide as needed . The dose of ICS could be reduced as soon as asthma is controlled . Some children do not seem to need continuous ICS treatment [4354778] Twenty-five patients with severe childhood asthma were treated with beclomethasone dipropionate . 21 of these children were receiving oral corticosteroid therapy in addition to disodium cromoglycate . Of the total treated , 21 children improved or maintained their asthma status on this treatment over an average period of 4 months , and were able to reduce and stop their regular oral corticosteroid dosage , but 4 children had to revert to their original therapy . No systemic or local toxic effects were experienced by any of the children . Beclomethasone dipropionate appears to be an effective drug in the treatment of severe childhood asthma in those patients who need corticosteroid therapy in addition to disodium cromoglycate [18178494] OBJECTIVE Demonstrating clinical benefit of higher doses of inhaled corticosteroids in asthma is frequently problematic owing to their relatively flat dose-response curve in this condition . In this study we compared the efficacy and safety of a fourfold difference in the dose of ciclesonide-ciclesonide 320 microg twice daily ( CIC640 ) versus ciclesonide 160 microg once daily (CIC160)-in patients with severe persistent asthma . METHODS Patients with bronchial asthma ( 6 months ) were included in this r and omized , double-blind study . After receiving fluticasone propionate 250 microg twice daily during run-in , patients were r and omized to CIC160 ( n=339 ) or CIC640 ( n=341 ) for 12 weeks . Primary endpoints were time to first asthma exacerbation and forced expiratory volume in 1s ( FEV(1 ) ) . Secondary endpoints included other lung function variables , asthma symptom scores and rescue medication use ( RMU ) . RESULTS Asthma exacerbations occurred in 12.7 % of patients receiving CIC160 and 6.7 % receiving CIC640 . CIC640 was superior for time to first exacerbation ( p=0.0050 , one-sided ) . FEV(1 ) increased significantly with CIC160 and CIC640 ( least squares mean+/-SE of mean : 269+/-31 and 332+/-31 mL , respectively ; p<0.0001 ) , with no significant difference between groups . Change in % predicted FEV(1 ) and morning peak expiratory flow ( PEF ) were significantly higher with CIC640 ( p<0.05 ) . Asthma symptom score sums and RMU decreased in both groups ; CIC640 was statistically superior ( p=0.0108 and 0.0005 , respectively ) . No unexpected adverse events were reported in either group and the majority of the events reported were mild or moderate in intensity . No significant changes in serum cortisol were observed from the baseline to the study end . Small decreases in creatinine-adjusted 24h urine cortisol levels from baseline were seen in both the treatment groups , which , due to the large patient numbers , were statistically significant ( p<0.05 ) ; however , no dose-response effect was seen and the difference between groups was not significant ( p=0.7892 ) . CONCLUSION CIC640 was superior to CIC160 for time to first exacerbation , % predicted FEV1 , morning PEF , asthma symptom score sum and RMU in patients with severe asthma ; both doses had similar tolerability profiles and no significant changes in serum cortisol were seen in either treatment group [22536582] BACKGROUND In 2010 , the Canadian Thoracic Society ( CTS ) published a Consensus Summary for the diagnosis and management of asthma in children six years of age and older , and adults , including an up date d Asthma Management Continuum . The CTS Asthma Clinical Assembly subsequently began a formal clinical practice guideline up date process , focusing , in this first iteration , on topics of controversy and ⁄or gaps in the previous guidelines . METHODS Four clinical questions were identified as a focus for the up date d guideline : the role of noninvasive measurements of airway inflammation for the adjustment of anti-inflammatory therapy ; the initiation of adjunct therapy to inhaled corticosteroids ( ICS ) for uncontrolled asthma ; the role of a single inhaler of an ICS⁄long-acting beta(2)-agonist combination as a reliever , and as a reliever and a controller ; and the escalation of controller medication for acute loss of asthma control as part of a self-management action plan . The expert panel followed an adaptation process to identify and appraise existing guidelines on the specified topics . In addition , literature search es were performed to identify relevant systematic review s and r and omized controlled trials . The panel formally assessed and grade d the evidence , and made 34 recommendations . RESULTS The up date d guideline recommendations outline a role for inclusion of assessment of sputum eosinophils , in addition to st and ard measures of asthma control , to guide adjustment of controller therapy in adults with moderate to severe asthma . Appraisal of the evidence regarding which adjunct controller therapy to add to ICS and at what ICS dose to begin adjunct therapy in children and adults with poor asthma control supported the 2010 CTS Consensus Summary recommendations . New recommendations for the adjustment of controller medication within written action plans are provided . Finally , priority areas for future research were identified . CONCLUSIONS The present clinical practice guideline is the first up date of the CTS Asthma Guidelines following the Canadian Respiratory Guidelines Committee 's new guideline development process . Tools and strategies to support guideline implementation will be developed and the CTS will continue to regularly provide up date s reflecting new evidence [12042586] OBJECTIVE To assess the long-term safety of hydrofluoroalkane 134a (HFA)-beclomethasone dipropionate ( BDP ) extrafine aerosol administered by the Autohaler compared with chlorofluorocarbon (CFC)-BDP administered by a press- and -breathe metered-dose inhaler ( pMDI ) and spacer ( + S ) in the treatment of children with asthma . METHODS This 12-month , open-label , r and omized , multicenter study enrolled 300 children who were aged 5 to 11 years and had well-controlled asthma on inhaled CFC-BDP or budesonide ; 256 patients were using doses within the recommended range ( 200 - 400 microg ) and were analyzed separately . Patients were r and omized in a 1:3 ratio to continue on CFC-BDP+S at approximately the same dose as they were using before study entry or switch to HFA-BDP at half the daily dose . RESULTS Asthma control was well maintained in the HFA-BDP group as evidence d by lung function tests and asthma symptoms compared with CFC-BDP+S at approximately twice the dose . There were no significant differences between the HFA-BDP 100 to 200 microg and CFC-BDP+S 200 to 400 microg treatment groups in mean change from baseline in height ( 5.23 cm vs 5.66 cm at month 12 , respectively ) or mean growth velocity from day 1 to month 12 ( 5.27 cm/y vs 5.71 cm/y , respectively ) . There were no significant differences between groups in adrenal function tests or markers of bone metabolism . CONCLUSIONS In this long-term study in children with asthma , extrafine HFA-BDP provided long-term maintenance of asthma control at approximately half the dose compared with CFC-BDP+S. There were no clinical ly meaningful differences between HFA-BDP extrafine aerosol and conventional CFC-BDP+S with regard to growth or other systemic effects [12016099] The goal of this study was to establish a reliable method to evaluate systemic bioavailability and to determine equisystemic effects ( microgram dose producing equal systemic cortisol suppression ) of inhaled corticosteroids ( ICS ) . Steroid naive asthma subjects ( n = 156 ) were enrolled at six centers . A 1-week doubling dose design was used for each of six ICS and matched placebos for a total of four doses . Systemic effect was evaluated by hourly plasma cortisol concentrations ( 8 P.M. to 8 A.M. ) , 12- and 24-hour urine cortisol concentrations , and a morning blood osteocalcin . The area under the concentration-time curve for hourly cortisol concentrations was the best outcome variable to assess systemic effect . For the six ICS and matching placebos ( beclomethasone-chlorofluorocarbon [ CFC ] , budesonide dry powder inhaler [ DPI ] , fluticasone DPI , fluticasone-CFC metered dose inhaler [ MDI ] , flunisolide-CFC , and triamcinolone-CFC ) , only the placebo group and fluticasone DPI did not demonstrate a significant dose-response effect . Thus microgram comparison of all ICS could only be performed at a 10 % cortisol suppression : flunisolide-CFC - 936 ; triamcinolone-CFC - 787 ; beclomethasone-CFC - 548 ; fluticasone DPI - 445 ; budesonide DPI - 268 ; fluticasone-CFC MDI - 111 . This study represents the first step in evaluation of ICS efficacy based on equisystemic ( cortisol suppression ) effects of a given ICS , rather than doses judged arbitrarily to be comparable on a microgram basis [15644830] OBJECTIVE To compare the safety of budesonide inhalation suspension ( BIS ) with placebo in infants 6 to 12 months of age with mild to moderate persistent asthma or recurrent wheeze . STUDY DESIGN In this multicenter , r and omized , double-blinded , parallel-group , placebo-controlled study , 141 patients received 0.5 mg BIS ( n = 48 ) , 1.0 mg BIS ( n = 44 ) , or placebo ( n = 49 ) once daily for 12 weeks . The primary variable was adrenal function , based on cosyntropin-stimulated plasma cortisol levels . Spontaneous adverse events and clinical laboratory findings also were monitored . RESULTS Overall , the types and frequencies of adverse events reported during the study were comparable across treatment groups . The response to cosyntropin stimulation was similar across treatment groups , with no significant difference between BIS treatment and placebo . CONCLUSIONS The safety profile of BIS was similar to that of placebo , with no suppressive effect on adrenal function in patients 6 to 12 months of age with mild to moderate persistent asthma or recurrent wheeze [9385125] BACKGROUND An inhaled glucocorticoid is currently the medication of choice for long-term control of persistent asthma in children . The role of long-acting beta2-adrenergic-receptor agonists , such as salmeterol , needs to be defined . METHODS We conducted a r and omized , double-blind , placebo-controlled , parallel-group , one-year study of 241 children ( mean [ + /-SD ] age , 9.3+/-2.4 years ) with clinical ly stable asthma and less than one month of prior glucocorticoid use . We compared inhaled beclomethasone dipropionate ( 200 microg twice daily ) with salmeterol xinafoate ( 50 microg twice daily ) and placebo ( lactose ) . The primary outcome measure , airway responsiveness ( as assessed with a methacholine challenge ) was evaluated before treatment ; after 3 , 6 , 9 , and 12 months of treatment ( 12 and 36 hours after study medications had been withheld ) ; and 2 weeks after the end of treatment . Spirometry , symptoms , use of rescue medication ( 200 microg of albuterol inhaled as needed ) , and adverse effects were also assessed . RESULTS During months 1 through 12 overall , beclomethasone was associated with significantly less airway hyperresponsiveness than salmeterol ( P= 0.003 ) or placebo ( P<0.001 ) . This effect was lost two weeks after treatment had been stopped . As compared with placebo , beclomethasone was associated with less variability between morning and evening in the peak expiratory flow ( P=0.002 ) , as was salmeterol ( P=0.02 ) . Beclomethasone was also associated with a reduced need for albuterol as rescue therapy ( P<0.001 ) and fewer withdrawals because of asthma exacerbations ( P=0.03 ) , but salmeterol was not ( P=0.09 and 0.55 , respectively ) . During months 1 through 12 , linear growth was 3.96 cm in the children receiving beclomethasone , as compared with 5.40 cm in the salmeterol group ( P=0.004 ) and 5.04 cm in the placebo group ( P=0.018 ) . Height was not measured after treatment ended . CONCLUSIONS Beclomethasone was effective in reducing airway hyperresponsiveness and in controlling symptoms of asthma , but it was associated with decreased linear growth . Salmeterol was not as effective as beclomethasone in reducing airway hyperresponsiveness or in controlling symptoms ; however , it was an effective bronchodilator and was not associated with rebound airway hyperresponsiveness , masking of symptoms , or adverse effects [4590668] Betamethasone valerate aerosol is a new compound for the treatment of asthma . Its clinical effectiveness was established in a double-blind cross-over trial in non-steroid-dependent asthmatic patients . At a dosage of 400 to 800 μg/day for three months there was no evidence of suppression of hypothalamic-pituitary-adrenal function , as assessed by tetracosactrin and insulin stress tests . A 12-month follow-up study of 120 patients using steroid aerosols ( betamethasone valerate or beclomethasone dipropionate ) indicated that tolerance does not develop and that a daily maintenance dose of 200 μg/day was adequate in most patients . Temporary lack of response was observed during episodes of sputum production or of heavy exposure to antigen . There were no observed side effects other than fungal infections of the respiratory tract . However , the incidence of c and idiasis of the pharynx ( 13 % ) and particularly of the larynx ( 5 % ) in apparently immunologically normal patients was disturbing . These infections were not seen in patients taking 200 μg/day . Though there is yet no evidence that fungal infections associated with steroid aerosols may penetrate the trachea and bronchi the possibility of this indicates that caution should be exercised in their use , particularly in long-term high dosage [16687711] BACKGROUND It is unknown whether inhaled corticosteroids can modify the subsequent development of asthma in preschool children at high risk for asthma . METHODS We r and omly assigned 285 participants two or three years of age with a positive asthma predictive index to treatment with fluticasone propionate ( at a dose of 88 mug twice daily ) or masked placebo for two years , followed by a one-year period without study medication . The primary outcome was the proportion of episode-free days during the observation year . RESULTS During the observation year , no significant differences were seen between the two groups in the proportion of episode-free days , the number of exacerbations , or lung function . During the treatment period , as compared with placebo use , use of the inhaled corticosteroid was associated with a greater proportion of episode-free days ( P=0.006 ) and a lower rate of exacerbations ( P<0.001 ) and of supplementary use of controller medication ( P<0.001 ) . In the inhaled-corticosteroid group , as compared with the placebo group , the mean increase in height was 1.1 cm less at 24 months ( P<0.001 ) , but by the end of the trial , the height increase was 0.7 cm less ( P=0.008 ) . During treatment , the inhaled corticosteroid reduced symptoms and exacerbations but slowed growth , albeit temporarily and not progressively . CONCLUSIONS In preschool children at high risk for asthma , two years of inhaled-corticosteroid therapy did not change the development of asthma symptoms or lung function during a third , treatment-free year . These findings do not provide support for a subsequent disease-modifying effect of inhaled corticosteroids after the treatment is discontinued . ( Clinical Trials.gov number , NCT00272441 . ) [16270721] In sensitive asthmatic children , the exposure to relevant allergens causes a deterioration of lung function and symptoms associated with an increase of inflammatory indices . The aim of this single-blind r and omized add-on study was to compare the effects of montelukast or formoterol added to low-dose budesonide in asthmatic allergic children exposed to relevant allergens . Twenty children ( 5 female subjects and 15 male subjects , aged 6 - 12 years ) were enrolled . Lung function and airway inflammatory indices ( exhaled nitric oxide [ eNO ] and sputum eosinophils ) were evaluated at T0 when children were not exposed to relevant allergens and at T1 after 15 days of natural effective allergen exposure . At T1 , pulmonary function tests and sputum eosinophils remained stable in both of the groups , without significant differences in comparison with T0 at baseline . Furthermore , formoterol plus budesonide was effective in preventing the expected increase in eNO from 26.46 + /- 2.62 ppb at T0 to 29.33 + /- 9.28 ppb at T1 ( not significant ) . However , in the group receiving montelukast plus budesonide , there was a significant decrease of eNO from baseline ( 30.78 + /- 6.87 ppb ) to T1 ( 18.17 + /- 6.60 ppb ) ( p < .05 ) . In allergic asthmatic children , the use of montelukast or formoterol combined with budesonide could offer a durable protective effect on symptoms , lung function , and inflammatory indices [11739137] Dose-dependent effects of inhaled corticosteroids have been described . Although it has been advised to start treatment with inhaled corticosteroids with a high dose tapering off subsequently ( stepdown approach ) , no clinical studies have assessed this strategy . We compared two different dosage schedules of inhaled fluticasone propionate ( FP ) in chronic persistent childhood asthma with respect to efficacy ( airways hyperresponsiveness [ PD(20 ) ] , lung function , exhaled nitric oxide [ eNO ] ) and safety ( height ) . During this double-blind study , children with asthma ( aged 6 - 10 yr ) were r and omized to receive either FP 200 microg/d ( constant dose approach ) or to start with 1000 microg/d with two monthly reductions to 500 , 200 , and 100 microg/d ( stepdown approach ) . PD(20 ) improved in both approaches during treatment with FP , with a significantly better PD(20 ) after 2 mo of 1000 microg/d followed by 500 microg/d in the stepdown approach versus 200 microg/d in the constant dose approach . No significant differences in PD(20 ) or other efficacy parameters were found after 1 yr . Changes in st and ing height were similar in both treatment approaches . This study showed no superior clinical effect of a stepdown approach compared with a constant dose strategy of FP for 1 yr in children with chronic persistent asthma [1355640] In a r and omized double-blind multicenter clinical study , 116 children with asthma were r and omly assigned to treatment with an inhaled beta-2-agonist ( salbutamol 0.2 mg ) plus an inhaled corticosteroid ( budesonide 0.2 mg ) three times a day ( BA+CS ) or to an inhaled beta-2-agonist ( salbutamol 0.2 mg ) plus a placebo three times a day ( BA+PL ) . After a median follow-up time of 22 months , 26 patients receiving BA+PL ( 45 % ) had withdrawn from r and omized treatment , mainly because of asthma symptoms , compared with three withdrawals in the patients receiving BA+CS ( p less than 0.0001 ) . The FEV1 , expressed as a percentage of the predicted value for age , sex , and height , showed an absolute increase of 7.0 % after 2 months of BA+CS compared with a decrease of 4.0 % after 2 months of BA+PL . This 11 % difference in percent predicted FEV1 ( 95 % confidence interval , 7 to 15 % ; p less than 0.0001 ) was then maintained after a median follow-up period of 22 months . Postbronchodilator FEV1 showed an absolute increase of 3.7 % predicted within 2 months in patients receiving BA+CS and an absolute decrease of 1.1 % predicted in children receiving BA+PL ( p = 0.0005 ) . Thereafter , this difference between the two treatment groups was maintained . Average peak expiratory flow rate ( PEFR ) increased from baseline by 36.6 L/min in the BA+CS group compared with 3.7 L/min in the BA+PL group ( p = 0.003 ) . This difference then remained for the median follow-up time of 22 months . ( ABSTRACT TRUNCATED AT 250 WORDS [2221590] Several short-term studies have shown that inhaled steroids can reduce airway hyper-responsiveness in asthma . To evaluate whether prolonged treatment can bring about full recovery , this double-blind , r and omized , controlled trial examined the effect of budesonide , 400 micrograms daily for 1 yr , on airway hyperresponsiveness . The time course and characteristics of improvements and associated changes in clinical asthma severity were also evaluated . Thirty-two stable adult asthmatics , requiring bronchodilators alone , were selected . Before and monthly throughout the study , airway responsiveness to methacholine was measured and clinical asthma severity assessed by question naire , daily bronchodilator use , and number of asthma exacerbations . Patients receiving budesonide showed a fourfold mean improvement in airway responsiveness compared with those receiving placebo ( p less than 0.0005 ) , whose responsiveness remained very stable . Fifteen of the 16 budesonide subjects improved and 5 returned to the normal range . Largest improvements occurred during the first 3 months but , in some , were still progressing slowly at 1 yr . Improvements in responsiveness were accompanied by significant improvements in asthma symptoms , bronchodilator use , and number of asthma exacerbations . The results show that regular , prolonged use of inhaled steroid can produce marked improvements in airway hyperresponsiveness , sometimes with full resolution , and these improvements are accompanied by clinical ly significant improvements in clinical asthma [10955700] This study is an extended follow‐up for 24 months of a 12‐week trial to study the long‐term clinical efficacy of low‐dose inhaled budesonide ( BUD ) once or twice daily in children with mild asthma . A total of 122 children ( mean age 9.7 years , girls/boys ; 42/80 ) with mild asthma ( FEV1 103.7 % of predicted , reversibility in FEV1 3.5 % , and fall in FEV1 afterexercise 12.2 % ) , not previously treated with inhaled steroids , were included in a double‐blind , r and omized , parallel‐group study . The children were treated with inhaled BUD 100 or 200 µg administered via Turbuhaler ® once daily in the morning , 100 µg twice daily , or placebo for 27 months . Exercise and methacholine challenges were performed at 3‐month intervals the first year and at 6‐month intervals the second year , in a total of seven visits . A significant dose‐response effect favoring BUD 200 µg daily ( vs 100 µg daily ) was found when comparing changes in FEV1 , FEF25 % , and FEV50 % ; the fall in FEV1 after an exercise test ; and the effect on blood eosinophils . Bronchial hyperreactivity to methacholine decreased significantly on three visits in patients treated with BUD 200 µg daily compared to placebo . Growth rate was not significantly affected except in children aged 7–11 years at baseline after 12 months of treatment . In conclusion , 100 or 200 µg daily of inhaled BUD for 27 months is safe and effective in protecting against exercise‐induced asthma and achieving nearly normal lung function . Baseline lung function was not significantly affected in this group of children with mild asthma [18805335] BACKGROUND Preliminary evidence is equivocal about the role of exhaled nitric oxide ( NO ) in clinical asthma management . We aim ed to assess whether measurement of exhaled NO , as a biomarker of airway inflammation , could increase the effectiveness of asthma treatment , when used as an adjunct to clinical care based on asthma guidelines for inner-city adolescents and young adults . METHODS We did a r and omised , double-blind , parallel-group trial at ten centres in the USA . We screened 780 inner-city patients , aged 12 - 20 years , who had persistent asthma . All patients completed a run-in period of 3 weeks on a regimen based on st and ard treatment . 546 eligible participants who adhered to treatment during this run-in period were then r and omly assigned to 46 weeks of either st and ard treatment , based on the guidelines of the National Asthma Education and Prevention Program ( NAEPP ) , or st and ard treatment modified on the basis of measurements of fraction of exhaled NO . The primary outcome was the number of days with asthma symptoms . We analysed patients on an intention-to-treat basis . This trial is registered with clinical trials.gov , number NCT00114413 . FINDINGS During the 46-week treatment period , the mean number of days with asthma symptoms did not differ between the treatment groups ( 1.93 [ 95 % CI 1.74 to 2.11 ] in the NO monitoring group vs 1.89 [ 1.71 to 2.07 ] in the control group ; difference 0.04 [ -0.22 to 0.29 ] , p=0.780 ) . Other symptoms , pulmonary function , and asthma exacerbations did not differ between groups . Patients in the NO monitoring group received higher doses of inhaled corticosteroids ( difference 119 mug per day , 95 % CI 49 to 189 , p=0.001 ) than controls . Adverse events did not differ between treatment groups ( p>0.1 for all adverse events ) . INTERPRETATION Conventional asthma management result ed in good control of symptoms in most participants . The addition of fraction of exhaled NO as an indicator of control of asthma result ed in higher doses of inhaled corticosteroids , without clinical ly important improvements in symptomatic asthma control [11027739] BACKGROUND Antiinflammatory therapies , such as inhaled corticosteroids or nedocromil , are recommended for children with asthma , although there is limited information on their long-term use . METHODS We r and omly assigned 1041 children from 5 through 12 years of age with mild-to-moderate asthma to receive 200 microg of budesonide ( 311 children ) , 8 mg of nedocromil ( 312 children ) , or placebo ( 418 children ) twice daily . We treated the participants for four to six years . All children used albuterol for asthma symptoms . RESULTS There was no significant difference between either treatment and placebo in the primary outcome , the degree of change in the forced expiratory volume in one second ( FEV1 , expressed as a percentage of the predicted value ) after the administration of a bronchodilator . As compared with the children assigned to placebo , the children assigned to receive budesonide had a significantly smaller decline in the ratio of FEV1 to forced vital capacity ( FVC , expressed as a percentage ) before the administration of a bronchodilator ( decline in FEV1:FVC , 0.2 percent vs. 1.8 percent ) . The children given budesonide also had lower airway responsiveness to methacholine , fewer hospitalizations ( 2.5 vs. 4.4 per 100 person-years ) , fewer urgent visits to a caregiver ( 12 vs. 22 per 100 person-years ) , greater reduction in the need for albuterol for symptoms , fewer courses of prednisone , and a smaller percentage of days on which additional asthma medications were needed . As compared with placebo , nedocromil significantly reduced urgent care visits ( 16 vs. 22 per 100 person-years ) and courses of prednisone . The mean increase in height in the budesonide group was 1.1 cm less than in the placebo group ( 22.7 vs. 23.8 cm , P=0.005 ) ; this difference was evident mostly within the first year . The height increase was similar in the nedocromil and placebo groups . CONCLUSIONS In children with mild-to-moderate asthma , neither budesonide nor nedocromil is better than placebo in terms of lung function , but inhaled budesonide improves airway responsiveness and provides better control of asthma than placebo or nedocromil . The side effects of budesonide are limited to a small , transient reduction in growth velocity [9196087] In a double-blind , parallel-group study , we examined the effect of short-term treatment with inhaled fluticasone propionate ( FP ) in a group of 20 nonsmoking asthmatic patients who required only beta2-agonists to control their symptoms . We administered FP ( 250 microg twice daily ) or matched placebo for 6 wk . Methacholine challenge was performed before treatment , after 3 wk , and at the end of treatment . Each patient underwent bronchoscopy with bronchoalveolar lavage ( BAL ) and bronchial biopsy before and after treatment . Eight patients in the placebo group and nine patients in the FP group completed the study . Bronchial responsiveness to methacholine decreased significantly only after 6 wk of treatment with FP ( p < 0.05 ) . When we compared the FP group with the placebo group , we observed a significant decrease only in the number of cells expressing intracellular adhesion molecule-1 ( ICAM-1 ) and MAC-1 ( p < 0.04 and p < 0.03 , respectively ) . Moreover , we saw that the tryptase level in BAL decreased ( p < 0.001 ) , whereas the eosinophil cationic protein ( ECP ) level did not change significantly . Additionally , the number of eosinophils and mast cells in the lamina propria in bronchial biopsies specimens was significantly smaller in the FP group than in the placebo group ( p < 0.02 and p < 0.01 , respectively ) . Additionally , in the FP group , we found that basement-membrane thickness was significantly decreased when compared with that of the placebo group ( p < 0.05 ) . In conclusion , our results show that short-term treatment with low-dose FP reduces inflammatory cell infiltration into the lamina propria in bronchial biopsy specimens . Moreover , short-term low-dose FP treatment might control the intensity of airway remodeling in mild asthma [337992] 1 . Beclomethasone dipropionate aerosol has been shown to be a highly effective treatment for asthma in childhood , with virtual absence of side effects at this age . 2 . When treatment is unsuccessful , this is usually due to failure to take it correctly and regularly . 3 . A good response is usually associated with an improvement in ventilatory function and a marked increase in growth velocity [16337447] BACKGROUND Inhaled corticosteroids are recommended as first-line therapy for persistent asthma . OBJECTIVE We sought to assess the efficacy and safety of ciclesonide once daily in patients with mild-to-moderate persistent asthma . METHODS An integrated analysis of 2 identical , multicenter , double-blind , r and omized , parallel-group , placebo-controlled trials was conducted . Patients ( n = 1015 ; aged > or = 12 years ) with mild-to-moderate asthma ( FEV1 of 60 % to 85 % of predicted value ) were r and omized to ciclesonide 80 microg ( CIC80 ) , 160 microg ( CIC160 ) , or 320 microg ( CIC320 ) , once daily ( exactuator doses ) in the morning or placebo for 12 weeks . RESULTS All ciclesonide groups showed significant improvements from baseline to week 12 in FEV1 compared with the placebo group ( CIC80 , 0.12 L [ P = .0007 ] ; CIC160 , 0.13 L [ P = .0004 ] ; and CIC320 , 0.14 L [ P < .0001 ] ) . Likewise , FEV1 percent predicted , morning and evening peak expiratory flow , 24-hour asthma symptom score , daily albuterol use , and nighttime awakenings were significantly improved in all ciclesonide groups compared with the placebo group . Overall ciclesonide safety profile and rates of oropharyngeal adverse events for all groups were low and similar to those of the placebo group . Fewer ciclesonide-treated patients exhibited asthma-aggravated adverse events , and fewer ciclesonide-treated patients discontinued the study for any reason or because of a lack of efficacy compared with those in the placebo group . No suppression of hypothalamic-pituitary-adrenal-axis function ( as assessed by means of 24-hour urinary cortisol levels corrected for creatinine and peak serum cortisol levels after stimulation with low-dose [ 1 microg ] cosyntropin ) was observed with any dose of ciclesonide . CONCLUSIONS In this integrated analysis , ciclesonide once daily administered in the morning is effective and well tolerated [3512282] Forty-five steroid-dependent asthmatic out patients were treated twice daily for 51 weeks with a new inhalation steroid , budesonide ( BUD ) , using a 750 ml spacer . During the initial 15 weeks the prednisone-sparing effects of a high daily dose ( 1600 micrograms ) and a conventional dose ( 400 micrograms per day ) were compared in a double-blind r and omized trial including 50 patients . During the remaining 36 weeks 45 patients were treated openly with 1600 micrograms daily . All patients used other antiasthmatic drugs which were maintained throughout the study , except for inhalations of beta-2 agonists that could be used whenever needed . All patients but 2 were able to reduce the daily dose of oral prednisone . The mean daily dose decreased from 13.9 mg to 5.3 mg . Eighteen patients ( 40 % ) were able to discontinue oral prednisone . Adrenal gl and function improved considerably as prednisone intake decreased . Oropharyngeal thrush frequency showed no change . No severe side effects were observed [7540898] Serum concentrations of growth hormone – dependent insulin – like growth factor I ( IGF – I ) and insulinlike growth factor binding protein–3 ( IGFBP–3 ) , the carboxy terminal propeptide of type I procollagen ( PICP ) , the carboxy terminal pyridinoline cross – linked telopeptide of type I collagen ( ICTP ) and the amino terminal propeptide of type III procollagen ( PIIINP ) were studied in 14 prepubertal children with asthma ( mean age 9.7 years ) during treatment with inhaled budesonide . The study design was a r and omized , crossover trial with two double – blind treatment periods ( 200 and 800 μg ) and one open , non – r and omized treatment period ( 400 μg ) . All periods were 18 days ’ duration . Budesonide treatment was associated with a dose – related suppressive trend in serum concentrations of PIIINP when the 400 μg period was included ( p < 0.01 ; z = –2.7 ) and when it was excluded from the calculations ( p < 0.01 ; z = –2.6 ) , indicating reduced synthesis of type III collagen . A similar trend was observed in ICTP levels when the 400 μg period was excluded from the calculations ( p= 0.05 ; z = –1.9 ) . No other statistically significant variations were seen [9544904] OBJECTIVE To determine whether inhaled fluticasone propionate has long-term effects on growth in children with persistent asthma . STUDY DESIGN In a double-blind , r and omized , parallel-group , multicenter study , 325 prepubescent children with persistent asthma and normal growth rates were treated with placebo or inhaled fluticasone propionate powder 50 microg or 100 microg administered twice daily by a breath-actuated device for 1 year . Growth was evaluated monthly , whereas other safety variables and pulmonary function were evaluated periodically . RESULTS The prepubescent patients showed no statistically significant differences in mean height , mean growth velocity , or mean skeletal age between any of the treatment groups at any time . Over a period of 1 year , mean height ( + /- SE ) increased 6.15 + /- 0.17 cm in the placebo group , 5.94 + /- 0.16 cm in the fluticasone propionate 50 microg group , and 5.73 + /- 0.13 cm in the fluticasone propionate 100 microg group ( p = 0.308 , overall ) . CONCLUSIONS Prepubescent children treated with fluticasone propionate 50 microg and 100 microg administered twice daily for 1 year grew at rates similar to placebo-treated control subjects and at rates equal to expected growth velocity for age [20622031] RATIONALE For children with symptomatic asthma despite low to moderate doses of inhaled corticosteroids , evidence is still lacking whether to add a long-acting bronchodilator or to increase the dose of inhaled corticosteroids . OBJECTIVE To evaluate whether salmeterol/fluticasone propionate ( SFP ) , 50/100 μg twice a day , is noninferior regarding symptom control compared with fluticasone propionate ( FP ) , 200 μg twice a day Diskus in children with symptomatic asthma . METHODS A multicenter , r and omized , parallel-group , double-blind study was performed comparing SFP and FP treatment during 26 weeks on asthma control and lung function . MEASUREMENTS AND MAIN RESULTS A total of 158 children , 6 - 16 years old , still symptomatic on FP , 100 μg twice a day , during a 4-week run-in period , were included . Percentage of symptom-free days during the last 10 weeks of the treatment period did not differ between treatment groups ( per protocol analysis : adjusted mean difference [ FP minus SFP ] 2.6 % ; 95 % confidence interval , -8.1 to 13.4 ) . Both groups showed substantial improvements of about 25 percent points in symptom-free days ( both P < 0.001 from baseline ) . Lung function measurements ( FEV(1 ) , FVC , PEF rate , and maximal expiratory flow ) did not differ between groups except for a slight advantage in maximal expiratory flow in the SFP group at 1 week . No differences were found between FP and SFP regarding exacerbation rates , adverse events , or growth . CONCLUSIONS In our study the efficacy on symptom control and lung function of the combination of a long-acting bronchodilator with inhaled corticosteroid is equal to doubling the dose of the inhaled corticosteroid in children still symptomatic on a moderate dose of inhaled corticosteroid [9925834] RATIONALE Topical antiinflammatory medications such as inhaled corticosteroids are recommended for therapy of asthma , but no formulation suitable for administration to infants and young children is available in the United States . METHODS This was a 12-week , multicenter , double-blind , r and omized , parallel-group study comparing the efficacy and safety of four dosing regimens of bude-sonide inhalation suspension ( BIS ) or placebo in 480 asthmatic infants and children ( 64 % boys ) , ages 6 months to 8 years , with moderate persistent asthma . Approximately 30 % of children were previously on inhaled corticosteroids that were discontinued before the study . Active treatments were comprised of BIS 0.25 mg once daily ( QD ) , 0.25 mg twice a day ( BID ) , 0.5 mg BID , or 1.0 mg QD . Efficacy was assessed by twice daily recording at home of asthma symptom scores and use of rescue medication , and discontinuation from the study because of worsening asthma and /or a requirement for systemic steroids . Peak flow measurements were recorded twice daily on diary and spirometry was recorded at clinic visits for those children able to perform these tests . Safety was assessed by reported adverse events and by cortisol testing ( adrenocorticotropic hormone stimulation ) in a subset of patients . RESULTS Patients enrolled had an average duration of asthma of 34 months ; the mean asthma symptom score was approximately 1.3 ( scale of 0 - 3 ) . All dosing regimens with BIS produced statistically significant improvement in various clinical efficacy measures for asthma control compared with placebo . The lowest dose used , 0.25 mg QD , was efficacious but with fewer efficacy parameters than seen with the other doses administered . Separation between active treatment and placebo in daytime and nighttime symptom scores were observed by week 2 of treatment for all BIS treatment regimens . A significant increase in peak flow measurement was observed in most active treatment groups compared with placebo in the subset of children able to do pulmonary function testing . All treatment groups showed numerical improvement in forced expiratory volume in 1 second but only the 0.5-mg BID dose was significantly different from placebo . Adverse events for the entire group and response to adrenocorticotropic hormone in a subgroup of children who underwent cortisol testing before and at the end of the treatment period were no different in budesonide-treated patients in comparison to placebo . CONCLUSION Results of this study demonstrate that BIS is effective and safe for infants and young children with moderate persistent asthma in a multiple dose range , and that QD dosing is an important option to be considered by the prescribing physician [9627589] OBJECTIVE To determine the efficacy and safety of budesonide delivered by an inhalation-driven dry powder inhaler ( Turbuhaler ) in children with moderate to severe persistent asthma . STUDY DESIGN In our r and omized , double-blind , placebo-controlled , parallel-group , multicenter study , a total of 404 children with asthma , who were aged 6 to 18 years and who had been receiving inhaled glucocorticosteroid therapy , were r and omly assigned to receive either 100 , 200 , or 400 micrograms of budesonide or placebo twice daily for 12 weeks . At baseline , mean forced expiratory volume in 1 second ( FEV1 ) was 74.6 % ( range , 30.7 % to 123.3 % ) of the predicted normal value . RESULTS Patients in each of the three budesonide treatment groups showed significant dose-related improvements in lung function ( morning peak expiratory flow and FEV1 ) , in asthma symptoms , and with a significant decrease in inhaled beta 2-agonist use in comparison with placebo . Improvements were evident within 2 weeks and were maintained throughout the 12 weeks . Budesonide treatment had no significant effect on hypothalamic-pituitary-adrenal axis function , and the incidence of reported adverse events was similar in all treatment groups . CONCLUSION Budesonide administered via a dry powder inhaler provided dose-related improvements in lung function and clinical status and was well tolerated by children ( 6 to 18 years of age ) with moderate to severe persistent asthma [4371672] Twenty-six children with asthma were treated with beclomethasone dipropionate aerosol in a dose adjusted to their symptoms for 13 to 20 months . 18 children in the group had been taking systemic steroids at the start of the trial and all were successfully weaned off them , mostly within 2 months . All but 1 of the children were satisfactorily controlled by beclomethasone , but 15 children needed short courses of oral steroids at times of severe exacerbations . There was no evidence of either suppression or acceleration of growth , nor was there any adrenal suppression as assessed at intervals by the estimation of the resting level of plasma cortisol and the response to tetracosactrin . No other side effects were encountered apart from exacerbations of eczema or rhinitis in some children previously on systemic steroids [8707781] Fluticasone propionate ( FP ) administered via metered-dose inhaler is a potent corticosteroid effective in the treatment of asthma . To evaluate the efficacy and safety of FP powder administered via a breath-activated inhaler ( Diskhaler ) , a multicenter , double-blind , r and omized , placebo-controlled , parallel-group study was conducted in adolescent and adult patients ( n = 331 ) with mild-to-moderate asthma previously treated with beta 2-agonist therapy alone . Patients received FP powder 50 , 100 , or 250 micrograms or placebo twice daily for 12 weeks . FP-treated patients compared with placebo-treated patients had significantly ( p < 0.001 ) greater improvements in morning predose forced expiratory volume in 1 sec ( 21 - 22 % increase vs. 9 % ) . Improvement in morning peak flow rate were also significantly ( p < 0.001 ) greater with FP than with placebo ( 8 - 10 % increase vs. 2 % increase ) . There was also a significant overall treatment difference in the frequency of inhaled albuterol use ( p < 0.001 ) and number of nighttime awakenings due to asthma ( p = 0.005 ) . There were no statistically significant difference among the FP treatment groups in any outcome measure . Physicians ' global assessment s also indicated significant ( p < 0.001 ) differences in efficacy , with 67 - 74 % of FP-treated patients rated as having " effective " or " very effective " treatment compared with 41 % of placebo-treated patients . Significant beneficial effects of FP were observed in lung function and diary card parameters after just 1 week of treatment . Adverse events were similar across treatment groups and primarily related to local irritation . Effect on hypothalamic-pituitary-adrenal axis function was minimal . In summary , all three dosages of inhaled FP powder were well tolerated and improved various asthma-related variables . Improvements in pulmonary function , beyond those achieved with beta 2-agonist therapy alone , were maintained for the duration of the 12-week study [25504972] BACKGROUND Treatment guidelines for asthma recommend inhaled corticosteroids ( ICS ) as first-line therapy for children with persistent asthma . Although ICS treatment is generally considered safe in children , the potential systemic adverse effects related to regular use of these drugs have been and continue to be a matter of concern , especially the effects on linear growth . OBJECTIVES To assess the impact of ICS on the linear growth of children with persistent asthma and to explore potential effect modifiers such as characteristics of available treatments ( molecule , dose , length of exposure , inhalation device ) and of treated children ( age , disease severity , compliance with treatment ) . SEARCH METHODS We search ed the Cochrane Airways Group Specialised Register of trials ( CAGR ) , which is derived from systematic search es of bibliographic data bases including CENTRAL , MEDLINE , EMBASE , CINAHL , AMED and PsycINFO ; we h and search ed respiratory journals and meeting abstract s. We also conducted a search of Clinical Trials.gov and manufacturers ' clinical trial data bases to look for potential relevant unpublished studies . The literature search was conducted in January 2014 . SELECTION CRITERIA Parallel-group r and omised controlled trials comparing daily use of ICS , delivered by any type of inhalation device for at least three months , versus placebo or non-steroidal drugs in children up to 18 years of age with persistent asthma . DATA COLLECTION AND ANALYSIS Two review authors independently performed study selection , data extraction and assessment of risk of bias in included studies . We conducted meta-analyses using the Cochrane statistical package RevMan 5.2 and Stata version 11.0 . We used the r and om-effects model for meta-analyses . We used mean differences ( MDs ) and 95 % CIs as the metrics for treatment effects . A negative value for MD indicates that ICS have suppressive effects on linear growth compared with controls . We performed a priori planned subgroup analyses to explore potential effect modifiers , such as ICS molecule , daily dose , inhalation device and age of the treated child . MAIN RESULTS We included 25 trials involving 8471 ( 5128 ICS-treated and 3343 control ) children with mild to moderate persistent asthma . Six molecules ( beclomethasone dipropionate , budesonide , ciclesonide , flunisolide , fluticasone propionate and mometasone furoate ) given at low or medium daily doses were used during a period of three months to four to six years . Most trials were blinded and over half of the trials had drop out rates of over 20 % . Compared with placebo or non-steroidal drugs , ICS produced a statistically significant reduction in linear growth velocity ( 14 trials with 5717 participants , MD -0.48 cm/y , 95 % CI -0.65 to -0.30 , moderate quality evidence ) and in the change from baseline in height ( 15 trials with 3275 participants ; MD -0.61 cm/y , 95 % CI -0.83 to -0.38 , moderate quality evidence ) during a one-year treatment period . Subgroup analysis showed a statistically significant group difference between six molecules in the mean reduction of linear growth velocity during one-year treatment ( Chi(2 ) = 26.1 , degrees of freedom ( df ) = 5 , P value < 0.0001 ) . The group difference persisted even when analysis was restricted to the trials using doses equivalent to 200 μg/d hydrofluoroalkane (HFA)-beclomethasone . Subgroup analyses did not show a statistically significant impact of daily dose ( low vs medium ) , inhalation device or participant age on the magnitude of ICS-induced suppression of linear growth velocity during a one-year treatment period . However , head-to-head comparisons are needed to assess the effects of different drug molecules , dose , inhalation device or patient age . No statistically significant difference in linear growth velocity was found between participants treated with ICS and controls during the second year of treatment ( five trials with 3174 participants ; MD -0.19 cm/y , 95 % CI -0.48 to 0.11 , P value 0.22 ) . Of two trials that reported linear growth velocity in the third year of treatment , one trial involving 667 participants showed similar growth velocity between the budesonide and placebo groups ( 5.34 cm/y vs 5.34 cm/y ) , and another trial involving 1974 participants showed lower growth velocity in the budesonide group compared with the placebo group ( MD -0.33 cm/y , 95 % CI -0.52 to -0.14 , P value 0.0005 ) . Among four trials reporting data on linear growth after treatment cessation , three did not describe statistically significant catch-up growth in the ICS group two to four months after treatment cessation . One trial showed accelerated linear growth velocity in the fluticasone group at 12 months after treatment cessation , but there remained a statistically significant difference of 0.7 cm in height between the fluticasone and placebo groups at the end of the three-year trial . One trial with follow-up into adulthood showed that participants of prepubertal age treated with budesonide 400 μg/d for a mean duration of 4.3 years had a mean reduction of 1.20 cm ( 95 % CI -1.90 to -0.50 ) in adult height compared with those treated with placebo . AUTHORS ' CONCLUSIONS Regular use of ICS at low or medium daily doses is associated with a mean reduction of 0.48 cm/y in linear growth velocity and a 0.61-cm change from baseline in height during a one-year treatment period in children with mild to moderate persistent asthma . The effect size of ICS on linear growth velocity appears to be associated more strongly with the ICS molecule than with the device or dose ( low to medium dose range ) . ICS-induced growth suppression seems to be maximal during the first year of therapy and less pronounced in subsequent years of treatment . However , additional studies are needed to better characterise the molecule dependency of growth suppression , particularly with newer molecules ( mometasone , ciclesonide ) , to specify the respective role of molecule , daily dose , inhalation device and patient age on the effect size of ICS , and to define the growth suppression effect of ICS treatment over a period of several years in children with persistent asthma . PLAIN LANGUAGE SUMMARY Do inhaled corticosteroids reduce growth in children with persistent asthma ? Review question : We review ed the evidence on whether inhaled corticosteroids ( ICS ) could affect growth in children with persistent asthma , that is , a more severe asthma that requires regular use of medications for control of symptoms . BACKGROUND Treatment guidelines for asthma recommend ICS as first-line therapy for children with persistent asthma . Although ICS treatment is generally considered safe in children , parents and physicians always remain concerned about the potential negative effect of ICS on growth . Search date : We search ed trials published until January 2014 . Study characteristics : We included in this review trials comparing daily use of corticosteroids , delivered by any type of inhalation device for at least three months , versus placebo or non-steroidal drugs in children up to 18 years of age with persistent asthma . KEY RESULTS Twenty-five trials involving 8471 children with mild to moderate persistent asthma ( 5128 treated with ICS and 3343 treated with placebo or non-steroidal drugs ) were included in this review . Eighty percent of these trials were conducted in more than two different centres and were called multi-centre studies ; five were international multi-centre studies conducted in high-income and low-income countries across Africa , Asia-Pacifica , Europe and the Americas . Sixty-eight percent were financially supported by pharmaceutical companies . Meta- analysis ( a statistical technique that combines the results of several studies and provides a high level of evidence ) suggests that children treated daily with ICS may grow approximately half a centimeter per year less than those not treated with these medications during the first year of treatment . The magnitude of ICS-related growth reduction may depend on the type of drug . Growth reduction seems to be maximal during the first year of therapy and less pronounced in subsequent years of treatment . Evidence provided by this review allows us to conclude that daily use of ICS can cause a small reduction in height in children up to 18 years of age with persistent asthma ; this effect seems minor compared with the known benefit of these medications for asthma control . QUALITY OF EVIDENCE Eleven of 25 trials did not report how they guaranteed that participants had an equal chance of receiving ICS or placebo or non-steroidal drugs . All but six trials did not report how research ers were kept unaware of the treatment assignment list . However , this method ological limitation may not significantly affect the quality of evidence because the results remained almost unchanged when we excluded these trials from the analysis [12567387] We set out to evaluate lung deposition , systemic availability , and basic pharmacokinetic parameters of beclomethasone dipropionate ( BDP ) in children with chronic asthma . Plasma levels of BDP , 17 and 21 beclomethasone monopropionate ( 17-BMP and 21-BMP ) , and beclomethasone were measured after an intravenous infusion of 60 microg BDP and after inhalation of A ) 100 microg HFA-BDP , B ) 200 microg HFA-BDP , C ) 200 microg HFA-BDP after ingestion of charcoal to block gastrointestinal ( GI ) absorption of drug , and D ) 400 microg CFC-BDP . A breath-actuated pMDI ( Autohaler ) was used for HFA inhalations , and a pMDI with a large volume spacer ( Volumatic ) for CFC inhalations . Treatments A-D were given in a r and omized , cross-over design . Fourteen patients aged 10 - 14 years completed all 5 study days . The mean systemic bioavailabilities in percent of dose leaving the canister valve ( ex-valve ) were 70 % ( 100 HFA ) , 74 % ( 200 HFA ) , 60 % ( 200 HFA + charcoal ) , and 27 % ( 400 microg CFC ) . After HFA treatment , 82 % of the systemically available dose was absorbed through the lungs , and 18 % from the gastrointestinal tract . The estimated bioavailability of BDP from the GI tract was 68 % . BDP was metabolized to 17-BMP within minutes . Mean steady-state volume of distribution of 17-BMP was 84 L , and the mean terminal half-life ( T((1/2 ) ) ) after the four inhalations was 2.7 hr ( range , 2.2 - 3.7 hr ) . Mean T((1/2 ) ) and clearance after i.v . administration were 1.7 hr and 0.9 L/min , respectively . The HFA Autohaler delivers approximately three times as much BDP to the intrapulmonary airways as a CFC-pMDI with a large volume spacer [16860173] BACKGROUND Ciclesonide is a new lung-activated inhaled corticosteroid ( ICS ) that has shown efficacy in previous placebo-controlled and comparative studies in patients with persistent asthma . It is important to compare new treatments with existing ICSs to obtain relative data concerning their efficacy and tolerability . OBJECTIVE This study compared the efficacy and tolerability of ciclesonide QD with budesonide BID in patients with asthma . METHODS This 12-week , r and omized study was conducted at 62 study sites across Europe . Male and female patients aged 12 to 75 years with primarily mild to moderate asthma were enrolled . This study was double blind with respect to the ciclesonide dose and open label for budesonide , as placebofor budesonide was not available . Patients were r and omly assigned to receive inhaled ciclesonide 80 or 320 microg QD ( morning ) or budesonide 200 microg BID for 12 weeks . Efficacy and tolerability assessment s were performed at weeks 0 ( baseline ) , 4 , 8 , and 12 . The primary end point was the change from baseline in forced expiratory volume in 1 second ( FEV1 ) at 12 weeks . Secondary end points were changes from baseline in morning peak expiratory flow ( PEF ) , asthma symptom scores , and rescue medication use . Tolerability was assessed throughout the study by monitoring of st and ard laboratory variables ( hematology and biochemistry ) ; physical examination , including vital signs ; reporting of adverse events ( AEs ) ; and 24-hour urinary cortisol as a measure of hypothalamic-pituitary-adrenal-axis function . RESULTS Five hundred fifty-four patients were r and omized ( 301 men , 253 women ; mean age , 41.3 years ; ciclesonide 80 microg QD , 182 patients ; ciclesonide 320 microg QD , 195 ; budesonide 200 microg BID , 177 ) . Demographic and baseline clinical characteristics , including age , sex , weight , and ( FEV1 ) were similar between the 3 groups . Compared with baseline values , week-12 FEV1 ( least squares mean [ LSM ] [ SEM ] A , + 0.267 [ 0.035 ] , + 0.256 [ 0.033 ] , and + 0.355 [ 0.034 ] L , respectively ; all , P<0.001 ) and morning PEF ( LSM [ SEM ] Delta , + 12 [ 5 ] , + 17 [ 4 ] , and + 21 [ 4 ] L/min , respectively ; all , P < or=0.008 ) were significantly improved with ciclesonide 80 and 320 microg QD and budesonide 200 microg BID . At 12 weeks , ciclesonide was found to be noninferior to budesonide with regard to mean changes from baseline in ( FEV1 ) ( intent to treat [ ITT ] : 97.5 % CI for ciclesonide 80 microg QD vs budesonide 200 microg BID , -0.192 to 0.015 ; 97.5 CI for ciclesonide 320 microg QD vs budesonide 200 microg BID , -0.200 to 0.001 ) and morning PEF ( ITT . 97.5 % CI for ciclesonide 80 microg QD vs budesonide 200 microg BID , -22 to 5 ; 97.5 % CI for ciclesonide 320 microg QD vs budesonide 200 microg BID , -17 to 10 ) . Similar findings were seen in the per- protocol population . Week-12 daily , daytime , and nighttime asthma symptom scores and rescue medication use were significantly decreased from baseline in all 3 treatment groups ( all , P<0.001 ) . The prevalences of AEs were similar across all 3 treatment groups . Week-12 mean urinary cortisol excretion was statistically similar to baseline with both ciclesonide doses ( Delta , -0.54 and + 0.16 nmol/mmol creatinine with ciclesonide 80 and 320 microg QD , respectively ) but was significantly reduced from baseline with budesonide ( Delta , -1.42 nmol/mmol creatinine ; P<0.05 ) . CONCLUSIONS The results of this study in patients with primarily mild to moderate asthma suggest that ciclesonide 80 and 320 microg QD were similar to budesonide 200 microg BID in improving pulmonary function , controlling asthma symptoms , and reducing the need for rescue medication use . Unlike budesonide , ciclesonide was not associated with significant urinary cortisol suppression in these patients [8546510] OBJECTIVES --To assess bone and collagen turnover in asthmatic children treated with dry powder budesonide from the Turbuhaler and dry powder beclomethasone dipropionate from the Diskhaler in a dose of 800 micrograms/day . SUBJECTS -- Thirteen prepubertal children with asthma . DESIGN --Open crossover study with two treatment periods and treatment free run-in and wash-out periods . All periods were of two weeks ' duration . At day 14 in each period blood sample s were taken for assessment of serum osteocalcin , the carboxyterminal propeptide of type I collagen ( PICP ) , and the aminoterminal propeptide of type III collagen ( PIIINP ) . At the same time urine was collected for assessment of creatinine corrected pyridinoline ( uPYR/cr ) and deoxypyridinoline ( udPYR/cr ) crosslinks . RESULTS --Osteocalcin concentrations were not influenced by any of the treatments . During budesonide treatment mean ( SEM ) PICP was reduced by 18 % ( 8 % ) ( p = 0.03 ) , PIIINP by 24 % ( 3 % ) ( p = 0.0002 ) , uPYR/cr by 16 % ( 6 % ) ( p = 0.03 ) , and udPYR/cr by 21 % ( 13 % ) ( p = 0.12 ) . During treatment with beclomethasone dipropionate mean ( SEM ) PICP was reduced by 20 % ( 6 % ) ( p = 0.01 ) , PIIINP by 36 % ( 3 % ) ( p = 0.0002 ) , uPYR/cr by 18 % ( 4 % ) ( p = 0.004 ) , and udPYR by 13 % ( 5 % ) ( p = 0.02 ) . The suppressive effect of beclomethasone dipropionate on PIIINP was more marked than that of budesonide ( p = 0.001 ) . CONCLUSION --Treatment with dry powder budesonide and beclomethasone dipropionate 800 micrograms/day is associated with suppression of bone and collagen turnover . The suppression seems to be more marked during treatment with beclomethasone dipropionate . Long term effects and effects of lower doses of budesonide and beclomethasone dipropionate on bone and collagen markers needs further study [10507269] BACKGROUND Inhaled glucocorticosteroids ( GCS ) are the most effective long-term controller medications for the treatment of persistent asthma . Currently , however , available delivery devices limit their use in young children . A nebulized formulation of budesonide has been developed to address the needs of infants and young children . OBJECTIVE To evaluate the efficacy and safety of once-daily budesonide inhalation suspension in children 6 months to 8 years old with mild persistent asthma not on inhaled GCS . METHODS Three hundred fifty-nine children were r and omized to receive once-daily budesonide inhalation suspension ( 0.25 mg , 0.50 mg , or 1.0 mg ) or placebo via a Pari LC-Jet Plus nebulizer for 12 weeks . Efficacy assessment s included nighttime/daytime asthma symptoms , pulmonary function ( subset of patients ) , rescue medication use , and treatment discontinuations . Safety was based on adverse events and assessment of HPA-axis function . RESULTS Demographics , baseline characteristics , asthma symptoms , and pulmonary function were similar across treatment groups . Mean nighttime/daytime asthma symptom scores were 1.19 + /- 0.63 and 1.34 + /- 0.53 , respectively . Mean duration of asthma was 36.3 months and mean FEV1 was 81.3 % of predicted with 27.7 % reversibility . Following 12 weeks of treatment , all budesonide inhalation suspension doses produced significant improvements in nighttime/daytime symptoms ( P < or = .049 ) and significant decreases in rescue medication use ( P < or = .038 ) compared with placebo . Significant improvements ( P < or = .044 ) in FEV1 were observed in the 0.5- and 1.0-mg budesonide inhalation suspension groups . There were no differences between doses of budesonide inhalation suspension . Adverse events and basal and ACTH-stimulated cortisol levels were similar among all groups . CONCLUSION Once-daily administration of budesonide inhalation suspension was well tolerated and effective for the treatment of mild persistent asthma in infants and young children not adequately controlled with bronchodilators or non-GCS antiinflammatory treatments [15065610] OBJECTIVE To evaluate the effects of treatment with fluticasone propionate vs placebo on bone , hypothalamic-pituitary-adrenal ( HPA ) axis function , and the eyes in patients with asthma . PATIENTS AND METHODS This r and omized , double-blind , placebo-controlled study of 160 patients with asthma who had minimal previous exposure to corticosteroids was conducted from July 1994 through June 1997 . Patients received fluticasone at 88 microg twice daily , fluticasone at 440 microg twice daily , or placebo twice daily for 2 years . Bone mineral density ( BMD ) was evaluated every 6 months by lumbar spine , proximal femur , and total body scans . Measurements of HPA axis function and ophthalmic evaluations were conducted at similar intervals . RESULTS Among the 3 groups , no significant differences were observed in BMD at week 104 ( at any anatomical site ) . Mean percent change from baseline in the lumbar spine was less than 1 % for all 3 groups . At all time points , HPA axis function was similar in the 88-microg fluticasone group compared with the placebo group . For mean change from baseline in corticotropin-stimulated peak cortisol ( P = .003 and P = .02 at weeks 24 and 52 , respectively ) and area under the stimulated plasma cortisol vs time curve ( P = .002 and P = .02 at weeks 24 and 52 , respectively ) , statistically significant reductions from baseline were observed in the 440-microg fluticasone group compared with the placebo group . These reductions of 10 % to 13 % from baseline were not accompanied by other signs of systemic effect and did not persist with continued treatment ( at weeks 76 and 104 ) . No important ocular changes were observed . CONCLUSION Long-term treatment with 88 microg of fluticasone twice daily was comparable to placebo in all skeletal , ophthalmic , and HPA axis function assessment s. Treatment with fluticasone at 440 microg twice daily result ed in no significant effects on BMD and a statistically significant but not clinical ly important temporary reduction in cortisol production [18266402] Background and objective : The efficacy and safety of twice-daily inhaled salmeterol/fluticasone propionate combination ( SFC ) therapy have been well established in the treatment of adults and adolescents with asthma . Once-daily administration of SFC could also be appropriate in patients with mild persistent asthma . This study aim ed to investigate whether once-daily SFC 50 μg/100 μg was at least as effective as fluticasone propionate ( FP ) 100 μg twice daily , and more effective than twice-daily placebo , over 52 weeks as initial maintenance therapy in patients with mild persistent asthma . Methods : This was a r and omized , double-blind , double-dummy , placebo-controlled , multicentre , parallel-group study carried out in primary and secondary care . Patients aged between 12 and 79 years with a documented clinical history of asthma for ≥6 months who were currently receiving inhaled short-acting β2-adrenoceptor agonists only were enrolled . Patients were r and omized to receive either once-daily inhaled SFC 50 μg/100 μg , twice-daily inhaled FP 100 μg ( i.e. twice the dose of FP compared with SFC ) or placebo for 52 weeks . The primary efficacy endpoints were mean morning peak expiratory flow ( PEF ) , as recorded by patients prior to the use of bronchodilator or study medication , and the rate of investigator-recorded asthma exacerbations . Results : Patients receiving twice-daily FP and once-daily SFC showed greater improvements in mean morning PEF compared with those receiving placebo ( FP , difference in means 20.1 L/min ; 95 % CI 14.7 , 25.5 ; p < 0.001 ; SFC , difference in means 14.8 L/min ; 95 % CI 9.4 , 20.2 ; p < 0.001 ) . The difference in adjusted mean PEF between once-daily SFC and twice-daily FP was —5.3 L/min ( 95 % CI −9.1,−1.6 ) . PEF results showed that once-daily SFC was non-inferior to twice-daily FP . Over 52 weeks , there was a 35 % reduction in exacerbation rates with once-daily SFC , which in this respect demonstrated superiority over placebo ( p < 0.001 ) . Non-inferiority between once-daily SFC and twice-daily FP with respect to exacerbation rates was not shown . Once-daily SFC significantly improved clinic forced expiratory flow between 25 % and 75 % of forced vital capacity ( difference in means 0.129 L/s ; p < 0.001 ) and clinic PEF ( difference in means 10.8 L/min ; p < 0.001 ) compared with twice-daily FP . Both treatments were well tolerated and the safety profile of each was similar to that seen with placebo . Conclusion : In patients with mild persistent asthma not previously receiving maintenance therapy , once-daily SFC 50 μg/100 μg is an effective treatment compared with placebo , and was non-inferior to twice-daily FP 100 μg with respect to mean morning PEF . However , in this study , once-daily SFC was not as efficacious as twice-daily FP in reducing asthma exacerbation rates . This study confirms the benefits of regular maintenance treatment in patients with mild persistent asthma [16802768] BACKGROUND Current asthma guidelines recommend inhaled glucocorticoids administered via pressurized metered-dose inhaler ( MDI ) with a holding chamber as the preferred therapy for young children with asthma . OBJECTIVE To evaluate the efficacy and safety of fluticasone propionate chlorofluorocarbon MDI use in preschool-aged children with asthma . METHODS R and omized , double-blind , placebo-controlled , parallel-group study of 332 children aged 24 to 47 months with asthma . Fluticasone propionate chlorofluorocarbon , 44 or 88 microg twice daily , or placebo ( chlorofluorocarbon propellant alone ) administered for 12 weeks via MDI with a valved holding chamber and an attached face mask . The primary efficacy measure was average change in 24-hour daily asthma symptom scores . Safety assessment s included adverse events , 12-hour urinary cortisol excretion , and growth . RESULTS Treatment failure ( ie , asthma exacerbation ) occurred in approximately half as many fluticasone propionate-treated patients ( 13%-14 % ) as placebo-treated patients ( 24 % ) . Compared with placebo users , patients treated with fluticasone propionate , 88 microg twice daily , had a 13 % greater improvement in the mean proportion of symptom- and albuterol-free days ( P = .02 ) ; asthma symptom scores and albuterol use were also significantly reduced . Patients treated with fluticasone propionate , 44 microg twice daily , had greater improvements than placebo-treated patients ; however , differences did not reach statistical significance . At end point , the growth velocities of fluticasone propionate-treated patients were within the range of those of placebo-treated patients . No clinical ly relevant changes in 12-hour overnight urinary cortisol excretion were observed . CONCLUSION Compared with placebo use , fluticasone propionate , 88 microg administered twice daily , significantly reduced asthma exacerbations , asthma symptoms , and rescue albuterol use and was well tolerated , with no clinical ly relevant systemic effects , as measured by growth velocity or 12-hour urinary cortisol excretion levels [17140647] BACKGROUND More evidence is needed on which to base recommendations for treatment of mild-moderate persistent asthma in school-aged children . OBJECTIVE The Pediatric Asthma Controller Trial ( PACT ) compared the effectiveness of 3 regimens in achieving asthma control . METHODS A total of 285 children ( ages 6 - 14 years ) with mild-moderate persistent asthma on the basis of symptoms , and with FEV(1 ) > or= 80 % predicted and methacholine FEV(1 ) PC(20 ) < or= 12.5 mg/mL , were r and omized to 1 of 3 double-blind 48-week treatments : fluticasone 100 microg twice daily ( fluticasone monotherapy ) , fluticasone 100 microg/salmeterol 50 microg in the morning and salmeterol 50 mug in the evening ( PACT combination ) , and montelukast 5 mg in the evening . Outcomes included asthma control days ( primary outcome ) , exacerbations , humanistic measurements , and pulmonary function measurements . RESULTS Fluticasone monotherapy and PACT combination were comparable in many patient-measured outcomes , including percent of asthma control days , but fluticasone monotherapy was superior for clinic-measured FEV(1)/forced vital capacity ( P = .015 ) , maximum bronchodilator response ( P = .009 ) , exhaled nitric oxide ( P < .001 ) , and PC(20 ) ( P < .001 ) . Fluticasone monotherapy was superior to montelukast for asthma control days ( 64.2 % vs 52.5 % ; P = .004 ) and for all other control outcomes . Growth over 48 weeks was not statistically different ( fluticasone , 5.3 cm ; PACT combination , 5.3 cm ; montelukast , 5.7 cm ) . CONCLUSION Both fluticasone monotherapy and PACT combination achieved greater improvements in asthma control days than montelukast . However , fluticasone monotherapy was superior to PACT combination in achieving other dimensions of asthma control . Growth was similar in all groups . CLINICAL IMPLICATION S Therefore , of the regimens tested , the PACT study findings favor fluticasone monotherapy in treating children with mild-moderate persistent asthma with FEV(1 ) > or= 80 % predicted , confirming current guideline recommendations [4352726] Thirty-one chronic perennial asthmatics aged from 2½ to 16 years were treated with beclomethasone dipropionate pressurized aerosols for up to 20 months . Of these , 16 patients dependent on oral corticosteroid or corticotrophin for up to 11 years were successfully transferred to this treatment , with one exception . Steroid withdrawal symptoms were slight . Loss of weight , disappearance of Cushingoid features , and resumption of growth indicated lack of systemic side effects . Fifteen others inadequately controlled on bronchodilators or disodium cromoglycate , were also effectively treated , and no clinical evidence of adrenal suppression was noted [14730655] Our objective was to evaluate the efficacy and safety of two doses of fluticasone propionate ( FP ) in young children with recurrent wheezing and risk factors for asthma . Our study design was a r and omized , double-blind , placebo-controlled comparison of inhaled FP 50 mcg twice daily ( FP 100 ) and 125 mcg twice daily ( FP 250 ) , for 6 months . Outcome measures included number of wheezing episodes , days on albuterol , height st and ard deviation score ( height SDS ) , osteocalcin ( OC ) , bone alkaline phosphatase fraction ( AKP ) , insulin-like growth factor-binding protein 3 ( IGFBP-3 ) , and serum levels of cortisol ( SC ) . Our subjects were 30 patients , aged 7 - 24 months . Mean wheezing episodes were 6.0 + /- 1.9 , 1.9 + /- 1.9 , and 2.8 + /- 1.2 ; mean days of albuterol use were 24.3 + /- 1.3 , 6.5 + /- 0.8 , and 9.1 + /- 0.8 , per patient for placebo , FP100 , and FP250 groups , respectively . There was a significant reduction in clinical outcome in the two FP groups compared to placebo ( P < 0.01 ) . No significant correlations were found between FP dosage and height SDS , OC , AKP , IGFBP-3 , and SC . In conclusion , in young children with asthmatic symptoms , FP at 50 and 125 mcg b.i.d . for 6 months significantly improved respiratory symptoms without causing significant side effects on growth and bone metabolism [20619624] OBJECTIVE To evaluate the efficacy and safety of three doses of ciclesonide ( with or without spacer ) in children with persistent asthma . PATIENTS AND METHODS This was a multicentre , double-blind , placebo-controlled , 12-week study of ciclesonide 40 , 80 or 160 μg ( once daily pm ) . Children ( 6 - 11 years ) were r and omised 1:1 to treatment via a metered dose inhaler ( MDI ) or MDI plus spacer . The primary variable was change from baseline in mean morning peak expiratory flow ( PEF ) . Secondary variables included : time to first lack of efficacy ( LOE ) , asthma control , forced expiratory volume in 1 s ( FEV(1 ) ) , asthma symptom score and quality of life ( QoL ) . Safety assessment s included : adverse events ( AEs ) , urinary cortisol excretion and body height . RESULTS In total , 1073 children received treatment . At endpoint , mean morning PEF significantly improved with all doses of ciclesonide vs. placebo . There was no difference over placebo in time to first LOE , but ciclesonide was superior to placebo on asthma control , symptom score , FEV(1 ) and QoL. There were no differences between the spacer or non-spacer subgroups . The incidences of AEs were comparable between treatment groups ( approximately 35 % ) and there were no between-group differences in body height or urinary cortisol . CONCLUSIONS Ciclesonide 40 - 160 μg once daily is effective and well tolerated in children with persistent asthma ; its efficacy and safety are unaffected by the use of a spacer . clinical trials.gov registration number : NCT00384189 [21839625] BACKGROUND Few large-scale studies have examined inhaled corticosteroid treatment in preschool children with recurrent wheeze . We assessed the effects of ciclesonide in preschool children with recurrent wheeze . METHODS We included children 2 - 6 yrs with recurrent wheeze and a positive asthma predictive index or aeroallergen sensitization to , excluding patients with episodic viral wheezing . After a 2 - 4-week baseline period , patients with ongoing symptoms or rescue medication use were r and omised to once-daily ciclesonide 40 , 80 , 160 μg or placebo for 24 weeks . RESULTS The number of wheeze exacerbations requiring systemic corticosteroids was unexpectedly low in all groups : 25 ( 10.2 % ) in placebo group , as compared to 11 ( 4.4 % ) , 18 ( 7.3 % ) , and 17 ( 6.7 % ) in ciclesonide 40 , 80 , and 160 μg , respectively . The difference in time to first exacerbation was not significantly different between groups ( p = 0.786 ) , but the difference in exacerbation rates between placebo and the pooled ciclesonide groups was ( p = 0.03 ) . Large and significant ( p < 0.0001 ) improvements in symptom scores and rescue medication use occurred in all groups , including placebo . Improvements in FEV(1 ) and FEF(25 - 75 ) ( measured in 284 4 - 6 yr olds ) were larger in the ciclesonide than in the placebo group . No differences in safety parameters ( adverse events , height growth , serum and urinary cortisol levels ) between ciclesonide and placebo were observed . CONCLUSIONS In preschool children with recurrent wheeze and a positive asthma predictive index , ciclesonide modestly reduces wheeze exacerbation rates and improves lung function . A large placebo response and unexpected selection of patients with mild disease may have affected outcomes , highlighting the heterogeneity of preschool wheezing disorders [20569973] BACKGROUND Inhaled corticosteroid ( ICS ) nonadherence is common among patients with asthma ; however , interventions to improve adherence have often been complex and not easily applied to large patient population s. OBJECTIVE To assess the effect of supplying patient adherence information to primary care providers . METHODS Patients and providers were members of a health system serving southeast Michigan . Providers ( 88 intervention ; 105 control ) and patients ( 1335 intervention ; 1363 control ) were r and omized together by practice . Patients were age 5 to 56 years , had a diagnosis of asthma , and had existing prescriptions for ICS medication . Adherence was estimated by using prescription and fill data . Unlike clinicians in the control arm , intervention arm providers could view up date d ICS adherence information on their patients via electronic prescription software , and further details on patient ICS use could be viewed by selecting that option . The primary outcome was ICS adherence in last 3 months of the study period . RESULTS At the study end for the intention-to-treat analysis , ICS adherence was not different among patients in the intervention arm compared with those in the control arm ( 21.3 % vs 23.3 % , respectively ; P = .553 ) . However , adherence was significantly higher among patients whose clinician elected to view their detailed adherence information ( 35.7 % ) compared with both control arm patients ( P = .026 ) and intervention arm patients whose provider did not view adherence data ( P = .002 ) . CONCLUSIONS Overall , providing adherence information to clinicians did not improve ICS use among patients with asthma . However , patient use may improve when clinicians are sufficiently interested in adherence to view the details of this medication use [8979288] Correlations between knemometric ( lower leg length ) growth rates and urine free cortisol excretion , respectively , and serum concentrations of IGF-I , IGF binding protein-3 , osteocalcin , carboxy terminal propeptide of type I collagen(PICP ) , carboxy terminal pryridinoline cross-linked telopeptide of type I procollagen ( ICTP ) , and amino terminal propeptide of type III procollagen(PIIINP ) were investigated in 17 asthmatic children aged 7 - 14 y during treatment with fluticasone propionate , 200 μg , and beclomethasone dipropionate , 400 and 800 μg/d , taken from dry powder inhalers . The study was a double blind , crossover trial with three active treatment periods and two wash-out periods . All periods were 15 d long . Overnight urine free cortisol/creatinine × 106 did not correlate with knemometric growth rates or any of the serum markers . Significant correlations ( Pearson 's correlation coefficient , P ) between knemometric growth rates and IGF-I ( 0.41 ; 0.006 ) , IGFBP-3 ( 0.35 ; 0.02 ) , PICP ( 0.44 ; 0.003 ) , ICTP ( 0.35 ; 0.001 ) , and PIIINP ( 0.46 ; 0.002 ) were found . Compared with fluticasone propionate , 200 μg , beclomethasone dipropionate , 400 and 800 μg , caused significant suppression of lower leg growth rate ( F = 12.41;p = 0.002 , and F = 23.30 ; p = 0.0001 , respectively ) and of urine free cortisol/creatinine × 106(F = 10.52 ; p = 0.003 , and F = 13.74;p = 0.001 ) . Beclomethasone , 800 μg , caused suppression of PICP compared with fluticasone propionate , 200 μg ( F = 8.31;p = 0.008 ) , and beclomethasone , 400 μg ( F = 7.53;p = 0.01 ) . Both low ( F = 6.82 ; p = 0.02 ) and high ( F = 23.35 ; p = 0.0001 ) doses of beclomethasone were associated with reduced concentrations of ICTP , the high dose being the most suppressive ( F = 4.42 ; p = 0.05 ) . Beclomethasone 400(F = 9.75 ; p = 0.004 ) and 800 μg ( F = 23.61;p = 0.0001 ) result ed in reduced levels of PIIINP . Reduced short-term knemometric growth rates in children treated with inhaled glucocorticosteroids reflect suppressive effects on type I and type III collagen turnover Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Inhaled corticosteroids ( ICS ) are the first-line treatment for children with persistent asthma . Their potential for growth suppression remains a matter of concern for parents and physicians . OBJECTIVES To assess whether increasing the dose of ICS is associated with slower linear growth , weight gain and skeletal maturation in children with asthma . In view of prevailing parents ' and physicians ' concerns about the growth suppressive effect of ICS , lack of or incomplete reporting of growth velocity in more than 86 % ( 19/22 ) of eligible paediatric trials , including those using beclomethasone and budesonide , is a matter of concern . PLAIN LANGUAGE SUMMARY Does altering the dose of inhaled corticosteroids make a difference in growth among children with asthma ? BACKGROUND Asthma guidelines recommend inhaled corticosteroids ( ICS ) as the first choice of treatment for children with persistent asthma that is not well controlled when only a reliever inhaler is used to treat symptoms . Steroids work by reducing inflammation in the lungs and are known to control underlying symptoms of asthma . However , parents and physicians remain concerned about the potential negative effect of ICS on growth . REVIEW QUESTION Does altering the dose of inhaled corticosteroids make a difference in the growth of children with asthma ? We studied whether a difference could be seen in the growth of children with persistent asthma who were using different doses of the same ICS molecule and the same delivery device . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

31082325

[22286745] Purpose Treatment of large cartilage lesions of the knee in weight-bearing areas is still a controversy and challenging topic . Autologous osteochondral mosaicplasty has proven to be a valid option for treatment but donor site morbidity with most frequently used autografts remains a source of concern . This study aims to assess clinical results and safety profile of autologous osteochondral graft from the upper tibio-fibular joint applied to reconstruct symptomatic osteochondral lesions of the knee . Methods Thirty-one patients ( 22 men and 9 women ) with grade 4 cartilage lesions in the knee were operated by mosaicplasty technique using autologous osteochondral graft from the upper tibio-fibular joint , between 1998 and 2006 . Clinical assessment included visual analog scale ( VAS ) for pain and Lysholm score . All patients were evaluated by MRI pre- and post-operatively regarding joint congruency as good , fair ( inferior to 1 mm incongruence ) , and poor ( incongruence higher than 1 mm registered in any frame ) . Donor zone status was evaluated according to specific protocol considering upper tibio-fibular joint instability , pain , neurological complications , lateral collateral ligament insufficiency , or ankle complaints . Results Mean age at surgery was 30.1 years ( SD 12.2 ) . In respect to lesion sites , 22 were located in weight-bearing area of medial femoral condyle , 7 in lateral femoral condyle , 1 in trochlea , and 1 in patella . Mean follow-up was 110.1 months ( SD 23.2 ) . Mean area of lesion was 3.3 cm2 ( SD 1.7 ) , and a variable number of cylinders were used , mean 2.5 ( SD 1.3 ) . Mean VAS score improved from 47.1 ( SD 10.1 ) to 20.0 ( SD 11.5 ) ; p = 0.00 . Similarly , mean Lysholm score increased from 45.7 ( SD 4.5 ) to 85.3 ( SD 7.0 ) ; p = 0.00 . The level of patient satisfaction was evaluated , and 28 patients declared to be satisfied/very satisfied and would do surgery again , while 3 declared as unsatisfied with the procedure and would not su bmi t to surgery again . These three patients had lower clinical scores and kept complaints related to the original problem but unrelated to donor zone . MRI score significantly improved at 18–24 months comparing with pre-operative ( p = 0.004 ) . No radiographic or clinical complications related to donor zone with implication in activity were registered . Conclusions This work corroborates that mosaicplasty technique using autologous osteochondral graft from the upper tibio-fibular joint is effective to treat osteochondral defects in the knee joint . No relevant complications related to donor zone were registered . Level of evidence Case series , Level IV [4028546] Abstract Purpose To compare long-term functional and radiological outcome following microfracture technique ( MF ) versus osteochondral autologous transplantation ( OAT ) mosaicplasty for treating focal chondral lesions of the knee . Methods Twenty-five patients ( mean age 32.3 years , SD 7.7 ) with a full-thickness ( International Cartilage Repair Society grade 3 or 4 ) chondral lesion of the articulating surface of the femur were r and omized to either MF ( n = 11 ) or OAT mosaicplasty ( n = 14 ) . At a median follow-up of 9.8 years ( range 4.9–11.4 ) , the patients were evaluated using Lysholm score ( n = 25 ) , Knee Injury and Osteoarthritis Outcome Score ( KOOS , n = 25 ) , isokinetic quadriceps measurement and hamstring strength measurement ( n = 22 ) and st and ing radiographs ( n = 23 ) . Results There were no significant differences in Lysholm score , KOOS , isokinetic muscle strength or radiographic osteoarthritis between MF-treated patients and OAT mosaicplasty-treated patients at follow-up . Mean Lysholm score at follow-up was 69.7 [ 95 % confidence interval ( CI ) , 55.1–84.4 ] for the MF group and 62.6 ( 95 % CI , 52.6–72.6 ) for the OAT mosaicplasty group . Conclusion At long-term follow-up , there were no significant differences between patients treated with MF and patients treated with OAT mosaicplasty in patient-reported outcomes , muscle strength or radiological outcome .Level of evidence Therapeutic study , Level II [25002462] Background : Autologous chondrocyte implantation ( ACI ) has been shown to be effective in the midterm for the treatment of symptomatic articular cartilage lesions of the knee , but few long-term series have been published . The multioperated chronic articular cartilage defect remains a difficult condition to treat . Purpose : To examine the long-term clinical results of ACI for large chronic articular cartilage defects , many treated as salvage . Study Design : Case series ; Level of evidence , 4 . Methods : This is a prospect i ve case series of 104 patients with a mean age of 30.2 years and a symptomatic lesion of the articular cartilage in the knee , who underwent ACI between 1998 and 2001 . The mean duration of symptoms before surgery was 7.8 years . The mean number of previous surgical procedures on the cartilage defect , excluding arthroscopic debridement , was 1.3 . The defects were large , with a mean size of 477.1 mm2 ( range , 120 - 2500 mm2 ) . The modified Cincinnati , Stanmore/Bentley , and visual analog scale for pain scoring systems were used to assess pain and functional outcomes at a minimum 10 years ( mean , 10.4 years ; range , 10 - 12 years ) . Results : Twenty-seven patients ( 26 % ) experienced graft failure at a mean of 5.7 years after ACI . Of the 73 patients who did not fail , 46 patients ( 63 % of patients with a surviving graft ) had an excellent result , 18 ( 25 % ) were good , 6 ( 8 % ) were fair , and 3 ( 4 % ) had a poor result . Of a total of 100 patients successfully followed up , 98 were satisfied with the ACI technique for their chronic knee pain and would undergo the procedure again . Conclusion : Autologous chondrocyte implantation can provide a long-term solution in more than 70 % of young patients of a difficult-to-treat group with large chronic articular cartilage lesions , even in the salvage situation [4297133] Objective : Fresh osteochondral allograft transplantation ( OCA ) is an increasingly available option for patients with damage to the bone-cartilage complex of the distal femur . This study prospect ively assesses osseous integration and early clinical results following fresh OCA with single or multiple cylindrical grafts to the femoral condyle . Design : Patients with grade 4 International Cartilage Repair Society ( ICRS ) defects of the distal femur were treated with OCA . Outcome measures were collected preoperatively and postoperatively at 6 , 12 , and 24 months . Computed tomography ( CT ) scans obtained at 6 months were used to assess degree of osseous incorporation regionally . Results : Thirty-four patients , with a mean age of 34.5 years ( range , 15 - 61 ) , with a mean femoral osteochondral lesion of 5.7 cm2 ( range , 1.5 - 15.0 ) due to focal osteoarthritis , osteochondritis dissecans , and avascular necrosis , are reported . Statistically significant ( P < 0.05 ) mean improvement in outcome scores at 2 years included Knee Injury and Osteoarthritis Outcomes Score ( KOOS ) pain , sports and recreation , quality of life , and International Knee Documentation Committee ( IKDC ) . CT imaging indicated grafts implanted to direct weightbearing regions had > 75 % incorporation ( 20/26 grafts ) compared to < 50 % incorporation in the indirect weightbearing regions ( 8/14 grafts ) . A greater degree of incorporation and earlier outcome improvement were found after single ( n = 23 ) compared to multiple ( n = 11 ) grafts . Conclusion : CT scans were used to assess osseous incorporation of fresh osteochondral allografts in a cohort that showed significant improvements after 2 years . Single-graft implantation is associated with stable incorporation of a greater percentage of the graft . Lesser incorporation appears more frequently with grafts in posterior indirect weightbearing regions of the condyle and multiple contiguous grafts [21460066] Background : There are currently several approaches being pursued to treat focal defects of articular cartilage , each having specific advantages or challenges . A single-stage procedure that uses autologous cartilage fragments , Cartilage Autograft Implantation System ( CAIS ) , is being evaluated in patients and may offer a clinical ly effective option . Purpose : To establish the safety of CAIS and to test whether CAIS improves quality of life by using st and ardized outcomes assessment tools . Study Design : R and omized controlled trial ; Level of evidence , 2 . Methods : Patients ( n = 29 ) were r and omized ( 1:2 ) with the intent to treat with either a control ( microfracture [ MFX ] ) or an experimental ( CAIS ) procedure . Patients were followed at predetermined time points for 2 years using several st and ardized outcomes assessment tools ( SF-36 , International Knee Documentation Committee [ IKDC ] , Knee injury and Osteoarthritis Outcome Score [ KOOS ] ) . Magnetic resonance imaging was performed at baseline , 3 weeks , and 6 , 12 , and 24 months . Results : Lesion size and International Cartilage Repair Society ( ICRS ) grade were similar in both groups . General outcome measures ( eg , physical component score of the SF-36 ) indicated an overall improvement in both groups , and no differences in the number of adverse effects were noted in comparisons between the CAIS and MFX groups . The IKDC score of the CAIS group was significantly higher ( 73.9 ± 14.72 at 12 months and 82.95 ± 14.88 at 24 months ) compared with the MFX group ( 57.78 ± 18.31 at 12 months and 59.5 ± 13.44 at 24 months ) . Select subdomains ( 4/5 ) in the KOOS instrument were significantly different at 12 and 18 months , and all subdomains ( Symptoms and Stiffness , Pain , Activities of Daily Living , Sports and Recreation , Knee-related Quality of Life ) were significantly increased at 24 months in CAIS with scores of 88.47 ± 11.68 , 90.64 ± 7.87 , 97.29 ± 3.8 , 78.16 ± 22.06 , and 69 ± 23.15 compared with 75 ± 9.31 , 78.94 ± 13.73 , 89.46 ± 8.13 , 51.67 ± 26.01 , and 37.15 ± 21.67 in the MFX group . These significant improvements were maintained at 24 months in both IKDC and KOOS . Qualitative analysis of the imaging data did not note differences between the 2 groups in fill of the graft bed , tissue integration , or presence of subchondral cysts . Patients treated with MFX had a significantly higher incidence of intralesional osteophyte formation ( 54 % and 70 % of total number of lesions treated ) at 6 and 12 months when compared with CAIS ( 8 % and 25 % of total number of lesions treated ) . Conclusion : The first clinical experience in using CAIS for treating patients with focal chondral defects indicates that it is a safe , feasible , and effective method that may improve long-term clinical outcomes [19846693] Background There is no consensus about the optimal time for weightbearing activities after matrix-associated autologous chon-drocyte implantation ( MACI ) of the femoral condyle . Hypothesis A comprehensive protocol after MACI on the femoral condyle with accelerated weightbearing leads to a better functional and radiographic outcome compared with the same comprehensive protocol with delayed weightbearing . Study Design R and omized controlled trial ; Level of evidence , 1 . Methods Thirty-one patients ( 22 male , 9 female ) after MACI on the femoral condyle were r and omly assigned to the accelerated weightbearing group ( group A ) or the delayed weightbearing group ( group B ) . Aside from increase and time of full weightbearing , both groups adhered to the same rehabilitation protocol and exercises . Patients were assessed preoperatively and at 4 , 12 , 24 , 52 , and 104 weeks after surgery . Clinical evaluation was performed by determining the subjective form of the International Knee Documentation Committee ( IKDC ) , the Tegner activity scale , and the Knee Injury and Osteoarthritis Outcome Score ( KOOS ) . Radiological outcome was evaluated by the MOCART score and the size and amount of bone marrow edema and effusion . Results In both groups , there were no differences with regard to the clinical outcome . For the radiological outcome , group A showed a higher prevalence of bone marrow edema after 6 months without correlation to the clinical outcome ( P 5 .06-.1 ) . However , after 104 weeks , there were no differences in the radiological outcome between group A and group B. Conclusion A rehabilitation protocol with accelerated weightbearing leads to good clinical and functional outcome after 2 years without jeopardizing the healing graft [25482347] BACKGROUND This study aims to document the long-term results in a group of patients treated with arthroscopic mosaicplasty for knee cartilage lesions , both in terms of clinical outcome and joint degeneration progression , evaluated by radiographs . METHODS 26 patients ( 19 men and 7 women , mean age 29 years , mean BMI 23 ) treated arthroscopically with mosaicplasty for cartilage defects of the femoral condyles ( mean/median/mode size 1.9 st and ard deviation , SD 0.6 cm(2 ) ) were prospect ively evaluated at 12 years follow-up . The clinical outcome was analyzed with IKDC and Tegner scores . Range of motion , transpatellar and suprapatellar circumferences were also measured . Radiographs with weight-bearing antero-posterior and Rosenberg projections were used for radiological evaluation in 18 patients , applying both Kellgren-Lawrence score and a direct joint line measurement to assess osteoarthritis . RESULTS A significant improvement in all clinical scores was obtained from the basal evaluation to the 12-year follow-up ( IKDC subjective score from 36.8 st and ard deviation , SD 13.0 to 77.3 st and ard deviation , SD 20.6 , P<0.0005 ; Tegner score from 2.9 st and ard deviation , SD 1.3 to 5.2 st and ard deviation , SD 2.5 , P<0.0005 ) , and better results in patients with a higher pre-injury activity level and those requiring fewer plugs . The radiographic evaluation showed significantly poorer Kellgren-Lawrence scores and a reduction of the joint line in the treated compartments . Knees with 3 - 4 plugs presented a significantly higher joint degeneration level with respect to those implanted with 1 - 2 plugs . CONCLUSIONS Mosaicplasty is an effective surgical option for small lesions of the femoral condyles . Although joint degeneration progression was present at 12 years , this did not affect significantly the clinical outcome which was satisfactory at long-term follow-up [22637204] BACKGROUND Despite introduction of autologous chondrocyte therapy for repair of hyaline articular cartilage injury in 1994 , microfracture remains a primary st and ard of care . NeoCart , an autologous cartilage tissue implant , was compared with microfracture in a multisite prospect i ve , r and omized trial of a tissue-engineered bioimplant for treating articular cartilage injuries in the knee . METHODS Thirty patients were r and omized at a ratio of two to one ( two were treated with an autologous cartilage tissue implant [ NeoCart ] for each patient treated with microfracture ) at the time of arthroscopic confirmation of an International Cartilage Repair Society ( ICRS ) grade -III lesion(s ) . Microfracture or cartilage biopsy was performed . NeoCart , produced by seeding a type-I collagen matrix scaffold with autogenous chondrocytes and bioreactor treatment , was implanted six weeks following arthroscopic cartilage biopsy . St and ard evaluations were performed with vali date d clinical outcomes measures . RESULTS Three , six , twelve , and twenty-four-month data are reported . The mean duration of follow-up ( and st and ard deviation ) was 26 ± 2 months . There were twenty-one patients in the NeoCart group and nine in the microfracture group . The mean age ( 40 ± 9 years ) , body mass index ( BMI ) ( 28 ± 4 kg/m2 ) , duration between the first symptoms and treatment ( 3 ± 5 years ) , and lesion size ( 287 ± 138 mm2 in the NeoCart group and 252 ± 135 mm2 in the microfracture group ) were similar between the groups . Adverse event rates per procedure did not differ between the treatment arms . The scores on the Short Form-36 ( SF-36 ) , Knee Injury and Osteoarthritis Outcome Score ( KOOS ) activities of daily living ( ADL ) scale , and International Knee Documentation Committee ( IKDC ) form improved from baseline ( p < 0.05 ) to two years postoperatively in both treatment groups . In the NeoCart group , improvement , compared with baseline , was significant ( p < 0.05 ) for all measures at six , twelve , and twenty-four months . Improvement in the NeoCart group was significantly greater ( p < 0.05 ) than that in the microfracture group for the KOOS pain score at six , twelve , and twenty-four months ; the KOOS symptom score at six months ; the IKDC , KOOS sports , and visual analog scale ( VAS ) pain scores at twelve and twenty-four months ; and the KOOS quality of life ( QOL ) score at twenty-four months . Analysis of covariance ( ANCOVA ) at one year indicated that the change in the KOOS pain ( p = 0.016 ) and IKDC ( p = 0.028 ) scores from pretreatment levels favored the NeoCart group . Significantly more NeoCart-treated patients ( p = 0.0125 ) had responded to therapy ( were therapeutic responders ) at six months ( 43 % versus 25 % in the microfracture group ) and twelve months ( 76 % versus 22 % in the microfracture group ) . This trend continued , as the proportion of NeoCart-treated patients ( fifteen of nineteen ) who were therapeutic responders at twenty-four months was greater than the proportion of microfracture-treated participants ( four of nine ) who were therapeutic responders at that time . CONCLUSIONS This r and omized study suggests that the safety of autologous cartilage tissue implantation , with use of the NeoCart technique , is similar to that of microfracture surgery and is associated with greater clinical efficacy at two years after treatment [12571292] Background : Current methods used to restore the joint surface in patients with localized articular cartilage defects include transplantation of an autologous osteochondral cylinder and implantation of autologous chondrocytes . The purpose of this study was to evaluate the clinical and histological outcomes of these two techniques . Methods : We performed a prospect i ve clinical study to investigate the two-year outcomes in forty patients with an articular cartilage lesion of the femoral condyle who had been r and omly treated with either transplantation of an autologous osteochondral cylinder or implantation of autologous chondrocytes . Biopsy specimens from representative patients of both groups were evaluated with histological staining , immunohistochemistry , and scanning electron microscopy . Results : According to the postoperative Lysholm score , the recovery after autologous chondrocyte implantation was slower than that after osteochondral transplantation at six months ( p ⩽ 0.015 ) , twelve months ( p ⩽ 0.001 ) , and twenty-four months ( p ⩽ 0.012 ) . On the basis of the Meyers score and the Tegner activity score , the results were equally good with the two methods two years after treatment . Histomorphological evaluation of biopsy specimens within two years after autologous chondrocyte implantation demonstrated a complete , mechanically stable resurfacing of the defect in all patients . The tissue consisted mainly of fibrocartilage , while localized areas of hyaline-like regenerative cartilage could be detected close to the subchondral bone . Although a gap remained at the site of the transplantation in all five biopsy specimens examined as long as two years after osteochondral cylinder transplantation , histomorphological analysis and scanning electron microscopy revealed no differences between the osteochondral transplants and the surrounding original cartilage . Conclusions : Both treatments result ed in a decrease in symptoms . However , the improvement provided by the autologous chondrocyte implantation lagged behind that provided by the osteochondral cylinder transplantation . Histologically , the defects treated with autologous chondrocyte implantation were primarily filled with fibrocartilage , whereas the osteochondral cylinder transplants retained their hyaline character , although there was a persistent interface between the transplant and the surrounding original cartilage . Limitations of our study included the small number of patients , the relatively short ( two-year ) follow-up , and the absence of a control group . Level of Evidence : Therapeutic study , Level II-2 ( poor- quality r and omized controlled trial [ e.g. , < 80 % follow-up ] ) . See Instructions to Authors for a complete description of levels of evidence [12012034] Abstract . Background and aims : Large osteochondral defects in the weight-bearing zone of the knee remain a challenging therapeutic problem . Surgical options include drilling , microfracturing , and transplantation of osteochondral plugs but are often insufficient for the treatment of large defects of the femoral condyle . Patients and methods : Large osteochondral defects of the femoral condyle ( mean defect size 7.2 cm2 range 3–20 ) were treated by transplantation of the autologous posterior femoral condyle . Between 1984 and 2000 , 29 patients were operated on : in 22 the medial , in 6 the lateral femoral condyle , and in one the trochlear groove was grafted . Thirteen patients underwent simultaneous high tibial valgus osteotomy . In the first series ( 1984–1999 ) the graft was temporarily fixed with a screw ( n=12 ) , but from 1999 we used a newly developed press-fit technique ( n=17 ) avoiding screw fixation of the graft . The operative technique comprising graft harvest , defect preparation , transplantation , and fixation is described . Patients were clinical ly evaluated using the Lysholm score , and magnetic resonance imaging with intravenous contrast was performed 6 and 12 weeks after surgery ( mean follow-up 17.7 months ( range 3–46 ) . Results : Pain and swelling were reduced in 26 patients . Three patients of the first series reported persistent problems and were subjectively not satisfied . The mean Lysholm score rose from preoperatively 52 to 77 points after 3 months , 74 after 6 , 88 after 12 , and 95 after 18 . Magnetic resonance imaging showed good graft viability in all cases . We saw one arthrofibrosis after 6 months but noted no problems related to the loss of the missing posterior condyle . Conclusion : Large osteochondral defects of the femoral condyle can be treated by transplantation of the autologous posterior femoral condyle . The use of only one osteochondral piece renders better approximation of the femoral cartilage curvature and thus joint congruence than in mosaic plasty . However , whether loss of the posterior condyle has a long-term negative impact on the knee joint remains to be eluci date [24664138] Background : Matrix-associated autologous chondrocyte transplantation ( MACT ) has become an established articular cartilage repair technique . It provides good short-term and midterm results ; however , long-term results are lacking . Purpose : To prospect ively assess the clinical outcome after MACT in the knee to report long-term results . Study Design : Case series ; Level of evidence , 4 . Methods : Fifty-three subjects ( females/males , 22/31 ; mean age , 32 ± 12 years ) were treated between 2000 and 2006 with a hyaluronan-based MACT product and were followed prospect ively . The mean body mass index ( BMI ) was 24.5 ± 3.8 kg/m2 and the mean defect size was 4.4 ± 1.9 cm2 . Fifty patients had single defects and 3 had multiple defects ( 41 medial femoral condyle , 6 lateral femoral condyle , 2 patella , 1 tibia ) . Two patients had 2 defects ( medial femoral condyle [MFC]/lateral femoral condyle and tibial/MFC ) , and in 1 case , multiple defects on the MFC were treated . The patients were stratified into 23 “ simple , ” 22 “ complex , ” and 8 “ salvage ” cases . Instability or malalignment was treated before or at the time of graft implantation . For 6 patients with small defects ( < 2 cm2 ) , microfracturing was used as first-line treatment before MACT . Clinical assessment was performed once a year with the subjective and objective International Knee Documentation Committee ( IKDC ) scores , Lysholm score , and a modified Cincinnati Knee Rating System . Results : The mean follow-up time was 9.07 ± 2.9 years ( range , 5 - 12 years ) . Treatment failure occurred in 12 of 53 cases ( 22.6 % ) an average of 2.99 ± 1.40 years after surgery . There was 1 failure ( 4.3 % ) among the simple cases , 4 failures ( 18.2 % ) in complex cases , and 7 failures ( 87.5 % ) in salvage cases . Statistically significant increases were observed in all scores at all time points compared with presurgery levels ( P < .05 ) . The subjective IKDC score improved from median 40.4 preoperatively to 74.7 at 10-year follow-up ( n = 13 patients ; P < .05 ) . Conclusion : MACT is an excellent surgical therapy for full-thickness cartilage defects of the knee , with good long-term results for simple defects . However , it should not be used in salvage cases [17372718] A biodegradable , hyaluronian-based biocompatible scaffold was used for autologous chondrocyte transplantation . This prospect i ve study analyzes a clinical outcome of 70 consecutive patients treated by arthroscopic autologous chondrocyte transplantation at minimum 24 months follow up ( 47 of these patients achieved minimum 36 months follow-up and 21 patients minimum 48 months follow-up ) in order to establish clear indication criteria for this type of treatment . 31 of these patients presented isolated chondral lesions , while 39 patients with associated lesions ( 23 ACL lesions , 28 meniscal lesions , 1 varus knee ) were treated during the same surgical procedure with cartilage harvesting . A statistically significant clinical improvement was shown just at 24 months and the second-look arthroscopy demonstrated a complete coverage of the grafted area with a hyaline cartilage-like tissue in 12 of 15 analyzed patients . A better clinical outcome was observed in young , well-trained patients and in traumatic lesions . Other factors , such as defect size , localization , previous and associated surgery did not influence significantly the results . This matrix autologous chondrocyte transplantation procedure simplifies the surgical procedure and can be performed arthroscopically , thus reducing surgical morbidity and recovery time [19339564] BACKGROUND Because of concerns about infections with the use of fresh osteoarticular allografts , osteoarticular allografts are currently stored hypothermically for a minimum of fourteen days to allow for serologic and microbiologic testing prior to implantation . Refrigerated osteoarticular allograft transplants are often used to treat symptomatic chondral and osteochondral defects in young , active patients . Chondrocyte viability has been shown to decrease substantially when allografts are stored for longer than twenty-eight days . The purpose of this study was to examine the clinical and functional outcomes of patients receiving refrigerated osteoarticular allografts between fifteen and twenty-eight days after procurement . METHODS Twenty-three consecutive patients ( twenty-three knees ) who underwent treatment of focal articular cartilage defects of the femoral condyles with refrigerated osteoarticular grafts were prospect ively followed for an average of three years . The average age of the implanted refrigerated allografts was 20.3 days . The patients were assessed preoperatively and postoperatively with vali date d outcome surveys . RESULTS The mean modified Cincinnati knee ratings significantly improved from baseline to the time of the final follow-up , with an increase from 27.3 to 36.5 on the subscale rating for function ( p<0.01 ) , from 21.9 to 32.5 on the subscale rating for symptoms ( p<0.03 ) , and from 49.2 to 69.0 for the overall score ( p<0.02 ) . The mean International Knee Documentation Committee subjective score improved from 52 points at baseline to 68.5 points at the time of the final follow-up ( p<0.03 ) . A significant improvement was also found for effusions and functional testing ( the single-leg hop ) ( p<0.001 for both ) . Radiographic evaluation at the time of the final follow-up revealed that twenty-two of the twenty-three grafts were in stable position with good osseous incorporation into host bone . No graft failure was encountered . CONCLUSIONS Transplantation of refrigerated osteoarticular allografts stored between fifteen and twenty-eight days provides significant functional and clinical improvement after an average follow-up of three years in patients treated for a full-thickness osteochondral defect of the femoral condyle , with similar outcomes to historical reports of patients with fresh allograft implants [25606529] PURPOSE to assess the efficacy of associating the microfracture technique with platelet-rich plasma ( PRP ) injections in the treatment of chondral lesions to promote acceleration and optimization of the healing process compared with the traditional microfracture approach . METHODS from September 2011 to August 2012 , 20 patients ( 9 males and 11 females , aged 30 - 55 years ) were treated . All presented with chondral lesions of the medial femoral condyle of the knee and a pain duration ranging from 8 to 12 months . The patients were r and omized into two groups ( A and B ) . Group A was treated with the microfracture technique and a total of three intra-articular injections of PRP . Group B was treated with microfractures alone . Clinical follow-up was performed at 3 , 6 and 12 months after treatment . Clinical function was assessed on the basis of the International Knee Documentation Committee ( IKDC ) score . Pain was evaluated using a visual analogue scale ( VAS ) . RESULTS the patients in group A had a mean baseline IKDC score of 31.2 , which rose to 84.2 at 12 months . The IKDC scores in group B were at 30.1 at baseline and 81 at 12 months . CONCLUSIONS the results of our study suggest that functional recovery and resolution of pain are obtained more quickly in PRP-treated patients . We also observed a better functional outcome in the patients treated with the combination of PRP and microfractures , even at 12 months , although the difference was not statistically significant . LEVEL OF EVIDENCE level II , r and omized clinical study [25090800] This study presents the prospect i ve two-year clinical and MRI outcome of autologous matrix-induced chondrogenesis ( AMIC ) for the treatment of patellofemoral cartilage defects in the knee . Ten patients were clinical ly prospect ively evaluated during 2 years . MRI data were analysed based on the original and modified MOCART ( Magnetic Resonance Observation of Cartilage Repair Tissue ) scoring system . A satisfying clinical improvement became apparent during the 24 months of follow-up . The MOCART scoring system revealed a slight tendency to deterioration on MRI between one and 2 years of follow-up . However , the difference was not statistical significant . All cases showed subchondral lamina changes . The formation of intralesional osteophytes was observed in 3 of the 10 patients ( 30 % ) . In conclusion , AMIC is safe and feasible for the treatment of symptomatic patellofemoral cartilage defects and result ed in a clinical improvement . However , the favourable clinical outcome of the AMIC technique was not confirmed by the MRI findings [26815276] Purpose The treatment of full-thickness cartilage defects of the knee is a common problem in orthopaedic surgery . Autologous chondrocyte transplantation ( ACT ) is one of the few reliable treatment options of cartilage defects with good long-term outcomes . The improvement of ACT led to the matrix-based ACT ( MACT ) . The purpose of the study was to compare two different commercially available MACT systems . Methods Eleven patients with a cartilage defect of the knee were treated with the MACI ® system and another nine patients with the CaRes ® implant . The patients were prospect ively followed and re-examined after one year . Results One year after surgery all but one patient have significantly improved in their clinical outcome . Both types of MACT revealed similar results in terms of increase in level of activity , pain relief and knee function . Conclusion The study showed that MACT is a good therapeutic option for full-size defects of the femoral condyle . The MACI ® implant seems to be easier to h and le which is reflected by smaller incisions and a shorter operation time [21531864] Background Autologous chondrocyte implantation ( ACI ) has been shown to have favorable results in the treatment of symptomatic chondral and osteochondral lesions . However , there are few reports on the outcomes of this technique in adolescents . Purpose The aim of this study was to assess pain relief and functional outcome in adolescents undergoing ACI . Study Design Case series ; Level of evidence , 4 . Methods Thirty-five adolescent patients undergoing ACI or matrix-assisted chondrocyte implantation ( MACI ) were identified from a larger cohort . Four patients were lost to follow-up , leaving 31 patients ( 24 ACI , 7 MACI ) . The mean age was 16.3 years ( range , 14 - 18 years ) with a mean follow-up of 66.3 months ( range , 12 - 126 months ) . There were 22 male and 9 female patients . All patients were symptomatic ; 30 had isolated lesions and 1 had multiple lesions . Patients were assessed preoperatively and post-operatively using the visual analog scale ( VAS ) score for pain , the Bentley Functional Rating Score , and the Modified Cincinnati Rating System . At 1 year postoperatively , patients were recalled for a diagnostic biopsy , which was successfully attained in 21 patients . Results The mean pain scores improved from 5 preoperatively to 1 postoperatively . The Bentley Functional Rating Score improved from 3 to 0 , while the Modified Cincinnati Rating System improved from 48 preoperatively to 92 postoperatively with 84 % of patients achieving excellent or good results . All postoperative scores exhibited significant improvement from preoperative scores . One patient underwent graft hypertrophy and 1 patient 's graft failed and was revised . Biopsy results revealed hyaline cartilage in 24 % of cases , mixed fibro/hyaline cartilage in 19 % , and fibrocartilage in 57 % . Conclusion Results show that , in this particular group who received ACI , patients experienced a reduction in pain and significant improvement in postoperative function after ACI or MACI . The authors believe that ACI is appropriate in the management of carefully selected adolescents with symptomatic chondral and osteochondral defects [19059899] Background Various approaches have been proposed to treat articular cartilage lesions , which are plagued by inherent limited healing potential . Purpose To compare the clinical outcome of patients treated with second-generation autologous chondrocyte implantation implants with those treated with the microfracture repair technique at 5-year follow-up . Study Design Cohort study ; Level of evidence , 2 . Methods Eighty active patients ( mean age , 29.8 years ) and grade III to IV cartilage lesions of the femoral condyles or trochlea were treated with arthroscopic second-generation autologous chondrocyte implantation Hyalograft C or microfracture ( 40 patients per group ) . Patients achieved a minimum 5-year follow-up and were prospect ively evaluated . Results Both groups showed statistically significant improvement of all clinical scores from preoperative interval to 5-year follow-up . There was a significant improvement for the International Knee Documentation Committee subjective score from preoperative to 5-year follow-up ( Wilcoxon test , P < .001 ) . In the microfracture group , the International Knee Documentation Committee objective score increased from 2.5 % normal and nearly normal knees before the operation to 75 % normal and nearly normal knees at 5-year follow-up , and the subjective score increased from 41.1 ± 12.3 preoperatively to 70.2 ± 14.7 at 5-year follow-up . In the group treated with Hyalograft C , the International Knee Documentation Committee objective score increased from 15 % normal and nearly normal knees before the operation to 90 % normal and nearly normal knees at 5-year follow-up , and its subjective score increased from 40.5 ± 15.2 preoperatively to 80.2 ± 19.1 at 5-year follow-up ( Wilcoxon test , P < .001 ) . When comparing the groups , better improvement of the International Knee Documentation Committee objective ( P < .001 ) and subjective ( P = .003 ) scores was observed in the Hyalograft C group at 5-year follow-up . The return to sports at 2 years was similar in both groups and remained stable after 5 years in the Hyalograft C group ; it worsened in the microfracture group . Conclusion Both methods have shown satisfactory clinical outcome at medium-term follow-up . Better clinical results and sport activity resumption were noted in the group treated with second-generation autologous chondrocyte transplantation [24663398] Purpose Focal chondral and osteochondral knee lesions are a common condition , particularly hard to treat , and often involve young active patients with high expectations in terms of symptomatic relief and return to sports . Autologous osteochondral transplantation allows the defect area to be restored with hyaline cartilage . The aim of this study is to analyse whether it represents a safe and effective treatment option for small – medium-sized knee chondral and osteochondral lesions in a young and active population . Methods Thirty-one patients ( 18 men , 13 women ; mean age 32 ± ten ; mean BMI 24 ± 3 ) affected by focal knee chondral and osteochondral lesions were enrolled and treated with autologous osteochondral transplantation . They were prospect ively followed-up for 24 months with the IKDC-subjective , IKDC- objective , and Tegner scores . Adverse events and failures were also reported , as well as the B and i score to detect symptoms from the donor area . Results A significant increase was reported in all the clinical scores adopted . In particular , the IKDC-subjective score increased from a basal value of 40.3 ± 16.2 to 62.6 ± 18.0 at the 12 months ’ evaluation , with a further significant increase up to 71.6 ± 20.5 at the final 24 months ’ follow-up ( p < 0.0005 ) . A positive trend was also found by analysing the IKDC- objective score . The Tegner score revealed a significant improvement from a basal value of 2.2 ± 1.8 to 3.7 ± 1.5 at the final evaluation ( p = 0.003 ) , although it was not possible to regain the same pre-injury sports activity level of 5.0 ± 2.2 . Two failures were reported . The B and i score revealed patients complaining of mild and moderate symptoms , not correlated to the lesion size . The presence of symptoms ascribable to the donor area was significantly correlated with a lower clinical outcome . Conclusions Autologous osteochondral transplantation proved to be , at short-term evaluation , a suitable option to treat small – medium sized chondral and osteochondral lesions . However , clinical improvement is slow and a significant percentage of patients develop symptoms attributable to the donor area , thus reducing the overall benefit of this procedure [16632362] Matrix-associated autologous chondrocyte transplantation/implantation ( MACT/MACI ) is a new operation procedure using a cell seeded collagen matrix for the treatment of localized full-thickness cartilage defects . A prospect i ve clinical investigation was carried out in order to clarify whether this proves suitable and confirms objective and subjective clinical improvement over a period of up to 5 years after operation . Thirty-eight patients with localised cartilage defects were treated with MACT . Within the context of clinical follow-up , these patients were evaluated for up to 5 years after the intervention . Four different scores ( Meyers score , Tegner-Lysholm activity score , Lysholm-Gillquist score , ICRS score ) as well as the results of six arthroscopies and biopsies obtained from four patients formed the basis of this study . For 15 patients , 5 or more years had elapsed since the operation at the time this study was completed . It was possible to obtain results 5 years postoperatively from 11 ( 73.3 % ) of these 15 patients . Overall , we included 25 patients into the evaluation with a 2-year or longer postoperative period . Five years after transplantation 8 out of 11 patients rated the function of their knee as much better or better than before . Three of the four scores showed significant improvement compared to the preoperative value . One score , the Tegner-Lysholm score showed improvement , which , however , did not prove to be significant . The significantly improved results on three scores after 5 years suggest that MACT represents a suitable but cost-intensive alternative in the treatment of local cartilage defects in the knee [20062969] Cartilage defects occur in approximately 12 % of the population and can result in significant function impairment and reduction in quality of life . Evidence for the variety of surgical treatments available is inconclusive . This study aim ed to compare the clinical outcomes of patients with symptomatic cartilage defects treated with matrix-induced autologous chondrocyte implantation ( MACI ™ or microfracture ( MF ) . Included patients were ≥18 and ≤50 years of age with symptomatic , post-traumatic , single , isolated chondral defects ( 4–10 cm2 ) and were r and omised to receive MACI ™ or MF . Patients were followed up 8–12 , 22–26 and 50–54 weeks post-operatively for efficacy and safety evaluation . Outcome measures were the Tegner , Lysholm and ICRS scores . Sixty patients were included in a r and omised study ( 40 MACI ™ , 20 MF ) . The difference between baseline and 24 months post-operatively for both treatment groups was significant for the Lysholm , Tegner , patient ICRS and surgeon ICRS scores ( all P < 0.0001 ) . However , MACI ™ was significantly more effective over time ( 24 months versus baseline ) than MF according to the Lysholm ( P = 0.005 ) , Tegner ( P = 0.04 ) , ICRS patient ( P = 0.03 ) and ICRS surgeon ( P = 0.02 ) scores . There were no safety issues related to MACI ™ or MF during the study . MACI ™ is superior to MF in the treatment of articular defects over 2 years . MACI ™ and MF are complementary procedures , depending on the size of the defect and symptom recurrence . The MACI ™ technique represents a significant advance over both first and second generation chondrocyte-based cartilage repair techniques for surgeons , patients , health care institutions and payers in terms of reproducibility , safety , intraoperative time , surgical simplicity and reduced invasiveness [17261573] Background Focal articular cartilage lesions of the knee in young patients present a therapeutic challenge . Little information is available pertaining to the results after implantation of prolonged fresh grafts . Hypothesis Prolonged fresh osteochondral allografts present a viable option for treating large full-thickness articular cartilage lesions . Study Design Case series ; Level of evidence , 4 . Methods This study presents the results of 25 consecutive patients who underwent prolonged fresh osteochondral allograft transplantation for defects in the femoral condyle . The average patient age was 35 years ( range , 17 - 49 years ) . The average length of follow-up was 35 months ( range , 24 - 67 months ) . Prospect i ve data were collected using several subjective scoring systems , as well as objective and radiographic assessment s. Results Statistically significant improvements ( P < .05 ) were seen for the Lysholm ( 39 to 67 ) , International Knee Documentation Committee scores ( 29 to 58 ) , all 5 components of the Knee injury and Osteoarthritis Outcome Score ( Pain , 43 to 73 ; Other Disease-Specific Symptoms , 46 to 64 ; Activities of Daily Living Function , 56 to 83 ; Sport and Recreation Function , 18 to 46 ; Knee-Related Quality of Life , 22 to 50 ) , and the Short Form-12 physical component score ( 36 to 40 ) . Overall , patients reported 84 % ( range , 25 % to 100 % ) satisfaction with their results and believed that the knee functioned at 79 % ( range , 35 % to 100 % ) of their unaffected knee . Radiographically , 22 of the grafts ( 88 % ) were incorporated into host bone . Conclusion Fresh osteochondral allograft transplantation is an acceptable intermediate procedure for treatment of localized osteochondral defects of the femur . At 2-year follow-up , it is well incorporated and offered consistent improvements in pain and function . Clinical Relevance Prolonged fresh allograft transplantation is a safe and effective technique for addressing symptomatic osteoarticular lesions in the knees of young patients [22316548] Background : Fresh-stored osteochondral allografts have been used successfully to resurface large chondral and osteochondral defects of the knee . However , there are limited data available for the return to athletic activity . Purpose : To review the rate of return to athletic activity after osteochondral allograft transplantation in the knee and to identify any potential risk factors for not returning to sport . Study Design : Case series ; Level of evidence , 4 . Methods : Forty-three athletes were treated with fresh-stored osteochondral allograft transplantation for symptomatic large chondral or osteochondral defects of the knee from 2000 to 2010 . The average age of the athletes ( 30 men , 13 women ) was 32.9 years ( range , 18 - 49 years ) . Patients were prospect ively evaluated by International Knee Documentation Committee ( IKDC ) , activities of daily living scale of the Knee Injury and Osteoarthritis Outcome Score ( KOOS ) , Marx Activity Rating Scale , and Cincinnati Sports Activity Scale scores . A multivariable regression analysis was performed to identify potential risk factors for failure to return to sport at the preinjury level . Results : At an average 2.5-year follow-up , limited return to sport was possible in 38 of 43 athletes ( 88 % ) , with full return to the preinjury level achieved in 34 of 43 athletes ( 79 % ) . In these 34 athletes , time to return to sport was 9.6 ± 3.0 months . Age ≥25 years ( P = .04 ) and preoperative duration of symptoms greater than 12 months ( odds ratio , 37 ; P = .003 ) negatively affected the ability to return to sport . In the athletes who returned to their previous level of competition , IKDC ( P < .001 ) , KOOS ( P = .02 ) , and Marx Activity Rating Scale ( P < .001 ) scores were all significantly greater than in those athletes who did not return to sport . Conclusion : Osteochondral allograft transplantation in an athletic population for chondral and osteochondral defects in the knee allows for a high rate of return to sport . Risk factors for not returning to sport included age ≥25 years and preoperative duration of symptoms ≥12 months [24166804] Background : Autologous chondrocyte implantation ( ACI ) has been associated with satisfying results . Still , it remains unclear when success or failure after ACI can be estimated . Purpose : To evaluate the clinical outcomes of cell-seeded collagen matrix – supported ACI ( ACI-Cs ) for the treatment of cartilage defects of the knee at 36 months and to determine a time point after ACI-Cs at which success or failure can be estimated . Study Design : Cohort study ; Level of evidence , 3 . Methods : A total of 80 patients with isolated full-thickness cartilage defects of the knee joint treated with ACI-Cs were prospect ively assessed before surgery as well as postoperatively by use of the International Knee Documentation Committee ( IKDC ) score and Lysholm knee score . Results : Preoperative IKDC and Lysholm scores increased from 49.6 and 59.5 , respectively , to 79.1 and 83.5 , respectively , at 36 months . Only half the patients ( 46.6 % ) with poor IKDC scores ( ie , < 70 ) at 6 months postoperatively showed continued poor or fair scores at 36 months ’ follow-up . The probability of poor scores at 36 months after surgery further increased to 0.61 and 0.81 , respectively , when scores were persistent at 12 and 24 months . All 3 patients ( 100 % ) with good IKDC scores ( ie , 81 - 90 ) at 6 months after surgery showed constant or even improved scores at 36 months ’ follow-up . Ninety-one percent of patients with good and excellent scores at 12 months and 83 % of patients with good and excellent scores at 24 months ( a total of 23 and 37 patients , respectively ) were able to maintain these scores at 36 months ’ follow-up . Similar results were obtained for the Lysholm score . Conclusion : With regard to the improvements in functional outcomes after ACI-Cs at 36 months after surgery , the technique described here appears to lead to satisfying and stable clinical results . This study helps the treating physician to predict the likeliness of further clinical improvements or constant unsatisfactory results after ACI . In patients with good/excellent scores shortly after surgery , deterioration of the knee ’s condition is rarely found . For patients with poor and fair postoperative scores , clinical outcomes are more difficult to predict , especially during the first year after the procedure [24051505] Abstract Purpose Microfracture is a well-established treatment procedure for chondral defects in high-dem and population with good short-term results . The purpose of our study was to evaluate long-term clinical outcome of microfracture treatment in athletes with full-thickness chondral defects . Methods Between 1991 and 2001 , 170 patients were treated with microfracture for full-thickness knee chondral lesions at our institute and 67 of them were included in this study and prospect ively followed up . Sixty-one athletes ( 91 % ) were available at final follow-up ( average 15.1 years ) . Average lesion size was 401 ± 27 mm2 . Lysholm , Tegner and International Knee Documentation Committee ( IKDC ) ( subjective– objective ) scores were utilized pre-operatively and at 2-year , 5-year and final follow-up ; Knee injury and Osteoarthritis Outcome Score ( KOOS ) , visual analog scale ( VAS ) and Marx scores were also collected at final follow-up . Results IKDC , Lysholm and Tegner scores increased significantly at 2 years , but gradually deteriorated at long term ; however , average scores were significantly above baseline at final follow-up . Seven patients ( 11 % ) were considered as failures as they underwent another operation because of reinjury or persistent pain during the first 5 years . Pain and swelling during strenuous activities was reported only in nine patients by the end of 2 years and in 35 patients at final follow-up . Patients with smaller lesions ( ≤400 mm² ) and younger patients ( ≤30 years ) showed significantly better results in KOOS , VAS and Marx scores . Radiographs performed at final follow-up showed evidence of progression of osteoarthritis changes in 40 % of the knees , with higher rate in older patients with large or multiple lesions ( p < 0.05 ) . Conclusions Microfracture when applied in young patients with smaller lesions can offer good clinical results at short- and long-term follow-up ; lesion size is more important prognostic factor of outcome than age . Deterioration of the clinical outcome should be expected after 2 and 5 years post-treatment , and degenerative changes are present at long-term follow-up , with higher rate in older athletes with large , multiple lesions . Level of evidence IV [25218576] Abstract Purpose Matrix-induced autologous chondrocyte implantation ( MACI ) has demonstrated effectiveness in treating isolated cartilage defects of the knee but medium- and long-term evidence and information on the management of postoperative complications or partially successful cases are sparse . This study hypothesised that MACI is effective for up to 5 years and that patients with posttreatment problems may go on to obtain clinical benefit from other interventions . Methods A follow-on , prospect i ve case series of patients recruited into a previous controlled , r and omised , prospect i ve study or newly enroled . Patients were followed up 6 , 12 , 24 and 60 months after surgery . Outcome measures were Tegner ( activity levels ) and Lysholm ( pain , stability , gait , clinical symptoms ) scores . Zone-specific subgroups were analysed 6 , 12 and 24 months postoperatively . Results Sixty-five patients were treated with MACI . Median Tegner score improved from II to IV at 12 months ; an improvement maintained to 60 months . Mean Lysholm score improved from 28.5 to 76.6 points ( ±19.8 ) at 24 months , settling back to 75.5 points after 5 years ( p > 0.0001 ) . No significant differences were identified in the zone-specific analysis . Posttreatment issues ( N = 12/18.5 % ) were resolved with microfracture , debridement , OATS or bone grafting . Conclusions MACI is safe and effective in the majority of patients . Patients in whom treatment is only partially successful can go on to obtain clinical benefit from other cartilage repair options . This study adds to the clinical evidence on the MACI procedure , offers insight into likely treatment outcomes , and highlights MACI ’s usefulness as part of an armamentarium of surgical approaches to the treatment of isolated knee defects . Level of evidence Prospect i ve case control study with no control group , Level III [23412171] Most studies suggested that arthroscopic microfracture is effective method at only less than 40 years of age . Thus , the authors thought that “ how can this indication regarding age be extended ? , ” and tried to find a way to use this technique effectively over 40 years of age . The aim of this study was the first to report the results regarding the PRP as an adjunct for arthroscopic microfracture in the early osteoarthritic ( OA ) knee with cartilage lesion over 40 years of age . 49 patients who underwent arthroscopic microfracture for cartilage lesion sized less than 4 cm2 with early OA , aged 40–50 years , were enrolled and r and omly divided into 2 groups : a control group with only arthroscopic microfracture ( 25 patients ) and a study group with arthroscopic microfracture and PRP ( 24 patients ) . The patients were prospect ively evaluated with VAS , IKDC score at preoperative and postoperative 1 , 6 , 12 , and 24 months . And we perform second arthroscopies in 10 patients of each group to identify the extent of cartilage restoration at 4–6 months postoperatively . There were significant improvements in clinical results between preoperative evaluation and postoperative 2 years in both groups ( p = 0.017 ) . In the postoperative 2 years , clinical results showed significantly better in the study group than in the control group ( p = 0.012 ) . In post-arthroscopic finding , hardness and elasticity degree was better in the study group . The PRP injection with arthroscopic microfracture would be improved the results in early osteoarthritic knee with cartilage lesion in 40–50 years old , and the indication of this technique could be extended to 50 years [20678705] PURPOSE We report the 2-year clinical results and identify prognostic factors in patients treated with autologous chondrocyte transplantation by use of a collagen membrane to seed the chondrocytes ( ACT-CS ) . METHODS This is a prospect i ve study of 59 patients who were treated with ACT-CS and followed up for 24 months . Clinical function was assessed by International Knee Documentation Committee ( IKDC-2000 ) , objective International Cartilage Repair Society , and Lysholm scores before surgery and at 6 , 12 , and 24 months after surgery . RESULTS On the basis of objective International Cartilage Repair Society ( ICRS ) rating , the percentage of patients rated A ( normal ) and B ( nearly normal ) increased from 33.9 % preoperatively to 92.5 % at 24 months after ACT-CS . IKDC and Lysholm scores increased from 50.1 points ( SD , 13.4 ) and 60.5 points ( SD , 9.4 ) , respectively , to 76.1 points ( SD , 15.2 ) ( P < .001 ) and 82.5 points ( SD , 13.7 ) ( P < .001 ) , respectively , at 24 months . The failure rate was highest , at 26.7 % at 2 years ' follow-up , in the subgroup of patients who underwent ACT-CS as a salvage procedure . The rate of failures in patients with isolated cartilage defects was 5.9 % . CONCLUSIONS ACT-CS represents a technical modification of membrane-associated autologous chondrocyte transplantation that combines easy h and ling and attractive application properties with reliable clinical results 24 months after surgery , especially in patients with isolated cartilage defects . Even though the failure rate was higher in patients with kissing lesions or mild osteoarthritis , ACT-CS also seems to improve function in a large proportion of such patients . LEVEL OF EVIDENCE Level IV , prospect i ve case series [22922521] Background : To date , few studies have been published reporting the 5-year follow-up of clinical and radiological outcomes for chondral defects treated with matrix-induced autologous chondrocyte implantation ( MACI ) . Hypothesis : A significant improvement in clinical and radiological outcomes after treatment of symptomatic , traumatic chondral defects of the knee with the MACI implant will be maintained up to 5 years after surgery . Study Design : Case series ; Level of evidence , 4 . Methods : A prospect i ve evaluation of the MACI procedure was performed in 21 patients with chondral defects of the knee . After the MACI procedure , patients were clinical ly assessed with the Knee injury and Osteoarthritis Outcome Score ( KOOS ) , the Tegner-Lysholm score , the International Knee Documentation Committee ( IKDC ) Subjective Knee Form , and the modified Cincinnati score at years 1 , 2 , and 5 . The quality of repair tissue was assessed by magnetic resonance imaging using the magnetic resonance observation of cartilage repair tissue ( MOCART ) score at months 3 and 6 and years 1 , 2 , and 5 . Results : Significant improvements ( P < .05 ) were observed for all 5 KOOS subcategories at year 1 and were maintained through year 5 in 90.5 % of patients ( 19/21 ) . Treatment failure occurred in only 9.5 % of patients ( 2/21 ) . Significant improvements ( P < .05 ) from baseline to year 5 were also observed for the IKDC score ( 30.1 to 74.3 ) , the modified Cincinnati score ( 38.1 to 79.6 ) , and the Tegner-Lysholm activity score ( 1.8 to 4.3 ) . Similarly , the MOCART score significantly improved ( P < .001 ) from baseline to year 5 ( 52.9 to 75.8 ) . After 5 years , complete filling ( 83 % ) and integration ( 82 % ) of the graft were seen in the majority of patients . Signs of subchondral bone edema were still present in 47 % of patients at 5 years . No product-specific adverse events were reported over the 5-year follow-up period . Conclusion : Patients treated with a MACI implant demonstrated significant clinical improvement and good quality repair tissue 5 years after surgery . The MACI procedure was shown to be a safe and effective treatment for symptomatic , traumatic chondral knee defects in this study [22637203] BACKGROUND There is limited information regarding direct comparisons of the outcome of osteochondral autograft transfer ( OAT ) mosaicplasty and microfracture for the treatment of isolated articular cartilage defects of the knee . The purpose of this retrospective comparative study was to compare the general health outcomes , knee function , and Marx Activity Rating Scale scores for patients treated with OAT or microfracture for symptomatic chondral defects of the femoral condyles or trochlea . We hypothesized that the patients in the two treatment groups would have similar clinical outcomes at intermediate-term follow-up . METHODS Ninety-six patients with full-thickness cartilage defects of the femoral condyles or trochlea were treated with either OAT mosaicplasty ( n = 48 ) or microfracture ( n = 48 ) . The average age of the patients ( thirty-two male and sixteen female in each group ) at the time of surgery was 29.7 years in the OAT group and 32.5 years in the microfracture group . Patients were prospect ively evaluated at baseline and at one , two , three , and five years postoperatively with use of vali date d clinical outcome measures including the Short Form-36 ( SF-36 ) physical component , International Knee Documentation Committee ( IKDC ) , Knee Outcome Survey activities of daily living , and Marx Activity Rating Scale instruments . Comparisons between outcomes before and after treatment or between outcomes after microfracture and mosaicplasty were made with use of two-tailed tests . RESULTS At the time of the latest follow-up , both groups demonstrated significant increases in SF-36 physical component , Knee Outcome Survey activities of daily living , and IKDC scores compared with baseline . These scores did not differ significantly between the two groups at any of the follow-up time points . However , the OAT group demonstrated a significantly greater improvement in the Marx Activity Rating Scale scores from baseline to the two-year ( p = 0.001 ) , three-year ( p = 0.03 ) , and five-year ( p = 0.02 ) time points compared with the microfracture group . CONCLUSIONS In the present retrospective comparative study , the hypothesis that patients treated with microfracture or OAT mosaicplasty for symptomatic articular cartilage defects of the femoral condyles or trochlea would have similar clinical outcomes at intermediate-term follow-up was affirmed for general health outcome and for knee function . However , patients treated with OAT mosaicplasty maintained a superior level of athletic activity compared with those treated with microfracture [25548122] Abstract Background Cell-based strategies that combine in vitro- exp and ed autologous chondrocytes with matrix scaffolds are currently preferred for full-thickness cartilage lesions of the knee ≥2 cm2 . Although this approach is reasonable , continuing advances in the field of cartilage repair will further exp and the options available to improve outcomes .Hypothesis/ purpose In the present clinical study , we compared the outcomes of matrix-induced autologous mesenchymal stem cell implantation ( m-AMI ) with matrix-induced autologous chondrocyte implantation ( m-ACI ) for the treatment of isolated chondral defects of the knee . Study design Prospect i ve , single-site , r and omized , single-blind pilot study . Methods Fourteen patients with isolated full-thickness chondral lesions of the knee > 2 cm2 were r and omized into two treatment groups : m-AMI and m-ACI . Outcomes were assessed pre-operatively and 3 , 6 , 12 and 24 months post-operatively . Results Clinical evaluations revealed that improvement from pre-operation to 24 months post-operation occurred in both groups ( p < 0.05 ) . At all follow-up intervals , m-AMI demonstrated significantly better functional outcomes ( motion deficit and straight leg raise strength ) than did m-ACI ( p < 0.05 ) . At all follow-up intervals , m-AMI demonstrated significantly better subjective sub-scale scores for pain , symptoms , activities of daily living and sport and recreation of the knee injury and osteoarthritis outcome score ( KOOS ) than did m-ACI ( p < 0.05 ) . Additionally , m-AMI demonstrated significantly better ( p < 0.05 ) scores than m-ACI for the quality of life sub-scale of the KOOS and visual analog scale ( VAS ) severity at the 6-month follow-up . The Tegner activity score and VAS frequency were not significantly different between the two groups . Graft failure was not observed on magnetic resonance imaging at the 24-month follow-up . m-AMI and m-ACI demonstrated very good-to-excellent and good-to-very good infill , respectively , with no adverse effects from the implant , regardless of the treatment . Conclusion For the treatment of isolated full-thickness chondral lesion of the knee , m-AMI can be used effectively and may potentially accelerate recovery . A larger patient cohort and follow-up supported by histological analyses are necessary to determine long-term outcomes [16093535] Background The ability of autologous chondrocyte transplantation to produce and maintain an effective articular cartilage repair under high mechanical dem and s has not been investigated . Hypothesis Autologous chondrocyte transplantation provides a reliable and durable repair of full-thickness knee articular cartilage lesions in high-dem and athletes . Study Design Case series ; Level of evidence , 4 . Methods A total of 45 soccer players were evaluated 41 ± 4 months after autologous chondrocyte transplantation for their ability to return to soccer , the timing of their return , skill level , and functional outcome rating by the Tegner activity rating scale score and Brittberg score . The factors influencing the return to sport were analyzed . Results Of these players , 72 % reported good to excellent results , with significant overall improvement of Tegner activity rating scale scores ; 33 % returned to soccer , including 83 % of competitive-level players and 16 % of recreational players . Of the returning players , 80 % returned to the same skill level and 87 % maintained their ability to play soccer at 52 ± 8 months postoperatively . Players who successfully returned to soccer were significantly younger and had a shorter preoperative duration of symptoms than did patients who did not return to the sport . Concomitant adjuvant procedures did not adversely affect the ability to return to soccer . Conclusion Repair of knee articular cartilage lesions by autologous chondrocyte transplantation in high-performance athletes is particularly successful in younger , competitive athletes with limited preoperative intervals [23001127] Background Treating patellofemoral articular cartilage lesions remains a challenging task in orthopedic surgery . Whereas microfracture and autologous chondrocyte implantation yield good results on femoral condyles , the therapeutic state of the art for treating patellofemoral lesions is yet to be determined . In this study , we compared the CaReS ® technique , which is a matrix-associated autologous chondrocyte implantation technique , to microfracture for treating patellofemoral articular cartilage lesions . Methods Between May 2003 and December 2005 , 17 patients with an isolated patellofemoral cartilage defect ( International Cartilage Repair Society III/IV ) were treated with the CaReS ® technique at our department . After adjusting for inclusion and exclusion criteria , ten of these patients could be included in this study ; ten patients treated with microfracture were chosen as a matched-pair group . Clinical outcome was evaluated 3 years after surgery by the 36-item Short Form Health Survey Question naire ( SF-36 ) , International Knee Documentation Committee ( IKDC ) subjective evaluation of the knee , Lysholm Score , and Cincinnati Modified Rating Scale scores . Results Patients treated with CaReS ® had statistically significantly improved IKDC , Lysholm , and Cincinnati scores 36 months after surgery compared with preoperatively . When comparing outcome between groups 36 months after surgery , there was no statistically difference in IKDC , Lysholm , and Cincinnati scores . Conclusions This is the first trial comparing the CaReS ® technique and microfracture for treating patellofemoral articular cartilage lesions , and results show that CaReS ® yields comparable results to microfracture . The small number of patients is a limiting factor of the study , leading to results without statistical significance . A multicentric prospect i ve r and omized study comparing the two procedures is desirable [21669155] Cartilage defects represent a common problem in orthopaedic practice . The knee is frequently involved and the medial femoral condyle is the most common localization . Predisposing factors are : traumas , inflammatory conditions and biomechanics alterations . Several surgical options are available once correct diagnosis is given and accurate patient evaluation has been performed . The aim of our study was to prospect ively evaluate functional results of modified autologous matrix induced chondrogenesis ( AMIC ) technique in a population of patients affected by focal cartilage defects A population of 17 patients was enrolled in this study . 10 patients were male , mean age at the time of surgery was 39 years , right side was involved in 11 cases . All patients were evaluated with accurate physical exam and complete imaging study . At an average FU of 36 months , mean IKDC score and Lysholm score improved from 32 to 82 and from 38 to 74 . 13 patients out of 17 ( 76.5 % ) were satisfied or extremely satisfied with their functional result . MRI control showed reduction of the defect area and subchondral oedema in 10 cases ( 58.8 % ) . AMIC technique is a relatively new option in the treatment of full thickness cartilage lesions . It enhances the advantages of microfractures since the Chondrogide membrane protects and stabilizes the blood plug acting as a matrix for new cartilage formation . First reports on AMIC technique , show comparable results to autologous chondrocyte implantation ( ACI ) with the advantage of a single stage technique and no donor site morbidity . AMIC technique represents a new option in the treatment of full thickness cartilage defect . It is safe and reliable . Our data are in accordance with previously reported series in literature and confirm the good objective and subjective results of this procedure [26742454] Numerous surgical techniques have been developed to treat osteochondral defects of the knee . A study reported encouraging outcomes of third-generation autologous chondrocyte implantation achieved using the solid agarose-alginate scaffold Cartipatch ® . Whether this scaffold is better than conventional techniques remains unclear . This multicenter r and omized controlled trial compared 2-year functional outcomes ( IKDC score ) after Cartipatch ® versus mosaicplasty in patients with isolated symptomatic femoral chondral defects ( ICRS III and IV ) measuring 2.5 - 7.5 cm(2 ) . In addition , a histological evaluation based on the O'Driscoll score was performed after 2 years . We needed 76 patients to demonstrate an at least 10-point subjective IKDC score difference with α = 5 % and 90 % power . During the enrolment period , we were able to include 55 patients , 30 of them were allocated at r and om to Cartipatch ® and 25 to mosaicplasty . After 2 years , eight patients had been lost to follow-up , six in the Cartipatch ® group , and two in the mosaicplasty group . The baseline characteristics of the two groups were not significantly different . The mean IKDC score and score improvement after 2 years were respectively 73.7 ± 20.1 and 31.8 ± 20.8 with Cartipatch ® and 81.5 ± 16.4 and 44.4 ± 15.2 with mosaicplasty . The 12.6-point absolute difference in favor of mosaicplasty is statistically significant . Twelve adverse events were recorded in the Cartipatch ® group against six in the mosaicplasty group . After 2 years , functional outcomes were significantly worse after Cartipatch ® treatment compared to mosaicplasty for isolated focal osteochondral defects of the femur [19448048] Background The healing potential of damaged articular cartilage is limited . The NeoCart is a tissue-engineered collagen matrix seeded with autogenous chondrocytes design ed for the repair of hyaline articular cartilage . Hypothesis The NeoCart implant is well tolerated in the human knee . Study Design Case series ; Level of evidence , 4 . Methods Eight patients ( treatment group ) with full-thickness cartilage injury were treated with the NeoCart and evaluated prospect ively . Autogenous chondrocytes provided by arthroscopic biopsy were seeded into a 3-dimensional type I collagen scaffold . The seeded scaffold was subjected to a tissue-engineering protocol including treatment with a bioreactor . Implantation of the prepared cartilage tissue patch was performed via miniarthrotomy and secured with a collagen bioadhesive . Evaluations through 24 months postoperatively included the subjective International Knee Documentation Committee question naire , visual analog scale , range of motion , and cartilage-sensitive magnetic resonance imaging ( MRI ) , including quantitative T2 mapping . Results Pain scores after NeoCart implantation were significantly lower than baseline at 12 and 24 months after the procedure ( P < .05 ) . Improved function and motion were also noted at 24 months . Six patients had 67 % to 100 % defect fill at 24 months with MRI evaluation . One patient had moderate ( 33%-66 % ) defect fill , and another patient had poor ( less than 33 % ) defect fill . Partial stratification of T2 values was observed for 2 patients at 12 months and 4 patients at 24 months . No patients experienced arthrofibrosis or implant hypertrophy . Conclusion Pain was significantly reduced 12 and 24 months after NeoCart treatment . Trends toward improved function and motion were observed 24 months after implantation . The MRI indicated implant stability and peripheral integration , defect fill without overgrowth , progressive maturation , and more organized cartilage formation [24714783] Background : R and omized controlled trials study ing the efficacy and safety of matrix-applied characterized autologous cultured chondrocytes ( MACI ) versus microfracture ( MFX ) for treating cartilage defects are limited . Purpose : To compare the clinical efficacy and safety of MACI versus MFX in the treatment of patients with symptomatic cartilage defects of the knee . Study Design : R and omized controlled clinical trial ; Level of evidence , 1 . Methods : Patients enrolled in the SUMMIT ( Demonstrate the Superiority of MACI implant to Microfracture Treatment ) trial had ≥1 symptomatic focal cartilage defect ( Outerbridge grade III or IV ; ≥3 cm2 ) of the femoral condyles or trochlea , with a baseline Knee Injury and Osteoarthritis Outcome Score ( KOOS ) pain value < 55 . The co– primary efficacy endpoint was the change in the KOOS pain and function subscores from baseline to 2 years . Histological evaluation and magnetic resonance imaging ( MRI ) assessment s of structural repair tissue , treatment failure , the remaining 3 KOOS subscales , and safety were also assessed . Results : Of the 144 patients treated , 137 ( 95 % ) completed the 2-year assessment . Patients had a mean age of 33.8 years and a mean lesion size of 4.8 cm2 . The mean KOOS pain and function subscores from baseline to 2 years were significantly more improved with MACI than with MFX ( pain : MACI , 37.0 to 82.5 vs MFX , 35.5 to 70.9 ; function : MACI , 14.9 to 60.9 vs MFX , 12.6 to 48.7 ; P = .001 ) . A significant improvement in scores was also observed on the KOOS subscales of activities of daily living ( MACI , 43.5 to 87.2 vs MFX , 42.6 to 75.8 ; P < .001 ) , knee-related quality of life ( MACI , 18.8 to 56.2 vs MFX , 17.2 to 47.3 ; P = .029 ) , and other symptoms ( MACI , 48.3 to 83.7 vs MFX , 44.4 to 72.2 ; P < .001 ) for patients treated with MACI compared with MFX . Repair tissue quality was good as assessed by histology/MRI , but no difference was shown between treatments . A low number of treatment failures ( nonresponders : MACI , 12.5 % vs MFX , 31.9 % ; P = .016 ) and no unexpected safety findings were reported . Conclusion : The treatment of symptomatic cartilage knee defects ≥3 cm2 in size using MACI was clinical ly and statistically significantly better than with MFX , with similar structural repair tissue and safety , in this heterogeneous patient population . Moreover , MACI offers a more efficacious alternative than MFX with a similar safety profile for the treatment of symptomatic articular cartilage defects of the knee [19846694] Background Damaged articular cartilage has limited capacity for self-repair . Autologous chondrocyte implantation using a characterized cell therapy product results in significantly better early structural repair as compared with microfracture in patients with symptomatic joint surface defects of the femoral condyles of the knee . Purpose To evaluate clinical outcome at 36 months after characterized chondrocyte implantation ( CCI ) versus microfracture ( MF ) . Study Design R and omized controlled trial ; Level of evidence , 1 . Methods Patients aged 18 to 50 years with single International Cartilage Repair Society ( ICRS ) grade III/IV symptomatic cartilage defects of the femoral condyles were r and omized to CCI ( n = 57 ) or MF ( n = 61 ) . Clinical outcome was measured over 36 months by the Knee injury and Osteoarthritis Outcome Score ( KOOS ) . Serial magnetic resonance imaging ( MRI ) scans were scored using the Magnetic resonance Observation of Cartilage Repair Tissue ( MOCART ) system and 9 additional items . Gene expression profile scores associated with ectopic cartilage formation were determined by RT-PCR . Results Baseline mean overall KOOS ( ±SE ) was comparable between the CCI and MF groups ( 56.30 ± 1.91 vs 59.46 ± 1.98 , respectively ) . Mean improvement ( ±SE ) from baseline to 36 months in overall KOOS was greater in the CCI group than the MF group ( 21.25 ± 3.60 vs 15.83 ± 3.48 , respectively ) , while in a mixed linear model analysis with time as a categorical variable , significant differences favoring CCI were shown in overall KOOS ( P = .048 ) and the subdomains of Pain ( P = .044 ) and QoL ( P = .036 ) . More CCI- than MF-treated patients were treatment responders ( 83 % vs 62 % , respectively ) . In patients with symptom onset of < 2 years , the mean improvement ( ±SE ) from baseline to 36 months in overall KOOS was greater with CCI than MF ( 24.98 ± 4.34 vs 16.50 ± 3.99 , respectively ) and even greater in patients with symptom onset of <3 years ( 26.08 ± 4.10 vs 17.09 ± 3.77 , respectively ) . Characterized chondrocyte implantation patients with high ( > 2 ) versus low ( < 2 ) gene profile scores showed greater improvement from baseline in mean overall KOOS ( ±SE ) at 36 months ( 28.91 ± 5.69 vs 18.18 ± 5.08 , respectively ) . Subchondral bone reaction significantly worsened over time with MF compared with CCI ( P < .05 ) . Conclusion Characterized chondrocyte implantation for the treatment of articular cartilage defects of the femoral condyles of the knee results in significantly better clinical outcome at 36 months in a r and omized trial compared with MF . Time to treatment and chondrocyte quality were shown to affect outcome [23729686] Background : Sex-specific outcomes have been reported in anterior cruciate ligament reconstruction as well as in osteoarthrosis progression , but there are currently no related published data on autologous chondrocyte implantation ( ACI ) . The present prospect i ve study was performed to investigate sex-dependent differences in the results after ACI . Hypothesis : The clinical and magnetic resonance imaging ( MRI ) results after ACI of the knee are influenced by the patient ’s sex . Study Design : Cohort study ; Level of evidence , 2 . Methods : The midterm clinical and MRI results of a cell-based fibrin-polymer graft for the treatment of full-thickness cartilage defects were evaluated preoperatively and 6 , 12 , and 48 months after surgery in 52 patients ( male : female ratio , 25:27 ; average age , 35.6 years ) . Depending on the sex and the location of the defects ( femoral condyles , n = 32 ; patellofemoral compartment , n = 20 ) , patients were assigned to 4 different groups . Baseline clinical scores were compared with follow-up data by paired Wilcoxon tests for the Lysholm score and the International Knee Documentation Committee ( IKDC ) scoring system . Sex-specific differences were evaluated with the Mann-Whitney U test . The MRI evaluation was performed with the Henderson score at final follow-up . Results : Clinical scores improved in all groups over the whole study period ( P < .05 ) . Compared with female patients , male patients achieved significantly better results in the Lysholm score at all time intervals and in the IKDC score at 6 and 12 months after surgery ( P < .05 ) . In a subgroup analysis , female patients with patellar defects had the worst results in both clinical scores . With the available number of patients , MRI evaluation at 48 months after surgery revealed no significant difference in defect fill between male and female patients ( P > .05 ) . The Pearson correlation coefficient between both clinical scores and the MRI parameters of defect fill and cartilage signal was significant ( P < .05 ) . Conclusion : Autologous chondrocyte implantation is a promising treatment option for full-thickness cartilage defects of male and female knee joints . Female patients with patellar defects have worse prognostic factors [17908884] BACKGROUND The optimal treatment for cartilage lesions has not yet been established . The objective of this r and omized trial was to compare autologous chondrocyte implantation with microfracture . This paper represents an up date , with presentation of the clinical results at five years . METHODS Eighty patients who had a single chronic symptomatic cartilage defect on the femoral condyle in a stable knee without general osteoarthritis were included in the study . Forty patients were treated with autologous chondrocyte implantation , and forty were treated with microfracture . We used the International Cartilage Repair Society , Lysholm , Short Form-36 , and Tegner forms to collect clinical data , and radiographs were evaluated with use of the Kellgren and Lawrence grading system . RESULTS At two and five years , both groups had significant clinical improvement compared with the preoperative status . At the five-year follow-up interval , there were nine failures ( 23 % ) in both groups compared with two failures of the autologous chondrocyte implantation and one failure of the microfracture treatment at two years . Younger patients did better in both groups . We did not find a correlation between histological quality and clinical outcome . However , none of the patients with the best- quality cartilage ( predominantly hyaline ) at the two-year mark had a later failure . One-third of the patients in both groups had radiographic evidence of early osteoarthritis at five years . CONCLUSIONS Both methods provided satisfactory results in 77 % of the patients at five years . There was no significant difference in the clinical and radiographic results between the two treatment groups and no correlation between the histological findings and the clinical outcome . One-third of the patients had early radiographic signs of osteoarthritis five years after the surgery . Further long-term follow-up is needed to determine if one method is better than the other and to study the progression of osteoarthritis [17724094] Background Articular cartilage lesions , with their inherent limited healing potential , remain a challenging problem for orthopaedic surgeons . Various approaches have been proposed to treat these lesions ; nevertheless , opinions on indications and clinical efficacy of these techniques are still controversial . Purpose To evaluate the outcome of osteochondral autografts for treatment of femoral condyle cartilage lesions at a medium-to long-term follow-up . Study Design Case series ; Level of evidence , 4 . Methods We prospect ively evaluated 30 patients ( mean age , 29.3 years ) with full-thickness knee chondral lesions ( < 2.5 cm2 ) treated with arthroscopic autologous osteochondral transplantation . Thirteen patients underwent previous surgery , while 17 patients were operated on for the first time . In 19 patients , associated procedures were performed . All patients were evaluated at 2- and 7-year follow-up . The International Cartilage Repair Society form , Tegner score , and magnetic resonance imaging were used for clinical evaluation . Results The International Cartilage Repair Society objective evaluation showed 76.7 % of patients had good or excellent results at 7-year follow-up , and International Knee Documentation Committee subjective score significantly improved from preoperative ( 34.8 ) to 7-year follow-up ( 71.8 ) . The Tegner evaluation showed a significant improvement after the surgery at 2- and 7-year follow-up ( from 2.9 to 6.2 and 5.6 , respectively ) ; however , we noticed reduced sports activity from 2- to 7-year follow-up . Magnetic resonance imaging evaluation showed good integration of the graft in the host bone and complete maintenance of the grafted cartilage in more than 60 % of cases . Conclusion The results of this technique at medium- to long-term follow-up are encouraging . This arthroscopic 1-step surgery appears to be a valid solution for treatment of small , grade III to IV cartilage defects [19966102] Background Autologous chondrocyte implantation ( ACI ) is frequently used to treat symptomatic defects of the articular cartilage . Purpose To test whether matrix-associated autologous chondrocyte implantation or the original periosteal flap technique provides superior outcomes in terms of clinical efficacy and safety . Study Design R and omized controlled trial ; Level of evidence , 2 . Methods Twenty-one patients ( mean age , 29.3 ± 9.1 years ) with symptomatic isolated full-thickness cartilage defects ( mean 4.1 ± 09 cm2 ) at the femoral condyle were r and omized to matrix-associated autologous chondrocyte implantation or the original periosteal flap technique . The primary outcome parameter was the postoperative change in knee function as assessed by the International Knee Documentation Committee ( IKDC ) score at 12 months after ACI . In addition , the IKDC score was assessed at 3 , 6 , 12 , and 24 months after surgery . Secondary outcome parameters were postoperative changes in health related quality of life ( Short Form-36 Health Survey ) , knee functionality ( Lysholm and Gillquist score ) , and physical activity ( Tegner Activity Score ) at 3 , 6 , 12 , and 24 months after ACI . Magnetic resonance imaging was performed to evaluate the cartilage 6 , 12 , and 24 months after ACI and rated using the Magnetic Resonance Observation of Cartilage Repair Tissue score . Adverse events were recorded to assess safety . Results The primary outcome parameter showed improvement of patients 1 year after autologous chondrocyte implantation , but there was no difference between the periosteal flap technique and matrix-associated ACI ( P = .5573 ) ; 2 years after ACI , a similar result was found ( P = .4994 ) . The study groups did not show differences in the Short Form-36 categories and in knee functionality as assessed by Tegner Activity Score 12 months ( P = .4063 ) and 24 months ( P = .1043 ) after ACI . There was a significant difference in the Lysholm and Gillquist score at 12 months ( P = .0449 ) and 24 months ( P = .0487 ) favoring the periosteal flap technique group . At 6 months after surgery , a significantly lower Magnetic Resonance Observation of Cartilage Repair score was obtained in the matrix-associated ACI group ( P = .0123 ) , corresponding to more normal magnetic resonance imaging diagnostic findings . Twelve and 24 months after ACI , the differences between the 2 groups were not significant ( 12 months , P = .2065 ; 24 months , P = .6926 ) . Adverse events were related to knee problems such as transplant delamination , development of an osseous spur , osteochondral dissection , and transplant hypertrophy . Systemic ( allergic , toxic , or autoimmune ) reactions did not occur . Conclusion There was no difference in the efficacy between the original and the advanced ACI technique 12 and 24 months after surgery regarding International Knee Documentation Committee , Tegner Activity Score , and Short Form-36 ; however , with respect to the Lysholm and Gillquist score , better efficacy was observed in the periosteal flap technique group [22483735] PURPOSE To determine the safety and efficacy of a new arthroscopic technique for matrix-induced autologous chondrocyte implantation ( MACI ) for articular cartilage defects in the knee . METHODS We undertook a prospect i ve evaluation of the first 20 patients treated with the MACI technique ( including 14 defects on the femoral condyle and 6 on the tibial plateau ) , followed up for 24 months after surgery . A 12-week structured rehabilitation program was undertaken by all patients . Patients underwent clinical assessment ( Knee Injury and Osteoarthritis Outcome Score , Short Form 36 Health Survey , visual analog pain scale , 6-minute walk test , knee range of motion ) before surgery and at 3 , 6 , 12 , and 24 months after surgery and underwent magnetic resonance imaging ( MRI ) assessment at 3 , 12 , and 24 months after surgery . MRI evaluation assessed 8 previously defined pertinent parameters of graft repair , as well as a combined MRI composite score . RESULTS A significant improvement ( P < .05 ) was shown throughout the postoperative time line for all Knee Injury and Osteoarthritis Outcome Score subscales , the physical component score of the Short Form 36 Health Survey , the frequency and severity of knee pain , and the 6-minute walk test . An improvement in pertinent morphologic parameters of graft repair was observed to 24 months , whereas a good to excellent graft infill score and MRI composite score were observed at 24 months after surgery in 90 % and 70 % of patients , respectively . CONCLUSIONS We report a comprehensive 24-month follow-up in the first 20 patients who underwent the arthroscopic MACI technique . This technique is a safe and efficacious procedure with improved clinical and radiologic outcomes over the 2-year period [23026726] BACKGROUND Autologous chondrocyte implantation ( ACI ) was introduced in 1987 in Sweden by Brittberg and Peterson for the treatment of severe chondral defects of the knee . Here , our objective was to evaluate mid-term outcomes of ACI in young athletic patients with deep chondral defects of the knee after trauma . HYPOTHESIS ACI is effective in filling full-thickness chondral defects of the knee . PATIENTS AND METHODS We prospect ively monitored 14 patients , with International Cartilage Repair Society grade III or IV lesions , who underwent ACI between 2001 and 2006 . St and ard evaluation measurements were used . Mean age at surgery was 37.7 years ( range , 30 - 45 ) . A history of surgery on the same knee was noted in ten ( 67 % ) patients . The defect was on the medial femoral condyle in 11 patients , lateral femoral condyle in two patients , and both femoral condyles in one patient . Mean defect surface area after debridement was 2.1cm(2 ) ( 1 - 6.3 ) . RESULTS After a mean follow-up of six years , improvements were noted in 12 ( 86 % ) patients , with an International Knee Documentation Committee ( IKDC ) score increase from 40 ( 27.6 - 65.5 ) to 60.2 ( 35.6 - 89.6 ) ( P=0.003 ) and a Brittberg-Perterson score decrease from 54.4 ( 11.8 - 98.2 ) to 32.9 ( 0 - 83.9 ) ( P=0.02 ) , between the preoperative assessment and last follow-up . The visual analogic scale pain score decreased from 66.3 ( 44 - 89 ) to 23.2 ( 0 - 77 ) ( P=0.0006 ) . In two ( 14 % ) patients , no improvements were detectable at last follow-up . The remaining 12 patients were satisfied and able to resume sporting activities , albeit at a less strenuous level . Two ACI-specific complications occurred , namely , periosteal hypertrophy treated with debridement in one patient and transplant delamination in another . DISCUSSION Our findings are consistent with previous reports but cover a longer follow-up period . Although the outcomes are promising , longer follow-ups are needed to confirm the long-term effectiveness of ACI . LEVEL OF EVIDENCE IV , prospect i ve therapeutic study [19865812] We compared the results of microfracture in single versus multiple symptomatic articular cartilage defects in the knee in 110 patients with a median age of 38 years ( range 15–60 ) . Cases of reoperation of the cartilage defect were classified as failures . Clinical outcome in non-failures was evaluated by the Lysholm score and grading of knee pain and function of the knee by the use of patient-administered visual analog scales ( VAS ; 0–100 ) . Data were prospect ively collected before the operation and at the 2- to 9-year follow-up . The single lesion or the largest of multiple lesions were located on the medial femoral condyle ( n = 62 ) , trochlea ( n = 18 ) , lateral tibia ( n = 11 ) , patella ( n = 10 ) or lateral femoral condyle ( n = 9 ) . We treated one ( n = 76 ) , two ( n = 27 ) or three ( n = 7 ) lesions with a median total area of 4 cm2 ( range 1–15 ) . A total of 24 failures ( 22 % ) were registered—18 % in the single-defect subgroup and 29 % in the multiple-defects subgroup . In the remaining group of patients ( n = 86 ) , the mean Lysholm score , mean pain-score ( 0 = no pain ; 100 = worst possible pain ) and mean function-score ( 0 = useless ; 100 = full function ) improved from 51 , 52 and 41 , respectively , to 71 ( P < 0.001 ) , 30 ( P < 0.001 ) and 69 ( P < 0.001 ) at the follow-up . The pain-score was significant lower ( P = 0.042 ) , and the function-score significantly higher ( P = 0.001 ) in the group of patients with a single lesion compared to the group with 2 or 3 lesions . The Lysholm score did not differ significantly between the two subgroups ( P = 0.06 ) [22422593] Background Many surgical techniques , including microfracture , periosteal and perichondral grafts , chondrocyte transplantation , and osteochondral grafts , have been studied in an attempt to restore damaged articular cartilage . However , there is no consensus regarding the best method to repair isolated articular cartilage defects of the knee . Questions / purpose sWe compared postoperative functional outcomes , followup MRI appearance , and arthroscopic examination after microfracture ( MF ) , osteochondral autograft transplantation ( OAT ) , or autologous chondrocyte implantation ( ACI ) . Methods We prospect ively investigated 30 knees with MF , 22 with OAT , and 18 with ACI . Minimum followup was 3 years ( mean , 5 years ; range , 3–10 years ) . We included only patients with isolated cartilage defects and without other knee injuries . The three procedures were compared in terms of function using the Lysholm knee evaluation scale , Tegner activity scale , and Hospital for Special Surgery ( HSS ) score ; modified Outerbridge cartilage grade s using MRI ; and International Cartilage Repair Society ( ICRS ) repair grade using arthroscopy . Results All three procedures showed improvement in functional scores . There were no differences in functional scores and postoperative MRI grade s among the groups . Arthroscopy at 1 year showed excellent or good results in 80 % after MF , 82 % after OAT , and 80 % after ACI . Our study did not show a clear benefit of either ACI or OAT over MF . Conclusions Owing to a lack of superiority of any one treatment , we believe MF is a reasonable option as a first-line therapy given its ease and affordability relative to ACI or OAT.Level of Evidence Level II , therapeutic study . See Guidelines for Authors for a complete description of levels of evidence [27474386] Background : Articular cartilage injury is frequently encountered , yet treatment options capable of providing durable cartilage repair are limited . Purpose : To investigate the medium-term clinical outcomes of cartilage repair using a 1-stage technique of a hyaluronic acid – based scaffold with activated bone marrow aspirate concentrate ( HA-BMAC ) and compare results with those of microfracture . A secondary aim of this study was to identify specific patient demographic factors and cartilage lesion characteristics that are associated with superior outcomes . Study Design : Cohort study ; Level of evidence , 2 . Methods : Fifty physically active patients ( mean age , 45 years ) with grade IV cartilage injury of the knee ( lesion size , 1.5 - 24 cm2 ) were treated with HA-BMAC or microfracture and were observed prospect ively for 5 years . Patients were placed into the HA-BMAC group if the health insurance policy of the treating institution supported this option ; otherwise , they were placed into the microfracture group . Objective and subjective clinical assessment tools were used preoperatively and at 2 and 5 years postoperatively to compare treatment outcomes . Results : Significant improvements in outcome scores were achieved in both treatment groups at 2 years ( P < .001 ) . In the microfracture group , 64 % were classified as normal or nearly normal according to the International Knee Documentation Committee ( IKDC ) objective score at 2 years , compared with 100 % of those treated with HA-BMAC ( P < .001 ) . Normal or nearly normal objective assessment s in the microfracture group declined significantly after 5 years to 28 % of patients ( P = .004 ) . All patients treated with HA-BMAC maintained improvement at 5 years according to Lysholm , Tegner , IKDC objective , and IKDC subjective scores . Tegner , IKDC objective , and Knee injury and Osteoarthritis Outcome Score ( KOOS ) assessment s demonstrated higher scores in the HA-BMAC treatment group compared with microfracture at 5 years . Lysholm and IKDC subjective scores were similar between treatment groups at 5 years . Poorer outcomes in the microfracture group were demonstrated in cases of lesions larger than 4 cm2 and nonsolitary lesions . Age greater than 45 years , large size of lesion , and treatment of multiple lesions were not associated with poorer outcome in patients treated with HA-BMAC . Conclusion : Repair of chondral injury using a hyaluronic acid – based scaffold with activated bone marrow aspirate concentrate provides better clinical outcomes and more durable cartilage repair at medium-term follow-up compared with microfracture . Positive short-term clinical outcomes can be achieved with either microfracture or HA-BMAC . Cartilage repair using HA-BMAC leads to successful medium-term outcomes independent of age or lesion size [24258020] Abstract Purpose The purpose of the study was to evaluate whether the biomembrane made of cartilage extracellular matrix , design ed to provide cartilage-like favourable environments as well as to prevent against washout of blood clot after microfracture , would enhance cartilage repair compared with the conventional microfracture technique . Methods A prospect i ve trial was design ed to compare the biomembrane cover after microfracture with conventional microfracture among patients with grade III – IV symptomatic cartilage defect in the knee joint . Patients aged 18–60 years were assigned to either the microfracture/biomembrane ( n = 45 ) or microfracture groups ( n = 19 ) . Among them , 24 knees in the microfracture/biomembrane and 12 knees in the microfracture were followed up for 2 years . Cartilage repair was assessed with magnetic resonance imagings taken 6 months , 1 year , and 2 years postoperatively , and the clinical outcomes were also recorded . Results Compared with conventional microfracture , microfracture/biomembrane result ed in greater degree of cartilage repair ( p = 0.043 ) . In the intra-group analysis , while microfracture showed moderate to good degree of cartilage repair in nearly 50 % of the patients ( 47 % at 6 months to 50 % at 2 years ; n.s . ) , microfracture/biomembrane maintained an equivalent degree of repair up to 2 years ( 88 % at 6 months to 75 % at 2 years ; n.s . ) . The clinical outcome at 2 years also showed improved knee score and satisfaction and decreased pain in each group , but the difference between the two groups was not statistically significant . Conclusions Compared with conventional microfracture , biomembrane cover after microfracture yielded superior outcome in terms of the degree of cartilage repair during 2 years of follow-up . This implies that initial protection of blood clot and immature repair tissue at the microfractured defect is important for the promotion of enhanced cartilage repair , which may be obtained by the application of a biomembrane . Level of evidence Prospect i ve comparative study , Level II [14996869] BACKGROUND New methods have been used , with promising results , to treat full-thickness cartilage defects . The objective of the present study was to compare autologous chondrocyte implantation with microfracture in a r and omized trial . We are not aware of any previous r and omized studies comparing these methods . METHODS Eighty patients without general osteoarthritis who had a single symptomatic cartilage defect on the femoral condyle in a stable knee were treated with autologous chondrocyte implantation or microfracture ( forty in each group ) . We used the International Cartilage Repair Society , Lysholm , Short Form-36 ( SF-36 ) , and Tegner forms to collect data . An independent observer performed a follow-up examination at twelve and twenty-four months . Two years postoperatively , arthroscopy with biopsy for histological evaluation was carried out . The histological evaluation was done by a pathologist and a clinical scientist , both of whom were blinded to each patient 's treatment . RESULTS In general , there were small differences between the two treatment groups . At two years , both groups had significant clinical improvement . According to the SF-36 physical component score at two years postoperatively , the improvement in the microfracture group was significantly better than that in the autologous chondrocyte implantation group ( p = 0.004 ) . Younger and more active patients did better in both groups . There were two failures in the autologous chondrocyte implantation group and one in the microfracture group . No serious complications were reported . Biopsy specimens were obtained from 84 % of the patients , and histological evaluation of repair tissues showed no significant differences between the two groups . We did not find any association between the histological quality of the tissue and the clinical outcome according to the scores on the Lysholm or SF-36 form or the visual analog scale . CONCLUSIONS Both methods had acceptable short-term clinical results . There was no significant difference in macroscopic or histological results between the two treatment groups and no association between the histological findings and the clinical outcome at the two-year time-point . LEVEL OF EVIDENCE Therapeutic study , Level I-1a ( r and omized controlled trial [ significant difference ] ) . See Instructions to Authors for a complete description of levels of evidence [17084294] PURPOSE Age-dependent studies about the clinical result after microfracture of cartilage lesions in the knee are still missing . This prospect i ve study was performed to discover age-dependent differences in the results after microfracture over a period of 36 months . METHODS Between 1999 and 2002 , 85 patients ( mean age , 39 years ) with full-thickness chondral lesions underwent the microfracture procedure and were evaluated preoperatively and at 6 , 18 , and 36 months after surgery . Depending on the patients ' age ( < or = 40 years or > 40 years ) and the localization of the defects ( femoral condyles , tibia , and patellofemoral joint ) , the patients were assigned to 6 different groups . Exclusion criteria were meniscal pathologic conditions , tibiofemoral malalignment , and ligament instabilities . Baseline clinical scores were compared with follow-up data by use of paired Wilcoxon tests for the modified Cincinnati knee score and the International Cartilage Repair Society ( ICRS ) score . RESULTS The scores improved in all groups over the whole study period ( P < .05 ) . Patients aged 40 years or younger had significantly better results ( P < .01 ) for both scores compared with older patients . Between 18 and 36 months after microfracture , the ICRS score deteriorated significantly ( P < .05 ) in patients aged over 40 years whereas younger patients with defects on the femoral condyles and on the tibia showed neither a significant improvement nor a significant deterioration in the ICRS score ( P > .1 ) . Magnetic resonance imaging 36 months after surgery revealed better defect filling and a better overall score in younger patients ( P < .05 ) . The Spearman coefficient of correlation between clinical and magnetic resonance imaging scores was 0.84 . CONCLUSIONS The clinical results after microfracture of full-thickness cartilage lesions in the knee are age-dependent . Deterioration begins 18 months after surgery and is significantly pronounced in patients aged older than 40 years . The best prognostic factor was found to be a patient age of 40 or younger with defects on the femoral condyles . LEVEL OF EVIDENCE Level IV , prognostic case series [21596901] Background Aging is responsible for degenerative changes in all cartilage elements , thus impairing its properties and healing potential . Most studies on surgical procedures for cartilage focus on young patients because these procedures are generally not considered suitable for older patients . Purpose To analyze the clinical outcome of cartilage lesion treatment using second-generation autologous chondrocyte implantation ( ACI ) techniques in patients more than 40 years old with no clear signs of osteoarthritis , to underst and their real potential in relation to aging , the failure rate , and complications in older patients . Study Design Case series ; Level of evidence , 4 . Methods Sixty-one patients with grade III to IV cartilaginous lesions of the condyles with no clear signs of osteoarthritis and a minimum age of 40 years were treated with second-generation ACI and prospect ively evaluated at 5 years ’ follow-up . Twenty-two patients were treated with arthroscopic Hyalograft C implantation , and 39 underwent the open Chondro-Gide MACI procedure . Results A significant improvement in both subjective and objective evaluations was observed . The International Knee Documentation Committee ( IKDC ) subjective score improved from 36.8 ± 8.4 to 68.1 ± 21.8 at the final evaluation . The failure rate was 20 % . A faster improvement was observed in the group treated with the arthroscopic Hyalograft C technique , whereas similar scores were found at the 24-month follow-up and final evaluation . Conclusion A clinical improvement was found in patients more than 40 years old , who in most cases benefited from second-generation ACI with good results lasting at medium-term follow-up . However , the results were inferior with respect to those previously found for younger population s , and the failure rate at medium-term follow-up was also higher . These findings were consistent in the 2 treatment groups . The only difference was the faster recovery when the arthroscopic approach was used

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### Context: [22286745] Purpose Treatment of large cartilage lesions of the knee in weight-bearing areas is still a controversy and challenging topic . Autologous osteochondral mosaicplasty has proven to be a valid option for treatment but donor site morbidity with most frequently used autografts remains a source of concern . This study aims to assess clinical results and safety profile of autologous osteochondral graft from the upper tibio-fibular joint applied to reconstruct symptomatic osteochondral lesions of the knee . Methods Thirty-one patients ( 22 men and 9 women ) with grade 4 cartilage lesions in the knee were operated by mosaicplasty technique using autologous osteochondral graft from the upper tibio-fibular joint , between 1998 and 2006 . Clinical assessment included visual analog scale ( VAS ) for pain and Lysholm score . All patients were evaluated by MRI pre- and post-operatively regarding joint congruency as good , fair ( inferior to 1 mm incongruence ) , and poor ( incongruence higher than 1 mm registered in any frame ) . Donor zone status was evaluated according to specific protocol considering upper tibio-fibular joint instability , pain , neurological complications , lateral collateral ligament insufficiency , or ankle complaints . Results Mean age at surgery was 30.1 years ( SD 12.2 ) . In respect to lesion sites , 22 were located in weight-bearing area of medial femoral condyle , 7 in lateral femoral condyle , 1 in trochlea , and 1 in patella . Mean follow-up was 110.1 months ( SD 23.2 ) . Mean area of lesion was 3.3 cm2 ( SD 1.7 ) , and a variable number of cylinders were used , mean 2.5 ( SD 1.3 ) . Mean VAS score improved from 47.1 ( SD 10.1 ) to 20.0 ( SD 11.5 ) ; p = 0.00 . Similarly , mean Lysholm score increased from 45.7 ( SD 4.5 ) to 85.3 ( SD 7.0 ) ; p = 0.00 . The level of patient satisfaction was evaluated , and 28 patients declared to be satisfied/very satisfied and would do surgery again , while 3 declared as unsatisfied with the procedure and would not su bmi t to surgery again . These three patients had lower clinical scores and kept complaints related to the original problem but unrelated to donor zone . MRI score significantly improved at 18–24 months comparing with pre-operative ( p = 0.004 ) . No radiographic or clinical complications related to donor zone with implication in activity were registered . Conclusions This work corroborates that mosaicplasty technique using autologous osteochondral graft from the upper tibio-fibular joint is effective to treat osteochondral defects in the knee joint . No relevant complications related to donor zone were registered . Level of evidence Case series , Level IV [4028546] Abstract Purpose To compare long-term functional and radiological outcome following microfracture technique ( MF ) versus osteochondral autologous transplantation ( OAT ) mosaicplasty for treating focal chondral lesions of the knee . Methods Twenty-five patients ( mean age 32.3 years , SD 7.7 ) with a full-thickness ( International Cartilage Repair Society grade 3 or 4 ) chondral lesion of the articulating surface of the femur were r and omized to either MF ( n = 11 ) or OAT mosaicplasty ( n = 14 ) . At a median follow-up of 9.8 years ( range 4.9–11.4 ) , the patients were evaluated using Lysholm score ( n = 25 ) , Knee Injury and Osteoarthritis Outcome Score ( KOOS , n = 25 ) , isokinetic quadriceps measurement and hamstring strength measurement ( n = 22 ) and st and ing radiographs ( n = 23 ) . Results There were no significant differences in Lysholm score , KOOS , isokinetic muscle strength or radiographic osteoarthritis between MF-treated patients and OAT mosaicplasty-treated patients at follow-up . Mean Lysholm score at follow-up was 69.7 [ 95 % confidence interval ( CI ) , 55.1–84.4 ] for the MF group and 62.6 ( 95 % CI , 52.6–72.6 ) for the OAT mosaicplasty group . Conclusion At long-term follow-up , there were no significant differences between patients treated with MF and patients treated with OAT mosaicplasty in patient-reported outcomes , muscle strength or radiological outcome .Level of evidence Therapeutic study , Level II [25002462] Background : Autologous chondrocyte implantation ( ACI ) has been shown to be effective in the midterm for the treatment of symptomatic articular cartilage lesions of the knee , but few long-term series have been published . The multioperated chronic articular cartilage defect remains a difficult condition to treat . Purpose : To examine the long-term clinical results of ACI for large chronic articular cartilage defects , many treated as salvage . Study Design : Case series ; Level of evidence , 4 . Methods : This is a prospect i ve case series of 104 patients with a mean age of 30.2 years and a symptomatic lesion of the articular cartilage in the knee , who underwent ACI between 1998 and 2001 . The mean duration of symptoms before surgery was 7.8 years . The mean number of previous surgical procedures on the cartilage defect , excluding arthroscopic debridement , was 1.3 . The defects were large , with a mean size of 477.1 mm2 ( range , 120 - 2500 mm2 ) . The modified Cincinnati , Stanmore/Bentley , and visual analog scale for pain scoring systems were used to assess pain and functional outcomes at a minimum 10 years ( mean , 10.4 years ; range , 10 - 12 years ) . Results : Twenty-seven patients ( 26 % ) experienced graft failure at a mean of 5.7 years after ACI . Of the 73 patients who did not fail , 46 patients ( 63 % of patients with a surviving graft ) had an excellent result , 18 ( 25 % ) were good , 6 ( 8 % ) were fair , and 3 ( 4 % ) had a poor result . Of a total of 100 patients successfully followed up , 98 were satisfied with the ACI technique for their chronic knee pain and would undergo the procedure again . Conclusion : Autologous chondrocyte implantation can provide a long-term solution in more than 70 % of young patients of a difficult-to-treat group with large chronic articular cartilage lesions , even in the salvage situation [4297133] Objective : Fresh osteochondral allograft transplantation ( OCA ) is an increasingly available option for patients with damage to the bone-cartilage complex of the distal femur . This study prospect ively assesses osseous integration and early clinical results following fresh OCA with single or multiple cylindrical grafts to the femoral condyle . Design : Patients with grade 4 International Cartilage Repair Society ( ICRS ) defects of the distal femur were treated with OCA . Outcome measures were collected preoperatively and postoperatively at 6 , 12 , and 24 months . Computed tomography ( CT ) scans obtained at 6 months were used to assess degree of osseous incorporation regionally . Results : Thirty-four patients , with a mean age of 34.5 years ( range , 15 - 61 ) , with a mean femoral osteochondral lesion of 5.7 cm2 ( range , 1.5 - 15.0 ) due to focal osteoarthritis , osteochondritis dissecans , and avascular necrosis , are reported . Statistically significant ( P < 0.05 ) mean improvement in outcome scores at 2 years included Knee Injury and Osteoarthritis Outcomes Score ( KOOS ) pain , sports and recreation , quality of life , and International Knee Documentation Committee ( IKDC ) . CT imaging indicated grafts implanted to direct weightbearing regions had > 75 % incorporation ( 20/26 grafts ) compared to < 50 % incorporation in the indirect weightbearing regions ( 8/14 grafts ) . A greater degree of incorporation and earlier outcome improvement were found after single ( n = 23 ) compared to multiple ( n = 11 ) grafts . Conclusion : CT scans were used to assess osseous incorporation of fresh osteochondral allografts in a cohort that showed significant improvements after 2 years . Single-graft implantation is associated with stable incorporation of a greater percentage of the graft . Lesser incorporation appears more frequently with grafts in posterior indirect weightbearing regions of the condyle and multiple contiguous grafts [21460066] Background : There are currently several approaches being pursued to treat focal defects of articular cartilage , each having specific advantages or challenges . A single-stage procedure that uses autologous cartilage fragments , Cartilage Autograft Implantation System ( CAIS ) , is being evaluated in patients and may offer a clinical ly effective option . Purpose : To establish the safety of CAIS and to test whether CAIS improves quality of life by using st and ardized outcomes assessment tools . Study Design : R and omized controlled trial ; Level of evidence , 2 . Methods : Patients ( n = 29 ) were r and omized ( 1:2 ) with the intent to treat with either a control ( microfracture [ MFX ] ) or an experimental ( CAIS ) procedure . Patients were followed at predetermined time points for 2 years using several st and ardized outcomes assessment tools ( SF-36 , International Knee Documentation Committee [ IKDC ] , Knee injury and Osteoarthritis Outcome Score [ KOOS ] ) . Magnetic resonance imaging was performed at baseline , 3 weeks , and 6 , 12 , and 24 months . Results : Lesion size and International Cartilage Repair Society ( ICRS ) grade were similar in both groups . General outcome measures ( eg , physical component score of the SF-36 ) indicated an overall improvement in both groups , and no differences in the number of adverse effects were noted in comparisons between the CAIS and MFX groups . The IKDC score of the CAIS group was significantly higher ( 73.9 ± 14.72 at 12 months and 82.95 ± 14.88 at 24 months ) compared with the MFX group ( 57.78 ± 18.31 at 12 months and 59.5 ± 13.44 at 24 months ) . Select subdomains ( 4/5 ) in the KOOS instrument were significantly different at 12 and 18 months , and all subdomains ( Symptoms and Stiffness , Pain , Activities of Daily Living , Sports and Recreation , Knee-related Quality of Life ) were significantly increased at 24 months in CAIS with scores of 88.47 ± 11.68 , 90.64 ± 7.87 , 97.29 ± 3.8 , 78.16 ± 22.06 , and 69 ± 23.15 compared with 75 ± 9.31 , 78.94 ± 13.73 , 89.46 ± 8.13 , 51.67 ± 26.01 , and 37.15 ± 21.67 in the MFX group . These significant improvements were maintained at 24 months in both IKDC and KOOS . Qualitative analysis of the imaging data did not note differences between the 2 groups in fill of the graft bed , tissue integration , or presence of subchondral cysts . Patients treated with MFX had a significantly higher incidence of intralesional osteophyte formation ( 54 % and 70 % of total number of lesions treated ) at 6 and 12 months when compared with CAIS ( 8 % and 25 % of total number of lesions treated ) . Conclusion : The first clinical experience in using CAIS for treating patients with focal chondral defects indicates that it is a safe , feasible , and effective method that may improve long-term clinical outcomes [19846693] Background There is no consensus about the optimal time for weightbearing activities after matrix-associated autologous chon-drocyte implantation ( MACI ) of the femoral condyle . Hypothesis A comprehensive protocol after MACI on the femoral condyle with accelerated weightbearing leads to a better functional and radiographic outcome compared with the same comprehensive protocol with delayed weightbearing . Study Design R and omized controlled trial ; Level of evidence , 1 . Methods Thirty-one patients ( 22 male , 9 female ) after MACI on the femoral condyle were r and omly assigned to the accelerated weightbearing group ( group A ) or the delayed weightbearing group ( group B ) . Aside from increase and time of full weightbearing , both groups adhered to the same rehabilitation protocol and exercises . Patients were assessed preoperatively and at 4 , 12 , 24 , 52 , and 104 weeks after surgery . Clinical evaluation was performed by determining the subjective form of the International Knee Documentation Committee ( IKDC ) , the Tegner activity scale , and the Knee Injury and Osteoarthritis Outcome Score ( KOOS ) . Radiological outcome was evaluated by the MOCART score and the size and amount of bone marrow edema and effusion . Results In both groups , there were no differences with regard to the clinical outcome . For the radiological outcome , group A showed a higher prevalence of bone marrow edema after 6 months without correlation to the clinical outcome ( P 5 .06-.1 ) . However , after 104 weeks , there were no differences in the radiological outcome between group A and group B. Conclusion A rehabilitation protocol with accelerated weightbearing leads to good clinical and functional outcome after 2 years without jeopardizing the healing graft [25482347] BACKGROUND This study aims to document the long-term results in a group of patients treated with arthroscopic mosaicplasty for knee cartilage lesions , both in terms of clinical outcome and joint degeneration progression , evaluated by radiographs . METHODS 26 patients ( 19 men and 7 women , mean age 29 years , mean BMI 23 ) treated arthroscopically with mosaicplasty for cartilage defects of the femoral condyles ( mean/median/mode size 1.9 st and ard deviation , SD 0.6 cm(2 ) ) were prospect ively evaluated at 12 years follow-up . The clinical outcome was analyzed with IKDC and Tegner scores . Range of motion , transpatellar and suprapatellar circumferences were also measured . Radiographs with weight-bearing antero-posterior and Rosenberg projections were used for radiological evaluation in 18 patients , applying both Kellgren-Lawrence score and a direct joint line measurement to assess osteoarthritis . RESULTS A significant improvement in all clinical scores was obtained from the basal evaluation to the 12-year follow-up ( IKDC subjective score from 36.8 st and ard deviation , SD 13.0 to 77.3 st and ard deviation , SD 20.6 , P<0.0005 ; Tegner score from 2.9 st and ard deviation , SD 1.3 to 5.2 st and ard deviation , SD 2.5 , P<0.0005 ) , and better results in patients with a higher pre-injury activity level and those requiring fewer plugs . The radiographic evaluation showed significantly poorer Kellgren-Lawrence scores and a reduction of the joint line in the treated compartments . Knees with 3 - 4 plugs presented a significantly higher joint degeneration level with respect to those implanted with 1 - 2 plugs . CONCLUSIONS Mosaicplasty is an effective surgical option for small lesions of the femoral condyles . Although joint degeneration progression was present at 12 years , this did not affect significantly the clinical outcome which was satisfactory at long-term follow-up [22637204] BACKGROUND Despite introduction of autologous chondrocyte therapy for repair of hyaline articular cartilage injury in 1994 , microfracture remains a primary st and ard of care . NeoCart , an autologous cartilage tissue implant , was compared with microfracture in a multisite prospect i ve , r and omized trial of a tissue-engineered bioimplant for treating articular cartilage injuries in the knee . METHODS Thirty patients were r and omized at a ratio of two to one ( two were treated with an autologous cartilage tissue implant [ NeoCart ] for each patient treated with microfracture ) at the time of arthroscopic confirmation of an International Cartilage Repair Society ( ICRS ) grade -III lesion(s ) . Microfracture or cartilage biopsy was performed . NeoCart , produced by seeding a type-I collagen matrix scaffold with autogenous chondrocytes and bioreactor treatment , was implanted six weeks following arthroscopic cartilage biopsy . St and ard evaluations were performed with vali date d clinical outcomes measures . RESULTS Three , six , twelve , and twenty-four-month data are reported . The mean duration of follow-up ( and st and ard deviation ) was 26 ± 2 months . There were twenty-one patients in the NeoCart group and nine in the microfracture group . The mean age ( 40 ± 9 years ) , body mass index ( BMI ) ( 28 ± 4 kg/m2 ) , duration between the first symptoms and treatment ( 3 ± 5 years ) , and lesion size ( 287 ± 138 mm2 in the NeoCart group and 252 ± 135 mm2 in the microfracture group ) were similar between the groups . Adverse event rates per procedure did not differ between the treatment arms . The scores on the Short Form-36 ( SF-36 ) , Knee Injury and Osteoarthritis Outcome Score ( KOOS ) activities of daily living ( ADL ) scale , and International Knee Documentation Committee ( IKDC ) form improved from baseline ( p < 0.05 ) to two years postoperatively in both treatment groups . In the NeoCart group , improvement , compared with baseline , was significant ( p < 0.05 ) for all measures at six , twelve , and twenty-four months . Improvement in the NeoCart group was significantly greater ( p < 0.05 ) than that in the microfracture group for the KOOS pain score at six , twelve , and twenty-four months ; the KOOS symptom score at six months ; the IKDC , KOOS sports , and visual analog scale ( VAS ) pain scores at twelve and twenty-four months ; and the KOOS quality of life ( QOL ) score at twenty-four months . Analysis of covariance ( ANCOVA ) at one year indicated that the change in the KOOS pain ( p = 0.016 ) and IKDC ( p = 0.028 ) scores from pretreatment levels favored the NeoCart group . Significantly more NeoCart-treated patients ( p = 0.0125 ) had responded to therapy ( were therapeutic responders ) at six months ( 43 % versus 25 % in the microfracture group ) and twelve months ( 76 % versus 22 % in the microfracture group ) . This trend continued , as the proportion of NeoCart-treated patients ( fifteen of nineteen ) who were therapeutic responders at twenty-four months was greater than the proportion of microfracture-treated participants ( four of nine ) who were therapeutic responders at that time . CONCLUSIONS This r and omized study suggests that the safety of autologous cartilage tissue implantation , with use of the NeoCart technique , is similar to that of microfracture surgery and is associated with greater clinical efficacy at two years after treatment [12571292] Background : Current methods used to restore the joint surface in patients with localized articular cartilage defects include transplantation of an autologous osteochondral cylinder and implantation of autologous chondrocytes . The purpose of this study was to evaluate the clinical and histological outcomes of these two techniques . Methods : We performed a prospect i ve clinical study to investigate the two-year outcomes in forty patients with an articular cartilage lesion of the femoral condyle who had been r and omly treated with either transplantation of an autologous osteochondral cylinder or implantation of autologous chondrocytes . Biopsy specimens from representative patients of both groups were evaluated with histological staining , immunohistochemistry , and scanning electron microscopy . Results : According to the postoperative Lysholm score , the recovery after autologous chondrocyte implantation was slower than that after osteochondral transplantation at six months ( p ⩽ 0.015 ) , twelve months ( p ⩽ 0.001 ) , and twenty-four months ( p ⩽ 0.012 ) . On the basis of the Meyers score and the Tegner activity score , the results were equally good with the two methods two years after treatment . Histomorphological evaluation of biopsy specimens within two years after autologous chondrocyte implantation demonstrated a complete , mechanically stable resurfacing of the defect in all patients . The tissue consisted mainly of fibrocartilage , while localized areas of hyaline-like regenerative cartilage could be detected close to the subchondral bone . Although a gap remained at the site of the transplantation in all five biopsy specimens examined as long as two years after osteochondral cylinder transplantation , histomorphological analysis and scanning electron microscopy revealed no differences between the osteochondral transplants and the surrounding original cartilage . Conclusions : Both treatments result ed in a decrease in symptoms . However , the improvement provided by the autologous chondrocyte implantation lagged behind that provided by the osteochondral cylinder transplantation . Histologically , the defects treated with autologous chondrocyte implantation were primarily filled with fibrocartilage , whereas the osteochondral cylinder transplants retained their hyaline character , although there was a persistent interface between the transplant and the surrounding original cartilage . Limitations of our study included the small number of patients , the relatively short ( two-year ) follow-up , and the absence of a control group . Level of Evidence : Therapeutic study , Level II-2 ( poor- quality r and omized controlled trial [ e.g. , < 80 % follow-up ] ) . See Instructions to Authors for a complete description of levels of evidence [12012034] Abstract . Background and aims : Large osteochondral defects in the weight-bearing zone of the knee remain a challenging therapeutic problem . Surgical options include drilling , microfracturing , and transplantation of osteochondral plugs but are often insufficient for the treatment of large defects of the femoral condyle . Patients and methods : Large osteochondral defects of the femoral condyle ( mean defect size 7.2 cm2 range 3–20 ) were treated by transplantation of the autologous posterior femoral condyle . Between 1984 and 2000 , 29 patients were operated on : in 22 the medial , in 6 the lateral femoral condyle , and in one the trochlear groove was grafted . Thirteen patients underwent simultaneous high tibial valgus osteotomy . In the first series ( 1984–1999 ) the graft was temporarily fixed with a screw ( n=12 ) , but from 1999 we used a newly developed press-fit technique ( n=17 ) avoiding screw fixation of the graft . The operative technique comprising graft harvest , defect preparation , transplantation , and fixation is described . Patients were clinical ly evaluated using the Lysholm score , and magnetic resonance imaging with intravenous contrast was performed 6 and 12 weeks after surgery ( mean follow-up 17.7 months ( range 3–46 ) . Results : Pain and swelling were reduced in 26 patients . Three patients of the first series reported persistent problems and were subjectively not satisfied . The mean Lysholm score rose from preoperatively 52 to 77 points after 3 months , 74 after 6 , 88 after 12 , and 95 after 18 . Magnetic resonance imaging showed good graft viability in all cases . We saw one arthrofibrosis after 6 months but noted no problems related to the loss of the missing posterior condyle . Conclusion : Large osteochondral defects of the femoral condyle can be treated by transplantation of the autologous posterior femoral condyle . The use of only one osteochondral piece renders better approximation of the femoral cartilage curvature and thus joint congruence than in mosaic plasty . However , whether loss of the posterior condyle has a long-term negative impact on the knee joint remains to be eluci date [24664138] Background : Matrix-associated autologous chondrocyte transplantation ( MACT ) has become an established articular cartilage repair technique . It provides good short-term and midterm results ; however , long-term results are lacking . Purpose : To prospect ively assess the clinical outcome after MACT in the knee to report long-term results . Study Design : Case series ; Level of evidence , 4 . Methods : Fifty-three subjects ( females/males , 22/31 ; mean age , 32 ± 12 years ) were treated between 2000 and 2006 with a hyaluronan-based MACT product and were followed prospect ively . The mean body mass index ( BMI ) was 24.5 ± 3.8 kg/m2 and the mean defect size was 4.4 ± 1.9 cm2 . Fifty patients had single defects and 3 had multiple defects ( 41 medial femoral condyle , 6 lateral femoral condyle , 2 patella , 1 tibia ) . Two patients had 2 defects ( medial femoral condyle [MFC]/lateral femoral condyle and tibial/MFC ) , and in 1 case , multiple defects on the MFC were treated . The patients were stratified into 23 “ simple , ” 22 “ complex , ” and 8 “ salvage ” cases . Instability or malalignment was treated before or at the time of graft implantation . For 6 patients with small defects ( < 2 cm2 ) , microfracturing was used as first-line treatment before MACT . Clinical assessment was performed once a year with the subjective and objective International Knee Documentation Committee ( IKDC ) scores , Lysholm score , and a modified Cincinnati Knee Rating System . Results : The mean follow-up time was 9.07 ± 2.9 years ( range , 5 - 12 years ) . Treatment failure occurred in 12 of 53 cases ( 22.6 % ) an average of 2.99 ± 1.40 years after surgery . There was 1 failure ( 4.3 % ) among the simple cases , 4 failures ( 18.2 % ) in complex cases , and 7 failures ( 87.5 % ) in salvage cases . Statistically significant increases were observed in all scores at all time points compared with presurgery levels ( P < .05 ) . The subjective IKDC score improved from median 40.4 preoperatively to 74.7 at 10-year follow-up ( n = 13 patients ; P < .05 ) . Conclusion : MACT is an excellent surgical therapy for full-thickness cartilage defects of the knee , with good long-term results for simple defects . However , it should not be used in salvage cases [17372718] A biodegradable , hyaluronian-based biocompatible scaffold was used for autologous chondrocyte transplantation . This prospect i ve study analyzes a clinical outcome of 70 consecutive patients treated by arthroscopic autologous chondrocyte transplantation at minimum 24 months follow up ( 47 of these patients achieved minimum 36 months follow-up and 21 patients minimum 48 months follow-up ) in order to establish clear indication criteria for this type of treatment . 31 of these patients presented isolated chondral lesions , while 39 patients with associated lesions ( 23 ACL lesions , 28 meniscal lesions , 1 varus knee ) were treated during the same surgical procedure with cartilage harvesting . A statistically significant clinical improvement was shown just at 24 months and the second-look arthroscopy demonstrated a complete coverage of the grafted area with a hyaline cartilage-like tissue in 12 of 15 analyzed patients . A better clinical outcome was observed in young , well-trained patients and in traumatic lesions . Other factors , such as defect size , localization , previous and associated surgery did not influence significantly the results . This matrix autologous chondrocyte transplantation procedure simplifies the surgical procedure and can be performed arthroscopically , thus reducing surgical morbidity and recovery time [19339564] BACKGROUND Because of concerns about infections with the use of fresh osteoarticular allografts , osteoarticular allografts are currently stored hypothermically for a minimum of fourteen days to allow for serologic and microbiologic testing prior to implantation . Refrigerated osteoarticular allograft transplants are often used to treat symptomatic chondral and osteochondral defects in young , active patients . Chondrocyte viability has been shown to decrease substantially when allografts are stored for longer than twenty-eight days . The purpose of this study was to examine the clinical and functional outcomes of patients receiving refrigerated osteoarticular allografts between fifteen and twenty-eight days after procurement . METHODS Twenty-three consecutive patients ( twenty-three knees ) who underwent treatment of focal articular cartilage defects of the femoral condyles with refrigerated osteoarticular grafts were prospect ively followed for an average of three years . The average age of the implanted refrigerated allografts was 20.3 days . The patients were assessed preoperatively and postoperatively with vali date d outcome surveys . RESULTS The mean modified Cincinnati knee ratings significantly improved from baseline to the time of the final follow-up , with an increase from 27.3 to 36.5 on the subscale rating for function ( p<0.01 ) , from 21.9 to 32.5 on the subscale rating for symptoms ( p<0.03 ) , and from 49.2 to 69.0 for the overall score ( p<0.02 ) . The mean International Knee Documentation Committee subjective score improved from 52 points at baseline to 68.5 points at the time of the final follow-up ( p<0.03 ) . A significant improvement was also found for effusions and functional testing ( the single-leg hop ) ( p<0.001 for both ) . Radiographic evaluation at the time of the final follow-up revealed that twenty-two of the twenty-three grafts were in stable position with good osseous incorporation into host bone . No graft failure was encountered . CONCLUSIONS Transplantation of refrigerated osteoarticular allografts stored between fifteen and twenty-eight days provides significant functional and clinical improvement after an average follow-up of three years in patients treated for a full-thickness osteochondral defect of the femoral condyle , with similar outcomes to historical reports of patients with fresh allograft implants [25606529] PURPOSE to assess the efficacy of associating the microfracture technique with platelet-rich plasma ( PRP ) injections in the treatment of chondral lesions to promote acceleration and optimization of the healing process compared with the traditional microfracture approach . METHODS from September 2011 to August 2012 , 20 patients ( 9 males and 11 females , aged 30 - 55 years ) were treated . All presented with chondral lesions of the medial femoral condyle of the knee and a pain duration ranging from 8 to 12 months . The patients were r and omized into two groups ( A and B ) . Group A was treated with the microfracture technique and a total of three intra-articular injections of PRP . Group B was treated with microfractures alone . Clinical follow-up was performed at 3 , 6 and 12 months after treatment . Clinical function was assessed on the basis of the International Knee Documentation Committee ( IKDC ) score . Pain was evaluated using a visual analogue scale ( VAS ) . RESULTS the patients in group A had a mean baseline IKDC score of 31.2 , which rose to 84.2 at 12 months . The IKDC scores in group B were at 30.1 at baseline and 81 at 12 months . CONCLUSIONS the results of our study suggest that functional recovery and resolution of pain are obtained more quickly in PRP-treated patients . We also observed a better functional outcome in the patients treated with the combination of PRP and microfractures , even at 12 months , although the difference was not statistically significant . LEVEL OF EVIDENCE level II , r and omized clinical study [25090800] This study presents the prospect i ve two-year clinical and MRI outcome of autologous matrix-induced chondrogenesis ( AMIC ) for the treatment of patellofemoral cartilage defects in the knee . Ten patients were clinical ly prospect ively evaluated during 2 years . MRI data were analysed based on the original and modified MOCART ( Magnetic Resonance Observation of Cartilage Repair Tissue ) scoring system . A satisfying clinical improvement became apparent during the 24 months of follow-up . The MOCART scoring system revealed a slight tendency to deterioration on MRI between one and 2 years of follow-up . However , the difference was not statistical significant . All cases showed subchondral lamina changes . The formation of intralesional osteophytes was observed in 3 of the 10 patients ( 30 % ) . In conclusion , AMIC is safe and feasible for the treatment of symptomatic patellofemoral cartilage defects and result ed in a clinical improvement . However , the favourable clinical outcome of the AMIC technique was not confirmed by the MRI findings [26815276] Purpose The treatment of full-thickness cartilage defects of the knee is a common problem in orthopaedic surgery . Autologous chondrocyte transplantation ( ACT ) is one of the few reliable treatment options of cartilage defects with good long-term outcomes . The improvement of ACT led to the matrix-based ACT ( MACT ) . The purpose of the study was to compare two different commercially available MACT systems . Methods Eleven patients with a cartilage defect of the knee were treated with the MACI ® system and another nine patients with the CaRes ® implant . The patients were prospect ively followed and re-examined after one year . Results One year after surgery all but one patient have significantly improved in their clinical outcome . Both types of MACT revealed similar results in terms of increase in level of activity , pain relief and knee function . Conclusion The study showed that MACT is a good therapeutic option for full-size defects of the femoral condyle . The MACI ® implant seems to be easier to h and le which is reflected by smaller incisions and a shorter operation time [21531864] Background Autologous chondrocyte implantation ( ACI ) has been shown to have favorable results in the treatment of symptomatic chondral and osteochondral lesions . However , there are few reports on the outcomes of this technique in adolescents . Purpose The aim of this study was to assess pain relief and functional outcome in adolescents undergoing ACI . Study Design Case series ; Level of evidence , 4 . Methods Thirty-five adolescent patients undergoing ACI or matrix-assisted chondrocyte implantation ( MACI ) were identified from a larger cohort . Four patients were lost to follow-up , leaving 31 patients ( 24 ACI , 7 MACI ) . The mean age was 16.3 years ( range , 14 - 18 years ) with a mean follow-up of 66.3 months ( range , 12 - 126 months ) . There were 22 male and 9 female patients . All patients were symptomatic ; 30 had isolated lesions and 1 had multiple lesions . Patients were assessed preoperatively and post-operatively using the visual analog scale ( VAS ) score for pain , the Bentley Functional Rating Score , and the Modified Cincinnati Rating System . At 1 year postoperatively , patients were recalled for a diagnostic biopsy , which was successfully attained in 21 patients . Results The mean pain scores improved from 5 preoperatively to 1 postoperatively . The Bentley Functional Rating Score improved from 3 to 0 , while the Modified Cincinnati Rating System improved from 48 preoperatively to 92 postoperatively with 84 % of patients achieving excellent or good results . All postoperative scores exhibited significant improvement from preoperative scores . One patient underwent graft hypertrophy and 1 patient 's graft failed and was revised . Biopsy results revealed hyaline cartilage in 24 % of cases , mixed fibro/hyaline cartilage in 19 % , and fibrocartilage in 57 % . Conclusion Results show that , in this particular group who received ACI , patients experienced a reduction in pain and significant improvement in postoperative function after ACI or MACI . The authors believe that ACI is appropriate in the management of carefully selected adolescents with symptomatic chondral and osteochondral defects [19059899] Background Various approaches have been proposed to treat articular cartilage lesions , which are plagued by inherent limited healing potential . Purpose To compare the clinical outcome of patients treated with second-generation autologous chondrocyte implantation implants with those treated with the microfracture repair technique at 5-year follow-up . Study Design Cohort study ; Level of evidence , 2 . Methods Eighty active patients ( mean age , 29.8 years ) and grade III to IV cartilage lesions of the femoral condyles or trochlea were treated with arthroscopic second-generation autologous chondrocyte implantation Hyalograft C or microfracture ( 40 patients per group ) . Patients achieved a minimum 5-year follow-up and were prospect ively evaluated . Results Both groups showed statistically significant improvement of all clinical scores from preoperative interval to 5-year follow-up . There was a significant improvement for the International Knee Documentation Committee subjective score from preoperative to 5-year follow-up ( Wilcoxon test , P < .001 ) . In the microfracture group , the International Knee Documentation Committee objective score increased from 2.5 % normal and nearly normal knees before the operation to 75 % normal and nearly normal knees at 5-year follow-up , and the subjective score increased from 41.1 ± 12.3 preoperatively to 70.2 ± 14.7 at 5-year follow-up . In the group treated with Hyalograft C , the International Knee Documentation Committee objective score increased from 15 % normal and nearly normal knees before the operation to 90 % normal and nearly normal knees at 5-year follow-up , and its subjective score increased from 40.5 ± 15.2 preoperatively to 80.2 ± 19.1 at 5-year follow-up ( Wilcoxon test , P < .001 ) . When comparing the groups , better improvement of the International Knee Documentation Committee objective ( P < .001 ) and subjective ( P = .003 ) scores was observed in the Hyalograft C group at 5-year follow-up . The return to sports at 2 years was similar in both groups and remained stable after 5 years in the Hyalograft C group ; it worsened in the microfracture group . Conclusion Both methods have shown satisfactory clinical outcome at medium-term follow-up . Better clinical results and sport activity resumption were noted in the group treated with second-generation autologous chondrocyte transplantation [24663398] Purpose Focal chondral and osteochondral knee lesions are a common condition , particularly hard to treat , and often involve young active patients with high expectations in terms of symptomatic relief and return to sports . Autologous osteochondral transplantation allows the defect area to be restored with hyaline cartilage . The aim of this study is to analyse whether it represents a safe and effective treatment option for small – medium-sized knee chondral and osteochondral lesions in a young and active population . Methods Thirty-one patients ( 18 men , 13 women ; mean age 32 ± ten ; mean BMI 24 ± 3 ) affected by focal knee chondral and osteochondral lesions were enrolled and treated with autologous osteochondral transplantation . They were prospect ively followed-up for 24 months with the IKDC-subjective , IKDC- objective , and Tegner scores . Adverse events and failures were also reported , as well as the B and i score to detect symptoms from the donor area . Results A significant increase was reported in all the clinical scores adopted . In particular , the IKDC-subjective score increased from a basal value of 40.3 ± 16.2 to 62.6 ± 18.0 at the 12 months ’ evaluation , with a further significant increase up to 71.6 ± 20.5 at the final 24 months ’ follow-up ( p < 0.0005 ) . A positive trend was also found by analysing the IKDC- objective score . The Tegner score revealed a significant improvement from a basal value of 2.2 ± 1.8 to 3.7 ± 1.5 at the final evaluation ( p = 0.003 ) , although it was not possible to regain the same pre-injury sports activity level of 5.0 ± 2.2 . Two failures were reported . The B and i score revealed patients complaining of mild and moderate symptoms , not correlated to the lesion size . The presence of symptoms ascribable to the donor area was significantly correlated with a lower clinical outcome . Conclusions Autologous osteochondral transplantation proved to be , at short-term evaluation , a suitable option to treat small – medium sized chondral and osteochondral lesions . However , clinical improvement is slow and a significant percentage of patients develop symptoms attributable to the donor area , thus reducing the overall benefit of this procedure [16632362] Matrix-associated autologous chondrocyte transplantation/implantation ( MACT/MACI ) is a new operation procedure using a cell seeded collagen matrix for the treatment of localized full-thickness cartilage defects . A prospect i ve clinical investigation was carried out in order to clarify whether this proves suitable and confirms objective and subjective clinical improvement over a period of up to 5 years after operation . Thirty-eight patients with localised cartilage defects were treated with MACT . Within the context of clinical follow-up , these patients were evaluated for up to 5 years after the intervention . Four different scores ( Meyers score , Tegner-Lysholm activity score , Lysholm-Gillquist score , ICRS score ) as well as the results of six arthroscopies and biopsies obtained from four patients formed the basis of this study . For 15 patients , 5 or more years had elapsed since the operation at the time this study was completed . It was possible to obtain results 5 years postoperatively from 11 ( 73.3 % ) of these 15 patients . Overall , we included 25 patients into the evaluation with a 2-year or longer postoperative period . Five years after transplantation 8 out of 11 patients rated the function of their knee as much better or better than before . Three of the four scores showed significant improvement compared to the preoperative value . One score , the Tegner-Lysholm score showed improvement , which , however , did not prove to be significant . The significantly improved results on three scores after 5 years suggest that MACT represents a suitable but cost-intensive alternative in the treatment of local cartilage defects in the knee [20062969] Cartilage defects occur in approximately 12 % of the population and can result in significant function impairment and reduction in quality of life . Evidence for the variety of surgical treatments available is inconclusive . This study aim ed to compare the clinical outcomes of patients with symptomatic cartilage defects treated with matrix-induced autologous chondrocyte implantation ( MACI ™ or microfracture ( MF ) . Included patients were ≥18 and ≤50 years of age with symptomatic , post-traumatic , single , isolated chondral defects ( 4–10 cm2 ) and were r and omised to receive MACI ™ or MF . Patients were followed up 8–12 , 22–26 and 50–54 weeks post-operatively for efficacy and safety evaluation . Outcome measures were the Tegner , Lysholm and ICRS scores . Sixty patients were included in a r and omised study ( 40 MACI ™ , 20 MF ) . The difference between baseline and 24 months post-operatively for both treatment groups was significant for the Lysholm , Tegner , patient ICRS and surgeon ICRS scores ( all P < 0.0001 ) . However , MACI ™ was significantly more effective over time ( 24 months versus baseline ) than MF according to the Lysholm ( P = 0.005 ) , Tegner ( P = 0.04 ) , ICRS patient ( P = 0.03 ) and ICRS surgeon ( P = 0.02 ) scores . There were no safety issues related to MACI ™ or MF during the study . MACI ™ is superior to MF in the treatment of articular defects over 2 years . MACI ™ and MF are complementary procedures , depending on the size of the defect and symptom recurrence . The MACI ™ technique represents a significant advance over both first and second generation chondrocyte-based cartilage repair techniques for surgeons , patients , health care institutions and payers in terms of reproducibility , safety , intraoperative time , surgical simplicity and reduced invasiveness [17261573] Background Focal articular cartilage lesions of the knee in young patients present a therapeutic challenge . Little information is available pertaining to the results after implantation of prolonged fresh grafts . Hypothesis Prolonged fresh osteochondral allografts present a viable option for treating large full-thickness articular cartilage lesions . Study Design Case series ; Level of evidence , 4 . Methods This study presents the results of 25 consecutive patients who underwent prolonged fresh osteochondral allograft transplantation for defects in the femoral condyle . The average patient age was 35 years ( range , 17 - 49 years ) . The average length of follow-up was 35 months ( range , 24 - 67 months ) . Prospect i ve data were collected using several subjective scoring systems , as well as objective and radiographic assessment s. Results Statistically significant improvements ( P < .05 ) were seen for the Lysholm ( 39 to 67 ) , International Knee Documentation Committee scores ( 29 to 58 ) , all 5 components of the Knee injury and Osteoarthritis Outcome Score ( Pain , 43 to 73 ; Other Disease-Specific Symptoms , 46 to 64 ; Activities of Daily Living Function , 56 to 83 ; Sport and Recreation Function , 18 to 46 ; Knee-Related Quality of Life , 22 to 50 ) , and the Short Form-12 physical component score ( 36 to 40 ) . Overall , patients reported 84 % ( range , 25 % to 100 % ) satisfaction with their results and believed that the knee functioned at 79 % ( range , 35 % to 100 % ) of their unaffected knee . Radiographically , 22 of the grafts ( 88 % ) were incorporated into host bone . Conclusion Fresh osteochondral allograft transplantation is an acceptable intermediate procedure for treatment of localized osteochondral defects of the femur . At 2-year follow-up , it is well incorporated and offered consistent improvements in pain and function . Clinical Relevance Prolonged fresh allograft transplantation is a safe and effective technique for addressing symptomatic osteoarticular lesions in the knees of young patients [22316548] Background : Fresh-stored osteochondral allografts have been used successfully to resurface large chondral and osteochondral defects of the knee . However , there are limited data available for the return to athletic activity . Purpose : To review the rate of return to athletic activity after osteochondral allograft transplantation in the knee and to identify any potential risk factors for not returning to sport . Study Design : Case series ; Level of evidence , 4 . Methods : Forty-three athletes were treated with fresh-stored osteochondral allograft transplantation for symptomatic large chondral or osteochondral defects of the knee from 2000 to 2010 . The average age of the athletes ( 30 men , 13 women ) was 32.9 years ( range , 18 - 49 years ) . Patients were prospect ively evaluated by International Knee Documentation Committee ( IKDC ) , activities of daily living scale of the Knee Injury and Osteoarthritis Outcome Score ( KOOS ) , Marx Activity Rating Scale , and Cincinnati Sports Activity Scale scores . A multivariable regression analysis was performed to identify potential risk factors for failure to return to sport at the preinjury level . Results : At an average 2.5-year follow-up , limited return to sport was possible in 38 of 43 athletes ( 88 % ) , with full return to the preinjury level achieved in 34 of 43 athletes ( 79 % ) . In these 34 athletes , time to return to sport was 9.6 ± 3.0 months . Age ≥25 years ( P = .04 ) and preoperative duration of symptoms greater than 12 months ( odds ratio , 37 ; P = .003 ) negatively affected the ability to return to sport . In the athletes who returned to their previous level of competition , IKDC ( P < .001 ) , KOOS ( P = .02 ) , and Marx Activity Rating Scale ( P < .001 ) scores were all significantly greater than in those athletes who did not return to sport . Conclusion : Osteochondral allograft transplantation in an athletic population for chondral and osteochondral defects in the knee allows for a high rate of return to sport . Risk factors for not returning to sport included age ≥25 years and preoperative duration of symptoms ≥12 months [24166804] Background : Autologous chondrocyte implantation ( ACI ) has been associated with satisfying results . Still , it remains unclear when success or failure after ACI can be estimated . Purpose : To evaluate the clinical outcomes of cell-seeded collagen matrix – supported ACI ( ACI-Cs ) for the treatment of cartilage defects of the knee at 36 months and to determine a time point after ACI-Cs at which success or failure can be estimated . Study Design : Cohort study ; Level of evidence , 3 . Methods : A total of 80 patients with isolated full-thickness cartilage defects of the knee joint treated with ACI-Cs were prospect ively assessed before surgery as well as postoperatively by use of the International Knee Documentation Committee ( IKDC ) score and Lysholm knee score . Results : Preoperative IKDC and Lysholm scores increased from 49.6 and 59.5 , respectively , to 79.1 and 83.5 , respectively , at 36 months . Only half the patients ( 46.6 % ) with poor IKDC scores ( ie , < 70 ) at 6 months postoperatively showed continued poor or fair scores at 36 months ’ follow-up . The probability of poor scores at 36 months after surgery further increased to 0.61 and 0.81 , respectively , when scores were persistent at 12 and 24 months . All 3 patients ( 100 % ) with good IKDC scores ( ie , 81 - 90 ) at 6 months after surgery showed constant or even improved scores at 36 months ’ follow-up . Ninety-one percent of patients with good and excellent scores at 12 months and 83 % of patients with good and excellent scores at 24 months ( a total of 23 and 37 patients , respectively ) were able to maintain these scores at 36 months ’ follow-up . Similar results were obtained for the Lysholm score . Conclusion : With regard to the improvements in functional outcomes after ACI-Cs at 36 months after surgery , the technique described here appears to lead to satisfying and stable clinical results . This study helps the treating physician to predict the likeliness of further clinical improvements or constant unsatisfactory results after ACI . In patients with good/excellent scores shortly after surgery , deterioration of the knee ’s condition is rarely found . For patients with poor and fair postoperative scores , clinical outcomes are more difficult to predict , especially during the first year after the procedure [24051505] Abstract Purpose Microfracture is a well-established treatment procedure for chondral defects in high-dem and population with good short-term results . The purpose of our study was to evaluate long-term clinical outcome of microfracture treatment in athletes with full-thickness chondral defects . Methods Between 1991 and 2001 , 170 patients were treated with microfracture for full-thickness knee chondral lesions at our institute and 67 of them were included in this study and prospect ively followed up . Sixty-one athletes ( 91 % ) were available at final follow-up ( average 15.1 years ) . Average lesion size was 401 ± 27 mm2 . Lysholm , Tegner and International Knee Documentation Committee ( IKDC ) ( subjective– objective ) scores were utilized pre-operatively and at 2-year , 5-year and final follow-up ; Knee injury and Osteoarthritis Outcome Score ( KOOS ) , visual analog scale ( VAS ) and Marx scores were also collected at final follow-up . Results IKDC , Lysholm and Tegner scores increased significantly at 2 years , but gradually deteriorated at long term ; however , average scores were significantly above baseline at final follow-up . Seven patients ( 11 % ) were considered as failures as they underwent another operation because of reinjury or persistent pain during the first 5 years . Pain and swelling during strenuous activities was reported only in nine patients by the end of 2 years and in 35 patients at final follow-up . Patients with smaller lesions ( ≤400 mm² ) and younger patients ( ≤30 years ) showed significantly better results in KOOS , VAS and Marx scores . Radiographs performed at final follow-up showed evidence of progression of osteoarthritis changes in 40 % of the knees , with higher rate in older patients with large or multiple lesions ( p < 0.05 ) . Conclusions Microfracture when applied in young patients with smaller lesions can offer good clinical results at short- and long-term follow-up ; lesion size is more important prognostic factor of outcome than age . Deterioration of the clinical outcome should be expected after 2 and 5 years post-treatment , and degenerative changes are present at long-term follow-up , with higher rate in older athletes with large , multiple lesions . Level of evidence IV [25218576] Abstract Purpose Matrix-induced autologous chondrocyte implantation ( MACI ) has demonstrated effectiveness in treating isolated cartilage defects of the knee but medium- and long-term evidence and information on the management of postoperative complications or partially successful cases are sparse . This study hypothesised that MACI is effective for up to 5 years and that patients with posttreatment problems may go on to obtain clinical benefit from other interventions . Methods A follow-on , prospect i ve case series of patients recruited into a previous controlled , r and omised , prospect i ve study or newly enroled . Patients were followed up 6 , 12 , 24 and 60 months after surgery . Outcome measures were Tegner ( activity levels ) and Lysholm ( pain , stability , gait , clinical symptoms ) scores . Zone-specific subgroups were analysed 6 , 12 and 24 months postoperatively . Results Sixty-five patients were treated with MACI . Median Tegner score improved from II to IV at 12 months ; an improvement maintained to 60 months . Mean Lysholm score improved from 28.5 to 76.6 points ( ±19.8 ) at 24 months , settling back to 75.5 points after 5 years ( p > 0.0001 ) . No significant differences were identified in the zone-specific analysis . Posttreatment issues ( N = 12/18.5 % ) were resolved with microfracture , debridement , OATS or bone grafting . Conclusions MACI is safe and effective in the majority of patients . Patients in whom treatment is only partially successful can go on to obtain clinical benefit from other cartilage repair options . This study adds to the clinical evidence on the MACI procedure , offers insight into likely treatment outcomes , and highlights MACI ’s usefulness as part of an armamentarium of surgical approaches to the treatment of isolated knee defects . Level of evidence Prospect i ve case control study with no control group , Level III [23412171] Most studies suggested that arthroscopic microfracture is effective method at only less than 40 years of age . Thus , the authors thought that “ how can this indication regarding age be extended ? , ” and tried to find a way to use this technique effectively over 40 years of age . The aim of this study was the first to report the results regarding the PRP as an adjunct for arthroscopic microfracture in the early osteoarthritic ( OA ) knee with cartilage lesion over 40 years of age . 49 patients who underwent arthroscopic microfracture for cartilage lesion sized less than 4 cm2 with early OA , aged 40–50 years , were enrolled and r and omly divided into 2 groups : a control group with only arthroscopic microfracture ( 25 patients ) and a study group with arthroscopic microfracture and PRP ( 24 patients ) . The patients were prospect ively evaluated with VAS , IKDC score at preoperative and postoperative 1 , 6 , 12 , and 24 months . And we perform second arthroscopies in 10 patients of each group to identify the extent of cartilage restoration at 4–6 months postoperatively . There were significant improvements in clinical results between preoperative evaluation and postoperative 2 years in both groups ( p = 0.017 ) . In the postoperative 2 years , clinical results showed significantly better in the study group than in the control group ( p = 0.012 ) . In post-arthroscopic finding , hardness and elasticity degree was better in the study group . The PRP injection with arthroscopic microfracture would be improved the results in early osteoarthritic knee with cartilage lesion in 40–50 years old , and the indication of this technique could be extended to 50 years [20678705] PURPOSE We report the 2-year clinical results and identify prognostic factors in patients treated with autologous chondrocyte transplantation by use of a collagen membrane to seed the chondrocytes ( ACT-CS ) . METHODS This is a prospect i ve study of 59 patients who were treated with ACT-CS and followed up for 24 months . Clinical function was assessed by International Knee Documentation Committee ( IKDC-2000 ) , objective International Cartilage Repair Society , and Lysholm scores before surgery and at 6 , 12 , and 24 months after surgery . RESULTS On the basis of objective International Cartilage Repair Society ( ICRS ) rating , the percentage of patients rated A ( normal ) and B ( nearly normal ) increased from 33.9 % preoperatively to 92.5 % at 24 months after ACT-CS . IKDC and Lysholm scores increased from 50.1 points ( SD , 13.4 ) and 60.5 points ( SD , 9.4 ) , respectively , to 76.1 points ( SD , 15.2 ) ( P < .001 ) and 82.5 points ( SD , 13.7 ) ( P < .001 ) , respectively , at 24 months . The failure rate was highest , at 26.7 % at 2 years ' follow-up , in the subgroup of patients who underwent ACT-CS as a salvage procedure . The rate of failures in patients with isolated cartilage defects was 5.9 % . CONCLUSIONS ACT-CS represents a technical modification of membrane-associated autologous chondrocyte transplantation that combines easy h and ling and attractive application properties with reliable clinical results 24 months after surgery , especially in patients with isolated cartilage defects . Even though the failure rate was higher in patients with kissing lesions or mild osteoarthritis , ACT-CS also seems to improve function in a large proportion of such patients . LEVEL OF EVIDENCE Level IV , prospect i ve case series [22922521] Background : To date , few studies have been published reporting the 5-year follow-up of clinical and radiological outcomes for chondral defects treated with matrix-induced autologous chondrocyte implantation ( MACI ) . Hypothesis : A significant improvement in clinical and radiological outcomes after treatment of symptomatic , traumatic chondral defects of the knee with the MACI implant will be maintained up to 5 years after surgery . Study Design : Case series ; Level of evidence , 4 . Methods : A prospect i ve evaluation of the MACI procedure was performed in 21 patients with chondral defects of the knee . After the MACI procedure , patients were clinical ly assessed with the Knee injury and Osteoarthritis Outcome Score ( KOOS ) , the Tegner-Lysholm score , the International Knee Documentation Committee ( IKDC ) Subjective Knee Form , and the modified Cincinnati score at years 1 , 2 , and 5 . The quality of repair tissue was assessed by magnetic resonance imaging using the magnetic resonance observation of cartilage repair tissue ( MOCART ) score at months 3 and 6 and years 1 , 2 , and 5 . Results : Significant improvements ( P < .05 ) were observed for all 5 KOOS subcategories at year 1 and were maintained through year 5 in 90.5 % of patients ( 19/21 ) . Treatment failure occurred in only 9.5 % of patients ( 2/21 ) . Significant improvements ( P < .05 ) from baseline to year 5 were also observed for the IKDC score ( 30.1 to 74.3 ) , the modified Cincinnati score ( 38.1 to 79.6 ) , and the Tegner-Lysholm activity score ( 1.8 to 4.3 ) . Similarly , the MOCART score significantly improved ( P < .001 ) from baseline to year 5 ( 52.9 to 75.8 ) . After 5 years , complete filling ( 83 % ) and integration ( 82 % ) of the graft were seen in the majority of patients . Signs of subchondral bone edema were still present in 47 % of patients at 5 years . No product-specific adverse events were reported over the 5-year follow-up period . Conclusion : Patients treated with a MACI implant demonstrated significant clinical improvement and good quality repair tissue 5 years after surgery . The MACI procedure was shown to be a safe and effective treatment for symptomatic , traumatic chondral knee defects in this study [22637203] BACKGROUND There is limited information regarding direct comparisons of the outcome of osteochondral autograft transfer ( OAT ) mosaicplasty and microfracture for the treatment of isolated articular cartilage defects of the knee . The purpose of this retrospective comparative study was to compare the general health outcomes , knee function , and Marx Activity Rating Scale scores for patients treated with OAT or microfracture for symptomatic chondral defects of the femoral condyles or trochlea . We hypothesized that the patients in the two treatment groups would have similar clinical outcomes at intermediate-term follow-up . METHODS Ninety-six patients with full-thickness cartilage defects of the femoral condyles or trochlea were treated with either OAT mosaicplasty ( n = 48 ) or microfracture ( n = 48 ) . The average age of the patients ( thirty-two male and sixteen female in each group ) at the time of surgery was 29.7 years in the OAT group and 32.5 years in the microfracture group . Patients were prospect ively evaluated at baseline and at one , two , three , and five years postoperatively with use of vali date d clinical outcome measures including the Short Form-36 ( SF-36 ) physical component , International Knee Documentation Committee ( IKDC ) , Knee Outcome Survey activities of daily living , and Marx Activity Rating Scale instruments . Comparisons between outcomes before and after treatment or between outcomes after microfracture and mosaicplasty were made with use of two-tailed tests . RESULTS At the time of the latest follow-up , both groups demonstrated significant increases in SF-36 physical component , Knee Outcome Survey activities of daily living , and IKDC scores compared with baseline . These scores did not differ significantly between the two groups at any of the follow-up time points . However , the OAT group demonstrated a significantly greater improvement in the Marx Activity Rating Scale scores from baseline to the two-year ( p = 0.001 ) , three-year ( p = 0.03 ) , and five-year ( p = 0.02 ) time points compared with the microfracture group . CONCLUSIONS In the present retrospective comparative study , the hypothesis that patients treated with microfracture or OAT mosaicplasty for symptomatic articular cartilage defects of the femoral condyles or trochlea would have similar clinical outcomes at intermediate-term follow-up was affirmed for general health outcome and for knee function . However , patients treated with OAT mosaicplasty maintained a superior level of athletic activity compared with those treated with microfracture [25548122] Abstract Background Cell-based strategies that combine in vitro- exp and ed autologous chondrocytes with matrix scaffolds are currently preferred for full-thickness cartilage lesions of the knee ≥2 cm2 . Although this approach is reasonable , continuing advances in the field of cartilage repair will further exp and the options available to improve outcomes .Hypothesis/ purpose In the present clinical study , we compared the outcomes of matrix-induced autologous mesenchymal stem cell implantation ( m-AMI ) with matrix-induced autologous chondrocyte implantation ( m-ACI ) for the treatment of isolated chondral defects of the knee . Study design Prospect i ve , single-site , r and omized , single-blind pilot study . Methods Fourteen patients with isolated full-thickness chondral lesions of the knee > 2 cm2 were r and omized into two treatment groups : m-AMI and m-ACI . Outcomes were assessed pre-operatively and 3 , 6 , 12 and 24 months post-operatively . Results Clinical evaluations revealed that improvement from pre-operation to 24 months post-operation occurred in both groups ( p < 0.05 ) . At all follow-up intervals , m-AMI demonstrated significantly better functional outcomes ( motion deficit and straight leg raise strength ) than did m-ACI ( p < 0.05 ) . At all follow-up intervals , m-AMI demonstrated significantly better subjective sub-scale scores for pain , symptoms , activities of daily living and sport and recreation of the knee injury and osteoarthritis outcome score ( KOOS ) than did m-ACI ( p < 0.05 ) . Additionally , m-AMI demonstrated significantly better ( p < 0.05 ) scores than m-ACI for the quality of life sub-scale of the KOOS and visual analog scale ( VAS ) severity at the 6-month follow-up . The Tegner activity score and VAS frequency were not significantly different between the two groups . Graft failure was not observed on magnetic resonance imaging at the 24-month follow-up . m-AMI and m-ACI demonstrated very good-to-excellent and good-to-very good infill , respectively , with no adverse effects from the implant , regardless of the treatment . Conclusion For the treatment of isolated full-thickness chondral lesion of the knee , m-AMI can be used effectively and may potentially accelerate recovery . A larger patient cohort and follow-up supported by histological analyses are necessary to determine long-term outcomes [16093535] Background The ability of autologous chondrocyte transplantation to produce and maintain an effective articular cartilage repair under high mechanical dem and s has not been investigated . Hypothesis Autologous chondrocyte transplantation provides a reliable and durable repair of full-thickness knee articular cartilage lesions in high-dem and athletes . Study Design Case series ; Level of evidence , 4 . Methods A total of 45 soccer players were evaluated 41 ± 4 months after autologous chondrocyte transplantation for their ability to return to soccer , the timing of their return , skill level , and functional outcome rating by the Tegner activity rating scale score and Brittberg score . The factors influencing the return to sport were analyzed . Results Of these players , 72 % reported good to excellent results , with significant overall improvement of Tegner activity rating scale scores ; 33 % returned to soccer , including 83 % of competitive-level players and 16 % of recreational players . Of the returning players , 80 % returned to the same skill level and 87 % maintained their ability to play soccer at 52 ± 8 months postoperatively . Players who successfully returned to soccer were significantly younger and had a shorter preoperative duration of symptoms than did patients who did not return to the sport . Concomitant adjuvant procedures did not adversely affect the ability to return to soccer . Conclusion Repair of knee articular cartilage lesions by autologous chondrocyte transplantation in high-performance athletes is particularly successful in younger , competitive athletes with limited preoperative intervals [23001127] Background Treating patellofemoral articular cartilage lesions remains a challenging task in orthopedic surgery . Whereas microfracture and autologous chondrocyte implantation yield good results on femoral condyles , the therapeutic state of the art for treating patellofemoral lesions is yet to be determined . In this study , we compared the CaReS ® technique , which is a matrix-associated autologous chondrocyte implantation technique , to microfracture for treating patellofemoral articular cartilage lesions . Methods Between May 2003 and December 2005 , 17 patients with an isolated patellofemoral cartilage defect ( International Cartilage Repair Society III/IV ) were treated with the CaReS ® technique at our department . After adjusting for inclusion and exclusion criteria , ten of these patients could be included in this study ; ten patients treated with microfracture were chosen as a matched-pair group . Clinical outcome was evaluated 3 years after surgery by the 36-item Short Form Health Survey Question naire ( SF-36 ) , International Knee Documentation Committee ( IKDC ) subjective evaluation of the knee , Lysholm Score , and Cincinnati Modified Rating Scale scores . Results Patients treated with CaReS ® had statistically significantly improved IKDC , Lysholm , and Cincinnati scores 36 months after surgery compared with preoperatively . When comparing outcome between groups 36 months after surgery , there was no statistically difference in IKDC , Lysholm , and Cincinnati scores . Conclusions This is the first trial comparing the CaReS ® technique and microfracture for treating patellofemoral articular cartilage lesions , and results show that CaReS ® yields comparable results to microfracture . The small number of patients is a limiting factor of the study , leading to results without statistical significance . A multicentric prospect i ve r and omized study comparing the two procedures is desirable [21669155] Cartilage defects represent a common problem in orthopaedic practice . The knee is frequently involved and the medial femoral condyle is the most common localization . Predisposing factors are : traumas , inflammatory conditions and biomechanics alterations . Several surgical options are available once correct diagnosis is given and accurate patient evaluation has been performed . The aim of our study was to prospect ively evaluate functional results of modified autologous matrix induced chondrogenesis ( AMIC ) technique in a population of patients affected by focal cartilage defects A population of 17 patients was enrolled in this study . 10 patients were male , mean age at the time of surgery was 39 years , right side was involved in 11 cases . All patients were evaluated with accurate physical exam and complete imaging study . At an average FU of 36 months , mean IKDC score and Lysholm score improved from 32 to 82 and from 38 to 74 . 13 patients out of 17 ( 76.5 % ) were satisfied or extremely satisfied with their functional result . MRI control showed reduction of the defect area and subchondral oedema in 10 cases ( 58.8 % ) . AMIC technique is a relatively new option in the treatment of full thickness cartilage lesions . It enhances the advantages of microfractures since the Chondrogide membrane protects and stabilizes the blood plug acting as a matrix for new cartilage formation . First reports on AMIC technique , show comparable results to autologous chondrocyte implantation ( ACI ) with the advantage of a single stage technique and no donor site morbidity . AMIC technique represents a new option in the treatment of full thickness cartilage defect . It is safe and reliable . Our data are in accordance with previously reported series in literature and confirm the good objective and subjective results of this procedure [26742454] Numerous surgical techniques have been developed to treat osteochondral defects of the knee . A study reported encouraging outcomes of third-generation autologous chondrocyte implantation achieved using the solid agarose-alginate scaffold Cartipatch ® . Whether this scaffold is better than conventional techniques remains unclear . This multicenter r and omized controlled trial compared 2-year functional outcomes ( IKDC score ) after Cartipatch ® versus mosaicplasty in patients with isolated symptomatic femoral chondral defects ( ICRS III and IV ) measuring 2.5 - 7.5 cm(2 ) . In addition , a histological evaluation based on the O'Driscoll score was performed after 2 years . We needed 76 patients to demonstrate an at least 10-point subjective IKDC score difference with α = 5 % and 90 % power . During the enrolment period , we were able to include 55 patients , 30 of them were allocated at r and om to Cartipatch ® and 25 to mosaicplasty . After 2 years , eight patients had been lost to follow-up , six in the Cartipatch ® group , and two in the mosaicplasty group . The baseline characteristics of the two groups were not significantly different . The mean IKDC score and score improvement after 2 years were respectively 73.7 ± 20.1 and 31.8 ± 20.8 with Cartipatch ® and 81.5 ± 16.4 and 44.4 ± 15.2 with mosaicplasty . The 12.6-point absolute difference in favor of mosaicplasty is statistically significant . Twelve adverse events were recorded in the Cartipatch ® group against six in the mosaicplasty group . After 2 years , functional outcomes were significantly worse after Cartipatch ® treatment compared to mosaicplasty for isolated focal osteochondral defects of the femur [19448048] Background The healing potential of damaged articular cartilage is limited . The NeoCart is a tissue-engineered collagen matrix seeded with autogenous chondrocytes design ed for the repair of hyaline articular cartilage . Hypothesis The NeoCart implant is well tolerated in the human knee . Study Design Case series ; Level of evidence , 4 . Methods Eight patients ( treatment group ) with full-thickness cartilage injury were treated with the NeoCart and evaluated prospect ively . Autogenous chondrocytes provided by arthroscopic biopsy were seeded into a 3-dimensional type I collagen scaffold . The seeded scaffold was subjected to a tissue-engineering protocol including treatment with a bioreactor . Implantation of the prepared cartilage tissue patch was performed via miniarthrotomy and secured with a collagen bioadhesive . Evaluations through 24 months postoperatively included the subjective International Knee Documentation Committee question naire , visual analog scale , range of motion , and cartilage-sensitive magnetic resonance imaging ( MRI ) , including quantitative T2 mapping . Results Pain scores after NeoCart implantation were significantly lower than baseline at 12 and 24 months after the procedure ( P < .05 ) . Improved function and motion were also noted at 24 months . Six patients had 67 % to 100 % defect fill at 24 months with MRI evaluation . One patient had moderate ( 33%-66 % ) defect fill , and another patient had poor ( less than 33 % ) defect fill . Partial stratification of T2 values was observed for 2 patients at 12 months and 4 patients at 24 months . No patients experienced arthrofibrosis or implant hypertrophy . Conclusion Pain was significantly reduced 12 and 24 months after NeoCart treatment . Trends toward improved function and motion were observed 24 months after implantation . The MRI indicated implant stability and peripheral integration , defect fill without overgrowth , progressive maturation , and more organized cartilage formation [24714783] Background : R and omized controlled trials study ing the efficacy and safety of matrix-applied characterized autologous cultured chondrocytes ( MACI ) versus microfracture ( MFX ) for treating cartilage defects are limited . Purpose : To compare the clinical efficacy and safety of MACI versus MFX in the treatment of patients with symptomatic cartilage defects of the knee . Study Design : R and omized controlled clinical trial ; Level of evidence , 1 . Methods : Patients enrolled in the SUMMIT ( Demonstrate the Superiority of MACI implant to Microfracture Treatment ) trial had ≥1 symptomatic focal cartilage defect ( Outerbridge grade III or IV ; ≥3 cm2 ) of the femoral condyles or trochlea , with a baseline Knee Injury and Osteoarthritis Outcome Score ( KOOS ) pain value < 55 . The co– primary efficacy endpoint was the change in the KOOS pain and function subscores from baseline to 2 years . Histological evaluation and magnetic resonance imaging ( MRI ) assessment s of structural repair tissue , treatment failure , the remaining 3 KOOS subscales , and safety were also assessed . Results : Of the 144 patients treated , 137 ( 95 % ) completed the 2-year assessment . Patients had a mean age of 33.8 years and a mean lesion size of 4.8 cm2 . The mean KOOS pain and function subscores from baseline to 2 years were significantly more improved with MACI than with MFX ( pain : MACI , 37.0 to 82.5 vs MFX , 35.5 to 70.9 ; function : MACI , 14.9 to 60.9 vs MFX , 12.6 to 48.7 ; P = .001 ) . A significant improvement in scores was also observed on the KOOS subscales of activities of daily living ( MACI , 43.5 to 87.2 vs MFX , 42.6 to 75.8 ; P < .001 ) , knee-related quality of life ( MACI , 18.8 to 56.2 vs MFX , 17.2 to 47.3 ; P = .029 ) , and other symptoms ( MACI , 48.3 to 83.7 vs MFX , 44.4 to 72.2 ; P < .001 ) for patients treated with MACI compared with MFX . Repair tissue quality was good as assessed by histology/MRI , but no difference was shown between treatments . A low number of treatment failures ( nonresponders : MACI , 12.5 % vs MFX , 31.9 % ; P = .016 ) and no unexpected safety findings were reported . Conclusion : The treatment of symptomatic cartilage knee defects ≥3 cm2 in size using MACI was clinical ly and statistically significantly better than with MFX , with similar structural repair tissue and safety , in this heterogeneous patient population . Moreover , MACI offers a more efficacious alternative than MFX with a similar safety profile for the treatment of symptomatic articular cartilage defects of the knee [19846694] Background Damaged articular cartilage has limited capacity for self-repair . Autologous chondrocyte implantation using a characterized cell therapy product results in significantly better early structural repair as compared with microfracture in patients with symptomatic joint surface defects of the femoral condyles of the knee . Purpose To evaluate clinical outcome at 36 months after characterized chondrocyte implantation ( CCI ) versus microfracture ( MF ) . Study Design R and omized controlled trial ; Level of evidence , 1 . Methods Patients aged 18 to 50 years with single International Cartilage Repair Society ( ICRS ) grade III/IV symptomatic cartilage defects of the femoral condyles were r and omized to CCI ( n = 57 ) or MF ( n = 61 ) . Clinical outcome was measured over 36 months by the Knee injury and Osteoarthritis Outcome Score ( KOOS ) . Serial magnetic resonance imaging ( MRI ) scans were scored using the Magnetic resonance Observation of Cartilage Repair Tissue ( MOCART ) system and 9 additional items . Gene expression profile scores associated with ectopic cartilage formation were determined by RT-PCR . Results Baseline mean overall KOOS ( ±SE ) was comparable between the CCI and MF groups ( 56.30 ± 1.91 vs 59.46 ± 1.98 , respectively ) . Mean improvement ( ±SE ) from baseline to 36 months in overall KOOS was greater in the CCI group than the MF group ( 21.25 ± 3.60 vs 15.83 ± 3.48 , respectively ) , while in a mixed linear model analysis with time as a categorical variable , significant differences favoring CCI were shown in overall KOOS ( P = .048 ) and the subdomains of Pain ( P = .044 ) and QoL ( P = .036 ) . More CCI- than MF-treated patients were treatment responders ( 83 % vs 62 % , respectively ) . In patients with symptom onset of < 2 years , the mean improvement ( ±SE ) from baseline to 36 months in overall KOOS was greater with CCI than MF ( 24.98 ± 4.34 vs 16.50 ± 3.99 , respectively ) and even greater in patients with symptom onset of <3 years ( 26.08 ± 4.10 vs 17.09 ± 3.77 , respectively ) . Characterized chondrocyte implantation patients with high ( > 2 ) versus low ( < 2 ) gene profile scores showed greater improvement from baseline in mean overall KOOS ( ±SE ) at 36 months ( 28.91 ± 5.69 vs 18.18 ± 5.08 , respectively ) . Subchondral bone reaction significantly worsened over time with MF compared with CCI ( P < .05 ) . Conclusion Characterized chondrocyte implantation for the treatment of articular cartilage defects of the femoral condyles of the knee results in significantly better clinical outcome at 36 months in a r and omized trial compared with MF . Time to treatment and chondrocyte quality were shown to affect outcome [23729686] Background : Sex-specific outcomes have been reported in anterior cruciate ligament reconstruction as well as in osteoarthrosis progression , but there are currently no related published data on autologous chondrocyte implantation ( ACI ) . The present prospect i ve study was performed to investigate sex-dependent differences in the results after ACI . Hypothesis : The clinical and magnetic resonance imaging ( MRI ) results after ACI of the knee are influenced by the patient ’s sex . Study Design : Cohort study ; Level of evidence , 2 . Methods : The midterm clinical and MRI results of a cell-based fibrin-polymer graft for the treatment of full-thickness cartilage defects were evaluated preoperatively and 6 , 12 , and 48 months after surgery in 52 patients ( male : female ratio , 25:27 ; average age , 35.6 years ) . Depending on the sex and the location of the defects ( femoral condyles , n = 32 ; patellofemoral compartment , n = 20 ) , patients were assigned to 4 different groups . Baseline clinical scores were compared with follow-up data by paired Wilcoxon tests for the Lysholm score and the International Knee Documentation Committee ( IKDC ) scoring system . Sex-specific differences were evaluated with the Mann-Whitney U test . The MRI evaluation was performed with the Henderson score at final follow-up . Results : Clinical scores improved in all groups over the whole study period ( P < .05 ) . Compared with female patients , male patients achieved significantly better results in the Lysholm score at all time intervals and in the IKDC score at 6 and 12 months after surgery ( P < .05 ) . In a subgroup analysis , female patients with patellar defects had the worst results in both clinical scores . With the available number of patients , MRI evaluation at 48 months after surgery revealed no significant difference in defect fill between male and female patients ( P > .05 ) . The Pearson correlation coefficient between both clinical scores and the MRI parameters of defect fill and cartilage signal was significant ( P < .05 ) . Conclusion : Autologous chondrocyte implantation is a promising treatment option for full-thickness cartilage defects of male and female knee joints . Female patients with patellar defects have worse prognostic factors [17908884] BACKGROUND The optimal treatment for cartilage lesions has not yet been established . The objective of this r and omized trial was to compare autologous chondrocyte implantation with microfracture . This paper represents an up date , with presentation of the clinical results at five years . METHODS Eighty patients who had a single chronic symptomatic cartilage defect on the femoral condyle in a stable knee without general osteoarthritis were included in the study . Forty patients were treated with autologous chondrocyte implantation , and forty were treated with microfracture . We used the International Cartilage Repair Society , Lysholm , Short Form-36 , and Tegner forms to collect clinical data , and radiographs were evaluated with use of the Kellgren and Lawrence grading system . RESULTS At two and five years , both groups had significant clinical improvement compared with the preoperative status . At the five-year follow-up interval , there were nine failures ( 23 % ) in both groups compared with two failures of the autologous chondrocyte implantation and one failure of the microfracture treatment at two years . Younger patients did better in both groups . We did not find a correlation between histological quality and clinical outcome . However , none of the patients with the best- quality cartilage ( predominantly hyaline ) at the two-year mark had a later failure . One-third of the patients in both groups had radiographic evidence of early osteoarthritis at five years . CONCLUSIONS Both methods provided satisfactory results in 77 % of the patients at five years . There was no significant difference in the clinical and radiographic results between the two treatment groups and no correlation between the histological findings and the clinical outcome . One-third of the patients had early radiographic signs of osteoarthritis five years after the surgery . Further long-term follow-up is needed to determine if one method is better than the other and to study the progression of osteoarthritis [17724094] Background Articular cartilage lesions , with their inherent limited healing potential , remain a challenging problem for orthopaedic surgeons . Various approaches have been proposed to treat these lesions ; nevertheless , opinions on indications and clinical efficacy of these techniques are still controversial . Purpose To evaluate the outcome of osteochondral autografts for treatment of femoral condyle cartilage lesions at a medium-to long-term follow-up . Study Design Case series ; Level of evidence , 4 . Methods We prospect ively evaluated 30 patients ( mean age , 29.3 years ) with full-thickness knee chondral lesions ( < 2.5 cm2 ) treated with arthroscopic autologous osteochondral transplantation . Thirteen patients underwent previous surgery , while 17 patients were operated on for the first time . In 19 patients , associated procedures were performed . All patients were evaluated at 2- and 7-year follow-up . The International Cartilage Repair Society form , Tegner score , and magnetic resonance imaging were used for clinical evaluation . Results The International Cartilage Repair Society objective evaluation showed 76.7 % of patients had good or excellent results at 7-year follow-up , and International Knee Documentation Committee subjective score significantly improved from preoperative ( 34.8 ) to 7-year follow-up ( 71.8 ) . The Tegner evaluation showed a significant improvement after the surgery at 2- and 7-year follow-up ( from 2.9 to 6.2 and 5.6 , respectively ) ; however , we noticed reduced sports activity from 2- to 7-year follow-up . Magnetic resonance imaging evaluation showed good integration of the graft in the host bone and complete maintenance of the grafted cartilage in more than 60 % of cases . Conclusion The results of this technique at medium- to long-term follow-up are encouraging . This arthroscopic 1-step surgery appears to be a valid solution for treatment of small , grade III to IV cartilage defects [19966102] Background Autologous chondrocyte implantation ( ACI ) is frequently used to treat symptomatic defects of the articular cartilage . Purpose To test whether matrix-associated autologous chondrocyte implantation or the original periosteal flap technique provides superior outcomes in terms of clinical efficacy and safety . Study Design R and omized controlled trial ; Level of evidence , 2 . Methods Twenty-one patients ( mean age , 29.3 ± 9.1 years ) with symptomatic isolated full-thickness cartilage defects ( mean 4.1 ± 09 cm2 ) at the femoral condyle were r and omized to matrix-associated autologous chondrocyte implantation or the original periosteal flap technique . The primary outcome parameter was the postoperative change in knee function as assessed by the International Knee Documentation Committee ( IKDC ) score at 12 months after ACI . In addition , the IKDC score was assessed at 3 , 6 , 12 , and 24 months after surgery . Secondary outcome parameters were postoperative changes in health related quality of life ( Short Form-36 Health Survey ) , knee functionality ( Lysholm and Gillquist score ) , and physical activity ( Tegner Activity Score ) at 3 , 6 , 12 , and 24 months after ACI . Magnetic resonance imaging was performed to evaluate the cartilage 6 , 12 , and 24 months after ACI and rated using the Magnetic Resonance Observation of Cartilage Repair Tissue score . Adverse events were recorded to assess safety . Results The primary outcome parameter showed improvement of patients 1 year after autologous chondrocyte implantation , but there was no difference between the periosteal flap technique and matrix-associated ACI ( P = .5573 ) ; 2 years after ACI , a similar result was found ( P = .4994 ) . The study groups did not show differences in the Short Form-36 categories and in knee functionality as assessed by Tegner Activity Score 12 months ( P = .4063 ) and 24 months ( P = .1043 ) after ACI . There was a significant difference in the Lysholm and Gillquist score at 12 months ( P = .0449 ) and 24 months ( P = .0487 ) favoring the periosteal flap technique group . At 6 months after surgery , a significantly lower Magnetic Resonance Observation of Cartilage Repair score was obtained in the matrix-associated ACI group ( P = .0123 ) , corresponding to more normal magnetic resonance imaging diagnostic findings . Twelve and 24 months after ACI , the differences between the 2 groups were not significant ( 12 months , P = .2065 ; 24 months , P = .6926 ) . Adverse events were related to knee problems such as transplant delamination , development of an osseous spur , osteochondral dissection , and transplant hypertrophy . Systemic ( allergic , toxic , or autoimmune ) reactions did not occur . Conclusion There was no difference in the efficacy between the original and the advanced ACI technique 12 and 24 months after surgery regarding International Knee Documentation Committee , Tegner Activity Score , and Short Form-36 ; however , with respect to the Lysholm and Gillquist score , better efficacy was observed in the periosteal flap technique group [22483735] PURPOSE To determine the safety and efficacy of a new arthroscopic technique for matrix-induced autologous chondrocyte implantation ( MACI ) for articular cartilage defects in the knee . METHODS We undertook a prospect i ve evaluation of the first 20 patients treated with the MACI technique ( including 14 defects on the femoral condyle and 6 on the tibial plateau ) , followed up for 24 months after surgery . A 12-week structured rehabilitation program was undertaken by all patients . Patients underwent clinical assessment ( Knee Injury and Osteoarthritis Outcome Score , Short Form 36 Health Survey , visual analog pain scale , 6-minute walk test , knee range of motion ) before surgery and at 3 , 6 , 12 , and 24 months after surgery and underwent magnetic resonance imaging ( MRI ) assessment at 3 , 12 , and 24 months after surgery . MRI evaluation assessed 8 previously defined pertinent parameters of graft repair , as well as a combined MRI composite score . RESULTS A significant improvement ( P < .05 ) was shown throughout the postoperative time line for all Knee Injury and Osteoarthritis Outcome Score subscales , the physical component score of the Short Form 36 Health Survey , the frequency and severity of knee pain , and the 6-minute walk test . An improvement in pertinent morphologic parameters of graft repair was observed to 24 months , whereas a good to excellent graft infill score and MRI composite score were observed at 24 months after surgery in 90 % and 70 % of patients , respectively . CONCLUSIONS We report a comprehensive 24-month follow-up in the first 20 patients who underwent the arthroscopic MACI technique . This technique is a safe and efficacious procedure with improved clinical and radiologic outcomes over the 2-year period [23026726] BACKGROUND Autologous chondrocyte implantation ( ACI ) was introduced in 1987 in Sweden by Brittberg and Peterson for the treatment of severe chondral defects of the knee . Here , our objective was to evaluate mid-term outcomes of ACI in young athletic patients with deep chondral defects of the knee after trauma . HYPOTHESIS ACI is effective in filling full-thickness chondral defects of the knee . PATIENTS AND METHODS We prospect ively monitored 14 patients , with International Cartilage Repair Society grade III or IV lesions , who underwent ACI between 2001 and 2006 . St and ard evaluation measurements were used . Mean age at surgery was 37.7 years ( range , 30 - 45 ) . A history of surgery on the same knee was noted in ten ( 67 % ) patients . The defect was on the medial femoral condyle in 11 patients , lateral femoral condyle in two patients , and both femoral condyles in one patient . Mean defect surface area after debridement was 2.1cm(2 ) ( 1 - 6.3 ) . RESULTS After a mean follow-up of six years , improvements were noted in 12 ( 86 % ) patients , with an International Knee Documentation Committee ( IKDC ) score increase from 40 ( 27.6 - 65.5 ) to 60.2 ( 35.6 - 89.6 ) ( P=0.003 ) and a Brittberg-Perterson score decrease from 54.4 ( 11.8 - 98.2 ) to 32.9 ( 0 - 83.9 ) ( P=0.02 ) , between the preoperative assessment and last follow-up . The visual analogic scale pain score decreased from 66.3 ( 44 - 89 ) to 23.2 ( 0 - 77 ) ( P=0.0006 ) . In two ( 14 % ) patients , no improvements were detectable at last follow-up . The remaining 12 patients were satisfied and able to resume sporting activities , albeit at a less strenuous level . Two ACI-specific complications occurred , namely , periosteal hypertrophy treated with debridement in one patient and transplant delamination in another . DISCUSSION Our findings are consistent with previous reports but cover a longer follow-up period . Although the outcomes are promising , longer follow-ups are needed to confirm the long-term effectiveness of ACI . LEVEL OF EVIDENCE IV , prospect i ve therapeutic study [19865812] We compared the results of microfracture in single versus multiple symptomatic articular cartilage defects in the knee in 110 patients with a median age of 38 years ( range 15–60 ) . Cases of reoperation of the cartilage defect were classified as failures . Clinical outcome in non-failures was evaluated by the Lysholm score and grading of knee pain and function of the knee by the use of patient-administered visual analog scales ( VAS ; 0–100 ) . Data were prospect ively collected before the operation and at the 2- to 9-year follow-up . The single lesion or the largest of multiple lesions were located on the medial femoral condyle ( n = 62 ) , trochlea ( n = 18 ) , lateral tibia ( n = 11 ) , patella ( n = 10 ) or lateral femoral condyle ( n = 9 ) . We treated one ( n = 76 ) , two ( n = 27 ) or three ( n = 7 ) lesions with a median total area of 4 cm2 ( range 1–15 ) . A total of 24 failures ( 22 % ) were registered—18 % in the single-defect subgroup and 29 % in the multiple-defects subgroup . In the remaining group of patients ( n = 86 ) , the mean Lysholm score , mean pain-score ( 0 = no pain ; 100 = worst possible pain ) and mean function-score ( 0 = useless ; 100 = full function ) improved from 51 , 52 and 41 , respectively , to 71 ( P < 0.001 ) , 30 ( P < 0.001 ) and 69 ( P < 0.001 ) at the follow-up . The pain-score was significant lower ( P = 0.042 ) , and the function-score significantly higher ( P = 0.001 ) in the group of patients with a single lesion compared to the group with 2 or 3 lesions . The Lysholm score did not differ significantly between the two subgroups ( P = 0.06 ) [22422593] Background Many surgical techniques , including microfracture , periosteal and perichondral grafts , chondrocyte transplantation , and osteochondral grafts , have been studied in an attempt to restore damaged articular cartilage . However , there is no consensus regarding the best method to repair isolated articular cartilage defects of the knee . Questions / purpose sWe compared postoperative functional outcomes , followup MRI appearance , and arthroscopic examination after microfracture ( MF ) , osteochondral autograft transplantation ( OAT ) , or autologous chondrocyte implantation ( ACI ) . Methods We prospect ively investigated 30 knees with MF , 22 with OAT , and 18 with ACI . Minimum followup was 3 years ( mean , 5 years ; range , 3–10 years ) . We included only patients with isolated cartilage defects and without other knee injuries . The three procedures were compared in terms of function using the Lysholm knee evaluation scale , Tegner activity scale , and Hospital for Special Surgery ( HSS ) score ; modified Outerbridge cartilage grade s using MRI ; and International Cartilage Repair Society ( ICRS ) repair grade using arthroscopy . Results All three procedures showed improvement in functional scores . There were no differences in functional scores and postoperative MRI grade s among the groups . Arthroscopy at 1 year showed excellent or good results in 80 % after MF , 82 % after OAT , and 80 % after ACI . Our study did not show a clear benefit of either ACI or OAT over MF . Conclusions Owing to a lack of superiority of any one treatment , we believe MF is a reasonable option as a first-line therapy given its ease and affordability relative to ACI or OAT.Level of Evidence Level II , therapeutic study . See Guidelines for Authors for a complete description of levels of evidence [27474386] Background : Articular cartilage injury is frequently encountered , yet treatment options capable of providing durable cartilage repair are limited . Purpose : To investigate the medium-term clinical outcomes of cartilage repair using a 1-stage technique of a hyaluronic acid – based scaffold with activated bone marrow aspirate concentrate ( HA-BMAC ) and compare results with those of microfracture . A secondary aim of this study was to identify specific patient demographic factors and cartilage lesion characteristics that are associated with superior outcomes . Study Design : Cohort study ; Level of evidence , 2 . Methods : Fifty physically active patients ( mean age , 45 years ) with grade IV cartilage injury of the knee ( lesion size , 1.5 - 24 cm2 ) were treated with HA-BMAC or microfracture and were observed prospect ively for 5 years . Patients were placed into the HA-BMAC group if the health insurance policy of the treating institution supported this option ; otherwise , they were placed into the microfracture group . Objective and subjective clinical assessment tools were used preoperatively and at 2 and 5 years postoperatively to compare treatment outcomes . Results : Significant improvements in outcome scores were achieved in both treatment groups at 2 years ( P < .001 ) . In the microfracture group , 64 % were classified as normal or nearly normal according to the International Knee Documentation Committee ( IKDC ) objective score at 2 years , compared with 100 % of those treated with HA-BMAC ( P < .001 ) . Normal or nearly normal objective assessment s in the microfracture group declined significantly after 5 years to 28 % of patients ( P = .004 ) . All patients treated with HA-BMAC maintained improvement at 5 years according to Lysholm , Tegner , IKDC objective , and IKDC subjective scores . Tegner , IKDC objective , and Knee injury and Osteoarthritis Outcome Score ( KOOS ) assessment s demonstrated higher scores in the HA-BMAC treatment group compared with microfracture at 5 years . Lysholm and IKDC subjective scores were similar between treatment groups at 5 years . Poorer outcomes in the microfracture group were demonstrated in cases of lesions larger than 4 cm2 and nonsolitary lesions . Age greater than 45 years , large size of lesion , and treatment of multiple lesions were not associated with poorer outcome in patients treated with HA-BMAC . Conclusion : Repair of chondral injury using a hyaluronic acid – based scaffold with activated bone marrow aspirate concentrate provides better clinical outcomes and more durable cartilage repair at medium-term follow-up compared with microfracture . Positive short-term clinical outcomes can be achieved with either microfracture or HA-BMAC . Cartilage repair using HA-BMAC leads to successful medium-term outcomes independent of age or lesion size [24258020] Abstract Purpose The purpose of the study was to evaluate whether the biomembrane made of cartilage extracellular matrix , design ed to provide cartilage-like favourable environments as well as to prevent against washout of blood clot after microfracture , would enhance cartilage repair compared with the conventional microfracture technique . Methods A prospect i ve trial was design ed to compare the biomembrane cover after microfracture with conventional microfracture among patients with grade III – IV symptomatic cartilage defect in the knee joint . Patients aged 18–60 years were assigned to either the microfracture/biomembrane ( n = 45 ) or microfracture groups ( n = 19 ) . Among them , 24 knees in the microfracture/biomembrane and 12 knees in the microfracture were followed up for 2 years . Cartilage repair was assessed with magnetic resonance imagings taken 6 months , 1 year , and 2 years postoperatively , and the clinical outcomes were also recorded . Results Compared with conventional microfracture , microfracture/biomembrane result ed in greater degree of cartilage repair ( p = 0.043 ) . In the intra-group analysis , while microfracture showed moderate to good degree of cartilage repair in nearly 50 % of the patients ( 47 % at 6 months to 50 % at 2 years ; n.s . ) , microfracture/biomembrane maintained an equivalent degree of repair up to 2 years ( 88 % at 6 months to 75 % at 2 years ; n.s . ) . The clinical outcome at 2 years also showed improved knee score and satisfaction and decreased pain in each group , but the difference between the two groups was not statistically significant . Conclusions Compared with conventional microfracture , biomembrane cover after microfracture yielded superior outcome in terms of the degree of cartilage repair during 2 years of follow-up . This implies that initial protection of blood clot and immature repair tissue at the microfractured defect is important for the promotion of enhanced cartilage repair , which may be obtained by the application of a biomembrane . Level of evidence Prospect i ve comparative study , Level II [14996869] BACKGROUND New methods have been used , with promising results , to treat full-thickness cartilage defects . The objective of the present study was to compare autologous chondrocyte implantation with microfracture in a r and omized trial . We are not aware of any previous r and omized studies comparing these methods . METHODS Eighty patients without general osteoarthritis who had a single symptomatic cartilage defect on the femoral condyle in a stable knee were treated with autologous chondrocyte implantation or microfracture ( forty in each group ) . We used the International Cartilage Repair Society , Lysholm , Short Form-36 ( SF-36 ) , and Tegner forms to collect data . An independent observer performed a follow-up examination at twelve and twenty-four months . Two years postoperatively , arthroscopy with biopsy for histological evaluation was carried out . The histological evaluation was done by a pathologist and a clinical scientist , both of whom were blinded to each patient 's treatment . RESULTS In general , there were small differences between the two treatment groups . At two years , both groups had significant clinical improvement . According to the SF-36 physical component score at two years postoperatively , the improvement in the microfracture group was significantly better than that in the autologous chondrocyte implantation group ( p = 0.004 ) . Younger and more active patients did better in both groups . There were two failures in the autologous chondrocyte implantation group and one in the microfracture group . No serious complications were reported . Biopsy specimens were obtained from 84 % of the patients , and histological evaluation of repair tissues showed no significant differences between the two groups . We did not find any association between the histological quality of the tissue and the clinical outcome according to the scores on the Lysholm or SF-36 form or the visual analog scale . CONCLUSIONS Both methods had acceptable short-term clinical results . There was no significant difference in macroscopic or histological results between the two treatment groups and no association between the histological findings and the clinical outcome at the two-year time-point . LEVEL OF EVIDENCE Therapeutic study , Level I-1a ( r and omized controlled trial [ significant difference ] ) . See Instructions to Authors for a complete description of levels of evidence [17084294] PURPOSE Age-dependent studies about the clinical result after microfracture of cartilage lesions in the knee are still missing . This prospect i ve study was performed to discover age-dependent differences in the results after microfracture over a period of 36 months . METHODS Between 1999 and 2002 , 85 patients ( mean age , 39 years ) with full-thickness chondral lesions underwent the microfracture procedure and were evaluated preoperatively and at 6 , 18 , and 36 months after surgery . Depending on the patients ' age ( < or = 40 years or > 40 years ) and the localization of the defects ( femoral condyles , tibia , and patellofemoral joint ) , the patients were assigned to 6 different groups . Exclusion criteria were meniscal pathologic conditions , tibiofemoral malalignment , and ligament instabilities . Baseline clinical scores were compared with follow-up data by use of paired Wilcoxon tests for the modified Cincinnati knee score and the International Cartilage Repair Society ( ICRS ) score . RESULTS The scores improved in all groups over the whole study period ( P < .05 ) . Patients aged 40 years or younger had significantly better results ( P < .01 ) for both scores compared with older patients . Between 18 and 36 months after microfracture , the ICRS score deteriorated significantly ( P < .05 ) in patients aged over 40 years whereas younger patients with defects on the femoral condyles and on the tibia showed neither a significant improvement nor a significant deterioration in the ICRS score ( P > .1 ) . Magnetic resonance imaging 36 months after surgery revealed better defect filling and a better overall score in younger patients ( P < .05 ) . The Spearman coefficient of correlation between clinical and magnetic resonance imaging scores was 0.84 . CONCLUSIONS The clinical results after microfracture of full-thickness cartilage lesions in the knee are age-dependent . Deterioration begins 18 months after surgery and is significantly pronounced in patients aged older than 40 years . The best prognostic factor was found to be a patient age of 40 or younger with defects on the femoral condyles . LEVEL OF EVIDENCE Level IV , prognostic case series [21596901] Background Aging is responsible for degenerative changes in all cartilage elements , thus impairing its properties and healing potential . Most studies on surgical procedures for cartilage focus on young patients because these procedures are generally not considered suitable for older patients . Purpose To analyze the clinical outcome of cartilage lesion treatment using second-generation autologous chondrocyte implantation ( ACI ) techniques in patients more than 40 years old with no clear signs of osteoarthritis , to underst and their real potential in relation to aging , the failure rate , and complications in older patients . Study Design Case series ; Level of evidence , 4 . Methods Sixty-one patients with grade III to IV cartilaginous lesions of the condyles with no clear signs of osteoarthritis and a minimum age of 40 years were treated with second-generation ACI and prospect ively evaluated at 5 years ’ follow-up . Twenty-two patients were treated with arthroscopic Hyalograft C implantation , and 39 underwent the open Chondro-Gide MACI procedure . Results A significant improvement in both subjective and objective evaluations was observed . The International Knee Documentation Committee ( IKDC ) subjective score improved from 36.8 ± 8.4 to 68.1 ± 21.8 at the final evaluation . The failure rate was 20 % . A faster improvement was observed in the group treated with the arthroscopic Hyalograft C technique , whereas similar scores were found at the 24-month follow-up and final evaluation . Conclusion A clinical improvement was found in patients more than 40 years old , who in most cases benefited from second-generation ACI with good results lasting at medium-term follow-up . However , the results were inferior with respect to those previously found for younger population s , and the failure rate at medium-term follow-up was also higher . These findings were consistent in the 2 treatment groups . The only difference was the faster recovery when the arthroscopic approach was used Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND The surfaces of the bones in the knee are covered with articular cartilage , a rubber-like substance that is very smooth , allowing frictionless movement in the joint and acting as a shock absorber . The cells that form the cartilage are called chondrocytes . Natural cartilage is called hyaline cartilage . Articular cartilage has very little capacity for self-repair , so damage may be permanent . Various methods have been used to try to repair cartilage . Autologous chondrocyte implantation ( ACI ) involves laboratory culture of cartilage-producing cells from the knee and then implanting them into the chondral defect . OBJECTIVE To assess the clinical effectiveness and cost-effectiveness of ACI in chondral defects in the knee , compared with microfracture ( MF ) . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

16856058

[2025036] Previous studies have found that there is a correlation between mothers ' haemoglobin concentration or packed cell volume and infants ' birth weight , and that iron supplementation increases mothers ' haemoglobin concentration . The purpose of this study , using the data of a large r and omised trial on iron prophylaxis during pregnancy , was to find out whether iron supplementation causes fetal growth to deteriorate . At their first antenatal visit , 2912 pregnant women were r and omised into non-routine iron and routine iron supplementation . The mean length of gestation was shorter in the non-routine group . Birth weight did not differ between the groups , but due to longer gestations boys in the group receiving routine iron were taller than in the non-routine group . In both groups , whether studied by various values of packed cell volume or correlation coefficients , the lower the packed cell volume , the heavier and taller the infant and heavier the placenta . These negative correlations could be seen even with a packed cell volume measured early in pregnancy . St and ardising for blood pressure did not influence the correlation coefficients . The correlation between a high ratio for packed cell volume and poor fetal growth thus may not be caused by iron supplementation , nor mediated by blood pressure , but by some other mechanism [3530158] Two hundred Hausa primigravidae at Zaria were divided into five groups in a r and omized double-blind trial of antenatal oral antimalarial prophylaxis , and haematinic supplements . Group 1 received no active treatment . Groups 2 to 5 were given chloroquine 600 mg base once , followed by proguanil 100 mg per day . In addition , group 3 received iron 60 mg daily , group 4 folic acid 1 mg daily , and group 5 iron plus folic acid . Forty-five percent were anaemic ( haemoglobin ( Hb ) less than 11.0 g dl-1 ) at first attendance before 24 weeks of gestation , and malaria parasitaemia ( predominantly Plasmodium falciparum ) was seen in 27 % , of whom 60 % were anaemic . The mean Hb fell during pregnancy in group 1 , and seven patients in this group had to be removed from the trial and treated for severe anaemia ( packed cell volume ( PCV ) less than 0.26 ) . Only five patients in the other groups developed severe anaemia ( P = 0.006 ) , two of whom had malaria following failure to take treatment . Patients in group 1 had the lowest mean Hb at 28 and 36 weeks of gestation , and patients receiving antimalarials and iron ( groups 3 and 5 ) had the highest Hb at 28 weeks , but differences were not significant , possibly due to removal from the trial of patients with severe anaemia . Anaemia ( Hb less than 12.0 g dl-1 ) at six weeks after delivery was observed in 61 % of those not receiving active treatment ( group 1 ) , in 39 % of those protected against malaria but not receiving iron supplements ( groups 2 and 4 ) and in only 18 % of patients receiving both antimalarials and iron ( groups 3 and 5 ) . Folic acid had no significant effect on mean Hb . Proguanil was confirmed to be a highly effective causal prophylaxis . Prevention of malaria , without folic acid supplements , reduced the frequency of megaloblastic erythropoiesis from 56 % to 25 % . Folic acid supplements abolished megaloblastosis , except in three patients who were apparently not taking the treatment prescribed . Red cell folate ( RCF ) concentrations were higher in subjects with malaria , probably due to intracellular synthesis by plasmodia . Infants of mothers not receiving antimalarials appeared to have an erythroid hyperplasia . Maternal folate supplements raised infants ' serum folate and RCF . Fourteen per cent had low birth weight ( less than 2500 g ) , and the perinatal death rate was 11 % ; the greatest number were in group 1 , but not significantly . A regime is proposed for the prevention of malaria , iron deficiency , folate deficiency and anaemia in pregnancy in the guinea savanna of Nigeria [3273871] Iron absorption from four prenatal multivitamin/multimineral preparations was compared in 36 healthy pregnant women in their second or third trimester of pregnancy . The products studied were the currently marketed formulations of Stuartnatal 1 + 1 , Stuart Prenatal , Materna , and Natalins Rx . Each fasted subject received each of the four preparations , according to a r and omized sequence , at intervals of three to seven days between drug administrations . Stuartnatal 1 + 1 demonstrated the best iron absorption . Total iron absorbed from Stuartnatal 1 + 1 and Stuart Prenatal was well above the additional daily 3.5 mg recommended during pregnancy . Following administration of Materna the amount of iron was only slightly above that recommended , and following Natalins Rx it was well below . All formulations were generally well tolerated by the subjects [7891047] OBJECTIVE To evaluate whether levels of iron status markers ( haemoglobin , serum transferrin saturation , serum ferritin ) in pregnant women , measured in the beginning of the second trimester , could be used to predict levels later in pregnancy , pre partum and post partum . DESIGN R and omized , double-blind , placebo-controlled parallel study . SETTING The Birth Clinic at the Department of Obstetrics , Herning Hospital , Herning , Denmark . SUBJECTS One hundred and twenty healthy pregnant women between 14 and 18 weeks of gestation . INTERVENTIONS Sixty-three women were allocated to treatment with tablets containing 66 mg ferrous iron ( as fumarate ) daily , and 57 women to treatment with placebo . MAIN OUTCOME MEASURES Haemoglobin , serum transferrin saturation , and serum ferritin were measured every 4th week during gestation , prior to delivery , and 1 and 8 weeks post partum . RESULTS Correlation matrices during pregnancy and post partum were calculated for each iron status marker separately in iron-treated and placebo-treated women . Haemoglobin , transferrin saturation and serum ferritin values at inclusion displayed steadily declining correlation coefficients with values obtained later in pregnancy . There were no clinical ly relevant correlations to values obtained 8 weeks or less prior to delivery , and no correlations to values post partum . Serum ferritin values at inclusion could not be used to predict values later in pregnancy or post partum . CONCLUSION Haemoglobin , transferrin saturation and serum ferritin values measured in the beginning of the second trimester appear to be unsuitable as guidelines for an individual iron prophylaxis in pregnant women [5926263] Bertino , J. R. , Ward , J. , Sartorelli , A. C. , and Silber , R. ( 1965 ) . 7 . clin . Invest . , 44 , 1028 . Bothwell , T. H. , Hurtardo , A. V. , Donohue , D. M. , and Finch , C. A. ( 1957 ) . Blood , 12 , 409 . Callender , S. T. , and Malpas , J. S. ( 1963 ) . Brit . med . 7 . , 2 , 1516 . Cockburn , F. , Sherman , J. D. , Ingall , D. , and Klein , R. ( 1965 ) . Proc . Soc . exp . Biol . ( N.Y. ) , 118 , 238 . Conrad , M. E. , Berman , A. , and Crosby , W. H. ( 1962 ) . Gastroenterology , 43 , 385 . Dacie , J. V. , and Lewis , S. M. ( 1963 ) . Practical Haematology , 3rd ed . London . Davis , A. E. , and Badenoch , J. ( 1962 ) . Lancet , 2 , 6 . Finch , C. A. , Coleman , D. H. , Motulsky , A. G. , Donohue , D. M. , and Reiff , R. H. ( 1956 ) . Blood , 11 , 807 . Herbert , V. ( 1963 ) . Amer . 7 . clan . Nutr . , 12 , 17 . Gottlieb , C. W. , and Altschule , M. D. ( 1965 ) . Lancet , 2 , 1052 [6881917] Iron and folate status of 203 pregnant women have been evaluated at 6 months gestation and on the same women and their newborn infants at delivery . The women who had , at 6 months gestation , a Hb level below 11 g/dl were systematic ally given iron supplements . Iron or placebo were r and omly allocated to the other women . At 6 months of pregnancy , one quarter of the women had a Hb level under 11 g/dl but one third had a serum ferritin level below 12 micrograms/l and more than half had low levels of serum and red cell folate . Iron supplements induced an increase both in Hb levels and in serum ferritin values ; however , no significant differences were observed in serum ferritin of the newborn infants , whether their mothers had received iron supplements or not . These results have led us to reconsider the value of ferritin levels at birth as an index of iron stores in the infant . Iron supplements had no effect on the folate status in mothers or infants or on the frequency of obstetrical complications . A significant relationship was found between maternal folate levels and length of gestation . Folate supplementation may reduce the incidence of premature delivery [12164031] RATIONALE It has been suggested that in pregnant women weekly iron supplements are as effective as daily supplements in preventing iron deficiency anaemia ( IDA ) . OBJECTIVE To compare the effectiveness of prophylactic antenatal oral iron supplements given weekly , thrice weekly and daily in preventing IDA in pregnancy . DESIGN A r and omised control trial . SETTING University antenatal clinic , ( UANC ) Galle . SUBJECTS AND METHOD An oral iron supplement containing 100 mg of elemental iron was r and omly given weekly ( n = 26 ) thrice weekly ( n = 35 ) and daily ( n = 31 ) to 92 women who were 14 to 24 weeks pregnant . Haemoglobin ( Hb ) , serum ferritin ( SF ) and haematocrit ( Hct ) were assessed before and after 12 to 20 weeks of supplementation and a logistic regression analysis carried out . RESULTS The risk of developing anaemia was significantly higher in the weekly ( odds ratio 15 , 95 % CI 1.4 - 165.6 , p < 0.03 ) and possibly higher in the thrice weekly ( odds ratio 3 , 95 % CI 0.3 - 30.3 , p = 0.3 ) groups . The risk of developing iron deficiency ( SF < 12 micrograms/l ) was also significantly higher in the weekly ( odds ratio 18 , 95 % CI 2.8 - 115.5 , p < 0.003 ) and thrice weekly ( odds ratio 10 , 95 % CI 1.6 - 64.8 , p < 0.02 ) groups . CONCLUSION Prophylactic oral iron supplements when given intermittently were not effective in preventing iron deficiency anaemia in pregnancy [8644682] The effect of daily rather than weekly iron supplementation was compared in women who were 8 - 24 wk pregnant . One group ( n = 68 ) received 60 mg Fe/d , the second group ( n = 71 ) received 120 mg Fe/wk , given at once . Supplementation lasted 11.3 wk on average , depending on gestational date at entry , and was not supervised . Hemoglobin increased in both groups ( P < 0.001 ) ; serum ferritin did not change significantly . There was no significant difference between groups for changes in hemoglobin and serum ferritin . In a subgroup of women with a hemoglobin concentration < 110 g/L at baseline ( n = 45 daily ; n = 54 weekly ) no significant within-group changes occurred in serum ferritin , but the change in the daily group was 4.1 micrograms/L higher than in the weekly group ( P = 0.049 ) . Compliance , as indicated by two positive stool tests , was approximately equal to 54.3 % in the daily group and 62.2 % in the weekly group . We conclude that for the complete sample of subjects , the treatment effect of daily compared with weekly supplementation was similar under conditions resembling a normal antenatal care program [8237866] The present investigation was undertaken to assess the efficacy of oral iron supplementation during pregnancy by using a gastric delivery system ( GDS ) . Three hundred seventy-six pregnant women between 16 and 35 y of age and 14 and 22 wk gestation were selected if mild anemia was present ( hemoglobin concentration 80 - 110 g/L ) . The participants were r and omly assigned to one of three study groups given no iron , two FeSO4 tablets ( 100 mg Fe ) daily , or one GDS capsule ( 50 mg Fe ) daily . Blood was obtained initially and after 6 and 12 wk for measurement of red blood cell and iron indexes , including serum transferrin receptor . There was a significant and comparable improvement in hematologic and iron-status measurements in the two groups of women given iron whereas iron deficiency evolved in women given no iron supplement . We conclude that by eliminating gastrointestinal side effects and reducing the administration frequency of an iron supplement to once daily , a GDS offers significant advantages for iron supplementation of pregnant women [2963533] Studies on the treatment and prevention of iron deficiency anemia , in pregnant and nonpregnant women and in men , were conducted in Thail and and Burma . The effects of the dose of Fe , duration of Fe administration , additional supplementation with folate , mode of supplement delivery ( either supervised or unsupervised ) , and the presence of Hb(AE ) were studied . The frequency and severity of side effects were also recorded . Fe administration result ed in an increase in hemoglobin concentration in all anemic individuals but approximately 20 % failed to reach normality . The length of administration and the dose influenced the results . Frequency and severity of side effects increased with the dose of Fe administered . Folate supplementation did not affect the results . It appears possible to integrate a program of prevention and treatment of Fe deficiency anemia in a primary health-care system but the constraints and limitations of achievable results should be recognized [15113952] Daily iron supplementation programs for pregnant women recommend amounts of iron that are considered by some to be excessive , and either lower-dose or less frequent iron supplementation regimens have been proposed . A r and omized , placebo-controlled study was performed to assess and compare the relative effectiveness of a weekly ( WS ) or twice weekly ( TW ) iron supplementation schedule in maintaining or achieving hemoglobin ( Hb ) levels at term considered to carry minimal maternal and fetal risk ( 90 - 130 g/L ) . Pregnant women ( n = 116 ) at wk 10 - 30 of gestation ( 63 WS and 53 TW ) were enrolled in the study ( 52 in WS and 44 TW completed the study ) . Women were r and omly allocated to receive a 120-mg oral dose of iron as ferrous sulfate and 0.5 mg of folic acid weekly ( n = 52 ) or 60 mg iron and 0.25 mg folic acid and a placebo twice weekly ( n = 44 ) . Hb , hematocrit , serum ferritin , and transferrin saturation were estimated at baseline and at 36 - 39 wk of gestation . Baseline dietary data and the presence and intensity of intestinal helminthic infections were assessed . The duration of supplementation was 14 + /- 4 wk and the median level of adherence was 60.5 % . Hb concentrations improved in women following the TW regimen and in women following WS who had low baseline Hb levels . About 89 % of WS women and 95 % of TW women maintained Hb levels at term ( between 90 g/L and 130 g/L ) , a range associated with optimal pregnancy outcomes . One woman in the TW group exhibited higher Hb levels that potentially carried perinatal risk ( > 130 g/L ) . Intermittent iron and folic acid supplementation may be a valid strategy when used as a preventive intervention in prenatal care setting [11053509] In the context of limited effectiveness of iron supplementation programs , intermittent iron supplementation is currently under debate as a possible alternative strategy that may enhance the effectiveness of operational programs . This field-based trial assessed the outcome of twice weekly iron supplementation compared to daily in Pakistan . A double-blind , r and omized , clinical trial was conducted in Northern Pakistan . Anemic pregnant women ( n = 191 ) were assigned to receive daily ( 200 mg ferrous sulfate ) or twice weekly ( 2 x 200 mg ferrous sulfate ) iron supplementation . Hemoglobin was measured at baseline and at 4-wk intervals for up to 12 wk . Serum ferritin was measured at baseline and 8 or 12 wk . Analysis was by intention to treat . The two groups did not differ in age , parity , sociodemographic characteristics , hemoglobin or serum ferritin concentrations at baseline . Women who received iron daily had a greater rise in hemoglobin compared with women who received iron twice weekly ( 17.8 + /- 1.8 vs. 3.8 + /- 1.2 g/L , P < 0.001 ) . The serum ferritin concentrations increased by 17.7 + /- 3.9 microgram/L ( P < 0.001 ) in the daily supplemented group and did not change in the twice weekly group . Daily iron supplementation remained superior to twice weekly supplementation after controlling initial hemoglobin Z-scores and duration of treatment . The body mass index ( BMI ) modified the effect of daily versus twice weekly iron supplementation . For every unit increase in BMI , the difference between the two treatment groups was reduced by 0.0014 ( final hemoglobin Z-score ; P = 0.027 ) . We recommend continuation of daily iron supplementation as opposed to intermittent iron supplementation in pregnant women in developing countries [6461243] The usefulness of serum ferritin levels in assessing iron stores in pregnant women before and after supplementation with iron was studied . One hundred thirty-five healthy pregnant women between 22 to 28 wk were r and omly allotted to daily dose regimes of 60 , 120 , or 240 mg of ferrous sulphate . The tablets were given after meals under strict personal supervision . Before supplementation , iron deficiency ( ferritin level less than 10 micrograms/L ) was present in 54.8 % of the pregnant women , compared to an incidence of 17.8 % when assessed by serum iron concentration of less than 50 micrograms/dl . The mean ferritin level of pregnant women was 14.15 micrograms/L and was less than one-half that of healthy single women and one-sixth of that of healthy males . Supplementation with oral iron for 12 wk produced an increase in ferritin levels in all the groups , but significant increases were seen only in women given 120 and 240 mg of ferrous sulphate with or without folic acid . However , there were no differences in final Hb levels among the supplemented groups [9356536] We studied the effect of iron supplementation on the iron status of mothers and on biochemical iron status and clinical and anthropometric measures in their infants . The subjects were 197 pregnant women selected at 28 wk + /- 21 d of gestation at a mother- and -child health center in Niamey , Niger . Ninety-nine women received 100 mg elemental Fe/d throughout the remainder of their pregnancies and 98 received placebo . The prevalence of anemia and iron deficiency decreased markedly during the last trimester of pregnancy in the iron-supplemented group but remained constant in the placebo group . Three months after delivery , the prevalence of anemia was significantly higher in the placebo group . At delivery , there were no differences between the two groups in cord blood iron variables . Three months after delivery , serum ferritin concentrations were significantly higher in infants of women in the iron-supplemented group . Mean length and Apgar scores were significantly higher in infants with mothers in the iron group than in those with mothers in the placebo group [12600867] BACKGROUND Little is known about the benefits of prenatal multivitamin and mineral supplements in reducing low birth weight . OBJECTIVE We conducted a r and omized , double-blind clinical trial in semirural Mexico to compare the effects of multiple micronutrient ( MM ) supplements with those of iron supplements during pregnancy on birth size . DESIGN Pregnant women ( n = 873 ) were recruited before 13 wk of gestation and received supplements 6 d/wk at home , as well as routine antenatal care , until delivery . Both supplements contained 60 mg Fe , but the MM group also received 1 - 1.5 times the recommended dietary allowances of several micronutrients . RESULTS At recruitment , the women in the 2 groups were not significantly different in age , parity , economic status , height , or hemoglobin concentration but differed significantly in marital status ( 4.6 % and 2.0 % of women in the MM and iron-only groups , respectively , were single mothers ) and mean ( + /- SD ) body mass index ( in kg/m(2 ) ; 24.6 + /- 4.3 and 23.8 + /- 3.9 in the iron-only and MM groups , respectively ) . Losses to follow-up ( 25 % ) and compliance ( 95 % ) did not differ significantly between the groups . In intent-to-treat analyses ( MM group : n = 323 ; iron-only group : n = 322 ) , mean ( + /- SD ) birth weight ( 2.981 + /- 0.391 and 2.977 + /- 0.393 kg in the MM and iron-only groups , respectively ) and birth length ( 48.61 + /- 1.82 and 48.66 + /- 1.83 cm in the MM and iron-only groups , respectively ) did not differ significantly between the groups . CONCLUSION These findings suggest that MM supplementation during pregnancy does not lead to greater infant birth size than does iron-only supplementation [12450908] BACKGROUND According to our current underst and ing , iron absorption with weekly iron supplements is not higher than that with daily supplements ( ie , there is no mucosal block ) . However , community-based trials have repeatedly shown that a weekly regimen is as effective as a daily one . Furthermore , when differences in absorption are found , they are commonly smaller than would be expected on the basis of differences in the amount of iron provided . The possibility of differential compliance between the regimens needs to be evaluated to explain these findings . OBJECTIVE Taking compliance into account , we compared the efficacy and trial effectiveness of weekly and daily iron supplementation during pregnancy . DESIGN In Bangladesh , 50 antenatal centers were r and omly assigned to prescribe either 2 doses of 60 mg Fe once weekly or 1 dose of 60 mg Fe/d . Compliance was monitored by using a pill bottle equipped with an electronic counting device . Hemoglobin concentrations were measured at baseline and after 4 , 8 , and 12 wk of supplementation . RESULTS There was no differential effect per iron tablet between weekly and daily regimens . A 12-wk daily regimen ( 68 % compliance ) produced a small but significantly greater hemoglobin response than did the weekly regimen ( 104 % compliance ) . The first 20 tablets consumed produced most of the effect ; after 40 tablets , there was no further response . CONCLUSIONS There was no evidence of a mucosal block in the daily regimen . Over 12 wk , 50 % of the amount of iron in a daily regimen was sufficient for maximum hemoglobin effect . The weekly regimen provided a large part of this amount , explaining the limited difference in effect . It appears that the current international recommendation for iron supplementation in pregnancy is higher than necessary [2596434] The use of hemoglobin as a predictor of response to iron therapy , for screening , and for prevalence estimates was studied . An Fe supplementation trial was performed in Quito , Ecuador , in which 412 pregnant women were r and omly assigned to treatment and control groups . Women in the treatment group received 390 mg ferrous sulfate/d for 2 mo . The prevalence of Fe deficiency as defined by response to therapy was found to be 60.8 % . Sensitivity and specificity were calculated at various cutoff points of hemoglobin . The estimates of sensitivity and specificity allow for the use of hemoglobin in screening for Fe deficiency anemia and in the estimation of the prevalence in population s with characteristics similar to those found in the sample of pregnant women in Quito . Hemoglobin was shown to be a good predictor of response to Fe treatment and a good estimate of prevalence of Fe deficiency when prevalence is high [8780347] Limited adherence to iron supplementation is thought to be a major reason for the low effectiveness of anemia-prevention programs . In rural Tanzania , women at 21 - 26 wk of gestation were r and omly given either 120 mg of a conventional ( Con ) iron supplement or 50 mg of a gastric-delivery-system ( GDS ) iron supplement for 12 wk . Adherence was assessed by using a pill bottle equipped with an electronic counting device . Adherence in the GDS group was 61 % compared with 42 % for the Con group . In both groups , women experiencing side effects had about one-third lower adherence . Fewer side effects were observed in the GDS group . In a subgroup of women with a low initial hemoglobin concentration ( < or = 120 g/L ) , the response to the iron supplements suggested that both of the applied doses were unnecessarily high for adequate hematologic response in a population with a marginal hemoglobin concentration . The GDS group appeared to require a dose one-fourth as high as that of the Con group for an equal effect on improving hemoglobin to normal concentrations [14522736] BACKGROUND The need for prophylactic iron during pregnancy is uncertain . OBJECTIVE We tested the hypothesis that administration of a daily iron supplement from enrollment to 28 wk of gestation to initially iron-replete , nonanemic pregnant women would reduce the prevalence of anemia at 28 wk and increase birth weight . DESIGN Between June 1995 and September 1998 , 513 low-income pregnant women in Clevel and were enrolled in the study before 20 wk of gestation . Of these , 275 had a hemoglobin concentration > /= 110 g/L and a ferritin concentration > /= 20 micro g/L and were r and omly assigned to receive a monthly supply of capsules containing either 30 mg Fe as ferrous sulfate or placebo until 28 wk of gestation . At 28 and 38 wk of gestation , women with a ferritin concentration of 12 to < 20 micro g/L or < 12 micro g/L received 30 and 60 mg Fe/d , respectively , regardless of initial assignment . Almost all the women received some supplemental iron during pregnancy . We obtained infant birth weight and gestational age at delivery for 117 and 96 of the 146 and 129 women r and omly assigned to receive iron and placebo , respectively . RESULTS Compared with placebo , iron supplementation from enrollment to 28 wk of gestation did not significantly affect the overall prevalence of anemia or the incidence of preterm births but led to a significantly higher mean ( + /- SD ) birth weight ( 206 + /- 565 g ; P = 0.010 ) , a significantly lower incidence of low-birth-weight infants ( 4 % compared with 17 % ; P = 0.003 ) , and a significantly lower incidence of preterm low-birth-weight infants ( 3 % compared with 10 % ; P = 0.017 ) . CONCLUSION Prenatal prophylactic iron supplementation deserves further examination as a measure to improve birth weight and potentially reduce health care costs [12816784] BACKGROUND Iron deficiency anemia ( IDA ) is common in pregnant women , but previous trials aim ed at preventing IDA used high-dose iron supplements that are known to cause gastrointestinal side effects . OBJECTIVE The objective was to assess the effect on maternal IDA and iron deficiency ( ID , without anemia ) of supplementing pregnant women with a low dosage ( 20 mg/d ) of iron . Effects on iron status were assessed at the time of delivery and at 6 mo postpartum . Gastrointestinal side effects were assessed at 24 and 36 wk of gestation . DESIGN This was a r and omized , double-blind , placebo-controlled trial of a 20-mg daily iron supplement ( ferrous sulfate ) given from 20 wk of gestation until delivery . RESULTS A total of 430 women were enrolled , and 386 ( 89.7 % ) completed the follow-up to 6 mo postpartum . At delivery , fewer women from the iron-supplemented group than from the placebo group had IDA [ 6/198 , or 3 % , compared with 20/185 , or 11 % ; relative risk ( RR ) : 0.28 ; 95 % CI : 0.12 , 0.68 ; P < 0.005 ] , and fewer women from the iron-supplemented group had ID ( 65/186 , or 35 % , compared with 102/176 , or 58 % ; RR : 0.60 ; 95 % CI : 0.48 , 0.76 ; P < 0.001 ) . There was no significant difference in gastrointestinal side effects between groups . At 6 mo postpartum , fewer women from the iron-supplemented group had ID ( 31/190 , or 16 % , compared with 51/177 , or 29 % ; RR : 0.57 ; 95 % CI : 0.38 , 0.84 ; P < 0.005 ) . The rate of IDA between the groups did not differ significantly at 6 mo postpartum . CONCLUSION Supplementing the diet of women with 20 mg Fe/d from week 20 of pregnancy until delivery is an effective strategy for preventing IDA and ID without side effects [6824608] Summary . Serum iron , serum iron‐binding capacity , serum ferritin and erythrocyte protoporphyrin were determined during uncomplicated pregnancy in 45 healthy women ; 22 were given oral iron while the others were given a placebo . When iron was not given , 15 out of 23 women had exhausted iron stores and iron deficiency at term , as judged from low serum ferritin , low serum transferrin saturation and high erythrocyte protoporphyrin values . Only seven of them had a haemoglobin concentration between 10 and 11 g/dl at term but none had values < 10 g/dl . In the iron‐treated group ( n=22 ) none of the women developed iron deficiency . Serum ferritin was the most sensitive and specific test of iron deficiency . A practical procedure to detect iron deficiency and to control iron supplementation in pregnancy is suggested [12780424] Background . The aims of the present study were to evaluate the recommendations by comparing compliance and adequacy of iron status at 6 weeks postpartum between one group given advice only and one group given advice plus iron supplement . In the latter group the efficacies of two iron preparations of different strengths and types were compared [6726596] The known increased need for iron during pregnancy appears to be met only in part by increased iron absorption and amenorrhea . Considerable dem and s are made on maternal iron stores and , since many women lack sufficient storage iron , pregnancy may be expected to cause iron deficiency . This may lead to anemia in pregnancy and post partum and could also have a bearing on the iron status of the fetus and the neonate . Based on these considerations , prophylactic supplementation of dietary iron is advocated but remains a disputed issue . In the present controlled , prospect i ve and longitudinal study changes in hematologic status , and in particular in iron stores , during pregnancy were investigated in 44 healthy Caucasian women with uncomplicated pregnancies and deliveries . They were r and omly assigned to a study group ( n = 21 ) receiving oral iron supplements from the 16th week of amenorrhea until 6 weeks post partum , and a control group ( n = 23 ) without iron supplementation . Maternal concentrations of hemoglobin , serum iron , serum transferrin and serum ferritin were determined at 16 , 28 and 36 weeks of amenorrhea , at delivery , and 6 and 12 weeks post partum . The same variables were determined in cord blood . Iron supplementation appeared to prevent the physiologic fall in hemoglobin and serum iron concentrations which occurred in the control group , but had little influence on the observed rise in transferrin concentrations . Ferritin levels in serum , which are known to reflect mobilisable iron stores , fell to 30 % of the initial values in the control group and to 70 % in the study group . Six and 12 weeks post partum ferritin levels were still low in the nonsupplemented group ( Tab . I ) . ( ABSTRACT TRUNCATED AT 250 WORDS [10696955] Background . The aim was to define reference values for hemoglobin , hematocrit and erythrocyte indices , i.e. erythrocyte count , mean corpuscular volume ( MCV ) , mean corpuscular hemoglobin ( MCH ) , mean corpuscular hemoglobin concentration ( MCHC ) , in normal pregnancy and after a normal delivery in non‐iron‐supplemented and iron supplemented women [12641613] Spatone Iron-Plus is a naturally occurring mineral water from Trefriw Wells Spa in Conwy County , North Wales , UK . It contains approximately 0.20 mg of iron per millilitre as ferrous sulphate and has been shown to provide iron in a highly bio-available form . A 24 ml sachet contains approximately 5 mg of iron . Iron deficiency is common in the obstetric population . However , compliance with traditional iron supplements is poor because of gastrointestinal side-effects . We design ed a r and omized , double-blind , placebo-controlled trial . A total of 102 low-risk antenatal patients , who were noncompliant with routinely prescribed ferrous sulphate tablets , were r and omized to receive 48 ml of Spatone water or placebo . The study was conducted between 22 and 28 weeks gestation . Primary outcome measures were compliance , gastrointestinal side-effects and changes in ferritin levels during the trial period . Compliance in the intervention group was 57 % compared with 67 % in the control group , P = 0.22 . Dyspepsia scores , as determined by a recognized and well-vali date d question naire , did not differ between the two groups . During the trial period , mean ferritin levels fell by 24 % in the Spatone Iron-Plus group compared with a mean fall of 51 % in ferritin levels among the control group , P = 0.016 [15777891] OBJECTIVE To compare the effect of daily oral iron supplementation with two injections of high dose parenteral iron . METHOD A total of 220 pregnant women with a singleton pregnancy and hemoglobin between 8 to 11 g% at 16 - 24 weeks gestation were identified and r and omly divided into two groups . Group A was started on daily oral iron therapy of 100 mg of elemental iron . Group B was given 250 mg of iron sorbitol intramuscularly and repeated at an interval of 4 - 6 weeks . Blood indices were evaluated at the beginning of study and at 36 weeks to see the effect after iron supplementation in the two groups . The data were analyzed using SPSS software , version 10.1 . RESULTS Definitive and comparable improvement in hemoglobin and all the blood indices ( hematocrit , MCH , MCHC , MCV , Serum iron and TIBC ) was observed . The absolute change in hemoglobin and hematocrit was 1.18+/-0.68 g% and 4.02+/-2.59 % in oral group , 1.34+/-0.77 g% and 4.93+/-3.65 % in parenteral group , respectively . Serum ferritin showed statistically significant absolute rise ( 10.43+/-7.92 microg/dl ) after parenteral iron supplementation as compared to oral iron supplementation ( 9.76+/-4.78 microg/dl ) . Obstetric outcome was comparable in two groups . CONCLUSION Two treatment regimens are biologically equivalent in terms of hematological response . Two high doses of intramuscular iron can be a good substitute to meet iron requirement in pregnancy [10878651] Objective : Intervention with iron supplementation , deworming , and information , education and communication ( IEC ) to improve the haematological status among each of the three trimesters of pregnant women in a rural community . Design : A community-based study was carried out using a two-group pre – post experimental design in a rural community . Setting : Two rural blocks in Vellore district were selected for the study . KV Kuppam block with a population of 120 , 000 and the adjacent Gudiyatham block with a population of 132 , 000 served as study and control areas for the study .Subjects : Using a multistage sampling , initially 50 % of the panchayats , the local village administrative units , were r and omly selected and all pregnant women were the subjects . In the pre-intervention survey 458 and 387 pregnant women had haemoglobin tested and the post-intervention survey covered 403 and 425 pregnant women in the study and control areas , respectively . Similarly serum ferritin was tested in a r and omly selected sub- sample with 254 and 191 pregnant women before intervention and in 216 and 223 pregnant women after intervention in both study and control areas , respectively . Intervention : Iron supplementation and deworming were provided to all pregnant women in the study area from the fourth month of their pregnancy . An intensive information , education and communication was carried out with facts on anaemia and diet modification to each pregnant woman , using a one-to-one approach in the community , and a group method in the mobile clinics . This was carried out for a period of 18 months . Results : A significant decrease in the prevalence of anaemia was found , from 56.1 % to 25.07 % ( P<0.001 ) , 73.4 % to 49.2 % ( P<0.001 ) and 68.8 % to 56.8 % ( P<0.01 ) among women in the first , second and third trimesters , respectively , in the intervention area . Significant ( P<0.001 ) increases in the mean haemoglobin of 0.85 g/dl ( 95 % CI 10.18–10.84 , 11.09–11.63 ) , 0.59 g/dl ( 95 % CI 9.98–10.34 , 10.55–10.95 ) and 0.36 g/dl ( 95 % CI 9.93–10.33 , 10.25–10.73 ) were also observed in each of the groups . Conclusion : A comprehensive community-based intervention with iron supplementation , helminthic treatment and increase in knowledge using IEC through effective strategies can improve the haematological status of pregnant women in each trimester . Sponsorship : Mother Care Project , John Snow Inc. , Funded by the United States Agency for International Development (USAID).European Journal of Clinical Nutrition ( 2000 ) 54 , [15766997] BACKGROUND Neonatal mortality is the biggest contributor to global mortality of children younger than 5 years , and low birthweight is a crucial underlying factor . We tested the hypotheses that antenatal multiple micronutrient supplementation would increase infant birthweight and gestational duration . METHODS We did a double-blind , r and omised controlled trial in Dhanusha district , Nepal . Women attending for antenatal care with singleton pregnancies at up to 20 weeks ' gestation were invited to participate . Participants were r and omly allocated either routine iron and folic acid supplements ( control ; n=600 ) or a multiple micronutrient supplement providing a recommended daily allowance of 15 vitamins and minerals ( intervention ; n=600 ) . Supplementation began at a minimum of 12 weeks ' gestation and continued until delivery . Primary outcome measures were birthweight and gestational duration . Analysis was by intention to treat . The study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N88625934 . FINDINGS Birthweight was available for 523/600 infants in the control group and 529/600 in the intervention group . Mean birthweight was 2733 g ( SD 422 ) in the control group and 2810 g ( 453 ) in the intervention group , representing a mean difference of 77 g ( 95 % CI 24 - 130 ; p=0.004 ) and a relative fall in the proportion of low birthweight by 25 % . No difference was recorded in the duration of gestation ( 0.2 weeks [ -0.1 to 0.4 ] ; p=0.12 ) , infant length ( 0.3 cm [ -0.1 to 0.6 ] ; p=0.16 ) , or head circumference ( 0.2 cm [ -0.1 to 0.4 ] ; p=0.18 ) . INTERPRETATION In a poor community in Nepal , consumption of a daily supplement containing a recommended daily allowance of 15 micronutrients in the second and third trimesters of pregnancy was associated with increased birthweight when compared with a st and ard iron and folic acid preparation . The effects on perinatal morbidity and mortality need further comparisons between studies . Published online March 3 , 2005 http://image.thelancet.com/extras/04art11045web.pdf [9351406] Background . The purpose of the present study was to evaluate the efficacy of low dose iron supplementation with and without a heme component , prescribed for women in the second half of pregnancy [10682464] OBJECTIVE To study the efficacy of iron supplementation during pregnancy and its influences on the outcome of pregnancy . METHODS A total of 369 pregnant women were enrolled in this study . According to the hemoglbin levels at recruitment , there were 2 groups : preventive ( Hb > or = 110 g/L ) and treatment ( Hb < 110 g/L ) groups . In the preventive group , women entered the study from 20 - 24 gestational weeks and were r and omly assigned to materna treatment ( n = 96 ) who took materna 1 tablet daily or control group ( n = 95 ) who took no other supplementation . In the treatment groups , women less than 36 gestational weeks were accepted . They were r and omly divided as materna ( n = 93 ) 1 tablet/d , ferrous sulfate 0.3 g tid/d ( n = 50 ) or Ferroids 1 tablet/d ( n = 35 ) groups . Both Hb and serum ferritin concentrations were determined at admission and immediately after delivery . In some cases serum ferritin in the umbilical vein were measured as well . Hemoglobin levels were examined every 4 weeks during the observational period . RESULTS In the preventive groups , maternal serum ferritin levels after materna treatment were significantly higher than that before treatment and the control group ( P < 0.05 ) . As for the anemia women , compared the serum ferritin concentration , materna treatment had significantly higher levels than that at admission ( P < 0.05 ) , and also higher than that in the ferrous sulfate or ferroids tratment groups ( P < 0.05 ) . The s-ferritin in the umbilical vein had no correlation with the paired maternal levels . There were no significant differences in the pregnancy outcomes among all the groups . CONCLUSION Materna can increase the iron storage and effectively improve the iron deficiency during pregnancy , and has no impact on the prgnancy outcomes [12186198] Side-effects of iron supplementation lead to poor compliance . A weekly-dose schedule of iron supplementation rather than a daily-dose regimen has been suggested to produce fewer side-effects , thereby achieving a higher compliance . This study compared side-effects of iron supplementation and their impact on compliance among pregnant women in Bangladesh . These women were assigned to receive either weekly doses of 2 x 60 mg iron ( one tablet each Friday morning and evening ) or a daily dose of 1 x 60 mg iron . Fifty antenatal care centres were r and omly assigned to prescribe either a weekly- or a daily-supplementation regimen ( 86 women in each group ) . Side-effects were assessed by recall after one month of supplementation and used for predicting compliance in the second and third months of supplementation . Compliance was monitored using a pill bottle equipped with an electronic counting device that recorded date and time whenever the pill bottle was opened . Of five gastrointestinal side-effects ( heartburn , nausea , vomiting , diarrhoea , or constipation ) assessed , vomiting occurred more frequently in the weekly group ( 21 % ) than in the daily group ( 11 % , p<0.05 ) . Compliance ( ratio between observed and recommended tablet intake ) was significantly higher in the weekly-supplementation regimen ( 93 % ) than in the daily-supplementation regimen ( 61 % , p<0.05 ) . Overall , gastrointestinal side-effects were not significantly associated with compliance . However , the presence of nausea and /or vomiting reduced compliance in both the regimens-but only among women from the lower socioeconomic group . In conclusion , weekly supplementation of iron in pregnancy had a higher compliance compared to daily supplementation of iron despite a higher frequency of side-effects . The findings support the view that gastrointestinal side-effects generally have a limited influence on compliance , at least in the dose ranges studied . Efforts to further reduce side-effects of iron supplementation may not be a successful strategy for improving compliance and effectiveness of antenatal iron supplementation [9829872] This paper addresses two questions : 1 ) What is the relation of hemoglobin in the second gestational month to preterm birth and low birth weight ? 2 ) How does the relation differ when hemoglobin in the fifth or eighth month or the lowest pregnancy hemoglobin are examined in place of first trimester values ? These relations were examined prospect ively in 829 women from Shanghai , China in 1991 - 1992 . The population was nearly homogeneous by race , parity , antenatal care , and smoking . Rates of birth outcomes were compared between hemoglobin categories based on 10 g/liter groupings , with 110 - 119 g/liter as the reference group . Rates of low birth weight and preterm birth ( but not small-for-gestational age ) were related to early pregnancy hemoglobin concentration in a U-shaped manner . The relative risks ( 95 % confidence intervals ) for preterm birth in women by g/liter of hemoglobin were 2.52 ( 0.95 - 6.64 ) for > or = 130 g/liter , 1.11 ( 0.41 - 2.99 ) for 120 - 129 g/liter , 1.64 ( 0.77 - 3.47 ) for 100 - 109 g/liter , 2.63 ( 1.17 - 5.90 ) for 90 - 99 g/liter , and 3.73 ( 1.36 - 10.23 ) for 60 - 89 g/liter . Use of hemoglobin values in the fifth or eighth month attenuated the association with preterm birth . When lowest pregnancy hemoglobin values were used , the association of anemia with both outcomes was obscured , and risk of preterm birth at high hemoglobin values increased dramatically [8635830] Eighty one pregnant women ( 20 + /- 2 weeks of gestation ) were assessed for their nutritional status . They were divided into three groups ; Group I women ( n = 30 ) were given 200 mg ferrous sulphate ( FeSO4 ) tablet per day for 15 weeks , Group II women ( n = 25 ) were given FeSO4 tablets along with 2,000,000 IU of vitamin A as single dose in beginning of study ; and Group III women ( n = 26 ) were not given any supplements and served as controls . To study impact of supplements on hematological profile of pregnant women , Hb , PCV , RBC , TS% , TIBC and serum levels of iron , zinc , copper , manganese and vitamin A were assessed at 20 + /- 2 weeks and 36 + /- 2 weeks of gestation by st and ard techniques . Pregnant women in Group I ( Fe suppl ) and group II ( Fe + vitamin A suppl ) had significantly ( p < 0.01 ) higher Hb , PCV , RBC , TS% and serum iron levels than the controls . Group II had significantly ( p < 0.05 ) higher values of these indices as compared to Group I. Levels of serum zinc , copper , manganese were not affected by supplements . Iron supplements improved the hematological profile of pregnant mothers but Fe + vitamin A supplements were more beneficial [8846152] Blood manganese levels and iron status indices were determined each trimester in 66 healthy pregnant women . Twenty-five were r and omly assigned to iron supplementation , 19 to placebo and 22 received dietary advise aim ed at increasing their dietary intake of fibre . Iron supplemented women had significantly higher levels of blood haemoglobin compared to the levels of the two other groups , and higher serum ferritin levels compared to the placebo group . No significant difference in blood manganese levels was observed among the three groups of women . There was a significant increase in blood manganese levels from one trimester to the next , which was slightly more pronounced in non supplemented women . The median values in the three trimesters were 154 ( range 79 - 360 ) nmol/L , 190 ( range 98 - 408 ) nmol/L , and 230 ( range 133 - 481 ) nmol/L , respectively . Pregnancy seems to change manganese status or otherwise influence manganese metabolism irrespective of iron status and iron supplementation [2583756] This study was conducted to determine the optimum dose of supplemental iron for prophylaxis against pregnancy anemia . One hundred and ten pregnant women were r and omly allocated to three groups : Group A receiving equivalent of 60 mg , group B 120 mg and Group C 240 mg , elemental iron as ferrous sulphate daily ; the content of folic acid was constant in all the three groups ( 0·5 mg ) . These women had at least consumed 90 tablets in 100±10 days . Blood was drawn at the beginning and at the end of the treatment . Fifty percent were anemic ( < 11g/100 ml ) . The hemoglobin levels rose similarly in all groups and the differences were statistically not significant . Fifty-six percent had depleted iron stores ( serum ferritin value < 12 μg/1 ) at the beginning of the study . Following therapy a statistically significant increase in iron stores was observed in group B and C as compared to group A. The difference between group B and C was not significant . The side effects increased with increasing doses of iron ; 32·4 % , 40·3 % and 72 % in group A , B and C respectively . Based on these findings , the authors advocate that optimum dose of iron should be 120 mg instead of 60 mg as is currently being used in the National Nutritional Anemia Prophylaxis Programme . * * * DIRECT SUPPORT * * * A08BC044 [1858501] 192 pregnant women were consecutively r and omized to either a vitamin‐mineral pill or a vitamin mineral pill with a high iron content in a prospect i ve , open , r and omized investigation . The participants were advised about iron‐rich foodstuffs twice during pregnancy . Iron status of the mother proved to be without any significance for the outcome of pregnancy . A serum ferritin level of 80 pmol/l in mid‐pregnancy followed by a control in the last trimester was suggested as a guide in deciding of whether or not to prescribe supplementary iron during pregnancy [15566454] AIM To compare the hematological parameters and pregnancy outcome in women receiving daily versus weekly iron supplements during pregnancy . METHODS A prospect i ve r and omized controlled study was carried out at the Department of Obstetrics and Gynaecology of the All India Institute of Medical Sciences , New Delhi , India , during which 111 women were r and omized to receive either 100 mg elemental iron daily ( n=55 ) or 200 mg elemental iron weekly ( n=56 ) . Hemogram and serum ferritin level estimation were carried out at the beginning of pregnancy and within the 32 - 34-week period of gestation . Side-effects , compliance and the number of tablets consumed were noted for each group . The mean birth weight , period of gestation at delivery and mode of delivery were also compared between the two intervention groups . RESULTS There was no significant difference in the mean hemoglobin levels between the two intervention groups at the end of an average 17 weeks of iron supplementation . However , among anemic women who received daily supplementation , there was a greater rise in hemoglobin compared with those receiving supplementation weekly . The serum ferritin level was lower in the weekly supplemented group compared with that in the daily . There was no difference in the mean birth weight , period of gestation and mode of delivery between the two groups . Side-effects and non-compliance were significantly higher ( P<0.001 ) in the daily supplemented group . CONCLUSIONS Weekly iron supplementation is an effective option for prophylaxis in non-anemic pregnant women , but has less than optimal benefit in anemic women [10326325] BACKGROUND The National Nutritional Anaemia Prophylaxis Programme ( NNAPP ) in India was launched in 1971 . However , anaemia continues to be a major public health problem . Partial coverage of the population , inadequate dose of the iron supplement , defective absorption due to intestinal infestations and problems with formulation have been recognized as factors responsible for its failure . Therefore , the bioavailability of iron from different formulations containing 60 mg of elemental iron and of tablets with varying doses of elemental iron was undertaken . METHODS One hundred and fifteen women were r and omly allotted to receive different formulations and doses of iron and then undergo iron tolerance tests . They received ferrous sulphate tablets containing 60 mg , 120 mg and 180 mg of elemental iron ; formulations containing 60 mg of elemental iron as pure ferrous sulphate salt , ferrous fumarate tablets , ferrous fumarate syrup , excipients added to pure ferrous sulphate salts , powdered ferrous sulphate tablets , iron tablets distributed by the NNAPP and pure ferrous salt in gelatin capsules . RESULTS The data obtained from 32 subjects were excluded because of non-compliance , intolerance of the medication and lack of results of blood tests . Data from the remaining 83 subjects indicated that increasing the dose of elemental iron from 60 mg to 180 mg improved the bioavailability of iron , but was associated with unacceptable side-effects . Also , liquid formulations of iron had a better bioavailability , with ferrous fumarate syrup and gelatin capsules being the most superior . CONCLUSION Providing the iron formulation with a high bioavailability should enable the NNAPP to be more successful in decreasing the prevalence of anaemia [8141223] OBJECTIVE Our purpose was to study the effect of hematinic supplementation on the maternal erythropoietin response during singleton pregnancy . STUDY DESIGN In a r and omized , double-blind trial 97 patients with a first-trimester hemoglobin level > or = 14.0 gm/dl received either iron and folic acid ( hematinic group , n = 53 ) or a placebo ( n = 44 ) . Serial hemoglobin , hematocrit , and serum erythropoietin were recorded from maternal blood and from cord blood on delivery . Serum ferritin was measured in the first trimester , at 36 weeks ' gestation , and in cord blood . RESULTS In both groups ( 1 ) the mean hemoglobin was lower ( p < 0.01 ) at 40 weeks ' gestation than when first examined and ( 2 ) the mean serum erythropoietin was higher ( p < 0.01 ) . The mean serum ferritin was lower ( p < 0.001 ) in both groups at 36 weeks ' gestation than at presentation but higher ( p = 0.04 ) in the hematinic group than in the placebo group . The mean hemoglobin and hematocrit were similar in the two groups until the third trimester but thereafter were higher ( p < 0.05 ) in the hematinic group . The mean maternal serum erythropoietin was higher ( p < 0.05 ) in the placebo group than in the hematinic group after 24 weeks ' gestation . The mean cord blood hematologic values were similar in the two groups . CONCLUSION Maternal serum erythropoietin increased during pregnancy , but this response was reduced in the third trimester in the hematinic-supplemented group [3511017] Recent studies suggest that infant behavior and psychological test performance are impaired by iron deficiency and may be improved by iron . Comparable studies have not been performed in older population s. Young women early in pregnancy whose nutritional intake may be impaired by poverty constitute a high-risk population . Women aged 14 - 24 years coming for prenatal care at or before 16 weeks gestation whose hematocrits were greater than or equal to 31 % were r and omized in a double-blind trial to receive vitamins supplemented with iron ( experimental group ) or vitamins alone ( controls ) . Hematologic status and tests of short-term memory and attention span were assessed at entry and conclusion of the one-month treatment period . The experimental group showed significant improvement on the most sensitive measure of short-term memory and three subtests . On comparison of the change between initial and final scores , the experimental group showed significant or borderline greater improvement than controls on three tests . These results indicated a beneficial effect of iron therapy on psychometric test-score performance [9699743] Objective To determine whether a high concentration of serum ferritin during the third trimester is a marker of sub clinical maternal infection and very preterm delivery and is associated with maternal nutritional status . Methods A total of 1162 gravidas was followed prospect ively from entry to prenatal care ( 15.0 ± 4.9 completed weeks ' gestation ) in Camden , New Jersey , between 1985 and 1995 . Multiple logistic regression and analysis of covariance were used to examine the influence of serum ferritin on the outcomes of interest . Results High concentrations of serum ferritin ( at or above the 90th percentile ) at week 28 , but not at entry to prenatal care , increased risk of preterm and very preterm delivery , but the risk changed if the concentration of ferritin declined from entry . If the concentration declined as expected , high ferritin concentration had no influence on outcome . If the concentration increased , then high ferritin concentration at week 28 was associated with very preterm delivery ( adjusted odds ratio [ AOR ] 8.77 ; 95 % confidence interval [ CI ] 3.90 , 19.72 ) , preterm delivery ( AOR 3.81 ; 95 % CI 1.93 , 7.52 ) , low birth weight ( AOR 5.15 ; 95 % CI 2.47 , 10.72 ) , clinical chorio-amnionitis ( AOR 2.56 ; 95 % CI 1.01 , 6.52 ) , and symptoms of “ flu ” as an index of unmeasured infection ( AOR 6.02 ; 95 % CI 1.16 , 31.17 ) . Factors associated with failure of the ferritin concentration to decline included iron deficiency anemia earlier in pregnancy ( AOR 3.98 ; 95 % CI 1.17 , 8.98 ) and lower levels of serum and red cell folate . Conclusion High serum ferritin concentration in the third trimester , result ing from a failure of ferritin to decline , is associated with very preterm delivery and markers of maternal infection . Iron deficiency anemia and other indicators reflecting poor maternal nutritional status earlier in pregnancy underlie this relationship [1062910] Abstract . Iron absorption , bone‐marrow smears and haematological parameters were repeatedly studied during pregnancy in 50 women . The same studies were repeated two months after delivery . The material was r and omly divided into two groups . Twenty‐four women were treated with 200 mg of ferrous iron daily while 26 were given placebo . The iron absorption was measured from radioiron‐labelled test doses of 100 mg ferrous iron in a whole‐body counter with high sensitivity [10422631] Abstract Assessment of the efficacy of iron therapy has usually been done in population s/ patients by monitoring changes in hemoglobin concentration , serum iron , percent transferrin saturation , and serum ferritin . In this study the protoporphyrin heme ( P/H ) ratio ( a measure of free erythrocyte protoporphyrin ) was measured before and after iron therapy in three groups of pregnant women , who received 60 mg ( group A ) , 120 mg ( group B ) , and 240 mg ( group C ) of elemental iron with folic acid ( 0.5 mg ) per day for a period of 12 weeks , to evaluate its efficacy to monitor iron therapy . The three groups were comparable regarding the initial mean Hb concentration and serum ferritin levels . The initial mean P/H ratios were markedly elevated in all three groups and were different in the three groups , being highest in group A ( 113.2±92.6 ) , intermediate in group B ( 87.5±62.5 ) , and lowest in group C ( 69.8±43.3 ) . The initial P/H ratio was significantly higher in group A than in group C ( p<0.05 ) . This probably affected the efficacy of iron therapy in the three groups . The P/H ratio decreased significantly in each of the three groups after iron therapy ( A and B : p<0.001 ; C p<0.01 ) . Mean Hb concentration and serum ferritin increased in all three groups post therapy ; however , the magnitude of change in P/H ratio in all three groups was much greater . This indicated that the predominant contributory factor for anemia was iron deficiency in this group of pregnant women . Serum iron and percent transferrin saturation are difficult to interpret in our population , as iron is freely available over the counter and is prescribed as soon as anemia is detected in patients ; therefore , the reduction in P/H ratio may be used to monitor response to iron therapy in population groups [8122498] In a r and omized , double‐blind , placebo controlled study of the effect of iron supplementation during pregnancy , iron status ( hemoglobin ( Hb ) , serum (S‐)transferrin saturation , S‐ferritin ) and S‐erythropoietin ( EPO ) were assessed in 120 healthy pregnant women at 14–16 weeks of gestation , and just before delivery ; 63 women were treated with 66 mg iron daily , and 57 with placebo . There were no differences in baseline values in the two groups . At term , the iron treated group had significantly higher Hb , transferrin saturation , S‐ferritin ( median 22 μg/1 vs. 14 μg/1 , ( p<0.0001 ) and lower S‐EPO compared to the placebo treated group . In the iron group , 30.2 % had exhausted iron stores ( i.e. S‐ferritin < 20 μg/1 ) , 6.3 % latent iron deficiency ( S‐ferritin < 20 μg/1 and transferrin saturation < 15 % ) , and no patients had iron deficiency anemia ( S‐ferritin < 20 μg/1 and transferrin saturation < 15 % and Hb < 110 g/1 ) . In the placebo group , 93.0 % had exhausted iron stores , 54.4 % latent iron deficiency , and 17.5 % iron deficiency anemia ; S‐EPO was inversely correlated to iron status markers : Hb , rs = −0.51,p<0.001 ; transferrin saturation , rs= −0.65,p<0.0001 ; S‐ferritin , rs= − 0.31 , R<0.01 , suggesting that the elevation in S‐EPO was secondary to iron deficient erythropoiesis . Newborns to iron treated mothers had higher cord S‐ferritin , median 155 μg/1 , than newborns to placebo treated mothers , median 118 ug/1 ( p<0.02 ) ; there were no differences in birth weight , transferrin saturation , or S‐EPO . Supplemental iron in a dose of 65 mg/day from the second trimester is sufficient to prevent iron deficiency in pregnant Danish women [2010577] This trial compares routine and selective iron supplementation during pregnancy to determine whether routine supplementation adversely affects fetal growth , increases infections and subjective adverse effects , and /or delays birth . At their first prenatal visit , 2912 pregnant women were r and omized into two groups ( 2694 gave birth ) . Compliance was satisfactory as measured by self-reports by mothers and hematocrit values in the third trimester . More women in the routinely supplemented group had subjected adverse effects . The groups were similar in regard to most of the other outcomes . In the selectively supplemented group , there was weak evidence for increase in sick-days , referrals to hospital outpatient clinic , cesarean section , blood transfusions , and infants who were diagnosed as having hyperviscosity . In the routine group , there were somewhat more women with gestations greater than or equal to 41 weeks and more dead infants . The subgroup analyses suggest that some of the apparently worse outcomes in the selective group were due to reactions of midwives and physicians to low hematocrit values [1802636] The effect of iron supplementation , 66 mg elemental iron daily , from the 16th week of gestation to delivery , on iron status markers during uncomplicated pregnancies was assessed in a r and omised , double-blind , placebo controlled study of 207 healthy women ( 100 iron treated , 107 placebo treated ) and their newborn babies . Haemoglobin ( Hb ) and serum ( S- ) human placental lactogen ( HPL ) were measured in all 207 females , while transferrin saturation , S-ferritin and S-erythropoietin ( EPO ) were measured in 120 females at monthly intervals . Hb : from 27th week of gestation to eight weeks post partum , the placebo treated group had significantly lower Hb levels than the iron treated group ( p less than 0.001 ) . Iron status markers : in the placebo group ( n = 57 ) , 92 % developed exhausted iron stores ( i.e. S-ferritin less than or equal to 20 micrograms/l ) , 65 % latent iron deficiency ( i.e. S-ferritin less than or equal to 20 micrograms/l and transferrin saturation less than 15 % ) , and 18 % iron deficiency anaemia ( i.e. S-ferritin less than or equal to 20 micrograms/l , transferrin saturation less than 15 % and Hb less than 110 g/l ) . In the iron treated group ( n = 63 ) , 54 % developed exhausted iron stores , 6 % latent iron deficiency , and none iron deficiency anaemia . S-EPO : the placebo group had significantly higher values than the iron treated group from the 27th week of gestation to one week post partum ( p less than 0.01 ) . S-HPL : levels were identical in placebo and iron treated females . Babies of iron treated mothers had higher S-ferritin than babies of placebo treated mothers ( p less than 0.02 ) . ( ABSTRACT TRUNCATED AT 250 WORDS [7992349] A r and omized , double-blind , placebo-controlled community-based trial of oral iron supplementation ( 200 mg ferrous sulphate daily ) administered to multigravid pregnant women by traditional birth attendants ( TBAs ) was carried out in a rural area of The Gambia . Iron supplementation led to a significant reduction in the prevalence of anaemia and of iron deficiency . Iron supplementation was not accompanied by increased susceptibility to malaria infection ; there was no difference in the prevalence and severity of peripheral blood or placental malaria infection between the 2 groups of women . The birth weight of children born to women who received iron prophylaxis was increased by an average of 56 g. It is concluded that oral iron prophylaxis can be successfully delivered through TBAs integrated into a primary health care programme . This simple intervention can produce significant beneficial effects on the health of the mother without inducing increased susceptibility to malaria and has the potential for reducing perinatal mortality by increasing birth weight [7901636] Nutritional anaemia , thought to be caused by iron deficiency , affects 50 - 70 % of pregnant women in the developing world . The influence of vitamin A and iron supplementation was studied in anaemic pregnant women in West Java , in a r and omised , double-masked , placebo-controlled field trial . 251 women aged 17 - 35 years , parity 0 - 4 , gestation 16 - 24 weeks , and haemoglobin between 80 and 109 g/L were r and omly allocated to four groups : vitamin A ( 2.4 mg retinol ) and placebo iron tablets ; iron ( 60 mg elemental iron ) and placebo vitamin A ; vitamin A and iron ; or both placebos , all daily for 8 weeks . Maximum haemoglobin was achieved with both vitamin A and iron supplementation ( 12.78 g/L , 95 % Cl 10.86 to 14.70 ) , with one-third of the response attributable to vitamin A ( 3.68 g/L , 2.03 to 5.33 ) and two-thirds to iron ( 7.71 g/L , 5.97 to 9.45 ) . After supplementation , the proportion of women who became non-anaemic was 35 % in the vitamin-A-supplemented group , 68 % in the iron-supplemented group , 97 % in the group supplemented with both , and 16 % in the placebo group . Improvement in vitamin A status may contribute to the control of anaemic pregnant women [12637400] Abstract Objective : To assess the impact on birth size and risk of low birth weight of alternative combinations of micronutrients given to pregnant women . Design : Double blind cluster r and omised controlled trial . Setting : Rural community in south eastern Nepal . Participants : 4926 pregnant women and 4130 live born infants . Interventions : 426 communities were r and omised to five regimens in which pregnant women received daily supplements of folic acid , folic acid-iron , folic acid-iron-zinc , or multiple micronutrients all given with vitamin A , or vitamin A alone ( control ) . Main outcome measures : Birth weight , length , and head and chest circumference assessed within 72 hours of birth . Low birth weight was defined < 2500 g. Results : Supplementation with maternal folic acid alone had no effect on birth size . Folic acid-iron increased mean birth weight by 37 g ( 95 % confidence interval −16 g to 90 g ) and reduced the percentage of low birthweight babies ( < 2500 g ) from 43 % to 34 % ( 16 % ; relative risk=0.84 , 0.72 to 0.99 ) . Folic acid-iron-zinc had no effect on birth size compared with controls . Multiple micronutrient supplementation increased birth weight by 64 g ( 12 g to 115 g ) and reduced the percentage of low birthweight babies by 14 % ( 0.86 , 0.74 to 0.99 ) . None of the supplement combinations reduced the incidence of preterm births . Folic acid-iron and multiple micronutrients increased head and chest circumference of babies , but not length . Conclusions : Antenatal folic acid-iron supplements modestly reduce the risk of low birth weight . Multiple micronutrients confer no additional benefit over folic acid-iron in reducing this risk . What is already known on this topic Deficiencies in micronutrients are common in women in developing countries and have been associated with low birth weight and preterm delivery What this study adds In rural Nepal maternal supplementation with folic acid-iron reduced the incidence of low birth weight by 16 % A multiple micronutrient supplement of 14 micronutrients , including folic acid , iron , and zinc , reduced low birth weight by 14 % , thus conferring no advantage over folic [9704770] OBJECTIVE Our purpose was to demonstrate reduced blood volume in preeclampsia compared with nonproteinuric gestational hypertension and normal pregnancy by use of independent measures of red blood cell and plasma volumes . STUDY DESIGN Red blood cells labeled with a nonradioactive stable isotope of chromium and Evans ' blue were infused in subjects with preeclampsia or gestational hypertension and normotensive pregnant controls . Blood was sample d eight times over 60 minutes for dye concentration and at 30 minutes for chromium analysis . RESULTS Total blood and plasma volumes are decreased in preeclampsia ( 2660 + /- 382 mL/m2 and 1790 + /- 332 mL/m2 , respectively ) compared with normotensive subjects ( 3217 + /- 391 mL/m2 , P < 0.001 and 2279 + /- 325 mL/m2 , P < .001 ) and gestational hypertension ( 3139 + /- 272 mL/m2 , P < .001 and 2132 + /- 265 mL/m2 , P = .003 ) . Total body/peripheral hematocrit ratio is increased in preeclampsia . CONCLUSIONS Blood volume , by measurement of red blood cell and plasma volumes , is reduced and has altered distribution in preeclampsia but is normal in gestational hypertension [7483113] The aim of this r and omized , double blind , placebo controlled parallel study was to evaluate whether iron status markers in pregnant women , measured early in the second trimester , could be used to predict levels later in pregnancy , and post partum . One hundred and twenty healthy pregnant women between 14 and 18 weeks of gestation were included . Sixty-three women were allocated to treatment with tablets containing 66 mg ferrous iron ( as fumarate ) daily , and 57 women to treatment with placebo . Haemoglobin , serum transferrin saturation , and serum ferritin were measured every fourth week during gestation , prior to delivery , one week and eight weeks post partum . Correlation matrices during pregnancy and post partum were calculated for each iron status marker , both in iron and placebo treated women . Haemoglobin , transferrin saturation and serum ferritin values at inclusion displayed steadily declining correlation coefficients with values obtained later in pregnancy . There were no clinical ly relevant correlations to values obtained eight weeks or less prior to delivery , or post partum . Serum ferritin values at inclusion could not be used to predict values later in pregnancy or post partum . Haemoglobin , transferrin saturation and serum ferritin values measured in the beginning of the second trimester appear unsuitable as guidelines for an individual iron prophylaxis during the remaining period of pregnancy [5551272] This study was planned to determine whether iron deficiency in pregnancy predisposed to the development of folate deficiency and also the smallest daily iron supplement that maintained haemoglobin levels in pregnancy . Three groups of women were given oral ferrous fumarate supplying 30 , 60 , and 120 mg of iron ; a fourth group was given 1 g of parenteral iron in early pregnancy followed by oral iron ( 60 mg ) ; a fifth group received a placebo . Tablets were taken once daily . Oral iron 30 mg once daily maintained haemoglobin levels throughout pregnancy . Women whose marrows lacked demonstrable iron at the 37th week had a significantly higher incidence of megaloblastic haemopoiesis ( 28·7 % ) than those with demonstrable iron stores ( 15·3 % ) ; women taking oral iron did not have a lower frequency of megaloblastosis than those given a placebo . We concluded that iron does not have a direct effect on folate status in pregnancy , that the association of iron deficiency and megaloblastic anaemia in pregnancy is the result of poor nutrition , and that there is no cause- and -effect relation between them [2672177] An iron supplementation trial versus placebo was performed in double blind on 191 attending at 3 month the antenatal clinic of Poissy maternity . Iron status of mothers and newborns was assessed at 3 , 5 , 7 month , during the delivery and 2 months after the delivery , using biochemical indicators ( hemoglobin level , serum ferritin ) . The compliance was good in 165 pregnant women ( 86 % of the initial sample ): 81 in the iron group , 84 in the placebo group . Among the placebo group , anemia ( Hb less than 11 g/dl ) was observed at the end of the pregnancy in 30 % of women . Depletion of iron stores started at 5 month . In the iron group , hemoglobin level increased significantly during the pregnancy and anemia was observed only in 3 % of women at the delivery . Iron status of newborns and two months after delivery was related to mothers iron status at delivery and particularly at the 7th month of pregnancy [11976463] OBJECTIVE To compare the effectivity of weekly versus daily iron therapy in reducing maternal anemia and to evaluate the association of maternal hemoglobin and fetal growth . DESIGN Prospect i ve . SETTING Tertiary care teaching hospital in an urban metropolis . METHOD 40 pregnant women received daily and 40 pregnant women received weekly oral therapy ( 335 mg of ferrous sulphate and 500 g folic acid ) for a period of 14 weeks . The age of each pregnant woman and their baseline anthropometric data ( weight , height and body mass index ) were estimated . Hemoglobin and hematocrit estimations were carried out during follow period at 4 wks , 8 wks and 14 weeks . Serum ferritin values as a marker of iron status were also calculated in both the groups initially , at 14 weeks and at the time of delivery . Fetal anthropometric indices of 137 full term neonates delivered to mothers included in either of the supplementation groups or admitted to the hospital were also studied in relation to maternal hemoglobin concentration . RESULTS Forty subjects each were initially r and omized into groups I and II . The age of pregnant women along with their baseline anthropometric data were similar in both groups . A total of 29 pregnant women in group I and 27 pregnant women in group II could be regularly followed up . The increase in hemoglobin and hematocrit values were similar in daily and weekly supplemented mothers . An intention to treat analysis also showed similar results . The ferritin values were similar at the start of supplementation and after 14 wks of weekly or daily iron therapy . Birth weight , crown heel length , head circumference of the neonate and placental weight increased significantly with rise in maternal hemoglobin levels . CONCLUSION Weekly iron supplementation is an effective mode of treating anemia among pregnant women and maternal anemia during pregnancy is adversely associated with fetal growth [9277046] Serum erythropoietin ( EPO ) and its relationship to hemoglobin ( Hb ) , iron status markers and iron supplementation during normal pregnancy was assessed in a longitudinal , placebo-controlled study on 118 women , 61 took daily tablets containing 66 mg ferrous iron from the second trimester until delivery and 57 took placebo . Blood sample s were obtained at 4-week intervals until delivery as well as post-partum . In the placebo-treated women , median serum EPO rose from 22.5 U/l at inclusion to 35.0 U/l at delivery ( P = 0.0001 ) . In the iron-treated women , median serum EPO rose from 23.9 to 29.9 U/l ( P = 0.0001 ) . Serum EPO showed a steeper increase in the placebo-treated women than in the iron-treated women ( P < 0.05 ) . After delivery , serum EPO became normal in both groups ( P = 0.0001 ) . Median Hb was lower in placebo-treated ( iron depleted ) than in iron-treated ( iron repleted ) women ( P < 0.05 ) . In the placebo-treated women there was a negative correlation and in the iron-treated women a positive correlation between serum EPO and Hb . In the placebo-treated women , inverse correlations existed between serum EPO and serum transferrin saturation and serum ferritin , reflecting the consequences of iron deficiency , whereas the iron-treated women displayed no correlation . A physiological , nonhypoxia-induced increase in EPO production accounts for the basic expansion of the red cell mass during pregnancy . In placebo-treated women , iron deficient erythropoiesis constitutes an additional hypoxic stimulus , which induces a further increase in serum EPO [6029952] IN a previous investigation of the effects of grade d micro-doses of folic acid ( pteroyl glutamic acid ) in pregnancy suggestive evidence has been obtained that the minimal oral requirement may lie in the region of 300 pg./day . This conclusion was based largely upon the measurement of the fasting post-partum serum folate or L. casei activity in a group of patients from a population where poor dietary intake of folic acid was common . In patients receiving no prophylactic folic acid or IOO pg./day the median post-partum serum folate level was subnormal , in those receiving 3oo , ug./day it was normal and in those receiving 4sopg./day it was supranormal ( Willoughby and Jewell , 1966 ) . As an extension of this investigation the incidence of maternal anaemia has now been assessed among a population of 3599 patients r and omly allocated at their first ante-natal [8383415] Objective ‐ To determine : 1 ) if 18 mg iron daily is sufficient to cover the iron need during normal pregnancy , and 2 ) if women , who will not need iron supplementation during pregnancy , can be identified by early screening [7660438] The influence of haemoglobin genotype on the response to iron supplementation was studied in a r and omized , double blind , placebo-controlled trial involving 497 multigravid pregnant women from a rural area of The Gambia . Women were r and omly allocated to receive either oral iron ( 60 mg elemental iron per day ) or placebo . At 36 weeks of pregnancy , women who had received oral iron during pregnancy had higher mean haemoglobin , packed cell volume , plasma iron and ferritin levels than did women who received placebo . Iron supplementation of pregnant women with the AA haemoglobin genotype also result ed in increases in the packed cell volume ( PCV ) and haemoglobin level measured after delivery , and in the birth weight of the infant . However , in AS women PCV and haemoglobin level at delivery were lower in the supplemented group and supplementation was also associated with reduced birth weights . In malaria endemic areas , pregnant women with the haemoglobin genotype AS may not benefit from iron supplementation during pregnancy [2791561] This article reports the design and feasibility of a r and omized controlled trial of the benefits of routine iron prophylaxis during pregnancy . The multicenter trial , supported by a small budget , relied on health service personnel in Finnish maternity centers . Iron prophylaxis has had an established position in Finnish maternity care , and iron is freely available . This contributed to our decision to ask for informed consent after r and omization . During a year , 2960 mothers were recruited by midwives in 27 maternity health centers and r and omized into two groups : selective and routine iron supplementation . Mothers were followed until the postpartum checkup , and data were collected by five different question naires and abstract ed from the infant 's patient record . Adherence of the midwives to the study protocol was satisfactory , as was mothers ' compliance with recommended treatments . However , because the study was design ed to compare two treatment policies , problems of nonmasking hamper of the biologic effects of iron . This trial encourages the use of existing health services and their personnel in evaluation of medical technology [15715531] Objective . To determine the lowest dose of iron preventative of iron deficiency and iron deficiency anemia in pregnancy [4009554] A r and omized , double-blind , crossover study was carried out on iron absorption from three prenatal supplements by women in the first trimester of pregnancy . The supplements were given to fasting subjects as a single pill early in the morning , and iron absorption was determined from measurements of serum iron performed during the course of the day . Iron absorption from two of the supplements was substantially less than the 3.5 mg recommended for the prevention of iron deficiency during pregnancy . The third supplement , containing reduced amounts of calcium and magnesium , provided on the average 3.6 mg of absorbed iron to the subjects . These results support previous findings in nonpregnant subjects that the availability of iron in a prenatal supplement is affected by the overall composition of the supplement [15253399] BACKGROUND Erythrocyte indices change in pregnancy , mainly due to physiological haemodilution and iron-deficient erythropoiesis . The present study was undertaken to determine the haematological indices during different periods of gestation in women receiving daily iron supplements and compare them with those in women receiving weekly iron supplements . METHODS Pregnant women < 20 weeks of gestation attending the antenatal clinic at the All India Institute of Medical Sciences were r and omized to receive either 100 mg elemental iron daily or 200 mg elemental iron weekly . The haemoglobin , haematocrit , mean corpuscular volume , mean corpuscular haemoglobin and mean corpuscular haemoglobin concentration were estimated at baseline , after 1 month , 3 months and at 34 weeks of gestation . RESULTS Changes consistent with physiological haemodilution in mid-term pregnancy were noted and the values at 34 weeks of gestation were not significantly different between the two groups . CONCLUSION The effects of intermittent iron supplementation on the erythrocyte indices in pregnancy are comparable with those observed with daily supplementation [2661878] The effect of anemia ( hematocrit less than or equal to 0.34 ) on subsequent preterm birth was prospect ively studied in 35,423 pregnancies . The incidence of preterm birth among women with and without anemia at each week during the third trimester was compared . Early in the third trimester , there was a weak association between anemia and preterm delivery . However , anemia early in the third trimester did not account for the substantial increase in preterm birth seen among black women . Anemia after 30 weeks ' gestation was not associated with preterm birth . Among women delivering term infants weighing 2500 g or more , the mean hematocrit rose 0.029 among black women and 0.021 among white women from 25 weeks to term . Compared with hematocrits at 40 weeks ' gestation , the odds ratios for anemia reached a maximum at 28 weeks and fell sharply as term approached . When the hematocrits of women in term labor were compared with those of women in preterm labor , a spurious dose-response effect for anemia was created . We conclude that anemia is not a strong factor in the pathogenesis of preterm birth and that comparison of hematocrits from women who are in preterm and term labor produces biased results [16740440] BACKGROUND We undertook this study to compare the effectiveness and safety of antenatal daily and weekly supplementation with iron , folic acid , and vitamin B(12 ) in healthy , pregnant women who were not anemic at gestational week 20 . METHODS Women with singleton pregnancies and blood hemoglobin ( Hb ) > 115 g/L at gestational week 20 ( equivalent to 105 g/L at sea level ) were r and omly assigned to two groups , one consuming one tablet containing 60 mg iron , 200 mug folic acid and 1 mug vitamin B(12 ) daily ( DS , n = 56 ) ; the other consuming two tablets once weekly ( WS , n = 60 ) . Blood Hb and serum ferritin concentrations were measured every 4 weeks from weeks 20 to 36 , and pregnancy outcomes were evaluated . RESULTS Mild anemia and hypoferritinemia throughout pregnancy occurred less frequently in DS than WS . None of the 116 women had Hb concentrations < 103 g/L at any evaluation point . In contrast , hemoconcentration ( Hb > 145 g/L ) from gestational week 28 onwards occurred in 11 % in DS and 2 % in WS . We observed ex post facto that hemoconcentration at gestational week 28 was associated with a significantly higher relative risk of low birth weight ( RR 6.23 , 95 % CI 1.46 - 26.57 ) and premature delivery ( RR 7.78 , 95 % CI 1.45 - 24.74 ) . CONCLUSIONS In women who were nonanemic at gestational week 20 , both schemes ( DS and WS ) prevented the occurrence of Hb levels < 100 g/L. DS women had a higher incidence of hemoconcentration . Hemoconcentration was associated with increased risk of low birth weight and premature delivery [627303] The failure to prescribe in antenatal clinics a well tolerated form of supplementary oral iron that provides an adequate iron supply for the successful maintainance of active erythropoiesis in pregnant women largely accounts for the frequent development of latent iron deficiency in the child-bearing age . The potential value of Plexafer-F * , a slow release ferrous sulphate preparation supplemented with folic acid , in reducing the high incidence of latent iron deficiency in pregnancy was assessed by conducting a r and omized clinical trial of Plexafer-F and ordinary ferrous sulphate B.P. with folic acid in eighty women presenting early in pregnancy with latent iron deficiency . At the end of the trial , which was started at the sixteenth week of pregnancy and which lasted for twenty weeks , normal haematological values were obtained in thirty-eight out of forty patients ( 95 % ) taking Plexafer-F , but only in twenty-four out of forty patients ( 60 % ) taking ferrous sulphate . A simple screening test run on stool specimens provided during antenatal visits to check regular ingestion of the iron preparations prescribed , revealed regular drug intake and no intolerance in all the patients receiving Plexafer-F , against an intolerance leading to failure of regular drug intake in 37.5 % of patients receiving ordinary ferrous sulphate [5134472] The side-effects of a new sustained release oral ferrous sulphate preparation have been evaluated in three separate double-blind studies . Each tablet contained 100 mg of ferrous iron and the dosage employed in all studies was 2 tablets daily . In a large series of blood donors r and omly divided into three groups the frequency and type of side-effects were compared to ferrous sulphate tablets and placebo . In two series of pregnant women the side-effects were studied with a cross-over technique using ferrous sulphate tablets as reference . Placebo was also included as a reference in one of these studies . In all series the frequency of nausea and epigastric pain was about the same for the sustained release preparation as for placebo . In all series ferrous sulphate tablets gave a significantly higher frequency of nausea than the sustained release tablets and placebo . Also the frequency of epigastric pain was found to be higher in blood donors but this could not be verified in pregnant women [4668759] Summary The effect of small doses of iron and folic acid in a single tablet in preventing anaemia in pregnancy has been assessed . Fifty mg . elemental iron and 400μg . folic acid were found to be satisfactory daily supplements for both ‘ good ’ and ‘ bad ’ tablet takers . Tablet counting and an occasional chemical test for the presence of iron in the faeces were compared as indicators of tablet consumption and the latter found to be superior . The high incidence of faulty tablet consumption indicates the need for some check in anaemic patients in pregnancy [7888886] Abstract Objective : To assess the relation of the lowest haemoglobin concentration in pregnancy with birth weight and the rates of low birth weight and preterm delivery in different ethnic groups . Design : Retrospective analysis of 153602 pregnancies with ethnic group and birth weight recorded on a regional pregnancy data base during 1988 - 91 . The haemoglobin measurement used was the lowest recorded during pregnancy . Setting : North West Thames region . Subjects : 115262 white women , 22206 Indo-Pakistanis , 4570 Afro-Caribbeans , 2642 mediterraneans , 3905 black Africans , 2351 orientals , and 2666 others . Main outcome measures : Birth weight and rates of low birth weight ( < 2500 g ) and preterm delivery ( < 37 completed weeks ) . Results : Maximum mean birth weight in white women was achieved with a lowest haemoglobin concentration in pregnancy of 85 - 95 g/l ; the lowest incidence of low birth weight and preterm labour occurred with a lowest haemoglobin of 95 - 105 g/l . A similar pattern occurred in all ethnic groups . Conclusions : The magnitude of the fall in haemoglobin concentration in pregnancy is related to birth weight ; failure of the haemoglobin concentration to fall below 105 g/l indicates an increased risk of low birth weight and preterm delivery . This phenomenon is seen in all ethnic groups . Some ethnic groups have higher rates of low birth weight and preterm delivery than white women , and they also have higher rates of low haemoglobin concentrations . This increased rate of “ anaemia , ” however , does not account for their higher rates of low birth weight , which occurs at all haemoglobin concentrations . Key messages Key messages Failure of the haemoglobin concentration to fall during pregnancy was associated with a five to sevenfold increase in the incidence of low birth weight and preterm birth Routine haematinic administration in pregnancy is unnecessary on fetal grounds for most pregnancies The mean corpuscular volume may be a better indicator of maternal iron deficiency , but this needs prospect i ve [138664] Hemoglobin ( Hb ) concentration , serum iron level , iron binding capacity and blood folate ( Lactobacillus casei ) activity were determined in 310 unselected pregnant Burmese women . Hb concentration was less than 11 g/dl in 72 % of the women ; the serum iron level was less than 50 mug/dl in 33 % ; serum folate activity was less than 3ng/ml in 13 % ; and red cell folate activity was less than 100 ng/ml in 17 % of the women . Ninety-six of the women in our study were r and omly divided into four groups , treated from the 22nd to the 25th week of pregnancy until full term with either ferrous sulfate containing 60 mg elemental iron twice daily , 5 mg folic acid twice daily , a combination of both , or a placebo only . At full term , Hb concentration fell in the groups given placebo or folic acid . On the other h and , in the groups given iron alone or iron plus folic acid there was an increase in Hb of 0.4 and 0.7 g/dl , respectively ( intergroup difference not statistically significant ) . Serum iron and blood folate levels fell in the groups not receiving the appropriate hematinic . In spite of deficient serum and red cell folate levels in 30 and 40 % , respectively , of the group on iron alone , the mean Hb concentration increased at full term and none of the women had a Hb concentration lower than 10 g/dl . Blood folate levels were lower in the iron-supplemented group than in the placebo group , indicating that iron deficiency does not aggravate the folate nutritional status [7631683] OBJECTIVE A r and omized trial comparing women who were given iron only if needed and those given iron prophylactically showed that routine prophylaxis is not crucial for mothers ' or infants ' health up to postpartum examination . This study investigated these infants ' and mothers ' subsequent health , as available in routine registers in a 7-year follow-up . STUDY DESIGN Original data ( N = 2693 ) were linked to the national population , birth , and hospital inpatient registers . RESULTS The outcomes in the two groups were very similar : there were no statistically significant differences in deaths after birth , number or timing of infants ' or mothers ' hospitalizations , reasons for mothers ' first hospitalization , number or timing of subsequent miscarriages or births , or problems or outcomes in the next birth . However , infants of the prophylactically supplemented group were more frequently hospitalized because of convulsions . CONCLUSION This study does not support routine iron prophylaxis for well-nourished pregnant women [10842553] A weekly iron/folate supplement was compared with a st and ard daily iron/folate supplement in pregnant women living in rural Malawi . Women were enrolled as they attended the local antenatal clinic , stratified by grade of anaemia and then r and omized to receive either 60 mg iron/0.25 mg folate per day ( n=211 ) or 120 mg iron/0.50 mg folate once a week ( n=202 ) . Supplementation was continued for a minimum of 8 weeks ( 10 weeks on average ) and was self administered by the women at home . Initial haemoglobin values for the daily ( μ=105.7g/l ) and weekly ( μ=104.4g/l ) groups as well as final haemoglobin values ( 107.5 g/l and 105.6 g/l , respectively ) did not differ significantly between the two groups . Haemoglobin values increased by similar levels in both groups with the subset of anaemic women increasing by an average of 6.3 g/l in the daily group ( n=70 ) and 5.9 g/l in the weekly group ( n=66 ) for all women . For compliant , anaemic women , the increases were 7.4 g/l and 6.6 g/l for the daily and weekly groups , respectively . Compliance , as indicated by self reporting and by regular counts of remaining tablets , was significantly higher in the weekly group ( 76 % compared with 60 % , P < 0.05 ) , however compliance was identical in both groups when assessed by a stool test for elemental iron . Reported side effects were significantly reduced in the weekly group ( 6 % compared with 17 % , P < 0.05 ) . We conclude that a weekly iron supplement given to pregnant women in rural Malawi has similar haematologic effects , and an improved side effect profile , in comparison with a st and ard daily supplement when administered through an existing primary healthcare programme , although both regimens are relatively unsuccessful in the reduction of anaemia prevalence during pregnancy [11787984] In the present study 67 non-anaemic women were r and omly allocated to either 100 mg or 15 mg iron daily at about the 10 . week of pregnancy . At about week 18 , 30 and 36 of pregnancy , as well as 6 weeks after delivery , hemoglobin and the serum concentrations of ferritin , vitamin B12 , folates , Zn , Cu and Se were monitored . Dietary allowances of other minerals and vitamins are also increased in pregnancy , and the 15 mg iron tablet was enriched with Zn ( 10 mg ) , Cu ( 2 mg ) , Se ( 50 microg ) , vitamin B12 ( 3 microg ) , and folate ( 0.1 mg ) . Neither ferritin , nor Cu , Zn or Se concentrations differed statistically significantly between the treatment groups during pregnancy . Ferritin and Zn appeared to decrease approximately parallel to the hemodilution , whereas Cu concentrations increased from a non-pregnant reference mean of 18 micromol Cu/L to a maximum mean of nearly 33 micromol Cu/L during pregnancy . Se decreased concomitantly to about 1.0 micromol Se/L. Serum folate ( around 15 micromol/L ) was essentially unaffected by pregnancy in the group given multivitamin/mineral supplementation , whereas the mean concentration fell below 10 micromol/L in the group supplemented with 100 mg iron daily . Our results indicate that supplementation of 15 mg Fe daily during pregnancy results in a small reduction of hemoglobin . It is suggested that additional supplementation with folate might be of importance to maintain the serum folate concentration during pregnancy [865369] Four haematinic supplements -- Slow-Fe , FGF , Ferro-Gradumet and Ferro-Grad tfolic -- were prospect ively studied in 103 healthy pregnant patients . Significant differences in the mean cell counts , haematocrit values , haemoglobin levels , iron-binding capacities and serum folate levels were noted . The changes paralleled the elemental iron present in the compount . In this series , side effects principally vomiting and constipation , were more frequent in the lower dose iron group . Form both the haematological status aspect and the lack of side effects , Ferro-Grad Folic and Ferro-Gradumet were superior to both FGF and Slow-Fe ( old formulation ) [29120032] The effect of oral iron prophylaxis on haemoglobin concentration ( Hb ) and haematocrit ( Hct ) has been studied in 300 pregnant women . From the 3rd to 4th month of pregnancy and until term the women were r and omly treated with 100 mg or 200 mg ferrous iron daily respectively as sustained‐release tablets ( Duroferon ® Duretter ® ) or 200 mg ferrous iron as rapidly disintegrating tablets [5683581] The serial trends of the whole blood folate level in two groups of patients have been followed throughout pregnancy and up to six weeks postpartum . In those receiving iron alone the whole blood folate remained normal until the test at six weeks after delivery , at which time over half were in the deficient range . There appears to be a delay before this test reflects the current folate status when this changes rapidly . In those receiving iron plus 330 μg . of folic acid a day the results at this time were close to those at the beginning of pregnancy . Subnormal whole blood folate , red cell folate , and serum folate values occurred close to term in patients receiving iron alone , but were not found in those also receiving folic acid . Megaloblastic changes occurred at term in three patients receiving iron alone in whom the whole blood folate had repeatedly been low in early pregnancy . The observations are consistent with the previous suggestion that 300 μg . of folic acid daily is a suitable supplement to prevent deficiency in late pregnancy and the puerperium [7117682] Forty patients were given one of two iron-folic acid tablets starting from the first ante-natal visit and continuing to parturition . Haemoglobin levels were measured at the commencement , at the end of the study and on at least one other occasion . A comparison was made of haemoglobin levels and side-effects [8081594] Eighty-four non-anaemic pregnant women were treated , starting between the 20th-24th week of Pregnancy , with Actiferrin Compositum--1 capsule per day -- from the 36th with 2 capsules per day up to childbirth . The group was compared with the results in 57 non-anaemic not treated pregnant women . Haematological parameters were recorded before the onset of treatment , during the first stage of labour and in neonates on the first day after delivery . By means of the non-paired t-test no significant differences were disclosed between the groups ; nevertheless the percentage values of haemoglobin , haematocrit , erythrocytes and serum iron were higher in the treated group , as compared with the non-treated one . Also the ferritin values in neonates of the non-treated group were lower , as compared with the treated group . The paired t-test was highly significant in the Actiferrin treated patients as regards haemoglobin , haematocrit and transferrin values . The results provide evidence that it is indicated to administer as a routine measure Actiferrin Compositum to all pregnant women as prevention of pre-partum anaemia of the mother and low ferritin levels in the neonate

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### Context: [2025036] Previous studies have found that there is a correlation between mothers ' haemoglobin concentration or packed cell volume and infants ' birth weight , and that iron supplementation increases mothers ' haemoglobin concentration . The purpose of this study , using the data of a large r and omised trial on iron prophylaxis during pregnancy , was to find out whether iron supplementation causes fetal growth to deteriorate . At their first antenatal visit , 2912 pregnant women were r and omised into non-routine iron and routine iron supplementation . The mean length of gestation was shorter in the non-routine group . Birth weight did not differ between the groups , but due to longer gestations boys in the group receiving routine iron were taller than in the non-routine group . In both groups , whether studied by various values of packed cell volume or correlation coefficients , the lower the packed cell volume , the heavier and taller the infant and heavier the placenta . These negative correlations could be seen even with a packed cell volume measured early in pregnancy . St and ardising for blood pressure did not influence the correlation coefficients . The correlation between a high ratio for packed cell volume and poor fetal growth thus may not be caused by iron supplementation , nor mediated by blood pressure , but by some other mechanism [3530158] Two hundred Hausa primigravidae at Zaria were divided into five groups in a r and omized double-blind trial of antenatal oral antimalarial prophylaxis , and haematinic supplements . Group 1 received no active treatment . Groups 2 to 5 were given chloroquine 600 mg base once , followed by proguanil 100 mg per day . In addition , group 3 received iron 60 mg daily , group 4 folic acid 1 mg daily , and group 5 iron plus folic acid . Forty-five percent were anaemic ( haemoglobin ( Hb ) less than 11.0 g dl-1 ) at first attendance before 24 weeks of gestation , and malaria parasitaemia ( predominantly Plasmodium falciparum ) was seen in 27 % , of whom 60 % were anaemic . The mean Hb fell during pregnancy in group 1 , and seven patients in this group had to be removed from the trial and treated for severe anaemia ( packed cell volume ( PCV ) less than 0.26 ) . Only five patients in the other groups developed severe anaemia ( P = 0.006 ) , two of whom had malaria following failure to take treatment . Patients in group 1 had the lowest mean Hb at 28 and 36 weeks of gestation , and patients receiving antimalarials and iron ( groups 3 and 5 ) had the highest Hb at 28 weeks , but differences were not significant , possibly due to removal from the trial of patients with severe anaemia . Anaemia ( Hb less than 12.0 g dl-1 ) at six weeks after delivery was observed in 61 % of those not receiving active treatment ( group 1 ) , in 39 % of those protected against malaria but not receiving iron supplements ( groups 2 and 4 ) and in only 18 % of patients receiving both antimalarials and iron ( groups 3 and 5 ) . Folic acid had no significant effect on mean Hb . Proguanil was confirmed to be a highly effective causal prophylaxis . Prevention of malaria , without folic acid supplements , reduced the frequency of megaloblastic erythropoiesis from 56 % to 25 % . Folic acid supplements abolished megaloblastosis , except in three patients who were apparently not taking the treatment prescribed . Red cell folate ( RCF ) concentrations were higher in subjects with malaria , probably due to intracellular synthesis by plasmodia . Infants of mothers not receiving antimalarials appeared to have an erythroid hyperplasia . Maternal folate supplements raised infants ' serum folate and RCF . Fourteen per cent had low birth weight ( less than 2500 g ) , and the perinatal death rate was 11 % ; the greatest number were in group 1 , but not significantly . A regime is proposed for the prevention of malaria , iron deficiency , folate deficiency and anaemia in pregnancy in the guinea savanna of Nigeria [3273871] Iron absorption from four prenatal multivitamin/multimineral preparations was compared in 36 healthy pregnant women in their second or third trimester of pregnancy . The products studied were the currently marketed formulations of Stuartnatal 1 + 1 , Stuart Prenatal , Materna , and Natalins Rx . Each fasted subject received each of the four preparations , according to a r and omized sequence , at intervals of three to seven days between drug administrations . Stuartnatal 1 + 1 demonstrated the best iron absorption . Total iron absorbed from Stuartnatal 1 + 1 and Stuart Prenatal was well above the additional daily 3.5 mg recommended during pregnancy . Following administration of Materna the amount of iron was only slightly above that recommended , and following Natalins Rx it was well below . All formulations were generally well tolerated by the subjects [7891047] OBJECTIVE To evaluate whether levels of iron status markers ( haemoglobin , serum transferrin saturation , serum ferritin ) in pregnant women , measured in the beginning of the second trimester , could be used to predict levels later in pregnancy , pre partum and post partum . DESIGN R and omized , double-blind , placebo-controlled parallel study . SETTING The Birth Clinic at the Department of Obstetrics , Herning Hospital , Herning , Denmark . SUBJECTS One hundred and twenty healthy pregnant women between 14 and 18 weeks of gestation . INTERVENTIONS Sixty-three women were allocated to treatment with tablets containing 66 mg ferrous iron ( as fumarate ) daily , and 57 women to treatment with placebo . MAIN OUTCOME MEASURES Haemoglobin , serum transferrin saturation , and serum ferritin were measured every 4th week during gestation , prior to delivery , and 1 and 8 weeks post partum . RESULTS Correlation matrices during pregnancy and post partum were calculated for each iron status marker separately in iron-treated and placebo-treated women . Haemoglobin , transferrin saturation and serum ferritin values at inclusion displayed steadily declining correlation coefficients with values obtained later in pregnancy . There were no clinical ly relevant correlations to values obtained 8 weeks or less prior to delivery , and no correlations to values post partum . Serum ferritin values at inclusion could not be used to predict values later in pregnancy or post partum . CONCLUSION Haemoglobin , transferrin saturation and serum ferritin values measured in the beginning of the second trimester appear to be unsuitable as guidelines for an individual iron prophylaxis in pregnant women [5926263] Bertino , J. R. , Ward , J. , Sartorelli , A. C. , and Silber , R. ( 1965 ) . 7 . clin . Invest . , 44 , 1028 . Bothwell , T. H. , Hurtardo , A. V. , Donohue , D. M. , and Finch , C. A. ( 1957 ) . Blood , 12 , 409 . Callender , S. T. , and Malpas , J. S. ( 1963 ) . Brit . med . 7 . , 2 , 1516 . Cockburn , F. , Sherman , J. D. , Ingall , D. , and Klein , R. ( 1965 ) . Proc . Soc . exp . Biol . ( N.Y. ) , 118 , 238 . Conrad , M. E. , Berman , A. , and Crosby , W. H. ( 1962 ) . Gastroenterology , 43 , 385 . Dacie , J. V. , and Lewis , S. M. ( 1963 ) . Practical Haematology , 3rd ed . London . Davis , A. E. , and Badenoch , J. ( 1962 ) . Lancet , 2 , 6 . Finch , C. A. , Coleman , D. H. , Motulsky , A. G. , Donohue , D. M. , and Reiff , R. H. ( 1956 ) . Blood , 11 , 807 . Herbert , V. ( 1963 ) . Amer . 7 . clan . Nutr . , 12 , 17 . Gottlieb , C. W. , and Altschule , M. D. ( 1965 ) . Lancet , 2 , 1052 [6881917] Iron and folate status of 203 pregnant women have been evaluated at 6 months gestation and on the same women and their newborn infants at delivery . The women who had , at 6 months gestation , a Hb level below 11 g/dl were systematic ally given iron supplements . Iron or placebo were r and omly allocated to the other women . At 6 months of pregnancy , one quarter of the women had a Hb level under 11 g/dl but one third had a serum ferritin level below 12 micrograms/l and more than half had low levels of serum and red cell folate . Iron supplements induced an increase both in Hb levels and in serum ferritin values ; however , no significant differences were observed in serum ferritin of the newborn infants , whether their mothers had received iron supplements or not . These results have led us to reconsider the value of ferritin levels at birth as an index of iron stores in the infant . Iron supplements had no effect on the folate status in mothers or infants or on the frequency of obstetrical complications . A significant relationship was found between maternal folate levels and length of gestation . Folate supplementation may reduce the incidence of premature delivery [12164031] RATIONALE It has been suggested that in pregnant women weekly iron supplements are as effective as daily supplements in preventing iron deficiency anaemia ( IDA ) . OBJECTIVE To compare the effectiveness of prophylactic antenatal oral iron supplements given weekly , thrice weekly and daily in preventing IDA in pregnancy . DESIGN A r and omised control trial . SETTING University antenatal clinic , ( UANC ) Galle . SUBJECTS AND METHOD An oral iron supplement containing 100 mg of elemental iron was r and omly given weekly ( n = 26 ) thrice weekly ( n = 35 ) and daily ( n = 31 ) to 92 women who were 14 to 24 weeks pregnant . Haemoglobin ( Hb ) , serum ferritin ( SF ) and haematocrit ( Hct ) were assessed before and after 12 to 20 weeks of supplementation and a logistic regression analysis carried out . RESULTS The risk of developing anaemia was significantly higher in the weekly ( odds ratio 15 , 95 % CI 1.4 - 165.6 , p < 0.03 ) and possibly higher in the thrice weekly ( odds ratio 3 , 95 % CI 0.3 - 30.3 , p = 0.3 ) groups . The risk of developing iron deficiency ( SF < 12 micrograms/l ) was also significantly higher in the weekly ( odds ratio 18 , 95 % CI 2.8 - 115.5 , p < 0.003 ) and thrice weekly ( odds ratio 10 , 95 % CI 1.6 - 64.8 , p < 0.02 ) groups . CONCLUSION Prophylactic oral iron supplements when given intermittently were not effective in preventing iron deficiency anaemia in pregnancy [8644682] The effect of daily rather than weekly iron supplementation was compared in women who were 8 - 24 wk pregnant . One group ( n = 68 ) received 60 mg Fe/d , the second group ( n = 71 ) received 120 mg Fe/wk , given at once . Supplementation lasted 11.3 wk on average , depending on gestational date at entry , and was not supervised . Hemoglobin increased in both groups ( P < 0.001 ) ; serum ferritin did not change significantly . There was no significant difference between groups for changes in hemoglobin and serum ferritin . In a subgroup of women with a hemoglobin concentration < 110 g/L at baseline ( n = 45 daily ; n = 54 weekly ) no significant within-group changes occurred in serum ferritin , but the change in the daily group was 4.1 micrograms/L higher than in the weekly group ( P = 0.049 ) . Compliance , as indicated by two positive stool tests , was approximately equal to 54.3 % in the daily group and 62.2 % in the weekly group . We conclude that for the complete sample of subjects , the treatment effect of daily compared with weekly supplementation was similar under conditions resembling a normal antenatal care program [8237866] The present investigation was undertaken to assess the efficacy of oral iron supplementation during pregnancy by using a gastric delivery system ( GDS ) . Three hundred seventy-six pregnant women between 16 and 35 y of age and 14 and 22 wk gestation were selected if mild anemia was present ( hemoglobin concentration 80 - 110 g/L ) . The participants were r and omly assigned to one of three study groups given no iron , two FeSO4 tablets ( 100 mg Fe ) daily , or one GDS capsule ( 50 mg Fe ) daily . Blood was obtained initially and after 6 and 12 wk for measurement of red blood cell and iron indexes , including serum transferrin receptor . There was a significant and comparable improvement in hematologic and iron-status measurements in the two groups of women given iron whereas iron deficiency evolved in women given no iron supplement . We conclude that by eliminating gastrointestinal side effects and reducing the administration frequency of an iron supplement to once daily , a GDS offers significant advantages for iron supplementation of pregnant women [2963533] Studies on the treatment and prevention of iron deficiency anemia , in pregnant and nonpregnant women and in men , were conducted in Thail and and Burma . The effects of the dose of Fe , duration of Fe administration , additional supplementation with folate , mode of supplement delivery ( either supervised or unsupervised ) , and the presence of Hb(AE ) were studied . The frequency and severity of side effects were also recorded . Fe administration result ed in an increase in hemoglobin concentration in all anemic individuals but approximately 20 % failed to reach normality . The length of administration and the dose influenced the results . Frequency and severity of side effects increased with the dose of Fe administered . Folate supplementation did not affect the results . It appears possible to integrate a program of prevention and treatment of Fe deficiency anemia in a primary health-care system but the constraints and limitations of achievable results should be recognized [15113952] Daily iron supplementation programs for pregnant women recommend amounts of iron that are considered by some to be excessive , and either lower-dose or less frequent iron supplementation regimens have been proposed . A r and omized , placebo-controlled study was performed to assess and compare the relative effectiveness of a weekly ( WS ) or twice weekly ( TW ) iron supplementation schedule in maintaining or achieving hemoglobin ( Hb ) levels at term considered to carry minimal maternal and fetal risk ( 90 - 130 g/L ) . Pregnant women ( n = 116 ) at wk 10 - 30 of gestation ( 63 WS and 53 TW ) were enrolled in the study ( 52 in WS and 44 TW completed the study ) . Women were r and omly allocated to receive a 120-mg oral dose of iron as ferrous sulfate and 0.5 mg of folic acid weekly ( n = 52 ) or 60 mg iron and 0.25 mg folic acid and a placebo twice weekly ( n = 44 ) . Hb , hematocrit , serum ferritin , and transferrin saturation were estimated at baseline and at 36 - 39 wk of gestation . Baseline dietary data and the presence and intensity of intestinal helminthic infections were assessed . The duration of supplementation was 14 + /- 4 wk and the median level of adherence was 60.5 % . Hb concentrations improved in women following the TW regimen and in women following WS who had low baseline Hb levels . About 89 % of WS women and 95 % of TW women maintained Hb levels at term ( between 90 g/L and 130 g/L ) , a range associated with optimal pregnancy outcomes . One woman in the TW group exhibited higher Hb levels that potentially carried perinatal risk ( > 130 g/L ) . Intermittent iron and folic acid supplementation may be a valid strategy when used as a preventive intervention in prenatal care setting [11053509] In the context of limited effectiveness of iron supplementation programs , intermittent iron supplementation is currently under debate as a possible alternative strategy that may enhance the effectiveness of operational programs . This field-based trial assessed the outcome of twice weekly iron supplementation compared to daily in Pakistan . A double-blind , r and omized , clinical trial was conducted in Northern Pakistan . Anemic pregnant women ( n = 191 ) were assigned to receive daily ( 200 mg ferrous sulfate ) or twice weekly ( 2 x 200 mg ferrous sulfate ) iron supplementation . Hemoglobin was measured at baseline and at 4-wk intervals for up to 12 wk . Serum ferritin was measured at baseline and 8 or 12 wk . Analysis was by intention to treat . The two groups did not differ in age , parity , sociodemographic characteristics , hemoglobin or serum ferritin concentrations at baseline . Women who received iron daily had a greater rise in hemoglobin compared with women who received iron twice weekly ( 17.8 + /- 1.8 vs. 3.8 + /- 1.2 g/L , P < 0.001 ) . The serum ferritin concentrations increased by 17.7 + /- 3.9 microgram/L ( P < 0.001 ) in the daily supplemented group and did not change in the twice weekly group . Daily iron supplementation remained superior to twice weekly supplementation after controlling initial hemoglobin Z-scores and duration of treatment . The body mass index ( BMI ) modified the effect of daily versus twice weekly iron supplementation . For every unit increase in BMI , the difference between the two treatment groups was reduced by 0.0014 ( final hemoglobin Z-score ; P = 0.027 ) . We recommend continuation of daily iron supplementation as opposed to intermittent iron supplementation in pregnant women in developing countries [6461243] The usefulness of serum ferritin levels in assessing iron stores in pregnant women before and after supplementation with iron was studied . One hundred thirty-five healthy pregnant women between 22 to 28 wk were r and omly allotted to daily dose regimes of 60 , 120 , or 240 mg of ferrous sulphate . The tablets were given after meals under strict personal supervision . Before supplementation , iron deficiency ( ferritin level less than 10 micrograms/L ) was present in 54.8 % of the pregnant women , compared to an incidence of 17.8 % when assessed by serum iron concentration of less than 50 micrograms/dl . The mean ferritin level of pregnant women was 14.15 micrograms/L and was less than one-half that of healthy single women and one-sixth of that of healthy males . Supplementation with oral iron for 12 wk produced an increase in ferritin levels in all the groups , but significant increases were seen only in women given 120 and 240 mg of ferrous sulphate with or without folic acid . However , there were no differences in final Hb levels among the supplemented groups [9356536] We studied the effect of iron supplementation on the iron status of mothers and on biochemical iron status and clinical and anthropometric measures in their infants . The subjects were 197 pregnant women selected at 28 wk + /- 21 d of gestation at a mother- and -child health center in Niamey , Niger . Ninety-nine women received 100 mg elemental Fe/d throughout the remainder of their pregnancies and 98 received placebo . The prevalence of anemia and iron deficiency decreased markedly during the last trimester of pregnancy in the iron-supplemented group but remained constant in the placebo group . Three months after delivery , the prevalence of anemia was significantly higher in the placebo group . At delivery , there were no differences between the two groups in cord blood iron variables . Three months after delivery , serum ferritin concentrations were significantly higher in infants of women in the iron-supplemented group . Mean length and Apgar scores were significantly higher in infants with mothers in the iron group than in those with mothers in the placebo group [12600867] BACKGROUND Little is known about the benefits of prenatal multivitamin and mineral supplements in reducing low birth weight . OBJECTIVE We conducted a r and omized , double-blind clinical trial in semirural Mexico to compare the effects of multiple micronutrient ( MM ) supplements with those of iron supplements during pregnancy on birth size . DESIGN Pregnant women ( n = 873 ) were recruited before 13 wk of gestation and received supplements 6 d/wk at home , as well as routine antenatal care , until delivery . Both supplements contained 60 mg Fe , but the MM group also received 1 - 1.5 times the recommended dietary allowances of several micronutrients . RESULTS At recruitment , the women in the 2 groups were not significantly different in age , parity , economic status , height , or hemoglobin concentration but differed significantly in marital status ( 4.6 % and 2.0 % of women in the MM and iron-only groups , respectively , were single mothers ) and mean ( + /- SD ) body mass index ( in kg/m(2 ) ; 24.6 + /- 4.3 and 23.8 + /- 3.9 in the iron-only and MM groups , respectively ) . Losses to follow-up ( 25 % ) and compliance ( 95 % ) did not differ significantly between the groups . In intent-to-treat analyses ( MM group : n = 323 ; iron-only group : n = 322 ) , mean ( + /- SD ) birth weight ( 2.981 + /- 0.391 and 2.977 + /- 0.393 kg in the MM and iron-only groups , respectively ) and birth length ( 48.61 + /- 1.82 and 48.66 + /- 1.83 cm in the MM and iron-only groups , respectively ) did not differ significantly between the groups . CONCLUSION These findings suggest that MM supplementation during pregnancy does not lead to greater infant birth size than does iron-only supplementation [12450908] BACKGROUND According to our current underst and ing , iron absorption with weekly iron supplements is not higher than that with daily supplements ( ie , there is no mucosal block ) . However , community-based trials have repeatedly shown that a weekly regimen is as effective as a daily one . Furthermore , when differences in absorption are found , they are commonly smaller than would be expected on the basis of differences in the amount of iron provided . The possibility of differential compliance between the regimens needs to be evaluated to explain these findings . OBJECTIVE Taking compliance into account , we compared the efficacy and trial effectiveness of weekly and daily iron supplementation during pregnancy . DESIGN In Bangladesh , 50 antenatal centers were r and omly assigned to prescribe either 2 doses of 60 mg Fe once weekly or 1 dose of 60 mg Fe/d . Compliance was monitored by using a pill bottle equipped with an electronic counting device . Hemoglobin concentrations were measured at baseline and after 4 , 8 , and 12 wk of supplementation . RESULTS There was no differential effect per iron tablet between weekly and daily regimens . A 12-wk daily regimen ( 68 % compliance ) produced a small but significantly greater hemoglobin response than did the weekly regimen ( 104 % compliance ) . The first 20 tablets consumed produced most of the effect ; after 40 tablets , there was no further response . CONCLUSIONS There was no evidence of a mucosal block in the daily regimen . Over 12 wk , 50 % of the amount of iron in a daily regimen was sufficient for maximum hemoglobin effect . The weekly regimen provided a large part of this amount , explaining the limited difference in effect . It appears that the current international recommendation for iron supplementation in pregnancy is higher than necessary [2596434] The use of hemoglobin as a predictor of response to iron therapy , for screening , and for prevalence estimates was studied . An Fe supplementation trial was performed in Quito , Ecuador , in which 412 pregnant women were r and omly assigned to treatment and control groups . Women in the treatment group received 390 mg ferrous sulfate/d for 2 mo . The prevalence of Fe deficiency as defined by response to therapy was found to be 60.8 % . Sensitivity and specificity were calculated at various cutoff points of hemoglobin . The estimates of sensitivity and specificity allow for the use of hemoglobin in screening for Fe deficiency anemia and in the estimation of the prevalence in population s with characteristics similar to those found in the sample of pregnant women in Quito . Hemoglobin was shown to be a good predictor of response to Fe treatment and a good estimate of prevalence of Fe deficiency when prevalence is high [8780347] Limited adherence to iron supplementation is thought to be a major reason for the low effectiveness of anemia-prevention programs . In rural Tanzania , women at 21 - 26 wk of gestation were r and omly given either 120 mg of a conventional ( Con ) iron supplement or 50 mg of a gastric-delivery-system ( GDS ) iron supplement for 12 wk . Adherence was assessed by using a pill bottle equipped with an electronic counting device . Adherence in the GDS group was 61 % compared with 42 % for the Con group . In both groups , women experiencing side effects had about one-third lower adherence . Fewer side effects were observed in the GDS group . In a subgroup of women with a low initial hemoglobin concentration ( < or = 120 g/L ) , the response to the iron supplements suggested that both of the applied doses were unnecessarily high for adequate hematologic response in a population with a marginal hemoglobin concentration . The GDS group appeared to require a dose one-fourth as high as that of the Con group for an equal effect on improving hemoglobin to normal concentrations [14522736] BACKGROUND The need for prophylactic iron during pregnancy is uncertain . OBJECTIVE We tested the hypothesis that administration of a daily iron supplement from enrollment to 28 wk of gestation to initially iron-replete , nonanemic pregnant women would reduce the prevalence of anemia at 28 wk and increase birth weight . DESIGN Between June 1995 and September 1998 , 513 low-income pregnant women in Clevel and were enrolled in the study before 20 wk of gestation . Of these , 275 had a hemoglobin concentration > /= 110 g/L and a ferritin concentration > /= 20 micro g/L and were r and omly assigned to receive a monthly supply of capsules containing either 30 mg Fe as ferrous sulfate or placebo until 28 wk of gestation . At 28 and 38 wk of gestation , women with a ferritin concentration of 12 to < 20 micro g/L or < 12 micro g/L received 30 and 60 mg Fe/d , respectively , regardless of initial assignment . Almost all the women received some supplemental iron during pregnancy . We obtained infant birth weight and gestational age at delivery for 117 and 96 of the 146 and 129 women r and omly assigned to receive iron and placebo , respectively . RESULTS Compared with placebo , iron supplementation from enrollment to 28 wk of gestation did not significantly affect the overall prevalence of anemia or the incidence of preterm births but led to a significantly higher mean ( + /- SD ) birth weight ( 206 + /- 565 g ; P = 0.010 ) , a significantly lower incidence of low-birth-weight infants ( 4 % compared with 17 % ; P = 0.003 ) , and a significantly lower incidence of preterm low-birth-weight infants ( 3 % compared with 10 % ; P = 0.017 ) . CONCLUSION Prenatal prophylactic iron supplementation deserves further examination as a measure to improve birth weight and potentially reduce health care costs [12816784] BACKGROUND Iron deficiency anemia ( IDA ) is common in pregnant women , but previous trials aim ed at preventing IDA used high-dose iron supplements that are known to cause gastrointestinal side effects . OBJECTIVE The objective was to assess the effect on maternal IDA and iron deficiency ( ID , without anemia ) of supplementing pregnant women with a low dosage ( 20 mg/d ) of iron . Effects on iron status were assessed at the time of delivery and at 6 mo postpartum . Gastrointestinal side effects were assessed at 24 and 36 wk of gestation . DESIGN This was a r and omized , double-blind , placebo-controlled trial of a 20-mg daily iron supplement ( ferrous sulfate ) given from 20 wk of gestation until delivery . RESULTS A total of 430 women were enrolled , and 386 ( 89.7 % ) completed the follow-up to 6 mo postpartum . At delivery , fewer women from the iron-supplemented group than from the placebo group had IDA [ 6/198 , or 3 % , compared with 20/185 , or 11 % ; relative risk ( RR ) : 0.28 ; 95 % CI : 0.12 , 0.68 ; P < 0.005 ] , and fewer women from the iron-supplemented group had ID ( 65/186 , or 35 % , compared with 102/176 , or 58 % ; RR : 0.60 ; 95 % CI : 0.48 , 0.76 ; P < 0.001 ) . There was no significant difference in gastrointestinal side effects between groups . At 6 mo postpartum , fewer women from the iron-supplemented group had ID ( 31/190 , or 16 % , compared with 51/177 , or 29 % ; RR : 0.57 ; 95 % CI : 0.38 , 0.84 ; P < 0.005 ) . The rate of IDA between the groups did not differ significantly at 6 mo postpartum . CONCLUSION Supplementing the diet of women with 20 mg Fe/d from week 20 of pregnancy until delivery is an effective strategy for preventing IDA and ID without side effects [6824608] Summary . Serum iron , serum iron‐binding capacity , serum ferritin and erythrocyte protoporphyrin were determined during uncomplicated pregnancy in 45 healthy women ; 22 were given oral iron while the others were given a placebo . When iron was not given , 15 out of 23 women had exhausted iron stores and iron deficiency at term , as judged from low serum ferritin , low serum transferrin saturation and high erythrocyte protoporphyrin values . Only seven of them had a haemoglobin concentration between 10 and 11 g/dl at term but none had values < 10 g/dl . In the iron‐treated group ( n=22 ) none of the women developed iron deficiency . Serum ferritin was the most sensitive and specific test of iron deficiency . A practical procedure to detect iron deficiency and to control iron supplementation in pregnancy is suggested [12780424] Background . The aims of the present study were to evaluate the recommendations by comparing compliance and adequacy of iron status at 6 weeks postpartum between one group given advice only and one group given advice plus iron supplement . In the latter group the efficacies of two iron preparations of different strengths and types were compared [6726596] The known increased need for iron during pregnancy appears to be met only in part by increased iron absorption and amenorrhea . Considerable dem and s are made on maternal iron stores and , since many women lack sufficient storage iron , pregnancy may be expected to cause iron deficiency . This may lead to anemia in pregnancy and post partum and could also have a bearing on the iron status of the fetus and the neonate . Based on these considerations , prophylactic supplementation of dietary iron is advocated but remains a disputed issue . In the present controlled , prospect i ve and longitudinal study changes in hematologic status , and in particular in iron stores , during pregnancy were investigated in 44 healthy Caucasian women with uncomplicated pregnancies and deliveries . They were r and omly assigned to a study group ( n = 21 ) receiving oral iron supplements from the 16th week of amenorrhea until 6 weeks post partum , and a control group ( n = 23 ) without iron supplementation . Maternal concentrations of hemoglobin , serum iron , serum transferrin and serum ferritin were determined at 16 , 28 and 36 weeks of amenorrhea , at delivery , and 6 and 12 weeks post partum . The same variables were determined in cord blood . Iron supplementation appeared to prevent the physiologic fall in hemoglobin and serum iron concentrations which occurred in the control group , but had little influence on the observed rise in transferrin concentrations . Ferritin levels in serum , which are known to reflect mobilisable iron stores , fell to 30 % of the initial values in the control group and to 70 % in the study group . Six and 12 weeks post partum ferritin levels were still low in the nonsupplemented group ( Tab . I ) . ( ABSTRACT TRUNCATED AT 250 WORDS [10696955] Background . The aim was to define reference values for hemoglobin , hematocrit and erythrocyte indices , i.e. erythrocyte count , mean corpuscular volume ( MCV ) , mean corpuscular hemoglobin ( MCH ) , mean corpuscular hemoglobin concentration ( MCHC ) , in normal pregnancy and after a normal delivery in non‐iron‐supplemented and iron supplemented women [12641613] Spatone Iron-Plus is a naturally occurring mineral water from Trefriw Wells Spa in Conwy County , North Wales , UK . It contains approximately 0.20 mg of iron per millilitre as ferrous sulphate and has been shown to provide iron in a highly bio-available form . A 24 ml sachet contains approximately 5 mg of iron . Iron deficiency is common in the obstetric population . However , compliance with traditional iron supplements is poor because of gastrointestinal side-effects . We design ed a r and omized , double-blind , placebo-controlled trial . A total of 102 low-risk antenatal patients , who were noncompliant with routinely prescribed ferrous sulphate tablets , were r and omized to receive 48 ml of Spatone water or placebo . The study was conducted between 22 and 28 weeks gestation . Primary outcome measures were compliance , gastrointestinal side-effects and changes in ferritin levels during the trial period . Compliance in the intervention group was 57 % compared with 67 % in the control group , P = 0.22 . Dyspepsia scores , as determined by a recognized and well-vali date d question naire , did not differ between the two groups . During the trial period , mean ferritin levels fell by 24 % in the Spatone Iron-Plus group compared with a mean fall of 51 % in ferritin levels among the control group , P = 0.016 [15777891] OBJECTIVE To compare the effect of daily oral iron supplementation with two injections of high dose parenteral iron . METHOD A total of 220 pregnant women with a singleton pregnancy and hemoglobin between 8 to 11 g% at 16 - 24 weeks gestation were identified and r and omly divided into two groups . Group A was started on daily oral iron therapy of 100 mg of elemental iron . Group B was given 250 mg of iron sorbitol intramuscularly and repeated at an interval of 4 - 6 weeks . Blood indices were evaluated at the beginning of study and at 36 weeks to see the effect after iron supplementation in the two groups . The data were analyzed using SPSS software , version 10.1 . RESULTS Definitive and comparable improvement in hemoglobin and all the blood indices ( hematocrit , MCH , MCHC , MCV , Serum iron and TIBC ) was observed . The absolute change in hemoglobin and hematocrit was 1.18+/-0.68 g% and 4.02+/-2.59 % in oral group , 1.34+/-0.77 g% and 4.93+/-3.65 % in parenteral group , respectively . Serum ferritin showed statistically significant absolute rise ( 10.43+/-7.92 microg/dl ) after parenteral iron supplementation as compared to oral iron supplementation ( 9.76+/-4.78 microg/dl ) . Obstetric outcome was comparable in two groups . CONCLUSION Two treatment regimens are biologically equivalent in terms of hematological response . Two high doses of intramuscular iron can be a good substitute to meet iron requirement in pregnancy [10878651] Objective : Intervention with iron supplementation , deworming , and information , education and communication ( IEC ) to improve the haematological status among each of the three trimesters of pregnant women in a rural community . Design : A community-based study was carried out using a two-group pre – post experimental design in a rural community . Setting : Two rural blocks in Vellore district were selected for the study . KV Kuppam block with a population of 120 , 000 and the adjacent Gudiyatham block with a population of 132 , 000 served as study and control areas for the study .Subjects : Using a multistage sampling , initially 50 % of the panchayats , the local village administrative units , were r and omly selected and all pregnant women were the subjects . In the pre-intervention survey 458 and 387 pregnant women had haemoglobin tested and the post-intervention survey covered 403 and 425 pregnant women in the study and control areas , respectively . Similarly serum ferritin was tested in a r and omly selected sub- sample with 254 and 191 pregnant women before intervention and in 216 and 223 pregnant women after intervention in both study and control areas , respectively . Intervention : Iron supplementation and deworming were provided to all pregnant women in the study area from the fourth month of their pregnancy . An intensive information , education and communication was carried out with facts on anaemia and diet modification to each pregnant woman , using a one-to-one approach in the community , and a group method in the mobile clinics . This was carried out for a period of 18 months . Results : A significant decrease in the prevalence of anaemia was found , from 56.1 % to 25.07 % ( P<0.001 ) , 73.4 % to 49.2 % ( P<0.001 ) and 68.8 % to 56.8 % ( P<0.01 ) among women in the first , second and third trimesters , respectively , in the intervention area . Significant ( P<0.001 ) increases in the mean haemoglobin of 0.85 g/dl ( 95 % CI 10.18–10.84 , 11.09–11.63 ) , 0.59 g/dl ( 95 % CI 9.98–10.34 , 10.55–10.95 ) and 0.36 g/dl ( 95 % CI 9.93–10.33 , 10.25–10.73 ) were also observed in each of the groups . Conclusion : A comprehensive community-based intervention with iron supplementation , helminthic treatment and increase in knowledge using IEC through effective strategies can improve the haematological status of pregnant women in each trimester . Sponsorship : Mother Care Project , John Snow Inc. , Funded by the United States Agency for International Development (USAID).European Journal of Clinical Nutrition ( 2000 ) 54 , [15766997] BACKGROUND Neonatal mortality is the biggest contributor to global mortality of children younger than 5 years , and low birthweight is a crucial underlying factor . We tested the hypotheses that antenatal multiple micronutrient supplementation would increase infant birthweight and gestational duration . METHODS We did a double-blind , r and omised controlled trial in Dhanusha district , Nepal . Women attending for antenatal care with singleton pregnancies at up to 20 weeks ' gestation were invited to participate . Participants were r and omly allocated either routine iron and folic acid supplements ( control ; n=600 ) or a multiple micronutrient supplement providing a recommended daily allowance of 15 vitamins and minerals ( intervention ; n=600 ) . Supplementation began at a minimum of 12 weeks ' gestation and continued until delivery . Primary outcome measures were birthweight and gestational duration . Analysis was by intention to treat . The study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N88625934 . FINDINGS Birthweight was available for 523/600 infants in the control group and 529/600 in the intervention group . Mean birthweight was 2733 g ( SD 422 ) in the control group and 2810 g ( 453 ) in the intervention group , representing a mean difference of 77 g ( 95 % CI 24 - 130 ; p=0.004 ) and a relative fall in the proportion of low birthweight by 25 % . No difference was recorded in the duration of gestation ( 0.2 weeks [ -0.1 to 0.4 ] ; p=0.12 ) , infant length ( 0.3 cm [ -0.1 to 0.6 ] ; p=0.16 ) , or head circumference ( 0.2 cm [ -0.1 to 0.4 ] ; p=0.18 ) . INTERPRETATION In a poor community in Nepal , consumption of a daily supplement containing a recommended daily allowance of 15 micronutrients in the second and third trimesters of pregnancy was associated with increased birthweight when compared with a st and ard iron and folic acid preparation . The effects on perinatal morbidity and mortality need further comparisons between studies . Published online March 3 , 2005 http://image.thelancet.com/extras/04art11045web.pdf [9351406] Background . The purpose of the present study was to evaluate the efficacy of low dose iron supplementation with and without a heme component , prescribed for women in the second half of pregnancy [10682464] OBJECTIVE To study the efficacy of iron supplementation during pregnancy and its influences on the outcome of pregnancy . METHODS A total of 369 pregnant women were enrolled in this study . According to the hemoglbin levels at recruitment , there were 2 groups : preventive ( Hb > or = 110 g/L ) and treatment ( Hb < 110 g/L ) groups . In the preventive group , women entered the study from 20 - 24 gestational weeks and were r and omly assigned to materna treatment ( n = 96 ) who took materna 1 tablet daily or control group ( n = 95 ) who took no other supplementation . In the treatment groups , women less than 36 gestational weeks were accepted . They were r and omly divided as materna ( n = 93 ) 1 tablet/d , ferrous sulfate 0.3 g tid/d ( n = 50 ) or Ferroids 1 tablet/d ( n = 35 ) groups . Both Hb and serum ferritin concentrations were determined at admission and immediately after delivery . In some cases serum ferritin in the umbilical vein were measured as well . Hemoglobin levels were examined every 4 weeks during the observational period . RESULTS In the preventive groups , maternal serum ferritin levels after materna treatment were significantly higher than that before treatment and the control group ( P < 0.05 ) . As for the anemia women , compared the serum ferritin concentration , materna treatment had significantly higher levels than that at admission ( P < 0.05 ) , and also higher than that in the ferrous sulfate or ferroids tratment groups ( P < 0.05 ) . The s-ferritin in the umbilical vein had no correlation with the paired maternal levels . There were no significant differences in the pregnancy outcomes among all the groups . CONCLUSION Materna can increase the iron storage and effectively improve the iron deficiency during pregnancy , and has no impact on the prgnancy outcomes [12186198] Side-effects of iron supplementation lead to poor compliance . A weekly-dose schedule of iron supplementation rather than a daily-dose regimen has been suggested to produce fewer side-effects , thereby achieving a higher compliance . This study compared side-effects of iron supplementation and their impact on compliance among pregnant women in Bangladesh . These women were assigned to receive either weekly doses of 2 x 60 mg iron ( one tablet each Friday morning and evening ) or a daily dose of 1 x 60 mg iron . Fifty antenatal care centres were r and omly assigned to prescribe either a weekly- or a daily-supplementation regimen ( 86 women in each group ) . Side-effects were assessed by recall after one month of supplementation and used for predicting compliance in the second and third months of supplementation . Compliance was monitored using a pill bottle equipped with an electronic counting device that recorded date and time whenever the pill bottle was opened . Of five gastrointestinal side-effects ( heartburn , nausea , vomiting , diarrhoea , or constipation ) assessed , vomiting occurred more frequently in the weekly group ( 21 % ) than in the daily group ( 11 % , p<0.05 ) . Compliance ( ratio between observed and recommended tablet intake ) was significantly higher in the weekly-supplementation regimen ( 93 % ) than in the daily-supplementation regimen ( 61 % , p<0.05 ) . Overall , gastrointestinal side-effects were not significantly associated with compliance . However , the presence of nausea and /or vomiting reduced compliance in both the regimens-but only among women from the lower socioeconomic group . In conclusion , weekly supplementation of iron in pregnancy had a higher compliance compared to daily supplementation of iron despite a higher frequency of side-effects . The findings support the view that gastrointestinal side-effects generally have a limited influence on compliance , at least in the dose ranges studied . Efforts to further reduce side-effects of iron supplementation may not be a successful strategy for improving compliance and effectiveness of antenatal iron supplementation [9829872] This paper addresses two questions : 1 ) What is the relation of hemoglobin in the second gestational month to preterm birth and low birth weight ? 2 ) How does the relation differ when hemoglobin in the fifth or eighth month or the lowest pregnancy hemoglobin are examined in place of first trimester values ? These relations were examined prospect ively in 829 women from Shanghai , China in 1991 - 1992 . The population was nearly homogeneous by race , parity , antenatal care , and smoking . Rates of birth outcomes were compared between hemoglobin categories based on 10 g/liter groupings , with 110 - 119 g/liter as the reference group . Rates of low birth weight and preterm birth ( but not small-for-gestational age ) were related to early pregnancy hemoglobin concentration in a U-shaped manner . The relative risks ( 95 % confidence intervals ) for preterm birth in women by g/liter of hemoglobin were 2.52 ( 0.95 - 6.64 ) for > or = 130 g/liter , 1.11 ( 0.41 - 2.99 ) for 120 - 129 g/liter , 1.64 ( 0.77 - 3.47 ) for 100 - 109 g/liter , 2.63 ( 1.17 - 5.90 ) for 90 - 99 g/liter , and 3.73 ( 1.36 - 10.23 ) for 60 - 89 g/liter . Use of hemoglobin values in the fifth or eighth month attenuated the association with preterm birth . When lowest pregnancy hemoglobin values were used , the association of anemia with both outcomes was obscured , and risk of preterm birth at high hemoglobin values increased dramatically [8635830] Eighty one pregnant women ( 20 + /- 2 weeks of gestation ) were assessed for their nutritional status . They were divided into three groups ; Group I women ( n = 30 ) were given 200 mg ferrous sulphate ( FeSO4 ) tablet per day for 15 weeks , Group II women ( n = 25 ) were given FeSO4 tablets along with 2,000,000 IU of vitamin A as single dose in beginning of study ; and Group III women ( n = 26 ) were not given any supplements and served as controls . To study impact of supplements on hematological profile of pregnant women , Hb , PCV , RBC , TS% , TIBC and serum levels of iron , zinc , copper , manganese and vitamin A were assessed at 20 + /- 2 weeks and 36 + /- 2 weeks of gestation by st and ard techniques . Pregnant women in Group I ( Fe suppl ) and group II ( Fe + vitamin A suppl ) had significantly ( p < 0.01 ) higher Hb , PCV , RBC , TS% and serum iron levels than the controls . Group II had significantly ( p < 0.05 ) higher values of these indices as compared to Group I. Levels of serum zinc , copper , manganese were not affected by supplements . Iron supplements improved the hematological profile of pregnant mothers but Fe + vitamin A supplements were more beneficial [8846152] Blood manganese levels and iron status indices were determined each trimester in 66 healthy pregnant women . Twenty-five were r and omly assigned to iron supplementation , 19 to placebo and 22 received dietary advise aim ed at increasing their dietary intake of fibre . Iron supplemented women had significantly higher levels of blood haemoglobin compared to the levels of the two other groups , and higher serum ferritin levels compared to the placebo group . No significant difference in blood manganese levels was observed among the three groups of women . There was a significant increase in blood manganese levels from one trimester to the next , which was slightly more pronounced in non supplemented women . The median values in the three trimesters were 154 ( range 79 - 360 ) nmol/L , 190 ( range 98 - 408 ) nmol/L , and 230 ( range 133 - 481 ) nmol/L , respectively . Pregnancy seems to change manganese status or otherwise influence manganese metabolism irrespective of iron status and iron supplementation [2583756] This study was conducted to determine the optimum dose of supplemental iron for prophylaxis against pregnancy anemia . One hundred and ten pregnant women were r and omly allocated to three groups : Group A receiving equivalent of 60 mg , group B 120 mg and Group C 240 mg , elemental iron as ferrous sulphate daily ; the content of folic acid was constant in all the three groups ( 0·5 mg ) . These women had at least consumed 90 tablets in 100±10 days . Blood was drawn at the beginning and at the end of the treatment . Fifty percent were anemic ( < 11g/100 ml ) . The hemoglobin levels rose similarly in all groups and the differences were statistically not significant . Fifty-six percent had depleted iron stores ( serum ferritin value < 12 μg/1 ) at the beginning of the study . Following therapy a statistically significant increase in iron stores was observed in group B and C as compared to group A. The difference between group B and C was not significant . The side effects increased with increasing doses of iron ; 32·4 % , 40·3 % and 72 % in group A , B and C respectively . Based on these findings , the authors advocate that optimum dose of iron should be 120 mg instead of 60 mg as is currently being used in the National Nutritional Anemia Prophylaxis Programme . * * * DIRECT SUPPORT * * * A08BC044 [1858501] 192 pregnant women were consecutively r and omized to either a vitamin‐mineral pill or a vitamin mineral pill with a high iron content in a prospect i ve , open , r and omized investigation . The participants were advised about iron‐rich foodstuffs twice during pregnancy . Iron status of the mother proved to be without any significance for the outcome of pregnancy . A serum ferritin level of 80 pmol/l in mid‐pregnancy followed by a control in the last trimester was suggested as a guide in deciding of whether or not to prescribe supplementary iron during pregnancy [15566454] AIM To compare the hematological parameters and pregnancy outcome in women receiving daily versus weekly iron supplements during pregnancy . METHODS A prospect i ve r and omized controlled study was carried out at the Department of Obstetrics and Gynaecology of the All India Institute of Medical Sciences , New Delhi , India , during which 111 women were r and omized to receive either 100 mg elemental iron daily ( n=55 ) or 200 mg elemental iron weekly ( n=56 ) . Hemogram and serum ferritin level estimation were carried out at the beginning of pregnancy and within the 32 - 34-week period of gestation . Side-effects , compliance and the number of tablets consumed were noted for each group . The mean birth weight , period of gestation at delivery and mode of delivery were also compared between the two intervention groups . RESULTS There was no significant difference in the mean hemoglobin levels between the two intervention groups at the end of an average 17 weeks of iron supplementation . However , among anemic women who received daily supplementation , there was a greater rise in hemoglobin compared with those receiving supplementation weekly . The serum ferritin level was lower in the weekly supplemented group compared with that in the daily . There was no difference in the mean birth weight , period of gestation and mode of delivery between the two groups . Side-effects and non-compliance were significantly higher ( P<0.001 ) in the daily supplemented group . CONCLUSIONS Weekly iron supplementation is an effective option for prophylaxis in non-anemic pregnant women , but has less than optimal benefit in anemic women [10326325] BACKGROUND The National Nutritional Anaemia Prophylaxis Programme ( NNAPP ) in India was launched in 1971 . However , anaemia continues to be a major public health problem . Partial coverage of the population , inadequate dose of the iron supplement , defective absorption due to intestinal infestations and problems with formulation have been recognized as factors responsible for its failure . Therefore , the bioavailability of iron from different formulations containing 60 mg of elemental iron and of tablets with varying doses of elemental iron was undertaken . METHODS One hundred and fifteen women were r and omly allotted to receive different formulations and doses of iron and then undergo iron tolerance tests . They received ferrous sulphate tablets containing 60 mg , 120 mg and 180 mg of elemental iron ; formulations containing 60 mg of elemental iron as pure ferrous sulphate salt , ferrous fumarate tablets , ferrous fumarate syrup , excipients added to pure ferrous sulphate salts , powdered ferrous sulphate tablets , iron tablets distributed by the NNAPP and pure ferrous salt in gelatin capsules . RESULTS The data obtained from 32 subjects were excluded because of non-compliance , intolerance of the medication and lack of results of blood tests . Data from the remaining 83 subjects indicated that increasing the dose of elemental iron from 60 mg to 180 mg improved the bioavailability of iron , but was associated with unacceptable side-effects . Also , liquid formulations of iron had a better bioavailability , with ferrous fumarate syrup and gelatin capsules being the most superior . CONCLUSION Providing the iron formulation with a high bioavailability should enable the NNAPP to be more successful in decreasing the prevalence of anaemia [8141223] OBJECTIVE Our purpose was to study the effect of hematinic supplementation on the maternal erythropoietin response during singleton pregnancy . STUDY DESIGN In a r and omized , double-blind trial 97 patients with a first-trimester hemoglobin level > or = 14.0 gm/dl received either iron and folic acid ( hematinic group , n = 53 ) or a placebo ( n = 44 ) . Serial hemoglobin , hematocrit , and serum erythropoietin were recorded from maternal blood and from cord blood on delivery . Serum ferritin was measured in the first trimester , at 36 weeks ' gestation , and in cord blood . RESULTS In both groups ( 1 ) the mean hemoglobin was lower ( p < 0.01 ) at 40 weeks ' gestation than when first examined and ( 2 ) the mean serum erythropoietin was higher ( p < 0.01 ) . The mean serum ferritin was lower ( p < 0.001 ) in both groups at 36 weeks ' gestation than at presentation but higher ( p = 0.04 ) in the hematinic group than in the placebo group . The mean hemoglobin and hematocrit were similar in the two groups until the third trimester but thereafter were higher ( p < 0.05 ) in the hematinic group . The mean maternal serum erythropoietin was higher ( p < 0.05 ) in the placebo group than in the hematinic group after 24 weeks ' gestation . The mean cord blood hematologic values were similar in the two groups . CONCLUSION Maternal serum erythropoietin increased during pregnancy , but this response was reduced in the third trimester in the hematinic-supplemented group [3511017] Recent studies suggest that infant behavior and psychological test performance are impaired by iron deficiency and may be improved by iron . Comparable studies have not been performed in older population s. Young women early in pregnancy whose nutritional intake may be impaired by poverty constitute a high-risk population . Women aged 14 - 24 years coming for prenatal care at or before 16 weeks gestation whose hematocrits were greater than or equal to 31 % were r and omized in a double-blind trial to receive vitamins supplemented with iron ( experimental group ) or vitamins alone ( controls ) . Hematologic status and tests of short-term memory and attention span were assessed at entry and conclusion of the one-month treatment period . The experimental group showed significant improvement on the most sensitive measure of short-term memory and three subtests . On comparison of the change between initial and final scores , the experimental group showed significant or borderline greater improvement than controls on three tests . These results indicated a beneficial effect of iron therapy on psychometric test-score performance [9699743] Objective To determine whether a high concentration of serum ferritin during the third trimester is a marker of sub clinical maternal infection and very preterm delivery and is associated with maternal nutritional status . Methods A total of 1162 gravidas was followed prospect ively from entry to prenatal care ( 15.0 ± 4.9 completed weeks ' gestation ) in Camden , New Jersey , between 1985 and 1995 . Multiple logistic regression and analysis of covariance were used to examine the influence of serum ferritin on the outcomes of interest . Results High concentrations of serum ferritin ( at or above the 90th percentile ) at week 28 , but not at entry to prenatal care , increased risk of preterm and very preterm delivery , but the risk changed if the concentration of ferritin declined from entry . If the concentration declined as expected , high ferritin concentration had no influence on outcome . If the concentration increased , then high ferritin concentration at week 28 was associated with very preterm delivery ( adjusted odds ratio [ AOR ] 8.77 ; 95 % confidence interval [ CI ] 3.90 , 19.72 ) , preterm delivery ( AOR 3.81 ; 95 % CI 1.93 , 7.52 ) , low birth weight ( AOR 5.15 ; 95 % CI 2.47 , 10.72 ) , clinical chorio-amnionitis ( AOR 2.56 ; 95 % CI 1.01 , 6.52 ) , and symptoms of “ flu ” as an index of unmeasured infection ( AOR 6.02 ; 95 % CI 1.16 , 31.17 ) . Factors associated with failure of the ferritin concentration to decline included iron deficiency anemia earlier in pregnancy ( AOR 3.98 ; 95 % CI 1.17 , 8.98 ) and lower levels of serum and red cell folate . Conclusion High serum ferritin concentration in the third trimester , result ing from a failure of ferritin to decline , is associated with very preterm delivery and markers of maternal infection . Iron deficiency anemia and other indicators reflecting poor maternal nutritional status earlier in pregnancy underlie this relationship [1062910] Abstract . Iron absorption , bone‐marrow smears and haematological parameters were repeatedly studied during pregnancy in 50 women . The same studies were repeated two months after delivery . The material was r and omly divided into two groups . Twenty‐four women were treated with 200 mg of ferrous iron daily while 26 were given placebo . The iron absorption was measured from radioiron‐labelled test doses of 100 mg ferrous iron in a whole‐body counter with high sensitivity [10422631] Abstract Assessment of the efficacy of iron therapy has usually been done in population s/ patients by monitoring changes in hemoglobin concentration , serum iron , percent transferrin saturation , and serum ferritin . In this study the protoporphyrin heme ( P/H ) ratio ( a measure of free erythrocyte protoporphyrin ) was measured before and after iron therapy in three groups of pregnant women , who received 60 mg ( group A ) , 120 mg ( group B ) , and 240 mg ( group C ) of elemental iron with folic acid ( 0.5 mg ) per day for a period of 12 weeks , to evaluate its efficacy to monitor iron therapy . The three groups were comparable regarding the initial mean Hb concentration and serum ferritin levels . The initial mean P/H ratios were markedly elevated in all three groups and were different in the three groups , being highest in group A ( 113.2±92.6 ) , intermediate in group B ( 87.5±62.5 ) , and lowest in group C ( 69.8±43.3 ) . The initial P/H ratio was significantly higher in group A than in group C ( p<0.05 ) . This probably affected the efficacy of iron therapy in the three groups . The P/H ratio decreased significantly in each of the three groups after iron therapy ( A and B : p<0.001 ; C p<0.01 ) . Mean Hb concentration and serum ferritin increased in all three groups post therapy ; however , the magnitude of change in P/H ratio in all three groups was much greater . This indicated that the predominant contributory factor for anemia was iron deficiency in this group of pregnant women . Serum iron and percent transferrin saturation are difficult to interpret in our population , as iron is freely available over the counter and is prescribed as soon as anemia is detected in patients ; therefore , the reduction in P/H ratio may be used to monitor response to iron therapy in population groups [8122498] In a r and omized , double‐blind , placebo controlled study of the effect of iron supplementation during pregnancy , iron status ( hemoglobin ( Hb ) , serum (S‐)transferrin saturation , S‐ferritin ) and S‐erythropoietin ( EPO ) were assessed in 120 healthy pregnant women at 14–16 weeks of gestation , and just before delivery ; 63 women were treated with 66 mg iron daily , and 57 with placebo . There were no differences in baseline values in the two groups . At term , the iron treated group had significantly higher Hb , transferrin saturation , S‐ferritin ( median 22 μg/1 vs. 14 μg/1 , ( p<0.0001 ) and lower S‐EPO compared to the placebo treated group . In the iron group , 30.2 % had exhausted iron stores ( i.e. S‐ferritin < 20 μg/1 ) , 6.3 % latent iron deficiency ( S‐ferritin < 20 μg/1 and transferrin saturation < 15 % ) , and no patients had iron deficiency anemia ( S‐ferritin < 20 μg/1 and transferrin saturation < 15 % and Hb < 110 g/1 ) . In the placebo group , 93.0 % had exhausted iron stores , 54.4 % latent iron deficiency , and 17.5 % iron deficiency anemia ; S‐EPO was inversely correlated to iron status markers : Hb , rs = −0.51,p<0.001 ; transferrin saturation , rs= −0.65,p<0.0001 ; S‐ferritin , rs= − 0.31 , R<0.01 , suggesting that the elevation in S‐EPO was secondary to iron deficient erythropoiesis . Newborns to iron treated mothers had higher cord S‐ferritin , median 155 μg/1 , than newborns to placebo treated mothers , median 118 ug/1 ( p<0.02 ) ; there were no differences in birth weight , transferrin saturation , or S‐EPO . Supplemental iron in a dose of 65 mg/day from the second trimester is sufficient to prevent iron deficiency in pregnant Danish women [2010577] This trial compares routine and selective iron supplementation during pregnancy to determine whether routine supplementation adversely affects fetal growth , increases infections and subjective adverse effects , and /or delays birth . At their first prenatal visit , 2912 pregnant women were r and omized into two groups ( 2694 gave birth ) . Compliance was satisfactory as measured by self-reports by mothers and hematocrit values in the third trimester . More women in the routinely supplemented group had subjected adverse effects . The groups were similar in regard to most of the other outcomes . In the selectively supplemented group , there was weak evidence for increase in sick-days , referrals to hospital outpatient clinic , cesarean section , blood transfusions , and infants who were diagnosed as having hyperviscosity . In the routine group , there were somewhat more women with gestations greater than or equal to 41 weeks and more dead infants . The subgroup analyses suggest that some of the apparently worse outcomes in the selective group were due to reactions of midwives and physicians to low hematocrit values [1802636] The effect of iron supplementation , 66 mg elemental iron daily , from the 16th week of gestation to delivery , on iron status markers during uncomplicated pregnancies was assessed in a r and omised , double-blind , placebo controlled study of 207 healthy women ( 100 iron treated , 107 placebo treated ) and their newborn babies . Haemoglobin ( Hb ) and serum ( S- ) human placental lactogen ( HPL ) were measured in all 207 females , while transferrin saturation , S-ferritin and S-erythropoietin ( EPO ) were measured in 120 females at monthly intervals . Hb : from 27th week of gestation to eight weeks post partum , the placebo treated group had significantly lower Hb levels than the iron treated group ( p less than 0.001 ) . Iron status markers : in the placebo group ( n = 57 ) , 92 % developed exhausted iron stores ( i.e. S-ferritin less than or equal to 20 micrograms/l ) , 65 % latent iron deficiency ( i.e. S-ferritin less than or equal to 20 micrograms/l and transferrin saturation less than 15 % ) , and 18 % iron deficiency anaemia ( i.e. S-ferritin less than or equal to 20 micrograms/l , transferrin saturation less than 15 % and Hb less than 110 g/l ) . In the iron treated group ( n = 63 ) , 54 % developed exhausted iron stores , 6 % latent iron deficiency , and none iron deficiency anaemia . S-EPO : the placebo group had significantly higher values than the iron treated group from the 27th week of gestation to one week post partum ( p less than 0.01 ) . S-HPL : levels were identical in placebo and iron treated females . Babies of iron treated mothers had higher S-ferritin than babies of placebo treated mothers ( p less than 0.02 ) . ( ABSTRACT TRUNCATED AT 250 WORDS [7992349] A r and omized , double-blind , placebo-controlled community-based trial of oral iron supplementation ( 200 mg ferrous sulphate daily ) administered to multigravid pregnant women by traditional birth attendants ( TBAs ) was carried out in a rural area of The Gambia . Iron supplementation led to a significant reduction in the prevalence of anaemia and of iron deficiency . Iron supplementation was not accompanied by increased susceptibility to malaria infection ; there was no difference in the prevalence and severity of peripheral blood or placental malaria infection between the 2 groups of women . The birth weight of children born to women who received iron prophylaxis was increased by an average of 56 g. It is concluded that oral iron prophylaxis can be successfully delivered through TBAs integrated into a primary health care programme . This simple intervention can produce significant beneficial effects on the health of the mother without inducing increased susceptibility to malaria and has the potential for reducing perinatal mortality by increasing birth weight [7901636] Nutritional anaemia , thought to be caused by iron deficiency , affects 50 - 70 % of pregnant women in the developing world . The influence of vitamin A and iron supplementation was studied in anaemic pregnant women in West Java , in a r and omised , double-masked , placebo-controlled field trial . 251 women aged 17 - 35 years , parity 0 - 4 , gestation 16 - 24 weeks , and haemoglobin between 80 and 109 g/L were r and omly allocated to four groups : vitamin A ( 2.4 mg retinol ) and placebo iron tablets ; iron ( 60 mg elemental iron ) and placebo vitamin A ; vitamin A and iron ; or both placebos , all daily for 8 weeks . Maximum haemoglobin was achieved with both vitamin A and iron supplementation ( 12.78 g/L , 95 % Cl 10.86 to 14.70 ) , with one-third of the response attributable to vitamin A ( 3.68 g/L , 2.03 to 5.33 ) and two-thirds to iron ( 7.71 g/L , 5.97 to 9.45 ) . After supplementation , the proportion of women who became non-anaemic was 35 % in the vitamin-A-supplemented group , 68 % in the iron-supplemented group , 97 % in the group supplemented with both , and 16 % in the placebo group . Improvement in vitamin A status may contribute to the control of anaemic pregnant women [12637400] Abstract Objective : To assess the impact on birth size and risk of low birth weight of alternative combinations of micronutrients given to pregnant women . Design : Double blind cluster r and omised controlled trial . Setting : Rural community in south eastern Nepal . Participants : 4926 pregnant women and 4130 live born infants . Interventions : 426 communities were r and omised to five regimens in which pregnant women received daily supplements of folic acid , folic acid-iron , folic acid-iron-zinc , or multiple micronutrients all given with vitamin A , or vitamin A alone ( control ) . Main outcome measures : Birth weight , length , and head and chest circumference assessed within 72 hours of birth . Low birth weight was defined < 2500 g. Results : Supplementation with maternal folic acid alone had no effect on birth size . Folic acid-iron increased mean birth weight by 37 g ( 95 % confidence interval −16 g to 90 g ) and reduced the percentage of low birthweight babies ( < 2500 g ) from 43 % to 34 % ( 16 % ; relative risk=0.84 , 0.72 to 0.99 ) . Folic acid-iron-zinc had no effect on birth size compared with controls . Multiple micronutrient supplementation increased birth weight by 64 g ( 12 g to 115 g ) and reduced the percentage of low birthweight babies by 14 % ( 0.86 , 0.74 to 0.99 ) . None of the supplement combinations reduced the incidence of preterm births . Folic acid-iron and multiple micronutrients increased head and chest circumference of babies , but not length . Conclusions : Antenatal folic acid-iron supplements modestly reduce the risk of low birth weight . Multiple micronutrients confer no additional benefit over folic acid-iron in reducing this risk . What is already known on this topic Deficiencies in micronutrients are common in women in developing countries and have been associated with low birth weight and preterm delivery What this study adds In rural Nepal maternal supplementation with folic acid-iron reduced the incidence of low birth weight by 16 % A multiple micronutrient supplement of 14 micronutrients , including folic acid , iron , and zinc , reduced low birth weight by 14 % , thus conferring no advantage over folic [9704770] OBJECTIVE Our purpose was to demonstrate reduced blood volume in preeclampsia compared with nonproteinuric gestational hypertension and normal pregnancy by use of independent measures of red blood cell and plasma volumes . STUDY DESIGN Red blood cells labeled with a nonradioactive stable isotope of chromium and Evans ' blue were infused in subjects with preeclampsia or gestational hypertension and normotensive pregnant controls . Blood was sample d eight times over 60 minutes for dye concentration and at 30 minutes for chromium analysis . RESULTS Total blood and plasma volumes are decreased in preeclampsia ( 2660 + /- 382 mL/m2 and 1790 + /- 332 mL/m2 , respectively ) compared with normotensive subjects ( 3217 + /- 391 mL/m2 , P < 0.001 and 2279 + /- 325 mL/m2 , P < .001 ) and gestational hypertension ( 3139 + /- 272 mL/m2 , P < .001 and 2132 + /- 265 mL/m2 , P = .003 ) . Total body/peripheral hematocrit ratio is increased in preeclampsia . CONCLUSIONS Blood volume , by measurement of red blood cell and plasma volumes , is reduced and has altered distribution in preeclampsia but is normal in gestational hypertension [7483113] The aim of this r and omized , double blind , placebo controlled parallel study was to evaluate whether iron status markers in pregnant women , measured early in the second trimester , could be used to predict levels later in pregnancy , and post partum . One hundred and twenty healthy pregnant women between 14 and 18 weeks of gestation were included . Sixty-three women were allocated to treatment with tablets containing 66 mg ferrous iron ( as fumarate ) daily , and 57 women to treatment with placebo . Haemoglobin , serum transferrin saturation , and serum ferritin were measured every fourth week during gestation , prior to delivery , one week and eight weeks post partum . Correlation matrices during pregnancy and post partum were calculated for each iron status marker , both in iron and placebo treated women . Haemoglobin , transferrin saturation and serum ferritin values at inclusion displayed steadily declining correlation coefficients with values obtained later in pregnancy . There were no clinical ly relevant correlations to values obtained eight weeks or less prior to delivery , or post partum . Serum ferritin values at inclusion could not be used to predict values later in pregnancy or post partum . Haemoglobin , transferrin saturation and serum ferritin values measured in the beginning of the second trimester appear unsuitable as guidelines for an individual iron prophylaxis during the remaining period of pregnancy [5551272] This study was planned to determine whether iron deficiency in pregnancy predisposed to the development of folate deficiency and also the smallest daily iron supplement that maintained haemoglobin levels in pregnancy . Three groups of women were given oral ferrous fumarate supplying 30 , 60 , and 120 mg of iron ; a fourth group was given 1 g of parenteral iron in early pregnancy followed by oral iron ( 60 mg ) ; a fifth group received a placebo . Tablets were taken once daily . Oral iron 30 mg once daily maintained haemoglobin levels throughout pregnancy . Women whose marrows lacked demonstrable iron at the 37th week had a significantly higher incidence of megaloblastic haemopoiesis ( 28·7 % ) than those with demonstrable iron stores ( 15·3 % ) ; women taking oral iron did not have a lower frequency of megaloblastosis than those given a placebo . We concluded that iron does not have a direct effect on folate status in pregnancy , that the association of iron deficiency and megaloblastic anaemia in pregnancy is the result of poor nutrition , and that there is no cause- and -effect relation between them [2672177] An iron supplementation trial versus placebo was performed in double blind on 191 attending at 3 month the antenatal clinic of Poissy maternity . Iron status of mothers and newborns was assessed at 3 , 5 , 7 month , during the delivery and 2 months after the delivery , using biochemical indicators ( hemoglobin level , serum ferritin ) . The compliance was good in 165 pregnant women ( 86 % of the initial sample ): 81 in the iron group , 84 in the placebo group . Among the placebo group , anemia ( Hb less than 11 g/dl ) was observed at the end of the pregnancy in 30 % of women . Depletion of iron stores started at 5 month . In the iron group , hemoglobin level increased significantly during the pregnancy and anemia was observed only in 3 % of women at the delivery . Iron status of newborns and two months after delivery was related to mothers iron status at delivery and particularly at the 7th month of pregnancy [11976463] OBJECTIVE To compare the effectivity of weekly versus daily iron therapy in reducing maternal anemia and to evaluate the association of maternal hemoglobin and fetal growth . DESIGN Prospect i ve . SETTING Tertiary care teaching hospital in an urban metropolis . METHOD 40 pregnant women received daily and 40 pregnant women received weekly oral therapy ( 335 mg of ferrous sulphate and 500 g folic acid ) for a period of 14 weeks . The age of each pregnant woman and their baseline anthropometric data ( weight , height and body mass index ) were estimated . Hemoglobin and hematocrit estimations were carried out during follow period at 4 wks , 8 wks and 14 weeks . Serum ferritin values as a marker of iron status were also calculated in both the groups initially , at 14 weeks and at the time of delivery . Fetal anthropometric indices of 137 full term neonates delivered to mothers included in either of the supplementation groups or admitted to the hospital were also studied in relation to maternal hemoglobin concentration . RESULTS Forty subjects each were initially r and omized into groups I and II . The age of pregnant women along with their baseline anthropometric data were similar in both groups . A total of 29 pregnant women in group I and 27 pregnant women in group II could be regularly followed up . The increase in hemoglobin and hematocrit values were similar in daily and weekly supplemented mothers . An intention to treat analysis also showed similar results . The ferritin values were similar at the start of supplementation and after 14 wks of weekly or daily iron therapy . Birth weight , crown heel length , head circumference of the neonate and placental weight increased significantly with rise in maternal hemoglobin levels . CONCLUSION Weekly iron supplementation is an effective mode of treating anemia among pregnant women and maternal anemia during pregnancy is adversely associated with fetal growth [9277046] Serum erythropoietin ( EPO ) and its relationship to hemoglobin ( Hb ) , iron status markers and iron supplementation during normal pregnancy was assessed in a longitudinal , placebo-controlled study on 118 women , 61 took daily tablets containing 66 mg ferrous iron from the second trimester until delivery and 57 took placebo . Blood sample s were obtained at 4-week intervals until delivery as well as post-partum . In the placebo-treated women , median serum EPO rose from 22.5 U/l at inclusion to 35.0 U/l at delivery ( P = 0.0001 ) . In the iron-treated women , median serum EPO rose from 23.9 to 29.9 U/l ( P = 0.0001 ) . Serum EPO showed a steeper increase in the placebo-treated women than in the iron-treated women ( P < 0.05 ) . After delivery , serum EPO became normal in both groups ( P = 0.0001 ) . Median Hb was lower in placebo-treated ( iron depleted ) than in iron-treated ( iron repleted ) women ( P < 0.05 ) . In the placebo-treated women there was a negative correlation and in the iron-treated women a positive correlation between serum EPO and Hb . In the placebo-treated women , inverse correlations existed between serum EPO and serum transferrin saturation and serum ferritin , reflecting the consequences of iron deficiency , whereas the iron-treated women displayed no correlation . A physiological , nonhypoxia-induced increase in EPO production accounts for the basic expansion of the red cell mass during pregnancy . In placebo-treated women , iron deficient erythropoiesis constitutes an additional hypoxic stimulus , which induces a further increase in serum EPO [6029952] IN a previous investigation of the effects of grade d micro-doses of folic acid ( pteroyl glutamic acid ) in pregnancy suggestive evidence has been obtained that the minimal oral requirement may lie in the region of 300 pg./day . This conclusion was based largely upon the measurement of the fasting post-partum serum folate or L. casei activity in a group of patients from a population where poor dietary intake of folic acid was common . In patients receiving no prophylactic folic acid or IOO pg./day the median post-partum serum folate level was subnormal , in those receiving 3oo , ug./day it was normal and in those receiving 4sopg./day it was supranormal ( Willoughby and Jewell , 1966 ) . As an extension of this investigation the incidence of maternal anaemia has now been assessed among a population of 3599 patients r and omly allocated at their first ante-natal [8383415] Objective ‐ To determine : 1 ) if 18 mg iron daily is sufficient to cover the iron need during normal pregnancy , and 2 ) if women , who will not need iron supplementation during pregnancy , can be identified by early screening [7660438] The influence of haemoglobin genotype on the response to iron supplementation was studied in a r and omized , double blind , placebo-controlled trial involving 497 multigravid pregnant women from a rural area of The Gambia . Women were r and omly allocated to receive either oral iron ( 60 mg elemental iron per day ) or placebo . At 36 weeks of pregnancy , women who had received oral iron during pregnancy had higher mean haemoglobin , packed cell volume , plasma iron and ferritin levels than did women who received placebo . Iron supplementation of pregnant women with the AA haemoglobin genotype also result ed in increases in the packed cell volume ( PCV ) and haemoglobin level measured after delivery , and in the birth weight of the infant . However , in AS women PCV and haemoglobin level at delivery were lower in the supplemented group and supplementation was also associated with reduced birth weights . In malaria endemic areas , pregnant women with the haemoglobin genotype AS may not benefit from iron supplementation during pregnancy [2791561] This article reports the design and feasibility of a r and omized controlled trial of the benefits of routine iron prophylaxis during pregnancy . The multicenter trial , supported by a small budget , relied on health service personnel in Finnish maternity centers . Iron prophylaxis has had an established position in Finnish maternity care , and iron is freely available . This contributed to our decision to ask for informed consent after r and omization . During a year , 2960 mothers were recruited by midwives in 27 maternity health centers and r and omized into two groups : selective and routine iron supplementation . Mothers were followed until the postpartum checkup , and data were collected by five different question naires and abstract ed from the infant 's patient record . Adherence of the midwives to the study protocol was satisfactory , as was mothers ' compliance with recommended treatments . However , because the study was design ed to compare two treatment policies , problems of nonmasking hamper of the biologic effects of iron . This trial encourages the use of existing health services and their personnel in evaluation of medical technology [15715531] Objective . To determine the lowest dose of iron preventative of iron deficiency and iron deficiency anemia in pregnancy [4009554] A r and omized , double-blind , crossover study was carried out on iron absorption from three prenatal supplements by women in the first trimester of pregnancy . The supplements were given to fasting subjects as a single pill early in the morning , and iron absorption was determined from measurements of serum iron performed during the course of the day . Iron absorption from two of the supplements was substantially less than the 3.5 mg recommended for the prevention of iron deficiency during pregnancy . The third supplement , containing reduced amounts of calcium and magnesium , provided on the average 3.6 mg of absorbed iron to the subjects . These results support previous findings in nonpregnant subjects that the availability of iron in a prenatal supplement is affected by the overall composition of the supplement [15253399] BACKGROUND Erythrocyte indices change in pregnancy , mainly due to physiological haemodilution and iron-deficient erythropoiesis . The present study was undertaken to determine the haematological indices during different periods of gestation in women receiving daily iron supplements and compare them with those in women receiving weekly iron supplements . METHODS Pregnant women < 20 weeks of gestation attending the antenatal clinic at the All India Institute of Medical Sciences were r and omized to receive either 100 mg elemental iron daily or 200 mg elemental iron weekly . The haemoglobin , haematocrit , mean corpuscular volume , mean corpuscular haemoglobin and mean corpuscular haemoglobin concentration were estimated at baseline , after 1 month , 3 months and at 34 weeks of gestation . RESULTS Changes consistent with physiological haemodilution in mid-term pregnancy were noted and the values at 34 weeks of gestation were not significantly different between the two groups . CONCLUSION The effects of intermittent iron supplementation on the erythrocyte indices in pregnancy are comparable with those observed with daily supplementation [2661878] The effect of anemia ( hematocrit less than or equal to 0.34 ) on subsequent preterm birth was prospect ively studied in 35,423 pregnancies . The incidence of preterm birth among women with and without anemia at each week during the third trimester was compared . Early in the third trimester , there was a weak association between anemia and preterm delivery . However , anemia early in the third trimester did not account for the substantial increase in preterm birth seen among black women . Anemia after 30 weeks ' gestation was not associated with preterm birth . Among women delivering term infants weighing 2500 g or more , the mean hematocrit rose 0.029 among black women and 0.021 among white women from 25 weeks to term . Compared with hematocrits at 40 weeks ' gestation , the odds ratios for anemia reached a maximum at 28 weeks and fell sharply as term approached . When the hematocrits of women in term labor were compared with those of women in preterm labor , a spurious dose-response effect for anemia was created . We conclude that anemia is not a strong factor in the pathogenesis of preterm birth and that comparison of hematocrits from women who are in preterm and term labor produces biased results [16740440] BACKGROUND We undertook this study to compare the effectiveness and safety of antenatal daily and weekly supplementation with iron , folic acid , and vitamin B(12 ) in healthy , pregnant women who were not anemic at gestational week 20 . METHODS Women with singleton pregnancies and blood hemoglobin ( Hb ) > 115 g/L at gestational week 20 ( equivalent to 105 g/L at sea level ) were r and omly assigned to two groups , one consuming one tablet containing 60 mg iron , 200 mug folic acid and 1 mug vitamin B(12 ) daily ( DS , n = 56 ) ; the other consuming two tablets once weekly ( WS , n = 60 ) . Blood Hb and serum ferritin concentrations were measured every 4 weeks from weeks 20 to 36 , and pregnancy outcomes were evaluated . RESULTS Mild anemia and hypoferritinemia throughout pregnancy occurred less frequently in DS than WS . None of the 116 women had Hb concentrations < 103 g/L at any evaluation point . In contrast , hemoconcentration ( Hb > 145 g/L ) from gestational week 28 onwards occurred in 11 % in DS and 2 % in WS . We observed ex post facto that hemoconcentration at gestational week 28 was associated with a significantly higher relative risk of low birth weight ( RR 6.23 , 95 % CI 1.46 - 26.57 ) and premature delivery ( RR 7.78 , 95 % CI 1.45 - 24.74 ) . CONCLUSIONS In women who were nonanemic at gestational week 20 , both schemes ( DS and WS ) prevented the occurrence of Hb levels < 100 g/L. DS women had a higher incidence of hemoconcentration . Hemoconcentration was associated with increased risk of low birth weight and premature delivery [627303] The failure to prescribe in antenatal clinics a well tolerated form of supplementary oral iron that provides an adequate iron supply for the successful maintainance of active erythropoiesis in pregnant women largely accounts for the frequent development of latent iron deficiency in the child-bearing age . The potential value of Plexafer-F * , a slow release ferrous sulphate preparation supplemented with folic acid , in reducing the high incidence of latent iron deficiency in pregnancy was assessed by conducting a r and omized clinical trial of Plexafer-F and ordinary ferrous sulphate B.P. with folic acid in eighty women presenting early in pregnancy with latent iron deficiency . At the end of the trial , which was started at the sixteenth week of pregnancy and which lasted for twenty weeks , normal haematological values were obtained in thirty-eight out of forty patients ( 95 % ) taking Plexafer-F , but only in twenty-four out of forty patients ( 60 % ) taking ferrous sulphate . A simple screening test run on stool specimens provided during antenatal visits to check regular ingestion of the iron preparations prescribed , revealed regular drug intake and no intolerance in all the patients receiving Plexafer-F , against an intolerance leading to failure of regular drug intake in 37.5 % of patients receiving ordinary ferrous sulphate [5134472] The side-effects of a new sustained release oral ferrous sulphate preparation have been evaluated in three separate double-blind studies . Each tablet contained 100 mg of ferrous iron and the dosage employed in all studies was 2 tablets daily . In a large series of blood donors r and omly divided into three groups the frequency and type of side-effects were compared to ferrous sulphate tablets and placebo . In two series of pregnant women the side-effects were studied with a cross-over technique using ferrous sulphate tablets as reference . Placebo was also included as a reference in one of these studies . In all series the frequency of nausea and epigastric pain was about the same for the sustained release preparation as for placebo . In all series ferrous sulphate tablets gave a significantly higher frequency of nausea than the sustained release tablets and placebo . Also the frequency of epigastric pain was found to be higher in blood donors but this could not be verified in pregnant women [4668759] Summary The effect of small doses of iron and folic acid in a single tablet in preventing anaemia in pregnancy has been assessed . Fifty mg . elemental iron and 400μg . folic acid were found to be satisfactory daily supplements for both ‘ good ’ and ‘ bad ’ tablet takers . Tablet counting and an occasional chemical test for the presence of iron in the faeces were compared as indicators of tablet consumption and the latter found to be superior . The high incidence of faulty tablet consumption indicates the need for some check in anaemic patients in pregnancy [7888886] Abstract Objective : To assess the relation of the lowest haemoglobin concentration in pregnancy with birth weight and the rates of low birth weight and preterm delivery in different ethnic groups . Design : Retrospective analysis of 153602 pregnancies with ethnic group and birth weight recorded on a regional pregnancy data base during 1988 - 91 . The haemoglobin measurement used was the lowest recorded during pregnancy . Setting : North West Thames region . Subjects : 115262 white women , 22206 Indo-Pakistanis , 4570 Afro-Caribbeans , 2642 mediterraneans , 3905 black Africans , 2351 orientals , and 2666 others . Main outcome measures : Birth weight and rates of low birth weight ( < 2500 g ) and preterm delivery ( < 37 completed weeks ) . Results : Maximum mean birth weight in white women was achieved with a lowest haemoglobin concentration in pregnancy of 85 - 95 g/l ; the lowest incidence of low birth weight and preterm labour occurred with a lowest haemoglobin of 95 - 105 g/l . A similar pattern occurred in all ethnic groups . Conclusions : The magnitude of the fall in haemoglobin concentration in pregnancy is related to birth weight ; failure of the haemoglobin concentration to fall below 105 g/l indicates an increased risk of low birth weight and preterm delivery . This phenomenon is seen in all ethnic groups . Some ethnic groups have higher rates of low birth weight and preterm delivery than white women , and they also have higher rates of low haemoglobin concentrations . This increased rate of “ anaemia , ” however , does not account for their higher rates of low birth weight , which occurs at all haemoglobin concentrations . Key messages Key messages Failure of the haemoglobin concentration to fall during pregnancy was associated with a five to sevenfold increase in the incidence of low birth weight and preterm birth Routine haematinic administration in pregnancy is unnecessary on fetal grounds for most pregnancies The mean corpuscular volume may be a better indicator of maternal iron deficiency , but this needs prospect i ve [138664] Hemoglobin ( Hb ) concentration , serum iron level , iron binding capacity and blood folate ( Lactobacillus casei ) activity were determined in 310 unselected pregnant Burmese women . Hb concentration was less than 11 g/dl in 72 % of the women ; the serum iron level was less than 50 mug/dl in 33 % ; serum folate activity was less than 3ng/ml in 13 % ; and red cell folate activity was less than 100 ng/ml in 17 % of the women . Ninety-six of the women in our study were r and omly divided into four groups , treated from the 22nd to the 25th week of pregnancy until full term with either ferrous sulfate containing 60 mg elemental iron twice daily , 5 mg folic acid twice daily , a combination of both , or a placebo only . At full term , Hb concentration fell in the groups given placebo or folic acid . On the other h and , in the groups given iron alone or iron plus folic acid there was an increase in Hb of 0.4 and 0.7 g/dl , respectively ( intergroup difference not statistically significant ) . Serum iron and blood folate levels fell in the groups not receiving the appropriate hematinic . In spite of deficient serum and red cell folate levels in 30 and 40 % , respectively , of the group on iron alone , the mean Hb concentration increased at full term and none of the women had a Hb concentration lower than 10 g/dl . Blood folate levels were lower in the iron-supplemented group than in the placebo group , indicating that iron deficiency does not aggravate the folate nutritional status [7631683] OBJECTIVE A r and omized trial comparing women who were given iron only if needed and those given iron prophylactically showed that routine prophylaxis is not crucial for mothers ' or infants ' health up to postpartum examination . This study investigated these infants ' and mothers ' subsequent health , as available in routine registers in a 7-year follow-up . STUDY DESIGN Original data ( N = 2693 ) were linked to the national population , birth , and hospital inpatient registers . RESULTS The outcomes in the two groups were very similar : there were no statistically significant differences in deaths after birth , number or timing of infants ' or mothers ' hospitalizations , reasons for mothers ' first hospitalization , number or timing of subsequent miscarriages or births , or problems or outcomes in the next birth . However , infants of the prophylactically supplemented group were more frequently hospitalized because of convulsions . CONCLUSION This study does not support routine iron prophylaxis for well-nourished pregnant women [10842553] A weekly iron/folate supplement was compared with a st and ard daily iron/folate supplement in pregnant women living in rural Malawi . Women were enrolled as they attended the local antenatal clinic , stratified by grade of anaemia and then r and omized to receive either 60 mg iron/0.25 mg folate per day ( n=211 ) or 120 mg iron/0.50 mg folate once a week ( n=202 ) . Supplementation was continued for a minimum of 8 weeks ( 10 weeks on average ) and was self administered by the women at home . Initial haemoglobin values for the daily ( μ=105.7g/l ) and weekly ( μ=104.4g/l ) groups as well as final haemoglobin values ( 107.5 g/l and 105.6 g/l , respectively ) did not differ significantly between the two groups . Haemoglobin values increased by similar levels in both groups with the subset of anaemic women increasing by an average of 6.3 g/l in the daily group ( n=70 ) and 5.9 g/l in the weekly group ( n=66 ) for all women . For compliant , anaemic women , the increases were 7.4 g/l and 6.6 g/l for the daily and weekly groups , respectively . Compliance , as indicated by self reporting and by regular counts of remaining tablets , was significantly higher in the weekly group ( 76 % compared with 60 % , P < 0.05 ) , however compliance was identical in both groups when assessed by a stool test for elemental iron . Reported side effects were significantly reduced in the weekly group ( 6 % compared with 17 % , P < 0.05 ) . We conclude that a weekly iron supplement given to pregnant women in rural Malawi has similar haematologic effects , and an improved side effect profile , in comparison with a st and ard daily supplement when administered through an existing primary healthcare programme , although both regimens are relatively unsuccessful in the reduction of anaemia prevalence during pregnancy [11787984] In the present study 67 non-anaemic women were r and omly allocated to either 100 mg or 15 mg iron daily at about the 10 . week of pregnancy . At about week 18 , 30 and 36 of pregnancy , as well as 6 weeks after delivery , hemoglobin and the serum concentrations of ferritin , vitamin B12 , folates , Zn , Cu and Se were monitored . Dietary allowances of other minerals and vitamins are also increased in pregnancy , and the 15 mg iron tablet was enriched with Zn ( 10 mg ) , Cu ( 2 mg ) , Se ( 50 microg ) , vitamin B12 ( 3 microg ) , and folate ( 0.1 mg ) . Neither ferritin , nor Cu , Zn or Se concentrations differed statistically significantly between the treatment groups during pregnancy . Ferritin and Zn appeared to decrease approximately parallel to the hemodilution , whereas Cu concentrations increased from a non-pregnant reference mean of 18 micromol Cu/L to a maximum mean of nearly 33 micromol Cu/L during pregnancy . Se decreased concomitantly to about 1.0 micromol Se/L. Serum folate ( around 15 micromol/L ) was essentially unaffected by pregnancy in the group given multivitamin/mineral supplementation , whereas the mean concentration fell below 10 micromol/L in the group supplemented with 100 mg iron daily . Our results indicate that supplementation of 15 mg Fe daily during pregnancy results in a small reduction of hemoglobin . It is suggested that additional supplementation with folate might be of importance to maintain the serum folate concentration during pregnancy [865369] Four haematinic supplements -- Slow-Fe , FGF , Ferro-Gradumet and Ferro-Grad tfolic -- were prospect ively studied in 103 healthy pregnant patients . Significant differences in the mean cell counts , haematocrit values , haemoglobin levels , iron-binding capacities and serum folate levels were noted . The changes paralleled the elemental iron present in the compount . In this series , side effects principally vomiting and constipation , were more frequent in the lower dose iron group . Form both the haematological status aspect and the lack of side effects , Ferro-Grad Folic and Ferro-Gradumet were superior to both FGF and Slow-Fe ( old formulation ) [29120032] The effect of oral iron prophylaxis on haemoglobin concentration ( Hb ) and haematocrit ( Hct ) has been studied in 300 pregnant women . From the 3rd to 4th month of pregnancy and until term the women were r and omly treated with 100 mg or 200 mg ferrous iron daily respectively as sustained‐release tablets ( Duroferon ® Duretter ® ) or 200 mg ferrous iron as rapidly disintegrating tablets [5683581] The serial trends of the whole blood folate level in two groups of patients have been followed throughout pregnancy and up to six weeks postpartum . In those receiving iron alone the whole blood folate remained normal until the test at six weeks after delivery , at which time over half were in the deficient range . There appears to be a delay before this test reflects the current folate status when this changes rapidly . In those receiving iron plus 330 μg . of folic acid a day the results at this time were close to those at the beginning of pregnancy . Subnormal whole blood folate , red cell folate , and serum folate values occurred close to term in patients receiving iron alone , but were not found in those also receiving folic acid . Megaloblastic changes occurred at term in three patients receiving iron alone in whom the whole blood folate had repeatedly been low in early pregnancy . The observations are consistent with the previous suggestion that 300 μg . of folic acid daily is a suitable supplement to prevent deficiency in late pregnancy and the puerperium [7117682] Forty patients were given one of two iron-folic acid tablets starting from the first ante-natal visit and continuing to parturition . Haemoglobin levels were measured at the commencement , at the end of the study and on at least one other occasion . A comparison was made of haemoglobin levels and side-effects [8081594] Eighty-four non-anaemic pregnant women were treated , starting between the 20th-24th week of Pregnancy , with Actiferrin Compositum--1 capsule per day -- from the 36th with 2 capsules per day up to childbirth . The group was compared with the results in 57 non-anaemic not treated pregnant women . Haematological parameters were recorded before the onset of treatment , during the first stage of labour and in neonates on the first day after delivery . By means of the non-paired t-test no significant differences were disclosed between the groups ; nevertheless the percentage values of haemoglobin , haematocrit , erythrocytes and serum iron were higher in the treated group , as compared with the non-treated one . Also the ferritin values in neonates of the non-treated group were lower , as compared with the treated group . The paired t-test was highly significant in the Actiferrin treated patients as regards haemoglobin , haematocrit and transferrin values . The results provide evidence that it is indicated to administer as a routine measure Actiferrin Compositum to all pregnant women as prevention of pre-partum anaemia of the mother and low ferritin levels in the neonate Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Intake of supplements containing iron or a combination of iron and folic acid by pregnant women may improve maternal health and pregnancy outcomes . Recently , intermittent supplementation regimens have been proposed as alternatives to daily regimens . OBJECTIVES To assess the effectiveness and safety of daily and intermittent use of iron or iron+folic acid supplements by pregnant women . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

17054249

[8656243] PURPOSE To investigate the benefit of chemotherapy in patients with symptomatic hormone-resistant prostate cancer using relevant end points of palliation in a r and omized controlled trial . PATIENTS AND METHODS We r and omized 161 hormone-refractory patients with pain to receive mitoxantrone plus prednisone or prednisone alone ( 10 mg daily ) . Nonresponding patients on prednisone could receive mitoxantrone subsequently . The primary end point was a palliative response defined as a 2-point decrease in pain as assessed by a 6-point pain scale completed by patients ( or complete loss of pain if initially 1 + ) without an increase in analgesic medication and maintained for two consecutive evaluations at least 3 weeks apart . Secondary end points were a decrease of > or = 50 % in use of analgesic medication without an increase in pain , duration of response , and survival . Health-related quality of life was evaluated with a series of linear analog self- assessment scales ( LASA and the Prostate Cancer-Specific Quality -of-Life Instrument [ PROSQOLI ] ) , the core question naire of the European Organization for Research and Treatment of Cancer ( EORTC ) , and a disease-specific module . RESULTS Palliative response was observed in 23 of 80 patients ( 29 % ; 95 % confidence interval , 19 % to 40 % ) who received mitoxantrone plus prednisone , and in 10 of 81 patients ( 12 % ; 95 % confidence interval , 6 % to 22 % ) who received prednisone alone ( P = .01 ) . An additional seven patients in each group reduced analgesic medication > or = 50 % without an increase in pain . The duration of palliation was longer in patients who received chemotherapy ( median , 43 and 18 weeks ; P < .0001 , log-rank ) . Eleven of 50 patients r and omized to prednisone treatment responded after addition of mitoxantrone . There was no difference in overall survival . Treatment was well tolerated , except for five episodes of possible cardiac toxicity in 130 patients who received mitoxantrone . Most responding patients had an improvement in quality -of-life scales and a decrease in serum prostate-specific antigen ( PSA ) level . CONCLUSION Chemotherapy with mitoxantrone and prednisone provides palliation for some patients with symptomatic hormone-resistant prostate cancer [7523606] PURPOSE Estramustine and etoposide ( VP-16 ) have been demonstrated to inhibit the growth of prostate cancer cells in experimental models . This led us to evaluate the effectiveness of this combination in the treatment of patients with metastatic prostate carcinoma refractory to hormone therapy . PATIENTS AND METHODS Estramustine 15 mg/kg/d and VP-16 50 mg/m2/d , were administered orally in divided doses for 21 days . Patients were then taken off therapy for 7 days and the cycle then repeated . Therapy continued until evidence of disease progression . RESULTS Forty-two patients have been enrolled onto this trial with a minimum of 40 weeks follow-up . Of 18 patients with measurable soft tissue disease , three demonstrated a complete response ( CR ) and six a partial response ( PR ) for longer than 2 months . Of these 18 patients , pretreatment prostate-specific antigen ( PSA ) levels decreased by at least 75 % in five men ( 28 % ) and by at least 50 % in nine ( 50 % ) . The median survival duration has not been reached in those patients who demonstrated a response either by soft tissue or PSA criteria . Of 24 patients with disease limited to bone , six ( 25 % ) demonstrated improvement and nine ( 38 % ) demonstrated stability in their bone scans . Five men ( 21 % ) demonstrated a decrease of at least 75 % in pretreatment PSA levels and 14 ( 58 % ) demonstrated at least a 50 % decrease ; the median survival duration has not been reached in these patients . Pretreatment performance status is an important predictor of survival . CONCLUSION We conclude that the combination of estramustine and VP-16 is an active oral regimen in hormone-refractory prostate cancer [7656906] The effect of a medroxyprogesterone acetate ( MPA ) plus epirubicin combination versus estramustine phosphate was evaluated in 149 prospect ively r and omized patients with hormone-resistant prostatic cancer . The estimated probability of being free from progression after 1 year was 17 % for the patients treated with estramustine and 29 % for the MPA-epirubicin group . There is a significant difference between the two groups regarding risk of progression ( p = 0.013 ) . However , no difference in survival was recorded ( p > 0.30 ) with about 60 % of the patients dead during the first year in both groups . Progression was highly correlated to sedimentation rate ( p < 0.001 ) and to performance index ( p = 0.002 ) . Heart failure occurred in a substantial number of patients in both groups which must be considered before starting therapy [6338251] Single and combination chemotherapy was compared in a clinical trial for men with advanced , metastatic prostate cancer who had received prior pelvic irradiation and had had progression of disease despite hormonal therapy . The 149 patients were r and omized to receive estramustine phosphate or cis-platinum alone or in combination . Of the 149 patients 25 ( 17 per cent ) were excluded from the study but 124 were evaluated for response and survival . Entry variables were distributed similarly among patients in each treatment arm . There were no complete or partial responders but there were nearly twice as many patients whose disease was stabilized ( 33 per cent ) on the combination regimen compared to estramustine phosphate ( 18 per cent ) and about a third more than for cis-platinum ( 21 per cent ) . Analysis of survival revealed some advantage for patients on combination therapy . Major toxicities for all treatments were nausea and vomiting ( 62 to 88 per cent ) and accompanying anorexia ( 72 to 95 per cent ) . Azotemia developed in 45 per cent of the patients receiving combination therapy . In addition an elevation in serum creatinine occurred in 22 per cent of the patients receiving combination therapy and in 17 per cent of those receiving cis-platinum alone . Myelosuppression occurred infrequently [15470214] BACKGROUND Mitoxantrone-based chemotherapy palliates pain without extending survival in men with progressive and rogen-independent prostate cancer . We compared docetaxel plus estramustine with mitoxantrone plus prednisone in men with metastatic , hormone-independent prostate cancer . METHODS We r and omly assigned 770 men to one of two treatments , each given in 21-day cycles : 280 mg of estramustine three times daily on days 1 through 5 , 60 mg of docetaxel per square meter of body-surface area on day 2 , and 60 mg of dexamethasone in three divided doses before docetaxel , or 12 mg of mitoxantrone per square meter on day 1 plus 5 mg of prednisone twice daily . The primary end point was overall survival ; secondary end points were progression-free survival , objective response rates , and post-treatment declines of at least 50 percent in serum prostate-specific antigen ( PSA ) levels . RESULTS Of 674 eligible patients , 338 were assigned to receive docetaxel and estramustine and 336 to receive mitoxantrone and prednisone . In an intention-to-treat analysis , the median overall survival was longer in the group given docetaxel and estramustine than in the group given mitoxantrone and prednisone ( 17.5 months vs. 15.6 months , P=0.02 by the log-rank test ) , and the corresponding hazard ratio for death was 0.80 ( 95 percent confidence interval , 0.67 to 0.97 ) . The median time to progression was 6.3 months in the group given docetaxel and estramustine and 3.2 months in the group given mitoxantrone and prednisone ( P<0.001 by the log-rank test ) . PSA declines of at least 50 percent occurred in 50 percent and 27 percent of patients , respectively ( P<0.001 ) , and objective tumor responses were observed in 17 percent and 11 percent of patients with bidimensionally measurable disease , respectively ( P=0.30 ) . Grade 3 or 4 neutropenic fevers ( P=0.01 ) , nausea and vomiting ( P<0.001 ) , and cardiovascular events ( P=0.001 ) were more common among patients receiving docetaxel and estramustine than among those receiving mitoxantrone and prednisone . Pain relief was similar in both groups . CONCLUSIONS The improvement in median survival of nearly two months with docetaxel and estramustine , as compared with mitoxantrone and prednisone , provides support for this approach in men with metastatic , and rogen-independent prostate cancer [6346476] Cisobitan , an organosilicon compound with estrogenic and antigonadotropic properties has been evaluated clinical ly in comparison with an estrogen preparation . In a multicenter study a total of 140 patients with well and moderately well differentiated prostatic cancer were r and omly allocated to treatment with Cisobitan or Estradurin/Etivex , 70 to each group . Of 34 patients with poorly differentiated prostatic cancer 18 were given Cisobitan-- and 16 were given Estracyt-treatment . Among the patients with well and moderately well differentiated prostatic cancer there were , disregarding mortality , no major differences in subjective , objective or laboratory response to the two kinds of treatment . The pattern of side effects was similar , but oedema requiring diuretics occurred more often in the estrogen treated group . There was a significant difference in mortality at 12 months between the groups , two in the Cisobitan group and ten in the estrogen treated group . Cancer was the cause of death in two patients in the estrogen treated group . All other patients succumbed in cardiovascular diseases . At 24 months the difference in mortality rate was less pronounced : Another ten patients had died in the Cisobitan treated group and seven among the estrogen treated patients . Cancer was responsible for the deaths in seven of the Cisobitan patients compared to four of the estrogen treated patients . Within three years one more patient in both groups had died . Of the 34 patients with poorly differentiated cancer , twelve were alive at the 24 months ' follow up , six in the Cisobitan group and six in the Estracyt group [9358213] OBJECTIVES Results of cytotoxic chemotherapy for hormone-resistant prostate cancer are not impressive . One of the substances which seems to have a therapeutic benefit is 5-fluorouracil ( 5-FU ) . The effect of 5-FU can be modulated by addition of folinic acid ( FA ) . We tested in a prospect i ve , r and omized phase II trial monotherapy with 5-FU versus the combination of 5-FU and high-dose FA . METHODS 25 patients received 600 mg/m2 5-FU , and 24 patients 400 mg/m2 FA plus 600 or 400 mg/m2 5-FU . They were treated for two cycles for 5 days in a 21-day interval followed by a weekly single-day application until progression occurred . Pain remission , toxicity , time to progression and survival were evaluated . RESULTS Both regimens led to a pain remission in nearly 70 % of the patients . Mucosal side effects like diarrhea and stomatitis occurred more often in the combination arm , whereas leukopenias were more frequent in the monotherapy are . We observed no statistically significant difference between the two treatment arms regarding time to progression and survival . CONCLUSIONS Although both regimens led to a pain remission , side effects are too severe to recommend these protocol s for st and ard treatment of hormone-resistant prostate cancer [142845] Abstract In this second nationally r and omized cooperative chemotherapy trial of the National Prostatic Cancer Project 125 patients with histologically confirmed progressing advanced carcinoma of the prostate ( clinical stage D ) who had had prior pelvic irradiation of at least 2,000R received as initial therapy 1 of 2 non-myelosuppressive agents — estramustine phosphate or streptozotocin — for comparison with patients r and omized to receive st and ard treatment . Patients whose disease was progressive after 12 weeks on chemotherapy were crossed over to receive the alternate therapeutic agent . Response to treatment was evaluated in 105 patients on the basis of previously established and defined criteria .All known prognostic factors were comparable among the 3 treatment arms . The objective response rates to therapy were 19 per cent in the st and ard arm ( stable only ) , 30 per cent in the estramustine phosphate arm ( stable and partial regression ) and 32 per cent in the streptozotocin arm ( stable arm ) . Thus far , 4 patients [1615614] One hundred eleven patients with endocrine-refractory Stage D prostate cancer were treated with weekly administration of 20 mg/m2 body surface area of doxorubicin hydrochloride ( Adriamycin ) . Fifty-seven were part of a r and omized study comparing doxorubicin and prednisone to prednisone alone . There were significantly more subjective responders in the doxorubicin group than in the prednisone group ( p less than 0.01 ) . The number of patients with evidence of stable disease was also higher during the chemotherapy arm compared with prednisone alone ( p = 0.02 ) . Patients taking doxorubicin had a slightly longer period of stable disease than did those taking prednisone ( p = 0.08 ) . Overall survival , however , was not prolonged ( p = 0.26 ) . Fifty-four patients took part in an open trial and 69 percent responded to treatment . All of these had clinical improvement . Side effects were minimal with cardiotoxicity noted in less than 15 percent among patients with side effects . Over 35 percent had no side effects . Thus single agent , weekly doxorubicin therapy as evaluated in our experience , while well tolerated and of subjective benefit , does not provide the patient with a significant longer progression-free survival or improved overall survival [2201425] The results of a r and omized , multicenter , cooperative group trial evaluating hormonal therapy with either megestrol acetate or dexamethasone in advanced , hormonally refractory prostate cancer are reported . Three of 29 patients ( ∼10 % ) on the megestrol acetate arm experienced an objective response lasting 41 , 84 , and 202 days , respectively , whereas two of 29 patients ( ∼7 % ) on the dexamethasone arm achieved an objective response lasting 359 and 512 days , respectively . Twenty of 29 patients ( ∼69 % ) on the megestrol acetate arm had stable disease lasting for a median duration of 117 days , whereas 21 of 29 patients ( 72 % ) on the dexamethasone arm had stable disease for a median duration of 86 days . Median survival of all patients was 9 months from initiation of treatment . The median survival for patients on the megestrol acetate arm was 268 days compared to 246 days for patients on the dexamethasone arm ( P = 0.2 ) . Neither dexamethasone nor megestrol acetate would seem to be of substantive value in altering the progression of advanced , hormonally refractory prostate cancer [10550143] PURPOSE Prostate-specific antigen ( PSA ) is a glycoprotein that is found almost exclusively in normal and neoplastic prostate cells . For patients with metastatic disease , changes in PSA will often ante date changes in bone scan . Furthermore , many but not all investigators have observed an association between a decline in PSA levels of 50 % or greater and survival . Since the majority of phase II clinical trials for patients with and rogen-independent prostate cancer ( AIPC ) have used PSA as a marker , we believed it was important for investigators to agree on definitions and values for a minimum set of parameters for eligibility and PSA declines and to develop a common approach to outcome analysis and reporting . We held a consensus conference with 26 leading investigators in the field of AIPC to define these parameters . RESULT We defined four patient groups : ( 1 ) progressive measurable disease , ( 2 ) progressive bone metastasis , ( 3 ) stable metastases and a rising PSA , and ( 4 ) rising PSA and no other evidence of metastatic disease . The purpose of determining the number of patients whose PSA level drops in a phase II trial of AIPC is to guide the selection of agents for further testing and phase III trials . We propose that investigators report at a minimum a PSA decline of at least 50 % and this must be confirmed by a second PSA value 4 or more weeks later . Patients may not demonstrate clinical or radiographic evidence of disease progression during this time period . Some investigators may want to report additional measures of PSA changes ( ie , 75 % decline , 90 % decline ) . Response duration and the time to PSA progression may also be important clinical end point . CONCLUSION Through this consensus conference , we believe we have developed practical guidelines for using PSA as a measurement of outcome . Furthermore , the use of common st and ards is important as we determine which agents should progress to r and omized trials which will use survival as an end point [1968505] This r and omised phase II study was performed in order to evaluate the effectiveness of a weekly chemotherapy regimen in advanced prostatic carcinoma patients ( stage D2 ) refractory to hormonal therapy . Seventy-two cases were studied : they were r and omised in a 2:1 ratio to receive either epirubicin ( 30 mg m-2 weekly ) or doxorubicin ( 25 mg m-2 weekly ) ; 48 patients received epirubicin and 24 received doxorubicin . After 12 courses of chemotherapy , the 45 evaluable patients in the epirubicin arm showed a response rate of 37.7 % and the 21 evaluable patients in the doxorubicin arm showed a response rate of 33.3 % ( P = 0.51 ) . Pain intensity , bone and prostatic tumour markers rapidly and significantly decreased in responders . An improvement in physical symptoms , functional conditions and in emotional well-being was observed in the majority of the treated patients . The histological analysis of bone metastases , performed before and after 12 courses of chemotherapy showed a significant reduction in neoplastic invasion and in new bone formation in responders . Cardiac performance worsened in five out of 45 patients and in ten out of 21 during the first 12 courses of epirubicin or doxorubicin respectively ( P = 0.014 ) . The median survival was 12.5 months in the epirubicin arm and 8.0 months in the doxorubicin arm ( P = 0.042 ) . Our data indicate that in advanced prostatic carcinoma , a weekly epirubicin regimen may give rapid palliative results , similar to that of doxorubicin , but with less side-effects [12610188] PURPOSE Several multicomponent regimens have been reported to be useful in advanced and rogen-independent prostate cancer . We used a r and omized phase II design to evaluate and compare two such regimens . Patients were accrued primarily in the community setting . PATIENTS AND METHODS Patients with progressive , and rogen-independent prostate cancer were r and omly assigned to one of two treatments : either ketoconazole/doxorubicin alternating with vinblastine/estramustine ( KA/VE ) or paclitaxel , estramustine , and oral etoposide ( TEE ) . Patients were prospect ively stratified on the basis of disease volume . The primary end points were response and overall survival time . RESULTS A total of 75 patients were registered ; 71 are included in the analysis . By the criterion of an 80 % prostate-specific antigen reduction maintained for at least 8 weeks , 11 ( 30 % ) of 37 patients in the TEE arm responded , whereas 11 ( 32 % ) of 34 assigned to KA/VE responded . Median survival was 16.9 months ( 95 % confidence interval [ CI ] , 10.5 to 21.2 months ) in the TEE arm and 23.4 months ( 95 % CI , 12.9 to 30.6 months ) for patients treated with KA/VE . Many patients ( 24 % ) failed to complete at least 6 weeks of therapy , including five ( 8 % ) treatment-related early deaths . CONCLUSION Each of these regimens produced clinical ly significant responses , and the observed median survival ( 18.9 months for all 71 patients ) compares favorably with previously published results , especially in the community setting . Nonetheless , it is apparent that these first-generation regimens must be applied judiciously , and thus we view efforts at better patient selection and the development of more tolerable therapies as higher priorities than carrying either of these regimens to phase III evaluation in the cooperative group setting [3904132] Summary Ninety-five patients with prostatic carcinoma , stages A-D and of all histological grade s were r and omized between a continuous and an intermittent treatment regimen of EstracytR ( estramustine phosphate ) . 77 patients were evaluated ( 46 with continuous and 31 with intermittent therapy ) . Remissions were seen in 13 ( 28 % ) and ( 13 % ) , respectively . Stable disease was recorded in 30 ( 65 % ) and 24 ( 77 % ) , respectively . Progression experienced 3 ( 6 % ) and 3 ( 10 % ) respectively . 19 % were unable to continue therapy due to intolerable gastrointestinal side effects ( 7 patients receiving continuous and 8 patients receiving intermittent therapy ) [2228066] Fifty-seven patients with advanced prostate cancer resistant to first-line hormonal therapy were treated with estramustine and additionally r and omized for treatment with clodronate or placebo . Clodronate treatment was started with 5 days intravenous administration ( 300 mg day[-1 ] ) and followed by oral treatment ( 1.6 g day[-1 ] ) for 12 months . Skeletal pain relief was only about 10 % better in the clodronate than in the placebo group . The results do not support the superiority of combined intravenous and oral treatment with clodronate compared with oral administration only [10765092] Objectives : To compare the quality of life ( QL ) of patients with poor prognosis M1 prostate cancer treated with orchiectomy alone ( ORCH ) or orchiectomy combined with adjuvant mitomycin C ( MMC ; 15 mg/m2 i.v . q 6 weeks : ORCH+MMC ; EORTC trial 30893 ) . Methods : Patients with newly diagnosed M1 poor prognosis prostate cancer completed a truncated version of the EORTC QLQ – C30 ( V 1.0 ) at r and omization ( baseline ) and every 6–12 weeks thereafter until going off the protocol . Five ad hoc questions assessing lower urinary tract symptoms were included in the QL question naire . Results : At least one QL form was completed by 177 of the 189 patients included in the trial , with baseline question naires available for 113 patients ( ORCH n = 52 ; ORCH+MMC n = 61 ) . In both arms , pain and urinary dysfunction improved during treatment . Compared with patients from the ORCH arm , the use of adjuvant MMC was associated with a significant reduction in global health status/QL and with impairment in 7 of 11 QL dimensions covered by the question naire . Some improvement in QL was observed after discontinuation of MMC . A survival benefit was not observed in the ORCH+MMC arm . Conclusions : Intravenous MMC ( 15 mg/m2 q 6 weeks ) can not be recommended as adjuvant treatment in M1 poor prognosis prostate cancer due to its negative impact on QL and lack of efficacy . In general , QL assessment s should be m and atory when adjuvant chemotherapy is evaluated in patients with metastatic prostate cancer [14751362] OBJECTIVES To evaluate prospect ively the combination of a luteinizing hormone-releasing hormone analog with a somatostatin analog and dexamethasone in patients with hormone-refractory prostate cancer ( HRPC ) in a r and omized Phase II study . HRPC presents a challenging therapeutic problem . Salvage chemotherapy is the usual approach at this stage of the disease . The combination of a luteinizing hormone-releasing hormone analog with a somatostatin analog and dexamethasone has produced objective clinical responses in HRPC . METHODS Forty patients with HRPC were r and omized to receive one of two treatments . Group 1 underwent chemotherapy ( estramustine 140 mg three times daily and etoposide 100 mg orally for 21 days ) and group 2 the combination of a somatostatin analog ( lanreotide 30 mg intramuscularly every 14 days ) and dexamethasone ( 4 mg tapered to 1 mg ) , in addition to and rogen ablation by orchiectomy or a luteinizing hormone-releasing hormone analog ( triptorelin 3.75 mg intramuscularly every 28 days ) . The clinical and prostate-specific antigen ( PSA ) response , overall survival , time to progression , and toxicity were compared between the two groups . RESULTS The data of 20 patients in group 1 and 18 in group 2 were analyzed . The demographic and clinical data were similar in the two groups at study entry . A PSA response ( decrease of greater than 50 % ) was observed in 45 % of group 1 and 44 % of group 2 . The difference was not statistically significant . A partial clinical response was observed in 29 % and 30 % of groups 1 and 2 , respectively . Again , the difference was not statistically significant . Changes in performance status and pain score during treatment were not significantly different in the two groups . Hematologic toxicity was more frequent in group 1 ( 80 % of patients ) , and mild diabetes was more frequent in group 2 ( 22 % of patients ) . The overall survival was 18.8 months in group 1 and 18 months in group 2 ( not statistically significant ) . The time to progression was 6 versus 4 months and , in the PSA responder subgroup , it was 8 versus 7.7 months in groups 1 and 2 , respectively ( neither difference was statistically significant ) . CONCLUSIONS The results of our r and omized Phase II study indicated that the new combination treatment ( luteinizing hormone-releasing hormone analog , somatostatin analog , and dexamethasone ) may be equally effective as salvage chemotherapy in patients with HRPC in terms of the clinical and PSA response , overall survival , and time to progression . A larger prospect i ve Phase III trial is required to confirm our observations [6343629] In this clinical trial of men with advanced prostatic cancer no longer responsive to hormone therapy 189 were r and omized to receive estramustine phosphate , methotrexate or cis-platinum . Response evaluations were done in 158 cases . Objective response rates ( complete , partial or stabilization of disease ) were 34 per cent for estramustine phosphate , 36 per cent for cis-platinum and 41 per cent for methotrexate . Subjective parameters indicated a substantial advantage for pain improvement with methotrexate or cis-platinum over estramustine phosphate . Probabilities of continued response indicated some advantage for methotrexate and median response duration s at this time were twice as long for methotrexate ( 32 weeks ) as for cis-platinum ( 16 weeks ) , with estramustine phosphate intermediate ( 23 weeks ) . Survival rates for the original treatment r and omization groups were not different at this time . Side effects of estramustine phosphate consisted primarily of nausea and vomiting and /or anorexia but to a lesser extent than with cis-platinum . These effects were somewhat less for methotrexate , for which the major side effects were stomatitis and leukopenia , as well as hepatic toxicity reflected by elevated serum glutamic oxaloacetic transaminase levels . Other side effects of cis-platinum were less than for methotrexate ( no stomatitis ) , except for signs of renal toxicity ( elevations in blood urea nitrogen and serum creatinine ) , which were greater . Methotrexate had a relatively high level of activity against metastatic , progressive , hormone nonresponsive prostatic cancer , with side effects that were substantial but manageable [2148830] A prospect i ve r and omized study has been carried out in order to compare three different treatment modalities for symptomatic metastatic hormone-resistant prostatic cancer . A total of 79 patients were included . One group was treated with estramustine phosphate , another with Epirubicin plus Medroxyprogesterone acetate ( MPA ) , while the third arm consisted of Epirubicin plus placebo . Best palliation was obtained by the combination of Epirubicin and MPA . This combination also seemed to be associated with the longest response duration [15226321] PURPOSE Both docetaxel and thalidomide have demonstrated activity in and rogen-independent prostate cancer ( AIPC ) . We compared the efficacy of docetaxel to docetaxel plus thalidomide in patients with AIPC . METHODS Seventy-five patients with chemotherapy-naïve metastatic AIPC were r and omly assigned to receive either docetaxel 30 mg/m(2 ) intravenously every week for 3 consecutive weeks , followed by a 1-week rest period ( n = 25 ) ; or docetaxel at the same dose and schedule , plus thalidomide 200 mg orally each day ( n = 50 ) . Prostate-specific antigen ( PSA ) consensus criteria and radiographic scans were used to determine the proportion of patients with a PSA decline , and time to progression . RESULTS After a median potential follow-up time of 26.4 months , the proportion of patients with a greater than 50 % decline in PSA was higher in the docetaxel/thalidomide group ( 53 % in the combined group , 37 % in docetaxel-alone arm ) . The median progression-free survival in the docetaxel group was 3.7 months and 5.9 months in the combined group ( P = .32 ) . At 18 months , overall survival in the docetaxel group was 42.9 % and 68.2 % in the combined group . Toxicities in both groups were manageable after administration of prophylactic low-molecular-weight heparin in the combination group . CONCLUSION In this r and omized phase II trial , the addition of thalidomide to docetaxel result ed in an encouraging PSA decline rate and overall median survival rate in patients with metastatic AIPC . After the prophylactic low-molecular-weight heparin was instituted to prevent venous thromboses , the combination regimen was well tolerated . Larger r and omized trials are warranted to assess the impact of this combination [11256836] OBJECTIVE This prospect i ve and r and omized clinical study was initiated to compare the efficacy and safety of combined and rogen blockade with combination with UFT in patients with untreated prostate cancer . METHODS A total of 142 patients were entered in this study between April 1990 and December 1992 . All patients received bilateral orchiectomy and 200 mg/day of diethylstilbestrol diphosphate . Of these patients , 70 patients were administered an additional 400 mg/day of UFT after r and omization . Either treatment was continued for at least 1 year or until objective progression occurred if the initial response was equal to or better than no change . The endpoints of this study were progression-free survival , cancer-specific survival and change of QOL scores . RESULTS A total of 136 patients were evaluable and 131 patients ( 96.3 % ) could be followed up with a median follow-up period of 1469 days . Both groups showed similar initial treatment response at 12 weeks , adverse effect and change of quality of life score during the first year after initiation of the treatment . There was a significantly longer progression-free survival and better but not significant cancer-specific survival in the endocrine chemotherapy group . The patients with earlier stage and initial serum prostate-specific antigen values < 40 ng/ml showed a good indication for this endocrine chemotherapy . CONCLUSION This endocrine chemotherapy was confirmed to be tolerable and significantly effective in the delay of disease progression , which leads to longer survival in patients with prostate cancer [3534315] A total of 67 patients with progressive stage D2 prostatic cancer refractory to orchiectomy was entered in a controlled clinical trial to test whether and rogen priming enhances the efficacy of cytotoxic drugs . All patients were treated continuously with aminoglutethimide and hydrocortisone to lower adrenal and rogen secretion and were given cyclic intravenous chemotherapy . In addition , the 34 patients r and omized to the stimulation arm received fluoxymesterone for 3 days before and on the day of chemotherapy . There was 33 controls . The median duration of followup was 24 months . A modestly higher response rate ( objective remission plus disease stabilization ) was observed in the stimulation arm ( 85 versus 72 per cent , p less than 0.05 ) when the analysis was restricted to the evaluable patients . However , a larger fraction of unevaluable patients was present in the stimulation group ( 41 versus 16 per cent ) , mostly as a result of toxicity from fluoxymesterone , which prompted early discontinuation of treatment . Thus , when data analysis included all patients the response rate actually was slightly higher in the control than in the stimulation arm ( 60 versus 50 per cent , p not significant ) . No difference was observed in median duration of response ( 9 months in both groups ) or over-all survival . Our data suggest that at least in those patients with advanced disease and rogen priming does not seem to enhance significantly the antitumor effect of the combination of amino-glutethimide and chemotherapy , and is associated with significant toxicity . These largely negative results may be explained by the large number of hormone-resistant cells present in tumors that have become refractory to orchiectomy [11069375] Objective To assess the role of mitozantrone , active in relapsed prostate cancer , as an adjuvant to hormonal treatment in patients with advanced prostate cancer [14747052] Despite improvements in early detection of prostate cancer when it is clinical ly localized-- and therefore most amenable to curative local therapies-- approximately 33 % of men with early prostate cancer will develop biochemical failure with a rising prostate-specific antigen ( PSA ) during follow-up . The early use of and rogen suppression in this group of men has changed the clinical picture of and rogen-independent disease . Now , there are men on and rogen suppression who will develop biochemical failure and remain free of clinical or radiographic evidence of metastatic disease for a period of time . There is no st and ard approach to this group of men , who have a rising PSA on and rogen deprivation , because there are little or no data about strategies that may improve survival , delay time to progression , or improve quality of life . Therefore , current management of this population remains controversial . In an effort to determine which of these 2 approaches -- second-line hormone therapy or chemotherapy -- is optimal in delaying the time to progression , the Eastern Cooperative Oncology Group ( ECOG ) developed protocol E1899 . Although both approaches offer the potential for response ( reduction in PSA and prolonging the time to clinical progression ) , they have very different toxicity profiles , making impact on quality of life another important end point . This r and omized trial evaluating second-line hormonal therapy using ketoconazole and hydrocortisone versus docetaxel and estramustine combination chemotherapy on progression-free survival in asymptomatic men with a rising PSA on and rogen ablation for prostate cancer is the subject of this article [12947070] PURPOSE To compare the incidence of palliative response in patients with hormone-resistant prostate cancer ( HRPC ) treated with mitoxantrone and prednisone ( MP ) plus clodronate with that of patients treated with MP plus placebo . MATERIAL S AND METHODS Men with HRPC , bone metastases , and bone pain were r and omly assigned to receive clodronate 1,500 mg administered intravenously ( IV ) or placebo every 3 weeks , in combination with mitoxantrone 12 mg/m2 IV every 3 weeks and prednisone 5 mg orally bid . Patients completed the present pain intensity ( PPI ) index and Prostate Cancer-Specific Quality -of-Life Instrument at each treatment visit and used a diary to record analgesic use on a daily basis . The primary end point was a reduction to zero or of two points in the PPI or a decrease of 50 % in analgesic intake , without increase in either . RESULTS The study accrued 209 eligible patients over 44 months . One hundred sixty patients ( 77 % ) had mild PPI scores ( 1 or 2 ) , and 49 ( 24 % ) had moderate PPI scores ( 3 or 4 ) . The primary end point of palliative response was achieved in 46 ( 46 % ) of 104 patients on the clodronate arm and in 41 ( 39 % ) of 105 patients on the placebo arm ( P = .54 ) . The median duration of response , symptomatic disease progression-free survival , overall survival , and overall quality of life were similar between the arms . Subgroup analysis suggested possible benefit in patients with more severe pain . CONCLUSION MP provides useful palliation in symptomatic men with HRPC . Clodronate does not increase the rate of palliative response or overall quality of life . Clodronate may be beneficial to patients who have moderate pain , but this requires further confirmation [15470213] BACKGROUND Mitoxantrone plus prednisone reduces pain and improves the quality of life in men with advanced , hormone-refractory prostate cancer , but it does not improve survival . We compared such treatment with docetaxel plus prednisone in men with this disease . METHODS From March 2000 through June 2002 , 1006 men with metastatic hormone-refractory prostate cancer received 5 mg of prednisone twice daily and were r and omly assigned to receive 12 mg of mitoxantrone per square meter of body-surface area every three weeks , 75 mg of docetaxel per square meter every three weeks , or 30 mg of docetaxel per square meter weekly for five of every six weeks . The primary end point was overall survival . Secondary end points were pain , prostate-specific antigen ( PSA ) levels , and the quality of life . All statistical comparisons were against mitoxantrone . RESULTS As compared with the men in the mitoxantrone group , men in the group given docetaxel every three weeks had a hazard ratio for death of 0.76 ( 95 percent confidence interval , 0.62 to 0.94 ; P=0.009 by the stratified log-rank test ) and those given weekly docetaxel had a hazard ratio for death of 0.91 ( 95 percent confidence interval , 0.75 to 1.11 ; P=0.36 ) . The median survival was 16.5 months in the mitoxantrone group , 18.9 months in the group given docetaxel every 3 weeks , and 17.4 months in the group given weekly docetaxel . Among these three groups , 32 percent , 45 percent , and 48 percent of men , respectively , had at least a 50 percent decrease in the serum PSA level ( P<0.001 for both comparisons with mitoxantrone ) ; 22 percent , 35 percent ( P=0.01 ) , and 31 percent ( P=0.08 ) had predefined reductions in pain ; and 13 percent , 22 percent ( P=0.009 ) , and 23 percent ( P=0.005 ) had improvements in the quality of life . Adverse events were also more common in the groups that received docetaxel . CONCLUSIONS When given with prednisone , treatment with docetaxel every three weeks led to superior survival and improved rates of response in terms of pain , serum PSA level , and quality of life , as compared with mitoxantrone plus prednisone [2213104] Cytotoxic chemotherapy has not provided survival benefit in metastatic prostate cancer , although it has been used most frequently in patients with far-advanced , refractory disease . To evaluate the effects of chemotherapy given earlier in the course of the disease , the Southwest Oncology Group ( SWOG ) performed a r and omized trial between September 1982 and October 1986 comparing endocrine therapy ( diethylstilbestrol [ DES ] or orchiectomy ) alone followed by cyclophosphamide-Adriamycin ( doxorubicin ; Adria Laboratories , Columbus , OH ) chemotherapy at progression versus initial combined chemo-endocrine therapy . One hundred forty-three patients were registered , and only six were declared ineligible . Patients on the combined chemo-endocrine therapy arm had a slightly higher response rate ( 63 % ) compared with endocrine therapy alone ( 48 % ) . A log-linear model of tumor response and treatment arm adjusted for the stratification factors favored the combination arm ( P = .059 ) . Only three of 27 patients on the endocrine therapy alone arm had an objective partial response when crossed over to chemotherapy , while two others had stable disease . Despite the difference in initial response rate , time to treatment failure and survival were identical in the two treatment arms . Seventy-seven percent of patients on the initial endocrine therapy alone arm have died ( median survival , 25.6 months ) compared with 78 % on the chemo-endocrine therapy arm ( median survival , 22.0 months ) . No significant effect of treatment on survival was observed even after adjustment for the stratification variables in a Cox regression model . Exploratory survival analyses with patients on both arms combined did show a marginally significant time to treatment failure and survival advantage for patients treated with DES rather than orchiectomy as initial endocrine therapy . Eighty-six percent of patients treated by orchiectomy have died compared with only 65 % of those treated with DES . These data do not support the addition of cytotoxic chemotherapy to initial endocrine therapy in patients with metastatic prostate cancer [7194733] Thirty‐two evaluable patients with metastatic carcinoma of the prostate were entered into a prospect i ve r and omized trial comparing cyclophosphamide ( CYC ) with a combination of cyclophosphamide , methotrexate , and fluorouracil ( CMF ) . Progressive disease after endocrine manipulation was noted in 97 % ( 31/32 ) of patients before entry . Stable disease ( S ) was observed in 9 of 17 patients treated with CYC . One partial response ( PR ) and seven stable responses occurred in the 15 CMF patients . Median duration of stable response was 4.5 months for CYC and 4.5 months on CMF . Median survival of patients with PR and S receiving CYC was 10.1 and for CMF 8.8 months . Patients with progressive disease survived a median 1.7 and 2.6 months with CYC and CMF , respectively . Toxicity was moderate , and no deaths were attributable to sepsis or bleeding . Almost all patients in this study had bone lesions as the dominant site of disease ; this made objective assessment of response difficult . There was no significant improvement in response conferred by the combination regimen . Although patients with metastatic prostatic cancer may benefit from chemotherapy , impressive clinical responses are uncommon [10679652] Megestrol acetate ( MA ) is a synthetic progestin with reported activity in both hormone‐sensitive and hormone‐refractory prostate carcinoma ( HRPC ) . Based on limited data suggesting a possible dose‐response effect , a trial was initiated to compare st and ard versus moderately high dose MA in HRPC [7230336] There were 121 men with hormonally refractory metastatic cancer of the prostate who were r and omized to receive estramustine phosphate or vincristine , or the combination of these 2 agents . All patients had received prior radiation therapy ( greater than 2,000 rad ) . There were 90 patients who could be compared for response . The objective response rates ( partial regression or stabilization of disease ) for the 3 treatment groups were 26 per cent for estramustine phosphate , 24 per cent for estramustine phosphate plus vincristine and 15 per cent for vincristine . Subjective parameters varied little among the 3 regimens . The median duration of response for those responding to estramustine phosphate was similar ( 20 weeks ) to that for vincristine ( 22 weeks ) and greater than that for the combination ( 13 weeks ) . The probability of survival did not differ significantly for patients r and omized to each of the 3 regimens . The addition of vincristine to estramustine phosphate did not enhance the response rate achieved by estramustine phosphate alone and vincristine alone produced the lowest response rate . Estramustine phosphate continues to be the most active agent in previously irradiated patients with hormonally refractory metastatic cancer of the prostate [936381] A total of 125 patients with progressing advanced prostatic cancer were entered into a chemotherapy study comparing cyclophosphamide , 5-fluorouracil , and st and ard therapy . Parameters of response were studied in 110 patients who could be evaluated . Thirty-six patients ( 33 per cent ) were considered to have an objective response , that is becoming stable ( 29 patients ) or in partial regression ( 7 patients ) . Negative response parameters ( predictors of a poor response to chemotherapy or st and ard theraphy leading to progress ) included ( 1 ) bone marrow evidence of prostatic cancer , ( 2 ) abnormal liver scan , ( 3 ) prior radiation therapy ( indirectly through increased toxicity to chemotherapy ) , and ( 4 ) lack of bilateral orchiectomy prior to r and omization . Positive indicators ( predictors of good responses ) included ( 1 ) reduction of primary tumor mass , especially after administration of 5-fluorouracil or cyclophosphamide , and ( 2 ) hemoglobin values . There were more objective responders to cyclophosphamide than st and ard therapy whether the hemoglobin was initially normal or low . Indeterminate parameters of response included weight gain , presence of bony or soft tissue metastases , relief of pain , performance status , excretory urography , and biochemical determinations of liver and renal function [9165581] Between 1984 and 1989 , 197 patients with T1 - 4 , NX , M1 , G2 - 3 or G3 prostate cancer were r and omized to treatment with 560 mg estramustine phosphate ( EMP , Estracyt , Emcyt ) or 3 mg diethylstilbestrol ( DES ) per day in a double blind study with stratification on presence or absence of cancer pain at start . A total of 194 patients were evaluated for efficacy of therapy . Time to progression ( p = 0.054 ) , to treatment failure ( p = 0.036 ) , cancer-specific survival ( p = 0.068 ) as well as overall survival ( p = 0.021 ) were longer in the DES group . There were more patients with prognostic parameters indicating bad prognosis in the EMP group . This trial was design ed to study whether EMP had better effect than DES as the primary treatment of high- grade , disseminated prostate cancer . The results did not confirm this hypothesis . On the contrary , treatment with DES had relatively good effect on this very aggressive form of prostate cancer [2528705] Ninety-two patients with D2 prostatic cancer were studied . Initial treatment was with either diethylstilboestrol ( DES ) or orchidectomy . Response to DES ( 5/63 , 81 % ) was significantly higher than for orchidectomy ( 18/29 , 62 % ; p less than 0.01 ) . However , duration of response and duration of survival were not significantly different for the 2 forms of hormonal therapy . Fifty-seven patients were r and omised to receive second-line treatment with either medroxyprogesterone acetate ( MPA ) , oral chlorambucil or combination chemotherapy ( adriamycin + cyclophosphamide + 5-fluoro-uracil ) . Response to second-line treatment was similar for all 3 regimens ( 46 % overall response ) . Most of the responses were disease stabilisation and , although there was symptomatic benefit , response to second-line therapy did not significantly improve survival compared to the survival experience of the group as a whole . It is concluded that palliative second-line treatment for advanced prostatic cancer should consist of the least toxic form of treatment which in this study was second-line hormone administration ( MPA ) [1540881] One hundred forty‐two patients with progressive , hormonally refractory advanced prostate carcinoma who had not received prior chemotherapy were r and omized to receive either combination chemotherapy with 5‐fluo‐rouracil ( 5‐FU ) , doxorubicin , and mitomycin C ( FAM ) or sequential chemotherapy with the same agents , i.e. , mitomycin C , followed by doxorubicin on disease progression , followed by 5‐FU . Objective tumor regressions were observed in 10 of 70 ( 14 % ) patients receiving the FAM treatment arm and 10 of 72 ( 14 % ) patients initially receiving mitomycin C. Of the 24 patients who received secondary therapy with doxorubicin alone , 3 ( 12.5 % ) achieved objective tumor regression . There were no responses among five patients who received tertiary therapy with 5‐FU alone . The median survival time for all patients treated with the combination arm was 8.7 months , compared with 7.1 months for patients who received the FAM arm ( P = 0.025 ) . However , this modes ! survival advantage in favor of the FAM treatment arm must be weighed against significantly more myelosuppression experienced by these patients . The chemotherapeutic regimens used in this study have only minor clinical value in the treatment of hormonally refractory advanced prostate cancer . Cancer 1992 ; 69:1440‐1444 [2462651] The present study was design ed to investigate the efficacy of various combinations of chemotherapeutic agents in the treatment of prostatic cancer in a group refractory to anti and rogenic therapy ( Group 1 ) and in a previous untreated group ( Group 2 ) . Therapeutic combinations of Estracyt ( E ) + Peplomycin ( P ) + Doxorubicin ( Do ) and P + Do + 5 FU ( F ) in Group 1 and E + P , Honvan ( Ds ) + P and E in Group 2 were carried out . The main objectives of this study were estimations of the efficacy of E and P in relation to the refractory cases of Group 1 and the efficacy of the combination E + P , in Group 2 . This is the first such prospect i ve , r and omized , controlled study to be carried out in Japan in relation to prostatic cancer . The results obtained in the present study indicated that chemotherapeutic regimens including E provide some enhanced efficacy , but that the efficacy with regard to refractory cases is poor ( 23.1 - 27.3 % ) , as has been reported of studies conducted in the USA and Europe . With regard to previously untreated cases , the E + P regimen achieved a relatively higher response rate than the other treatments ( 72.7 vs 44.5 or 50.0 % ) . In the comparison of survival times and survival curves , there were no statistically significant differences among the various treatment subgroups . A comparison of survival curves revealed the interesting finding that the PAP-related response showed a clear correlation to the survival curves of Group 2 patients [141326] In the 36 months since its inception , the National Prostatic Cancer Project treatment subgroup has r and omly assigned over 360 patients with progressive advanced prostatic cancer who were no longer responsive to endocrine manipulation to either one of four different clinical studies . The initial study demonstrated a clear superiority for 5-fluorouracil ( 5-FU ) and cyclophosphamide over continued conventional therapy . Beneficial responses were documented and are associated with increased survival rates and relief from pain and other symptoms . A proportionately larger number of patients obtained clinical benefit ( stable and partial regression ) on cyclophosphamide than on st and ard or 5-FU therapy . The criteria for evaluation of patients are supported by the survival data , ie , responders have survived for a longer period of time than those patients who continued in progression . Preliminary data from the subsequent protocol s have documented a 30 % response ( stable and partial regression ) in patients receiving oral estramustine phosphate and definite responses in patients treated with DTIC ; Too few patients have been treated with Leo 1031 to offer total response rates at this time , although the early results are promising . These clinical studies have firmly established a place for chemotherapy in the management of prostatic cancer . New trials will introduce single- and multiple-drug chemotherapy at earlier phases of the clinical course of prostatic cancer patients [11134196] PURPOSE Time to progression ( TTP ) , overall survival , and quality of life ( QL ) were compared in patients with hormone-resistant prostate cancer ( HRPC ) treated with prednisone ( 5 mg orally , four times a day ) or flutamide ( 250 mg orally , three times a day ) . PATIENTS AND METHODS Symptomatic patients were r and omized to receive either prednisone ( 101 patients ) or flutamide ( 100 patients ) . Subjective response was assessed based on performance status , the use of analgesics , and the need to apply alternative palliative treatment . Prostate-specific antigen (PSA)-based biochemical response ( > or= 50 % reduction of baseline PSA ) was recorded . At baseline and at 6-week intervals during follow-up , patients completed the European Organization for Research and Treatment of Cancer Quality of Life Question naire C-30 . RESULTS There was no difference between the groups in median TTP ( prednisone , 3.4 months ; flutamide , 2.3 months ) or overall survival ( prednisone , 10.6 months ; flutamide , 11.2 months ) . In the prednisone group , 56 % of the patients experienced a subjective response , compared with 45 % in the flutamide group ( P : = .18 ) . The median response duration was 4.8 months for prednisone and 4.2 months for flutamide . A biochemical response was observed in 21 % and 23 % of the prednisone and flutamide groups , respectively . Gastrointestinal toxicity was the reason for trial discontinuation in seven patients receiving flutamide and two patients receiving prednisone . The QL assessment parameters favored the use of prednisone with statistically significant differences in pain , fatigue , role functioning , appetite loss , gastrointestinal distress , and overall QL . CONCLUSION In symptomatic HRPC , treatment with prednisone or flutamide leads to similar rates of TTP and overall survival and no difference in subjective or biochemical response . The QL results favor the use of low-cost prednisone in patients with HRPC [1423178] Background . Between August 1984 and November 1989 , the Hoosier Oncology Group conducted a Phase III study comparing cyclophosphamide ( CTX ) with cyclophosphamide , doxorubicin , and methotrexate ( CAM ) in patients with hormone‐refractory metastatic prostatic cancer to determine whether the addition of doxorubicin and methotrexate to the cyclophosphamide regimen conferred any survival advantage [14747047] Currently , approximately 30,000 men die annually of metastatic , hormone-refractory prostate cancer . And rogen blockade is palliative and is generally effective for an average of 2 to 3 years until a patient develops and rogen-independent disease . Newer chemotherapeutic regimens can induce remissions in approximately 50 % of patients ; however , median survival for patients with and rogen-independent disease is still 8 to 12 months . The strategy of using chemotherapy regimens after and rogen blockade has been proved noncurative , and new approaches are needed to attempt to cure patients with advanced disease . It has been demonstrated in the pre clinical setting that and rogen withdrawal induces apoptosis in cancer cells in both the Shinogi breast cancer model and the LNCaP prostate cancer model . In both of these models , and rogen withdrawal was not curative , and the tumors grew back in a hormone-independent state . It is possible that the addition of chemotherapy at the time of initial and rogen ablation will improve cell kill by potentiating apoptosis , thereby killing cells that might otherwise have mutated to the and rogen-independent state if allowed to continue to cycle and grow . The rationale behind Radiation Therapy Oncology Group ( RTOG ) P-0014 is to demonstrate in a r and omized phase 3 trial that giving patients chemotherapy at the beginning of and rogen blockade may improve patient survival [1104900] The National Prostatic Cancer Project has r and omized this study for endocrine-resistant prostatic cancer patients for treatment with st and ard hormonal or other therapies compared to 5-fluorouracil and cyclophosphamide . Both agents were found at the probability level of 0.05 to have a significant advantage over st and ard treatment in terms of objective response , subjective improvement and minimal toxicity . Additional chemotherapy protocol s are currently under way . This r and omized trial is the first report of such a national study completed to date . We are much encouraged by this program and believe that additional agents now under consideration will provide additionally encouraging results [7017170] This is the fifth completed r and omized clinical trial of the National Prostatic Cancer Project . There were 125 patients with histologically confirmed relapsing clinical stage D prostatic cancer r and omized to receive hydroxyurea , methyl-chloroethyl-cyclohexy-nitrosourea or cyclophosphamide . All patients had received and failed previous hormonal therapy . Patients whose disease progressed after 12 weeks on the initial therapy were crossed over or r and omized to receive an alternate drug . There were 98 patients available for comparison of treatments . Objective responses included patients with complete or partial regression as well as stable disease . The response rates were 35 per cent for cyclophosphamide , 30 per cent for methyl-chloroethyl-cyclohexy-nitrosourea and 15 per cent for hydroxyurea . Subjective response parameters included improvement in performance status and relief of pain . Pain was improved in a fifth of the patients on each treatment area . Methyl-chloroethyl-cyclohexy-nitrosourea and hydroxyurea showed activity in advanced prostatic cancer patients but at the expense of excessive toxicity . Cyclophosphamide continues to be the most active single agent in this type of patient , particularly with regard to duration of response and survival . There was a statistically demonstrable advantage for cyclophosphamide over hydroxyurea and a marginal advantage over methyl-chloroethyl-cyclohexy-nitrosourea in survival experience [11344001] Eighty-nine patients with progressive prostate cancer despite suppression of testosterone and withdrawal of anti- and rogens were studied . This was a relatively advanced population , with 63 of 89 having either osseous metastases ( mets ) beyond the axial skeleton or visceral mets . Patients were r and omly assigned to receive either ketoconazole alone , or ketoconazole with weekly doxorubicin . All patients received replacement hydrocortisone . The primary endpoints were response and survival . Based on PSA reduction criteria ( > /= 80 % maintained for at least 8 weeks ) , 14 of 45 patients ( 31 % ) in the single-agent ketoconazole arm responded . Sixteen of 44 patients ( 36 % ) in the combination ketoconazole/doxorubicin arm responded . There were no important differences between the two treatments in any outcome measure . The median overall survival for all patients was 12.5 months ; median time to progression was 3.3 months . Toxicity was significant with both regimens , and more severe in the doxorubicin arm . Fully 20 % of patients in each arm discontinued therapy due to intolerable side effects . Each of these regimens is toxic , and produced responses in fewer than half of treated patients . Although the observed median survival does compare favorably with reports from similar cohorts treated in the community , the potential benefit is only modest . In our view , neither of these regimens is sufficiently promising to justify phase 3 evaluation [15774240] BACKGROUND Recent phase III studies in hormone refractory prostate cancer ( HRPC ) showed an improvement in terms of overall survival ( OS ) , objective response ( OR ) and biochemical response ( BR ) ; however , chemotherapy is usually accompanied by negative side effects that determines poor quality of life ( QoL ) and only marginally improves individual clinical response ( ICR ) in terms of pain relief and performance status . Ellagic acid is a polyphenol that is found in many species of flowering plants . It is an antioxidant that determines apoptosis , down regulation of IGF-II , activates p21 ( waf1/Cip1 ) , mediates the cumulative effect on G1/S transition phase and prevents destruction of p-53 gene by cancer cells . ENDPOINTS The aim of this study was to assess the effects of ellagic acid support therapy on toxicity , OR , ICR and BR in HRPC patients treated with estramustine phosphate and vinorelbine . MATERIAL S AND METHODS Patients with HRPC were r and omly distributed in two study groups : a control group ( group A ) who underwent chemotherapy with vinorelbine and estramustine phosphate , and an experimental group ( group B ) where chemotherapy regimen was associated with ellagic acid . RESULTS The mean number of chemotherapy cycles/patient was 4 ( range 3 - 8 cycles ) and 6.5 ( range 5 - 11 ) in group A and B patients , respectively . A reduction in systemic toxicity , statistically significant for neutropenia , associated with better results in term of OR rate , ICR , and BR were observed in group B compared with group A. On the contrary no significant difference in OS and PFS was detected between groups . CONCLUSIONS our study suggests that the use of ellagic acid as support therapy reduces chemotherapy induced toxicity , in particular neutropenia , in HRCP patients ; however , further studies are required to confirm our results [1831397] A series of 105 patients with metastatic prostatic cancer , having progressed on first-line hormonal treatment , were r and omised to high-dose medroxyprogesterone acetate ( MPA ) 1000 mg i.m . daily for 15 days , followed by 1000 mg weekly ( 53 patients ) , or to estramustine 280 mg per os twice daily ( 52 patients ) . The treatment was discontinued because of side effects in 3 of 51 evaluable MPA-treated patients and in 8 of 51 evaluable estramustine-treated patients . Progression-free survival was short in both groups and no statistically significant difference between them was observed . After 1 year , 70 % of the patients had died and there was no statistically significant difference between the 2 treatments in the cumulative observed survival rates . According to modified SPCG criteria , remissions lasting from 12 to 56 weeks were noted in 13 MPA-treated patients and in 4 estramustine-treated patients . This difference was statistically significant . After cross-over , 6 of 33 patients in the MPA group had a remission compared with 1 of 24 in the estramustine group . It was concluded that the response rate , considering both subjective and objective response criteria , was better with MPA and the side effects were fewer [6340081] In patients with metastatic hormone-relapsed adenocarcinoma of the prostate , adriamycin was compared to 5-fluorouracil in a r and omized trial in 99 patients and adriamycin alone was studied in an open trial in 48 patients . Response to adriamycin was superior as judged by response of measurable disease ( 25 vs 8 % ; P less than 0.05 ) and survival ( median 29 vs 24 weeks ; Cox analysis , P less than 0.03 ) , but comparable as judged by acid phosphatase response . Ambulatory status and site of metastases influenced rate of response to chemotherapy . Activity level , site of metastases , weight loss , and the symptom of protein aversion were prognostic factors for survival . Hematologic and gastrointestinal toxicity were frequent but were tolerated satisfactorily . Adriamycin therapy may be beneficial in patients with prostatic cancer after hormone therapy [10506613] PURPOSE To compare vinblastine versus the combination of vinblastine plus estramustine as treatment for patients with hormone-refractory prostate cancer ( HRPC ) . PATIENTS AND METHODS A total of 201 patients with metastatic prostate cancer , progressive after hormonal therapy and anti and rogen withdrawal ( if prior anti and rogen treatment ) , were r and omized to receive vinblastine ( V ) 4 mg/m(2 ) by intravenous bolus weekly for 6 weeks followed by 2 weeks off , either alone or together with estramustine phosphate ( EM-V ) 600 mg/m(2 ) PO days 1 through 42 , repeated every 8 weeks . Of 193 eligible patients , 98 received V , and 95 received EM-V. RESULTS Overall survival trended in favor of EM-V but was not significantly different as determined by Kaplan-Meier analysis ( P = .08 ) . Median survival was 11.9 months for EM-V and 9.2 months for V. EM-V was superior to V for secondary end points of time to progression ( P < . 001 , stratified log rank test ; median 3.7 v 2.2 months , respectively ) and for proportion of patients with > /= 50 % prostate-specific antigen ( PSA ) decline sustained for at least 3 monthly measurements ( 25.2 % v 3.2 % , respectively ; P < .0001 ) . Granulocytopenia was significantly less for EM-V compared with V ( grade 2 , 3 , and 4 = 7 % , 7 % , and 1 % v 27 % , 18 % and 9 % , respectively ; P < .0001 ) ; however , grade 2 or worse nausea ( 26 % v 7 % , respectively ; P = .0002 ) and extremity edema ( 22 % v 8 % , respectively ; P = .005 ) were more frequent for EM-V. CONCLUSION Although overall survival was not significantly greater for the combination , EM-V was superior to V for time to progression and PSA improvement . These results encourage further study of estramustine-based antimicrotubule drug combinations in HRPC [7206052] The Southeastern Cancer Study Group has evaluated 5-fluorouracil administered intravenously weekly at a dosage of 600 mg . per M.2 as a single agent , and the 3-drug combination of cyclophosphamide , doxorubicin and 5-fluorouracil in patients with metastatic carcinoma of the bladder and of the prostate previously untreated with cytotoxic chemotherapy in a prospect ively r and omized phase II study . In 4 of 18 patients with bladder carcinoma 5-fluorouracil induced an objective response , and cyclophosphamide , doxorubicin and 5-fluorouracil induced an objective response in 3 of 21 patients . In patients with prostatic carcinoma 5-fluorouracil induced an objective response as measured by a 50 per cent decrease in prostatic acid phosphatase determined in a central reference laboratory in 3 of 25 patients and objective stability by National Prostatic Cancer Project criteria in 14 of 29 patients . Cyclophosphamide , doxorubicin and 5-fluorouracil induced an objective response in 7 of 22 patients and objective stability in 20 of 29 . Thus , 5-fluorouracil administered in an adequate weekly dosage is established as an effective single agent in some patients with stage D carcinoma of the bladder or prostate . However , there is no significant added benefit as measured by survival obtained for these patients by combining cyclophosphamide and doxorubicin with 5-fluorouracil [8691702] BACKGROUND Prognosis of hormone-refractory prostatic cancer is dismal . We evaluated the efficacy of cytotoxic chemotherapy in combination with hormone therapy in patients with newly diagnosed metastatic prostatic cancer . METHODS From February 1984 to March 1992 , 39 newly diagnosed patients with stage D2 prostatic cancer were r and omized to orchiectomy plus diethylistilbestrol diphosphate or orchiectomy plus diethylstilbestrol diphosphate plus combination chemotherapy with cisplatin and methotrexate . RESULTS There was not significant difference in survival or progression-free survival between the two groups . CONCLUSION Chemotherapy has not been proved to prolong survival or progression-free survival in patients who received hormone therapy [731810] Patients with poorly differentiated prostatic carcinoma and skeletal metastases were r and omized to treatment with 2.6-cis-diphenylhexamethylcyclotetrasiloxane ( 2.6-cis ) and estramustine-17-phosphate ( estramustine ) . Parallel with the clinical study a group of non-r and omized patients were treated with 2.6-cis . Cytological regression of the tumor could be registered in half of the estramustine group but not in the 2.6-cis group . There were no drug-related changes in blood chemistry , kidney function tests , hematology or liver enzymes . There was in increase in acid and alkaline phosphatase in both groups but more pronounced in the 2.6-cis group . In both groups follicle-stimulating and luteinizing hormone values were depressed . Testicular and penis atrophy was observed in the 2.6-cis group . Relief of pain and marked improvement of conditions occurred in the majority of the cases in both groups . In general , no tumor regression was observed during administration of 300 mg . 2.6-cis daily for at least 3 months . Some tumor regression was noted during 600 mg . estramustine therapy daily [12441935] PURPOSE We compared median time to treatment failure of men with asymptomatic , hormone refractory , progressive prostate cancer treated with mitoxantrone plus prednisone versus prednisone alone . MATERIAL S AND METHODS In a multicenter phase III trial 120 men with asymptomatic , progressive , hormone refractory prostate cancer were r and omly assigned to treatment with mitoxantrone and prednisone or prednisone alone . Patients received 12 mg./m . mitoxantrone intravenously once every 3 weeks for 6 cycles and 5 mg . prednisone twice daily with or without mitoxantrone . Time to treatment failure was assessed as an aggregate end point comprised of time to disease progression , time to toxicity or death , or time to initiation of alternate therapy . RESULTS Median followup was 21.8 months . Median time to treatment failure and median time to progression were the same : time to treatment failure and time to progression in the mitoxantrone and prednisone group was 8.1 months compared to 4.1 months in the prednisone alone group ( p = 0.017 versus p = 0.018 ) . More patients ( 27 or 48 % ) treated with mitoxantrone and prednisone achieved a 50 % or greater reduction in prostate specific antigen levels than those who received only prednisone ( 15 or 24 % , p = 0.007 ) . There was no significant difference in median survival between the 2 groups , which was 23 and 19 months , respectively . Death was mainly attributable to disease progression . CONCLUSIONS Patients with hormone refractory prostate cancer who are asymptomatic but had progressive disease had a significantly higher response rate when treated with mitoxantrone and prednisone as demonstrated by the 50 % or greater decrease in prostate specific antigen compared to treatment with prednisone alone . Time to treatment failure was significantly prolonged in the chemotherapy treated group but survival rates were not different [1948120] Based on the results of several small clinical studies , the experimental data of J. T. Isaacs , and the theoretical considerations about the heterogeneity of prostatic cancer , we investigated the effect of simultaneous hormone-chemotherapy in previously untreated advanced prostatic cancer . Patients ( n = 145 ; 117 stage D , 28 clinical stage C ) up to an age of 80 years with histologically confirmed and previously untreated prostatic cancer were entered into the study . All patients received hormonal therapy with surgical castration and long-term administration of flutamide . Following castration , the patients were divided r and omly into two groups . Group I patients received simultaneous chemotherapy starting 4 weeks after castration with weekly administration of 25 mg/m2 of 4-epirubicin intravenously for 18 weeks . Patients in group II initially had only hormonal therapy and did not receive chemotherapy until they progressed . Both groups were assessed at intervals of 3 months with respect to subjective and objective response according to the National Prostatic Cancer Project criteria . Quality of life was assessed monthly by the patients during the first 6 months and every 3 months thereafter . Evaluation of the baseline data showed that both groups were comparable with respect to prognostic factors . The first statistical analysis revealed the significant superiority of the combined treatment with respect to response rates ( P = .005 ) , median time to progression ( P = .1 ) , and survival time ( P = .01 ) . Analysis of the patients ' self- assessment data showed that , to date , chemotherapy had not exerted an unfavorable influence on quality of life . These results are very preliminary and should be h and led with care . However , the data suggest that an early combined chemotherapy-hormonal treatment is beneficial for at least a subset of patients , and warrants further clinical investigation [1030548] The response and duration of survival were evaluated for patients with stage D relapsing prostatic cancer who were r and omized to cyclophosphamide (Cytoxan),5-fluorouracil ( 5-FU ) or st and ard therapy , or to subsequent chemotherapies . The chemotherapies on initial r and omization were superior to the st and ard therapy in the number of responders and duration of response . Survival was longer for responders ( stable or partial regression ) on chemotherapy by comparison to responders ( stable only ) on st and ard therapy . The survival for patients receiving initial and crossover chemotherapy was significantly improved for patients who responded to therapy . Chemotherapy of advanced relapsing stage D prostatic cancer is more beneficially treated by specific chemotherapy as shown in this r and omized study [9170576] BACKGROUND In order to examine the usefulness of chemohormonal therapy , we conducted a multicentered r and omized trial comparing hormonal therapy , using a luteinizing hormone-releasing hormone ( LH-RH ) agonist , with chemohormonal therapy , hormonal therapy plus cyclophosphamide ( CPM ) , in patients with newly diagnosed clinical stage D prostatic cancer . METHODS Between January 1991 and March 1995 , 41 evaluable patients with stage D prostatic cancer were r and omized into 2 groups : group A ( hormonal therapy alone ) , goserelin acetate depot 3.6 mg subcutaneously every 4 weeks : group B ( chemohormonal therapy ) , goserelin acetate depot 3.6 mg subcutaneously and CPM 1000 mg/m2 intravenously every 4 weeks . The responses to the therapies were evaluated based on the criteria of The Japanese Urological Association . RESULTS There were no significant differences between the 2 groups with regard to objective and subjective response rates . No advantage in chemohormonal therapy was observed in the survival rate and progression-free survival rate . However , the survival rate and progression-free survival rate of responders were significantly higher than those of nonresponders in both groups . When the results were categorized by histologic grade patients with poorly-differentiated adenocarcinoma had significantly higher response rates , survival rates , and disease-progression-free survival rates in Group B compared to similar patients in Group A. CONCLUSIONS We conclude that chemohormonal therapy does not definitely improve the clinical response and prognosis of patients with stage D prostatic cancer ; however , for patients with poorly-differentiated adenocarcinoma , chemohormonal therapy is a useful treatment [2126739] Patients with hormone escaped advanced progressive prostate cancer were r and omized either to receive either high-dose Estramustine phosphate orally or Mitomycin C by i.v . injection every 6 weeks until signs of progression or death supervened . Patients on both arms progressed rapidly , with a median time to progression of 5 months and a median length of survival of only 10 months . Toxicity was very considerable in both arms [10735891] PURPOSE Suramin is a novel agent that has demonstrated preliminary evidence of antitumor activity in hormone-refractory prostate cancer ( HRPC ) . A prospect i ve r and omized clinical trial was design ed to evaluate pain and opioid analgesic intake as surrogates for antitumor response in HRPC patients with significant , opioid analgesic-dependent pain . PATIENTS AND METHODS A double-blind , placebo-controlled trial r and omized patients to receive a 78-day , outpatient regimen of either suramin plus hydrocortisone ( HC , 40 mg/d ) or placebo plus HC . Treatment assignment was unblinded when either disease progression or dose-limiting toxicity occurred ; placebo patients were allowed to cross-over to open-label suramin plus HC . In addition to pain and opioid analgesic intake , prostate-specific antigen ( PSA ) response , time to disease progression , quality of life , performance status , and survival were compared . RESULTS Overall mean reductions in combined pain and opioid analgesic intake were greater for suramin plus HC ( rank sum P = .0001 ) . Pain response was achieved in a higher proportion of patients receiving suramin than placebo ( 43 % v 28 % ; P = .001 ) , and duration of response was longer for suramin responders ( median , 240 v 69 days ; P = .0027 ) . Time to disease progression was longer ( relative risk = 1.5 ; 95 % confidence interval , 1.2 to 1.9 ) and the proportion of patients with a greater than 50 % decline in PSA was higher ( 33 % v 16 % ; P = .01 ) in patients who received suramin . Neither quality of life nor performance status was decreased by suramin treatment , and overall survival was similar . Most adverse events were of mild or moderate intensity and were easily managed medically . CONCLUSION Outpatient treatment with suramin plus HC is well tolerated and provides moderate palliative benefit and delay in disease progression for patients with symptomatic HRPC [10561316] PURPOSE Approximately 40,000 men die each year of hormone-refractory prostate cancer ( HRPC ) . The results of treatment with chemotherapy have been disappointing to date , with no trials demonstrating a benefit with respect to survival duration . Corticosteroids and mitoxantrone each have been shown to be active agents in this disease . The purpose of this study was to demonstrate an advantage of mitoxantrone and hydrocortisone ( M+H ) over hydrocortisone alone with respect to survival duration . PATIENTS AND METHODS Two hundred forty-two patients with HRPC were r and omized to receive either M+H or hydrocortisone alone . Patients were monitored for survival , time to disease progression , time to treatment failure , response , and quality -of-life ( QOL ) parameters . RESULTS Treatment in both arms was well tolerated . Although there was a delay in time to treatment failure and disease progression in favor of M+H over hydrocortisone alone , there was no difference in overall survival ( 12.3 months for M+H v 12.6 months for hydrocortisone alone ) . There was an indication that QOL was better with M+H , in particular with respect to pain control . CONCLUSION M+H generated more frequent responses and a delay in both time to treatment failure and disease progression compared with hydrocortisone alone . In addition , there was a possible benefit of M+H with respect to pain control over hydrocortisone alone . No improvement in survival was observed . Although M+H could be viewed as a palliative option for patients with HRPC , new drugs and novel strategies are needed to improve survival for this disease [3518596] We report here in the interim analysis of an ongoing r and omized clinical trial design ed to test whether and rogen priming enhances tumor chemosensitivity in men with stage D prostate cancer refractory to orchiectomy . All patients are continuously treated with aminoglutethimide and hydrocortisone , to lower adrenal and rogen secretion , and are given cyclic chemotherapy . Patients in the stimulation arm receive also the synthetic and rogen , fluoxymesterone , for 3 days before and on the day of chemotherapy . Of 57 patients entered to date , 41 have received adequate treatment to be evaluable . Response to therapy ( objective remissions + stabilizations of disease ) occurred in 17 of 18 evaluable patients ( 94 % ) r and omized to the stimulation arm , and in 16 of 23 evaluable patients ( 70 % ) in the control group ( p less than 0.025 ) . Duration of response was not significantly different in the two groups ( median : 9 months in the stimulation and 12 months in the control arm ) . With 30 % of the total of 57 patients still alive , survival is not significantly different in the stimulation ( median : 13 months ) and control arm ( median : 16 months ) . As expected , patients who responded to treatment lived significantly longer than those who failed to benefit . Two episodes of reversible spinal cord compression occurred during and rogen administration . ( The risk of this serious side effect may be reduced by performing a screening myelogram to rule out sub clinical spinal metastasis ) . Our preliminary data suggest that and rogen priming may enhance the tumoricidal effect of cytotoxic drugs in advanced prostate cancer . The lack of improvement in duration of response and survival may be explained by the large fraction of hormone-independent cells probably present in patients with tumors refractory to orchiectomy [3538611] This prospect i ve r and omized study in nonhormonally responsive adenocarcinoma of the prostate shows that response rates to melphalan vs cyclophosphamide groups were virtually identical [15520061] BACKGROUND Vinorelbine ( VRL ) has been shown to be active in hormone-refractory prostate cancer ( HRPC ) in phase II studies , alone or in combination . Its moderate toxicity profile is well tolerated in elderly patients . PATIENTS AND METHODS Patients with metastatic prostate cancer , progressive after primary hormonal therapy , were r and omised to receive intravenous VRL 30 mg/m2 on days 1 and 8 every 3 weeks , and hydrocortisone 40 mg/day or hydrocortisone alone until disease progression . Centres could choose to add aminoglutethimide 1000 mg/day to hydrocortisone as second-line hormone therapy ( HT ) for all their patients . R and omisation was stratified by centre . Further chemotherapy was allowed after progression . The primary end point was progression-free survival ( PFS ) . The final analysis was performed on a total of 414 patients . Reported results were all based on intention-to-treat analyses . All progressions and responses were review ed by an independent panel . RESULTS PFS was significantly prolonged in the VRL plus HT arm compared with the HT alone arm , according to the statistical hypothesis of the protocol ( P=0.055 in the two-sided log-rank test with a pre-specified significance level of 10 % ) . The 6-month PFS rates were 33.2 % versus 22.8 % , and the median duration s of PFS were 3.7 versus 2.8 months . In the multivariate Cox analysis , which included age , Karnofsky performance status ( PS ) , haemoglobin , alkaline phosphatase at study entry and number of prior hormonal treatments , the P value was decreased to 0.005 . The prostate-specific antigen ( PSA ) response rate ( > or = 50 % decline sustained for at least 6 weeks ) was significantly higher for VRL plus HT compared with HT ( 30.1 % versus 19.2 % ; P=0.01 ) . Clinical benefit , defined as a decrease in pain intensity or analgesic consumption or an improvement of Karnofsky PS for at least 9 weeks , and at least stable assessment in the other two , was also more frequently observed in patients who received VRL plus HT versus HT alone ( 30.6 % and 19.2 % ; P=0.008 ) . There was no statistical difference in overall survival . Forty-three per cent of patients in the HT arm received at least one line of further chemotherapy after progression , compared with 28 % of patients in the VRL-based arm . Aminoglutethimide did not seem to result in better efficacy for either arm . VRL plus HT was well tolerated , with a median administered relative dose intensity of 90 % ; grade 4 neutropenia occurred in 6.5 % of patients and non-haematological toxicity was rare . CONCLUSIONS The combination of VRL and hydrocortisone compared with hydrocortisone alone result ed in improved clinical benefit , PFS and PSA response rate . This therapeutic gain is similar to that previously reported with mitoxantrone in combination with low-dose corticosteroids . There was no gain in survival ; however , the combination is well tolerated in this elderly group of patients , who often present cardiac co-morbidities , and therefore offers an active and safe therapeutic option for patients with hormone-refractory prostate cancer [15329902] Liposomal encapsulation of doxorubicin has been shown to reduce nonspecific delivery of this agent to normal tissue and to increase specific delivery to malignant cells . On the basis of doxorubicin 's demonstrated clinical efficacy against hormone‐refractory prostate carcinoma ( HRPCA ) , the authors conducted a prospect i ve , r and omized Phase II clinical trial to evaluate the feasibility , toxicity , and therapeutic efficacy associated with the pegylated form of this agent [3525866] In a r and omized phase III trial performed by the Urological Group of the European Organization for Research on Treatment of Cancer low dose estramustine phosphate ( 280 mg . twice daily for 8 weeks and 140 mg . twice daily thereafter ) was compared to diethylstilbestrol ( 1 mg . 3 times daily ) in patients with stages T3 to T4 , M0 or M1 prostatic cancer . Of 248 patients entered 227 were evaluable for analysis : 115 received estramustine phosphate and 112 received diethylstilbestrol . The best response of the local tumor as assessed by palpation was seen in patients receiving diethylstilbestrol . There was no significant difference between treatments for response rate of metastases , interval to local progression , distant progression , over-all survival and death of carcinoma of the prostate . Duration of survival was correlated with the assessment of local response as determined by palpation . The response of distant lesions also was correlated closely with survival . Diethylstilbestrol ( 1 mg . 3 times daily ) was associated with a significantly worse degree of cardiovascular toxicity than estramustine phosphate . This finding was especially obvious in patients who had no history of cardiovascular disease . Gastrointestinal toxicity occurred in 25 patients treated with estramustine phosphate , including 6 in whom cessation of treatment was necessary . Further studies are required to determine the optimum dose of diethylstilbestrol and estramustine phosphate , and to establish the best form of hormonal treatment for prostatic carcinoma [12225339] BACKGROUND Patients with hormone relapsed prostate cancer ( HRPC ) are often treated with flutamide or diethylstilboestrol . However , which of these two options is the best treatment for HRPC remains unclear . METHODS We carried out a prospect i ve study to determine and compare the prostate-specific antigen ( PSA ) response and survival in patients with hormone relapsed prostate cancer ( HRPC ) , all of whom had previously shown a good response to medical or surgical castration . The patients were r and omised to treatment with diethylstilboestrol ( DES ) and aspirin , or the anti and rogen flutamide . In addition , quality of life was determined by interview and question naire . RESULTS Twenty-eight patients were r and omised for treatment options . There was a significantly greater fall in the PSA ( 65 % vs 35 % ; P = 0.034 ) after treatment with diethylstilboestrol compared to treatment with flutamide . Median survival also rose after treatment with diethylstilboestrol ( 18 months ) compared to flutamide ( 11 months ) , but this difference did not reach statistical significance . There was no difference in the quality of life parameters between the two groups . There were no cardiovascular complications in the stilboestrol group . CONCLUSIONS In HRPC , treatment with stilboestrol is associated with a greater PSA fall and an increase in median survival when compared to flutamide treatment [11685731] New therapeutic alternatives are needed to improve outcomes in patients with and rogen-independent prostate cancer ( AIPC ) . For several years , research ers at the National Cancer Institute have been interested in elucidating the importance of angiogenesis in the pathogenesis of prostate cancer and in identifying inhibitors of this process . Thalidomide has been shown to inhibit the ability of tumors to recruit new blood vessels . In a recent phase II trial of thalidomide in AIPC , 28 % of patients achieved a prostate-specific antigen ( PSA ) decrease of > 40 % . The taxane docetaxel also produces PSA and measurable disease responses when used as monotherapy or as a component of combination chemotherapy for AIPC . Thus , based on the single-agent activity of thalidomide and docetaxel , we initiated a r and omized phase II study of weekly docetaxel with or without thalidomide , 200 mg at bedtime , in patients with chemotherapy-naive metastatic AIPC . Docetaxel , 30 mg/m(2 ) intravenously , was administered every 7 days for 3 weeks , followed by a 1-week rest period . Both regimens have been well tolerated among the first 59 treated patients , with a near absence of grade ( 3/4 ) myelosuppression . Fatigue , hyperglycemia , and pulmonary toxicity were seen in both groups . Thrombotic events have been seen in the combination arm . Thirty-five percent ( 6 of 17 ) of the patients receiving docetaxel alone and 53 % ( 19 of 36 ) of those receiving docetaxel and thalidomide have had a PSA decrease of at least 50 % . Combining a cytotoxic agent with an angiogenesis inhibitor is a promising area of investigation for prostate cancer management [10561202] PURPOSE To evaluate the combination of intravenous ( IV ) paclitaxel , oral estramustine , and oral etoposide in patients with advanced hormone-refractory prostate cancer . PATIENTS AND METHODS Forty patients with carcinoma of the prostate that was progressing despite hormonal therapy and who had undergone anti and rogen withdrawal ( if previously treated with an anti and rogen ) were enrolled onto this phase II trial . Patients were treated with oral estramustine 280 mg tid and oral etoposide 100 mg/d for 7 days , with paclitaxel 135 mg/m(2 ) IV over 1 hour on day 2 of each 21-day treatment cycle . Patients received a maximum of six cycles of therapy . RESULTS Thirty-seven patients were assessable for response . Twenty-two had measurable disease at baseline ; response was not assessable in six of these patients . Overall response was 45 % ( 10 of 22 patients ; 95 % confidence interval [ CI ] , 24 % to 68 % ) , and response was 63 % ( 10 of 16 ) in assessable patients . Twenty-six patients had a > or = 50 % decrease from their baseline prostate-specific antigen levels during therapy , for a response rate of 65 % ( 95 % CI , 48 % to 79 % ) by this criterion . Median duration of response was 3.2 months , with an estimated median survival of 12.8 months . Major toxicities of therapy were leukopenia ( eight patients had > or = grade 4 leukopenia ) and anemia . Hematologic toxicity seemed to be associated with liver metastases . Serial measurements in 24 patients using the Functional Assessment of Cancer Therapy-Prostate ( FACT-P ) showed no significant change in quality of life ( QOL ) as a result of therapy . CONCLUSION The combination of IV paclitaxel , oral estramustine , and oral etoposide is active in patients with advanced prostate cancer . The regimen is tolerable and does not have a significant impact on QOL as measured by the FACT-P in a limited sample of patients [10431581] To evaluate the efficacy of chemoendocrine therapy for the initial treatment of stage D2 prostate cancer , we conducted a prospect i ve r and omized study which compared combined and rogen blockade alone to that combined with UFT . Twenty-one patients received LH-RH agonist and flutamide ( Group-A ) , and 23 patients received LH-RH agonist , flutamide and UFT ( Group-B ) . The overall response rate and the PSA response rate of Group-A was 71.4 % and 100 % respectively , against 65.2 % and 90 % , respectively in Group-B. The median follow-up period was 24 months . The 2-year progression-free survival rate of Group-A was 7.4 % and that of Group-B was 15.9 % . The response rate and progression-free survival rate did not differ significantly between the 2 groups . Liver dysfunction due to flutamide was common in both groups , and a total of 4 patients did not continue the treatment because of this adverse effect . We conclude that in patients with stage D2 prostate cancer , treatment with combined and rogen blockade and UFT is not superior to treatment with combined and rogen blockade alone [969073] This National Cooperative Study has r and omly compared the usefulness of 5-fluorouracil ( 5-FU ) , cyclophosphamide ( Cytoxan ) and st and ard therapy in patients with advanced carcinoma of the prostate ( Stage D ) . All patients studied were endocrine failures and were in progression . Favorable responses were seen with all three treatments regardless of histologic grade . Actual tumor regression occurred only in patients who received either 5-FU or cyclophosphamide . In patients with poorly differentiated or anaplastic tumors treated with cyclophosphamide , progression of disease was significantly less rapid than in patients treated with 5-FU or st and ard therapy . However , favorable responders could not always be identified in advance on the basis of histologic grade alone [12177096] PURPOSE To test the hypothesis that the efficacy and toxicity of suramin in the treatment of patients with hormone-refractory prostate cancer was dose dependent . PATIENTS AND METHODS Patients were r and omized with equal probability to receive low- , intermediate- , or high-dose suramin ( total doses 3.192 , 5.320 , and 7.661 g/m(2 ) , respectively ) . Overall survival , time to progression , and response rate ( prostate-specific antigen [ PSA ] and objective ) for each treatment arm were compared . Relationships between plasma suramin concentrations and response , toxicity , and survival were also evaluated . RESULTS Three hundred ninety patients were r and omized . For the low- , intermediate- , and high-dose arms , the median survival time was 16 , 14 , and 13 months , respectively ( P = .49 ) . The objective response rate was 9 % , 7 % , and 15 % , respectively ( P = .10 ) . PSA response rates were 24 % , 28 % , and 34 % , respectively ( P = .082 ) . L and mark analyses of a 50 % decline in PSA at 20 weeks showed a significant correlation with survival . There was a dose-response relationship between dose and toxicity . After adjusting for treatment arm , the measured suramin concentration was not associated with clinical response , PSA response , survival , or toxicity . CONCLUSION Although high-dose suramin was associated with higher objective and PSA response rates , these were not statistically significant . Overall , no dose-response relationship was observed for survival or progression-free survival , but toxicity was increased with the higher dose . Patients treated with the low-dose level experienced modest toxicity , making it the preferred arm on this study . The lack of a dose-response relationship and the toxicity profile observed raise questions regarding the utility of suramin , particularly high-dose suramin , as administered on this schedule [370420] In this third cooperative chemotherapy trial of the National Prostatic Cancer Project 165 patients with histologically confirmed , relapsing clinical stage D prostatic cancer were r and omized to receive either imidazole-carboxamide , procarbazine or cyclophosphamide . All patients had received and failed previous hormonal therapy . Patients whose disease progressed after 12 weeks on initial therapy were crossed over or r and omized to receive an alternate drug . There were 129 patients available for comparison of treatments . The objective response rates ( partial regression plus stable disease ) were 26 % for cyclophosphamide , 27 % for imidazole-carboxamide and 14 % for procarbazine . Subjective responses were noted in pain relief , improvement in performance status and weight gain . Procarbazine was associated with excessive toxicity , result ing in many patients ( 28 % ) discontinuing therapy within the first 3 weeks and closure of this particular arm of the study . The regimen of initial imidazole-carboxamide therapy with a later cross-over to cyclophosphamide when the disease continues to progress is associated with the longest increase in survival . Imidazole-carboxamide and cyclophosphamide appear to be active agents in advanced prostatic cancer and are worthy of continued use in this disease [6259722] In a prospect i ve r and omized multicenter trial patients with highly or moderately differentiated prostatic carcinoma , previously untreated , were allotted either to oral Estramustine phosphate or to intramuscular polyestradiol phosphate plus oral ethinyl estradiol . As regards frequency and duration of tumour remission there was no statistical difference between the two groups . Nor did they differ significantly with respect to adverse reactions . This is an interim report and will be followed later on by a final evaluation [7536271] The therapeutic benefit of chemotherapy in and rogen independent prostate cancer is limited . 5-Fluorouracil has been reported to have modest antitumor activity in and rogen independent prostate cancer . Although alpha-interferon is inactive as a single agent in prostate cancer , pre clinical data indicate that it increases the in vitro cytotoxicity of 5-fluorouracil against a variety of malignant cells . We evaluated the relative antitumor activity and tolerance of 5-fluorouracil versus 5-fluorouracil plus alpha-interferon in 50 patients with histologically confirmed metastatic adenocarcinoma of the prostate . These patients had progressive disease in the presence of castrate levels of testosterone . A prospect i ve r and omized phase II open labeled trial was performed because of the difficulty in measuring responses in patients with metastatic prostate cancer . Of 23 patients treated with 5-fluorouracil alone and 28 treated with 5-fluorouracil plus alpha-interferon 17 and 23 , respectively , were evaluable for response and toxicity , and 5 and 5 , respectively , were evaluable for toxicity only . Only 2 of 17 ( 11.7 % ) and 4 of 23 ( 17 % ) patients , respectively , showed a greater than 50 % decrease in serum prostate specific antigen ( no significant difference ) . There was no difference in duration of response or duration of survival between the 2 groups ( mean duration of response 8.64 and 6.17 weeks , respectively , and mean duration of survival 33.70 and 38.65 weeks , respectively ) . Both regimens caused significant morbidity ( mucositis and neurotoxicity ) and 3 treatment related deaths at the high 5-fluorouracil doses . 5-Fluorouracil alone and with alpha-interferon at the doses used have minimal antitumor activity against and rogen independent prostate cancer and , therefore , should not be tested further in these patients . And rogen independent prostate cancer selected using our criteria is a rapidly progressive disease , and these patients are an ideal target population for phase II studies [1383436] PURPOSE Estramustine phosphate ( EMP ) and vinblastine are two microtubule inhibitors with distinct molecular targets and at least additive antimicrotubule effects in vitro . Their modest single-agent activities in hormone-refractory prostate cancer , nonoverlapping toxicities , and lack of cross-resistance prompted a phase II trial in hormone-refractory prostate cancer . PATIENTS AND METHODS Thirty-six assessable patients at the Fox Chase Cancer Center and seven Fox Chase Cancer Center Network institutions were treated with oral EMP 600 mg/m2 on days 1 to 42 and vinblastine 4 mg/m2 intravenously ( IV ) once a week for 6 weeks . Courses were repeated every 8 weeks . Response assessment was based on a change in serum prostate-specific antigen ( PSA ) levels and was correlated with change in pain scores . RESULTS PSA decreased from baseline by at least 50 % in 22 patients ( 61.1 % ) and by > or = 75 % in eight patients ( 22.2 % ) . A 50 % or more decrease in PSA on three successive 2-week measurements together with an improved or stable pain score , performance status , and measurable soft tissue disease ( if present ) was required for a partial response ( PR ) , which occurred in 11 patients for an overall response rate of 30.5 % ( 95 % confidence interval , 15.6 % to 45.6 % ) . In seven patients with measurable nonosseous disease , there was one PR ( 14 % ) and one minor response ( MR ) . In 28 patients with assessable pain , major pain responses occurred in 12 ( 42.9 % ) . PSA response ( > or = 50 % decrease times three measurements ) was predictive of major pain response with a 93.7 % specificity , a 50 % sensitivity , and a positive predictive value of 85.7 % . CONCLUSION We conclude that EMP and vinblastine is an active combination in hormone-refractory prostate cancer [6362815] Over a 24‐month period , the Southwest Oncology Group ( SWOG ) conducted a r and omized prospect i ve chemotherapeutic trial in 158 patients with advanced prostatic cancer . Patients were initially r and omized to receive either a combination of Adriamycin and cyclophosphamide ( AC ) or a single agent , hydroxyurea ( H ) , and then crossed over to the other treatment on failure . Of the 137 evaluable patients , 43 ( 31 % ) had classically measurable metastatic disease in the lymph nodes , skin , chest , or liver . Focusing their efforts on this subset of patients with measurable disease , the authors of this report found the combination AC to have a superior response rate to the single agent , hydroxyurea . Objective response to AC was seen in 6 of 19 ( 32 % ) and in only one of 24 ( 4 % ) patients r and omized to hydroxyurea ( P = 0.06 , Fisher 's exact test ) . However , in the larger group of 137 evaluable patients , a survival advantage was not seen for those individuals treated with AC . Failure to demonstrate a survival advantage for an objective ly superior drug combination would suggest the need for more active phase II agents in this disease [3139279] From April 1983 to March 1985 , 265 patients with newly diagnosed metastatic prostate cancer were r and omized to one of three treatment protocol s : ( 1 ) diethylstilbestrol ( DES ) or bilateral Orchiectomy , ( 2 ) the leutinizing hormone‐releasing hormone ( LHRH ) analog buserelin , or ( 3 ) methotrexate plus DES or orchiectomy . In 261 evaluable patients there was no significant difference in survival between the three groups . However , progression‐free survival ( PFS ) was significantly different ( P < 0.0005 , log‐rank test ) . Of the possible pairwise comparisons for PFS , two showed significance : buserelin was inferior to DES/ orchiectomy ( P < 0.05 ) and buserelin was inferior to methotrexate plus DES/orchiectomy ( P < 0.0001 )

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### Context: [8656243] PURPOSE To investigate the benefit of chemotherapy in patients with symptomatic hormone-resistant prostate cancer using relevant end points of palliation in a r and omized controlled trial . PATIENTS AND METHODS We r and omized 161 hormone-refractory patients with pain to receive mitoxantrone plus prednisone or prednisone alone ( 10 mg daily ) . Nonresponding patients on prednisone could receive mitoxantrone subsequently . The primary end point was a palliative response defined as a 2-point decrease in pain as assessed by a 6-point pain scale completed by patients ( or complete loss of pain if initially 1 + ) without an increase in analgesic medication and maintained for two consecutive evaluations at least 3 weeks apart . Secondary end points were a decrease of > or = 50 % in use of analgesic medication without an increase in pain , duration of response , and survival . Health-related quality of life was evaluated with a series of linear analog self- assessment scales ( LASA and the Prostate Cancer-Specific Quality -of-Life Instrument [ PROSQOLI ] ) , the core question naire of the European Organization for Research and Treatment of Cancer ( EORTC ) , and a disease-specific module . RESULTS Palliative response was observed in 23 of 80 patients ( 29 % ; 95 % confidence interval , 19 % to 40 % ) who received mitoxantrone plus prednisone , and in 10 of 81 patients ( 12 % ; 95 % confidence interval , 6 % to 22 % ) who received prednisone alone ( P = .01 ) . An additional seven patients in each group reduced analgesic medication > or = 50 % without an increase in pain . The duration of palliation was longer in patients who received chemotherapy ( median , 43 and 18 weeks ; P < .0001 , log-rank ) . Eleven of 50 patients r and omized to prednisone treatment responded after addition of mitoxantrone . There was no difference in overall survival . Treatment was well tolerated , except for five episodes of possible cardiac toxicity in 130 patients who received mitoxantrone . Most responding patients had an improvement in quality -of-life scales and a decrease in serum prostate-specific antigen ( PSA ) level . CONCLUSION Chemotherapy with mitoxantrone and prednisone provides palliation for some patients with symptomatic hormone-resistant prostate cancer [7523606] PURPOSE Estramustine and etoposide ( VP-16 ) have been demonstrated to inhibit the growth of prostate cancer cells in experimental models . This led us to evaluate the effectiveness of this combination in the treatment of patients with metastatic prostate carcinoma refractory to hormone therapy . PATIENTS AND METHODS Estramustine 15 mg/kg/d and VP-16 50 mg/m2/d , were administered orally in divided doses for 21 days . Patients were then taken off therapy for 7 days and the cycle then repeated . Therapy continued until evidence of disease progression . RESULTS Forty-two patients have been enrolled onto this trial with a minimum of 40 weeks follow-up . Of 18 patients with measurable soft tissue disease , three demonstrated a complete response ( CR ) and six a partial response ( PR ) for longer than 2 months . Of these 18 patients , pretreatment prostate-specific antigen ( PSA ) levels decreased by at least 75 % in five men ( 28 % ) and by at least 50 % in nine ( 50 % ) . The median survival duration has not been reached in those patients who demonstrated a response either by soft tissue or PSA criteria . Of 24 patients with disease limited to bone , six ( 25 % ) demonstrated improvement and nine ( 38 % ) demonstrated stability in their bone scans . Five men ( 21 % ) demonstrated a decrease of at least 75 % in pretreatment PSA levels and 14 ( 58 % ) demonstrated at least a 50 % decrease ; the median survival duration has not been reached in these patients . Pretreatment performance status is an important predictor of survival . CONCLUSION We conclude that the combination of estramustine and VP-16 is an active oral regimen in hormone-refractory prostate cancer [7656906] The effect of a medroxyprogesterone acetate ( MPA ) plus epirubicin combination versus estramustine phosphate was evaluated in 149 prospect ively r and omized patients with hormone-resistant prostatic cancer . The estimated probability of being free from progression after 1 year was 17 % for the patients treated with estramustine and 29 % for the MPA-epirubicin group . There is a significant difference between the two groups regarding risk of progression ( p = 0.013 ) . However , no difference in survival was recorded ( p > 0.30 ) with about 60 % of the patients dead during the first year in both groups . Progression was highly correlated to sedimentation rate ( p < 0.001 ) and to performance index ( p = 0.002 ) . Heart failure occurred in a substantial number of patients in both groups which must be considered before starting therapy [6338251] Single and combination chemotherapy was compared in a clinical trial for men with advanced , metastatic prostate cancer who had received prior pelvic irradiation and had had progression of disease despite hormonal therapy . The 149 patients were r and omized to receive estramustine phosphate or cis-platinum alone or in combination . Of the 149 patients 25 ( 17 per cent ) were excluded from the study but 124 were evaluated for response and survival . Entry variables were distributed similarly among patients in each treatment arm . There were no complete or partial responders but there were nearly twice as many patients whose disease was stabilized ( 33 per cent ) on the combination regimen compared to estramustine phosphate ( 18 per cent ) and about a third more than for cis-platinum ( 21 per cent ) . Analysis of survival revealed some advantage for patients on combination therapy . Major toxicities for all treatments were nausea and vomiting ( 62 to 88 per cent ) and accompanying anorexia ( 72 to 95 per cent ) . Azotemia developed in 45 per cent of the patients receiving combination therapy . In addition an elevation in serum creatinine occurred in 22 per cent of the patients receiving combination therapy and in 17 per cent of those receiving cis-platinum alone . Myelosuppression occurred infrequently [15470214] BACKGROUND Mitoxantrone-based chemotherapy palliates pain without extending survival in men with progressive and rogen-independent prostate cancer . We compared docetaxel plus estramustine with mitoxantrone plus prednisone in men with metastatic , hormone-independent prostate cancer . METHODS We r and omly assigned 770 men to one of two treatments , each given in 21-day cycles : 280 mg of estramustine three times daily on days 1 through 5 , 60 mg of docetaxel per square meter of body-surface area on day 2 , and 60 mg of dexamethasone in three divided doses before docetaxel , or 12 mg of mitoxantrone per square meter on day 1 plus 5 mg of prednisone twice daily . The primary end point was overall survival ; secondary end points were progression-free survival , objective response rates , and post-treatment declines of at least 50 percent in serum prostate-specific antigen ( PSA ) levels . RESULTS Of 674 eligible patients , 338 were assigned to receive docetaxel and estramustine and 336 to receive mitoxantrone and prednisone . In an intention-to-treat analysis , the median overall survival was longer in the group given docetaxel and estramustine than in the group given mitoxantrone and prednisone ( 17.5 months vs. 15.6 months , P=0.02 by the log-rank test ) , and the corresponding hazard ratio for death was 0.80 ( 95 percent confidence interval , 0.67 to 0.97 ) . The median time to progression was 6.3 months in the group given docetaxel and estramustine and 3.2 months in the group given mitoxantrone and prednisone ( P<0.001 by the log-rank test ) . PSA declines of at least 50 percent occurred in 50 percent and 27 percent of patients , respectively ( P<0.001 ) , and objective tumor responses were observed in 17 percent and 11 percent of patients with bidimensionally measurable disease , respectively ( P=0.30 ) . Grade 3 or 4 neutropenic fevers ( P=0.01 ) , nausea and vomiting ( P<0.001 ) , and cardiovascular events ( P=0.001 ) were more common among patients receiving docetaxel and estramustine than among those receiving mitoxantrone and prednisone . Pain relief was similar in both groups . CONCLUSIONS The improvement in median survival of nearly two months with docetaxel and estramustine , as compared with mitoxantrone and prednisone , provides support for this approach in men with metastatic , and rogen-independent prostate cancer [6346476] Cisobitan , an organosilicon compound with estrogenic and antigonadotropic properties has been evaluated clinical ly in comparison with an estrogen preparation . In a multicenter study a total of 140 patients with well and moderately well differentiated prostatic cancer were r and omly allocated to treatment with Cisobitan or Estradurin/Etivex , 70 to each group . Of 34 patients with poorly differentiated prostatic cancer 18 were given Cisobitan-- and 16 were given Estracyt-treatment . Among the patients with well and moderately well differentiated prostatic cancer there were , disregarding mortality , no major differences in subjective , objective or laboratory response to the two kinds of treatment . The pattern of side effects was similar , but oedema requiring diuretics occurred more often in the estrogen treated group . There was a significant difference in mortality at 12 months between the groups , two in the Cisobitan group and ten in the estrogen treated group . Cancer was the cause of death in two patients in the estrogen treated group . All other patients succumbed in cardiovascular diseases . At 24 months the difference in mortality rate was less pronounced : Another ten patients had died in the Cisobitan treated group and seven among the estrogen treated patients . Cancer was responsible for the deaths in seven of the Cisobitan patients compared to four of the estrogen treated patients . Within three years one more patient in both groups had died . Of the 34 patients with poorly differentiated cancer , twelve were alive at the 24 months ' follow up , six in the Cisobitan group and six in the Estracyt group [9358213] OBJECTIVES Results of cytotoxic chemotherapy for hormone-resistant prostate cancer are not impressive . One of the substances which seems to have a therapeutic benefit is 5-fluorouracil ( 5-FU ) . The effect of 5-FU can be modulated by addition of folinic acid ( FA ) . We tested in a prospect i ve , r and omized phase II trial monotherapy with 5-FU versus the combination of 5-FU and high-dose FA . METHODS 25 patients received 600 mg/m2 5-FU , and 24 patients 400 mg/m2 FA plus 600 or 400 mg/m2 5-FU . They were treated for two cycles for 5 days in a 21-day interval followed by a weekly single-day application until progression occurred . Pain remission , toxicity , time to progression and survival were evaluated . RESULTS Both regimens led to a pain remission in nearly 70 % of the patients . Mucosal side effects like diarrhea and stomatitis occurred more often in the combination arm , whereas leukopenias were more frequent in the monotherapy are . We observed no statistically significant difference between the two treatment arms regarding time to progression and survival . CONCLUSIONS Although both regimens led to a pain remission , side effects are too severe to recommend these protocol s for st and ard treatment of hormone-resistant prostate cancer [142845] Abstract In this second nationally r and omized cooperative chemotherapy trial of the National Prostatic Cancer Project 125 patients with histologically confirmed progressing advanced carcinoma of the prostate ( clinical stage D ) who had had prior pelvic irradiation of at least 2,000R received as initial therapy 1 of 2 non-myelosuppressive agents — estramustine phosphate or streptozotocin — for comparison with patients r and omized to receive st and ard treatment . Patients whose disease was progressive after 12 weeks on chemotherapy were crossed over to receive the alternate therapeutic agent . Response to treatment was evaluated in 105 patients on the basis of previously established and defined criteria .All known prognostic factors were comparable among the 3 treatment arms . The objective response rates to therapy were 19 per cent in the st and ard arm ( stable only ) , 30 per cent in the estramustine phosphate arm ( stable and partial regression ) and 32 per cent in the streptozotocin arm ( stable arm ) . Thus far , 4 patients [1615614] One hundred eleven patients with endocrine-refractory Stage D prostate cancer were treated with weekly administration of 20 mg/m2 body surface area of doxorubicin hydrochloride ( Adriamycin ) . Fifty-seven were part of a r and omized study comparing doxorubicin and prednisone to prednisone alone . There were significantly more subjective responders in the doxorubicin group than in the prednisone group ( p less than 0.01 ) . The number of patients with evidence of stable disease was also higher during the chemotherapy arm compared with prednisone alone ( p = 0.02 ) . Patients taking doxorubicin had a slightly longer period of stable disease than did those taking prednisone ( p = 0.08 ) . Overall survival , however , was not prolonged ( p = 0.26 ) . Fifty-four patients took part in an open trial and 69 percent responded to treatment . All of these had clinical improvement . Side effects were minimal with cardiotoxicity noted in less than 15 percent among patients with side effects . Over 35 percent had no side effects . Thus single agent , weekly doxorubicin therapy as evaluated in our experience , while well tolerated and of subjective benefit , does not provide the patient with a significant longer progression-free survival or improved overall survival [2201425] The results of a r and omized , multicenter , cooperative group trial evaluating hormonal therapy with either megestrol acetate or dexamethasone in advanced , hormonally refractory prostate cancer are reported . Three of 29 patients ( ∼10 % ) on the megestrol acetate arm experienced an objective response lasting 41 , 84 , and 202 days , respectively , whereas two of 29 patients ( ∼7 % ) on the dexamethasone arm achieved an objective response lasting 359 and 512 days , respectively . Twenty of 29 patients ( ∼69 % ) on the megestrol acetate arm had stable disease lasting for a median duration of 117 days , whereas 21 of 29 patients ( 72 % ) on the dexamethasone arm had stable disease for a median duration of 86 days . Median survival of all patients was 9 months from initiation of treatment . The median survival for patients on the megestrol acetate arm was 268 days compared to 246 days for patients on the dexamethasone arm ( P = 0.2 ) . Neither dexamethasone nor megestrol acetate would seem to be of substantive value in altering the progression of advanced , hormonally refractory prostate cancer [10550143] PURPOSE Prostate-specific antigen ( PSA ) is a glycoprotein that is found almost exclusively in normal and neoplastic prostate cells . For patients with metastatic disease , changes in PSA will often ante date changes in bone scan . Furthermore , many but not all investigators have observed an association between a decline in PSA levels of 50 % or greater and survival . Since the majority of phase II clinical trials for patients with and rogen-independent prostate cancer ( AIPC ) have used PSA as a marker , we believed it was important for investigators to agree on definitions and values for a minimum set of parameters for eligibility and PSA declines and to develop a common approach to outcome analysis and reporting . We held a consensus conference with 26 leading investigators in the field of AIPC to define these parameters . RESULT We defined four patient groups : ( 1 ) progressive measurable disease , ( 2 ) progressive bone metastasis , ( 3 ) stable metastases and a rising PSA , and ( 4 ) rising PSA and no other evidence of metastatic disease . The purpose of determining the number of patients whose PSA level drops in a phase II trial of AIPC is to guide the selection of agents for further testing and phase III trials . We propose that investigators report at a minimum a PSA decline of at least 50 % and this must be confirmed by a second PSA value 4 or more weeks later . Patients may not demonstrate clinical or radiographic evidence of disease progression during this time period . Some investigators may want to report additional measures of PSA changes ( ie , 75 % decline , 90 % decline ) . Response duration and the time to PSA progression may also be important clinical end point . CONCLUSION Through this consensus conference , we believe we have developed practical guidelines for using PSA as a measurement of outcome . Furthermore , the use of common st and ards is important as we determine which agents should progress to r and omized trials which will use survival as an end point [1968505] This r and omised phase II study was performed in order to evaluate the effectiveness of a weekly chemotherapy regimen in advanced prostatic carcinoma patients ( stage D2 ) refractory to hormonal therapy . Seventy-two cases were studied : they were r and omised in a 2:1 ratio to receive either epirubicin ( 30 mg m-2 weekly ) or doxorubicin ( 25 mg m-2 weekly ) ; 48 patients received epirubicin and 24 received doxorubicin . After 12 courses of chemotherapy , the 45 evaluable patients in the epirubicin arm showed a response rate of 37.7 % and the 21 evaluable patients in the doxorubicin arm showed a response rate of 33.3 % ( P = 0.51 ) . Pain intensity , bone and prostatic tumour markers rapidly and significantly decreased in responders . An improvement in physical symptoms , functional conditions and in emotional well-being was observed in the majority of the treated patients . The histological analysis of bone metastases , performed before and after 12 courses of chemotherapy showed a significant reduction in neoplastic invasion and in new bone formation in responders . Cardiac performance worsened in five out of 45 patients and in ten out of 21 during the first 12 courses of epirubicin or doxorubicin respectively ( P = 0.014 ) . The median survival was 12.5 months in the epirubicin arm and 8.0 months in the doxorubicin arm ( P = 0.042 ) . Our data indicate that in advanced prostatic carcinoma , a weekly epirubicin regimen may give rapid palliative results , similar to that of doxorubicin , but with less side-effects [12610188] PURPOSE Several multicomponent regimens have been reported to be useful in advanced and rogen-independent prostate cancer . We used a r and omized phase II design to evaluate and compare two such regimens . Patients were accrued primarily in the community setting . PATIENTS AND METHODS Patients with progressive , and rogen-independent prostate cancer were r and omly assigned to one of two treatments : either ketoconazole/doxorubicin alternating with vinblastine/estramustine ( KA/VE ) or paclitaxel , estramustine , and oral etoposide ( TEE ) . Patients were prospect ively stratified on the basis of disease volume . The primary end points were response and overall survival time . RESULTS A total of 75 patients were registered ; 71 are included in the analysis . By the criterion of an 80 % prostate-specific antigen reduction maintained for at least 8 weeks , 11 ( 30 % ) of 37 patients in the TEE arm responded , whereas 11 ( 32 % ) of 34 assigned to KA/VE responded . Median survival was 16.9 months ( 95 % confidence interval [ CI ] , 10.5 to 21.2 months ) in the TEE arm and 23.4 months ( 95 % CI , 12.9 to 30.6 months ) for patients treated with KA/VE . Many patients ( 24 % ) failed to complete at least 6 weeks of therapy , including five ( 8 % ) treatment-related early deaths . CONCLUSION Each of these regimens produced clinical ly significant responses , and the observed median survival ( 18.9 months for all 71 patients ) compares favorably with previously published results , especially in the community setting . Nonetheless , it is apparent that these first-generation regimens must be applied judiciously , and thus we view efforts at better patient selection and the development of more tolerable therapies as higher priorities than carrying either of these regimens to phase III evaluation in the cooperative group setting [3904132] Summary Ninety-five patients with prostatic carcinoma , stages A-D and of all histological grade s were r and omized between a continuous and an intermittent treatment regimen of EstracytR ( estramustine phosphate ) . 77 patients were evaluated ( 46 with continuous and 31 with intermittent therapy ) . Remissions were seen in 13 ( 28 % ) and ( 13 % ) , respectively . Stable disease was recorded in 30 ( 65 % ) and 24 ( 77 % ) , respectively . Progression experienced 3 ( 6 % ) and 3 ( 10 % ) respectively . 19 % were unable to continue therapy due to intolerable gastrointestinal side effects ( 7 patients receiving continuous and 8 patients receiving intermittent therapy ) [2228066] Fifty-seven patients with advanced prostate cancer resistant to first-line hormonal therapy were treated with estramustine and additionally r and omized for treatment with clodronate or placebo . Clodronate treatment was started with 5 days intravenous administration ( 300 mg day[-1 ] ) and followed by oral treatment ( 1.6 g day[-1 ] ) for 12 months . Skeletal pain relief was only about 10 % better in the clodronate than in the placebo group . The results do not support the superiority of combined intravenous and oral treatment with clodronate compared with oral administration only [10765092] Objectives : To compare the quality of life ( QL ) of patients with poor prognosis M1 prostate cancer treated with orchiectomy alone ( ORCH ) or orchiectomy combined with adjuvant mitomycin C ( MMC ; 15 mg/m2 i.v . q 6 weeks : ORCH+MMC ; EORTC trial 30893 ) . Methods : Patients with newly diagnosed M1 poor prognosis prostate cancer completed a truncated version of the EORTC QLQ – C30 ( V 1.0 ) at r and omization ( baseline ) and every 6–12 weeks thereafter until going off the protocol . Five ad hoc questions assessing lower urinary tract symptoms were included in the QL question naire . Results : At least one QL form was completed by 177 of the 189 patients included in the trial , with baseline question naires available for 113 patients ( ORCH n = 52 ; ORCH+MMC n = 61 ) . In both arms , pain and urinary dysfunction improved during treatment . Compared with patients from the ORCH arm , the use of adjuvant MMC was associated with a significant reduction in global health status/QL and with impairment in 7 of 11 QL dimensions covered by the question naire . Some improvement in QL was observed after discontinuation of MMC . A survival benefit was not observed in the ORCH+MMC arm . Conclusions : Intravenous MMC ( 15 mg/m2 q 6 weeks ) can not be recommended as adjuvant treatment in M1 poor prognosis prostate cancer due to its negative impact on QL and lack of efficacy . In general , QL assessment s should be m and atory when adjuvant chemotherapy is evaluated in patients with metastatic prostate cancer [14751362] OBJECTIVES To evaluate prospect ively the combination of a luteinizing hormone-releasing hormone analog with a somatostatin analog and dexamethasone in patients with hormone-refractory prostate cancer ( HRPC ) in a r and omized Phase II study . HRPC presents a challenging therapeutic problem . Salvage chemotherapy is the usual approach at this stage of the disease . The combination of a luteinizing hormone-releasing hormone analog with a somatostatin analog and dexamethasone has produced objective clinical responses in HRPC . METHODS Forty patients with HRPC were r and omized to receive one of two treatments . Group 1 underwent chemotherapy ( estramustine 140 mg three times daily and etoposide 100 mg orally for 21 days ) and group 2 the combination of a somatostatin analog ( lanreotide 30 mg intramuscularly every 14 days ) and dexamethasone ( 4 mg tapered to 1 mg ) , in addition to and rogen ablation by orchiectomy or a luteinizing hormone-releasing hormone analog ( triptorelin 3.75 mg intramuscularly every 28 days ) . The clinical and prostate-specific antigen ( PSA ) response , overall survival , time to progression , and toxicity were compared between the two groups . RESULTS The data of 20 patients in group 1 and 18 in group 2 were analyzed . The demographic and clinical data were similar in the two groups at study entry . A PSA response ( decrease of greater than 50 % ) was observed in 45 % of group 1 and 44 % of group 2 . The difference was not statistically significant . A partial clinical response was observed in 29 % and 30 % of groups 1 and 2 , respectively . Again , the difference was not statistically significant . Changes in performance status and pain score during treatment were not significantly different in the two groups . Hematologic toxicity was more frequent in group 1 ( 80 % of patients ) , and mild diabetes was more frequent in group 2 ( 22 % of patients ) . The overall survival was 18.8 months in group 1 and 18 months in group 2 ( not statistically significant ) . The time to progression was 6 versus 4 months and , in the PSA responder subgroup , it was 8 versus 7.7 months in groups 1 and 2 , respectively ( neither difference was statistically significant ) . CONCLUSIONS The results of our r and omized Phase II study indicated that the new combination treatment ( luteinizing hormone-releasing hormone analog , somatostatin analog , and dexamethasone ) may be equally effective as salvage chemotherapy in patients with HRPC in terms of the clinical and PSA response , overall survival , and time to progression . A larger prospect i ve Phase III trial is required to confirm our observations [6343629] In this clinical trial of men with advanced prostatic cancer no longer responsive to hormone therapy 189 were r and omized to receive estramustine phosphate , methotrexate or cis-platinum . Response evaluations were done in 158 cases . Objective response rates ( complete , partial or stabilization of disease ) were 34 per cent for estramustine phosphate , 36 per cent for cis-platinum and 41 per cent for methotrexate . Subjective parameters indicated a substantial advantage for pain improvement with methotrexate or cis-platinum over estramustine phosphate . Probabilities of continued response indicated some advantage for methotrexate and median response duration s at this time were twice as long for methotrexate ( 32 weeks ) as for cis-platinum ( 16 weeks ) , with estramustine phosphate intermediate ( 23 weeks ) . Survival rates for the original treatment r and omization groups were not different at this time . Side effects of estramustine phosphate consisted primarily of nausea and vomiting and /or anorexia but to a lesser extent than with cis-platinum . These effects were somewhat less for methotrexate , for which the major side effects were stomatitis and leukopenia , as well as hepatic toxicity reflected by elevated serum glutamic oxaloacetic transaminase levels . Other side effects of cis-platinum were less than for methotrexate ( no stomatitis ) , except for signs of renal toxicity ( elevations in blood urea nitrogen and serum creatinine ) , which were greater . Methotrexate had a relatively high level of activity against metastatic , progressive , hormone nonresponsive prostatic cancer , with side effects that were substantial but manageable [2148830] A prospect i ve r and omized study has been carried out in order to compare three different treatment modalities for symptomatic metastatic hormone-resistant prostatic cancer . A total of 79 patients were included . One group was treated with estramustine phosphate , another with Epirubicin plus Medroxyprogesterone acetate ( MPA ) , while the third arm consisted of Epirubicin plus placebo . Best palliation was obtained by the combination of Epirubicin and MPA . This combination also seemed to be associated with the longest response duration [15226321] PURPOSE Both docetaxel and thalidomide have demonstrated activity in and rogen-independent prostate cancer ( AIPC ) . We compared the efficacy of docetaxel to docetaxel plus thalidomide in patients with AIPC . METHODS Seventy-five patients with chemotherapy-naïve metastatic AIPC were r and omly assigned to receive either docetaxel 30 mg/m(2 ) intravenously every week for 3 consecutive weeks , followed by a 1-week rest period ( n = 25 ) ; or docetaxel at the same dose and schedule , plus thalidomide 200 mg orally each day ( n = 50 ) . Prostate-specific antigen ( PSA ) consensus criteria and radiographic scans were used to determine the proportion of patients with a PSA decline , and time to progression . RESULTS After a median potential follow-up time of 26.4 months , the proportion of patients with a greater than 50 % decline in PSA was higher in the docetaxel/thalidomide group ( 53 % in the combined group , 37 % in docetaxel-alone arm ) . The median progression-free survival in the docetaxel group was 3.7 months and 5.9 months in the combined group ( P = .32 ) . At 18 months , overall survival in the docetaxel group was 42.9 % and 68.2 % in the combined group . Toxicities in both groups were manageable after administration of prophylactic low-molecular-weight heparin in the combination group . CONCLUSION In this r and omized phase II trial , the addition of thalidomide to docetaxel result ed in an encouraging PSA decline rate and overall median survival rate in patients with metastatic AIPC . After the prophylactic low-molecular-weight heparin was instituted to prevent venous thromboses , the combination regimen was well tolerated . Larger r and omized trials are warranted to assess the impact of this combination [11256836] OBJECTIVE This prospect i ve and r and omized clinical study was initiated to compare the efficacy and safety of combined and rogen blockade with combination with UFT in patients with untreated prostate cancer . METHODS A total of 142 patients were entered in this study between April 1990 and December 1992 . All patients received bilateral orchiectomy and 200 mg/day of diethylstilbestrol diphosphate . Of these patients , 70 patients were administered an additional 400 mg/day of UFT after r and omization . Either treatment was continued for at least 1 year or until objective progression occurred if the initial response was equal to or better than no change . The endpoints of this study were progression-free survival , cancer-specific survival and change of QOL scores . RESULTS A total of 136 patients were evaluable and 131 patients ( 96.3 % ) could be followed up with a median follow-up period of 1469 days . Both groups showed similar initial treatment response at 12 weeks , adverse effect and change of quality of life score during the first year after initiation of the treatment . There was a significantly longer progression-free survival and better but not significant cancer-specific survival in the endocrine chemotherapy group . The patients with earlier stage and initial serum prostate-specific antigen values < 40 ng/ml showed a good indication for this endocrine chemotherapy . CONCLUSION This endocrine chemotherapy was confirmed to be tolerable and significantly effective in the delay of disease progression , which leads to longer survival in patients with prostate cancer [3534315] A total of 67 patients with progressive stage D2 prostatic cancer refractory to orchiectomy was entered in a controlled clinical trial to test whether and rogen priming enhances the efficacy of cytotoxic drugs . All patients were treated continuously with aminoglutethimide and hydrocortisone to lower adrenal and rogen secretion and were given cyclic intravenous chemotherapy . In addition , the 34 patients r and omized to the stimulation arm received fluoxymesterone for 3 days before and on the day of chemotherapy . There was 33 controls . The median duration of followup was 24 months . A modestly higher response rate ( objective remission plus disease stabilization ) was observed in the stimulation arm ( 85 versus 72 per cent , p less than 0.05 ) when the analysis was restricted to the evaluable patients . However , a larger fraction of unevaluable patients was present in the stimulation group ( 41 versus 16 per cent ) , mostly as a result of toxicity from fluoxymesterone , which prompted early discontinuation of treatment . Thus , when data analysis included all patients the response rate actually was slightly higher in the control than in the stimulation arm ( 60 versus 50 per cent , p not significant ) . No difference was observed in median duration of response ( 9 months in both groups ) or over-all survival . Our data suggest that at least in those patients with advanced disease and rogen priming does not seem to enhance significantly the antitumor effect of the combination of amino-glutethimide and chemotherapy , and is associated with significant toxicity . These largely negative results may be explained by the large number of hormone-resistant cells present in tumors that have become refractory to orchiectomy [11069375] Objective To assess the role of mitozantrone , active in relapsed prostate cancer , as an adjuvant to hormonal treatment in patients with advanced prostate cancer [14747052] Despite improvements in early detection of prostate cancer when it is clinical ly localized-- and therefore most amenable to curative local therapies-- approximately 33 % of men with early prostate cancer will develop biochemical failure with a rising prostate-specific antigen ( PSA ) during follow-up . The early use of and rogen suppression in this group of men has changed the clinical picture of and rogen-independent disease . Now , there are men on and rogen suppression who will develop biochemical failure and remain free of clinical or radiographic evidence of metastatic disease for a period of time . There is no st and ard approach to this group of men , who have a rising PSA on and rogen deprivation , because there are little or no data about strategies that may improve survival , delay time to progression , or improve quality of life . Therefore , current management of this population remains controversial . In an effort to determine which of these 2 approaches -- second-line hormone therapy or chemotherapy -- is optimal in delaying the time to progression , the Eastern Cooperative Oncology Group ( ECOG ) developed protocol E1899 . Although both approaches offer the potential for response ( reduction in PSA and prolonging the time to clinical progression ) , they have very different toxicity profiles , making impact on quality of life another important end point . This r and omized trial evaluating second-line hormonal therapy using ketoconazole and hydrocortisone versus docetaxel and estramustine combination chemotherapy on progression-free survival in asymptomatic men with a rising PSA on and rogen ablation for prostate cancer is the subject of this article [12947070] PURPOSE To compare the incidence of palliative response in patients with hormone-resistant prostate cancer ( HRPC ) treated with mitoxantrone and prednisone ( MP ) plus clodronate with that of patients treated with MP plus placebo . MATERIAL S AND METHODS Men with HRPC , bone metastases , and bone pain were r and omly assigned to receive clodronate 1,500 mg administered intravenously ( IV ) or placebo every 3 weeks , in combination with mitoxantrone 12 mg/m2 IV every 3 weeks and prednisone 5 mg orally bid . Patients completed the present pain intensity ( PPI ) index and Prostate Cancer-Specific Quality -of-Life Instrument at each treatment visit and used a diary to record analgesic use on a daily basis . The primary end point was a reduction to zero or of two points in the PPI or a decrease of 50 % in analgesic intake , without increase in either . RESULTS The study accrued 209 eligible patients over 44 months . One hundred sixty patients ( 77 % ) had mild PPI scores ( 1 or 2 ) , and 49 ( 24 % ) had moderate PPI scores ( 3 or 4 ) . The primary end point of palliative response was achieved in 46 ( 46 % ) of 104 patients on the clodronate arm and in 41 ( 39 % ) of 105 patients on the placebo arm ( P = .54 ) . The median duration of response , symptomatic disease progression-free survival , overall survival , and overall quality of life were similar between the arms . Subgroup analysis suggested possible benefit in patients with more severe pain . CONCLUSION MP provides useful palliation in symptomatic men with HRPC . Clodronate does not increase the rate of palliative response or overall quality of life . Clodronate may be beneficial to patients who have moderate pain , but this requires further confirmation [15470213] BACKGROUND Mitoxantrone plus prednisone reduces pain and improves the quality of life in men with advanced , hormone-refractory prostate cancer , but it does not improve survival . We compared such treatment with docetaxel plus prednisone in men with this disease . METHODS From March 2000 through June 2002 , 1006 men with metastatic hormone-refractory prostate cancer received 5 mg of prednisone twice daily and were r and omly assigned to receive 12 mg of mitoxantrone per square meter of body-surface area every three weeks , 75 mg of docetaxel per square meter every three weeks , or 30 mg of docetaxel per square meter weekly for five of every six weeks . The primary end point was overall survival . Secondary end points were pain , prostate-specific antigen ( PSA ) levels , and the quality of life . All statistical comparisons were against mitoxantrone . RESULTS As compared with the men in the mitoxantrone group , men in the group given docetaxel every three weeks had a hazard ratio for death of 0.76 ( 95 percent confidence interval , 0.62 to 0.94 ; P=0.009 by the stratified log-rank test ) and those given weekly docetaxel had a hazard ratio for death of 0.91 ( 95 percent confidence interval , 0.75 to 1.11 ; P=0.36 ) . The median survival was 16.5 months in the mitoxantrone group , 18.9 months in the group given docetaxel every 3 weeks , and 17.4 months in the group given weekly docetaxel . Among these three groups , 32 percent , 45 percent , and 48 percent of men , respectively , had at least a 50 percent decrease in the serum PSA level ( P<0.001 for both comparisons with mitoxantrone ) ; 22 percent , 35 percent ( P=0.01 ) , and 31 percent ( P=0.08 ) had predefined reductions in pain ; and 13 percent , 22 percent ( P=0.009 ) , and 23 percent ( P=0.005 ) had improvements in the quality of life . Adverse events were also more common in the groups that received docetaxel . CONCLUSIONS When given with prednisone , treatment with docetaxel every three weeks led to superior survival and improved rates of response in terms of pain , serum PSA level , and quality of life , as compared with mitoxantrone plus prednisone [2213104] Cytotoxic chemotherapy has not provided survival benefit in metastatic prostate cancer , although it has been used most frequently in patients with far-advanced , refractory disease . To evaluate the effects of chemotherapy given earlier in the course of the disease , the Southwest Oncology Group ( SWOG ) performed a r and omized trial between September 1982 and October 1986 comparing endocrine therapy ( diethylstilbestrol [ DES ] or orchiectomy ) alone followed by cyclophosphamide-Adriamycin ( doxorubicin ; Adria Laboratories , Columbus , OH ) chemotherapy at progression versus initial combined chemo-endocrine therapy . One hundred forty-three patients were registered , and only six were declared ineligible . Patients on the combined chemo-endocrine therapy arm had a slightly higher response rate ( 63 % ) compared with endocrine therapy alone ( 48 % ) . A log-linear model of tumor response and treatment arm adjusted for the stratification factors favored the combination arm ( P = .059 ) . Only three of 27 patients on the endocrine therapy alone arm had an objective partial response when crossed over to chemotherapy , while two others had stable disease . Despite the difference in initial response rate , time to treatment failure and survival were identical in the two treatment arms . Seventy-seven percent of patients on the initial endocrine therapy alone arm have died ( median survival , 25.6 months ) compared with 78 % on the chemo-endocrine therapy arm ( median survival , 22.0 months ) . No significant effect of treatment on survival was observed even after adjustment for the stratification variables in a Cox regression model . Exploratory survival analyses with patients on both arms combined did show a marginally significant time to treatment failure and survival advantage for patients treated with DES rather than orchiectomy as initial endocrine therapy . Eighty-six percent of patients treated by orchiectomy have died compared with only 65 % of those treated with DES . These data do not support the addition of cytotoxic chemotherapy to initial endocrine therapy in patients with metastatic prostate cancer [7194733] Thirty‐two evaluable patients with metastatic carcinoma of the prostate were entered into a prospect i ve r and omized trial comparing cyclophosphamide ( CYC ) with a combination of cyclophosphamide , methotrexate , and fluorouracil ( CMF ) . Progressive disease after endocrine manipulation was noted in 97 % ( 31/32 ) of patients before entry . Stable disease ( S ) was observed in 9 of 17 patients treated with CYC . One partial response ( PR ) and seven stable responses occurred in the 15 CMF patients . Median duration of stable response was 4.5 months for CYC and 4.5 months on CMF . Median survival of patients with PR and S receiving CYC was 10.1 and for CMF 8.8 months . Patients with progressive disease survived a median 1.7 and 2.6 months with CYC and CMF , respectively . Toxicity was moderate , and no deaths were attributable to sepsis or bleeding . Almost all patients in this study had bone lesions as the dominant site of disease ; this made objective assessment of response difficult . There was no significant improvement in response conferred by the combination regimen . Although patients with metastatic prostatic cancer may benefit from chemotherapy , impressive clinical responses are uncommon [10679652] Megestrol acetate ( MA ) is a synthetic progestin with reported activity in both hormone‐sensitive and hormone‐refractory prostate carcinoma ( HRPC ) . Based on limited data suggesting a possible dose‐response effect , a trial was initiated to compare st and ard versus moderately high dose MA in HRPC [7230336] There were 121 men with hormonally refractory metastatic cancer of the prostate who were r and omized to receive estramustine phosphate or vincristine , or the combination of these 2 agents . All patients had received prior radiation therapy ( greater than 2,000 rad ) . There were 90 patients who could be compared for response . The objective response rates ( partial regression or stabilization of disease ) for the 3 treatment groups were 26 per cent for estramustine phosphate , 24 per cent for estramustine phosphate plus vincristine and 15 per cent for vincristine . Subjective parameters varied little among the 3 regimens . The median duration of response for those responding to estramustine phosphate was similar ( 20 weeks ) to that for vincristine ( 22 weeks ) and greater than that for the combination ( 13 weeks ) . The probability of survival did not differ significantly for patients r and omized to each of the 3 regimens . The addition of vincristine to estramustine phosphate did not enhance the response rate achieved by estramustine phosphate alone and vincristine alone produced the lowest response rate . Estramustine phosphate continues to be the most active agent in previously irradiated patients with hormonally refractory metastatic cancer of the prostate [936381] A total of 125 patients with progressing advanced prostatic cancer were entered into a chemotherapy study comparing cyclophosphamide , 5-fluorouracil , and st and ard therapy . Parameters of response were studied in 110 patients who could be evaluated . Thirty-six patients ( 33 per cent ) were considered to have an objective response , that is becoming stable ( 29 patients ) or in partial regression ( 7 patients ) . Negative response parameters ( predictors of a poor response to chemotherapy or st and ard theraphy leading to progress ) included ( 1 ) bone marrow evidence of prostatic cancer , ( 2 ) abnormal liver scan , ( 3 ) prior radiation therapy ( indirectly through increased toxicity to chemotherapy ) , and ( 4 ) lack of bilateral orchiectomy prior to r and omization . Positive indicators ( predictors of good responses ) included ( 1 ) reduction of primary tumor mass , especially after administration of 5-fluorouracil or cyclophosphamide , and ( 2 ) hemoglobin values . There were more objective responders to cyclophosphamide than st and ard therapy whether the hemoglobin was initially normal or low . Indeterminate parameters of response included weight gain , presence of bony or soft tissue metastases , relief of pain , performance status , excretory urography , and biochemical determinations of liver and renal function [9165581] Between 1984 and 1989 , 197 patients with T1 - 4 , NX , M1 , G2 - 3 or G3 prostate cancer were r and omized to treatment with 560 mg estramustine phosphate ( EMP , Estracyt , Emcyt ) or 3 mg diethylstilbestrol ( DES ) per day in a double blind study with stratification on presence or absence of cancer pain at start . A total of 194 patients were evaluated for efficacy of therapy . Time to progression ( p = 0.054 ) , to treatment failure ( p = 0.036 ) , cancer-specific survival ( p = 0.068 ) as well as overall survival ( p = 0.021 ) were longer in the DES group . There were more patients with prognostic parameters indicating bad prognosis in the EMP group . This trial was design ed to study whether EMP had better effect than DES as the primary treatment of high- grade , disseminated prostate cancer . The results did not confirm this hypothesis . On the contrary , treatment with DES had relatively good effect on this very aggressive form of prostate cancer [2528705] Ninety-two patients with D2 prostatic cancer were studied . Initial treatment was with either diethylstilboestrol ( DES ) or orchidectomy . Response to DES ( 5/63 , 81 % ) was significantly higher than for orchidectomy ( 18/29 , 62 % ; p less than 0.01 ) . However , duration of response and duration of survival were not significantly different for the 2 forms of hormonal therapy . Fifty-seven patients were r and omised to receive second-line treatment with either medroxyprogesterone acetate ( MPA ) , oral chlorambucil or combination chemotherapy ( adriamycin + cyclophosphamide + 5-fluoro-uracil ) . Response to second-line treatment was similar for all 3 regimens ( 46 % overall response ) . Most of the responses were disease stabilisation and , although there was symptomatic benefit , response to second-line therapy did not significantly improve survival compared to the survival experience of the group as a whole . It is concluded that palliative second-line treatment for advanced prostatic cancer should consist of the least toxic form of treatment which in this study was second-line hormone administration ( MPA ) [1540881] One hundred forty‐two patients with progressive , hormonally refractory advanced prostate carcinoma who had not received prior chemotherapy were r and omized to receive either combination chemotherapy with 5‐fluo‐rouracil ( 5‐FU ) , doxorubicin , and mitomycin C ( FAM ) or sequential chemotherapy with the same agents , i.e. , mitomycin C , followed by doxorubicin on disease progression , followed by 5‐FU . Objective tumor regressions were observed in 10 of 70 ( 14 % ) patients receiving the FAM treatment arm and 10 of 72 ( 14 % ) patients initially receiving mitomycin C. Of the 24 patients who received secondary therapy with doxorubicin alone , 3 ( 12.5 % ) achieved objective tumor regression . There were no responses among five patients who received tertiary therapy with 5‐FU alone . The median survival time for all patients treated with the combination arm was 8.7 months , compared with 7.1 months for patients who received the FAM arm ( P = 0.025 ) . However , this modes ! survival advantage in favor of the FAM treatment arm must be weighed against significantly more myelosuppression experienced by these patients . The chemotherapeutic regimens used in this study have only minor clinical value in the treatment of hormonally refractory advanced prostate cancer . Cancer 1992 ; 69:1440‐1444 [2462651] The present study was design ed to investigate the efficacy of various combinations of chemotherapeutic agents in the treatment of prostatic cancer in a group refractory to anti and rogenic therapy ( Group 1 ) and in a previous untreated group ( Group 2 ) . Therapeutic combinations of Estracyt ( E ) + Peplomycin ( P ) + Doxorubicin ( Do ) and P + Do + 5 FU ( F ) in Group 1 and E + P , Honvan ( Ds ) + P and E in Group 2 were carried out . The main objectives of this study were estimations of the efficacy of E and P in relation to the refractory cases of Group 1 and the efficacy of the combination E + P , in Group 2 . This is the first such prospect i ve , r and omized , controlled study to be carried out in Japan in relation to prostatic cancer . The results obtained in the present study indicated that chemotherapeutic regimens including E provide some enhanced efficacy , but that the efficacy with regard to refractory cases is poor ( 23.1 - 27.3 % ) , as has been reported of studies conducted in the USA and Europe . With regard to previously untreated cases , the E + P regimen achieved a relatively higher response rate than the other treatments ( 72.7 vs 44.5 or 50.0 % ) . In the comparison of survival times and survival curves , there were no statistically significant differences among the various treatment subgroups . A comparison of survival curves revealed the interesting finding that the PAP-related response showed a clear correlation to the survival curves of Group 2 patients [141326] In the 36 months since its inception , the National Prostatic Cancer Project treatment subgroup has r and omly assigned over 360 patients with progressive advanced prostatic cancer who were no longer responsive to endocrine manipulation to either one of four different clinical studies . The initial study demonstrated a clear superiority for 5-fluorouracil ( 5-FU ) and cyclophosphamide over continued conventional therapy . Beneficial responses were documented and are associated with increased survival rates and relief from pain and other symptoms . A proportionately larger number of patients obtained clinical benefit ( stable and partial regression ) on cyclophosphamide than on st and ard or 5-FU therapy . The criteria for evaluation of patients are supported by the survival data , ie , responders have survived for a longer period of time than those patients who continued in progression . Preliminary data from the subsequent protocol s have documented a 30 % response ( stable and partial regression ) in patients receiving oral estramustine phosphate and definite responses in patients treated with DTIC ; Too few patients have been treated with Leo 1031 to offer total response rates at this time , although the early results are promising . These clinical studies have firmly established a place for chemotherapy in the management of prostatic cancer . New trials will introduce single- and multiple-drug chemotherapy at earlier phases of the clinical course of prostatic cancer patients [11134196] PURPOSE Time to progression ( TTP ) , overall survival , and quality of life ( QL ) were compared in patients with hormone-resistant prostate cancer ( HRPC ) treated with prednisone ( 5 mg orally , four times a day ) or flutamide ( 250 mg orally , three times a day ) . PATIENTS AND METHODS Symptomatic patients were r and omized to receive either prednisone ( 101 patients ) or flutamide ( 100 patients ) . Subjective response was assessed based on performance status , the use of analgesics , and the need to apply alternative palliative treatment . Prostate-specific antigen (PSA)-based biochemical response ( > or= 50 % reduction of baseline PSA ) was recorded . At baseline and at 6-week intervals during follow-up , patients completed the European Organization for Research and Treatment of Cancer Quality of Life Question naire C-30 . RESULTS There was no difference between the groups in median TTP ( prednisone , 3.4 months ; flutamide , 2.3 months ) or overall survival ( prednisone , 10.6 months ; flutamide , 11.2 months ) . In the prednisone group , 56 % of the patients experienced a subjective response , compared with 45 % in the flutamide group ( P : = .18 ) . The median response duration was 4.8 months for prednisone and 4.2 months for flutamide . A biochemical response was observed in 21 % and 23 % of the prednisone and flutamide groups , respectively . Gastrointestinal toxicity was the reason for trial discontinuation in seven patients receiving flutamide and two patients receiving prednisone . The QL assessment parameters favored the use of prednisone with statistically significant differences in pain , fatigue , role functioning , appetite loss , gastrointestinal distress , and overall QL . CONCLUSION In symptomatic HRPC , treatment with prednisone or flutamide leads to similar rates of TTP and overall survival and no difference in subjective or biochemical response . The QL results favor the use of low-cost prednisone in patients with HRPC [1423178] Background . Between August 1984 and November 1989 , the Hoosier Oncology Group conducted a Phase III study comparing cyclophosphamide ( CTX ) with cyclophosphamide , doxorubicin , and methotrexate ( CAM ) in patients with hormone‐refractory metastatic prostatic cancer to determine whether the addition of doxorubicin and methotrexate to the cyclophosphamide regimen conferred any survival advantage [14747047] Currently , approximately 30,000 men die annually of metastatic , hormone-refractory prostate cancer . And rogen blockade is palliative and is generally effective for an average of 2 to 3 years until a patient develops and rogen-independent disease . Newer chemotherapeutic regimens can induce remissions in approximately 50 % of patients ; however , median survival for patients with and rogen-independent disease is still 8 to 12 months . The strategy of using chemotherapy regimens after and rogen blockade has been proved noncurative , and new approaches are needed to attempt to cure patients with advanced disease . It has been demonstrated in the pre clinical setting that and rogen withdrawal induces apoptosis in cancer cells in both the Shinogi breast cancer model and the LNCaP prostate cancer model . In both of these models , and rogen withdrawal was not curative , and the tumors grew back in a hormone-independent state . It is possible that the addition of chemotherapy at the time of initial and rogen ablation will improve cell kill by potentiating apoptosis , thereby killing cells that might otherwise have mutated to the and rogen-independent state if allowed to continue to cycle and grow . The rationale behind Radiation Therapy Oncology Group ( RTOG ) P-0014 is to demonstrate in a r and omized phase 3 trial that giving patients chemotherapy at the beginning of and rogen blockade may improve patient survival [1104900] The National Prostatic Cancer Project has r and omized this study for endocrine-resistant prostatic cancer patients for treatment with st and ard hormonal or other therapies compared to 5-fluorouracil and cyclophosphamide . Both agents were found at the probability level of 0.05 to have a significant advantage over st and ard treatment in terms of objective response , subjective improvement and minimal toxicity . Additional chemotherapy protocol s are currently under way . This r and omized trial is the first report of such a national study completed to date . We are much encouraged by this program and believe that additional agents now under consideration will provide additionally encouraging results [7017170] This is the fifth completed r and omized clinical trial of the National Prostatic Cancer Project . There were 125 patients with histologically confirmed relapsing clinical stage D prostatic cancer r and omized to receive hydroxyurea , methyl-chloroethyl-cyclohexy-nitrosourea or cyclophosphamide . All patients had received and failed previous hormonal therapy . Patients whose disease progressed after 12 weeks on the initial therapy were crossed over or r and omized to receive an alternate drug . There were 98 patients available for comparison of treatments . Objective responses included patients with complete or partial regression as well as stable disease . The response rates were 35 per cent for cyclophosphamide , 30 per cent for methyl-chloroethyl-cyclohexy-nitrosourea and 15 per cent for hydroxyurea . Subjective response parameters included improvement in performance status and relief of pain . Pain was improved in a fifth of the patients on each treatment area . Methyl-chloroethyl-cyclohexy-nitrosourea and hydroxyurea showed activity in advanced prostatic cancer patients but at the expense of excessive toxicity . Cyclophosphamide continues to be the most active single agent in this type of patient , particularly with regard to duration of response and survival . There was a statistically demonstrable advantage for cyclophosphamide over hydroxyurea and a marginal advantage over methyl-chloroethyl-cyclohexy-nitrosourea in survival experience [11344001] Eighty-nine patients with progressive prostate cancer despite suppression of testosterone and withdrawal of anti- and rogens were studied . This was a relatively advanced population , with 63 of 89 having either osseous metastases ( mets ) beyond the axial skeleton or visceral mets . Patients were r and omly assigned to receive either ketoconazole alone , or ketoconazole with weekly doxorubicin . All patients received replacement hydrocortisone . The primary endpoints were response and survival . Based on PSA reduction criteria ( > /= 80 % maintained for at least 8 weeks ) , 14 of 45 patients ( 31 % ) in the single-agent ketoconazole arm responded . Sixteen of 44 patients ( 36 % ) in the combination ketoconazole/doxorubicin arm responded . There were no important differences between the two treatments in any outcome measure . The median overall survival for all patients was 12.5 months ; median time to progression was 3.3 months . Toxicity was significant with both regimens , and more severe in the doxorubicin arm . Fully 20 % of patients in each arm discontinued therapy due to intolerable side effects . Each of these regimens is toxic , and produced responses in fewer than half of treated patients . Although the observed median survival does compare favorably with reports from similar cohorts treated in the community , the potential benefit is only modest . In our view , neither of these regimens is sufficiently promising to justify phase 3 evaluation [15774240] BACKGROUND Recent phase III studies in hormone refractory prostate cancer ( HRPC ) showed an improvement in terms of overall survival ( OS ) , objective response ( OR ) and biochemical response ( BR ) ; however , chemotherapy is usually accompanied by negative side effects that determines poor quality of life ( QoL ) and only marginally improves individual clinical response ( ICR ) in terms of pain relief and performance status . Ellagic acid is a polyphenol that is found in many species of flowering plants . It is an antioxidant that determines apoptosis , down regulation of IGF-II , activates p21 ( waf1/Cip1 ) , mediates the cumulative effect on G1/S transition phase and prevents destruction of p-53 gene by cancer cells . ENDPOINTS The aim of this study was to assess the effects of ellagic acid support therapy on toxicity , OR , ICR and BR in HRPC patients treated with estramustine phosphate and vinorelbine . MATERIAL S AND METHODS Patients with HRPC were r and omly distributed in two study groups : a control group ( group A ) who underwent chemotherapy with vinorelbine and estramustine phosphate , and an experimental group ( group B ) where chemotherapy regimen was associated with ellagic acid . RESULTS The mean number of chemotherapy cycles/patient was 4 ( range 3 - 8 cycles ) and 6.5 ( range 5 - 11 ) in group A and B patients , respectively . A reduction in systemic toxicity , statistically significant for neutropenia , associated with better results in term of OR rate , ICR , and BR were observed in group B compared with group A. On the contrary no significant difference in OS and PFS was detected between groups . CONCLUSIONS our study suggests that the use of ellagic acid as support therapy reduces chemotherapy induced toxicity , in particular neutropenia , in HRCP patients ; however , further studies are required to confirm our results [1831397] A series of 105 patients with metastatic prostatic cancer , having progressed on first-line hormonal treatment , were r and omised to high-dose medroxyprogesterone acetate ( MPA ) 1000 mg i.m . daily for 15 days , followed by 1000 mg weekly ( 53 patients ) , or to estramustine 280 mg per os twice daily ( 52 patients ) . The treatment was discontinued because of side effects in 3 of 51 evaluable MPA-treated patients and in 8 of 51 evaluable estramustine-treated patients . Progression-free survival was short in both groups and no statistically significant difference between them was observed . After 1 year , 70 % of the patients had died and there was no statistically significant difference between the 2 treatments in the cumulative observed survival rates . According to modified SPCG criteria , remissions lasting from 12 to 56 weeks were noted in 13 MPA-treated patients and in 4 estramustine-treated patients . This difference was statistically significant . After cross-over , 6 of 33 patients in the MPA group had a remission compared with 1 of 24 in the estramustine group . It was concluded that the response rate , considering both subjective and objective response criteria , was better with MPA and the side effects were fewer [6340081] In patients with metastatic hormone-relapsed adenocarcinoma of the prostate , adriamycin was compared to 5-fluorouracil in a r and omized trial in 99 patients and adriamycin alone was studied in an open trial in 48 patients . Response to adriamycin was superior as judged by response of measurable disease ( 25 vs 8 % ; P less than 0.05 ) and survival ( median 29 vs 24 weeks ; Cox analysis , P less than 0.03 ) , but comparable as judged by acid phosphatase response . Ambulatory status and site of metastases influenced rate of response to chemotherapy . Activity level , site of metastases , weight loss , and the symptom of protein aversion were prognostic factors for survival . Hematologic and gastrointestinal toxicity were frequent but were tolerated satisfactorily . Adriamycin therapy may be beneficial in patients with prostatic cancer after hormone therapy [10506613] PURPOSE To compare vinblastine versus the combination of vinblastine plus estramustine as treatment for patients with hormone-refractory prostate cancer ( HRPC ) . PATIENTS AND METHODS A total of 201 patients with metastatic prostate cancer , progressive after hormonal therapy and anti and rogen withdrawal ( if prior anti and rogen treatment ) , were r and omized to receive vinblastine ( V ) 4 mg/m(2 ) by intravenous bolus weekly for 6 weeks followed by 2 weeks off , either alone or together with estramustine phosphate ( EM-V ) 600 mg/m(2 ) PO days 1 through 42 , repeated every 8 weeks . Of 193 eligible patients , 98 received V , and 95 received EM-V. RESULTS Overall survival trended in favor of EM-V but was not significantly different as determined by Kaplan-Meier analysis ( P = .08 ) . Median survival was 11.9 months for EM-V and 9.2 months for V. EM-V was superior to V for secondary end points of time to progression ( P < . 001 , stratified log rank test ; median 3.7 v 2.2 months , respectively ) and for proportion of patients with > /= 50 % prostate-specific antigen ( PSA ) decline sustained for at least 3 monthly measurements ( 25.2 % v 3.2 % , respectively ; P < .0001 ) . Granulocytopenia was significantly less for EM-V compared with V ( grade 2 , 3 , and 4 = 7 % , 7 % , and 1 % v 27 % , 18 % and 9 % , respectively ; P < .0001 ) ; however , grade 2 or worse nausea ( 26 % v 7 % , respectively ; P = .0002 ) and extremity edema ( 22 % v 8 % , respectively ; P = .005 ) were more frequent for EM-V. CONCLUSION Although overall survival was not significantly greater for the combination , EM-V was superior to V for time to progression and PSA improvement . These results encourage further study of estramustine-based antimicrotubule drug combinations in HRPC [7206052] The Southeastern Cancer Study Group has evaluated 5-fluorouracil administered intravenously weekly at a dosage of 600 mg . per M.2 as a single agent , and the 3-drug combination of cyclophosphamide , doxorubicin and 5-fluorouracil in patients with metastatic carcinoma of the bladder and of the prostate previously untreated with cytotoxic chemotherapy in a prospect ively r and omized phase II study . In 4 of 18 patients with bladder carcinoma 5-fluorouracil induced an objective response , and cyclophosphamide , doxorubicin and 5-fluorouracil induced an objective response in 3 of 21 patients . In patients with prostatic carcinoma 5-fluorouracil induced an objective response as measured by a 50 per cent decrease in prostatic acid phosphatase determined in a central reference laboratory in 3 of 25 patients and objective stability by National Prostatic Cancer Project criteria in 14 of 29 patients . Cyclophosphamide , doxorubicin and 5-fluorouracil induced an objective response in 7 of 22 patients and objective stability in 20 of 29 . Thus , 5-fluorouracil administered in an adequate weekly dosage is established as an effective single agent in some patients with stage D carcinoma of the bladder or prostate . However , there is no significant added benefit as measured by survival obtained for these patients by combining cyclophosphamide and doxorubicin with 5-fluorouracil [8691702] BACKGROUND Prognosis of hormone-refractory prostatic cancer is dismal . We evaluated the efficacy of cytotoxic chemotherapy in combination with hormone therapy in patients with newly diagnosed metastatic prostatic cancer . METHODS From February 1984 to March 1992 , 39 newly diagnosed patients with stage D2 prostatic cancer were r and omized to orchiectomy plus diethylistilbestrol diphosphate or orchiectomy plus diethylstilbestrol diphosphate plus combination chemotherapy with cisplatin and methotrexate . RESULTS There was not significant difference in survival or progression-free survival between the two groups . CONCLUSION Chemotherapy has not been proved to prolong survival or progression-free survival in patients who received hormone therapy [731810] Patients with poorly differentiated prostatic carcinoma and skeletal metastases were r and omized to treatment with 2.6-cis-diphenylhexamethylcyclotetrasiloxane ( 2.6-cis ) and estramustine-17-phosphate ( estramustine ) . Parallel with the clinical study a group of non-r and omized patients were treated with 2.6-cis . Cytological regression of the tumor could be registered in half of the estramustine group but not in the 2.6-cis group . There were no drug-related changes in blood chemistry , kidney function tests , hematology or liver enzymes . There was in increase in acid and alkaline phosphatase in both groups but more pronounced in the 2.6-cis group . In both groups follicle-stimulating and luteinizing hormone values were depressed . Testicular and penis atrophy was observed in the 2.6-cis group . Relief of pain and marked improvement of conditions occurred in the majority of the cases in both groups . In general , no tumor regression was observed during administration of 300 mg . 2.6-cis daily for at least 3 months . Some tumor regression was noted during 600 mg . estramustine therapy daily [12441935] PURPOSE We compared median time to treatment failure of men with asymptomatic , hormone refractory , progressive prostate cancer treated with mitoxantrone plus prednisone versus prednisone alone . MATERIAL S AND METHODS In a multicenter phase III trial 120 men with asymptomatic , progressive , hormone refractory prostate cancer were r and omly assigned to treatment with mitoxantrone and prednisone or prednisone alone . Patients received 12 mg./m . mitoxantrone intravenously once every 3 weeks for 6 cycles and 5 mg . prednisone twice daily with or without mitoxantrone . Time to treatment failure was assessed as an aggregate end point comprised of time to disease progression , time to toxicity or death , or time to initiation of alternate therapy . RESULTS Median followup was 21.8 months . Median time to treatment failure and median time to progression were the same : time to treatment failure and time to progression in the mitoxantrone and prednisone group was 8.1 months compared to 4.1 months in the prednisone alone group ( p = 0.017 versus p = 0.018 ) . More patients ( 27 or 48 % ) treated with mitoxantrone and prednisone achieved a 50 % or greater reduction in prostate specific antigen levels than those who received only prednisone ( 15 or 24 % , p = 0.007 ) . There was no significant difference in median survival between the 2 groups , which was 23 and 19 months , respectively . Death was mainly attributable to disease progression . CONCLUSIONS Patients with hormone refractory prostate cancer who are asymptomatic but had progressive disease had a significantly higher response rate when treated with mitoxantrone and prednisone as demonstrated by the 50 % or greater decrease in prostate specific antigen compared to treatment with prednisone alone . Time to treatment failure was significantly prolonged in the chemotherapy treated group but survival rates were not different [1948120] Based on the results of several small clinical studies , the experimental data of J. T. Isaacs , and the theoretical considerations about the heterogeneity of prostatic cancer , we investigated the effect of simultaneous hormone-chemotherapy in previously untreated advanced prostatic cancer . Patients ( n = 145 ; 117 stage D , 28 clinical stage C ) up to an age of 80 years with histologically confirmed and previously untreated prostatic cancer were entered into the study . All patients received hormonal therapy with surgical castration and long-term administration of flutamide . Following castration , the patients were divided r and omly into two groups . Group I patients received simultaneous chemotherapy starting 4 weeks after castration with weekly administration of 25 mg/m2 of 4-epirubicin intravenously for 18 weeks . Patients in group II initially had only hormonal therapy and did not receive chemotherapy until they progressed . Both groups were assessed at intervals of 3 months with respect to subjective and objective response according to the National Prostatic Cancer Project criteria . Quality of life was assessed monthly by the patients during the first 6 months and every 3 months thereafter . Evaluation of the baseline data showed that both groups were comparable with respect to prognostic factors . The first statistical analysis revealed the significant superiority of the combined treatment with respect to response rates ( P = .005 ) , median time to progression ( P = .1 ) , and survival time ( P = .01 ) . Analysis of the patients ' self- assessment data showed that , to date , chemotherapy had not exerted an unfavorable influence on quality of life . These results are very preliminary and should be h and led with care . However , the data suggest that an early combined chemotherapy-hormonal treatment is beneficial for at least a subset of patients , and warrants further clinical investigation [1030548] The response and duration of survival were evaluated for patients with stage D relapsing prostatic cancer who were r and omized to cyclophosphamide (Cytoxan),5-fluorouracil ( 5-FU ) or st and ard therapy , or to subsequent chemotherapies . The chemotherapies on initial r and omization were superior to the st and ard therapy in the number of responders and duration of response . Survival was longer for responders ( stable or partial regression ) on chemotherapy by comparison to responders ( stable only ) on st and ard therapy . The survival for patients receiving initial and crossover chemotherapy was significantly improved for patients who responded to therapy . Chemotherapy of advanced relapsing stage D prostatic cancer is more beneficially treated by specific chemotherapy as shown in this r and omized study [9170576] BACKGROUND In order to examine the usefulness of chemohormonal therapy , we conducted a multicentered r and omized trial comparing hormonal therapy , using a luteinizing hormone-releasing hormone ( LH-RH ) agonist , with chemohormonal therapy , hormonal therapy plus cyclophosphamide ( CPM ) , in patients with newly diagnosed clinical stage D prostatic cancer . METHODS Between January 1991 and March 1995 , 41 evaluable patients with stage D prostatic cancer were r and omized into 2 groups : group A ( hormonal therapy alone ) , goserelin acetate depot 3.6 mg subcutaneously every 4 weeks : group B ( chemohormonal therapy ) , goserelin acetate depot 3.6 mg subcutaneously and CPM 1000 mg/m2 intravenously every 4 weeks . The responses to the therapies were evaluated based on the criteria of The Japanese Urological Association . RESULTS There were no significant differences between the 2 groups with regard to objective and subjective response rates . No advantage in chemohormonal therapy was observed in the survival rate and progression-free survival rate . However , the survival rate and progression-free survival rate of responders were significantly higher than those of nonresponders in both groups . When the results were categorized by histologic grade patients with poorly-differentiated adenocarcinoma had significantly higher response rates , survival rates , and disease-progression-free survival rates in Group B compared to similar patients in Group A. CONCLUSIONS We conclude that chemohormonal therapy does not definitely improve the clinical response and prognosis of patients with stage D prostatic cancer ; however , for patients with poorly-differentiated adenocarcinoma , chemohormonal therapy is a useful treatment [2126739] Patients with hormone escaped advanced progressive prostate cancer were r and omized either to receive either high-dose Estramustine phosphate orally or Mitomycin C by i.v . injection every 6 weeks until signs of progression or death supervened . Patients on both arms progressed rapidly , with a median time to progression of 5 months and a median length of survival of only 10 months . Toxicity was very considerable in both arms [10735891] PURPOSE Suramin is a novel agent that has demonstrated preliminary evidence of antitumor activity in hormone-refractory prostate cancer ( HRPC ) . A prospect i ve r and omized clinical trial was design ed to evaluate pain and opioid analgesic intake as surrogates for antitumor response in HRPC patients with significant , opioid analgesic-dependent pain . PATIENTS AND METHODS A double-blind , placebo-controlled trial r and omized patients to receive a 78-day , outpatient regimen of either suramin plus hydrocortisone ( HC , 40 mg/d ) or placebo plus HC . Treatment assignment was unblinded when either disease progression or dose-limiting toxicity occurred ; placebo patients were allowed to cross-over to open-label suramin plus HC . In addition to pain and opioid analgesic intake , prostate-specific antigen ( PSA ) response , time to disease progression , quality of life , performance status , and survival were compared . RESULTS Overall mean reductions in combined pain and opioid analgesic intake were greater for suramin plus HC ( rank sum P = .0001 ) . Pain response was achieved in a higher proportion of patients receiving suramin than placebo ( 43 % v 28 % ; P = .001 ) , and duration of response was longer for suramin responders ( median , 240 v 69 days ; P = .0027 ) . Time to disease progression was longer ( relative risk = 1.5 ; 95 % confidence interval , 1.2 to 1.9 ) and the proportion of patients with a greater than 50 % decline in PSA was higher ( 33 % v 16 % ; P = .01 ) in patients who received suramin . Neither quality of life nor performance status was decreased by suramin treatment , and overall survival was similar . Most adverse events were of mild or moderate intensity and were easily managed medically . CONCLUSION Outpatient treatment with suramin plus HC is well tolerated and provides moderate palliative benefit and delay in disease progression for patients with symptomatic HRPC [10561316] PURPOSE Approximately 40,000 men die each year of hormone-refractory prostate cancer ( HRPC ) . The results of treatment with chemotherapy have been disappointing to date , with no trials demonstrating a benefit with respect to survival duration . Corticosteroids and mitoxantrone each have been shown to be active agents in this disease . The purpose of this study was to demonstrate an advantage of mitoxantrone and hydrocortisone ( M+H ) over hydrocortisone alone with respect to survival duration . PATIENTS AND METHODS Two hundred forty-two patients with HRPC were r and omized to receive either M+H or hydrocortisone alone . Patients were monitored for survival , time to disease progression , time to treatment failure , response , and quality -of-life ( QOL ) parameters . RESULTS Treatment in both arms was well tolerated . Although there was a delay in time to treatment failure and disease progression in favor of M+H over hydrocortisone alone , there was no difference in overall survival ( 12.3 months for M+H v 12.6 months for hydrocortisone alone ) . There was an indication that QOL was better with M+H , in particular with respect to pain control . CONCLUSION M+H generated more frequent responses and a delay in both time to treatment failure and disease progression compared with hydrocortisone alone . In addition , there was a possible benefit of M+H with respect to pain control over hydrocortisone alone . No improvement in survival was observed . Although M+H could be viewed as a palliative option for patients with HRPC , new drugs and novel strategies are needed to improve survival for this disease [3518596] We report here in the interim analysis of an ongoing r and omized clinical trial design ed to test whether and rogen priming enhances tumor chemosensitivity in men with stage D prostate cancer refractory to orchiectomy . All patients are continuously treated with aminoglutethimide and hydrocortisone , to lower adrenal and rogen secretion , and are given cyclic chemotherapy . Patients in the stimulation arm receive also the synthetic and rogen , fluoxymesterone , for 3 days before and on the day of chemotherapy . Of 57 patients entered to date , 41 have received adequate treatment to be evaluable . Response to therapy ( objective remissions + stabilizations of disease ) occurred in 17 of 18 evaluable patients ( 94 % ) r and omized to the stimulation arm , and in 16 of 23 evaluable patients ( 70 % ) in the control group ( p less than 0.025 ) . Duration of response was not significantly different in the two groups ( median : 9 months in the stimulation and 12 months in the control arm ) . With 30 % of the total of 57 patients still alive , survival is not significantly different in the stimulation ( median : 13 months ) and control arm ( median : 16 months ) . As expected , patients who responded to treatment lived significantly longer than those who failed to benefit . Two episodes of reversible spinal cord compression occurred during and rogen administration . ( The risk of this serious side effect may be reduced by performing a screening myelogram to rule out sub clinical spinal metastasis ) . Our preliminary data suggest that and rogen priming may enhance the tumoricidal effect of cytotoxic drugs in advanced prostate cancer . The lack of improvement in duration of response and survival may be explained by the large fraction of hormone-independent cells probably present in patients with tumors refractory to orchiectomy [3538611] This prospect i ve r and omized study in nonhormonally responsive adenocarcinoma of the prostate shows that response rates to melphalan vs cyclophosphamide groups were virtually identical [15520061] BACKGROUND Vinorelbine ( VRL ) has been shown to be active in hormone-refractory prostate cancer ( HRPC ) in phase II studies , alone or in combination . Its moderate toxicity profile is well tolerated in elderly patients . PATIENTS AND METHODS Patients with metastatic prostate cancer , progressive after primary hormonal therapy , were r and omised to receive intravenous VRL 30 mg/m2 on days 1 and 8 every 3 weeks , and hydrocortisone 40 mg/day or hydrocortisone alone until disease progression . Centres could choose to add aminoglutethimide 1000 mg/day to hydrocortisone as second-line hormone therapy ( HT ) for all their patients . R and omisation was stratified by centre . Further chemotherapy was allowed after progression . The primary end point was progression-free survival ( PFS ) . The final analysis was performed on a total of 414 patients . Reported results were all based on intention-to-treat analyses . All progressions and responses were review ed by an independent panel . RESULTS PFS was significantly prolonged in the VRL plus HT arm compared with the HT alone arm , according to the statistical hypothesis of the protocol ( P=0.055 in the two-sided log-rank test with a pre-specified significance level of 10 % ) . The 6-month PFS rates were 33.2 % versus 22.8 % , and the median duration s of PFS were 3.7 versus 2.8 months . In the multivariate Cox analysis , which included age , Karnofsky performance status ( PS ) , haemoglobin , alkaline phosphatase at study entry and number of prior hormonal treatments , the P value was decreased to 0.005 . The prostate-specific antigen ( PSA ) response rate ( > or = 50 % decline sustained for at least 6 weeks ) was significantly higher for VRL plus HT compared with HT ( 30.1 % versus 19.2 % ; P=0.01 ) . Clinical benefit , defined as a decrease in pain intensity or analgesic consumption or an improvement of Karnofsky PS for at least 9 weeks , and at least stable assessment in the other two , was also more frequently observed in patients who received VRL plus HT versus HT alone ( 30.6 % and 19.2 % ; P=0.008 ) . There was no statistical difference in overall survival . Forty-three per cent of patients in the HT arm received at least one line of further chemotherapy after progression , compared with 28 % of patients in the VRL-based arm . Aminoglutethimide did not seem to result in better efficacy for either arm . VRL plus HT was well tolerated , with a median administered relative dose intensity of 90 % ; grade 4 neutropenia occurred in 6.5 % of patients and non-haematological toxicity was rare . CONCLUSIONS The combination of VRL and hydrocortisone compared with hydrocortisone alone result ed in improved clinical benefit , PFS and PSA response rate . This therapeutic gain is similar to that previously reported with mitoxantrone in combination with low-dose corticosteroids . There was no gain in survival ; however , the combination is well tolerated in this elderly group of patients , who often present cardiac co-morbidities , and therefore offers an active and safe therapeutic option for patients with hormone-refractory prostate cancer [15329902] Liposomal encapsulation of doxorubicin has been shown to reduce nonspecific delivery of this agent to normal tissue and to increase specific delivery to malignant cells . On the basis of doxorubicin 's demonstrated clinical efficacy against hormone‐refractory prostate carcinoma ( HRPCA ) , the authors conducted a prospect i ve , r and omized Phase II clinical trial to evaluate the feasibility , toxicity , and therapeutic efficacy associated with the pegylated form of this agent [3525866] In a r and omized phase III trial performed by the Urological Group of the European Organization for Research on Treatment of Cancer low dose estramustine phosphate ( 280 mg . twice daily for 8 weeks and 140 mg . twice daily thereafter ) was compared to diethylstilbestrol ( 1 mg . 3 times daily ) in patients with stages T3 to T4 , M0 or M1 prostatic cancer . Of 248 patients entered 227 were evaluable for analysis : 115 received estramustine phosphate and 112 received diethylstilbestrol . The best response of the local tumor as assessed by palpation was seen in patients receiving diethylstilbestrol . There was no significant difference between treatments for response rate of metastases , interval to local progression , distant progression , over-all survival and death of carcinoma of the prostate . Duration of survival was correlated with the assessment of local response as determined by palpation . The response of distant lesions also was correlated closely with survival . Diethylstilbestrol ( 1 mg . 3 times daily ) was associated with a significantly worse degree of cardiovascular toxicity than estramustine phosphate . This finding was especially obvious in patients who had no history of cardiovascular disease . Gastrointestinal toxicity occurred in 25 patients treated with estramustine phosphate , including 6 in whom cessation of treatment was necessary . Further studies are required to determine the optimum dose of diethylstilbestrol and estramustine phosphate , and to establish the best form of hormonal treatment for prostatic carcinoma [12225339] BACKGROUND Patients with hormone relapsed prostate cancer ( HRPC ) are often treated with flutamide or diethylstilboestrol . However , which of these two options is the best treatment for HRPC remains unclear . METHODS We carried out a prospect i ve study to determine and compare the prostate-specific antigen ( PSA ) response and survival in patients with hormone relapsed prostate cancer ( HRPC ) , all of whom had previously shown a good response to medical or surgical castration . The patients were r and omised to treatment with diethylstilboestrol ( DES ) and aspirin , or the anti and rogen flutamide . In addition , quality of life was determined by interview and question naire . RESULTS Twenty-eight patients were r and omised for treatment options . There was a significantly greater fall in the PSA ( 65 % vs 35 % ; P = 0.034 ) after treatment with diethylstilboestrol compared to treatment with flutamide . Median survival also rose after treatment with diethylstilboestrol ( 18 months ) compared to flutamide ( 11 months ) , but this difference did not reach statistical significance . There was no difference in the quality of life parameters between the two groups . There were no cardiovascular complications in the stilboestrol group . CONCLUSIONS In HRPC , treatment with stilboestrol is associated with a greater PSA fall and an increase in median survival when compared to flutamide treatment [11685731] New therapeutic alternatives are needed to improve outcomes in patients with and rogen-independent prostate cancer ( AIPC ) . For several years , research ers at the National Cancer Institute have been interested in elucidating the importance of angiogenesis in the pathogenesis of prostate cancer and in identifying inhibitors of this process . Thalidomide has been shown to inhibit the ability of tumors to recruit new blood vessels . In a recent phase II trial of thalidomide in AIPC , 28 % of patients achieved a prostate-specific antigen ( PSA ) decrease of > 40 % . The taxane docetaxel also produces PSA and measurable disease responses when used as monotherapy or as a component of combination chemotherapy for AIPC . Thus , based on the single-agent activity of thalidomide and docetaxel , we initiated a r and omized phase II study of weekly docetaxel with or without thalidomide , 200 mg at bedtime , in patients with chemotherapy-naive metastatic AIPC . Docetaxel , 30 mg/m(2 ) intravenously , was administered every 7 days for 3 weeks , followed by a 1-week rest period . Both regimens have been well tolerated among the first 59 treated patients , with a near absence of grade ( 3/4 ) myelosuppression . Fatigue , hyperglycemia , and pulmonary toxicity were seen in both groups . Thrombotic events have been seen in the combination arm . Thirty-five percent ( 6 of 17 ) of the patients receiving docetaxel alone and 53 % ( 19 of 36 ) of those receiving docetaxel and thalidomide have had a PSA decrease of at least 50 % . Combining a cytotoxic agent with an angiogenesis inhibitor is a promising area of investigation for prostate cancer management [10561202] PURPOSE To evaluate the combination of intravenous ( IV ) paclitaxel , oral estramustine , and oral etoposide in patients with advanced hormone-refractory prostate cancer . PATIENTS AND METHODS Forty patients with carcinoma of the prostate that was progressing despite hormonal therapy and who had undergone anti and rogen withdrawal ( if previously treated with an anti and rogen ) were enrolled onto this phase II trial . Patients were treated with oral estramustine 280 mg tid and oral etoposide 100 mg/d for 7 days , with paclitaxel 135 mg/m(2 ) IV over 1 hour on day 2 of each 21-day treatment cycle . Patients received a maximum of six cycles of therapy . RESULTS Thirty-seven patients were assessable for response . Twenty-two had measurable disease at baseline ; response was not assessable in six of these patients . Overall response was 45 % ( 10 of 22 patients ; 95 % confidence interval [ CI ] , 24 % to 68 % ) , and response was 63 % ( 10 of 16 ) in assessable patients . Twenty-six patients had a > or = 50 % decrease from their baseline prostate-specific antigen levels during therapy , for a response rate of 65 % ( 95 % CI , 48 % to 79 % ) by this criterion . Median duration of response was 3.2 months , with an estimated median survival of 12.8 months . Major toxicities of therapy were leukopenia ( eight patients had > or = grade 4 leukopenia ) and anemia . Hematologic toxicity seemed to be associated with liver metastases . Serial measurements in 24 patients using the Functional Assessment of Cancer Therapy-Prostate ( FACT-P ) showed no significant change in quality of life ( QOL ) as a result of therapy . CONCLUSION The combination of IV paclitaxel , oral estramustine , and oral etoposide is active in patients with advanced prostate cancer . The regimen is tolerable and does not have a significant impact on QOL as measured by the FACT-P in a limited sample of patients [10431581] To evaluate the efficacy of chemoendocrine therapy for the initial treatment of stage D2 prostate cancer , we conducted a prospect i ve r and omized study which compared combined and rogen blockade alone to that combined with UFT . Twenty-one patients received LH-RH agonist and flutamide ( Group-A ) , and 23 patients received LH-RH agonist , flutamide and UFT ( Group-B ) . The overall response rate and the PSA response rate of Group-A was 71.4 % and 100 % respectively , against 65.2 % and 90 % , respectively in Group-B. The median follow-up period was 24 months . The 2-year progression-free survival rate of Group-A was 7.4 % and that of Group-B was 15.9 % . The response rate and progression-free survival rate did not differ significantly between the 2 groups . Liver dysfunction due to flutamide was common in both groups , and a total of 4 patients did not continue the treatment because of this adverse effect . We conclude that in patients with stage D2 prostate cancer , treatment with combined and rogen blockade and UFT is not superior to treatment with combined and rogen blockade alone [969073] This National Cooperative Study has r and omly compared the usefulness of 5-fluorouracil ( 5-FU ) , cyclophosphamide ( Cytoxan ) and st and ard therapy in patients with advanced carcinoma of the prostate ( Stage D ) . All patients studied were endocrine failures and were in progression . Favorable responses were seen with all three treatments regardless of histologic grade . Actual tumor regression occurred only in patients who received either 5-FU or cyclophosphamide . In patients with poorly differentiated or anaplastic tumors treated with cyclophosphamide , progression of disease was significantly less rapid than in patients treated with 5-FU or st and ard therapy . However , favorable responders could not always be identified in advance on the basis of histologic grade alone [12177096] PURPOSE To test the hypothesis that the efficacy and toxicity of suramin in the treatment of patients with hormone-refractory prostate cancer was dose dependent . PATIENTS AND METHODS Patients were r and omized with equal probability to receive low- , intermediate- , or high-dose suramin ( total doses 3.192 , 5.320 , and 7.661 g/m(2 ) , respectively ) . Overall survival , time to progression , and response rate ( prostate-specific antigen [ PSA ] and objective ) for each treatment arm were compared . Relationships between plasma suramin concentrations and response , toxicity , and survival were also evaluated . RESULTS Three hundred ninety patients were r and omized . For the low- , intermediate- , and high-dose arms , the median survival time was 16 , 14 , and 13 months , respectively ( P = .49 ) . The objective response rate was 9 % , 7 % , and 15 % , respectively ( P = .10 ) . PSA response rates were 24 % , 28 % , and 34 % , respectively ( P = .082 ) . L and mark analyses of a 50 % decline in PSA at 20 weeks showed a significant correlation with survival . There was a dose-response relationship between dose and toxicity . After adjusting for treatment arm , the measured suramin concentration was not associated with clinical response , PSA response , survival , or toxicity . CONCLUSION Although high-dose suramin was associated with higher objective and PSA response rates , these were not statistically significant . Overall , no dose-response relationship was observed for survival or progression-free survival , but toxicity was increased with the higher dose . Patients treated with the low-dose level experienced modest toxicity , making it the preferred arm on this study . The lack of a dose-response relationship and the toxicity profile observed raise questions regarding the utility of suramin , particularly high-dose suramin , as administered on this schedule [370420] In this third cooperative chemotherapy trial of the National Prostatic Cancer Project 165 patients with histologically confirmed , relapsing clinical stage D prostatic cancer were r and omized to receive either imidazole-carboxamide , procarbazine or cyclophosphamide . All patients had received and failed previous hormonal therapy . Patients whose disease progressed after 12 weeks on initial therapy were crossed over or r and omized to receive an alternate drug . There were 129 patients available for comparison of treatments . The objective response rates ( partial regression plus stable disease ) were 26 % for cyclophosphamide , 27 % for imidazole-carboxamide and 14 % for procarbazine . Subjective responses were noted in pain relief , improvement in performance status and weight gain . Procarbazine was associated with excessive toxicity , result ing in many patients ( 28 % ) discontinuing therapy within the first 3 weeks and closure of this particular arm of the study . The regimen of initial imidazole-carboxamide therapy with a later cross-over to cyclophosphamide when the disease continues to progress is associated with the longest increase in survival . Imidazole-carboxamide and cyclophosphamide appear to be active agents in advanced prostatic cancer and are worthy of continued use in this disease [6259722] In a prospect i ve r and omized multicenter trial patients with highly or moderately differentiated prostatic carcinoma , previously untreated , were allotted either to oral Estramustine phosphate or to intramuscular polyestradiol phosphate plus oral ethinyl estradiol . As regards frequency and duration of tumour remission there was no statistical difference between the two groups . Nor did they differ significantly with respect to adverse reactions . This is an interim report and will be followed later on by a final evaluation [7536271] The therapeutic benefit of chemotherapy in and rogen independent prostate cancer is limited . 5-Fluorouracil has been reported to have modest antitumor activity in and rogen independent prostate cancer . Although alpha-interferon is inactive as a single agent in prostate cancer , pre clinical data indicate that it increases the in vitro cytotoxicity of 5-fluorouracil against a variety of malignant cells . We evaluated the relative antitumor activity and tolerance of 5-fluorouracil versus 5-fluorouracil plus alpha-interferon in 50 patients with histologically confirmed metastatic adenocarcinoma of the prostate . These patients had progressive disease in the presence of castrate levels of testosterone . A prospect i ve r and omized phase II open labeled trial was performed because of the difficulty in measuring responses in patients with metastatic prostate cancer . Of 23 patients treated with 5-fluorouracil alone and 28 treated with 5-fluorouracil plus alpha-interferon 17 and 23 , respectively , were evaluable for response and toxicity , and 5 and 5 , respectively , were evaluable for toxicity only . Only 2 of 17 ( 11.7 % ) and 4 of 23 ( 17 % ) patients , respectively , showed a greater than 50 % decrease in serum prostate specific antigen ( no significant difference ) . There was no difference in duration of response or duration of survival between the 2 groups ( mean duration of response 8.64 and 6.17 weeks , respectively , and mean duration of survival 33.70 and 38.65 weeks , respectively ) . Both regimens caused significant morbidity ( mucositis and neurotoxicity ) and 3 treatment related deaths at the high 5-fluorouracil doses . 5-Fluorouracil alone and with alpha-interferon at the doses used have minimal antitumor activity against and rogen independent prostate cancer and , therefore , should not be tested further in these patients . And rogen independent prostate cancer selected using our criteria is a rapidly progressive disease , and these patients are an ideal target population for phase II studies [1383436] PURPOSE Estramustine phosphate ( EMP ) and vinblastine are two microtubule inhibitors with distinct molecular targets and at least additive antimicrotubule effects in vitro . Their modest single-agent activities in hormone-refractory prostate cancer , nonoverlapping toxicities , and lack of cross-resistance prompted a phase II trial in hormone-refractory prostate cancer . PATIENTS AND METHODS Thirty-six assessable patients at the Fox Chase Cancer Center and seven Fox Chase Cancer Center Network institutions were treated with oral EMP 600 mg/m2 on days 1 to 42 and vinblastine 4 mg/m2 intravenously ( IV ) once a week for 6 weeks . Courses were repeated every 8 weeks . Response assessment was based on a change in serum prostate-specific antigen ( PSA ) levels and was correlated with change in pain scores . RESULTS PSA decreased from baseline by at least 50 % in 22 patients ( 61.1 % ) and by > or = 75 % in eight patients ( 22.2 % ) . A 50 % or more decrease in PSA on three successive 2-week measurements together with an improved or stable pain score , performance status , and measurable soft tissue disease ( if present ) was required for a partial response ( PR ) , which occurred in 11 patients for an overall response rate of 30.5 % ( 95 % confidence interval , 15.6 % to 45.6 % ) . In seven patients with measurable nonosseous disease , there was one PR ( 14 % ) and one minor response ( MR ) . In 28 patients with assessable pain , major pain responses occurred in 12 ( 42.9 % ) . PSA response ( > or = 50 % decrease times three measurements ) was predictive of major pain response with a 93.7 % specificity , a 50 % sensitivity , and a positive predictive value of 85.7 % . CONCLUSION We conclude that EMP and vinblastine is an active combination in hormone-refractory prostate cancer [6362815] Over a 24‐month period , the Southwest Oncology Group ( SWOG ) conducted a r and omized prospect i ve chemotherapeutic trial in 158 patients with advanced prostatic cancer . Patients were initially r and omized to receive either a combination of Adriamycin and cyclophosphamide ( AC ) or a single agent , hydroxyurea ( H ) , and then crossed over to the other treatment on failure . Of the 137 evaluable patients , 43 ( 31 % ) had classically measurable metastatic disease in the lymph nodes , skin , chest , or liver . Focusing their efforts on this subset of patients with measurable disease , the authors of this report found the combination AC to have a superior response rate to the single agent , hydroxyurea . Objective response to AC was seen in 6 of 19 ( 32 % ) and in only one of 24 ( 4 % ) patients r and omized to hydroxyurea ( P = 0.06 , Fisher 's exact test ) . However , in the larger group of 137 evaluable patients , a survival advantage was not seen for those individuals treated with AC . Failure to demonstrate a survival advantage for an objective ly superior drug combination would suggest the need for more active phase II agents in this disease [3139279] From April 1983 to March 1985 , 265 patients with newly diagnosed metastatic prostate cancer were r and omized to one of three treatment protocol s : ( 1 ) diethylstilbestrol ( DES ) or bilateral Orchiectomy , ( 2 ) the leutinizing hormone‐releasing hormone ( LHRH ) analog buserelin , or ( 3 ) methotrexate plus DES or orchiectomy . In 261 evaluable patients there was no significant difference in survival between the three groups . However , progression‐free survival ( PFS ) was significantly different ( P < 0.0005 , log‐rank test ) . Of the possible pairwise comparisons for PFS , two showed significance : buserelin was inferior to DES/ orchiectomy ( P < 0.05 ) and buserelin was inferior to methotrexate plus DES/orchiectomy ( P < 0.0001 ) Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Children 's fear about dental treatment may lead to behaviour management problems for the dentist , which can be a barrier to the successful dental treatment of children . Sedation can be used to relieve anxiety and manage behaviour in children undergoing dental treatment . There is a need to determine from published research which agents , dosages and regimens are effective . OBJECTIVES To evaluate the efficacy and relative efficacy of conscious sedation agents and dosages for behaviour management in paediatric dentistry . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

21975770

[1486669] A r and omized , double-masked trial was carried out in rural Nepal to investigate the incidence and severity of acute side-effects among neonates ( < 1 month of age ) and infants aged 1 - 6 months who received a large , oral dose of vitamin A ( 15,000 retinol equivalents ( RE ) ( 50,000 IU ) and 30,000 RE ( 100,000 IU ) , respectively ) or placebo ( 75 RE ( 250 IU ) and 150 RE ( 500 IU ) , respectively ) in oil . Infants ( vitamin A group , n = 1461 ; controls , n = 1379 ) were assessed for vomiting , loose stools , fever , and irritability during the 24 hours before and after dosing . Fontanelles were palpated 24 hours after dosing . Neonates exhibited no excess risk of adverse side-effects after receiving 15,000 RE . Compared with controls the older infants who ingested 30,000 RE had a 1.6 % excess rate of vomiting ( 95 % confidence interval ( CI ) : 0.2 - 3.0 % ) and a 0.5 % excess rate ( 95 % CI : -0.1 to 1.1 % ) in the occurrence of bulging fontanelles . There were no other significant differences in the older infants . The controlled , periodic distribution of a single 15,000 RE dose of vitamin A therefore confers no apparent acute risk to young infants ; a 30,000 RE dose is associated with a minimum risk of transient , acute side-effects [7867131] A placebo-controlled trial was carried out among 2067 Indonesian neonates to assess the safety of administering one oral 52-mumol ( 50,000 IU ) dose of vitamin A. Infants were assessed for potential acute side-effects before and throughout 48 hours after the dose . The first 965 infants were examined by cranial ultrasound before and at 24 hours after dosing to rule out intracranial haemorrhage and determine the resistive index ( RI ) of the anterior cerebral artery using duplex Doppler . Groups were comparable at the baseline . A bulging fontanelle occurred in the control and vitamin A groups , respectively , among 2.7 % and 4.6 % of the infants at 24 hours , and 2.4 % and 4.5 % of the infants at 48 hours . The groups did not differ in any other sign or symptom assessed . No infant developed intracranial haemorrhage . Mean RI values were normal and not different between groups at baseline or at 24 hours . Mean RI fell during the 24 hours , as normally occurs ; the mean decrease was nearly identical in the two groups . A bulging fontanelle was not associated with increased rates of any sign or symptom or with an increase in RI . The 52-mumol dose of oral vitamin A may cause a small increase in intracranial volume in a small proportion of infants , but no increase in intracranial pressure . Acute side-effects following this intervention were rare and mild [18558641] Objective To investigate the effect of high dose vitamin A supplementation given with BCG vaccine at birth in an African setting with high infant mortality . Design R and omised placebo controlled trial . Setting B and i m Health Project ’s demographic surveillance system in Guinea-Bissau , covering approximately 90 000 inhabitants . Participants 4345 infants due to receive BCG . Intervention Infants were r and omised to 50 000 IU vitamin A or placebo and followed until age 12 months . Main outcome measure Mortality rate ratios . Results 174 children died during follow-up ( mortality=47/1000 person-years ) . Vitamin A supplementation was not significantly associated with mortality ; the mortality rate ratio was 1.07 ( 95 % confidence interval 0.79 to 1.44 ) . The effect was 1.00 ( 0.65 to 1.56 ) during the first four months and 1.13 ( 0.75 to 1.68 ) from 4 to 12 months of age . The mortality rate ratio in boys was 0.84 ( 0.55 to 1.27 ) compared with 1.39 ( 0.90 to 2.14 ) in girls ( P for interaction=0.10 ) . An explorative analysis revealed a strong interaction between vitamin A and season of administration . Conclusions Vitamin A supplementation given with BCG vaccine at birth had no significant benefit in this African setting . Although little doubt exists that vitamin A supplementation reduces mortality in older children , a global recommendation of supplementation for all newborn infants may not contribute to better survival . Trial registration Clinical trials NCT00168597 [11697418] Vitamin A deficiency is associated with increased morbidity and mortality from diarrheal disease , measles , and malaria . It has been proposed that vitamin A supplementation could be linked with childhood immunization programs to improve child health . We conducted a r and omized , double‐blind , placebo‐controlled clinical trial to evaluate the impact of linking vitamin A supplementation with the Exp and ed Programme on Immunization on morbidity and child growth . In West Java , Indonesia , 467 six‐week‐old infants were r and omized to receive 7.5 mg retinol equivalent ( RE ) , 15 mg RE , or placebo with childhood immunization contacts at 6 , 10 , and 14 wks and 9 mo of age . Child growth was assessed through anthropometry , and morbidity histories were obtained . Vitamin A supplementation had no apparent impact upon linear or ponderal growth or infectious disease morbidity in the first 15 mo of age when integrated with the Exp and ed Programme on Immunization [7598058] The effect of supplementing 11,918 infants < 1 mo and 1 - 5 mo of age with vitamin A ( 15,000 and 30,000 micrograms retinol equivalents or 50,000 and 100,000 IU , respectively ) or a placebo on subsequent 4-mo mortality was assessed in a r and omized , double-masked community trial in the rural plains of Nepal . There were 130 deaths ( 51.6/1000 child-y ) in the control group and 150 deaths ( 57.1/1000 child-y ) in the vitamin A group , yielding a relative risk of 1.11 ( 95 % CI : 0.86 , 1.42 ) , which is indicative of no overall effect on early infant mortality . There was a tendency for the relative risk of mortality among vitamin A recipients to rise with improved nutritional status . These results suggest that distribution of a large oral dose of vitamin A to infants < 5 - 6 mo of age may not benefit short-term survival . This is in contrast with the results of trials in which older infants and children in this same population were supplemented [10024613] The effects of maternal postpartum vitamin A or beta-carotene supplementation on maternal and infant serum retinol concentrations , modified relative dose-response ( MRDR ) ratios and breast milk vitamin A concentrations were assessed during a community-based trial in Matlab , Bangladesh . At 1 - 3 wk postpartum , women were r and omly assigned to receive either ( 1 ) a single dose of 200,000 international units [ 60,000 retinol equivalents ( RE ) ] vitamin A followed by daily placebos ( n = 74 ) , ( 2 ) daily doses of beta-carotene [ 7.8 mg ( 1300 RE ) ] ( n = 73 ) or ( 3 ) daily placebos ( n = 73 ) until 9 mo postpartum . Compared to placebos , vitamin A supplementation result ed in lower maternal MRDR ratios ( i.e. , increased liver stores ) and higher milk vitamin A concentrations at 3 mo , but these improvements were not sustained . The beta-carotene supplementation acted more slowly , result ing in milk vitamin A concentrations higher than the placebo group only at 9 mo . Irrespective of treatment group , over 50 % of women produced milk with low vitamin A concentrations ( < /=1.05 micromol/L or < /=0.28 micromol/g fat ) throughout the study . Overall , mean maternal serum retinol concentrations were not affected by supplementation . Compared to the placebo group , the mean MRDR ratio of 6-mo-old infants was higher in the vitamin A group . Infants ( 33 % ) had serum retinol concentrations < 0.70 micromol/L and 88 % had MRDR ratios > /=0 . 06 . We conclude that while both interventions were beneficial , neither was sufficient to correct the underlying sub clinical vitamin A deficiency in these women nor to bring their infants into adequate vitamin A status [16251628] It has been suggested that administering vitamin A with the measles vaccine may reduce the vaccine 's immunogenicity . This trial examined the effect of supplementing vitamin A during the early months of life on infants ' immune responses to tetanus and polio vaccines . Young infants ( n = 1085 ) were enrolled and individually r and omized into 1 of 4 groups in a factorial , double-blind , placebo-controlled trial . Three vitamin A supplementation strategies were investigated : 1 ) supplementation of breast-feeding mothers with 60 mg retinol equivalent ( RE ) vitamin A within 4 wk of delivery ; 2 ) Exp and ed Program on Immunization (EPI)-linked supplementation of infants with 7.5 mg RE vitamin A at 6 , 10 , and 14 wk ; and 3 ) combined mother and child supplementations . A 4th group in which mother and child were given placebos served as controls . Blood sample s were collected from each child at 6 wk and 6 mo of age to measure antipolio antibody titer , antitetanus toxoid antibodies , and avidity of antibodies to tetanus . Of the infants r and omized into the 4 arms of the study , 767 ( 71 % ) completed follow-up at 6 mo of age . Follow-up rates were similar in all 4 arms ( 69 - 72 % , P = 0.8 ) . Antibody titers were relatively high in all 4 groups at both 6 wk and 6 mo of age , with no differences among the groups . We found no evidence that vitamin A supplementation affects infants ' antibody responses to tetanus toxoid or oral polio vaccine delivered at EPI contacts [10837300] BACKGROUND The effect of vitamin A supplementation on the survival of infants aged < 6 mo is unclear . Because most infant deaths occur in the first few month of life , maternal supplementation may improve infant survival . OBJECTIVES The objective was to assess the effect of maternal vitamin A or beta-carotene supplementation on fetal loss and survival of infants < 6 mo of age . DESIGN Married women of reproductive age in 270 wards of Sarlahi district , Nepal , were eligible to participate . Wards were r and omly assigned to have women receive weekly doses of 7000 microg retinol equivalents as retinyl palmitate ( vitamin A ) , 42 mg all-trans-beta-carotene , or placebo . Pregnancies were followed until miscarriage , stillbirth , maternal death , or live birth of one or more infants , who were followed through 24 wk of age . RESULTS A total of 43559 women were enrolled ; 15832 contributed 17373 pregnancies and 15987 live born infants to the trial . The rate of fetal loss was 92.0/1000 pregnancies in the placebo group , comparable with rates in the vitamin A and beta-carotene groups , which had relative risks of 1.06 ( 95 % CI : 0.91 , 1.25 ) and 1.03 ( 95 % CI : 0.87 , 1.19 ) , respectively . The 24-wk mortality rate was 70.8/1000 live births in the placebo group , comparable with rates in the vitamin A and beta-carotene groups , which had relative risks of 1.05 ( 95 % CI : 0.87 , 1.25 ) and 1.03 ( 95 % CI : 0.86 , 1.22 ) , respectively . CONCLUSIONS Small weekly doses of vitamin A or beta-carotene given to women before conception , during pregnancy , and through 24 wk postpartum did not improve fetal or early infant survival in Nepal [8598547] At immunization contact , 165 infants 2.5 mo old were r and omly assigned to receive either 15 mg vitamin A ( retinyl palmitate ) or placebo . Three doses were given at monthly intervals with each diphtheria , pertussis , tetanus and oral polio ( DPT/OPV ) immunization dose . The diarrhea and acute respiratory infection ( ARI ) morbidity was similar in the vitamin A and placebo groups . However , the duration ( days per child-year , mean + /- SD ) of ARI was less in the vitamin A group compared with placebo group ( 27.6 + /- 17.1 vs. 40.8 + /- 22.7 ; P = 0.005 ) . Fasting retinol concentrations were measured at entry and in 61 infants , the relative dose response ( RDR ) test was done 1 mo after the third dose of vitamin A. Eighty-five percent of the infants had serum retinol concentration < 0.70 mol/L at entry . After 3 mo the serum retinol levels improved significantly in both groups , and in the vitamin A-supplemented group the serum retinol concentration was significantly better than that in the placebo group ( P= 0.02 ) . However , 61 % of the infants remained deficient despite vitamin A supplementation . Among vitamin A-supplemented infants only , diarrhea and ARI morbidity during the 3-mo period were compared in children with normal versus children with abnormal RDR at the end of the supplementation period . The ARI episodes were more frequent in the supplemented infants who remained vitamin A deficient at the end of the 3 mo ( P = 0.027 ) . Also , the cumulative duration ( days , mean + /- SD ) of fever and cough was 5.0 + /- 2.8 in the normal versus 11.2 + /- 6.0 in the deficient group ( P = 0.04 ) . The results of this study suggest that a large proportion of infants remain vitamin A deficient even after large dose vitamin A supplementation because of frequent respiratory infections , particularly those accompanied by fever [14668283] BACKGROUND We previously reported that maternal micronutrient supplementation in rural Nepal decreased low birth weight by approximately 15 % . OBJECTIVE We examined the effect of daily maternal micronutrient supplementation on fetal loss and infant mortality . DESIGN The study was a double-blind , cluster-r and omized , controlled trial among 4926 pregnant women and their 4130 infants in rural Nepal . In addition to vitamin A ( 1000 microg retinol equivalents ) , the intervention groups received either folic acid ( FA ; 400 microg ) , FA + iron ( 60 mg ) , FA + iron + zinc ( 30 mg ) , or multiple micronutrients ( MNs ; the foregoing plus 10 microg vitamin D , 10 mg vitamin E , 1.6 mg thiamine , 1.8 mg riboflavin , 2.2 mg vitamin B-6 , 2.6 microg vitamin B-12 , 100 mg vitamin C , 64 microg vitamin K , 20 mg niacin , 2 mg Cu , and 100 mg Mg ) . The control group received vitamin A only . RESULTS None of the supplements reduced fetal loss . Compared with control infants , infants whose mothers received FA alone or with iron or iron + zinc had a consistent pattern of 15 - 20 % lower 3-mo mortality ; this pattern was not observed with MNs . The effect on mortality was restricted to preterm infants , among whom the relative risks ( RRs ) were 0.36 ( 95 % CI : 0.18 , 0.75 ) for FA , 0.53 ( 0.30 , 0.92 ) for FA + iron , 0.77 ( 0.45 , 1.32 ) for FA + iron + zinc , and 0.70 ( 0.41 , 1.17 ) for MNs . Among term infants , the RR for mortality was close to 1 for all supplements except MNs ( RR : 1.74 ; 95 % CI : 1.00 , 3.04 ) . CONCLUSIONS Maternal micronutrient supplementation failed to reduce overall fetal loss or early infant mortality . Among preterm infants , FA alone or with iron reduced mortality in the first 3 mo of life . MNs may increase mortality risk among term infants , but this effect needs further evaluation [11160543] Nasopharyngeal colonization is a risk factor for pneumococcal disease , a leading cause of complications and death in infants . We assessed the impact of vitamin A supplementation in reducing pneumococcal colonization in infants from an area with endemic vitamin A deficiency . We recruited 464 2-mo-old infants from a rural area in South India . Infants were r and omly assigned to receive two 7000-microg retinol equivalent doses of vitamin A ( n = 239 ) or placebo ( n = 225 ) orally at birth , and nasopharyngeal specimens were collected at ages 2 , 4 and 6 mo . We studied the effect of vitamin A on culture-confirmed pneumococcal colonization and on the distribution of pneumococcal serotypes . Analyses were conducted by intention-to-treat . The risk of colonization among infants aged 4 mo who were not colonized by age 2 mo was significantly reduced in the vitamin A group compared with the placebo group [ odds ratio 0.51 ( 0.28 , 0.92 ) , P = 0.02 ) . The odds of colonization were 27 % lower in the treatment group than in the placebo group [ odds ratio 0.73 ( 0.48 , 1.1 ) , P = 0.13 ] . No differences were detected in the prevalence of invasive serotypes . The risk of colonization with penicillin-resistant isolates was 74 % lower in the vitamin A group than in the placebo group at 2 mo of age . However , the prevalence of penicillin-resistant isolates was only 4 % . Neonatal vitamin A supplementation may play a role in lowering morbidity rates associated with pneumococcal disease by delaying the age at which colonization occurs [15699235] BACKGROUND Young infants are at risk of vitamin A deficiency . Supplementation of breastfeeding mothers improves the vitamin A status of their infants , but there are no data regarding its effect on infant mortality , and data on the effect of directly supplementing infants during the first few weeks of life are conflicting . OBJECTIVE The objective was to measure the effect on infant mortality of supplementing neonates and their HIV-negative mothers with single , large doses of vitamin A during the immediate postpartum period . DESIGN A r and omized , placebo-controlled , 2-by-2 factorial design trial was conducted in 14,110 mothers and their infants ; 9208 of the mothers were HIV-negative at delivery , remained such during the postpartum year , and were retained in the current analysis . The infants were r and omly assigned within 96 h of delivery to 1 of 4 treatment groups : mothers and infants received vitamin A ( Aa ) , mothers received vitamin A and infants received placebo ( Ap ) , mothers received placebo and infants received vitamin A ( Pa ) , and both mothers and infants received placebo ( Pp ) . The vitamin A dose in the mothers was 400,000 IU and in the infants was 50,000 IU . The mother-infant pairs were followed to 12 mo . RESULTS Hazard ratios ( 95 % CI ) for 12 mo mortality among infants in the maternal-supplemented and infant-supplemented groups were 1.17 ( 0.87 , 1.58 ) and 1.08 ( 0.80 , 1.46 ) , respectively . Hazard ratios ( 95 % CI ) for the Aa , Ap , and Pa groups compared with the Pp group were 1.28 ( 0.83 , 1.98 ) , 1.27 ( 0.82 , 1.97 ) , and 1.18 ( 0.76 , 1.83 ) , respectively . These data indicate no overall effect . Serum retinol concentrations among a sub sample of women were similar to reference norms . CONCLUSION Postpartum maternal or neonatal vitamin A supplementation may not reduce infant mortality in infants of HIV-negative women with an apparently adequate vitamin A status [10573548] A r and omized , double-blind , placebo-controlled trial was conducted to evaluate the effect of simultaneous vitamin A supplementation and diphtheria , pertussis and tetanus ( DPT ) vaccination on the antibody levels . Infants aged 6 - 17 wk ( n = 56 ) were r and omly given 15 mg oral vitamin A or placebo at the time of their DPT immunization . Three such doses were given at monthly intervals . Immunoglobulin ( Ig ) G antibodies to diphtheria , pertussis and tetanus were assayed on enrollment and 1 mo after the third dose . Baseline antibody concentrations to diphtheria , pertussis and tetanus did not differ between the vitamin A-supplemented and placebo-treated groups . The postdose antibody to diphtheria level was significantly greater in the vitamin A than in the placebo-treated group . The geometric mean + /- SEM antibody levels ( mg/L ) were 22.9 + /- 1.2 and 11.0 + /- 1.3 in the vitamin A and placebo groups , respectively ( P = 0.029 ) . The postsupplementation concentrations of antibodies to pertussis and tetanus did not differ between the two groups . These results suggest that antibody response to diphtheria vaccination was potentiated by simultaneous vitamin A administration and DPT immunization [8988926] One hundred twenty infants were r and omly assigned to receive either 15 mg vitamin A or placebo with each of three DPT/OPV ( diphtheria , pertussis , tetanus/oral polio vaccine ) immunizations at monthly intervals . Sixty-two received vitamin A and 58 received placebo . One month after the third supplementation dose , the response to the delayed cutaneous hypersensitivity test [ multitest cell-mediated immunity ( CMI ) skin evaluation ] for tetanus , diphtheria , and tuberculin ( purified protein derivative , PPD ) was the same in the vitamin A and placebo infants . The number of anergic infants was 17 ( 27 % ) and 19 ( 33 % ) in the vitamin A and placebo groups , respectively . The number of positive tests among well-nourished infants was significantly higher than that in malnourished infants irrespective of supplementation ( P < 0.001 ) . Among the infants with adequate serum retinol concentrations ( > 0.7 mumol/L ) after supplementation , the vitamin A-supplemented infants had a significantly higher proportion of positive CMI tests than the placebo infants ( chi-square test : 8.99 , P = 0.008 ) . Among the infants with low serum retinol concentrations ( < 0.7 mumol/L ) after supplementation , vitamin A supplementation had no effect on CMI response . These results indicate that CMI in young infants was positively affected by vitamin A supplementation only in those infants whose vitamin A status was adequate ( ie , serum retinol > 0.7 mumol/L ) at the time of the CMI test . CMI was consistently better in well-nourished infants irrespective of supplementation [10702176] BACKGROUND Conflicting results have been reported regarding the relative performance of serum retinol , the modified-relative-dose-response ( MRDR ) ratio , and breast-milk vitamin A concentrations in detecting changes in maternal vitamin A status . OBJECTIVE We used receiver operating characteristic analyses and st and ardized differences to compare the ability of these indicators to detect a response to postpartum vitamin A supplementation in lactating Bangladeshi women . DESIGN At 2 wk postpartum , women were r and omly assigned to receive either a single dose of vitamin A [ 200000 IU ( 60000 retinol equivalents ) ; n = 74 ] or placebo ( n = 73 ) . Data from maternal serum and breast milk collected 3 mo postpartum and from infant serum collected 6 mo postpartum were used to examine the ability of serum retinol , the MRDR ratio , and breast-milk vitamin A to discriminate between individuals in the supplemented and unsupplemented groups . Breast milk was collected by expressing the entire contents of one breast that had not been used to feed an infant for > or = 2 h ( full sample s ) or without controlling the time since the last breast-feeding episode ( casual sample s ) . RESULTS Casual breast-milk sample s performed better than full breast-milk sample s in detecting a response to maternal supplementation . The MRDR ratio performed better than serum retinol in both the women and their infants . Overall , the most responsive indicator was the measurement of breast-milk vitamin A per gram of fat in casual breast-milk sample s. CONCLUSIONS Breast-milk vitamin A and the MRDR ratio are responsive indicators of vitamin A status , especially in women with mild vitamin A deficiency [16825698] BACKGROUND Anemia is prevalent in infants in developing countries . Its etiology is multifactorial and includes vitamin A deficiency . OBJECTIVE Our primary aim was to measure the effect of maternal or neonatal vitamin A supplementation ( or both ) on hemoglobin and anemia in Zimbabwean infants . Our secondary aim was to identify the underlying causes of postnatal anemia . DESIGN A r and omized , placebo-controlled trial was conducted in 14 110 mothers and their infants ; 2854 infants were r and omly selected for the anemia sub study , of whom 1592 were successfully observed for 8 - 14 mo and formed the study sample . Infants were r and omly assigned within 96 h of delivery to 1 of 4 treatment groups : mothers and infants received vitamin A ; mothers received vitamin A and infants received placebo ; mothers received placebo and infants received vitamin A ; and mothers and infants received placebo . The vitamin A doses were 400,000 and 50,000 IU in the mothers and infants , respectively . RESULTS Vitamin A supplementation had no effect on hemoglobin or anemia ( hemoglobin < 105 g/L ) in unadjusted or adjusted analyses . Infant HIV infection independently increased anemia risk > 6-fold . Additional predictors of anemia in HIV-negative and -positive infants were male sex and lower total body iron at birth . In addition , in HIV-positive infants , the risk of anemia increased with early infection , low maternal CD4 + lymphocyte count at recruitment , and frequent morbidity . Six-month plasma ferritin concentrations < 12 microg/L were a risk factor in HIV-negative but not in HIV-positive infants . Maternal HIV infection alone did not cause anemia . CONCLUSION Prevention of infantile anemia should include efforts to increase the birth endowment of iron and prevent HIV infection [8463867] For regions where vitamin A deficiency is common , high dose vitamin A supplementation of lactating mothers is currently recommended , but the effects of this intervention have not been carefully evaluated . We conducted a r and omized , double-blind trial in which 153 Indonesian mothers 1 - 3 wk postpartum received either a capsule containing 312 mumol of vitamin A as retinyl palmitate or a placebo . Mothers ' serum retinol concentrations in the vitamin A group tended to be lower than in the placebo group at baseline but higher at 3 mo postpartum ( 1.39 vs. 1.24 mumol/L , P = 0.03 ) and 6 mo postpartum ( 1.23 vs. 1.08 mumol/L , P < 0.01 ) . The milk retinol concentrations of the vitamin A group were higher than those of the placebo group by 0.48 to 1.18 mumol/L at 1 - 8 mo postpartum ( P < 0.05 ) . Among the infants at 6 mo of age , the prevalences of low serum retinol concentration ( < 0.52 mumol/L ) were 36 and 15 % in the placebo and vitamin A groups , respectively ( P < 0.005 ) , and the prevalences of low vitamin A stores ( assessed by relative dose response ) were 23 and 10 % , respectively ( P < 0.03 ) . High dose vitamin A supplementation of lactating mothers is an efficacious way to improve the vitamin A status of both mother and breast-fed infant [11340108] Night blindness occurs commonly among women during pregnancy in rural NEPAL : We examined the relationship between maternal night blindness and the risk of mortality occurring among infants in the first 6 mo of life . Stratified analysis by maternal night blindness status during pregnancy was done for 10,000 women participating in a r and omized , placebo-controlled trial of vitamin A and beta-carotene supplementation . Mortality of infants of non-night blind women in all three supplementation groups was similar , and when combined , was 63/1000 live births . Relative to this , mortality was higher by 63 % [ 95 % confidence interval ( CI ) : 9 - 138 % ) and 50 % ( 95 % CI : -3 to 133 % ) among infants of night blind women receiving placebo and beta-carotene , respectively , but only by 14 % ( 95 % CI : -33 to 93 % ) among those receiving vitamin A. Thus , 6-mo mortality was higher among infants of women who had night blindness during pregnancy . Maternal receipt of vitamin A reduced this risk [17449592] Vitamin A supplementation reduces child mortality and severe morbidity in less developed countries , and the Exp and ed Program on Immunization ( EPI ) offers an ideal opportunity to deliver supplements in developing countries . High-dose vitamin A supplementation has been shown to have no effect on the immunogenicity of oral polio vaccine , tetanus toxoid , pertussis , or on measles vaccine given at 9 mo , but a negative effect on measles vaccine administered at 6 mo and a potentiating effect on diphtheria vaccine . Its effect on the antibody response to hepatitis B and Haemophilus influenzae type b antigens has not yet been established . To assess these effects , the present trial was carried out in the Offinso district of Ghana ; 1077 infants were enrolled shortly after birth and r and omized either to receive or not to receive 15 mg retinol equivalent with vitamin A together with the pentavalent " diphtheria-polio-tetanus-Haemophilus influenzae b-hepatitis B " vaccine at 6 , 10 , and 14 wk of age . All mothers received a postpartum supplement of 120 mg retinol equivalent vitamin A as per national policy . Blood sample s were taken from infants at 6 and 18 wk of age . The results are based on 888 infants ( 82.4 % ) who completed the trial . The vitamin A supplementation did not affect the immune response to Haemophilus influenzae type b , but there was a significant improvement in the immune response to hepatitis B vaccine ( 93.9 vs. 90.2 % , P = 0.04 ) . However , given the high percentage of infants with seroprotection in the control group , it is doubtful that inclusion of vitamin A in the EPI would be justified on these grounds alone [17951487] Vitamin A supplementation reduces mortality in young children in areas of endemic vitamin A deficiency . However , it has no impact on the incidence of common morbidities . This discrepancy has been explained by an impact on case fatality , although with the exception of hospitalized measles cases , there is little direct evidence to support this hypothesis . We assessed the impact of newborn dosing with vitamin A on the incidence and case fatality of common childhood morbidities in early infancy in a community-based , r and omized trial in South India . Morbidity for each day in the previous 2 wk was assessed for the first 6 mo of life . A total of 11,619 live-born infants were enrolled and r and omized to receive either 48,000 IU ( 50.4 micromol retinol ) of oral vitamin A or placebo following delivery . There was no difference between treatment groups in the incidence of acute or chronic diarrhea , dysentery , or fever but a small increased incidence of acute respiratory illness ( ARI ) . Case fatality for diarrhea and fever were significantly reduced in the vitamin A group compared with placebo ( relative case fatality [ 95 % CI ] of 0.50 [ 0.27 , 0.90 ] and 0.60 [ 0.40 , 0.88 ] , respectively ) . There was a trend in reduction of case fatality for various definitions of ARI , but the evidence for this effect was modest . Survival analysis among those with morbid episodes confirmed the case fatality analysis . This trial demonstrated that the reduction in overall mortality due to newborn vitamin A dosing was driven primarily by a reduction in case fatality among infants [9152680] Objectives : To evaluate the effect of vitamin A supplementation 24 h after delivery on breastmilk retinol concentration . Methods : Fifty low income women were r and omly assigned to a single oral dose of 209 μmol of Vitamin A or none at delivery . Maternal serum and breastmilk retinol levels and infant morbidity and anthropometry were serially assessed . Results : Mean ( 95 % CI ) serum retinol levels increased in the supplemented mothers at 2.77 ( 2.3 , 3.2 ) compared to 1.15 ( 0.9 , 1.4 ) μmol/l in controls ( P<0.05 ) and remained at a significantly higher level of 1.59 ( 1.4 , 1.8 ) μmul/l compared to 1.33 ( 1.8 , 1.5 ) μmol/l in the control group ( P<0.001 ) up to a period of three months . Breastmilk retinol concentration was also greater at 24 h after supplementation , mean ( CI ) 11.34 ( 9.0 , 13.7 ) μmol/l , compared to 2.95 ( 2.3 , 3.6 ) μmol/l in the control group ( P<0.0001 ) , and remained higher for the next six months at 1.06 ( 0.9 , , 1.3 ) μmol/l compared to 0.73 ( 0.6 , 0.8 ) μmol/l in the control group ( P<0.02 ) . Infants of the supplemented mothers had reduced mean duration of respiratory tract infection of 3.1 ( 2.7 , 3.5 ) days compared to 3.7 ( 3.3 , 4.2 ) days ( P<0.03 ) and mean incidence of febrile illness 0.1 ( 0.1 , 0.1 ) compared to control infants 0.3 ( 0.3 , 0.3 ) days , ( P<0.002 ) . Conclusion : Vitamin A supplementation of malnourished mothers maintains higher breastmilk retinol concentration for at least six months and reduces the duration of respiratory tract infection and febrile illness in their breastfed infants . Sponsorship : The study was supported by the International Centre for Diarrhoeal Disease Research and the United States Agency for International Development [17391562] Postpartum vitamin A supplementation of mothers and infants is recommended , but the efficacy has been question ed . In this double-blind , placebo-controlled trial , Kenyan mother-infant pairs were r and omised to maternal vitamin A ( 400,000 IU ) or placebo < 24 h postpartum , and infant vitamin A ( 100,000 IU ) or placebo at 14 weeks . Milk retinol was determined at weeks 4 , 14 and 26 , and maternal and infant serum retinol at weeks 14 and 26 . Infant retinol stores were assessed at week 26 , using a modified relative dose response ( MRDR ) test . Among 564 women , serum retinol at 36 weeks gestation was 0.81 ( SD 0.21 ) micromol/l , and 33.3 % were<0.7 micromol/l . Maternal serum retinol was not different between groups , but milk retinol was higher in the vitamin A group : ( 0.67 v. 0.60 micromol/l ; 0.52 v. 0.44 micromol/l ; 0.50 v. 0.44 micromol/l at 4 , 14 and 26 weeks , respectively ) . When expressed per gram fat , milk retinol was higher in the vitamin A group only at 4 weeks . Infant serum retinol was not different between groups . However , although most infants had deficient vitamin A stores ( MRDR>0.06 % ) at 26 weeks , vitamin A to infants , but not mothers , result ed in a lower proportion of infants with deficient vitamin A stores ( 69 v. 78 % ) . High-dose postpartum vitamin A supplementation failed to increase serum retinol and infant stores , despite modest effects on milk retinol . Infant supplementation , however , increased stores . There is a need for a better underst and ing of factors affecting absorption and metabolism of vitamin [9605804] BACKGROUND In HIV-1-infected women , poor micronutrient status has been associated with faster progression of HIV-1 disease and adverse birth outcomes . We assessed the effects of vitamin A and multivitamins on birth outcomes in such women . METHODS In Tanzania , 1075 HIV-1-infected pregnant women at between 12 and 27 weeks ' gestation received placebo ( n=267 ) , vitamin A ( n=269 ) , multivitamins excluding vitamin A ( n=269 ) , or multivitamins including vitamin A ( n=270 ) in a r and omised , double-blind , placebo-controlled trial with a 2x2 factorial design . We measured the effects of multivitamins and vitamin A on birth outcomes and counts of T lymphocyte subsets . We did analyses by intention to treat . RESULTS 30 fetal deaths occurred among women assigned multivitamins compared with 49 among those not on multivitamins ( relative risk 0.61 [ 95 % CI 0.39 - 0.94 ] p=0.02 ) . Multivitamin supplementation decreased the risk of low birthweight ( < 2500 g ) by 44 % ( 0.56 [ 0.38 - 0.82 ] p=0.003 ) , severe preterm birth ( < 34 weeks of gestation ) by 39 % ( 0.61 [ 0.38 - 0.96 ] p=0.03 ) , and small size for gestational age at birth by 43 % ( 0.57 [ 0.39 - 0.82 ] p=0.002 ) . Vitamin A supplementation had no significant effect on these variables . Multivitamins , but not vitamin A , result ed in a significant increase in CD4 , CD8 , and CD3 counts . INTERPRETATION Multivitamin supplementation is a low-cost way of substantially decreasing adverse pregnancy outcomes and increasing T-cell counts in HIV-1-infected women . The clinical relevance of our findings for vertical transmission and clinical progression of HIV-1 disease is yet to be ascertained [12896935] Abstract Objective To assess the impact of supplementing newborn infants with vitamin A on mortality at age 6 months . Design Community based , r and omised , double blind , placebo controlled trial . Setting Two rural districts of Tamil Nadu , southern India . Participants 11 619 newborn infants allocated 24 000 IU oral vitamin A or placebo on days 1 and 2 after delivery . Main outcome measure Primary outcome measure was mortality at age 6 months . Results Infants in the vitamin A group had a 22 % reduction in total mortality ( 95%confidence interval 4 % to 37 % ) compared with those in the placebo group . Vitamin A had an impact on mortality between two weeks and three months after treatment , with no additional impact after three months . Conclusion Supplementing newborn infants with vitamin A can significantly reduce early infant mortality [12897218] Background and objective : In developing countries low maternal vitamin A stores combined with increased dem and s of pregnancy and lactation may lead to its deficiency in breastfed infants . This study evaluates the effects of maternal supplementation with a high dose of vitamin A on the serum retinol levels of exclusively breastfed infants , and their morbidity in the first six months of life . Setting : Hospital based . Study design : R and omised controlled trial . Subjects and methods : Mothers of the test group ( n=150 ) were orally supplemented with a single dose of retinol ( 209 μmol ) soon after delivery and were advised exclusive breastfeeding for six months . Before supplementation retinol levels were estimated in the mothers ’ and newborns ’ blood , and in colostrum . On follow up , breastmilk and infants ’ serum retinol contents were assessed monthly for six months . Retinol level < 0.7 μmol/l indicated vitamin A deficiency . Morbidity patterns like vitamin A deficiency , diarrhoea , febrile illnesses , acute respiratory infection , measles , and ear infection were also studied and compared between the two groups . Results : Presupplement mean maternal serum retinol levels were 0.98 and 0.92 μmol/l and mean breastmilk levels were 3.85 and 3.92 μmol/l in the test and control groups respectively ( p>0.05 ) . Mean cord blood retinol levels were also comparable ( 0.68 v 0.64 μmol/l ) . After supplementation , the test group showed a rise in mean breastmilk retinol content ( 12.08 v 2.96 μmol/l ) which remained significantly higher for four months . The infants ’ mean serum retinol level , initially 322.06 % of the baseline value , was significantly higher for five months . In the control group , significant numbers of mothers and infants showed deficient breastmilk and serum retinol throughout the follow up ( p<0.01 ) . Decreased incidence and duration of various diseases were also found in the test group suggesting lesser morbidity . Conclusion : Maternal supplementation with single megadose vitamin A is an effective strategy for vitamin A prophylaxis of exclusively breastfed infants of 0–6 months [12173139] Vitamin A is essential for immunity and growth . A controlled clinical that involved 697 human immunodeficiency virus (HIV)-infected pregnant women was conducted to determine whether vitamin A prevents anemia , low birth weight , growth failure , HIV transmission , and mortality . Women received daily doses of iron and folate , either alone or combined with vitamin A ( 3 mg retinol equivalent ) , from 18 - 28 weeks ' gestation until delivery . In the vitamin A and control groups , respectively , the mean ( + /-SE ) birth weights were 2895+/-31 g and 2805+/-32 g ( P=.05 ) , the proportions of low-birth-weight infants were 14.0 % and 21.1 % ( P=.03 ) , the proportions of anemic infants at 6 weeks postpartum were 23.4 % and 40.6 % ( P<.001 ) , and the respective cumulative proportions of infants who were HIV infected at 6 weeks and 24 months of age were 26.6 % and 27.8 % ( P=.76 ) and 27.7 % and 32.8 % ( P=.21 ) . Receipt of vitamin A improved birth weight and neonatal growth and reduced anemia , but it did not affect perinatal HIV transmission [7488807] To evaluate the safety of vitamin A supplementation in early infancy using DPT/OPV immunization contracts , a double‐blind , r and omized , placebo‐controlled trial was conducted in Bangladesh . One hundred and sixty‐seven infants received three doses of either 25 000 IU of vitamin A or a placebo at about 6.5 , 11.8 and 17.0 weeks of age . Trained physicians examined each of the infants on days 1 , 2 , 3 and 8 after supplementation . Nine infants ( 10.5 % ) supplemented with vitamin A had episodes of bulging of the fontanelle compared with two infants ( 2.5 % ) in the placebo group ( p < 0.05 ) . Twelve of the 14 episodes occurred in infants supplemented with vitamin A. Of these 12 episodes , none occurred with the first dose , 3 occurred with the second and 9 with the third dose . The higher incidence of bulging of the fontanelle in the vitamin A group relative to the placebo group and its temporal association with the vitamin A doses are suggestive of a causal association . The finding that increased numbers of vitamin A doses were associated with a higher probability of bulging of the fontanelle suggests a cumulative effect . Bulging fontanelle , clinical trial , safety , toxicity , vitamin [16479521] BACKGROUND Low maternal serum retinol level is a risk factor for mother-to-child transmission ( MTCT ) of human immunodeficiency virus ( HIV ) . Multiple-large-dose vitamin A supplementation of HIV-positive children reduces mortality . The World Health Organization recommends single-large-dose vitamin A supplementation for postpartum women in areas of prevalent vitamin A deficiency ; neonatal dosing is under consideration . We investigated the effect that single-large-dose maternal/neonatal vitamin A supplementation has on MTCT , HIV-free survival , and mortality in HIV-exposed infants . METHODS A total of 14,110 mother-infant pairs were enrolled < or = 96 h after delivery , and both mother and infant , mother only , infant only , or neither received vitamin A supplementation in a r and omized , placebo-controlled trial with a 2 x 2 factorial design . All but 4 mothers initiated breast-feeding . A total of 4495 infants born to HIV-positive women were included in the present analysis . RESULTS Neither maternal nor neonatal vitamin A supplementation significantly affected postnatal MTCT or overall mortality between baseline and 24 months . However , the timing of infant HIV infection modified the effect that supplementation had on mortality . Vitamin A supplementation had no effect in infants who were polymerase chain reaction ( PCR ) positive [ corrected ] for HIV at baseline . In infants who were PCR negative at baseline and PCR positive at 6 weeks , neonatal supplementation reduced mortality by 28 % ( P=.01 ) , but maternal supplementation had no effect . In infants who were PCR negative at 6 weeks , all 3 vitamin A regimens were associated with ~2-fold higher mortality ( P < or = .05 ) . CONCLUSIONS Targeted vitamin A supplementation of HIV-positive children prolongs their survival . However , postpartum maternal and neonatal vitamin A supplementation may hasten progression to death in breast-fed children who are PCR negative at 6 weeks . These findings raise concern about universal maternal or neonatal vitamin A supplementation in HIV-endemic areas [17586304] BACKGROUND Most developing countries have adopted a st and ard WHO dosing schedule for vitamin A supplementation . However , in 2002 the International Vitamin A Consultative Group ( IVACG ) Annecy Accord recommended a new high-dose regimen for mothers and infants . Our aim was to test whether the new high-dose regimen of vitamin A supplementation would increase maternal and infant plasma vitamin A , reduce infant Helicobacter pylori infection and nasopharyngeal pneumococcal carriage , and improve infant gut epithelial integrity . METHODS In an area of moderate vitamin A deficiency in rural Gambia , 220 mother-infant pairs were enrolled in a r and omised double-blind trial between September , 2001 , and October , 2004 , that compared the IVACG high dose with the WHO dose . The primary endpoints were levels of maternal and infant plasma vitamin A , H pylori infection , pneumococcal carriage , and gut epithelial integrity . The trial is registered as IS RCT N 98554309 . FINDINGS 197 infants completed follow-up to 12 months ( 99 high dose and 98 WHO dose ) . There were no adverse events at dosing . No differences were found in the primary outcomes for high-dose versus WHO schedule : maternal vitamin A concentration at 2 months + 0.02 micromol/L ( 95 % CI -0.10 to 0.15 ) ; infant vitamin A at 5 months + 0.01 micromol/L ( -0.06 to 0.08 ) ; H pylori infection at 12 months -0.3 % ( -14.7 to 14.2 ) ; maternal pneumococcal carriage at 12 months -2.0 % ( -13.7 to 9.7 ) ; infant pneumococcal carriage at 12 months -4.1 % ( -15.8 to 7.6 ) ; infant gut mucosal damage at 12 months 5.2 % ( -8.7 to 19.2 ) . There were more clinic attendances by the high-dose group in the first 6 months of life ( p=0.018 ) . INTERPRETATION Our results do not lend support to the proposal to increase the existing WHO st and ard dosing schedule for vitamin A in areas of moderate vitamin A deficiency . Caution is urged for future studies because trials have shown possible adverse effects of higher doses of vitamin A , and potential negative interactions with the exp and ed programme on immunisation ( EPI ) vaccines [17538544] Objective : To determine whether the combined intervention of 50 000 IU vitamin A administered together with Bacille Calmette-Guerin ( BCG ) vaccination at birth was associated with adverse events , in particular bulging fontanels and adverse reactions to BCG.Subjects/ Methods : From an ongoing trial , 2145 infants r and omized to 50 000 IU vitamin A or placebo with BCG vaccination were recruited . Adverse events were monitored in two different ways : ( A ) daily clinical examinations by a medical doctor during the first 3 days post supplementation ; ( B ) weekly interviews by a trained assistant during the first month post supplementation . Results : In part A , 1271 infants were enrolled , in part B 2078 . Vitamin A supplementation ( VAS ) was associated with a relative risk ( RR ) of bulging fontanels of 1.16 ( 95 % confidence interval (CI)=0.82–1.65 ) . The rate of health care contacts and various symptoms during the first month were comparable between the groups . VAS was associated with larger peak local reactions to BCG vaccination in boys , but not in girls ( P-value for test of interaction between VAS and sex=0.02 ) . Conclusion : 50 000 IU vitamin A with BCG was not associated with adverse events . The observed sex-differential effect of VAS on local reaction to BCG is in line with other observations of sex-differential effects of VAS [1676467] Community trials of the efficacy of vitamin A supplementation in reducing preschool childhood mortality have produced conflicting results . To resolve the question , a r and omised , double-masked , placebo-controlled community trial of 28,630 children aged 6 - 72 months was carried out in rural Nepal , an area representative of the Gangetic flood plain of South Asia . R and omisation was carried out by administrative ward ; the vitamin-A-supplemented children received 60,000 retinol equivalents every 4 months and placebo-treated children received identical capsules containing 300 retinol equivalents . After 12 months , the relative risk of death in the vitamin-A-supplemented compared with the control group was 0.70 ( 95 % confidence interval 0.56 - 0.88 ) , equivalent to a 30 % reduction in mortality . The trial , which had been planned to last 2 years , was discontinued . The reduction in mortality was present in both sexes ( relative risk for boys 0.77 ; for girls 0.65 ) , at all ages ( range of relative risks 0.83 - 0.50 ) , and throughout the year ( 0.76 - 0.67 ) . The reduction in mortality risk was not affected by acute nutritional status , as measured by arm circumference . Thus , periodic vitamin A delivery in the community can greatly reduce child mortality in developing countries [17931488] OBJECTIVE To assess the effect of retinyl palmitate supplementation on colostrum retinol levels , investigating the influence of maternal variables ( age , type of delivery , and biochemical nutritional status ) on these levels . METHOD The study included 33 mothers receiving care at the Januário Cicco Maternity School , in the city of Natal , Rio Gr and e do Norte , Brazil . In the first hours after delivery , blood and colostrum sample s were collected . Another colostrum sample was collected six hours after maternal supplementation with 200,000 IU of retinyl palmitate . Serum and colostrum retinol levels were determined by high-performance liquid chromatography . RESULTS The mean retinol level in colostrum before the supplementation was 110.8 + /- 82.3 microg/dL , and after supplementation it was 164.4 + /- 106.5 microg/dL ( P < 0.025 ) . Of the 33 mothers , 12 of them either did not respond to supplementation or had an increase of less than 10 % in colostrum retinol levels ; serum retinol in these women was significantly lower as compared to the responders ( P = 0.024 ) . In comparison to women with a normal delivery , the mothers who underwent cesarean delivery ( 64 % ) had lower serum retinol levels , but not lower colostrum retinol levels ( P = 0.036 ) . Maternal age did not influence retinol levels in either serum or colostrum . CONCLUSION The increase in colostrum retinol levels following vitamin A supplementation was sufficient to guarantee double the retinol requirements of a newborn infant [8772901] OBJECTIVES To assess the impact of Vitamin A supplementation to the mother soon after delivery and to the infant at six months on morbidity in infancy . DESIGN R and omized double blind placebo controlled field trial . SETTING 51 villages in two contiguous Primary Health Centers in Villupuram Health Unit District of Tamil Nadu , South India . SUBJECTS 909 newly delivered mother- and -infant pairs . INTERVENTIONS Both mother and infant received Vitamin A ( 300,000 IU for mothers and 200,000 IU for children ) in 311 instances ( AA ) ; mother received Vitamin A but infant received Placebo in 301 instances ( AP ) ; and both mother and infant received Placebo in the remaining 297 instances ( PP ) . MAIN OUTCOME MEASURES Incidence of diarrhea and Acute Respiratory Infection ( ARI ) ; distributions of infants by frequency of episodes and number of infected days . RESULTS 233 in the AA Group and 228 each in the AP and PP Groups were followed up regularly . The incidence of diarrhea in these infants was 97.4 % , 96.9 % and 94.7 % in the three groups , mean number of diarrheal episodes was 4.4 , 4.6 and 4.2 and median number of days in infancy with diarrhea was 26 , 26 and 22 days , respectively . For ARI , the incidences were 96.6 % , 95.6 % and 96.1 % , means were 4.8 , 5.1 and 4.8 episodes , and the medians were 32 , 34 and 34 days , respectively . CONCLUSIONS Prophylactic administration of mega doses of Vitamin A to the mother soon after delivery and to the infant at six months do not have any beneficial impact on the incidence of diarrhea and ARI in infancy [9707874] OBJECTIVE To explore the effect of maternal supplementation of vitamin A on the immune response to oral polio vaccine in breastfed infants . DESIGN R and omized controlled trial . SETTING Hospital based . METHODS One hundred mothers having uncomplicated deliveries r and omly received either 200,000 IU vitamin A orally ( Experimental ) or placebo ( Control ) . All the newborns were given a dose of oral polio vaccine within 72 hours after birth and were breastfed . Type specific neutralizing antibodies to polio viruses in test sera diluted from 1:4 to 1:512 and serum retinol levels were determined from the cord blood and at the age of 6 weeks . Breast milk retinol levels were determined at 3 , 10 , 30 , 45 and 90 days of lactation . RESULTS Seroconversion to OPV and geometric means of antibody titers to the three types of polio viruses were comparable between the groups of infants belonging to the experimental and control mothers . Breast milk retinol levels were significantly higher in the experimental group upto 45 - 90 days of lactation . Majority of the infants at birth had serum retinol levels < 15 micrograms/dl which improved significantly by 6 weeks irrespective of the maternal supplementation status . CONCLUSIONS Maternal vitamin A supplementation soon after delivery improves vitamin A intakes of breastfed infants during the first 3 months and has no interference with the seroconversion to a neonatal dose of OPV . OPV administered to newborn in turn has no adverse effect on the vitamin A status of the breastfed infants [2835853] Objective To investigate the effect of vitamin A supplementation and BCG vaccination at birth in low birthweight neonates . Design R and omised , placebo controlled , two by two factorial trial . Setting Bissau , Guinea-Bissau . Participants 1717 low birthweight neonates born at the national hospital . Intervention Neonates who weighed less than 2.5 kg were r and omly assigned to 25 000 IU vitamin A or placebo , as well as to early BCG vaccine or the usual late BCG vaccine , and were followed until age 12 months . Main outcome measure Mortality , calculated as mortality rate ratios ( MRRs ) , after follow-up to 12 months of age for infants who received vitamin A supplementation compared with those who received placebo . Results No interaction was observed between vitamin A supplementation and BCG vaccine allocation ( P=0.73 ) . Vitamin A supplementation at birth was not significantly associated with mortality : the MRR of vitamin A supplementation compared with placebo , controlled for r and omisation to “ early BCG ” versus “ no early BCG ” was 1.08 ( 95 % CI 0.79 to 1.47 ) . Stratification by sex revealed a significant interaction between vitamin A supplementation and sex ( P=0.046 ) , the MRR of vitamin A supplementation being 0.74 ( 95 % CI 0.45 to 1.22 ) in boys and 1.42 ( 95 % CI 0.94 to 2.15 ) in girls . When these data were combined with data from a complementary trial among normal birthweight neonates in Guinea-Bissau , the combined estimate of the effect of neonatal vitamin A supplementation on mortality was 1.08 ( 95 % CI 0.87 to 1.33 ) ; 0.80 ( 95 % CI 0.58 to 1.10 ) in boys and 1.41 ( 95 % CI 1.04 to 1.90 ) in girls ( P=0.01 for interaction between neonatal vitamin A and sex ) . Conclusions The combined results of this trial and the complementary trial among normal birthweight neonates have now shown that , overall , it would not be beneficial to implement a neonatal vitamin A supplementation policy in Guinea-Bissau . Worryingly , the trials show that vitamin A supplementation at birth can be harmful in girls . Previous studies and future trials should investigate the possibility that vitamin A supplementation has sex differential effects . Trial registration Clinical Trials.gov NCT00168610 [18595969] OBJECTIVES . We assessed the effect of supplementing newborns with 50000 IU of vitamin A on all-cause infant mortality through 24 weeks of age . PATIENTS AND METHODS . This was a community-based , double-masked , cluster-r and omized , placebo-controlled trial conducted in 19 unions in rural northwest Bangladesh . The study was nested into and balanced across treatment arms of an ongoing placebo-controlled , weekly maternal vitamin A or β-carotene supplementation trial . Study -defined sectors ( N = 596 ) were evenly r and omized for newborns of participating mothers to receive a single , oral supplement of vitamin A ( 50000 IU ) or placebo as droplets of oil squeezed from a gelatinous capsule . Mothers provided informed consent for newborn participation at ∼28 weeks ' gestation . After birth , typically at home ( where > 90 % of births occurred ) , infants were supplemented and their vital status was followed through 24 weeks of age . The main outcome measure was mortality through 24 weeks of age . RESULTS . We obtained maternal consent to dose 17116 live-born infants ( 99.8 % of all eligible ) among whom 15937 ( 93.1 % ) were visited to be supplemented < 30 days after birth and for whom vital status at 24 weeks of age was known . Dosed infants ( n = 15902 [ 99.8 % ] ) received their study supplement at a median age of 7 hours . Relative to control subjects , the risk of death in vitamin A – supplemented infants was 0.85 , reflecting a 15 % reduction in all-cause mortality . Protective relative risks were indistinguishable by infant gender , gestational age , birth weight , age at dosing , maternal age , parity , or across the 3 treatment arms of the maternal supplementation trial . CONCLUSIONS . Newborn vitamin A dosing improved infant survival through the first 6 months of life in Bangladesh . These results corroborate previous findings from studies in Indonesia and India and provide additional evidence that vitamin A supplementation shortly after birth can reduce infant mortality in South Asia [8618182] OBJECTIVE To determine whether vitamin A supplementation at birth could reduce infant morbidity and mortality . STUDY DESIGN We conducted a placebo-controlled trial among 2067 Indonesian neonates who received either 52 micromol ( 50,000 IU ) orally administered vitamin A or placebo on the first day of life . Infants were followed up at 1 year to determine the impact of this intervention on infant mortality . A subgroup ( n = 470 ) was also examined at 4 and 6 months of age to examine the impact on morbidity . RESULTS Vital status was confirmed in 89 % of infants in both groups at 1 year . There were 19 deaths in the control group and 7 in the vitamin A group ( relative risk = 0.36 ; 95 % confidence interval = 0.16 , 0.87 ) . The impact was stronger among boys , infants of normal compared with low birth weight , and those of greater ponderal index . Among infants examined at 4 months of age , the 1-week period prevalence of common morbidities was similar for vitamin A and control infants . However , during this same 4-month period , 73 % and 51 % more control infants were brought for medical treatment for cough ( p = 0.008 ) and fever ( p = 0.063 ) , respectively . CONCLUSIONS Neonatal vitamin A supplementation may reduce the infant mortality rate and the prevalence of severe respiratory infection among young infants [10771879] The mutual interactions of measles vaccine and vitamin A dose when administered simultaneously to 9 month old infants are explored in this study . One hundred healthy infants of 9 months of age received EZ strain of measles vaccine in the routine immunization clinic along with either 100,000 IU of vitamin A or a placebo orally . Blood sample s were collected before and 4 weeks after intervention . They were coded and analysed for serum retinol and Hemagglutination Inhibition ( HI ) antibodies to measles . Ninety five per cent of the infants were seronegative to measles prior to vaccination with a seroconversion rate of 63 % in the control group and a significantly higher percent of 83.7 % in the experimental group ( P < 0.01 ) . Seroconversion was not related to initial serum retinol levels in either of the groups . 42 % of infants had serum retinol levels less than 20 ug/dl before administration of the vaccine and both the groups showed improvement in vitamin A status following intervention , the increase being significant in the experimental group ( from 22.4 ± 1.32 to 26.0 ± 1.07 ; P < 0.05 ) . The results indicate that majority of the infants at 9 months of age were seronegative to measles . Seroconversion to measles vaccine in the routine immunization clinics was low . Simultaneous administration of vitamin A and measles vaccine had beneficial effects on vitamin A status as well as seroconversion rates to the vaccine in 9 months old infants [11965510] Objective : To investigate whether supplementation with vitamin A together with iron of Indonesian pregnant women decreases morbidity and improves growth of their infants during the first year of life . Design : Women from a rural area in West Java , Indonesia , were r and omly assigned on an individual basis to double-blind supplementation once weekly from ∼18 weeks of pregnancy until delivery . Supplementation comprised 120 mg iron and 500 µg folic acid with or without 4800 RE vitamin A. Their newborn infants were followed up during the first year of life : weight , length , morbidity and food intake were assessed monthly . Results : Infants whose mothers had taken vitamin A supplements during pregnancy had similar weight , length , weight gain and growth as their counterparts during the follow-up period . The proportions of infants with reported symptoms of morbidity were similar in the vitamin A plus iron group and the iron group . In addition immunisation coverage and feeding mode did not differ between the groups . All infants were breast-fed , but exclusive breast-feeding rapidly declined at 4 months of age . Infants with serum retinol concentrations > 0.70 µmol/l increased their weight and length more during the first 6 months of life and had higher weight-for-age Z-scores during the first year of life than infants with serum retinol concentrations ≤0.70 µmol/l . Serum retinol concentrations were not associated with morbidity . Conclusion : In this study , vitamin A supplementation in conjunction with iron supplementation of pregnant women did not improve growth or reduce morbidity of their infants during the first year of life . Sponsorship : Netherl and s Organization for Scientific Research -Netherl and s Foundation for the Advancement of Tropical Research ( NWO-WOTRO ) ( WV 93 - 280 ) , the Neys-van Hoogstraten Foundation ( IN 114 ) , The Netherl and s and the German Agency for Technical Cooperation (GTZ)/South East Asian Ministers of Education Organization , Tropical Medicine ( SEAMEO-TROPMED ) , Indonesia [8102669] A double-blind , r and omised , placebo-controlled trial was conducted to evaluate the safety and toxicity of vitamin A supplementation within the Exp and ed Programme on Immunisation ( EPI ) in rural Bangladesh . 191 infants received 3 doses of either 50,000 IU of vitamin A or placebo at about 1.5 , 2.5 , and 3.5 months and were examined on days 1 , 2 , 3 , and 8 after supplementation . 11 infants ( 11.5 % ) supplemented with vitamin A had episodes of bulging of the fontanelle as opposed to 1 ( 1 % ) in the placebo group . 16 of the 17 events occurred in the vitamin A supplemented group . No other side effects were noted . There was a tendency towards a cumulative effect of toxicity with increasing doses [12351954] Background : HIV-1 transmission through breastfeeding is a global problem and has been associated with poor maternal micronutrient status . Methods : A total of 1078 HIV-infected pregnant women from Tanzania were r and omly assigned to vitamin A or multivitamins excluding A from approximately 20 weeks ’ gestation and throughout lactation . Results : Multivitamins excluding A had no effect on the total risk of HIV-1 transmission ( RR 1.04 , 95 % CI 0.82–1.32 , P = 0.76 ) . Vitamin A increased the risk of transmission ( RR 1.38 , 95 % CI 1.09–1.76 , P = 0.009 ) . Multivitamins were associated with non-statistically significant reductions in transmission through breastfeeding , and mortality by 24 months among those alive and not infected at 6 weeks . Multivitamins significantly reduced breastfeeding transmission in infants of mothers with low baseline lymphocyte counts ( RR 0.37 ; 95 % CI 0.16–0.85 , P = 0.02 ) compared with infants of mothers with higher counts ( RR 0.99 , 95 % CI 0.68–1.45 , P = 0.97 ; P-for-interaction 0.03 ) . Multivitamins also protected against transmission among mothers with a high erythrocyte sedimentation rate ( P-for-interaction 0.06 ) , low hemoglobin ( P-for-interaction 0.06 ) , and low birthweight babies ( P-for-interaction 0.04 ) . Multivitamins reduced death and prolonged HIV-free survival significantly among children born to women with low maternal immunological or nutritional status . Vitamin A alone increased breastfeeding transmission but had no effect on mortality by 24 months . Conclusion : Vitamin A increased the risk of HIV-1 transmission . Multivitamin ( B , C , and E ) supplementation of breastfeeding mothers reduced child mortality and HIV-1 transmission through breastfeeding among immunologically and nutritionally compromised women . The provision of these supplements to HIV-infected lactating women should be considered [11219162] Summary The World Health Organization recommends that 100,000 IU of vitamin A be given to infants between 6 and 12 months of age at the same time as measles vaccination in order to prevent vitamin A deficiency . In the present study , our aim was to assess the effect of vitamin A supplementation on T-cell subsets in a r and omized factorial design , seeking a possible modifying effect of measles vaccination . Three hundred children were allocated either to two doses of measles vaccine at 6 and 9 months of age or to poliomyelitis vaccine at age 6 months and measles vaccine at age 9 months . Within each group , infants were to receive two doses of vitamin A or two doses of placebo at 6 and 9 months of age . We found no significant effect of vitamin A supplementation on CD4 and CD8 T-cell subsets at 3 and 9 months after supplementation . We found no effect of measles vaccine and no interaction between vitamin A supplementation and measles vaccine . Based on these observations , vitamin A supplementation does not seem to have a strong long-term effect on CD4 and CD8 T-cell subsets in infants without clinical vitamin A deficiency [7656887] OBJECTIVE To investigate whether monthly administration of vitamin A at routine immunisation produces any side-effects , and to examine the effect of this supplementation on the vitamin A nutrition status of infants . DESIGN A double-blind r and omised placebo-controlled clinical trial . SETTING Immunisation clinic of a large diarrhoea treatment centre . SUBJECTS Infants aged 6 - 17 weeks who will receive their first diphtheria-pertussis-tetanus/oral polio vaccine ( DPT/OPV ) dose . METHODS Infants were r and omly assigned to receive either 25,000 IU vitamin A or placebo . Three such doses were given with each immunisation dose at monthly intervals . Infants were examined by a physician before and during 24 h after the doses and any signs of toxicity were recorded . Venous blood was drawn at entry and 1 month after the 3rd dose for retinol assay . RESULTS One hundred and one infants received vitamin A and 98 received placebo . Decreased feeding , irritability , diarrhoea , and vomiting were comparable between the two groups . In the vitamin A group five infants developed bulging fontanelle ; three of them developed it once ( after 1st , 2nd and 3rd dose respectively ) , one developed it twice ( after both the 2nd and 3rd dose ) , and the other infant after all three doses . In the placebo group a single child developed bulging fontanelle after the 3rd dose . In all the cases the bulging disappeared within 48 h of onset except in one infant , in whom it subsided at 60 h. The total bulging episodes in the vitamin A and placebo groups were 8 and 1 respectively ( RR = 7.7 ; P < 0.04 ) . However , none of these infants had irritability . At entry fasting retinol level was < 10 micrograms/dl in 35 % infants and in 87 % infants it was < 20 micrograms/dl . After the third dose fasting retinol level was marginally better in the vitamin A group ( mean + /- s.d . : 21.9 + /- 8.2 vs 19.2 + /- 7.8 ; P = 0.05 ) . However , 47 % infants receiving supplementation still had serum retinol level < 20 micrograms/dl . CONCLUSION The results suggest that administration of 25,000 IU of vitamin A in young infants along with routine immunisations , though associated with increased incidence of transient bulging fontanelle without any associated adverse signs or symptoms , may still be inadequate to prevent deficiency in this population . SPONSORSHIP This study was funded by the United States Agency for International Development ( USAID ) under grant no. DPE-5986-A-1009 - 00 with the International Centre for Diarrhoeal Disease Research , Bangladesh ( ICDDR , B ) . The ICDDR , B is supported by countries and agencies which share its concern for the health problems of developing countries [11086300] OBJECTIVE To assess the Vitamin A status of pregnant women in their third trimester using maternal serum retinol levels as the indicator ; and ( ii ) To assess the impact of postpartum Vitamin A supplementation on the Vitamin A status of exclusively breastfed infants . DESIGN Prospect i ve r and omized single blind controlled study . SETTING Teaching Hospital . SUBJECTS 109 apparently healthy primi and second gravida women registered at the antenatal clinic were included in the study and followed up for three months postpartum . Serum retinol levels of pregnant mothers in their third trimester ( 35 - 37 weeks ) and cord blood levels after delivery were estimated . Mothers were then assigned to two groups . The experimental group included 53 mothers who received a single dose of 2 lakh units of Vitamin A orally . The control group had 56 mothers who did not receive Vitamin A. Mothers and infants were followed up for three months . The serum retinol of infants and the breast milk retinol levels were estimated at the end of three months and the results were compared . The growth of the infants was also monitored . RESULTS Sub clinical Vitamin A deficiency was seen in 29.67 % of pregnant women . At the end of three months , 69.6 % of mothers in the control group had breast milk retinol levels below 30 mg/dl , as opposed to 36.1 % in the experimental group . Forty five per cent of infants in the control group had sub clinical vitamin A deficiency compared to none in the experimental group . There was no difference in the growth of infants in the two groups . However , the infant serum and the breast milk retinol levels were significantly higher in the supplemented group . CONCLUSION There is a high prevalence of inapparent Vitamin A deficiency ( 29.7 % ) in pregnant women in their third trimester from lower socio-economic strata . Postpartum Vitamin A supplementation had a beneficial impact on the infant serum retional and the breast milk retinol level but no effect on infant growth [20435345] BACKGROUND A previous trial in Nepal showed that supplementation with vitamin A or its precursor ( betacarotene ) in women of reproductive age reduced pregnancy-related mortality by 44 % ( 95 % CI 16 - 63 ) . We assessed the effect of vitamin A supplementation in women in Ghana . METHODS ObaapaVitA was a cluster-r and omised , double-blind , placebo-controlled trial undertaken in seven districts in Brong Ahafo Region in Ghana . The trial area was divided into 1086 small geographical clusters of compounds with fieldwork areas consisting of four contiguous clusters . All women of reproductive age ( 15 - 45 years ) who gave informed consent and who planned to remain in the area for at least 3 months were recruited . Participants were r and omly assigned by cluster of residence to receive a vitamin A supplement ( 25 000 IU retinol equivalents ) or placebo capsule orally once every week . R and omisation was blocked and based on an independent , computer-generated list of numbers , with two clusters in each fieldwork area allocated to vitamin A supplementation and two to placebo . Capsules were distributed during home visits undertaken every 4 weeks , when data were gathered on pregnancies , births , and deaths . Primary outcomes were pregnancy-related mortality and all-cause female mortality . Cause of death was established by verbal post mortems . Analysis was by intention to treat ( ITT ) with r and om-effects regression to account for the cluster-r and omised design . Adverse events were synonymous with the trial outcomes . This trial is registered with Clinical Trials.gov , number NCT00211341 . FINDINGS 544 clusters ( 104 484 women ) were r and omly assigned to vitamin A supplementation and 542 clusters ( 103 297 women ) were assigned to placebo . The main reason for participant drop out was migration out of the study area . In the ITT analysis , there were 39 601 pregnancies and 138 pregnancy-related deaths in the vitamin A supplementation group ( 348 deaths per 100 000 pregnancies ) compared with 39 234 pregnancies and 148 pregnancy-related deaths in the placebo group ( 377 per 100 000 pregnancies ) ; adjusted odds ratio 0.92 , 95 % CI 0.73 - 1.17 ; p=0.51 . 1326 women died in 292 560 woman-years in the vitamin A supplementation group ( 453 deaths per 100 000 years ) compared with 1298 deaths in 289 310 woman-years in the placebo group ( 449 per 100 000 years ) ; adjusted rate ratio 1.01 , 0.93 - 1.09 ; p=0.85 . INTERPRETATION The body of evidence , although limited , does not support inclusion of vitamin A supplementation for women in either safe motherhood or child survival strategies . FUNDING UK Department for International Development , and USAID [10465076] OBJECTIVE Poor vitamin A status has been associated with a higher risk for mother-to-child transmission of HIV-1 and there is contradictory evidence on the impact of vitamin A on perinatal outcome . We therefore assessed the effect of vitamin A supplementation to mothers on birth outcome and mother-to-child transmission of HIV-1 . DESIGN AND METHODS In Durban , South Africa 728 pregnant HIV infected women received either vitamin A ( 368 ) or placebo ( 360 ) in a r and omized , double-blind trial . The vitamin A treatment consisted of a daily dose of 5000 IU retinyl palmitate and 30 mg beta-carotene during the third trimester of pregnancy and 200000 IU retinyl palmitate at delivery . HIV infection results were available on 632 children who were included in the Kaplan-Meier transmission analysis . Results are reported on mother-to-child transmission rates up to 3 months of age . RESULTS There was no difference in the risk of HIV infection by 3 months of age between the vitamin A [ 20.3 % ; 95 % confidence interval ( CI ) , 15.7 - 24.9 ] and placebo groups ( 22.3 % ; 95 % CI , 17.5 - 27.1 ) , nor were there differences in foetal or infant mortality rates between the two groups . Women receiving vitamin A supplement were , however , less likely to have a preterm delivery ( 11.4 % in the vitamin A and 17.4 % in the placebo group ; P = 0.03 ) and among the 80 preterm deliveries , those assigned to the vitamin A group were less likely to be infected ( 17.9 % ; 95 % CI , 3.5 - 32.2 ) than those assigned to the placebo group ( 33.8 % ; 95 % CI , 19.8 - 47.8 ) . CONCLUSION Vitamin A supplementation , a low-cost intervention , does not appear to be effective in reducing overall mother-to-child transmission of HIV ; however , its potential for reducing the incidence of preterm births , and the risk of mother-to-child transmission of HIV in these infants needs further investigation [20684711] BACKGROUND Prophylactic vitamin A supplementation ( VAS ) reduces mortality and may reduce morbidity associated with diarrhea in children > 6 months of age . Rotavirus is the most common cause of acute dehydrating diarrhea among children worldwide . METHODS In a r and omized placebo-controlled study of 50,000 IU of vitamin A versus placebo given with bacille Calmette-Guérin vaccine at birth , 287 infants were followed up with weekly interviews and stool sample obtainment to test the hypothesis that VAS reduced the risk of rotavirus infection . RESULTS VAS was associated with increased risk of rotavirus infection and diarrhea ( incidence rate ratio [ IRR ] of infection , 1.72 [ 95 % confidence interval ( CI ) , 1.04 - 2.85 ] ; IRR of diarrhea , 3.74 [ 95 % CI , 1.40 - 9.98 ] ) among children < 6 months of age . There was no effect in older children . VAS had a beneficial effect on nonrotavirus diarrhea in boys < 6 months of age ( IRR , 0.51 ; 95 % CI , 0.27 - 0.95 ) and a detrimental effect in girls > 6 months of age ( IRR , 1.84 ; 95 % CI , 0.96 - 3.55 ) . CONCLUSION VAS at birth did not reduce rotavirus morbidity . The effect of VAS on nonrotavirus diarrhea may differ by sex , being more beneficial in boys . Clinical trials registration . NCT00168597

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### Context: [1486669] A r and omized , double-masked trial was carried out in rural Nepal to investigate the incidence and severity of acute side-effects among neonates ( < 1 month of age ) and infants aged 1 - 6 months who received a large , oral dose of vitamin A ( 15,000 retinol equivalents ( RE ) ( 50,000 IU ) and 30,000 RE ( 100,000 IU ) , respectively ) or placebo ( 75 RE ( 250 IU ) and 150 RE ( 500 IU ) , respectively ) in oil . Infants ( vitamin A group , n = 1461 ; controls , n = 1379 ) were assessed for vomiting , loose stools , fever , and irritability during the 24 hours before and after dosing . Fontanelles were palpated 24 hours after dosing . Neonates exhibited no excess risk of adverse side-effects after receiving 15,000 RE . Compared with controls the older infants who ingested 30,000 RE had a 1.6 % excess rate of vomiting ( 95 % confidence interval ( CI ) : 0.2 - 3.0 % ) and a 0.5 % excess rate ( 95 % CI : -0.1 to 1.1 % ) in the occurrence of bulging fontanelles . There were no other significant differences in the older infants . The controlled , periodic distribution of a single 15,000 RE dose of vitamin A therefore confers no apparent acute risk to young infants ; a 30,000 RE dose is associated with a minimum risk of transient , acute side-effects [7867131] A placebo-controlled trial was carried out among 2067 Indonesian neonates to assess the safety of administering one oral 52-mumol ( 50,000 IU ) dose of vitamin A. Infants were assessed for potential acute side-effects before and throughout 48 hours after the dose . The first 965 infants were examined by cranial ultrasound before and at 24 hours after dosing to rule out intracranial haemorrhage and determine the resistive index ( RI ) of the anterior cerebral artery using duplex Doppler . Groups were comparable at the baseline . A bulging fontanelle occurred in the control and vitamin A groups , respectively , among 2.7 % and 4.6 % of the infants at 24 hours , and 2.4 % and 4.5 % of the infants at 48 hours . The groups did not differ in any other sign or symptom assessed . No infant developed intracranial haemorrhage . Mean RI values were normal and not different between groups at baseline or at 24 hours . Mean RI fell during the 24 hours , as normally occurs ; the mean decrease was nearly identical in the two groups . A bulging fontanelle was not associated with increased rates of any sign or symptom or with an increase in RI . The 52-mumol dose of oral vitamin A may cause a small increase in intracranial volume in a small proportion of infants , but no increase in intracranial pressure . Acute side-effects following this intervention were rare and mild [18558641] Objective To investigate the effect of high dose vitamin A supplementation given with BCG vaccine at birth in an African setting with high infant mortality . Design R and omised placebo controlled trial . Setting B and i m Health Project ’s demographic surveillance system in Guinea-Bissau , covering approximately 90 000 inhabitants . Participants 4345 infants due to receive BCG . Intervention Infants were r and omised to 50 000 IU vitamin A or placebo and followed until age 12 months . Main outcome measure Mortality rate ratios . Results 174 children died during follow-up ( mortality=47/1000 person-years ) . Vitamin A supplementation was not significantly associated with mortality ; the mortality rate ratio was 1.07 ( 95 % confidence interval 0.79 to 1.44 ) . The effect was 1.00 ( 0.65 to 1.56 ) during the first four months and 1.13 ( 0.75 to 1.68 ) from 4 to 12 months of age . The mortality rate ratio in boys was 0.84 ( 0.55 to 1.27 ) compared with 1.39 ( 0.90 to 2.14 ) in girls ( P for interaction=0.10 ) . An explorative analysis revealed a strong interaction between vitamin A and season of administration . Conclusions Vitamin A supplementation given with BCG vaccine at birth had no significant benefit in this African setting . Although little doubt exists that vitamin A supplementation reduces mortality in older children , a global recommendation of supplementation for all newborn infants may not contribute to better survival . Trial registration Clinical trials NCT00168597 [11697418] Vitamin A deficiency is associated with increased morbidity and mortality from diarrheal disease , measles , and malaria . It has been proposed that vitamin A supplementation could be linked with childhood immunization programs to improve child health . We conducted a r and omized , double‐blind , placebo‐controlled clinical trial to evaluate the impact of linking vitamin A supplementation with the Exp and ed Programme on Immunization on morbidity and child growth . In West Java , Indonesia , 467 six‐week‐old infants were r and omized to receive 7.5 mg retinol equivalent ( RE ) , 15 mg RE , or placebo with childhood immunization contacts at 6 , 10 , and 14 wks and 9 mo of age . Child growth was assessed through anthropometry , and morbidity histories were obtained . Vitamin A supplementation had no apparent impact upon linear or ponderal growth or infectious disease morbidity in the first 15 mo of age when integrated with the Exp and ed Programme on Immunization [7598058] The effect of supplementing 11,918 infants < 1 mo and 1 - 5 mo of age with vitamin A ( 15,000 and 30,000 micrograms retinol equivalents or 50,000 and 100,000 IU , respectively ) or a placebo on subsequent 4-mo mortality was assessed in a r and omized , double-masked community trial in the rural plains of Nepal . There were 130 deaths ( 51.6/1000 child-y ) in the control group and 150 deaths ( 57.1/1000 child-y ) in the vitamin A group , yielding a relative risk of 1.11 ( 95 % CI : 0.86 , 1.42 ) , which is indicative of no overall effect on early infant mortality . There was a tendency for the relative risk of mortality among vitamin A recipients to rise with improved nutritional status . These results suggest that distribution of a large oral dose of vitamin A to infants < 5 - 6 mo of age may not benefit short-term survival . This is in contrast with the results of trials in which older infants and children in this same population were supplemented [10024613] The effects of maternal postpartum vitamin A or beta-carotene supplementation on maternal and infant serum retinol concentrations , modified relative dose-response ( MRDR ) ratios and breast milk vitamin A concentrations were assessed during a community-based trial in Matlab , Bangladesh . At 1 - 3 wk postpartum , women were r and omly assigned to receive either ( 1 ) a single dose of 200,000 international units [ 60,000 retinol equivalents ( RE ) ] vitamin A followed by daily placebos ( n = 74 ) , ( 2 ) daily doses of beta-carotene [ 7.8 mg ( 1300 RE ) ] ( n = 73 ) or ( 3 ) daily placebos ( n = 73 ) until 9 mo postpartum . Compared to placebos , vitamin A supplementation result ed in lower maternal MRDR ratios ( i.e. , increased liver stores ) and higher milk vitamin A concentrations at 3 mo , but these improvements were not sustained . The beta-carotene supplementation acted more slowly , result ing in milk vitamin A concentrations higher than the placebo group only at 9 mo . Irrespective of treatment group , over 50 % of women produced milk with low vitamin A concentrations ( < /=1.05 micromol/L or < /=0.28 micromol/g fat ) throughout the study . Overall , mean maternal serum retinol concentrations were not affected by supplementation . Compared to the placebo group , the mean MRDR ratio of 6-mo-old infants was higher in the vitamin A group . Infants ( 33 % ) had serum retinol concentrations < 0.70 micromol/L and 88 % had MRDR ratios > /=0 . 06 . We conclude that while both interventions were beneficial , neither was sufficient to correct the underlying sub clinical vitamin A deficiency in these women nor to bring their infants into adequate vitamin A status [16251628] It has been suggested that administering vitamin A with the measles vaccine may reduce the vaccine 's immunogenicity . This trial examined the effect of supplementing vitamin A during the early months of life on infants ' immune responses to tetanus and polio vaccines . Young infants ( n = 1085 ) were enrolled and individually r and omized into 1 of 4 groups in a factorial , double-blind , placebo-controlled trial . Three vitamin A supplementation strategies were investigated : 1 ) supplementation of breast-feeding mothers with 60 mg retinol equivalent ( RE ) vitamin A within 4 wk of delivery ; 2 ) Exp and ed Program on Immunization (EPI)-linked supplementation of infants with 7.5 mg RE vitamin A at 6 , 10 , and 14 wk ; and 3 ) combined mother and child supplementations . A 4th group in which mother and child were given placebos served as controls . Blood sample s were collected from each child at 6 wk and 6 mo of age to measure antipolio antibody titer , antitetanus toxoid antibodies , and avidity of antibodies to tetanus . Of the infants r and omized into the 4 arms of the study , 767 ( 71 % ) completed follow-up at 6 mo of age . Follow-up rates were similar in all 4 arms ( 69 - 72 % , P = 0.8 ) . Antibody titers were relatively high in all 4 groups at both 6 wk and 6 mo of age , with no differences among the groups . We found no evidence that vitamin A supplementation affects infants ' antibody responses to tetanus toxoid or oral polio vaccine delivered at EPI contacts [10837300] BACKGROUND The effect of vitamin A supplementation on the survival of infants aged < 6 mo is unclear . Because most infant deaths occur in the first few month of life , maternal supplementation may improve infant survival . OBJECTIVES The objective was to assess the effect of maternal vitamin A or beta-carotene supplementation on fetal loss and survival of infants < 6 mo of age . DESIGN Married women of reproductive age in 270 wards of Sarlahi district , Nepal , were eligible to participate . Wards were r and omly assigned to have women receive weekly doses of 7000 microg retinol equivalents as retinyl palmitate ( vitamin A ) , 42 mg all-trans-beta-carotene , or placebo . Pregnancies were followed until miscarriage , stillbirth , maternal death , or live birth of one or more infants , who were followed through 24 wk of age . RESULTS A total of 43559 women were enrolled ; 15832 contributed 17373 pregnancies and 15987 live born infants to the trial . The rate of fetal loss was 92.0/1000 pregnancies in the placebo group , comparable with rates in the vitamin A and beta-carotene groups , which had relative risks of 1.06 ( 95 % CI : 0.91 , 1.25 ) and 1.03 ( 95 % CI : 0.87 , 1.19 ) , respectively . The 24-wk mortality rate was 70.8/1000 live births in the placebo group , comparable with rates in the vitamin A and beta-carotene groups , which had relative risks of 1.05 ( 95 % CI : 0.87 , 1.25 ) and 1.03 ( 95 % CI : 0.86 , 1.22 ) , respectively . CONCLUSIONS Small weekly doses of vitamin A or beta-carotene given to women before conception , during pregnancy , and through 24 wk postpartum did not improve fetal or early infant survival in Nepal [8598547] At immunization contact , 165 infants 2.5 mo old were r and omly assigned to receive either 15 mg vitamin A ( retinyl palmitate ) or placebo . Three doses were given at monthly intervals with each diphtheria , pertussis , tetanus and oral polio ( DPT/OPV ) immunization dose . The diarrhea and acute respiratory infection ( ARI ) morbidity was similar in the vitamin A and placebo groups . However , the duration ( days per child-year , mean + /- SD ) of ARI was less in the vitamin A group compared with placebo group ( 27.6 + /- 17.1 vs. 40.8 + /- 22.7 ; P = 0.005 ) . Fasting retinol concentrations were measured at entry and in 61 infants , the relative dose response ( RDR ) test was done 1 mo after the third dose of vitamin A. Eighty-five percent of the infants had serum retinol concentration < 0.70 mol/L at entry . After 3 mo the serum retinol levels improved significantly in both groups , and in the vitamin A-supplemented group the serum retinol concentration was significantly better than that in the placebo group ( P= 0.02 ) . However , 61 % of the infants remained deficient despite vitamin A supplementation . Among vitamin A-supplemented infants only , diarrhea and ARI morbidity during the 3-mo period were compared in children with normal versus children with abnormal RDR at the end of the supplementation period . The ARI episodes were more frequent in the supplemented infants who remained vitamin A deficient at the end of the 3 mo ( P = 0.027 ) . Also , the cumulative duration ( days , mean + /- SD ) of fever and cough was 5.0 + /- 2.8 in the normal versus 11.2 + /- 6.0 in the deficient group ( P = 0.04 ) . The results of this study suggest that a large proportion of infants remain vitamin A deficient even after large dose vitamin A supplementation because of frequent respiratory infections , particularly those accompanied by fever [14668283] BACKGROUND We previously reported that maternal micronutrient supplementation in rural Nepal decreased low birth weight by approximately 15 % . OBJECTIVE We examined the effect of daily maternal micronutrient supplementation on fetal loss and infant mortality . DESIGN The study was a double-blind , cluster-r and omized , controlled trial among 4926 pregnant women and their 4130 infants in rural Nepal . In addition to vitamin A ( 1000 microg retinol equivalents ) , the intervention groups received either folic acid ( FA ; 400 microg ) , FA + iron ( 60 mg ) , FA + iron + zinc ( 30 mg ) , or multiple micronutrients ( MNs ; the foregoing plus 10 microg vitamin D , 10 mg vitamin E , 1.6 mg thiamine , 1.8 mg riboflavin , 2.2 mg vitamin B-6 , 2.6 microg vitamin B-12 , 100 mg vitamin C , 64 microg vitamin K , 20 mg niacin , 2 mg Cu , and 100 mg Mg ) . The control group received vitamin A only . RESULTS None of the supplements reduced fetal loss . Compared with control infants , infants whose mothers received FA alone or with iron or iron + zinc had a consistent pattern of 15 - 20 % lower 3-mo mortality ; this pattern was not observed with MNs . The effect on mortality was restricted to preterm infants , among whom the relative risks ( RRs ) were 0.36 ( 95 % CI : 0.18 , 0.75 ) for FA , 0.53 ( 0.30 , 0.92 ) for FA + iron , 0.77 ( 0.45 , 1.32 ) for FA + iron + zinc , and 0.70 ( 0.41 , 1.17 ) for MNs . Among term infants , the RR for mortality was close to 1 for all supplements except MNs ( RR : 1.74 ; 95 % CI : 1.00 , 3.04 ) . CONCLUSIONS Maternal micronutrient supplementation failed to reduce overall fetal loss or early infant mortality . Among preterm infants , FA alone or with iron reduced mortality in the first 3 mo of life . MNs may increase mortality risk among term infants , but this effect needs further evaluation [11160543] Nasopharyngeal colonization is a risk factor for pneumococcal disease , a leading cause of complications and death in infants . We assessed the impact of vitamin A supplementation in reducing pneumococcal colonization in infants from an area with endemic vitamin A deficiency . We recruited 464 2-mo-old infants from a rural area in South India . Infants were r and omly assigned to receive two 7000-microg retinol equivalent doses of vitamin A ( n = 239 ) or placebo ( n = 225 ) orally at birth , and nasopharyngeal specimens were collected at ages 2 , 4 and 6 mo . We studied the effect of vitamin A on culture-confirmed pneumococcal colonization and on the distribution of pneumococcal serotypes . Analyses were conducted by intention-to-treat . The risk of colonization among infants aged 4 mo who were not colonized by age 2 mo was significantly reduced in the vitamin A group compared with the placebo group [ odds ratio 0.51 ( 0.28 , 0.92 ) , P = 0.02 ) . The odds of colonization were 27 % lower in the treatment group than in the placebo group [ odds ratio 0.73 ( 0.48 , 1.1 ) , P = 0.13 ] . No differences were detected in the prevalence of invasive serotypes . The risk of colonization with penicillin-resistant isolates was 74 % lower in the vitamin A group than in the placebo group at 2 mo of age . However , the prevalence of penicillin-resistant isolates was only 4 % . Neonatal vitamin A supplementation may play a role in lowering morbidity rates associated with pneumococcal disease by delaying the age at which colonization occurs [15699235] BACKGROUND Young infants are at risk of vitamin A deficiency . Supplementation of breastfeeding mothers improves the vitamin A status of their infants , but there are no data regarding its effect on infant mortality , and data on the effect of directly supplementing infants during the first few weeks of life are conflicting . OBJECTIVE The objective was to measure the effect on infant mortality of supplementing neonates and their HIV-negative mothers with single , large doses of vitamin A during the immediate postpartum period . DESIGN A r and omized , placebo-controlled , 2-by-2 factorial design trial was conducted in 14,110 mothers and their infants ; 9208 of the mothers were HIV-negative at delivery , remained such during the postpartum year , and were retained in the current analysis . The infants were r and omly assigned within 96 h of delivery to 1 of 4 treatment groups : mothers and infants received vitamin A ( Aa ) , mothers received vitamin A and infants received placebo ( Ap ) , mothers received placebo and infants received vitamin A ( Pa ) , and both mothers and infants received placebo ( Pp ) . The vitamin A dose in the mothers was 400,000 IU and in the infants was 50,000 IU . The mother-infant pairs were followed to 12 mo . RESULTS Hazard ratios ( 95 % CI ) for 12 mo mortality among infants in the maternal-supplemented and infant-supplemented groups were 1.17 ( 0.87 , 1.58 ) and 1.08 ( 0.80 , 1.46 ) , respectively . Hazard ratios ( 95 % CI ) for the Aa , Ap , and Pa groups compared with the Pp group were 1.28 ( 0.83 , 1.98 ) , 1.27 ( 0.82 , 1.97 ) , and 1.18 ( 0.76 , 1.83 ) , respectively . These data indicate no overall effect . Serum retinol concentrations among a sub sample of women were similar to reference norms . CONCLUSION Postpartum maternal or neonatal vitamin A supplementation may not reduce infant mortality in infants of HIV-negative women with an apparently adequate vitamin A status [10573548] A r and omized , double-blind , placebo-controlled trial was conducted to evaluate the effect of simultaneous vitamin A supplementation and diphtheria , pertussis and tetanus ( DPT ) vaccination on the antibody levels . Infants aged 6 - 17 wk ( n = 56 ) were r and omly given 15 mg oral vitamin A or placebo at the time of their DPT immunization . Three such doses were given at monthly intervals . Immunoglobulin ( Ig ) G antibodies to diphtheria , pertussis and tetanus were assayed on enrollment and 1 mo after the third dose . Baseline antibody concentrations to diphtheria , pertussis and tetanus did not differ between the vitamin A-supplemented and placebo-treated groups . The postdose antibody to diphtheria level was significantly greater in the vitamin A than in the placebo-treated group . The geometric mean + /- SEM antibody levels ( mg/L ) were 22.9 + /- 1.2 and 11.0 + /- 1.3 in the vitamin A and placebo groups , respectively ( P = 0.029 ) . The postsupplementation concentrations of antibodies to pertussis and tetanus did not differ between the two groups . These results suggest that antibody response to diphtheria vaccination was potentiated by simultaneous vitamin A administration and DPT immunization [8988926] One hundred twenty infants were r and omly assigned to receive either 15 mg vitamin A or placebo with each of three DPT/OPV ( diphtheria , pertussis , tetanus/oral polio vaccine ) immunizations at monthly intervals . Sixty-two received vitamin A and 58 received placebo . One month after the third supplementation dose , the response to the delayed cutaneous hypersensitivity test [ multitest cell-mediated immunity ( CMI ) skin evaluation ] for tetanus , diphtheria , and tuberculin ( purified protein derivative , PPD ) was the same in the vitamin A and placebo infants . The number of anergic infants was 17 ( 27 % ) and 19 ( 33 % ) in the vitamin A and placebo groups , respectively . The number of positive tests among well-nourished infants was significantly higher than that in malnourished infants irrespective of supplementation ( P < 0.001 ) . Among the infants with adequate serum retinol concentrations ( > 0.7 mumol/L ) after supplementation , the vitamin A-supplemented infants had a significantly higher proportion of positive CMI tests than the placebo infants ( chi-square test : 8.99 , P = 0.008 ) . Among the infants with low serum retinol concentrations ( < 0.7 mumol/L ) after supplementation , vitamin A supplementation had no effect on CMI response . These results indicate that CMI in young infants was positively affected by vitamin A supplementation only in those infants whose vitamin A status was adequate ( ie , serum retinol > 0.7 mumol/L ) at the time of the CMI test . CMI was consistently better in well-nourished infants irrespective of supplementation [10702176] BACKGROUND Conflicting results have been reported regarding the relative performance of serum retinol , the modified-relative-dose-response ( MRDR ) ratio , and breast-milk vitamin A concentrations in detecting changes in maternal vitamin A status . OBJECTIVE We used receiver operating characteristic analyses and st and ardized differences to compare the ability of these indicators to detect a response to postpartum vitamin A supplementation in lactating Bangladeshi women . DESIGN At 2 wk postpartum , women were r and omly assigned to receive either a single dose of vitamin A [ 200000 IU ( 60000 retinol equivalents ) ; n = 74 ] or placebo ( n = 73 ) . Data from maternal serum and breast milk collected 3 mo postpartum and from infant serum collected 6 mo postpartum were used to examine the ability of serum retinol , the MRDR ratio , and breast-milk vitamin A to discriminate between individuals in the supplemented and unsupplemented groups . Breast milk was collected by expressing the entire contents of one breast that had not been used to feed an infant for > or = 2 h ( full sample s ) or without controlling the time since the last breast-feeding episode ( casual sample s ) . RESULTS Casual breast-milk sample s performed better than full breast-milk sample s in detecting a response to maternal supplementation . The MRDR ratio performed better than serum retinol in both the women and their infants . Overall , the most responsive indicator was the measurement of breast-milk vitamin A per gram of fat in casual breast-milk sample s. CONCLUSIONS Breast-milk vitamin A and the MRDR ratio are responsive indicators of vitamin A status , especially in women with mild vitamin A deficiency [16825698] BACKGROUND Anemia is prevalent in infants in developing countries . Its etiology is multifactorial and includes vitamin A deficiency . OBJECTIVE Our primary aim was to measure the effect of maternal or neonatal vitamin A supplementation ( or both ) on hemoglobin and anemia in Zimbabwean infants . Our secondary aim was to identify the underlying causes of postnatal anemia . DESIGN A r and omized , placebo-controlled trial was conducted in 14 110 mothers and their infants ; 2854 infants were r and omly selected for the anemia sub study , of whom 1592 were successfully observed for 8 - 14 mo and formed the study sample . Infants were r and omly assigned within 96 h of delivery to 1 of 4 treatment groups : mothers and infants received vitamin A ; mothers received vitamin A and infants received placebo ; mothers received placebo and infants received vitamin A ; and mothers and infants received placebo . The vitamin A doses were 400,000 and 50,000 IU in the mothers and infants , respectively . RESULTS Vitamin A supplementation had no effect on hemoglobin or anemia ( hemoglobin < 105 g/L ) in unadjusted or adjusted analyses . Infant HIV infection independently increased anemia risk > 6-fold . Additional predictors of anemia in HIV-negative and -positive infants were male sex and lower total body iron at birth . In addition , in HIV-positive infants , the risk of anemia increased with early infection , low maternal CD4 + lymphocyte count at recruitment , and frequent morbidity . Six-month plasma ferritin concentrations < 12 microg/L were a risk factor in HIV-negative but not in HIV-positive infants . Maternal HIV infection alone did not cause anemia . CONCLUSION Prevention of infantile anemia should include efforts to increase the birth endowment of iron and prevent HIV infection [8463867] For regions where vitamin A deficiency is common , high dose vitamin A supplementation of lactating mothers is currently recommended , but the effects of this intervention have not been carefully evaluated . We conducted a r and omized , double-blind trial in which 153 Indonesian mothers 1 - 3 wk postpartum received either a capsule containing 312 mumol of vitamin A as retinyl palmitate or a placebo . Mothers ' serum retinol concentrations in the vitamin A group tended to be lower than in the placebo group at baseline but higher at 3 mo postpartum ( 1.39 vs. 1.24 mumol/L , P = 0.03 ) and 6 mo postpartum ( 1.23 vs. 1.08 mumol/L , P < 0.01 ) . The milk retinol concentrations of the vitamin A group were higher than those of the placebo group by 0.48 to 1.18 mumol/L at 1 - 8 mo postpartum ( P < 0.05 ) . Among the infants at 6 mo of age , the prevalences of low serum retinol concentration ( < 0.52 mumol/L ) were 36 and 15 % in the placebo and vitamin A groups , respectively ( P < 0.005 ) , and the prevalences of low vitamin A stores ( assessed by relative dose response ) were 23 and 10 % , respectively ( P < 0.03 ) . High dose vitamin A supplementation of lactating mothers is an efficacious way to improve the vitamin A status of both mother and breast-fed infant [11340108] Night blindness occurs commonly among women during pregnancy in rural NEPAL : We examined the relationship between maternal night blindness and the risk of mortality occurring among infants in the first 6 mo of life . Stratified analysis by maternal night blindness status during pregnancy was done for 10,000 women participating in a r and omized , placebo-controlled trial of vitamin A and beta-carotene supplementation . Mortality of infants of non-night blind women in all three supplementation groups was similar , and when combined , was 63/1000 live births . Relative to this , mortality was higher by 63 % [ 95 % confidence interval ( CI ) : 9 - 138 % ) and 50 % ( 95 % CI : -3 to 133 % ) among infants of night blind women receiving placebo and beta-carotene , respectively , but only by 14 % ( 95 % CI : -33 to 93 % ) among those receiving vitamin A. Thus , 6-mo mortality was higher among infants of women who had night blindness during pregnancy . Maternal receipt of vitamin A reduced this risk [17449592] Vitamin A supplementation reduces child mortality and severe morbidity in less developed countries , and the Exp and ed Program on Immunization ( EPI ) offers an ideal opportunity to deliver supplements in developing countries . High-dose vitamin A supplementation has been shown to have no effect on the immunogenicity of oral polio vaccine , tetanus toxoid , pertussis , or on measles vaccine given at 9 mo , but a negative effect on measles vaccine administered at 6 mo and a potentiating effect on diphtheria vaccine . Its effect on the antibody response to hepatitis B and Haemophilus influenzae type b antigens has not yet been established . To assess these effects , the present trial was carried out in the Offinso district of Ghana ; 1077 infants were enrolled shortly after birth and r and omized either to receive or not to receive 15 mg retinol equivalent with vitamin A together with the pentavalent " diphtheria-polio-tetanus-Haemophilus influenzae b-hepatitis B " vaccine at 6 , 10 , and 14 wk of age . All mothers received a postpartum supplement of 120 mg retinol equivalent vitamin A as per national policy . Blood sample s were taken from infants at 6 and 18 wk of age . The results are based on 888 infants ( 82.4 % ) who completed the trial . The vitamin A supplementation did not affect the immune response to Haemophilus influenzae type b , but there was a significant improvement in the immune response to hepatitis B vaccine ( 93.9 vs. 90.2 % , P = 0.04 ) . However , given the high percentage of infants with seroprotection in the control group , it is doubtful that inclusion of vitamin A in the EPI would be justified on these grounds alone [17951487] Vitamin A supplementation reduces mortality in young children in areas of endemic vitamin A deficiency . However , it has no impact on the incidence of common morbidities . This discrepancy has been explained by an impact on case fatality , although with the exception of hospitalized measles cases , there is little direct evidence to support this hypothesis . We assessed the impact of newborn dosing with vitamin A on the incidence and case fatality of common childhood morbidities in early infancy in a community-based , r and omized trial in South India . Morbidity for each day in the previous 2 wk was assessed for the first 6 mo of life . A total of 11,619 live-born infants were enrolled and r and omized to receive either 48,000 IU ( 50.4 micromol retinol ) of oral vitamin A or placebo following delivery . There was no difference between treatment groups in the incidence of acute or chronic diarrhea , dysentery , or fever but a small increased incidence of acute respiratory illness ( ARI ) . Case fatality for diarrhea and fever were significantly reduced in the vitamin A group compared with placebo ( relative case fatality [ 95 % CI ] of 0.50 [ 0.27 , 0.90 ] and 0.60 [ 0.40 , 0.88 ] , respectively ) . There was a trend in reduction of case fatality for various definitions of ARI , but the evidence for this effect was modest . Survival analysis among those with morbid episodes confirmed the case fatality analysis . This trial demonstrated that the reduction in overall mortality due to newborn vitamin A dosing was driven primarily by a reduction in case fatality among infants [9152680] Objectives : To evaluate the effect of vitamin A supplementation 24 h after delivery on breastmilk retinol concentration . Methods : Fifty low income women were r and omly assigned to a single oral dose of 209 μmol of Vitamin A or none at delivery . Maternal serum and breastmilk retinol levels and infant morbidity and anthropometry were serially assessed . Results : Mean ( 95 % CI ) serum retinol levels increased in the supplemented mothers at 2.77 ( 2.3 , 3.2 ) compared to 1.15 ( 0.9 , 1.4 ) μmol/l in controls ( P<0.05 ) and remained at a significantly higher level of 1.59 ( 1.4 , 1.8 ) μmul/l compared to 1.33 ( 1.8 , 1.5 ) μmol/l in the control group ( P<0.001 ) up to a period of three months . Breastmilk retinol concentration was also greater at 24 h after supplementation , mean ( CI ) 11.34 ( 9.0 , 13.7 ) μmol/l , compared to 2.95 ( 2.3 , 3.6 ) μmol/l in the control group ( P<0.0001 ) , and remained higher for the next six months at 1.06 ( 0.9 , , 1.3 ) μmol/l compared to 0.73 ( 0.6 , 0.8 ) μmol/l in the control group ( P<0.02 ) . Infants of the supplemented mothers had reduced mean duration of respiratory tract infection of 3.1 ( 2.7 , 3.5 ) days compared to 3.7 ( 3.3 , 4.2 ) days ( P<0.03 ) and mean incidence of febrile illness 0.1 ( 0.1 , 0.1 ) compared to control infants 0.3 ( 0.3 , 0.3 ) days , ( P<0.002 ) . Conclusion : Vitamin A supplementation of malnourished mothers maintains higher breastmilk retinol concentration for at least six months and reduces the duration of respiratory tract infection and febrile illness in their breastfed infants . Sponsorship : The study was supported by the International Centre for Diarrhoeal Disease Research and the United States Agency for International Development [17391562] Postpartum vitamin A supplementation of mothers and infants is recommended , but the efficacy has been question ed . In this double-blind , placebo-controlled trial , Kenyan mother-infant pairs were r and omised to maternal vitamin A ( 400,000 IU ) or placebo < 24 h postpartum , and infant vitamin A ( 100,000 IU ) or placebo at 14 weeks . Milk retinol was determined at weeks 4 , 14 and 26 , and maternal and infant serum retinol at weeks 14 and 26 . Infant retinol stores were assessed at week 26 , using a modified relative dose response ( MRDR ) test . Among 564 women , serum retinol at 36 weeks gestation was 0.81 ( SD 0.21 ) micromol/l , and 33.3 % were<0.7 micromol/l . Maternal serum retinol was not different between groups , but milk retinol was higher in the vitamin A group : ( 0.67 v. 0.60 micromol/l ; 0.52 v. 0.44 micromol/l ; 0.50 v. 0.44 micromol/l at 4 , 14 and 26 weeks , respectively ) . When expressed per gram fat , milk retinol was higher in the vitamin A group only at 4 weeks . Infant serum retinol was not different between groups . However , although most infants had deficient vitamin A stores ( MRDR>0.06 % ) at 26 weeks , vitamin A to infants , but not mothers , result ed in a lower proportion of infants with deficient vitamin A stores ( 69 v. 78 % ) . High-dose postpartum vitamin A supplementation failed to increase serum retinol and infant stores , despite modest effects on milk retinol . Infant supplementation , however , increased stores . There is a need for a better underst and ing of factors affecting absorption and metabolism of vitamin [9605804] BACKGROUND In HIV-1-infected women , poor micronutrient status has been associated with faster progression of HIV-1 disease and adverse birth outcomes . We assessed the effects of vitamin A and multivitamins on birth outcomes in such women . METHODS In Tanzania , 1075 HIV-1-infected pregnant women at between 12 and 27 weeks ' gestation received placebo ( n=267 ) , vitamin A ( n=269 ) , multivitamins excluding vitamin A ( n=269 ) , or multivitamins including vitamin A ( n=270 ) in a r and omised , double-blind , placebo-controlled trial with a 2x2 factorial design . We measured the effects of multivitamins and vitamin A on birth outcomes and counts of T lymphocyte subsets . We did analyses by intention to treat . RESULTS 30 fetal deaths occurred among women assigned multivitamins compared with 49 among those not on multivitamins ( relative risk 0.61 [ 95 % CI 0.39 - 0.94 ] p=0.02 ) . Multivitamin supplementation decreased the risk of low birthweight ( < 2500 g ) by 44 % ( 0.56 [ 0.38 - 0.82 ] p=0.003 ) , severe preterm birth ( < 34 weeks of gestation ) by 39 % ( 0.61 [ 0.38 - 0.96 ] p=0.03 ) , and small size for gestational age at birth by 43 % ( 0.57 [ 0.39 - 0.82 ] p=0.002 ) . Vitamin A supplementation had no significant effect on these variables . Multivitamins , but not vitamin A , result ed in a significant increase in CD4 , CD8 , and CD3 counts . INTERPRETATION Multivitamin supplementation is a low-cost way of substantially decreasing adverse pregnancy outcomes and increasing T-cell counts in HIV-1-infected women . The clinical relevance of our findings for vertical transmission and clinical progression of HIV-1 disease is yet to be ascertained [12896935] Abstract Objective To assess the impact of supplementing newborn infants with vitamin A on mortality at age 6 months . Design Community based , r and omised , double blind , placebo controlled trial . Setting Two rural districts of Tamil Nadu , southern India . Participants 11 619 newborn infants allocated 24 000 IU oral vitamin A or placebo on days 1 and 2 after delivery . Main outcome measure Primary outcome measure was mortality at age 6 months . Results Infants in the vitamin A group had a 22 % reduction in total mortality ( 95%confidence interval 4 % to 37 % ) compared with those in the placebo group . Vitamin A had an impact on mortality between two weeks and three months after treatment , with no additional impact after three months . Conclusion Supplementing newborn infants with vitamin A can significantly reduce early infant mortality [12897218] Background and objective : In developing countries low maternal vitamin A stores combined with increased dem and s of pregnancy and lactation may lead to its deficiency in breastfed infants . This study evaluates the effects of maternal supplementation with a high dose of vitamin A on the serum retinol levels of exclusively breastfed infants , and their morbidity in the first six months of life . Setting : Hospital based . Study design : R and omised controlled trial . Subjects and methods : Mothers of the test group ( n=150 ) were orally supplemented with a single dose of retinol ( 209 μmol ) soon after delivery and were advised exclusive breastfeeding for six months . Before supplementation retinol levels were estimated in the mothers ’ and newborns ’ blood , and in colostrum . On follow up , breastmilk and infants ’ serum retinol contents were assessed monthly for six months . Retinol level < 0.7 μmol/l indicated vitamin A deficiency . Morbidity patterns like vitamin A deficiency , diarrhoea , febrile illnesses , acute respiratory infection , measles , and ear infection were also studied and compared between the two groups . Results : Presupplement mean maternal serum retinol levels were 0.98 and 0.92 μmol/l and mean breastmilk levels were 3.85 and 3.92 μmol/l in the test and control groups respectively ( p>0.05 ) . Mean cord blood retinol levels were also comparable ( 0.68 v 0.64 μmol/l ) . After supplementation , the test group showed a rise in mean breastmilk retinol content ( 12.08 v 2.96 μmol/l ) which remained significantly higher for four months . The infants ’ mean serum retinol level , initially 322.06 % of the baseline value , was significantly higher for five months . In the control group , significant numbers of mothers and infants showed deficient breastmilk and serum retinol throughout the follow up ( p<0.01 ) . Decreased incidence and duration of various diseases were also found in the test group suggesting lesser morbidity . Conclusion : Maternal supplementation with single megadose vitamin A is an effective strategy for vitamin A prophylaxis of exclusively breastfed infants of 0–6 months [12173139] Vitamin A is essential for immunity and growth . A controlled clinical that involved 697 human immunodeficiency virus (HIV)-infected pregnant women was conducted to determine whether vitamin A prevents anemia , low birth weight , growth failure , HIV transmission , and mortality . Women received daily doses of iron and folate , either alone or combined with vitamin A ( 3 mg retinol equivalent ) , from 18 - 28 weeks ' gestation until delivery . In the vitamin A and control groups , respectively , the mean ( + /-SE ) birth weights were 2895+/-31 g and 2805+/-32 g ( P=.05 ) , the proportions of low-birth-weight infants were 14.0 % and 21.1 % ( P=.03 ) , the proportions of anemic infants at 6 weeks postpartum were 23.4 % and 40.6 % ( P<.001 ) , and the respective cumulative proportions of infants who were HIV infected at 6 weeks and 24 months of age were 26.6 % and 27.8 % ( P=.76 ) and 27.7 % and 32.8 % ( P=.21 ) . Receipt of vitamin A improved birth weight and neonatal growth and reduced anemia , but it did not affect perinatal HIV transmission [7488807] To evaluate the safety of vitamin A supplementation in early infancy using DPT/OPV immunization contracts , a double‐blind , r and omized , placebo‐controlled trial was conducted in Bangladesh . One hundred and sixty‐seven infants received three doses of either 25 000 IU of vitamin A or a placebo at about 6.5 , 11.8 and 17.0 weeks of age . Trained physicians examined each of the infants on days 1 , 2 , 3 and 8 after supplementation . Nine infants ( 10.5 % ) supplemented with vitamin A had episodes of bulging of the fontanelle compared with two infants ( 2.5 % ) in the placebo group ( p < 0.05 ) . Twelve of the 14 episodes occurred in infants supplemented with vitamin A. Of these 12 episodes , none occurred with the first dose , 3 occurred with the second and 9 with the third dose . The higher incidence of bulging of the fontanelle in the vitamin A group relative to the placebo group and its temporal association with the vitamin A doses are suggestive of a causal association . The finding that increased numbers of vitamin A doses were associated with a higher probability of bulging of the fontanelle suggests a cumulative effect . Bulging fontanelle , clinical trial , safety , toxicity , vitamin [16479521] BACKGROUND Low maternal serum retinol level is a risk factor for mother-to-child transmission ( MTCT ) of human immunodeficiency virus ( HIV ) . Multiple-large-dose vitamin A supplementation of HIV-positive children reduces mortality . The World Health Organization recommends single-large-dose vitamin A supplementation for postpartum women in areas of prevalent vitamin A deficiency ; neonatal dosing is under consideration . We investigated the effect that single-large-dose maternal/neonatal vitamin A supplementation has on MTCT , HIV-free survival , and mortality in HIV-exposed infants . METHODS A total of 14,110 mother-infant pairs were enrolled < or = 96 h after delivery , and both mother and infant , mother only , infant only , or neither received vitamin A supplementation in a r and omized , placebo-controlled trial with a 2 x 2 factorial design . All but 4 mothers initiated breast-feeding . A total of 4495 infants born to HIV-positive women were included in the present analysis . RESULTS Neither maternal nor neonatal vitamin A supplementation significantly affected postnatal MTCT or overall mortality between baseline and 24 months . However , the timing of infant HIV infection modified the effect that supplementation had on mortality . Vitamin A supplementation had no effect in infants who were polymerase chain reaction ( PCR ) positive [ corrected ] for HIV at baseline . In infants who were PCR negative at baseline and PCR positive at 6 weeks , neonatal supplementation reduced mortality by 28 % ( P=.01 ) , but maternal supplementation had no effect . In infants who were PCR negative at 6 weeks , all 3 vitamin A regimens were associated with ~2-fold higher mortality ( P < or = .05 ) . CONCLUSIONS Targeted vitamin A supplementation of HIV-positive children prolongs their survival . However , postpartum maternal and neonatal vitamin A supplementation may hasten progression to death in breast-fed children who are PCR negative at 6 weeks . These findings raise concern about universal maternal or neonatal vitamin A supplementation in HIV-endemic areas [17586304] BACKGROUND Most developing countries have adopted a st and ard WHO dosing schedule for vitamin A supplementation . However , in 2002 the International Vitamin A Consultative Group ( IVACG ) Annecy Accord recommended a new high-dose regimen for mothers and infants . Our aim was to test whether the new high-dose regimen of vitamin A supplementation would increase maternal and infant plasma vitamin A , reduce infant Helicobacter pylori infection and nasopharyngeal pneumococcal carriage , and improve infant gut epithelial integrity . METHODS In an area of moderate vitamin A deficiency in rural Gambia , 220 mother-infant pairs were enrolled in a r and omised double-blind trial between September , 2001 , and October , 2004 , that compared the IVACG high dose with the WHO dose . The primary endpoints were levels of maternal and infant plasma vitamin A , H pylori infection , pneumococcal carriage , and gut epithelial integrity . The trial is registered as IS RCT N 98554309 . FINDINGS 197 infants completed follow-up to 12 months ( 99 high dose and 98 WHO dose ) . There were no adverse events at dosing . No differences were found in the primary outcomes for high-dose versus WHO schedule : maternal vitamin A concentration at 2 months + 0.02 micromol/L ( 95 % CI -0.10 to 0.15 ) ; infant vitamin A at 5 months + 0.01 micromol/L ( -0.06 to 0.08 ) ; H pylori infection at 12 months -0.3 % ( -14.7 to 14.2 ) ; maternal pneumococcal carriage at 12 months -2.0 % ( -13.7 to 9.7 ) ; infant pneumococcal carriage at 12 months -4.1 % ( -15.8 to 7.6 ) ; infant gut mucosal damage at 12 months 5.2 % ( -8.7 to 19.2 ) . There were more clinic attendances by the high-dose group in the first 6 months of life ( p=0.018 ) . INTERPRETATION Our results do not lend support to the proposal to increase the existing WHO st and ard dosing schedule for vitamin A in areas of moderate vitamin A deficiency . Caution is urged for future studies because trials have shown possible adverse effects of higher doses of vitamin A , and potential negative interactions with the exp and ed programme on immunisation ( EPI ) vaccines [17538544] Objective : To determine whether the combined intervention of 50 000 IU vitamin A administered together with Bacille Calmette-Guerin ( BCG ) vaccination at birth was associated with adverse events , in particular bulging fontanels and adverse reactions to BCG.Subjects/ Methods : From an ongoing trial , 2145 infants r and omized to 50 000 IU vitamin A or placebo with BCG vaccination were recruited . Adverse events were monitored in two different ways : ( A ) daily clinical examinations by a medical doctor during the first 3 days post supplementation ; ( B ) weekly interviews by a trained assistant during the first month post supplementation . Results : In part A , 1271 infants were enrolled , in part B 2078 . Vitamin A supplementation ( VAS ) was associated with a relative risk ( RR ) of bulging fontanels of 1.16 ( 95 % confidence interval (CI)=0.82–1.65 ) . The rate of health care contacts and various symptoms during the first month were comparable between the groups . VAS was associated with larger peak local reactions to BCG vaccination in boys , but not in girls ( P-value for test of interaction between VAS and sex=0.02 ) . Conclusion : 50 000 IU vitamin A with BCG was not associated with adverse events . The observed sex-differential effect of VAS on local reaction to BCG is in line with other observations of sex-differential effects of VAS [1676467] Community trials of the efficacy of vitamin A supplementation in reducing preschool childhood mortality have produced conflicting results . To resolve the question , a r and omised , double-masked , placebo-controlled community trial of 28,630 children aged 6 - 72 months was carried out in rural Nepal , an area representative of the Gangetic flood plain of South Asia . R and omisation was carried out by administrative ward ; the vitamin-A-supplemented children received 60,000 retinol equivalents every 4 months and placebo-treated children received identical capsules containing 300 retinol equivalents . After 12 months , the relative risk of death in the vitamin-A-supplemented compared with the control group was 0.70 ( 95 % confidence interval 0.56 - 0.88 ) , equivalent to a 30 % reduction in mortality . The trial , which had been planned to last 2 years , was discontinued . The reduction in mortality was present in both sexes ( relative risk for boys 0.77 ; for girls 0.65 ) , at all ages ( range of relative risks 0.83 - 0.50 ) , and throughout the year ( 0.76 - 0.67 ) . The reduction in mortality risk was not affected by acute nutritional status , as measured by arm circumference . Thus , periodic vitamin A delivery in the community can greatly reduce child mortality in developing countries [17931488] OBJECTIVE To assess the effect of retinyl palmitate supplementation on colostrum retinol levels , investigating the influence of maternal variables ( age , type of delivery , and biochemical nutritional status ) on these levels . METHOD The study included 33 mothers receiving care at the Januário Cicco Maternity School , in the city of Natal , Rio Gr and e do Norte , Brazil . In the first hours after delivery , blood and colostrum sample s were collected . Another colostrum sample was collected six hours after maternal supplementation with 200,000 IU of retinyl palmitate . Serum and colostrum retinol levels were determined by high-performance liquid chromatography . RESULTS The mean retinol level in colostrum before the supplementation was 110.8 + /- 82.3 microg/dL , and after supplementation it was 164.4 + /- 106.5 microg/dL ( P < 0.025 ) . Of the 33 mothers , 12 of them either did not respond to supplementation or had an increase of less than 10 % in colostrum retinol levels ; serum retinol in these women was significantly lower as compared to the responders ( P = 0.024 ) . In comparison to women with a normal delivery , the mothers who underwent cesarean delivery ( 64 % ) had lower serum retinol levels , but not lower colostrum retinol levels ( P = 0.036 ) . Maternal age did not influence retinol levels in either serum or colostrum . CONCLUSION The increase in colostrum retinol levels following vitamin A supplementation was sufficient to guarantee double the retinol requirements of a newborn infant [8772901] OBJECTIVES To assess the impact of Vitamin A supplementation to the mother soon after delivery and to the infant at six months on morbidity in infancy . DESIGN R and omized double blind placebo controlled field trial . SETTING 51 villages in two contiguous Primary Health Centers in Villupuram Health Unit District of Tamil Nadu , South India . SUBJECTS 909 newly delivered mother- and -infant pairs . INTERVENTIONS Both mother and infant received Vitamin A ( 300,000 IU for mothers and 200,000 IU for children ) in 311 instances ( AA ) ; mother received Vitamin A but infant received Placebo in 301 instances ( AP ) ; and both mother and infant received Placebo in the remaining 297 instances ( PP ) . MAIN OUTCOME MEASURES Incidence of diarrhea and Acute Respiratory Infection ( ARI ) ; distributions of infants by frequency of episodes and number of infected days . RESULTS 233 in the AA Group and 228 each in the AP and PP Groups were followed up regularly . The incidence of diarrhea in these infants was 97.4 % , 96.9 % and 94.7 % in the three groups , mean number of diarrheal episodes was 4.4 , 4.6 and 4.2 and median number of days in infancy with diarrhea was 26 , 26 and 22 days , respectively . For ARI , the incidences were 96.6 % , 95.6 % and 96.1 % , means were 4.8 , 5.1 and 4.8 episodes , and the medians were 32 , 34 and 34 days , respectively . CONCLUSIONS Prophylactic administration of mega doses of Vitamin A to the mother soon after delivery and to the infant at six months do not have any beneficial impact on the incidence of diarrhea and ARI in infancy [9707874] OBJECTIVE To explore the effect of maternal supplementation of vitamin A on the immune response to oral polio vaccine in breastfed infants . DESIGN R and omized controlled trial . SETTING Hospital based . METHODS One hundred mothers having uncomplicated deliveries r and omly received either 200,000 IU vitamin A orally ( Experimental ) or placebo ( Control ) . All the newborns were given a dose of oral polio vaccine within 72 hours after birth and were breastfed . Type specific neutralizing antibodies to polio viruses in test sera diluted from 1:4 to 1:512 and serum retinol levels were determined from the cord blood and at the age of 6 weeks . Breast milk retinol levels were determined at 3 , 10 , 30 , 45 and 90 days of lactation . RESULTS Seroconversion to OPV and geometric means of antibody titers to the three types of polio viruses were comparable between the groups of infants belonging to the experimental and control mothers . Breast milk retinol levels were significantly higher in the experimental group upto 45 - 90 days of lactation . Majority of the infants at birth had serum retinol levels < 15 micrograms/dl which improved significantly by 6 weeks irrespective of the maternal supplementation status . CONCLUSIONS Maternal vitamin A supplementation soon after delivery improves vitamin A intakes of breastfed infants during the first 3 months and has no interference with the seroconversion to a neonatal dose of OPV . OPV administered to newborn in turn has no adverse effect on the vitamin A status of the breastfed infants [2835853] Objective To investigate the effect of vitamin A supplementation and BCG vaccination at birth in low birthweight neonates . Design R and omised , placebo controlled , two by two factorial trial . Setting Bissau , Guinea-Bissau . Participants 1717 low birthweight neonates born at the national hospital . Intervention Neonates who weighed less than 2.5 kg were r and omly assigned to 25 000 IU vitamin A or placebo , as well as to early BCG vaccine or the usual late BCG vaccine , and were followed until age 12 months . Main outcome measure Mortality , calculated as mortality rate ratios ( MRRs ) , after follow-up to 12 months of age for infants who received vitamin A supplementation compared with those who received placebo . Results No interaction was observed between vitamin A supplementation and BCG vaccine allocation ( P=0.73 ) . Vitamin A supplementation at birth was not significantly associated with mortality : the MRR of vitamin A supplementation compared with placebo , controlled for r and omisation to “ early BCG ” versus “ no early BCG ” was 1.08 ( 95 % CI 0.79 to 1.47 ) . Stratification by sex revealed a significant interaction between vitamin A supplementation and sex ( P=0.046 ) , the MRR of vitamin A supplementation being 0.74 ( 95 % CI 0.45 to 1.22 ) in boys and 1.42 ( 95 % CI 0.94 to 2.15 ) in girls . When these data were combined with data from a complementary trial among normal birthweight neonates in Guinea-Bissau , the combined estimate of the effect of neonatal vitamin A supplementation on mortality was 1.08 ( 95 % CI 0.87 to 1.33 ) ; 0.80 ( 95 % CI 0.58 to 1.10 ) in boys and 1.41 ( 95 % CI 1.04 to 1.90 ) in girls ( P=0.01 for interaction between neonatal vitamin A and sex ) . Conclusions The combined results of this trial and the complementary trial among normal birthweight neonates have now shown that , overall , it would not be beneficial to implement a neonatal vitamin A supplementation policy in Guinea-Bissau . Worryingly , the trials show that vitamin A supplementation at birth can be harmful in girls . Previous studies and future trials should investigate the possibility that vitamin A supplementation has sex differential effects . Trial registration Clinical Trials.gov NCT00168610 [18595969] OBJECTIVES . We assessed the effect of supplementing newborns with 50000 IU of vitamin A on all-cause infant mortality through 24 weeks of age . PATIENTS AND METHODS . This was a community-based , double-masked , cluster-r and omized , placebo-controlled trial conducted in 19 unions in rural northwest Bangladesh . The study was nested into and balanced across treatment arms of an ongoing placebo-controlled , weekly maternal vitamin A or β-carotene supplementation trial . Study -defined sectors ( N = 596 ) were evenly r and omized for newborns of participating mothers to receive a single , oral supplement of vitamin A ( 50000 IU ) or placebo as droplets of oil squeezed from a gelatinous capsule . Mothers provided informed consent for newborn participation at ∼28 weeks ' gestation . After birth , typically at home ( where > 90 % of births occurred ) , infants were supplemented and their vital status was followed through 24 weeks of age . The main outcome measure was mortality through 24 weeks of age . RESULTS . We obtained maternal consent to dose 17116 live-born infants ( 99.8 % of all eligible ) among whom 15937 ( 93.1 % ) were visited to be supplemented < 30 days after birth and for whom vital status at 24 weeks of age was known . Dosed infants ( n = 15902 [ 99.8 % ] ) received their study supplement at a median age of 7 hours . Relative to control subjects , the risk of death in vitamin A – supplemented infants was 0.85 , reflecting a 15 % reduction in all-cause mortality . Protective relative risks were indistinguishable by infant gender , gestational age , birth weight , age at dosing , maternal age , parity , or across the 3 treatment arms of the maternal supplementation trial . CONCLUSIONS . Newborn vitamin A dosing improved infant survival through the first 6 months of life in Bangladesh . These results corroborate previous findings from studies in Indonesia and India and provide additional evidence that vitamin A supplementation shortly after birth can reduce infant mortality in South Asia [8618182] OBJECTIVE To determine whether vitamin A supplementation at birth could reduce infant morbidity and mortality . STUDY DESIGN We conducted a placebo-controlled trial among 2067 Indonesian neonates who received either 52 micromol ( 50,000 IU ) orally administered vitamin A or placebo on the first day of life . Infants were followed up at 1 year to determine the impact of this intervention on infant mortality . A subgroup ( n = 470 ) was also examined at 4 and 6 months of age to examine the impact on morbidity . RESULTS Vital status was confirmed in 89 % of infants in both groups at 1 year . There were 19 deaths in the control group and 7 in the vitamin A group ( relative risk = 0.36 ; 95 % confidence interval = 0.16 , 0.87 ) . The impact was stronger among boys , infants of normal compared with low birth weight , and those of greater ponderal index . Among infants examined at 4 months of age , the 1-week period prevalence of common morbidities was similar for vitamin A and control infants . However , during this same 4-month period , 73 % and 51 % more control infants were brought for medical treatment for cough ( p = 0.008 ) and fever ( p = 0.063 ) , respectively . CONCLUSIONS Neonatal vitamin A supplementation may reduce the infant mortality rate and the prevalence of severe respiratory infection among young infants [10771879] The mutual interactions of measles vaccine and vitamin A dose when administered simultaneously to 9 month old infants are explored in this study . One hundred healthy infants of 9 months of age received EZ strain of measles vaccine in the routine immunization clinic along with either 100,000 IU of vitamin A or a placebo orally . Blood sample s were collected before and 4 weeks after intervention . They were coded and analysed for serum retinol and Hemagglutination Inhibition ( HI ) antibodies to measles . Ninety five per cent of the infants were seronegative to measles prior to vaccination with a seroconversion rate of 63 % in the control group and a significantly higher percent of 83.7 % in the experimental group ( P < 0.01 ) . Seroconversion was not related to initial serum retinol levels in either of the groups . 42 % of infants had serum retinol levels less than 20 ug/dl before administration of the vaccine and both the groups showed improvement in vitamin A status following intervention , the increase being significant in the experimental group ( from 22.4 ± 1.32 to 26.0 ± 1.07 ; P < 0.05 ) . The results indicate that majority of the infants at 9 months of age were seronegative to measles . Seroconversion to measles vaccine in the routine immunization clinics was low . Simultaneous administration of vitamin A and measles vaccine had beneficial effects on vitamin A status as well as seroconversion rates to the vaccine in 9 months old infants [11965510] Objective : To investigate whether supplementation with vitamin A together with iron of Indonesian pregnant women decreases morbidity and improves growth of their infants during the first year of life . Design : Women from a rural area in West Java , Indonesia , were r and omly assigned on an individual basis to double-blind supplementation once weekly from ∼18 weeks of pregnancy until delivery . Supplementation comprised 120 mg iron and 500 µg folic acid with or without 4800 RE vitamin A. Their newborn infants were followed up during the first year of life : weight , length , morbidity and food intake were assessed monthly . Results : Infants whose mothers had taken vitamin A supplements during pregnancy had similar weight , length , weight gain and growth as their counterparts during the follow-up period . The proportions of infants with reported symptoms of morbidity were similar in the vitamin A plus iron group and the iron group . In addition immunisation coverage and feeding mode did not differ between the groups . All infants were breast-fed , but exclusive breast-feeding rapidly declined at 4 months of age . Infants with serum retinol concentrations > 0.70 µmol/l increased their weight and length more during the first 6 months of life and had higher weight-for-age Z-scores during the first year of life than infants with serum retinol concentrations ≤0.70 µmol/l . Serum retinol concentrations were not associated with morbidity . Conclusion : In this study , vitamin A supplementation in conjunction with iron supplementation of pregnant women did not improve growth or reduce morbidity of their infants during the first year of life . Sponsorship : Netherl and s Organization for Scientific Research -Netherl and s Foundation for the Advancement of Tropical Research ( NWO-WOTRO ) ( WV 93 - 280 ) , the Neys-van Hoogstraten Foundation ( IN 114 ) , The Netherl and s and the German Agency for Technical Cooperation (GTZ)/South East Asian Ministers of Education Organization , Tropical Medicine ( SEAMEO-TROPMED ) , Indonesia [8102669] A double-blind , r and omised , placebo-controlled trial was conducted to evaluate the safety and toxicity of vitamin A supplementation within the Exp and ed Programme on Immunisation ( EPI ) in rural Bangladesh . 191 infants received 3 doses of either 50,000 IU of vitamin A or placebo at about 1.5 , 2.5 , and 3.5 months and were examined on days 1 , 2 , 3 , and 8 after supplementation . 11 infants ( 11.5 % ) supplemented with vitamin A had episodes of bulging of the fontanelle as opposed to 1 ( 1 % ) in the placebo group . 16 of the 17 events occurred in the vitamin A supplemented group . No other side effects were noted . There was a tendency towards a cumulative effect of toxicity with increasing doses [12351954] Background : HIV-1 transmission through breastfeeding is a global problem and has been associated with poor maternal micronutrient status . Methods : A total of 1078 HIV-infected pregnant women from Tanzania were r and omly assigned to vitamin A or multivitamins excluding A from approximately 20 weeks ’ gestation and throughout lactation . Results : Multivitamins excluding A had no effect on the total risk of HIV-1 transmission ( RR 1.04 , 95 % CI 0.82–1.32 , P = 0.76 ) . Vitamin A increased the risk of transmission ( RR 1.38 , 95 % CI 1.09–1.76 , P = 0.009 ) . Multivitamins were associated with non-statistically significant reductions in transmission through breastfeeding , and mortality by 24 months among those alive and not infected at 6 weeks . Multivitamins significantly reduced breastfeeding transmission in infants of mothers with low baseline lymphocyte counts ( RR 0.37 ; 95 % CI 0.16–0.85 , P = 0.02 ) compared with infants of mothers with higher counts ( RR 0.99 , 95 % CI 0.68–1.45 , P = 0.97 ; P-for-interaction 0.03 ) . Multivitamins also protected against transmission among mothers with a high erythrocyte sedimentation rate ( P-for-interaction 0.06 ) , low hemoglobin ( P-for-interaction 0.06 ) , and low birthweight babies ( P-for-interaction 0.04 ) . Multivitamins reduced death and prolonged HIV-free survival significantly among children born to women with low maternal immunological or nutritional status . Vitamin A alone increased breastfeeding transmission but had no effect on mortality by 24 months . Conclusion : Vitamin A increased the risk of HIV-1 transmission . Multivitamin ( B , C , and E ) supplementation of breastfeeding mothers reduced child mortality and HIV-1 transmission through breastfeeding among immunologically and nutritionally compromised women . The provision of these supplements to HIV-infected lactating women should be considered [11219162] Summary The World Health Organization recommends that 100,000 IU of vitamin A be given to infants between 6 and 12 months of age at the same time as measles vaccination in order to prevent vitamin A deficiency . In the present study , our aim was to assess the effect of vitamin A supplementation on T-cell subsets in a r and omized factorial design , seeking a possible modifying effect of measles vaccination . Three hundred children were allocated either to two doses of measles vaccine at 6 and 9 months of age or to poliomyelitis vaccine at age 6 months and measles vaccine at age 9 months . Within each group , infants were to receive two doses of vitamin A or two doses of placebo at 6 and 9 months of age . We found no significant effect of vitamin A supplementation on CD4 and CD8 T-cell subsets at 3 and 9 months after supplementation . We found no effect of measles vaccine and no interaction between vitamin A supplementation and measles vaccine . Based on these observations , vitamin A supplementation does not seem to have a strong long-term effect on CD4 and CD8 T-cell subsets in infants without clinical vitamin A deficiency [7656887] OBJECTIVE To investigate whether monthly administration of vitamin A at routine immunisation produces any side-effects , and to examine the effect of this supplementation on the vitamin A nutrition status of infants . DESIGN A double-blind r and omised placebo-controlled clinical trial . SETTING Immunisation clinic of a large diarrhoea treatment centre . SUBJECTS Infants aged 6 - 17 weeks who will receive their first diphtheria-pertussis-tetanus/oral polio vaccine ( DPT/OPV ) dose . METHODS Infants were r and omly assigned to receive either 25,000 IU vitamin A or placebo . Three such doses were given with each immunisation dose at monthly intervals . Infants were examined by a physician before and during 24 h after the doses and any signs of toxicity were recorded . Venous blood was drawn at entry and 1 month after the 3rd dose for retinol assay . RESULTS One hundred and one infants received vitamin A and 98 received placebo . Decreased feeding , irritability , diarrhoea , and vomiting were comparable between the two groups . In the vitamin A group five infants developed bulging fontanelle ; three of them developed it once ( after 1st , 2nd and 3rd dose respectively ) , one developed it twice ( after both the 2nd and 3rd dose ) , and the other infant after all three doses . In the placebo group a single child developed bulging fontanelle after the 3rd dose . In all the cases the bulging disappeared within 48 h of onset except in one infant , in whom it subsided at 60 h. The total bulging episodes in the vitamin A and placebo groups were 8 and 1 respectively ( RR = 7.7 ; P < 0.04 ) . However , none of these infants had irritability . At entry fasting retinol level was < 10 micrograms/dl in 35 % infants and in 87 % infants it was < 20 micrograms/dl . After the third dose fasting retinol level was marginally better in the vitamin A group ( mean + /- s.d . : 21.9 + /- 8.2 vs 19.2 + /- 7.8 ; P = 0.05 ) . However , 47 % infants receiving supplementation still had serum retinol level < 20 micrograms/dl . CONCLUSION The results suggest that administration of 25,000 IU of vitamin A in young infants along with routine immunisations , though associated with increased incidence of transient bulging fontanelle without any associated adverse signs or symptoms , may still be inadequate to prevent deficiency in this population . SPONSORSHIP This study was funded by the United States Agency for International Development ( USAID ) under grant no. DPE-5986-A-1009 - 00 with the International Centre for Diarrhoeal Disease Research , Bangladesh ( ICDDR , B ) . The ICDDR , B is supported by countries and agencies which share its concern for the health problems of developing countries [11086300] OBJECTIVE To assess the Vitamin A status of pregnant women in their third trimester using maternal serum retinol levels as the indicator ; and ( ii ) To assess the impact of postpartum Vitamin A supplementation on the Vitamin A status of exclusively breastfed infants . DESIGN Prospect i ve r and omized single blind controlled study . SETTING Teaching Hospital . SUBJECTS 109 apparently healthy primi and second gravida women registered at the antenatal clinic were included in the study and followed up for three months postpartum . Serum retinol levels of pregnant mothers in their third trimester ( 35 - 37 weeks ) and cord blood levels after delivery were estimated . Mothers were then assigned to two groups . The experimental group included 53 mothers who received a single dose of 2 lakh units of Vitamin A orally . The control group had 56 mothers who did not receive Vitamin A. Mothers and infants were followed up for three months . The serum retinol of infants and the breast milk retinol levels were estimated at the end of three months and the results were compared . The growth of the infants was also monitored . RESULTS Sub clinical Vitamin A deficiency was seen in 29.67 % of pregnant women . At the end of three months , 69.6 % of mothers in the control group had breast milk retinol levels below 30 mg/dl , as opposed to 36.1 % in the experimental group . Forty five per cent of infants in the control group had sub clinical vitamin A deficiency compared to none in the experimental group . There was no difference in the growth of infants in the two groups . However , the infant serum and the breast milk retinol levels were significantly higher in the supplemented group . CONCLUSION There is a high prevalence of inapparent Vitamin A deficiency ( 29.7 % ) in pregnant women in their third trimester from lower socio-economic strata . Postpartum Vitamin A supplementation had a beneficial impact on the infant serum retional and the breast milk retinol level but no effect on infant growth [20435345] BACKGROUND A previous trial in Nepal showed that supplementation with vitamin A or its precursor ( betacarotene ) in women of reproductive age reduced pregnancy-related mortality by 44 % ( 95 % CI 16 - 63 ) . We assessed the effect of vitamin A supplementation in women in Ghana . METHODS ObaapaVitA was a cluster-r and omised , double-blind , placebo-controlled trial undertaken in seven districts in Brong Ahafo Region in Ghana . The trial area was divided into 1086 small geographical clusters of compounds with fieldwork areas consisting of four contiguous clusters . All women of reproductive age ( 15 - 45 years ) who gave informed consent and who planned to remain in the area for at least 3 months were recruited . Participants were r and omly assigned by cluster of residence to receive a vitamin A supplement ( 25 000 IU retinol equivalents ) or placebo capsule orally once every week . R and omisation was blocked and based on an independent , computer-generated list of numbers , with two clusters in each fieldwork area allocated to vitamin A supplementation and two to placebo . Capsules were distributed during home visits undertaken every 4 weeks , when data were gathered on pregnancies , births , and deaths . Primary outcomes were pregnancy-related mortality and all-cause female mortality . Cause of death was established by verbal post mortems . Analysis was by intention to treat ( ITT ) with r and om-effects regression to account for the cluster-r and omised design . Adverse events were synonymous with the trial outcomes . This trial is registered with Clinical Trials.gov , number NCT00211341 . FINDINGS 544 clusters ( 104 484 women ) were r and omly assigned to vitamin A supplementation and 542 clusters ( 103 297 women ) were assigned to placebo . The main reason for participant drop out was migration out of the study area . In the ITT analysis , there were 39 601 pregnancies and 138 pregnancy-related deaths in the vitamin A supplementation group ( 348 deaths per 100 000 pregnancies ) compared with 39 234 pregnancies and 148 pregnancy-related deaths in the placebo group ( 377 per 100 000 pregnancies ) ; adjusted odds ratio 0.92 , 95 % CI 0.73 - 1.17 ; p=0.51 . 1326 women died in 292 560 woman-years in the vitamin A supplementation group ( 453 deaths per 100 000 years ) compared with 1298 deaths in 289 310 woman-years in the placebo group ( 449 per 100 000 years ) ; adjusted rate ratio 1.01 , 0.93 - 1.09 ; p=0.85 . INTERPRETATION The body of evidence , although limited , does not support inclusion of vitamin A supplementation for women in either safe motherhood or child survival strategies . FUNDING UK Department for International Development , and USAID [10465076] OBJECTIVE Poor vitamin A status has been associated with a higher risk for mother-to-child transmission of HIV-1 and there is contradictory evidence on the impact of vitamin A on perinatal outcome . We therefore assessed the effect of vitamin A supplementation to mothers on birth outcome and mother-to-child transmission of HIV-1 . DESIGN AND METHODS In Durban , South Africa 728 pregnant HIV infected women received either vitamin A ( 368 ) or placebo ( 360 ) in a r and omized , double-blind trial . The vitamin A treatment consisted of a daily dose of 5000 IU retinyl palmitate and 30 mg beta-carotene during the third trimester of pregnancy and 200000 IU retinyl palmitate at delivery . HIV infection results were available on 632 children who were included in the Kaplan-Meier transmission analysis . Results are reported on mother-to-child transmission rates up to 3 months of age . RESULTS There was no difference in the risk of HIV infection by 3 months of age between the vitamin A [ 20.3 % ; 95 % confidence interval ( CI ) , 15.7 - 24.9 ] and placebo groups ( 22.3 % ; 95 % CI , 17.5 - 27.1 ) , nor were there differences in foetal or infant mortality rates between the two groups . Women receiving vitamin A supplement were , however , less likely to have a preterm delivery ( 11.4 % in the vitamin A and 17.4 % in the placebo group ; P = 0.03 ) and among the 80 preterm deliveries , those assigned to the vitamin A group were less likely to be infected ( 17.9 % ; 95 % CI , 3.5 - 32.2 ) than those assigned to the placebo group ( 33.8 % ; 95 % CI , 19.8 - 47.8 ) . CONCLUSION Vitamin A supplementation , a low-cost intervention , does not appear to be effective in reducing overall mother-to-child transmission of HIV ; however , its potential for reducing the incidence of preterm births , and the risk of mother-to-child transmission of HIV in these infants needs further investigation [20684711] BACKGROUND Prophylactic vitamin A supplementation ( VAS ) reduces mortality and may reduce morbidity associated with diarrhea in children > 6 months of age . Rotavirus is the most common cause of acute dehydrating diarrhea among children worldwide . METHODS In a r and omized placebo-controlled study of 50,000 IU of vitamin A versus placebo given with bacille Calmette-Guérin vaccine at birth , 287 infants were followed up with weekly interviews and stool sample obtainment to test the hypothesis that VAS reduced the risk of rotavirus infection . RESULTS VAS was associated with increased risk of rotavirus infection and diarrhea ( incidence rate ratio [ IRR ] of infection , 1.72 [ 95 % confidence interval ( CI ) , 1.04 - 2.85 ] ; IRR of diarrhea , 3.74 [ 95 % CI , 1.40 - 9.98 ] ) among children < 6 months of age . There was no effect in older children . VAS had a beneficial effect on nonrotavirus diarrhea in boys < 6 months of age ( IRR , 0.51 ; 95 % CI , 0.27 - 0.95 ) and a detrimental effect in girls > 6 months of age ( IRR , 1.84 ; 95 % CI , 0.96 - 3.55 ) . CONCLUSION VAS at birth did not reduce rotavirus morbidity . The effect of VAS on nonrotavirus diarrhea may differ by sex , being more beneficial in boys . Clinical trials registration . NCT00168597 Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Vitamin A deficiency is a significant public health problem in low- and middle-income countries . Vitamin A supplementation provided to infants less than six months of age is one of the strategies to improve the nutrition of infants at high risk of vitamin A deficiency and thus potentially reduce their mortality and morbidity . OBJECTIVES To evaluate the effect of synthetic vitamin A supplementation in infants one to six months of age in low- and middle-income countries , irrespective of maternal antenatal or postnatal vitamin A supplementation status , on mortality , morbidity and adverse effects . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

26081254

[8555131] 544 children operated upon for uncomplicated appendicitis were r and omised into three groups . Group I received no antibiotics , patients in Group II were administered one single pre-operative dose of metronidazole ( 10 mg/kg ) and patients in Group III received both both metronidazole ( 20 mg/kg ) and cefuroxime ( 50 mg/kg ) in a single preoperative dose . The rate of infectious complications in Group I was 6.3 % but only 2.1 and 2.3 in Groups II and III , respectively . Among patients with a normal appendix or patients with simple appendicitis there was no difference in the rate of post-operative infections between the three different groups . However , in patients with gangrenous appendicitis the rate of postoperative infections was significantly lower in the two groups who received preoperative antibiotics ( 1.8 % and 3.0 % respectively ) than in the group receiving no prophylactic antibiotics ( infection rate 14 % ) . It is concluded that a single preoperative dose of metronidazole significantly decreases the rate of postoperative infectious complications in children with appendicitis . No further improvement could be demonstrated if cefuroxime against aerobic organisms was added [7640447] A total of 231 children with acute appendicitis were treated at our hospitals during the 10 years between 1984 and 1993 , 53 of whom had a perforated appendix . These 53 patients were r and omly assigned to two groups at the time of surgery according to the different procedures performed . Thus , 29 children were managed by appendectomy followed by peritoneal lavage using a large amount of saline , and intravenous antibiotic therapy consisting of aminoglycoside and cephem ( lavage group ) , while the other 24 children were treated by appendectomy with silicon tube drainage and the same systemic antibiotic therapy ( drainage group ) . The mean length of hospitalization , and the mean duration s of fever and the need for fasting after laparotomy in the lavage group were significantly less than those in the drainage group : 10.1 versus 18.8 days , 2.8 versus 7.7 days , and 1.8 versus 3.5 days , respectively . The operation wounds healed well in the lavage group due to the fact that there was no drain . Wound infections occurred in two children from the lavage group and six from the drainage group . Intra-abdominal abscesses occurred in two children from the drainage group . Accordingly , peritoneal lavage appears to be superior to intraperitoneal tube drainage for the management of perforated appendicitis in children [14691709] Background : The aim of this study was to evaluate prospect ively whether laparoscopic ( LA ) and open appendectomy ( OA ) are equally safe and feasible in the treatment of pediatric appendicitis . Methods : A total of 517 children with acute appendicitis were r and omly assigned to undergo LA or OA appendectomy , based on the schedule of the attending surgeon on call . Patient age , sex , postoperative diagnosis , operating time , level of training of surgical resident , length of postoperative hospitalization , and minor and major postoperative complications were recorded . Chi-square analysis and the Student t-test were used for statistical analysis . Results : In all , 376 OA and 141 LA were performed . The two groups were comparable in terms of patient demographics and the incidence of perforated appendicitis . The operative time was also similar ( 47.3 ± 19.7 vs 49.9 ± 12.9 min ) . The overall incidence of minor or major complications was 11.2 % in the OA group and 9.9 % in the LA group . Conclusion : Pediatric patients with appendicitis can safely be offered laparoscopic appendectomy without incurring a greater risk for complications . Nevertheless , a higher ( but not significantly higher ) abscess rate was found in patients with perforated appendicitis who underwent laparoscopy [24951281] BACKGROUND For decades , urgent operation has been considered the only appropriate management of acute appendicitis in children . The purpose of this study was to investigate the feasibility of nonoperative management of uncomplicated acute appendicitis in children . STUDY DESIGN A prospect i ve nonr and omized clinical trial of children with uncomplicated acute appendicitis comparing nonoperative management with urgent appendectomy was performed . The primary result was 30-day success rate of nonoperative management . Secondary outcomes included comparisons of disability days , missed school days , hospital length of stay , and measures of quality of life and health care satisfaction . RESULTS Seventy-seven patients were enrolled during October 2012 to October 2013 ; 30 chose nonoperative management and 47 chose surgery . There were no significant differences in demographic or clinical characteristics . The immediate and 30-day success rates of nonoperative management were 93 % ( 28 of 30 ) and 90 % ( 27 of 30 ) . There was no evidence of progression of appendicitis to rupture at the time of surgery in the 3 patients for whom nonoperative management failed . Compared with the surgery group , the nonoperative group had fewer disability days ( 3 vs 17 days ; p < 0.0001 ) , returned to school more quickly ( 3 vs 5 days ; p = 0.008 ) , and exhibited higher quality of life scores in both the child ( 93 vs 88 ; p = 0.01 ) and the parent ( 96 vs 90 ; p = 0.03 ) , but incurred a longer length of stay ( 38 vs 20 hours ; p < 0.0001 ) . CONCLUSIONS Nonoperative management of uncomplicated acute appendicitis in children is feasible , with a high 30-day success rate and short-term benefits that include quicker recovery and improved quality of life scores . Additional follow-up will allow for determination of longer-term success rate , safety , and cost effectiveness [2883223] Eighty-four cases of non-perforated appendicitis in children were r and omly allocated to receive either oxytetracycline lavage alone or oxytetracycline lavage plus peroperative intravenous metronidazole and cefuroxime . The wound infection rate with the oxytetracycline lavage alone was 4.4 % compared with 7.7 % when metronidazole and cefuroxime were added . These rates were not significantly different . This study supports the use of oxytetracycline lavage alone as effective prophylaxis against wound infection in non-perforated appendicitis of childhood [21683209] PURPOSE The current study examined the impact of immediate laparoscopic surgery vs nonoperative initial management followed by interval appendectomy for appendicitis with abscess on child and family psychosocial well-being . METHODS After obtaining Internal Review Board approval , 40 patients presenting with a perforated appendicitis and a well-formed abscess were r and omized to surgical condition . Parents were asked to complete child quality of life and parenting stress ratings at presentation , at 2 weeks postadmission , and at approximately 12 weeks postadmission ( 2 weeks postoperation for the interval appendectomy group ) . RESULTS Children in the interval arm experienced trends toward poorer quality of life at 2 and 12 weeks postadmission . However , no group differences in parenting stress were observed at 2 weeks postoperation . At 12 weeks postadmission , participants in the interval condition demonstrated significant impairment in both frequency and difficulty of problems contributing to parenting distress . CONCLUSION Families experience significant parenting distress related to the child 's functioning and disruption in the child 's quality of life that may be because of the delay in fully resolving the child 's medical condition . In addition , parents experience negative consequences to their own stress as a result of the delay before the child 's appendectomy [6342959] A total of 133 children , aged 16 months to 15 years ( mean 6.7 years ) , with presumptive acute appendicitis , was included in a double-blind , placebo-controlled trial of the short-term ( 72 hour ) use of metronidazole suppositories as prophylaxis against post-operative infection . There was no significant difference in the incidence or severity of wound infection or post-operative intra-abdominal sepsis between the metronidazole-treated and placebo groups . It is suggested that intra-rectal metronidazole , when used exclusively , is not sufficient for effective prophylaxis for appendicitis in childhood [3499502] Sulbactam is a beta-lactamase inhibitor , which when administered with ampicillin , increases the latter agents antibacterial activity against beta-lactamase producing organisms . One hundred children between the ages of 5 and 14 undergoing emergency appendectomy were entered into a prospect i ve r and omized trial comparing sulbactam and ampicillin ( SA ) with metronidazole and cefotaxime ( MC ) as prophylaxis against postoperative wound infection . Patients in whom the appendix was perforated or gangrenous received a 72-hour course of antibiotics , others received a single dose only . The overall wound infection rate was 8 % ( 14 % in patients with perforation or gangrene and 4 % in those without ) . There was no difference in infection rate between the two antibiotic groups ; there were three wound infections and one subphrenic abscess in patients receiving SA and four wound infections in patients receiving MC . SA , therefore , appears to be a suitable antibiotic combination for use as prophylaxis in appendicitis in children [6749270] The authors question the need to give prophylactic antibiotics perioperatively in all cases of acute appendicitis without perforation to reduce the rate of wound infection . A retrospective study of 82 patients showed a wound infection rate of 4.8 % ; 3 of 53 patients who did not receive antibiotics had a wound infection compared with 1 of 29 patients who received antibiotics . A prospect i ve double-blind clinical trial was performed comparing the results of perioperative administration of cefam and ole and placebo . One of 21 patients who received the placebo had a wound infection ; none of the 21 patients given cefam and ole had infection . Thus , the authors conclude that , although reports in the literature suggest that antibiotics given perioperatively decrease the rate of wound infection in acute appendicitis without perforation , the incidence of such infection is too low to warrant routine administration . They suggest that such antibiotic use be reserved for those suspected of having more serious disease [6363670] A prospect i ve , r and omized , double-blind clinical trial was undertaken comparing gentamicin , ampicillin , and clindamycin ( GAC ) to gentamicin , ampicillin , and placebo ( GAP ) in children with complicated appendicitis . Of the 64 patients enrolled in this study , 33 were assigned to the GAC group and 31 received GAP . A single GAC patient ( 3 % ) was considered a therapeutic failure in comparison to seven children ( 23 % ) in the GAP group ( P less than 0.05 ) . Duration of fever was significantly prolonged in the GAP patients ( 4.7 + /- .8 days versus 2.9 + /- .5 days ) when compared to the clindamycin treated children ( P less than 0.05 ) . Duration of leukocytosis was 3.2 + /- .4 days for GAC patients and 4.9 + /- .9 days for those on the GAP protocol ( P = 0.08 ) . On the basis of this experience the routine use of gentamicin , ampicillin , and clindamycin is recommended for all children with complicated appendicitis [16736333] Background Appendectomy has been the treatment for acute appendicitis for over 120 years . Antibiotic treatment has occasionally been used in small uncontrolled studies , instead of operation , but this alternative has never before been tried in a multicenter r and omized trial . Patients and Methods Male patients , 18–50 years of age , admitted to six different hospitals in Sweden between 1996 and 1999 were enrolled in the study . No women were enrolled by decision of the local ethics committee . If appendectomy was planned , patients were asked to participate , and those who agreed were r and omized either to surgery or to antibiotic therapy . Patients r and omized to surgery were operated on with open surgery or laparoscopically . Those r and omized to antibiotic therapy were treated intravenously for 2 days , followed by oral treatment for 10 days . If symptoms did not resolve within 24 hours , an appendectomy was performed . Participants were monitored at the end of 1 week , 6 weeks , and 1 year . Results During the study period 252 men participated , 124 in the surgery group and 128 in the antibiotic group . The frequency of appendicitis was 97 % in the surgery group and 5 % had a perforated appendix . The complication rate was 14 % in the surgery group . In the antibiotic group 86 % improved without surgery ; 18 patients were operated on within 24 hours , and the diagnosis of acute appendicitis was confirmed in all but one patient , and he was suffering from terminal ileitis . There were seven patients ( 5 % ) with a perforated appendix in this group . The rate of recurrence of symptoms of appendicitis among the 111 patients treated with antibiotics was 14 % during the 1-year follow-up . Conclusions Acute nonperforated appendicitis can be treated successfully with antibiotics . However , there is a risk of recurrence in cases of acute appendicitis , and this risk should be compared with the risk of complications after appendectomy [23982816] BACKGROUND The primary objective of this study was to compare triple therapy with ertapenem treatments in pediatric patients with perforated appendicitis , especially in terms of postoperative infectious complications . The secondary objective of this study was to assess the relative impact of therapy with ertapenem and triple antibiotic regimen on the emergence of resistant bacteria in bowel flora in the patients . MATERIAL S AND METHODS Children aged 3 months to 17 years with perforated appendicitis were r and omized 1:1 to receive ertapenem or triple therapy . Serial rectal cultures were obtained from participants enrolled in the study , allowing assessment of the relative impact of therapy with ertapenem and triple therapy on bowel colonization by resistant bacteria . RESULTS In this study , 107 patients were included . No difference existed in time to full oral intake and regular diet , the length of antibiotic therapy , the length of the postoperative hospitalization , or the length of hospital stay between the two groups . Patients in the triple-therapy group were more likely to suffer from a postoperative infectious complication than those in the ertapenem group ( 6/54 vs. 2/53 , p > 0.05 ) . Bowel colonization with resistant organisms at the end of therapy in the triple-therapy group was significantly different than in the ertapenem group ( 35.2 vs. 11.3 % , p < 0.05 ) . CONCLUSIONS Bowel colonization with resistant bacteria was less likely to occur after ertapenem treatment than triple therapy . The results of this trial suggest that ertapenem may be a useful option that could eliminate the need for combination and /or multidosed antibiotic regimens for the empiric treatment of perforated appendicitis in children [15902475] Despite aggressive surgical treatment , rational antibiotic therapy , and modern intensive care , generalised peritonitis remains a major threat in the paediatric age group . Several adjuvant strategies such as peritoneal saline lavage and peritoneal drainage have been utilised . Taurolidine , derived from the amino acid taurine , has bactericidic , antiendotoxic , and antiinflammatory properties . It has been introduced previously for intraoperative peritoneal lavage in treating peritonitis in adults . The aim of our study was to evaluate the effect of peritoneal taurolidine lavage on the clinical course and serological inflammation markers in children with perforated appendicitis and localised peritonitis . A series of 27 children presenting with appendicitis between January 1999 and July 2001 were included in the study after parental informed consent . All patients underwent open appendectomy . Taurolidine peritoneal lavage was applied in 15 r and omly selected children ( eight girls and seven boys ; mean age 10 years and 10 months ) . Twelve children received saline peritoneal lavage and served as the control group ( six girls and six boys ; mean age 9 years and 7 months ) . Blood was taken preoperatively and on postoperative days 1 , 3 , 7 , and 14 . Full blood cell count , C-reactive protein , endotoxin , interleukin-1 , interleukin-6 , soluble interleukin-2 receptor , tumour necrosis factor α , and procalcitonin were investigated to evaluate the serological course of inflammation . Both groups initially presented with severe inflammation as evidence d clinical ly and serologically . The clinical postoperative course was uneventful in 13/15 patients in the treatment group and 10/12 patients in the control group . The remaining patients presented complications : intraperitoneal abscess or early postoperative bowel obstruction . With regard to the serological inflammatory parameters , no significant differences were found between the two groups except for the soluble interleukin-2-receptor on the 7th postoperative day . In conclusion , the expected reduction of endotoxin levels and inflammatory activity in the treatment group was not evident . A significant advantage of adjuvant peritoneal taurolidine lavage in the surgical therapy of children with localised peritonitis due to appendicitis could not be shown in our study [21283958] BACKGROUND 4 methods are used in pediatric laparoscopic surgery to close trocar wounds . While tissue adhesives or adhesive strips have been shown to produce fewer wound complications and a better cosmetic result compared to trans- or only subcutaneous sutures , the choice of technique is still often based on the surgeon 's personal experience . Thus , the objective of this trial was to assess the impact of tissue adhesives ( Dermabond ™ ) compared to adhesive strips ( Steri-Strip ™ ) on potential complications of wound healing , wound pain , cosmetic outcome , and patient satisfaction after laparoscopic appendectomy in children . METHODS 49 patients undergoing laparoscopic appendectomy were enrolled in this prospect i ve r and omized trial . In every patient , two 5-mm and one 10-mm port-site incision was closed either with Dermabond ™ or Steri-Strip ™ after placing subcuticular absorbable sutures ( 4 - 0 Vicryl ™ ) . Postoperative complications , pain , and patient satisfaction with scars were evaluated at follow-up on day 10 and day 90 after the operation using a question naire and a visual analogue scale ( VAS ) . Photographs of scars taken on day 90 were evaluated on a VAS by 2 pediatric surgeons blinded to the closure method used . RESULTS According to the surgeons ' evaluation of the cosmetic outcome , a significant difference between the 2 groups with regard to the cosmetic score was found on day 90 of follow-up , favoring Steri-Strip ™ wound closure ( p < 0.05 ) . On day 10 and 90 there were no statistical differences between the 2 methods as regards the result of patient evaluations ( p > 0.05 ) . Only one wound infection ( 4 % ) was observed in the Steri-Strip ™ group ( n = 25 ) on day 10 . At follow-up on day 90 two patients ( 9.1 % ) in the Dermabond ™ group and one ( 4.8 % ) in the Steri-strip ™ group complained of wound pain ( p = 0.52 ) . CONCLUSIONS Both tissue adhesives and adhesive strips are excellent " no needle " alternatives for the closure of laparoscopic port-site incisions in children . As regards cosmetic outcome , Steri-Strip ™ wound closure seems to be the most suitable and is also the less expensive technique [4240443] Objective To determine the extent and nature of selective non-reporting of harm outcomes in clinical studies that were eligible for inclusion in a cohort of systematic review s. Design Cohort study of systematic review s from two data bases . Setting Outcome reporting bias in trials for harm outcomes ( ORBIT II ) in systematic review s from the Cochrane Library and a separate cohort of systematic review s of adverse events . Participants 92 systematic review s of r and omised controlled trials and non-r and omised studies published in the Cochrane Library between issue 9 , 2012 and issue 2 , 2013 ( Cochrane cohort ) and 230 systematic review s published between 1 January 2007 and 31 December 2011 in other publications , synthesis ing data on harm outcomes ( adverse event cohort ) . Methods A 13 point classification system for missing outcome data on harm was developed and applied to the studies . Results 86 % ( 79/92 ) of review s in the Cochrane cohort did not include full data from the main harm outcome of interest of each review for all of the eligible studies included within that review ; 76 % ( 173/230 ) for the adverse event cohort . Overall , the single primary harm outcome was inadequately reported in 76 % ( 705/931 ) of the studies included in the 92 review s from the Cochrane cohort and not reported in 47 % ( 4159/8837 ) of the 230 review s in the adverse event cohort . In a sample of primary studies not reporting on the single primary harm outcome in the review , scrutiny of the study publication revealed that outcome reporting bias was suspected in nearly two thirds ( 63 % , 248/393 ) . Conclusions The number of review s suspected of outcome reporting bias as a result of missing or partially reported harm related outcomes from at least one eligible study is high . The declaration of important harms and the quality of the reporting of harm outcomes must be improved in both primary studies and systematic review [20639825] This prospect i ve comparative study was conducted in the department of Pediatric Surgery , Dhaka Shishu ( children ) Hospital during the period of June 2007 to September 2008 with the children of < 12 years , diagnosed as acute Appendicitis . Patient selection was done by simple r and om technique by means of lottery . For open Appendectomy ( OA ) conventional method & for Laparoscopic Appendectomy ( LA ) 3 trocher technique was applied . Data was analyzed with the help of SPSS version 10 . In this study 60 cases with acute Appendicitis including both gender were studied by two groups , group-A include 30 cases for laparoscopic and group-B include 30 cases for open appendectomy . Postoperative pain was assessed in both groups by using FLACC scale and compared at 1st 6-hours , 24 hours , 72 hours , 96 hours & at day 7 . At 1st 6-hours , most of the children 24(80 % ) of group A had moderate pain whereas 17(56.7 % ) children of group B had severe pain ( p<0.001 ) . At 24 hours most of the patient 17(56.7 % ) of group A had mild pain compared to 27 ( 90 % ) patients of group B had moderate pain ( p<0.0001 ) . At 48 hours in group A most of the children 23(76.7 % ) had mild pain compared to moderate pain in 18(60 % ) children of group B ( p<0.0001 ) . Subsequently at 72 hours and at 96 hours most of the patients of LA group were free of pain compared to OA group . At final follow-up on day 7 , 29(96.7 % ) children of group A had no pain compared to 26(86.7 % ) of group B. Regarding analgesics requirement both qualitative & quantitative requirements of analgesics were less in LA group than OA group . About post operative wound infection in group A only 1(3.3 % ) case had developed post operative wound infection whereas in group B 7(23.3 % ) cases had . The mean ( + /-SD ) of post operative length of hospital stay was 52.00+/-11.62 ( range 48 - 96 ) hours for group A and 76.00+/-12.74 ( range 48 - 96 ) hours for group B children ( p<0.001 ) . Laparoscopic Appendectomy is more effective , preferable & superior procedure than that of open Appendectomy to reduce the post operative morbidity in children undergone appendectomy for acute appendicitis [1902992] This prospect i ve , r and omized , double-blind study compares the efficacy , safety and cost-effectiveness of ampicillin , gentamicin and clindamycin ( AGC ) or cefotaxime and clindamycin ( CC ) for the treatment of children with complicated appendicitis . Ninety-seven children were r and omized . Forty-seven were assigned to the AGC regimen and 50 received CC . Forty-two patients in the AGC group had an appropriate therapeutic outcome , whereas 48 of 50 children who received CC completed the trial successfully ( p = NS ) . There were no differences between the groups with reference to the duration of antibiotic administration , fever , leukocytosis or length of hospitalization . Complications of therapy were uncommon and neither regimen demonstrated a significant advantage from an economic st and point . We concluded that , in childhood , complicated appendicitis can be treated with either CC or AGC with equal efficacy [25072441] OBJECTIVE The aim of this study was to evaluate the feasibility and safety of nonoperative treatment of acute nonperforated appendicitis with antibiotics in children . METHODS A pilot r and omized controlled trial was performed comparing nonoperative treatment with antibiotics versus surgery for acute appendicitis in children . Patients with imaging-confirmed acute nonperforated appendicitis who would normally have had emergency appendectomy were r and omized either to treatment with antibiotics or to surgery . Follow-up was for 1 year . RESULTS Fifty patients were enrolled ; 26 were r and omized to surgery and 24 to nonoperative treatment with antibiotics . All children in the surgery group had histopathologically confirmed acute appendicitis , and there were no significant complications in this group . Two of 24 patients in the nonoperative treatment group had appendectomy within the time of primary antibiotic treatment and 1 patient after 9 months for recurrent acute appendicitis . Another 6 patients have had an appendectomy due to recurrent abdominal pain ( n = 5 ) or parental wish ( n = 1 ) during the follow-up period ; none of these 6 patients had evidence of appendicitis on histopathological examination . CONCLUSIONS Twenty-two of 24 patients ( 92 % ) treated with antibiotics had initial resolution of symptoms . Of these 22 , only 1 patient ( 5 % ) had recurrence of acute appendicitis during follow-up . Overall , 62 % of patients have not had an appendectomy during the follow-up period . This pilot trial suggests that nonoperative treatment of acute appendicitis in children is feasible and safe and that further investigation of nonoperative treatment is warranted [21733727] BACKGROUND There is evidence that aminoglycosides given in a single daily dose ( once daily dose , ODD ) are as effective and safe as multiple daily doses ( MDD ) . However , the published pharmacokinetic and pharmacodynamic data are overly representative of pediatric population s in Europe and the USA , and not representative of low or middle-income countries such as Costa Rica , in which the patient population might differ from those in higher income setting s. METHODS A double-blind , r and omized clinical trial of the efficacy and safety of ODD vs. MDD amikacin therapy was conducted for children aged 2 - 12 years with an intraoperative diagnosis of perforated appendicitis . One hundred patients were r and omized following a one-to-one r and omization to receive either amikacin 7.5 mg/kg every 8 h ( MDD ) or 22.5 mg/kg as a single dose ( ODD ) . Patients in both groups were given clindamycin 10 mg/kg every 6 h. Efficacy was evaluated by the occurrence of intra-abdominal abscesses , documented by abdominal ultrasound , and therapeutic failure . Safety was determined by the presence of renal or cochlear toxicity . RESULTS Fifty patients were enrolled in each group . There were no statistically significant differences in the incidence of intra-abdominal abscesses or therapeutic failures , or in the occurrence of cochlear or renal toxicity , between the MDD and ODD treatment groups . CONCLUSIONS In this patient population of Costa Rican children with perforated appendicitis , we found that amikacin ODD is as safe and effective as the MDD regimen . This could have implication s for national health systems such as that in Costa Rica , as ODD is presumably a more economic option and may reduce the cost of antibiotic treatment in patients with perforated appendicitis . This would need to be confirmed through an economic analysis , which is outside the purview of this paper [2788460] Aims : The purpose of this study was to compare open versus laparoscopic appendicectomy ( LA ) in complicated appendicitis . Material s and Methods : We prospect ively analyzed all children over a 2-year period who underwent appendicectomy in a single institution and found 30 cases of complicated appendicitis diagnosed on the table and confirmed by histopathology . These children were allocated r and omly into Group 1 if they had LA and Group 2 if they had open appendicectomy ( OA ) , solely based on surgeon assessment . The parameters assessed were duration of symptoms before surgery , use of postoperative parenteral analgesia , timing of initiation of feeds after surgery , postoperative complications and duration of postoperative stay . Results : Of the 30 patients with complicated appendicitis , 12 patients in Group 1 underwent LA and 18 patients in Group 2 underwent OA . The two groups were comparable for age and sex . Children in Group 1 were found to need less parenteral analgesia ( two out of 12 versus six out of 18 ) . Postoperatively , feeds were started earlier in Group 1 than in Group 2 ( 2.5 days versus 3.7 days ) . The average postoperative hospital stay was 5 days in Group 1 and 7.5 days in Group 2 . There were only minor wound infections in Group1 as against two major complications in Group 2 . There was no mortality in either group . Conclusions : In complicated appendicitis , laparoscopic approach carries definite advantages with less postoperative morbidity and hospital stay . It is a feasible and better alternative than the open approach in complicated appendicitis [21339413] OBJECTIVE To compare the effectiveness and adverse event rates of early vs interval appendectomy in children with perforated appendicitis . DESIGN Nonblinded r and omized trial . SETTING A tertiary-referral urban children 's hospital . PATIENTS A total of 131 patients younger than 18 years with a preoperative diagnosis of perforated appendicitis . INTERVENTIONS Early appendectomy ( within 24 hours of admission ) vs interval appendectomy ( 6 - 8 weeks after diagnosis ) . MAIN OUTCOME MEASURES Time away from normal activities ( days ) . Secondary outcomes included the overall adverse event rates and the rate of predefined specific adverse events ( eg , intra-abdominal abscess , surgical site infection , unplanned readmission ) . RESULTS Early appendectomy , compared with interval appendectomy , significantly reduced the time away from normal activities ( mean , 13.8 vs 19.4 days ; P < .001 ) . The overall adverse event rate was 30 % for early appendectomy vs 55 % for interval appendectomy ( relative risk with interval appendectomy , 1.86 ; 95 % confidence interval , 1.21 - 2.87 ; P = .003 ) . Of the patients r and omized to interval appendectomy , 23 ( 34 % ) had an appendectomy earlier than planned owing to failure to improve ( n = 17 ) , recurrent appendicitis ( n = 5 ) , or other reasons ( n = 1 ) . CONCLUSIONS Early appendectomy significantly reduced the time away from normal activities . The overall adverse event rate after early appendectomy was significantly lower compared with interval appendectomy . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00435032 [11298617] Appendicectomy is the most common emergency surgical operation in children . The aim of this study was to compare recovery after appendicectomy using either a laparoscopic or an open technique in children [11269551] Patients and surgeons frequently opt for laparoscopic appendectomy for treatment of acute appendicitis . Clinical studies have shown this approach to be a reasonable alternative to open appendectomy . The objective of the current study was to assess the outcome of laparoscopic appendectomy using three different techniques . The study sample consisted of 150 children with acute appendicitis who underwent surgery at Al-Azhar University Hospitals , Cairo , Egypt , and at Al Mishary Hospital in Riyadh , Saudi Arabia , between October 1997 and October 1999 . The patients were allocated to undergo extracorporeal laparoscopic appendectomy , Endoloop laparoscopic appendectomy , or EndoGIA ( Ethicon Endo-surgery , Inc. , Cincinnati , OH , USA ) laparoscopic appendectomy . All patients were assessed for the severity of the disease at baseline using clinical and hematologic indicators . The ages of the children ranged from 7 to 14 years , with a mean of 10 years ( SD , 2.14 years ) . Of the children , 55.3 % were female . The results showed that children who underwent laparoscopic appendectomy using the EndoGIA had statistically significant shorter operating times , did not have complications , and had the shortest duration of hospital stay ( although duration of hospital stay did not reach the statistically significant level of P > 0.05 ) . Therefore , the study showed that laparoscopic appendectomy using the EndoGIA is the procedure that is most recommended , except for the relatively high cost of the disposable material s. Endoloop laparoscopic technique was the second most preferable procedure , and the least preferred procedure was extracorporeal laparoscopically assisted appendectomy . The major drawback of the last technique is the high frequency of complications . Endoloop laparoscopic appendectomy with a purse-string suture can be performed safely if the EndoGIA is not available [1925965] A prospect i ve r and omized study was undertaken to compare the use of the combination of gentamicin and clindamycin with single agent , cefoxitin , in the treatment of perforated appendicitis in the pediatric patient . In a 3-year period from 1986 to 1989 , 56 patients with perforated appendicitis were r and omized . Twenty-nine patients received cefoxitin , and 27 patients received gentamicin and clindamycin . Antibiotics were started before operation and continued for a minimum of 6 days after operation . Skin and subcutaneous tissues were left open at surgery and closed secondarily after day 3 , if they appeared to be clean . Wounds were considered infected if they developed increased purulence with positive wound cultures . Age range was similar in both groups , with a mean of 9 years ( range , 1 to 17 years ) ; 28 were boys and 28 were girls . No changes in antibiotics were required for reasons of susceptibility . No adverse drug reactions occurred in either group . The most common organisms were Escherichia coli in 35 cases ( 62 % ) and Bacteroides species in 26 cases ( 46 % ) . No difference was noted in infection complications in the two groups nor in length of hospital stay . Therefore , no difference is evident in the use of cefoxitin versus gentamicin and clindamycin in the treatment of perforated appendicitis in terms of disease or drug-related complications [8638833] Background The benefit of laparoscopy to patients has been clearly established in adults undergoing cholecystectomy . Results are less clear for appendectomy . The current study was undertaken to compare the respective 3-day postoperative periods after laparoscopic and open appendectomy in children . Methods Sixty-three children ( aged 8 - 15 yr ) scheduled for appendectomy were r and omly assigned to two groups : open and laparoscopic . Postoperative evaluation included delay of postoperative recovery ( walking and feeding ) , pain assessment by visual analog scale during the 3 subsequent days , amount of nalbuphine administered via a patient-controlled analgesia system during the first 48 h and responses by children , parents , and nurses on the overall quality of analgesia . Results There was no difference between groups for demographic data ( particularly macroscopic aspect of appendix ) , analgesia , sedation , delay before eating and walking , incidence of urinary retention , nausea , vomiting . Operative time was longer ( P less or equal to 0.05 ) in the laparoscopic group ( 54+/-17 min ) than in the open group ( 39 + /-18 min ) . Thirty five percent of the children had pain at the shoulder in the LAP group versus ten percent in the open group ( P less or equal to 0.05 ) . Conclusions Laparoscopy did not improve analgesia and postoperative recovery after appendectomy in children [1625127] A prospect i ve , r and omized , clinical study was done to evaluate the place of prophylactic antibiotics in uncomplicated childhood appendicitis . One hundred patients with uncomplicated appendicitis were r and omly assigned to one of four groups , each consisting of 25 cases . Group 1 patients did not receive prophylactic antibiotic . Group 2 , group 3 , and group 4 patients received ornidazole , penicillin plus tobramycin , and piperacillin , respectively . The use of prophylactic antibiotics did not yield better results than the use of placebos . The rarity of infectious complications after uncomplicated appendicectomy may be unique for children . Although the need for antibiotic prophylaxis is well documented in adults , the rarity of infectious complications makes it highly question able in the treatment of uncomplicated appendicitis in children [10231206] To demonstrate the efficacy of oral metronidazole ( OM ) in simple or complicated appendicitis with localized peritonitis , a r and omized prospect i ve study was carried out in 1083 patients , ranging in age from 4 to 50 years ( mean age , 21.38 ) . The patients were r and omly divided into two groups . The study group ( SG ) ( 524 patients ) received OM ( 500 mg for adults , 7 - 10 mg/kg if less than 15 years ) 2 - 3 hours before operation . The drug was continued 4 to 5 hours after operation , every 8 hours , for three doses if the appendix was mild to severely inflamed . In the case of complicated appendicitis ( 114 patients ) , the same dose was given for 3 to 6 days , depending on the absence or presence of pus . Ceftizoxime was administered to the control group ( CG ) ( 559 patients ) 2 to 3 hours before operation and then postoperatively every 6 hours for three doses if the appendix was mild to severely inflamed . The complicated cases in the CG ( 120 patients ) received a combination of penicillin , chloramphenicol , and gentamicin for 3 to 6 days , depending on the absence or presence of pus . The serum concentration of metronidazole measured in 43 patients was at bactericidal level in 40 ( mean + /- SD st and ard deviation , 10.65 + /- 4.89 microg/mL ) . The rate of wound infection was not significantly different in the SG and the CG with the same degree of pathology ( 3.17 % vs 2.96 % if uncomplicated ; 15.78 % vs 14.16 % if complicated , respectively ) . Pelvic collection occurred in four adults and one child in the CG with perforated appendicitis ( 4.16 % ) . The same complication developed in two adults and two children in the SG with perforated appendicitis ( 3.5 % ) . All six adults and one of the children in the SG had to be re-explored , whereas the remaining two children responded to conservative management ( OM and gentamicin ) . In uncomplicated cases , hospital stay and hospital charge were both almost the same in both groups . However , length of hospitalization was nearly 1 day shorter and hospital cost per day was about 30 per cent less in complicated cases in the SG as compared with the CG . Conclusively , OM may not only substitute parenteral antibiotics in acute appendicitis as a prophylactic agent , but it may also be used as a cost-effective drug and is more convenient to the patient [11257737] BACKGROUND The use of antibiotics in uncomplicated appendicitis in children , remains the area of controversy . The aim of the study was to assess the necessity of antibiotic administration in nonperforated appendicitis in children . MATERIAL AND METHODS The design of the study was a double blind r and omized controlled trial , with a follow-up of 4 to 20 months . SETTING Surgical Department in a University Pediatric Hospital . PATIENTS One hundred and eighty seven out of 249 children subjected to emergency appendectomies met the inclusion criteria , with 35 eligible but not included in the study . The remaining 152 patients were r and omized ; 41 had complicated appendicitis , 3 other diagnosis , 108 were analyzed within 3 study groups : 1 ( n = 31 ) no antibiotic , 2 ( n = 41 ) one dose , 3 ( n = 36 ) 5-day course . Open appendectomy was a surgical procedure and Ceftriaxone 1.0 g i.v . was administered . Investigated parameters were : body temperature , WBC , bowel sounds , wound healing , recovery and morbidity . RESULTS Valid outcome data were available for 90 of 108 r and omized patients . Protocol s of 18 children due to fever > 39 degrees C , upper airway infection or allergy were disclosed . In the remaining 90 children , there were no differences in WBC and oral feeding between groups 1 ( n = 24 ) , 2 ( n = 35 ) and 3 ( n = 31 ) . Group 1 and 2 had a higher mean temperature on day 1 post-op , without any clinical significance . A higher mean temperature was noted on day 5 post-op in group 1 , due to wound infection in one patient . There were no intraabdominal abscesses . The only other complications were 2 adhesion small bowel obstructions ( in groups 1 and 2 each ) . CONCLUSION Routine use of antibiotics in nonperforated appendicitis in children is not necessary [12194123] BACKGROUND / PURPOSE Laparoscopic appendectomy is an accepted way of dealing with suspected uncomplicated appendicitis in children . The role of laparoscopy in complicated acute appendicitis is more controversial . The purpose of this trial was to compare laparoscopic appendectomy with open appendectomy in children with complicated appendicitis . METHODS A total of 102 children with suspected acute appendicitis were selected r and omly to undergo either a laparoscopic or an open appendectomy . The outcomes of 25 children with complicated appendicitis , 13 in the laparoscopic group and 12 in the open appendectomy group , were analyzed . Children , their parents , and research nurses were blinded to which procedure had been performed and remained blinded until the control visit 7 days after the operation . All 25 children completed a 30-day follow-up . RESULTS There were no differences in terms of patients ' age , sex , weight , height , and appendiceal histology between the 2 groups . All laparoscopic procedures were completed without conversion . The mean ( + /-SD ) operating time was 63 ( + /-31 ) minutes in the laparoscopic group and 37 ( + /-18 ) minutes in the open appendectomy group ( mean difference 26 minutes , 95 % CI 5 to 47 minutes , P = .02 ) . There were 2 major complications in the laparoscopic group in children with appendiceal masses . One child had an entero-cutaneous fistula of the residual appendiceal tip that needed open reoperation . Another child had a pelvic abscess that resolved with antibiotic treatment . Superficial wound infections were encountered in 2 patients in the open appendectomy group . CONCLUSIONS Laparoscopic appendectomy is an alternative to open procedure in children with complicated appendicitis . Good surgical judgement is necessary in patients with an established appendiceal abscess [3312564] This is a prospect i ve and r and omized study of 100 patients with acute appendicitis who were less than 10 years old , in which four different antibiotic regimens commonly in use against gram-negative and anaerobic bacteria were compared in terms of postoperative septic complications . The antibiotics were begun immediately preoperatively and continued for five days . Ten percent of the patients developed infection complications , with 4 % requiring further surgery . The best results were obtained with cefoxitin ( 4 % of infection ) , metronidazole plus amikacin and latamoxef ( 8 % ) , while the regimen of clindamycin plus amikacin was associated with the greatest number of complications ( 20 % ) . On analyzing the main microbiologic findings of the study , we conclude that some sort of antibiotic treatment is indicated in all types of appendicitis , due to the occult presence of bacteria in the peritoneal cavity , even without clinical evidence of gangrene or perforation . Further , we emphasize the significance of Streptococcus faecalis as being responsible , along with Escherichia coli and Bacteroides fragilis , for serious postoperative complications [21044931] Background and Aims : Appendectomy wounds are still commonly closed with non-absorbable sutures . Stitch removal has financial costs and causes anxiety in children . Our aim was to compare interrupted non-absorbable ( NA ) and continuous intradermal absorbable ( A ) sutures in appendectomy wounds to evaluate whether absorbable suturing increases the risk of complications . Material and Methods : 198 children ( age 4–18 years ) including perforated cases were prospect ively r and omized into two groups ( NA and A skin closure ) . The wounds and inflammatory markers were evaluated on the first two postoperative days . The appearance of the wound was evaluated one week postoperatively by a district nurse . Follow-up data were obtained from 166 patients ( 87 in NA group and 79 in A group ) . Results : In NA group 86 % and in A group 81 % had appendicitis ( 8 % and 15.6 % perforated and 9.3 % and 25 % gangrenous cases in NA and A groups , respectively ) . The total wound infection rate was low , 1.8 % ( 2.3 % in NA Group and 1.3 % in A Group ) . No differences in the inflammatory markers or the appearance of the wound were noted between the groups , but nine children in NA Group ( 10.3 % ) had a partial wound dehiscence after stitch removal . Conclusion : Appendectomy wounds in children can be closed with continuous , absorbable sutures , even in complicated cases [14706955] BACKGROUND Laparoscopic procedures are performed commonly in children . In general , the cost containment of laparoscopic surgery in children has not been evaluated . OBJECTIVE To compare the costs of laparoscopic appendectomy with those of open appendectomy . DESIGN Prospect i ve clinical trial between November 1 , 1997 , and April 30 , 2000 . For analysis , cost of supplies , operation room use , and recovery in the hospital and after discharge was evaluated . Costs common to both groups were not determined . SETTING Operations performed in a university hospital . Patients Eighty-seven children aged 4 to 15 years who underwent appendectomy for suspected appendicitis . Patients were r and omized to laparoscopic or open appendectomy . Intervention Laparoscopic appendectomies performed with the same st and ard set of reusable equipment . MAIN OUTCOME MEASURES Cost surplus of the laparoscopic procedure and recovery after surgery were evaluated , to determine the costs and effects of laparoscopic appendectomy compared with those of open appendectomy in children . RESULTS Excess operating and complication costs per procedure were 96 euros ( EUR ) in laparoscopic appendectomy . The increased operative expenses were offset by a shorter hospital stay , result ing in a marginal difference of 53 EUR in itemized total costs between the 2 procedures ( total cost , 1023 EUR in the laparoscopic appendectomy group and 970 EUR in the open appendectomy group ) . After laparoscopic appendectomy , children returned to school and sports earlier than those who had had an open appendectomy . CONCLUSION Laparoscopic appendectomy was marginally more expensive , but it allowed earlier return to normal daily activities than open appendectomy [2899496] Summary In an attempt to reduce postoperative sepsis , a series of r and omised , double-blind studies was begun in 1982 , using cefotaxime as backbone therapy . Up to 1985 ( stages I and II ) , the best results were obtained using a combination of cefotaxime ( 75 mg/kg intravenously in 3 doses at 12-hourly intervals ) plus metronidazole ( 10 mg/kg intravenously in 3 doses ) , both drugs administered 1 hour before surgery ( preoperatively ) or at anaesthetic induction ( perioperatively ) . In 300 consecutive cases , the wound infection rates were 1 % in uncomplicated acute appendicitis and 5 % in perforated/gangrenous appendices . The present study ( stage III ) reports the findings in 401 consecutive patients : 215 treated with the above regimen , either pre-or perioperatively ( group 1 ) and 186 who additionally had peritoneal lavage with cefotaxime 2 g/L during surgery ( group 2 ) . There were 16 wound infections overall , 2 among patients administered prophylaxis preoperatively and 14 in those administered prophylaxis perioperatively . All produced mixed cultures , with Escherichia coli , Streptococcus milleri and Bacteroides fragilis predominating . The overall figures for postoperative sepsis are 12/215 ( 5.6 % ) in the non-lavage group and 8/186 ( 4.3 % ) in the lavage group . Among patients with a perforated and /or gangrenous appendix , the wound infection rate was 8/72 ( 11.1 % ) in the non-lavage group ( group 1 ) and 4/66 ( 6.1 % ) in the lavage group ( group 2 ) . Each group had 2 cases of pelvic abscess [11877640] BACKGROUND / PURPOSE Laparoscopic Appendectomy ( LA ) is a safe procedure in adults result ing in shorter hospitalization and sooner return to activity . The relative merits of LA and open appendectomy ( OA ) are evaluated in this first prospect i ve and r and omized study in children . METHODS A total of 129 children with appendicitis were included . Forty-three boys and 45 girls , age 1 to 16 years , were enrolled . R and omization was determined by sealed assignment card . OA utilized a 3- to 4-cm right lower quadrant , muscle-splitting incision . Wounds were closed without drains . Antibiotics , when used , consisted of gentamycin , clindamycin , and ampicillin . LA was performed by experienced surgeons utilizing a 3-trocar technique with reusable instruments . Twenty-one children ( 24 % ) were perforated . Patients were discharged as soon as they were taking a diet and afebrile . Statistical comparisons were by Fisher 's Exact and Wilcoxon rank-sum tests . RESULTS There were no differences in postoperative analgesia , resumption of oral intake , length of hospitalization , return to normal activities , or morbidity . Laparoscopic appendectomy was associated with longer operating times and increased cost . CONCLUSIONS Laparoscopic appendectomy in children is not associated with the same advantages reported in adults . LA is a more expensive alternative and offers no advantages related to pain relief , length of stay , return to normal activities , or morbidity [18558169] INTRODUCTION Appendicitis is the most common emergency condition in children . Historically , a 3-drug regimen consisting of ampicillin , gentamicin , and clindamycin ( AGC ) has been used postoperatively for perforated appendicitis . A retrospective review at our institution has found single day dosing of ceftriaxone and metronidazole ( CM ) to be a more simple and cost-effective antibiotic strategy . Therefore , we performed a prospect i ve , r and omized trial to compare efficacy and cost-effectiveness of these 2 regimens . METHODS After internal review board approval ( IRB no. 04 12 - 149 ) , children found to have perforated appendicitis at appendectomy were r and omized to either once daily dosing of CM ( 2 total doses per day ) or st and ard dosing of AGC ( 11 total doses per day ) . Perforation was defined as an identifiable hole in the appendix . The operative approach ( laparoscopic ) , length of antibiotic use , and criteria for discharge were st and ardized for the groups . Based on our retrospective analysis using length of postoperative hospitalization as a primary end point , a sample size of 100 patients was calculated for an alpha of .5 and a power of 0.82 . RESULTS One hundred patients underwent laparoscopic appendectomy for perforated appendicitis . On presentation , there were no differences in sex distribution , days of symptoms , temperature , or leukocyte count . There was no difference in abscess rate or wound infections between groups . The CM group result ed in significantly less antibiotic charges then the AGC group . CONCLUSIONS Once daily dosing with the 2-drug regimen ( CM ) offers a more efficient , cost-effective antibiotic management in children with perforated appendicitis without compromising infection control when compared to a traditional 3-drug regimen [20620320] INTRODUCTION In a previous prospect i ve r and omized trial , we found a once-a-day regimen of ceftriaxone and metronidazole to be an efficient , cost-effective treatment for children with perforated appendicitis . In this study , we evaluated the safety of discharging patients to complete an oral course of antibiotics . METHODS Children found to have perforated appendicitis at the time of laparoscopic appendectomy were enrolled in the study . Perforation was defined as a hole in the appendix or fecalith in the abdomen . Patients were r and omized to antibiotic treatment with either once daily dosing of ceftriaxone and metronidazole for a minimum of 5 days ( intravenous [ IV ] arm ) or discharge to home on oral amoxicillin/clavulanate when tolerating a regular diet ( IV/PO arm ) to complete 7 days . RESULTS One hundred two patients underwent laparoscopic appendectomy for perforated appendicitis . On presentation , there were no differences in age , weight , sex distribution , days of symptoms , maximum temperature , or leukocyte count between the 2 groups . There was no difference in the postoperative abscess rate between the two treatment groups . Discharge was possible before day 5 in 42 % of the patients in the IV/PO arm . CONCLUSIONS When patients are able to tolerate a regular diet , completing the course of antibiotics orally decreases hospitalization with no effect on the risk of postoperative abscess formation [17660129] BACKGROUND Conventionally the appendix is removed through a right lower quadrant transverse incision or a gridiron incision approximately 5 cm in length . In this modern era of minimally invasive surgery , there is a lot of emphasis on cosmesis and early recovery . We performed a prospect i ve , double blind , r and omised trial to evaluate a new incision for appendectomy to compare with conventional appendectomy . METHODS One hundred and twenty patients , aged between 3 and 18 years , were r and omized to receive either small access appendectomy ( SAA ) ( n=60 , 53 acute appendicitis and 7 interval appendectomy ) or conventional appendectomy ( CAP ) ( n=60 , 55 acute appendicitis and 5 interval appendectomy ) . SAA was performed through an incision in the lateral 1/3 of the spino-umbilical line , lateral to McBurney 's point . The caecum along with the appendix could be delivered through this small incision easily as the ileal loops did not interfere with the delivery . All patients suspected of acute appendicitis were evaluated by the modified Alvarado 's system to reduce the rate of negative appendectomies . Patients with diffuse peritonitis were excluded . RESULTS The demographic data for the two groups were similar . The SAA group required less analgesics ( p<0.001 ) , had earlier ambulation and shorter hospital stay ( p<0.001 ) , and better cosmetic score ( p<0.001 ) , but the operation took longer ( p<0.001 ) compared to the CAP group . CONCLUSION We conclude that SAA can be done safely without the need for any special equipment , with definite advantages over conventional appendectomy [21550483] BACKGROUND Research ers have suggested that antibiotics could cure acute appendicitis . We assessed the efficacy of amoxicillin plus clavulanic acid by comparison with emergency appendicectomy for treatment of patients with uncomplicated acute appendicitis . METHODS In this open-label , non-inferiority , r and omised trial , adult patients ( aged 18 - 68 years ) with uncomplicated acute appendicitis , as assessed by CT scan , were enrolled at six university hospitals in France . A computer-generated r and omisation sequence was used to allocate patients r and omly in a 1:1 ratio to receive amoxicillin plus clavulanic acid ( 3 g per day ) for 8 - 15 days or emergency appendicectomy . The primary endpoint was occurrence of postintervention peritonitis within 30 days of treatment initiation . Non-inferiority was shown if the upper limit of the two-sided 95 % CI for the difference in rates was lower than 10 percentage points . Both intention-to-treat and per- protocol analyses were done . This trial is registered with Clinical Trials.gov , number NCT00135603 . FINDINGS Of 243 patients r and omised , 123 were allocated to the antibiotic group and 120 to the appendicectomy group . Four were excluded from analysis because of early dropout before receiving the intervention , leaving 239 ( antibiotic group , 120 ; appendicectomy group , 119 ) patients for intention-to-treat analysis . 30-day postintervention peritonitis was significantly more frequent in the antibiotic group ( 8 % , n=9 ) than in the appendicectomy group ( 2 % , n=2 ; treatment difference 5·8 ; 95 % CI 0·3 - 12·1 ) . In the appendicectomy group , despite CT-scan assessment , 21 ( 18 % ) of 119 patients were unexpectedly identified at surgery to have complicated appendicitis with peritonitis . In the antibiotic group , 14 ( 12 % [ 7·1 - 18·6 ] ) of 120 underwent an appendicectomy during the first 30 days and 30 ( 29 % [ 21·4 - 38·9 ] ) of 102 underwent appendicectomy between 1 month and 1 year , 26 of whom had acute appendicitis ( recurrence rate 26 % ; 18·0 - 34·7 ) . INTERPRETATION Amoxicillin plus clavulanic acid was not non-inferior to emergency appendicectomy for treatment of acute appendicitis . Identification of predictive markers on CT scans might enable improved targeting of antibiotic treatment . FUNDING French Ministry of Health , Programme Hospitalier de Recherche Clinique 2002 [1608680] The efficacy of imipenem-cilastatin was compared with that of tobramycin and metronidazole for the treatment of appendicitis-associated abdominal infections in children in an open , r and omized trial . Two hundred eighteen patients between 2.5 and 16.8 years of age hospitalized for appendectomy because of suspected acute appendicitis were allocated to 5 treatment groups . The appendix was perforated in 54 ( 33.8 % ) of the 160 cases with appendicitis . All patients responded favorably to treatment . Infection in the wound coccurred in 15 of 125 ( 12.0 % ) of those without preoperative [11558012] 43 children between the ages of 7 and 15 years with clinical symptoms of acute appendicitis were r and omised to an open appendectomy ( OA ) or a laparoscopic appendectomy ( LA ) . There were 15 acute cases of appendicitis and 5 perforated appendices in the OA group and 17 acute appendicitis , 3 cases of perforated appendices and 3 other diagnoses in the LA group . The operative time was a little shorter in the OA group . There were no differences in hospital stay or the postoperative course of the patients . In the LA group , there were two minor complications , no other complications were seen . When comparing the two surgical methods in the consistent group of patients with non-perforated acute appendicitis no statistical differences were seen in the operative time , hospital stay or in the recovery of the patients between the OA and the LA groups . We conclude that LA has no significant benefit over OA in routine use . In paediatric patients we recommend an open approach for clinical ly typical acute appendicitis , but there should be no hesitation to choose laparoscopic approach when the clinical diagnosis is unclear [11735866] HYPOTHESIS For children with perforated appendicitis , the use of a prolonged course of intravenous ( i.v . ) antibiotics is equivalent to a short course of i.v . antibiotics followed by sequential conversion to oral ( PO ) antibiotics . DESIGN Prospect i ve , r and omized , clinical trial . SETTING Multicenter study in tertiary children 's hospitals . PATIENTS Children ( aged 5 - 18 years ) with perforated appendicitis found at laparotomy . INTERVENTION Children were r and omized after appendectomy either to a 10-day course of a combination of i.v . ampicillin , gentamicin sulfate , and clindamycin ( n = 10 ) ; or to a short course of a combination of i.v . ampicillin , gentamicin , and clindamycin , followed by conversion to a combination of p.o . amoxicillin and clavulanate potassium plus metronidazole ( n = 16 ) . MAIN OUTCOME MEASURES The primary outcome measure was clinical success , which was rated as complete , partial , or failure . Secondary outcome measures included return of oral intake , duration of fever , return of normal white blood cell count , and patient charges . Treatment equivalence was determined using confidence interval analysis . RESULTS We found treatment equivalence between the i.v . and i.v./p.o . groups , with 6 ( 60 % ) complete and 4 ( 40 % ) partial successes for the 10 patients in the i.v . group and 15 ( 94 % ) complete and 1 ( 6 % ) partial successes for the 16 patients in the i.v./p.o . group ( P < or = .05 ) . There was no difference in return of oral intake , duration of fever , or return of normal white blood cell count between the groups . Conversion to oral therapy results in savings of approximately $ 1500 per case . CONCLUSION There is treatment equivalence between prolonged i.v . therapy and i.v . therapy followed by conversion to oral antibiotic therapy in children with perforated appendicitis [12883855] Peritoneal drainage in children with uncomplicated perforated appendicitis ( UPA ) is still controversial . Many pediatric surgeons prefer not to drain the peritoneal cavity in such cases . However , there is no r and omized controlled study performed in children . We aim ed to study the effects of peritoneal drainage in children with UPA in a r and omized prospect i ve trial . One hundred and forty consecutive patients with UPA were divided r and omly into 2 groups . Group I ( 70 patients ) consisted of cases with peritoneal drainage , and group II ( 70 patients ) without drainage . UPA is defined as perforated appendicitis with no more discoloration of peritoneal fluid after peritoneal wash out . Cases with localized abscess in the peritoneum were excluded from the study . In all patients , the ages , duration of symptoms , nasogastric drainage and hospitalization , and complications after surgery were recorded . The duration of hospitalization and nasogastric draining time were significantly lower in patients without peritoneal drainage . There was no difference in postoperative complications between the two groups . The onset of oral intake after surgery was significantly earlier in group II patients . Placing drains in the peritoneum does not improve outcome in UPA . Therefore , we do not recommend routine drainage of children with UPA [22342789] BACKGROUND The methods of surgical care for children with perforated appendicitis are controversial . Some surgeons prefer early appendectomy ; others prefer initial nonoperative management followed by interval appendectomy . Determining which of these two therapies is most cost-effective was the goal of this study . STUDY DESIGN We conducted a prospect i ve , r and omized trial in children with a preoperative diagnosis of perforated appendicitis . Patients were r and omized to early or interval appendectomy . Overall hospital costs were extracted from the hospital 's internal cost accounting system and the two treatment groups were compared using an intention-to-treat analysis . Nonparametric data were reported as median ± st and ard deviation ( or range ) and compared using a Wilcoxon rank sum test . RESULTS One hundred thirty-one patients were r and omized to either early ( n = 64 ) or interval ( n = 67 ) appendectomy . Hospital charges and costs were significantly lower in patients r and omized to early appendectomy . Total median hospital costs were $ 17,450 ( range $ 7,020 to $ 55,993 ) for patients treated with early appendectomy vs $ 22,518 ( range $ 4,722 to $ 135,338 ) for those in the interval appendectomy group . Median hospital costs more than doubled in patients who experienced an adverse event ( $ 15,245 vs $ 35,391 , p < 0.0001 ) . Unplanned readmissions also increased costs significantly and were more frequent in patients r and omized to interval appendectomy . CONCLUSIONS In a prospect i ve r and omized trial , hospital charges and costs were significantly lower for early appendectomy when compared with interval appendectomy . The increased costs were related primarily to the significant increase in adverse events , including unplanned readmissions , seen in the interval appendectomy group [4601029] The effect of topical ampicillin on the rate of wound infection after emergency appendicectomy was studied in a prospect i ve controlled trial of 200 patients . Sixteen per cent of patients in the control group developed a wound injection compared with 3 per cent of those receiving ampicillin powder in the wound ( P<0.01 ) . When patients with peritonitis were considered , 64 per cent of the 14 patients in the control group developed a wound infection compared with 13 per cent of the 15 patients in the ampicillin group [957060] INTRAPERITONEAL ANTIBIOTICS have been used for over 30 Deyr . spite numerous experimental and clinical investigations , their role in clinical peritonitis has not been clarified . A number of retrospective studies have included patients of varying ages with peritonitis of diverse origins . Appendicitis , with generalized peritonitis in children is still a major clinical problem . The benefits of systemic antibiotics in these cases remains controversial and the use of intraperitoneal antibiotics has not been widely reported . At the Children 's Memorial Hospital we have carried out a double-blind controlled study of the effects of intraperitoneal and wound irrigation with kanamycin in cases of perforated appendicitis . METHODS Children with perforated appendicitis and established peritonitis undergoing operation from April 1969 to July 1974 were included in this study . Cultures of peritoneal fluid or pus were obtained on each patient . The use of systemic antibiotics and ~.eritoneal or wound drainage was left to the discretion of the surgeon . Kanamycin and placebo solutions were supplied in numerically coded vials , previously r and omized by Bristol Laboratories . These were added to identically coded 500 ml bottles of normal saline by the hospital pharmacy prior to use . Before closure of the peritoneum the peritoneal cavity and the wound were irrigated with either a 0.25 % solution of kanamycin or with normal saline . No attempt was made to suction all of the irrigant . A volume of 20 ml/kg of body weight was used up to a maximum of 500 ml . Irrigation with the kanamycin solution delivered 50 mg of drug/kg body weight . Each patient was specifically observed during the intraoperative and postoperative periods for signs of respiratory depression . None exhibited any sign of depression or other evidence of drug toxicity . The postoperative courses of 79 patients with perforated appendicitis were analyzed . This patient population included 37 boys and 42 girls . Nineteen were black , 59 white , and one oriental . Forty-eight per cent were between six and 10 yr of age ; 24 % were 13 mo to 5 yr ; and 28 % , 11 - 16 yr . Wound infections that necessitated the drainage of a primarily closed wound or prevented a planned delayed primary closure were distinguished from wounds showing only prolonged or purulent drainage at sites of peritoneal or wound drains . Localized intra-abdominal abscesses requiring operative drainage have been listed separately from presumed pelvic phlegmons that resolved spontaneously [24439594] BACKGROUND Single site laparoscopy for appendectomy is a technique with several case series suggesting a cosmetic advantage , but without prospect i ve comparative data . We conducted a prospect i ve , r and omized trial comparing single site laparoscopic appendectomy to the st and ard 3-port approach , including scar assessment at early and long-term follow-up . METHODS Enrolled patients over 12years old and parents of patients less than 12years old were asked to complete the vali date d Patient Scar Assessment Question naire ( PSAQ ) at early follow-up around 6weeks and by phone after 18months . The PSAQ consists of 4 scored subscales : Appearance , Consciousness , Appearance Satisfaction , and Symptom Satisfaction . Each subscale has a set of questions with a 4-point categorical response ( 1=most favorable , 4=least favorable ) . The sum of the scores quantifies each subscale . RESULTS Early question naires were obtained from 98 3-port and 100 single-site patients with the single-site approach producing superior overall scar assessment ( P=0.003 ) . By telephone follow-up , question naires were completed by 49 3-port and 56 single-site patients at a median of 25 ( 18 - 32 ) months . In this longer-term follow-up , overall scar assessment was not significantly different between groups ( P=0.06 ) . CONCLUSION Patients or parents express superior scar assessment with the single site approach at early follow-up , but this difference disappears in the long-term [21946218] Background : Laparoscopic appendectomy through a single umbilical incision is an emerging approach supported by several case series . However , to date , prospect i ve comparative data are lacking . Therefore , we conducted a prospect i ve , r and omized trial comparing single site umbilical laparoscopic appendectomy to 3-port laparoscopic appendectomy . Methods : After Internal Review Board approval , patients were r and omized to laparoscopic appendectomy via a single umbilical incision or st and ard 3-port access . The primary outcome variable was postoperative wound infection . Using a power of 0.9 and an alpha of 0.05 , 180 patients were calculated for each arm . Patients with perforated appendicitis were excluded . The technique of ligation/division of the appendix and mesoappendix was left to the surgeon 's discretion . There were 7 participating surgeons dictated by the call schedule . All patients received the same preoperative antibiotics and postoperative management was controlled . Results : There were 360 patients were enrolled between August 2009 and November 2010 . There were no differences in patient characteristics at presentation . There was no difference in wound infection rate , time to regular diet , length of hospitalization , or time to return to full activity . Operative time , doses of narcotics , surgical difficultly and hospital charges were greater with the single site approach . Also , the mean operative time was 5 minutes longer for the single site group . Conclusion : The single site umbilical laparoscopic approach to appendectomy produces longer operative times result ing in greater charges . However , these small differences are likely of marginal clinical relevance . The study was registered with clinical trials.gov at the inception of enrollment ( NCT00981136 ) [9298911] OBJECTIVE To compare the therapeutic efficacy of four antibiotic regimens : penicillin , tobramycin , and clindamycin ; penicillin , tobramycin , and ornidazole ; piperacillin alone ; and ceftriaxone and ornidazole in the treatment of children operated on for perforated appendicitis . DESIGN Prospect i ve r and omised study . SETTING Teaching hospital , Turkey . SUBJECTS 200 patients aged between 1 and 16 years treated from December 1991 to December 1995 who were r and omly assigned to one of four groups each consisting of 50 patients . INTERVENTIONS Preoperative antibiotics given intravenously , peritoneal drainage by Penrose drains without irrigation , appendicectomy with the inversion of the stump by a purse string , taking peritoneal swabs , and primary skin closure . MAIN OUTCOME MEASURES Comparability of the groups , duration of fever , leucocytosis , antibiotic treatment , stay in hospital , nasogastric intubation , and drainage , as well as results of cultures and complications . RESULTS There were no significant differences between the groups for any variable studied . The predominant bacterial species were Escherichia coli , Klebsiella spp , Pseudomonas spp , Fusobacteria , and Peptostreptococci which were appropriately covered by all the antibiotic regimens . Fourteen patients had complications including wound infections ( n = 10 ) , prolonged ileus ( n = 2 ) and intra-abdominal abscess ( n = 2 ) all of which were treated conservatively . There was no mortality and no major complications . All regimens had the same clinical and bacteriological efficacy . CONCLUSION There is no gold st and ard for antimicrobial chemotherapy in perforated appendicitis . Different antibiotic combinations or a single broad spectrum antibiotic , which include both aerobic and anaerobic coverage , can safely be used in children with perforated appendicitis [23239295] Background Single-incision laparoscopic surgery ( SILS ) is a novel area of minimally invasive surgery that uses a single incision to minimize all ports to one site . The end result is an incision that can be strategically placed in the umbilicus for a perceived scarless abdomen . The authors rationalized that a r and omized controlled trial was important given the rapid popularization of this approach . Methods An institutional review board-approved prospect i ve r and omized trial compared patients undergoing SILS ( SILS-A ) and conventional laparoscopic ( LAP-A ) appendectomy at a free-st and ing children ’s hospital during a median follow-up period of 2.2 years . Results A total of 50 patients ( 50 % boys and 67 % Hispanics ) were r and omized equally to SILS-A and LAP-A. The patients ranged in age from 3 to 15 years without a difference between the two groups . Half ( 50 % ) of these patients were younger than 8 years . The technique for SILS-A involved a single supraumbilical curvilinear skin incision with three fascial incisions . Ports were inserted to varying depths to minimize restriction of instrument movement . Coaxial visualization was improved by the use of a 30 ° scope . To achieve technical comparability with the LAP-A , a stapler device was used , which required upsizing a 5 mm port to a 12 mm port . The mean duration of the operation was 46.8 ± 3.7 min ( range , 22–120 min ) compared with 34.8 ± 2.5 min ( range , 18–77 min ) for st and ard LAP-A ( p = 0.010 ) . No conversions occurred , and the two groups did not differ in hospital length of stay . The postoperative complications consisted of one wound seroma in the SILS-A group ( nonsignificant difference ) , and no hernias were seen . No difference in readmissions , diet tolerance , fever , or postoperative pain was noted between the two groups . Conclusions The findings show the SILS approach to be feasible in the pediatric population despite the limited abdominal domain in younger children . Although SILS operating room times currently are longer than for LAP-A , they are comparable , and no other outcomes differed appreciably between the two techniques at the time of hospitalization or during the follow-up period [20105610] INTRODUCTION Perforated appendicitis is a common condition in children , which , in a small number of patients , may be complicated by a well-formed abscess . Initial nonoperative management with percutaneous drainage/aspiration of the abscess followed by intravenous antibiotics usually allows for an uneventful interval appendectomy . Although this strategy has become well accepted , there are no published data comparing initial nonoperative management ( drainage/interval appendectomy ) to appendectomy upon presentation with an abscess . Therefore , we conducted a r and omized trial comparing these 2 management strategies . METHODS After internal review board approval ( # 06 11 - 164 ) , children who presented with a well-defined abdominal abscess by computed tomographic imaging were r and omized on admission to laparoscopic appendectomy or intravenous antibiotics with percutaneous drainage of the abscess ( when possible ) , followed by interval laparoscopic appendectomy approximately 10 weeks later . This was a pilot study with a sample size of 40 , which was based on our recent volume of patients presenting with appendicitis and abscess . RESULTS On presentation , there were no differences between the 2 groups regarding age , weight , body mass index , sex distribution , temperature , leukocyte count , number of abscesses , or greatest 2-dimensional area of abscess in the axial view . Regarding outcomes , there were no differences in length of total hospitalization , recurrent abscess rates , or overall charges . There was a trend toward a longer operating time in patients undergoing initial appendectomy ( 61 minutes versus 42 minutes mean , P = .06 ) . CONCLUSIONS Although initial laparoscopic appendectomy trends toward a requiring longer operative time , there seems to be no advantages between these strategies in terms of total hospitalization , recurrent abscess rate , or total charges [1090718] From a controlled therapeutic trial extending for more than 2 yr and involving 69 patients with appendicitis and peritonitis a clear-cut statistically significant result emerged . There was a major reduction in the incidence of intraperitoneal abscesses using cephaloridine by the intraperitoneal as opposed to the systemic route . After r and omized selection into treatment and control groups , cephaloridine , 25 mg/kg was given by injection every 6 hr for 48 hr to the treatment group by i.p . installation and to the control group by systemic injection . Both groups received initial intraoperative peritoneal lavage with normal saline and also continued systemic injections of cephaloridine on postoperative days 3 , 4 , and 5 . Only one out of 36 patients in the treatment group developed a residual intraperitoneal abscess , as opposed to six abscesses developing in 33 patients in the control group . Technical problems and complications of the method were trivial and have not prevented us from continuing and extending the applications of the method [22294719] There is a growing recognition that insufficient attention has been paid to the selection of the outcomes to measure in clinical trials and clinical audit . Outcomes need to be relevant to patients , clinicians , purchasers and policy-makers if the findings of research are to influence practice and future research . In addition , st and ardization of outcomes is needed to combine data from different studies to allow evidence synthesis and to compare data sets . Inconsistent choice of outcome measures means that many meta-analyses are unable to include data from all the relevant studies . For example , the five most accessed Cochrane review s in 2009 , together with the top cited review in that year , all described inconsistencies in the outcomes reported in eligible trials . A call for the st and ardization of outcomes is a regular conclusion of systematic review s. Furthermore , outcome reporting bias , defined as the bias arising from selecting outcomes for publication based on the results , affects many r and omized trials and ‘ is an under-recognized problem that affects the conclusions in a substantial proportion of Cochrane review s ’ . That bias is likely to affect systematic review s more widely as well as affecting individual studies when considered on their own . Similar problems occur with clinical audit , highlighting the importance of establishing national audits that use and report the same outcomes for all participants . All these issues could be addressed with the development and application of agreed st and ardized sets of outcomes that have been termed ‘ core outcome sets ’ . These should be measured and reported , as a minimum , in all relevant clinical trials and national clinical audits for a specific condition . Adopting a core outcome set does not imply that a particular study , review or audit should be restricted to only those outcomes . Rather , the expectation is that , as a minimum , core outcomes will always be collected and reported to allow the results of trials to be compared , contrasted and combined as appropriate . The adoption of core outcomes would have implication s across all areas of research in health and health care , reduce heterogeneity between trials , and lead to research that is more likely to have measured relevant outcomes . Importantly , they would enhance the value of evidence synthesis by reducing the risk of outcome reporting bias and ensuring that all trials contribute usable information . In addition , they will increase the efficiency and value of research . An important rationale for core outcome sets is that outcomes currently reported for trials do not consistently reflect endpoints that are meaningful for patients . Examples exist where trials failed to include all outcomes important to patients and where involvement of patients has identified an outcome that might not have been considered by practitioners on their own . Despite increasing recognition of the importance of incorporating patients ’ opinions , their involvement has been limited . Recent regulatory guidance in the USA requires documented evidence of patient input during the development of instruments to measure patient reported outcomes ( PROs ) . However , measurement of PROs in clinical trials is hampered by the multiplicity and heterogeneity of tools currently available . Many generic , disease and domain-specific instruments have been developed and vali date d , each containing multiple scales and items . As a result , synthesis of PRO data from trials is difficult and review s aim ing to summarize treatment effect according to PROs may fail . There is synergy between the development of core outcome sets for trials and work to select up to seven outcomes that are important to patients for inclusion in Summary of Findings tables in systematic review s. Developed by the GRADE group ( http://www . grade workinggroup.org ) , Cochrane review s have featured such tables since 2008 , and they play a key role in presenting research in guidelines , such as those produced by the World Health Organization ( WHO ) . The development of core outcome sets needs to be accelerated and undertaken in ways that maximize efficiency . The COMET ( Core Outcome Measures in Effectiveness Trials , http://www.comet-initiative.org ) Initiative in the UK brings together research ers interested in the development and application of core outcome sets . These include key participants in a collaboration of research ers in rheumatology who have done the most notable work to date in this area . The COMET Initiative was launched in January 2010 , with a second meeting in July 2011 . Attendees included trialists , systematic review ers , patients , clinicians , journal editors , research funders , policy-makers , people responsible for trials registries and regulators . Data on individual studies , both published and ongoing , are being included in a free , publically available internet-based re source . This will be up date d periodically , to minimize the risk of duplication . Seventy-eight published or ongoing studies have already been entered into the repository . In addition , published review s of outcomes used in clinical trials or studies examining patients ’ views , will be entered [2024227] St and ard therapy for childhood ruptured appendicitis includes combination antibiotic therapy with ampicillin , gentamicin and clindamycin . Complicated dosing schedules and the possibility of aminoglycoside toxicity make alternatives desirable . One such alternative is Timentin ( a combination agent of ticarcillin disodium and clavulanate potassium ) . This agent has a more convenient dose schedule than st and ard therapy and eliminates the possibility of aminoglycoside ototoxicity and nephrotoxicity . It is active in vitro against most pathogens associated with ruptured appendicitis in children . The preliminary results of an ongoing prospect i ve , open label , r and omized trial comparing ticarcillin and clavulanate with ampicillin , gentamicin and clindamycin in childhood ruptured appendicitis are reported herein . While further evaluation is necessary , we have found single agent therapy with ticarcillin and clavulanate to be equivalent in safety and efficacy to st and ard combination therapy . Also discussed are the relative merits of immediate versus delayed primary closure of the abdominal wound after appendectomy [2691477] This multicentre trial compared the clinical efficacy of amoxycillin/clavulanate used as a single-agent therapy with that of the three-agent combination usually prescribed in the post-operative period for appendicular peritonitis in children . Only bacteriologically documented peritoneal infections were included . Sixty-four patients were r and omly distributed between two groups : Group A ( 29 cases ) treated with amoxycillin/clavulanate , first administered iv ( 100 mg/kg/day ) followed by conversion to the oral route ( 50 mg/kg/day ) once the patient had been afebrile for 48 h ; Group B ( 35 cases ) first treated by the iv route with benzylpenicillin ( 100,000 IU/kg/day ) plus netilmicin ( 5 mg/kg/day ) plus metronidazole ( 30 mg/kg/day ) followed by conversion to the oral route for metronidazole ( 30 mg/kg/day ) . In both groups , the total duration of parenteral and oral treatment was not less than five days . A total of 180 bacterial strains were recovered from peritoneal fluid sample s obtained during surgery ; 86 % of these were sensitive to amoxycillin/clavulanate . Clinical efficacy , assessed on the basis of time until return to normal temperature and gut transit and duration of hospitalization , was identical in both groups , with follow-up monitoring on day 30 showing recovery in all cases . Cure was obtained without any problems of infection in 25/29 patients in group A and in 34/35 patients in group B ( non-significant difference ) . Tolerance was excellent and identical in the two groups with the exception of three cases of thrombophlebitis which occurred in group B. The results of this study suggest that amoxycillin/clavulanate may be useful as single-agent therapy as a first-line curative treatment for appendicular peritonitis in children [2183940] One hundred children with peritonitis result ing from a perforated appendix were treated with ceftazidime or netilmicin . Metronidazole was added to both groups to treat the anaerobic organisms commonly associated with the infecting aerobic organisms in peritonitis . Escherichia coli was the most common aerobe found in peritoneal pus . Wound infection occurred in nine patients of the netilmicin group and in none treated with ceftazidime ( P less than 0.01 ) . No bacterial resistance was evident in the ceftazidime group , but gram-positive streptococci found in eight patients were resistant to netilmicin . Thus it is recommended that an antibiotic of the penicillin group be added if netilmicin is used to treat peritonitis . The results indicate that ceftazidime was more effective than netilmicin in the treatment of children with peritonitis result ing from a perforated appendix [1558500] In a 3-year period , 63 consecutive patients with advanced perforated ( n=53 ) and gangrenous ( n=10 ) appendicitis were allocated to undergo either immediate wound closure or delayed primary wound closure after emergency appendectomy . The incidence of wound infection between delayed primary wound closure and immediate wound closure was similar ( 24.0 % and 21.1 % , respectively ) . The duration for complete healing of infected wounds was slightly shorter in the group undergoing delayed primary wound closure ( mean + /- SD , 24.3 + /- 9.2 days ) than in the group undergoing immediate wound closure ( mean + /- SD , 32.6 + /- 16.5 days ) , but the difference was not significant . However , healing of noninfected wounds was significantly prolonged in the group undergoing delayed primary wound closure ( mean + /- SD , 19.3 + /- 10.1 days ) compared with the group undergoing immediate wound closure ( mean + /- SD , 7.0 + /- 0 days ) . The latter had been shown to associate with more nonseptic wound complications and therefore required longer rehabilitation . Our study showed that delayed primary closure did not offer additional advantage over immediate closure in the treatment of wounds associated with advanced appendicitis in children [22824858] Objective : To investigate clinical benefits of warm , humidified carbon dioxide ( CO2 ) insufflation for acute laparoscopic appendicectomy on postoperative pain and recovery in children ( age 8–14 years ) . Background : Conventional CO2 insufflation leads to desiccation-related peritoneal inflammation and injury , which is preventable with warm , humidified CO2 gas . We hypothesized that reduced peritoneal desiccation would improve patient-centered outcomes in children after laparoscopic appendicectomy . Method : A double-blinded , r and omized controlled trial was conducted . Intervention group participants received warm ( 37 ° C ) , humidified ( 98 % relative humidity ) CO2 gas insufflation , whereas control participants received st and ard room temperature ( 20 ° C ) gas with 0 % relative humidity . Perioperative analgesia and anesthesia were st and ardized . Postoperative opiate usage was converted to morphine equivalent daily dosages ( MEDD ) for comparison , and pain intensity at rest and on moving was rated by participants using visual analog scales . Postoperative recovery and return to normal activities was assessed using a question naire on day 10 . Results : Between February 2010 and March 2011 , a total of 190 participants were r and omized . Both intervention and control groups were matched at baseline . Postoperative MEDD and pain scores were also similar . There were no differences in postoperative recovery parameters . Conclusions : Warm , humidified CO2 insufflation for acute laparoscopic appendicectomy has no short-term clinical benefits on postoperative outcomes in pediatric patients ( Clinical Trials.gov trial identifying code : NCT01027455 )

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### Context: [8555131] 544 children operated upon for uncomplicated appendicitis were r and omised into three groups . Group I received no antibiotics , patients in Group II were administered one single pre-operative dose of metronidazole ( 10 mg/kg ) and patients in Group III received both both metronidazole ( 20 mg/kg ) and cefuroxime ( 50 mg/kg ) in a single preoperative dose . The rate of infectious complications in Group I was 6.3 % but only 2.1 and 2.3 in Groups II and III , respectively . Among patients with a normal appendix or patients with simple appendicitis there was no difference in the rate of post-operative infections between the three different groups . However , in patients with gangrenous appendicitis the rate of postoperative infections was significantly lower in the two groups who received preoperative antibiotics ( 1.8 % and 3.0 % respectively ) than in the group receiving no prophylactic antibiotics ( infection rate 14 % ) . It is concluded that a single preoperative dose of metronidazole significantly decreases the rate of postoperative infectious complications in children with appendicitis . No further improvement could be demonstrated if cefuroxime against aerobic organisms was added [7640447] A total of 231 children with acute appendicitis were treated at our hospitals during the 10 years between 1984 and 1993 , 53 of whom had a perforated appendix . These 53 patients were r and omly assigned to two groups at the time of surgery according to the different procedures performed . Thus , 29 children were managed by appendectomy followed by peritoneal lavage using a large amount of saline , and intravenous antibiotic therapy consisting of aminoglycoside and cephem ( lavage group ) , while the other 24 children were treated by appendectomy with silicon tube drainage and the same systemic antibiotic therapy ( drainage group ) . The mean length of hospitalization , and the mean duration s of fever and the need for fasting after laparotomy in the lavage group were significantly less than those in the drainage group : 10.1 versus 18.8 days , 2.8 versus 7.7 days , and 1.8 versus 3.5 days , respectively . The operation wounds healed well in the lavage group due to the fact that there was no drain . Wound infections occurred in two children from the lavage group and six from the drainage group . Intra-abdominal abscesses occurred in two children from the drainage group . Accordingly , peritoneal lavage appears to be superior to intraperitoneal tube drainage for the management of perforated appendicitis in children [14691709] Background : The aim of this study was to evaluate prospect ively whether laparoscopic ( LA ) and open appendectomy ( OA ) are equally safe and feasible in the treatment of pediatric appendicitis . Methods : A total of 517 children with acute appendicitis were r and omly assigned to undergo LA or OA appendectomy , based on the schedule of the attending surgeon on call . Patient age , sex , postoperative diagnosis , operating time , level of training of surgical resident , length of postoperative hospitalization , and minor and major postoperative complications were recorded . Chi-square analysis and the Student t-test were used for statistical analysis . Results : In all , 376 OA and 141 LA were performed . The two groups were comparable in terms of patient demographics and the incidence of perforated appendicitis . The operative time was also similar ( 47.3 ± 19.7 vs 49.9 ± 12.9 min ) . The overall incidence of minor or major complications was 11.2 % in the OA group and 9.9 % in the LA group . Conclusion : Pediatric patients with appendicitis can safely be offered laparoscopic appendectomy without incurring a greater risk for complications . Nevertheless , a higher ( but not significantly higher ) abscess rate was found in patients with perforated appendicitis who underwent laparoscopy [24951281] BACKGROUND For decades , urgent operation has been considered the only appropriate management of acute appendicitis in children . The purpose of this study was to investigate the feasibility of nonoperative management of uncomplicated acute appendicitis in children . STUDY DESIGN A prospect i ve nonr and omized clinical trial of children with uncomplicated acute appendicitis comparing nonoperative management with urgent appendectomy was performed . The primary result was 30-day success rate of nonoperative management . Secondary outcomes included comparisons of disability days , missed school days , hospital length of stay , and measures of quality of life and health care satisfaction . RESULTS Seventy-seven patients were enrolled during October 2012 to October 2013 ; 30 chose nonoperative management and 47 chose surgery . There were no significant differences in demographic or clinical characteristics . The immediate and 30-day success rates of nonoperative management were 93 % ( 28 of 30 ) and 90 % ( 27 of 30 ) . There was no evidence of progression of appendicitis to rupture at the time of surgery in the 3 patients for whom nonoperative management failed . Compared with the surgery group , the nonoperative group had fewer disability days ( 3 vs 17 days ; p < 0.0001 ) , returned to school more quickly ( 3 vs 5 days ; p = 0.008 ) , and exhibited higher quality of life scores in both the child ( 93 vs 88 ; p = 0.01 ) and the parent ( 96 vs 90 ; p = 0.03 ) , but incurred a longer length of stay ( 38 vs 20 hours ; p < 0.0001 ) . CONCLUSIONS Nonoperative management of uncomplicated acute appendicitis in children is feasible , with a high 30-day success rate and short-term benefits that include quicker recovery and improved quality of life scores . Additional follow-up will allow for determination of longer-term success rate , safety , and cost effectiveness [2883223] Eighty-four cases of non-perforated appendicitis in children were r and omly allocated to receive either oxytetracycline lavage alone or oxytetracycline lavage plus peroperative intravenous metronidazole and cefuroxime . The wound infection rate with the oxytetracycline lavage alone was 4.4 % compared with 7.7 % when metronidazole and cefuroxime were added . These rates were not significantly different . This study supports the use of oxytetracycline lavage alone as effective prophylaxis against wound infection in non-perforated appendicitis of childhood [21683209] PURPOSE The current study examined the impact of immediate laparoscopic surgery vs nonoperative initial management followed by interval appendectomy for appendicitis with abscess on child and family psychosocial well-being . METHODS After obtaining Internal Review Board approval , 40 patients presenting with a perforated appendicitis and a well-formed abscess were r and omized to surgical condition . Parents were asked to complete child quality of life and parenting stress ratings at presentation , at 2 weeks postadmission , and at approximately 12 weeks postadmission ( 2 weeks postoperation for the interval appendectomy group ) . RESULTS Children in the interval arm experienced trends toward poorer quality of life at 2 and 12 weeks postadmission . However , no group differences in parenting stress were observed at 2 weeks postoperation . At 12 weeks postadmission , participants in the interval condition demonstrated significant impairment in both frequency and difficulty of problems contributing to parenting distress . CONCLUSION Families experience significant parenting distress related to the child 's functioning and disruption in the child 's quality of life that may be because of the delay in fully resolving the child 's medical condition . In addition , parents experience negative consequences to their own stress as a result of the delay before the child 's appendectomy [6342959] A total of 133 children , aged 16 months to 15 years ( mean 6.7 years ) , with presumptive acute appendicitis , was included in a double-blind , placebo-controlled trial of the short-term ( 72 hour ) use of metronidazole suppositories as prophylaxis against post-operative infection . There was no significant difference in the incidence or severity of wound infection or post-operative intra-abdominal sepsis between the metronidazole-treated and placebo groups . It is suggested that intra-rectal metronidazole , when used exclusively , is not sufficient for effective prophylaxis for appendicitis in childhood [3499502] Sulbactam is a beta-lactamase inhibitor , which when administered with ampicillin , increases the latter agents antibacterial activity against beta-lactamase producing organisms . One hundred children between the ages of 5 and 14 undergoing emergency appendectomy were entered into a prospect i ve r and omized trial comparing sulbactam and ampicillin ( SA ) with metronidazole and cefotaxime ( MC ) as prophylaxis against postoperative wound infection . Patients in whom the appendix was perforated or gangrenous received a 72-hour course of antibiotics , others received a single dose only . The overall wound infection rate was 8 % ( 14 % in patients with perforation or gangrene and 4 % in those without ) . There was no difference in infection rate between the two antibiotic groups ; there were three wound infections and one subphrenic abscess in patients receiving SA and four wound infections in patients receiving MC . SA , therefore , appears to be a suitable antibiotic combination for use as prophylaxis in appendicitis in children [6749270] The authors question the need to give prophylactic antibiotics perioperatively in all cases of acute appendicitis without perforation to reduce the rate of wound infection . A retrospective study of 82 patients showed a wound infection rate of 4.8 % ; 3 of 53 patients who did not receive antibiotics had a wound infection compared with 1 of 29 patients who received antibiotics . A prospect i ve double-blind clinical trial was performed comparing the results of perioperative administration of cefam and ole and placebo . One of 21 patients who received the placebo had a wound infection ; none of the 21 patients given cefam and ole had infection . Thus , the authors conclude that , although reports in the literature suggest that antibiotics given perioperatively decrease the rate of wound infection in acute appendicitis without perforation , the incidence of such infection is too low to warrant routine administration . They suggest that such antibiotic use be reserved for those suspected of having more serious disease [6363670] A prospect i ve , r and omized , double-blind clinical trial was undertaken comparing gentamicin , ampicillin , and clindamycin ( GAC ) to gentamicin , ampicillin , and placebo ( GAP ) in children with complicated appendicitis . Of the 64 patients enrolled in this study , 33 were assigned to the GAC group and 31 received GAP . A single GAC patient ( 3 % ) was considered a therapeutic failure in comparison to seven children ( 23 % ) in the GAP group ( P less than 0.05 ) . Duration of fever was significantly prolonged in the GAP patients ( 4.7 + /- .8 days versus 2.9 + /- .5 days ) when compared to the clindamycin treated children ( P less than 0.05 ) . Duration of leukocytosis was 3.2 + /- .4 days for GAC patients and 4.9 + /- .9 days for those on the GAP protocol ( P = 0.08 ) . On the basis of this experience the routine use of gentamicin , ampicillin , and clindamycin is recommended for all children with complicated appendicitis [16736333] Background Appendectomy has been the treatment for acute appendicitis for over 120 years . Antibiotic treatment has occasionally been used in small uncontrolled studies , instead of operation , but this alternative has never before been tried in a multicenter r and omized trial . Patients and Methods Male patients , 18–50 years of age , admitted to six different hospitals in Sweden between 1996 and 1999 were enrolled in the study . No women were enrolled by decision of the local ethics committee . If appendectomy was planned , patients were asked to participate , and those who agreed were r and omized either to surgery or to antibiotic therapy . Patients r and omized to surgery were operated on with open surgery or laparoscopically . Those r and omized to antibiotic therapy were treated intravenously for 2 days , followed by oral treatment for 10 days . If symptoms did not resolve within 24 hours , an appendectomy was performed . Participants were monitored at the end of 1 week , 6 weeks , and 1 year . Results During the study period 252 men participated , 124 in the surgery group and 128 in the antibiotic group . The frequency of appendicitis was 97 % in the surgery group and 5 % had a perforated appendix . The complication rate was 14 % in the surgery group . In the antibiotic group 86 % improved without surgery ; 18 patients were operated on within 24 hours , and the diagnosis of acute appendicitis was confirmed in all but one patient , and he was suffering from terminal ileitis . There were seven patients ( 5 % ) with a perforated appendix in this group . The rate of recurrence of symptoms of appendicitis among the 111 patients treated with antibiotics was 14 % during the 1-year follow-up . Conclusions Acute nonperforated appendicitis can be treated successfully with antibiotics . However , there is a risk of recurrence in cases of acute appendicitis , and this risk should be compared with the risk of complications after appendectomy [23982816] BACKGROUND The primary objective of this study was to compare triple therapy with ertapenem treatments in pediatric patients with perforated appendicitis , especially in terms of postoperative infectious complications . The secondary objective of this study was to assess the relative impact of therapy with ertapenem and triple antibiotic regimen on the emergence of resistant bacteria in bowel flora in the patients . MATERIAL S AND METHODS Children aged 3 months to 17 years with perforated appendicitis were r and omized 1:1 to receive ertapenem or triple therapy . Serial rectal cultures were obtained from participants enrolled in the study , allowing assessment of the relative impact of therapy with ertapenem and triple therapy on bowel colonization by resistant bacteria . RESULTS In this study , 107 patients were included . No difference existed in time to full oral intake and regular diet , the length of antibiotic therapy , the length of the postoperative hospitalization , or the length of hospital stay between the two groups . Patients in the triple-therapy group were more likely to suffer from a postoperative infectious complication than those in the ertapenem group ( 6/54 vs. 2/53 , p > 0.05 ) . Bowel colonization with resistant organisms at the end of therapy in the triple-therapy group was significantly different than in the ertapenem group ( 35.2 vs. 11.3 % , p < 0.05 ) . CONCLUSIONS Bowel colonization with resistant bacteria was less likely to occur after ertapenem treatment than triple therapy . The results of this trial suggest that ertapenem may be a useful option that could eliminate the need for combination and /or multidosed antibiotic regimens for the empiric treatment of perforated appendicitis in children [15902475] Despite aggressive surgical treatment , rational antibiotic therapy , and modern intensive care , generalised peritonitis remains a major threat in the paediatric age group . Several adjuvant strategies such as peritoneal saline lavage and peritoneal drainage have been utilised . Taurolidine , derived from the amino acid taurine , has bactericidic , antiendotoxic , and antiinflammatory properties . It has been introduced previously for intraoperative peritoneal lavage in treating peritonitis in adults . The aim of our study was to evaluate the effect of peritoneal taurolidine lavage on the clinical course and serological inflammation markers in children with perforated appendicitis and localised peritonitis . A series of 27 children presenting with appendicitis between January 1999 and July 2001 were included in the study after parental informed consent . All patients underwent open appendectomy . Taurolidine peritoneal lavage was applied in 15 r and omly selected children ( eight girls and seven boys ; mean age 10 years and 10 months ) . Twelve children received saline peritoneal lavage and served as the control group ( six girls and six boys ; mean age 9 years and 7 months ) . Blood was taken preoperatively and on postoperative days 1 , 3 , 7 , and 14 . Full blood cell count , C-reactive protein , endotoxin , interleukin-1 , interleukin-6 , soluble interleukin-2 receptor , tumour necrosis factor α , and procalcitonin were investigated to evaluate the serological course of inflammation . Both groups initially presented with severe inflammation as evidence d clinical ly and serologically . The clinical postoperative course was uneventful in 13/15 patients in the treatment group and 10/12 patients in the control group . The remaining patients presented complications : intraperitoneal abscess or early postoperative bowel obstruction . With regard to the serological inflammatory parameters , no significant differences were found between the two groups except for the soluble interleukin-2-receptor on the 7th postoperative day . In conclusion , the expected reduction of endotoxin levels and inflammatory activity in the treatment group was not evident . A significant advantage of adjuvant peritoneal taurolidine lavage in the surgical therapy of children with localised peritonitis due to appendicitis could not be shown in our study [21283958] BACKGROUND 4 methods are used in pediatric laparoscopic surgery to close trocar wounds . While tissue adhesives or adhesive strips have been shown to produce fewer wound complications and a better cosmetic result compared to trans- or only subcutaneous sutures , the choice of technique is still often based on the surgeon 's personal experience . Thus , the objective of this trial was to assess the impact of tissue adhesives ( Dermabond ™ ) compared to adhesive strips ( Steri-Strip ™ ) on potential complications of wound healing , wound pain , cosmetic outcome , and patient satisfaction after laparoscopic appendectomy in children . METHODS 49 patients undergoing laparoscopic appendectomy were enrolled in this prospect i ve r and omized trial . In every patient , two 5-mm and one 10-mm port-site incision was closed either with Dermabond ™ or Steri-Strip ™ after placing subcuticular absorbable sutures ( 4 - 0 Vicryl ™ ) . Postoperative complications , pain , and patient satisfaction with scars were evaluated at follow-up on day 10 and day 90 after the operation using a question naire and a visual analogue scale ( VAS ) . Photographs of scars taken on day 90 were evaluated on a VAS by 2 pediatric surgeons blinded to the closure method used . RESULTS According to the surgeons ' evaluation of the cosmetic outcome , a significant difference between the 2 groups with regard to the cosmetic score was found on day 90 of follow-up , favoring Steri-Strip ™ wound closure ( p < 0.05 ) . On day 10 and 90 there were no statistical differences between the 2 methods as regards the result of patient evaluations ( p > 0.05 ) . Only one wound infection ( 4 % ) was observed in the Steri-Strip ™ group ( n = 25 ) on day 10 . At follow-up on day 90 two patients ( 9.1 % ) in the Dermabond ™ group and one ( 4.8 % ) in the Steri-strip ™ group complained of wound pain ( p = 0.52 ) . CONCLUSIONS Both tissue adhesives and adhesive strips are excellent " no needle " alternatives for the closure of laparoscopic port-site incisions in children . As regards cosmetic outcome , Steri-Strip ™ wound closure seems to be the most suitable and is also the less expensive technique [4240443] Objective To determine the extent and nature of selective non-reporting of harm outcomes in clinical studies that were eligible for inclusion in a cohort of systematic review s. Design Cohort study of systematic review s from two data bases . Setting Outcome reporting bias in trials for harm outcomes ( ORBIT II ) in systematic review s from the Cochrane Library and a separate cohort of systematic review s of adverse events . Participants 92 systematic review s of r and omised controlled trials and non-r and omised studies published in the Cochrane Library between issue 9 , 2012 and issue 2 , 2013 ( Cochrane cohort ) and 230 systematic review s published between 1 January 2007 and 31 December 2011 in other publications , synthesis ing data on harm outcomes ( adverse event cohort ) . Methods A 13 point classification system for missing outcome data on harm was developed and applied to the studies . Results 86 % ( 79/92 ) of review s in the Cochrane cohort did not include full data from the main harm outcome of interest of each review for all of the eligible studies included within that review ; 76 % ( 173/230 ) for the adverse event cohort . Overall , the single primary harm outcome was inadequately reported in 76 % ( 705/931 ) of the studies included in the 92 review s from the Cochrane cohort and not reported in 47 % ( 4159/8837 ) of the 230 review s in the adverse event cohort . In a sample of primary studies not reporting on the single primary harm outcome in the review , scrutiny of the study publication revealed that outcome reporting bias was suspected in nearly two thirds ( 63 % , 248/393 ) . Conclusions The number of review s suspected of outcome reporting bias as a result of missing or partially reported harm related outcomes from at least one eligible study is high . The declaration of important harms and the quality of the reporting of harm outcomes must be improved in both primary studies and systematic review [20639825] This prospect i ve comparative study was conducted in the department of Pediatric Surgery , Dhaka Shishu ( children ) Hospital during the period of June 2007 to September 2008 with the children of < 12 years , diagnosed as acute Appendicitis . Patient selection was done by simple r and om technique by means of lottery . For open Appendectomy ( OA ) conventional method & for Laparoscopic Appendectomy ( LA ) 3 trocher technique was applied . Data was analyzed with the help of SPSS version 10 . In this study 60 cases with acute Appendicitis including both gender were studied by two groups , group-A include 30 cases for laparoscopic and group-B include 30 cases for open appendectomy . Postoperative pain was assessed in both groups by using FLACC scale and compared at 1st 6-hours , 24 hours , 72 hours , 96 hours & at day 7 . At 1st 6-hours , most of the children 24(80 % ) of group A had moderate pain whereas 17(56.7 % ) children of group B had severe pain ( p<0.001 ) . At 24 hours most of the patient 17(56.7 % ) of group A had mild pain compared to 27 ( 90 % ) patients of group B had moderate pain ( p<0.0001 ) . At 48 hours in group A most of the children 23(76.7 % ) had mild pain compared to moderate pain in 18(60 % ) children of group B ( p<0.0001 ) . Subsequently at 72 hours and at 96 hours most of the patients of LA group were free of pain compared to OA group . At final follow-up on day 7 , 29(96.7 % ) children of group A had no pain compared to 26(86.7 % ) of group B. Regarding analgesics requirement both qualitative & quantitative requirements of analgesics were less in LA group than OA group . About post operative wound infection in group A only 1(3.3 % ) case had developed post operative wound infection whereas in group B 7(23.3 % ) cases had . The mean ( + /-SD ) of post operative length of hospital stay was 52.00+/-11.62 ( range 48 - 96 ) hours for group A and 76.00+/-12.74 ( range 48 - 96 ) hours for group B children ( p<0.001 ) . Laparoscopic Appendectomy is more effective , preferable & superior procedure than that of open Appendectomy to reduce the post operative morbidity in children undergone appendectomy for acute appendicitis [1902992] This prospect i ve , r and omized , double-blind study compares the efficacy , safety and cost-effectiveness of ampicillin , gentamicin and clindamycin ( AGC ) or cefotaxime and clindamycin ( CC ) for the treatment of children with complicated appendicitis . Ninety-seven children were r and omized . Forty-seven were assigned to the AGC regimen and 50 received CC . Forty-two patients in the AGC group had an appropriate therapeutic outcome , whereas 48 of 50 children who received CC completed the trial successfully ( p = NS ) . There were no differences between the groups with reference to the duration of antibiotic administration , fever , leukocytosis or length of hospitalization . Complications of therapy were uncommon and neither regimen demonstrated a significant advantage from an economic st and point . We concluded that , in childhood , complicated appendicitis can be treated with either CC or AGC with equal efficacy [25072441] OBJECTIVE The aim of this study was to evaluate the feasibility and safety of nonoperative treatment of acute nonperforated appendicitis with antibiotics in children . METHODS A pilot r and omized controlled trial was performed comparing nonoperative treatment with antibiotics versus surgery for acute appendicitis in children . Patients with imaging-confirmed acute nonperforated appendicitis who would normally have had emergency appendectomy were r and omized either to treatment with antibiotics or to surgery . Follow-up was for 1 year . RESULTS Fifty patients were enrolled ; 26 were r and omized to surgery and 24 to nonoperative treatment with antibiotics . All children in the surgery group had histopathologically confirmed acute appendicitis , and there were no significant complications in this group . Two of 24 patients in the nonoperative treatment group had appendectomy within the time of primary antibiotic treatment and 1 patient after 9 months for recurrent acute appendicitis . Another 6 patients have had an appendectomy due to recurrent abdominal pain ( n = 5 ) or parental wish ( n = 1 ) during the follow-up period ; none of these 6 patients had evidence of appendicitis on histopathological examination . CONCLUSIONS Twenty-two of 24 patients ( 92 % ) treated with antibiotics had initial resolution of symptoms . Of these 22 , only 1 patient ( 5 % ) had recurrence of acute appendicitis during follow-up . Overall , 62 % of patients have not had an appendectomy during the follow-up period . This pilot trial suggests that nonoperative treatment of acute appendicitis in children is feasible and safe and that further investigation of nonoperative treatment is warranted [21733727] BACKGROUND There is evidence that aminoglycosides given in a single daily dose ( once daily dose , ODD ) are as effective and safe as multiple daily doses ( MDD ) . However , the published pharmacokinetic and pharmacodynamic data are overly representative of pediatric population s in Europe and the USA , and not representative of low or middle-income countries such as Costa Rica , in which the patient population might differ from those in higher income setting s. METHODS A double-blind , r and omized clinical trial of the efficacy and safety of ODD vs. MDD amikacin therapy was conducted for children aged 2 - 12 years with an intraoperative diagnosis of perforated appendicitis . One hundred patients were r and omized following a one-to-one r and omization to receive either amikacin 7.5 mg/kg every 8 h ( MDD ) or 22.5 mg/kg as a single dose ( ODD ) . Patients in both groups were given clindamycin 10 mg/kg every 6 h. Efficacy was evaluated by the occurrence of intra-abdominal abscesses , documented by abdominal ultrasound , and therapeutic failure . Safety was determined by the presence of renal or cochlear toxicity . RESULTS Fifty patients were enrolled in each group . There were no statistically significant differences in the incidence of intra-abdominal abscesses or therapeutic failures , or in the occurrence of cochlear or renal toxicity , between the MDD and ODD treatment groups . CONCLUSIONS In this patient population of Costa Rican children with perforated appendicitis , we found that amikacin ODD is as safe and effective as the MDD regimen . This could have implication s for national health systems such as that in Costa Rica , as ODD is presumably a more economic option and may reduce the cost of antibiotic treatment in patients with perforated appendicitis . This would need to be confirmed through an economic analysis , which is outside the purview of this paper [2788460] Aims : The purpose of this study was to compare open versus laparoscopic appendicectomy ( LA ) in complicated appendicitis . Material s and Methods : We prospect ively analyzed all children over a 2-year period who underwent appendicectomy in a single institution and found 30 cases of complicated appendicitis diagnosed on the table and confirmed by histopathology . These children were allocated r and omly into Group 1 if they had LA and Group 2 if they had open appendicectomy ( OA ) , solely based on surgeon assessment . The parameters assessed were duration of symptoms before surgery , use of postoperative parenteral analgesia , timing of initiation of feeds after surgery , postoperative complications and duration of postoperative stay . Results : Of the 30 patients with complicated appendicitis , 12 patients in Group 1 underwent LA and 18 patients in Group 2 underwent OA . The two groups were comparable for age and sex . Children in Group 1 were found to need less parenteral analgesia ( two out of 12 versus six out of 18 ) . Postoperatively , feeds were started earlier in Group 1 than in Group 2 ( 2.5 days versus 3.7 days ) . The average postoperative hospital stay was 5 days in Group 1 and 7.5 days in Group 2 . There were only minor wound infections in Group1 as against two major complications in Group 2 . There was no mortality in either group . Conclusions : In complicated appendicitis , laparoscopic approach carries definite advantages with less postoperative morbidity and hospital stay . It is a feasible and better alternative than the open approach in complicated appendicitis [21339413] OBJECTIVE To compare the effectiveness and adverse event rates of early vs interval appendectomy in children with perforated appendicitis . DESIGN Nonblinded r and omized trial . SETTING A tertiary-referral urban children 's hospital . PATIENTS A total of 131 patients younger than 18 years with a preoperative diagnosis of perforated appendicitis . INTERVENTIONS Early appendectomy ( within 24 hours of admission ) vs interval appendectomy ( 6 - 8 weeks after diagnosis ) . MAIN OUTCOME MEASURES Time away from normal activities ( days ) . Secondary outcomes included the overall adverse event rates and the rate of predefined specific adverse events ( eg , intra-abdominal abscess , surgical site infection , unplanned readmission ) . RESULTS Early appendectomy , compared with interval appendectomy , significantly reduced the time away from normal activities ( mean , 13.8 vs 19.4 days ; P < .001 ) . The overall adverse event rate was 30 % for early appendectomy vs 55 % for interval appendectomy ( relative risk with interval appendectomy , 1.86 ; 95 % confidence interval , 1.21 - 2.87 ; P = .003 ) . Of the patients r and omized to interval appendectomy , 23 ( 34 % ) had an appendectomy earlier than planned owing to failure to improve ( n = 17 ) , recurrent appendicitis ( n = 5 ) , or other reasons ( n = 1 ) . CONCLUSIONS Early appendectomy significantly reduced the time away from normal activities . The overall adverse event rate after early appendectomy was significantly lower compared with interval appendectomy . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00435032 [11298617] Appendicectomy is the most common emergency surgical operation in children . The aim of this study was to compare recovery after appendicectomy using either a laparoscopic or an open technique in children [11269551] Patients and surgeons frequently opt for laparoscopic appendectomy for treatment of acute appendicitis . Clinical studies have shown this approach to be a reasonable alternative to open appendectomy . The objective of the current study was to assess the outcome of laparoscopic appendectomy using three different techniques . The study sample consisted of 150 children with acute appendicitis who underwent surgery at Al-Azhar University Hospitals , Cairo , Egypt , and at Al Mishary Hospital in Riyadh , Saudi Arabia , between October 1997 and October 1999 . The patients were allocated to undergo extracorporeal laparoscopic appendectomy , Endoloop laparoscopic appendectomy , or EndoGIA ( Ethicon Endo-surgery , Inc. , Cincinnati , OH , USA ) laparoscopic appendectomy . All patients were assessed for the severity of the disease at baseline using clinical and hematologic indicators . The ages of the children ranged from 7 to 14 years , with a mean of 10 years ( SD , 2.14 years ) . Of the children , 55.3 % were female . The results showed that children who underwent laparoscopic appendectomy using the EndoGIA had statistically significant shorter operating times , did not have complications , and had the shortest duration of hospital stay ( although duration of hospital stay did not reach the statistically significant level of P > 0.05 ) . Therefore , the study showed that laparoscopic appendectomy using the EndoGIA is the procedure that is most recommended , except for the relatively high cost of the disposable material s. Endoloop laparoscopic technique was the second most preferable procedure , and the least preferred procedure was extracorporeal laparoscopically assisted appendectomy . The major drawback of the last technique is the high frequency of complications . Endoloop laparoscopic appendectomy with a purse-string suture can be performed safely if the EndoGIA is not available [1925965] A prospect i ve r and omized study was undertaken to compare the use of the combination of gentamicin and clindamycin with single agent , cefoxitin , in the treatment of perforated appendicitis in the pediatric patient . In a 3-year period from 1986 to 1989 , 56 patients with perforated appendicitis were r and omized . Twenty-nine patients received cefoxitin , and 27 patients received gentamicin and clindamycin . Antibiotics were started before operation and continued for a minimum of 6 days after operation . Skin and subcutaneous tissues were left open at surgery and closed secondarily after day 3 , if they appeared to be clean . Wounds were considered infected if they developed increased purulence with positive wound cultures . Age range was similar in both groups , with a mean of 9 years ( range , 1 to 17 years ) ; 28 were boys and 28 were girls . No changes in antibiotics were required for reasons of susceptibility . No adverse drug reactions occurred in either group . The most common organisms were Escherichia coli in 35 cases ( 62 % ) and Bacteroides species in 26 cases ( 46 % ) . No difference was noted in infection complications in the two groups nor in length of hospital stay . Therefore , no difference is evident in the use of cefoxitin versus gentamicin and clindamycin in the treatment of perforated appendicitis in terms of disease or drug-related complications [8638833] Background The benefit of laparoscopy to patients has been clearly established in adults undergoing cholecystectomy . Results are less clear for appendectomy . The current study was undertaken to compare the respective 3-day postoperative periods after laparoscopic and open appendectomy in children . Methods Sixty-three children ( aged 8 - 15 yr ) scheduled for appendectomy were r and omly assigned to two groups : open and laparoscopic . Postoperative evaluation included delay of postoperative recovery ( walking and feeding ) , pain assessment by visual analog scale during the 3 subsequent days , amount of nalbuphine administered via a patient-controlled analgesia system during the first 48 h and responses by children , parents , and nurses on the overall quality of analgesia . Results There was no difference between groups for demographic data ( particularly macroscopic aspect of appendix ) , analgesia , sedation , delay before eating and walking , incidence of urinary retention , nausea , vomiting . Operative time was longer ( P less or equal to 0.05 ) in the laparoscopic group ( 54+/-17 min ) than in the open group ( 39 + /-18 min ) . Thirty five percent of the children had pain at the shoulder in the LAP group versus ten percent in the open group ( P less or equal to 0.05 ) . Conclusions Laparoscopy did not improve analgesia and postoperative recovery after appendectomy in children [1625127] A prospect i ve , r and omized , clinical study was done to evaluate the place of prophylactic antibiotics in uncomplicated childhood appendicitis . One hundred patients with uncomplicated appendicitis were r and omly assigned to one of four groups , each consisting of 25 cases . Group 1 patients did not receive prophylactic antibiotic . Group 2 , group 3 , and group 4 patients received ornidazole , penicillin plus tobramycin , and piperacillin , respectively . The use of prophylactic antibiotics did not yield better results than the use of placebos . The rarity of infectious complications after uncomplicated appendicectomy may be unique for children . Although the need for antibiotic prophylaxis is well documented in adults , the rarity of infectious complications makes it highly question able in the treatment of uncomplicated appendicitis in children [10231206] To demonstrate the efficacy of oral metronidazole ( OM ) in simple or complicated appendicitis with localized peritonitis , a r and omized prospect i ve study was carried out in 1083 patients , ranging in age from 4 to 50 years ( mean age , 21.38 ) . The patients were r and omly divided into two groups . The study group ( SG ) ( 524 patients ) received OM ( 500 mg for adults , 7 - 10 mg/kg if less than 15 years ) 2 - 3 hours before operation . The drug was continued 4 to 5 hours after operation , every 8 hours , for three doses if the appendix was mild to severely inflamed . In the case of complicated appendicitis ( 114 patients ) , the same dose was given for 3 to 6 days , depending on the absence or presence of pus . Ceftizoxime was administered to the control group ( CG ) ( 559 patients ) 2 to 3 hours before operation and then postoperatively every 6 hours for three doses if the appendix was mild to severely inflamed . The complicated cases in the CG ( 120 patients ) received a combination of penicillin , chloramphenicol , and gentamicin for 3 to 6 days , depending on the absence or presence of pus . The serum concentration of metronidazole measured in 43 patients was at bactericidal level in 40 ( mean + /- SD st and ard deviation , 10.65 + /- 4.89 microg/mL ) . The rate of wound infection was not significantly different in the SG and the CG with the same degree of pathology ( 3.17 % vs 2.96 % if uncomplicated ; 15.78 % vs 14.16 % if complicated , respectively ) . Pelvic collection occurred in four adults and one child in the CG with perforated appendicitis ( 4.16 % ) . The same complication developed in two adults and two children in the SG with perforated appendicitis ( 3.5 % ) . All six adults and one of the children in the SG had to be re-explored , whereas the remaining two children responded to conservative management ( OM and gentamicin ) . In uncomplicated cases , hospital stay and hospital charge were both almost the same in both groups . However , length of hospitalization was nearly 1 day shorter and hospital cost per day was about 30 per cent less in complicated cases in the SG as compared with the CG . Conclusively , OM may not only substitute parenteral antibiotics in acute appendicitis as a prophylactic agent , but it may also be used as a cost-effective drug and is more convenient to the patient [11257737] BACKGROUND The use of antibiotics in uncomplicated appendicitis in children , remains the area of controversy . The aim of the study was to assess the necessity of antibiotic administration in nonperforated appendicitis in children . MATERIAL AND METHODS The design of the study was a double blind r and omized controlled trial , with a follow-up of 4 to 20 months . SETTING Surgical Department in a University Pediatric Hospital . PATIENTS One hundred and eighty seven out of 249 children subjected to emergency appendectomies met the inclusion criteria , with 35 eligible but not included in the study . The remaining 152 patients were r and omized ; 41 had complicated appendicitis , 3 other diagnosis , 108 were analyzed within 3 study groups : 1 ( n = 31 ) no antibiotic , 2 ( n = 41 ) one dose , 3 ( n = 36 ) 5-day course . Open appendectomy was a surgical procedure and Ceftriaxone 1.0 g i.v . was administered . Investigated parameters were : body temperature , WBC , bowel sounds , wound healing , recovery and morbidity . RESULTS Valid outcome data were available for 90 of 108 r and omized patients . Protocol s of 18 children due to fever > 39 degrees C , upper airway infection or allergy were disclosed . In the remaining 90 children , there were no differences in WBC and oral feeding between groups 1 ( n = 24 ) , 2 ( n = 35 ) and 3 ( n = 31 ) . Group 1 and 2 had a higher mean temperature on day 1 post-op , without any clinical significance . A higher mean temperature was noted on day 5 post-op in group 1 , due to wound infection in one patient . There were no intraabdominal abscesses . The only other complications were 2 adhesion small bowel obstructions ( in groups 1 and 2 each ) . CONCLUSION Routine use of antibiotics in nonperforated appendicitis in children is not necessary [12194123] BACKGROUND / PURPOSE Laparoscopic appendectomy is an accepted way of dealing with suspected uncomplicated appendicitis in children . The role of laparoscopy in complicated acute appendicitis is more controversial . The purpose of this trial was to compare laparoscopic appendectomy with open appendectomy in children with complicated appendicitis . METHODS A total of 102 children with suspected acute appendicitis were selected r and omly to undergo either a laparoscopic or an open appendectomy . The outcomes of 25 children with complicated appendicitis , 13 in the laparoscopic group and 12 in the open appendectomy group , were analyzed . Children , their parents , and research nurses were blinded to which procedure had been performed and remained blinded until the control visit 7 days after the operation . All 25 children completed a 30-day follow-up . RESULTS There were no differences in terms of patients ' age , sex , weight , height , and appendiceal histology between the 2 groups . All laparoscopic procedures were completed without conversion . The mean ( + /-SD ) operating time was 63 ( + /-31 ) minutes in the laparoscopic group and 37 ( + /-18 ) minutes in the open appendectomy group ( mean difference 26 minutes , 95 % CI 5 to 47 minutes , P = .02 ) . There were 2 major complications in the laparoscopic group in children with appendiceal masses . One child had an entero-cutaneous fistula of the residual appendiceal tip that needed open reoperation . Another child had a pelvic abscess that resolved with antibiotic treatment . Superficial wound infections were encountered in 2 patients in the open appendectomy group . CONCLUSIONS Laparoscopic appendectomy is an alternative to open procedure in children with complicated appendicitis . Good surgical judgement is necessary in patients with an established appendiceal abscess [3312564] This is a prospect i ve and r and omized study of 100 patients with acute appendicitis who were less than 10 years old , in which four different antibiotic regimens commonly in use against gram-negative and anaerobic bacteria were compared in terms of postoperative septic complications . The antibiotics were begun immediately preoperatively and continued for five days . Ten percent of the patients developed infection complications , with 4 % requiring further surgery . The best results were obtained with cefoxitin ( 4 % of infection ) , metronidazole plus amikacin and latamoxef ( 8 % ) , while the regimen of clindamycin plus amikacin was associated with the greatest number of complications ( 20 % ) . On analyzing the main microbiologic findings of the study , we conclude that some sort of antibiotic treatment is indicated in all types of appendicitis , due to the occult presence of bacteria in the peritoneal cavity , even without clinical evidence of gangrene or perforation . Further , we emphasize the significance of Streptococcus faecalis as being responsible , along with Escherichia coli and Bacteroides fragilis , for serious postoperative complications [21044931] Background and Aims : Appendectomy wounds are still commonly closed with non-absorbable sutures . Stitch removal has financial costs and causes anxiety in children . Our aim was to compare interrupted non-absorbable ( NA ) and continuous intradermal absorbable ( A ) sutures in appendectomy wounds to evaluate whether absorbable suturing increases the risk of complications . Material and Methods : 198 children ( age 4–18 years ) including perforated cases were prospect ively r and omized into two groups ( NA and A skin closure ) . The wounds and inflammatory markers were evaluated on the first two postoperative days . The appearance of the wound was evaluated one week postoperatively by a district nurse . Follow-up data were obtained from 166 patients ( 87 in NA group and 79 in A group ) . Results : In NA group 86 % and in A group 81 % had appendicitis ( 8 % and 15.6 % perforated and 9.3 % and 25 % gangrenous cases in NA and A groups , respectively ) . The total wound infection rate was low , 1.8 % ( 2.3 % in NA Group and 1.3 % in A Group ) . No differences in the inflammatory markers or the appearance of the wound were noted between the groups , but nine children in NA Group ( 10.3 % ) had a partial wound dehiscence after stitch removal . Conclusion : Appendectomy wounds in children can be closed with continuous , absorbable sutures , even in complicated cases [14706955] BACKGROUND Laparoscopic procedures are performed commonly in children . In general , the cost containment of laparoscopic surgery in children has not been evaluated . OBJECTIVE To compare the costs of laparoscopic appendectomy with those of open appendectomy . DESIGN Prospect i ve clinical trial between November 1 , 1997 , and April 30 , 2000 . For analysis , cost of supplies , operation room use , and recovery in the hospital and after discharge was evaluated . Costs common to both groups were not determined . SETTING Operations performed in a university hospital . Patients Eighty-seven children aged 4 to 15 years who underwent appendectomy for suspected appendicitis . Patients were r and omized to laparoscopic or open appendectomy . Intervention Laparoscopic appendectomies performed with the same st and ard set of reusable equipment . MAIN OUTCOME MEASURES Cost surplus of the laparoscopic procedure and recovery after surgery were evaluated , to determine the costs and effects of laparoscopic appendectomy compared with those of open appendectomy in children . RESULTS Excess operating and complication costs per procedure were 96 euros ( EUR ) in laparoscopic appendectomy . The increased operative expenses were offset by a shorter hospital stay , result ing in a marginal difference of 53 EUR in itemized total costs between the 2 procedures ( total cost , 1023 EUR in the laparoscopic appendectomy group and 970 EUR in the open appendectomy group ) . After laparoscopic appendectomy , children returned to school and sports earlier than those who had had an open appendectomy . CONCLUSION Laparoscopic appendectomy was marginally more expensive , but it allowed earlier return to normal daily activities than open appendectomy [2899496] Summary In an attempt to reduce postoperative sepsis , a series of r and omised , double-blind studies was begun in 1982 , using cefotaxime as backbone therapy . Up to 1985 ( stages I and II ) , the best results were obtained using a combination of cefotaxime ( 75 mg/kg intravenously in 3 doses at 12-hourly intervals ) plus metronidazole ( 10 mg/kg intravenously in 3 doses ) , both drugs administered 1 hour before surgery ( preoperatively ) or at anaesthetic induction ( perioperatively ) . In 300 consecutive cases , the wound infection rates were 1 % in uncomplicated acute appendicitis and 5 % in perforated/gangrenous appendices . The present study ( stage III ) reports the findings in 401 consecutive patients : 215 treated with the above regimen , either pre-or perioperatively ( group 1 ) and 186 who additionally had peritoneal lavage with cefotaxime 2 g/L during surgery ( group 2 ) . There were 16 wound infections overall , 2 among patients administered prophylaxis preoperatively and 14 in those administered prophylaxis perioperatively . All produced mixed cultures , with Escherichia coli , Streptococcus milleri and Bacteroides fragilis predominating . The overall figures for postoperative sepsis are 12/215 ( 5.6 % ) in the non-lavage group and 8/186 ( 4.3 % ) in the lavage group . Among patients with a perforated and /or gangrenous appendix , the wound infection rate was 8/72 ( 11.1 % ) in the non-lavage group ( group 1 ) and 4/66 ( 6.1 % ) in the lavage group ( group 2 ) . Each group had 2 cases of pelvic abscess [11877640] BACKGROUND / PURPOSE Laparoscopic Appendectomy ( LA ) is a safe procedure in adults result ing in shorter hospitalization and sooner return to activity . The relative merits of LA and open appendectomy ( OA ) are evaluated in this first prospect i ve and r and omized study in children . METHODS A total of 129 children with appendicitis were included . Forty-three boys and 45 girls , age 1 to 16 years , were enrolled . R and omization was determined by sealed assignment card . OA utilized a 3- to 4-cm right lower quadrant , muscle-splitting incision . Wounds were closed without drains . Antibiotics , when used , consisted of gentamycin , clindamycin , and ampicillin . LA was performed by experienced surgeons utilizing a 3-trocar technique with reusable instruments . Twenty-one children ( 24 % ) were perforated . Patients were discharged as soon as they were taking a diet and afebrile . Statistical comparisons were by Fisher 's Exact and Wilcoxon rank-sum tests . RESULTS There were no differences in postoperative analgesia , resumption of oral intake , length of hospitalization , return to normal activities , or morbidity . Laparoscopic appendectomy was associated with longer operating times and increased cost . CONCLUSIONS Laparoscopic appendectomy in children is not associated with the same advantages reported in adults . LA is a more expensive alternative and offers no advantages related to pain relief , length of stay , return to normal activities , or morbidity [18558169] INTRODUCTION Appendicitis is the most common emergency condition in children . Historically , a 3-drug regimen consisting of ampicillin , gentamicin , and clindamycin ( AGC ) has been used postoperatively for perforated appendicitis . A retrospective review at our institution has found single day dosing of ceftriaxone and metronidazole ( CM ) to be a more simple and cost-effective antibiotic strategy . Therefore , we performed a prospect i ve , r and omized trial to compare efficacy and cost-effectiveness of these 2 regimens . METHODS After internal review board approval ( IRB no. 04 12 - 149 ) , children found to have perforated appendicitis at appendectomy were r and omized to either once daily dosing of CM ( 2 total doses per day ) or st and ard dosing of AGC ( 11 total doses per day ) . Perforation was defined as an identifiable hole in the appendix . The operative approach ( laparoscopic ) , length of antibiotic use , and criteria for discharge were st and ardized for the groups . Based on our retrospective analysis using length of postoperative hospitalization as a primary end point , a sample size of 100 patients was calculated for an alpha of .5 and a power of 0.82 . RESULTS One hundred patients underwent laparoscopic appendectomy for perforated appendicitis . On presentation , there were no differences in sex distribution , days of symptoms , temperature , or leukocyte count . There was no difference in abscess rate or wound infections between groups . The CM group result ed in significantly less antibiotic charges then the AGC group . CONCLUSIONS Once daily dosing with the 2-drug regimen ( CM ) offers a more efficient , cost-effective antibiotic management in children with perforated appendicitis without compromising infection control when compared to a traditional 3-drug regimen [20620320] INTRODUCTION In a previous prospect i ve r and omized trial , we found a once-a-day regimen of ceftriaxone and metronidazole to be an efficient , cost-effective treatment for children with perforated appendicitis . In this study , we evaluated the safety of discharging patients to complete an oral course of antibiotics . METHODS Children found to have perforated appendicitis at the time of laparoscopic appendectomy were enrolled in the study . Perforation was defined as a hole in the appendix or fecalith in the abdomen . Patients were r and omized to antibiotic treatment with either once daily dosing of ceftriaxone and metronidazole for a minimum of 5 days ( intravenous [ IV ] arm ) or discharge to home on oral amoxicillin/clavulanate when tolerating a regular diet ( IV/PO arm ) to complete 7 days . RESULTS One hundred two patients underwent laparoscopic appendectomy for perforated appendicitis . On presentation , there were no differences in age , weight , sex distribution , days of symptoms , maximum temperature , or leukocyte count between the 2 groups . There was no difference in the postoperative abscess rate between the two treatment groups . Discharge was possible before day 5 in 42 % of the patients in the IV/PO arm . CONCLUSIONS When patients are able to tolerate a regular diet , completing the course of antibiotics orally decreases hospitalization with no effect on the risk of postoperative abscess formation [17660129] BACKGROUND Conventionally the appendix is removed through a right lower quadrant transverse incision or a gridiron incision approximately 5 cm in length . In this modern era of minimally invasive surgery , there is a lot of emphasis on cosmesis and early recovery . We performed a prospect i ve , double blind , r and omised trial to evaluate a new incision for appendectomy to compare with conventional appendectomy . METHODS One hundred and twenty patients , aged between 3 and 18 years , were r and omized to receive either small access appendectomy ( SAA ) ( n=60 , 53 acute appendicitis and 7 interval appendectomy ) or conventional appendectomy ( CAP ) ( n=60 , 55 acute appendicitis and 5 interval appendectomy ) . SAA was performed through an incision in the lateral 1/3 of the spino-umbilical line , lateral to McBurney 's point . The caecum along with the appendix could be delivered through this small incision easily as the ileal loops did not interfere with the delivery . All patients suspected of acute appendicitis were evaluated by the modified Alvarado 's system to reduce the rate of negative appendectomies . Patients with diffuse peritonitis were excluded . RESULTS The demographic data for the two groups were similar . The SAA group required less analgesics ( p<0.001 ) , had earlier ambulation and shorter hospital stay ( p<0.001 ) , and better cosmetic score ( p<0.001 ) , but the operation took longer ( p<0.001 ) compared to the CAP group . CONCLUSION We conclude that SAA can be done safely without the need for any special equipment , with definite advantages over conventional appendectomy [21550483] BACKGROUND Research ers have suggested that antibiotics could cure acute appendicitis . We assessed the efficacy of amoxicillin plus clavulanic acid by comparison with emergency appendicectomy for treatment of patients with uncomplicated acute appendicitis . METHODS In this open-label , non-inferiority , r and omised trial , adult patients ( aged 18 - 68 years ) with uncomplicated acute appendicitis , as assessed by CT scan , were enrolled at six university hospitals in France . A computer-generated r and omisation sequence was used to allocate patients r and omly in a 1:1 ratio to receive amoxicillin plus clavulanic acid ( 3 g per day ) for 8 - 15 days or emergency appendicectomy . The primary endpoint was occurrence of postintervention peritonitis within 30 days of treatment initiation . Non-inferiority was shown if the upper limit of the two-sided 95 % CI for the difference in rates was lower than 10 percentage points . Both intention-to-treat and per- protocol analyses were done . This trial is registered with Clinical Trials.gov , number NCT00135603 . FINDINGS Of 243 patients r and omised , 123 were allocated to the antibiotic group and 120 to the appendicectomy group . Four were excluded from analysis because of early dropout before receiving the intervention , leaving 239 ( antibiotic group , 120 ; appendicectomy group , 119 ) patients for intention-to-treat analysis . 30-day postintervention peritonitis was significantly more frequent in the antibiotic group ( 8 % , n=9 ) than in the appendicectomy group ( 2 % , n=2 ; treatment difference 5·8 ; 95 % CI 0·3 - 12·1 ) . In the appendicectomy group , despite CT-scan assessment , 21 ( 18 % ) of 119 patients were unexpectedly identified at surgery to have complicated appendicitis with peritonitis . In the antibiotic group , 14 ( 12 % [ 7·1 - 18·6 ] ) of 120 underwent an appendicectomy during the first 30 days and 30 ( 29 % [ 21·4 - 38·9 ] ) of 102 underwent appendicectomy between 1 month and 1 year , 26 of whom had acute appendicitis ( recurrence rate 26 % ; 18·0 - 34·7 ) . INTERPRETATION Amoxicillin plus clavulanic acid was not non-inferior to emergency appendicectomy for treatment of acute appendicitis . Identification of predictive markers on CT scans might enable improved targeting of antibiotic treatment . FUNDING French Ministry of Health , Programme Hospitalier de Recherche Clinique 2002 [1608680] The efficacy of imipenem-cilastatin was compared with that of tobramycin and metronidazole for the treatment of appendicitis-associated abdominal infections in children in an open , r and omized trial . Two hundred eighteen patients between 2.5 and 16.8 years of age hospitalized for appendectomy because of suspected acute appendicitis were allocated to 5 treatment groups . The appendix was perforated in 54 ( 33.8 % ) of the 160 cases with appendicitis . All patients responded favorably to treatment . Infection in the wound coccurred in 15 of 125 ( 12.0 % ) of those without preoperative [11558012] 43 children between the ages of 7 and 15 years with clinical symptoms of acute appendicitis were r and omised to an open appendectomy ( OA ) or a laparoscopic appendectomy ( LA ) . There were 15 acute cases of appendicitis and 5 perforated appendices in the OA group and 17 acute appendicitis , 3 cases of perforated appendices and 3 other diagnoses in the LA group . The operative time was a little shorter in the OA group . There were no differences in hospital stay or the postoperative course of the patients . In the LA group , there were two minor complications , no other complications were seen . When comparing the two surgical methods in the consistent group of patients with non-perforated acute appendicitis no statistical differences were seen in the operative time , hospital stay or in the recovery of the patients between the OA and the LA groups . We conclude that LA has no significant benefit over OA in routine use . In paediatric patients we recommend an open approach for clinical ly typical acute appendicitis , but there should be no hesitation to choose laparoscopic approach when the clinical diagnosis is unclear [11735866] HYPOTHESIS For children with perforated appendicitis , the use of a prolonged course of intravenous ( i.v . ) antibiotics is equivalent to a short course of i.v . antibiotics followed by sequential conversion to oral ( PO ) antibiotics . DESIGN Prospect i ve , r and omized , clinical trial . SETTING Multicenter study in tertiary children 's hospitals . PATIENTS Children ( aged 5 - 18 years ) with perforated appendicitis found at laparotomy . INTERVENTION Children were r and omized after appendectomy either to a 10-day course of a combination of i.v . ampicillin , gentamicin sulfate , and clindamycin ( n = 10 ) ; or to a short course of a combination of i.v . ampicillin , gentamicin , and clindamycin , followed by conversion to a combination of p.o . amoxicillin and clavulanate potassium plus metronidazole ( n = 16 ) . MAIN OUTCOME MEASURES The primary outcome measure was clinical success , which was rated as complete , partial , or failure . Secondary outcome measures included return of oral intake , duration of fever , return of normal white blood cell count , and patient charges . Treatment equivalence was determined using confidence interval analysis . RESULTS We found treatment equivalence between the i.v . and i.v./p.o . groups , with 6 ( 60 % ) complete and 4 ( 40 % ) partial successes for the 10 patients in the i.v . group and 15 ( 94 % ) complete and 1 ( 6 % ) partial successes for the 16 patients in the i.v./p.o . group ( P < or = .05 ) . There was no difference in return of oral intake , duration of fever , or return of normal white blood cell count between the groups . Conversion to oral therapy results in savings of approximately $ 1500 per case . CONCLUSION There is treatment equivalence between prolonged i.v . therapy and i.v . therapy followed by conversion to oral antibiotic therapy in children with perforated appendicitis [12883855] Peritoneal drainage in children with uncomplicated perforated appendicitis ( UPA ) is still controversial . Many pediatric surgeons prefer not to drain the peritoneal cavity in such cases . However , there is no r and omized controlled study performed in children . We aim ed to study the effects of peritoneal drainage in children with UPA in a r and omized prospect i ve trial . One hundred and forty consecutive patients with UPA were divided r and omly into 2 groups . Group I ( 70 patients ) consisted of cases with peritoneal drainage , and group II ( 70 patients ) without drainage . UPA is defined as perforated appendicitis with no more discoloration of peritoneal fluid after peritoneal wash out . Cases with localized abscess in the peritoneum were excluded from the study . In all patients , the ages , duration of symptoms , nasogastric drainage and hospitalization , and complications after surgery were recorded . The duration of hospitalization and nasogastric draining time were significantly lower in patients without peritoneal drainage . There was no difference in postoperative complications between the two groups . The onset of oral intake after surgery was significantly earlier in group II patients . Placing drains in the peritoneum does not improve outcome in UPA . Therefore , we do not recommend routine drainage of children with UPA [22342789] BACKGROUND The methods of surgical care for children with perforated appendicitis are controversial . Some surgeons prefer early appendectomy ; others prefer initial nonoperative management followed by interval appendectomy . Determining which of these two therapies is most cost-effective was the goal of this study . STUDY DESIGN We conducted a prospect i ve , r and omized trial in children with a preoperative diagnosis of perforated appendicitis . Patients were r and omized to early or interval appendectomy . Overall hospital costs were extracted from the hospital 's internal cost accounting system and the two treatment groups were compared using an intention-to-treat analysis . Nonparametric data were reported as median ± st and ard deviation ( or range ) and compared using a Wilcoxon rank sum test . RESULTS One hundred thirty-one patients were r and omized to either early ( n = 64 ) or interval ( n = 67 ) appendectomy . Hospital charges and costs were significantly lower in patients r and omized to early appendectomy . Total median hospital costs were $ 17,450 ( range $ 7,020 to $ 55,993 ) for patients treated with early appendectomy vs $ 22,518 ( range $ 4,722 to $ 135,338 ) for those in the interval appendectomy group . Median hospital costs more than doubled in patients who experienced an adverse event ( $ 15,245 vs $ 35,391 , p < 0.0001 ) . Unplanned readmissions also increased costs significantly and were more frequent in patients r and omized to interval appendectomy . CONCLUSIONS In a prospect i ve r and omized trial , hospital charges and costs were significantly lower for early appendectomy when compared with interval appendectomy . The increased costs were related primarily to the significant increase in adverse events , including unplanned readmissions , seen in the interval appendectomy group [4601029] The effect of topical ampicillin on the rate of wound infection after emergency appendicectomy was studied in a prospect i ve controlled trial of 200 patients . Sixteen per cent of patients in the control group developed a wound injection compared with 3 per cent of those receiving ampicillin powder in the wound ( P<0.01 ) . When patients with peritonitis were considered , 64 per cent of the 14 patients in the control group developed a wound infection compared with 13 per cent of the 15 patients in the ampicillin group [957060] INTRAPERITONEAL ANTIBIOTICS have been used for over 30 Deyr . spite numerous experimental and clinical investigations , their role in clinical peritonitis has not been clarified . A number of retrospective studies have included patients of varying ages with peritonitis of diverse origins . Appendicitis , with generalized peritonitis in children is still a major clinical problem . The benefits of systemic antibiotics in these cases remains controversial and the use of intraperitoneal antibiotics has not been widely reported . At the Children 's Memorial Hospital we have carried out a double-blind controlled study of the effects of intraperitoneal and wound irrigation with kanamycin in cases of perforated appendicitis . METHODS Children with perforated appendicitis and established peritonitis undergoing operation from April 1969 to July 1974 were included in this study . Cultures of peritoneal fluid or pus were obtained on each patient . The use of systemic antibiotics and ~.eritoneal or wound drainage was left to the discretion of the surgeon . Kanamycin and placebo solutions were supplied in numerically coded vials , previously r and omized by Bristol Laboratories . These were added to identically coded 500 ml bottles of normal saline by the hospital pharmacy prior to use . Before closure of the peritoneum the peritoneal cavity and the wound were irrigated with either a 0.25 % solution of kanamycin or with normal saline . No attempt was made to suction all of the irrigant . A volume of 20 ml/kg of body weight was used up to a maximum of 500 ml . Irrigation with the kanamycin solution delivered 50 mg of drug/kg body weight . Each patient was specifically observed during the intraoperative and postoperative periods for signs of respiratory depression . None exhibited any sign of depression or other evidence of drug toxicity . The postoperative courses of 79 patients with perforated appendicitis were analyzed . This patient population included 37 boys and 42 girls . Nineteen were black , 59 white , and one oriental . Forty-eight per cent were between six and 10 yr of age ; 24 % were 13 mo to 5 yr ; and 28 % , 11 - 16 yr . Wound infections that necessitated the drainage of a primarily closed wound or prevented a planned delayed primary closure were distinguished from wounds showing only prolonged or purulent drainage at sites of peritoneal or wound drains . Localized intra-abdominal abscesses requiring operative drainage have been listed separately from presumed pelvic phlegmons that resolved spontaneously [24439594] BACKGROUND Single site laparoscopy for appendectomy is a technique with several case series suggesting a cosmetic advantage , but without prospect i ve comparative data . We conducted a prospect i ve , r and omized trial comparing single site laparoscopic appendectomy to the st and ard 3-port approach , including scar assessment at early and long-term follow-up . METHODS Enrolled patients over 12years old and parents of patients less than 12years old were asked to complete the vali date d Patient Scar Assessment Question naire ( PSAQ ) at early follow-up around 6weeks and by phone after 18months . The PSAQ consists of 4 scored subscales : Appearance , Consciousness , Appearance Satisfaction , and Symptom Satisfaction . Each subscale has a set of questions with a 4-point categorical response ( 1=most favorable , 4=least favorable ) . The sum of the scores quantifies each subscale . RESULTS Early question naires were obtained from 98 3-port and 100 single-site patients with the single-site approach producing superior overall scar assessment ( P=0.003 ) . By telephone follow-up , question naires were completed by 49 3-port and 56 single-site patients at a median of 25 ( 18 - 32 ) months . In this longer-term follow-up , overall scar assessment was not significantly different between groups ( P=0.06 ) . CONCLUSION Patients or parents express superior scar assessment with the single site approach at early follow-up , but this difference disappears in the long-term [21946218] Background : Laparoscopic appendectomy through a single umbilical incision is an emerging approach supported by several case series . However , to date , prospect i ve comparative data are lacking . Therefore , we conducted a prospect i ve , r and omized trial comparing single site umbilical laparoscopic appendectomy to 3-port laparoscopic appendectomy . Methods : After Internal Review Board approval , patients were r and omized to laparoscopic appendectomy via a single umbilical incision or st and ard 3-port access . The primary outcome variable was postoperative wound infection . Using a power of 0.9 and an alpha of 0.05 , 180 patients were calculated for each arm . Patients with perforated appendicitis were excluded . The technique of ligation/division of the appendix and mesoappendix was left to the surgeon 's discretion . There were 7 participating surgeons dictated by the call schedule . All patients received the same preoperative antibiotics and postoperative management was controlled . Results : There were 360 patients were enrolled between August 2009 and November 2010 . There were no differences in patient characteristics at presentation . There was no difference in wound infection rate , time to regular diet , length of hospitalization , or time to return to full activity . Operative time , doses of narcotics , surgical difficultly and hospital charges were greater with the single site approach . Also , the mean operative time was 5 minutes longer for the single site group . Conclusion : The single site umbilical laparoscopic approach to appendectomy produces longer operative times result ing in greater charges . However , these small differences are likely of marginal clinical relevance . The study was registered with clinical trials.gov at the inception of enrollment ( NCT00981136 ) [9298911] OBJECTIVE To compare the therapeutic efficacy of four antibiotic regimens : penicillin , tobramycin , and clindamycin ; penicillin , tobramycin , and ornidazole ; piperacillin alone ; and ceftriaxone and ornidazole in the treatment of children operated on for perforated appendicitis . DESIGN Prospect i ve r and omised study . SETTING Teaching hospital , Turkey . SUBJECTS 200 patients aged between 1 and 16 years treated from December 1991 to December 1995 who were r and omly assigned to one of four groups each consisting of 50 patients . INTERVENTIONS Preoperative antibiotics given intravenously , peritoneal drainage by Penrose drains without irrigation , appendicectomy with the inversion of the stump by a purse string , taking peritoneal swabs , and primary skin closure . MAIN OUTCOME MEASURES Comparability of the groups , duration of fever , leucocytosis , antibiotic treatment , stay in hospital , nasogastric intubation , and drainage , as well as results of cultures and complications . RESULTS There were no significant differences between the groups for any variable studied . The predominant bacterial species were Escherichia coli , Klebsiella spp , Pseudomonas spp , Fusobacteria , and Peptostreptococci which were appropriately covered by all the antibiotic regimens . Fourteen patients had complications including wound infections ( n = 10 ) , prolonged ileus ( n = 2 ) and intra-abdominal abscess ( n = 2 ) all of which were treated conservatively . There was no mortality and no major complications . All regimens had the same clinical and bacteriological efficacy . CONCLUSION There is no gold st and ard for antimicrobial chemotherapy in perforated appendicitis . Different antibiotic combinations or a single broad spectrum antibiotic , which include both aerobic and anaerobic coverage , can safely be used in children with perforated appendicitis [23239295] Background Single-incision laparoscopic surgery ( SILS ) is a novel area of minimally invasive surgery that uses a single incision to minimize all ports to one site . The end result is an incision that can be strategically placed in the umbilicus for a perceived scarless abdomen . The authors rationalized that a r and omized controlled trial was important given the rapid popularization of this approach . Methods An institutional review board-approved prospect i ve r and omized trial compared patients undergoing SILS ( SILS-A ) and conventional laparoscopic ( LAP-A ) appendectomy at a free-st and ing children ’s hospital during a median follow-up period of 2.2 years . Results A total of 50 patients ( 50 % boys and 67 % Hispanics ) were r and omized equally to SILS-A and LAP-A. The patients ranged in age from 3 to 15 years without a difference between the two groups . Half ( 50 % ) of these patients were younger than 8 years . The technique for SILS-A involved a single supraumbilical curvilinear skin incision with three fascial incisions . Ports were inserted to varying depths to minimize restriction of instrument movement . Coaxial visualization was improved by the use of a 30 ° scope . To achieve technical comparability with the LAP-A , a stapler device was used , which required upsizing a 5 mm port to a 12 mm port . The mean duration of the operation was 46.8 ± 3.7 min ( range , 22–120 min ) compared with 34.8 ± 2.5 min ( range , 18–77 min ) for st and ard LAP-A ( p = 0.010 ) . No conversions occurred , and the two groups did not differ in hospital length of stay . The postoperative complications consisted of one wound seroma in the SILS-A group ( nonsignificant difference ) , and no hernias were seen . No difference in readmissions , diet tolerance , fever , or postoperative pain was noted between the two groups . Conclusions The findings show the SILS approach to be feasible in the pediatric population despite the limited abdominal domain in younger children . Although SILS operating room times currently are longer than for LAP-A , they are comparable , and no other outcomes differed appreciably between the two techniques at the time of hospitalization or during the follow-up period [20105610] INTRODUCTION Perforated appendicitis is a common condition in children , which , in a small number of patients , may be complicated by a well-formed abscess . Initial nonoperative management with percutaneous drainage/aspiration of the abscess followed by intravenous antibiotics usually allows for an uneventful interval appendectomy . Although this strategy has become well accepted , there are no published data comparing initial nonoperative management ( drainage/interval appendectomy ) to appendectomy upon presentation with an abscess . Therefore , we conducted a r and omized trial comparing these 2 management strategies . METHODS After internal review board approval ( # 06 11 - 164 ) , children who presented with a well-defined abdominal abscess by computed tomographic imaging were r and omized on admission to laparoscopic appendectomy or intravenous antibiotics with percutaneous drainage of the abscess ( when possible ) , followed by interval laparoscopic appendectomy approximately 10 weeks later . This was a pilot study with a sample size of 40 , which was based on our recent volume of patients presenting with appendicitis and abscess . RESULTS On presentation , there were no differences between the 2 groups regarding age , weight , body mass index , sex distribution , temperature , leukocyte count , number of abscesses , or greatest 2-dimensional area of abscess in the axial view . Regarding outcomes , there were no differences in length of total hospitalization , recurrent abscess rates , or overall charges . There was a trend toward a longer operating time in patients undergoing initial appendectomy ( 61 minutes versus 42 minutes mean , P = .06 ) . CONCLUSIONS Although initial laparoscopic appendectomy trends toward a requiring longer operative time , there seems to be no advantages between these strategies in terms of total hospitalization , recurrent abscess rate , or total charges [1090718] From a controlled therapeutic trial extending for more than 2 yr and involving 69 patients with appendicitis and peritonitis a clear-cut statistically significant result emerged . There was a major reduction in the incidence of intraperitoneal abscesses using cephaloridine by the intraperitoneal as opposed to the systemic route . After r and omized selection into treatment and control groups , cephaloridine , 25 mg/kg was given by injection every 6 hr for 48 hr to the treatment group by i.p . installation and to the control group by systemic injection . Both groups received initial intraoperative peritoneal lavage with normal saline and also continued systemic injections of cephaloridine on postoperative days 3 , 4 , and 5 . Only one out of 36 patients in the treatment group developed a residual intraperitoneal abscess , as opposed to six abscesses developing in 33 patients in the control group . Technical problems and complications of the method were trivial and have not prevented us from continuing and extending the applications of the method [22294719] There is a growing recognition that insufficient attention has been paid to the selection of the outcomes to measure in clinical trials and clinical audit . Outcomes need to be relevant to patients , clinicians , purchasers and policy-makers if the findings of research are to influence practice and future research . In addition , st and ardization of outcomes is needed to combine data from different studies to allow evidence synthesis and to compare data sets . Inconsistent choice of outcome measures means that many meta-analyses are unable to include data from all the relevant studies . For example , the five most accessed Cochrane review s in 2009 , together with the top cited review in that year , all described inconsistencies in the outcomes reported in eligible trials . A call for the st and ardization of outcomes is a regular conclusion of systematic review s. Furthermore , outcome reporting bias , defined as the bias arising from selecting outcomes for publication based on the results , affects many r and omized trials and ‘ is an under-recognized problem that affects the conclusions in a substantial proportion of Cochrane review s ’ . That bias is likely to affect systematic review s more widely as well as affecting individual studies when considered on their own . Similar problems occur with clinical audit , highlighting the importance of establishing national audits that use and report the same outcomes for all participants . All these issues could be addressed with the development and application of agreed st and ardized sets of outcomes that have been termed ‘ core outcome sets ’ . These should be measured and reported , as a minimum , in all relevant clinical trials and national clinical audits for a specific condition . Adopting a core outcome set does not imply that a particular study , review or audit should be restricted to only those outcomes . Rather , the expectation is that , as a minimum , core outcomes will always be collected and reported to allow the results of trials to be compared , contrasted and combined as appropriate . The adoption of core outcomes would have implication s across all areas of research in health and health care , reduce heterogeneity between trials , and lead to research that is more likely to have measured relevant outcomes . Importantly , they would enhance the value of evidence synthesis by reducing the risk of outcome reporting bias and ensuring that all trials contribute usable information . In addition , they will increase the efficiency and value of research . An important rationale for core outcome sets is that outcomes currently reported for trials do not consistently reflect endpoints that are meaningful for patients . Examples exist where trials failed to include all outcomes important to patients and where involvement of patients has identified an outcome that might not have been considered by practitioners on their own . Despite increasing recognition of the importance of incorporating patients ’ opinions , their involvement has been limited . Recent regulatory guidance in the USA requires documented evidence of patient input during the development of instruments to measure patient reported outcomes ( PROs ) . However , measurement of PROs in clinical trials is hampered by the multiplicity and heterogeneity of tools currently available . Many generic , disease and domain-specific instruments have been developed and vali date d , each containing multiple scales and items . As a result , synthesis of PRO data from trials is difficult and review s aim ing to summarize treatment effect according to PROs may fail . There is synergy between the development of core outcome sets for trials and work to select up to seven outcomes that are important to patients for inclusion in Summary of Findings tables in systematic review s. Developed by the GRADE group ( http://www . grade workinggroup.org ) , Cochrane review s have featured such tables since 2008 , and they play a key role in presenting research in guidelines , such as those produced by the World Health Organization ( WHO ) . The development of core outcome sets needs to be accelerated and undertaken in ways that maximize efficiency . The COMET ( Core Outcome Measures in Effectiveness Trials , http://www.comet-initiative.org ) Initiative in the UK brings together research ers interested in the development and application of core outcome sets . These include key participants in a collaboration of research ers in rheumatology who have done the most notable work to date in this area . The COMET Initiative was launched in January 2010 , with a second meeting in July 2011 . Attendees included trialists , systematic review ers , patients , clinicians , journal editors , research funders , policy-makers , people responsible for trials registries and regulators . Data on individual studies , both published and ongoing , are being included in a free , publically available internet-based re source . This will be up date d periodically , to minimize the risk of duplication . Seventy-eight published or ongoing studies have already been entered into the repository . In addition , published review s of outcomes used in clinical trials or studies examining patients ’ views , will be entered [2024227] St and ard therapy for childhood ruptured appendicitis includes combination antibiotic therapy with ampicillin , gentamicin and clindamycin . Complicated dosing schedules and the possibility of aminoglycoside toxicity make alternatives desirable . One such alternative is Timentin ( a combination agent of ticarcillin disodium and clavulanate potassium ) . This agent has a more convenient dose schedule than st and ard therapy and eliminates the possibility of aminoglycoside ototoxicity and nephrotoxicity . It is active in vitro against most pathogens associated with ruptured appendicitis in children . The preliminary results of an ongoing prospect i ve , open label , r and omized trial comparing ticarcillin and clavulanate with ampicillin , gentamicin and clindamycin in childhood ruptured appendicitis are reported herein . While further evaluation is necessary , we have found single agent therapy with ticarcillin and clavulanate to be equivalent in safety and efficacy to st and ard combination therapy . Also discussed are the relative merits of immediate versus delayed primary closure of the abdominal wound after appendectomy [2691477] This multicentre trial compared the clinical efficacy of amoxycillin/clavulanate used as a single-agent therapy with that of the three-agent combination usually prescribed in the post-operative period for appendicular peritonitis in children . Only bacteriologically documented peritoneal infections were included . Sixty-four patients were r and omly distributed between two groups : Group A ( 29 cases ) treated with amoxycillin/clavulanate , first administered iv ( 100 mg/kg/day ) followed by conversion to the oral route ( 50 mg/kg/day ) once the patient had been afebrile for 48 h ; Group B ( 35 cases ) first treated by the iv route with benzylpenicillin ( 100,000 IU/kg/day ) plus netilmicin ( 5 mg/kg/day ) plus metronidazole ( 30 mg/kg/day ) followed by conversion to the oral route for metronidazole ( 30 mg/kg/day ) . In both groups , the total duration of parenteral and oral treatment was not less than five days . A total of 180 bacterial strains were recovered from peritoneal fluid sample s obtained during surgery ; 86 % of these were sensitive to amoxycillin/clavulanate . Clinical efficacy , assessed on the basis of time until return to normal temperature and gut transit and duration of hospitalization , was identical in both groups , with follow-up monitoring on day 30 showing recovery in all cases . Cure was obtained without any problems of infection in 25/29 patients in group A and in 34/35 patients in group B ( non-significant difference ) . Tolerance was excellent and identical in the two groups with the exception of three cases of thrombophlebitis which occurred in group B. The results of this study suggest that amoxycillin/clavulanate may be useful as single-agent therapy as a first-line curative treatment for appendicular peritonitis in children [2183940] One hundred children with peritonitis result ing from a perforated appendix were treated with ceftazidime or netilmicin . Metronidazole was added to both groups to treat the anaerobic organisms commonly associated with the infecting aerobic organisms in peritonitis . Escherichia coli was the most common aerobe found in peritoneal pus . Wound infection occurred in nine patients of the netilmicin group and in none treated with ceftazidime ( P less than 0.01 ) . No bacterial resistance was evident in the ceftazidime group , but gram-positive streptococci found in eight patients were resistant to netilmicin . Thus it is recommended that an antibiotic of the penicillin group be added if netilmicin is used to treat peritonitis . The results indicate that ceftazidime was more effective than netilmicin in the treatment of children with peritonitis result ing from a perforated appendix [1558500] In a 3-year period , 63 consecutive patients with advanced perforated ( n=53 ) and gangrenous ( n=10 ) appendicitis were allocated to undergo either immediate wound closure or delayed primary wound closure after emergency appendectomy . The incidence of wound infection between delayed primary wound closure and immediate wound closure was similar ( 24.0 % and 21.1 % , respectively ) . The duration for complete healing of infected wounds was slightly shorter in the group undergoing delayed primary wound closure ( mean + /- SD , 24.3 + /- 9.2 days ) than in the group undergoing immediate wound closure ( mean + /- SD , 32.6 + /- 16.5 days ) , but the difference was not significant . However , healing of noninfected wounds was significantly prolonged in the group undergoing delayed primary wound closure ( mean + /- SD , 19.3 + /- 10.1 days ) compared with the group undergoing immediate wound closure ( mean + /- SD , 7.0 + /- 0 days ) . The latter had been shown to associate with more nonseptic wound complications and therefore required longer rehabilitation . Our study showed that delayed primary closure did not offer additional advantage over immediate closure in the treatment of wounds associated with advanced appendicitis in children [22824858] Objective : To investigate clinical benefits of warm , humidified carbon dioxide ( CO2 ) insufflation for acute laparoscopic appendicectomy on postoperative pain and recovery in children ( age 8–14 years ) . Background : Conventional CO2 insufflation leads to desiccation-related peritoneal inflammation and injury , which is preventable with warm , humidified CO2 gas . We hypothesized that reduced peritoneal desiccation would improve patient-centered outcomes in children after laparoscopic appendicectomy . Method : A double-blinded , r and omized controlled trial was conducted . Intervention group participants received warm ( 37 ° C ) , humidified ( 98 % relative humidity ) CO2 gas insufflation , whereas control participants received st and ard room temperature ( 20 ° C ) gas with 0 % relative humidity . Perioperative analgesia and anesthesia were st and ardized . Postoperative opiate usage was converted to morphine equivalent daily dosages ( MEDD ) for comparison , and pain intensity at rest and on moving was rated by participants using visual analog scales . Postoperative recovery and return to normal activities was assessed using a question naire on day 10 . Results : Between February 2010 and March 2011 , a total of 190 participants were r and omized . Both intervention and control groups were matched at baseline . Postoperative MEDD and pain scores were also similar . There were no differences in postoperative recovery parameters . Conclusions : Warm , humidified CO2 insufflation for acute laparoscopic appendicectomy has no short-term clinical benefits on postoperative outcomes in pediatric patients ( Clinical Trials.gov trial identifying code : NCT01027455 ) Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Treadmill training , with or without body weight support using a harness , is used in rehabilitation and might help to improve walking after stroke . This is an up date of the Cochrane review first published in 2003 and up date d in 2005 and 2014 . OBJECTIVES To determine if treadmill training and body weight support , individually or in combination , improve walking ability , quality of life , activities of daily living , dependency or death , and institutionalisation or death , compared with other physiotherapy gait-training interventions after stroke . The secondary objective was to determine the safety and acceptability of this method of gait training . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

28688674

[25154822] PURPOSE Combining cisplatin or cetuximab with radiation improves overall survival ( OS ) of patients with stage III or IV head and neck carcinoma ( HNC ) . Cetuximab plus platinum regimens also increase OS in metastatic HNC . The Radiation Therapy Oncology Group launched a phase III trial to test the hypothesis that adding cetuximab to the radiation-cisplatin platform improves progression-free survival ( PFS ) . PATIENTS AND METHODS Eligible patients with stage III or IV HNC were r and omly assigned to receive radiation and cisplatin without ( arm A ) or with ( arm B ) cetuximab . Acute and late reactions were scored using Common Terminology Criteria for Adverse Events ( version 3 ) . Outcomes were correlated with patient and tumor features and markers . RESULTS Of 891 analyzed patients , 630 were alive at analysis ( median follow-up , 3.8 years ) . Cetuximab plus cisplatin-radiation , versus cisplatin-radiation alone , result ed in more frequent interruptions in radiation therapy ( 26.9 % v. 15.1 % , respectively ) ; similar cisplatin delivery ( mean , 185.7 mg/m2 v. 191.1 mg/m2 , respectively ) ; and more grade 3 to 4 radiation mucositis ( 43.2 % v. 33.3 % , respectively ) , rash , fatigue , anorexia , and hypokalemia , but not more late toxicity . No differences were found between arms A and B in 30-day mortality ( 1.8 % v. 2.0 % , respectively ; P = .81 ) , 3-year PFS ( 61.2 % v. 58.9 % , respectively ; P = .76 ) , 3-year OS ( 72.9 % v. 75.8 % , respectively ; P = .32 ) , locoregional failure ( 19.9 % v. 25.9 % , respectively ; P = .97 ) , or distant metastasis ( 13.0 % v. 9.7 % , respectively ; P = .08 ) . Patients with p16-positive oropharyngeal carcinoma ( OPC ) , compared with patients with p16-negative OPC , had better 3-year probability of PFS ( 72.8 % v. 49.2 % , respectively ; P < .001 ) and OS ( 85.6 % v. 60.1 % , respectively ; P < .001 ) , but tumor epidermal growth factor receptor ( EGFR ) expression did not distinguish outcome . CONCLUSION Adding cetuximab to radiation-cisplatin did not improve outcome and hence should not be prescribed routinely . PFS and OS were higher in patients with p16-positive OPC , but outcomes did not differ by EGFR expression [20572581] Aim and background Radiotherapy is the conventional treatment for locally advanced inoperable head and neck squamous cell carcinoma . However , the poor therapeutic results justify the development of radiochemotherapy combinations . In an attempt to improve local control and survival in patients with stage III and IV unresectable head and neck squamous cell carcinoma and based on the results of our previous dose escalation study , we undertook a prospect i ve multicentric r and omized trial . Material s and methods From November 1992 through December 1995 , a total of 164 patients were r and omized to receive radiotherapy alone ( arm I ) or combined ( arm II ) with daily low-dose carboplatin . Results The 3 , 5 and 10-year local-regional recurrence-free survival rates were better in arm II(21.7 % , 15.1 % and 15.1 % , respectively ) than in arm I ( 15 % , 10.7 % and 10.7 % ) , but without statistical significance ( P = 0.11 ) . The 3 , 5 and 10-year disease-free survival rates showed the same positive trend for arm II ( 16 % , 6.8 % and 6.8 % vs 9 % , 5.5 % and 5.5 % , in arm I , respectively ) , again without statistical significance ( P = 0.09 ) . Instead , a statistical advantage was found in overall survival rates at 3 , 5 and 10-years ( 28.9 % , 9 % and 5.5 % in arm II and 11.1 % , 6.9 % and 6.9 % in arm I , respectively ) ( P = 0.02 ) . The 3 , 5 and 10-year local-regional recurrence-free survival rates in stage IV disease were statistically better in arm II ( 21.5 % , 15.9 % and 15.9 % ) than in arm I ( 12.8 % , 7.7 % and 7.7 % , respectively ) ( P = 0.04 ) . Conclusions Long-term results in both treatment arms of the trial appear less positive than most published series . However , our findings do not exclude that carboplatin may be beneficial , but the benefit in local control must be lower than the 15 % assumed to dimension the trial [7918123] BACKGROUND Single-modality radiotherapy is still considered st and ard treatment for patients with locally advanced unresectable cancer of the head and neck . As treatment outcome is poor , attempts to integrate chemotherapy into the overall management of these patients are ongoing . PATIENTS AND METHODS A r and omized study was undertaken to compare a sequential with a simultaneous chemoradiotherapy program . Between February 1986 and February 1991 , 93 eligible patients with locally advanced unresectable cancer of the head and neck were stratified by WHO PS , T and N class and primary site and then r and omized to receive either three courses of neoadjuvant chemotherapy with cisplatin ( 100 mg/m2 i.v . d 1 ) and 5-fluorouracil 1000 mg/m2/days 1 - 5 by continuous i.v . infusion every 3 weeks prior to definitive conventional radiotherapy of 65 - 70 Gy ( sequential treatment ) , or cisplatin 100 mg/m2 on days 1 , 22 , 43 given simultaneously for the duration of the same conventional radiotherapy ( simultaneous treatment ) . RESULTS At the end of the entire treatment 18 complete responses ( 47 % ) in the sequential-treatment arm and 18 ( 41 % ) in the simultaneous treatment arm were obtained . No statistically significant differences in the 5-yr progression-free survival , in the median time to loco-regional and distant progression and in the 5-yr overall survival were observed . Leukopenia was more frequent in the simultaneous than in the sequential arm ( p = 0.03 ) , whereas alopecia ( p = 0.008 ) and phlebitis ( p < 0.0001 ) were more frequent in the sequential-treatment arm . A better compliance was associated with the concomitant treatment , with 87 % of the patients completing the entire radiotherapy program versus 63 % of those in the sequential arm ( p = 0.01 ) . CONCLUSIONS In the present study , the two treatment arms showed similar activity ( complete response , progression-free and overall survival rates ) . Compliance to treatment was better in the concomitant arm . These data suggest that concomitant chemo-radiation therapy might be considered an option in unresectable locally advanced cancer of the head and neck . Phase III studies are needed in order to establish the superiority of this combination of cisplatin and radiotherapy versus radiotherapy alone [23041591] BACKGROUND Cetuximab combined with radiotherapy ( RT ) is a treatment option for head and neck cancer . The objectives of this r and omized , phase II trial were to evaluate the efficacy and safety of cetuximab maintenance therapy following definitive RT with concomitant cetuximab in patients with oropharyngeal cancer . PATIENTS AND METHODS Ninety-one patients with stage III-IV M0 oropharyngeal tumors were r and omly assigned to the treatment with accelerated concomitant boost RT ( 69.9 Gy ) + cetuximab or the same treatment with the addition of 12 consecutive weeks of cetuximab maintenance therapy . The primary end point was locoregional control ( LRC ) at 1 year . RESULTS LRC at 1 year was superior among patients in the experimental arm , treated with cetuximab maintenance ( 59 % versus 47 % ) . However , LRC was similar between both arms after 2 years of follow-up , as a result of increased locoregional recurrences after the first year in the maintenance group . Patients treated with adjuvant cetuximab do recover very soon from toxic effect after combined treatment . CONCLUSIONS Twelve weeks of cetuximab maintenance therapy after concomitant cetuximab + RT in locally advanced oropharyngeal carcinoma is feasible and improves clinical outcomes measured at 1 year . This improvement is not maintained after the second year suggesting that epidermal growth factor receptor blockade is not sufficient to completely eliminate the minimal residual disease [6680215] This study was design ed to ascertain whether a prior reduction of tumor size by drugs could affect the final outcome of tumors treated with radiation . 142 patients with head and neck cancer ( oropharynx , maxillary antrum and intra-oral ) were r and omized for the study . In 72 cases , irradiation was preceded by a continuous intra-arterial infusion of 3 - 5 mg/day methotrexate to a total dose of 90 - 120 mg ; the other 70 patients were treated with radiotherapy alone . Chemotherapy , given prior to radiotherapy , caused a shift in the tumor stage ( i.e. a reduction in tumor size ) in more than one third of the cases . The overall 5-year survival was 43 % in the combined treatment group and 25 % in the group treated with radiation alone ( statistical difference : p less than .05 ) . However , when analysed separately the difference was statistically significant only in oral cavity tumors ( 5-year survival of 54 % in the combined modality group vs. 27 % in the control group ) , although local control rates after both single and combined modalities were not statistically different from those of oropharynx and maxillary antrum tumors . In these last lesions , however , the dissemination of disease was more frequent ; therefore , the lack of improvement of cure rate with the combined modality in these cases seems to be related to both the higher tendency of these tumors to disseminate and the low effectiveness of intra-arterial chemotherapy in controlling distant metastases . Mild and transient local and systemic toxicities were observed during chemotherapy infusion , but no radiosensitising effect on normal skin and mucosa was seen during radiotherapy in patients who had received pre-irradiation chemotherapy [15547184] In 1986 , we initiated a multicenter , r and omized trial to compare induction chemotherapy with cisplatin and 5-fluorouracil followed by locoregional treatment ( surgery and radiotherapy or radiotherapy alone ) with locoregional treatment alone in patients with head and neck squamous cell carcinoma . Here we report the long-term results of the trial . A total of 237 patients with nonmetastatic stage III or IV head and neck carcinoma were r and omly assigned to receive four cycles of neoadjuvant chemotherapy followed by locoregional treatment ( group A ) or locoregional treatment alone ( group B ) . Among all patients , overall survival at 5 and 10 years was 23 % ( 95 % confidence interval [ CI ] = 15.3 % to 30.9 % ) and 19 % ( 95 % CI = 11.6 % to 26.4 % ) , respectively , for those in group A and 16 % ( 95 % CI = 9.6 % to 23.4 % ) and 9 % ( 95 % CI = 3.5 % to 14.7 % ) , respectively , for those in group B ( P = .13 ) . Among operable patients , we observed no difference between group A and group B in overall survival at 5 and 10 years ( group A , 31 % [ 95 % CI = 14.9 % to 47.3 % ] and 22.7 % [ 95 % CI = 7.1 % to 38.3 % ] , respectively ; group B , 43.3 % [ 95 % CI = 25.6 % to 61.0 % ] and 14.2 % [ 95 % CI = 0.1 % to 28.3 % ] , respectively ; P = .73 ) . Among inoperable patients , overall survival at 5 and 10 years was 21 % ( 95 % CI = 12.3 % to 30.1 % ) and 16 % ( 95 % CI = 7.7 % to 23.9 % ) , respectively , for group A and 8 % ( 95 % CI = 1.5 % to 12.3 % ) and 6 % ( 95 % CI = 0.1 % to 9.1 % ) , respectively , for group B ( log-rank P = .04 ) . Four cycles of neoadjuvant chemotherapy is a promising approach for treating patients with inoperable advanced head and neck cancer but not for treating patients with operable disease [14657228] PURPOSE We report the 5-year survival and late toxicity results of a r and omized clinical trial , which showed a 3-year improvement in overall survival and locoregional control of stage III or IV oropharynx carcinoma , using concomitant radiochemotherapy ( arm B ) , compared with st and ard radiotherapy ( arm A ) . PATIENTS AND METHODS A total of 226 patients were entered onto a phase III multicenter r and omized trial comparing radiotherapy alone ( 70 Gy in 35 fractions ; arm A ) with concomitant radiochemotherapy ( 70 Gy in 35 fractions with three cycles of a 4-day regimen comprising carboplatin and fluorouracil ; arm B ) . Prognostic factors were evaluated by univariate and multivariate analysis . Five-year late toxicity was evaluated using National Cancer Institute Common Toxicity Criteria for neurological toxicity , hearing , taste , m and ibula , and teeth damage , and Radiation Therapy Oncology Group toxicity criteria for skin , salivary gl and , and mucosa . RESULTS Five-year overall survival , specific disease-free survival , and locoregional control rates were 22 % and 16 % ( log-rank P = .05 ) , 27 % and 15 % ( P = .01 ) , and 48 % and 25 % ( P = .002 ) , in arm B and arm A , respectively . Stage IV , hemoglobin level lower than 125 g/L , and st and ard treatment were independent prognostic factors of short survival and locoregional failure by univariate and multivariate analysis . One or more grade 3 to 4 complications occurred in 56 % of the patients in arm B , compared with 30 % in arm A ( P was not significant ) . CONCLUSION Concomitant radiochemotherapy improved overall survival and locoregional control rates and does not statistically increase severe late morbidity . Anemia was the most important prognostic factor for survival in both arms [16508679] OBJECTIVES This single-institution study evaluates the feasibility of accelerated fractionation radiotherapy ( AF ) with and without mitomycin C ( MMC ) in the treatment of locally advanced head and neck cancer . PATIENTS AND METHODS Between May 1998 and October 2001 , sixty patients with locally advanced stage III and IV of head and neck cancer were r and omized into three treatment arms : ( 1 ) conventional fractionation radiotherapy ( CF ) ( 5 fractions per week ) ; ( 2 ) accelerated fractionation radiotherapy ( AF ) ( 6 fractions per week ) ; and ( 3 ) AF plus Mitomycin C ( MMC ) . RESULTS The 2-year overall survival ( OS ) of the whole group was 21 % . The OS according to treatment arm was 23 % , 20 % , and 28 % in CF , AF , and AF+MMC arms respectively ( p<0.19 ) . The 2-year loco-regional control ( LC ) rate was 22 % for the whole group of patients . The LC was 10 % , 25 % , and 30 % for the CF , AF , and AF+MMC respectively ( p=0.27 ) . The only significant parameters for OS and LC were performance status and pre-treatment hemoglobin level . Mucositis grade s 3 & 4 occurred in 70 % and 90 % of the patients in the AF and AF+MMC arm respectively compared to 55 % of patients in the CF arm ( p=0.04 ) . However the addition of MMC did not significantly increase the incidence or severity of mucositis between AF and AF+MMC ( p=0.13 ) . Hematological toxicity grade s 3 & 4 were significantly higher after MMC ( occurred in 40 % of patients versus 10 % and 5 % in CF and AF arms respectively , p=0.04 ) . There was no statistically significant difference in the incidence of grade 3 dryness of mouth ( p=0.06 ) , fibrosis ( p=0.6 ) , or lymphoedema ( p=0.39 ) among the three arms . CONCLUSION There was a trend for improvement of LC and OS rates with the use of AF and the addition of MMC to AF compared to CF radiotherapy , although the difference was not statistically significant . The small number of the patients in each treatment arm and the inclusion of multiple tumor sites may contribute to these statistically insignificant results . Accordingly we advise 85 to continue the trial with inclusion of a larger number of patients and restrict tumor sites to one major site [17960012] BACKGROUND Phase 2 studies suggest that the st and ard regimen of cisplatin and fluorouracil ( PF ) plus docetaxel ( TPF ) improves outcomes in squamous-cell carcinoma of the head and neck . We compared TPF with PF as induction chemotherapy in patients with locoregionally advanced , unresectable disease . METHODS We r and omly assigned eligible patients between the ages of 18 and 70 years who had stage III or stage IV disease and no distant metastases to receive either TPF ( docetaxel and cisplatin , day 1 ; fluorouracil by continuous infusion , days 1 to 5 ) or PF every 3 weeks for four cycles . Patients without progression of disease received radiotherapy within 4 to 7 weeks after completing chemotherapy . The primary end point was progression-free survival . RESULTS A total of 358 patients underwent r and omization , with 177 assigned to the TPF group and 181 to the PF group . At a median follow-up of 32.5 months , the median progression-free survival was 11.0 months in the TPF group and 8.2 months in the PF group ( hazard ratio for disease progression or death in the TPF group , 0.72 ; P=0.007 ) . Treatment with TPF result ed in a reduction in the risk of death of 27 % ( P=0.02 ) , with a median overall survival of 18.8 months , as compared with 14.5 months in the PF group . There were more grade 3 or 4 events of leukopenia and neutropenia in the TPF group and more grade 3 or 4 events of thrombocytopenia , nausea , vomiting , stomatitis , and hearing loss in the PF group . The rates of death from toxic effects were 2.3 % in the TPF group and 5.5 % in the PF group . CONCLUSIONS As compared with the st and ard regimen of cisplatin and fluorouracil , induction chemotherapy with the addition of docetaxel significantly improved progression-free and overall survival in patients with unresectable squamous-cell carcinoma of the head and neck . ( Clinical Trials.gov number , NCT00003888 [ Clinical Trials.gov ] . ) [20448462] The prognosis of patients with advanced head and neck cancer remain dismal . For this tumor type , elevated levels of EGFR are associated with a shorter disease free survival and time to treatment failure , reflecting a more aggressive phenotype . Nimotuzumab is a humanized monoclonal antibody that recognizes domain III of the extracellular region of the EGFR , within an area that overlaps with both the surface patch recognized by cetuximab and the binding site for EGF . In order to assess the efficacy of nimotuzumab in combination with radiotherapy , a controlled , double blind , r and omized clinical trial was conducted in 106 advanced squamous cell carcinoma of the head and neck patients , mostly , unfit for chemo-radiotherapy . Control patients received a placebo and radiotherapy . Treatment was safe and the most frequent adverse events consisted on grade I or II asthenia , fever , headache and chills . No skin rash was detected . A significant complete response rate improvement was found in the group of patients treated with nimotuzumab as compared to the placebo . In the intent to treat analysis , a trend towards survival benefit for nimotuzumab treated subjects was found . The survival benefit became significant when applying the Harrington-Fleming test , a weighted log-rank that underscores the detection of differences deferred on time . In addition , a preliminary biomarker investigation showed a significant survival improvement for nimotuzumab treated patients as compared to controls for subjects with EGFR positive tumors . All patients showed a quality of life improvement and a reduction of the general and specific symptoms of the disease [15449338] Mixed treatment comparison ( MTC ) meta- analysis is a generalization of st and ard pairwise meta- analysis for A vs B trials , to data structures that include , for example , A vs B , B vs C , and A vs C trials . There are two roles for MTC : one is to strengthen inference concerning the relative efficacy of two treatments , by including both ' direct ' and ' indirect ' comparisons . The other is to facilitate simultaneous inference regarding all treatments , in order for example to select the best treatment . In this paper , we present a range of Bayesian hierarchical models using the Markov chain Monte Carlo software WinBUGS . These are multivariate r and om effects models that allow for variation in true treatment effects across trials . We consider models where the between-trials variance is homogeneous across treatment comparisons as well as heterogeneous variance models . We also compare models with fixed ( unconstrained ) baseline study effects with models with r and om baselines drawn from a common distribution . These models are applied to an illustrative data set and posterior parameter distributions are compared . We discuss model critique and model selection , illustrating the role of Bayesian deviance analysis , and node-based model criticism . The assumptions underlying the MTC models and their parameterization are also discussed [25782685] Purpose Concurrent chemoradiotherapy ( CRT ) is the st and ard treatment for advanced head and neck squamous cell carcinoma . In this phase II r and omized study , the efficacy and toxicity of docetaxel , cisplatin and 5-fluorouracil induction chemotherapy ( ICT ) followed by concurrent CRT was compared with those after st and ard CRT alone in patients with locally advanced , unresectable head and neck cancer . Patients and methods Between January 2007 and June 2009 , 66 patients with advanced ( stage III or IV ) unresectable squamous cell carcinoma of the head and neck ( oral cavity , oropharynx , hypopharynx , and larynx ) were r and omly assigned to two groups : one receiving two cycles of docetaxel , cisplatin , and 5-fluorouracil ICT followed by CRT with three cycles of cisplatin and one treated by CRT alone . Response rate , local tumor control ( LTC ) , locoregional tumor control ( LRTC ) , overall survival ( OS ) , progression-free survival ( PFS ) , and toxicity results were assessed . Results Three patients from the ICT + CRT group did not appear at the first treatment , so a total of 63 patients were evaluated in the study ( 30 ICT + CRT group and 33 CRT group ) . Three patients died of febrile neutropenia after ICT . The median follow-up time for surviving patients was 63 months ( range 53–82 months ) . The rate of radiologic complete response was 63 % following ICT + CRT , whereas 70 % after CRT alone . There were no significant differences in the 3-year rates of LTC ( 56 vs. 57 % ) , LRTC ( 42 vs. 50 % ) , OS ( 43 vs. 55 % ) , and PFS ( 41 vs. 50 % ) in the ICT + CRT group and in the CRT group , respectively . The rate of grade 3–4 neutropenia was significantly higher in the ICT + CRT group than in the CRT group ( 37 and 12 % ; p = 0.024 ) . Late toxicity ( grade 2 or 3 xerostomia ) developed in 59 and 42 % in the ICT + CRT and CRT groups , respectively . Conclusion The addition of ICT to CRT did not show any advantage in our phase II trial , while the incidence of adverse events increased . The three deaths as a consequence of ICT call attention to the importance of adequate patient selection if ICT is considered . ZusammenfassungHintergrundSimultane Chemoradiotherapie ( CRT ) ist eine St and ardtherapie beim fortgeschrittenen Plattenepithelkarzinom i m Kopf-Hals-Bereich . In dieser r and omisierten Phase-II-Studie wurden die Wirksamkeit und Toxizität einer Induktionschemotherapie ( ICT ) mit Docetaxel , Cisplatin und 5-Fluorouracil gefolgt von simultaner CRT mit der CRT allein bei Patienten mit lokal fortgeschrittenen , irresektablen Kopf-Hals-Tumoren verglichen . Patienten und Method enZwischen Januar 2007 und Juni 2009 wurden 66 Patienten mit fortgeschrittenem ( Stadium III oder IV ) , inoperablem Plattenepithelkarzinom i m Kopf-Hals-Bereich ( Mundhöhle , Oropharynx , Hypopharynx , Larynx ) nach dem Zufallsprinzip in 2 Gruppen eingeteilt . Die eine Gruppe erhielt 2 Zyklen der Docetaxel- , Cisplatin- und 5-Fluorouracil-ICT gefolgt von CRT mit 3 Zyklen Cisplatin , die and ere Gruppe erhielt nur CRT . Ansprechrate , lokale Tumorkontrolle ( LTC ) , lokoregionale Tumorkontrolle ( LRTC ) , Gesamtüberleben ( OS ) , progressionsfreies Überleben ( PFS ) und toxischer Effekt wurden verglichen . ErgebnisseDrei Patienten der Gruppe mit ICT + CRT erschienen bei der ersten Beh and lung nicht , so dass insgesamt 63 Patienten in der Studie ausgewertet wurden ( 30 in der Gruppe ICT + CRT , 33 in der CRT-Gruppe ) . Drei Patienten starben an febriler Neutropenie nach ICT . Die mediane Nachbeobachtungszeit der überlebenden Patienten betrug 63 Monate ( Spanne 53–82 Monate ) . Die Rate des radiologischen vollständigen Ansprechens war 63 % nach ICT + CRT vs. 70 % nach CRT allein . Es gab keinen signifikanten Unterschied in der 3-Jahres-Rate bei LTC ( 56 vs. 57 % ) , LRTC ( 42 vs. 50 % ) , OS ( 43 vs. 55 % ) und PFS ( 41 vs. 50 % ) zwischen der Gruppe mit ICT + CRT und den mit CRT beh and elten Patienten . Die Rate von Neutropenie mit einem Grad 3–4 lag in der Gruppe mit ICT + CRT deutlich höher als in der CRT-Gruppe ( 37 und 12 % ; p = 0,024 ) . Späte Toxizität ( Grad-2- und Grad-3-Xerostomie ) ereignete sich in der Gruppe mit ICT + CRT und in der CRT-Gruppe in jeweils 59 vs. 42 % .SchlussfolgerungDie Kombination von ICT und CRT erbrachte in unserer Phase-II-Studie keine Vorteile , wobei die Gesamtinzidenz der unerwünschten Ereignisse stieg . Die 3 Todesfälle infolge ICT weisen auf die Wichtigkeit der Patientenauswahl i m Falle einer ICT-Beh and lung hin [9165133] BACKGROUND AND PURPOSE In 1986 a prospect i ve , r and omized , multi-centre trial for evaluation of neoadjuvant chemotherapy with cisplatin and 5-fluorouracil in the treatment of advanced squamous cell carcinoma of the head and neck was initiated . As survival in this group of patients is poor the purpose was to find a possible survival benefit of the chemotherapy in addition to radiotherapy compared to radiotherapy only . METHODS Four-hundred sixty-one patients from Denmark , Norway and Sweden with tumors in oral cavity , oropharynx , hypopharynx and larynx were r and omized to receive either st and ard treatment ( radiotherapy or radiotherapy followed by surgery ) or neoadjuvant chemotherapy followed by st and ard treatment . Chemotherapy included three courses of cisplatin 100 mg/m2 i.v . infusion on day 1 followed by 5-fluorouracil 1000 mg/m2 per day continuous i.v . infusion for 120 hours . Radiotherapy 64 - 70 Gy in 2 Gy per fraction , 5 times/week , was given to patients in both treatment arms . RESULTS Response rate was 71 % for patients r and omized to chemotherapy-radiotherapy and 66 % for patients r and omized to st and ard treatment ( not statistically significant ) . Residual tumors were excised if possible . After surgery 62 % of the patients r and omized to chemotherapy-radiotherapy and 60 % of the patients in the st and ard treatment group were clinical ly tumor free . CONCLUSIONS No statistically significant benefit in survival was observed for patients treated with neoadjuvant chemotherapy followed by radiotherapy . Nor was there any impact of chemotherapy on the number of patients achieving loco-regional tumor control after primary treatment [1642879] Summary Treatment results of irradiation as a single treatment for advanced stage IV unresectable head and neck cancer remains uniformly poor and apparently has not changed with the most recent improvements in oncological care . Despite several negative results of r and omized studies , neoadjuvant or concomitant chemotherapy and radiotherapy seems to improve the number of complete responses and also the duration of disease-free survival . The present study was design ed to determine the feasibility , potential risks and benefits of the two methods of combined treatment and radiotherapy alone on the management of advanced unresectable squamous cell carcinoma of the upper respiratory and digestive system . From 1983 to 1986 , 90 patients entered the trial . Thirty patients were r and omized to each study group : radiotherapy alone ( 70 Gy ) ; neoadjuvant chemotherapy ( vinblastine , mitomycin , cisplatin , and bleomycin ) and radiotherapy ; concomitant chemotherapy ( cisplatin and bleomycin ) and radiotherapy . An increased frequency of complete responses ( 33 % ) was seen in patients treated with the two different combinations of chemotherapy and irradiation compared to irradiation alone ( 10 % ) . However , toxicity was more common in patients treated with the two modalities of combined treatment and there were no differences in overall survival rates ( P = 0.706 ) [20032123] BACKGROUND Concomitant chemoradiotherapy ( CT/RT ) is the st and ard treatment of locally advanced squamous cell carcinoma of the head and neck ( SCCHN ) . We evaluated the efficacy of induction docetaxel ( Taxotere ) , cisplatin , and 5-fluorouracil ( TPF ) before CT/RT versus CT/RT alone . PATIENTS AND METHODS Patients with stage III-IVM0 SCCHN , Eastern Cooperative Oncology Group performance status of zero to one , were r and omly assigned to receive CT/RT alone ( arm A : two cycles of cisplatin 20 mg/m(2 ) , days1 - 4 , plus 5-fluorouracil 800 mg/m(2)/day 96 h continuous infusion , during weeks 1 and 6 of radiotherapy ) or three cycles of TPF ( arm B : docetaxel 75 mg/m(2 ) and cisplatin 80 mg/m(2 ) , day 1 , and 5-fluorouracil 800 mg/m(2)/day 96 h continuous infusion , every 3 weeks ) followed by the same CT/RT . The primary end point was the rate of radiologic complete response ( CR ) at 6 - 8 weeks after the end of CT/RT . RESULTS A total of 101 patients were r and omly allocated to the study ( 51 arm A ; 50 arm B ) . CR rates were 21.2 % ( arm A ) versus 50 % ( arm B ) . Median progression-free survival and overall survival were , respectively , 19.7 and 33.3 months ( arm A ) and 30.4 and 39.6 months ( arm B ) . Hematologic and non-hematologic toxic effects during CT/RT were similar in the two arms . CONCLUSION Induction TPF followed by CT/RT was associated with higher radiologic CR in patients with locally advanced SCCHN with no negative impact on CT/RT feasibility [6162599] A clinical trial comparing Bleomycin ( BLM ) plus radiation against radiation alone is reported . One hundred and fifty-seven previously untreated T3 and T4 and N0 , N1 or N2 buccal squamous cell carcinomas were entered . Eighty-four of these received the combined therapy and 73 were controls . Cobalt-60 teletherapy using two opposing fields was employed . BLM was administered intra-arterially in 42 patients , intravenously in 22 patients and intramuscularly in 20 patients . The 73 controls received physiological saline as a placebo . Total clinical healing of the lesion within the volume of irradiation eight weeks after the end of radiotherapy was termed a favourable response . Anything else was a failure . Five-year recurrence-free rates and disease-free survival were also evaluated . The favourable response rate in the study group was 78.6 % and in the control 19.1 % . The corresponding recurrence-free rates and five-year survival rates were 71.8 % and 17 % , and 65.5 and 23.5 % respectively . The main toxic features were acute mucositis , pneumonitis and dermatitis [16683383] Aims and Background To compare conventional fractionation ( CF ) radiation therapy ( RT ) , arm A , versus a split-course accelerated hyperfractionated schedule ( S-AHF ) , arm B , versus CFRT plus concomitant chemotherapy ( CT ) , arm C , in terms of five-year survival and toxicity for squamous cell tumors of the oropharynx . Methods and Study Design Between January 1993 and June 1998 , 192 previously untreated patients with stage III and IV oropharyngeal carcinoma ( excluding T1N1 and T2N1 ) were enrolled in a multicenter r and omized phase III trial ( ORO 93 - 01 ) . In arms A and C , 66 to 70 Gy in 33 to 35 fractions was administered five days a week for six and a half to seven weeks . In arm B , the dose delivered was 64 to 67.2 Gy in two fractions of 1.6 Gy every day , five days a week , with a planned two-week split at 38.4 Gy . In arm C the CT regimen consisted of three cycles of carboplatin and 5-fluorouracil ( CBDCA 75 mg/m2 on days 1 to 4 and 5-FU 1000 mg/m2 i.v . on days 1 to 4 every 28 days ) . Results No statistically significant difference was found in five-year overall survival ( P = 0.39 ) : 21 % for arm A , 21 % for arm B , and 40 % for arm C. Similarly , there was no statistically significant difference in terms of five-year relapse-free survival : 15 % for arm A , 17 % for arm B , and 36 % for arm C. There was a slight trend towards better five-year locoregional control ( P = 0.07 ) for the combined arm : patients without locoregional relapse were 48 % in arm C , 21 % in arm A and 18 % in arm B. Locoregional control was significantly better when arm C was compared with arms A and B combined ( P = 0.02 ; arm A+B 20 % ; arm C 48 % ) . Distant metastases were fairly balanced in the three arms ( A : 14 ; B : 9 ; C : 11 ) , with a tendency towards more frequent isolated distant metastasis development in arm C ( 8 of 11 [ 72 % ] versus 7 of 23 [ 30 % ] in arms A+B ) . Five-year second-tumor-free survival was 85 % . The 13 second tumors were equally distributed and were mainly correlated with tobacco and alcohol consumption ( five lung , two esophagus , two oral cavity , one larynx , one pancreas , one hepatocarcinoma , one myeloma ) . Arm C showed slightly more G3 + late side effects involving subcutaneous tissues and mucosa , although significant late sequelae were relatively uncommon and the mucosal side effects were mostly transient . The occurrence of persistent G3 xerostomia was comparable in the three treatment arms . Conclusions The results obtained with the combination of CT and RT compared with RT alone did not reach statistical significance , but combined treatment almost doubled the five-year overall survival , relapse-free survival and locoregional control rate . Patients with advanced squamous cell carcinomas of the oropharynx who are medically suitable for the combined approach should be treated with a combination of radiotherapy and chemotherapy . The occurrence of second tumors is relatively common in these patients and may contribute substantially to the causes of death [2465852] Between 1978 and 1981 , 85 patients with advanced squamous cell carcinoma of the head and neck were r and omized to receive induction VBM followed by radiotherapy , or radiotherapy alone . The shortest follow-up is thus 6 years . The median survival of patients receiving induction chemotherapy was 46 weeks , that of the radiotherapy group alone was 75 weeks . As the two groups were not balanced despite r and omization , multivariate methods ( GLIM ) were used to identify significant prognostic factors . These were : response to radiotherapy ( P less than 0.001 ) , nodal status ( P less than 0.001 ) , age ( P less than 0.01 ) , and histological grade ( P less than 0.01 ) . Neither treatment with , nor response to , chemotherapy had a significant effect on survival [26644536] PURPOSE No r and omized trials have been conducted to directly compare radiotherapy ( RT ) with concomitant cisplatin ( CDDP ) versus concomitant cetuximab ( CTX ) as first-line treatment of locally advanced squamous cell carcinoma of the head and neck . In this r and omized trial , we compared these two treatment regimens in terms of compliance , toxicity , and efficacy . PATIENTS AND METHODS Eligible patients were r and omly assigned in a 1:1 ratio to receive either CDDP 40 mg/m(2 ) once per week or CTX 400 mg/m(2 ) as loading dose followed by CTX 250 mg/m(2 ) once per week concomitant to radical RT . For primary end points , compliance to treatment was defined as number of days of treatment discontinuation and drug dosage reduction . The acute toxicity rate was defined according to the National Cancer Institute Common Toxicity Criteria . Efficacy end points were local recurrence-free survival , metastasis-free survival , cancer-specific survival , and overall survival . RESULTS The study was discontinued early because of slow accrual after the enrollment of 70 patients . RT discontinuation for more than 10 days occurred in 13 % of patients given CTX and 0 % given CDDP ( P = .05 ) . Drug dosage reduction occurred in 34 % given CTX and 53 % given CDDP ( difference not significant ) . Toxicity profiles differed between the two arms , with hematologic , renal , and GI toxicities more frequent in the CDDP arm , and cutaneous toxicity and the need for nutritional support more frequent in the CTX arm . Serious adverse events related to treatment , including four versus one toxic deaths , were higher in the CTX arm ( 19 % v 3 % , P = .044 ) . Locoregional control , patterns of failure , and survivals were similar between the treatment arms . CONCLUSION CTX concomitant to RT lowered compliance and increased acute toxicity rates . Efficacy outcomes were similar in both arms . These results raise the issue of appropriately selecting patients with head and neck cancer who can benefit from CTX in combination with RT [9719123] PURPOSE To compare the efficacy of concomitant irradiation with mitomycin C and bleomycin in patients with inoperable head and neck carcinoma with radiotherapy alone . METHODS AND MATERIAL S Between March 1991 and December 1993 , 64 patients with inoperable head and neck carcinoma ( 41 with oropharyngeal site ) were r and omized to radiotherapy alone ( group A ) or radiotherapy combined with simultaneous application of mitomycin C and bleomycin ( group B ) . In both groups patients were irradiated five times weekly with 2 Gy to a total dose of 66 - 70 Gy . The planned concomitant treatment in group B was : bleomycin 5 units twice a week i.m . , total dose 70 units , mitomycin C 15 mg/m2 i.v . after delivery of 10 Gy , and 10 mg/m2 i.v . on the last day of radiotherapy . To enhance the effect of these two drugs , patients received also nicotinamide , chlorpromazine , and dicoumarol . Because significantly better results were achieved in arm B for patients with inoperable oropharyngeal carcinoma , the study was closed and such patients were after December 1993 routinely treated with the combined therapy ( as in arm B ) . Until October 1996 , we treated and followed up 48 such consecutive patients . RESULTS Median follow-up of our study patients is 42 months . Complete remission ( CR ) rate in group A was 31 % and in group B 59 % ( p = 0.04 ) ; disease-free survival ( DFS ) in group A was 8 % and in group B 37 % ( P = 0.01 ) ; and overall survival ( OS ) was 7 % in group A and 26 % in group B ( p = 0.08 ) . CR rate for patients with oropharyngeal carcinoma was 29 % in group A ( N = 21 ) and 75 % in group B ( N = 20 ) ( p = 0.007 ) ; DFS in group A was 10 % and in group B 48 % ( p = 0.001 ) ; and the OS was 10 % in group A and 38 % in group B ( p = 0.019 ) . In patients with inoperable oropharyngeal carcinoma treated after December 1993 , complete remission was achieved in 32/48 ( 67 % , 95 % CI : 52%-80 % ) . DFS at the median follow-up of 14 months was 60 % ( 95 % CI 43 - 77 % ) and OS 58 % ( 95 % CI 42 - 74 % ) . CONCLUSION From the results of our study it seems that the concomitant treatment significantly improves CR rate , DFS , and OS in patients with inoperable oropharyngeal carcinoma in comparison with radiotherapy alone [8938220] The purpose of the present study was to determine the safety and efficacy of induction chemotherapy followed by concomitant chemoradiotherapy . Thirty-eight patients were r and omised to receive induction chemotherapy , consisting of cyclophosphamide and methotrexate followed by concomitant 5-fluorouracil and irradiation ( study group ) or irradiation alone ( control group ) . There were non-significant differences in the initial tumor clearance rates in the two groups . Median disease-free survival ( in complete responders ) was 17 months ( 6 - 60 + ) vs 11 months ( 5 - 60 + ) ( p = 0.407 ) and overall survival 11 months ( 1 - 60 + ) vs 14 months ( 2 - 60 + ) ( p = 0.428 ) in the study and control groups respectively . Acute morbidity and deaths during intervention were higher in the study group ( p = 0.007 ) . This study suggests that induction along with concomitant chemoradiotherapy is too toxic for routine use and also fails to provide a survival benefit [16275937] PURPOSE To compare the antitumor activity and toxicity of the two induction chemotherapy treatments of paclitaxel , cisplatin , and fluorouracil ( FU ; PCF ) versus st and ard cisplatin and FU ( CF ) , both followed by chemoradiotherapy ( CRT ) , in locally advanced head and neck cancer ( HNC ) . PATIENTS AND METHODS Eligibility criteria included biopsy-proven , previously untreated , stage III or IV locally advanced HNC . Patients received either CF ( cisplatin 100 mg/m2 on day 1 plus FU 1000 [ corrected ] mg/m2 continuous infusion on days 1 through 5 ) or PCF ( paclitaxel 175 mg/m2 on day 1 , cisplatin 100 mg/m2 on day 2 , and FU 500 mg/m2 continuous infusion on days 2 through 6 ) ; both regimens were administered for three cycles every 21 days . Patients with complete response ( CR ) or partial response of greater than 80 % in primary tumor received additional CRT ( cisplatin 100 mg/m2 on days 1 , 22 , and 43 plus 70 Gy ) . RESULTS A total of 382 eligible patients were r and omly assigned to CF ( n = 193 ) or PCF ( n = 189 ) . The CR rate was 14 % in the CF arm v 33 % in the PCF arm ( P < .001 ) . Median time to treatment failure was 12 months in the CF arm compared with 20 months in the PCF arm ( log-rank test , P = .006 ; Tarone-Ware , P = .003 ) . PCF patients had a trend to longer overall survival ( OS ; 37 months in CF arm v 43 months in PCF arm ; log-rank test , P = .06 ; Tarone-Ware , P = .03 ) . This difference was more evident in patients with unresectable disease ( OS : 26 months in CF arm v 36 months in PCF arm ; log-rank test , P = .04 ; Tarone-Ware , P = .03 ) . CF patients had a higher occurrence of grade 2 to 4 mucositis than PCF patients ( 53 % v 16 % , respectively ; P < .001 ) . CONCLUSION Induction chemotherapy with PCF was better tolerated and result ed in a higher CR rate than CF . However , new trials that compare induction chemotherapy plus CRT versus CRT alone are needed to better define the role of neoadjuvant treatment [25049329] PURPOSE Induction chemotherapy ( IC ) before radiotherapy lowers distant failure ( DF ) rates in locally advanced squamous cell carcinoma of the head and neck ( SCCHN ) . The goal of this phase III trial was to determine whether IC before chemoradiotherapy ( CRT ) further improves survival compared with CRT alone in patients with N2 or N3 disease . PATIENTS AND METHODS Treatment-naive patients with nonmetastatic N2 or N3 SCCHN were r and omly assigned to CRT alone ( CRT arm ; docetaxel , fluorouracil , and hydroxyurea plus radiotherapy 0.15 Gy twice per day every other week ) versus two 21-day cycles of IC ( docetaxel 75 mg/m(2 ) on day 1 , cisplatin 75 mg/m(2 ) on day 1 , and fluorouracil 750 mg/m(2 ) on days 1 to 5 ) followed by the same CRT regimen ( IC + CRT arm ) . The primary end point was overall survival ( OS ) . Secondary end points included DF-free survival , failure pattern , and recurrence-free survival ( RFS ) . RESULTS A total of 285 patients were r and omly assigned . The most common grade 3 to 4 toxicities during IC were febrile neutropenia ( 11 % ) and mucositis ( 9 % ) ; during CRT ( both arms combined ) , they were mucositis ( 49 % ) , dermatitis ( 21 % ) , and leukopenia ( 18 % ) . Serious adverse events were more common in the IC arm ( 47 % v 28 % ; P = .002 ) . With a minimum follow-up of 30 months , there were no statistically significant differences in OS ( hazard ratio , 0.91 ; 95 % CI , 0.59 to 1.41 ) , RFS , or DF-free survival . CONCLUSION IC did not translate into improved OS compared with CRT alone . However , the study was underpowered because it did not meet the planned accrual target , and OS was higher than predicted in both arms . IC can not be recommended routinely in patients with N2 or N3 locally advanced SCCHN [24256848] BACKGROUND Concurrent chemoradiotherapy ( CCRT ) is the st and ard treatment for patients with unresectable , nonmetastatic locoregionally advanced squamous-cell carcinoma of the head and neck ( LASCCHN ) . This r and omized , open-label , phase III clinical trial compared the efficacy between st and ard CCRT and two different induction chemotherapy ( ICT ) regimens followed by CCRT . PATIENTS AND METHODS Patients with untreated LASCCHN were r and omly assigned to ICT ( three cycles ) , with either docetaxel ( Taxotere ) , cisplatin and 5-fluorouracil ( TPF arm ) or cisplatin and 5-fluorouracil ( PF arm ) , followed by CCRT [ 7 weeks of radiotherapy ( RT ) with cisplatin 100 mg/m(2 ) on days 1 , 22 and 43 ] ; or 7 weeks of CCRT alone . The primary end points were progression-free survival ( PFS ) and time-to-treatment failure ( TTF ) . RESULTS In the intention-to-treat ( ITT ) population ( n = 439 ) , the median PFS times were 14.6 ( 95 % CI , 11.6 - 20.4 ) , 14.3 ( 95 % CI , 11.8 - 19.3 ) and 13.8 months ( 95 % CI , 11.0 - 17.5 ) at TPF-CCRT , PF-CCRT and CCRT arms , respectively ( log-rank P = 0.56 ) . The median TTF were 7.9 ( 95 % CI , 5.9 - 11.8 ) , 7.9 ( 95 % CI , 6.5 - 11.8 ) and 8.2 months ( 95 % CI , 6.7 - 12.6 ) for TPF-CCRT , PF-CCRT and CCRT alone , respectively ( log-rank P = 0.90 ) . There were no statistically significant differences for overall survival ( OS ) . Toxic effects from ICT-CCRT were manageable . CONCLUSION Overall , this trial failed to show any advantage of ICT-CCRT over CCRT alone in patients with unresectable LASCCHN [25596659] BACKGROUND We aim ed to compare panitumumab , a fully human monoclonal antibody against EGFR , plus radiotherapy with chemoradiotherapy in patients with unresected , locally advanced squamous-cell carcinoma of the head and neck . METHODS In this international , open-label , r and omised , controlled , phase 2 trial , we recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 22 sites in eight countries worldwide . Patients aged 18 years and older with stage III , IVa , or IVb , previously untreated , measurable ( ≥ 10 mm for at least one dimension ) , locally advanced squamous-cell carcinoma of the head and neck ( non-nasopharygeal ) and an Eastern Cooperative Oncology Group performance status of 0 - 1 were r and omly assigned ( 2:3 ) by an independent vendor to open-label chemoradiotherapy ( two cycles of cisplatin 100 mg/m(2 ) during radiotherapy ) or to radiotherapy plus panitumumab ( three cycles of panitumumab 9 mg/kg every 3 weeks administered with radiotherapy ) using a stratified r and omisation with a block size of five . All patients received 70 - 72 Gy to gross tumour and 54 Gy to areas of sub clinical disease with accelerated fractionation radiotherapy . The primary endpoint was local-regional control at 2 years , analysed in all r and omly assigned patients who received at least one dose of their assigned protocol -specific treatment ( chemotherapy , radiation , or panitumumab ) . The trial is closed and this is the final analysis . This study is registered with Clinical Trials.gov , number NCT00547157 . FINDINGS Between Nov 30 , 2007 , and Nov 16 , 2009 , 152 patients were enrolled , and 151 received treatment ( 61 in the chemoradiotherapy group and 90 in the radiotherapy plus panitumumab group ) . Local-regional control at 2 years was 61 % ( 95 % CI 47 - 72 ) in the chemoradiotherapy group and 51 % ( 40 - 62 ) in the radiotherapy plus panitumumab group . The most frequent grade 3 - 4 adverse events were mucosal inflammation ( 25 [ 40 % ] of 62 patients in the chemoradiotherapy group vs 37 [ 42 % ] of 89 patients in the radiotherapy plus panitumumab group ) , dysphagia ( 20 [ 32 % ] vs 36 [ 40 % ] ) , and radiation skin injury ( seven [ 11 % ] vs 21 [ 24 % ] ) . Serious adverse events were reported in 25 ( 40 % ) of 62 patients in the chemoradiotherapy group and in 30 ( 34 % ) of 89 patients in the radiotherapy plus panitumumab group . INTERPRETATION Panitumumab can not replace cisplatin in the combined treatment with radiotherapy for unresected stage III-IVb squamous-cell carcinoma of the head and neck , and the role of EGFR inhibition in locally advanced squamous-cell carcinoma of the head and neck needs to be reassessed . FUNDING Amgen [2451135] This trial of treatment for head and neck carcinoma was initiated in 1973 by the European Organization for Research and Treatment of Cancer . Its purpose was to investigate the value of single-agent chemotherapy with bleomycin ( BLM ) given during the course of a conventional treatment by external radiotherapy ( RT ) compared to treatment by external RT alone . In this r and omized study , we compared treatment results in 2 groups of patients with squamous cell carcinoma of the oropharynx ( T2 , T3 , and T4 ; International Union Against Cancer classification ) . One group of 92 patients was treated by RT at the prescribed dose of 70 Gy . The other group of 107 patients received radiation according to the same protocol and simultaneously received i m injection of BLM at a dose of 15 mg twice a week , 2 hours prior to the session of RT , for a total dose of 150 mg in 5 weeks . The occurrence of local toxic effects ( i.e. , mucositis and epidermatitis ) was significantly greater in the RT-BLM group ( RT-BLM , 72 % , vs. RT , 21 % ) . Primary tumor response 6 weeks after completion of RT was the same in both arms of the study ( RT , 68 % , vs. RT-BLM , 67 % ) . The 6-year survival rate was 24 % ( RT-BLM ) versus 22 % ( RT ) . Long-term analysis ( 10 yr ) is given [12506176] PURPOSE The Head and Neck Intergroup conducted a phase III r and omized trial to test the benefit of adding chemotherapy to radiation in patients with unresectable squamous cell head and neck cancer . PATIENTS AND METHODS Eligible patients were r and omly assigned between arm A ( the control ) , single daily fractionated radiation ( 70 Gy at 2 Gy/d ) ; arm B , identical radiation therapy with concurrent bolus cisplatin , given on days 1 , 22 , and 43 ; and arm C , a split course of single daily fractionated radiation and three cycles of concurrent infusional fluorouracil and bolus cisplatin chemotherapy , 30 Gy given with the first cycle and 30 to 40 Gy given with the third cycle . Surgical resection was encouraged if possible after the second chemotherapy cycle on arm C and , if necessary , as salvage therapy on all three treatment arms . Survival data were compared between each experimental arm and the control arm using a one-sided log-rank test . RESULTS Between 1992 and 1999 , 295 patients were entered on this trial . This did not meet the accrual goal of 362 patients and result ed in premature study closure . Grade 3 or worse toxicity occurred in 52 % of patients enrolled in arm A , compared with 89 % enrolled in arm B ( P < .0001 ) and 77 % enrolled in arm C ( P < .001 ) . With a median follow-up of 41 months , the 3-year projected overall survival for patients enrolled in arm A is 23 % , compared with 37 % for arm B ( P = .014 ) and 27 % for arm C ( P = not significant ) . CONCLUSION The addition of concurrent high-dose , single-agent cisplatin to conventional single daily fractionated radiation significantly improves survival , although it also increases toxicity . The loss of efficacy result ing from split-course radiation was not offset by either multiagent chemotherapy or the possibility of midcourse surgery [25596660] BACKGROUND Panitumumab is a fully human monoclonal antibody that targets EGFR . We aim ed to compare chemoradiotherapy plus panitumumab with chemoradiotherapy alone in patients with unresected , locally advanced squamous-cell carcinoma of the head and neck . METHODS In this international , open-label , r and omised , controlled , phase 2 trial , we recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 41 sites in nine countries worldwide . Patients aged 18 years and older with stage III , IVa , or IVb , previously untreated , measurable ( ≥ 10 mm for at least one dimension ) , locally advanced squamous-cell carcinoma of the head and neck ( non-nasopharygeal ) and an Eastern Cooperative Oncology Group performance status of 0 - 1 were r and omly assigned ( 2:3 ) by an independent vendor to open-label chemoradiotherapy ( three cycles of cisplatin 100 mg/m(2 ) ) or panitumumab plus chemoradiotherapy ( three cycles of intravenous panitumumab 9.0 mg/kg every 3 weeks plus cisplatin 75 mg/m(2 ) ) using stratified r and omisation with a block size of five . All patients received 70 Gy to gross tumour and 50 Gy to areas at risk for sub clinical disease with st and ard fractionation . The primary endpoint was local-regional control at 2 years , analysed in all r and omised patients who received at least one dose of their assigned protocol -specific treatment ( chemotherapy , radiation , or panitumumab ) . The trial is closed and this is the final analysis . This trial is registered with Clinical Trials.gov , number NCT00500760 . FINDINGS Between Oct 26 , 2007 , and March 26 , 2009 , 153 patients were enrolled and 150 received treatment ( 63 in the chemoradiotherapy group and 87 in the panitumumab plus chemoradiotherapy group ) . Local-regional control at 2 years was 68 % ( 95 % CI 54 - 78 ) in the chemoradiotherapy group and 61 % ( 50 - 71 ) in the panitumumab plus chemoradiotherapy group . The most frequent grade 3 - 4 adverse events were dysphagia ( 17 [ 27 % ] of 63 patients in the chemoradiotherapy group vs 35 [ 40 % ] of 87 in the panitumumab plus chemoradiotherapy group ) , mucosal inflammation ( 15 [ 24 % ] vs 48 [ 55 % ] ) , and radiation skin injury ( eight [ 13 % ] vs 27 [ 31 % ] ) . Serious adverse events were reported in 20 ( 32 % ) of 63 patients in the chemoradiotherapy group and in 37 ( 43 % ) of 87 patients in the panitumumab plus chemoradiotherapy group . INTERPRETATION In patients with locally advanced squamous-cell carcinoma of the head and neck , the addition of panitumumab to st and ard fractionation radiotherapy and cisplatin did not confer any benefit , and the role of EGFR inhibition in these patients needs to be reassessed . FUNDING Amgen [18669465] PURPOSE To investigate the impact of treatment-related toxicity on health-related quality of life ( HRQoL ) among patients with head and neck squamous cell carcinoma treated with radiotherapy either alone or in combination with chemotherapy or surgery . PATIENTS AND METHODS The study sample was composed of 425 disease-free patients . Toxicity was scored according to the European Organisation for Research and Treatment of Cancer (EORTC)/Radiation Therapy Oncology Group ( RTOG ) late radiation-induced morbidity scoring system . HRQoL was assessed using the EORTC Quality of Life Question naire C30 . These assessment s took place at 6 , 12 , 18 , and 24 months after completion of radiotherapy . The analysis was performed using a multivariate analysis of variance . RESULTS Of the six RTOG scales investigated , two significantly affected self-reported HRQoL , salivary gl and ( RTOG(xerostomia ) ) and esophagus/pharynx ( RTOG(swallowing ) ) . Although RTOG(xerostomia ) was reported most frequently , HRQoL was most affected by RTOG(swallowing ) , particularly in the first 18 months after completion of radiotherapy . CONCLUSION Late radiation-induced toxicity , particularly RTOG(swallowing ) and RTOG(xerostomia ) , has a significant impact on the more general dimensions of HRQoL. These findings suggest that the development of new radiation-induced delivery techniques should not only focus on reduction of the dose to the salivary gl and s , but also on anatomic structures that are involved in swallowing [20888709] PURPOSE The Head and Neck Intergroup conducted a Phase III r and omized trial to determine whether the addition weekly cisplatin to daily radiation therapy ( RT ) would improve survival in patients with unresectable squamous cell head- and -neck carcinoma . METHODS AND MATERIAL S Eligible patients were r and omized to RT ( 70 Gy at 1.8 - 2 Gy/day ) or to the identical RT with weekly cisplatin dosed at 20 mg/m(2 ) . Failure-free survival ( FFS ) and overall survival ( OS ) curves were estimated with the Kaplan-Meier method and compared with the log rank test . RESULTS Between 1982 and 1987 , 371 patients were accrued , and 308 patients were found eligible for analysis . Median follow-up was 62 months . The median FFS was 6.5 and 7.2 months for the RT and RT + cisplatin groups , respectively ( p = 0.30 ) . The p value for the treatment difference was p = 0.096 in multivariate modeling of FFS ( compared to a p = 0.30 in univariate analysis ) . Expected acute toxicities were significantly increased with the addition of cisplatin except for in-field RT toxicities . Late toxicities were not significantly different except for significantly more esophageal ( 9 % vs. 3 % , p = 0.03 ) and laryngeal ( 11 % vs. 4 % , p = 0.05 ) late toxicities in the RT + cisplatin group . CONCLUSION The addition of concurrent weekly cisplatin at 20 mg/m(2 ) to daily radiation did not improve survival , although there was evidence of activity . Low-dose weekly cisplatin seems to have modest tumor radiosensitization but can increase the risk of late swallowing complications [15534360] PURPOSE To determine whether the application of two courses of cisplatin simultaneously with hyperfractionated radiotherapy improves the outcome in locally advanced and /or node-positive nonmetastatic carcinomas of the head and neck , compared with hyperfractionated radiotherapy alone . PATIENTS AND METHODS From July 1994 to July 2000 , 224 patients with squamous cell carcinomas of the head and neck ( excluding nasopharynx and paranasal sinus ) were r and omly assigned to hyperfractionated radiotherapy ( median dose , 74.4 Gy ; 1.2 Gy twice daily ) or the same radiotherapy combined with two cycles of concomitant cisplatin ( 20 mg/m2 on 5 days of weeks 1 and 5 ) . The primary end point was time to any treatment failure ; secondary end points were locoregional failure , metastatic relapse , overall survival , and late toxicity . RESULTS There was no difference in radiotherapy between both treatment arms ( 74.4 Gy in 44 days ) . The full cisplatin dose was applied in 93 % and 71 % of patients during the first and second treatment cycles , respectively . Acute toxicity was similar in both arms . Median time to any treatment failure was not significantly different between treatment arms ( 19 months for combined treatment and 16 months for radiotherapy only , respectively ) and the failure-free rate at 2.5 years was 45 % and 33 % , respectively . Locoregional control and distant disease-free survival were significantly improved with cisplatin ( log-rank test , P = .039 and .011 , respectively ) . The difference in overall survival did not reach significance ( log-rank test , P = .147 ) . Late toxicity was comparable in both treatment groups . CONCLUSION The therapeutic index of hyperfractionated radiotherapy is improved by concomitant cisplatin [175693] In 1961 , a r and omized study was begun at the University of Wisconsin Medical Center in which the treatment of advanced squamous cell carcinoma of the head and neck with radiation therapy was compared with combined treatment with radiation therapy and 5-Fluorouracil . One hundred and thirty-six patients with primary lesions in the oral cavity , the base of the tongue , and the oropharynx were analyzed . Both local control and survival were better in the combined treatment group than in the group with radiation therapy alone . However , in only the oral cavity patient population was the difference statistically significant . Both acute and late complications were also increased in this group of patients who received combined treatment [7013971] Between 1975 and 1978 , 23 patients with Stage IV , unresectable , squamous cell carcinoma of the head and neck were r and omized to receive radiotherapy ( RT , 11 patients ) , or radiotherapy‐chemotherapy ( RT & CT , 12 patients ) . The response rate for the 12 RT & CT patients was four complete remissions ( CR ) and four partial remissions ( PR ) ; the 11 RT patients had one CR and three PR . The presence of a responses ( CR or PR ) significantly enhanced the median survival ( 14 vs. 5 months ; P = 0.005 ) . The duration of objectives remission was longer among the RT & CT patients when compared with RT patients ( 6 vs. 2.3 months , P = 0.18 ) . The median survival of the RT & CT group was 12 months compared with 5.6 months for the RT group ( P = 0.13 ) . One RT & CT patient remains alive with disease at 44 months , one RT patient remains alive without disease at 30 months . The present chemotherapy regimen did not modify the pattern of failure and only marginally increased patient survival . It did , however , increase the response rate . The authors plan to reactivate the trial with modification in the induction chemotherapy and the addition of postradiation maintenance CT consisting of sequential bleomycin and cis‐platinum [16376489] BACKGROUND Unresectable carcinomas of the oropharynx and hypopharynx still have a poor long-term prognosis . Following a previous phase II study , this phase III multicenter trial was conducted between November 1997 and March 2002 . METHODS Nontreated , strictly unresectable cases were eligible . Twice-daily radiation : two fractions of 1.2 Gy/day , 5 days per week , with no split ( D1 - ->D46 ) . Total tumor doses : 80.4 Gy/46 day ( oropharynx ) , 75.6 Gy/44 day ( hypopharynx ) . Chemotherapy ( arm B ) : Cisplatin 100 mg/m2 ( D1 , D22 , D43 ) ; 5FU , continuous infusion ( D1 - ->D5 ) , 750 mg/m2/day cycle 1 ; 430 mg/m2/day cycles 2 and 3 . RESULTS A total of 163 evaluable patients . Grade 3 - 4 acute mucositis 82.6 % arm B/69.5 % arm A ( NS ) ; Grade 3 - 4 neutropenia 33.3 % arm B/2.4 % arm A ( p < 0.05 ) . Enteral nutrition through gastrostomy tube was more frequent in arm B before treatment and at 6 months ( p < 0.01 ) . At 24 months , overall survival ( OS ) , disease-free survival ( DFS ) , and specific survival ( SS ) were significantly better in arm B. OS : 37.8 % arm B vs. 20.1 % arm A ( p = 0.038 ) ; DFS : 48.2 % vs. 25.2 % ( p = 0.002 ) ; SS : 44.5 % vs. 30.2 % ( p = 0.021 ) . No significant difference between the two arms in the amount of side effects at 1 and 2 years . CONCLUSION For these unresectable cases , chemoradiation provides better outcome than radiation alone , even with an " aggressive " dose-intensity radiotherapy schedule [384188] Fifty-eight patients with advanced head and neck cancer were entered into a r and omised trial comparing radical radiation therapy to the primary tumour and associated lymph node areas with a combination of radiation therapy plus chemotherapy . The distribution of tumour types and stages was similar in the two treatment groups . The response rates to radiation therapy alone ( 50 % complete plus parital response ) and to radiation therapy plus chemotherapy ( 60 % complete plus partial response ) were not significantly different . However , a significant difference in survival was found between the two groups . The median duration of survival for the patients treated by means of radiation therapy alone was 18 weeks ; that for the combined therapy was 36 weeks . The combination of radical radiation therapy plus intermittent high-dose chemotherapy was well tolerated and appears to be an approach that warrants further trial [2262356] From January 1978 to January 1988 , 859 patients with T3-T4 , NO-3 , MO were r and omly allocated to receive either : Group A--60Co 60 , 60 Gy in 30 fractions ; Group B--60Co , 70.4 Gy in 64 fractions ; Group C--60Co , 60 Gy in 30 fractions plus chemotherapy ( 5 Fu , 250 mg/m2/IV every 2 days ) . Chemotherapy and radiotherapy were combined simultaneously . The average age was 56 years ; the male/female ratio was 802/57 . Median performance status ( ECOG scale ) was 1 ( range 0 - 2 ) . The TNM distribution as UICC criteria was T3 529 patients ; T4 330 patients ; No 217 patients ; N1 52 patients ; N2 319 patients ; and N3 271 patients . The primary sites were nasopharynx 92 , oral cavity 252 , hypopharynx 119 , larynx 310 , and others ( sinuses and unknown primary ) 86 . Complete response was achieved in 188/277 patients in Group A ( 67.8 % ) , 254/282 patients in Group B ( 90 % ) , and 289/300 in Group C ( 96.3 % ) . All patients were followed and statistical analysis shows a significant improvement in median duration of response , as well as survival for Groups B and C compared with Group A. No significant differences were seen between Group B and C. The acute toxicity was mucositis , skin toxicity , bone marrow depression . A mean temporary weight loss of 4.9 Kg was observed with a range of 2.3 - 10.5 Kg [16464538] PURPOSE To prove an expected benefit of concurrent radiochemotherapy ( RCT ) , a two-arm r and omized multicentric study was performed . In a subgroup analysis the influence of pretherapeutical hemoglobin level ( p-Hb ) on survival under locoregional control ( SLC ) was tested . PATIENTS AND METHODS The study included primarily untreated Stage III/IV ( International Union Against Cancer [ UICC ] ) oropharyngeal and hypopharyngeal carcinomas . Patients were r and omized to receive either hyperfractionated ( hf ) and accelerated ( acc ) RCT with two cycles 5-fluorouracil ( 600 mg/m(2)/day ) and carboplatin ( 70 mg/m(2)/day ) on Days 1 - 5 and 29 - 33 or hf-acc radiotherapy ( RT ) alone . Total RT dose in both arms was 69.9 Gy in 38 days in concomitant boost technique . RESULTS After a median follow-up time of 57 months , SLC is significantly better in RCT than in RT ( p = 0.01 ) , with median SLC of 17 months and 11 months , respectively . Also overall survival ( OS ) shows a benefit for RCT ( p = 0.016 ) , with a median survival of 23 months for RCT and 16 months for RT . However , the benefit in SLC and OS is not seen in hypopharyngeal carcinomas . In a multivariate analysis of oropharyngeal cancer patients , p-Hb levels lower than 12.7 g/dL result ed in lower SLC compared with higher p-Hb levels up to 13.8 g/dL. P-Hb levels > 13.8 g/dL did not further improve SLC . CONCLUSIONS Hyperfractionated-accelerated RCT is superior to hf-acc RT in oropharyngeal carcinomas . P-Hb levels > 13.8 g/dL do not further improve SLC [18270337] BACKGROUND The improved prognosis for patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma ( HNSCC ) relative to HPV-negative HNSCC observed in retrospective analyses remains to be confirmed in a prospect i ve clinical trial . METHODS We prospect ively evaluated the association of tumor HPV status with therapeutic response and survival among 96 patients with stage III or IV HNSCC of the oropharynx or larynx who participated in an Eastern Cooperative Oncology Group ( ECOG ) phase II trial and who received two cycles of induction chemotherapy with intravenous paclitaxel and carboplatin followed by concomitant weekly intravenous paclitaxel and st and ard fractionation radiation therapy . The presence or absence of HPV oncogenic types in tumors was determined by multiplex polymerase chain reaction ( PCR ) and in situ hybridization . Two-year overall and progression-free survival for HPV-positive and HPV-negative patients were estimated by Kaplan-Meier analysis . The relative hazard of mortality and progression for HPV-positive vs HPV-negative patients after adjustment for age , ECOG performance status , stage , and other covariables was estimated by use of a multivariable Cox proportional hazards model . All statistical tests were two-sided . RESULTS Genomic DNA of oncogenic HPV types 16 , 33 , or 35 was located within tumor cell nuclei of 40 % ( 95 % confidence interval [ CI ] = 30 % to 50 % ) of patients with HNSCC of the oropharynx or larynx by in situ hybridization and PCR . Compared with patients with HPV-negative tumors , patients with HPV-positive tumors had higher response rates after induction chemotherapy ( 82 % vs 55 % , difference = 27 % , 95 % CI = 9.3 % to 44.7 % , P = .01 ) and after chemoradiation treatment ( 84 % vs 57 % , difference = 27 % , 95 % CI = 9.7 % to 44.3 % , P = .007 ) . After a median follow-up of 39.1 months , patients with HPV-positive tumors had improved overall survival ( 2-year overall survival = 95 % [ 95 % CI = 87 % to 100 % ] vs 62 % [ 95 % CI = 49 % to 74 % ] , difference = 33 % , 95 % CI = 18.6 % to 47.4 % , P = .005 , log-rank test ) and , after adjustment for age , tumor stage , and ECOG performance status , lower risks of progression ( hazard ratio [ HR ] = 0.27 , 95 % CI = 0.10 to 0.75 ) , and death from any cause ( HR = 0.36 , 95 % CI = 0.15 to 0.85 ) than those with HPV-negative tumors . CONCLUSION For patients with HNSCC of the oropharynx , tumor HPV status is strongly associated with therapeutic response and survival [23182993] PURPOSE To report the long-term results of the Intergroup Radiation Therapy Oncology Group 91 - 11 study evaluating the contribution of chemotherapy added to radiation therapy ( RT ) for larynx preservation . PATIENTS AND METHODS Patients with stage III or IV glottic or supraglottic squamous cell cancer were r and omly assigned to induction cisplatin/fluorouracil ( PF ) followed by RT ( control arm ) , concomitant cisplatin/RT , or RT alone . The composite end point of laryngectomy-free survival ( LFS ) was the primary end point . RESULTS Five hundred twenty patients were analyzed . Median follow-up for surviving patients is 10.8 years . Both chemotherapy regimens significantly improved LFS compared with RT alone ( induction chemotherapy v RT alone : hazard ratio [ HR ] , 0.75 ; 95 % CI , 0.59 to 0.95 ; P = .02 ; concomitant chemotherapy v RT alone : HR , 0.78 ; 95 % CI , 0.78 to 0.98 ; P = .03 ) . Overall survival did not differ significantly , although there was a possibility of worse outcome with concomitant relative to induction chemotherapy ( HR , 1.25 ; 95 % CI , 0.98 to 1.61 ; P = .08 ) . Concomitant cisplatin/RT significantly improved the larynx preservation rate over induction PF followed by RT ( HR , 0.58 ; 95 % CI , 0.37 to 0.89 ; P = .0050 ) and over RT alone ( P < .001 ) , whereas induction PF followed by RT was not better than treatment with RT alone ( HR , 1.26 ; 95 % CI , 0.88 to 1.82 ; P = .35 ) . No difference in late effects was detected , but deaths not attributed to larynx cancer or treatment were higher with concomitant chemotherapy ( 30.8 % v 20.8 % with induction chemotherapy and 16.9 % with RT alone ) . CONCLUSION These 10-year results show that induction PF followed by RT and concomitant cisplatin/RT show similar efficacy for the composite end point of LFS . Locoregional control and larynx preservation were significantly improved with concomitant cisplatin/RT compared with the induction arm or RT alone . New strategies that improve organ preservation and function with less morbidity are needed [21300466] PURPOSE To compare the long-term outcome of treatment with concomitant cisplatin and hyperfractionated radiotherapy versus treatment with hyperfractionated radiotherapy alone in patients with locally advanced head and neck cancer . METHODS AND MATERIAL S From July 1994 to July 2000 , a total of 224 patients with squamous cell carcinoma of the head and neck were r and omized to receive either hyperfractionated radiotherapy alone ( median total dose , 74.4 Gy ; 1.2 Gy twice daily ; 5 days per week ) or the same radiotherapy combined with two cycles of cisplatin ( 20 mg/m(2 ) for 5 consecutive days during weeks 1 and 5 ) . The primary endpoint was the time to any treatment failure ; secondary endpoints were locoregional failure , metastatic failure , overall survival , and late toxicity assessed according to Radiation Therapy Oncology Group criteria . RESULTS Median follow-up was 9.5 years ( range , 0.1 - 15.4 years ) . Median time to any treatment failure was not significantly different between treatment arms ( hazard ratio [ HR ] , 1.2 [ 95 % confidence interval { CI } , 0.9 - 1.7 ; p = 0.17 ] ) . Rates of locoregional failure-free survival ( HR , 1.5 [ 95 % CI , 1.1 - 2.1 ; p = 0.02 ] ) , distant metastasis-free survival ( HR , 1.6 [ 95 % CI , 1.1 - 2.5 ; p = 0.02 ] ) , and cancer-specific survival ( HR , 1.6 [ 95 % CI , 1.0 - 2.5 ; p = 0.03 ] ) were significantly improved in the combined-treatment arm , with no difference in major late toxicity between treatment arms . However , overall survival was not significantly different ( HR , 1.3 [ 95 % CI , 0.9 - 1.8 ; p = 0.11 ] ) . CONCLUSIONS After long-term follow-up , combined-treatment with cisplatin and hyperfractionated radiotherapy maintained improved rates of locoregional control , distant metastasis-free survival , and cancer-specific survival compared to that of hyperfractionated radiotherapy alone , with no difference in major late toxicity [9165134] Between January 1988 and December 1991 , 159 patients with Stage III/IV ( M0 ) squamous cell carcinoma of the head and neck were r and omized to receive st and ard fraction RT ( 70 Gy ) ( group I ) or the same RT plus either 6 mg/m2 of cisplatin ( CDPP ) ( group II ) or 25 mg/ m2 of carboplatin ( CBDCA ) both given daily during RT ( group III ) . Patients in groups II and III had significantly higher overall response rates then those in group I ( P = 0.011 and P = 0.0025 , respectively ) with no difference between groups II and III ( P = 0.60 ) . They also had significantly longer median survival time ( MST ) and higher 5-year survival rates than those in group I ( MST , 32 months ( 32 % ) and 30 months ( 29 % ) versus 16 months ( 15 % ) , respectively ; P = 0.011 and P = 0.019 , respectively ) , with no difference between the two RT/CHT groups . Median time to local recurrence ( MTLR ) and 5-year local recurrence-free survival ( LRFS ) were significantly higher for both RT/CHT when compared to RT alone ( MTLR , not attained yet and 30 months versus 10 months , respectively ; 5-year LRFS , 51 % and 48 % versus 27 % , respectively ; P = 0.018 and P = 0.040 , respectively ) with no difference between the two RT/CHT groups . There was no difference between the three treatment groups regarding regional lymph node and distant metastasis control . Apart from acute high grade ( > or =3 ) hematological toxicity that was significantly more frequent in the two RT/CHT groups and no different between the two RT/CHT groups , other acute high grade toxicity was similar between the three treatment groups . Late high grade toxicity was infrequent and similar between the three treatment groups [9552032] PURPOSE A prospect i ve r and omized multicenter trial was performed to evaluate the contribution of simultaneously administered chemotherapy ( CT ) and radiotherapy ( RT ) in previously untreated patients with unresectable stage III/IV head and neck cancer . PATIENTS AND METHODS Patients with locoregionally advanced head and neck cancer were treated either with RT alone ( arm A ) or simultaneous RT plus CT ( RCT ; arm B ) . RT was identical in both arms and administered in three courses with 13 fractions of 1.8 Gy each twice daily . During one course , from day 3 to 11 , 23.4 Gy was delivered . In arm B , cisplatin ( CDDP ) 60 mg/m2 , fluorouracil ( 5-FU ) 350 mg/m2 by intravenous ( i.v . ) bolus , and leucovorin ( LV ) 50 mg/m2 by i.v . bolus were given on day 2 , and 5-FU 350 mg/m2/24 hour by continuous infusion and LV 100 mg/m2/24 hours by continuous infusion were given from day 2 to 5 . Treatment was repeated on days 22 and 44 ; a total RT dose of 70.2 Gy was administered . Treatment breaks were scheduled from days 12 to 21 and days 34 to 43 . RESULTS From 1989 to 1993 , 298 patients were enrolled and 270 patients were assessable . Acute mucositis grade 3 or 4 was more frequent in arm B ( 38 % ) than in arm A ( 16 % ) ( P < .001 ) . Total treatment time was significantly longer in arm B than in arm A ( P < .001 ) due to prolonged breaks . According to hematologic toxicity , scheduled drug doses were given in 74 % of patients for the second course and 46 % for the third course . The 3-year overall survival rate was 24 % in arm A and 48 % in arm B ( P < .0003 ) . The 3-year locoregional control rate was 17 % in arm A and 36 % in arm B ( P < .004 ) . Both arms showed similar distant failure patterns ( arm A , 13 of 140 ; arm B , 12 of 130 ) . Serious late side effects were not significantly different between treatment arms ( arm A , 6.4 % ; arm B , 10 % ; not significant ) . CONCLUSION Concomitant CT offered improved disease control and survival in advanced head and neck cancer patients . Due to increased acute toxicity , more supportive care is dem and ed when CT is given simultaneously . Increased total treatment time does not exert a negative impact on outcome in this combined modality regimen [19897418] BACKGROUND Previous results from our phase 3 r and omised trial showed that adding cetuximab to primary radiotherapy increased overall survival in patients with locoregionally advanced squamous-cell carcinoma of the head and neck ( LASCCHN ) at 3 years . Here we report the 5-year survival data , and investigate the relation between cetuximab-induced rash and survival . METHODS Patients with LASCCHN of the oropharynx , hypopharynx , or larynx with measurable disease were r and omly allocated in a 1:1 ratio to receive either comprehensive head and neck radiotherapy alone for 6 - 7 weeks or radiotherapy plus weekly doses of cetuximab : 400 mg/m(2 ) initial dose , followed by seven weekly doses at 250 mg/m(2 ) . R and omisation was done with an adaptive minimisation technique to balance assignments across stratification factors of Karnofsky performance score , T stage , N stage , and radiation fractionation . The trial was un-blinded . The primary endpoint was locoregional control , with a secondary endpoint of survival . Following discussion s with the US Food and Drug Administration , the data set was locked , except for queries to the sites about overall survival , before our previous report in 2006 , so that an independent review could be done . Analyses were done on an intention-to-treat basis . Following completion of treatment , patients underwent physical examination and radiographic imaging every 4 months for 2 years , and then every 6 months thereafter . The trial is registered at www . Clinical Trials.gov , number NCT00004227 . FINDINGS Patients were r and omly assigned to receive radiotherapy with ( n=211 ) or without ( n=213 ) cetuximab , and all patients were followed for survival . Up date d median overall survival for patients treated with cetuximab and radiotherapy was 49.0 months ( 95 % CI 32.8 - 69.5 ) versus 29.3 months ( 20.6 - 41.4 ) in the radiotherapy-alone group ( hazard ratio [ HR ] 0.73 , 95 % CI 0.56 - 0.95 ; p=0.018 ) . 5-year overall survival was 45.6 % in the cetuximab-plus-radiotherapy group and 36.4 % in the radiotherapy-alone group . Additionally , for the patients treated with cetuximab , overall survival was significantly improved in those who experienced an acneiform rash of at least grade 2 severity compared with patients with no rash or grade 1 rash ( HR 0.49 , 0.34 - 0.72 ; p=0.002 ) . INTERPRETATION For patients with LASCCHN , cetuximab plus radiotherapy significantly improves overall survival at 5 years compared with radiotherapy alone , confirming cetuximab plus radiotherapy as an important treatment option in this group of patients . Cetuximab-treated patients with prominent cetuximab-induced rash ( grade 2 or above ) have better survival than patients with no or grade 1 rash . FUNDING ImClone Systems , Merck KGaA , and Bristol-Myers Squibb [21233014] BACKGROUND At a minimum follow-up of 2 years , the TAX 324 study showed a significant survival benefit of induction chemotherapy with docetaxel , cisplatin , and fluorouracil ( TPF ) versus cisplatin and fluorouracil ( PF ) in locally advanced head and neck cancer . We report the long-term results at 5 years ' minimum follow-up . METHODS TAX 324 was a r and omised , open-label phase 3 trial comparing three cycles of TPF induction chemotherapy ( docetaxel 75 mg/m(2 ) , followed by intravenous cisplatin 100 mg/m(2 ) and fluorouracil 1000 mg/m(2 ) per day , administered as a continuous 24-h infusion for 4 days ) with three cycles of PF ( intravenous cisplatin 100 mg/m(2 ) , followed by fluorouracil 1000 mg/m(2 ) per day as a continuous 24-h infusion for 5 days ) in patients with stage III or IV squamous-cell carcinoma of the head or neck . Both regimens were followed by 7 weeks of chemoradiotherapy with concomitant weekly carboplatin . R and omisation was done central ly with the use of a biased-coin minimisation technique . At study entry , patients were stratified according to the site of the primary tumour , nodal status ( N0 or N1 vs N2 or N3 ) , and institution . For this long-term analysis , data as of Dec 1 , 2008 , were gathered retrospectively from patients ' medical records . Overall and progression-free survival were the primary endpoints . Tracheostomy and dependence on a gastric feeding tube were used as surrogate measures for treatment-related long-term toxicity . The intention-to-treat analysis included data from all 501 patients ( 255 TPF , 246 PF ) ; data from the initial analysis in 2005 were used for 61 patients who were lost to follow-up . TAX 324 was registered at Clinical Trials.gov , NCT00273546 . FINDINGS Median follow-up was 72·2 months ( 95 % CI 68·8 - 75·5 ) . Overall survival was significantly better after treatment with TPF versus PF ( hazard ratio [ HR ] 0·74 , 95 % CI 0·58 - 0·94 ) , with an estimated 5-year survival of 52 % in patients treated with TPF and 42 % in those receiving PF . Median survival was 70·6 months ( 95 % CI 49·0 - 89·0 ) in the TPF group versus 34·8 months ( 22·6 - 48·0 ) in the PF group ( p=0·014 ) . Progression-free survival was also significantly better in patients treated with TPF ( median 38·1 months , 95 % CI 19·3 - 66·1 , vs 13·2 months , 10·6 - 20·7 ; HR 0·75 , 95 % CI 0·60 - 0·94 ) . We detected no significant difference in dependence on gastric feeding tubes and tracheostomies between treatment groups . In the TPF group , three ( 3 % ) of 91 patients remained feeding-tube dependent , compared with eight ( 11 % ) of 71 patients in the PF group . Six ( 7 % ) of 92 patients had tracheostomies in the TPF group , versus eight ( 11 % ) of 71 in the PF group . INTERPRETATION Induction chemotherapy with TPF provides long-term survival benefit compared with PF in locally advanced head and neck cancer . Patients who are c and i date s for induction chemotherapy should be treated with TPF . FUNDING Sanofi-Aventis [26304911] BACKGROUND We investigated the efficacy of cetuximab when added to induction chemotherapy followed by concurrent chemoradiotherapy ( CCRT ) in patients with locally advanced head and neck squamous cell carcinoma . METHODS Patients were r and omized to receive three cycles of docetaxel and cisplatin ( TP regimen ) with or without cetuximab ( TP plus cetuximab [ CTP ] vs. TP ) as induction chemotherapy . Patients in the CTP arm received CCRT with cetuximab and cisplatin , whereas patients in the TP arm received cisplatin alone . The primary endpoint was the objective response rate ( ORR ) after induction chemotherapy . RESULTS Overall , 92 patients were enrolled . The ORRs for induction chemotherapy in the CTP and TP arms were not different ( 81 % vs. 82 % ) . Adding cetuximab lowered the completion rate of induction chemotherapy and CCRT and result ed in more frequent dose reductions of the induction chemotherapy , although this did not reach statistical significance . In the CTP and TP arms , respectively , the 3-year progression-free survival ( PFS ) rates were 70 % and 56 % ( p = .359 ) , and the overall survival ( OS ) rates were 88 % and 74 % ( p = .313 ) . When limited to patients who completed induction chemotherapy , 3-year PFS rates of 78 % and 59 % ( p = .085 ) and OS rates of 94 % and 73 % ( p = .045 ) were observed in the CTP and TP arms , respectively . CONCLUSION Adding cetuximab to sequential treatment did not increase the treatment efficacy and result ed in greater toxicity . In the intent-to-treat population , neither PFS nor OS was improved by the addition of cetuximab to sequential treatment ; however , a suggestion of improved survival outcomes was observed in patients completing cetuximab-containing induction chemotherapy [1642831] Fifty-eight patients with either advanced or unresectable squamous cell carcinoma of the head and neck were r and omly selected to receive either twice daily radiation alone or twice daily radiation plus concomitant chemotherapy with cisplatin and fluorouracil ( 5-fluorouracil ) . There was no advantage in survival or time to progression with the addition of chemotherapy to twice daily radiation for patients with advanced resectable cancers . In the group of patients with unresectable cancers , however , there was a statistically significant advantage to the addition of chemotherapy , both in terms of disease-free survival and date to progression [15299181] The primary objective of the present r and omized phase III trial was to compare the 3-yr survival rate of patients treated with st and ard fractionated radiotherapy ( RT ) alone or with the same RT concomitantly with cisplatin ( DDP ) or carboplatin ( Cb ) . From January 1995 until July 1999 , 124 patients with histologically proven locally advanced non-nasopharyngeal head and neck cancer ( HNC ) were r and omized to receive either RT monotherapy ( 70Gy , Group A ) or the same RT concomitantly with DDP ( 100 mg/m2 on d 2 , 22 , 42 , Group B ) or Cb ( 7 AUC on d 2 , 22 , 42 , Group C ) . There were no significant differences in complete response rates between patients treated with RT alone or combined chemoradiotherapy . However , median time to progression ( TTP ) and overall survival ( OS ) were significantly longer in patients treated with concomitant chemoradiotherapy . Thus , median TTP was 6.3 , 45.2 , and 17.7 mo in groups A , B , and C respectively ( p=0.0002 ) . Similarly , median OS was 12.2 , 48.6 , and 24.5 mo , respectively ( p=0.0003 ) . At 3 yr follow-up , 17.5 % of patients in group A were alive compared to 52 % in group B and 42 % in group C ( p<0.001 ) . Patients treated with concomitant chemoradiotherapy experienced more frequently severe hematological toxicity . Also , severe nausea/vomiting was more pronounced in group B , as expected . The present study clearly demonstrated that concomitant chemoradiotherapy with platinum analogs significantly prolongs 3-yr survival and median OS in patients with locally advanced HNC compared to conventional RT alone [6203024] Fifty-eight patients with advanced head and neck cancer were entered into a r and omised trial comparing chemotherapy ( DDP + bleomycin ) alone , multiple daily fractionated radiation therapy , and multimodality therapy consisting of chemotherapy plus multiple fractionated radiation therapy . Multimodal therapy gave a significantly higher response rate ( 69 % ) than either single-treatment modality . The use of a multiple daily dose fractionation allowed radiation therapy to be completed over 10 treatment days , and the addition of chemotherapy to the radiation treatment did not significantly increase toxicity . Patients receiving multimodal therapy also survived significantly longer ( median 50 weeks ) than those receiving single-modality therapy ( median 24 weeks ) [19276670] Purpose : Induction chemotherapy has shown to provide consistent benefit for local control in primary treatment of advanced oropharyngeal cancer . The beneficial role of chemoradiation following induction chemotherapy over concurrent chemoradiation has not been evaluated . Present study evaluates the same prospect ively . Method : Out of 135 patients of locally advanced oropharyngeal carcinoma , 105 patients were found eligible and r and omized to treat either with induction chemotherapy consisting of 2 - 3 cycles of cisplatin and 5- Florouracil followed by low dose weekly cisplatin based chemoradiotherapy ( treatment arm : n=48 ) or chemoradiotherapy only ( control arm : n=57 ) . The primary tumor and regional lymph drainage areas received 66 - 70 Gy in 6.5 to 7 weeks by fractionated dose schedule . Results : The response rate and acute toxicity ( primary end points ) in both the arms were found to be similar ( P>0.05 ) The points disease free survival and overall survival ( secondary end points ) were significantly ( [19449227] Conclusions . Conventional radiotherapy with concurrent cisplatin is significantly superior to induction cisplatin fluorouracil chemotherapy followed by radiotherapy in terms of laryngeal preservation in patients with T3 hypopharyngeal carcinoma . Despite a high rate of laryngeal preservation no survival benefit was recorded in this selected population . Objectives . To compare conventional radiotherapy with concurrent cisplatin to induction chemotherapy with cisplatin fluorouracil followed by conventional radiotherapy . The primary end point was the preservation of the larynx . The secondary end points included toxicity , causes of death , and survival rates . Patients and methods . Seventy-one adult patients with previously untreated resectable T3 pyriform sinus squamous cell carcinoma were enrolled in the multicenter prospect i ve r and omized phase III trial . They were evaluated for organ preservation , survival rates , and toxic reactions . Results . The rates of laryngeal preservation at 2 years were 68 % for the induction chemotherapy ( IC ) group and 92 % for the chemoradiotherapy ( CR ) group ( p = 0.016 ) . At 2 years , the event-free survival rates were 36 % and 41 % for the IC group and CR group , respectively [23460709] PURPOSE The combination of cisplatin and radiotherapy is a st and ard treatment for patients with locally advanced squamous cell carcinoma of the head and neck ( SCCHN ) . Cetuximab-radiotherapy is superior to radiotherapy alone in this population , validating epidermal growth factor receptor ( EGFR ) as a target . Erlotinib is a small-molecule inhibitor of EGFR . Adding EGFR inhibition to st and ard cisplatin-radiotherapy may improve efficacy . PATIENTS AND METHODS Patients with locally advanced SCCHN were r and omly assigned to receive cisplatin 100 mg/m(2 ) on days 1 , 22 , and 43 combined with 70 Gy of radiotherapy ( arm A ) or the same chemoradiotherapy with erlotinib 150 mg per day , starting 1 week before radiotherapy and continued to its completion ( arm B ) . The primary end point was complete response rate ( CRR ) , evaluated by central review . The secondary end point was progression-free survival ( PFS ) . Available tumors were tested for p16 and EGFR by fluorescent in situ hybridization . RESULTS Between December 2006 and October 2011 , 204 patients were r and omly assigned . Arms were well balanced for all patient characteristics including p16 , with the exception of more women on arm A. Patients on arm B had more rash , but treatment arms did not differ regarding rates of other grade 3 or 4 toxicities . Arm A had a CRR of 40 % and arm B had a CRR of 52 % ( P = .08 ) when evaluated by central review . With a median follow-up time of 26 months and 54 progression events , there was no difference in PFS ( hazard ratio , 0.9 ; P = .71 ) . CONCLUSION Erlotinib did not increase the toxicity of cisplatin and radiotherapy in patients with locally advanced HNSCC but failed to significantly increase CRR or PFS [2806549] Summary Background Between 1990 and 2000 , we examined the effect of timing of non-platinum chemotherapy when combined with radiotherapy . We aim ed to determine whether giving chemotherapy concurrently with radiotherapy or as maintenance therapy , or both , affected clinical outcome . Here we report survival and recurrence after 10 years of follow-up . Methods Between Jan 15 , 1990 , and June 20 , 2000 , 966 patients were recruited from 34 centres in the UK and two centres from Malta and Turkey . Patients with locally advanced head and neck cancer , and who had not previously undergone surgery , were r and omly assigned to one of four groups in a 3:2:2:2 ratio , stratified by centre and chemotherapy regimen : radical radiotherapy alone ( n=233 ) ; radiotherapy with two courses of chemotherapy given simultaneously on days 1 and 14 of radiotherapy ( SIM alone ; n=166 ) ; or 14 and 28 days after completing radiotherapy ( SUB alone , n=160 ) ; or both ( SIM+SUB ; n=154 ) . Chemotherapy was either methotrexate alone , or vincristine , bleomycin , methotrexate , and fluorouracil . Patients who had previously undergone radical surgery to remove their tumour were only r and omised to radiotherapy alone ( n=135 ) or SIM alone ( n=118 ) , in a 3:2 ratio . The primary endpoints were overall survival ( from r and omisation ) , and event-free survival ( EFS ; recurrence , new tumour , or death ; whichever occurred first ) among patients who were disease-free 6 months after r and omisation . Analyses were by intention to treat . This trial is registered at www . Clinical trials.gov , number NCT00002476 . Findings All 966 patients were included in the analyses . Among patients who did not undergo surgery , the median overall survival was 2·6 years ( 99 % CI 1·9–4·2 ) in the radiotherapy alone group , 4·7 ( 2·6–7·8 ) years in the SIM alone group , 2·3 ( 1·6–3·5 ) years in the SUB alone group , and 2·7 ( 1·6–4·7 ) years in the SIM+SUB group ( p=0·10 ) . The corresponding median EFS were 1·0 ( 0·7–1·4 ) , 2·2 ( 1·1–6·0 ) , 1·0 ( 0·6–1·5 ) , and 1·0 ( 0·6–2·0 ) years ( p=0·005 ) , respectively . For every 100 patients given SIM alone , there are 11 fewer EFS events ( 99 % CI 1–21 ) , compared with 100 given radiotherapy , 10 years after treatment . Among the patients who had previously undergone surgery , median overall survival was 5·0 ( 99 % CI 1·8–8·0 ) and 4·6 ( 2·2–7·6 ) years in the radiotherapy alone and SIM alone groups ( p=0·70 ) , respectively , with corresponding median EFS of 3·7 ( 99 % CI 1·1–5·9 ) and 3·0 ( 1·2–5·6 ) years ( p=0·85 ) , respectively . The percentage of patients who had a significant toxicity during treatment were : 11 % ( radiotherapy alone , n=25 ) , 28 % ( SIM alone , n=47 ) , 12 % ( SUB alone , n=19 ) , and 36 % ( SIM+SUB , n=55 ) among patients without previous surgery ; and 9 % ( radiotherapy alone , n=12 ) and 20 % ( SIM alone , n=24 ) among those who had undergone previous surgery . The most common toxicity during treatment was mucositis . The percentage of patients who had a significant toxicity at least 6 months after r and omisation were : 6 % ( radiotherapy alone , n=13 ) , 6 % ( SIM alone , n=10 ) , 4 % ( SUB alone , n=7 ) , and 6 % ( SIM+SUB , n=9 ) among patients who had no previous surgery ; and 7 % ( radiotherapy alone , n=10 ) and 11 % ( SIM alone , n=13 ) among those who had undergone previous surgery . The most common toxicity 6 months after treatment was xerostomia , but this occurred in 3 % or less of patients in each group . Interpretation Concurrent non-platinum chemoradiotherapy reduces recurrences , new tumours , and deaths in patients who have not undergone previous surgery , even 10 years after starting treatment . Chemotherapy given after radiotherapy ( with or without concurrent chemotherapy ) is ineffective . Patients who have undergone previous surgery for head and neck cancer do not benefit from non-platinum chemotherapy . Funding Cancer Research UK , with support from University College London and University College London Hospital Comprehensive Biomedical Research Centre [23265705] BACKGROUND This r and omised Phase II study assessed the activity and safety of concurrent chemoradiotherapy ( CRT ) and lapatinib followed by maintenance treatment in locally advanced , unresected stage III/IVA/IVB head and neck cancer . PATIENTS AND METHODS Patients were r and omised 1:1 to concurrent CRT and placebo followed by placebo or concurrent CRT and lapatinib followed by lapatinib . Treatment continued until disease progression or study withdrawal . Primary end-point was complete response rate ( CRR ) by independent review 6 months post-CRT . RESULTS Sixty-seven patients ( median age 56 years ; 97 % Eastern Cooperative Oncology Group performance status ≤1 ; 82 % stage IV ) were recruited . CRT dose intensities were unaffected by lapatinib : median radiation dose 70 Gy ( lapatinib , placebo ) , duration 49 ( lapatinib ) and 50 days ( placebo ) ; median cisplatin dose 260 mg/m(2 ) ( lapatinib ) and 280 mg/m(2 ) ( placebo ) . Lapatinib combined with CRT was well-tolerated . Grade 3/4 toxicities during CRT were balanced between arms , with the exception of an excess of grade 3 diarrhoea ( 6 % versus 0 % ) and rash ( 9 % versus 3 % ) and two grade 4 cardiac events in the lapatinib arm . CRR at 6 months post-CRT was 53 % with lapatinib versus 36 % with placebo in the intent-to-treat population . The progression-free survival ( PFS ) and overall survival rates at 18 months were 55 % versus 41 % and 68 % versus 57 % for the lapatinib and placebo arms , respectively . The difference between study arms was greatest in p16-negative disease ( median PFS > 20.4 months [ lapatinib ] versus 10.9 [ placebo ] ) . CONCLUSION Lapatinib combined with CRT is well-tolerated with numeric increases in CRR at 6 months post-CRT and median PFS in p16-negative disease

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### Context: [25154822] PURPOSE Combining cisplatin or cetuximab with radiation improves overall survival ( OS ) of patients with stage III or IV head and neck carcinoma ( HNC ) . Cetuximab plus platinum regimens also increase OS in metastatic HNC . The Radiation Therapy Oncology Group launched a phase III trial to test the hypothesis that adding cetuximab to the radiation-cisplatin platform improves progression-free survival ( PFS ) . PATIENTS AND METHODS Eligible patients with stage III or IV HNC were r and omly assigned to receive radiation and cisplatin without ( arm A ) or with ( arm B ) cetuximab . Acute and late reactions were scored using Common Terminology Criteria for Adverse Events ( version 3 ) . Outcomes were correlated with patient and tumor features and markers . RESULTS Of 891 analyzed patients , 630 were alive at analysis ( median follow-up , 3.8 years ) . Cetuximab plus cisplatin-radiation , versus cisplatin-radiation alone , result ed in more frequent interruptions in radiation therapy ( 26.9 % v. 15.1 % , respectively ) ; similar cisplatin delivery ( mean , 185.7 mg/m2 v. 191.1 mg/m2 , respectively ) ; and more grade 3 to 4 radiation mucositis ( 43.2 % v. 33.3 % , respectively ) , rash , fatigue , anorexia , and hypokalemia , but not more late toxicity . No differences were found between arms A and B in 30-day mortality ( 1.8 % v. 2.0 % , respectively ; P = .81 ) , 3-year PFS ( 61.2 % v. 58.9 % , respectively ; P = .76 ) , 3-year OS ( 72.9 % v. 75.8 % , respectively ; P = .32 ) , locoregional failure ( 19.9 % v. 25.9 % , respectively ; P = .97 ) , or distant metastasis ( 13.0 % v. 9.7 % , respectively ; P = .08 ) . Patients with p16-positive oropharyngeal carcinoma ( OPC ) , compared with patients with p16-negative OPC , had better 3-year probability of PFS ( 72.8 % v. 49.2 % , respectively ; P < .001 ) and OS ( 85.6 % v. 60.1 % , respectively ; P < .001 ) , but tumor epidermal growth factor receptor ( EGFR ) expression did not distinguish outcome . CONCLUSION Adding cetuximab to radiation-cisplatin did not improve outcome and hence should not be prescribed routinely . PFS and OS were higher in patients with p16-positive OPC , but outcomes did not differ by EGFR expression [20572581] Aim and background Radiotherapy is the conventional treatment for locally advanced inoperable head and neck squamous cell carcinoma . However , the poor therapeutic results justify the development of radiochemotherapy combinations . In an attempt to improve local control and survival in patients with stage III and IV unresectable head and neck squamous cell carcinoma and based on the results of our previous dose escalation study , we undertook a prospect i ve multicentric r and omized trial . Material s and methods From November 1992 through December 1995 , a total of 164 patients were r and omized to receive radiotherapy alone ( arm I ) or combined ( arm II ) with daily low-dose carboplatin . Results The 3 , 5 and 10-year local-regional recurrence-free survival rates were better in arm II(21.7 % , 15.1 % and 15.1 % , respectively ) than in arm I ( 15 % , 10.7 % and 10.7 % ) , but without statistical significance ( P = 0.11 ) . The 3 , 5 and 10-year disease-free survival rates showed the same positive trend for arm II ( 16 % , 6.8 % and 6.8 % vs 9 % , 5.5 % and 5.5 % , in arm I , respectively ) , again without statistical significance ( P = 0.09 ) . Instead , a statistical advantage was found in overall survival rates at 3 , 5 and 10-years ( 28.9 % , 9 % and 5.5 % in arm II and 11.1 % , 6.9 % and 6.9 % in arm I , respectively ) ( P = 0.02 ) . The 3 , 5 and 10-year local-regional recurrence-free survival rates in stage IV disease were statistically better in arm II ( 21.5 % , 15.9 % and 15.9 % ) than in arm I ( 12.8 % , 7.7 % and 7.7 % , respectively ) ( P = 0.04 ) . Conclusions Long-term results in both treatment arms of the trial appear less positive than most published series . However , our findings do not exclude that carboplatin may be beneficial , but the benefit in local control must be lower than the 15 % assumed to dimension the trial [7918123] BACKGROUND Single-modality radiotherapy is still considered st and ard treatment for patients with locally advanced unresectable cancer of the head and neck . As treatment outcome is poor , attempts to integrate chemotherapy into the overall management of these patients are ongoing . PATIENTS AND METHODS A r and omized study was undertaken to compare a sequential with a simultaneous chemoradiotherapy program . Between February 1986 and February 1991 , 93 eligible patients with locally advanced unresectable cancer of the head and neck were stratified by WHO PS , T and N class and primary site and then r and omized to receive either three courses of neoadjuvant chemotherapy with cisplatin ( 100 mg/m2 i.v . d 1 ) and 5-fluorouracil 1000 mg/m2/days 1 - 5 by continuous i.v . infusion every 3 weeks prior to definitive conventional radiotherapy of 65 - 70 Gy ( sequential treatment ) , or cisplatin 100 mg/m2 on days 1 , 22 , 43 given simultaneously for the duration of the same conventional radiotherapy ( simultaneous treatment ) . RESULTS At the end of the entire treatment 18 complete responses ( 47 % ) in the sequential-treatment arm and 18 ( 41 % ) in the simultaneous treatment arm were obtained . No statistically significant differences in the 5-yr progression-free survival , in the median time to loco-regional and distant progression and in the 5-yr overall survival were observed . Leukopenia was more frequent in the simultaneous than in the sequential arm ( p = 0.03 ) , whereas alopecia ( p = 0.008 ) and phlebitis ( p < 0.0001 ) were more frequent in the sequential-treatment arm . A better compliance was associated with the concomitant treatment , with 87 % of the patients completing the entire radiotherapy program versus 63 % of those in the sequential arm ( p = 0.01 ) . CONCLUSIONS In the present study , the two treatment arms showed similar activity ( complete response , progression-free and overall survival rates ) . Compliance to treatment was better in the concomitant arm . These data suggest that concomitant chemo-radiation therapy might be considered an option in unresectable locally advanced cancer of the head and neck . Phase III studies are needed in order to establish the superiority of this combination of cisplatin and radiotherapy versus radiotherapy alone [23041591] BACKGROUND Cetuximab combined with radiotherapy ( RT ) is a treatment option for head and neck cancer . The objectives of this r and omized , phase II trial were to evaluate the efficacy and safety of cetuximab maintenance therapy following definitive RT with concomitant cetuximab in patients with oropharyngeal cancer . PATIENTS AND METHODS Ninety-one patients with stage III-IV M0 oropharyngeal tumors were r and omly assigned to the treatment with accelerated concomitant boost RT ( 69.9 Gy ) + cetuximab or the same treatment with the addition of 12 consecutive weeks of cetuximab maintenance therapy . The primary end point was locoregional control ( LRC ) at 1 year . RESULTS LRC at 1 year was superior among patients in the experimental arm , treated with cetuximab maintenance ( 59 % versus 47 % ) . However , LRC was similar between both arms after 2 years of follow-up , as a result of increased locoregional recurrences after the first year in the maintenance group . Patients treated with adjuvant cetuximab do recover very soon from toxic effect after combined treatment . CONCLUSIONS Twelve weeks of cetuximab maintenance therapy after concomitant cetuximab + RT in locally advanced oropharyngeal carcinoma is feasible and improves clinical outcomes measured at 1 year . This improvement is not maintained after the second year suggesting that epidermal growth factor receptor blockade is not sufficient to completely eliminate the minimal residual disease [6680215] This study was design ed to ascertain whether a prior reduction of tumor size by drugs could affect the final outcome of tumors treated with radiation . 142 patients with head and neck cancer ( oropharynx , maxillary antrum and intra-oral ) were r and omized for the study . In 72 cases , irradiation was preceded by a continuous intra-arterial infusion of 3 - 5 mg/day methotrexate to a total dose of 90 - 120 mg ; the other 70 patients were treated with radiotherapy alone . Chemotherapy , given prior to radiotherapy , caused a shift in the tumor stage ( i.e. a reduction in tumor size ) in more than one third of the cases . The overall 5-year survival was 43 % in the combined treatment group and 25 % in the group treated with radiation alone ( statistical difference : p less than .05 ) . However , when analysed separately the difference was statistically significant only in oral cavity tumors ( 5-year survival of 54 % in the combined modality group vs. 27 % in the control group ) , although local control rates after both single and combined modalities were not statistically different from those of oropharynx and maxillary antrum tumors . In these last lesions , however , the dissemination of disease was more frequent ; therefore , the lack of improvement of cure rate with the combined modality in these cases seems to be related to both the higher tendency of these tumors to disseminate and the low effectiveness of intra-arterial chemotherapy in controlling distant metastases . Mild and transient local and systemic toxicities were observed during chemotherapy infusion , but no radiosensitising effect on normal skin and mucosa was seen during radiotherapy in patients who had received pre-irradiation chemotherapy [15547184] In 1986 , we initiated a multicenter , r and omized trial to compare induction chemotherapy with cisplatin and 5-fluorouracil followed by locoregional treatment ( surgery and radiotherapy or radiotherapy alone ) with locoregional treatment alone in patients with head and neck squamous cell carcinoma . Here we report the long-term results of the trial . A total of 237 patients with nonmetastatic stage III or IV head and neck carcinoma were r and omly assigned to receive four cycles of neoadjuvant chemotherapy followed by locoregional treatment ( group A ) or locoregional treatment alone ( group B ) . Among all patients , overall survival at 5 and 10 years was 23 % ( 95 % confidence interval [ CI ] = 15.3 % to 30.9 % ) and 19 % ( 95 % CI = 11.6 % to 26.4 % ) , respectively , for those in group A and 16 % ( 95 % CI = 9.6 % to 23.4 % ) and 9 % ( 95 % CI = 3.5 % to 14.7 % ) , respectively , for those in group B ( P = .13 ) . Among operable patients , we observed no difference between group A and group B in overall survival at 5 and 10 years ( group A , 31 % [ 95 % CI = 14.9 % to 47.3 % ] and 22.7 % [ 95 % CI = 7.1 % to 38.3 % ] , respectively ; group B , 43.3 % [ 95 % CI = 25.6 % to 61.0 % ] and 14.2 % [ 95 % CI = 0.1 % to 28.3 % ] , respectively ; P = .73 ) . Among inoperable patients , overall survival at 5 and 10 years was 21 % ( 95 % CI = 12.3 % to 30.1 % ) and 16 % ( 95 % CI = 7.7 % to 23.9 % ) , respectively , for group A and 8 % ( 95 % CI = 1.5 % to 12.3 % ) and 6 % ( 95 % CI = 0.1 % to 9.1 % ) , respectively , for group B ( log-rank P = .04 ) . Four cycles of neoadjuvant chemotherapy is a promising approach for treating patients with inoperable advanced head and neck cancer but not for treating patients with operable disease [14657228] PURPOSE We report the 5-year survival and late toxicity results of a r and omized clinical trial , which showed a 3-year improvement in overall survival and locoregional control of stage III or IV oropharynx carcinoma , using concomitant radiochemotherapy ( arm B ) , compared with st and ard radiotherapy ( arm A ) . PATIENTS AND METHODS A total of 226 patients were entered onto a phase III multicenter r and omized trial comparing radiotherapy alone ( 70 Gy in 35 fractions ; arm A ) with concomitant radiochemotherapy ( 70 Gy in 35 fractions with three cycles of a 4-day regimen comprising carboplatin and fluorouracil ; arm B ) . Prognostic factors were evaluated by univariate and multivariate analysis . Five-year late toxicity was evaluated using National Cancer Institute Common Toxicity Criteria for neurological toxicity , hearing , taste , m and ibula , and teeth damage , and Radiation Therapy Oncology Group toxicity criteria for skin , salivary gl and , and mucosa . RESULTS Five-year overall survival , specific disease-free survival , and locoregional control rates were 22 % and 16 % ( log-rank P = .05 ) , 27 % and 15 % ( P = .01 ) , and 48 % and 25 % ( P = .002 ) , in arm B and arm A , respectively . Stage IV , hemoglobin level lower than 125 g/L , and st and ard treatment were independent prognostic factors of short survival and locoregional failure by univariate and multivariate analysis . One or more grade 3 to 4 complications occurred in 56 % of the patients in arm B , compared with 30 % in arm A ( P was not significant ) . CONCLUSION Concomitant radiochemotherapy improved overall survival and locoregional control rates and does not statistically increase severe late morbidity . Anemia was the most important prognostic factor for survival in both arms [16508679] OBJECTIVES This single-institution study evaluates the feasibility of accelerated fractionation radiotherapy ( AF ) with and without mitomycin C ( MMC ) in the treatment of locally advanced head and neck cancer . PATIENTS AND METHODS Between May 1998 and October 2001 , sixty patients with locally advanced stage III and IV of head and neck cancer were r and omized into three treatment arms : ( 1 ) conventional fractionation radiotherapy ( CF ) ( 5 fractions per week ) ; ( 2 ) accelerated fractionation radiotherapy ( AF ) ( 6 fractions per week ) ; and ( 3 ) AF plus Mitomycin C ( MMC ) . RESULTS The 2-year overall survival ( OS ) of the whole group was 21 % . The OS according to treatment arm was 23 % , 20 % , and 28 % in CF , AF , and AF+MMC arms respectively ( p<0.19 ) . The 2-year loco-regional control ( LC ) rate was 22 % for the whole group of patients . The LC was 10 % , 25 % , and 30 % for the CF , AF , and AF+MMC respectively ( p=0.27 ) . The only significant parameters for OS and LC were performance status and pre-treatment hemoglobin level . Mucositis grade s 3 & 4 occurred in 70 % and 90 % of the patients in the AF and AF+MMC arm respectively compared to 55 % of patients in the CF arm ( p=0.04 ) . However the addition of MMC did not significantly increase the incidence or severity of mucositis between AF and AF+MMC ( p=0.13 ) . Hematological toxicity grade s 3 & 4 were significantly higher after MMC ( occurred in 40 % of patients versus 10 % and 5 % in CF and AF arms respectively , p=0.04 ) . There was no statistically significant difference in the incidence of grade 3 dryness of mouth ( p=0.06 ) , fibrosis ( p=0.6 ) , or lymphoedema ( p=0.39 ) among the three arms . CONCLUSION There was a trend for improvement of LC and OS rates with the use of AF and the addition of MMC to AF compared to CF radiotherapy , although the difference was not statistically significant . The small number of the patients in each treatment arm and the inclusion of multiple tumor sites may contribute to these statistically insignificant results . Accordingly we advise 85 to continue the trial with inclusion of a larger number of patients and restrict tumor sites to one major site [17960012] BACKGROUND Phase 2 studies suggest that the st and ard regimen of cisplatin and fluorouracil ( PF ) plus docetaxel ( TPF ) improves outcomes in squamous-cell carcinoma of the head and neck . We compared TPF with PF as induction chemotherapy in patients with locoregionally advanced , unresectable disease . METHODS We r and omly assigned eligible patients between the ages of 18 and 70 years who had stage III or stage IV disease and no distant metastases to receive either TPF ( docetaxel and cisplatin , day 1 ; fluorouracil by continuous infusion , days 1 to 5 ) or PF every 3 weeks for four cycles . Patients without progression of disease received radiotherapy within 4 to 7 weeks after completing chemotherapy . The primary end point was progression-free survival . RESULTS A total of 358 patients underwent r and omization , with 177 assigned to the TPF group and 181 to the PF group . At a median follow-up of 32.5 months , the median progression-free survival was 11.0 months in the TPF group and 8.2 months in the PF group ( hazard ratio for disease progression or death in the TPF group , 0.72 ; P=0.007 ) . Treatment with TPF result ed in a reduction in the risk of death of 27 % ( P=0.02 ) , with a median overall survival of 18.8 months , as compared with 14.5 months in the PF group . There were more grade 3 or 4 events of leukopenia and neutropenia in the TPF group and more grade 3 or 4 events of thrombocytopenia , nausea , vomiting , stomatitis , and hearing loss in the PF group . The rates of death from toxic effects were 2.3 % in the TPF group and 5.5 % in the PF group . CONCLUSIONS As compared with the st and ard regimen of cisplatin and fluorouracil , induction chemotherapy with the addition of docetaxel significantly improved progression-free and overall survival in patients with unresectable squamous-cell carcinoma of the head and neck . ( Clinical Trials.gov number , NCT00003888 [ Clinical Trials.gov ] . ) [20448462] The prognosis of patients with advanced head and neck cancer remain dismal . For this tumor type , elevated levels of EGFR are associated with a shorter disease free survival and time to treatment failure , reflecting a more aggressive phenotype . Nimotuzumab is a humanized monoclonal antibody that recognizes domain III of the extracellular region of the EGFR , within an area that overlaps with both the surface patch recognized by cetuximab and the binding site for EGF . In order to assess the efficacy of nimotuzumab in combination with radiotherapy , a controlled , double blind , r and omized clinical trial was conducted in 106 advanced squamous cell carcinoma of the head and neck patients , mostly , unfit for chemo-radiotherapy . Control patients received a placebo and radiotherapy . Treatment was safe and the most frequent adverse events consisted on grade I or II asthenia , fever , headache and chills . No skin rash was detected . A significant complete response rate improvement was found in the group of patients treated with nimotuzumab as compared to the placebo . In the intent to treat analysis , a trend towards survival benefit for nimotuzumab treated subjects was found . The survival benefit became significant when applying the Harrington-Fleming test , a weighted log-rank that underscores the detection of differences deferred on time . In addition , a preliminary biomarker investigation showed a significant survival improvement for nimotuzumab treated patients as compared to controls for subjects with EGFR positive tumors . All patients showed a quality of life improvement and a reduction of the general and specific symptoms of the disease [15449338] Mixed treatment comparison ( MTC ) meta- analysis is a generalization of st and ard pairwise meta- analysis for A vs B trials , to data structures that include , for example , A vs B , B vs C , and A vs C trials . There are two roles for MTC : one is to strengthen inference concerning the relative efficacy of two treatments , by including both ' direct ' and ' indirect ' comparisons . The other is to facilitate simultaneous inference regarding all treatments , in order for example to select the best treatment . In this paper , we present a range of Bayesian hierarchical models using the Markov chain Monte Carlo software WinBUGS . These are multivariate r and om effects models that allow for variation in true treatment effects across trials . We consider models where the between-trials variance is homogeneous across treatment comparisons as well as heterogeneous variance models . We also compare models with fixed ( unconstrained ) baseline study effects with models with r and om baselines drawn from a common distribution . These models are applied to an illustrative data set and posterior parameter distributions are compared . We discuss model critique and model selection , illustrating the role of Bayesian deviance analysis , and node-based model criticism . The assumptions underlying the MTC models and their parameterization are also discussed [25782685] Purpose Concurrent chemoradiotherapy ( CRT ) is the st and ard treatment for advanced head and neck squamous cell carcinoma . In this phase II r and omized study , the efficacy and toxicity of docetaxel , cisplatin and 5-fluorouracil induction chemotherapy ( ICT ) followed by concurrent CRT was compared with those after st and ard CRT alone in patients with locally advanced , unresectable head and neck cancer . Patients and methods Between January 2007 and June 2009 , 66 patients with advanced ( stage III or IV ) unresectable squamous cell carcinoma of the head and neck ( oral cavity , oropharynx , hypopharynx , and larynx ) were r and omly assigned to two groups : one receiving two cycles of docetaxel , cisplatin , and 5-fluorouracil ICT followed by CRT with three cycles of cisplatin and one treated by CRT alone . Response rate , local tumor control ( LTC ) , locoregional tumor control ( LRTC ) , overall survival ( OS ) , progression-free survival ( PFS ) , and toxicity results were assessed . Results Three patients from the ICT + CRT group did not appear at the first treatment , so a total of 63 patients were evaluated in the study ( 30 ICT + CRT group and 33 CRT group ) . Three patients died of febrile neutropenia after ICT . The median follow-up time for surviving patients was 63 months ( range 53–82 months ) . The rate of radiologic complete response was 63 % following ICT + CRT , whereas 70 % after CRT alone . There were no significant differences in the 3-year rates of LTC ( 56 vs. 57 % ) , LRTC ( 42 vs. 50 % ) , OS ( 43 vs. 55 % ) , and PFS ( 41 vs. 50 % ) in the ICT + CRT group and in the CRT group , respectively . The rate of grade 3–4 neutropenia was significantly higher in the ICT + CRT group than in the CRT group ( 37 and 12 % ; p = 0.024 ) . Late toxicity ( grade 2 or 3 xerostomia ) developed in 59 and 42 % in the ICT + CRT and CRT groups , respectively . Conclusion The addition of ICT to CRT did not show any advantage in our phase II trial , while the incidence of adverse events increased . The three deaths as a consequence of ICT call attention to the importance of adequate patient selection if ICT is considered . ZusammenfassungHintergrundSimultane Chemoradiotherapie ( CRT ) ist eine St and ardtherapie beim fortgeschrittenen Plattenepithelkarzinom i m Kopf-Hals-Bereich . In dieser r and omisierten Phase-II-Studie wurden die Wirksamkeit und Toxizität einer Induktionschemotherapie ( ICT ) mit Docetaxel , Cisplatin und 5-Fluorouracil gefolgt von simultaner CRT mit der CRT allein bei Patienten mit lokal fortgeschrittenen , irresektablen Kopf-Hals-Tumoren verglichen . Patienten und Method enZwischen Januar 2007 und Juni 2009 wurden 66 Patienten mit fortgeschrittenem ( Stadium III oder IV ) , inoperablem Plattenepithelkarzinom i m Kopf-Hals-Bereich ( Mundhöhle , Oropharynx , Hypopharynx , Larynx ) nach dem Zufallsprinzip in 2 Gruppen eingeteilt . Die eine Gruppe erhielt 2 Zyklen der Docetaxel- , Cisplatin- und 5-Fluorouracil-ICT gefolgt von CRT mit 3 Zyklen Cisplatin , die and ere Gruppe erhielt nur CRT . Ansprechrate , lokale Tumorkontrolle ( LTC ) , lokoregionale Tumorkontrolle ( LRTC ) , Gesamtüberleben ( OS ) , progressionsfreies Überleben ( PFS ) und toxischer Effekt wurden verglichen . ErgebnisseDrei Patienten der Gruppe mit ICT + CRT erschienen bei der ersten Beh and lung nicht , so dass insgesamt 63 Patienten in der Studie ausgewertet wurden ( 30 in der Gruppe ICT + CRT , 33 in der CRT-Gruppe ) . Drei Patienten starben an febriler Neutropenie nach ICT . Die mediane Nachbeobachtungszeit der überlebenden Patienten betrug 63 Monate ( Spanne 53–82 Monate ) . Die Rate des radiologischen vollständigen Ansprechens war 63 % nach ICT + CRT vs. 70 % nach CRT allein . Es gab keinen signifikanten Unterschied in der 3-Jahres-Rate bei LTC ( 56 vs. 57 % ) , LRTC ( 42 vs. 50 % ) , OS ( 43 vs. 55 % ) und PFS ( 41 vs. 50 % ) zwischen der Gruppe mit ICT + CRT und den mit CRT beh and elten Patienten . Die Rate von Neutropenie mit einem Grad 3–4 lag in der Gruppe mit ICT + CRT deutlich höher als in der CRT-Gruppe ( 37 und 12 % ; p = 0,024 ) . Späte Toxizität ( Grad-2- und Grad-3-Xerostomie ) ereignete sich in der Gruppe mit ICT + CRT und in der CRT-Gruppe in jeweils 59 vs. 42 % .SchlussfolgerungDie Kombination von ICT und CRT erbrachte in unserer Phase-II-Studie keine Vorteile , wobei die Gesamtinzidenz der unerwünschten Ereignisse stieg . Die 3 Todesfälle infolge ICT weisen auf die Wichtigkeit der Patientenauswahl i m Falle einer ICT-Beh and lung hin [9165133] BACKGROUND AND PURPOSE In 1986 a prospect i ve , r and omized , multi-centre trial for evaluation of neoadjuvant chemotherapy with cisplatin and 5-fluorouracil in the treatment of advanced squamous cell carcinoma of the head and neck was initiated . As survival in this group of patients is poor the purpose was to find a possible survival benefit of the chemotherapy in addition to radiotherapy compared to radiotherapy only . METHODS Four-hundred sixty-one patients from Denmark , Norway and Sweden with tumors in oral cavity , oropharynx , hypopharynx and larynx were r and omized to receive either st and ard treatment ( radiotherapy or radiotherapy followed by surgery ) or neoadjuvant chemotherapy followed by st and ard treatment . Chemotherapy included three courses of cisplatin 100 mg/m2 i.v . infusion on day 1 followed by 5-fluorouracil 1000 mg/m2 per day continuous i.v . infusion for 120 hours . Radiotherapy 64 - 70 Gy in 2 Gy per fraction , 5 times/week , was given to patients in both treatment arms . RESULTS Response rate was 71 % for patients r and omized to chemotherapy-radiotherapy and 66 % for patients r and omized to st and ard treatment ( not statistically significant ) . Residual tumors were excised if possible . After surgery 62 % of the patients r and omized to chemotherapy-radiotherapy and 60 % of the patients in the st and ard treatment group were clinical ly tumor free . CONCLUSIONS No statistically significant benefit in survival was observed for patients treated with neoadjuvant chemotherapy followed by radiotherapy . Nor was there any impact of chemotherapy on the number of patients achieving loco-regional tumor control after primary treatment [1642879] Summary Treatment results of irradiation as a single treatment for advanced stage IV unresectable head and neck cancer remains uniformly poor and apparently has not changed with the most recent improvements in oncological care . Despite several negative results of r and omized studies , neoadjuvant or concomitant chemotherapy and radiotherapy seems to improve the number of complete responses and also the duration of disease-free survival . The present study was design ed to determine the feasibility , potential risks and benefits of the two methods of combined treatment and radiotherapy alone on the management of advanced unresectable squamous cell carcinoma of the upper respiratory and digestive system . From 1983 to 1986 , 90 patients entered the trial . Thirty patients were r and omized to each study group : radiotherapy alone ( 70 Gy ) ; neoadjuvant chemotherapy ( vinblastine , mitomycin , cisplatin , and bleomycin ) and radiotherapy ; concomitant chemotherapy ( cisplatin and bleomycin ) and radiotherapy . An increased frequency of complete responses ( 33 % ) was seen in patients treated with the two different combinations of chemotherapy and irradiation compared to irradiation alone ( 10 % ) . However , toxicity was more common in patients treated with the two modalities of combined treatment and there were no differences in overall survival rates ( P = 0.706 ) [20032123] BACKGROUND Concomitant chemoradiotherapy ( CT/RT ) is the st and ard treatment of locally advanced squamous cell carcinoma of the head and neck ( SCCHN ) . We evaluated the efficacy of induction docetaxel ( Taxotere ) , cisplatin , and 5-fluorouracil ( TPF ) before CT/RT versus CT/RT alone . PATIENTS AND METHODS Patients with stage III-IVM0 SCCHN , Eastern Cooperative Oncology Group performance status of zero to one , were r and omly assigned to receive CT/RT alone ( arm A : two cycles of cisplatin 20 mg/m(2 ) , days1 - 4 , plus 5-fluorouracil 800 mg/m(2)/day 96 h continuous infusion , during weeks 1 and 6 of radiotherapy ) or three cycles of TPF ( arm B : docetaxel 75 mg/m(2 ) and cisplatin 80 mg/m(2 ) , day 1 , and 5-fluorouracil 800 mg/m(2)/day 96 h continuous infusion , every 3 weeks ) followed by the same CT/RT . The primary end point was the rate of radiologic complete response ( CR ) at 6 - 8 weeks after the end of CT/RT . RESULTS A total of 101 patients were r and omly allocated to the study ( 51 arm A ; 50 arm B ) . CR rates were 21.2 % ( arm A ) versus 50 % ( arm B ) . Median progression-free survival and overall survival were , respectively , 19.7 and 33.3 months ( arm A ) and 30.4 and 39.6 months ( arm B ) . Hematologic and non-hematologic toxic effects during CT/RT were similar in the two arms . CONCLUSION Induction TPF followed by CT/RT was associated with higher radiologic CR in patients with locally advanced SCCHN with no negative impact on CT/RT feasibility [6162599] A clinical trial comparing Bleomycin ( BLM ) plus radiation against radiation alone is reported . One hundred and fifty-seven previously untreated T3 and T4 and N0 , N1 or N2 buccal squamous cell carcinomas were entered . Eighty-four of these received the combined therapy and 73 were controls . Cobalt-60 teletherapy using two opposing fields was employed . BLM was administered intra-arterially in 42 patients , intravenously in 22 patients and intramuscularly in 20 patients . The 73 controls received physiological saline as a placebo . Total clinical healing of the lesion within the volume of irradiation eight weeks after the end of radiotherapy was termed a favourable response . Anything else was a failure . Five-year recurrence-free rates and disease-free survival were also evaluated . The favourable response rate in the study group was 78.6 % and in the control 19.1 % . The corresponding recurrence-free rates and five-year survival rates were 71.8 % and 17 % , and 65.5 and 23.5 % respectively . The main toxic features were acute mucositis , pneumonitis and dermatitis [16683383] Aims and Background To compare conventional fractionation ( CF ) radiation therapy ( RT ) , arm A , versus a split-course accelerated hyperfractionated schedule ( S-AHF ) , arm B , versus CFRT plus concomitant chemotherapy ( CT ) , arm C , in terms of five-year survival and toxicity for squamous cell tumors of the oropharynx . Methods and Study Design Between January 1993 and June 1998 , 192 previously untreated patients with stage III and IV oropharyngeal carcinoma ( excluding T1N1 and T2N1 ) were enrolled in a multicenter r and omized phase III trial ( ORO 93 - 01 ) . In arms A and C , 66 to 70 Gy in 33 to 35 fractions was administered five days a week for six and a half to seven weeks . In arm B , the dose delivered was 64 to 67.2 Gy in two fractions of 1.6 Gy every day , five days a week , with a planned two-week split at 38.4 Gy . In arm C the CT regimen consisted of three cycles of carboplatin and 5-fluorouracil ( CBDCA 75 mg/m2 on days 1 to 4 and 5-FU 1000 mg/m2 i.v . on days 1 to 4 every 28 days ) . Results No statistically significant difference was found in five-year overall survival ( P = 0.39 ) : 21 % for arm A , 21 % for arm B , and 40 % for arm C. Similarly , there was no statistically significant difference in terms of five-year relapse-free survival : 15 % for arm A , 17 % for arm B , and 36 % for arm C. There was a slight trend towards better five-year locoregional control ( P = 0.07 ) for the combined arm : patients without locoregional relapse were 48 % in arm C , 21 % in arm A and 18 % in arm B. Locoregional control was significantly better when arm C was compared with arms A and B combined ( P = 0.02 ; arm A+B 20 % ; arm C 48 % ) . Distant metastases were fairly balanced in the three arms ( A : 14 ; B : 9 ; C : 11 ) , with a tendency towards more frequent isolated distant metastasis development in arm C ( 8 of 11 [ 72 % ] versus 7 of 23 [ 30 % ] in arms A+B ) . Five-year second-tumor-free survival was 85 % . The 13 second tumors were equally distributed and were mainly correlated with tobacco and alcohol consumption ( five lung , two esophagus , two oral cavity , one larynx , one pancreas , one hepatocarcinoma , one myeloma ) . Arm C showed slightly more G3 + late side effects involving subcutaneous tissues and mucosa , although significant late sequelae were relatively uncommon and the mucosal side effects were mostly transient . The occurrence of persistent G3 xerostomia was comparable in the three treatment arms . Conclusions The results obtained with the combination of CT and RT compared with RT alone did not reach statistical significance , but combined treatment almost doubled the five-year overall survival , relapse-free survival and locoregional control rate . Patients with advanced squamous cell carcinomas of the oropharynx who are medically suitable for the combined approach should be treated with a combination of radiotherapy and chemotherapy . The occurrence of second tumors is relatively common in these patients and may contribute substantially to the causes of death [2465852] Between 1978 and 1981 , 85 patients with advanced squamous cell carcinoma of the head and neck were r and omized to receive induction VBM followed by radiotherapy , or radiotherapy alone . The shortest follow-up is thus 6 years . The median survival of patients receiving induction chemotherapy was 46 weeks , that of the radiotherapy group alone was 75 weeks . As the two groups were not balanced despite r and omization , multivariate methods ( GLIM ) were used to identify significant prognostic factors . These were : response to radiotherapy ( P less than 0.001 ) , nodal status ( P less than 0.001 ) , age ( P less than 0.01 ) , and histological grade ( P less than 0.01 ) . Neither treatment with , nor response to , chemotherapy had a significant effect on survival [26644536] PURPOSE No r and omized trials have been conducted to directly compare radiotherapy ( RT ) with concomitant cisplatin ( CDDP ) versus concomitant cetuximab ( CTX ) as first-line treatment of locally advanced squamous cell carcinoma of the head and neck . In this r and omized trial , we compared these two treatment regimens in terms of compliance , toxicity , and efficacy . PATIENTS AND METHODS Eligible patients were r and omly assigned in a 1:1 ratio to receive either CDDP 40 mg/m(2 ) once per week or CTX 400 mg/m(2 ) as loading dose followed by CTX 250 mg/m(2 ) once per week concomitant to radical RT . For primary end points , compliance to treatment was defined as number of days of treatment discontinuation and drug dosage reduction . The acute toxicity rate was defined according to the National Cancer Institute Common Toxicity Criteria . Efficacy end points were local recurrence-free survival , metastasis-free survival , cancer-specific survival , and overall survival . RESULTS The study was discontinued early because of slow accrual after the enrollment of 70 patients . RT discontinuation for more than 10 days occurred in 13 % of patients given CTX and 0 % given CDDP ( P = .05 ) . Drug dosage reduction occurred in 34 % given CTX and 53 % given CDDP ( difference not significant ) . Toxicity profiles differed between the two arms , with hematologic , renal , and GI toxicities more frequent in the CDDP arm , and cutaneous toxicity and the need for nutritional support more frequent in the CTX arm . Serious adverse events related to treatment , including four versus one toxic deaths , were higher in the CTX arm ( 19 % v 3 % , P = .044 ) . Locoregional control , patterns of failure , and survivals were similar between the treatment arms . CONCLUSION CTX concomitant to RT lowered compliance and increased acute toxicity rates . Efficacy outcomes were similar in both arms . These results raise the issue of appropriately selecting patients with head and neck cancer who can benefit from CTX in combination with RT [9719123] PURPOSE To compare the efficacy of concomitant irradiation with mitomycin C and bleomycin in patients with inoperable head and neck carcinoma with radiotherapy alone . METHODS AND MATERIAL S Between March 1991 and December 1993 , 64 patients with inoperable head and neck carcinoma ( 41 with oropharyngeal site ) were r and omized to radiotherapy alone ( group A ) or radiotherapy combined with simultaneous application of mitomycin C and bleomycin ( group B ) . In both groups patients were irradiated five times weekly with 2 Gy to a total dose of 66 - 70 Gy . The planned concomitant treatment in group B was : bleomycin 5 units twice a week i.m . , total dose 70 units , mitomycin C 15 mg/m2 i.v . after delivery of 10 Gy , and 10 mg/m2 i.v . on the last day of radiotherapy . To enhance the effect of these two drugs , patients received also nicotinamide , chlorpromazine , and dicoumarol . Because significantly better results were achieved in arm B for patients with inoperable oropharyngeal carcinoma , the study was closed and such patients were after December 1993 routinely treated with the combined therapy ( as in arm B ) . Until October 1996 , we treated and followed up 48 such consecutive patients . RESULTS Median follow-up of our study patients is 42 months . Complete remission ( CR ) rate in group A was 31 % and in group B 59 % ( p = 0.04 ) ; disease-free survival ( DFS ) in group A was 8 % and in group B 37 % ( P = 0.01 ) ; and overall survival ( OS ) was 7 % in group A and 26 % in group B ( p = 0.08 ) . CR rate for patients with oropharyngeal carcinoma was 29 % in group A ( N = 21 ) and 75 % in group B ( N = 20 ) ( p = 0.007 ) ; DFS in group A was 10 % and in group B 48 % ( p = 0.001 ) ; and the OS was 10 % in group A and 38 % in group B ( p = 0.019 ) . In patients with inoperable oropharyngeal carcinoma treated after December 1993 , complete remission was achieved in 32/48 ( 67 % , 95 % CI : 52%-80 % ) . DFS at the median follow-up of 14 months was 60 % ( 95 % CI 43 - 77 % ) and OS 58 % ( 95 % CI 42 - 74 % ) . CONCLUSION From the results of our study it seems that the concomitant treatment significantly improves CR rate , DFS , and OS in patients with inoperable oropharyngeal carcinoma in comparison with radiotherapy alone [8938220] The purpose of the present study was to determine the safety and efficacy of induction chemotherapy followed by concomitant chemoradiotherapy . Thirty-eight patients were r and omised to receive induction chemotherapy , consisting of cyclophosphamide and methotrexate followed by concomitant 5-fluorouracil and irradiation ( study group ) or irradiation alone ( control group ) . There were non-significant differences in the initial tumor clearance rates in the two groups . Median disease-free survival ( in complete responders ) was 17 months ( 6 - 60 + ) vs 11 months ( 5 - 60 + ) ( p = 0.407 ) and overall survival 11 months ( 1 - 60 + ) vs 14 months ( 2 - 60 + ) ( p = 0.428 ) in the study and control groups respectively . Acute morbidity and deaths during intervention were higher in the study group ( p = 0.007 ) . This study suggests that induction along with concomitant chemoradiotherapy is too toxic for routine use and also fails to provide a survival benefit [16275937] PURPOSE To compare the antitumor activity and toxicity of the two induction chemotherapy treatments of paclitaxel , cisplatin , and fluorouracil ( FU ; PCF ) versus st and ard cisplatin and FU ( CF ) , both followed by chemoradiotherapy ( CRT ) , in locally advanced head and neck cancer ( HNC ) . PATIENTS AND METHODS Eligibility criteria included biopsy-proven , previously untreated , stage III or IV locally advanced HNC . Patients received either CF ( cisplatin 100 mg/m2 on day 1 plus FU 1000 [ corrected ] mg/m2 continuous infusion on days 1 through 5 ) or PCF ( paclitaxel 175 mg/m2 on day 1 , cisplatin 100 mg/m2 on day 2 , and FU 500 mg/m2 continuous infusion on days 2 through 6 ) ; both regimens were administered for three cycles every 21 days . Patients with complete response ( CR ) or partial response of greater than 80 % in primary tumor received additional CRT ( cisplatin 100 mg/m2 on days 1 , 22 , and 43 plus 70 Gy ) . RESULTS A total of 382 eligible patients were r and omly assigned to CF ( n = 193 ) or PCF ( n = 189 ) . The CR rate was 14 % in the CF arm v 33 % in the PCF arm ( P < .001 ) . Median time to treatment failure was 12 months in the CF arm compared with 20 months in the PCF arm ( log-rank test , P = .006 ; Tarone-Ware , P = .003 ) . PCF patients had a trend to longer overall survival ( OS ; 37 months in CF arm v 43 months in PCF arm ; log-rank test , P = .06 ; Tarone-Ware , P = .03 ) . This difference was more evident in patients with unresectable disease ( OS : 26 months in CF arm v 36 months in PCF arm ; log-rank test , P = .04 ; Tarone-Ware , P = .03 ) . CF patients had a higher occurrence of grade 2 to 4 mucositis than PCF patients ( 53 % v 16 % , respectively ; P < .001 ) . CONCLUSION Induction chemotherapy with PCF was better tolerated and result ed in a higher CR rate than CF . However , new trials that compare induction chemotherapy plus CRT versus CRT alone are needed to better define the role of neoadjuvant treatment [25049329] PURPOSE Induction chemotherapy ( IC ) before radiotherapy lowers distant failure ( DF ) rates in locally advanced squamous cell carcinoma of the head and neck ( SCCHN ) . The goal of this phase III trial was to determine whether IC before chemoradiotherapy ( CRT ) further improves survival compared with CRT alone in patients with N2 or N3 disease . PATIENTS AND METHODS Treatment-naive patients with nonmetastatic N2 or N3 SCCHN were r and omly assigned to CRT alone ( CRT arm ; docetaxel , fluorouracil , and hydroxyurea plus radiotherapy 0.15 Gy twice per day every other week ) versus two 21-day cycles of IC ( docetaxel 75 mg/m(2 ) on day 1 , cisplatin 75 mg/m(2 ) on day 1 , and fluorouracil 750 mg/m(2 ) on days 1 to 5 ) followed by the same CRT regimen ( IC + CRT arm ) . The primary end point was overall survival ( OS ) . Secondary end points included DF-free survival , failure pattern , and recurrence-free survival ( RFS ) . RESULTS A total of 285 patients were r and omly assigned . The most common grade 3 to 4 toxicities during IC were febrile neutropenia ( 11 % ) and mucositis ( 9 % ) ; during CRT ( both arms combined ) , they were mucositis ( 49 % ) , dermatitis ( 21 % ) , and leukopenia ( 18 % ) . Serious adverse events were more common in the IC arm ( 47 % v 28 % ; P = .002 ) . With a minimum follow-up of 30 months , there were no statistically significant differences in OS ( hazard ratio , 0.91 ; 95 % CI , 0.59 to 1.41 ) , RFS , or DF-free survival . CONCLUSION IC did not translate into improved OS compared with CRT alone . However , the study was underpowered because it did not meet the planned accrual target , and OS was higher than predicted in both arms . IC can not be recommended routinely in patients with N2 or N3 locally advanced SCCHN [24256848] BACKGROUND Concurrent chemoradiotherapy ( CCRT ) is the st and ard treatment for patients with unresectable , nonmetastatic locoregionally advanced squamous-cell carcinoma of the head and neck ( LASCCHN ) . This r and omized , open-label , phase III clinical trial compared the efficacy between st and ard CCRT and two different induction chemotherapy ( ICT ) regimens followed by CCRT . PATIENTS AND METHODS Patients with untreated LASCCHN were r and omly assigned to ICT ( three cycles ) , with either docetaxel ( Taxotere ) , cisplatin and 5-fluorouracil ( TPF arm ) or cisplatin and 5-fluorouracil ( PF arm ) , followed by CCRT [ 7 weeks of radiotherapy ( RT ) with cisplatin 100 mg/m(2 ) on days 1 , 22 and 43 ] ; or 7 weeks of CCRT alone . The primary end points were progression-free survival ( PFS ) and time-to-treatment failure ( TTF ) . RESULTS In the intention-to-treat ( ITT ) population ( n = 439 ) , the median PFS times were 14.6 ( 95 % CI , 11.6 - 20.4 ) , 14.3 ( 95 % CI , 11.8 - 19.3 ) and 13.8 months ( 95 % CI , 11.0 - 17.5 ) at TPF-CCRT , PF-CCRT and CCRT arms , respectively ( log-rank P = 0.56 ) . The median TTF were 7.9 ( 95 % CI , 5.9 - 11.8 ) , 7.9 ( 95 % CI , 6.5 - 11.8 ) and 8.2 months ( 95 % CI , 6.7 - 12.6 ) for TPF-CCRT , PF-CCRT and CCRT alone , respectively ( log-rank P = 0.90 ) . There were no statistically significant differences for overall survival ( OS ) . Toxic effects from ICT-CCRT were manageable . CONCLUSION Overall , this trial failed to show any advantage of ICT-CCRT over CCRT alone in patients with unresectable LASCCHN [25596659] BACKGROUND We aim ed to compare panitumumab , a fully human monoclonal antibody against EGFR , plus radiotherapy with chemoradiotherapy in patients with unresected , locally advanced squamous-cell carcinoma of the head and neck . METHODS In this international , open-label , r and omised , controlled , phase 2 trial , we recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 22 sites in eight countries worldwide . Patients aged 18 years and older with stage III , IVa , or IVb , previously untreated , measurable ( ≥ 10 mm for at least one dimension ) , locally advanced squamous-cell carcinoma of the head and neck ( non-nasopharygeal ) and an Eastern Cooperative Oncology Group performance status of 0 - 1 were r and omly assigned ( 2:3 ) by an independent vendor to open-label chemoradiotherapy ( two cycles of cisplatin 100 mg/m(2 ) during radiotherapy ) or to radiotherapy plus panitumumab ( three cycles of panitumumab 9 mg/kg every 3 weeks administered with radiotherapy ) using a stratified r and omisation with a block size of five . All patients received 70 - 72 Gy to gross tumour and 54 Gy to areas of sub clinical disease with accelerated fractionation radiotherapy . The primary endpoint was local-regional control at 2 years , analysed in all r and omly assigned patients who received at least one dose of their assigned protocol -specific treatment ( chemotherapy , radiation , or panitumumab ) . The trial is closed and this is the final analysis . This study is registered with Clinical Trials.gov , number NCT00547157 . FINDINGS Between Nov 30 , 2007 , and Nov 16 , 2009 , 152 patients were enrolled , and 151 received treatment ( 61 in the chemoradiotherapy group and 90 in the radiotherapy plus panitumumab group ) . Local-regional control at 2 years was 61 % ( 95 % CI 47 - 72 ) in the chemoradiotherapy group and 51 % ( 40 - 62 ) in the radiotherapy plus panitumumab group . The most frequent grade 3 - 4 adverse events were mucosal inflammation ( 25 [ 40 % ] of 62 patients in the chemoradiotherapy group vs 37 [ 42 % ] of 89 patients in the radiotherapy plus panitumumab group ) , dysphagia ( 20 [ 32 % ] vs 36 [ 40 % ] ) , and radiation skin injury ( seven [ 11 % ] vs 21 [ 24 % ] ) . Serious adverse events were reported in 25 ( 40 % ) of 62 patients in the chemoradiotherapy group and in 30 ( 34 % ) of 89 patients in the radiotherapy plus panitumumab group . INTERPRETATION Panitumumab can not replace cisplatin in the combined treatment with radiotherapy for unresected stage III-IVb squamous-cell carcinoma of the head and neck , and the role of EGFR inhibition in locally advanced squamous-cell carcinoma of the head and neck needs to be reassessed . FUNDING Amgen [2451135] This trial of treatment for head and neck carcinoma was initiated in 1973 by the European Organization for Research and Treatment of Cancer . Its purpose was to investigate the value of single-agent chemotherapy with bleomycin ( BLM ) given during the course of a conventional treatment by external radiotherapy ( RT ) compared to treatment by external RT alone . In this r and omized study , we compared treatment results in 2 groups of patients with squamous cell carcinoma of the oropharynx ( T2 , T3 , and T4 ; International Union Against Cancer classification ) . One group of 92 patients was treated by RT at the prescribed dose of 70 Gy . The other group of 107 patients received radiation according to the same protocol and simultaneously received i m injection of BLM at a dose of 15 mg twice a week , 2 hours prior to the session of RT , for a total dose of 150 mg in 5 weeks . The occurrence of local toxic effects ( i.e. , mucositis and epidermatitis ) was significantly greater in the RT-BLM group ( RT-BLM , 72 % , vs. RT , 21 % ) . Primary tumor response 6 weeks after completion of RT was the same in both arms of the study ( RT , 68 % , vs. RT-BLM , 67 % ) . The 6-year survival rate was 24 % ( RT-BLM ) versus 22 % ( RT ) . Long-term analysis ( 10 yr ) is given [12506176] PURPOSE The Head and Neck Intergroup conducted a phase III r and omized trial to test the benefit of adding chemotherapy to radiation in patients with unresectable squamous cell head and neck cancer . PATIENTS AND METHODS Eligible patients were r and omly assigned between arm A ( the control ) , single daily fractionated radiation ( 70 Gy at 2 Gy/d ) ; arm B , identical radiation therapy with concurrent bolus cisplatin , given on days 1 , 22 , and 43 ; and arm C , a split course of single daily fractionated radiation and three cycles of concurrent infusional fluorouracil and bolus cisplatin chemotherapy , 30 Gy given with the first cycle and 30 to 40 Gy given with the third cycle . Surgical resection was encouraged if possible after the second chemotherapy cycle on arm C and , if necessary , as salvage therapy on all three treatment arms . Survival data were compared between each experimental arm and the control arm using a one-sided log-rank test . RESULTS Between 1992 and 1999 , 295 patients were entered on this trial . This did not meet the accrual goal of 362 patients and result ed in premature study closure . Grade 3 or worse toxicity occurred in 52 % of patients enrolled in arm A , compared with 89 % enrolled in arm B ( P < .0001 ) and 77 % enrolled in arm C ( P < .001 ) . With a median follow-up of 41 months , the 3-year projected overall survival for patients enrolled in arm A is 23 % , compared with 37 % for arm B ( P = .014 ) and 27 % for arm C ( P = not significant ) . CONCLUSION The addition of concurrent high-dose , single-agent cisplatin to conventional single daily fractionated radiation significantly improves survival , although it also increases toxicity . The loss of efficacy result ing from split-course radiation was not offset by either multiagent chemotherapy or the possibility of midcourse surgery [25596660] BACKGROUND Panitumumab is a fully human monoclonal antibody that targets EGFR . We aim ed to compare chemoradiotherapy plus panitumumab with chemoradiotherapy alone in patients with unresected , locally advanced squamous-cell carcinoma of the head and neck . METHODS In this international , open-label , r and omised , controlled , phase 2 trial , we recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 41 sites in nine countries worldwide . Patients aged 18 years and older with stage III , IVa , or IVb , previously untreated , measurable ( ≥ 10 mm for at least one dimension ) , locally advanced squamous-cell carcinoma of the head and neck ( non-nasopharygeal ) and an Eastern Cooperative Oncology Group performance status of 0 - 1 were r and omly assigned ( 2:3 ) by an independent vendor to open-label chemoradiotherapy ( three cycles of cisplatin 100 mg/m(2 ) ) or panitumumab plus chemoradiotherapy ( three cycles of intravenous panitumumab 9.0 mg/kg every 3 weeks plus cisplatin 75 mg/m(2 ) ) using stratified r and omisation with a block size of five . All patients received 70 Gy to gross tumour and 50 Gy to areas at risk for sub clinical disease with st and ard fractionation . The primary endpoint was local-regional control at 2 years , analysed in all r and omised patients who received at least one dose of their assigned protocol -specific treatment ( chemotherapy , radiation , or panitumumab ) . The trial is closed and this is the final analysis . This trial is registered with Clinical Trials.gov , number NCT00500760 . FINDINGS Between Oct 26 , 2007 , and March 26 , 2009 , 153 patients were enrolled and 150 received treatment ( 63 in the chemoradiotherapy group and 87 in the panitumumab plus chemoradiotherapy group ) . Local-regional control at 2 years was 68 % ( 95 % CI 54 - 78 ) in the chemoradiotherapy group and 61 % ( 50 - 71 ) in the panitumumab plus chemoradiotherapy group . The most frequent grade 3 - 4 adverse events were dysphagia ( 17 [ 27 % ] of 63 patients in the chemoradiotherapy group vs 35 [ 40 % ] of 87 in the panitumumab plus chemoradiotherapy group ) , mucosal inflammation ( 15 [ 24 % ] vs 48 [ 55 % ] ) , and radiation skin injury ( eight [ 13 % ] vs 27 [ 31 % ] ) . Serious adverse events were reported in 20 ( 32 % ) of 63 patients in the chemoradiotherapy group and in 37 ( 43 % ) of 87 patients in the panitumumab plus chemoradiotherapy group . INTERPRETATION In patients with locally advanced squamous-cell carcinoma of the head and neck , the addition of panitumumab to st and ard fractionation radiotherapy and cisplatin did not confer any benefit , and the role of EGFR inhibition in these patients needs to be reassessed . FUNDING Amgen [18669465] PURPOSE To investigate the impact of treatment-related toxicity on health-related quality of life ( HRQoL ) among patients with head and neck squamous cell carcinoma treated with radiotherapy either alone or in combination with chemotherapy or surgery . PATIENTS AND METHODS The study sample was composed of 425 disease-free patients . Toxicity was scored according to the European Organisation for Research and Treatment of Cancer (EORTC)/Radiation Therapy Oncology Group ( RTOG ) late radiation-induced morbidity scoring system . HRQoL was assessed using the EORTC Quality of Life Question naire C30 . These assessment s took place at 6 , 12 , 18 , and 24 months after completion of radiotherapy . The analysis was performed using a multivariate analysis of variance . RESULTS Of the six RTOG scales investigated , two significantly affected self-reported HRQoL , salivary gl and ( RTOG(xerostomia ) ) and esophagus/pharynx ( RTOG(swallowing ) ) . Although RTOG(xerostomia ) was reported most frequently , HRQoL was most affected by RTOG(swallowing ) , particularly in the first 18 months after completion of radiotherapy . CONCLUSION Late radiation-induced toxicity , particularly RTOG(swallowing ) and RTOG(xerostomia ) , has a significant impact on the more general dimensions of HRQoL. These findings suggest that the development of new radiation-induced delivery techniques should not only focus on reduction of the dose to the salivary gl and s , but also on anatomic structures that are involved in swallowing [20888709] PURPOSE The Head and Neck Intergroup conducted a Phase III r and omized trial to determine whether the addition weekly cisplatin to daily radiation therapy ( RT ) would improve survival in patients with unresectable squamous cell head- and -neck carcinoma . METHODS AND MATERIAL S Eligible patients were r and omized to RT ( 70 Gy at 1.8 - 2 Gy/day ) or to the identical RT with weekly cisplatin dosed at 20 mg/m(2 ) . Failure-free survival ( FFS ) and overall survival ( OS ) curves were estimated with the Kaplan-Meier method and compared with the log rank test . RESULTS Between 1982 and 1987 , 371 patients were accrued , and 308 patients were found eligible for analysis . Median follow-up was 62 months . The median FFS was 6.5 and 7.2 months for the RT and RT + cisplatin groups , respectively ( p = 0.30 ) . The p value for the treatment difference was p = 0.096 in multivariate modeling of FFS ( compared to a p = 0.30 in univariate analysis ) . Expected acute toxicities were significantly increased with the addition of cisplatin except for in-field RT toxicities . Late toxicities were not significantly different except for significantly more esophageal ( 9 % vs. 3 % , p = 0.03 ) and laryngeal ( 11 % vs. 4 % , p = 0.05 ) late toxicities in the RT + cisplatin group . CONCLUSION The addition of concurrent weekly cisplatin at 20 mg/m(2 ) to daily radiation did not improve survival , although there was evidence of activity . Low-dose weekly cisplatin seems to have modest tumor radiosensitization but can increase the risk of late swallowing complications [15534360] PURPOSE To determine whether the application of two courses of cisplatin simultaneously with hyperfractionated radiotherapy improves the outcome in locally advanced and /or node-positive nonmetastatic carcinomas of the head and neck , compared with hyperfractionated radiotherapy alone . PATIENTS AND METHODS From July 1994 to July 2000 , 224 patients with squamous cell carcinomas of the head and neck ( excluding nasopharynx and paranasal sinus ) were r and omly assigned to hyperfractionated radiotherapy ( median dose , 74.4 Gy ; 1.2 Gy twice daily ) or the same radiotherapy combined with two cycles of concomitant cisplatin ( 20 mg/m2 on 5 days of weeks 1 and 5 ) . The primary end point was time to any treatment failure ; secondary end points were locoregional failure , metastatic relapse , overall survival , and late toxicity . RESULTS There was no difference in radiotherapy between both treatment arms ( 74.4 Gy in 44 days ) . The full cisplatin dose was applied in 93 % and 71 % of patients during the first and second treatment cycles , respectively . Acute toxicity was similar in both arms . Median time to any treatment failure was not significantly different between treatment arms ( 19 months for combined treatment and 16 months for radiotherapy only , respectively ) and the failure-free rate at 2.5 years was 45 % and 33 % , respectively . Locoregional control and distant disease-free survival were significantly improved with cisplatin ( log-rank test , P = .039 and .011 , respectively ) . The difference in overall survival did not reach significance ( log-rank test , P = .147 ) . Late toxicity was comparable in both treatment groups . CONCLUSION The therapeutic index of hyperfractionated radiotherapy is improved by concomitant cisplatin [175693] In 1961 , a r and omized study was begun at the University of Wisconsin Medical Center in which the treatment of advanced squamous cell carcinoma of the head and neck with radiation therapy was compared with combined treatment with radiation therapy and 5-Fluorouracil . One hundred and thirty-six patients with primary lesions in the oral cavity , the base of the tongue , and the oropharynx were analyzed . Both local control and survival were better in the combined treatment group than in the group with radiation therapy alone . However , in only the oral cavity patient population was the difference statistically significant . Both acute and late complications were also increased in this group of patients who received combined treatment [7013971] Between 1975 and 1978 , 23 patients with Stage IV , unresectable , squamous cell carcinoma of the head and neck were r and omized to receive radiotherapy ( RT , 11 patients ) , or radiotherapy‐chemotherapy ( RT & CT , 12 patients ) . The response rate for the 12 RT & CT patients was four complete remissions ( CR ) and four partial remissions ( PR ) ; the 11 RT patients had one CR and three PR . The presence of a responses ( CR or PR ) significantly enhanced the median survival ( 14 vs. 5 months ; P = 0.005 ) . The duration of objectives remission was longer among the RT & CT patients when compared with RT patients ( 6 vs. 2.3 months , P = 0.18 ) . The median survival of the RT & CT group was 12 months compared with 5.6 months for the RT group ( P = 0.13 ) . One RT & CT patient remains alive with disease at 44 months , one RT patient remains alive without disease at 30 months . The present chemotherapy regimen did not modify the pattern of failure and only marginally increased patient survival . It did , however , increase the response rate . The authors plan to reactivate the trial with modification in the induction chemotherapy and the addition of postradiation maintenance CT consisting of sequential bleomycin and cis‐platinum [16376489] BACKGROUND Unresectable carcinomas of the oropharynx and hypopharynx still have a poor long-term prognosis . Following a previous phase II study , this phase III multicenter trial was conducted between November 1997 and March 2002 . METHODS Nontreated , strictly unresectable cases were eligible . Twice-daily radiation : two fractions of 1.2 Gy/day , 5 days per week , with no split ( D1 - ->D46 ) . Total tumor doses : 80.4 Gy/46 day ( oropharynx ) , 75.6 Gy/44 day ( hypopharynx ) . Chemotherapy ( arm B ) : Cisplatin 100 mg/m2 ( D1 , D22 , D43 ) ; 5FU , continuous infusion ( D1 - ->D5 ) , 750 mg/m2/day cycle 1 ; 430 mg/m2/day cycles 2 and 3 . RESULTS A total of 163 evaluable patients . Grade 3 - 4 acute mucositis 82.6 % arm B/69.5 % arm A ( NS ) ; Grade 3 - 4 neutropenia 33.3 % arm B/2.4 % arm A ( p < 0.05 ) . Enteral nutrition through gastrostomy tube was more frequent in arm B before treatment and at 6 months ( p < 0.01 ) . At 24 months , overall survival ( OS ) , disease-free survival ( DFS ) , and specific survival ( SS ) were significantly better in arm B. OS : 37.8 % arm B vs. 20.1 % arm A ( p = 0.038 ) ; DFS : 48.2 % vs. 25.2 % ( p = 0.002 ) ; SS : 44.5 % vs. 30.2 % ( p = 0.021 ) . No significant difference between the two arms in the amount of side effects at 1 and 2 years . CONCLUSION For these unresectable cases , chemoradiation provides better outcome than radiation alone , even with an " aggressive " dose-intensity radiotherapy schedule [384188] Fifty-eight patients with advanced head and neck cancer were entered into a r and omised trial comparing radical radiation therapy to the primary tumour and associated lymph node areas with a combination of radiation therapy plus chemotherapy . The distribution of tumour types and stages was similar in the two treatment groups . The response rates to radiation therapy alone ( 50 % complete plus parital response ) and to radiation therapy plus chemotherapy ( 60 % complete plus partial response ) were not significantly different . However , a significant difference in survival was found between the two groups . The median duration of survival for the patients treated by means of radiation therapy alone was 18 weeks ; that for the combined therapy was 36 weeks . The combination of radical radiation therapy plus intermittent high-dose chemotherapy was well tolerated and appears to be an approach that warrants further trial [2262356] From January 1978 to January 1988 , 859 patients with T3-T4 , NO-3 , MO were r and omly allocated to receive either : Group A--60Co 60 , 60 Gy in 30 fractions ; Group B--60Co , 70.4 Gy in 64 fractions ; Group C--60Co , 60 Gy in 30 fractions plus chemotherapy ( 5 Fu , 250 mg/m2/IV every 2 days ) . Chemotherapy and radiotherapy were combined simultaneously . The average age was 56 years ; the male/female ratio was 802/57 . Median performance status ( ECOG scale ) was 1 ( range 0 - 2 ) . The TNM distribution as UICC criteria was T3 529 patients ; T4 330 patients ; No 217 patients ; N1 52 patients ; N2 319 patients ; and N3 271 patients . The primary sites were nasopharynx 92 , oral cavity 252 , hypopharynx 119 , larynx 310 , and others ( sinuses and unknown primary ) 86 . Complete response was achieved in 188/277 patients in Group A ( 67.8 % ) , 254/282 patients in Group B ( 90 % ) , and 289/300 in Group C ( 96.3 % ) . All patients were followed and statistical analysis shows a significant improvement in median duration of response , as well as survival for Groups B and C compared with Group A. No significant differences were seen between Group B and C. The acute toxicity was mucositis , skin toxicity , bone marrow depression . A mean temporary weight loss of 4.9 Kg was observed with a range of 2.3 - 10.5 Kg [16464538] PURPOSE To prove an expected benefit of concurrent radiochemotherapy ( RCT ) , a two-arm r and omized multicentric study was performed . In a subgroup analysis the influence of pretherapeutical hemoglobin level ( p-Hb ) on survival under locoregional control ( SLC ) was tested . PATIENTS AND METHODS The study included primarily untreated Stage III/IV ( International Union Against Cancer [ UICC ] ) oropharyngeal and hypopharyngeal carcinomas . Patients were r and omized to receive either hyperfractionated ( hf ) and accelerated ( acc ) RCT with two cycles 5-fluorouracil ( 600 mg/m(2)/day ) and carboplatin ( 70 mg/m(2)/day ) on Days 1 - 5 and 29 - 33 or hf-acc radiotherapy ( RT ) alone . Total RT dose in both arms was 69.9 Gy in 38 days in concomitant boost technique . RESULTS After a median follow-up time of 57 months , SLC is significantly better in RCT than in RT ( p = 0.01 ) , with median SLC of 17 months and 11 months , respectively . Also overall survival ( OS ) shows a benefit for RCT ( p = 0.016 ) , with a median survival of 23 months for RCT and 16 months for RT . However , the benefit in SLC and OS is not seen in hypopharyngeal carcinomas . In a multivariate analysis of oropharyngeal cancer patients , p-Hb levels lower than 12.7 g/dL result ed in lower SLC compared with higher p-Hb levels up to 13.8 g/dL. P-Hb levels > 13.8 g/dL did not further improve SLC . CONCLUSIONS Hyperfractionated-accelerated RCT is superior to hf-acc RT in oropharyngeal carcinomas . P-Hb levels > 13.8 g/dL do not further improve SLC [18270337] BACKGROUND The improved prognosis for patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma ( HNSCC ) relative to HPV-negative HNSCC observed in retrospective analyses remains to be confirmed in a prospect i ve clinical trial . METHODS We prospect ively evaluated the association of tumor HPV status with therapeutic response and survival among 96 patients with stage III or IV HNSCC of the oropharynx or larynx who participated in an Eastern Cooperative Oncology Group ( ECOG ) phase II trial and who received two cycles of induction chemotherapy with intravenous paclitaxel and carboplatin followed by concomitant weekly intravenous paclitaxel and st and ard fractionation radiation therapy . The presence or absence of HPV oncogenic types in tumors was determined by multiplex polymerase chain reaction ( PCR ) and in situ hybridization . Two-year overall and progression-free survival for HPV-positive and HPV-negative patients were estimated by Kaplan-Meier analysis . The relative hazard of mortality and progression for HPV-positive vs HPV-negative patients after adjustment for age , ECOG performance status , stage , and other covariables was estimated by use of a multivariable Cox proportional hazards model . All statistical tests were two-sided . RESULTS Genomic DNA of oncogenic HPV types 16 , 33 , or 35 was located within tumor cell nuclei of 40 % ( 95 % confidence interval [ CI ] = 30 % to 50 % ) of patients with HNSCC of the oropharynx or larynx by in situ hybridization and PCR . Compared with patients with HPV-negative tumors , patients with HPV-positive tumors had higher response rates after induction chemotherapy ( 82 % vs 55 % , difference = 27 % , 95 % CI = 9.3 % to 44.7 % , P = .01 ) and after chemoradiation treatment ( 84 % vs 57 % , difference = 27 % , 95 % CI = 9.7 % to 44.3 % , P = .007 ) . After a median follow-up of 39.1 months , patients with HPV-positive tumors had improved overall survival ( 2-year overall survival = 95 % [ 95 % CI = 87 % to 100 % ] vs 62 % [ 95 % CI = 49 % to 74 % ] , difference = 33 % , 95 % CI = 18.6 % to 47.4 % , P = .005 , log-rank test ) and , after adjustment for age , tumor stage , and ECOG performance status , lower risks of progression ( hazard ratio [ HR ] = 0.27 , 95 % CI = 0.10 to 0.75 ) , and death from any cause ( HR = 0.36 , 95 % CI = 0.15 to 0.85 ) than those with HPV-negative tumors . CONCLUSION For patients with HNSCC of the oropharynx , tumor HPV status is strongly associated with therapeutic response and survival [23182993] PURPOSE To report the long-term results of the Intergroup Radiation Therapy Oncology Group 91 - 11 study evaluating the contribution of chemotherapy added to radiation therapy ( RT ) for larynx preservation . PATIENTS AND METHODS Patients with stage III or IV glottic or supraglottic squamous cell cancer were r and omly assigned to induction cisplatin/fluorouracil ( PF ) followed by RT ( control arm ) , concomitant cisplatin/RT , or RT alone . The composite end point of laryngectomy-free survival ( LFS ) was the primary end point . RESULTS Five hundred twenty patients were analyzed . Median follow-up for surviving patients is 10.8 years . Both chemotherapy regimens significantly improved LFS compared with RT alone ( induction chemotherapy v RT alone : hazard ratio [ HR ] , 0.75 ; 95 % CI , 0.59 to 0.95 ; P = .02 ; concomitant chemotherapy v RT alone : HR , 0.78 ; 95 % CI , 0.78 to 0.98 ; P = .03 ) . Overall survival did not differ significantly , although there was a possibility of worse outcome with concomitant relative to induction chemotherapy ( HR , 1.25 ; 95 % CI , 0.98 to 1.61 ; P = .08 ) . Concomitant cisplatin/RT significantly improved the larynx preservation rate over induction PF followed by RT ( HR , 0.58 ; 95 % CI , 0.37 to 0.89 ; P = .0050 ) and over RT alone ( P < .001 ) , whereas induction PF followed by RT was not better than treatment with RT alone ( HR , 1.26 ; 95 % CI , 0.88 to 1.82 ; P = .35 ) . No difference in late effects was detected , but deaths not attributed to larynx cancer or treatment were higher with concomitant chemotherapy ( 30.8 % v 20.8 % with induction chemotherapy and 16.9 % with RT alone ) . CONCLUSION These 10-year results show that induction PF followed by RT and concomitant cisplatin/RT show similar efficacy for the composite end point of LFS . Locoregional control and larynx preservation were significantly improved with concomitant cisplatin/RT compared with the induction arm or RT alone . New strategies that improve organ preservation and function with less morbidity are needed [21300466] PURPOSE To compare the long-term outcome of treatment with concomitant cisplatin and hyperfractionated radiotherapy versus treatment with hyperfractionated radiotherapy alone in patients with locally advanced head and neck cancer . METHODS AND MATERIAL S From July 1994 to July 2000 , a total of 224 patients with squamous cell carcinoma of the head and neck were r and omized to receive either hyperfractionated radiotherapy alone ( median total dose , 74.4 Gy ; 1.2 Gy twice daily ; 5 days per week ) or the same radiotherapy combined with two cycles of cisplatin ( 20 mg/m(2 ) for 5 consecutive days during weeks 1 and 5 ) . The primary endpoint was the time to any treatment failure ; secondary endpoints were locoregional failure , metastatic failure , overall survival , and late toxicity assessed according to Radiation Therapy Oncology Group criteria . RESULTS Median follow-up was 9.5 years ( range , 0.1 - 15.4 years ) . Median time to any treatment failure was not significantly different between treatment arms ( hazard ratio [ HR ] , 1.2 [ 95 % confidence interval { CI } , 0.9 - 1.7 ; p = 0.17 ] ) . Rates of locoregional failure-free survival ( HR , 1.5 [ 95 % CI , 1.1 - 2.1 ; p = 0.02 ] ) , distant metastasis-free survival ( HR , 1.6 [ 95 % CI , 1.1 - 2.5 ; p = 0.02 ] ) , and cancer-specific survival ( HR , 1.6 [ 95 % CI , 1.0 - 2.5 ; p = 0.03 ] ) were significantly improved in the combined-treatment arm , with no difference in major late toxicity between treatment arms . However , overall survival was not significantly different ( HR , 1.3 [ 95 % CI , 0.9 - 1.8 ; p = 0.11 ] ) . CONCLUSIONS After long-term follow-up , combined-treatment with cisplatin and hyperfractionated radiotherapy maintained improved rates of locoregional control , distant metastasis-free survival , and cancer-specific survival compared to that of hyperfractionated radiotherapy alone , with no difference in major late toxicity [9165134] Between January 1988 and December 1991 , 159 patients with Stage III/IV ( M0 ) squamous cell carcinoma of the head and neck were r and omized to receive st and ard fraction RT ( 70 Gy ) ( group I ) or the same RT plus either 6 mg/m2 of cisplatin ( CDPP ) ( group II ) or 25 mg/ m2 of carboplatin ( CBDCA ) both given daily during RT ( group III ) . Patients in groups II and III had significantly higher overall response rates then those in group I ( P = 0.011 and P = 0.0025 , respectively ) with no difference between groups II and III ( P = 0.60 ) . They also had significantly longer median survival time ( MST ) and higher 5-year survival rates than those in group I ( MST , 32 months ( 32 % ) and 30 months ( 29 % ) versus 16 months ( 15 % ) , respectively ; P = 0.011 and P = 0.019 , respectively ) , with no difference between the two RT/CHT groups . Median time to local recurrence ( MTLR ) and 5-year local recurrence-free survival ( LRFS ) were significantly higher for both RT/CHT when compared to RT alone ( MTLR , not attained yet and 30 months versus 10 months , respectively ; 5-year LRFS , 51 % and 48 % versus 27 % , respectively ; P = 0.018 and P = 0.040 , respectively ) with no difference between the two RT/CHT groups . There was no difference between the three treatment groups regarding regional lymph node and distant metastasis control . Apart from acute high grade ( > or =3 ) hematological toxicity that was significantly more frequent in the two RT/CHT groups and no different between the two RT/CHT groups , other acute high grade toxicity was similar between the three treatment groups . Late high grade toxicity was infrequent and similar between the three treatment groups [9552032] PURPOSE A prospect i ve r and omized multicenter trial was performed to evaluate the contribution of simultaneously administered chemotherapy ( CT ) and radiotherapy ( RT ) in previously untreated patients with unresectable stage III/IV head and neck cancer . PATIENTS AND METHODS Patients with locoregionally advanced head and neck cancer were treated either with RT alone ( arm A ) or simultaneous RT plus CT ( RCT ; arm B ) . RT was identical in both arms and administered in three courses with 13 fractions of 1.8 Gy each twice daily . During one course , from day 3 to 11 , 23.4 Gy was delivered . In arm B , cisplatin ( CDDP ) 60 mg/m2 , fluorouracil ( 5-FU ) 350 mg/m2 by intravenous ( i.v . ) bolus , and leucovorin ( LV ) 50 mg/m2 by i.v . bolus were given on day 2 , and 5-FU 350 mg/m2/24 hour by continuous infusion and LV 100 mg/m2/24 hours by continuous infusion were given from day 2 to 5 . Treatment was repeated on days 22 and 44 ; a total RT dose of 70.2 Gy was administered . Treatment breaks were scheduled from days 12 to 21 and days 34 to 43 . RESULTS From 1989 to 1993 , 298 patients were enrolled and 270 patients were assessable . Acute mucositis grade 3 or 4 was more frequent in arm B ( 38 % ) than in arm A ( 16 % ) ( P < .001 ) . Total treatment time was significantly longer in arm B than in arm A ( P < .001 ) due to prolonged breaks . According to hematologic toxicity , scheduled drug doses were given in 74 % of patients for the second course and 46 % for the third course . The 3-year overall survival rate was 24 % in arm A and 48 % in arm B ( P < .0003 ) . The 3-year locoregional control rate was 17 % in arm A and 36 % in arm B ( P < .004 ) . Both arms showed similar distant failure patterns ( arm A , 13 of 140 ; arm B , 12 of 130 ) . Serious late side effects were not significantly different between treatment arms ( arm A , 6.4 % ; arm B , 10 % ; not significant ) . CONCLUSION Concomitant CT offered improved disease control and survival in advanced head and neck cancer patients . Due to increased acute toxicity , more supportive care is dem and ed when CT is given simultaneously . Increased total treatment time does not exert a negative impact on outcome in this combined modality regimen [19897418] BACKGROUND Previous results from our phase 3 r and omised trial showed that adding cetuximab to primary radiotherapy increased overall survival in patients with locoregionally advanced squamous-cell carcinoma of the head and neck ( LASCCHN ) at 3 years . Here we report the 5-year survival data , and investigate the relation between cetuximab-induced rash and survival . METHODS Patients with LASCCHN of the oropharynx , hypopharynx , or larynx with measurable disease were r and omly allocated in a 1:1 ratio to receive either comprehensive head and neck radiotherapy alone for 6 - 7 weeks or radiotherapy plus weekly doses of cetuximab : 400 mg/m(2 ) initial dose , followed by seven weekly doses at 250 mg/m(2 ) . R and omisation was done with an adaptive minimisation technique to balance assignments across stratification factors of Karnofsky performance score , T stage , N stage , and radiation fractionation . The trial was un-blinded . The primary endpoint was locoregional control , with a secondary endpoint of survival . Following discussion s with the US Food and Drug Administration , the data set was locked , except for queries to the sites about overall survival , before our previous report in 2006 , so that an independent review could be done . Analyses were done on an intention-to-treat basis . Following completion of treatment , patients underwent physical examination and radiographic imaging every 4 months for 2 years , and then every 6 months thereafter . The trial is registered at www . Clinical Trials.gov , number NCT00004227 . FINDINGS Patients were r and omly assigned to receive radiotherapy with ( n=211 ) or without ( n=213 ) cetuximab , and all patients were followed for survival . Up date d median overall survival for patients treated with cetuximab and radiotherapy was 49.0 months ( 95 % CI 32.8 - 69.5 ) versus 29.3 months ( 20.6 - 41.4 ) in the radiotherapy-alone group ( hazard ratio [ HR ] 0.73 , 95 % CI 0.56 - 0.95 ; p=0.018 ) . 5-year overall survival was 45.6 % in the cetuximab-plus-radiotherapy group and 36.4 % in the radiotherapy-alone group . Additionally , for the patients treated with cetuximab , overall survival was significantly improved in those who experienced an acneiform rash of at least grade 2 severity compared with patients with no rash or grade 1 rash ( HR 0.49 , 0.34 - 0.72 ; p=0.002 ) . INTERPRETATION For patients with LASCCHN , cetuximab plus radiotherapy significantly improves overall survival at 5 years compared with radiotherapy alone , confirming cetuximab plus radiotherapy as an important treatment option in this group of patients . Cetuximab-treated patients with prominent cetuximab-induced rash ( grade 2 or above ) have better survival than patients with no or grade 1 rash . FUNDING ImClone Systems , Merck KGaA , and Bristol-Myers Squibb [21233014] BACKGROUND At a minimum follow-up of 2 years , the TAX 324 study showed a significant survival benefit of induction chemotherapy with docetaxel , cisplatin , and fluorouracil ( TPF ) versus cisplatin and fluorouracil ( PF ) in locally advanced head and neck cancer . We report the long-term results at 5 years ' minimum follow-up . METHODS TAX 324 was a r and omised , open-label phase 3 trial comparing three cycles of TPF induction chemotherapy ( docetaxel 75 mg/m(2 ) , followed by intravenous cisplatin 100 mg/m(2 ) and fluorouracil 1000 mg/m(2 ) per day , administered as a continuous 24-h infusion for 4 days ) with three cycles of PF ( intravenous cisplatin 100 mg/m(2 ) , followed by fluorouracil 1000 mg/m(2 ) per day as a continuous 24-h infusion for 5 days ) in patients with stage III or IV squamous-cell carcinoma of the head or neck . Both regimens were followed by 7 weeks of chemoradiotherapy with concomitant weekly carboplatin . R and omisation was done central ly with the use of a biased-coin minimisation technique . At study entry , patients were stratified according to the site of the primary tumour , nodal status ( N0 or N1 vs N2 or N3 ) , and institution . For this long-term analysis , data as of Dec 1 , 2008 , were gathered retrospectively from patients ' medical records . Overall and progression-free survival were the primary endpoints . Tracheostomy and dependence on a gastric feeding tube were used as surrogate measures for treatment-related long-term toxicity . The intention-to-treat analysis included data from all 501 patients ( 255 TPF , 246 PF ) ; data from the initial analysis in 2005 were used for 61 patients who were lost to follow-up . TAX 324 was registered at Clinical Trials.gov , NCT00273546 . FINDINGS Median follow-up was 72·2 months ( 95 % CI 68·8 - 75·5 ) . Overall survival was significantly better after treatment with TPF versus PF ( hazard ratio [ HR ] 0·74 , 95 % CI 0·58 - 0·94 ) , with an estimated 5-year survival of 52 % in patients treated with TPF and 42 % in those receiving PF . Median survival was 70·6 months ( 95 % CI 49·0 - 89·0 ) in the TPF group versus 34·8 months ( 22·6 - 48·0 ) in the PF group ( p=0·014 ) . Progression-free survival was also significantly better in patients treated with TPF ( median 38·1 months , 95 % CI 19·3 - 66·1 , vs 13·2 months , 10·6 - 20·7 ; HR 0·75 , 95 % CI 0·60 - 0·94 ) . We detected no significant difference in dependence on gastric feeding tubes and tracheostomies between treatment groups . In the TPF group , three ( 3 % ) of 91 patients remained feeding-tube dependent , compared with eight ( 11 % ) of 71 patients in the PF group . Six ( 7 % ) of 92 patients had tracheostomies in the TPF group , versus eight ( 11 % ) of 71 in the PF group . INTERPRETATION Induction chemotherapy with TPF provides long-term survival benefit compared with PF in locally advanced head and neck cancer . Patients who are c and i date s for induction chemotherapy should be treated with TPF . FUNDING Sanofi-Aventis [26304911] BACKGROUND We investigated the efficacy of cetuximab when added to induction chemotherapy followed by concurrent chemoradiotherapy ( CCRT ) in patients with locally advanced head and neck squamous cell carcinoma . METHODS Patients were r and omized to receive three cycles of docetaxel and cisplatin ( TP regimen ) with or without cetuximab ( TP plus cetuximab [ CTP ] vs. TP ) as induction chemotherapy . Patients in the CTP arm received CCRT with cetuximab and cisplatin , whereas patients in the TP arm received cisplatin alone . The primary endpoint was the objective response rate ( ORR ) after induction chemotherapy . RESULTS Overall , 92 patients were enrolled . The ORRs for induction chemotherapy in the CTP and TP arms were not different ( 81 % vs. 82 % ) . Adding cetuximab lowered the completion rate of induction chemotherapy and CCRT and result ed in more frequent dose reductions of the induction chemotherapy , although this did not reach statistical significance . In the CTP and TP arms , respectively , the 3-year progression-free survival ( PFS ) rates were 70 % and 56 % ( p = .359 ) , and the overall survival ( OS ) rates were 88 % and 74 % ( p = .313 ) . When limited to patients who completed induction chemotherapy , 3-year PFS rates of 78 % and 59 % ( p = .085 ) and OS rates of 94 % and 73 % ( p = .045 ) were observed in the CTP and TP arms , respectively . CONCLUSION Adding cetuximab to sequential treatment did not increase the treatment efficacy and result ed in greater toxicity . In the intent-to-treat population , neither PFS nor OS was improved by the addition of cetuximab to sequential treatment ; however , a suggestion of improved survival outcomes was observed in patients completing cetuximab-containing induction chemotherapy [1642831] Fifty-eight patients with either advanced or unresectable squamous cell carcinoma of the head and neck were r and omly selected to receive either twice daily radiation alone or twice daily radiation plus concomitant chemotherapy with cisplatin and fluorouracil ( 5-fluorouracil ) . There was no advantage in survival or time to progression with the addition of chemotherapy to twice daily radiation for patients with advanced resectable cancers . In the group of patients with unresectable cancers , however , there was a statistically significant advantage to the addition of chemotherapy , both in terms of disease-free survival and date to progression [15299181] The primary objective of the present r and omized phase III trial was to compare the 3-yr survival rate of patients treated with st and ard fractionated radiotherapy ( RT ) alone or with the same RT concomitantly with cisplatin ( DDP ) or carboplatin ( Cb ) . From January 1995 until July 1999 , 124 patients with histologically proven locally advanced non-nasopharyngeal head and neck cancer ( HNC ) were r and omized to receive either RT monotherapy ( 70Gy , Group A ) or the same RT concomitantly with DDP ( 100 mg/m2 on d 2 , 22 , 42 , Group B ) or Cb ( 7 AUC on d 2 , 22 , 42 , Group C ) . There were no significant differences in complete response rates between patients treated with RT alone or combined chemoradiotherapy . However , median time to progression ( TTP ) and overall survival ( OS ) were significantly longer in patients treated with concomitant chemoradiotherapy . Thus , median TTP was 6.3 , 45.2 , and 17.7 mo in groups A , B , and C respectively ( p=0.0002 ) . Similarly , median OS was 12.2 , 48.6 , and 24.5 mo , respectively ( p=0.0003 ) . At 3 yr follow-up , 17.5 % of patients in group A were alive compared to 52 % in group B and 42 % in group C ( p<0.001 ) . Patients treated with concomitant chemoradiotherapy experienced more frequently severe hematological toxicity . Also , severe nausea/vomiting was more pronounced in group B , as expected . The present study clearly demonstrated that concomitant chemoradiotherapy with platinum analogs significantly prolongs 3-yr survival and median OS in patients with locally advanced HNC compared to conventional RT alone [6203024] Fifty-eight patients with advanced head and neck cancer were entered into a r and omised trial comparing chemotherapy ( DDP + bleomycin ) alone , multiple daily fractionated radiation therapy , and multimodality therapy consisting of chemotherapy plus multiple fractionated radiation therapy . Multimodal therapy gave a significantly higher response rate ( 69 % ) than either single-treatment modality . The use of a multiple daily dose fractionation allowed radiation therapy to be completed over 10 treatment days , and the addition of chemotherapy to the radiation treatment did not significantly increase toxicity . Patients receiving multimodal therapy also survived significantly longer ( median 50 weeks ) than those receiving single-modality therapy ( median 24 weeks ) [19276670] Purpose : Induction chemotherapy has shown to provide consistent benefit for local control in primary treatment of advanced oropharyngeal cancer . The beneficial role of chemoradiation following induction chemotherapy over concurrent chemoradiation has not been evaluated . Present study evaluates the same prospect ively . Method : Out of 135 patients of locally advanced oropharyngeal carcinoma , 105 patients were found eligible and r and omized to treat either with induction chemotherapy consisting of 2 - 3 cycles of cisplatin and 5- Florouracil followed by low dose weekly cisplatin based chemoradiotherapy ( treatment arm : n=48 ) or chemoradiotherapy only ( control arm : n=57 ) . The primary tumor and regional lymph drainage areas received 66 - 70 Gy in 6.5 to 7 weeks by fractionated dose schedule . Results : The response rate and acute toxicity ( primary end points ) in both the arms were found to be similar ( P>0.05 ) The points disease free survival and overall survival ( secondary end points ) were significantly ( [19449227] Conclusions . Conventional radiotherapy with concurrent cisplatin is significantly superior to induction cisplatin fluorouracil chemotherapy followed by radiotherapy in terms of laryngeal preservation in patients with T3 hypopharyngeal carcinoma . Despite a high rate of laryngeal preservation no survival benefit was recorded in this selected population . Objectives . To compare conventional radiotherapy with concurrent cisplatin to induction chemotherapy with cisplatin fluorouracil followed by conventional radiotherapy . The primary end point was the preservation of the larynx . The secondary end points included toxicity , causes of death , and survival rates . Patients and methods . Seventy-one adult patients with previously untreated resectable T3 pyriform sinus squamous cell carcinoma were enrolled in the multicenter prospect i ve r and omized phase III trial . They were evaluated for organ preservation , survival rates , and toxic reactions . Results . The rates of laryngeal preservation at 2 years were 68 % for the induction chemotherapy ( IC ) group and 92 % for the chemoradiotherapy ( CR ) group ( p = 0.016 ) . At 2 years , the event-free survival rates were 36 % and 41 % for the IC group and CR group , respectively [23460709] PURPOSE The combination of cisplatin and radiotherapy is a st and ard treatment for patients with locally advanced squamous cell carcinoma of the head and neck ( SCCHN ) . Cetuximab-radiotherapy is superior to radiotherapy alone in this population , validating epidermal growth factor receptor ( EGFR ) as a target . Erlotinib is a small-molecule inhibitor of EGFR . Adding EGFR inhibition to st and ard cisplatin-radiotherapy may improve efficacy . PATIENTS AND METHODS Patients with locally advanced SCCHN were r and omly assigned to receive cisplatin 100 mg/m(2 ) on days 1 , 22 , and 43 combined with 70 Gy of radiotherapy ( arm A ) or the same chemoradiotherapy with erlotinib 150 mg per day , starting 1 week before radiotherapy and continued to its completion ( arm B ) . The primary end point was complete response rate ( CRR ) , evaluated by central review . The secondary end point was progression-free survival ( PFS ) . Available tumors were tested for p16 and EGFR by fluorescent in situ hybridization . RESULTS Between December 2006 and October 2011 , 204 patients were r and omly assigned . Arms were well balanced for all patient characteristics including p16 , with the exception of more women on arm A. Patients on arm B had more rash , but treatment arms did not differ regarding rates of other grade 3 or 4 toxicities . Arm A had a CRR of 40 % and arm B had a CRR of 52 % ( P = .08 ) when evaluated by central review . With a median follow-up time of 26 months and 54 progression events , there was no difference in PFS ( hazard ratio , 0.9 ; P = .71 ) . CONCLUSION Erlotinib did not increase the toxicity of cisplatin and radiotherapy in patients with locally advanced HNSCC but failed to significantly increase CRR or PFS [2806549] Summary Background Between 1990 and 2000 , we examined the effect of timing of non-platinum chemotherapy when combined with radiotherapy . We aim ed to determine whether giving chemotherapy concurrently with radiotherapy or as maintenance therapy , or both , affected clinical outcome . Here we report survival and recurrence after 10 years of follow-up . Methods Between Jan 15 , 1990 , and June 20 , 2000 , 966 patients were recruited from 34 centres in the UK and two centres from Malta and Turkey . Patients with locally advanced head and neck cancer , and who had not previously undergone surgery , were r and omly assigned to one of four groups in a 3:2:2:2 ratio , stratified by centre and chemotherapy regimen : radical radiotherapy alone ( n=233 ) ; radiotherapy with two courses of chemotherapy given simultaneously on days 1 and 14 of radiotherapy ( SIM alone ; n=166 ) ; or 14 and 28 days after completing radiotherapy ( SUB alone , n=160 ) ; or both ( SIM+SUB ; n=154 ) . Chemotherapy was either methotrexate alone , or vincristine , bleomycin , methotrexate , and fluorouracil . Patients who had previously undergone radical surgery to remove their tumour were only r and omised to radiotherapy alone ( n=135 ) or SIM alone ( n=118 ) , in a 3:2 ratio . The primary endpoints were overall survival ( from r and omisation ) , and event-free survival ( EFS ; recurrence , new tumour , or death ; whichever occurred first ) among patients who were disease-free 6 months after r and omisation . Analyses were by intention to treat . This trial is registered at www . Clinical trials.gov , number NCT00002476 . Findings All 966 patients were included in the analyses . Among patients who did not undergo surgery , the median overall survival was 2·6 years ( 99 % CI 1·9–4·2 ) in the radiotherapy alone group , 4·7 ( 2·6–7·8 ) years in the SIM alone group , 2·3 ( 1·6–3·5 ) years in the SUB alone group , and 2·7 ( 1·6–4·7 ) years in the SIM+SUB group ( p=0·10 ) . The corresponding median EFS were 1·0 ( 0·7–1·4 ) , 2·2 ( 1·1–6·0 ) , 1·0 ( 0·6–1·5 ) , and 1·0 ( 0·6–2·0 ) years ( p=0·005 ) , respectively . For every 100 patients given SIM alone , there are 11 fewer EFS events ( 99 % CI 1–21 ) , compared with 100 given radiotherapy , 10 years after treatment . Among the patients who had previously undergone surgery , median overall survival was 5·0 ( 99 % CI 1·8–8·0 ) and 4·6 ( 2·2–7·6 ) years in the radiotherapy alone and SIM alone groups ( p=0·70 ) , respectively , with corresponding median EFS of 3·7 ( 99 % CI 1·1–5·9 ) and 3·0 ( 1·2–5·6 ) years ( p=0·85 ) , respectively . The percentage of patients who had a significant toxicity during treatment were : 11 % ( radiotherapy alone , n=25 ) , 28 % ( SIM alone , n=47 ) , 12 % ( SUB alone , n=19 ) , and 36 % ( SIM+SUB , n=55 ) among patients without previous surgery ; and 9 % ( radiotherapy alone , n=12 ) and 20 % ( SIM alone , n=24 ) among those who had undergone previous surgery . The most common toxicity during treatment was mucositis . The percentage of patients who had a significant toxicity at least 6 months after r and omisation were : 6 % ( radiotherapy alone , n=13 ) , 6 % ( SIM alone , n=10 ) , 4 % ( SUB alone , n=7 ) , and 6 % ( SIM+SUB , n=9 ) among patients who had no previous surgery ; and 7 % ( radiotherapy alone , n=10 ) and 11 % ( SIM alone , n=13 ) among those who had undergone previous surgery . The most common toxicity 6 months after treatment was xerostomia , but this occurred in 3 % or less of patients in each group . Interpretation Concurrent non-platinum chemoradiotherapy reduces recurrences , new tumours , and deaths in patients who have not undergone previous surgery , even 10 years after starting treatment . Chemotherapy given after radiotherapy ( with or without concurrent chemotherapy ) is ineffective . Patients who have undergone previous surgery for head and neck cancer do not benefit from non-platinum chemotherapy . Funding Cancer Research UK , with support from University College London and University College London Hospital Comprehensive Biomedical Research Centre [23265705] BACKGROUND This r and omised Phase II study assessed the activity and safety of concurrent chemoradiotherapy ( CRT ) and lapatinib followed by maintenance treatment in locally advanced , unresected stage III/IVA/IVB head and neck cancer . PATIENTS AND METHODS Patients were r and omised 1:1 to concurrent CRT and placebo followed by placebo or concurrent CRT and lapatinib followed by lapatinib . Treatment continued until disease progression or study withdrawal . Primary end-point was complete response rate ( CRR ) by independent review 6 months post-CRT . RESULTS Sixty-seven patients ( median age 56 years ; 97 % Eastern Cooperative Oncology Group performance status ≤1 ; 82 % stage IV ) were recruited . CRT dose intensities were unaffected by lapatinib : median radiation dose 70 Gy ( lapatinib , placebo ) , duration 49 ( lapatinib ) and 50 days ( placebo ) ; median cisplatin dose 260 mg/m(2 ) ( lapatinib ) and 280 mg/m(2 ) ( placebo ) . Lapatinib combined with CRT was well-tolerated . Grade 3/4 toxicities during CRT were balanced between arms , with the exception of an excess of grade 3 diarrhoea ( 6 % versus 0 % ) and rash ( 9 % versus 3 % ) and two grade 4 cardiac events in the lapatinib arm . CRR at 6 months post-CRT was 53 % with lapatinib versus 36 % with placebo in the intent-to-treat population . The progression-free survival ( PFS ) and overall survival rates at 18 months were 55 % versus 41 % and 68 % versus 57 % for the lapatinib and placebo arms , respectively . The difference between study arms was greatest in p16-negative disease ( median PFS > 20.4 months [ lapatinib ] versus 10.9 [ placebo ] ) . CONCLUSION Lapatinib combined with CRT is well-tolerated with numeric increases in CRR at 6 months post-CRT and median PFS in p16-negative disease Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Oral cavity and oropharyngeal cancers are frequently described as part of a group of oral cancers or head and neck cancer . Treatment of oral cavity cancer is generally surgery followed by radiotherapy , whereas oropharyngeal cancers , which are more likely to be advanced at the time of diagnosis , are managed with radiotherapy or chemoradiation . Surgery for oral cancers can be disfiguring and both surgery and radiotherapy have significant functional side effects , notably impaired ability to eat , drink and talk . The development of new chemotherapy agents , new combinations of agents and changes in the relative timing of surgery , radiotherapy , and chemotherapy treatments may potentially bring about increases in both survival and quality of life for this group of patients . OBJECTIVES To determine whether chemotherapy , in addition to radiotherapy and /or surgery for oral cavity and oropharyngeal cancer results in improved survival , disease free survival , progression free survival , locoregional control and reduced recurrence of disease . To determine which regimen and time of administration ( induction , concomitant or adjuvant ) is associated with better outcomes . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

23269860

[2674556] Background : Certolizumab pegol is a PEGylated tumour necrosis factor inhibitor . Objective : To evaluate the efficacy and safety of certolizumab pegol versus placebo , plus methotrexate ( MTX ) , in patients with active rheumatoid arthritis ( RA ) . Methods : An international , multicentre , phase 3 , r and omised , double-blind , placebo-controlled study in active adult-onset RA . Patients ( n = 619 ) were r and omised 2:2:1 to subcutaneous certolizumab pegol ( liquid formulation ) 400 mg at weeks 0 , 2 and 4 followed by 200 mg or 400 mg plus MTX , or placebo plus MTX , every 2 weeks for 24 weeks . The primary end point was ACR20 response at week 24 . Secondary end points included ACR50 and ACR70 responses , change from baseline in modified Total Sharp Score , ACR core set variables and physical function . Results : Significantly more patients in the certolizumab pegol 200 mg and 400 mg groups achieved an ACR20 response versus placebo ( p⩽0.001 ) ; rates were 57.3 % , 57.6 % and 8.7 % , respectively . Certolizumab pegol 200 and 400 mg also significantly inhibited radiographic progression ; mean changes from baseline in mTSS at week 24 were 0.2 and −0.4 , respectively , versus 1.2 for placebo ( rank analysis p⩽0.01 ) . Certolizumab pegol-treated patients reported rapid and significant improvements in physical function versus placebo ; mean changes from baseline in HAQ-DI at week 24 were −0.50 and −0.50 , respectively , versus −0.14 for placebo ( p⩽0.001 ) . Most adverse events were mild or moderate , with low incidence of withdrawals due to adverse events . Five patients developed tuberculosis . Conclusion : Certolizumab pegol plus MTX was more efficacious than placebo plus MTX , rapidly and significantly improving signs and symptoms of RA and physical function and inhibiting radiographic progression . Trial registration number : [2732899] Objectives : To evaluate the safety and efficacy of 5-year , long-term tocilizumab monotherapy for patients with rheumatoid arthritis . Methods : In an open-label , long-term extension trial following an initial 3-month r and omised phase II trial , 143 of the 163 patients who participated in the initial blinded study received tocilizumab monotherapy ( 8 mg/kg ) every 4 weeks . Concomitant therapy with non-steroidal anti-inflammatory drugs and /or oral prednisolone ( 10 mg daily maximum ) was permitted . All patients were evaluated with American College of Rheumatology ( ACR ) improvement criteria , disease activity score ( DAS ) in 28 joints , and the European League Against Rheumatism response , as well as for safety issues . Results : 143 patients were enrolled in the open-label , long-term extension trial and 94 ( 66 % ) patients had completed 5 years as of March 2007 . 32 patients ( 22 % ) withdrew from the study due to adverse events and one patient ( 0.7 % ) due to unsatisfactory response . 14 patients withdrew because of the patient ’s request or other reasons . The serious adverse event rate was 27.5 events per 100 patient-years , with 5.7 serious infections per 100 patient-years , based on a total tocilizumab exposure of 612 patient-years . Of the 88 patients receiving corticosteroids at baseline , 78 ( 88.6 % ) were able to decrease their corticosteroid dose and 28 ( 31.8 % ) discontinued corticosteroids . At 5 years , 79/94 ( 84.0 % ) , 65/94 ( 69.1 % ) and 41/94 ( 43.6 % ) of the patients achieved ACR20 , ACR50 , and ACR70 improvement criteria , respectively . Remission defined as DAS28 less than 2.6 was achieved in 52/94 ( 55.3 % ) of the patients . Conclusion : In this 5-year extension study , tocilizumab demonstrated sustained long-term efficacy and a generally good safety profile [2674549] Objective : The phase III GO-FORWARD study examined the efficacy and safety of golimumab in patients with active rheumatoid arthritis ( RA ) despite methotrexate therapy . Methods : Patients were r and omly assigned in a 3 : 3 : 2 : 2 ratio to receive placebo injections plus methotrexate capsules ( group 1 , n = 133 ) , golimumab 100 mg injections plus placebo capsules ( group 2 , n = 133 ) , golimumab 50 mg injections plus methotrexate capsules ( group 3 , n = 89 ) , or golimumab 100 mg injections plus methotrexate capsules ( group 4 , n = 89 ) . Injections were administered subcutaneously every 4 weeks . The co- primary endpoints were the proportion of patients with 20 % or greater improvement in the American College of Rheumatology criteria ( ACR20 ) at week 14 and the change from baseline in the health assessment question naire-disability index ( HAQ-DI ) score at week 24 . Results : The proportion of patients who achieved an ACR20 response at week 14 was 33.1 % in the placebo plus methotrexate group , 44.4 % ( p = 0.059 ) in the golimumab 100 mg plus placebo group , 55.1 % ( p = 0.001 ) in the golimumab 50 mg plus methotrexate group and 56.2 % ( p<0.001 ) in the golimumab 100 mg plus methotrexate group . At week 24 , median improvements from baseline in HAQ-DI scores were 0.13 , 0.13 ( p = 0.240 ) , 0.38 ( p<0.001 ) and 0.50 ( p<0.001 ) , respectively . During the placebo-controlled portion of the study ( to week 16 ) , serious adverse events occurred in 2.3 % , 3.8 % , 5.6 % and 9.0 % of patients and serious infections occurred in 0.8 % , 0.8 % , 2.2 % and 5.6 % , respectively . Conclusion : The addition of golimumab to methotrexate in patients with active RA despite methotrexate therapy significantly reduced the signs and symptoms of RA and improved physical function [18358926] BACKGROUND Interleukin 6 is involved in the pathogenesis of rheumatoid arthritis via its broad effects on immune and inflammatory responses . Our aim was to assess the therapeutic effects of blocking interleukin 6 by inhibition of the interleukin-6 receptor with tocilizumab in patients with rheumatoid arthritis . METHODS In this double-blind , r and omised , placebo-controlled , parallel group phase III study , 623 patients with moderate to severe active rheumatoid arthritis were r and omly assigned with an interactive voice response system , stratified by site with a r and omisation list provided by the study sponsor , to receive tocilizumab 8 mg/kg ( n=205 ) , tocilizumab 4 mg/kg ( 214 ) , or placebo ( 204 ) intravenously every 4 weeks , with methotrexate at stable pre- study doses ( 10 - 25 mg/week ) . Rescue therapy with tocilizumab 8 mg/kg was offered at week 16 to patients with less than 20 % improvement in both swollen and tender joint counts . The primary endpoint was the proportion of patients with 20 % improvement in signs and symptoms of rheumatoid arthritis according to American College of Rheumatology criteria ( ACR20 response ) at week 24 . Analyses were by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00106548 . FINDINGS The intention-to-treat analysis population consisted of 622 patients : one patient in the 4 mg/kg group did not receive study treatment and was thus excluded . At 24 weeks , ACR20 responses were seen in more patients receiving tocilizumab than in those receiving placebo ( 120 [ 59 % ] patients in the 8 mg/kg group , 102 [ 48 % ] in the 4 mg/kg group , 54 [ 26 % ] in the placebo group ; odds ratio 4.0 [ 95 % CI 2.6 - 6.1 ] , p<0.0001 for 8 mg/kg vs placebo ; and 2.6 [ 1.7 - 3.9 ] , p<0.0001 for 4 mg/kg vs placebo ) . More people receiving tocilizumab than those receiving placebo had at least one adverse event ( 143 [ 69 % ] in the 8 mg/kg group ; 151 [ 71 % ] in the 4 mg/kg group ; 129 [ 63 % ] in the placebo group ) . The most common serious adverse events were serious infections or infestations , reported by six patients in the 8 mg/kg group , three in the 4 mg/kg group , and two in the placebo group . INTERPRETATION Tocilizumab could be an effective therapeutic approach in patients with moderate to severe active rheumatoid arthritis . FUNDING F Hoffmann-La Roche , Chugai Pharmaceutical [9920948] BACKGROUND Patients treated with methotrexate for rheumatoid arthritis often improve but continue to have active disease . This study was undertaken to determine whether the addition of etanercept , a soluble tumor necrosis factor receptor (p75):Fc fusion protein ( TNFR : Fc ) , to methotrexate therapy would provide additional benefit to patients who had persistent rheumatoid arthritis despite receiving methotrexate . METHODS In a 24-week , double-blind trial , we r and omly assigned 89 patients with persistently active rheumatoid arthritis despite at least 6 months of methotrexate therapy at a stable dose of 15 to 25 mg per week ( or as low as 10 mg per week for patients unable to tolerate higher doses ) to receive either etanercept ( 25 mg ) or placebo subcutaneously twice weekly while continuing to receive methotrexate . The primary measure of clinical response was the American College of Rheumatology criteria for a 20 percent improvement in measures of disease activity ( ACR 20 ) at 24 weeks . RESULTS The addition of etanercept to methotrexate therapy result ed in rapid and sustained improvement . At 24 weeks , 71 percent of the patients receiving etanercept plus methotrexate and 27 percent of those receiving placebo plus methotrexate met the ACR 20 criteria ( P<0.001 ) ; 39 percent of the patients receiving etanercept plus methotrexate and 3 percent of those receiving placebo plus methotrexate met the ACR 50 criteria ( for a 50 percent improvement ) ( P<0.001 ) . Patients receiving etanercept plus methotrexate had significantly better outcomes according to all measures of disease activity . The only adverse events associated with etanercept were mild injection-site reactions , and no patient withdrew from the study because of adverse events associated with etanercept . CONCLUSIONS In patients with persistently active rheumatoid arthritis , the combination of etanercept and methotrexate was safe and well tolerated and provided significantly greater clinical benefit than methotrexate alone [2938895] Objectives This phase III study evaluated the efficacy and safety of rituximab plus methotrexate ( MTX ) in patients with active rheumatoid arthritis ( RA ) who had an inadequate response to MTX and who were naïve to prior biological treatment . Methods Patients with active disease on stable MTX ( 10–25 mg/week ) were r and omised to rituximab 2 × 500 mg ( n=168 ) , rituximab 2 × 1000 mg ( n=172 ) , or placebo ( n=172 ) . From week 24 , patients not in remission ( Disease Activity Score ( 28 joints ) ≥2.6 ) received a second course of rituximab ; patients initially assigned to placebo switched to rituximab 2 × 500 mg . The primary end point was American College of Rheumatology 20 ( ACR20 ) response at week 24 . All patients were followed until week 48 . Results At week 24 , both doses of rituximab showed statistically superior efficacy ( p<0.0001 ) to placebo ( ACR20 : 54 % , 51 % and 23 % ; rituximab ( 2 × 500 mg ) + MTX , rituximab ( 2 × 1000 mg ) + MTX and placebo + MTX , respectively ) . Secondary end points were also significantly improved for both rituximab groups compared with placebo . Further improvements in both rituximab arms were observed from week 24 to week 48 . Rituximab + MTX was well tolerated , demonstrating comparable safety to placebo + MTX through to week 24 , and between rituximab doses through to week 48 . Conclusions Rituximab ( at 2 × 500 mg and 2 × 1000 mg ) plus MTX significantly improved clinical outcomes at week 24 , which were further improved by week 48 . No significant differences in either clinical or safety outcomes were apparent between the rituximab doses [2668560] This multicenter , double-blind study evaluated the effects of three doses of adalimumab in Japanese patients with rheumatoid arthritis ( RA ) . Patients were r and omized to placebo ( n = 87 ) or adalimumab 20 mg ( n = 87 ) , 40 mg ( n = 91 ) , or 80 mg ( n = 87 ) every other week for 24 weeks . The primary efficacy endpoint was the American College of Rheumatology criteria for 20 % improvement ( ACR20 ) at Week 24 . At Week 24 , all adalimumab treatment groups achieved statistically significantly better ACR20 response rates ( 20 mg : 28.7 % , P < 0.05 ; 40 mg : 44.0 % , P < 0.001 ; and 80 mg : 50.6 % , P < 0.001 ) versus placebo ( 13.8 % ) , as well as statistically significantly greater ACR50 and ACR70 responses for the two higher adalimumab doses versus placebo . Rates of adverse events were comparable between the adalimumab groups and the placebo group , except for injection-site reactions , which occurred in more adalimumab-treated patients . Adalimumab 20 , 40 , and 80 mg were safe and effective in Japanese patients ; however , the greatest responses occurred with the 40 and 80 mg doses . These results and comparable ACR20 responses in Western patients support adalimumab 40 mg every other week as the appropriate dosage to treat RA in Japanese patients [19578810] Tumour necrosis factor alpha ( TNF-α ) and interlekin-6 ( IL-6 ) are key inflammatory cytokines in the pathogenesis of rheumatoid arthritis ( RA ) , a disease also associated with endothelial perturbation and increased serum levels of adhesion molecules . As relationships between these processes and molecules are unclear , we tested the hypotheses ( a ) that TNF-α and IL-6 are linked to endothelial activation/damage and levels of soluble adhesion molecules , and ( b ) that intensive anti-inflammatory treatment improves levels of these indices . We recruited 66 patients with RA , 48 community controls ( CC ) , and 25 disease controls ( DC ) . Plasma TNF-α and IL-6 were compared to markers of vascular biology ( vWF , sE-sel ) , soluble adhesion molecules ( sICAM , sVCAM ) and routine inflammatory markers ( CRP and ESR ) . Blood was obtained at baseline and at 1 week and again 4 weeks after anti-inflammatory treatment in a subgroup of 29 patients with RA . With the exception of sE-selectin , RA patients had increased levels of all plasma markers compared to the HCs , whilst levels in the DCs were largely intermediate between RA and the CCs . Within the RA group , sEsel correlated with both CRP and ESR whilst TNF-α correlated with sVCAM ( all r > 0.32 , P < 0.01 ) . After 1 week of combined anti-inflammatory therapy , only CRP , ESR , sEsel and sVCAM were significantly reduced ( all P < 0.05 ) . In RA , endothelial activation ( as sEsel ) correlates with classical markers of inflammation and is reduced by intensive anti-inflammatory medications [3375587] Objectives To compare health-related quality of life ( HRQoL ) before and after treatment with etanercept in patients with moderate to severe rheumatoid arthritis ( RA ) , psoriatic arthritis ( PsA ) and psoriasis using spydergram representations . Methods Data from r and omised , controlled trials of etanercept in patients with RA , PsA and psoriasis were analysed . HRQoL was assessed by the medical outcomes survey short form 36 ( SF-36 ) physical ( PCS ) and mental ( MCS ) component summary and domain scores . Baseline comparisons with age and gender-matched norms and treatment-associated changes in domain scores were quantified using spydergrams and the health utility SF-6D measure . Results Mean baseline PCS scores were lower than age and gender-matched norms in patients with RA and PsA , but near normative values in patients with psoriasis ; MCS scores at baseline were near normal in PsA and psoriasis but low in RA . Treatment with etanercept result ed in improvements in PCS and MCS scores as well as individual SF-36 domains across all indications . Mean baseline SF-6D scores were higher in psoriasis than in RA or PsA ; clinical ly meaningful improvements in SF-6D were observed in all three patient population s following treatment with etanercept . Conclusions Patients with RA , PsA and psoriasis demonstrated unique HRQoL profiles at baseline . Treatment with etanercept was associated with improvements in PCS and MCS scores as well as individual domain scores in patients with RA , PsA and psoriasis [15449338] Mixed treatment comparison ( MTC ) meta- analysis is a generalization of st and ard pairwise meta- analysis for A vs B trials , to data structures that include , for example , A vs B , B vs C , and A vs C trials . There are two roles for MTC : one is to strengthen inference concerning the relative efficacy of two treatments , by including both ' direct ' and ' indirect ' comparisons . The other is to facilitate simultaneous inference regarding all treatments , in order for example to select the best treatment . In this paper , we present a range of Bayesian hierarchical models using the Markov chain Monte Carlo software WinBUGS . These are multivariate r and om effects models that allow for variation in true treatment effects across trials . We consider models where the between-trials variance is homogeneous across treatment comparisons as well as heterogeneous variance models . We also compare models with fixed ( unconstrained ) baseline study effects with models with r and om baselines drawn from a common distribution . These models are applied to an illustrative data set and posterior parameter distributions are compared . We discuss model critique and model selection , illustrating the role of Bayesian deviance analysis , and node-based model criticism . The assumptions underlying the MTC models and their parameterization are also discussed [2564802] Objectives : This double-blind trial evaluated the efficacy and safety of abatacept or infliximab vs placebo . The primary objective of this study was to evaluate the mean change from baseline in Disease Activity Score ( based on erythrocyte sedimentation rates ; DAS28 ( ESR ) ) for the abatacept vs placebo groups at day 197 . Methods : Patients with rheumatoid arthritis ( RA ) and an inadequate response to methotrexate ( MTX ) were r and omised 3:3:2 to abatacept ( ∼10 mg/kg every 4 weeks , n = 156 ) , infliximab ( 3 mg/kg every 8 weeks , n = 165 ) , or placebo ( every 4 weeks , n = 110 ) and background MTX . Safety and efficacy were assessed throughout the study . Results : Similar patient demographics and clinical characteristics were present at baseline between groups , with mean scores of ∼1.7 for HAQ-DI and 6.8 for DAS28 ( ESR ) . At 6 months , mean changes in DAS28 ( ESR ) were significantly greater for abatacept vs placebo ( –2.53 vs –1.48 , p<0.001 ) and infliximab vs placebo ( –2.25 vs –1.48 , p<0.001 ) . For abatacept vs infliximab treatment at day 365 , reductions in the DAS28 ( ESR ) were –2.88 vs –2.25 . At day 365 , the following response rates were observed for abatacept and infliximab , respectively : American College of Rheumatology ( ACR ) 20 , 72.4 and 55.8 % ; ACR 50 , 45.5 and 36.4 % ; ACR 70 , 26.3 and 20.6 % ; low disease activity score ( LDAS ) , 35.3 and 22.4 % ; DAS28-defined remission , 18.7 and 12.2 % ; good European League Against Rheumatism ( EULAR ) responses , 32.0 and 18.5 % ; and Health Assessment Question naire Disability Index ( HAQ-DI ) , 57.7 and 52.7 % . Mean changes in physical component summary ( PCS ) were 9.5 and 7.6 , and mental component summary ( MCS ) were 6.0 and 4.0 , for abatacept and infliximab , respectively . Over 1 year , adverse events ( AEs ) ( 89.1 vs 93.3 % ) , serious AEs ( SAEs ) ( 9.6 vs 18.2 % ) , serious infections ( 1.9 vs 8.5 % ) and discontinuations due to AEs ( 3.2 vs 7.3 % ) and SAEs ( 2.6 vs 3.6 % ) were lower with abatacept than infliximab . Conclusions : In this study , abatacept and infliximab ( 3 mg/kg every 8 weeks ) demonstrated similar efficacy . Overall , abatacept had a relatively more acceptable safety and tolerability profile , with fewer SAEs , serious infections , acute infusional events and discontinuations due to AEs than the infliximab group . Trial registration number : NCT00095147 [15308515] OBJECTIVES To compare the short term clinical and biological effects of intravenous ( i.v . ) pulse methylprednisolone ( MP ) and infliximab ( IFX ) in patients with severe active rheumatoid arthritis ( RA ) despite methotrexate ( MTX ) treatment . METHODS Patients with active RA despite MTX treatment were r and omly allocated to receive a single i.v . infusion of MP ( 1 g ) or three i.v . infusions of IFX ( 3 mg/kg ) on weeks 0 , 2 , and 6 . Patients were " blindly " evaluated for disease activity measures . Quality of life ( QoL ) was evaluated through the SF-36 health survey . Serum matrix metalloproteinase-3 ( MMP-3 ) titres were measured at baseline , weeks 2 and 6 . RESULTS Compared with baseline , significant improvement was noted in all activity measures , including serum C reactive protein ( CRP ) titres , in the IFX group only . At week 14 , 6/9 ( 67 % ) and 4/9 ( 44 % ) IFX patients met the ACR20 and 50 response criteria , while this was the case in only 1/12 ( 8 % ) and 0/12 ( 0 % ) MP patients , respectively ( p<0.05 ) . None of the QoL scales improved with MP treatment , whereas some did so in the IFX group . Serum MMP-3 titres significantly decreased ( 41 % drop ) at week 6 in the IFX group , while no changes were seen in patients given MP . CONCLUSION This short term r and omised comparative study demonstrates that TNF blockade is better than MP pulse therapy in a subset of patients with severe refractory RA , with improvement in not only clinical parameters of disease activity but also biological inflammatory indices , such as serum CRP and MMP-3 titres [14614165] BACKGROUND Effective new therapies are needed for rheumatoid arthritis . Current therapies target the products of activated macrophages ; however , T cells also have an important role in rheumatoid arthritis . A fusion protein -- cytotoxic T-lymphocyte-associated antigen 4-IgG1 (CTLA4Ig)--is the first in a new class of drugs known as costimulation blockers being evaluated for the treatment of rheumatoid arthritis . CTLA4Ig binds to CD80 and CD86 on antigen-presenting cells , blocking the engagement of CD28 on T cells and preventing T-cell activation . A preliminary study showed that CTLA4Ig may be effective for the treatment of rheumatoid arthritis . METHODS We r and omly assigned patients with active rheumatoid arthritis despite methotrexate therapy to receive 2 mg of CTLA4Ig per kilogram of body weight ( 105 patients ) , 10 mg of CTLA4Ig per kilogram ( 115 patients ) , or placebo ( 119 patients ) for six months . All patients also received methotrexate therapy during the study . The clinical response was assessed at six months with use of the criteria of the American College of Rheumatology ( ACR ) , which define the response according to its extent : 20 percent ( ACR 20 ) , 50 percent ( ACR 50 ) , or 70 percent ( ACR 70 ) . Additional end points included measures of the health-related quality of life . RESULTS Patients treated with 10 mg of CTLA4Ig per kilogram were more likely to have an ACR 20 than were patients who received placebo ( 60 percent vs. 35 percent , P<0.001 ) . Significantly higher rates of ACR 50 and ACR 70 responses were seen in both CTLA4Ig groups than in the placebo group . The group given 10 mg of CTLA4Ig per kilogram had clinical ly meaningful and statistically significant improvements in all eight subscales of the Medical Outcomes 36-Item Short-Form General Health Survey . CTLA4Ig was well tolerated , with an overall safety profile similar to that of placebo . CONCLUSIONS In patients with active rheumatoid arthritis who were receiving methotrexate , treatment with CTLA4Ig significantly improved the signs and symptoms of rheumatoid arthritis and the health-related quality of life . CTLA4Ig is a promising new therapy for rheumatoid arthritis [12096230] BACKGROUND It is 40 yr since the last age- and sex-specific estimates of the prevalence of rheumatoid arthritis ( RA ) for the UK were published . Since then the classification criteria for RA have been revised and there has been evidence of a fall in the incidence of RA , especially in women . OBJECTIVES To estimate the age- and sex-specific point prevalence of RA ( defined as fulfilment of a modification of the 1987 ACR classification criteria for RA on the day of assessment ) . The estimate was made in the primary care setting in Norfolk , UK . METHODS A stratified r and om sample was drawn from seven age and gender b and s. The 7050 individuals selected were mailed a screening question naire . Positive responders were invited to attend for a clinical examination . The sample was matched against the names in the Norfolk Arthritis Register ( NOAR ) , a register of incident cases of inflammatory polyarthritis which has been in existence since 1990 . RESULTS The overall response rate was 82 % . Sixty-six cases of RA were identified . Extrapolated to the population of the UK , the overall minimum prevalence of RA is 1.16 % in women and 0.44 % in men . A number of incident cases of RA previously notified to NOAR were not identified as cases in the survey because they had entered into treatment-induced remission . In addition , some cases who failed to attend for examination had significant disability . These prevalence figures are therefore an underestimate . CONCLUSIONS The prevalence of RA in women , but not in men , in the UK may have fallen since the 1950s [12528101] OBJECTIVE To evaluate the efficacy and safety of adalimumab ( D2E7 ) , a fully human monoclonal tumor necrosis factor alpha antibody , in combination with methotrexate ( MTX ) in patients with active rheumatoid arthritis ( RA ) despite treatment with MTX . METHODS In a 24-week , r and omized , double-blind , placebo-controlled study , 271 patients with active RA were r and omly assigned to receive injections of adalimumab ( 20 mg , 40 mg , or 80 mg subcutaneously ) or placebo every other week while continuing to take their long-term stable dosage of MTX . The primary efficacy end point was the American College of Rheumatology criteria for 20 % improvement ( ACR20 ) at 24 weeks . RESULTS An ACR20 response at week 24 was achieved by a significantly greater proportion of patients in the 20-mg , 40-mg , and 80-mg adalimumab plus MTX groups ( 47.8 % , 67.2 % , and 65.8 % , respectively ) than in the placebo plus MTX group ( 14.5 % ) ( P < 0.001 ) . ACR50 response rates with the 20-mg , 40-mg , and 80-mg adalimumab dosages ( 31.9 % , 55.2 % , and 42.5 % , respectively ) were significantly greater than that with placebo ( 8.1 % ) ( P = 0.003 , P < 0.001 , and P < 0.001 , respectively ) . The 40-mg and 80-mg doses of adalimumab were associated with an ACR70 response ( 26.9 % and 19.2 % , respectively ) that was statistically significantly greater than that with placebo ( 4.8 % ) ( P < 0.001 and P = 0.020 ) . Responses were rapid , with the greatest proportion of adalimumab-treated patients achieving an ACR20 response at the first scheduled visit ( week 1 ) . Adalimumab was safe and well tolerated ; comparable numbers of adalimumab-treated patients and placebo-treated patients reported adverse events . CONCLUSION The addition of adalimumab at a dosage of 20 mg , 40 mg , or 80 mg administered subcutaneously every other week to long-term MTX therapy in patients with active RA provided significant , rapid , and sustained improvement in disease activity over 24 weeks compared with MTX plus placebo [16606651] Objective : To compare the efficacy and safety of etanercept and sulfasalazine , alone and in combination , in patients with active rheumatoid arthritis despite sulfasalazine treatment . Methods : A double-blind , r and omised study in adult patients with active rheumatoid arthritis despite stable sulfasalazine ( 2–3 g/day ) treatment . The primary end point was a 20 % response by the American College of Rheumatology ( ACR ) criteria at 24 weeks . Results : At baseline , the three treatment groups ( sulfasalazine , n = 50 ; etanercept , n = 103 ; etanercept and sulfasalazine , n = 101 ) were comparable for demographic variables and disease activity . Lack of efficacy was the primary reason for discontinuation ( sulfasalazine , n = 12 ; etanercept , n = 1 ; etanercept and sulfasalazine , n = 4 ; p<0.001 ) . Significantly more patients receiving etanercept , alone or in combination ( 74 % for each ) , achieved ACR 20 responses at 24 weeks than those receiving sulfasalazine ( 28 % ; p<0.01 ) . Similarly , more patients in the etanercept groups achieved ACR 50 and ACR 70 responses than those in the sulfasalazine group ( p<0.01 ) . In the groups receiving etanercept , significant differences in the ACR core components were observed by week 2 compared with those receiving sulfasalazine alone ( p<0.01 ) . The incidences of several common adverse events ( headache , nausea , asthenia ) were lower with etanercept alone than with the combination ( p<0.05 ) , but infections and injection site reactions were higher with etanercept alone ( p<0.05 ) . The safety profiles of both etanercept treatment groups were comparable with previous experience of etanercept . Conclusions : For all efficacy variables assessed , etanercept alone or in combination with sulfasalazine result ed in substantial and similar improvement in disease activity from baseline to week 24 compared with sulfasalazine alone in patients with active rheumatoid arthritis despite their sulfasalazine treatment . All three treatments were generally well tolerated [20574649] The superiority of the combination therapy of methotrexate ( MTX ) and anti-tumor necrosis factor ( TNF ) biological agents over anti-TNF monotherapy in MTX-naïve patients with rheumatoid arthritis ( RA ) has been demonstrated . We investigated the efficacy and safety of continuation versus discontinuation of MTX at the commencement of etanercept ( ETN ) in patients with active RA despite MTX therapy . In total , 151 patients with active RA despite treatment with MTX were r and omized to either ETN 25 mg twice a week and MTX 6–8 mg/week ( the E + M group ) or ETN alone ( the E group ) . Co- primary endpoints included the European League Against Rheumatism ( EULAR ) good response rate and the American College of Rheumatology ( ACR ) 50 response rate at week 24 . Demographic and clinical features between groups at baseline were similar . The EULAR good response rates were significantly higher in the E + M group ( 52 % ) than in the E group ( 33 % ) at week 24 ( p = 0.0001 ) . Although the ACR50 response rate , one of the co- primary endpoints , and the ACR70 response rate at week 24 were not significantly greater in the E + M group ( 64 and 38 % , respectively ) than in the E group ( 48 and 26 % , respectively ) , the ACR20 response rate was significantly greater in the E + M group ( 90 % ) than in the E group ( 64 % ; p = 0.0002 ) . Safety profiles were similar for the groups . Thus , MTX should be continued at the commencement of ETN therapy , even in RA patients who show an inappropriate response to MTX [2674555] Background : Tumour necrosis factor α ( TNFα ) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis ( RA ) . Treatment with TNFα inhibitors reduces disease activity and improves outcomes for patients with RA . This study evaluated the efficacy and safety of certolizumab pegol 400 mg , a novel , poly-(ethylene glycol ) (PEG)ylated , Fc-free TNFα inhibitor , as monotherapy in patients with active RA . Methods : In this 24-week , multicentre , r and omised , double-blind , placebo-controlled study , 220 patients previously failing ⩾1 disease-modifying antirheumatic drug ( DMARD ) were r and omised 1:1 to receive subcutaneous certolizumab pegol 400 mg ( n = 111 ) or placebo ( n = 109 ) every 4 weeks . The primary endpoint was 20 % improvement according to the American College of Rheumatology criteria ( ACR20 ) at week 24 . Secondary endpoints included ACR50/70 response , ACR component scores , 28-joint Disease Activity Score Erythrocyte Sedimentation Rate 3 ( DAS28(ESR)3 ) , patient-reported outcomes ( including physical function , health-related quality of life ( HRQoL ) , pain and fatigue ) and safety . Results : At week 24 , the ACR20 response rates were 45.5 % for certolizumab pegol 400 mg every 4 weeks vs 9.3 % for placebo ( p<0.001 ) . Differences for certolizumab pegol vs placebo in the ACR20 response were statistically significant as early as week 1 through to week 24 ( p<0.001 ) . Significant improvements in ACR50 , ACR components , DAS28(ESR)3 and all patient-reported outcomes were also observed early with certolizumab pegol and were sustained throughout the study . Most adverse events were mild or moderate and no deaths or cases of tuberculosis were reported . Conclusions : Treatment with certolizumab pegol 400 mg monotherapy every 4 weeks effectively reduced the signs and symptoms of active RA in patients previously failing ⩾1 DMARD compared with placebo , and demonstrated an acceptable safety profile . Trial registration number : NCT00548834 [2638601] We investigated the clinical efficacy and safety of tocilizumab ( a humanized anti-IL-6 receptor antibody ) monotherapy in active rheumatoid arthritis ( RA ) patients with an inadequate response to low dose methotrexate ( MTX ) . In a multicenter , double-blind , r and omized , controlled trial , 125 patients were allocated to receive either tocilizumab 8 mg/kg every 4 weeks plus MTX placebo ( tocilizumab group ) or tocilizumab placebo plus MTX 8 mg/week ( control group ) for 24 weeks . The clinical responses were measured using the American College of Rheumatology ( ACR ) criteria and the Disease Activity Score in 28 joints . Serum vascular endothelial growth factor ( VEGF ) levels were also monitored . At week 24 , 25.0 % in the control group and 80.3 % in the tocilizumab group achieved ACR20 response . The tocilizumab group showed superior ACR response criteria over control at all time points . Additionally , serum VEGF levels were significantly decreased by tocilizumab treatment . The overall incidences of adverse events ( AEs ) were 72 and 92 % ( serious AEs : 4.7 and 6.6 % ; serious infections : 1.6 and 3.3 % ) in the control and the tocilizumab groups , respectively . All serious adverse events improved by adequate treatment . Tocilizumab monotherapy was well tolerated and provided an excellent clinical benefit in active RA patients with an inadequate response to low dose MTX [16947782] OBJECTIVE To establish the safety and efficacy of repeat infusions of tocilizumab ( previously known as MRA ) , a humanized anti-interleukin-6 ( IL-6 ) receptor antibody , alone and in combination with methotrexate ( MTX ) , for the treatment of rheumatoid arthritis ( RA ) . METHODS The study group comprised 359 patients with active RA in whom the response to MTX was inadequate . During a stabilization period , these patients received their current dose of MTX for at least 4 weeks . Following stabilization , they were r and omized to 1 of 7 treatment arms , as follows : tocilizumab at doses of 2 mg/kg , 4 mg/kg , or 8 mg/kg either as monotherapy or in combination with MTX , or MTX plus placebo . RESULTS A 20 % response ( improvement ) according to the American College of Rheumatology criteria ( ACR20 response ) was achieved by 61 % and 63 % of patients receiving 4 mg/kg and 8 mg/kg of tocilizumab as monotherapy , respectively , and by 63 % and 74 % of patients receiving those doses of tocilizumab plus MTX , respectively , compared with 41 % of patients receiving placebo plus MTX . Statistically significant ACR50 and ACR70 responses were observed in patients receiving combination therapy with either 4 mg/kg or 8 mg/kg of tocilizumab plus MTX ( P < 0.05 ) . A dose-related reduction in the Disease Activity Score in 28 joints was observed from week 4 onward , in all patients except those receiving monotherapy with 2 mg/kg of tocilizumab . In the majority of patients who received 8 mg/kg of tocilizumab , the C-reactive protein level/erythrocyte sedimentation rate normalized , while placebo plus MTX had little effect on these laboratory parameters . Tocilizumab was mostly well tolerated , with a safety profile similar to that of other biologic and immunosuppressive therapies . Alanine transaminase and aspartate transaminase levels followed a sawtooth pattern ( rising and falling between infusions ) . There were moderate but reversible increases in the nonfasting total cholesterol and triglyceride levels and reversible reductions in the high-density lipoprotein cholesterol and neutrophil levels . There were 2 cases of sepsis , both of which occurred in patients who were receiving combination therapy with 8 mg/kg of tocilizumab plus MTX . CONCLUSION These results indicate that targeted blockade of IL-6 signaling is a highly efficacious and promising means of decreasing disease activity in RA [18975346] OBJECTIVE To evaluate the efficacy and safety of 2 dosage regimens of lyophilized certolizumab pegol ( a novel PEGylated anti-tumor necrosis factor agent ) as adjunctive therapy to methotrexate ( MTX ) in patients with active rheumatoid arthritis ( RA ) with an inadequate response to MTX therapy alone . METHODS In this 52-week , phase III , multicenter , r and omized , double-blind , placebo-controlled , parallel-group trial , 982 patients were r and omized 2:2:1 to receive treatment with subcutaneous certolizumab pegol at an initial dosage of 400 mg given at weeks 0 , 2 , and 4 , with a subsequent dosage of 200 mg or 400 mg given every 2 weeks , plus MTX , or placebo plus MTX . Co- primary end points were the response rate at week 24 according to the American College of Rheumatology 20 % criteria for improvement ( ACR20 ) and the mean change from baseline in the modified total Sharp score at week 52 . RESULTS At week 24 , ACR20 response rates using nonresponder imputation for the certolizumab pegol 200-mg and 400-mg groups were 58.8 % and 60.8 % , respectively , as compared with 13.6 % for the placebo group . Differences in ACR20 response rates versus placebo were significant at week 1 and were sustained to week 52 ( P < 0.001 ) . At week 52 , mean radiographic progression from baseline was reduced in patients treated with certolizumab pegol 200 mg ( 0.4 Sharp units ) or 400 mg ( 0.2 Sharp units ) as compared with that in placebo-treated patients ( 2.8 Sharp units ) ( P < 0.001 by rank analysis ) . Improvements in all ACR core set of disease activity measures , including physical function , were observed by week 1 with both certolizumab pegol dosage regimens . Most adverse events were mild or moderate . CONCLUSION Treatment with certolizumab pegol 200 or 400 mg plus MTX result ed in a rapid and sustained reduction in RA signs and symptoms , inhibited the progression of structural joint damage , and improved physical function as compared with placebo plus MTX treatment in RA patients with an incomplete response to MTX [15188351] OBJECTIVE Interleukin-6 ( IL-6 ) is a pleiotropic cytokine that regulates the immune response , inflammation , and hematopoiesis . Overproduction of IL-6 plays pathologic roles in rheumatoid arthritis ( RA ) , and the blockade of IL-6 may be therapeutically effective for the disease . This study was undertaken to evaluate the safety and efficacy of a humanized anti-IL-6 receptor antibody , MRA , in patients with RA . METHODS In a multicenter , double-blind , placebo-controlled trial , 164 patients with refractory RA were r and omized to receive either MRA ( 4 mg/kg body weight or 8 mg/kg body weight ) or placebo . MRA was administered intravenously every 4 weeks for a total of 3 months . The clinical responses were measured using the American College of Rheumatology ( ACR ) criteria . RESULTS Treatment with MRA reduced disease activity in a dose-dependent manner . At 3 months , 78 % of patients in the 8-mg group , 57 % in the 4-mg group , and 11 % in the placebo group achieved at least a 20 % improvement in disease activity according to the ACR criteria ( an ACR20 response ) ( P < 0.001 for 8-mg group versus placebo ) . Forty percent of patients in the 8-mg group and 1.9 % in the placebo group achieved an ACR50 response ( P < 0.001 ) . The overall incidences of adverse events were 56 % , 59 % , and 51 % in the placebo , 4-mg , and 8-mg groups , respectively , and the adverse events were not dose dependent . A blood cholesterol increase was observed in 44.0 % of the patients . Liver function disorders and decreases in white blood cell counts were also observed , but these were mild and transient . There was no increase in antinuclear antibodies or anti-DNA antibodies . Anti-MRA antibodies were detected in 2 patients . CONCLUSION Treatment with MRA was generally well tolerated and significantly reduced the disease activity of RA [15001324] BACKGROUND Etanercept and methotrexate are effective in the treatment of rheumatoid arthritis but no data exist on concurrent initiation or use of the combination compared with either drug alone . We aim ed to assess combination treatment with etanercept and methotrexate versus the monotherapies in patients with rheumatoid arthritis . METHODS In a double-blind , r and omised , clinical efficacy , safety , and radiographic study , 686 patients with active rheumatoid arthritis were r and omly allocated to treatment with etanercept 25 mg ( subcutaneously twice a week ) , oral methotrexate ( up to 20 mg every week ) , or the combination . Clinical response was assessed by criteria of the American College of Rheumatology ( ACR ) . The primary efficacy endpoint was the numeric index of the ACR response ( ACR-N ) area under the curve ( AUC ) over the first 24 weeks . The primary radiographic endpoint was change from baseline to week 52 in total joint damage and was assessed with the modified Sharp score . Analysis was by intention to treat . FINDINGS Four patients did not receive any drug ; thus 682 were studied . ACR-N AUC at 24 weeks was greater for the combination group compared with etanercept alone and methotrexate alone ( 18.3%-years [ 95 % CI 17.1 - 19.6 ] vs 14.7%-years [ 13.5 - 16.0 ] , p<0.0001 , and 12.2%-years [ 11.0 - 13.4 ] , p<0.0001 ; respectively ) . The mean difference in ACR-N AUC between combination and methotrexate alone was 6.1 ( 95 % CI 4.5 - 7.8 , p<0.0001 ) and between etanercept and methotrexate was 2.5 ( 0.8 - 4.2 , p=0.0034 ) . The combination was more efficacious than methotrexate or etanercept alone in retardation of joint damage ( mean total Sharp score -0.54 [ 95 % CI -1.00 to -0.07 ] vs 2.80 [ 1.08 to 4.51 ] , p<0.0001 , and 0.52 [ -0.10 to 1.15 ] , p=0.0006 ; respectively ) . The mean difference in total Sharp score between combination and methotrexate alone was -3.34 ( 95 % CI -4.86 to -1.81 , p<0.0001 ) and between etanercept and methotrexate was -27 ( -3.81 to -0.74 , p=0.0469 ) . The number of patients reporting infections or adverse events was similar in all groups . INTERPRETATION The combination of etanercept and methotrexate was significantly better in reduction of disease activity , improvement of functional disability , and retardation of radiographic progression compared with methotrexate or etanercept alone . These findings bring us closer to achievement of remission and repair of structural damage in rheumatoid arthritis [14872476] OBJECTIVE To evaluate the safety , efficacy , and pharmacokinetics of 50 mg etanercept administered subcutaneously once weekly in adult patients with active rheumatoid arthritis ( RA ) . METHODS Four hundred twenty RA patients were r and omized to receive , in a blinded manner , the study drug for up to 16 weeks : 214 patients received 50 mg etanercept once weekly , 153 received 25 mg etanercept twice weekly , and 53 received placebo for 8 weeks followed by 25 mg etanercept twice weekly for 8 weeks . Efficacy and safety were assessed at weeks 8 and 16 . Pharmacokinetic analyses were performed on serum sample s from patients at selected study sites . The primary efficacy end point was achievement of the American College of Rheumatology ( ACR ) 20 % improvement criteria ( ACR20 response ) at week 8 . RESULTS An ACR20 response was achieved at week 8 by 50 % of the patients receiving 50 mg etanercept once weekly , by 49 % of the patients receiving 25 mg etanercept twice weekly , and by 19 % of the patients in the placebo group ( P < /= 0.0001 for each etanercept group versus placebo ) . Similarly , achievement of the ACR50 response was attained by 18 % of patients in each of the 2 etanercept groups , compared with 6 % of patients in the placebo group ( P < 0.03 for each comparison ) . Pharmacokinetics of the 2 etanercept regimens were similar at steady state . No clinical ly significant differences in efficacy or safety were observed between the 2 etanercept groups . CONCLUSION Safety , efficacy , and pharmacokinetics were comparable between the 2 etanercept dosing regimens . Thus , comparable clinical outcomes are to be expected when patients are treated with etanercept administered either as 50 mg once weekly or as 25 mg twice weekly [10075615] BACKGROUND In a phase II study , etanercept ( recombinant human tumor necrosis factor receptor [p75]:Fc fusion protein ) safely produced rapid , dose-dependent improvement in rheumatoid arthritis over 3 months . OBJECTIVE To confirm the benefit of etanercept therapy of longer duration and simplified dosing in patients with rheumatoid arthritis . DESIGN R and omized , double-blind , placebo-controlled trial with blinded joint assessors . SETTING 13 North American centers . PATIENTS 234 patients with active rheumatoid arthritis who had an inadequate response to disease-modifying antirheumatic drugs . INTERVENTION Twice-weekly subcutaneous injections of etanercept , 10 or 25 mg , or placebo for 6 months . MEASUREMENTS The primary end points were 20 % and 50 % improvement in disease activity according to American College of Rheumatology ( ACR ) responses at 3 and 6 months . Other end points were 70 % ACR responses at 3 and 6 months and other measures of disease activity at 3 and 6 months . RESULTS Etanercept significantly reduced disease activity in a dose-related fashion . At 3 months , 62 % of the patients receiving 25 mg of etanercept and 23 % of the placebo recipients achieved 20 % ACR response ( P < 0.001 ) . At 6 months , 59 % of the 25-mg group and 11 % of the placebo group achieved a 20 % ACR response ( P < 0.001 ) ; 40 % and 5 % , respectively , achieved a 50 % ACR response ( P < 0.01 ) . The respective mean percentage reduction in the number of tender and swollen joints at 6 months was 56 % and 47 % in the 25-mg group and 6 % and -7 % in the placebo group ( P < 0.05 ) . Significantly more etanercept recipients achieved a 70 % ACR response , minimal disease status ( 0 to 5 affected joints ) , and improved quality of life . Etanercept was well tolerated , with no dose-limiting toxic effects . CONCLUSIONS Etanercept can safely provide rapid , significant , and sustained benefit in patients with active rheumatoid arthritis [16572442] OBJECTIVE To assess the risk of serious infections following 22 weeks of infliximab therapy , and to further characterize the safety profile of infliximab in combination with background treatments during 1 year in patients with rheumatoid arthritis ( RA ) with various comorbidities . METHODS Patients with active RA despite receiving methotrexate ( MTX ) were r and omly assigned to receive infusions of placebo ( group 1 , n=363 ) , 3 mg/kg infliximab ( group 2 , n=360 ) , or 10 mg/kg infliximab ( group 3 , n=361 ) at weeks 0 , 2 , 6 , and 14 . At week 22 , patients in placebo group 1 began receiving 3 mg/kg infliximab , and patients in group 3 continued to receive an infliximab dose of 10 mg/kg . Patients in group 2 who failed to meet predefined response criteria received increasing doses of infliximab in increments of 1.5 mg/kg . RESULTS At week 22 , the relative risk of developing serious infections in groups 2 and 3 , compared with group 1 , was 1.0 ( 95 % confidence interval [ 95 % CI ] 0.3 - 3.1 , P=0.995 ) and 3.1 ( 95 % CI 1.2 - 7.9 , P=0.013 ) , respectively . The incidence of serious adverse events was 7.8 % in groups 2 and 3 compared with 7.5 % in group 1 . From week 22 to week 54 , 11.8 % , 9.9 % , and 10.3 % of patients in groups 1 , 2 , and 3 , respectively , reported occurrences of serious adverse events . Through week 54 , 1 patient in group 1 , 2 patients in group 2 , and 4 patients in group 3 developed active tuberculosis . CONCLUSION The risk of serious infections in patients receiving the approved infliximab dose of 3 mg/kg plus MTX was similar to that in patients receiving MTX alone . Patients receiving the unapproved induction regimen of 10 mg/kg infliximab plus MTX followed by a 10 mg/kg maintenance regimen had an increased risk of serious infections through week 22 [16464988] Objective : To evaluate the efficacy and safety of etanercept ( ETN ) monotherapy compared with combination ETN and methotrexate ( MTX ) treatment in patients with rheumatoid arthritis who had an inadequate response to MTX monotherapy . ( The response was defined by the presence of Disease Activity Score-28 joint count ( DAS28 ) ⩾3.2 or a combination of ⩾5 swollen joints , ⩾5 painful joints and erythrocyte sedimentation rate ⩾10 mm/h . ) Methods : Patients with active rheumatoid arthritis taking MTX ⩾12.5 mg/week for ⩾3 months were included in this 16 week , r and omised , open-label study . Patients were r and omly assigned to either ETN ( 25 mg subcutaneous injection twice weekly ) added to the baseline dose of MTX or ETN monotherapy . Results : 315 patients were r and omised to ETN ( n = 160 ) or ETN plus MTX ( n = 155 ) . The primary end point , DAS28 ( 4 ) improvement of > 1.2 units , was achieved by 72.8 % and 75.2 % of patients treated with ETN and those treated with ETN plus MTX , respectively , with no significant difference ( p = 0.658 ) between the two groups . The European League Against Rheumatism response criteria of good or moderate response was attained by 80.0 % of patients in the ETN group and by 82.4 % of patients in the ETN plus MTX group . American College of Rheumatology 20 % , 50 % and 70 % response rates achieved by both groups were also similar : 71.0 % v 67.1 % , 41.9 % v 40.1 % and 17.4 % v 18.4 % , respectively . The rates of adverse and serious adverse events were similar between the treatment groups . Conclusion : Both the addition of ETN to MTX and the substitution of ETN for MTX in patients with rheumatoid arthritis who had an inadequate response to MTX result ed in substantial improvements in clinical signs and symptoms and were generally well-tolerated treatment strategies for improving clinical signs and symptoms of rheumatoid arthritis [16395748] OBJECTIVE A placebo controlled , double-blind trial ( DBT ) was conducted for Japanese patients with active rheumatoid arthritis ( RA ) despite treatment with low dose methotrexate ( MTX ) to evaluate the efficacy and safety of infliximab . Extended treatment with infliximab was conducted in an open-label trial ( OLT ) . METHODS In the DBT , 147 patients were r and omly assigned and treated with a placebo or 3 mg/kg or 10 mg/kg infliximab at Weeks 0 , 2 and 6 , combined with MTX . In the OLT , 129 patients from the DBT received 3 mg/kg infliximab every 8 weeks . RESULTS The mean dose of MTX was 7.2 + /- 2.0 mg/week . Significantly more patients receiving 3 mg/kg ( 61.2 % ) and 10 mg/kg (52.9%)infliximab achieved a 20 % improvement according to the American College of Rheumatology ( ACR ) criteria at Week 14 , compared to placebo ( 23.4 % ) ( p < 0.001 ) . There was no significant difference in incidence of adverse events among the treatment groups . In patients receiving infliximab in the DBT , 11.6 % of patients with serum infliximab just before the OLT developed antibodies to infliximab ( ATI ) in the OLT , whereas 62.2 % of patients without serum infliximab did . In patients receiving placebo in the DBT , 43.9 % developed ATI . CONCLUSION The efficacy and safety of infliximab combined with low dose MTX were similar to those of the ATTRACT study . The data from the DBT and OLT also supported the importance of an induction treatment of infliximab , followed by a maintenance treatment without a long interval , giving stable serum concentrations in order to prevent formation of ATI [9219699] BACKGROUND Tumor necrosis factor ( TNF ) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis , and antagonism of TNF may reduce the activity of the disease . This study evaluated the safety and efficacy of a novel TNF antagonist - a recombinant fusion protein that consists of the soluble TNF receptor ( p75 ) linked to the Fc portion of human IgG1 ( TNFR : Fc ) . METHODS In this multicenter , double-blind trial , we r and omly assigned 180 patients with refractory rheumatoid arthritis to receive subcutaneous injections of placebo or one of three doses of TNFR : Fc ( 0.25 , 2 , or 16 mg per square meter of body-surface area ) twice weekly for three months . The clinical response was measured by changes in composite symptoms of arthritis defined according to American College of Rheumatology criteria . RESULTS Treatment with TNFR : Fc led to significant reductions in disease activity , and the therapeutic effects of TNFR : Fc were dose-related . At three months , 75 percent of the patients in the group assigned to 16 mg of TNFR : Fc per square meter had improvement of 20 percent or more in symptoms , as compared with 14 percent in the placebo group ( P<0.001 ) . In the group assigned to 16 mg per square meter , the mean percent reduction in the number of tender or swollen joints at three months was 61 percent , as compared with 25 percent in the placebo group ( P<0.001 ) . The most common adverse events were mild injection-site reactions and mild upper respiratory tract symptoms . There were no dose-limiting toxic effects , and no antibodies to TNFR : Fc were detected in serum sample s. CONCLUSIONS In this three-month trial TNFR : Fc was safe , well tolerated , and associated with improvement in the inflammatory symptoms of rheumatoid arthritis [15146410] OBJECTIVE To determine the potential for additive or synergistic effects of combination therapy with the selective anti-tumor necrosis factor alpha agent etanercept and the anti-interleukin-1 agent anakinra . METHODS Two hundred forty-four patients in whom rheumatoid arthritis ( RA ) was active despite methotrexate therapy were treated with subcutaneous etanercept only ( 25 mg twice weekly ) , full-dosage etanercept ( 25 mg twice weekly ) plus anakinra ( 100 mg/day ) , or half-dosage etanercept ( 25 mg once weekly ) plus anakinra ( 100 mg/day ) for 6 months in a double-blind study at 41 centers in the US . Patients had never previously received anticytokine therapy . Patient response was measured with the American College of Rheumatology ( ACR ) core set criteria , a health-related quality -of-life question naire , and the Disease Activity Score . Safety was assessed by the number of adverse events and clinical laboratory values . Plasma concentrations of both agents and antibody formation against both agents were also assessed . RESULTS Combination therapy with etanercept plus anakinra provided no treatment benefit over etanercept alone , regardless of the regimen , but was associated with an increased safety risk . Thirty-one percent of the patients treated with full-dosage etanercept plus anakinra achieved an ACR 50 % response , compared with 41 % of the patients treated with etanercept only . This result was not statistically significant ( P = 0.914 ) . The incidence of serious infections ( 0 % for etanercept alone , 3.7 - 7.4 % for combination therapy ) , injection-site reactions , and neutropenia was increased with combination therapy . Combination therapy had no effect on the pharmacokinetics or immunogenicity of either agent . CONCLUSION Combination therapy with etanercept and anakinra provides no added benefit and an increased risk compared with etanercept alone and is not recommended for the treatment of patients with RA [15082480] OBJECTIVE To evaluate the efficacy and safety of monotherapy with adalimumab in patients with RA for whom previous DMARD treatment has failed . METHODS In a 26 week , double blind , placebo controlled , phase III trial , 544 patients with RA were r and omised to monotherapy with adalimumab 20 mg every other week , 20 mg weekly , 40 mg every other week , 40 mg weekly , or placebo . The primary efficacy end point was > or = 20 % improvement in the ACR core criteria ( ACR20 response ) . Secondary efficacy end points included ACR50 , ACR70 , EULAR responses , and the Disability Index of the Health Assessment Question naire ( HAQ DI ) . RESULTS After 26 weeks , patients treated with adalimumab 20 mg every other week , 20 mg weekly , 40 mg every other week , and 40 mg weekly had significantly better response rates than those treated with placebo : ACR20 ( 35.8 % , 39.3 % , 46.0 % , 53.4 % , respectively v 19.1 % ; p < or = 0.01 ) ; ACR50 ( 18.9 % , 20.5 % , 22.1 % , 35.0 % v 8.2 % ; p < or = 0.05 ) ; ACR70 ( 8.5 % , 9.8 % , 12.4 % , 18.4 % v 1.8 % ; p < or = 0.05 ) . Moderate EULAR response rates were significantly greater with adalimumab than with placebo ( 41.5 % , 48.2 % , 55.8 % , 63.1 % v 26.4 % ; p < or = 0.05 ) . Patients treated with adalimumab achieved better improvements in mean HAQ DI than those receiving placebo ( -0.29 , -0.39 , -0.38 , -0.49 v -0.07 ; p < or = 0.01 ) . No significant differences were found between adalimumab and placebo treated patients for serious adverse events , serious infections , or malignancies . Injection site reaction occurred in 10.6 % and 0.9 % of adalimumab and placebo treated patients , respectively ( p < or = 0.05 ) . CONCLUSION Among patients with RA for whom previous DMARD treatment had failed , adalimumab monotherapy achieved significant , rapid , and sustained improvements in disease activity and improved physical function and was safe and well tolerated [16014203] OBJECTIVES To survey the frequency of use of indirect comparisons in systematic review s and evaluate the methods used in their analysis and interpretation . Also to identify alternative statistical approaches for the analysis of indirect comparisons , to assess the properties of different statistical methods used for performing indirect comparisons and to compare direct and indirect estimates of the same effects within review s. DATA SOURCES Electronic data bases . REVIEW METHODS The Data base of Abstract s of Review s of Effects ( DARE ) was search ed for systematic review s involving meta- analysis of r and omised controlled trials ( RCTs ) that reported both direct and indirect comparisons , or indirect comparisons alone . A systematic review of MEDLINE and other data bases was carried out to identify published methods for analysing indirect comparisons . Study design s were created using data from the International Stroke Trial . R and om sample s of patients receiving aspirin , heparin or placebo in 16 centres were used to create meta-analyses , with half of the trials comparing aspirin and placebo and half heparin and placebo . Methods for indirect comparisons were used to estimate the contrast between aspirin and heparin . The whole process was repeated 1000 times and the results were compared with direct comparisons and also theoretical results . Further detailed case studies comparing the results from both direct and indirect comparisons of the same effects were undertaken . RESULTS Of the review s identified through DARE , 31/327 ( 9.5 % ) included indirect comparisons . A further five review s including indirect comparisons were identified through electronic search ing . Few review s carried out a formal analysis and some based analysis on the naive addition of data from the treatment arms of interest . Few method ological papers were identified . Some valid approaches for aggregate data that could be applied using st and ard software were found : the adjusted indirect comparison , meta-regression and , for binary data only , multiple logistic regression ( fixed effect models only ) . Simulation studies showed that the naive method is liable to bias and also produces over-precise answers . Several methods provide correct answers if strong but unverifiable assumptions are fulfilled . Four times as many similarly sized trials are needed for the indirect approach to have the same power as directly r and omised comparisons . Detailed case studies comparing direct and indirect comparisons of the same effect show considerable statistical discrepancies , but the direction of such discrepancy is unpredictable . CONCLUSIONS Direct evidence from good- quality RCTs should be used wherever possible . Without this evidence , it may be necessary to look for indirect comparisons from RCTs . However , the results may be susceptible to bias . When making indirect comparisons within a systematic review , an adjusted indirect comparison method should ideally be used employing the r and om effects model . If both direct and indirect comparisons are possible within a review , it is recommended that these be done separately before considering whether to pool data . There is a need to evaluate methods for the analysis of indirect comparisons for continuous data and for empirical research into how different methods of indirect comparison perform in cases where there is a large treatment effect . Further study is needed into when it is appropriate to look at indirect comparisons and when to combine both direct and indirect comparisons . Research into how evidence from indirect comparisons compares to that from non-r and omised studies may also be warranted . Investigations using individual patient data from a meta- analysis of several RCTs using different protocol s and an evaluation of the impact of choosing different binary effect measures for the inverse variance method would also be useful [19369178] BACKGROUND / PURPOSE Adalimumab is a fully humanized monoclonal antibody that blocks tumor necrosis factor (TNF)-alpha , which is effective in the treatment of patients with rheumatoid arthritis ( RA ) . The purpose of this study was to compare the efficacy and safety of adalimumab plus methotrexate ( MTX ) and MTX alone in Taiwanese patients with active RA . METHODS Forty-seven patients with active RA who were maintained on MTX therapy at a stable dose of 10 - 15 mg/week for 4 weeks were r and omized blindly to receive adalimumab 40 mg ( n = 35 ) or placebo ( n = 12 ) by subcutaneous injection every other week over a period of 12 weeks . The primary endpoint was a reduction in tender and swollen joint counts of 20 % ( ACR20 ) , 50 % ( ACR50 ) and 70 % ( ACR70 ) , as determined by the American College of Rheumatology criteria in week 12 . The occurrence of treatment-emergent adverse events ( TEAEs ) was the primary safety variable . RESULTS Addition of adalimumab to MTX result ed in a significant reduction in the number of swollen joints ( 12.6 vs. 5.6 ; p = 0.011 ) , patients ' global assessment of disease activity ( 18.0 vs. 4.8 ; p = 0.040 ) , pain visual analog scale ( 18.3 vs. 1.3 ; p = 0.015 ) , and disability indices of the Health Assessment Question naire ( 0.6 vs. 0.2 ; p = 0.031 ) , compared with MTX alone after 12 weeks of therapy . Overall improvement in disease activity was assessed by ACR20 ( 54.3 % vs. 33.3 % ) , ACR50 ( 34.3 % vs. 16.7 % ) and ACR70 ( 14.3 % vs. 0 % ) , and all favored the adalimumab plus MTX group . TEAEs were comparable between the treatment groups , except for a slightly higher incidence of severe infection in the adalimumab plus MTX group . CONCLUSION Adalimumab in combination with MTX is well tolerated and provides significantly more clinical benefits than MTX alone in Taiwanese patients with active RA [16785475] Context Abatacept , an agent that selectively modulates the co-stimulatory signal required for T-cell activation , may benefit some patients with rheumatoid arthritis . Contribution This 1-year , r and omized , double-blind trial compared once-monthly infusions of abatacept with placebo in 652 patients with symptomatic rheumatoid arthritis despite ongoing methotrexate treatment . Compared with placebo recipients , patients who received abatacept more often had improved physical function , more frequently met st and ard response criteria , and less often had radiographic progression of joint damage . They also had serious infections ( 2.5 % vs. 0.9 % ) and infusion reactions more often . Implication s Adding abatacept can reduce disease activity in patients with rheumatoid arthritis and an inadequate response to methotrexate . The Editors Rheumatoid arthritis is characterized by synovial membrane hyperplasia and inflammatory cell infiltrate , including activated T cells ( 1 ) . T cells contribute to the initiation and perpetuation of rheumatoid arthritis immunopathology , leading to inflammation and , ultimately , joint destruction . Activated T cells proliferate and induce monocytes , macrophages , and synovial fibroblasts to produce proinflammatory cytokines , such as tumor necrosis factor- , interleukin-1 , and interleukin-6 ( 1 ) , and stimulate osteoclastogenesis and matrix metalloproteinase secretion ( 2 ) , as well as immunoglobulin production by B cells ( 3 ) . The central role of activated T cells in rheumatoid arthritis immunopathology makes T-cell activation a rational therapeutic target . T cells require 2 signals for full activation : an antigen-specific signal ( signal 1 ) and a co-stimulatory signal ( signal 2 ) ( 4 ) . One of the best-characterized co-stimulatory pathways is the engagement of CD80 or CD86 on antigen-presenting cells with CD28 on T cells ( 5 ) . In the normal immune response , endogenous cytotoxic T-lymphocyte antigen-4 ( CTLA-4 ) downregulates CD28-mediated T-cell activation by binding to CD80 or CD86 with higher avidity than CD28 ( 6 ) . Abatacept is a soluble , recombinant , fully human fusion protein , comprising the extracellular domain of CTLA-4 and the Fc portion of IgG1 , modified to prevent complement fixation . Abatacept is the first in a new class of agents for treating rheumatoid arthritis that selectively modulate the co-stimulatory signal required for full T-cell activation . A phase IIa study of patients with rheumatoid arthritis and an inadequate response to disease-modifying antirheumatic drugs showed the efficacy of abatacept as monotherapy ( 7 ) . In a phase IIb study of abatacept plus methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate , signs and symptoms of rheumatoid arthritis , physical function , and health-related quality of life statistically significantly improved over 1 year ( 8 , 9 ) . We present findings from the phase III , 1-year Abatacept in Inadequate Responders to Methotrexate ( AIM ) trial , which was design ed to further evaluate the safety and clinical efficacy of abatacept plus methotrexate and to assess the effects of abatacept on the radiographic progression of structural damage . Methods The institutional review boards or independent ethics committees approved a common clinical protocol for each site , and we performed the study in accordance with the ethical principles of the Declaration of Helsinki . All patients provided written informed consent to the study protocol before r and omization . Patients Eligible patients were at least 18 years of age , had had rheumatoid arthritis for at least 1 year , and met the American Rheumatism Association criteria for rheumatoid arthritis ( 10 ) . Rheumatoid arthritis was persistent and active despite methotrexate treatment . All patients must have been treated with methotrexate ( 15 mg/wk ) for 3 months or longer , with a stable dose for 28 days before enrollment . We required patients to undergo a washout of all other disease-modifying antirheumatic drugs at least 28 days before r and omization . We allowed corticosteroid use , with dosages equal to 10 mg of prednisone or less per day , stabilized for 25 days before r and omization . At r and omization , we required patients to have 10 or more swollen joints , 12 or more tender joints , and C-reactive protein levels of 10.0 mg/L or greater ( normal range , 1.0 mg/L to 4.0 mg/L ) while receiving methotrexate . We required tuberculin skin testing before r and omization . We excluded patients with a positive tuberculin skin test result unless they had completed treatment for latent tuberculosis before enrollment . Study Design Our 1-year , multicenter , multinational , r and omized , double-blind , placebo-controlled study aim ed to compare the efficacy and safety of abatacept versus placebo in combination with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate treatment . We used a central r and omization system , and the Drug Management Group within Bristol-Myers Squibb , Princeton , New Jersey , generated the r and omization schedule . Stratification per site was not performed . Patients were r and omly assigned in a 2:1 ratio to receive either a fixed dose of abatacept , approximately 10 mg/kg of body weight , or placebo . Patients weighing less than 60 kg , 60 to 100 kg , or more than 100 kg received 500 mg , 750 mg , or 1000 mg of abatacept , respectively . We administered study medication by 30-minute intravenous infusion on days 1 , 15 , and 29 and then every 28 days up to and including day 337 . No premedication was required . The protocol specified that all patients were to receive methotrexate , 15 mg or more per week , although methotrexate at 10 mg per week was acceptable if the patient had a history of toxicity . During the first 6 months , we did not allow adjustments in methotrexate dose , except in cases of toxicity . We permitted use of stable dosages of nonsteroidal anti-inflammatory drugs and corticosteroid dosages equal to 10 mg of prednisone or less per day . Between 6 and 12 months , we allowed the following adjustments , as the investigator deemed necessary : 1 ) adjustment in methotrexate dose , 2 ) addition of 1 other disease-modifying antirheumatic drug ( hydroxychloroquine , sulfasalazine , gold , or azathioprine ) , or 3 ) adjustment in corticosteroid dose equal to 10 mg of prednisone or less per day . However , investigators were blinded to treatment group assignment throughout the 1-year study . Clinical Efficacy Measures Our 3 primary objectives were to evaluate the proportion of patients in each group with a 20 % improvement in American College of Rheumatology ( ACR ) response criteria ( ACR 20 ) at 6 months , the proportion of patients in each group with clinical ly significant improvement ( 0.3 unit ) in the Health Assessment Question naire Disability Index ( HAQ-DI ) score ( 11 ) at 1 year , and the radiographic progression of joint erosions ( assessed by comparing changes from baseline in the Genant-modified Sharp score ) ( 12 , 13 ) at 1 year . Table 1 summarizes the outcome measures used to assess the response to treatment . Table 1 . Outcome Measures for Assessing Response to Treatment of Rheumatoid Arthritis * Secondary objectives included assessing ACR 50 and ACR 70 responses at 6 months and all ACR responses at 1 year . In addition , we determined the proportions of patients achieving a major clinical response and a protocol -defined extended major clinical response at 1 year . We also assessed changes in disease activity by using the Disease Activity Score 28 ( DAS28 ) ( 20 , 21 ) . We assessed improvements in physical function over 1 year by using the HAQ-DI , which measures physical function during daily activities ( 22 ) . We evaluated changes in health-related quality of life by using the Medical Outcomes Study Short Form-36 Health Survey ( SF-36 ) ( 17 ) , which evaluates physical and mental health status ( Table 1 ) ( 18 , 19 ) . Physicians blinded to treatment group assignment performed assessment s at enrollment and at every visit before treatment administration on days 1 , 15 , and 29 ; every 28 days up to and including day 169 ( 6 months ) ; and on days 225 , 281 , and 365 ( 1 year ) . Radiographic Evaluation We performed st and ardized radiography of the h and s or wrists and feet at baseline and at 1 year or upon early termination ( if applicable ) . Two independent expert readers who were blinded to treatment group assignment , chronological order of radiography , and patients ' clinical response assessed all radiographic images for changes in erosion and joint-space narrowing by using the Genant-modified Sharp scoring system . Safety and Immunogenicity We monitored all patients who received at least 1 dose of the study medication for adverse events , serious adverse events , infusion reactions , clinical laboratory test abnormalities , and clinical ly significant changes in vital signs . Adverse events were self-reported by the patient and elicited by general question ing and examination at each visit . We attributed an adverse event to the study treatment on the basis of the investigator 's opinion , and we deemed an event as serious by st and ard regulatory definition . An external safety advisory panel , consisting of 5 physicians ( 3 rheumatologists , 1 oncologist , and 1 infectious disease expert ) , assessed overall safety in a blinded fashion by using reports of adverse events and laboratory results on a quarterly basis . We obtained serum sample s before infusions on days 1 , 29 , 85 , 169 , 281 , and 365 or 28 days after the last dose of the study medication in patients who discontinued before 1 year . We assessed immunogenicity by immunoassay to measure the antibody response to the entire abatacept molecule and also specifically to the CTLA-4 portion of the molecule ( 7 ) . Statistical Analysis The protocol estimated that 680 patients would need to be enrolled to r and omly assign 540 patients . We based sample sizes on a 5 % level of significance ( 2-tailed ) . The study had 99 % power to detect a difference of 20 % in ACR 20 between the 2 groups . On the basis of the [16482646] OBJECTIVE To assess the safety and efficacy of etanercept 50 mg administered twice weekly versus 25 mg administered twice weekly as monotherapy in patients with tumor necrosis factor-alpha ( TNF-alpha ) blocker-naäve active rheumatoid arthritis ( RA ) . METHODS Seventy-seven patients with RA were r and omized in an unequal allocation ( 2:1 ) in a blinded fashion to receive either 50 mg ( 51 patients ) or 25 mg ( 26 patients ) of etanercept twice a week for 24 weeks . RESULTS The primary outcome measure , the ACR-N AUC at 24 weeks , showed no difference between the 2 dose groups . In addition , there was no difference in ACR 20 , 50 , and 70 responses or in EULAR response criteria by Week 24 . There were no statistically significant differences between the 2 groups in the proportion of patients with any non-infectious adverse event . The proportion of patients with upper respiratory tract infections was significantly higher in patients receiving 50 mg etanercept compared with those receiving 25 mg ( 26 % vs 4 % , p = 0.027 ) . CONCLUSION Etanercept as a monotherapy at 50 mg twice weekly does not provide increased efficacy when compared to the st and ard dose of 25 mg twice weekly in TNF-alpha blocker-naäve patients [20079321] OBJECTIVE To investigate the efficacy and safety of adalimumab plus methotrexate ( MTX ) for the treatment of rheumatoid arthritis ( RA ) . METHODS This is a multi-center , r and omized , double-blind , parallel-group , and placebo-controlled clinical study , included a total of 302 cases of active rheumatoid arthritis , r and omized into three groups of observation : 40 mg adalimumab ( 121 cases ) , 80 mg adalimumab ( 121 cases ) , or placebo ( 60 cases ) . Upon enrollment , all subjects had been previously treated with MTX for at least 3 months , and their doses of drug had remained stable for at least 28 days . The double-blind phase lasted for 12 weeks , during which the subjects were administered with adalimumab or placebo subcutaneously every other week . Then the subjects entered into another 12 weeks of open-label study , which included subcutaneous injection of 40 mg adalimumab every other week . In both the double-blind and the open-label periods , all subjects were maintained concomitantly with MTX that had already been used before this study . The primary efficacy variables were evaluated on basis of American College of Rheumatology (ACR)20 response rate at week 12 . The secondary efficacy variables included : ACR20 response rate at week 24 ; ACR50 and ACR70 response rates at weeks 12 and 24 ; and changes at weeks 12 and 24 compared with baseline observations for tender and swollen joint counts , as well as the assessment of pain with visual analog scale ( VAS ) , the physician 's and the patient 's global assessment of disease activity ( VAS ) , and the analysis on health assessment question naire ( HAQ ) and health related quality of life ( HRQL ) measured by Short Form-36 ( SF-36 ) ; The safety variables mainly included adverse events ( AE ) . RESULT During the double-blind period , subjects treated with 40 mg of adalimumab , 57.0 % achieved ACR20 response at week 12 ( P = 0.004 versus placebo ) , and subjects treated with 80 mg of adalimumab , 51.2 % achieved ACR20 response at week 12 ( P = 0.026 versus placebo ) , and only 35.0 % of subjects treated with placebo achieved ACR20 response at week 12 . On the other h and , 32.2 % of subjects receiving 40 mg of adalimumab achieved ACR50 response ( P = 0.009 versus placebo ) , and 15.7 % achieved ACR70 response ( P = 0.007 versus placebo ) at week 12 . Subjects treated with 40 mg of adalimumab got a better result versus placebo at week 12 for tender joint count , swollen joint count , and improvement in C-reactive protein ; and subjects treated with 80 mg of adalimumab were also seen an amelioration versus placebo at week 12 for swollen joint count , and improvement in C-reactive protein ; all of these findings were statistically significant in differences . During the open-label period all subjects received 40 mg of adalimumab , and response rates for ACR20 , ACR50 , and ACR70 in the two treatment groups of 40 mg and 80 mg adalimumab were maintained or improved from week 12 to week 24 ( being 73.1 % , 40.3 % and 17.6 % respectively for 40 mg group ; 71.1 % , 39.5 % and 17.5 % respectively for 80 mg group ) ; while response in the original placebo group ( being 67.8 % , 44.1 % and 18.6 % ) increased during the 12-week open-label period to match that of the original adalimumab treatment groups . While for changes in tender and swollen joint counts , VAS , HAQ , SF-36 , a significant improvement was seen at week 24 when compared with baseline and week 12 values . Throughout the double-blind and open-label period , adverse events reported in > /= 5 % of subjects at least possibly associated with the study drug were upper respiratory tract infection , nasopharyngitis , and injection site itching , mostly being mild to moderate in severity . There were 3 cases of tuberculosis reported during this study . And 3 cases of serious adverse event ( SAE ) were reported among the adalimumab subjects during the double-blind period , which were determined as unrelated or probably unrelated to the study drug . And 8 cases ( 2.7 % ) of SAE were seen among the adalimumab subjects during the open-label period , 3 of which were at least possibly unrelated with the study drug . All SAEs reported were consistent to those seen in other adalimumab trials . No other unexpected safety signals were reported . CONCLUSION Adalimumab plus MTX is better than single MTX in efficacy for the treatment of RA . Being generally safe and well tolerated , adalimumab plus MTX can significantly increase the response rate , continuously reduce the arthritic signs , symptoms and the inflammatory factors in patients , and also be helpful for reducing disabilities and improving the global quality of life for the patients [18383539] OBJECTIVE To assess the efficacy , safety , and pharmacology of subcutaneous administration of golimumab in patients with active rheumatoid arthritis ( RA ) despite treatment with methotrexate ( MTX ) . METHODS Patients were r and omly assigned in a double-blinded manner to receive injections of placebo plus MTX or 50 mg or 100 mg golimumab every 2 or 4 weeks plus MTX through week 48 . Patients originally assigned to receive injections every 2 weeks had the interval increased to every 4 weeks starting at week 20 . The primary end point was the proportion of patients meeting the American College of Rheumatology 20 % improvement criteria ( achieving an ACR20 response ) at week 16 . The study was powered to detect a difference in the primary end point when the combined golimumab groups and at least 1 of the individual dose groups were compared with placebo . RESULTS The primary end point was attained . Sixty-one percent of patients in the combined golimumab plus MTX dose groups achieved an ACR20 response at week 16 compared with 37 % of patients in the placebo plus MTX group ( P=0.010 ) . In addition , 79 % of patients in the group receiving 100 mg golimumab every 2 weeks achieved an ACR20 response ( P<0.001 versus placebo ) . Through week 20 ( after which patients receiving placebo were switched to active infliximab therapy ) , serious adverse events were reported in 9 % of patients in the combined golimumab groups and in 6 % of patients in the placebo group . CONCLUSION Golimumab plus MTX effectively reduces the signs and symptoms of RA and is generally well tolerated in patients with an inadequate response to MTX [18821691] OBJECTIVE To examine the efficacy and safety of the humanized anti-interleukin-6 receptor antibody tocilizumab combined with conventional disease-modifying antirheumatic drugs ( DMARDs ) in patients with active rheumatoid arthritis ( RA ) . METHODS A total of 1,220 patients were r and omized ( 2:1 ratio ) in the phase III , double-blind , placebo-controlled , multicenter TOWARD ( Tocilizumab in Combination With Traditional DMARD Therapy ) study . Patients remained on stable doses of DMARDs and received tocilizumab 8 mg/kg or placebo ( control group ) every 4 weeks for 24 weeks . RESULTS At week 24 , the proportion of patients achieving a response according to the American College of Rheumatology criteria for 20 % improvement ( ACR20 ) was significantly greater in the tocilizumab plus DMARD group than in the control group ( 61 % versus 25 % ; P<0.0001 ) . Secondary end points including 50 % or 70 % improvement ( ACR50/70 ) , the Disease Activity Score in 28 joints ( DAS28 ) , DAS28 remission responses ( DAS28<2.6 ) , European League Against Rheumatism responses , and systemic markers such as the C-reactive protein and hemoglobin levels showed superiority of tocilizumab plus DMARDs over DMARDs alone . Seventy-three percent of patients in the tocilizumab group had > or=1 adverse event ( AE ) , compared with 61 % of patients in the control group . AEs leading to withdrawal from the study were infrequent ( 4 % of patients in the tocilizumab group and 2 % of those in the control group ) . Serious AEs occurred in 6.7 % and 4.3 % of patients in the tocilizumab and control groups , respectively , and serious infections occurred in 2.7 % and 1.9 % , respectively . Elevations in the alanine aminotransferase level , from normal at baseline to > 3-fold the upper limit of normal , occurred in 4 % of patients in the tocilizumab group and 1 % of those in the control group , and elevated total cholesterol levels were observed in 23 % and 6 % of patients , respectively . Sixteen patients started lipid-lowering therapy during the study . Grade 3 neutropenia occurred in 3.7 % of patients receiving tocilizumab and none of the patients in the control group , and no grade 4 neutropenia was reported . CONCLUSION Tocilizumab combined with any of the DMARDs evaluated was safe and effective in reducing articular and systemic symptoms in patients with an inadequate response to these agents [15340661] BACKGROUND AND PURPOSE Etanercept ( Enbrel ) , a recombinant tumor necrosis factor receptor fusion protein , has been shown to be effective in the treatment of patients with rheumatoid arthritis ( RA ) . The purpose of this study was to compare the efficacy and safety of etanercept in combination with methotrexate ( MTX ) and MTX alone in Taiwanese patients with active RA . METHODS In this double-blind study , 58 patients with active RA who were maintained on MTX therapy at a stable dose of 12.5 to 20 mg per week for 4 weeks were r and omized to receive either etanercept 25 mg ( n = 29 ) or placebo ( n = 29 ) by subcutaneous injection twice weekly over a period of 12 weeks . The primary endpoint was the reduction of tender and swollen joint counts by 20 % ( ACR 20 ) , 50 % ( ACR 50 ) , and 70 % ( ACR 70 ) as determined by the American College of Rheumatology criteria at the 12th week . RESULTS The addition of etanercept to MTX result ed in a greater reduction in the number of tender ( 7.00 vs 2.45 , p = 0.012 ) and swollen joints ( 8.55 vs 3.86 , p = 0.017 ) , and in serum levels of C-reactive protein ( 1.26 mg/dL vs 0.45 mg/dL , p = 0.014 ) compared to MTX alone after 12 weeks of therapy . In addition , the global assessment of disease activity by both physicians and patients , duration of morning stiffness , pain visual analog scale score , and Health Assessment Question naire were all improved by etanercept plus MTX therapy . Results for the overall improvement in disease activity assessed by ACR 20 ( 90 % vs 34 % ) , ACR 50 ( 66 % vs 10 % ) and ACR 70 ( 24 % vs 0 % ) all favored the etanercept plus MTX group . However , the adverse events were comparable between the 2 treatment groups . CONCLUSION Etanercept in combination with MTX was well tolerated and provided significantly more clinical benefit than MTX alone in Taiwanese patients with active RA [20131276] OBJECTIVE To assess the efficacy and safety of intravenous administration of golimumab in patients with rheumatoid arthritis ( RA ) . METHODS Adult patients with RA in whom disease activity was persistent despite treatment with methotrexate ( MTX ) at a dosage of 15 - 25 mg/week for > or = 4 weeks were r and omized to receive intravenous infusions of placebo plus MTX or intravenous infusions of golimumab at a dose of 2 mg/kg or 4 mg/kg , with or without MTX , every 12 weeks through week 48 . Patients with < 20 % improvement in the swollen and tender joint counts could enter early escape and receive additional active treatment ( week 16 ) or could have their dose regimen adjusted ( week 24 ) . The primary end point was the proportion of patients achieving a 50 % response according to the American College of Rheumatology improvement criteria ( ACR50 ) at week 14 . RESULTS The primary study end point was not met ( at week 14 , an ACR50 response was observed in 21 % of the patients treated with golimumab plus MTX compared with 13 % of the patients treated with placebo plus MTX [ P = 0.051 ] ) . By week 24 , significantly more patients treated with golimumab plus MTX had achieved an ACR50 response . Differences in the proportion of patients achieving an ACR50 response between the group receiving golimumab monotherapy and the group receiving placebo plus MTX were not significant at either week 14 ( 16 % versus 13 % ) or week 24 ( 10 % versus 9 % ) . At week 48 , the proportions of patients achieving ACR20 and ACR50 responses were highest among those who had received golimumab 4 mg/kg plus MTX ( 70 % and 48 % , respectively ) . Concomitant treatment with MTX was associated with a lower incidence of antibodies to golimumab . The most commonly reported adverse events through week 48 were infections ( 48 % of patients treated with golimumab with or without MTX and 41 % of patients receiving placebo plus MTX ) . CONCLUSION The primary end point was not met . However , intravenously administered golimumab plus MTX appears to have benefit in the longer-term reduction of RA signs/symptoms in MTX-resistant patients , with no unexpected safety concerns

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### Context: [2674556] Background : Certolizumab pegol is a PEGylated tumour necrosis factor inhibitor . Objective : To evaluate the efficacy and safety of certolizumab pegol versus placebo , plus methotrexate ( MTX ) , in patients with active rheumatoid arthritis ( RA ) . Methods : An international , multicentre , phase 3 , r and omised , double-blind , placebo-controlled study in active adult-onset RA . Patients ( n = 619 ) were r and omised 2:2:1 to subcutaneous certolizumab pegol ( liquid formulation ) 400 mg at weeks 0 , 2 and 4 followed by 200 mg or 400 mg plus MTX , or placebo plus MTX , every 2 weeks for 24 weeks . The primary end point was ACR20 response at week 24 . Secondary end points included ACR50 and ACR70 responses , change from baseline in modified Total Sharp Score , ACR core set variables and physical function . Results : Significantly more patients in the certolizumab pegol 200 mg and 400 mg groups achieved an ACR20 response versus placebo ( p⩽0.001 ) ; rates were 57.3 % , 57.6 % and 8.7 % , respectively . Certolizumab pegol 200 and 400 mg also significantly inhibited radiographic progression ; mean changes from baseline in mTSS at week 24 were 0.2 and −0.4 , respectively , versus 1.2 for placebo ( rank analysis p⩽0.01 ) . Certolizumab pegol-treated patients reported rapid and significant improvements in physical function versus placebo ; mean changes from baseline in HAQ-DI at week 24 were −0.50 and −0.50 , respectively , versus −0.14 for placebo ( p⩽0.001 ) . Most adverse events were mild or moderate , with low incidence of withdrawals due to adverse events . Five patients developed tuberculosis . Conclusion : Certolizumab pegol plus MTX was more efficacious than placebo plus MTX , rapidly and significantly improving signs and symptoms of RA and physical function and inhibiting radiographic progression . Trial registration number : [2732899] Objectives : To evaluate the safety and efficacy of 5-year , long-term tocilizumab monotherapy for patients with rheumatoid arthritis . Methods : In an open-label , long-term extension trial following an initial 3-month r and omised phase II trial , 143 of the 163 patients who participated in the initial blinded study received tocilizumab monotherapy ( 8 mg/kg ) every 4 weeks . Concomitant therapy with non-steroidal anti-inflammatory drugs and /or oral prednisolone ( 10 mg daily maximum ) was permitted . All patients were evaluated with American College of Rheumatology ( ACR ) improvement criteria , disease activity score ( DAS ) in 28 joints , and the European League Against Rheumatism response , as well as for safety issues . Results : 143 patients were enrolled in the open-label , long-term extension trial and 94 ( 66 % ) patients had completed 5 years as of March 2007 . 32 patients ( 22 % ) withdrew from the study due to adverse events and one patient ( 0.7 % ) due to unsatisfactory response . 14 patients withdrew because of the patient ’s request or other reasons . The serious adverse event rate was 27.5 events per 100 patient-years , with 5.7 serious infections per 100 patient-years , based on a total tocilizumab exposure of 612 patient-years . Of the 88 patients receiving corticosteroids at baseline , 78 ( 88.6 % ) were able to decrease their corticosteroid dose and 28 ( 31.8 % ) discontinued corticosteroids . At 5 years , 79/94 ( 84.0 % ) , 65/94 ( 69.1 % ) and 41/94 ( 43.6 % ) of the patients achieved ACR20 , ACR50 , and ACR70 improvement criteria , respectively . Remission defined as DAS28 less than 2.6 was achieved in 52/94 ( 55.3 % ) of the patients . Conclusion : In this 5-year extension study , tocilizumab demonstrated sustained long-term efficacy and a generally good safety profile [2674549] Objective : The phase III GO-FORWARD study examined the efficacy and safety of golimumab in patients with active rheumatoid arthritis ( RA ) despite methotrexate therapy . Methods : Patients were r and omly assigned in a 3 : 3 : 2 : 2 ratio to receive placebo injections plus methotrexate capsules ( group 1 , n = 133 ) , golimumab 100 mg injections plus placebo capsules ( group 2 , n = 133 ) , golimumab 50 mg injections plus methotrexate capsules ( group 3 , n = 89 ) , or golimumab 100 mg injections plus methotrexate capsules ( group 4 , n = 89 ) . Injections were administered subcutaneously every 4 weeks . The co- primary endpoints were the proportion of patients with 20 % or greater improvement in the American College of Rheumatology criteria ( ACR20 ) at week 14 and the change from baseline in the health assessment question naire-disability index ( HAQ-DI ) score at week 24 . Results : The proportion of patients who achieved an ACR20 response at week 14 was 33.1 % in the placebo plus methotrexate group , 44.4 % ( p = 0.059 ) in the golimumab 100 mg plus placebo group , 55.1 % ( p = 0.001 ) in the golimumab 50 mg plus methotrexate group and 56.2 % ( p<0.001 ) in the golimumab 100 mg plus methotrexate group . At week 24 , median improvements from baseline in HAQ-DI scores were 0.13 , 0.13 ( p = 0.240 ) , 0.38 ( p<0.001 ) and 0.50 ( p<0.001 ) , respectively . During the placebo-controlled portion of the study ( to week 16 ) , serious adverse events occurred in 2.3 % , 3.8 % , 5.6 % and 9.0 % of patients and serious infections occurred in 0.8 % , 0.8 % , 2.2 % and 5.6 % , respectively . Conclusion : The addition of golimumab to methotrexate in patients with active RA despite methotrexate therapy significantly reduced the signs and symptoms of RA and improved physical function [18358926] BACKGROUND Interleukin 6 is involved in the pathogenesis of rheumatoid arthritis via its broad effects on immune and inflammatory responses . Our aim was to assess the therapeutic effects of blocking interleukin 6 by inhibition of the interleukin-6 receptor with tocilizumab in patients with rheumatoid arthritis . METHODS In this double-blind , r and omised , placebo-controlled , parallel group phase III study , 623 patients with moderate to severe active rheumatoid arthritis were r and omly assigned with an interactive voice response system , stratified by site with a r and omisation list provided by the study sponsor , to receive tocilizumab 8 mg/kg ( n=205 ) , tocilizumab 4 mg/kg ( 214 ) , or placebo ( 204 ) intravenously every 4 weeks , with methotrexate at stable pre- study doses ( 10 - 25 mg/week ) . Rescue therapy with tocilizumab 8 mg/kg was offered at week 16 to patients with less than 20 % improvement in both swollen and tender joint counts . The primary endpoint was the proportion of patients with 20 % improvement in signs and symptoms of rheumatoid arthritis according to American College of Rheumatology criteria ( ACR20 response ) at week 24 . Analyses were by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00106548 . FINDINGS The intention-to-treat analysis population consisted of 622 patients : one patient in the 4 mg/kg group did not receive study treatment and was thus excluded . At 24 weeks , ACR20 responses were seen in more patients receiving tocilizumab than in those receiving placebo ( 120 [ 59 % ] patients in the 8 mg/kg group , 102 [ 48 % ] in the 4 mg/kg group , 54 [ 26 % ] in the placebo group ; odds ratio 4.0 [ 95 % CI 2.6 - 6.1 ] , p<0.0001 for 8 mg/kg vs placebo ; and 2.6 [ 1.7 - 3.9 ] , p<0.0001 for 4 mg/kg vs placebo ) . More people receiving tocilizumab than those receiving placebo had at least one adverse event ( 143 [ 69 % ] in the 8 mg/kg group ; 151 [ 71 % ] in the 4 mg/kg group ; 129 [ 63 % ] in the placebo group ) . The most common serious adverse events were serious infections or infestations , reported by six patients in the 8 mg/kg group , three in the 4 mg/kg group , and two in the placebo group . INTERPRETATION Tocilizumab could be an effective therapeutic approach in patients with moderate to severe active rheumatoid arthritis . FUNDING F Hoffmann-La Roche , Chugai Pharmaceutical [9920948] BACKGROUND Patients treated with methotrexate for rheumatoid arthritis often improve but continue to have active disease . This study was undertaken to determine whether the addition of etanercept , a soluble tumor necrosis factor receptor (p75):Fc fusion protein ( TNFR : Fc ) , to methotrexate therapy would provide additional benefit to patients who had persistent rheumatoid arthritis despite receiving methotrexate . METHODS In a 24-week , double-blind trial , we r and omly assigned 89 patients with persistently active rheumatoid arthritis despite at least 6 months of methotrexate therapy at a stable dose of 15 to 25 mg per week ( or as low as 10 mg per week for patients unable to tolerate higher doses ) to receive either etanercept ( 25 mg ) or placebo subcutaneously twice weekly while continuing to receive methotrexate . The primary measure of clinical response was the American College of Rheumatology criteria for a 20 percent improvement in measures of disease activity ( ACR 20 ) at 24 weeks . RESULTS The addition of etanercept to methotrexate therapy result ed in rapid and sustained improvement . At 24 weeks , 71 percent of the patients receiving etanercept plus methotrexate and 27 percent of those receiving placebo plus methotrexate met the ACR 20 criteria ( P<0.001 ) ; 39 percent of the patients receiving etanercept plus methotrexate and 3 percent of those receiving placebo plus methotrexate met the ACR 50 criteria ( for a 50 percent improvement ) ( P<0.001 ) . Patients receiving etanercept plus methotrexate had significantly better outcomes according to all measures of disease activity . The only adverse events associated with etanercept were mild injection-site reactions , and no patient withdrew from the study because of adverse events associated with etanercept . CONCLUSIONS In patients with persistently active rheumatoid arthritis , the combination of etanercept and methotrexate was safe and well tolerated and provided significantly greater clinical benefit than methotrexate alone [2938895] Objectives This phase III study evaluated the efficacy and safety of rituximab plus methotrexate ( MTX ) in patients with active rheumatoid arthritis ( RA ) who had an inadequate response to MTX and who were naïve to prior biological treatment . Methods Patients with active disease on stable MTX ( 10–25 mg/week ) were r and omised to rituximab 2 × 500 mg ( n=168 ) , rituximab 2 × 1000 mg ( n=172 ) , or placebo ( n=172 ) . From week 24 , patients not in remission ( Disease Activity Score ( 28 joints ) ≥2.6 ) received a second course of rituximab ; patients initially assigned to placebo switched to rituximab 2 × 500 mg . The primary end point was American College of Rheumatology 20 ( ACR20 ) response at week 24 . All patients were followed until week 48 . Results At week 24 , both doses of rituximab showed statistically superior efficacy ( p<0.0001 ) to placebo ( ACR20 : 54 % , 51 % and 23 % ; rituximab ( 2 × 500 mg ) + MTX , rituximab ( 2 × 1000 mg ) + MTX and placebo + MTX , respectively ) . Secondary end points were also significantly improved for both rituximab groups compared with placebo . Further improvements in both rituximab arms were observed from week 24 to week 48 . Rituximab + MTX was well tolerated , demonstrating comparable safety to placebo + MTX through to week 24 , and between rituximab doses through to week 48 . Conclusions Rituximab ( at 2 × 500 mg and 2 × 1000 mg ) plus MTX significantly improved clinical outcomes at week 24 , which were further improved by week 48 . No significant differences in either clinical or safety outcomes were apparent between the rituximab doses [2668560] This multicenter , double-blind study evaluated the effects of three doses of adalimumab in Japanese patients with rheumatoid arthritis ( RA ) . Patients were r and omized to placebo ( n = 87 ) or adalimumab 20 mg ( n = 87 ) , 40 mg ( n = 91 ) , or 80 mg ( n = 87 ) every other week for 24 weeks . The primary efficacy endpoint was the American College of Rheumatology criteria for 20 % improvement ( ACR20 ) at Week 24 . At Week 24 , all adalimumab treatment groups achieved statistically significantly better ACR20 response rates ( 20 mg : 28.7 % , P < 0.05 ; 40 mg : 44.0 % , P < 0.001 ; and 80 mg : 50.6 % , P < 0.001 ) versus placebo ( 13.8 % ) , as well as statistically significantly greater ACR50 and ACR70 responses for the two higher adalimumab doses versus placebo . Rates of adverse events were comparable between the adalimumab groups and the placebo group , except for injection-site reactions , which occurred in more adalimumab-treated patients . Adalimumab 20 , 40 , and 80 mg were safe and effective in Japanese patients ; however , the greatest responses occurred with the 40 and 80 mg doses . These results and comparable ACR20 responses in Western patients support adalimumab 40 mg every other week as the appropriate dosage to treat RA in Japanese patients [19578810] Tumour necrosis factor alpha ( TNF-α ) and interlekin-6 ( IL-6 ) are key inflammatory cytokines in the pathogenesis of rheumatoid arthritis ( RA ) , a disease also associated with endothelial perturbation and increased serum levels of adhesion molecules . As relationships between these processes and molecules are unclear , we tested the hypotheses ( a ) that TNF-α and IL-6 are linked to endothelial activation/damage and levels of soluble adhesion molecules , and ( b ) that intensive anti-inflammatory treatment improves levels of these indices . We recruited 66 patients with RA , 48 community controls ( CC ) , and 25 disease controls ( DC ) . Plasma TNF-α and IL-6 were compared to markers of vascular biology ( vWF , sE-sel ) , soluble adhesion molecules ( sICAM , sVCAM ) and routine inflammatory markers ( CRP and ESR ) . Blood was obtained at baseline and at 1 week and again 4 weeks after anti-inflammatory treatment in a subgroup of 29 patients with RA . With the exception of sE-selectin , RA patients had increased levels of all plasma markers compared to the HCs , whilst levels in the DCs were largely intermediate between RA and the CCs . Within the RA group , sEsel correlated with both CRP and ESR whilst TNF-α correlated with sVCAM ( all r > 0.32 , P < 0.01 ) . After 1 week of combined anti-inflammatory therapy , only CRP , ESR , sEsel and sVCAM were significantly reduced ( all P < 0.05 ) . In RA , endothelial activation ( as sEsel ) correlates with classical markers of inflammation and is reduced by intensive anti-inflammatory medications [3375587] Objectives To compare health-related quality of life ( HRQoL ) before and after treatment with etanercept in patients with moderate to severe rheumatoid arthritis ( RA ) , psoriatic arthritis ( PsA ) and psoriasis using spydergram representations . Methods Data from r and omised , controlled trials of etanercept in patients with RA , PsA and psoriasis were analysed . HRQoL was assessed by the medical outcomes survey short form 36 ( SF-36 ) physical ( PCS ) and mental ( MCS ) component summary and domain scores . Baseline comparisons with age and gender-matched norms and treatment-associated changes in domain scores were quantified using spydergrams and the health utility SF-6D measure . Results Mean baseline PCS scores were lower than age and gender-matched norms in patients with RA and PsA , but near normative values in patients with psoriasis ; MCS scores at baseline were near normal in PsA and psoriasis but low in RA . Treatment with etanercept result ed in improvements in PCS and MCS scores as well as individual SF-36 domains across all indications . Mean baseline SF-6D scores were higher in psoriasis than in RA or PsA ; clinical ly meaningful improvements in SF-6D were observed in all three patient population s following treatment with etanercept . Conclusions Patients with RA , PsA and psoriasis demonstrated unique HRQoL profiles at baseline . Treatment with etanercept was associated with improvements in PCS and MCS scores as well as individual domain scores in patients with RA , PsA and psoriasis [15449338] Mixed treatment comparison ( MTC ) meta- analysis is a generalization of st and ard pairwise meta- analysis for A vs B trials , to data structures that include , for example , A vs B , B vs C , and A vs C trials . There are two roles for MTC : one is to strengthen inference concerning the relative efficacy of two treatments , by including both ' direct ' and ' indirect ' comparisons . The other is to facilitate simultaneous inference regarding all treatments , in order for example to select the best treatment . In this paper , we present a range of Bayesian hierarchical models using the Markov chain Monte Carlo software WinBUGS . These are multivariate r and om effects models that allow for variation in true treatment effects across trials . We consider models where the between-trials variance is homogeneous across treatment comparisons as well as heterogeneous variance models . We also compare models with fixed ( unconstrained ) baseline study effects with models with r and om baselines drawn from a common distribution . These models are applied to an illustrative data set and posterior parameter distributions are compared . We discuss model critique and model selection , illustrating the role of Bayesian deviance analysis , and node-based model criticism . The assumptions underlying the MTC models and their parameterization are also discussed [2564802] Objectives : This double-blind trial evaluated the efficacy and safety of abatacept or infliximab vs placebo . The primary objective of this study was to evaluate the mean change from baseline in Disease Activity Score ( based on erythrocyte sedimentation rates ; DAS28 ( ESR ) ) for the abatacept vs placebo groups at day 197 . Methods : Patients with rheumatoid arthritis ( RA ) and an inadequate response to methotrexate ( MTX ) were r and omised 3:3:2 to abatacept ( ∼10 mg/kg every 4 weeks , n = 156 ) , infliximab ( 3 mg/kg every 8 weeks , n = 165 ) , or placebo ( every 4 weeks , n = 110 ) and background MTX . Safety and efficacy were assessed throughout the study . Results : Similar patient demographics and clinical characteristics were present at baseline between groups , with mean scores of ∼1.7 for HAQ-DI and 6.8 for DAS28 ( ESR ) . At 6 months , mean changes in DAS28 ( ESR ) were significantly greater for abatacept vs placebo ( –2.53 vs –1.48 , p<0.001 ) and infliximab vs placebo ( –2.25 vs –1.48 , p<0.001 ) . For abatacept vs infliximab treatment at day 365 , reductions in the DAS28 ( ESR ) were –2.88 vs –2.25 . At day 365 , the following response rates were observed for abatacept and infliximab , respectively : American College of Rheumatology ( ACR ) 20 , 72.4 and 55.8 % ; ACR 50 , 45.5 and 36.4 % ; ACR 70 , 26.3 and 20.6 % ; low disease activity score ( LDAS ) , 35.3 and 22.4 % ; DAS28-defined remission , 18.7 and 12.2 % ; good European League Against Rheumatism ( EULAR ) responses , 32.0 and 18.5 % ; and Health Assessment Question naire Disability Index ( HAQ-DI ) , 57.7 and 52.7 % . Mean changes in physical component summary ( PCS ) were 9.5 and 7.6 , and mental component summary ( MCS ) were 6.0 and 4.0 , for abatacept and infliximab , respectively . Over 1 year , adverse events ( AEs ) ( 89.1 vs 93.3 % ) , serious AEs ( SAEs ) ( 9.6 vs 18.2 % ) , serious infections ( 1.9 vs 8.5 % ) and discontinuations due to AEs ( 3.2 vs 7.3 % ) and SAEs ( 2.6 vs 3.6 % ) were lower with abatacept than infliximab . Conclusions : In this study , abatacept and infliximab ( 3 mg/kg every 8 weeks ) demonstrated similar efficacy . Overall , abatacept had a relatively more acceptable safety and tolerability profile , with fewer SAEs , serious infections , acute infusional events and discontinuations due to AEs than the infliximab group . Trial registration number : NCT00095147 [15308515] OBJECTIVES To compare the short term clinical and biological effects of intravenous ( i.v . ) pulse methylprednisolone ( MP ) and infliximab ( IFX ) in patients with severe active rheumatoid arthritis ( RA ) despite methotrexate ( MTX ) treatment . METHODS Patients with active RA despite MTX treatment were r and omly allocated to receive a single i.v . infusion of MP ( 1 g ) or three i.v . infusions of IFX ( 3 mg/kg ) on weeks 0 , 2 , and 6 . Patients were " blindly " evaluated for disease activity measures . Quality of life ( QoL ) was evaluated through the SF-36 health survey . Serum matrix metalloproteinase-3 ( MMP-3 ) titres were measured at baseline , weeks 2 and 6 . RESULTS Compared with baseline , significant improvement was noted in all activity measures , including serum C reactive protein ( CRP ) titres , in the IFX group only . At week 14 , 6/9 ( 67 % ) and 4/9 ( 44 % ) IFX patients met the ACR20 and 50 response criteria , while this was the case in only 1/12 ( 8 % ) and 0/12 ( 0 % ) MP patients , respectively ( p<0.05 ) . None of the QoL scales improved with MP treatment , whereas some did so in the IFX group . Serum MMP-3 titres significantly decreased ( 41 % drop ) at week 6 in the IFX group , while no changes were seen in patients given MP . CONCLUSION This short term r and omised comparative study demonstrates that TNF blockade is better than MP pulse therapy in a subset of patients with severe refractory RA , with improvement in not only clinical parameters of disease activity but also biological inflammatory indices , such as serum CRP and MMP-3 titres [14614165] BACKGROUND Effective new therapies are needed for rheumatoid arthritis . Current therapies target the products of activated macrophages ; however , T cells also have an important role in rheumatoid arthritis . A fusion protein -- cytotoxic T-lymphocyte-associated antigen 4-IgG1 (CTLA4Ig)--is the first in a new class of drugs known as costimulation blockers being evaluated for the treatment of rheumatoid arthritis . CTLA4Ig binds to CD80 and CD86 on antigen-presenting cells , blocking the engagement of CD28 on T cells and preventing T-cell activation . A preliminary study showed that CTLA4Ig may be effective for the treatment of rheumatoid arthritis . METHODS We r and omly assigned patients with active rheumatoid arthritis despite methotrexate therapy to receive 2 mg of CTLA4Ig per kilogram of body weight ( 105 patients ) , 10 mg of CTLA4Ig per kilogram ( 115 patients ) , or placebo ( 119 patients ) for six months . All patients also received methotrexate therapy during the study . The clinical response was assessed at six months with use of the criteria of the American College of Rheumatology ( ACR ) , which define the response according to its extent : 20 percent ( ACR 20 ) , 50 percent ( ACR 50 ) , or 70 percent ( ACR 70 ) . Additional end points included measures of the health-related quality of life . RESULTS Patients treated with 10 mg of CTLA4Ig per kilogram were more likely to have an ACR 20 than were patients who received placebo ( 60 percent vs. 35 percent , P<0.001 ) . Significantly higher rates of ACR 50 and ACR 70 responses were seen in both CTLA4Ig groups than in the placebo group . The group given 10 mg of CTLA4Ig per kilogram had clinical ly meaningful and statistically significant improvements in all eight subscales of the Medical Outcomes 36-Item Short-Form General Health Survey . CTLA4Ig was well tolerated , with an overall safety profile similar to that of placebo . CONCLUSIONS In patients with active rheumatoid arthritis who were receiving methotrexate , treatment with CTLA4Ig significantly improved the signs and symptoms of rheumatoid arthritis and the health-related quality of life . CTLA4Ig is a promising new therapy for rheumatoid arthritis [12096230] BACKGROUND It is 40 yr since the last age- and sex-specific estimates of the prevalence of rheumatoid arthritis ( RA ) for the UK were published . Since then the classification criteria for RA have been revised and there has been evidence of a fall in the incidence of RA , especially in women . OBJECTIVES To estimate the age- and sex-specific point prevalence of RA ( defined as fulfilment of a modification of the 1987 ACR classification criteria for RA on the day of assessment ) . The estimate was made in the primary care setting in Norfolk , UK . METHODS A stratified r and om sample was drawn from seven age and gender b and s. The 7050 individuals selected were mailed a screening question naire . Positive responders were invited to attend for a clinical examination . The sample was matched against the names in the Norfolk Arthritis Register ( NOAR ) , a register of incident cases of inflammatory polyarthritis which has been in existence since 1990 . RESULTS The overall response rate was 82 % . Sixty-six cases of RA were identified . Extrapolated to the population of the UK , the overall minimum prevalence of RA is 1.16 % in women and 0.44 % in men . A number of incident cases of RA previously notified to NOAR were not identified as cases in the survey because they had entered into treatment-induced remission . In addition , some cases who failed to attend for examination had significant disability . These prevalence figures are therefore an underestimate . CONCLUSIONS The prevalence of RA in women , but not in men , in the UK may have fallen since the 1950s [12528101] OBJECTIVE To evaluate the efficacy and safety of adalimumab ( D2E7 ) , a fully human monoclonal tumor necrosis factor alpha antibody , in combination with methotrexate ( MTX ) in patients with active rheumatoid arthritis ( RA ) despite treatment with MTX . METHODS In a 24-week , r and omized , double-blind , placebo-controlled study , 271 patients with active RA were r and omly assigned to receive injections of adalimumab ( 20 mg , 40 mg , or 80 mg subcutaneously ) or placebo every other week while continuing to take their long-term stable dosage of MTX . The primary efficacy end point was the American College of Rheumatology criteria for 20 % improvement ( ACR20 ) at 24 weeks . RESULTS An ACR20 response at week 24 was achieved by a significantly greater proportion of patients in the 20-mg , 40-mg , and 80-mg adalimumab plus MTX groups ( 47.8 % , 67.2 % , and 65.8 % , respectively ) than in the placebo plus MTX group ( 14.5 % ) ( P < 0.001 ) . ACR50 response rates with the 20-mg , 40-mg , and 80-mg adalimumab dosages ( 31.9 % , 55.2 % , and 42.5 % , respectively ) were significantly greater than that with placebo ( 8.1 % ) ( P = 0.003 , P < 0.001 , and P < 0.001 , respectively ) . The 40-mg and 80-mg doses of adalimumab were associated with an ACR70 response ( 26.9 % and 19.2 % , respectively ) that was statistically significantly greater than that with placebo ( 4.8 % ) ( P < 0.001 and P = 0.020 ) . Responses were rapid , with the greatest proportion of adalimumab-treated patients achieving an ACR20 response at the first scheduled visit ( week 1 ) . Adalimumab was safe and well tolerated ; comparable numbers of adalimumab-treated patients and placebo-treated patients reported adverse events . CONCLUSION The addition of adalimumab at a dosage of 20 mg , 40 mg , or 80 mg administered subcutaneously every other week to long-term MTX therapy in patients with active RA provided significant , rapid , and sustained improvement in disease activity over 24 weeks compared with MTX plus placebo [16606651] Objective : To compare the efficacy and safety of etanercept and sulfasalazine , alone and in combination , in patients with active rheumatoid arthritis despite sulfasalazine treatment . Methods : A double-blind , r and omised study in adult patients with active rheumatoid arthritis despite stable sulfasalazine ( 2–3 g/day ) treatment . The primary end point was a 20 % response by the American College of Rheumatology ( ACR ) criteria at 24 weeks . Results : At baseline , the three treatment groups ( sulfasalazine , n = 50 ; etanercept , n = 103 ; etanercept and sulfasalazine , n = 101 ) were comparable for demographic variables and disease activity . Lack of efficacy was the primary reason for discontinuation ( sulfasalazine , n = 12 ; etanercept , n = 1 ; etanercept and sulfasalazine , n = 4 ; p<0.001 ) . Significantly more patients receiving etanercept , alone or in combination ( 74 % for each ) , achieved ACR 20 responses at 24 weeks than those receiving sulfasalazine ( 28 % ; p<0.01 ) . Similarly , more patients in the etanercept groups achieved ACR 50 and ACR 70 responses than those in the sulfasalazine group ( p<0.01 ) . In the groups receiving etanercept , significant differences in the ACR core components were observed by week 2 compared with those receiving sulfasalazine alone ( p<0.01 ) . The incidences of several common adverse events ( headache , nausea , asthenia ) were lower with etanercept alone than with the combination ( p<0.05 ) , but infections and injection site reactions were higher with etanercept alone ( p<0.05 ) . The safety profiles of both etanercept treatment groups were comparable with previous experience of etanercept . Conclusions : For all efficacy variables assessed , etanercept alone or in combination with sulfasalazine result ed in substantial and similar improvement in disease activity from baseline to week 24 compared with sulfasalazine alone in patients with active rheumatoid arthritis despite their sulfasalazine treatment . All three treatments were generally well tolerated [20574649] The superiority of the combination therapy of methotrexate ( MTX ) and anti-tumor necrosis factor ( TNF ) biological agents over anti-TNF monotherapy in MTX-naïve patients with rheumatoid arthritis ( RA ) has been demonstrated . We investigated the efficacy and safety of continuation versus discontinuation of MTX at the commencement of etanercept ( ETN ) in patients with active RA despite MTX therapy . In total , 151 patients with active RA despite treatment with MTX were r and omized to either ETN 25 mg twice a week and MTX 6–8 mg/week ( the E + M group ) or ETN alone ( the E group ) . Co- primary endpoints included the European League Against Rheumatism ( EULAR ) good response rate and the American College of Rheumatology ( ACR ) 50 response rate at week 24 . Demographic and clinical features between groups at baseline were similar . The EULAR good response rates were significantly higher in the E + M group ( 52 % ) than in the E group ( 33 % ) at week 24 ( p = 0.0001 ) . Although the ACR50 response rate , one of the co- primary endpoints , and the ACR70 response rate at week 24 were not significantly greater in the E + M group ( 64 and 38 % , respectively ) than in the E group ( 48 and 26 % , respectively ) , the ACR20 response rate was significantly greater in the E + M group ( 90 % ) than in the E group ( 64 % ; p = 0.0002 ) . Safety profiles were similar for the groups . Thus , MTX should be continued at the commencement of ETN therapy , even in RA patients who show an inappropriate response to MTX [2674555] Background : Tumour necrosis factor α ( TNFα ) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis ( RA ) . Treatment with TNFα inhibitors reduces disease activity and improves outcomes for patients with RA . This study evaluated the efficacy and safety of certolizumab pegol 400 mg , a novel , poly-(ethylene glycol ) (PEG)ylated , Fc-free TNFα inhibitor , as monotherapy in patients with active RA . Methods : In this 24-week , multicentre , r and omised , double-blind , placebo-controlled study , 220 patients previously failing ⩾1 disease-modifying antirheumatic drug ( DMARD ) were r and omised 1:1 to receive subcutaneous certolizumab pegol 400 mg ( n = 111 ) or placebo ( n = 109 ) every 4 weeks . The primary endpoint was 20 % improvement according to the American College of Rheumatology criteria ( ACR20 ) at week 24 . Secondary endpoints included ACR50/70 response , ACR component scores , 28-joint Disease Activity Score Erythrocyte Sedimentation Rate 3 ( DAS28(ESR)3 ) , patient-reported outcomes ( including physical function , health-related quality of life ( HRQoL ) , pain and fatigue ) and safety . Results : At week 24 , the ACR20 response rates were 45.5 % for certolizumab pegol 400 mg every 4 weeks vs 9.3 % for placebo ( p<0.001 ) . Differences for certolizumab pegol vs placebo in the ACR20 response were statistically significant as early as week 1 through to week 24 ( p<0.001 ) . Significant improvements in ACR50 , ACR components , DAS28(ESR)3 and all patient-reported outcomes were also observed early with certolizumab pegol and were sustained throughout the study . Most adverse events were mild or moderate and no deaths or cases of tuberculosis were reported . Conclusions : Treatment with certolizumab pegol 400 mg monotherapy every 4 weeks effectively reduced the signs and symptoms of active RA in patients previously failing ⩾1 DMARD compared with placebo , and demonstrated an acceptable safety profile . Trial registration number : NCT00548834 [2638601] We investigated the clinical efficacy and safety of tocilizumab ( a humanized anti-IL-6 receptor antibody ) monotherapy in active rheumatoid arthritis ( RA ) patients with an inadequate response to low dose methotrexate ( MTX ) . In a multicenter , double-blind , r and omized , controlled trial , 125 patients were allocated to receive either tocilizumab 8 mg/kg every 4 weeks plus MTX placebo ( tocilizumab group ) or tocilizumab placebo plus MTX 8 mg/week ( control group ) for 24 weeks . The clinical responses were measured using the American College of Rheumatology ( ACR ) criteria and the Disease Activity Score in 28 joints . Serum vascular endothelial growth factor ( VEGF ) levels were also monitored . At week 24 , 25.0 % in the control group and 80.3 % in the tocilizumab group achieved ACR20 response . The tocilizumab group showed superior ACR response criteria over control at all time points . Additionally , serum VEGF levels were significantly decreased by tocilizumab treatment . The overall incidences of adverse events ( AEs ) were 72 and 92 % ( serious AEs : 4.7 and 6.6 % ; serious infections : 1.6 and 3.3 % ) in the control and the tocilizumab groups , respectively . All serious adverse events improved by adequate treatment . Tocilizumab monotherapy was well tolerated and provided an excellent clinical benefit in active RA patients with an inadequate response to low dose MTX [16947782] OBJECTIVE To establish the safety and efficacy of repeat infusions of tocilizumab ( previously known as MRA ) , a humanized anti-interleukin-6 ( IL-6 ) receptor antibody , alone and in combination with methotrexate ( MTX ) , for the treatment of rheumatoid arthritis ( RA ) . METHODS The study group comprised 359 patients with active RA in whom the response to MTX was inadequate . During a stabilization period , these patients received their current dose of MTX for at least 4 weeks . Following stabilization , they were r and omized to 1 of 7 treatment arms , as follows : tocilizumab at doses of 2 mg/kg , 4 mg/kg , or 8 mg/kg either as monotherapy or in combination with MTX , or MTX plus placebo . RESULTS A 20 % response ( improvement ) according to the American College of Rheumatology criteria ( ACR20 response ) was achieved by 61 % and 63 % of patients receiving 4 mg/kg and 8 mg/kg of tocilizumab as monotherapy , respectively , and by 63 % and 74 % of patients receiving those doses of tocilizumab plus MTX , respectively , compared with 41 % of patients receiving placebo plus MTX . Statistically significant ACR50 and ACR70 responses were observed in patients receiving combination therapy with either 4 mg/kg or 8 mg/kg of tocilizumab plus MTX ( P < 0.05 ) . A dose-related reduction in the Disease Activity Score in 28 joints was observed from week 4 onward , in all patients except those receiving monotherapy with 2 mg/kg of tocilizumab . In the majority of patients who received 8 mg/kg of tocilizumab , the C-reactive protein level/erythrocyte sedimentation rate normalized , while placebo plus MTX had little effect on these laboratory parameters . Tocilizumab was mostly well tolerated , with a safety profile similar to that of other biologic and immunosuppressive therapies . Alanine transaminase and aspartate transaminase levels followed a sawtooth pattern ( rising and falling between infusions ) . There were moderate but reversible increases in the nonfasting total cholesterol and triglyceride levels and reversible reductions in the high-density lipoprotein cholesterol and neutrophil levels . There were 2 cases of sepsis , both of which occurred in patients who were receiving combination therapy with 8 mg/kg of tocilizumab plus MTX . CONCLUSION These results indicate that targeted blockade of IL-6 signaling is a highly efficacious and promising means of decreasing disease activity in RA [18975346] OBJECTIVE To evaluate the efficacy and safety of 2 dosage regimens of lyophilized certolizumab pegol ( a novel PEGylated anti-tumor necrosis factor agent ) as adjunctive therapy to methotrexate ( MTX ) in patients with active rheumatoid arthritis ( RA ) with an inadequate response to MTX therapy alone . METHODS In this 52-week , phase III , multicenter , r and omized , double-blind , placebo-controlled , parallel-group trial , 982 patients were r and omized 2:2:1 to receive treatment with subcutaneous certolizumab pegol at an initial dosage of 400 mg given at weeks 0 , 2 , and 4 , with a subsequent dosage of 200 mg or 400 mg given every 2 weeks , plus MTX , or placebo plus MTX . Co- primary end points were the response rate at week 24 according to the American College of Rheumatology 20 % criteria for improvement ( ACR20 ) and the mean change from baseline in the modified total Sharp score at week 52 . RESULTS At week 24 , ACR20 response rates using nonresponder imputation for the certolizumab pegol 200-mg and 400-mg groups were 58.8 % and 60.8 % , respectively , as compared with 13.6 % for the placebo group . Differences in ACR20 response rates versus placebo were significant at week 1 and were sustained to week 52 ( P < 0.001 ) . At week 52 , mean radiographic progression from baseline was reduced in patients treated with certolizumab pegol 200 mg ( 0.4 Sharp units ) or 400 mg ( 0.2 Sharp units ) as compared with that in placebo-treated patients ( 2.8 Sharp units ) ( P < 0.001 by rank analysis ) . Improvements in all ACR core set of disease activity measures , including physical function , were observed by week 1 with both certolizumab pegol dosage regimens . Most adverse events were mild or moderate . CONCLUSION Treatment with certolizumab pegol 200 or 400 mg plus MTX result ed in a rapid and sustained reduction in RA signs and symptoms , inhibited the progression of structural joint damage , and improved physical function as compared with placebo plus MTX treatment in RA patients with an incomplete response to MTX [15188351] OBJECTIVE Interleukin-6 ( IL-6 ) is a pleiotropic cytokine that regulates the immune response , inflammation , and hematopoiesis . Overproduction of IL-6 plays pathologic roles in rheumatoid arthritis ( RA ) , and the blockade of IL-6 may be therapeutically effective for the disease . This study was undertaken to evaluate the safety and efficacy of a humanized anti-IL-6 receptor antibody , MRA , in patients with RA . METHODS In a multicenter , double-blind , placebo-controlled trial , 164 patients with refractory RA were r and omized to receive either MRA ( 4 mg/kg body weight or 8 mg/kg body weight ) or placebo . MRA was administered intravenously every 4 weeks for a total of 3 months . The clinical responses were measured using the American College of Rheumatology ( ACR ) criteria . RESULTS Treatment with MRA reduced disease activity in a dose-dependent manner . At 3 months , 78 % of patients in the 8-mg group , 57 % in the 4-mg group , and 11 % in the placebo group achieved at least a 20 % improvement in disease activity according to the ACR criteria ( an ACR20 response ) ( P < 0.001 for 8-mg group versus placebo ) . Forty percent of patients in the 8-mg group and 1.9 % in the placebo group achieved an ACR50 response ( P < 0.001 ) . The overall incidences of adverse events were 56 % , 59 % , and 51 % in the placebo , 4-mg , and 8-mg groups , respectively , and the adverse events were not dose dependent . A blood cholesterol increase was observed in 44.0 % of the patients . Liver function disorders and decreases in white blood cell counts were also observed , but these were mild and transient . There was no increase in antinuclear antibodies or anti-DNA antibodies . Anti-MRA antibodies were detected in 2 patients . CONCLUSION Treatment with MRA was generally well tolerated and significantly reduced the disease activity of RA [15001324] BACKGROUND Etanercept and methotrexate are effective in the treatment of rheumatoid arthritis but no data exist on concurrent initiation or use of the combination compared with either drug alone . We aim ed to assess combination treatment with etanercept and methotrexate versus the monotherapies in patients with rheumatoid arthritis . METHODS In a double-blind , r and omised , clinical efficacy , safety , and radiographic study , 686 patients with active rheumatoid arthritis were r and omly allocated to treatment with etanercept 25 mg ( subcutaneously twice a week ) , oral methotrexate ( up to 20 mg every week ) , or the combination . Clinical response was assessed by criteria of the American College of Rheumatology ( ACR ) . The primary efficacy endpoint was the numeric index of the ACR response ( ACR-N ) area under the curve ( AUC ) over the first 24 weeks . The primary radiographic endpoint was change from baseline to week 52 in total joint damage and was assessed with the modified Sharp score . Analysis was by intention to treat . FINDINGS Four patients did not receive any drug ; thus 682 were studied . ACR-N AUC at 24 weeks was greater for the combination group compared with etanercept alone and methotrexate alone ( 18.3%-years [ 95 % CI 17.1 - 19.6 ] vs 14.7%-years [ 13.5 - 16.0 ] , p<0.0001 , and 12.2%-years [ 11.0 - 13.4 ] , p<0.0001 ; respectively ) . The mean difference in ACR-N AUC between combination and methotrexate alone was 6.1 ( 95 % CI 4.5 - 7.8 , p<0.0001 ) and between etanercept and methotrexate was 2.5 ( 0.8 - 4.2 , p=0.0034 ) . The combination was more efficacious than methotrexate or etanercept alone in retardation of joint damage ( mean total Sharp score -0.54 [ 95 % CI -1.00 to -0.07 ] vs 2.80 [ 1.08 to 4.51 ] , p<0.0001 , and 0.52 [ -0.10 to 1.15 ] , p=0.0006 ; respectively ) . The mean difference in total Sharp score between combination and methotrexate alone was -3.34 ( 95 % CI -4.86 to -1.81 , p<0.0001 ) and between etanercept and methotrexate was -27 ( -3.81 to -0.74 , p=0.0469 ) . The number of patients reporting infections or adverse events was similar in all groups . INTERPRETATION The combination of etanercept and methotrexate was significantly better in reduction of disease activity , improvement of functional disability , and retardation of radiographic progression compared with methotrexate or etanercept alone . These findings bring us closer to achievement of remission and repair of structural damage in rheumatoid arthritis [14872476] OBJECTIVE To evaluate the safety , efficacy , and pharmacokinetics of 50 mg etanercept administered subcutaneously once weekly in adult patients with active rheumatoid arthritis ( RA ) . METHODS Four hundred twenty RA patients were r and omized to receive , in a blinded manner , the study drug for up to 16 weeks : 214 patients received 50 mg etanercept once weekly , 153 received 25 mg etanercept twice weekly , and 53 received placebo for 8 weeks followed by 25 mg etanercept twice weekly for 8 weeks . Efficacy and safety were assessed at weeks 8 and 16 . Pharmacokinetic analyses were performed on serum sample s from patients at selected study sites . The primary efficacy end point was achievement of the American College of Rheumatology ( ACR ) 20 % improvement criteria ( ACR20 response ) at week 8 . RESULTS An ACR20 response was achieved at week 8 by 50 % of the patients receiving 50 mg etanercept once weekly , by 49 % of the patients receiving 25 mg etanercept twice weekly , and by 19 % of the patients in the placebo group ( P < /= 0.0001 for each etanercept group versus placebo ) . Similarly , achievement of the ACR50 response was attained by 18 % of patients in each of the 2 etanercept groups , compared with 6 % of patients in the placebo group ( P < 0.03 for each comparison ) . Pharmacokinetics of the 2 etanercept regimens were similar at steady state . No clinical ly significant differences in efficacy or safety were observed between the 2 etanercept groups . CONCLUSION Safety , efficacy , and pharmacokinetics were comparable between the 2 etanercept dosing regimens . Thus , comparable clinical outcomes are to be expected when patients are treated with etanercept administered either as 50 mg once weekly or as 25 mg twice weekly [10075615] BACKGROUND In a phase II study , etanercept ( recombinant human tumor necrosis factor receptor [p75]:Fc fusion protein ) safely produced rapid , dose-dependent improvement in rheumatoid arthritis over 3 months . OBJECTIVE To confirm the benefit of etanercept therapy of longer duration and simplified dosing in patients with rheumatoid arthritis . DESIGN R and omized , double-blind , placebo-controlled trial with blinded joint assessors . SETTING 13 North American centers . PATIENTS 234 patients with active rheumatoid arthritis who had an inadequate response to disease-modifying antirheumatic drugs . INTERVENTION Twice-weekly subcutaneous injections of etanercept , 10 or 25 mg , or placebo for 6 months . MEASUREMENTS The primary end points were 20 % and 50 % improvement in disease activity according to American College of Rheumatology ( ACR ) responses at 3 and 6 months . Other end points were 70 % ACR responses at 3 and 6 months and other measures of disease activity at 3 and 6 months . RESULTS Etanercept significantly reduced disease activity in a dose-related fashion . At 3 months , 62 % of the patients receiving 25 mg of etanercept and 23 % of the placebo recipients achieved 20 % ACR response ( P < 0.001 ) . At 6 months , 59 % of the 25-mg group and 11 % of the placebo group achieved a 20 % ACR response ( P < 0.001 ) ; 40 % and 5 % , respectively , achieved a 50 % ACR response ( P < 0.01 ) . The respective mean percentage reduction in the number of tender and swollen joints at 6 months was 56 % and 47 % in the 25-mg group and 6 % and -7 % in the placebo group ( P < 0.05 ) . Significantly more etanercept recipients achieved a 70 % ACR response , minimal disease status ( 0 to 5 affected joints ) , and improved quality of life . Etanercept was well tolerated , with no dose-limiting toxic effects . CONCLUSIONS Etanercept can safely provide rapid , significant , and sustained benefit in patients with active rheumatoid arthritis [16572442] OBJECTIVE To assess the risk of serious infections following 22 weeks of infliximab therapy , and to further characterize the safety profile of infliximab in combination with background treatments during 1 year in patients with rheumatoid arthritis ( RA ) with various comorbidities . METHODS Patients with active RA despite receiving methotrexate ( MTX ) were r and omly assigned to receive infusions of placebo ( group 1 , n=363 ) , 3 mg/kg infliximab ( group 2 , n=360 ) , or 10 mg/kg infliximab ( group 3 , n=361 ) at weeks 0 , 2 , 6 , and 14 . At week 22 , patients in placebo group 1 began receiving 3 mg/kg infliximab , and patients in group 3 continued to receive an infliximab dose of 10 mg/kg . Patients in group 2 who failed to meet predefined response criteria received increasing doses of infliximab in increments of 1.5 mg/kg . RESULTS At week 22 , the relative risk of developing serious infections in groups 2 and 3 , compared with group 1 , was 1.0 ( 95 % confidence interval [ 95 % CI ] 0.3 - 3.1 , P=0.995 ) and 3.1 ( 95 % CI 1.2 - 7.9 , P=0.013 ) , respectively . The incidence of serious adverse events was 7.8 % in groups 2 and 3 compared with 7.5 % in group 1 . From week 22 to week 54 , 11.8 % , 9.9 % , and 10.3 % of patients in groups 1 , 2 , and 3 , respectively , reported occurrences of serious adverse events . Through week 54 , 1 patient in group 1 , 2 patients in group 2 , and 4 patients in group 3 developed active tuberculosis . CONCLUSION The risk of serious infections in patients receiving the approved infliximab dose of 3 mg/kg plus MTX was similar to that in patients receiving MTX alone . Patients receiving the unapproved induction regimen of 10 mg/kg infliximab plus MTX followed by a 10 mg/kg maintenance regimen had an increased risk of serious infections through week 22 [16464988] Objective : To evaluate the efficacy and safety of etanercept ( ETN ) monotherapy compared with combination ETN and methotrexate ( MTX ) treatment in patients with rheumatoid arthritis who had an inadequate response to MTX monotherapy . ( The response was defined by the presence of Disease Activity Score-28 joint count ( DAS28 ) ⩾3.2 or a combination of ⩾5 swollen joints , ⩾5 painful joints and erythrocyte sedimentation rate ⩾10 mm/h . ) Methods : Patients with active rheumatoid arthritis taking MTX ⩾12.5 mg/week for ⩾3 months were included in this 16 week , r and omised , open-label study . Patients were r and omly assigned to either ETN ( 25 mg subcutaneous injection twice weekly ) added to the baseline dose of MTX or ETN monotherapy . Results : 315 patients were r and omised to ETN ( n = 160 ) or ETN plus MTX ( n = 155 ) . The primary end point , DAS28 ( 4 ) improvement of > 1.2 units , was achieved by 72.8 % and 75.2 % of patients treated with ETN and those treated with ETN plus MTX , respectively , with no significant difference ( p = 0.658 ) between the two groups . The European League Against Rheumatism response criteria of good or moderate response was attained by 80.0 % of patients in the ETN group and by 82.4 % of patients in the ETN plus MTX group . American College of Rheumatology 20 % , 50 % and 70 % response rates achieved by both groups were also similar : 71.0 % v 67.1 % , 41.9 % v 40.1 % and 17.4 % v 18.4 % , respectively . The rates of adverse and serious adverse events were similar between the treatment groups . Conclusion : Both the addition of ETN to MTX and the substitution of ETN for MTX in patients with rheumatoid arthritis who had an inadequate response to MTX result ed in substantial improvements in clinical signs and symptoms and were generally well-tolerated treatment strategies for improving clinical signs and symptoms of rheumatoid arthritis [16395748] OBJECTIVE A placebo controlled , double-blind trial ( DBT ) was conducted for Japanese patients with active rheumatoid arthritis ( RA ) despite treatment with low dose methotrexate ( MTX ) to evaluate the efficacy and safety of infliximab . Extended treatment with infliximab was conducted in an open-label trial ( OLT ) . METHODS In the DBT , 147 patients were r and omly assigned and treated with a placebo or 3 mg/kg or 10 mg/kg infliximab at Weeks 0 , 2 and 6 , combined with MTX . In the OLT , 129 patients from the DBT received 3 mg/kg infliximab every 8 weeks . RESULTS The mean dose of MTX was 7.2 + /- 2.0 mg/week . Significantly more patients receiving 3 mg/kg ( 61.2 % ) and 10 mg/kg (52.9%)infliximab achieved a 20 % improvement according to the American College of Rheumatology ( ACR ) criteria at Week 14 , compared to placebo ( 23.4 % ) ( p < 0.001 ) . There was no significant difference in incidence of adverse events among the treatment groups . In patients receiving infliximab in the DBT , 11.6 % of patients with serum infliximab just before the OLT developed antibodies to infliximab ( ATI ) in the OLT , whereas 62.2 % of patients without serum infliximab did . In patients receiving placebo in the DBT , 43.9 % developed ATI . CONCLUSION The efficacy and safety of infliximab combined with low dose MTX were similar to those of the ATTRACT study . The data from the DBT and OLT also supported the importance of an induction treatment of infliximab , followed by a maintenance treatment without a long interval , giving stable serum concentrations in order to prevent formation of ATI [9219699] BACKGROUND Tumor necrosis factor ( TNF ) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis , and antagonism of TNF may reduce the activity of the disease . This study evaluated the safety and efficacy of a novel TNF antagonist - a recombinant fusion protein that consists of the soluble TNF receptor ( p75 ) linked to the Fc portion of human IgG1 ( TNFR : Fc ) . METHODS In this multicenter , double-blind trial , we r and omly assigned 180 patients with refractory rheumatoid arthritis to receive subcutaneous injections of placebo or one of three doses of TNFR : Fc ( 0.25 , 2 , or 16 mg per square meter of body-surface area ) twice weekly for three months . The clinical response was measured by changes in composite symptoms of arthritis defined according to American College of Rheumatology criteria . RESULTS Treatment with TNFR : Fc led to significant reductions in disease activity , and the therapeutic effects of TNFR : Fc were dose-related . At three months , 75 percent of the patients in the group assigned to 16 mg of TNFR : Fc per square meter had improvement of 20 percent or more in symptoms , as compared with 14 percent in the placebo group ( P<0.001 ) . In the group assigned to 16 mg per square meter , the mean percent reduction in the number of tender or swollen joints at three months was 61 percent , as compared with 25 percent in the placebo group ( P<0.001 ) . The most common adverse events were mild injection-site reactions and mild upper respiratory tract symptoms . There were no dose-limiting toxic effects , and no antibodies to TNFR : Fc were detected in serum sample s. CONCLUSIONS In this three-month trial TNFR : Fc was safe , well tolerated , and associated with improvement in the inflammatory symptoms of rheumatoid arthritis [15146410] OBJECTIVE To determine the potential for additive or synergistic effects of combination therapy with the selective anti-tumor necrosis factor alpha agent etanercept and the anti-interleukin-1 agent anakinra . METHODS Two hundred forty-four patients in whom rheumatoid arthritis ( RA ) was active despite methotrexate therapy were treated with subcutaneous etanercept only ( 25 mg twice weekly ) , full-dosage etanercept ( 25 mg twice weekly ) plus anakinra ( 100 mg/day ) , or half-dosage etanercept ( 25 mg once weekly ) plus anakinra ( 100 mg/day ) for 6 months in a double-blind study at 41 centers in the US . Patients had never previously received anticytokine therapy . Patient response was measured with the American College of Rheumatology ( ACR ) core set criteria , a health-related quality -of-life question naire , and the Disease Activity Score . Safety was assessed by the number of adverse events and clinical laboratory values . Plasma concentrations of both agents and antibody formation against both agents were also assessed . RESULTS Combination therapy with etanercept plus anakinra provided no treatment benefit over etanercept alone , regardless of the regimen , but was associated with an increased safety risk . Thirty-one percent of the patients treated with full-dosage etanercept plus anakinra achieved an ACR 50 % response , compared with 41 % of the patients treated with etanercept only . This result was not statistically significant ( P = 0.914 ) . The incidence of serious infections ( 0 % for etanercept alone , 3.7 - 7.4 % for combination therapy ) , injection-site reactions , and neutropenia was increased with combination therapy . Combination therapy had no effect on the pharmacokinetics or immunogenicity of either agent . CONCLUSION Combination therapy with etanercept and anakinra provides no added benefit and an increased risk compared with etanercept alone and is not recommended for the treatment of patients with RA [15082480] OBJECTIVE To evaluate the efficacy and safety of monotherapy with adalimumab in patients with RA for whom previous DMARD treatment has failed . METHODS In a 26 week , double blind , placebo controlled , phase III trial , 544 patients with RA were r and omised to monotherapy with adalimumab 20 mg every other week , 20 mg weekly , 40 mg every other week , 40 mg weekly , or placebo . The primary efficacy end point was > or = 20 % improvement in the ACR core criteria ( ACR20 response ) . Secondary efficacy end points included ACR50 , ACR70 , EULAR responses , and the Disability Index of the Health Assessment Question naire ( HAQ DI ) . RESULTS After 26 weeks , patients treated with adalimumab 20 mg every other week , 20 mg weekly , 40 mg every other week , and 40 mg weekly had significantly better response rates than those treated with placebo : ACR20 ( 35.8 % , 39.3 % , 46.0 % , 53.4 % , respectively v 19.1 % ; p < or = 0.01 ) ; ACR50 ( 18.9 % , 20.5 % , 22.1 % , 35.0 % v 8.2 % ; p < or = 0.05 ) ; ACR70 ( 8.5 % , 9.8 % , 12.4 % , 18.4 % v 1.8 % ; p < or = 0.05 ) . Moderate EULAR response rates were significantly greater with adalimumab than with placebo ( 41.5 % , 48.2 % , 55.8 % , 63.1 % v 26.4 % ; p < or = 0.05 ) . Patients treated with adalimumab achieved better improvements in mean HAQ DI than those receiving placebo ( -0.29 , -0.39 , -0.38 , -0.49 v -0.07 ; p < or = 0.01 ) . No significant differences were found between adalimumab and placebo treated patients for serious adverse events , serious infections , or malignancies . Injection site reaction occurred in 10.6 % and 0.9 % of adalimumab and placebo treated patients , respectively ( p < or = 0.05 ) . CONCLUSION Among patients with RA for whom previous DMARD treatment had failed , adalimumab monotherapy achieved significant , rapid , and sustained improvements in disease activity and improved physical function and was safe and well tolerated [16014203] OBJECTIVES To survey the frequency of use of indirect comparisons in systematic review s and evaluate the methods used in their analysis and interpretation . Also to identify alternative statistical approaches for the analysis of indirect comparisons , to assess the properties of different statistical methods used for performing indirect comparisons and to compare direct and indirect estimates of the same effects within review s. DATA SOURCES Electronic data bases . REVIEW METHODS The Data base of Abstract s of Review s of Effects ( DARE ) was search ed for systematic review s involving meta- analysis of r and omised controlled trials ( RCTs ) that reported both direct and indirect comparisons , or indirect comparisons alone . A systematic review of MEDLINE and other data bases was carried out to identify published methods for analysing indirect comparisons . Study design s were created using data from the International Stroke Trial . R and om sample s of patients receiving aspirin , heparin or placebo in 16 centres were used to create meta-analyses , with half of the trials comparing aspirin and placebo and half heparin and placebo . Methods for indirect comparisons were used to estimate the contrast between aspirin and heparin . The whole process was repeated 1000 times and the results were compared with direct comparisons and also theoretical results . Further detailed case studies comparing the results from both direct and indirect comparisons of the same effects were undertaken . RESULTS Of the review s identified through DARE , 31/327 ( 9.5 % ) included indirect comparisons . A further five review s including indirect comparisons were identified through electronic search ing . Few review s carried out a formal analysis and some based analysis on the naive addition of data from the treatment arms of interest . Few method ological papers were identified . Some valid approaches for aggregate data that could be applied using st and ard software were found : the adjusted indirect comparison , meta-regression and , for binary data only , multiple logistic regression ( fixed effect models only ) . Simulation studies showed that the naive method is liable to bias and also produces over-precise answers . Several methods provide correct answers if strong but unverifiable assumptions are fulfilled . Four times as many similarly sized trials are needed for the indirect approach to have the same power as directly r and omised comparisons . Detailed case studies comparing direct and indirect comparisons of the same effect show considerable statistical discrepancies , but the direction of such discrepancy is unpredictable . CONCLUSIONS Direct evidence from good- quality RCTs should be used wherever possible . Without this evidence , it may be necessary to look for indirect comparisons from RCTs . However , the results may be susceptible to bias . When making indirect comparisons within a systematic review , an adjusted indirect comparison method should ideally be used employing the r and om effects model . If both direct and indirect comparisons are possible within a review , it is recommended that these be done separately before considering whether to pool data . There is a need to evaluate methods for the analysis of indirect comparisons for continuous data and for empirical research into how different methods of indirect comparison perform in cases where there is a large treatment effect . Further study is needed into when it is appropriate to look at indirect comparisons and when to combine both direct and indirect comparisons . Research into how evidence from indirect comparisons compares to that from non-r and omised studies may also be warranted . Investigations using individual patient data from a meta- analysis of several RCTs using different protocol s and an evaluation of the impact of choosing different binary effect measures for the inverse variance method would also be useful [19369178] BACKGROUND / PURPOSE Adalimumab is a fully humanized monoclonal antibody that blocks tumor necrosis factor (TNF)-alpha , which is effective in the treatment of patients with rheumatoid arthritis ( RA ) . The purpose of this study was to compare the efficacy and safety of adalimumab plus methotrexate ( MTX ) and MTX alone in Taiwanese patients with active RA . METHODS Forty-seven patients with active RA who were maintained on MTX therapy at a stable dose of 10 - 15 mg/week for 4 weeks were r and omized blindly to receive adalimumab 40 mg ( n = 35 ) or placebo ( n = 12 ) by subcutaneous injection every other week over a period of 12 weeks . The primary endpoint was a reduction in tender and swollen joint counts of 20 % ( ACR20 ) , 50 % ( ACR50 ) and 70 % ( ACR70 ) , as determined by the American College of Rheumatology criteria in week 12 . The occurrence of treatment-emergent adverse events ( TEAEs ) was the primary safety variable . RESULTS Addition of adalimumab to MTX result ed in a significant reduction in the number of swollen joints ( 12.6 vs. 5.6 ; p = 0.011 ) , patients ' global assessment of disease activity ( 18.0 vs. 4.8 ; p = 0.040 ) , pain visual analog scale ( 18.3 vs. 1.3 ; p = 0.015 ) , and disability indices of the Health Assessment Question naire ( 0.6 vs. 0.2 ; p = 0.031 ) , compared with MTX alone after 12 weeks of therapy . Overall improvement in disease activity was assessed by ACR20 ( 54.3 % vs. 33.3 % ) , ACR50 ( 34.3 % vs. 16.7 % ) and ACR70 ( 14.3 % vs. 0 % ) , and all favored the adalimumab plus MTX group . TEAEs were comparable between the treatment groups , except for a slightly higher incidence of severe infection in the adalimumab plus MTX group . CONCLUSION Adalimumab in combination with MTX is well tolerated and provides significantly more clinical benefits than MTX alone in Taiwanese patients with active RA [16785475] Context Abatacept , an agent that selectively modulates the co-stimulatory signal required for T-cell activation , may benefit some patients with rheumatoid arthritis . Contribution This 1-year , r and omized , double-blind trial compared once-monthly infusions of abatacept with placebo in 652 patients with symptomatic rheumatoid arthritis despite ongoing methotrexate treatment . Compared with placebo recipients , patients who received abatacept more often had improved physical function , more frequently met st and ard response criteria , and less often had radiographic progression of joint damage . They also had serious infections ( 2.5 % vs. 0.9 % ) and infusion reactions more often . Implication s Adding abatacept can reduce disease activity in patients with rheumatoid arthritis and an inadequate response to methotrexate . The Editors Rheumatoid arthritis is characterized by synovial membrane hyperplasia and inflammatory cell infiltrate , including activated T cells ( 1 ) . T cells contribute to the initiation and perpetuation of rheumatoid arthritis immunopathology , leading to inflammation and , ultimately , joint destruction . Activated T cells proliferate and induce monocytes , macrophages , and synovial fibroblasts to produce proinflammatory cytokines , such as tumor necrosis factor- , interleukin-1 , and interleukin-6 ( 1 ) , and stimulate osteoclastogenesis and matrix metalloproteinase secretion ( 2 ) , as well as immunoglobulin production by B cells ( 3 ) . The central role of activated T cells in rheumatoid arthritis immunopathology makes T-cell activation a rational therapeutic target . T cells require 2 signals for full activation : an antigen-specific signal ( signal 1 ) and a co-stimulatory signal ( signal 2 ) ( 4 ) . One of the best-characterized co-stimulatory pathways is the engagement of CD80 or CD86 on antigen-presenting cells with CD28 on T cells ( 5 ) . In the normal immune response , endogenous cytotoxic T-lymphocyte antigen-4 ( CTLA-4 ) downregulates CD28-mediated T-cell activation by binding to CD80 or CD86 with higher avidity than CD28 ( 6 ) . Abatacept is a soluble , recombinant , fully human fusion protein , comprising the extracellular domain of CTLA-4 and the Fc portion of IgG1 , modified to prevent complement fixation . Abatacept is the first in a new class of agents for treating rheumatoid arthritis that selectively modulate the co-stimulatory signal required for full T-cell activation . A phase IIa study of patients with rheumatoid arthritis and an inadequate response to disease-modifying antirheumatic drugs showed the efficacy of abatacept as monotherapy ( 7 ) . In a phase IIb study of abatacept plus methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate , signs and symptoms of rheumatoid arthritis , physical function , and health-related quality of life statistically significantly improved over 1 year ( 8 , 9 ) . We present findings from the phase III , 1-year Abatacept in Inadequate Responders to Methotrexate ( AIM ) trial , which was design ed to further evaluate the safety and clinical efficacy of abatacept plus methotrexate and to assess the effects of abatacept on the radiographic progression of structural damage . Methods The institutional review boards or independent ethics committees approved a common clinical protocol for each site , and we performed the study in accordance with the ethical principles of the Declaration of Helsinki . All patients provided written informed consent to the study protocol before r and omization . Patients Eligible patients were at least 18 years of age , had had rheumatoid arthritis for at least 1 year , and met the American Rheumatism Association criteria for rheumatoid arthritis ( 10 ) . Rheumatoid arthritis was persistent and active despite methotrexate treatment . All patients must have been treated with methotrexate ( 15 mg/wk ) for 3 months or longer , with a stable dose for 28 days before enrollment . We required patients to undergo a washout of all other disease-modifying antirheumatic drugs at least 28 days before r and omization . We allowed corticosteroid use , with dosages equal to 10 mg of prednisone or less per day , stabilized for 25 days before r and omization . At r and omization , we required patients to have 10 or more swollen joints , 12 or more tender joints , and C-reactive protein levels of 10.0 mg/L or greater ( normal range , 1.0 mg/L to 4.0 mg/L ) while receiving methotrexate . We required tuberculin skin testing before r and omization . We excluded patients with a positive tuberculin skin test result unless they had completed treatment for latent tuberculosis before enrollment . Study Design Our 1-year , multicenter , multinational , r and omized , double-blind , placebo-controlled study aim ed to compare the efficacy and safety of abatacept versus placebo in combination with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate treatment . We used a central r and omization system , and the Drug Management Group within Bristol-Myers Squibb , Princeton , New Jersey , generated the r and omization schedule . Stratification per site was not performed . Patients were r and omly assigned in a 2:1 ratio to receive either a fixed dose of abatacept , approximately 10 mg/kg of body weight , or placebo . Patients weighing less than 60 kg , 60 to 100 kg , or more than 100 kg received 500 mg , 750 mg , or 1000 mg of abatacept , respectively . We administered study medication by 30-minute intravenous infusion on days 1 , 15 , and 29 and then every 28 days up to and including day 337 . No premedication was required . The protocol specified that all patients were to receive methotrexate , 15 mg or more per week , although methotrexate at 10 mg per week was acceptable if the patient had a history of toxicity . During the first 6 months , we did not allow adjustments in methotrexate dose , except in cases of toxicity . We permitted use of stable dosages of nonsteroidal anti-inflammatory drugs and corticosteroid dosages equal to 10 mg of prednisone or less per day . Between 6 and 12 months , we allowed the following adjustments , as the investigator deemed necessary : 1 ) adjustment in methotrexate dose , 2 ) addition of 1 other disease-modifying antirheumatic drug ( hydroxychloroquine , sulfasalazine , gold , or azathioprine ) , or 3 ) adjustment in corticosteroid dose equal to 10 mg of prednisone or less per day . However , investigators were blinded to treatment group assignment throughout the 1-year study . Clinical Efficacy Measures Our 3 primary objectives were to evaluate the proportion of patients in each group with a 20 % improvement in American College of Rheumatology ( ACR ) response criteria ( ACR 20 ) at 6 months , the proportion of patients in each group with clinical ly significant improvement ( 0.3 unit ) in the Health Assessment Question naire Disability Index ( HAQ-DI ) score ( 11 ) at 1 year , and the radiographic progression of joint erosions ( assessed by comparing changes from baseline in the Genant-modified Sharp score ) ( 12 , 13 ) at 1 year . Table 1 summarizes the outcome measures used to assess the response to treatment . Table 1 . Outcome Measures for Assessing Response to Treatment of Rheumatoid Arthritis * Secondary objectives included assessing ACR 50 and ACR 70 responses at 6 months and all ACR responses at 1 year . In addition , we determined the proportions of patients achieving a major clinical response and a protocol -defined extended major clinical response at 1 year . We also assessed changes in disease activity by using the Disease Activity Score 28 ( DAS28 ) ( 20 , 21 ) . We assessed improvements in physical function over 1 year by using the HAQ-DI , which measures physical function during daily activities ( 22 ) . We evaluated changes in health-related quality of life by using the Medical Outcomes Study Short Form-36 Health Survey ( SF-36 ) ( 17 ) , which evaluates physical and mental health status ( Table 1 ) ( 18 , 19 ) . Physicians blinded to treatment group assignment performed assessment s at enrollment and at every visit before treatment administration on days 1 , 15 , and 29 ; every 28 days up to and including day 169 ( 6 months ) ; and on days 225 , 281 , and 365 ( 1 year ) . Radiographic Evaluation We performed st and ardized radiography of the h and s or wrists and feet at baseline and at 1 year or upon early termination ( if applicable ) . Two independent expert readers who were blinded to treatment group assignment , chronological order of radiography , and patients ' clinical response assessed all radiographic images for changes in erosion and joint-space narrowing by using the Genant-modified Sharp scoring system . Safety and Immunogenicity We monitored all patients who received at least 1 dose of the study medication for adverse events , serious adverse events , infusion reactions , clinical laboratory test abnormalities , and clinical ly significant changes in vital signs . Adverse events were self-reported by the patient and elicited by general question ing and examination at each visit . We attributed an adverse event to the study treatment on the basis of the investigator 's opinion , and we deemed an event as serious by st and ard regulatory definition . An external safety advisory panel , consisting of 5 physicians ( 3 rheumatologists , 1 oncologist , and 1 infectious disease expert ) , assessed overall safety in a blinded fashion by using reports of adverse events and laboratory results on a quarterly basis . We obtained serum sample s before infusions on days 1 , 29 , 85 , 169 , 281 , and 365 or 28 days after the last dose of the study medication in patients who discontinued before 1 year . We assessed immunogenicity by immunoassay to measure the antibody response to the entire abatacept molecule and also specifically to the CTLA-4 portion of the molecule ( 7 ) . Statistical Analysis The protocol estimated that 680 patients would need to be enrolled to r and omly assign 540 patients . We based sample sizes on a 5 % level of significance ( 2-tailed ) . The study had 99 % power to detect a difference of 20 % in ACR 20 between the 2 groups . On the basis of the [16482646] OBJECTIVE To assess the safety and efficacy of etanercept 50 mg administered twice weekly versus 25 mg administered twice weekly as monotherapy in patients with tumor necrosis factor-alpha ( TNF-alpha ) blocker-naäve active rheumatoid arthritis ( RA ) . METHODS Seventy-seven patients with RA were r and omized in an unequal allocation ( 2:1 ) in a blinded fashion to receive either 50 mg ( 51 patients ) or 25 mg ( 26 patients ) of etanercept twice a week for 24 weeks . RESULTS The primary outcome measure , the ACR-N AUC at 24 weeks , showed no difference between the 2 dose groups . In addition , there was no difference in ACR 20 , 50 , and 70 responses or in EULAR response criteria by Week 24 . There were no statistically significant differences between the 2 groups in the proportion of patients with any non-infectious adverse event . The proportion of patients with upper respiratory tract infections was significantly higher in patients receiving 50 mg etanercept compared with those receiving 25 mg ( 26 % vs 4 % , p = 0.027 ) . CONCLUSION Etanercept as a monotherapy at 50 mg twice weekly does not provide increased efficacy when compared to the st and ard dose of 25 mg twice weekly in TNF-alpha blocker-naäve patients [20079321] OBJECTIVE To investigate the efficacy and safety of adalimumab plus methotrexate ( MTX ) for the treatment of rheumatoid arthritis ( RA ) . METHODS This is a multi-center , r and omized , double-blind , parallel-group , and placebo-controlled clinical study , included a total of 302 cases of active rheumatoid arthritis , r and omized into three groups of observation : 40 mg adalimumab ( 121 cases ) , 80 mg adalimumab ( 121 cases ) , or placebo ( 60 cases ) . Upon enrollment , all subjects had been previously treated with MTX for at least 3 months , and their doses of drug had remained stable for at least 28 days . The double-blind phase lasted for 12 weeks , during which the subjects were administered with adalimumab or placebo subcutaneously every other week . Then the subjects entered into another 12 weeks of open-label study , which included subcutaneous injection of 40 mg adalimumab every other week . In both the double-blind and the open-label periods , all subjects were maintained concomitantly with MTX that had already been used before this study . The primary efficacy variables were evaluated on basis of American College of Rheumatology (ACR)20 response rate at week 12 . The secondary efficacy variables included : ACR20 response rate at week 24 ; ACR50 and ACR70 response rates at weeks 12 and 24 ; and changes at weeks 12 and 24 compared with baseline observations for tender and swollen joint counts , as well as the assessment of pain with visual analog scale ( VAS ) , the physician 's and the patient 's global assessment of disease activity ( VAS ) , and the analysis on health assessment question naire ( HAQ ) and health related quality of life ( HRQL ) measured by Short Form-36 ( SF-36 ) ; The safety variables mainly included adverse events ( AE ) . RESULT During the double-blind period , subjects treated with 40 mg of adalimumab , 57.0 % achieved ACR20 response at week 12 ( P = 0.004 versus placebo ) , and subjects treated with 80 mg of adalimumab , 51.2 % achieved ACR20 response at week 12 ( P = 0.026 versus placebo ) , and only 35.0 % of subjects treated with placebo achieved ACR20 response at week 12 . On the other h and , 32.2 % of subjects receiving 40 mg of adalimumab achieved ACR50 response ( P = 0.009 versus placebo ) , and 15.7 % achieved ACR70 response ( P = 0.007 versus placebo ) at week 12 . Subjects treated with 40 mg of adalimumab got a better result versus placebo at week 12 for tender joint count , swollen joint count , and improvement in C-reactive protein ; and subjects treated with 80 mg of adalimumab were also seen an amelioration versus placebo at week 12 for swollen joint count , and improvement in C-reactive protein ; all of these findings were statistically significant in differences . During the open-label period all subjects received 40 mg of adalimumab , and response rates for ACR20 , ACR50 , and ACR70 in the two treatment groups of 40 mg and 80 mg adalimumab were maintained or improved from week 12 to week 24 ( being 73.1 % , 40.3 % and 17.6 % respectively for 40 mg group ; 71.1 % , 39.5 % and 17.5 % respectively for 80 mg group ) ; while response in the original placebo group ( being 67.8 % , 44.1 % and 18.6 % ) increased during the 12-week open-label period to match that of the original adalimumab treatment groups . While for changes in tender and swollen joint counts , VAS , HAQ , SF-36 , a significant improvement was seen at week 24 when compared with baseline and week 12 values . Throughout the double-blind and open-label period , adverse events reported in > /= 5 % of subjects at least possibly associated with the study drug were upper respiratory tract infection , nasopharyngitis , and injection site itching , mostly being mild to moderate in severity . There were 3 cases of tuberculosis reported during this study . And 3 cases of serious adverse event ( SAE ) were reported among the adalimumab subjects during the double-blind period , which were determined as unrelated or probably unrelated to the study drug . And 8 cases ( 2.7 % ) of SAE were seen among the adalimumab subjects during the open-label period , 3 of which were at least possibly unrelated with the study drug . All SAEs reported were consistent to those seen in other adalimumab trials . No other unexpected safety signals were reported . CONCLUSION Adalimumab plus MTX is better than single MTX in efficacy for the treatment of RA . Being generally safe and well tolerated , adalimumab plus MTX can significantly increase the response rate , continuously reduce the arthritic signs , symptoms and the inflammatory factors in patients , and also be helpful for reducing disabilities and improving the global quality of life for the patients [18383539] OBJECTIVE To assess the efficacy , safety , and pharmacology of subcutaneous administration of golimumab in patients with active rheumatoid arthritis ( RA ) despite treatment with methotrexate ( MTX ) . METHODS Patients were r and omly assigned in a double-blinded manner to receive injections of placebo plus MTX or 50 mg or 100 mg golimumab every 2 or 4 weeks plus MTX through week 48 . Patients originally assigned to receive injections every 2 weeks had the interval increased to every 4 weeks starting at week 20 . The primary end point was the proportion of patients meeting the American College of Rheumatology 20 % improvement criteria ( achieving an ACR20 response ) at week 16 . The study was powered to detect a difference in the primary end point when the combined golimumab groups and at least 1 of the individual dose groups were compared with placebo . RESULTS The primary end point was attained . Sixty-one percent of patients in the combined golimumab plus MTX dose groups achieved an ACR20 response at week 16 compared with 37 % of patients in the placebo plus MTX group ( P=0.010 ) . In addition , 79 % of patients in the group receiving 100 mg golimumab every 2 weeks achieved an ACR20 response ( P<0.001 versus placebo ) . Through week 20 ( after which patients receiving placebo were switched to active infliximab therapy ) , serious adverse events were reported in 9 % of patients in the combined golimumab groups and in 6 % of patients in the placebo group . CONCLUSION Golimumab plus MTX effectively reduces the signs and symptoms of RA and is generally well tolerated in patients with an inadequate response to MTX [18821691] OBJECTIVE To examine the efficacy and safety of the humanized anti-interleukin-6 receptor antibody tocilizumab combined with conventional disease-modifying antirheumatic drugs ( DMARDs ) in patients with active rheumatoid arthritis ( RA ) . METHODS A total of 1,220 patients were r and omized ( 2:1 ratio ) in the phase III , double-blind , placebo-controlled , multicenter TOWARD ( Tocilizumab in Combination With Traditional DMARD Therapy ) study . Patients remained on stable doses of DMARDs and received tocilizumab 8 mg/kg or placebo ( control group ) every 4 weeks for 24 weeks . RESULTS At week 24 , the proportion of patients achieving a response according to the American College of Rheumatology criteria for 20 % improvement ( ACR20 ) was significantly greater in the tocilizumab plus DMARD group than in the control group ( 61 % versus 25 % ; P<0.0001 ) . Secondary end points including 50 % or 70 % improvement ( ACR50/70 ) , the Disease Activity Score in 28 joints ( DAS28 ) , DAS28 remission responses ( DAS28<2.6 ) , European League Against Rheumatism responses , and systemic markers such as the C-reactive protein and hemoglobin levels showed superiority of tocilizumab plus DMARDs over DMARDs alone . Seventy-three percent of patients in the tocilizumab group had > or=1 adverse event ( AE ) , compared with 61 % of patients in the control group . AEs leading to withdrawal from the study were infrequent ( 4 % of patients in the tocilizumab group and 2 % of those in the control group ) . Serious AEs occurred in 6.7 % and 4.3 % of patients in the tocilizumab and control groups , respectively , and serious infections occurred in 2.7 % and 1.9 % , respectively . Elevations in the alanine aminotransferase level , from normal at baseline to > 3-fold the upper limit of normal , occurred in 4 % of patients in the tocilizumab group and 1 % of those in the control group , and elevated total cholesterol levels were observed in 23 % and 6 % of patients , respectively . Sixteen patients started lipid-lowering therapy during the study . Grade 3 neutropenia occurred in 3.7 % of patients receiving tocilizumab and none of the patients in the control group , and no grade 4 neutropenia was reported . CONCLUSION Tocilizumab combined with any of the DMARDs evaluated was safe and effective in reducing articular and systemic symptoms in patients with an inadequate response to these agents [15340661] BACKGROUND AND PURPOSE Etanercept ( Enbrel ) , a recombinant tumor necrosis factor receptor fusion protein , has been shown to be effective in the treatment of patients with rheumatoid arthritis ( RA ) . The purpose of this study was to compare the efficacy and safety of etanercept in combination with methotrexate ( MTX ) and MTX alone in Taiwanese patients with active RA . METHODS In this double-blind study , 58 patients with active RA who were maintained on MTX therapy at a stable dose of 12.5 to 20 mg per week for 4 weeks were r and omized to receive either etanercept 25 mg ( n = 29 ) or placebo ( n = 29 ) by subcutaneous injection twice weekly over a period of 12 weeks . The primary endpoint was the reduction of tender and swollen joint counts by 20 % ( ACR 20 ) , 50 % ( ACR 50 ) , and 70 % ( ACR 70 ) as determined by the American College of Rheumatology criteria at the 12th week . RESULTS The addition of etanercept to MTX result ed in a greater reduction in the number of tender ( 7.00 vs 2.45 , p = 0.012 ) and swollen joints ( 8.55 vs 3.86 , p = 0.017 ) , and in serum levels of C-reactive protein ( 1.26 mg/dL vs 0.45 mg/dL , p = 0.014 ) compared to MTX alone after 12 weeks of therapy . In addition , the global assessment of disease activity by both physicians and patients , duration of morning stiffness , pain visual analog scale score , and Health Assessment Question naire were all improved by etanercept plus MTX therapy . Results for the overall improvement in disease activity assessed by ACR 20 ( 90 % vs 34 % ) , ACR 50 ( 66 % vs 10 % ) and ACR 70 ( 24 % vs 0 % ) all favored the etanercept plus MTX group . However , the adverse events were comparable between the 2 treatment groups . CONCLUSION Etanercept in combination with MTX was well tolerated and provided significantly more clinical benefit than MTX alone in Taiwanese patients with active RA [20131276] OBJECTIVE To assess the efficacy and safety of intravenous administration of golimumab in patients with rheumatoid arthritis ( RA ) . METHODS Adult patients with RA in whom disease activity was persistent despite treatment with methotrexate ( MTX ) at a dosage of 15 - 25 mg/week for > or = 4 weeks were r and omized to receive intravenous infusions of placebo plus MTX or intravenous infusions of golimumab at a dose of 2 mg/kg or 4 mg/kg , with or without MTX , every 12 weeks through week 48 . Patients with < 20 % improvement in the swollen and tender joint counts could enter early escape and receive additional active treatment ( week 16 ) or could have their dose regimen adjusted ( week 24 ) . The primary end point was the proportion of patients achieving a 50 % response according to the American College of Rheumatology improvement criteria ( ACR50 ) at week 14 . RESULTS The primary study end point was not met ( at week 14 , an ACR50 response was observed in 21 % of the patients treated with golimumab plus MTX compared with 13 % of the patients treated with placebo plus MTX [ P = 0.051 ] ) . By week 24 , significantly more patients treated with golimumab plus MTX had achieved an ACR50 response . Differences in the proportion of patients achieving an ACR50 response between the group receiving golimumab monotherapy and the group receiving placebo plus MTX were not significant at either week 14 ( 16 % versus 13 % ) or week 24 ( 10 % versus 9 % ) . At week 48 , the proportions of patients achieving ACR20 and ACR50 responses were highest among those who had received golimumab 4 mg/kg plus MTX ( 70 % and 48 % , respectively ) . Concomitant treatment with MTX was associated with a lower incidence of antibodies to golimumab . The most commonly reported adverse events through week 48 were infections ( 48 % of patients treated with golimumab with or without MTX and 41 % of patients receiving placebo plus MTX ) . CONCLUSION The primary end point was not met . However , intravenously administered golimumab plus MTX appears to have benefit in the longer-term reduction of RA signs/symptoms in MTX-resistant patients , with no unexpected safety concerns Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: OBJECTIVES Rheumatoid arthritis ( RA ) is a chronic inflammatory disease associated with increasing disability , reduced quality of life and substantial costs ( as a result of both intervention acquisition and hospitalisation ) . The objective was to assess the clinical effectiveness and cost-effectiveness of seven biologic disease-modifying antirheumatic drugs ( bDMARDs ) compared with each other and conventional disease-modifying antirheumatic drugs ( cDMARDs ) . Sensitivity analyses were undertaken to explore the impact of including RCTs with a small proportion of bDMARD experienced patients and where MTX exposure was deemed insufficient . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

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[11296183] STUDY OBJECTIVES To determine whether sedation with propofol would lead to shorter times to tracheal extubation and ICU length of stay than sedation with midazolam . DESIGN Multicenter , r and omized , open label . SETTING Four academic tertiary-care ICUs in Canada . PATIENTS Critically ill patients requiring continuous sedation while receiving mechanical ventilation . INTERVENTIONS R and om allocation by predicted requirement for mechanical ventilation ( short sedation stratum , < 24 h ; medium sedation stratum , > or = 24 and < 72 h ; and long sedation stratum , > or = 72 h ) to sedation regimens utilizing propofol or midazolam . MEASUREMENTS AND RESULTS Using an intention-to-treat analysis , patients r and omized to receive propofol in the short sedation stratum ( propofol , 21 patients ; midazolam , 26 patients ) and the long sedation stratum ( propofol , 4 patients ; midazolam , 10 patients ) were extubated earlier ( short sedation stratum : propofol , 5.6 h ; midazolam , 11.9 h ; long sedation stratum : propofol , 8.4 h ; midazolam , 46.8 h ; p < 0.05 ) . Pooled results showed that patients treated with propofol ( n = 46 ) were extubated earlier than those treated with midazolam ( n = 53 ) ( 6.7 vs 24.7 h , respectively ; p < 0.05 ) following discontinuation of the sedation but were not discharged from ICU earlier ( 94.0 vs 63.7 h , respectively ; p = 0.26 ) . Propofol-treated patients spent a larger percentage of time at the target Ramsay sedation level than midazolam-treated patients ( 60.2 % vs 44.0 % , respectively ; p < 0.05 ) . Using a treatment-received analysis , propofol sedation either did not differ from midazolam sedation in time to tracheal extubation or ICU discharge ( sedation duration , < 24 h ) or was associated with earlier tracheal extubation but longer time to ICU discharge ( sedation duration , > or = 24 h , < 72 h , or > or = 72 h ) . CONCLUSIONS The use of propofol sedation allowed for more rapid tracheal extubation than when midazolam sedation was employed . This did not result in earlier ICU discharge [3786847] The aim of this study was to observe the impact of dexmedetomidine on postoperative myocardial injury in patients undergoing off-pump coronary artery bypass ( OPCAB ) grafting . One hundred and sixty-two patients who were undergoing OPCAB surgery were r and omly divided into control and dexmedetomidine groups ( groups C and Dex , respectively ) . Following the first vascular anastomosis grafting , the patients in group Dex received a continuous intravenous infusion of 0.2–0.5 μg/kg/h dexmedetomidine , until they were transferred to the Cardiac Surgery intensive care unit ( ICU ) for 12 h. Patients in group C received physiological saline intraoperatively and an intravenous infusion of 2–4 mg/kg/h isopropylphenol for postoperative sedation . Invasive arterial pressure and heart rate were continuously monitored for 5 min subsequent to entry into the operating theatre ( T0 ) , immediately following surgery ( T1 ) , 12 h post-surgery ( T2 ) , 24 h post-surgery(T3 ) , 48 h post-surgery(T4 ) and 72 h post-surgery ( T5 ) . Blood sample s were taken to determine the plasma levels of cardiac troponin I ( cTnI ) and creatine kinase-MB ( CK-MB ) at each time point . At 72 h post-surgery , a dynamic electrocardiogram was monitored . The blood pressure , heart rate , levels of cTnI , CK-MB , norepinephrine and cortisol , and postoperative arrhythmic events in the patients in group Dex all decreased compared with those in group C. The duration of mechanical ventilation and ICU residence time were also shorter than those in the control group ( P<0.05 ) . Dexmedetomidine reduced post-surgical myocardial injury in patients who had undergone OPCAB surgery [21744187] Objective To compare the efficacy of dexmedetomidine versus morphine as a sedative/analgesic among post-operative cardiac surgery patients . Method A r and omized controlled open-label study was performed at the cardiothoracic intensive care unit of Penang Hospital , Malaysia . A total of 28 patients who underwent cardiac surgeries were r and omly assigned to receive either dexmedetomidine or morphine . Both groups were similar in terms of preoperative baseline characteristics . Efficacy measures included sedation scores and pain intensity and requirements for additional sedative/analgesic . Mean heart rate and arterial blood pressure were used as safety measures . Other measures were additional inotropes , extubation time and other concurrent medications . Results The mean dose of dexmedetomidine infused was 0.12 [ SD 0.03 ] μg kg−1 h−1 , while that of morphine was 13.2 [ SD 5.84 ] μg kg−1 h−1 . Dexmedetomidine group showed more benefits in sedation and pain levels , additional sedative/analgesic requirements , and extubation time . No significant differences between the two groups for the outcome measures , except heart rate , which was significantly lower in the dexmedetomidine group . Conclusion This preliminary study suggests that dexmedetomidine was at least comparable to morphine in terms of efficacy and safety among cardiac surgery patients . Further studies with larger sample s are recommended in order to determine the significant effects of the outcome measures [26203971] BACKGROUND Patients and medical staff are exposed to high noise levels in ICUs , which may have a negative impact on their health . Due to the diversity of noise sources present , including the operating noise of medical devices , staff conversations and the unwrapping of disposables , noise profiles are varied . Psychoacoustics deals with the analysis of sound , focusing on its effects on physiological perception and stress . OBJECTIVES The aim of our study was to examine and to classify noise and its psychoacoustic properties in different locations in our ICU at different times . The impact of noise on subjective parameters and stress-related physiological data was also assessed with and without interventional methods . DESIGN A r and omised , controlled , single-blinded clinical trial . SETTING University Hospital , from November 2010 to May 2011 . PATIENTS One hundred and forty-four patients in the ICU . INTERVENTIONS In the first part , multidisciplinary psychoacoustic measurement was performed on the patients in our ICU . In the subsequent clinical trial , patients were equipped with effective earplugs , less effective earplugs and no earplugs . Thereafter , active noise cancellation headphones with or without sound masking were employed on a third patient population . MAIN OUTCOME MEASURES Cortisol and & agr;-amylase in saliva , skin conductance measures , vital signs , psychoacoustic analyses and two st and ardised question naires [ State-Trait Anxiety Inventory ( STAI ) and Hospital Anxiety and Depression Scale ( HADS ) ] were assessed . RESULTS In the first part , the mean ± st and ard deviation ( SD ) subjective loudness was 9.2 ± 4.0 sone . Although absolute sound pressure level and loudness were lower during the night , the number of loud events increased significantly . Skin conductance in the earplug groups was significantly reduced in comparison to that in the control population but not the active noise reduction groups . Nevertheless , noise reduction was found to be comfortable for most patients . CONCLUSION Noise in the ICU is of high clinical relevance . Diverse noise reduction methods , such as earplugs and active noise cancellation , are available . The avoidance of unnecessary noise , however , should be the primary focus . TRIAL REGISTRATION German Clinical Trials Register ( DRKS00000534 ) [4353161] Background and Aims : Patients on ventilatory support in intensive care unit ( ICU ) require sedation and analgesia to facilitate mechanical ventilation and endotracheal tube tolerance . The selection of the agent should be such that it does not interfere with the early extubation of the patients . We compared the efficacy of dexmedetomidine with midazolam to facilitate extubation of patients from mechanical ventilation in terms of the sedative properties , cardiovascular responses , ventilation , and extubation characteristics and safety profile . Material s and Methods : A total of 40 adult , mechanically ventilated patients of either sex , aged 18 - 60 years , meeting the st and ard criteria for weaning , r and omized into 2 groups of 20 patients each , received intravenous infusion of dexmedetomidine ( 0.2 - 0.7 mcg/kg/h ) or midazolam ( 0.04 - 0.2 mg/kg/h ) as needed for Ramsay sedation scale 2 - 4 . Extubation following st and ard extubation protocol was done . Time for extubation and vital parameters were regularly recorded . Results : The time to extubation in the dexmedetomidine group was significantly lower than in the midazolam group . Heart rate and blood pressure was significantly lower in dexmedetomidine group than the midazolam group at most of the times . Conclusions : Dexmedetomidine has clinical ly relevant benefits compared with midazolam in facilitating extubation due to its shorter time to extubation , more hemodynamic stability , easy arousability , and lack of respiratory depression [3580615] Introduction This study hypothesised that a reduction of sound during the night using earplugs could be beneficial in the prevention of intensive care delirium . Two research questions were formulated . First , does the use of earplugs during the night reduce the onset of delirium or confusion in the ICU ? Second , does the use of earplugs during the night improve the quality of sleep in the ICU ? Methods A r and omized clinical trial included adult intensive care patients in an intervention group of 69 patients sleeping with earplugs during the night and a control group of 67 patients sleeping without earplugs during the night . The research ers were blinded during data collection . Assignment was performed by an independent nurse research er using a computer program . Eligible patients had an expected length of stay in the ICU of more than 24 hours , were Dutch- or English-speaking and scored a minimum Glasgow Coma Scale of 10 . Delirium was assessed using the vali date d NEECHAM scale , sleep perception was reported by the patient in response to five questions . Results The use of earplugs during the night lowered the incidence of confusion in the studied intensive care patients . A vast improvement was shown by a Hazard Ratio of 0.47 ( 95 % confidence interval ( CI ) 0.27 to 0.82 ) . Also , patients sleeping with earplugs developed confusion later than the patients sleeping without earplugs . After the first night in the ICU , patients sleeping with earplugs reported a better sleep perception . Conclusions Earplugs may be a useful instrument in the prevention of confusion or delirium . The beneficial effects seem to be strongest within 48 hours after admission . The relation between sleep , sound and delirium , however , needs further research .Trial registration Current Controlled Trials IS RCT [18073360] CONTEXT Lorazepam is currently recommended for sustained sedation of mechanically ventilated intensive care unit ( ICU ) patients , but this and other benzodiazepine drugs may contribute to acute brain dysfunction , ie , delirium and coma , associated with prolonged hospital stays , costs , and increased mortality . Dexmedetomidine induces sedation via different central nervous system receptors than the benzodiazepine drugs and may lower the risk of acute brain dysfunction . OBJECTIVE To determine whether dexmedetomidine reduces the duration of delirium and coma in mechanically ventilated ICU patients while providing adequate sedation as compared with lorazepam . DESIGN , SETTING , PATIENTS , AND INTERVENTION Double-blind , r and omized controlled trial of 106 adult mechanically ventilated medical and surgical ICU patients at 2 tertiary care centers between August 2004 and April 2006 . Patients were se date d with dexmedetomidine or lorazepam for as many as 120 hours . Study drugs were titrated to achieve the desired level of sedation , measured using the Richmond Agitation-Sedation Scale ( RASS ) . Patients were monitored twice daily for delirium using the Confusion Assessment Method for the ICU ( CAM-ICU ) . MAIN OUTCOME MEASURES Days alive without delirium or coma and percentage of days spent within 1 RASS point of the sedation goal . RESULTS Sedation with dexmedetomidine result ed in more days alive without delirium or coma ( median days , 7.0 vs 3.0 ; P = .01 ) and a lower prevalence of coma ( 63 % vs 92 % ; P < .001 ) than sedation with lorazepam . Patients se date d with dexmedetomidine spent more time within 1 RASS point of their sedation goal compared with patients se date d with lorazepam ( median percentage of days , 80 % vs 67 % ; P = .04 ) . The 28-day mortality in the dexmedetomidine group was 17 % vs 27 % in the lorazepam group ( P = .18 ) and cost of care was similar between groups . More patients in the dexmedetomidine group ( 42 % vs 31 % ; P = .61 ) were able to complete post-ICU neuropsychological testing , with similar scores in the tests evaluating global cognitive , motor speed , and attention functions . The 12-month time to death was 363 days in the dexmedetomidine group vs 188 days in the lorazepam group ( P = .48 ) . CONCLUSION In mechanically ventilated ICU patients managed with individualized targeted sedation , use of a dexmedetomidine infusion result ed in more days alive without delirium or coma and more time at the targeted level of sedation than with a lorazepam infusion . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00095251 [4118508] Background and Objectives : Patients on mechanical ventilation in intensive care unit ( ICU ) are often uncomfortable because of anxiety , pain , and endotracheal intubation ; therefore , require sedation . Alpha-2 agonists are known to produce sedation . We compared clonidine and dexmedetomidine as sole agents for sedation . Study Design : Prospect i ve , r and omized , controlled open-label study . Material s and Methods : A total of 70 patients requiring a minimum of 12 h of mechanical ventilation with concomitant sedation , were r and omly allocated into two groups . Group C ( n = 35 ) received intravenous ( IV ) clonidine ( 1 μg/kg/h titrated up to 2 μg/kg/h to attain target sedation ) , and Group D ( n = 35 ) received IV dexmedetomidine for sedation ( loading 0.7 μg/kg and maintenance 0.2 μg/kg/h titrated up to 0.7 μg/kg/h to achieve target sedation ) . A Ramsay Sedation Score of 3 - 4 was considered as target sedation . Additional sedation with diazepam was given when required to achieve target sedation . The quality of sedation , hemodynamic changes and adverse effects were noted and compared between the two groups . Results : Target sedation was achieved in 86 % observations in Group D and 62 % in Group C ( P = 0.04 ) . Additional sedation was needed by more patients in Group C compared with Group D ( 14 and 8 in Groups C and D , respectively , P = 0.034 ) , mainly due to concomitant hypotension on increasing the dose of clonidine . Hypotension was the most common side-effect in Group C , occurring in 11/35 patients of Group C and 3/35 patients of Group D ( P = 0.02 ) . Rebound hypertension was seen in four patients receiving clonidine , but none in receiving dexmedetomidine . Conclusion : Both clonidine and dexmedetomidine produced effective sedation ; however , the hemodynamic stability provided by dexmedetomidine gives it an edge over clonidine for short-term sedation of ICU patients [15959548] BACKGROUND Propofol is often used for sedation in the intensive care unit . The aim of this study was to compare the efficacy and endocrine response of propofol vs. the new alpha2-agonist dexmedetomidine for sedation in surgical intensive care patients who need postoperative short-term ventilation . METHODS Our work is a r and omized clinical study conducted on sixty adult patients who required postoperative short term ventilation and sedation . The patients were allocated r and omly , to receive IV infusion of either dexmedetomidine 0.2 - 0.5 microg/kg/h or propofol 0.5 - 1 mg/kg/h . Hemodynamic parameters , Ramsay sedation score , extubation time and serum cortisol and interleukin-6 ( IL-6 ) levels were measured . RESULTS Ramsay sedation score was 4.1+/-1 and 4+/-0.9 for propofol and dexmedetomidine , respectively , ( p=0.59 . ) Total fentanyl dose in the propofol group was 75+/-15 microg compared to 15+/-10.5 microg in the dexmedetomidine group , ( p=0.0045 ) . Patients who received dexmedetomidine infusion had significantly lower heart rates compared to patients who received propofol infusion , ( p=0.041 ) . Pre-infusion serum concentrations of IL-6 were comparable in both groups , while the 24 h post-infusion levels were insignificantly decreased in both groups compared to pre-infusion level , ( p=0.36 ) . There were no intergroup differences in serum cortisol concentrations ( p=0.231 ) . CONCLUSIONS Dexmedetomidine and propofol are safe sedative drugs for postoperative mechanichally ventilated patients . Patients were easily aroused to co-operate without showing signs of irritations with less fentanyl analgesia in the dexmedetomidine group . Dexmedetomidine and propofol do not inhibit adrenal function , but they may influence the inflammatory response [4047690] Context : Critically ill patients requiring mechanical ventilation frequently need sedatives and analgesics to facilitate their care . Dexmedetomidine , a short-acting alpha-2-agonist , possesses anxiolytic , anesthetic , hypnotic , and analgesic properties . Aims : The objective of this study was to evaluate the efficacy and safety of dexmedetomidine in comparison to propofol in the management of sedation for post-operative intensive care unit ( ICU ) patients , as a sedative agent . Setting s and Design : Teaching hospital , A phase III , prospect i ve , open , r and omized and comparative . Material s and Methods : Thirty patients who were ambulatory and who required the post-operative mechanical ventilation or post-operative sedation were enrolled , in which 15 patients received Dexmedetomidine and remaining 15 patients received propofol . All these patients were treated for the period of 8 to 24 h. Statistical Analysis Used : Data were analyzed using Student 's t-test and Chi-square test . The value of P < 0.05 was considered as statistically significant . Results : Demographic data were comparable . Pulse rate , respiratory rate and blood pressure were comparable . Depth of sedation and extubation time were similar . To maintain analgesia throughout the study period , patients receiving propofol infusions required significantly more analgesics than patients receiving Dexmedetomidine . Conclusions : Dexmedetomidine appears to be a safe and acceptable ICU sedative agent when both the clinician 's and patient 's perspectives are considered [15891317] Objective : Dexmedetomidine ( DEX ) may provide a sedation level that enables sleep and communication , with less amnesia and pain medication requirements , during mechanical ventilation . Our study directly assessed patient-perceived satisfaction with coronary artery bypass graft surgery after administration of DEX or propofol for intensive care unit ( ICU ) sedation . Design : Prospect i ve , r and omized clinical study with subsequent question naire administration . Setting : Tertiary care surgical ICU . Patients : A total of 89 adult , nonemergent , coronary artery bypass graft patients with an expected length of intubation of < 24 hrs . Interventions : Patients were r and omized to either DEX or propofol ; drug administration was performed via st and ardized anesthesia and nursing protocol s. Measurements : Patients reported perceptions of their ICU experience after mechanical ventilation with a modified numerical-scale Hewitt question naire , vali date d specifically for ICU patients . Patients were question ed regarding awareness , recall , generalized comfort , level of pain , ability to interact with healthcare providers and family , feelings of agitation and anxiety , perceived ease of extubation , ability to sleep or rest , and satisfaction with ICU experience . Main Results : Groups were well matched at baseline , with a mean ± sd age of 63.0 ± 10.4 yrs and weight of 88.7 ± 16.7 kg . No difference was observed for length of surgery , length of intubation , or ICU stay ( p > .05 ) . DEX patients perceived a shorter length of intubation ( p = .044 ) . A deeper sedation level was found in the propofol group ( p = .021 ) , with similar morphine and midazolam requirements ( p = .317 ) . Patient-rated level of overall awareness as a marker of amnesia did not differ between groups ( p = .653 ) . The ability to rest or sleep trended toward significance favoring propofol ( p = .051 ) . On evaluation of question naire ratings , DEX patients expressed more discomfort ( p = .046 ) , pain ( p = .096 ) , and sleeping difficulty ( p = .036 ) . Similar comfort levels were reported during extubation ( p = .179 ) . Conclusions : Despite theoretical advantages of DEX to improve overall patient satisfaction , the two agents provide similar responses to amnesia and pain control . According to our findings , DEX does not seem to have any advantage compared with propofol for short-term sedation after coronary artery bypass graft surgery [2717438] Introduction Agitated delirium is common in patients undergoing mechanical ventilation , and is often treated with haloperidol despite concerns about safety and efficacy . Use of conventional sedatives to control agitation can preclude extubation . Dexmedetomidine , a novel sedative and anxiolytic agent , may have particular utility in these patients . We sought to compare the efficacy of haloperidol and dexmedetomidine in facilitating extubation . Methods We conducted a r and omised , open-label , parallel-groups pilot trial in the medical and surgical intensive care unit of a university hospital . Twenty patients undergoing mechanical ventilation in whom extubation was not possible solely because of agitated delirium were r and omised to receive an infusion of either haloperidol 0.5 to 2 mg/hour or dexmedetomidine 0.2 to 0.7 μg/kg/hr , with or without loading doses of 2.5 mg haloperidol or 1 μg/kg dexmedetomidine , according to clinician preference . Results Dexmedetomidine significantly shortened median time to extubation from 42.5 ( IQR 23.2 to 117.8 ) to 19.9 ( IQR 7.3 to 24 ) hours ( P = 0.016 ) . Dexmedetomidine significantly decreased ICU length of stay , from 6.5 ( IQR 4 to 9 ) to 1.5 ( IQR 1 to 3 ) days ( P = 0.004 ) after study drug commencement . Of patients who required ongoing propofol sedation , the proportion of time propofol was required was halved in those who received dexmedetomidine ( 79.5 % ( 95 % CI 61.8 to 97.2 % ) vs. 41.2 % ( 95 % CI 0 to 88.1 % ) of the time intubated ; P = 0.05 ) . No patients were reintubated ; three receiving haloperidol could not be successfully extubated and underwent tracheostomy . One patient prematurely discontinued haloperidol due to QTc interval prolongation . Conclusions In this preliminary pilot study , we found dexmedetomidine a promising agent for the treatment of ICU-associated delirious agitation , and we suggest this warrants further testing in a definitive double-blind multi-centre trial . Trial registration Clinical trials.gov [4391192] Introduction Intensive care unit ( ICU ) environmental factors such as noise and light have been cited as important causes of sleep deprivation in critically ill patients . Previous studies indicated that using earplugs and eye masks can improve REM sleep in healthy subjects in simulated ICU environment , and improve sleep quality in ICU patients . This study aim ed to determine the effects of using earplugs and eye masks with relaxing background music on sleep , melatonin and cortisol levels in ICU patients . Methods Fifty patients who underwent a scheduled cardiac surgery and were expected to stay at least 2 nights in Cardiac Surgical ICU ( CSICU ) were included . They were r and omized to sleep with or without earplugs and eye masks combined with 30-minute relaxing music during the postoperative nights in CSICU . Urine was analyzed for nocturnal melatonin and cortisol levels . Subjective sleep quality was evaluated using the Chinese version of Richards-Campbell Sleep Question naire ( a visual analog scale , ranging 0–100 ) . Results Data from 45 patients ( 20 in intervention group , 25 in control group ) were analyzed . Significant differences were found between groups in depth of sleep , falling asleep , awakenings , falling asleep again after awakening and overall sleep quality ( P < 0.05 ) . Perceived sleep quality was better in the intervention group . No group differences were found in urinary melatonin levels and cortisol levels for the night before surgery , and the first and second nights post-surgery ( P > 0.05 ) . The urinary melatonin levels of the first and second postoperative nights were significantly lower than those of the night before surgery ( P = 0.01 ) . The opposite pattern was seen with urinary cortisol levels ( P = 0.00 ) . Conclusion This combination of non-pharmacological interventions is useful for promoting sleep in ICU adult patients ; however , any influence on nocturnal melatonin levels and cortisol level may have been masked by several factors such as the timing of surgery , medication use and individual differences . Larger scale studies would be needed to examine the potential influences of these factors on biological markers and intervention efficacy on sleep . Trial registration Chinese Clinical Trial Registry : ChiCTR-IOR-14005511 . Registered 21 November 2014 [21521683] BACKGROUND We evaluated the use of dexmedetomidine to facilitate the weaning of delirious postoperative patients from mechanical ventilation . METHODS We included 72 consecutive patients who underwent elective cardiac surgery in this prospect i ve observational study . Each patient had failed at least 1 trial of continuous positive airway pressure ( CPAP ) and had agitation . Patients were assessed with the Richmond Agitation-Sedation Scale ( RASS ) and the Confusion Assessment Method for the Intensive Care Unit ( CAMICU ) 12 to 18 hours after their admission to the ICU . Midazolam and fentanyl were then given to all patients according to the sedation protocol . At 36 hours in the ICU , patients who had agitation and an inability to wean were r and omly divided into 2 groups : group M , 34 patients who continued to follow the routine sedative protocol ; and group D , 38 patients who were given dexmedetomidine . Arterial blood gas measurements , hemodynamic parameters , and time to extubation were recorded . Statistical analysis was performed with GraphPad InStat ( version 2.02 for DOS ) . RESULTS All patients tested positive in the CAM-ICU assessment , and all had a delirium diagnosis . The 38 patients in group D tolerated a spontaneous breathing trial with CPAP and were extubated after a mean ( ±SD ) of 49.619 ± 6.96 hours . The 2 groups had significantly different extubation times ( 58.389 ± 3.958 hours versus 49.619 ± 6.96 hours ) . The 2 groups had significantly different RASS scores at 48 and 60 hours and significantly different heart rates and PO2 values at 12 and 24 hours . The 2 groups showed no significant differences with regard to hemodynamic parameters . CONCLUSIONS Dexmedetomidine may help to eliminate the emergence of agitation and can be a good treatment choice for the delirium state after cardiac surgery [3961039] Background : Sedation after open heart surgery is important in preventing stress on the heart . The unique sedative features of propofol prompted us to evaluate its potential clinical role in the sedation of post-CABG patients . Objectives : To compare propofol-based sedation to midazolam-based sedation after coronary artery bypass graft ( CABG ) surgery in the intensive care unit ( ICU ) . Patients and Methods : Fifty patients who were admitted to the ICU after CABG surgery was r and omized into two groups to receive sedation with either midazolam or propofol infusions ; and additional analgesia was administered if required . Inclusion criteria were as follows : patients 40 - 60 years old , hemodynamic stability , ejection fraction ( EF ) more than 40 % ; exclusion criteria included patients who required intra-aortic balloon pump or inotropic drugs post-bypass . The same protocol of anesthetic medications was used in both groups . Depth of sedation was monitored using the Ramsay sedation score ( RSS ) . Invasive mean arterial pressure ( MAP ) and heart rate ( HR ) , arterial blood gas ( ABG ) and ventilatory parameters were monitored continuously after the start of study drug and until the patients were extubated . Results : The depth of sedation was almost the same in the two groups ( RSS=4.5 in midazolam group vs 4.7 in propofol group ; P = 0.259 ) but the total dose of fentanyl in the midazolam group was significantly more than the propofol group ( 12.5 mg/hr vs 4 mg/hr ) ( P = 0.0039 ) . No significant differences were found in MAP ( P = 0.51 ) and HR ( P = 0.41 ) between the groups . The mean extubation time in patients se date d with propofol was shorter than those se date d with midazolam ( 102 ± 27 min vs 245 ± 42 min , respectively ; P < 0.05 ) but the ICU discharge time was not shorter ( 47.5 hr vs 36.3 hr , respectively ; P = 0.24 ) . Conclusions : Propofol provided a safe and acceptable sedation for post-CABG surgical patients , significantly reduced the requirement for analgesics , and allowed for more rapid tracheal extubation than midazolam but did not result in earlier ICU discharge [19327948] PURPOSE This study compares the effectiveness of midazolam and dexmedetomidine for the sedation of eclampsia patients admitted to our intensive care unit ( ICU ) . PATIENTS AND METHODS Forty women with eclampsia requiring termination of pregnancy by caesarean delivery were r and omized in to 2 groups of 20 to receive either midazolam or dexmedetomidine . The midazolam group received a loading dose of 0.05 mg/kg followed by an infusion of 0.1 mg kg(-1 ) h(-1 ) . The dexmedetomidine group loading dose was 1 microg/kg per 20 minutes , followed by continuous infusion at 0.7 microg kg(-1 ) h(-1 ) . Heart rate , blood pressure , Ramsey sedation score , antihypertensive need , convulsion fits , and duration in ICU were monitored and recorded all through the ICU stay . RESULTS Dexmedetomidine markedly reduced heart rates for the first 24 hours ( P < .05 ) compared with midazolam , but there were no differences at 48 and 72 hours . Mean arterial blood pressures were similar in the 2 groups ( P > .05 ) , although in the dexmedetomidine group , it was lower at 5 , 6 , 12 , and 24 hours compared with the first 4 hours ( P < .05 ) . Moreover , fewer patients given dexmedetomidine required nitroglycerine and nitroprusside ( P < .05 ) . The duration of ICU stay was less in the dexmedetomidine group , 45.5 hours ( range , 15 - 118 hours ) , than in the midazolam group , 83 hours ( minimum-maximum , 15 - 312 hours ) . CONCLUSION Dexmedetomidine sedation in eclampsia patients is effective in reducing the dem and for antihypertensive medicine and duration of ICU stay [8477016] The use and the hemodynamic effects of propofol and midazolam were studied during titrated continuous infusions to deep sedation ( sedation level 5 : asleep , sluggish response to light glabellar tap or loud auditory stimulus ) following coronary artery surgery . The drugs were compared in 30 ventilated patients in an open r and omized study . The duration of infusion was approximately 570 minutes in both groups . After a loading dose of propofol ( 1 mg/kg ) or midazolam ( 0.07 mg/kg ) , the infusion rates were 2.71 + /- 1.13 mg/kg/h and 0.092 + /- 0.028 mg/kg/h , respectively . An analgesic infusion of sufentanil was also given in both groups . In the midazolam group , to maintain the predetermined level of sedation , more frequent additional bolus doses ( 4.7 + /- 1.8 ; P < 0.001 ) and infusion rate adjustments ( 5.3 + /- 1.6 ; P < 0.001 ) were required than for similar sedation in the propofol group ( 2.3 + /- 1.0 bolus doses and 3.3 + /- 1.2 adjustments ) . The time from stopping sedation to patient responsiveness was 11 + /- 8 minutes in the propofol group and 72 + /- 70 minutes in the midazolam group ( P < 0.001 ) , and the time from stopping sedation to extubation was 250 + /- 135 minutes and 391 + /- 128 minutes ( P < 0.014 ) , respectively . Following the loading dose of propofol , there was a fall in blood pressure ( BP ) ( mean from 80 + /- 11 mmHg to 67.5 + /- 10 mmHg ; P < 0.05 ) . After approximately 15 minutes , BP started to rise but remained below pretreatment level throughout sedation . ( ABSTRACT TRUNCATED AT 250 WORDS [19833271] STUDY OBJECTIVE To compare the effects of an intravenous infusion of propofol and the alpha-2 adrenoceptor , dexmedetomidine , on inflammatory responses and intraabdominal pressure ( IAP ) in severe sepsis after abdominal surgery , specifically , serum cytokine levels ( interleukin [IL]-1 , IL-6 , and tumor necrosis factor [TNF]-alpha ) and IAP . DESIGN Prospect i ve , single-center study . SETTING University hospital . PATIENTS 40 adult ICU patients who had undergone ileus surgery and who were expected to require postoperative sedation and ventilation . INTERVENTIONS Patients received either a loading dose infusion of propofol ( Group P ; n = 20 ) one mg/kg over 15 minutes followed by a maintenance dose of one to three mg/kg/hr ( n = 20 , Group P ) or a loading dose of dexmedetomidine of one microg/kg over 10 minutes followed by a maintenance dose of 0.2 - 2.5 microg/kg/h ( n = 20 , Group D ) at the 24th hour . MEASUREMENTS Biochemical and hemodynamic parameters , cytokine levels , and IAP were recorded before the start of the study and at the 24th and 48th hours . MAIN RESULTS TNF-alpha levels were significantly lower at the 24th hour ( 14.66 + /- 4.40 pg/mL vs. 21.21 + /- 11.37 pg/mL , respectively ) and at the 48th hour ( 21.25 + /- 15.85 pg/mL vs. 46.55 + /- 35.99 pg/mL , respectively ) in Group D. IL-1 levels were significantly lower at the 24th hour ( 5.03 + /- 0.15 pg/mL vs. 6.23 + /- 2.09 pg/mL , respectively ) and the 48th hour ( 5.01 + /- 0.37 pg/mL vs. 6.42 + /- 2.76 pg/mL , respectively ) in Group D. IL-6 levels were significantly lower at the 24th hour ( 253.1 + /- 303.6 pg/mL and 511.3 + /- 374.8 pg/mL , respectively ) and at the 48th hour ( 343.5 + /- 393.4 pg/mL and 503.7 + /- 306.4 pg/mL , respectively ) in Group D. Intraabdominal pressure also was significantly lower at the 24th hour ( 12.35 + /- 5.84 mmHg vs. 18.1 + /- 2.84 mmHg , respectively ) and the 48th hour ( 13.9 + /- 6.15 mmHg vs. 18.7 + /- 3.46 mmHg , respectively ) in Group D. CONCLUSION Dexmedetomidine infusion decreases TNF-a , IL-1 , and IL-6 levels and IAP more than a propofol infusion [8681594] OBJECTIVES To compare the effectiveness , characteristics , duration of action , hemodynamic and biochemical effects , and side effects of propofol and midazolam used for continuous intravenous sedation of ventilated critically ill patients . DESIGN Multicenter , prospect i ve , r and omized , nonblinded study . SETTING Nine Spanish general intensive care units ( ICUs ) . PATIENTS Ninety-eight patients admitted to the ICU who were mechanically ventilated and required sedation for a minimum of 48 hrs . INTERVENTIONS Propofol or midazolam was used for induction and maintenance of continuous intravenous sedation for a maximum of 5 days . The effectiveness of those two regimens was assessed according to their effects on ventilatory management and the presence of agitation . MEASUREMENTS AND MAIN RESULTS In 93 % of the patients studied , there was a medical cause necessitating mechanical ventilation . The mean ( + /-SD ) duration of sedation was 81 + /- 25 hrs and 88 + /- 27 hrs for the propofol and midazolam groups , respectively . The induction dose was 2.24 + /- 0.43 mg/kg over 318 + /- 363 secs for propofol , and 0.22 + /-0.07 mg/kg over 33 + /-29 secs for midazolam . The maintenance dose was 2.8 + /-1.1 mg/kg/hr for propofol and 0.14 + /- 0.10 mg/kg/hr for midazolam . There was no difference regarding the opiate and muscle relaxant requirements between the two groups . Sedation with propofol was more effective in achieving patient-ventilator synchrony than that with midazolam after the first hour of treatment ( p < .01 ) . Patients se date d with propofol awoke more rapidly and with less variability that those patients se date d with midazolam ( 23 + /- 16 mins vs. 137 + /- 185 mins , respectively , p < .05 ) , particularly in those patients requiring deep sedation ( 27 + /- 16 mins vs. 237 + /- 222 mins , respectively , p < .01 ) . No hemodynamic or biochemical changes were detected in any of the treatment groups . During induction , five patients in the propofol group and two patients in the midazolam group had hypotension . CONCLUSIONS In this population of critically ill patients , propofol is an effective and safe alternative for sedation , with some advantages , such as short duration of action and high effectiveness over the conventional regimen with benzodiazepines and opiates [2570958] 101 critically ill patients admitted to five intensive-care units were allocated r and omly to receive a continuous intravenous infusion of either propofol or midazolam for sedation for up to 24 h. In addition , morphine was given to provide analgesia . The mean duration of infusion was 20.2 h ( range 3.0 - 24.5 ) in the propofol group and 21.3 h ( 4.0 - 47.0 ) in the midazolam group and infusion rates were 1.77 mg/kg/h ( range 0.40 - 5.00 ) and 0.10 mg/kg/h ( 0.01 - 0.26 ) , respectively . The infusion rates were adjusted as necessary , and the desired level of sedation was achieved easily in most patients in both groups . There were slight falls in arterial pressure , but there were no significant differences between the groups . Heart rate was lower in patients who received propofol . Some small changes occurred in biochemical and haematological variables in both groups , but they were not clinical ly significant . There was no indication that either drug substantially impaired adrenal steroidogenesis . When the infusion was discontinued , there was less variability in recovery of consciousness in patients who had received propofol . In a subgroup of patients , weaning from mechanical ventilation was achieved significantly faster after discontinuation of propofol than of midazolam . Propofol proved to be a satisfactory agent for sedation of these critically ill patients and compared favourably with midazolam [19567759] BACKGROUND Delirium is a neurobehavioral syndrome caused by the transient disruption of normal neuronal activity secondary to systemic disturbances . OBJECTIVE The authors investigated the effects of postoperative sedation on the development of delirium in patients undergoing cardiac-valve procedures . METHODS Patients underwent elective cardiac surgery with a st and ardized intraoperative anesthesia protocol , followed by r and om assignment to one of three postoperative sedation protocol s : dexmedetomidine , propofol , or midazolam . RESULTS The incidence of delirium for patients receiving dexmedetomidine was 3 % , for those receiving propofol was 50 % , and for patients receiving midazolam , 50 % . Patients who developed postoperative delirium experienced significantly longer intensive-care stays and longer total hospitalization . CONCLUSION The findings of this open-label , r and omized clinical investigation suggest that postoperative sedation with dexmedetomidine was associated with significantly lower rates of postoperative delirium and lower care costs [23448434] BACKGROUND The study aim was to compare the efficacy of dexmedetomidine vs midazolam for sedation during the early postoperative period in adolescents who underwent scoliosis surgery . METHODS We performed a prospect i ve , r and omized trial in an intensive care unit ( ICU ) in a tertiary care center . In this study , 42 patients ( American Society of Anesthesiology physical status I and II ) who underwent scoliosis surgery were divided into two groups according to sedation protocol s : group dexmedetomidine ( DEX ) ( n = 22 ) and group midazolam ( MDZ ) ( n = 20 ) . Adolescents ( 12 - 18 years ) requiring mechanical ventilation underwent a continuous infusion of either dexmedetomidine ( group DEX ; starting dose , 0.4 μg·kg(-1 ) · h(-1 ) ) or midazolam ( group MDZ ; starting dose , 0.1 mg·kg(-1 ) · h(-1 ) ) with intermittent fentanyl , as needed . The efficacy of sedation was assessed using the Richmond Agitation Sedation Scale ( RASS ) . Quality of pain relief was measured using the Numeric Visual Analog Scale ( NVAS ) . Delirium was determined in patients in the RASS range of -2 to + 1 using the Confusion Assessment Method for the ICU ( CAM-ICU ) . Fentanyl consumption , incidence of delirium , NVAS scores , and hemodynamics were recorded postoperatively at 2 , 4 , 6 , and 24 h in the ICU . RESULTS The NVAS pain scores and fentanyl consumption at all the evaluation time points were significantly higher in group MDZ than those in group DEX ( P < 0.05 ) . Further , total fentanyl consumption in group MDZ was significantly higher than that in group DEX ( P < 0.05 ) . Delirium was significantly higher in the group MDZ than that in group DEX ( 31.3 % vs 12.5 % ) when analyzed as the endpoint of CAM-ICU ( P < 0.05 ) . The heart rate was significantly lower in group DEX compared with that in group MDZ at all the evaluation time points ( P < 0.05 ) . CONCLUSION Dexmedetomidine was associated with the decreased postoperative fentanyl consumption , NVAS scores , and a decreased incidence of delirium . These findings may be beneficial for managing sedation protocol s in adolescents who have undergone scoliosis surgery [18795253] Purpose To compare dexmedetomidine ( DEX ) with st and ard care ( SC , either propofol or midazolam ) for long-term sedation in terms of maintaining target sedation and length of intensive care unit ( ICU ) stay . Methods A pilot , phase III , double-blind multicenter study in r and omized medical and surgical patients ( n = 85 ) within the first 72 h of ICU stay with an expected ICU stay of ≥48 h and sedation need for ≥24 h after r and omization . Patients were assigned to either DEX ( ≤1.4 μg kg−1 h−1 ; n = 41 ) or SC ( n = 44 ) , with daily sedation stops . Results Non-inferiority of DEX versus SC was not confirmed . Target Richmond agitation – sedation score ( RASS ) was reached a median of 64 % ( DEX ) and 63 % ( SC ) of the sedation time ( ns ) . The length of ICU stay was similar in DEX and SC . Patients with RASS target 0–3 ( DEX 78 % , SC 80 % ) were at target sedation 74 % ( DEX ) and 64 % ( SC ) of the time ( ns ) , whereas those with RASS target −4 or less reached the target 42 % ( DEX ) and 62 % ( SC ) of the time ( P = .006 ) . Post hoc analyses suggested shorter duration of mechanical ventilation for DEX ( P = 0.025 ) . Conclusions This pilot study suggests that in long-term sedation , DEX is comparable to SC in maintaining sedation targets of RASS 0 to −3 but not suitable for deep sedation ( RASS −4 or less ) . DEX had no effect on length of ICU stay . Its effects on other relevant clinical outcomes , such as duration of mechanical ventilation , should be tested further [22975538] OBJECTIVE To compare the efficacy and safety of sedation with dexmedetomidine vs. midazolam for patients with acute cardiogenic pulmonary edema and hypoxemia during the treatment of non-invasive ventilation ( NIV ) . METHODS The intensive care unit ( ICU ) patients treated in our hospital between March 2008 and August 2011 who had acute pulmonary edema and hyoxemia in NIV failure due to patient refusal to continue the NIV sessions ( due to discomfort ) were enrolled in this study . The patients were divided into two groups by the r and om numerical table method . They were treated with either midazolam ( 29 cases ) or dexmedetomidine ( 33 cases ) . The patients were se date d ( Ramsay scale 2 - 3 ) by a continuous perfusion of midazolam or dexmedetomidine during the NIV session . Cardiorespiratory and ventilatory parameters , the results of the blood gas analysis , and adverse events were prospect ively recorded . The main outcome measure was the percentage of endotracheal intubation during NIV . Secondary endpoints included the duration of non-invasive mechanical ventilation , length of ICU stay , and adverse events . RESULTS In both groups of patients , the expected sedative scores were obtained . The cardiorespiratory symptoms and signs ( oxygenation index , pH value , and respiratory rate ) were significantly improved in both groups . In the dexmedetomidine-treated group , the patients had a further decreased percentage of failure of NIV requiring endotracheal intubation ( ETI ) and a more prolonged mean time to ETI ( p=0.042 , p=0.024 ) . Furthermore , when compared with the group treated with midazolam , the overall duration of mechanical ventilation and the duration of ICU hospitalization in the group treated with dexmedetomidine were markedly decreased , and weaning from mechanical ventilation was easier ( p=0.010 , p=0.042 ) . Despite the fact that more dexmedetomidine-treated patients developed bradycardia ( 18.2 % vs. 0 , p=0.016 ) , no patients required an intervention or interruption of study drug infusion . Conversely , the incidence of respiratory infections and vomiting was lower in the dexmedetomidine-treated patients ( p=0.026 , p=0.010 ) . CONCLUSION Dexmedetomidine led to a more desired level of awaking sedation , shortened the duration of mechanical ventilation and the length of the ICU stay , and further reduced the prevalence of nosocomial infection for NIV sedation in patients with acute cardiogenic pulmonary edema . It appears to provide several advantages and safe control compared with the γ-amino butyric acid ( GABA ) agonist midazolam [19786862] Background : Commonly used sedatives/analgesics can increase the risk of postoperative complications , including delirium . This double-blinded study assessed the neurobehavioral , hemodynamic , and sedative characteristics of dexmedetomidine compared with morphine-based regimen after cardiac surgery at equivalent levels of sedation and analgesia . Methods : A total of 306 patients at least 60 yr old were r and omized to receive dexmedetomidine ( 0.1–0.7 & mgr;g · kg−1 · h−1 ) or morphine ( 10 - 70 & mgr;g · kg−1 · h−1 ) with open-label propofol titrated to a target Motor Activity Assessment Scale of 2–4 . Primary outcome was the prevalence of delirium measured daily via Confusion Assessment Method for intensive care . Secondary outcomes included ventilation time , additional sedation/analgesia , and hemodynamic and adverse effects . Results : Of all sedation assessment s , 75.2 % of dexmedetomidine and 79.6 % ( P = 0.516 ) of morphine treatment were in the target range . Delirium incidence was comparable between dexmedetomidine 13 ( 8.6 % ) and morphine 22 ( 15.0 % ) ( relative risk 0.571 , 95 % confidence interval [ CI ] 0.256–1.099 , P = 0.088 ) , however , dexmedetomidine-managed patients spent 3 fewer days ( 2 [ 1–7 ] versus 5 [ 2–12 ] ) in delirium ( 95 % CI 1.09–6.67 , P = 0.0317 ) . The incidence of delirium was significantly less in a small subgroup requiring intraaortic balloon pump and treated with dexmedetomidine ( 3 of 20 [ 15 % ] versus 9 of 25 [ 36 % ] ) ( relative risk 0.416 , 95 % CI 0.152–0.637 , P = 0.001 ) . Dexmedetomidine-treated patients were more likely to be extubated earlier ( relative risk 1.27 , 95 % CI 1.01–1.60 , P = 0.040 , log-rank P = 0.036 ) , experienced less systolic hypotension ( 23 % versus 38.1 % , P = 0.006 ) , required less norepinephrine ( P < 0.001 ) , but had more bradycardia ( 16.45 % versus 6.12 % , P = 0.006 ) than morphine treatment . Conclusion : Dexmedetomidine reduced the duration but not the incidence of delirium after cardiac surgery with effective analgesia/sedation , less hypotension , less vasopressor requirement , and more bradycardia versus morphine regimen [26575144] Background : Postoperative delirium ( POD ) is a serious complication after cardiac surgery . Use of dexmedetomidine to prevent delirium is controversial . The authors hypothesized that dexmedetomidine sedation after cardiac surgery would reduce the incidence of POD . Methods : After institutional ethics review board approval , and informed consent , a single-blinded , prospect i ve , r and omized controlled trial was conducted in patients 60 yr or older undergoing cardiac surgery . Patients with a history of serious mental illness , delirium , and severe dementia were excluded . Upon admission to intensive care unit ( ICU ) , patients received either dexmedetomidine ( 0.4 & mgr;g/kg bolus followed by 0.2 to 0.7 & mgr;g kg−1 h−1 infusion ) or propofol ( 25 to 50 & mgr;g kg−1 min−1 infusion ) according to a computer-generated r and omization code in blocks of four . Assessment of delirium was performed with confusion assessment method for ICU or confusion assessment method after discharge from ICU at 12-h intervals during the 5 postoperative days . Primary outcome was the incidence of POD . Results : POD was present in 16 of 91 ( 17.5 % ) and 29 of 92 ( 31.5 % ) patients in dexmedetomidine and propofol groups , respectively ( odds ratio , 0.46 ; 95 % CI , 0.23 to 0.92 ; P = 0.028 ) . Median onset of POD was on postoperative day 2 ( 1 to 4 days ) versus 1 ( 1 to 4 days ) , P = 0.027 , and duration of POD 2 days ( 1 to 4 days ) versus 3 days ( 1 to 5 days ) , P = 0.04 , in dexmedetomidine and propofol groups , respectively . Conclusions : When compared with propofol , dexmedetomidine sedation reduced incidence , delayed onset , and shortened duration of POD in elderly patients after cardiac surgery . The absolute risk reduction for POD was 14 % , with a number needed to treat of 7.1 [22965457] Context Volatile anaesthetics may have direct cardioprotective properties due to effects similar to ischaemic preconditioning and postconditioning . Clinical results in cardiac surgery patients are controversial and may be related to the timing of administration of anaesthetics intraoperatively . Objective We hypothesised that the cardioprotective effect of sevoflurane in coronary bypass graft surgical patients would be greater if administration during anaesthesia continued in the ICU for at least 4 h postoperatively until weaning from mechanical ventilation . Design Double-blind , double-dummy , prospect i ve , r and omised and controlled clinical trial . Setting In a single centre between June 2006 and June 2007 . Patients Seventy-five adult patients were assigned r and omly to receive anaesthesia and postoperative sedation either with propofol ( control , n = 37 ) or sevoflurane ( n = 36 ) . Interventions Myocardial biomarkers were measured before surgery , at the time of admission to the intensive care unit and at 6 , 24 , 48 and 72 h. The need for inotropic support , and lengths of stay in the intensive care unit and hospital were also recorded . Main outcome measures Elevation of myocardial biomarkers was the primary endpoint . The secondary endpoints were haemodynamic events and lengths of stay in the intensive care unit and hospital . Results Necrosis biomarkers increased significantly in the postoperative period in both groups with no significant differences at any time . Inotropic support was needed in 72.7 and 54.3 % of patients in the propofol and sevoflurane groups , respectively ( P = 0.086 ) . There were no significant differences in haemodynamic variables , incidence of arrhythmias , myocardial ischaemia or and lengths of stay in the ICU and hospital between the two groups . Conclusion In patients undergoing coronary bypass graft surgery , continuous administration of sevoflurane as a sedative in the ICU for at least 4 h postoperatively did not yield significant improvements in the extent and time course of myocardial damage biomarkers compared to propofol [16540958] Objective : To compare duration of mechanical ventilation for patients r and omized to receive lorazepam by intermittent bolus administration vs. continuous infusions of propofol using protocol s that include scheduled daily interruption of sedation . Design : A r and omized open-label trial enrolling patients from October 2001 to March 2004 . Setting : Medical intensive care units of two tertiary care medical centers . Patients : Adult patients expected to require mechanical ventilation for > 48 hrs and who required ≥10 mg of lorazepam or a continuous infusion of a sedative to achieve adequate sedation . Interventions : Patients were r and omized to receive lorazepam by intermittent bolus administration or propofol by continuous infusion to maintain a Ramsay score of 2–3 . Sedation was interrupted on a daily basis for both groups . Measurements and Main Results : The primary outcome was median ventilator days . Secondary outcomes included 28-day ventilator-free survival , intensive care unit and hospital length of stay , and hospital mortality . Median ventilator days were significantly lower in the daily interruption propofol group compared with the intermittent bolus lorazepam group ( 5.8 vs. 8.4 , p = .04 ) . The difference was largest for hospital survivors ( 4.4 vs. 9.0 , p = .006 ) . There was a trend toward greater ventilator-free survival for patients in the daily interruption propofol group ( median 18.5 days for propofol vs. 10.2 for lorazepam , p = .06 ) . Hospital mortality was not different . Conclusions : For medical patients requiring > 48 hrs of mechanical ventilation , sedation with propofol results in significantly fewer ventilator days compared with intermittent lorazepam when sedatives are interrupted daily [8062564] Objective To compare the safety and effectiveness of propofol ( 2,6-diisopropylphenol ) to midazolam for sedation of mechanically ventilated patients after coronary artery bypass grafting . Design Open , r and omized , prospect i ve trial . Setting Cardiothoracic intensive care unit ( ICU ) , Clevel and Clinic Foundation . Patients Eighty-four patients with normal or moderately impaired left ventricular function who underwent elective coronary artery bypass graft surgery under high-dose opioid anesthesia . Interventions Patients were r and omly selected to receive either propofol ( mean loading dose 0.24 mg/kg ; mean maintenance dose 0.76 mg/kg/hr ) or midazolam ( mean loading dose 0.012 mg/kg ; mean maintenance dose 0.018 mg/kg/hr ) . Infusion rates were titrated to keep patients comfortable , drowsy , and responsive to verbal stimulation . Study duration , 8 to 12 hrs ; infusions were started in the ICU when patients were awake and hemodynamically stable . Measurements and Main Results During therapy , both groups had lower mean arterial pressures and heart rates compared with baseline measurements ; however , the propofol group had significantly lower heart rates than the midazolam group during the first 2 hrs of infusion . The propofol group also had significantly lower blood pressure measurements 5 and 10 mins after the initial dose , although there was no difference during infusion . Baseline cardiac output was measured before starting the infusion , and measurements were repeated during continuous infusion at 4 , 8 , and 12 hrs . Cardiac output values were similar . Propofol maintenance infusions ranged from 3 to 30 μg/kg/min and midazolam infusions ranged from 0.1 to 0.7 μg/kg/min . At these infusion rates . both groups had adequate sedation , based on nurse and patient evaluations ; however , the propofol group used significantly lower total doses of sodium nitroprusside and supplemental opioids . Conclusions Both propofol and midazolam provided safe and effective sedation of coronary artery bypass graft patients recovering from high-dose opioid anesthesia . The reduced need for both antihypertensive medication and opioids seen in the propofol group may be advantageous . However , the hypotension seen after the initial bolus dose of propofol may be a concern . No difference between the two drugs could be demonstrated in time to extubation or ICU discharge , although it is probable that time to extubation was governed more by residual operative opioids than the study agents . ( Crit Care Med 1994 ; 22:1415–1423 [25055491] PURPOSE OF THE STUDY To compare the efficacy of Dexmedetomidine and Propofol for short-term controlled sedation and analgesia in the early postoperative period after cardiac surgery . METHODS We performed open r and omized prospect i ve comparative study in 55 cardiovascular surgery patients . In the early postoperative period 28 patients received infusion of Dexmedetomidine ( 0.2 - 0.7 microg/kg per hour ) while 27 patients --Propofol ( 0.3 - 2(system text of symbol ) ) . Analgesia was carried out with Ketoprofen 100 mg/12h and additional 20 mg of Trimeperidine in case of pain intensity > or = 3 points ( 5-level verbal pain score ) . Sedation and agitation level ( RASS scale ) , speed of awakening ( Aldrete score ) , duration of mechanical ventilation and stay in the ICU , need for additional opioid injections , type and frequency of side effects were evaluated . RESULTS We did n't find any significant differences in the duration of mechanical ventilation or rate of awakening after the end of infusion between the groups . Dexmedetomidine in the majority of cases result ed in mild or moderate sedation , Propofol -- in deeper level of sedation . Retro grade amnesia was reached significantly more often ( p < 0.05 ) in Dexmetomedine group . The daily dose of Trimeperidine in Propofol group was significantly higher ( 8 mg and 18 mg on average , p = 0.02 ) . Differences in side effects between the groups were noted -- bradycardia ( Dexmetomedine--10 ( 39 % ) , Propofol--3 ( 11 % ) , p = 0.004 ) arterial hypotension ( Dexmetomedine--9 ( 32 % ) , Propofol--15 ( 59 % ) , p = 0.002 ) and general malaise ( Dexmetomedine--2 ( 7 % ) , Propofol--6 ( 24 % ) , p = 0.001 ) . The length of stay in the ICU in Dexmetomedine group was significantly lower ( 1,1 days vs 2,6 days respectively , p = 0.006 ) . CONCLUSIONS To compare with Propofol Dexmetomedine induces less sedation level and more often provides retro grade amnesia with the same duration of mechanical ventilation and awakening rate . Dexmetomedine provides its own analgesic effect and shortens the length of patient 's stay in ICU . Bradycardia was noted more frequently in Dexmedetomidine while arterial hypotension , general malaise and delirium -- in Propofol group [11878517] The alpha2 agonist dexmedetomidine is a new sedative and analgesic agent which is licensed in the USA for post-operative intensive care sedation . We compared dexmedetomidine with propofol in patients requiring sedation in intensive care . Twenty adult patients expected to require a minimum of 8 h artificial ventilation after surgery were r and omized to receive sedation with either dexmedetomidine or propofol infusions . Additional analgesia , if required , was provided by an alfentanil infusion . Depth of sedation was monitored using both the Ramsay sedation score ( RSS ) and the bispectral index ( BIS ) . Cardiovascular , respiratory , biochemical and haematological data were obtained . Patients ' perceptions of their intensive care stay were assessed using the Hewitt question naire . Sedation was equivalent in the two groups [ median ( interquartile range ) : RSS , propofol group 5 ( 4 - 5 ) , dexmedetomidine group 5 ( 4 - 6 ) ( P=0.68 ) ; BIS , propofol group 53 ( 41 - 64 ) , dexmedetomidine group 46 ( 36 - 58 ) ; P=0.32 ] , but the propofol group received three times more alfentanil compared with patients se date d with dexmedetomidine [ 2.5 ( 2.2 - 2.9 ) mg h(-1 ) versus 0.8 ( 0.65 - 1.2 ) mg h(-1 ) ( P=0.004 ) ] . No differences were found in arterial pressures between the groups , but heart rate was significantly lower in the dexmedetomidine group [ mean ( SD ) 75 ( 6 ) vs 90 ( 4 ) beats min(-1 ) ] . Extubation times were similar and rapid with the use of both sedative agents [ median ( range ) 28 ( 20 - 50 ) and 29 ( 15 - 50 ) min ( P=0.63 ) respectively for the propofol and dexmedetomidine groups ] . No adverse events related to the sedative infusions occurred in either group . Despite ventilation and intubation , patients se date d with dexmedetomidine could be easily roused to cooperate with procedures ( e.g. physiotherapy , radiology ) without showing irritation . From the clinician 's and patient 's perspectives , dexmedetomidine is a safe and acceptable sedative agent for those requiring intensive care . The rate pressure product is reduced in patients receiving dexmedetomidine , which may protect against myocardial ischaemia . Dexmedetomidine reduces the requirement for opioid analgesia [22436955] CONTEXT Long-term sedation with midazolam or propofol in intensive care units ( ICUs ) has serious adverse effects . Dexmedetomidine , an α(2)-agonist available for ICU sedation , may reduce the duration of mechanical ventilation and enhance patient comfort . OBJECTIVE To determine the efficacy of dexmedetomidine vs midazolam or propofol ( preferred usual care ) in maintaining sedation ; reducing duration of mechanical ventilation ; and improving patients ' interaction with nursing care . DESIGN , SETTING , AND PATIENTS Two phase 3 multicenter , r and omized , double-blind trials carried out from 2007 to 2010 . The MIDEX trial compared midazolam with dexmedetomidine in ICUs of 44 centers in 9 European countries ; the PRODEX trial compared propofol with dexmedetomidine in 31 centers in 6 European countries and 2 centers in Russia . Included were adult ICU patients receiving mechanical ventilation who needed light to moderate sedation for more than 24 hours ( midazolam , n = 251 , vs dexmedetomidine , n = 249 ; propofol , n = 247 , vs dexmedetomidine , n = 251 ) . INTERVENTIONS Sedation with dexmedetomidine , midazolam , or propofol ; daily sedation stops ; and spontaneous breathing trials . MAIN OUTCOME MEASURES For each trial , we tested whether dexmedetomidine was noninferior to control with respect to proportion of time at target sedation level ( measured by Richmond Agitation-Sedation Scale ) and superior to control with respect to duration of mechanical ventilation . Secondary end points were patients ' ability to communicate pain ( measured using a visual analogue scale [ VAS ] ) and length of ICU stay . Time at target sedation was analyzed in per- protocol population ( midazolam , n = 233 , vs dexmedetomidine , n = 227 ; propofol , n = 214 , vs dexmedetomidine , n = 223 ) . RESULTS Dexmedetomidine/midazolam ratio in time at target sedation was 1.07 ( 95 % CI , 0.97 - 1.18 ) and dexmedetomidine/propofol , 1.00 ( 95 % CI , 0.92 - 1.08 ) . Median duration of mechanical ventilation appeared shorter with dexmedetomidine ( 123 hours [ IQR , 67 - 337 ] ) vs midazolam ( 164 hours [ IQR , 92 - 380 ] ; P = .03 ) but not with dexmedetomidine ( 97 hours [ IQR , 45 - 257 ] ) vs propofol ( 118 hours [ IQR , 48 - 327 ] ; P = .24 ) . Patients ' interaction ( measured using VAS ) was improved with dexmedetomidine ( estimated score difference vs midazolam , 19.7 [ 95 % CI , 15.2 - 24.2 ] ; P < .001 ; and vs propofol , 11.2 [ 95 % CI , 6.4 - 15.9 ] ; P < .001 ) . Length of ICU and hospital stay and mortality were similar . Dexmedetomidine vs midazolam patients had more hypotension ( 51/247 [ 20.6 % ] vs 29/250 [ 11.6 % ] ; P = .007 ) and bradycardia ( 35/247 [ 14.2 % ] vs 13/250 [ 5.2 % ] ; P < .001 ) . CONCLUSIONS Among ICU patients receiving prolonged mechanical ventilation , dexmedetomidine was not inferior to midazolam and propofol in maintaining light to moderate sedation . Dexmedetomidine reduced duration of mechanical ventilation compared with midazolam and improved patients ' ability to communicate pain compared with midazolam and propofol . More adverse effects were associated with dexmedetomidine . TRIAL REGISTRATION clinical trials.gov Identifiers : NCT00481312 , NCT00479661 [9470082] Objective : To compare the efficacy , safety , and cost of midazolam and propofol in prolonged sedation of critically ill patients . Design : R and omized , prospect i ve study . Setting : General intensive care unit ( ICU ) in a 1100-bed teaching hospital . Patients : 67 critically ill , mechanically ventilated patients . Interventions : Patients were invasively monitored and mechanically ventilated . A loading dose [ midazolam 0.11 ± 0.02 ( SEM ) mg · kg−1 , propofol 1.3 ± 0.2 mg · kg−1 ] was administered , followed by continuous infusion , titrated to achieve a predetermined sedation score . Sedation was continued as long as clinical ly indicated . Measurements and results : Mean duration of sedation was 141 and 99 h ( NS ) for midazolam and propofol , respectively , at mean hourly doses of 0.070 ± 0.003 mg · kg−1 midazolam and 1.80 ± 0.08 mg · kg−1 propofol . Overall , 68 % of propofol patients versus 31 % of midazolam ( p<0.001 ) patients had a > 20 % decrease in systolic blood pressure after the loading dose , and 26 versus 45 % ( p<0.01 ) showed a 25 % decrease in spontaneous minute volume . Propofol required more daily dose adjustments ( 2.1 ± 0.1 vs 1.4 ± 0.1 , p<0.001 ) . Nurserated quality of sedation with midazolam was higher ( 8.2 ± 0.1 vs 7.3 ± 0.1 on a 10-cm visual analog scale , p<0.001 ) . Resumption of spontaneous respiration was equally rapid . Recovery was faster after propofol ( p<0.02 ) , albeit with a higher degree of agitation . Amnesia was evident in all midazolam patients but in only a third of propofol patients . The cost of propofol was 4–5 times higher . Conclusions : Both drugs afforded reliable , safe , and controllable long-term sedation in ICU patients and rapid weaning from mechanical ventilation . Midazolam depressed respiration , allowed better maintenance of sedation , and yielded complete amnesia at a lower cost , while propofol caused more cardiovascular depression during induction [19854793] Delirium and transient neurologic dysfunctions ( TND ) often complicate the postoperative course after surgery for acute type-A aortic dissection ( AAD ) . We evaluated the role of clonidine on neurological outcome and respiratory function in 30 consecutive patients undergoing surgery for AAD . Patients were prospect ively r and omized to receive either clonidine ( 0.5 microg/kg bolus , followed by continuous infusion at 1 - 2 microg/kg/h ) or placebo ( NaCl 0.9 % ) in on starting and throughout the weaning period from the mechanical ventilation . Incidence of delirium and TND , Delirium Detection Score ( DDS ) , weaning parameters [ respiratory rate to tidal volume ratio - f/VT ; pressure-frequency product ( PFP ) ; partial pressure of arterial oxygen to fractional inspired oxygen concentration ( PaO(2)/FiO(2 ) ) ; partial pressure of carbon dioxide ( PaCO(2 ) ) ] , weaning duration and intensive care unit ( ICU ) length of stay were recorded . The two groups were similar for preoperative and operative variables and also for the incidence of postoperative complications . DDS was lower in the clonidine group ( P<0.001 ) . Patients weaned with clonidine showed lower f/VT and PFP , higher PaO(2)/FiO(2 ) and PaCO(2 ) , lower DDS , weaning period and the related ICU length of stay ( P<0.001 ) . This was further confirmed in patients developing delirium/TND . Intravenous clonidine after surgery for AAD reduces the severity of delirium , improves the respiratory function , shortens the weaning duration and the ICU length of stay [22420466] Abstract Objectives . Intravenous sedation in the intensive care unit ( ICU ) may contribute to altered consciousness and prolonged mechanical ventilation . We tested the hypothesis that replacing intravenous propofol with inhaled sevoflurane for sedation after cardiac surgery would lead to shorter wake-up times , quicker patient cooperation , and less delusional memories . Design . Following coronary artery bypass surgery with cardiopulmonary bypass , 100 patients were r and omized to sedation with sevoflurane via the anesthetic conserving device or propofol . Study drugs were administered for a minimum of 2 hours until criteria for extubation were met . Primary endpoints were time from drug stop to extubation and to adequate verbal response . Secondary endpoints were adverse recovery events , memories reported in the ICU Memory Tool test , and ICU/hospital stay . Results . Median time from drug stop to extubation ( interquartile range/total range ) was shorter after sevoflurane compared to propofol sedation ; 10 ( 10/100 ) minutes versus 25 ( 21/240 ) minutes ( p < 0.001 ) . Time from extubation to adequate verbal response was shorter ( p = 0.036 ) . No differences were found in secondary endpoints . Conclusions . Sevoflurane sedation after cardiac surgery leads to shorter wake-up times and quicker cooperation compared to propofol . No differences were seen in ICU-stay , adverse memories or recovery events in our short-term sedation [9590313] OBJECTIVES To evaluate and compare the clinical efficacy , impact on hemodynamics , safety profiles , and cost of combined administration of propofol and midazolam ( synergistic sedation ) vs. midazolam and propofol administered as sole agents , for sedation of mechanically ventilated patients after coronary artery bypass grafting . DESIGN Prospect i ve , controlled , r and omized , double-blind clinical trial . SETTING Intensive care unit of SCIAS-Hospital de Barcelona . PATIENTS Seventy-five mechanically ventilated patients who underwent coronary artery bypass graft surgery under low-dose opioid anesthesia . INTERVENTIONS According to the double-blind method , patients were r and omly assigned to receive propofol ( n = 25 ) , midazolam ( n = 25 ) , or propofol combined with midazolam ( n = 25 ) . Infusion rates were adjusted to stay between 8 and 11 points on Glasgow Coma Score modified by Cook and Palma . MEASUREMENTS AND MAIN RESULTS Mean + /- SD duration of sedation was 14.4 + /- 1.5 hrs , 14.1 + /- 1.1 hrs , and 14.7 + /- 1.9 hrs for the propofol , midazolam , and synergistic groups , respectively . The induction dose was 0.55 + /- 0.05 mg/kg for propofol as sole agent , 0.05 + /- 0.01 mg/kg for midazolam as sole agent , and 0.22 + /- 0.03 mg/kg for propofol administered in combination with 0.02 + /- 0.00 mg/kg of midazolam ( p = .001 ) . The maintenance dose was 1.20 + /- 0.03 mg/kg/hr for propofol as sole agent , 0.08 + /- 0.01 mg/kg/hr for midazolam as sole agent , and 0.50 + /- 0.09 mg/kg/hr for propofol administered in combination with 0.03 + /- 0.01 mg/kg/hr of midazolam ( p < .001 ) . All sedative regimens achieved similar efficacy in percentage of hours of adequate sedation ( 93 % for propofol , 88 % for midazolam , and 90 % for the synergistic group , respectively ) . After induction , both propofol and midazolam groups had significant decreases in systolic blood pressure , diastolic blood pressure , left atrial pressure , and heart rate . Patients in the synergistic group had significant bradycardia throughout the study , without impairment in other hemodynamic parameters . Patients se date d with propofol or synergistic regimen awoke sooner and could be extubated before those patients se date d with midazolam ( 0.9 + /- 0.3 hrs and 1.2 + /- 0.6 hrs vs. 2.3 + /- 0.8 hrs , respectively , p = .01 ) . Synergistic sedation produced cost savings of 28 % with respect to midazolam and 68 % with respect to propofol . CONCLUSIONS In the study conditions , the new synergistic treatment with propofol and midazolam administered together is an effective and safe alternative for sedation , with some advantages over the conventional regimen with propofol or midazolam administered as sole agents , such as absence of hemodynamic impairment , > 68 % reduction in maintenance dose , and lower pharmaceutical cost [8605792] OBJECTIVES To evaluate and compare the clinical efficacy , impact on hemodynamic and oxygen transport variables , safety profiles , and cost efficiency of sedation and anxiolysis with lorazepam vs. continuous infusion of midazolam in critically ill , intensive care unit patients . DESIGN Multicenter , prospect i ve , r and omized , open-label study . SETTING Teaching hospitals . PATIENTS Ninety-five critically ill , mechanically ventilated patients with fiberoptic pulmonary artery catheters in place were r and omly assigned to receive short-term ( 8 hrs ) sedation with either intermittent intravenous injection lorazepam ( group A , n = 50 ) or continuous intravenous infusion midazolam ( group B , n = 45 ) titrated to clinical response . MEASUREMENTS AND MAIN RESULTS The severity of illness , demographic characteristics , levels of anxiety and agitation , hemodynamic parameters , oxygen transport variables , quality of sedation , nursing acceptance , and laboratory chemistries reflecting drug safety were recorded . There were no significant differences with regard to demographic data , hemodynamic and oxygen transport variables , or levels of anxiety/agitation between the two groups at baseline , 5 mins , 30 mins , and 4 and 8 hrs after administration of sedation . There were no significant differences in the quality of sedation or anxiolysis . Midazolam-treated patients used significantly larger amounts of drug for similar levels of sedation and anxiolysis ( 14.4 + /- 1.2 mg/8 hrs vs. 1.6 + /- 0.1 mg/8 hrs , p = .001 ) . Both drugs were safely administered and patient and nurse satisfaction was similar . CONCLUSIONS Sedation and anxiolysis with lorazepam and midazolam in critically ill patients is safe and clinical ly effective . Hemodynamic and oxygen transport variables are similarly affected by both drugs . The dose of midazolam required for sedation is much larger than the dose of lorazepam required for sedation , and midazolam is therefore less cost-efficient [8989173] OBJECTIVE To compare the effectiveness of sedation , the time required for weaning , and the costs of prolonged sedation of critically ill mechanically ventilated patients with midazolam and propofol . DESIGN Open-label , r and omized , prospect i ve , phase IV clinical trial . SETTING Medical and surgical intensive care unit ( ICU ) in a community hospital . PATIENTS All ICU admissions ( medical , surgical and trauma ) requiring mechanical ventilation for > 24 hrs . A total of 108 patients were included in the study . INTERVENTIONS Patients were r and omized to receive midazolam or propofol . The dose range allowed for each drug was 0.1 to 0.5 mg/kg/hr for midazolam and 1 to 6 mg/kg/hr for propofol . The lowest dose that achieved an adequate patient-ventilator synchrony was infused . All patients received 0.5 mg/kg/24 hrs of morphine chloride . MEASUREMENTS AND MAIN RESULTS The level of sedation was quantified by the Ramsay scale every 2 hrs until weaning from mechanical ventilation was started . If sedation could not be achieved by infusing the highest dose of midazolam or propofol , the case was recorded as a therapeutic failure . In the propofol group , serum triglycerides were determined every 72 hrs . Concentrations of > 500 mg/dL were also recorded as a therapeutic failure . When the patient was ready for weaning according to defined criteria , sedation was interrupted abruptly and the time from interruption of sedation to the first T-bridge trial and to extubation was measured . Cost analysis was performed based on the cost of intensive care in our unit ( $ 54/hr ) . In the midazolam group ( n = 54 ) , 15 ( 27.8 % ) patients died ; 11 ( 20.4 % ) patients had therapeutic failure ; and 28 ( 51.8 % ) patients were subjected to a T-bridge trial . In the propofol group ( n = 54 ) , these proportions were 11 ( 20.4 % ) , 18 ( 33.4 % [ including seven due to inadequate sedation , and 11 due to hypertriglyceridemia ] ) , and 25 ( 46.2 % ) , respectively . None of these values was significantly different between the two groups . Duration of sedation was 141.7 + /- 89.4 ( SD ) hrs and 139.7 + /- 84.7 hrs ( p = NS ) , and cost ( US dollars ) attributed to sedation was $ 378 + /- 342 and $ 1,047 + /- 794 ( p = .0001 ) for the midazolam and propofol groups , respectively . In the midazolam group , time from discontinuation of the drug infusion to extubation was 97.9 + /- 54.6 hrs ( 48.9 + /- 47.2 hrs to the first disconnection , and 49.0 + /- 23.7 hrs to extubation ) . In the propofol group , time from discontinuation of the drug infusion to extubation was 34.8 + /- 29.4 hrs ( 4.0 + /- 3.9 hrs to the first disconnection , and 30.8 + /- 29.2 hrs to extubation ) . The difference between the two groups in the weaning time was 63.1 + /- 12.5 ( SEM ) hrs ( p < .0001 ) . Cost per patient in the midazolam group ( including ICU therapy and sedation with midazolam ) was $ 10,828 + /- 5,734 . Cost per patient in the propofol group was $ 9,466 + /- 5,820 , $ 1,362 less than in the midazolam group . CONCLUSIONS In our population of critically ill patients se date d with midazolam or propofol over prolonged periods , midazolam and propofol were equally effective as sedative agents . However , despite remarkable differences in the cost of sedation with these two agents , the economic profile is more favorable for propofol than for midazolam due to a shorter weaning time associated with propofol administration [25604219] OBJECTIVE To evaluate the efficacy and safety of dexmedetomidine for post-operative elder patients on mechanical ventilation ( MV ) . METHODS For this r and omized controlled trial , 108 cases of post-operative patients on MV were enrolled and assigned into either dexmedetomidine group ( n = 54 ) or propofol group ( n = 54 ) for sedation . And propofol was used for rescue . The dose of sedation was regulated by Ramsay score for maintaining a sedative score of 3 - 4 . In both groups , fentanyl was provided intravenously continually for analgesia . The amount of fentanyl was adjusted according to the numerical rating scale ( NRS ) score for maintaining an analgesic score of 0 - 3 . The average Ramsay score , the frequency of propofol , the highest score of NRS , the total dosage of fentanyl and recovery time were compared . Additional outcomes included duration of mechanical ventilation and intensive care unit ( ICU ) length . And the incidence of delirium and cardiovascular adverse events were compared for two groups . RESULTS No significant inter-group difference existed in the effectiveness of sedation . Compare with propofol group , the highest score of NRS decreased ( 1.8 ± 1.12 vs 3.1 ± 1.24 , P < 0.05 ) , the total dosage of fentanyl significantly decreased ( 427.6 ± 14.1 vs 658.4 ± 27.3 µg , P < 0.05 ) and recovery time became significantly shortened ( 0.3 ± 0.02 h vs 1.1 ± 0.3 h , P < 0.05 ) in dexmedetomidine group . Median duration of mechanical ventilation in dexmedetomidine group ( 21.0 h , 95%CI : 18.6 - 21.4 h ) was significantly shorter than that in propofol group ( 28.0 h , 95%CI : 25.6 - 30.4 h ) ( P < 0.05 ) . No inter-group differences existed in the ICU length of stay and the incidence of delirium . Two cases in dexmedetomidine group developed bradycardia while hypotension occurred in two cases of propofol group . CONCLUSION Sedative effects of dexmedetomidine are safe and effective for post-operative elder patients on MV . And it offers a better efficacy of analgesia and shorter duration s of MV and recovery time . But dexmedetomidine had no significant influence on the ICU length of stay or the incidence of delirium [14579210] OBJECTIVE To compare dexmedetomidine-based to propofol-based sedation after coronary artery bypass graft ( CABG ) surgery in the intensive care unit ( ICU ) . DESIGN R and omized , open label . SETTING Twenty-five centers in the United States and Canada . PARTICIPANTS Two hundred ninety-five adults undergoing CABG surgery . INTERVENTIONS At sternal closure , patients in group A received 1.0 microg/kg of dexmedetomidine over 20 minutes and then 0.2 to 0.7 microg/kg/h to maintain a Ramsay sedation score > or =3 during assisted ventilation and > or = 2 after extubation . Patients could be given propofol for additional sedation if necessary ; group B patients received propofol-based care according to each investigator 's st and ard practice . MEASUREMENTS AND MAIN RESULTS Mean sedation levels were within target ranges in both groups . Mean times to weaning and extubation were similar , although fewer dexmedetomidine patients remained on the ventilator beyond 8 hours . Morphine use was significantly reduced in the dexmedetomidine group . Only 28 % of the dexmedetomidine patients required morphine for pain relief while ventilated versus 69 % of propofol-based patients ( p < 0.001 ) . Propofol patients required 4 times the mean dose of morphine while in the ICU . Mean blood pressure increased initially in both groups , then decreased to 3 mmHg below baseline in dexmedetomidine patients ; mean arterial pressure remained at 9 mmHg above baseline in propofol patients . No ventricular tachycardia occurred in the dexmedetomidine-se date d patients compared with 5 % of the propofol patients ( p = 0.007 ) . Respiratory rates and blood gases were similar . Fewer dexmedetomidine patients received beta-blockers ( p = 0.014 ) , antiemetics ( p = 0.015 ) , nonsteroidal anti-inflammatory drugs ( p < 0.001 ) , epinephrine ( p = 0.030 ) , or high-dose diuretics ( p < 0.001 ) . CONCLUSION Dexmedetomidine provided safe and effective sedation for post-CABG surgical patients and significantly reduced the use of analgesics , beta-blockers , antiemetics , epinephrine , and diuretics [25493968] Objective : Delirium is common during critical illness and associated with adverse outcomes . We compared characteristics and outcomes of delirious and nondelirious patients enrolled in a multicenter trial comparing protocol ized sedation with protocol ized sedation plus daily sedation interruption . Design : R and omized trial . Setting : Sixteen North American medical and surgical ICUs . Patients : Four hundred thirty critically ill , mechanically ventilated adults . Interventions : All patients had hourly titration of opioid and benzodiazepine infusions using a vali date d sedation scale . For patients in the interruption group , infusions were resumed , if indicated , at half of previous doses . Delirium screening occurred daily ; positive screening was defined as an Intensive Care Delirium Screening Checklist score of 4 or more at any time . Measurements and Main Results : Delirium was diagnosed in 226 of 420 assessed patients ( 53.8 % ) . Coma was identified in 32.7 % of delirious compared with 22.7 % of nondelirious patients ( p = 0.03 ) . The median time to onset of delirium was 3.5 days ( interquartile range , 2–7 ) , and the median duration of delirium was 2 days ( interquartile range , 1–4 ) . Delirious patients were more likely to be male ( 61.1 % vs 46.6 % ; p = 0.005 ) , have a surgical/trauma diagnosis ( 21.2 % vs 11.0 % ; p = 0.030 ) , and history of tobacco ( 31.5 % vs 16.2 % ; p = 0.002 ) or alcohol use ( 34.6 % vs 20.9 % ; p = 0.009 ) . Patients with positive delirium screening had longer duration of ventilation ( 13 vs 7 d ; p < 0.001 ) , ICU stay ( 12 vs 8 d ; p < 0.0001 ) , and hospital stay ( 24 vs 15 d ; p < 0.0001 ) . Delirious patients were more likely to be physically restrained ( 86.3 % vs 76.7 % ; p = 0.014 ) and undergo tracheostomy ( 34.6 % vs 15.5 % ; p < 0.0001 ) . Antecedent factors independently associated with delirium onset were restraint use ( hazard ratio , 1.87 ; 95 % CI , 1.33–2.63 ; p = 0.0003 ) , antipsychotic administration ( hazard ratio , 1.67 ; 95 % CI , 1.005–2.767 ; p = 0.047 ) , and midazolam dose ( hazard ratio , 0.998 ; 95 % CI , 0.997–1.0 ; p = 0.049 ) . There was no difference in delirium prevalence or duration between the interruption and control groups . Conclusion : In mechanically ventilated adults , delirium was common and associated with longer duration of ventilation and hospitalization . Physical restraint was most strongly associated with delirium [9054252] Background Alpha2 ‐Adrenergic agonists decrease sympathetic tone with ensuing attenuation of neuroendocrine and hemodynamic responses to anesthesia and surgery . The effects of dexmedetomidine , a highly specific alpha2 ‐adrenergic agonist , on these responses have not been reported in patients undergoing coronary artery bypass grafting . Methods Eighty patients scheduled for elective coronary artery bypass grafting received , in a double‐blind manner , either a saline placebo or a dexmedetomidine infusion , initially 50 ng [ center dot ] kg‐1 [ center dot ] min‐1 for 30 min before induction of anesthesia with fentanyl , and then 7 ng [ center dot ] kg‐1 [ center dot ] min‐1 until the end of surgery . Filling pressures , blood pressure , and heart rate were controlled by intravenous fluid and by supplemental anesthetics and vasoactive drugs . Results Compared with placebo , dexmedetomidine decreased plasma norepinephrine concentrations by 90 % , attenuated the increase of blood pressure during anesthesia ( 3 vs. 24 mmHg ) and surgery ( 2 vs. 14 mmHg ) , but increased slightly the need for intravenous fluid challenge ( 29 vs. 20 patients ) and induced more hypotension during cardiopulmonary bypass ( 9 vs. 0 patients ) . Dexmedetomidine decreased the incidence of intraoperative ( 2 vs. 13 patients ) and postoperative ( 5 vs. 16 patients ) tachycardia . Dexmedetomidine also decreased the need for additional doses of fentanyl ( 3.1 vs. 5.4 ) , the increments of enflurane ( 4.4 vs. 5.6 ) , the need for beta blockers ( 3 vs. 11 patients ) , and the incidence of fentanyl‐induced muscle rigidity ( 15 vs. 33 patients ) and postoperative shivering ( 13 vs. 23 patients ) . Conclusions Intraoperative intravenous infusion of dexmedetomidine to patients undergoing coronary artery revascularization decreased intraoperative sympathetic tone and attenuated hyperdynamic responses to anesthesia and surgery but increased the propensity toward hypotension [21944176] OBJECTIVE To study sedative effect and safety of dexmedetomidine and midazolam for post-operative patients undergoing mechanical ventilation(MV ) in surgical intensive care unit(SICU ) . METHODS Two hundred cases of post-operative patients undergoing MV with tracheal intubation in SICU were enrolled and divided into two groups by r and om numerical table method . They were treated either with midazolam ( 98 cases ) or dexmedetomidine ( 102 cases ) . In both groups fentanyl was given intravenously continually for analgesia . The amount of fentanyl was adjusted according to Prince-Henry analgesic score to keep on 1 - 2 analgesic score ; the dose of sedation was regulated by Riker sedative and restless score ( SAS ) maintain 2 - 4 sedative score . During the course , parameters of the ventilator , electrocardiogram , heart rate(HR ) , blood pressure , respiratory rate , pulse oxygen saturation ( SpO(2 ) ) , blood gas analysis were observed and registered continuously . The amount of the drug , duration of MV , and incidence of side-effects such as hypotension , bradycardia , delirium , nausea , etc . were recorded in two groups . RESULTS In all the patients in two groups taking dexmedetomidine or midazolam expected sedative and analgesia scores were obtained . In the group with dexmedetomidine , the patients were aroused easier with adequate sedation , and when compared with the group with midazolam , dose of fentanyl ( μg × kg(-1) × h(-1 ) ) was significantly smaller ( 0.23±0.13 vs. 0.41±0.12 , P<0.01 ) , duration of MV ( hours ) was clearly shorter ( 7.20±6.29 vs. 12.44±8.96 , P<0.01 ) , the rates of hypotension ( 27.45 % vs. 11.22 % ) and bradycardia ( 24.51 % vs. 10.20 % ) were significantly higher ( both P<0.05 ) , the rate of delirium was clearly lower ( 3.92 % vs. 31.63 % , P<0.01 ) , the rate of nausea showed a slight decrease ( 9.80 % vs. 11.22 % , P>0.05 ) . The patients in the group with dexmedetomidine were divided into two subgroups of hypotension and non-hypotension . The quantity of blood loss during operation ( ml/kg ) , amount of fluid infusion during operation ( ml × kg(-1) × h(-1 ) ) , blood lactic acid concentration ( mmol/L ) on the day of surgical operation and the 1st day post-operative showed no significant difference between these subgroups ( quantity of blood loss on the day of surgical operation : 12.79±12.13 vs. 13.52±11.62 ; amount of fluid infusion during surgical operation : 11.91±4.59 vs. 13.09±7.05;blood lactic acid concentration on the day of operation : 1.88±1.07 vs. 1.71±0.87 , blood lactic acid concentration on the 1st day post-operative:1.43±0.98 vs. 1.37±0.79 , all P>0.05 ) . CONCLUSION Sedative effect of dexmedetomidine is satisfactory for patients undergoing MV after operation , with the property of easier arousal , lower delirium rate , and it helps to shorten the duration of MV with reduction the dosage of fentanyl by 50 % . However , it is necessary to enhance observation in order to prevent and control hypotension and bradycardia [27132448] OBJECTIVE To compare the sedative effect and safety of dexmedetomidine and midazolam in the intensive care unit ( ICU ) patients undergoing ventilator bundle treatment . METHODS A prospect i ve single-blind r and omized controlled trial ( RCT ) was conducted . Ninety patients receiving ICU ventilator-assisted therapy and ventilator bundle treatments for more than 3 days in the First Department of Critical Care Medicine of the Second Hospital of Lanzhou University from January 2013 to December 2014 were enrolled . The patients were r and omly divided into two groups for sedative treatment . The patients in dexmedetomidine group ( n = 42 ) were given dexmedetomidine 0.2 - 0.7 μg x kg(-1 ) x h(-1 ) to achieve a goal of satisfactory sedation [ Richmond agitation-sedation scale ( RASS ) score 0 to - 2 during the day , and -1 to -3 at night ) . The patients in midazolam group ( n = 48 ) were given midazolam 2 - 3 mg intravenously first , and then 0.05 mg x kg(-1 ) x h(-1 ) for maintenance . The drug dose was adjusted according to RASS every 4 hours to maintain the appropriate sedation depth . The patients in both groups received continuous intravenous infusion of fentanyl for analgesia . Ventilator bundle treatments included the head of a bed up 30 degrees to 45 degrees , awaken and extubation appraisal , daily use of proton pump inhibitors for peptic ulcer prevention , prevention of deep vein thrombosis ( DVT ) , chlorhexidine mouth nursing , and removal of sputum by suction from subglottic area . When the patients in both groups obtained satisfactory target sedation , daily awakening was conducted , and spontaneous breathing test ( SBT ) was carried out to determine optional weaning time . When the condition was optimal , weaning was conducted , otherwise ventilator bundle treatments were continued . The systolic blood pressure ( SBP ) , diastolic blood pressure ( DBP ) , mean arterial pressure ( MAP ) , heart rate ( HR ) , respiratory frequency ( RR ) were monitored before and 15 , 30 , 60 , 120 , 180 minutes after the treatment , and at the moment of extubation and 30 minutes after extubation . The duration of mechanical ventilation , extubation time , length of ICU stay , and the incidence of adverse events were also recorded . RESULTS Both dexmedetomidine and midazolam could give rise to sedation with same score of analgesia in patients in both groups , and similar effect of sedation and analgesia could be achieved . Compared with midazolam , dexmedetomidine could significantly reduce the duration of mechanical ventilation ( hours : 108.33 ± 21.96 vs. 119.85 ± 20.29 , t = -2.586 , P = 0.011 ) , earlier extubation time ( hours : 112.95 ± 22.20 vs. 128.58 ± 26.18 , = -3.031 , P = 0.003 ) , length of ICU stay ( hours : 149.21 ± 20.47 vs. 163.88 ± 33.59 , = -2.457 , P = 0.016 ) , the incidence of delirium [ 9.5 % ( 4/42 ) vs. 31.2 % ( 15/48 ) , χ2 = 6.349 , P = 0.012 ] , but it would elevate the incidence of severe hypotension [ 28.6 % ( 12/42 ) vs. 8.3 % ( 4/48 ) , χ2 = 6.277 , P = 0.012 ] and severe bradycardia [ 19.0 % ( 8/42 ) vs. 8.3 % ( 4/48 ) , χ2 = 2.225 , P = 0.136 ] . Both drugs could lower SBP , DBP , MAP , and HR , and the effect in dexmedetomidine group was more significant from 60 minutes after treatment [ SBP ( mmHg , 1 mmHg = 0.133 kPa ) : 113.12 ± 14.42 vs. 124.40 ± 15.79 , DBP ( mmHg ) : 69.02 ± 9.62 vs. 76.94 ± 10.41 , MAP ( mmHg ) : 83.76 ± 10.50 vs. 92.77 ± 11.87 , HR ( bpm ) : 79.19 ± 12.28 vs. 87.42 ± 17.77 , P < 0.05 or P < 0.01 ] . Both sedatives could significantly lower the rate of spontaneous breathing , and the effect of midazolam group was more significant from 60 minutes after treatment compared with dexmedetomidine group ( times/min : 18.27 ± 4.29 vs. 20.07 ± 4.11 , P < 0.05 ) . CONCLUSIONS The sedative effects of dexmedetomidine in the ICU patients treated with ventilator bundle treatment are satisfactory , and it can shorten the duration of mechanical ventilation , extubation time and length of ICU stay , reduce the incidence of delirium . However , monitoring should be strengthened in order to prevented and control the adverse effects such as severe hypotension and severe bradycardia [26975647] IMPORTANCE Effective therapy has not been established for patients with agitated delirium receiving mechanical ventilation . OBJECTIVE To determine the effectiveness of dexmedetomidine when added to st and ard care in patients with agitated delirium receiving mechanical ventilation . DESIGN , SETTING , AND PARTICIPANTS The Dexmedetomidine to Lessen ICU Agitation ( DahLIA ) study was a double-blind , placebo-controlled , parallel-group r and omized clinical trial involving 74 adult patients in whom extubation was considered inappropriate because of the severity of agitation and delirium . The study was conducted at 15 intensive care units in Australia and New Zeal and from May 2011 until December 2013 . Patients with advanced dementia or traumatic brain injury were excluded . INTERVENTIONS Bedside nursing staff administered dexmedetomidine ( or placebo ) initially at a rate of 0.5 µg/kg/h and then titrated to rates between 0 and 1.5 µg/kg/h to achieve physician-prescribed sedation goals . The study drug or placebo was continued until no longer required or up to 7 days . All other care was at the discretion of the treating physician . MAIN OUTCOMES AND MEASURES Ventilator-free hours in the 7 days following r and omization . There were 21 reported secondary outcomes that were defined a priori . RESULTS Of the 74 r and omized patients ( median age , 57 years ; 18 [ 24 % ] women ) , 2 withdrew consent later and 1 was found to have been r and omized incorrectly , leaving 39 patients in the dexmedetomidine group and 32 patients in the placebo group for analysis . Dexmedetomidine increased ventilator-free hours at 7 days compared with placebo ( median , 144.8 hours vs 127.5 hours , respectively ; median difference between groups , 17.0 hours [ 95 % CI , 4.0 to 33.2 hours ] ; P = .01 ) . Among the 21 a priori secondary outcomes , none were significantly worse with dexmedetomidine , and several showed statistically significant benefit , including reduced time to extubation ( median , 21.9 hours vs 44.3 hours with placebo ; median difference between groups , 19.5 hours [ 95 % CI , 5.3 to 31.1 hours ] ; P < .001 ) and accelerated resolution of delirium ( median , 23.3 hours vs 40.0 hours ; median difference between groups , 16.0 hours [ 95 % CI , 3.0 to 28.0 hours ] ; P = .01 ) . Using hierarchical Cox modeling to adjust for imbalanced baseline characteristics , allocation to dexmedetomidine was significantly associated with earlier extubation ( hazard ratio , 0.47 [ 95 % CI , 0.27 - 0.82 ] ; P = .007 ) . CONCLUSIONS AND RELEVANCE Among patients with agitated delirium receiving mechanical ventilation in the intensive care unit , the addition of dexmedetomidine to st and ard care compared with st and ard care alone ( placebo ) result ed in more ventilator-free hours at 7 days . The findings support the use of dexmedetomidine in patients such as these . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01151865

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### Context: [11296183] STUDY OBJECTIVES To determine whether sedation with propofol would lead to shorter times to tracheal extubation and ICU length of stay than sedation with midazolam . DESIGN Multicenter , r and omized , open label . SETTING Four academic tertiary-care ICUs in Canada . PATIENTS Critically ill patients requiring continuous sedation while receiving mechanical ventilation . INTERVENTIONS R and om allocation by predicted requirement for mechanical ventilation ( short sedation stratum , < 24 h ; medium sedation stratum , > or = 24 and < 72 h ; and long sedation stratum , > or = 72 h ) to sedation regimens utilizing propofol or midazolam . MEASUREMENTS AND RESULTS Using an intention-to-treat analysis , patients r and omized to receive propofol in the short sedation stratum ( propofol , 21 patients ; midazolam , 26 patients ) and the long sedation stratum ( propofol , 4 patients ; midazolam , 10 patients ) were extubated earlier ( short sedation stratum : propofol , 5.6 h ; midazolam , 11.9 h ; long sedation stratum : propofol , 8.4 h ; midazolam , 46.8 h ; p < 0.05 ) . Pooled results showed that patients treated with propofol ( n = 46 ) were extubated earlier than those treated with midazolam ( n = 53 ) ( 6.7 vs 24.7 h , respectively ; p < 0.05 ) following discontinuation of the sedation but were not discharged from ICU earlier ( 94.0 vs 63.7 h , respectively ; p = 0.26 ) . Propofol-treated patients spent a larger percentage of time at the target Ramsay sedation level than midazolam-treated patients ( 60.2 % vs 44.0 % , respectively ; p < 0.05 ) . Using a treatment-received analysis , propofol sedation either did not differ from midazolam sedation in time to tracheal extubation or ICU discharge ( sedation duration , < 24 h ) or was associated with earlier tracheal extubation but longer time to ICU discharge ( sedation duration , > or = 24 h , < 72 h , or > or = 72 h ) . CONCLUSIONS The use of propofol sedation allowed for more rapid tracheal extubation than when midazolam sedation was employed . This did not result in earlier ICU discharge [3786847] The aim of this study was to observe the impact of dexmedetomidine on postoperative myocardial injury in patients undergoing off-pump coronary artery bypass ( OPCAB ) grafting . One hundred and sixty-two patients who were undergoing OPCAB surgery were r and omly divided into control and dexmedetomidine groups ( groups C and Dex , respectively ) . Following the first vascular anastomosis grafting , the patients in group Dex received a continuous intravenous infusion of 0.2–0.5 μg/kg/h dexmedetomidine , until they were transferred to the Cardiac Surgery intensive care unit ( ICU ) for 12 h. Patients in group C received physiological saline intraoperatively and an intravenous infusion of 2–4 mg/kg/h isopropylphenol for postoperative sedation . Invasive arterial pressure and heart rate were continuously monitored for 5 min subsequent to entry into the operating theatre ( T0 ) , immediately following surgery ( T1 ) , 12 h post-surgery ( T2 ) , 24 h post-surgery(T3 ) , 48 h post-surgery(T4 ) and 72 h post-surgery ( T5 ) . Blood sample s were taken to determine the plasma levels of cardiac troponin I ( cTnI ) and creatine kinase-MB ( CK-MB ) at each time point . At 72 h post-surgery , a dynamic electrocardiogram was monitored . The blood pressure , heart rate , levels of cTnI , CK-MB , norepinephrine and cortisol , and postoperative arrhythmic events in the patients in group Dex all decreased compared with those in group C. The duration of mechanical ventilation and ICU residence time were also shorter than those in the control group ( P<0.05 ) . Dexmedetomidine reduced post-surgical myocardial injury in patients who had undergone OPCAB surgery [21744187] Objective To compare the efficacy of dexmedetomidine versus morphine as a sedative/analgesic among post-operative cardiac surgery patients . Method A r and omized controlled open-label study was performed at the cardiothoracic intensive care unit of Penang Hospital , Malaysia . A total of 28 patients who underwent cardiac surgeries were r and omly assigned to receive either dexmedetomidine or morphine . Both groups were similar in terms of preoperative baseline characteristics . Efficacy measures included sedation scores and pain intensity and requirements for additional sedative/analgesic . Mean heart rate and arterial blood pressure were used as safety measures . Other measures were additional inotropes , extubation time and other concurrent medications . Results The mean dose of dexmedetomidine infused was 0.12 [ SD 0.03 ] μg kg−1 h−1 , while that of morphine was 13.2 [ SD 5.84 ] μg kg−1 h−1 . Dexmedetomidine group showed more benefits in sedation and pain levels , additional sedative/analgesic requirements , and extubation time . No significant differences between the two groups for the outcome measures , except heart rate , which was significantly lower in the dexmedetomidine group . Conclusion This preliminary study suggests that dexmedetomidine was at least comparable to morphine in terms of efficacy and safety among cardiac surgery patients . Further studies with larger sample s are recommended in order to determine the significant effects of the outcome measures [26203971] BACKGROUND Patients and medical staff are exposed to high noise levels in ICUs , which may have a negative impact on their health . Due to the diversity of noise sources present , including the operating noise of medical devices , staff conversations and the unwrapping of disposables , noise profiles are varied . Psychoacoustics deals with the analysis of sound , focusing on its effects on physiological perception and stress . OBJECTIVES The aim of our study was to examine and to classify noise and its psychoacoustic properties in different locations in our ICU at different times . The impact of noise on subjective parameters and stress-related physiological data was also assessed with and without interventional methods . DESIGN A r and omised , controlled , single-blinded clinical trial . SETTING University Hospital , from November 2010 to May 2011 . PATIENTS One hundred and forty-four patients in the ICU . INTERVENTIONS In the first part , multidisciplinary psychoacoustic measurement was performed on the patients in our ICU . In the subsequent clinical trial , patients were equipped with effective earplugs , less effective earplugs and no earplugs . Thereafter , active noise cancellation headphones with or without sound masking were employed on a third patient population . MAIN OUTCOME MEASURES Cortisol and & agr;-amylase in saliva , skin conductance measures , vital signs , psychoacoustic analyses and two st and ardised question naires [ State-Trait Anxiety Inventory ( STAI ) and Hospital Anxiety and Depression Scale ( HADS ) ] were assessed . RESULTS In the first part , the mean ± st and ard deviation ( SD ) subjective loudness was 9.2 ± 4.0 sone . Although absolute sound pressure level and loudness were lower during the night , the number of loud events increased significantly . Skin conductance in the earplug groups was significantly reduced in comparison to that in the control population but not the active noise reduction groups . Nevertheless , noise reduction was found to be comfortable for most patients . CONCLUSION Noise in the ICU is of high clinical relevance . Diverse noise reduction methods , such as earplugs and active noise cancellation , are available . The avoidance of unnecessary noise , however , should be the primary focus . TRIAL REGISTRATION German Clinical Trials Register ( DRKS00000534 ) [4353161] Background and Aims : Patients on ventilatory support in intensive care unit ( ICU ) require sedation and analgesia to facilitate mechanical ventilation and endotracheal tube tolerance . The selection of the agent should be such that it does not interfere with the early extubation of the patients . We compared the efficacy of dexmedetomidine with midazolam to facilitate extubation of patients from mechanical ventilation in terms of the sedative properties , cardiovascular responses , ventilation , and extubation characteristics and safety profile . Material s and Methods : A total of 40 adult , mechanically ventilated patients of either sex , aged 18 - 60 years , meeting the st and ard criteria for weaning , r and omized into 2 groups of 20 patients each , received intravenous infusion of dexmedetomidine ( 0.2 - 0.7 mcg/kg/h ) or midazolam ( 0.04 - 0.2 mg/kg/h ) as needed for Ramsay sedation scale 2 - 4 . Extubation following st and ard extubation protocol was done . Time for extubation and vital parameters were regularly recorded . Results : The time to extubation in the dexmedetomidine group was significantly lower than in the midazolam group . Heart rate and blood pressure was significantly lower in dexmedetomidine group than the midazolam group at most of the times . Conclusions : Dexmedetomidine has clinical ly relevant benefits compared with midazolam in facilitating extubation due to its shorter time to extubation , more hemodynamic stability , easy arousability , and lack of respiratory depression [3580615] Introduction This study hypothesised that a reduction of sound during the night using earplugs could be beneficial in the prevention of intensive care delirium . Two research questions were formulated . First , does the use of earplugs during the night reduce the onset of delirium or confusion in the ICU ? Second , does the use of earplugs during the night improve the quality of sleep in the ICU ? Methods A r and omized clinical trial included adult intensive care patients in an intervention group of 69 patients sleeping with earplugs during the night and a control group of 67 patients sleeping without earplugs during the night . The research ers were blinded during data collection . Assignment was performed by an independent nurse research er using a computer program . Eligible patients had an expected length of stay in the ICU of more than 24 hours , were Dutch- or English-speaking and scored a minimum Glasgow Coma Scale of 10 . Delirium was assessed using the vali date d NEECHAM scale , sleep perception was reported by the patient in response to five questions . Results The use of earplugs during the night lowered the incidence of confusion in the studied intensive care patients . A vast improvement was shown by a Hazard Ratio of 0.47 ( 95 % confidence interval ( CI ) 0.27 to 0.82 ) . Also , patients sleeping with earplugs developed confusion later than the patients sleeping without earplugs . After the first night in the ICU , patients sleeping with earplugs reported a better sleep perception . Conclusions Earplugs may be a useful instrument in the prevention of confusion or delirium . The beneficial effects seem to be strongest within 48 hours after admission . The relation between sleep , sound and delirium , however , needs further research .Trial registration Current Controlled Trials IS RCT [18073360] CONTEXT Lorazepam is currently recommended for sustained sedation of mechanically ventilated intensive care unit ( ICU ) patients , but this and other benzodiazepine drugs may contribute to acute brain dysfunction , ie , delirium and coma , associated with prolonged hospital stays , costs , and increased mortality . Dexmedetomidine induces sedation via different central nervous system receptors than the benzodiazepine drugs and may lower the risk of acute brain dysfunction . OBJECTIVE To determine whether dexmedetomidine reduces the duration of delirium and coma in mechanically ventilated ICU patients while providing adequate sedation as compared with lorazepam . DESIGN , SETTING , PATIENTS , AND INTERVENTION Double-blind , r and omized controlled trial of 106 adult mechanically ventilated medical and surgical ICU patients at 2 tertiary care centers between August 2004 and April 2006 . Patients were se date d with dexmedetomidine or lorazepam for as many as 120 hours . Study drugs were titrated to achieve the desired level of sedation , measured using the Richmond Agitation-Sedation Scale ( RASS ) . Patients were monitored twice daily for delirium using the Confusion Assessment Method for the ICU ( CAM-ICU ) . MAIN OUTCOME MEASURES Days alive without delirium or coma and percentage of days spent within 1 RASS point of the sedation goal . RESULTS Sedation with dexmedetomidine result ed in more days alive without delirium or coma ( median days , 7.0 vs 3.0 ; P = .01 ) and a lower prevalence of coma ( 63 % vs 92 % ; P < .001 ) than sedation with lorazepam . Patients se date d with dexmedetomidine spent more time within 1 RASS point of their sedation goal compared with patients se date d with lorazepam ( median percentage of days , 80 % vs 67 % ; P = .04 ) . The 28-day mortality in the dexmedetomidine group was 17 % vs 27 % in the lorazepam group ( P = .18 ) and cost of care was similar between groups . More patients in the dexmedetomidine group ( 42 % vs 31 % ; P = .61 ) were able to complete post-ICU neuropsychological testing , with similar scores in the tests evaluating global cognitive , motor speed , and attention functions . The 12-month time to death was 363 days in the dexmedetomidine group vs 188 days in the lorazepam group ( P = .48 ) . CONCLUSION In mechanically ventilated ICU patients managed with individualized targeted sedation , use of a dexmedetomidine infusion result ed in more days alive without delirium or coma and more time at the targeted level of sedation than with a lorazepam infusion . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00095251 [4118508] Background and Objectives : Patients on mechanical ventilation in intensive care unit ( ICU ) are often uncomfortable because of anxiety , pain , and endotracheal intubation ; therefore , require sedation . Alpha-2 agonists are known to produce sedation . We compared clonidine and dexmedetomidine as sole agents for sedation . Study Design : Prospect i ve , r and omized , controlled open-label study . Material s and Methods : A total of 70 patients requiring a minimum of 12 h of mechanical ventilation with concomitant sedation , were r and omly allocated into two groups . Group C ( n = 35 ) received intravenous ( IV ) clonidine ( 1 μg/kg/h titrated up to 2 μg/kg/h to attain target sedation ) , and Group D ( n = 35 ) received IV dexmedetomidine for sedation ( loading 0.7 μg/kg and maintenance 0.2 μg/kg/h titrated up to 0.7 μg/kg/h to achieve target sedation ) . A Ramsay Sedation Score of 3 - 4 was considered as target sedation . Additional sedation with diazepam was given when required to achieve target sedation . The quality of sedation , hemodynamic changes and adverse effects were noted and compared between the two groups . Results : Target sedation was achieved in 86 % observations in Group D and 62 % in Group C ( P = 0.04 ) . Additional sedation was needed by more patients in Group C compared with Group D ( 14 and 8 in Groups C and D , respectively , P = 0.034 ) , mainly due to concomitant hypotension on increasing the dose of clonidine . Hypotension was the most common side-effect in Group C , occurring in 11/35 patients of Group C and 3/35 patients of Group D ( P = 0.02 ) . Rebound hypertension was seen in four patients receiving clonidine , but none in receiving dexmedetomidine . Conclusion : Both clonidine and dexmedetomidine produced effective sedation ; however , the hemodynamic stability provided by dexmedetomidine gives it an edge over clonidine for short-term sedation of ICU patients [15959548] BACKGROUND Propofol is often used for sedation in the intensive care unit . The aim of this study was to compare the efficacy and endocrine response of propofol vs. the new alpha2-agonist dexmedetomidine for sedation in surgical intensive care patients who need postoperative short-term ventilation . METHODS Our work is a r and omized clinical study conducted on sixty adult patients who required postoperative short term ventilation and sedation . The patients were allocated r and omly , to receive IV infusion of either dexmedetomidine 0.2 - 0.5 microg/kg/h or propofol 0.5 - 1 mg/kg/h . Hemodynamic parameters , Ramsay sedation score , extubation time and serum cortisol and interleukin-6 ( IL-6 ) levels were measured . RESULTS Ramsay sedation score was 4.1+/-1 and 4+/-0.9 for propofol and dexmedetomidine , respectively , ( p=0.59 . ) Total fentanyl dose in the propofol group was 75+/-15 microg compared to 15+/-10.5 microg in the dexmedetomidine group , ( p=0.0045 ) . Patients who received dexmedetomidine infusion had significantly lower heart rates compared to patients who received propofol infusion , ( p=0.041 ) . Pre-infusion serum concentrations of IL-6 were comparable in both groups , while the 24 h post-infusion levels were insignificantly decreased in both groups compared to pre-infusion level , ( p=0.36 ) . There were no intergroup differences in serum cortisol concentrations ( p=0.231 ) . CONCLUSIONS Dexmedetomidine and propofol are safe sedative drugs for postoperative mechanichally ventilated patients . Patients were easily aroused to co-operate without showing signs of irritations with less fentanyl analgesia in the dexmedetomidine group . Dexmedetomidine and propofol do not inhibit adrenal function , but they may influence the inflammatory response [4047690] Context : Critically ill patients requiring mechanical ventilation frequently need sedatives and analgesics to facilitate their care . Dexmedetomidine , a short-acting alpha-2-agonist , possesses anxiolytic , anesthetic , hypnotic , and analgesic properties . Aims : The objective of this study was to evaluate the efficacy and safety of dexmedetomidine in comparison to propofol in the management of sedation for post-operative intensive care unit ( ICU ) patients , as a sedative agent . Setting s and Design : Teaching hospital , A phase III , prospect i ve , open , r and omized and comparative . Material s and Methods : Thirty patients who were ambulatory and who required the post-operative mechanical ventilation or post-operative sedation were enrolled , in which 15 patients received Dexmedetomidine and remaining 15 patients received propofol . All these patients were treated for the period of 8 to 24 h. Statistical Analysis Used : Data were analyzed using Student 's t-test and Chi-square test . The value of P < 0.05 was considered as statistically significant . Results : Demographic data were comparable . Pulse rate , respiratory rate and blood pressure were comparable . Depth of sedation and extubation time were similar . To maintain analgesia throughout the study period , patients receiving propofol infusions required significantly more analgesics than patients receiving Dexmedetomidine . Conclusions : Dexmedetomidine appears to be a safe and acceptable ICU sedative agent when both the clinician 's and patient 's perspectives are considered [15891317] Objective : Dexmedetomidine ( DEX ) may provide a sedation level that enables sleep and communication , with less amnesia and pain medication requirements , during mechanical ventilation . Our study directly assessed patient-perceived satisfaction with coronary artery bypass graft surgery after administration of DEX or propofol for intensive care unit ( ICU ) sedation . Design : Prospect i ve , r and omized clinical study with subsequent question naire administration . Setting : Tertiary care surgical ICU . Patients : A total of 89 adult , nonemergent , coronary artery bypass graft patients with an expected length of intubation of < 24 hrs . Interventions : Patients were r and omized to either DEX or propofol ; drug administration was performed via st and ardized anesthesia and nursing protocol s. Measurements : Patients reported perceptions of their ICU experience after mechanical ventilation with a modified numerical-scale Hewitt question naire , vali date d specifically for ICU patients . Patients were question ed regarding awareness , recall , generalized comfort , level of pain , ability to interact with healthcare providers and family , feelings of agitation and anxiety , perceived ease of extubation , ability to sleep or rest , and satisfaction with ICU experience . Main Results : Groups were well matched at baseline , with a mean ± sd age of 63.0 ± 10.4 yrs and weight of 88.7 ± 16.7 kg . No difference was observed for length of surgery , length of intubation , or ICU stay ( p > .05 ) . DEX patients perceived a shorter length of intubation ( p = .044 ) . A deeper sedation level was found in the propofol group ( p = .021 ) , with similar morphine and midazolam requirements ( p = .317 ) . Patient-rated level of overall awareness as a marker of amnesia did not differ between groups ( p = .653 ) . The ability to rest or sleep trended toward significance favoring propofol ( p = .051 ) . On evaluation of question naire ratings , DEX patients expressed more discomfort ( p = .046 ) , pain ( p = .096 ) , and sleeping difficulty ( p = .036 ) . Similar comfort levels were reported during extubation ( p = .179 ) . Conclusions : Despite theoretical advantages of DEX to improve overall patient satisfaction , the two agents provide similar responses to amnesia and pain control . According to our findings , DEX does not seem to have any advantage compared with propofol for short-term sedation after coronary artery bypass graft surgery [2717438] Introduction Agitated delirium is common in patients undergoing mechanical ventilation , and is often treated with haloperidol despite concerns about safety and efficacy . Use of conventional sedatives to control agitation can preclude extubation . Dexmedetomidine , a novel sedative and anxiolytic agent , may have particular utility in these patients . We sought to compare the efficacy of haloperidol and dexmedetomidine in facilitating extubation . Methods We conducted a r and omised , open-label , parallel-groups pilot trial in the medical and surgical intensive care unit of a university hospital . Twenty patients undergoing mechanical ventilation in whom extubation was not possible solely because of agitated delirium were r and omised to receive an infusion of either haloperidol 0.5 to 2 mg/hour or dexmedetomidine 0.2 to 0.7 μg/kg/hr , with or without loading doses of 2.5 mg haloperidol or 1 μg/kg dexmedetomidine , according to clinician preference . Results Dexmedetomidine significantly shortened median time to extubation from 42.5 ( IQR 23.2 to 117.8 ) to 19.9 ( IQR 7.3 to 24 ) hours ( P = 0.016 ) . Dexmedetomidine significantly decreased ICU length of stay , from 6.5 ( IQR 4 to 9 ) to 1.5 ( IQR 1 to 3 ) days ( P = 0.004 ) after study drug commencement . Of patients who required ongoing propofol sedation , the proportion of time propofol was required was halved in those who received dexmedetomidine ( 79.5 % ( 95 % CI 61.8 to 97.2 % ) vs. 41.2 % ( 95 % CI 0 to 88.1 % ) of the time intubated ; P = 0.05 ) . No patients were reintubated ; three receiving haloperidol could not be successfully extubated and underwent tracheostomy . One patient prematurely discontinued haloperidol due to QTc interval prolongation . Conclusions In this preliminary pilot study , we found dexmedetomidine a promising agent for the treatment of ICU-associated delirious agitation , and we suggest this warrants further testing in a definitive double-blind multi-centre trial . Trial registration Clinical trials.gov [4391192] Introduction Intensive care unit ( ICU ) environmental factors such as noise and light have been cited as important causes of sleep deprivation in critically ill patients . Previous studies indicated that using earplugs and eye masks can improve REM sleep in healthy subjects in simulated ICU environment , and improve sleep quality in ICU patients . This study aim ed to determine the effects of using earplugs and eye masks with relaxing background music on sleep , melatonin and cortisol levels in ICU patients . Methods Fifty patients who underwent a scheduled cardiac surgery and were expected to stay at least 2 nights in Cardiac Surgical ICU ( CSICU ) were included . They were r and omized to sleep with or without earplugs and eye masks combined with 30-minute relaxing music during the postoperative nights in CSICU . Urine was analyzed for nocturnal melatonin and cortisol levels . Subjective sleep quality was evaluated using the Chinese version of Richards-Campbell Sleep Question naire ( a visual analog scale , ranging 0–100 ) . Results Data from 45 patients ( 20 in intervention group , 25 in control group ) were analyzed . Significant differences were found between groups in depth of sleep , falling asleep , awakenings , falling asleep again after awakening and overall sleep quality ( P < 0.05 ) . Perceived sleep quality was better in the intervention group . No group differences were found in urinary melatonin levels and cortisol levels for the night before surgery , and the first and second nights post-surgery ( P > 0.05 ) . The urinary melatonin levels of the first and second postoperative nights were significantly lower than those of the night before surgery ( P = 0.01 ) . The opposite pattern was seen with urinary cortisol levels ( P = 0.00 ) . Conclusion This combination of non-pharmacological interventions is useful for promoting sleep in ICU adult patients ; however , any influence on nocturnal melatonin levels and cortisol level may have been masked by several factors such as the timing of surgery , medication use and individual differences . Larger scale studies would be needed to examine the potential influences of these factors on biological markers and intervention efficacy on sleep . Trial registration Chinese Clinical Trial Registry : ChiCTR-IOR-14005511 . Registered 21 November 2014 [21521683] BACKGROUND We evaluated the use of dexmedetomidine to facilitate the weaning of delirious postoperative patients from mechanical ventilation . METHODS We included 72 consecutive patients who underwent elective cardiac surgery in this prospect i ve observational study . Each patient had failed at least 1 trial of continuous positive airway pressure ( CPAP ) and had agitation . Patients were assessed with the Richmond Agitation-Sedation Scale ( RASS ) and the Confusion Assessment Method for the Intensive Care Unit ( CAMICU ) 12 to 18 hours after their admission to the ICU . Midazolam and fentanyl were then given to all patients according to the sedation protocol . At 36 hours in the ICU , patients who had agitation and an inability to wean were r and omly divided into 2 groups : group M , 34 patients who continued to follow the routine sedative protocol ; and group D , 38 patients who were given dexmedetomidine . Arterial blood gas measurements , hemodynamic parameters , and time to extubation were recorded . Statistical analysis was performed with GraphPad InStat ( version 2.02 for DOS ) . RESULTS All patients tested positive in the CAM-ICU assessment , and all had a delirium diagnosis . The 38 patients in group D tolerated a spontaneous breathing trial with CPAP and were extubated after a mean ( ±SD ) of 49.619 ± 6.96 hours . The 2 groups had significantly different extubation times ( 58.389 ± 3.958 hours versus 49.619 ± 6.96 hours ) . The 2 groups had significantly different RASS scores at 48 and 60 hours and significantly different heart rates and PO2 values at 12 and 24 hours . The 2 groups showed no significant differences with regard to hemodynamic parameters . CONCLUSIONS Dexmedetomidine may help to eliminate the emergence of agitation and can be a good treatment choice for the delirium state after cardiac surgery [3961039] Background : Sedation after open heart surgery is important in preventing stress on the heart . The unique sedative features of propofol prompted us to evaluate its potential clinical role in the sedation of post-CABG patients . Objectives : To compare propofol-based sedation to midazolam-based sedation after coronary artery bypass graft ( CABG ) surgery in the intensive care unit ( ICU ) . Patients and Methods : Fifty patients who were admitted to the ICU after CABG surgery was r and omized into two groups to receive sedation with either midazolam or propofol infusions ; and additional analgesia was administered if required . Inclusion criteria were as follows : patients 40 - 60 years old , hemodynamic stability , ejection fraction ( EF ) more than 40 % ; exclusion criteria included patients who required intra-aortic balloon pump or inotropic drugs post-bypass . The same protocol of anesthetic medications was used in both groups . Depth of sedation was monitored using the Ramsay sedation score ( RSS ) . Invasive mean arterial pressure ( MAP ) and heart rate ( HR ) , arterial blood gas ( ABG ) and ventilatory parameters were monitored continuously after the start of study drug and until the patients were extubated . Results : The depth of sedation was almost the same in the two groups ( RSS=4.5 in midazolam group vs 4.7 in propofol group ; P = 0.259 ) but the total dose of fentanyl in the midazolam group was significantly more than the propofol group ( 12.5 mg/hr vs 4 mg/hr ) ( P = 0.0039 ) . No significant differences were found in MAP ( P = 0.51 ) and HR ( P = 0.41 ) between the groups . The mean extubation time in patients se date d with propofol was shorter than those se date d with midazolam ( 102 ± 27 min vs 245 ± 42 min , respectively ; P < 0.05 ) but the ICU discharge time was not shorter ( 47.5 hr vs 36.3 hr , respectively ; P = 0.24 ) . Conclusions : Propofol provided a safe and acceptable sedation for post-CABG surgical patients , significantly reduced the requirement for analgesics , and allowed for more rapid tracheal extubation than midazolam but did not result in earlier ICU discharge [19327948] PURPOSE This study compares the effectiveness of midazolam and dexmedetomidine for the sedation of eclampsia patients admitted to our intensive care unit ( ICU ) . PATIENTS AND METHODS Forty women with eclampsia requiring termination of pregnancy by caesarean delivery were r and omized in to 2 groups of 20 to receive either midazolam or dexmedetomidine . The midazolam group received a loading dose of 0.05 mg/kg followed by an infusion of 0.1 mg kg(-1 ) h(-1 ) . The dexmedetomidine group loading dose was 1 microg/kg per 20 minutes , followed by continuous infusion at 0.7 microg kg(-1 ) h(-1 ) . Heart rate , blood pressure , Ramsey sedation score , antihypertensive need , convulsion fits , and duration in ICU were monitored and recorded all through the ICU stay . RESULTS Dexmedetomidine markedly reduced heart rates for the first 24 hours ( P < .05 ) compared with midazolam , but there were no differences at 48 and 72 hours . Mean arterial blood pressures were similar in the 2 groups ( P > .05 ) , although in the dexmedetomidine group , it was lower at 5 , 6 , 12 , and 24 hours compared with the first 4 hours ( P < .05 ) . Moreover , fewer patients given dexmedetomidine required nitroglycerine and nitroprusside ( P < .05 ) . The duration of ICU stay was less in the dexmedetomidine group , 45.5 hours ( range , 15 - 118 hours ) , than in the midazolam group , 83 hours ( minimum-maximum , 15 - 312 hours ) . CONCLUSION Dexmedetomidine sedation in eclampsia patients is effective in reducing the dem and for antihypertensive medicine and duration of ICU stay [8477016] The use and the hemodynamic effects of propofol and midazolam were studied during titrated continuous infusions to deep sedation ( sedation level 5 : asleep , sluggish response to light glabellar tap or loud auditory stimulus ) following coronary artery surgery . The drugs were compared in 30 ventilated patients in an open r and omized study . The duration of infusion was approximately 570 minutes in both groups . After a loading dose of propofol ( 1 mg/kg ) or midazolam ( 0.07 mg/kg ) , the infusion rates were 2.71 + /- 1.13 mg/kg/h and 0.092 + /- 0.028 mg/kg/h , respectively . An analgesic infusion of sufentanil was also given in both groups . In the midazolam group , to maintain the predetermined level of sedation , more frequent additional bolus doses ( 4.7 + /- 1.8 ; P < 0.001 ) and infusion rate adjustments ( 5.3 + /- 1.6 ; P < 0.001 ) were required than for similar sedation in the propofol group ( 2.3 + /- 1.0 bolus doses and 3.3 + /- 1.2 adjustments ) . The time from stopping sedation to patient responsiveness was 11 + /- 8 minutes in the propofol group and 72 + /- 70 minutes in the midazolam group ( P < 0.001 ) , and the time from stopping sedation to extubation was 250 + /- 135 minutes and 391 + /- 128 minutes ( P < 0.014 ) , respectively . Following the loading dose of propofol , there was a fall in blood pressure ( BP ) ( mean from 80 + /- 11 mmHg to 67.5 + /- 10 mmHg ; P < 0.05 ) . After approximately 15 minutes , BP started to rise but remained below pretreatment level throughout sedation . ( ABSTRACT TRUNCATED AT 250 WORDS [19833271] STUDY OBJECTIVE To compare the effects of an intravenous infusion of propofol and the alpha-2 adrenoceptor , dexmedetomidine , on inflammatory responses and intraabdominal pressure ( IAP ) in severe sepsis after abdominal surgery , specifically , serum cytokine levels ( interleukin [IL]-1 , IL-6 , and tumor necrosis factor [TNF]-alpha ) and IAP . DESIGN Prospect i ve , single-center study . SETTING University hospital . PATIENTS 40 adult ICU patients who had undergone ileus surgery and who were expected to require postoperative sedation and ventilation . INTERVENTIONS Patients received either a loading dose infusion of propofol ( Group P ; n = 20 ) one mg/kg over 15 minutes followed by a maintenance dose of one to three mg/kg/hr ( n = 20 , Group P ) or a loading dose of dexmedetomidine of one microg/kg over 10 minutes followed by a maintenance dose of 0.2 - 2.5 microg/kg/h ( n = 20 , Group D ) at the 24th hour . MEASUREMENTS Biochemical and hemodynamic parameters , cytokine levels , and IAP were recorded before the start of the study and at the 24th and 48th hours . MAIN RESULTS TNF-alpha levels were significantly lower at the 24th hour ( 14.66 + /- 4.40 pg/mL vs. 21.21 + /- 11.37 pg/mL , respectively ) and at the 48th hour ( 21.25 + /- 15.85 pg/mL vs. 46.55 + /- 35.99 pg/mL , respectively ) in Group D. IL-1 levels were significantly lower at the 24th hour ( 5.03 + /- 0.15 pg/mL vs. 6.23 + /- 2.09 pg/mL , respectively ) and the 48th hour ( 5.01 + /- 0.37 pg/mL vs. 6.42 + /- 2.76 pg/mL , respectively ) in Group D. IL-6 levels were significantly lower at the 24th hour ( 253.1 + /- 303.6 pg/mL and 511.3 + /- 374.8 pg/mL , respectively ) and at the 48th hour ( 343.5 + /- 393.4 pg/mL and 503.7 + /- 306.4 pg/mL , respectively ) in Group D. Intraabdominal pressure also was significantly lower at the 24th hour ( 12.35 + /- 5.84 mmHg vs. 18.1 + /- 2.84 mmHg , respectively ) and the 48th hour ( 13.9 + /- 6.15 mmHg vs. 18.7 + /- 3.46 mmHg , respectively ) in Group D. CONCLUSION Dexmedetomidine infusion decreases TNF-a , IL-1 , and IL-6 levels and IAP more than a propofol infusion [8681594] OBJECTIVES To compare the effectiveness , characteristics , duration of action , hemodynamic and biochemical effects , and side effects of propofol and midazolam used for continuous intravenous sedation of ventilated critically ill patients . DESIGN Multicenter , prospect i ve , r and omized , nonblinded study . SETTING Nine Spanish general intensive care units ( ICUs ) . PATIENTS Ninety-eight patients admitted to the ICU who were mechanically ventilated and required sedation for a minimum of 48 hrs . INTERVENTIONS Propofol or midazolam was used for induction and maintenance of continuous intravenous sedation for a maximum of 5 days . The effectiveness of those two regimens was assessed according to their effects on ventilatory management and the presence of agitation . MEASUREMENTS AND MAIN RESULTS In 93 % of the patients studied , there was a medical cause necessitating mechanical ventilation . The mean ( + /-SD ) duration of sedation was 81 + /- 25 hrs and 88 + /- 27 hrs for the propofol and midazolam groups , respectively . The induction dose was 2.24 + /- 0.43 mg/kg over 318 + /- 363 secs for propofol , and 0.22 + /-0.07 mg/kg over 33 + /-29 secs for midazolam . The maintenance dose was 2.8 + /-1.1 mg/kg/hr for propofol and 0.14 + /- 0.10 mg/kg/hr for midazolam . There was no difference regarding the opiate and muscle relaxant requirements between the two groups . Sedation with propofol was more effective in achieving patient-ventilator synchrony than that with midazolam after the first hour of treatment ( p < .01 ) . Patients se date d with propofol awoke more rapidly and with less variability that those patients se date d with midazolam ( 23 + /- 16 mins vs. 137 + /- 185 mins , respectively , p < .05 ) , particularly in those patients requiring deep sedation ( 27 + /- 16 mins vs. 237 + /- 222 mins , respectively , p < .01 ) . No hemodynamic or biochemical changes were detected in any of the treatment groups . During induction , five patients in the propofol group and two patients in the midazolam group had hypotension . CONCLUSIONS In this population of critically ill patients , propofol is an effective and safe alternative for sedation , with some advantages , such as short duration of action and high effectiveness over the conventional regimen with benzodiazepines and opiates [2570958] 101 critically ill patients admitted to five intensive-care units were allocated r and omly to receive a continuous intravenous infusion of either propofol or midazolam for sedation for up to 24 h. In addition , morphine was given to provide analgesia . The mean duration of infusion was 20.2 h ( range 3.0 - 24.5 ) in the propofol group and 21.3 h ( 4.0 - 47.0 ) in the midazolam group and infusion rates were 1.77 mg/kg/h ( range 0.40 - 5.00 ) and 0.10 mg/kg/h ( 0.01 - 0.26 ) , respectively . The infusion rates were adjusted as necessary , and the desired level of sedation was achieved easily in most patients in both groups . There were slight falls in arterial pressure , but there were no significant differences between the groups . Heart rate was lower in patients who received propofol . Some small changes occurred in biochemical and haematological variables in both groups , but they were not clinical ly significant . There was no indication that either drug substantially impaired adrenal steroidogenesis . When the infusion was discontinued , there was less variability in recovery of consciousness in patients who had received propofol . In a subgroup of patients , weaning from mechanical ventilation was achieved significantly faster after discontinuation of propofol than of midazolam . Propofol proved to be a satisfactory agent for sedation of these critically ill patients and compared favourably with midazolam [19567759] BACKGROUND Delirium is a neurobehavioral syndrome caused by the transient disruption of normal neuronal activity secondary to systemic disturbances . OBJECTIVE The authors investigated the effects of postoperative sedation on the development of delirium in patients undergoing cardiac-valve procedures . METHODS Patients underwent elective cardiac surgery with a st and ardized intraoperative anesthesia protocol , followed by r and om assignment to one of three postoperative sedation protocol s : dexmedetomidine , propofol , or midazolam . RESULTS The incidence of delirium for patients receiving dexmedetomidine was 3 % , for those receiving propofol was 50 % , and for patients receiving midazolam , 50 % . Patients who developed postoperative delirium experienced significantly longer intensive-care stays and longer total hospitalization . CONCLUSION The findings of this open-label , r and omized clinical investigation suggest that postoperative sedation with dexmedetomidine was associated with significantly lower rates of postoperative delirium and lower care costs [23448434] BACKGROUND The study aim was to compare the efficacy of dexmedetomidine vs midazolam for sedation during the early postoperative period in adolescents who underwent scoliosis surgery . METHODS We performed a prospect i ve , r and omized trial in an intensive care unit ( ICU ) in a tertiary care center . In this study , 42 patients ( American Society of Anesthesiology physical status I and II ) who underwent scoliosis surgery were divided into two groups according to sedation protocol s : group dexmedetomidine ( DEX ) ( n = 22 ) and group midazolam ( MDZ ) ( n = 20 ) . Adolescents ( 12 - 18 years ) requiring mechanical ventilation underwent a continuous infusion of either dexmedetomidine ( group DEX ; starting dose , 0.4 μg·kg(-1 ) · h(-1 ) ) or midazolam ( group MDZ ; starting dose , 0.1 mg·kg(-1 ) · h(-1 ) ) with intermittent fentanyl , as needed . The efficacy of sedation was assessed using the Richmond Agitation Sedation Scale ( RASS ) . Quality of pain relief was measured using the Numeric Visual Analog Scale ( NVAS ) . Delirium was determined in patients in the RASS range of -2 to + 1 using the Confusion Assessment Method for the ICU ( CAM-ICU ) . Fentanyl consumption , incidence of delirium , NVAS scores , and hemodynamics were recorded postoperatively at 2 , 4 , 6 , and 24 h in the ICU . RESULTS The NVAS pain scores and fentanyl consumption at all the evaluation time points were significantly higher in group MDZ than those in group DEX ( P < 0.05 ) . Further , total fentanyl consumption in group MDZ was significantly higher than that in group DEX ( P < 0.05 ) . Delirium was significantly higher in the group MDZ than that in group DEX ( 31.3 % vs 12.5 % ) when analyzed as the endpoint of CAM-ICU ( P < 0.05 ) . The heart rate was significantly lower in group DEX compared with that in group MDZ at all the evaluation time points ( P < 0.05 ) . CONCLUSION Dexmedetomidine was associated with the decreased postoperative fentanyl consumption , NVAS scores , and a decreased incidence of delirium . These findings may be beneficial for managing sedation protocol s in adolescents who have undergone scoliosis surgery [18795253] Purpose To compare dexmedetomidine ( DEX ) with st and ard care ( SC , either propofol or midazolam ) for long-term sedation in terms of maintaining target sedation and length of intensive care unit ( ICU ) stay . Methods A pilot , phase III , double-blind multicenter study in r and omized medical and surgical patients ( n = 85 ) within the first 72 h of ICU stay with an expected ICU stay of ≥48 h and sedation need for ≥24 h after r and omization . Patients were assigned to either DEX ( ≤1.4 μg kg−1 h−1 ; n = 41 ) or SC ( n = 44 ) , with daily sedation stops . Results Non-inferiority of DEX versus SC was not confirmed . Target Richmond agitation – sedation score ( RASS ) was reached a median of 64 % ( DEX ) and 63 % ( SC ) of the sedation time ( ns ) . The length of ICU stay was similar in DEX and SC . Patients with RASS target 0–3 ( DEX 78 % , SC 80 % ) were at target sedation 74 % ( DEX ) and 64 % ( SC ) of the time ( ns ) , whereas those with RASS target −4 or less reached the target 42 % ( DEX ) and 62 % ( SC ) of the time ( P = .006 ) . Post hoc analyses suggested shorter duration of mechanical ventilation for DEX ( P = 0.025 ) . Conclusions This pilot study suggests that in long-term sedation , DEX is comparable to SC in maintaining sedation targets of RASS 0 to −3 but not suitable for deep sedation ( RASS −4 or less ) . DEX had no effect on length of ICU stay . Its effects on other relevant clinical outcomes , such as duration of mechanical ventilation , should be tested further [22975538] OBJECTIVE To compare the efficacy and safety of sedation with dexmedetomidine vs. midazolam for patients with acute cardiogenic pulmonary edema and hypoxemia during the treatment of non-invasive ventilation ( NIV ) . METHODS The intensive care unit ( ICU ) patients treated in our hospital between March 2008 and August 2011 who had acute pulmonary edema and hyoxemia in NIV failure due to patient refusal to continue the NIV sessions ( due to discomfort ) were enrolled in this study . The patients were divided into two groups by the r and om numerical table method . They were treated with either midazolam ( 29 cases ) or dexmedetomidine ( 33 cases ) . The patients were se date d ( Ramsay scale 2 - 3 ) by a continuous perfusion of midazolam or dexmedetomidine during the NIV session . Cardiorespiratory and ventilatory parameters , the results of the blood gas analysis , and adverse events were prospect ively recorded . The main outcome measure was the percentage of endotracheal intubation during NIV . Secondary endpoints included the duration of non-invasive mechanical ventilation , length of ICU stay , and adverse events . RESULTS In both groups of patients , the expected sedative scores were obtained . The cardiorespiratory symptoms and signs ( oxygenation index , pH value , and respiratory rate ) were significantly improved in both groups . In the dexmedetomidine-treated group , the patients had a further decreased percentage of failure of NIV requiring endotracheal intubation ( ETI ) and a more prolonged mean time to ETI ( p=0.042 , p=0.024 ) . Furthermore , when compared with the group treated with midazolam , the overall duration of mechanical ventilation and the duration of ICU hospitalization in the group treated with dexmedetomidine were markedly decreased , and weaning from mechanical ventilation was easier ( p=0.010 , p=0.042 ) . Despite the fact that more dexmedetomidine-treated patients developed bradycardia ( 18.2 % vs. 0 , p=0.016 ) , no patients required an intervention or interruption of study drug infusion . Conversely , the incidence of respiratory infections and vomiting was lower in the dexmedetomidine-treated patients ( p=0.026 , p=0.010 ) . CONCLUSION Dexmedetomidine led to a more desired level of awaking sedation , shortened the duration of mechanical ventilation and the length of the ICU stay , and further reduced the prevalence of nosocomial infection for NIV sedation in patients with acute cardiogenic pulmonary edema . It appears to provide several advantages and safe control compared with the γ-amino butyric acid ( GABA ) agonist midazolam [19786862] Background : Commonly used sedatives/analgesics can increase the risk of postoperative complications , including delirium . This double-blinded study assessed the neurobehavioral , hemodynamic , and sedative characteristics of dexmedetomidine compared with morphine-based regimen after cardiac surgery at equivalent levels of sedation and analgesia . Methods : A total of 306 patients at least 60 yr old were r and omized to receive dexmedetomidine ( 0.1–0.7 & mgr;g · kg−1 · h−1 ) or morphine ( 10 - 70 & mgr;g · kg−1 · h−1 ) with open-label propofol titrated to a target Motor Activity Assessment Scale of 2–4 . Primary outcome was the prevalence of delirium measured daily via Confusion Assessment Method for intensive care . Secondary outcomes included ventilation time , additional sedation/analgesia , and hemodynamic and adverse effects . Results : Of all sedation assessment s , 75.2 % of dexmedetomidine and 79.6 % ( P = 0.516 ) of morphine treatment were in the target range . Delirium incidence was comparable between dexmedetomidine 13 ( 8.6 % ) and morphine 22 ( 15.0 % ) ( relative risk 0.571 , 95 % confidence interval [ CI ] 0.256–1.099 , P = 0.088 ) , however , dexmedetomidine-managed patients spent 3 fewer days ( 2 [ 1–7 ] versus 5 [ 2–12 ] ) in delirium ( 95 % CI 1.09–6.67 , P = 0.0317 ) . The incidence of delirium was significantly less in a small subgroup requiring intraaortic balloon pump and treated with dexmedetomidine ( 3 of 20 [ 15 % ] versus 9 of 25 [ 36 % ] ) ( relative risk 0.416 , 95 % CI 0.152–0.637 , P = 0.001 ) . Dexmedetomidine-treated patients were more likely to be extubated earlier ( relative risk 1.27 , 95 % CI 1.01–1.60 , P = 0.040 , log-rank P = 0.036 ) , experienced less systolic hypotension ( 23 % versus 38.1 % , P = 0.006 ) , required less norepinephrine ( P < 0.001 ) , but had more bradycardia ( 16.45 % versus 6.12 % , P = 0.006 ) than morphine treatment . Conclusion : Dexmedetomidine reduced the duration but not the incidence of delirium after cardiac surgery with effective analgesia/sedation , less hypotension , less vasopressor requirement , and more bradycardia versus morphine regimen [26575144] Background : Postoperative delirium ( POD ) is a serious complication after cardiac surgery . Use of dexmedetomidine to prevent delirium is controversial . The authors hypothesized that dexmedetomidine sedation after cardiac surgery would reduce the incidence of POD . Methods : After institutional ethics review board approval , and informed consent , a single-blinded , prospect i ve , r and omized controlled trial was conducted in patients 60 yr or older undergoing cardiac surgery . Patients with a history of serious mental illness , delirium , and severe dementia were excluded . Upon admission to intensive care unit ( ICU ) , patients received either dexmedetomidine ( 0.4 & mgr;g/kg bolus followed by 0.2 to 0.7 & mgr;g kg−1 h−1 infusion ) or propofol ( 25 to 50 & mgr;g kg−1 min−1 infusion ) according to a computer-generated r and omization code in blocks of four . Assessment of delirium was performed with confusion assessment method for ICU or confusion assessment method after discharge from ICU at 12-h intervals during the 5 postoperative days . Primary outcome was the incidence of POD . Results : POD was present in 16 of 91 ( 17.5 % ) and 29 of 92 ( 31.5 % ) patients in dexmedetomidine and propofol groups , respectively ( odds ratio , 0.46 ; 95 % CI , 0.23 to 0.92 ; P = 0.028 ) . Median onset of POD was on postoperative day 2 ( 1 to 4 days ) versus 1 ( 1 to 4 days ) , P = 0.027 , and duration of POD 2 days ( 1 to 4 days ) versus 3 days ( 1 to 5 days ) , P = 0.04 , in dexmedetomidine and propofol groups , respectively . Conclusions : When compared with propofol , dexmedetomidine sedation reduced incidence , delayed onset , and shortened duration of POD in elderly patients after cardiac surgery . The absolute risk reduction for POD was 14 % , with a number needed to treat of 7.1 [22965457] Context Volatile anaesthetics may have direct cardioprotective properties due to effects similar to ischaemic preconditioning and postconditioning . Clinical results in cardiac surgery patients are controversial and may be related to the timing of administration of anaesthetics intraoperatively . Objective We hypothesised that the cardioprotective effect of sevoflurane in coronary bypass graft surgical patients would be greater if administration during anaesthesia continued in the ICU for at least 4 h postoperatively until weaning from mechanical ventilation . Design Double-blind , double-dummy , prospect i ve , r and omised and controlled clinical trial . Setting In a single centre between June 2006 and June 2007 . Patients Seventy-five adult patients were assigned r and omly to receive anaesthesia and postoperative sedation either with propofol ( control , n = 37 ) or sevoflurane ( n = 36 ) . Interventions Myocardial biomarkers were measured before surgery , at the time of admission to the intensive care unit and at 6 , 24 , 48 and 72 h. The need for inotropic support , and lengths of stay in the intensive care unit and hospital were also recorded . Main outcome measures Elevation of myocardial biomarkers was the primary endpoint . The secondary endpoints were haemodynamic events and lengths of stay in the intensive care unit and hospital . Results Necrosis biomarkers increased significantly in the postoperative period in both groups with no significant differences at any time . Inotropic support was needed in 72.7 and 54.3 % of patients in the propofol and sevoflurane groups , respectively ( P = 0.086 ) . There were no significant differences in haemodynamic variables , incidence of arrhythmias , myocardial ischaemia or and lengths of stay in the ICU and hospital between the two groups . Conclusion In patients undergoing coronary bypass graft surgery , continuous administration of sevoflurane as a sedative in the ICU for at least 4 h postoperatively did not yield significant improvements in the extent and time course of myocardial damage biomarkers compared to propofol [16540958] Objective : To compare duration of mechanical ventilation for patients r and omized to receive lorazepam by intermittent bolus administration vs. continuous infusions of propofol using protocol s that include scheduled daily interruption of sedation . Design : A r and omized open-label trial enrolling patients from October 2001 to March 2004 . Setting : Medical intensive care units of two tertiary care medical centers . Patients : Adult patients expected to require mechanical ventilation for > 48 hrs and who required ≥10 mg of lorazepam or a continuous infusion of a sedative to achieve adequate sedation . Interventions : Patients were r and omized to receive lorazepam by intermittent bolus administration or propofol by continuous infusion to maintain a Ramsay score of 2–3 . Sedation was interrupted on a daily basis for both groups . Measurements and Main Results : The primary outcome was median ventilator days . Secondary outcomes included 28-day ventilator-free survival , intensive care unit and hospital length of stay , and hospital mortality . Median ventilator days were significantly lower in the daily interruption propofol group compared with the intermittent bolus lorazepam group ( 5.8 vs. 8.4 , p = .04 ) . The difference was largest for hospital survivors ( 4.4 vs. 9.0 , p = .006 ) . There was a trend toward greater ventilator-free survival for patients in the daily interruption propofol group ( median 18.5 days for propofol vs. 10.2 for lorazepam , p = .06 ) . Hospital mortality was not different . Conclusions : For medical patients requiring > 48 hrs of mechanical ventilation , sedation with propofol results in significantly fewer ventilator days compared with intermittent lorazepam when sedatives are interrupted daily [8062564] Objective To compare the safety and effectiveness of propofol ( 2,6-diisopropylphenol ) to midazolam for sedation of mechanically ventilated patients after coronary artery bypass grafting . Design Open , r and omized , prospect i ve trial . Setting Cardiothoracic intensive care unit ( ICU ) , Clevel and Clinic Foundation . Patients Eighty-four patients with normal or moderately impaired left ventricular function who underwent elective coronary artery bypass graft surgery under high-dose opioid anesthesia . Interventions Patients were r and omly selected to receive either propofol ( mean loading dose 0.24 mg/kg ; mean maintenance dose 0.76 mg/kg/hr ) or midazolam ( mean loading dose 0.012 mg/kg ; mean maintenance dose 0.018 mg/kg/hr ) . Infusion rates were titrated to keep patients comfortable , drowsy , and responsive to verbal stimulation . Study duration , 8 to 12 hrs ; infusions were started in the ICU when patients were awake and hemodynamically stable . Measurements and Main Results During therapy , both groups had lower mean arterial pressures and heart rates compared with baseline measurements ; however , the propofol group had significantly lower heart rates than the midazolam group during the first 2 hrs of infusion . The propofol group also had significantly lower blood pressure measurements 5 and 10 mins after the initial dose , although there was no difference during infusion . Baseline cardiac output was measured before starting the infusion , and measurements were repeated during continuous infusion at 4 , 8 , and 12 hrs . Cardiac output values were similar . Propofol maintenance infusions ranged from 3 to 30 μg/kg/min and midazolam infusions ranged from 0.1 to 0.7 μg/kg/min . At these infusion rates . both groups had adequate sedation , based on nurse and patient evaluations ; however , the propofol group used significantly lower total doses of sodium nitroprusside and supplemental opioids . Conclusions Both propofol and midazolam provided safe and effective sedation of coronary artery bypass graft patients recovering from high-dose opioid anesthesia . The reduced need for both antihypertensive medication and opioids seen in the propofol group may be advantageous . However , the hypotension seen after the initial bolus dose of propofol may be a concern . No difference between the two drugs could be demonstrated in time to extubation or ICU discharge , although it is probable that time to extubation was governed more by residual operative opioids than the study agents . ( Crit Care Med 1994 ; 22:1415–1423 [25055491] PURPOSE OF THE STUDY To compare the efficacy of Dexmedetomidine and Propofol for short-term controlled sedation and analgesia in the early postoperative period after cardiac surgery . METHODS We performed open r and omized prospect i ve comparative study in 55 cardiovascular surgery patients . In the early postoperative period 28 patients received infusion of Dexmedetomidine ( 0.2 - 0.7 microg/kg per hour ) while 27 patients --Propofol ( 0.3 - 2(system text of symbol ) ) . Analgesia was carried out with Ketoprofen 100 mg/12h and additional 20 mg of Trimeperidine in case of pain intensity > or = 3 points ( 5-level verbal pain score ) . Sedation and agitation level ( RASS scale ) , speed of awakening ( Aldrete score ) , duration of mechanical ventilation and stay in the ICU , need for additional opioid injections , type and frequency of side effects were evaluated . RESULTS We did n't find any significant differences in the duration of mechanical ventilation or rate of awakening after the end of infusion between the groups . Dexmedetomidine in the majority of cases result ed in mild or moderate sedation , Propofol -- in deeper level of sedation . Retro grade amnesia was reached significantly more often ( p < 0.05 ) in Dexmetomedine group . The daily dose of Trimeperidine in Propofol group was significantly higher ( 8 mg and 18 mg on average , p = 0.02 ) . Differences in side effects between the groups were noted -- bradycardia ( Dexmetomedine--10 ( 39 % ) , Propofol--3 ( 11 % ) , p = 0.004 ) arterial hypotension ( Dexmetomedine--9 ( 32 % ) , Propofol--15 ( 59 % ) , p = 0.002 ) and general malaise ( Dexmetomedine--2 ( 7 % ) , Propofol--6 ( 24 % ) , p = 0.001 ) . The length of stay in the ICU in Dexmetomedine group was significantly lower ( 1,1 days vs 2,6 days respectively , p = 0.006 ) . CONCLUSIONS To compare with Propofol Dexmetomedine induces less sedation level and more often provides retro grade amnesia with the same duration of mechanical ventilation and awakening rate . Dexmetomedine provides its own analgesic effect and shortens the length of patient 's stay in ICU . Bradycardia was noted more frequently in Dexmedetomidine while arterial hypotension , general malaise and delirium -- in Propofol group [11878517] The alpha2 agonist dexmedetomidine is a new sedative and analgesic agent which is licensed in the USA for post-operative intensive care sedation . We compared dexmedetomidine with propofol in patients requiring sedation in intensive care . Twenty adult patients expected to require a minimum of 8 h artificial ventilation after surgery were r and omized to receive sedation with either dexmedetomidine or propofol infusions . Additional analgesia , if required , was provided by an alfentanil infusion . Depth of sedation was monitored using both the Ramsay sedation score ( RSS ) and the bispectral index ( BIS ) . Cardiovascular , respiratory , biochemical and haematological data were obtained . Patients ' perceptions of their intensive care stay were assessed using the Hewitt question naire . Sedation was equivalent in the two groups [ median ( interquartile range ) : RSS , propofol group 5 ( 4 - 5 ) , dexmedetomidine group 5 ( 4 - 6 ) ( P=0.68 ) ; BIS , propofol group 53 ( 41 - 64 ) , dexmedetomidine group 46 ( 36 - 58 ) ; P=0.32 ] , but the propofol group received three times more alfentanil compared with patients se date d with dexmedetomidine [ 2.5 ( 2.2 - 2.9 ) mg h(-1 ) versus 0.8 ( 0.65 - 1.2 ) mg h(-1 ) ( P=0.004 ) ] . No differences were found in arterial pressures between the groups , but heart rate was significantly lower in the dexmedetomidine group [ mean ( SD ) 75 ( 6 ) vs 90 ( 4 ) beats min(-1 ) ] . Extubation times were similar and rapid with the use of both sedative agents [ median ( range ) 28 ( 20 - 50 ) and 29 ( 15 - 50 ) min ( P=0.63 ) respectively for the propofol and dexmedetomidine groups ] . No adverse events related to the sedative infusions occurred in either group . Despite ventilation and intubation , patients se date d with dexmedetomidine could be easily roused to cooperate with procedures ( e.g. physiotherapy , radiology ) without showing irritation . From the clinician 's and patient 's perspectives , dexmedetomidine is a safe and acceptable sedative agent for those requiring intensive care . The rate pressure product is reduced in patients receiving dexmedetomidine , which may protect against myocardial ischaemia . Dexmedetomidine reduces the requirement for opioid analgesia [22436955] CONTEXT Long-term sedation with midazolam or propofol in intensive care units ( ICUs ) has serious adverse effects . Dexmedetomidine , an α(2)-agonist available for ICU sedation , may reduce the duration of mechanical ventilation and enhance patient comfort . OBJECTIVE To determine the efficacy of dexmedetomidine vs midazolam or propofol ( preferred usual care ) in maintaining sedation ; reducing duration of mechanical ventilation ; and improving patients ' interaction with nursing care . DESIGN , SETTING , AND PATIENTS Two phase 3 multicenter , r and omized , double-blind trials carried out from 2007 to 2010 . The MIDEX trial compared midazolam with dexmedetomidine in ICUs of 44 centers in 9 European countries ; the PRODEX trial compared propofol with dexmedetomidine in 31 centers in 6 European countries and 2 centers in Russia . Included were adult ICU patients receiving mechanical ventilation who needed light to moderate sedation for more than 24 hours ( midazolam , n = 251 , vs dexmedetomidine , n = 249 ; propofol , n = 247 , vs dexmedetomidine , n = 251 ) . INTERVENTIONS Sedation with dexmedetomidine , midazolam , or propofol ; daily sedation stops ; and spontaneous breathing trials . MAIN OUTCOME MEASURES For each trial , we tested whether dexmedetomidine was noninferior to control with respect to proportion of time at target sedation level ( measured by Richmond Agitation-Sedation Scale ) and superior to control with respect to duration of mechanical ventilation . Secondary end points were patients ' ability to communicate pain ( measured using a visual analogue scale [ VAS ] ) and length of ICU stay . Time at target sedation was analyzed in per- protocol population ( midazolam , n = 233 , vs dexmedetomidine , n = 227 ; propofol , n = 214 , vs dexmedetomidine , n = 223 ) . RESULTS Dexmedetomidine/midazolam ratio in time at target sedation was 1.07 ( 95 % CI , 0.97 - 1.18 ) and dexmedetomidine/propofol , 1.00 ( 95 % CI , 0.92 - 1.08 ) . Median duration of mechanical ventilation appeared shorter with dexmedetomidine ( 123 hours [ IQR , 67 - 337 ] ) vs midazolam ( 164 hours [ IQR , 92 - 380 ] ; P = .03 ) but not with dexmedetomidine ( 97 hours [ IQR , 45 - 257 ] ) vs propofol ( 118 hours [ IQR , 48 - 327 ] ; P = .24 ) . Patients ' interaction ( measured using VAS ) was improved with dexmedetomidine ( estimated score difference vs midazolam , 19.7 [ 95 % CI , 15.2 - 24.2 ] ; P < .001 ; and vs propofol , 11.2 [ 95 % CI , 6.4 - 15.9 ] ; P < .001 ) . Length of ICU and hospital stay and mortality were similar . Dexmedetomidine vs midazolam patients had more hypotension ( 51/247 [ 20.6 % ] vs 29/250 [ 11.6 % ] ; P = .007 ) and bradycardia ( 35/247 [ 14.2 % ] vs 13/250 [ 5.2 % ] ; P < .001 ) . CONCLUSIONS Among ICU patients receiving prolonged mechanical ventilation , dexmedetomidine was not inferior to midazolam and propofol in maintaining light to moderate sedation . Dexmedetomidine reduced duration of mechanical ventilation compared with midazolam and improved patients ' ability to communicate pain compared with midazolam and propofol . More adverse effects were associated with dexmedetomidine . TRIAL REGISTRATION clinical trials.gov Identifiers : NCT00481312 , NCT00479661 [9470082] Objective : To compare the efficacy , safety , and cost of midazolam and propofol in prolonged sedation of critically ill patients . Design : R and omized , prospect i ve study . Setting : General intensive care unit ( ICU ) in a 1100-bed teaching hospital . Patients : 67 critically ill , mechanically ventilated patients . Interventions : Patients were invasively monitored and mechanically ventilated . A loading dose [ midazolam 0.11 ± 0.02 ( SEM ) mg · kg−1 , propofol 1.3 ± 0.2 mg · kg−1 ] was administered , followed by continuous infusion , titrated to achieve a predetermined sedation score . Sedation was continued as long as clinical ly indicated . Measurements and results : Mean duration of sedation was 141 and 99 h ( NS ) for midazolam and propofol , respectively , at mean hourly doses of 0.070 ± 0.003 mg · kg−1 midazolam and 1.80 ± 0.08 mg · kg−1 propofol . Overall , 68 % of propofol patients versus 31 % of midazolam ( p<0.001 ) patients had a > 20 % decrease in systolic blood pressure after the loading dose , and 26 versus 45 % ( p<0.01 ) showed a 25 % decrease in spontaneous minute volume . Propofol required more daily dose adjustments ( 2.1 ± 0.1 vs 1.4 ± 0.1 , p<0.001 ) . Nurserated quality of sedation with midazolam was higher ( 8.2 ± 0.1 vs 7.3 ± 0.1 on a 10-cm visual analog scale , p<0.001 ) . Resumption of spontaneous respiration was equally rapid . Recovery was faster after propofol ( p<0.02 ) , albeit with a higher degree of agitation . Amnesia was evident in all midazolam patients but in only a third of propofol patients . The cost of propofol was 4–5 times higher . Conclusions : Both drugs afforded reliable , safe , and controllable long-term sedation in ICU patients and rapid weaning from mechanical ventilation . Midazolam depressed respiration , allowed better maintenance of sedation , and yielded complete amnesia at a lower cost , while propofol caused more cardiovascular depression during induction [19854793] Delirium and transient neurologic dysfunctions ( TND ) often complicate the postoperative course after surgery for acute type-A aortic dissection ( AAD ) . We evaluated the role of clonidine on neurological outcome and respiratory function in 30 consecutive patients undergoing surgery for AAD . Patients were prospect ively r and omized to receive either clonidine ( 0.5 microg/kg bolus , followed by continuous infusion at 1 - 2 microg/kg/h ) or placebo ( NaCl 0.9 % ) in on starting and throughout the weaning period from the mechanical ventilation . Incidence of delirium and TND , Delirium Detection Score ( DDS ) , weaning parameters [ respiratory rate to tidal volume ratio - f/VT ; pressure-frequency product ( PFP ) ; partial pressure of arterial oxygen to fractional inspired oxygen concentration ( PaO(2)/FiO(2 ) ) ; partial pressure of carbon dioxide ( PaCO(2 ) ) ] , weaning duration and intensive care unit ( ICU ) length of stay were recorded . The two groups were similar for preoperative and operative variables and also for the incidence of postoperative complications . DDS was lower in the clonidine group ( P<0.001 ) . Patients weaned with clonidine showed lower f/VT and PFP , higher PaO(2)/FiO(2 ) and PaCO(2 ) , lower DDS , weaning period and the related ICU length of stay ( P<0.001 ) . This was further confirmed in patients developing delirium/TND . Intravenous clonidine after surgery for AAD reduces the severity of delirium , improves the respiratory function , shortens the weaning duration and the ICU length of stay [22420466] Abstract Objectives . Intravenous sedation in the intensive care unit ( ICU ) may contribute to altered consciousness and prolonged mechanical ventilation . We tested the hypothesis that replacing intravenous propofol with inhaled sevoflurane for sedation after cardiac surgery would lead to shorter wake-up times , quicker patient cooperation , and less delusional memories . Design . Following coronary artery bypass surgery with cardiopulmonary bypass , 100 patients were r and omized to sedation with sevoflurane via the anesthetic conserving device or propofol . Study drugs were administered for a minimum of 2 hours until criteria for extubation were met . Primary endpoints were time from drug stop to extubation and to adequate verbal response . Secondary endpoints were adverse recovery events , memories reported in the ICU Memory Tool test , and ICU/hospital stay . Results . Median time from drug stop to extubation ( interquartile range/total range ) was shorter after sevoflurane compared to propofol sedation ; 10 ( 10/100 ) minutes versus 25 ( 21/240 ) minutes ( p < 0.001 ) . Time from extubation to adequate verbal response was shorter ( p = 0.036 ) . No differences were found in secondary endpoints . Conclusions . Sevoflurane sedation after cardiac surgery leads to shorter wake-up times and quicker cooperation compared to propofol . No differences were seen in ICU-stay , adverse memories or recovery events in our short-term sedation [9590313] OBJECTIVES To evaluate and compare the clinical efficacy , impact on hemodynamics , safety profiles , and cost of combined administration of propofol and midazolam ( synergistic sedation ) vs. midazolam and propofol administered as sole agents , for sedation of mechanically ventilated patients after coronary artery bypass grafting . DESIGN Prospect i ve , controlled , r and omized , double-blind clinical trial . SETTING Intensive care unit of SCIAS-Hospital de Barcelona . PATIENTS Seventy-five mechanically ventilated patients who underwent coronary artery bypass graft surgery under low-dose opioid anesthesia . INTERVENTIONS According to the double-blind method , patients were r and omly assigned to receive propofol ( n = 25 ) , midazolam ( n = 25 ) , or propofol combined with midazolam ( n = 25 ) . Infusion rates were adjusted to stay between 8 and 11 points on Glasgow Coma Score modified by Cook and Palma . MEASUREMENTS AND MAIN RESULTS Mean + /- SD duration of sedation was 14.4 + /- 1.5 hrs , 14.1 + /- 1.1 hrs , and 14.7 + /- 1.9 hrs for the propofol , midazolam , and synergistic groups , respectively . The induction dose was 0.55 + /- 0.05 mg/kg for propofol as sole agent , 0.05 + /- 0.01 mg/kg for midazolam as sole agent , and 0.22 + /- 0.03 mg/kg for propofol administered in combination with 0.02 + /- 0.00 mg/kg of midazolam ( p = .001 ) . The maintenance dose was 1.20 + /- 0.03 mg/kg/hr for propofol as sole agent , 0.08 + /- 0.01 mg/kg/hr for midazolam as sole agent , and 0.50 + /- 0.09 mg/kg/hr for propofol administered in combination with 0.03 + /- 0.01 mg/kg/hr of midazolam ( p < .001 ) . All sedative regimens achieved similar efficacy in percentage of hours of adequate sedation ( 93 % for propofol , 88 % for midazolam , and 90 % for the synergistic group , respectively ) . After induction , both propofol and midazolam groups had significant decreases in systolic blood pressure , diastolic blood pressure , left atrial pressure , and heart rate . Patients in the synergistic group had significant bradycardia throughout the study , without impairment in other hemodynamic parameters . Patients se date d with propofol or synergistic regimen awoke sooner and could be extubated before those patients se date d with midazolam ( 0.9 + /- 0.3 hrs and 1.2 + /- 0.6 hrs vs. 2.3 + /- 0.8 hrs , respectively , p = .01 ) . Synergistic sedation produced cost savings of 28 % with respect to midazolam and 68 % with respect to propofol . CONCLUSIONS In the study conditions , the new synergistic treatment with propofol and midazolam administered together is an effective and safe alternative for sedation , with some advantages over the conventional regimen with propofol or midazolam administered as sole agents , such as absence of hemodynamic impairment , > 68 % reduction in maintenance dose , and lower pharmaceutical cost [8605792] OBJECTIVES To evaluate and compare the clinical efficacy , impact on hemodynamic and oxygen transport variables , safety profiles , and cost efficiency of sedation and anxiolysis with lorazepam vs. continuous infusion of midazolam in critically ill , intensive care unit patients . DESIGN Multicenter , prospect i ve , r and omized , open-label study . SETTING Teaching hospitals . PATIENTS Ninety-five critically ill , mechanically ventilated patients with fiberoptic pulmonary artery catheters in place were r and omly assigned to receive short-term ( 8 hrs ) sedation with either intermittent intravenous injection lorazepam ( group A , n = 50 ) or continuous intravenous infusion midazolam ( group B , n = 45 ) titrated to clinical response . MEASUREMENTS AND MAIN RESULTS The severity of illness , demographic characteristics , levels of anxiety and agitation , hemodynamic parameters , oxygen transport variables , quality of sedation , nursing acceptance , and laboratory chemistries reflecting drug safety were recorded . There were no significant differences with regard to demographic data , hemodynamic and oxygen transport variables , or levels of anxiety/agitation between the two groups at baseline , 5 mins , 30 mins , and 4 and 8 hrs after administration of sedation . There were no significant differences in the quality of sedation or anxiolysis . Midazolam-treated patients used significantly larger amounts of drug for similar levels of sedation and anxiolysis ( 14.4 + /- 1.2 mg/8 hrs vs. 1.6 + /- 0.1 mg/8 hrs , p = .001 ) . Both drugs were safely administered and patient and nurse satisfaction was similar . CONCLUSIONS Sedation and anxiolysis with lorazepam and midazolam in critically ill patients is safe and clinical ly effective . Hemodynamic and oxygen transport variables are similarly affected by both drugs . The dose of midazolam required for sedation is much larger than the dose of lorazepam required for sedation , and midazolam is therefore less cost-efficient [8989173] OBJECTIVE To compare the effectiveness of sedation , the time required for weaning , and the costs of prolonged sedation of critically ill mechanically ventilated patients with midazolam and propofol . DESIGN Open-label , r and omized , prospect i ve , phase IV clinical trial . SETTING Medical and surgical intensive care unit ( ICU ) in a community hospital . PATIENTS All ICU admissions ( medical , surgical and trauma ) requiring mechanical ventilation for > 24 hrs . A total of 108 patients were included in the study . INTERVENTIONS Patients were r and omized to receive midazolam or propofol . The dose range allowed for each drug was 0.1 to 0.5 mg/kg/hr for midazolam and 1 to 6 mg/kg/hr for propofol . The lowest dose that achieved an adequate patient-ventilator synchrony was infused . All patients received 0.5 mg/kg/24 hrs of morphine chloride . MEASUREMENTS AND MAIN RESULTS The level of sedation was quantified by the Ramsay scale every 2 hrs until weaning from mechanical ventilation was started . If sedation could not be achieved by infusing the highest dose of midazolam or propofol , the case was recorded as a therapeutic failure . In the propofol group , serum triglycerides were determined every 72 hrs . Concentrations of > 500 mg/dL were also recorded as a therapeutic failure . When the patient was ready for weaning according to defined criteria , sedation was interrupted abruptly and the time from interruption of sedation to the first T-bridge trial and to extubation was measured . Cost analysis was performed based on the cost of intensive care in our unit ( $ 54/hr ) . In the midazolam group ( n = 54 ) , 15 ( 27.8 % ) patients died ; 11 ( 20.4 % ) patients had therapeutic failure ; and 28 ( 51.8 % ) patients were subjected to a T-bridge trial . In the propofol group ( n = 54 ) , these proportions were 11 ( 20.4 % ) , 18 ( 33.4 % [ including seven due to inadequate sedation , and 11 due to hypertriglyceridemia ] ) , and 25 ( 46.2 % ) , respectively . None of these values was significantly different between the two groups . Duration of sedation was 141.7 + /- 89.4 ( SD ) hrs and 139.7 + /- 84.7 hrs ( p = NS ) , and cost ( US dollars ) attributed to sedation was $ 378 + /- 342 and $ 1,047 + /- 794 ( p = .0001 ) for the midazolam and propofol groups , respectively . In the midazolam group , time from discontinuation of the drug infusion to extubation was 97.9 + /- 54.6 hrs ( 48.9 + /- 47.2 hrs to the first disconnection , and 49.0 + /- 23.7 hrs to extubation ) . In the propofol group , time from discontinuation of the drug infusion to extubation was 34.8 + /- 29.4 hrs ( 4.0 + /- 3.9 hrs to the first disconnection , and 30.8 + /- 29.2 hrs to extubation ) . The difference between the two groups in the weaning time was 63.1 + /- 12.5 ( SEM ) hrs ( p < .0001 ) . Cost per patient in the midazolam group ( including ICU therapy and sedation with midazolam ) was $ 10,828 + /- 5,734 . Cost per patient in the propofol group was $ 9,466 + /- 5,820 , $ 1,362 less than in the midazolam group . CONCLUSIONS In our population of critically ill patients se date d with midazolam or propofol over prolonged periods , midazolam and propofol were equally effective as sedative agents . However , despite remarkable differences in the cost of sedation with these two agents , the economic profile is more favorable for propofol than for midazolam due to a shorter weaning time associated with propofol administration [25604219] OBJECTIVE To evaluate the efficacy and safety of dexmedetomidine for post-operative elder patients on mechanical ventilation ( MV ) . METHODS For this r and omized controlled trial , 108 cases of post-operative patients on MV were enrolled and assigned into either dexmedetomidine group ( n = 54 ) or propofol group ( n = 54 ) for sedation . And propofol was used for rescue . The dose of sedation was regulated by Ramsay score for maintaining a sedative score of 3 - 4 . In both groups , fentanyl was provided intravenously continually for analgesia . The amount of fentanyl was adjusted according to the numerical rating scale ( NRS ) score for maintaining an analgesic score of 0 - 3 . The average Ramsay score , the frequency of propofol , the highest score of NRS , the total dosage of fentanyl and recovery time were compared . Additional outcomes included duration of mechanical ventilation and intensive care unit ( ICU ) length . And the incidence of delirium and cardiovascular adverse events were compared for two groups . RESULTS No significant inter-group difference existed in the effectiveness of sedation . Compare with propofol group , the highest score of NRS decreased ( 1.8 ± 1.12 vs 3.1 ± 1.24 , P < 0.05 ) , the total dosage of fentanyl significantly decreased ( 427.6 ± 14.1 vs 658.4 ± 27.3 µg , P < 0.05 ) and recovery time became significantly shortened ( 0.3 ± 0.02 h vs 1.1 ± 0.3 h , P < 0.05 ) in dexmedetomidine group . Median duration of mechanical ventilation in dexmedetomidine group ( 21.0 h , 95%CI : 18.6 - 21.4 h ) was significantly shorter than that in propofol group ( 28.0 h , 95%CI : 25.6 - 30.4 h ) ( P < 0.05 ) . No inter-group differences existed in the ICU length of stay and the incidence of delirium . Two cases in dexmedetomidine group developed bradycardia while hypotension occurred in two cases of propofol group . CONCLUSION Sedative effects of dexmedetomidine are safe and effective for post-operative elder patients on MV . And it offers a better efficacy of analgesia and shorter duration s of MV and recovery time . But dexmedetomidine had no significant influence on the ICU length of stay or the incidence of delirium [14579210] OBJECTIVE To compare dexmedetomidine-based to propofol-based sedation after coronary artery bypass graft ( CABG ) surgery in the intensive care unit ( ICU ) . DESIGN R and omized , open label . SETTING Twenty-five centers in the United States and Canada . PARTICIPANTS Two hundred ninety-five adults undergoing CABG surgery . INTERVENTIONS At sternal closure , patients in group A received 1.0 microg/kg of dexmedetomidine over 20 minutes and then 0.2 to 0.7 microg/kg/h to maintain a Ramsay sedation score > or =3 during assisted ventilation and > or = 2 after extubation . Patients could be given propofol for additional sedation if necessary ; group B patients received propofol-based care according to each investigator 's st and ard practice . MEASUREMENTS AND MAIN RESULTS Mean sedation levels were within target ranges in both groups . Mean times to weaning and extubation were similar , although fewer dexmedetomidine patients remained on the ventilator beyond 8 hours . Morphine use was significantly reduced in the dexmedetomidine group . Only 28 % of the dexmedetomidine patients required morphine for pain relief while ventilated versus 69 % of propofol-based patients ( p < 0.001 ) . Propofol patients required 4 times the mean dose of morphine while in the ICU . Mean blood pressure increased initially in both groups , then decreased to 3 mmHg below baseline in dexmedetomidine patients ; mean arterial pressure remained at 9 mmHg above baseline in propofol patients . No ventricular tachycardia occurred in the dexmedetomidine-se date d patients compared with 5 % of the propofol patients ( p = 0.007 ) . Respiratory rates and blood gases were similar . Fewer dexmedetomidine patients received beta-blockers ( p = 0.014 ) , antiemetics ( p = 0.015 ) , nonsteroidal anti-inflammatory drugs ( p < 0.001 ) , epinephrine ( p = 0.030 ) , or high-dose diuretics ( p < 0.001 ) . CONCLUSION Dexmedetomidine provided safe and effective sedation for post-CABG surgical patients and significantly reduced the use of analgesics , beta-blockers , antiemetics , epinephrine , and diuretics [25493968] Objective : Delirium is common during critical illness and associated with adverse outcomes . We compared characteristics and outcomes of delirious and nondelirious patients enrolled in a multicenter trial comparing protocol ized sedation with protocol ized sedation plus daily sedation interruption . Design : R and omized trial . Setting : Sixteen North American medical and surgical ICUs . Patients : Four hundred thirty critically ill , mechanically ventilated adults . Interventions : All patients had hourly titration of opioid and benzodiazepine infusions using a vali date d sedation scale . For patients in the interruption group , infusions were resumed , if indicated , at half of previous doses . Delirium screening occurred daily ; positive screening was defined as an Intensive Care Delirium Screening Checklist score of 4 or more at any time . Measurements and Main Results : Delirium was diagnosed in 226 of 420 assessed patients ( 53.8 % ) . Coma was identified in 32.7 % of delirious compared with 22.7 % of nondelirious patients ( p = 0.03 ) . The median time to onset of delirium was 3.5 days ( interquartile range , 2–7 ) , and the median duration of delirium was 2 days ( interquartile range , 1–4 ) . Delirious patients were more likely to be male ( 61.1 % vs 46.6 % ; p = 0.005 ) , have a surgical/trauma diagnosis ( 21.2 % vs 11.0 % ; p = 0.030 ) , and history of tobacco ( 31.5 % vs 16.2 % ; p = 0.002 ) or alcohol use ( 34.6 % vs 20.9 % ; p = 0.009 ) . Patients with positive delirium screening had longer duration of ventilation ( 13 vs 7 d ; p < 0.001 ) , ICU stay ( 12 vs 8 d ; p < 0.0001 ) , and hospital stay ( 24 vs 15 d ; p < 0.0001 ) . Delirious patients were more likely to be physically restrained ( 86.3 % vs 76.7 % ; p = 0.014 ) and undergo tracheostomy ( 34.6 % vs 15.5 % ; p < 0.0001 ) . Antecedent factors independently associated with delirium onset were restraint use ( hazard ratio , 1.87 ; 95 % CI , 1.33–2.63 ; p = 0.0003 ) , antipsychotic administration ( hazard ratio , 1.67 ; 95 % CI , 1.005–2.767 ; p = 0.047 ) , and midazolam dose ( hazard ratio , 0.998 ; 95 % CI , 0.997–1.0 ; p = 0.049 ) . There was no difference in delirium prevalence or duration between the interruption and control groups . Conclusion : In mechanically ventilated adults , delirium was common and associated with longer duration of ventilation and hospitalization . Physical restraint was most strongly associated with delirium [9054252] Background Alpha2 ‐Adrenergic agonists decrease sympathetic tone with ensuing attenuation of neuroendocrine and hemodynamic responses to anesthesia and surgery . The effects of dexmedetomidine , a highly specific alpha2 ‐adrenergic agonist , on these responses have not been reported in patients undergoing coronary artery bypass grafting . Methods Eighty patients scheduled for elective coronary artery bypass grafting received , in a double‐blind manner , either a saline placebo or a dexmedetomidine infusion , initially 50 ng [ center dot ] kg‐1 [ center dot ] min‐1 for 30 min before induction of anesthesia with fentanyl , and then 7 ng [ center dot ] kg‐1 [ center dot ] min‐1 until the end of surgery . Filling pressures , blood pressure , and heart rate were controlled by intravenous fluid and by supplemental anesthetics and vasoactive drugs . Results Compared with placebo , dexmedetomidine decreased plasma norepinephrine concentrations by 90 % , attenuated the increase of blood pressure during anesthesia ( 3 vs. 24 mmHg ) and surgery ( 2 vs. 14 mmHg ) , but increased slightly the need for intravenous fluid challenge ( 29 vs. 20 patients ) and induced more hypotension during cardiopulmonary bypass ( 9 vs. 0 patients ) . Dexmedetomidine decreased the incidence of intraoperative ( 2 vs. 13 patients ) and postoperative ( 5 vs. 16 patients ) tachycardia . Dexmedetomidine also decreased the need for additional doses of fentanyl ( 3.1 vs. 5.4 ) , the increments of enflurane ( 4.4 vs. 5.6 ) , the need for beta blockers ( 3 vs. 11 patients ) , and the incidence of fentanyl‐induced muscle rigidity ( 15 vs. 33 patients ) and postoperative shivering ( 13 vs. 23 patients ) . Conclusions Intraoperative intravenous infusion of dexmedetomidine to patients undergoing coronary artery revascularization decreased intraoperative sympathetic tone and attenuated hyperdynamic responses to anesthesia and surgery but increased the propensity toward hypotension [21944176] OBJECTIVE To study sedative effect and safety of dexmedetomidine and midazolam for post-operative patients undergoing mechanical ventilation(MV ) in surgical intensive care unit(SICU ) . METHODS Two hundred cases of post-operative patients undergoing MV with tracheal intubation in SICU were enrolled and divided into two groups by r and om numerical table method . They were treated either with midazolam ( 98 cases ) or dexmedetomidine ( 102 cases ) . In both groups fentanyl was given intravenously continually for analgesia . The amount of fentanyl was adjusted according to Prince-Henry analgesic score to keep on 1 - 2 analgesic score ; the dose of sedation was regulated by Riker sedative and restless score ( SAS ) maintain 2 - 4 sedative score . During the course , parameters of the ventilator , electrocardiogram , heart rate(HR ) , blood pressure , respiratory rate , pulse oxygen saturation ( SpO(2 ) ) , blood gas analysis were observed and registered continuously . The amount of the drug , duration of MV , and incidence of side-effects such as hypotension , bradycardia , delirium , nausea , etc . were recorded in two groups . RESULTS In all the patients in two groups taking dexmedetomidine or midazolam expected sedative and analgesia scores were obtained . In the group with dexmedetomidine , the patients were aroused easier with adequate sedation , and when compared with the group with midazolam , dose of fentanyl ( μg × kg(-1) × h(-1 ) ) was significantly smaller ( 0.23±0.13 vs. 0.41±0.12 , P<0.01 ) , duration of MV ( hours ) was clearly shorter ( 7.20±6.29 vs. 12.44±8.96 , P<0.01 ) , the rates of hypotension ( 27.45 % vs. 11.22 % ) and bradycardia ( 24.51 % vs. 10.20 % ) were significantly higher ( both P<0.05 ) , the rate of delirium was clearly lower ( 3.92 % vs. 31.63 % , P<0.01 ) , the rate of nausea showed a slight decrease ( 9.80 % vs. 11.22 % , P>0.05 ) . The patients in the group with dexmedetomidine were divided into two subgroups of hypotension and non-hypotension . The quantity of blood loss during operation ( ml/kg ) , amount of fluid infusion during operation ( ml × kg(-1) × h(-1 ) ) , blood lactic acid concentration ( mmol/L ) on the day of surgical operation and the 1st day post-operative showed no significant difference between these subgroups ( quantity of blood loss on the day of surgical operation : 12.79±12.13 vs. 13.52±11.62 ; amount of fluid infusion during surgical operation : 11.91±4.59 vs. 13.09±7.05;blood lactic acid concentration on the day of operation : 1.88±1.07 vs. 1.71±0.87 , blood lactic acid concentration on the 1st day post-operative:1.43±0.98 vs. 1.37±0.79 , all P>0.05 ) . CONCLUSION Sedative effect of dexmedetomidine is satisfactory for patients undergoing MV after operation , with the property of easier arousal , lower delirium rate , and it helps to shorten the duration of MV with reduction the dosage of fentanyl by 50 % . However , it is necessary to enhance observation in order to prevent and control hypotension and bradycardia [27132448] OBJECTIVE To compare the sedative effect and safety of dexmedetomidine and midazolam in the intensive care unit ( ICU ) patients undergoing ventilator bundle treatment . METHODS A prospect i ve single-blind r and omized controlled trial ( RCT ) was conducted . Ninety patients receiving ICU ventilator-assisted therapy and ventilator bundle treatments for more than 3 days in the First Department of Critical Care Medicine of the Second Hospital of Lanzhou University from January 2013 to December 2014 were enrolled . The patients were r and omly divided into two groups for sedative treatment . The patients in dexmedetomidine group ( n = 42 ) were given dexmedetomidine 0.2 - 0.7 μg x kg(-1 ) x h(-1 ) to achieve a goal of satisfactory sedation [ Richmond agitation-sedation scale ( RASS ) score 0 to - 2 during the day , and -1 to -3 at night ) . The patients in midazolam group ( n = 48 ) were given midazolam 2 - 3 mg intravenously first , and then 0.05 mg x kg(-1 ) x h(-1 ) for maintenance . The drug dose was adjusted according to RASS every 4 hours to maintain the appropriate sedation depth . The patients in both groups received continuous intravenous infusion of fentanyl for analgesia . Ventilator bundle treatments included the head of a bed up 30 degrees to 45 degrees , awaken and extubation appraisal , daily use of proton pump inhibitors for peptic ulcer prevention , prevention of deep vein thrombosis ( DVT ) , chlorhexidine mouth nursing , and removal of sputum by suction from subglottic area . When the patients in both groups obtained satisfactory target sedation , daily awakening was conducted , and spontaneous breathing test ( SBT ) was carried out to determine optional weaning time . When the condition was optimal , weaning was conducted , otherwise ventilator bundle treatments were continued . The systolic blood pressure ( SBP ) , diastolic blood pressure ( DBP ) , mean arterial pressure ( MAP ) , heart rate ( HR ) , respiratory frequency ( RR ) were monitored before and 15 , 30 , 60 , 120 , 180 minutes after the treatment , and at the moment of extubation and 30 minutes after extubation . The duration of mechanical ventilation , extubation time , length of ICU stay , and the incidence of adverse events were also recorded . RESULTS Both dexmedetomidine and midazolam could give rise to sedation with same score of analgesia in patients in both groups , and similar effect of sedation and analgesia could be achieved . Compared with midazolam , dexmedetomidine could significantly reduce the duration of mechanical ventilation ( hours : 108.33 ± 21.96 vs. 119.85 ± 20.29 , t = -2.586 , P = 0.011 ) , earlier extubation time ( hours : 112.95 ± 22.20 vs. 128.58 ± 26.18 , = -3.031 , P = 0.003 ) , length of ICU stay ( hours : 149.21 ± 20.47 vs. 163.88 ± 33.59 , = -2.457 , P = 0.016 ) , the incidence of delirium [ 9.5 % ( 4/42 ) vs. 31.2 % ( 15/48 ) , χ2 = 6.349 , P = 0.012 ] , but it would elevate the incidence of severe hypotension [ 28.6 % ( 12/42 ) vs. 8.3 % ( 4/48 ) , χ2 = 6.277 , P = 0.012 ] and severe bradycardia [ 19.0 % ( 8/42 ) vs. 8.3 % ( 4/48 ) , χ2 = 2.225 , P = 0.136 ] . Both drugs could lower SBP , DBP , MAP , and HR , and the effect in dexmedetomidine group was more significant from 60 minutes after treatment [ SBP ( mmHg , 1 mmHg = 0.133 kPa ) : 113.12 ± 14.42 vs. 124.40 ± 15.79 , DBP ( mmHg ) : 69.02 ± 9.62 vs. 76.94 ± 10.41 , MAP ( mmHg ) : 83.76 ± 10.50 vs. 92.77 ± 11.87 , HR ( bpm ) : 79.19 ± 12.28 vs. 87.42 ± 17.77 , P < 0.05 or P < 0.01 ] . Both sedatives could significantly lower the rate of spontaneous breathing , and the effect of midazolam group was more significant from 60 minutes after treatment compared with dexmedetomidine group ( times/min : 18.27 ± 4.29 vs. 20.07 ± 4.11 , P < 0.05 ) . CONCLUSIONS The sedative effects of dexmedetomidine in the ICU patients treated with ventilator bundle treatment are satisfactory , and it can shorten the duration of mechanical ventilation , extubation time and length of ICU stay , reduce the incidence of delirium . However , monitoring should be strengthened in order to prevented and control the adverse effects such as severe hypotension and severe bradycardia [26975647] IMPORTANCE Effective therapy has not been established for patients with agitated delirium receiving mechanical ventilation . OBJECTIVE To determine the effectiveness of dexmedetomidine when added to st and ard care in patients with agitated delirium receiving mechanical ventilation . DESIGN , SETTING , AND PARTICIPANTS The Dexmedetomidine to Lessen ICU Agitation ( DahLIA ) study was a double-blind , placebo-controlled , parallel-group r and omized clinical trial involving 74 adult patients in whom extubation was considered inappropriate because of the severity of agitation and delirium . The study was conducted at 15 intensive care units in Australia and New Zeal and from May 2011 until December 2013 . Patients with advanced dementia or traumatic brain injury were excluded . INTERVENTIONS Bedside nursing staff administered dexmedetomidine ( or placebo ) initially at a rate of 0.5 µg/kg/h and then titrated to rates between 0 and 1.5 µg/kg/h to achieve physician-prescribed sedation goals . The study drug or placebo was continued until no longer required or up to 7 days . All other care was at the discretion of the treating physician . MAIN OUTCOMES AND MEASURES Ventilator-free hours in the 7 days following r and omization . There were 21 reported secondary outcomes that were defined a priori . RESULTS Of the 74 r and omized patients ( median age , 57 years ; 18 [ 24 % ] women ) , 2 withdrew consent later and 1 was found to have been r and omized incorrectly , leaving 39 patients in the dexmedetomidine group and 32 patients in the placebo group for analysis . Dexmedetomidine increased ventilator-free hours at 7 days compared with placebo ( median , 144.8 hours vs 127.5 hours , respectively ; median difference between groups , 17.0 hours [ 95 % CI , 4.0 to 33.2 hours ] ; P = .01 ) . Among the 21 a priori secondary outcomes , none were significantly worse with dexmedetomidine , and several showed statistically significant benefit , including reduced time to extubation ( median , 21.9 hours vs 44.3 hours with placebo ; median difference between groups , 19.5 hours [ 95 % CI , 5.3 to 31.1 hours ] ; P < .001 ) and accelerated resolution of delirium ( median , 23.3 hours vs 40.0 hours ; median difference between groups , 16.0 hours [ 95 % CI , 3.0 to 28.0 hours ] ; P = .01 ) . Using hierarchical Cox modeling to adjust for imbalanced baseline characteristics , allocation to dexmedetomidine was significantly associated with earlier extubation ( hazard ratio , 0.47 [ 95 % CI , 0.27 - 0.82 ] ; P = .007 ) . CONCLUSIONS AND RELEVANCE Among patients with agitated delirium receiving mechanical ventilation in the intensive care unit , the addition of dexmedetomidine to st and ard care compared with st and ard care alone ( placebo ) result ed in more ventilator-free hours at 7 days . The findings support the use of dexmedetomidine in patients such as these . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01151865 Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: CONTEXT Sedation has become an integral part of critical care practice in minimizing patient discomfort ; however , sedatives have adverse effects and the potential to prolong mechanical ventilation , which may increase health care costs . OBJECTIVE To determine which form of sedation is associated with optimal sedation , the shortest time to extubation , and length of intensive care unit ( ICU ) stay . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

15846637

[12171841] OBJECTIVES To compare the therapeutic ratio of chlorofluorocarbon ( CFC ) and hydrofluoroalkane-134a ( HFA ) formulations of fluticasone propionate ( FP ) . METHODS We performed a r and omized , placebo-controlled , crossover study comparing 6 weeks of treatment with FP using 500 micro g/d and 1,000 microg/d formulations of CFC and HFA . The primary end points were provocative dose of methacholine causing a 20 % fall in FEV1 ( PD20 ) and overnight urinary cortisol/creatinine excretion . RESULTS Eighteen patients with mild-to-moderate asthma and geometric mean ( SEM ) PD20 of 82.3 micro g ( 19.2 micro g ) completed the study . All treatments significantly improved PD20 values and morning peak expiratory flow vs placebo , while 1,000 microg/d was significantly better than 500 microg/d for the CFC formulation of FP ( CFC-FP ) but not the HFA formulation of FP ( HFA-FP ) . Only 1,000 microg/d of CFC-FP caused significant suppression of overnight urinary cortisol/creatinine compared to placebo . There were no differences between formulations at either dose . CONCLUSIONS The increased airway benefit with CFC-FP > 500 microg/d was offset by greater systemic effects . Although HFA-FP had fewer systemic effects than CFC-FP at 1,000 microg/d , there was no benefit to increasing HFA-FP to > 500 microg/d [2365805] In Vitro and in vivo data have demonstrated that there are detectable differences between inhaled corticosteroids commonly used to treat asthma . However , controversy still remains as to whether these differences translate into clinical benefits . This 12-week , international , r and omized , doubleblind , parallel-group study was undertaken to compare the efficacy and safety of fluticasone propionate ( FP ) 800 μg daily , administered as a powder via the Diskhaler ® , and budesonide ( BUD ) 1600 μg daily , administered using the Turbuhaler ® , in adult patients with moderate-tosevere asthma . A total of 518 patients participated in the study , 256 of whom received FP and 262 BUD . Assessment of mean morning peak expiratory flow ( PEF ) over the 12-week treatment period revealed a statistically significant difference in efficacy between FP 800 μg daily and BUD 1600 μg daily in favour of FP ( p = 0.003 ) , with an overall improvement of 20.9 l/min with FP compared with 12.4 l/min on BUD . Statistically significant differences in favour of FP were seen over the 12 weeks for mean evening PEF ( p = 0.04 ) , diurnal PEF variation ( p = 0.03 ) and percentage predicted PEF ( p = 0.003 ) , as well as forced expiratory volume ( p = 0.008 ) , forced vital capacity ( p = 0.02 ) and PEF ( p = 0.005 ) measured at clinic visits . The median percentage of symptom-free nights increased over the 12-week study period in both treatment groups , with similar changes seen for the median percentage of days with symptom score < 2 , rescue medication use and exacerbations of asthma . The incidence of adverse events was found to be comparable in the two treatment groups . The geometric mean ratios of serum cortisol levels were found to be 1.03 for FP , indicating no mean hypothalamic-pituitary-adrenal axis suppression from baseline , and 0.93 for BUD ( p = 0.0002 compared with FP ) . In summary , FP 800 μg daily showed a greater efficacy/safety ratio in the treatment of moderate-to-severe asthma than BUD 1600 μg daily [9196354] OBJECTIVE To investigate effects on adrenal function of fluticasone , a recently released inhaled steroid preparation with lower systemic bioavailability than beclomethasone dipropionate . METHODS 34 children on high doses ( 400 - 909 μg/m2/d ) of inhaled beclomethasone dipropionate or budesonide were recruited into a double blind , crossover study investigating the effects on adrenal function of beclomethasone and fluticasone propionate , given using a st and ard spacer ( Volumatic ) . The 24 hour excretion rates of total cortisol and cortisol metabolites were determined at baseline ( after a two week run in ) , after six weeks treatment with an equal dose of beclomethasone , and after six weeks of treatment with half the dose of fluticasone , both given through a spacer device . RESULTS The comparison of effects between fluticasone and beclomethasone during treatment periods , although favouring fluticasone in all measured variables , reached significance only after correction for urinary creatinine excretion ( tetrahydrocortisol and 5α-tetrahydrocortisol geometric means : 424 v 341 μg/m2/d ) . The baseline data showed adrenal suppression in the children taking beclomethasone ( total cortisol geometric means : 975 v 1542 μg/d ) and a dose related suppression in the children taking budesonide . Suppressed adrenal function in the children who were taking beclomethasone at baseline subsequently improved with fluticasone and beclomethasone during treatment periods . CONCLUSIONS Fluticasone is less likely to suppress adrenal function than beclomethasone at therapeutically equivalent doses . The baseline data also support the cl aim that spacer devices should be used for the administration of high doses of inhaled topical steroids [11897984] BACKGROUND A clinical model is needed to compare inhaled corticosteroids ( ICSs ) with respect to efficacy . OBJECTIVE The purpose of this investigation was to compare the relative beneficial and systemic effects in a dose-response relationship for 2 ICSs . METHODS A 24-week , parallel , open-label , multicenter trial examined the benefit-risk ratio of 2 ICSs in persistent asthma . Benefit was assessed by improvements in FEV(1 ) and PC(20 ) ; risk was assessed by overnight plasma cortisol suppression . Thirty subjects were r and omized to either beclomethasone dipropionate ( BDP ) 168 , 672 , and 1344 microg/day ( n = 15 ) or fluticasone propionate ( FP ) 88 , 352 , and 704 microg/day ( n = 15 ) , both administered by means of a metered dose inhaler ( MDI ) with chlorofluorocarbon propellant via a spacer , in 3 consecutive 6-week intervals ; this was followed by 3 weeks of FP dry powder inhaler ( DPI ) 2000 microg/day . RESULTS Maximum FEV(1 ) response occurred with the low dose for FP-MDI and the medium dose for BDP-MDI and was not further increased by treatment with FP-DPI . Near-maximum methacholine PC(20 ) improvement occurred with the low dose for FP-MDI and the medium dose for BDP-MDI . Both BDP-MDI and FP-MDI caused dose-dependent cortisol suppression . Responsiveness to ICS treatment was found to vary markedly among subjects . Good ( > 15 % ) FEV(1 ) response , in contrast to poor ( < 5 % ) response , was found to be associated with high exhaled nitric oxide ( median , 17.6 vs 11.1 ppb ) , high bronchodilator reversibility ( 25.2 % vs 8.8 % ) , and a low FEV(1)/forced vital capacity ratio ( 0.63 vs 0.73 ) before treatment . Excellent ( > 3 doubling dilutions ) improvement in PC(20 ) , in contrast to poor ( < 1 doubling dilution ) improvement , was found to be associated with high sputum eosinophil levels ( 3.4 % vs 0.1 % ) and older age at onset of asthma ( age , 20 - 29 years vs < 10 years ) . CONCLUSIONS Near-maximal FEV(1 ) and PC(20 ) effects occurred with low-medium dose for both ICSs in the subjects studied . High-dose ICS therapy did not significantly increase the efficacy measures that were evaluated , but it did increase the systemic effect measure , overnight cortisol secretion . Significant intersubject variability in response occurred with both ICSs . It is possible that higher doses of ICSs are necessary to manage more severe patients or to achieve goals of therapy not evaluated in this study , such as prevention of asthma exacerbations [8779128] BACKGROUND : A study was performed to compare the adrenal suppression caused by inhaled fluticasone propionate and budesonide on a microgram equivalent basis , each given by metered dose inhaler to asthmatic patients . METHODS : Twelve asthmatic patients of mean age 29.9 years , with a forced expiratory volume in one second ( FEV1 ) 92.9 % predicted and forced expiratory flow 25 - 75 % ( FEF25 - 75 ) 69.5 % predicted , on less than or equal to 400 micrograms/day inhaled corticosteroid , were studied in a double blind placebo controlled crossover design comparing single doses of inhaled budesonide 400 , 1000 , 1600 , 2000 micrograms and fluticasone propionate 500 , 1000 , 1500 , 2000 micrograms . Doses were administered at 22.00 hours by metered dose inhaler with mouth rinsing and measurements were made in the laboratory 10 hours later . RESULTS : Serum cortisol levels compared with placebo ( mean 325.2 nmol/l ) were suppressed by fluticasone at doses of 1500 micrograms ( 211.6 nmol/l ) and 2000 micrograms ( 112.3 nmol/l ) and by budesonide at 2000 micrograms ( 243.4 nmol/l ) . Fluticasone propionate 2000 micrograms produced lower absolute serum cortisol levels than budesonide 2000 micrograms ( 95 % CI for difference 42.9 to 219.2 ) . The dose ratio ( geometric mean ) for the relative potency was 2.89 fold ( 95 % CI 1.19 to 7.07 ) . In terms of percentage suppression versus placebo , fluticasone propionate also produced greater effects ( means and 95 % CI for difference ) : budesonide 1600 micrograms ( 16.0 ) versus fluticasone propionate 1500 micrograms ( 40.9 ) ( 95 % CI -0.6 to 50.6 ) , budesonide 2000 micrograms ( 26.0 ) versus fluticasone 2000 micrograms ( 65.2 ) ( 95 % CI 10.5 to 67.8 ) . Individual serum cortisol levels at the two highest doses showed 15 of 24 patients below the normal limit of the reference range ( 150 nmol/l ) for fluticasone and five of 24 for budesonide . Fluticasone propionate also caused greater ACTH suppression than budesonide ( as % versus placebo ) : budesonide 1600 micrograms ( 12.0 ) versus fluticasone propionate 1500 micrograms ( 31.9 ) ( 95 % CI 7.6 to 32.1 ) , budesonide 2000 micrograms ( 13.5 ) versus fluticasone propionate 2000 micrograms ( 44.4 ) ( 95 % CI 13.2 to 48.7 ) . For overnight 10 hour urinary cortisol ( nmol/10 hours ) there was a difference between the lowest doses of the two drugs : budesonide 400 micrograms ( 37.2 ) versus fluticasone propionate 500 micrograms ( 19.9 ) ( 95 % CI 6.9 to 27.8 ) . CONCLUSIONS : Like budesonide the systemic bioactivity of fluticasone propionate is mainly due to lung vascular absorption . Fluticasone propionate exhibited at least twofold greater adrenal suppression than budesonide on a microgram equivalent basis in asthmatic patients [11392363] This study was carried out in an attempt to compare the efficacy and safety of fluticasone propionate ( FP ) at the half dose of budesonide ( BUD ) and beclamethasone dipropionate ( BD ) in childhood asthma . Ninety-six children with moderate to severe asthma ( 9.6 ± 2.17 years ) whose asthma was already controlled on BUD ( n = 52 ) or BD ( n = 44 ) were recruited into the study . In the first part of the study ( the first 12 weeks ) each group was followed with three weekly lung function measurements , daily diary records , and peak expiratory flow ( PEF ) measurements on the initial medication . At the end of 6 weeks , drugs were switched to a half dose of FP , and the subjects were followed for another 6 weeks . Blood sample s were obtained for osteocalcin and plasma cortisol levels after each treatment period . In the second part of the study , 50 patients continued to take FP at the half dose of BUD or BD for another 30 weeks . Clinic visits , including lung function and PEF measurements , were conducted every 10 weeks . After 6 weeks of FP treatment , there was a small but statistically significant decrease in FEV1 and FEF25–75 in both groups ( BUD and BD ) without any significant obstruction . These mild changes in lung function measurements continued during long-term follow-up . However , there was no statistically significant further decrease in any lung function parameters while receiving FP ( visits 3–8 ) ( coefficient = −0.00751 L/day , p = 0.39 for FEF25–75 and coefficient = −0.00910 L/sec/day , p = 0.055 for FEV1 ) . There were no significant changes in the morning and evening PEF measurements and diurnal PEF variations after 6 weeks of treatment with FP compared with BUD and BD treatments . There were no significant changes in basal cortisol and osteocalcin levels before or after 6 weeks of FP treatment ( p > 0.05 ) . The present study concluded that , although FP at the half dose of BUD or BD seems to maintain reasonable control of the disease symptoms , a mild but significant and persistent decrease in lung function parameters may indicate that FP may not be twice as potent as BUD or BD in childhood asthma by evaluation of lung functions . This conclusion must be further verified with long-term studies [14512127] BACKGROUND Inhaled corticosteroids are established first-line anti-inflammatory treatment for asthma . Clinical trials comparing inhaled corticosteroids must take into consideration that because of their excellent effect at low doses , they typically induce a near-maximal response in asthma patients . OBJECTIVE The aim of the present dose-response study was to estimate the minimal effective doses ( MEDs ) of budesonide and of fluticasone propionate via dry-powder inhaler in adults with mild to moderate asthma . METHODS This was a r and omized , double-blind , double-dummy , parallel-group , multicenter , dose-reduction trial performed in adults to compare these 2 inhaled corticosteroids . After a 4- to 6-week run-in period with beclomethasone dipropionate 2000 pg/d , patients fulfilling defined criteria for asthma control were r and omly allocated to treatment with budesonide or fluticasone , both administered BID at a total of 800 pg/d . At 5-week intervals , the dose was reduced to 400 and then 200 pg/d ( 200 and 100 pg BID ) if asthma control was maintained according to further defined criteria . The MED was defined as the last dose level before deterioration of asthma control . RESULTS Subjects were 197 asthmatic patients with a mean age of 40.6 years in the budesonide group and 41.5 years in the fluticasone group . In both groups , baseline mean forced expiratory volume in 1 second ( FEV(1 ) ) was 79.4 % of the predicted normal volume and baseline mean FEV(1 ) reversibility was 22.3 % . The median MED for both groups was 400 microg/d , with no detectable difference in dis-tributions . The budesonide-to-fluticasone ratio for the geometric mean MED was 123 % ( 95 % CI , 99 - 153 [ not significant ] ) . No statistically significant differences regarding lung function , symptom scores , or rescue medication usage were found between the treatment groups during the first treatment period . Adverse-event profiles were similar in both groups , and no unexpected adverse events were considered to be caused by the study drugs . CONCLUSION This effect-controlled study did not detect a statistically significant difference between the MEDs for budesonide and fluticasone via dry-powder inhaler in adults with mild to moderate asthma [12324672] Background : With the transition to hydrofluoroalkane-134a propellants in metered dose inhalers , it is important to consider the efficacy and safety profiles of formulations containing inhaled corticosteroids . We examined the airway and systemic effects of hydrofluoroalkane-134a fluticasone propionate ( FLU-HFA ) and beclomethasone dipropionate ( BEC-HFA ) at recommended labelled doses . Methods : Twenty mild to moderate asthmatics were r and omised in crossover fashion to receive 6 weeks of 500 μg/day followed by 1000 μg/day FLU-HFA and BEC-HFA . Measurements were made at baseline after placebo run in and washout , and after each r and omised treatment . The primary airway outcome for benefit was the dose of methacholine provoking a fall in forced expiratory volume in 1 second ( FEV1 ) of 20 % or more ( methacholine PD20 ) and for systemic adverse effects was overnight urinary cortisol/creatinine ( OUCC ) . Results : For mean responses , both doses of BEC-HFA and FLU-HFA produced significant improvements in PD20 compared with baseline . The improvement was not significantly greater with 1000 μg/day FLU-HFA versus BEC-HFA , a 1.69 fold difference ( 95 % CI 0.94 to 3.04 ) . Both doses of BEC-HFA but not FLU-HFA caused significant suppression of OUCC compared with baseline , with significantly ( p<0.05 ) lower values at 1000 μg/day for BEC-HFA versus FLU-HFA ( 1.97 fold difference ( 95 % CI 1.28 to 3.02 ) ) . Conclusion : There was no difference in the airway and systemic effects in patients with mild to moderate asthma between FLU-HFA and BEC-HFA at a dose of 500 μg/day . At 1000 μg/day there was increased systemic bioactivity with BEC-HFA compared with FLU-HFA , without any gain in airway efficacy [9516029] Abstract Objective : The aim of this study was to evaluate the steady-state effects of once-daily inhaled fluticasone propionate ( FP ) and budesonide ( BUD ) on adrenocortical activity in asthmatic patients . Methods : Ten asthmatic patients with a mean age of 31.2 years , a mean forced expiratory volume in 1 s ( FEV1 ) of 91 % predicted and a forced mid-expiratory flow ( FEF25–75 ) of 62.3 % predicted were studied in a single-blind r and omised crossover design comparing placebo ( PL ) , FP ( 375 μg per day and 750 μg per day ) and BUD ( 400 μg per day and 800 μg per day ) all given once daily for 4 days at each dose via a pressurised metered dose inhaler ( pMDI ) at 0800 hours . After 4 days of treatment , plasma cortisol was measured at 0800 hours ( 24 h after the last dose ) and a 10-h overnight urine collection was taken , 14 h after the last dose ( 2200–0800 hours ) for analysis of cortisol and creatinine excretion . Results : Plasma cortisol levels ( nmol · l−1 , as geometric mean ) at 0800 hours demonstrated a significant difference between the highest doses of FP and BUD ( 424.1 vs 510.3 nmol · l−1 , respectively ) but not between the low doses ( 506.8 vs 514.9 nmol · l−1 ; PL 532.2 nmol · l−1 ) . For the highest dose FP ( 750 μg ) this equated to 20 % suppression of 0800 hours plasma cortisol . Likewise , for overnight urinary cortisol output ( nmol · 10 h−1 , as geometric mean ) , there was a significant difference at the high doses of FP and BUD ( 25.5 vs 38.2 nmol · 10 h−1 ) , but not at the low doses 31.3 vs 34.8 nmol · 10 h−1 ; PL 32.0 nmol · 10 h−1 . For the overnight urinary cortisol/creatinine ratio ( nmol · mmol−1 , as geometric mean ) there was a similar trend ; 4.5 vs 6.1 nmol · mmol−1 for high dose and 5.6 vs 6.3 nmol · mmol−1 for low dose ; PL 5.9 nmol · mmol−1 . Conclusion : Repeated doses of FP 750 μg once daily caused greater adrenal suppression than BUD 800 μg once daily , when comparing effects on plasma cortisol levels at 0800 hours , 24 h after the last dose , as well as effects on overnight urinary cortisol output . Neither FP 375 μg once daily nor BUD 400 μg once daily produced detectable adrenal suppression [15878495] Qvar Autohaler efficacy on asthma control , assessed with E. Juniper asthma control question naire ( ACQ ) , was compared with fluticasone and budesonide . An open r and omized study , stratified ( 2:1 ) on the intake of long-acting beta2-mimetics ( LAbeta2 ) , was performed in patients with moderate to severe poorly controlled asthma ( defined by at least one nocturnal discomfort in the last 5 days or a mean of 2 puffs of short-acting beta2-mimetics in the last 7 days or exercise dyspnea ) despite treatment with beclomethasone < or = 1000 microg/day ( or equivalent ) . 460 patients received Qvar Autohaler 800 microg/day ( n = 149 ) , fluticasone Diskus 1000 microg/day ( n = 149 ) or budesonide Turbuhaler 1600 microg/day ( n = 162 ) during 12 weeks . Asthma control improved in all groups , with no difference between groups . For patients treated with LAbeta2 ( n = 286 ) a significantly greater improvement of the ACQ score was obtained with Qvar Autohaler versus fluticasone ( 1.0 + /- 1.0 vs. 0.6 + /- 0.9 ; P = 0.019 ) , but not versus budesonide ( 0.9 + /- 0.9 ) . Pulmonary function test improvements were similar in the 3 groups . The significant improvement in asthma control in patients receiving LAbeta2 suggests potential advantages for extrafine aerosols as part of anti-inflammatory treatment optimization [8211872] BACKGROUND --High dose inhaled glucocorticosteroids are increasingly used in the management of patients with moderate to severe asthma . Although effective , they may cause systemic side effects . Fluticasone propionate is a topically active inhaled glucocorticosteroid which has few systemic effects at high doses . METHODS --Fluticasone propionate , 1.5 mg per day , was compared with beclomethasone dipropionate at the same dose for one year in patients with symptomatic moderate to severe asthma ; 142 patients received fluticasone propionate and 132 received beclomethasone dipropionate . The study was multicentre , double blind and of a parallel design . For the first three months patients attended the clinic every four weeks and completed daily diary cards . For the next nine months they were only seen at three monthly intervals in the clinic . RESULTS --During the first three months diary card peak expiratory flow ( PEF ) rate and lung function measurements in the clinic showed significantly greater improvement in patients receiving fluticasone propionate ( difference in morning PEF 15 l/min ( 95 % CI 6 to 25 ) ) , and these differences were apparent at the end of the first week . The improved lung function was maintained throughout the 12 month period and the number of severe exacerbations in patients receiving fluticasone propionate was reduced by 8 % compared with those receiving beclomethasone dipropionate . No significant differences between the two groups were observed in morning plasma cortisol levels , urinary free cortisol levels , or response to synthetic ACTH stimulation . In addition , both the rates of withdrawal and of adverse events were low , and there were fewer exacerbations of asthma with fluticasone propionate than beclomethasone dipropionate . CONCLUSIONS --This study shows that fluticasone propionate in a daily dose of 1.5 mg results in a significantly greater increase in PEF and asthma control than the same dose of beclomethasone dipropionate , with no increase in systemic or other side effects [9039246] BACKGROUND : In a previous single dosing comparison between fluticasone propionate and budesonide differences in cortisol levels measured at 08.00 hours were observed at doses in excess of 1000 micrograms . The aim of this study was to compare the adrenal suppression caused by chronic twice daily dosing with inhaled fluticasone propionate ( FP ) and budesonide ( B ) given on a microgram equivalent basis by metered dose inhaler to asthmatic patients . METHODS : Twelve stable asthmatic patients of mean age 29.7 years with forced expiratory volume in one second ( FEV1 ) 89.0 % predicted and mid forced expiratory flow ( FEF25 - 75 ) 58.9 % predicted , on 400 micrograms/day or less of inhaled corticosteroid , were studied in a double blind , placebo controlled , crossover design comparing inhaled budesonide and fluticasone propionate in doses of 250 micrograms , 500 micrograms , and 1000 micrograms twice daily . Each dose was given at 08.00 hours and 22.00 hours for four days by metered dose inhaler with mouth rinsing . Measurements were made of overnight urinary cortisol excretion and plasma cortisol levels at 08.00 hours , 10 hours after the eighth dose . RESULTS : The plasma cortisol levels ( nmol/ l ) at 08.00 hours showed that fluticasone propionate produced lower cortisol levels than budesonide at all three dose levels : F500 333.8 , B500 415.2 ( 95 % CI 28.9 to 134.0 ) ; F1000 308.3 , B1000 380.3 ( 95 % CI 10.5 to 133.5 ) ; F2000 207.3 , B2000 318.5 ( 95 % CI 5.8 to 216.7 ) ; placebo 399.9 . Fluticasone produced greater effects than budesonide on the overnight urinary cortisol/creatinine ratio ( nmol/mmol ) at all three dose levels : F500 3.12 , B500 5.55 ( 95 % CI 0.16 to 3.79 ) ; F1000 2.54 , B1000 6.12 ( 95 % CI 1.25 to 5.91 ) ; F2000 2.07 , B2000 6.09 ( 95 % CI 0.88 to 7.18 ) ; placebo 5.23 . CONCLUSIONS : With repeated dosing across a dose range of 250 - 1000 micrograms twice daily , fluticasone propionate produced significantly greater adrenal suppression than budesonide for both plasma and urinary cortisol . It was therefore possible to demonstrate differences between fluticasone and budesonide at lower doses with chronic dosing from those previously found with single dosing when given on a microgram equivalent basis in asthmatic patients . Factors contributing to the systemic adverse activity profile of fluticasone comprise enhanced receptor potency , prolonged receptor residency time , greater tissue retention , and a longer elimination half life [11695935] OBJECTIVE To compare the long-term effect of treatment with fluticasone propionate or beclomethasone dipropionate on growth in asthmatic children . DESIGN Prospect i ve , multicenter , r and omized , double-blind , parallel-group study . SETTING Children requiring regular treatment with inhaled corticosteroids and with a sexual maturity rating of Tanner stage 1 ( prepubertal ) . PATIENTS Three hundred forty-three children aged 4 to 11 years with asthma . The growth population ( excluding patients with protocol violations likely to affect growth measurements ) included 277 patients . INTERVENTIONS Fluticasone propionate or beclomethasone dipropionate , both at a dosage of 200 microg administered twice daily via a dry powder inhaler ( Diskhaler ) for 12 months . MAIN OUTCOME MEASURES Growth velocity , lung function , and serum and urinary cortisol levels . RESULTS The adjusted mean growth velocity in the fluticasone group was significantly greater than that in the beclomethasone group ( 5.01 [ SE , 0.14 ] vs 4.10 [ SE , 0.15 ] cm/y ; difference , 0.91 cm ; 95 % confidence interval , 0.63 - 1.20 cm ; P<.001 ) . Both treatments improved lung function , with significant differences in favor of fluticasone . Adverse events were similar in both groups , and there were no significant differences in effect on serum and urinary cortisol levels . CONCLUSIONS The more favorable risk-benefit ratio of fluticasone indicates that this agent is preferable to beclomethasone for the long-term treatment of children with asthma , especially if moderate doses are required [7713201] We wanted to evaluate the improvement in efficacy when increasing the daily dose of inhaled steroids and to compare the efficacy , safety , and tolerance of 1.6 mg beclomethasone dipropionate ( BDP ) with that of 2.0 mg fluticasone propionate ( FP ) . The study was a r and omized , double-blind , 3 month , multicentre study . One hundred and thirty four asthmatics currently using inhaled steroids ( 0.4 - 1.6 mg BDP or budesonide ( BUD ) ) were stratified according to pretrial daily steroid use . Within each stratum they were r and omized to either 1.6 mg BDP or 2.0 mg FP . A significant increase in the primary efficacy variables , i.e. mean morning and evening peak expiratory flow ( PEF ) ( approximately 20 l.min-1 ) during the treatment period , was found for both treatments . No significant differences between the drugs were revealed for these primary or any other secondary efficacy variables ( use of beta 2-agonists , symptom scores , and PEF , forced vital capacity ( FVC ) , forced expiratory volume in one second ( FEV1 ) recorded at the clinical visits ) . However , significant differences between treatments occurred regarding decrease of serum cortisol and adrenocorticotropic hormone . We conclude that , although both treatments gave statistically significant increases in efficacy parameters when compared with baseline , the increases were so small that they can be regarded as being clinical ly unimportant . Daily doses of BDP , 1.6 mg , and FP , 2.0 mg , had comparable effects on lung function . A suppression of the hypothalamic pituitary adrenal ( HPA ) axis was only found with a daily dose of 2 mg FP [10836329] Inhaled steroids are frequently used in childhood asthma , but concerns based on limited objective evidence remain , regarding long-term side-effects . In this study the systemic effects of st and ard doses of inhaled steroids in childhood asthma were assessed , comparing beclomethasone dipropionate ( BDP ) with fluticasone propionate ( FP ) . The study was prospect i ve , r and omized and double-blind . Twenty-three steroid-naive children with moderately severe asthma , aged 5 - 10 yrs , were allocated either BDP ( 400 microg x day(-1 ) or FP ( 200 microg x day(-1 ) ) using a metered-dose inhaler with a spacer . Asthma control was assessed at regular intervals over 20 months . Fasting morning blood and overnight urine sample s were collected for estimation of serum cortisol , serum 1-carboxyterminal telopeptide ( ICTP ) , serum osteocalcin and urine deoxypyridinoline ( DPD ) . Bone mineral density ( BMD ) was measured at each visit . None of the markers of bone turnover showed any change during the study period . BMD increased at normal rates with age . Serum cortisol significantly decreased on BDP , but not on FP . A significant difference in growth rates was found between the groups , with a slower rate of growth towards the end of the observation period in the BDP group . In conclusion when taken in a relatively modest dose over a period of time , beclomethasone dipropionate had significant effects on the hypothalamic-pituitary-adrenal axis and statural growth in childhood asthma . These systemic effects were not seen with an equipotent dose of fluticasone propionate [11182010] BACKGROUND The potential for long term adverse effects from inhaled corticosteroids relates to their systemic absorption , usually assessed from proxy markers in short term studies . When fluticasone propionate and budesonide have been compared in this way the results have been inconsistent . To determine whether this is because of the subjects studied or the sensitivity of the systemic marker used , we have compared the effects of fluticasone propionate and budesonide in healthy and asthmatic subjects and investigated the effect of treatment on three systemic markers . METHODS Forty six healthy subjects were r and omised to receive inhaled fluticasone propionate 1500 μg/day ( via an Accuhaler ) , budesonide 1600 μg/day ( via a Turbuhaler ) , or placebo ; 31 subjects with moderately severe asthma were r and omised to receive the same doses of fluticasone propionate or budesonide but not placebo . Systemic effects in healthy and asthmatic subjects were compared after 7 days . Treatment was continued for another 21 days in the subjects with asthma when systemic effects and asthma control were assessed . RESULTS At baseline healthy subjects had higher urinary levels of total cortisol metabolites ( TCM ) than subjects with asthma . After 7 days of treatment with fluticasone propionate urinary TCM levels in the healthy subjects were significantly lower than in the subjects with asthma ( mean difference between groups 1663 μg/day , 95 % CI 328 to 2938 ) . This was not the case with budesonide , however , where urinary TCM levels in the healthy subjects remained above those in the asthmatic subjects ( mean difference between groups 1210 μg/day , 95 % CI –484 to 2904 ) . Urinary TCM levels were considerably more sensitive to the effects of inhaled corticosteroids than morning serum cortisol or osteocalcin concentrations . Only budesonide reduced the serum level of osteocalcin . CONCLUSIONS When given by dry powder inhaler for 7 days , fluticasone propionate 1500 μg/day has a greater effect on the hypothalamic-pituitary-adrenal axis in healthy subjects than in subjects with asthma , but this is not the case for budesonide 1600 μg/day . These findings , together with the differences in sensitivity between systemic markers , explain many of the discrepancies in the literature [9230238] Few thorough comparisons of the systemic effects of inhaled corticosteroids in children are available . The aim of this study was to compare the effect of budesonide and fluticasone propionate on short-term lower leg growth . Fluticasone propionate , budesonide and placebo were administered for 2 weeks in a r and omized , double-blind , double-dummy , cross-over design . Twenty four children aged 6 - 12 yrs received 200 microg x day(-1 ) of each drug , or placebo . Another 24 children aged 6 - 12 years received 400 microg x day(-1 ) of each drug , or placebo . Dry powder inhalers were used . Lower leg length was measured by knemometry twice a week during all three treatment periods , and 24 h cortisol excretion in the urine was measured at the end of each period . In the low-dose group , lower leg growth rate was the same during treatment with placebo ( 0.35 mm x week(-1 ) ) , fluticasone propionate ( 0.38 mm x week(-1 ) ) or budesonide ( 0.26 mm x week(-1 ) ) . No significant difference ( p=0.39 ) in lower leg growth rate was found between treatment with 400 microg x day(-1 ) budesonide ( 0.30 mm x week(-1 ) ) and 400 microg fluticasone propionate treatment ( 0.37 mm x week(-1 ) ) . Growth rate during treatment with budesonide , 400 microg x day(-1 ) , was significantly lower than during placebo treatment ( 0.52 mm x week(-1 ) ) . Cortisol excretion in the urine during treatment with 200 microg x day(-1 ) fluticasone propionate was significantly reduced as compared with placebo ( p=0.006 ) , but not when compared with 200 microg x day(-1 ) budesonide ( p=0.07 ) . Budesonide 200 microg x day(-1 ) was not significantly different from placebo . Fluticasone propionate and budesonide , both at 400 microg x day(-1 ) , result ed in a significant reduction in cortisol excretion in the urine as compared with placebo ( p=0.001 ) . It is concluded that , dose-for-dose , budesonide Turbuhaler and fluticasone propionate Diskhaler have similar systemic effects [8947070] The aim of this study was to compare fluticasone propionate ( FP ) with budesonide ( BUD ) at a dose of 400 microg x day(-1 ) in the treatment of children with asthma . Two hundred and twenty nine children with mild-to-moderate asthma , currently receiving 200 - 400 microg x day(-1 ) of inhaled corticosteroid , were r and omized to receive either 400 microg x day(-1 ) of FP from the Diskhaler ( registered trade mark of the Glaxo Group of Companies ) or 400 microg x day(-1 ) of BUD from the Turbuhaler ( registered trade mark of Astra Pharmaceuticals Ltd ) for 8 weeks , in a parallel-group , double-blind , double-dummy study . Primary efficacy was assessed by measurement of daily peak expiratory flow ( PEF ) . In addition , pulmonary function tests were performed at each clinic visit and a self-administered patient-centred question naire was completed by one parent of each patient at the start and end of study treatment . Mean morning PEF increased following treatment both with FP and BUD , but was significantly higher following treatment with FP during Weeks 1 - 4 ( p=0.015 ) and Weeks 1 - 8 ( p=0.019 ) . Similar results were found for mean evening PEF and percentage predicted morning and evening PEF . Children receiving FP experienced significantly less disruption in their physical activities ( i.e. sports , games ) because of their asthma compared to children treated with BUD ( p=0.03 ) . Mean cortisol levels increased in both groups , but the increase was significantly higher in the FP group at 4 weeks ( p=0.022 ) . Serum and urine markers of bone formation and resorption changed very little and showed no consistent pattern of change . Fluticasone propionate at a dosage of 400 microg x day(-1 ) from the Diskhaler provided a more rapid and greater improvement in lung function in children with mild-to-moderate asthma than BUD 400 microg day(-1 ) from the Turbuhaler . Both treatments were well-tolerated , with a similar safety profile [14694242] Background : It is important to be able to compare the efficacy and systemic effects of inhaled corticosteroids but their slow onset of action makes it difficult to measure the maximum response to a given dose . Submaximal responses could be compared if the time course of action of the inhaled corticosteroids being compared was similar . We have compared the time course of action of fluticasone and budesonide , measuring response as change in the provocative dose of adenosine monophosphate causing a 20 % fall in forced expiratory volume in 1 second ( PD20AMP ) . Methods : Eighteen subjects with mild asthma , aged 18–65 , took part in a three way r and omised crossover study . Subjects took fluticasone ( 1500 μg/day ) , budesonide ( 1600 μg/day ) , and placebo each for 4 weeks with a washout period of at least 2 weeks between treatments ; PD20AMP and forced expiratory volume in 1 second ( FEV1 ) were measured during and after treatment . The time taken to achieve 50 % of the maximum response ( T50 % ) was compared as a measure of onset of action . Results : There was a progressive increase in PD20AMP during the 4 weeks of treatment with both fluticasone and budesonide but not placebo ; the increase after 1 and 4 weeks was 2.28 and 4.50 doubling doses ( DD ) for fluticasone and 2.49 and 3.65 DD for budesonide . T50 % was 9.3 days for fluticasone and 7.5 days for budesonide with a median difference between fluticasone and budesonide of 0.1 days ( 95 % CI −1.4 to 2.65 ) . There was a wide range of response to both inhaled corticosteroids but good correlation between the response to fluticasone and budesonide within subjects . FEV1 and morning peak expiratory flow rate ( PEFR ) increased during the first week of both active treatments and were stable thereafter . There was a small progressive improvement in nocturnal symptoms with both active treatments . Conclusion : PD20AMP was a more sensitive marker of response to inhaled corticosteroid therapy than FEV1 and PEFR . The time course of action of fluticasone and budesonide on PD20AMP is similar , suggesting that comparative studies of their efficacy using 1 or 2 week treatment periods are valid . When a new inhaled corticosteroid becomes available , a pilot study comparing its time course of action with that of an established corticosteroid should allow comparative studies to be performed more efficiently [12763981] Abstract Objectives To determine whether the dose of inhaled corticosteroids can be stepped down in patients with chronic stable asthma while maintaining control . Design One year , r and omised controlled , double blind , parallel group trial . Setting General practice s throughout western and central Scotl and . Participants 259 adult patients with asthma receiving regular treatment with inhaled corticosteroids at high dose ( mean dose 1430 μg beclomethasone dipropionate ) . Interventions Participants were allocated to receive either no alteration to their dose of inhaled corticosteroid ( control ) or a 50 % reduction in their dose if they met criteria for stable asthma ( stepdown ) . Main outcome measures Comparison of asthma exacerbation rates , asthma related visits to general practice and hospital , health status measures , and corticosteroid dosage between the two groups . Results The proportions of subjects with asthma exacerbations were not significantly different ( stepdown 31 % , control 26 % , P=0.354 ) . Similarly , the numbers of visits to general practice or hospital and the disease specific and generic measures of health status over the one year period were not significantly different . On average the stepdown group received 348 μg ( 95 % confidence interval 202 μgto494 μg ) of beclomethasone dipropionate less per day than the controls ( a difference of 25 % ) , with no difference in the annual dose of oral corticosteroids between the two treatment regimens . Conclusions By adopting a stepdown approach to the use of inhaled steroids at high doses in asthma a reduction in the dose can be achieved without compromising asthma control [10325897] BACKGROUND Inhaled corticosteroids are recognised as the most effective agents in the treatment of asthma . However , concerns have been expressed about the effects of high doses of inhaled corticosteroids on safety in relation to bone resorption and formation . This study measures the effects of two inhaled corticosteroids on bone markers and bone mineral density ( BMD ) over one year . METHODS A one year r and omised , prospect i ve , open parallel study comparing inhaled fluticasone propionate ( FP ) , 500 μg twice daily in 30 patients , and budesonide ( BUD ) , 800 μg twice daily in 29 patients , delivered by metered dose inhaler and large volume spacers was performed in adults with moderate to severe asthma . Biochemical markers of bone turnover ( osteocalcin , procollagen type 1 C-terminal propeptide ( PICP ) , immunoreactive free deoxypyridinoline ( iFDpd ) , N-terminal crosslinked telopeptides of type I collagen ( NTx ) ) , BMD at the spine and femoral neck , and serum cortisol concentrations were measured at baseline and 12 months later . RESULTS There were no significant differences between the inhaled steroids on bone markers of bone resorption and formation or bone mineral density . Bone mineral density of the spine increased slightly in both groups over the 12 month period . Serum osteocalcin levels increased from baseline in both treatment groups ( FP 16.9 % , p = 0.02 ; BUD 14.3 % , p = 0.04 ) . PICP did not differ significantly from baseline . Both markers of bone resorption ( iFDpd , NTx ) varied considerably with no significant changes after one year . There was a significant correlation in percentage change from baseline between BMD of the spine and osteocalcin at 12 months ( r = 0.4 , p = 0.017 ) . Mean serum cortisol levels remained within the normal range in both groups following treatment . CONCLUSION There was no evidence of a decrease in BMD during 12 months of treatment with high doses of either FP or BUD . The change in spine BMD correlated with the increase in osteocalcin . Studies extending over several years are needed to establish whether these findings persist [11555383] OBJECTIVE High-dose inhaled corticosteroids ( ICS ) have been associated with the same side-effects as oral corticosteroids . Beclomethasone dipropionate ( BDP ) and budesonide ( BUD ) in doses greater than 2000 microg/day are used regularly in severe asthma , despite the fact that safety and efficacy data at such high doses are limited . Fluticasone propionate ( FP ) has been promoted as being twice as potent clinical ly as BDP or BUD at doses of 2000 microg/day or less with a similar safety profile . The aim of this study was to compare the efficacy and safety of FP with BDP and BUD in 133 symptomatic adult asthmatics requiring at least 1750 microg/day of BDP or BUD . METHODOLOGY Patients fulfilling the entry criteria were r and omized to receive either their regular ICS medication or FP at approximately half the microgram dose for 6 months in an open , parallel group study . The primary efficacy measure was based on morning peak expiratory flow measurements recorded by patients on daily record cards , while determination of safety was based on a number of endpoints including changes in bone turnover indices , the incidence of topical side-effects and assessment s of quality of life . RESULTS It was shown that patients who were switched to FP , but not those continuing with BDP or BUD , had significant increases in levels of morning serum cortisol and the urine cortisol : creatinine ratio while maintaining asthma control . Serum osteocalcin and the pyridinoline : creatinine ratio , as well as the deoxypyridinoline : creatinine ratio , were also shown to increase only in the FP group . Subjective assessment s such as quality of life score , the incidence and ease of bruising , and reports of hoarseness also favoured the FP group . CONCLUSIONS It is concluded that , at the doses studied and with the delivery devices used clinical ly , FP is at least as effective as BDP/BUD in the management of severe asthma and may offer clinical advantages with respect to steroid-related adverse effects [9850348] Abstract : There is a dearth of data on long-term effects of inhaled corticosteroids ( ICS ) on bone architecture in childhood asthma . This study was design ed to assess the possible effects of two different inhaled steroids on bone mineral density ( BMD ) in steroid-native , prepubertal children . Twenty-three children were r and omized to receive equipotent doses of either fluticasone propionate ( 100 mg twice daily ) or beclomethasone dipropionate ( 200 mg twice daily ) . They were followed up over a period of 20 months with regular dual-energy X-ray absorptiometry scans for BMD . Densitometry of lumbar spine and total body showed a significant increase over time , which followed the normal patterns for growth . No difference was observed between the two subgroups . There was no change in fat distribution over time and no increase in percentage total body fat . As expected , girls had significantly higher total body fat . This absence of deleterious effects suggests that in the st and ard doses used neither beclomethasone nor fluticasone has any significant effect on bone density over a moderate period of time . Further studies should continue monitoring BMD through the critical years of bone mass accumulation during adolescence [10868712] This r and omized , double-blind , double-dummy , multicentre cross-over study compared the effects on the hypothalamic-pituitary-adrenal ( HPA ) axis of fluticasone propionate ( 750 microg twice daily given via the Diskus ) and budesonide ( 800 microg twice daily given via the Turbuhaler ) . Two treatment periods of 2 weeks each were preceded by a 2-week run-in period and separated by a 2-week washout period . During run-in and washout , patients received beclomethasone dipropionate ( BDP ) or budesonide at a constant dose of 1500 - 1600 microg day(-1 ) . Sixty patients aged 18 - 75 years with moderate to severe asthma not fully controlled by treatment with 1500 - 1600 microg day(-1 ) budesonide or BDP entered run-in and 45 completed the study . HPA axis suppression was assessed by morning serum cortisol ( area under the curve from 08.00 to 10.30 hours ) and 12-h nocturnal urinary cortisol excretion , measured at the end of run-in ( baseline 1 ) , at the end of washout ( baseline 2 ) , and at the end of each treatment period . Neither budesonide nor fluticasone produced significant suppression of either parameter compared to baselines . Only a few patients had serum-cortisol and urinary cortisol values below the normal range , before and after treatment . This shows that the patients did not have adrenal suppression before entering the study . The ratio between the AUC serum cortisol measured after fluticasone treatment and after budesonide treatment was 0.99 ( 95 % CI 0.92 - 1.06 ) , indicating equivalent effects on the HPA axis . This result was achieved after having omitted two patients ' results , due to their very sensitive reaction to budesonide , but not to fluticasone . Two exacerbations of acute asthma occurred during budesonide treatment and none during fluticasone treatment . Both treatments were well tolerated . In conclusion , budesonide 1600 microg day(-1 ) via Turbuhaler and fluticasone propionate 1500 microg day(-1 ) via Diskus had no clinical effects on the HPA axis in patients with moderate to severe asthma [12000495] In the treatment of asthma , inhaled steroids are more effective than cromolyn , whereas the latter offers extreme safety . The aim of the present pilot study was to evaluate , contemporarily , efficacy and safety aspects of different asthma treatment modalities . In 75 school-age children ( mean age 9.5 years ; range 5.5 - 14.7 years ) , treatment of asthma was started with budesonide ( BUD , n = 30 ) , fluticasone propionate ( FP , n = 30 ) or cromones ( CROM , n = 15 ) . BUD was used at a dose of 800 microg/day during the first 2 months and at 400 microg/day thereafter . The respective FP doses were 500 and 200 microg/day . Efficacy of the treatment was assessed by measuring forced expiratory volume in 1 second ( FEV1 ) and by evaluating the use of bronchodilators . Side-effects of the treatment were evaluated by following growth of the children and by performing low-dose adrenocorticotropin ( ACTH ) testing . At 4 months FEV1 had improved by a mean of 8.2 % in the BUD group and by 5.4 % in the FP group ( p < 0.01 vs. baseline in both groups ; NS between BUD and FP groups ) . The use of bronchodilators had decreased from five doses/week to one dose/week in the BUD group ( p < 0.05 ) , and from three doses/week to one dose/week in the FP group ( p < 0.01 ) ( NS between the groups ) . In the CROM group , the FEV1 value and the use of bronchodilators did not change . The treatment was unsuccessful on the basis of FEV1 decrease and increased bronchodilator use in , respectively , 30 and 15 % of the BUD- , 20 and 7 % of the FP- , and 50 and 47 % of the CROM-treated children . Therefore , to prevent one treatment failure in the CROM group , between three and five children would need to move to treatment with steroids . The treatment had measurable systemic effects on the basis of height st and ard deviation ( SD ) score decrease and minor adrenocortical suppression in , respectively , 60 and 30 % of the BUD- , 27 and 17 % of the FP- , and 20 and 0 % of the CROM-treated children . Therefore , to avoid systemic effects in one steroid-treated child , three BUD- and six to 14 FP-treated children would need to move to treatment with CROM . In conclusion , in school-age children asthma should be treated first with inhaled steroids . It is probable that the best combination of efficacy and safety can be achieved by using low steroid doses [8323338] Short-term lower leg growth was investigated with twice weekly knemometry measurements in 19 schoolchildren with mild asthma during treatment with daily doses of 200 micrograms fluticasone propionate , 400 micrograms , and 800 micrograms beclomethasone dipropionate from a dry powder inhaler . The design was a r and omised , double blind , crossover trial . After a run in period of four days ( period 1 ) the children were allocated to a sequence of active treatments in periods 2 , 4 , and 6 . In periods 3 and 5 ( wash out ) placebo was given . All periods except the run in were two weeks long . The mean lower leg growth velocities during the wash out periods were 0.61 and 0.80 mm/week . Mean growth velocities during treatment with fluticasone propionate and low and high doses of beclomethasone dipropionate were 0.34 , 0.09 , and 0.06 mm/week respectively . Compared with fluticasone propionate , treatment with beclomethasone dipropionate 400 and 800 micrograms/day was associated with a statistically significant reduction in growth velocity [11112113] Inhaled corticosteroids have become the mainstay treatment of bronchial asthma . However , simultaneous evaluations of efficacy and side effects are few . This study aim ed to compare the relative effect of fluticasone propionate ( FP ) and budesonide ( BUD ) on bronchial responsiveness and endogenous cortisol secretion in adults with asthma . The study was double-blind and included 66 adults with asthma , who were r and omized to FP ( n = 33 ) or BUD ( n = 33 ) . Pre study , all participants were clinical ly stable , using inhaled corticosteroids and hyperresponsive to methacholine . Eligible patients were r and omized to three consecutive 2-wk periods with either FP 250 microg twice daily , FP 500 microg twice daily , and FP 1,000 microg twice daily , or BUD 400 microg twice daily , BUD 800 microg twice daily , and BUD 1,600 microg twice daily , delivered by Diskhaler and Turbuhaler , respectively . Before r and omization and at the end of each treatment , bronchial methacholine PD(20 ) , 24-h urinary cortisol excretion ( 24-h UC ) , plasma cortisol , serum osteocalcin , and blood eosinophils were determined . The relative PD(20 ) potency between FP and BUD was 2.51 ( 95 % CI , 1.05 - 5.99 ; p < 0 . 05 ) , while the relative 24-h UC potency was 0.60 ( 95 % CI , 0.44 - 0.83 ; p < 0.01 ) . The differential therapeutic ratio ( FP/BUD ) based on PD(20 ) potency and 24-h UC was 4.18 ( 95 % CI , 1.16 - 15.03 ; p < 0.05 ) . The difference in systemic potency was also seen for plasma cortisol , serum osteocalcin , and blood eosinophils . Therapeutic ratio over a wide dose range , determined by impact on bronchial responsiveness and endogenous corticosteroid production , seems to favor FP [8215522] This study was design ed to compare the efficacy and safety of a new inhaled corticosteroid , fluticasone propionate at a total daily dose of 200 micrograms , with beclomethasone dipropionate 400 micrograms/day in childhood asthma . A total of 398 asthmatic children ( aged 4 - 19 years ) were r and omised to receive either fluticasone propionate 200 micrograms daily or beclomethasone dipropionate 400 micrograms daily for six weeks inhaled via a spacer device from a metered dose inhaler . During the study the patients recorded morning and evening peak expiratory flow rate ( PEFR ) , symptom scores , and use of beta 2 agonist rescue medication . In addition , clinic visit PEFR and forced expiratory volume in one second were measured . Safety was assessed by recording all adverse events and by performing routine biochemistry and haematology screens including plasma cortisol concentration before and after treatment . For the purpose s of analysis the diary card data were grouped into three periods : week 3 ( days 15 - 21 ) , week 6 ( days 36 - 42 ) , and weeks 1 - 6 ( days 1 - 42 ) . The results showed no significant difference between treatments on most efficacy parameters . However , there were significant differences in changes from baseline in favour of fluticasone propionate for % predicted morning PEFR both at week 3 ( fluticasone propionate 6.1 % , beclomethasone dipropionate 3.9 % ) and at week 6 ( fluticasone propionate 8.3 % , beclomethasone dipropionate 5 . 9 % ) and % predicted evening PEFR at week 6 ( fluticasone propionate 7.3 % , beclomethasone dipropionate 4.9 % and over weeks 1 - 6 ( fluticasone propionate 5.5 % , beclomethasone dipropionate 3.6 % . Comparison between groups showed that the group receiving fluticasone propionate had a lower % of days with symptom-free exercise at week 6 ( fluticasone propionate 87 % , beclomethasone dipropionate 81 % ) and % days without rescue medication at week 6 ( fluticasone propionate 87 % , beclomethasone dipropionate 80 % ) and over weeks 1 - 6 ( fluticasone propionate 80 % , beclomethasone dipropionate 73 % ) . Except for a higher incidence of sore throat in the fluticasone propionate group , the two treatments did not differ with regard to safety . There was no evidence of adrenal suppression with either treatment . In conclusion , fluticasone propionate 200 microgram daily ws at least as effective and as well tolerated as beclomethasone dipropionate 400 microgram daily in childhood asthma [8706770] The systemic effects of single and multiple doses of inhaled fluticasone propionate ( FP ) and budesonide were examined in 24 healthy male volunteers ( age range 18–29 years ) . The study was of an open , placebo-controlled , r and omized , three-way crossover design . On each study day , multiple blood sample s were taken over a 20 h period after drug administration ( after a single dose and after the last of seven doses ) and area under the curve ( AUC0–20 ) for plasma cortisol and white blood cell ( WBC ) counts was calculated . Results : The present study shows that multiple dosing with FP 1.0 mg b.i.d . for 3.5 days ( seven doses ) result ed in a marked cortisol suppression from placebo which , at 55 % , was more than double that seen with a single dose ( 25 % suppression ) . Multiple dosing with budesonide 0.8 mg b.i.d . result ed in a 34 % suppression in plasma cortisol compared with a suppression of 26 % with a single dose . The increase in systemic activity of FP after multiple dosing is confirmed by both the number of subjects with 0800 hours plasma cortisol values below normal limits and by the changes in WBC and differential counts . Conclusion : The results of the present study confirm previous findings with regard to the more marked systemic effect of FP following multiple dosing as compared with a single dose . This increase in systemic effect from single dosing to multiple dosing is significantly greater for FP than for budesonide [9700034] Bronchial inflammation plays a central role in asthma . We investigated whether parameters of inflammation were increased in peripheral blood . Furthermore , we tested whether fluticasone propionate ( FP ) , a new inhaled corticosteroid ( ICS ) , and beclomethasone dipropionate ( BDP ) affected these parameters . FP 750 μg/day and BDP 1500 μg/day were compared in a r and omized , crossover study consisting of two 6‐week treatment periods , each preceded by a 3‐week placebo period . Twenty‐one patients with symptomatic asthma completed the study . The results were compared with those of six normal subjects ( controls ) . Immunophenotyping of inflammatory cells was performed in whole blood , and serum eosinophil cationic protein ( ECP ) was measured . With regard to clinical efficacy , ICS increased PCjo histamine by more than 1.9 doubling doses and FEV , by more than 0.34 1 . The number of CD3/HLA‐DR+ lymphocytes was significantly increased in asthmatics compared to the normal subjects , both after placebo ( P<0.01 ) and after therapy ( P<0.05 ) . The CD3/HLA‐DR‐H lymphocytes decreased significantly after treatment with FP ( P<0.05 ) . Serum ECP was elevated in patients without ICS and decreased after treatment with BDP ( P<0.001 ) . In conclusion , the number of CD3/HLA‐DR‐I‐ lymphocytes and serum ECP levels were raised in the peripheral blood of symptomatic asthmatics , and decreased by clinical ly effective doses of ICS . In this respect , FP 750 ng/day was at least as effective as BDP 1500 μg/day [18370529] Abstract Objective : The objective of this study was to assess the relative cost effectiveness of fluticasone via metered dose inhaler and budesonide via Turbuhaler ® in corticosteroid-naive patients with moderate asthma from a third-party payer perspective ( German Sickness Funds ) . Patients and Methods : A retrospective economic assessment of direct medication costs of treatment was performed on data from a prospect i ve , r and omised , parallel group , 6-week clinical trial . 457 corticosteroid-naive patients between the ages of 18 and 70 years with moderate asthma were included in the intention-to-treat analysis . Results : The fluticasone group had a higher proportion of successfully treated patients ( those with a peak expiratory flow rate improvement of ≥10 % ) [ 47 vs 42 % ] , a higher average proportion of symptom-free days ( 40 vs 34 % ) and lower direct healthcare costs [ 1997 Deutschmarks ( DM ) ] per day ( DM4.23 vs DM5.19 ) than the budesonide group . Therefore , the daily costs per successfully treated patient ( DM9.00 vs DM12.36 ) and the cost per symptom-free day ( DM10.58 vs DM15.26 ) were both lower with fluticasone than with budesonide . Sensitivity analysis demonstrated that these results were relatively robust over a wide range of plausible assumptions . Conclusion : These results showed that from the perspective of a third-party payer , fluticasone was more cost effective than budesonide over the 6-week study period [11379810] BACKGROUND Inhaled corticosteroids provide first-line treatment for asthma . An advance to improve potency was to produce new molecules with increased glucocorticoid receptor affinity ( eg , fluticasone propionate [ FP ] ) . An alternative is to deliver more medication to both the large and small airway inflammation of asthma by using an extrafine aerosol ( eg , beclomethasone dipropionate extrafine aerosol [ BDP-extrafinel ) . OBJECTIVE To demonstrate clinical equivalence of BDP-extrafine ( 400 microg daily ) and FP ( 400 microg daily ) in symptomatic asthmatic patients over the course of 6 weeks . METHODS This was a double-blind , double-dummy , parallel-group , multicenter , 6-week study in adults with asthma taking conventional FP 100 to 250 microg daily or equivalent , and displaying signs/symptoms of active disease requiring additional therapy . RESULTS Eighty-eight patients were r and omized to BDP-extrafine ( and FP-placebo ) and 84 to FP ( and BDP-placebo ) . There were no significant differences between treatments with respect to symptom control , as evidence d by mean change from baseline in percentage days without asthma symptoms/nights without sleep disturbance observed at weeks 1 to 2 , 3 to 4 , or 5 to 6 . Mean changes from baseline in AM PEFR at weeks 5 to 6 for BDP-extrafine ( 19.0 ) and FP ( 30.5 ) were equivalent ( P = 0.022 for equivalence ) . There were significant ( P < 0.001 ) within-treatment-group differences in mean change from baseline in AM PEFR at weeks 1 to 2 for both treatments . There was no difference in the incidence of patients reporting at least one adverse event during the study ( BDP-extrafine 41 % ; FP 37 % ) . Mean percentage change from baseline for AM plasma cortisol at week 6 was + 17.7 % for BDP-extrafine and + 4.2 % for FP ( P = 0.066 for difference ) . CONCLUSIONS BDP-extrafine and FP at doses of 400 microg daily provided equivalent asthma control in patients with symptomatic asthma and exhibited similar safety profiles [8092438] A total of 261 patients with symptomatic , mild to moderate asthma were r and omized to treatment in this 4‐week , double‐blind , parallel‐group comparison of fluticasone propionate 200 μg/d with beclomethasone dipropionate 400 μg/d . Improvements from both treatments were seen in diary card data . Morning peak expiratory flow rate ( PEFR ) improved from 375 to 390 and 371 to 382 1/min with fluticasone propionate and beclomethasone dipropionate , respectively . Symptom scores , percentage of symptom‐free days and nights , and use of rescue ( β2‐agonist medication also improved , as did clinical lung function . With the exception of percentage of rescue‐free days , which was greater for beclomethasone dipropionate , none of the differences between the groups were statistically significant . There was a significant difference between treatments in the number of rescue‐free days over days 1–28 ; however , there was no difference between treatments in the number of rescue‐free days over days 1‐14 , nor was there any difference in the number of inhalations of rescue medication used throughout the study . Very few adverse effects were reported . Although all mean plasma cortisol values were within the normal range , they were significantly different between treatments , rising from 402 to 429 nmol/1 with fluticasone propionate , and falling from 435 to 394 nmol/1 with beclomethasone dipropionate ( P= 0.006 ) . Mean stimulated cortisol levels 30 min after tetracosactin injection were also significantly greater with fluticasone propionate ( P = 0.024 ) . In conclusion , fluticasone propionate 200 μg/d is as effective as beclomethasone dipropionate 400 μg/d with less effect on plasma cortisol levels [7491551] BACKGROUND --Fluticasone propionate is a new inhaled corticosteroid with a 2:1 efficacy ratio compared with beclomethasone dipropionate with regard to lung function and symptom scores , without increased systemic activity . The aim of this study was to investigate whether this was also the case for bronchial hyperresponsiveness , assessed by both a direct ( histamine ) and an indirect ( ultrasonically nebulised distilled water ( UNDW ) ) provocation test . METHODS --Fluticasone propionate , 750 micrograms/day , and beclomethasone dipropionate , 1500 micrograms/day , were compared in a r and omised , double blind , crossover study consisting of two six week treatment periods , each preceded by a three week single blind placebo period . Twenty one non-smoking asthmatics ( mean forced expiratory volume in one second ( FEV1 ) 74.7 % predicted , mean PC20histamine 0.36 mg/ml ) completed the study . RESULTS --Fluticasone propionate and beclomethasone dipropionate improved FEV1 , peak flow rates , asthma symptoms , and bronchial hyperresponsiveness to the same extent . Both fluticasone propionate and beclomethasone dipropionate caused an increase in PC20histamine ( mean 2.29 [ 95 % confidence interval 1.45 to 3.13 ] and 1.95 [ 1.07 to 2.84 ] doubling doses , respectively ) and in PD20UNDW ( 1.12 [ 0.55 to 1.70 ] and 1.28 [ 0.88 to 1.70 ] doubling doses , respectively ) . Neither treatment changed morning serum cortisol levels , but fluticasone propionate decreased the number of peripheral blood eosinophils less than beclomethasone dipropionate , indicating smaller systemic effects of fluticasone propionate . CONCLUSIONS --These findings show that fluticasone propionate is as effective as twice the dose of beclomethasone dipropionate on bronchial hyperresponsiveness , assessed by provocation with both histamine and UNDW , without increased systemic activity [9215245] BACKGROUND New inhaled glucocorticosteroids and inhalers are being developed . Their clinical equipotency is difficult to assess and is often discussed . OBJECTIVE This study was carried out to compare the effect of budesonide Turbuhaler and fluticasone propionate ( FP ) Diskhaler in a dose reduction study in children ( ages 5 to 16 years ) with asthma . METHODS Children treated with budesonide administered through a pressurized metered-dose inhaler with a large volume spacer had their budesonide dose gradually reduced to define the minimal effective dose with this delivery system . After this period , 217 children were r and omly allocated to treatment with half the dose of either budesonide Turbukaler or FP Diskhaler for 5 weeks in a double-blind trial . If no deterioration in asthma control was seen , the dose was further reduced by 50 % at 5-week intervals until deterioration in asthma control was seen . Throughout the study , morning and evening peak expiratory flow , symptoms , and use of rescue beta 2-agonist were recorded in diaries . Lung function tests and a st and ardized exercise test were performed at the clinic at the end of each treatment period . Urine cortisol excretion ( 24 hours ) was measured before and after the first 5-week treatment period . St and ardized criteria for deterioration in asthma control , based on diary card variables and exercise testing , were used to determine the minimal effective dose for each patient ; and from this , the number of dose reduction steps was calculated . RESULTS No statistically significant difference was seen in number of dose reduction steps from baseline or in minimal effective dose between the two treatments ; mean reduction was 1.59 dose steps for budesonide Turbuhaler and 1.65 dose steps for FP Diskhaler ( p = 0.52 ) , and minimal effective dose was 188 micrograms for budesonide Turbuhaler and 180 micrograms for FP Diskhaler . After these dose reductions , the same level of asthma control was observed in the budesonide Turbuhaler and FP Diskhaler groups . Furthermore , no statistically significant differences between the two inhaler-drug combinations were seen in daytime or nighttime symptoms , morning and evening peak expiratory flow , use of rescue beta 2-agonist , lung functions at the clinic , exercise-induced fall in lung function , or 24-hour urinary cortisol excretion during the first 5-week period . CONCLUSION Microgram for microgram , budesonide Turbuhaler and FP Diskhaler are equally effective in treatment of children with moderate asthma [8984708] BACKGROUND : The aim of this study was to compare the systemic bioactivity of inhaled budesonide ( B ) and fluticasone propionate ( F ) , each given by large volume spacer , on a microgram equivalent basis in asthmatic children . METHODS : Ten stable asthmatic children of mean age 11 years and forced expiratory volume in one second ( FEV1 ) 81.6 % predicted , who were receiving treatment with < or = 400 micrograms/day of inhaled corticosteroid , were studied in a placebo controlled single blind ( investigator blind ) r and omised crossover design comparing single doses of inhaled budesonide and fluticasone propionate 400 micrograms , 800 micrograms , and 1250 micrograms . Doses were given at 20.00 hours with mouth rinsing and an overnight 12 hour urine sample was collected for estimation of free cortisol and creatinine excretion . RESULTS : The results of overnight 12 hour urinary cortisol output ( nmol/12 hours ) showed suppression with all doses of fluticasone propionate ( as geometric means ) : F400 micrograms ( 11.99 ) , F800 micrograms ( 6.49 ) , F1250 micrograms ( 7.00 ) compared with placebo ( 24.43 ) , whereas budesonide caused no suppression at any dose . A comparison of the drugs showed that there were differences at 800 micrograms and 1250 micrograms levels for urinary cortisol : B800 micrograms versus F800 micrograms ( 2.65-fold , 95 % CI 1.26 to 5.58 ) , B1250 micrograms versus F1250 micrograms ( 2.94-fold , 95 % CI 1.67 to 5.15 ) . The results for the cortisol/creatinine ratio were similar to that of urinary cortisol , with fluticasone causing suppression at all doses and with differences between the drugs at 800 micrograms and 1250 micrograms . CONCLUSIONS : Single doses of inhaled fluticasone produce greater systemic bioactivity than budesonide when given by large volume spacer on a microgram equivalent basis in asthmatic children . The systemic bioactivity of fluticasone , like budesonide , is due mainly to lung bioavailability [10542974] The purpose of this study was to investigate the comparative efficacy and safety of equal doses of inhaled fluticasone propionate ( FP ) and inhaled budesonide ( BUD ) using their respective dry powder inhalers in a population of severe asthmatics requiring high doses of inhaled corticosteroid . This double-blind double-dummy parallel-group study compared the effects of 24 weeks of treatment with FP ( 2000 micrograms daily via a Diskhaler inhaler ; Glaxo Wellcome , Evreux , France ) and BUD ( 2000 micrograms daily via a Turbuhaler inhaler ; Astra Pharmaceuticals , Rijswijka , Netherl and s ) on lung function and asthma exacerbations in 395 patients with asthma . FP was statistically significantly superior to BUD with respect to the percentage of symptom-free days ( P = 0.02 ) , the incidence of days free from rescue bronchodilator usage ( P = 0.02 ) and the distribution of change in peak expiratory flow ( PEF ) expressed as a percentage of the predicted PEF ( P = 0.04 ) . During the treatment period FP was statistically significantly superior to BUD for change in forced expiratory volume in 1 sec ( FEV1 ) at 8 , 16 and 24 weeks , change in the median daytime symptom score during weeks 5 - 16 , for incidence of symptom-free days and incidence of days free from rescue bronchodilator usage during weeks 17 - 24 . There was no significant difference between FP and BUD with respect to the number of patients experiencing one or more asthma exacerbation ( 33.8 and 28.4 % of patients , respectively ) . There was , however , evidence that the exacerbations were clinical ly less severe in patients treated with FP , in that the time to resolution was quicker ( 11.0 vs. 14.7 days ; P = 0.035 ) , mean duration of all exacerbations ( for an individual patient ) tended to be shorter ( 18.5 vs. 23.6 days ; P = 0.12 ) , the time off work was reduced ( 4.2 vs. 7.6 days ; P = 0.012 ) and the lowest PEF recorded during the exacerbation was higher ( 301 vs. 263 l min-1 ; P = 0.07 ) . There were no clinical ly relevant differences in the safety ( serum cortisol levels , markers of bone turnover , adverse events ) of FP and BUD at these microgram equivalent doses . The patients recruited into this study , in retrospect , probably had no need for such high doses of inhaled corticosteroid but , irrespective of this , FP at microgram equivalent doses showed evidence of superior efficacy to BUD with respect to lung function and severity of asthma exacerbations without producing any greater adverse systemic effect [9337826] BACKGROUND In a previous single dosing study in asthmatic school children fluticasone propionate produced significantly greater suppression of overnight urinary cortisol excretion than budesonide at high doses of 800 micrograms/day or greater . The aim of this study was to assess whether conventional lower doses of both drugs cause adrenal suppression when given at steady state twice daily by large volume spacer on a microgram equivalent basis in asthmatic school children . METHODS Eight school children of mean age 12.1 years with stable asthma of mild to moderate severity ( forced expiratory volume in one second ( FEV1 ) 78.6 % predicted , mid forced expiratory flow rate ( FEF25 - 75 ) 72.5 % predicted ) , on 400 micrograms/day or less of inhaled corticosteroid , were studied in a single blind ( investigator blind ) , placebo controlled , crossover design comparing inhaled budesonide and fluticasone propionate 100 micrograms bid and 200 micrograms bid . Each dose was given at 08.00 hours and 20.00 hours for four days by metered dose inhaler via their respective large volume spacers with mouth rinsing . Measurements were made of overnight urinary cortisol and creatinine excretion after the eighth dose . RESULTS Neither drug produced significant suppression of overnight urinary cortisol or cortisol/creatinine excretion compared with pooled placebo and there were no differences between the drugs . Only one subject with each drug at 200 micrograms twice daily had abnormally low urinary cortisol excretion of < 10 nmol/12 hours . Ratios for the fold difference between active treatment versus placebo for urinary cortisol excretion were ( as means and 95 % confidence intervals for difference ) : budesonide 100 micrograms b.i.d 1.03 ( 95 % CI 0.46 to 1.61 ) , budesonide 200 micrograms b.i.d 1.04 ( 95 % CI 0.62 to 1.46 ) ; fluticasone 100 micrograms b.i.d 1.11 ( 0.45 to 1.77 ) , fluticasone 200 micrograms b.i.d 1.12 ( 0.78 to 1.47 ) . Likewise , there were no significant differences in overnight urinary cortisol/creatinine excretion . CONCLUSIONS With repeated twice daily administration at steady state across a dose range of 200 - 400 micrograms/day no evidence of significant adrenal suppression was found using the sensitive marker of overnight urinary cortisol excretion for either fluticasone propionate or budesonide given via a large volume spacer . These results emphasise the good safety profile in children of these inhaled steroids at conventional dose levels , which have proven antiasthmatic efficacy [9616537] The inhaled corticosteroid fluticasone propionate ( FP ) was introduced into the Thorpewood General Practice , Norwich , U.K. in 1993 -initially in treating relatively severe asthmatics . Observed beneficial effects led to exp and ed use particularly for poorly controlled asthma not responsive to increased inhaled anti-inflammatories . However , an early review suggested little advantage over existing agents ( l ) , and FP was marketed at a price premium . The aims of this study were to investigate whether continued and exp and ing use of FP was justified in terms of improved clinical outcomes , and if such improvements were associated with reduced NHS costs ( off setting more expensive prescriptions ) . A controlled , retrospective , nonr and omized primary care audit compared clinical outcomes and asthma management costs 1 year prior to and 1 year into FP therapy [10390394] We assessed the systemic effects of budesonide ( BUD ) and fluticasone propionate ( FP ) in 23 patients with asthma , using a double-blind , placebo-controlled , double-dummy , and cross-over design . The following five treatments were given in a r and omized order for 1 wk with a washout period in between of 2 wk : ( 1 ) placebo ; ( 2 ) FP , 200 micrograms twice a day , inhaled from a Diskhaler ; ( 3 ) FP , 1,000 micrograms twice a day , inhaled from a Diskhaler ; ( 4 ) BUD , 200 micrograms twice a day , inhaled from a Turbuhaler ; and ( 5 ) BUD , 800 micrograms twice a day , inhaled from a Turbuhaler . The primary variable was the area under the curve of serum cortisol versus time ( AUC0 - 20 ) , derived from serum sample s taken every 2 h over a 20-h period following the last evening dose at 10:00 P.M. The lower doses of BUD and FLU did not cause any adrenal suppression . Compared with placebo , however , FP ( 1 , 000 micrograms , twice daily and BUD ( 800 micrograms , twice daily ) decreased the AUC0 - 20 by 34 and 16 % , respectively . Fluticasone ( 1,000 micrograms , twice daily ) was more suppressive than BUD ( 800 micrograms , twice daily ) ( p = 0.0006 ) . The FEV1 , measured the morning after the last inhalation , was significantly higher after the active treatments , compared with placebo ( p < 0.02 ) , but did not differ between all active treatments . We conclude that high doses of BUD and FP ( in particular the latter ) , inhaled via their respective dry powder inhalers for 1 wk , result in a measurable systemic activity in patients with asthma [8959118] This study was design ed primarily to assess the safety and tolerability of fluticasone propionate ( FP ) 1 mg day-1 by comparison with beclomethasone dipropionate ( BDP ) 2 mg day-1 over a 12-month study period . Lung function data were also recorded and used to determine whether the potency ratio between the two inhaled corticosteroids observed in previous studies was maintained in the long-term . Two hundred and thirteen patients with an established clinical history of severe chronic asthma and who were currently receiving between 1000 micrograms and 2000 micrograms day-1 of inhaled steroids were r and omized to treatment in a ratio of 3:1 for FP : BDP ( 159 patients FP ; 54 patients BDP ) , both via metered dose inhalers . Both treatments were well tolerated with a similar adverse event profile . No unexpected adverse events were recorded . Most adverse events were related to the patients ' asthma , an intercurrent infection or underlying atopy . The incidence of pharmacologically predictable adverse events was equally low in both treatment groups as was the incidence of events suggestive of systemic steroid effect . Mean serum cortisol levels remained within the normal range at all visits for both treatments . At 12 months , however , the mean cortisol levels for the FP group had risen 4 % above the baseline value but had dropped 15 % below for the BDP group , giving a ratio of FP : BDP of 1.22 ; P = 0.01 ; 95 % confidence limits ( CL ) 1.05 - 1.43 . Fluticasone propionate 1 mg day-1 was at least as effective as BDP 2 mg day-1 in improving lung function ( PEF , FEV1 and FVC ) over this period . Moreover , the difference in FEV1 values at 6 months was significantly greater for the FP group than for the BDP group ( P = 0.04 ; difference = 0.12 1 ; 95 % CL = 0.01 , 0.24 1 ) . The difference between treatments in the amount of FEV1 reversibility was also significantly greater for FP at 12 months ( difference in treatments = -3 % ; 95 % CL = - 7 - 0 % ; P = 0.044 ) . This study supports previous studies and suggests that FP is likely to be of benefit in the long-term treatment of chronic severe asthma [10329812] BACKGROUND Inhaled corticosteroids are recommended for the treatment of persistent asthma . Comparative clinical studies evaluating 2 or more doses of these agents are few . OBJECTIVE We sought to compare the efficacy and safety of 2 doses of fluticasone propionate ( 88 micrograms twice daily and 220 micrograms twice daily ) with 2 doses of beclomethasone dipropionate ( 168 micrograms twice daily and 336 micrograms twice daily ) in subjects with persistent asthma . METHODS Three hundred ninety-nine subjects participated in this r and omized , double-blind , parallel-group clinical trial . Eligible subjects were using daily inhaled corticosteroids and had an FEV1 of 45 % to 80 % of predicted value . Clinic visits , including spirometry , were conducted every 1 to 2 weeks . Subjects recorded symptoms , use of albuterol , and peak expiratory flows on daily diary cards . RESULTS Fluticasone propionate treatment result ed in significantly ( P < /=.034 ) greater improvements in objective pulmonary function parameters than did beclomethasone dipropionate treatment and significantly greater reductions in daily albuterol use ( P < /=.010 ) and asthma symptoms ( P < /=.027 ) . Both low-dose ( 88 micrograms twice daily ) and medium-dose ( 220 micrograms twice daily ) fluticasone propionate significantly increased FEV1 compared with higher doses of beclomethasone dipropionate ( P = . 006 ) . Low-dose and medium-dose fluticasone propionate improved FEV1 by 0.31 L ( 14 % ) and 0.36 L ( 15 % ) , respectively , compared with improvements of 0.18 L ( 8 % ) and 0.21 L ( 9 % ) with low-dose and medium-dose beclomethasone dipropionate . The adverse event profiles were similar for both medications . CONCLUSION Fluticasone propionate provides greater asthma control at roughly half the dose of beclomethasone dipropionate , with a comparable adverse event profile [10190915] OBJECTIVE To compare the efficacy and adverse effects of inhaled fluticasone propionate ( FP ) , 400 microgram/d , with those of budesonide ( BUD ) , 800 microgram/d , in children with moderate to severe asthma . METHODS Three hundred thirty-three children , ages 4 to 12 years , receiving inhaled corticosteroids were enrolled in a double-blind , double-dummy , r and omized , parallel-group study . After a 2-week run-in phase , 166 children received FP and 167 received BUD for 20 weeks . The primary outcome variable was mean morning peak expiratory flow ; the 2 treatments were to be regarded as equivalent if the 90 % CI for the treatment difference was within + /- 15 L/min . Pulmonary function , height , and diary cards were assessed at each visit ; and morning serum cortisol levels were determined before and after treatment . RESULTS Baseline peak expiratory flow was similar , FP 236 + /- 72 ( SD ) L/min and BUD 229 + /- 74 , increasing after treatment to 277 + /- 41 and 257 + /- 28 , a difference between treatments of 12 L/min ( 90 % CI 6 - 19 L/min ; P = .002 ) . Symptom control and use of rescue medication were the same . Cortisol levels after treatment were 199 nmol/L ( FP ) and 183 nmol/L ( BUD ) ( treatment ratio = 1.09 ; 90 % CI 0.98 - 1.21 ; P = .172 ) . Linear growth was less in those receiving BUD ( mean difference , 6.2 mm ; 95 % CI 2.9 - 9.6 ; P = .0003 ) . CONCLUSION FP at half the dose was superior to BUD in improving peak expiratory flow and comparable in controlling symptoms . Growth was reduced with BUD compared with FP , but there was no difference in serum cortisol suppression or hepatic or renal function [9519234] The efficacy and tolerability of fluticasone propionate ( FP ) 2 mg daily via a metered-dose inhaler and Volumatic ( Glaxo Wellcome ) spacer device was compared with nebulized budesonide ( nBUD ) , 2 and 4 mg daily , in a multi-centre , open-label , cross-over study of adult asthmatics . Patients received , in r and om order , either 4 weeks of treatment with FP followed by 4 weeks of treatment with nBUD , or vice versa , with an intervening 4 week ' wash-out ' period between treatments . Thirty patients completed the study , of whom 24 were evaluable . In terms of the primary efficacy parameter , change in mean morning peak expiratory flow ( PEF ) ( l min-1 ) from baseline to the fourth week of each treatment period , FP was more effective than nBUD [ mean difference ( FP-nBUD ) 21.1 l min-1 , P = 0.007 , 95 % CI ( 6.5 , 35.7 ) ] . Sub-group analysis demonstrated FP to be superior to the 4 mg nBUD [ mean treatment difference ( FP-nBUD ) 42.9 l min-1 , P = 0.026 , 95 % CI ( 7.1 , 78.8 ) ] and at least as efficacious as the 2 mg nBUD sub-group [ mean treatment difference ( FP-nBUD ) 10.2 l min-1 , P = 0.211 , 95 % CI ( -6.5 , 26.9 ) ] . Furthermore , larger reductions in diurnal variation were observed during FP treatment [ mean treatment difference ( FP-nBUD ) -4.4 percentage points , P = 0.028 , 95 % CI ( -8.4 , -0.5 ) ] . There was no significant difference between the treatments for the proportion of symptom-free 24 h periods . Of those expressing a preference , significantly more patients found FP via a metered-dose inhaler and spacer device both easier to administer ( 78 % , P = 0.007 ) and more convenient to take ( 76 % , P = 0.008 ) than nebulized budesonide . In addition , cost per patient analysis showed that nebulized budesonide was from 1.7 to 3.5 times more expensive than FP [9131947] AIMS The present study was undertaken to see whether the difference in plasma cortisol suppression between single and repeated dosing of fluticasone propionate ( FP ) can be explained by systemic accumulation . METHODS Twelve healthy subjects ( six women ) were given , in a crossover fashion , a single dose inhalation ( 1000 micrograms ) of FP via Diskhaler and repeated inhalations ( 1000 micrograms twice daily ) every 12 h during 7 days . There was a washout period of 2 weeks between the treatments . An intravenous dose of 20 micrograms FP was given as a reference . Plasma concentrations of FP for each treatment were determined by liquid chromatography plus t and em mass spectrometry . Plasma cortisol after the inhaled doses was determined using an immunoassay and was compared with baseline values . RESULTS The average plasma concentration of FP was about 1.7 times higher after multiple inhalations than after a single dose . Systemic availability , mainly attributable to pulmonary deposition , was 15.6 [13.6 - 18.0]% of the nominal dose . Daytime plasma cortisol suppression vs baseline was 47 [20 - 65]% and 95 [93 - 97]% for the single and repeated doses , respectivley . CONCLUSIONS To conclude , a slow elimination of FP leads to accumulation during repeated dosing . This accumulation may explain the marked decrease in plasma cortisol seen during treatment with fluticasone propionate within the clinical dose range [12911833] OBJECTIVE Changes in health-related quality of life ( HRQoL ) were evaluated in adults with severe asthma following inhaled corticosteroid treatment with high-dose beclomethasone dipropionate or budesonide ( BDP/BUD ) and compared with fluticasone propionate taken at approximately half the dose of BDP/BUD . METHODOLOGY HRQoL was assessed as part of an open , multicentre , r and omized , parallel-group study in Australia evaluating the safety and efficacy of switching to fluticasone propionate ( FP ) 1000 - 2000 micro g/day ( n = 67 ) compared with remaining on BDP/BUD > /=1750 micro g/day ( n = 66 ) for 6 months . Patients completed two HRQoL question naires , the Asthma Quality of Life Question naire ( AQLQ ) and the Medical Outcomes Study Short Form-36 ( SF-36 ) , at baseline and at weeks 12 and 24 . A change in AQLQ score of > /=0.5 was considered to be clinical ly meaningful . RESULTS There were significant improvements in HRQoL with FP on four of the eight dimensions on the SF-36 ( i.e. physical functioning , general health , role-emotional , and mental health ) , while there were no significant improvements in HRQoL in the BDP/BUD group . Overall , patients in the FP group experienced significantly greater improvement ( P < 0.001 ) in AQLQ scores at weeks 12 and 24 compared with the BDP/BUD group . On the individual domains of the AQLQ , there were significant treatment differences ( P < 0.01 ) in favour of FP in three of the four domains ( activity limitations [ 0.92 ] , symptoms [ 0.73 ] , and emotional function [ 1.02 ] ) . Mean differences between groups for overall score and these three domains were also clinical ly meaningful . CONCLUSION Patients with severe asthma who received FP ( at approximately half the dose of BDP/BUD ) experienced statistically significant , as well as clinical ly meaningful , improvements in their [8979288] Correlations between knemometric ( lower leg length ) growth rates and urine free cortisol excretion , respectively , and serum concentrations of IGF-I , IGF binding protein-3 , osteocalcin , carboxy terminal propeptide of type I collagen(PICP ) , carboxy terminal pryridinoline cross-linked telopeptide of type I procollagen ( ICTP ) , and amino terminal propeptide of type III procollagen(PIIINP ) were investigated in 17 asthmatic children aged 7 - 14 y during treatment with fluticasone propionate , 200 μg , and beclomethasone dipropionate , 400 and 800 μg/d , taken from dry powder inhalers . The study was a double blind , crossover trial with three active treatment periods and two wash-out periods . All periods were 15 d long . Overnight urine free cortisol/creatinine × 106 did not correlate with knemometric growth rates or any of the serum markers . Significant correlations ( Pearson 's correlation coefficient , P ) between knemometric growth rates and IGF-I ( 0.41 ; 0.006 ) , IGFBP-3 ( 0.35 ; 0.02 ) , PICP ( 0.44 ; 0.003 ) , ICTP ( 0.35 ; 0.001 ) , and PIIINP ( 0.46 ; 0.002 ) were found . Compared with fluticasone propionate , 200 μg , beclomethasone dipropionate , 400 and 800 μg , caused significant suppression of lower leg growth rate ( F = 12.41;p = 0.002 , and F = 23.30 ; p = 0.0001 , respectively ) and of urine free cortisol/creatinine × 106(F = 10.52 ; p = 0.003 , and F = 13.74;p = 0.001 ) . Beclomethasone , 800 μg , caused suppression of PICP compared with fluticasone propionate , 200 μg ( F = 8.31;p = 0.008 ) , and beclomethasone , 400 μg ( F = 7.53;p = 0.01 ) . Both low ( F = 6.82 ; p = 0.02 ) and high ( F = 23.35 ; p = 0.0001 ) doses of beclomethasone were associated with reduced concentrations of ICTP , the high dose being the most suppressive ( F = 4.42 ; p = 0.05 ) . Beclomethasone 400(F = 9.75 ; p = 0.004 ) and 800 μg ( F = 23.61;p = 0.0001 ) result ed in reduced levels of PIIINP . Reduced short-term knemometric growth rates in children treated with inhaled glucocorticosteroids reflect suppressive effects on type I and type III collagen turnover

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### Context: [12171841] OBJECTIVES To compare the therapeutic ratio of chlorofluorocarbon ( CFC ) and hydrofluoroalkane-134a ( HFA ) formulations of fluticasone propionate ( FP ) . METHODS We performed a r and omized , placebo-controlled , crossover study comparing 6 weeks of treatment with FP using 500 micro g/d and 1,000 microg/d formulations of CFC and HFA . The primary end points were provocative dose of methacholine causing a 20 % fall in FEV1 ( PD20 ) and overnight urinary cortisol/creatinine excretion . RESULTS Eighteen patients with mild-to-moderate asthma and geometric mean ( SEM ) PD20 of 82.3 micro g ( 19.2 micro g ) completed the study . All treatments significantly improved PD20 values and morning peak expiratory flow vs placebo , while 1,000 microg/d was significantly better than 500 microg/d for the CFC formulation of FP ( CFC-FP ) but not the HFA formulation of FP ( HFA-FP ) . Only 1,000 microg/d of CFC-FP caused significant suppression of overnight urinary cortisol/creatinine compared to placebo . There were no differences between formulations at either dose . CONCLUSIONS The increased airway benefit with CFC-FP > 500 microg/d was offset by greater systemic effects . Although HFA-FP had fewer systemic effects than CFC-FP at 1,000 microg/d , there was no benefit to increasing HFA-FP to > 500 microg/d [2365805] In Vitro and in vivo data have demonstrated that there are detectable differences between inhaled corticosteroids commonly used to treat asthma . However , controversy still remains as to whether these differences translate into clinical benefits . This 12-week , international , r and omized , doubleblind , parallel-group study was undertaken to compare the efficacy and safety of fluticasone propionate ( FP ) 800 μg daily , administered as a powder via the Diskhaler ® , and budesonide ( BUD ) 1600 μg daily , administered using the Turbuhaler ® , in adult patients with moderate-tosevere asthma . A total of 518 patients participated in the study , 256 of whom received FP and 262 BUD . Assessment of mean morning peak expiratory flow ( PEF ) over the 12-week treatment period revealed a statistically significant difference in efficacy between FP 800 μg daily and BUD 1600 μg daily in favour of FP ( p = 0.003 ) , with an overall improvement of 20.9 l/min with FP compared with 12.4 l/min on BUD . Statistically significant differences in favour of FP were seen over the 12 weeks for mean evening PEF ( p = 0.04 ) , diurnal PEF variation ( p = 0.03 ) and percentage predicted PEF ( p = 0.003 ) , as well as forced expiratory volume ( p = 0.008 ) , forced vital capacity ( p = 0.02 ) and PEF ( p = 0.005 ) measured at clinic visits . The median percentage of symptom-free nights increased over the 12-week study period in both treatment groups , with similar changes seen for the median percentage of days with symptom score < 2 , rescue medication use and exacerbations of asthma . The incidence of adverse events was found to be comparable in the two treatment groups . The geometric mean ratios of serum cortisol levels were found to be 1.03 for FP , indicating no mean hypothalamic-pituitary-adrenal axis suppression from baseline , and 0.93 for BUD ( p = 0.0002 compared with FP ) . In summary , FP 800 μg daily showed a greater efficacy/safety ratio in the treatment of moderate-to-severe asthma than BUD 1600 μg daily [9196354] OBJECTIVE To investigate effects on adrenal function of fluticasone , a recently released inhaled steroid preparation with lower systemic bioavailability than beclomethasone dipropionate . METHODS 34 children on high doses ( 400 - 909 μg/m2/d ) of inhaled beclomethasone dipropionate or budesonide were recruited into a double blind , crossover study investigating the effects on adrenal function of beclomethasone and fluticasone propionate , given using a st and ard spacer ( Volumatic ) . The 24 hour excretion rates of total cortisol and cortisol metabolites were determined at baseline ( after a two week run in ) , after six weeks treatment with an equal dose of beclomethasone , and after six weeks of treatment with half the dose of fluticasone , both given through a spacer device . RESULTS The comparison of effects between fluticasone and beclomethasone during treatment periods , although favouring fluticasone in all measured variables , reached significance only after correction for urinary creatinine excretion ( tetrahydrocortisol and 5α-tetrahydrocortisol geometric means : 424 v 341 μg/m2/d ) . The baseline data showed adrenal suppression in the children taking beclomethasone ( total cortisol geometric means : 975 v 1542 μg/d ) and a dose related suppression in the children taking budesonide . Suppressed adrenal function in the children who were taking beclomethasone at baseline subsequently improved with fluticasone and beclomethasone during treatment periods . CONCLUSIONS Fluticasone is less likely to suppress adrenal function than beclomethasone at therapeutically equivalent doses . The baseline data also support the cl aim that spacer devices should be used for the administration of high doses of inhaled topical steroids [11897984] BACKGROUND A clinical model is needed to compare inhaled corticosteroids ( ICSs ) with respect to efficacy . OBJECTIVE The purpose of this investigation was to compare the relative beneficial and systemic effects in a dose-response relationship for 2 ICSs . METHODS A 24-week , parallel , open-label , multicenter trial examined the benefit-risk ratio of 2 ICSs in persistent asthma . Benefit was assessed by improvements in FEV(1 ) and PC(20 ) ; risk was assessed by overnight plasma cortisol suppression . Thirty subjects were r and omized to either beclomethasone dipropionate ( BDP ) 168 , 672 , and 1344 microg/day ( n = 15 ) or fluticasone propionate ( FP ) 88 , 352 , and 704 microg/day ( n = 15 ) , both administered by means of a metered dose inhaler ( MDI ) with chlorofluorocarbon propellant via a spacer , in 3 consecutive 6-week intervals ; this was followed by 3 weeks of FP dry powder inhaler ( DPI ) 2000 microg/day . RESULTS Maximum FEV(1 ) response occurred with the low dose for FP-MDI and the medium dose for BDP-MDI and was not further increased by treatment with FP-DPI . Near-maximum methacholine PC(20 ) improvement occurred with the low dose for FP-MDI and the medium dose for BDP-MDI . Both BDP-MDI and FP-MDI caused dose-dependent cortisol suppression . Responsiveness to ICS treatment was found to vary markedly among subjects . Good ( > 15 % ) FEV(1 ) response , in contrast to poor ( < 5 % ) response , was found to be associated with high exhaled nitric oxide ( median , 17.6 vs 11.1 ppb ) , high bronchodilator reversibility ( 25.2 % vs 8.8 % ) , and a low FEV(1)/forced vital capacity ratio ( 0.63 vs 0.73 ) before treatment . Excellent ( > 3 doubling dilutions ) improvement in PC(20 ) , in contrast to poor ( < 1 doubling dilution ) improvement , was found to be associated with high sputum eosinophil levels ( 3.4 % vs 0.1 % ) and older age at onset of asthma ( age , 20 - 29 years vs < 10 years ) . CONCLUSIONS Near-maximal FEV(1 ) and PC(20 ) effects occurred with low-medium dose for both ICSs in the subjects studied . High-dose ICS therapy did not significantly increase the efficacy measures that were evaluated , but it did increase the systemic effect measure , overnight cortisol secretion . Significant intersubject variability in response occurred with both ICSs . It is possible that higher doses of ICSs are necessary to manage more severe patients or to achieve goals of therapy not evaluated in this study , such as prevention of asthma exacerbations [8779128] BACKGROUND : A study was performed to compare the adrenal suppression caused by inhaled fluticasone propionate and budesonide on a microgram equivalent basis , each given by metered dose inhaler to asthmatic patients . METHODS : Twelve asthmatic patients of mean age 29.9 years , with a forced expiratory volume in one second ( FEV1 ) 92.9 % predicted and forced expiratory flow 25 - 75 % ( FEF25 - 75 ) 69.5 % predicted , on less than or equal to 400 micrograms/day inhaled corticosteroid , were studied in a double blind placebo controlled crossover design comparing single doses of inhaled budesonide 400 , 1000 , 1600 , 2000 micrograms and fluticasone propionate 500 , 1000 , 1500 , 2000 micrograms . Doses were administered at 22.00 hours by metered dose inhaler with mouth rinsing and measurements were made in the laboratory 10 hours later . RESULTS : Serum cortisol levels compared with placebo ( mean 325.2 nmol/l ) were suppressed by fluticasone at doses of 1500 micrograms ( 211.6 nmol/l ) and 2000 micrograms ( 112.3 nmol/l ) and by budesonide at 2000 micrograms ( 243.4 nmol/l ) . Fluticasone propionate 2000 micrograms produced lower absolute serum cortisol levels than budesonide 2000 micrograms ( 95 % CI for difference 42.9 to 219.2 ) . The dose ratio ( geometric mean ) for the relative potency was 2.89 fold ( 95 % CI 1.19 to 7.07 ) . In terms of percentage suppression versus placebo , fluticasone propionate also produced greater effects ( means and 95 % CI for difference ) : budesonide 1600 micrograms ( 16.0 ) versus fluticasone propionate 1500 micrograms ( 40.9 ) ( 95 % CI -0.6 to 50.6 ) , budesonide 2000 micrograms ( 26.0 ) versus fluticasone 2000 micrograms ( 65.2 ) ( 95 % CI 10.5 to 67.8 ) . Individual serum cortisol levels at the two highest doses showed 15 of 24 patients below the normal limit of the reference range ( 150 nmol/l ) for fluticasone and five of 24 for budesonide . Fluticasone propionate also caused greater ACTH suppression than budesonide ( as % versus placebo ) : budesonide 1600 micrograms ( 12.0 ) versus fluticasone propionate 1500 micrograms ( 31.9 ) ( 95 % CI 7.6 to 32.1 ) , budesonide 2000 micrograms ( 13.5 ) versus fluticasone propionate 2000 micrograms ( 44.4 ) ( 95 % CI 13.2 to 48.7 ) . For overnight 10 hour urinary cortisol ( nmol/10 hours ) there was a difference between the lowest doses of the two drugs : budesonide 400 micrograms ( 37.2 ) versus fluticasone propionate 500 micrograms ( 19.9 ) ( 95 % CI 6.9 to 27.8 ) . CONCLUSIONS : Like budesonide the systemic bioactivity of fluticasone propionate is mainly due to lung vascular absorption . Fluticasone propionate exhibited at least twofold greater adrenal suppression than budesonide on a microgram equivalent basis in asthmatic patients [11392363] This study was carried out in an attempt to compare the efficacy and safety of fluticasone propionate ( FP ) at the half dose of budesonide ( BUD ) and beclamethasone dipropionate ( BD ) in childhood asthma . Ninety-six children with moderate to severe asthma ( 9.6 ± 2.17 years ) whose asthma was already controlled on BUD ( n = 52 ) or BD ( n = 44 ) were recruited into the study . In the first part of the study ( the first 12 weeks ) each group was followed with three weekly lung function measurements , daily diary records , and peak expiratory flow ( PEF ) measurements on the initial medication . At the end of 6 weeks , drugs were switched to a half dose of FP , and the subjects were followed for another 6 weeks . Blood sample s were obtained for osteocalcin and plasma cortisol levels after each treatment period . In the second part of the study , 50 patients continued to take FP at the half dose of BUD or BD for another 30 weeks . Clinic visits , including lung function and PEF measurements , were conducted every 10 weeks . After 6 weeks of FP treatment , there was a small but statistically significant decrease in FEV1 and FEF25–75 in both groups ( BUD and BD ) without any significant obstruction . These mild changes in lung function measurements continued during long-term follow-up . However , there was no statistically significant further decrease in any lung function parameters while receiving FP ( visits 3–8 ) ( coefficient = −0.00751 L/day , p = 0.39 for FEF25–75 and coefficient = −0.00910 L/sec/day , p = 0.055 for FEV1 ) . There were no significant changes in the morning and evening PEF measurements and diurnal PEF variations after 6 weeks of treatment with FP compared with BUD and BD treatments . There were no significant changes in basal cortisol and osteocalcin levels before or after 6 weeks of FP treatment ( p > 0.05 ) . The present study concluded that , although FP at the half dose of BUD or BD seems to maintain reasonable control of the disease symptoms , a mild but significant and persistent decrease in lung function parameters may indicate that FP may not be twice as potent as BUD or BD in childhood asthma by evaluation of lung functions . This conclusion must be further verified with long-term studies [14512127] BACKGROUND Inhaled corticosteroids are established first-line anti-inflammatory treatment for asthma . Clinical trials comparing inhaled corticosteroids must take into consideration that because of their excellent effect at low doses , they typically induce a near-maximal response in asthma patients . OBJECTIVE The aim of the present dose-response study was to estimate the minimal effective doses ( MEDs ) of budesonide and of fluticasone propionate via dry-powder inhaler in adults with mild to moderate asthma . METHODS This was a r and omized , double-blind , double-dummy , parallel-group , multicenter , dose-reduction trial performed in adults to compare these 2 inhaled corticosteroids . After a 4- to 6-week run-in period with beclomethasone dipropionate 2000 pg/d , patients fulfilling defined criteria for asthma control were r and omly allocated to treatment with budesonide or fluticasone , both administered BID at a total of 800 pg/d . At 5-week intervals , the dose was reduced to 400 and then 200 pg/d ( 200 and 100 pg BID ) if asthma control was maintained according to further defined criteria . The MED was defined as the last dose level before deterioration of asthma control . RESULTS Subjects were 197 asthmatic patients with a mean age of 40.6 years in the budesonide group and 41.5 years in the fluticasone group . In both groups , baseline mean forced expiratory volume in 1 second ( FEV(1 ) ) was 79.4 % of the predicted normal volume and baseline mean FEV(1 ) reversibility was 22.3 % . The median MED for both groups was 400 microg/d , with no detectable difference in dis-tributions . The budesonide-to-fluticasone ratio for the geometric mean MED was 123 % ( 95 % CI , 99 - 153 [ not significant ] ) . No statistically significant differences regarding lung function , symptom scores , or rescue medication usage were found between the treatment groups during the first treatment period . Adverse-event profiles were similar in both groups , and no unexpected adverse events were considered to be caused by the study drugs . CONCLUSION This effect-controlled study did not detect a statistically significant difference between the MEDs for budesonide and fluticasone via dry-powder inhaler in adults with mild to moderate asthma [12324672] Background : With the transition to hydrofluoroalkane-134a propellants in metered dose inhalers , it is important to consider the efficacy and safety profiles of formulations containing inhaled corticosteroids . We examined the airway and systemic effects of hydrofluoroalkane-134a fluticasone propionate ( FLU-HFA ) and beclomethasone dipropionate ( BEC-HFA ) at recommended labelled doses . Methods : Twenty mild to moderate asthmatics were r and omised in crossover fashion to receive 6 weeks of 500 μg/day followed by 1000 μg/day FLU-HFA and BEC-HFA . Measurements were made at baseline after placebo run in and washout , and after each r and omised treatment . The primary airway outcome for benefit was the dose of methacholine provoking a fall in forced expiratory volume in 1 second ( FEV1 ) of 20 % or more ( methacholine PD20 ) and for systemic adverse effects was overnight urinary cortisol/creatinine ( OUCC ) . Results : For mean responses , both doses of BEC-HFA and FLU-HFA produced significant improvements in PD20 compared with baseline . The improvement was not significantly greater with 1000 μg/day FLU-HFA versus BEC-HFA , a 1.69 fold difference ( 95 % CI 0.94 to 3.04 ) . Both doses of BEC-HFA but not FLU-HFA caused significant suppression of OUCC compared with baseline , with significantly ( p<0.05 ) lower values at 1000 μg/day for BEC-HFA versus FLU-HFA ( 1.97 fold difference ( 95 % CI 1.28 to 3.02 ) ) . Conclusion : There was no difference in the airway and systemic effects in patients with mild to moderate asthma between FLU-HFA and BEC-HFA at a dose of 500 μg/day . At 1000 μg/day there was increased systemic bioactivity with BEC-HFA compared with FLU-HFA , without any gain in airway efficacy [9516029] Abstract Objective : The aim of this study was to evaluate the steady-state effects of once-daily inhaled fluticasone propionate ( FP ) and budesonide ( BUD ) on adrenocortical activity in asthmatic patients . Methods : Ten asthmatic patients with a mean age of 31.2 years , a mean forced expiratory volume in 1 s ( FEV1 ) of 91 % predicted and a forced mid-expiratory flow ( FEF25–75 ) of 62.3 % predicted were studied in a single-blind r and omised crossover design comparing placebo ( PL ) , FP ( 375 μg per day and 750 μg per day ) and BUD ( 400 μg per day and 800 μg per day ) all given once daily for 4 days at each dose via a pressurised metered dose inhaler ( pMDI ) at 0800 hours . After 4 days of treatment , plasma cortisol was measured at 0800 hours ( 24 h after the last dose ) and a 10-h overnight urine collection was taken , 14 h after the last dose ( 2200–0800 hours ) for analysis of cortisol and creatinine excretion . Results : Plasma cortisol levels ( nmol · l−1 , as geometric mean ) at 0800 hours demonstrated a significant difference between the highest doses of FP and BUD ( 424.1 vs 510.3 nmol · l−1 , respectively ) but not between the low doses ( 506.8 vs 514.9 nmol · l−1 ; PL 532.2 nmol · l−1 ) . For the highest dose FP ( 750 μg ) this equated to 20 % suppression of 0800 hours plasma cortisol . Likewise , for overnight urinary cortisol output ( nmol · 10 h−1 , as geometric mean ) , there was a significant difference at the high doses of FP and BUD ( 25.5 vs 38.2 nmol · 10 h−1 ) , but not at the low doses 31.3 vs 34.8 nmol · 10 h−1 ; PL 32.0 nmol · 10 h−1 . For the overnight urinary cortisol/creatinine ratio ( nmol · mmol−1 , as geometric mean ) there was a similar trend ; 4.5 vs 6.1 nmol · mmol−1 for high dose and 5.6 vs 6.3 nmol · mmol−1 for low dose ; PL 5.9 nmol · mmol−1 . Conclusion : Repeated doses of FP 750 μg once daily caused greater adrenal suppression than BUD 800 μg once daily , when comparing effects on plasma cortisol levels at 0800 hours , 24 h after the last dose , as well as effects on overnight urinary cortisol output . Neither FP 375 μg once daily nor BUD 400 μg once daily produced detectable adrenal suppression [15878495] Qvar Autohaler efficacy on asthma control , assessed with E. Juniper asthma control question naire ( ACQ ) , was compared with fluticasone and budesonide . An open r and omized study , stratified ( 2:1 ) on the intake of long-acting beta2-mimetics ( LAbeta2 ) , was performed in patients with moderate to severe poorly controlled asthma ( defined by at least one nocturnal discomfort in the last 5 days or a mean of 2 puffs of short-acting beta2-mimetics in the last 7 days or exercise dyspnea ) despite treatment with beclomethasone < or = 1000 microg/day ( or equivalent ) . 460 patients received Qvar Autohaler 800 microg/day ( n = 149 ) , fluticasone Diskus 1000 microg/day ( n = 149 ) or budesonide Turbuhaler 1600 microg/day ( n = 162 ) during 12 weeks . Asthma control improved in all groups , with no difference between groups . For patients treated with LAbeta2 ( n = 286 ) a significantly greater improvement of the ACQ score was obtained with Qvar Autohaler versus fluticasone ( 1.0 + /- 1.0 vs. 0.6 + /- 0.9 ; P = 0.019 ) , but not versus budesonide ( 0.9 + /- 0.9 ) . Pulmonary function test improvements were similar in the 3 groups . The significant improvement in asthma control in patients receiving LAbeta2 suggests potential advantages for extrafine aerosols as part of anti-inflammatory treatment optimization [8211872] BACKGROUND --High dose inhaled glucocorticosteroids are increasingly used in the management of patients with moderate to severe asthma . Although effective , they may cause systemic side effects . Fluticasone propionate is a topically active inhaled glucocorticosteroid which has few systemic effects at high doses . METHODS --Fluticasone propionate , 1.5 mg per day , was compared with beclomethasone dipropionate at the same dose for one year in patients with symptomatic moderate to severe asthma ; 142 patients received fluticasone propionate and 132 received beclomethasone dipropionate . The study was multicentre , double blind and of a parallel design . For the first three months patients attended the clinic every four weeks and completed daily diary cards . For the next nine months they were only seen at three monthly intervals in the clinic . RESULTS --During the first three months diary card peak expiratory flow ( PEF ) rate and lung function measurements in the clinic showed significantly greater improvement in patients receiving fluticasone propionate ( difference in morning PEF 15 l/min ( 95 % CI 6 to 25 ) ) , and these differences were apparent at the end of the first week . The improved lung function was maintained throughout the 12 month period and the number of severe exacerbations in patients receiving fluticasone propionate was reduced by 8 % compared with those receiving beclomethasone dipropionate . No significant differences between the two groups were observed in morning plasma cortisol levels , urinary free cortisol levels , or response to synthetic ACTH stimulation . In addition , both the rates of withdrawal and of adverse events were low , and there were fewer exacerbations of asthma with fluticasone propionate than beclomethasone dipropionate . CONCLUSIONS --This study shows that fluticasone propionate in a daily dose of 1.5 mg results in a significantly greater increase in PEF and asthma control than the same dose of beclomethasone dipropionate , with no increase in systemic or other side effects [9039246] BACKGROUND : In a previous single dosing comparison between fluticasone propionate and budesonide differences in cortisol levels measured at 08.00 hours were observed at doses in excess of 1000 micrograms . The aim of this study was to compare the adrenal suppression caused by chronic twice daily dosing with inhaled fluticasone propionate ( FP ) and budesonide ( B ) given on a microgram equivalent basis by metered dose inhaler to asthmatic patients . METHODS : Twelve stable asthmatic patients of mean age 29.7 years with forced expiratory volume in one second ( FEV1 ) 89.0 % predicted and mid forced expiratory flow ( FEF25 - 75 ) 58.9 % predicted , on 400 micrograms/day or less of inhaled corticosteroid , were studied in a double blind , placebo controlled , crossover design comparing inhaled budesonide and fluticasone propionate in doses of 250 micrograms , 500 micrograms , and 1000 micrograms twice daily . Each dose was given at 08.00 hours and 22.00 hours for four days by metered dose inhaler with mouth rinsing . Measurements were made of overnight urinary cortisol excretion and plasma cortisol levels at 08.00 hours , 10 hours after the eighth dose . RESULTS : The plasma cortisol levels ( nmol/ l ) at 08.00 hours showed that fluticasone propionate produced lower cortisol levels than budesonide at all three dose levels : F500 333.8 , B500 415.2 ( 95 % CI 28.9 to 134.0 ) ; F1000 308.3 , B1000 380.3 ( 95 % CI 10.5 to 133.5 ) ; F2000 207.3 , B2000 318.5 ( 95 % CI 5.8 to 216.7 ) ; placebo 399.9 . Fluticasone produced greater effects than budesonide on the overnight urinary cortisol/creatinine ratio ( nmol/mmol ) at all three dose levels : F500 3.12 , B500 5.55 ( 95 % CI 0.16 to 3.79 ) ; F1000 2.54 , B1000 6.12 ( 95 % CI 1.25 to 5.91 ) ; F2000 2.07 , B2000 6.09 ( 95 % CI 0.88 to 7.18 ) ; placebo 5.23 . CONCLUSIONS : With repeated dosing across a dose range of 250 - 1000 micrograms twice daily , fluticasone propionate produced significantly greater adrenal suppression than budesonide for both plasma and urinary cortisol . It was therefore possible to demonstrate differences between fluticasone and budesonide at lower doses with chronic dosing from those previously found with single dosing when given on a microgram equivalent basis in asthmatic patients . Factors contributing to the systemic adverse activity profile of fluticasone comprise enhanced receptor potency , prolonged receptor residency time , greater tissue retention , and a longer elimination half life [11695935] OBJECTIVE To compare the long-term effect of treatment with fluticasone propionate or beclomethasone dipropionate on growth in asthmatic children . DESIGN Prospect i ve , multicenter , r and omized , double-blind , parallel-group study . SETTING Children requiring regular treatment with inhaled corticosteroids and with a sexual maturity rating of Tanner stage 1 ( prepubertal ) . PATIENTS Three hundred forty-three children aged 4 to 11 years with asthma . The growth population ( excluding patients with protocol violations likely to affect growth measurements ) included 277 patients . INTERVENTIONS Fluticasone propionate or beclomethasone dipropionate , both at a dosage of 200 microg administered twice daily via a dry powder inhaler ( Diskhaler ) for 12 months . MAIN OUTCOME MEASURES Growth velocity , lung function , and serum and urinary cortisol levels . RESULTS The adjusted mean growth velocity in the fluticasone group was significantly greater than that in the beclomethasone group ( 5.01 [ SE , 0.14 ] vs 4.10 [ SE , 0.15 ] cm/y ; difference , 0.91 cm ; 95 % confidence interval , 0.63 - 1.20 cm ; P<.001 ) . Both treatments improved lung function , with significant differences in favor of fluticasone . Adverse events were similar in both groups , and there were no significant differences in effect on serum and urinary cortisol levels . CONCLUSIONS The more favorable risk-benefit ratio of fluticasone indicates that this agent is preferable to beclomethasone for the long-term treatment of children with asthma , especially if moderate doses are required [7713201] We wanted to evaluate the improvement in efficacy when increasing the daily dose of inhaled steroids and to compare the efficacy , safety , and tolerance of 1.6 mg beclomethasone dipropionate ( BDP ) with that of 2.0 mg fluticasone propionate ( FP ) . The study was a r and omized , double-blind , 3 month , multicentre study . One hundred and thirty four asthmatics currently using inhaled steroids ( 0.4 - 1.6 mg BDP or budesonide ( BUD ) ) were stratified according to pretrial daily steroid use . Within each stratum they were r and omized to either 1.6 mg BDP or 2.0 mg FP . A significant increase in the primary efficacy variables , i.e. mean morning and evening peak expiratory flow ( PEF ) ( approximately 20 l.min-1 ) during the treatment period , was found for both treatments . No significant differences between the drugs were revealed for these primary or any other secondary efficacy variables ( use of beta 2-agonists , symptom scores , and PEF , forced vital capacity ( FVC ) , forced expiratory volume in one second ( FEV1 ) recorded at the clinical visits ) . However , significant differences between treatments occurred regarding decrease of serum cortisol and adrenocorticotropic hormone . We conclude that , although both treatments gave statistically significant increases in efficacy parameters when compared with baseline , the increases were so small that they can be regarded as being clinical ly unimportant . Daily doses of BDP , 1.6 mg , and FP , 2.0 mg , had comparable effects on lung function . A suppression of the hypothalamic pituitary adrenal ( HPA ) axis was only found with a daily dose of 2 mg FP [10836329] Inhaled steroids are frequently used in childhood asthma , but concerns based on limited objective evidence remain , regarding long-term side-effects . In this study the systemic effects of st and ard doses of inhaled steroids in childhood asthma were assessed , comparing beclomethasone dipropionate ( BDP ) with fluticasone propionate ( FP ) . The study was prospect i ve , r and omized and double-blind . Twenty-three steroid-naive children with moderately severe asthma , aged 5 - 10 yrs , were allocated either BDP ( 400 microg x day(-1 ) or FP ( 200 microg x day(-1 ) ) using a metered-dose inhaler with a spacer . Asthma control was assessed at regular intervals over 20 months . Fasting morning blood and overnight urine sample s were collected for estimation of serum cortisol , serum 1-carboxyterminal telopeptide ( ICTP ) , serum osteocalcin and urine deoxypyridinoline ( DPD ) . Bone mineral density ( BMD ) was measured at each visit . None of the markers of bone turnover showed any change during the study period . BMD increased at normal rates with age . Serum cortisol significantly decreased on BDP , but not on FP . A significant difference in growth rates was found between the groups , with a slower rate of growth towards the end of the observation period in the BDP group . In conclusion when taken in a relatively modest dose over a period of time , beclomethasone dipropionate had significant effects on the hypothalamic-pituitary-adrenal axis and statural growth in childhood asthma . These systemic effects were not seen with an equipotent dose of fluticasone propionate [11182010] BACKGROUND The potential for long term adverse effects from inhaled corticosteroids relates to their systemic absorption , usually assessed from proxy markers in short term studies . When fluticasone propionate and budesonide have been compared in this way the results have been inconsistent . To determine whether this is because of the subjects studied or the sensitivity of the systemic marker used , we have compared the effects of fluticasone propionate and budesonide in healthy and asthmatic subjects and investigated the effect of treatment on three systemic markers . METHODS Forty six healthy subjects were r and omised to receive inhaled fluticasone propionate 1500 μg/day ( via an Accuhaler ) , budesonide 1600 μg/day ( via a Turbuhaler ) , or placebo ; 31 subjects with moderately severe asthma were r and omised to receive the same doses of fluticasone propionate or budesonide but not placebo . Systemic effects in healthy and asthmatic subjects were compared after 7 days . Treatment was continued for another 21 days in the subjects with asthma when systemic effects and asthma control were assessed . RESULTS At baseline healthy subjects had higher urinary levels of total cortisol metabolites ( TCM ) than subjects with asthma . After 7 days of treatment with fluticasone propionate urinary TCM levels in the healthy subjects were significantly lower than in the subjects with asthma ( mean difference between groups 1663 μg/day , 95 % CI 328 to 2938 ) . This was not the case with budesonide , however , where urinary TCM levels in the healthy subjects remained above those in the asthmatic subjects ( mean difference between groups 1210 μg/day , 95 % CI –484 to 2904 ) . Urinary TCM levels were considerably more sensitive to the effects of inhaled corticosteroids than morning serum cortisol or osteocalcin concentrations . Only budesonide reduced the serum level of osteocalcin . CONCLUSIONS When given by dry powder inhaler for 7 days , fluticasone propionate 1500 μg/day has a greater effect on the hypothalamic-pituitary-adrenal axis in healthy subjects than in subjects with asthma , but this is not the case for budesonide 1600 μg/day . These findings , together with the differences in sensitivity between systemic markers , explain many of the discrepancies in the literature [9230238] Few thorough comparisons of the systemic effects of inhaled corticosteroids in children are available . The aim of this study was to compare the effect of budesonide and fluticasone propionate on short-term lower leg growth . Fluticasone propionate , budesonide and placebo were administered for 2 weeks in a r and omized , double-blind , double-dummy , cross-over design . Twenty four children aged 6 - 12 yrs received 200 microg x day(-1 ) of each drug , or placebo . Another 24 children aged 6 - 12 years received 400 microg x day(-1 ) of each drug , or placebo . Dry powder inhalers were used . Lower leg length was measured by knemometry twice a week during all three treatment periods , and 24 h cortisol excretion in the urine was measured at the end of each period . In the low-dose group , lower leg growth rate was the same during treatment with placebo ( 0.35 mm x week(-1 ) ) , fluticasone propionate ( 0.38 mm x week(-1 ) ) or budesonide ( 0.26 mm x week(-1 ) ) . No significant difference ( p=0.39 ) in lower leg growth rate was found between treatment with 400 microg x day(-1 ) budesonide ( 0.30 mm x week(-1 ) ) and 400 microg fluticasone propionate treatment ( 0.37 mm x week(-1 ) ) . Growth rate during treatment with budesonide , 400 microg x day(-1 ) , was significantly lower than during placebo treatment ( 0.52 mm x week(-1 ) ) . Cortisol excretion in the urine during treatment with 200 microg x day(-1 ) fluticasone propionate was significantly reduced as compared with placebo ( p=0.006 ) , but not when compared with 200 microg x day(-1 ) budesonide ( p=0.07 ) . Budesonide 200 microg x day(-1 ) was not significantly different from placebo . Fluticasone propionate and budesonide , both at 400 microg x day(-1 ) , result ed in a significant reduction in cortisol excretion in the urine as compared with placebo ( p=0.001 ) . It is concluded that , dose-for-dose , budesonide Turbuhaler and fluticasone propionate Diskhaler have similar systemic effects [8947070] The aim of this study was to compare fluticasone propionate ( FP ) with budesonide ( BUD ) at a dose of 400 microg x day(-1 ) in the treatment of children with asthma . Two hundred and twenty nine children with mild-to-moderate asthma , currently receiving 200 - 400 microg x day(-1 ) of inhaled corticosteroid , were r and omized to receive either 400 microg x day(-1 ) of FP from the Diskhaler ( registered trade mark of the Glaxo Group of Companies ) or 400 microg x day(-1 ) of BUD from the Turbuhaler ( registered trade mark of Astra Pharmaceuticals Ltd ) for 8 weeks , in a parallel-group , double-blind , double-dummy study . Primary efficacy was assessed by measurement of daily peak expiratory flow ( PEF ) . In addition , pulmonary function tests were performed at each clinic visit and a self-administered patient-centred question naire was completed by one parent of each patient at the start and end of study treatment . Mean morning PEF increased following treatment both with FP and BUD , but was significantly higher following treatment with FP during Weeks 1 - 4 ( p=0.015 ) and Weeks 1 - 8 ( p=0.019 ) . Similar results were found for mean evening PEF and percentage predicted morning and evening PEF . Children receiving FP experienced significantly less disruption in their physical activities ( i.e. sports , games ) because of their asthma compared to children treated with BUD ( p=0.03 ) . Mean cortisol levels increased in both groups , but the increase was significantly higher in the FP group at 4 weeks ( p=0.022 ) . Serum and urine markers of bone formation and resorption changed very little and showed no consistent pattern of change . Fluticasone propionate at a dosage of 400 microg x day(-1 ) from the Diskhaler provided a more rapid and greater improvement in lung function in children with mild-to-moderate asthma than BUD 400 microg day(-1 ) from the Turbuhaler . Both treatments were well-tolerated , with a similar safety profile [14694242] Background : It is important to be able to compare the efficacy and systemic effects of inhaled corticosteroids but their slow onset of action makes it difficult to measure the maximum response to a given dose . Submaximal responses could be compared if the time course of action of the inhaled corticosteroids being compared was similar . We have compared the time course of action of fluticasone and budesonide , measuring response as change in the provocative dose of adenosine monophosphate causing a 20 % fall in forced expiratory volume in 1 second ( PD20AMP ) . Methods : Eighteen subjects with mild asthma , aged 18–65 , took part in a three way r and omised crossover study . Subjects took fluticasone ( 1500 μg/day ) , budesonide ( 1600 μg/day ) , and placebo each for 4 weeks with a washout period of at least 2 weeks between treatments ; PD20AMP and forced expiratory volume in 1 second ( FEV1 ) were measured during and after treatment . The time taken to achieve 50 % of the maximum response ( T50 % ) was compared as a measure of onset of action . Results : There was a progressive increase in PD20AMP during the 4 weeks of treatment with both fluticasone and budesonide but not placebo ; the increase after 1 and 4 weeks was 2.28 and 4.50 doubling doses ( DD ) for fluticasone and 2.49 and 3.65 DD for budesonide . T50 % was 9.3 days for fluticasone and 7.5 days for budesonide with a median difference between fluticasone and budesonide of 0.1 days ( 95 % CI −1.4 to 2.65 ) . There was a wide range of response to both inhaled corticosteroids but good correlation between the response to fluticasone and budesonide within subjects . FEV1 and morning peak expiratory flow rate ( PEFR ) increased during the first week of both active treatments and were stable thereafter . There was a small progressive improvement in nocturnal symptoms with both active treatments . Conclusion : PD20AMP was a more sensitive marker of response to inhaled corticosteroid therapy than FEV1 and PEFR . The time course of action of fluticasone and budesonide on PD20AMP is similar , suggesting that comparative studies of their efficacy using 1 or 2 week treatment periods are valid . When a new inhaled corticosteroid becomes available , a pilot study comparing its time course of action with that of an established corticosteroid should allow comparative studies to be performed more efficiently [12763981] Abstract Objectives To determine whether the dose of inhaled corticosteroids can be stepped down in patients with chronic stable asthma while maintaining control . Design One year , r and omised controlled , double blind , parallel group trial . Setting General practice s throughout western and central Scotl and . Participants 259 adult patients with asthma receiving regular treatment with inhaled corticosteroids at high dose ( mean dose 1430 μg beclomethasone dipropionate ) . Interventions Participants were allocated to receive either no alteration to their dose of inhaled corticosteroid ( control ) or a 50 % reduction in their dose if they met criteria for stable asthma ( stepdown ) . Main outcome measures Comparison of asthma exacerbation rates , asthma related visits to general practice and hospital , health status measures , and corticosteroid dosage between the two groups . Results The proportions of subjects with asthma exacerbations were not significantly different ( stepdown 31 % , control 26 % , P=0.354 ) . Similarly , the numbers of visits to general practice or hospital and the disease specific and generic measures of health status over the one year period were not significantly different . On average the stepdown group received 348 μg ( 95 % confidence interval 202 μgto494 μg ) of beclomethasone dipropionate less per day than the controls ( a difference of 25 % ) , with no difference in the annual dose of oral corticosteroids between the two treatment regimens . Conclusions By adopting a stepdown approach to the use of inhaled steroids at high doses in asthma a reduction in the dose can be achieved without compromising asthma control [10325897] BACKGROUND Inhaled corticosteroids are recognised as the most effective agents in the treatment of asthma . However , concerns have been expressed about the effects of high doses of inhaled corticosteroids on safety in relation to bone resorption and formation . This study measures the effects of two inhaled corticosteroids on bone markers and bone mineral density ( BMD ) over one year . METHODS A one year r and omised , prospect i ve , open parallel study comparing inhaled fluticasone propionate ( FP ) , 500 μg twice daily in 30 patients , and budesonide ( BUD ) , 800 μg twice daily in 29 patients , delivered by metered dose inhaler and large volume spacers was performed in adults with moderate to severe asthma . Biochemical markers of bone turnover ( osteocalcin , procollagen type 1 C-terminal propeptide ( PICP ) , immunoreactive free deoxypyridinoline ( iFDpd ) , N-terminal crosslinked telopeptides of type I collagen ( NTx ) ) , BMD at the spine and femoral neck , and serum cortisol concentrations were measured at baseline and 12 months later . RESULTS There were no significant differences between the inhaled steroids on bone markers of bone resorption and formation or bone mineral density . Bone mineral density of the spine increased slightly in both groups over the 12 month period . Serum osteocalcin levels increased from baseline in both treatment groups ( FP 16.9 % , p = 0.02 ; BUD 14.3 % , p = 0.04 ) . PICP did not differ significantly from baseline . Both markers of bone resorption ( iFDpd , NTx ) varied considerably with no significant changes after one year . There was a significant correlation in percentage change from baseline between BMD of the spine and osteocalcin at 12 months ( r = 0.4 , p = 0.017 ) . Mean serum cortisol levels remained within the normal range in both groups following treatment . CONCLUSION There was no evidence of a decrease in BMD during 12 months of treatment with high doses of either FP or BUD . The change in spine BMD correlated with the increase in osteocalcin . Studies extending over several years are needed to establish whether these findings persist [11555383] OBJECTIVE High-dose inhaled corticosteroids ( ICS ) have been associated with the same side-effects as oral corticosteroids . Beclomethasone dipropionate ( BDP ) and budesonide ( BUD ) in doses greater than 2000 microg/day are used regularly in severe asthma , despite the fact that safety and efficacy data at such high doses are limited . Fluticasone propionate ( FP ) has been promoted as being twice as potent clinical ly as BDP or BUD at doses of 2000 microg/day or less with a similar safety profile . The aim of this study was to compare the efficacy and safety of FP with BDP and BUD in 133 symptomatic adult asthmatics requiring at least 1750 microg/day of BDP or BUD . METHODOLOGY Patients fulfilling the entry criteria were r and omized to receive either their regular ICS medication or FP at approximately half the microgram dose for 6 months in an open , parallel group study . The primary efficacy measure was based on morning peak expiratory flow measurements recorded by patients on daily record cards , while determination of safety was based on a number of endpoints including changes in bone turnover indices , the incidence of topical side-effects and assessment s of quality of life . RESULTS It was shown that patients who were switched to FP , but not those continuing with BDP or BUD , had significant increases in levels of morning serum cortisol and the urine cortisol : creatinine ratio while maintaining asthma control . Serum osteocalcin and the pyridinoline : creatinine ratio , as well as the deoxypyridinoline : creatinine ratio , were also shown to increase only in the FP group . Subjective assessment s such as quality of life score , the incidence and ease of bruising , and reports of hoarseness also favoured the FP group . CONCLUSIONS It is concluded that , at the doses studied and with the delivery devices used clinical ly , FP is at least as effective as BDP/BUD in the management of severe asthma and may offer clinical advantages with respect to steroid-related adverse effects [9850348] Abstract : There is a dearth of data on long-term effects of inhaled corticosteroids ( ICS ) on bone architecture in childhood asthma . This study was design ed to assess the possible effects of two different inhaled steroids on bone mineral density ( BMD ) in steroid-native , prepubertal children . Twenty-three children were r and omized to receive equipotent doses of either fluticasone propionate ( 100 mg twice daily ) or beclomethasone dipropionate ( 200 mg twice daily ) . They were followed up over a period of 20 months with regular dual-energy X-ray absorptiometry scans for BMD . Densitometry of lumbar spine and total body showed a significant increase over time , which followed the normal patterns for growth . No difference was observed between the two subgroups . There was no change in fat distribution over time and no increase in percentage total body fat . As expected , girls had significantly higher total body fat . This absence of deleterious effects suggests that in the st and ard doses used neither beclomethasone nor fluticasone has any significant effect on bone density over a moderate period of time . Further studies should continue monitoring BMD through the critical years of bone mass accumulation during adolescence [10868712] This r and omized , double-blind , double-dummy , multicentre cross-over study compared the effects on the hypothalamic-pituitary-adrenal ( HPA ) axis of fluticasone propionate ( 750 microg twice daily given via the Diskus ) and budesonide ( 800 microg twice daily given via the Turbuhaler ) . Two treatment periods of 2 weeks each were preceded by a 2-week run-in period and separated by a 2-week washout period . During run-in and washout , patients received beclomethasone dipropionate ( BDP ) or budesonide at a constant dose of 1500 - 1600 microg day(-1 ) . Sixty patients aged 18 - 75 years with moderate to severe asthma not fully controlled by treatment with 1500 - 1600 microg day(-1 ) budesonide or BDP entered run-in and 45 completed the study . HPA axis suppression was assessed by morning serum cortisol ( area under the curve from 08.00 to 10.30 hours ) and 12-h nocturnal urinary cortisol excretion , measured at the end of run-in ( baseline 1 ) , at the end of washout ( baseline 2 ) , and at the end of each treatment period . Neither budesonide nor fluticasone produced significant suppression of either parameter compared to baselines . Only a few patients had serum-cortisol and urinary cortisol values below the normal range , before and after treatment . This shows that the patients did not have adrenal suppression before entering the study . The ratio between the AUC serum cortisol measured after fluticasone treatment and after budesonide treatment was 0.99 ( 95 % CI 0.92 - 1.06 ) , indicating equivalent effects on the HPA axis . This result was achieved after having omitted two patients ' results , due to their very sensitive reaction to budesonide , but not to fluticasone . Two exacerbations of acute asthma occurred during budesonide treatment and none during fluticasone treatment . Both treatments were well tolerated . In conclusion , budesonide 1600 microg day(-1 ) via Turbuhaler and fluticasone propionate 1500 microg day(-1 ) via Diskus had no clinical effects on the HPA axis in patients with moderate to severe asthma [12000495] In the treatment of asthma , inhaled steroids are more effective than cromolyn , whereas the latter offers extreme safety . The aim of the present pilot study was to evaluate , contemporarily , efficacy and safety aspects of different asthma treatment modalities . In 75 school-age children ( mean age 9.5 years ; range 5.5 - 14.7 years ) , treatment of asthma was started with budesonide ( BUD , n = 30 ) , fluticasone propionate ( FP , n = 30 ) or cromones ( CROM , n = 15 ) . BUD was used at a dose of 800 microg/day during the first 2 months and at 400 microg/day thereafter . The respective FP doses were 500 and 200 microg/day . Efficacy of the treatment was assessed by measuring forced expiratory volume in 1 second ( FEV1 ) and by evaluating the use of bronchodilators . Side-effects of the treatment were evaluated by following growth of the children and by performing low-dose adrenocorticotropin ( ACTH ) testing . At 4 months FEV1 had improved by a mean of 8.2 % in the BUD group and by 5.4 % in the FP group ( p < 0.01 vs. baseline in both groups ; NS between BUD and FP groups ) . The use of bronchodilators had decreased from five doses/week to one dose/week in the BUD group ( p < 0.05 ) , and from three doses/week to one dose/week in the FP group ( p < 0.01 ) ( NS between the groups ) . In the CROM group , the FEV1 value and the use of bronchodilators did not change . The treatment was unsuccessful on the basis of FEV1 decrease and increased bronchodilator use in , respectively , 30 and 15 % of the BUD- , 20 and 7 % of the FP- , and 50 and 47 % of the CROM-treated children . Therefore , to prevent one treatment failure in the CROM group , between three and five children would need to move to treatment with steroids . The treatment had measurable systemic effects on the basis of height st and ard deviation ( SD ) score decrease and minor adrenocortical suppression in , respectively , 60 and 30 % of the BUD- , 27 and 17 % of the FP- , and 20 and 0 % of the CROM-treated children . Therefore , to avoid systemic effects in one steroid-treated child , three BUD- and six to 14 FP-treated children would need to move to treatment with CROM . In conclusion , in school-age children asthma should be treated first with inhaled steroids . It is probable that the best combination of efficacy and safety can be achieved by using low steroid doses [8323338] Short-term lower leg growth was investigated with twice weekly knemometry measurements in 19 schoolchildren with mild asthma during treatment with daily doses of 200 micrograms fluticasone propionate , 400 micrograms , and 800 micrograms beclomethasone dipropionate from a dry powder inhaler . The design was a r and omised , double blind , crossover trial . After a run in period of four days ( period 1 ) the children were allocated to a sequence of active treatments in periods 2 , 4 , and 6 . In periods 3 and 5 ( wash out ) placebo was given . All periods except the run in were two weeks long . The mean lower leg growth velocities during the wash out periods were 0.61 and 0.80 mm/week . Mean growth velocities during treatment with fluticasone propionate and low and high doses of beclomethasone dipropionate were 0.34 , 0.09 , and 0.06 mm/week respectively . Compared with fluticasone propionate , treatment with beclomethasone dipropionate 400 and 800 micrograms/day was associated with a statistically significant reduction in growth velocity [11112113] Inhaled corticosteroids have become the mainstay treatment of bronchial asthma . However , simultaneous evaluations of efficacy and side effects are few . This study aim ed to compare the relative effect of fluticasone propionate ( FP ) and budesonide ( BUD ) on bronchial responsiveness and endogenous cortisol secretion in adults with asthma . The study was double-blind and included 66 adults with asthma , who were r and omized to FP ( n = 33 ) or BUD ( n = 33 ) . Pre study , all participants were clinical ly stable , using inhaled corticosteroids and hyperresponsive to methacholine . Eligible patients were r and omized to three consecutive 2-wk periods with either FP 250 microg twice daily , FP 500 microg twice daily , and FP 1,000 microg twice daily , or BUD 400 microg twice daily , BUD 800 microg twice daily , and BUD 1,600 microg twice daily , delivered by Diskhaler and Turbuhaler , respectively . Before r and omization and at the end of each treatment , bronchial methacholine PD(20 ) , 24-h urinary cortisol excretion ( 24-h UC ) , plasma cortisol , serum osteocalcin , and blood eosinophils were determined . The relative PD(20 ) potency between FP and BUD was 2.51 ( 95 % CI , 1.05 - 5.99 ; p < 0 . 05 ) , while the relative 24-h UC potency was 0.60 ( 95 % CI , 0.44 - 0.83 ; p < 0.01 ) . The differential therapeutic ratio ( FP/BUD ) based on PD(20 ) potency and 24-h UC was 4.18 ( 95 % CI , 1.16 - 15.03 ; p < 0.05 ) . The difference in systemic potency was also seen for plasma cortisol , serum osteocalcin , and blood eosinophils . Therapeutic ratio over a wide dose range , determined by impact on bronchial responsiveness and endogenous corticosteroid production , seems to favor FP [8215522] This study was design ed to compare the efficacy and safety of a new inhaled corticosteroid , fluticasone propionate at a total daily dose of 200 micrograms , with beclomethasone dipropionate 400 micrograms/day in childhood asthma . A total of 398 asthmatic children ( aged 4 - 19 years ) were r and omised to receive either fluticasone propionate 200 micrograms daily or beclomethasone dipropionate 400 micrograms daily for six weeks inhaled via a spacer device from a metered dose inhaler . During the study the patients recorded morning and evening peak expiratory flow rate ( PEFR ) , symptom scores , and use of beta 2 agonist rescue medication . In addition , clinic visit PEFR and forced expiratory volume in one second were measured . Safety was assessed by recording all adverse events and by performing routine biochemistry and haematology screens including plasma cortisol concentration before and after treatment . For the purpose s of analysis the diary card data were grouped into three periods : week 3 ( days 15 - 21 ) , week 6 ( days 36 - 42 ) , and weeks 1 - 6 ( days 1 - 42 ) . The results showed no significant difference between treatments on most efficacy parameters . However , there were significant differences in changes from baseline in favour of fluticasone propionate for % predicted morning PEFR both at week 3 ( fluticasone propionate 6.1 % , beclomethasone dipropionate 3.9 % ) and at week 6 ( fluticasone propionate 8.3 % , beclomethasone dipropionate 5 . 9 % ) and % predicted evening PEFR at week 6 ( fluticasone propionate 7.3 % , beclomethasone dipropionate 4.9 % and over weeks 1 - 6 ( fluticasone propionate 5.5 % , beclomethasone dipropionate 3.6 % . Comparison between groups showed that the group receiving fluticasone propionate had a lower % of days with symptom-free exercise at week 6 ( fluticasone propionate 87 % , beclomethasone dipropionate 81 % ) and % days without rescue medication at week 6 ( fluticasone propionate 87 % , beclomethasone dipropionate 80 % ) and over weeks 1 - 6 ( fluticasone propionate 80 % , beclomethasone dipropionate 73 % ) . Except for a higher incidence of sore throat in the fluticasone propionate group , the two treatments did not differ with regard to safety . There was no evidence of adrenal suppression with either treatment . In conclusion , fluticasone propionate 200 microgram daily ws at least as effective and as well tolerated as beclomethasone dipropionate 400 microgram daily in childhood asthma [8706770] The systemic effects of single and multiple doses of inhaled fluticasone propionate ( FP ) and budesonide were examined in 24 healthy male volunteers ( age range 18–29 years ) . The study was of an open , placebo-controlled , r and omized , three-way crossover design . On each study day , multiple blood sample s were taken over a 20 h period after drug administration ( after a single dose and after the last of seven doses ) and area under the curve ( AUC0–20 ) for plasma cortisol and white blood cell ( WBC ) counts was calculated . Results : The present study shows that multiple dosing with FP 1.0 mg b.i.d . for 3.5 days ( seven doses ) result ed in a marked cortisol suppression from placebo which , at 55 % , was more than double that seen with a single dose ( 25 % suppression ) . Multiple dosing with budesonide 0.8 mg b.i.d . result ed in a 34 % suppression in plasma cortisol compared with a suppression of 26 % with a single dose . The increase in systemic activity of FP after multiple dosing is confirmed by both the number of subjects with 0800 hours plasma cortisol values below normal limits and by the changes in WBC and differential counts . Conclusion : The results of the present study confirm previous findings with regard to the more marked systemic effect of FP following multiple dosing as compared with a single dose . This increase in systemic effect from single dosing to multiple dosing is significantly greater for FP than for budesonide [9700034] Bronchial inflammation plays a central role in asthma . We investigated whether parameters of inflammation were increased in peripheral blood . Furthermore , we tested whether fluticasone propionate ( FP ) , a new inhaled corticosteroid ( ICS ) , and beclomethasone dipropionate ( BDP ) affected these parameters . FP 750 μg/day and BDP 1500 μg/day were compared in a r and omized , crossover study consisting of two 6‐week treatment periods , each preceded by a 3‐week placebo period . Twenty‐one patients with symptomatic asthma completed the study . The results were compared with those of six normal subjects ( controls ) . Immunophenotyping of inflammatory cells was performed in whole blood , and serum eosinophil cationic protein ( ECP ) was measured . With regard to clinical efficacy , ICS increased PCjo histamine by more than 1.9 doubling doses and FEV , by more than 0.34 1 . The number of CD3/HLA‐DR+ lymphocytes was significantly increased in asthmatics compared to the normal subjects , both after placebo ( P<0.01 ) and after therapy ( P<0.05 ) . The CD3/HLA‐DR‐H lymphocytes decreased significantly after treatment with FP ( P<0.05 ) . Serum ECP was elevated in patients without ICS and decreased after treatment with BDP ( P<0.001 ) . In conclusion , the number of CD3/HLA‐DR‐I‐ lymphocytes and serum ECP levels were raised in the peripheral blood of symptomatic asthmatics , and decreased by clinical ly effective doses of ICS . In this respect , FP 750 ng/day was at least as effective as BDP 1500 μg/day [18370529] Abstract Objective : The objective of this study was to assess the relative cost effectiveness of fluticasone via metered dose inhaler and budesonide via Turbuhaler ® in corticosteroid-naive patients with moderate asthma from a third-party payer perspective ( German Sickness Funds ) . Patients and Methods : A retrospective economic assessment of direct medication costs of treatment was performed on data from a prospect i ve , r and omised , parallel group , 6-week clinical trial . 457 corticosteroid-naive patients between the ages of 18 and 70 years with moderate asthma were included in the intention-to-treat analysis . Results : The fluticasone group had a higher proportion of successfully treated patients ( those with a peak expiratory flow rate improvement of ≥10 % ) [ 47 vs 42 % ] , a higher average proportion of symptom-free days ( 40 vs 34 % ) and lower direct healthcare costs [ 1997 Deutschmarks ( DM ) ] per day ( DM4.23 vs DM5.19 ) than the budesonide group . Therefore , the daily costs per successfully treated patient ( DM9.00 vs DM12.36 ) and the cost per symptom-free day ( DM10.58 vs DM15.26 ) were both lower with fluticasone than with budesonide . Sensitivity analysis demonstrated that these results were relatively robust over a wide range of plausible assumptions . Conclusion : These results showed that from the perspective of a third-party payer , fluticasone was more cost effective than budesonide over the 6-week study period [11379810] BACKGROUND Inhaled corticosteroids provide first-line treatment for asthma . An advance to improve potency was to produce new molecules with increased glucocorticoid receptor affinity ( eg , fluticasone propionate [ FP ] ) . An alternative is to deliver more medication to both the large and small airway inflammation of asthma by using an extrafine aerosol ( eg , beclomethasone dipropionate extrafine aerosol [ BDP-extrafinel ) . OBJECTIVE To demonstrate clinical equivalence of BDP-extrafine ( 400 microg daily ) and FP ( 400 microg daily ) in symptomatic asthmatic patients over the course of 6 weeks . METHODS This was a double-blind , double-dummy , parallel-group , multicenter , 6-week study in adults with asthma taking conventional FP 100 to 250 microg daily or equivalent , and displaying signs/symptoms of active disease requiring additional therapy . RESULTS Eighty-eight patients were r and omized to BDP-extrafine ( and FP-placebo ) and 84 to FP ( and BDP-placebo ) . There were no significant differences between treatments with respect to symptom control , as evidence d by mean change from baseline in percentage days without asthma symptoms/nights without sleep disturbance observed at weeks 1 to 2 , 3 to 4 , or 5 to 6 . Mean changes from baseline in AM PEFR at weeks 5 to 6 for BDP-extrafine ( 19.0 ) and FP ( 30.5 ) were equivalent ( P = 0.022 for equivalence ) . There were significant ( P < 0.001 ) within-treatment-group differences in mean change from baseline in AM PEFR at weeks 1 to 2 for both treatments . There was no difference in the incidence of patients reporting at least one adverse event during the study ( BDP-extrafine 41 % ; FP 37 % ) . Mean percentage change from baseline for AM plasma cortisol at week 6 was + 17.7 % for BDP-extrafine and + 4.2 % for FP ( P = 0.066 for difference ) . CONCLUSIONS BDP-extrafine and FP at doses of 400 microg daily provided equivalent asthma control in patients with symptomatic asthma and exhibited similar safety profiles [8092438] A total of 261 patients with symptomatic , mild to moderate asthma were r and omized to treatment in this 4‐week , double‐blind , parallel‐group comparison of fluticasone propionate 200 μg/d with beclomethasone dipropionate 400 μg/d . Improvements from both treatments were seen in diary card data . Morning peak expiratory flow rate ( PEFR ) improved from 375 to 390 and 371 to 382 1/min with fluticasone propionate and beclomethasone dipropionate , respectively . Symptom scores , percentage of symptom‐free days and nights , and use of rescue ( β2‐agonist medication also improved , as did clinical lung function . With the exception of percentage of rescue‐free days , which was greater for beclomethasone dipropionate , none of the differences between the groups were statistically significant . There was a significant difference between treatments in the number of rescue‐free days over days 1–28 ; however , there was no difference between treatments in the number of rescue‐free days over days 1‐14 , nor was there any difference in the number of inhalations of rescue medication used throughout the study . Very few adverse effects were reported . Although all mean plasma cortisol values were within the normal range , they were significantly different between treatments , rising from 402 to 429 nmol/1 with fluticasone propionate , and falling from 435 to 394 nmol/1 with beclomethasone dipropionate ( P= 0.006 ) . Mean stimulated cortisol levels 30 min after tetracosactin injection were also significantly greater with fluticasone propionate ( P = 0.024 ) . In conclusion , fluticasone propionate 200 μg/d is as effective as beclomethasone dipropionate 400 μg/d with less effect on plasma cortisol levels [7491551] BACKGROUND --Fluticasone propionate is a new inhaled corticosteroid with a 2:1 efficacy ratio compared with beclomethasone dipropionate with regard to lung function and symptom scores , without increased systemic activity . The aim of this study was to investigate whether this was also the case for bronchial hyperresponsiveness , assessed by both a direct ( histamine ) and an indirect ( ultrasonically nebulised distilled water ( UNDW ) ) provocation test . METHODS --Fluticasone propionate , 750 micrograms/day , and beclomethasone dipropionate , 1500 micrograms/day , were compared in a r and omised , double blind , crossover study consisting of two six week treatment periods , each preceded by a three week single blind placebo period . Twenty one non-smoking asthmatics ( mean forced expiratory volume in one second ( FEV1 ) 74.7 % predicted , mean PC20histamine 0.36 mg/ml ) completed the study . RESULTS --Fluticasone propionate and beclomethasone dipropionate improved FEV1 , peak flow rates , asthma symptoms , and bronchial hyperresponsiveness to the same extent . Both fluticasone propionate and beclomethasone dipropionate caused an increase in PC20histamine ( mean 2.29 [ 95 % confidence interval 1.45 to 3.13 ] and 1.95 [ 1.07 to 2.84 ] doubling doses , respectively ) and in PD20UNDW ( 1.12 [ 0.55 to 1.70 ] and 1.28 [ 0.88 to 1.70 ] doubling doses , respectively ) . Neither treatment changed morning serum cortisol levels , but fluticasone propionate decreased the number of peripheral blood eosinophils less than beclomethasone dipropionate , indicating smaller systemic effects of fluticasone propionate . CONCLUSIONS --These findings show that fluticasone propionate is as effective as twice the dose of beclomethasone dipropionate on bronchial hyperresponsiveness , assessed by provocation with both histamine and UNDW , without increased systemic activity [9215245] BACKGROUND New inhaled glucocorticosteroids and inhalers are being developed . Their clinical equipotency is difficult to assess and is often discussed . OBJECTIVE This study was carried out to compare the effect of budesonide Turbuhaler and fluticasone propionate ( FP ) Diskhaler in a dose reduction study in children ( ages 5 to 16 years ) with asthma . METHODS Children treated with budesonide administered through a pressurized metered-dose inhaler with a large volume spacer had their budesonide dose gradually reduced to define the minimal effective dose with this delivery system . After this period , 217 children were r and omly allocated to treatment with half the dose of either budesonide Turbukaler or FP Diskhaler for 5 weeks in a double-blind trial . If no deterioration in asthma control was seen , the dose was further reduced by 50 % at 5-week intervals until deterioration in asthma control was seen . Throughout the study , morning and evening peak expiratory flow , symptoms , and use of rescue beta 2-agonist were recorded in diaries . Lung function tests and a st and ardized exercise test were performed at the clinic at the end of each treatment period . Urine cortisol excretion ( 24 hours ) was measured before and after the first 5-week treatment period . St and ardized criteria for deterioration in asthma control , based on diary card variables and exercise testing , were used to determine the minimal effective dose for each patient ; and from this , the number of dose reduction steps was calculated . RESULTS No statistically significant difference was seen in number of dose reduction steps from baseline or in minimal effective dose between the two treatments ; mean reduction was 1.59 dose steps for budesonide Turbuhaler and 1.65 dose steps for FP Diskhaler ( p = 0.52 ) , and minimal effective dose was 188 micrograms for budesonide Turbuhaler and 180 micrograms for FP Diskhaler . After these dose reductions , the same level of asthma control was observed in the budesonide Turbuhaler and FP Diskhaler groups . Furthermore , no statistically significant differences between the two inhaler-drug combinations were seen in daytime or nighttime symptoms , morning and evening peak expiratory flow , use of rescue beta 2-agonist , lung functions at the clinic , exercise-induced fall in lung function , or 24-hour urinary cortisol excretion during the first 5-week period . CONCLUSION Microgram for microgram , budesonide Turbuhaler and FP Diskhaler are equally effective in treatment of children with moderate asthma [8984708] BACKGROUND : The aim of this study was to compare the systemic bioactivity of inhaled budesonide ( B ) and fluticasone propionate ( F ) , each given by large volume spacer , on a microgram equivalent basis in asthmatic children . METHODS : Ten stable asthmatic children of mean age 11 years and forced expiratory volume in one second ( FEV1 ) 81.6 % predicted , who were receiving treatment with < or = 400 micrograms/day of inhaled corticosteroid , were studied in a placebo controlled single blind ( investigator blind ) r and omised crossover design comparing single doses of inhaled budesonide and fluticasone propionate 400 micrograms , 800 micrograms , and 1250 micrograms . Doses were given at 20.00 hours with mouth rinsing and an overnight 12 hour urine sample was collected for estimation of free cortisol and creatinine excretion . RESULTS : The results of overnight 12 hour urinary cortisol output ( nmol/12 hours ) showed suppression with all doses of fluticasone propionate ( as geometric means ) : F400 micrograms ( 11.99 ) , F800 micrograms ( 6.49 ) , F1250 micrograms ( 7.00 ) compared with placebo ( 24.43 ) , whereas budesonide caused no suppression at any dose . A comparison of the drugs showed that there were differences at 800 micrograms and 1250 micrograms levels for urinary cortisol : B800 micrograms versus F800 micrograms ( 2.65-fold , 95 % CI 1.26 to 5.58 ) , B1250 micrograms versus F1250 micrograms ( 2.94-fold , 95 % CI 1.67 to 5.15 ) . The results for the cortisol/creatinine ratio were similar to that of urinary cortisol , with fluticasone causing suppression at all doses and with differences between the drugs at 800 micrograms and 1250 micrograms . CONCLUSIONS : Single doses of inhaled fluticasone produce greater systemic bioactivity than budesonide when given by large volume spacer on a microgram equivalent basis in asthmatic children . The systemic bioactivity of fluticasone , like budesonide , is due mainly to lung bioavailability [10542974] The purpose of this study was to investigate the comparative efficacy and safety of equal doses of inhaled fluticasone propionate ( FP ) and inhaled budesonide ( BUD ) using their respective dry powder inhalers in a population of severe asthmatics requiring high doses of inhaled corticosteroid . This double-blind double-dummy parallel-group study compared the effects of 24 weeks of treatment with FP ( 2000 micrograms daily via a Diskhaler inhaler ; Glaxo Wellcome , Evreux , France ) and BUD ( 2000 micrograms daily via a Turbuhaler inhaler ; Astra Pharmaceuticals , Rijswijka , Netherl and s ) on lung function and asthma exacerbations in 395 patients with asthma . FP was statistically significantly superior to BUD with respect to the percentage of symptom-free days ( P = 0.02 ) , the incidence of days free from rescue bronchodilator usage ( P = 0.02 ) and the distribution of change in peak expiratory flow ( PEF ) expressed as a percentage of the predicted PEF ( P = 0.04 ) . During the treatment period FP was statistically significantly superior to BUD for change in forced expiratory volume in 1 sec ( FEV1 ) at 8 , 16 and 24 weeks , change in the median daytime symptom score during weeks 5 - 16 , for incidence of symptom-free days and incidence of days free from rescue bronchodilator usage during weeks 17 - 24 . There was no significant difference between FP and BUD with respect to the number of patients experiencing one or more asthma exacerbation ( 33.8 and 28.4 % of patients , respectively ) . There was , however , evidence that the exacerbations were clinical ly less severe in patients treated with FP , in that the time to resolution was quicker ( 11.0 vs. 14.7 days ; P = 0.035 ) , mean duration of all exacerbations ( for an individual patient ) tended to be shorter ( 18.5 vs. 23.6 days ; P = 0.12 ) , the time off work was reduced ( 4.2 vs. 7.6 days ; P = 0.012 ) and the lowest PEF recorded during the exacerbation was higher ( 301 vs. 263 l min-1 ; P = 0.07 ) . There were no clinical ly relevant differences in the safety ( serum cortisol levels , markers of bone turnover , adverse events ) of FP and BUD at these microgram equivalent doses . The patients recruited into this study , in retrospect , probably had no need for such high doses of inhaled corticosteroid but , irrespective of this , FP at microgram equivalent doses showed evidence of superior efficacy to BUD with respect to lung function and severity of asthma exacerbations without producing any greater adverse systemic effect [9337826] BACKGROUND In a previous single dosing study in asthmatic school children fluticasone propionate produced significantly greater suppression of overnight urinary cortisol excretion than budesonide at high doses of 800 micrograms/day or greater . The aim of this study was to assess whether conventional lower doses of both drugs cause adrenal suppression when given at steady state twice daily by large volume spacer on a microgram equivalent basis in asthmatic school children . METHODS Eight school children of mean age 12.1 years with stable asthma of mild to moderate severity ( forced expiratory volume in one second ( FEV1 ) 78.6 % predicted , mid forced expiratory flow rate ( FEF25 - 75 ) 72.5 % predicted ) , on 400 micrograms/day or less of inhaled corticosteroid , were studied in a single blind ( investigator blind ) , placebo controlled , crossover design comparing inhaled budesonide and fluticasone propionate 100 micrograms bid and 200 micrograms bid . Each dose was given at 08.00 hours and 20.00 hours for four days by metered dose inhaler via their respective large volume spacers with mouth rinsing . Measurements were made of overnight urinary cortisol and creatinine excretion after the eighth dose . RESULTS Neither drug produced significant suppression of overnight urinary cortisol or cortisol/creatinine excretion compared with pooled placebo and there were no differences between the drugs . Only one subject with each drug at 200 micrograms twice daily had abnormally low urinary cortisol excretion of < 10 nmol/12 hours . Ratios for the fold difference between active treatment versus placebo for urinary cortisol excretion were ( as means and 95 % confidence intervals for difference ) : budesonide 100 micrograms b.i.d 1.03 ( 95 % CI 0.46 to 1.61 ) , budesonide 200 micrograms b.i.d 1.04 ( 95 % CI 0.62 to 1.46 ) ; fluticasone 100 micrograms b.i.d 1.11 ( 0.45 to 1.77 ) , fluticasone 200 micrograms b.i.d 1.12 ( 0.78 to 1.47 ) . Likewise , there were no significant differences in overnight urinary cortisol/creatinine excretion . CONCLUSIONS With repeated twice daily administration at steady state across a dose range of 200 - 400 micrograms/day no evidence of significant adrenal suppression was found using the sensitive marker of overnight urinary cortisol excretion for either fluticasone propionate or budesonide given via a large volume spacer . These results emphasise the good safety profile in children of these inhaled steroids at conventional dose levels , which have proven antiasthmatic efficacy [9616537] The inhaled corticosteroid fluticasone propionate ( FP ) was introduced into the Thorpewood General Practice , Norwich , U.K. in 1993 -initially in treating relatively severe asthmatics . Observed beneficial effects led to exp and ed use particularly for poorly controlled asthma not responsive to increased inhaled anti-inflammatories . However , an early review suggested little advantage over existing agents ( l ) , and FP was marketed at a price premium . The aims of this study were to investigate whether continued and exp and ing use of FP was justified in terms of improved clinical outcomes , and if such improvements were associated with reduced NHS costs ( off setting more expensive prescriptions ) . A controlled , retrospective , nonr and omized primary care audit compared clinical outcomes and asthma management costs 1 year prior to and 1 year into FP therapy [10390394] We assessed the systemic effects of budesonide ( BUD ) and fluticasone propionate ( FP ) in 23 patients with asthma , using a double-blind , placebo-controlled , double-dummy , and cross-over design . The following five treatments were given in a r and omized order for 1 wk with a washout period in between of 2 wk : ( 1 ) placebo ; ( 2 ) FP , 200 micrograms twice a day , inhaled from a Diskhaler ; ( 3 ) FP , 1,000 micrograms twice a day , inhaled from a Diskhaler ; ( 4 ) BUD , 200 micrograms twice a day , inhaled from a Turbuhaler ; and ( 5 ) BUD , 800 micrograms twice a day , inhaled from a Turbuhaler . The primary variable was the area under the curve of serum cortisol versus time ( AUC0 - 20 ) , derived from serum sample s taken every 2 h over a 20-h period following the last evening dose at 10:00 P.M. The lower doses of BUD and FLU did not cause any adrenal suppression . Compared with placebo , however , FP ( 1 , 000 micrograms , twice daily and BUD ( 800 micrograms , twice daily ) decreased the AUC0 - 20 by 34 and 16 % , respectively . Fluticasone ( 1,000 micrograms , twice daily ) was more suppressive than BUD ( 800 micrograms , twice daily ) ( p = 0.0006 ) . The FEV1 , measured the morning after the last inhalation , was significantly higher after the active treatments , compared with placebo ( p < 0.02 ) , but did not differ between all active treatments . We conclude that high doses of BUD and FP ( in particular the latter ) , inhaled via their respective dry powder inhalers for 1 wk , result in a measurable systemic activity in patients with asthma [8959118] This study was design ed primarily to assess the safety and tolerability of fluticasone propionate ( FP ) 1 mg day-1 by comparison with beclomethasone dipropionate ( BDP ) 2 mg day-1 over a 12-month study period . Lung function data were also recorded and used to determine whether the potency ratio between the two inhaled corticosteroids observed in previous studies was maintained in the long-term . Two hundred and thirteen patients with an established clinical history of severe chronic asthma and who were currently receiving between 1000 micrograms and 2000 micrograms day-1 of inhaled steroids were r and omized to treatment in a ratio of 3:1 for FP : BDP ( 159 patients FP ; 54 patients BDP ) , both via metered dose inhalers . Both treatments were well tolerated with a similar adverse event profile . No unexpected adverse events were recorded . Most adverse events were related to the patients ' asthma , an intercurrent infection or underlying atopy . The incidence of pharmacologically predictable adverse events was equally low in both treatment groups as was the incidence of events suggestive of systemic steroid effect . Mean serum cortisol levels remained within the normal range at all visits for both treatments . At 12 months , however , the mean cortisol levels for the FP group had risen 4 % above the baseline value but had dropped 15 % below for the BDP group , giving a ratio of FP : BDP of 1.22 ; P = 0.01 ; 95 % confidence limits ( CL ) 1.05 - 1.43 . Fluticasone propionate 1 mg day-1 was at least as effective as BDP 2 mg day-1 in improving lung function ( PEF , FEV1 and FVC ) over this period . Moreover , the difference in FEV1 values at 6 months was significantly greater for the FP group than for the BDP group ( P = 0.04 ; difference = 0.12 1 ; 95 % CL = 0.01 , 0.24 1 ) . The difference between treatments in the amount of FEV1 reversibility was also significantly greater for FP at 12 months ( difference in treatments = -3 % ; 95 % CL = - 7 - 0 % ; P = 0.044 ) . This study supports previous studies and suggests that FP is likely to be of benefit in the long-term treatment of chronic severe asthma [10329812] BACKGROUND Inhaled corticosteroids are recommended for the treatment of persistent asthma . Comparative clinical studies evaluating 2 or more doses of these agents are few . OBJECTIVE We sought to compare the efficacy and safety of 2 doses of fluticasone propionate ( 88 micrograms twice daily and 220 micrograms twice daily ) with 2 doses of beclomethasone dipropionate ( 168 micrograms twice daily and 336 micrograms twice daily ) in subjects with persistent asthma . METHODS Three hundred ninety-nine subjects participated in this r and omized , double-blind , parallel-group clinical trial . Eligible subjects were using daily inhaled corticosteroids and had an FEV1 of 45 % to 80 % of predicted value . Clinic visits , including spirometry , were conducted every 1 to 2 weeks . Subjects recorded symptoms , use of albuterol , and peak expiratory flows on daily diary cards . RESULTS Fluticasone propionate treatment result ed in significantly ( P < /=.034 ) greater improvements in objective pulmonary function parameters than did beclomethasone dipropionate treatment and significantly greater reductions in daily albuterol use ( P < /=.010 ) and asthma symptoms ( P < /=.027 ) . Both low-dose ( 88 micrograms twice daily ) and medium-dose ( 220 micrograms twice daily ) fluticasone propionate significantly increased FEV1 compared with higher doses of beclomethasone dipropionate ( P = . 006 ) . Low-dose and medium-dose fluticasone propionate improved FEV1 by 0.31 L ( 14 % ) and 0.36 L ( 15 % ) , respectively , compared with improvements of 0.18 L ( 8 % ) and 0.21 L ( 9 % ) with low-dose and medium-dose beclomethasone dipropionate . The adverse event profiles were similar for both medications . CONCLUSION Fluticasone propionate provides greater asthma control at roughly half the dose of beclomethasone dipropionate , with a comparable adverse event profile [10190915] OBJECTIVE To compare the efficacy and adverse effects of inhaled fluticasone propionate ( FP ) , 400 microgram/d , with those of budesonide ( BUD ) , 800 microgram/d , in children with moderate to severe asthma . METHODS Three hundred thirty-three children , ages 4 to 12 years , receiving inhaled corticosteroids were enrolled in a double-blind , double-dummy , r and omized , parallel-group study . After a 2-week run-in phase , 166 children received FP and 167 received BUD for 20 weeks . The primary outcome variable was mean morning peak expiratory flow ; the 2 treatments were to be regarded as equivalent if the 90 % CI for the treatment difference was within + /- 15 L/min . Pulmonary function , height , and diary cards were assessed at each visit ; and morning serum cortisol levels were determined before and after treatment . RESULTS Baseline peak expiratory flow was similar , FP 236 + /- 72 ( SD ) L/min and BUD 229 + /- 74 , increasing after treatment to 277 + /- 41 and 257 + /- 28 , a difference between treatments of 12 L/min ( 90 % CI 6 - 19 L/min ; P = .002 ) . Symptom control and use of rescue medication were the same . Cortisol levels after treatment were 199 nmol/L ( FP ) and 183 nmol/L ( BUD ) ( treatment ratio = 1.09 ; 90 % CI 0.98 - 1.21 ; P = .172 ) . Linear growth was less in those receiving BUD ( mean difference , 6.2 mm ; 95 % CI 2.9 - 9.6 ; P = .0003 ) . CONCLUSION FP at half the dose was superior to BUD in improving peak expiratory flow and comparable in controlling symptoms . Growth was reduced with BUD compared with FP , but there was no difference in serum cortisol suppression or hepatic or renal function [9519234] The efficacy and tolerability of fluticasone propionate ( FP ) 2 mg daily via a metered-dose inhaler and Volumatic ( Glaxo Wellcome ) spacer device was compared with nebulized budesonide ( nBUD ) , 2 and 4 mg daily , in a multi-centre , open-label , cross-over study of adult asthmatics . Patients received , in r and om order , either 4 weeks of treatment with FP followed by 4 weeks of treatment with nBUD , or vice versa , with an intervening 4 week ' wash-out ' period between treatments . Thirty patients completed the study , of whom 24 were evaluable . In terms of the primary efficacy parameter , change in mean morning peak expiratory flow ( PEF ) ( l min-1 ) from baseline to the fourth week of each treatment period , FP was more effective than nBUD [ mean difference ( FP-nBUD ) 21.1 l min-1 , P = 0.007 , 95 % CI ( 6.5 , 35.7 ) ] . Sub-group analysis demonstrated FP to be superior to the 4 mg nBUD [ mean treatment difference ( FP-nBUD ) 42.9 l min-1 , P = 0.026 , 95 % CI ( 7.1 , 78.8 ) ] and at least as efficacious as the 2 mg nBUD sub-group [ mean treatment difference ( FP-nBUD ) 10.2 l min-1 , P = 0.211 , 95 % CI ( -6.5 , 26.9 ) ] . Furthermore , larger reductions in diurnal variation were observed during FP treatment [ mean treatment difference ( FP-nBUD ) -4.4 percentage points , P = 0.028 , 95 % CI ( -8.4 , -0.5 ) ] . There was no significant difference between the treatments for the proportion of symptom-free 24 h periods . Of those expressing a preference , significantly more patients found FP via a metered-dose inhaler and spacer device both easier to administer ( 78 % , P = 0.007 ) and more convenient to take ( 76 % , P = 0.008 ) than nebulized budesonide . In addition , cost per patient analysis showed that nebulized budesonide was from 1.7 to 3.5 times more expensive than FP [9131947] AIMS The present study was undertaken to see whether the difference in plasma cortisol suppression between single and repeated dosing of fluticasone propionate ( FP ) can be explained by systemic accumulation . METHODS Twelve healthy subjects ( six women ) were given , in a crossover fashion , a single dose inhalation ( 1000 micrograms ) of FP via Diskhaler and repeated inhalations ( 1000 micrograms twice daily ) every 12 h during 7 days . There was a washout period of 2 weeks between the treatments . An intravenous dose of 20 micrograms FP was given as a reference . Plasma concentrations of FP for each treatment were determined by liquid chromatography plus t and em mass spectrometry . Plasma cortisol after the inhaled doses was determined using an immunoassay and was compared with baseline values . RESULTS The average plasma concentration of FP was about 1.7 times higher after multiple inhalations than after a single dose . Systemic availability , mainly attributable to pulmonary deposition , was 15.6 [13.6 - 18.0]% of the nominal dose . Daytime plasma cortisol suppression vs baseline was 47 [20 - 65]% and 95 [93 - 97]% for the single and repeated doses , respectivley . CONCLUSIONS To conclude , a slow elimination of FP leads to accumulation during repeated dosing . This accumulation may explain the marked decrease in plasma cortisol seen during treatment with fluticasone propionate within the clinical dose range [12911833] OBJECTIVE Changes in health-related quality of life ( HRQoL ) were evaluated in adults with severe asthma following inhaled corticosteroid treatment with high-dose beclomethasone dipropionate or budesonide ( BDP/BUD ) and compared with fluticasone propionate taken at approximately half the dose of BDP/BUD . METHODOLOGY HRQoL was assessed as part of an open , multicentre , r and omized , parallel-group study in Australia evaluating the safety and efficacy of switching to fluticasone propionate ( FP ) 1000 - 2000 micro g/day ( n = 67 ) compared with remaining on BDP/BUD > /=1750 micro g/day ( n = 66 ) for 6 months . Patients completed two HRQoL question naires , the Asthma Quality of Life Question naire ( AQLQ ) and the Medical Outcomes Study Short Form-36 ( SF-36 ) , at baseline and at weeks 12 and 24 . A change in AQLQ score of > /=0.5 was considered to be clinical ly meaningful . RESULTS There were significant improvements in HRQoL with FP on four of the eight dimensions on the SF-36 ( i.e. physical functioning , general health , role-emotional , and mental health ) , while there were no significant improvements in HRQoL in the BDP/BUD group . Overall , patients in the FP group experienced significantly greater improvement ( P < 0.001 ) in AQLQ scores at weeks 12 and 24 compared with the BDP/BUD group . On the individual domains of the AQLQ , there were significant treatment differences ( P < 0.01 ) in favour of FP in three of the four domains ( activity limitations [ 0.92 ] , symptoms [ 0.73 ] , and emotional function [ 1.02 ] ) . Mean differences between groups for overall score and these three domains were also clinical ly meaningful . CONCLUSION Patients with severe asthma who received FP ( at approximately half the dose of BDP/BUD ) experienced statistically significant , as well as clinical ly meaningful , improvements in their [8979288] Correlations between knemometric ( lower leg length ) growth rates and urine free cortisol excretion , respectively , and serum concentrations of IGF-I , IGF binding protein-3 , osteocalcin , carboxy terminal propeptide of type I collagen(PICP ) , carboxy terminal pryridinoline cross-linked telopeptide of type I procollagen ( ICTP ) , and amino terminal propeptide of type III procollagen(PIIINP ) were investigated in 17 asthmatic children aged 7 - 14 y during treatment with fluticasone propionate , 200 μg , and beclomethasone dipropionate , 400 and 800 μg/d , taken from dry powder inhalers . The study was a double blind , crossover trial with three active treatment periods and two wash-out periods . All periods were 15 d long . Overnight urine free cortisol/creatinine × 106 did not correlate with knemometric growth rates or any of the serum markers . Significant correlations ( Pearson 's correlation coefficient , P ) between knemometric growth rates and IGF-I ( 0.41 ; 0.006 ) , IGFBP-3 ( 0.35 ; 0.02 ) , PICP ( 0.44 ; 0.003 ) , ICTP ( 0.35 ; 0.001 ) , and PIIINP ( 0.46 ; 0.002 ) were found . Compared with fluticasone propionate , 200 μg , beclomethasone dipropionate , 400 and 800 μg , caused significant suppression of lower leg growth rate ( F = 12.41;p = 0.002 , and F = 23.30 ; p = 0.0001 , respectively ) and of urine free cortisol/creatinine × 106(F = 10.52 ; p = 0.003 , and F = 13.74;p = 0.001 ) . Beclomethasone , 800 μg , caused suppression of PICP compared with fluticasone propionate , 200 μg ( F = 8.31;p = 0.008 ) , and beclomethasone , 400 μg ( F = 7.53;p = 0.01 ) . Both low ( F = 6.82 ; p = 0.02 ) and high ( F = 23.35 ; p = 0.0001 ) doses of beclomethasone were associated with reduced concentrations of ICTP , the high dose being the most suppressive ( F = 4.42 ; p = 0.05 ) . Beclomethasone 400(F = 9.75 ; p = 0.004 ) and 800 μg ( F = 23.61;p = 0.0001 ) result ed in reduced levels of PIIINP . Reduced short-term knemometric growth rates in children treated with inhaled glucocorticosteroids reflect suppressive effects on type I and type III collagen turnover Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Beclomethasone dipropionate ( BDP ) and budesonide ( BUD ) are commonly prescribed inhaled corticosteroids for the treatment of asthma . Fluticasone propionate ( FP ) is newer agent with greater potency in in-vitro assays . OBJECTIVES To compare the efficacy and safety of Fluticasone to Beclomethasone or Budesonide in the treatment of chronic asthma . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

20229280

[18564952] OBJECTIVES To compare outcomes in perception of pain and disability for a group of patients suffering with chronic low-back pain ( CLBP ) when managed in a hospital by either a regional pain clinic or a chiropractor . DESIGN The study was a pragmatic , r and omized , controlled trial . SETTING The trial was performed at a National Health Service ( NHS ) hospital outpatient clinic ( pain clinic ) in the United Kingdom . SUBJECTS AND INTERVENTIONS Patients with CLBP ( i.e. , symptom duration of > 12 weeks ) referred to a regional pain clinic ( outpatient hospital clinic ) were assessed and r and omized to either chiropractic or pain-clinic management for a period of 8 weeks . The study was pragmatic , allowing for normal treatment protocol s to be used . Treatment was administered in an NHS hospital setting . OUTCOME MEASURES The Rol and -Morris Disability Question naire ( RMDQ ) and Numerical Rating Scale were used to assess changes in perceived disability and pain . Mean values at weeks 0 , 2 , 4 , 6 , and 8 were calculated . The mean differences between week 0 and week 8 were compared across the two treatment groups using Student 's t-tests . Ninety-five percent ( 95 % ) confidence intervals ( CIs ) for the differences between groups were calculated . RESULTS R and omization placed 12 patients in the pain clinic and 18 in the chiropractic group , of which 11 and 16 , respectively , completed the trial . At 8 weeks , the mean improvement in RMDQ was 5.5 points greater for the chiropractic group ( decrease in disability by 5.9 ) than for the pain-clinic group ( 0.36 ) ( 95 % CI 2.0 points to 9.0 points ; p = 0.004 ) . Reduction in mean pain intensity at week 8 was 1.8 points greater for the chiropractic group than for the pain-clinic group ( p = 0.023 ) . CONCLUSIONS This study suggests that chiropractic management administered in an NHS setting may be effective for reducing levels of disability and perceived pain during the period of treatment for a sub population of patients with CLBP [15556955] Abstract Objective To estimate the effect of adding exercise classes , spinal manipulation delivered in NHS or private premises , or manipulation followed by exercise to “ best care ” in general practice for patients consulting with back pain . Fig 1 Progress of the UK BEAM trial Design Pragmatic r and omised trial with factorial design . Setting 181 general practice s in Medical Research Council General Practice Research Framework ; 63 community setting s around 14 centres across the United Kingdom . Participants 1334 patients consulting their general practice s about low back pain . Main outcome measures Scores on the Rol and Morris disability question naire at three and 12 months , adjusted for centre and baseline scores . Results All groups improved over time . Exercise improved mean disability question naire scores at three months by 1.4 ( 95 % confidence interval 0.6 to 2.1 ) more than “ best care . ” For manipulation the additional improvement was 1.6 ( 0.8 to 2.3 ) at three months and 1.0 ( 0.2 to 1.8 ) at 12 months . For manipulation followed by exercise the additional improvement was 1.9 ( 1.2 to 2.6 ) at three months and 1.3 ( 0.5 to 2.1 ) at 12 months . No significant differences in outcome occurred between manipulation in NHS premises and in private premises . No serious adverse events occurred . Conclusions Relative to “ best care ” in general practice , manipulation followed by exercise achieved a moderate benefit at three months and a small benefit at 12 months ; spinal manipulation achieved a small to moderate benefit at three months and a small benefit at 12 months ; and exercise achieved a small benefit at three months but not 12 months [17893311] BACKGROUND To our knowledge , verum acupuncture has never been directly compared with sham acupuncture and guideline -based conventional therapy in patients with chronic low back pain . METHODS A patient- and observer-blinded r and omized controlled trial conducted in Germany involving 340 outpatient practice s , including 1162 patients aged 18 to 86 years ( mean + /- SD age , 50 + /- 15 years ) with a history of chronic low back pain for a mean of 8 years . Patients underwent ten 30-minute sessions , generally 2 sessions per week , of verum acupuncture ( n = 387 ) according to principles of traditional Chinese medicine ; sham acupuncture ( n = 387 ) consisting of superficial needling at nonacupuncture points ; or conventional therapy , a combination of drugs , physical therapy , and exercise ( n = 388 ) . Five additional sessions were offered to patients who had a partial response to treatment ( 10%-50 % reduction in pain intensity ) . Primary outcome was response after 6 months , defined as 33 % improvement or better on 3 pain-related items on the Von Korff Chronic Pain Grade Scale question naire or 12 % improvement or better on the back-specific Hanover Functional Ability Question naire . Patients who were unblinded or had recourse to other than permitted concomitant therapies during follow-up were classified as nonresponders regardless of symptom improvement . RESULTS At 6 months , response rate was 47.6 % in the verum acupuncture group , 44.2 % in the sham acupuncture group , and 27.4 % in the conventional therapy group . Differences among groups were as follows : verum vs sham , 3.4 % ( 95 % confidence interval , -3.7 % to 10.3 % ; P = .39 ) ; verum vs conventional therapy , 20.2 % ( 95 % confidence interval , 13.4 % to 26.7 % ; P < .001 ) ; and sham vs conventional therapy , 16.8 % ( 95 % confidence interval , 10.1 % to 23.4 % ; P < .001 . CONCLUSIONS Low back pain improved after acupuncture treatment for at least 6 months . Effectiveness of acupuncture , either verum or sham , was almost twice that of conventional therapy [16916857] Background and Objective : Psychological factors are assumed to predict persistent or recurrent musculoskeletal pain . The influence of psychological factors in patients with low-back pain ( LBP ) or shoulder pain was explored to study whether there is similarity regarding the factors that predict persisting pain and disability . Methods : Patients presenting in primary care with a new episode of shoulder pain or non-specific (sub)acute low back pain ( LBP ) were enrolled in a prospect i ve study . In both patient groups , pain catastrophising , distress , somatisation and fear-avoidance beliefs were measured at baseline . Primary outcome measures at 3 months were ( 1 ) persistent symptoms , and ( 2 ) < 30 % reduction in functional disability . Multivariate logistic regression analysis was used to study the associations between psychological factors and outcome . Results : A total of 587 patients with shoulder pain and 171 patients with LBP were enrolled in the study . In patients with shoulder pain , most associations of psychological factors with outcome were weak and not significant . Only in patients with longer symptom duration at baseline ( ⩾3 months ) were higher scores on catastrophising significantly associated with persistent symptoms ( p = 0.04 ) . In patients with LBP , psychological factors were more strongly associated with poor outcome , although most associations were not significant . Conclusion : Psychological factors , with the exception of fear-avoidance beliefs , are more strongly associated with persistent pain and disability in patients with LBP than in those with shoulder pain . This seems to indicate that in a primary care population the influence of psychological factors on outcome may vary across patients with different types of pain [12890859] OBJECTIVE To determine if acupuncture is an effective , safe adjunctive treatment to st and ard therapy for chronic low back pain ( LBP ) in older patients . METHODS The inclusion criteria for subjects were : ( i ) LBP > or = 12 weeks and ( ii ) age > or = 60 yr ; the exclusion criteria were ( i ) spinal tumour , infection or fracture and ( ii ) associated neurological symptoms . The subjects were r and omized to two groups . The control group of subjects continued their usual care as directed by their physicians , i.e. NSAIDs , muscle relaxants , paracetamol and back exercises . Subjects in the acupuncture group in addition received biweekly acupuncture with electrical stimulation for 5 weeks . Outcome was measured by the modified Rol and Disability Question naire ( RDQ ) at weeks 0 , 2 , 6 and 9 . The primary outcome measure was change in RDQ score between weeks 0 and 6 . RESULTS Fifty-five patients were enrolled , with eight drop-outs . Twenty-four subjects were r and omized to the acupuncture group and 23 were r and omized to the control group . Acupuncture subjects had a significant decrease in RDQ score of 4.1 + /- 3.9 at week 6 , compared with a mean decrease of 0.7 + /- 2.8 in the control group ( P = 0.001 ) . This effect was maintained for up to 4 weeks after treatment at week 9 , with a decrease in RDQ of 3.5 + /- 4.4 from baseline , compared with 0.43 + /- 2.7 in the control group ( P = 0.007 ) . The mean global transition score was higher in the acupuncture group , 3.7 + /- 1.2 , indicating greater improvement , compared with the score in the control group , 2.5 + /- 0.9 ( P < 0.001 ) . Fewer acupuncture subjects had medication-related side-effects compared with the control group . CONCLUSIONS Acupuncture is an effective , safe adjunctive treatment for chronic LBP in older patients [10936472] PURPOSE Herbal medicines are widely used for the treatment of pain , although there is not much information on their effectiveness . This study was design ed to evaluate the effectiveness of willow ( Salix ) bark extract , which is widely used in Europe , for the treatment of low back pain . SUBJECTS AND METHODS We enrolled 210 patients with an exacerbation of chronic low back pain who reported current pain of 5 or more ( out of 10 ) on a visual analog scale . They were r and omly assigned to receive an oral willow bark extract with either 120 mg ( low dose ) or 240 mg ( high dose ) of salicin , or placebo , with tramadol as the sole rescue medication , in a 4-week blinded trial . The principal outcome measure was the proportion of patients who were pain-free without tramadol for at least 5 days during the final week of the study . RESULTS The treatment and placebo groups were similar at baseline in 114 of 120 clinical features . A total of 191 patients completed the study . The numbers of pain-free patients in the last week of treatment were 27 ( 39 % ) of 65 in the group receiving high-dose extract , 15 ( 21 % ) of 67 in the group receiving low-dose extract , and 4 ( 6 % ) of 59 in the placebo group ( P < 0.001 ) . The response in the high-dose group was evident after only 1 week of treatment . Significantly more patients in the placebo group required tramadol ( P < 0.001 ) during each week of the study . One patient suffered a severe allergic reaction , perhaps to the extract . CONCLUSION Willow bark extract may be a useful and safe treatment for low back pain [23194854] In a study that indicates more definitive investigation is needed , 118 patients with chronic back problems seeking treatment for acute attacks of pain were included in a 4-week r and omised double-blinded study on the safety and effectiveness of an extract of Harpagophytum procumbens . Both , the treatment and the placebo were administered in the form of two tablets taken three times per day ; the treatment group had a daily consumption equal to 6,000 mg of crude preparation ( 50 mg harpagoside , the putative active ingredient ) . The treatment and placebo groups were well matched in physical characteristics ; in the severity , duration , nature and accompaniments of their pain ; and in laboratory indices of organ system function . 109 patients completed the study . The study was originally design ed to measure Harpagophytum 's effectiveness by measuring the use of supplementary pain-killer Tramadol over its final 3 weeks . However , this did not differ between the Harpagophytum and placebo groups nor was the consumption closely related to the amount of pain . Further analysis , though , revealed that 9 out of 51 patients who received the extract were pain free at the end of treatment compared to only 1 out of 54 patients who received placebo . A modification of the Arhus index was used as an additional measure , covering the more global impact . The percentage change was greater in those patients who received Harpagophytum extract than in those who received placebo , but inferential testing ( Mann Whitney ) allowed only 94 % degree of confidence that this had not arisen by chance . The Arhus index reduction was based on improvement in pain . This indication of effectiveness , and the absence of demonstrable adverse effects show that more definite clinical studies of Harpagophytum extract will be worthwhile [17250965] Abstract Practice guidelines recommend various types of exercise and manipulative therapy for chronic back pain but there have been few head‐to‐head comparisons of these interventions . We conducted a r and omized controlled trial to compare effects of general exercise , motor control exercise and manipulative therapy on function and perceived effect of intervention in patients with chronic back pain . Two hundred and forty adults with non‐specific low back pain ⩾3 months were allocated to groups that received 8 weeks of general exercise , motor control exercise or spinal manipulative therapy . General exercise included strengthening , stretching and aerobic exercises . Motor control exercise involved retraining specific trunk muscles using ultrasound feedback . Spinal manipulative therapy included joint mobilization and manipulation . Primary outcomes were patient‐specific function ( PSFS , 3–30 ) and global perceived effect ( GPE , −5 to 5 ) at 8 weeks . These outcomes were also measured at 6 and 12 months . Follow‐up was 93 % at 8 weeks and 88 % at 6 and 12 months . The motor control exercise group had slightly better outcomes than the general exercise group at 8 weeks ( between‐group difference : PSFS 2.9 , 95 % CI : 0.9–4.8 ; GPE 1.7 , 95 % CI : 0.9–2.4 ) , as did the spinal manipulative therapy group ( PSFS 2.3 , 95 % CI : 0.4–4.2 ; GPE 1.2 , 95 % CI : 0.4–2.0 ) . The groups had similar outcomes at 6 and 12 months . Motor control exercise and spinal manipulative therapy produce slightly better short‐term function and perceptions of effect than general exercise , but not better medium or long‐term effects , in patients with chronic non‐specific back pain [12865832] Study Design . A r and omized controlled clinical trial was conducted . Objective . To compare medication , needle acupuncture , and spinal manipulation for managing chronic ( > 13 weeks duration ) spinal pain because the value of medicinal and popular forms of alternative care for chronic spinal pain syndromes is uncertain . Summary of Background Data . Between February 1999 and October 2001 , 115 patients without contraindication for the three treatment regimens were enrolled at the public hospital ’s multidisciplinary spinal pain unit . Methods . One of three separate intervention protocol s was used : medication , needle acupuncture , or chiropractic spinal manipulation . Patients were assessed before treatment by a sports medical physician for exclusion criteria and by a research assistant using the Oswestry Back Pain Disability Index ( Oswestry ) , the Neck Disability Index ( NDI ) , the Short-Form-36 Health Survey question naire ( SF-36 ) , visual analog scales ( VAS ) of pain intensity and ranges of movement . These instruments were administered again at 2 , 5 , and 9 weeks after the beginning of treatment . Results . R and omization proved to be successful . The highest proportion of early ( asymptomatic status ) recovery was found for manipulation ( 27.3 % ) , followed by acupuncture ( 9.4 % ) and medication ( 5 % ) . Manipulation achieved the best overall results , with improvements of 50 % ( P = 0.01 ) on the Oswestry scale , 38 % ( P = 0.08 ) on the NDI , 47 % ( P < 0.001 ) on the SF-36 , and 50 % ( P < 0.01 ) on the VAS for back pain , 38 % ( P < 0.001 ) for lumbar st and ing flexion , 20 % ( P < 0.001 ) for lumbar sitting flexion , 25 % ( P = 0.1 ) for cervical sitting flexion , and 18 % ( P = 0.02 ) for cervical sitting extension . However , on the VAS for neck pain , acupuncture showed a better result than manipulation ( 50%vs 42 % ) . Conclusions . The consistency of the results provides , despite some discussed shortcomings of this study , evidence that in patients with chronic spinal pain , manipulation , if not contraindicated , results in greater short-term improvement than acupuncture or medication . However , the data do not strongly support the use of only manipulation , only acupuncture , or only nonsteroidal antiinflammatory drugs for the treatment of chronic spinal pain . The results from this exploratory study need confirmation from future larger studies [16816766] Study Design . Prospect i ve study with 6 weeks of follow-up . Objective . To examine the predictors of outcome for patients with (sub)acute low back pain ( LBP ) receiving usual care ( UC ) or a minimal intervention strategy ( MIS ) aim ed at psychosocial factors . Summary of Background Data . A r and omized controlled trial in general practice showed no differences in average effect between UC and MIS . Methods . Socio-demographic variables , characteristics of LBP , and psychosocial factors were included as potential predictors of outcome . The outcome clinical ly important improvement was defined as a reduction of at least 30 % on functional disability plus patient perceived recovery . Logistic regression analyses were used to study the associations between predictors and outcome at 6 weeks follow-up . Results . In the UC group ( n = 163 ) , the multivariable model included a shorter duration of the LBP episode , few previous episodes , less pain catastrophizing , and good perceived general health . The area under the curve ( AUC ) of the model was 0.77 ( 95 % confidence interval , 0.70–0.85 ) . In the MIS group ( n = 142 ) , the multivariable model included less somatizing symptoms , more solicitous responses by an important other , lower perceived risk for chronic LBP , more fear avoidance beliefs , higher level of education , and shorter duration of the LBP episode . This AUC was 0.78 ( 95 % confidence interval , 0.71–0.86 ) . Conclusions . As we found two different profiles , our approach may contribute to the important question : what intervention works for whom [8140876] A controlled study of different modes of acupuncture stimulation was conducted on patients fulfilling clinical criteria for chronic low back pain of nociceptive origin . Forty patients were r and omly entered into the study . Thirty had three trial treatments with manual stimulation of needles ( MS ) , electrical low frequency stimulation at 2 Hz ( LF ) , and high – frequency stimulation at 80 Hz ( HF ) , and then continued treatment with the mode they felt most benefitted them . Ten patients were put on the waiting list for treatment but served as the untreated control group . The results were evaluated after 6 weeks and at 6 months for : activity related to pain ; mobility ; verbal descriptors of pain and the patient 's subjective assessment of his condition . After 6 weeks , patients receiving treatment showed significant improvement ( P < 0.05 to P < 0.001 ) on three of the four measures compared to the untreated controls . After 6 months a similar measure of significant improvement was seen in patients continuing with low – frequency ( LF ) acupuncture , but not in those groups continuing with manual stimulation ( MS ) or high – frequency ( HF ) acupunture . The results suggest that 2 Hz electrical stimulation is the mode of choice when using acupuncture in the treatment of chronic nociceptive low back pain [16505266] BACKGROUND Acupuncture is widely used by patients with low back pain , although its effectiveness is unclear . We investigated the efficacy of acupuncture compared with minimal acupuncture and with no acupuncture in patients with chronic low back pain . METHODS Patients were r and omized to treatment with acupuncture , minimal acupuncture ( superficial needling at nonacupuncture points ) , or a waiting list control . Acupuncture and minimal acupuncture were administered by specialized acupuncture physicians in 30 outpatient centers , and consisted of 12 sessions per patient over 8 weeks . Patients completed st and ardized question naires at baseline and at 8 , 26 , and 52 weeks after r and omization . The primary outcome variable was the change in low back pain intensity from baseline to the end of week 8 , as determined on a visual analog scale ( range , 0 - 100 mm ) . RESULTS A total of 298 patients ( 67.8 % female ; mean + /- SD age , 59 + /- 9 years ) were included . Between baseline and week 8 , pain intensity decreased by a mean + /- SD of 28.7 + /- 30.3 mm in the acupuncture group , 23.6 + /- 31.0 mm in the minimal acupuncture group , and 6.9 + /- 22.0 mm in the waiting list group . The difference for the acupuncture vs minimal acupuncture group was 5.1 mm ( 95 % confidence interval , -3.7 to 13.9 mm ; P = .26 ) , and the difference for the acupuncture vs waiting list group was 21.7 mm ( 95 % confidence interval , 13.9 - 30.0 mm ; P<.001 ) . Also , at 26 ( P=.96 ) and 52 ( P=.61 ) weeks , pain did not differ significantly between the acupuncture and the minimal acupuncture groups . CONCLUSION Acupuncture was more effective in improving pain than no acupuncture treatment in patients with chronic low back pain , whereas there were no significant differences between acupuncture and minimal acupuncture [16648741] Study Design . R and omized , single blind , controlled trial . Objective . To determine the efficacy of 2 components of musculoskeletal physiotherapy on chronic low back disorder . Summary of Background Data . Musculoskeletal physiotherapy encompasses many treatment methods , however , manual therapy and exercises to rehabilitate spinal stabilization are the most frequently used . Despite their popularity , scant evidence supports their use on subjects with chronic low back disorder . Methods . A total of 346 subjects were r and omized to manual therapy , a 10-week spinal stabilization rehabilitation program , or a minimal intervention control group . Data were collected at baseline , and 3 , 6 , 12 , and 24 months after intervention . Outcome measures recorded intensity of low back pain , disability , h and icap , medication , and quality of life . There were 4 main variables combined in a primary component analysis to form a single outcome measure ( i.e. , a measure of dysfunction ) . Results . The results indicated statistically significant improvements in favor of the spinal stabilization group at the 6-month stage in pain ( 65.9 % reduction in symptoms ) and dysfunction ( combined mean reduction of 134 , st and ard error 23.84 ) , and at the 1-year stage in medication ( 34.3 % reduction in medication ) , dysfunction ( combined mean reduction of 134 , st and ard error 18.2 ) , and disability ( mean difference in change 15.71 Oswestry Disability Index , 95 % confidence interval 19.3–10.01 ) . Conclusions . As a component of musculoskeletal physiotherapy , the spinal stabilization program is more effective than manually applied therapy or an education booklet in treating chronic low back disorder over time . Both manual therapy and the spinal stabilization program are significantly effective in pain reduction in comparison to an active control . To our knowledge and up until now , this result has not been shown in patients with chronic low back disorder [16798792] In a r and omized controlled trial plus a nonr and omized cohort , the authors investigated the effectiveness and costs of acupuncture in addition to routine care in the treatment of chronic low back pain and assessed whether the effects of acupuncture differed in r and omized and nonr and omized patients . In 2001 , German patients with chronic low back pain were allocated to an acupuncture group or a no-acupuncture control group . Persons who did not consent to r and omization were included in a nonr and omized acupuncture group . All patients were allowed to receive routine medical care in addition to study treatment . Back function ( Hannover Functional Ability Question naire ) , pain , and quality of life were assessed at baseline and after 3 and 6 months , and cost-effectiveness was analyzed . Of 11,630 patients ( mean age=52.9 years ( st and ard deviation , 13.7 ) ; 59 % female ) , 1,549 were r and omized to the acupuncture group and 1,544 to the control group ; 8,537 were included in the nonr and omized acupuncture group . At 3 months , back function improved by 12.1 ( st and ard error ( SE ) , 0.4 ) to 74.5 ( SE , 0.4 ) points in the acupuncture group and by 2.7 ( SE , 0.4 ) to 65.1 ( SE , 0.4 ) points among controls ( difference=9.4 points ( 95 % confidence interval 8.3 , 10.5 ) ; p<0.001 ) . Nonr and omized patients had more severe symptoms at baseline and showed improvements in back function similar to those seen in r and omized patients . The incremental cost-effectiveness ratio was euro10,526 ( euros ) per quality -adjusted life year . Acupuncture plus routine care was associated with marked clinical improvements in these patients and was relatively cost-effective [16103840] Study Design . An observational prospect i ve cohort study in general practice . Objectives . To describe the clinical course and to identify predictors of recovery , changes in pain intensity , and changes in functional disability in patients with neck or shoulder symptoms at 3- and 12-month follow-up . Summary of Background Data . Knowledge on the clinical course and predictors of outcome in neck and shoulder symptoms is limited . Such knowledge would facilitate treatment decisions and may help to inform patients about their prognosis . Methods . Four hundred and forty-three patients who consulted their general practitioner with neck or shoulder symptoms participated in the study . Baseline scores of pain and disability , symptom characteristics , sociodemographic and psychological factors , social support , physical activity , general health , and comorbidity were investigated as possible predictors of recovery , changes in pain intensity , and changes in functional disability using multiple regression analyses . Results . The recovery rate was low ; 24 % of the patients reported recovery at 3 months and 32 % reported recovery at 12-month follow-up . Duration of the symptoms before consulting the GP and a history of neck or shoulder symptoms increased the probability of an unfavorable outcome . Furthermore , less vitality and more worrying were consistently associated with poorer outcome after 3 and 12 months . The area under the receiver-operator characteristic curve for the model predicting recovery was 0.8 at 3 months and 0.75 at 12 months . The explained variance of the models on pain and functional disability ranged from 43 to 54 % . Conclusions . The results found in this study indicate that besides clinical characteristics , psychological factors also predict the outcome of neck and shoulder symptoms [16881095] OBJECTIVE To investigate the course of lateral epicondylitis and identify prognostic indicators associated with short- and longterm outcome of pain intensity . METHODS We prospect ively followed patients ( n = 349 ) from 2 r and omized controlled trials investigating conservative interventions for lateral epicondylitis in primary care . Uni- and multivariate linear regression analyses were used to investigate the association between potential prognostic indicators and pain intensity ( 0 - 100 point scale ) measured at 1 , 6 , and 12 months after r and omization . Potential prognostic factors were duration of elbow complaints , concomitant neck pain , concomitant shoulder pain , previous elbow complaints , baseline pain scores , age , gender , involvement of dominant side , social class , and work status . The variables " study " and " treatment " were included as covariates in all models . RESULTS Pain scores at 1 month followup were higher in patients with severe pain , a long duration of elbow complaints , and concomitant shoulder pain . At 12 month followup , the only different prognostic indicator for poor outcome was concomitant neck pain , in place of shoulder pain . Patients from higher social classes reported lower pain scores at 12 month followup than patients from lower social classes . CONCLUSIONS Lateral epicondylitis seems to be a self-limiting condition in most patients . Long duration of elbow complaints , concomitant neck pain , and severe pain at presentation are associated with poor outcome at 12 months . Our results will help care providers give patients accurate information regarding their prognosis and assist in medical decision-making [11932074] & NA ; There is some evidence for the efficacy of acupuncture in chronic low‐back pain ( LBP ) , but it remains unclear whether acupuncture is superior to placebo . In a r and omized , blinded , placebo‐controlled trial , we evaluated the effect of traditional acupuncture in chronic LBP . A total of 131 consecutive out‐ patients of the Department of Orthopaedics , University Goettingen , Germany , ( age=48.1 years , 58.5 % female , duration of pain : 9.6 years ) with non‐radiating LBP for at least 6 months and a normal neurological examination were r and omized to one of three groups over 12 weeks . Each group received active physiotherapy over 12 weeks . The control group ( n=46 ) received no further treatment , the acupuncture group ( n=40 ) received 20 sessions of traditional acupuncture and the sham‐acupuncture group ( n=45 ) 20 sessions of minimal acupuncture . Changes from baseline to the end of treatment and to 9‐month follow‐up were assessed in pain intensity and in pain disability , and secondary in psychological distress and in spine flexion , compared by intervention groups . Acupuncture was superior to the control condition ( physiotherapy ) regarding pain intensity ( P=0.000 ) , pain disability ( P=0.000 ) , and psychological distress ( P=0.020 ) at the end of treatment . Compared to sham‐acupuncture , acupuncture reduced psychological distress ( P=0.040 ) only . At 9‐month follow‐up , the superiority of acupuncture compared to the control condition became less and acupuncture was not different to sham‐acupuncture . We found a significant improvement by traditional acupuncture in chronic LBP compared to routine care ( physiotherapy ) but not compared to sham‐acupuncture . The trial demonstrated a placebo effect of traditional acupuncture in chronic LBP [11752510] OBJECTIVES To compare the effects of a proprietary extract of willow bark ( Assalix ) and a selective inhibitor ( rofecoxib ) of the enzyme cyclo-oxygenase-2 ( COX-2 ) . METHODS An open , r and omized , post-marketing study was carried out in an out- patients clinic on two groups of patients aged 18 to 80 yr presenting over a 6-month period with acute exacerbations of low back pain . Using computer-generated r and om list , 114 patients were allocated to receive a daily dose of herbal extract containing 240 mg of salicin [ PAID ( phyto-anti-inflammatory drug ) group ] and 114 were allocated to receive 12.5 mg of the synthetic COX-2 inhibitor rofecoxib [ NSAID ( non-steroidal anti-inflammatory drug ) group ] . The doses were chosen according to existing recommendations . All patients were free to use whatever additional conventional treatments were thought necessary . The outcome measures were a modified Arhus index , its pain component and the Total Pain Index . RESULTS Groups were well matched . After 4 weeks of treatment , the Arhus index had improved by about 20 % , its pain component by about 30 % and the Total Pain Index by about 35 % . The number of pain-free patients ( visual analogue scale score < 2 ) was about 20 in each group . About 60 % of the patients in each group responded well to the treatment ( as judged by an improvement of > /=30 % in the Total Pain Index relative to its baseline ) . The improvement was also reflected reasonably well in the physicians ' and patients ' judgements of the effectiveness of treatment , which were largely concordant . Few patients of either group resorted to the additional conventional treatment options . The incidence of adverse events was similar in the two groups . Treatment with rofecoxib was about 40 % more expensive than that with Assalix . CONCLUSION There was no significant difference in effectiveness between the two treatments at the doses chosen . Treatment with Assalix was less expensive [15726029] OBJECTIVE To assess the long-term benefits of medication , needle acupuncture , and spinal manipulation as exclusive and st and ardized treatment regimens in patients with chronic ( > 13 weeks ) spinal pain syndromes . STUDY DESIGN Extended follow-up ( > 1 year ) of a r and omized clinical trial was conducted at the multidisciplinary spinal pain unit of Townsville 's General Hospital between February 1999 and October 2001 . PATIENTS AND METHODS Of the 115 patients originally r and omized , 69 had exclusively been treated with the r and omly allocated treatment during the 9-week treatment period ( results at 9 weeks were reported earlier ) . These patients were followed up and assessed again 1 year after inception into the study reapplying the same instruments ( ie , Oswestry Back Pain Index , Neck Disability Index , Short-Form-36 , and Visual Analogue Scales ) . Question naires were obtained from 62 patients reflecting a retention proportion of 90 % . The main analysis was restricted to 40 patients who had received exclusively the r and omly allocated treatment for the whole observation period since r and omization . RESULTS Comparisons of initial and extended follow-up question naires to assess absolute efficacy showed that only the application of spinal manipulation revealed broad-based long-term benefit : 5 of the 7 main outcome measures showed significant improvements compared with only 1 item in each of the acupuncture and the medication groups . CONCLUSIONS In patients with chronic spinal pain syndromes , spinal manipulation , if not contraindicated , may be the only treatment modality of the assessed regimens that provides broad and significant long-term benefit [1574327] Background Previous clinical trials have assessed the percentage of participants who utilized further health care after a period of conservative care for low back pain , however no chiropractic clinical trial has determined the total amount of care during this time and any differences based on assigned treatment group . The objective of this clinical trial follow-up was to assess if there was a difference in the total number of office visits for low back pain over one year after a four week clinical trial of either a form of physical therapy ( Exercise Program ) or a form of chiropractic care ( Flexion Distraction ) for chronic low back pain . Methods In this r and omized clinical trial follow up study , 195 participants were followed for one year after a four-week period of either a form of chiropractic care ( FD ) or a form of physical therapy ( EP ) . Weekly structured telephone interview questions regarded visitation of various health care practitioners and the practice of self-care for low back pain . Results Participants in the physical therapy group demonstrated on average significantly more visits to any health care provider and to a general practitioner during the year after trial care ( p < 0.05 ) . No group differences were noted in the number of visits to a chiropractor or physical therapist . Self-care was initiated by nearly every participant in both groups . Conclusion During a one-year follow-up , participants previously r and omized to physical therapy attended significantly more health care visits than those participants who received chiropractic care [6446852] The acupuncture treatment situation was beneficial to the majority of people with low back pain . This was shown by the use of short-term controls and long-term controls , although the latter were not intended in the study design . After acupuncture , there was a 51 % pain reduction in the average pain score in the Immediate Treatment Group . The short-term controls , the Delayed Treatment Group , had no reduction whatsoever in their pain scores at the comparable followup period . Later , the Delayed Treatment Group bere also treated by acupuncturists , and reported 62 % less pain . When these two treatment groups were compared at 40 weeks with long-term controls ( Inadequate Treatment Group ) , the Inadequate Treatment Group still had the same pain scores , on the average , as when they enrolled in the study . Both treatment groups , on the average , had 30 % lower pain scores . Furthermore , 58 % of the treatment groups felt that they were definitely improved at 40 weeks , while only 11 % of the Inadequate Treatment Group felt definitely improved at 40 weeks [14581111] & NA ; The efficacy and tolerance of a capsicum plaster in non‐specific low back pain was investigated in a double‐blind , r and omised , placebo‐controlled multicentre parallel group study . A total of 320 patients were r and omly assigned to two groups of n=160 subjects treated by the active or the placebo plaster . The main outcome measures used were a compound pain subscore of the Arhus low back rating scale ( continuous variable ) , and a response criterion of a reduction in pain subscore=30 % from baseline to final assessment ( secondary , non‐continuous variable ) . In addition , the partial pain scores , disability and mobility restriction subscores , the total score of the Arhus low back rating scale , the global evaluation of efficacy by investigator and patient , adverse events , a patient question naire on use of the plaster , and an evaluation of tolerance by investigator and patient were obtained . After 3 weeks treatment with capsicum and placebo plaster respectively , the compound pain subscore was reduced by 42 % ( capsicum ) and 31 % ( placebo ) from values on entry . Responder rate was 67 % versus 49 % ( p=0.002 ) . The investigators rated efficacy as “ excellent ” or “ good ” by 74 % and 36 % ; the patient 's efficacy rating “ symptomfree ” or “ improved ” reached 82 % and 50 % . Adverse local drug reactions were found in 12 patients ( 7.5 % ) on capsicum and 5 ( 3.1 % ) on placebo . No systemic side‐effects were observed . The superiority of the treatment of chronic non‐specific low back pain with capsicum plaster compared to placebo was clinical ly relevant and highly statistically significant . The capsicum plaster offers a genuine alternative in the treatment of non‐specific low back pain [15105215] Acupuncture is an established adjuvant analgesic modality for the treatment of chronic pain . Electrical stimulation of acupuncture points is considered to increase acupuncture analgesia . In this prospect i ve , r and omized , double-blind , controlled study we tested the hypothesis that auricular electroacupuncture ( EA ) relieves pain more effectively than conventional manual auricular acupuncture ( CO ) in chronic low back pain patients with insufficient pain relief ( visual analogue scale [ VAS ] ≥5 ) treated with st and ardized analgesic therapy . Disposable acupuncture needles were inserted in the auricular acupuncture points 29 , 40 , and 55 of the dominant side and connected to a newly developed battery-powered miniaturized stimulator worn behind the ear . Patients were r and omized into group EA ( n = 31 ) with continuous low-frequency auricular EA ( 1 Hz biphasic constant current of 2 mA ) and group CO ( n = 30 ) without electrical stimulation ( sham-electroacupuncture ) . Treatment was performed once weekly for 6 wk , and in each group needles were withdrawn 48 h after insertion . During the study period and a 3-mo follow-up , patients were asked to complete the McGill question naire . Psychological well being , activity level , quality of sleep , and pain intensity were assessed by means of VAS ; moreover , analgesic drug consumption was documented . Pain relief was significantly better in group EA during the study and the follow-up period as compared with group CO . Similarly , psychological well-being , activity , and sleep were significantly improved in group EA versus group CO , the consumption of analgesic rescue medication was less , and more patients returned to full-time employment . Neuropathic pain in particular improved in patients treated with EA . There were no adverse side effects . These results are the first to demonstrate that continuous EA stimulation of auricular acupuncture points improves the treatment of chronic low back pain in an outpatient population [11765591] Topically applied capsaicin ( CAS 404 - 86 - 4 ) induces the release of substance P , a neurotransmitter , from sensory C-fibres . In addition , there is a specific blockade of transport and de-novo synthesis of substance P. As a result , repeated applications of capsaicin bring about a long lasting desensitisation to pain ( increase of pain threshold ) . The desensitising effect is fully reversible . The confirmed pharmacodynamic actions and a number of double-blind clinical studies indicate that local capsicum preparations are very suitable for the treatment of neuropathic pain or musculoskeletal disorders , with or without inflammatory components . In a double-blind , r and omised parallel-group study a capsicum plaster was compared with a placebo for 3 weeks in 154 patients with non-specific back pain . Inclusion criteria were a history of back pain for a minimum period of 3 months and a degree of pain of 5 or more on an eleven grade visual analogue scale . The principal target variable consisted of the score of 3 combined pain scales . Secondary efficacy measures were tests of mobility , a disability index ( in the context of Arhus low back rating scale ) and global assessment s by physicians and patients . For patients to be rated as responders their total pain score at the final examination after 3 weeks of treatment had to show a reduction by at least 30 % of the baseline value . The study unequivocally achieved the target criterion with a rate of responders in the capsicum group of 60.8 % against 42.1 % in the placebo group ( p = 0.0219 ) . The sum of the 3 separate pain scales decreased more markedly in the capsicum group than in the placebo group ( 38.5 % compared to 28.0 % ; p = 0.002 ) . Relatively slight improvements of the impaired mobility and the functional status are explained by the characteristics of the disorder treated . The efficacy ratings by observers and patients was definitely in favour of capsicum . Adverse effects -- mostly harmless and resolving spontaneously -- were reported by 15 patients in the capsicum group and by 9 in the placebo group . The tolerance ratings by investigators and patients were superior to the placebo product . This , however , partly is due to the local pharmacological actions of the drug . As in comparably positive r and omised studies with capsaicin cream in patients with osteoarthritis or fibromyalgia it was shown that a capsicum plaster preparation can also be used to advantage in chronic non-specific back pain [16426760] Abstract Shoulder pain is common in primary care and has an unfavourable outcome in many patients . Information about predictors of outcome is scarce and inconsistent . The objective of this study was to develop clinical prediction rules for calculating the absolute risk of persistent shoulder symptoms for individual patients , 6 weeks and 6 month after the first consultation in general practice . A prospect i ve cohort study with 6 months follow‐up was carried out in three geographic areas in The Netherl and s. In this study , 587 patients with a new episode of shoulder pain were included . The main outcome measure was persistent symptoms at 6 weeks and 6 months , perceived by the patient . Potential predictors included the results of a physical examination , sociodemographic variables , disease characteristics ( duration of symptoms , pain intensity , disability and comorbidity ) , physical activity , physical workload and psychosocial factors . Response rates to the follow‐up question naires were 83 % at 6 weeks and 92 % at 6 months . A longer duration of symptoms , gradual onset of pain and high pain severity at presentation were consistently associated with persistent symptoms at 6 weeks and 6 months . The discriminative validity of our prediction rules was satisfactory with area under the curves of 0.74 ( 95 % CI 0.70 , 0.79 ) at 6 weeks and 0.67 ( 95 % CI 0.63 , 0.71 ) at 6 months . The performance of our rules needs to be tested in other population s of patients with shoulder pain to enable valid and reliable use of the rules in everyday clinical practice [14600536] Objective To assess the efficacy of acupuncture in the treatment of chronic low back pain . Methods Patients ( n = 60 ) with chronic low back pain were recruited and r and omly allocated to either Acupuncture therapy or Placebo transcutaneous electrical nerve stimulation ( TENS ) groups . Patients were treated weekly for 6 weeks , and blinded assessment s were carried out pre- and post-treatment using the McGill Pain Question naire ( MPQ ) and visual analog scales ( VAS ) for pain , the Short-form 36 quality -of-life question naire , and a simple range of motion measurement . A total of 46 patients completed the trial and were followed up at 6 months . Results Analysis of results using t tests showed that in both groups there were significant pre-post improvements for all scores , except for MPQ scores in the Placebo-TENS group . There was no significant difference between the 2 groups for any of the outcome measures at the end of treatment . Results from the 6-month follow-up would suggest that the response was better in the acupuncture group . Discussion Further research is necessary to fully assess the efficacy of this treatment in combating chronic low back pain using larger sample sizes or alternative control groups [12972723] Background : We report on the study design and protocol s of two r and omized controlled trials ( Acupuncture R and omized Trials = ART ) that investigate the efficacy of acupuncture in the treatment of chronic low back pain and osteoarthritis of the knee , respectively . Objective : To investigate whether acupuncture is more efficacious than ( a ) no treatment or ( b ) minimal acupuncture in the treatment of low back pain and osteoarthritis . Design : Two r and omized , controlled , multicenter trials with three treatment arms and a total follow-up time of 52 weeks . Setting : 30 practitioners and outpatient units in Germany specialized in acupuncture treatment . Patients : 300 patients will be included in each study . In the low back pain trial , patients will be included according to clinical diagnosis . In the osteoarthritis pain trial , patients will be included according to the American College of Rheumatology criteria . Interventions : Patients are r and omly assigned to receive either ( 1 ) semi-st and ardized acupuncture ( 150 patients ) , ( 2 ) minimal acupuncture at non-acupuncture points ( 75 patients ) , or ( 3 ) no treatment for two months followed by semi-st and ardized acupuncture ( 75 patients , waiting list control ) . Acupuncture treatment consists of 12 sessions per patient over a period of 8 weeks . Main Outcome Measure : The main outcome measure is the difference between baseline and the end of the 8-week treatment period in the following parameters : pain intensity as measured by a visual analogue scale ( VAS ; 0–100 mm ) in the low back pain trial and by the Western Ontario and McMaster Universities Osteoarthritis Score ( WOMAC ) in the osteoarthritis trial . Outlook : The results of these two studies ( available in 2004 ) will provide health care providers and policy makers with the information needed to make scientifically sound assessment s of acupuncture therapy [16970535] OBJECTIVE Descriptions of the interventions used in acupuncture studies are often incomplete . The aim of this paper is to describe participating trial physicians and interventions in a r and omised trial of acupuncture for low back pain . DESIGN Three-armed , r and omized , controlled multicenter trial with 1-year follow-up . A total of 301 patients with low-back pain were r and omized to 12 sessions of semist and ardized acupuncture ( at least six local and two distant points needled bilaterally from a selection of predefined points , but individual choice of additional body or ear acupuncture points possible ) , minimal acupuncture ( superficial needling of at least 6 of 10 predefined , bilateral , distant nonacupuncture points ) , or a waiting list control ( 2 months no acupuncture followed by semist and ardised acupuncture described above ) . OUTCOME MEASURES Participating trial physicians and interventions . RESULTS Forty-five ( 45 ) physicians specializing in acupuncture ( mean age 44 + /- 7.8 years , 23 ( 51 % ) female ) in 30 outpatient centers in Germany provided the interventions . The median duration of acupuncture training of trial physicians was 350 hours ( range 140 - 2508 ) . The most frequently reported Chinese diagnosis was Kidney deficiency ( 39 % ) , followed by qi and Blood stagnation ( 24 % ) , and bi syndrome ( 20 % ) . The total number of needles used was 17.3 + /- 4.2 in the acupuncture group compared to 12.3 + /- 1.2 in the minimal acupuncture group . In total , 40 physicians ( 89 % ) stated that they would have treated patients similarly or in exactly the same way outside of the trial , whereas 5 ( 11 % ) stated that they would have treated patients differently . CONCLUSIONS For most trial physicians , the semist and ardized acupuncture strategy used in this trial was an acceptable compromise for an efficacy study . However , a relevant minority of participating trial physicians stated that they would have treated patients differently outside of the trial [10422654] Sixty patients aged 60 or over with back pain for at least 6 months were recruited from General Practitioner referrals and r and omized to 4 weeks of treatment with acupuncture or transcutaneous electrical nerve stimulation ( TENS ) . All treatments were administered by the same physiotherapist and both groups had the same contact with him . The following were measured at baseline , completion and at a 3-month follow-up by an independent observer blinded to treatment received : ( 1 ) pain severity on visual analogue scale ( VAS ) ; ( 2 ) pain subscale of Nottingham Health Profile ( NHP ) ; ( 3 ) number of analgesic tablets consumed in previous week ; ( 4 ) spinal flexion from C7 to S1 . Thirty-two patients were r and omized to acupuncture and 28 to TENS ; only three withdrew ( two from acupuncture , one from TENS ) . Significant improvements were shown on VAS ( P < 0.001 ) , NHP ( P < 0.001 ) and tablet count ( P < 0.05 ) between baseline and completion in both groups , these improvements remaining significant comparing baseline with follow-up with a further non-significant improvement in VAS and NHP in the acupuncture group . The acupuncture but not the TENS patients showed a small but statistically significant improvement ( P < 0.05 ) in mean spinal flexion between baseline and completion which was not maintained at follow-up . Thus in these elderly patients with chronic back pain both acupuncture and TENS had demonstrable benefits which outlasted the treatment period . Acupuncture may improve spinal flexion . This trial can not exclude the possibility that both treatments are ' placebos ' [16540864] Study Design . R and omized clinical trial . Objective . Compare outcomes of patients with low back pain receiving treatments matched or unmatched to their subgrouping based on initial clinical presentation . Summary of Background Data . Patients with “ nonspecific ” low back pain are often viewed as a homogeneous group , equally likely to respond to any particular intervention . Others have proposed methods for subgrouping patients as a means for determining the treatment most likely to benefit patients with particular characteristics . Methods . Patients with low back pain of less than 90 days ’ duration referred to physical therapy were examined before treatment and classified into one of three subgroups based on the type of treatment believed most likely to benefit the patient ( manipulation , stabilization exercise , or specific exercise ) . Patients were r and omly assigned to receive manipulation , stabilization exercises , or specific exercise treatment during a 4-week treatment period . Disability was assessed in the short-term ( 4 weeks ) and long-term ( 1 year ) using the Oswestry . Comparisons were made between patients receiving treatment matched to their subgroup , versus those receiving unmatched treatment . Results . A total of 123 patients participated ( mean age , 37.7 ± 10.7 years ; 45 % female ) . Patients receiving matched treatments experienced greater short- and long-term reductions in disability than those receiving unmatched treatments . After 4 weeks , the difference favoring the matched treatment group was 6.6 Oswestry points ( 95 % CI , 0.70–12.5 ) , and at long-term follow-up the difference was 8.3 points ( 95 % CI , 2.5–14.1 ) . Compliers-only analysis of long-term outcomes yielded a similar result . Conclusions . Nonspecific low back pain should not be viewed as a homogenous condition . Outcomes can be improved when subgrouping is used to guide treatment decision-making [16618043] Introduction There is some evidence for the efficacy of acupuncture , but it remains unclear whether trigger point acupuncture is effective . Our objective was to evaluate the effects of trigger point acupuncture on pain and quality of life in chronic low back pain patients compared with sham acupuncture . Methods Twenty-six consecutive out- patients ( 17 women , 9 men ; age range : 65–91 years ) from the Department of Orthopaedic Surgery , Meiji University of Oriental Medicine , with non-radiating low back pain for at least six months and normal neurological examination , were r and omised to two groups . Each group received one phase of trigger point acupuncture and one of sham acupuncture with a three week washout period between them , over 12 weeks . Group A ( n=13 ) received trigger point acupuncture in the first phase and sham acupuncture in the second . Group B ( n=13 ) received the same interventions in the reverse order . Outcome measures were pain intensity ( visual analogue scale , VAS ) and Rol and Morris Question naire . Results Nineteen patients were included in the analysis . At the end of the first treatment phase , group A receiving trigger point acupuncture scored significantly lower VAS ( P<0.001 ) and Rol and Morris Question naire scores ( P<0.01 ) than the sham control group . There were significant within-group reductions in pain in both groups during the trigger point acupuncture phase but not in the sham treatment phase . However , the beneficial effects were not sustained . Conclusion These results suggest that trigger point acupuncture may have greater short term effects on low back pain in elderly patients than sham acupuncture [15628774] Objective There is some evidence for the efficacy of acupuncture in chronic low back pain , but it remains unclear which acupuncture modes are most effective . Our objective was to evaluate the effects of two different modes of trigger point acupuncture on pain and quality of life in chronic low back pain patients compared to st and ard acupuncture treatment . Methods Thirty five consecutive out- patients ( 25 women , 10 men ; age range : 65–81 years ) from the Department of Orthopaedic Surgery , Meiji University of Oriental Medicine , with non-radiating low back pain for at least six months and normal neurological examination , were r and omised to one of three groups over 12 weeks . Each group received two phases of acupuncture treatment with an interval between them . Nine patients dropped out during the course of the study . The st and ard acupuncture group ( n=9 ) received treatment at traditional acupuncture points for low back pain , while the other acupuncture groups received superficial ( n=9 ) or deep ( n=9 ) treatments on trigger points . Outcome measures were VAS pain intensity and Rol and Morris Question naire . Results After treatment , the group that received deep needling to trigger points reported less pain intensity and improved quality of life compared to the st and ard acupuncture group or the group that received superficial needling to trigger points , but the differences were not statistically significant . There was a significant reduction in pain intensity between the treatment and interval in the group that received deep needling to trigger points ( P<0.01 ) , but not in the st and ard acupuncture group or the group that received superficial needling to trigger points . Conclusion These results suggest that deep needling to trigger points may be more effective in the treatment of low back pain in elderly patients than either st and ard acupuncture therapy , or superficial needling to trigger points [16970536] OBJECTIVE Flexion distraction is a commonly used form of chiropractic care with chiropractor utilization rates of 58 % . However , no previous r and omized clinical trial has assessed the effectiveness of this form of care . The objective of this investigation was to compare the pain and disability during the year after active care based on treatment group allocation ( Flexion Distraction versus Exercise Program ) . STUDY DESIGN R and omized clinical trial , follow-up . SUBJECTS Two hundred and thirty-five ( 235 ) subjects who were previously r and omized to either chiropractic care ( flexion distraction ) or physical therapy ( exercise program ) within a clinical trial . OUTCOME MEASURES Subjects were followed for 1 year via mailed question naires to assess levels of pain ( Visual Analog Scale ) and dysfunction ( Rol and Morris ) . RESULTS Study subjects had a decrease in pain and disability after intervention regardless of which group they attended ( p < 0.002 ) , however , during the year after care , subjects who received chiropractic care ( flexion distraction therapy ) had significantly lower pain scores than subjects who received physical therapy ( exercise program ) ( p = 0.02 ) . CONCLUSIONS In this first trial on flexion distraction care , flexion distraction was found to be more effective in reducing pain for 1 year when compared to a form of physical therapy [10478769] OBJECTIVE To compare needle acupuncture , medication ( tenoxicam with ranitidine ) , and spinal manipulation for managing chronic ( > 13 weeks duration ) spinal pain syndromes . DESIGN Prospect i ve , r and omized , independently assessed preintervention and postintervention clinical pilot trial . SETTING Specialized spinal pain syndrome out-patient unit at Townsville General Hospital , Queensl and , Australia . SUBJECTS Seventy-seven patients ( without contraindication to manipulation or medication ) were recruited . INTERVENTIONS One of three separate , clearly defined intervention protocol s : needle acupuncture , nonsteroidal anti-inflammatory medication , or chiropractic spinal manipulation . MAIN OUTCOME MEASURES Main outcome measures were changes ( 4 weeks vs. initial visit ) in the scores of the ( 1 ) Oswestry Back Pain Disability Index , ( 2 ) Neck Disability Index , and ( 3 ) three visual analogue scales of local pain intensity . RESULTS R and omization was successful . After a median intervention period of 30 days , spinal manipulation was the only intervention that achieved statistically significant improvements ( all expressed as percentages of the original scores ) with ( 1 ) a reduction of 30.7 % on the Oswestry scale , ( 2 ) an improvement of 25 % on the neck disability index , and ( 3 ) reductions on the visual analogue scale of 50 % for low back pain , 46 % for upper back pain , and 33 % for neck pain ( all P<.001 ) . Neither of the other interventions showed any significant improvement on any of the outcome measures . CONCLUSIONS The consistency of the results provides , in spite of several discussed shortcomings of this pilot study , evidence that in patients with chronic spinal pain syndromes spinal manipulation , if not contraindicated , results in greater improvement than acupuncture and medicine [6446774] Fifty-six male patients who had chronic low-back pain of at least 12 weeks ' duration ( average duration , 28.6 weeks ) and who had failed to respond to traditional medical or surgical therapy were entered into a r and omized clinical trial to compare the relative efficacies of the Clinic 's st and ard therapy regimen with and without dry needling at muscle motor points . Before entering the trial , all patients had undergone without improvement eight weeks of the Clinic 's st and ard therapy regimen of physiotherapy , remedial exercises , and occupational therapy . The 29 study subjects and 27 control patients then continued with this regimen , but the study subjects also received needling at muscle motor points once or twice a week ( average number of treatments , 7.9 ) . All patients were assessed at the time of discharge , 12 weeks after discharge , and at the time of writing ( average , 27.3 weeks ) . The group that had been treated with needling was found to be clearly and significantly better than the control group ( P > 0.005 , N = 53 ) with regard to status at discharge , status at 12 weeks ' follow-up , and status at final follow-up . At final followup , 18 of the 29 study subjects had returned to their original or equivalent jobs and 10 had returned to lighter employment . In the control group , only four had returned to their original work and 14 to lighter employment ; nine were still disabled . The results seem to justify the procedure in chronic low-back patients in whom myofascial pain ( the majority ) rather than skeletal irritation is the dominant disabling feature [12838090] Study Design . A r and omized controlled trial was conducted . Objective . To determine the efficacy of osteopathic manipulative treatment as a complementary treatment for chronic nonspecific low back pain . Summary of Background Data . Osteopathic manipulative treatment may be useful for acute or subacute low back pain . However , its role in chronic low back pain is unclear . Methods . This trial was conducted in a university-based clinic from 2000 through 2001 . Of the 199 subjects who responded to recruitment procedures , 91 met the eligibility criteria . They were r and omized , with 82 patients completing the 1-month follow-up evaluation , 71 completing the 3-month evaluation , and 66 completing the 6-month evaluation . The subjects were r and omized to osteopathic manipulative treatment , sham manipulation , or a no-intervention control group , and they were allowed to continue their usual care for low back pain . The main outcomes included the SF-36 Health Survey , a 10-cm visual analog scale for overall back pain , the Rol and –Morris Disability Question naire , lost work or school days because of back pain , and satisfaction with back care . Results . As compared with the no-intervention control subjects , the patients who received osteopathic manipulative treatment reported greater improvements in back pain , greater satisfaction with back care throughout the trial , better physical functioning and mental health at 1 month , and fewer cotreatments at 6 months . The subjects who received sham manipulation also reported greater improvements in back pain and physical functioning and greater satisfaction than the no-intervention control subjects . There were no significant benefits with osteopathic manipulative treatment , as compared with sham manipulation . Conclusions . Osteopathic manipulative treatment and sham manipulation both appear to provide some benefits when used in addition to usual care for the treatment of chronic nonspecific low back pain . It remains unclear whether the benefits of osteopathic manipulative treatment can be attributed to the manipulative techniques themselves or whether they are related to other aspects of osteopathic manipulative treatment , such as range of motion activities or time spent interacting with patients , which may represent placebo effects [12509627] OBJECTIVE This r and omized , double-dummy , double-blind pilot study of acutely exacerbated low back pain was aim ed to inform a definitive comparison between Doloteffin , a proprietary extract of Harpagophytum , and rofecoxib , a selective inhibitor of cyclo-oxygenase-2 ( COX-2 ) . METHODS Forty-four patients ( phyto-anti-inflammatory drug-PAID-group ) received a daily dose of Doloteffin containing , inter alia , 60 mg of harpagoside for 6 weeks and 44 ( non-steroidal anti-inflammatory drug-NSAID-group ) received 12.5 mg/day of rofecoxib . All were allowed rescue medication of up to 400 mg/day of tramadol . Several outcome measures were examined at various intervals to obtain estimates of effect size and variability that might be used to decide the most suitable principal outcome measure and corresponding numbers required for a definitive study . RESULTS Forty-three PAID and 36 NSAID patients completed the study . Ten PAID and 5 NSAID patients reported no pain without rescue medication for at least 5 days of the 6th week of treatment . Eighteen PAID and 12 NSAID patients had more than a 50 % reduction in the week 's average of their pain scores between the 1st and 6th weeks . The mean percentage decrease from baseline in the pain component of the Arhus Index was 23 ( S.D. 52 ) in PAID and 26 ( S.D. 43 ) in NSAID . The corresponding measures for the overall Arhus Index were 11 ( 31 ) and 16 ( 24 ) and , for the Health Assessment Question naire , 7 ( 8) and 6 ( 7 ) . Tramadol was used by 21 PAID patients and 13 NSAID patients . Fourteen patients in each group experienced 39 adverse effects , of which 28 ( 13 in PAID ) were judged to some degree attributable to the study medications . CONCLUSION Though no significant intergroup differences were demonstrable , large numbers will be needed to show equivalence [2439856] 81 patients with chronic low back pain ( average duration 10 years ) were r and omised to two treatment groups . 40 received an empirically devised regimen of forceful spinal manipulation and injections of a dextrose-glycerine-phenol ( " proliferant " ) solution into soft-tissue structures , as part of a programme to decrease pain and disability . The other 41 patients received parallel treatment in which the main differences were less extensive initial local anaesthesia and manipulation , and substitution of saline for proliferant . Neither patients nor assessors knew which treatment had been given . When assessed by disability scores the experimental group had greater improvement than the control group at one ( p less than 0.001 ) , three ( p less than 0.004 ) , and six ( p less than 0.001 ) months from the end of treatment ; at six months an improvement of more than 50 % was recorded in 35 of the experimental group versus 16 of the control group and the numbers free from disability were 15 and 4 , respectively ( p less than 0.003 ) . Visual analogue pain scores and pain diagrams likewise showed significant advantages for the experimental regimen [7936710] Low Back Pain Rating scale is an index scale which includes measurements of pain intensity , disability , and physical impairment . The scale was design ed to monitor the outcome of clinical trials of low back pain treatment . It has been vali date d in 58 patients following first-time discectomy . The scale rating can be rapidly carried out and requires no special aids . With slight modification it can be used in office and telephone interviews , as well as postal question naires . These modifications only slightly reduce the quantity of information gathered . In the study , a high rater agreement ( 97.7 % ) was found without level difference between two observers using the scale . The validation process included : construct validity , criterion-related validity and item bias , relative to Global Assessment s pronounced by the patient and an experienced clinician . Low Back Pain Rating scale hs been shown to be valid and reliable in the assessment of low back pain [16508555] Study Design . Cohort study . Objectives . To estimate the Minimal Clinical ly Important Change ( MCIC ) of the pain intensity numerical rating scale ( PI-NRS ) , the Quebec Back Pain Disability Scale ( QBPDS ) , and the Euroqol ( EQ ) in patients with low back pain . Summary of Background Data . MCIC can provide valuable information for research ers , healthcare providers , and policymakers . Methods . Data from a r and omized controlled trial with 442 patients with low back pain were used . The MCIC was estimated over a 12-week period , and three different methods were used : 1 ) mean change scores , 2 ) minimal detectable change , and 3 ) optimal cutoff point in receiver operant curves . The global perceived effect scale ( GPE ) was used as an external criterion . The effect of initial scores on the MCIC was also assessed . Results . The MCIC of the PI-NRS ranged from 3.5 to 4.7 points in (sub)acute patients and 2.5 to 4.5 points in chronic patients with low back pain . The MCIC of the QBPDS was estimated between 17.5 to 32.9 points and 8.5 to 24.6 points for (sub)acute and chronic patients with low back pain . The MCIC for the EQ ranged from 0.07 to 0.58 in (sub)acute patients and 0.09 to 0.28 in patients with chronic low back pain . Conclusion . Reporting the percentage of patients who have made a MCIC adds to the interpretability of study results . We present a range of MCIC values and advocate the choice of a single MCIC value according to the specific context [2946016] & NA ; Fifty‐four patients treated in a 3‐week inpatient rehabilitation program were r and omly assigned to and accepted treatment with electroacupuncture ( n = 17 ) , TENS ( low intensity transcutaneous nerve stimulation , n = 18 ) , and TENS dead‐battery ( placebo , n = 18 ) . Outcome measures included estimates of pain ( on a Visual Analogue Scale ) and disability by both physician and patient , physical measures of trunk strength and spine range of motion , as well as the patient 's perceptions of the relative contribution of the education , exercise training , and the electrical stimulation . Analyses of variance were utilized to determine effects of treatment ( electroacupuncture , TENS , placebo ) across time ( admission , discharge , and return ) for the outcome measures . There were no significant differences between treatment groups with respect to their overall rehabilitation . All 3 treatment groups ranked the contribution of the education as being greater than the electrical stimulation . However , the electroacupuncture group consistently demonstrated greater improvement on the outcome measures than the other treatment groups . For the visual analogue scale measure of average pain , there was a statistical trend at the return visit suggesting that the acupuncture group was experiencing less pain [10101629] Two daily doses of oral Harpagophytum extract WS 1531 ( 600 and 1200 , respectively , containing 50 and 100 mg of the marker harpagoside ) were compared with placebo over 4 weeks in a r and omized , double-blind study in 197 patients with chronic susceptibility to back pain and current exacerbations that were producing pain worse than 5 on a 0 - 10 visual analogue scale . The principal outcome measure , based on pilot studies , was the number of patients who were pain free without the permitted rescue medication ( tramadol ) for 5 days out of the last week . The treatment and placebo groups were well matched in physical characteristics , in the severity of pain , duration , nature and accompaniments of their pain , the Arhus low back pain index and in laboratory indices of organ system function . A total of 183 patients completed the study . The numbers of pain-free patients were three , six and 10 in the placebo group ( P ) , the Harpagophytum 600 group ( H600 ) and the Harpagophytum 1200 group ( H1200 ) respectively ( P = 0.027 , one-tailed Cochrane-Armitage test ) . The majority of responders ' were patients who had suffered less than 42 days of pain , and subgroup analyses suggested that the effect was confined to patients with more severe and radiating pain accompanied by neurological deficit . However , subsidiary analyses , concentrating on the current pain component of the Arhus index , painted a slightly different picture , with the benefits seeming , if anything , to be greatest in the H600 group and in patients without more severe pain , radiation or neurological deficit . Patients with more pain tended to use more tramadol , but even severe and unbearable pain would not guarantee that tramadol would be used at all , and certainly not to the maximum permitted dose . There was no evidence for Harpagophytum-related side-effects , except possibly for mild and infrequent gastrointestinal symptoms [11783809] Objective The authors sought to determine whether a series of needle acupuncture treatments produced long-term relief of chronic low back pain . Design A blinded placebo-controlled study with an independent observer . The patients were r and omized to receive manual acupuncture , electroacupuncture , or active placebo ( mock transcutaneous electrical nerve stimulation ) . Subjects were examined and monitored by an investigator who was blinded to the treatment given . Setting A tertiary-level pain clinic at a Swedish university hospital . Patients Fifty consecutive patients ( 33 women , 17 men ; mean age , 49.8 years ) with chronic low back pain ( mean pain duration , 9.5 years ) and without rhizopathy or history of acupuncture treatment were included in the study . Interventions Treatments were given once per week for 8 weeks . Two further treatments were given during the follow-up assessment period of 6 months or longer . Outcome Measures The independent observer made a global assessment of the patients 1 , 3 , and 6 months after treatment . The patients kept pain diaries to score pain intensity twice daily , analgesic intake , and quality of sleep daily , and activity level weekly . Results At the 1-month independent assessment , 16 of 34 patients in the acupuncture groups and 2 of 16 patients in the placebo group showed improvement ( p < 0.05 ) . At the 6-month follow-up assessment , 14 of 34 patients in the acupuncture groups and 2 of 16 patients in the placebo group showed improvement ( p < 0.05 ) . A significant decrease in pain intensities occurred at 1 and 3 months in the acupuncture groups compared with the placebo group . There was a significant improvement in return to work , quality of sleep , and analgesic intake in subjects treated with acupuncture . Conclusions The authors found a long-term pain-relieving effect of needle acupuncture compared with true placebo in some patients with chronic nociceptive low back pain [7849747] The professional literature contains relatively few r and omized-control studies that have assessed the efficacy of physical therapy approaches to the management of patients with chronic low back pain ( CLBP ) . The purpose s of this study were : 1 ) to investigate the effects of physical agents , joint manipulation , low-tech exercise , and high-tech exercise on objective measures of CLBP ; 2 ) to track the length of CLBP relief ; and 3 ) to determine treatment cost-effectiveness . Two-hundred-fifty subjects ( 68 females , 182 males ; ages 34 - 51 years ) with CLBP following an L5 laminectomy were r and omly assigned into five separate groups for a treatment period of 8 weeks . Chronic low back pain status was measured by modified-modified Schober , Cybex Liftask , and Oswestry procedures . Results revealed that : 1 ) only low-tech and high-tech exercise produced significant improvements ( p < .05 ) in CLBP , 2 ) the mean period of CLBP relief ranged from 1.6 weeks ( control ) to 91.4 weeks ( low-tech exercise ) , and 3 ) low-tech exercise was most cost-effective . It was concluded that : 1 ) low-tech and high-tech exercise were the only effective treatments for CLBP , 2 ) low-tech exercise produced the longest period of CLBP relief , and 3 ) low-tech exercise was the most cost-effective form of treatment . Clinical ly , low-tech exercise may be the treatment method of choice for the effective management of chronic low back pain [6217745] Acupuncture treatment of chronic low back pain was studied in a placebo-controlled double-blind crossover trial completed by 77 patients . The patients had significantly increased depression , neuroticism , and hypochondriasis scores . Initial pain levels correlated with state-anxiety , depression , pain duration , and abnormal illness behavior measures , as well as with the intake of psychotropic but not analgesic medication . Overall reduction in pain score was 26 percent for acupuncture and 22 percent for placebo treatment ; the difference was not significant ( p greater than 0.6 ) . Analgesic drug intake was reduced to a similar extent in both groups . During the first phase of treatment , patients receiving acupuncture had a greater but not significantly different reduction in pain rating scores compared with those receiving placebo ( t = 0.52 ; p greater than 0.6 ) . This group showed significantly lower pain scores ( p less than 0.05 ) in the second phase of the trial while receiving placebo treatment . Overall reduction in individual patient 's pain score was best predicted by initial pain severity ( r = 0.43 ; p less than 0.001 ) and psychotropic drug intake ( r = 0.37 ; p less than 0.001 ) . None of the variables tested predicted which patients would specifically respond to acupuncture or placebo [14629854] BACKGROUND The efficacy of acupuncture treatment for chronic low-back pain has not been reliably proven because of a lack of good quality studies , leading to the necessity of developing the German Acupuncture Trial for Chronic Low-Back Pain ( GERAC-cLBP ) study . OBJECTIVE The aim is to assess the effectiveness of traditional Chinese acupuncture for chronic low-back pain compared to sham acupuncture and with a conventional st and ard therapy . METHODS This trial is a nationwide , multicenter , r and omized , prospect i ve , partially blinded study . The primary endpoint is the success rate after 6 months . Success is defined as an improvement of 33 % or more of three pain-related items on the Van-Korff Pain Score or an improvement of 12 % or more in the disability measured by the Hanover Functional Ability Question naire . Assessment of the effectiveness of the blinding of patients to the form of acupuncture they received will be conducted . All clinical endpoints are assessed central ly by blinded independent observers . The sample size , with a total of 1062 patients to be enrolled , is based on power calculations . Independent central r and omization , data collection , data processing , and statistical analysis are provided . Success rates will be tested for differences using two-sided Fisher exact tests . In the primary analysis , all tests will be carried out on the basis of the intention-to-treat principle . Secondary analyses will be conducted according to protocol approaches . TRIAL STATUS The pilot phase of the trial started in February 2002 , the estimated duration of the study is 2.5 years . Enrollment is anticipated to be completed in the winter of 2003 . CONCLUSION The GERAC-cLBP study is currently the world 's largest controlled trial of the effectiveness of acupuncture treatment for low-back pain . It will contribute to the evaluation of efficacy by means of evidence based medicine [15897822] Study Design . A prospect i ve , r and omized controlled trial . Objective . To examine long-term effects and costs of combined manipulative treatment , stabilizing exercises , and physician consultation compared with physician consultation alone for chronic low back pain ( cLBP ) . Summary of Background Data . An obvious gap exists in knowledge concerning long-term efficacy and cost-effectiveness of manipulative treatment methods . Methods . Of 204 patients with cLBP whose Oswestry Disability Index ( ODI ) was at least 16 % , 102 were r and omized into a combined manipulative treatment , exercise , and physician consultation group ( i.e. , a combination group ) , and 102 to a consultation alone group . All patients were clinical ly examined , informed about their back pain , and encouraged to stay active and exercise according to specific instructions based on clinical evaluation . Treatment included 4 sessions of manual therapy and stabilizing exercises aim ed at correcting the lumbopelvic rhythm . Question naires inquired about pain ( visual analog scale [ VAS ] ) , disability ( ODI ) , health-related quality of life ( 15D Quality of Life Instrument ) , satisfaction with care , and costs . Results . Significant improvement occurred in both groups on every self-rated outcome measurement . Within 2 years , the combination group showed only a slightly more significant reduction in VAS ( P = 0.01 , analysis of variance ) but clearly higher patient satisfaction ( P = 0.001 , Pearson & khgr;2 ) as compared to the consultation group . Incremental analysis showed that for combined group compared to consultation group , a one-point change in VAS scale cost $ 512 . Conclusions . Physician consultation alone was more cost-effective for both health care use and work absenteeism , and led to equal improvement in disability and health-related quality of life . It seems obvious that encouraging information and advice are major elements for the treatment of patients with cLBP [158752] Preliminary findings are presented of a double-blind , crossover trial comparing the effects of traditional with placebo acupuncture in relieving chronic low back pain . 77 patients completed the study . Following initial assessment and baseline readings , patients had a 4-week course of active or placebo treatment given twice weekly . After a 4 week rest period patients received the alternate treatment , using the same time schedule . A 4 week follow-up period completed the trial . Using visual analogue scale readings as a measure of pain there was no cumulative difference in pain reduction achieved by traditional as compared with placebo acupuncture treatment . Both groups achieved a 55 % overall reduction in pain level at the end of the trial , compared with initial baseline readings

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### Context: [18564952] OBJECTIVES To compare outcomes in perception of pain and disability for a group of patients suffering with chronic low-back pain ( CLBP ) when managed in a hospital by either a regional pain clinic or a chiropractor . DESIGN The study was a pragmatic , r and omized , controlled trial . SETTING The trial was performed at a National Health Service ( NHS ) hospital outpatient clinic ( pain clinic ) in the United Kingdom . SUBJECTS AND INTERVENTIONS Patients with CLBP ( i.e. , symptom duration of > 12 weeks ) referred to a regional pain clinic ( outpatient hospital clinic ) were assessed and r and omized to either chiropractic or pain-clinic management for a period of 8 weeks . The study was pragmatic , allowing for normal treatment protocol s to be used . Treatment was administered in an NHS hospital setting . OUTCOME MEASURES The Rol and -Morris Disability Question naire ( RMDQ ) and Numerical Rating Scale were used to assess changes in perceived disability and pain . Mean values at weeks 0 , 2 , 4 , 6 , and 8 were calculated . The mean differences between week 0 and week 8 were compared across the two treatment groups using Student 's t-tests . Ninety-five percent ( 95 % ) confidence intervals ( CIs ) for the differences between groups were calculated . RESULTS R and omization placed 12 patients in the pain clinic and 18 in the chiropractic group , of which 11 and 16 , respectively , completed the trial . At 8 weeks , the mean improvement in RMDQ was 5.5 points greater for the chiropractic group ( decrease in disability by 5.9 ) than for the pain-clinic group ( 0.36 ) ( 95 % CI 2.0 points to 9.0 points ; p = 0.004 ) . Reduction in mean pain intensity at week 8 was 1.8 points greater for the chiropractic group than for the pain-clinic group ( p = 0.023 ) . CONCLUSIONS This study suggests that chiropractic management administered in an NHS setting may be effective for reducing levels of disability and perceived pain during the period of treatment for a sub population of patients with CLBP [15556955] Abstract Objective To estimate the effect of adding exercise classes , spinal manipulation delivered in NHS or private premises , or manipulation followed by exercise to “ best care ” in general practice for patients consulting with back pain . Fig 1 Progress of the UK BEAM trial Design Pragmatic r and omised trial with factorial design . Setting 181 general practice s in Medical Research Council General Practice Research Framework ; 63 community setting s around 14 centres across the United Kingdom . Participants 1334 patients consulting their general practice s about low back pain . Main outcome measures Scores on the Rol and Morris disability question naire at three and 12 months , adjusted for centre and baseline scores . Results All groups improved over time . Exercise improved mean disability question naire scores at three months by 1.4 ( 95 % confidence interval 0.6 to 2.1 ) more than “ best care . ” For manipulation the additional improvement was 1.6 ( 0.8 to 2.3 ) at three months and 1.0 ( 0.2 to 1.8 ) at 12 months . For manipulation followed by exercise the additional improvement was 1.9 ( 1.2 to 2.6 ) at three months and 1.3 ( 0.5 to 2.1 ) at 12 months . No significant differences in outcome occurred between manipulation in NHS premises and in private premises . No serious adverse events occurred . Conclusions Relative to “ best care ” in general practice , manipulation followed by exercise achieved a moderate benefit at three months and a small benefit at 12 months ; spinal manipulation achieved a small to moderate benefit at three months and a small benefit at 12 months ; and exercise achieved a small benefit at three months but not 12 months [17893311] BACKGROUND To our knowledge , verum acupuncture has never been directly compared with sham acupuncture and guideline -based conventional therapy in patients with chronic low back pain . METHODS A patient- and observer-blinded r and omized controlled trial conducted in Germany involving 340 outpatient practice s , including 1162 patients aged 18 to 86 years ( mean + /- SD age , 50 + /- 15 years ) with a history of chronic low back pain for a mean of 8 years . Patients underwent ten 30-minute sessions , generally 2 sessions per week , of verum acupuncture ( n = 387 ) according to principles of traditional Chinese medicine ; sham acupuncture ( n = 387 ) consisting of superficial needling at nonacupuncture points ; or conventional therapy , a combination of drugs , physical therapy , and exercise ( n = 388 ) . Five additional sessions were offered to patients who had a partial response to treatment ( 10%-50 % reduction in pain intensity ) . Primary outcome was response after 6 months , defined as 33 % improvement or better on 3 pain-related items on the Von Korff Chronic Pain Grade Scale question naire or 12 % improvement or better on the back-specific Hanover Functional Ability Question naire . Patients who were unblinded or had recourse to other than permitted concomitant therapies during follow-up were classified as nonresponders regardless of symptom improvement . RESULTS At 6 months , response rate was 47.6 % in the verum acupuncture group , 44.2 % in the sham acupuncture group , and 27.4 % in the conventional therapy group . Differences among groups were as follows : verum vs sham , 3.4 % ( 95 % confidence interval , -3.7 % to 10.3 % ; P = .39 ) ; verum vs conventional therapy , 20.2 % ( 95 % confidence interval , 13.4 % to 26.7 % ; P < .001 ) ; and sham vs conventional therapy , 16.8 % ( 95 % confidence interval , 10.1 % to 23.4 % ; P < .001 . CONCLUSIONS Low back pain improved after acupuncture treatment for at least 6 months . Effectiveness of acupuncture , either verum or sham , was almost twice that of conventional therapy [16916857] Background and Objective : Psychological factors are assumed to predict persistent or recurrent musculoskeletal pain . The influence of psychological factors in patients with low-back pain ( LBP ) or shoulder pain was explored to study whether there is similarity regarding the factors that predict persisting pain and disability . Methods : Patients presenting in primary care with a new episode of shoulder pain or non-specific (sub)acute low back pain ( LBP ) were enrolled in a prospect i ve study . In both patient groups , pain catastrophising , distress , somatisation and fear-avoidance beliefs were measured at baseline . Primary outcome measures at 3 months were ( 1 ) persistent symptoms , and ( 2 ) < 30 % reduction in functional disability . Multivariate logistic regression analysis was used to study the associations between psychological factors and outcome . Results : A total of 587 patients with shoulder pain and 171 patients with LBP were enrolled in the study . In patients with shoulder pain , most associations of psychological factors with outcome were weak and not significant . Only in patients with longer symptom duration at baseline ( ⩾3 months ) were higher scores on catastrophising significantly associated with persistent symptoms ( p = 0.04 ) . In patients with LBP , psychological factors were more strongly associated with poor outcome , although most associations were not significant . Conclusion : Psychological factors , with the exception of fear-avoidance beliefs , are more strongly associated with persistent pain and disability in patients with LBP than in those with shoulder pain . This seems to indicate that in a primary care population the influence of psychological factors on outcome may vary across patients with different types of pain [12890859] OBJECTIVE To determine if acupuncture is an effective , safe adjunctive treatment to st and ard therapy for chronic low back pain ( LBP ) in older patients . METHODS The inclusion criteria for subjects were : ( i ) LBP > or = 12 weeks and ( ii ) age > or = 60 yr ; the exclusion criteria were ( i ) spinal tumour , infection or fracture and ( ii ) associated neurological symptoms . The subjects were r and omized to two groups . The control group of subjects continued their usual care as directed by their physicians , i.e. NSAIDs , muscle relaxants , paracetamol and back exercises . Subjects in the acupuncture group in addition received biweekly acupuncture with electrical stimulation for 5 weeks . Outcome was measured by the modified Rol and Disability Question naire ( RDQ ) at weeks 0 , 2 , 6 and 9 . The primary outcome measure was change in RDQ score between weeks 0 and 6 . RESULTS Fifty-five patients were enrolled , with eight drop-outs . Twenty-four subjects were r and omized to the acupuncture group and 23 were r and omized to the control group . Acupuncture subjects had a significant decrease in RDQ score of 4.1 + /- 3.9 at week 6 , compared with a mean decrease of 0.7 + /- 2.8 in the control group ( P = 0.001 ) . This effect was maintained for up to 4 weeks after treatment at week 9 , with a decrease in RDQ of 3.5 + /- 4.4 from baseline , compared with 0.43 + /- 2.7 in the control group ( P = 0.007 ) . The mean global transition score was higher in the acupuncture group , 3.7 + /- 1.2 , indicating greater improvement , compared with the score in the control group , 2.5 + /- 0.9 ( P < 0.001 ) . Fewer acupuncture subjects had medication-related side-effects compared with the control group . CONCLUSIONS Acupuncture is an effective , safe adjunctive treatment for chronic LBP in older patients [10936472] PURPOSE Herbal medicines are widely used for the treatment of pain , although there is not much information on their effectiveness . This study was design ed to evaluate the effectiveness of willow ( Salix ) bark extract , which is widely used in Europe , for the treatment of low back pain . SUBJECTS AND METHODS We enrolled 210 patients with an exacerbation of chronic low back pain who reported current pain of 5 or more ( out of 10 ) on a visual analog scale . They were r and omly assigned to receive an oral willow bark extract with either 120 mg ( low dose ) or 240 mg ( high dose ) of salicin , or placebo , with tramadol as the sole rescue medication , in a 4-week blinded trial . The principal outcome measure was the proportion of patients who were pain-free without tramadol for at least 5 days during the final week of the study . RESULTS The treatment and placebo groups were similar at baseline in 114 of 120 clinical features . A total of 191 patients completed the study . The numbers of pain-free patients in the last week of treatment were 27 ( 39 % ) of 65 in the group receiving high-dose extract , 15 ( 21 % ) of 67 in the group receiving low-dose extract , and 4 ( 6 % ) of 59 in the placebo group ( P < 0.001 ) . The response in the high-dose group was evident after only 1 week of treatment . Significantly more patients in the placebo group required tramadol ( P < 0.001 ) during each week of the study . One patient suffered a severe allergic reaction , perhaps to the extract . CONCLUSION Willow bark extract may be a useful and safe treatment for low back pain [23194854] In a study that indicates more definitive investigation is needed , 118 patients with chronic back problems seeking treatment for acute attacks of pain were included in a 4-week r and omised double-blinded study on the safety and effectiveness of an extract of Harpagophytum procumbens . Both , the treatment and the placebo were administered in the form of two tablets taken three times per day ; the treatment group had a daily consumption equal to 6,000 mg of crude preparation ( 50 mg harpagoside , the putative active ingredient ) . The treatment and placebo groups were well matched in physical characteristics ; in the severity , duration , nature and accompaniments of their pain ; and in laboratory indices of organ system function . 109 patients completed the study . The study was originally design ed to measure Harpagophytum 's effectiveness by measuring the use of supplementary pain-killer Tramadol over its final 3 weeks . However , this did not differ between the Harpagophytum and placebo groups nor was the consumption closely related to the amount of pain . Further analysis , though , revealed that 9 out of 51 patients who received the extract were pain free at the end of treatment compared to only 1 out of 54 patients who received placebo . A modification of the Arhus index was used as an additional measure , covering the more global impact . The percentage change was greater in those patients who received Harpagophytum extract than in those who received placebo , but inferential testing ( Mann Whitney ) allowed only 94 % degree of confidence that this had not arisen by chance . The Arhus index reduction was based on improvement in pain . This indication of effectiveness , and the absence of demonstrable adverse effects show that more definite clinical studies of Harpagophytum extract will be worthwhile [17250965] Abstract Practice guidelines recommend various types of exercise and manipulative therapy for chronic back pain but there have been few head‐to‐head comparisons of these interventions . We conducted a r and omized controlled trial to compare effects of general exercise , motor control exercise and manipulative therapy on function and perceived effect of intervention in patients with chronic back pain . Two hundred and forty adults with non‐specific low back pain ⩾3 months were allocated to groups that received 8 weeks of general exercise , motor control exercise or spinal manipulative therapy . General exercise included strengthening , stretching and aerobic exercises . Motor control exercise involved retraining specific trunk muscles using ultrasound feedback . Spinal manipulative therapy included joint mobilization and manipulation . Primary outcomes were patient‐specific function ( PSFS , 3–30 ) and global perceived effect ( GPE , −5 to 5 ) at 8 weeks . These outcomes were also measured at 6 and 12 months . Follow‐up was 93 % at 8 weeks and 88 % at 6 and 12 months . The motor control exercise group had slightly better outcomes than the general exercise group at 8 weeks ( between‐group difference : PSFS 2.9 , 95 % CI : 0.9–4.8 ; GPE 1.7 , 95 % CI : 0.9–2.4 ) , as did the spinal manipulative therapy group ( PSFS 2.3 , 95 % CI : 0.4–4.2 ; GPE 1.2 , 95 % CI : 0.4–2.0 ) . The groups had similar outcomes at 6 and 12 months . Motor control exercise and spinal manipulative therapy produce slightly better short‐term function and perceptions of effect than general exercise , but not better medium or long‐term effects , in patients with chronic non‐specific back pain [12865832] Study Design . A r and omized controlled clinical trial was conducted . Objective . To compare medication , needle acupuncture , and spinal manipulation for managing chronic ( > 13 weeks duration ) spinal pain because the value of medicinal and popular forms of alternative care for chronic spinal pain syndromes is uncertain . Summary of Background Data . Between February 1999 and October 2001 , 115 patients without contraindication for the three treatment regimens were enrolled at the public hospital ’s multidisciplinary spinal pain unit . Methods . One of three separate intervention protocol s was used : medication , needle acupuncture , or chiropractic spinal manipulation . Patients were assessed before treatment by a sports medical physician for exclusion criteria and by a research assistant using the Oswestry Back Pain Disability Index ( Oswestry ) , the Neck Disability Index ( NDI ) , the Short-Form-36 Health Survey question naire ( SF-36 ) , visual analog scales ( VAS ) of pain intensity and ranges of movement . These instruments were administered again at 2 , 5 , and 9 weeks after the beginning of treatment . Results . R and omization proved to be successful . The highest proportion of early ( asymptomatic status ) recovery was found for manipulation ( 27.3 % ) , followed by acupuncture ( 9.4 % ) and medication ( 5 % ) . Manipulation achieved the best overall results , with improvements of 50 % ( P = 0.01 ) on the Oswestry scale , 38 % ( P = 0.08 ) on the NDI , 47 % ( P < 0.001 ) on the SF-36 , and 50 % ( P < 0.01 ) on the VAS for back pain , 38 % ( P < 0.001 ) for lumbar st and ing flexion , 20 % ( P < 0.001 ) for lumbar sitting flexion , 25 % ( P = 0.1 ) for cervical sitting flexion , and 18 % ( P = 0.02 ) for cervical sitting extension . However , on the VAS for neck pain , acupuncture showed a better result than manipulation ( 50%vs 42 % ) . Conclusions . The consistency of the results provides , despite some discussed shortcomings of this study , evidence that in patients with chronic spinal pain , manipulation , if not contraindicated , results in greater short-term improvement than acupuncture or medication . However , the data do not strongly support the use of only manipulation , only acupuncture , or only nonsteroidal antiinflammatory drugs for the treatment of chronic spinal pain . The results from this exploratory study need confirmation from future larger studies [16816766] Study Design . Prospect i ve study with 6 weeks of follow-up . Objective . To examine the predictors of outcome for patients with (sub)acute low back pain ( LBP ) receiving usual care ( UC ) or a minimal intervention strategy ( MIS ) aim ed at psychosocial factors . Summary of Background Data . A r and omized controlled trial in general practice showed no differences in average effect between UC and MIS . Methods . Socio-demographic variables , characteristics of LBP , and psychosocial factors were included as potential predictors of outcome . The outcome clinical ly important improvement was defined as a reduction of at least 30 % on functional disability plus patient perceived recovery . Logistic regression analyses were used to study the associations between predictors and outcome at 6 weeks follow-up . Results . In the UC group ( n = 163 ) , the multivariable model included a shorter duration of the LBP episode , few previous episodes , less pain catastrophizing , and good perceived general health . The area under the curve ( AUC ) of the model was 0.77 ( 95 % confidence interval , 0.70–0.85 ) . In the MIS group ( n = 142 ) , the multivariable model included less somatizing symptoms , more solicitous responses by an important other , lower perceived risk for chronic LBP , more fear avoidance beliefs , higher level of education , and shorter duration of the LBP episode . This AUC was 0.78 ( 95 % confidence interval , 0.71–0.86 ) . Conclusions . As we found two different profiles , our approach may contribute to the important question : what intervention works for whom [8140876] A controlled study of different modes of acupuncture stimulation was conducted on patients fulfilling clinical criteria for chronic low back pain of nociceptive origin . Forty patients were r and omly entered into the study . Thirty had three trial treatments with manual stimulation of needles ( MS ) , electrical low frequency stimulation at 2 Hz ( LF ) , and high – frequency stimulation at 80 Hz ( HF ) , and then continued treatment with the mode they felt most benefitted them . Ten patients were put on the waiting list for treatment but served as the untreated control group . The results were evaluated after 6 weeks and at 6 months for : activity related to pain ; mobility ; verbal descriptors of pain and the patient 's subjective assessment of his condition . After 6 weeks , patients receiving treatment showed significant improvement ( P < 0.05 to P < 0.001 ) on three of the four measures compared to the untreated controls . After 6 months a similar measure of significant improvement was seen in patients continuing with low – frequency ( LF ) acupuncture , but not in those groups continuing with manual stimulation ( MS ) or high – frequency ( HF ) acupunture . The results suggest that 2 Hz electrical stimulation is the mode of choice when using acupuncture in the treatment of chronic nociceptive low back pain [16505266] BACKGROUND Acupuncture is widely used by patients with low back pain , although its effectiveness is unclear . We investigated the efficacy of acupuncture compared with minimal acupuncture and with no acupuncture in patients with chronic low back pain . METHODS Patients were r and omized to treatment with acupuncture , minimal acupuncture ( superficial needling at nonacupuncture points ) , or a waiting list control . Acupuncture and minimal acupuncture were administered by specialized acupuncture physicians in 30 outpatient centers , and consisted of 12 sessions per patient over 8 weeks . Patients completed st and ardized question naires at baseline and at 8 , 26 , and 52 weeks after r and omization . The primary outcome variable was the change in low back pain intensity from baseline to the end of week 8 , as determined on a visual analog scale ( range , 0 - 100 mm ) . RESULTS A total of 298 patients ( 67.8 % female ; mean + /- SD age , 59 + /- 9 years ) were included . Between baseline and week 8 , pain intensity decreased by a mean + /- SD of 28.7 + /- 30.3 mm in the acupuncture group , 23.6 + /- 31.0 mm in the minimal acupuncture group , and 6.9 + /- 22.0 mm in the waiting list group . The difference for the acupuncture vs minimal acupuncture group was 5.1 mm ( 95 % confidence interval , -3.7 to 13.9 mm ; P = .26 ) , and the difference for the acupuncture vs waiting list group was 21.7 mm ( 95 % confidence interval , 13.9 - 30.0 mm ; P<.001 ) . Also , at 26 ( P=.96 ) and 52 ( P=.61 ) weeks , pain did not differ significantly between the acupuncture and the minimal acupuncture groups . CONCLUSION Acupuncture was more effective in improving pain than no acupuncture treatment in patients with chronic low back pain , whereas there were no significant differences between acupuncture and minimal acupuncture [16648741] Study Design . R and omized , single blind , controlled trial . Objective . To determine the efficacy of 2 components of musculoskeletal physiotherapy on chronic low back disorder . Summary of Background Data . Musculoskeletal physiotherapy encompasses many treatment methods , however , manual therapy and exercises to rehabilitate spinal stabilization are the most frequently used . Despite their popularity , scant evidence supports their use on subjects with chronic low back disorder . Methods . A total of 346 subjects were r and omized to manual therapy , a 10-week spinal stabilization rehabilitation program , or a minimal intervention control group . Data were collected at baseline , and 3 , 6 , 12 , and 24 months after intervention . Outcome measures recorded intensity of low back pain , disability , h and icap , medication , and quality of life . There were 4 main variables combined in a primary component analysis to form a single outcome measure ( i.e. , a measure of dysfunction ) . Results . The results indicated statistically significant improvements in favor of the spinal stabilization group at the 6-month stage in pain ( 65.9 % reduction in symptoms ) and dysfunction ( combined mean reduction of 134 , st and ard error 23.84 ) , and at the 1-year stage in medication ( 34.3 % reduction in medication ) , dysfunction ( combined mean reduction of 134 , st and ard error 18.2 ) , and disability ( mean difference in change 15.71 Oswestry Disability Index , 95 % confidence interval 19.3–10.01 ) . Conclusions . As a component of musculoskeletal physiotherapy , the spinal stabilization program is more effective than manually applied therapy or an education booklet in treating chronic low back disorder over time . Both manual therapy and the spinal stabilization program are significantly effective in pain reduction in comparison to an active control . To our knowledge and up until now , this result has not been shown in patients with chronic low back disorder [16798792] In a r and omized controlled trial plus a nonr and omized cohort , the authors investigated the effectiveness and costs of acupuncture in addition to routine care in the treatment of chronic low back pain and assessed whether the effects of acupuncture differed in r and omized and nonr and omized patients . In 2001 , German patients with chronic low back pain were allocated to an acupuncture group or a no-acupuncture control group . Persons who did not consent to r and omization were included in a nonr and omized acupuncture group . All patients were allowed to receive routine medical care in addition to study treatment . Back function ( Hannover Functional Ability Question naire ) , pain , and quality of life were assessed at baseline and after 3 and 6 months , and cost-effectiveness was analyzed . Of 11,630 patients ( mean age=52.9 years ( st and ard deviation , 13.7 ) ; 59 % female ) , 1,549 were r and omized to the acupuncture group and 1,544 to the control group ; 8,537 were included in the nonr and omized acupuncture group . At 3 months , back function improved by 12.1 ( st and ard error ( SE ) , 0.4 ) to 74.5 ( SE , 0.4 ) points in the acupuncture group and by 2.7 ( SE , 0.4 ) to 65.1 ( SE , 0.4 ) points among controls ( difference=9.4 points ( 95 % confidence interval 8.3 , 10.5 ) ; p<0.001 ) . Nonr and omized patients had more severe symptoms at baseline and showed improvements in back function similar to those seen in r and omized patients . The incremental cost-effectiveness ratio was euro10,526 ( euros ) per quality -adjusted life year . Acupuncture plus routine care was associated with marked clinical improvements in these patients and was relatively cost-effective [16103840] Study Design . An observational prospect i ve cohort study in general practice . Objectives . To describe the clinical course and to identify predictors of recovery , changes in pain intensity , and changes in functional disability in patients with neck or shoulder symptoms at 3- and 12-month follow-up . Summary of Background Data . Knowledge on the clinical course and predictors of outcome in neck and shoulder symptoms is limited . Such knowledge would facilitate treatment decisions and may help to inform patients about their prognosis . Methods . Four hundred and forty-three patients who consulted their general practitioner with neck or shoulder symptoms participated in the study . Baseline scores of pain and disability , symptom characteristics , sociodemographic and psychological factors , social support , physical activity , general health , and comorbidity were investigated as possible predictors of recovery , changes in pain intensity , and changes in functional disability using multiple regression analyses . Results . The recovery rate was low ; 24 % of the patients reported recovery at 3 months and 32 % reported recovery at 12-month follow-up . Duration of the symptoms before consulting the GP and a history of neck or shoulder symptoms increased the probability of an unfavorable outcome . Furthermore , less vitality and more worrying were consistently associated with poorer outcome after 3 and 12 months . The area under the receiver-operator characteristic curve for the model predicting recovery was 0.8 at 3 months and 0.75 at 12 months . The explained variance of the models on pain and functional disability ranged from 43 to 54 % . Conclusions . The results found in this study indicate that besides clinical characteristics , psychological factors also predict the outcome of neck and shoulder symptoms [16881095] OBJECTIVE To investigate the course of lateral epicondylitis and identify prognostic indicators associated with short- and longterm outcome of pain intensity . METHODS We prospect ively followed patients ( n = 349 ) from 2 r and omized controlled trials investigating conservative interventions for lateral epicondylitis in primary care . Uni- and multivariate linear regression analyses were used to investigate the association between potential prognostic indicators and pain intensity ( 0 - 100 point scale ) measured at 1 , 6 , and 12 months after r and omization . Potential prognostic factors were duration of elbow complaints , concomitant neck pain , concomitant shoulder pain , previous elbow complaints , baseline pain scores , age , gender , involvement of dominant side , social class , and work status . The variables " study " and " treatment " were included as covariates in all models . RESULTS Pain scores at 1 month followup were higher in patients with severe pain , a long duration of elbow complaints , and concomitant shoulder pain . At 12 month followup , the only different prognostic indicator for poor outcome was concomitant neck pain , in place of shoulder pain . Patients from higher social classes reported lower pain scores at 12 month followup than patients from lower social classes . CONCLUSIONS Lateral epicondylitis seems to be a self-limiting condition in most patients . Long duration of elbow complaints , concomitant neck pain , and severe pain at presentation are associated with poor outcome at 12 months . Our results will help care providers give patients accurate information regarding their prognosis and assist in medical decision-making [11932074] & NA ; There is some evidence for the efficacy of acupuncture in chronic low‐back pain ( LBP ) , but it remains unclear whether acupuncture is superior to placebo . In a r and omized , blinded , placebo‐controlled trial , we evaluated the effect of traditional acupuncture in chronic LBP . A total of 131 consecutive out‐ patients of the Department of Orthopaedics , University Goettingen , Germany , ( age=48.1 years , 58.5 % female , duration of pain : 9.6 years ) with non‐radiating LBP for at least 6 months and a normal neurological examination were r and omized to one of three groups over 12 weeks . Each group received active physiotherapy over 12 weeks . The control group ( n=46 ) received no further treatment , the acupuncture group ( n=40 ) received 20 sessions of traditional acupuncture and the sham‐acupuncture group ( n=45 ) 20 sessions of minimal acupuncture . Changes from baseline to the end of treatment and to 9‐month follow‐up were assessed in pain intensity and in pain disability , and secondary in psychological distress and in spine flexion , compared by intervention groups . Acupuncture was superior to the control condition ( physiotherapy ) regarding pain intensity ( P=0.000 ) , pain disability ( P=0.000 ) , and psychological distress ( P=0.020 ) at the end of treatment . Compared to sham‐acupuncture , acupuncture reduced psychological distress ( P=0.040 ) only . At 9‐month follow‐up , the superiority of acupuncture compared to the control condition became less and acupuncture was not different to sham‐acupuncture . We found a significant improvement by traditional acupuncture in chronic LBP compared to routine care ( physiotherapy ) but not compared to sham‐acupuncture . The trial demonstrated a placebo effect of traditional acupuncture in chronic LBP [11752510] OBJECTIVES To compare the effects of a proprietary extract of willow bark ( Assalix ) and a selective inhibitor ( rofecoxib ) of the enzyme cyclo-oxygenase-2 ( COX-2 ) . METHODS An open , r and omized , post-marketing study was carried out in an out- patients clinic on two groups of patients aged 18 to 80 yr presenting over a 6-month period with acute exacerbations of low back pain . Using computer-generated r and om list , 114 patients were allocated to receive a daily dose of herbal extract containing 240 mg of salicin [ PAID ( phyto-anti-inflammatory drug ) group ] and 114 were allocated to receive 12.5 mg of the synthetic COX-2 inhibitor rofecoxib [ NSAID ( non-steroidal anti-inflammatory drug ) group ] . The doses were chosen according to existing recommendations . All patients were free to use whatever additional conventional treatments were thought necessary . The outcome measures were a modified Arhus index , its pain component and the Total Pain Index . RESULTS Groups were well matched . After 4 weeks of treatment , the Arhus index had improved by about 20 % , its pain component by about 30 % and the Total Pain Index by about 35 % . The number of pain-free patients ( visual analogue scale score < 2 ) was about 20 in each group . About 60 % of the patients in each group responded well to the treatment ( as judged by an improvement of > /=30 % in the Total Pain Index relative to its baseline ) . The improvement was also reflected reasonably well in the physicians ' and patients ' judgements of the effectiveness of treatment , which were largely concordant . Few patients of either group resorted to the additional conventional treatment options . The incidence of adverse events was similar in the two groups . Treatment with rofecoxib was about 40 % more expensive than that with Assalix . CONCLUSION There was no significant difference in effectiveness between the two treatments at the doses chosen . Treatment with Assalix was less expensive [15726029] OBJECTIVE To assess the long-term benefits of medication , needle acupuncture , and spinal manipulation as exclusive and st and ardized treatment regimens in patients with chronic ( > 13 weeks ) spinal pain syndromes . STUDY DESIGN Extended follow-up ( > 1 year ) of a r and omized clinical trial was conducted at the multidisciplinary spinal pain unit of Townsville 's General Hospital between February 1999 and October 2001 . PATIENTS AND METHODS Of the 115 patients originally r and omized , 69 had exclusively been treated with the r and omly allocated treatment during the 9-week treatment period ( results at 9 weeks were reported earlier ) . These patients were followed up and assessed again 1 year after inception into the study reapplying the same instruments ( ie , Oswestry Back Pain Index , Neck Disability Index , Short-Form-36 , and Visual Analogue Scales ) . Question naires were obtained from 62 patients reflecting a retention proportion of 90 % . The main analysis was restricted to 40 patients who had received exclusively the r and omly allocated treatment for the whole observation period since r and omization . RESULTS Comparisons of initial and extended follow-up question naires to assess absolute efficacy showed that only the application of spinal manipulation revealed broad-based long-term benefit : 5 of the 7 main outcome measures showed significant improvements compared with only 1 item in each of the acupuncture and the medication groups . CONCLUSIONS In patients with chronic spinal pain syndromes , spinal manipulation , if not contraindicated , may be the only treatment modality of the assessed regimens that provides broad and significant long-term benefit [1574327] Background Previous clinical trials have assessed the percentage of participants who utilized further health care after a period of conservative care for low back pain , however no chiropractic clinical trial has determined the total amount of care during this time and any differences based on assigned treatment group . The objective of this clinical trial follow-up was to assess if there was a difference in the total number of office visits for low back pain over one year after a four week clinical trial of either a form of physical therapy ( Exercise Program ) or a form of chiropractic care ( Flexion Distraction ) for chronic low back pain . Methods In this r and omized clinical trial follow up study , 195 participants were followed for one year after a four-week period of either a form of chiropractic care ( FD ) or a form of physical therapy ( EP ) . Weekly structured telephone interview questions regarded visitation of various health care practitioners and the practice of self-care for low back pain . Results Participants in the physical therapy group demonstrated on average significantly more visits to any health care provider and to a general practitioner during the year after trial care ( p < 0.05 ) . No group differences were noted in the number of visits to a chiropractor or physical therapist . Self-care was initiated by nearly every participant in both groups . Conclusion During a one-year follow-up , participants previously r and omized to physical therapy attended significantly more health care visits than those participants who received chiropractic care [6446852] The acupuncture treatment situation was beneficial to the majority of people with low back pain . This was shown by the use of short-term controls and long-term controls , although the latter were not intended in the study design . After acupuncture , there was a 51 % pain reduction in the average pain score in the Immediate Treatment Group . The short-term controls , the Delayed Treatment Group , had no reduction whatsoever in their pain scores at the comparable followup period . Later , the Delayed Treatment Group bere also treated by acupuncturists , and reported 62 % less pain . When these two treatment groups were compared at 40 weeks with long-term controls ( Inadequate Treatment Group ) , the Inadequate Treatment Group still had the same pain scores , on the average , as when they enrolled in the study . Both treatment groups , on the average , had 30 % lower pain scores . Furthermore , 58 % of the treatment groups felt that they were definitely improved at 40 weeks , while only 11 % of the Inadequate Treatment Group felt definitely improved at 40 weeks [14581111] & NA ; The efficacy and tolerance of a capsicum plaster in non‐specific low back pain was investigated in a double‐blind , r and omised , placebo‐controlled multicentre parallel group study . A total of 320 patients were r and omly assigned to two groups of n=160 subjects treated by the active or the placebo plaster . The main outcome measures used were a compound pain subscore of the Arhus low back rating scale ( continuous variable ) , and a response criterion of a reduction in pain subscore=30 % from baseline to final assessment ( secondary , non‐continuous variable ) . In addition , the partial pain scores , disability and mobility restriction subscores , the total score of the Arhus low back rating scale , the global evaluation of efficacy by investigator and patient , adverse events , a patient question naire on use of the plaster , and an evaluation of tolerance by investigator and patient were obtained . After 3 weeks treatment with capsicum and placebo plaster respectively , the compound pain subscore was reduced by 42 % ( capsicum ) and 31 % ( placebo ) from values on entry . Responder rate was 67 % versus 49 % ( p=0.002 ) . The investigators rated efficacy as “ excellent ” or “ good ” by 74 % and 36 % ; the patient 's efficacy rating “ symptomfree ” or “ improved ” reached 82 % and 50 % . Adverse local drug reactions were found in 12 patients ( 7.5 % ) on capsicum and 5 ( 3.1 % ) on placebo . No systemic side‐effects were observed . The superiority of the treatment of chronic non‐specific low back pain with capsicum plaster compared to placebo was clinical ly relevant and highly statistically significant . The capsicum plaster offers a genuine alternative in the treatment of non‐specific low back pain [15105215] Acupuncture is an established adjuvant analgesic modality for the treatment of chronic pain . Electrical stimulation of acupuncture points is considered to increase acupuncture analgesia . In this prospect i ve , r and omized , double-blind , controlled study we tested the hypothesis that auricular electroacupuncture ( EA ) relieves pain more effectively than conventional manual auricular acupuncture ( CO ) in chronic low back pain patients with insufficient pain relief ( visual analogue scale [ VAS ] ≥5 ) treated with st and ardized analgesic therapy . Disposable acupuncture needles were inserted in the auricular acupuncture points 29 , 40 , and 55 of the dominant side and connected to a newly developed battery-powered miniaturized stimulator worn behind the ear . Patients were r and omized into group EA ( n = 31 ) with continuous low-frequency auricular EA ( 1 Hz biphasic constant current of 2 mA ) and group CO ( n = 30 ) without electrical stimulation ( sham-electroacupuncture ) . Treatment was performed once weekly for 6 wk , and in each group needles were withdrawn 48 h after insertion . During the study period and a 3-mo follow-up , patients were asked to complete the McGill question naire . Psychological well being , activity level , quality of sleep , and pain intensity were assessed by means of VAS ; moreover , analgesic drug consumption was documented . Pain relief was significantly better in group EA during the study and the follow-up period as compared with group CO . Similarly , psychological well-being , activity , and sleep were significantly improved in group EA versus group CO , the consumption of analgesic rescue medication was less , and more patients returned to full-time employment . Neuropathic pain in particular improved in patients treated with EA . There were no adverse side effects . These results are the first to demonstrate that continuous EA stimulation of auricular acupuncture points improves the treatment of chronic low back pain in an outpatient population [11765591] Topically applied capsaicin ( CAS 404 - 86 - 4 ) induces the release of substance P , a neurotransmitter , from sensory C-fibres . In addition , there is a specific blockade of transport and de-novo synthesis of substance P. As a result , repeated applications of capsaicin bring about a long lasting desensitisation to pain ( increase of pain threshold ) . The desensitising effect is fully reversible . The confirmed pharmacodynamic actions and a number of double-blind clinical studies indicate that local capsicum preparations are very suitable for the treatment of neuropathic pain or musculoskeletal disorders , with or without inflammatory components . In a double-blind , r and omised parallel-group study a capsicum plaster was compared with a placebo for 3 weeks in 154 patients with non-specific back pain . Inclusion criteria were a history of back pain for a minimum period of 3 months and a degree of pain of 5 or more on an eleven grade visual analogue scale . The principal target variable consisted of the score of 3 combined pain scales . Secondary efficacy measures were tests of mobility , a disability index ( in the context of Arhus low back rating scale ) and global assessment s by physicians and patients . For patients to be rated as responders their total pain score at the final examination after 3 weeks of treatment had to show a reduction by at least 30 % of the baseline value . The study unequivocally achieved the target criterion with a rate of responders in the capsicum group of 60.8 % against 42.1 % in the placebo group ( p = 0.0219 ) . The sum of the 3 separate pain scales decreased more markedly in the capsicum group than in the placebo group ( 38.5 % compared to 28.0 % ; p = 0.002 ) . Relatively slight improvements of the impaired mobility and the functional status are explained by the characteristics of the disorder treated . The efficacy ratings by observers and patients was definitely in favour of capsicum . Adverse effects -- mostly harmless and resolving spontaneously -- were reported by 15 patients in the capsicum group and by 9 in the placebo group . The tolerance ratings by investigators and patients were superior to the placebo product . This , however , partly is due to the local pharmacological actions of the drug . As in comparably positive r and omised studies with capsaicin cream in patients with osteoarthritis or fibromyalgia it was shown that a capsicum plaster preparation can also be used to advantage in chronic non-specific back pain [16426760] Abstract Shoulder pain is common in primary care and has an unfavourable outcome in many patients . Information about predictors of outcome is scarce and inconsistent . The objective of this study was to develop clinical prediction rules for calculating the absolute risk of persistent shoulder symptoms for individual patients , 6 weeks and 6 month after the first consultation in general practice . A prospect i ve cohort study with 6 months follow‐up was carried out in three geographic areas in The Netherl and s. In this study , 587 patients with a new episode of shoulder pain were included . The main outcome measure was persistent symptoms at 6 weeks and 6 months , perceived by the patient . Potential predictors included the results of a physical examination , sociodemographic variables , disease characteristics ( duration of symptoms , pain intensity , disability and comorbidity ) , physical activity , physical workload and psychosocial factors . Response rates to the follow‐up question naires were 83 % at 6 weeks and 92 % at 6 months . A longer duration of symptoms , gradual onset of pain and high pain severity at presentation were consistently associated with persistent symptoms at 6 weeks and 6 months . The discriminative validity of our prediction rules was satisfactory with area under the curves of 0.74 ( 95 % CI 0.70 , 0.79 ) at 6 weeks and 0.67 ( 95 % CI 0.63 , 0.71 ) at 6 months . The performance of our rules needs to be tested in other population s of patients with shoulder pain to enable valid and reliable use of the rules in everyday clinical practice [14600536] Objective To assess the efficacy of acupuncture in the treatment of chronic low back pain . Methods Patients ( n = 60 ) with chronic low back pain were recruited and r and omly allocated to either Acupuncture therapy or Placebo transcutaneous electrical nerve stimulation ( TENS ) groups . Patients were treated weekly for 6 weeks , and blinded assessment s were carried out pre- and post-treatment using the McGill Pain Question naire ( MPQ ) and visual analog scales ( VAS ) for pain , the Short-form 36 quality -of-life question naire , and a simple range of motion measurement . A total of 46 patients completed the trial and were followed up at 6 months . Results Analysis of results using t tests showed that in both groups there were significant pre-post improvements for all scores , except for MPQ scores in the Placebo-TENS group . There was no significant difference between the 2 groups for any of the outcome measures at the end of treatment . Results from the 6-month follow-up would suggest that the response was better in the acupuncture group . Discussion Further research is necessary to fully assess the efficacy of this treatment in combating chronic low back pain using larger sample sizes or alternative control groups [12972723] Background : We report on the study design and protocol s of two r and omized controlled trials ( Acupuncture R and omized Trials = ART ) that investigate the efficacy of acupuncture in the treatment of chronic low back pain and osteoarthritis of the knee , respectively . Objective : To investigate whether acupuncture is more efficacious than ( a ) no treatment or ( b ) minimal acupuncture in the treatment of low back pain and osteoarthritis . Design : Two r and omized , controlled , multicenter trials with three treatment arms and a total follow-up time of 52 weeks . Setting : 30 practitioners and outpatient units in Germany specialized in acupuncture treatment . Patients : 300 patients will be included in each study . In the low back pain trial , patients will be included according to clinical diagnosis . In the osteoarthritis pain trial , patients will be included according to the American College of Rheumatology criteria . Interventions : Patients are r and omly assigned to receive either ( 1 ) semi-st and ardized acupuncture ( 150 patients ) , ( 2 ) minimal acupuncture at non-acupuncture points ( 75 patients ) , or ( 3 ) no treatment for two months followed by semi-st and ardized acupuncture ( 75 patients , waiting list control ) . Acupuncture treatment consists of 12 sessions per patient over a period of 8 weeks . Main Outcome Measure : The main outcome measure is the difference between baseline and the end of the 8-week treatment period in the following parameters : pain intensity as measured by a visual analogue scale ( VAS ; 0–100 mm ) in the low back pain trial and by the Western Ontario and McMaster Universities Osteoarthritis Score ( WOMAC ) in the osteoarthritis trial . Outlook : The results of these two studies ( available in 2004 ) will provide health care providers and policy makers with the information needed to make scientifically sound assessment s of acupuncture therapy [16970535] OBJECTIVE Descriptions of the interventions used in acupuncture studies are often incomplete . The aim of this paper is to describe participating trial physicians and interventions in a r and omised trial of acupuncture for low back pain . DESIGN Three-armed , r and omized , controlled multicenter trial with 1-year follow-up . A total of 301 patients with low-back pain were r and omized to 12 sessions of semist and ardized acupuncture ( at least six local and two distant points needled bilaterally from a selection of predefined points , but individual choice of additional body or ear acupuncture points possible ) , minimal acupuncture ( superficial needling of at least 6 of 10 predefined , bilateral , distant nonacupuncture points ) , or a waiting list control ( 2 months no acupuncture followed by semist and ardised acupuncture described above ) . OUTCOME MEASURES Participating trial physicians and interventions . RESULTS Forty-five ( 45 ) physicians specializing in acupuncture ( mean age 44 + /- 7.8 years , 23 ( 51 % ) female ) in 30 outpatient centers in Germany provided the interventions . The median duration of acupuncture training of trial physicians was 350 hours ( range 140 - 2508 ) . The most frequently reported Chinese diagnosis was Kidney deficiency ( 39 % ) , followed by qi and Blood stagnation ( 24 % ) , and bi syndrome ( 20 % ) . The total number of needles used was 17.3 + /- 4.2 in the acupuncture group compared to 12.3 + /- 1.2 in the minimal acupuncture group . In total , 40 physicians ( 89 % ) stated that they would have treated patients similarly or in exactly the same way outside of the trial , whereas 5 ( 11 % ) stated that they would have treated patients differently . CONCLUSIONS For most trial physicians , the semist and ardized acupuncture strategy used in this trial was an acceptable compromise for an efficacy study . However , a relevant minority of participating trial physicians stated that they would have treated patients differently outside of the trial [10422654] Sixty patients aged 60 or over with back pain for at least 6 months were recruited from General Practitioner referrals and r and omized to 4 weeks of treatment with acupuncture or transcutaneous electrical nerve stimulation ( TENS ) . All treatments were administered by the same physiotherapist and both groups had the same contact with him . The following were measured at baseline , completion and at a 3-month follow-up by an independent observer blinded to treatment received : ( 1 ) pain severity on visual analogue scale ( VAS ) ; ( 2 ) pain subscale of Nottingham Health Profile ( NHP ) ; ( 3 ) number of analgesic tablets consumed in previous week ; ( 4 ) spinal flexion from C7 to S1 . Thirty-two patients were r and omized to acupuncture and 28 to TENS ; only three withdrew ( two from acupuncture , one from TENS ) . Significant improvements were shown on VAS ( P < 0.001 ) , NHP ( P < 0.001 ) and tablet count ( P < 0.05 ) between baseline and completion in both groups , these improvements remaining significant comparing baseline with follow-up with a further non-significant improvement in VAS and NHP in the acupuncture group . The acupuncture but not the TENS patients showed a small but statistically significant improvement ( P < 0.05 ) in mean spinal flexion between baseline and completion which was not maintained at follow-up . Thus in these elderly patients with chronic back pain both acupuncture and TENS had demonstrable benefits which outlasted the treatment period . Acupuncture may improve spinal flexion . This trial can not exclude the possibility that both treatments are ' placebos ' [16540864] Study Design . R and omized clinical trial . Objective . Compare outcomes of patients with low back pain receiving treatments matched or unmatched to their subgrouping based on initial clinical presentation . Summary of Background Data . Patients with “ nonspecific ” low back pain are often viewed as a homogeneous group , equally likely to respond to any particular intervention . Others have proposed methods for subgrouping patients as a means for determining the treatment most likely to benefit patients with particular characteristics . Methods . Patients with low back pain of less than 90 days ’ duration referred to physical therapy were examined before treatment and classified into one of three subgroups based on the type of treatment believed most likely to benefit the patient ( manipulation , stabilization exercise , or specific exercise ) . Patients were r and omly assigned to receive manipulation , stabilization exercises , or specific exercise treatment during a 4-week treatment period . Disability was assessed in the short-term ( 4 weeks ) and long-term ( 1 year ) using the Oswestry . Comparisons were made between patients receiving treatment matched to their subgroup , versus those receiving unmatched treatment . Results . A total of 123 patients participated ( mean age , 37.7 ± 10.7 years ; 45 % female ) . Patients receiving matched treatments experienced greater short- and long-term reductions in disability than those receiving unmatched treatments . After 4 weeks , the difference favoring the matched treatment group was 6.6 Oswestry points ( 95 % CI , 0.70–12.5 ) , and at long-term follow-up the difference was 8.3 points ( 95 % CI , 2.5–14.1 ) . Compliers-only analysis of long-term outcomes yielded a similar result . Conclusions . Nonspecific low back pain should not be viewed as a homogenous condition . Outcomes can be improved when subgrouping is used to guide treatment decision-making [16618043] Introduction There is some evidence for the efficacy of acupuncture , but it remains unclear whether trigger point acupuncture is effective . Our objective was to evaluate the effects of trigger point acupuncture on pain and quality of life in chronic low back pain patients compared with sham acupuncture . Methods Twenty-six consecutive out- patients ( 17 women , 9 men ; age range : 65–91 years ) from the Department of Orthopaedic Surgery , Meiji University of Oriental Medicine , with non-radiating low back pain for at least six months and normal neurological examination , were r and omised to two groups . Each group received one phase of trigger point acupuncture and one of sham acupuncture with a three week washout period between them , over 12 weeks . Group A ( n=13 ) received trigger point acupuncture in the first phase and sham acupuncture in the second . Group B ( n=13 ) received the same interventions in the reverse order . Outcome measures were pain intensity ( visual analogue scale , VAS ) and Rol and Morris Question naire . Results Nineteen patients were included in the analysis . At the end of the first treatment phase , group A receiving trigger point acupuncture scored significantly lower VAS ( P<0.001 ) and Rol and Morris Question naire scores ( P<0.01 ) than the sham control group . There were significant within-group reductions in pain in both groups during the trigger point acupuncture phase but not in the sham treatment phase . However , the beneficial effects were not sustained . Conclusion These results suggest that trigger point acupuncture may have greater short term effects on low back pain in elderly patients than sham acupuncture [15628774] Objective There is some evidence for the efficacy of acupuncture in chronic low back pain , but it remains unclear which acupuncture modes are most effective . Our objective was to evaluate the effects of two different modes of trigger point acupuncture on pain and quality of life in chronic low back pain patients compared to st and ard acupuncture treatment . Methods Thirty five consecutive out- patients ( 25 women , 10 men ; age range : 65–81 years ) from the Department of Orthopaedic Surgery , Meiji University of Oriental Medicine , with non-radiating low back pain for at least six months and normal neurological examination , were r and omised to one of three groups over 12 weeks . Each group received two phases of acupuncture treatment with an interval between them . Nine patients dropped out during the course of the study . The st and ard acupuncture group ( n=9 ) received treatment at traditional acupuncture points for low back pain , while the other acupuncture groups received superficial ( n=9 ) or deep ( n=9 ) treatments on trigger points . Outcome measures were VAS pain intensity and Rol and Morris Question naire . Results After treatment , the group that received deep needling to trigger points reported less pain intensity and improved quality of life compared to the st and ard acupuncture group or the group that received superficial needling to trigger points , but the differences were not statistically significant . There was a significant reduction in pain intensity between the treatment and interval in the group that received deep needling to trigger points ( P<0.01 ) , but not in the st and ard acupuncture group or the group that received superficial needling to trigger points . Conclusion These results suggest that deep needling to trigger points may be more effective in the treatment of low back pain in elderly patients than either st and ard acupuncture therapy , or superficial needling to trigger points [16970536] OBJECTIVE Flexion distraction is a commonly used form of chiropractic care with chiropractor utilization rates of 58 % . However , no previous r and omized clinical trial has assessed the effectiveness of this form of care . The objective of this investigation was to compare the pain and disability during the year after active care based on treatment group allocation ( Flexion Distraction versus Exercise Program ) . STUDY DESIGN R and omized clinical trial , follow-up . SUBJECTS Two hundred and thirty-five ( 235 ) subjects who were previously r and omized to either chiropractic care ( flexion distraction ) or physical therapy ( exercise program ) within a clinical trial . OUTCOME MEASURES Subjects were followed for 1 year via mailed question naires to assess levels of pain ( Visual Analog Scale ) and dysfunction ( Rol and Morris ) . RESULTS Study subjects had a decrease in pain and disability after intervention regardless of which group they attended ( p < 0.002 ) , however , during the year after care , subjects who received chiropractic care ( flexion distraction therapy ) had significantly lower pain scores than subjects who received physical therapy ( exercise program ) ( p = 0.02 ) . CONCLUSIONS In this first trial on flexion distraction care , flexion distraction was found to be more effective in reducing pain for 1 year when compared to a form of physical therapy [10478769] OBJECTIVE To compare needle acupuncture , medication ( tenoxicam with ranitidine ) , and spinal manipulation for managing chronic ( > 13 weeks duration ) spinal pain syndromes . DESIGN Prospect i ve , r and omized , independently assessed preintervention and postintervention clinical pilot trial . SETTING Specialized spinal pain syndrome out-patient unit at Townsville General Hospital , Queensl and , Australia . SUBJECTS Seventy-seven patients ( without contraindication to manipulation or medication ) were recruited . INTERVENTIONS One of three separate , clearly defined intervention protocol s : needle acupuncture , nonsteroidal anti-inflammatory medication , or chiropractic spinal manipulation . MAIN OUTCOME MEASURES Main outcome measures were changes ( 4 weeks vs. initial visit ) in the scores of the ( 1 ) Oswestry Back Pain Disability Index , ( 2 ) Neck Disability Index , and ( 3 ) three visual analogue scales of local pain intensity . RESULTS R and omization was successful . After a median intervention period of 30 days , spinal manipulation was the only intervention that achieved statistically significant improvements ( all expressed as percentages of the original scores ) with ( 1 ) a reduction of 30.7 % on the Oswestry scale , ( 2 ) an improvement of 25 % on the neck disability index , and ( 3 ) reductions on the visual analogue scale of 50 % for low back pain , 46 % for upper back pain , and 33 % for neck pain ( all P<.001 ) . Neither of the other interventions showed any significant improvement on any of the outcome measures . CONCLUSIONS The consistency of the results provides , in spite of several discussed shortcomings of this pilot study , evidence that in patients with chronic spinal pain syndromes spinal manipulation , if not contraindicated , results in greater improvement than acupuncture and medicine [6446774] Fifty-six male patients who had chronic low-back pain of at least 12 weeks ' duration ( average duration , 28.6 weeks ) and who had failed to respond to traditional medical or surgical therapy were entered into a r and omized clinical trial to compare the relative efficacies of the Clinic 's st and ard therapy regimen with and without dry needling at muscle motor points . Before entering the trial , all patients had undergone without improvement eight weeks of the Clinic 's st and ard therapy regimen of physiotherapy , remedial exercises , and occupational therapy . The 29 study subjects and 27 control patients then continued with this regimen , but the study subjects also received needling at muscle motor points once or twice a week ( average number of treatments , 7.9 ) . All patients were assessed at the time of discharge , 12 weeks after discharge , and at the time of writing ( average , 27.3 weeks ) . The group that had been treated with needling was found to be clearly and significantly better than the control group ( P > 0.005 , N = 53 ) with regard to status at discharge , status at 12 weeks ' follow-up , and status at final follow-up . At final followup , 18 of the 29 study subjects had returned to their original or equivalent jobs and 10 had returned to lighter employment . In the control group , only four had returned to their original work and 14 to lighter employment ; nine were still disabled . The results seem to justify the procedure in chronic low-back patients in whom myofascial pain ( the majority ) rather than skeletal irritation is the dominant disabling feature [12838090] Study Design . A r and omized controlled trial was conducted . Objective . To determine the efficacy of osteopathic manipulative treatment as a complementary treatment for chronic nonspecific low back pain . Summary of Background Data . Osteopathic manipulative treatment may be useful for acute or subacute low back pain . However , its role in chronic low back pain is unclear . Methods . This trial was conducted in a university-based clinic from 2000 through 2001 . Of the 199 subjects who responded to recruitment procedures , 91 met the eligibility criteria . They were r and omized , with 82 patients completing the 1-month follow-up evaluation , 71 completing the 3-month evaluation , and 66 completing the 6-month evaluation . The subjects were r and omized to osteopathic manipulative treatment , sham manipulation , or a no-intervention control group , and they were allowed to continue their usual care for low back pain . The main outcomes included the SF-36 Health Survey , a 10-cm visual analog scale for overall back pain , the Rol and –Morris Disability Question naire , lost work or school days because of back pain , and satisfaction with back care . Results . As compared with the no-intervention control subjects , the patients who received osteopathic manipulative treatment reported greater improvements in back pain , greater satisfaction with back care throughout the trial , better physical functioning and mental health at 1 month , and fewer cotreatments at 6 months . The subjects who received sham manipulation also reported greater improvements in back pain and physical functioning and greater satisfaction than the no-intervention control subjects . There were no significant benefits with osteopathic manipulative treatment , as compared with sham manipulation . Conclusions . Osteopathic manipulative treatment and sham manipulation both appear to provide some benefits when used in addition to usual care for the treatment of chronic nonspecific low back pain . It remains unclear whether the benefits of osteopathic manipulative treatment can be attributed to the manipulative techniques themselves or whether they are related to other aspects of osteopathic manipulative treatment , such as range of motion activities or time spent interacting with patients , which may represent placebo effects [12509627] OBJECTIVE This r and omized , double-dummy , double-blind pilot study of acutely exacerbated low back pain was aim ed to inform a definitive comparison between Doloteffin , a proprietary extract of Harpagophytum , and rofecoxib , a selective inhibitor of cyclo-oxygenase-2 ( COX-2 ) . METHODS Forty-four patients ( phyto-anti-inflammatory drug-PAID-group ) received a daily dose of Doloteffin containing , inter alia , 60 mg of harpagoside for 6 weeks and 44 ( non-steroidal anti-inflammatory drug-NSAID-group ) received 12.5 mg/day of rofecoxib . All were allowed rescue medication of up to 400 mg/day of tramadol . Several outcome measures were examined at various intervals to obtain estimates of effect size and variability that might be used to decide the most suitable principal outcome measure and corresponding numbers required for a definitive study . RESULTS Forty-three PAID and 36 NSAID patients completed the study . Ten PAID and 5 NSAID patients reported no pain without rescue medication for at least 5 days of the 6th week of treatment . Eighteen PAID and 12 NSAID patients had more than a 50 % reduction in the week 's average of their pain scores between the 1st and 6th weeks . The mean percentage decrease from baseline in the pain component of the Arhus Index was 23 ( S.D. 52 ) in PAID and 26 ( S.D. 43 ) in NSAID . The corresponding measures for the overall Arhus Index were 11 ( 31 ) and 16 ( 24 ) and , for the Health Assessment Question naire , 7 ( 8) and 6 ( 7 ) . Tramadol was used by 21 PAID patients and 13 NSAID patients . Fourteen patients in each group experienced 39 adverse effects , of which 28 ( 13 in PAID ) were judged to some degree attributable to the study medications . CONCLUSION Though no significant intergroup differences were demonstrable , large numbers will be needed to show equivalence [2439856] 81 patients with chronic low back pain ( average duration 10 years ) were r and omised to two treatment groups . 40 received an empirically devised regimen of forceful spinal manipulation and injections of a dextrose-glycerine-phenol ( " proliferant " ) solution into soft-tissue structures , as part of a programme to decrease pain and disability . The other 41 patients received parallel treatment in which the main differences were less extensive initial local anaesthesia and manipulation , and substitution of saline for proliferant . Neither patients nor assessors knew which treatment had been given . When assessed by disability scores the experimental group had greater improvement than the control group at one ( p less than 0.001 ) , three ( p less than 0.004 ) , and six ( p less than 0.001 ) months from the end of treatment ; at six months an improvement of more than 50 % was recorded in 35 of the experimental group versus 16 of the control group and the numbers free from disability were 15 and 4 , respectively ( p less than 0.003 ) . Visual analogue pain scores and pain diagrams likewise showed significant advantages for the experimental regimen [7936710] Low Back Pain Rating scale is an index scale which includes measurements of pain intensity , disability , and physical impairment . The scale was design ed to monitor the outcome of clinical trials of low back pain treatment . It has been vali date d in 58 patients following first-time discectomy . The scale rating can be rapidly carried out and requires no special aids . With slight modification it can be used in office and telephone interviews , as well as postal question naires . These modifications only slightly reduce the quantity of information gathered . In the study , a high rater agreement ( 97.7 % ) was found without level difference between two observers using the scale . The validation process included : construct validity , criterion-related validity and item bias , relative to Global Assessment s pronounced by the patient and an experienced clinician . Low Back Pain Rating scale hs been shown to be valid and reliable in the assessment of low back pain [16508555] Study Design . Cohort study . Objectives . To estimate the Minimal Clinical ly Important Change ( MCIC ) of the pain intensity numerical rating scale ( PI-NRS ) , the Quebec Back Pain Disability Scale ( QBPDS ) , and the Euroqol ( EQ ) in patients with low back pain . Summary of Background Data . MCIC can provide valuable information for research ers , healthcare providers , and policymakers . Methods . Data from a r and omized controlled trial with 442 patients with low back pain were used . The MCIC was estimated over a 12-week period , and three different methods were used : 1 ) mean change scores , 2 ) minimal detectable change , and 3 ) optimal cutoff point in receiver operant curves . The global perceived effect scale ( GPE ) was used as an external criterion . The effect of initial scores on the MCIC was also assessed . Results . The MCIC of the PI-NRS ranged from 3.5 to 4.7 points in (sub)acute patients and 2.5 to 4.5 points in chronic patients with low back pain . The MCIC of the QBPDS was estimated between 17.5 to 32.9 points and 8.5 to 24.6 points for (sub)acute and chronic patients with low back pain . The MCIC for the EQ ranged from 0.07 to 0.58 in (sub)acute patients and 0.09 to 0.28 in patients with chronic low back pain . Conclusion . Reporting the percentage of patients who have made a MCIC adds to the interpretability of study results . We present a range of MCIC values and advocate the choice of a single MCIC value according to the specific context [2946016] & NA ; Fifty‐four patients treated in a 3‐week inpatient rehabilitation program were r and omly assigned to and accepted treatment with electroacupuncture ( n = 17 ) , TENS ( low intensity transcutaneous nerve stimulation , n = 18 ) , and TENS dead‐battery ( placebo , n = 18 ) . Outcome measures included estimates of pain ( on a Visual Analogue Scale ) and disability by both physician and patient , physical measures of trunk strength and spine range of motion , as well as the patient 's perceptions of the relative contribution of the education , exercise training , and the electrical stimulation . Analyses of variance were utilized to determine effects of treatment ( electroacupuncture , TENS , placebo ) across time ( admission , discharge , and return ) for the outcome measures . There were no significant differences between treatment groups with respect to their overall rehabilitation . All 3 treatment groups ranked the contribution of the education as being greater than the electrical stimulation . However , the electroacupuncture group consistently demonstrated greater improvement on the outcome measures than the other treatment groups . For the visual analogue scale measure of average pain , there was a statistical trend at the return visit suggesting that the acupuncture group was experiencing less pain [10101629] Two daily doses of oral Harpagophytum extract WS 1531 ( 600 and 1200 , respectively , containing 50 and 100 mg of the marker harpagoside ) were compared with placebo over 4 weeks in a r and omized , double-blind study in 197 patients with chronic susceptibility to back pain and current exacerbations that were producing pain worse than 5 on a 0 - 10 visual analogue scale . The principal outcome measure , based on pilot studies , was the number of patients who were pain free without the permitted rescue medication ( tramadol ) for 5 days out of the last week . The treatment and placebo groups were well matched in physical characteristics , in the severity of pain , duration , nature and accompaniments of their pain , the Arhus low back pain index and in laboratory indices of organ system function . A total of 183 patients completed the study . The numbers of pain-free patients were three , six and 10 in the placebo group ( P ) , the Harpagophytum 600 group ( H600 ) and the Harpagophytum 1200 group ( H1200 ) respectively ( P = 0.027 , one-tailed Cochrane-Armitage test ) . The majority of responders ' were patients who had suffered less than 42 days of pain , and subgroup analyses suggested that the effect was confined to patients with more severe and radiating pain accompanied by neurological deficit . However , subsidiary analyses , concentrating on the current pain component of the Arhus index , painted a slightly different picture , with the benefits seeming , if anything , to be greatest in the H600 group and in patients without more severe pain , radiation or neurological deficit . Patients with more pain tended to use more tramadol , but even severe and unbearable pain would not guarantee that tramadol would be used at all , and certainly not to the maximum permitted dose . There was no evidence for Harpagophytum-related side-effects , except possibly for mild and infrequent gastrointestinal symptoms [11783809] Objective The authors sought to determine whether a series of needle acupuncture treatments produced long-term relief of chronic low back pain . Design A blinded placebo-controlled study with an independent observer . The patients were r and omized to receive manual acupuncture , electroacupuncture , or active placebo ( mock transcutaneous electrical nerve stimulation ) . Subjects were examined and monitored by an investigator who was blinded to the treatment given . Setting A tertiary-level pain clinic at a Swedish university hospital . Patients Fifty consecutive patients ( 33 women , 17 men ; mean age , 49.8 years ) with chronic low back pain ( mean pain duration , 9.5 years ) and without rhizopathy or history of acupuncture treatment were included in the study . Interventions Treatments were given once per week for 8 weeks . Two further treatments were given during the follow-up assessment period of 6 months or longer . Outcome Measures The independent observer made a global assessment of the patients 1 , 3 , and 6 months after treatment . The patients kept pain diaries to score pain intensity twice daily , analgesic intake , and quality of sleep daily , and activity level weekly . Results At the 1-month independent assessment , 16 of 34 patients in the acupuncture groups and 2 of 16 patients in the placebo group showed improvement ( p < 0.05 ) . At the 6-month follow-up assessment , 14 of 34 patients in the acupuncture groups and 2 of 16 patients in the placebo group showed improvement ( p < 0.05 ) . A significant decrease in pain intensities occurred at 1 and 3 months in the acupuncture groups compared with the placebo group . There was a significant improvement in return to work , quality of sleep , and analgesic intake in subjects treated with acupuncture . Conclusions The authors found a long-term pain-relieving effect of needle acupuncture compared with true placebo in some patients with chronic nociceptive low back pain [7849747] The professional literature contains relatively few r and omized-control studies that have assessed the efficacy of physical therapy approaches to the management of patients with chronic low back pain ( CLBP ) . The purpose s of this study were : 1 ) to investigate the effects of physical agents , joint manipulation , low-tech exercise , and high-tech exercise on objective measures of CLBP ; 2 ) to track the length of CLBP relief ; and 3 ) to determine treatment cost-effectiveness . Two-hundred-fifty subjects ( 68 females , 182 males ; ages 34 - 51 years ) with CLBP following an L5 laminectomy were r and omly assigned into five separate groups for a treatment period of 8 weeks . Chronic low back pain status was measured by modified-modified Schober , Cybex Liftask , and Oswestry procedures . Results revealed that : 1 ) only low-tech and high-tech exercise produced significant improvements ( p < .05 ) in CLBP , 2 ) the mean period of CLBP relief ranged from 1.6 weeks ( control ) to 91.4 weeks ( low-tech exercise ) , and 3 ) low-tech exercise was most cost-effective . It was concluded that : 1 ) low-tech and high-tech exercise were the only effective treatments for CLBP , 2 ) low-tech exercise produced the longest period of CLBP relief , and 3 ) low-tech exercise was the most cost-effective form of treatment . Clinical ly , low-tech exercise may be the treatment method of choice for the effective management of chronic low back pain [6217745] Acupuncture treatment of chronic low back pain was studied in a placebo-controlled double-blind crossover trial completed by 77 patients . The patients had significantly increased depression , neuroticism , and hypochondriasis scores . Initial pain levels correlated with state-anxiety , depression , pain duration , and abnormal illness behavior measures , as well as with the intake of psychotropic but not analgesic medication . Overall reduction in pain score was 26 percent for acupuncture and 22 percent for placebo treatment ; the difference was not significant ( p greater than 0.6 ) . Analgesic drug intake was reduced to a similar extent in both groups . During the first phase of treatment , patients receiving acupuncture had a greater but not significantly different reduction in pain rating scores compared with those receiving placebo ( t = 0.52 ; p greater than 0.6 ) . This group showed significantly lower pain scores ( p less than 0.05 ) in the second phase of the trial while receiving placebo treatment . Overall reduction in individual patient 's pain score was best predicted by initial pain severity ( r = 0.43 ; p less than 0.001 ) and psychotropic drug intake ( r = 0.37 ; p less than 0.001 ) . None of the variables tested predicted which patients would specifically respond to acupuncture or placebo [14629854] BACKGROUND The efficacy of acupuncture treatment for chronic low-back pain has not been reliably proven because of a lack of good quality studies , leading to the necessity of developing the German Acupuncture Trial for Chronic Low-Back Pain ( GERAC-cLBP ) study . OBJECTIVE The aim is to assess the effectiveness of traditional Chinese acupuncture for chronic low-back pain compared to sham acupuncture and with a conventional st and ard therapy . METHODS This trial is a nationwide , multicenter , r and omized , prospect i ve , partially blinded study . The primary endpoint is the success rate after 6 months . Success is defined as an improvement of 33 % or more of three pain-related items on the Van-Korff Pain Score or an improvement of 12 % or more in the disability measured by the Hanover Functional Ability Question naire . Assessment of the effectiveness of the blinding of patients to the form of acupuncture they received will be conducted . All clinical endpoints are assessed central ly by blinded independent observers . The sample size , with a total of 1062 patients to be enrolled , is based on power calculations . Independent central r and omization , data collection , data processing , and statistical analysis are provided . Success rates will be tested for differences using two-sided Fisher exact tests . In the primary analysis , all tests will be carried out on the basis of the intention-to-treat principle . Secondary analyses will be conducted according to protocol approaches . TRIAL STATUS The pilot phase of the trial started in February 2002 , the estimated duration of the study is 2.5 years . Enrollment is anticipated to be completed in the winter of 2003 . CONCLUSION The GERAC-cLBP study is currently the world 's largest controlled trial of the effectiveness of acupuncture treatment for low-back pain . It will contribute to the evaluation of efficacy by means of evidence based medicine [15897822] Study Design . A prospect i ve , r and omized controlled trial . Objective . To examine long-term effects and costs of combined manipulative treatment , stabilizing exercises , and physician consultation compared with physician consultation alone for chronic low back pain ( cLBP ) . Summary of Background Data . An obvious gap exists in knowledge concerning long-term efficacy and cost-effectiveness of manipulative treatment methods . Methods . Of 204 patients with cLBP whose Oswestry Disability Index ( ODI ) was at least 16 % , 102 were r and omized into a combined manipulative treatment , exercise , and physician consultation group ( i.e. , a combination group ) , and 102 to a consultation alone group . All patients were clinical ly examined , informed about their back pain , and encouraged to stay active and exercise according to specific instructions based on clinical evaluation . Treatment included 4 sessions of manual therapy and stabilizing exercises aim ed at correcting the lumbopelvic rhythm . Question naires inquired about pain ( visual analog scale [ VAS ] ) , disability ( ODI ) , health-related quality of life ( 15D Quality of Life Instrument ) , satisfaction with care , and costs . Results . Significant improvement occurred in both groups on every self-rated outcome measurement . Within 2 years , the combination group showed only a slightly more significant reduction in VAS ( P = 0.01 , analysis of variance ) but clearly higher patient satisfaction ( P = 0.001 , Pearson & khgr;2 ) as compared to the consultation group . Incremental analysis showed that for combined group compared to consultation group , a one-point change in VAS scale cost $ 512 . Conclusions . Physician consultation alone was more cost-effective for both health care use and work absenteeism , and led to equal improvement in disability and health-related quality of life . It seems obvious that encouraging information and advice are major elements for the treatment of patients with cLBP [158752] Preliminary findings are presented of a double-blind , crossover trial comparing the effects of traditional with placebo acupuncture in relieving chronic low back pain . 77 patients completed the study . Following initial assessment and baseline readings , patients had a 4-week course of active or placebo treatment given twice weekly . After a 4 week rest period patients received the alternate treatment , using the same time schedule . A 4 week follow-up period completed the trial . Using visual analogue scale readings as a measure of pain there was no cumulative difference in pain reduction achieved by traditional as compared with placebo acupuncture treatment . Both groups achieved a 55 % overall reduction in pain level at the end of the trial , compared with initial baseline readings Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Although acupuncture is widely used for chronic pain , there remains considerable controversy as to its value . We aim ed to determine the effect size of acupuncture for 4 chronic pain conditions : back and neck pain , osteoarthritis , chronic headache , and shoulder pain . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

31175810

[25733649] BACKGROUND Moderate acute malnutrition ( MAM ) , defined as weight-for-length z score between -3 and -2 or midupper arm circumference between 11.5 and 12.5 cm , affects ∼33 million children aged < 5 y worldwide . OBJECTIVE The objective was to compare the effects of 4 dietary supplements for the treatment of MAM . DESIGN Twelve community health centers in rural Mali were r and omly assigned to provide to 1264 MAM children aged 6 - 35 mo one of 4 dietary supplements containing ∼500 kcal/d for 12 wk : 1 ) ready-to-use , lipid-based supplementary food ( RUSF ) ; 2 ) special corn-soy blend ( CSB++ ) ; 3 ) locally processed , fortified flour ( Misola ) ; or 4 ) locally milled flours plus oil , sugar , and micronutrient powder ( LMF ) . RESULTS In total , 1178 children ( 93.2 % ) completed the study . The adjusted mean ( 95 % CI ) change in weight ( kg ) from baseline was greater with RUSF than with the locally processed blends and was intermediate with CSB++ [ 1.16 ( 1.08 , 1.24 ) for RUSF , 1.04 ( 0.96 , 1.13 ) for CSB++ , 0.91 ( 0.82 , 0.99 ) for Misola , and 0.83 ( 0.74 , 0.92 ) for LMF ; P < 0.001 ] . For length change , RUSF and CSB++ differed significantly from LMF . Sustained recovery rates were higher with RUSF ( 73 % ) than with Misola ( 61 % ) and LMF ( 58 % ) , P < 0.0001 ; CSB++ recovery rates ( 68 % ) did not differ from any of the other groups . CONCLUSIONS RUSF was more effective , but more costly , than other dietary supplements for the treatment of MAM ; CSB++ yielded intermediate results . The benefits of treatment should be considered in relation to product costs and availability [19633578] Objectives : Human milk ( HM ) is the optimal source of nutrition for premature infants ; however , it is unclear whether HM alone is sufficient to meet their elevated nutritional requirements early after hospital discharge . We previously reported that premature infants ( 750–1800 g birth weight ) fed HM containing extra nutrients for 12 weeks after discharge had dietary intakes closer to recommended levels and grew more rapidly than those fed HM alone . The objectives of the present article are to examine the impact of this intervention on bone mineralization , body composition , and HM use up to 1 year . Data are also presented on general developmental level at 18-month corrected age ( CA ) . Patients and Methods : At discharge , predominantly HM-fed infants were r and omized to receive for 12 weeks either approximately half of their feedings containing a multinutrient fortifier ( intervention , n = 19 ) or all of their feedings as HM alone ( control , n = 20 ) . Results : Intervention infants remained longer ( P < 0.001 ) and had greater whole-body bone mineral content ( P = 0.02 ) until 12-month CA compared with controls . Intervention infants born less than or equal to 1250 g continued to have a larger mean head circumference throughout the first year of life ( P < 0.0001 ) . Human milk feeding ( mL · kg−1 · day−1 ) differed between groups at 6- ( P = 0.035 ) , but not 12-month CA . No statistically significant differences were found between groups in the mental , motor , or behavior rating scale scores of the Bayley II at 18-month CA . Conclusions : Adding a multinutrient fortifier to HM provided to predominantly HM-fed premature infants early after discharge results in sustained differences in weight , length , and whole-body bone mineral content , and in smaller babies , head circumference for the first year of life [19881394] Background and Objectives : Postdischarge formulas with extra energy and protein improve short-term growth but may also influence long-term body composition in an unwanted manner . Energy- and protein-enriched formulas with an increased protein-to-energy ratio improves gain of lean mass . The objective of the study was to investigate whether feeding a nutrient-enriched formula without extra energy after term , usually 3 to 4 weeks after discharge , would influence growth and body composition in infancy . Methods : In this r and omized controlled trial preterm infants were fed fortified human milk or preterm formula until term . At term , 102 infants were r and omized to a nutrient-enriched formula without extra energy or st and ard formula until 6 months corrected age . Twenty-six infants received unfortified human milk after term . At term and 6 months corrected age , anthropometry and a dual-energy x-ray absorptiometry ( DEXA ) scan were performed . Lean and fat mass ( FM ) were corrected for height . Results : There were no differences in growth or body size between the feeding groups . Infants fed the enriched formula gained less FM and had lower FM corrected for body size at 6 months corrected age than infants fed st and ard formula . Infants fed human milk had lower lean mass and higher FM corrected for body size at 6 months corrected age than formula-fed infants . Conclusions : Feeding nutrient-enriched formula without extra energy after term does not change quantity of growth but does influence type of weight gain and body composition of preterm infants . Infants fed the nutrient-enriched formula had lower FM corrected for body size at 6 months corrected age than infants fed st and ard formula or human milk [28374648] Background : There is no consensus over best approaches to reliably prevent malnutrition in rural communities in low-income countries . Objective : We compared the effectiveness of 2 lipid-based ready-to-use supplementary foods ( RUSFs ) differing in dairy protein content to improve the nutritional status of mothers and at-risk infants and young children in rural Guinea-Bissau . Methods : A 3-month cluster-r and omized controlled pilot trial of 2 RUSFs was conducted with 692 mothers and 580 mildly or moderately malnourished infants ( 6 - 23 months ) and children ( 24 - 59 months ) from 13 villages . The RUSFs contained either 478 ( mothers , children ) or 239 kcal/d ( infants ) with 15 % or 33 % of protein from dairy and were distributed at community health centers 5 d/wk . Controls were wait-listed to receive RUSF . Primary outcomes were mid-upper arm circumference ( MUAC ) in mothers , and weight-for-age and height-for-age z-scores ( WAZ and HAZ ) in infants and children . Results : There was a significant effect of the RUSF-33 % on MUAC in mothers ( P = .03 ) . The WAZ and HAZ increased substantially , by ≈1 z-score , in infants and children ( P < .01 ) independent of group r and omization . In children , but not infants , baseline WAZ and change in maternal MUAC were associated with change in WAZ ( β = .07 , P = .02 ) . Conclusion : Ready-to-use supplementary foods with higher dairy protein content had a significant benefit in village mothers , supporting a comparable recent finding in preschool children . In addition , supplementation of children < 2 years result ed in improved growth independent of family nutritional status , whereas success in older children was associated with change in maternal nutrition , suggesting the need for community-level education about preventing malnutrition in older , as well as younger , children [22952176] BACKGROUND Improved complementary feeding is cited as a critical factor for reducing stunting . Consumption of meats has been advocated , but its efficacy in low-re source setting s has not been tested . OBJECTIVE The objective was to test the hypothesis that daily intake of 30 to 45 g meat from 6 to 18 mo of age would result in greater linear growth velocity and improved micronutrient status in comparison with an equicaloric multimicronutrient-fortified cereal . DESIGN This was a cluster r and omized efficacy trial conducted in the Democratic Republic of Congo , Zambia , Guatemala , and Pakistan . Individual daily portions of study foods and education messages to enhance complementary feeding were delivered to participants . Blood tests were obtained at trial completion . RESULTS A total of 532 ( 86.1 % ) and 530 ( 85.8 % ) participants from the meat and cereal arms , respectively , completed the study . Linear growth velocity did not differ between treatment groups : 1.00 ( 95 % CI : 0.99 , 1.02 ) and 1.02 ( 95 % CI : 1.00 , 1.04 ) cm/mo for the meat and cereal groups , respectively ( P = 0.39 ) . From baseline to 18 mo , stunting [ length-for-age z score ( LAZ ) < -2.0 ] rates increased from ~33 % to nearly 50 % . Years of maternal education and maternal height were positively associated with linear growth velocity ( P = 0.0006 and 0.003 , respectively ) ; LAZ at 6 mo was negatively associated ( P < 0.0001 ) . Anemia rates did not differ by group ; iron deficiency was significantly lower in the cereal group . CONCLUSION The high rate of stunting at baseline and the lack of effect of either the meat or multiple micronutrient-fortified cereal intervention to reverse its progression argue for multifaceted interventions beginning in the pre- and early postnatal periods [22152430] OBJECTIVE To examine the effects of animal- source foods on toddler growth . DESIGN A 5-month comparison feeding intervention study with one of three millet-based porridges r and omized to eighteen feeding stations serving 303 children aged 11 - 40 months . Feeding stations served plain millet porridge ( Plain group ) , porridge with milk ( Milk group ) or porridge with beef ( Meat group ) . Anthropometry , morbidity and food intake were measured at baseline and regular intervals . Longitudinal mixed models were used to analyse growth . SETTING Embu , Kenya . SUBJECTS Two hundred and seventy-four children were included in final analyses . RESULTS Linear growth was significantly greater for the Milk group than the Meat group ( P = 0·0025 ) . Slope of growth of mid-arm muscle area of the Plain group was significantly greater than in the Meat group ( P = 0·0046 ) , while the Milk group 's mid-upper arm circumference growth rate was significantly greater than the Meat group 's ( P = 0·0418 ) . The Milk and Plain groups ' measures did not differ . CONCLUSIONS Milk and meat porridges did not have a significantly greater effect on growth than plain porridge in this undernourished population . Linear growth was influenced by more than energy intakes , as the Plain group 's total body weight-adjusted energy intakes were significantly greater than the Meat group 's , although linear growth did not differ . Energy intakes may be more important for growth in arm muscle . The diverse age distribution in the study makes interpretation difficult . A longer study period , larger sample size and more focused age group would improve clarity of the results [18287372] Poor complementary feeding practice s are associated with stunting and growth faltering throughout the developing world . The objective was to compare the effect of using peanut-/soy-based fortified spread ( FS ) and corn porridge fortified with fish powder ( FP ) as complementary foods on growth in rural Malawian children . A total of 240 children were enrolled at the age of 6 mo and r and omized to receive FS or FP . Both complementary foods provided 836 kJ/d from 6 to 9 mo of age and 1254 kJ/d from 9 to 18 mo of age . Children were followed monthly for anthropometry and fortnightly for the symptoms of fever , cough , or diarrhea until they were 18 mo old . Zn and Se status were assessed at 6 and 12 mo . The primary outcomes were the rates of weight and length gain from 6 - 12 mo and from 12 - 18 mo . Children who received FS gained 110 g more ( 95 % CI 220 to 10 ) from 6 - 12 mo of age than children receiving FP . Weight gain did not differ between children receiving FS and FP between 12 and 18 mo of age , nor did statural growth from 6 to 12 mo or 12 to 18 mo . A total of 23 % of all children were Zn deficient at 6 mo of age and this increased to 37 % at 12 mo of age . Neither FS nor FP was associated with significantly improved Zn status . FS was associated with better weight gain from 6 - 12 mo of age and may be useful in conjunction with additional interventions to improve infant growth in the developing world [2239797] The effect of prenatal energy supplementation on maternal anthropometry was assessed in a controlled , r and omized trial in Madura , East Java . At 26 - 28 wk of gestation women were either given 465 kcal/d ( HE group ) or 52 kcal/d ( LE group ) . Two hundred seventy-six women were enrolled in the HE group and 266 women , in the LE group . Supplement intake was variable . Testing of effect by treatment and compliance was thus done by subcategories ( HE 1 - 3 and LE 1 - 3 , corresponding to less than 45 , 45 - 89 , and greater than or equal to 90 packets of supplement consumed ) . Analysis of variance did not show significant differences among the six subcategories in third-trimester weight gain , sum of skinfold thicknesses , 4-wk postpartum weight , or body mass index . In this population energy supplementation for the short duration of the last 90 - 110 d of pregnancy was not sufficient to improve maternal nutrition as judged by anthropometry [3279745] The effects on pregnancy outcome and maternal iron status of powdered milk ( PUR ) and a milk-based fortified product ( V-N ) were compared in a group of underweight gravidas . These take-home products were distributed during regular prenatal visits . Women in the V-N group had greater weight gain ( 12.29 vs 11.31 kg , p less than 0.05 ) and mean birth weights ( 3178 vs 3105 g , p less than 0.05 ) than those in the PUR group . Values for various indicators of maternal Fe status were also higher in the V-N group . Compared with self-selected noncompliers , similar in all control variables to compliers , children of women who consumed powdered milk or the milk-based fortified product had mean birth weights that were higher by 258 and 335 g , respectively . Data indicate a beneficial effect of the fortified product on both maternal nutritional status and fetal growth [7625343] Infants eat primarily to satisfy energy needs and the safe amount of protein in infant formulas ( ie , the amount adequate for nearly all infants ) is therefore expressed as the protein-energy ratio . We studied male infants aged 8 - 112 d fed milk-based formulas . One group ( experimental group ) was fed formulas that provided protein-energy ratios of 3.73 g/MJ ( 1.56 g/100 kcal ) from 8 to 27 d of age , gradually decreasing to 2.99 g/MJ ( 1.25 g/100 kcal ) from 84 to 111 d of age . Growth rates and serum albumin and urea nitrogen of these infants were compared with those of a concurrently studied control group and a previously studied large reference group . Gains in weight and concentrations of serum albumin of the three groups were not significantly different . Gains in length were significantly less for the experimental group than for the reference group . Serum urea nitrogen was significantly less in the experimental group than in the control group or reference group . We conclude that the protein-energy ratios of the experimental formula diet were below the safe level . Because the decrease in growth rate of the experimental group was rather small ( demonstrable only in comparison with the large reference group ) , and because serum albumin of the experimental group increased with age as in normally nourished infants , we suspect that the safe protein-energy ratio of infant formulas lies closer to the ratios fed to the experimental group than to the ratio [ approximately 5.0 g/MJ ( 2.1 g/100 kcal ) ] in currently marketed milk-based formulas [7282613] The effect of food supplementation on physical growth during the last trimester of pregnancy and the first 3 yr of life was studied in a sample of families at risk of malnutrition living in the urban slums of Bogota , Colombia . Families in which the mother was pregnant and at least one-half of the children under 5 yr of age were below 85 % of weight for age were selected for the study . All were provided with free obstetrical and pediatric care . The families were then r and omly assigned to control and supplemented groups . The supplemented families received a daily allotment of 600 cal or 30 g of protein per capita for home consumption from the onset of the 3rd trimester of pregnancy until the subject children reached the age of 3 yr . Calorie consumption from the supplement by the study children ( offspring of the target pregnancy ) was 458 ± 249 calories at age 18 months and 363 ± 283 cal at age 36 months . Protein consumption at those ages was 34 . 1 ± 20.6 and 23.6 ± 19.7 g,'day . However , substitution of the supplement for foods from the regular diet result ed in net supplementation of approximately 200 cal and 22 g of protein per day . There were significant differences in weight between supplemented and control groups beginning at age 3 months and in length beginning at age 6 months . Supplementation reduced the total prevalence of malnutrition ( Gomez classification ) only slightly ; at 36 months of age , 72 % of the supplemented group and 77.8 % of the control group were malnourished . On the other h and , the prevalence of moderate and severe malnutrition ( Gomez II and III ) , was significantly reduced by supplementation . At 36 months , 20.6 % of the control group and 8.8 % of the supplemented group fell into those categories . Despite improved physical growth in the supplemented group , their height and weight remained substantially below those of the high socioeconomic Colombian st and ards . The failure of supplementation to close the gap between low and high socioeconomic groups was attributed , in part , to the high incidence of diarrheal disease among subjects of the study . It is postulated that simple provision of food supplements , without effective prevention of diarrheal disease , is likely to have limited effects on physical growth among disadvantaged children . Am . J. Clin . Nutr . 34 : 1885 - 1892 , 1981 [17158417] BACKGROUND Despite the theoretical benefits of nutrient-enriched formula given to preterm infants after hospital discharge , its role in reversing growth deficits after hospital discharge remains poorly defined . OBJECTIVE The aim was to determine the effect of different formulas on the growth , bone mass , and body composition of preterm infants after hospital discharge . DESIGN This was a r and omized , double blind comparison of a nutrient-enriched formula ( EF ) and a formula for term infants ( TF ) given for 1 y after hospital discharge . Compared with the TF , the EF had a higher energy density and higher contents of protein , calcium , and phosphorus ( by 10 % , 21 % , 44 % , and 11 % , respectively ) and higher contents of almost all other nutrients ( by > or=10 % ) . RESULTS Birth weights of the infants were 630 - 1620 g ( median : 1250 g ) and gestational ages were 24 - 34 wk ( median : 29 wk ) . TF result ed in significantly greater weight , length , head circumference measurements , and their respective z scores on the basis of age- and sex-specific norms . At the end of the study , the mean z scores for the corrected age of infants in the TF group were -0.37 for weight , 0.001 for length , and 0.50 for head circumference . The TF group also had significantly greater dual-energy X-ray absorptiometry measured bone and lean and fat mass than did the EF group ( P < 0.05 for all comparisons ) . CONCLUSIONS The use of EF for preterm infants after hospital discharge shows no advantage over TF in growth , bone mineralization , and body composition . More studies are needed to determine the optimal postdischarge nutrition support for preterm infants [9001369] The long-term benefits of early childhood supplementation and the extent to which catch-up growth occurs following linear growth retardation remain controversial . Stunted children ( height-for-age < -2 SD of NCHS references , n = 122 ) recruited from a survey of poor neighborhoods in Kingston , Jamaica , participated in a 2-yr r and omized , controlled trial of supplementation beginning at ages 9 - 24 mo . A group of 32 non-stunted children from the same neighborhoods was also followed . Four years after the intervention ended , when children were 7 to 8 y old , there were no effects of supplementation on any anthropometric measure . From the end of the trial until follow-up , the children who had been supplemented gained 1.2 cm less ( P < 0.05 ) than the non-supplemented children , approximately the same amount as they had gained during the trial compared with the non-supplemented children . After adjustment for regression to the mean , the height-for-age of stunted children ( supplemented and non-supplemented combined ) increased from enrollment to follow-up by 0.31 Z-score ( 95 % CI 0.17 , 0.46 ) . The height-for-age of the non-stunted children also increased ( 0.96 Z-score ; 95 % CI 0.70 , 1.22 ) . Our results suggest that some catch-up growth is possible even when children remain in poor environments . Long-term benefits of supplementation to growth may not be achieved when intervention begins after age 12 mo in children who have already become undernourished [8839497] The effect of supplementation on growth was tested by means of four similar controlled r and omized trials in the Congo ( n = 120 ) , Senegal ( n = 110 ) , Bolivia ( n = 127 ) , and New Caledonia ( n = 90 ) . Four-month-old infants were r and omly allocated to supplement or control groups . A cereal-based precooked porridge was offered twice daily for 3 mo and consumption was monitored . Both groups were free to eat local food . At 7 mo of age , all infants were still breast-fed in the Congo , Senegal , and Bolivia compared with 47 % in New Caledonia . Mean daily consumption of the supplement varied among countries ( 558 - 790 kJ/d ) . Mean length at 4 mo was lowest in Bolivia , higher in Senegal and the Congo , and near the National Center for Health Statistics reference in New Caledonia . The mean 4 - 7 mo length increment was 0.48 cm higher for supplemented than for control infants in Senegal ( P < 0.05 ) , whereas weight increments did not differ . No significant effect was found in the other countries [25332329] BACKGROUND High intake of cow-milk protein in formula-fed infants is associated with higher weight gain and increased adiposity , which have led to recommendations to limit protein intake in later infancy . The impact of protein from meats for breastfed infants during complementary feeding may be different . OBJECTIVE We examined the effect of protein from meat as complementary foods on growth and metabolic profiles of breastfed infants . DESIGN This was a secondary analysis from a trial in which exclusively breastfed infants ( 5 - 6 mo old from the Denver , CO , metro area ) were r and omly assigned to receive commercially available pureed meats ( Meat group ; n = 14 ) or infant cereal ( Cereal group ; n = 28 ) as their primary complementary feedings for ∼ 5 mo . Anthropometric measures and diet records were collected monthly from 5 to 9 mo of age ; intakes from complementary feeding and breast milk were assessed at 9 mo of age . RESULTS The Meat group had significantly higher protein intake , whereas energy , carbohydrate , and fat intakes from complementary feeding did not differ by group over time . At 9 mo of age , mean ( ± SEM ) intakes of total ( complementary feeding plus breast milk ) protein were 2.9 ± 0.6 and 1.4 ± 0.4 g · kg(-1 ) · d(-1 ) , ∼ 17 % and ∼ 9 % of daily energy intake , for Meat and Cereal groups , respectively ( P < 0.001 ) . From 5 to 9 mo of age , the weight-for-age z score ( WAZ ) and length-for-age z score ( LAZ ) increased in the Meat group ( ΔWAZ : 0.24 ± 0.19 ; ΔLAZ : 0.14 ± 0.12 ) and decreased in the Cereal group ( ΔWAZ : -0.07 ± 0.17 ; ΔLAZ : -0.27 ± 0.24 ) ( P-group by time < 0.05 ) . The change in weight-for-length z score did not differ between groups . Total protein intake at 9 mo of age and baseline WAZ were important predictors of changes in the WAZ ( R(2 ) = 0.23 , P = 0.01 ) . CONCLUSION In breastfed infants , higher protein intake from meats was associated with greater linear growth and weight gain but without excessive gain in adiposity , suggesting that potential risks of high protein intake may differ between breastfed and formula-fed infants and by the source of protein [6365516] The effect of maternal supplementation during both gestation and lactation on infant growth from birth to 12 mth was investigated in the double-blind , r and omly allocated control trial conducted in Taiwan by the late Bacon F. Chow . The supplement was a milk-based formula providing 800 kcal and 40 g protein daily . The placebo provided less than 40 kcal per diem but resembled the supplement in appearance . Supplementation was limited to mothers and began after birth of one infant and continued without interruption until weaning of a second infant . Supplement effects were tested by comparing both supplement and placebo groups and first- and second-infant groups with respect to weight , length and head circumference . Both comparisons of growth curves and analyses of variance were carried out . Both strategies agreed in failing to detect differences in growth between supplement and placebo groups . However , differences were found between first and second infants in the supplement group [6819029] Unselective dietary protein energy supplementation of Asian mothers at Sorrento Maternity Hospital did not enhance intrauterine growth . The effect of selective supplementation was therefore studied . Forty-five mothers who at 28 weeks were known to be nutritionally at risk ( triceps increment less than or equal to 20 microns/week between 18 and 28 weeks ) received one of three supplements during the third trimester : ( a ) vitamins only -- a multivitamin sachet daily containing vitamins A , B , C , and D ; ( b ) energy--42 - 125 MJ ( 10 000 - 30 000 kcal ) , all from carbohydrate , plus vitamins ; ( c ) protein energy -- energy and vitamins as before , but with 5 - 10 % of energy from milk protein . Eighty-three mothers regarded as adequately nourished at 28 weeks also received one of the three supplements . In the nutritionally at-risk mothers the protein energy supplement was associated with a heavier crude birth weight and heavier weight for gestational age . Supplementation did not lead to improved intrauterine growth in those mothers who were adequately nourished . The differential effect of supplementation depending on the mothers ' nutritional state during the second trimester may explain apparently conflicting results of other studies where some have shown a substantial effect of supplementation and others only a small effect . This effect of intervention is further evidence that " poor nutrition " contributes to poor intrauterine growth in selected mothers , even in developed countries [25833972] BACKGROUND Poor nutritional quality of complementary foods often limits growth . Animal source foods , such as milk or meat , are often unaffordable . Local affordable alternatives are needed . OBJECTIVE We evaluate the efficacy of 2 newly developed , rice-based complementary food products : WinFood ( WF ) with small fish and edible spiders and WinFood-Lite ( WF-L ) fortified with small fish , against 2 existing fortified corn-soy blend products , CSB+ ( purely plant based ) and CSB++ ( 8 % dried skimmed milk ) . DESIGN In total , 419 infants aged 6 mo were enrolled in this r and omized , single-blinded study for 9 mo , design ed primarily to assess increments in fat-free mass by a deuterium dilution technique and change in plasma ferritin and soluble transferrin receptor . Secondary endpoints were changes in anthropometric variables , including knee-heel length . Data were analyzed by the intention-to-treat approach . RESULTS There was no difference in fat-free mass increment in WF or WF-L compared with CSB+ [ WF : + 0.04 kg ( 95 % CI : -0.20 , 0.28 kg ) ; WF-L : + 0.14 kg ( 95 % CI : -0.10 , 0.38 kg ) ] or CSB++ [ WF : -0.03 kg ( 95 % CI : -0.27 , 0.21 kg ) ; WF-L : + 0.07 kg ( 95 % CI : -0.18 , 0.31 kg ) ] and no effect on iron status . The 1.7-mm ( 95 % CI : -0.1 , 3.5 mm ) greater increase in knee-heel length in WF-L than in CSB+ was not significant . CONCLUSIONS No difference was found between the locally produced products ( WF and WF-L ) and the CSBs . Micronutrient fortification may be necessary , and small fish may be an affordable alternative to milk to improve complementary foods . The dietary role of edible spiders needs to be further explored . This trial was registered at controlled-trials.com as IS RCT N19918531 [24622805] BACKGROUND Early nutrition is recognized as a target for the effective prevention of childhood obesity . Protein intake was associated with more rapid weight gain during infancy-a known risk factor for later obesity . OBJECTIVE We tested whether the reduction of protein in infant formula reduces body mass index ( BMI ; in kg/m(2 ) ) and the prevalence of obesity at 6 y of age . DESIGN The Childhood Obesity Project was conducted as a European multicenter , double-blind , r and omized clinical trial that enrolled healthy infants born between October 2002 and July 2004 . Formula-fed infants ( n = 1090 ) were r and omly assigned to receive higher protein (HP)- or lower protein (LP)-content formula ( within recommended amounts ) in the first year of life ; breastfed infants ( n = 588 ) were enrolled as an observational reference group . We measured the weight and height of 448 ( 41 % ) formula-fed children at 6 y of age . BMI was the primary outcome . RESULTS HP children had a significantly higher BMI ( by 0.51 ; 95 % CI : 0.13 , 0.90 ; P = 0.009 ) at 6 y of age . The risk of becoming obese in the HP group was 2.43 ( 95 % CI : 1.12 , 5.27 ; P = 0.024 ) times that in the LP group . There was a tendency for a higher weight in HP children ( 0.67 kg ; 95 % CI : -0.04 , 1.39 kg ; P = 0.064 ) but no difference in height between the intervention groups . Anthropometric measurements were similar in the LP and breastfed groups . CONCLUSIONS Infant formula with a lower protein content reduces BMI and obesity risk at school age . Avoidance of infant foods that provide excessive protein intakes could contribute to a reduction in childhood obesity . This trial was registered at clinical trials.gov as NCT00338689 [12739919] Ninety-two subjects ages 36 to 60 months who had picky-eater behavior and evidence of growth faltering were r and omized to receive either nutrition counseling alone , or nutrition counseling plus a nutritional supplement ( Study ) for 90 days . The Study group had significantly greater increases in weight and height . There were no significant differences between groups in changes in appetite or activity levels , or in gastrointestinal symptom scores . The percent of subjects who developed upper respiratory tract infections was significantly lower in the Study group . These data suggest that a nutritional supplement in addition to nutrition counseling promote catch-up growth and may contribute to lower rates of infectious disease in children with picky eater behavior [24500150] BACKGROUND Observational studies have indicated that differences in the composition of human milk and infant formula yield benefits in cognitive development and early growth for breastfed infants . OBJECTIVE The objective was to test the hypothesis that feeding an infant formula with reduced energy and protein densities and supplemented with bovine milk fat globule membrane ( MFGM ) reduces differences in cognitive development and early growth between formula-fed and breastfed infants . DESIGN In a prospect i ve , double-blind , r and omized controlled trial , 160 infants < 2 mo of age were r and omly assigned to be fed an MFGM-supplemented , low-energy , low-protein experimental formula ( EF ) or a st and ard formula ( SF ) until 6 mo of age . The energy and protein contents of the EF and SF were 60 and 66 kcal/100 mL and 1.20 and 1.27 g/100 mL , respectively . A breastfed reference ( BFR ) group consisted of 80 infants . RESULTS At 12 mo of age , the cognitive score ( mean ± SD ) on testing with the Bayley Scales of Infant and Toddler Development , Third Edition , was significantly higher in the EF group than in the SF group ( 105.8 ± 9.2 compared with 101.8 ± 8.0 ; P = 0.008 ) but was not significantly different from that in the BFR group ( 106.4 ± 9.5 ; P = 0.73 ) . The EF group ingested larger volumes of formula than did the SF group ( 864 ± 174 compared with 797 ± 165 mL/d ; P = 0.022 ) , fully compensating for the lower energy density . No significant differences in linear growth , weight gain , body mass index , percentage body fat , or head circumference were found between the EF and SF groups . CONCLUSIONS MFGM supplementation to infant formula narrows the gap in cognitive development between breastfed and formula-fed infants . Between 2 and 6 mo of age , formula-fed term infants have the capacity to upregulate their ingested volumes when the energy density of formula is reduced from 66 to 60 kcal/100 [19386747] BACKGROUND Protein intake during infancy was associated with rapid early weight gain and later obesity in observational studies . OBJECTIVE The objective was to test the hypothesis that higher protein intake in infancy leads to more rapid length and weight gain in the first 2 y of life . DESIGN In a multicenter European study , 1138 healthy , formula-fed infants were r and omly assigned to receive cow milk-based infant and follow-on formula with lower ( 1.77 and 2.2 g protein/100 kcal , respectively ) or higher ( 2.9 and 4.4 g protein/100 kcal , respectively ) protein contents for the first year . For comparison , 619 exclusively breastfed children were also followed . Weight , length , weight-for-length , and BMI were determined at inclusion and at 3 , 6 , 12 , and 24 mo of age . The primary endpoints were length and weight at 24 mo of age , expressed as length and weight-for-length z scores based on the 2006 World Health Organization growth st and ards . RESULTS Six hundred thirty-six children in the lower ( n = 313 ) and higher ( n = 323 ) protein formula groups and 298 children in the breastfed group were followed until 24 mo . Length was not different between r and omized groups at any time . At 24 mo , the weight-for-length z score of infants in the lower protein formula group was 0.20 ( 0.06 , 0.34 ) lower than that of the higher protein group and did not differ from that of the breastfed reference group . CONCLUSIONS A higher protein content of infant formula is associated with higher weight in the first 2 y of life but has no effect on length . Lower protein intake in infancy might diminish the later risk of overweight and obesity . This trial was registered at clinical trials.gov as NCT00338689 [26154030] Objectives : Infant formulas provide more protein than breast milk . High protein intakes may place infants at risk of later obesity . The present study tested whether a formula with protein content below the regulatory level supports normal growth from age 3 months . Methods : R and omized double-blind trial enrolled healthy infants less than age 3 months . At 3 months , formula-fed infants were assigned to experimental ( EXPL , 1.61 g protein/100 kcal ; modified bovine whey proteins with caseinoglycomacropeptide removed ) or control ( CTRL 2.15 g protein/100 kcal ; unmodified bovine milk protein with a whey/casein ratio of 60/40 ) formula ; breast-fed ( BF ) infants were enrolled in a reference group . Complementary foods were allowed in small amounts from 4 to 6 months and unrestricted after 6 months . Results : Weight gain ( g/day ) from 3 to 6 months was similar in the EXPL and CTRL groups ( EXPL-CTRL −0.84 g/day ; 95 % confidence interval −2.25 to 0.57 ) and faster in the EXPL and CTRL groups than in the BF group . Weight analyzed longitudinally from 4 to 12 months was lower in the EXPL group than in the CTRL group ( P = 0.031 ) but higher than in the BF group ( P < 0.0001 ) . Longitudinal analysis of odds ratios from 4 to 12 months indicated fewer infants with weight > 85th percentile in the EXPL group than in the CTRL group ( P = 0.015 ) . Length z scores were lower than , and body mass index z scores were similar to , World Health Organization St and ards in all of the groups . Serum biochemical parameters in the EXPL group reflected lower protein intake and were closer to parameters in the BF infants than in the CTRL group . Conclusions : A formula with 1.61 g of protein/100 kcal supports normal growth of infants after age 3 months . This protein content is adequate if provided from a high- quality source [4689999] Background : Growth faltering in the first 2 years of life is high in South Asia where prevalence of stunting is estimated at 40–50 % . Although nutrition counselling has shown modest benefits , few intervention trials of food supplementation exist showing improvements in growth and prevention of stunting . Methods : A cluster-r and omized controlled trial was conducted in rural Bangladesh to test the effect of two local , ready-to-use foods ( chickpea and rice-lentil based ) and a fortified blended food ( wheat-soy-blend++ , WSB++ ) compared with Plumpy’doz , all with nutrition counselling vs nutrition counselling alone ( control ) on outcomes of linear growth ( length and length-for-age z-score , LAZ ) , stunting ( LAZ < −2 ) , weight-for-length z-score ( WLZ ) and wasting ( WLZ < −2 ) in children 6–18 months of age . Children ( n = 5536 ) were enrolled at 6 months of age and , in the food groups , provided with one of the allocated supplements daily for a year . Results : Growth deceleration occurred from 6 to 18 months of age but deceleration in LAZ was lower ( by 0.02–0.04/month ) in the Plumpy’doz ( P = 0.02 ) , rice-lentil ( < 0.01 ) , and chickpea ( < 0.01 ) groups relative to control , whereas WLZ decline was lower only in Plumpy’doz and chickpea groups . WSB++ did not impact on these outcomes . The prevalence of stunting was 44 % at 18 months in the control group , but lower by 5–6 % ( P ≤ 0.01 ) in those receiving Plumpy’doz and chickpea . Mean length and LAZ at 18 months were higher by 0.27–0.30 cm and 0.07–0.10 ( all P < 0.05 ) , respectively , in all four food groups relative to the control . Conclusions : In rural Bangladesh , small amounts of daily fortified complementary foods , provided for a year in addition to nutrition counselling , modestly increased linear growth and reduced stunting at 18 months of age [7722707] Supplementary feeding programs are common in developing countries . These programs often can not demonstrate an impact on child growth , however , possibly because they tend to reach older children . This study examines the impact of nutritional supplementation on annual growth rates in length and weight from birth to 7 y of age in 1208 rural Guatemalan children . A series of multiple linear regression models is used to control for initial body size , diarrheal disease , home diet , socioeconomic status and gender . During the first year of life , each 100 kcal/d ( 418 kJ ) of supplement was associated with approximately 9 mm in additional length gain and 350 g in additional weight gain ; the benefit decreased to approximately 5 mm in length gain and 250 g in weight gain during the 2nd y of life . Between 24 and 36 mo of age , supplement only had a significant impact on length . There was no impact of nutritional supplementation on growth between 3 and 7 y of age . Patterns were the same if supplement intakes were expressed as a percent of recommended allowances or growth was expressed as a percent of the expected rate . These impacts of nutritional supplementation on growth coincide with the ages when growth velocities , as well as growth deficits , are greatest in this population [26607935] BACKGROUND Maternal undernutrition and newborn stunting [ birth length-for-age z score ( LAZ ) < -2 ] are common in Bangladesh . OBJECTIVE The objective was to evaluate the effect of lipid-based nutrient supplements for pregnant and lactating women ( LNS-PLs ) on birth outcomes . DESIGN We conducted a cluster-r and omized effectiveness trial ( the Rang-Din Nutrition Study ) within a community health program in rural Bangladesh . We enrolled 4011 pregnant women at ≤20 gestational weeks ; 48 clusters received iron and folic acid ( IFA ; 60 mg Fe + 400 μg folic acid ) and 16 clusters received LNS-PLs ( 20 g/d , 118 kcal ) containing essential fatty acids and 22 vitamins and minerals . Both of the supplements were intended for daily consumption until delivery . Primary outcomes were birth weight and length . RESULTS Infants in the LNS-PL group had higher birth weights ( 2629 ± 408 compared with 2588 ± 413 g ; P = 0.007 ) , weight-for-age z scores ( -1.48 ± 1.01 compared with -1.59 ± 1.02 ; P = 0.006 ) , head-circumference-for-age z scores ( HCZs ; -1.26 ± 1.08 compared with -1.34 ± 1.12 ; P = 0.028 ) , and body mass index z scores ( -1.57 ± 1.05 compared with -1.66 ± 1.03 ; P = 0.005 ) than those in the IFA group ; in adjusted models , the differences in length ( 47.6 ± 0.07 compared with 47.4 ± 0.04 cm ; P = 0.043 ) and LAZ ( -1.15 ± 0.04 compared with -1.24 ± 0.02 ; P = 0.035 ) were also significant . LNS-PLs reduced the risk of newborn stunting ( 18.7 % compared with 22.6 % ; RR : 0.83 ; 95 % CI : 0.71 , 0.97 ) and small head size ( HCZ < -2 ) ( 20.7 % compared with 24.9 % ; RR : 0.85 ; 95 % CI : 0.73 , 0.98 ) . The effects of LNS-PL on newborn stunting were greatest in infants born before a 10-wk interruption in LNS-PL distribution ( n = 1301 ; 15.7 % compared with 23.6 % ; adjusted RR : 0.69 ; 95 % CI : 0.53 , 0.89 ) and in infants born to women ≤24 y of age or with household food insecurity . CONCLUSION Prenatal lipid-based nutrient supplements can improve birth outcomes in Bangladeshi women , especially those at higher risk of fetal growth restriction . This trial was registered at clinical trials.gov as NCT01715038 [5593178] Background Children with moderate acute malnutrition ( MAM ) are treated with lipid-based nutrient supplement ( LNS ) or corn-soy blend ( CSB ) . We assessed the effectiveness of ( a ) matrix , i.e. , LNS or CSB , ( b ) soy quality , i.e. , soy isolate ( SI ) or dehulled soy ( DS ) , and ( c ) percentage of total protein from dry skimmed milk , i.e. , 0 % , 20 % , or 50 % , in increasing fat-free tissue accretion . Methods and findings Between September 9 , 2013 , and August 29 , 2014 , a r and omised 2 × 2 × 3 factorial trial recruited 6- to 23-month-old children with MAM in Burkina Faso . The intervention comprised 12 weeks of food supplementation providing 500 kcal/day as LNS or CSB , each containing SI or DS , and 0 % , 20 % , or 50 % of protein from milk . Fat-free mass ( FFM ) was assessed by deuterium dilution technique . By dividing FFM by length squared , the primary outcome was expressed independent of length as FFM index ( FFMI ) accretion over 12 weeks . Other outcomes comprised recovery rate and additional anthropometric measures . Of 1,609 children , 4 died , 61 were lost to follow-up , and 119 were transferred out due to supplementation being switched to non-experimental products . No children developed allergic reaction . At inclusion , 95 % were breastfed , mean ( SD ) weight was 6.91 kg ( 0.93 ) , with 83.5 % ( 5.5 ) FFM . In the whole cohort , weight increased 0.90 kg ( 95 % CI 0.88 , 0.93 ; p < 0.01 ) comprising 93.5 % ( 95 % CI 89.5 , 97.3 ) FFM . As compared to children who received CSB , FFMI accretion was increased by 0.083 kg/m2 ( 95 % CI 0.003 , 0.163 ; p = 0.042 ) in those who received LNS . In contrast , SI did not increase FFMI compared to DS ( mean difference 0.038 kg/m2 ; 95 % CI −0.041 , 0.118 ; p = 0.35 ) , irrespective of matrix . Having 20 % milk protein was associated with 0.097 kg/m2 ( 95 % CI −0.002 , 0.196 ) greater FFMI accretion than having 0 % milk protein , although this difference was not significant ( p = 0.055 ) , and there was no effect of 50 % milk protein ( 0.049 kg/m2 ; 95 % CI −0.047 , 0.146 ; p = 0.32 ) . There was no effect modification by season , admission criteria , or baseline FFMI , stunting , inflammation , or breastfeeding ( p > 0.05 ) . LNS compared to CSB result ed in 128 g ( 95 % CI 67 , 190 ; p < 0.01 ) greater weight gain if both contained SI , but there was no difference between LNS and CSB if both contained DS ( mean difference 22 g ; 95 % CI −40 , 84 ; p = 0.49 ) ( interaction p = 0.017 ) . Accordingly , SI compared to DS increased weight by 89 g ( 95 % CI 27 , 150 ; p = 0.005 ) when combined with LNS , but not when combined with CSB . A limitation of this and other food supplementation trials is that it is not possible to collect reliable data on individual adherence . Conclusions Based on this study , children with MAM mainly gain fat-free tissue when rehabilitated . Nevertheless , LNS yields more fat-free tissue and higher recovery rates than CSB . Moreover , current LNSs with DS may be improved by shifting to SI . The role of milk relative to soy merits further research . Trial registration IS RCT N registry IS RCT [16946216] OBJECTIVE : To evaluate the effects of dietary calcium ( Ca ) intervention on adolescent pregnant mothers and their newborns . METHODS : Seventy-two pregnant adolescent mothers were r and omized into one of 3 groups : control , orange juice fortified with calcium , and dairy . The orange juice and dairy groups were required to take more than 1,200 mg Ca . Calcium tablets were added for those not able to meet required Ca . Maternal and infant weight , length , and blood pressure ( BP ) were recorded . Maternal dietary records were evaluated . Mother ’s blood was drawn for serum Ca , phosphate ( P ) , magnesium ( Mg ) , and vitamin 25-hydroxyvitamin D ( D ) . Cord blood was collected for serum Ca and D. Newborn total body Ca was determined . RESULTS : All mothers were similar in weight , height , and BP . Mothers in the orange juice plus calcium and dairy groups had higher intakes of Ca ( 1,472 mg and 1,771 mg ) than controls ( 862 mg ) . One half of the mothers in the orange juice plus calcium group required Ca tablets . Mothers in the dairy group had higher intakes of P , D , and Mg , higher serum folate and D , and higher cord D levels . Mothers in the orange juice plus calcium group had higher serum P but lower serum folate and D. Infants ( 3,517±273 g ) in the dairy group were heavier than infants in the control ( 3,277±177 g ) and orange juice plus calcium ( 3,292±165 g ) groups . Infants in the dairy group had higher total body calcium than control infants . CONCLUSION : Calcium diet supplemented with dairy products during adolescent pregnancy result ed in higher maternal vitamin D and folate serum levels and higher newborn weight and bone mineralization compared with controls . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00320125 LEVEL OF EVIDENCE : [6988785] This r and omized controlled trial of nutritional supplementation in pregnancy , in a poor black urban population in the United States , aim ed to increase the birth weight and influence the postnatal development of the offspring of mothers at high risk of having low birth weight infants . The execution of the research design and adherence to the treatment regimen among the experimental population appeared adequate for a reasonable test of the treatments . At birth , the only significant favorable effect of supplementation observed was the prevention of depressed birth weight among the offspring of mothers who smoked heavily . With balanced protein-calorie supplementation , length of gestation was increased , the proportion of low-birth-weight infants reduced , and mean birth weight raised by 41 gm ( not statistically significant ) . With high protein supplementation , there was an excess of very early premature births and associated neonatal deaths , and there was significant growth retardation up to 37 weeks of gestation . At 1 year of age , significant effects of high protein supplement were found on three psychological measures : visual habituation , visual dishabituation , and mean length of free play episodes . These measures were unrelated to measures of growth at birth and at 1 year of age . There were no detectable residual adverse effects of high protein supplementation at 1 year of age [2333739] Abstract . The optimum level and ratios of protein to be used in cow 's milk formula has recently been under discussion . Healthy term infants were fed from birth exclusively human milk or a formula that varied in protein level or whey : casein ratio : ( A ) 1.4 g/dl ; 55:45 , ( B ) 1.5 g/dl ; 55:45 , ( C ) 1.3 g/dl ; 55:45 , ( D ) 1.4 g/dl ; 60:40 , ( E ) 1.4 g/dl ; 20:80 . Infants were followed for 12 weeks and blood sample s were taken at 2 , 4 , 8 and 12 weeks . Anthropometric indices did not show any significant differences among groups . Plasma amino acid and BUN levels of the C group were closest to the breast‐fed group , while the formula with the highest protein level ( B ) result ed in high values for some amino acids . When comparing the formulas with 1.4 g protein/dl , the high casein group had the lowest plasma tryptophan levels . Taurine was added to all formulas at a level similar to that of breast milk ; plasma taurine levels were similar for all groups . All formulas contained 0.7 mg iron and 0.7 mg zinc/dl ; no differences were found among the groups in hematological indices or serum trace elements . These data show that feeding a formula with 1.3 g protein/dl and 55:45 whey : casein ratio from birth will result in growth and metabolic indices similar to those of breast‐fed infants , although some plasma amino acid levels are not identical , 1990 [25631295] OBJECTIVE We conducted a cluster-r and omized controlled trial to assess the efficacy of a cereal made from caterpillars , a micronutrient-rich , locally available alternative animal- source food , on reducing stunting and anaemia in infants in the Democratic Republic of Congo . DESIGN Six-month-old infants were cluster r and omized to receive either caterpillar cereal daily until 18 months of age or the usual diet . At 18 months of age , anthropometric measurements and biological sample s were collected . SETTING The rural Equateur Province in the Democratic Republic of Congo . SUBJECTS One hundred and seventy-five infants followed from 6 to 18 months of age . RESULTS Stunting was common at 6 months ( 35 % ) and the prevalence increased until 18 months ( 69 % ) . There was no difference in stunting prevalence at 18 months between the intervention and control groups ( 67 % v. 71 % , P = 0.69 ) . Infants in the cereal group had higher Hb concentration than infants in the control group ( 10.7 v. 10.1 g/dl , P = 0.03 ) and fewer were anaemic ( 26 v. 50 % , P = 0.006 ) , although there was no difference in estimates of body Fe stores ( 6.7 v. 7.2 mg/kg body weight , P = 0.44 ) . CONCLUSIONS Supplementation of complementary foods with caterpillar cereal did not reduce the prevalence of stunting at 18 months of age . However , infants who consumed caterpillar cereal had higher Hb concentration and fewer were anaemic , suggesting that caterpillar cereal might have some beneficial effect . The high prevalence of stunting at 6 months and the lack of response to this micronutrient-rich supplement suggest that factors other than dietary deficiencies also contribute to stunting [28588101] This rigorously conducted trial showed that when offered early in complementary feeding , the food-based intervention of eggs produced a large effect size on child growth . BACKGROUND : Eggs are a good source of nutrients for growth and development . We hypothesized that introducing eggs early during complementary feeding would improve child nutrition . METHODS : A r and omized controlled trial was conducted in Cotopaxi Province , Ecuador , from March to December 2015 . Children ages 6 to 9 months were r and omly assigned to treatment ( 1 egg per day for 6 months [ n = 83 ] ) and control ( no intervention [ n = 80 ] ) groups . Both arms received social marketing messages to encourage participation in the Lulun Project ( lulun meaning “ egg ” in Kichwa ) . All households were visited once per week to monitor morbidity symptoms , distribute eggs , and monitor egg intakes ( for egg group only ) . Baseline and end point outcome measures included anthropometry , dietary intake frequencies , and morbidity symptoms . RESULTS : Mothers or other caregivers reported no allergic reactions to the eggs . Generalized linear regression modeling showed the egg intervention increased length-for-age z score by 0.63 ( 95 % confidence interval [ CI ] , 0.38–0.88 ) and weight-for-age z score by 0.61 ( 95 % CI , 0.45–0.77 ) . Log-binomial models with robust Poisson indicated a reduced prevalence of stunting by 47 % ( prevalence ratio [ PR ] , 0.53 ; 95 % CI , 0.37–0.77 ) and underweight by 74 % ( PR , 0.26 ; 95 % CI , 0.10–0.70 ) . Children in the treatment group had higher dietary intakes of eggs ( PR , 1.57 ; 95 % CI , 1.28–1.92 ) and reduced intake of sugar-sweetened foods ( PR , 0.71 ; 95 % CI , 0.51–0.97 ) compared with control . CONCLUSIONS : The findings supported our hypothesis that early introduction of eggs significantly improved growth in young children . Generally accessible to vulnerable groups , eggs have the potential to contribute to global targets to reduce stunting [24808482] BACKGROUND Management of moderate acute malnutrition ( MAM ) is , currently , focused on food supplementation approaches . However , the sustainability of these strategies remains weak in low- and middle-income countries . In food-secure setting s , an educational/behavioral intervention could be an alternative for improving MAM management . OBJECTIVE This study compared the effectiveness of weekly context -appropriate child-centered counseling ( CCC ) , with an improved corn-soy blend [ corn-soy blend with added micronutrients ( CSB++ ) ] or a locally produced ready-to-use supplementary food ( RUSF ) , in treating MAM through first-line rural health services . DESIGN We used a cluster r and omized controlled trial design with 3 arms , involving 18 rural health centers ( 6 by arm ) and children aged 6 - 24 mo with uncomplicated MAM . In the first arm ( CCC ) , trained health workers provided weekly personalized counseling to caretakers . In the 2 other arms , children received weekly either 455 g CSB++ or 350 g locally produced soy-based RUSF . Both food supplements provided ∼250 kcal/d . RESULTS The recovery rate after 3 mo of treatment was significantly lower with CCC ( 57.8 % ) than with CSB++ ( 74.5 % ) and RUSF ( 74.2 % ) ( P < 0001 ) . Mothers ' attendance at health facilities was also substantially lower in the CCC arm ( P < 0001 ) ; this arm had a high defaulter rate ( P < 0.003 ) . When the analysis was adjusted for attendance , we did not find a significant difference between the 3 arms , with incidence rate ratios of 1.14 ( 95 % CI : 0.99 , 1.31 ) and 1.13 ( 95 % CI : 0.98 , 1.30 ) for the CSB++ and RUSF arms , respectively , compared with the CCC arm . CONCLUSION Whereas supplement-based treatment of MAM was found to be more effective than the provision of CCC , we hypothesize that appropriate and specific nutrition counseling centered on children 's needs , through primary health facilities , might be an alternative strategy for MAM treatment in rural food-secure areas , provided that attendance at counseling sessions by the caregiver is ensured . This trial was registered at clinical trials.gov as NCT01115647 [3048373] Summary . The effect of two levels of energy supplementation in the last trimester of pregnancy on birthweight was tested in a controlled r and omized trial in three villages in Madura , East Java . The high and low energy supplements provided 1·95 MJ ( 465 kcal ) and 218 kj ( 52 kcal ) per day respectively . In the baseline period the home diet provided on average 6·28 MJ ( 1500 kcal ) ( SD 2·1 MJ ( 499 kcal ) ) and 41g(SD 13 g ) of protein . The mean birthweight was 2835 g and the rate of low birth‐weight 12·2 % . In the experimental period the home diet was better . The average intake ranged from 6·45 to 7·19 MJ ( 1541–1717 kcal ) and 41·4–44·2 g per day , depending on the degree of compliance . Mean birth‐weight increased by 100 g and the rate of low birthweight dropped to 9·5 % . There was no difference between the high and low energy supplemented group as a whole , probably due to the masking effect of the better home diet in the experimental period . It is likely that a positive effect of energy supplementation on birthweight was restricted to the group of pregnant women with the lowest home dietary intake and /or a low prepregnant weight . In this community targeting of supplementation to lean seasons and /or to women with a low prepregnant weight may be cost‐effective [19174829] Background / Objectives : High protein intake has been associated with increased growth . This may be linked to increased concentrations of insulin-like growth factor I ( IGF-I ) , which seems to be influenced by the diet , especially its protein component . The short-term effects of high protein intake in late infancy are not known . The objective was to investigate the effects of high protein intake in the form of whole milk ( WM ) on growth and IGF-I from 9 to 12 months of age . Subjects/ Methods : Healthy infants ( n=83 ) were r and omized to receive either WM or infant formula and fish oil or no fish oil ( 2 × 2 design ) . Anthropometric variables , IGF-I concentrations , serum urea nitrogen ( SUN ) and diet were recorded before and after the intervention . Results : Intake of WM significantly increased the protein energy percentage ( PE% ; P⩽0.001 ) and SUN ( P=0.01 ) , whereas there was no effect on size . The milk intervention increased IGF-I in boys ( P=0.034 ) but not in girls . Intake of fish oil had no effect on the outcomes . Including all infants in the analysis there was a significant correlation between weight and IGF-I at 12 months ( r=0.316 , P=0.017 ) , and PE% was positively associated with IGF-I after adjusting for sex and breastfeeding at both 9 ( r=0.329 , P=0.015 ) and 12 months ( r=0.272 , P=0.044 ) . Conclusions : R and omization to WM had no overall effect on growth . However , the positive effect of WM on IGF-I in boys and the positive association between PE% intake and IGF-I at 9 and 12 months is consistent with the hypothesis that a high milk intake stimulates growth [8458314] Malnourished children ( mean age 1.2 years ) referred from public health clinics to a paediatric metabolic ward in Kingston , Jamaica , were enrolled for treatment in a community-based health care project and were r and omly allocated to one of two groups . The first group was treated at home with metronidazole and then for 6 months using the st and ard health care provided from local clinics by community health aides . The second group was given the same drug and home treatment , but in addition received a high energy supplement of 3.31 MJ daily for 3 months . We have previously shown a significant advantage in both weight and height gain for a group given the same supplement in contrast with st and ard health care controls ( Heikens et al. , 1989 , Eur . J. Clin . Nutr . 43 , 145 - 160 ) , and in this study test the addition of a drug treatment aim ed at reducing malabsorbtion due to a possible microbial overgrowth of the small bowel in malnourished children . This paper reports anthropometric findings showing significant benefits from both the drug and nutritional treatments . Greatest gains were by the group given both treatments , but the group given the antibiotic treatment , without energy supplementation , also made better growth recovery than did controls . Only 8 % of the children treated with metronidazole failed to respond to community-based intervention and were admitted to hospital , compared with 19 % for the other groups ( P < 0.05 ) . These findings support targetted high-energy supplementation for the rehabilitation of moderately malnourished children receiving health clinic care , and suggest further that such programs should include antibiotic treatment directed at SBBO [16954961] Objective : Excess protein in infant formula may lead to renal overload and play a role in later obesity . The objective of this controlled , prospect i ve , r and omized , double-blind study was to assess the suitability and safety of a modified protein content infant formula and its noninferiority as compared to a conventional formula . Patients and Methods : Healthy term infants age < 7 days were either breast-fed or r and omized to be fed exclusively with a conventional casein-predominant formula ( protein/energy ratio : 2.6 g/100 kcal ) or the isocaloric whey-predominant study formula ( protein/energy ratio : 1.8 g/100 kcal ) for 120 days . Primary outcome was daily weight gain between D0 and D120 ( noninferiority criterion : difference in daily weight gain ≤4 g ) . Secondary outcomes were daily gain in weight , length , head circumference and body mass index at monthly intervals . Tolerance and safety were assessed at each visit . Results : 162 infants were enrolled , 84 % of the formula-fed infants and 36 % of the breast-fed infants completing the study . Mean daily weight gain from D0 to D120 in the formula-fed groups differed by 0.38 g/day [ 95 % CI : −2.59 ; 1.83 ] signifying the noninferiority of the study formula . Secondary outcomes did not differ between the 2 groups at any time and were comparable to outcomes in the breast-fed group . Tolerance was good and adverse events were not different between study groups . Conclusions : The whey-predominant study infant formula with a protein/energy ratio of 1.8 g/100 kcal and enhanced protein efficiency is safe and not inferior to a conventional formula in ensuring normal growth during the first four months of life [12604972] Objectives The aim of this study was to evaluate the nutritional efficacy and bifidogenic characteristics of a new infant formula containing partially hydrolyzed whey protein , modified vegetable oil with a high & bgr;-palmitic acid content , prebiotic oligosaccharides , and starch . Methods In a double-blind study , healthy formula-fed term infants aged younger than 2 weeks were r and omized to receive either the new infant formula ( NF ) or a st and ard formula ( SF ) until the age of 12 weeks . Anthropometric measurements were taken at enrollment , 6 weeks , and 12 weeks . In a sub sample of infants , blood sample s were taken at 6 weeks and stool sample s were taken at enrollment and 6 weeks . Blood sample s were analyzed for biochemical measures of protein status and amino acids , and stools were analyzed for total bacteria and bifidobacteria . Mothers completed a feeding diary and question naire at 6 and 10 weeks . Results One hundred fifty-four infants were enrolled in the study ; 102 completed the trial . The growth of infants in both formula groups was in line with published growth curves . During the first 6 weeks , NF girls gained more weight and head circumference than the SF girls . These velocity differences were not maintained throughout the 12-week study period . The NF stools had a higher proportion of bifidobacteria at 6 weeks compared with the SF stools , and they were softer . There were no clinical ly significant differences in the blood biochemical and amino acid values between groups . Both formulas were well tolerated by the infants . Conclusions When compared with a st and ard infant formula , the new formula supported satisfactory growth , led to higher counts of bifidobacteria in the feces , produced blood bio-chemical values typical of formula-fed infants , and was well tolerated [16131023] OBJECTIVE To investigate the effect of yogurt supplementation on the growth of preschool children in Beijing suburbs . METHODS Four hundred and two preschool children ( 217 males , 185 females ) , aged 3 - 5 years , whose height for age and /or weight for age were less than the reference level , were selected as subjects from 7 kindergartens in Beijing Fangshan District . The subjects were divided r and omly into control group ( CG , 201 ) and yogurt supplemented group ( YG , 201 ) . Each subject in YG was given one serving of yogurt ( 125 g ) for 5 days a week from March to December in 2001 , while nothing additional was provided to CG . All subjects kept their usual diet during the study . Anthropometry ( body height and weight and upper-arm circumference ) and the bone mineral density ( BMD ) of forearm were measured every 3 months . Disease status and dietary intake were also recorded and assessed . RESULTS The intake of calcium , zinc , and vitamin B2 in YG was significantly higher than that in CG . The incidence and duration of upper-respiratory infection and diarrhea of children in YG were significantly less than those in CG . The height gain of children in YG was significantly higher than that in CG after yogurt was supplemented for 3 , 6 , and 9 months ( P<0.05 ) ( 1.90+/-0.49 cm vs 1.77+/-0.54 cm , 3.83+/-0.57 cm vs 3.64+/-0.66 cm and 5.43+/-0.69 cm vs 5.24+/-0.76 cm , respectively ) . The weight gain of children in YG was significantly higher than that in CG after yogurt was supplemented for 3 , 6 , and 9 months ( P<0.05 ) ( 0.70+/-0.43 kg vs 0.49+/-0.35 kg , 0.98+/-0.62 kg vs 0.80+/-0.60 kg and 1.42+/-0.76 kg vs 1.20+/-0.67 kg , respectively ) . The BMD of children in YG was significantly higher than that in CG after yogurt was supplemented for 9 months ( P<0.05 ) ( 0.415+/-0.058 g/cm2 vs 0.400+/-0.065 g/cm2 ) . CONCLUSION Yogurt is beneficial to the improvement of calcium , zinc , and vitamin B2 intake , the decreasing of the incidence and duration of upper-respiratory infection and diarrhea , and the promotion of the health and the growth and development of preschool children [25639137] Background . Because of its contribution to dietary diversity and to favorable intakes of micronutrients , including iron and zinc , meat is hypothesized to be a valuable complementary food for the infant and young child . However , the evidence base remains limited . Objective . To compare the difference in anthropometric measurements of rural Chinese infants and toddlers 6 to 18 months of age who received a daily supplement of meat or cereal for 12 months . Methods . This cluster-r and omized , controlled study provided a daily supplement of either meat ( n = 514 , 20 clusters ) or cereal ( n = 957 , 40 clusters ) starting as a first complementary food at 6 months of age . Anthropometric measurements were assessed longitudinally . Results . After 12 months of intervention , the meat group ( Δ13.01 ± 1.9 cm ) had greater ( p = .01 ) linear growth than the cereal group ( Δ12.75 ± 1.8 cm ) and a smaller decrease in length-for-age z-score ( LAZ ) over time ( –0.43 ± 0.72 in the meat group vs. –0.54 ± 0.67 in the cereal group ) , after adjustment for baseline length , LAZ , maternal education , work status , and maternal height and weight . Conclusions . Linear growth was modestly greater in the meat group than in the cereal group . LAZ was substantially negative at 6 months , and the intervention did not prevent ongoing decline over the course of the study [7030223] Twelve hundred and fifty-one pregnant women were contacted and their infants followed to age 5 years . Nine hundred and fifty-one ( 76 % ) children completed the trial . Measurements were made of birthweight , length , head circumference , and triceps skinfold at 10 days , and of weight , height , head circumference , and triceps at 5 years . Throughout the entire period of the study half the families , selected at r and om , were supplied with milk tokens entitling the mother , while pregnant , and all children under age 5 years , to 1 pint of milk a day at half its current price . The tokens led to a small increase in milk purchases by the families and to a small increase in milk drunk by the children . However no effect was detected in any growth measurement either in the total group , or in a more " vulnerable " group of children from the largest families [24411489] BACKGROUND & AIMS Protein source , macronutrient composition and content of long chain-polyunsaturated fatty acids ( LC-PUFA ) of infant formulae may influence infant growth . We aim ed to assess the effect of a modified infant formula on growth . METHODS In a r and omized , double-blind trial , 213 healthy term infants consumed isoenergetic study formulae ( intervention formula - IF , control formula - CF ) from the first month of life until the age of 120 days . IF ( 1.89 g protein/100 kcal ) contained α-lactalbumin ( ALAB ) and LC-PUFA , while CF ( 2.30 g protein/100 kcal ) provided st and ard whey and no LC-PUFA . Anthropometry and dietary intake were regularly assessed . A venous blood sample was obtained on day 120 . RESULTS Both formulae were well-accepted without significant differences in health related observations . Weight gain was not statistically different between formula groups ( IF : 30.2 ± 6.3 vs. CF : 28.3 ± 6.5 g/day , mean ± SD , P = 0.06 ) . Length gain was higher in IF ( 0.11 ± 0.02 vs. 0.10 ± 0.02 cm/day , P = 0.02 ) . Energy intake from formula was higher in CF at 90 and 120 days ( IF : 509 ± 117 and 528 ± 123 vs. CF : 569 ± 152 and 617 ± 169 kcal/day , P < 0.01 ) . Protein intake in CF was significantly higher at each assessment . Growth per energy intake was higher in IF compared to CF for weight ( 6.45 ± 2.01 vs. 5.67 ± 2.21 g/100 kcal , P = 0.02 ) and length ( 0.23 ± 0.08 vs. 0.20 ± 0.08 mm/100 kcal , P = 0.04 ) . CONCLUSIONS The modified infant formula with reduced protein content with added ALAB and LC-PUFA , meets infant requirements of protein for adequate growth . The increased energetic efficiency of the new infant formula might result from improved protein composition by added ALAB . Apparently minor differences in composition can markedly affect energetic efficiency for growth . The study was registered at Clinical Trials.gov ( NCT01094080 ) [11335744] Objective . At hospital discharge , preterm infants may have low body stores of nutrients , deficient bone mineralization , and an accumulated energy deficit . This double-blind , r and omized study evaluated the growth of premature infants with birth weights < 1800 g who were fed a 22 kcal/fl oz nutrient-enriched postdischarge formula ( PDF ) or a 20 kcal/fl oz term-infant formula ( TF ) from hospital discharge to 12 months ' corrected age ( CA ) . Methods . Infants were r and omized to PDF or TF a few days before hospital discharge with stratification by gender and birth weight ( < 1250 g or ≥1250 g ) . The formulas were fed to 12 months ' CA . Growth was evaluated using analysis of variance controlling for site , feeding , gender , and birth weight group . Interaction effects were also assessed . Secondary analyses included a repeated measures analysis and growth modeling . Results . One hundred twenty-five infants were r and omized ; 74 completed to 6 months ' CA and 53 to 12 months ' CA . PDF-fed infants weighed more than TF-fed infants at 1 and 2 months ' CA , gained more weight from study day 1 to 1 and 2 months ' CA , and were longer at 3 months ' CA . There were significant interactions between feeding and birth weight group — among infants with birth weights < 1250 g , those fed PDF weighed more at 6 months ' CA , were longer at 6 months ' CA , had larger head circumferences at term 1 , 3 , 6 , and 12 months ' CA , and gained more in head circumference from study day 1 to term and to 1 month CA . The repeated measures and growth modeling analyses confirmed the analysis of variance results . The PDF formula seemed to be of particular benefit for the growth of male infants . Infants fed the PDF consumed less formula and had higher protein intakes at several time points . Energy intakes , however , were not different . Conclusions . Growth was improved in preterm infants fed a nutrient-enriched postdischarge formula after hospital discharge to 12 months ' CA . Beneficial effects were most evident among infants with birth weights < 1250 g , particularly for head circumference measurements [25833980] BACKGROUND The International Lipid-Based Nutrient Supplements Project developed a small-quantity ( 20 g/d ) lipid-based nutrient supplement ( LNS ) for pregnant and lactating women . OBJECTIVE We evaluated the effects of prenatal LNS supplementation on fetal growth . DESIGN In a community-based , partially double-blind , individually r and omized controlled trial , 1320 women ≤20 wk pregnant received 60 mg Fe/400 μg folic acid ( IFA ) , or 1 - 2 Recommended Dietary Allowances of 18 micronutrients , including 20 mg Fe ( MMN ) , or LNS with the same micronutrients as the MMN group , plus 4 minerals and macronutrients contributing 118 kcal ( LNS ) daily until delivery . Fetal growth was compared across groups by using intention-to-treat analysis . The primary outcome was birth length . RESULTS This analysis included 1057 women ( IFA = 349 , MMN = 354 , LNS = 354 ) . Groups did not differ significantly in mean birth length , length-for-age z score ( LAZ ) , head circumference , or percentage low birth length but differed in mean birth weight ( P = 0.044 ) , weight-for-age z score ( WAZ ; P = 0.046 ) , and BMI -for-age z score ( BMI Z ; P = 0.040 ) , with a trend toward differences in low birth weight ( P = 0.069 ) . In pairwise comparisons , the LNS group had greater mean birth weight ( + 85 g ; P = 0.040 ) , WAZ ( + 0.19 ; P = 0.045 ) , and BMI Z ( + 0.21 ; P = 0.035 ) and a lower risk of low birth weight ( RR : 0.61 , 95 % CI : 0.39 , 0.96 ; P = 0.032 ) than did the IFA group . The other group differences were not significant . The effect of intervention was modified by mother 's parity , age , height , baseline hemoglobin , household food insecurity , and child sex , with parity being the most consistent modifier . Among primiparous women ( IFA = 131 ; MMN = 110 ; LNS = 128 ) , the LNS group had greater mean birth length ( + 0.91 cm ; P = 0.001 ) , LAZ ( + 0.47 ; P = 0.001 ) , weight ( + 237 g ; P < 0.001 ) , WAZ ( + 0.56 ; P < 0.001 ) , BMI Z ( + 0.52 ; P < 0.001 ) , head circumference ( 0.50 cm ; P = 0.017 ) , and head circumference-for-age z score ( + 0.40 ; P = 0.022 ) than did the IFA group ; similar differences were found when comparing the LNS and MMN groups among primiparous women , and no group differences were found among multiparous women . CONCLUSION Prenatal LNS supplementation can improve fetal growth among vulnerable women in Ghana , particularly primiparous women . This trial was registered at clinical trials.gov as NCT00970866 [25926413] BACKGROUND Intrauterine growth restriction may be reduced by supplementing maternal diets during pregnancy , but few studies have assessed the impact of combined prenatal and postnatal interventions on child growth . OBJECTIVE We tested a hypothesis that provision of small-quantity lipid-based nutrient supplements ( SQ-LNSs ) to mothers in pregnancy and 6 mo postpartum and to their infants from 6 to 18 mo of age would promote infant and child growth in the study area in rural Malawi . METHODS We enrolled 869 pregnant women in a r and omized trial in Malawi . During pregnancy and 6 mo thereafter , the women received daily 1 capsule of iron-folic acid ( IFA ) , 1 capsule containing 18 micronutrients ( MMN ) , or one 20-g sachet of SQ-LNS [ lipid-based nutrient supplements ( LNS ) , containing 21 MMN , protein , carbohydrates , essential fatty acids , and 118 kcal ] . Children in the IFA and MMN groups received no supplementation ; children in the LNS group received SQ-LNSs from 6 to 18 mo . Primary outcome was child length at 18 mo . RESULTS At 18 mo , the mean length in the IFA , MMN , and LNS groups was 77.0 , 76.9 , and 76.8 cm ( P = 0.90 ) , respectively , and the prevalence of stunting was 32.7 % , 35.6 % , and 37.9 % ( P = 0.54 ) , respectively . No intergroup differences were found in the mean weight , head circumference , or midupper arm circumference or the proportions with low z scores for these variables ( P > 0.05 ) . Covariate adjustment did not change the analysis results , and the associations between the intervention and child length were not modified by maternal parity , age , or nutritional status ( P > 0.10 ) . CONCLUSIONS The findings do not support a hypothesis that provision of SQ-LNSs to women in pregnancy and postpartum and to children from 6 to 18 mo of age would promote child growth in this Malawian study area . This trial was registered at clinical trials.gov as NCT01239693 [12352513] Background Protein quality of breast milk is superior to that of formula proteins . To ensure that the protein intake is sufficient , starter formulas with conventional protein composition provide a protein/energy ratio of 2.2–2.5 g per 100 kcal to infants , which is much higher than that supplied with breast milk . Several studies have shown that formula-fed infants have higher plasma or serum urea concentrations than breast-fed infants do . We tested if feeding formulas with improved protein quality and a protein content corresponding to the minimum level that is consistent with international recommendations ( 1.8 g/100 kcal ) allows patients to achieve normal growth and plasma urea concentrations . Methods Healthy term infants were enrolled into the study and were either breast-fed or r and omly assigned to three formula-fed groups . Formula-fed infants received either a st and ard formula with a protein/energy ratio of 2.2 g/100 kcal , whereas the two other groups received formulas with a protein/energy ratio of 1.8g/100 kcal differing mainly by their source of protein . Subjects received breast milk or these formulas ad libitum as the sole source of energy from birth to four months of age in a controlled blind design ( except for the breast-fed group ) . Anthropometric measurements ( body weight and length ) were obtained at birth , at 30 , 60 , 90 , and 120 days . Energy and protein intakes were calculated from three-day dietary records . Blood was collected for biochemical measurements at 30 , 60 , and 120 days . Results No differences were found between the four feeding groups for weight- and length-gains or for body mass indices ( BMI ) . No differences in energy intakes between the formula-fed groups could be found , whereas protein intakes were less in infants fed the 1.8 g/100 kcal formulas . Plasma urea levels of the infants fed the 1.8 g/100 kcal formulas were closer to those found in the breast-fed infants . Conclusion Improvement of the amino acid profile permits a whey predominant starter formula with 1.8 g protein per 100 kcal to meet the needs of normal term infants during the first four months of life [19369380] BACKGROUND The short- and long-term effects of feeding with hydrolyzed formulas on growth are uncertain . OBJECTIVE Our aim was to investigate the potential differences in body mass index ( BMI ) over the first 6 y of life between infants fed with partially hydrolyzed whey ( pHF-W ) , extensively hydrolyzed whey ( eHF-W ) , extensively hydrolyzed casein ( eHF-C ) , or cow-milk formula ( CMF ) and infants exclusively breastfed for the first 16 wk of life . DESIGN We established a prospect i ve , r and omized , double-blind trial of full-term neonates with atopic heredity in the German birth cohort followed by the German Infant Nutritional Intervention Study through the first 6 y of life . Intention-to-treat and per- protocol analyses of absolute and World Health Organization-st and ardized BMI trajectories for 1840 infants ( pHF-W : n = 253 ; eHF-W : n = 265 ; eHF-C : n = 250 , CMF : n = 276 ; breastfed : n = 796 ) were performed . RESULTS No significant differences in absolute or World Health Organization-st and ardized BMI trajectories were found among the pHF-W , eHF-W , CMF , and breastfed groups during the 6-y follow-up . However , in the eHF-C group , both intention-to-treat and per- protocol analyses showed a significantly slower sex-adjusted BMI gain through the 8th to 48th week of life ( -0.1 to -0.2 lower BMI z score ) but not beyond . Analyses of weight and length revealed that this difference is due to a slightly diminished weight gain in the first year of life because growth in length did not differ among study groups for the entire follow-up . CONCLUSIONS To our knowledge , this is the first r and omized trial investigating both short- and long-term effects of partially and extensively hydrolyzed formula ( pHF-W , eHF-W , eHF-C ) , CMF , and breastfeeding on growth in one trial . Feeding with eHF-C led to a transient lower weight gain in the first year of life . No long-term consequences of different formulas on BMI were observed [23795976] Low nutritional value of complementary foods is associated with high incidence of childhood growth stunting in low-income countries . This study was done to test a hypothesis that dietary complementation with lipid-based nutrient supplements ( LNS ) promotes linear growth and reduces the incidence of severe stunting among at-risk infants . A total of 840 6-month-old healthy infants in rural Malawi were enrolled to a r and omised assessor-blinded trial . The participants received 12-month supplementation with nothing , milk-LNS , soy-LNS , or corn-soy blend ( CSB ) . Supplements provided micronutrients and approximately 280 kcal energy per day . Outcomes were incidence of severe and very severe stunting [ length-for-age z-score , ( LAZ ) < -3.00 and < -3.50 , respectively ] , and change in LAZ . The incidence of severe stunting was 11.8 % , 8.2 % , 9.1 % and 15.5 % ( P = 0.098 ) and that of very severe stunting 7.4 % , 2.9 % , 8.0 % and 6.4 % ( P = 0.138 ) in control , milk-LNS , soy-LNS and CSB groups , respectively . Between 9 and 12 months of age , the mean change in LAZ was -0.15 , -0.02 , -0.12 and -0.18 ( P = 0.045 ) for control , milk-LNS , soy-LNS and CSB groups , respectively . There was no significant between-group difference in linear growth during other age-intervals . Although participants who received milk-LNS had the lowest incidence of severe and very severe stunting , the differences between the groups were smaller than expected . Thus , the results do not provide conclusive evidence on a causal association between the LNS supplementation and the lower incidence of stunting . Exploratory analyses suggest that provision of milk-LNS , but not soy-LNS promotes linear growth among at-risk infants mainly between 9 and 12 months of age [1517950] Several recent studies have demonstrated significantly lower plasma total tryptophan concentrations in formula-fed than in breast-fed infants . We have measured prepr and ial plasma amino acid concentrations in infants breast-fed or fed a formula with a protein concentration of 1–57 g/dl and with a whey/casein ratio of 60:40 or a formula with a protein concentration of 1.37 g/dl and a whey/casein ratio of 40:60 and fortified with 10 mg/dl ( 15 mg/100 kcal ) of tryptophan . Healthy term infants ( 10 per group ) were either breast-fed from birth or r and omly assigned to one of the two study formulas . At 4 and 12 weeks of age , anthropometric measurements were performed and blood sample s were obtained . During the study period of 12 weeks , all infants showed normal growth ( weight , length , and head circumference ) and there were no statistically significant differences between the groups . The plasma concentrations of the essential amino acids phenylalanine , threonine , valine , and lysine were significantly lower in the breast-fed group than in both formula-fed groups . For tyrosine , methionine , leucine , histidine , isoleucine , and arginine , no significant differences could be found between the feeding groups . Concentration of total plasma tryptophan was significantly higher in the breast-fed group than in the group fed the tryptophan-unfortified formula , but no statistically significant difference could be found between the plasma tryptophan concentration in the breast-fed group versus the group fed the tryptophan-fortified formula . The results indicate that tryptophan fortification of adapted formula is necessary to achieve plasma total tryptophan concentrations similar to those found in breast-fed infants . The data also confirm that a formula with reduced protein concentration will support normal growth and will produce a plasma amino acid profile not much different from that of a conventional type of formula [8632935] OBJECTIVE To evaluate the adequacy of protein intakes now recommended as safe for infants and toddlers . METHODS Subjects were recovering malnourished infants , age 5.3 to 17.9 months , length age ( LA ) 2.5 to 6.4 months , weight age ( WA ) 1.5 to 5.2 months , weight/length ( W/L ) 78 % to 100 % of National Center for Health Statistics data ; and toddlers age 11.4 to 31.6 months , LA 6.1 to 17.9 months , WA 3.9 to 12.0 months , W/L 79 % to 99 % . Infants were assigned at r and om to formulas with 5.5 % , 6.7 % , or 8.0 % energy as 60:40 whey : casein protein . The 5.5 % was based on FAO-WHO-UNU safe protein and average energy for ages 2.5 to 6.0 months . Toddlers received 4.7 % ( recommended for 6 to 18 months ) , 6.4 % , or 8.0 % . Identical concentrations ( weight/kcal ) of other nutrients were maintained ; intakes were adjusted weekly to reach , in 90 days , the 50th percentile of weight for a LA 3 months greater than the initial one . RESULTS Infants consumed 125 + /- 11 ( SD ) , 116 + /- 10 , and 126 + /- kcal and 1.7 + /- 0.1 , 1.9 + /- 0.2 , and 2.5 + /- 0.3 g protein kg-1 . d-1 ; gained 2.4 + /- 0.7 , 2.9 + /- 0.7 , and 2.6 + /- 0.5 months in LA , and reached a W/L of 105 + /- 5 , 103 + /- 6 , and 105 + /- 5 % of reference . Sum of four fat-folds ( sigma FF ) grew 13.1 + /- 6.9 , 10.4 + /- 4.8 , and 11.7 + /- 5.3 mm to 32.5 + /- 5.2 , 31.7 + /- 4.7 , and 30.5 + /- 5.5 mm ; arm muscle areas ( AMA ) 57 % , 51 % , 70 % to 1004 + /- 109 , 1017 + /- 110 , and 1004 + /- 116 mm2 , still low ; arm fat areas ( AFA ) 93 % , 66 % , and 93 % to higher-than-normal 598 + /- 105 , 610 + /- 101 , and 541 + /- 116 mm2 . Regression of intake on weight gain estimated energy for maintenance + activity to be 81.0 + /- 7.5 ( SEM ) kcal . kg-1 . d-1 , and cost of gain ( storage + metabolic cost ) as 7.6 + /- 1.7 kcal/g , with no significant effect of % protein . Toddlers consumed 107 + /- 9 , 103 + /- 12 , and 105 + /- 10 kcal and 1.3 + /- 0.1 , 1.6 + /- 0.2 , and 2.1 + /- 0.2 g protein . kg-1 . d-1 , gained 3.3 + /- 0.7 , 2.9 + /- 0.6 , and 3.3 + /- 0.7 months in LA ; to a W/L of 102 + /- 1 , 102 + /- 3 , and 101 + /- 4 % . Sigma FF grew 9.2 + /- 4.0 , 7.4 + /- 4.3 , and 6.0 + /- 3.8 to 28.9 + /- 5.2 , 30.5 + /- 3.7 , and 27.0 + /- 2.7 mm ; AMA 31 % , 33 % , and 34 % to 1121 + /- 115 , 1124 + /- 110 , and 1117 + /- 120 mm2 ; AFA 53 % , 44 % , and 45 % to higher-than normal 578 + /- 106 , 636 + /- 99 , and 569 + /- 68 mm2 . Cost of maintenance + activity was 70.8 + /- 3.8 ( SEM ) kcal . kg-1 . d-1 , that of weight gain 9.7 + /- 1.35 kcal/g , with no effect of % protein . CONCLUSIONS Within age groups , there were no significant protein-related differences in growth . In both infants and toddlers , high-energy intakes result ed in mild obesity , with lean body mass still deficient . Protein intakes two SD below the means in the lowest protein/energy cells , 1.5 g . kg-1 . d-1 for infants and 1.1 g times kg-1 . d-1 for toddlers , should still be safe for nearly all children of comparable biological ages [6073440] Infant formulas have been conventionally prepared with an excess of total protein in order to provide sufficient amounts of essential amino acids to the rapidly growing infant . However , this practice leads to higher than necessary protein intake during early infant development , inducing accelerated growth patterns correlated with the development of chronic diseases later in life . This study was aim ed at assessing the safety of an infant formula enriched with bovine alpha-lactalbumin containing a total protein concentration very close to that of human milk , and determining its efficacy in the support of healthy infant growth from the first month to the fourth month of age . Healthy full-term infants ≤40 days of age were r and omized in this controlled single blind trial to one of the following infant formulas : IF 1 ( containing 1.0 g protein/dL ; n = 30 ) , IF 2 ( containing 1.3 g protein/dL ; n = 24 ) , and IF 3 ( containing 1.5 g protein/dL ; n = 42 ) . A control group consisting of exclusively breastfed infants ( HM ; n = 212 ) was included in the study . Anthropometric measurements and Z-scores were evaluated at baseline , at 1 month of age , and at 4 months of age . Weight gain ( g/day ) was similar in the IF 1 and the HM groups ( p = 0.644 ) , and it was significantly greater in the IF 2 and IF 3 groups than in the HM group . Growth patterns in both breastfed or IF-fed infants were in accordance with the World Health Organization ( WHO ) growth st and ards . At four months of age , the mean weight-for-age Z-score ( WAZ ) adjusted for initial value in the IF 1 group was similar to that of the HM group and significantly lower than that of the IF 2 and IF 3 groups ( p = 0.031 and p = 0.014 for IF 2 and IF 3 , respectively ) . Length-for-age ( LAZ ) adjusted for initial value was similar among all groups at four months of age . From 1 to 4 months of life , IF 1 containing 1.0 g protein/dL promotes growth and weight gain similar to those observed in exclusively breastfed infants . As this is a first approach to study ing an IF containing total protein in a level below that recommended by international committees on nutrition , further investigations are needed to support these findings evaluating infant ’s metabolic profile and growth in the long term [26063066] BACKGROUND Complementing infant diets with lipid-based nutrient supplements ( LNSs ) has been suggested to improve growth and reduce morbidity , but the daily quantity and the milk content of LNSs affect their cost . OBJECTIVE We tested the hypotheses that the change in mean length-for-age z score ( LAZ ) for infants provided with 10 - 40 g LNSs/d from ages 6 to 18 mo would be greater than that for infants receiving no dietary intervention at the same age and that provision of LNSs that did not contain milk would be as good as milk-containing LNSs in promoting linear growth . METHODS We enrolled in a r and omized single-blind trial 6-mo-old infants who were allocated to 1 of 6 groups to receive 10 , 20 , or 40 g LNSs/d containing milk powder ; 20 or 40 g milk-free LNSs/d ; or no supplement until 18 mo of age . The primary outcome was change in LAZ . RESULTS Of the 1932 enrolled infants , 78 ( 4.0 % ) died and 319 ( 16.5 % ) dropped out during the trial . The overall reported supplement consumption was 71.6 % of days , with no difference between the groups ( P = 0.26 ) . The overall mean ± SD length and LAZ changes were 13.0 ± 2.1 cm and -0.45 ± 0.77 z score units , respectively , which did not differ between the groups ( P = 0.66 for length and P = 0.74 for LAZ ) . The difference in mean LAZ change in the no-milk LNS group compared with the milk LNS group was -0.02 ( 95 % CI : -0.10 , 0.06 ; P = 0.72 ) . CONCLUSION Our results do not support the hypothesis that LNS supplementation during infancy and childhood promotes length gain or prevents stunting between 6 and 18 mo of age in Malawi . This trial was registered at clinical trials.gov as NCT00945698 [26864368] BACKGROUND The utility of dairy ingredients in the supplementary foods used in the treatment of childhood moderate acute malnutrition ( MAM ) remains unsettled . OBJECTIVE We evaluated the effectiveness of a peanut-based ready-to-use supplementary food ( RUSF ) with soy protein compared with a novel RUSF containing dairy ingredients in the form of whey permeate and whey protein concentrate in the treatment of children with MAM . DESIGN We conducted a r and omized , double-blind clinical effectiveness trial involving rural Malawian and Mozambican children 6 - 59 mo of age with MAM treated with either soy RUSF or a novel whey RUSF treatment of ~75 kcal · kg(-1 ) · d(-1 ) for up to 12 wk . RESULTS The proportion of children that recovered from MAM was significantly higher in the group that received whey RUSF ( 960 of 1144 ; 83.9 % ) than in the group that received soy RUSF ( 874 of 1086 ; 80.5 % ; P < 0.04 ; risk difference 3.4 % , 95 % CI : 0.3 % , 6.6 % ) . Children who consumed whey RUSF also demonstrated better growth markers , with a higher mean midupper arm circumference ( MUAC ) at the time of discharge ( P < 0.009 ) , greater MUAC gain during the course of treatment ( P < 0.003 ) , higher mean weight-for-height z score at discharge ( P < 0.008 ) , and greater weight gain ( P < 0.05 ) . No significant differences were identified in length gain or time to recovery between the 2 groups . CONCLUSION This study highlights the importance of milk protein in the treatment of MAM , because the use of a novel whey RUSF result ed in higher recovery rates and improved growth than did soy RUSF , although the whey RUSF supplement provided less total protein and energy than the soy RUSF . This study was registered at clinical trials.gov as NCT01790048

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### Context: [25733649] BACKGROUND Moderate acute malnutrition ( MAM ) , defined as weight-for-length z score between -3 and -2 or midupper arm circumference between 11.5 and 12.5 cm , affects ∼33 million children aged < 5 y worldwide . OBJECTIVE The objective was to compare the effects of 4 dietary supplements for the treatment of MAM . DESIGN Twelve community health centers in rural Mali were r and omly assigned to provide to 1264 MAM children aged 6 - 35 mo one of 4 dietary supplements containing ∼500 kcal/d for 12 wk : 1 ) ready-to-use , lipid-based supplementary food ( RUSF ) ; 2 ) special corn-soy blend ( CSB++ ) ; 3 ) locally processed , fortified flour ( Misola ) ; or 4 ) locally milled flours plus oil , sugar , and micronutrient powder ( LMF ) . RESULTS In total , 1178 children ( 93.2 % ) completed the study . The adjusted mean ( 95 % CI ) change in weight ( kg ) from baseline was greater with RUSF than with the locally processed blends and was intermediate with CSB++ [ 1.16 ( 1.08 , 1.24 ) for RUSF , 1.04 ( 0.96 , 1.13 ) for CSB++ , 0.91 ( 0.82 , 0.99 ) for Misola , and 0.83 ( 0.74 , 0.92 ) for LMF ; P < 0.001 ] . For length change , RUSF and CSB++ differed significantly from LMF . Sustained recovery rates were higher with RUSF ( 73 % ) than with Misola ( 61 % ) and LMF ( 58 % ) , P < 0.0001 ; CSB++ recovery rates ( 68 % ) did not differ from any of the other groups . CONCLUSIONS RUSF was more effective , but more costly , than other dietary supplements for the treatment of MAM ; CSB++ yielded intermediate results . The benefits of treatment should be considered in relation to product costs and availability [19633578] Objectives : Human milk ( HM ) is the optimal source of nutrition for premature infants ; however , it is unclear whether HM alone is sufficient to meet their elevated nutritional requirements early after hospital discharge . We previously reported that premature infants ( 750–1800 g birth weight ) fed HM containing extra nutrients for 12 weeks after discharge had dietary intakes closer to recommended levels and grew more rapidly than those fed HM alone . The objectives of the present article are to examine the impact of this intervention on bone mineralization , body composition , and HM use up to 1 year . Data are also presented on general developmental level at 18-month corrected age ( CA ) . Patients and Methods : At discharge , predominantly HM-fed infants were r and omized to receive for 12 weeks either approximately half of their feedings containing a multinutrient fortifier ( intervention , n = 19 ) or all of their feedings as HM alone ( control , n = 20 ) . Results : Intervention infants remained longer ( P < 0.001 ) and had greater whole-body bone mineral content ( P = 0.02 ) until 12-month CA compared with controls . Intervention infants born less than or equal to 1250 g continued to have a larger mean head circumference throughout the first year of life ( P < 0.0001 ) . Human milk feeding ( mL · kg−1 · day−1 ) differed between groups at 6- ( P = 0.035 ) , but not 12-month CA . No statistically significant differences were found between groups in the mental , motor , or behavior rating scale scores of the Bayley II at 18-month CA . Conclusions : Adding a multinutrient fortifier to HM provided to predominantly HM-fed premature infants early after discharge results in sustained differences in weight , length , and whole-body bone mineral content , and in smaller babies , head circumference for the first year of life [19881394] Background and Objectives : Postdischarge formulas with extra energy and protein improve short-term growth but may also influence long-term body composition in an unwanted manner . Energy- and protein-enriched formulas with an increased protein-to-energy ratio improves gain of lean mass . The objective of the study was to investigate whether feeding a nutrient-enriched formula without extra energy after term , usually 3 to 4 weeks after discharge , would influence growth and body composition in infancy . Methods : In this r and omized controlled trial preterm infants were fed fortified human milk or preterm formula until term . At term , 102 infants were r and omized to a nutrient-enriched formula without extra energy or st and ard formula until 6 months corrected age . Twenty-six infants received unfortified human milk after term . At term and 6 months corrected age , anthropometry and a dual-energy x-ray absorptiometry ( DEXA ) scan were performed . Lean and fat mass ( FM ) were corrected for height . Results : There were no differences in growth or body size between the feeding groups . Infants fed the enriched formula gained less FM and had lower FM corrected for body size at 6 months corrected age than infants fed st and ard formula . Infants fed human milk had lower lean mass and higher FM corrected for body size at 6 months corrected age than formula-fed infants . Conclusions : Feeding nutrient-enriched formula without extra energy after term does not change quantity of growth but does influence type of weight gain and body composition of preterm infants . Infants fed the nutrient-enriched formula had lower FM corrected for body size at 6 months corrected age than infants fed st and ard formula or human milk [28374648] Background : There is no consensus over best approaches to reliably prevent malnutrition in rural communities in low-income countries . Objective : We compared the effectiveness of 2 lipid-based ready-to-use supplementary foods ( RUSFs ) differing in dairy protein content to improve the nutritional status of mothers and at-risk infants and young children in rural Guinea-Bissau . Methods : A 3-month cluster-r and omized controlled pilot trial of 2 RUSFs was conducted with 692 mothers and 580 mildly or moderately malnourished infants ( 6 - 23 months ) and children ( 24 - 59 months ) from 13 villages . The RUSFs contained either 478 ( mothers , children ) or 239 kcal/d ( infants ) with 15 % or 33 % of protein from dairy and were distributed at community health centers 5 d/wk . Controls were wait-listed to receive RUSF . Primary outcomes were mid-upper arm circumference ( MUAC ) in mothers , and weight-for-age and height-for-age z-scores ( WAZ and HAZ ) in infants and children . Results : There was a significant effect of the RUSF-33 % on MUAC in mothers ( P = .03 ) . The WAZ and HAZ increased substantially , by ≈1 z-score , in infants and children ( P < .01 ) independent of group r and omization . In children , but not infants , baseline WAZ and change in maternal MUAC were associated with change in WAZ ( β = .07 , P = .02 ) . Conclusion : Ready-to-use supplementary foods with higher dairy protein content had a significant benefit in village mothers , supporting a comparable recent finding in preschool children . In addition , supplementation of children < 2 years result ed in improved growth independent of family nutritional status , whereas success in older children was associated with change in maternal nutrition , suggesting the need for community-level education about preventing malnutrition in older , as well as younger , children [22952176] BACKGROUND Improved complementary feeding is cited as a critical factor for reducing stunting . Consumption of meats has been advocated , but its efficacy in low-re source setting s has not been tested . OBJECTIVE The objective was to test the hypothesis that daily intake of 30 to 45 g meat from 6 to 18 mo of age would result in greater linear growth velocity and improved micronutrient status in comparison with an equicaloric multimicronutrient-fortified cereal . DESIGN This was a cluster r and omized efficacy trial conducted in the Democratic Republic of Congo , Zambia , Guatemala , and Pakistan . Individual daily portions of study foods and education messages to enhance complementary feeding were delivered to participants . Blood tests were obtained at trial completion . RESULTS A total of 532 ( 86.1 % ) and 530 ( 85.8 % ) participants from the meat and cereal arms , respectively , completed the study . Linear growth velocity did not differ between treatment groups : 1.00 ( 95 % CI : 0.99 , 1.02 ) and 1.02 ( 95 % CI : 1.00 , 1.04 ) cm/mo for the meat and cereal groups , respectively ( P = 0.39 ) . From baseline to 18 mo , stunting [ length-for-age z score ( LAZ ) < -2.0 ] rates increased from ~33 % to nearly 50 % . Years of maternal education and maternal height were positively associated with linear growth velocity ( P = 0.0006 and 0.003 , respectively ) ; LAZ at 6 mo was negatively associated ( P < 0.0001 ) . Anemia rates did not differ by group ; iron deficiency was significantly lower in the cereal group . CONCLUSION The high rate of stunting at baseline and the lack of effect of either the meat or multiple micronutrient-fortified cereal intervention to reverse its progression argue for multifaceted interventions beginning in the pre- and early postnatal periods [22152430] OBJECTIVE To examine the effects of animal- source foods on toddler growth . DESIGN A 5-month comparison feeding intervention study with one of three millet-based porridges r and omized to eighteen feeding stations serving 303 children aged 11 - 40 months . Feeding stations served plain millet porridge ( Plain group ) , porridge with milk ( Milk group ) or porridge with beef ( Meat group ) . Anthropometry , morbidity and food intake were measured at baseline and regular intervals . Longitudinal mixed models were used to analyse growth . SETTING Embu , Kenya . SUBJECTS Two hundred and seventy-four children were included in final analyses . RESULTS Linear growth was significantly greater for the Milk group than the Meat group ( P = 0·0025 ) . Slope of growth of mid-arm muscle area of the Plain group was significantly greater than in the Meat group ( P = 0·0046 ) , while the Milk group 's mid-upper arm circumference growth rate was significantly greater than the Meat group 's ( P = 0·0418 ) . The Milk and Plain groups ' measures did not differ . CONCLUSIONS Milk and meat porridges did not have a significantly greater effect on growth than plain porridge in this undernourished population . Linear growth was influenced by more than energy intakes , as the Plain group 's total body weight-adjusted energy intakes were significantly greater than the Meat group 's , although linear growth did not differ . Energy intakes may be more important for growth in arm muscle . The diverse age distribution in the study makes interpretation difficult . A longer study period , larger sample size and more focused age group would improve clarity of the results [18287372] Poor complementary feeding practice s are associated with stunting and growth faltering throughout the developing world . The objective was to compare the effect of using peanut-/soy-based fortified spread ( FS ) and corn porridge fortified with fish powder ( FP ) as complementary foods on growth in rural Malawian children . A total of 240 children were enrolled at the age of 6 mo and r and omized to receive FS or FP . Both complementary foods provided 836 kJ/d from 6 to 9 mo of age and 1254 kJ/d from 9 to 18 mo of age . Children were followed monthly for anthropometry and fortnightly for the symptoms of fever , cough , or diarrhea until they were 18 mo old . Zn and Se status were assessed at 6 and 12 mo . The primary outcomes were the rates of weight and length gain from 6 - 12 mo and from 12 - 18 mo . Children who received FS gained 110 g more ( 95 % CI 220 to 10 ) from 6 - 12 mo of age than children receiving FP . Weight gain did not differ between children receiving FS and FP between 12 and 18 mo of age , nor did statural growth from 6 to 12 mo or 12 to 18 mo . A total of 23 % of all children were Zn deficient at 6 mo of age and this increased to 37 % at 12 mo of age . Neither FS nor FP was associated with significantly improved Zn status . FS was associated with better weight gain from 6 - 12 mo of age and may be useful in conjunction with additional interventions to improve infant growth in the developing world [2239797] The effect of prenatal energy supplementation on maternal anthropometry was assessed in a controlled , r and omized trial in Madura , East Java . At 26 - 28 wk of gestation women were either given 465 kcal/d ( HE group ) or 52 kcal/d ( LE group ) . Two hundred seventy-six women were enrolled in the HE group and 266 women , in the LE group . Supplement intake was variable . Testing of effect by treatment and compliance was thus done by subcategories ( HE 1 - 3 and LE 1 - 3 , corresponding to less than 45 , 45 - 89 , and greater than or equal to 90 packets of supplement consumed ) . Analysis of variance did not show significant differences among the six subcategories in third-trimester weight gain , sum of skinfold thicknesses , 4-wk postpartum weight , or body mass index . In this population energy supplementation for the short duration of the last 90 - 110 d of pregnancy was not sufficient to improve maternal nutrition as judged by anthropometry [3279745] The effects on pregnancy outcome and maternal iron status of powdered milk ( PUR ) and a milk-based fortified product ( V-N ) were compared in a group of underweight gravidas . These take-home products were distributed during regular prenatal visits . Women in the V-N group had greater weight gain ( 12.29 vs 11.31 kg , p less than 0.05 ) and mean birth weights ( 3178 vs 3105 g , p less than 0.05 ) than those in the PUR group . Values for various indicators of maternal Fe status were also higher in the V-N group . Compared with self-selected noncompliers , similar in all control variables to compliers , children of women who consumed powdered milk or the milk-based fortified product had mean birth weights that were higher by 258 and 335 g , respectively . Data indicate a beneficial effect of the fortified product on both maternal nutritional status and fetal growth [7625343] Infants eat primarily to satisfy energy needs and the safe amount of protein in infant formulas ( ie , the amount adequate for nearly all infants ) is therefore expressed as the protein-energy ratio . We studied male infants aged 8 - 112 d fed milk-based formulas . One group ( experimental group ) was fed formulas that provided protein-energy ratios of 3.73 g/MJ ( 1.56 g/100 kcal ) from 8 to 27 d of age , gradually decreasing to 2.99 g/MJ ( 1.25 g/100 kcal ) from 84 to 111 d of age . Growth rates and serum albumin and urea nitrogen of these infants were compared with those of a concurrently studied control group and a previously studied large reference group . Gains in weight and concentrations of serum albumin of the three groups were not significantly different . Gains in length were significantly less for the experimental group than for the reference group . Serum urea nitrogen was significantly less in the experimental group than in the control group or reference group . We conclude that the protein-energy ratios of the experimental formula diet were below the safe level . Because the decrease in growth rate of the experimental group was rather small ( demonstrable only in comparison with the large reference group ) , and because serum albumin of the experimental group increased with age as in normally nourished infants , we suspect that the safe protein-energy ratio of infant formulas lies closer to the ratios fed to the experimental group than to the ratio [ approximately 5.0 g/MJ ( 2.1 g/100 kcal ) ] in currently marketed milk-based formulas [7282613] The effect of food supplementation on physical growth during the last trimester of pregnancy and the first 3 yr of life was studied in a sample of families at risk of malnutrition living in the urban slums of Bogota , Colombia . Families in which the mother was pregnant and at least one-half of the children under 5 yr of age were below 85 % of weight for age were selected for the study . All were provided with free obstetrical and pediatric care . The families were then r and omly assigned to control and supplemented groups . The supplemented families received a daily allotment of 600 cal or 30 g of protein per capita for home consumption from the onset of the 3rd trimester of pregnancy until the subject children reached the age of 3 yr . Calorie consumption from the supplement by the study children ( offspring of the target pregnancy ) was 458 ± 249 calories at age 18 months and 363 ± 283 cal at age 36 months . Protein consumption at those ages was 34 . 1 ± 20.6 and 23.6 ± 19.7 g,'day . However , substitution of the supplement for foods from the regular diet result ed in net supplementation of approximately 200 cal and 22 g of protein per day . There were significant differences in weight between supplemented and control groups beginning at age 3 months and in length beginning at age 6 months . Supplementation reduced the total prevalence of malnutrition ( Gomez classification ) only slightly ; at 36 months of age , 72 % of the supplemented group and 77.8 % of the control group were malnourished . On the other h and , the prevalence of moderate and severe malnutrition ( Gomez II and III ) , was significantly reduced by supplementation . At 36 months , 20.6 % of the control group and 8.8 % of the supplemented group fell into those categories . Despite improved physical growth in the supplemented group , their height and weight remained substantially below those of the high socioeconomic Colombian st and ards . The failure of supplementation to close the gap between low and high socioeconomic groups was attributed , in part , to the high incidence of diarrheal disease among subjects of the study . It is postulated that simple provision of food supplements , without effective prevention of diarrheal disease , is likely to have limited effects on physical growth among disadvantaged children . Am . J. Clin . Nutr . 34 : 1885 - 1892 , 1981 [17158417] BACKGROUND Despite the theoretical benefits of nutrient-enriched formula given to preterm infants after hospital discharge , its role in reversing growth deficits after hospital discharge remains poorly defined . OBJECTIVE The aim was to determine the effect of different formulas on the growth , bone mass , and body composition of preterm infants after hospital discharge . DESIGN This was a r and omized , double blind comparison of a nutrient-enriched formula ( EF ) and a formula for term infants ( TF ) given for 1 y after hospital discharge . Compared with the TF , the EF had a higher energy density and higher contents of protein , calcium , and phosphorus ( by 10 % , 21 % , 44 % , and 11 % , respectively ) and higher contents of almost all other nutrients ( by > or=10 % ) . RESULTS Birth weights of the infants were 630 - 1620 g ( median : 1250 g ) and gestational ages were 24 - 34 wk ( median : 29 wk ) . TF result ed in significantly greater weight , length , head circumference measurements , and their respective z scores on the basis of age- and sex-specific norms . At the end of the study , the mean z scores for the corrected age of infants in the TF group were -0.37 for weight , 0.001 for length , and 0.50 for head circumference . The TF group also had significantly greater dual-energy X-ray absorptiometry measured bone and lean and fat mass than did the EF group ( P < 0.05 for all comparisons ) . CONCLUSIONS The use of EF for preterm infants after hospital discharge shows no advantage over TF in growth , bone mineralization , and body composition . More studies are needed to determine the optimal postdischarge nutrition support for preterm infants [9001369] The long-term benefits of early childhood supplementation and the extent to which catch-up growth occurs following linear growth retardation remain controversial . Stunted children ( height-for-age < -2 SD of NCHS references , n = 122 ) recruited from a survey of poor neighborhoods in Kingston , Jamaica , participated in a 2-yr r and omized , controlled trial of supplementation beginning at ages 9 - 24 mo . A group of 32 non-stunted children from the same neighborhoods was also followed . Four years after the intervention ended , when children were 7 to 8 y old , there were no effects of supplementation on any anthropometric measure . From the end of the trial until follow-up , the children who had been supplemented gained 1.2 cm less ( P < 0.05 ) than the non-supplemented children , approximately the same amount as they had gained during the trial compared with the non-supplemented children . After adjustment for regression to the mean , the height-for-age of stunted children ( supplemented and non-supplemented combined ) increased from enrollment to follow-up by 0.31 Z-score ( 95 % CI 0.17 , 0.46 ) . The height-for-age of the non-stunted children also increased ( 0.96 Z-score ; 95 % CI 0.70 , 1.22 ) . Our results suggest that some catch-up growth is possible even when children remain in poor environments . Long-term benefits of supplementation to growth may not be achieved when intervention begins after age 12 mo in children who have already become undernourished [8839497] The effect of supplementation on growth was tested by means of four similar controlled r and omized trials in the Congo ( n = 120 ) , Senegal ( n = 110 ) , Bolivia ( n = 127 ) , and New Caledonia ( n = 90 ) . Four-month-old infants were r and omly allocated to supplement or control groups . A cereal-based precooked porridge was offered twice daily for 3 mo and consumption was monitored . Both groups were free to eat local food . At 7 mo of age , all infants were still breast-fed in the Congo , Senegal , and Bolivia compared with 47 % in New Caledonia . Mean daily consumption of the supplement varied among countries ( 558 - 790 kJ/d ) . Mean length at 4 mo was lowest in Bolivia , higher in Senegal and the Congo , and near the National Center for Health Statistics reference in New Caledonia . The mean 4 - 7 mo length increment was 0.48 cm higher for supplemented than for control infants in Senegal ( P < 0.05 ) , whereas weight increments did not differ . No significant effect was found in the other countries [25332329] BACKGROUND High intake of cow-milk protein in formula-fed infants is associated with higher weight gain and increased adiposity , which have led to recommendations to limit protein intake in later infancy . The impact of protein from meats for breastfed infants during complementary feeding may be different . OBJECTIVE We examined the effect of protein from meat as complementary foods on growth and metabolic profiles of breastfed infants . DESIGN This was a secondary analysis from a trial in which exclusively breastfed infants ( 5 - 6 mo old from the Denver , CO , metro area ) were r and omly assigned to receive commercially available pureed meats ( Meat group ; n = 14 ) or infant cereal ( Cereal group ; n = 28 ) as their primary complementary feedings for ∼ 5 mo . Anthropometric measures and diet records were collected monthly from 5 to 9 mo of age ; intakes from complementary feeding and breast milk were assessed at 9 mo of age . RESULTS The Meat group had significantly higher protein intake , whereas energy , carbohydrate , and fat intakes from complementary feeding did not differ by group over time . At 9 mo of age , mean ( ± SEM ) intakes of total ( complementary feeding plus breast milk ) protein were 2.9 ± 0.6 and 1.4 ± 0.4 g · kg(-1 ) · d(-1 ) , ∼ 17 % and ∼ 9 % of daily energy intake , for Meat and Cereal groups , respectively ( P < 0.001 ) . From 5 to 9 mo of age , the weight-for-age z score ( WAZ ) and length-for-age z score ( LAZ ) increased in the Meat group ( ΔWAZ : 0.24 ± 0.19 ; ΔLAZ : 0.14 ± 0.12 ) and decreased in the Cereal group ( ΔWAZ : -0.07 ± 0.17 ; ΔLAZ : -0.27 ± 0.24 ) ( P-group by time < 0.05 ) . The change in weight-for-length z score did not differ between groups . Total protein intake at 9 mo of age and baseline WAZ were important predictors of changes in the WAZ ( R(2 ) = 0.23 , P = 0.01 ) . CONCLUSION In breastfed infants , higher protein intake from meats was associated with greater linear growth and weight gain but without excessive gain in adiposity , suggesting that potential risks of high protein intake may differ between breastfed and formula-fed infants and by the source of protein [6365516] The effect of maternal supplementation during both gestation and lactation on infant growth from birth to 12 mth was investigated in the double-blind , r and omly allocated control trial conducted in Taiwan by the late Bacon F. Chow . The supplement was a milk-based formula providing 800 kcal and 40 g protein daily . The placebo provided less than 40 kcal per diem but resembled the supplement in appearance . Supplementation was limited to mothers and began after birth of one infant and continued without interruption until weaning of a second infant . Supplement effects were tested by comparing both supplement and placebo groups and first- and second-infant groups with respect to weight , length and head circumference . Both comparisons of growth curves and analyses of variance were carried out . Both strategies agreed in failing to detect differences in growth between supplement and placebo groups . However , differences were found between first and second infants in the supplement group [6819029] Unselective dietary protein energy supplementation of Asian mothers at Sorrento Maternity Hospital did not enhance intrauterine growth . The effect of selective supplementation was therefore studied . Forty-five mothers who at 28 weeks were known to be nutritionally at risk ( triceps increment less than or equal to 20 microns/week between 18 and 28 weeks ) received one of three supplements during the third trimester : ( a ) vitamins only -- a multivitamin sachet daily containing vitamins A , B , C , and D ; ( b ) energy--42 - 125 MJ ( 10 000 - 30 000 kcal ) , all from carbohydrate , plus vitamins ; ( c ) protein energy -- energy and vitamins as before , but with 5 - 10 % of energy from milk protein . Eighty-three mothers regarded as adequately nourished at 28 weeks also received one of the three supplements . In the nutritionally at-risk mothers the protein energy supplement was associated with a heavier crude birth weight and heavier weight for gestational age . Supplementation did not lead to improved intrauterine growth in those mothers who were adequately nourished . The differential effect of supplementation depending on the mothers ' nutritional state during the second trimester may explain apparently conflicting results of other studies where some have shown a substantial effect of supplementation and others only a small effect . This effect of intervention is further evidence that " poor nutrition " contributes to poor intrauterine growth in selected mothers , even in developed countries [25833972] BACKGROUND Poor nutritional quality of complementary foods often limits growth . Animal source foods , such as milk or meat , are often unaffordable . Local affordable alternatives are needed . OBJECTIVE We evaluate the efficacy of 2 newly developed , rice-based complementary food products : WinFood ( WF ) with small fish and edible spiders and WinFood-Lite ( WF-L ) fortified with small fish , against 2 existing fortified corn-soy blend products , CSB+ ( purely plant based ) and CSB++ ( 8 % dried skimmed milk ) . DESIGN In total , 419 infants aged 6 mo were enrolled in this r and omized , single-blinded study for 9 mo , design ed primarily to assess increments in fat-free mass by a deuterium dilution technique and change in plasma ferritin and soluble transferrin receptor . Secondary endpoints were changes in anthropometric variables , including knee-heel length . Data were analyzed by the intention-to-treat approach . RESULTS There was no difference in fat-free mass increment in WF or WF-L compared with CSB+ [ WF : + 0.04 kg ( 95 % CI : -0.20 , 0.28 kg ) ; WF-L : + 0.14 kg ( 95 % CI : -0.10 , 0.38 kg ) ] or CSB++ [ WF : -0.03 kg ( 95 % CI : -0.27 , 0.21 kg ) ; WF-L : + 0.07 kg ( 95 % CI : -0.18 , 0.31 kg ) ] and no effect on iron status . The 1.7-mm ( 95 % CI : -0.1 , 3.5 mm ) greater increase in knee-heel length in WF-L than in CSB+ was not significant . CONCLUSIONS No difference was found between the locally produced products ( WF and WF-L ) and the CSBs . Micronutrient fortification may be necessary , and small fish may be an affordable alternative to milk to improve complementary foods . The dietary role of edible spiders needs to be further explored . This trial was registered at controlled-trials.com as IS RCT N19918531 [24622805] BACKGROUND Early nutrition is recognized as a target for the effective prevention of childhood obesity . Protein intake was associated with more rapid weight gain during infancy-a known risk factor for later obesity . OBJECTIVE We tested whether the reduction of protein in infant formula reduces body mass index ( BMI ; in kg/m(2 ) ) and the prevalence of obesity at 6 y of age . DESIGN The Childhood Obesity Project was conducted as a European multicenter , double-blind , r and omized clinical trial that enrolled healthy infants born between October 2002 and July 2004 . Formula-fed infants ( n = 1090 ) were r and omly assigned to receive higher protein (HP)- or lower protein (LP)-content formula ( within recommended amounts ) in the first year of life ; breastfed infants ( n = 588 ) were enrolled as an observational reference group . We measured the weight and height of 448 ( 41 % ) formula-fed children at 6 y of age . BMI was the primary outcome . RESULTS HP children had a significantly higher BMI ( by 0.51 ; 95 % CI : 0.13 , 0.90 ; P = 0.009 ) at 6 y of age . The risk of becoming obese in the HP group was 2.43 ( 95 % CI : 1.12 , 5.27 ; P = 0.024 ) times that in the LP group . There was a tendency for a higher weight in HP children ( 0.67 kg ; 95 % CI : -0.04 , 1.39 kg ; P = 0.064 ) but no difference in height between the intervention groups . Anthropometric measurements were similar in the LP and breastfed groups . CONCLUSIONS Infant formula with a lower protein content reduces BMI and obesity risk at school age . Avoidance of infant foods that provide excessive protein intakes could contribute to a reduction in childhood obesity . This trial was registered at clinical trials.gov as NCT00338689 [12739919] Ninety-two subjects ages 36 to 60 months who had picky-eater behavior and evidence of growth faltering were r and omized to receive either nutrition counseling alone , or nutrition counseling plus a nutritional supplement ( Study ) for 90 days . The Study group had significantly greater increases in weight and height . There were no significant differences between groups in changes in appetite or activity levels , or in gastrointestinal symptom scores . The percent of subjects who developed upper respiratory tract infections was significantly lower in the Study group . These data suggest that a nutritional supplement in addition to nutrition counseling promote catch-up growth and may contribute to lower rates of infectious disease in children with picky eater behavior [24500150] BACKGROUND Observational studies have indicated that differences in the composition of human milk and infant formula yield benefits in cognitive development and early growth for breastfed infants . OBJECTIVE The objective was to test the hypothesis that feeding an infant formula with reduced energy and protein densities and supplemented with bovine milk fat globule membrane ( MFGM ) reduces differences in cognitive development and early growth between formula-fed and breastfed infants . DESIGN In a prospect i ve , double-blind , r and omized controlled trial , 160 infants < 2 mo of age were r and omly assigned to be fed an MFGM-supplemented , low-energy , low-protein experimental formula ( EF ) or a st and ard formula ( SF ) until 6 mo of age . The energy and protein contents of the EF and SF were 60 and 66 kcal/100 mL and 1.20 and 1.27 g/100 mL , respectively . A breastfed reference ( BFR ) group consisted of 80 infants . RESULTS At 12 mo of age , the cognitive score ( mean ± SD ) on testing with the Bayley Scales of Infant and Toddler Development , Third Edition , was significantly higher in the EF group than in the SF group ( 105.8 ± 9.2 compared with 101.8 ± 8.0 ; P = 0.008 ) but was not significantly different from that in the BFR group ( 106.4 ± 9.5 ; P = 0.73 ) . The EF group ingested larger volumes of formula than did the SF group ( 864 ± 174 compared with 797 ± 165 mL/d ; P = 0.022 ) , fully compensating for the lower energy density . No significant differences in linear growth , weight gain , body mass index , percentage body fat , or head circumference were found between the EF and SF groups . CONCLUSIONS MFGM supplementation to infant formula narrows the gap in cognitive development between breastfed and formula-fed infants . Between 2 and 6 mo of age , formula-fed term infants have the capacity to upregulate their ingested volumes when the energy density of formula is reduced from 66 to 60 kcal/100 [19386747] BACKGROUND Protein intake during infancy was associated with rapid early weight gain and later obesity in observational studies . OBJECTIVE The objective was to test the hypothesis that higher protein intake in infancy leads to more rapid length and weight gain in the first 2 y of life . DESIGN In a multicenter European study , 1138 healthy , formula-fed infants were r and omly assigned to receive cow milk-based infant and follow-on formula with lower ( 1.77 and 2.2 g protein/100 kcal , respectively ) or higher ( 2.9 and 4.4 g protein/100 kcal , respectively ) protein contents for the first year . For comparison , 619 exclusively breastfed children were also followed . Weight , length , weight-for-length , and BMI were determined at inclusion and at 3 , 6 , 12 , and 24 mo of age . The primary endpoints were length and weight at 24 mo of age , expressed as length and weight-for-length z scores based on the 2006 World Health Organization growth st and ards . RESULTS Six hundred thirty-six children in the lower ( n = 313 ) and higher ( n = 323 ) protein formula groups and 298 children in the breastfed group were followed until 24 mo . Length was not different between r and omized groups at any time . At 24 mo , the weight-for-length z score of infants in the lower protein formula group was 0.20 ( 0.06 , 0.34 ) lower than that of the higher protein group and did not differ from that of the breastfed reference group . CONCLUSIONS A higher protein content of infant formula is associated with higher weight in the first 2 y of life but has no effect on length . Lower protein intake in infancy might diminish the later risk of overweight and obesity . This trial was registered at clinical trials.gov as NCT00338689 [26154030] Objectives : Infant formulas provide more protein than breast milk . High protein intakes may place infants at risk of later obesity . The present study tested whether a formula with protein content below the regulatory level supports normal growth from age 3 months . Methods : R and omized double-blind trial enrolled healthy infants less than age 3 months . At 3 months , formula-fed infants were assigned to experimental ( EXPL , 1.61 g protein/100 kcal ; modified bovine whey proteins with caseinoglycomacropeptide removed ) or control ( CTRL 2.15 g protein/100 kcal ; unmodified bovine milk protein with a whey/casein ratio of 60/40 ) formula ; breast-fed ( BF ) infants were enrolled in a reference group . Complementary foods were allowed in small amounts from 4 to 6 months and unrestricted after 6 months . Results : Weight gain ( g/day ) from 3 to 6 months was similar in the EXPL and CTRL groups ( EXPL-CTRL −0.84 g/day ; 95 % confidence interval −2.25 to 0.57 ) and faster in the EXPL and CTRL groups than in the BF group . Weight analyzed longitudinally from 4 to 12 months was lower in the EXPL group than in the CTRL group ( P = 0.031 ) but higher than in the BF group ( P < 0.0001 ) . Longitudinal analysis of odds ratios from 4 to 12 months indicated fewer infants with weight > 85th percentile in the EXPL group than in the CTRL group ( P = 0.015 ) . Length z scores were lower than , and body mass index z scores were similar to , World Health Organization St and ards in all of the groups . Serum biochemical parameters in the EXPL group reflected lower protein intake and were closer to parameters in the BF infants than in the CTRL group . Conclusions : A formula with 1.61 g of protein/100 kcal supports normal growth of infants after age 3 months . This protein content is adequate if provided from a high- quality source [4689999] Background : Growth faltering in the first 2 years of life is high in South Asia where prevalence of stunting is estimated at 40–50 % . Although nutrition counselling has shown modest benefits , few intervention trials of food supplementation exist showing improvements in growth and prevention of stunting . Methods : A cluster-r and omized controlled trial was conducted in rural Bangladesh to test the effect of two local , ready-to-use foods ( chickpea and rice-lentil based ) and a fortified blended food ( wheat-soy-blend++ , WSB++ ) compared with Plumpy’doz , all with nutrition counselling vs nutrition counselling alone ( control ) on outcomes of linear growth ( length and length-for-age z-score , LAZ ) , stunting ( LAZ < −2 ) , weight-for-length z-score ( WLZ ) and wasting ( WLZ < −2 ) in children 6–18 months of age . Children ( n = 5536 ) were enrolled at 6 months of age and , in the food groups , provided with one of the allocated supplements daily for a year . Results : Growth deceleration occurred from 6 to 18 months of age but deceleration in LAZ was lower ( by 0.02–0.04/month ) in the Plumpy’doz ( P = 0.02 ) , rice-lentil ( < 0.01 ) , and chickpea ( < 0.01 ) groups relative to control , whereas WLZ decline was lower only in Plumpy’doz and chickpea groups . WSB++ did not impact on these outcomes . The prevalence of stunting was 44 % at 18 months in the control group , but lower by 5–6 % ( P ≤ 0.01 ) in those receiving Plumpy’doz and chickpea . Mean length and LAZ at 18 months were higher by 0.27–0.30 cm and 0.07–0.10 ( all P < 0.05 ) , respectively , in all four food groups relative to the control . Conclusions : In rural Bangladesh , small amounts of daily fortified complementary foods , provided for a year in addition to nutrition counselling , modestly increased linear growth and reduced stunting at 18 months of age [7722707] Supplementary feeding programs are common in developing countries . These programs often can not demonstrate an impact on child growth , however , possibly because they tend to reach older children . This study examines the impact of nutritional supplementation on annual growth rates in length and weight from birth to 7 y of age in 1208 rural Guatemalan children . A series of multiple linear regression models is used to control for initial body size , diarrheal disease , home diet , socioeconomic status and gender . During the first year of life , each 100 kcal/d ( 418 kJ ) of supplement was associated with approximately 9 mm in additional length gain and 350 g in additional weight gain ; the benefit decreased to approximately 5 mm in length gain and 250 g in weight gain during the 2nd y of life . Between 24 and 36 mo of age , supplement only had a significant impact on length . There was no impact of nutritional supplementation on growth between 3 and 7 y of age . Patterns were the same if supplement intakes were expressed as a percent of recommended allowances or growth was expressed as a percent of the expected rate . These impacts of nutritional supplementation on growth coincide with the ages when growth velocities , as well as growth deficits , are greatest in this population [26607935] BACKGROUND Maternal undernutrition and newborn stunting [ birth length-for-age z score ( LAZ ) < -2 ] are common in Bangladesh . OBJECTIVE The objective was to evaluate the effect of lipid-based nutrient supplements for pregnant and lactating women ( LNS-PLs ) on birth outcomes . DESIGN We conducted a cluster-r and omized effectiveness trial ( the Rang-Din Nutrition Study ) within a community health program in rural Bangladesh . We enrolled 4011 pregnant women at ≤20 gestational weeks ; 48 clusters received iron and folic acid ( IFA ; 60 mg Fe + 400 μg folic acid ) and 16 clusters received LNS-PLs ( 20 g/d , 118 kcal ) containing essential fatty acids and 22 vitamins and minerals . Both of the supplements were intended for daily consumption until delivery . Primary outcomes were birth weight and length . RESULTS Infants in the LNS-PL group had higher birth weights ( 2629 ± 408 compared with 2588 ± 413 g ; P = 0.007 ) , weight-for-age z scores ( -1.48 ± 1.01 compared with -1.59 ± 1.02 ; P = 0.006 ) , head-circumference-for-age z scores ( HCZs ; -1.26 ± 1.08 compared with -1.34 ± 1.12 ; P = 0.028 ) , and body mass index z scores ( -1.57 ± 1.05 compared with -1.66 ± 1.03 ; P = 0.005 ) than those in the IFA group ; in adjusted models , the differences in length ( 47.6 ± 0.07 compared with 47.4 ± 0.04 cm ; P = 0.043 ) and LAZ ( -1.15 ± 0.04 compared with -1.24 ± 0.02 ; P = 0.035 ) were also significant . LNS-PLs reduced the risk of newborn stunting ( 18.7 % compared with 22.6 % ; RR : 0.83 ; 95 % CI : 0.71 , 0.97 ) and small head size ( HCZ < -2 ) ( 20.7 % compared with 24.9 % ; RR : 0.85 ; 95 % CI : 0.73 , 0.98 ) . The effects of LNS-PL on newborn stunting were greatest in infants born before a 10-wk interruption in LNS-PL distribution ( n = 1301 ; 15.7 % compared with 23.6 % ; adjusted RR : 0.69 ; 95 % CI : 0.53 , 0.89 ) and in infants born to women ≤24 y of age or with household food insecurity . CONCLUSION Prenatal lipid-based nutrient supplements can improve birth outcomes in Bangladeshi women , especially those at higher risk of fetal growth restriction . This trial was registered at clinical trials.gov as NCT01715038 [5593178] Background Children with moderate acute malnutrition ( MAM ) are treated with lipid-based nutrient supplement ( LNS ) or corn-soy blend ( CSB ) . We assessed the effectiveness of ( a ) matrix , i.e. , LNS or CSB , ( b ) soy quality , i.e. , soy isolate ( SI ) or dehulled soy ( DS ) , and ( c ) percentage of total protein from dry skimmed milk , i.e. , 0 % , 20 % , or 50 % , in increasing fat-free tissue accretion . Methods and findings Between September 9 , 2013 , and August 29 , 2014 , a r and omised 2 × 2 × 3 factorial trial recruited 6- to 23-month-old children with MAM in Burkina Faso . The intervention comprised 12 weeks of food supplementation providing 500 kcal/day as LNS or CSB , each containing SI or DS , and 0 % , 20 % , or 50 % of protein from milk . Fat-free mass ( FFM ) was assessed by deuterium dilution technique . By dividing FFM by length squared , the primary outcome was expressed independent of length as FFM index ( FFMI ) accretion over 12 weeks . Other outcomes comprised recovery rate and additional anthropometric measures . Of 1,609 children , 4 died , 61 were lost to follow-up , and 119 were transferred out due to supplementation being switched to non-experimental products . No children developed allergic reaction . At inclusion , 95 % were breastfed , mean ( SD ) weight was 6.91 kg ( 0.93 ) , with 83.5 % ( 5.5 ) FFM . In the whole cohort , weight increased 0.90 kg ( 95 % CI 0.88 , 0.93 ; p < 0.01 ) comprising 93.5 % ( 95 % CI 89.5 , 97.3 ) FFM . As compared to children who received CSB , FFMI accretion was increased by 0.083 kg/m2 ( 95 % CI 0.003 , 0.163 ; p = 0.042 ) in those who received LNS . In contrast , SI did not increase FFMI compared to DS ( mean difference 0.038 kg/m2 ; 95 % CI −0.041 , 0.118 ; p = 0.35 ) , irrespective of matrix . Having 20 % milk protein was associated with 0.097 kg/m2 ( 95 % CI −0.002 , 0.196 ) greater FFMI accretion than having 0 % milk protein , although this difference was not significant ( p = 0.055 ) , and there was no effect of 50 % milk protein ( 0.049 kg/m2 ; 95 % CI −0.047 , 0.146 ; p = 0.32 ) . There was no effect modification by season , admission criteria , or baseline FFMI , stunting , inflammation , or breastfeeding ( p > 0.05 ) . LNS compared to CSB result ed in 128 g ( 95 % CI 67 , 190 ; p < 0.01 ) greater weight gain if both contained SI , but there was no difference between LNS and CSB if both contained DS ( mean difference 22 g ; 95 % CI −40 , 84 ; p = 0.49 ) ( interaction p = 0.017 ) . Accordingly , SI compared to DS increased weight by 89 g ( 95 % CI 27 , 150 ; p = 0.005 ) when combined with LNS , but not when combined with CSB . A limitation of this and other food supplementation trials is that it is not possible to collect reliable data on individual adherence . Conclusions Based on this study , children with MAM mainly gain fat-free tissue when rehabilitated . Nevertheless , LNS yields more fat-free tissue and higher recovery rates than CSB . Moreover , current LNSs with DS may be improved by shifting to SI . The role of milk relative to soy merits further research . Trial registration IS RCT N registry IS RCT [16946216] OBJECTIVE : To evaluate the effects of dietary calcium ( Ca ) intervention on adolescent pregnant mothers and their newborns . METHODS : Seventy-two pregnant adolescent mothers were r and omized into one of 3 groups : control , orange juice fortified with calcium , and dairy . The orange juice and dairy groups were required to take more than 1,200 mg Ca . Calcium tablets were added for those not able to meet required Ca . Maternal and infant weight , length , and blood pressure ( BP ) were recorded . Maternal dietary records were evaluated . Mother ’s blood was drawn for serum Ca , phosphate ( P ) , magnesium ( Mg ) , and vitamin 25-hydroxyvitamin D ( D ) . Cord blood was collected for serum Ca and D. Newborn total body Ca was determined . RESULTS : All mothers were similar in weight , height , and BP . Mothers in the orange juice plus calcium and dairy groups had higher intakes of Ca ( 1,472 mg and 1,771 mg ) than controls ( 862 mg ) . One half of the mothers in the orange juice plus calcium group required Ca tablets . Mothers in the dairy group had higher intakes of P , D , and Mg , higher serum folate and D , and higher cord D levels . Mothers in the orange juice plus calcium group had higher serum P but lower serum folate and D. Infants ( 3,517±273 g ) in the dairy group were heavier than infants in the control ( 3,277±177 g ) and orange juice plus calcium ( 3,292±165 g ) groups . Infants in the dairy group had higher total body calcium than control infants . CONCLUSION : Calcium diet supplemented with dairy products during adolescent pregnancy result ed in higher maternal vitamin D and folate serum levels and higher newborn weight and bone mineralization compared with controls . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00320125 LEVEL OF EVIDENCE : [6988785] This r and omized controlled trial of nutritional supplementation in pregnancy , in a poor black urban population in the United States , aim ed to increase the birth weight and influence the postnatal development of the offspring of mothers at high risk of having low birth weight infants . The execution of the research design and adherence to the treatment regimen among the experimental population appeared adequate for a reasonable test of the treatments . At birth , the only significant favorable effect of supplementation observed was the prevention of depressed birth weight among the offspring of mothers who smoked heavily . With balanced protein-calorie supplementation , length of gestation was increased , the proportion of low-birth-weight infants reduced , and mean birth weight raised by 41 gm ( not statistically significant ) . With high protein supplementation , there was an excess of very early premature births and associated neonatal deaths , and there was significant growth retardation up to 37 weeks of gestation . At 1 year of age , significant effects of high protein supplement were found on three psychological measures : visual habituation , visual dishabituation , and mean length of free play episodes . These measures were unrelated to measures of growth at birth and at 1 year of age . There were no detectable residual adverse effects of high protein supplementation at 1 year of age [2333739] Abstract . The optimum level and ratios of protein to be used in cow 's milk formula has recently been under discussion . Healthy term infants were fed from birth exclusively human milk or a formula that varied in protein level or whey : casein ratio : ( A ) 1.4 g/dl ; 55:45 , ( B ) 1.5 g/dl ; 55:45 , ( C ) 1.3 g/dl ; 55:45 , ( D ) 1.4 g/dl ; 60:40 , ( E ) 1.4 g/dl ; 20:80 . Infants were followed for 12 weeks and blood sample s were taken at 2 , 4 , 8 and 12 weeks . Anthropometric indices did not show any significant differences among groups . Plasma amino acid and BUN levels of the C group were closest to the breast‐fed group , while the formula with the highest protein level ( B ) result ed in high values for some amino acids . When comparing the formulas with 1.4 g protein/dl , the high casein group had the lowest plasma tryptophan levels . Taurine was added to all formulas at a level similar to that of breast milk ; plasma taurine levels were similar for all groups . All formulas contained 0.7 mg iron and 0.7 mg zinc/dl ; no differences were found among the groups in hematological indices or serum trace elements . These data show that feeding a formula with 1.3 g protein/dl and 55:45 whey : casein ratio from birth will result in growth and metabolic indices similar to those of breast‐fed infants , although some plasma amino acid levels are not identical , 1990 [25631295] OBJECTIVE We conducted a cluster-r and omized controlled trial to assess the efficacy of a cereal made from caterpillars , a micronutrient-rich , locally available alternative animal- source food , on reducing stunting and anaemia in infants in the Democratic Republic of Congo . DESIGN Six-month-old infants were cluster r and omized to receive either caterpillar cereal daily until 18 months of age or the usual diet . At 18 months of age , anthropometric measurements and biological sample s were collected . SETTING The rural Equateur Province in the Democratic Republic of Congo . SUBJECTS One hundred and seventy-five infants followed from 6 to 18 months of age . RESULTS Stunting was common at 6 months ( 35 % ) and the prevalence increased until 18 months ( 69 % ) . There was no difference in stunting prevalence at 18 months between the intervention and control groups ( 67 % v. 71 % , P = 0.69 ) . Infants in the cereal group had higher Hb concentration than infants in the control group ( 10.7 v. 10.1 g/dl , P = 0.03 ) and fewer were anaemic ( 26 v. 50 % , P = 0.006 ) , although there was no difference in estimates of body Fe stores ( 6.7 v. 7.2 mg/kg body weight , P = 0.44 ) . CONCLUSIONS Supplementation of complementary foods with caterpillar cereal did not reduce the prevalence of stunting at 18 months of age . However , infants who consumed caterpillar cereal had higher Hb concentration and fewer were anaemic , suggesting that caterpillar cereal might have some beneficial effect . The high prevalence of stunting at 6 months and the lack of response to this micronutrient-rich supplement suggest that factors other than dietary deficiencies also contribute to stunting [28588101] This rigorously conducted trial showed that when offered early in complementary feeding , the food-based intervention of eggs produced a large effect size on child growth . BACKGROUND : Eggs are a good source of nutrients for growth and development . We hypothesized that introducing eggs early during complementary feeding would improve child nutrition . METHODS : A r and omized controlled trial was conducted in Cotopaxi Province , Ecuador , from March to December 2015 . Children ages 6 to 9 months were r and omly assigned to treatment ( 1 egg per day for 6 months [ n = 83 ] ) and control ( no intervention [ n = 80 ] ) groups . Both arms received social marketing messages to encourage participation in the Lulun Project ( lulun meaning “ egg ” in Kichwa ) . All households were visited once per week to monitor morbidity symptoms , distribute eggs , and monitor egg intakes ( for egg group only ) . Baseline and end point outcome measures included anthropometry , dietary intake frequencies , and morbidity symptoms . RESULTS : Mothers or other caregivers reported no allergic reactions to the eggs . Generalized linear regression modeling showed the egg intervention increased length-for-age z score by 0.63 ( 95 % confidence interval [ CI ] , 0.38–0.88 ) and weight-for-age z score by 0.61 ( 95 % CI , 0.45–0.77 ) . Log-binomial models with robust Poisson indicated a reduced prevalence of stunting by 47 % ( prevalence ratio [ PR ] , 0.53 ; 95 % CI , 0.37–0.77 ) and underweight by 74 % ( PR , 0.26 ; 95 % CI , 0.10–0.70 ) . Children in the treatment group had higher dietary intakes of eggs ( PR , 1.57 ; 95 % CI , 1.28–1.92 ) and reduced intake of sugar-sweetened foods ( PR , 0.71 ; 95 % CI , 0.51–0.97 ) compared with control . CONCLUSIONS : The findings supported our hypothesis that early introduction of eggs significantly improved growth in young children . Generally accessible to vulnerable groups , eggs have the potential to contribute to global targets to reduce stunting [24808482] BACKGROUND Management of moderate acute malnutrition ( MAM ) is , currently , focused on food supplementation approaches . However , the sustainability of these strategies remains weak in low- and middle-income countries . In food-secure setting s , an educational/behavioral intervention could be an alternative for improving MAM management . OBJECTIVE This study compared the effectiveness of weekly context -appropriate child-centered counseling ( CCC ) , with an improved corn-soy blend [ corn-soy blend with added micronutrients ( CSB++ ) ] or a locally produced ready-to-use supplementary food ( RUSF ) , in treating MAM through first-line rural health services . DESIGN We used a cluster r and omized controlled trial design with 3 arms , involving 18 rural health centers ( 6 by arm ) and children aged 6 - 24 mo with uncomplicated MAM . In the first arm ( CCC ) , trained health workers provided weekly personalized counseling to caretakers . In the 2 other arms , children received weekly either 455 g CSB++ or 350 g locally produced soy-based RUSF . Both food supplements provided ∼250 kcal/d . RESULTS The recovery rate after 3 mo of treatment was significantly lower with CCC ( 57.8 % ) than with CSB++ ( 74.5 % ) and RUSF ( 74.2 % ) ( P < 0001 ) . Mothers ' attendance at health facilities was also substantially lower in the CCC arm ( P < 0001 ) ; this arm had a high defaulter rate ( P < 0.003 ) . When the analysis was adjusted for attendance , we did not find a significant difference between the 3 arms , with incidence rate ratios of 1.14 ( 95 % CI : 0.99 , 1.31 ) and 1.13 ( 95 % CI : 0.98 , 1.30 ) for the CSB++ and RUSF arms , respectively , compared with the CCC arm . CONCLUSION Whereas supplement-based treatment of MAM was found to be more effective than the provision of CCC , we hypothesize that appropriate and specific nutrition counseling centered on children 's needs , through primary health facilities , might be an alternative strategy for MAM treatment in rural food-secure areas , provided that attendance at counseling sessions by the caregiver is ensured . This trial was registered at clinical trials.gov as NCT01115647 [3048373] Summary . The effect of two levels of energy supplementation in the last trimester of pregnancy on birthweight was tested in a controlled r and omized trial in three villages in Madura , East Java . The high and low energy supplements provided 1·95 MJ ( 465 kcal ) and 218 kj ( 52 kcal ) per day respectively . In the baseline period the home diet provided on average 6·28 MJ ( 1500 kcal ) ( SD 2·1 MJ ( 499 kcal ) ) and 41g(SD 13 g ) of protein . The mean birthweight was 2835 g and the rate of low birth‐weight 12·2 % . In the experimental period the home diet was better . The average intake ranged from 6·45 to 7·19 MJ ( 1541–1717 kcal ) and 41·4–44·2 g per day , depending on the degree of compliance . Mean birth‐weight increased by 100 g and the rate of low birthweight dropped to 9·5 % . There was no difference between the high and low energy supplemented group as a whole , probably due to the masking effect of the better home diet in the experimental period . It is likely that a positive effect of energy supplementation on birthweight was restricted to the group of pregnant women with the lowest home dietary intake and /or a low prepregnant weight . In this community targeting of supplementation to lean seasons and /or to women with a low prepregnant weight may be cost‐effective [19174829] Background / Objectives : High protein intake has been associated with increased growth . This may be linked to increased concentrations of insulin-like growth factor I ( IGF-I ) , which seems to be influenced by the diet , especially its protein component . The short-term effects of high protein intake in late infancy are not known . The objective was to investigate the effects of high protein intake in the form of whole milk ( WM ) on growth and IGF-I from 9 to 12 months of age . Subjects/ Methods : Healthy infants ( n=83 ) were r and omized to receive either WM or infant formula and fish oil or no fish oil ( 2 × 2 design ) . Anthropometric variables , IGF-I concentrations , serum urea nitrogen ( SUN ) and diet were recorded before and after the intervention . Results : Intake of WM significantly increased the protein energy percentage ( PE% ; P⩽0.001 ) and SUN ( P=0.01 ) , whereas there was no effect on size . The milk intervention increased IGF-I in boys ( P=0.034 ) but not in girls . Intake of fish oil had no effect on the outcomes . Including all infants in the analysis there was a significant correlation between weight and IGF-I at 12 months ( r=0.316 , P=0.017 ) , and PE% was positively associated with IGF-I after adjusting for sex and breastfeeding at both 9 ( r=0.329 , P=0.015 ) and 12 months ( r=0.272 , P=0.044 ) . Conclusions : R and omization to WM had no overall effect on growth . However , the positive effect of WM on IGF-I in boys and the positive association between PE% intake and IGF-I at 9 and 12 months is consistent with the hypothesis that a high milk intake stimulates growth [8458314] Malnourished children ( mean age 1.2 years ) referred from public health clinics to a paediatric metabolic ward in Kingston , Jamaica , were enrolled for treatment in a community-based health care project and were r and omly allocated to one of two groups . The first group was treated at home with metronidazole and then for 6 months using the st and ard health care provided from local clinics by community health aides . The second group was given the same drug and home treatment , but in addition received a high energy supplement of 3.31 MJ daily for 3 months . We have previously shown a significant advantage in both weight and height gain for a group given the same supplement in contrast with st and ard health care controls ( Heikens et al. , 1989 , Eur . J. Clin . Nutr . 43 , 145 - 160 ) , and in this study test the addition of a drug treatment aim ed at reducing malabsorbtion due to a possible microbial overgrowth of the small bowel in malnourished children . This paper reports anthropometric findings showing significant benefits from both the drug and nutritional treatments . Greatest gains were by the group given both treatments , but the group given the antibiotic treatment , without energy supplementation , also made better growth recovery than did controls . Only 8 % of the children treated with metronidazole failed to respond to community-based intervention and were admitted to hospital , compared with 19 % for the other groups ( P < 0.05 ) . These findings support targetted high-energy supplementation for the rehabilitation of moderately malnourished children receiving health clinic care , and suggest further that such programs should include antibiotic treatment directed at SBBO [16954961] Objective : Excess protein in infant formula may lead to renal overload and play a role in later obesity . The objective of this controlled , prospect i ve , r and omized , double-blind study was to assess the suitability and safety of a modified protein content infant formula and its noninferiority as compared to a conventional formula . Patients and Methods : Healthy term infants age < 7 days were either breast-fed or r and omized to be fed exclusively with a conventional casein-predominant formula ( protein/energy ratio : 2.6 g/100 kcal ) or the isocaloric whey-predominant study formula ( protein/energy ratio : 1.8 g/100 kcal ) for 120 days . Primary outcome was daily weight gain between D0 and D120 ( noninferiority criterion : difference in daily weight gain ≤4 g ) . Secondary outcomes were daily gain in weight , length , head circumference and body mass index at monthly intervals . Tolerance and safety were assessed at each visit . Results : 162 infants were enrolled , 84 % of the formula-fed infants and 36 % of the breast-fed infants completing the study . Mean daily weight gain from D0 to D120 in the formula-fed groups differed by 0.38 g/day [ 95 % CI : −2.59 ; 1.83 ] signifying the noninferiority of the study formula . Secondary outcomes did not differ between the 2 groups at any time and were comparable to outcomes in the breast-fed group . Tolerance was good and adverse events were not different between study groups . Conclusions : The whey-predominant study infant formula with a protein/energy ratio of 1.8 g/100 kcal and enhanced protein efficiency is safe and not inferior to a conventional formula in ensuring normal growth during the first four months of life [12604972] Objectives The aim of this study was to evaluate the nutritional efficacy and bifidogenic characteristics of a new infant formula containing partially hydrolyzed whey protein , modified vegetable oil with a high & bgr;-palmitic acid content , prebiotic oligosaccharides , and starch . Methods In a double-blind study , healthy formula-fed term infants aged younger than 2 weeks were r and omized to receive either the new infant formula ( NF ) or a st and ard formula ( SF ) until the age of 12 weeks . Anthropometric measurements were taken at enrollment , 6 weeks , and 12 weeks . In a sub sample of infants , blood sample s were taken at 6 weeks and stool sample s were taken at enrollment and 6 weeks . Blood sample s were analyzed for biochemical measures of protein status and amino acids , and stools were analyzed for total bacteria and bifidobacteria . Mothers completed a feeding diary and question naire at 6 and 10 weeks . Results One hundred fifty-four infants were enrolled in the study ; 102 completed the trial . The growth of infants in both formula groups was in line with published growth curves . During the first 6 weeks , NF girls gained more weight and head circumference than the SF girls . These velocity differences were not maintained throughout the 12-week study period . The NF stools had a higher proportion of bifidobacteria at 6 weeks compared with the SF stools , and they were softer . There were no clinical ly significant differences in the blood biochemical and amino acid values between groups . Both formulas were well tolerated by the infants . Conclusions When compared with a st and ard infant formula , the new formula supported satisfactory growth , led to higher counts of bifidobacteria in the feces , produced blood bio-chemical values typical of formula-fed infants , and was well tolerated [16131023] OBJECTIVE To investigate the effect of yogurt supplementation on the growth of preschool children in Beijing suburbs . METHODS Four hundred and two preschool children ( 217 males , 185 females ) , aged 3 - 5 years , whose height for age and /or weight for age were less than the reference level , were selected as subjects from 7 kindergartens in Beijing Fangshan District . The subjects were divided r and omly into control group ( CG , 201 ) and yogurt supplemented group ( YG , 201 ) . Each subject in YG was given one serving of yogurt ( 125 g ) for 5 days a week from March to December in 2001 , while nothing additional was provided to CG . All subjects kept their usual diet during the study . Anthropometry ( body height and weight and upper-arm circumference ) and the bone mineral density ( BMD ) of forearm were measured every 3 months . Disease status and dietary intake were also recorded and assessed . RESULTS The intake of calcium , zinc , and vitamin B2 in YG was significantly higher than that in CG . The incidence and duration of upper-respiratory infection and diarrhea of children in YG were significantly less than those in CG . The height gain of children in YG was significantly higher than that in CG after yogurt was supplemented for 3 , 6 , and 9 months ( P<0.05 ) ( 1.90+/-0.49 cm vs 1.77+/-0.54 cm , 3.83+/-0.57 cm vs 3.64+/-0.66 cm and 5.43+/-0.69 cm vs 5.24+/-0.76 cm , respectively ) . The weight gain of children in YG was significantly higher than that in CG after yogurt was supplemented for 3 , 6 , and 9 months ( P<0.05 ) ( 0.70+/-0.43 kg vs 0.49+/-0.35 kg , 0.98+/-0.62 kg vs 0.80+/-0.60 kg and 1.42+/-0.76 kg vs 1.20+/-0.67 kg , respectively ) . The BMD of children in YG was significantly higher than that in CG after yogurt was supplemented for 9 months ( P<0.05 ) ( 0.415+/-0.058 g/cm2 vs 0.400+/-0.065 g/cm2 ) . CONCLUSION Yogurt is beneficial to the improvement of calcium , zinc , and vitamin B2 intake , the decreasing of the incidence and duration of upper-respiratory infection and diarrhea , and the promotion of the health and the growth and development of preschool children [25639137] Background . Because of its contribution to dietary diversity and to favorable intakes of micronutrients , including iron and zinc , meat is hypothesized to be a valuable complementary food for the infant and young child . However , the evidence base remains limited . Objective . To compare the difference in anthropometric measurements of rural Chinese infants and toddlers 6 to 18 months of age who received a daily supplement of meat or cereal for 12 months . Methods . This cluster-r and omized , controlled study provided a daily supplement of either meat ( n = 514 , 20 clusters ) or cereal ( n = 957 , 40 clusters ) starting as a first complementary food at 6 months of age . Anthropometric measurements were assessed longitudinally . Results . After 12 months of intervention , the meat group ( Δ13.01 ± 1.9 cm ) had greater ( p = .01 ) linear growth than the cereal group ( Δ12.75 ± 1.8 cm ) and a smaller decrease in length-for-age z-score ( LAZ ) over time ( –0.43 ± 0.72 in the meat group vs. –0.54 ± 0.67 in the cereal group ) , after adjustment for baseline length , LAZ , maternal education , work status , and maternal height and weight . Conclusions . Linear growth was modestly greater in the meat group than in the cereal group . LAZ was substantially negative at 6 months , and the intervention did not prevent ongoing decline over the course of the study [7030223] Twelve hundred and fifty-one pregnant women were contacted and their infants followed to age 5 years . Nine hundred and fifty-one ( 76 % ) children completed the trial . Measurements were made of birthweight , length , head circumference , and triceps skinfold at 10 days , and of weight , height , head circumference , and triceps at 5 years . Throughout the entire period of the study half the families , selected at r and om , were supplied with milk tokens entitling the mother , while pregnant , and all children under age 5 years , to 1 pint of milk a day at half its current price . The tokens led to a small increase in milk purchases by the families and to a small increase in milk drunk by the children . However no effect was detected in any growth measurement either in the total group , or in a more " vulnerable " group of children from the largest families [24411489] BACKGROUND & AIMS Protein source , macronutrient composition and content of long chain-polyunsaturated fatty acids ( LC-PUFA ) of infant formulae may influence infant growth . We aim ed to assess the effect of a modified infant formula on growth . METHODS In a r and omized , double-blind trial , 213 healthy term infants consumed isoenergetic study formulae ( intervention formula - IF , control formula - CF ) from the first month of life until the age of 120 days . IF ( 1.89 g protein/100 kcal ) contained α-lactalbumin ( ALAB ) and LC-PUFA , while CF ( 2.30 g protein/100 kcal ) provided st and ard whey and no LC-PUFA . Anthropometry and dietary intake were regularly assessed . A venous blood sample was obtained on day 120 . RESULTS Both formulae were well-accepted without significant differences in health related observations . Weight gain was not statistically different between formula groups ( IF : 30.2 ± 6.3 vs. CF : 28.3 ± 6.5 g/day , mean ± SD , P = 0.06 ) . Length gain was higher in IF ( 0.11 ± 0.02 vs. 0.10 ± 0.02 cm/day , P = 0.02 ) . Energy intake from formula was higher in CF at 90 and 120 days ( IF : 509 ± 117 and 528 ± 123 vs. CF : 569 ± 152 and 617 ± 169 kcal/day , P < 0.01 ) . Protein intake in CF was significantly higher at each assessment . Growth per energy intake was higher in IF compared to CF for weight ( 6.45 ± 2.01 vs. 5.67 ± 2.21 g/100 kcal , P = 0.02 ) and length ( 0.23 ± 0.08 vs. 0.20 ± 0.08 mm/100 kcal , P = 0.04 ) . CONCLUSIONS The modified infant formula with reduced protein content with added ALAB and LC-PUFA , meets infant requirements of protein for adequate growth . The increased energetic efficiency of the new infant formula might result from improved protein composition by added ALAB . Apparently minor differences in composition can markedly affect energetic efficiency for growth . The study was registered at Clinical Trials.gov ( NCT01094080 ) [11335744] Objective . At hospital discharge , preterm infants may have low body stores of nutrients , deficient bone mineralization , and an accumulated energy deficit . This double-blind , r and omized study evaluated the growth of premature infants with birth weights < 1800 g who were fed a 22 kcal/fl oz nutrient-enriched postdischarge formula ( PDF ) or a 20 kcal/fl oz term-infant formula ( TF ) from hospital discharge to 12 months ' corrected age ( CA ) . Methods . Infants were r and omized to PDF or TF a few days before hospital discharge with stratification by gender and birth weight ( < 1250 g or ≥1250 g ) . The formulas were fed to 12 months ' CA . Growth was evaluated using analysis of variance controlling for site , feeding , gender , and birth weight group . Interaction effects were also assessed . Secondary analyses included a repeated measures analysis and growth modeling . Results . One hundred twenty-five infants were r and omized ; 74 completed to 6 months ' CA and 53 to 12 months ' CA . PDF-fed infants weighed more than TF-fed infants at 1 and 2 months ' CA , gained more weight from study day 1 to 1 and 2 months ' CA , and were longer at 3 months ' CA . There were significant interactions between feeding and birth weight group — among infants with birth weights < 1250 g , those fed PDF weighed more at 6 months ' CA , were longer at 6 months ' CA , had larger head circumferences at term 1 , 3 , 6 , and 12 months ' CA , and gained more in head circumference from study day 1 to term and to 1 month CA . The repeated measures and growth modeling analyses confirmed the analysis of variance results . The PDF formula seemed to be of particular benefit for the growth of male infants . Infants fed the PDF consumed less formula and had higher protein intakes at several time points . Energy intakes , however , were not different . Conclusions . Growth was improved in preterm infants fed a nutrient-enriched postdischarge formula after hospital discharge to 12 months ' CA . Beneficial effects were most evident among infants with birth weights < 1250 g , particularly for head circumference measurements [25833980] BACKGROUND The International Lipid-Based Nutrient Supplements Project developed a small-quantity ( 20 g/d ) lipid-based nutrient supplement ( LNS ) for pregnant and lactating women . OBJECTIVE We evaluated the effects of prenatal LNS supplementation on fetal growth . DESIGN In a community-based , partially double-blind , individually r and omized controlled trial , 1320 women ≤20 wk pregnant received 60 mg Fe/400 μg folic acid ( IFA ) , or 1 - 2 Recommended Dietary Allowances of 18 micronutrients , including 20 mg Fe ( MMN ) , or LNS with the same micronutrients as the MMN group , plus 4 minerals and macronutrients contributing 118 kcal ( LNS ) daily until delivery . Fetal growth was compared across groups by using intention-to-treat analysis . The primary outcome was birth length . RESULTS This analysis included 1057 women ( IFA = 349 , MMN = 354 , LNS = 354 ) . Groups did not differ significantly in mean birth length , length-for-age z score ( LAZ ) , head circumference , or percentage low birth length but differed in mean birth weight ( P = 0.044 ) , weight-for-age z score ( WAZ ; P = 0.046 ) , and BMI -for-age z score ( BMI Z ; P = 0.040 ) , with a trend toward differences in low birth weight ( P = 0.069 ) . In pairwise comparisons , the LNS group had greater mean birth weight ( + 85 g ; P = 0.040 ) , WAZ ( + 0.19 ; P = 0.045 ) , and BMI Z ( + 0.21 ; P = 0.035 ) and a lower risk of low birth weight ( RR : 0.61 , 95 % CI : 0.39 , 0.96 ; P = 0.032 ) than did the IFA group . The other group differences were not significant . The effect of intervention was modified by mother 's parity , age , height , baseline hemoglobin , household food insecurity , and child sex , with parity being the most consistent modifier . Among primiparous women ( IFA = 131 ; MMN = 110 ; LNS = 128 ) , the LNS group had greater mean birth length ( + 0.91 cm ; P = 0.001 ) , LAZ ( + 0.47 ; P = 0.001 ) , weight ( + 237 g ; P < 0.001 ) , WAZ ( + 0.56 ; P < 0.001 ) , BMI Z ( + 0.52 ; P < 0.001 ) , head circumference ( 0.50 cm ; P = 0.017 ) , and head circumference-for-age z score ( + 0.40 ; P = 0.022 ) than did the IFA group ; similar differences were found when comparing the LNS and MMN groups among primiparous women , and no group differences were found among multiparous women . CONCLUSION Prenatal LNS supplementation can improve fetal growth among vulnerable women in Ghana , particularly primiparous women . This trial was registered at clinical trials.gov as NCT00970866 [25926413] BACKGROUND Intrauterine growth restriction may be reduced by supplementing maternal diets during pregnancy , but few studies have assessed the impact of combined prenatal and postnatal interventions on child growth . OBJECTIVE We tested a hypothesis that provision of small-quantity lipid-based nutrient supplements ( SQ-LNSs ) to mothers in pregnancy and 6 mo postpartum and to their infants from 6 to 18 mo of age would promote infant and child growth in the study area in rural Malawi . METHODS We enrolled 869 pregnant women in a r and omized trial in Malawi . During pregnancy and 6 mo thereafter , the women received daily 1 capsule of iron-folic acid ( IFA ) , 1 capsule containing 18 micronutrients ( MMN ) , or one 20-g sachet of SQ-LNS [ lipid-based nutrient supplements ( LNS ) , containing 21 MMN , protein , carbohydrates , essential fatty acids , and 118 kcal ] . Children in the IFA and MMN groups received no supplementation ; children in the LNS group received SQ-LNSs from 6 to 18 mo . Primary outcome was child length at 18 mo . RESULTS At 18 mo , the mean length in the IFA , MMN , and LNS groups was 77.0 , 76.9 , and 76.8 cm ( P = 0.90 ) , respectively , and the prevalence of stunting was 32.7 % , 35.6 % , and 37.9 % ( P = 0.54 ) , respectively . No intergroup differences were found in the mean weight , head circumference , or midupper arm circumference or the proportions with low z scores for these variables ( P > 0.05 ) . Covariate adjustment did not change the analysis results , and the associations between the intervention and child length were not modified by maternal parity , age , or nutritional status ( P > 0.10 ) . CONCLUSIONS The findings do not support a hypothesis that provision of SQ-LNSs to women in pregnancy and postpartum and to children from 6 to 18 mo of age would promote child growth in this Malawian study area . This trial was registered at clinical trials.gov as NCT01239693 [12352513] Background Protein quality of breast milk is superior to that of formula proteins . To ensure that the protein intake is sufficient , starter formulas with conventional protein composition provide a protein/energy ratio of 2.2–2.5 g per 100 kcal to infants , which is much higher than that supplied with breast milk . Several studies have shown that formula-fed infants have higher plasma or serum urea concentrations than breast-fed infants do . We tested if feeding formulas with improved protein quality and a protein content corresponding to the minimum level that is consistent with international recommendations ( 1.8 g/100 kcal ) allows patients to achieve normal growth and plasma urea concentrations . Methods Healthy term infants were enrolled into the study and were either breast-fed or r and omly assigned to three formula-fed groups . Formula-fed infants received either a st and ard formula with a protein/energy ratio of 2.2 g/100 kcal , whereas the two other groups received formulas with a protein/energy ratio of 1.8g/100 kcal differing mainly by their source of protein . Subjects received breast milk or these formulas ad libitum as the sole source of energy from birth to four months of age in a controlled blind design ( except for the breast-fed group ) . Anthropometric measurements ( body weight and length ) were obtained at birth , at 30 , 60 , 90 , and 120 days . Energy and protein intakes were calculated from three-day dietary records . Blood was collected for biochemical measurements at 30 , 60 , and 120 days . Results No differences were found between the four feeding groups for weight- and length-gains or for body mass indices ( BMI ) . No differences in energy intakes between the formula-fed groups could be found , whereas protein intakes were less in infants fed the 1.8 g/100 kcal formulas . Plasma urea levels of the infants fed the 1.8 g/100 kcal formulas were closer to those found in the breast-fed infants . Conclusion Improvement of the amino acid profile permits a whey predominant starter formula with 1.8 g protein per 100 kcal to meet the needs of normal term infants during the first four months of life [19369380] BACKGROUND The short- and long-term effects of feeding with hydrolyzed formulas on growth are uncertain . OBJECTIVE Our aim was to investigate the potential differences in body mass index ( BMI ) over the first 6 y of life between infants fed with partially hydrolyzed whey ( pHF-W ) , extensively hydrolyzed whey ( eHF-W ) , extensively hydrolyzed casein ( eHF-C ) , or cow-milk formula ( CMF ) and infants exclusively breastfed for the first 16 wk of life . DESIGN We established a prospect i ve , r and omized , double-blind trial of full-term neonates with atopic heredity in the German birth cohort followed by the German Infant Nutritional Intervention Study through the first 6 y of life . Intention-to-treat and per- protocol analyses of absolute and World Health Organization-st and ardized BMI trajectories for 1840 infants ( pHF-W : n = 253 ; eHF-W : n = 265 ; eHF-C : n = 250 , CMF : n = 276 ; breastfed : n = 796 ) were performed . RESULTS No significant differences in absolute or World Health Organization-st and ardized BMI trajectories were found among the pHF-W , eHF-W , CMF , and breastfed groups during the 6-y follow-up . However , in the eHF-C group , both intention-to-treat and per- protocol analyses showed a significantly slower sex-adjusted BMI gain through the 8th to 48th week of life ( -0.1 to -0.2 lower BMI z score ) but not beyond . Analyses of weight and length revealed that this difference is due to a slightly diminished weight gain in the first year of life because growth in length did not differ among study groups for the entire follow-up . CONCLUSIONS To our knowledge , this is the first r and omized trial investigating both short- and long-term effects of partially and extensively hydrolyzed formula ( pHF-W , eHF-W , eHF-C ) , CMF , and breastfeeding on growth in one trial . Feeding with eHF-C led to a transient lower weight gain in the first year of life . No long-term consequences of different formulas on BMI were observed [23795976] Low nutritional value of complementary foods is associated with high incidence of childhood growth stunting in low-income countries . This study was done to test a hypothesis that dietary complementation with lipid-based nutrient supplements ( LNS ) promotes linear growth and reduces the incidence of severe stunting among at-risk infants . A total of 840 6-month-old healthy infants in rural Malawi were enrolled to a r and omised assessor-blinded trial . The participants received 12-month supplementation with nothing , milk-LNS , soy-LNS , or corn-soy blend ( CSB ) . Supplements provided micronutrients and approximately 280 kcal energy per day . Outcomes were incidence of severe and very severe stunting [ length-for-age z-score , ( LAZ ) < -3.00 and < -3.50 , respectively ] , and change in LAZ . The incidence of severe stunting was 11.8 % , 8.2 % , 9.1 % and 15.5 % ( P = 0.098 ) and that of very severe stunting 7.4 % , 2.9 % , 8.0 % and 6.4 % ( P = 0.138 ) in control , milk-LNS , soy-LNS and CSB groups , respectively . Between 9 and 12 months of age , the mean change in LAZ was -0.15 , -0.02 , -0.12 and -0.18 ( P = 0.045 ) for control , milk-LNS , soy-LNS and CSB groups , respectively . There was no significant between-group difference in linear growth during other age-intervals . Although participants who received milk-LNS had the lowest incidence of severe and very severe stunting , the differences between the groups were smaller than expected . Thus , the results do not provide conclusive evidence on a causal association between the LNS supplementation and the lower incidence of stunting . Exploratory analyses suggest that provision of milk-LNS , but not soy-LNS promotes linear growth among at-risk infants mainly between 9 and 12 months of age [1517950] Several recent studies have demonstrated significantly lower plasma total tryptophan concentrations in formula-fed than in breast-fed infants . We have measured prepr and ial plasma amino acid concentrations in infants breast-fed or fed a formula with a protein concentration of 1–57 g/dl and with a whey/casein ratio of 60:40 or a formula with a protein concentration of 1.37 g/dl and a whey/casein ratio of 40:60 and fortified with 10 mg/dl ( 15 mg/100 kcal ) of tryptophan . Healthy term infants ( 10 per group ) were either breast-fed from birth or r and omly assigned to one of the two study formulas . At 4 and 12 weeks of age , anthropometric measurements were performed and blood sample s were obtained . During the study period of 12 weeks , all infants showed normal growth ( weight , length , and head circumference ) and there were no statistically significant differences between the groups . The plasma concentrations of the essential amino acids phenylalanine , threonine , valine , and lysine were significantly lower in the breast-fed group than in both formula-fed groups . For tyrosine , methionine , leucine , histidine , isoleucine , and arginine , no significant differences could be found between the feeding groups . Concentration of total plasma tryptophan was significantly higher in the breast-fed group than in the group fed the tryptophan-unfortified formula , but no statistically significant difference could be found between the plasma tryptophan concentration in the breast-fed group versus the group fed the tryptophan-fortified formula . The results indicate that tryptophan fortification of adapted formula is necessary to achieve plasma total tryptophan concentrations similar to those found in breast-fed infants . The data also confirm that a formula with reduced protein concentration will support normal growth and will produce a plasma amino acid profile not much different from that of a conventional type of formula [8632935] OBJECTIVE To evaluate the adequacy of protein intakes now recommended as safe for infants and toddlers . METHODS Subjects were recovering malnourished infants , age 5.3 to 17.9 months , length age ( LA ) 2.5 to 6.4 months , weight age ( WA ) 1.5 to 5.2 months , weight/length ( W/L ) 78 % to 100 % of National Center for Health Statistics data ; and toddlers age 11.4 to 31.6 months , LA 6.1 to 17.9 months , WA 3.9 to 12.0 months , W/L 79 % to 99 % . Infants were assigned at r and om to formulas with 5.5 % , 6.7 % , or 8.0 % energy as 60:40 whey : casein protein . The 5.5 % was based on FAO-WHO-UNU safe protein and average energy for ages 2.5 to 6.0 months . Toddlers received 4.7 % ( recommended for 6 to 18 months ) , 6.4 % , or 8.0 % . Identical concentrations ( weight/kcal ) of other nutrients were maintained ; intakes were adjusted weekly to reach , in 90 days , the 50th percentile of weight for a LA 3 months greater than the initial one . RESULTS Infants consumed 125 + /- 11 ( SD ) , 116 + /- 10 , and 126 + /- kcal and 1.7 + /- 0.1 , 1.9 + /- 0.2 , and 2.5 + /- 0.3 g protein kg-1 . d-1 ; gained 2.4 + /- 0.7 , 2.9 + /- 0.7 , and 2.6 + /- 0.5 months in LA , and reached a W/L of 105 + /- 5 , 103 + /- 6 , and 105 + /- 5 % of reference . Sum of four fat-folds ( sigma FF ) grew 13.1 + /- 6.9 , 10.4 + /- 4.8 , and 11.7 + /- 5.3 mm to 32.5 + /- 5.2 , 31.7 + /- 4.7 , and 30.5 + /- 5.5 mm ; arm muscle areas ( AMA ) 57 % , 51 % , 70 % to 1004 + /- 109 , 1017 + /- 110 , and 1004 + /- 116 mm2 , still low ; arm fat areas ( AFA ) 93 % , 66 % , and 93 % to higher-than-normal 598 + /- 105 , 610 + /- 101 , and 541 + /- 116 mm2 . Regression of intake on weight gain estimated energy for maintenance + activity to be 81.0 + /- 7.5 ( SEM ) kcal . kg-1 . d-1 , and cost of gain ( storage + metabolic cost ) as 7.6 + /- 1.7 kcal/g , with no significant effect of % protein . Toddlers consumed 107 + /- 9 , 103 + /- 12 , and 105 + /- 10 kcal and 1.3 + /- 0.1 , 1.6 + /- 0.2 , and 2.1 + /- 0.2 g protein . kg-1 . d-1 , gained 3.3 + /- 0.7 , 2.9 + /- 0.6 , and 3.3 + /- 0.7 months in LA ; to a W/L of 102 + /- 1 , 102 + /- 3 , and 101 + /- 4 % . Sigma FF grew 9.2 + /- 4.0 , 7.4 + /- 4.3 , and 6.0 + /- 3.8 to 28.9 + /- 5.2 , 30.5 + /- 3.7 , and 27.0 + /- 2.7 mm ; AMA 31 % , 33 % , and 34 % to 1121 + /- 115 , 1124 + /- 110 , and 1117 + /- 120 mm2 ; AFA 53 % , 44 % , and 45 % to higher-than normal 578 + /- 106 , 636 + /- 99 , and 569 + /- 68 mm2 . Cost of maintenance + activity was 70.8 + /- 3.8 ( SEM ) kcal . kg-1 . d-1 , that of weight gain 9.7 + /- 1.35 kcal/g , with no effect of % protein . CONCLUSIONS Within age groups , there were no significant protein-related differences in growth . In both infants and toddlers , high-energy intakes result ed in mild obesity , with lean body mass still deficient . Protein intakes two SD below the means in the lowest protein/energy cells , 1.5 g . kg-1 . d-1 for infants and 1.1 g times kg-1 . d-1 for toddlers , should still be safe for nearly all children of comparable biological ages [6073440] Infant formulas have been conventionally prepared with an excess of total protein in order to provide sufficient amounts of essential amino acids to the rapidly growing infant . However , this practice leads to higher than necessary protein intake during early infant development , inducing accelerated growth patterns correlated with the development of chronic diseases later in life . This study was aim ed at assessing the safety of an infant formula enriched with bovine alpha-lactalbumin containing a total protein concentration very close to that of human milk , and determining its efficacy in the support of healthy infant growth from the first month to the fourth month of age . Healthy full-term infants ≤40 days of age were r and omized in this controlled single blind trial to one of the following infant formulas : IF 1 ( containing 1.0 g protein/dL ; n = 30 ) , IF 2 ( containing 1.3 g protein/dL ; n = 24 ) , and IF 3 ( containing 1.5 g protein/dL ; n = 42 ) . A control group consisting of exclusively breastfed infants ( HM ; n = 212 ) was included in the study . Anthropometric measurements and Z-scores were evaluated at baseline , at 1 month of age , and at 4 months of age . Weight gain ( g/day ) was similar in the IF 1 and the HM groups ( p = 0.644 ) , and it was significantly greater in the IF 2 and IF 3 groups than in the HM group . Growth patterns in both breastfed or IF-fed infants were in accordance with the World Health Organization ( WHO ) growth st and ards . At four months of age , the mean weight-for-age Z-score ( WAZ ) adjusted for initial value in the IF 1 group was similar to that of the HM group and significantly lower than that of the IF 2 and IF 3 groups ( p = 0.031 and p = 0.014 for IF 2 and IF 3 , respectively ) . Length-for-age ( LAZ ) adjusted for initial value was similar among all groups at four months of age . From 1 to 4 months of life , IF 1 containing 1.0 g protein/dL promotes growth and weight gain similar to those observed in exclusively breastfed infants . As this is a first approach to study ing an IF containing total protein in a level below that recommended by international committees on nutrition , further investigations are needed to support these findings evaluating infant ’s metabolic profile and growth in the long term [26063066] BACKGROUND Complementing infant diets with lipid-based nutrient supplements ( LNSs ) has been suggested to improve growth and reduce morbidity , but the daily quantity and the milk content of LNSs affect their cost . OBJECTIVE We tested the hypotheses that the change in mean length-for-age z score ( LAZ ) for infants provided with 10 - 40 g LNSs/d from ages 6 to 18 mo would be greater than that for infants receiving no dietary intervention at the same age and that provision of LNSs that did not contain milk would be as good as milk-containing LNSs in promoting linear growth . METHODS We enrolled in a r and omized single-blind trial 6-mo-old infants who were allocated to 1 of 6 groups to receive 10 , 20 , or 40 g LNSs/d containing milk powder ; 20 or 40 g milk-free LNSs/d ; or no supplement until 18 mo of age . The primary outcome was change in LAZ . RESULTS Of the 1932 enrolled infants , 78 ( 4.0 % ) died and 319 ( 16.5 % ) dropped out during the trial . The overall reported supplement consumption was 71.6 % of days , with no difference between the groups ( P = 0.26 ) . The overall mean ± SD length and LAZ changes were 13.0 ± 2.1 cm and -0.45 ± 0.77 z score units , respectively , which did not differ between the groups ( P = 0.66 for length and P = 0.74 for LAZ ) . The difference in mean LAZ change in the no-milk LNS group compared with the milk LNS group was -0.02 ( 95 % CI : -0.10 , 0.06 ; P = 0.72 ) . CONCLUSION Our results do not support the hypothesis that LNS supplementation during infancy and childhood promotes length gain or prevents stunting between 6 and 18 mo of age in Malawi . This trial was registered at clinical trials.gov as NCT00945698 [26864368] BACKGROUND The utility of dairy ingredients in the supplementary foods used in the treatment of childhood moderate acute malnutrition ( MAM ) remains unsettled . OBJECTIVE We evaluated the effectiveness of a peanut-based ready-to-use supplementary food ( RUSF ) with soy protein compared with a novel RUSF containing dairy ingredients in the form of whey permeate and whey protein concentrate in the treatment of children with MAM . DESIGN We conducted a r and omized , double-blind clinical effectiveness trial involving rural Malawian and Mozambican children 6 - 59 mo of age with MAM treated with either soy RUSF or a novel whey RUSF treatment of ~75 kcal · kg(-1 ) · d(-1 ) for up to 12 wk . RESULTS The proportion of children that recovered from MAM was significantly higher in the group that received whey RUSF ( 960 of 1144 ; 83.9 % ) than in the group that received soy RUSF ( 874 of 1086 ; 80.5 % ; P < 0.04 ; risk difference 3.4 % , 95 % CI : 0.3 % , 6.6 % ) . Children who consumed whey RUSF also demonstrated better growth markers , with a higher mean midupper arm circumference ( MUAC ) at the time of discharge ( P < 0.009 ) , greater MUAC gain during the course of treatment ( P < 0.003 ) , higher mean weight-for-height z score at discharge ( P < 0.008 ) , and greater weight gain ( P < 0.05 ) . No significant differences were identified in length gain or time to recovery between the 2 groups . CONCLUSION This study highlights the importance of milk protein in the treatment of MAM , because the use of a novel whey RUSF result ed in higher recovery rates and improved growth than did soy RUSF , although the whey RUSF supplement provided less total protein and energy than the soy RUSF . This study was registered at clinical trials.gov as NCT01790048 Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Gestational weight gain is positively associated with fetal growth , and observational studies of food supplementation in pregnancy have reported increases in gestational weight gain and fetal growth . OBJECTIVES To assess the effects of education during pregnancy to increase energy and protein intake , or of actual energy and protein supplementation , on energy and protein intake , and the effect on maternal and infant health outcomes . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

25046211

[3027109] Background Debate continues as to whether acute bronchodilator responsiveness ( BDR ) predicts long-term outcomes in COPD . Furthermore , there is no consensus on a threshold for BDR . Methods At baseline and during the 4-year Underst and ing Potential Long-term Improvements in Function with Tiotropium ( UPLIFT ® ) trial , patients had spirometry performed before and after administration of ipratropium bromide 80 mcg and albuterol 400 mcg . Patients were split according to three BDR thresholds : ≥12 % + ≥200 mL above baseline ( criterion A ) , ≥15 % above baseline ( criterion B ) ; and ≥10 % absolute increase in percent predicted FEV1 values ( criterion C ) . Several outcomes ( pre-dose spirometry , exacerbations , St. George 's Respiratory Question naire [ SGRQ ] total score ) were assessed according to presence or absence of BDR in the treatment groups . Results 5783 of 5993 r and omized patients had evaluable pre- and post-bronchodilator spirometry at baseline . Mean age ( SD ) was 64 ( 8) years , with 75 % men , mean post-bronchodilator FEV1 1.33 ± 0.44 L ( 47.6 ± 12.7 % predicted ) and 30 % current smokers . At baseline , 52 % , 66 % , and 39 % of patients had acute BDR using criterion A , B , and C , respectively . The presence of BDR was variable at follow-up visits . Statistically significant improvements in spirometry and health outcomes occurred with tiotropium regardless of the baseline BDR or criterion used . Conclusions A large proportion of COPD patients demonstrate significant acute BDR . BDR in these patients is variable over time and differs according to the criterion used . BDR status at baseline does not predict long-term response to tiotropium . Assessment of acute BDR should not be used as a decision-making tool when prescribing tiotropium to patients with COPD [19717481] UPLIFT ( Underst and ing Potential Long-Term Improvements in Function with Tiotropium ) , a 4-yr trial of tiotropium in chronic obstructive pulmonary disease , allowed for assessment of smoking status on long-term responses to maintenance bronchodilator therapy . 5,993 patients were r and omised ( tiotropium/placebo ) . Lung function , St George 's Respiratory Question naire , exacerbations and adverse events were followed . Patients were characterised as continuing smokers ( CS ) , continuing ex-smokers ( CE ) , or intermittent smokers ( IS ) based on self-reporting smoking behaviour . 60 % , 14 % and 26 % of patients were CE , CS and IS , respectively . The rate of forced expiratory volume in 1 s ( FEV1 ) decline for placebo patients was most rapid in CS ( -51±4 , -36±2 and -23±2 mL·yr−1 in CS , IS , and CE , respectively ) . Tiotropium did not alter FEV1 decline , but was associated with significant improvements in pre- and post-bronchodilator FEV1 over placebo that persisted throughout the 4-yr trial for each smoking status ( pre-bronchodilator : 125 , 55 and 97 mL at 48 months in CS , IS and CE , respectively ; p≤0.0003 ) . Tiotropium reduced exacerbation risk in CS ( HR ( 95%CI ) 0.81 ( 0.68–0.97 ) ) , in CE ( 0.86 ( 0.79–0.93 ) ) and trended towards significance in IS ( 0.89 ( 0.80–1.01 ) ) . At 4 yrs , St George ’s Respiratory Question naire for tiotropium patients improved the most in CS ( -4.62 units , p = 0.0006 ) and the least in IS ( -0.54 units , p = 0.55 ) , compared with control . Tiotropium provided long-term benefits irrespective of smoking status , although differences among categories were observed [18836213] BACKGROUND Previous studies showing that tiotropium improves multiple end points in patients with chronic obstructive pulmonary disease ( COPD ) led us to examine the long-term effects of tiotropium therapy . METHODS In this r and omized , double-blind trial , we compared 4 years of therapy with either tiotropium or placebo in patients with COPD who were permitted to use all respiratory medications except inhaled anticholinergic drugs . The patients were at least 40 years of age , with a forced expiratory volume in 1 second ( FEV(1 ) ) of 70 % or less after bronchodilation and a ratio of FEV(1 ) to forced vital capacity ( FVC ) of 70 % or less . Co primary end points were the rate of decline in the mean FEV(1 ) before and after bronchodilation beginning on day 30 . Secondary end points included measures of FVC , changes in response on St. George 's Respiratory Question naire ( SGRQ ) , exacerbations of COPD , and mortality . RESULTS Of a total of 5993 patients ( mean age , 65+/-8 years ) with a mean FEV(1 ) of 1.32+/-0.44 liters after bronchodilation ( 48 % of predicted value ) , we r and omly assigned 2987 to the tiotropium group and 3006 to the placebo group . Mean absolute improvements in FEV(1 ) in the tiotropium group were maintained throughout the trial ( ranging from 87 to 103 ml before bronchodilation and from 47 to 65 ml after bronchodilation ) , as compared with the placebo group ( P<0.001 ) . After day 30 , the differences between the two groups in the rate of decline in the mean FEV(1 ) before and after bronchodilation were not significant . The mean absolute total score on the SGRQ was improved ( lower ) in the tiotropium group , as compared with the placebo group , at each time point throughout the 4-year period ( ranging from 2.3 to 3.3 units , P<0.001 ) . At 4 years and 30 days , tiotropium was associated with a reduction in the risks of exacerbations , related hospitalizations , and respiratory failure . CONCLUSIONS In patients with COPD , therapy with tiotropium was associated with improvements in lung function , quality of life , and exacerbations during a 4-year period but did not significantly reduce the rate of decline in FEV(1 ) . ( Clinical Trials.gov number , NCT00144339 . [2650608] Background Exercise training improves exercise tolerance in chronic obstructive pulmonary disease ( COPD ) . Tiotropium 18 μg once daily induces sustained bronchodilation throughout the day and reduces hyperinflation , one of the pathophysiological factors contributing to exertional dyspnea in COPD patients . Aim To determine whether tiotropium enhances the effects of exercise training in patients with COPD . Design Multicenter , 25 week r and omized , double-blind , placebo-controlled , parallel-group study . Setting Twelve Italian Pulmonary Units practicing pulmonary rehabilitation . Patients and intervention Two hundred thirty four COPD patients ( 196 males ; mean age : 67.4 ± 7.6 ; forced expiratory volume at 1 second ( FEV1 ) : 41.4 ± 13.0 % predicted ) were r and omised to tiotropium 18 μg or placebo inhalation capsules taken once daily . Both groups underwent a 8 week pulmonary rehabilitation program ( PR ) consisting of 3 exercise training session per week . Measurements Baseline , at the end of PR and after 12 weeks , patients completed pulmonary function testing , six minute walking test ( 6MWT ) , the Baseline and Transition Dyspnea Index ( BDI and TDI ) , and the St. George ’s Respiratory Question naire ( SGRQ ) . Results Relative to placebo , tiotropium had larger trough and post- study drug FEV1 responses on all test days . At the end of and 12 weeks following PR , patients on tiotropium showed no statistically significant differences in 6MWT compared to patients on placebo . Compared to the period immediately prior to PR , the mean improvement in 6MWT was only 29.7 meters ( 7.1 % ) for the combined cohort . Mean TDI focal scores at the end of PR were 3.60 for tiotropium and 2.25 for placebo ( p < 0.01 ) . At 12 weeks after PR , TDI focal scores were 2.71 for tiotropium and 2.11 for placebo ( p = 0.16 ) . Reduction in all four SGRQ component scores , indicating an improvement in health-related quality of life , was observed for the tiotropium group over the duration of the study compared to placebo but the differences were not statistically significant . During the study period , there were fewer exacerbations and exacerbation days in the tiotropium group . Conclusion Although significant improvements were observed with perceived dyspnea , compared to placebo , the addition of tiotropium to pulmonary rehabilitation did not improve the 6MWT [18256071] The degree of acute improvement in spirometric indices after bronchodilator inhalation varies among chronic obstructive pulmonary disease ( COPD ) patients , and depends upon the type and dose of bronchodilator and the timing of administration . Acute bronchodilator responsiveness at baseline was examined in a large cohort of patients with moderate-to-very-severe COPD participating in the Underst and ing Potential Long-term Impacts on Function with Tiotropium ( UPLIFT ) trial , a 4-yr r and omised double-blind trial evaluating the efficacy of 18 μg tiotropium daily in reducing the rate of decline in lung function . After wash-out of respiratory medications , patients received 80 μg ipratropium followed by 400 μg salbutamol . Spirometry was performed before and 90 min following ipratropium administration . The criteria used for forced expiratory volume in one second ( FEV1 ) responsiveness were : ≥12 % increase over baseline and ≥200 mL ; ≥15 % increase over baseline ; and ≥10 % absolute increase in the percentage predicted value . Of the patients , 5,756 had data meeting the criteria for analysis ( age 64.5 yrs ; 75 % male ; baseline FEV1 1.10 L ( 39.3 % predicted ) and forced vital capacity ( FVC ) 2.63 L ) . Compared with baseline , mean improvements were 229 mL in FEV1 and 407 mL in FVC . Of these patients , 53.9 % had ≥12 % and ≥200 mL improvement in FEV1 , 65.6 % had ≥15 % improvement in FEV1 , and 38.6 % had ≥10 % absolute increase in FEV1 % pred . The majority of patients with moderate-to-very-severe chronic obstructive pulmonary disease demonstrate meaningful increases in lung function following administration of inhaled anticholinergic plus sympathomimetic bronchodilators [16305289] STUDY OBJECTIVES To examine electrocardiographic findings after short- and long-term tiotropium therapy in patients with chronic obstructive pulmonary disease ( COPD ) , and to establish previously reported symptomatic efficacy . DESIGN R and omized , double-blind , placebo-controlled , parallel-group study . SETTING Twelve outpatient investigational centers in the United States . PATIENTS One hundred ninety-six patients with COPD . INTERVENTIONS Patients received either tiotropium 18 mug once/day or placebo , delivered by the H and iHaler device . MEASUREMENTS AND MAIN RESULTS Electrocardiography ( predose and 5 min postdose ) and 24-hour Holter monitoring were performed at baseline and after 8 and 12 weeks of treatment with tiotropium 18 microg once/day or placebo . Efficacy measures ( spirometry , global COPD ratings , scores on the EuroQol Health Question naire [ EQ-5D ] , albuterol inhaler as needed ) were included to demonstrate that the study population exhibited the characteristic improvements observed in previous tiotropium studies . Mean baseline forced expiratory volume in 1 second ( FEV1 ) was 1.03 L. Mean changes in heart rate from baseline were similar in both groups . No differences were noted in the percentage of patients developing rhythm or conduction abnormalities detected with electrocardiography or Holter monitoring . Frequency of premature beats and mean maximal changes in PR , QRS , QT , QTcB , and QTcF intervals were similar in both groups . No patients developed new-onset QT or QTc intervals greater than 500 msec , and no differences were noted in the percentage of patients developing new QT prolongation less than 30 msec , 30 - 60 msec , or greater than 60 msec . At 12 weeks , predose and postdose improvements in FEV1 were 184 and 265 ml , respectively , with tiotropium versus placebo ( p<0.001 ) . Physician and patient global COPD ratings and the EQ-5D visual analog scale scores were improved with tiotropium ( p<0.05 ) ; as-needed albuterol was reduced by 25 % relative to placebo ( p<0.05 ) . CONCLUSION Tiotropium provided spirometric and symptomatic benefits in patients with COPD and was not associated with evidence of electrocardiographic changes in heart rate , rhythm , QT intervals , or conduction [20979799] OBJECTIVE To compare the efficacy and safety between tiotropium capsule and placebo in a 12-week treatment in patients with chronic obstructive pulmonary disease ( COPD ) . METHODS A multi-center , r and omized , double-blind , and placebo-control clinical trial was conducted in 205 patients with stable COPD . They were r and omized into inhaled tiotropium 18 µg once daily or placebo , lasting for 12 weeks . The spirometry was conducted at baseline , 6 and 12 weeks after treatment . RESULTS A total of 205 patients with stable stage I or II COPD were r and omized to tiotropium and placebo groups . The improvement rate of clinical symptom in the tiotropium group was 25.2 % ( 26/103 ) after a 12 week treatment , but that of the control group was 4.9 % ( 5/102 ) . The forced expiratory volume in one second ( FEV₁ ) and forced vital capacity ( FVC ) in the tiotropium group increased ( 0.2 ± 0.3 ) L and ( 19.2 ± 29.1)% after the 12 week therapy , but only ( 0.0 ± 0.2 ) L and ( 0.8 ± 18.2)% in the placebo group . The rate of adverse reaction in the tiotropium group was 7.8 % ( 8/103 ) , but in the placebo group was 12.8 % ( 13/102 ) . The difference between the 2 groups was not significant . All adverse reactions were mild , including dry mouth and sore throat . CONCLUSIONS This trial confirmed that tiotropium powder 18 µg once daily relieved dyspnea , prevented aggravation and improved pulmonary function , clinical symptoms and life quality . Tiotropium was a safe and effective once-daily anticholinergic bronchodilator as first-line maintenance therapy in COPD [3321723] Patients with COPD are frequently prescribed inhaled corticosteroids ( ICS ) ; however , it is unclear whether the treatment with ICS might modify responses to inhaled bronchodilators . Two 6-month , r and omized , placebo-controlled , double-blind , double-dummy , parallel-group studies of tiotropium 18 μg once daily , compared with salmeterol , 50 μg bid , had been conducted in patients with moderate-to-severe COPD . Efficacy was assessed by spirometry , transition dyspnea index ( TDI ) , St. George ’s Respiratory Question naire ( SGRQ ) , and exacerbations . Data from both studies were combined to form subgroups with regard to concurrent use of ICS . 796 patients receiving ICS were separately analyzed from 390 patients not receiving ICS . Mean age was 64 years , and pre-bronchodilator FEV1 was 1.06 L ( ICS group ) and 1.13 L ( non-ICS group ) . Both bronchodilators increased morning mean ± SE pre-dose FEV1 compared with placebo ( ICS groups : tiotropium 110 ± 20 mL , salmeterol 80 ± 20 mL ; non-ICS groups : tiotropium 150 ± 30 mL , salmeterol 110 ± 30 mL ; p > 0.05 for tiotropium vs salmeterol ) . Improvements in TDI and SGRQ and frequency of exacerbations also tended to be more profound for tiotropium . Treatment with tiotropium in patients with moderate-to-severe COPD was superior to salmeterol in lung function , irrespective of concurrent use of ICS [17504798] Chronic obstructive pulmonary disease ( COPD ) patients experiencing frequent exacerbations demonstrate increased stable-state airway inflammation . Tiotropium has been shown to reduce exacerbation frequency , but its effect on airway inflammation is unknown . The aim of the present study was to investigate the effect of tiotropium on sputum inflammatory markers and exacerbation frequency . Patients ( n = 142 ) were r and omised to receive tiotropium or placebo in addition to their usual medication for 1 yr . Sputum and serum cytokines were assayed by ELISA and exacerbation frequency calculated using a symptom-based diary . There was no difference in the area under the curve for sputum interleukin (IL)-6 or myeloperoxidase between the groups , but sputum IL-8 level was increased in the tiotropium arm . There was no difference between start and end of study in serum IL-6 or C-reactive protein level . Tiotropium was associated with a 52 % reduction in exacerbation frequency ( 1.17 versus 2.46 exacerbations·yr−1 ) . Of patients on tiotropium , 43 % experienced at least one exacerbation , compared with 64 % on placebo . The total number of exacerbation days was reduced compared with placebo ( 17.3 versus 34.5 days ) . Tiotropium reduces exacerbation frequency in chronic obstructive pulmonary disease , but this effect does not appear to be due to a reduction in airway or systemic inflammation [17690120] Premature discontinuation from clinical trials may bias results against effective therapies . In the present study mortality rates were retrospectively review ed in a 6-month , r and omised , placebo-controlled trial in which tiotropium 18 μg daily was shown to decrease chronic obstructive pulmonary disease exacerbations . Patients participated for 6 months even if trial medication was prematurely discontinued . Exposure-adjusted incidence rates ( IRs ) were calculated for r and omisation – end trial , r and omisation – end trial drug ( 0–ED ) and end trial drug – end trial ( ED – ET ) . Of 1,829 patients ( forced expiratory volume in one second 1.04 L ( 36 % predicted ) , mean age 68 yrs , 99 % male ) , 16 % tiotropium and 27 % placebo patients prematurely stopped trial medication . The number of fatal events for the entire cohort was : 62 all cause , including 16 cardiac and 16 lower respiratory . IRs for fatal events per 100 patient-yrs were higher in the discontinued period : 1.9 ( 0–ED ) versus 23.0 ( ED – ET ) in the tiotropium group and 1.8 versus 19.0 in the placebo group . Respective IRs for fatal cardiac events were 0.7 versus 2.8 ( tiotropium ) and 0.5 versus 6.2 ( placebo ) ; for fatal lower respiratory events were 0.7 versus 2.8 ( tiotropium ) and 0.8 versus 5.4 ( placebo ) . Rate ratios ( tiotropium/placebo ) for fatal events were lower in the discontinued period : 1.4 versus 0.5 for cardiac and 0.9 versus 0.5 for lower respiratory . Higher incidence rates of fatal events occurred following premature discontinuation of study medication . Incomplete information from rate ratios occurs as a result of failure to consider outcomes of patients who discontinue early from clinical trials [17693107] This study evaluated whether the effect of tiotropium on the change in trough forced expiratory volume in 1s ( FEV1 ) , vs. placebo , is affected by smoking status . In a 3-month , double-blind study in 31 centres in Portugal , 311 ( 289 completed ) patients were r and omised to tiotropium 18 microg once daily or placebo . Baseline mean ( st and ard deviation ( SD ) ) FEV1 was 1.11 ( 0.39 ) l in the tiotropium group and 1.13 ( 0.39 ) l in the placebo group . Patients had an average smoking history of 55 ( 25.7 ) pack-years ; 80 ( 26 % ) were smokers and 224 ( 74 % ) were ex-smokers . The primary end-point was change in morning pre-dose ( i.e. trough ) FEV1 after 12 weeks . Trough FEV1 at 12 weeks was significantly improved with tiotropium vs. placebo : the difference in means was 102 ml , P=0.0011 , 95 % confidence interval ( CI ) ( 41 , 164 ) . The difference in means in smokers was 138 ml , P=0.0105 , CI ( 32 , 244 ) ; in ex-smokers it was 66 ml , P=0.0375 , CI ( 3 , 129 ) . The difference between smokers and ex-smokers was not statistically significant ( P=0.6982 ) and may be due to greater variability and differences in disease severity . The significant improvement in lung function in patients treated with tiotropium vs. placebo in both smokers and ex-smokers suggests that tiotropium is an effective and well-tolerated therapy in chronic obstructive pulmonary disease ( COPD ) , regardless of smoking status [20180870] BACKGROUND In 2003 , chronic obstructive pulmonary disease ( COPD ) accounted for 46 % of the burden of chronic respiratory disease in the Australian community . In the 65 - 74-year-old age group , COPD was the sixth leading cause of disability for men and the seventh for women . AIMS To measure the influence of disease severity , COPD phenotype and comorbidities on acute health service utilization and direct acute care costs in patients admitted with COPD . METHODS Prospect i ve cohort study of 80 patients admitted to the Royal Melbourne Hospital in 2001 - 2002 for an exacerbation of COPD . Patients were followed for 12 months and data were collected on acute care utilization . Direct hospital costs were derived using Transition II , an activity-based costing system . Individual patient costs were then modelled to ascertain which patient factors influenced total direct hospital costs . RESULTS Direct costs were calculated for 225 episodes of care , the median cost per admission was AU$3124 ( interquartile range $ 1393 to $ 5045 ) . The median direct cost of acute care management per patient per year was AU$7273 ( interquartile range $ 3957 to $ 14 448 ) . In a multivariate analysis using linear regression modelling , factors predictive of higher annual costs were increasing age ( P= 0.041 ) , use of domiciliary oxygen ( P= 0.008 ) and the presence of chronic heart failure ( P= 0.006 ) . CONCLUSION This model has identified a number of patient factors that predict higher acute care costs and awareness of these can be used for service planning to meet the needs of patients admitted with COPD [20418083] BACKGROUND Gender differences may occur in many chronic diseases . We have examined the influence of gender in chronic obstructive pulmonary disease ( COPD ) on long-term responses to tiotropium . METHODS Subgroup analysis of data from the Underst and ing the Potential Long-term Impact of Tiotropium ( UPLIFT ) trial ( 4-year , r and omized , double-blind , placebo-controlled trial of tiotropium in patients with COPD ) . RESULTS Of 5992 patients , 75 % were men and 25 % women . Mean age was 65 and 63 years , respectively . Baseline post-bronchodilator forced expiratory volume in 1s ( FEV(1))=47 % predicted(men ) and 49 % predicted(women ) . St George 's Respiratory Question naire ( SGRQ ) total score was 44.9 and 48.7units , respectively . At 48 months , improvement in trough FEV(1 ) over control was 92mL(men ) and 77mL(women ) ( p<0.001 for both ) , with no differences in the rate of decline ( trial primary endpoint ) . Hazard ratio ( HR ) ( 95 % confidence interval [ CI ] ) for first exacerbation ( tiotropium/placebo ) was 0.87(0.81 , 0.93)(men ) and 0.83(0.74 , 0.94)(women ) . Number of exacerbations ( per patient-year ) was reduced with tiotropium in men ( from 0.82 to 0.71 ) and women ( from 0.92 to 0.77 ) ( p<0.005 for both ) . HR ( 95 % CI ) for a hospitalized exacerbation was 0.89(0.79 , 0.99 ) and 0.77(0.62 , 0.94 ) , respectively . HR ( 95 % CI ) for mortality during treatment was 0.85(0.72 , 0.99)(men ) and 0.85(0.62 , 1.18)(women ) . Improvements in SGRQ total score ( tiotropium-control ) at 1 , 2 , 3 and 4 years were : -2.8 , -2.3 , -3.6 , -2.4(men ) and -2.7 , -2.6 , -2.6 , -2.1(women ) ( p<0.05 for all ) . CONCLUSION Long-term treatment of COPD with tiotropium improves lung function , exacerbations and health status in men and women , with similar magnitudes of benefit . Boehringer Ingelheim trial 205.235 ; Clinical Trials.gov : NCT00144339 [2629970] Clinical manifestations of chronic obstructive pulmonary disease ( COPD ) , including airflow limitation , dyspnea , and activity limitation , ultimately lead to impaired health-related quality of life ( HRQoL ) . This 9-month , r and omized , double-blind , multicenter study compared the effect of once-daily tiotropium 18 μg and placebo on HRQoL , spirometric parameters , and exacerbations in 554 patients with moderate-to-severe COPD . HRQoL was assessed using the St. George ’s Respiratory Question naire ( SGRQ ) and the new 8-item Visual Simplified Respiratory Question naire ( VSRQ ) , which is currently being vali date d. The primary efficacy endpoint was the proportion of patients achieving a reduction of at least 4 units in the SGRQ total score at study end ( Month 9 ) . Mean ± SD baseline SGRQ total score was 47.4 ± 18.1 . Significantly more tiotropium-treated patients achieved a reduction of at least 4 units in the SGRQ score vs placebo at study end ( 59.1 % vs 48.2 % , respectively ; p = 0.029 ) . Tiotropium significantly improved spirometric parameters ( forced expiratory volume in 1 second [ FEV1 ] : 0.11 ± 0.02 L vs 0.01 ± 0.02 L ; between-group difference : 0.10 ± 0.03 L , p = 0.0001 ) and reduced exacerbations vs placebo . Maintenance treatment with tiotropium provided significant and clinical ly relevant improvements in HRQoL , as measured by the SGRQ [3190346] Background The rate of decline in forced expiratory volume in 1 second ( FEV1 ) is representative of the natural history of COPD . Sparse information exists regarding the associations between the magnitude of annualised loss of FEV1 with other endpoints . Methods Retrospective analysis of UPLIFT ® trial ( four-year , r and omized , double-blind , placebo-controlled trial of tiotropium 18 μg daily in chronic obstructive pulmonary disease [ COPD ] , n = 5993 ) . Decline of FEV1 was analysed with r and om co-efficient regression . Patients were categorised according to quartiles based on the rate of decline ( RoD ) in post-bronchodilator FEV1 . The St George 's Respiratory Question naire ( SGRQ ) total score , exacerbations and mortality were assessed within each quartile . Results Mean ( st and ard error [ SE ] ) post-bronchodilator FEV1 increased in the first quartile ( Q1 ) by 37 ( 1 ) mL/year . The other quartiles showed annualised declines in FEV1 ( mL/year ) as follows : Q2 = 24 ( 1 ) , Q3 = 59 ( 1 ) and Q4 = 125 ( 2 ) . Age , gender , respiratory medication use at baseline and SGRQ did not distinguish groups . The patient subgroup with the largest RoD had less severe lung disease at baseline and contained a higher proportion of current smokers . The percentage of patients with ≥ 1 exacerbation showed a minimal difference from the lowest to the largest RoD , but exacerbation rates increased with increasing RoD. The highest proportion of patients with ≥ 1 hospitalised exacerbation was in Q4 ( Q1 = 19.5 % [ tiotropium ] , 26 % [ control ] ; Q4 = 33.8 % [ tiotropium ] and 33.1 % [ control ] ) . Time to first exacerbation and hospitalised exacerbation was shorter with increasing RoD. Rate of decline in SGRQ increased in direct proportion to each quartile . The group with the largest RoD had the highest mortality . Conclusion Patients can be grouped into different RoD quartiles with the observation of different clinical outcomes indicating that specific ( or more aggressive ) approaches to management may be needed . Trial Registration Clinical Trials.gov number , [1913915] Background Clinical trials of tiotropium have principally recruited patients from secondary care with more severe chronic obstructive pulmonary disease ( COPD ) , and typically had included limitation of concomitant medication . In primary care , which is the most common setting for COPD management , many patients may have milder disease , and also may take a broad range of concomitant medication . Methods This r and omised , placebo-controlled , parallel-group , 12-week , 44-centre study investigated the efficacy ( trough forced expiratory volume in 1 second [ FEV1 ] response ) and safety of additional treatment with once-daily tiotropium 18 μg via the H and iHaler ® in a primary care COPD population ( tiotropium : N = 191 , FEV1 = 1.25 L [ 47.91 % predicted ] ; placebo : N = 183 , FEV1 = 1.32 L [ 49.86 % predicted ] ) . Secondary endpoints included : trough forced vital capacity ( FVC ) response , weekly use of rescue short-acting β-agonist , and exacerbation of COPD ( complex of respiratory symptoms/events of > 3 days in duration requiring a change in treatment ) . Treatment effects were determined using non-parametric analysis . Results At Week 12 , median improvement in trough FEV1 response with tiotropium versus placebo was 0.06 L ( p = 0.0102 ) . The improvement was consistent across baseline treatment and COPD severity . Median improvement in FVC at 2 , 6 and 12 weeks was 0.12 L ( p < 0.001 ) . The percentage of patients with ≥1 exacerbation was reduced ( tiotropium 9.5 % ; placebo 17.9 % ; p = 0.0147 ) , independent of disease severity . Rescue medication usage was significantly reduced in the tiotropium group compared with placebo . Adverse event profile was consistent with previous studies . Conclusion Tiotropium provides additional benefits to usual primary care management in a representative COPD population .Trial registration The identifier is : NCT00274079 [15764761] STUDY OBJECTIVES Pulmonary rehabilitation ( PR ) improves exercise tolerance in COPD patients . Tiotropium is a once-daily , inhaled anticholinergic bronchodilator that provides sustained 24-h improvements in airflow and lung hyperinflation reduction . We hypothesized that ventilatory mechanics improvements from tiotropium would permit enhanced ability to train muscles of ambulation and therefore augment exercise tolerance benefits of PR . DESIGN In a r and omized , double-blind , placebo-controlled trial ( tiotropium , n = 47 ; placebo , n = 44 ) , tiotropium ( 18 microg qd ) was administered to COPD patients participating in 8 weeks of PR ( treadmill training three times a week ; > /= 30 min per session ) at 17 sites . Study drug was administered 5 weeks prior to , 8 weeks during , and 12 weeks following PR . The primary end point was treadmill walking ( 0 % incline ) endurance time at 80 % of maximum speed attained in an initial incremental test . The transition dyspnea index ( TDI ) , St. George 's respiratory question naire ( SGRQ ) , and rescue albuterol use were secondary end points . PARTICIPANTS Mean age of the 93 participants was 67 years , 57 % were men , and mean FEV(1 ) was 0.88 L ( 34 % predicted ) . RESULTS Mean endurance time differences ( tiotropium minus placebo ) prior to PR , at the end of PR , and 12 weeks after PR were 1.65 min ( p = 0.183 ) , 5.35 min ( p = 0.025 ) , and 6.60 min ( p = 0.018 ) , respectively . Mean TDI focal scores at the end of PR were 1.75 for tiotropium and 0.91 for placebo ( p > 0.05 ) . At 12 weeks after PR , TDI focal scores were 1.75 for tiotropium and 0.08 for placebo ( p < 0.05 ) . Relative to placebo , tiotropium improved SGRQ total scores by 3.86 at the end of PR and 4.44 at 12 weeks after PR ( p > 0.05 ) . Mean albuterol use declined following PR plus tiotropium , compared to PR alone ( p < /= 0.05 for 17 of 25 weeks ) . CONCLUSIONS Tiotropium in combination with PR improved endurance of a constant work rate treadmill task and produced clinical ly meaningful improvements in dyspnea and health status compared to PR alone . Improvements with tiotropium were sustained for 3 months following PR completion [20185426] The aim of the present study was investigate the long-term effect of tiotropium as first maintenance respiratory medication in chronic obstructive pulmonary disease ( COPD ) . A 4-yr , r and omised , multicentre , double-blind , parallel-group , placebo-controlled trial ( Underst and ing Potential Long-term Impacts on Function with Tiotropium ( UPLIFT ® ) ) was conducted . Analysis focused on the effect of tiotropium versus matching placebo in the 810 ( 13.5 % ) COPD patients not on other maintenance treatment ( long-acting & bgr;-agonists , inhaled corticosteroids , theophyllines or anticholinergics ) at r and omisation . Spirometry , health-related quality of life ( St George ’s Respiratory Question naire ( SGRQ ) score ) , exacerbations of COPD and mortality were also analysed . 403 patients ( mean±sd age 63±8 yrs , post-bronchodilator forced expiratory volume in 1 s ( FEV1 ) 53±12 % predicted ) received tiotropium and 407 ( 64±8 yrs of age , post-bronchodilator FEV1 51±12 % pred ) received placebo . Post-bronchodilator FEV1 decline was 42±4 mL·yr−1 in the tiotropium group and 53±4 mL·yr−1 in the placebo group ( p = 0.026 ) . At 48 months , the morning pre-dose FEV1 was 134 mL higher in the tiotropium group compared to the placebo group ( p<0.001 ) . SGRQ total score declined more slowly in the tiotropium group ( difference of 1.05±0.34 units·yr−1 ; p = 0.002 ) . This was particularly significant for the impact ( difference of 1.08±0.37 units·yr−1 ; p = 0.004 ) and activity ( 1.44±0.40 units·yr−1 ; p<0.001 ) domains , but not for symptoms ( 0.26±0.50 units·yr−1 ; p = 0.6 ) . At 48 months , the difference in total score was 4.6 units ( p<0.001 ) with tiotropium compared to placebo . In patients with COPD who are not on maintenance therapy , tiotropium is associated with significant benefits in disease progression [11866001] Currently available inhaled bronchodilators used as therapy for chronic obstructive pulmonary disease ( COPD ) necessitate multiple daily dosing . The present study evaluates the long-term safety and efficacy of tiotropium , a new once-daily anticholinergic in COPD . Patients with stable COPD ( age 65.2±8.7 yrs ( mean±sd ) , n=921 ) were enrolled in two identical r and omized double-blind placebo-controlled 1-yr studies . Patients inhaled tiotropium 18 µg or placebo ( mean screening forced expiratory volume in one second ( FEV1 ) 1.01 versus 0.99 L , 39.1 and 38.1 % of the predicted value ) once daily as a dry powder . The primary spirometric outcome was trough FEV1 ( i.e. FEV1 prior to dosing ) . Changes in dyspnoea were measured using the Transition Dyspnea Index , and health status with the disease-specific St. George 's Respiratory Question naire and the generic Short Form 36 . Medication use and adverse events were recorded . Tiotropium provided significantly superior bronchodilation relative to placebo for trough FEV1 response ( ∼12 % over baseline ) ( p<0.01 ) and mean response during the 3 h following dosing ( ∼22 % over baseline ) ( p<0.001 ) over the 12-month period . Tiotropium recipients showed less dyspnoea ( p<0.001 ) , superior health status scores , and fewer COPD exacerbations and hospitalizations ( p<0.05 ) . Adverse events were comparable with placebo , except for dry mouth incidence ( tiotropium 16.0 % versus placebo 2.7 % , p<0.05 ) . Tiotropium is an effective , once-daily bronchodilator that reduces dyspnoea and chronic obstructive pulmonary disease exacerbation frequency and improves health status . This suggests that tiotropium will make an important contribution to chronic obstructive pulmonary disease therapy [17996436] The aim of these studies was to compare the efficacy and the safety of tiotropium , delivered via Respimat Soft Mist Inhaler ( SMI ) , a novel multi-dose , propellant-free inhaler , with ipratropium pressurized metered-dose inhaler ( pMDI ) in chronic obstructive pulmonary disease ( COPD ) patients . Two identical , 12-week , multi-national , r and omized , double-blind , double-dummy , parallel-group , active- and placebo-controlled studies were performed . COPD patients were r and omized to treatment with either inhaled tiotropium ( 5 or 10 microg ) via Respimat SMI administered once daily , ipratropium ( 36 microg ) pMDI QID or placebo . The primary endpoint was the mean trough forced expiratory volume in 1s ( FEV(1 ) ) response after 12 weeks of treatment . Secondary endpoints included other spirometry measures and rescue medication use . A total of 719 patients were r and omized ; the majority were male ( 69 % ) with a mean pre-bronchodilator FEV(1 ) ( % predicted ) of 40.7 % . The mean treatment differences between tiotropium 5 and 10 microg and placebo for the primary endpoint ( mean trough FEV(1 ) response at week 12 ) were 0.118 and 0.149L , respectively ( both P<0.0001 ) . Treatment differences between tiotropium 5 and 10 microg and ipratropium were 0.064L ( P=0.006 ) and 0.095L ( P<0.0001 ) . The increases in peak FEV(1 ) , FEV(1 ) AUC((0 - 6h ) ) and FVC for both tiotropium doses were statistically superior to placebo ( P<0.01 ) and higher than ipratropium . All active treatments significantly reduced the rescue medication use compared with placebo , but only tiotropium 10 microg was statistically superior to ipratropium ( P=0.04 ) . The incidence of adverse events was comparable across groups . In conclusion , tiotropium 5 and 10 microg daily , delivered via Respimat SMI , significantly improved lung function compared with ipratropium pMDI and placebo [11083677] STUDY OBJECTIVE To compare the bronchodilator efficacy and safety of tiotropium and placebo . DESIGN A 3-month , r and omized , double-blind , placebo-controlled , multicenter trial . SETTING Outpatient . PATIENTS Four hundred seventy patients with stable COPD ( mean FEV(1 ) = 38.6 % predicted ) . INTERVENTIONS Tiotropium 18 microg ( N = 279 ) or placebo ( N = 191 ) given once daily via a lactose-based dry-powder inhaler device . MEASUREMENTS AND RESULTS Spirometry was evaluated on days 1 , 8 , 50 , and 92 . Data were expressed as the mean trough ( ie , before morning dose ; 23 to 24 h after previous dose ) and average response observed in the 3 h after the dose was received . Tiotropium produced significant improvement in trough FEV(1 ) and FVC , averaging 12 % greater than baseline on day 8 ; these improvements were maintained on days 50 and 92 . The average postdose FEV(1 ) was 16 % greater than baseline on day 1 and 20 % greater than baseline on day 92 ; FVC was 17 % greater than baseline on day 1 and 19 % greater than baseline on day 92 . Tiotropium was significantly more effective than placebo in both trough and average FEV(1 ) and FVC response ( p < 0.001 ) . These spirometric effects were corroborated by significant improvements in daily morning and evening peak expiratory flow rate , as well as a reduction in " as-needed " albuterol use . Symptoms of wheezing and shortness of breath were significantly less in patients receiving tiotropium , and the physician global assessment noted overall improvements with those treated with tiotropium relative to placebo . The most common reported adverse event after tiotropium was dry mouth ( 9.3 % vs 1.6 % relative to placebo ; p < 0.05 ) . CONCLUSIONS These data demonstrate that tiotropium is a safe and effective once-daily anticholinergic bronchodilator and should prove useful as first-line maintenance therapy in COPD [15250751] Abstract Background : Healthcare costs for chronic obstructive pulmonary disease ( COPD ) have continued to increase with the increasing prevalence of the disease . New interventions that can reduce the medical costs of COPD are needed . Tiotropium bromide , a once-daily inhaled anticholinergic , has been evaluated in patients with COPD enrolled in two 1-year r and omised , double-blind , placebo-controlled ( usual care ) trials which showed the drug reduced exacerbations and improved spirometry , dyspnoea , and health status . Objective : To retrospectively assess the direct costs of medical care for COPD in a US healthcare setting for patients treated with tiotropium in addition to usual care compared with usual care alone over a 1-year timeframe . The study was based on re source utilisation in the two previously described trials . Methods : Re source utilisation and clinical data were prospect ively collected for the two 1-year , r and omised , double-blind trials of tiotropium plus usual care versus usual care alone ( placebo ) in 921 patients with COPD . Usual care was defined as any medication for COPD used prior to the trial except anticholinergics and long-acting β-adrenoceptor agonists . Medical care re source utilisation was recorded at every scheduled visit in each trial . Mean total costs were calculated retrospectively by combining the re sources utilised with the appropriate unit costs ( 1999 US dollars ) , excluding study drug ( tiotropium ) costs . Results : Compared with usual care , patients receiving tiotropium in addition to usual care had significantly fewer COPD exacerbations ( 20 % decrease ) , hospitalisations ( 44 % reduction ) and hospital days ( 50 % reduction ) . Utilisation of re sources other than hospitalisation did not differ between study groups . As a consequence , patients receiving tiotropium had significantly lower mean per- patient costs of hospitalisation compared with patients receiving usual care alone ( tiotropium $ US1738 ± $ US259 ; placebo $ US2793 ± $ US453 ) . The mean difference in the cost of hospitalisation ( result ing from all causes , including COPD ) between treatment groups was -$US1056 ( 95 % CI -$US2078 , -$US34 ) , and the difference in total healthcare costs ( excluding study drug acquisition cost ) was -$US1043 ( 95 % CI -$US2136 , $ US48 ) in favour of tiotropium . The cost of hospital admissions accounted for 48 % of the total direct medical costs in this trial . Conclusions : As hospitalisation is a large contributor to the cost of COPD , the addition of tiotropium to usual care therapy may have the potential to reduce the economic burden of COPD in a US healthcare setting . However , as our study did not consider the acquisition cost of tiotropium , further economic evaluation including this cost is needed to address whether tiotropium is cost saving compared with usual care ( placebo ) [21482091] BACKGROUND In COPD , improvements in lung mechanics following bronchodilator , measured using the forced oscillation technique ( FOT ) , are more sensitive than spirometry at detecting improvement in lung function following bronchodilator . The relationship between these improvements in lung mechanics and improvements in functional outcomes , such as exertional dyspnoea , following bronchodilator , in COPD is unknown . METHODS 17 COPD subjects were recruited into a double blind placebo controlled r and omised cross over study . Dyspnoea was induced using a st and ardised six-minute walk test ( 6 MWT ) , and measured by borg score throughout the test . Measurement of respiratory system conductance ( Grs ) , respiratory system reactance ( Xrs ) , inspiratory capacity ( IC ) and spirometry were made at baseline and 1 h after a single dose of either 18 μg of tiotropium bromide plus 200 μg salbutamol , or placebo . RESULTS Subjects had a mean baseline FEV(1 ) of 45.5 ± 11.0 % predicted . The bronchodilator induced reduction in exertional dyspnoea correlated significantly with the increase in Grs ( r(s ) = 0.59 , p = 0.01 ) and approached significance with FEV(1 ) ( r(s ) = 0.45 , p = 0.07 ) but not with FVC ( r(s ) = 0.30 , p = 0.24 ) , Xrs ( r(s ) = 0.19 , p = 0.47 ) or IC ( r(s ) = -0.08 , p = 0.78 ) . Increase in Grs was the best and sole predictor of reduction in exertional dyspnoea , explaining 41 % of the variance . There was no additional contribution to the model from the increase in FEV(1 ) or IC . CONCLUSION Bronchodilator induced improvements in exertional dyspnoea in moderate to severe COPD are predicted by improvements in Grs , measured by FOT , independent of improvements in spirometry or hyperinflation . The findings suggest that FOT may be useful for measuring response to bronchodilator in COPD [14509555] Loss of bronchodilator effectiveness or tolerance has been observed with inhaled beta-agonists but not with inhaled anticholinergic medications . Initially , tolerance is reflected in loss of bronchial protection against stimuli followed by loss of bronchodilator properties . However , generally such observations have been reported in asthma . A 6-month r and omized , double-dummy placebo-controlled trial comparing tiotropium to salmeterol provided the opportunity to examine spirometric tolerance to long-acting beta-agonists in patients with COPD . Spirometry was measured over 12h at baseline and at days 15 , 57 , 116 and 169 . Changes over time from baseline were compared relative to changes observed with placebo . A total of 623 patients participated ( tiotropium = 209 , salmeterol = 213 , placebo = 201 ) . The groups were similar in age ( mean = 65 years ) , gender ( 75 % men ) , and baseline FEV1 ( mean = 1.08 + /- 0.37l [ 40 + /- 12 % predicted ] ) . Relative to placebo , both active drugs improved morning pre-drug , peak and average FEV1 and FVC throughout the trial . However , from day 1 to 169 , salmeterol was associated with a higher decline in average FEV1 and FVC ( 0 - 12h ) ( difference from placebo : -36 and -115 ml , P < 0.05 ) , which was most prominent over the 8 - 12 h period ( difference from placebo : -45 and -138 ml , P < 0.01 ) . Significant declines in peak FVC relative to placebo ( -83 ml , P < 0.05 ) but not FEV1 ( -12ml ) were observed with salmeterol . Tiotropium was associated with further improvements in spirometry from days 1 to 15 and no evidence of tolerance from day 15 to the end of the trial . In conclusion , tolerance to pharmacologic bronchodilation occurs with long-acting beta-agonists such as salmeterol and not with inhaled anticholinergics [16698259] INTRODUCTION Use of maintenance bronchodilator therapy is currently recommended in symptomatic patients with Chronic obstructive pulmonary disease ( COPD ) and in those with Stage II or greater COPD as defined by the Global Initiative for Chronic Obstructive Lung Disease ( GOLD ) . Because no prospect i ve data describe when rescue therapy alone is insufficient or the optimal time to start maintenance therapy , it is unclear whether maintenance therapy has benefits in milder disease . To explore potential benefits we asked : Does once-daily tiotropium improve lung function , health status , and /or symptoms in " undertreated " COPD patients ( i.e. , those who are not receiving maintenance bronchodilator therapy ) or patients considered by their health care providers as having milder disease ? METHODS A post-hoc analysis of data from COPD patients participating in two , 1-year , placebo-controlled trials with tiotropium was performed . Patients were defined as " undertreated " if they received no respiratory medication or only as-needed short-acting beta-agonists prior to enrollment . Measures included serial spirometry , Transition Dyspnea Index ( TDI ) , and St. George 's Respiratory Question naire ( SGRQ ) . RESULTS Of 921 patients enrolled , 218 ( 23.7 % ) were " undertreated " : 130 received tiotropium ; 88 received placebo . Demographics for the two treatment groups were comparable . Tiotropium-treated patients had significantly improved forced expiratory volume in 1s ( FEV1 ) and forced vital capacity ( FVC ) compared with patients using placebo on all study days . Additionally , TDI and SGRQ scores significantly improved with tiotropium compared with placebo . CONCLUSIONS Once-daily tiotropium provides significant improvement in lung function , health status , and dyspnea when used as maintenance therapy in undertreated COPD patients who were not previously receiving maintenance bronchodilator therapy [21539680] BACKGROUND AND OBJECTIVE Studies in respiratory diseases other than chronic obstructive pulmonary disease suggest potentially differing responses to medications among patients from different regions . We report a subgroup analysis of patients recruited to Asian centres from a previously reported 4-year COPD trial . METHODS Subgroup analysis from a r and omized , double-blinded , placebo-controlled trial of tiotropium 18 µg daily in COPD . Primary end-point was rate of decline in FEV(1 ) . Secondary end-points included spirometry at individual time points , health-related quality of life ( St George 's Respiratory Question naire ) , exacerbations and mortality . RESULTS Of 5992 patients , 362 were from Asian centres ( 100 from Japan ) . Mean age 66 years , 95 % men , 13 % current smokers , BMI : 21 kg/m(2 ) ; post-bronchodilator FEV(1 ) : 44 % predicted ; St George 's Respiratory Question naire total score : 44 units . No treatment effect was observed for rate of decline in FEV(1 ) although annual decline was less in Asian patients . Morning pre-bronchodilator FEV(1 ) and forced vital capacity improved in Asian patients ( P < 0.05 ) . Tiotropium reduced number of exacerbations ( rate ratio ( 95 % confidence interval ( CI ) ) : 0.73 ( 0.57 - 0.94 ) ) . Hazard ratios ( 95%CI ) for exacerbations and hospitalized exacerbations ( tiotropium/control ) were 0.81 ( 0.62 - 1.05 ) and 0.85 ( 0.61 - 1.19 ) , respectively . St George 's Respiratory Question naire total score improved by 1.5 - 6.1 units ( P < 0.05 for months 18 , 24 , 30 and 36 ) with tiotropium . Fatal events occurred in 34 tiotropium ( 18.5 % ) and 42 control ( 23.6 % ) patients . CONCLUSIONS In COPD patients from Asia , tiotropium improves lung function , improves health-related quality of life and reduces exacerbations over 4 years of treatment [19592475] BACKGROUND The clinical trial safety data base for tiotropium has been augmented with a 4-year trial in patients with COPD , which provides an opportunity to better evaluate the cardiovascular ( CV ) profile of tiotropium . METHODS Trials with the following criteria were considered : > or = 4 weeks , r and omized , double-blind , parallel-group , placebo-controlled . Inclusion /exclusion criteria were similar , including spirometry-confirmed COPD , > or = 10 pack-year smoking , and age > or = 40 years . Adverse events were collected throughout each trial using st and ardized case report forms . Incidence rates ( IRs ) were determined from the total number of patients with an event divided by total time at risk . Rate ratios ( RRs ) and 95 % CI for tiotropium/placebo were calculated . IRs were determined for all-cause mortality and selected CV events , including a composite CV end point encompassing CV deaths , nonfatal myocardial infa rct ion ( MI ) , nonfatal stroke , and the terms sudden death , sudden cardiac death , and cardiac death . RESULTS There were 19,545 patients r and omized : 10,846 ( tiotropium ) and 8,699 ( placebo ) from 30 trials . Mean FEV(1 ) = 1.15 + /- 0.46 L ( 41 + /- 14 % predicted ) , 76 % men , mean age = 65 + /- 9 years . Cumulative exposure to study drug was 13,146 ( tiotropium ) and 11,095 ( placebo ) patient-years . For all-cause mortality , the IR was 3.44 ( tiotropium ) and 4.10 ( placebo ) per 100 patient-years ( RR [ 95 % CI ] = 0.88 [ 0.77 - 0.999 ] ) . IR for the CV end point was 2.15 ( tiotropium ) and 2.67 ( placebo ) per 100 patient-years ( RR [ 95 % CI ] = 0.83 ( 0.71 - 0.98 ] ) . The IR for the CV mortality excluding nonfatal MI and stroke was 0.91 ( tiotropium ) and 1.24 ( placebo ) per 100 patient-years ( RR [ 95 % CI ] = 0.77 [ 0.60 - 0.98 ] ) . For total MI , cardiac failure , and stroke the RRs ( 95 % CI ) were 0.78 ( 0.59 - 1.02 ) , 0.82 ( 0.69 - 0.98 ) , and 1.03 ( 0.79 - 1.35 ) , respectively . CONCLUSION Tiotropium was associated with a reduction in the risk of all-cause mortality , CV mortality , and CV events [18060091] BACKGROUND Patients with chronic obstructive pulmonary disease ( COPD ) who smoke have a greater annual rate of decline in forced expiratory volume in 1 s ( FEV(1 ) ) than those patients who have stopped smoking . OBJECTIVES To assess the effect of tiotropium on pre-dose ( trough ) FEV(1 ) in patients with COPD followed in Canada . METHODS A total of 913 patients were r and omly assigned to receive either tiotropium 18 mug once daily ( n=608 ) or placebo ( usual care minus inhaled anticholinergics ) ( n=305 ) for 48 weeks in the present r and omized , double-blind , parallel-group study . The effect of tiotropium on measurements of lung function ( FEV(1 ) , FEV(6 ) and forced vital capacity ) , symptoms , health-related quality of life ( St George 's Respiratory Question naire ) and exacerbations were examined . RESULTS Tiotropium improved trough FEV(1 ) in both current and ex-smokers compared with placebo . Baseline FEV(1 ) in smokers and ex-smokers was 1.03 L and 0.93 L , respectively ( P<0.001 ) . At week 48 , the mean difference between the tiotropium and placebo groups was 0.14+/-0.04 L ( P<0.001 ) in the smoker group and 0.08+/-0.02 L ( P<0.0001 ) in the ex-smoker group . Tiotropium also significantly improved trough forced vital capacity and FEV(6 ) compared with placebo throughout the treatment period ( P<0.05 , for all ) . Furthermore , tiotropium significantly improved the St George 's Respiratory Question naire total score compared with placebo at week 48 ( 40.9 versus 43.7 units , P<0.005 ) . CONCLUSIONS Compared with the placebo group , tiotropium provides sustained improvements in lung function in patients with COPD , with improvements for smokers and ex-smokers [21159499] STUDY OBJECTIVE Novel evaluation of protective effect of tiotropium against induced dynamic hyperinflation ( DH ) during metronome paced hyperventilation ( MPH ) in moderate COPD . METHODS Prospect i ve , r and omized , double-blind , placebo control , crossover study . Lung function measured pre/post MPH at 30 breaths/min for 20 s in 29 ( 18 M ) COPD patients ( GOLD Stage 2 ) age 70±9 yr ( mean ± SD ) before and after 30 days of 18 μg tiotropium bromide vs placebo . Lung CT scored for emphysema ( ES ) . RESULTS At baseline post 180 μg aerosolized albuterol sulfate , FEV(1 ) : 1.8±0.6 L ( 69±6 % pred ) and ≥60 % predicted in all , and 14 of 29 had FEV(1 ) ( L ) ≥70 % predicted with FEV(1)/FVC 58±8 % . After 29 days + 23 h post tiotropium ( trough ) there was significant decrease only in FRC/TLC% ( p=0.04 ) ; after 30 days + 2 h post tiotropium ( peak ) significant increase only in FEV(1 ) ( L ) ( p=0.03 ) compared to placebo . Results post MPH induced DH at baseline and after 30 days and 2 h post placebo or tiotropium were similar with decrease in IC 0.44±0.06 L ( p<0.001 ) . Correlation between ES and increased FEV(1 ) ( L ) at peak tiotropium : r=0.19 , p=0.96 and decreased FRC/TLC% at trough tiotropium : r=-0.26 , p=0.36 . CONCLUSION In moderate COPD , tiotropium did not reduce MPH induced DH and reduction in IC . However , at peak tiotropium , there was significant bronchodilation in FEV(1 ) ( L ) and at trough a decrease in FRC/TLC% compared to placebo despite varying emphysema [16484769] Background : Chronic obstructive pulmonary disease ( COPD ) is characterized by airflow limitation , which results in the progressive development of dyspnea and exercise limitation . Objective and Methods : To compare the effect of tiotropium with placebo on forced vital capacity ( FVC ) in patients with moderate-to-severe COPD and lung hyperinflation , using exercise endurance , dyspnea and health-related quality of life ( HRQoL ) as secondary endpoints . One hundred patients were r and omized to receive either tiotropium 18 µg once daily or placebo for 12 weeks . Results : Trough ( predose ) FVC was significantly improved with tiotropium compared to placebo on day 42 ( 0.27 ± 0.08 liters ) and 84 ( 0.20 ± 0.08 liters ; p < 0.05 for both ) . Trough inspiratory capacity ( IC ) was also significantly improved with tiotropium compared to placebo on day 42 ( 0.16 ± 0.07 liters ) and 84 ( 0.15 ± 0.07 liters ; p < 0.05 for both ) . Tiotropium increased the mean distance walked during the shuttle walking test by 33 ± 12 ( day 42 ) and 36 ± 14 m ( day 84 ) compared to placebo ( p < 0.05 for both ) . On day 84 , 59 % of the patients in the tiotropium group and 35 % of the patients in the placebo group had significant and clinical ly meaningful improvements in the St. George ’s Respiratory Question naire total score ( p < 0.05 ) . Numerical decreases in the focal score in the Transition Dyspnea Index in patients receiving tiotropium versus placebo suggest that tiotropium also improved dyspnea during activities of daily living . Conclusion : Tiotropium 18 µg once daily reduced hyperinflation with consequent improvements in walking distance and HRQoL in patients with COPD and lung hyperinflation [2528216] Background Improvements in ventilatory mechanics with tiotropium increases exercise tolerance during pulmonary rehabilitation . We wondered whether tiotropium also increased physical activities outside of pulmonary rehabilitation . Methods COPD patients participating in 8 weeks of pulmonary rehabilitation were studied in a r and omized , double-blind , placebo-controlled trial of tiotropium 18 μg daily ( tiotropium = 47 , placebo = 44 ) . Study drug was administered for 5 weeks prior to , 8 weeks during , and 12 weeks following pulmonary rehabilitation . Patients completed a question naire documenting participation in pre-defined activities outside of pulmonary rehabilitation during the 2 weeks prior to each visit . Patients who su bmi tted an activity question naire at week 4 and on at least one subsequent visit were included in the analysis . For each patient , the number of sessions was multiplied with the duration of each activity and then summed to give overall activity duration . Results Patients ( n = 46 ) had mean age of 67 years , mean baseline FEV1 of 0.84 L ( 33 % predicted ) . Mean ( SE ) increase in duration of activities ( minutes during 2 weeks prior to each visit ) from week 4 ( prior to PR ) to week 13 ( end of PR ) was 145 ( 84 ) minutes with tiotropium and 66 ( 96 ) minutes with placebo . The increase from week 4 to week 25 ( end of follow-up ) was 262 ( 96 ) and 60 ( 93 ) minutes for the respective groups . Increases in activity duration from week 4 to weeks 17 , 21 , and 25 were statistically significant with tiotropium . No statistical differences over time were observed within the placebo-treated group and differences between groups were not significant . Conclusions Tiotropium appears to amplify the effectiveness of pulmonary rehabilitation as seen by increases in patient self-reported participation in physical activities [16761228] BACKGROUND Aim of this study was to evaluate the efficacy of inhaled Tiotropium bromide in COPD patients of different severities in pneumological practice s during a three months clinical trial . METHODS A r and omized , double blind , placebo controlled study including COPD - patients ( FEV1/FVC < 70 % , FEV1 < or = 70 % predicted ; age > or = 40 years ; > or = 10 pack years ) of different severities was performed . The efficacy of 18 microg Tiotropium bromide once daily on lung function and exacerbations over 12 weeks was evaluated by respective pulmonary function tests ( spirometry ) before ( trough value ) and 2 hours after inhalation of study medication . RESULTS 1639 patients ( 1236 Tiotropium bromide , 403 placebo ; FEV1 reversibility after 200 microg Ipratropium bromide + 200 microg Fenoterol : 7.9 + /- 7.5 % predicted [ mean + /- sd ] ) were r and omized . After 12 weeks of treatment Tiotropium bromide led to significant increases of trough FEV1 ( 23 - 24 h after last inhalation ; + 79 + /- 17 ml ) , and 2 h after Tiotropium bromide inhalation ( + 128 + /- 19 ml ) ( all values vs. placebo , adjusted mean + /- se , p < 0.0001 ) . FVC and IVC were also improved significantly . In mild COPD ( FEV1 > or = 50 - 70 % ) improvements were most pronounced ( trough FEV1 + 113 + /- 29 ml , 2 h post-inhalation + 181 + /- 33 ml ; all values vs. placebo . , p < 0.0001 ) . 14.6 % of patients treated with Tiotropium bromide had a COPD exacerbation vs. 19.9 % of patients treated with placebo ( p = 0.0151 ) . The time to first exacerbation was prolonged ( p = 0.0092 vs. placebo ) . CONCLUSION Tiotropium bromide 18 microg once daily led to a persistent improvement of lung function and a reduction of exacerbations in patients with COPD of different severities [19729663] RATIONALE In the 4-year UPLIFT trial , tiotropium improved lung function and health-related quality of life and decreased exacerbations compared with usual respiratory medications except inhaled anticholinergics in patients with chronic obstructive pulmonary disease ( COPD ) . Mortality and its causes was a secondary endpoint in UPLIFT . OBJECTIVES We describe the effect of tiotropium on survival and analyze differences between mortality during treatment and during follow-up of discontinued patients . METHODS This study involved a r and omized , double-blind trial comparing tiotropium with placebo in patients with COPD ( > or=40 yr of age ; postbronchodilator FEV(1 ) < or=70 % ; FEV(1)/FVC < or=70 % ) . Mortality was evaluated during treatment and with follow-up of discontinued patients . Cause of death was adjudicated by an endpoint committee . MEASUREMENTS AND MAIN RESULTS A total of 5,993 patients were r and omized , 3,006 to placebo and 2,987 to tiotropium . While patients were receiving treatment , there were 792 deaths , with a lower risk in the tiotropium group ( hazard ratio , 0.84 ; 95 % confidence interval [ CI ] , 0.73 - 0.97 ) . Statistical significance was observed at the end of the protocol -defined treatment period ( P = 0.034 ) but not 30 days thereafter ( P = 0.086 ) . Adjustment by GOLD stage , sex , age , baseline smoking behavior , and baseline respiratory medications subgroups did not alter the results of the analysis . The most common causes of death adjudicated by an independent end-point committee were lower respiratory , cancer , general disorders , and cardiac disorders . The hazard ratios for lower respiratory and cardiac mortality during treatment were 0.86 ( 95 % CI , 0.68 - 1.09 ) and 0.86 ( 95 % CI , 0.75 - 0.99 ) , respectively . CONCLUSIONS Treatment with tiotropium over 4 years is associated with decreased mortality , with the effect being most prominent in the cardiac and respiratory systems [12725879] Ths object of this study was to examine validity , meaningful effect sizes , and patterns of response of the Transition Dyspnea Index ( TDI ) in a clinical trial cohort of chronic obstructive pulmonary disease ( COPD ) patients . The design was a retrospective analysis of data from a r and omized , double-blind placebo-controlled clinical trial . We analyzed fifty clinical investigation sites in United States . There were 921 patients with stable COPD . Tiotropium 18 microg dry powder or matching placebo was used . Patients were allowed to remain on usual care less ipratropium bromide . Construct validity was demonstrated by significant correlations ( P < .05 ) between Baseline Dyspnea Index ( BDI ) and other baseline measures , as well as between TDI and changes in other measures at the end of 1 year . Concurrent validity was observed by the significant correlation between TDI and dyspnea diary responses . Changes in TDI focal score were in the range of one unit when the group was stratified by a minimal change in the physician 's global evaluation . Significantly less ( P < .05 ) supplemental albuterol was observed in the group of responders defined by a one-unit improvement in TDI . Responders also had few exacerbations and better health status . The validity of the TDI is supported in a large clinical trial setting . A one-unit change in the TDI focal score represented the minimal important difference [18536860] AIMS Evaluation of tiotropium efficacy in patients with mild chronic obstructive pulmonary disease ( COPD ) defined by the 2003 Swedish Society of Respiratory Medicine guidelines ( post-bronchodilator FEV1/FVC < 70 % ; FEV1 > 60 % predicted ) . METHODS In this 12-week , r and omised , double-blind , placebo-controlled study of tiotropium 18 mcg once daily versus placebo , respiratory function was assessed on Days 1 , 15 and 85 ( baseline : pre-dose Day 1 ) . RESULTS Mean+/-SD baseline FEV1 ( % predicted ) was 73.4+/-12.5 ( tiotropium , n=107 ; placebo , n=117 ) . Tiotropium significantly improved change from baseline in area under the curve from pre-dose to 2 hours post-dose ( AUC0 - 2 h ) FEV1 versus placebo , by 166+/-26 mL ( mean+/-SE ) at study end ( p<0.0001 ) . With tiotropium , there were significant increases in the change in AUC0 - 2 h FVC versus baseline , and trough FEV1 and FVC , versus placebo , on all test days ( p<0.01 ) . Adverse event rates were similar . CONCLUSION Compared with placebo , tiotropium improved lung function in patients with mild COPD [19317104] The UPLIFT study ( Underst and ing Potential Long-term Impacts on Function with Tiotropium ) was a double-blind , r and omised , international , multicentric , placebo-controlled clinical trial , investigating with tiotropium ( Spiriva ) the change in the annual rate of decline in FEV1 in chronic obstructive pulmonary disease ( COPD ) . Secondary end points included COPD exacerbation rate with or without hospitalisation , lung function , quality of life and mortality . 5.993 patients were r and omized . In this article , we briefly describe the most important results of the study . While tiotropium did not alter the annual rate of decline in FEV1 ( pre and postbronchodilatation ) , it improved lung function and quality of life , and reduced exacerbations and hospitalisations by comparison with control for up to 4 years . Tiotropium also reduced respiratory and cardiac morbidity [20620037] In this r and omised double-blind study , patients > or=40 years old with COPD , a smoking history of > or=10 pack-years , a pre-bronchodilator FEV(1 ) of < or=60 % predicted and an FEV(1)/FVC of < or=70 % received tiotropium 5 microg or placebo via Respimat inhaler once daily for 48 weeks . Other medications were permitted except inhaled anticholinergics . Co- primary endpoints were trough FEV(1 ) and the time to first exacerbation . Adverse events were followed and vital status regularly assessed . In all , 3991 patients ( mean age , 65 years [ SD , 9 years ] ) were evaluable . Mean baseline FEV(1 ) was 1.11 L ( 0.40 L ) or 40 % ( 12 % ) of predicted normal . Adjusted mean differences in trough FEV(1 ) and trough FVC at Week 48 ( tiotropium minus placebo ) were 102 and 168 ml respectively ( p < 0.0001 , both ) . Tiotropium delayed time to first exacerbation relative to placebo ( hazard ratio [ HR ] , 0.69 [ 95 % CI , 0.63 - 0.77 ] ) and time to first hospital-treated exacerbation ( HR , 0.73 [ 0.59 - 0.90 ] ) . SGRQ score at Week 48 was 2.9 units lower with tiotropium ( p < 0.0001 ) . Adverse and serious adverse events were balanced across treatment groups and similar in profile to previous tiotropium trials . The rate ratio for a major adverse cardiovascular event during the treatment period + 30 days was 1.12 ( 0.67 - 1.86 ) . By the end of planned treatment ( Day 337 ) 52 patients on tiotropium ( incidence rate per 100 years , 2.94 ) and 38 on placebo ( 2.13 ) had died ( HR = 1.38 [ 0.91 - 2.10 ] ; p = 0.13 ) . Lung function , exacerbations and quality of life were improved by tiotropium 5 microg Respimat but a numerical imbalance was seen in all-cause mortality . The protocol is registered on the European Clinical Trials Data base as trial number 2006 - 001009 - 27 and in the Clinical Trials.gov data base as NCT00387088 [12114338] BACKGROUND Tiotropium , a once-daily anticholinergic , and salmeterol represent two inhaled , long-acting bronchodilators from different pharmacologic classes . A trial was design ed to examine the efficacy and safety of both compounds with multiple outcome measures , including lung function , dyspnea , and health-related quality of life ( HRQoL ) in patients with COPD . METHODS A 6-month , r and omized , placebo-controlled , double-blind , double-dummy , parallel-group study of tiotropium , 18 microg once daily via dry-powder inhaler , compared with salmeterol , 50 microg bid via metered-dose inhaler , was conducted in patients with COPD . Efficacy was assessed by 12-h monitoring of spirometry , transition dyspnea index ( TDI ) , and the St. George 's Respiratory Question naire ( SGRQ ) . RESULTS A total of 623 patients participated ( tiotropium , n= 209 ; salmeterol , n = 213 ; and placebo , n = 201 ) . The groups were similar in age ( mean , 65 years ) , gender ( 75 % men ) , and baseline FEV(1 ) ( mean , 1.08 + /- 0.37 L ; percent predicted , 40 + /- 12 % [ + /- SD ] ) . Compared with placebo treatment , the mean predose morning FEV(1 ) following 6 months of therapy increased significantly more for the tiotropium group ( 0.14 L ) than the salmeterol group ( 0.09 L ; p < 0.01 ) . The average FEV(1 ) ( 0 to 12 h ) for tiotropium was statistically superior to salmeterol ( difference , 0.08 L ; p < 0.001 ) . Tiotropium improved TDI focal score by 1.02 U compared with placebo ( p = 0.01 ) , whereas there was no significant change in TDI focal score with salmeterol ( 0.24 U ) . Tiotropium was superior to salmeterol in improving TDI focal score ( p < 0.05 ) . At 6 months , the mean improvement in SGRQ total score vs baseline was tiotropium , - 5.14 U ( p < 0.05 vs placebo ) ; salmeterol , - 3.54 U ( p = 0.4 vs placebo ) ; and placebo , - 2.43 U. A statistically higher proportion of patients receiving tiotropium achieved at least a 4-U change in SGRQ score compared to patients receiving placebo . Both active drugs reduced the need for rescue albuterol ( p < 0.0001 ) . CONCLUSIONS Tiotropium once daily produces superior bronchodilation , improvements in dyspnea , and proportion of patients achieving meaningful changes in HRQoL compared to twice-daily salmeterol in patients with COPD [17920256] BACKGROUND Chronic obstructive pulmonary disease ( COPD ) and asthma have different diagnostic criteria and treatment paradigms . Both are common and can occur in the same patient . We sought to determine the spirometric effects of tiotropium in COPD patients with concomitant asthma . METHODS A 12-week r and omized , double-blind , placebo-controlled , parallel group trial with tiotropium 18 mcg daily was performed . Patients continued usual respiratory medications except for inhaled anticholinergics . INCLUSION CRITERIA Physician diagnosis of COPD and asthma , age > or= 40 years , smoking > 10 pack years , post-bronchodilator forced expiratory volume in 1s ( FEV(1))<80 % predicted , FEV(1)/forced vital capacity (FVC)<70 % , > or= 12 % , and > or= 200 ml increase in FEV(1 ) following inhaled bronchodilator , treatment with inhaled steroids > or= 1 year . Spirometry was measured serially for 6h on days 1 , 29 and 85 . RESULTS Four hundred and seventy-two patients were r and omized . Baseline characteristics were balanced . Mean age=59.6 years , 61.4 % were men , and FEV(1)=1.55l ( 53.0 % predicted ) . Improvements at 12 weeks with tiotropium were observed for the primary endpoint FEV(1 ) area under the curve ( AUC ) from 0 to 6h ( difference=186+/-24 ml , p<0.001 ) and for morning pre-dose FEV(1 ) ( difference=98+/-23 ml , p<0.001 ) . Significant differences in favor of tiotropium were observed for pre-dose FVC ( difference=128+/-34 ml , p<0.001 ) and FVC AUC 0 - 6h ( difference=232+/-35 ml , p<0.001 ) . Compared to baseline , the mean weekly number of daily puffs of prn salbutamol was reduced by 0.05+/-0.12 puffs/day in the placebo group and by 0.50+/-0.12 puffs/day in the tiotropium group at week 12 ( p<0.05 ) . CONCLUSIONS Patients with COPD and concomitant asthma achieve spirometric improvements with tiotropium along with symptomatic benefit as seen by reduced need for rescue medication [20724131] Whilst recent large-scale studies have provided much evidence on the natural history and therapeutic response in patients with chronic obstructive pulmonary disease ( COPD ) , relatively little is known about the effect in younger patients . We report a pre-specified post-hoc analysis of 356 patients with COPD ≤ 50 years old from the four year r and omised , double blind placebo controlled Underst and ing Potential Long Term Impact on Function with Tiotropium ( UPLIFT ) trial . Inclusion criteria included a post-bronchodilator forced expiratory volume in 1 s ( FEV(1 ) ) of ≤70 % , FEV(1)/FVC < 0.70 , age ≥40 years , and smoking history of ≥10 pack years . Younger patients had a mean FEV(1 ) of 1.24 L ( 39 % predicted ) and an impaired health-related quality of life ( St. George 's Respiratory Question naire ( SGRQ ) ) compared to the entire UPLIFT population . There were 40.2 % women and 51.1 % current smokers in the younger age group . Tiotropium was associated with a sustained improvement in spirometry and SGRQ . Mean decline in post-bronchodilator FEV(1 ) was 58 ml/year ( placebo ) vs. 38 ml/year ( tiotropium ) ( p = 0.01 ) . Corresponding values for pre-bronchodilator FEV(1 ) were 41 ml/year ( placebo ) compared with 34 ml/year ( tiotropium ) ( p = 0.34 ) . The hazard ratio ( 95%CI ) for an exacerbation in the younger age group was 0.87(0.68 , 1.13 ) ) . The rate of exacerbations was reduced by tiotropium ( rate ratio ( 95%CI ) = 0.73(0.56 , 0.95 ) ) . Tiotropium result ed in sustained bronchodilation , improved quality of life , and a decreased exacerbation rate in younger patients . Tiotropium also result ed in a significant reduction in the decline in post-bronchodilator FEV(1 ) , suggesting possible disease modification by tiotropium in younger patients with COPD [16144890] Context Tiotropium , a new once-daily inhaled anticholinergic bronchodilator , has been shown to improve lung function in patients with chronic obstructive pulmonary disease ( COPD ) . Previous studies have suggested that it may also decrease the frequency of exacerbations and hospitalizations in these patients . Contribution This r and omized , parallel-group , double-blind , placebo-controlled study in patients with moderate to severe COPD showed a small but statistically significant decrease in the exacerbation rate during the 6-month study period . Caution s The study period was relatively short , and the beneficial effects were modest . The Editors Exacerbations of chronic obstructive pulmonary disease ( COPD ) can lead to costly and clinical ly significant consequences . Proven treatments for exacerbations are only modestly effective ( 1 , 2 ) . Recovery from even mild exacerbations may be protracted ( 3 ) . Frequent exacerbations are associated with impaired quality of life and a more rapid decline in lung function over time ( 4 , 5 ) . Patients with severe exacerbations commonly seek care in emergency departments , and many of these patients are hospitalized . In 2000 , COPD was responsible for 1.5 million emergency department visits and 726000 hospitalizations in the United States ( 6 ) . Economic analyses suggest that hospitalization alone consumes up to 70 % of all medical expenses for patients with COPD ( 7 , 8) . Interventions that reduce the frequency or severity of exacerbations are a highly desirable but poorly met medical need . An expert panel convened by the National Heart , Lung , and Blood Institute assigned a high priority to clinical research that might improve the management of COPD exacerbations ( 9 ) . Tiotropium is a newly developed , once-daily inhaled anticholinergic bronchodilator . Because of its very slow dissociation from muscarinic M3 receptors , 1 inhaled dose produces sustained bronchodilation for at least 24 hours ( 10 ) . In controlled clinical trials , compared with placebo or the short-acting anticholinergic bronchodilator ipratropium , tiotropium improved lung function , dyspnea , and health-related quality of life in patients with COPD ( 11 , 12 ) . An analysis of adverse event reports su bmi tted during those studies suggested that tiotropium might also reduce exacerbation and COPD -related hospitalization rates . Therefore , we design ed a clinical trial to prospect ively test the hypothesis that tiotropium reduces exacerbations and hospitalizations due to COPD . Methods Study Design Our study was a parallel-group , r and omized , double-blind , placebo-controlled trial in patients with moderate to severe COPD conducted at 26 Veterans Affairs medical centers in the United States . The sole intervention was tiotropium given by inhalation once daily . The principal outcomes were the percentage of patients experiencing at least 1 exacerbation and the percentage of patients with at least 1 hospitalization due to a COPD exacerbation during a 6-month treatment period . The protocol is consistent with the principles of Helsinki . The institutional review boards of participating medical centers approved the study . All trial participants provided written informed consent . Patients All men and women receiving medical care at participating Veterans Affairs medical centers were potential study participants . We enrolled enough participants to ensure a minimum of 1800 r and omly assigned patients . Eligibility criteria included an age of 40 years or older , a cigarette smoking history of 10 pack-years or more , a clinical diagnosis of COPD , and an FEV1 of 60 % predicted or less and 70 % or less of the FVC . Exclusion criteria were a clinical diagnosis of asthma , a myocardial infa rct ion within the previous 6 months , a serious cardiac arrhythmia or hospitalization for heart failure within the previous year , known moderate to severe renal impairment , moderate to severe symptomatic prostatic hypertrophy or bladder-neck obstruction , narrow-angle glaucoma , current radiation or chemotherapy for a malignant condition , or inability to give informed consent . We also excluded patients who took systemic corticosteroids at unstable doses , or in regular daily doses of 20 mg or more of prednisone ( or equivalent ) , or who had not fully recovered from an exacerbation for at least 30 days before the first study visit . We gathered baseline data on respiratory disease and other relevant medical history by question naire . Procedures We allocated eligible patients in equal numbers to receive tiotropium or placebo according to a central ly generated blocked r and omization list . We generated a single r and omization and assigned blocks to centers . We provided r and omly assigned patients with training and detailed instructions on the use of the dry powder inhalation device ( H and iHaler , Boehringer Ingelheim Pharma GmbH & Co. KG , Biberach , Germany ) ( 13 ) . Blinding of supplies was performed at Boehringer Ingelheim before distribution to investigational sites . The double-blind remained in place until all patients were clinical ly complete or until a serious adverse event required unblinding . Each morning during the trial , patients inhaled 1 capsule of tiotropium ( 18 g ) or 1 identical placebo capsule . Participants otherwise received usual medical care , except that they could not take any open-label anticholinergic bronchodilator . They continued taking all other respiratory medications ( including inhaled corticosteroids and long-acting -agonists ) , and primary providers were allowed to prescribe additional medications according to medical need . Primary providers also prescribed antibiotics and systemic steroid prescriptions for exacerbations without restrictions . For purpose s of recall , patients kept a daily diary throughout the treatment period , recording information about specific respiratory symptoms , medications taken for exacerbations , clinic visits , and hospitalizations . We collected information about exacerbations and health care utilization by interviews when patients made site visits at 3 and 6 months and by telephone calls at 1-month intervals between visits . We assessed study drug adherence by query and by counting returned capsules . Participants performed spirometry before and 90 minutes after inhalation of study drug at baseline and again at the 3-month and 6-month visits . We encouraged patients to complete study visits and to provide all requested medical information even if they prematurely discontinued the study drug therapy . However , patients who discontinued the study drug therapy did not have 90-minute postinhalation spirometry testing at subsequent study visits . All open-label bronchodilators and the study drug were withheld overnight before spirometry . Study sites performed spirometry by using a common predictive nomogram with equipment and methods that conformed to American Thoracic Society recommendations ( 14 , 15 ) . Objectives We aim ed to determine whether tiotropium decreased COPD exacerbations and hospitalizations due to exacerbations . Outcome Measures The co primary outcomes were the percentage of patients with a COPD exacerbation and the percentage of patients with a hospitalization due to COPD exacerbation . We defined an exacerbation as a complex of respiratory symptoms ( increase or new-onset ) of more than 1 of the following : cough , sputum , wheezing , dyspnea , or chest tightness with a duration of at least 3 days requiring treatment with antibiotics or systemic steroids , hospitalization , or both . The study team at each site requested discharge summaries for all hospitalizations , wherever they occurred . We identified hospitalizations due to COPD exacerbations from events on case report forms that met the protocol definition of an exacerbation and where review of discharge summaries and other available medical records indicated that the event result ed in a hospitalization . We also considered an event to be a hospitalization if a patient was held and treated for an acute respiratory condition in an urgent care department or in an observation unit for longer than 24 hours . Admissions to nursing homes or other extended care facilities were not considered hospitalizations . Secondary outcomes included time to first COPD exacerbation and time to first hospitalization due to COPD exacerbation , the frequencies of exacerbations and of exacerbation-related health care utilization ( hospitalizations , hospitalization days , unscheduled clinic visits , antibiotic treatment days , and systemic corticosteroid treatment days ) , the frequencies of all-cause hospitalizations and hospitalization days , and results of spirometry . Statistical Analysis We analyzed the data by using a modified intention-to-treat principle . Therefore , we included all available data for the patients with any follow-up contact who took at least 1 capsule of study drug in the analysis up to their first event ( for the time-to-event end points ) or their withdrawal from the trial . For the time-to-event end points , we censored patients without an event at the end of their participation in the trial . Although we intended to follow all patients for the full 6 months , some patients were lost to follow-up . We h and led missing data by using longitudinal data analysis methods ( spirometry ) , analysis of observed data only ( number of events ) , or analysis methods for censored data ( time-to-event data ) . For the percentage of patients with an event , we considered that patients who discontinued the study drug therapy before having an event did not have an event . We analyzed the co primary end points by using a CochranMantelHaenszel test with center as a stratum . We used a stepwise procedure to test the percentage of patients with an exacerbation and , if rejected , to test percentage of patients with a hospitalization due to COPD exacerbation , each at a 2-sided level of 0.05 . Because of the prespecified closed testing procedure , no adjustment for multiplicity was required . We calculated that a sample size of 1800 patients would have 80 % power to

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### Context: [3027109] Background Debate continues as to whether acute bronchodilator responsiveness ( BDR ) predicts long-term outcomes in COPD . Furthermore , there is no consensus on a threshold for BDR . Methods At baseline and during the 4-year Underst and ing Potential Long-term Improvements in Function with Tiotropium ( UPLIFT ® ) trial , patients had spirometry performed before and after administration of ipratropium bromide 80 mcg and albuterol 400 mcg . Patients were split according to three BDR thresholds : ≥12 % + ≥200 mL above baseline ( criterion A ) , ≥15 % above baseline ( criterion B ) ; and ≥10 % absolute increase in percent predicted FEV1 values ( criterion C ) . Several outcomes ( pre-dose spirometry , exacerbations , St. George 's Respiratory Question naire [ SGRQ ] total score ) were assessed according to presence or absence of BDR in the treatment groups . Results 5783 of 5993 r and omized patients had evaluable pre- and post-bronchodilator spirometry at baseline . Mean age ( SD ) was 64 ( 8) years , with 75 % men , mean post-bronchodilator FEV1 1.33 ± 0.44 L ( 47.6 ± 12.7 % predicted ) and 30 % current smokers . At baseline , 52 % , 66 % , and 39 % of patients had acute BDR using criterion A , B , and C , respectively . The presence of BDR was variable at follow-up visits . Statistically significant improvements in spirometry and health outcomes occurred with tiotropium regardless of the baseline BDR or criterion used . Conclusions A large proportion of COPD patients demonstrate significant acute BDR . BDR in these patients is variable over time and differs according to the criterion used . BDR status at baseline does not predict long-term response to tiotropium . Assessment of acute BDR should not be used as a decision-making tool when prescribing tiotropium to patients with COPD [19717481] UPLIFT ( Underst and ing Potential Long-Term Improvements in Function with Tiotropium ) , a 4-yr trial of tiotropium in chronic obstructive pulmonary disease , allowed for assessment of smoking status on long-term responses to maintenance bronchodilator therapy . 5,993 patients were r and omised ( tiotropium/placebo ) . Lung function , St George 's Respiratory Question naire , exacerbations and adverse events were followed . Patients were characterised as continuing smokers ( CS ) , continuing ex-smokers ( CE ) , or intermittent smokers ( IS ) based on self-reporting smoking behaviour . 60 % , 14 % and 26 % of patients were CE , CS and IS , respectively . The rate of forced expiratory volume in 1 s ( FEV1 ) decline for placebo patients was most rapid in CS ( -51±4 , -36±2 and -23±2 mL·yr−1 in CS , IS , and CE , respectively ) . Tiotropium did not alter FEV1 decline , but was associated with significant improvements in pre- and post-bronchodilator FEV1 over placebo that persisted throughout the 4-yr trial for each smoking status ( pre-bronchodilator : 125 , 55 and 97 mL at 48 months in CS , IS and CE , respectively ; p≤0.0003 ) . Tiotropium reduced exacerbation risk in CS ( HR ( 95%CI ) 0.81 ( 0.68–0.97 ) ) , in CE ( 0.86 ( 0.79–0.93 ) ) and trended towards significance in IS ( 0.89 ( 0.80–1.01 ) ) . At 4 yrs , St George ’s Respiratory Question naire for tiotropium patients improved the most in CS ( -4.62 units , p = 0.0006 ) and the least in IS ( -0.54 units , p = 0.55 ) , compared with control . Tiotropium provided long-term benefits irrespective of smoking status , although differences among categories were observed [18836213] BACKGROUND Previous studies showing that tiotropium improves multiple end points in patients with chronic obstructive pulmonary disease ( COPD ) led us to examine the long-term effects of tiotropium therapy . METHODS In this r and omized , double-blind trial , we compared 4 years of therapy with either tiotropium or placebo in patients with COPD who were permitted to use all respiratory medications except inhaled anticholinergic drugs . The patients were at least 40 years of age , with a forced expiratory volume in 1 second ( FEV(1 ) ) of 70 % or less after bronchodilation and a ratio of FEV(1 ) to forced vital capacity ( FVC ) of 70 % or less . Co primary end points were the rate of decline in the mean FEV(1 ) before and after bronchodilation beginning on day 30 . Secondary end points included measures of FVC , changes in response on St. George 's Respiratory Question naire ( SGRQ ) , exacerbations of COPD , and mortality . RESULTS Of a total of 5993 patients ( mean age , 65+/-8 years ) with a mean FEV(1 ) of 1.32+/-0.44 liters after bronchodilation ( 48 % of predicted value ) , we r and omly assigned 2987 to the tiotropium group and 3006 to the placebo group . Mean absolute improvements in FEV(1 ) in the tiotropium group were maintained throughout the trial ( ranging from 87 to 103 ml before bronchodilation and from 47 to 65 ml after bronchodilation ) , as compared with the placebo group ( P<0.001 ) . After day 30 , the differences between the two groups in the rate of decline in the mean FEV(1 ) before and after bronchodilation were not significant . The mean absolute total score on the SGRQ was improved ( lower ) in the tiotropium group , as compared with the placebo group , at each time point throughout the 4-year period ( ranging from 2.3 to 3.3 units , P<0.001 ) . At 4 years and 30 days , tiotropium was associated with a reduction in the risks of exacerbations , related hospitalizations , and respiratory failure . CONCLUSIONS In patients with COPD , therapy with tiotropium was associated with improvements in lung function , quality of life , and exacerbations during a 4-year period but did not significantly reduce the rate of decline in FEV(1 ) . ( Clinical Trials.gov number , NCT00144339 . [2650608] Background Exercise training improves exercise tolerance in chronic obstructive pulmonary disease ( COPD ) . Tiotropium 18 μg once daily induces sustained bronchodilation throughout the day and reduces hyperinflation , one of the pathophysiological factors contributing to exertional dyspnea in COPD patients . Aim To determine whether tiotropium enhances the effects of exercise training in patients with COPD . Design Multicenter , 25 week r and omized , double-blind , placebo-controlled , parallel-group study . Setting Twelve Italian Pulmonary Units practicing pulmonary rehabilitation . Patients and intervention Two hundred thirty four COPD patients ( 196 males ; mean age : 67.4 ± 7.6 ; forced expiratory volume at 1 second ( FEV1 ) : 41.4 ± 13.0 % predicted ) were r and omised to tiotropium 18 μg or placebo inhalation capsules taken once daily . Both groups underwent a 8 week pulmonary rehabilitation program ( PR ) consisting of 3 exercise training session per week . Measurements Baseline , at the end of PR and after 12 weeks , patients completed pulmonary function testing , six minute walking test ( 6MWT ) , the Baseline and Transition Dyspnea Index ( BDI and TDI ) , and the St. George ’s Respiratory Question naire ( SGRQ ) . Results Relative to placebo , tiotropium had larger trough and post- study drug FEV1 responses on all test days . At the end of and 12 weeks following PR , patients on tiotropium showed no statistically significant differences in 6MWT compared to patients on placebo . Compared to the period immediately prior to PR , the mean improvement in 6MWT was only 29.7 meters ( 7.1 % ) for the combined cohort . Mean TDI focal scores at the end of PR were 3.60 for tiotropium and 2.25 for placebo ( p < 0.01 ) . At 12 weeks after PR , TDI focal scores were 2.71 for tiotropium and 2.11 for placebo ( p = 0.16 ) . Reduction in all four SGRQ component scores , indicating an improvement in health-related quality of life , was observed for the tiotropium group over the duration of the study compared to placebo but the differences were not statistically significant . During the study period , there were fewer exacerbations and exacerbation days in the tiotropium group . Conclusion Although significant improvements were observed with perceived dyspnea , compared to placebo , the addition of tiotropium to pulmonary rehabilitation did not improve the 6MWT [18256071] The degree of acute improvement in spirometric indices after bronchodilator inhalation varies among chronic obstructive pulmonary disease ( COPD ) patients , and depends upon the type and dose of bronchodilator and the timing of administration . Acute bronchodilator responsiveness at baseline was examined in a large cohort of patients with moderate-to-very-severe COPD participating in the Underst and ing Potential Long-term Impacts on Function with Tiotropium ( UPLIFT ) trial , a 4-yr r and omised double-blind trial evaluating the efficacy of 18 μg tiotropium daily in reducing the rate of decline in lung function . After wash-out of respiratory medications , patients received 80 μg ipratropium followed by 400 μg salbutamol . Spirometry was performed before and 90 min following ipratropium administration . The criteria used for forced expiratory volume in one second ( FEV1 ) responsiveness were : ≥12 % increase over baseline and ≥200 mL ; ≥15 % increase over baseline ; and ≥10 % absolute increase in the percentage predicted value . Of the patients , 5,756 had data meeting the criteria for analysis ( age 64.5 yrs ; 75 % male ; baseline FEV1 1.10 L ( 39.3 % predicted ) and forced vital capacity ( FVC ) 2.63 L ) . Compared with baseline , mean improvements were 229 mL in FEV1 and 407 mL in FVC . Of these patients , 53.9 % had ≥12 % and ≥200 mL improvement in FEV1 , 65.6 % had ≥15 % improvement in FEV1 , and 38.6 % had ≥10 % absolute increase in FEV1 % pred . The majority of patients with moderate-to-very-severe chronic obstructive pulmonary disease demonstrate meaningful increases in lung function following administration of inhaled anticholinergic plus sympathomimetic bronchodilators [16305289] STUDY OBJECTIVES To examine electrocardiographic findings after short- and long-term tiotropium therapy in patients with chronic obstructive pulmonary disease ( COPD ) , and to establish previously reported symptomatic efficacy . DESIGN R and omized , double-blind , placebo-controlled , parallel-group study . SETTING Twelve outpatient investigational centers in the United States . PATIENTS One hundred ninety-six patients with COPD . INTERVENTIONS Patients received either tiotropium 18 mug once/day or placebo , delivered by the H and iHaler device . MEASUREMENTS AND MAIN RESULTS Electrocardiography ( predose and 5 min postdose ) and 24-hour Holter monitoring were performed at baseline and after 8 and 12 weeks of treatment with tiotropium 18 microg once/day or placebo . Efficacy measures ( spirometry , global COPD ratings , scores on the EuroQol Health Question naire [ EQ-5D ] , albuterol inhaler as needed ) were included to demonstrate that the study population exhibited the characteristic improvements observed in previous tiotropium studies . Mean baseline forced expiratory volume in 1 second ( FEV1 ) was 1.03 L. Mean changes in heart rate from baseline were similar in both groups . No differences were noted in the percentage of patients developing rhythm or conduction abnormalities detected with electrocardiography or Holter monitoring . Frequency of premature beats and mean maximal changes in PR , QRS , QT , QTcB , and QTcF intervals were similar in both groups . No patients developed new-onset QT or QTc intervals greater than 500 msec , and no differences were noted in the percentage of patients developing new QT prolongation less than 30 msec , 30 - 60 msec , or greater than 60 msec . At 12 weeks , predose and postdose improvements in FEV1 were 184 and 265 ml , respectively , with tiotropium versus placebo ( p<0.001 ) . Physician and patient global COPD ratings and the EQ-5D visual analog scale scores were improved with tiotropium ( p<0.05 ) ; as-needed albuterol was reduced by 25 % relative to placebo ( p<0.05 ) . CONCLUSION Tiotropium provided spirometric and symptomatic benefits in patients with COPD and was not associated with evidence of electrocardiographic changes in heart rate , rhythm , QT intervals , or conduction [20979799] OBJECTIVE To compare the efficacy and safety between tiotropium capsule and placebo in a 12-week treatment in patients with chronic obstructive pulmonary disease ( COPD ) . METHODS A multi-center , r and omized , double-blind , and placebo-control clinical trial was conducted in 205 patients with stable COPD . They were r and omized into inhaled tiotropium 18 µg once daily or placebo , lasting for 12 weeks . The spirometry was conducted at baseline , 6 and 12 weeks after treatment . RESULTS A total of 205 patients with stable stage I or II COPD were r and omized to tiotropium and placebo groups . The improvement rate of clinical symptom in the tiotropium group was 25.2 % ( 26/103 ) after a 12 week treatment , but that of the control group was 4.9 % ( 5/102 ) . The forced expiratory volume in one second ( FEV₁ ) and forced vital capacity ( FVC ) in the tiotropium group increased ( 0.2 ± 0.3 ) L and ( 19.2 ± 29.1)% after the 12 week therapy , but only ( 0.0 ± 0.2 ) L and ( 0.8 ± 18.2)% in the placebo group . The rate of adverse reaction in the tiotropium group was 7.8 % ( 8/103 ) , but in the placebo group was 12.8 % ( 13/102 ) . The difference between the 2 groups was not significant . All adverse reactions were mild , including dry mouth and sore throat . CONCLUSIONS This trial confirmed that tiotropium powder 18 µg once daily relieved dyspnea , prevented aggravation and improved pulmonary function , clinical symptoms and life quality . Tiotropium was a safe and effective once-daily anticholinergic bronchodilator as first-line maintenance therapy in COPD [3321723] Patients with COPD are frequently prescribed inhaled corticosteroids ( ICS ) ; however , it is unclear whether the treatment with ICS might modify responses to inhaled bronchodilators . Two 6-month , r and omized , placebo-controlled , double-blind , double-dummy , parallel-group studies of tiotropium 18 μg once daily , compared with salmeterol , 50 μg bid , had been conducted in patients with moderate-to-severe COPD . Efficacy was assessed by spirometry , transition dyspnea index ( TDI ) , St. George ’s Respiratory Question naire ( SGRQ ) , and exacerbations . Data from both studies were combined to form subgroups with regard to concurrent use of ICS . 796 patients receiving ICS were separately analyzed from 390 patients not receiving ICS . Mean age was 64 years , and pre-bronchodilator FEV1 was 1.06 L ( ICS group ) and 1.13 L ( non-ICS group ) . Both bronchodilators increased morning mean ± SE pre-dose FEV1 compared with placebo ( ICS groups : tiotropium 110 ± 20 mL , salmeterol 80 ± 20 mL ; non-ICS groups : tiotropium 150 ± 30 mL , salmeterol 110 ± 30 mL ; p > 0.05 for tiotropium vs salmeterol ) . Improvements in TDI and SGRQ and frequency of exacerbations also tended to be more profound for tiotropium . Treatment with tiotropium in patients with moderate-to-severe COPD was superior to salmeterol in lung function , irrespective of concurrent use of ICS [17504798] Chronic obstructive pulmonary disease ( COPD ) patients experiencing frequent exacerbations demonstrate increased stable-state airway inflammation . Tiotropium has been shown to reduce exacerbation frequency , but its effect on airway inflammation is unknown . The aim of the present study was to investigate the effect of tiotropium on sputum inflammatory markers and exacerbation frequency . Patients ( n = 142 ) were r and omised to receive tiotropium or placebo in addition to their usual medication for 1 yr . Sputum and serum cytokines were assayed by ELISA and exacerbation frequency calculated using a symptom-based diary . There was no difference in the area under the curve for sputum interleukin (IL)-6 or myeloperoxidase between the groups , but sputum IL-8 level was increased in the tiotropium arm . There was no difference between start and end of study in serum IL-6 or C-reactive protein level . Tiotropium was associated with a 52 % reduction in exacerbation frequency ( 1.17 versus 2.46 exacerbations·yr−1 ) . Of patients on tiotropium , 43 % experienced at least one exacerbation , compared with 64 % on placebo . The total number of exacerbation days was reduced compared with placebo ( 17.3 versus 34.5 days ) . Tiotropium reduces exacerbation frequency in chronic obstructive pulmonary disease , but this effect does not appear to be due to a reduction in airway or systemic inflammation [17690120] Premature discontinuation from clinical trials may bias results against effective therapies . In the present study mortality rates were retrospectively review ed in a 6-month , r and omised , placebo-controlled trial in which tiotropium 18 μg daily was shown to decrease chronic obstructive pulmonary disease exacerbations . Patients participated for 6 months even if trial medication was prematurely discontinued . Exposure-adjusted incidence rates ( IRs ) were calculated for r and omisation – end trial , r and omisation – end trial drug ( 0–ED ) and end trial drug – end trial ( ED – ET ) . Of 1,829 patients ( forced expiratory volume in one second 1.04 L ( 36 % predicted ) , mean age 68 yrs , 99 % male ) , 16 % tiotropium and 27 % placebo patients prematurely stopped trial medication . The number of fatal events for the entire cohort was : 62 all cause , including 16 cardiac and 16 lower respiratory . IRs for fatal events per 100 patient-yrs were higher in the discontinued period : 1.9 ( 0–ED ) versus 23.0 ( ED – ET ) in the tiotropium group and 1.8 versus 19.0 in the placebo group . Respective IRs for fatal cardiac events were 0.7 versus 2.8 ( tiotropium ) and 0.5 versus 6.2 ( placebo ) ; for fatal lower respiratory events were 0.7 versus 2.8 ( tiotropium ) and 0.8 versus 5.4 ( placebo ) . Rate ratios ( tiotropium/placebo ) for fatal events were lower in the discontinued period : 1.4 versus 0.5 for cardiac and 0.9 versus 0.5 for lower respiratory . Higher incidence rates of fatal events occurred following premature discontinuation of study medication . Incomplete information from rate ratios occurs as a result of failure to consider outcomes of patients who discontinue early from clinical trials [17693107] This study evaluated whether the effect of tiotropium on the change in trough forced expiratory volume in 1s ( FEV1 ) , vs. placebo , is affected by smoking status . In a 3-month , double-blind study in 31 centres in Portugal , 311 ( 289 completed ) patients were r and omised to tiotropium 18 microg once daily or placebo . Baseline mean ( st and ard deviation ( SD ) ) FEV1 was 1.11 ( 0.39 ) l in the tiotropium group and 1.13 ( 0.39 ) l in the placebo group . Patients had an average smoking history of 55 ( 25.7 ) pack-years ; 80 ( 26 % ) were smokers and 224 ( 74 % ) were ex-smokers . The primary end-point was change in morning pre-dose ( i.e. trough ) FEV1 after 12 weeks . Trough FEV1 at 12 weeks was significantly improved with tiotropium vs. placebo : the difference in means was 102 ml , P=0.0011 , 95 % confidence interval ( CI ) ( 41 , 164 ) . The difference in means in smokers was 138 ml , P=0.0105 , CI ( 32 , 244 ) ; in ex-smokers it was 66 ml , P=0.0375 , CI ( 3 , 129 ) . The difference between smokers and ex-smokers was not statistically significant ( P=0.6982 ) and may be due to greater variability and differences in disease severity . The significant improvement in lung function in patients treated with tiotropium vs. placebo in both smokers and ex-smokers suggests that tiotropium is an effective and well-tolerated therapy in chronic obstructive pulmonary disease ( COPD ) , regardless of smoking status [20180870] BACKGROUND In 2003 , chronic obstructive pulmonary disease ( COPD ) accounted for 46 % of the burden of chronic respiratory disease in the Australian community . In the 65 - 74-year-old age group , COPD was the sixth leading cause of disability for men and the seventh for women . AIMS To measure the influence of disease severity , COPD phenotype and comorbidities on acute health service utilization and direct acute care costs in patients admitted with COPD . METHODS Prospect i ve cohort study of 80 patients admitted to the Royal Melbourne Hospital in 2001 - 2002 for an exacerbation of COPD . Patients were followed for 12 months and data were collected on acute care utilization . Direct hospital costs were derived using Transition II , an activity-based costing system . Individual patient costs were then modelled to ascertain which patient factors influenced total direct hospital costs . RESULTS Direct costs were calculated for 225 episodes of care , the median cost per admission was AU$3124 ( interquartile range $ 1393 to $ 5045 ) . The median direct cost of acute care management per patient per year was AU$7273 ( interquartile range $ 3957 to $ 14 448 ) . In a multivariate analysis using linear regression modelling , factors predictive of higher annual costs were increasing age ( P= 0.041 ) , use of domiciliary oxygen ( P= 0.008 ) and the presence of chronic heart failure ( P= 0.006 ) . CONCLUSION This model has identified a number of patient factors that predict higher acute care costs and awareness of these can be used for service planning to meet the needs of patients admitted with COPD [20418083] BACKGROUND Gender differences may occur in many chronic diseases . We have examined the influence of gender in chronic obstructive pulmonary disease ( COPD ) on long-term responses to tiotropium . METHODS Subgroup analysis of data from the Underst and ing the Potential Long-term Impact of Tiotropium ( UPLIFT ) trial ( 4-year , r and omized , double-blind , placebo-controlled trial of tiotropium in patients with COPD ) . RESULTS Of 5992 patients , 75 % were men and 25 % women . Mean age was 65 and 63 years , respectively . Baseline post-bronchodilator forced expiratory volume in 1s ( FEV(1))=47 % predicted(men ) and 49 % predicted(women ) . St George 's Respiratory Question naire ( SGRQ ) total score was 44.9 and 48.7units , respectively . At 48 months , improvement in trough FEV(1 ) over control was 92mL(men ) and 77mL(women ) ( p<0.001 for both ) , with no differences in the rate of decline ( trial primary endpoint ) . Hazard ratio ( HR ) ( 95 % confidence interval [ CI ] ) for first exacerbation ( tiotropium/placebo ) was 0.87(0.81 , 0.93)(men ) and 0.83(0.74 , 0.94)(women ) . Number of exacerbations ( per patient-year ) was reduced with tiotropium in men ( from 0.82 to 0.71 ) and women ( from 0.92 to 0.77 ) ( p<0.005 for both ) . HR ( 95 % CI ) for a hospitalized exacerbation was 0.89(0.79 , 0.99 ) and 0.77(0.62 , 0.94 ) , respectively . HR ( 95 % CI ) for mortality during treatment was 0.85(0.72 , 0.99)(men ) and 0.85(0.62 , 1.18)(women ) . Improvements in SGRQ total score ( tiotropium-control ) at 1 , 2 , 3 and 4 years were : -2.8 , -2.3 , -3.6 , -2.4(men ) and -2.7 , -2.6 , -2.6 , -2.1(women ) ( p<0.05 for all ) . CONCLUSION Long-term treatment of COPD with tiotropium improves lung function , exacerbations and health status in men and women , with similar magnitudes of benefit . Boehringer Ingelheim trial 205.235 ; Clinical Trials.gov : NCT00144339 [2629970] Clinical manifestations of chronic obstructive pulmonary disease ( COPD ) , including airflow limitation , dyspnea , and activity limitation , ultimately lead to impaired health-related quality of life ( HRQoL ) . This 9-month , r and omized , double-blind , multicenter study compared the effect of once-daily tiotropium 18 μg and placebo on HRQoL , spirometric parameters , and exacerbations in 554 patients with moderate-to-severe COPD . HRQoL was assessed using the St. George ’s Respiratory Question naire ( SGRQ ) and the new 8-item Visual Simplified Respiratory Question naire ( VSRQ ) , which is currently being vali date d. The primary efficacy endpoint was the proportion of patients achieving a reduction of at least 4 units in the SGRQ total score at study end ( Month 9 ) . Mean ± SD baseline SGRQ total score was 47.4 ± 18.1 . Significantly more tiotropium-treated patients achieved a reduction of at least 4 units in the SGRQ score vs placebo at study end ( 59.1 % vs 48.2 % , respectively ; p = 0.029 ) . Tiotropium significantly improved spirometric parameters ( forced expiratory volume in 1 second [ FEV1 ] : 0.11 ± 0.02 L vs 0.01 ± 0.02 L ; between-group difference : 0.10 ± 0.03 L , p = 0.0001 ) and reduced exacerbations vs placebo . Maintenance treatment with tiotropium provided significant and clinical ly relevant improvements in HRQoL , as measured by the SGRQ [3190346] Background The rate of decline in forced expiratory volume in 1 second ( FEV1 ) is representative of the natural history of COPD . Sparse information exists regarding the associations between the magnitude of annualised loss of FEV1 with other endpoints . Methods Retrospective analysis of UPLIFT ® trial ( four-year , r and omized , double-blind , placebo-controlled trial of tiotropium 18 μg daily in chronic obstructive pulmonary disease [ COPD ] , n = 5993 ) . Decline of FEV1 was analysed with r and om co-efficient regression . Patients were categorised according to quartiles based on the rate of decline ( RoD ) in post-bronchodilator FEV1 . The St George 's Respiratory Question naire ( SGRQ ) total score , exacerbations and mortality were assessed within each quartile . Results Mean ( st and ard error [ SE ] ) post-bronchodilator FEV1 increased in the first quartile ( Q1 ) by 37 ( 1 ) mL/year . The other quartiles showed annualised declines in FEV1 ( mL/year ) as follows : Q2 = 24 ( 1 ) , Q3 = 59 ( 1 ) and Q4 = 125 ( 2 ) . Age , gender , respiratory medication use at baseline and SGRQ did not distinguish groups . The patient subgroup with the largest RoD had less severe lung disease at baseline and contained a higher proportion of current smokers . The percentage of patients with ≥ 1 exacerbation showed a minimal difference from the lowest to the largest RoD , but exacerbation rates increased with increasing RoD. The highest proportion of patients with ≥ 1 hospitalised exacerbation was in Q4 ( Q1 = 19.5 % [ tiotropium ] , 26 % [ control ] ; Q4 = 33.8 % [ tiotropium ] and 33.1 % [ control ] ) . Time to first exacerbation and hospitalised exacerbation was shorter with increasing RoD. Rate of decline in SGRQ increased in direct proportion to each quartile . The group with the largest RoD had the highest mortality . Conclusion Patients can be grouped into different RoD quartiles with the observation of different clinical outcomes indicating that specific ( or more aggressive ) approaches to management may be needed . Trial Registration Clinical Trials.gov number , [1913915] Background Clinical trials of tiotropium have principally recruited patients from secondary care with more severe chronic obstructive pulmonary disease ( COPD ) , and typically had included limitation of concomitant medication . In primary care , which is the most common setting for COPD management , many patients may have milder disease , and also may take a broad range of concomitant medication . Methods This r and omised , placebo-controlled , parallel-group , 12-week , 44-centre study investigated the efficacy ( trough forced expiratory volume in 1 second [ FEV1 ] response ) and safety of additional treatment with once-daily tiotropium 18 μg via the H and iHaler ® in a primary care COPD population ( tiotropium : N = 191 , FEV1 = 1.25 L [ 47.91 % predicted ] ; placebo : N = 183 , FEV1 = 1.32 L [ 49.86 % predicted ] ) . Secondary endpoints included : trough forced vital capacity ( FVC ) response , weekly use of rescue short-acting β-agonist , and exacerbation of COPD ( complex of respiratory symptoms/events of > 3 days in duration requiring a change in treatment ) . Treatment effects were determined using non-parametric analysis . Results At Week 12 , median improvement in trough FEV1 response with tiotropium versus placebo was 0.06 L ( p = 0.0102 ) . The improvement was consistent across baseline treatment and COPD severity . Median improvement in FVC at 2 , 6 and 12 weeks was 0.12 L ( p < 0.001 ) . The percentage of patients with ≥1 exacerbation was reduced ( tiotropium 9.5 % ; placebo 17.9 % ; p = 0.0147 ) , independent of disease severity . Rescue medication usage was significantly reduced in the tiotropium group compared with placebo . Adverse event profile was consistent with previous studies . Conclusion Tiotropium provides additional benefits to usual primary care management in a representative COPD population .Trial registration The identifier is : NCT00274079 [15764761] STUDY OBJECTIVES Pulmonary rehabilitation ( PR ) improves exercise tolerance in COPD patients . Tiotropium is a once-daily , inhaled anticholinergic bronchodilator that provides sustained 24-h improvements in airflow and lung hyperinflation reduction . We hypothesized that ventilatory mechanics improvements from tiotropium would permit enhanced ability to train muscles of ambulation and therefore augment exercise tolerance benefits of PR . DESIGN In a r and omized , double-blind , placebo-controlled trial ( tiotropium , n = 47 ; placebo , n = 44 ) , tiotropium ( 18 microg qd ) was administered to COPD patients participating in 8 weeks of PR ( treadmill training three times a week ; > /= 30 min per session ) at 17 sites . Study drug was administered 5 weeks prior to , 8 weeks during , and 12 weeks following PR . The primary end point was treadmill walking ( 0 % incline ) endurance time at 80 % of maximum speed attained in an initial incremental test . The transition dyspnea index ( TDI ) , St. George 's respiratory question naire ( SGRQ ) , and rescue albuterol use were secondary end points . PARTICIPANTS Mean age of the 93 participants was 67 years , 57 % were men , and mean FEV(1 ) was 0.88 L ( 34 % predicted ) . RESULTS Mean endurance time differences ( tiotropium minus placebo ) prior to PR , at the end of PR , and 12 weeks after PR were 1.65 min ( p = 0.183 ) , 5.35 min ( p = 0.025 ) , and 6.60 min ( p = 0.018 ) , respectively . Mean TDI focal scores at the end of PR were 1.75 for tiotropium and 0.91 for placebo ( p > 0.05 ) . At 12 weeks after PR , TDI focal scores were 1.75 for tiotropium and 0.08 for placebo ( p < 0.05 ) . Relative to placebo , tiotropium improved SGRQ total scores by 3.86 at the end of PR and 4.44 at 12 weeks after PR ( p > 0.05 ) . Mean albuterol use declined following PR plus tiotropium , compared to PR alone ( p < /= 0.05 for 17 of 25 weeks ) . CONCLUSIONS Tiotropium in combination with PR improved endurance of a constant work rate treadmill task and produced clinical ly meaningful improvements in dyspnea and health status compared to PR alone . Improvements with tiotropium were sustained for 3 months following PR completion [20185426] The aim of the present study was investigate the long-term effect of tiotropium as first maintenance respiratory medication in chronic obstructive pulmonary disease ( COPD ) . A 4-yr , r and omised , multicentre , double-blind , parallel-group , placebo-controlled trial ( Underst and ing Potential Long-term Impacts on Function with Tiotropium ( UPLIFT ® ) ) was conducted . Analysis focused on the effect of tiotropium versus matching placebo in the 810 ( 13.5 % ) COPD patients not on other maintenance treatment ( long-acting & bgr;-agonists , inhaled corticosteroids , theophyllines or anticholinergics ) at r and omisation . Spirometry , health-related quality of life ( St George ’s Respiratory Question naire ( SGRQ ) score ) , exacerbations of COPD and mortality were also analysed . 403 patients ( mean±sd age 63±8 yrs , post-bronchodilator forced expiratory volume in 1 s ( FEV1 ) 53±12 % predicted ) received tiotropium and 407 ( 64±8 yrs of age , post-bronchodilator FEV1 51±12 % pred ) received placebo . Post-bronchodilator FEV1 decline was 42±4 mL·yr−1 in the tiotropium group and 53±4 mL·yr−1 in the placebo group ( p = 0.026 ) . At 48 months , the morning pre-dose FEV1 was 134 mL higher in the tiotropium group compared to the placebo group ( p<0.001 ) . SGRQ total score declined more slowly in the tiotropium group ( difference of 1.05±0.34 units·yr−1 ; p = 0.002 ) . This was particularly significant for the impact ( difference of 1.08±0.37 units·yr−1 ; p = 0.004 ) and activity ( 1.44±0.40 units·yr−1 ; p<0.001 ) domains , but not for symptoms ( 0.26±0.50 units·yr−1 ; p = 0.6 ) . At 48 months , the difference in total score was 4.6 units ( p<0.001 ) with tiotropium compared to placebo . In patients with COPD who are not on maintenance therapy , tiotropium is associated with significant benefits in disease progression [11866001] Currently available inhaled bronchodilators used as therapy for chronic obstructive pulmonary disease ( COPD ) necessitate multiple daily dosing . The present study evaluates the long-term safety and efficacy of tiotropium , a new once-daily anticholinergic in COPD . Patients with stable COPD ( age 65.2±8.7 yrs ( mean±sd ) , n=921 ) were enrolled in two identical r and omized double-blind placebo-controlled 1-yr studies . Patients inhaled tiotropium 18 µg or placebo ( mean screening forced expiratory volume in one second ( FEV1 ) 1.01 versus 0.99 L , 39.1 and 38.1 % of the predicted value ) once daily as a dry powder . The primary spirometric outcome was trough FEV1 ( i.e. FEV1 prior to dosing ) . Changes in dyspnoea were measured using the Transition Dyspnea Index , and health status with the disease-specific St. George 's Respiratory Question naire and the generic Short Form 36 . Medication use and adverse events were recorded . Tiotropium provided significantly superior bronchodilation relative to placebo for trough FEV1 response ( ∼12 % over baseline ) ( p<0.01 ) and mean response during the 3 h following dosing ( ∼22 % over baseline ) ( p<0.001 ) over the 12-month period . Tiotropium recipients showed less dyspnoea ( p<0.001 ) , superior health status scores , and fewer COPD exacerbations and hospitalizations ( p<0.05 ) . Adverse events were comparable with placebo , except for dry mouth incidence ( tiotropium 16.0 % versus placebo 2.7 % , p<0.05 ) . Tiotropium is an effective , once-daily bronchodilator that reduces dyspnoea and chronic obstructive pulmonary disease exacerbation frequency and improves health status . This suggests that tiotropium will make an important contribution to chronic obstructive pulmonary disease therapy [17996436] The aim of these studies was to compare the efficacy and the safety of tiotropium , delivered via Respimat Soft Mist Inhaler ( SMI ) , a novel multi-dose , propellant-free inhaler , with ipratropium pressurized metered-dose inhaler ( pMDI ) in chronic obstructive pulmonary disease ( COPD ) patients . Two identical , 12-week , multi-national , r and omized , double-blind , double-dummy , parallel-group , active- and placebo-controlled studies were performed . COPD patients were r and omized to treatment with either inhaled tiotropium ( 5 or 10 microg ) via Respimat SMI administered once daily , ipratropium ( 36 microg ) pMDI QID or placebo . The primary endpoint was the mean trough forced expiratory volume in 1s ( FEV(1 ) ) response after 12 weeks of treatment . Secondary endpoints included other spirometry measures and rescue medication use . A total of 719 patients were r and omized ; the majority were male ( 69 % ) with a mean pre-bronchodilator FEV(1 ) ( % predicted ) of 40.7 % . The mean treatment differences between tiotropium 5 and 10 microg and placebo for the primary endpoint ( mean trough FEV(1 ) response at week 12 ) were 0.118 and 0.149L , respectively ( both P<0.0001 ) . Treatment differences between tiotropium 5 and 10 microg and ipratropium were 0.064L ( P=0.006 ) and 0.095L ( P<0.0001 ) . The increases in peak FEV(1 ) , FEV(1 ) AUC((0 - 6h ) ) and FVC for both tiotropium doses were statistically superior to placebo ( P<0.01 ) and higher than ipratropium . All active treatments significantly reduced the rescue medication use compared with placebo , but only tiotropium 10 microg was statistically superior to ipratropium ( P=0.04 ) . The incidence of adverse events was comparable across groups . In conclusion , tiotropium 5 and 10 microg daily , delivered via Respimat SMI , significantly improved lung function compared with ipratropium pMDI and placebo [11083677] STUDY OBJECTIVE To compare the bronchodilator efficacy and safety of tiotropium and placebo . DESIGN A 3-month , r and omized , double-blind , placebo-controlled , multicenter trial . SETTING Outpatient . PATIENTS Four hundred seventy patients with stable COPD ( mean FEV(1 ) = 38.6 % predicted ) . INTERVENTIONS Tiotropium 18 microg ( N = 279 ) or placebo ( N = 191 ) given once daily via a lactose-based dry-powder inhaler device . MEASUREMENTS AND RESULTS Spirometry was evaluated on days 1 , 8 , 50 , and 92 . Data were expressed as the mean trough ( ie , before morning dose ; 23 to 24 h after previous dose ) and average response observed in the 3 h after the dose was received . Tiotropium produced significant improvement in trough FEV(1 ) and FVC , averaging 12 % greater than baseline on day 8 ; these improvements were maintained on days 50 and 92 . The average postdose FEV(1 ) was 16 % greater than baseline on day 1 and 20 % greater than baseline on day 92 ; FVC was 17 % greater than baseline on day 1 and 19 % greater than baseline on day 92 . Tiotropium was significantly more effective than placebo in both trough and average FEV(1 ) and FVC response ( p < 0.001 ) . These spirometric effects were corroborated by significant improvements in daily morning and evening peak expiratory flow rate , as well as a reduction in " as-needed " albuterol use . Symptoms of wheezing and shortness of breath were significantly less in patients receiving tiotropium , and the physician global assessment noted overall improvements with those treated with tiotropium relative to placebo . The most common reported adverse event after tiotropium was dry mouth ( 9.3 % vs 1.6 % relative to placebo ; p < 0.05 ) . CONCLUSIONS These data demonstrate that tiotropium is a safe and effective once-daily anticholinergic bronchodilator and should prove useful as first-line maintenance therapy in COPD [15250751] Abstract Background : Healthcare costs for chronic obstructive pulmonary disease ( COPD ) have continued to increase with the increasing prevalence of the disease . New interventions that can reduce the medical costs of COPD are needed . Tiotropium bromide , a once-daily inhaled anticholinergic , has been evaluated in patients with COPD enrolled in two 1-year r and omised , double-blind , placebo-controlled ( usual care ) trials which showed the drug reduced exacerbations and improved spirometry , dyspnoea , and health status . Objective : To retrospectively assess the direct costs of medical care for COPD in a US healthcare setting for patients treated with tiotropium in addition to usual care compared with usual care alone over a 1-year timeframe . The study was based on re source utilisation in the two previously described trials . Methods : Re source utilisation and clinical data were prospect ively collected for the two 1-year , r and omised , double-blind trials of tiotropium plus usual care versus usual care alone ( placebo ) in 921 patients with COPD . Usual care was defined as any medication for COPD used prior to the trial except anticholinergics and long-acting β-adrenoceptor agonists . Medical care re source utilisation was recorded at every scheduled visit in each trial . Mean total costs were calculated retrospectively by combining the re sources utilised with the appropriate unit costs ( 1999 US dollars ) , excluding study drug ( tiotropium ) costs . Results : Compared with usual care , patients receiving tiotropium in addition to usual care had significantly fewer COPD exacerbations ( 20 % decrease ) , hospitalisations ( 44 % reduction ) and hospital days ( 50 % reduction ) . Utilisation of re sources other than hospitalisation did not differ between study groups . As a consequence , patients receiving tiotropium had significantly lower mean per- patient costs of hospitalisation compared with patients receiving usual care alone ( tiotropium $ US1738 ± $ US259 ; placebo $ US2793 ± $ US453 ) . The mean difference in the cost of hospitalisation ( result ing from all causes , including COPD ) between treatment groups was -$US1056 ( 95 % CI -$US2078 , -$US34 ) , and the difference in total healthcare costs ( excluding study drug acquisition cost ) was -$US1043 ( 95 % CI -$US2136 , $ US48 ) in favour of tiotropium . The cost of hospital admissions accounted for 48 % of the total direct medical costs in this trial . Conclusions : As hospitalisation is a large contributor to the cost of COPD , the addition of tiotropium to usual care therapy may have the potential to reduce the economic burden of COPD in a US healthcare setting . However , as our study did not consider the acquisition cost of tiotropium , further economic evaluation including this cost is needed to address whether tiotropium is cost saving compared with usual care ( placebo ) [21482091] BACKGROUND In COPD , improvements in lung mechanics following bronchodilator , measured using the forced oscillation technique ( FOT ) , are more sensitive than spirometry at detecting improvement in lung function following bronchodilator . The relationship between these improvements in lung mechanics and improvements in functional outcomes , such as exertional dyspnoea , following bronchodilator , in COPD is unknown . METHODS 17 COPD subjects were recruited into a double blind placebo controlled r and omised cross over study . Dyspnoea was induced using a st and ardised six-minute walk test ( 6 MWT ) , and measured by borg score throughout the test . Measurement of respiratory system conductance ( Grs ) , respiratory system reactance ( Xrs ) , inspiratory capacity ( IC ) and spirometry were made at baseline and 1 h after a single dose of either 18 μg of tiotropium bromide plus 200 μg salbutamol , or placebo . RESULTS Subjects had a mean baseline FEV(1 ) of 45.5 ± 11.0 % predicted . The bronchodilator induced reduction in exertional dyspnoea correlated significantly with the increase in Grs ( r(s ) = 0.59 , p = 0.01 ) and approached significance with FEV(1 ) ( r(s ) = 0.45 , p = 0.07 ) but not with FVC ( r(s ) = 0.30 , p = 0.24 ) , Xrs ( r(s ) = 0.19 , p = 0.47 ) or IC ( r(s ) = -0.08 , p = 0.78 ) . Increase in Grs was the best and sole predictor of reduction in exertional dyspnoea , explaining 41 % of the variance . There was no additional contribution to the model from the increase in FEV(1 ) or IC . CONCLUSION Bronchodilator induced improvements in exertional dyspnoea in moderate to severe COPD are predicted by improvements in Grs , measured by FOT , independent of improvements in spirometry or hyperinflation . The findings suggest that FOT may be useful for measuring response to bronchodilator in COPD [14509555] Loss of bronchodilator effectiveness or tolerance has been observed with inhaled beta-agonists but not with inhaled anticholinergic medications . Initially , tolerance is reflected in loss of bronchial protection against stimuli followed by loss of bronchodilator properties . However , generally such observations have been reported in asthma . A 6-month r and omized , double-dummy placebo-controlled trial comparing tiotropium to salmeterol provided the opportunity to examine spirometric tolerance to long-acting beta-agonists in patients with COPD . Spirometry was measured over 12h at baseline and at days 15 , 57 , 116 and 169 . Changes over time from baseline were compared relative to changes observed with placebo . A total of 623 patients participated ( tiotropium = 209 , salmeterol = 213 , placebo = 201 ) . The groups were similar in age ( mean = 65 years ) , gender ( 75 % men ) , and baseline FEV1 ( mean = 1.08 + /- 0.37l [ 40 + /- 12 % predicted ] ) . Relative to placebo , both active drugs improved morning pre-drug , peak and average FEV1 and FVC throughout the trial . However , from day 1 to 169 , salmeterol was associated with a higher decline in average FEV1 and FVC ( 0 - 12h ) ( difference from placebo : -36 and -115 ml , P < 0.05 ) , which was most prominent over the 8 - 12 h period ( difference from placebo : -45 and -138 ml , P < 0.01 ) . Significant declines in peak FVC relative to placebo ( -83 ml , P < 0.05 ) but not FEV1 ( -12ml ) were observed with salmeterol . Tiotropium was associated with further improvements in spirometry from days 1 to 15 and no evidence of tolerance from day 15 to the end of the trial . In conclusion , tolerance to pharmacologic bronchodilation occurs with long-acting beta-agonists such as salmeterol and not with inhaled anticholinergics [16698259] INTRODUCTION Use of maintenance bronchodilator therapy is currently recommended in symptomatic patients with Chronic obstructive pulmonary disease ( COPD ) and in those with Stage II or greater COPD as defined by the Global Initiative for Chronic Obstructive Lung Disease ( GOLD ) . Because no prospect i ve data describe when rescue therapy alone is insufficient or the optimal time to start maintenance therapy , it is unclear whether maintenance therapy has benefits in milder disease . To explore potential benefits we asked : Does once-daily tiotropium improve lung function , health status , and /or symptoms in " undertreated " COPD patients ( i.e. , those who are not receiving maintenance bronchodilator therapy ) or patients considered by their health care providers as having milder disease ? METHODS A post-hoc analysis of data from COPD patients participating in two , 1-year , placebo-controlled trials with tiotropium was performed . Patients were defined as " undertreated " if they received no respiratory medication or only as-needed short-acting beta-agonists prior to enrollment . Measures included serial spirometry , Transition Dyspnea Index ( TDI ) , and St. George 's Respiratory Question naire ( SGRQ ) . RESULTS Of 921 patients enrolled , 218 ( 23.7 % ) were " undertreated " : 130 received tiotropium ; 88 received placebo . Demographics for the two treatment groups were comparable . Tiotropium-treated patients had significantly improved forced expiratory volume in 1s ( FEV1 ) and forced vital capacity ( FVC ) compared with patients using placebo on all study days . Additionally , TDI and SGRQ scores significantly improved with tiotropium compared with placebo . CONCLUSIONS Once-daily tiotropium provides significant improvement in lung function , health status , and dyspnea when used as maintenance therapy in undertreated COPD patients who were not previously receiving maintenance bronchodilator therapy [21539680] BACKGROUND AND OBJECTIVE Studies in respiratory diseases other than chronic obstructive pulmonary disease suggest potentially differing responses to medications among patients from different regions . We report a subgroup analysis of patients recruited to Asian centres from a previously reported 4-year COPD trial . METHODS Subgroup analysis from a r and omized , double-blinded , placebo-controlled trial of tiotropium 18 µg daily in COPD . Primary end-point was rate of decline in FEV(1 ) . Secondary end-points included spirometry at individual time points , health-related quality of life ( St George 's Respiratory Question naire ) , exacerbations and mortality . RESULTS Of 5992 patients , 362 were from Asian centres ( 100 from Japan ) . Mean age 66 years , 95 % men , 13 % current smokers , BMI : 21 kg/m(2 ) ; post-bronchodilator FEV(1 ) : 44 % predicted ; St George 's Respiratory Question naire total score : 44 units . No treatment effect was observed for rate of decline in FEV(1 ) although annual decline was less in Asian patients . Morning pre-bronchodilator FEV(1 ) and forced vital capacity improved in Asian patients ( P < 0.05 ) . Tiotropium reduced number of exacerbations ( rate ratio ( 95 % confidence interval ( CI ) ) : 0.73 ( 0.57 - 0.94 ) ) . Hazard ratios ( 95%CI ) for exacerbations and hospitalized exacerbations ( tiotropium/control ) were 0.81 ( 0.62 - 1.05 ) and 0.85 ( 0.61 - 1.19 ) , respectively . St George 's Respiratory Question naire total score improved by 1.5 - 6.1 units ( P < 0.05 for months 18 , 24 , 30 and 36 ) with tiotropium . Fatal events occurred in 34 tiotropium ( 18.5 % ) and 42 control ( 23.6 % ) patients . CONCLUSIONS In COPD patients from Asia , tiotropium improves lung function , improves health-related quality of life and reduces exacerbations over 4 years of treatment [19592475] BACKGROUND The clinical trial safety data base for tiotropium has been augmented with a 4-year trial in patients with COPD , which provides an opportunity to better evaluate the cardiovascular ( CV ) profile of tiotropium . METHODS Trials with the following criteria were considered : > or = 4 weeks , r and omized , double-blind , parallel-group , placebo-controlled . Inclusion /exclusion criteria were similar , including spirometry-confirmed COPD , > or = 10 pack-year smoking , and age > or = 40 years . Adverse events were collected throughout each trial using st and ardized case report forms . Incidence rates ( IRs ) were determined from the total number of patients with an event divided by total time at risk . Rate ratios ( RRs ) and 95 % CI for tiotropium/placebo were calculated . IRs were determined for all-cause mortality and selected CV events , including a composite CV end point encompassing CV deaths , nonfatal myocardial infa rct ion ( MI ) , nonfatal stroke , and the terms sudden death , sudden cardiac death , and cardiac death . RESULTS There were 19,545 patients r and omized : 10,846 ( tiotropium ) and 8,699 ( placebo ) from 30 trials . Mean FEV(1 ) = 1.15 + /- 0.46 L ( 41 + /- 14 % predicted ) , 76 % men , mean age = 65 + /- 9 years . Cumulative exposure to study drug was 13,146 ( tiotropium ) and 11,095 ( placebo ) patient-years . For all-cause mortality , the IR was 3.44 ( tiotropium ) and 4.10 ( placebo ) per 100 patient-years ( RR [ 95 % CI ] = 0.88 [ 0.77 - 0.999 ] ) . IR for the CV end point was 2.15 ( tiotropium ) and 2.67 ( placebo ) per 100 patient-years ( RR [ 95 % CI ] = 0.83 ( 0.71 - 0.98 ] ) . The IR for the CV mortality excluding nonfatal MI and stroke was 0.91 ( tiotropium ) and 1.24 ( placebo ) per 100 patient-years ( RR [ 95 % CI ] = 0.77 [ 0.60 - 0.98 ] ) . For total MI , cardiac failure , and stroke the RRs ( 95 % CI ) were 0.78 ( 0.59 - 1.02 ) , 0.82 ( 0.69 - 0.98 ) , and 1.03 ( 0.79 - 1.35 ) , respectively . CONCLUSION Tiotropium was associated with a reduction in the risk of all-cause mortality , CV mortality , and CV events [18060091] BACKGROUND Patients with chronic obstructive pulmonary disease ( COPD ) who smoke have a greater annual rate of decline in forced expiratory volume in 1 s ( FEV(1 ) ) than those patients who have stopped smoking . OBJECTIVES To assess the effect of tiotropium on pre-dose ( trough ) FEV(1 ) in patients with COPD followed in Canada . METHODS A total of 913 patients were r and omly assigned to receive either tiotropium 18 mug once daily ( n=608 ) or placebo ( usual care minus inhaled anticholinergics ) ( n=305 ) for 48 weeks in the present r and omized , double-blind , parallel-group study . The effect of tiotropium on measurements of lung function ( FEV(1 ) , FEV(6 ) and forced vital capacity ) , symptoms , health-related quality of life ( St George 's Respiratory Question naire ) and exacerbations were examined . RESULTS Tiotropium improved trough FEV(1 ) in both current and ex-smokers compared with placebo . Baseline FEV(1 ) in smokers and ex-smokers was 1.03 L and 0.93 L , respectively ( P<0.001 ) . At week 48 , the mean difference between the tiotropium and placebo groups was 0.14+/-0.04 L ( P<0.001 ) in the smoker group and 0.08+/-0.02 L ( P<0.0001 ) in the ex-smoker group . Tiotropium also significantly improved trough forced vital capacity and FEV(6 ) compared with placebo throughout the treatment period ( P<0.05 , for all ) . Furthermore , tiotropium significantly improved the St George 's Respiratory Question naire total score compared with placebo at week 48 ( 40.9 versus 43.7 units , P<0.005 ) . CONCLUSIONS Compared with the placebo group , tiotropium provides sustained improvements in lung function in patients with COPD , with improvements for smokers and ex-smokers [21159499] STUDY OBJECTIVE Novel evaluation of protective effect of tiotropium against induced dynamic hyperinflation ( DH ) during metronome paced hyperventilation ( MPH ) in moderate COPD . METHODS Prospect i ve , r and omized , double-blind , placebo control , crossover study . Lung function measured pre/post MPH at 30 breaths/min for 20 s in 29 ( 18 M ) COPD patients ( GOLD Stage 2 ) age 70±9 yr ( mean ± SD ) before and after 30 days of 18 μg tiotropium bromide vs placebo . Lung CT scored for emphysema ( ES ) . RESULTS At baseline post 180 μg aerosolized albuterol sulfate , FEV(1 ) : 1.8±0.6 L ( 69±6 % pred ) and ≥60 % predicted in all , and 14 of 29 had FEV(1 ) ( L ) ≥70 % predicted with FEV(1)/FVC 58±8 % . After 29 days + 23 h post tiotropium ( trough ) there was significant decrease only in FRC/TLC% ( p=0.04 ) ; after 30 days + 2 h post tiotropium ( peak ) significant increase only in FEV(1 ) ( L ) ( p=0.03 ) compared to placebo . Results post MPH induced DH at baseline and after 30 days and 2 h post placebo or tiotropium were similar with decrease in IC 0.44±0.06 L ( p<0.001 ) . Correlation between ES and increased FEV(1 ) ( L ) at peak tiotropium : r=0.19 , p=0.96 and decreased FRC/TLC% at trough tiotropium : r=-0.26 , p=0.36 . CONCLUSION In moderate COPD , tiotropium did not reduce MPH induced DH and reduction in IC . However , at peak tiotropium , there was significant bronchodilation in FEV(1 ) ( L ) and at trough a decrease in FRC/TLC% compared to placebo despite varying emphysema [16484769] Background : Chronic obstructive pulmonary disease ( COPD ) is characterized by airflow limitation , which results in the progressive development of dyspnea and exercise limitation . Objective and Methods : To compare the effect of tiotropium with placebo on forced vital capacity ( FVC ) in patients with moderate-to-severe COPD and lung hyperinflation , using exercise endurance , dyspnea and health-related quality of life ( HRQoL ) as secondary endpoints . One hundred patients were r and omized to receive either tiotropium 18 µg once daily or placebo for 12 weeks . Results : Trough ( predose ) FVC was significantly improved with tiotropium compared to placebo on day 42 ( 0.27 ± 0.08 liters ) and 84 ( 0.20 ± 0.08 liters ; p < 0.05 for both ) . Trough inspiratory capacity ( IC ) was also significantly improved with tiotropium compared to placebo on day 42 ( 0.16 ± 0.07 liters ) and 84 ( 0.15 ± 0.07 liters ; p < 0.05 for both ) . Tiotropium increased the mean distance walked during the shuttle walking test by 33 ± 12 ( day 42 ) and 36 ± 14 m ( day 84 ) compared to placebo ( p < 0.05 for both ) . On day 84 , 59 % of the patients in the tiotropium group and 35 % of the patients in the placebo group had significant and clinical ly meaningful improvements in the St. George ’s Respiratory Question naire total score ( p < 0.05 ) . Numerical decreases in the focal score in the Transition Dyspnea Index in patients receiving tiotropium versus placebo suggest that tiotropium also improved dyspnea during activities of daily living . Conclusion : Tiotropium 18 µg once daily reduced hyperinflation with consequent improvements in walking distance and HRQoL in patients with COPD and lung hyperinflation [2528216] Background Improvements in ventilatory mechanics with tiotropium increases exercise tolerance during pulmonary rehabilitation . We wondered whether tiotropium also increased physical activities outside of pulmonary rehabilitation . Methods COPD patients participating in 8 weeks of pulmonary rehabilitation were studied in a r and omized , double-blind , placebo-controlled trial of tiotropium 18 μg daily ( tiotropium = 47 , placebo = 44 ) . Study drug was administered for 5 weeks prior to , 8 weeks during , and 12 weeks following pulmonary rehabilitation . Patients completed a question naire documenting participation in pre-defined activities outside of pulmonary rehabilitation during the 2 weeks prior to each visit . Patients who su bmi tted an activity question naire at week 4 and on at least one subsequent visit were included in the analysis . For each patient , the number of sessions was multiplied with the duration of each activity and then summed to give overall activity duration . Results Patients ( n = 46 ) had mean age of 67 years , mean baseline FEV1 of 0.84 L ( 33 % predicted ) . Mean ( SE ) increase in duration of activities ( minutes during 2 weeks prior to each visit ) from week 4 ( prior to PR ) to week 13 ( end of PR ) was 145 ( 84 ) minutes with tiotropium and 66 ( 96 ) minutes with placebo . The increase from week 4 to week 25 ( end of follow-up ) was 262 ( 96 ) and 60 ( 93 ) minutes for the respective groups . Increases in activity duration from week 4 to weeks 17 , 21 , and 25 were statistically significant with tiotropium . No statistical differences over time were observed within the placebo-treated group and differences between groups were not significant . Conclusions Tiotropium appears to amplify the effectiveness of pulmonary rehabilitation as seen by increases in patient self-reported participation in physical activities [16761228] BACKGROUND Aim of this study was to evaluate the efficacy of inhaled Tiotropium bromide in COPD patients of different severities in pneumological practice s during a three months clinical trial . METHODS A r and omized , double blind , placebo controlled study including COPD - patients ( FEV1/FVC < 70 % , FEV1 < or = 70 % predicted ; age > or = 40 years ; > or = 10 pack years ) of different severities was performed . The efficacy of 18 microg Tiotropium bromide once daily on lung function and exacerbations over 12 weeks was evaluated by respective pulmonary function tests ( spirometry ) before ( trough value ) and 2 hours after inhalation of study medication . RESULTS 1639 patients ( 1236 Tiotropium bromide , 403 placebo ; FEV1 reversibility after 200 microg Ipratropium bromide + 200 microg Fenoterol : 7.9 + /- 7.5 % predicted [ mean + /- sd ] ) were r and omized . After 12 weeks of treatment Tiotropium bromide led to significant increases of trough FEV1 ( 23 - 24 h after last inhalation ; + 79 + /- 17 ml ) , and 2 h after Tiotropium bromide inhalation ( + 128 + /- 19 ml ) ( all values vs. placebo , adjusted mean + /- se , p < 0.0001 ) . FVC and IVC were also improved significantly . In mild COPD ( FEV1 > or = 50 - 70 % ) improvements were most pronounced ( trough FEV1 + 113 + /- 29 ml , 2 h post-inhalation + 181 + /- 33 ml ; all values vs. placebo . , p < 0.0001 ) . 14.6 % of patients treated with Tiotropium bromide had a COPD exacerbation vs. 19.9 % of patients treated with placebo ( p = 0.0151 ) . The time to first exacerbation was prolonged ( p = 0.0092 vs. placebo ) . CONCLUSION Tiotropium bromide 18 microg once daily led to a persistent improvement of lung function and a reduction of exacerbations in patients with COPD of different severities [19729663] RATIONALE In the 4-year UPLIFT trial , tiotropium improved lung function and health-related quality of life and decreased exacerbations compared with usual respiratory medications except inhaled anticholinergics in patients with chronic obstructive pulmonary disease ( COPD ) . Mortality and its causes was a secondary endpoint in UPLIFT . OBJECTIVES We describe the effect of tiotropium on survival and analyze differences between mortality during treatment and during follow-up of discontinued patients . METHODS This study involved a r and omized , double-blind trial comparing tiotropium with placebo in patients with COPD ( > or=40 yr of age ; postbronchodilator FEV(1 ) < or=70 % ; FEV(1)/FVC < or=70 % ) . Mortality was evaluated during treatment and with follow-up of discontinued patients . Cause of death was adjudicated by an endpoint committee . MEASUREMENTS AND MAIN RESULTS A total of 5,993 patients were r and omized , 3,006 to placebo and 2,987 to tiotropium . While patients were receiving treatment , there were 792 deaths , with a lower risk in the tiotropium group ( hazard ratio , 0.84 ; 95 % confidence interval [ CI ] , 0.73 - 0.97 ) . Statistical significance was observed at the end of the protocol -defined treatment period ( P = 0.034 ) but not 30 days thereafter ( P = 0.086 ) . Adjustment by GOLD stage , sex , age , baseline smoking behavior , and baseline respiratory medications subgroups did not alter the results of the analysis . The most common causes of death adjudicated by an independent end-point committee were lower respiratory , cancer , general disorders , and cardiac disorders . The hazard ratios for lower respiratory and cardiac mortality during treatment were 0.86 ( 95 % CI , 0.68 - 1.09 ) and 0.86 ( 95 % CI , 0.75 - 0.99 ) , respectively . CONCLUSIONS Treatment with tiotropium over 4 years is associated with decreased mortality , with the effect being most prominent in the cardiac and respiratory systems [12725879] Ths object of this study was to examine validity , meaningful effect sizes , and patterns of response of the Transition Dyspnea Index ( TDI ) in a clinical trial cohort of chronic obstructive pulmonary disease ( COPD ) patients . The design was a retrospective analysis of data from a r and omized , double-blind placebo-controlled clinical trial . We analyzed fifty clinical investigation sites in United States . There were 921 patients with stable COPD . Tiotropium 18 microg dry powder or matching placebo was used . Patients were allowed to remain on usual care less ipratropium bromide . Construct validity was demonstrated by significant correlations ( P < .05 ) between Baseline Dyspnea Index ( BDI ) and other baseline measures , as well as between TDI and changes in other measures at the end of 1 year . Concurrent validity was observed by the significant correlation between TDI and dyspnea diary responses . Changes in TDI focal score were in the range of one unit when the group was stratified by a minimal change in the physician 's global evaluation . Significantly less ( P < .05 ) supplemental albuterol was observed in the group of responders defined by a one-unit improvement in TDI . Responders also had few exacerbations and better health status . The validity of the TDI is supported in a large clinical trial setting . A one-unit change in the TDI focal score represented the minimal important difference [18536860] AIMS Evaluation of tiotropium efficacy in patients with mild chronic obstructive pulmonary disease ( COPD ) defined by the 2003 Swedish Society of Respiratory Medicine guidelines ( post-bronchodilator FEV1/FVC < 70 % ; FEV1 > 60 % predicted ) . METHODS In this 12-week , r and omised , double-blind , placebo-controlled study of tiotropium 18 mcg once daily versus placebo , respiratory function was assessed on Days 1 , 15 and 85 ( baseline : pre-dose Day 1 ) . RESULTS Mean+/-SD baseline FEV1 ( % predicted ) was 73.4+/-12.5 ( tiotropium , n=107 ; placebo , n=117 ) . Tiotropium significantly improved change from baseline in area under the curve from pre-dose to 2 hours post-dose ( AUC0 - 2 h ) FEV1 versus placebo , by 166+/-26 mL ( mean+/-SE ) at study end ( p<0.0001 ) . With tiotropium , there were significant increases in the change in AUC0 - 2 h FVC versus baseline , and trough FEV1 and FVC , versus placebo , on all test days ( p<0.01 ) . Adverse event rates were similar . CONCLUSION Compared with placebo , tiotropium improved lung function in patients with mild COPD [19317104] The UPLIFT study ( Underst and ing Potential Long-term Impacts on Function with Tiotropium ) was a double-blind , r and omised , international , multicentric , placebo-controlled clinical trial , investigating with tiotropium ( Spiriva ) the change in the annual rate of decline in FEV1 in chronic obstructive pulmonary disease ( COPD ) . Secondary end points included COPD exacerbation rate with or without hospitalisation , lung function , quality of life and mortality . 5.993 patients were r and omized . In this article , we briefly describe the most important results of the study . While tiotropium did not alter the annual rate of decline in FEV1 ( pre and postbronchodilatation ) , it improved lung function and quality of life , and reduced exacerbations and hospitalisations by comparison with control for up to 4 years . Tiotropium also reduced respiratory and cardiac morbidity [20620037] In this r and omised double-blind study , patients > or=40 years old with COPD , a smoking history of > or=10 pack-years , a pre-bronchodilator FEV(1 ) of < or=60 % predicted and an FEV(1)/FVC of < or=70 % received tiotropium 5 microg or placebo via Respimat inhaler once daily for 48 weeks . Other medications were permitted except inhaled anticholinergics . Co- primary endpoints were trough FEV(1 ) and the time to first exacerbation . Adverse events were followed and vital status regularly assessed . In all , 3991 patients ( mean age , 65 years [ SD , 9 years ] ) were evaluable . Mean baseline FEV(1 ) was 1.11 L ( 0.40 L ) or 40 % ( 12 % ) of predicted normal . Adjusted mean differences in trough FEV(1 ) and trough FVC at Week 48 ( tiotropium minus placebo ) were 102 and 168 ml respectively ( p < 0.0001 , both ) . Tiotropium delayed time to first exacerbation relative to placebo ( hazard ratio [ HR ] , 0.69 [ 95 % CI , 0.63 - 0.77 ] ) and time to first hospital-treated exacerbation ( HR , 0.73 [ 0.59 - 0.90 ] ) . SGRQ score at Week 48 was 2.9 units lower with tiotropium ( p < 0.0001 ) . Adverse and serious adverse events were balanced across treatment groups and similar in profile to previous tiotropium trials . The rate ratio for a major adverse cardiovascular event during the treatment period + 30 days was 1.12 ( 0.67 - 1.86 ) . By the end of planned treatment ( Day 337 ) 52 patients on tiotropium ( incidence rate per 100 years , 2.94 ) and 38 on placebo ( 2.13 ) had died ( HR = 1.38 [ 0.91 - 2.10 ] ; p = 0.13 ) . Lung function , exacerbations and quality of life were improved by tiotropium 5 microg Respimat but a numerical imbalance was seen in all-cause mortality . The protocol is registered on the European Clinical Trials Data base as trial number 2006 - 001009 - 27 and in the Clinical Trials.gov data base as NCT00387088 [12114338] BACKGROUND Tiotropium , a once-daily anticholinergic , and salmeterol represent two inhaled , long-acting bronchodilators from different pharmacologic classes . A trial was design ed to examine the efficacy and safety of both compounds with multiple outcome measures , including lung function , dyspnea , and health-related quality of life ( HRQoL ) in patients with COPD . METHODS A 6-month , r and omized , placebo-controlled , double-blind , double-dummy , parallel-group study of tiotropium , 18 microg once daily via dry-powder inhaler , compared with salmeterol , 50 microg bid via metered-dose inhaler , was conducted in patients with COPD . Efficacy was assessed by 12-h monitoring of spirometry , transition dyspnea index ( TDI ) , and the St. George 's Respiratory Question naire ( SGRQ ) . RESULTS A total of 623 patients participated ( tiotropium , n= 209 ; salmeterol , n = 213 ; and placebo , n = 201 ) . The groups were similar in age ( mean , 65 years ) , gender ( 75 % men ) , and baseline FEV(1 ) ( mean , 1.08 + /- 0.37 L ; percent predicted , 40 + /- 12 % [ + /- SD ] ) . Compared with placebo treatment , the mean predose morning FEV(1 ) following 6 months of therapy increased significantly more for the tiotropium group ( 0.14 L ) than the salmeterol group ( 0.09 L ; p < 0.01 ) . The average FEV(1 ) ( 0 to 12 h ) for tiotropium was statistically superior to salmeterol ( difference , 0.08 L ; p < 0.001 ) . Tiotropium improved TDI focal score by 1.02 U compared with placebo ( p = 0.01 ) , whereas there was no significant change in TDI focal score with salmeterol ( 0.24 U ) . Tiotropium was superior to salmeterol in improving TDI focal score ( p < 0.05 ) . At 6 months , the mean improvement in SGRQ total score vs baseline was tiotropium , - 5.14 U ( p < 0.05 vs placebo ) ; salmeterol , - 3.54 U ( p = 0.4 vs placebo ) ; and placebo , - 2.43 U. A statistically higher proportion of patients receiving tiotropium achieved at least a 4-U change in SGRQ score compared to patients receiving placebo . Both active drugs reduced the need for rescue albuterol ( p < 0.0001 ) . CONCLUSIONS Tiotropium once daily produces superior bronchodilation , improvements in dyspnea , and proportion of patients achieving meaningful changes in HRQoL compared to twice-daily salmeterol in patients with COPD [17920256] BACKGROUND Chronic obstructive pulmonary disease ( COPD ) and asthma have different diagnostic criteria and treatment paradigms . Both are common and can occur in the same patient . We sought to determine the spirometric effects of tiotropium in COPD patients with concomitant asthma . METHODS A 12-week r and omized , double-blind , placebo-controlled , parallel group trial with tiotropium 18 mcg daily was performed . Patients continued usual respiratory medications except for inhaled anticholinergics . INCLUSION CRITERIA Physician diagnosis of COPD and asthma , age > or= 40 years , smoking > 10 pack years , post-bronchodilator forced expiratory volume in 1s ( FEV(1))<80 % predicted , FEV(1)/forced vital capacity (FVC)<70 % , > or= 12 % , and > or= 200 ml increase in FEV(1 ) following inhaled bronchodilator , treatment with inhaled steroids > or= 1 year . Spirometry was measured serially for 6h on days 1 , 29 and 85 . RESULTS Four hundred and seventy-two patients were r and omized . Baseline characteristics were balanced . Mean age=59.6 years , 61.4 % were men , and FEV(1)=1.55l ( 53.0 % predicted ) . Improvements at 12 weeks with tiotropium were observed for the primary endpoint FEV(1 ) area under the curve ( AUC ) from 0 to 6h ( difference=186+/-24 ml , p<0.001 ) and for morning pre-dose FEV(1 ) ( difference=98+/-23 ml , p<0.001 ) . Significant differences in favor of tiotropium were observed for pre-dose FVC ( difference=128+/-34 ml , p<0.001 ) and FVC AUC 0 - 6h ( difference=232+/-35 ml , p<0.001 ) . Compared to baseline , the mean weekly number of daily puffs of prn salbutamol was reduced by 0.05+/-0.12 puffs/day in the placebo group and by 0.50+/-0.12 puffs/day in the tiotropium group at week 12 ( p<0.05 ) . CONCLUSIONS Patients with COPD and concomitant asthma achieve spirometric improvements with tiotropium along with symptomatic benefit as seen by reduced need for rescue medication [20724131] Whilst recent large-scale studies have provided much evidence on the natural history and therapeutic response in patients with chronic obstructive pulmonary disease ( COPD ) , relatively little is known about the effect in younger patients . We report a pre-specified post-hoc analysis of 356 patients with COPD ≤ 50 years old from the four year r and omised , double blind placebo controlled Underst and ing Potential Long Term Impact on Function with Tiotropium ( UPLIFT ) trial . Inclusion criteria included a post-bronchodilator forced expiratory volume in 1 s ( FEV(1 ) ) of ≤70 % , FEV(1)/FVC < 0.70 , age ≥40 years , and smoking history of ≥10 pack years . Younger patients had a mean FEV(1 ) of 1.24 L ( 39 % predicted ) and an impaired health-related quality of life ( St. George 's Respiratory Question naire ( SGRQ ) ) compared to the entire UPLIFT population . There were 40.2 % women and 51.1 % current smokers in the younger age group . Tiotropium was associated with a sustained improvement in spirometry and SGRQ . Mean decline in post-bronchodilator FEV(1 ) was 58 ml/year ( placebo ) vs. 38 ml/year ( tiotropium ) ( p = 0.01 ) . Corresponding values for pre-bronchodilator FEV(1 ) were 41 ml/year ( placebo ) compared with 34 ml/year ( tiotropium ) ( p = 0.34 ) . The hazard ratio ( 95%CI ) for an exacerbation in the younger age group was 0.87(0.68 , 1.13 ) ) . The rate of exacerbations was reduced by tiotropium ( rate ratio ( 95%CI ) = 0.73(0.56 , 0.95 ) ) . Tiotropium result ed in sustained bronchodilation , improved quality of life , and a decreased exacerbation rate in younger patients . Tiotropium also result ed in a significant reduction in the decline in post-bronchodilator FEV(1 ) , suggesting possible disease modification by tiotropium in younger patients with COPD [16144890] Context Tiotropium , a new once-daily inhaled anticholinergic bronchodilator , has been shown to improve lung function in patients with chronic obstructive pulmonary disease ( COPD ) . Previous studies have suggested that it may also decrease the frequency of exacerbations and hospitalizations in these patients . Contribution This r and omized , parallel-group , double-blind , placebo-controlled study in patients with moderate to severe COPD showed a small but statistically significant decrease in the exacerbation rate during the 6-month study period . Caution s The study period was relatively short , and the beneficial effects were modest . The Editors Exacerbations of chronic obstructive pulmonary disease ( COPD ) can lead to costly and clinical ly significant consequences . Proven treatments for exacerbations are only modestly effective ( 1 , 2 ) . Recovery from even mild exacerbations may be protracted ( 3 ) . Frequent exacerbations are associated with impaired quality of life and a more rapid decline in lung function over time ( 4 , 5 ) . Patients with severe exacerbations commonly seek care in emergency departments , and many of these patients are hospitalized . In 2000 , COPD was responsible for 1.5 million emergency department visits and 726000 hospitalizations in the United States ( 6 ) . Economic analyses suggest that hospitalization alone consumes up to 70 % of all medical expenses for patients with COPD ( 7 , 8) . Interventions that reduce the frequency or severity of exacerbations are a highly desirable but poorly met medical need . An expert panel convened by the National Heart , Lung , and Blood Institute assigned a high priority to clinical research that might improve the management of COPD exacerbations ( 9 ) . Tiotropium is a newly developed , once-daily inhaled anticholinergic bronchodilator . Because of its very slow dissociation from muscarinic M3 receptors , 1 inhaled dose produces sustained bronchodilation for at least 24 hours ( 10 ) . In controlled clinical trials , compared with placebo or the short-acting anticholinergic bronchodilator ipratropium , tiotropium improved lung function , dyspnea , and health-related quality of life in patients with COPD ( 11 , 12 ) . An analysis of adverse event reports su bmi tted during those studies suggested that tiotropium might also reduce exacerbation and COPD -related hospitalization rates . Therefore , we design ed a clinical trial to prospect ively test the hypothesis that tiotropium reduces exacerbations and hospitalizations due to COPD . Methods Study Design Our study was a parallel-group , r and omized , double-blind , placebo-controlled trial in patients with moderate to severe COPD conducted at 26 Veterans Affairs medical centers in the United States . The sole intervention was tiotropium given by inhalation once daily . The principal outcomes were the percentage of patients experiencing at least 1 exacerbation and the percentage of patients with at least 1 hospitalization due to a COPD exacerbation during a 6-month treatment period . The protocol is consistent with the principles of Helsinki . The institutional review boards of participating medical centers approved the study . All trial participants provided written informed consent . Patients All men and women receiving medical care at participating Veterans Affairs medical centers were potential study participants . We enrolled enough participants to ensure a minimum of 1800 r and omly assigned patients . Eligibility criteria included an age of 40 years or older , a cigarette smoking history of 10 pack-years or more , a clinical diagnosis of COPD , and an FEV1 of 60 % predicted or less and 70 % or less of the FVC . Exclusion criteria were a clinical diagnosis of asthma , a myocardial infa rct ion within the previous 6 months , a serious cardiac arrhythmia or hospitalization for heart failure within the previous year , known moderate to severe renal impairment , moderate to severe symptomatic prostatic hypertrophy or bladder-neck obstruction , narrow-angle glaucoma , current radiation or chemotherapy for a malignant condition , or inability to give informed consent . We also excluded patients who took systemic corticosteroids at unstable doses , or in regular daily doses of 20 mg or more of prednisone ( or equivalent ) , or who had not fully recovered from an exacerbation for at least 30 days before the first study visit . We gathered baseline data on respiratory disease and other relevant medical history by question naire . Procedures We allocated eligible patients in equal numbers to receive tiotropium or placebo according to a central ly generated blocked r and omization list . We generated a single r and omization and assigned blocks to centers . We provided r and omly assigned patients with training and detailed instructions on the use of the dry powder inhalation device ( H and iHaler , Boehringer Ingelheim Pharma GmbH & Co. KG , Biberach , Germany ) ( 13 ) . Blinding of supplies was performed at Boehringer Ingelheim before distribution to investigational sites . The double-blind remained in place until all patients were clinical ly complete or until a serious adverse event required unblinding . Each morning during the trial , patients inhaled 1 capsule of tiotropium ( 18 g ) or 1 identical placebo capsule . Participants otherwise received usual medical care , except that they could not take any open-label anticholinergic bronchodilator . They continued taking all other respiratory medications ( including inhaled corticosteroids and long-acting -agonists ) , and primary providers were allowed to prescribe additional medications according to medical need . Primary providers also prescribed antibiotics and systemic steroid prescriptions for exacerbations without restrictions . For purpose s of recall , patients kept a daily diary throughout the treatment period , recording information about specific respiratory symptoms , medications taken for exacerbations , clinic visits , and hospitalizations . We collected information about exacerbations and health care utilization by interviews when patients made site visits at 3 and 6 months and by telephone calls at 1-month intervals between visits . We assessed study drug adherence by query and by counting returned capsules . Participants performed spirometry before and 90 minutes after inhalation of study drug at baseline and again at the 3-month and 6-month visits . We encouraged patients to complete study visits and to provide all requested medical information even if they prematurely discontinued the study drug therapy . However , patients who discontinued the study drug therapy did not have 90-minute postinhalation spirometry testing at subsequent study visits . All open-label bronchodilators and the study drug were withheld overnight before spirometry . Study sites performed spirometry by using a common predictive nomogram with equipment and methods that conformed to American Thoracic Society recommendations ( 14 , 15 ) . Objectives We aim ed to determine whether tiotropium decreased COPD exacerbations and hospitalizations due to exacerbations . Outcome Measures The co primary outcomes were the percentage of patients with a COPD exacerbation and the percentage of patients with a hospitalization due to COPD exacerbation . We defined an exacerbation as a complex of respiratory symptoms ( increase or new-onset ) of more than 1 of the following : cough , sputum , wheezing , dyspnea , or chest tightness with a duration of at least 3 days requiring treatment with antibiotics or systemic steroids , hospitalization , or both . The study team at each site requested discharge summaries for all hospitalizations , wherever they occurred . We identified hospitalizations due to COPD exacerbations from events on case report forms that met the protocol definition of an exacerbation and where review of discharge summaries and other available medical records indicated that the event result ed in a hospitalization . We also considered an event to be a hospitalization if a patient was held and treated for an acute respiratory condition in an urgent care department or in an observation unit for longer than 24 hours . Admissions to nursing homes or other extended care facilities were not considered hospitalizations . Secondary outcomes included time to first COPD exacerbation and time to first hospitalization due to COPD exacerbation , the frequencies of exacerbations and of exacerbation-related health care utilization ( hospitalizations , hospitalization days , unscheduled clinic visits , antibiotic treatment days , and systemic corticosteroid treatment days ) , the frequencies of all-cause hospitalizations and hospitalization days , and results of spirometry . Statistical Analysis We analyzed the data by using a modified intention-to-treat principle . Therefore , we included all available data for the patients with any follow-up contact who took at least 1 capsule of study drug in the analysis up to their first event ( for the time-to-event end points ) or their withdrawal from the trial . For the time-to-event end points , we censored patients without an event at the end of their participation in the trial . Although we intended to follow all patients for the full 6 months , some patients were lost to follow-up . We h and led missing data by using longitudinal data analysis methods ( spirometry ) , analysis of observed data only ( number of events ) , or analysis methods for censored data ( time-to-event data ) . For the percentage of patients with an event , we considered that patients who discontinued the study drug therapy before having an event did not have an event . We analyzed the co primary end points by using a CochranMantelHaenszel test with center as a stratum . We used a stepwise procedure to test the percentage of patients with an exacerbation and , if rejected , to test percentage of patients with a hospitalization due to COPD exacerbation , each at a 2-sided level of 0.05 . Because of the prespecified closed testing procedure , no adjustment for multiplicity was required . We calculated that a sample size of 1800 patients would have 80 % power to Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Pharmacological therapy for chronic obstructive pulmonary disease ( COPD ) is aim ed at relieving symptoms , improving quality of life and preventing or treating exacerbations . Treatment tends to begin with one inhaler , and additional therapies are introduced as necessary . For persistent or worsening symptoms , long-acting inhaled therapies taken once or twice daily are preferred over short-acting inhalers . Several Cochrane review s have looked at the risks and benefits of specific long-acting inhaled therapies compared with placebo or other treatments . However for patients and clinicians , it is important to underst and the merits of these treatments relative to each other , and whether a particular class of inhaled therapies is more beneficial than the others . OBJECTIVES To assess the efficacy of treatment options for patients whose chronic obstructive pulmonary disease can not be controlled by short-acting therapies alone . The review will not look at combination therapies usually considered later in the course of the disease . How does long-term efficacy compare between different pharmacological treatments for COPD ? 2 . Are there limitations in the current evidence base that may compromise the conclusions drawn by this network meta- analysis ? If so , what are the implication s for future research ? AUTHORS ' CONCLUSIONS This network meta- analysis compares four different classes of long-acting inhalers for people with COPD who need more than short-acting bronchodilators . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

12917970

[6218645] Eight patients with exercise-induced asthma participated in a single-blind trial comparing the protective effects of inhaled lignocaine ( estimated dose 48 mg ) , sodium cromoglycate ( estimated dose 12 mg ) , and ipratropium bromide ( estimated dose 120 μg ) . Saline was used as control . Effects were assessed from the mean maximal percentage fall in forced expiratory volume in one second ( FEV1 ) and maximal mid-expiratory flow rates ( MMFR ) after they had run on a treadmill for eight minutes . There was no significant change in baseline FEV1 or MMFR before each agent was given . Saline , lignocaine , and sodium cromoglycate did not alter the mean baseline FEV1 or MMFR significantly . Ipratropium caused bronchodilatation with an increase of 16·3 % in the mean FEV1 ( p<0·001 ) and of 43·4 % in the mean MMFR ( p<0·05 ) . After exercise the maximal percentage falls in FEV1 ( means and SEM ) after saline , lignocaine , sodium cromoglycate , and ipratropium bromide were 38·1 % ( 5·0 ) , 34·5 % ( 6·1 ) , 11·3 % ( 3·7 ) , and 19·3 % ( 7·4 ) respectively . Similarly , the mean maximal falls in MMFR after saline , lignocaine , sodium cromoglycate , and ipratropium bromide were 54·4 % ( 5·2 ) , 52·9 % ( 7·7 ) , 23·6 % ( 6·6 ) , and 32·1 % ( 10·5 ) respectively . The inhibitory effects of sodium cromoglycate and ipratropium bromide were significant whereas lignocaine failed to produce an effect . These results suggest that mediator release is an important factor in exercise-induced asthma and that in some patients the effects of the mediators may be on the postsynaptic muscarinic receptors . Local anaesthesia of sensory vagal receptors , on the other h and , does not prevent exercise asthma and these receptors do not appear to have any important role in exercise-induced bronchoconstriction [2975285] The effects of ipratropium bromide ( 80 and 200 micrograms ) and placebo on the basal bronchial tone and on methacholine-induced bronchoconstriction were investigated in 10 asthmatic patients in a placebo-controlled double-blind manner . Bronchial hyperreactivity to methacholine was confirmed at a pretrial bronchial challenge . The patients were r and omly allocated to two groups in which the drug was inhaled from either metered-dose inhalers ( MDI ) or powder capsules . With the high dosage , the bronchodilation result ing from powder capsules was somewhat more pronounced than that achieved with the MDI . Otherwise the bronchodilator effect of ipratropium bromide and the protection afforded by the drug against methacholine-induced bronchoconstriction were similar in the two groups . In five patients the bronchodilator effect was better and in four patients the tolerance to methacholine was greater after the higher ipratropium dosage than after the lower one . In two patients ipratropium bromide had no bronchodilator effect but gave good protection against methacholine-induced bronchoconstriction . It is concluded that some patients benefit from a dosage of ipratropium bromide higher than that usually recommended and that an anticholinergic effect on the bronchi is possible even in the absence of the bronchodilator effect in the basal state [9708227] BACKGROUND In acute asthma the optimal duration of treatment with combination β agonist and anticholinergic nebuliser solutions is unknown ; most studies have investigated single doses or treatment for up to 12 hours . To determine whether longer treatment with ipratropium bromide might aid recovery a study was undertaken in 106 patients with acute asthma . METHODS A double blind , r and omised , placebo controlled , three group study was performed with all patients receiving ipratropium for 12 hours and salbutamol for 60 hours after admission ( both nebulised four hourly ) , systemic steroids and , if necessary , theophylline . At 12 hours ipratropium was stopped in group I ( n = 35 ) but was continued in the other two groups , and at 36 hours ipratropium was also stopped in group II ( n = 35 ) while patients in group III ( n = 36 ) continued with ipratropium for 60 hours . Spirometric tests were performed before and after salbutamol , and again 30 and 60 minutes after ipratropium or placebo at 12 , 36 and 60 hours . Peak flow rates ( PEFR ) were measured before and after each nebulisation . RESULTS There were no differences between the groups in PEFR on admission ( group I : 214 l/min , group II : 198 l/min , group III : 221 l/min ) , or mean forced expiratory volume in one second ( FEV1 ) at 12 hours ( group I : 1.8 l , group II : 2.0 l , group III : 2.2 l ) , 36 hours ( group I : 2.1 l , group II : 2.3 l , group III : 2.4 l ) , or at 60 hours ( group I : 2.2 l , group II : 2.3 l , group III 2.5 l ) . Despite this , median time to discharge was significantly higher for patients in group I ( 5.4 days ) than for those in groups II ( 4.1 days ) and III ( 4.0 days ) . CONCLUSIONS Combination nebulised therapy can be continued beyond 12 hours and up to 36 hours after admission with improved recovery time . Lung function testing may not reflect the full benefit of treatment [3327703] In order to determine the duration of action of the inhaled anticholinergic agent oxitropium bromide , a controlled study of the effect of pre-treatment with oxitropium bromide 200 micrograms against cholinergic challenge was carried out in ten asthmatic subjects ( 6 children , 4 adults ) . After baseline measurements of lung function ( FEV1 and sGaw ) and methacholine PC20 ( the concentration of methacholine to produce a 20 % fall in FEV1 ) oxitropium bromide or placebo were inhaled double-blind on 2 separate days . Lung function and methacholine PC20 were then measured at 1 , 3 and 6 h post dosing . Oxitropium bromide caused significant protection from methacholine challenge for 6 h ( p less than 0.05 ) [2947462] A multi-center , double-blind , 90-day study compared an ipratropium bromide metered-dose inhaler ( 40 microgram four times a day ) with a metaproterenol metered-dose inhaler ( 1,500 micrograms four times a day ) in 164 patients with asthma ; of the 144 patients who completed the study , 71 received ipratropium and 73 received metaproterenol . Our results suggest that both drugs were equally effective bronchodilators . Although the shape of the pulmonary function response curves suggested that ipratropium has different bronchodilator kinetics than metaproterenol ( in that it has a slower onset of action and a more prolonged duration ) , comparison of the areas under the curves for the two drugs showed that there was no statistical difference between ipratropium or metaproterenol . The only significant side effects noted with ipratropium were cough and exacerbation of symptoms ; no anticholinergic side effects were noted [6236727] Forty-nine asymptomatic asthmatic children who showed exercise induced bronchospasm ( EIB ) , received in a r and omized double-blind fashion one of the four following drugs administered through nebulizer and facial mask : salbutamol 4 mg ( 13 patients ) , disodium chromoglycate 20 mg ( 12 patients ) , ipratroprium bromide 0.4 mg ( 12 patients ) , placebo ( 12 patients ) . They performed exercise fifteen minutes after receiving the drugs and spirometries were done 0 , 5 , 10 , 15 and 20 minutes after the end of the exercise . Bronchodilation was noticed 15 minutes after the administration of salbutamol and ipratroprium bromide but not after cromoglycate or placebo . No patient receiving either salbutamol or cromoglycate had EIB whereas it occurred in 50 % of those receiving ipratroprium bromide and 91.6 % of those receiving placebo [2959208] Thirty seven children with acute asthma were given nebulised ipratropium or placebo 30 minutes after their first dose of salbutamol and eight hourly thereafter . There were no significant differences between the two groups in clinical scores , peak expiratory flow rates , length of stay in hospital , or the need for oral steroids [7226953] Six asthmatic children were studied to determine whether supplemental , parenteral atropine would increase the effects of bronchodilation and protection against exercise-induced bronchoconstriction after maximal effects had been achieved by inhalation . First , we determined the amount of inhaled atropine sulfate that would give maximal bronchodilation for each patient at rest . This quantity of atropine was design ated as " A. " Then all subjects exercised for five sessions with the following pre-exercise treatments in a r and om order : ( a ) inhaled distilled water plus intramuscular ( IM ) saline solution ; ( b ) inhaled A dose of atropine plus IM saline solution ; ( c ) inhaled distilled water plus 0.35 mg IM atropine ; ( d ) inhaled A dose of atropine plus 0.35 mg IM atropine ; and ( e ) inhaled double the A dose plus IM saline solution . The results showed that the combination of inhaled and IM atropine had the greatest bronchodilation effect and the greatest protection against exercise-induced bronchoconstriction . Atropine inhalation alone ( A dose ) or IM injection ( 0.35 mg ) was not as effective in bronchodilation or in alleviation of exercise-induced bronchoconstriction . Doubling the dose of inhalation ( 2A ) did not increase the effects of the A dose . These results support the hypothesis that inhaled atropine does not reach all the airways where cholinergic receptors are present [2951818] Until now very few studies have been performed on the prevention of exercise-induced asthma ( EIA ) in children with ipratropium bromide + fenoterol . This is why we decided to study 30 children aged between 6 and 15 years , whose EIA was confirmed by a test including a 6-min free race on day 1 of the study . The criterion was a decrease of more than 20 % of the basal values of forced expiratory volume in 1 s ( FEV1 ) or FMF . Children whose FEV1 or FMF baseline values were under 60 % of those expected according to Polgard tables were excluded . Three tests were performed , the first to determine EIA , the second was performed 72 h later after inhalation of placebo . 72 h after day 2 the patients returned in order to repeat the test , but this time , aerosol therapy with the combination ipratropium + fenoterol was applied prior to the race . The dosage of the combination was 1 puff of aerosol per 10 kg body weight , up to a maximum of 4 puffs . Each puff of the combination contains 0.02 mg of ipratropium bromide and 0.05 mg fenoterol . Functional assessment of children was carried out by means of forced spirometry . There were no significant differences between the placebo group and the group which received no medication , but there was a significant difference between the treated group and the other two , not only in the FEV1 and FMF values but also in forced vital capacity TEST . ( ABSTRACT TRUNCATED AT 250 WORDS [810767] A number of drugs are known to inhibit exercise-induced asthma ( EIA ) , but the results in some cases have been difficult to interpret due to the techniques employed . A comparative study was carried out in a group of children to investigate the effects of salbutamol , choline theophyllinate , cromolyn sodium , atropine , and placebo . The exercise test took the form of six minutes of st and ardized treadmill running . All the drugs , but not the placebo , were able to inhibit EIA ti a significant degree , the effect being most marked with salbutamol . Cromolyn sodium caused no bronchodilatation at rest , while all the other drugs were brondhocilators , the effect being most marked with the atropine during exercise . It was impossible to distinguish the type of drug used for inhibition of EIA if it caused bronchodilatation at rest . The manner in which an exercise test can be used to investigate the duration of action or site of action of drugs is noted [3792086] Glycopyrrolate , a quaternary ammonium anticholinergic compound is a potentially useful bronchodilator . To determine the efficacy , optimal dose , and duration of action of inhaled glycopyrrolate , we gave the drug to 11 asthmatic patients . Each subject received placebo or glycopyrrolate ( 100 , 200 , 600 , or 1,200 micrograms ) by inhalation in a double-blind , r and omized , crossover design . Measurements included FEV1 , FVC , heart rate , and blood pressure before administration of the drug and periodically for 12 hours . For eight hours following all doses of glycopyrrolate , both FEV1 and FVC ( both as percent of predicted ) were significantly greater for drug than for placebo . Glycopyrrolate may be a useful long-acting drug for the treatment of asthma [6457620] Abstract We have examined the role of cholinergic reflex mechanisms in non-allergic bronchial hyperresponsiveness by examining the effect of pretreatment with ipratropium bromide ( a cholinergic antagonist ) and fenoterol ( a β 2 -adrenergic agonist ) on histamine- and methacholine-induced bronchoconstriction . Twelve adult asthmatics inhaled histamine acid phosphate and methacholine to determine the provocative concentration causing a fall in FEV 1 of 20 % ( PC 20 ) , after double-blind r and omized administration of ipratropium bromide ( 80 μg ) , fenoterol ( 800 μg ) or placebo . Ipratropium increased the mean PC 20 methacholine from 1.12 to 59.67 mg/ml ( P 20 increased from 1.17 to 1.93 mg/ml . This was not statistically significant after correction for any change in base-line FEV 1 . Fenoterol increased the mean PC 20 methacholine from 1.12 to 17.76 mg/ml ( P 20 histamine from 1.17 to 10.61 mg/ml ( P P = 0.001 ) . No such relationship was found with fenoterol and methacholine or with ipratropium and histamine or methacholine . Inhalation of high doses of methacholine appeared to induce late asthmatic responses in four subjects , similar to those observed after inhalation of allergen by sensitized subjects . We conclude that : 1 . 1.|Cholinergic reflex mechanisms are not important in histamine-induced bronchoconstriction or in the pathogenesis of non-allergic bronchial hyperresponsiveness . 2 . 2.|The degree of non-allergic hyperresponsiveness to histamine may be related to the severity of β-receptor dysfunction . 3 . 3.|High concentrations ( doses ) of methacholine may induce responses of the late asthmatic type [8181333] STUDY OBJECTIVE To evaluate the effects of nebulized ipratropium bromide on intraocular pressures and pupillary responses in children with asthma . DESIGN A double-blind , r and omized , crossover study . SETTING Children 's Hospital of Winnipeg , University of Manitoba . PATIENTS OR PARTICIPANTS Age 6 to 17 years with asthma . INTERVENTION Nebulized ipratropium bromide added to albuterol sulfate , albuterol alone , or saline solution was given by face mask and nebulizer . Before and 0.5 h after nebulization , intraocular pressures ( mm Hg ) , pupillary size ( mm ) , and pupillary responses were measured . In a subsequent open study , patients who had been admitted to hospital with acute asthma who were treated with nebulized ipratropium bromide were recruited for measurement of intraocular pressures , pupillary size , and pupillary responses . MEASUREMENTS AND RESULTS Twenty patients completed the double-blind study , and 26 patients completed the open study . There were no changes in intraocular pressures , pupillary size , or pupillary response after any treatment on any study day in either the double-blind or the open studies . CONCLUSION In children with asthma , who have no pre-existing ocular abnormalities , the risk of an adverse reaction to nebulized ipratropium bromide delivered by face mask inadvertently absorbed in the eye is extremely small [9018183] STUDY OBJECTIVE To determine the effect of adding the nebulized anticholinergic drug ipratropium bromide to st and ard therapy compared with st and ard therapy alone for acute severe asthma ( peak expiratory flow rate [ PEFR ] < 50 % of predicted ) in children presenting to the emergency department . METHODS Ninety children aged 6 to 18 years were r and omly assigned to two groups in a prospect i ve , double-blind , placebo-controlled study performed in the ED of an urban children 's hospital . All children received nebulized albuterol solution ( .15 mg/kg ) every 30 minutes , and all received oral steroids with the second dose of albuterol . Children in group 1 received ipratropium bromide ( 500 micrograms/dose ) with the first and third dose of albuterol those in group 2 received saline placebo instead of ipratropium . Pulmonary functions ( PEFR and 1-second forced expiratory volume [ FEV1 ] ) and physiologic measurements were assessed every 30 minutes up to 120 minutes . By chance , the baseline values for percent of predicted PEFR and FEV1 differed between the two groups . Therefore a multivariate model accounting for both time and baseline effects was used to compare the response between groups . RESULTS On average , and adjusting for baseline measures , children in the ipratropium group had a significantly greater improvement in percent of predicted PEFR than did children in the placebo group at 60 minutes ( P = .02 ) , 90 minutes ( P = .002 ) , and 120 minutes ( P < .0001 ) . The improvement in percent predicted FEV1 was significantly greater for children in the ipratropium group only at 120 minutes ( P = .013 ) . Nine children ( 20 % ) from the ipratropium group and 14 ( 31.1 % ) from the control group were admitted ( P = .33 , chi 2 ) . There were no significant adverse effects attributable to the ipratropium , and there was no relation between ipratropium use and changes in pulse , respiratory rate , blood pressure , or oxygen saturation . CONCLUSION We detected significant improvement in pulmonary function studies over 120 minutes in children with severe asthma who were given nebulized ipratropium combined with albuterol and oral steroids , compared with children who received the st and ard therapy . Further study is needed to determine whether early use of ipratropium decreases the need for hospitalization [10213547] BACKGROUND Inhalation therapy with sodium cromoglycate is recommended as the first-line prophylactic treatment for moderate asthma in children . The availability of spacer devices with face-masks has extended the applicability of metered-dose inhalers to younger children . We studied the feasibility and effects of this therapy compared with placebo in children aged 1 - 4 years . METHODS 218 children aged 1 - 4 years with moderate asthma were recruited through 151 general practitioners between March , 1995 , and March , 1996 . They were r and omly assigned sodium cromoglycate ( 10 mg three times daily ) or placebo , given by inhaler with spacer device and face-mask for 5 months . Rescue medication ( ipratropium plus fenoterol aerosol ) was available during the baseline period of 1 month and the intervention period . Parents completed a daily symptom-score list . The primary outcome measure was the proportion of symptom-free days in months 2 to 5 . Analysis was by both intention to treat and on treatment . FINDINGS 167 ( 77 % ) children completed the trial . 131 ( 78 % ) of these children used at least 80 % of the recommended dose . Of the 51 children who stopped prematurely , 23 had difficulties with inhaled treatment . The mean proportion of symptom-free days for both groups was greater for the treatment period than for the baseline period ( 95 % CI for mean difference 5.1 to 17.5 cromoglycate , 11.9 to 23.3 placebo ) . However there were no differences between the sodium cromoglycate and placebo groups in the proportion of symptom-free days ( mean 65.7 [ SD 25.3 ] vs 64.3 [24.5]% ; 95 % CI for difference -8.46 to 5.70 ) or in any other outcome measure . INTERPRETATION Our study in a general practice setting shows that inhalation therapy with a spacer device and face-mask is feasible in a majority of children below the age of 4 years . However , long-term prophylactic therapy with inhaled sodium cromoglycate is not more effective than placebo in this age-group [1535321] Although adenosine-induced bronchoconstriction is mainly due to mast cell mediator release , vagal reflexes have also been implicated in this response . We have investigated the effect of a specific muscarinic-receptor antagonist , ipratropium bromide , on methacholine- and adenosine-induced bronchoconstriction in a r and omized , placebo-controlled , double-blind study of 12 asthmatic subjects . Airway response was evaluated as forced expiratory volume in one second ( FEV1 ) . Inhaled ipratropium bromide ( 40 micrograms ) , administered 20 min prior to bronchoprovocation , increased the provocation dose of inhaled methacholine and adenosine required to reduce FEV1 by 20 % from baseline ( PD20 ) from 0.11 to 0.79 mg ( p less than 0.01 ) and from 0.57 to 1.27 mg ( p less than 0.01 ) , respectively . The mean baseline FEV1 values after administration of ipratropium bromide were significantly higher than after placebo administration ( p less than 0.05 ) . However , there was no correlation between the degree of bronchodilatation and dose-ratios for methacholine and adenosine . The findings of the present study implicate vagal reflexes in the bronchospastic response induced by inhaled adenosine in asthma [2963059] A study was performed to compare the efficacy and safety of two therapeutic regimens for the treatment of children presenting to the emergency department with acute asthma . A regimen of inhaled salbutamol alone was compared to inhaled salbutamol combined with ipratropium bromide . Twenty-five children ranging in age from 5 to 15 years were enrolled in the study . Children with FEV1 less than or equal to 55 % predicted were eligible to participate in the study . Subjects were r and omized in a double-blind fashion into one of two treatment groups . Both groups received an initial dose of salbutamol by nebulizer of 150 micrograms/kg ( 0.03 cc/kg ) , followed by six consecutive doses of 50 micrograms/kg ( 0.01 cc/kg ) at 20-minute intervals . In one group of subjects , 250 micrograms ( 1.0 ml ) of ipratropium bromide respirator solution was added to the salbutamol administered at the time of the initial inhalation , and at 40 and 80 minutes , whereas the remaining subjects received a placebo with salbutamol at those times . Formal one-way statistical ANOVA with change in percent predicted FEV1 as a response variable confirmed there was a statistically significant difference at all time points caused by drug regimen during the 150-minute observation period . There was no significant difference in side effects reported in the two groups . Significant additional bronchodilation achieved with salbutamol and ipratropium bromide together indicates that there is likely a substantial cholinergic element to the bronchospasm observed in acute exacerbations of asthma in the pediatric age group [779554] The ability of atropine to inhibit exercise-induced bronchospasm was evaluated in 18 children with chronic , perennial asthma . In 17 of 18 patients , exercise-induced bronchospasm was blocked by prior inhalation of 0.1 mg per kg of atropine sulfate , administered in a r and omized single blind fashion . In 14 of these 17 patients , significant bronchodilatation occured after the combination of atropine and exercise . Placebo failed to inhibit exercise-induced bronchospasm in any patient . These results suggest that the parasympathetic nervous system has a role in the mediation of exercise-induced bronchospasm in children [2532229] We studied the effects of the anticholinergic ipratropium bromide ( 40 micrograms three times daily ) and the beta-agonist , fenoterol ( 0.2 mg three times daily ) , both administered by powder inhaler , on bronchial hyperresponsiveness ( BHR ) to histamine in children , aged 7 to 15 years with mild stable asthma and limited bronchoconstriction who had a highly increased BHR . The double-blind , r and omized , parallel study was conducted and performed in spring and early summer . BHR and FEV1 were measured on two occasions , before the start of treatment and monthly thereafter for 4 months . Symptoms , peak expiratory flow , and concomitant medication were registered daily . Nine of the 12 patients receiving ipratropium bromide and all eight patients receiving fenoterol completed the study . Patients completing treatment had few symptoms and were in a stable condition throughout the treatment period . Neither the administration of ipratropium bromide nor fenoterol result ed in a significant change of BHR . We concluded that long-term treatment with ipratropium bromide or fenoterol had no effect on BHR in children with mild stable asthma [6230034] Ipratropium ( 40 micrograms ) and theophylline ( oxtriphylline 400 mg ) were administered to 24 asthmatics in a r and omized double-blind placebo controlled trial . The combination of these agents produced additive bronchodilation for up to two hours , with a 23 percent maximal increase in FEV1 . This regimen promises to be safe , effective therapy for patients with asthma [2958950] Thirty one children with asthma were given 40 micrograms of ipratropium bromide and identical placebo by inhalation three times a day in a double blind , r and omised crossover study to test the ability of an anticholinergic drug to modify the diurnal variation in airway calibre and bronchial reactivity . Subjects measured peak expiratory flow rate approximately eight hourly , before and after inhaled salbutamol , for four week periods . Paired t tests and cosinor analysis were used to assess the diurnal variation in airway calibre from the peak expiratory flow rate recorded before salbutamol and to assess the diurnal variation in bronchodilator responsiveness from the increase in peak expiratory flow rate after salbutamol . Maintenance treatment with ipratropium bromide 40 micrograms three times daily reduced the provocative dose of histamine which caused a 20 % fall in FEV1 ( geometric mean PD20 = 0.78 v 0.49 mg/ml , p less than 0.05 ) , despite an eight to 12 hour gap between the last dose of ipratropium and histamine challenge . It did not , however , diminish the diurnal variation in airway calibre ( mean amplitude = 12.7 v 10.1 ) or in bronchodilator responsiveness ( mean amplitude = 62.4 v 63.5 ) . There was no improvement in the clinical state of subjects while they were taking ipratropium bromide [141471] The new anticholinergic compound Sch 1000 ( ipratropium bromide ) has been reported to be an effective bronchodilator without significant atropine-like side effects . We evaluated the effectiveness of different doses of nebulized Sch 1000 ( 40 microgram and 80 microgram ) aerosolized atropine sulfate ( 1 mg ) and placebo in the prevention of exercise-induced bronchospasm ( EIB ) in 20 children with atopic bronchial asthma . A r and om , crossover double-blind protocol was used . St and ard exercise on a cycloergometer was used to induce EIB . Pulmonary function was determined before and after drug administration and exercise . Following no treatment or placebo , exercise result ed in average reductions of 33 % to 43 % in plethysmographic specific airway conductance ( SGaw ) , of 20 % to 25 % in forced expiratory volume in 1 sec ( FEV1 ) , and of 25 % to 32 % in maximal midexpiratory flow rate . Exercise following no treatment or placebo result ed in average increases of 23 % to 30 % in thoracic gas volume ( Vtg ) . Prior to exercise atropine and either dose of Sch 1000 caused significant increases in SGaw ( 48 % to 59 % ) . After pretreatment with Sch 1000 or atropine , exercise caused SGaw to fall to values that were not significantly different from pretreatment medication values , but were significantly higher than values following exercise without pretreatment or after pretreatment with placebo . No significant differences were noted between the effects of atropine and Sch 1000 on EIB . We conclude that at the doses used atropine and Sch 1000 cause equivalent degrees of bronchodilation but neither drug specifically inhibits EIB [2874047] The effect of adding ipratropium bromide to treatment with beta-2-adrenoceptor agonists was studied in 13 asthmatic children in a double-blind cross-over trial . In the acute phase of the study inhalation of salbutamol 0.1 mg/kg followed by inhalation of 0.25 mg of ipratropium bromide was found to improve pulmonary function variables to a significantly greater extent than salbutamol followed by placebo . The combined therapy also provided significantly better protection than salbutamol plus placebo against exercise-induced asthma . Maintenance treatment with ipratropium bromide ( two inhalations four times daily , 20 micrograms per inhalation ) in combination with oral terbutaline and aerosolized salbutamol did not alleviate asthmatic symptoms or pulmonary function variables to a degree beyond that achieved with the beta-stimulants alone . There were no side effects associated with the ipratropium bromide treatment . These data suggest that higher doses of ipratropium bromide than are presently used should be tested for maintenance treatment of chronic asthma [6236576] Isocapnic hyperventilation dose response curves were constructed for 11 asthmatic children before and after pretreatment with placebo or ipratropium bromide , 40 - 1500 micrograms given by inhalation , on three separate days . The response before and after placebo was highly reproducible ( within subject coefficient of variation 7.5 % , 18 % , and 22 % for intervals of two hours , within two weeks , and over two weeks ) . It was independent of baseline lung function . Complete protection against hyperventilation induced asthma was achieved by ipratropium bromide 40 micrograms in six children and by 200 micrograms or more in a further four . The remaining child was unaffected by any dose of ipratropium up to 1500 micrograms . The dose of ipratropium required for protection was better related to the subjects ' requirement for regular medication than to their sensitivity to hyperventilation or baseline lung function [2951804] 16 hyperreactive asthmatics were challenged with an ultrasonic mist of H2O at the same time of day on 4 usually consecutive days 2 h after premedication with placebo , fenoterol ( 200 micrograms ) , ipratropium bromide ( 80 micrograms ) and Duovent ( fenoterol 200 micrograms + ipratropium bromide 80 micrograms ) , given in r and om order and double-blind conditions . The challenge test consisted of 3 exposures of 30 , 60 and 120 s with 4-min intervals . Specific airway resistance ( sRaw ) was measured under basal conditions and 1 , 2 and 3 min after each exposure . FEV1 was measured under basal conditions and immediately after the last sRaw measurement . Fenoterol afforded a good protection ; ipratropium bromide alone was ineffective but enhanced the protective effect of fenoterol when the two drugs were given in combination ( Duovent ) . A similar effect was also observed after a second challenge performed 1 h ( 9 patients ) or 3 h ( 6 patients ) after the first one , which was performed 2 h after premedication [2932137] Twenty-four consecutive patients admitted to hospital with severe acute asthma were studied . Eleven were given 10 mg salbutamol by nebulizer followed 2 hours later by 500 micrograms of nebulized ipratropium bromide . These patients had a greater response in PEFR than 13 patients given two doses of 10 mg salbutamol 2 hours apart [6451257] Ipratropium bromide was given to patients admitted to hospital with acute asthma . A cumulative-dose-response technique in six patients showed that 500 micrograms given by nebuliser produced a maximal increase in peak expiratory flow rate . This dose of ipratropium bromide was included in a regimen in which it was given either two hours before or two hours after nebulised salbutamol to 22 patients . Ipratropium bromide given on admission was as effective as nebulised salbutamol . The two drugs in sequence produced greater bronchodilatation than either used alone , and the mean peak expiratory flow rate rose by 96 % in four hours . Thus giving ipratropium bromide in addition to salbutamol in severe asthma enhances the bronchodilator effect . Further studies are needed to determine whether the same effect may be obtained by giving two maximal doses of salbutamol two hours apart [6459045] We studied the effect of ipratropium on exercise-induced bronchoconstriction ( EIB ) at cold or warm temperatures . Although pulmonary function was better with ipratropium , its benefit was related to pre-exercise bronchodilation and not prevention of EIB . Ipratropium did not affect the augmented EIB in cold weather . Therefore , these phenomena are not primarily mediated via cholinergic mechanisms [2936370] Varying doses of nebulized salbutamol , ipratropium bromide and a combination of both were given to 20 asthmatic children . All therapies produced effective bronchodilation . Ten mg salbutamol caused elevation of pulse rate and finger tremor whilst the duration of action of 0.6 mg salbutamol was too short . Dose-response effects were clearly seen with salbutamol but not with ipratropium bromide . A summation effect was not demonstrated when the medications were combined [2958282] Fifteen children with exercise-induced asthma ( EIA ) participated in a double-blind trial comparing the protective effects of inhaled sodium cromoglycate ( 20 mg/2ml ) , ipratropium bromide ( 500 μg/2ml ) and verapamil ( 5 mg/2ml ) . Saline was used as control . There was no significant difference in base line pulmonary function before and after the administration of each agent . After exercise the maximal percentage fall in the forced expiratory volume in 1 s ( FEV-1 ) ( means and SD ) were 40.9±17.2 after inhalation of saline , 15.3±11.7 after sodium cromoglycate , 36.2±21.4 after verapamil and 21.7±17.7 after ipratropium bromide . The inhibitory effects of sodium cromoglycate and ipratropium bromide were significant whereas verapamil failed to produce any effect . To see if a double dose of verapamil is more effective , nine different children with EIA were provoked by the same st and ardized treadmill running after giving a placebo ( 4 ml saline ) and after verapamil ( 10 mg in 4 ml ) . Despite the double dose , again verapamil was ineffective even though the protection index doubled that obtained with the lower dose . The results suggest that the calcium antagonist ( verapamil ) had almost no effect on the prevention of EIA in the children studied [123712] Atropine is known to be an effective bonrchodilator . We studied the effectiveness of aerosol Sch 1000 , a derivative of atropine , in relieving bronchoconstriction in asthma . A single dose of drug was effective within 5 min , and the effect had a duration of 4 hours . No side effects were noted . The major effect of the drug appeared to be in large airways [10103297] Objective . To determine if the addition of ipratropium bromide to the emergency department ( ED ) treatment of childhood asthma reduces time to discharge , number of nebulizer treatments before discharge , and the rate of hospitalization . Methods . Patients > 12 months of age were eligible if they were to be treated according to a st and ardized ED protocol for acute asthma with nebulized albuterol ( 2.5 mg/dose if weight < 30 kg , otherwise 5 mg/dose ) and oral prednisone or prednisolone ( 2 mg/kg up to 80 mg ) . Subjects were r and omized to receive either ipratropium ( 250 μg/dose ) or normal saline ( 1 mL/dose ) with each of the first three nebulized albuterol doses . Further treatment after the first hour was determined by physicians blinded to subject group assignment . Records were review ed to determine the length of time to discharge home from the ED , number of doses of albuterol given before discharge , and the number of patients admitted to the hospital . Results . Four hundred twenty-seven patients were r and omized to ipratropium or control groups ; these groups were similar in all baseline measures . Among patients discharged from the ED , ipratropium group subjects had 13 % shorter treatment time ( mean , 185 minutes , vs control , 213 minutes ) and fewer total albuterol doses ( median , three , vs control , four ) . Admission rates did not differ significantly ( 18 % , vs control , 22 % ) . Conclusions . The addition of three doses of ipratropium to an ED treatment protocol for acute asthma was associated with reductions in duration and amount of treatment before discharge [2301781] Seventeen hospitalized children with acute asthma , ages 7 to 15 years , were studied to determine the efficacy of simultaneous administration of atropine sulfate and isoetharine . Combination therapy was superior in 11/17 ( 65 % ) patients while isoetharine alone was superior in 4/17 ( 23 % ) patients ( P = .037 ) . We conclude that simultaneous administration of combination therapy is safe and beneficial in some children with acute asthma [154747] In thirteen patients with extrinsic asthma the effects of placebo , sodium cromoglycate , ipratropium bromide , and ipratropium bromide plus sodium cromoglycate were studied in a r and om double-blind fashion to assess their inhibitory action in exercise-induced asthma ( EIA ) . Exercise testing consisted of steady state running on an inclined treadmill for up to eight minutes . In eight of the 13 patients studied the baseline ratio of expiratory flow at 50 % vital capacity ( VC ) breathing helium-oxygen ( V50He ) to V50air was over 1.20 and they were called responders ; the remaining five patients were called non-responders . There was a significantly lower baseline maximum mid-expiratory flow rate ( MMEF ) in non-responders ( P less than 0.02 ) as compared to responders but no difference in forced expiratory volume in one second ( FEV1 ) or forced vital capacity ( FVC ) . Sodium cromoglycate ( P less than 0.02 ) , ipratropium bromide ( P less than 0.01 ) , and ipratropium bromide plus spdium cromoglycate ( P less than 0.01 ) all significantly inhibited the percentage fall in FEV1 after exercise in the responders . Ipratropium bromide had no preventive action on non-responders , unlike sodium cromoglycate ( P less than 0.05 ) and ipratropium bromide plus sodium cromoglycate ( P less than 0.02 ) . It is postulated that mediator release is an important factor in development of EIA in most extrinsic asthmatics , whereas cholinergic mechanisms are relevant only in those patients in whom the main site of airflow obstruction is in the large central airways [2942116] Treatment with nebulised salbutamol or a mixture of salbutamol and ipratropium was given to 138 children . Length of hospital stay and number of nebulised doses required did not differ . In severe asthma response was greater with salbutamol alone . In mild asthma response was greater with combined treatment [10193252] OBJECTIVES To determine whether children with severe acute asthma treated with large doses of inhaled salbutamol , inhaled ipratropium , and intravenous steroids are conferred any further benefits by the addition of aminophylline given intravenously . STUDY DESIGN R and omised , double blind , placebo controlled trial of 163 children admitted to hospital with asthma who were unresponsive to nebulised salbutamol . RESULTS The placebo and treatment groups of children were similar at baseline . The 48 children in the aminophylline group had a greater improvement in spirometry at six hours and a higher oxygen saturation in the first 30 hours . Five subjects in the placebo group were intubated and ventilated after enrolment compared with none in the aminophylline group . CONCLUSIONS Aminophylline continues to have a place in the management of severe acute asthma in children unresponsive to initial treatment [6213382] In two groups of patients , 15 with asthma and 15 with chronic bronchitis , the bronchodilator effects of ipratropium bromide , of fenoterol plus theophylline , and of the combination of the three drugs , were compared using a double-blind , single-dose , placebo-controlled format . Ipratropium bromide caused rapid bronchodilatation which was not significantly different in asthmatic patients and patients with bronchitis ( delta FEV1 = .29 L in one hour in asthmatic patients , .18 L in patients with bronchitis ) . In contrast , fenoterol plus theophylline induced a considerably greater effect in asthmatic patients ( delta FEV1 = .41 L in one hour ) than in those with bronchitis ( delta FEV1 = .07 in one hour ) . The use of the three drugs in combination compared with ipratropium bromide alone , or fenoterol plus theophylline alone , result ed in a significant additional bronchodilatation in asthmatic patients . In the patients with bronchitis , the triple combination was clearly superior to fenoterol plus theophylline . A similar trend was present in comparing the triple combination to ipratropium bromide , but the difference did not reach statistical significance . There was no evidence of synergism when ipratropium bromide was combined with fenoterol plus theophylline in that the total bronchodilator effect was approximately additive . Asthmatic patients and the physician were able to distinguish the triple combination from placebo . No such ability was demonstrated with respect to those with bronchitis . All three drugs were well tolerated . Side effects were mostly mild , and none was related to the use of ipratropium [8497679] Inhaled bronchodilator therapy in young asthmatic children reduces symptoms and improves lung function . After a single dose of therapy , however , lung function may still be abnormal , as evidence d by an elevated function residual capacity ( FRC ) . The aims of this study were to assess if a second dose of bronchodilator therapy result ed in further improvement in lung function and to determine whether additional therapy was more effective if given as a second dose of a beta-adrenergic agonist or if instead an anticholinergic was used . Twenty-one asthmatics ( median age 7.5 years ) received in r and om order on two separate occasions , 1 week apart , either two doses of terbutaline ( 500 micrograms ) or terbutaline plus ipratropium bromide ( 20 micrograms ) . FRC and peak expiratory flow rate ( PEFR ) were measured immediately prior to and then 20 min after each dose of bronchodilator therapy . In the group , overall FRC and PEFR improved after the first and second dose of bronchodilator , regardless of regime used , the response to the second dose , however , was smaller than the first dose . There was no significant difference overall between the two regimes in baseline FRC or PEFR , or FRC and PEFR measured after each dose of bronchodilator . Eight children failed to show a significant change in FRC following two doses of terbutaline , but seven of these eight did have a significant change in FRC in response to the combination of terbutaline and ipratropium bromide . We conclude that a second dose of bronchodilator therapy does further improve lung function . Our results suggest the more efficacious regime consists of a combination of single doses of ipratropium bromide and terbutaline [2951807] Beta 2-adrenergic and anticholinergic drugs have shown an action in modulating bronchial hyperreactivity to various stimuli ( chemical , physical , immunological , pharmacological ) . The aim of our study was to compare the efficacy of a combination of ipratropium bromide and fenoterol ( Duovent ) with the activity of single drugs in the prevention of histamine-induced bronchospasm . Twenty-six atopic asthmatic subjects were examined in a double-blind trial , during an asymptomatic period , with a FEV1 value not lower than 20 % of the predicted normal value . During 4 consecutive days all patients received 2 puffs , respectively , of Duovent ( 200 micrograms fenoterol + 40 micrograms ipratropium bromide ) , fenoterol ( 400 micrograms ) , ipratropium bromide ( 80 micrograms ) and placebo in a r and omized order . PD20 values were evaluated after each drug administration : after 2 h in 16 patients and after 5 h in the other 10 patients . The data were modified to log values , and statistical analysis was performed by two-way analysis of variance . This study showed that Duovent and fenoterol have a protective effect against histamine-induced bronchospasm with a significant increase in the PD20 values 2 h ( p less than 0.01 ) and 5 h ( p less than 0.05 ) after treatment when compared to placebo . Duovent inhalation determined a more protective effect than other drugs but not significantly when compared to fenoterol . Some advantages in the modulation of bronchial reactivity could be seen from using Duovent because with the lower dose of the beta 2-adrenergic drug the same results could be obtained without side-effects [2974463] In a r and omized , double-blind , parallel-group trial , 47 children with acute asthma received a combination of ipratropium bromide solution ( 250 micrograms ) and fenoterol hydrobromide solution ( 625 micrograms ) , fenoterol solution ( 625 micrograms ) alone , or ipratropium solution ( 250 micrograms ) alone , administered by face mask and nebulizer , with the dose repeated 60 minutes later . The groups did not differ significantly with regard to age , pulmonary function at baseline , or any other variable . They were monitored at 30 , 60 , 90 , and 120 minutes by use of a clinical score , oxygen saturation , and pulmonary function tests . At the end of the study , albuterol was administered to assess residual bronchoconstriction . Clinical scores improved significantly after treatment in all groups at all times compared with baseline . The greatest improvement in FEV1 was seen in the patients treated with ipratropium/fenoterol , whether considered as absolute change , change in percent predicted , or percent change from baseline . Ipratropium/fenoterol was significantly better than fenoterol alone only when considered as percent change from baseline . Improvement in flow at mid and low lung volumes was significantly greater for the ipratropium/fenoterol combination than for ipratropium alone ; no significant differences were noted between ipratropium/fenoterol and fenoterol for flow at mid and low lung volumes . Treatment with albuterol did not significantly improve pulmonary function in the groups receiving ipratropium/fenoterol or fenoterol alone , but it did increase flow at all lung volumes in the group receiving ipratropium alone . No patient complained spontaneously of any adverse reactions , and no clinical ly significant changes in heart rate or systolic or diastolic blood pressures occurred . ( ABSTRACT TRUNCATED AT 250 WORDS [1190614] To evaluate the role of the parasympathetic nervous system in the mediation and maintenance of reversible airway obstruction in perennially asthmatic children , we measured pulmonary function in 18 patients before and after the administration of atropine sulfate aerosol . The bronchodilatory effects of atropine were compared with those of isoproterenol hydrochloride and placebo aerosols . Placebo aerosol did not change any of the pulmonary functions tested . Atropine and isoproterenol aerosols improved forced expiratory flows , airway resistance , and specific airway conductance significantly and to the same degree . Hyperinflation was significantly lessened by atropine , but not by isoproterenol . Because atropine is not a direct smooth muscle relaxant , but rather a selective blocker of cholinergically induced smooth muscle tone , any significant improvement in the lung function of chronically asthmatic children by atropine suggests that at least some of their reversible airway obstruction is induced and maintained by parasympathetically mediated bronchial smooth muscle constriction [11148512] OBJECTIVE To determine whether the addition of repeated doses of nebulized ipratropium bromide ( IB ) to a st and ardized inpatient asthma care algorithm ( ACA ) for children with status asthmaticus improves clinical outcome . STUDY DESIGN Children with acute asthma ( N = 210 ) age 1 to 18 years admitted to the ACA were assigned to the intervention or placebo group in r and omized double-blind fashion . Both groups received nebulized albuterol , systemic corticosteroids , and oxygen according to the ACA . The intervention group received 250 microg IB combined with 2.5 mg albuterol by jet nebulization in a dosing schedule determined by the ACA phase . The placebo group received isotonic saline solution substituted for IB . Progression through each ACA phase occurred based on assessment s of oxygenation , air exchange , wheezing , accessory muscle use , and respiratory rate performed at prescribed intervals . RESULTS No significant differences were observed between treatment groups in hospital length of stay ( P = .46 ) , asthma carepath progression ( P = .37 ) , requirement for additional therapy , or adverse effects . Children > 6 years ( N = 70 ) treated with IB had shorter mean hospital length of stay ( P = .03 ) and more rapid mean asthma carepath progression ( P = .02 ) than children in the placebo group . However , after adjustment was done for baseline group differences , the observed benefit of IB therapy in older children no longer reached statistical significance . CONCLUSION The routine addition of repeated doses of nebulized IB to a st and ardized regimen of systemic corticosteroids and frequently administered beta-2 agonists confers no significant enhancement of clinical outcome for the treatment of hospitalized children with status asthmaticus [6455096] The bronchodilator activity in nebulised salbutamol , ipratropium bromide , clemastine , and a placebo was studied in 14 asthmatic children aged between 3 and 5 years . Changes in lung function were monitored by measuring peak expiratory flow rate and total respiratory resistance using a modification of the forced oscillation technique . Ipratropium bromide produced a degree of bronchodilation similar to that of salbutamol , but the bronchodilatory activity of clemastine was not appreciably better than for the placebo [2531051] The effects of nebulized solutions of ipratropium bromide and fenoterol combined were compared with the response to either preparation alone in single dose and longer-term administration in children who had asthma . The combination produced a slightly greater response than either alone , especially in peak expiratory flow . Over a 1-month period , there were no significant differences in symptom scores or lung function parameters between the combination of ipratropium bromide and fenoterol and fenoterol alone in a group of children who had asthma . It is possible that the addition of ipratropium bromide to a sympathomimetic drug may be useful in a subgroup of asthmatics , particularly if there is a considerable large airway contribution to bronchial narrowing [10936118] STUDY OBJECTIVES To assess the safety and efficacy of salmeterol xinafoate as an adjunct to conventional therapy for the in-hospital management of acute asthma . DESIGN A prospect i ve , double-blind , r and omized placebo-controlled trial . SETTING Medical wards of a large university-based hospital . PATIENTS Forty-three patients admitted for an acute exacerbation of asthma . INTERVENTIONS Salmeterol ( 42 microg ) or two puffs of placebo every 12 h in addition to st and ard therapy ( short-acting beta-agonists , corticosteroids , and anticholinergic agents ) . RESULTS No clinical ly adverse effects were seen with the addition of salmeterol to conventional therapy . After salmeterol , there was no difference in pulse , respiratory rate , oxygen saturation by pulse oximetry , severity of symptoms , or dyspnea score . Patients receiving salmeterol had greater FEV(1 ) percent improvements than the placebo group at 12 , 24 , 36 , and 48 h. These findings were not statistically significant . By paired Student 's t tests , there were significant improvements in FEV(1 ) ( p = 0.03 ) and FVC ( p = 0.03 ) in the salmeterol group after 48 h of treatment with no comparable improvement in the placebo group . In a subgroup analysis of patients with an initial FEV(1 ) < or = 1.5 L , the absolute FEV(1 ) percent improvement for salmeterol vs placebo was 51 % vs 16 % at 24 h and 54 % vs 40 % at 48 h. The relative FEV(1 ) percent improvement for salmeterol vs placebo was 17 % vs 8 % at 24 h and 18 % vs 14 % at 48 h. CONCLUSION The addition of salmeterol to conventional therapy is safe and may benefit hospitalized patients with asthma . Further studies are needed to clarify its role in the treatment of acute exacerbation of asthma [8003853] In a r and omized , double-blind , placebo-controlled study , we investigated the protective effects of ipratropium bromide 160 micrograms and 320 micrograms and terbutaline 500 micrograms on ultrasonically nebulized distilled water (UNDW)-induced bronchoconstriction in nine stable asthmatic patients . Both drugs caused a significant increase ( P < 0.001 ) in baseline FEV1 with no significant differences between the drugs or both doses of ipratropium bromide . Pre-inhalation of ipratropium bromide 320 micrograms and terbutaline 500 micrograms inhibited UNDW-induced bronchoconstriction ( P < 0.01 ) , whereas ipratropium bromide 160 micrograms had no protective effect . The protective effects of ipratropium bromide showed a large interindividual variation . There was no correlation between the increase in baseline FEV1 and PD20 UNDW , indicating that the protective effect on UNDW-induced bronchoconstriction is not dependent on the bronchodilation induced by terbutaline and ipratropium bromide . It also appears that the UNDW-induced bronchoconstriction is at least partly vagally mediated [6219156] The role of the anticholinergic drug , ipratropium bromide , in maintenance antiasthmatic therapy was evaluated in a double-blind crossover trial of three bronchodilator regimens : ( 1 ) inhaled ipratropium , placebo , and oral oxtriphylline ; ( 2 ) inhaled fenoterol , placebo , and oral oxtriphylline ; and ( 3 ) both inhaled ipratropium and fenoterol plus oral oxtriphylline . Twenty-two asthmatics were treated with all three regimens , each for 1 mo , allocated in r and om sequence . On the first and last treatment days of each month , spirometric measurements were performed before and 0.5 , 1 , 2 , 3 , 4 , and 6 hr after administration of the test drugs . On the first treatment day of each month , all regimens produced significant bronchodilatation at 30 min after dose , an improvement that declined between 3 and 6 hr after dose . After continuous administration for 1 mo the two combinations employing fenoterol showed a decline in bronchodilator responsiveness from the initial treatment day , measured as the level of response ( V50 ) or duration of response ( FEV1 , VC ) . Ipratropium plus oxtriphylline showed no such decline , suggesting the development of tolerance to long-term administration of fenoterol . Overall benefit at the end of 1 mo , measured as the area under the curves of FEV1 , VC , or V50 vs time after dose , was greatest for the triple drug regimen . There were no differences in heart rate , blood pressure response , or side effects among the three treatments . It is concluded that when the anticholinergic drug ipratropium is administered concurrently with an inhaled beta 2 agonist and an oral theophylline derivative , increased bronchodilatation occurs with no detectable additional side effects [9787684] OBJECTIVES To compare the effectiveness and safety of alternative nebulized drug protocol s in children with mild or moderate asthma exacerbations . METHODS We conducted a blinded , r and omized , controlled trial with a 2 x 2 factorial design . Two interventions , nebulized salbutamol in frequent low doses ( 0.075 mg/kg every 30 minutes ) and the addition of ipratropium bromide ( 250 micrograms ) , were compared with salbutamol in hourly high doses ( 0.15 mg/kg every 60 minutes ) in children with mild or moderate acute asthma . The primary end point was the improvement in respiratory resistance . Secondary end points included oxygen saturation , corticosteroid use , patient disposition , and relapse status . RESULTS A total of 298 participants aged 3 to 17 years were studied , and 15 % were admitted to the hospital ; 14 % of the children had relapses . No increased bronchodilation was associated with frequent low doses versus hourly high doses of salbutamol ( RR = 0.9 [ 95 % confidence interval 0.7 , 1.3 ] ) or the addition of ipratropium bromide versus placebo ( RR = 1.0 [ 0.8 , 1.3 ] ) . No group differences were observed in secondary end points . Salbutamol in frequent low doses was associated with increased vomiting ( RR = 2.5 [ 1.1 , 6.0 ] ) . CONCLUSION Our results do not support the use of frequent low doses of nebulized salbutamol or the addition of ipratropium bromide compared with hourly high doses of salbutamol in children with mild or moderate asthma [7699549] OBJECTIVE The objective of this trial was to determine the efficacy of frequent nebulized ipratropium added to high-dose albuterol therapy in children with severe asthma . METHODS One hundred twenty children ( 5 to 17 years ) of age ) with severe acute asthma ( forced expiratory volume in 1 second ( FEV1 ) , < 50 % of the predicted value ) were enrolled into a r and omized double-blind three-arm placebo-controlled trial comparing three groups : group 1 , three doses of nebulized ipratropium bromide within 60 minutes ( 250 micrograms/dose ) ; group 2 , one dose of ipratropium ; group 3 , no ipratropium . All patients were also treated with three doses of nebulized albuterol within 60 minutes ( 0.15 mg/kg per dose ) . Pulmonary function and clinical measures were assessed every 20 minutes for up to 120 minutes . RESULTS The groups were comparable at baseline . At 120 minutes , the mean percentage of predicted FEV1 improved from 33.4 % to 56.7 % in group 1 , from 34.2 % to 52.3 % in group 2 , and from 35.4 % to 48.4 % in group 3 ( p = 0.0001 ) . The differences between groups were larger in those children with a baseline FEV1 < or = 30 % of the predicted value : FEV1 increased from 24.5 % to 50.9 % in group 1 , from 25.0 % to 39.8 % in group 2 , and from 25.9 % to 36.5 % in group 3 ( p = 0.0001 ) . In group 1 , 38 % of the patients were hospitalized after the study , 44 % in group 2 , and 46 % in group 3 ( p value not significant ) . However , in patients with FEV1 < or = 30 % , the hospitalization rates were 27 % in group 1 , 56 % in group 2 , and 83 % in group 3 ( p = 0.027 ) . There were no toxic effects attributable to ipratropium . CONCLUSION The addition of repeated doses of nebulized ipratropium to frequent high-dose albuterol therapy in patients with acute severe asthma is both safe and more effective than albuterol alone ; its use in patients with very severe asthma may reduce hospitalizations [8933892] We examined the resolution of the bronchial spasm induced by methacholine after administration of a dose sufficient to provoke PD20 to study , in patients with bronchial asthma , how spontaneous resolution ( as opposed to bronchodilator-induced resolution ) takes place . According to a r and omization criterion , the patients were divided into four groups : 1 ) resolution induced by salbutamol ( S ) , 2 ) by ipratropium bromide ( I ) , 3 ) after placebo ( P ) and 4 ) spontaneous resolution ( R ) . In brief , we observed that variations in FEV1 after methacholine PD20 , reach statistically significant levels after 15 minutes in patients from groups ( S ) and ( I ) , after 30 minutes in patients from groups ( P ) and ( R ) ( p < 0.05 ) . Comparing the phenomenon at various intervals in the four experimental situation , we found a pairing trend : groups ( S ) and ( I ) on the one h and , and groups ( P ) and ( R ) on the other . On the whole , this phenomenon shows that pharmacological treatment accelerates the process of spontaneous resolution of the bronchial spasm induced by methacholine which , in our experience , beings to show after 15 minutes , and that after 60 minutes , there are no statistically significant differences in the four groups . It is our opinion that closer examination of this phenomenon may provide greater knowledge of the mechanisms that come into play during the phase after stimulation of the muscarinic receptors and that reasonably involve the system to eliminate the muscarinic drug [137921] The efficacy and acceptability of ipratropium given by metered-dose inhaler were evaluated in two double-blind crossover tests against placebo , one preceding and one following a 2-wk period of continual open-label ipratropium treatment . Ten patients with chronic bronchitis and 10 with bronchial asthma participated . Ipratropium produced increase in FEV 1 of more than 15 % within 5 min of inhalation , and this effect was maintained for 4 to 5 hr . Statistically significant mean increases over the FEV 1 baseline values were recorded after ipratropium treatment in both the initial and the final crossover tests . There were no adverse reactions to any of the placebo or ipratropium test doses or to the ipratropium treatment . Serial electrocardiograms , laboratory tests , blood pressure , and pulse rate showed no change from lthe baseline . Sputum volume and dry-weight determinations in the patients with bronchitis before and after the 14-day treatment revealed no changes [1387512] Ulrik CS , Backer V , Bach‐Mortensen N. Bronchodilating effect of ipratropium bromide inhalation powder and aerosol in children and adolescents with stable bronchial asthma [2968769] The capacity of salbutamol 0.3 mg ( SAL ) , disodium cromoglycate 3 mg ( DSCG ) , a combination ( SAL + DSCG ) , and ipratropium bromide 80 ug ( IB ) , all given as metered aerosols to prevent exercise‐induced ( EIA ) , was compared with that of a placebo , a peroral lactose pill . Seven children participated , having reproducible EIA provoked by running on a treadmill at a heart rate of 170 sustained for 6 min . FEV , and volume of trapped gas ( VTG ) , defined as the air volume released during rebreathing oxygen with maximum breaths at the end of a multiple breath nitrogen wash out , were used as tests of spasm in large and small airways . SAL and SAL + DSCG offered complete protection in large and small airways . DSCG and IB prevented EIA in large airways ( FEVj ) to 95 % , but only to about 50 % in small airways ( VTG ) . SAL or SAL + DSCG gave significantly better protection ( FEV1 and VTG ) than DSCG and IB ( P < 0.01 ) . Differences between DSCG and IB were not statistically significant . DSCG or propellant caused significant irritation and spasm in small airways ( VTG ) before exercise . Most subjects seemed to obtain satisfactory protection against EIA by β2‐agonists [2145790] Inhaled albuterol ( A ) ( salbutamol ) alone and albuterol plus ipratropium bromide ( IB ) were administered to 12 asthmatic children . Following administration of A alone or in combination with IB , there was a significant increase in FEV1 and FEF . Significant statistical difference in favor of the association A plus IB was observed at 120 and 240 minutes for FEV1 and in the period 120 , 180 , and 240 minutes for FEF . The additive effect was present both in the large and small airways . The short-lived additive effect of A plus IB suggests the opportunity to increase the frequency of drug administration in patients with severe bronchial obstruction [150323] n the 1960 's . Boehringer-Ingelheim , Ltd synthesized a 1 . s e n e of atropine derivatives , including N isopm pylnortropine tropic acid ester methyl bromide ( Atru vent ) . This drug is class8ed pharmacologically as an anticholinergic and its mechanism of action is vagal inhibition which prevents reflex bronchoconstriction . When given parenterafly , it bas anticbolinergic activity equal to or more potent than atropine . However , when administered by inhalation as a metered aerosol low doses are effective in the bronchial @ee ( local effect ) and do not show any atropine-like side effects . It may therefore be characterized as a peripheral anticholinergic , exercising particularly high spasmolytic activity in the bronchial region . The portion of Atrovent which adheres to the oral and pharyngeal mucosa and is later & lowed is poorly absorbed and therefore does not produce atropine-like effects even after high doses . Because of i b lack of cardiac effects Atrovent may be considered as a therapeutic alternative to beta-adrenergic bmnchodilators , especially for patients who are particularly sensitive to sympatbomimetic stimulation . Thirteen patients with asthma , as defined by the American Thoracic Society , were studied during a stable period of their disease . There were six males and seven females ranging in age from 18 to 52 yean ( mean 25 yean ) wbose asthma varied from miM to severe . Reversible bronchospasm was confirmed at the enby into the study by demonstrating an improvement of at least 15 percent increase in FEV , . within 30 minutes fouowing two inhalations of isoproterend from a metered dose inhaler . Isoproterenol ( 0.15 mg ) was used as a control in a double-blind comparison with Atrovent ( 0.40 mg ) administered at one dosage level , so that each patient received a total of two beatments with an interval of at least 24 hours between treatments . The sequence of treatments was r and omized [2203617] The bronchodilator effect of nebulized AMN , albuterol and their combination was evaluated in 16 steroid-dependent asthmatic children . In phase 1 , maximal bronchodilation was determined by dose-response studies on separate days . Maximal bronchodilator dose of each drug was administered either alone or in combination during phase 2 . In phase 1 , 0.11 + /- 0.01 mg/kg of albuterol and 0.03 mg/kg of AMN produced maximum bronchodilation . In phase 2 , the peak response to albuterol occurred within 30 min and to AMN , at 60 min . Maximal FEV1 achieved after AMN was 90 percent of the maximal achieved after albuterol . AMN FEV1 response was better than for placebo for 3 h ; that for albuterol was better for 4 h. Combination therapy produced a peak response similar to that of albuterol but was better than albuterol by 6 h. Thus , the maximum bronchodilator effect of AMN is less than that of albuterol in asthmatic children , but the combination may extend the period of bronchodilatation [2521989] Thirteen children with perennial bronchial asthma , with a mean age of 11.2 years , were studied concerning the bronchodilatory effect of ipratropium bromide in cumulative doses . All the children had reduced basal forced expiratory flow ( FEV1 ) and bronchial reversibility of at least 20 % after inhalation of salbutamol . The study had a double-blind design with a crossover technique . The inhaled dose of ipratropium bromide solution was increased stepwise from 25 micrograms to 500 micrograms and saline was used as the placebo . FEV1 was recorded 20 , 40 , and 60 minutes after inhalation of the test solution . At the lower ipratropium bromide dose levels no bronchodilatory effect was seen , but 60 minutes after the inhalation of 500 micrograms ipratropium bromide the increase in the FEV1 was significantly greater than that after placebo . Additional inhalation of salbutamol caused no further rise in FEV1 . At the 500-micrograms level a fall in the heart rate was noted . No side effects occurred . We concluded that ipratropium bromide has bronchodilatory properties in childhood asthma when given in sufficiently high doses [151547] Eleven patients with bronchial asthma and 10 with chronic bronchitis were treated over four consecutive 3-day periods , firstly with aerosols either of ipratropium bromide ( 40 microgram four times a day ) or of salbutamol ( 200 microgram four times daily ) by r and om allocation , then the alternate drug , next by both drugs together , and finally with prednisolone ( 10 mg three times daily ) in addition to both drugs . The effects of these four treatment periods were assessed both clinical ly and by measuring ventilatory capacity , nitrogen slope and progressive exercise testing . Ipratropium bromide and salbutamol produced approximately equal improvements in both diseases , with salbutamol showing a marginal advantage in patients with asthma . The combination of both drugs together more than doubled the FEV1 change in both groups of patients . The addition of prednisolone to both drugs produced a marginal advantage only in those with asthma [1360776] Oxatomide is a potent inhibitor of both the release and effects of allergic mediators and is similar to calcium antagonists in chemical structure . It prevents histamine release by inhibiting not only the increase in calcium intake , but also intracellular calcium release . We investigated its effect on methacholine-induced and exercise-induced bronchoconstriction in asthmatic children . Methacholine challenges were performed after oral administration of 0.88 mg/kg oxatomide or placebo in nine asthmatic children in a double-blind placebo-controlled study . Respiratory thresholds were improved in seven patients and log PC20 in the oxatomide group ( 6.65 + /- 1.34 micrograms/mL ) was significantly higher than that in the placebo group ( 5.74 + /- 1.04 micrograms/mL ) ( P < .05 ) . Exercise challenges were performed after oral administration of 1.5 mg/kg oxatomide or placebo in eight asthmatic children in a double-blind placebo-controlled study . Oxatomide produced acute bronchodilatation with 6.1 % improvement on an average in FEV1 . The mean maximal % fall obtained by oxatomide was 13.5 % , while that by placebo was 22 % ( P < .05 ) . These results indicate that oxatomide reduces nonspecific bronchial hyperresponsiveness [7958119] A combination dose aerosol of fenoterol hydrobromide ( 200 micrograms ) and ipratropium bromide ( 80 micrograms ) was compared with aerosolized salbutamol ( 200 micrograms ) in 10 stable asthmatic patients . With both treatments a statistically significant improvement was noticed in both FEV1 and PEF measurements starting after 15 minutes and continuing until 330 to 360 minutes . No statistically significant differences in one second Forced Vital Capacity ( FEV1 ) and Peak Expiratory Flow ( PEF ) was noted between the two treatments . No side effect was noticed . As a result , it was concluded that in bronchial asthmatic patients , the bronchodilator effects of the combination of a beta-2 agonist with anticholinergic drugs was as effective and lasted as long as salbutamol . This combination , in order to prevent cardiovascular complications , could be selected as a suitable treatment for those patients who need high doses of beta-2 agonist drugs [3428339] Summary A vagal mechanism appears to be involved in the development of exercise-induced asthma ( EIA ) , although previous studies have failed to demonstrate a protective effect of anticholinergic drugs against post-exercise bronchoconstriction . To reassess this hypothesis the effect of a new anticholinergic drug , Oxitropium Bromide ( OTB ) has been studied in ten subjects with documented EIA.There was no change after inhalation of a placebo . Administration of OTB led to bronchodilatation and totally blocked post-exercise bronchoconstriction in 7 patients , and it did so partly in 2 . The response to the drug appeared to depend on pretest respiratory function . Thus , the anticholinergic drug OTB may protect against EIA in most patients , confirming the role of a vagal cholinergic mechanism in EIA [4631042] arthritis of the right hip . It was then discovered that he had had mild diarrhoea for over 10 years . On examination there were no significant abnormal physical signs except restricted movements of his right hip ; no abdominal tumour could be felt . Sigmoidoscopy revealed a moderate degree of proctitis and biopsy showed the features of chronic ulcerative colitis , but there was no premalignant change in the rectal mucosa . Barium enema revealed extensive ulcerative colitis with a constant stricture in the transverse colon ( fig. 2 ) . At operation [6447269] The effect of 40 microgram of SCH 1000 ( ipratropium bromide , an anticholinergic agent ) on bronchodilation and suppression of exercise-induced bronchospasm ( EIB ) was compared with 400 microgram of fenoterol and a placebo in a single-blind controlled study . Twenty-seven r and omly selected asthmatic children performed a st and ardized treadmill exercise challenge and the 17 children who were shown to have EIB continued in the study . Pulmonary function was evaluated before and after drug administration and exercise . When individual results were analyzed and grouped according to the responsiveness of EIB to the drugs , two patterns emerged : ( 1 ) the EIB was more severe in those ( 6/17 ) children who did not respond to either drug than in the rest of children ; ( 2 ) the resting pulmonary function was significantly better in the children ( 4/17 ) who responded to both drugs than in those ( 7/17 ) who responded to fenoterol alone . In conclusion SCH 1000 was shown to be an effective bronchodilator comparable to , but no better than , fenoterol . It had minimal side effects . As an EIB inhibitor it depended on relatively normal base line pulmonary function and only a moderate deterioration following exercise , whereas fenoterol depended on the exercise response alone . Although anticholinergic drugs are not very extensively used , SCH 1000 may be useful in some patients where the beta 2 adrenergic drugs cause signficant side effects or are contraindicated [6461943] Eighteen children between 6 and 14 years of age with perennial asthma were studied over two four-week treatment periods . Ipratropium bromide , given in addition to their current treatment , was compared with placebo using a double-blind crossover technique . The period of treatment with ipratropium was associated with a significant reduction in symptoms during both day and night and significantly higher morning peak expiratory flow rates [6239021] IPRATROPIUM BROMIDE is a quaternary isopropyl derivative of the muscarinic antagonist atropine that has bronchodilator properties when administered topically via the respiratory airways . Because of its quaternary nature , it is poorly absorbed into the bloodstream after direct application into the bronchial tree ; the cardiovascular side effects are thus minimal . For these reasons ipratropium could represent a significant advance in therapy , especially considering its alternative mode of action via blockade of the cholinergic system rather than stimulation of ~adrenoceptors . Initial information on ipratropium solution has indicated that a dose of 250 # g can be given safely to preschool children with asthma and that the bronchodilation is comparable to that achieved by salbutamol . ~ The purpose of our study was to determine the optimal dosage of ipratropium solution when administered by aqueous nebulization , by constructing a dose-response curve in children of school age . [2931507] NEBULIZED specific beta-2 agonists such as salbutamol ( albuterol ) are widely preferred as the first-line drugs of choice for treating acute asthma in Children . Many studies have shown their efficacy as well as convenience in delivery ) , 2 Administration of frequent small doses ( 50 t ~ g/kg/dose every 20 minutes ) of nebulized salbutamol is safe and superior to the more conventional hourly dosing ( 150 /~g/kg/dose ) , producing a smoother rise in forced expiratory volume in 1 second and an earlier peak response without deterioration between doses ) However , even with this aggressive approach , significant residual airways obstruction remains despite additional doses of salbutamol . This suggests that the residual airways obstruction is related to factors unresponsive to beta-2 bronchodilators , such as mucosal edema , secretions , or cholinergic bronchomotor .tone . Ipratropium bromide is a quaternary ammonium derivative of atropine . When delivered by inhalation , it produces a local anticholinergic effect with no systemic absorption ? . 5 It is a potent bronchodilator , comparable to beta-2 agonists , and has been found to be very Useful , especially in adults with chronic bronchitis ? . 5 Our study was design ed to determine whether ipratropium bromide , by its anticholinergic action , could improve the residual airways obstruction seen after treatment with salbutamol alone . [11348957] STUDY OBJECTIVE To determine whether adding IV theophylline to an aggressive regimen of inhaled and IV beta-agonists , inhaled ipratropium , and IV methylprednisolone would enhance the recovery of children with severe status asthmaticus admitted to the pediatric ICU ( PICU ) . DESIGN A prospect i ve , r and omized , controlled trial . Asthma scoring was performed by investigators not involved in treatment decisions and blinded to group assignment . SETTING The PICU of an urban , university-affiliated , tertiary-care children 's hospital . PATIENTS Children with a diagnosis of status asthmaticus who were admitted to the PICU for < or = 2 h and who were in severe distress , as indicated by a modified Wood-Downes clinical asthma score ( CAS ) of > or = 5 . INTERVENTIONS All subjects initially received continuous albuterol nebulizations ; intermittent , inhaled ipratropium ; and IV methylprednisolone . The theophylline group was also administered infusions of IV theophylline to achieve serum concentrations of 12 to 17 microg/mL. A CAS was tabulated twice daily . MEASUREMENTS AND RESULTS Forty-seven children ( median age , 8.3 years ; range , 13 months to 17 years ) completed the study . Twenty-three children received theophylline . The baseline CASs of both groups were similar and included three subjects receiving mechanical ventilation in each group . All subjects receiving mechanical ventilation and theophylline were intubated before drug infusion . Among the 41 subjects who were not receiving mechanical ventilation , those receiving theophylline achieved a CAS of < or = 3 sooner than control subjects ( 18.6 + /- 2.7 h vs 31.1 + /- 4.5 h ; p < 0.05 ) . Theophylline had no effect on the length of PICU stay or the total incidence of side effects . Subjects receiving theophylline had more emesis ( p < 0.05 ) , and control patients had more tremor ( p < 0.05 ) . CONCLUSIONS Theophylline safely hastened the recovery of children in severe status asthmaticus who were also receiving albuterol , ipratropium , and methylprednisolone . The role of theophylline in the management of asthmatic children in impending respiratory failure should be reexamined [3160273] Postexertional wheezing is an important clinical sign of nonspecific airway hyperreactivity . We have studied wheezing after exercise in 6 asthmatic subjects , 13 to 20 yr of age , using spectral analysis of recorded tracheal sounds . Automated spectral characterization was used to measure wheezing as a proportion of respiratory time . Anticholinergic treatment with ipratropium bromide ( Atrovent ) was compared with placebo to investigate effects on postexertional wheezing , and pulmonary function was compared with the result of respiratory sound analysis . Atrovent did not abolish exercise-induced bronchospasm but improved preexercise lung function and thereby caused a parallel upward shift in the response curves . Wheezing after Atrovent was significantly less , later in onset , and mainly expiratory at 20 min after exercise . Wheezing as a percentage of total respiratory time correlated well with FEV1 , Vmax50 , and SGaw . Analysis of respiratory sounds and automated quantification of wheezing may be a useful complementary test of bronchial obstruction in asthma [2948430] The effects of the beta 2-adrenergic agonist salbutamol ( 0.02 mL/kg of a 0.5 % solution ) and the cholinergic antagonist ipratropium bromide ( 2 mL of a 0.025 % solution ) , administered alone or in combination at different doses , were evaluated in 48 asthmatic children using a single-dose , double-blind , crossover design . Spirometric measurements were taken before and 10 , 30 , 60 , 120 , 180 , 240 , 300 , and 360 minutes after administration of the drugs . All regimens produced significant bronchodilatation 10 to 30 minutes after administration . The improvement began to decline three to four hours after inhalation , particularly when ipratropium bromide was administered alone . The administration of the salbutamol plus ipratropium combination did not significantly improve pulmonary function values as compared to salbutamol alone . The effects of salbutamol and ipratropium bromide in half-dose or full-dose combinations were indistinguishable . No significant adverse effects on blood pressure or heart rate were observed [347990] In a double-blind study in 23 asthmatic patients Sch 1000 was found to be an effective bronchodilator with an onset of effect within 15 minutes and a duration of four hours . It was effective on both small and large airways [6119168] Two groups of eight asthmatic children carried out serial treadmill exercise tests at 2‐hourly intervals , after double‐blind premedication with oxatomide ( 2 mg/kg by mouth ) , sodium cromoglycate powder ( 20 mg by inhalation ) or matched placebo preparations . The drugs were studied in one group up to 6 hr and in the other group ( omitting sodium cromoglycate ) from 4 to 10hr after administration . Peak expiratory flow rate was measured before and after exercise to give an index of exercise‐induced asthma [2525377] A double-blind crossover study was performed on 33 children with asthma to compare the effectiveness of nebulized solutions of preservative-containing and preservative-free ipratropium bromide . Both solutions produced bronchodilation . No significant differences were found between the two solutions at any time after nebulization in minimum and maximum changes from baseline value or in the areas under the lung function time curves . The presently formulated preservative-containing ipratropium bromide solution was not shown to be inferior to a preservative-free compound [2244710] The combination of nebulized atropine methylnitrate ( AMN ) and a beta-agonist has been shown to produce greater and longer lasting bronchodilation than either drug alone . We examined the efficacy of the combination in diminishing the " morning dipping " in PEFR in eight hospitalized but stable asthmatics . The patients received nebulized albuterol along with either AMN ( AMN + ALB ) or placebo ( ALB ) in a r and om double-blind cross-over fashion at 10 PM on four nights . PEFR and FEV1 were recorded at 6 PM , 10 PM , and 6 AM before the administration of bronchodilators . There was no statistically significant difference between ALB and AMN + ALB in reducing the morning dipping in these patients [7719260] The study was carried out on 19 patients with moderate and severe bronchial asthma . During three days after the initial spirometric evaluation the patients received -- on the first day 0.5 mg of pirenzepine in nebulization ( P ) , on the second day 0.25 mg of ipratropium bromide ( IB ) , on the third day both substances together . Ventilatory parameters were monitored on the 5th , 20th , 40th and 60th minute following nebulization . The observed parameters did not differ significantly between both groups . Pirenzepine given after ipratropium bromide increased FEV1 from 1.89 L to 2.37 L ( p < 0.01 ) . The observed results imply that pirenzepine given with ipratropium bromide induce a significant bronchodilating effect and could be added to therapy of bronchial asthma [9353508] Abstract Objectives : To determine the effect of regular prophylactic inhaled corticosteroids on wheezing episodes associated with viral infection in school age children . Design : R and omised , double blind , placebo controlled trial . Setting : Community based study in Southampton . Subjects : 104 children aged 7 to 9 years who had had wheezing in association with symptoms of upper and lower respiratory tract infection in the preceding 12 months . Interventions : After a run in period of 2–6 weeks children were r and omly allocated twice daily inhaled beclomethasone dipropionate 200 μg or placebo through a Diskhaler for 6 months with a wash out period of 2 months . Children were assessed monthly . Main outcome measures : Forced expiratory volume in 1 second ( FEV1 ) ; bronchial responsiveness to methacholine ( PD20 ) ; percentage of days with symptoms of upper and lower respiratory tract infection with frequency , severity , and duration of episodes of upper and lower respiratory symptoms and of reduced peak expiratory flow rate . Results : During the treatment period there was a significant increase in mean FEV1 ( 1.63 v 1.53 l ; adjusted difference 0.09 l ( 95 % confidence interval 0.04 to 0.14 ) ; P=0.001 ) and methacholine PD20 ( 12.8 v 7.2 μmol/l ; adjusted ratio of means 1.7 ( 1.2 to 2.4 ) ; P=0.007 ) in children receiving beclomethasone dipropionate compared with placebo . There were , however , no significant differences in the percentage of days with symptoms or in the frequency , severity , or duration of episodes of upper or lower respiratory symptoms or of reduced peak expiratory flow rate during the treatment period between the two groups . Conclusions : Although lung function is improved with regular beclomethasone dipropionate 400 μg/day , this treatment offers no clinical ly significant benefit in school age children with wheezing episodes associated with viral infection . Key messages Increasing evidence suggests that episodic wheezing in children in association with viral infections is a separate entity from atopic asthma Although inhaled corticosteroids are beneficial in asthma , their role in treating wheezing associated with viral infections is unclear In this study regular inhaled corticosteroids result ed in improved lung function and decreased bronchial responsiveness but did not have any effect on episodes of wheezing Inhaled corticosteroids are of little benefit in children with episodic wheezing associated with viral [3155982] frequent development of tachyphylaxis apart from numerous other toxic reactions and the painfulness of the injections . The main advantage of dimercaprol is that the molecule is not charged , is soluble in lipids , and is able to cross the blood-brain barrier fairly easily compared with penicillamine , trientine dihydrochloride , and unithiol , which are highly charged . Treatment with unithiol was started in two other patients . The first developed a fever of 39"C four hours after the test dose and a 50 ° , fall in the leucocyte count . A further challenge dose caused a similar reaction and treatment was not pursued . This patient was subsequently managed with tetrathiomolyb date .3 The second patient took unithiol for 10 days before refusing it because of intense nausea and a change in taste . Other patients have received single test doses , and the result ing cupruresis has been comparable with that after penicillamine and trientine dihydrochloride in most cases . Unithiol may well prove to be yet one more fall back treatment for patients who develop intolerance to penicillamine [7719261] The bronchodilatory activity of Berodual in comparison to Fenoterol and Ipratropium Bromide was investigated in a group of 59 children aged 8 - 15 years , suffering from mild bronchial asthma in a symptoms-free period . The relaxing activity was monitored dynamically by means of the analysis of flow-volume curve measurements . We have found that the bronchodilatory activity of Berodual was faster , stronger and longer in comparison to Fenoterol and Ipratropium Bromide [7016106] : The efficacy of adding oral or inhaled atropine sulphate to the maintenance therapy of 12 children with severe chronic asthma was assessed using a double blind crossover study lasting three months . There was no obvious subjective or objective clinical difference between either form of atropine sulphate and placebo . Twice daily peak flow rates were not significantly different for the three treatment periods . However , during oral atropine therapy there was a significant improvement in FEV1/ VC ( P < 0.05 ) and in RV/TLC ( P < 0.05 ) compared to placebo . Inhaled atropine had no significant effect on baseline pulmonary function testing . No side effects were encountered . Further clinical trials are necessary to confirm the beneficial effect of long term oral atropine sulphate in the treatment of children with severe chronic asthma [6240599] In a double blind r and omized study during a period of 2 weeks we compared the therapeutic effectiveness and side effects of IK-6-Inhaletten ( 0.1 mg Fenoterol + 0.04 mg Ipratropiumbromide ) and SCH 1000-Inhaletten ( 0.2 mg Ipratropiumbromide ) in 39 children ( 4 - 14 years ) suffering from mild , moderate or severe asthma bronchiale . All measurements were performed with a whole body plethysmograph . In contrast to SCH 1000-inhalation after inhalation of IK-6-Inhaletten , we found a good improvement of the total airway resistance Rtot , the specific airway resistance SRaw and the forced exspiratory volume FEV1 . Especially SRaw was significantly diminished compared to the less effective SCH 1000-inhalation . IK-6-inhalation allowed to decrease the amount of bronchospasmolytic therapy in our group of patients . We did not observe any severe side effects after inhalation of IK-6 or SCH 1000 . In summary , we recommend the application of the IK-6-Inhaletten in children suffering from mild and moderate asthma bronchiale [2951802] Exercise-induced asthma ( EIA ) is a frequent symptom in asthmatic patients . The study of drugs which inhibit EIA is very important because EIA seriously limits the life of the patients . In addition , this study could allow further insights to be gained into the pathogenesis of the phenomenon . The aim of the present study is to evaluate the duration of the protective effect of fenoterol alone or in combination with ipratropium bromide administered 5 h before exercise . For this purpose we studied 12 asthmatic patients ( 7 males and 5 females , mean age 23 , range 7 - 41 years ) with EIA , in clinical and functional stable state . Respiratory function parameters were measured before and 5 h after the administration of fenoterol 400 or 200 micrograms , or fenoterol 200 micrograms plus ipratropium bromide 80 micrograms ( Duovent ) , or placebo in r and omized order . Then , such parameters were measured at 5 , 15 , 30 , and 60 min after exercise , which consisted of free running up and down the stairs . The results show that , at 5 h after the administration of each drug , the protective action against EIA is only partial . However , the intense bronchodilation afforded by the ' active ' drugs , and particularly by 400 micrograms of fenoterol , keeps post-exertional respiratory parameters above the baseline values [2951828] A blind r and omized cross-over comparative study of salbutamol and the combination fenoterol/ipratropium was carried out in 20 patients with mild to moderate bronchial asthma ; clinical and functional serial parameters were evaluated . The combination was more effective than salbutamol in preventing crisis and incidence of cough and wheezing , and in the spirometric results . There were no significant differences in expectoration and the functional parameters improved not only in flow but also in volume . Pathogenesis is discussed

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### Context: [6218645] Eight patients with exercise-induced asthma participated in a single-blind trial comparing the protective effects of inhaled lignocaine ( estimated dose 48 mg ) , sodium cromoglycate ( estimated dose 12 mg ) , and ipratropium bromide ( estimated dose 120 μg ) . Saline was used as control . Effects were assessed from the mean maximal percentage fall in forced expiratory volume in one second ( FEV1 ) and maximal mid-expiratory flow rates ( MMFR ) after they had run on a treadmill for eight minutes . There was no significant change in baseline FEV1 or MMFR before each agent was given . Saline , lignocaine , and sodium cromoglycate did not alter the mean baseline FEV1 or MMFR significantly . Ipratropium caused bronchodilatation with an increase of 16·3 % in the mean FEV1 ( p<0·001 ) and of 43·4 % in the mean MMFR ( p<0·05 ) . After exercise the maximal percentage falls in FEV1 ( means and SEM ) after saline , lignocaine , sodium cromoglycate , and ipratropium bromide were 38·1 % ( 5·0 ) , 34·5 % ( 6·1 ) , 11·3 % ( 3·7 ) , and 19·3 % ( 7·4 ) respectively . Similarly , the mean maximal falls in MMFR after saline , lignocaine , sodium cromoglycate , and ipratropium bromide were 54·4 % ( 5·2 ) , 52·9 % ( 7·7 ) , 23·6 % ( 6·6 ) , and 32·1 % ( 10·5 ) respectively . The inhibitory effects of sodium cromoglycate and ipratropium bromide were significant whereas lignocaine failed to produce an effect . These results suggest that mediator release is an important factor in exercise-induced asthma and that in some patients the effects of the mediators may be on the postsynaptic muscarinic receptors . Local anaesthesia of sensory vagal receptors , on the other h and , does not prevent exercise asthma and these receptors do not appear to have any important role in exercise-induced bronchoconstriction [2975285] The effects of ipratropium bromide ( 80 and 200 micrograms ) and placebo on the basal bronchial tone and on methacholine-induced bronchoconstriction were investigated in 10 asthmatic patients in a placebo-controlled double-blind manner . Bronchial hyperreactivity to methacholine was confirmed at a pretrial bronchial challenge . The patients were r and omly allocated to two groups in which the drug was inhaled from either metered-dose inhalers ( MDI ) or powder capsules . With the high dosage , the bronchodilation result ing from powder capsules was somewhat more pronounced than that achieved with the MDI . Otherwise the bronchodilator effect of ipratropium bromide and the protection afforded by the drug against methacholine-induced bronchoconstriction were similar in the two groups . In five patients the bronchodilator effect was better and in four patients the tolerance to methacholine was greater after the higher ipratropium dosage than after the lower one . In two patients ipratropium bromide had no bronchodilator effect but gave good protection against methacholine-induced bronchoconstriction . It is concluded that some patients benefit from a dosage of ipratropium bromide higher than that usually recommended and that an anticholinergic effect on the bronchi is possible even in the absence of the bronchodilator effect in the basal state [9708227] BACKGROUND In acute asthma the optimal duration of treatment with combination β agonist and anticholinergic nebuliser solutions is unknown ; most studies have investigated single doses or treatment for up to 12 hours . To determine whether longer treatment with ipratropium bromide might aid recovery a study was undertaken in 106 patients with acute asthma . METHODS A double blind , r and omised , placebo controlled , three group study was performed with all patients receiving ipratropium for 12 hours and salbutamol for 60 hours after admission ( both nebulised four hourly ) , systemic steroids and , if necessary , theophylline . At 12 hours ipratropium was stopped in group I ( n = 35 ) but was continued in the other two groups , and at 36 hours ipratropium was also stopped in group II ( n = 35 ) while patients in group III ( n = 36 ) continued with ipratropium for 60 hours . Spirometric tests were performed before and after salbutamol , and again 30 and 60 minutes after ipratropium or placebo at 12 , 36 and 60 hours . Peak flow rates ( PEFR ) were measured before and after each nebulisation . RESULTS There were no differences between the groups in PEFR on admission ( group I : 214 l/min , group II : 198 l/min , group III : 221 l/min ) , or mean forced expiratory volume in one second ( FEV1 ) at 12 hours ( group I : 1.8 l , group II : 2.0 l , group III : 2.2 l ) , 36 hours ( group I : 2.1 l , group II : 2.3 l , group III : 2.4 l ) , or at 60 hours ( group I : 2.2 l , group II : 2.3 l , group III 2.5 l ) . Despite this , median time to discharge was significantly higher for patients in group I ( 5.4 days ) than for those in groups II ( 4.1 days ) and III ( 4.0 days ) . CONCLUSIONS Combination nebulised therapy can be continued beyond 12 hours and up to 36 hours after admission with improved recovery time . Lung function testing may not reflect the full benefit of treatment [3327703] In order to determine the duration of action of the inhaled anticholinergic agent oxitropium bromide , a controlled study of the effect of pre-treatment with oxitropium bromide 200 micrograms against cholinergic challenge was carried out in ten asthmatic subjects ( 6 children , 4 adults ) . After baseline measurements of lung function ( FEV1 and sGaw ) and methacholine PC20 ( the concentration of methacholine to produce a 20 % fall in FEV1 ) oxitropium bromide or placebo were inhaled double-blind on 2 separate days . Lung function and methacholine PC20 were then measured at 1 , 3 and 6 h post dosing . Oxitropium bromide caused significant protection from methacholine challenge for 6 h ( p less than 0.05 ) [2947462] A multi-center , double-blind , 90-day study compared an ipratropium bromide metered-dose inhaler ( 40 microgram four times a day ) with a metaproterenol metered-dose inhaler ( 1,500 micrograms four times a day ) in 164 patients with asthma ; of the 144 patients who completed the study , 71 received ipratropium and 73 received metaproterenol . Our results suggest that both drugs were equally effective bronchodilators . Although the shape of the pulmonary function response curves suggested that ipratropium has different bronchodilator kinetics than metaproterenol ( in that it has a slower onset of action and a more prolonged duration ) , comparison of the areas under the curves for the two drugs showed that there was no statistical difference between ipratropium or metaproterenol . The only significant side effects noted with ipratropium were cough and exacerbation of symptoms ; no anticholinergic side effects were noted [6236727] Forty-nine asymptomatic asthmatic children who showed exercise induced bronchospasm ( EIB ) , received in a r and omized double-blind fashion one of the four following drugs administered through nebulizer and facial mask : salbutamol 4 mg ( 13 patients ) , disodium chromoglycate 20 mg ( 12 patients ) , ipratroprium bromide 0.4 mg ( 12 patients ) , placebo ( 12 patients ) . They performed exercise fifteen minutes after receiving the drugs and spirometries were done 0 , 5 , 10 , 15 and 20 minutes after the end of the exercise . Bronchodilation was noticed 15 minutes after the administration of salbutamol and ipratroprium bromide but not after cromoglycate or placebo . No patient receiving either salbutamol or cromoglycate had EIB whereas it occurred in 50 % of those receiving ipratroprium bromide and 91.6 % of those receiving placebo [2959208] Thirty seven children with acute asthma were given nebulised ipratropium or placebo 30 minutes after their first dose of salbutamol and eight hourly thereafter . There were no significant differences between the two groups in clinical scores , peak expiratory flow rates , length of stay in hospital , or the need for oral steroids [7226953] Six asthmatic children were studied to determine whether supplemental , parenteral atropine would increase the effects of bronchodilation and protection against exercise-induced bronchoconstriction after maximal effects had been achieved by inhalation . First , we determined the amount of inhaled atropine sulfate that would give maximal bronchodilation for each patient at rest . This quantity of atropine was design ated as " A. " Then all subjects exercised for five sessions with the following pre-exercise treatments in a r and om order : ( a ) inhaled distilled water plus intramuscular ( IM ) saline solution ; ( b ) inhaled A dose of atropine plus IM saline solution ; ( c ) inhaled distilled water plus 0.35 mg IM atropine ; ( d ) inhaled A dose of atropine plus 0.35 mg IM atropine ; and ( e ) inhaled double the A dose plus IM saline solution . The results showed that the combination of inhaled and IM atropine had the greatest bronchodilation effect and the greatest protection against exercise-induced bronchoconstriction . Atropine inhalation alone ( A dose ) or IM injection ( 0.35 mg ) was not as effective in bronchodilation or in alleviation of exercise-induced bronchoconstriction . Doubling the dose of inhalation ( 2A ) did not increase the effects of the A dose . These results support the hypothesis that inhaled atropine does not reach all the airways where cholinergic receptors are present [2951818] Until now very few studies have been performed on the prevention of exercise-induced asthma ( EIA ) in children with ipratropium bromide + fenoterol . This is why we decided to study 30 children aged between 6 and 15 years , whose EIA was confirmed by a test including a 6-min free race on day 1 of the study . The criterion was a decrease of more than 20 % of the basal values of forced expiratory volume in 1 s ( FEV1 ) or FMF . Children whose FEV1 or FMF baseline values were under 60 % of those expected according to Polgard tables were excluded . Three tests were performed , the first to determine EIA , the second was performed 72 h later after inhalation of placebo . 72 h after day 2 the patients returned in order to repeat the test , but this time , aerosol therapy with the combination ipratropium + fenoterol was applied prior to the race . The dosage of the combination was 1 puff of aerosol per 10 kg body weight , up to a maximum of 4 puffs . Each puff of the combination contains 0.02 mg of ipratropium bromide and 0.05 mg fenoterol . Functional assessment of children was carried out by means of forced spirometry . There were no significant differences between the placebo group and the group which received no medication , but there was a significant difference between the treated group and the other two , not only in the FEV1 and FMF values but also in forced vital capacity TEST . ( ABSTRACT TRUNCATED AT 250 WORDS [810767] A number of drugs are known to inhibit exercise-induced asthma ( EIA ) , but the results in some cases have been difficult to interpret due to the techniques employed . A comparative study was carried out in a group of children to investigate the effects of salbutamol , choline theophyllinate , cromolyn sodium , atropine , and placebo . The exercise test took the form of six minutes of st and ardized treadmill running . All the drugs , but not the placebo , were able to inhibit EIA ti a significant degree , the effect being most marked with salbutamol . Cromolyn sodium caused no bronchodilatation at rest , while all the other drugs were brondhocilators , the effect being most marked with the atropine during exercise . It was impossible to distinguish the type of drug used for inhibition of EIA if it caused bronchodilatation at rest . The manner in which an exercise test can be used to investigate the duration of action or site of action of drugs is noted [3792086] Glycopyrrolate , a quaternary ammonium anticholinergic compound is a potentially useful bronchodilator . To determine the efficacy , optimal dose , and duration of action of inhaled glycopyrrolate , we gave the drug to 11 asthmatic patients . Each subject received placebo or glycopyrrolate ( 100 , 200 , 600 , or 1,200 micrograms ) by inhalation in a double-blind , r and omized , crossover design . Measurements included FEV1 , FVC , heart rate , and blood pressure before administration of the drug and periodically for 12 hours . For eight hours following all doses of glycopyrrolate , both FEV1 and FVC ( both as percent of predicted ) were significantly greater for drug than for placebo . Glycopyrrolate may be a useful long-acting drug for the treatment of asthma [6457620] Abstract We have examined the role of cholinergic reflex mechanisms in non-allergic bronchial hyperresponsiveness by examining the effect of pretreatment with ipratropium bromide ( a cholinergic antagonist ) and fenoterol ( a β 2 -adrenergic agonist ) on histamine- and methacholine-induced bronchoconstriction . Twelve adult asthmatics inhaled histamine acid phosphate and methacholine to determine the provocative concentration causing a fall in FEV 1 of 20 % ( PC 20 ) , after double-blind r and omized administration of ipratropium bromide ( 80 μg ) , fenoterol ( 800 μg ) or placebo . Ipratropium increased the mean PC 20 methacholine from 1.12 to 59.67 mg/ml ( P 20 increased from 1.17 to 1.93 mg/ml . This was not statistically significant after correction for any change in base-line FEV 1 . Fenoterol increased the mean PC 20 methacholine from 1.12 to 17.76 mg/ml ( P 20 histamine from 1.17 to 10.61 mg/ml ( P P = 0.001 ) . No such relationship was found with fenoterol and methacholine or with ipratropium and histamine or methacholine . Inhalation of high doses of methacholine appeared to induce late asthmatic responses in four subjects , similar to those observed after inhalation of allergen by sensitized subjects . We conclude that : 1 . 1.|Cholinergic reflex mechanisms are not important in histamine-induced bronchoconstriction or in the pathogenesis of non-allergic bronchial hyperresponsiveness . 2 . 2.|The degree of non-allergic hyperresponsiveness to histamine may be related to the severity of β-receptor dysfunction . 3 . 3.|High concentrations ( doses ) of methacholine may induce responses of the late asthmatic type [8181333] STUDY OBJECTIVE To evaluate the effects of nebulized ipratropium bromide on intraocular pressures and pupillary responses in children with asthma . DESIGN A double-blind , r and omized , crossover study . SETTING Children 's Hospital of Winnipeg , University of Manitoba . PATIENTS OR PARTICIPANTS Age 6 to 17 years with asthma . INTERVENTION Nebulized ipratropium bromide added to albuterol sulfate , albuterol alone , or saline solution was given by face mask and nebulizer . Before and 0.5 h after nebulization , intraocular pressures ( mm Hg ) , pupillary size ( mm ) , and pupillary responses were measured . In a subsequent open study , patients who had been admitted to hospital with acute asthma who were treated with nebulized ipratropium bromide were recruited for measurement of intraocular pressures , pupillary size , and pupillary responses . MEASUREMENTS AND RESULTS Twenty patients completed the double-blind study , and 26 patients completed the open study . There were no changes in intraocular pressures , pupillary size , or pupillary response after any treatment on any study day in either the double-blind or the open studies . CONCLUSION In children with asthma , who have no pre-existing ocular abnormalities , the risk of an adverse reaction to nebulized ipratropium bromide delivered by face mask inadvertently absorbed in the eye is extremely small [9018183] STUDY OBJECTIVE To determine the effect of adding the nebulized anticholinergic drug ipratropium bromide to st and ard therapy compared with st and ard therapy alone for acute severe asthma ( peak expiratory flow rate [ PEFR ] < 50 % of predicted ) in children presenting to the emergency department . METHODS Ninety children aged 6 to 18 years were r and omly assigned to two groups in a prospect i ve , double-blind , placebo-controlled study performed in the ED of an urban children 's hospital . All children received nebulized albuterol solution ( .15 mg/kg ) every 30 minutes , and all received oral steroids with the second dose of albuterol . Children in group 1 received ipratropium bromide ( 500 micrograms/dose ) with the first and third dose of albuterol those in group 2 received saline placebo instead of ipratropium . Pulmonary functions ( PEFR and 1-second forced expiratory volume [ FEV1 ] ) and physiologic measurements were assessed every 30 minutes up to 120 minutes . By chance , the baseline values for percent of predicted PEFR and FEV1 differed between the two groups . Therefore a multivariate model accounting for both time and baseline effects was used to compare the response between groups . RESULTS On average , and adjusting for baseline measures , children in the ipratropium group had a significantly greater improvement in percent of predicted PEFR than did children in the placebo group at 60 minutes ( P = .02 ) , 90 minutes ( P = .002 ) , and 120 minutes ( P < .0001 ) . The improvement in percent predicted FEV1 was significantly greater for children in the ipratropium group only at 120 minutes ( P = .013 ) . Nine children ( 20 % ) from the ipratropium group and 14 ( 31.1 % ) from the control group were admitted ( P = .33 , chi 2 ) . There were no significant adverse effects attributable to the ipratropium , and there was no relation between ipratropium use and changes in pulse , respiratory rate , blood pressure , or oxygen saturation . CONCLUSION We detected significant improvement in pulmonary function studies over 120 minutes in children with severe asthma who were given nebulized ipratropium combined with albuterol and oral steroids , compared with children who received the st and ard therapy . Further study is needed to determine whether early use of ipratropium decreases the need for hospitalization [10213547] BACKGROUND Inhalation therapy with sodium cromoglycate is recommended as the first-line prophylactic treatment for moderate asthma in children . The availability of spacer devices with face-masks has extended the applicability of metered-dose inhalers to younger children . We studied the feasibility and effects of this therapy compared with placebo in children aged 1 - 4 years . METHODS 218 children aged 1 - 4 years with moderate asthma were recruited through 151 general practitioners between March , 1995 , and March , 1996 . They were r and omly assigned sodium cromoglycate ( 10 mg three times daily ) or placebo , given by inhaler with spacer device and face-mask for 5 months . Rescue medication ( ipratropium plus fenoterol aerosol ) was available during the baseline period of 1 month and the intervention period . Parents completed a daily symptom-score list . The primary outcome measure was the proportion of symptom-free days in months 2 to 5 . Analysis was by both intention to treat and on treatment . FINDINGS 167 ( 77 % ) children completed the trial . 131 ( 78 % ) of these children used at least 80 % of the recommended dose . Of the 51 children who stopped prematurely , 23 had difficulties with inhaled treatment . The mean proportion of symptom-free days for both groups was greater for the treatment period than for the baseline period ( 95 % CI for mean difference 5.1 to 17.5 cromoglycate , 11.9 to 23.3 placebo ) . However there were no differences between the sodium cromoglycate and placebo groups in the proportion of symptom-free days ( mean 65.7 [ SD 25.3 ] vs 64.3 [24.5]% ; 95 % CI for difference -8.46 to 5.70 ) or in any other outcome measure . INTERPRETATION Our study in a general practice setting shows that inhalation therapy with a spacer device and face-mask is feasible in a majority of children below the age of 4 years . However , long-term prophylactic therapy with inhaled sodium cromoglycate is not more effective than placebo in this age-group [1535321] Although adenosine-induced bronchoconstriction is mainly due to mast cell mediator release , vagal reflexes have also been implicated in this response . We have investigated the effect of a specific muscarinic-receptor antagonist , ipratropium bromide , on methacholine- and adenosine-induced bronchoconstriction in a r and omized , placebo-controlled , double-blind study of 12 asthmatic subjects . Airway response was evaluated as forced expiratory volume in one second ( FEV1 ) . Inhaled ipratropium bromide ( 40 micrograms ) , administered 20 min prior to bronchoprovocation , increased the provocation dose of inhaled methacholine and adenosine required to reduce FEV1 by 20 % from baseline ( PD20 ) from 0.11 to 0.79 mg ( p less than 0.01 ) and from 0.57 to 1.27 mg ( p less than 0.01 ) , respectively . The mean baseline FEV1 values after administration of ipratropium bromide were significantly higher than after placebo administration ( p less than 0.05 ) . However , there was no correlation between the degree of bronchodilatation and dose-ratios for methacholine and adenosine . The findings of the present study implicate vagal reflexes in the bronchospastic response induced by inhaled adenosine in asthma [2963059] A study was performed to compare the efficacy and safety of two therapeutic regimens for the treatment of children presenting to the emergency department with acute asthma . A regimen of inhaled salbutamol alone was compared to inhaled salbutamol combined with ipratropium bromide . Twenty-five children ranging in age from 5 to 15 years were enrolled in the study . Children with FEV1 less than or equal to 55 % predicted were eligible to participate in the study . Subjects were r and omized in a double-blind fashion into one of two treatment groups . Both groups received an initial dose of salbutamol by nebulizer of 150 micrograms/kg ( 0.03 cc/kg ) , followed by six consecutive doses of 50 micrograms/kg ( 0.01 cc/kg ) at 20-minute intervals . In one group of subjects , 250 micrograms ( 1.0 ml ) of ipratropium bromide respirator solution was added to the salbutamol administered at the time of the initial inhalation , and at 40 and 80 minutes , whereas the remaining subjects received a placebo with salbutamol at those times . Formal one-way statistical ANOVA with change in percent predicted FEV1 as a response variable confirmed there was a statistically significant difference at all time points caused by drug regimen during the 150-minute observation period . There was no significant difference in side effects reported in the two groups . Significant additional bronchodilation achieved with salbutamol and ipratropium bromide together indicates that there is likely a substantial cholinergic element to the bronchospasm observed in acute exacerbations of asthma in the pediatric age group [779554] The ability of atropine to inhibit exercise-induced bronchospasm was evaluated in 18 children with chronic , perennial asthma . In 17 of 18 patients , exercise-induced bronchospasm was blocked by prior inhalation of 0.1 mg per kg of atropine sulfate , administered in a r and omized single blind fashion . In 14 of these 17 patients , significant bronchodilatation occured after the combination of atropine and exercise . Placebo failed to inhibit exercise-induced bronchospasm in any patient . These results suggest that the parasympathetic nervous system has a role in the mediation of exercise-induced bronchospasm in children [2532229] We studied the effects of the anticholinergic ipratropium bromide ( 40 micrograms three times daily ) and the beta-agonist , fenoterol ( 0.2 mg three times daily ) , both administered by powder inhaler , on bronchial hyperresponsiveness ( BHR ) to histamine in children , aged 7 to 15 years with mild stable asthma and limited bronchoconstriction who had a highly increased BHR . The double-blind , r and omized , parallel study was conducted and performed in spring and early summer . BHR and FEV1 were measured on two occasions , before the start of treatment and monthly thereafter for 4 months . Symptoms , peak expiratory flow , and concomitant medication were registered daily . Nine of the 12 patients receiving ipratropium bromide and all eight patients receiving fenoterol completed the study . Patients completing treatment had few symptoms and were in a stable condition throughout the treatment period . Neither the administration of ipratropium bromide nor fenoterol result ed in a significant change of BHR . We concluded that long-term treatment with ipratropium bromide or fenoterol had no effect on BHR in children with mild stable asthma [6230034] Ipratropium ( 40 micrograms ) and theophylline ( oxtriphylline 400 mg ) were administered to 24 asthmatics in a r and omized double-blind placebo controlled trial . The combination of these agents produced additive bronchodilation for up to two hours , with a 23 percent maximal increase in FEV1 . This regimen promises to be safe , effective therapy for patients with asthma [2958950] Thirty one children with asthma were given 40 micrograms of ipratropium bromide and identical placebo by inhalation three times a day in a double blind , r and omised crossover study to test the ability of an anticholinergic drug to modify the diurnal variation in airway calibre and bronchial reactivity . Subjects measured peak expiratory flow rate approximately eight hourly , before and after inhaled salbutamol , for four week periods . Paired t tests and cosinor analysis were used to assess the diurnal variation in airway calibre from the peak expiratory flow rate recorded before salbutamol and to assess the diurnal variation in bronchodilator responsiveness from the increase in peak expiratory flow rate after salbutamol . Maintenance treatment with ipratropium bromide 40 micrograms three times daily reduced the provocative dose of histamine which caused a 20 % fall in FEV1 ( geometric mean PD20 = 0.78 v 0.49 mg/ml , p less than 0.05 ) , despite an eight to 12 hour gap between the last dose of ipratropium and histamine challenge . It did not , however , diminish the diurnal variation in airway calibre ( mean amplitude = 12.7 v 10.1 ) or in bronchodilator responsiveness ( mean amplitude = 62.4 v 63.5 ) . There was no improvement in the clinical state of subjects while they were taking ipratropium bromide [141471] The new anticholinergic compound Sch 1000 ( ipratropium bromide ) has been reported to be an effective bronchodilator without significant atropine-like side effects . We evaluated the effectiveness of different doses of nebulized Sch 1000 ( 40 microgram and 80 microgram ) aerosolized atropine sulfate ( 1 mg ) and placebo in the prevention of exercise-induced bronchospasm ( EIB ) in 20 children with atopic bronchial asthma . A r and om , crossover double-blind protocol was used . St and ard exercise on a cycloergometer was used to induce EIB . Pulmonary function was determined before and after drug administration and exercise . Following no treatment or placebo , exercise result ed in average reductions of 33 % to 43 % in plethysmographic specific airway conductance ( SGaw ) , of 20 % to 25 % in forced expiratory volume in 1 sec ( FEV1 ) , and of 25 % to 32 % in maximal midexpiratory flow rate . Exercise following no treatment or placebo result ed in average increases of 23 % to 30 % in thoracic gas volume ( Vtg ) . Prior to exercise atropine and either dose of Sch 1000 caused significant increases in SGaw ( 48 % to 59 % ) . After pretreatment with Sch 1000 or atropine , exercise caused SGaw to fall to values that were not significantly different from pretreatment medication values , but were significantly higher than values following exercise without pretreatment or after pretreatment with placebo . No significant differences were noted between the effects of atropine and Sch 1000 on EIB . We conclude that at the doses used atropine and Sch 1000 cause equivalent degrees of bronchodilation but neither drug specifically inhibits EIB [2874047] The effect of adding ipratropium bromide to treatment with beta-2-adrenoceptor agonists was studied in 13 asthmatic children in a double-blind cross-over trial . In the acute phase of the study inhalation of salbutamol 0.1 mg/kg followed by inhalation of 0.25 mg of ipratropium bromide was found to improve pulmonary function variables to a significantly greater extent than salbutamol followed by placebo . The combined therapy also provided significantly better protection than salbutamol plus placebo against exercise-induced asthma . Maintenance treatment with ipratropium bromide ( two inhalations four times daily , 20 micrograms per inhalation ) in combination with oral terbutaline and aerosolized salbutamol did not alleviate asthmatic symptoms or pulmonary function variables to a degree beyond that achieved with the beta-stimulants alone . There were no side effects associated with the ipratropium bromide treatment . These data suggest that higher doses of ipratropium bromide than are presently used should be tested for maintenance treatment of chronic asthma [6236576] Isocapnic hyperventilation dose response curves were constructed for 11 asthmatic children before and after pretreatment with placebo or ipratropium bromide , 40 - 1500 micrograms given by inhalation , on three separate days . The response before and after placebo was highly reproducible ( within subject coefficient of variation 7.5 % , 18 % , and 22 % for intervals of two hours , within two weeks , and over two weeks ) . It was independent of baseline lung function . Complete protection against hyperventilation induced asthma was achieved by ipratropium bromide 40 micrograms in six children and by 200 micrograms or more in a further four . The remaining child was unaffected by any dose of ipratropium up to 1500 micrograms . The dose of ipratropium required for protection was better related to the subjects ' requirement for regular medication than to their sensitivity to hyperventilation or baseline lung function [2951804] 16 hyperreactive asthmatics were challenged with an ultrasonic mist of H2O at the same time of day on 4 usually consecutive days 2 h after premedication with placebo , fenoterol ( 200 micrograms ) , ipratropium bromide ( 80 micrograms ) and Duovent ( fenoterol 200 micrograms + ipratropium bromide 80 micrograms ) , given in r and om order and double-blind conditions . The challenge test consisted of 3 exposures of 30 , 60 and 120 s with 4-min intervals . Specific airway resistance ( sRaw ) was measured under basal conditions and 1 , 2 and 3 min after each exposure . FEV1 was measured under basal conditions and immediately after the last sRaw measurement . Fenoterol afforded a good protection ; ipratropium bromide alone was ineffective but enhanced the protective effect of fenoterol when the two drugs were given in combination ( Duovent ) . A similar effect was also observed after a second challenge performed 1 h ( 9 patients ) or 3 h ( 6 patients ) after the first one , which was performed 2 h after premedication [2932137] Twenty-four consecutive patients admitted to hospital with severe acute asthma were studied . Eleven were given 10 mg salbutamol by nebulizer followed 2 hours later by 500 micrograms of nebulized ipratropium bromide . These patients had a greater response in PEFR than 13 patients given two doses of 10 mg salbutamol 2 hours apart [6451257] Ipratropium bromide was given to patients admitted to hospital with acute asthma . A cumulative-dose-response technique in six patients showed that 500 micrograms given by nebuliser produced a maximal increase in peak expiratory flow rate . This dose of ipratropium bromide was included in a regimen in which it was given either two hours before or two hours after nebulised salbutamol to 22 patients . Ipratropium bromide given on admission was as effective as nebulised salbutamol . The two drugs in sequence produced greater bronchodilatation than either used alone , and the mean peak expiratory flow rate rose by 96 % in four hours . Thus giving ipratropium bromide in addition to salbutamol in severe asthma enhances the bronchodilator effect . Further studies are needed to determine whether the same effect may be obtained by giving two maximal doses of salbutamol two hours apart [6459045] We studied the effect of ipratropium on exercise-induced bronchoconstriction ( EIB ) at cold or warm temperatures . Although pulmonary function was better with ipratropium , its benefit was related to pre-exercise bronchodilation and not prevention of EIB . Ipratropium did not affect the augmented EIB in cold weather . Therefore , these phenomena are not primarily mediated via cholinergic mechanisms [2936370] Varying doses of nebulized salbutamol , ipratropium bromide and a combination of both were given to 20 asthmatic children . All therapies produced effective bronchodilation . Ten mg salbutamol caused elevation of pulse rate and finger tremor whilst the duration of action of 0.6 mg salbutamol was too short . Dose-response effects were clearly seen with salbutamol but not with ipratropium bromide . A summation effect was not demonstrated when the medications were combined [2958282] Fifteen children with exercise-induced asthma ( EIA ) participated in a double-blind trial comparing the protective effects of inhaled sodium cromoglycate ( 20 mg/2ml ) , ipratropium bromide ( 500 μg/2ml ) and verapamil ( 5 mg/2ml ) . Saline was used as control . There was no significant difference in base line pulmonary function before and after the administration of each agent . After exercise the maximal percentage fall in the forced expiratory volume in 1 s ( FEV-1 ) ( means and SD ) were 40.9±17.2 after inhalation of saline , 15.3±11.7 after sodium cromoglycate , 36.2±21.4 after verapamil and 21.7±17.7 after ipratropium bromide . The inhibitory effects of sodium cromoglycate and ipratropium bromide were significant whereas verapamil failed to produce any effect . To see if a double dose of verapamil is more effective , nine different children with EIA were provoked by the same st and ardized treadmill running after giving a placebo ( 4 ml saline ) and after verapamil ( 10 mg in 4 ml ) . Despite the double dose , again verapamil was ineffective even though the protection index doubled that obtained with the lower dose . The results suggest that the calcium antagonist ( verapamil ) had almost no effect on the prevention of EIA in the children studied [123712] Atropine is known to be an effective bonrchodilator . We studied the effectiveness of aerosol Sch 1000 , a derivative of atropine , in relieving bronchoconstriction in asthma . A single dose of drug was effective within 5 min , and the effect had a duration of 4 hours . No side effects were noted . The major effect of the drug appeared to be in large airways [10103297] Objective . To determine if the addition of ipratropium bromide to the emergency department ( ED ) treatment of childhood asthma reduces time to discharge , number of nebulizer treatments before discharge , and the rate of hospitalization . Methods . Patients > 12 months of age were eligible if they were to be treated according to a st and ardized ED protocol for acute asthma with nebulized albuterol ( 2.5 mg/dose if weight < 30 kg , otherwise 5 mg/dose ) and oral prednisone or prednisolone ( 2 mg/kg up to 80 mg ) . Subjects were r and omized to receive either ipratropium ( 250 μg/dose ) or normal saline ( 1 mL/dose ) with each of the first three nebulized albuterol doses . Further treatment after the first hour was determined by physicians blinded to subject group assignment . Records were review ed to determine the length of time to discharge home from the ED , number of doses of albuterol given before discharge , and the number of patients admitted to the hospital . Results . Four hundred twenty-seven patients were r and omized to ipratropium or control groups ; these groups were similar in all baseline measures . Among patients discharged from the ED , ipratropium group subjects had 13 % shorter treatment time ( mean , 185 minutes , vs control , 213 minutes ) and fewer total albuterol doses ( median , three , vs control , four ) . Admission rates did not differ significantly ( 18 % , vs control , 22 % ) . Conclusions . The addition of three doses of ipratropium to an ED treatment protocol for acute asthma was associated with reductions in duration and amount of treatment before discharge [2301781] Seventeen hospitalized children with acute asthma , ages 7 to 15 years , were studied to determine the efficacy of simultaneous administration of atropine sulfate and isoetharine . Combination therapy was superior in 11/17 ( 65 % ) patients while isoetharine alone was superior in 4/17 ( 23 % ) patients ( P = .037 ) . We conclude that simultaneous administration of combination therapy is safe and beneficial in some children with acute asthma [154747] In thirteen patients with extrinsic asthma the effects of placebo , sodium cromoglycate , ipratropium bromide , and ipratropium bromide plus sodium cromoglycate were studied in a r and om double-blind fashion to assess their inhibitory action in exercise-induced asthma ( EIA ) . Exercise testing consisted of steady state running on an inclined treadmill for up to eight minutes . In eight of the 13 patients studied the baseline ratio of expiratory flow at 50 % vital capacity ( VC ) breathing helium-oxygen ( V50He ) to V50air was over 1.20 and they were called responders ; the remaining five patients were called non-responders . There was a significantly lower baseline maximum mid-expiratory flow rate ( MMEF ) in non-responders ( P less than 0.02 ) as compared to responders but no difference in forced expiratory volume in one second ( FEV1 ) or forced vital capacity ( FVC ) . Sodium cromoglycate ( P less than 0.02 ) , ipratropium bromide ( P less than 0.01 ) , and ipratropium bromide plus spdium cromoglycate ( P less than 0.01 ) all significantly inhibited the percentage fall in FEV1 after exercise in the responders . Ipratropium bromide had no preventive action on non-responders , unlike sodium cromoglycate ( P less than 0.05 ) and ipratropium bromide plus sodium cromoglycate ( P less than 0.02 ) . It is postulated that mediator release is an important factor in development of EIA in most extrinsic asthmatics , whereas cholinergic mechanisms are relevant only in those patients in whom the main site of airflow obstruction is in the large central airways [2942116] Treatment with nebulised salbutamol or a mixture of salbutamol and ipratropium was given to 138 children . Length of hospital stay and number of nebulised doses required did not differ . In severe asthma response was greater with salbutamol alone . In mild asthma response was greater with combined treatment [10193252] OBJECTIVES To determine whether children with severe acute asthma treated with large doses of inhaled salbutamol , inhaled ipratropium , and intravenous steroids are conferred any further benefits by the addition of aminophylline given intravenously . STUDY DESIGN R and omised , double blind , placebo controlled trial of 163 children admitted to hospital with asthma who were unresponsive to nebulised salbutamol . RESULTS The placebo and treatment groups of children were similar at baseline . The 48 children in the aminophylline group had a greater improvement in spirometry at six hours and a higher oxygen saturation in the first 30 hours . Five subjects in the placebo group were intubated and ventilated after enrolment compared with none in the aminophylline group . CONCLUSIONS Aminophylline continues to have a place in the management of severe acute asthma in children unresponsive to initial treatment [6213382] In two groups of patients , 15 with asthma and 15 with chronic bronchitis , the bronchodilator effects of ipratropium bromide , of fenoterol plus theophylline , and of the combination of the three drugs , were compared using a double-blind , single-dose , placebo-controlled format . Ipratropium bromide caused rapid bronchodilatation which was not significantly different in asthmatic patients and patients with bronchitis ( delta FEV1 = .29 L in one hour in asthmatic patients , .18 L in patients with bronchitis ) . In contrast , fenoterol plus theophylline induced a considerably greater effect in asthmatic patients ( delta FEV1 = .41 L in one hour ) than in those with bronchitis ( delta FEV1 = .07 in one hour ) . The use of the three drugs in combination compared with ipratropium bromide alone , or fenoterol plus theophylline alone , result ed in a significant additional bronchodilatation in asthmatic patients . In the patients with bronchitis , the triple combination was clearly superior to fenoterol plus theophylline . A similar trend was present in comparing the triple combination to ipratropium bromide , but the difference did not reach statistical significance . There was no evidence of synergism when ipratropium bromide was combined with fenoterol plus theophylline in that the total bronchodilator effect was approximately additive . Asthmatic patients and the physician were able to distinguish the triple combination from placebo . No such ability was demonstrated with respect to those with bronchitis . All three drugs were well tolerated . Side effects were mostly mild , and none was related to the use of ipratropium [8497679] Inhaled bronchodilator therapy in young asthmatic children reduces symptoms and improves lung function . After a single dose of therapy , however , lung function may still be abnormal , as evidence d by an elevated function residual capacity ( FRC ) . The aims of this study were to assess if a second dose of bronchodilator therapy result ed in further improvement in lung function and to determine whether additional therapy was more effective if given as a second dose of a beta-adrenergic agonist or if instead an anticholinergic was used . Twenty-one asthmatics ( median age 7.5 years ) received in r and om order on two separate occasions , 1 week apart , either two doses of terbutaline ( 500 micrograms ) or terbutaline plus ipratropium bromide ( 20 micrograms ) . FRC and peak expiratory flow rate ( PEFR ) were measured immediately prior to and then 20 min after each dose of bronchodilator therapy . In the group , overall FRC and PEFR improved after the first and second dose of bronchodilator , regardless of regime used , the response to the second dose , however , was smaller than the first dose . There was no significant difference overall between the two regimes in baseline FRC or PEFR , or FRC and PEFR measured after each dose of bronchodilator . Eight children failed to show a significant change in FRC following two doses of terbutaline , but seven of these eight did have a significant change in FRC in response to the combination of terbutaline and ipratropium bromide . We conclude that a second dose of bronchodilator therapy does further improve lung function . Our results suggest the more efficacious regime consists of a combination of single doses of ipratropium bromide and terbutaline [2951807] Beta 2-adrenergic and anticholinergic drugs have shown an action in modulating bronchial hyperreactivity to various stimuli ( chemical , physical , immunological , pharmacological ) . The aim of our study was to compare the efficacy of a combination of ipratropium bromide and fenoterol ( Duovent ) with the activity of single drugs in the prevention of histamine-induced bronchospasm . Twenty-six atopic asthmatic subjects were examined in a double-blind trial , during an asymptomatic period , with a FEV1 value not lower than 20 % of the predicted normal value . During 4 consecutive days all patients received 2 puffs , respectively , of Duovent ( 200 micrograms fenoterol + 40 micrograms ipratropium bromide ) , fenoterol ( 400 micrograms ) , ipratropium bromide ( 80 micrograms ) and placebo in a r and omized order . PD20 values were evaluated after each drug administration : after 2 h in 16 patients and after 5 h in the other 10 patients . The data were modified to log values , and statistical analysis was performed by two-way analysis of variance . This study showed that Duovent and fenoterol have a protective effect against histamine-induced bronchospasm with a significant increase in the PD20 values 2 h ( p less than 0.01 ) and 5 h ( p less than 0.05 ) after treatment when compared to placebo . Duovent inhalation determined a more protective effect than other drugs but not significantly when compared to fenoterol . Some advantages in the modulation of bronchial reactivity could be seen from using Duovent because with the lower dose of the beta 2-adrenergic drug the same results could be obtained without side-effects [2974463] In a r and omized , double-blind , parallel-group trial , 47 children with acute asthma received a combination of ipratropium bromide solution ( 250 micrograms ) and fenoterol hydrobromide solution ( 625 micrograms ) , fenoterol solution ( 625 micrograms ) alone , or ipratropium solution ( 250 micrograms ) alone , administered by face mask and nebulizer , with the dose repeated 60 minutes later . The groups did not differ significantly with regard to age , pulmonary function at baseline , or any other variable . They were monitored at 30 , 60 , 90 , and 120 minutes by use of a clinical score , oxygen saturation , and pulmonary function tests . At the end of the study , albuterol was administered to assess residual bronchoconstriction . Clinical scores improved significantly after treatment in all groups at all times compared with baseline . The greatest improvement in FEV1 was seen in the patients treated with ipratropium/fenoterol , whether considered as absolute change , change in percent predicted , or percent change from baseline . Ipratropium/fenoterol was significantly better than fenoterol alone only when considered as percent change from baseline . Improvement in flow at mid and low lung volumes was significantly greater for the ipratropium/fenoterol combination than for ipratropium alone ; no significant differences were noted between ipratropium/fenoterol and fenoterol for flow at mid and low lung volumes . Treatment with albuterol did not significantly improve pulmonary function in the groups receiving ipratropium/fenoterol or fenoterol alone , but it did increase flow at all lung volumes in the group receiving ipratropium alone . No patient complained spontaneously of any adverse reactions , and no clinical ly significant changes in heart rate or systolic or diastolic blood pressures occurred . ( ABSTRACT TRUNCATED AT 250 WORDS [1190614] To evaluate the role of the parasympathetic nervous system in the mediation and maintenance of reversible airway obstruction in perennially asthmatic children , we measured pulmonary function in 18 patients before and after the administration of atropine sulfate aerosol . The bronchodilatory effects of atropine were compared with those of isoproterenol hydrochloride and placebo aerosols . Placebo aerosol did not change any of the pulmonary functions tested . Atropine and isoproterenol aerosols improved forced expiratory flows , airway resistance , and specific airway conductance significantly and to the same degree . Hyperinflation was significantly lessened by atropine , but not by isoproterenol . Because atropine is not a direct smooth muscle relaxant , but rather a selective blocker of cholinergically induced smooth muscle tone , any significant improvement in the lung function of chronically asthmatic children by atropine suggests that at least some of their reversible airway obstruction is induced and maintained by parasympathetically mediated bronchial smooth muscle constriction [11148512] OBJECTIVE To determine whether the addition of repeated doses of nebulized ipratropium bromide ( IB ) to a st and ardized inpatient asthma care algorithm ( ACA ) for children with status asthmaticus improves clinical outcome . STUDY DESIGN Children with acute asthma ( N = 210 ) age 1 to 18 years admitted to the ACA were assigned to the intervention or placebo group in r and omized double-blind fashion . Both groups received nebulized albuterol , systemic corticosteroids , and oxygen according to the ACA . The intervention group received 250 microg IB combined with 2.5 mg albuterol by jet nebulization in a dosing schedule determined by the ACA phase . The placebo group received isotonic saline solution substituted for IB . Progression through each ACA phase occurred based on assessment s of oxygenation , air exchange , wheezing , accessory muscle use , and respiratory rate performed at prescribed intervals . RESULTS No significant differences were observed between treatment groups in hospital length of stay ( P = .46 ) , asthma carepath progression ( P = .37 ) , requirement for additional therapy , or adverse effects . Children > 6 years ( N = 70 ) treated with IB had shorter mean hospital length of stay ( P = .03 ) and more rapid mean asthma carepath progression ( P = .02 ) than children in the placebo group . However , after adjustment was done for baseline group differences , the observed benefit of IB therapy in older children no longer reached statistical significance . CONCLUSION The routine addition of repeated doses of nebulized IB to a st and ardized regimen of systemic corticosteroids and frequently administered beta-2 agonists confers no significant enhancement of clinical outcome for the treatment of hospitalized children with status asthmaticus [6455096] The bronchodilator activity in nebulised salbutamol , ipratropium bromide , clemastine , and a placebo was studied in 14 asthmatic children aged between 3 and 5 years . Changes in lung function were monitored by measuring peak expiratory flow rate and total respiratory resistance using a modification of the forced oscillation technique . Ipratropium bromide produced a degree of bronchodilation similar to that of salbutamol , but the bronchodilatory activity of clemastine was not appreciably better than for the placebo [2531051] The effects of nebulized solutions of ipratropium bromide and fenoterol combined were compared with the response to either preparation alone in single dose and longer-term administration in children who had asthma . The combination produced a slightly greater response than either alone , especially in peak expiratory flow . Over a 1-month period , there were no significant differences in symptom scores or lung function parameters between the combination of ipratropium bromide and fenoterol and fenoterol alone in a group of children who had asthma . It is possible that the addition of ipratropium bromide to a sympathomimetic drug may be useful in a subgroup of asthmatics , particularly if there is a considerable large airway contribution to bronchial narrowing [10936118] STUDY OBJECTIVES To assess the safety and efficacy of salmeterol xinafoate as an adjunct to conventional therapy for the in-hospital management of acute asthma . DESIGN A prospect i ve , double-blind , r and omized placebo-controlled trial . SETTING Medical wards of a large university-based hospital . PATIENTS Forty-three patients admitted for an acute exacerbation of asthma . INTERVENTIONS Salmeterol ( 42 microg ) or two puffs of placebo every 12 h in addition to st and ard therapy ( short-acting beta-agonists , corticosteroids , and anticholinergic agents ) . RESULTS No clinical ly adverse effects were seen with the addition of salmeterol to conventional therapy . After salmeterol , there was no difference in pulse , respiratory rate , oxygen saturation by pulse oximetry , severity of symptoms , or dyspnea score . Patients receiving salmeterol had greater FEV(1 ) percent improvements than the placebo group at 12 , 24 , 36 , and 48 h. These findings were not statistically significant . By paired Student 's t tests , there were significant improvements in FEV(1 ) ( p = 0.03 ) and FVC ( p = 0.03 ) in the salmeterol group after 48 h of treatment with no comparable improvement in the placebo group . In a subgroup analysis of patients with an initial FEV(1 ) < or = 1.5 L , the absolute FEV(1 ) percent improvement for salmeterol vs placebo was 51 % vs 16 % at 24 h and 54 % vs 40 % at 48 h. The relative FEV(1 ) percent improvement for salmeterol vs placebo was 17 % vs 8 % at 24 h and 18 % vs 14 % at 48 h. CONCLUSION The addition of salmeterol to conventional therapy is safe and may benefit hospitalized patients with asthma . Further studies are needed to clarify its role in the treatment of acute exacerbation of asthma [8003853] In a r and omized , double-blind , placebo-controlled study , we investigated the protective effects of ipratropium bromide 160 micrograms and 320 micrograms and terbutaline 500 micrograms on ultrasonically nebulized distilled water (UNDW)-induced bronchoconstriction in nine stable asthmatic patients . Both drugs caused a significant increase ( P < 0.001 ) in baseline FEV1 with no significant differences between the drugs or both doses of ipratropium bromide . Pre-inhalation of ipratropium bromide 320 micrograms and terbutaline 500 micrograms inhibited UNDW-induced bronchoconstriction ( P < 0.01 ) , whereas ipratropium bromide 160 micrograms had no protective effect . The protective effects of ipratropium bromide showed a large interindividual variation . There was no correlation between the increase in baseline FEV1 and PD20 UNDW , indicating that the protective effect on UNDW-induced bronchoconstriction is not dependent on the bronchodilation induced by terbutaline and ipratropium bromide . It also appears that the UNDW-induced bronchoconstriction is at least partly vagally mediated [6219156] The role of the anticholinergic drug , ipratropium bromide , in maintenance antiasthmatic therapy was evaluated in a double-blind crossover trial of three bronchodilator regimens : ( 1 ) inhaled ipratropium , placebo , and oral oxtriphylline ; ( 2 ) inhaled fenoterol , placebo , and oral oxtriphylline ; and ( 3 ) both inhaled ipratropium and fenoterol plus oral oxtriphylline . Twenty-two asthmatics were treated with all three regimens , each for 1 mo , allocated in r and om sequence . On the first and last treatment days of each month , spirometric measurements were performed before and 0.5 , 1 , 2 , 3 , 4 , and 6 hr after administration of the test drugs . On the first treatment day of each month , all regimens produced significant bronchodilatation at 30 min after dose , an improvement that declined between 3 and 6 hr after dose . After continuous administration for 1 mo the two combinations employing fenoterol showed a decline in bronchodilator responsiveness from the initial treatment day , measured as the level of response ( V50 ) or duration of response ( FEV1 , VC ) . Ipratropium plus oxtriphylline showed no such decline , suggesting the development of tolerance to long-term administration of fenoterol . Overall benefit at the end of 1 mo , measured as the area under the curves of FEV1 , VC , or V50 vs time after dose , was greatest for the triple drug regimen . There were no differences in heart rate , blood pressure response , or side effects among the three treatments . It is concluded that when the anticholinergic drug ipratropium is administered concurrently with an inhaled beta 2 agonist and an oral theophylline derivative , increased bronchodilatation occurs with no detectable additional side effects [9787684] OBJECTIVES To compare the effectiveness and safety of alternative nebulized drug protocol s in children with mild or moderate asthma exacerbations . METHODS We conducted a blinded , r and omized , controlled trial with a 2 x 2 factorial design . Two interventions , nebulized salbutamol in frequent low doses ( 0.075 mg/kg every 30 minutes ) and the addition of ipratropium bromide ( 250 micrograms ) , were compared with salbutamol in hourly high doses ( 0.15 mg/kg every 60 minutes ) in children with mild or moderate acute asthma . The primary end point was the improvement in respiratory resistance . Secondary end points included oxygen saturation , corticosteroid use , patient disposition , and relapse status . RESULTS A total of 298 participants aged 3 to 17 years were studied , and 15 % were admitted to the hospital ; 14 % of the children had relapses . No increased bronchodilation was associated with frequent low doses versus hourly high doses of salbutamol ( RR = 0.9 [ 95 % confidence interval 0.7 , 1.3 ] ) or the addition of ipratropium bromide versus placebo ( RR = 1.0 [ 0.8 , 1.3 ] ) . No group differences were observed in secondary end points . Salbutamol in frequent low doses was associated with increased vomiting ( RR = 2.5 [ 1.1 , 6.0 ] ) . CONCLUSION Our results do not support the use of frequent low doses of nebulized salbutamol or the addition of ipratropium bromide compared with hourly high doses of salbutamol in children with mild or moderate asthma [7699549] OBJECTIVE The objective of this trial was to determine the efficacy of frequent nebulized ipratropium added to high-dose albuterol therapy in children with severe asthma . METHODS One hundred twenty children ( 5 to 17 years ) of age ) with severe acute asthma ( forced expiratory volume in 1 second ( FEV1 ) , < 50 % of the predicted value ) were enrolled into a r and omized double-blind three-arm placebo-controlled trial comparing three groups : group 1 , three doses of nebulized ipratropium bromide within 60 minutes ( 250 micrograms/dose ) ; group 2 , one dose of ipratropium ; group 3 , no ipratropium . All patients were also treated with three doses of nebulized albuterol within 60 minutes ( 0.15 mg/kg per dose ) . Pulmonary function and clinical measures were assessed every 20 minutes for up to 120 minutes . RESULTS The groups were comparable at baseline . At 120 minutes , the mean percentage of predicted FEV1 improved from 33.4 % to 56.7 % in group 1 , from 34.2 % to 52.3 % in group 2 , and from 35.4 % to 48.4 % in group 3 ( p = 0.0001 ) . The differences between groups were larger in those children with a baseline FEV1 < or = 30 % of the predicted value : FEV1 increased from 24.5 % to 50.9 % in group 1 , from 25.0 % to 39.8 % in group 2 , and from 25.9 % to 36.5 % in group 3 ( p = 0.0001 ) . In group 1 , 38 % of the patients were hospitalized after the study , 44 % in group 2 , and 46 % in group 3 ( p value not significant ) . However , in patients with FEV1 < or = 30 % , the hospitalization rates were 27 % in group 1 , 56 % in group 2 , and 83 % in group 3 ( p = 0.027 ) . There were no toxic effects attributable to ipratropium . CONCLUSION The addition of repeated doses of nebulized ipratropium to frequent high-dose albuterol therapy in patients with acute severe asthma is both safe and more effective than albuterol alone ; its use in patients with very severe asthma may reduce hospitalizations [8933892] We examined the resolution of the bronchial spasm induced by methacholine after administration of a dose sufficient to provoke PD20 to study , in patients with bronchial asthma , how spontaneous resolution ( as opposed to bronchodilator-induced resolution ) takes place . According to a r and omization criterion , the patients were divided into four groups : 1 ) resolution induced by salbutamol ( S ) , 2 ) by ipratropium bromide ( I ) , 3 ) after placebo ( P ) and 4 ) spontaneous resolution ( R ) . In brief , we observed that variations in FEV1 after methacholine PD20 , reach statistically significant levels after 15 minutes in patients from groups ( S ) and ( I ) , after 30 minutes in patients from groups ( P ) and ( R ) ( p < 0.05 ) . Comparing the phenomenon at various intervals in the four experimental situation , we found a pairing trend : groups ( S ) and ( I ) on the one h and , and groups ( P ) and ( R ) on the other . On the whole , this phenomenon shows that pharmacological treatment accelerates the process of spontaneous resolution of the bronchial spasm induced by methacholine which , in our experience , beings to show after 15 minutes , and that after 60 minutes , there are no statistically significant differences in the four groups . It is our opinion that closer examination of this phenomenon may provide greater knowledge of the mechanisms that come into play during the phase after stimulation of the muscarinic receptors and that reasonably involve the system to eliminate the muscarinic drug [137921] The efficacy and acceptability of ipratropium given by metered-dose inhaler were evaluated in two double-blind crossover tests against placebo , one preceding and one following a 2-wk period of continual open-label ipratropium treatment . Ten patients with chronic bronchitis and 10 with bronchial asthma participated . Ipratropium produced increase in FEV 1 of more than 15 % within 5 min of inhalation , and this effect was maintained for 4 to 5 hr . Statistically significant mean increases over the FEV 1 baseline values were recorded after ipratropium treatment in both the initial and the final crossover tests . There were no adverse reactions to any of the placebo or ipratropium test doses or to the ipratropium treatment . Serial electrocardiograms , laboratory tests , blood pressure , and pulse rate showed no change from lthe baseline . Sputum volume and dry-weight determinations in the patients with bronchitis before and after the 14-day treatment revealed no changes [1387512] Ulrik CS , Backer V , Bach‐Mortensen N. Bronchodilating effect of ipratropium bromide inhalation powder and aerosol in children and adolescents with stable bronchial asthma [2968769] The capacity of salbutamol 0.3 mg ( SAL ) , disodium cromoglycate 3 mg ( DSCG ) , a combination ( SAL + DSCG ) , and ipratropium bromide 80 ug ( IB ) , all given as metered aerosols to prevent exercise‐induced ( EIA ) , was compared with that of a placebo , a peroral lactose pill . Seven children participated , having reproducible EIA provoked by running on a treadmill at a heart rate of 170 sustained for 6 min . FEV , and volume of trapped gas ( VTG ) , defined as the air volume released during rebreathing oxygen with maximum breaths at the end of a multiple breath nitrogen wash out , were used as tests of spasm in large and small airways . SAL and SAL + DSCG offered complete protection in large and small airways . DSCG and IB prevented EIA in large airways ( FEVj ) to 95 % , but only to about 50 % in small airways ( VTG ) . SAL or SAL + DSCG gave significantly better protection ( FEV1 and VTG ) than DSCG and IB ( P < 0.01 ) . Differences between DSCG and IB were not statistically significant . DSCG or propellant caused significant irritation and spasm in small airways ( VTG ) before exercise . Most subjects seemed to obtain satisfactory protection against EIA by β2‐agonists [2145790] Inhaled albuterol ( A ) ( salbutamol ) alone and albuterol plus ipratropium bromide ( IB ) were administered to 12 asthmatic children . Following administration of A alone or in combination with IB , there was a significant increase in FEV1 and FEF . Significant statistical difference in favor of the association A plus IB was observed at 120 and 240 minutes for FEV1 and in the period 120 , 180 , and 240 minutes for FEF . The additive effect was present both in the large and small airways . The short-lived additive effect of A plus IB suggests the opportunity to increase the frequency of drug administration in patients with severe bronchial obstruction [150323] n the 1960 's . Boehringer-Ingelheim , Ltd synthesized a 1 . s e n e of atropine derivatives , including N isopm pylnortropine tropic acid ester methyl bromide ( Atru vent ) . This drug is class8ed pharmacologically as an anticholinergic and its mechanism of action is vagal inhibition which prevents reflex bronchoconstriction . When given parenterafly , it bas anticbolinergic activity equal to or more potent than atropine . However , when administered by inhalation as a metered aerosol low doses are effective in the bronchial @ee ( local effect ) and do not show any atropine-like side effects . It may therefore be characterized as a peripheral anticholinergic , exercising particularly high spasmolytic activity in the bronchial region . The portion of Atrovent which adheres to the oral and pharyngeal mucosa and is later & lowed is poorly absorbed and therefore does not produce atropine-like effects even after high doses . Because of i b lack of cardiac effects Atrovent may be considered as a therapeutic alternative to beta-adrenergic bmnchodilators , especially for patients who are particularly sensitive to sympatbomimetic stimulation . Thirteen patients with asthma , as defined by the American Thoracic Society , were studied during a stable period of their disease . There were six males and seven females ranging in age from 18 to 52 yean ( mean 25 yean ) wbose asthma varied from miM to severe . Reversible bronchospasm was confirmed at the enby into the study by demonstrating an improvement of at least 15 percent increase in FEV , . within 30 minutes fouowing two inhalations of isoproterend from a metered dose inhaler . Isoproterenol ( 0.15 mg ) was used as a control in a double-blind comparison with Atrovent ( 0.40 mg ) administered at one dosage level , so that each patient received a total of two beatments with an interval of at least 24 hours between treatments . The sequence of treatments was r and omized [2203617] The bronchodilator effect of nebulized AMN , albuterol and their combination was evaluated in 16 steroid-dependent asthmatic children . In phase 1 , maximal bronchodilation was determined by dose-response studies on separate days . Maximal bronchodilator dose of each drug was administered either alone or in combination during phase 2 . In phase 1 , 0.11 + /- 0.01 mg/kg of albuterol and 0.03 mg/kg of AMN produced maximum bronchodilation . In phase 2 , the peak response to albuterol occurred within 30 min and to AMN , at 60 min . Maximal FEV1 achieved after AMN was 90 percent of the maximal achieved after albuterol . AMN FEV1 response was better than for placebo for 3 h ; that for albuterol was better for 4 h. Combination therapy produced a peak response similar to that of albuterol but was better than albuterol by 6 h. Thus , the maximum bronchodilator effect of AMN is less than that of albuterol in asthmatic children , but the combination may extend the period of bronchodilatation [2521989] Thirteen children with perennial bronchial asthma , with a mean age of 11.2 years , were studied concerning the bronchodilatory effect of ipratropium bromide in cumulative doses . All the children had reduced basal forced expiratory flow ( FEV1 ) and bronchial reversibility of at least 20 % after inhalation of salbutamol . The study had a double-blind design with a crossover technique . The inhaled dose of ipratropium bromide solution was increased stepwise from 25 micrograms to 500 micrograms and saline was used as the placebo . FEV1 was recorded 20 , 40 , and 60 minutes after inhalation of the test solution . At the lower ipratropium bromide dose levels no bronchodilatory effect was seen , but 60 minutes after the inhalation of 500 micrograms ipratropium bromide the increase in the FEV1 was significantly greater than that after placebo . Additional inhalation of salbutamol caused no further rise in FEV1 . At the 500-micrograms level a fall in the heart rate was noted . No side effects occurred . We concluded that ipratropium bromide has bronchodilatory properties in childhood asthma when given in sufficiently high doses [151547] Eleven patients with bronchial asthma and 10 with chronic bronchitis were treated over four consecutive 3-day periods , firstly with aerosols either of ipratropium bromide ( 40 microgram four times a day ) or of salbutamol ( 200 microgram four times daily ) by r and om allocation , then the alternate drug , next by both drugs together , and finally with prednisolone ( 10 mg three times daily ) in addition to both drugs . The effects of these four treatment periods were assessed both clinical ly and by measuring ventilatory capacity , nitrogen slope and progressive exercise testing . Ipratropium bromide and salbutamol produced approximately equal improvements in both diseases , with salbutamol showing a marginal advantage in patients with asthma . The combination of both drugs together more than doubled the FEV1 change in both groups of patients . The addition of prednisolone to both drugs produced a marginal advantage only in those with asthma [1360776] Oxatomide is a potent inhibitor of both the release and effects of allergic mediators and is similar to calcium antagonists in chemical structure . It prevents histamine release by inhibiting not only the increase in calcium intake , but also intracellular calcium release . We investigated its effect on methacholine-induced and exercise-induced bronchoconstriction in asthmatic children . Methacholine challenges were performed after oral administration of 0.88 mg/kg oxatomide or placebo in nine asthmatic children in a double-blind placebo-controlled study . Respiratory thresholds were improved in seven patients and log PC20 in the oxatomide group ( 6.65 + /- 1.34 micrograms/mL ) was significantly higher than that in the placebo group ( 5.74 + /- 1.04 micrograms/mL ) ( P < .05 ) . Exercise challenges were performed after oral administration of 1.5 mg/kg oxatomide or placebo in eight asthmatic children in a double-blind placebo-controlled study . Oxatomide produced acute bronchodilatation with 6.1 % improvement on an average in FEV1 . The mean maximal % fall obtained by oxatomide was 13.5 % , while that by placebo was 22 % ( P < .05 ) . These results indicate that oxatomide reduces nonspecific bronchial hyperresponsiveness [7958119] A combination dose aerosol of fenoterol hydrobromide ( 200 micrograms ) and ipratropium bromide ( 80 micrograms ) was compared with aerosolized salbutamol ( 200 micrograms ) in 10 stable asthmatic patients . With both treatments a statistically significant improvement was noticed in both FEV1 and PEF measurements starting after 15 minutes and continuing until 330 to 360 minutes . No statistically significant differences in one second Forced Vital Capacity ( FEV1 ) and Peak Expiratory Flow ( PEF ) was noted between the two treatments . No side effect was noticed . As a result , it was concluded that in bronchial asthmatic patients , the bronchodilator effects of the combination of a beta-2 agonist with anticholinergic drugs was as effective and lasted as long as salbutamol . This combination , in order to prevent cardiovascular complications , could be selected as a suitable treatment for those patients who need high doses of beta-2 agonist drugs [3428339] Summary A vagal mechanism appears to be involved in the development of exercise-induced asthma ( EIA ) , although previous studies have failed to demonstrate a protective effect of anticholinergic drugs against post-exercise bronchoconstriction . To reassess this hypothesis the effect of a new anticholinergic drug , Oxitropium Bromide ( OTB ) has been studied in ten subjects with documented EIA.There was no change after inhalation of a placebo . Administration of OTB led to bronchodilatation and totally blocked post-exercise bronchoconstriction in 7 patients , and it did so partly in 2 . The response to the drug appeared to depend on pretest respiratory function . Thus , the anticholinergic drug OTB may protect against EIA in most patients , confirming the role of a vagal cholinergic mechanism in EIA [4631042] arthritis of the right hip . It was then discovered that he had had mild diarrhoea for over 10 years . On examination there were no significant abnormal physical signs except restricted movements of his right hip ; no abdominal tumour could be felt . Sigmoidoscopy revealed a moderate degree of proctitis and biopsy showed the features of chronic ulcerative colitis , but there was no premalignant change in the rectal mucosa . Barium enema revealed extensive ulcerative colitis with a constant stricture in the transverse colon ( fig. 2 ) . At operation [6447269] The effect of 40 microgram of SCH 1000 ( ipratropium bromide , an anticholinergic agent ) on bronchodilation and suppression of exercise-induced bronchospasm ( EIB ) was compared with 400 microgram of fenoterol and a placebo in a single-blind controlled study . Twenty-seven r and omly selected asthmatic children performed a st and ardized treadmill exercise challenge and the 17 children who were shown to have EIB continued in the study . Pulmonary function was evaluated before and after drug administration and exercise . When individual results were analyzed and grouped according to the responsiveness of EIB to the drugs , two patterns emerged : ( 1 ) the EIB was more severe in those ( 6/17 ) children who did not respond to either drug than in the rest of children ; ( 2 ) the resting pulmonary function was significantly better in the children ( 4/17 ) who responded to both drugs than in those ( 7/17 ) who responded to fenoterol alone . In conclusion SCH 1000 was shown to be an effective bronchodilator comparable to , but no better than , fenoterol . It had minimal side effects . As an EIB inhibitor it depended on relatively normal base line pulmonary function and only a moderate deterioration following exercise , whereas fenoterol depended on the exercise response alone . Although anticholinergic drugs are not very extensively used , SCH 1000 may be useful in some patients where the beta 2 adrenergic drugs cause signficant side effects or are contraindicated [6461943] Eighteen children between 6 and 14 years of age with perennial asthma were studied over two four-week treatment periods . Ipratropium bromide , given in addition to their current treatment , was compared with placebo using a double-blind crossover technique . The period of treatment with ipratropium was associated with a significant reduction in symptoms during both day and night and significantly higher morning peak expiratory flow rates [6239021] IPRATROPIUM BROMIDE is a quaternary isopropyl derivative of the muscarinic antagonist atropine that has bronchodilator properties when administered topically via the respiratory airways . Because of its quaternary nature , it is poorly absorbed into the bloodstream after direct application into the bronchial tree ; the cardiovascular side effects are thus minimal . For these reasons ipratropium could represent a significant advance in therapy , especially considering its alternative mode of action via blockade of the cholinergic system rather than stimulation of ~adrenoceptors . Initial information on ipratropium solution has indicated that a dose of 250 # g can be given safely to preschool children with asthma and that the bronchodilation is comparable to that achieved by salbutamol . ~ The purpose of our study was to determine the optimal dosage of ipratropium solution when administered by aqueous nebulization , by constructing a dose-response curve in children of school age . [2931507] NEBULIZED specific beta-2 agonists such as salbutamol ( albuterol ) are widely preferred as the first-line drugs of choice for treating acute asthma in Children . Many studies have shown their efficacy as well as convenience in delivery ) , 2 Administration of frequent small doses ( 50 t ~ g/kg/dose every 20 minutes ) of nebulized salbutamol is safe and superior to the more conventional hourly dosing ( 150 /~g/kg/dose ) , producing a smoother rise in forced expiratory volume in 1 second and an earlier peak response without deterioration between doses ) However , even with this aggressive approach , significant residual airways obstruction remains despite additional doses of salbutamol . This suggests that the residual airways obstruction is related to factors unresponsive to beta-2 bronchodilators , such as mucosal edema , secretions , or cholinergic bronchomotor .tone . Ipratropium bromide is a quaternary ammonium derivative of atropine . When delivered by inhalation , it produces a local anticholinergic effect with no systemic absorption ? . 5 It is a potent bronchodilator , comparable to beta-2 agonists , and has been found to be very Useful , especially in adults with chronic bronchitis ? . 5 Our study was design ed to determine whether ipratropium bromide , by its anticholinergic action , could improve the residual airways obstruction seen after treatment with salbutamol alone . [11348957] STUDY OBJECTIVE To determine whether adding IV theophylline to an aggressive regimen of inhaled and IV beta-agonists , inhaled ipratropium , and IV methylprednisolone would enhance the recovery of children with severe status asthmaticus admitted to the pediatric ICU ( PICU ) . DESIGN A prospect i ve , r and omized , controlled trial . Asthma scoring was performed by investigators not involved in treatment decisions and blinded to group assignment . SETTING The PICU of an urban , university-affiliated , tertiary-care children 's hospital . PATIENTS Children with a diagnosis of status asthmaticus who were admitted to the PICU for < or = 2 h and who were in severe distress , as indicated by a modified Wood-Downes clinical asthma score ( CAS ) of > or = 5 . INTERVENTIONS All subjects initially received continuous albuterol nebulizations ; intermittent , inhaled ipratropium ; and IV methylprednisolone . The theophylline group was also administered infusions of IV theophylline to achieve serum concentrations of 12 to 17 microg/mL. A CAS was tabulated twice daily . MEASUREMENTS AND RESULTS Forty-seven children ( median age , 8.3 years ; range , 13 months to 17 years ) completed the study . Twenty-three children received theophylline . The baseline CASs of both groups were similar and included three subjects receiving mechanical ventilation in each group . All subjects receiving mechanical ventilation and theophylline were intubated before drug infusion . Among the 41 subjects who were not receiving mechanical ventilation , those receiving theophylline achieved a CAS of < or = 3 sooner than control subjects ( 18.6 + /- 2.7 h vs 31.1 + /- 4.5 h ; p < 0.05 ) . Theophylline had no effect on the length of PICU stay or the total incidence of side effects . Subjects receiving theophylline had more emesis ( p < 0.05 ) , and control patients had more tremor ( p < 0.05 ) . CONCLUSIONS Theophylline safely hastened the recovery of children in severe status asthmaticus who were also receiving albuterol , ipratropium , and methylprednisolone . The role of theophylline in the management of asthmatic children in impending respiratory failure should be reexamined [3160273] Postexertional wheezing is an important clinical sign of nonspecific airway hyperreactivity . We have studied wheezing after exercise in 6 asthmatic subjects , 13 to 20 yr of age , using spectral analysis of recorded tracheal sounds . Automated spectral characterization was used to measure wheezing as a proportion of respiratory time . Anticholinergic treatment with ipratropium bromide ( Atrovent ) was compared with placebo to investigate effects on postexertional wheezing , and pulmonary function was compared with the result of respiratory sound analysis . Atrovent did not abolish exercise-induced bronchospasm but improved preexercise lung function and thereby caused a parallel upward shift in the response curves . Wheezing after Atrovent was significantly less , later in onset , and mainly expiratory at 20 min after exercise . Wheezing as a percentage of total respiratory time correlated well with FEV1 , Vmax50 , and SGaw . Analysis of respiratory sounds and automated quantification of wheezing may be a useful complementary test of bronchial obstruction in asthma [2948430] The effects of the beta 2-adrenergic agonist salbutamol ( 0.02 mL/kg of a 0.5 % solution ) and the cholinergic antagonist ipratropium bromide ( 2 mL of a 0.025 % solution ) , administered alone or in combination at different doses , were evaluated in 48 asthmatic children using a single-dose , double-blind , crossover design . Spirometric measurements were taken before and 10 , 30 , 60 , 120 , 180 , 240 , 300 , and 360 minutes after administration of the drugs . All regimens produced significant bronchodilatation 10 to 30 minutes after administration . The improvement began to decline three to four hours after inhalation , particularly when ipratropium bromide was administered alone . The administration of the salbutamol plus ipratropium combination did not significantly improve pulmonary function values as compared to salbutamol alone . The effects of salbutamol and ipratropium bromide in half-dose or full-dose combinations were indistinguishable . No significant adverse effects on blood pressure or heart rate were observed [347990] In a double-blind study in 23 asthmatic patients Sch 1000 was found to be an effective bronchodilator with an onset of effect within 15 minutes and a duration of four hours . It was effective on both small and large airways [6119168] Two groups of eight asthmatic children carried out serial treadmill exercise tests at 2‐hourly intervals , after double‐blind premedication with oxatomide ( 2 mg/kg by mouth ) , sodium cromoglycate powder ( 20 mg by inhalation ) or matched placebo preparations . The drugs were studied in one group up to 6 hr and in the other group ( omitting sodium cromoglycate ) from 4 to 10hr after administration . Peak expiratory flow rate was measured before and after exercise to give an index of exercise‐induced asthma [2525377] A double-blind crossover study was performed on 33 children with asthma to compare the effectiveness of nebulized solutions of preservative-containing and preservative-free ipratropium bromide . Both solutions produced bronchodilation . No significant differences were found between the two solutions at any time after nebulization in minimum and maximum changes from baseline value or in the areas under the lung function time curves . The presently formulated preservative-containing ipratropium bromide solution was not shown to be inferior to a preservative-free compound [2244710] The combination of nebulized atropine methylnitrate ( AMN ) and a beta-agonist has been shown to produce greater and longer lasting bronchodilation than either drug alone . We examined the efficacy of the combination in diminishing the " morning dipping " in PEFR in eight hospitalized but stable asthmatics . The patients received nebulized albuterol along with either AMN ( AMN + ALB ) or placebo ( ALB ) in a r and om double-blind cross-over fashion at 10 PM on four nights . PEFR and FEV1 were recorded at 6 PM , 10 PM , and 6 AM before the administration of bronchodilators . There was no statistically significant difference between ALB and AMN + ALB in reducing the morning dipping in these patients [7719260] The study was carried out on 19 patients with moderate and severe bronchial asthma . During three days after the initial spirometric evaluation the patients received -- on the first day 0.5 mg of pirenzepine in nebulization ( P ) , on the second day 0.25 mg of ipratropium bromide ( IB ) , on the third day both substances together . Ventilatory parameters were monitored on the 5th , 20th , 40th and 60th minute following nebulization . The observed parameters did not differ significantly between both groups . Pirenzepine given after ipratropium bromide increased FEV1 from 1.89 L to 2.37 L ( p < 0.01 ) . The observed results imply that pirenzepine given with ipratropium bromide induce a significant bronchodilating effect and could be added to therapy of bronchial asthma [9353508] Abstract Objectives : To determine the effect of regular prophylactic inhaled corticosteroids on wheezing episodes associated with viral infection in school age children . Design : R and omised , double blind , placebo controlled trial . Setting : Community based study in Southampton . Subjects : 104 children aged 7 to 9 years who had had wheezing in association with symptoms of upper and lower respiratory tract infection in the preceding 12 months . Interventions : After a run in period of 2–6 weeks children were r and omly allocated twice daily inhaled beclomethasone dipropionate 200 μg or placebo through a Diskhaler for 6 months with a wash out period of 2 months . Children were assessed monthly . Main outcome measures : Forced expiratory volume in 1 second ( FEV1 ) ; bronchial responsiveness to methacholine ( PD20 ) ; percentage of days with symptoms of upper and lower respiratory tract infection with frequency , severity , and duration of episodes of upper and lower respiratory symptoms and of reduced peak expiratory flow rate . Results : During the treatment period there was a significant increase in mean FEV1 ( 1.63 v 1.53 l ; adjusted difference 0.09 l ( 95 % confidence interval 0.04 to 0.14 ) ; P=0.001 ) and methacholine PD20 ( 12.8 v 7.2 μmol/l ; adjusted ratio of means 1.7 ( 1.2 to 2.4 ) ; P=0.007 ) in children receiving beclomethasone dipropionate compared with placebo . There were , however , no significant differences in the percentage of days with symptoms or in the frequency , severity , or duration of episodes of upper or lower respiratory symptoms or of reduced peak expiratory flow rate during the treatment period between the two groups . Conclusions : Although lung function is improved with regular beclomethasone dipropionate 400 μg/day , this treatment offers no clinical ly significant benefit in school age children with wheezing episodes associated with viral infection . Key messages Increasing evidence suggests that episodic wheezing in children in association with viral infections is a separate entity from atopic asthma Although inhaled corticosteroids are beneficial in asthma , their role in treating wheezing associated with viral infections is unclear In this study regular inhaled corticosteroids result ed in improved lung function and decreased bronchial responsiveness but did not have any effect on episodes of wheezing Inhaled corticosteroids are of little benefit in children with episodic wheezing associated with viral [3155982] frequent development of tachyphylaxis apart from numerous other toxic reactions and the painfulness of the injections . The main advantage of dimercaprol is that the molecule is not charged , is soluble in lipids , and is able to cross the blood-brain barrier fairly easily compared with penicillamine , trientine dihydrochloride , and unithiol , which are highly charged . Treatment with unithiol was started in two other patients . The first developed a fever of 39"C four hours after the test dose and a 50 ° , fall in the leucocyte count . A further challenge dose caused a similar reaction and treatment was not pursued . This patient was subsequently managed with tetrathiomolyb date .3 The second patient took unithiol for 10 days before refusing it because of intense nausea and a change in taste . Other patients have received single test doses , and the result ing cupruresis has been comparable with that after penicillamine and trientine dihydrochloride in most cases . Unithiol may well prove to be yet one more fall back treatment for patients who develop intolerance to penicillamine [7719261] The bronchodilatory activity of Berodual in comparison to Fenoterol and Ipratropium Bromide was investigated in a group of 59 children aged 8 - 15 years , suffering from mild bronchial asthma in a symptoms-free period . The relaxing activity was monitored dynamically by means of the analysis of flow-volume curve measurements . We have found that the bronchodilatory activity of Berodual was faster , stronger and longer in comparison to Fenoterol and Ipratropium Bromide [7016106] : The efficacy of adding oral or inhaled atropine sulphate to the maintenance therapy of 12 children with severe chronic asthma was assessed using a double blind crossover study lasting three months . There was no obvious subjective or objective clinical difference between either form of atropine sulphate and placebo . Twice daily peak flow rates were not significantly different for the three treatment periods . However , during oral atropine therapy there was a significant improvement in FEV1/ VC ( P < 0.05 ) and in RV/TLC ( P < 0.05 ) compared to placebo . Inhaled atropine had no significant effect on baseline pulmonary function testing . No side effects were encountered . Further clinical trials are necessary to confirm the beneficial effect of long term oral atropine sulphate in the treatment of children with severe chronic asthma [6240599] In a double blind r and omized study during a period of 2 weeks we compared the therapeutic effectiveness and side effects of IK-6-Inhaletten ( 0.1 mg Fenoterol + 0.04 mg Ipratropiumbromide ) and SCH 1000-Inhaletten ( 0.2 mg Ipratropiumbromide ) in 39 children ( 4 - 14 years ) suffering from mild , moderate or severe asthma bronchiale . All measurements were performed with a whole body plethysmograph . In contrast to SCH 1000-inhalation after inhalation of IK-6-Inhaletten , we found a good improvement of the total airway resistance Rtot , the specific airway resistance SRaw and the forced exspiratory volume FEV1 . Especially SRaw was significantly diminished compared to the less effective SCH 1000-inhalation . IK-6-inhalation allowed to decrease the amount of bronchospasmolytic therapy in our group of patients . We did not observe any severe side effects after inhalation of IK-6 or SCH 1000 . In summary , we recommend the application of the IK-6-Inhaletten in children suffering from mild and moderate asthma bronchiale [2951802] Exercise-induced asthma ( EIA ) is a frequent symptom in asthmatic patients . The study of drugs which inhibit EIA is very important because EIA seriously limits the life of the patients . In addition , this study could allow further insights to be gained into the pathogenesis of the phenomenon . The aim of the present study is to evaluate the duration of the protective effect of fenoterol alone or in combination with ipratropium bromide administered 5 h before exercise . For this purpose we studied 12 asthmatic patients ( 7 males and 5 females , mean age 23 , range 7 - 41 years ) with EIA , in clinical and functional stable state . Respiratory function parameters were measured before and 5 h after the administration of fenoterol 400 or 200 micrograms , or fenoterol 200 micrograms plus ipratropium bromide 80 micrograms ( Duovent ) , or placebo in r and omized order . Then , such parameters were measured at 5 , 15 , 30 , and 60 min after exercise , which consisted of free running up and down the stairs . The results show that , at 5 h after the administration of each drug , the protective action against EIA is only partial . However , the intense bronchodilation afforded by the ' active ' drugs , and particularly by 400 micrograms of fenoterol , keeps post-exertional respiratory parameters above the baseline values [2951828] A blind r and omized cross-over comparative study of salbutamol and the combination fenoterol/ipratropium was carried out in 20 patients with mild to moderate bronchial asthma ; clinical and functional serial parameters were evaluated . The combination was more effective than salbutamol in preventing crisis and incidence of cough and wheezing , and in the spirometric results . There were no significant differences in expectoration and the functional parameters improved not only in flow but also in volume . Pathogenesis is discussed Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND It is well known that physical exercise can trigger asthma symptoms and can induce bronchial obstruction in people without clinical asthma . International guidelines on asthma management recommend the use of beta2-agonists at any stage of the disease . At present , however , no consensus has been reached about the efficacy and safety of beta2-agonists in the pretreatment of exercise-induced asthma and exercise-induced bronchoconstriction . For the purpose of the present review , both of these conditions are referred to by the acronymous EIA , independently from the presence of an underlying chronic clinical disease . OBJECTIVES To assess the effects of inhaled short- and long-acting beta2-agonists , compared with placebo , in the pretreatment of children and adults with exercise-induced asthma ( or exercise-induced bronchoconstriction ) . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

23543547

[20120789] Background Efforts to determine the impact of prenatal multivitamin supplementation on birth outcome have been carried out in several developing countries . A review of factors that would impact the effectiveness of prenatal supplementation under normal field conditions is currently lacking and will be required for exp and ed supplementation programs . An efficacy trial of a multiple micronutrient supplement for pregnant women was conducted in rural western China , and additional information on side effects , rates of adherence , program inputs , and cost was also gathered . Objectives To examine reports of side effects and rates of adherence to prenatal multiple micronutrient supplementation in comparison with supplementation with folic acid and with iron – folic acid , and to describe inputs and costs associated with prenatal supplementation in China . Methods A cluster-r and omized , double-blind , controlled trial was conducted in two rural counties in northwest China . All pregnant women in villages were r and omly assigned to take daily supplements of folic acid , iron – folic acid , or a recommended daily allowance of 15 vitamins and minerals from enrollment until delivery . Information was collected from the women on side effects and adherence . Program inputs and costs of supplementation were tracked . Descriptive statistics were used for the analysis . The biological effectiveness of prenatal multiple micronutrient supplements is reported elsewhere . Results Less than 4 % of women withdrew from the study because of side effects . Adherence to supplementation was high : the supplements were consumed on more than 90 % of the days on which they were available for consumption . The mean number of supplements consumed was high at 165 capsules , and about 40 % consumed the recommended 180 supplements during pregnancy . Conclusions High adherence to a prenatal supplement schedule can be achieved when mothers have frequent contact with trained health workers and a reliable supply of supplements [3530158] Two hundred Hausa primigravidae at Zaria were divided into five groups in a r and omized double-blind trial of antenatal oral antimalarial prophylaxis , and haematinic supplements . Group 1 received no active treatment . Groups 2 to 5 were given chloroquine 600 mg base once , followed by proguanil 100 mg per day . In addition , group 3 received iron 60 mg daily , group 4 folic acid 1 mg daily , and group 5 iron plus folic acid . Forty-five percent were anaemic ( haemoglobin ( Hb ) less than 11.0 g dl-1 ) at first attendance before 24 weeks of gestation , and malaria parasitaemia ( predominantly Plasmodium falciparum ) was seen in 27 % , of whom 60 % were anaemic . The mean Hb fell during pregnancy in group 1 , and seven patients in this group had to be removed from the trial and treated for severe anaemia ( packed cell volume ( PCV ) less than 0.26 ) . Only five patients in the other groups developed severe anaemia ( P = 0.006 ) , two of whom had malaria following failure to take treatment . Patients in group 1 had the lowest mean Hb at 28 and 36 weeks of gestation , and patients receiving antimalarials and iron ( groups 3 and 5 ) had the highest Hb at 28 weeks , but differences were not significant , possibly due to removal from the trial of patients with severe anaemia . Anaemia ( Hb less than 12.0 g dl-1 ) at six weeks after delivery was observed in 61 % of those not receiving active treatment ( group 1 ) , in 39 % of those protected against malaria but not receiving iron supplements ( groups 2 and 4 ) and in only 18 % of patients receiving both antimalarials and iron ( groups 3 and 5 ) . Folic acid had no significant effect on mean Hb . Proguanil was confirmed to be a highly effective causal prophylaxis . Prevention of malaria , without folic acid supplements , reduced the frequency of megaloblastic erythropoiesis from 56 % to 25 % . Folic acid supplements abolished megaloblastosis , except in three patients who were apparently not taking the treatment prescribed . Red cell folate ( RCF ) concentrations were higher in subjects with malaria , probably due to intracellular synthesis by plasmodia . Infants of mothers not receiving antimalarials appeared to have an erythroid hyperplasia . Maternal folate supplements raised infants ' serum folate and RCF . Fourteen per cent had low birth weight ( less than 2500 g ) , and the perinatal death rate was 11 % ; the greatest number were in group 1 , but not significantly . A regime is proposed for the prevention of malaria , iron deficiency , folate deficiency and anaemia in pregnancy in the guinea savanna of Nigeria [1263177] In a controlled , prospect i ve trial , the effects of giving ferrous sulphate 50 mg daily to 76 pregnant women was compared with giving ferrous sulphate 50 mg daily plus folic acid 0.5 mg daily to 82 women in 12 general practice s in South-east Engl and .No differences in obstetric complications were found between the two groups , although the evidence of some of the listed complications may be too rare for detection in a sample of patients of this size [18831691] UNLABELLED Sulfadoxine-pyrimethamine ( SP ) inhibits folate metabolism by the malaria parasite . We investigated the association between folate levels and SP failure in pregnant women . Data from a trial to assess the effect that folate supplementation has on SP failure in 467 pregnant women were analyzed . Plasma folate levels were determined at enrollment and at day 7 . High baseline folate levels , high parasite densities , and age < 20 years were risk factors for SP failure . High-dose ( 5 mg daily ) folate supplementation or high folate levels at day 7 were independent risk factors . Therefore , pregnant women receiving SP should receive low-/moderate-dose folate supplementation . TRIAL REGISTRATION http://www . clinical trials.gov identifier : NCT00130065 [5926263] Bertino , J. R. , Ward , J. , Sartorelli , A. C. , and Silber , R. ( 1965 ) . 7 . clin . Invest . , 44 , 1028 . Bothwell , T. H. , Hurtardo , A. V. , Donohue , D. M. , and Finch , C. A. ( 1957 ) . Blood , 12 , 409 . Callender , S. T. , and Malpas , J. S. ( 1963 ) . Brit . med . 7 . , 2 , 1516 . Cockburn , F. , Sherman , J. D. , Ingall , D. , and Klein , R. ( 1965 ) . Proc . Soc . exp . Biol . ( N.Y. ) , 118 , 238 . Conrad , M. E. , Berman , A. , and Crosby , W. H. ( 1962 ) . Gastroenterology , 43 , 385 . Dacie , J. V. , and Lewis , S. M. ( 1963 ) . Practical Haematology , 3rd ed . London . Davis , A. E. , and Badenoch , J. ( 1962 ) . Lancet , 2 , 6 . Finch , C. A. , Coleman , D. H. , Motulsky , A. G. , Donohue , D. M. , and Reiff , R. H. ( 1956 ) . Blood , 11 , 807 . Herbert , V. ( 1963 ) . Amer . 7 . clan . Nutr . , 12 , 17 . Gottlieb , C. W. , and Altschule , M. D. ( 1965 ) . Lancet , 2 , 1052 [16870008] The hypothesis was tested that the additional dietary uptake of n-3 fatty acids , in particular of DHA and 5-methyltetrahydrofolate ( 5-MTHF ) , during the second half of pregnancy would influence proliferation and apoptosis in the full-term human placenta . The diets of pregnant women from Spain ( n 55 ) were supplemented with modified fish oil and /or 5-MTHF or placebo , and assigned in a r and om , double-blind manner to one of the four groups . Immunohistochemistry and immunoblotting were used to detect placental proliferation and apoptosis with monoclonal antibodies for key proteins that reflected the extent of both processes : proliferation cell nuclear antigen ( PCNA ) , p53 , cytokeratin 18 neoepitope . The PCNA level in the fish oil/5-MTHF-treated group was higher by 66 % ( P < 0.05 ) than that of the placebo group , whereas the levels of p53 and cytokeratin 18 neoepitope were unaffected by treatment . PCNA expression was altered only in the trophoblast compartment ( placebo 11.1 ( se 0.5 ) % v. combination 21.5 ( se 1.2 ) % ; P < 0.05 ) , whereas the proportion of nuclei stained in endothelial and other stromal cells was similar in the placebo and combined treatment groups . No correlation was found between fish oil or 5-MTHF supplementation and the levels of the proteins . The present data suggest that supplementation with fish oil and /or 5-MTHF had no effect on the parameters reflecting placental proliferation and apoptosis . A defined combination of DHA and 5-MTHF may , however , affect placental proliferation [14608063] Iron deficiency is one of the main causes of anemia during pregnancy , although other micronutrient deficiencies may play a role . We examined the effects of daily antenatal and postnatal supplementation with four combinations of micronutrients on maternal hematologic indicators in a double-masked r and omized controlled community trial . Communities , called sectors , were r and omly assigned to supplementation with folic acid ( 400 microg ) , folic acid plus iron ( 60 mg ) , folic acid plus iron and zinc ( 30 mg ) and folic acid plus iron , zinc and 11 other micronutrients , each at the approximate recommended daily allowance for pregnancy all given with vitamin A as retinol acetate ( 1000 microg retinol equivalent ) , or vitamin A alone as the control group . Hemoglobin ( Hb ) and indicators of iron status were assessed at baseline and at 32 wk of gestation . At 6-wk postpartum , Hb assessment was repeated using a finger stick . Severely anemic women ( Hb < 70 g/L ) were treated according to WHO recommendations . Folic acid alone had no effect on maternal anemia or iron status . Hb concentrations were 14 g/L , [ 95 % confidence limits ( CL ) , 8.3 - 19.2 ] , 10.0 g/L ( CL , 5.2 - 14.8 ) and 9.4 g/L ( CL , 4.7 - 14.1 ) higher in the groups receiving folic acid plus iron , folic acid plus iron and zinc and folic acid plus iron , zinc and multiple micronutrients , respectively , relative to the control . Anemia in the third trimester was reduced by 54 % with folic acid plus iron , by 48 % with folic acid plus iron and zinc and by 36 % with folic acid plus iron , zinc and multiple micronutrients supplementation , relative to the control ( P < 0.05 ) . Thus , the combinations of folic acid plus iron and zinc and folic acid plus iron , zinc and multiple micronutrients provided no additional benefit in improving maternal hematologic status during pregnancy compared with folic acid plus iron . The level of compliance and baseline Hb concentrations modified the effect of iron [17490978] BACKGROUND Pregnant women usually meet their increased energy needs but do not always meet their increased micronutrient requirements . The supply of both folic acid and docosahexaenoic acid ( DHA ) has been related to positive pregnancy and infant outcomes . OBJECTIVE We aim ed to assess whether fish-oil ( FO ) supplementation with or without folate from gestation week 22 to birth improves maternal and fetal n-3 long-chain polyunsaturated fatty acid ( n-3 LC-PUFA ) status . DESIGN We conducted a multicenter ( Germany , Hungary , and Spain ) , r and omized , double-blind , 2 x 2 factorial , placebo-controlled trial . From gestation week 22 until delivery , 311 pregnant women received daily a preparation with FO [ 0.5 g DHA and 0.15 g eicosapentaenoic acid ( EPA ) ] , 400 microg methyltetrahydrofolic acid ( MTHF ) , FO with MTHF , or placebo . Outcome measures included maternal and cord plasma DHA and EPA contents at gestation weeks 20 and 30 and at delivery , indicators of pregnancy outcome , and fetal development . RESULTS FO significantly ( P<0.001 ) increased maternal DHA and EPA ( % by wt ) , as shown by 3-factor repeated- measures ANOVA ( ie , MTHF , FO , and time ) with adjustment for maternal baseline DHA and EPA . In addition , FO significantly ( P<0.001 ) increased cord blood DHA ( % by wt ; 2-factor ANOVA ) . MTHF was significantly ( P=0.046 ) associated with increased maternal DHA ( % by wt ) . There was no FO x MTHF interaction for the time course of DHA or EPA ( P=0.927 and 0.893 ) . Pregnancy outcomes and fetal development did not differ significantly among the intervention groups . CONCLUSIONS FO supplementation from gestation week 22 until delivery improves fetal n-3 LC-PUFA status and attenuates depletion of maternal stores . MTHF may further enhance maternal n-3 LC-PUFA proportions [18806105] In rural China , many pregnant women in their third trimester suffer from anemia ( 48 % ) and iron deficiency ( ID ; 42 % ) , often with coexisting deficiencies of retinol and riboflavin . We investigated the effect of retinol and riboflavin supplementation in addition to iron plus folic acid on anemia and subjective well-being in pregnant women . The study was a 2-mo , double-blind , r and omized trial . Subjects ( n = 366 ) with anemia [ hemoglobin ( Hb ) < /= 105 g/L ] were r and omly assigned to 4 groups , all receiving 60 mg/d iron and 400 mug/d folic acid . The iron+folic acid ( IF ) group ( n = 93 ) served as reference , the iron+folic acid+retinol group ( IFA ) ( n = 91 ) was treated with 2000 mug retinol , the iron+folic acid+riboflavin group ( IFB ) ( n = 91 ) with 1.0 mg riboflavin , and the iron+folic acid+retinol+riboflavin group ( IFAB ) ( n = 91 ) with retinol and riboflavin . After the 2-mo intervention , the Hb concentration increased in all 4 groups ( P < 0.001 ) . The increase in the IFAB group was 5.4 + /- 1.1 g/L greater than in the IF group ( P < 0.001 ) . The reduced prevalence of anemia ( Hb < 110g/L ) and ID anemia were significantly greater in the groups supplemented with retinol and /or riboflavin than in the IF group . Moreover , gastrointestinal symptoms were less prevalent in the IFA group than in the IF group ( P < 0.05 ) and improved well-being was more prevalent in the groups receiving additional retinol and /or riboflavin than in the IF group ( P < 0.05 ) . Thus , a combination of iron , folic acid , retinol , and riboflavin was more effective than iron plus folic acid alone . Multimicronutrient supplementation may be worthwhile for pregnant women in rural China [14668283] BACKGROUND We previously reported that maternal micronutrient supplementation in rural Nepal decreased low birth weight by approximately 15 % . OBJECTIVE We examined the effect of daily maternal micronutrient supplementation on fetal loss and infant mortality . DESIGN The study was a double-blind , cluster-r and omized , controlled trial among 4926 pregnant women and their 4130 infants in rural Nepal . In addition to vitamin A ( 1000 microg retinol equivalents ) , the intervention groups received either folic acid ( FA ; 400 microg ) , FA + iron ( 60 mg ) , FA + iron + zinc ( 30 mg ) , or multiple micronutrients ( MNs ; the foregoing plus 10 microg vitamin D , 10 mg vitamin E , 1.6 mg thiamine , 1.8 mg riboflavin , 2.2 mg vitamin B-6 , 2.6 microg vitamin B-12 , 100 mg vitamin C , 64 microg vitamin K , 20 mg niacin , 2 mg Cu , and 100 mg Mg ) . The control group received vitamin A only . RESULTS None of the supplements reduced fetal loss . Compared with control infants , infants whose mothers received FA alone or with iron or iron + zinc had a consistent pattern of 15 - 20 % lower 3-mo mortality ; this pattern was not observed with MNs . The effect on mortality was restricted to preterm infants , among whom the relative risks ( RRs ) were 0.36 ( 95 % CI : 0.18 , 0.75 ) for FA , 0.53 ( 0.30 , 0.92 ) for FA + iron , 0.77 ( 0.45 , 1.32 ) for FA + iron + zinc , and 0.70 ( 0.41 , 1.17 ) for MNs . Among term infants , the RR for mortality was close to 1 for all supplements except MNs ( RR : 1.74 ; 95 % CI : 1.00 , 3.04 ) . CONCLUSIONS Maternal micronutrient supplementation failed to reduce overall fetal loss or early infant mortality . Among preterm infants , FA alone or with iron reduced mortality in the first 3 mo of life . MNs may increase mortality risk among term infants , but this effect needs further evaluation [11435509] To investigate the effects of pregnancy on folate metabolism , we conducted an 84-d study in second-trimester ( gestational wk 14 - 25 ) pregnant women ( n = 6 ) and nonpregnant controls ( n = 6 ) with stable-isotopic tracer methods . All subjects were fed a diet containing approximately 272 nmol/d ( 120 microg/d ) folate from food , along with supplemental folic acid that contained 15 % [ 3',5'-(2)H(2 ) ] folic acid ( [(2)H(2)]folic acid ) during d 1 - -41 and that was unlabeled during d 42 - -84 to yield a constant total folate intake of 1.02 or 1.93 micromol/d ( 450 or 850 microg/d ) . Isotopic enrichment of plasma folate , urinary folate and the urinary folate catabolites para-aminobenzoylglutamate ( pABG ) and para-acetamidobenzoylglutamate ( ApABG ) was determined at intervals throughout the study . The labeling of pABG and ApABG reflected that of tissue folate pools from which the catabolites originate . After the intake of labeled folic acid was terminated on d 41 , labeling of urinary folate exhibited a biphasic exponential decline with distinct fast and slow components . In contrast , during d 42 - -84 , the enrichment of urinary pABG and ApABG exhibited primarily monophasic exponential decline , and plasma folate underwent little decline of labeling during this period . Pregnant women and controls did not differ in estimates of body folate pool size and most aspects of the excretion of labeled urinary folate and catabolites , rates of decline of excretion , and areas under the curves for folate and catabolite excretion . Pregnant women , however , tended to have a slower rate of decline of pABG than ApABG and higher enrichment at d 42 of ApABG and pABG . These data support and extend our previous findings indicating that pregnancy ( gestational wk 14 - -26 ) causes subtle changes in folate metabolism but does not elicit substantial increases in the rate or extent of folate turnover at these moderately high folate intakes [9446844] Measurement of the urinary folate catabolites , para-aminobenzoylglutamate ( pABG ) and the more predominant acetylated form , acetamidobenzoylglutamate ( apABG ) , has been used to assess folate requirements in both pregnant and nonpregnant women . Folate catabolite excretion has been reported to be significantly higher in pregnant women ( second trimester ) compared with nonpregnant controls . The primary goals of this study were to determine if pregnant women in a controlled metabolic study excreted higher quantities of urinary folate catabolites than nonpregnant controls and if catabolite excretion was influenced by folate intake . We evaluated the effect of gestation and folate intake on the urinary excretion of apABG and pABG in pregnant women ( n = 12 ; wk 14 - 26 gestation ) and nonpregnant controls ( n = 12 ) assigned to consume folate levels approximating the current ( 400 microg/d ) and previous ( 800 microg/d ) RDA . Subjects were fed a controlled diet containing 120 microg folate/d and either 330 or 730 microg synthetic folic acid/d . In contrast to previously reported data , no differences in mean folate catabolite excretion were detected between pregnant and nonpregnant subjects . Catabolite excretion ( pABG + apABG ) decreased significantly relative to initial values in pregnant women consuming 450 microg folate/d ( -40 + /- 20 % ; mean + /- SD ) and final mean excretion was significantly lower in the pregnant women consuming 450 microg folate/d ( 86 + /- 32 nmol/d ) compared with 850 microg folate/d ( 148 + /- 20 nmol/d ) . Data from this study indicate that second trimester pregnant women do not excrete more folate catabolites than nonpregnant controls and that consumption of 450 vs. 850 microg folate/d results in a significant reduction in the quantity of folate catabolites excreted [16600929] BACKGROUND Previously we showed that women in rural Nepal experience multiple micronutrient deficiencies in early pregnancy . OBJECTIVE This study examined the effects of daily antenatal micronutrient supplementation on changes in the biochemical status of several micronutrients during pregnancy . DESIGN In Nepal , we conducted a r and omized controlled trial in which 4 combinations of micronutrients ( folic acid , folic acid + iron , folic acid + iron + zinc , and a multiple micronutrient supplement containing folic acid , iron , zinc , and 11 other nutrients ) plus vitamin A , or vitamin A alone as a control , were given daily during pregnancy . In a sub sample of subjects ( n = 740 ) , blood was collected both before supplementation and at approximately 32 wk of gestation . RESULTS In the control group , serum concentrations of zinc , riboflavin , and vitamins B-12 and B-6 decreased , whereas those of copper and alpha-tocopherol increased , from the first to the third trimester . Concentrations of serum folate , 25-hydroxyvitamin D , and undercarboxylated prothrombin remained unchanged . Supplementation with folic acid alone or folic acid + iron decreased folate deficiency . However , the addition of zinc failed to increase serum folate , which suggests a negative inhibition ; multiple micronutrient supplementation increased serum folate . Folic acid + iron + zinc failed to improve zinc status but reduced sub clinical infection . Multiple micronutrient supplementation decreased the prevalence of serum riboflavin , vitamin B-6 , vitamin B-12 , folate , and vitamin D deficiencies but had no effect on infection . CONCLUSIONS In rural Nepal , antenatal supplementation with multiple micronutrients can ameliorate , to some extent , the burden of deficiency . The implication s of such biochemical improvements in the absence of functional and health benefits remain unclear [2711281] Higher folate needs are present during pregnancy , which may lead to tissular deficiency in the mother and to depleted newborn folate reserves . The aim of this work was to assess the prevalence of folate deficiency and to establish the rates of serum and red cell folate in two groups of mothers and newborn infants , one receiving only iron and the other iron and folate during pregnancy . The rates of serum and red cell folate found at the end of pregnancy were significantly higher in the group which received folate ; however , the percentage of cases with tissular folate deficiency was low in both groups , with no significant difference ( 3.8 % and 1.3 % , respectively ) . These findings , along with the lack of effect of supplemental folate on erythropoiesis , pose some questions on the usefulness of supplemental folate during pregnancy in our country [7588512] OBJECTIVE To determine by biochemical methods the nutritional status of pre- and post-natal Turkish women and its relationship with offspring anthropometry . DESIGN Longitudinal study . SETTING Health centres in Istanbul and Izmit , research department and university hospital laboratories . SUBJECTS R and omly selected group of women attending health centres at 13 - 17 weeks gestation ( n = 130 ) ; same sample of women at 28 - 32 weeks gestation ( n = 88 ) and 13 - 17 weeks post-partum ( n = 95 ) ; offspring at 13 - 17 weeks post-partum ( n = 90 ) . INTERVENTIONS Blood sample s taken from mothers at all three stages and analysed for ferritin , iron , zinc , calcium , alkaline phosphatase , total protein , albumin , vitamins B2 , B6 , B12 , A , E , beta-carotene and folate levels ; question naire completed for recording medical and socio-demographic background . Anthropometric measurements taken from mothers and offspring . RESULTS High percentages of subjects were at risk for deficiencies of vitamin B12 ( 48.8 % ) and folate ( 59.7 % ) in early pregnancy ; ferritin ( 52.3 % ) , zinc ( 72.3 % ) , vitamin B2 ( 38.8 % ) , vitamin B12 ( 80.9 % ) , and folate ( 76.4 % ) during late pregnancy ; and ferritin ( 39.0 % ) , vitamins B2 ( 43.1 % ) , B6 ( 36.4 % ) , B12 ( 60.0 % ) , and folate ( 73.3 % ) at the post-partum stage . Bone loss was indicated in 55.0 % and 80.0 % of the subjects in late pregnancy and post-partum respectively . Haematocrit in later pregnancy correlated strongly with prenatal body fat ( P < 0.001 ) . Infant anthropometry at 13 - 17 weeks post-partum was significantly affected by pre-natal weight gain and a number of maternal blood nutrients in pregnancy and post-partum . CONCLUSIONS Nutrition education programmes and enrichment of the staple food with iron , zinc , calcium , and the B vitamins should be considered [7619925] To study the relation of maternal periconceptional vitamin use to the risk of a congenital urinary tract anomaly ( CUTA ) , we conducted a case-control study using the Washington State Birth Defect Registry . We identified CUTA cases with no known chromosomal abnormality in seven counties in western Washington State occurring between January 1 , 1990 , and December 31 , 1991 . We r and omly selected a sample , as controls , of all infants delivered in five large hospitals in King County who did not have a birth defect and who were born in the same year as the cases . About 55 % of all infants in King County and a smaller proportion of infants in the other six counties are delivered in these five hospitals . We interviewed mothers of 118 cases and 369 controls to obtain information about their vitamin use during the pregnancy and during the year before the conception . After adjustment for maternal race , family income , county of maternal residence , and birth year , we found that women who used multivitamins during the first trimester had only 15 % the risk of bearing a child with a CUTA compared with women who did not take vitamins [ odds ratio ( OR ) = 0.15 ; 95 % confidence interval ( CI ) = 0.05–0.43 ] . The reduction was smaller for use restricted to the second or third trimesters ( OR = 0.31 ; 95 % CI = 0.09–1.02 ) . Among women who used vitamins during the first trimester , vitamin use before conception was not associated with any further reduction in the risk , nor did there appear to be an association with the amount or br and of vitamin used . Restricting the analysis to residents of King County did not change the results . Our results indicate that prenatal multivitamin use , particularly during the first trimester , may reduce the risk of a CUTA . Because all of the preparations taken by study participants contained many vitamins as well as folic acid , it was not possible to identify which one ( or several ) chemical(s ) may have been responsible for the reduced risk of a CUTA [8324432] OBJECTIVE --To study the effect of periconceptional multivitamin supplementation on neural tube defects and other congenital abnormality entities . DESIGN --R and omised controlled trial of supplementation with multivitamins and trace elements . SETTING --Hungarian family planning programme . SUBJECTS--4156 pregnancies with known outcome and 3713 infants evaluated in the eighth month of life . INTERVENTIONS --A single tablet of a multivitamin including 0.8 mg of folic acid or trace elements supplement daily for at least one month before conception and at least two months after conception . MAIN OUTCOME MEASURES --Number of major and mild congenital abnormalities . RESULTS --The rate of all major congenital abnormalities was significantly lower in the group given vitamins than in the group given trace elements and this difference can not be explained totally by the significant reduction of neural tube defects . The rate of major congenital abnormalities other than neural tube defects and genetic syndromes was 9.0/1000 in pregnancies with known outcome in the vitamin group and 16.6/1000 in the trace element group ; relative risk 1.85 ( 95 % confidence interval 1.02 to 3.38 ) ; difference , 7.6/1000 . The rate of all major congenital abnormalities other than neural tube defects and genetic syndromes diagnosed up to the eighth month of life was 14.7/1000 informative pregnancies in the vitamin group and 28.3/1000 in the trace element group ; relative risk 1.95 ( 1.23 to 3.09 ) ; difference , 13.6/1000 . The rate of some congenital abnormalities was lower in the vitamin group than in the trace element group but the differences for each group of abnormalities were not significant . CONCLUSIONS --Periconceptional multivitamin supplementation can reduce not only the rate of neural tube defects but also the rate of other major non-genetic syndromatic congenital abnormalities . Further studies are needed to differentiate the chance effect and vitamin dependent effect [7007454] A double-blind study evaluated the effects of systemic and topical folate on gingival inflammation during the fourth and eighth months of pregnancy . Thirty women were r and omly divided into three groups . Group A received placebo mouthwash and tablets ; Group B ; placebo mouthwash and 5 mg folate tablets ; Group C : folate mouthwash and placebo tablets . Supplementation lasted for 14 days during months 4 and 8 . Subjects took one tablet daily and rinsed twice daily for 1 min with the mouthwash . At the start and finish of each 14-day period , fasting serum and red cell folate levels were estimated and oral status assessed by a plaque index ( P1I ) , a gingival index ( GI ) , and gingival exu date flow meter ( GEF ) . Subjects completed 1-week diet sheets which were analysed for dietary folate . All groups were similar in each parameter at the start . Correlation was demonstrated between GI and P1I , and between GI and GEF . GI tended to increase throughout pregnancy in all groups except Group C , when in the eighth month there was a highly significant improvement ( 0.001 less than P 0.01 ) despite no significant change in P1I . Although dietary intake of folate was significantly higher during the eighth month in Group C as compared with Groups A and B , ( 0.001 less than P less than 0.01 ) , the folate mouthwash produced highly significantly improvement in gingival health in pregnancy [19368922] OBJECTIVE To examine the effect of supplemental prenatal folic acid , folic acid-iron , folic acid-iron-zinc , and multiple micronutrients on maternal morbidity in rural Nepal . METHODS A cluster-r and omized double-masked controlled trial of pregnant women who received daily supplements from early pregnancy through 3 months post partum as per the treatment allocation . Women were interviewed at birth about labor and delivery complications and for 9 days post partum to obtain 24-hour histories of morbidity . RESULTS A total of 3986 ( 97.3 % ) women completed an interview regarding labor and delivery ; morbidity history was available for 3564 ( 87.0 % ) women . Folic acid-iron reduced the risk of postpartum hemorrhage ( relative risk [ RR ] 0.59 ; 95 % confidence interval [ CI ] 0.35 - 0.98 ) . Risk of dysfunctional labor increased with multiple micronutrient supplementation ( RR 1.28 ; 95 % CI , 1.01 - 1.60 ) , although preterm premature rupture of membrane decreased ( RR 0.40 ; 95 % CI , 0.21 - 0.79 ) . Puerperal sepsis was lower in those receiving folic acid-iron , folic acid-iron-zinc , and multiple micronutrients compared with controls ( P<0.05 ) . CONCLUSION Prenatal folic acid-iron supplementation reduced the risk of obstetric complications in this South Asian setting [19139780] OBJECTIVE To evaluate the effect of high dose and low dose folic acid on the levels of hemocysteine ( Hcy ) concentration during the first trimester of pregnancy and at delivery , and to examine the association of Hcy serum levels and preeclampsia . METHODS In a single blinded r and omized clinical trial , which was conducted in Tabriz , Iran , from 2005 - 2008 , 246 nulliparous pregnant women in 2 similar groups , received folic acid daily from early pregnancy until delivery ( 5 mg/day in group one and 0.5 mg/ day in group 2 ) . The incidence of hypertension and laboratory changes in the levels of serum Hcy , lactate dehydrogenase , and uric acid in addition to the levels of urine creatinine and protein were compared between the groups . RESULTS There was no presence of any type of hypertension in each group . The systolic blood pressures ( BP ) ( mm Hg ) at the first trimester were 114.01 + /- 8.78 for group one , 114.16 + /- 9.05 for group 2 , and at delivery , 117.24 + /- 6.91 for group one , and 117.23 + /- 11.48 for group 2 ( p=0.32 ) . The diastolic BP at the first trimester were 74.90 + /- 7.45 for group one , 73.30 + /- 8.90 for group 2 , and at delivery 76.46 + /- 5.58 for group one , and 76.69 + /- 8.62 for group 2 ( p=0.42 ) . Although the level of Hcy ( micromol/L ) decreased significantly at the delivery time in group one ( 11.81+/- 3.85 decreased to 6.44 + /- 1.88 ) , and 2 ( 9.08+/- 3.24 , decreased to 7.44 + /- 2.99 ) , this decrement was more significant in the first group ( p<0.001 ) . CONCLUSION The results show that folic acid supplement throughout pregnancy , irrespective of the dosage , could eliminate hypertensive disorders , and decreases serum level of Hcy , although it is reduced more significant in the first group [1617124] Objectives : Sulfadoxine-pyrimethamine ( SP ) is an antimalarial drug that acts on the folate metabolism of the malaria parasite . We investigated whether folate ( FA ) supplementation in a high or a low dose affects the efficacy of SP for the treatment of uncomplicated malaria in pregnant women . Design : This was a r and omized , placebo-controlled , double-blind trial . Setting : The trial was carried out at three hospitals in western Kenya . Participants : The participants were 488 pregnant women presenting at their first antenatal visit with uncomplicated malaria parasitaemia ( density of ≥ 500 parasites/μl ) , a haemoglobin level higher than 7 g/dl , a gestational age between 17 and 34 weeks , and no history of antimalarial or FA use , or sulfa allergy . A total of 415 women completed the study . Interventions : All participants received SP and iron supplementation . They were r and omized to the following arms : FA 5 mg , FA 0.4 mg , or FA placebo . After 14 days , all participants continued with FA 5 mg daily as per national guidelines . Participants were followed at days 2 , 3 , 7 , 14 , 21 , and 28 or until treatment failure . Outcome Measures : The outcomes were SP failure rate and change in haemoglobin at day 14 . Results : The proportion of treatment failure at day 14 was 13.9 % ( 19/137 ) in the placebo group , 14.5 % ( 20/138 ) in the FA 0.4 mg arm ( adjusted hazard ratio [ AHR ] , 1.07 ; 98.7 % confidence interval [ CI ] , 0.48 to 2.37 ; p = 0.8 ) , and 27.1 % ( 38/140 ) in the FA 5 mg arm ( AHR , 2.19 ; 98.7 % CI , 1.09 to 4.40 ; p = 0.005 ) . The haemoglobin levels at day 14 were not different relative to placebo ( mean difference for FA 5 mg , 0.17 g/dl ; 98.7 % CI , −0.19 to 0.52 ; and for FA 0.4 mg , 0.14 g/dl ; 98.7 % CI , −0.21 to 0.49 ) . Conclusions : Concomitant use of 5 mg FA supplementation compromises the efficacy of SP for the treatment of uncomplicated malaria in pregnant women . Countries that use SP for treatment or prevention of malaria in pregnancy need to evaluate their antenatal policy on timing or dose of FA supplementation [21177506] CONTEXT Iron and zinc are important for the development of both intellectual and motor skills . Few studies have examined whether iron and zinc supplementation during gestation , a critical period of central nervous system development , affects children 's later functioning . OBJECTIVE To examine intellectual and motor functioning of children whose mothers received micronutrient supplementation during pregnancy . DESIGN , SETTING , AND PARTICIPANTS Cohort follow-up of 676 children aged 7 to 9 years in June 2007-April 2009 who had been born to women in 4 of 5 groups of a community-based , double-blind , r and omized controlled trial of prenatal micronutrient supplementation between 1999 and 2001 in rural Nepal . Study children were also in the placebo group of a subsequent preschool iron and zinc supplementation trial . INTERVENTIONS Women whose children were followed up had been r and omly assigned to receive daily iron/folic acid , iron/folic acid/zinc , or multiple micronutrients containing these plus 11 other micronutrients , all with vitamin A , vs a control group of vitamin A alone from early pregnancy through 3 months postpartum . These children did not receive additional micronutrient supplementation other than biannual vitamin A supplementation . MAIN OUTCOME MEASURES Children 's intellectual functioning , assessed using the Universal Nonverbal Intelligence Test ( UNIT ) ; tests of executive function , including go/no-go , the Stroop test , and backward digit span ; and motor function , assessed using the Movement Assessment Battery for Children ( MABC ) and finger-tapping test . RESULTS The difference across outcomes was significant ( Bonferroni-adjusted P < .001 ) for iron/folic acid vs control but not for other supplement groups . The mean UNIT T score in the iron/folic acid group was 51.7 ( SD , 8.5 ) and in the control group was 48.2 ( SD , 10.2 ) , with an adjusted mean difference of 2.38 ( 95 % confidence interval [ CI ] , 0.06 - 4.70 ; P = .04 ) . Differences were not significant between the control group and either the iron/folic acid/zinc ( 0.73 ; 95 % CI , -0.95 to 2.42 ) or multiple micronutrient ( 1.00 ; 95 % CI , -0.55 to 2.56 ) groups . In tests of executive function , scores were better in the iron/folic acid group relative to the control group for the Stroop test ( adjusted mean difference in proportion who failed , -0.14 ; 95 % CI , -0.23 to -0.04 ) and backward digit span ( adjusted mean difference , 0.36 ; 95 % CI , 0.01 - 0.71 ) but not for the go/no-go test . The MABC score was lower ( better ) in the iron/folic acid group compared with the control group but not after adjustment for confounders ( mean difference , -1.47 ; 95 % CI , -3.06 to 0.12 ; P = .07 ) . Finger-tapping test scores were higher ( mean difference , 2.05 ; 95 % CI , 0.87 - 3.24 ; P = .001 ) in the iron/folic acid group . CONCLUSION Aspects of intellectual functioning including working memory , inhibitory control , and fine motor functioning among offspring were positively associated with prenatal iron/folic acid supplementation in an area where iron deficiency is prevalent . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00115271 [19778983] The long-term benefits of antenatal iron supplementation in child survival are not known . In 1999 - 2001 , 4,926 pregnant women in rural Nepal participated in a cluster-r and omized , double-masked , controlled trial involving 4 alternative combinations of micronutrient supplements , each containing vitamin A. The authors examined the impact on birth weight and early infant mortality in comparison with controls , who received vitamin A only . They followed the surviving offspring of these women at approximately age 7 years to study effects of in utero supplementation on survival . Of 4,130 livebirths , 209 infants died in the first 3 months and 8 were lost to follow-up . Of those remaining , 3,761 were followed , 150 died between ages 3 months and 7 years , and 152 were lost to follow-up . Mortality rates per 1,000 child-years from birth to age 7 years differed by maternal supplementation group , as follows : folic acid , 13.4 ; folic acid-iron , 10.3 ; folic acid-iron-zinc , 12.0 ; multiple micronutrients ; 14.0 ; and controls , 15.2 . Hazard ratios were 0.90 ( 95 % confidence interval ( CI ) : 0.65 , 1.22 ) , 0.69 ( 95 % CI : 0.49 , 0.99 ) , 0.80 ( 95 % CI : 0.58 , 1.11 ) , and 0.93 ( 95 % CI : 0.66 , 1.31 ) , respectively , in the 4 supplementation groups . Maternal iron-folic acid supplementation reduced mortality among these children by 31 % between birth and age 7 years . These results provide additional motivation for strengthening antenatal iron-folic acid programs [9219461] BACKGROUND Zinc and folate are important for fetal growth . However , the relationship between the dietary intake of these nutrients and pregnancy outcome is not settled . METHODS A prospect i ve study was conducted to ascertain the relationship between maternal dietary zinc and folate intake ( n = 1398 ) , serum zinc and folate levels ( n = 289 ) , and infant birthweight . Twenty-four hour recalls were used to measure energy , zinc , folate and other nutrient intakes at 18 and 30 weeks of gestation . Subjects in the study were offered daily folic acid ( 1.0 mg ) and iron ( 60 mg as ferrous sulfate ) at enrollment . RESULTS Maternal zinc nutriture as assessed by serum and dietary intake was not associated with birthweight or length of gestation . There was a small but significant positive association between maternal folate intake and adjusted infant birthweight ( beta = 0.05 , p = 0.03 ) . The indirect measures of maternal nutritional status including maternal pre-pregnancy weight ( beta = 8.0 , p = 0.0001 ) and weight gain during pregnancy ( beta = 18.1 , p = 0.0001 ) were stronger predictors of adjusted infant birthweight as compared to energy intake and intake of zinc and folate . An increase of 320 , 290 , and 48 g in infant birthweight was associated with the 90th-10th percentile difference for pre-pregnancy weight , weight gain during pregnancy , and folate intake respectively . CONCLUSION These results indicate that pre-pregnancy weight and weight gain during pregnancy are both strong predictors of infant birthweight . Folate intake , although significantly associated with birthweight , was a weak predictor while maternal intake of zinc and other nutrients was not associated with birthweight [4865965] Our interest in the problem of folic acid and pregnancy was aroused by the work of Hibbard and Hibbard : “ Aetiological factors in abruptio placentae ” 1963 ( 12 ) . Though the frequency of abruptio placentae at our department is by no means so high as that at Millroad Maternity Hospital , Liverpool , the complication is serious because of its foetal mortality . We therefore thought it advisable to try folic acid prophylaxis during pregnancy in an attempt to decrease the frequency of abruptio placentae . Later investigations ( 14 , 20 ) have , however , shown that if folic acid treatment is not started until pregnancy has been diagnosed , it will hardly be able to reduce the frequency of abruptio placentae and abortion . In Great Britain megaloblastic anaemia due to folic acid deficiency is common during pregnancy ( 4 , 5 , 6 , 7 , 8 , 13 , 15 , 16 , IS ) , while in Sweden only a few cases have been reported . This discrepancy can be explained only partly by differences in interest in the diagnosis and diagnostic facilities available . In a thoroughly examined series Hansen found megaloblastic anaemia in less than 0.1 % of all pregnant women during a 3 1/2-year-period in Gothenburg ( 9 ) . A poor composition of the diet was thought to be a main causal factor of folic acid deficiency in the series reported from [22085869] Background / Objectives : Little is known about the long-term effects of maternal multi-micronutrient supplementation on the growth of children during early childhood . In this follow-up study , the effects of maternal supplementation with multi-micronutrients in pregnancy on postnatal child growth are examined . Subjects/ Methods : A longitudinal follow-up of a subset of newborns ( n=1388 ) whose mothers were r and omly assigned to receive the supplements of folic acid , iron – folic acid or multi-micronutrients daily during pregnancy in the original trial was conducted . Children ’s weight and length were measured and assessed during monthly home visits from birth to 30 months of age . Results : The pooled prevalence rate of stunting over different time points during the first 30 months was 13.5 , 14.9 and 12.1 % for the folic acid group , iron – folic acid group and multi-micronutrient group , respectively . However , there were no significant differences in the pooled odds of stunting in children between the multi-micronutrient group and the folic acid ( odds ratio ( OR ) 0.97 , 95 % confidence interval ( CI ) : 0.74–1.26 ) , and between the multi-micronutrient group and the iron – folic acid group ( OR 0.82 , 95 % CI : 0.63–1.07 ) . Similar results for the three groups were found for the occurrences of underweight and wasting in children . Furthermore , no significant differences were observed in length , weight , length-for-age , weight-for-age and weight-for-length Z-scores among the three treatment groups . Conclusions : Currently , available evidence is insufficient to support a greater advantage of the effect of maternal multi-micronutrient supplementation on child growth over iron – folic acid or folic acid only supplementation during the first 30 months [16941105] Objective Elevated plasma homocysteine has been implicated in vascular changes compatible with atherosis and endothelial dysfunction similar to the vascular changes of the placenta in preeclampsia . Previous reports have indicated an increased incidence of hyperohomocysteinemia in preeclamptic patients . The aim of this study was to examine the association of homocysteine levels and preeclampsia in our patients . Study design Prospect i ve study of 28 preeclamptic patients that were matched with 26 normal controls of the same gestational age . Results The preeclamptic group had an increased incidence of cesarean sections ( 75 % ) , of growth retarded fetuses ( 50 % ) , intrauterine deaths ( 7 % ) and placental abruptions ( 7 % ) . Mean levels of homocysteine were significantly elevated in the preeclamptic than in control group ( 11.11 vs. 6.40 μmol/l , P < 0.001 ) . There were no differences between the groups regarding the levels of folic acid ( 11.12 vs. 9.73 ng/ml , P = 0.55 ) and vitamin B12 ( 295.76 vs. 356.15 pg/ml , P = 0.43 ) . Conclusion It is concluded that in our study homocysteine levels are significantly elevated in patients with preeclampsia compared with control group , while no vitamin deficiencies were observed [19474130] BACKGROUND We previously reported that a r and omized controlled trial of antenatal micronutrient supplements in rural Nepal decreased the risk of low birth weight by approximately 15 % . OBJECTIVE The objective was to examine the effects of micronutrient supplementation on growth and body composition in children of supplemented mothers through school age . DESIGN Mothers received 1 of 5 micronutrient supplements daily : folic acid , folic acid + iron , folic acid + iron + zinc , multiple micronutrients , or a control . All of the supplements contained vitamin A. Children born during this trial were revisited at age 6 - 8 y to measure height , weight , midupper arm circumference , waist circumference , and triceps and subscapular skinfold thicknesses . Arm fat and muscle area were estimated by using st and ard formulas , and height-for-age , weight-for-age , and body mass index-for-age z scores were calculated by using the World Health Organization growth st and ard . RESULTS Of the 3771 surviving children , 3324 were revisited and consented to anthropometric measurements . Maternal supplementation with folic acid + iron + zinc result ed in an increase in mean height ( 0.64 cm ; 95 % CI : 0.04 , 1.25 ) and a reduction in mean triceps skinfold thickness ( -0.25 mm ; 95 % CI : -0.44 , -0.06 ) , subscapular skinfold thickness ( -0.20 mm ; 95 % CI : -0.33 , -0.06 ) , and arm fat area ( -0.18 cm(2 ) ; -0.34 , -0.01 ) . No significant differences were found between groups in mean weight or body mass index-for-age z scores , waist circumference , or arm muscle area . Other micronutrient combinations including a multiple micronutrient formulation failed to show a growth benefit . CONCLUSION Antenatal supplementation with zinc may benefit child growth , particularly in areas where a deficiency of this nutrient is common [5476865] It has been shown that the incidence of megaloblastic anaemia in a group of 463 r and omly selected pregnant women receiving iron was 12 times as high as in a control group of 235 pregnant women receiving iron and folic acid . The incidence of all types of anaemia in the women receiving iron alone was more than three times the incidence in those having iron and folic acid . Some women who were not anaemic or who had normoblastic anaemia had serum folate levels in the same range as the women with megaloblastic anaemia , but none of the women with megaloblastic anaemia had high serum folate levels . The labile fraction of the serum folate was no more reliable than the total serum folate as a diagnostic criterion of megaloblastic erythropoiesis in the individual case . The blood group distribution in the women with megaloblastic anaemia was the same as in the general population . Babies born to mothers with megaloblastic anaemia tended to be smaller than the rest , although there was no difference in the placental weights . The significance of these findings is discussed [16137113] In this placebo controlled , r and omised , double blind trial , pregnant women received from the 20th week of gestation onwards either 500 mg docosahexaenoic acid ( DHA ) , 400 mg 5-methyl-tetra-hydro-folate ( 5-MTHF ) , or placebo , or a combination of 500 mg DHA and 400 mg 5-MTHF . The dietary supplements were well tolerated ; the dropout rates did not differ significantly in the active arms of the study ( 10 % to 19 % ) from that seen in the placebo group ( 13 % ) . DHA supplementation result ed in significant enhancement of the contribution of DHA to maternal , placental and venous cord blood lipids [8882400] The objective in the Hungarian r and omised double-blind controlled trial was to study the preventive effect of periconceptional multivitamin supplementation on neural tube-defects and other congenital abnormalities . There were 2,471 and 2,391 informative offspring ( prenatally diagnosed and terminated malformed fetuses , stillborn fetuses , and liveborn infants ) in the multivitamin and placebo-like trace element groups , respectively . A single tablet either of a multivitamin containing 0.8 mg of folic acid or trace element supplement was given daily for at least one month before conception and at least until the date of the second missed menstrual period . The total rate of major congenital abnormalities was 20.6/1,000 in the multivitamin and 40.6/1,000 in the trace element group . After the exclusion of six cases of neural-tube defects in the trace element group the difference was very highly significant [ P = 0.0003 ; relative risk of 0.54 ( 95 % CI 0.39 , 0.76 ) ] . Multivitamin supplementation appeared to result in a significant reduction in the rate of urinary tract abnormalities , mainly obstructive defects , and in the rate of sporadic cardiovascular malformations , mainly ventricular septal defects . This report is regarded as a hypothesis-generating study encouraging others to see if the result can be repeated [12637400] Abstract Objective : To assess the impact on birth size and risk of low birth weight of alternative combinations of micronutrients given to pregnant women . Design : Double blind cluster r and omised controlled trial . Setting : Rural community in south eastern Nepal . Participants : 4926 pregnant women and 4130 live born infants . Interventions : 426 communities were r and omised to five regimens in which pregnant women received daily supplements of folic acid , folic acid-iron , folic acid-iron-zinc , or multiple micronutrients all given with vitamin A , or vitamin A alone ( control ) . Main outcome measures : Birth weight , length , and head and chest circumference assessed within 72 hours of birth . Low birth weight was defined < 2500 g. Results : Supplementation with maternal folic acid alone had no effect on birth size . Folic acid-iron increased mean birth weight by 37 g ( 95 % confidence interval −16 g to 90 g ) and reduced the percentage of low birthweight babies ( < 2500 g ) from 43 % to 34 % ( 16 % ; relative risk=0.84 , 0.72 to 0.99 ) . Folic acid-iron-zinc had no effect on birth size compared with controls . Multiple micronutrient supplementation increased birth weight by 64 g ( 12 g to 115 g ) and reduced the percentage of low birthweight babies by 14 % ( 0.86 , 0.74 to 0.99 ) . None of the supplement combinations reduced the incidence of preterm births . Folic acid-iron and multiple micronutrients increased head and chest circumference of babies , but not length . Conclusions : Antenatal folic acid-iron supplements modestly reduce the risk of low birth weight . Multiple micronutrients confer no additional benefit over folic acid-iron in reducing this risk . What is already known on this topic Deficiencies in micronutrients are common in women in developing countries and have been associated with low birth weight and preterm delivery What this study adds In rural Nepal maternal supplementation with folic acid-iron reduced the incidence of low birth weight by 16 % A multiple micronutrient supplement of 14 micronutrients , including folic acid , iron , and zinc , reduced low birth weight by 14 % , thus conferring no advantage over folic [8909485] OBJECTIVE The preventive efficacy of the periconceptional use of multivitamins is well established for neural tube defects , much less so for other birth defects . We conducted a population -based , case-control study to assess the effects of multivitamin use on the risk for conotruncal defects , a group of severe heart defects that includes transposition of the great arteries , tetralogy of Fallot , and truncus arteriosus . METHODS From the population -based Atlanta Birth Defects Case-Control Study , we identified 158 case infants with conotruncal defects and 3026 unaffected , r and omly chosen control infants , born from 1968 through 1980 to mothers residing in metropolitan Atlanta . Periconceptional multivitamin use was defined as reported regular use from 3 months before conception through the third month of pregnancy . We present the results of the crude analysis , because the multivariate model yielded essentially identical results . RESULTS Mothers who reported periconceptional multivitamin use had a 43 % lower risk of having infants with conotruncal defects ( odds ratio [ OR ] , 0.57 ; 95 % confidence interval [ CI ] , 0.33 to 1.00 ) than did mothers who reported no use . The estimated relative risk was lowest for isolated conotruncal defects ( OR , 0.41 ; 95 % CI , 0.20 to 0.84 ) compared with those associated with noncardiac defects ( OR , 0.91 ; 95 % CI , 0.33 to 2.52 ) or a recognized syndrome ( OR , 1.82 ; 95 % CI , 0.31 to 10.67 ) . Among anatomic subgroups of defects , transposition of the great arteries showed the greatest reduction in risk ( OR , 0.36 ; 95 % CI , 0.15 to 0.89 ) . CONCLUSIONS Periconceptional multivitamin use is associated with a reduced risk for conotruncal defects . These findings could have major implication s for the prevention of these birth defects [563620] The efficacy of prophylactic treatment with ferrous sulfate ( 80 mg Fe++ ) and the combination of ferrous sulfate with folic acid ( 80 mg Fe++ and 350 microgram folic acid ) were studied in a double blind trial in the 20th , and again in the 30th and 36th week of pregnancy ( 29 patients ) . At the beginning of the treatment ( 20th week ) 29 % of the patients showed a pathologically reduced serum folic acid level . Combined therapy has a favorable effect on the folic acid levels in the serum and red blood cells ; this was confirmed statistically . At the end of pregnancy , 69 % of the patients of the control group ( ferrous sulfate ) showed a pathologically reduced serum level and 23 % a subnormal level in erythrocytes . These results un question ably justify the prophylactic prescription of folic acid during pregnancy [1508382] An open , r and omised multicentre study was carried out to compare pregnant women , treated with calcium folinate ( Citofolin Bracco S.p . A. ) 15 mg/day per os starting from the 12th or 20th week of gestation , with an untreated group . The results obtained confirm the efficacy of calcium folinate treatment on the trends of parameters analysed ( serum and endoerythrocytic folatemia , hemoglobin and sideremia ) which remained within the normal range . Moreover , no adverse effects of any type were reported during the study [21849596] BACKGROUND The influence of prenatal long-chain polyunsaturated fatty acids ( LC-PUFAs ) and folate on neurologic development remains controversial . OBJECTIVE The objective was to assess the long-term effects of n-3 ( omega-3 ) LC-PUFA supplementation , 5-methyltetrahydrofolate ( 5-MTHF ) supplementation , or both in pregnant women on cognitive development of offspring at 6.5 y of age . DESIGN This was a follow-up study of the NUHEAL ( Nutraceuticals for a Healthier Life ) cohort . Healthy pregnant women in 3 European centers were r and omly assigned to 4 intervention groups . From the 20th week of pregnancy until delivery , they received a daily supplement of 500 mg docosahexaenoic acid ( DHA ) + 150 mg eicosapentaenoic acid [ fish oil ( FO ) ] , 400 μg 5-MTHF , or both or a placebo . Infants received formula containing 0.5 % DHA and 0.4 % arachidonic acid ( AA ) if they were born to mothers receiving FO supplements or were virtually free of DHA and AA until the age of 6 mo if they belonged to the groups that were not supplemented with FO . Fatty acids and folate concentrations were determined in maternal blood at weeks 20 and 30 of pregnancy , at delivery , and in cord blood . Cognitive function was assessed at 6.5 y of age with the Kaufman Assessment Battery for Children ( K-ABC ) . RESULTS We observed no significant differences in K-ABC scores between intervention groups . Higher DHA in maternal erythrocytes at delivery was associated with a Mental Processing Composite Score higher than the 50th percentile in the offspring . CONCLUSION We observed no significant effect of supplementation on the cognitive function of children , but maternal DHA status may be related to later cognitive function in children . This trial was registered at clinical trials.gov as NCT01180933 [6029952] IN a previous investigation of the effects of grade d micro-doses of folic acid ( pteroyl glutamic acid ) in pregnancy suggestive evidence has been obtained that the minimal oral requirement may lie in the region of 300 pg./day . This conclusion was based largely upon the measurement of the fasting post-partum serum folate or L. casei activity in a group of patients from a population where poor dietary intake of folic acid was common . In patients receiving no prophylactic folic acid or IOO pg./day the median post-partum serum folate level was subnormal , in those receiving 3oo , ug./day it was normal and in those receiving 4sopg./day it was supranormal ( Willoughby and Jewell , 1966 ) . As an extension of this investigation the incidence of maternal anaemia has now been assessed among a population of 3599 patients r and omly allocated at their first ante-natal [5460838] Folic acid administered to pregnant Bantu , whose diet is low in folate , was associated with a significant reduction in the incidence of prematurity . No such effect could be demonstrated in White patients subsisting on an average Western diet . This suggests that folate deficiency may contribute to the “ pregnancy wastage ” in population s whose dietary folate intake is low , and is a further indication for folic acid supplementation during pregnancy in these groups [15262481] It is well established that folic acid supplementation in early pregnancy significantly reduces the incidence of neural tube defects ( NTDs ) [ 1 ] . Consistent with national guidelines [ 2 ] , it is current practice in the UK to advise pregnant women to take folic acid supplementation until 12 weeks gestation . A recent report , however , suggests that supplementation with folic acid throughout pregnancy may effect a reduction in adverse pregnancy outcomes [ 3 ] , although this is not yet confirmed . If folic acid supplementation throughout pregnancy led to a reduction in such outcomes , it would be a safe , simple , and inexpensive therapeutic intervention [20211038] Maternal supplementation with long-chain PUFA , to improve infant neurological development , might cause additional increase of oxidative stress . Pregnant women aged 18 - 41 years were r and omised into one of four supplementation groups . From week 22 on , they received supplements containing either modified fish oil ( n 69 ) , 5-methyl-tetrahydro-folate ( n 65 ) , both ( n 64 ) , or placebo ( n 72 ) . Plasma Trolox-equivalent antioxidative capacity ( TEAC ) , concentrations of alpha-tocopherol , retinol , beta-carotene , free thiol groups , uric acid and thiobarbituric acid-reactive substances ( TBARS ) were determined at weeks 20 and 30 and at delivery . The studied antioxidants showed no significant differences between the four supplementation groups . At week 30 plasma TBARS levels were found to be significantly higher in the fish oil group ( 0.80 ( sem 0.04 ) micromol/l ) than in the folate ( 0.67 ( sem 0.03 ) micromol/l ; P = 0.024 ) and control ( 0.69 ( sem 0.04 ) micromol/l ; P = 0.01 ) groups . Concentrations of retinol and free thiol groups decreased during pregnancy , whereas uric acid increased and beta-carotene as well as TEAC showed only minor changes . Fish oil supplementation during the second half of pregnancy appears not to decrease antioxidant status . The increased TBARS levels at week 30 may indicate a period of increased oxidative stress in plasma at this time [18644934] Objective : Micronutrient deficiencies during pregnancy may be linked to poor newborn health and poor host defences against infection . We assessed newborn morbidity to determine the effect of four combinations of antenatal micronutrient supplements . Design : Cluster-r and omised , double-masked , controlled trial . Setting : Rural community in Nepal . Interventions : Women received daily supplements from early pregnancy through to 3 months postpartum of vitamin A alone ( control ) or vitamin A with folic acid , folic acid plus iron , folic acid plus iron plus zinc or a multiple micronutrient supplement containing these and 11 other nutrients . Main outcome measures : Infants were visited in their home at birth ( n = 3927 ) and for each of 9 days thereafter to elicit a 24-h history of nine infant morbidity symptoms , measure infant respiratory rate and axial temperature , and assess the infant for chest indrawing . At 6 weeks of age , infants were visited again in their homes to elicit a 30-day and 7-day history of 10 morbidity symptoms using parental recall . Results : Maternal micronutrient supplementation had no effect on 10-day morbidity or morbidity 30-day and 7-day morbidity assessed at 6 weeks of age all relative risks were close to 1 . Symptoms of birth asphyxia increased by about 60 % ( p<0.05 ) in infants of women who received the multiple micronutrient supplement compared with the control . Symptoms of combinations of sepsis , preterm and birth asphyxia were associated with 8- to 14-fold increased odds of 6-month infant mortality . Conclusions : None of the combinations of antenatal micronutrient supplements tested improved symptoms of neonatal morbidity in the first 10 days of life or at 6 weeks of age . Further research is needed to eluci date the association and mechanism of increased risk of birth asphyxia following maternal multiple micronutrient supplementation . Trial registration numbers : NCT00115271 [7047579] A former double-blind study evaluated the effect of a 14-day period of systemic and topical folate supplementation on gingival inflammation during pregnancy ( Pack & Thomson 1980 ) . The current experiment was similar to the earlier one except that supplementation was for 28 days during the eighth month only . Thirty women during their 32nd week of pregnancy were r and omly divided into three equal groups . Control Group A received placebo mouthwash ( MW ) and placebo tablets ; Group B received placebo MW and one 5 mg folate tablet daily ; Group C received placebo tablets and rinsed with folate MW twice daily for 1 min . At the beginning and end of the experimental period , oral status was determined using a plaque index ( PlI ) and a gingival index ( GI ) . Each subject furnished a 1-week diet record which was analysed for dietary folate . No differences in parameters existed between groups at the commencement of the study except for folate levels which were lower in Group B. Results confirmed the findings of the former experiment . Group C showed highly significant improvement in GI despite no significant changes in PlI ( 0.001 less than P less than 0.01 ) , whilst in Group B , changes in gingival health were not statistically significant ( 0.05 less than P less than 0.10 ) . No significant changes were demonstrated in Group A. Folate levels increased significantly in Groups B and C. Dietary folate was similar in all groups [138664] Hemoglobin ( Hb ) concentration , serum iron level , iron binding capacity and blood folate ( Lactobacillus casei ) activity were determined in 310 unselected pregnant Burmese women . Hb concentration was less than 11 g/dl in 72 % of the women ; the serum iron level was less than 50 mug/dl in 33 % ; serum folate activity was less than 3ng/ml in 13 % ; and red cell folate activity was less than 100 ng/ml in 17 % of the women . Ninety-six of the women in our study were r and omly divided into four groups , treated from the 22nd to the 25th week of pregnancy until full term with either ferrous sulfate containing 60 mg elemental iron twice daily , 5 mg folic acid twice daily , a combination of both , or a placebo only . At full term , Hb concentration fell in the groups given placebo or folic acid . On the other h and , in the groups given iron alone or iron plus folic acid there was an increase in Hb of 0.4 and 0.7 g/dl , respectively ( intergroup difference not statistically significant ) . Serum iron and blood folate levels fell in the groups not receiving the appropriate hematinic . In spite of deficient serum and red cell folate levels in 30 and 40 % , respectively , of the group on iron alone , the mean Hb concentration increased at full term and none of the women had a Hb concentration lower than 10 g/dl . Blood folate levels were lower in the iron-supplemented group than in the placebo group , indicating that iron deficiency does not aggravate the folate nutritional status [5683581] The serial trends of the whole blood folate level in two groups of patients have been followed throughout pregnancy and up to six weeks postpartum . In those receiving iron alone the whole blood folate remained normal until the test at six weeks after delivery , at which time over half were in the deficient range . There appears to be a delay before this test reflects the current folate status when this changes rapidly . In those receiving iron plus 330 μg . of folic acid a day the results at this time were close to those at the beginning of pregnancy . Subnormal whole blood folate , red cell folate , and serum folate values occurred close to term in patients receiving iron alone , but were not found in those also receiving folic acid . Megaloblastic changes occurred at term in three patients receiving iron alone in whom the whole blood folate had repeatedly been low in early pregnancy . The observations are consistent with the previous suggestion that 300 μg . of folic acid daily is a suitable supplement to prevent deficiency in late pregnancy and the puerperium [883006] Investigations on 114 anaemic pregnant women revealed that megaloblastosis occurred in more than half . A therapeutic follow-up approach clearly indicated that vitamin B12-deficiency was fairly common in such patients ; the need of iron supplementation in many of them for achieving complete remission emphasized the poor status of iron stores . All patients with normoblastic marrow achieved full remission with iron therapy alone . The deficiency of haematinic factors appears to be largely due to poor nutrition [21865563] Questions have been raised about potentially negative effects of antenatal folic acid use in population s with a high prevalence of vitamin B-12 deficiency . Our objective was to examine the association between maternal folate and vitamin B-12 status in pregnancy on offspring insulin resistance and examine whether the effects of maternal micronutrient supplementation varied by baseline maternal folate and /or vitamin B-12 status . Pregnant women were cluster r and omized to receive daily supplements containing vitamin A alone or with folic acid , folic acid+iron , folic acid+iron+zinc , or a multiple micronutrient . In a sub sample ( n = 1132 ) , micronutrient status biomarkers were analyzed at baseline and late pregnancy . Children born to the women who participated in the trial were visited at 6 - 8 y of age . Fasting plasma glucose and insulin were used to estimate insulin resistance using the homeostasis model assessment ( HOMA-IR ) . Children whose mothers were deficient in vitamin B-12 ( < 148 pmol/L , 27 % ) during early pregnancy had a 26.7 % increase in HOMA-IR ( P = 0.02 ) , but there was no association with maternal folate status . Among children born to women who were vitamin B-12 deficient at baseline , the percent difference in HOMA-IR compared to the control group was 15.1 % ( 95 % CI : -35.9 , 106.4 ) , 4.9 % ( -41.6 , 88.5 ) , 3.3 % ( -38.4 , 73.5 ) , and 18.1 % ( -29.0 , 96.7 ) in the folic acid , folic acid-iron , folic acid-iron-zinc , and multiple micronutrient supplementation groups , respectively , none of which were significant . Maternal vitamin B-12 deficiency is associated with an elevated risk of insulin resistance , but supplementation with folic acid or other micronutrients led to no significant change in insulin resistance in school-aged offspring [26105254] INTRODUCTION Observational studies suggest that folic acid supplementation during pregnancy can reduce the risk of preeclampsia ( PE ) . No r and omized controlled trial has been conducted to demonstrate the effect of folic acid supplementation on PE . OBJECTIVES FACT aims to determine efficacy on a new PE prevention strategy of high dose folic acid supplementation from early pregnancy ( 8(0/7 ) to 16(6/7)weeks of gestation ) until delivery in women with high risk of developing PE . METHODS DESIGN FACT is an international , multi-centre , double-blind , placebo controlled clinical trial of 3656 women . Eligible women will be r and omised in a 1:1 ratio to folic acid 4.0 mg or placebo . POPULATION Pregnant women ( 8(0/7 ) and 16(6/7 ) weeks of gestation ) ⩾18 years of age , taking ⩽1.1 mg of folic acid supplementation who fulfill at least one of the following identified risk factors for PE . Pre-existing hypertension ( blood pressure ⩾90mmHg on two separate occasions or at least 4h apart prior to r and omization , or use of antihypertensive medication during this pregnancy specifically for the treatment of hypertension prior to r and omization ) , pre-pregnancy diabetes ( Type I or Type II DM ) , twin pregnancy , history of PE in a previous pregnancy , BMI ⩾35kg/m(2 ) within 3 months prior this pregnancy or during the first trimester of this pregnancy . PRIMARY OUTCOME PE is defined as blood pressure ⩾d90mmHg on two occasions ⩾4 h apart and proteinuria developed in women greater than 20 weeks of gestation . Or HELLP ( Haemolysis , Elevated , Liver Enzymes , Low Platelets ) syndrome Or superimposed PE , defined as history of pre-existing hypertension ( diagnosed pre-pregnancy or before 20 weeks ' gestation ) with new proteinuria . Proteinuria is defined as : Analysis plan : Intent-to-Treat ( ITT ) population will be analyzed . Chi-square test will be used in the comparison of incidence of PE between the intervention and placebo groups for analysis of the primary outcome . RESULTS The Ottawa Hospital r and omized the first FACT subject in April 2011 . As of February 29th , 2012 , 62 subjects have been r and omized . There are currently 18 Canadian sites participating in FACT , of which 10 are actively recruiting and 8 are pending site activation . Internationally , Argentina , Australia and the United Kingdom are anticipating first recruits in the late spring of 2012 . Israel and Holl and are expected to begin enrolment as early as the fall of 2012 . CONCLUSION Recruitment is on target and expected to end August 2014 . Results from this large scale trial will provide a definitive answer to the important question whether folic acid supplementation can prevent PE

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### Context: [20120789] Background Efforts to determine the impact of prenatal multivitamin supplementation on birth outcome have been carried out in several developing countries . A review of factors that would impact the effectiveness of prenatal supplementation under normal field conditions is currently lacking and will be required for exp and ed supplementation programs . An efficacy trial of a multiple micronutrient supplement for pregnant women was conducted in rural western China , and additional information on side effects , rates of adherence , program inputs , and cost was also gathered . Objectives To examine reports of side effects and rates of adherence to prenatal multiple micronutrient supplementation in comparison with supplementation with folic acid and with iron – folic acid , and to describe inputs and costs associated with prenatal supplementation in China . Methods A cluster-r and omized , double-blind , controlled trial was conducted in two rural counties in northwest China . All pregnant women in villages were r and omly assigned to take daily supplements of folic acid , iron – folic acid , or a recommended daily allowance of 15 vitamins and minerals from enrollment until delivery . Information was collected from the women on side effects and adherence . Program inputs and costs of supplementation were tracked . Descriptive statistics were used for the analysis . The biological effectiveness of prenatal multiple micronutrient supplements is reported elsewhere . Results Less than 4 % of women withdrew from the study because of side effects . Adherence to supplementation was high : the supplements were consumed on more than 90 % of the days on which they were available for consumption . The mean number of supplements consumed was high at 165 capsules , and about 40 % consumed the recommended 180 supplements during pregnancy . Conclusions High adherence to a prenatal supplement schedule can be achieved when mothers have frequent contact with trained health workers and a reliable supply of supplements [3530158] Two hundred Hausa primigravidae at Zaria were divided into five groups in a r and omized double-blind trial of antenatal oral antimalarial prophylaxis , and haematinic supplements . Group 1 received no active treatment . Groups 2 to 5 were given chloroquine 600 mg base once , followed by proguanil 100 mg per day . In addition , group 3 received iron 60 mg daily , group 4 folic acid 1 mg daily , and group 5 iron plus folic acid . Forty-five percent were anaemic ( haemoglobin ( Hb ) less than 11.0 g dl-1 ) at first attendance before 24 weeks of gestation , and malaria parasitaemia ( predominantly Plasmodium falciparum ) was seen in 27 % , of whom 60 % were anaemic . The mean Hb fell during pregnancy in group 1 , and seven patients in this group had to be removed from the trial and treated for severe anaemia ( packed cell volume ( PCV ) less than 0.26 ) . Only five patients in the other groups developed severe anaemia ( P = 0.006 ) , two of whom had malaria following failure to take treatment . Patients in group 1 had the lowest mean Hb at 28 and 36 weeks of gestation , and patients receiving antimalarials and iron ( groups 3 and 5 ) had the highest Hb at 28 weeks , but differences were not significant , possibly due to removal from the trial of patients with severe anaemia . Anaemia ( Hb less than 12.0 g dl-1 ) at six weeks after delivery was observed in 61 % of those not receiving active treatment ( group 1 ) , in 39 % of those protected against malaria but not receiving iron supplements ( groups 2 and 4 ) and in only 18 % of patients receiving both antimalarials and iron ( groups 3 and 5 ) . Folic acid had no significant effect on mean Hb . Proguanil was confirmed to be a highly effective causal prophylaxis . Prevention of malaria , without folic acid supplements , reduced the frequency of megaloblastic erythropoiesis from 56 % to 25 % . Folic acid supplements abolished megaloblastosis , except in three patients who were apparently not taking the treatment prescribed . Red cell folate ( RCF ) concentrations were higher in subjects with malaria , probably due to intracellular synthesis by plasmodia . Infants of mothers not receiving antimalarials appeared to have an erythroid hyperplasia . Maternal folate supplements raised infants ' serum folate and RCF . Fourteen per cent had low birth weight ( less than 2500 g ) , and the perinatal death rate was 11 % ; the greatest number were in group 1 , but not significantly . A regime is proposed for the prevention of malaria , iron deficiency , folate deficiency and anaemia in pregnancy in the guinea savanna of Nigeria [1263177] In a controlled , prospect i ve trial , the effects of giving ferrous sulphate 50 mg daily to 76 pregnant women was compared with giving ferrous sulphate 50 mg daily plus folic acid 0.5 mg daily to 82 women in 12 general practice s in South-east Engl and .No differences in obstetric complications were found between the two groups , although the evidence of some of the listed complications may be too rare for detection in a sample of patients of this size [18831691] UNLABELLED Sulfadoxine-pyrimethamine ( SP ) inhibits folate metabolism by the malaria parasite . We investigated the association between folate levels and SP failure in pregnant women . Data from a trial to assess the effect that folate supplementation has on SP failure in 467 pregnant women were analyzed . Plasma folate levels were determined at enrollment and at day 7 . High baseline folate levels , high parasite densities , and age < 20 years were risk factors for SP failure . High-dose ( 5 mg daily ) folate supplementation or high folate levels at day 7 were independent risk factors . Therefore , pregnant women receiving SP should receive low-/moderate-dose folate supplementation . TRIAL REGISTRATION http://www . clinical trials.gov identifier : NCT00130065 [5926263] Bertino , J. R. , Ward , J. , Sartorelli , A. C. , and Silber , R. ( 1965 ) . 7 . clin . Invest . , 44 , 1028 . Bothwell , T. H. , Hurtardo , A. V. , Donohue , D. M. , and Finch , C. A. ( 1957 ) . Blood , 12 , 409 . Callender , S. T. , and Malpas , J. S. ( 1963 ) . Brit . med . 7 . , 2 , 1516 . Cockburn , F. , Sherman , J. D. , Ingall , D. , and Klein , R. ( 1965 ) . Proc . Soc . exp . Biol . ( N.Y. ) , 118 , 238 . Conrad , M. E. , Berman , A. , and Crosby , W. H. ( 1962 ) . Gastroenterology , 43 , 385 . Dacie , J. V. , and Lewis , S. M. ( 1963 ) . Practical Haematology , 3rd ed . London . Davis , A. E. , and Badenoch , J. ( 1962 ) . Lancet , 2 , 6 . Finch , C. A. , Coleman , D. H. , Motulsky , A. G. , Donohue , D. M. , and Reiff , R. H. ( 1956 ) . Blood , 11 , 807 . Herbert , V. ( 1963 ) . Amer . 7 . clan . Nutr . , 12 , 17 . Gottlieb , C. W. , and Altschule , M. D. ( 1965 ) . Lancet , 2 , 1052 [16870008] The hypothesis was tested that the additional dietary uptake of n-3 fatty acids , in particular of DHA and 5-methyltetrahydrofolate ( 5-MTHF ) , during the second half of pregnancy would influence proliferation and apoptosis in the full-term human placenta . The diets of pregnant women from Spain ( n 55 ) were supplemented with modified fish oil and /or 5-MTHF or placebo , and assigned in a r and om , double-blind manner to one of the four groups . Immunohistochemistry and immunoblotting were used to detect placental proliferation and apoptosis with monoclonal antibodies for key proteins that reflected the extent of both processes : proliferation cell nuclear antigen ( PCNA ) , p53 , cytokeratin 18 neoepitope . The PCNA level in the fish oil/5-MTHF-treated group was higher by 66 % ( P < 0.05 ) than that of the placebo group , whereas the levels of p53 and cytokeratin 18 neoepitope were unaffected by treatment . PCNA expression was altered only in the trophoblast compartment ( placebo 11.1 ( se 0.5 ) % v. combination 21.5 ( se 1.2 ) % ; P < 0.05 ) , whereas the proportion of nuclei stained in endothelial and other stromal cells was similar in the placebo and combined treatment groups . No correlation was found between fish oil or 5-MTHF supplementation and the levels of the proteins . The present data suggest that supplementation with fish oil and /or 5-MTHF had no effect on the parameters reflecting placental proliferation and apoptosis . A defined combination of DHA and 5-MTHF may , however , affect placental proliferation [14608063] Iron deficiency is one of the main causes of anemia during pregnancy , although other micronutrient deficiencies may play a role . We examined the effects of daily antenatal and postnatal supplementation with four combinations of micronutrients on maternal hematologic indicators in a double-masked r and omized controlled community trial . Communities , called sectors , were r and omly assigned to supplementation with folic acid ( 400 microg ) , folic acid plus iron ( 60 mg ) , folic acid plus iron and zinc ( 30 mg ) and folic acid plus iron , zinc and 11 other micronutrients , each at the approximate recommended daily allowance for pregnancy all given with vitamin A as retinol acetate ( 1000 microg retinol equivalent ) , or vitamin A alone as the control group . Hemoglobin ( Hb ) and indicators of iron status were assessed at baseline and at 32 wk of gestation . At 6-wk postpartum , Hb assessment was repeated using a finger stick . Severely anemic women ( Hb < 70 g/L ) were treated according to WHO recommendations . Folic acid alone had no effect on maternal anemia or iron status . Hb concentrations were 14 g/L , [ 95 % confidence limits ( CL ) , 8.3 - 19.2 ] , 10.0 g/L ( CL , 5.2 - 14.8 ) and 9.4 g/L ( CL , 4.7 - 14.1 ) higher in the groups receiving folic acid plus iron , folic acid plus iron and zinc and folic acid plus iron , zinc and multiple micronutrients , respectively , relative to the control . Anemia in the third trimester was reduced by 54 % with folic acid plus iron , by 48 % with folic acid plus iron and zinc and by 36 % with folic acid plus iron , zinc and multiple micronutrients supplementation , relative to the control ( P < 0.05 ) . Thus , the combinations of folic acid plus iron and zinc and folic acid plus iron , zinc and multiple micronutrients provided no additional benefit in improving maternal hematologic status during pregnancy compared with folic acid plus iron . The level of compliance and baseline Hb concentrations modified the effect of iron [17490978] BACKGROUND Pregnant women usually meet their increased energy needs but do not always meet their increased micronutrient requirements . The supply of both folic acid and docosahexaenoic acid ( DHA ) has been related to positive pregnancy and infant outcomes . OBJECTIVE We aim ed to assess whether fish-oil ( FO ) supplementation with or without folate from gestation week 22 to birth improves maternal and fetal n-3 long-chain polyunsaturated fatty acid ( n-3 LC-PUFA ) status . DESIGN We conducted a multicenter ( Germany , Hungary , and Spain ) , r and omized , double-blind , 2 x 2 factorial , placebo-controlled trial . From gestation week 22 until delivery , 311 pregnant women received daily a preparation with FO [ 0.5 g DHA and 0.15 g eicosapentaenoic acid ( EPA ) ] , 400 microg methyltetrahydrofolic acid ( MTHF ) , FO with MTHF , or placebo . Outcome measures included maternal and cord plasma DHA and EPA contents at gestation weeks 20 and 30 and at delivery , indicators of pregnancy outcome , and fetal development . RESULTS FO significantly ( P<0.001 ) increased maternal DHA and EPA ( % by wt ) , as shown by 3-factor repeated- measures ANOVA ( ie , MTHF , FO , and time ) with adjustment for maternal baseline DHA and EPA . In addition , FO significantly ( P<0.001 ) increased cord blood DHA ( % by wt ; 2-factor ANOVA ) . MTHF was significantly ( P=0.046 ) associated with increased maternal DHA ( % by wt ) . There was no FO x MTHF interaction for the time course of DHA or EPA ( P=0.927 and 0.893 ) . Pregnancy outcomes and fetal development did not differ significantly among the intervention groups . CONCLUSIONS FO supplementation from gestation week 22 until delivery improves fetal n-3 LC-PUFA status and attenuates depletion of maternal stores . MTHF may further enhance maternal n-3 LC-PUFA proportions [18806105] In rural China , many pregnant women in their third trimester suffer from anemia ( 48 % ) and iron deficiency ( ID ; 42 % ) , often with coexisting deficiencies of retinol and riboflavin . We investigated the effect of retinol and riboflavin supplementation in addition to iron plus folic acid on anemia and subjective well-being in pregnant women . The study was a 2-mo , double-blind , r and omized trial . Subjects ( n = 366 ) with anemia [ hemoglobin ( Hb ) < /= 105 g/L ] were r and omly assigned to 4 groups , all receiving 60 mg/d iron and 400 mug/d folic acid . The iron+folic acid ( IF ) group ( n = 93 ) served as reference , the iron+folic acid+retinol group ( IFA ) ( n = 91 ) was treated with 2000 mug retinol , the iron+folic acid+riboflavin group ( IFB ) ( n = 91 ) with 1.0 mg riboflavin , and the iron+folic acid+retinol+riboflavin group ( IFAB ) ( n = 91 ) with retinol and riboflavin . After the 2-mo intervention , the Hb concentration increased in all 4 groups ( P < 0.001 ) . The increase in the IFAB group was 5.4 + /- 1.1 g/L greater than in the IF group ( P < 0.001 ) . The reduced prevalence of anemia ( Hb < 110g/L ) and ID anemia were significantly greater in the groups supplemented with retinol and /or riboflavin than in the IF group . Moreover , gastrointestinal symptoms were less prevalent in the IFA group than in the IF group ( P < 0.05 ) and improved well-being was more prevalent in the groups receiving additional retinol and /or riboflavin than in the IF group ( P < 0.05 ) . Thus , a combination of iron , folic acid , retinol , and riboflavin was more effective than iron plus folic acid alone . Multimicronutrient supplementation may be worthwhile for pregnant women in rural China [14668283] BACKGROUND We previously reported that maternal micronutrient supplementation in rural Nepal decreased low birth weight by approximately 15 % . OBJECTIVE We examined the effect of daily maternal micronutrient supplementation on fetal loss and infant mortality . DESIGN The study was a double-blind , cluster-r and omized , controlled trial among 4926 pregnant women and their 4130 infants in rural Nepal . In addition to vitamin A ( 1000 microg retinol equivalents ) , the intervention groups received either folic acid ( FA ; 400 microg ) , FA + iron ( 60 mg ) , FA + iron + zinc ( 30 mg ) , or multiple micronutrients ( MNs ; the foregoing plus 10 microg vitamin D , 10 mg vitamin E , 1.6 mg thiamine , 1.8 mg riboflavin , 2.2 mg vitamin B-6 , 2.6 microg vitamin B-12 , 100 mg vitamin C , 64 microg vitamin K , 20 mg niacin , 2 mg Cu , and 100 mg Mg ) . The control group received vitamin A only . RESULTS None of the supplements reduced fetal loss . Compared with control infants , infants whose mothers received FA alone or with iron or iron + zinc had a consistent pattern of 15 - 20 % lower 3-mo mortality ; this pattern was not observed with MNs . The effect on mortality was restricted to preterm infants , among whom the relative risks ( RRs ) were 0.36 ( 95 % CI : 0.18 , 0.75 ) for FA , 0.53 ( 0.30 , 0.92 ) for FA + iron , 0.77 ( 0.45 , 1.32 ) for FA + iron + zinc , and 0.70 ( 0.41 , 1.17 ) for MNs . Among term infants , the RR for mortality was close to 1 for all supplements except MNs ( RR : 1.74 ; 95 % CI : 1.00 , 3.04 ) . CONCLUSIONS Maternal micronutrient supplementation failed to reduce overall fetal loss or early infant mortality . Among preterm infants , FA alone or with iron reduced mortality in the first 3 mo of life . MNs may increase mortality risk among term infants , but this effect needs further evaluation [11435509] To investigate the effects of pregnancy on folate metabolism , we conducted an 84-d study in second-trimester ( gestational wk 14 - 25 ) pregnant women ( n = 6 ) and nonpregnant controls ( n = 6 ) with stable-isotopic tracer methods . All subjects were fed a diet containing approximately 272 nmol/d ( 120 microg/d ) folate from food , along with supplemental folic acid that contained 15 % [ 3',5'-(2)H(2 ) ] folic acid ( [(2)H(2)]folic acid ) during d 1 - -41 and that was unlabeled during d 42 - -84 to yield a constant total folate intake of 1.02 or 1.93 micromol/d ( 450 or 850 microg/d ) . Isotopic enrichment of plasma folate , urinary folate and the urinary folate catabolites para-aminobenzoylglutamate ( pABG ) and para-acetamidobenzoylglutamate ( ApABG ) was determined at intervals throughout the study . The labeling of pABG and ApABG reflected that of tissue folate pools from which the catabolites originate . After the intake of labeled folic acid was terminated on d 41 , labeling of urinary folate exhibited a biphasic exponential decline with distinct fast and slow components . In contrast , during d 42 - -84 , the enrichment of urinary pABG and ApABG exhibited primarily monophasic exponential decline , and plasma folate underwent little decline of labeling during this period . Pregnant women and controls did not differ in estimates of body folate pool size and most aspects of the excretion of labeled urinary folate and catabolites , rates of decline of excretion , and areas under the curves for folate and catabolite excretion . Pregnant women , however , tended to have a slower rate of decline of pABG than ApABG and higher enrichment at d 42 of ApABG and pABG . These data support and extend our previous findings indicating that pregnancy ( gestational wk 14 - -26 ) causes subtle changes in folate metabolism but does not elicit substantial increases in the rate or extent of folate turnover at these moderately high folate intakes [9446844] Measurement of the urinary folate catabolites , para-aminobenzoylglutamate ( pABG ) and the more predominant acetylated form , acetamidobenzoylglutamate ( apABG ) , has been used to assess folate requirements in both pregnant and nonpregnant women . Folate catabolite excretion has been reported to be significantly higher in pregnant women ( second trimester ) compared with nonpregnant controls . The primary goals of this study were to determine if pregnant women in a controlled metabolic study excreted higher quantities of urinary folate catabolites than nonpregnant controls and if catabolite excretion was influenced by folate intake . We evaluated the effect of gestation and folate intake on the urinary excretion of apABG and pABG in pregnant women ( n = 12 ; wk 14 - 26 gestation ) and nonpregnant controls ( n = 12 ) assigned to consume folate levels approximating the current ( 400 microg/d ) and previous ( 800 microg/d ) RDA . Subjects were fed a controlled diet containing 120 microg folate/d and either 330 or 730 microg synthetic folic acid/d . In contrast to previously reported data , no differences in mean folate catabolite excretion were detected between pregnant and nonpregnant subjects . Catabolite excretion ( pABG + apABG ) decreased significantly relative to initial values in pregnant women consuming 450 microg folate/d ( -40 + /- 20 % ; mean + /- SD ) and final mean excretion was significantly lower in the pregnant women consuming 450 microg folate/d ( 86 + /- 32 nmol/d ) compared with 850 microg folate/d ( 148 + /- 20 nmol/d ) . Data from this study indicate that second trimester pregnant women do not excrete more folate catabolites than nonpregnant controls and that consumption of 450 vs. 850 microg folate/d results in a significant reduction in the quantity of folate catabolites excreted [16600929] BACKGROUND Previously we showed that women in rural Nepal experience multiple micronutrient deficiencies in early pregnancy . OBJECTIVE This study examined the effects of daily antenatal micronutrient supplementation on changes in the biochemical status of several micronutrients during pregnancy . DESIGN In Nepal , we conducted a r and omized controlled trial in which 4 combinations of micronutrients ( folic acid , folic acid + iron , folic acid + iron + zinc , and a multiple micronutrient supplement containing folic acid , iron , zinc , and 11 other nutrients ) plus vitamin A , or vitamin A alone as a control , were given daily during pregnancy . In a sub sample of subjects ( n = 740 ) , blood was collected both before supplementation and at approximately 32 wk of gestation . RESULTS In the control group , serum concentrations of zinc , riboflavin , and vitamins B-12 and B-6 decreased , whereas those of copper and alpha-tocopherol increased , from the first to the third trimester . Concentrations of serum folate , 25-hydroxyvitamin D , and undercarboxylated prothrombin remained unchanged . Supplementation with folic acid alone or folic acid + iron decreased folate deficiency . However , the addition of zinc failed to increase serum folate , which suggests a negative inhibition ; multiple micronutrient supplementation increased serum folate . Folic acid + iron + zinc failed to improve zinc status but reduced sub clinical infection . Multiple micronutrient supplementation decreased the prevalence of serum riboflavin , vitamin B-6 , vitamin B-12 , folate , and vitamin D deficiencies but had no effect on infection . CONCLUSIONS In rural Nepal , antenatal supplementation with multiple micronutrients can ameliorate , to some extent , the burden of deficiency . The implication s of such biochemical improvements in the absence of functional and health benefits remain unclear [2711281] Higher folate needs are present during pregnancy , which may lead to tissular deficiency in the mother and to depleted newborn folate reserves . The aim of this work was to assess the prevalence of folate deficiency and to establish the rates of serum and red cell folate in two groups of mothers and newborn infants , one receiving only iron and the other iron and folate during pregnancy . The rates of serum and red cell folate found at the end of pregnancy were significantly higher in the group which received folate ; however , the percentage of cases with tissular folate deficiency was low in both groups , with no significant difference ( 3.8 % and 1.3 % , respectively ) . These findings , along with the lack of effect of supplemental folate on erythropoiesis , pose some questions on the usefulness of supplemental folate during pregnancy in our country [7588512] OBJECTIVE To determine by biochemical methods the nutritional status of pre- and post-natal Turkish women and its relationship with offspring anthropometry . DESIGN Longitudinal study . SETTING Health centres in Istanbul and Izmit , research department and university hospital laboratories . SUBJECTS R and omly selected group of women attending health centres at 13 - 17 weeks gestation ( n = 130 ) ; same sample of women at 28 - 32 weeks gestation ( n = 88 ) and 13 - 17 weeks post-partum ( n = 95 ) ; offspring at 13 - 17 weeks post-partum ( n = 90 ) . INTERVENTIONS Blood sample s taken from mothers at all three stages and analysed for ferritin , iron , zinc , calcium , alkaline phosphatase , total protein , albumin , vitamins B2 , B6 , B12 , A , E , beta-carotene and folate levels ; question naire completed for recording medical and socio-demographic background . Anthropometric measurements taken from mothers and offspring . RESULTS High percentages of subjects were at risk for deficiencies of vitamin B12 ( 48.8 % ) and folate ( 59.7 % ) in early pregnancy ; ferritin ( 52.3 % ) , zinc ( 72.3 % ) , vitamin B2 ( 38.8 % ) , vitamin B12 ( 80.9 % ) , and folate ( 76.4 % ) during late pregnancy ; and ferritin ( 39.0 % ) , vitamins B2 ( 43.1 % ) , B6 ( 36.4 % ) , B12 ( 60.0 % ) , and folate ( 73.3 % ) at the post-partum stage . Bone loss was indicated in 55.0 % and 80.0 % of the subjects in late pregnancy and post-partum respectively . Haematocrit in later pregnancy correlated strongly with prenatal body fat ( P < 0.001 ) . Infant anthropometry at 13 - 17 weeks post-partum was significantly affected by pre-natal weight gain and a number of maternal blood nutrients in pregnancy and post-partum . CONCLUSIONS Nutrition education programmes and enrichment of the staple food with iron , zinc , calcium , and the B vitamins should be considered [7619925] To study the relation of maternal periconceptional vitamin use to the risk of a congenital urinary tract anomaly ( CUTA ) , we conducted a case-control study using the Washington State Birth Defect Registry . We identified CUTA cases with no known chromosomal abnormality in seven counties in western Washington State occurring between January 1 , 1990 , and December 31 , 1991 . We r and omly selected a sample , as controls , of all infants delivered in five large hospitals in King County who did not have a birth defect and who were born in the same year as the cases . About 55 % of all infants in King County and a smaller proportion of infants in the other six counties are delivered in these five hospitals . We interviewed mothers of 118 cases and 369 controls to obtain information about their vitamin use during the pregnancy and during the year before the conception . After adjustment for maternal race , family income , county of maternal residence , and birth year , we found that women who used multivitamins during the first trimester had only 15 % the risk of bearing a child with a CUTA compared with women who did not take vitamins [ odds ratio ( OR ) = 0.15 ; 95 % confidence interval ( CI ) = 0.05–0.43 ] . The reduction was smaller for use restricted to the second or third trimesters ( OR = 0.31 ; 95 % CI = 0.09–1.02 ) . Among women who used vitamins during the first trimester , vitamin use before conception was not associated with any further reduction in the risk , nor did there appear to be an association with the amount or br and of vitamin used . Restricting the analysis to residents of King County did not change the results . Our results indicate that prenatal multivitamin use , particularly during the first trimester , may reduce the risk of a CUTA . Because all of the preparations taken by study participants contained many vitamins as well as folic acid , it was not possible to identify which one ( or several ) chemical(s ) may have been responsible for the reduced risk of a CUTA [8324432] OBJECTIVE --To study the effect of periconceptional multivitamin supplementation on neural tube defects and other congenital abnormality entities . DESIGN --R and omised controlled trial of supplementation with multivitamins and trace elements . SETTING --Hungarian family planning programme . SUBJECTS--4156 pregnancies with known outcome and 3713 infants evaluated in the eighth month of life . INTERVENTIONS --A single tablet of a multivitamin including 0.8 mg of folic acid or trace elements supplement daily for at least one month before conception and at least two months after conception . MAIN OUTCOME MEASURES --Number of major and mild congenital abnormalities . RESULTS --The rate of all major congenital abnormalities was significantly lower in the group given vitamins than in the group given trace elements and this difference can not be explained totally by the significant reduction of neural tube defects . The rate of major congenital abnormalities other than neural tube defects and genetic syndromes was 9.0/1000 in pregnancies with known outcome in the vitamin group and 16.6/1000 in the trace element group ; relative risk 1.85 ( 95 % confidence interval 1.02 to 3.38 ) ; difference , 7.6/1000 . The rate of all major congenital abnormalities other than neural tube defects and genetic syndromes diagnosed up to the eighth month of life was 14.7/1000 informative pregnancies in the vitamin group and 28.3/1000 in the trace element group ; relative risk 1.95 ( 1.23 to 3.09 ) ; difference , 13.6/1000 . The rate of some congenital abnormalities was lower in the vitamin group than in the trace element group but the differences for each group of abnormalities were not significant . CONCLUSIONS --Periconceptional multivitamin supplementation can reduce not only the rate of neural tube defects but also the rate of other major non-genetic syndromatic congenital abnormalities . Further studies are needed to differentiate the chance effect and vitamin dependent effect [7007454] A double-blind study evaluated the effects of systemic and topical folate on gingival inflammation during the fourth and eighth months of pregnancy . Thirty women were r and omly divided into three groups . Group A received placebo mouthwash and tablets ; Group B ; placebo mouthwash and 5 mg folate tablets ; Group C : folate mouthwash and placebo tablets . Supplementation lasted for 14 days during months 4 and 8 . Subjects took one tablet daily and rinsed twice daily for 1 min with the mouthwash . At the start and finish of each 14-day period , fasting serum and red cell folate levels were estimated and oral status assessed by a plaque index ( P1I ) , a gingival index ( GI ) , and gingival exu date flow meter ( GEF ) . Subjects completed 1-week diet sheets which were analysed for dietary folate . All groups were similar in each parameter at the start . Correlation was demonstrated between GI and P1I , and between GI and GEF . GI tended to increase throughout pregnancy in all groups except Group C , when in the eighth month there was a highly significant improvement ( 0.001 less than P 0.01 ) despite no significant change in P1I . Although dietary intake of folate was significantly higher during the eighth month in Group C as compared with Groups A and B , ( 0.001 less than P less than 0.01 ) , the folate mouthwash produced highly significantly improvement in gingival health in pregnancy [19368922] OBJECTIVE To examine the effect of supplemental prenatal folic acid , folic acid-iron , folic acid-iron-zinc , and multiple micronutrients on maternal morbidity in rural Nepal . METHODS A cluster-r and omized double-masked controlled trial of pregnant women who received daily supplements from early pregnancy through 3 months post partum as per the treatment allocation . Women were interviewed at birth about labor and delivery complications and for 9 days post partum to obtain 24-hour histories of morbidity . RESULTS A total of 3986 ( 97.3 % ) women completed an interview regarding labor and delivery ; morbidity history was available for 3564 ( 87.0 % ) women . Folic acid-iron reduced the risk of postpartum hemorrhage ( relative risk [ RR ] 0.59 ; 95 % confidence interval [ CI ] 0.35 - 0.98 ) . Risk of dysfunctional labor increased with multiple micronutrient supplementation ( RR 1.28 ; 95 % CI , 1.01 - 1.60 ) , although preterm premature rupture of membrane decreased ( RR 0.40 ; 95 % CI , 0.21 - 0.79 ) . Puerperal sepsis was lower in those receiving folic acid-iron , folic acid-iron-zinc , and multiple micronutrients compared with controls ( P<0.05 ) . CONCLUSION Prenatal folic acid-iron supplementation reduced the risk of obstetric complications in this South Asian setting [19139780] OBJECTIVE To evaluate the effect of high dose and low dose folic acid on the levels of hemocysteine ( Hcy ) concentration during the first trimester of pregnancy and at delivery , and to examine the association of Hcy serum levels and preeclampsia . METHODS In a single blinded r and omized clinical trial , which was conducted in Tabriz , Iran , from 2005 - 2008 , 246 nulliparous pregnant women in 2 similar groups , received folic acid daily from early pregnancy until delivery ( 5 mg/day in group one and 0.5 mg/ day in group 2 ) . The incidence of hypertension and laboratory changes in the levels of serum Hcy , lactate dehydrogenase , and uric acid in addition to the levels of urine creatinine and protein were compared between the groups . RESULTS There was no presence of any type of hypertension in each group . The systolic blood pressures ( BP ) ( mm Hg ) at the first trimester were 114.01 + /- 8.78 for group one , 114.16 + /- 9.05 for group 2 , and at delivery , 117.24 + /- 6.91 for group one , and 117.23 + /- 11.48 for group 2 ( p=0.32 ) . The diastolic BP at the first trimester were 74.90 + /- 7.45 for group one , 73.30 + /- 8.90 for group 2 , and at delivery 76.46 + /- 5.58 for group one , and 76.69 + /- 8.62 for group 2 ( p=0.42 ) . Although the level of Hcy ( micromol/L ) decreased significantly at the delivery time in group one ( 11.81+/- 3.85 decreased to 6.44 + /- 1.88 ) , and 2 ( 9.08+/- 3.24 , decreased to 7.44 + /- 2.99 ) , this decrement was more significant in the first group ( p<0.001 ) . CONCLUSION The results show that folic acid supplement throughout pregnancy , irrespective of the dosage , could eliminate hypertensive disorders , and decreases serum level of Hcy , although it is reduced more significant in the first group [1617124] Objectives : Sulfadoxine-pyrimethamine ( SP ) is an antimalarial drug that acts on the folate metabolism of the malaria parasite . We investigated whether folate ( FA ) supplementation in a high or a low dose affects the efficacy of SP for the treatment of uncomplicated malaria in pregnant women . Design : This was a r and omized , placebo-controlled , double-blind trial . Setting : The trial was carried out at three hospitals in western Kenya . Participants : The participants were 488 pregnant women presenting at their first antenatal visit with uncomplicated malaria parasitaemia ( density of ≥ 500 parasites/μl ) , a haemoglobin level higher than 7 g/dl , a gestational age between 17 and 34 weeks , and no history of antimalarial or FA use , or sulfa allergy . A total of 415 women completed the study . Interventions : All participants received SP and iron supplementation . They were r and omized to the following arms : FA 5 mg , FA 0.4 mg , or FA placebo . After 14 days , all participants continued with FA 5 mg daily as per national guidelines . Participants were followed at days 2 , 3 , 7 , 14 , 21 , and 28 or until treatment failure . Outcome Measures : The outcomes were SP failure rate and change in haemoglobin at day 14 . Results : The proportion of treatment failure at day 14 was 13.9 % ( 19/137 ) in the placebo group , 14.5 % ( 20/138 ) in the FA 0.4 mg arm ( adjusted hazard ratio [ AHR ] , 1.07 ; 98.7 % confidence interval [ CI ] , 0.48 to 2.37 ; p = 0.8 ) , and 27.1 % ( 38/140 ) in the FA 5 mg arm ( AHR , 2.19 ; 98.7 % CI , 1.09 to 4.40 ; p = 0.005 ) . The haemoglobin levels at day 14 were not different relative to placebo ( mean difference for FA 5 mg , 0.17 g/dl ; 98.7 % CI , −0.19 to 0.52 ; and for FA 0.4 mg , 0.14 g/dl ; 98.7 % CI , −0.21 to 0.49 ) . Conclusions : Concomitant use of 5 mg FA supplementation compromises the efficacy of SP for the treatment of uncomplicated malaria in pregnant women . Countries that use SP for treatment or prevention of malaria in pregnancy need to evaluate their antenatal policy on timing or dose of FA supplementation [21177506] CONTEXT Iron and zinc are important for the development of both intellectual and motor skills . Few studies have examined whether iron and zinc supplementation during gestation , a critical period of central nervous system development , affects children 's later functioning . OBJECTIVE To examine intellectual and motor functioning of children whose mothers received micronutrient supplementation during pregnancy . DESIGN , SETTING , AND PARTICIPANTS Cohort follow-up of 676 children aged 7 to 9 years in June 2007-April 2009 who had been born to women in 4 of 5 groups of a community-based , double-blind , r and omized controlled trial of prenatal micronutrient supplementation between 1999 and 2001 in rural Nepal . Study children were also in the placebo group of a subsequent preschool iron and zinc supplementation trial . INTERVENTIONS Women whose children were followed up had been r and omly assigned to receive daily iron/folic acid , iron/folic acid/zinc , or multiple micronutrients containing these plus 11 other micronutrients , all with vitamin A , vs a control group of vitamin A alone from early pregnancy through 3 months postpartum . These children did not receive additional micronutrient supplementation other than biannual vitamin A supplementation . MAIN OUTCOME MEASURES Children 's intellectual functioning , assessed using the Universal Nonverbal Intelligence Test ( UNIT ) ; tests of executive function , including go/no-go , the Stroop test , and backward digit span ; and motor function , assessed using the Movement Assessment Battery for Children ( MABC ) and finger-tapping test . RESULTS The difference across outcomes was significant ( Bonferroni-adjusted P < .001 ) for iron/folic acid vs control but not for other supplement groups . The mean UNIT T score in the iron/folic acid group was 51.7 ( SD , 8.5 ) and in the control group was 48.2 ( SD , 10.2 ) , with an adjusted mean difference of 2.38 ( 95 % confidence interval [ CI ] , 0.06 - 4.70 ; P = .04 ) . Differences were not significant between the control group and either the iron/folic acid/zinc ( 0.73 ; 95 % CI , -0.95 to 2.42 ) or multiple micronutrient ( 1.00 ; 95 % CI , -0.55 to 2.56 ) groups . In tests of executive function , scores were better in the iron/folic acid group relative to the control group for the Stroop test ( adjusted mean difference in proportion who failed , -0.14 ; 95 % CI , -0.23 to -0.04 ) and backward digit span ( adjusted mean difference , 0.36 ; 95 % CI , 0.01 - 0.71 ) but not for the go/no-go test . The MABC score was lower ( better ) in the iron/folic acid group compared with the control group but not after adjustment for confounders ( mean difference , -1.47 ; 95 % CI , -3.06 to 0.12 ; P = .07 ) . Finger-tapping test scores were higher ( mean difference , 2.05 ; 95 % CI , 0.87 - 3.24 ; P = .001 ) in the iron/folic acid group . CONCLUSION Aspects of intellectual functioning including working memory , inhibitory control , and fine motor functioning among offspring were positively associated with prenatal iron/folic acid supplementation in an area where iron deficiency is prevalent . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00115271 [19778983] The long-term benefits of antenatal iron supplementation in child survival are not known . In 1999 - 2001 , 4,926 pregnant women in rural Nepal participated in a cluster-r and omized , double-masked , controlled trial involving 4 alternative combinations of micronutrient supplements , each containing vitamin A. The authors examined the impact on birth weight and early infant mortality in comparison with controls , who received vitamin A only . They followed the surviving offspring of these women at approximately age 7 years to study effects of in utero supplementation on survival . Of 4,130 livebirths , 209 infants died in the first 3 months and 8 were lost to follow-up . Of those remaining , 3,761 were followed , 150 died between ages 3 months and 7 years , and 152 were lost to follow-up . Mortality rates per 1,000 child-years from birth to age 7 years differed by maternal supplementation group , as follows : folic acid , 13.4 ; folic acid-iron , 10.3 ; folic acid-iron-zinc , 12.0 ; multiple micronutrients ; 14.0 ; and controls , 15.2 . Hazard ratios were 0.90 ( 95 % confidence interval ( CI ) : 0.65 , 1.22 ) , 0.69 ( 95 % CI : 0.49 , 0.99 ) , 0.80 ( 95 % CI : 0.58 , 1.11 ) , and 0.93 ( 95 % CI : 0.66 , 1.31 ) , respectively , in the 4 supplementation groups . Maternal iron-folic acid supplementation reduced mortality among these children by 31 % between birth and age 7 years . These results provide additional motivation for strengthening antenatal iron-folic acid programs [9219461] BACKGROUND Zinc and folate are important for fetal growth . However , the relationship between the dietary intake of these nutrients and pregnancy outcome is not settled . METHODS A prospect i ve study was conducted to ascertain the relationship between maternal dietary zinc and folate intake ( n = 1398 ) , serum zinc and folate levels ( n = 289 ) , and infant birthweight . Twenty-four hour recalls were used to measure energy , zinc , folate and other nutrient intakes at 18 and 30 weeks of gestation . Subjects in the study were offered daily folic acid ( 1.0 mg ) and iron ( 60 mg as ferrous sulfate ) at enrollment . RESULTS Maternal zinc nutriture as assessed by serum and dietary intake was not associated with birthweight or length of gestation . There was a small but significant positive association between maternal folate intake and adjusted infant birthweight ( beta = 0.05 , p = 0.03 ) . The indirect measures of maternal nutritional status including maternal pre-pregnancy weight ( beta = 8.0 , p = 0.0001 ) and weight gain during pregnancy ( beta = 18.1 , p = 0.0001 ) were stronger predictors of adjusted infant birthweight as compared to energy intake and intake of zinc and folate . An increase of 320 , 290 , and 48 g in infant birthweight was associated with the 90th-10th percentile difference for pre-pregnancy weight , weight gain during pregnancy , and folate intake respectively . CONCLUSION These results indicate that pre-pregnancy weight and weight gain during pregnancy are both strong predictors of infant birthweight . Folate intake , although significantly associated with birthweight , was a weak predictor while maternal intake of zinc and other nutrients was not associated with birthweight [4865965] Our interest in the problem of folic acid and pregnancy was aroused by the work of Hibbard and Hibbard : “ Aetiological factors in abruptio placentae ” 1963 ( 12 ) . Though the frequency of abruptio placentae at our department is by no means so high as that at Millroad Maternity Hospital , Liverpool , the complication is serious because of its foetal mortality . We therefore thought it advisable to try folic acid prophylaxis during pregnancy in an attempt to decrease the frequency of abruptio placentae . Later investigations ( 14 , 20 ) have , however , shown that if folic acid treatment is not started until pregnancy has been diagnosed , it will hardly be able to reduce the frequency of abruptio placentae and abortion . In Great Britain megaloblastic anaemia due to folic acid deficiency is common during pregnancy ( 4 , 5 , 6 , 7 , 8 , 13 , 15 , 16 , IS ) , while in Sweden only a few cases have been reported . This discrepancy can be explained only partly by differences in interest in the diagnosis and diagnostic facilities available . In a thoroughly examined series Hansen found megaloblastic anaemia in less than 0.1 % of all pregnant women during a 3 1/2-year-period in Gothenburg ( 9 ) . A poor composition of the diet was thought to be a main causal factor of folic acid deficiency in the series reported from [22085869] Background / Objectives : Little is known about the long-term effects of maternal multi-micronutrient supplementation on the growth of children during early childhood . In this follow-up study , the effects of maternal supplementation with multi-micronutrients in pregnancy on postnatal child growth are examined . Subjects/ Methods : A longitudinal follow-up of a subset of newborns ( n=1388 ) whose mothers were r and omly assigned to receive the supplements of folic acid , iron – folic acid or multi-micronutrients daily during pregnancy in the original trial was conducted . Children ’s weight and length were measured and assessed during monthly home visits from birth to 30 months of age . Results : The pooled prevalence rate of stunting over different time points during the first 30 months was 13.5 , 14.9 and 12.1 % for the folic acid group , iron – folic acid group and multi-micronutrient group , respectively . However , there were no significant differences in the pooled odds of stunting in children between the multi-micronutrient group and the folic acid ( odds ratio ( OR ) 0.97 , 95 % confidence interval ( CI ) : 0.74–1.26 ) , and between the multi-micronutrient group and the iron – folic acid group ( OR 0.82 , 95 % CI : 0.63–1.07 ) . Similar results for the three groups were found for the occurrences of underweight and wasting in children . Furthermore , no significant differences were observed in length , weight , length-for-age , weight-for-age and weight-for-length Z-scores among the three treatment groups . Conclusions : Currently , available evidence is insufficient to support a greater advantage of the effect of maternal multi-micronutrient supplementation on child growth over iron – folic acid or folic acid only supplementation during the first 30 months [16941105] Objective Elevated plasma homocysteine has been implicated in vascular changes compatible with atherosis and endothelial dysfunction similar to the vascular changes of the placenta in preeclampsia . Previous reports have indicated an increased incidence of hyperohomocysteinemia in preeclamptic patients . The aim of this study was to examine the association of homocysteine levels and preeclampsia in our patients . Study design Prospect i ve study of 28 preeclamptic patients that were matched with 26 normal controls of the same gestational age . Results The preeclamptic group had an increased incidence of cesarean sections ( 75 % ) , of growth retarded fetuses ( 50 % ) , intrauterine deaths ( 7 % ) and placental abruptions ( 7 % ) . Mean levels of homocysteine were significantly elevated in the preeclamptic than in control group ( 11.11 vs. 6.40 μmol/l , P < 0.001 ) . There were no differences between the groups regarding the levels of folic acid ( 11.12 vs. 9.73 ng/ml , P = 0.55 ) and vitamin B12 ( 295.76 vs. 356.15 pg/ml , P = 0.43 ) . Conclusion It is concluded that in our study homocysteine levels are significantly elevated in patients with preeclampsia compared with control group , while no vitamin deficiencies were observed [19474130] BACKGROUND We previously reported that a r and omized controlled trial of antenatal micronutrient supplements in rural Nepal decreased the risk of low birth weight by approximately 15 % . OBJECTIVE The objective was to examine the effects of micronutrient supplementation on growth and body composition in children of supplemented mothers through school age . DESIGN Mothers received 1 of 5 micronutrient supplements daily : folic acid , folic acid + iron , folic acid + iron + zinc , multiple micronutrients , or a control . All of the supplements contained vitamin A. Children born during this trial were revisited at age 6 - 8 y to measure height , weight , midupper arm circumference , waist circumference , and triceps and subscapular skinfold thicknesses . Arm fat and muscle area were estimated by using st and ard formulas , and height-for-age , weight-for-age , and body mass index-for-age z scores were calculated by using the World Health Organization growth st and ard . RESULTS Of the 3771 surviving children , 3324 were revisited and consented to anthropometric measurements . Maternal supplementation with folic acid + iron + zinc result ed in an increase in mean height ( 0.64 cm ; 95 % CI : 0.04 , 1.25 ) and a reduction in mean triceps skinfold thickness ( -0.25 mm ; 95 % CI : -0.44 , -0.06 ) , subscapular skinfold thickness ( -0.20 mm ; 95 % CI : -0.33 , -0.06 ) , and arm fat area ( -0.18 cm(2 ) ; -0.34 , -0.01 ) . No significant differences were found between groups in mean weight or body mass index-for-age z scores , waist circumference , or arm muscle area . Other micronutrient combinations including a multiple micronutrient formulation failed to show a growth benefit . CONCLUSION Antenatal supplementation with zinc may benefit child growth , particularly in areas where a deficiency of this nutrient is common [5476865] It has been shown that the incidence of megaloblastic anaemia in a group of 463 r and omly selected pregnant women receiving iron was 12 times as high as in a control group of 235 pregnant women receiving iron and folic acid . The incidence of all types of anaemia in the women receiving iron alone was more than three times the incidence in those having iron and folic acid . Some women who were not anaemic or who had normoblastic anaemia had serum folate levels in the same range as the women with megaloblastic anaemia , but none of the women with megaloblastic anaemia had high serum folate levels . The labile fraction of the serum folate was no more reliable than the total serum folate as a diagnostic criterion of megaloblastic erythropoiesis in the individual case . The blood group distribution in the women with megaloblastic anaemia was the same as in the general population . Babies born to mothers with megaloblastic anaemia tended to be smaller than the rest , although there was no difference in the placental weights . The significance of these findings is discussed [16137113] In this placebo controlled , r and omised , double blind trial , pregnant women received from the 20th week of gestation onwards either 500 mg docosahexaenoic acid ( DHA ) , 400 mg 5-methyl-tetra-hydro-folate ( 5-MTHF ) , or placebo , or a combination of 500 mg DHA and 400 mg 5-MTHF . The dietary supplements were well tolerated ; the dropout rates did not differ significantly in the active arms of the study ( 10 % to 19 % ) from that seen in the placebo group ( 13 % ) . DHA supplementation result ed in significant enhancement of the contribution of DHA to maternal , placental and venous cord blood lipids [8882400] The objective in the Hungarian r and omised double-blind controlled trial was to study the preventive effect of periconceptional multivitamin supplementation on neural tube-defects and other congenital abnormalities . There were 2,471 and 2,391 informative offspring ( prenatally diagnosed and terminated malformed fetuses , stillborn fetuses , and liveborn infants ) in the multivitamin and placebo-like trace element groups , respectively . A single tablet either of a multivitamin containing 0.8 mg of folic acid or trace element supplement was given daily for at least one month before conception and at least until the date of the second missed menstrual period . The total rate of major congenital abnormalities was 20.6/1,000 in the multivitamin and 40.6/1,000 in the trace element group . After the exclusion of six cases of neural-tube defects in the trace element group the difference was very highly significant [ P = 0.0003 ; relative risk of 0.54 ( 95 % CI 0.39 , 0.76 ) ] . Multivitamin supplementation appeared to result in a significant reduction in the rate of urinary tract abnormalities , mainly obstructive defects , and in the rate of sporadic cardiovascular malformations , mainly ventricular septal defects . This report is regarded as a hypothesis-generating study encouraging others to see if the result can be repeated [12637400] Abstract Objective : To assess the impact on birth size and risk of low birth weight of alternative combinations of micronutrients given to pregnant women . Design : Double blind cluster r and omised controlled trial . Setting : Rural community in south eastern Nepal . Participants : 4926 pregnant women and 4130 live born infants . Interventions : 426 communities were r and omised to five regimens in which pregnant women received daily supplements of folic acid , folic acid-iron , folic acid-iron-zinc , or multiple micronutrients all given with vitamin A , or vitamin A alone ( control ) . Main outcome measures : Birth weight , length , and head and chest circumference assessed within 72 hours of birth . Low birth weight was defined < 2500 g. Results : Supplementation with maternal folic acid alone had no effect on birth size . Folic acid-iron increased mean birth weight by 37 g ( 95 % confidence interval −16 g to 90 g ) and reduced the percentage of low birthweight babies ( < 2500 g ) from 43 % to 34 % ( 16 % ; relative risk=0.84 , 0.72 to 0.99 ) . Folic acid-iron-zinc had no effect on birth size compared with controls . Multiple micronutrient supplementation increased birth weight by 64 g ( 12 g to 115 g ) and reduced the percentage of low birthweight babies by 14 % ( 0.86 , 0.74 to 0.99 ) . None of the supplement combinations reduced the incidence of preterm births . Folic acid-iron and multiple micronutrients increased head and chest circumference of babies , but not length . Conclusions : Antenatal folic acid-iron supplements modestly reduce the risk of low birth weight . Multiple micronutrients confer no additional benefit over folic acid-iron in reducing this risk . What is already known on this topic Deficiencies in micronutrients are common in women in developing countries and have been associated with low birth weight and preterm delivery What this study adds In rural Nepal maternal supplementation with folic acid-iron reduced the incidence of low birth weight by 16 % A multiple micronutrient supplement of 14 micronutrients , including folic acid , iron , and zinc , reduced low birth weight by 14 % , thus conferring no advantage over folic [8909485] OBJECTIVE The preventive efficacy of the periconceptional use of multivitamins is well established for neural tube defects , much less so for other birth defects . We conducted a population -based , case-control study to assess the effects of multivitamin use on the risk for conotruncal defects , a group of severe heart defects that includes transposition of the great arteries , tetralogy of Fallot , and truncus arteriosus . METHODS From the population -based Atlanta Birth Defects Case-Control Study , we identified 158 case infants with conotruncal defects and 3026 unaffected , r and omly chosen control infants , born from 1968 through 1980 to mothers residing in metropolitan Atlanta . Periconceptional multivitamin use was defined as reported regular use from 3 months before conception through the third month of pregnancy . We present the results of the crude analysis , because the multivariate model yielded essentially identical results . RESULTS Mothers who reported periconceptional multivitamin use had a 43 % lower risk of having infants with conotruncal defects ( odds ratio [ OR ] , 0.57 ; 95 % confidence interval [ CI ] , 0.33 to 1.00 ) than did mothers who reported no use . The estimated relative risk was lowest for isolated conotruncal defects ( OR , 0.41 ; 95 % CI , 0.20 to 0.84 ) compared with those associated with noncardiac defects ( OR , 0.91 ; 95 % CI , 0.33 to 2.52 ) or a recognized syndrome ( OR , 1.82 ; 95 % CI , 0.31 to 10.67 ) . Among anatomic subgroups of defects , transposition of the great arteries showed the greatest reduction in risk ( OR , 0.36 ; 95 % CI , 0.15 to 0.89 ) . CONCLUSIONS Periconceptional multivitamin use is associated with a reduced risk for conotruncal defects . These findings could have major implication s for the prevention of these birth defects [563620] The efficacy of prophylactic treatment with ferrous sulfate ( 80 mg Fe++ ) and the combination of ferrous sulfate with folic acid ( 80 mg Fe++ and 350 microgram folic acid ) were studied in a double blind trial in the 20th , and again in the 30th and 36th week of pregnancy ( 29 patients ) . At the beginning of the treatment ( 20th week ) 29 % of the patients showed a pathologically reduced serum folic acid level . Combined therapy has a favorable effect on the folic acid levels in the serum and red blood cells ; this was confirmed statistically . At the end of pregnancy , 69 % of the patients of the control group ( ferrous sulfate ) showed a pathologically reduced serum level and 23 % a subnormal level in erythrocytes . These results un question ably justify the prophylactic prescription of folic acid during pregnancy [1508382] An open , r and omised multicentre study was carried out to compare pregnant women , treated with calcium folinate ( Citofolin Bracco S.p . A. ) 15 mg/day per os starting from the 12th or 20th week of gestation , with an untreated group . The results obtained confirm the efficacy of calcium folinate treatment on the trends of parameters analysed ( serum and endoerythrocytic folatemia , hemoglobin and sideremia ) which remained within the normal range . Moreover , no adverse effects of any type were reported during the study [21849596] BACKGROUND The influence of prenatal long-chain polyunsaturated fatty acids ( LC-PUFAs ) and folate on neurologic development remains controversial . OBJECTIVE The objective was to assess the long-term effects of n-3 ( omega-3 ) LC-PUFA supplementation , 5-methyltetrahydrofolate ( 5-MTHF ) supplementation , or both in pregnant women on cognitive development of offspring at 6.5 y of age . DESIGN This was a follow-up study of the NUHEAL ( Nutraceuticals for a Healthier Life ) cohort . Healthy pregnant women in 3 European centers were r and omly assigned to 4 intervention groups . From the 20th week of pregnancy until delivery , they received a daily supplement of 500 mg docosahexaenoic acid ( DHA ) + 150 mg eicosapentaenoic acid [ fish oil ( FO ) ] , 400 μg 5-MTHF , or both or a placebo . Infants received formula containing 0.5 % DHA and 0.4 % arachidonic acid ( AA ) if they were born to mothers receiving FO supplements or were virtually free of DHA and AA until the age of 6 mo if they belonged to the groups that were not supplemented with FO . Fatty acids and folate concentrations were determined in maternal blood at weeks 20 and 30 of pregnancy , at delivery , and in cord blood . Cognitive function was assessed at 6.5 y of age with the Kaufman Assessment Battery for Children ( K-ABC ) . RESULTS We observed no significant differences in K-ABC scores between intervention groups . Higher DHA in maternal erythrocytes at delivery was associated with a Mental Processing Composite Score higher than the 50th percentile in the offspring . CONCLUSION We observed no significant effect of supplementation on the cognitive function of children , but maternal DHA status may be related to later cognitive function in children . This trial was registered at clinical trials.gov as NCT01180933 [6029952] IN a previous investigation of the effects of grade d micro-doses of folic acid ( pteroyl glutamic acid ) in pregnancy suggestive evidence has been obtained that the minimal oral requirement may lie in the region of 300 pg./day . This conclusion was based largely upon the measurement of the fasting post-partum serum folate or L. casei activity in a group of patients from a population where poor dietary intake of folic acid was common . In patients receiving no prophylactic folic acid or IOO pg./day the median post-partum serum folate level was subnormal , in those receiving 3oo , ug./day it was normal and in those receiving 4sopg./day it was supranormal ( Willoughby and Jewell , 1966 ) . As an extension of this investigation the incidence of maternal anaemia has now been assessed among a population of 3599 patients r and omly allocated at their first ante-natal [5460838] Folic acid administered to pregnant Bantu , whose diet is low in folate , was associated with a significant reduction in the incidence of prematurity . No such effect could be demonstrated in White patients subsisting on an average Western diet . This suggests that folate deficiency may contribute to the “ pregnancy wastage ” in population s whose dietary folate intake is low , and is a further indication for folic acid supplementation during pregnancy in these groups [15262481] It is well established that folic acid supplementation in early pregnancy significantly reduces the incidence of neural tube defects ( NTDs ) [ 1 ] . Consistent with national guidelines [ 2 ] , it is current practice in the UK to advise pregnant women to take folic acid supplementation until 12 weeks gestation . A recent report , however , suggests that supplementation with folic acid throughout pregnancy may effect a reduction in adverse pregnancy outcomes [ 3 ] , although this is not yet confirmed . If folic acid supplementation throughout pregnancy led to a reduction in such outcomes , it would be a safe , simple , and inexpensive therapeutic intervention [20211038] Maternal supplementation with long-chain PUFA , to improve infant neurological development , might cause additional increase of oxidative stress . Pregnant women aged 18 - 41 years were r and omised into one of four supplementation groups . From week 22 on , they received supplements containing either modified fish oil ( n 69 ) , 5-methyl-tetrahydro-folate ( n 65 ) , both ( n 64 ) , or placebo ( n 72 ) . Plasma Trolox-equivalent antioxidative capacity ( TEAC ) , concentrations of alpha-tocopherol , retinol , beta-carotene , free thiol groups , uric acid and thiobarbituric acid-reactive substances ( TBARS ) were determined at weeks 20 and 30 and at delivery . The studied antioxidants showed no significant differences between the four supplementation groups . At week 30 plasma TBARS levels were found to be significantly higher in the fish oil group ( 0.80 ( sem 0.04 ) micromol/l ) than in the folate ( 0.67 ( sem 0.03 ) micromol/l ; P = 0.024 ) and control ( 0.69 ( sem 0.04 ) micromol/l ; P = 0.01 ) groups . Concentrations of retinol and free thiol groups decreased during pregnancy , whereas uric acid increased and beta-carotene as well as TEAC showed only minor changes . Fish oil supplementation during the second half of pregnancy appears not to decrease antioxidant status . The increased TBARS levels at week 30 may indicate a period of increased oxidative stress in plasma at this time [18644934] Objective : Micronutrient deficiencies during pregnancy may be linked to poor newborn health and poor host defences against infection . We assessed newborn morbidity to determine the effect of four combinations of antenatal micronutrient supplements . Design : Cluster-r and omised , double-masked , controlled trial . Setting : Rural community in Nepal . Interventions : Women received daily supplements from early pregnancy through to 3 months postpartum of vitamin A alone ( control ) or vitamin A with folic acid , folic acid plus iron , folic acid plus iron plus zinc or a multiple micronutrient supplement containing these and 11 other nutrients . Main outcome measures : Infants were visited in their home at birth ( n = 3927 ) and for each of 9 days thereafter to elicit a 24-h history of nine infant morbidity symptoms , measure infant respiratory rate and axial temperature , and assess the infant for chest indrawing . At 6 weeks of age , infants were visited again in their homes to elicit a 30-day and 7-day history of 10 morbidity symptoms using parental recall . Results : Maternal micronutrient supplementation had no effect on 10-day morbidity or morbidity 30-day and 7-day morbidity assessed at 6 weeks of age all relative risks were close to 1 . Symptoms of birth asphyxia increased by about 60 % ( p<0.05 ) in infants of women who received the multiple micronutrient supplement compared with the control . Symptoms of combinations of sepsis , preterm and birth asphyxia were associated with 8- to 14-fold increased odds of 6-month infant mortality . Conclusions : None of the combinations of antenatal micronutrient supplements tested improved symptoms of neonatal morbidity in the first 10 days of life or at 6 weeks of age . Further research is needed to eluci date the association and mechanism of increased risk of birth asphyxia following maternal multiple micronutrient supplementation . Trial registration numbers : NCT00115271 [7047579] A former double-blind study evaluated the effect of a 14-day period of systemic and topical folate supplementation on gingival inflammation during pregnancy ( Pack & Thomson 1980 ) . The current experiment was similar to the earlier one except that supplementation was for 28 days during the eighth month only . Thirty women during their 32nd week of pregnancy were r and omly divided into three equal groups . Control Group A received placebo mouthwash ( MW ) and placebo tablets ; Group B received placebo MW and one 5 mg folate tablet daily ; Group C received placebo tablets and rinsed with folate MW twice daily for 1 min . At the beginning and end of the experimental period , oral status was determined using a plaque index ( PlI ) and a gingival index ( GI ) . Each subject furnished a 1-week diet record which was analysed for dietary folate . No differences in parameters existed between groups at the commencement of the study except for folate levels which were lower in Group B. Results confirmed the findings of the former experiment . Group C showed highly significant improvement in GI despite no significant changes in PlI ( 0.001 less than P less than 0.01 ) , whilst in Group B , changes in gingival health were not statistically significant ( 0.05 less than P less than 0.10 ) . No significant changes were demonstrated in Group A. Folate levels increased significantly in Groups B and C. Dietary folate was similar in all groups [138664] Hemoglobin ( Hb ) concentration , serum iron level , iron binding capacity and blood folate ( Lactobacillus casei ) activity were determined in 310 unselected pregnant Burmese women . Hb concentration was less than 11 g/dl in 72 % of the women ; the serum iron level was less than 50 mug/dl in 33 % ; serum folate activity was less than 3ng/ml in 13 % ; and red cell folate activity was less than 100 ng/ml in 17 % of the women . Ninety-six of the women in our study were r and omly divided into four groups , treated from the 22nd to the 25th week of pregnancy until full term with either ferrous sulfate containing 60 mg elemental iron twice daily , 5 mg folic acid twice daily , a combination of both , or a placebo only . At full term , Hb concentration fell in the groups given placebo or folic acid . On the other h and , in the groups given iron alone or iron plus folic acid there was an increase in Hb of 0.4 and 0.7 g/dl , respectively ( intergroup difference not statistically significant ) . Serum iron and blood folate levels fell in the groups not receiving the appropriate hematinic . In spite of deficient serum and red cell folate levels in 30 and 40 % , respectively , of the group on iron alone , the mean Hb concentration increased at full term and none of the women had a Hb concentration lower than 10 g/dl . Blood folate levels were lower in the iron-supplemented group than in the placebo group , indicating that iron deficiency does not aggravate the folate nutritional status [5683581] The serial trends of the whole blood folate level in two groups of patients have been followed throughout pregnancy and up to six weeks postpartum . In those receiving iron alone the whole blood folate remained normal until the test at six weeks after delivery , at which time over half were in the deficient range . There appears to be a delay before this test reflects the current folate status when this changes rapidly . In those receiving iron plus 330 μg . of folic acid a day the results at this time were close to those at the beginning of pregnancy . Subnormal whole blood folate , red cell folate , and serum folate values occurred close to term in patients receiving iron alone , but were not found in those also receiving folic acid . Megaloblastic changes occurred at term in three patients receiving iron alone in whom the whole blood folate had repeatedly been low in early pregnancy . The observations are consistent with the previous suggestion that 300 μg . of folic acid daily is a suitable supplement to prevent deficiency in late pregnancy and the puerperium [883006] Investigations on 114 anaemic pregnant women revealed that megaloblastosis occurred in more than half . A therapeutic follow-up approach clearly indicated that vitamin B12-deficiency was fairly common in such patients ; the need of iron supplementation in many of them for achieving complete remission emphasized the poor status of iron stores . All patients with normoblastic marrow achieved full remission with iron therapy alone . The deficiency of haematinic factors appears to be largely due to poor nutrition [21865563] Questions have been raised about potentially negative effects of antenatal folic acid use in population s with a high prevalence of vitamin B-12 deficiency . Our objective was to examine the association between maternal folate and vitamin B-12 status in pregnancy on offspring insulin resistance and examine whether the effects of maternal micronutrient supplementation varied by baseline maternal folate and /or vitamin B-12 status . Pregnant women were cluster r and omized to receive daily supplements containing vitamin A alone or with folic acid , folic acid+iron , folic acid+iron+zinc , or a multiple micronutrient . In a sub sample ( n = 1132 ) , micronutrient status biomarkers were analyzed at baseline and late pregnancy . Children born to the women who participated in the trial were visited at 6 - 8 y of age . Fasting plasma glucose and insulin were used to estimate insulin resistance using the homeostasis model assessment ( HOMA-IR ) . Children whose mothers were deficient in vitamin B-12 ( < 148 pmol/L , 27 % ) during early pregnancy had a 26.7 % increase in HOMA-IR ( P = 0.02 ) , but there was no association with maternal folate status . Among children born to women who were vitamin B-12 deficient at baseline , the percent difference in HOMA-IR compared to the control group was 15.1 % ( 95 % CI : -35.9 , 106.4 ) , 4.9 % ( -41.6 , 88.5 ) , 3.3 % ( -38.4 , 73.5 ) , and 18.1 % ( -29.0 , 96.7 ) in the folic acid , folic acid-iron , folic acid-iron-zinc , and multiple micronutrient supplementation groups , respectively , none of which were significant . Maternal vitamin B-12 deficiency is associated with an elevated risk of insulin resistance , but supplementation with folic acid or other micronutrients led to no significant change in insulin resistance in school-aged offspring [26105254] INTRODUCTION Observational studies suggest that folic acid supplementation during pregnancy can reduce the risk of preeclampsia ( PE ) . No r and omized controlled trial has been conducted to demonstrate the effect of folic acid supplementation on PE . OBJECTIVES FACT aims to determine efficacy on a new PE prevention strategy of high dose folic acid supplementation from early pregnancy ( 8(0/7 ) to 16(6/7)weeks of gestation ) until delivery in women with high risk of developing PE . METHODS DESIGN FACT is an international , multi-centre , double-blind , placebo controlled clinical trial of 3656 women . Eligible women will be r and omised in a 1:1 ratio to folic acid 4.0 mg or placebo . POPULATION Pregnant women ( 8(0/7 ) and 16(6/7 ) weeks of gestation ) ⩾18 years of age , taking ⩽1.1 mg of folic acid supplementation who fulfill at least one of the following identified risk factors for PE . Pre-existing hypertension ( blood pressure ⩾90mmHg on two separate occasions or at least 4h apart prior to r and omization , or use of antihypertensive medication during this pregnancy specifically for the treatment of hypertension prior to r and omization ) , pre-pregnancy diabetes ( Type I or Type II DM ) , twin pregnancy , history of PE in a previous pregnancy , BMI ⩾35kg/m(2 ) within 3 months prior this pregnancy or during the first trimester of this pregnancy . PRIMARY OUTCOME PE is defined as blood pressure ⩾d90mmHg on two occasions ⩾4 h apart and proteinuria developed in women greater than 20 weeks of gestation . Or HELLP ( Haemolysis , Elevated , Liver Enzymes , Low Platelets ) syndrome Or superimposed PE , defined as history of pre-existing hypertension ( diagnosed pre-pregnancy or before 20 weeks ' gestation ) with new proteinuria . Proteinuria is defined as : Analysis plan : Intent-to-Treat ( ITT ) population will be analyzed . Chi-square test will be used in the comparison of incidence of PE between the intervention and placebo groups for analysis of the primary outcome . RESULTS The Ottawa Hospital r and omized the first FACT subject in April 2011 . As of February 29th , 2012 , 62 subjects have been r and omized . There are currently 18 Canadian sites participating in FACT , of which 10 are actively recruiting and 8 are pending site activation . Internationally , Argentina , Australia and the United Kingdom are anticipating first recruits in the late spring of 2012 . Israel and Holl and are expected to begin enrolment as early as the fall of 2012 . CONCLUSION Recruitment is on target and expected to end August 2014 . Results from this large scale trial will provide a definitive answer to the important question whether folic acid supplementation can prevent PE Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Iron and folic acid supplementation has been the preferred intervention to improve iron stores and prevent anaemia among pregnant women , and it is thought to improve other maternal and birth outcomes . OBJECTIVES To assess the effects of daily oral iron supplements for pregnant women , either alone or in conjunction with folic acid , or with other vitamins and minerals as a public health intervention in antenatal care . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

15495113

[3885438] The more important known pathogenetic mechanisms apparently responsible for the development of adult respiratory distress syndrome ( ARDS ) are briefly discussed . Reactions in the development of ARDS for which corticosteroids are possibly beneficial are pointed out . A prospect i ve study involving 92 patients was design ed to determine the prophylactic value of methylprednisolone sodium succinate ( MPSS ) ( Solu-Medrol ; Upjohn ) in preventing ARDS . MPSS was administered to 47 seriously injured patients and omitted from the management regimen of 45 patients comparable as regards age and severity of injury . The percentage of patients who developed ARDS was significantly lower in the group that received MPSS than in the control group [11215748] We investigated the effect of octreotide in the treatment of severe acute pancreatitis in a case – control study . Experimental and clinical studies on the effect of octreotide in the treatment of acute pancreatitis have shown controversial results . Since January 1992 , we have been conducting a prospect i ve r and omized study on the effect of octreotide in severe acute pancreatitis , in three hospitals in Israel . The entering criteria included three or more of the Ranson prognostic signs and CT findings of severe pancreatitis . Patients were r and omly assigned to conservative treatment either with or without octreotide ( 0.1 mg subcutaneously three times a day ) . The end points of the study included : complication rate ( ARDS , sepsis , renal failure , pseudocyst , fistula , and abscess ) , length of hospital stay , and mortality . From January 1992 to December 1996 , 60 patients entered the study . After evaluating the files , 10 patients were excluded due to failure to meet the entering criteria , incomplete data , or incorrect diagnosis . Of the remaining 50 patients , 25 were assigned to octreotide ( treatment group ) and 25 to conservative treatment only ( control group ) . The two groups matched with regard to age , sex , etiology , and severity of the disease . The complication rate was lower in the treatment group with regard to sepsis ( 24 % vs 76 % , P = 0.0002 ) and ARDS ( 28 % vs 56 % , P = 0.04 ) . The hospital stay was shorter in the treatment group ( 20.6 vs 33.1 days , P = 0.04 ) . Two patients died in the treatment group and eight in the control group ( P < 0.019 ) . These results suggest that octreotide may have a beneficial effect in the treatment of severe acute pancreatitis [8275731] OBJECTIVE To determine the effects of intravenous N-acetylcysteine ( NAC ) on the development of severe adult respiratory distress syndrome ( ARDS ) and mortality rate in patients with mild-to-moderate acute lung injury and to analyze the duration of ventilatory support and FIO2 required as well as the evolution of the lung injury score . SETTING Three university hospital ICUs and one regional ICU in Switzerl and . PATIENTS Sixty-one adult patients presenting with mild-to-moderate acute lung injury and various predisposing factors for ARDS received either NAC , 40 mg/kg/d , or placebo intravenously for 3 days . MEASUREMENTS Respiratory dysfunction was assessed daily according to the need for mechanical ventilation and FIO2 , the evolution of the lung injury score , and the PaO2/FIO2 ratio . The cardiovascular state , liver function , and kidney function were also monitored . Data were collected at admission ( day 0 ) , during the first 3 days , and on the day of discharge from the ICU . RESULTS The NAC and placebo groups ( 32 and 29 patients , respectively ) were comparable at ICU admission for severity of illness assessed by the simplified acute physiology score ( SAPS ) ( 10.8 + /- 4.6 vs 10.9 + /- 4.8 ) and lung injury score ( LIS ) ( 1.39 + /- 0.95 vs 1.11 + /- 1.08 ) ( mean + /- SD ) . Three patients in each group developed ARDS . The 1-month mortality rate was 22 percent for the NAC group and 35 percent for the placebo group ( difference not statistically significant ) . At admission , 22 of 32 patients ( 69 percent ) in the NAC group were mechanically ventilated compared with 22 of 29 ( 76 percent ) in the placebo group . At the end of the treatment period ( day 3 ) , 5 of 29 ( 17 percent ) in the NAC group and 12 of 25 ( 48 percent ) in the placebo group were still receiving ventilatory support ( p = 0.01 ) , The FIO2 was 0.37 less than admission value ( day 0 ) in the NAC group , and 0.20 less in the placebo group ( p < 0.04 ) ; the oxygenation index ( PaO2/FIO2 ) improved significantly ( p < 0.05 ) from day 0 to day 3 only in the NAC-treated group . The LIS showed a significant regression ( p = 0.003 ) in the NAC-treated group during the first 10 days of treatment : no change was observed in the placebo group . No adverse effects were observed during the treatment with NAC . CONCLUSIONS Intravenous NAC treatment during 72 h improved systemic oxygenation and reduced the need for ventilatory support in patients presenting with mild-to-moderate acute lung injury subsequent to a variety of underlying diseases . Development of ARDS and mortality were not reduced significantly by this therapy [10793162] BACKGROUND Traditional approaches to mechanical ventilation use tidal volumes of 10 to 15 ml per kilogram of body weight and may cause stretch-induced lung injury in patients with acute lung injury and the acute respiratory distress syndrome . We therefore conducted a trial to determine whether ventilation with lower tidal volumes would improve the clinical outcomes in these patients . METHODS Patients with acute lung injury and the acute respiratory distress syndrome were enrolled in a multicenter , r and omized trial . The trial compared traditional ventilation treatment , which involved an initial tidal volume of 12 ml per kilogram of predicted body weight and an airway pressure measured after a 0.5-second pause at the end of inspiration ( plateau pressure ) of 50 cm of water or less , with ventilation with a lower tidal volume , which involved an initial tidal volume of 6 ml per kilogram of predicted body weight and a plateau pressure of 30 cm of water or less . The primary outcomes were death before a patient was discharged home and was breathing without assistance and the number of days without ventilator use from day 1 to day 28 . RESULTS The trial was stopped after the enrollment of 861 patients because mortality was lower in the group treated with lower tidal volumes than in the group treated with traditional tidal volumes ( 31.0 percent vs. 39.8 percent , P=0.007 ) , and the number of days without ventilator use during the first 28 days after r and omization was greater in this group ( mean [ + /-SD ] , 12+/-11 vs. 10+/-11 ; P=0.007 ) . The mean tidal volumes on days 1 to 3 were 6.2+/-0.8 and 11.8+/-0.8 ml per kilogram of predicted body weight ( P<0.001 ) , respectively , and the mean plateau pressures were 25+/-6 and 33+/-8 cm of water ( P<0.001 ) , respectively . CONCLUSIONS In patients with acute lung injury and the acute respiratory distress syndrome , mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use [8222677] Objective : To determine if ketoconazole , a thromboxane A2 synthetase inhibitor , given within the first 24 hrs after diagnosis and arrival in the intensive care unit ( ICU ) would decrease the frequency of adult respiratory distress syndrome in the septic patient population . Design : Prospect i ve , r and omized , double-blind , placeocontrolled study . Setting : Twelve-bed , surgical ICU in a university-affiliated hospital . Patients : Fifty-four consecutive patients admitted to the surgical ICU with the diagnosis of sepsis composed the study sample . Sepsis was defined as including two or more of the following signs in a patient with a systolic blood pressure of < 80 mm Hg or a systemic vascular resistance of < 800 dyne-sec/cm5 : a ) temperature ≥39 ° C or ≤35 ° C ; b ) white blood cell count of > 12,000 leukocytes , or ≤4000 leukocytes/μL , or ≥20 % immature cells ; c ) positive blood culture ; d ) known or strongly suspected source of infection from which a known pathogen was cultured . Interventions : Patients were r and omized to receive either ketoconazole ( 400 mg ) or placebo in a double-blind fashion as early as possible and in < 24 hrs after surgical ICU admission or after the diagnosis of sepsis was established . Measurements and Main Results : Adult respiratory distress syndrome ( ARDS ) was diagnosed if the following criteria were met : a ) intrapulmonary shunt of > 20 % , or a PaO2/Fio2 ratio of < 150 requiring ventilatory support for > 48 hrs ; b ) pulmonary artery occlusion pressure of < 18 nun Hg and no clinical signs of heart failure ; and c ) diffuse infiltrates on chest radiograph . Treatment result ed in significant ( p = .002 ) reduction in the frequency of ARDS compared with the placebo group , 64 % vs. 15 % in the ketoconazole treated group . The mortality rate was also reduced from 39 % in the placebo group to 15 % in the ketoconazole group ( p = .05 ) . A statistically significant reduction in ventilator and ICU days was not achieved . Conclusions : Ketoconazole ( 400 mg through the gastrointestinal tract ) given early in the septic course may prevent ARDS and decrease the mortality rate in high-risk , septic patients . ( Crit Care Med 1993 ; 21:1635–1642 [4028748] Because the formation of platelet thrombi has been incriminated in the development of the adult respiratory distress syndrome ( ARDS ) , we tested trie hypothesis that early administration of antiplatelet agents might protect the lungs in patients at risk to develop ARDS after circulatory shock . This double-blinded study included 40 patients treated with either 3 mg/kg ± 24 h of dipyridamole or a corresponding dose of placebo after an episode of hemorrhagic , traumatic , or septic shock . Each patient also received 100 mg of aspirin daily . Arterial blood gases and chest x-rays were not significantly different between dipyridamole and placebo groups . Moreover , two patients receiving dipyridamole but none receiving placebo developed ARDS . This pilot study does not support a beneficial effect of dipyridamole in the prevention of ARDS after circulatory shock [2436506] The possible beneficial effect of aprotinin , a broad protease inhibitor , on the incidence and outcome of ARDS was examined in two complementary studies . In the first study , the effect of aprotinin was assessed in 147 patients admitted with multiple trauma or shock . In the 57 patients who developed ARDS , mortality was significantly less in those who had previously received aprotinin ( 8/20 , 40 % ) than in those who had not ( 26/37 , 70 % ) . Although both treatment groups were well matched , this was a retrospective study and a second prospect i ve , r and omised , controlled study was therefore carried out . In 78 patients at risk of ARDS , there was no significant difference between treated and control patients in the incidence , duration or severity of ARDS , or in mortality or other major complications . It is concluded that aprotinin is not effective in improving any aspect of ARDS or its outcome in seriously ill patients [12649125] We performed a phase I/II trial in North America of a recombinant surfactant protein C-based surfactant ( Venticute ) as treatment for the acute respiratory distress syndrome . Patients were prospect ively r and omized to receive either st and ard therapy or st and ard therapy plus one of two doses of exogenous surfactant given four times over 24 hours . Surfactant administration was well tolerated . No significant treatment benefit was associated with surfactant treatment . Bronchoalveolar lavage of treated patients at 48 hours reflected the presence of exogenous surfactant components , did not show evidence of improved surface tension lowering function , and had interleukin-6 concentrations that were significantly lower than control group values , consistent with an antiinflammatory treatment effect . The presence of exogenous surfactant was not detected in lavage fluid obtained at 120 hours . Future studies might rationally employ larger surfactant doses and a more prolonged dosing schedule [7930026] Objective To evaluate the effects of HA-1A , a human monoclonal antiendotoxin antibody , in septic patients with ARDS . Design Sub study of a multicenter , double-blinded , placebo-controlled trial of HA-1A in septic patients . Patients 63 septic patients with ARDS at the time of study entry . InterventionA single intravenous injection of HA-1A ( 100 mg ) or placebo . Results A quantitative radiographic score , the PaO2/FIO2 ratio and an index of the severity of ARDS did not show a significant difference between the treatment and placebo groups at 3 , 5 and 7 days after treatment . The duration of endotracheal intubation did not differ between the two groups . 15 of 30 HA-1A treated patients ( 50 % ) and 23 of 33 placebo-treated patients ( 69.7 % ) died within 28 days . The daily mortality was always lower in the HA-1A group , but this difference was not statistically significant at 28 days . The 28-day survival curves for the two treatment groups adjusted by covariate analysis were not significantly different ( p=0.07 ) . Using logistic regression , a significant independent effect of HA-1A treatment was detected upon the early survival rate at 7 days ( p=0.03 ) but not at 14 and 28 days . Conclusion A single injection of HA-1A in septic patients with ARDS did not reverse acute respiratory failure or improve long-term survival [12576938] Objective To determine the safety and efficacy of filgrastim ( r-metHuG-CSF ) in combination with intravenous antibiotics to reduce the rate of mortality in patients with pneumonia and sepsis . Design This study was multicenter , double-blind , and r and omized . Setting Intensive care units Patients Adult patients with bacterial pneumonia , either acquired or nosocomial , as confirmed by chest radiograph and positive culture or Gram-negative stain , and severe sepsis , defined as sepsis-induced hypotension or organ dysfunction . Interventions St and ard antibiotic therapy with or without filgrastim ( 300 & mgr;g/day ) or placebo administered as a 30-min intravenous infusion . The study drug was started within 24 hrs of enrollment and was continued for 5 days or until the white blood cell count reached > 75.0 × 109 cells/L. Measurements and Main Results The primary end point was the occurrence of mortality through day 29 ; secondary end points included occurrence of subsequent organ dysfunction , time to discharge from intensive care unit , number of days on mechanical ventilatory support , and time to death . Study -related observations were recorded through day 10 and included vital signs , onset of organ dysfunction , clinical laboratory variables , and adverse events . Filgrastim increased the white blood cell count to a median peak of 31.7 × 109 cells/L from a baseline of 12.3 × 109 cells/L. The two groups were well matched and did not differ significantly with regard to severe adverse events , time to death , occurrence of end-organ dysfunction , days of intensive care unit hospitalization , or days on mechanical ventilatory support . Mortality was low in both treatment groups ; the mortality rate in patients with adult respiratory distress syndrome was similar between the two groups . Conclusions The addition of filgrastim to the antibiotic and supportive care treatment of patients with pneumonia complicated by severe sepsis appeared to be safe , but not efficacious in reducing mortality rates or complications from this infection [10439747] UNLABELLED Hydrogen peroxide ( H2O2 ) levels are increased in the exhaled breath of patients with the acute respiratory distress syndrome ( ARDS ) . Because liposome-encapsulated prostagl and in E1 ( PGE1 ) downregulates the CD11/CD18 receptor of the neutrophil , thereby limiting endothelial adhesion , the use of this drug should decrease the excretion of H2O2 in the expiratory condensate of patients with ARDS . Patients > 11 yr of age with ARDS ( diffuse , patchy infiltrates by chest radiograph ; Pao2/fraction of inspired oxygen [ P/F ] ratio < or = 200 mm Hg ; pulmonary capillary wedge pressure < or = 18 mm Hg ; and the requirement for mechanical ventilation ) were r and omized to receive placebo ( n = 14 ) or escalating doses ( 0.15 - 3.6 micrograms/kg ) of liposomal PGE1 ( n = 14 ) every 6 h for up to 7 days . Condensate was collected every morning from the expiratory tubing that was submerged in an ice saltwater bath ( -5 degrees C ) . H2O2 levels were measured by using a horseradish peroxidase assay . Other data collected included white blood cell count and P/F ratios . There was no significant difference in the concentration of H2O2 in the expiratory condensate between the liposomal PGE1 group and the control group either before ( 0.99 + /- 0.52 vs 0.93 + /- 0.48 mumol/L ) or during treatment ( 1.04 + /- 0.45 vs 0.76 + /- 0.25 mumol/L ) . Liposomal PGE1 treatment improved the P/F ratio and decreased the white blood cell count over time . Despite its ability to downregulate the CD11/CD18 neutrophil receptor , liposomal PGE1 did not reduce exhaled H2O2 excretion . IMPLICATION S White blood cells ( WBC ) are thought to be part of the cause of the acute respiratory distress syndrome , a lung disease . WBC in the lung produce hydrogen peroxide , which is exhaled . Liposomal PGE1 inhibits WBC function but was found to have no effect in decreasing exhaled hydrogen peroxide in patients with the acute respiratory distress syndrome [8156252] The inappropriate endogenous secretion of tumour necrosis factor ( TNF ) could play a role in the pathogenesis of acute respiratory distress syndrome ( ARDS ) , one of the most frequent causes of death in cancer patients . Because of its capacity to inhibit TNF secretion in vitro , pentoxifylline ( PTX ) could be extremely useful in ARDS therapy . In this study 30 advanced cancer patients with ARDS were r and omized to receive either the conventional care or conventional care plus PTX ( 100 mg i.v . twice a day for 7 days followed by an oral administration of 400 mg three times a day ) to evaluate the efficacy of PTX in reducing TNF serum levels and in improving the symptoms of this syndrome . Serum levels of TNF were measured before and after 7 days of therapy . The percentage of patients alive at 7 days was significantly higher in the PTX-treated group than in the controls ( 12/15 versus 3/15 ; P<0.001 ) . The mean survival time was significantly higher in the PTX-treated group than in the controls . A clinical and /or radiological improvement was obtained in 11/15 patients treated with PTX and in only 2/15 patients in the conventional care group ( P<0.01 ) . TNF mean levels significantly decrease in the PTX-treated group . These data confirm in vivo the capacity of PTX to inhibit TNF secretion in patients with ARDS . Moreover PTX therapy may improve the symptoms related to ARDS without particular toxic effects [9459113] PURPOSE Intravenous N-acetylcysteine ( NAC ) has been reported to improve systemic oxygenation and reduce the need for ventilatory support in patients with an acute lung injury . In the more serious form , namely established adult respiratory distress syndrome ( ARDS ) ( PaO2/FIO2 < or = 200 mm Hg ) , we tested the hypothesis that treatment with intravenous NAC may be beneficial . MATERIAL S AND METHODS Respiratory dysfunction was grade d daily according to the need for mechanical ventilation and FIO2 and to the evolution of the lung injury score ( LIS ) and the PaO2/FIO2 ratio in 42 patients with established ARDS receiving either NAC 190 mg/kg/day or placebo as a continuous intravenous infusion over the first 3 days of their clinical course . RESULTS NAC and placebo groups ( 22 and 20 patients , respectively ) were comparable for demographic characteristics , ARDS categories , severity of illness ( simplified acute physiology score [ SAPS II ] ) LIS and PaO2/FIO2 ratio . Mortality rate was 32 % for the NAC and 25 % for the placebo group ( difference not significant ) . At admission ( day 1 ) , 91 % of patients in the NAC and 95 % in the placebo group required ventilatory support ; at days 2 , 3 , 5 , and 7 after admission , the percentage of patients receiving ventilatory support was not significantly reduced for both groups in comparison with day 1 . Moreover , there were no differences between the two groups at the same observation days . In both groups , the FIO2 was significantly lower and the PaO2/FIO2 ratio was significantly higher than the initial values during the evolution ( FiO2 at day 3 , P < .01 for NAC and P < .05 for placebo ; PaO2/FIO2 at day 3 : P < .01 for NAC and P < .02 for placebo ) , but this improvement was similar for both groups and , moreover , the between-group comparison was never significantly different at the various collection days . The LIS decreased significantly in NAC group between days 1 and 3 ( 2.23 + /- 0.62 v 1.76 + /- 0.17 ; P < .05 ) , whereas no changes were observed in the placebo group ; at day 5 , there was a significant difference between the two groups ( 1.53 + /- 0.21 for the NAC v 2.15 + /- 0.19 for the placebo group ; P < .05 ) . In the prevalent sepsis category ( 10 patients in the NAC and 9 in the placebo group ) , the mortality rate , the need of ventilatory support , the intensive care unit stay , and the PaO2/FIO2 evolution did not differ significantly in both subgroups . CONCLUSIONS In this relatively small group of patients presenting with an established ARDS subsequent to a variety of underlying diseases , intravenous NAC treatment during 72 hours neither improved systemic oxygenation nor reduced the need for ventilatory support [10903215] Accumulating evidence strongly suggests that ventilatory strategy has an important impact on development of lung injury and patient outcome . Adverse ventilatory strategies have been shown to cause release of pulmonary-derived cytokines and may permit bacterial translocation from the lung to the systemic circulation . Because endotoxin is a potent and clinical ly important stimulant of cytokine-mediated systemic inflammatory responses that can lead to multiorgan failure , we investigated the effects of ventilatory strategy on lung-to-systemic translocation of endotoxin . We studied the effects of protective ( tidal volume [ VT ] 5 ml . kg(-)(1 ) , positive end-expiratory pressure [ PEEP ] 10 to 12.5 cm H(2)O ) versus nonprotective ( VT 12 ml . kg(-)(1 ) , PEEP zero ) ventilatory strategy on translocation of endotracheally instilled endotoxin . Anesthetized New Zeal and White rabbits were subjected to saline lung lavage , and 32 were r and omized to one of four groups : PS ( protective ventilation + instilled saline ) ; PE ( protective ventilation + instilled endotoxin ) ; NS ( nonprotective ventilation + instilled saline ) ; NE ( nonprotective ventilation + instilled endotoxin ) , and ventilated for 3 h. Plasma endotoxin levels increased significantly in the NE group , and remained low and unchanged in the other groups . Peak levels of plasma tumor necrosis factor-alpha ( TNF-alpha ) were higher in NE versus other groups . Pa(O(2 ) ) and mean arterial pressure ( Pa ) were lowest , and requirement for pressor and bicarbonate support greatest , in the NE group . Finally , plasma endotoxin levels were significantly greater in eventual nonsurvivors than survivors . These data provide convincing evidence for pulmonary translocation of lung-derived endotoxin . This translocation depends on ventilatory strategy , and suggests a pathophysiologic link between ventilatory strategy and outcome [11171733] STUDY OBJECTIVES Evaluate the safety of filgrastim ( recombinant methionyl human granulocyte colony-stimulating factor ) administration , combined with st and ard therapy , in patients with pneumonia and either septic shock or severe sepsis who were receiving mechanical ventilation . DESIGN Multicenter , double-blind , r and omized , placebo-controlled study . SETTING ICU , multicenter . PATIENTS Eighteen patients with pneumonia and hypotension , or in the absence of shock , two or more end-organ dysfunctions , were enrolled and treated . Baseline acute physiology and chronic health evaluation II scores and median age for the filgrastim ( n = 12 ) and placebo ( n = 6 ) groups were 25.0 and 49.5 years and 31.5 and 56.5 years , respectively . INTERVENTION Filgrastim ( 300 microg ) or placebo was administered IV daily for up to 5 days . MEASUREMENTS AND RESULTS Study end points included safety ; biological response , including endogenous cytokine levels , endotoxin levels , and neutrophil counts ; and mortality . Cytokine and endotoxin levels were highly variable in both groups . By day 29 , 3 of 12 filgrastim-treated patients and 4 of 6 placebo-treated patients had died . There were no differences in types and occurrences of adverse events , including ARDS , or in outcome between the two groups . Three of four placebo-treated patients had persistent bacterial growth on bronchoscopy repeated after 48 h compared with 2 of 10 filgrastim-treated patients . CONCLUSION Filgrastim appeared to be well tolerated in this population of patients with pneumonia and severe sepsis or septic shock . Larger studies to determine the benefit of filgrastim in patients with pneumonia and sepsis or organ dysfunction are warranted [9669790] CONTEXT No pharmacological therapeutic protocol has been found effective in modifying the clinical course of acute respiratory distress syndrome ( ARDS ) and mortality remains greater than 50 % . OBJECTIVE To determine the effects of prolonged methylprednisolone therapy on lung function and mortality in patients with unresolving ARDS . DESIGN R and omized , double-blind , placebo-controlled trial . SETTING Medical intensive care units of 4 medical centers . PARTICIPANTS Twenty-four patients with severe ARDS who had failed to improve lung injury score ( LIS ) by the seventh day of respiratory failure . INTERVENTIONS Sixteen patients received methylprednisolone and 8 received placebo . Methylprednisolone dose was initially 2 mg/kg per day and the duration of treatment was 32 days . Four patients whose LIS failed to improve by at least 1 point after 10 days of treatment were blindly crossed over to the alternative treatment . MAIN OUTCOME MEASURES Primary outcome measures were improvement in lung function and mortality . Secondary outcome measures were improvement in multiple organ dysfunction syndrome ( MODS ) and development of nosocomial infections . RESULTS Physiological characteristics at the onset of ARDS were similar in both groups . At study entry ( day 9 [ SD , 3 ] of ARDS ) , the 2 groups had similar LIS , ratios of PaO2 to fraction of inspired oxygen ( FIO2 ) , and MODS scores . Changes observed by study day 10 for methylprednisolone vs placebo were as follows : reduced LIS ( mean [ SEM ] , 1.7 [ 0.1 ] vs 3.0 [ 0.2 ] ; P<.001 ) ; improved ratio of PaO2 to FIO2 ( mean [ SEM ] , 262 [ 19 ] vs 148 [ 35 ] ; P<.001 ) ; decreased MODS score ( mean [ SEM ] , 0.7 [ 0.2 ] vs 1.8 [ 0.3 ] ; P<.001 ) ; and successful extubation ( 7 vs 0 ; P=.05 ) . For the treatment group vs the placebo group , mortality associated with the intensive care unit was 0 ( 0 % ) of 16 vs 5 ( 62 % ) of 8 ( P=.002 ) and hospital-associated mortality was 2 ( 12 % ) of 16 vs 5 ( 62 % ) of 8 ( P=.03 ) . The rate of infections per day of treatment was similar in both groups , and pneumonia was frequently detected in the absence of fever . CONCLUSIONS In this study , prolonged administration of methylprednisolone in patients with unresolving ARDS was associated with improvement in lung injury and MODS scores and reduced mortality [11685297] Abstract . Objective : To evaluate the safety of liposomal PGE1 ( TLC C-53 ) in patients with acute respiratory distress syndrome ( ARDS ) , and determine its efficacy in improving oxygenation and reducing ventilator dependency . Design : A multi-centre , r and omized , double-blind , placebo-controlled clinical study . Setting : Thirty-one hospitals in six European countries . Patients : One hundred two patients with ARDS . Interventions : Patients were r and omized in a 2:1 ratio to receive infusions of either the study drug TLC C-53 or placebo . Infusions were given over 60 min every 6 h for 7 days . The dose of study drug started at 0.6 µg/kg per h , rising over 24 h to a maximum dose of 1.8 µg/kg per h. Measurements and main results : Seventy patients received the study drug and 32 placebo . Sixty-nine patients ( 47 treatment , 22 placebo ) completed the study protocol . Patients were monitored for changes in the PaO2/FIO2 ratio , changes in lung compliance , time to off-ventilator and 28-day mortality , in addition to basic haematological and haemodynamic parameters . There were no significant differences in demographics and baseline characteristics between the two groups . There were no differences in the time to off-ventilation ( 16 days with treatment , 16.6 days with placebo , p=0.94 ) or in 28-day mortality ( 30 % with treatment , 28 % with placebo , p=0.78 ) . There was a difference in the time to achieve a PaO2/FIO2 ratio above 300 in favour of TLC C-53 ( 10.3 versus 26.5 days ) but this was not statistically significant ( p=0.23 ) . Conclusions : TLC C-53 was generally well-tolerated but failed to reduce mortality or duration of mechanical ventilation [7627383] BACKGROUND Experimental and clinical studies on the effect of octreotide in the treatment of patients with acute pancreatitis have presented controversial results . Since January 1992 , we have been conducting a prospect i ve r and omized study on the clinical effect of octreotide in severe acute pancreatitis , at three hospitals in Israel . STUDY DESIGN The entering criteria included three or more of the Ranson 's prognostic signs and computed tomographic findings of severe pancreatitis . Patients were r and omly assigned to conservative treatment either with or without octreotide ( 0.1 mg injected subcutaneously three times a day ) . The end points of the study included : complication rate ( adult respiratory distress syndrome [ ARDS ] , sepsis , renal failure , pseudocyst , fistula , and abscess ) , length of hospital stay , and mortality . RESULTS During the first two years ( from January 1992 to December 1993 ) , 51 patients entered the study . After evaluation , 13 patients were excluded due to failure to meet the entering criteria , incomplete data , or incorrect diagnosis . Of the remaining 38 patients , 19 were assigned to octreotide ( treatment group ) and 19 to conservative treatment alone ( control group ) . The two groups were matched with regard to age , sex , etiology , and severity of disease . The complication rate was lower in the treatment group compared with the control group with regard to sepsis ( 26 compared with 74 percent , p = 0.004 ) and ARDS ( 37 compared with 63 percent , p = 0.1 ) . The hospital stay was shorter in the treatment group compared with the control group ( 17.9 compared with 34.1 days , p = 0.02 ) . Death occurred in two patients in the treatment group and six patients in the control group . CONCLUSIONS Although some of the parameters did not reach statistical significance , these preliminary results suggest that octreotide may have a beneficial effect in the treatment of patients with severe acute pancreatitis . This study is scheduled to continue for two more years [11902249] Objective To determine whether the administration of lisofylline ( 1-[5R-hydroxyhexyl]-3,7-dimethylxanthine ) would decrease mortality in patients with acute lung injury ( ALI ) or acute respiratory distress syndrome ( ARDS ) . Design A prospect i ve , r and omized , double-blind , placebo-controlled , multicenter study . Setting Intensive care units at 21 hospitals at the ten centers constituting the ARDS Clinical Trials Network . Patients A total of 235 patients who met eligibility criteria were enrolled in the study ( 116 into the lisofylline group , 119 into the placebo group ) . Interventions Patients were r and omized to receive either lisofylline or placebo . The dose of lisofylline was 3 mg/kg with a maximum dose of 300 mg intravenously every 6 hrs . The intravenous solution of study drug was administered over 10 mins every 6 hrs . Dosing was continued for 20 days or until the patient achieved 48 hrs of unassisted breathing . Measurements and Main Results The trial was stopped by the Data Safety Monitoring Board for futility at the first scheduled interim analysis . The patient groups had similar characteristics at enrollment . No significant safety concerns were associated with lisofylline therapy . There was no significant difference between groups in the number of patients who had died at 28 days ( 31.9 % lisofylline vs. 24.7 % placebo , p = .215 ) . There was no significant difference between the lisofylline and placebo groups in terms of resolution of organ failures , ventilator-free days , infection-related deaths , or development of serious infection during the 28-day study period . The median number of organ failure – free days for the five nonpulmonary organ failures examined ( cardiovascular , central nervous system , coagulation , hepatic , and renal ) was not different between the lisofylline and placebo groups . Although lisofylline has been reported to decrease circulating free fatty acid levels , we did not find any such treatment effect compared with placebo . Conclusions In this study , there was no evidence that lisofylline had beneficial effects in the treatment of established ALI/ARDS [9847275] Because animal studies have demonstrated that mechanical ventilation at high volume and pressure can be deleterious to the lungs , limitation of airway pressure , allowing hypercapnia if necessary , is already used for ventilation of acute respiratory distress syndrome ( ARDS ) . Whether a systematic and more drastic reduction is necessary is debatable . A multicenter r and omized study was undertaken to compare a strategy aim ed at limiting the end-inspiratory plateau pressure to 25 cm H2O , using tidal volume ( VT ) below 10 ml/kg of body weight , versus a more conventional ventilatory approach ( with regard to current practice ) using VT at 10 ml/kg or above and close to normal PaCO2 . Both arms used a similar level of positive end-expiratory pressure . A total of 116 patients with ARDS and no organ failure other than the lung were enrolled over 32 mo in 25 centers . The two groups were similar at inclusion . Patients in the two arms were ventilated with different VT ( 7.1 + /- 1.3 versus 10.3 + /- 1.7 ml/kg at Day 1 , p < 0.001 ) and plateau pressures ( 25.7 + /- 5 . 0 versus 31.7 + /- 6.6 cm H2O at Day 1 , p < 0.001 ) , result ing in different PaCO2 ( 59.5 + /- 15.0 versus 41.3 + /- 7.6 mm Hg , p < 0.001 ) and pH ( 7.28 + /- 0.09 versus 7.4 + /- 0.09 , p < 0.001 ) , but a similar level of oxygenation . The new approach did not reduce mortality at Day 60 ( 46.6 % versus 37.9 % in control subjects , p = 0.38 ) , the duration of mechanical ventilation ( 23.1 + /- 20.2 versus 21.4 + /- 16 . 3 d , p = 0.85 ) , the incidence of pneumothorax ( 14 % versus 12 % , p = 0 . 78 ) , or the secondary occurrence of multiple organ failure ( 41 % versus 41 % , p = 1 ) . We conclude that no benefit could be observed with reduced VT titrated to reach plateau pressures around 25 cm H2O compared with a more conventional approach in which normocapnia was achieved with plateau pressures already below 35 cm H2O [11740262] OBJECTIVE To determine whether granulocyte colony-stimulating factor ( G-CSF ) administration changes leukocyte deformability result ing in lung injury in patients with sepsis . METHODS Twenty-five consecutive septic patients were divided r and omly into two groups . Twelve patients were given recombinant human G-CSF subcutaneously at 2 microg/kg once a day for 5 days ( group G ) . The remaining 13 patients were given sterilized saline as placebo ( group N ) . Leukocyte count ; concentrations of C-reactive protein ( CRP ) and thrombomodulin ( TM ) ; respiratory index ( RI ) and lung injury score ( LIS ) ; and APACHE II score and Goris MOF index were determined before and after G-CSF or placebo administration . Leukocyte deformability was observed in a microchannel array etched on a single-crystal silicon tip , which simulates the microvasculature . The number of microchannels obstructed ( NOM ) by stiffened leukocytes was counted . Transit time ( TT ) , that is , the time taken for 100 microL of whole blood to pass through the microchannel , was determined . RESULTS G-CSF administration significantly increased leukocyte count and decreased CRP concentration . In group G , both NOM and TT increased significantly 5 days after G-CSF administration ; they did not change in group N. However , RI , LIS , and TM did not change , suggesting that no patient developed lung injury . CONCLUSION G-CSF causes leukocyte stiffness but attenuates inflammatory response without inducing lung injury in septic patients [9105072] Lung surfactant is deficient in patients with acute respiratory distress syndrome ( ARDS ) . We performed a r and omized , prospect i ve , controlled , open-label clinical study of administration of a bovine surfactant to patients with ARDS to obtain preliminary information about its safety and efficacy . Patients received either surfactant by endotracheal instillation in addition to st and ard therapy or st and ard therapy only . Three different groups of patients receiving surfactant were studied : patients receiving up to eight doses of 50 mg phospholipids/kg , those receiving up to eight doses of 100 mg phospholipids/kg , and those receiving up to four doses of 100 mg phospholipids/kg . Outcome measures included ventilatory support parameters , arterial blood gases , organ system failures , bronchoalveolar lavage ( BAL ) analyses , immunologic analyses , survival , and adverse events during the 28-d study period . Fifty-nine study patients were evaluable ; 43 in the surfactant group and 16 in the control group . The FI(O2 ) at 120 h after treatment began was significantly decreased only for patients who received up to four doses of 100 mg phospholipids/kg surfactant as compared with control patients ( p = 0.011 ) . Mortality in the same group of patients was 18.8 % , as compared with 43.8 % in the control group ( p = 0.075 ) . The surfactant instillation was generally well tolerated , and no safety concerns were identified . This pilot study presents preliminary evidence that surfactant might have therapeutic benefit for patients with ARDS , and provides rationale for further clinical study of this agent [3516085] A 7-day infusion of prostagl and in E1 ( PGE1 ) , an immunomodulator , was evaluated in a prospect i ve , r and omized , placebo-controlled , double-blinded trial in surgical patients with the adult respiratory distress syndrome ( ARDS ) . The drug seemed to improve pulmonary function — only two PGE1 patients died with severe pulmonary failure compared with nine placebo patients ( p = 0.01 ) . Survival at 30 days after the end of the infusion— the predetermined end point of the study —was significantly better in the patients given PGE1 ( p = 0.03 ) , with 15 of 21 PGE1 patients ( 71 % ) alive at this time compared with seven of 20 placebo patients ( 35 % ) . Improvement in overall survival in the PGE , patients did not reach statistical significance ( p = 0.08 ) . Overall survival in patients initially free of severe organ failure , however , was significantly better in the PGE , patients ( p = 0.03 ) . Of the six PGE1 patients free of severe organ failure at time of entry , all survived to leave the hospital ; of the 10 placebo patients initially free of severe organ failure , four survived . The drug had no serious side effects and did not potentiate susceptibility to infection . PGE1 is a promising agent for the treatment of ARDS [3285017] Effective prophylaxis against acute respiratory failure ( ARDS ) has not been established . This study investigated whether or not ketoconazole could prevent ARDS in critically ill surgical patients . Seventy-one Surgical Intensive Care Unit ( SICU ) patients without liver dysfunction received either ketoconazole ( n = 35 ) , 200 mg daily via the gastrointestinal tract , or placebo ( n = 36 ) , for 21 days or until discharge from the SICU , in a prospect i ve , r and omized , double-blind study . Patients were monitored clinical ly for signs of ARDS , defined as all the following : intrapulmonary shunt greater than 15 % , a PaO2/FIO2 ratio less than 150 , normal central venous , pulmonary capillary wedge , or left atrial pressure , no other cause of hypoxemia , and a consistent chest X-ray . Thirteen patients ( 18 % ) developed ARDS with significantly increased mortality versus non-ARDS patients ( 69 % vs. 29 % ) . The incidence of ARDS was decreased among ketoconazole patients compared to placebo ( 6 % vs. 31 % ; p less than 0.01 ) , as was median SICU stay ( 7.0 days vs. 15.5 days ; p less than 0.05 ) , and median SICU cost ( + 5,600 . vs. + 12,400 . ; p less than 0.05 ) . Mortality is increased with ARDS after trauma and surgery . We conclude that ketoconazole prevents ARDS , shortens SICU stay , and lowers hospital costs [1569622] The effects of prostagl and in E1 ( PGE1 ) on non-pulmonary vital organs in critically ill patients are not well defined . This study evaluated the role of exogenous PGE1 in systemic homeostasis during the adult respiratory distress syndrome ( ARDS ) . Indicators of end-organ function were analyzed retrospectively in 146 septic or post-trauma patients with ARDS who received PGE1 ( 30/ng/kg/min ) or placebo IV for up to 7 days in a r and omized , double-blind clinical trial . Hemodynamic variables and serum levels of creatinine , bilirubin , and SGOT , platelet count , and changes in the white blood cell count were measured daily . Our results indicate that mean arterial pressure , pulmonary artery pressure , and systemic and pulmonary vascular resistance indices were significantly lower in the PGE1 group versus the placebo-treated group . Cardiac index , stroke index , and oxygen delivery index were significantly increased in the PGE1 group . Serum bilirubin and SGOT were decreased significantly among PGE1-treated patients compared with placebo-treated patients , while the white blood cell count increased more significantly from baseline values with PGE1 treatment . Intergroup differences in platelet count and serum creatinine levels were not statistically significant . The results indicate that PGE1 improves cardiovascular performance , hepatic function , and leukocyte availability during clinical ARDS . Prostagl and in E1 did not affect platelet counts and renal function in this study [11308438] CONTEXT When clinicians assess the validity of r and omized controlled trials ( RCTs ) , they commonly evaluate the blinding status of individuals in the RCT . The terminology authors often use to convey blinding status ( single , double , and triple blinding ) may be open to various interpretations . OBJECTIVE To determine physician interpretations and textbook definitions of RCT blinding terms . DESIGN AND SETTING Observational study undertaken at 3 Canadian university tertiary care centers between February and May 1999 . PARTICIPANTS Ninety-one internal medicine physicians who responded to a survey . MAIN OUTCOME MEASURES Respondents identified which of the following groups they thought were blinded in single- , double- , and triple-blinded RCTs : participants , health care providers , data collectors , judicial assessors of outcomes , data analysts , and personnel who write the article . Definitions from 25 systematic ally identified textbooks published since 1990 providing definitions for single , double , or triple blinding . RESULTS Physician respondents identified 10 , 17 , and 15 unique interpretations of single , double , and triple blinding , respectively , and textbooks provided 5 , 9 , and 7 different definitions of each . The frequencies of the most common physician interpretation and textbook definition were 75 % ( 95 % confidence interval [ CI ] , 65%-83 % ) and 74 % ( 95 % CI , 52%-90 % ) for single blinding , 38 % ( 95 % CI , 28%-49 % ) and 43 % ( 95 % CI , 24%-63 % ) for double blinding , and 18 % ( 95 % CI , 10%-28 % ) and 14 % ( 95 % CI , 0%-58 % ) for triple blinding , respectively . CONCLUSIONS Our study suggests that both physicians and textbooks vary greatly in their interpretations and definitions of single , double , and triple blinding . Explicit statements about the blinding status of specific groups involved in RCTs should replace the current ambiguous terminology [10638663] This study investigates the effects of N-acetylcysteine ( NAC ) and rutin on the lung oxidative burden of patients with early adult respiratory distress syndrome ( ARDS ) . The protection was evaluated by measuring expired ethane and malondialdehyde ( MDA ) , and oxidized ( GSSG ) and reduced glutathione ( GSH ) in the epithelial lining fluid of 36 patients who developed ARDS less than 24 hours before enrollment in the study . The patients were r and omly assigned to 3 groups , receiving 250 mL 5 % dextrose in water ( group 1 ) , NAC 50 mg/kg body weight in 5 % dextrose ( group 2 ) , and NAC 50 mg/kg + rutin 5 mg/kg in 5 % dextrose ( group 3 ) . Ethane and MDA concentrations were significantly reduced in the treatment groups after day 6 . GSH was 30 % increased in the treatment groups . No significant variations were observed in the control group until day 9 . The trial confirms that NAC and rutin are efficient in protecting the lungs of patients with ARDS [7933425] OBJECTIVE To evaluate the safety and potential efficacy of aerosolized surfactant in intubated patients with adult respiratory distress syndrome ( ARDS ) . DESIGN A prospect i ve , double-blind , placebo-controlled , r and omized , parallel , multicenter pilot clinical trial . PATIENTS A total of 51 patients with sepsis-induced ARDS were entered into the study within 18 hours of developing sepsis or sepsis syndrome . INTERVENTION Patients were r and omized into four treatment groups in a 2:1:2:1 ratio , as follows : 12 hours of surfactant per day , 12 hours of 0.6 % saline per day , 24 hours of surfactant per day , and 24 hours of 0.6 % saline per day . Surfactant or saline was aerosolized continuously for up to 5 days using an in-line nebulizer that aerosolized only during inspiration . MAIN OUTCOME MEASURES Ventilatory data , arterial blood gases , and hemodynamic parameters were measured at baseline , every 4 or 8 hours during the 5 days of treatment , 24 hours after treatment , and 30 days after treatment , at which time mortality was also assessed . Safety was evaluated throughout the 30 days of the study . RESULTS Surfactant was administered safely in ventilated patients when given continuously throughout the 5 days using the nebulizer system . Although there were no differences in any physiological parameters between the treatment groups , there was a dose-dependent trend in reduction of mortality from 47 % in the combined placebo group to 41 % and 35 % in the groups treated with 12 hours and 24 hours of surfactant per day , respectively . CONCLUSIONS Aerosolized surfactant was well tolerated when administered on a continuous basis for up to 5 days ; however , at the doses given , it did not result in significant improvements in patients with sepsis-induced ARDS [12119223] Granulocyte-macrophage colony-stimulating factor ( GM-CSF ) stimulates hemopoiesis and effector functions of granulocytes and macrophages and is involved in pulmonary surfactant homeostasis . We investigated whether GM-CSF therapy improved clinical ly diagnosed severe sepsis and respiratory dysfunction in critically ill patients . This r and omized , double-blind , placebo-controlled phase II study added low-dose ( 3 mcg/kg ) intravenous recombinant human GM-CSF daily for 5 days to conventional therapy in 10 patients , with a further eight patients receiving placebo . GM-CSF-treated patients showed improvement in Pa(O(2))/FI(O(2 ) ) over 5 days ( p = 0.02 ) and increased peripheral blood neutrophils ( p = 0.08 ) , whereas alveolar neutrophils decreased ( p = 0.02 ) . GM-CSF therapy was not associated with decreased 30-day survival or with increased acute respiratory distress syndrome or extrapulmonary organ dysfunction . GM-CSF therapy was associated with increased blood granulocyte superoxide production and restoration or preservation of blood and alveolar leukocyte phagocytic function . We conclude that low-dose GM-CSF was associated with improved gas exchange without pulmonary neutrophil infiltration , despite functional activation of both circulating neutrophils and pulmonary phagocytes . In addition , GM-CSF therapy was not associated with worsened acute respiratory distress syndrome or the multiple organ dysfunction syndrome , suggesting a homeostatic role for GM-CSF in sepsis-related pulmonary dysfunction [9781722] OBJECTIVE To study the effects of surfactant administration on the left lung after surgical repair of descending aortic aneurysms on postoperative respiratory failure . DESIGN R and omized , prospect i ve , controlled study . SETTING Clinical investigation . PATIENTS Eleven patients with respiratory failure associated with thoracic aneurysm surgery . INTERVENTION Eleven adult patients with acute respiratory failure ( PaO2/FIO2 < 300 torr [ < 40 kPa ] ) after surgical repair of descending aortic aneurysms . The artificial surfactant ( 30 mg/kg ) was given to the operated side of the lung by intrabronchial instillation in six patients ( surfactant group ) , whereas nothing was instilled in the other five patients ( control group ) . MEASUREMENTS AND MAIN RESULTS Hemodynamic parameters , blood gas , and peak inspiratory pressure were measured at the end of surgery , before surfactant instillation , and at 2 , 6 , 12 , 24 , and 48 hrs after surfactant instillation . At the end of surgery , the mean + /- SEM values of the PaO2/FIO2 ratio were 204 + /- 25 torr ( 27.2 + /- 3.3 kPa ) in the surfactant group and 240 + /- 26 torr ( 32.0 + /- 3.5 kPa ) in the control group . After 2 , 6 , 12 , and 48 hrs , improvements in the PaO2/FIO2 ratios were observed in the surfactant group , whereas the control group showed no improvement . Two hours after surfactant instillation , the mean value in the PaO2/FIO2 ratio was significantly higher in the surfactant group ( 318 + /- 24 torr [ 42.4 + /- 3.2 kPa ] ) ( p < .05 ) compared with the control group values ( 240 + /- 34 torr [ 32 + /- 4.5 kPa ] ) . CONCLUSION Surfactant administration immediately after surgery restored gas exchange in postoperative respiratory failure associated with thoracic aneurysm surgery [3315478] From November 1 , 1982 through December 31 , 1985 , there were 19 centers and 382 patients that evaluated the effect of methylprednisolone sodium succinate ( MPSS ) on the septic syndrome . Seventeen of these centers enrolled 304 patients in a prospect i ve , r and omized , double-blind , placebo-controlled study to determine if early treatment with MPSS would decrease the incidence of severity of the adult respiratory distress syndrome ( ARDS ) in patients at risk of ARDS from sepsis . To ensure early institution of the MPSS or placebo therapy ( PLA ) , patients with the presumptive diagnosis of sepsis were identified . That diagnosis was based on the presence of fever or hypothermia ( temperature greater than 38.3 degrees C or less than 35.5 degrees C , rectal ) , tachypnea ( greater than 20 bpm ) , tachycardia ( greater than 90 bpm ) and the presence of one of the following indices of organ dysfunction : a change in mental status , hypoxemia , elevated lactate levels or oliguria . The treatment , either MPSS 30 mg/kg or PLA , was given in four 20-minute infusions six hours apart and was initiated within two hours of the presumptive diagnosis of sepsis . The development and reversal of the adult respiratory distress syndrome ( ARDS ) was followed and result ed in data on 304 of the 382 r and omized patients . A trend toward increased incidence of ARDS was seen in the MPSS group 50/152 ( 32 percent ) compared to the placebo group 38/152(25 percent ) p = 0.10 . Significantly fewer MPSS patients reversed their ARDS 15/50 ( 31 percent ) compared to placebo 23/38 ( 61 percent ) p = 0.005 . The 14-day mortality in patients with ARDS treated with MPSS was 26/50 ( 52 percent ) compared to placebo 8/22 ( 22 percent ) p = 0.004 . We conclude that early treatment of septic syndrome with MPSS does not prevent the development of ARDS . Additionally , MPSS treatment impedes the reversal of ARDS and increases the mortality rate in patients with ARDS [10501747] Background : Despite intensive research , there are no universally accepted clinical definitions for acute lung injury ( ALI ) or the acute respiratory distress syndrome ( ARDS ) . A recent joint American-European Consensus Conference on ARDS formally defined the difference between ALI and ARDS based on the degree of oxygenation impairment . However , this definition may not reflect the true prevalence , severity and prognosis of these syndromes . Methods : During a 22-month period , 56 consecutive mechanically ventilated patients who met the American-European Consensus definition for ARDS [ arterial oxygen tension/fractional inspired oxygen ( PaO2/FIO2≤ 200 mmHg regardless of the level of positive end-expiratory pressure ( PEEP ) , bilateral pulmonary infiltrates , and no evidence of left heart failure ] were admitted into the intensive care units ( ICU ) of the Hospital del Pino , Las Palmas , Spain , and prospect ively studied . The diagnosis of ALI and ARDS was made by a PEEP-FIO2 trial , 24 h after patients met the Consensus inclusion criteria . Patients were classified as having ALI–24 h if the PaO2/FIO2 was > 150 mmHg with PEEP = 5 cmH2O , and ARDS–24 h if the PaO2 /FIO2 was ≤ 150 mmHg with PEEP ≥ 5 cmH2O . Results : Overall mortality was 43 % ( 24 of 56 ) . However , 24 h after inclusion , PaO2 response to PEEP 5 cmH2O allowed the separation of our patients into two different groups : 31 patients met our ALI–24 h criteria ( PaO2/FIO2 > 150 mmHg ) and their mortality was 22.6 % ; 25 patients met our ARDS–24 h criteria ( PaO2/FIO2≤ 150 mmHg ) and their mortality was 68 % ( p = 0.0016 ) . The differences in the respiratory severity index during the first 24 h of inclusion , PaO2/FIO2 ratio at baseline and at 24 h , maximum plateau airway pressure , maximum level of PEEP , and number of organ system failures during the ICU stay were statistically significant . Conclusions : Since the use of PEEP in the American-European Consensus criteria for ARDS is not m and atory , that definition does not reflect the true severity of lung damage and outcome . Our data support the need for guidelines based on a specific method of evaluating oxygenation status before the American-European Consensus definition is adopted [3202402] We conducted a prospect i ve , r and omized , double-blind study to determine whether high-dose methylprednisolone could prevent parenchymal lung injury , including the adult respiratory distress syndrome ( ARDS ) , or improve mortality when administered early in septic shock . All patients already hospitalized in or newly admitted to the medical and surgical intensive care units at San Francisco General Hospital between September 1 , 1983 and August 29 , 1986 were eligible for admission to the study if they had either ( 1 ) an increase in temperature of 1.5 degrees C and a decrease in systolic blood pressure of 20 mm Hg or more from baseline values ( in already hospitalized patients ) , or ( 2 ) a temperature greater than 38.5 degrees C or less than 35.5 degrees C and a systolic blood pressure of less than 90 mm Hg ( in newly admitted patients ) . Patients meeting these criteria were excluded if they ( 1 ) had severe immunodeficiency , ( 2 ) were less than 18 or greater than 76 yr of age , ( 3 ) had multilobar roentgenographic infiltrates , or ( 4 ) were already receiving corticosteroids . Eighty-seven patients enrolled in the study received either methylprednisolone , 30 mg/kg per dose , or mannitol placebo for a total of 4 doses every 6 h , following the presumptive diagnosis of septic shock . Of these patients , 75 ultimately were determined on the basis of culture results to have actually had septic shock at the time of entry . Thirteen of the patients who received methylprednisolone developed ARDS , compared to 14 patients who received placebo . Lesser degrees of parenchymal lung injury did not differ between the 2 groups . ( ABSTRACT TRUNCATED AT 250 WORDS [2278610] The adult respiratory distress syndrome ( ARDS ) , often referred to as non-cardiac pulmonary oedema , is now regarded as a very complicated inflammatory process with oedema being only one facet . In recognition of this , pharmacologic therapy with anti-inflammatory corticosteroids was used widely until the completion of r and omized clinical trials . Unfortunately , corticosteroids have not been proved to be useful in preventing ARDS in septic patients nor in patients with established ARDS and this has led to investigations with pharmacologic agents which are safer and more specifically targeted to certain parts of the inflammatory process . We have examined the role of the glutathione anti-oxidant system in the sheep model of ARDS as well as in patients with established ARDS through use of intravenous N-acetylcysteine ( NAC ) . We have found that the response to endotoxin is markedly blunted in sheep treated with NAC . In our controlled clinical trials with NAC we found that patients with ARDS have depressed plasma and red cell glutathione concentrations , that these levels are substantially increased by therapy with intravenous NAC and there are measurable clinical responses to treatment with regard to increased oxygen delivery , improved lung compliance and resolution of pulmonary oedema [9070471] BACKGROUND In patients with sepsis the production of arachidonic acid metabolites by cyclooxygenase increases , but the pathophysiologic role of these prostagl and ins is unclear . In animal models , inhibition of cyclooxygenase by treatment with ibuprofen before the onset of sepsis reduces physiologic abnormalities and improves survival . In pilot studies of patients with sepsis , treatment with ibuprofen led to improvements in gas exchange and airway mechanics . METHODS From October 1989 to March 1995 , we conducted a r and omized , double-blind , placebo-controlled trial of intravenous ibuprofen ( 10 mg per kilogram of body weight [ maximal dose , 800 mg ] , given every six hours for eight doses ) in 455 patients who had sepsis , defined as fever , tachycardia , tachypnea , and acute failure of at least one organ system . RESULTS In the ibuprofen group , but not the placebo group , there were significant declines in urinary levels of prostacyclin and thromboxane , temperature , heart rate , oxygen consumption , and lactic acidosis . With ibuprofen therapy there was no increased incidence of renal dysfunction , gastrointestinal bleeding , or other adverse events . However , treatment with ibuprofen did not reduce the incidence or duration of shock or the acute respiratory distress syndrome and did not significantly improve the rate of survival at 30 days ( mortality , 37 percent with ibuprofen vs 40 percent with placebo ) . CONCLUSIONS In patients with sepsis , treatment with ibuprofen reduces levels of prostacyclin and thromboxane and decreases fever , tachycardia , oxygen consumption , and lactic acidosis , but it does not prevent the development of shock or the acute respiratory distress syndrome and does not improve survival [10470755] OBJECTIVE To assess the safety and potential efficacy of a mechanical ventilation strategy design ed to reduce stretch-induced lung injury in acute respiratory distress syndrome . DESIGN Prospect i ve , r and omized , controlled clinical trial . SETTING Eight intensive care units in four teaching hospitals . PATIENTS Fifty-two patients with acute respiratory distress syndrome . INTERVENTIONS Traditional tidal volume patients : tidal volume 10 - 12 mL/kg ideal body weight , reduced if inspiratory plateau pressure was > 55 cm H2O ( 7.3 kPa ) . Small tidal volume patients : tidal volume 5 - 8 mL/kg ideal body weight , to keep plateau pressure < 30 cm H2O ( 4.0 kPa ) . MEASUREMENTS AND MAIN RESULTS Mean tidal volumes during the first 5 days in traditional and small tidal volume patients were 10.2 and 7.3 mL/kg , respectively ( p < .001 ) , with mean plateau pressure = 30.6 and 24.9 cm H2O ( 3.3 kPa ) , respectively ( p < .001 ) . There were no significant differences in requirements for positive end-expiratory pressure or FIO2 , fluid intakes/outputs , requirements for vasopressors , sedatives , or neuromuscular blocking agents , percentage of patients that achieved unassisted breathing , ventilator days , or mortality . CONCLUSIONS The reduced tidal volume strategy used in this study was safe . Failure to observe beneficial effects of small tidal volume ventilation treatment in important clinical outcome variables may have occurred because a ) the sample size was too small to discern small treatment effects ; b ) the differences in tidal volumes and plateau pressures were modest ; or c ) reduced tidal volume ventilation is not beneficial [8618579] BACKGROUND Patients with acute respiratory distress syndrome ( ARDS ) have a deficiency of surfactant . Surfactant replacement improves physiologic function in such patients , and preliminary data suggest that it may improve survival . METHODS We conducted a prospect i ve , multicenter , double-blind , r and omized , placebo-controlled trial involving 725 patients with sepsis-induced ARDS . Patients were stratified according to the risk of death at base line ( indicated by their score on the Acute Physiological and Chronic Health Evaluation [ APACHE III ] index ) and r and omly assigned to receive either continuously administered synthetic surfactant ( 13.5 mg of dipalmitoylphosphatidylcholine per milliliter , 364 patients ) or placebo ( o.45 percent saline ; 361 patients ) in aerosolized form for up to five days . RESULTS The demographic and physiologic characteristics of the two treatment groups were similar at base line . The mean ( + /- SD ) age was 50 + /- 17 years in the surfactant group and 53 + /- 18 years in the placebo group , and the mean APACHE III scores at r and omization were 70.4 + /- 25 and 70.5 + /- 25 , respectively . Hemodynamic measures , measures of oxygenation , duration of mechanical ventilation , and length of stay in intensive care unit did not differ significantly in the two groups . Survival at 30 days was 60 percent for both groups . Survival was similar in the groups when analyzed according to APACHE III score , cause of death , time of onset and severity of ARDS , presence or absence of documented sepsis , underlying disease , whether or not there was a do-not-resuscitate order , and medical center . Increased secretions were significantly more frequent in the surfactant group ; the rates of other complications were similar in the two groups . CONCLUSIONS The continuous administration of aerosolized synthetic surfactant to patients with sepsis-induced ARDS had no significant effect on 30-day survival , length of stay in the intensive care unit , duration of mechanical ventilation , or physiologic function [1952438] Arachidonic acid metabolites , especially thromboxane-A2 and prostacyclin , have been shown to be increased in experimental models of sepsis and the adult respiratory distress syndrome ( ARDS ) and play a major pathophysiologic role . This study was design ed to determine if these metabolites are increased in human sepsis syndrome and if inhibition of fatty acid cyclooxygenase affects their formation and their pathophysiologic sequelae . We conducted a double-blind , placebo-controlled trial of ibuprofen ( 800 mg given rectally every 4 h for three doses ) in 30 patients with sepsis syndrome defined by abnormal vital signs , the appearance of serious infection , and at least one major organ failure . Urinary concentrations of the metabolite of thromboxane-A2 , 2,3-dinor-TxB2 , and prostacyclin , 2,3-dinor-6-keto-prostagl and in F2 alpha , were elevated 10 to 20 times normal and declined to four to five times normal by 12 h after entry in the ibuprofen-treated group and remained elevated in the placebo-treated patients . The urinary concentration of TxB2 and 6-keto-prostagl and in F1 alpha , which reflect renal production of TxA2 and prostacyclin , respectively , were also increased approximately 10-fold over normal and were subsequently decreased by ibuprofen . Coincident with the reduction in metabolite levels , the ibuprofen-treated group , but not the placebo-treated group , experienced a significant decline in temperature , heart rate , and peak airway pressure , and a trend towards more rapid reversal of shock ( p = 0.12 ) . ( ABSTRACT TRUNCATED AT 250 WORDS [9449727] BACKGROUND In patients with the acute respiratory distress syndrome , massive alveolar collapse and cyclic lung reopening and overdistention during mechanical ventilation may perpetuate alveolar injury . We determined whether a ventilatory strategy design ed to minimize such lung injuries could reduce not only pulmonary complications but also mortality at 28 days in patients with the acute respiratory distress syndrome . METHODS We r and omly assigned 53 patients with early acute respiratory distress syndrome ( including 28 described previously ) , all of whom were receiving identical hemodynamic and general support , to conventional or protective mechanical ventilation . Conventional ventilation was based on the strategy of maintaining the lowest positive end-expiratory pressure ( PEEP ) for acceptable oxygenation , with a tidal volume of 12 ml per kilogram of body weight and normal arterial carbon dioxide levels ( 35 to 38 mm Hg ) . Protective ventilation involved end-expiratory pressures above the lower inflection point on the static pressure-volume curve , a tidal volume of less than 6 ml per kilogram , driving pressures of less than 20 cm of water above the PEEP value , permissive hypercapnia , and preferential use of pressure-limited ventilatory modes . RESULTS After 28 days , 11 of 29 patients ( 38 percent ) in the protective-ventilation group had died , as compared with 17 of 24 ( 71 percent ) in the conventional-ventilation group ( P<0.001 ) . The rates of weaning from mechanical ventilation were 66 percent in the protective-ventilation group and 29 percent in the conventional-ventilation group ( P=0.005 ) : the rates of clinical barotrauma were 7 percent and 42 percent , respectively ( P=0.02 ) , despite the use of higher PEEP and mean airway pressures in the protective-ventilation group . The difference in survival to hospital discharge was not significant ; 13 of 29 patients ( 45 percent ) in the protective-ventilation group died in the hospital , as compared with 17 of 24 in the conventional-ventilation group ( 71 percent , P=0.37 ) . CONCLUSIONS As compared with conventional ventilation , the protective strategy was associated with improved survival at 28 days , a higher rate of weaning from mechanical ventilation , and a lower rate of barotrauma in patients with the acute respiratory distress syndrome . Protective ventilation was not associated with a higher rate of survival to hospital discharge [7774238] OBJECTIVE To evaluate the safety and efficacy of E5 , a murine , monoclonal antibody directed against endotoxin , in the treatment of patients with Gram-negative sepsis . DESIGN A multicenter , r and omized , double-blind , placebo-controlled trial . SETTING Fifty-three hospitals across the United States , including university medical centers , Veterans Affairs Medical Centers , and community hospitals . PATIENTS 847 patients were r and omized into this study . Enrolled patients met criteria for three conditions : a ) known or suspected Gram-negative infection ; b ) clinical evidence of sepsis ; and c ) signs of end-organ dysfunction . Patients with refractory shock were excluded from the study . INTERVENTIONS Two doses of E5 ( 2 mg/kg/day by intravenous infusion 24 hrs apart ) , or placebo that was identical in appearance were administered . In addition , all patients received st and ard supportive therapy and broad-spectrum antibiotics . MEASUREMENTS AND MAIN RESULTS The primary end point was mortality over 30 days . Secondary outcome measures included the resolution and prevention of organ failure in the same two population s. Additionally , the safety of E5 was evaluated . There was no significant improvement in survival over 30 days among patients with Gram-negative sepsis who received E5 compared with those patients who received placebo ( n = 530 ; p = .21 ) . In addition , E5 did not improve survival for patients with Gram-negative sepsis and organ failure ( n = 139 ; p = .3 ) . However , a significantly greater percentage of patients with Gram-negative sepsis experienced resolution of major organ failure if they received E5 , compared with those patients who received placebo ( n = 139 ; 48 % E5 vs. 25 % placebo ; p = .005 ) . This result extended to all patients who entered the study with one or more major organ failures , regardless of the etiology of the infection ( n = 225 ; 41 % E5 vs. 27 % placebo ; p = .024 ) . E5 also provided protection against the development of some organ failures , but significant prevention was only observed for adult respiratory distress syndrome ( p = .007 ) and central nervous system dysfunction ( p = .050 ) . Hypersensitivity reactions attributable to E5 occurred in 2.6 % of patients . An asymptomatic antibody response occurred in 44 % of the E5-treated patients and in 12 % of the patients who received placebo . CONCLUSIONS In this study , E5 did not reduce mortality in nonshock patients with Gram-negative sepsis whether or not those patients also had organ failure . However , E5 did result in greater resolution of organ failure in patients with Gram-negative sepsis . This benefit extended to those patients with suspected Gram-negative etiology . This finding is important because patients with suspected Gram-negative sepsis and organ failure can be identified without waiting for culture results . In addition , E5 result ed in the prevention of adult respiratory distress syndrome and central nervous system organ failure . However , more studies are needed to determine if this result can be extended to organ failure in general . E5 is safe as a treatment for patients with Gram-negative sepsis [12163791] Objective Trials of potential new therapies in acute lung injury are difficult and expensive to conduct . This article is design ed to determine the utility , behavior , and statistical properties of a new primary end point for such trials , ventilator-free days , defined as days alive and free from mechanical ventilation . Describing the nuances of this outcome measure is particularly important because using it , while ignoring mortality , could result in misleading conclusions . Design To develop a model for the duration of ventilation and mortality and fit the model by using data from a recently completed clinical trial . To determine the appropriate test statistic for the new measure and derive a formula for power . To determine a formula for the probability that the test statistic will reject the null hypothesis and mortality will simultaneously show improvement . To plot power curves for the test statistic and determine sample sizes for reasonable alternative hypotheses . Setting Intensive care units . Patients Patients with acute respiratory distress syndrome or acute lung injury as defined by the American-European Consensus Conference . Main Results The proposed model fit the clinical data . Ventilator-free days were improved by lower tidal volume ventilation , but the improvement was mostly caused by the improved mortality rate , so trials that expected similar effects would only have modest increase in power if they used ventilator-free days as their primary end point rather than 28-day mortality . Similar results were obtained using the model in two groups segregated by low or high Acute Physiology and Chronic Health Evaluation score . On the other h and , if patients are divided into two groups on the basis of the lung injury score , both the duration of ventilation and mortality are lower in the low lung injury score group . A trial of a treatment that had a similar clinical effect would have a large increase in power , allowing for a reduction in the required sample size . Conclusions Use of ventilator-free days as a trial end point allows smaller sample sizes if it is assumed that the treatment being tested simultaneously reduces the duration of ventilation and improves mortality . It is unlikely that a treatment that led to higher mortality could lead to a statistically significant improvement in ventilator-free days . This would be especially true if the treatment were also required to produce a nominal improvement in mortality [2350875] The purpose of this investigation was to evaluate the magnitude and duration of changes in lung function and oxygen transport in patients with adult respiratory distress syndrome ( ARDS ) receiving indomethacin . Ten patients with ARDS were r and omized to receive intravenously either a single 50 mg dose of indomethacin or placebo . Comparing 1 hr postinfusion levels to baseline observations in the indomethacin group , PaO2 increased to 125 + /- 13 torr from 93 + /- 8 torr , PaO2/FIO2 ratio increased to 223 + /- 24 from 160 + /- 5 , and Qs/Qt dropped to 0.20 + /- 0.03 from 0.27 + /- 0.03 ( all P less than 0.05 ) . These alterations in oxygenation gradually returned to baseline levels over the ensuing 8 hr . No such changes were noted in the placebo group [10470753] OBJECTIVE To evaluate the safety and efficacy of an intravenous liposomal dispersion of prostagl and in E1 as TLC C-53 in the treatment of patients with acute respiratory distress syndrome ( ARDS ) . DESIGN R and omized , prospect i ve , multicenter , double-blind , placebo-controlled , phase III clinical trial . SETTING Forty-seven community and university-affiliated hospitals in the United States . PATIENTS A total of 350 patients with ARDS were enrolled in this clinical trial . INTERVENTION Patients were prospect ively r and omized in a 1:1 ratio to receive either liposomal prostagl and in E1 or placebo . The study drug was infused intravenously for 60 mins every 6 hrs for 7 days starting with a dosage of 0.15 microg/kg/hr . The dose was increased every 12 hrs until the maximal dose ( 3.6 microg/kg/hr ) was attained or intolerance to further increases developed . Patients received st and ard aggressive medical/surgical care during the infusion period . OUTCOME MEASURES The primary outcome measure was the time it took to wean the patient from the ventilator . Secondary end points included time to improvement of the PaO2/FIO2 ratio ( defined as first PaO2/FIO2 > 300 mm Hg ) , day 28 mortality , ventilator dependence at day 8 , changes in PaO2/FIO2 , incidence of and time to development/resolution of organ failure other than ARDS . RESULTS A total of 348 patients could be evaluated for efficacy . The distribution of variables at baseline describing gender , lung injury scores , Acute Physiology and Chronic Health Evaluation II scores , PaO2/FIO2 , pulmonary compliance , and time from onset of ARDS or from institution of mechanical ventilation to the first dose of study drug was similar among patients in the liposomal prostagl and in E1 ( n = 177 ) and the placebo ( n = 171 ) treatment arms . There was no significant difference in the number of days to the discontinuation of ventilation in the liposomal prostagl and in E1 group compared with the placebo group ( median number of days to off mechanical ventilation , 16.9 in patients receiving liposomal prostagl and in E1 and 19.6 in those administered placebo ; p = .94 ) . Similarly , mortality at day 28 was not significantly different in the two groups ( day 28 mortality , 57 of 176 ( 32 % ) in the liposomal prostagl and in E1 group and 50 of 170 ( 29 % ) in patients receiving placebo ; p = .55 ) . In contrast , treatment with liposomal prostagl and in E1 was associated with a significantly shorter time to reach a PaO2/FIO2 ratio of > 300 mm Hg ( median number of days to reaching a PaO2/FIO2 ratio > 300 mm Hg : 9.8 days in the liposomal prostagl and in E1 group and 13.7 days in patients receiving the placebo ; p = .02 ) . Among the subgroups examined , time to off mechanical ventilation was significantly reduced in patients who received at least 85 % of a full dose ( i.e. , > 45.9 microg/kg ) of liposomal prostagl and in E1 ( median number of days to discontinuation of ventilation , 10.3 in the liposomal prostagl and in E1 group and 16.3 days in patients receiving placebo ; p = .05 ) . The overall incidence of serious adverse events was not significantly different in the liposomal prostagl and in E1 ( 40 % ) or placebo-treated ( 37 % ) groups . Drug-related adverse events of all kinds were reported in 69 % of the patients receiving liposomal prostagl and in E1 compared with 33 % of the placebo group , with hypotension and hypoxia ( occurring in 52 % and 24 % of the liposomal prostagl and in E1-treated patients , respectively , and 17 % and 5 % of the placebo-treated patients , respectively ) being noted most frequently . CONCLUSIONS In the intent-to-treat population of patients with ARDS , treatment with liposomal prostagl and in E1 accelerated improvement in indexes of oxygenation but did not decrease the duration of mechanical ventilation and did not improve day 28 survival [2306970] Because PGE1 previously has been reported to increase survival of patients with ARDS , we evaluated physiologic effects and side effects of PGE1 in a prospect i ve open-label study of patients with ARDS . Seventeen patients with ARDS who did not have significant renal or hepatic dysfunction received PGE1 by continuous central venous infusion ( 30 ng/kg/min ) . Seventeen control patients with ARDS without renal or hepatic dysfunction who had similar APACHE II and ARDS scores and causes of ARDS did not receive PGE1 . Prostagl and in E1 significantly decreased the SVRI and oxygen extraction ratio . Concentrations of total and polymorphonuclear leukocytes , but not platelets , increased significantly during PGE1 infusion , but did not change in control patients . There was no change in the Do2I and Vo2I during the course of the PGE1 infusion . There were no differences in Do2I and Vo2I during PGE1 infusion between survivors and nonsurvivors . Prostagl and in E1 was infused for a mean of 5.9 + /- 1.8 days ( + /- SD ) and was discontinued on ten occasions in seven patients because of supraventricular dysrhythmias ( n = 4 ) , hypotension ( n = 3 ) , thrombocytopenia ( n = 3 ) , and cardiac arrest ( n = 2 ) . Nonsurvivors had PGE1 discontinued prematurely more frequently than survivors ( 56 percent [ 5/9 ] vs 25 percent [ 2/8 ] , respectively ) . The prevalence of multiple-system organ failure and the in-hospital mortality of both PGE1-treated and control patients were not different . Although PGE1 causes significant systemic vasodilation and possibly decreased intrapulmonary polymorphonuclear leukocyte sequestration , PGE1 does not influence multiple-system organ failure or mortality of patients with ARDS without renal or hepatic dysfunction [9449728] BACKGROUND A strategy of mechanical ventilation that limits airway pressure and tidal volume while permitting hypercapnia has been recommended for patients with the acute respiratory distress syndrome . The goal is to reduce lung injury due to overdistention . However , the efficacy of this approach has not been established . METHODS Within 24 hours of intubation , patients at high risk for the acute respiratory distress syndrome were r and omly assigned to either pressure- and volume-limited ventilation ( limited-ventilation group ) , with the peak inspiratory pressure maintained at 30 cm of water or less and the tidal volume at 8 ml per kilogram of body weight or less , or to conventional ventilation ( control group ) , with the peak inspiratory pressure allowed to rise as high as 50 cm of water and the tidal volume at 10 to 15 ml per kilogram . All other ventilatory variables were similar in the two groups . RESULTS A total of 120 patients with similar clinical features underwent r and omization ( 60 in each group ) . The patients in the limited-ventilation and control groups were exposed to different mean ( + /-SD ) tidal volumes ( 7.2+/-0.8 vs. 10.8+/-1.0 ml per kilogram , respectively ; P<0.001 ) and peak inspiratory pressures ( 23.6+/-5.8 vs. 34.0+/-11.0 cm of water , P<0.001 ) . Mortality was 50 percent in the limited-ventilation group and 47 percent in the control group ( relative risk , 1.07 ; 95 percent confidence interval , 0.72 to 1.57 ; P=0.72 ) . In the limited-ventilation group , permissive hypercapnia ( arterial carbon dioxide tension , > 50 mm Hg ) was more common ( 52 percent vs. 28 percent , P=0.009 ) , more marked ( 54.4+/-18.8 vs. 45.7+/-9.8 mm Hg , P=0.002 ) , and more prolonged ( 146+/-265 vs. 25+/-22 hours , P=0.017 ) than in the control group . The incidence of barotrauma , the highest multiple-organ-dysfunction score , and the number of episodes of organ failure were similar in the two groups ; however , the numbers of patients who required paralytic agents ( 23 vs. 13 , P=0.05 ) and dialysis for renal failure ( 13 vs. 5 , P= 0.04 ) were greater in the limited-ventilation group than in the control group . CONCLUSIONS In patients at high risk for the acute respiratory distress syndrome , a strategy of mechanical ventilation that limits peak inspiratory pressure and tidal volume does not appear to reduce mortality and may increase morbidity [8365305] BACKGROUND Septic shock is frequently complicated by a syndrome of disseminated intravascular coagulation ( DIC ) . Numerous uncontrolled clinical studies have reported that antithrombin III ( ATIII ) substitution might prevent DIC and death in septic shock . METHODS We conducted a r and omized double-blind placebo-controlled trial in patients with a documented septic shock and DIC . The patients received either a placebo or ATIII ( 90 to 120 IU/kg in loading dose , then 90 to 120 IU/kg/d during 4 days ) . Administration of fresh frozen plasma , platelets , and fibrinogen concentrates was restricted to patients with hemorrhages and severe decreases in prothrombin time , platelet count , and fibrinogen levels . RESULTS Thirty-five patients entered the study ( 18 placebo , 17 ATIII ) . Both groups were well balanced for all demographic , hemodynamic , and biologic data . Three patients were excluded before the treatment allocation code was broken . In the ATIII group , ATIII levels were rapidly corrected and remained over normal levels until day 10 ; sequential protein C and protein S levels were not modified . The duration of DIC was significantly reduced : in the ATIII group , 64 percent of patients were cured of DIC at day 2 , and 71 percent were cured at the end of treatment vs in the placebo group , 11 percent ( p < 0.01 ) and 33 percent ( p < 0.05 ) , respectively . In the 32 included patients , the mortality in ICU was reduced by 44 percent in the ATIII group ( p = 0.22 , NS ) . Care loads and transfusion requirements were not different . No side effect was observed . CONCLUSIONS Mortality was reduced by 44 percent in this trial , but the difference did not reach the statistical significance . Circulating protein C and protein S levels were not modified by ATIII supplementation . High doses of ATIII concentrates significantly improved sepsis-induced DIC during septic shock . The trend toward improved survival suggests further r and omized studies [1617983] Objective To examine whether the antioxidant N-acetylcysteine could ameliorate the course of the adult respiratory distress syndrome ( ARDS ) in man . Design R and omized , double-blind , placebo-controlled study . Setting Medical and surgical ICU in a regional hospital . Patients Sixty-six ICU patients with ARDS . Interventions Patients with ARDS ( Pao2/FIO2 ratio < 250 torr ) were treated with either the antioxidant N-acetylcysteine 150 mg/kg as a loading dose and then 20 mg/kg/hr , or with placebo for 6 days . Measurements and Main Results No improvement could be demonstrated in the Pao2/FIO2 ratio in the study group as compared with the control group on any day . Pulmonary compliance was higher in the N-acetylcysteine group than in the placebo group on all days , but this difference did not reach the chosen 5 % level of significance . No difference between the two groups could be demonstrated on chest radiograph or on survival rate . We documented that N-acetylcysteine acts as an anticoagulant and perhaps decreases pulmonary fibrin uptake during ARDS . Conclusions N-acetylcysteine might be of benefit in ARDS . Before further clinical studies are started , problems with N-acetylcysteine and coagulation have to be eluci date d in order to find out whether N-acetylcysteine could have a beneficial effect in the treatment of ARDS [8565513] OBJECTIVE To evaluate the safety and efficacy of liposomal prostagl and in E1 ( TLC C-53 ) in the treatment of patients with the acute respiratory distress syndrome ( ARDS ) . DESIGN R and omized , prospect i ve , multicenter , double-blind , placebo-controlled , phase II clinical trial . SETTING Eight community and university-affiliated hospitals in the United States . PATIENTS Twenty-five patients with ARDS . INTERVENTIONS Patients were prospect ively r and omized in an unbalanced ratio within each site to receive either TLC C-53 ( n = 17 ) or placebo ( n = 8) . Study drug was infused intravenously over 60 mins every 6 hrs for a 7-day period , starting at a dose of 0.15 micrograms/kg/hr . The dose was increased every 12 hrs until the maximal dose ( 3.6 micrograms/kg/hr ) was attained , intolerance to further increases developed , or invasive monitoring was discontinued . Patients received st and ard , aggressive , medical/surgical care throughout the trial . MEASUREMENTS AND MAIN RESULTS Outcome measurements were Pao2/FI0(2 ) , dynamic pulmonary compliance , ventilator dependence on day 8 , and 28-day all-cause mortality rate . At baseline , the distribution of variables describing Lung Injury Scores , Acute Physiology and Chronic Health Evaluation II scores , Pao2/FI0(2 ) , pulmonary compliance , and time from onset of ARDS to first dose of study drug was similar between patients in the TLC C-53 and placebo treatment groups . On day 8 , all eight patients given placebo required mechanical ventilation , while eight of 17 patients given TLC C-53 were healthy enough to be removed from the ventilator ( p = .03 ) . Improvement in PaO2/FIO2 during the initial 8-day study period was greater in patients receiving TLC C-53 . This trend achieved statistical significance on day 3 , when the increase in PaO2/FIO2 from baseline was 82.5 + /- 14.6 in the TLC C-53 group compared with 28.3 + /- 22.1 in the placebo group ( p = .05 ) . By day 8 , lung compliance also increased from baseline significantly more in TLC C-53 patients than in placebo patients ( 5.7 + /- 1.7 vs -1.5 + /- 1.8 mL/cm H2O ; p = .01 ) . The 28-day mortality rate was 6 % ( 1/17 patients ) in the TLC C-53 group and 25 % ( 2/8 patients ) in the placebo group ( p = .23 ) . Drug-related adverse events were reported in 82 % of the patients receiving TLC C-53 compared with 38 % of the placebo group , with half of the adverse events in the TLC C-53 group being localized infusion site irritation . TLC C-53 was hemodynamically well tolerated , with transient hypotension occurring in three patients . CONCLUSIONS In patients with ARDS , TLC C-53 was associated with improved oxygenation , increased lung compliance , and decreased ventilator dependency [9228372] OBJECTIVE To determine the levels of glutathione and cysteine in patients with ARDS and examine the effect of treatment with N-acetylcysteine ( NAC ) and L-2-oxothiazolidine-4-carboxylate ( Procysteine ; Clintec Technologies Inc ; Chicago [ OTZ ] ) on these levels and on common physiologic abnormalities , and organ dysfunction associated with ARDS . DESIGN R and omized , double-blind , placebo-controlled , prospect i ve clinical trial . SETTING ICUs in five clinical centers in the United States and Canada . PATIENTS Patients meeting a predetermined definition of ARDS and requiring mechanical ventilation . INTERVENTION St and ard care for ARDS and I.V. infusion , every 8 h for 10 days , of one of the following : NAC ( 70 mg/kg , n=14 ) , OTZ ( 63 mg/kg , n=17 ) , or placebo ( n=15 ) . MAIN RESULTS Both antioxidants effectively repleted RBC glutathione gradually over the 10-day treatment period ( 47 % and 49 % increases from baseline values for NAC and OTZ , respectively ) . There was no difference in mortality among groups ( placebo , 40 % ; NAC , 36 % ; OTZ , 35 % ) . However , the number of days of acute lung injury was decreased and there was also a significant increase in cardiac index in both treatment groups ( NAC/OTZ [+]14 % ; placebo [-]6 % ) . CONCLUSIONS Our findings suggest that repletion of glutathione may safely be accomplished with NAC or OTZ in patients with acute lung injury/ARDS . Such treatment may shorten the duration of acute lung injury , but larger studies are needed to confirm this [3317054] Corticosteroids are widely used as therapy for the adult respiratory distress syndrome ( ARDS ) without proof of efficacy . We conducted a prospect i ve , r and omized , double-blind , placebo-controlled trial of methylprednisolone therapy in 99 patients with refractory hypoxemia , diffuse bilateral infiltrates on chest radiography and absence of congestive heart failure documented by pulmonary-artery catheterization . The causes of ARDS included sepsis ( 27 percent ) , aspiration pneumonia ( 18 percent ) , pancreatitis ( 4 percent ) , shock ( 2 percent ) , fat emboli ( 1 percent ) , and miscellaneous causes or more than one cause ( 42 percent ) . Fifty patients received methylprednisolone ( 30 mg per kilogram of body weight every six hours for 24 hours ) , and 49 received placebo according to the same schedule . Serial measurements were made of pulmonary shunting , the ratio of partial pressure of arterial oxygen to partial pressure of alveolar oxygen , the chest radiograph severity score , total thoracic compliance , and pulmonary-artery pressure . We observed no statistical differences between groups in these characteristics upon entry or during the five days after entry . Forty-five days after entry there were no differences between the methylprednisolone and placebo groups in mortality ( respectively , 30 of 50 [ 60 percent ; 95 percent confidence interval , 46 to 74 ] and 31 of 49 [ 63 percent ; 95 percent confidence interval , 49 to 77 ] ; P = 0.74 ) or in the reversal of ARDS ( 18 of 50 [ 36 percent ] vs. 19 of 49 [ 39 percent ] ; P = 0.77 ) . However , the relatively wide confidence intervals in the mortality data make it impossible to exclude a small effect of treatment . Infectious complications were similar in the methylprednisolone group ( 8 of 50 [ 16 percent ] ) and the placebo group ( 5 of 49 [ 10 percent ] ; P = 0.60 ) . Our data suggest that in patients with established ARDS due to sepsis , aspiration , or a mixed cause , high-dose methylprednisolone does not affect outcome [9546417] Pentoxifylline , an inhibitor of tumor necrosis factor , has been evaluated as an antimalarial agent in combination with artesunate in 45 patients with severe falciparum malaria . Patients were admitted to the intensive care unit at the Hospital for Tropical Diseases in Bangkok , Thail and , and r and omly assigned to treatment for 72 hr with a combination of intravenously administered artesunate and 1 ) placebo , 2 ) low-dose pentoxifylline ( 0.83 mg/kg/hr ) , or 3 ) high-dose pentoxifylline ( 1.67 mg/kg/hr ) . All 45 patients had one or more manifestations of severe malaria such as cerebral malaria ( n = 18 ) , renal failure requiring hemodialysis ( n = 9 ) , azotemia ( n = 8) , jaundice ( n = 25 ) , or hyperparasitemia ( n = 30 ) . The overall severity was comparable in the three groups . Clinical outcome was assessed with respect to the parasite clearance time and the fever clearance time in all patients . In addition , a number of subsidiary outcome variables were examined in specific subgroups , including the recovery time from coma for patients with cerebral malaria , the duration of intubation in patients with respiratory distress , the number of hemodialysis treatments needed for patients with acute renal failure , and the number of units of blood administered to patients requiring transfusion . Concentrations of tumor necrosis factor were reduced in all three groups at 48 hr after treatment . No significant differences among the three treatment groups were found for any of the outcome variables examined . We conclude that the addition of pentoxifylline to artesunate therapy for severe malaria produced no evident clinical benefit [7271345] The effects of massive steroids on pulmonary function after hypovolemic shock were tested in 114 injured patients who received an average of 13 transfusions , 760 ml plasma , and 11.7 L crystalloid solution ; by r and om selection , 54 patients received methylprednisolone ( 1 g in operating room plus 3,578 mg average during the next three days ) . The patients who received steroids had a significant increase in central venous pressure and a decrease in arterial oxygen tension ( PaO2 ) compared with control patients . The inspired oxygen concentration was similar for both groups ; the FiO2/PO2 , therefore , was significantly deranged ( p= ≤ 0.05 ) in steroid patients ( 0.45 ± 0.05 SE vs 0.37 ± 0.02 SE ) . The patients who received steroids had an insignificantly increased pulmonary shunt ( 25 vs 22 % ) , number of days on a volume ventilator ( 5.1 vs 3.0 days ) , and number of deaths ( seven vs two ) . Massive steroids neither prevent nor ameliorate pulmonary failure after shock ; indeed , steroids may aggravate pulmonary failure after [9054282] At the end of a long week in the office , you sink back into your chair , reflecting on some of the more memorable patients you cared for and counseled . Through gentle history taking , you discovered that urinary incontinence is the underlying cause of an elderly patient 's increasing social isolation . During a careful physical examination , you detected bruising on the torso of a woman with chronic headaches and began to explore the longst and ing abusive relationship between the woman and her alcoholic partner . You discontinued procainamide therapy in a 72-year-old man who had asymptomatic premature ventricular contractions after myocardial infa rct ion . To prevent bleeding from esophageal varices , you started -blocker therapy in a woman with long-st and ing cryptogenic cirrhosis and portal hypertension . In couples ' therapy , discussing the future quality of life of a middle-aged gay man with human immunodeficiency virus infection , you journeyed through emotionally intense dialogue about advance directives . You presented the risk factors for major and minor bleeding to a 39-year-old woman who was considering warfarin therapy because of recently diagnosed atrial fibrillation and valvular heart disease . You listened to , made diagnoses for , treated , advised , and comforted many patients . Yet there were some hiccoughs in your practice along the way . You stumbled while debating the pros and cons of breast cancer screening with a healthy 48-year-old woman who has been staying current with information on the Internet . You question ed the merits of a personalized walking program suggested to you by a motivated 66-year-old man with severe claudication . Explaining that you wanted to review the best current evidence on these issues , you resolved to address your uncertainties before these patients made their next office visits , in a week 's time . Sighing deeply , you acknowledge that you have little time to read . You subscribe to three journals , which you browse months after they arrive-either when your journal stack becomes precariously high or when your guilt is sufficiently motivational . You sometimes find the conclusions of individual articles conflicting or confusing . You know that some of the decisions and suggestions you made this week , specifically your decisions about stopping procainamide therapy and starting -blocker therapy and your advice about bleeding risks from anticoagulant therapy , were based on the best current research evidence [ 1 - 3 ] . On the other h and , your patients ' inquiries about breast cancer screening and exercise treatment for claudication highlight your need for a concise , current , rigorous synthesis of the best available evidence on each of these topics : in brief , a systematic review [ 4 , 5 ] . Incorporating Research Evidence into Clinical Decision Making The foregoing scenario is familiar to practitioners . In a typical week , we encounter patients with diverse problems ; exercise numerous clinical , interpersonal , and technical skills ; and make many decisions . The factors that affect these decisions and their outcomes are complex . For instance , each patient has unique sociodemographic characteristics , cultural circumstances , and personal preferences . Each physician has unique knowledge , experiences , and values . Moreover , practitioners and their patients make decisions within the context of a rapidly changing health care system that influences the availability , accessibility , and cost of diagnostic tests and therapies [ 6 ] . Timely , useful evidence from the biomedical literature should be an integral component of clinical decision making . If one treatment has been shown to be better than another , we need to know , so that we can recommend the treatment to the appropriate patients . The worldwide effort to develop new tests and treatments , and to determine their usefulness , has never been stronger , and our patients and their families expect us to be fonts of the knowledge that results from this effort [ 7 ] . Unfortunately , it is easy for current best research evidence to pass us by [ 8 ] . We may lack the time , motivation , and basic skills needed to find , critically appraise , and synthesize information , all of which we must do if we are to integrate the results of original studies into our practice . Fortunately , several potent methods are emerging that can greatly enhance our ability to interpret and apply research evidence ; foremost among them is the systematic review . This article begins a series in Annals that will examine systematic review s in detail and explore their many applications . Systematic review s represent the best chance that most practitioners will have to underst and and accurately apply the key signals arising from the robust and increasingly productive search for solutions to medical problems . A properly conducted systematic review faithfully summarizes the evidence from all relevant studies on the topic of interest , and it does so concisely and transparently . What Is a Systematic Review ? Systematic review s are scientific investigations in themselves , with pre-planned methods and an assembly of original studies as their subjects . They synthesize the results of multiple primary investigations by using strategies that limit bias and r and om error [ 9 , 10 ] . These strategies include a comprehensive search of all potentially relevant articles and the use of explicit , reproducible criteria in the selection of articles for review . Primary research design s and study characteristics are appraised , data are synthesized , and results are interpreted . When the results of primary studies are summarized but not statistically combined , the review may be called a qualitative systematic review . A quantitative systematic review , or meta- analysis , is a systematic review that uses statistical methods to combine the results of two or more studies . The term overview is sometimes used to denote a systematic review , whether quantitative or qualitative . Summaries of research that lack explicit descriptions of systematic methods are often called narrative review s. Review articles are one type of integrative publication ; practice guidelines , economic evaluations , and clinical decision analyses are others . These other types of integrative articles often incorporate the results of systematic review s. For example , practice guidelines are systematic ally developed statements intended to assist practitioners and patients with decisions about appropriate health care for specific clinical circumstances [ 11 ] . Evidence -based practice guidelines are based on systematic review s of the literature , appropriately adapted to local circumstances and values . Economic evaluations compare both the costs and the consequences of different courses of action ; the knowledge of consequences that are considered in these evaluations is often generated by systematic review s of primary studies . Decision analyses quantify both the likelihood and the valuation of the expected outcomes associated with competing alternatives . Differences between Systematic and Narrative Review s All review s , narrative and systematic alike , are retrospective , observational research studies and are therefore subject to systematic and r and om error . Accordingly , the quality of a review - and thus its worth-depends on the extent to which scientific review methods have been used to minimize error and bias . This is the key feature that distinguishes traditional narrative review s from systematic review s ( Table 1 ) . If a review is prepared according to the steps outlined in the right column of Table 1 , it is more likely to be systematic and to provide unbiased conclusions . If review methods approximate those found in the middle column of Table 1 , the article is more likely to be a narrative review , and the conclusions are less likely to be based on an unbiased summary of all relevant evidence . Table 1 . Differences between Narrative Review s and Systematic Review s Systematic review s are generated to answer specific , often narrow , clinical questions in depth . These questions can be formulated explicitly according to four variables : a specific population and setting ( such as elderly out patients ) , the condition of interest ( for example , hypertension ) , an exposure to a test or treatment ( such as pharmacologic management ) , and one or more specific outcomes ( such as cardiovascular and cerebrovascular events and mortality ) [ 12 ] . Thus , an example of a well-formulated , clinical ly relevant question is , Does pharmacologic treatment of hypertension in the elderly prevent strokes and myocardial infa rct ions or delay death ? If the question that is driving the review is not clear from the title , abstract , or introduction , or if no methods section is included , the paper is more likely to be a narrative review than a systematic review [ 13 ] . Most narrative review articles deal with a broad range of issues related to a given topic rather than addressing a particular issue in depth [ 9 ] . For example , a narrative review on diabetes ( such as that which might be found in a textbook chapter ) might include sections on the physiology and pathophysiology of carbohydrate , lipid , and protein metabolism ; the epidemiology of and prognosis associated with diabetes ; diagnostic and screening approaches ; and preventive , therapeutic , rehabilitative , and palliative interventions . Thus , narrative review s may be most useful for obtaining a broad perspective on a topic ; they are less often useful in furnishing quantitative answers to specific clinical questions . Narrative review s are appropriate for describing the history or development of a problem and its management . Narrative review s may better describe cutting-edge developments if research is scant or preliminary or if studies are very limited by flawed design or execution [ 13 ] . They may be particularly useful for discussing data in light of underlying theory and context . Narrative review s can draw analogies and can conceptually integrate two independent fields of research , such as [3979000] Levels of thromboxane B2 ( TxB2 ) , the stable metabolite of thromboxine A2 , are elevated in human and experimental septic shock . The thromboxane synthetase inhibitor dazoxiben has improved survival and decreased pulmonary hypertension in experimental endotoxemia . A r and omized prospect i ve study of 10 patients with the clinical diagnosis of sepsis and early adult respiratory distress syndrome ( hypoxemia , radiologic evidence of the syndrome , and intrapulmonary shunt > 20 % ) was performed to test the efficacy of dazoxiben in ameliorating the effects of human sepsis . Five subjects received dazoxiben and five received placebo . Dazoxiben , 100 mg , or placebo was injected intravenously every 4 hours for a maximum of 72 hours . Plasma immunoreactive TxB2 ( iTxB2 ) levels were determined by radioimmunoassay . Before dazoxiben , the plasma iTxB2 level was 752 ±261 pg/ml ( n = 5 ) and was reduced within 1 hour to 333 ±137 pg/ml . The plasma levels of iTxB2 remained significantly decreased with subsequent doses of dazoxiben and it was 201 ± 67 pg/ml ( n = 4 ) 60 hours after dosing . In contrast , placebo had no significant effect on plasma iTxB2 levels ( n = 5 ) throughout the entire period of observation . Dazoxiben did not induce any significant changes in pulmonary or systemic vascular resistance , intrapulmonary shunting , clotting studies , or extravascular lung water . One of the five subjects in the placebo group died and two of the five subjects in the dazoxiben group died . We conclude that dazoxiben was safe and effectively lowered plasma iTxB2 levels in patients with sepsis and incipient adult respiratory distress symptom , but did not significantly alter the hemodynamic and pulmonary sequelae of established sepsis [8674324] OBJECTIVE No means exist for predicting the acute respiratory distress syndrome ( ARDS ) , which complicates sepsis , trauma , and a variety of clinical disorders . Because activation of phospholipid-signaling pathways involving the acyl chains oleate and linoleate may initiate and amplify the inflammatory response , and thereby lead to the development of ARDS , we examined whether serum concentrations of these bioactive lipids increase and are predictive of ARDS in at-risk patients . DESIGN Part I : A prospect i ve , single-blind trial . Part II : A prospect i ve , r and omized , double-blind trial . SETTING General intensive therapy units in five university teaching hospitals . SUBJECTS Part I : Thirty-nine healthy control patients were studied to determine normal distribution of serum acyl values , followed by 30 patients admitted with onset of sepsis , trauma , or development of ARDS ( within 24 hrs of admission ) over a 1-yr period . Part II : Eight patients admitted with sepsis syndrome over a 2-month period . INTERVENTIONS Part II : Patients were r and omized to receive the substituted methylxanthine , lisofylline ( CT1501R ) , or an identically presented placebo . MEASUREMENTS AND MAIN RESULTS We measured the serum free fatty acid concentrations in the 39 healthy control subjects , and then we prospect ively examined the serum free fatty acid concentrations in 30 age-matched patients in sample s obtained within 24 hrs from the onset of sepsis , trauma , or development of ARDS . We then prospect ively studied eight septic , at-risk patients who were matched for age , Acute Physiology and Chronic Health Evaluation II scores , Multiple Organ Failure index , and Glasgow Coma Score , in a double-blind , placebo-controlled , pilot study . These patients included four patients who received no treatment and four patients who received lisofylline , a compound that decreases serum unsaturated free fatty acids and diminishes acute lung injury in animals caused by sepsis and /or trauma . The calculated ratios of serum free fatty acids ( Le . , the ratio of C18 unsaturated fatty acids linoleate and oleate to fully saturated palmitate , C16:0 ) increased and predicted the development of ARDS in at-risk patients . Serum sample s from the 30 patients , obtained within 24 hrs from the onset of sepsis , trauma , or development of ARDS , had significantly increased mean acyl chain ratios ( 1.42 + /- 0.35 [ SD ] ) compared with healthy control subjects ( 0.86 + /- 0.25 ; p < .01 ) . Sera from 13 patients with sepsis or trauma who did not develop ARDS ( group A [ at-risk , non-pre-ARDS ] ) also had increased acyl ratios ( 1.23 + /- 0.27 ) compared with sera from healthy control subjects ( 0.86 + /- 0.25 ; p < .01 ) . Sera from seven patients who subsequently developed ARDS ( group B [ at-risk , pre-ARDS ] ) had higher acyl ratios ( 1.70 + /- 0.21 ) than group A at-risk patients who did not develop ARDS ( 1.23 + /- 0.27 ; p < .01 ) or healthy control subjects ( 0.86 + /- 0.25 ; p < .001 ) . Sera from ten group C patients with ARDS at the time of admission to the study had the highest acyl ratios ( 1.80 + /- 0.75 ) , which exceeded values for healthy control subjects ( p < .001 ) and group A at-risk patients without ARDS ( p = .01 ) , but were not significantly different then group B at-risk , pre-ARDS patients ( p = .17 ) . Prospect i ve study of eight septic , at-risk patients demonstrated significantly ( p < .05 ) increased serum acyl ratios in the four untreated patients ( findings consistent with the first study ) but a significantly ( p = .02 ) reduced ratio in the four at-risk patients treated with lisofyline . CONCLUSIONS Increases in unsaturated serum acyl chain ratios differentiate between healthy and seriously iII patients , and identify those patients likely to develop ARDS . Thus , the serum acyl ratio may not only prospect ively identify and facilitate the assessment of new treatments in patients at highest risk for developing ARDS , but may also lead to new insights about the pathogenesis of ARDS [10950800] This study assessed the safety and efficacy of filgrastim ( r-metHuG-CSF [ recombinant human methionine granulocyte colony-stimulating factor ] ) , when combined with intravenous ( IV ) antibiotics , in the treatment of hospitalized adult patients with multilobar community-acquired pneumonia ( CAP ) . Four hundred eighty patients were r and omized to receive placebo ( n=243 ) or filgrastim 300 microg/day ( n=237 ) , in addition to st and ard therapy . Treatment with study drug was continued for 10 days , until the peak white blood cell ( WBC ) count reached 75x109/L , until discharge from the hospital , until death , or until IV antibiotics were discontinued . Study -related observations continued through day 29 . Filgrastim increased WBC counts ( baseline median , 13.3x109/L ; median peak , 43 . 8x109/L ) . The 2 treatment groups were not statistically different with respect to the study end points ; however , there was a trend toward reduction of mortality in patients with pneumococcal bacteremia . Although further studies will be required to vali date this observation , filgrastim was safe and well tolerated when administered to patients with multilobar CAP [12794395] OBJECTIVE Platelet-activating factor ( PAF ) is a potent proinflammatory mediator implicated in the pathogenesis of both severe sepsis and acute respiratory distress syndrome . One of the regulatory pathways for PAF involves degradation to the inactive metabolite lyso-PAF by the enzyme PAF acetylhydrolase ( PAF-AH ) . Because reduced concentrations of the natural form of PAF-AH have been reported in septic patients , the present study was conducted to determine whether treatment with recombinant human PAF-AH ( rPAF-AH , Pafase ) was safe when administered after the onset of severe sepsis and whether it decreases the prevalence of acute respiratory distress syndrome and 28-day all-cause mortality . DESIGN A prospect i ve , r and omized , double-blind , placebo-controlled , multicenter trial . SETTING Thirty-three medical and surgical intensive care units located in the United States . PATIENTS A total of 127 patients with severe sepsis , but without established acute respiratory distress syndrome , were enrolled in the study . R and omization occurred within 12 hrs of the onset of severe sepsis . Patients then received 1.0 mg/kg rPAF-AH ( n = 45 ) , 5.0 mg/kg rPAF-AH ( n = 39 ) , or placebo ( n = 43 ) administered intravenously , once daily , for five consecutive days . MEASUREMENTS AND MAIN RESULTS Demographic and baseline clinical characteristics of the three treatment groups were similar , except for a significantly higher prevalence of respiratory tract infections as the cause of severe sepsis in patients treated with 1.0 mg/kg rPAF-AH . There were no treatment-related deaths , and the overall prevalence of adverse events was similar among rPAF-AH-treated and placebo-treated patients . There were no significant differences in the prevalence of acute respiratory distress syndrome among the three treatment groups . However , 28-day all-cause mortality was 21 % in the 1.0 mg/kg rPAF-AH group , 28 % in the 5.0 mg/kg rPAF-AH group , and 44 % in the placebo group ( overall chi-square p = .07 ; 1.0 mg/kg rPAF-AH vs. placebo , p = .03 ) . A trend toward reduced multiple organ dysfunction also was observed in the 1.0 mg/kg rPAF-AH group compared with the placebo group ( p = .11 ) . CONCLUSION The results from this study indicate that rPAF-AH was well tolerated and should be pursued as a potential new treatment to decrease mortality in patients with severe sepsis

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### Context: [3885438] The more important known pathogenetic mechanisms apparently responsible for the development of adult respiratory distress syndrome ( ARDS ) are briefly discussed . Reactions in the development of ARDS for which corticosteroids are possibly beneficial are pointed out . A prospect i ve study involving 92 patients was design ed to determine the prophylactic value of methylprednisolone sodium succinate ( MPSS ) ( Solu-Medrol ; Upjohn ) in preventing ARDS . MPSS was administered to 47 seriously injured patients and omitted from the management regimen of 45 patients comparable as regards age and severity of injury . The percentage of patients who developed ARDS was significantly lower in the group that received MPSS than in the control group [11215748] We investigated the effect of octreotide in the treatment of severe acute pancreatitis in a case – control study . Experimental and clinical studies on the effect of octreotide in the treatment of acute pancreatitis have shown controversial results . Since January 1992 , we have been conducting a prospect i ve r and omized study on the effect of octreotide in severe acute pancreatitis , in three hospitals in Israel . The entering criteria included three or more of the Ranson prognostic signs and CT findings of severe pancreatitis . Patients were r and omly assigned to conservative treatment either with or without octreotide ( 0.1 mg subcutaneously three times a day ) . The end points of the study included : complication rate ( ARDS , sepsis , renal failure , pseudocyst , fistula , and abscess ) , length of hospital stay , and mortality . From January 1992 to December 1996 , 60 patients entered the study . After evaluating the files , 10 patients were excluded due to failure to meet the entering criteria , incomplete data , or incorrect diagnosis . Of the remaining 50 patients , 25 were assigned to octreotide ( treatment group ) and 25 to conservative treatment only ( control group ) . The two groups matched with regard to age , sex , etiology , and severity of the disease . The complication rate was lower in the treatment group with regard to sepsis ( 24 % vs 76 % , P = 0.0002 ) and ARDS ( 28 % vs 56 % , P = 0.04 ) . The hospital stay was shorter in the treatment group ( 20.6 vs 33.1 days , P = 0.04 ) . Two patients died in the treatment group and eight in the control group ( P < 0.019 ) . These results suggest that octreotide may have a beneficial effect in the treatment of severe acute pancreatitis [8275731] OBJECTIVE To determine the effects of intravenous N-acetylcysteine ( NAC ) on the development of severe adult respiratory distress syndrome ( ARDS ) and mortality rate in patients with mild-to-moderate acute lung injury and to analyze the duration of ventilatory support and FIO2 required as well as the evolution of the lung injury score . SETTING Three university hospital ICUs and one regional ICU in Switzerl and . PATIENTS Sixty-one adult patients presenting with mild-to-moderate acute lung injury and various predisposing factors for ARDS received either NAC , 40 mg/kg/d , or placebo intravenously for 3 days . MEASUREMENTS Respiratory dysfunction was assessed daily according to the need for mechanical ventilation and FIO2 , the evolution of the lung injury score , and the PaO2/FIO2 ratio . The cardiovascular state , liver function , and kidney function were also monitored . Data were collected at admission ( day 0 ) , during the first 3 days , and on the day of discharge from the ICU . RESULTS The NAC and placebo groups ( 32 and 29 patients , respectively ) were comparable at ICU admission for severity of illness assessed by the simplified acute physiology score ( SAPS ) ( 10.8 + /- 4.6 vs 10.9 + /- 4.8 ) and lung injury score ( LIS ) ( 1.39 + /- 0.95 vs 1.11 + /- 1.08 ) ( mean + /- SD ) . Three patients in each group developed ARDS . The 1-month mortality rate was 22 percent for the NAC group and 35 percent for the placebo group ( difference not statistically significant ) . At admission , 22 of 32 patients ( 69 percent ) in the NAC group were mechanically ventilated compared with 22 of 29 ( 76 percent ) in the placebo group . At the end of the treatment period ( day 3 ) , 5 of 29 ( 17 percent ) in the NAC group and 12 of 25 ( 48 percent ) in the placebo group were still receiving ventilatory support ( p = 0.01 ) , The FIO2 was 0.37 less than admission value ( day 0 ) in the NAC group , and 0.20 less in the placebo group ( p < 0.04 ) ; the oxygenation index ( PaO2/FIO2 ) improved significantly ( p < 0.05 ) from day 0 to day 3 only in the NAC-treated group . The LIS showed a significant regression ( p = 0.003 ) in the NAC-treated group during the first 10 days of treatment : no change was observed in the placebo group . No adverse effects were observed during the treatment with NAC . CONCLUSIONS Intravenous NAC treatment during 72 h improved systemic oxygenation and reduced the need for ventilatory support in patients presenting with mild-to-moderate acute lung injury subsequent to a variety of underlying diseases . Development of ARDS and mortality were not reduced significantly by this therapy [10793162] BACKGROUND Traditional approaches to mechanical ventilation use tidal volumes of 10 to 15 ml per kilogram of body weight and may cause stretch-induced lung injury in patients with acute lung injury and the acute respiratory distress syndrome . We therefore conducted a trial to determine whether ventilation with lower tidal volumes would improve the clinical outcomes in these patients . METHODS Patients with acute lung injury and the acute respiratory distress syndrome were enrolled in a multicenter , r and omized trial . The trial compared traditional ventilation treatment , which involved an initial tidal volume of 12 ml per kilogram of predicted body weight and an airway pressure measured after a 0.5-second pause at the end of inspiration ( plateau pressure ) of 50 cm of water or less , with ventilation with a lower tidal volume , which involved an initial tidal volume of 6 ml per kilogram of predicted body weight and a plateau pressure of 30 cm of water or less . The primary outcomes were death before a patient was discharged home and was breathing without assistance and the number of days without ventilator use from day 1 to day 28 . RESULTS The trial was stopped after the enrollment of 861 patients because mortality was lower in the group treated with lower tidal volumes than in the group treated with traditional tidal volumes ( 31.0 percent vs. 39.8 percent , P=0.007 ) , and the number of days without ventilator use during the first 28 days after r and omization was greater in this group ( mean [ + /-SD ] , 12+/-11 vs. 10+/-11 ; P=0.007 ) . The mean tidal volumes on days 1 to 3 were 6.2+/-0.8 and 11.8+/-0.8 ml per kilogram of predicted body weight ( P<0.001 ) , respectively , and the mean plateau pressures were 25+/-6 and 33+/-8 cm of water ( P<0.001 ) , respectively . CONCLUSIONS In patients with acute lung injury and the acute respiratory distress syndrome , mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use [8222677] Objective : To determine if ketoconazole , a thromboxane A2 synthetase inhibitor , given within the first 24 hrs after diagnosis and arrival in the intensive care unit ( ICU ) would decrease the frequency of adult respiratory distress syndrome in the septic patient population . Design : Prospect i ve , r and omized , double-blind , placeocontrolled study . Setting : Twelve-bed , surgical ICU in a university-affiliated hospital . Patients : Fifty-four consecutive patients admitted to the surgical ICU with the diagnosis of sepsis composed the study sample . Sepsis was defined as including two or more of the following signs in a patient with a systolic blood pressure of < 80 mm Hg or a systemic vascular resistance of < 800 dyne-sec/cm5 : a ) temperature ≥39 ° C or ≤35 ° C ; b ) white blood cell count of > 12,000 leukocytes , or ≤4000 leukocytes/μL , or ≥20 % immature cells ; c ) positive blood culture ; d ) known or strongly suspected source of infection from which a known pathogen was cultured . Interventions : Patients were r and omized to receive either ketoconazole ( 400 mg ) or placebo in a double-blind fashion as early as possible and in < 24 hrs after surgical ICU admission or after the diagnosis of sepsis was established . Measurements and Main Results : Adult respiratory distress syndrome ( ARDS ) was diagnosed if the following criteria were met : a ) intrapulmonary shunt of > 20 % , or a PaO2/Fio2 ratio of < 150 requiring ventilatory support for > 48 hrs ; b ) pulmonary artery occlusion pressure of < 18 nun Hg and no clinical signs of heart failure ; and c ) diffuse infiltrates on chest radiograph . Treatment result ed in significant ( p = .002 ) reduction in the frequency of ARDS compared with the placebo group , 64 % vs. 15 % in the ketoconazole treated group . The mortality rate was also reduced from 39 % in the placebo group to 15 % in the ketoconazole group ( p = .05 ) . A statistically significant reduction in ventilator and ICU days was not achieved . Conclusions : Ketoconazole ( 400 mg through the gastrointestinal tract ) given early in the septic course may prevent ARDS and decrease the mortality rate in high-risk , septic patients . ( Crit Care Med 1993 ; 21:1635–1642 [4028748] Because the formation of platelet thrombi has been incriminated in the development of the adult respiratory distress syndrome ( ARDS ) , we tested trie hypothesis that early administration of antiplatelet agents might protect the lungs in patients at risk to develop ARDS after circulatory shock . This double-blinded study included 40 patients treated with either 3 mg/kg ± 24 h of dipyridamole or a corresponding dose of placebo after an episode of hemorrhagic , traumatic , or septic shock . Each patient also received 100 mg of aspirin daily . Arterial blood gases and chest x-rays were not significantly different between dipyridamole and placebo groups . Moreover , two patients receiving dipyridamole but none receiving placebo developed ARDS . This pilot study does not support a beneficial effect of dipyridamole in the prevention of ARDS after circulatory shock [2436506] The possible beneficial effect of aprotinin , a broad protease inhibitor , on the incidence and outcome of ARDS was examined in two complementary studies . In the first study , the effect of aprotinin was assessed in 147 patients admitted with multiple trauma or shock . In the 57 patients who developed ARDS , mortality was significantly less in those who had previously received aprotinin ( 8/20 , 40 % ) than in those who had not ( 26/37 , 70 % ) . Although both treatment groups were well matched , this was a retrospective study and a second prospect i ve , r and omised , controlled study was therefore carried out . In 78 patients at risk of ARDS , there was no significant difference between treated and control patients in the incidence , duration or severity of ARDS , or in mortality or other major complications . It is concluded that aprotinin is not effective in improving any aspect of ARDS or its outcome in seriously ill patients [12649125] We performed a phase I/II trial in North America of a recombinant surfactant protein C-based surfactant ( Venticute ) as treatment for the acute respiratory distress syndrome . Patients were prospect ively r and omized to receive either st and ard therapy or st and ard therapy plus one of two doses of exogenous surfactant given four times over 24 hours . Surfactant administration was well tolerated . No significant treatment benefit was associated with surfactant treatment . Bronchoalveolar lavage of treated patients at 48 hours reflected the presence of exogenous surfactant components , did not show evidence of improved surface tension lowering function , and had interleukin-6 concentrations that were significantly lower than control group values , consistent with an antiinflammatory treatment effect . The presence of exogenous surfactant was not detected in lavage fluid obtained at 120 hours . Future studies might rationally employ larger surfactant doses and a more prolonged dosing schedule [7930026] Objective To evaluate the effects of HA-1A , a human monoclonal antiendotoxin antibody , in septic patients with ARDS . Design Sub study of a multicenter , double-blinded , placebo-controlled trial of HA-1A in septic patients . Patients 63 septic patients with ARDS at the time of study entry . InterventionA single intravenous injection of HA-1A ( 100 mg ) or placebo . Results A quantitative radiographic score , the PaO2/FIO2 ratio and an index of the severity of ARDS did not show a significant difference between the treatment and placebo groups at 3 , 5 and 7 days after treatment . The duration of endotracheal intubation did not differ between the two groups . 15 of 30 HA-1A treated patients ( 50 % ) and 23 of 33 placebo-treated patients ( 69.7 % ) died within 28 days . The daily mortality was always lower in the HA-1A group , but this difference was not statistically significant at 28 days . The 28-day survival curves for the two treatment groups adjusted by covariate analysis were not significantly different ( p=0.07 ) . Using logistic regression , a significant independent effect of HA-1A treatment was detected upon the early survival rate at 7 days ( p=0.03 ) but not at 14 and 28 days . Conclusion A single injection of HA-1A in septic patients with ARDS did not reverse acute respiratory failure or improve long-term survival [12576938] Objective To determine the safety and efficacy of filgrastim ( r-metHuG-CSF ) in combination with intravenous antibiotics to reduce the rate of mortality in patients with pneumonia and sepsis . Design This study was multicenter , double-blind , and r and omized . Setting Intensive care units Patients Adult patients with bacterial pneumonia , either acquired or nosocomial , as confirmed by chest radiograph and positive culture or Gram-negative stain , and severe sepsis , defined as sepsis-induced hypotension or organ dysfunction . Interventions St and ard antibiotic therapy with or without filgrastim ( 300 & mgr;g/day ) or placebo administered as a 30-min intravenous infusion . The study drug was started within 24 hrs of enrollment and was continued for 5 days or until the white blood cell count reached > 75.0 × 109 cells/L. Measurements and Main Results The primary end point was the occurrence of mortality through day 29 ; secondary end points included occurrence of subsequent organ dysfunction , time to discharge from intensive care unit , number of days on mechanical ventilatory support , and time to death . Study -related observations were recorded through day 10 and included vital signs , onset of organ dysfunction , clinical laboratory variables , and adverse events . Filgrastim increased the white blood cell count to a median peak of 31.7 × 109 cells/L from a baseline of 12.3 × 109 cells/L. The two groups were well matched and did not differ significantly with regard to severe adverse events , time to death , occurrence of end-organ dysfunction , days of intensive care unit hospitalization , or days on mechanical ventilatory support . Mortality was low in both treatment groups ; the mortality rate in patients with adult respiratory distress syndrome was similar between the two groups . Conclusions The addition of filgrastim to the antibiotic and supportive care treatment of patients with pneumonia complicated by severe sepsis appeared to be safe , but not efficacious in reducing mortality rates or complications from this infection [10439747] UNLABELLED Hydrogen peroxide ( H2O2 ) levels are increased in the exhaled breath of patients with the acute respiratory distress syndrome ( ARDS ) . Because liposome-encapsulated prostagl and in E1 ( PGE1 ) downregulates the CD11/CD18 receptor of the neutrophil , thereby limiting endothelial adhesion , the use of this drug should decrease the excretion of H2O2 in the expiratory condensate of patients with ARDS . Patients > 11 yr of age with ARDS ( diffuse , patchy infiltrates by chest radiograph ; Pao2/fraction of inspired oxygen [ P/F ] ratio < or = 200 mm Hg ; pulmonary capillary wedge pressure < or = 18 mm Hg ; and the requirement for mechanical ventilation ) were r and omized to receive placebo ( n = 14 ) or escalating doses ( 0.15 - 3.6 micrograms/kg ) of liposomal PGE1 ( n = 14 ) every 6 h for up to 7 days . Condensate was collected every morning from the expiratory tubing that was submerged in an ice saltwater bath ( -5 degrees C ) . H2O2 levels were measured by using a horseradish peroxidase assay . Other data collected included white blood cell count and P/F ratios . There was no significant difference in the concentration of H2O2 in the expiratory condensate between the liposomal PGE1 group and the control group either before ( 0.99 + /- 0.52 vs 0.93 + /- 0.48 mumol/L ) or during treatment ( 1.04 + /- 0.45 vs 0.76 + /- 0.25 mumol/L ) . Liposomal PGE1 treatment improved the P/F ratio and decreased the white blood cell count over time . Despite its ability to downregulate the CD11/CD18 neutrophil receptor , liposomal PGE1 did not reduce exhaled H2O2 excretion . IMPLICATION S White blood cells ( WBC ) are thought to be part of the cause of the acute respiratory distress syndrome , a lung disease . WBC in the lung produce hydrogen peroxide , which is exhaled . Liposomal PGE1 inhibits WBC function but was found to have no effect in decreasing exhaled hydrogen peroxide in patients with the acute respiratory distress syndrome [8156252] The inappropriate endogenous secretion of tumour necrosis factor ( TNF ) could play a role in the pathogenesis of acute respiratory distress syndrome ( ARDS ) , one of the most frequent causes of death in cancer patients . Because of its capacity to inhibit TNF secretion in vitro , pentoxifylline ( PTX ) could be extremely useful in ARDS therapy . In this study 30 advanced cancer patients with ARDS were r and omized to receive either the conventional care or conventional care plus PTX ( 100 mg i.v . twice a day for 7 days followed by an oral administration of 400 mg three times a day ) to evaluate the efficacy of PTX in reducing TNF serum levels and in improving the symptoms of this syndrome . Serum levels of TNF were measured before and after 7 days of therapy . The percentage of patients alive at 7 days was significantly higher in the PTX-treated group than in the controls ( 12/15 versus 3/15 ; P<0.001 ) . The mean survival time was significantly higher in the PTX-treated group than in the controls . A clinical and /or radiological improvement was obtained in 11/15 patients treated with PTX and in only 2/15 patients in the conventional care group ( P<0.01 ) . TNF mean levels significantly decrease in the PTX-treated group . These data confirm in vivo the capacity of PTX to inhibit TNF secretion in patients with ARDS . Moreover PTX therapy may improve the symptoms related to ARDS without particular toxic effects [9459113] PURPOSE Intravenous N-acetylcysteine ( NAC ) has been reported to improve systemic oxygenation and reduce the need for ventilatory support in patients with an acute lung injury . In the more serious form , namely established adult respiratory distress syndrome ( ARDS ) ( PaO2/FIO2 < or = 200 mm Hg ) , we tested the hypothesis that treatment with intravenous NAC may be beneficial . MATERIAL S AND METHODS Respiratory dysfunction was grade d daily according to the need for mechanical ventilation and FIO2 and to the evolution of the lung injury score ( LIS ) and the PaO2/FIO2 ratio in 42 patients with established ARDS receiving either NAC 190 mg/kg/day or placebo as a continuous intravenous infusion over the first 3 days of their clinical course . RESULTS NAC and placebo groups ( 22 and 20 patients , respectively ) were comparable for demographic characteristics , ARDS categories , severity of illness ( simplified acute physiology score [ SAPS II ] ) LIS and PaO2/FIO2 ratio . Mortality rate was 32 % for the NAC and 25 % for the placebo group ( difference not significant ) . At admission ( day 1 ) , 91 % of patients in the NAC and 95 % in the placebo group required ventilatory support ; at days 2 , 3 , 5 , and 7 after admission , the percentage of patients receiving ventilatory support was not significantly reduced for both groups in comparison with day 1 . Moreover , there were no differences between the two groups at the same observation days . In both groups , the FIO2 was significantly lower and the PaO2/FIO2 ratio was significantly higher than the initial values during the evolution ( FiO2 at day 3 , P < .01 for NAC and P < .05 for placebo ; PaO2/FIO2 at day 3 : P < .01 for NAC and P < .02 for placebo ) , but this improvement was similar for both groups and , moreover , the between-group comparison was never significantly different at the various collection days . The LIS decreased significantly in NAC group between days 1 and 3 ( 2.23 + /- 0.62 v 1.76 + /- 0.17 ; P < .05 ) , whereas no changes were observed in the placebo group ; at day 5 , there was a significant difference between the two groups ( 1.53 + /- 0.21 for the NAC v 2.15 + /- 0.19 for the placebo group ; P < .05 ) . In the prevalent sepsis category ( 10 patients in the NAC and 9 in the placebo group ) , the mortality rate , the need of ventilatory support , the intensive care unit stay , and the PaO2/FIO2 evolution did not differ significantly in both subgroups . CONCLUSIONS In this relatively small group of patients presenting with an established ARDS subsequent to a variety of underlying diseases , intravenous NAC treatment during 72 hours neither improved systemic oxygenation nor reduced the need for ventilatory support [10903215] Accumulating evidence strongly suggests that ventilatory strategy has an important impact on development of lung injury and patient outcome . Adverse ventilatory strategies have been shown to cause release of pulmonary-derived cytokines and may permit bacterial translocation from the lung to the systemic circulation . Because endotoxin is a potent and clinical ly important stimulant of cytokine-mediated systemic inflammatory responses that can lead to multiorgan failure , we investigated the effects of ventilatory strategy on lung-to-systemic translocation of endotoxin . We studied the effects of protective ( tidal volume [ VT ] 5 ml . kg(-)(1 ) , positive end-expiratory pressure [ PEEP ] 10 to 12.5 cm H(2)O ) versus nonprotective ( VT 12 ml . kg(-)(1 ) , PEEP zero ) ventilatory strategy on translocation of endotracheally instilled endotoxin . Anesthetized New Zeal and White rabbits were subjected to saline lung lavage , and 32 were r and omized to one of four groups : PS ( protective ventilation + instilled saline ) ; PE ( protective ventilation + instilled endotoxin ) ; NS ( nonprotective ventilation + instilled saline ) ; NE ( nonprotective ventilation + instilled endotoxin ) , and ventilated for 3 h. Plasma endotoxin levels increased significantly in the NE group , and remained low and unchanged in the other groups . Peak levels of plasma tumor necrosis factor-alpha ( TNF-alpha ) were higher in NE versus other groups . Pa(O(2 ) ) and mean arterial pressure ( Pa ) were lowest , and requirement for pressor and bicarbonate support greatest , in the NE group . Finally , plasma endotoxin levels were significantly greater in eventual nonsurvivors than survivors . These data provide convincing evidence for pulmonary translocation of lung-derived endotoxin . This translocation depends on ventilatory strategy , and suggests a pathophysiologic link between ventilatory strategy and outcome [11171733] STUDY OBJECTIVES Evaluate the safety of filgrastim ( recombinant methionyl human granulocyte colony-stimulating factor ) administration , combined with st and ard therapy , in patients with pneumonia and either septic shock or severe sepsis who were receiving mechanical ventilation . DESIGN Multicenter , double-blind , r and omized , placebo-controlled study . SETTING ICU , multicenter . PATIENTS Eighteen patients with pneumonia and hypotension , or in the absence of shock , two or more end-organ dysfunctions , were enrolled and treated . Baseline acute physiology and chronic health evaluation II scores and median age for the filgrastim ( n = 12 ) and placebo ( n = 6 ) groups were 25.0 and 49.5 years and 31.5 and 56.5 years , respectively . INTERVENTION Filgrastim ( 300 microg ) or placebo was administered IV daily for up to 5 days . MEASUREMENTS AND RESULTS Study end points included safety ; biological response , including endogenous cytokine levels , endotoxin levels , and neutrophil counts ; and mortality . Cytokine and endotoxin levels were highly variable in both groups . By day 29 , 3 of 12 filgrastim-treated patients and 4 of 6 placebo-treated patients had died . There were no differences in types and occurrences of adverse events , including ARDS , or in outcome between the two groups . Three of four placebo-treated patients had persistent bacterial growth on bronchoscopy repeated after 48 h compared with 2 of 10 filgrastim-treated patients . CONCLUSION Filgrastim appeared to be well tolerated in this population of patients with pneumonia and severe sepsis or septic shock . Larger studies to determine the benefit of filgrastim in patients with pneumonia and sepsis or organ dysfunction are warranted [9669790] CONTEXT No pharmacological therapeutic protocol has been found effective in modifying the clinical course of acute respiratory distress syndrome ( ARDS ) and mortality remains greater than 50 % . OBJECTIVE To determine the effects of prolonged methylprednisolone therapy on lung function and mortality in patients with unresolving ARDS . DESIGN R and omized , double-blind , placebo-controlled trial . SETTING Medical intensive care units of 4 medical centers . PARTICIPANTS Twenty-four patients with severe ARDS who had failed to improve lung injury score ( LIS ) by the seventh day of respiratory failure . INTERVENTIONS Sixteen patients received methylprednisolone and 8 received placebo . Methylprednisolone dose was initially 2 mg/kg per day and the duration of treatment was 32 days . Four patients whose LIS failed to improve by at least 1 point after 10 days of treatment were blindly crossed over to the alternative treatment . MAIN OUTCOME MEASURES Primary outcome measures were improvement in lung function and mortality . Secondary outcome measures were improvement in multiple organ dysfunction syndrome ( MODS ) and development of nosocomial infections . RESULTS Physiological characteristics at the onset of ARDS were similar in both groups . At study entry ( day 9 [ SD , 3 ] of ARDS ) , the 2 groups had similar LIS , ratios of PaO2 to fraction of inspired oxygen ( FIO2 ) , and MODS scores . Changes observed by study day 10 for methylprednisolone vs placebo were as follows : reduced LIS ( mean [ SEM ] , 1.7 [ 0.1 ] vs 3.0 [ 0.2 ] ; P<.001 ) ; improved ratio of PaO2 to FIO2 ( mean [ SEM ] , 262 [ 19 ] vs 148 [ 35 ] ; P<.001 ) ; decreased MODS score ( mean [ SEM ] , 0.7 [ 0.2 ] vs 1.8 [ 0.3 ] ; P<.001 ) ; and successful extubation ( 7 vs 0 ; P=.05 ) . For the treatment group vs the placebo group , mortality associated with the intensive care unit was 0 ( 0 % ) of 16 vs 5 ( 62 % ) of 8 ( P=.002 ) and hospital-associated mortality was 2 ( 12 % ) of 16 vs 5 ( 62 % ) of 8 ( P=.03 ) . The rate of infections per day of treatment was similar in both groups , and pneumonia was frequently detected in the absence of fever . CONCLUSIONS In this study , prolonged administration of methylprednisolone in patients with unresolving ARDS was associated with improvement in lung injury and MODS scores and reduced mortality [11685297] Abstract . Objective : To evaluate the safety of liposomal PGE1 ( TLC C-53 ) in patients with acute respiratory distress syndrome ( ARDS ) , and determine its efficacy in improving oxygenation and reducing ventilator dependency . Design : A multi-centre , r and omized , double-blind , placebo-controlled clinical study . Setting : Thirty-one hospitals in six European countries . Patients : One hundred two patients with ARDS . Interventions : Patients were r and omized in a 2:1 ratio to receive infusions of either the study drug TLC C-53 or placebo . Infusions were given over 60 min every 6 h for 7 days . The dose of study drug started at 0.6 µg/kg per h , rising over 24 h to a maximum dose of 1.8 µg/kg per h. Measurements and main results : Seventy patients received the study drug and 32 placebo . Sixty-nine patients ( 47 treatment , 22 placebo ) completed the study protocol . Patients were monitored for changes in the PaO2/FIO2 ratio , changes in lung compliance , time to off-ventilator and 28-day mortality , in addition to basic haematological and haemodynamic parameters . There were no significant differences in demographics and baseline characteristics between the two groups . There were no differences in the time to off-ventilation ( 16 days with treatment , 16.6 days with placebo , p=0.94 ) or in 28-day mortality ( 30 % with treatment , 28 % with placebo , p=0.78 ) . There was a difference in the time to achieve a PaO2/FIO2 ratio above 300 in favour of TLC C-53 ( 10.3 versus 26.5 days ) but this was not statistically significant ( p=0.23 ) . Conclusions : TLC C-53 was generally well-tolerated but failed to reduce mortality or duration of mechanical ventilation [7627383] BACKGROUND Experimental and clinical studies on the effect of octreotide in the treatment of patients with acute pancreatitis have presented controversial results . Since January 1992 , we have been conducting a prospect i ve r and omized study on the clinical effect of octreotide in severe acute pancreatitis , at three hospitals in Israel . STUDY DESIGN The entering criteria included three or more of the Ranson 's prognostic signs and computed tomographic findings of severe pancreatitis . Patients were r and omly assigned to conservative treatment either with or without octreotide ( 0.1 mg injected subcutaneously three times a day ) . The end points of the study included : complication rate ( adult respiratory distress syndrome [ ARDS ] , sepsis , renal failure , pseudocyst , fistula , and abscess ) , length of hospital stay , and mortality . RESULTS During the first two years ( from January 1992 to December 1993 ) , 51 patients entered the study . After evaluation , 13 patients were excluded due to failure to meet the entering criteria , incomplete data , or incorrect diagnosis . Of the remaining 38 patients , 19 were assigned to octreotide ( treatment group ) and 19 to conservative treatment alone ( control group ) . The two groups were matched with regard to age , sex , etiology , and severity of disease . The complication rate was lower in the treatment group compared with the control group with regard to sepsis ( 26 compared with 74 percent , p = 0.004 ) and ARDS ( 37 compared with 63 percent , p = 0.1 ) . The hospital stay was shorter in the treatment group compared with the control group ( 17.9 compared with 34.1 days , p = 0.02 ) . Death occurred in two patients in the treatment group and six patients in the control group . CONCLUSIONS Although some of the parameters did not reach statistical significance , these preliminary results suggest that octreotide may have a beneficial effect in the treatment of patients with severe acute pancreatitis . This study is scheduled to continue for two more years [11902249] Objective To determine whether the administration of lisofylline ( 1-[5R-hydroxyhexyl]-3,7-dimethylxanthine ) would decrease mortality in patients with acute lung injury ( ALI ) or acute respiratory distress syndrome ( ARDS ) . Design A prospect i ve , r and omized , double-blind , placebo-controlled , multicenter study . Setting Intensive care units at 21 hospitals at the ten centers constituting the ARDS Clinical Trials Network . Patients A total of 235 patients who met eligibility criteria were enrolled in the study ( 116 into the lisofylline group , 119 into the placebo group ) . Interventions Patients were r and omized to receive either lisofylline or placebo . The dose of lisofylline was 3 mg/kg with a maximum dose of 300 mg intravenously every 6 hrs . The intravenous solution of study drug was administered over 10 mins every 6 hrs . Dosing was continued for 20 days or until the patient achieved 48 hrs of unassisted breathing . Measurements and Main Results The trial was stopped by the Data Safety Monitoring Board for futility at the first scheduled interim analysis . The patient groups had similar characteristics at enrollment . No significant safety concerns were associated with lisofylline therapy . There was no significant difference between groups in the number of patients who had died at 28 days ( 31.9 % lisofylline vs. 24.7 % placebo , p = .215 ) . There was no significant difference between the lisofylline and placebo groups in terms of resolution of organ failures , ventilator-free days , infection-related deaths , or development of serious infection during the 28-day study period . The median number of organ failure – free days for the five nonpulmonary organ failures examined ( cardiovascular , central nervous system , coagulation , hepatic , and renal ) was not different between the lisofylline and placebo groups . Although lisofylline has been reported to decrease circulating free fatty acid levels , we did not find any such treatment effect compared with placebo . Conclusions In this study , there was no evidence that lisofylline had beneficial effects in the treatment of established ALI/ARDS [9847275] Because animal studies have demonstrated that mechanical ventilation at high volume and pressure can be deleterious to the lungs , limitation of airway pressure , allowing hypercapnia if necessary , is already used for ventilation of acute respiratory distress syndrome ( ARDS ) . Whether a systematic and more drastic reduction is necessary is debatable . A multicenter r and omized study was undertaken to compare a strategy aim ed at limiting the end-inspiratory plateau pressure to 25 cm H2O , using tidal volume ( VT ) below 10 ml/kg of body weight , versus a more conventional ventilatory approach ( with regard to current practice ) using VT at 10 ml/kg or above and close to normal PaCO2 . Both arms used a similar level of positive end-expiratory pressure . A total of 116 patients with ARDS and no organ failure other than the lung were enrolled over 32 mo in 25 centers . The two groups were similar at inclusion . Patients in the two arms were ventilated with different VT ( 7.1 + /- 1.3 versus 10.3 + /- 1.7 ml/kg at Day 1 , p < 0.001 ) and plateau pressures ( 25.7 + /- 5 . 0 versus 31.7 + /- 6.6 cm H2O at Day 1 , p < 0.001 ) , result ing in different PaCO2 ( 59.5 + /- 15.0 versus 41.3 + /- 7.6 mm Hg , p < 0.001 ) and pH ( 7.28 + /- 0.09 versus 7.4 + /- 0.09 , p < 0.001 ) , but a similar level of oxygenation . The new approach did not reduce mortality at Day 60 ( 46.6 % versus 37.9 % in control subjects , p = 0.38 ) , the duration of mechanical ventilation ( 23.1 + /- 20.2 versus 21.4 + /- 16 . 3 d , p = 0.85 ) , the incidence of pneumothorax ( 14 % versus 12 % , p = 0 . 78 ) , or the secondary occurrence of multiple organ failure ( 41 % versus 41 % , p = 1 ) . We conclude that no benefit could be observed with reduced VT titrated to reach plateau pressures around 25 cm H2O compared with a more conventional approach in which normocapnia was achieved with plateau pressures already below 35 cm H2O [11740262] OBJECTIVE To determine whether granulocyte colony-stimulating factor ( G-CSF ) administration changes leukocyte deformability result ing in lung injury in patients with sepsis . METHODS Twenty-five consecutive septic patients were divided r and omly into two groups . Twelve patients were given recombinant human G-CSF subcutaneously at 2 microg/kg once a day for 5 days ( group G ) . The remaining 13 patients were given sterilized saline as placebo ( group N ) . Leukocyte count ; concentrations of C-reactive protein ( CRP ) and thrombomodulin ( TM ) ; respiratory index ( RI ) and lung injury score ( LIS ) ; and APACHE II score and Goris MOF index were determined before and after G-CSF or placebo administration . Leukocyte deformability was observed in a microchannel array etched on a single-crystal silicon tip , which simulates the microvasculature . The number of microchannels obstructed ( NOM ) by stiffened leukocytes was counted . Transit time ( TT ) , that is , the time taken for 100 microL of whole blood to pass through the microchannel , was determined . RESULTS G-CSF administration significantly increased leukocyte count and decreased CRP concentration . In group G , both NOM and TT increased significantly 5 days after G-CSF administration ; they did not change in group N. However , RI , LIS , and TM did not change , suggesting that no patient developed lung injury . CONCLUSION G-CSF causes leukocyte stiffness but attenuates inflammatory response without inducing lung injury in septic patients [9105072] Lung surfactant is deficient in patients with acute respiratory distress syndrome ( ARDS ) . We performed a r and omized , prospect i ve , controlled , open-label clinical study of administration of a bovine surfactant to patients with ARDS to obtain preliminary information about its safety and efficacy . Patients received either surfactant by endotracheal instillation in addition to st and ard therapy or st and ard therapy only . Three different groups of patients receiving surfactant were studied : patients receiving up to eight doses of 50 mg phospholipids/kg , those receiving up to eight doses of 100 mg phospholipids/kg , and those receiving up to four doses of 100 mg phospholipids/kg . Outcome measures included ventilatory support parameters , arterial blood gases , organ system failures , bronchoalveolar lavage ( BAL ) analyses , immunologic analyses , survival , and adverse events during the 28-d study period . Fifty-nine study patients were evaluable ; 43 in the surfactant group and 16 in the control group . The FI(O2 ) at 120 h after treatment began was significantly decreased only for patients who received up to four doses of 100 mg phospholipids/kg surfactant as compared with control patients ( p = 0.011 ) . Mortality in the same group of patients was 18.8 % , as compared with 43.8 % in the control group ( p = 0.075 ) . The surfactant instillation was generally well tolerated , and no safety concerns were identified . This pilot study presents preliminary evidence that surfactant might have therapeutic benefit for patients with ARDS , and provides rationale for further clinical study of this agent [3516085] A 7-day infusion of prostagl and in E1 ( PGE1 ) , an immunomodulator , was evaluated in a prospect i ve , r and omized , placebo-controlled , double-blinded trial in surgical patients with the adult respiratory distress syndrome ( ARDS ) . The drug seemed to improve pulmonary function — only two PGE1 patients died with severe pulmonary failure compared with nine placebo patients ( p = 0.01 ) . Survival at 30 days after the end of the infusion— the predetermined end point of the study —was significantly better in the patients given PGE1 ( p = 0.03 ) , with 15 of 21 PGE1 patients ( 71 % ) alive at this time compared with seven of 20 placebo patients ( 35 % ) . Improvement in overall survival in the PGE , patients did not reach statistical significance ( p = 0.08 ) . Overall survival in patients initially free of severe organ failure , however , was significantly better in the PGE , patients ( p = 0.03 ) . Of the six PGE1 patients free of severe organ failure at time of entry , all survived to leave the hospital ; of the 10 placebo patients initially free of severe organ failure , four survived . The drug had no serious side effects and did not potentiate susceptibility to infection . PGE1 is a promising agent for the treatment of ARDS [3285017] Effective prophylaxis against acute respiratory failure ( ARDS ) has not been established . This study investigated whether or not ketoconazole could prevent ARDS in critically ill surgical patients . Seventy-one Surgical Intensive Care Unit ( SICU ) patients without liver dysfunction received either ketoconazole ( n = 35 ) , 200 mg daily via the gastrointestinal tract , or placebo ( n = 36 ) , for 21 days or until discharge from the SICU , in a prospect i ve , r and omized , double-blind study . Patients were monitored clinical ly for signs of ARDS , defined as all the following : intrapulmonary shunt greater than 15 % , a PaO2/FIO2 ratio less than 150 , normal central venous , pulmonary capillary wedge , or left atrial pressure , no other cause of hypoxemia , and a consistent chest X-ray . Thirteen patients ( 18 % ) developed ARDS with significantly increased mortality versus non-ARDS patients ( 69 % vs. 29 % ) . The incidence of ARDS was decreased among ketoconazole patients compared to placebo ( 6 % vs. 31 % ; p less than 0.01 ) , as was median SICU stay ( 7.0 days vs. 15.5 days ; p less than 0.05 ) , and median SICU cost ( + 5,600 . vs. + 12,400 . ; p less than 0.05 ) . Mortality is increased with ARDS after trauma and surgery . We conclude that ketoconazole prevents ARDS , shortens SICU stay , and lowers hospital costs [1569622] The effects of prostagl and in E1 ( PGE1 ) on non-pulmonary vital organs in critically ill patients are not well defined . This study evaluated the role of exogenous PGE1 in systemic homeostasis during the adult respiratory distress syndrome ( ARDS ) . Indicators of end-organ function were analyzed retrospectively in 146 septic or post-trauma patients with ARDS who received PGE1 ( 30/ng/kg/min ) or placebo IV for up to 7 days in a r and omized , double-blind clinical trial . Hemodynamic variables and serum levels of creatinine , bilirubin , and SGOT , platelet count , and changes in the white blood cell count were measured daily . Our results indicate that mean arterial pressure , pulmonary artery pressure , and systemic and pulmonary vascular resistance indices were significantly lower in the PGE1 group versus the placebo-treated group . Cardiac index , stroke index , and oxygen delivery index were significantly increased in the PGE1 group . Serum bilirubin and SGOT were decreased significantly among PGE1-treated patients compared with placebo-treated patients , while the white blood cell count increased more significantly from baseline values with PGE1 treatment . Intergroup differences in platelet count and serum creatinine levels were not statistically significant . The results indicate that PGE1 improves cardiovascular performance , hepatic function , and leukocyte availability during clinical ARDS . Prostagl and in E1 did not affect platelet counts and renal function in this study [11308438] CONTEXT When clinicians assess the validity of r and omized controlled trials ( RCTs ) , they commonly evaluate the blinding status of individuals in the RCT . The terminology authors often use to convey blinding status ( single , double , and triple blinding ) may be open to various interpretations . OBJECTIVE To determine physician interpretations and textbook definitions of RCT blinding terms . DESIGN AND SETTING Observational study undertaken at 3 Canadian university tertiary care centers between February and May 1999 . PARTICIPANTS Ninety-one internal medicine physicians who responded to a survey . MAIN OUTCOME MEASURES Respondents identified which of the following groups they thought were blinded in single- , double- , and triple-blinded RCTs : participants , health care providers , data collectors , judicial assessors of outcomes , data analysts , and personnel who write the article . Definitions from 25 systematic ally identified textbooks published since 1990 providing definitions for single , double , or triple blinding . RESULTS Physician respondents identified 10 , 17 , and 15 unique interpretations of single , double , and triple blinding , respectively , and textbooks provided 5 , 9 , and 7 different definitions of each . The frequencies of the most common physician interpretation and textbook definition were 75 % ( 95 % confidence interval [ CI ] , 65%-83 % ) and 74 % ( 95 % CI , 52%-90 % ) for single blinding , 38 % ( 95 % CI , 28%-49 % ) and 43 % ( 95 % CI , 24%-63 % ) for double blinding , and 18 % ( 95 % CI , 10%-28 % ) and 14 % ( 95 % CI , 0%-58 % ) for triple blinding , respectively . CONCLUSIONS Our study suggests that both physicians and textbooks vary greatly in their interpretations and definitions of single , double , and triple blinding . Explicit statements about the blinding status of specific groups involved in RCTs should replace the current ambiguous terminology [10638663] This study investigates the effects of N-acetylcysteine ( NAC ) and rutin on the lung oxidative burden of patients with early adult respiratory distress syndrome ( ARDS ) . The protection was evaluated by measuring expired ethane and malondialdehyde ( MDA ) , and oxidized ( GSSG ) and reduced glutathione ( GSH ) in the epithelial lining fluid of 36 patients who developed ARDS less than 24 hours before enrollment in the study . The patients were r and omly assigned to 3 groups , receiving 250 mL 5 % dextrose in water ( group 1 ) , NAC 50 mg/kg body weight in 5 % dextrose ( group 2 ) , and NAC 50 mg/kg + rutin 5 mg/kg in 5 % dextrose ( group 3 ) . Ethane and MDA concentrations were significantly reduced in the treatment groups after day 6 . GSH was 30 % increased in the treatment groups . No significant variations were observed in the control group until day 9 . The trial confirms that NAC and rutin are efficient in protecting the lungs of patients with ARDS [7933425] OBJECTIVE To evaluate the safety and potential efficacy of aerosolized surfactant in intubated patients with adult respiratory distress syndrome ( ARDS ) . DESIGN A prospect i ve , double-blind , placebo-controlled , r and omized , parallel , multicenter pilot clinical trial . PATIENTS A total of 51 patients with sepsis-induced ARDS were entered into the study within 18 hours of developing sepsis or sepsis syndrome . INTERVENTION Patients were r and omized into four treatment groups in a 2:1:2:1 ratio , as follows : 12 hours of surfactant per day , 12 hours of 0.6 % saline per day , 24 hours of surfactant per day , and 24 hours of 0.6 % saline per day . Surfactant or saline was aerosolized continuously for up to 5 days using an in-line nebulizer that aerosolized only during inspiration . MAIN OUTCOME MEASURES Ventilatory data , arterial blood gases , and hemodynamic parameters were measured at baseline , every 4 or 8 hours during the 5 days of treatment , 24 hours after treatment , and 30 days after treatment , at which time mortality was also assessed . Safety was evaluated throughout the 30 days of the study . RESULTS Surfactant was administered safely in ventilated patients when given continuously throughout the 5 days using the nebulizer system . Although there were no differences in any physiological parameters between the treatment groups , there was a dose-dependent trend in reduction of mortality from 47 % in the combined placebo group to 41 % and 35 % in the groups treated with 12 hours and 24 hours of surfactant per day , respectively . CONCLUSIONS Aerosolized surfactant was well tolerated when administered on a continuous basis for up to 5 days ; however , at the doses given , it did not result in significant improvements in patients with sepsis-induced ARDS [12119223] Granulocyte-macrophage colony-stimulating factor ( GM-CSF ) stimulates hemopoiesis and effector functions of granulocytes and macrophages and is involved in pulmonary surfactant homeostasis . We investigated whether GM-CSF therapy improved clinical ly diagnosed severe sepsis and respiratory dysfunction in critically ill patients . This r and omized , double-blind , placebo-controlled phase II study added low-dose ( 3 mcg/kg ) intravenous recombinant human GM-CSF daily for 5 days to conventional therapy in 10 patients , with a further eight patients receiving placebo . GM-CSF-treated patients showed improvement in Pa(O(2))/FI(O(2 ) ) over 5 days ( p = 0.02 ) and increased peripheral blood neutrophils ( p = 0.08 ) , whereas alveolar neutrophils decreased ( p = 0.02 ) . GM-CSF therapy was not associated with decreased 30-day survival or with increased acute respiratory distress syndrome or extrapulmonary organ dysfunction . GM-CSF therapy was associated with increased blood granulocyte superoxide production and restoration or preservation of blood and alveolar leukocyte phagocytic function . We conclude that low-dose GM-CSF was associated with improved gas exchange without pulmonary neutrophil infiltration , despite functional activation of both circulating neutrophils and pulmonary phagocytes . In addition , GM-CSF therapy was not associated with worsened acute respiratory distress syndrome or the multiple organ dysfunction syndrome , suggesting a homeostatic role for GM-CSF in sepsis-related pulmonary dysfunction [9781722] OBJECTIVE To study the effects of surfactant administration on the left lung after surgical repair of descending aortic aneurysms on postoperative respiratory failure . DESIGN R and omized , prospect i ve , controlled study . SETTING Clinical investigation . PATIENTS Eleven patients with respiratory failure associated with thoracic aneurysm surgery . INTERVENTION Eleven adult patients with acute respiratory failure ( PaO2/FIO2 < 300 torr [ < 40 kPa ] ) after surgical repair of descending aortic aneurysms . The artificial surfactant ( 30 mg/kg ) was given to the operated side of the lung by intrabronchial instillation in six patients ( surfactant group ) , whereas nothing was instilled in the other five patients ( control group ) . MEASUREMENTS AND MAIN RESULTS Hemodynamic parameters , blood gas , and peak inspiratory pressure were measured at the end of surgery , before surfactant instillation , and at 2 , 6 , 12 , 24 , and 48 hrs after surfactant instillation . At the end of surgery , the mean + /- SEM values of the PaO2/FIO2 ratio were 204 + /- 25 torr ( 27.2 + /- 3.3 kPa ) in the surfactant group and 240 + /- 26 torr ( 32.0 + /- 3.5 kPa ) in the control group . After 2 , 6 , 12 , and 48 hrs , improvements in the PaO2/FIO2 ratios were observed in the surfactant group , whereas the control group showed no improvement . Two hours after surfactant instillation , the mean value in the PaO2/FIO2 ratio was significantly higher in the surfactant group ( 318 + /- 24 torr [ 42.4 + /- 3.2 kPa ] ) ( p < .05 ) compared with the control group values ( 240 + /- 34 torr [ 32 + /- 4.5 kPa ] ) . CONCLUSION Surfactant administration immediately after surgery restored gas exchange in postoperative respiratory failure associated with thoracic aneurysm surgery [3315478] From November 1 , 1982 through December 31 , 1985 , there were 19 centers and 382 patients that evaluated the effect of methylprednisolone sodium succinate ( MPSS ) on the septic syndrome . Seventeen of these centers enrolled 304 patients in a prospect i ve , r and omized , double-blind , placebo-controlled study to determine if early treatment with MPSS would decrease the incidence of severity of the adult respiratory distress syndrome ( ARDS ) in patients at risk of ARDS from sepsis . To ensure early institution of the MPSS or placebo therapy ( PLA ) , patients with the presumptive diagnosis of sepsis were identified . That diagnosis was based on the presence of fever or hypothermia ( temperature greater than 38.3 degrees C or less than 35.5 degrees C , rectal ) , tachypnea ( greater than 20 bpm ) , tachycardia ( greater than 90 bpm ) and the presence of one of the following indices of organ dysfunction : a change in mental status , hypoxemia , elevated lactate levels or oliguria . The treatment , either MPSS 30 mg/kg or PLA , was given in four 20-minute infusions six hours apart and was initiated within two hours of the presumptive diagnosis of sepsis . The development and reversal of the adult respiratory distress syndrome ( ARDS ) was followed and result ed in data on 304 of the 382 r and omized patients . A trend toward increased incidence of ARDS was seen in the MPSS group 50/152 ( 32 percent ) compared to the placebo group 38/152(25 percent ) p = 0.10 . Significantly fewer MPSS patients reversed their ARDS 15/50 ( 31 percent ) compared to placebo 23/38 ( 61 percent ) p = 0.005 . The 14-day mortality in patients with ARDS treated with MPSS was 26/50 ( 52 percent ) compared to placebo 8/22 ( 22 percent ) p = 0.004 . We conclude that early treatment of septic syndrome with MPSS does not prevent the development of ARDS . Additionally , MPSS treatment impedes the reversal of ARDS and increases the mortality rate in patients with ARDS [10501747] Background : Despite intensive research , there are no universally accepted clinical definitions for acute lung injury ( ALI ) or the acute respiratory distress syndrome ( ARDS ) . A recent joint American-European Consensus Conference on ARDS formally defined the difference between ALI and ARDS based on the degree of oxygenation impairment . However , this definition may not reflect the true prevalence , severity and prognosis of these syndromes . Methods : During a 22-month period , 56 consecutive mechanically ventilated patients who met the American-European Consensus definition for ARDS [ arterial oxygen tension/fractional inspired oxygen ( PaO2/FIO2≤ 200 mmHg regardless of the level of positive end-expiratory pressure ( PEEP ) , bilateral pulmonary infiltrates , and no evidence of left heart failure ] were admitted into the intensive care units ( ICU ) of the Hospital del Pino , Las Palmas , Spain , and prospect ively studied . The diagnosis of ALI and ARDS was made by a PEEP-FIO2 trial , 24 h after patients met the Consensus inclusion criteria . Patients were classified as having ALI–24 h if the PaO2/FIO2 was > 150 mmHg with PEEP = 5 cmH2O , and ARDS–24 h if the PaO2 /FIO2 was ≤ 150 mmHg with PEEP ≥ 5 cmH2O . Results : Overall mortality was 43 % ( 24 of 56 ) . However , 24 h after inclusion , PaO2 response to PEEP 5 cmH2O allowed the separation of our patients into two different groups : 31 patients met our ALI–24 h criteria ( PaO2/FIO2 > 150 mmHg ) and their mortality was 22.6 % ; 25 patients met our ARDS–24 h criteria ( PaO2/FIO2≤ 150 mmHg ) and their mortality was 68 % ( p = 0.0016 ) . The differences in the respiratory severity index during the first 24 h of inclusion , PaO2/FIO2 ratio at baseline and at 24 h , maximum plateau airway pressure , maximum level of PEEP , and number of organ system failures during the ICU stay were statistically significant . Conclusions : Since the use of PEEP in the American-European Consensus criteria for ARDS is not m and atory , that definition does not reflect the true severity of lung damage and outcome . Our data support the need for guidelines based on a specific method of evaluating oxygenation status before the American-European Consensus definition is adopted [3202402] We conducted a prospect i ve , r and omized , double-blind study to determine whether high-dose methylprednisolone could prevent parenchymal lung injury , including the adult respiratory distress syndrome ( ARDS ) , or improve mortality when administered early in septic shock . All patients already hospitalized in or newly admitted to the medical and surgical intensive care units at San Francisco General Hospital between September 1 , 1983 and August 29 , 1986 were eligible for admission to the study if they had either ( 1 ) an increase in temperature of 1.5 degrees C and a decrease in systolic blood pressure of 20 mm Hg or more from baseline values ( in already hospitalized patients ) , or ( 2 ) a temperature greater than 38.5 degrees C or less than 35.5 degrees C and a systolic blood pressure of less than 90 mm Hg ( in newly admitted patients ) . Patients meeting these criteria were excluded if they ( 1 ) had severe immunodeficiency , ( 2 ) were less than 18 or greater than 76 yr of age , ( 3 ) had multilobar roentgenographic infiltrates , or ( 4 ) were already receiving corticosteroids . Eighty-seven patients enrolled in the study received either methylprednisolone , 30 mg/kg per dose , or mannitol placebo for a total of 4 doses every 6 h , following the presumptive diagnosis of septic shock . Of these patients , 75 ultimately were determined on the basis of culture results to have actually had septic shock at the time of entry . Thirteen of the patients who received methylprednisolone developed ARDS , compared to 14 patients who received placebo . Lesser degrees of parenchymal lung injury did not differ between the 2 groups . ( ABSTRACT TRUNCATED AT 250 WORDS [2278610] The adult respiratory distress syndrome ( ARDS ) , often referred to as non-cardiac pulmonary oedema , is now regarded as a very complicated inflammatory process with oedema being only one facet . In recognition of this , pharmacologic therapy with anti-inflammatory corticosteroids was used widely until the completion of r and omized clinical trials . Unfortunately , corticosteroids have not been proved to be useful in preventing ARDS in septic patients nor in patients with established ARDS and this has led to investigations with pharmacologic agents which are safer and more specifically targeted to certain parts of the inflammatory process . We have examined the role of the glutathione anti-oxidant system in the sheep model of ARDS as well as in patients with established ARDS through use of intravenous N-acetylcysteine ( NAC ) . We have found that the response to endotoxin is markedly blunted in sheep treated with NAC . In our controlled clinical trials with NAC we found that patients with ARDS have depressed plasma and red cell glutathione concentrations , that these levels are substantially increased by therapy with intravenous NAC and there are measurable clinical responses to treatment with regard to increased oxygen delivery , improved lung compliance and resolution of pulmonary oedema [9070471] BACKGROUND In patients with sepsis the production of arachidonic acid metabolites by cyclooxygenase increases , but the pathophysiologic role of these prostagl and ins is unclear . In animal models , inhibition of cyclooxygenase by treatment with ibuprofen before the onset of sepsis reduces physiologic abnormalities and improves survival . In pilot studies of patients with sepsis , treatment with ibuprofen led to improvements in gas exchange and airway mechanics . METHODS From October 1989 to March 1995 , we conducted a r and omized , double-blind , placebo-controlled trial of intravenous ibuprofen ( 10 mg per kilogram of body weight [ maximal dose , 800 mg ] , given every six hours for eight doses ) in 455 patients who had sepsis , defined as fever , tachycardia , tachypnea , and acute failure of at least one organ system . RESULTS In the ibuprofen group , but not the placebo group , there were significant declines in urinary levels of prostacyclin and thromboxane , temperature , heart rate , oxygen consumption , and lactic acidosis . With ibuprofen therapy there was no increased incidence of renal dysfunction , gastrointestinal bleeding , or other adverse events . However , treatment with ibuprofen did not reduce the incidence or duration of shock or the acute respiratory distress syndrome and did not significantly improve the rate of survival at 30 days ( mortality , 37 percent with ibuprofen vs 40 percent with placebo ) . CONCLUSIONS In patients with sepsis , treatment with ibuprofen reduces levels of prostacyclin and thromboxane and decreases fever , tachycardia , oxygen consumption , and lactic acidosis , but it does not prevent the development of shock or the acute respiratory distress syndrome and does not improve survival [10470755] OBJECTIVE To assess the safety and potential efficacy of a mechanical ventilation strategy design ed to reduce stretch-induced lung injury in acute respiratory distress syndrome . DESIGN Prospect i ve , r and omized , controlled clinical trial . SETTING Eight intensive care units in four teaching hospitals . PATIENTS Fifty-two patients with acute respiratory distress syndrome . INTERVENTIONS Traditional tidal volume patients : tidal volume 10 - 12 mL/kg ideal body weight , reduced if inspiratory plateau pressure was > 55 cm H2O ( 7.3 kPa ) . Small tidal volume patients : tidal volume 5 - 8 mL/kg ideal body weight , to keep plateau pressure < 30 cm H2O ( 4.0 kPa ) . MEASUREMENTS AND MAIN RESULTS Mean tidal volumes during the first 5 days in traditional and small tidal volume patients were 10.2 and 7.3 mL/kg , respectively ( p < .001 ) , with mean plateau pressure = 30.6 and 24.9 cm H2O ( 3.3 kPa ) , respectively ( p < .001 ) . There were no significant differences in requirements for positive end-expiratory pressure or FIO2 , fluid intakes/outputs , requirements for vasopressors , sedatives , or neuromuscular blocking agents , percentage of patients that achieved unassisted breathing , ventilator days , or mortality . CONCLUSIONS The reduced tidal volume strategy used in this study was safe . Failure to observe beneficial effects of small tidal volume ventilation treatment in important clinical outcome variables may have occurred because a ) the sample size was too small to discern small treatment effects ; b ) the differences in tidal volumes and plateau pressures were modest ; or c ) reduced tidal volume ventilation is not beneficial [8618579] BACKGROUND Patients with acute respiratory distress syndrome ( ARDS ) have a deficiency of surfactant . Surfactant replacement improves physiologic function in such patients , and preliminary data suggest that it may improve survival . METHODS We conducted a prospect i ve , multicenter , double-blind , r and omized , placebo-controlled trial involving 725 patients with sepsis-induced ARDS . Patients were stratified according to the risk of death at base line ( indicated by their score on the Acute Physiological and Chronic Health Evaluation [ APACHE III ] index ) and r and omly assigned to receive either continuously administered synthetic surfactant ( 13.5 mg of dipalmitoylphosphatidylcholine per milliliter , 364 patients ) or placebo ( o.45 percent saline ; 361 patients ) in aerosolized form for up to five days . RESULTS The demographic and physiologic characteristics of the two treatment groups were similar at base line . The mean ( + /- SD ) age was 50 + /- 17 years in the surfactant group and 53 + /- 18 years in the placebo group , and the mean APACHE III scores at r and omization were 70.4 + /- 25 and 70.5 + /- 25 , respectively . Hemodynamic measures , measures of oxygenation , duration of mechanical ventilation , and length of stay in intensive care unit did not differ significantly in the two groups . Survival at 30 days was 60 percent for both groups . Survival was similar in the groups when analyzed according to APACHE III score , cause of death , time of onset and severity of ARDS , presence or absence of documented sepsis , underlying disease , whether or not there was a do-not-resuscitate order , and medical center . Increased secretions were significantly more frequent in the surfactant group ; the rates of other complications were similar in the two groups . CONCLUSIONS The continuous administration of aerosolized synthetic surfactant to patients with sepsis-induced ARDS had no significant effect on 30-day survival , length of stay in the intensive care unit , duration of mechanical ventilation , or physiologic function [1952438] Arachidonic acid metabolites , especially thromboxane-A2 and prostacyclin , have been shown to be increased in experimental models of sepsis and the adult respiratory distress syndrome ( ARDS ) and play a major pathophysiologic role . This study was design ed to determine if these metabolites are increased in human sepsis syndrome and if inhibition of fatty acid cyclooxygenase affects their formation and their pathophysiologic sequelae . We conducted a double-blind , placebo-controlled trial of ibuprofen ( 800 mg given rectally every 4 h for three doses ) in 30 patients with sepsis syndrome defined by abnormal vital signs , the appearance of serious infection , and at least one major organ failure . Urinary concentrations of the metabolite of thromboxane-A2 , 2,3-dinor-TxB2 , and prostacyclin , 2,3-dinor-6-keto-prostagl and in F2 alpha , were elevated 10 to 20 times normal and declined to four to five times normal by 12 h after entry in the ibuprofen-treated group and remained elevated in the placebo-treated patients . The urinary concentration of TxB2 and 6-keto-prostagl and in F1 alpha , which reflect renal production of TxA2 and prostacyclin , respectively , were also increased approximately 10-fold over normal and were subsequently decreased by ibuprofen . Coincident with the reduction in metabolite levels , the ibuprofen-treated group , but not the placebo-treated group , experienced a significant decline in temperature , heart rate , and peak airway pressure , and a trend towards more rapid reversal of shock ( p = 0.12 ) . ( ABSTRACT TRUNCATED AT 250 WORDS [9449727] BACKGROUND In patients with the acute respiratory distress syndrome , massive alveolar collapse and cyclic lung reopening and overdistention during mechanical ventilation may perpetuate alveolar injury . We determined whether a ventilatory strategy design ed to minimize such lung injuries could reduce not only pulmonary complications but also mortality at 28 days in patients with the acute respiratory distress syndrome . METHODS We r and omly assigned 53 patients with early acute respiratory distress syndrome ( including 28 described previously ) , all of whom were receiving identical hemodynamic and general support , to conventional or protective mechanical ventilation . Conventional ventilation was based on the strategy of maintaining the lowest positive end-expiratory pressure ( PEEP ) for acceptable oxygenation , with a tidal volume of 12 ml per kilogram of body weight and normal arterial carbon dioxide levels ( 35 to 38 mm Hg ) . Protective ventilation involved end-expiratory pressures above the lower inflection point on the static pressure-volume curve , a tidal volume of less than 6 ml per kilogram , driving pressures of less than 20 cm of water above the PEEP value , permissive hypercapnia , and preferential use of pressure-limited ventilatory modes . RESULTS After 28 days , 11 of 29 patients ( 38 percent ) in the protective-ventilation group had died , as compared with 17 of 24 ( 71 percent ) in the conventional-ventilation group ( P<0.001 ) . The rates of weaning from mechanical ventilation were 66 percent in the protective-ventilation group and 29 percent in the conventional-ventilation group ( P=0.005 ) : the rates of clinical barotrauma were 7 percent and 42 percent , respectively ( P=0.02 ) , despite the use of higher PEEP and mean airway pressures in the protective-ventilation group . The difference in survival to hospital discharge was not significant ; 13 of 29 patients ( 45 percent ) in the protective-ventilation group died in the hospital , as compared with 17 of 24 in the conventional-ventilation group ( 71 percent , P=0.37 ) . CONCLUSIONS As compared with conventional ventilation , the protective strategy was associated with improved survival at 28 days , a higher rate of weaning from mechanical ventilation , and a lower rate of barotrauma in patients with the acute respiratory distress syndrome . Protective ventilation was not associated with a higher rate of survival to hospital discharge [7774238] OBJECTIVE To evaluate the safety and efficacy of E5 , a murine , monoclonal antibody directed against endotoxin , in the treatment of patients with Gram-negative sepsis . DESIGN A multicenter , r and omized , double-blind , placebo-controlled trial . SETTING Fifty-three hospitals across the United States , including university medical centers , Veterans Affairs Medical Centers , and community hospitals . PATIENTS 847 patients were r and omized into this study . Enrolled patients met criteria for three conditions : a ) known or suspected Gram-negative infection ; b ) clinical evidence of sepsis ; and c ) signs of end-organ dysfunction . Patients with refractory shock were excluded from the study . INTERVENTIONS Two doses of E5 ( 2 mg/kg/day by intravenous infusion 24 hrs apart ) , or placebo that was identical in appearance were administered . In addition , all patients received st and ard supportive therapy and broad-spectrum antibiotics . MEASUREMENTS AND MAIN RESULTS The primary end point was mortality over 30 days . Secondary outcome measures included the resolution and prevention of organ failure in the same two population s. Additionally , the safety of E5 was evaluated . There was no significant improvement in survival over 30 days among patients with Gram-negative sepsis who received E5 compared with those patients who received placebo ( n = 530 ; p = .21 ) . In addition , E5 did not improve survival for patients with Gram-negative sepsis and organ failure ( n = 139 ; p = .3 ) . However , a significantly greater percentage of patients with Gram-negative sepsis experienced resolution of major organ failure if they received E5 , compared with those patients who received placebo ( n = 139 ; 48 % E5 vs. 25 % placebo ; p = .005 ) . This result extended to all patients who entered the study with one or more major organ failures , regardless of the etiology of the infection ( n = 225 ; 41 % E5 vs. 27 % placebo ; p = .024 ) . E5 also provided protection against the development of some organ failures , but significant prevention was only observed for adult respiratory distress syndrome ( p = .007 ) and central nervous system dysfunction ( p = .050 ) . Hypersensitivity reactions attributable to E5 occurred in 2.6 % of patients . An asymptomatic antibody response occurred in 44 % of the E5-treated patients and in 12 % of the patients who received placebo . CONCLUSIONS In this study , E5 did not reduce mortality in nonshock patients with Gram-negative sepsis whether or not those patients also had organ failure . However , E5 did result in greater resolution of organ failure in patients with Gram-negative sepsis . This benefit extended to those patients with suspected Gram-negative etiology . This finding is important because patients with suspected Gram-negative sepsis and organ failure can be identified without waiting for culture results . In addition , E5 result ed in the prevention of adult respiratory distress syndrome and central nervous system organ failure . However , more studies are needed to determine if this result can be extended to organ failure in general . E5 is safe as a treatment for patients with Gram-negative sepsis [12163791] Objective Trials of potential new therapies in acute lung injury are difficult and expensive to conduct . This article is design ed to determine the utility , behavior , and statistical properties of a new primary end point for such trials , ventilator-free days , defined as days alive and free from mechanical ventilation . Describing the nuances of this outcome measure is particularly important because using it , while ignoring mortality , could result in misleading conclusions . Design To develop a model for the duration of ventilation and mortality and fit the model by using data from a recently completed clinical trial . To determine the appropriate test statistic for the new measure and derive a formula for power . To determine a formula for the probability that the test statistic will reject the null hypothesis and mortality will simultaneously show improvement . To plot power curves for the test statistic and determine sample sizes for reasonable alternative hypotheses . Setting Intensive care units . Patients Patients with acute respiratory distress syndrome or acute lung injury as defined by the American-European Consensus Conference . Main Results The proposed model fit the clinical data . Ventilator-free days were improved by lower tidal volume ventilation , but the improvement was mostly caused by the improved mortality rate , so trials that expected similar effects would only have modest increase in power if they used ventilator-free days as their primary end point rather than 28-day mortality . Similar results were obtained using the model in two groups segregated by low or high Acute Physiology and Chronic Health Evaluation score . On the other h and , if patients are divided into two groups on the basis of the lung injury score , both the duration of ventilation and mortality are lower in the low lung injury score group . A trial of a treatment that had a similar clinical effect would have a large increase in power , allowing for a reduction in the required sample size . Conclusions Use of ventilator-free days as a trial end point allows smaller sample sizes if it is assumed that the treatment being tested simultaneously reduces the duration of ventilation and improves mortality . It is unlikely that a treatment that led to higher mortality could lead to a statistically significant improvement in ventilator-free days . This would be especially true if the treatment were also required to produce a nominal improvement in mortality [2350875] The purpose of this investigation was to evaluate the magnitude and duration of changes in lung function and oxygen transport in patients with adult respiratory distress syndrome ( ARDS ) receiving indomethacin . Ten patients with ARDS were r and omized to receive intravenously either a single 50 mg dose of indomethacin or placebo . Comparing 1 hr postinfusion levels to baseline observations in the indomethacin group , PaO2 increased to 125 + /- 13 torr from 93 + /- 8 torr , PaO2/FIO2 ratio increased to 223 + /- 24 from 160 + /- 5 , and Qs/Qt dropped to 0.20 + /- 0.03 from 0.27 + /- 0.03 ( all P less than 0.05 ) . These alterations in oxygenation gradually returned to baseline levels over the ensuing 8 hr . No such changes were noted in the placebo group [10470753] OBJECTIVE To evaluate the safety and efficacy of an intravenous liposomal dispersion of prostagl and in E1 as TLC C-53 in the treatment of patients with acute respiratory distress syndrome ( ARDS ) . DESIGN R and omized , prospect i ve , multicenter , double-blind , placebo-controlled , phase III clinical trial . SETTING Forty-seven community and university-affiliated hospitals in the United States . PATIENTS A total of 350 patients with ARDS were enrolled in this clinical trial . INTERVENTION Patients were prospect ively r and omized in a 1:1 ratio to receive either liposomal prostagl and in E1 or placebo . The study drug was infused intravenously for 60 mins every 6 hrs for 7 days starting with a dosage of 0.15 microg/kg/hr . The dose was increased every 12 hrs until the maximal dose ( 3.6 microg/kg/hr ) was attained or intolerance to further increases developed . Patients received st and ard aggressive medical/surgical care during the infusion period . OUTCOME MEASURES The primary outcome measure was the time it took to wean the patient from the ventilator . Secondary end points included time to improvement of the PaO2/FIO2 ratio ( defined as first PaO2/FIO2 > 300 mm Hg ) , day 28 mortality , ventilator dependence at day 8 , changes in PaO2/FIO2 , incidence of and time to development/resolution of organ failure other than ARDS . RESULTS A total of 348 patients could be evaluated for efficacy . The distribution of variables at baseline describing gender , lung injury scores , Acute Physiology and Chronic Health Evaluation II scores , PaO2/FIO2 , pulmonary compliance , and time from onset of ARDS or from institution of mechanical ventilation to the first dose of study drug was similar among patients in the liposomal prostagl and in E1 ( n = 177 ) and the placebo ( n = 171 ) treatment arms . There was no significant difference in the number of days to the discontinuation of ventilation in the liposomal prostagl and in E1 group compared with the placebo group ( median number of days to off mechanical ventilation , 16.9 in patients receiving liposomal prostagl and in E1 and 19.6 in those administered placebo ; p = .94 ) . Similarly , mortality at day 28 was not significantly different in the two groups ( day 28 mortality , 57 of 176 ( 32 % ) in the liposomal prostagl and in E1 group and 50 of 170 ( 29 % ) in patients receiving placebo ; p = .55 ) . In contrast , treatment with liposomal prostagl and in E1 was associated with a significantly shorter time to reach a PaO2/FIO2 ratio of > 300 mm Hg ( median number of days to reaching a PaO2/FIO2 ratio > 300 mm Hg : 9.8 days in the liposomal prostagl and in E1 group and 13.7 days in patients receiving the placebo ; p = .02 ) . Among the subgroups examined , time to off mechanical ventilation was significantly reduced in patients who received at least 85 % of a full dose ( i.e. , > 45.9 microg/kg ) of liposomal prostagl and in E1 ( median number of days to discontinuation of ventilation , 10.3 in the liposomal prostagl and in E1 group and 16.3 days in patients receiving placebo ; p = .05 ) . The overall incidence of serious adverse events was not significantly different in the liposomal prostagl and in E1 ( 40 % ) or placebo-treated ( 37 % ) groups . Drug-related adverse events of all kinds were reported in 69 % of the patients receiving liposomal prostagl and in E1 compared with 33 % of the placebo group , with hypotension and hypoxia ( occurring in 52 % and 24 % of the liposomal prostagl and in E1-treated patients , respectively , and 17 % and 5 % of the placebo-treated patients , respectively ) being noted most frequently . CONCLUSIONS In the intent-to-treat population of patients with ARDS , treatment with liposomal prostagl and in E1 accelerated improvement in indexes of oxygenation but did not decrease the duration of mechanical ventilation and did not improve day 28 survival [2306970] Because PGE1 previously has been reported to increase survival of patients with ARDS , we evaluated physiologic effects and side effects of PGE1 in a prospect i ve open-label study of patients with ARDS . Seventeen patients with ARDS who did not have significant renal or hepatic dysfunction received PGE1 by continuous central venous infusion ( 30 ng/kg/min ) . Seventeen control patients with ARDS without renal or hepatic dysfunction who had similar APACHE II and ARDS scores and causes of ARDS did not receive PGE1 . Prostagl and in E1 significantly decreased the SVRI and oxygen extraction ratio . Concentrations of total and polymorphonuclear leukocytes , but not platelets , increased significantly during PGE1 infusion , but did not change in control patients . There was no change in the Do2I and Vo2I during the course of the PGE1 infusion . There were no differences in Do2I and Vo2I during PGE1 infusion between survivors and nonsurvivors . Prostagl and in E1 was infused for a mean of 5.9 + /- 1.8 days ( + /- SD ) and was discontinued on ten occasions in seven patients because of supraventricular dysrhythmias ( n = 4 ) , hypotension ( n = 3 ) , thrombocytopenia ( n = 3 ) , and cardiac arrest ( n = 2 ) . Nonsurvivors had PGE1 discontinued prematurely more frequently than survivors ( 56 percent [ 5/9 ] vs 25 percent [ 2/8 ] , respectively ) . The prevalence of multiple-system organ failure and the in-hospital mortality of both PGE1-treated and control patients were not different . Although PGE1 causes significant systemic vasodilation and possibly decreased intrapulmonary polymorphonuclear leukocyte sequestration , PGE1 does not influence multiple-system organ failure or mortality of patients with ARDS without renal or hepatic dysfunction [9449728] BACKGROUND A strategy of mechanical ventilation that limits airway pressure and tidal volume while permitting hypercapnia has been recommended for patients with the acute respiratory distress syndrome . The goal is to reduce lung injury due to overdistention . However , the efficacy of this approach has not been established . METHODS Within 24 hours of intubation , patients at high risk for the acute respiratory distress syndrome were r and omly assigned to either pressure- and volume-limited ventilation ( limited-ventilation group ) , with the peak inspiratory pressure maintained at 30 cm of water or less and the tidal volume at 8 ml per kilogram of body weight or less , or to conventional ventilation ( control group ) , with the peak inspiratory pressure allowed to rise as high as 50 cm of water and the tidal volume at 10 to 15 ml per kilogram . All other ventilatory variables were similar in the two groups . RESULTS A total of 120 patients with similar clinical features underwent r and omization ( 60 in each group ) . The patients in the limited-ventilation and control groups were exposed to different mean ( + /-SD ) tidal volumes ( 7.2+/-0.8 vs. 10.8+/-1.0 ml per kilogram , respectively ; P<0.001 ) and peak inspiratory pressures ( 23.6+/-5.8 vs. 34.0+/-11.0 cm of water , P<0.001 ) . Mortality was 50 percent in the limited-ventilation group and 47 percent in the control group ( relative risk , 1.07 ; 95 percent confidence interval , 0.72 to 1.57 ; P=0.72 ) . In the limited-ventilation group , permissive hypercapnia ( arterial carbon dioxide tension , > 50 mm Hg ) was more common ( 52 percent vs. 28 percent , P=0.009 ) , more marked ( 54.4+/-18.8 vs. 45.7+/-9.8 mm Hg , P=0.002 ) , and more prolonged ( 146+/-265 vs. 25+/-22 hours , P=0.017 ) than in the control group . The incidence of barotrauma , the highest multiple-organ-dysfunction score , and the number of episodes of organ failure were similar in the two groups ; however , the numbers of patients who required paralytic agents ( 23 vs. 13 , P=0.05 ) and dialysis for renal failure ( 13 vs. 5 , P= 0.04 ) were greater in the limited-ventilation group than in the control group . CONCLUSIONS In patients at high risk for the acute respiratory distress syndrome , a strategy of mechanical ventilation that limits peak inspiratory pressure and tidal volume does not appear to reduce mortality and may increase morbidity [8365305] BACKGROUND Septic shock is frequently complicated by a syndrome of disseminated intravascular coagulation ( DIC ) . Numerous uncontrolled clinical studies have reported that antithrombin III ( ATIII ) substitution might prevent DIC and death in septic shock . METHODS We conducted a r and omized double-blind placebo-controlled trial in patients with a documented septic shock and DIC . The patients received either a placebo or ATIII ( 90 to 120 IU/kg in loading dose , then 90 to 120 IU/kg/d during 4 days ) . Administration of fresh frozen plasma , platelets , and fibrinogen concentrates was restricted to patients with hemorrhages and severe decreases in prothrombin time , platelet count , and fibrinogen levels . RESULTS Thirty-five patients entered the study ( 18 placebo , 17 ATIII ) . Both groups were well balanced for all demographic , hemodynamic , and biologic data . Three patients were excluded before the treatment allocation code was broken . In the ATIII group , ATIII levels were rapidly corrected and remained over normal levels until day 10 ; sequential protein C and protein S levels were not modified . The duration of DIC was significantly reduced : in the ATIII group , 64 percent of patients were cured of DIC at day 2 , and 71 percent were cured at the end of treatment vs in the placebo group , 11 percent ( p < 0.01 ) and 33 percent ( p < 0.05 ) , respectively . In the 32 included patients , the mortality in ICU was reduced by 44 percent in the ATIII group ( p = 0.22 , NS ) . Care loads and transfusion requirements were not different . No side effect was observed . CONCLUSIONS Mortality was reduced by 44 percent in this trial , but the difference did not reach the statistical significance . Circulating protein C and protein S levels were not modified by ATIII supplementation . High doses of ATIII concentrates significantly improved sepsis-induced DIC during septic shock . The trend toward improved survival suggests further r and omized studies [1617983] Objective To examine whether the antioxidant N-acetylcysteine could ameliorate the course of the adult respiratory distress syndrome ( ARDS ) in man . Design R and omized , double-blind , placebo-controlled study . Setting Medical and surgical ICU in a regional hospital . Patients Sixty-six ICU patients with ARDS . Interventions Patients with ARDS ( Pao2/FIO2 ratio < 250 torr ) were treated with either the antioxidant N-acetylcysteine 150 mg/kg as a loading dose and then 20 mg/kg/hr , or with placebo for 6 days . Measurements and Main Results No improvement could be demonstrated in the Pao2/FIO2 ratio in the study group as compared with the control group on any day . Pulmonary compliance was higher in the N-acetylcysteine group than in the placebo group on all days , but this difference did not reach the chosen 5 % level of significance . No difference between the two groups could be demonstrated on chest radiograph or on survival rate . We documented that N-acetylcysteine acts as an anticoagulant and perhaps decreases pulmonary fibrin uptake during ARDS . Conclusions N-acetylcysteine might be of benefit in ARDS . Before further clinical studies are started , problems with N-acetylcysteine and coagulation have to be eluci date d in order to find out whether N-acetylcysteine could have a beneficial effect in the treatment of ARDS [8565513] OBJECTIVE To evaluate the safety and efficacy of liposomal prostagl and in E1 ( TLC C-53 ) in the treatment of patients with the acute respiratory distress syndrome ( ARDS ) . DESIGN R and omized , prospect i ve , multicenter , double-blind , placebo-controlled , phase II clinical trial . SETTING Eight community and university-affiliated hospitals in the United States . PATIENTS Twenty-five patients with ARDS . INTERVENTIONS Patients were prospect ively r and omized in an unbalanced ratio within each site to receive either TLC C-53 ( n = 17 ) or placebo ( n = 8) . Study drug was infused intravenously over 60 mins every 6 hrs for a 7-day period , starting at a dose of 0.15 micrograms/kg/hr . The dose was increased every 12 hrs until the maximal dose ( 3.6 micrograms/kg/hr ) was attained , intolerance to further increases developed , or invasive monitoring was discontinued . Patients received st and ard , aggressive , medical/surgical care throughout the trial . MEASUREMENTS AND MAIN RESULTS Outcome measurements were Pao2/FI0(2 ) , dynamic pulmonary compliance , ventilator dependence on day 8 , and 28-day all-cause mortality rate . At baseline , the distribution of variables describing Lung Injury Scores , Acute Physiology and Chronic Health Evaluation II scores , Pao2/FI0(2 ) , pulmonary compliance , and time from onset of ARDS to first dose of study drug was similar between patients in the TLC C-53 and placebo treatment groups . On day 8 , all eight patients given placebo required mechanical ventilation , while eight of 17 patients given TLC C-53 were healthy enough to be removed from the ventilator ( p = .03 ) . Improvement in PaO2/FIO2 during the initial 8-day study period was greater in patients receiving TLC C-53 . This trend achieved statistical significance on day 3 , when the increase in PaO2/FIO2 from baseline was 82.5 + /- 14.6 in the TLC C-53 group compared with 28.3 + /- 22.1 in the placebo group ( p = .05 ) . By day 8 , lung compliance also increased from baseline significantly more in TLC C-53 patients than in placebo patients ( 5.7 + /- 1.7 vs -1.5 + /- 1.8 mL/cm H2O ; p = .01 ) . The 28-day mortality rate was 6 % ( 1/17 patients ) in the TLC C-53 group and 25 % ( 2/8 patients ) in the placebo group ( p = .23 ) . Drug-related adverse events were reported in 82 % of the patients receiving TLC C-53 compared with 38 % of the placebo group , with half of the adverse events in the TLC C-53 group being localized infusion site irritation . TLC C-53 was hemodynamically well tolerated , with transient hypotension occurring in three patients . CONCLUSIONS In patients with ARDS , TLC C-53 was associated with improved oxygenation , increased lung compliance , and decreased ventilator dependency [9228372] OBJECTIVE To determine the levels of glutathione and cysteine in patients with ARDS and examine the effect of treatment with N-acetylcysteine ( NAC ) and L-2-oxothiazolidine-4-carboxylate ( Procysteine ; Clintec Technologies Inc ; Chicago [ OTZ ] ) on these levels and on common physiologic abnormalities , and organ dysfunction associated with ARDS . DESIGN R and omized , double-blind , placebo-controlled , prospect i ve clinical trial . SETTING ICUs in five clinical centers in the United States and Canada . PATIENTS Patients meeting a predetermined definition of ARDS and requiring mechanical ventilation . INTERVENTION St and ard care for ARDS and I.V. infusion , every 8 h for 10 days , of one of the following : NAC ( 70 mg/kg , n=14 ) , OTZ ( 63 mg/kg , n=17 ) , or placebo ( n=15 ) . MAIN RESULTS Both antioxidants effectively repleted RBC glutathione gradually over the 10-day treatment period ( 47 % and 49 % increases from baseline values for NAC and OTZ , respectively ) . There was no difference in mortality among groups ( placebo , 40 % ; NAC , 36 % ; OTZ , 35 % ) . However , the number of days of acute lung injury was decreased and there was also a significant increase in cardiac index in both treatment groups ( NAC/OTZ [+]14 % ; placebo [-]6 % ) . CONCLUSIONS Our findings suggest that repletion of glutathione may safely be accomplished with NAC or OTZ in patients with acute lung injury/ARDS . Such treatment may shorten the duration of acute lung injury , but larger studies are needed to confirm this [3317054] Corticosteroids are widely used as therapy for the adult respiratory distress syndrome ( ARDS ) without proof of efficacy . We conducted a prospect i ve , r and omized , double-blind , placebo-controlled trial of methylprednisolone therapy in 99 patients with refractory hypoxemia , diffuse bilateral infiltrates on chest radiography and absence of congestive heart failure documented by pulmonary-artery catheterization . The causes of ARDS included sepsis ( 27 percent ) , aspiration pneumonia ( 18 percent ) , pancreatitis ( 4 percent ) , shock ( 2 percent ) , fat emboli ( 1 percent ) , and miscellaneous causes or more than one cause ( 42 percent ) . Fifty patients received methylprednisolone ( 30 mg per kilogram of body weight every six hours for 24 hours ) , and 49 received placebo according to the same schedule . Serial measurements were made of pulmonary shunting , the ratio of partial pressure of arterial oxygen to partial pressure of alveolar oxygen , the chest radiograph severity score , total thoracic compliance , and pulmonary-artery pressure . We observed no statistical differences between groups in these characteristics upon entry or during the five days after entry . Forty-five days after entry there were no differences between the methylprednisolone and placebo groups in mortality ( respectively , 30 of 50 [ 60 percent ; 95 percent confidence interval , 46 to 74 ] and 31 of 49 [ 63 percent ; 95 percent confidence interval , 49 to 77 ] ; P = 0.74 ) or in the reversal of ARDS ( 18 of 50 [ 36 percent ] vs. 19 of 49 [ 39 percent ] ; P = 0.77 ) . However , the relatively wide confidence intervals in the mortality data make it impossible to exclude a small effect of treatment . Infectious complications were similar in the methylprednisolone group ( 8 of 50 [ 16 percent ] ) and the placebo group ( 5 of 49 [ 10 percent ] ; P = 0.60 ) . Our data suggest that in patients with established ARDS due to sepsis , aspiration , or a mixed cause , high-dose methylprednisolone does not affect outcome [9546417] Pentoxifylline , an inhibitor of tumor necrosis factor , has been evaluated as an antimalarial agent in combination with artesunate in 45 patients with severe falciparum malaria . Patients were admitted to the intensive care unit at the Hospital for Tropical Diseases in Bangkok , Thail and , and r and omly assigned to treatment for 72 hr with a combination of intravenously administered artesunate and 1 ) placebo , 2 ) low-dose pentoxifylline ( 0.83 mg/kg/hr ) , or 3 ) high-dose pentoxifylline ( 1.67 mg/kg/hr ) . All 45 patients had one or more manifestations of severe malaria such as cerebral malaria ( n = 18 ) , renal failure requiring hemodialysis ( n = 9 ) , azotemia ( n = 8) , jaundice ( n = 25 ) , or hyperparasitemia ( n = 30 ) . The overall severity was comparable in the three groups . Clinical outcome was assessed with respect to the parasite clearance time and the fever clearance time in all patients . In addition , a number of subsidiary outcome variables were examined in specific subgroups , including the recovery time from coma for patients with cerebral malaria , the duration of intubation in patients with respiratory distress , the number of hemodialysis treatments needed for patients with acute renal failure , and the number of units of blood administered to patients requiring transfusion . Concentrations of tumor necrosis factor were reduced in all three groups at 48 hr after treatment . No significant differences among the three treatment groups were found for any of the outcome variables examined . We conclude that the addition of pentoxifylline to artesunate therapy for severe malaria produced no evident clinical benefit [7271345] The effects of massive steroids on pulmonary function after hypovolemic shock were tested in 114 injured patients who received an average of 13 transfusions , 760 ml plasma , and 11.7 L crystalloid solution ; by r and om selection , 54 patients received methylprednisolone ( 1 g in operating room plus 3,578 mg average during the next three days ) . The patients who received steroids had a significant increase in central venous pressure and a decrease in arterial oxygen tension ( PaO2 ) compared with control patients . The inspired oxygen concentration was similar for both groups ; the FiO2/PO2 , therefore , was significantly deranged ( p= ≤ 0.05 ) in steroid patients ( 0.45 ± 0.05 SE vs 0.37 ± 0.02 SE ) . The patients who received steroids had an insignificantly increased pulmonary shunt ( 25 vs 22 % ) , number of days on a volume ventilator ( 5.1 vs 3.0 days ) , and number of deaths ( seven vs two ) . Massive steroids neither prevent nor ameliorate pulmonary failure after shock ; indeed , steroids may aggravate pulmonary failure after [9054282] At the end of a long week in the office , you sink back into your chair , reflecting on some of the more memorable patients you cared for and counseled . Through gentle history taking , you discovered that urinary incontinence is the underlying cause of an elderly patient 's increasing social isolation . During a careful physical examination , you detected bruising on the torso of a woman with chronic headaches and began to explore the longst and ing abusive relationship between the woman and her alcoholic partner . You discontinued procainamide therapy in a 72-year-old man who had asymptomatic premature ventricular contractions after myocardial infa rct ion . To prevent bleeding from esophageal varices , you started -blocker therapy in a woman with long-st and ing cryptogenic cirrhosis and portal hypertension . In couples ' therapy , discussing the future quality of life of a middle-aged gay man with human immunodeficiency virus infection , you journeyed through emotionally intense dialogue about advance directives . You presented the risk factors for major and minor bleeding to a 39-year-old woman who was considering warfarin therapy because of recently diagnosed atrial fibrillation and valvular heart disease . You listened to , made diagnoses for , treated , advised , and comforted many patients . Yet there were some hiccoughs in your practice along the way . You stumbled while debating the pros and cons of breast cancer screening with a healthy 48-year-old woman who has been staying current with information on the Internet . You question ed the merits of a personalized walking program suggested to you by a motivated 66-year-old man with severe claudication . Explaining that you wanted to review the best current evidence on these issues , you resolved to address your uncertainties before these patients made their next office visits , in a week 's time . Sighing deeply , you acknowledge that you have little time to read . You subscribe to three journals , which you browse months after they arrive-either when your journal stack becomes precariously high or when your guilt is sufficiently motivational . You sometimes find the conclusions of individual articles conflicting or confusing . You know that some of the decisions and suggestions you made this week , specifically your decisions about stopping procainamide therapy and starting -blocker therapy and your advice about bleeding risks from anticoagulant therapy , were based on the best current research evidence [ 1 - 3 ] . On the other h and , your patients ' inquiries about breast cancer screening and exercise treatment for claudication highlight your need for a concise , current , rigorous synthesis of the best available evidence on each of these topics : in brief , a systematic review [ 4 , 5 ] . Incorporating Research Evidence into Clinical Decision Making The foregoing scenario is familiar to practitioners . In a typical week , we encounter patients with diverse problems ; exercise numerous clinical , interpersonal , and technical skills ; and make many decisions . The factors that affect these decisions and their outcomes are complex . For instance , each patient has unique sociodemographic characteristics , cultural circumstances , and personal preferences . Each physician has unique knowledge , experiences , and values . Moreover , practitioners and their patients make decisions within the context of a rapidly changing health care system that influences the availability , accessibility , and cost of diagnostic tests and therapies [ 6 ] . Timely , useful evidence from the biomedical literature should be an integral component of clinical decision making . If one treatment has been shown to be better than another , we need to know , so that we can recommend the treatment to the appropriate patients . The worldwide effort to develop new tests and treatments , and to determine their usefulness , has never been stronger , and our patients and their families expect us to be fonts of the knowledge that results from this effort [ 7 ] . Unfortunately , it is easy for current best research evidence to pass us by [ 8 ] . We may lack the time , motivation , and basic skills needed to find , critically appraise , and synthesize information , all of which we must do if we are to integrate the results of original studies into our practice . Fortunately , several potent methods are emerging that can greatly enhance our ability to interpret and apply research evidence ; foremost among them is the systematic review . This article begins a series in Annals that will examine systematic review s in detail and explore their many applications . Systematic review s represent the best chance that most practitioners will have to underst and and accurately apply the key signals arising from the robust and increasingly productive search for solutions to medical problems . A properly conducted systematic review faithfully summarizes the evidence from all relevant studies on the topic of interest , and it does so concisely and transparently . What Is a Systematic Review ? Systematic review s are scientific investigations in themselves , with pre-planned methods and an assembly of original studies as their subjects . They synthesize the results of multiple primary investigations by using strategies that limit bias and r and om error [ 9 , 10 ] . These strategies include a comprehensive search of all potentially relevant articles and the use of explicit , reproducible criteria in the selection of articles for review . Primary research design s and study characteristics are appraised , data are synthesized , and results are interpreted . When the results of primary studies are summarized but not statistically combined , the review may be called a qualitative systematic review . A quantitative systematic review , or meta- analysis , is a systematic review that uses statistical methods to combine the results of two or more studies . The term overview is sometimes used to denote a systematic review , whether quantitative or qualitative . Summaries of research that lack explicit descriptions of systematic methods are often called narrative review s. Review articles are one type of integrative publication ; practice guidelines , economic evaluations , and clinical decision analyses are others . These other types of integrative articles often incorporate the results of systematic review s. For example , practice guidelines are systematic ally developed statements intended to assist practitioners and patients with decisions about appropriate health care for specific clinical circumstances [ 11 ] . Evidence -based practice guidelines are based on systematic review s of the literature , appropriately adapted to local circumstances and values . Economic evaluations compare both the costs and the consequences of different courses of action ; the knowledge of consequences that are considered in these evaluations is often generated by systematic review s of primary studies . Decision analyses quantify both the likelihood and the valuation of the expected outcomes associated with competing alternatives . Differences between Systematic and Narrative Review s All review s , narrative and systematic alike , are retrospective , observational research studies and are therefore subject to systematic and r and om error . Accordingly , the quality of a review - and thus its worth-depends on the extent to which scientific review methods have been used to minimize error and bias . This is the key feature that distinguishes traditional narrative review s from systematic review s ( Table 1 ) . If a review is prepared according to the steps outlined in the right column of Table 1 , it is more likely to be systematic and to provide unbiased conclusions . If review methods approximate those found in the middle column of Table 1 , the article is more likely to be a narrative review , and the conclusions are less likely to be based on an unbiased summary of all relevant evidence . Table 1 . Differences between Narrative Review s and Systematic Review s Systematic review s are generated to answer specific , often narrow , clinical questions in depth . These questions can be formulated explicitly according to four variables : a specific population and setting ( such as elderly out patients ) , the condition of interest ( for example , hypertension ) , an exposure to a test or treatment ( such as pharmacologic management ) , and one or more specific outcomes ( such as cardiovascular and cerebrovascular events and mortality ) [ 12 ] . Thus , an example of a well-formulated , clinical ly relevant question is , Does pharmacologic treatment of hypertension in the elderly prevent strokes and myocardial infa rct ions or delay death ? If the question that is driving the review is not clear from the title , abstract , or introduction , or if no methods section is included , the paper is more likely to be a narrative review than a systematic review [ 13 ] . Most narrative review articles deal with a broad range of issues related to a given topic rather than addressing a particular issue in depth [ 9 ] . For example , a narrative review on diabetes ( such as that which might be found in a textbook chapter ) might include sections on the physiology and pathophysiology of carbohydrate , lipid , and protein metabolism ; the epidemiology of and prognosis associated with diabetes ; diagnostic and screening approaches ; and preventive , therapeutic , rehabilitative , and palliative interventions . Thus , narrative review s may be most useful for obtaining a broad perspective on a topic ; they are less often useful in furnishing quantitative answers to specific clinical questions . Narrative review s are appropriate for describing the history or development of a problem and its management . Narrative review s may better describe cutting-edge developments if research is scant or preliminary or if studies are very limited by flawed design or execution [ 13 ] . They may be particularly useful for discussing data in light of underlying theory and context . Narrative review s can draw analogies and can conceptually integrate two independent fields of research , such as [3979000] Levels of thromboxane B2 ( TxB2 ) , the stable metabolite of thromboxine A2 , are elevated in human and experimental septic shock . The thromboxane synthetase inhibitor dazoxiben has improved survival and decreased pulmonary hypertension in experimental endotoxemia . A r and omized prospect i ve study of 10 patients with the clinical diagnosis of sepsis and early adult respiratory distress syndrome ( hypoxemia , radiologic evidence of the syndrome , and intrapulmonary shunt > 20 % ) was performed to test the efficacy of dazoxiben in ameliorating the effects of human sepsis . Five subjects received dazoxiben and five received placebo . Dazoxiben , 100 mg , or placebo was injected intravenously every 4 hours for a maximum of 72 hours . Plasma immunoreactive TxB2 ( iTxB2 ) levels were determined by radioimmunoassay . Before dazoxiben , the plasma iTxB2 level was 752 ±261 pg/ml ( n = 5 ) and was reduced within 1 hour to 333 ±137 pg/ml . The plasma levels of iTxB2 remained significantly decreased with subsequent doses of dazoxiben and it was 201 ± 67 pg/ml ( n = 4 ) 60 hours after dosing . In contrast , placebo had no significant effect on plasma iTxB2 levels ( n = 5 ) throughout the entire period of observation . Dazoxiben did not induce any significant changes in pulmonary or systemic vascular resistance , intrapulmonary shunting , clotting studies , or extravascular lung water . One of the five subjects in the placebo group died and two of the five subjects in the dazoxiben group died . We conclude that dazoxiben was safe and effectively lowered plasma iTxB2 levels in patients with sepsis and incipient adult respiratory distress symptom , but did not significantly alter the hemodynamic and pulmonary sequelae of established sepsis [8674324] OBJECTIVE No means exist for predicting the acute respiratory distress syndrome ( ARDS ) , which complicates sepsis , trauma , and a variety of clinical disorders . Because activation of phospholipid-signaling pathways involving the acyl chains oleate and linoleate may initiate and amplify the inflammatory response , and thereby lead to the development of ARDS , we examined whether serum concentrations of these bioactive lipids increase and are predictive of ARDS in at-risk patients . DESIGN Part I : A prospect i ve , single-blind trial . Part II : A prospect i ve , r and omized , double-blind trial . SETTING General intensive therapy units in five university teaching hospitals . SUBJECTS Part I : Thirty-nine healthy control patients were studied to determine normal distribution of serum acyl values , followed by 30 patients admitted with onset of sepsis , trauma , or development of ARDS ( within 24 hrs of admission ) over a 1-yr period . Part II : Eight patients admitted with sepsis syndrome over a 2-month period . INTERVENTIONS Part II : Patients were r and omized to receive the substituted methylxanthine , lisofylline ( CT1501R ) , or an identically presented placebo . MEASUREMENTS AND MAIN RESULTS We measured the serum free fatty acid concentrations in the 39 healthy control subjects , and then we prospect ively examined the serum free fatty acid concentrations in 30 age-matched patients in sample s obtained within 24 hrs from the onset of sepsis , trauma , or development of ARDS . We then prospect ively studied eight septic , at-risk patients who were matched for age , Acute Physiology and Chronic Health Evaluation II scores , Multiple Organ Failure index , and Glasgow Coma Score , in a double-blind , placebo-controlled , pilot study . These patients included four patients who received no treatment and four patients who received lisofylline , a compound that decreases serum unsaturated free fatty acids and diminishes acute lung injury in animals caused by sepsis and /or trauma . The calculated ratios of serum free fatty acids ( Le . , the ratio of C18 unsaturated fatty acids linoleate and oleate to fully saturated palmitate , C16:0 ) increased and predicted the development of ARDS in at-risk patients . Serum sample s from the 30 patients , obtained within 24 hrs from the onset of sepsis , trauma , or development of ARDS , had significantly increased mean acyl chain ratios ( 1.42 + /- 0.35 [ SD ] ) compared with healthy control subjects ( 0.86 + /- 0.25 ; p < .01 ) . Sera from 13 patients with sepsis or trauma who did not develop ARDS ( group A [ at-risk , non-pre-ARDS ] ) also had increased acyl ratios ( 1.23 + /- 0.27 ) compared with sera from healthy control subjects ( 0.86 + /- 0.25 ; p < .01 ) . Sera from seven patients who subsequently developed ARDS ( group B [ at-risk , pre-ARDS ] ) had higher acyl ratios ( 1.70 + /- 0.21 ) than group A at-risk patients who did not develop ARDS ( 1.23 + /- 0.27 ; p < .01 ) or healthy control subjects ( 0.86 + /- 0.25 ; p < .001 ) . Sera from ten group C patients with ARDS at the time of admission to the study had the highest acyl ratios ( 1.80 + /- 0.75 ) , which exceeded values for healthy control subjects ( p < .001 ) and group A at-risk patients without ARDS ( p = .01 ) , but were not significantly different then group B at-risk , pre-ARDS patients ( p = .17 ) . Prospect i ve study of eight septic , at-risk patients demonstrated significantly ( p < .05 ) increased serum acyl ratios in the four untreated patients ( findings consistent with the first study ) but a significantly ( p = .02 ) reduced ratio in the four at-risk patients treated with lisofyline . CONCLUSIONS Increases in unsaturated serum acyl chain ratios differentiate between healthy and seriously iII patients , and identify those patients likely to develop ARDS . Thus , the serum acyl ratio may not only prospect ively identify and facilitate the assessment of new treatments in patients at highest risk for developing ARDS , but may also lead to new insights about the pathogenesis of ARDS [10950800] This study assessed the safety and efficacy of filgrastim ( r-metHuG-CSF [ recombinant human methionine granulocyte colony-stimulating factor ] ) , when combined with intravenous ( IV ) antibiotics , in the treatment of hospitalized adult patients with multilobar community-acquired pneumonia ( CAP ) . Four hundred eighty patients were r and omized to receive placebo ( n=243 ) or filgrastim 300 microg/day ( n=237 ) , in addition to st and ard therapy . Treatment with study drug was continued for 10 days , until the peak white blood cell ( WBC ) count reached 75x109/L , until discharge from the hospital , until death , or until IV antibiotics were discontinued . Study -related observations continued through day 29 . Filgrastim increased WBC counts ( baseline median , 13.3x109/L ; median peak , 43 . 8x109/L ) . The 2 treatment groups were not statistically different with respect to the study end points ; however , there was a trend toward reduction of mortality in patients with pneumococcal bacteremia . Although further studies will be required to vali date this observation , filgrastim was safe and well tolerated when administered to patients with multilobar CAP [12794395] OBJECTIVE Platelet-activating factor ( PAF ) is a potent proinflammatory mediator implicated in the pathogenesis of both severe sepsis and acute respiratory distress syndrome . One of the regulatory pathways for PAF involves degradation to the inactive metabolite lyso-PAF by the enzyme PAF acetylhydrolase ( PAF-AH ) . Because reduced concentrations of the natural form of PAF-AH have been reported in septic patients , the present study was conducted to determine whether treatment with recombinant human PAF-AH ( rPAF-AH , Pafase ) was safe when administered after the onset of severe sepsis and whether it decreases the prevalence of acute respiratory distress syndrome and 28-day all-cause mortality . DESIGN A prospect i ve , r and omized , double-blind , placebo-controlled , multicenter trial . SETTING Thirty-three medical and surgical intensive care units located in the United States . PATIENTS A total of 127 patients with severe sepsis , but without established acute respiratory distress syndrome , were enrolled in the study . R and omization occurred within 12 hrs of the onset of severe sepsis . Patients then received 1.0 mg/kg rPAF-AH ( n = 45 ) , 5.0 mg/kg rPAF-AH ( n = 39 ) , or placebo ( n = 43 ) administered intravenously , once daily , for five consecutive days . MEASUREMENTS AND MAIN RESULTS Demographic and baseline clinical characteristics of the three treatment groups were similar , except for a significantly higher prevalence of respiratory tract infections as the cause of severe sepsis in patients treated with 1.0 mg/kg rPAF-AH . There were no treatment-related deaths , and the overall prevalence of adverse events was similar among rPAF-AH-treated and placebo-treated patients . There were no significant differences in the prevalence of acute respiratory distress syndrome among the three treatment groups . However , 28-day all-cause mortality was 21 % in the 1.0 mg/kg rPAF-AH group , 28 % in the 5.0 mg/kg rPAF-AH group , and 44 % in the placebo group ( overall chi-square p = .07 ; 1.0 mg/kg rPAF-AH vs. placebo , p = .03 ) . A trend toward reduced multiple organ dysfunction also was observed in the 1.0 mg/kg rPAF-AH group compared with the placebo group ( p = .11 ) . CONCLUSION The results from this study indicate that rPAF-AH was well tolerated and should be pursued as a potential new treatment to decrease mortality in patients with severe sepsis Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: OBJECTIVE A systematic review of weaning and extubation for pediatric patients on mechanical ventilation . CONCLUSIONS Despite the importance of minimizing time on mechanical ventilation , only limited guidance on weaning and extubation is available from the pediatric literature . A significant proportion of patients being evaluated for weaning are actually ready for extubation , suggesting that weaning is often not considered early enough in the course of ventilation . Indications for extubation are even less clear , although a trial of spontaneous breathing would seem a prerequisite . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

26390230

[10848924] Pranlukast ( 8‐[p‐(4‐phenylbutyloxy ) benzol ] amino‐2‐[tetrazol‐5‐yl]‐4‐oxo‐4H‐1‐benzopyran hemihydrate ) , a selective cysteinyl leukotriene receptor antagonist , has been reported to exhibit not only antileukotrine activity but also pharmacological activity including antieosinophilic effects [10193369] BACKGROUND It has been reported that pranlukast reduces the antigen induced immediate and late phase asthmatic responses , airway hyperreactivity to acetylcholine , and pulmonary eosinophil accumulation in guinea pigs . A study was undertaken to test the hypothesis that pranlukast may reduce the number of inflammatory cells in the bronchial mucosa of patients with asthma . METHODS A double blind , placebo controlled study was performed in 17 mild to moderate asthmatic subjects to examine changes in inflammatory cell infiltration in response to pranlukast ( 225 mg orally twice per day for four weeks ) . Comparisons of the mean daily β2 agonist use , symptom score , FEV1 percentage predicted , and airway methacholine responsiveness were made before and after treatment . Using fibreoptic bronchoscopy , bronchial biopsy specimens were obtained before and after treatment with either pranlukast ( n = 10 ) or placebo ( n = 7 ) . Immunohistology was performed using monoclonal antibodies for CD3 , CD4 , CD8 , CD68 , NP57 , AA1 , EG1 , EG2 , γGTP and CD19 . RESULTS When the pranlukast and placebo treated groups were compared there were decreases in β2agonist use , symptom score , and airway methacholine responsiveness after pranlukast but no increase in FEV1 was seen . The clinical response in patients treated with pranlukast was accompanied by a reduction in CD3 ( median difference –37 , 95 % confidence interval ( CI ) –69 to –1 ; p<0.05 ) , CD4 ( median difference –28 , 95 % CI –49 to –8 ; p<0.01 ) , AA1 ( median difference –15 , 95 % CI –26 to 0 ; p<0.05 ) and EG2 positive cells ( 95 % CI –35 to 0 ; p<0.05 ) , but not in EG1 positive eosinophils , γGTP positive cells , and CD19 positive plasma cells . CONCLUSIONS These results support the view that pranlukast may act by inhibition of bronchial inflammation in patients with asthma [4155393] Background Asthma affects mainly Venezuela ’s urban and poor majority . Exacerbations bring about a high dem and in health services , thus becoming a significant public health problem . In general , asthma control programs ( GINA ) with use of inhaled steroid medications have proven effective , although their implementation in real life remains cumbersome . Montelukast could be a useful and practical tool for these deprived socioeconomic sectors . Methods This real-life pilot study was conducted in a prospect i ve , double blinded , placebo-controlled manner with r and omized and parallel groups . Asthmatics that had never used leukotriene modifiers were recruited and followed-up every three months . The main outcome was the number of exacerbations meriting use of nebulized bronchodilators administered by the health care system . Results Eighty-eight asthmatic patients were enrolled , between children and adults . Groups were comparable in : demographic data , previous use of other medications , ACT scores , pulmonary functions ( Wright Peak Flow meter ) , allergy status ( Skin Prick Test ) as well as adherence to the prescribed Montelukast treatment . By an intention to treat ( ITT ) , a total of 64 patients were included for analysis . For the three and six months time points the difference between placebo and Montelukast was found to be significant ( p < 0.03 and p < 0.04 , respectively ) . Such trends continued for the rest of the year , but without statistical significance , due to patient attrition . Conclusions This real-life pilot study shows that a simplified strategy with oral Montelukast was practical and effective in controlling exacerbations in an asthmatic population of a vulnerable community from Caracas . Such an approach reinforces the role of primary care in asthma treatment [23380218] OBJECTIVE Many asthmatic patients are unable to quit cigarettes ; therefore information is needed on treatment options for smokers . This study evaluates 10 mg/d montelukast and 250 μg of fluticasone propionate twice daily , each compared with placebo , in patients with self-reported active smoking ( unable to quit ) and asthma . METHODS Patients ( ages 18 - 55 years , with asthma [ ≥1 year ] , FEV1 of 60 % to 90 % of predicted value , airway reversibility [ ≥12 % ] , and self-reported active smoking [ ≥0.5 to ≤2 packs per day ] ) were r and omized ( after a 3-week , single-blind , placebo , run-in period ) to 1 of 3 parallel , 6-month , double-blind treatment arms . The primary efficacy end point was the percentage of days with asthma control during treatment . Adverse experiences ( AEs ) were also evaluated . RESULTS There were 347 , 336 , and 336 patients r and omized to montelukast , fluticasone , and placebo , respectively . The mean percentage of days with asthma control over 6 months of treatment was 45 % ( montelukast , P < .05 vs placebo ) , 49 % ( fluticasone , P < .001 vs placebo ) , and 39 % ( placebo ) ; the difference between montelukast and fluticasone was not significant ( P = .14 ) . Patients with a smoking history of ≤11 pack years ( the median value ) tended to show more benefit with fluticasone , whereas those with a smoking history of > 11 pack years tended to show more benefit with montelukast . AEs occurred in similar proportions among treatment groups . CONCLUSIONS In a population of asthmatic patients actively smoking cigarettes , both 10 mg/d montelukast and 250 μg of fluticasone propionate twice daily significantly increased the mean percentage of days with asthma control compared with placebo [21370724] BACKGROUND Leukotrienes , especially LTC4 , are important inflammatory mediators in allergic and nonallergic inflammation of the entire airways . Of particular interest are numerous theories regarding the pathogenesis of aspirin intolerance with subsequent hyperproduction of leukotrienes and inhibition of cyclooxygenase . OBJECTIVE To examine the influence of the cysteinyl-leukotriene receptor antagonist montelukast on clinical symptoms and inflammatory markers in nasal lavage fluid in patients with bronchial asthma and nasal polyps , and determine its dependency on aspirin sensitization . METHODS Twenty-four patients ( 7 women , 17 men ; median age , 55.5 years ) with nasal polyps and controlled asthma ( n=12 with aspirin intolerance ) were treated with 10 mg montelukast once daily for 6 weeks in a blinded , placebo-controlled fashion . The placebo phase was r and omly assigned 4 weeks before ( n=12 ) or after treatment ( n=12 ) . Symptom score , rhinoendoscopy , rhinomanometry , smears for eosinophils , and nasal lavages for the determination of different mediators were performed . RESULTS Compared to placebo , there were significant improvements in the nasal symptom score and airflow limitation as well as a reduction in the inflammatory mediators in nasal lavage fluid after treatment . Furthermore , reduced eosinophils in nasal smears and peripheral blood were observed 2 and 6 weeks after treatment . CONCLUSION Leukotriene 1 receptor blockade led to a significant decrease in eosinophil inflammation accompanied by a reduction in other mediators such as neurokinin A and substance P in the nasal lavage fluid of patients with nasal polyps and asthma , with or without aspirin intolerance [15462688] SUMMARY Objective : The objective of this study was to evaluate montelukast 10 mg daily as treatment for allergic rhinitis in patients with symptomatic allergic rhinitis and active asthma during the allergy season . Methods : This was a multicenter study of 831 patients ( ages 15 years–85 years ) with seasonal allergen sensitivity , active symptoms of seasonal allergic rhinitis , and active asthma . Following a single-blind , placebo run-in period of 3 days–5 days , patients were r and omized to oral montelukast 10 mg ( n = 415 ) or placebo ( n = 416 ) daily during the 2-week , double-blind , active-treatment period . Main outcome measures : The primary endpoint was Daily Rhinitis Symptoms score , average of Daytime Nasal Symptoms and Nighttime Symptoms , as self-rated by patients on a 0–3 scale on daily diaries . Results : Montelukast reduced the Daily Rhinitis Symptoms score : difference between montelukast and placebo in mean change from baseline was –0.12 [ 95 % CI –0.18 , –0.06 ; p ≤ 0.001 ] . Similar improvements were seen in Daytime Nasal Symptoms ( –0.14 [ –0.21 , –0.07 ; p ≤ 0.001 ] ) and Nighttime Symptoms ( –0.10 [ –0.16,–0.04 ; p ≤ 0.001 ] ) . Improvements ( p < 0.05 ) were seen in Daytime Eye Symptoms and in the secondary endpoints of Global Evaluations of AR by Patient and by Physician , and Rhinoconjunctivitis Quality of Life . In exploratory analyses , improvement in rhinitis symptoms was numerically ( though not statistically ) larger in patients with greater levels of asthma at study start . Montelukast provided benefit in the Global Evaluations of Asthma by Patient and by Physician : mean differences were –0.24 [ –0.41 , –0.06 ; p = 0.008 ] and –0.17 [ –0.33,–0.01 ; p = 0.037 ] . Similarly , as-needed β-agonist use ( puffs/day ) was reduced with montelukast ( p ≤ 0.005 ) . Conclusion : Montelukast provides significant relief from symptoms of seasonal allergic rhinitis , while also conferring a benefit for asthma , in patients with both allergic rhinitis and asthma [10075616] For patients with persistent asthma , the National Asthma Education and Prevention Program recommends the regular use of controller medications to provide long-term control , together with as-needed use of rescue medications ( 1 ) . Inhaled corticosteroids are currently the most commonly used controller medications ( 1 ) . Although inhalation into the airway has advantages in terms of both safety and efficacy , problems with compliance with inhaled agents may limit their real-world effectiveness , especially in elderly and pediatric patients ( 2 , 3 ) . Cysteinyl leukotrienes are important pro-inflammatory mediators of asthma ( 4 ) . Recent clinical studies of leukotriene receptor antagonists ( 5 - 7 ) and a 5-lipoxygenase inhibitor ( 8) have shown these agents to have clinical benefit in patients with chronic asthma , and treatment guidelines now consider these agents alternative , first-line controller medications ( 1 ) . Recent studies showed that montelukast , a potent and specific leukotriene receptor antagonist ( 9 ) , had efficacy in adult ( over a 12-week period ) and pediatric ( over an 8-week period ) patient with chronic asthma and had a tolerability profile similar to that of placebo ( 10 - 12 ) . To date , no comparisons of leukotriene receptor antagonists and inhaled corticosteroids have been published . Our placebo-controlled , parallel-group study , which was primarily design ed to compare the effect of montelukast with that of placebo in a phase III clinical development trial , also compared montelukast and inhaled beclomethasone in patients with chronic asthma who require the daily use of a controller medication . Methods Patients Healthy , nonsmoking , male and female patients 15 years of age and older were eligible to participate if they had had asthma for at least 1 year before the initial study evaluation . Each patient also had to have 1 ) an FEV1 between 50 % and 85 % of predicted value , 2 ) an increase of at least 15 % in absolute FEV1 after the use of inhaled -agonist on at least two of three visits during period 1 [ see below ] , 3 ) a daytime asthma symptom score of at least 64 [ of a possible 336 ] , and 4 ) average daily use of at least one puff of as-needed , short-acting , inhaled -agonist ( salbutamol ) . Patients were excluded from the study if they had used inhaled and oral corticosteroids , cromolyn , or nedocromil within 4 weeks before the initial evaluation ; had used long-acting -agonists , antimuscarinics , and newly instituted theophylline within 2 weeks before the initial evaluation ; or had used long-acting antihistamines ( for example , they could not have used astemizole within 3 months of the initial evaluation , and they could not have used terfenadine or loratadine within 2 weeks of the initial evaluation ) . Intermittent use of short-acting antihistamines was allowed , and immunotherapy was permitted if it had been started at least 6 months before the initial study evaluation and if the monthly dose remained constant . Protocol Our r and omized , double-dummy , placebo-controlled , parallel-group trial had a 2-week , single-blind placebo run-in period ( period 1 ) ; a 12-week , double-blind treatment period ( period 2 ) ; and a 3-week , double-blind placebo washout period [ period 3 ] . Eligible patients were r and omly assigned to one of three treatment regimens : 1 ) montelukast , 10 mg once daily in the evening ; 2 ) inhaled beclomethasone , 200 g twice daily ; or 3 ) placebo . The ratio of montelukast recipients to beclomethasone recipients to placebo recipients was 3:2:2 , with a blocking factor of 7 , according to a single , computer-generated allocation schedule . Patients , investigators , and coordinating center staff were blinded to the treatment schedule until all corrections to the data base were completed . During period 3 , a subset of patients originally assigned to receive active treatment ( approximately 40 , as determined by the allocation schedule ) was switched to placebo in a blinded manner . The other patients originally assigned to receive active treatment continued to receive that treatment . This allowed us to assess withdrawal from therapy . The study was done at 36 clinical centers in 19 countries in Europe , Africa , Australia , Central America , and South America . The study protocol and informed consent were approved by local ethics review committees . All participants gave written informed consent before participation ; consent of parents or guardians was obtained for patients younger than 18 years of age . Patients were recruited from the patient pool of each clinical study center and through local newspaper advertisements . Medication The study medication consisted of 10-mg montelukast film-coated tablets , placebo tablets that were identical in appearance to the montelukast tablets , beclomethasone ( 100 g/puff ) in inhalers ( Allen & Hanburys , Stockley Park , United Kingdom ) , and placebo in inhalers identical to those used for beclomethasone . Patients were instructed to take one tablet at bedtime and to take two puffs from the inhaler ( using the AeroChamber spacer device [ Clement Clark , Columbus , Ohio ] ) at bedtime and in the morning . Short-acting , inhaled -agonist ( salbutamol , 100 g/puff ) ( Allen & Hanburys ) was to be used as needed . Patients with worsening episodes of asthma that required additional therapy were treated with oral corticosteroids according to a st and ard protocol . Patients who had more than two worsening episodes of asthma requiring corticosteroid therapy were dropped from the study . Measurements Central ized spirometry training was done according to st and ard American Thoracic Society criteria before the start of the study . Spirometry was done at each visit after inhaled -agonist therapy had been withheld for at least 6 hours , theophylline therapy had been withheld for at least 24 hours , and antihistamine therapy had been withheld for at least 48 hours . At least three spirometry maneuvers were done , and the largest FEV1 was reported . Spirometry data were transmitted electronically to a central data base and monitored continuously for quality , and feedback was given to the study centers ( 13 ) . If quality was not maintained , sites were visited by coordinating center personnel . Answers to four questions on daytime asthma symptoms and one question on nocturnal awakenings were collected on a daily diary card , as were morning and evening peak expiratory flow rate and daily use of as-needed salbutamol . With respect to daytime asthma symptoms , patients used a 7-point scale ( on which 0 means best and 6 means worst ) to rate the severity of symptoms , their frequency , the degree to which they were bothersome , and their impact on daily activities . These ratings were combined into a mean daily score . Nocturnal awakenings were evaluated by the patient 's response ( on a four-point scale ) to a single question ( 14 ) . The validation of these questions has been published elsewhere ( 14 ) . Peak expiratory flow was measured in the morning and in the evening immediately before study medication was taken . The best of three measurements was recorded . Prespecified end points other than peak expiratory flow included peripheral blood eosinophil counts , global evaluations by physicians and patients ( on a 7-point scale , on which 6 means very much worse and 0 means very much better ) ( 7 ) , and asthma-specific quality of life ( 15 ) . Asthma outcome end points , including asthma attacks ( defined as worsening asthma requiring oral corticosteroid treatment or an unscheduled visit to a physician , emergency department , or hospital ) , percentage of days with asthma exacerbations , and percentage of asthma-control days ( as defined elsewhere [ 11 , 16 ] ) , were also evaluated . The diary card , the Asthma Quality -of-Life Question naire ( 15 ) , and the global evaluation questions were translated from English into appropriate local language s and were vali date d for linguistic equivalence and cultural differences ( 17 ) . Patient compliance with study therapy was determined by weighing inhalers and counting tablets . The weight of a full canister was determined by averaging the weights of at least 50 canisters of beclomethasone and placebo . A st and ard puff weight was determined by repeatedly actuating and weighing 10 canisters . Laboratory safety tests , including hematologic tests , serum biochemistry analysis , and urinalysis , were done at prespecified visits , and the results were analyzed by a central laboratory . The central laboratory also determined eosinophil counts with an automated cell counter . Statistical Analysis Our primary objective was to compare montelukast with placebo with respect to two prespecified primary end points : FEV1 and daytime symptom score . Other objectives were to compare beclomethasone with placebo and to compare montelukast with beclomethasone in a stepwise manner in accordance with the Dunnet-Tamhane approach , with the comparison of montelukast and beclomethasone prespecified as an estimation of the difference using 95 % CIs ( 18 ) . No multiplicity adjustments were made for each of the secondary end points , which were prespecified as supportive . The analysis for each efficacy end point included all patients who had a measurement taken at baseline and at least one measurement taken after r and omization . Treatment responses were calculated as the average change or percentage change from baseline to period 2 ; the baseline value was the average value for period 1 . With SAS software ( SAS Institute , Inc. , Cary , North Carolina ) , we used an analysis of variance ( ANOVA ) model to estimate treatment group means and between-group differences and to construct 95 % CIs by using the least-square means and the differences in least-square means . The model contained factors for treatment , study center , and stratum ( theophylline use ) . The consistency of the treatment effect across study centers , strata , and subgroups ( which were formed according to sex , age , ethnicity , history of allergic rhinitis , and history of exercise-induced asthma ) was assessed by interaction testing done using the ANOVA model with an [11888953] OBJECTIVE Leukotrienes ( LTs ) are involved in airway eosinophilic inflammation in patients with asthma . We examined the effects of a cysteinyl LT 1-receptor antagonist , montelukast , on sputum eosinophil levels , and the correlation between sputum eosinophils and bronchodilatation in patients with asthma . DESIGN Double-blind , r and omized , crossover study . SETTING University hospital and private hospital . PATIENTS Twenty-nine patients with mild-to-moderate asthma . INTERVENTIONS Montelukast , 10 mg , and placebo tablet , once daily , each for 4 weeks . MEASUREMENTS Sputum eosinophils analyzed using hypertonic saline solution-induced sputum and airway hyperresponsiveness to histamine were evaluated before and after treatment . In addition , morning and evening peak expiratory flow ( PEF ) , asthma symptoms , and peripheral blood eosinophil levels were assessed . RESULTS The percentage of eosinophils in sputum decreased from 24.6 + /- 12.3 % at baseline to 15.1 + /- 11.8 % after montelukast treatment , for a change of - 9.5 + /- 12.7 % ( n = 20 ) . During placebo administration , the percentage of eosinophils fell from 21.3 + /- 12.1 % to 21.0 + /- 11.5 % , result ing in a decrease of - 0.3 + /- 10.8 % ( n = 20 ) . There was a statistically significant difference in the change in sputum eosinophil levels between these two periods ( p < 0.005 ) . The number of peripheral blood eosinophils also significantly decreased after montelukast treatment ( 314.1 + /- 237.6/mL ) compared with placebo ( 413.1 + /- 232.1/mL ; p < 0.005 , n = 21 ) . Although morning and evening PEF values were significantly improved from baseline after montelukast treatment ( p < 0.01 , n = 20 ) , asthma symptoms and airway responsiveness to histamine were not significantly altered . Furthermore , there was no significant correlation between the decrease in sputum eosinophils and the increase in PEF . CONCLUSION These results suggest that montelukast has anti-inflammatory effects on the airway in patients with asthma , and that its bronchodilatory effect is not solely dependent on a decrease in airway eosinophilia [12449158] The present study aim ed at comparing the effects of a dose reduction of inhaled corticosteroids on lung function , indirect measures of airway inflammation and clinical scores during treatment with a leucotriene receptor antagonist . In 50 patients ( mean forced expiratory volume in one second ( FEV1 ) 94 % predicted ) , steroid doses ( 800 µg beclomethasone dipropionate ) were first reduced to 50 % and then to 25 % , for 6 weeks each . One group received a placebo and the other group received montelukast ( 10 mg ) . The first reduction did not cause significant effects . During the second , FEV1 and peak expiratory flow decreased in both groups ( p<0.001 ) . Daytime symptoms were not altered with placebo but were reduced by montelukast ( p<0.05 ) . Night-time symptoms were slightly elevated with placebo ( p<0.05 ) but not montelukast , as well as the use of supplemental salbutamol . Changes in provocative concentration of methacholine causing a 20 % fall in FEV1 ( PC20 ) , sputum eosinophils and exhaled nitric oxide were mostly nonsignificant for both placebo and montelukast . These data demonstrate that a 75 % reduction in the dose of steroid given to patients with asthma led to a deterioration in lung function not prevented by montelukast , whereas changes in clinical state seemed to favour montelukast treatment . It therefore appears that potential effects of montelukast , in the presence of low-dose steroids , could not be attributed to single indices of lung function or airway inflammation [14674932] Background : Controlled clinical trials on the effects of leukotriene antagonists on asthma‐like symptoms , bronchial hyperresponsiveness and airway inflammation have not been performed in elite athletes [15136379] STUDY OBJECTIVES We have previously found that vascular endothelial growth factor ( VEGF ) levels in induced sputum were increased in asthmatic patients , and that its levels were closely associated with the degree of airway obstruction and microvascular permeability . Therefore , this study was design ed to examine the effects of pranlukast , a selective leukotriene receptor antagonist , on VEGF levels in induced sputum from steroid-untreated or steroid-treated asthmatic patients . DESIGN Double-blind , r and omized , placebo-controlled , crossover study . SETTING University hospital . PARTICIPANTS Twenty-three asthmatic patients ( steroid-untreated , 13 patients ; steroid-treated , 10 patients ) and 10 healthy control subjects . INTERVENTIONS All asthmatic patients received 4-weeks of therapy with pranlukast ( 225 mg bid ) , and sputum induction was performed before and after the 4-week treatment course . MEASUREMENTS AND RESULTS In steroid-untreated asthmatic patients , the mean percentage of eosinophils ( % EOS ) and mean eosinophil cationic protein ( ECP ) levels in induced sputum were significantly decreased after 4 weeks of pranlukast administration ( % EOS : before , 16.7 % [ SD , 7.1 % ] ; after , 12.3 % [ SD , 4.0 % ] ; p = 0.03 ; ECP levels : before , 774 ng/mL [ SD , 258 ng/mL ] ; after , 564 ng/mL [ SD , 204 ng/mL ] ; p = 0.034 ) . Moreover , VEGF levels in the induced sputum and the airway vascular permeability index also were decreased after pranlukast administration ( VEGF levels : before , 5,670 pg/mL [ SD , 1,780 pg/mL ] ; after , 4,380 pg/mL [ SD , 1,540 pg/mL ] ; p = 0.026 ; airway vascular permeability index : before , 0.032 [ SD , 0.012 ] ; after , 0.017 [ SD , 0.006 ] ; p = 0.01 ) . In addition , the change in airway vascular permeability index from before to after pranlukast administration was significantly correlated with the change in VEGF levels ( r = 0.782 ; p = 0.007 ) . However , in steroid-treated asthmatic patients there was no significant difference in mean VEGF levels in induced sputum between placebo administration ( before , 3,640 pg/mL [ SD , 1,020 pg/mL ] ; after , 3,640 pg/mL [ SD , 960 pg/mL ] and pranlukast administration ( before , 3,660 pg/mL [ SD , 940 pg/mL ] ; after , 2,950 pg/mL [ SD , 890 pg/mL ] ) . CONCLUSIONS Pranlukast administration decreased airway microvascular permeability through , at least in part , a decrease in airway VEGF levels in steroid-untreated asthmatic patients . However , it is likely that pranlukast administration added little efficacy to inhaled corticosteroid therapy for reduction in airway VEGF levels [12612294] Background : Proinflammatory leukotrienes , which are not completely inhibited by inhaled corticosteroids , may contribute to asthmatic problems . A 16 week multicentre , r and omised , double blind , controlled study was undertaken to study the efficacy of adding oral montelukast , a leukotriene receptor antagonist , to a constant dose of inhaled budesonide . Methods : A total of 639 patients aged 18–70 years with forced expiratory volume in 1 second ( FEV1 ) ≥55 % predicted and a minimum predefined level of asthma symptoms during a 2 week placebo run in period were r and omised to receive montelukast 10 mg ( n=326 ) or placebo ( n=313 ) once daily for 16 weeks . All patients received a constant dose of budesonide ( 400–1600 μg/day ) by Turbuhaler throughout the study . Results : Mean FEV1 at baseline was 81 % predicted . The median percentage of asthma exacerbation days was 35 % lower ( 3.1 % v 4.8 % ; p=0.03 ) and the median percentage of asthma free days was 56 % higher ( 66.1 % v 42.3 % ; p=0.001 ) in the montelukast group than in the placebo group . Patients receiving concomitant treatment with montelukast had significantly ( p<0.05 ) fewer nocturnal awakenings and significantly ( p<0.05 ) greater improvements in β agonist use and morning peak expiratory flow rate ( PEFR ) . Conclusions : For patients with mild airway obstruction and persistent asthma symptoms despite budesonide treatment , concomitant treatment with montelukast significantly improves asthma control [15640321] Sputum eosinophilia is a sensitive predictor of benefit from corticosteroid treatment . Montelukast is a cysteinyl leukotriene antagonist , which also reduces sputum and blood eosinophils . The present study examined the possibility that montelukast has an added eosinophil-lowering effect in subjects with asthma who are corticosteroid responsive but relatively corticosteroid resistant . A total of 14 clinical ly stable adults with asthma requiring minimum treatment with a high-dose inhaled steroid or prednisone , with baseline sputum eosinophilia ( ≥5 % ) , were r and omised to receive 4 weeks of 10 mg montelukast or placebo daily in a double-blind crossover trial . The primary outcome was the effect of treatment on the percentage of sputum eosinophils . Secondary outcomes were changes in the blood eosinophil count , symptoms , forced expiratory volume in one second , peak expiratory flow and the need for salbutamol . The median ( interquartile range , i.e. 75th–25th centile ) for sputum eosinophils at baseline was 15.7 % ( 22 ) . The effect of adding montelukast was not significantly different from that of placebo , sputum eosinophils being 9.3 % ( 18.9 ) after montelukast and 11.3 % ( 22.8 ) after placebo . No difference was detected on secondary outcomes . No crossover interactions were observed . In conclusion , the addition of montelukast to existing high-dose corticosteroid therapy in subjects with asthma with elevated sputum eosinophils does not provide additional attenuation of airway eosinophilia [15681495] Background : Inhaled corticosteroids and leukotriene receptor antagonists reduce airway eosinophilia and have been used as first line anti-inflammatory therapy for mild persistent asthma . Methods : A multicentre , r and omised , placebo controlled , parallel group study was performed to compare the anti-inflammatory effects of fluticasone propionate and montelukast as measured by sputum eosinophils in 50 adults with symptomatic steroid naive asthma and sputum eosinophilia of ⩾3.5 % . Results : Eighteen patients received low dose fluticasone ( 250 μg/day ) , 19 received montelukast ( 10 mg/day ) , and 13 were given placebo for 8 weeks . Fluticasone treatment result ed in a greater reduction in sputum eosinophils ( geometric mean ( SD ) 11.9 (2.3)% to 1.7 (5.1)% ) than montelukast ( 10.7 (2.3)% to 6.9 (3.8)% ; p = 0.04 ) or placebo ( 15.4 (2.4)% to 7.8 (4.2)% ; p = 0.002 ) , and improvement in FEV1 ( mean ( SD ) 2.6 ( 0.9 ) l to 3.0 ( 0.9 ) l ) than montelukast ( 2.8 ( 0.7 ) l to 2.8 ( 0.9 ) l ; p = 0.02 ) or placebo ( 2.4 ( 0.8 ) l to 2.4 ( 0.9 ) l ; p = 0.01 ) . Treatment with fluticasone suppressed sputum eosinophilia within a week while montelukast only attenuated it . The effect of montelukast was maximal at 1 week and was maintained over 4 weeks . The effect of fluticasone was maintained over 8 weeks while that of montelukast was not . Conclusions : Montelukast is not as effective as low dose fluticasone in reducing or maintaining an anti-inflammatory effect in steroid naïve eosinophilic asthma [10489822] Leukotrienes are pro-inflammatory mediators which may contribute to tissue , sputum , and blood eosinophilia seen in allergic and inflammatory diseases , including asthma . Montelukast is a cysteinyl leukotriene1 ( CysLT1 ) receptor antagonist which improves asthma control ; the aim of this study was to investigate its effect on induced sputum eosinophils . Montelukast 10 mg ( n=19 ) or placebo ( n=21 ) were administered orally once in the evening for 4 weeks to 40 chronic adult asthmatic patients , aged 19 - 64 yrs , in a double-blind , r and omized , parallel group study . Patients were included if , at pre study , they had > 5 % sputum eosinophils , symptomatic asthma with a forced expiratory volume in one second > or = 65 % of the predicted value and were being treated only with " as needed " inhaled beta2-agonists . In addition to sputum eosinophils , blood eosinophils and clinical endpoints were also assessed . Four weeks of montelukast treatment decreased sputum eosinophils from 7.5 % to 3.9 % ( 3.6 % decrease , 95 % confidence interval ( CI ) -16.6 - 0.4 ) . In contrast , placebo treatment was associated with an increase in sputum eosinophils from 14.5 % to 17.9 % ( 3.4 % increase , 95 % CI -3.5 - 9.8 ) . The least squares mean difference between groups ( -11.3 % , 95 % CI -21.1-(-1.4 ) ) was significant ( p=0.026 ) . Compared with placebo , montelukast significantly reduced blood eosinophils ( p=0.009 ) , asthma symptoms ( p=0.001 ) and beta2-agonist use ( p<0.001 ) while significantly increasing morning peak expiratory flow ( p=0.001 ) . Montelukast was generally well tolerated in this study , with a safety profile similar to the placebo . These results demonstrate that montelukast decreases airway eosinophilic inflammation in addition to improving clinical parameters . Its efficacy in the treatment of chronic asthma may be due , in part , to the effect on airway inflammation [12570120] The distribution of responses in study population s provides a novel method of comparing the benefit of two treatments . This 6‐week , r and omised , placebo-controlled , double-blind study compared the effectiveness of oral montelukast with inhaled beclomethasone in chronic asthma by assessing the distribution and overlap of patient responses to therapy , as measured by a clinical outcome ( asthma control days ) . A total of 730 adult patients with asthma , age 15–65 yrs , with a forced expiratory volume in one second ( FEV1 ) at baseline of 50–85 % of predicted and ≥15 % improvement in FEV1 after inhaled β‐agonist were enrolled . After a 2–week placebo run-in period , patients were r and omly allocated to receive montelukast ( 10 mg once daily ) , inhaled beclomethasone ( 200 µg twice daily ) or placebo . The primary end-point ( per cent of asthma control days ) was compared between treatments as the overlap in the response distributions . The overlap of the distribution of responses between the montelukast and beclomethasone groups was 89 % for per cent asthma control days and 96 % for change from baseline in FEV1 . The mean ( ±sd ) per cent asthma control days in the montelukast and beclomethasone groups was significantly higher than that in the placebo group ( placebo 40.0±35.8 , montelukast 50.7±37.1 , beclomethasone 57.9±36.1 ) . The mean differences between montelukast and placebo , beclomethasone and placebo , and montelukast and beclomethasone were significant . The mean per cent change ( ±sd ) from baseline in FEV1 was 12.1±18.7 and 13.9±20.8 in the montelukast and beclomethasone groups , respectively , and significantly greater than that in the placebo group ( 6.4±20.1 ) ; there was no significant difference between the montelukast and beclomethasone groups in mean values or response distribution . There was also no difference among treatment groups in the frequency of adverse experiences . A comparison of the response distribution is an important approach to comparing therapies ; montelukast and beclomethasone provided similar response distributions for the end-point of per cent asthma control days over a 6‐week treatment period [15478381] BACKGROUND Antileukotriene agents have been shown to be beneficial in chronic asthma . Although patients with cough variant asthma have cough with minimal wheezing and dyspnea , airway hyperresponsiveness from chronic inflammation is believed to be the underlying mechanism . OBJECTIVE To evaluate the effectiveness of montelukast , a leukotriene receptor antagonist , in the treatment of cough variant asthma . METHODS Fourteen patients with cough variant asthma participated in a r and omized , double-blind , placebo-controlled trial with a 7- to 10-day baseline period and a 4-week treatment period with montelukast , 10 mg , or placebo daily . Inclusion criteria were ( 1 ) chronic cough with a duration of at least 4 weeks with minimal or no wheezing or dyspnea and ( 2 ) forced expiratory volume in 1 second of 50 % to 85 % of predicted and reversibility of 12 % with use of an inhaled beta-agonist or forced expiratory volume in 1 second greater than 85 % and positive methacholine challenge results . Patients fulfilled the minimum criteria for cough frequency and symptom scores for r and omization . RESULTS Eight patients received montelukast and 6 received placebo . The primary efficacy variable , mean percentage change from baseline in cough frequency , was significantly improved by the second week , and by the fourth week the mean percentage change from baseline was 75.7 % for the treatment group and 20.7 % for the placebo group . CONCLUSIONS The leukotriene receptor antagonist montelukast seems to be effective in the treatment of cough variant asthma . Larger studies are recommended to confirm this effect [9377612] The efficacy of the oral leukotriene-receptor antagonist zafirlukast was assessed as maintenance therapy for patients with mild-to-moderate asthma . A total of 762 patients aged 12 to 76 years were enrolled in a 13-week , multicenter , double-masked , placebo-controlled , parallel-group trial and r and omly assigned to receive either zafirlukast ( 20 mg twice daily ) or placebo . Patients were maintained on as-needed beta-agonist therapy throughout the study and had to have a cumulative daytime asthma symptoms score > or = 8 ( on a daily scale of 0 to 3 ) over 7 consecutive days before r and omization . Efficacy was assessed by changes in symptoms , beta-agonist use , and pulmonary function . Safety was assessed by adverse experiences , laboratory test results , physical examination , and electrocardiography . Zafirlukast significantly decreased daytime asthma symptoms scores ( -26.5 % ) , nighttime awakenings ( -19.8 % ) , mornings with asthma ( -29.0 % ) , and beta-agonist use ( -22.3 % ) and significantly increased morning peak expiratory flow rate ( 6.9 % ) and forced expiratory volume in 1 second ( 6.3 % ) compared with placebo . Changes in symptoms , beta-agonist use , and pulmonary function occurred within 2 days of zafirlukast treatment and continued throughout the trial . Zafirlukast was well tolerated . Pharyngitis and headache were the most common adverse events , occurring with similar frequency in both the zafirlukast and placebo groups . No clinical ly significant changes were observed in laboratory test results , findings on physical examination , or electrocardiographic findings . We conclude that zafirlukast produces early and sustained effects in the treatment of mild-to-moderate asthma [23786930] Background Evidence has demonstrated that the distal lung , which includes airways of < 2 mm in diameter and lung parenchyma , constitutes an important component of asthma pathology . Cysteinyl leukotrienes ( CysLTs ) are potent proinflammatory mediators and bronchoconstrictors involved in the asthmatic process . Guidelines recommend the leukotriene‐modifying agents for asthma treatment . We hypothesized that a leukotriene receptor antagonist with an inhaled corticosteroid ( ICS ) and long‐acting & bgr;2 agonist ( LABA ) combination would improve small airways function in moderate‐to‐severe asthmatics evaluated by physiological tests and high‐resolution computed tomography ( H RCT ) analysis . This study was performed at a tertiary university hospital in Beijing . Methods This was a r and omized , double‐blind , parallel study performed in 38 patients with moderate‐to‐severe asthma treated with salmeterol/fluticasone ( SFC ) plus montelukast ( SFC+M ) or SFC plus placebo over 24 weeks . Small airway function was assessed by physiological studies and H RCT image analysis . Results Montelukast significantly improved air trapping as expressed by the residual volume (RV)/total lung capacity ( TLC ) . Over 24 weeks of treatment , RV/TLC was improved by (15.41±6.67)% in patients receiving SFC+M while RV/TLC was decreased by (8.57±10.26)% in patients receiving SFC alone , the difference between the two groups was significant ( P=0.02 ) . There was a trend towards a significant difference in forced expiratory volume in the first second (FEV1)/forced vital capacity ( FVC ) in the SFC+M group compared to that in the SFC group ( (17.87±8.17)% vs. (12.28±9.20)% , P=0.056 ) . There was no significant change in percentage wall area ( WA% ) after 24 weeks of add‐on treatment with montelukast . Patients receiving SFC+M showed significant improvement in the ratio of CT‐determined values at full expiration to those at full inspiration ( E/I ratio ) ( 0.894±0.005 vs. 0.871±0.003 , P=0.002 ) . Conclusion We have shown , using lung function tests and H RCT image technique , that add‐on therapy with montelukast improves distal lung function reflected by air trapping , but not airway wall thickness in moderate‐to‐severe asthma . ( Clinical Trials.gov number , NCT00699062 [17046300] BACKGROUND Pulmonary function tests ( PFTs ) and especially spirometry measures are useful tools in evaluating early response to treatment of asthma in children mainly due to their worldwide availability . The aim of our study was to determine the effects of anti-asthma treatment in children , equally on FEV(1 ) , FEF25 - 75 % , R(int ) and SR(aw ) values . METHODS Children 6 - 18 years of age with moderate atopic asthma were r and omized to 4-week , placebo-controlled , double-blind trial . Patients were r and omly allocated to receive 200 microg budesonide ( B ) ( n=29 ) , 5 or 10 mg ( according to age ) montelukast ( M ) ( n=29 ) , 200 microg B + 5 or 10 mg M ( n=29 ) , 200 microg B + 9 microg formoterol ( F ) ( n=29 ) or placebo ( n=27 ) . FEV(1 , ) FEF25 - 75 % , R(int ) , SR(aw ) were measured before and after treatment . RESULTS R(int ) , SR(aw ) , FEV(1 ) improved significantly in all active treatment groups while FEF25 - 75 % improved significantly only in BM group and M group . Combination therapy , showed significantly greater effects on R(int ) than monotherapy : BM group compared to B group ( P=0.01 ) and M group ( P=0.03 ) and BF group compared to B group ( P=0.01 ) and M group ( P=0.04 ) . CONCLUSION This study shows that using single parameter for monitoring asthma can be misleading . Using combination of lung function techniques provides better assessment of treatment . Results of our study confirm this hypothesis . The best effect on large and small airways was achieved with combined anti-inflammatory therapy [16680924] BACKGROUND Montelukast is a widely used controller agent in childhood asthma . It is modestly effective in reducing symptoms , decreasing the need for rescue albuterol , and improving forced expiratory volume in 1 second ( FEV1 ) . OBJECTIVE To determine whether montelukast therapy improves peripheral airway obstruction as measured by lung volumes , air trapping , airway resistance ( Raw ) , and specific conductance ( Sgaw ) . METHODS Twenty-one children aged 9 to 18 years with mild-to-moderate asthma were r and omized into a double-blind , placebo-controlled study to receive montelukast ( 5 or 10 mg ) or matching placebo daily for 8 weeks . Symptoms and albuterol use were recorded twice daily , and exhaled nitric oxide measurement , forced oscillometry , spirometry , and body box plethysmography ( before and after beta-agonist use ) were performed at r and omization and at 2 , 4 , 6 , and 8 weeks . Circulating eosinophil counts and serum eosinophil cationic protein ( ECP ) levels were obtained at r and omization and at 8 weeks . RESULTS Montelukast-treated patients had lower residual volume ( P = .05 ) , residual volume-total lung capacity ratio ( P = .04 ) , Raw ( P = .02 ) , Sgaw ( P = .03 ) , and serum ECP levels ( P = .02 ) at 8 weeks compared with those treated with placebo . There was a trend toward reduced daytime and nighttime albuterol use , although the difference did not reach statistical significance . There were no significant differences in FEV1 , FEV1-forced vital capacity ratio , exhaled nitric oxide levels , or daytime and nighttime symptom scores between the 2 groups . CONCLUSIONS Montelukast therapy was associated with less air trapping , hyperinflation , and Raw and better Sgaw compared with placebo . Lower serum ECP levels , a surrogate measure of airway inflammation , were associated with improvements in lung function [14609035] BACKGROUND Zafirlukast is a leukotriene receptor antagonist that was invented to treat patients with chronic asthma . METHODS To evaluate whether the zafirlukast improved the peak expiratory flow rate ( PEFR ) and clinical symptoms , 31 asthmatic patients with moderate persistent asthma who received regular inhaled corticosteroid were r and omly divided into the study group ( N = 17 ) . They received the zafirlukast 20 mg bid for 4 weeks , and the control group ( N = 14 ) received a placebo . Daily morning and evening PEFR and St. George 's Respiratory Question naire ( SGRQ ) scoring were recorded respectively . The levels of serum IgE and urine leukotriene E4 before and after treatment were measured using enzyme linked immunosorbent assay and enzyme immunoassay kits . RESULTS In the zafirlukast treated group , the morning PEFR was significantly improved from 314.4 + /- 20.6 to 340.6 + /- 18.3 L/min ( N = 17 , p < 0.05 ) after 4 weeks of treatment , while the control group did not show any significant changes . The zafirlukast group had significant improvement in their symptom scores of SGRQ from 48.6 + /- 4.6 to 33.8 + /- 4.7 ( N = 17 , p < 0.05 ) . However , the placebo did not improve the symptom scores . CONCLUSION Leukotriene receptor antagonists effectively improved symptoms and benefited lung function for moderate persistent asthmatic patients who had received regular treatments with inhaled steroids [11929492] Background Levels of an immunoregulatory and anti‐inflammatory cytokine IL‐10 are reduced in asthmatic airways , potentially contributing to more intense inflammation . Triamcinolone has anti‐inflammatory properties and the anti‐inflammatory effects of montelukast and formoterol have been discussed [16236835] BACKGROUND Asthma and allergic rhinitis are both highly prevalent diseases and often coexist in patients . OBJECTIVE To investigate the effect of rhinitis therapy on asthma outcomes in adult and adolescent patients with both seasonal allergic rhinitis ( SAR ) and persistent asthma . METHODS A total of 863 patients ( mean baseline FEV1 81 % predicted ) were r and omized to receive open-label fluticasone propionate/salmeterol ( FSC ) , 100/50 microg bid for 4 weeks , plus either blinded fluticasone propionate aqueous nasal spray ( FPANS ) 200 microg/d , montelukast 10 mg/d , or placebo . Patients kept daily records of peak expiratory flow ( PEF ) , asthma , and rhinitis symptoms and rescue albuterol use . RESULTS FPANS added to FSC result ed in superior outcomes for daytime total nasal symptom scores ( D-TNSS ) and individual daytime nasal specific symptoms ( congestion , rhinorrhea , sneezing , and itching ) compared with montelukast plus FSC and placebo plus FSC ( p < or = 0.001 ) . Montelukast plus FSC was superior to placebo plus FSC only for D-TNSS and itching and sneezing . Morning PEF , asthma symptoms , and rescue albuterol use improved significantly ( p < or = 0.001 ) in all treatment groups , but improvements were comparable across the treatment groups . CONCLUSION In patients with persistent asthma treated with FSC , the addition of montelukast or FPANS for the treatment of SAR result ed in no additional improvements in overall asthma control compared with FSC alone . However , FPANS provided superior rhinitis control compared with montelukast . These data suggest that asthma and rhinitis should each be optimally treated [10353583] BACKGROUND New drug evaluations in patients with mild asthma are sometimes complicated by enrollment of patients whose disease is too mild to show improvement with therapy . A peak expiratory flow ( PEF ) variability criterion may help to more clearly define a mild asthmatic population . OBJECTIVE To evaluate the effectiveness of zafirlukast ( 20 mg twice daily ) and cromolyn sodium ( 1600 microg four times daily ) compared with placebo as first-line therapy for mild asthma using a retrospective analysis , which stratified patients by PEF variability ( < 10 % or > or = 10 % ) . STUDY DESIGN Symptomatic patients ( daytime asthma symptoms score > or = 8) were r and omized to 13 weeks of treatment in a double-blind , double-dummy , placebo-controlled , parallel-group , multicenter trial . PATIENTS AND METHODS Patients ( n = 287 ) were nonsmokers ( age > or = 12 years ) with reversible airway disease , a forced expiratory volume in one second ( FEV1 ) of > or = 55 % of predicted , and previous treatment with beta2-agonist or theophylline only . Assessment s included changes from baseline to endpoint in daytime and nocturnal asthma symptoms , beta2-agonist use , PEF , and FEV1 . Response to treatment was assessed by predetermined diary card and FEV1 criteria . Safety was determined from adverse events and laboratory test results . RESULTS No significant treatment effects were seen across efficacy measures for patients with PEF variability < 10 % . For patients with PEF variability > or = 10 % , both active treatments significantly ( P < .05 ) decreased the daytime asthma symptoms score , nighttime awakenings , and beta2-agonist use , and increased morning PEF and FEV1 compared with placebo . Response to diary card criteria was 70 % and 75 % for zafirlukast and cromolyn , respectively ; response to FEV1 criteria was 47 % for both treatments . All treatments were tolerated well by patients . CONCLUSIONS Zafirlukast and cromolyn are effective first-line therapies for mild asthma , with both therapies producing greater benefits in patients whose PEF variability was > or = 10 % . In prospect i ve trials to evaluate therapies in patients with mild asthma , it may be worthwhile to include PEF variability with a 10 % cutoff either as an inclusion criteria or as a tool for subset analysis [11842294] BACKGROUND Anti-inflammatory properties of leukotriene modifiers and their effect on bronchial hyperresponsiveness have not been studied in children with asthma . OBJECTIVE The primary objective of this study was to determine the changes in serum levels of inflammatory mediators , clinical efficacy , and bronchial hyperresponsiveness after treatment with montelukast . METHODS In this double-blind , r and omized , placebo-controlled trial , 39 children with mild-to-moderate atopic asthma were r and omly allocated to receive montelukast or placebo for 6 weeks . Main outcome measures were changes in serum concentrations of soluble interleukin 2 receptor ( sIL-2R ) , IL-4 , and soluble intercellular adhesion molecule 1 ( sICAM-1 ) ; peripheral blood eosinophil count ; and eosinophilic cationic protein ( ECP ) . Asthma severity score , FEV(1 ) , and bronchial hyperreactivity ( BHR ) for histamine were secondary end points . RESULTS Compared to placebo , serum concentrations of IL-4 , sICAM-1 , and ECP and eosinophil blood counts significantly decreased after 6 weeks of treatment with montelukast . Montelukast significantly improved asthma control and FEV(1 ) . Montelukast result ed in within-group significant decrease in levels of serum sIL-2R ( 611 vs. 483 pg/mL ) , IL-4 ( 0.123 vs 0.102 pg/mL ) , sICAM-1 ( 280 vs. 244 ng/mL ) , and ECP ( 74 vs. 59 microg/mL ) and in eosinophil blood counts ( 349 vs. 310 cells/mm(3 ) ) . Mean FEV(1 ) value changed from 85 % of predicted to 95 % ( P < .001 ) and for histamine ( PC(20)H ) from 2.8 mg/mL to 3.8 mg/mL ( P < .001 ) after treatment with montelukast . There was no significant difference between montelukast and placebo recipients in the serum concentrations of sIL-2R and PC(20)H after treatment . CONCLUSION Montelukast provides clinical benefit to patients with chronic asthma and decreases bronchial hyperresponsiveness . Montelukast caused a statistically significant decrease of serum concentrations in cytokine , ICAM-1 , and ECP and peripheral blood eosinophil counts over the 6-week treatment period . This observation raises the possibility that leukotriene receptor antagonists , such as montelukast , may have effects on parameters of asthmatic inflammation [9679847] BACKGROUND The cysteinyl leukotrienes are important mediators of bronchial asthma . The clinical effect of montelukast , a potent cysteinyl leukotriene-receptor antagonist , was investigated in a r and omized , placebo-controlled , multicenter , parallel-group , dose-ranging study . METHODS After a 3-week , single-blind , placebo run-in period , 343 asthmatic patients ( FEV1 40 % to 80 % of the predicted value with an improvement in FEV1 of at least 15 % [ absolute value ] after receiving inhaled beta-agonists on at least two occasions ) were r and omly assigned to one of six treatment groups : placebo ; 10 , 100 , or 200 mg once daily montelukast in the evening ; or 10 or 50 mg twice daily montelukast for a 6-week , double-blind treatment period followed by a 1-week placebo washout period . All patients used inhaled , short-acting beta-agonists as needed . RESULTS All montelukast doses caused similar and significant differences compared with placebo in asthma control endpoints . The least-square mean difference between pooled montelukast groups and placebo in the percentage change from baseline in morning FEV1 ( 10.30 % ; 95 % CI : 5.56 to 15.04 ) , as-needed beta-agonist use ( -0.98 puffs ; 95 % CI : -1.53 to -0.44 ) , morning peak expiratory flow rate ( 18.80 L/min ; 95 % CI : 8.62 to 28.98 ) , physicians ' and patients ' global evaluations , and asthma-specific quality -of-life scores were all significant ( p < or = 0.050 ) . The incidence of adverse experiences was not dose related and was similar between placebo and montelukast treatment . CONCLUSION Montelukast caused a significant improvement in chronic asthma at an oral , once daily evening dose as low as 10 mg [12190656] Background Oral leukotriene receptor antagonists have been shown to have efficacy in chronic asthma [12740532] Background : Asthma and seasonal allergic rhinitis ( SAR ) are recognized as manifestations of a single airway disease . Desloratadine has demonstrated efficacy in treating SAR symptoms , including nasal obstruction . Methods : Safety and efficacy of desloratadine and montelukast each were assessed in a double-blind , placebo-controlled trial of patients with SAR and symptoms of asthma , who were assigned r and omly to once-daily treatment with desloratadine 5 mg , montelukast 10 mg , or placebo for 4 weeks . Change from baseline of AM/PM reflective total asthma symptom severity scores ( TASS ) , FEV1 , individual asthma symptom scores , and β2-agonist usage were assessed . Results : Desloratadine and montelukast each were associated with statistically significant reductions from baseline in the mean TASS averaged over the 4-week period ( p ≤0.022 vs. placebo ) . Individual asthma symptom scores also improved significantly for both therapies ( p ≤ 0.05 ) . Patients treated with desloratadine or montelukast demonstrated improvement from baseline in FEV1 versus placebo ; significant improvement was seen in a subset of patients with baseline FEV1 < 80 % of predicted normal ( both p < 0.05 ) . Both active therapies significantly reduced β2-agonist use ( both p < 0.01 ) . Improvements for both therapies were comparable for all efficacy parameters ; they were tolerated well with adverse event profiles similar to placebo . Conclusions : Asthma symptoms and β2-agonist were improved significantly in patients with concomitant SAR and asthma treated with desloratadine 5 mg as well as montelukast 10 mg once daily . Both therapies significantly improved FEV1 in a subset of patients with FEV1 < 80 % of predicted normal at entry . Improvements in asthma symptoms were comparable for both active treatment groups [9227718] BACKGROUND Leukotriene receptor antagonists have been shown to protect against bronchoconstriction induced by antigens , exercise , and cold air . There are relatively few clinical studies reported in patients with asthma . The present study is the first clinical evaluation of pranlukast ( SB 205312 , ONO-1078 ) outside Japan in patients with asthma . METHODS A r and omised , double blind , placebo controlled , parallel group , multicentre four week study of the safety and tolerability of oral pranlukast , 225 or 337.5 mg twice daily , was performed in patients with mild to moderate asthma . Preliminary efficacy data were obtained ; the main efficacy variables evaluated were forced expiratory volume in one second ( FEV1 ) and morning domiciliary ( home ) peak expiratory flow rates ( PEFR ) . Clinic PEFR and daytime and night-time asthma symptom scores were also recorded . RESULTS Compared with the placebo group the improvement in morning home PEFR was statistically significant at all time points for patients receiving pranlukast 337.5 mg twice daily and at weeks 1 and 2 for those treated with pranlukast in a dose of 225 mg twice daily . Mean morning home PEFR increased by 10.8 to 18.61/min ( 95 % CI 0.2 to 29.3 l/min ) in patients treated with pranlukast compared with a slight deterioration in those given placebo . FEV1 significantly increased within one hour after the first dose of pranlukast compared with baseline and this increase was maintained for eight hours . Improvements in trough FEV1-that is , at the end of the dosing interval-were statistically significant for the group treated with pranlukast 225 mg twice daily compared with placebo at week 4 . Mean increases in FEV1 ranged from 210 ml to 340 ml ( 95 % CI 60 to 500 ml ) at trough in the pranlukast group . Patients treated with pranlukast also showed improvements in summary symptom and night-time asthma scores . Pranlukast was well tolerated , and no drug related changes in haematological and biochemical variables were observed . CONCLUSIONS Pranlukast , an oral leukotriene receptor antagonist , is well tolerated and is effective for the treatment of asthma . It increased FEV1 within one hour of dosing , improved patient summary symptom and night-time asthma scores , and reduced the use of rescue bronchodilators , thus providing further evidence of a role for leukotrienes in the pathogenesis of asthma [18951618] BACKGROUND Clinical trials in children with moderate-to-severe persistent asthma are limited . OBJECTIVE We sought to determine whether azithromycin or montelukast are inhaled corticosteroid sparing . METHODS The budesonide dose ( with salmeterol [ 50 microg ] twice daily ) necessary to achieve control was determined in children 6 to 17 years of age with moderate-to-severe persistent asthma . After a budesonide-stable period of 6 weeks , children were r and omized in a double-masked , parallel , multicenter study to receive once-nightly azithromycin , montelukast , or matching placebos plus the established controlling dose of budesonide ( minimum , 400 microg twice daily ) and salmeterol twice daily . Primary outcome was time from r and omization to inadequate asthma control after sequential budesonide dose reduction . RESULTS Of 292 children screened , only 55 were r and omized . Inadequate adherence to study medication ( n = 80 ) and improved asthma control under close medical supervision ( n = 49 ) were the major reasons for r and omization failure . A futility analysis was requested by the Data Safety Monitoring Board . In data available for analyses , no differences were noted for either treatment compared with placebo in time to inadequate control status ( median : azithromycin , 8.4 weeks [ 95 % confidence limit , 4.3 - 17.3 ] ; montelukast , 13.9 weeks [ 95 % confidence limit , 4.7 - 20.6 ] ; placebo , 19.1 weeks [ 95 % confidence limit , 11.7-infinity ] ) , with no difference between the groups ( log-rank test , P = .49 ) . The futility analysis indicated that even if the planned sample size was reached , the results of this negative study were unlikely to be different , and the trial was prematurely terminated . CONCLUSION Based on these results , neither azithromycin nor montelukast is likely to be an effective inhaled corticosteroid-sparing alternative in children with moderate-to-severe persistent asthma [11485708] OBJECTIVE The objective of our study was to compare the efficacy and safety of fluticasone propionate ( an inhaled corticosteroid ) with zafirlukast ( a leukotriene modifier ) for persistent asthma . STUDY DESIGN In this r and omized placebo-controlled , parallel-group , double-blind , double-dummy trial , patients underwent an 8- to 14-day run-in period followed by 12 weeks of treatment with inhaled fluticasone propionate ( 88 mg twice daily by metered-dose inhaler ) , oral zafirlukast ( 20 mg twice daily ) , or placebo . POPULATION We included a total of 338 persistent asthma patients , 12 years of age or older , using short-acting b2-agonists alone . OUTCOMES measured Efficacy outcomes included changes in pulmonary function , asthma symptoms , rescue albuterol use , nighttime awakenings due to asthma , and quality of life . Safety outcomes included asthma exacerbations , adverse events , and clinical ly significant laboratory test results . RESULTS After 12 weeks of treatment , patients taking fluticasone propionate experienced significantly greater improvements in all clinical parameters ( symptom scores , percentages of symptom-free and albuterol-free days , albuterol use , and nighttime awakenings ) compared with patients taking zafirlukast ( P < .05 ) or placebo ( P < .05 ) . Treatment with fluticasone propionate result ed in significantly greater improvements in pulmonary function compared with zafirlukast ( P < .05 ) or placebo ( P < .05 ) . Fewer fluticasone propionate patients ( 4 % ) had an exacerbation requiring oral corticosteroids compared with those taking zafirlukast ( 12 % ) or placebo ( 10 % ) . CONCLUSIONS Inhaled fluticasone propionate is more effective than zafirlukast in controlling asthma symptoms , improving pulmonary function , and improving quality of life for patients who are symptomatic with the use of short-acting b2-agonists alone [17166989] STUDY OBJECTIVES The distal airways are likely to contribute to asthma pathobiology and symptoms but have rarely been specifically evaluated in relation to systemic oral therapy . We hypothesized that treatment with montelukast , an oral cysteinyl-leukotriene receptor antagonist , would improve both proximal and distal lung physiology in patients with mild asthma . DESIGN R and omized , double-blind , crossover design . SETTING Academic referral center . PATIENTS Subjects with mild asthma limited to using short-acting inhaled beta(2)-agonists . INTERVENTIONS Nineteen subjects with mild asthma underwent a baseline assessment of lung function , lung mechanics , and symptoms , followed by r and omization to therapy with montelukast , 10 mg taken in the evening , or placebo in a crossover , double-blind fashion . Each treatment phase lasted 4 weeks , with a 2-week washout period . A repeat evaluation was performed during the last week of each treatment phase . MEASUREMENTS AND RESULTS Montelukast result ed in improvement in ( mean + /- SD ) proximal and distal lung function parameters ( change in FEV(1 ) : montelukast , 0.16 + /- 0.06 L ; placebo , -0.05 + /- 0.05 L ; p = 0.008 ) ; change in specific conductance : montelukast , 7.2 + /- 2.9 % predicted ; placebo , -17 + /- 8 % predicted ; p = 0.007 ; change in % predicted residual volume [ RV ] : montelukast , 18.4 + /- 8.3 % predicted ; placebo , 3.0 + /- 2.9 % predicted ; p = 0.05 ) . Improvement in symptoms ( ie , wheeze and chest tightness ) correlated with improvements in RV while receiving montelukast , but not while receiving placebo ( Pearson coefficients : 0.55 and 0.66 , respectively ; p < 0.008 and 0.04 , respectively ) . CONCLUSIONS The systemically acting oral agent montelukast improves proximal and distal lung physiology . Improvements in distal lung function correlate with improvements in asthma symptoms [8087328] The efficacy of 6 wk of therapy with oral ICI 204,219 , a selective leukotriene D4 ( LTD4 ) receptor antagonist , was evaluated in subjects with moderate asthma during a multicenter , double-blind , r and omized , placebo-controlled , dose-ranging study . Subjects who entered the trial had been chronically treated for asthma with beta agonist alone or in combination with theophylline . Subjects were r and omized to treatment with twice daily doses of ICI 204,219 ( 5 , 10 , or 20 mg ) or placebo if they had an FEV1 between 40 and 75 % of predicted values without bronchodilator therapy and a daytime asthma score > 10 ( range 0 to 21 per wk ) for 7 consecutive d. Efficacy was evaluated from the results of symptom assessment s , pulmonary function tests , and rescue medication use . Of 276 subjects r and omized to treatment , 266 ( 10 mg , n = 66 ; 20 mg , n = 67 ; 40 mg , n = 67 ; placebo , n = 66 ) were analyzed for efficacy . Diary card assessment s showed that treatment with increasing doses of ICI 204,219 linearly improved five efficacy criteria without increasing the number or severity of adverse events . The 40 mg dose was more effective than placebo ( p < 0.05 ) in reducing nighttime awakenings , first morning asthma symptoms , the daytime asthma score , and albuterol use and in increasing evening peak expiratory flow ( PEF ) rates as well as FEV1 . Compared with baseline measurements , the 40 mg dose decreased awakenings by 46 % , albuterol use by 30 % , and daytime symptoms by 26 % and increased FEV1 by 11 % . ICI 204,219 improves objective and subjective measures of asthma severity in moderately ill asthmatic subjects and may provide a new treatment option for the disease [10398629] Abstract Objective : To determine the ability of montelukast , a leukotriene receptor antagonist , to allow tapering of inhaled corticosteroids in clinical ly stable asthmatic patients . Design : Double blind , r and omised , placebo controlled , parallel group study . After a single blind placebo run in period , during which ( at most ) two inhaled corticosteroids dose decreases occurred , qualifying , clinical ly stable patients were allocated r and omly to receive montelukast ( 10 mg tablet ) or matching placebo once daily at bedtime for up to 12 weeks . Setting : 23 academic asthma centres in United States , Canada , and Europe . Participants : 226 clinical ly stable patients with chronic asthma receiving high doses of inhaled corticosteroids ( 113 r and omised to montelukast and 113 to placebo ) . Interventions : Every 2 weeks , the inhaled corticosteroids dose was tapered , maintained , or increased ( rescue ) based on a st and ardised clinical score . Main outcome measures : Last tolerated dose of inhaled corticosteroids . Results : Compared with placebo , montelukast allowed significant ( P=0.046 ) reduction in the inhaled corticosteroid dose ( montelukast 47 % v placebo 30 % ; least square mean difference 17.6 % , 95 % confidence interval 0.3 to 34.8 ) . Fewer patients on montelukast ( 18 ( 16 % ) v 34 ( 30 % ) placebo , P=0.01 ) required discontinuation because of failed rescue . Conclusions : Montelukast reduces the need for inhaled corticosteroids among patients requiring moderate to high doses of corticosteroid to maintain asthma control . Key messages Leukotriene receptor antagonists have complementary action to inhaled corticosteroids in asthma Many patients receive higher doses of inhaled corticosteroids than clinical ly required In this placebo controlled trial , montelukast allowed significant reduction of inhaled corticosteroid doses Fewer patients receiving montelukast had failed rescue than patients receiving [15526805] OBJECTIVES To compare the effects of addition of montelukast or salmeterol to inhaled corticosteroids ( ICS ) on the response to rescue beta2-agonist use after exercise-induced bronchoconstriction . METHODS A double-blind , placebo-controlled study was performed at 16 centers in the United States . Patients with asthma ( n = 122 , ages 15 - 58 ) whose symptoms were uncontrolled on Low-dose inhaled fluticasone and who had a history of exercise-induced worsening of asthma were r and omized to receive either montelukast ( 10 mg once daily ) , salmeterol ( 50microg twice daily ) , or placebo for 4 weeks . St and ardized spirometry after exercise challenge and beta2-agonist rescue was performed at baseline , week 1 and 4 . RESULTS Maximum achievable forced expiratory volume in 1 s ( FEV1 ) percent predicted after rescue beta2-agonist improved in the montelukast ( + 1.5 % ) and placebo ( + 1.2 % ) groups at 4 weeks , but diminished in the salmeterol ( -3.9 % ) group ( P < 0.001 ) . Although pre-exercise FEV1 was greatest with salmeterol ( P = 0.10 ) , patients taking montelukast had significantly greater protection from an exercise-induced decrease in FEV1 than those taking salmeterol ( P < 0.001 ) . Both the magnitude and rate of rescue bronchodilation were greater with montelukast compared with salmeterol ( P < 0.001 ) . Five minutes after rescue beta2-agonist , 92 % of patients taking montelukast and 68 % of those taking placebo had recovered to pre-exercise levels , whereas only 50 % of those taking salmeterol had recovered to pre-exercise levels . CONCLUSION In patients whose asthma symptoms remain uncontrolled using ICS , addition of montelukast permits a greater and more rapid rescue bronchodilation with a short-acting beta2-agonist than addition of salmeterol and provides consistent and clinical ly meaningful protection against exercise-induced bronchoconstriction [15572850] Mild persistent asthma is most effectively controlled with inhaled corticosteroids . Leukotriene receptor antagonists have complementary effects to corticosteroids on inflammation control . The additional effect of a leukotriene receptor antagonist , zafirlukast , was investigated in stable asthma patients under control with inhaled budesonide . We conducted a r and omised , double-blind , placebo-controlled , single center trial to investigate the effects of add-on zafirlukast treatment to budesonide , on symptom score , pulmonary function , bronchial responsiveness , and serum levels of eosinophilic cationic protein ( ECP ) and antioxidant capacity in stable asthmatic patients under control with inhaled budesonide . The present study included 21 mild or moderate asthmatic patients ( 8 males and 13 females ) , who were stable at least for 6 weeks with inhaled budesonide ( 400 microg/day ) . Serum total antioxidant capacity ( TAC ) and ECP levels were measured , and symptom scoring , spirometry , and bronchial provocation with methacholine were performed . Then , the patients were r and omised to use either placebo or oral zafirlukast ( 40 mg/day ) in addition to budesonide for 6 weeks . At the 6th week , symptom scoring , spirometry , and bronchial provocation tests were repeated and serum TAC and ECP levels were measured again . After add-on zafirlukast treatment to budesonide , forced expiratory volume in 1 second ( FEV(1 ) ) , TAC and ECP values did not change significantly ( p > 0.05 ) but bronchial hyperresponsiveness and symptom score decreased significantly ( p = 0.022 ) compared to baseline . Thus , in stable asthmatic patients , add-on zafirlukast treatment to budesonide improves symptoms and decreases bronchial hyperresponsiveness [9625400] OBJECTIVES To determine the clinical effect of oral montelukast sodium , a leukotriene receptor antagonist , in asthmatic patients aged 15 years or more . DESIGN R and omized , multicenter , double-blind , placebo-controlled , parallel-group study . A 2-week , single-blind , placebo run-in period was followed by a 12-week , double-blind treatment period ( montelukast sodium , 10 mg , or matching placebo , once daily at bedtime ) and a 3-week , double-blind , washout period . SETTING / PATIENTS Fifty clinical centers r and omly allocated 681 patients with chronic , stable asthma to receive placebo or montelukast after demonstrating a forced expiratory volume in 1 second 50 % to 85 % of the predicted value , at least a 15 % improvement in forced expiratory volume in 1 second ( absolute value ) after inhaled beta-agonist administration , a minimal predefined level of daytime asthma symptoms , and inhaled beta-agonist use . Twenty-three percent of the patients used concomitant inhaled corticosteroids . PRIMARY END POINTS : Forced expiratory volume in 1 second and daytime asthma symptoms . RESULTS Montelukast improved airway obstruction ( forced expiratory volume in 1 second , morning and evening peak expiratory flow rate ) and patient-reported end points ( daytime asthma symptoms , " as-needed " beta-agonist use , nocturnal awakenings ) ( P<.001 compared with placebo ) . Montelukast provided near-maximal effect in these end points within the first day of treatment . Tolerance and rebound worsening of asthma did not occur . Montelukast improved outcome end points , including asthma exacerbations , asthma control days ( P<.001 compared with placebo ) , and decreased peripheral blood eosinophil counts ( P<.001 compared with placebo ) . The incidence of adverse events and discontinuations from therapy were similar in the montelukast and placebo groups . CONCLUSIONS Montelukast , compared with placebo , significantly improved asthma control during a 12-week treatment period . Montelukast was generally well tolerated , with an adverse event profile comparable with that of placebo [9847434] BACKGROUND Previous trials demonstrated the effectiveness of the leukotriene receptor antagonist zafirlukast in patients with mild-to-moderate asthma . OBJECTIVES We sought to assess the efficacy and safety of zafirlukast and its effect on patients ' quality of life ( QOL ) during a 13-week , double-blind , placebo-controlled , multicenter trial in adults and adolescents with moderate reversible airflow obstruction . METHODS Patients ( age range , 12 to 68 years ) with total daytime asthma symptoms scores of 10 or greater over 7 consecutive days ( maximum , 21/wk ) , FEV1 45 % or greater but less than or equal to 80 % of predicted value ( > /=6 hours after beta2 -agonist ) , and reversible airway disease were r and omized to 20 mg zafirlukast twice daily ( nZ = 231 ) or placebo twice daily ( nP = 223 ) . Efficacy was assessed from changes in daytime and nocturnal symptoms , beta2 -agonist use , nasal congestion score , and pulmonary function . QOL was evaluated with a disease-specific Asthma Quality of Life Question naire . Safety was determined from adverse event information and clinical laboratory test results . RESULTS Zafirlukast was significantly ( P < .001 ) more effective than placebo , with reductions from baseline in the daytime asthma symptoms score ( -23 % ) , nighttime awakenings with asthma ( -19 % ) , and beta2 -agonist use ( -24 % ) and improvements from baseline in morning ( + 25 L/min ) and evening ( + 18 L/min ) peak expiratory flow rates . Compared with placebo , zafirlukast significantly ( P < /=.018 ) improved scores for QOL domains ( activity limitations , symptoms , emotional function , and exposure to environmental stimuli ) and overall QOL , with a significantly greater proportion of zafirlukast-treated patients demonstrating clinical ly meaningful improvements ( > /=0.5-unit change from baseline ; P < /=.037 ) . The safety profile of zafirlukast was clinical ly indistinguishable from that of placebo . CONCLUSIONS Zafirlukast is effective and well tolerated and improves QOL in the long-term treatment of patients with moderate reversible airflow obstruction [11779723] Leukotriene antagonists block the proinflammatory actions of leukotrienes ( LT ) and have been introduced as new treatments for asthma . Conventional therapy with glucocorticosteroids does not inhibit the bio synthesis of leukotrienes . We therefore tested whether addition of the leukotriene receptor antagonist montelukast was of therapeutic benefit in a group of aspirin-intolerant patients with asthma of whom 90 % already were treated with moderate to high doses of glucocorticosteroids . Under double-blind conditions , 80 aspirin-intolerant patients with asthma were r and omized to receive 4 wk oral treatment of either 10 mg of montelukast or placebo once daily at bedtime . Pulmonary function was measured as forced expiratory volume in 1 s ( FEV(1 ) ) once a week in the clinic and daily as morning and evening peak expiratory flow rate ( PEFR ) . Asthma symptoms and use of rescue bronchodilator were also recorded daily . Asthma specific quality of life ( QoL ) was assessed before and after the treatments . The group receiving montelukast showed a remarkable improvement of their asthma , whereas the group given placebo showed no change . Thus , from equal baseline values , the mean difference between the groups over the 4-wk treatment period was 10.2 % for FEV(1 ) and 28.0 L for morning PEFR ( p for both < 0.001 ) . The improved pulmonary function in the group receiving montelukast occurred at the same time as 27 % less bronchodilator was used ( p < 0.05 ) , and it was associated with fewer asthma symptoms than in the group given placebo , including 1.3 nights more of sleep per week and 54 % fewer asthma exacerbations ( p < 0.05 ) . There was also an improvement in asthma-specific QoL ( p < 0.05 ) . The therapeutic response to montelukast was consistent across patients with different baseline characteristics and did not correlate with baseline urinary LTE(4 ) . Addition of a leukotriene receptor antagonist such as montelukast improves asthma in aspirin-intolerant patients over and above what can be achieved by glucocorticosteroids [19632710] BACKGROUND Information that enhances expectations about drug effectiveness improves the response to placebos for pain . Although asthma symptoms often improve with placebo , it is not known whether the response to placebo or active treatment can be augmented by increasing expectation of benefit . OBJECTIVE The study objective was to determine whether response to placebo or a leukotriene antagonist ( montelukast ) can be augmented by messages that increase expectation of benefit . METHODS A r and omized 20-center controlled trial enrolled 601 asthmatic patients with poor symptom control who were assigned to one of 5 study groups . Participants were r and omly assigned to one of 4 treatment groups in a factorial design ( ie , placebo with enhanced messages , placebo with neutral messages , montelukast with enhanced messages , or montelukast with neutral messages ) or to usual care . Assignment to study drug was double masked , assignment to message content was single masked , and usual care was not masked . The enhanced message aim ed to increase expectation of benefit from the drug . The primary outcome was mean change in daily peak flow over 4 weeks . Secondary outcomes included lung function and asthma symptom control . RESULTS Peak flow and other lung function measures were not improved in participants assigned to the enhanced message groups versus the neutral messages groups for either montelukast or placebo ; no differences were noted between the neutral placebo and usual care groups . Placebo-treated participants had improved asthma control with the enhanced message but not montelukast-treated participants ; the neutral placebo group did have improved asthma control compared with the usual care group after adjusting for baseline difference . Headaches were more common in participants provided messages that mentioned headache as a montelukast side effect . CONCLUSIONS Optimistic drug presentation augments the placebo effect for patient-reported outcomes ( asthma control ) but not lung function . However , the effect of montelukast was not enhanced by optimistic messages regarding treatment effectiveness

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### Context: [10848924] Pranlukast ( 8‐[p‐(4‐phenylbutyloxy ) benzol ] amino‐2‐[tetrazol‐5‐yl]‐4‐oxo‐4H‐1‐benzopyran hemihydrate ) , a selective cysteinyl leukotriene receptor antagonist , has been reported to exhibit not only antileukotrine activity but also pharmacological activity including antieosinophilic effects [10193369] BACKGROUND It has been reported that pranlukast reduces the antigen induced immediate and late phase asthmatic responses , airway hyperreactivity to acetylcholine , and pulmonary eosinophil accumulation in guinea pigs . A study was undertaken to test the hypothesis that pranlukast may reduce the number of inflammatory cells in the bronchial mucosa of patients with asthma . METHODS A double blind , placebo controlled study was performed in 17 mild to moderate asthmatic subjects to examine changes in inflammatory cell infiltration in response to pranlukast ( 225 mg orally twice per day for four weeks ) . Comparisons of the mean daily β2 agonist use , symptom score , FEV1 percentage predicted , and airway methacholine responsiveness were made before and after treatment . Using fibreoptic bronchoscopy , bronchial biopsy specimens were obtained before and after treatment with either pranlukast ( n = 10 ) or placebo ( n = 7 ) . Immunohistology was performed using monoclonal antibodies for CD3 , CD4 , CD8 , CD68 , NP57 , AA1 , EG1 , EG2 , γGTP and CD19 . RESULTS When the pranlukast and placebo treated groups were compared there were decreases in β2agonist use , symptom score , and airway methacholine responsiveness after pranlukast but no increase in FEV1 was seen . The clinical response in patients treated with pranlukast was accompanied by a reduction in CD3 ( median difference –37 , 95 % confidence interval ( CI ) –69 to –1 ; p<0.05 ) , CD4 ( median difference –28 , 95 % CI –49 to –8 ; p<0.01 ) , AA1 ( median difference –15 , 95 % CI –26 to 0 ; p<0.05 ) and EG2 positive cells ( 95 % CI –35 to 0 ; p<0.05 ) , but not in EG1 positive eosinophils , γGTP positive cells , and CD19 positive plasma cells . CONCLUSIONS These results support the view that pranlukast may act by inhibition of bronchial inflammation in patients with asthma [4155393] Background Asthma affects mainly Venezuela ’s urban and poor majority . Exacerbations bring about a high dem and in health services , thus becoming a significant public health problem . In general , asthma control programs ( GINA ) with use of inhaled steroid medications have proven effective , although their implementation in real life remains cumbersome . Montelukast could be a useful and practical tool for these deprived socioeconomic sectors . Methods This real-life pilot study was conducted in a prospect i ve , double blinded , placebo-controlled manner with r and omized and parallel groups . Asthmatics that had never used leukotriene modifiers were recruited and followed-up every three months . The main outcome was the number of exacerbations meriting use of nebulized bronchodilators administered by the health care system . Results Eighty-eight asthmatic patients were enrolled , between children and adults . Groups were comparable in : demographic data , previous use of other medications , ACT scores , pulmonary functions ( Wright Peak Flow meter ) , allergy status ( Skin Prick Test ) as well as adherence to the prescribed Montelukast treatment . By an intention to treat ( ITT ) , a total of 64 patients were included for analysis . For the three and six months time points the difference between placebo and Montelukast was found to be significant ( p < 0.03 and p < 0.04 , respectively ) . Such trends continued for the rest of the year , but without statistical significance , due to patient attrition . Conclusions This real-life pilot study shows that a simplified strategy with oral Montelukast was practical and effective in controlling exacerbations in an asthmatic population of a vulnerable community from Caracas . Such an approach reinforces the role of primary care in asthma treatment [23380218] OBJECTIVE Many asthmatic patients are unable to quit cigarettes ; therefore information is needed on treatment options for smokers . This study evaluates 10 mg/d montelukast and 250 μg of fluticasone propionate twice daily , each compared with placebo , in patients with self-reported active smoking ( unable to quit ) and asthma . METHODS Patients ( ages 18 - 55 years , with asthma [ ≥1 year ] , FEV1 of 60 % to 90 % of predicted value , airway reversibility [ ≥12 % ] , and self-reported active smoking [ ≥0.5 to ≤2 packs per day ] ) were r and omized ( after a 3-week , single-blind , placebo , run-in period ) to 1 of 3 parallel , 6-month , double-blind treatment arms . The primary efficacy end point was the percentage of days with asthma control during treatment . Adverse experiences ( AEs ) were also evaluated . RESULTS There were 347 , 336 , and 336 patients r and omized to montelukast , fluticasone , and placebo , respectively . The mean percentage of days with asthma control over 6 months of treatment was 45 % ( montelukast , P < .05 vs placebo ) , 49 % ( fluticasone , P < .001 vs placebo ) , and 39 % ( placebo ) ; the difference between montelukast and fluticasone was not significant ( P = .14 ) . Patients with a smoking history of ≤11 pack years ( the median value ) tended to show more benefit with fluticasone , whereas those with a smoking history of > 11 pack years tended to show more benefit with montelukast . AEs occurred in similar proportions among treatment groups . CONCLUSIONS In a population of asthmatic patients actively smoking cigarettes , both 10 mg/d montelukast and 250 μg of fluticasone propionate twice daily significantly increased the mean percentage of days with asthma control compared with placebo [21370724] BACKGROUND Leukotrienes , especially LTC4 , are important inflammatory mediators in allergic and nonallergic inflammation of the entire airways . Of particular interest are numerous theories regarding the pathogenesis of aspirin intolerance with subsequent hyperproduction of leukotrienes and inhibition of cyclooxygenase . OBJECTIVE To examine the influence of the cysteinyl-leukotriene receptor antagonist montelukast on clinical symptoms and inflammatory markers in nasal lavage fluid in patients with bronchial asthma and nasal polyps , and determine its dependency on aspirin sensitization . METHODS Twenty-four patients ( 7 women , 17 men ; median age , 55.5 years ) with nasal polyps and controlled asthma ( n=12 with aspirin intolerance ) were treated with 10 mg montelukast once daily for 6 weeks in a blinded , placebo-controlled fashion . The placebo phase was r and omly assigned 4 weeks before ( n=12 ) or after treatment ( n=12 ) . Symptom score , rhinoendoscopy , rhinomanometry , smears for eosinophils , and nasal lavages for the determination of different mediators were performed . RESULTS Compared to placebo , there were significant improvements in the nasal symptom score and airflow limitation as well as a reduction in the inflammatory mediators in nasal lavage fluid after treatment . Furthermore , reduced eosinophils in nasal smears and peripheral blood were observed 2 and 6 weeks after treatment . CONCLUSION Leukotriene 1 receptor blockade led to a significant decrease in eosinophil inflammation accompanied by a reduction in other mediators such as neurokinin A and substance P in the nasal lavage fluid of patients with nasal polyps and asthma , with or without aspirin intolerance [15462688] SUMMARY Objective : The objective of this study was to evaluate montelukast 10 mg daily as treatment for allergic rhinitis in patients with symptomatic allergic rhinitis and active asthma during the allergy season . Methods : This was a multicenter study of 831 patients ( ages 15 years–85 years ) with seasonal allergen sensitivity , active symptoms of seasonal allergic rhinitis , and active asthma . Following a single-blind , placebo run-in period of 3 days–5 days , patients were r and omized to oral montelukast 10 mg ( n = 415 ) or placebo ( n = 416 ) daily during the 2-week , double-blind , active-treatment period . Main outcome measures : The primary endpoint was Daily Rhinitis Symptoms score , average of Daytime Nasal Symptoms and Nighttime Symptoms , as self-rated by patients on a 0–3 scale on daily diaries . Results : Montelukast reduced the Daily Rhinitis Symptoms score : difference between montelukast and placebo in mean change from baseline was –0.12 [ 95 % CI –0.18 , –0.06 ; p ≤ 0.001 ] . Similar improvements were seen in Daytime Nasal Symptoms ( –0.14 [ –0.21 , –0.07 ; p ≤ 0.001 ] ) and Nighttime Symptoms ( –0.10 [ –0.16,–0.04 ; p ≤ 0.001 ] ) . Improvements ( p < 0.05 ) were seen in Daytime Eye Symptoms and in the secondary endpoints of Global Evaluations of AR by Patient and by Physician , and Rhinoconjunctivitis Quality of Life . In exploratory analyses , improvement in rhinitis symptoms was numerically ( though not statistically ) larger in patients with greater levels of asthma at study start . Montelukast provided benefit in the Global Evaluations of Asthma by Patient and by Physician : mean differences were –0.24 [ –0.41 , –0.06 ; p = 0.008 ] and –0.17 [ –0.33,–0.01 ; p = 0.037 ] . Similarly , as-needed β-agonist use ( puffs/day ) was reduced with montelukast ( p ≤ 0.005 ) . Conclusion : Montelukast provides significant relief from symptoms of seasonal allergic rhinitis , while also conferring a benefit for asthma , in patients with both allergic rhinitis and asthma [10075616] For patients with persistent asthma , the National Asthma Education and Prevention Program recommends the regular use of controller medications to provide long-term control , together with as-needed use of rescue medications ( 1 ) . Inhaled corticosteroids are currently the most commonly used controller medications ( 1 ) . Although inhalation into the airway has advantages in terms of both safety and efficacy , problems with compliance with inhaled agents may limit their real-world effectiveness , especially in elderly and pediatric patients ( 2 , 3 ) . Cysteinyl leukotrienes are important pro-inflammatory mediators of asthma ( 4 ) . Recent clinical studies of leukotriene receptor antagonists ( 5 - 7 ) and a 5-lipoxygenase inhibitor ( 8) have shown these agents to have clinical benefit in patients with chronic asthma , and treatment guidelines now consider these agents alternative , first-line controller medications ( 1 ) . Recent studies showed that montelukast , a potent and specific leukotriene receptor antagonist ( 9 ) , had efficacy in adult ( over a 12-week period ) and pediatric ( over an 8-week period ) patient with chronic asthma and had a tolerability profile similar to that of placebo ( 10 - 12 ) . To date , no comparisons of leukotriene receptor antagonists and inhaled corticosteroids have been published . Our placebo-controlled , parallel-group study , which was primarily design ed to compare the effect of montelukast with that of placebo in a phase III clinical development trial , also compared montelukast and inhaled beclomethasone in patients with chronic asthma who require the daily use of a controller medication . Methods Patients Healthy , nonsmoking , male and female patients 15 years of age and older were eligible to participate if they had had asthma for at least 1 year before the initial study evaluation . Each patient also had to have 1 ) an FEV1 between 50 % and 85 % of predicted value , 2 ) an increase of at least 15 % in absolute FEV1 after the use of inhaled -agonist on at least two of three visits during period 1 [ see below ] , 3 ) a daytime asthma symptom score of at least 64 [ of a possible 336 ] , and 4 ) average daily use of at least one puff of as-needed , short-acting , inhaled -agonist ( salbutamol ) . Patients were excluded from the study if they had used inhaled and oral corticosteroids , cromolyn , or nedocromil within 4 weeks before the initial evaluation ; had used long-acting -agonists , antimuscarinics , and newly instituted theophylline within 2 weeks before the initial evaluation ; or had used long-acting antihistamines ( for example , they could not have used astemizole within 3 months of the initial evaluation , and they could not have used terfenadine or loratadine within 2 weeks of the initial evaluation ) . Intermittent use of short-acting antihistamines was allowed , and immunotherapy was permitted if it had been started at least 6 months before the initial study evaluation and if the monthly dose remained constant . Protocol Our r and omized , double-dummy , placebo-controlled , parallel-group trial had a 2-week , single-blind placebo run-in period ( period 1 ) ; a 12-week , double-blind treatment period ( period 2 ) ; and a 3-week , double-blind placebo washout period [ period 3 ] . Eligible patients were r and omly assigned to one of three treatment regimens : 1 ) montelukast , 10 mg once daily in the evening ; 2 ) inhaled beclomethasone , 200 g twice daily ; or 3 ) placebo . The ratio of montelukast recipients to beclomethasone recipients to placebo recipients was 3:2:2 , with a blocking factor of 7 , according to a single , computer-generated allocation schedule . Patients , investigators , and coordinating center staff were blinded to the treatment schedule until all corrections to the data base were completed . During period 3 , a subset of patients originally assigned to receive active treatment ( approximately 40 , as determined by the allocation schedule ) was switched to placebo in a blinded manner . The other patients originally assigned to receive active treatment continued to receive that treatment . This allowed us to assess withdrawal from therapy . The study was done at 36 clinical centers in 19 countries in Europe , Africa , Australia , Central America , and South America . The study protocol and informed consent were approved by local ethics review committees . All participants gave written informed consent before participation ; consent of parents or guardians was obtained for patients younger than 18 years of age . Patients were recruited from the patient pool of each clinical study center and through local newspaper advertisements . Medication The study medication consisted of 10-mg montelukast film-coated tablets , placebo tablets that were identical in appearance to the montelukast tablets , beclomethasone ( 100 g/puff ) in inhalers ( Allen & Hanburys , Stockley Park , United Kingdom ) , and placebo in inhalers identical to those used for beclomethasone . Patients were instructed to take one tablet at bedtime and to take two puffs from the inhaler ( using the AeroChamber spacer device [ Clement Clark , Columbus , Ohio ] ) at bedtime and in the morning . Short-acting , inhaled -agonist ( salbutamol , 100 g/puff ) ( Allen & Hanburys ) was to be used as needed . Patients with worsening episodes of asthma that required additional therapy were treated with oral corticosteroids according to a st and ard protocol . Patients who had more than two worsening episodes of asthma requiring corticosteroid therapy were dropped from the study . Measurements Central ized spirometry training was done according to st and ard American Thoracic Society criteria before the start of the study . Spirometry was done at each visit after inhaled -agonist therapy had been withheld for at least 6 hours , theophylline therapy had been withheld for at least 24 hours , and antihistamine therapy had been withheld for at least 48 hours . At least three spirometry maneuvers were done , and the largest FEV1 was reported . Spirometry data were transmitted electronically to a central data base and monitored continuously for quality , and feedback was given to the study centers ( 13 ) . If quality was not maintained , sites were visited by coordinating center personnel . Answers to four questions on daytime asthma symptoms and one question on nocturnal awakenings were collected on a daily diary card , as were morning and evening peak expiratory flow rate and daily use of as-needed salbutamol . With respect to daytime asthma symptoms , patients used a 7-point scale ( on which 0 means best and 6 means worst ) to rate the severity of symptoms , their frequency , the degree to which they were bothersome , and their impact on daily activities . These ratings were combined into a mean daily score . Nocturnal awakenings were evaluated by the patient 's response ( on a four-point scale ) to a single question ( 14 ) . The validation of these questions has been published elsewhere ( 14 ) . Peak expiratory flow was measured in the morning and in the evening immediately before study medication was taken . The best of three measurements was recorded . Prespecified end points other than peak expiratory flow included peripheral blood eosinophil counts , global evaluations by physicians and patients ( on a 7-point scale , on which 6 means very much worse and 0 means very much better ) ( 7 ) , and asthma-specific quality of life ( 15 ) . Asthma outcome end points , including asthma attacks ( defined as worsening asthma requiring oral corticosteroid treatment or an unscheduled visit to a physician , emergency department , or hospital ) , percentage of days with asthma exacerbations , and percentage of asthma-control days ( as defined elsewhere [ 11 , 16 ] ) , were also evaluated . The diary card , the Asthma Quality -of-Life Question naire ( 15 ) , and the global evaluation questions were translated from English into appropriate local language s and were vali date d for linguistic equivalence and cultural differences ( 17 ) . Patient compliance with study therapy was determined by weighing inhalers and counting tablets . The weight of a full canister was determined by averaging the weights of at least 50 canisters of beclomethasone and placebo . A st and ard puff weight was determined by repeatedly actuating and weighing 10 canisters . Laboratory safety tests , including hematologic tests , serum biochemistry analysis , and urinalysis , were done at prespecified visits , and the results were analyzed by a central laboratory . The central laboratory also determined eosinophil counts with an automated cell counter . Statistical Analysis Our primary objective was to compare montelukast with placebo with respect to two prespecified primary end points : FEV1 and daytime symptom score . Other objectives were to compare beclomethasone with placebo and to compare montelukast with beclomethasone in a stepwise manner in accordance with the Dunnet-Tamhane approach , with the comparison of montelukast and beclomethasone prespecified as an estimation of the difference using 95 % CIs ( 18 ) . No multiplicity adjustments were made for each of the secondary end points , which were prespecified as supportive . The analysis for each efficacy end point included all patients who had a measurement taken at baseline and at least one measurement taken after r and omization . Treatment responses were calculated as the average change or percentage change from baseline to period 2 ; the baseline value was the average value for period 1 . With SAS software ( SAS Institute , Inc. , Cary , North Carolina ) , we used an analysis of variance ( ANOVA ) model to estimate treatment group means and between-group differences and to construct 95 % CIs by using the least-square means and the differences in least-square means . The model contained factors for treatment , study center , and stratum ( theophylline use ) . The consistency of the treatment effect across study centers , strata , and subgroups ( which were formed according to sex , age , ethnicity , history of allergic rhinitis , and history of exercise-induced asthma ) was assessed by interaction testing done using the ANOVA model with an [11888953] OBJECTIVE Leukotrienes ( LTs ) are involved in airway eosinophilic inflammation in patients with asthma . We examined the effects of a cysteinyl LT 1-receptor antagonist , montelukast , on sputum eosinophil levels , and the correlation between sputum eosinophils and bronchodilatation in patients with asthma . DESIGN Double-blind , r and omized , crossover study . SETTING University hospital and private hospital . PATIENTS Twenty-nine patients with mild-to-moderate asthma . INTERVENTIONS Montelukast , 10 mg , and placebo tablet , once daily , each for 4 weeks . MEASUREMENTS Sputum eosinophils analyzed using hypertonic saline solution-induced sputum and airway hyperresponsiveness to histamine were evaluated before and after treatment . In addition , morning and evening peak expiratory flow ( PEF ) , asthma symptoms , and peripheral blood eosinophil levels were assessed . RESULTS The percentage of eosinophils in sputum decreased from 24.6 + /- 12.3 % at baseline to 15.1 + /- 11.8 % after montelukast treatment , for a change of - 9.5 + /- 12.7 % ( n = 20 ) . During placebo administration , the percentage of eosinophils fell from 21.3 + /- 12.1 % to 21.0 + /- 11.5 % , result ing in a decrease of - 0.3 + /- 10.8 % ( n = 20 ) . There was a statistically significant difference in the change in sputum eosinophil levels between these two periods ( p < 0.005 ) . The number of peripheral blood eosinophils also significantly decreased after montelukast treatment ( 314.1 + /- 237.6/mL ) compared with placebo ( 413.1 + /- 232.1/mL ; p < 0.005 , n = 21 ) . Although morning and evening PEF values were significantly improved from baseline after montelukast treatment ( p < 0.01 , n = 20 ) , asthma symptoms and airway responsiveness to histamine were not significantly altered . Furthermore , there was no significant correlation between the decrease in sputum eosinophils and the increase in PEF . CONCLUSION These results suggest that montelukast has anti-inflammatory effects on the airway in patients with asthma , and that its bronchodilatory effect is not solely dependent on a decrease in airway eosinophilia [12449158] The present study aim ed at comparing the effects of a dose reduction of inhaled corticosteroids on lung function , indirect measures of airway inflammation and clinical scores during treatment with a leucotriene receptor antagonist . In 50 patients ( mean forced expiratory volume in one second ( FEV1 ) 94 % predicted ) , steroid doses ( 800 µg beclomethasone dipropionate ) were first reduced to 50 % and then to 25 % , for 6 weeks each . One group received a placebo and the other group received montelukast ( 10 mg ) . The first reduction did not cause significant effects . During the second , FEV1 and peak expiratory flow decreased in both groups ( p<0.001 ) . Daytime symptoms were not altered with placebo but were reduced by montelukast ( p<0.05 ) . Night-time symptoms were slightly elevated with placebo ( p<0.05 ) but not montelukast , as well as the use of supplemental salbutamol . Changes in provocative concentration of methacholine causing a 20 % fall in FEV1 ( PC20 ) , sputum eosinophils and exhaled nitric oxide were mostly nonsignificant for both placebo and montelukast . These data demonstrate that a 75 % reduction in the dose of steroid given to patients with asthma led to a deterioration in lung function not prevented by montelukast , whereas changes in clinical state seemed to favour montelukast treatment . It therefore appears that potential effects of montelukast , in the presence of low-dose steroids , could not be attributed to single indices of lung function or airway inflammation [14674932] Background : Controlled clinical trials on the effects of leukotriene antagonists on asthma‐like symptoms , bronchial hyperresponsiveness and airway inflammation have not been performed in elite athletes [15136379] STUDY OBJECTIVES We have previously found that vascular endothelial growth factor ( VEGF ) levels in induced sputum were increased in asthmatic patients , and that its levels were closely associated with the degree of airway obstruction and microvascular permeability . Therefore , this study was design ed to examine the effects of pranlukast , a selective leukotriene receptor antagonist , on VEGF levels in induced sputum from steroid-untreated or steroid-treated asthmatic patients . DESIGN Double-blind , r and omized , placebo-controlled , crossover study . SETTING University hospital . PARTICIPANTS Twenty-three asthmatic patients ( steroid-untreated , 13 patients ; steroid-treated , 10 patients ) and 10 healthy control subjects . INTERVENTIONS All asthmatic patients received 4-weeks of therapy with pranlukast ( 225 mg bid ) , and sputum induction was performed before and after the 4-week treatment course . MEASUREMENTS AND RESULTS In steroid-untreated asthmatic patients , the mean percentage of eosinophils ( % EOS ) and mean eosinophil cationic protein ( ECP ) levels in induced sputum were significantly decreased after 4 weeks of pranlukast administration ( % EOS : before , 16.7 % [ SD , 7.1 % ] ; after , 12.3 % [ SD , 4.0 % ] ; p = 0.03 ; ECP levels : before , 774 ng/mL [ SD , 258 ng/mL ] ; after , 564 ng/mL [ SD , 204 ng/mL ] ; p = 0.034 ) . Moreover , VEGF levels in the induced sputum and the airway vascular permeability index also were decreased after pranlukast administration ( VEGF levels : before , 5,670 pg/mL [ SD , 1,780 pg/mL ] ; after , 4,380 pg/mL [ SD , 1,540 pg/mL ] ; p = 0.026 ; airway vascular permeability index : before , 0.032 [ SD , 0.012 ] ; after , 0.017 [ SD , 0.006 ] ; p = 0.01 ) . In addition , the change in airway vascular permeability index from before to after pranlukast administration was significantly correlated with the change in VEGF levels ( r = 0.782 ; p = 0.007 ) . However , in steroid-treated asthmatic patients there was no significant difference in mean VEGF levels in induced sputum between placebo administration ( before , 3,640 pg/mL [ SD , 1,020 pg/mL ] ; after , 3,640 pg/mL [ SD , 960 pg/mL ] and pranlukast administration ( before , 3,660 pg/mL [ SD , 940 pg/mL ] ; after , 2,950 pg/mL [ SD , 890 pg/mL ] ) . CONCLUSIONS Pranlukast administration decreased airway microvascular permeability through , at least in part , a decrease in airway VEGF levels in steroid-untreated asthmatic patients . However , it is likely that pranlukast administration added little efficacy to inhaled corticosteroid therapy for reduction in airway VEGF levels [12612294] Background : Proinflammatory leukotrienes , which are not completely inhibited by inhaled corticosteroids , may contribute to asthmatic problems . A 16 week multicentre , r and omised , double blind , controlled study was undertaken to study the efficacy of adding oral montelukast , a leukotriene receptor antagonist , to a constant dose of inhaled budesonide . Methods : A total of 639 patients aged 18–70 years with forced expiratory volume in 1 second ( FEV1 ) ≥55 % predicted and a minimum predefined level of asthma symptoms during a 2 week placebo run in period were r and omised to receive montelukast 10 mg ( n=326 ) or placebo ( n=313 ) once daily for 16 weeks . All patients received a constant dose of budesonide ( 400–1600 μg/day ) by Turbuhaler throughout the study . Results : Mean FEV1 at baseline was 81 % predicted . The median percentage of asthma exacerbation days was 35 % lower ( 3.1 % v 4.8 % ; p=0.03 ) and the median percentage of asthma free days was 56 % higher ( 66.1 % v 42.3 % ; p=0.001 ) in the montelukast group than in the placebo group . Patients receiving concomitant treatment with montelukast had significantly ( p<0.05 ) fewer nocturnal awakenings and significantly ( p<0.05 ) greater improvements in β agonist use and morning peak expiratory flow rate ( PEFR ) . Conclusions : For patients with mild airway obstruction and persistent asthma symptoms despite budesonide treatment , concomitant treatment with montelukast significantly improves asthma control [15640321] Sputum eosinophilia is a sensitive predictor of benefit from corticosteroid treatment . Montelukast is a cysteinyl leukotriene antagonist , which also reduces sputum and blood eosinophils . The present study examined the possibility that montelukast has an added eosinophil-lowering effect in subjects with asthma who are corticosteroid responsive but relatively corticosteroid resistant . A total of 14 clinical ly stable adults with asthma requiring minimum treatment with a high-dose inhaled steroid or prednisone , with baseline sputum eosinophilia ( ≥5 % ) , were r and omised to receive 4 weeks of 10 mg montelukast or placebo daily in a double-blind crossover trial . The primary outcome was the effect of treatment on the percentage of sputum eosinophils . Secondary outcomes were changes in the blood eosinophil count , symptoms , forced expiratory volume in one second , peak expiratory flow and the need for salbutamol . The median ( interquartile range , i.e. 75th–25th centile ) for sputum eosinophils at baseline was 15.7 % ( 22 ) . The effect of adding montelukast was not significantly different from that of placebo , sputum eosinophils being 9.3 % ( 18.9 ) after montelukast and 11.3 % ( 22.8 ) after placebo . No difference was detected on secondary outcomes . No crossover interactions were observed . In conclusion , the addition of montelukast to existing high-dose corticosteroid therapy in subjects with asthma with elevated sputum eosinophils does not provide additional attenuation of airway eosinophilia [15681495] Background : Inhaled corticosteroids and leukotriene receptor antagonists reduce airway eosinophilia and have been used as first line anti-inflammatory therapy for mild persistent asthma . Methods : A multicentre , r and omised , placebo controlled , parallel group study was performed to compare the anti-inflammatory effects of fluticasone propionate and montelukast as measured by sputum eosinophils in 50 adults with symptomatic steroid naive asthma and sputum eosinophilia of ⩾3.5 % . Results : Eighteen patients received low dose fluticasone ( 250 μg/day ) , 19 received montelukast ( 10 mg/day ) , and 13 were given placebo for 8 weeks . Fluticasone treatment result ed in a greater reduction in sputum eosinophils ( geometric mean ( SD ) 11.9 (2.3)% to 1.7 (5.1)% ) than montelukast ( 10.7 (2.3)% to 6.9 (3.8)% ; p = 0.04 ) or placebo ( 15.4 (2.4)% to 7.8 (4.2)% ; p = 0.002 ) , and improvement in FEV1 ( mean ( SD ) 2.6 ( 0.9 ) l to 3.0 ( 0.9 ) l ) than montelukast ( 2.8 ( 0.7 ) l to 2.8 ( 0.9 ) l ; p = 0.02 ) or placebo ( 2.4 ( 0.8 ) l to 2.4 ( 0.9 ) l ; p = 0.01 ) . Treatment with fluticasone suppressed sputum eosinophilia within a week while montelukast only attenuated it . The effect of montelukast was maximal at 1 week and was maintained over 4 weeks . The effect of fluticasone was maintained over 8 weeks while that of montelukast was not . Conclusions : Montelukast is not as effective as low dose fluticasone in reducing or maintaining an anti-inflammatory effect in steroid naïve eosinophilic asthma [10489822] Leukotrienes are pro-inflammatory mediators which may contribute to tissue , sputum , and blood eosinophilia seen in allergic and inflammatory diseases , including asthma . Montelukast is a cysteinyl leukotriene1 ( CysLT1 ) receptor antagonist which improves asthma control ; the aim of this study was to investigate its effect on induced sputum eosinophils . Montelukast 10 mg ( n=19 ) or placebo ( n=21 ) were administered orally once in the evening for 4 weeks to 40 chronic adult asthmatic patients , aged 19 - 64 yrs , in a double-blind , r and omized , parallel group study . Patients were included if , at pre study , they had > 5 % sputum eosinophils , symptomatic asthma with a forced expiratory volume in one second > or = 65 % of the predicted value and were being treated only with " as needed " inhaled beta2-agonists . In addition to sputum eosinophils , blood eosinophils and clinical endpoints were also assessed . Four weeks of montelukast treatment decreased sputum eosinophils from 7.5 % to 3.9 % ( 3.6 % decrease , 95 % confidence interval ( CI ) -16.6 - 0.4 ) . In contrast , placebo treatment was associated with an increase in sputum eosinophils from 14.5 % to 17.9 % ( 3.4 % increase , 95 % CI -3.5 - 9.8 ) . The least squares mean difference between groups ( -11.3 % , 95 % CI -21.1-(-1.4 ) ) was significant ( p=0.026 ) . Compared with placebo , montelukast significantly reduced blood eosinophils ( p=0.009 ) , asthma symptoms ( p=0.001 ) and beta2-agonist use ( p<0.001 ) while significantly increasing morning peak expiratory flow ( p=0.001 ) . Montelukast was generally well tolerated in this study , with a safety profile similar to the placebo . These results demonstrate that montelukast decreases airway eosinophilic inflammation in addition to improving clinical parameters . Its efficacy in the treatment of chronic asthma may be due , in part , to the effect on airway inflammation [12570120] The distribution of responses in study population s provides a novel method of comparing the benefit of two treatments . This 6‐week , r and omised , placebo-controlled , double-blind study compared the effectiveness of oral montelukast with inhaled beclomethasone in chronic asthma by assessing the distribution and overlap of patient responses to therapy , as measured by a clinical outcome ( asthma control days ) . A total of 730 adult patients with asthma , age 15–65 yrs , with a forced expiratory volume in one second ( FEV1 ) at baseline of 50–85 % of predicted and ≥15 % improvement in FEV1 after inhaled β‐agonist were enrolled . After a 2–week placebo run-in period , patients were r and omly allocated to receive montelukast ( 10 mg once daily ) , inhaled beclomethasone ( 200 µg twice daily ) or placebo . The primary end-point ( per cent of asthma control days ) was compared between treatments as the overlap in the response distributions . The overlap of the distribution of responses between the montelukast and beclomethasone groups was 89 % for per cent asthma control days and 96 % for change from baseline in FEV1 . The mean ( ±sd ) per cent asthma control days in the montelukast and beclomethasone groups was significantly higher than that in the placebo group ( placebo 40.0±35.8 , montelukast 50.7±37.1 , beclomethasone 57.9±36.1 ) . The mean differences between montelukast and placebo , beclomethasone and placebo , and montelukast and beclomethasone were significant . The mean per cent change ( ±sd ) from baseline in FEV1 was 12.1±18.7 and 13.9±20.8 in the montelukast and beclomethasone groups , respectively , and significantly greater than that in the placebo group ( 6.4±20.1 ) ; there was no significant difference between the montelukast and beclomethasone groups in mean values or response distribution . There was also no difference among treatment groups in the frequency of adverse experiences . A comparison of the response distribution is an important approach to comparing therapies ; montelukast and beclomethasone provided similar response distributions for the end-point of per cent asthma control days over a 6‐week treatment period [15478381] BACKGROUND Antileukotriene agents have been shown to be beneficial in chronic asthma . Although patients with cough variant asthma have cough with minimal wheezing and dyspnea , airway hyperresponsiveness from chronic inflammation is believed to be the underlying mechanism . OBJECTIVE To evaluate the effectiveness of montelukast , a leukotriene receptor antagonist , in the treatment of cough variant asthma . METHODS Fourteen patients with cough variant asthma participated in a r and omized , double-blind , placebo-controlled trial with a 7- to 10-day baseline period and a 4-week treatment period with montelukast , 10 mg , or placebo daily . Inclusion criteria were ( 1 ) chronic cough with a duration of at least 4 weeks with minimal or no wheezing or dyspnea and ( 2 ) forced expiratory volume in 1 second of 50 % to 85 % of predicted and reversibility of 12 % with use of an inhaled beta-agonist or forced expiratory volume in 1 second greater than 85 % and positive methacholine challenge results . Patients fulfilled the minimum criteria for cough frequency and symptom scores for r and omization . RESULTS Eight patients received montelukast and 6 received placebo . The primary efficacy variable , mean percentage change from baseline in cough frequency , was significantly improved by the second week , and by the fourth week the mean percentage change from baseline was 75.7 % for the treatment group and 20.7 % for the placebo group . CONCLUSIONS The leukotriene receptor antagonist montelukast seems to be effective in the treatment of cough variant asthma . Larger studies are recommended to confirm this effect [9377612] The efficacy of the oral leukotriene-receptor antagonist zafirlukast was assessed as maintenance therapy for patients with mild-to-moderate asthma . A total of 762 patients aged 12 to 76 years were enrolled in a 13-week , multicenter , double-masked , placebo-controlled , parallel-group trial and r and omly assigned to receive either zafirlukast ( 20 mg twice daily ) or placebo . Patients were maintained on as-needed beta-agonist therapy throughout the study and had to have a cumulative daytime asthma symptoms score > or = 8 ( on a daily scale of 0 to 3 ) over 7 consecutive days before r and omization . Efficacy was assessed by changes in symptoms , beta-agonist use , and pulmonary function . Safety was assessed by adverse experiences , laboratory test results , physical examination , and electrocardiography . Zafirlukast significantly decreased daytime asthma symptoms scores ( -26.5 % ) , nighttime awakenings ( -19.8 % ) , mornings with asthma ( -29.0 % ) , and beta-agonist use ( -22.3 % ) and significantly increased morning peak expiratory flow rate ( 6.9 % ) and forced expiratory volume in 1 second ( 6.3 % ) compared with placebo . Changes in symptoms , beta-agonist use , and pulmonary function occurred within 2 days of zafirlukast treatment and continued throughout the trial . Zafirlukast was well tolerated . Pharyngitis and headache were the most common adverse events , occurring with similar frequency in both the zafirlukast and placebo groups . No clinical ly significant changes were observed in laboratory test results , findings on physical examination , or electrocardiographic findings . We conclude that zafirlukast produces early and sustained effects in the treatment of mild-to-moderate asthma [23786930] Background Evidence has demonstrated that the distal lung , which includes airways of < 2 mm in diameter and lung parenchyma , constitutes an important component of asthma pathology . Cysteinyl leukotrienes ( CysLTs ) are potent proinflammatory mediators and bronchoconstrictors involved in the asthmatic process . Guidelines recommend the leukotriene‐modifying agents for asthma treatment . We hypothesized that a leukotriene receptor antagonist with an inhaled corticosteroid ( ICS ) and long‐acting & bgr;2 agonist ( LABA ) combination would improve small airways function in moderate‐to‐severe asthmatics evaluated by physiological tests and high‐resolution computed tomography ( H RCT ) analysis . This study was performed at a tertiary university hospital in Beijing . Methods This was a r and omized , double‐blind , parallel study performed in 38 patients with moderate‐to‐severe asthma treated with salmeterol/fluticasone ( SFC ) plus montelukast ( SFC+M ) or SFC plus placebo over 24 weeks . Small airway function was assessed by physiological studies and H RCT image analysis . Results Montelukast significantly improved air trapping as expressed by the residual volume (RV)/total lung capacity ( TLC ) . Over 24 weeks of treatment , RV/TLC was improved by (15.41±6.67)% in patients receiving SFC+M while RV/TLC was decreased by (8.57±10.26)% in patients receiving SFC alone , the difference between the two groups was significant ( P=0.02 ) . There was a trend towards a significant difference in forced expiratory volume in the first second (FEV1)/forced vital capacity ( FVC ) in the SFC+M group compared to that in the SFC group ( (17.87±8.17)% vs. (12.28±9.20)% , P=0.056 ) . There was no significant change in percentage wall area ( WA% ) after 24 weeks of add‐on treatment with montelukast . Patients receiving SFC+M showed significant improvement in the ratio of CT‐determined values at full expiration to those at full inspiration ( E/I ratio ) ( 0.894±0.005 vs. 0.871±0.003 , P=0.002 ) . Conclusion We have shown , using lung function tests and H RCT image technique , that add‐on therapy with montelukast improves distal lung function reflected by air trapping , but not airway wall thickness in moderate‐to‐severe asthma . ( Clinical Trials.gov number , NCT00699062 [17046300] BACKGROUND Pulmonary function tests ( PFTs ) and especially spirometry measures are useful tools in evaluating early response to treatment of asthma in children mainly due to their worldwide availability . The aim of our study was to determine the effects of anti-asthma treatment in children , equally on FEV(1 ) , FEF25 - 75 % , R(int ) and SR(aw ) values . METHODS Children 6 - 18 years of age with moderate atopic asthma were r and omized to 4-week , placebo-controlled , double-blind trial . Patients were r and omly allocated to receive 200 microg budesonide ( B ) ( n=29 ) , 5 or 10 mg ( according to age ) montelukast ( M ) ( n=29 ) , 200 microg B + 5 or 10 mg M ( n=29 ) , 200 microg B + 9 microg formoterol ( F ) ( n=29 ) or placebo ( n=27 ) . FEV(1 , ) FEF25 - 75 % , R(int ) , SR(aw ) were measured before and after treatment . RESULTS R(int ) , SR(aw ) , FEV(1 ) improved significantly in all active treatment groups while FEF25 - 75 % improved significantly only in BM group and M group . Combination therapy , showed significantly greater effects on R(int ) than monotherapy : BM group compared to B group ( P=0.01 ) and M group ( P=0.03 ) and BF group compared to B group ( P=0.01 ) and M group ( P=0.04 ) . CONCLUSION This study shows that using single parameter for monitoring asthma can be misleading . Using combination of lung function techniques provides better assessment of treatment . Results of our study confirm this hypothesis . The best effect on large and small airways was achieved with combined anti-inflammatory therapy [16680924] BACKGROUND Montelukast is a widely used controller agent in childhood asthma . It is modestly effective in reducing symptoms , decreasing the need for rescue albuterol , and improving forced expiratory volume in 1 second ( FEV1 ) . OBJECTIVE To determine whether montelukast therapy improves peripheral airway obstruction as measured by lung volumes , air trapping , airway resistance ( Raw ) , and specific conductance ( Sgaw ) . METHODS Twenty-one children aged 9 to 18 years with mild-to-moderate asthma were r and omized into a double-blind , placebo-controlled study to receive montelukast ( 5 or 10 mg ) or matching placebo daily for 8 weeks . Symptoms and albuterol use were recorded twice daily , and exhaled nitric oxide measurement , forced oscillometry , spirometry , and body box plethysmography ( before and after beta-agonist use ) were performed at r and omization and at 2 , 4 , 6 , and 8 weeks . Circulating eosinophil counts and serum eosinophil cationic protein ( ECP ) levels were obtained at r and omization and at 8 weeks . RESULTS Montelukast-treated patients had lower residual volume ( P = .05 ) , residual volume-total lung capacity ratio ( P = .04 ) , Raw ( P = .02 ) , Sgaw ( P = .03 ) , and serum ECP levels ( P = .02 ) at 8 weeks compared with those treated with placebo . There was a trend toward reduced daytime and nighttime albuterol use , although the difference did not reach statistical significance . There were no significant differences in FEV1 , FEV1-forced vital capacity ratio , exhaled nitric oxide levels , or daytime and nighttime symptom scores between the 2 groups . CONCLUSIONS Montelukast therapy was associated with less air trapping , hyperinflation , and Raw and better Sgaw compared with placebo . Lower serum ECP levels , a surrogate measure of airway inflammation , were associated with improvements in lung function [14609035] BACKGROUND Zafirlukast is a leukotriene receptor antagonist that was invented to treat patients with chronic asthma . METHODS To evaluate whether the zafirlukast improved the peak expiratory flow rate ( PEFR ) and clinical symptoms , 31 asthmatic patients with moderate persistent asthma who received regular inhaled corticosteroid were r and omly divided into the study group ( N = 17 ) . They received the zafirlukast 20 mg bid for 4 weeks , and the control group ( N = 14 ) received a placebo . Daily morning and evening PEFR and St. George 's Respiratory Question naire ( SGRQ ) scoring were recorded respectively . The levels of serum IgE and urine leukotriene E4 before and after treatment were measured using enzyme linked immunosorbent assay and enzyme immunoassay kits . RESULTS In the zafirlukast treated group , the morning PEFR was significantly improved from 314.4 + /- 20.6 to 340.6 + /- 18.3 L/min ( N = 17 , p < 0.05 ) after 4 weeks of treatment , while the control group did not show any significant changes . The zafirlukast group had significant improvement in their symptom scores of SGRQ from 48.6 + /- 4.6 to 33.8 + /- 4.7 ( N = 17 , p < 0.05 ) . However , the placebo did not improve the symptom scores . CONCLUSION Leukotriene receptor antagonists effectively improved symptoms and benefited lung function for moderate persistent asthmatic patients who had received regular treatments with inhaled steroids [11929492] Background Levels of an immunoregulatory and anti‐inflammatory cytokine IL‐10 are reduced in asthmatic airways , potentially contributing to more intense inflammation . Triamcinolone has anti‐inflammatory properties and the anti‐inflammatory effects of montelukast and formoterol have been discussed [16236835] BACKGROUND Asthma and allergic rhinitis are both highly prevalent diseases and often coexist in patients . OBJECTIVE To investigate the effect of rhinitis therapy on asthma outcomes in adult and adolescent patients with both seasonal allergic rhinitis ( SAR ) and persistent asthma . METHODS A total of 863 patients ( mean baseline FEV1 81 % predicted ) were r and omized to receive open-label fluticasone propionate/salmeterol ( FSC ) , 100/50 microg bid for 4 weeks , plus either blinded fluticasone propionate aqueous nasal spray ( FPANS ) 200 microg/d , montelukast 10 mg/d , or placebo . Patients kept daily records of peak expiratory flow ( PEF ) , asthma , and rhinitis symptoms and rescue albuterol use . RESULTS FPANS added to FSC result ed in superior outcomes for daytime total nasal symptom scores ( D-TNSS ) and individual daytime nasal specific symptoms ( congestion , rhinorrhea , sneezing , and itching ) compared with montelukast plus FSC and placebo plus FSC ( p < or = 0.001 ) . Montelukast plus FSC was superior to placebo plus FSC only for D-TNSS and itching and sneezing . Morning PEF , asthma symptoms , and rescue albuterol use improved significantly ( p < or = 0.001 ) in all treatment groups , but improvements were comparable across the treatment groups . CONCLUSION In patients with persistent asthma treated with FSC , the addition of montelukast or FPANS for the treatment of SAR result ed in no additional improvements in overall asthma control compared with FSC alone . However , FPANS provided superior rhinitis control compared with montelukast . These data suggest that asthma and rhinitis should each be optimally treated [10353583] BACKGROUND New drug evaluations in patients with mild asthma are sometimes complicated by enrollment of patients whose disease is too mild to show improvement with therapy . A peak expiratory flow ( PEF ) variability criterion may help to more clearly define a mild asthmatic population . OBJECTIVE To evaluate the effectiveness of zafirlukast ( 20 mg twice daily ) and cromolyn sodium ( 1600 microg four times daily ) compared with placebo as first-line therapy for mild asthma using a retrospective analysis , which stratified patients by PEF variability ( < 10 % or > or = 10 % ) . STUDY DESIGN Symptomatic patients ( daytime asthma symptoms score > or = 8) were r and omized to 13 weeks of treatment in a double-blind , double-dummy , placebo-controlled , parallel-group , multicenter trial . PATIENTS AND METHODS Patients ( n = 287 ) were nonsmokers ( age > or = 12 years ) with reversible airway disease , a forced expiratory volume in one second ( FEV1 ) of > or = 55 % of predicted , and previous treatment with beta2-agonist or theophylline only . Assessment s included changes from baseline to endpoint in daytime and nocturnal asthma symptoms , beta2-agonist use , PEF , and FEV1 . Response to treatment was assessed by predetermined diary card and FEV1 criteria . Safety was determined from adverse events and laboratory test results . RESULTS No significant treatment effects were seen across efficacy measures for patients with PEF variability < 10 % . For patients with PEF variability > or = 10 % , both active treatments significantly ( P < .05 ) decreased the daytime asthma symptoms score , nighttime awakenings , and beta2-agonist use , and increased morning PEF and FEV1 compared with placebo . Response to diary card criteria was 70 % and 75 % for zafirlukast and cromolyn , respectively ; response to FEV1 criteria was 47 % for both treatments . All treatments were tolerated well by patients . CONCLUSIONS Zafirlukast and cromolyn are effective first-line therapies for mild asthma , with both therapies producing greater benefits in patients whose PEF variability was > or = 10 % . In prospect i ve trials to evaluate therapies in patients with mild asthma , it may be worthwhile to include PEF variability with a 10 % cutoff either as an inclusion criteria or as a tool for subset analysis [11842294] BACKGROUND Anti-inflammatory properties of leukotriene modifiers and their effect on bronchial hyperresponsiveness have not been studied in children with asthma . OBJECTIVE The primary objective of this study was to determine the changes in serum levels of inflammatory mediators , clinical efficacy , and bronchial hyperresponsiveness after treatment with montelukast . METHODS In this double-blind , r and omized , placebo-controlled trial , 39 children with mild-to-moderate atopic asthma were r and omly allocated to receive montelukast or placebo for 6 weeks . Main outcome measures were changes in serum concentrations of soluble interleukin 2 receptor ( sIL-2R ) , IL-4 , and soluble intercellular adhesion molecule 1 ( sICAM-1 ) ; peripheral blood eosinophil count ; and eosinophilic cationic protein ( ECP ) . Asthma severity score , FEV(1 ) , and bronchial hyperreactivity ( BHR ) for histamine were secondary end points . RESULTS Compared to placebo , serum concentrations of IL-4 , sICAM-1 , and ECP and eosinophil blood counts significantly decreased after 6 weeks of treatment with montelukast . Montelukast significantly improved asthma control and FEV(1 ) . Montelukast result ed in within-group significant decrease in levels of serum sIL-2R ( 611 vs. 483 pg/mL ) , IL-4 ( 0.123 vs 0.102 pg/mL ) , sICAM-1 ( 280 vs. 244 ng/mL ) , and ECP ( 74 vs. 59 microg/mL ) and in eosinophil blood counts ( 349 vs. 310 cells/mm(3 ) ) . Mean FEV(1 ) value changed from 85 % of predicted to 95 % ( P < .001 ) and for histamine ( PC(20)H ) from 2.8 mg/mL to 3.8 mg/mL ( P < .001 ) after treatment with montelukast . There was no significant difference between montelukast and placebo recipients in the serum concentrations of sIL-2R and PC(20)H after treatment . CONCLUSION Montelukast provides clinical benefit to patients with chronic asthma and decreases bronchial hyperresponsiveness . Montelukast caused a statistically significant decrease of serum concentrations in cytokine , ICAM-1 , and ECP and peripheral blood eosinophil counts over the 6-week treatment period . This observation raises the possibility that leukotriene receptor antagonists , such as montelukast , may have effects on parameters of asthmatic inflammation [9679847] BACKGROUND The cysteinyl leukotrienes are important mediators of bronchial asthma . The clinical effect of montelukast , a potent cysteinyl leukotriene-receptor antagonist , was investigated in a r and omized , placebo-controlled , multicenter , parallel-group , dose-ranging study . METHODS After a 3-week , single-blind , placebo run-in period , 343 asthmatic patients ( FEV1 40 % to 80 % of the predicted value with an improvement in FEV1 of at least 15 % [ absolute value ] after receiving inhaled beta-agonists on at least two occasions ) were r and omly assigned to one of six treatment groups : placebo ; 10 , 100 , or 200 mg once daily montelukast in the evening ; or 10 or 50 mg twice daily montelukast for a 6-week , double-blind treatment period followed by a 1-week placebo washout period . All patients used inhaled , short-acting beta-agonists as needed . RESULTS All montelukast doses caused similar and significant differences compared with placebo in asthma control endpoints . The least-square mean difference between pooled montelukast groups and placebo in the percentage change from baseline in morning FEV1 ( 10.30 % ; 95 % CI : 5.56 to 15.04 ) , as-needed beta-agonist use ( -0.98 puffs ; 95 % CI : -1.53 to -0.44 ) , morning peak expiratory flow rate ( 18.80 L/min ; 95 % CI : 8.62 to 28.98 ) , physicians ' and patients ' global evaluations , and asthma-specific quality -of-life scores were all significant ( p < or = 0.050 ) . The incidence of adverse experiences was not dose related and was similar between placebo and montelukast treatment . CONCLUSION Montelukast caused a significant improvement in chronic asthma at an oral , once daily evening dose as low as 10 mg [12190656] Background Oral leukotriene receptor antagonists have been shown to have efficacy in chronic asthma [12740532] Background : Asthma and seasonal allergic rhinitis ( SAR ) are recognized as manifestations of a single airway disease . Desloratadine has demonstrated efficacy in treating SAR symptoms , including nasal obstruction . Methods : Safety and efficacy of desloratadine and montelukast each were assessed in a double-blind , placebo-controlled trial of patients with SAR and symptoms of asthma , who were assigned r and omly to once-daily treatment with desloratadine 5 mg , montelukast 10 mg , or placebo for 4 weeks . Change from baseline of AM/PM reflective total asthma symptom severity scores ( TASS ) , FEV1 , individual asthma symptom scores , and β2-agonist usage were assessed . Results : Desloratadine and montelukast each were associated with statistically significant reductions from baseline in the mean TASS averaged over the 4-week period ( p ≤0.022 vs. placebo ) . Individual asthma symptom scores also improved significantly for both therapies ( p ≤ 0.05 ) . Patients treated with desloratadine or montelukast demonstrated improvement from baseline in FEV1 versus placebo ; significant improvement was seen in a subset of patients with baseline FEV1 < 80 % of predicted normal ( both p < 0.05 ) . Both active therapies significantly reduced β2-agonist use ( both p < 0.01 ) . Improvements for both therapies were comparable for all efficacy parameters ; they were tolerated well with adverse event profiles similar to placebo . Conclusions : Asthma symptoms and β2-agonist were improved significantly in patients with concomitant SAR and asthma treated with desloratadine 5 mg as well as montelukast 10 mg once daily . Both therapies significantly improved FEV1 in a subset of patients with FEV1 < 80 % of predicted normal at entry . Improvements in asthma symptoms were comparable for both active treatment groups [9227718] BACKGROUND Leukotriene receptor antagonists have been shown to protect against bronchoconstriction induced by antigens , exercise , and cold air . There are relatively few clinical studies reported in patients with asthma . The present study is the first clinical evaluation of pranlukast ( SB 205312 , ONO-1078 ) outside Japan in patients with asthma . METHODS A r and omised , double blind , placebo controlled , parallel group , multicentre four week study of the safety and tolerability of oral pranlukast , 225 or 337.5 mg twice daily , was performed in patients with mild to moderate asthma . Preliminary efficacy data were obtained ; the main efficacy variables evaluated were forced expiratory volume in one second ( FEV1 ) and morning domiciliary ( home ) peak expiratory flow rates ( PEFR ) . Clinic PEFR and daytime and night-time asthma symptom scores were also recorded . RESULTS Compared with the placebo group the improvement in morning home PEFR was statistically significant at all time points for patients receiving pranlukast 337.5 mg twice daily and at weeks 1 and 2 for those treated with pranlukast in a dose of 225 mg twice daily . Mean morning home PEFR increased by 10.8 to 18.61/min ( 95 % CI 0.2 to 29.3 l/min ) in patients treated with pranlukast compared with a slight deterioration in those given placebo . FEV1 significantly increased within one hour after the first dose of pranlukast compared with baseline and this increase was maintained for eight hours . Improvements in trough FEV1-that is , at the end of the dosing interval-were statistically significant for the group treated with pranlukast 225 mg twice daily compared with placebo at week 4 . Mean increases in FEV1 ranged from 210 ml to 340 ml ( 95 % CI 60 to 500 ml ) at trough in the pranlukast group . Patients treated with pranlukast also showed improvements in summary symptom and night-time asthma scores . Pranlukast was well tolerated , and no drug related changes in haematological and biochemical variables were observed . CONCLUSIONS Pranlukast , an oral leukotriene receptor antagonist , is well tolerated and is effective for the treatment of asthma . It increased FEV1 within one hour of dosing , improved patient summary symptom and night-time asthma scores , and reduced the use of rescue bronchodilators , thus providing further evidence of a role for leukotrienes in the pathogenesis of asthma [18951618] BACKGROUND Clinical trials in children with moderate-to-severe persistent asthma are limited . OBJECTIVE We sought to determine whether azithromycin or montelukast are inhaled corticosteroid sparing . METHODS The budesonide dose ( with salmeterol [ 50 microg ] twice daily ) necessary to achieve control was determined in children 6 to 17 years of age with moderate-to-severe persistent asthma . After a budesonide-stable period of 6 weeks , children were r and omized in a double-masked , parallel , multicenter study to receive once-nightly azithromycin , montelukast , or matching placebos plus the established controlling dose of budesonide ( minimum , 400 microg twice daily ) and salmeterol twice daily . Primary outcome was time from r and omization to inadequate asthma control after sequential budesonide dose reduction . RESULTS Of 292 children screened , only 55 were r and omized . Inadequate adherence to study medication ( n = 80 ) and improved asthma control under close medical supervision ( n = 49 ) were the major reasons for r and omization failure . A futility analysis was requested by the Data Safety Monitoring Board . In data available for analyses , no differences were noted for either treatment compared with placebo in time to inadequate control status ( median : azithromycin , 8.4 weeks [ 95 % confidence limit , 4.3 - 17.3 ] ; montelukast , 13.9 weeks [ 95 % confidence limit , 4.7 - 20.6 ] ; placebo , 19.1 weeks [ 95 % confidence limit , 11.7-infinity ] ) , with no difference between the groups ( log-rank test , P = .49 ) . The futility analysis indicated that even if the planned sample size was reached , the results of this negative study were unlikely to be different , and the trial was prematurely terminated . CONCLUSION Based on these results , neither azithromycin nor montelukast is likely to be an effective inhaled corticosteroid-sparing alternative in children with moderate-to-severe persistent asthma [11485708] OBJECTIVE The objective of our study was to compare the efficacy and safety of fluticasone propionate ( an inhaled corticosteroid ) with zafirlukast ( a leukotriene modifier ) for persistent asthma . STUDY DESIGN In this r and omized placebo-controlled , parallel-group , double-blind , double-dummy trial , patients underwent an 8- to 14-day run-in period followed by 12 weeks of treatment with inhaled fluticasone propionate ( 88 mg twice daily by metered-dose inhaler ) , oral zafirlukast ( 20 mg twice daily ) , or placebo . POPULATION We included a total of 338 persistent asthma patients , 12 years of age or older , using short-acting b2-agonists alone . OUTCOMES measured Efficacy outcomes included changes in pulmonary function , asthma symptoms , rescue albuterol use , nighttime awakenings due to asthma , and quality of life . Safety outcomes included asthma exacerbations , adverse events , and clinical ly significant laboratory test results . RESULTS After 12 weeks of treatment , patients taking fluticasone propionate experienced significantly greater improvements in all clinical parameters ( symptom scores , percentages of symptom-free and albuterol-free days , albuterol use , and nighttime awakenings ) compared with patients taking zafirlukast ( P < .05 ) or placebo ( P < .05 ) . Treatment with fluticasone propionate result ed in significantly greater improvements in pulmonary function compared with zafirlukast ( P < .05 ) or placebo ( P < .05 ) . Fewer fluticasone propionate patients ( 4 % ) had an exacerbation requiring oral corticosteroids compared with those taking zafirlukast ( 12 % ) or placebo ( 10 % ) . CONCLUSIONS Inhaled fluticasone propionate is more effective than zafirlukast in controlling asthma symptoms , improving pulmonary function , and improving quality of life for patients who are symptomatic with the use of short-acting b2-agonists alone [17166989] STUDY OBJECTIVES The distal airways are likely to contribute to asthma pathobiology and symptoms but have rarely been specifically evaluated in relation to systemic oral therapy . We hypothesized that treatment with montelukast , an oral cysteinyl-leukotriene receptor antagonist , would improve both proximal and distal lung physiology in patients with mild asthma . DESIGN R and omized , double-blind , crossover design . SETTING Academic referral center . PATIENTS Subjects with mild asthma limited to using short-acting inhaled beta(2)-agonists . INTERVENTIONS Nineteen subjects with mild asthma underwent a baseline assessment of lung function , lung mechanics , and symptoms , followed by r and omization to therapy with montelukast , 10 mg taken in the evening , or placebo in a crossover , double-blind fashion . Each treatment phase lasted 4 weeks , with a 2-week washout period . A repeat evaluation was performed during the last week of each treatment phase . MEASUREMENTS AND RESULTS Montelukast result ed in improvement in ( mean + /- SD ) proximal and distal lung function parameters ( change in FEV(1 ) : montelukast , 0.16 + /- 0.06 L ; placebo , -0.05 + /- 0.05 L ; p = 0.008 ) ; change in specific conductance : montelukast , 7.2 + /- 2.9 % predicted ; placebo , -17 + /- 8 % predicted ; p = 0.007 ; change in % predicted residual volume [ RV ] : montelukast , 18.4 + /- 8.3 % predicted ; placebo , 3.0 + /- 2.9 % predicted ; p = 0.05 ) . Improvement in symptoms ( ie , wheeze and chest tightness ) correlated with improvements in RV while receiving montelukast , but not while receiving placebo ( Pearson coefficients : 0.55 and 0.66 , respectively ; p < 0.008 and 0.04 , respectively ) . CONCLUSIONS The systemically acting oral agent montelukast improves proximal and distal lung physiology . Improvements in distal lung function correlate with improvements in asthma symptoms [8087328] The efficacy of 6 wk of therapy with oral ICI 204,219 , a selective leukotriene D4 ( LTD4 ) receptor antagonist , was evaluated in subjects with moderate asthma during a multicenter , double-blind , r and omized , placebo-controlled , dose-ranging study . Subjects who entered the trial had been chronically treated for asthma with beta agonist alone or in combination with theophylline . Subjects were r and omized to treatment with twice daily doses of ICI 204,219 ( 5 , 10 , or 20 mg ) or placebo if they had an FEV1 between 40 and 75 % of predicted values without bronchodilator therapy and a daytime asthma score > 10 ( range 0 to 21 per wk ) for 7 consecutive d. Efficacy was evaluated from the results of symptom assessment s , pulmonary function tests , and rescue medication use . Of 276 subjects r and omized to treatment , 266 ( 10 mg , n = 66 ; 20 mg , n = 67 ; 40 mg , n = 67 ; placebo , n = 66 ) were analyzed for efficacy . Diary card assessment s showed that treatment with increasing doses of ICI 204,219 linearly improved five efficacy criteria without increasing the number or severity of adverse events . The 40 mg dose was more effective than placebo ( p < 0.05 ) in reducing nighttime awakenings , first morning asthma symptoms , the daytime asthma score , and albuterol use and in increasing evening peak expiratory flow ( PEF ) rates as well as FEV1 . Compared with baseline measurements , the 40 mg dose decreased awakenings by 46 % , albuterol use by 30 % , and daytime symptoms by 26 % and increased FEV1 by 11 % . ICI 204,219 improves objective and subjective measures of asthma severity in moderately ill asthmatic subjects and may provide a new treatment option for the disease [10398629] Abstract Objective : To determine the ability of montelukast , a leukotriene receptor antagonist , to allow tapering of inhaled corticosteroids in clinical ly stable asthmatic patients . Design : Double blind , r and omised , placebo controlled , parallel group study . After a single blind placebo run in period , during which ( at most ) two inhaled corticosteroids dose decreases occurred , qualifying , clinical ly stable patients were allocated r and omly to receive montelukast ( 10 mg tablet ) or matching placebo once daily at bedtime for up to 12 weeks . Setting : 23 academic asthma centres in United States , Canada , and Europe . Participants : 226 clinical ly stable patients with chronic asthma receiving high doses of inhaled corticosteroids ( 113 r and omised to montelukast and 113 to placebo ) . Interventions : Every 2 weeks , the inhaled corticosteroids dose was tapered , maintained , or increased ( rescue ) based on a st and ardised clinical score . Main outcome measures : Last tolerated dose of inhaled corticosteroids . Results : Compared with placebo , montelukast allowed significant ( P=0.046 ) reduction in the inhaled corticosteroid dose ( montelukast 47 % v placebo 30 % ; least square mean difference 17.6 % , 95 % confidence interval 0.3 to 34.8 ) . Fewer patients on montelukast ( 18 ( 16 % ) v 34 ( 30 % ) placebo , P=0.01 ) required discontinuation because of failed rescue . Conclusions : Montelukast reduces the need for inhaled corticosteroids among patients requiring moderate to high doses of corticosteroid to maintain asthma control . Key messages Leukotriene receptor antagonists have complementary action to inhaled corticosteroids in asthma Many patients receive higher doses of inhaled corticosteroids than clinical ly required In this placebo controlled trial , montelukast allowed significant reduction of inhaled corticosteroid doses Fewer patients receiving montelukast had failed rescue than patients receiving [15526805] OBJECTIVES To compare the effects of addition of montelukast or salmeterol to inhaled corticosteroids ( ICS ) on the response to rescue beta2-agonist use after exercise-induced bronchoconstriction . METHODS A double-blind , placebo-controlled study was performed at 16 centers in the United States . Patients with asthma ( n = 122 , ages 15 - 58 ) whose symptoms were uncontrolled on Low-dose inhaled fluticasone and who had a history of exercise-induced worsening of asthma were r and omized to receive either montelukast ( 10 mg once daily ) , salmeterol ( 50microg twice daily ) , or placebo for 4 weeks . St and ardized spirometry after exercise challenge and beta2-agonist rescue was performed at baseline , week 1 and 4 . RESULTS Maximum achievable forced expiratory volume in 1 s ( FEV1 ) percent predicted after rescue beta2-agonist improved in the montelukast ( + 1.5 % ) and placebo ( + 1.2 % ) groups at 4 weeks , but diminished in the salmeterol ( -3.9 % ) group ( P < 0.001 ) . Although pre-exercise FEV1 was greatest with salmeterol ( P = 0.10 ) , patients taking montelukast had significantly greater protection from an exercise-induced decrease in FEV1 than those taking salmeterol ( P < 0.001 ) . Both the magnitude and rate of rescue bronchodilation were greater with montelukast compared with salmeterol ( P < 0.001 ) . Five minutes after rescue beta2-agonist , 92 % of patients taking montelukast and 68 % of those taking placebo had recovered to pre-exercise levels , whereas only 50 % of those taking salmeterol had recovered to pre-exercise levels . CONCLUSION In patients whose asthma symptoms remain uncontrolled using ICS , addition of montelukast permits a greater and more rapid rescue bronchodilation with a short-acting beta2-agonist than addition of salmeterol and provides consistent and clinical ly meaningful protection against exercise-induced bronchoconstriction [15572850] Mild persistent asthma is most effectively controlled with inhaled corticosteroids . Leukotriene receptor antagonists have complementary effects to corticosteroids on inflammation control . The additional effect of a leukotriene receptor antagonist , zafirlukast , was investigated in stable asthma patients under control with inhaled budesonide . We conducted a r and omised , double-blind , placebo-controlled , single center trial to investigate the effects of add-on zafirlukast treatment to budesonide , on symptom score , pulmonary function , bronchial responsiveness , and serum levels of eosinophilic cationic protein ( ECP ) and antioxidant capacity in stable asthmatic patients under control with inhaled budesonide . The present study included 21 mild or moderate asthmatic patients ( 8 males and 13 females ) , who were stable at least for 6 weeks with inhaled budesonide ( 400 microg/day ) . Serum total antioxidant capacity ( TAC ) and ECP levels were measured , and symptom scoring , spirometry , and bronchial provocation with methacholine were performed . Then , the patients were r and omised to use either placebo or oral zafirlukast ( 40 mg/day ) in addition to budesonide for 6 weeks . At the 6th week , symptom scoring , spirometry , and bronchial provocation tests were repeated and serum TAC and ECP levels were measured again . After add-on zafirlukast treatment to budesonide , forced expiratory volume in 1 second ( FEV(1 ) ) , TAC and ECP values did not change significantly ( p > 0.05 ) but bronchial hyperresponsiveness and symptom score decreased significantly ( p = 0.022 ) compared to baseline . Thus , in stable asthmatic patients , add-on zafirlukast treatment to budesonide improves symptoms and decreases bronchial hyperresponsiveness [9625400] OBJECTIVES To determine the clinical effect of oral montelukast sodium , a leukotriene receptor antagonist , in asthmatic patients aged 15 years or more . DESIGN R and omized , multicenter , double-blind , placebo-controlled , parallel-group study . A 2-week , single-blind , placebo run-in period was followed by a 12-week , double-blind treatment period ( montelukast sodium , 10 mg , or matching placebo , once daily at bedtime ) and a 3-week , double-blind , washout period . SETTING / PATIENTS Fifty clinical centers r and omly allocated 681 patients with chronic , stable asthma to receive placebo or montelukast after demonstrating a forced expiratory volume in 1 second 50 % to 85 % of the predicted value , at least a 15 % improvement in forced expiratory volume in 1 second ( absolute value ) after inhaled beta-agonist administration , a minimal predefined level of daytime asthma symptoms , and inhaled beta-agonist use . Twenty-three percent of the patients used concomitant inhaled corticosteroids . PRIMARY END POINTS : Forced expiratory volume in 1 second and daytime asthma symptoms . RESULTS Montelukast improved airway obstruction ( forced expiratory volume in 1 second , morning and evening peak expiratory flow rate ) and patient-reported end points ( daytime asthma symptoms , " as-needed " beta-agonist use , nocturnal awakenings ) ( P<.001 compared with placebo ) . Montelukast provided near-maximal effect in these end points within the first day of treatment . Tolerance and rebound worsening of asthma did not occur . Montelukast improved outcome end points , including asthma exacerbations , asthma control days ( P<.001 compared with placebo ) , and decreased peripheral blood eosinophil counts ( P<.001 compared with placebo ) . The incidence of adverse events and discontinuations from therapy were similar in the montelukast and placebo groups . CONCLUSIONS Montelukast , compared with placebo , significantly improved asthma control during a 12-week treatment period . Montelukast was generally well tolerated , with an adverse event profile comparable with that of placebo [9847434] BACKGROUND Previous trials demonstrated the effectiveness of the leukotriene receptor antagonist zafirlukast in patients with mild-to-moderate asthma . OBJECTIVES We sought to assess the efficacy and safety of zafirlukast and its effect on patients ' quality of life ( QOL ) during a 13-week , double-blind , placebo-controlled , multicenter trial in adults and adolescents with moderate reversible airflow obstruction . METHODS Patients ( age range , 12 to 68 years ) with total daytime asthma symptoms scores of 10 or greater over 7 consecutive days ( maximum , 21/wk ) , FEV1 45 % or greater but less than or equal to 80 % of predicted value ( > /=6 hours after beta2 -agonist ) , and reversible airway disease were r and omized to 20 mg zafirlukast twice daily ( nZ = 231 ) or placebo twice daily ( nP = 223 ) . Efficacy was assessed from changes in daytime and nocturnal symptoms , beta2 -agonist use , nasal congestion score , and pulmonary function . QOL was evaluated with a disease-specific Asthma Quality of Life Question naire . Safety was determined from adverse event information and clinical laboratory test results . RESULTS Zafirlukast was significantly ( P < .001 ) more effective than placebo , with reductions from baseline in the daytime asthma symptoms score ( -23 % ) , nighttime awakenings with asthma ( -19 % ) , and beta2 -agonist use ( -24 % ) and improvements from baseline in morning ( + 25 L/min ) and evening ( + 18 L/min ) peak expiratory flow rates . Compared with placebo , zafirlukast significantly ( P < /=.018 ) improved scores for QOL domains ( activity limitations , symptoms , emotional function , and exposure to environmental stimuli ) and overall QOL , with a significantly greater proportion of zafirlukast-treated patients demonstrating clinical ly meaningful improvements ( > /=0.5-unit change from baseline ; P < /=.037 ) . The safety profile of zafirlukast was clinical ly indistinguishable from that of placebo . CONCLUSIONS Zafirlukast is effective and well tolerated and improves QOL in the long-term treatment of patients with moderate reversible airflow obstruction [11779723] Leukotriene antagonists block the proinflammatory actions of leukotrienes ( LT ) and have been introduced as new treatments for asthma . Conventional therapy with glucocorticosteroids does not inhibit the bio synthesis of leukotrienes . We therefore tested whether addition of the leukotriene receptor antagonist montelukast was of therapeutic benefit in a group of aspirin-intolerant patients with asthma of whom 90 % already were treated with moderate to high doses of glucocorticosteroids . Under double-blind conditions , 80 aspirin-intolerant patients with asthma were r and omized to receive 4 wk oral treatment of either 10 mg of montelukast or placebo once daily at bedtime . Pulmonary function was measured as forced expiratory volume in 1 s ( FEV(1 ) ) once a week in the clinic and daily as morning and evening peak expiratory flow rate ( PEFR ) . Asthma symptoms and use of rescue bronchodilator were also recorded daily . Asthma specific quality of life ( QoL ) was assessed before and after the treatments . The group receiving montelukast showed a remarkable improvement of their asthma , whereas the group given placebo showed no change . Thus , from equal baseline values , the mean difference between the groups over the 4-wk treatment period was 10.2 % for FEV(1 ) and 28.0 L for morning PEFR ( p for both < 0.001 ) . The improved pulmonary function in the group receiving montelukast occurred at the same time as 27 % less bronchodilator was used ( p < 0.05 ) , and it was associated with fewer asthma symptoms than in the group given placebo , including 1.3 nights more of sleep per week and 54 % fewer asthma exacerbations ( p < 0.05 ) . There was also an improvement in asthma-specific QoL ( p < 0.05 ) . The therapeutic response to montelukast was consistent across patients with different baseline characteristics and did not correlate with baseline urinary LTE(4 ) . Addition of a leukotriene receptor antagonist such as montelukast improves asthma in aspirin-intolerant patients over and above what can be achieved by glucocorticosteroids [19632710] BACKGROUND Information that enhances expectations about drug effectiveness improves the response to placebos for pain . Although asthma symptoms often improve with placebo , it is not known whether the response to placebo or active treatment can be augmented by increasing expectation of benefit . OBJECTIVE The study objective was to determine whether response to placebo or a leukotriene antagonist ( montelukast ) can be augmented by messages that increase expectation of benefit . METHODS A r and omized 20-center controlled trial enrolled 601 asthmatic patients with poor symptom control who were assigned to one of 5 study groups . Participants were r and omly assigned to one of 4 treatment groups in a factorial design ( ie , placebo with enhanced messages , placebo with neutral messages , montelukast with enhanced messages , or montelukast with neutral messages ) or to usual care . Assignment to study drug was double masked , assignment to message content was single masked , and usual care was not masked . The enhanced message aim ed to increase expectation of benefit from the drug . The primary outcome was mean change in daily peak flow over 4 weeks . Secondary outcomes included lung function and asthma symptom control . RESULTS Peak flow and other lung function measures were not improved in participants assigned to the enhanced message groups versus the neutral messages groups for either montelukast or placebo ; no differences were noted between the neutral placebo and usual care groups . Placebo-treated participants had improved asthma control with the enhanced message but not montelukast-treated participants ; the neutral placebo group did have improved asthma control compared with the usual care group after adjusting for baseline difference . Headaches were more common in participants provided messages that mentioned headache as a montelukast side effect . CONCLUSIONS Optimistic drug presentation augments the placebo effect for patient-reported outcomes ( asthma control ) but not lung function . However , the effect of montelukast was not enhanced by optimistic messages regarding treatment effectiveness Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Asthma management guidelines recommend low-dose inhaled corticosteroids ( ICS ) as first-line therapy for adults and adolescents with persistent asthma . The addition of anti-leukotriene agents to ICS offers a therapeutic option in cases of suboptimal control with daily ICS . OBJECTIVES To assess the efficacy and safety of anti-leukotriene agents added to ICS compared with the same dose , an increased dose or a tapering dose of ICS ( in both arms ) for adults and adolescents 12 years of age and older with persistent asthma . Also , to determine whether any characteristics of participants or treatments might affect the magnitude of response . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

27917777

[15512142] We set out to reevaluate the hypothesis that high normal ( negative ) results of 50 g oral glucose challenge test or high normal glucose level on 100 g oral glucose tolerance test are associated with complications of pregnancy and delivery . This was a prospect i ve study involving 735 nondiabetic women . The first group ( n=352 ) was made up of pregnant women with normal 50 g oral glucose challenge test without previous history of diabetes mellitus or gestational diabetes . The second group ( n=383 ) was made up of pregnant women without previous history of diabetes mellitus or gestational diabetes with an abnormal 50 g oral glucose challenge test and with normal 100 g oral glucose tolerance test and not more than one previous delivery . In nondiabetic women , we demonstrated a positive correlation between high normal 50 g glucose challenge test values and the incidence of preeclampsia , caesarean section rate , macrosomia , neonatal hyperlipidaemia and minor congenital abnormalities . We failed to confirm any relationship to any pregnancy complication in pregnant women with 2-hour glucose levels in the range 6.7 - 9.1 mmol/l on the 100 g oral glucose tolerance test . We have demonstrated a positive relationship between the incidence of premature rupture of membranes and 1-hour glucose level , caesarean section rate and maternal 1-hour glucose level or 1-hour glucose level minus fasting glucose level of 4.2 mmol/l , instrumental delivery rate and maternal 3-hour glucose level , incidence of neonatal macrosomia and 1-hour glucose level , and incidence of neonatal hyperlipidaemia and at least one high but normal glucose level on the 100 g oral glucose tolerance test . With regard to pregnancy and delivery complications there were no significant difference if the high normal value is on the 50 g glucose challenge test or on the 100 g oral glucose tolerance test . It is concluded that one high normal 100 g oral glucose tolerance test or high normal 50 g glucose challenge test are associated with adverse pregnancy and delivery outcome . Nondiabetic women with 50 g glucose challenge test value of 6.1 mmol/l and /or 100 g oral glucose tolerance test values of 5 mmol/l have a favourable pregnancy and delivery outcome [2571044] OBJECTIVE —We investigated the effects of normal variations in maternal glycemia on birth size and other birth outcomes . RESEARCH DESIGN AND METHODS —Women in two unselected birth cohorts , one retrospective ( n = 3,158 ) and one prospect i ve ( n = 668 ) , underwent an oral glucose challenge at 28 weeks of gestation . In the retrospective study , glycemia was linked to routine birth records . In the prospect i ve study , offspring adiposity was assessed by skinfold thickness from birth to age 24 months . RESULTS —In the retrospective study , within the nondiabetic range ( 2.1–7.8 mmol/l ) , each 1 mmol/l rise in the mother 's 60-min glucose level was associated with a ( mean ± SEM ) 2.1 ± 0.8 % ( P = 0.006 ) rise in absolute risk of assisted vaginal delivery , a 3.4 ± 0.8 % ( P < 0.0001 ) rise in emergency cesarean delivery , a 3.1 ± 0.7 % ( P < 0.0001 ) rise in elective cesarean delivery , and a 46 ± 8 g ( P < 0.0001 ) increase in offspring birth weight . In the prospect i ve study , fetal macrosomia ( birth weight > 90th centile ) was independently related to the mother 's fasting glucose ( odds ratio 2.61 per + 1 mmol/l [ 95 % CI 1.15–5.93 ] ) and prepregnancy BMI ( 1.10 per + 1 kg/m2 [ 1.04–1.18 ] ) . The mother 's higher fasting glycemia ( P = 0.004 ) , lower insulin sensitivity ( P = 0.01 ) , and lower insulin secretion ( P = 0.02 ) were independently related to greater offspring adiposity at birth . During postnatal follow-up , the correlation between the mother 's glycemia and offspring adiposity disappeared by 3 months , whereas prepregnancy BMI was associated with offspring adiposity that was only apparent at 12 and 24 months ( both P < 0.05 ) . CONCLUSIONS —Prepregnancy BMI , pregnancy glycemia , insulin sensitivity , and insulin secretion all contribute to offspring adiposity and macrosomia and may be separate targets for intervention to optimize birth outcomes and later offspring health [4218974] Aims /hypothesisTo determine the extent to which gestational fasting and postload levels of glucose explain differences in infant fat mass between UK-born Pakistani and white British infants . Methods Analyses were undertaken in a prospect i ve pregnancy cohort study of 1,415 women and their singleton live-born infants ( 629 white British and 786 Pakistani ) . Infant fat mass was assessed by cord-blood leptin levels and fetal insulin secretion by cord-blood insulin levels . Maternal OGTTs were completed at 26–28 weeks of gestation . Results Pakistani women had higher fasting and postload glucose levels and greater incidence of gestational diabetes than white British women . Higher fasting and postload glucose levels were associated with higher cord-blood levels of insulin and leptin in all participants , irrespective of ethnicity . Cord-blood leptin levels were 16 % ( 95 % CI 6 , 26 ) higher in Pakistani than in white British infants . After adjustment for fasting glucose levels , this difference attenuated to 7 % ( −3 , 16 ) , and with additional adjustment for cord-blood insulin levels it attenuated further to 5 % ( −4 , 14 ) . Path analyses supported the hypothesis that fasting glucose levels mediate the relationship of Pakistani ethnicity to greater fat mass at birth , as measured by cord-blood leptin levels ; on average , 19 % of this mediation involved fetal insulin secretion . Postload glucose levels did not act as an important mediator of ethnic differences in cord-blood leptin levels . Results were very similar when 130 women with gestational diabetes were removed . Conclusions /interpretationThese novel findings suggest a role of maternal pregnancy glycaemia in mediating differences in fat mass between Pakistani and white British infants [4526580] Aims /hypothesisGestational diabetes mellitus ( GDM ) is associated with increased risks to mother and child , but globally agreed diagnostic criteria remain elusive . Identification of women with GDM is important , as treatment reduces adverse outcomes such as perinatal death , shoulder dystocia and neonatal hypoglycaemia . Recently , the UK ’s National Institute for Health and Care Excellence ( NICE ) recommended new diagnostic thresholds for GDM which are different from the International Association of the Diabetes and Pregnancy Study Groups ( IADPSG ) criteria endorsed by the WHO . The study aim was to assess neonatal and obstetric outcomes among women who would test positive for the IADPSG criteria but negative for the NICE 2015 criteria . Methods Data from 25,543 consecutive singleton live births ( 2004–2008 ) were obtained retrospectively from hospital records . Women were screened with a r and om plasma glucose ( RPG ; 12–16 weeks ) and a 50 g glucose challenge test ( GCT ; 26–28 weeks ) . If RPG > 7.0 mmol/l , GCT > 7.7 mmol/l or symptoms were present , a 75 g OGTT was offered ( n = 3,848 ) . Results In this study , GDM prevalence was 4.13 % ( NICE 2015 ) and 4.62 % ( IADPSG ) . Women who ‘ fell through the net ’ , testing NICE-negative but IADPSG-positive ( n = 387 ) , had a higher risk of having a large-for-gestational-age ( LGA ) infant ( birthweight > 90th percentile for gestational age ; adjusted OR [ 95 % CI ] 3.12 [ 2.44 , 3.98 ] ) , Caesarean delivery ( 1.44 [ 1.15 , 1.81 ] ) and polyhydramnios ( 6.90 [ 3.94 , 12.08 ] ) compared with women with negative screening results and no OGTT ( n = 21,695 ) . LGA risk was highest among women with fasting plasma glucose 5.1–5.5 mmol/l ( n = 167 ) : the mean birthweight was 350 g above that of the reference population and 37.7 % of infants were LGA . Conclusions /interpretationThe IADPSG criteria identify women at substantial risk of complications who would not be identified by the NICE 2015 criteria [21220735] Background — Maternal diabetes mellitus in pregnancy results in greater offspring adiposity at birth . It is unclear whether it is associated with greater adiposity into adulthood , and if so , whether this is via intrauterine mechanisms or shared familial characteristics . Methods and Results — A record-linkage prospect i ve cohort study of 280 866 singleton-born Swedish men from 248 293 families was used to explore the intrauterine effect of maternal diabetes mellitus on offspring body mass index ( BMI ) in early adulthood . Maternal diabetes mellitus during pregnancy was associated with greater mean BMI at age 18 in their sons . The difference in BMI was similar within brothers and between nonsiblings . BMI of men whose mothers had diabetes mellitus during their pregnancy was on average 0.94 kg/m2 greater ( 95 % confidence interval [ CI ] , 0.35 to 1.52 ) than in their brothers born before their mother was diagnosed with diabetes , after adjustment for birth year , maternal age , parity and education , birth weight , gestational age , and age at assessment of BMI . Early-pregnancy BMI was positively associated with son 's BMI between nonsiblings , but there was no association within brothers . Adjustment of the maternal diabetes-offspring BMI association for maternal BMI did not alter the association either within brothers or between nonsiblings . Results were also robust to sensitivity analyses restricting the within-sibling analyses to siblings born within 3 years of each other . Conclusion — Maternal diabetes mellitus has long-term consequences for greater BMI in offspring ; this association is likely to be via intrauterine mechanisms , and is independent of maternal BMI in early pregnancy [21083860] Please cite this paper as : Ijäs H , Vääräsmäki M , Morin‐Papunen L , Keravuo R , Ebeling T , Saarela T , Raudaskoski T. Metformin should be considered in the treatment of gestational diabetes : a prospect i ve r and omised study . BJOG 2011;118:880–885 [17684614] OBJECTIVES To study glibenclamide as a treatment for gestational diabetes mellitus ( GDM ) and its impact on newborn birth weight and neonatal glycemia as compared to insulin . METHODS A r and omized and open-label clinical trial , conducted from October 1st , 2003 to March 8 , 2005 . Seventy-two pregnant women with gestational diabetes mellitus requiring drug therapy were r and omized and allocated into two groups -- insulin and glibenclamide . RESULTS The general characteristics in both groups were similar , except for the results of the 75 g OGTT , which were higher in the glibenclamide group ( p= 0.02 ) . Maternal fasting and postpr and ial glucose levels presented no difference . Six ( 18.75 % ) pregnant women received the maximum dose of glibenclamide with no glycemic control . The birth weight was higher in the group treated with glibenclamide ( p= 0.01 ) , and the incidence of macrosomic newborns statistically different ( p= 0.01 ) . Neonatal hypoglycemia was more frequent ( p= 0.01 ) in newborns of glibenclamide group , with one single case of persistent hypoglycemia . CONCLUSION Glibenclamide can be the first line drug for glycemic control in most GDM patients . The birth weight and incidence of hypoglycemia were higher in the glibenclamide group , but with one single case of persistent hypoglycemia that required intravenous infusion of glucose [21494772] Aims /hypothesisNew diagnostic criteria for gestational diabetes mellitus ( GDM ) have recently been published . We wished to evaluate what impact these new criteria would have on GDM prevalence and outcomes in a predominantly European population . Methods The Atlantic Diabetes In Pregnancy ( DIP ) programme performed screening for GDM in 5,500 women with an oral glucose tolerance test at 24–28 weeks . GDM was defined according to the new International Association of Diabetes and Pregnancy Study Groups ( IADPSG ) criteria and compared with previous WHO criteria ; maternal and neonatal adverse outcomes were prospect ively recorded . Results Of the participants , 12.4 % and 9.4 % were diagnosed with GDM using IADPSG and WHO criteria , respectively . IADPSG GDM pregnancies were associated with a statistically significant increased incidence of adverse maternal outcomes ( gestational hypertension , polyhydramnios and Caesarean section ) and neonatal outcomes ( prematurity , large for gestational age , neonatal unit admission , neonatal hypoglycaemia and respiratory distress ) . The odds ratio for the development of these adverse outcomes remained significant after adjustment for maternal age , body mass index and non-European ethnicity . Those women who were classified as having normal glucose tolerance by WHO criteria but as having GDM by IADPSG criteria also had significant adverse pregnancy outcomes . Conclusions /interpretationGDM prevalence is higher when using newer IADPSG , compared with WHO , criteria , and these women and their offspring experience significant adverse pregnancy outcomes . Higher rates of GDM pose a challenge to healthcare systems , but improved screening provides an opportunity to attempt to reduce the associated morbidity for mother and child [22505499] Abstract Objective : To evaluate the perinatal impact of metformin and glyburide in the treatment of gestational diabetes mellitus ( GDM ) . Methods : A r and omized clinical trial conducted from July 2008 until September 2010 studied 200 pregnant women with GDM who required adjunctive therapy to diet and physical activity . Patients were r and omized to use metformin ( n=104 ) or glyburide ( n=96 ) . The drugs were replaced by insulin when they reached the maximum dose without glycemic control . Assessed outcomes : weight and neonatal blood glucose . Results : : No difference was found ( P>0.05 ) between the groups regarding maternal age , gestational age at inclusion , body mass index , glucose levels in oral glucose tolerance test ( OGTT ) 75 g and glycemic control . Difference was found in the number of previous pregnancies ( 2.84 vs. 2.47 , P=0.04 ) and weight gain during pregnancy ( 7.78 vs. 9.84 , P=0.04 ) in the metformin group and glyburide respectively . The perinatal results showed no difference ( P>0.05 ) in the percentage of cesarean deliveries , gestational age at delivery , number of newborns large for gestational age ( LGA ) , neonatal hypoglycemia , admission to intensive care unit and perinatal death . We found differences in weight ( 3193 g vs. 3387 g , P=0.01 ) and ponderal index ( 2.87 vs. 2.96 , P=0.05 ) of newborns , and in neonatal blood glucose levels at the 1st ( 59.78 vs. 54.08 , P=0.01 ) and 3rd h ( 61.53 vs. 55.89 , P=0.01 ) after birth between the metformin and glyburide groups respectively . Conclusions : Weight and ponderal index were lower in the newborns of the metformin group ; glucose levels ( 1st and 3rd h after birth ) were lower in the glyburide group [7631672] OBJECTIVE Our purpose was to assess maternal-fetal outcomes in patients with increasing carbohydrate intolerance not meeting the current criteria for the diagnosis of gestational diabetes . STUDY DESIGN We conducted a prospect i ve analytic cohort study in which nondiabetic women aged > or = 24 years , receiving prenatal care in three Toronto teaching hospitals , were eligible for enrollment . A glucose challenge test and an oral glucose tolerance test were administered at 26 and 28 weeks ' gestation , respectively ; risk factors for unfavorable maternal-fetal outcomes were recorded . Caregivers and patients were blinded to glucose values except when test results met the current criteria for gestational diabetes . RESULTS Of 4274 patients screened , 3836 ( 90 % ) continued to the diagnostic oral glucose tolerance test . The study cohort was formed by the 3637 ( 95 % ) patients without gestational diabetes , carrying singleton fetuses . Increasing carbohydrate intolerance in women without overt gestational diabetes was associated with a significantly increased incidence of cesarean sections , preeclampsia , macrosomia , and need for phototherapy , as well as an increased length of maternal and neonatal hospital stay . Multivariate analysis showed that increasing carbohydrate intolerance is an independent predictor for various unfavorable outcomes . CONCLUSION Increasing maternal carbohydrate intolerance in pregnant women without gestational diabetes is associated with a grade d increase in adverse maternal-fetal outcomes [11597616] OBJECTIVES To assess the prevalence and association of frequently used screening risk factors for gestational diabetes mellitus ( GDM ) and to compare the validity and cost of universal screening with risk factor screening . METHOD A cross-sectional survey of 768 pregnant women at > or = 24 weeks ' gestation who were attending the antenatal clinic at the Hospital Universiti Kebangsaan Malaysia ( HUKM ) was made . Risk factors were determined using a question naire . An abnormal oral glucose tolerance test was defined as a 2-h post-pr and ial blood sugar level of > or = 7.8 mmol/l . RESULTS A total of 191 pregnant mothers ( 24.9 % ) had GDM . The most commonly identified screening factors were positive family history of diabetes mellitus ( 31.4 % ) , history of spontaneous abortion ( 17.8 % ) , vaginal discharge and pruritus vulvae in current pregnancy ( 16.0 % ) , and maternal age greater than 35 years ( 14.7 % ) . Five hundred and thirteen mothers ( 66.8 % ) had at least one risk factor . All screening risk factors , except past history of diabetes mellitus in previous pregnancy and maternal age , were not significantly associated with abnormal glucose tolerance ( GT ) . Risk factor screening gave a sensitivity of 72.2 % and a specificity of 35.0 % . Universal screening would cost RM 12.06 while traditional risk factor screening would cost RM 11.15 per identified case and will have missed 53 of the 191 cases . CONCLUSIONS Risk factor screening scored poorly in predicting GDM . Cost analysis of universal compared with traditional risk factor screening showed a negligible difference . Thus universal screening appears to be the most reliable method of diagnosing GDM [18826999] CONTEXT A past history of gestational diabetes mellitus ( GDM ) confers a very high risk of postpartum development of diabetes , particularly type 2 diabetes . OBJECTIVE The Diabetes Prevention Program ( DPP ) sought to identify individuals with impaired glucose tolerance ( IGT ) and intervene in an effort to prevent or delay their progression to diabetes . This analysis examined the differences between women enrolled in DPP with and without a reported history of GDM . DESIGN The DPP was a r and omized , controlled clinical trial . SETTING The study was a multicenter , National Institutes of Health-sponsored trial carried out at 27 centers including academic and Indian Health Services sites . PATIENTS A total of 2190 women were r and omized into the DPP and provided information for past history of GDM . This analysis addressed the differences between those 350 women providing a past history of GDM and those 1416 women with a previous live birth but no history of GDM . INTERVENTIONS Subjects were r and omized to either st and ard lifestyle and placebo or metformin therapy or to an intensive lifestyle intervention . MAIN OUTCOMES The primary outcome was the time to development of diabetes ascertained by semiannual fasting plasma glucose and annual oral glucose tolerance testing . Assessment s of insulin secretion and insulin sensitivity were also performed . RESULTS Whereas entering the study with similar glucose levels , women with a history of GDM r and omized to placebo had a crude incidence rate of diabetes 71 % higher than that of women without such a history . Among women reporting a history of GDM , both intensive lifestyle and metformin therapy reduced the incidence of diabetes by approximately 50 % compared with the placebo group , whereas this reduction was 49 and 14 % , respectively in parous women without GDM . These data suggest that metformin may be more effective in women with a GDM history as compared with those without . CONCLUSIONS Progression to diabetes is more common in women with a history of GDM compared with those without GDM history despite equivalent degrees of IGT at baseline . Both intensive lifestyle and metformin are highly effective in delaying or preventing diabetes in women with IGT and a history of GDM [20809381] Aims /hypothesisThe cost-effectiveness of eight strategies for screening for gestational diabetes ( including no screening ) was estimated with respect to the level of individual patient risk . Methods Cost – utility analysis using a decision analytic model populated with efficacy evidence pooled from recent r and omised controlled trials , from the funding perspective of the National Health Service in Engl and and Wales . Seven screening strategies using various combinations of screening and diagnostic tests were tested in addition to no screening . The primary outcome measure was the incremental cost per quality -adjusted life-year ( QALY ) over a lifetime . Results The strategy that has the greatest likelihood of being cost-effective is dependent on the risk of gestational diabetes mellitus for each individual woman . When gestational diabetes mellitus risk is < 1 % then the no screening/treatment strategy is cost-effective ; where risk is between 1.0 % and 4.2 % fasting plasma glucose followed by OGTT is most likely to be cost-effective ; and where risk is > 4.2 % , universal OGTT is most likely to be cost-effective . However , acceptability of the test alters the most cost-effective strategy . Conclusions /interpretationScreening for gestational diabetes can be cost-effective . The best strategy is dependent on the underlying risk of each individual and the acceptability of the tests used . The current study suggests that if a woman ’s individual risk of gestational diabetes could be accurately predicted , then healthcare re source allocation could be improved by providing an individualised screening strategy [24424076] Background / Objectives : The current study was performed to investigate the effects of the Dietary Approaches to Stop Hypertension ( DASH ) eating plan on pregnancy outcomes in pregnant women with gestational diabetes mellitus (GDM).Subjects/ Methods : This r and omized controlled clinical trial was performed among 52 women diagnosed with GDM . Participants were r and omly assigned to consume either the control ( n=26 ) or the DASH diet ( n=26 ) for 4 weeks . The control diet was design ed to contain 45–55 % carbohydrates , 15–20 % protein and 25–30 % total fat . The DASH diet was rich in fruits , vegetables , whole grains and low-fat dairy products , and contained lower amounts of saturated fats , cholesterol and refined grains with a total of 2400 mg/day sodium . The numbers of women who commenced insulin therapy after dietary intervention , the mode of delivery and prevalence of polyhydramnios were assessed . The length , weight and head circumference of infants were measured during the first 24 h after birth . Results : Whereas 46.2 % of women in the DASH diet needed to have a cesarean section , this percentage for the control group was 80.8 % ( P=0.01 ) . The percentage of those who needed to commence insulin therapy after intervention was also significantly different between the two groups ( 23 % for DASH vs 73 % for control group , P<0.0001 ) . Infants born to mothers on the DASH diet had significantly lower weight ( 3222.7 vs 3818.8 g , P<0.0001 ) , head circumference ( 34.2 vs 35.1 cm , P=0.01 ) and ponderal index ( 2.50 vs 2.87 kg/m3 , P<0.0001 ) compared with those born to mothers on the control diet . Conclusions : In conclusion , consumption of DASH diet for 4 weeks among pregnant women with GDM result ed in improved pregnancy outcomes [20827864] OBJECTIVE To determine if pregnancies with an abnormal glucose challenge test ( GCT ) but a normal ( GTT ) are at increased risk for fetal macrosomia or an adverse pregnancy outcome . STUDY DESIGN This prospect i ve observational study matched women with an abnormal glucose challenge test and a normal GTT with the next patient with a normal GCT . RESULTS Over 12 months , 107 women with abnormal GCT were matched with 107 women with normal GCT . Women with an abnormal GCT were older ( 27.3 vs. 24.7 , p = 0.001 ) and less likely to be African-American ( OR = 2.2 , 95 % CI 1.06 - 4.49 ) but no more likely to have an adverse pregnancy outcome . ROC curves could not differentiate between macrosomic vs non-macrosomic newborns using GCT values . CONCLUSION Women with an abnormal GCT but a normal GTT are more likely to be older , less likely to be African-American , but no more likely to have an adverse pregnancy outcome or a macrosomic fetus [24243635] CONTEXT Gestational hyperglycemia increases the risk of obesity and diabetes in offspring later in life . OBJECTIVE We examined the relationship between gestational glycemia and neonatal adiposity in a multiethnic cohort of Singaporean neonates . DESIGN A prospect i ve mother-offspring cohort study recruited 1247 pregnant mothers ( 57.2 % Chinese , 25.5 % Malay , 17.3 % Indian ) and performed 75-g , 2-hour oral glucose tolerance tests at 26 - 28 weeks ' gestation ; glucose levels were available for 1081 participants . Neonatal anthropometry ( birth weight , length , triceps , and subscapular skinfolds ) was measured , and percentage body fat ( % BF ) was derived using our published equation . Associations of maternal glucose with excessive neonatal adiposity [ large for gestational age ; % BF ; and sum of skinfolds (∑SFT)>90th centile ] were assessed using multiple logistic regression analyses . RESULTS Adjusting for potential confounders we observed strong positive continuous associations across the range of maternal fasting and 2-hour glucose in relation to excessive neonatal adiposity ; each 1 SD increase in fasting glucose was associated with 1.31 [ 95 % confidence interval ( CI ) 1.10 - 1.55 ] , 1.72 ( 95 % CI 1.31 - 2.27 ) and 1.64 ( 95 % CI 1.32 - 2.03 ) increases in odds ratios for large for gestational age and % BF and ∑SFT greater than the 90th centile , respectively . Corresponding odds ratios for 2-hour glucose were 1.11 ( 95 % CI 0.92 - 1.33 ) , 1.55 ( 95 % CI 1.10 - 2.20 ) , and 1.40 ( 95 % CI 1.10 - 1.79 ) , respectively . The influence of high maternal fasting glucose on neonatal ∑SFT was less pronounced in Indians compared with Chinese ( interaction P=.005 ) . CONCLUSIONS A continuous relationship between maternal glycemia and excessive neonatal adiposity extends across the range of maternal glycemia . Compared with Chinese infants , Indian infants may be less susceptible to excessive adiposity from high maternal glucose levels [3831638] The data for medical decision analyses are often unreliable . Traditional sensitivity analysis --varying one or more probability or utility estimates from baseline values to see if the optimal strategy changes -- is cumbersome if more than two values are allowed to vary concurrently . This paper describes a practical method for probabilistic sensitivity analysis , in which uncertainties in all values are considered simultaneously . The uncertainty in each probability and utility is assumed to possess a probability distribution . For ease of application we have used a parametric model that permits each distribution to be specified by two values : the baseline estimate and a bound ( upper or lower ) of the 95 percent confidence interval . Following multiple simulations of the decision tree in which each probability and utility is r and omly assigned a value within its distribution , the following results are recorded : ( a ) the mean and st and ard deviation of the expected utility of each strategy ; ( b ) the frequency with which each strategy is optimal ; ( c ) the frequency with which each strategy " buys " or " costs " a specified amount of utility relative to the remaining strategies . As illustrated by an application to a previously published decision analysis , this technique is easy to use and can be a valuable addition to the armamentarium of the decision analyst [15449338] Mixed treatment comparison ( MTC ) meta- analysis is a generalization of st and ard pairwise meta- analysis for A vs B trials , to data structures that include , for example , A vs B , B vs C , and A vs C trials . There are two roles for MTC : one is to strengthen inference concerning the relative efficacy of two treatments , by including both ' direct ' and ' indirect ' comparisons . The other is to facilitate simultaneous inference regarding all treatments , in order for example to select the best treatment . In this paper , we present a range of Bayesian hierarchical models using the Markov chain Monte Carlo software WinBUGS . These are multivariate r and om effects models that allow for variation in true treatment effects across trials . We consider models where the between-trials variance is homogeneous across treatment comparisons as well as heterogeneous variance models . We also compare models with fixed ( unconstrained ) baseline study effects with models with r and om baselines drawn from a common distribution . These models are applied to an illustrative data set and posterior parameter distributions are compared . We discuss model critique and model selection , illustrating the role of Bayesian deviance analysis , and node-based model criticism . The assumptions underlying the MTC models and their parameterization are also discussed [4673084] Summary Background Diagnosis of gestational diabetes predicts risk of infants who are large for gestational age ( LGA ) and with high adiposity , which in turn aims to predict a future risk of obesity in the offspring . South Asian women have higher risk of gestational diabetes , lower risk of LGA , and on average give birth to infants with greater adiposity than do white European women . Whether the same diagnostic criteria for gestational diabetes should apply to both groups of women is unclear . We aim ed to assess the association between maternal glucose and adverse perinatal outcomes to ascertain whether thresholds used to diagnose gestational diabetes should differ between south Asian and white British women . We also aim ed to assess whether ethnic origin affected prevalence of gestational diabetes irrespective of criteria used . Methods We used data ( including results of a 26–28 week gestation oral glucose tolerance test ) of women from the Born in Bradford study , a prospect i ve study that recruited women attending the antenatal clinic at the Bradford Royal Infirmary , UK , between 2007 and 2011 and who intended to give birth to their infant in that hospital . We studied the association between fasting and 2 h post-load glucose and three primary outcomes ( LGA [ defined as birthweight > 90th percentile for gestational age ] , high infant adiposity [ sum of skinfolds > 90th percentile for gestational age ] , and caesarean section ) . We calculated adjusted odds ratios ( ORs ) and their 95 % confidence intervals ( CIs ) for a 1 SD increase in fasting and post-load glucose . We established fasting and post-load glucose thresholds that equated to an OR of 1·75 for LGA and high infant adiposity in each group of women to identify ethnic-specific criteria for diagnosis of gestational diabetes . Findings Of 13 773 pregnancies , 3420 were excluded from analyses . Of 10 353 eligible pregnancies , 4088 women were white British , 5408 were south Asian , and 857 were of other ethnic origin . The adjusted ORs of LGA per 1 SD fasting glucose were 1·22 ( 95 % CI 1·08–1·38 ) in white British women and 1·43 ( 1·23–1·67 ) in south Asian women ( pinteraction with ethnicity = 0·39 ) . Results for high infant adiposity were 1·35 ( 1·23–1·49 ) and 1·35 ( 1·18–1·54 ; pinteraction with ethnicity=0·98 ) , and for caesarean section they were 1·06 ( 0·97–1·16 ) and 1·11 ( 1·02–1·20 ; pinteraction with ethnicity=0·47 ) . Associations between post-load glucose and the three primary outcomes were weaker than for fasting glucose . A fasting glucose concentration of 5·4 mmol/L or a 2 h post-load level of 7·5 mmol/L identified white British women with 75 % or higher relative risk of LGA or high infant adiposity ; in south Asian women , the cutoffs were 5·2 mmol/L or 7·2 mml/L ; in the whole cohort , the cutoffs were 5·3 mmol/L or 7·5 mml/L. The prevalence of gestational diabetes in our cohort ranged from 1·2 % to 8·7 % in white British women and 4 % to 24 % in south Asian women using six different criteria . Compared with the application of our whole-cohort criteria , use of our ethnic-specific criteria increased the prevalence of gestational diabetes in south Asian women from 17·4 % ( 95 % CI 16·4–18·4 ) to 24·2 % ( 23·1–25·3 ) . Interpretation Our data support the use of lower fasting and post-load glucose thresholds to diagnose gestational diabetes in south Asian than white British women . They also suggest that diagnostic criteria for gestational diabetes recommended by UK NICE might underestimate the prevalence of gestational diabetes compared with our criteria or those recommended by the International Association of Diabetes and Pregnancy Study Groups and WHO , especially in south Asian women . Funding The National Institute for Health Research [9240606] OBJECTIVES The purpose of this study was to determine whether strict maternal glycemic control for the treatment of gestational diabetes lessened the risk of fetal macrosomia , birth trauma , neonatal hypoglycemia , and operative delivery . The aim of the pilot study was to prepare for a multicenter trial by assessing patient acceptance of the study , by determining realistic accrual rates , and by detecting any major adverse outcomes in the control group that received routine obstetric care . STUDY DESIGN The study was a prospect i ve r and omized controlled trial comparing fetal-neonatal and maternal outcomes in 300 women with gestational diabetes . Women r and omized to the treatment arm were managed by strict glycemic control and tertiary level obstetric care , and women in the control arm received routine obstetric care . RESULTS Three hundred women with gestational diabetes mellitus were studied . There was no difference in maternal age , weight , or length of gestation between groups . The treatment mean birth weight was 3437 + /- 575 gm compared with 3544 + /- 601 gm in the control group , a difference of 107 gm ( not significant ) . Macrosomia rates were similar . There was no birth trauma in either group . The frequency of neonatal hypoglycemia and other metabolic complications was the same . The mode of delivery also showed similar patterns . The treatment group had significantly lower prepr and ial and postpr and ial glucose levels by 32 weeks ' gestation , which continued to term . CONCLUSION This pilot study suggests that intensive treatment of gestational diabetes mellitus may have little effect on birth weight , birth trauma , operative delivery , or neonatal metabolic disorders . It has demonstrated the safety of proceeding to a multicenter trial of sufficient sample size to confirm these findings [23001377] Aims /hypothesisIt is currently not clear how to construct a time- and cost-effective screening strategy for gestational diabetes mellitus ( GDM ) . Thus , we elaborated a simple screening algorithm combining ( 1 ) fasting plasma glucose ( FPG ) measurement ; and ( 2 ) a multivariable risk estimation model focused on individuals with normal FPG levels to decide if a further OGTT is indicated . Methods A total of 1,336 women were prospect ively screened for several risk factors for GDM within a multicentre study conducted in Austria . Of 714 women ( 53.4 % ) who developed GDM using recent diagnostic guidelines , 461 were sufficiently screened with FPG . A risk prediction score was finally developed using data from the remaining 253 women with GDM and 622 healthy women . The screening algorithm was vali date d with a further 258 pregnant women . Results A risk estimation model including history of GDM , glycosuria , family history of diabetes , age , preconception dyslipidaemia and ethnic origin , in addition to FPG , was accurate for detecting GDM in participants with normal FPG . Including an FPG pretest , the receiver operating characteristic AUC of the screening algorithm was 0.90 ( 95 % CI 0.88 , 0.91 ) . A cut-off value of 0.20 was able to differentiate between low and intermediate risk for GDM with a high sensitivity . Comparable results were seen with the validation cohort . Moreover , we demonstrated an independent association between values derived from the risk estimation and macrosomia in offspring ( OR 3.03 , 95 % CI 1.79 , 5.19 , p < 0.001 ) . Conclusions /interpretationThis study demonstrates a new concept for accurate but cheap GDM screening . This approach should be further evaluated in different population s to ensure an optimised diagnostic algorithm [15951574] BACKGROUND We conducted a r and omized clinical trial to determine whether treatment of women with gestational diabetes mellitus reduced the risk of perinatal complications . METHODS We r and omly assigned women between 24 and 34 weeks ' gestation who had gestational diabetes to receive dietary advice , blood glucose monitoring , and insulin therapy as needed ( the intervention group ) or routine care . Primary outcomes included serious perinatal complications ( defined as death , shoulder dystocia , bone fracture , and nerve palsy ) , admission to the neonatal nursery , jaundice requiring phototherapy , induction of labor , cesarean birth , and maternal anxiety , depression , and health status . RESULTS The rate of serious perinatal complications was significantly lower among the infants of the 490 women in the intervention group than among the infants of the 510 women in the routine-care group ( 1 percent vs. 4 percent ; relative risk adjusted for maternal age , race or ethnic group , and parity , 0.33 ; 95 percent confidence interval , 0.14 to 0.75 ; P=0.01 ) . However , more infants of women in the intervention group were admitted to the neonatal nursery ( 71 percent vs. 61 percent ; adjusted relative risk , 1.13 ; 95 percent confidence interval , 1.03 to 1.23 ; P=0.01 ) . Women in the intervention group had a higher rate of induction of labor than the women in the routine-care group ( 39 percent vs. 29 percent ; adjusted relative risk , 1.36 ; 95 percent confidence interval , 1.15 to 1.62 ; P<0.001 ) , although the rates of cesarean delivery were similar ( 31 percent and 32 percent , respectively ; adjusted relative risk , 0.97 ; 95 percent confidence interval , 0.81 to 1.16 ; P=0.73 ) . At three months post partum , data on the women 's mood and quality of life , available for 573 women , revealed lower rates of depression and higher scores , consistent with improved health status , in the intervention group . CONCLUSIONS Treatment of gestational diabetes reduces serious perinatal morbidity and may also improve the woman 's health-related quality of life [19841891] Aims /hypothesisThe aim of the study was to examine the association of existing diabetes ( i.e. already diagnosed prior to pregnancy ) , gestational diabetes and glycosuria ( both diagnosed and ascertained during pregnancy ) with birthweight and future offspring BMI , waist circumference and fat mass ( assessed by dual x-ray emission absorptiometry ) . Methods A prospect i ve pregnancy/birth cohort study was performed using data from the Avon Longitudinal Study of Parents and Children . Results Among 10,591 mother – offspring pairs included in analyses with birth size , women with existing diabetes ( n = 40 ) , those diagnosed with gestational diabetes ( n = 53 ) and those with at least two episodes of + + glycosuria ( n = 372 ) had greater mean birthweight and odds for macrosomia ( birthweight > 4,000 g ) than women with none of these . Adjusted odds ratios for macrosomia were 3.56 ( 95 % CI 1.53–8.28 ) , 5.50 ( 95 % CI 1.18–10.30 ) and 1.58 ( 95 % CI 1.18–2.12 ) for existing diabetes , gestational diabetes and glycosuria , respectively . Among 6,842 mother – offspring pairs with anthropometric measurements at age 9–11 years , maternal gestational diabetes and glycosuria ( but not existing diabetes ) were associated with increased offspring odds of general or central overweight/obesity . For gestational diabetes , these associations attenuated towards the null with adjustment for maternal prepregnancy BMI , but independent associations remained for glycosuria . The adjusted odds ratio for general overweight/obesity when comparing women with at least two episodes of + + glycosuria with those with no evidence of diabetes or glycosuria was 1.35 ( 95 % CI 1.00–1.82 ) and that for central obesity ( top 10 % waist circumference vs all others ) was 1.31 ( 95 % CI 1.00–1.72 ) . Conclusions /interpretationThese results provide some evidence for a long-term effect of maternal glycaemia in pregnancy on offspring obesity risk [23020608] AIMS We compared metformin with insulin as treatment of gestational diabetes mellitus ( GDM ) . Furthermore , we aim ed to characterize metformin-treated patients needing additional insulin to achieve prespecified glucose targets . METHODS We conducted a single centre r and omized controlled study with non-inferiority design comparing metformin and insulin in the treatment of 217 GDM patients having birth weight as primary outcome variable . RESULTS There were no significant differences in mean birth weight expressed in grams [ + 15 ( 90 % confidence interval ( CI ) : -121 to 89 ) ] or SD units [ + 0.04 ( 90 % CI : -0.27 to 0.18 ) ] between the metformin and insulin groups . There were no significant differences in neonatal or maternal data between the groups . Only 23 ( 20.9 % ) of the 110 patients in the metformin group needed additional insulin . Compared with the patients on metformin only , those needing additional insulin were older ( p = 0.04 ) , their oral glucose tolerance test had been performed earlier and diabetes therapy started earlier in gestation ( p = 0.01 and p = 0.004 , respectively ) . The risk for additional insulin was 4.6-fold in women with baseline serum fructosamine concentration above median compared with those below median . CONCLUSIONS Metformin is an effective alternative to insulin in the treatment of GDM patients . Serum fructosamine may help in predicting the adequacy of metformin treatment alone [18161398] OBJECTIVE To compare glycemic control and neonatal outcomes in women with gestational diabetes mellitus ( GDM ) treated with metformin vs. insulin . STUDY DESIGN Women with GDM not controlled with diet and exercise were r and omized to metformin ( n = 32 ) or insulin ( n = 31 ) . The levels of glycemic control as well as maternal/neonatal complications were evaluated . RESULTS The mean ( + /- SD ) fasting and 2-hour postpr and ial blood glucose did not differ statistically between the 2 treatment groups . No patient failed metformin and required insulin . The majority ( 27/32 ) were easily controlled on the initial dosage ( 500 mg twice a day ) . Gestational age at entry and delivery ( p = 0.077 , 0.412 ) were similar . The difference in the rate of cesarean delivery was not statistically significant between the 2 groups ( p = 0.102 ) . Neonatal statistics were also not different between the metformin and insulin groups : birth weight , Apgar score at 5 minutes , respiratory distress syndrome , hyperbilirubinemia , neonatal hypoglycemia and neonatal intensive care unit admission ( p = 0.144 - 0.373 ) . CONCLUSION Based on these preliminary data , metformin appears to be an effective alternative to insulin in the treatment of GDM [19477547] AIM A prediction rule for gestational diabetes mellitus ( GDM ) could be helpful in early detection and increased efficiency of screening . A prediction rule by means of a clinical scoring system is available , but has never been vali date d externally . The aim of this study was to vali date the scoring system . METHODS We used data from a prospect i ve cohort study . Women were assigned a score based on age , BMI and ethnicity . Performance of the scoring system was evaluated in terms of discrimination and calibration ( agreement between clinical score and observed probability of GDM ) . We compared the efficiency of a screening strategy derived from the scoring system with conventional screening . RESULTS We studied 1266 women . Forty-seven women had GDM ( 3.7 % ) . The scoring system discriminated moderately ( area under the curve=0.64 ( 95 % CI 0.56 - 0.72 ) ) . Calibration was limited ( chi(2)=8.89 , p=0.06 ) . The screening strategy derived from the scoring system reduced the number of women needed to be screened with 25 % for a comparable detection rate to universal screening . CONCLUSION Despite moderate discriminative capacity and calibration of the scoring system , the screening strategy based on the scoring system appears clinical ly useful . There is need for better prediction models for GDM [3634172] Background : Few studies have been done on the use of metformin in pregnancy and their results were not similar , therefore this research is performed to compare neonatal outcomes of metformin and insulin in the treatment of gestational diabetes . Methods : In this prospect i ve r and omized trial , 200 pregnant women within their 24th to 34th weeks of gestation with gestational diabetes , single fetus pregnancy , and in need of hyperglycemia treatment were entered and grouped as either metformin or insulin . Data related to maternal and neonatal outcomes were recorded and analyzed . Results : Considering data recorded of HbA1c at the beginning of pregnancy , pregnancy induced hypertension , preeclampsia , birth weight , dystocia , first and 5th min APGAR , neonatal sepsis , rout of delivery , liver function tests of neonate , hypoglycemia , anomaly , and still birth , there were no significant statistical differences between groups . The end pregnancy HbA1c , maternal weight gain during pregnancy , preterm labor , neonatal jaundice , respiratory distress and hospitalization of infants were higher in insulin group . Conclusions : Considering data from this study , metformin is efficient to control hyperglycemia in pregnancy . It is suggested performing more studies to evaluate long term side effects of metformin in pregnancy with higher sample size and longer follow-up of newborns [3791414] Objective : To describe how maternal obesity prevalence varies by established international and South Asian specific body mass index ( BMI ) cut-offs in women of Pakistani origin and investigate whether different BMI thresholds can help to identify women at risk of adverse pregnancy and birth outcomes . Design : Prospect i ve bi-ethnic birth cohort study ( the Born in Bradford ( BiB ) cohort ) . Setting : Bradford , a deprived city in the North of the UK . Participants : A total of 8478 South Asian and White British pregnant women participated in the BiB cohort study .Main outcome measures : Maternal obesity prevalence ; prevalence of known obesity-related adverse pregnancy outcomes : mode of birth , hypertensive disorders of pregnancy ( HDP ) , gestational diabetes , macrosomia and pre-term births . Results : Application of South Asian BMI cut-offs increased prevalence of obesity in Pakistani women from 18.8 ( 95 % confidence interval ( CI ) 17.6–19.9 ) to 30.9 % ( 95 % CI 29.5–32.2 ) . With the exception of pre-term births , there was a positive linear relationship between BMI and prevalence of adverse pregnancy and birth outcomes , across almost the whole BMI distribution . Risk of gestational diabetes and HDP increased more sharply in Pakistani women after a BMI threshold of at least 30 kg m−2 , but there was no evidence of a sharp increase in any risk factors at the new , lower thresholds suggested for use in South Asian women . BMI was a good single predictor of outcomes ( area under the receiver operating curve : 0.596–0.685 for different outcomes ) ; prediction was more discriminatory and accurate with BMI as a continuous variable than as a binary variable for any possible cut-off point . Conclusion : Applying the new South Asian threshold to pregnant women would markedly increase those who were referred for monitoring and lifestyle advice . However , our results suggest that lowering the BMI threshold in South Asian women would not improve the predictive ability for identifying those who were at risk of adverse pregnancy outcomes [21268030] OBJECTIVE To develop a model for the prediction of gestational diabetes mellitus ( GDM ) from maternal characteristics and biochemical markers at 11 to 13 weeks ' gestation . METHODS A prospect i ve screening study on early prediction of pregnancy complications ( n = 11 , 464 ) , including 297 ( 2.6 % ) cases of GDM was used to create the predictive model of GDM based on maternal characteristics . Maternal serum concentrations of adiponectin , follistatin-like-3 ( FSTL3 ) and sex hormone-binding globulin ( SHBG ) were measured in a case-control study of 80 women who developed GDM and 300 controls . RESULTS In the screening study , maternal age , body mass index , racial origin , previous history of GDM and macrosomic neonate were significant independent predictors of future GDM . In the GDM group , compared to controls , the median multiple of the normal median adiponectin ( 0.66 ; IQR : 0.5 - 0.9 vs 1.02 ; IQR : 0.7 - 1.29 ) and SHBG ( 0.81 ; IQR : 0.6 - 1.04 vs 1.02 ; IQR : 0.8 - 1.2 ) was lower ( p < 0.05 ) , but FSTL3 was not significantly different . In screening for GDM by maternal characteristics , the detection rate was 61.6 % at a false-positive rate of 20 % and the detection increased to 74.1 % by the addition of adiponectin and SHBG . CONCLUSION First-trimester screening for GDM can be provided by a combination of maternal characteristics and biomarkers [11679455] OBJECTIVE To compare management based on maternal glycemic criteria with management based on relaxed glycemic criteria and fetal abdominal circumference ( AC ) measurements in order to select patients for insulin treatment of gestational diabetes mellitus ( GDM ) with fasting hyperglycemia . RESEARCH DESIGN AND METHODS In a pilot study , 98 women with fasting plasma glucose ( FPG ) concentrations of 105 - 120 mg/dl were r and omized . The st and ard group received insulin treatment . The experimental group received insulin if the AC , measured monthly , was > or = 70th percentile and /or if any venous FPG measurement was > 120 mg/dl . Power was projected to detect a 250-g difference in birth weights . RESULTS Gestational ages , maternal glycemia , and AC percentiles were similar at r and omization . After initiation of protocol , venous FPG ( P = 0.003 ) and capillary blood glucose levels ( P = 0.049 ) were significantly lower in the st and ard group . Birth weights ( 3,271 + /- 458 vs. 3,369 + /- 461 g ) , frequencies of birth weights > 90th percentile ( 6.3 vs 8.3 % ) , and neonatal morbidity ( 25 vs. 25 % ) did not differ significantly between the st and ard and experimental groups , respectively . The cesarean delivery rate was significantly lower ( 14.6 vs. 33.3 % , P = 0.03 ) in the st and ard group ; this difference was not explained by birth weights . In the experimental group , infants of women who did not receive insulin had lower birth weights than infants of mothers treated with insulin ( 3,180 + /- 425 vs. 3,482 + /- 451 g , P = 0.03 ) . CONCLUSIONS In women with GDM and fasting hyperglycemia , glucose plus fetal AC measurements identified pregnancies at low risk for macrosomia and result ed in the avoidance of insulin therapy in 38 % of patients without increasing rates of neonatal morbidity [23508404] This paper is concerned with whether mothers who are more adipose or have higher glucose levels during pregnancy may overfeed their developing infants in utero and in doing so may set them on a pathway to greater adiposity throughout their lives . If this is the case , then the more adipose daughters of these mothers may also subsequently overfeed their infants in utero , thereby perpetuating the risk of greater adiposity across generations . I begin with the historical context of how gestational diabetes was first recognized and early evidence that diabetes in pregnancy results in increased birth size and adiposity . I then consider four questions , which are the main focus of the paper . Each of the four questions involves an exposure during pregnancy and evidence concerned with whether the exposure is causally related to offspring adiposity via intra-uterine mechanisms . The four related exposures are : ( i ) pregnancy diabetes ; ( ii ) extreme maternal pregnancy obesity ( 440 kg/m or meeting criteria for bariatric surgery ) ; ( iii ) incrementally greater pre-/early pregnancy adiposity across the whole distribution seen in pregnant women ; and ( iv ) gestational weight gain . Since r and omized controlled trial evidence is not available I focus on methods that can provide the best causal evidence from observational data such as negative control studies , family comparisons and using genetic variants as instrumental variables ( i.e. Mendelian r and omization studies ) . Having addressed these four questions I go on to briefly discuss the possible role of epigenetic modification mediating any effects of maternal exposures on offspring outcomes . I conclude with a discussion about the future research and policy implication s of evidence to date in this field [2858199] OBJECTIVE Gestational diabetes mellitus ( GDM ) may cause obesity in the offspring . The objective was to assess the effect of treatment for mild GDM on the BMI of 4- to 5-year-old children . RESEARCH DESIGN AND METHODS Participants were 199 mothers who participated in a r and omized controlled trial of the treatment of mild GDM during pregnancy and their children . Trained nurses measured the height and weight of the children at preschool visits in a state-wide surveillance program in the state of South Australia . The main outcome measure was age- and sex-specific BMI Z score based on st and ards of the International Obesity Task Force . RESULTS At birth , prevalence of macrosomia ( birth weight ≥4,000 g ) was 5.3 % among the 94 children whose mothers were in the intervention group , and 21.9 % among the 105 children in the routine care control group . At 4- to 5-years-old , mean ( SD ) BMI Z score was 0.49 ( 1.20 ) in intervention children and 0.41 ( 1.40 ) among controls . The difference between treatment groups was 0.08 ( 95 % CI −0.29 to 0.44 ) , an estimate minimally changed by adjustment for maternal race , parity , age , and socio-economic index ( 0.08 [ −0.29 to 0.45 ] ) . Evaluating BMI ≥85th percentile rather than continuous BMI Z score gave similarly null results . CONCLUSIONS Although treatment of GDM substantially reduced macrosomia at birth , it did not result in a change in BMI at age 4- to 5-years-old [2188182] One hundred eight gestational diabetics were r and omized to receive either diet alone or diet plus insulin ( 20 units NPH and 10 units regular ) for glycemic control . Blood glucose levels were evaluated weekly in a high-risk clinic where medical and nutritional support and counseling were provided . Among 68 women successfully treated for a minimum of 6 weeks , the mean birth weight , macrosomia rate , and ponderal index were reduced significantly in the insulin- treated group . Insulin reduced birth weights significantly in women with a delivery weight of 200 lb or more ( 4060 ± 342 versus 3397 ± 640 g ) and in those with a delivery weight less than 200 lb ( 3324 ± 448 versus 3047 ± 394 g ) . No patient with good glucose control and a maternal delivery weight under 200 lb had a newborn over 4000 g. Patients failing glycemic control were at greatest risk ( 30 % ) for fetal overgrowth whether initially receiving insulin or not . Maternal obesity or failure to achieve glycemic control should alert the clinician to a substantially increased risk of macrosomia [20542272] OBJECTIVE To assess blood glucose control and neonatal outcomes when women with gestational diabetes mellitus ( GDM ) were treated with metformin or glyburide . METHODS When an appropriate diet was insufficient to control their blood glucose levels , women with GDM were r and omized to a glyburide or a metformin treatment group . If the maximum dose was reached , the assessed drug was replaced by insulin . The primary outcome measures analyzed were maternal glucose levels during pregnancy , birth weight , and neonatal glucose levels . RESULTS The only significant difference in outcome between the 2 treatment drugs was that maternal weight gain during pregnancy was less in the metformin ( n=40 ) than in the glyburide group ( n=32 ) ( 10.3 kg vs 7.6 kg ; P=0.02 ) . No differences were found in treatment failure , mean level of fasting or postpr and ial plasma glucose , rate of participants with glycated hemoglobin , birth weight , rate of large-for-gestational-age newborns , or newborns with hypoglycemia . CONCLUSION The treatment of GDM with metformin or glyburide was found to be equivalent for both women and newborns [16572914] OBJECTIVE To estimate the prevalence of and associated factors in gestational diabetes mellitus ( GDM ) and its seasonal variation . STUDY DESIGN A clinic-based , prospect i ve , case register study was conducted from January 1996 to December 1997 . A total of 4,942 consecutive Caucasian , pregnant women aged 15 - 46 years , free of a history of diabetes mellitus , underwent r and om plasma glucose screening and a 75-g , 2-hour oral glucose tolerance test in Plymouth , U.K. The mean ( SD ) age of the women was 28.2 ( 5.5 ) years . Women with and without GDM were compared . RESULTS The prevalence of GDM among the subjects was 1.8 % ( 95 % CI 1.4,2.2 ) . The prevalence of GDM increased with the mother 's age and r and om plasma glucose level and decreased with the duration of pregnancy . Using a stepwise binary logistic regression model , older age ( relative prevalence [ RP ] 1.08 [ 95 % CI 1.04 , 1.12 ] ) and higher r and om plasma glucose ( RP 2.99 [ 95 % CI 2.51 , 3.551 ) were significant predictors of GDM . The monthly prevalence of GDM ranged from 2.9 % ( 95 % CI 1.5 , 5.0 ) in June to 1.1 % ( 95 % CI 0.3,2.8 ) in November . The seasonal GDM rate ranged from 2.3 % ( 95 % CI 1.5 , 3.2 ) in spring to 1.4 % ( 95 % CI 0.8 , 2.3 ) in winter . The differences were not statistically significant for either the month ( p = 0.82 ) or season ( p = 0.41 ) . CONCLUSION The prevalence ( 1.8 % ) of GDM in this representative sample of Caucasian pregnant women was lower than the 3 - 5 % typically reported in other European and North American studies , and there was no seasonal pattern [7660761] Objective . To evaluate the accuracy of diagnosing gestational diabetes mellitus ( GDM ) by a 2‐h blood glucose value ≥9.0 mmol/l in the 75 g oral glucose tolerance test ( OGTT ) . The maternal and neonatal outcome in women with a 2‐h blood glucose value just below this limit , 8.0–8.9 mmol/l , is analyzed . The outcome is compared to a r and omly selected control group [15804783] Objective : To evaluate the association between obesity , glucose challenge test ( GCT ) and pregnancy outcome . Methods : A prospect i ve cohort study of 6854 consecutive gravid patients screened for gestational diabetes ( GDM ) using 50-gram GCT , at 24–28 weeks ' gestation was performed . A screening value ⩾ 130 mg/dl was followed by 100 gr oral GTT . Patients who were diagnosed with GDM were excluded . For purpose of analysis patients were categorized by prepregnancy BMI and by different GCT thresholds . Maternal outcome was defined by rate of preeclampsia , gestational age at delivery , cesarean section ( CS ) rate and the need for labor induction . Neonatal outcome was defined by fetal size ( macrosomia/LGA ) , arterial cord pH , respiratory complications and neonatal intensive care unit ( NICU ) admission . Results : Overall , a positive GCT result ( GCT ⩾ 130 mg/dl ) was identified in 2541/6854 ( 37 % ) women . GDM was further diagnosed in 464/6854 ( 6.8 % ) of subjects . In both groups of screening results ( > 130 mg/dl and < 130 mg/dl ) , the obese women were significantly older , gained more weight during pregnancy and had a lower rate of nulliparity in comparison to the non obese women . The obese women had higher rates of macrosomia , LGA and induction of labor . No difference was found in mean birth weight , the total rate of cesarean section , preterm delivery , 5 minute Apgar score ⩽ 7 , mean arterial cord pH , NICU admission and a need for respiratory support in comparison to non obese women in both groups of screening results . A gradual increase in the rate of macrosomia , LGA and cesarean section was identified in both obese and non-obese women in relation to increasing GCT severity categories . Conclusion : Fetal size and cesarean section rate are associated with the degree of carbohydrate intolerance ( screening results ) . Furthermore , obesity remains the main contributor impacting fetal size [19375570] OBJECTIVE We hypothesized that body composition would be similar among neonates of women with gestational diabetes ( GDM ) treated with glyburide or insulin . STUDY DESIGN Women with GDM requiring medical therapy were r and omized to insulin or glyburide . The primary outcome was percent neonatal fat mass measured by total body electrical conductivity . Secondary outcomes included anthropometrics , glycemic control , and biomarkers . Statistical analysis included Student t test , chi(2 ) , and regression modeling . RESULTS Eighty-two neonates underwent postnatal measurements . Baseline factors were not different by group . Neonatal percent fat mass did not differ between treatment groups ( 11.2 + /- 4.2 vs 12.8 + /- 5.7 ) . Fat mass , body mass index , ponderal index , skinfold sum , and arm fat area were not different when analyzed by intent to treat or actual treatment group . Cord concentrations of biomarkers were also similar . CONCLUSION There was no difference in neonatal adiposity in infants of women treated for GDM with glyburide or insulin [22542118] OBJECTIVE We evaluated whether improvements in pregnancy outcomes after treatment of mild gestational diabetes mellitus differed in magnitude on the basis of fetal gender . STUDY DESIGN This is a secondary analysis of a masked r and omized controlled trial of treatment for mild gestational diabetes mellitus . The results included preeclampsia or gestational hypertension , birthweight , neonatal fat mass , and composite adverse outcomes for both neonate ( preterm birth , small for gestational age , or neonatal intensive care unit admission ) and mother ( labor induction , cesarean delivery , preeclampsia , or gestational hypertension ) . After stratification according to fetal gender , the interaction of gender with treatment status was estimated for these outcomes . RESULTS Of the 469 pregnancies with male fetuses , 244 pregnancies were assigned r and omly to treatment , and 225 pregnancies were assigned r and omly to routine care . Of the 463 pregnancies with female fetuses , 233 pregnancies were assigned r and omly to treatment , and 230 pregnancies were assigned r and omly to routine care . The interaction of gender with treatment status was significant for fat mass ( P = .04 ) and birthweight percentile ( P = .02 ) . Among women who were assigned to the treatment group , male offspring were significantly more likely to have both a lower birthweight percentile ( 50.7 ± 29.2 vs 62.5 ± 30.2 percentile ; P < .0001 ) and less neonatal fat mass ( 487 ± 229.6 g vs 416.6 ± 172.8 g ; P = .0005 , ) whereas these differences were not significant among female offspring . There was no interaction between fetal gender and treatment group with regard to other outcomes . CONCLUSION The magnitude of the reduction of a newborn 's birthweight percentile and neonatal fat mass that were related to the treatment of mild gestational diabetes mellitus appears greater for male neonates [20653150] OBJECTIVE The objective of the study was to compare premixed insulin aspart 30 ( BIAsp 30 ) vs premixed human insulin 30 ( BHI 30 ) on efficacy , safety , fetal and perinatal outcomes in pregnancies associated with gestational diabetes mellitus [ GDM ] . This was the first r and omized study to use pre mixed insulin analogue [ BIAsp ] in GDM . METHODS The study population consisted of 76 GDM women assigned to BIAsp 30 ( group A ) and an equal number to BHI 30 ( group B ) . RESULTS There was no statistically significant difference between the age , BMI , gestational weeks and glycemic level at entry between the group A and group B women ( p > 0.05 ) . There was no statistical difference between the two groups in glycemic control or insulin dose ( p > 0.05 ) before confinement . The frequency of birth weight of new born above 90 percentile was 6.8 % in Group 1 and 9.2 % in Group 2 . The proportion of macrosomia was higher in Group 2 when compared to Group 1 , however the difference was not statistically significant ( P = 0.819 ) . CONCLUSION BIAsp was safe during pregnancy and pregnant women found it convenient due to meal time dosing . Fetal outcome using BIAsp was also comparable with BHI 30 [2992182] OBJECTIVE To examine the association between levels of hyperglycemia , determined by each prenatal oral glucose tolerance test ( OGTT ) value ( fasting , 1 and 2 h ) , and maternal and perinatal outcomes and to determine whether the risk for these outcomes differs for women whose value(s ) equaled or exceeded the thresholds for gestational diabetes mellitus ( GDM ) established by the International Association of Diabetes in Pregnancy Study Groups ( IADPSG ) . RESEARCH DESIGN AND METHODS This article discusses a retrospective study of 8,711 women , delivering at ≥20 weeks ' gestation , who had a prenatal 2-h 75-g OGTT without a prior 50-g challenge and were not treated with insulin , glyburide , diet , and /or exercise during pregnancy . Associations between adverse outcomes and elevated OGTT values are reported . RESULTS After excluding treated women , 19.4 % of the remaining women had IADPSG-defined GDM . Continuous fasting , 1- and 2-h OGTT measures , and GDM ( yes/no ) were significantly associated with most adverse outcomes . However , the magnitude and significance of risk for these outcomes differed by various combinations of abnormal glucose values . Women with normal fasting and elevated postload values were at higher risk for preterm delivery , gestational hypertension , and having an infant with hyperbilirubinema , whereas women with elevated fasting and normal postload values were at higher risk of having a large-for-gestational-age infant , compared with women without GDM . CONCLUSIONS Risks for different adverse outcomes vary depending on which single or combined IADPSG-defined OGTT thresholds are equaled or exceeded . Prospect i ve studies are needed to determine whether changing pre- and postpr and ial glucose targets during pregnancy will more uniformly reduce adverse outcomes [14634573] OBJECTIVE This study was performed to prospect ively evaluate a screening model for gestational diabetes mellitus on the basis of clinical risk indicators . STUDY DESIGN In a prospect i ve multicenter study with 5235 consecutive pregnant women , diagnostic testing with a 2-hour 75-g oral glucose tolerance test was routinely performed in women with risk indicators and offered to women without risk indicators as part of the study . RESULTS Forty-four percent of the women underwent testing , 43 % declined participation , 6 % did not speak Danish , and 7 % could not be contacted . By extrapolation of the results from tested women to the whole group in question , a 2.4 % prevalence of gestational diabetes mellitus was calculated . Sensitivity and specificity of the model was 80.6 ( 73.7 - 87.6 ) and 64.8 ( 63.5 - 66.1 ) , respectively ( 95 % CIs ) . CONCLUSION Under ideal conditions , sensitivity of the model was comparable with universal screening by fasting glucose or a 1-hour 50-g glucose challenge test . Both screening and diagnostic testing could be avoided in two thirds of all pregnant women [18211656] RATIONALE , AIMS AND OBJECTIVE To investigate whether the introduction of a programme of optimising drug treatment , intensive education and self-monitoring of patients diagnosed with gestational diabetes mellitus ( GDM ) at an early stage ( < 20 gestational weeks ) , will improve management outcomes as determined by objective measures of patient knowledge about diabetes , glycaemia control , maternal/neonatal complications , and health-related quality of life . METHODS The study was a r and omized , controlled , longitudinal , prospect i ve clinical trial performed at Al-Ain Hospital , Al-Ain , United Arab Emirates . Over an 18-month period , patients diagnosed with GDM were recruited and were r and omly assigned to either an intervention or a control group , in a ratio of 3:2 . Intervention patients received a structured pharmaceutical care service ( including education and introduction of intensive self-monitoring ) while control patients received traditional services . Patients were followed up from time of recruitment until 6 months postnatally at scheduled outpatient clinics . A range of clinical and humanistic outcome measures , including maternal and neonatal complications , were used to assess the impact of the intervention . RESULTS A total of 165 patients ( 99 intervention , 66 control ) completed the study . The intervention patients exhibited a range of benefits from the provision of the programme when compared with control group patients . Statistically significant ( P < 0.05 ) improvements were shown in the intervention group for knowledge of diabetes , health-related quality of life ( as determined by the SF36 ) , control of plasma glucose and HbA(1c ) , maternal complications [ e.g. decreased incidence of pre-eclampsia ( 5.1 % vs. 16.7 % ) , eclampsia ( 1.0 % vs. 7.6 % ) , episodes of severe hyperglycaemia ( 3.0 % vs. 19.7 % ) and need for Caesarean section ( 7.1 % vs. 18.2 % ) ] , and neonatal complications [ e.g. decreased incidence of neonatal hypoglycaemia ( 2.0 % vs. 10.6 % ) , respiratory distress at birth ( 4.0 % vs. 15.2 % ) , hyperbilirubinaemia ( 1.0 % vs. 12.1 % ) and large for gestational age ( 9.0 % vs. 22.7 % ) ] . CONCLUSION The research provides clear evidence that provision of pharmaceutical care adds value to the management of GDM as exemplified by improved maternal and neonatal outcomes [11194427] Summary : A r and omised controlled trial was design ed to determine the effect of moderate 30 % maternal dietary energy restriction on the requirement for maternal insulin therapy and the incidence of macrosomia in gestational diabetes . Although the control group restricted their intake to a level similar to that of the intervention group ( 6845 kiloJoules ( kJ ) versus 6579 kJ ) , the result ing cohort could not identify any adverse effect of energy restriction in pregnancy . Energy restriction did not alter the frequency of insulin therapy ( 17.5 % in the intervention group and 16.9 % in the control group ) . Mean birth weight ( 3461 g in the intervention group and 3267 g in the control group ) was not affected . There was a trend in the intervention group towards later gestational age at commencement of insulin therapy ( 33 weeks versus 31 weeks ) and lower maximum daily insulin dose ( 23 units versus 60 units ) which did not reach statistical significance . Energy restriction did not cause an increase in ketonemia [3921038] A cost analysis of glucose screening was studied prospect ively in 434 patients . All patients underwent a 50-gm oral glucose load followed by a 1-hour plasma glucose screen test at 28 weeks ( + /- 2 weeks ) . Patients with a screen test greater than or equal to 130 mg/dl plasma glucose were further tested with an oral glucose tolerance test . Also , previously described clinical risk factors for diabetes were documented on all patients . A 3.3 % prevalence of gestational diabetes was found in 178 patients with risk factors , compared with 2.4 % of 256 patients without risk factors , not a significant difference . Ten of the 12 gestational diabetics were at least 24 years old , so that screening only this subgroup would still retain a good sensitivity ( 83 % ) but at half the cost of universal screening . Screening on the basis of risk factors other than age is inefficient . Though testing only patients who are 24 years of age or older is more cost effective than universal screening , an individual decision must be made regarding its reduced sensitivity [17972060] Aims /hypothesisThe aim of this study was to investigate whether the higher prevalence of insulin resistance and glucose intolerance in urban compared with rural Indian men is related to their higher adiposity ( percentage body fat ) and the associated inflammatory state . Methods We studied 149 rural , 142 urban slum and 150 urban middle-class male residents ( age 30–50 years ) , who were selected by stratified r and om sampling . We measured body fat ( bioimpedance ) , waist circumference , glucose tolerance ( 75 g OGTT ) , insulin resistance [ homeostasis model assessment ( HOMA-IR ) ] , beta cell function ( insulinogenic index ) and inflammatory markers ( total leucocyte count , IL-6 , TNF-α and C-reactive protein ) . Results Adiposity , waist circumference , HOMA-IR , insulinogenic index and both fasting and 120 min plasma glucose concentrations increased progressively from rural through to urban slum and urban middle-class men . Inflammatory markers were higher in urban than in rural men . Adiposity was strongly related to HOMA-IR ( r = 0.57 , p < 0.001 ) and to insulinogenic index and glycaemic parameters ( r = 0.25 , p < 0.001 for both ) . Adiposity explained approximately two thirds of the difference in HOMA-IR between the urban middle-class men and the rural and slum residents , but its contribution to the difference in insulinogenic index and 120 min plasma glucose concentration was not significant . Inclusion of C-reactive protein , IL-6 and total leucocyte count in the models did not further explain these results , nor did the inclusion of waist circumference . There was a significant residual difference after these adjustments . Conclusions /interpretationAdiposity is a major contributor to the difference in insulin resistance between rural and urban Indian men ; there was no additional contribution from inflammation or central obesity . Other unmeasured factors also seem to contribute to the metabolic differences between rural and urban men [23068960] AIMS To evaluate the effect of metformin and insulin in glycemic control and compare pregnancy outcome in women with gestational diabetes mellitus ( GDM ) . METHODS This r and omized controlled trial was conducted in GDM women with singleton pregnancy and gestational age between 20 and 34 weeks who did not achieve glycemic control on diet were assigned r and omly to receive either metformin ( n=80 ) or insulin ( n=80 ) . The primary outcomes were maternal glycemic control and birth weight . The secondary outcomes were neonatal and obstetric complications . RESULTS Two groups were comparable regarding the maternal characteristics . Two groups were similar in mean FBS ( P=0.68 ) and postpr and ial measurements ( P=0.87 ) throughout GDM treatment . The neonates of metformin group had less rate of birth weight centile > 90 than insulin group ( RR : 0.5 , 95 % CI : 0.3 - 0.9 , P=0.012 ) . Maternal weight gain was reduced in the metformin group ( P<0.001 ) . Two groups were comparable according to neonatal and obstetric complications ( P>0.05 ) . In metformin group 14 % of women needed to supplemental insulin to achieve euglycemia . CONCLUSION Metformin is an effective and safe alternative treatment to insulin for women with GDM . This study does not show significant risk of maternal or neonatal adverse outcome with the use of metformin [8053871] Summary : We determined in nondiabetic women , the relationship of plasma glucose values obtained 2 hours after a 75 g oral glucose challenge test ( GCT ) at 16–20 weeks ' gestation , with the incidence of macrosomia in term deliveries ( 37–41 weeks ' gestation ) . From 1988–1990 , in a systematic screening programme data collected prospect ively from 1,331 women were analysed retrospectively . Women with gestational diabetes or impaired glucose tolerance ( n = 53 ) were excluded . The rest ( n = 1,278 ) had no evidence of glucose intolerance including 1,215 women with normal plasma glucose by GCT ( < 7.8 mmol/L 2 hours after 75 g oral glucose load ) and 63 women with abnormal GCT but no abnormal value at a glucose tolerance test . The GCT values were divided into 5 groups : Group A ( < 4.5 mmol/L ) , B ( 4.5‐5.5 mmol/L ) , C ( 5.6‐6.6 mmol/L ) , D ( 6.7‐7.7 mmol/L ) and E ( > 7.8 mmol/L ) . The variables studied were age , parity , gestational age at delivery and incidence of macrosomia [5936737] The purpose of this study was to examine pregnancy outcome in women with abnormal oral glucose tolerance tests , in relation to treatment with diet and insulin . Glucose tolerance tests , done because of well-known historical risk factors , were considered abnormal if two or more readings exceeded the following : fasting , 110 ; 1 hour , 170 ; 2 hours , 120 ; and 3 hours , 110 ( all in mg/100 mL , measured as total reducing substances in whole venous blood ) . Those with positive tests were divided r and omly into a “ positive-control ” group ( n 308 ) that received st and ard prenatal care or a “ positive-treated ” group ( n 307 ) that received dietary instructions ( 30 kcal/kg ideal body weight , 40 % as carbohydrate , and 1.5–2 g protein/kg body weight ) and insulin ( initial dose 10 U per day of intermediate-acting insulin , adjusted subsequently as directed by blood and urine studies ) , beginning at usually about 32 weeks . A third group ( n 328 ) , termed “ negative controls , ” had exhibited normal glucose tolerance testing . The three groups were similar , except that those with abnormal glucose tolerance tended to be older and heavier , as expected . With respect to outcome , infants with birth weights exceeding 9 lb were three times as frequent in positive-control subjects as in either positive-treated subjects or negative controls ( 13.1 % , 4.3 % , and 3.7 % , respectively ) . Perinatal deaths ( 28 weeks ’ gestation through 14 days after birth ) were similar in the two positive groups ( 4.9 % in control and 4.3 % in treated ) and significantly higher than in negative controls ( 1.9 % ) , with the increase involving both fetal and neonatal components . The conclusions were 1 ) abnormal glucose tolerance during pregnancy leads to larger infants and higher perinatal mortality and 2 ) treatment with diet and insulin ameliorates the former but not the latter . This study concerned what O’Sullivan called potential diabetes and others at the time termed latent or chemical diabetes or prediabetes , but what today we refer to as gestational diabetes . Acceptance of it as a pathologic entity was far from unanimous in 1966 . O’Sullivan resolved the controversy with this large , well- design ed , and well-analyzed clinical trial . The immediate influence was two-fold . In the first place , it settled the existing disagreement as to whether or not impaired glucose tolerance adversely influences pregnancy outcome ; large infants occurred three times as frequently and perinatal deaths were more than doubled in women with abnormal carbohydrate metabolism . Second , the findings of the intervention trial indicated clearly that treatment of gestational diabetes with diet and insulin in late gestation normalizes birth weight ( although it did not seem to influence perinatal mortality ) , a finding confirmed a number of times by subsequent investigators . Incidentally , the frequencies of both fetal and neonatal deaths may seem high , but it needs to be remembered that this experience ante date d the advent of modern fetal surveillance and neonatal intensive care . John B. O’Sullivan , a pioneer in clinical research in gestational diabetes , was an internist . He defined st and ards for the oral glucose tolerance test in pregnancy that , though modified slightly by subsequent investigators , are basically those in use today . Born in 1926 , he received his medical education in his native Irel and before immigrating to the United States in 1955 . After further training in internal medicine at the Lahey Clinic , he took a faculty position at the Boston University School of Medicine , where he did his original work on early diabetes as medical director of the Prenatal Metabolism Clinic at Boston City Hospital and chief of medicine at St. Margaret ’s Hospital . In addition to his position as Associate Professor at Boston University , he also served on the faculties of the Harvard and Yale medical schools . Later he was director of employee health for the Liberty Mutual Insurance Company . He died of cancer in August 2001 [10691156] Aims Gestational diabetes mellitus ( GDM ) is associated with adverse maternal and fetal outcome . Screening for GDM is therefore recommended but the best screening method remains controversial . This prospect i ve , r and omized study compared a risk factor‐based screening programme with a universally based one [1748256] Forty-one patients with gestational diabetes requiring insulin were enrolled in a r and omized study to investigate the efficacy of an exercise program in normalizing glucose tolerance . Seventeen of 21 patients completed the exercise program while maintaining normoglycemia and obviating insulin therapy . Maternal and neonatal complications did not differ between the study and control groups . The type of program described appears to be safe and can serve as a model for exercise prescription for pregnant diabetic women to attain improved glucose tolerance [15995269] OBJECTIVES Muscle-thin but adipose ( ' thin-fat ' ) body composition of south Asian adults contributes to their high risk of type 2 diabetes . Studies in Pune , India showed that this phenotype is present at birth . We aim ed to determine if south Indian babies have a ' thin-fat ' phenotype and if this persists in childhood . DESIGN Prospect i ve cohort study . SETTING Holdsworth Memorial Hospital , Mysore , India . SUBJECTS Children ( n = 663 ) whose mothers were recruited from the antenatal clinics . METHODS Weight , length , head , mid-upper-arm , abdominal circumferences ; triceps and subscapular skinfolds were measured at birth , one and four years , and compared with white Caucasian babies born in Southampton , UK ( birth ) , and UK and Dutch growth st and ards ( one and four years ) . RESULTS Mysore babies were lighter ( 2983 g vs 3472 g ; -1.10 SD , CI -1.16 , -1.02 ) and smaller in all body measurements than UK neonates ( P < 0.001 ) . The deficit was greatest for mid-upper-arm ( -1.07 SD ) , head ( -0.89 SD ) and abdominal circumferences ( -0.73 SD ) , and least for length ( -0.25 SD ) and subscapular skinfold thickness ( -0.19 SD ) . Predictors of skinfold thickness were maternal body mass index ( P < 0.001 ) and socio-economic status ( P = 0.05 ) . At four years , subscapular skinfold thickness was larger than UK ( + 0.18 SD , CI + 0.11 , + 0.25 ; P < 0.001 ) and Dutch st and ards ( + 0.61 SD , CI + 0.51 , + 0.71 ; P < 0.001 ) , despite all other body measurements remaining smaller . Predictors of 4-year skinfold thickness were neonatal skinfold thickness ( P = 0.001 ) and maternal insulin concentrations ( P = 0.05 ) . CONCLUSIONS Mysore newborns have a ' thin-fat ' phenotype . This may reflect the action of genes and /or the ' maternal environment ' . The phenotype persists in childhood , and may be the forerunner of a diabetogenic adult phenotype [10586979] Infant macrosomia is a serious medical concern . Pregnant women who do not meet the specific diagnosis for gestational diabetes may still have glucose-mediated macrosomia . In Santa Barbara County all pregnant women are screened for gestational diabetes at 24 - 28 weeks with a 50-g , 1-hr glucose challenge test ( GCT ) . All patients who fail this test are placed on a st and ard euglycemic diet ( 40 % carbohydrate , 20 % protein , 40 % fat ) and perform home glucose monitoring of fasting and postpr and ial glucose levels . The objective of this study was to examine the effectiveness of this treatment program in decreasing infant macrosomia , maternal and infant morbidity , maternal complications , and operative delivery . We studied 103 women who had a positive GCT , but a negative 100-g , 3-hr oral glucose tolerance test ( OGTT ) . The women were r and omly assigned to either experimental or control groups with experimental women receiving dietary counseling and home glucose monitoring instruction ( HBGM ) . HBGM diaries were review ed weekly by clinic nurses . All women had hemoglobin A1c ( HbA1c ) tests at 28 and 32 weeks . Maternal and fetal charts were review ed to determine delivery type and complications , indications for cesarean section ( C-section ) , and infant gestational age , gender , Apgar scores , birth weight , morbidities , and congenital anomalies . Of the 103 women , 5 women required insulin treatment , 1 woman had an abortion , and 14 women were indeterminate regarding compliance or were control women who received diet counseling and HBGM . The results are based on 83 women--48 control and 35 experimental . There were no significant differences between the groups for age , parity , or weight at 28 - 30 weeks or 37 weeks to delivery , or HbA1c at 28 weeks . HbA1c was significantly higher in control women at 32 weeks . Birth weight expressed in grams or as a percentile specific for gender , ethnicity , and gestational age was significantly higher in control infants . Birth weight was significantly correlated with maternal intake weight , weight at 28 - 30 weeks , and weight at delivery and with HbA1c at 32 weeks ' gestation . There were no significant differences between groups for maternal complications . Groups were significantly different for mode of delivery with experimental women having more induced vaginal deliveries but fewer repeat C-sections than control women . Groups were not different for primary C-sections . Women who fail the GCT , but not the OGTT and thus do not receive the diagnosis of GDM are still at risk for delivering a macrosomic infant and operative delivery . Our program of treatment for all women who fail the GCT improves outcome by reducing infant birth weight and the number of cesarean sections [1992702] This prospect i ve investigation evaluated the reproducibility of the 100 gm oral glucose tolerance test . Sixty-four obstetric patients with greater than or equal to 135 mg/dl on the 50 gm oral glucose screening test were scheduled for the 100 gm test . All patients repeated the oral glucose tolerance test in 1 to 2 weeks . Both tests included a preparatory diet , and testing conditions were identical . There were no significant differences in the mean test values at each testing interval when the entire study population was considered . Patients were then divided into four groups according to the outcome of the two tests . Forty-eight of 64 ( 75 % ) had normal results at each testing period ( group 1 ) ; 11 of 64 ( 17 % ) had initially normal results and abnormal results on retest ( group 2 ) ; 3 of 64 ( 5 % ) had initially abnormal results and normal results on retest ( group 3 ) ; 2 of 64 ( 3 % ) had abnormal results at both testing phases ( group 4 ) . There were no significant differences between oral glucose tolerance test results within groups 1 and 4 . However , significant differences occurred within groups 2 and 3 between the two tests . Group 2 patients had a greater frequency of an abnormal 1-hour value on the test than group 1 patients ( p = 0.001 ) . Overall , the reproducibility of the oral glucose tolerance test was 78 % ( 50 of 64 ) . We recommend the oral glucose tolerance test be repeated when the 1-hour value is abnormal or when the fasting blood sugar , 1-hour , and 2-hour values are near the upper end of the normal range [11036118] BACKGROUND Women with gestational diabetes mellitus are rarely treated with a sulfonylurea drug , because of concern about teratogenicity and neonatal hypoglycemia . There is little information about the efficacy of these drugs in this group of women . METHODS We studied 404 women with singleton pregnancies and gestational diabetes that required treatment . The women were r and omly assigned between 11 and 33 weeks of gestation to receive glyburide or insulin according to an intensified treatment protocol . The primary end point was achievement of the desired level of glycemic control . Secondary end points included maternal and neonatal complications . RESULTS The mean ( + /-SD ) pretreatment blood glucose concentration as measured at home for one week was 114+/-19 mg per deciliter ( 6.4+/-1.1 mmol per liter ) in the glyburide group and 116+/-22 mg per deciliter ( 6.5+/-1.2 mmol per liter ) in the insulin group ( P=0.33 ) . The mean concentrations during treatment were 105+/-16 mg per deciliter ( 5.9+/-0.9 mmol per liter ) in the glyburide group and 105+/-18 mg per deciliter ( 5.9+/-1.0 mmol per liter ) in the insulin group ( P=0.99 ) . Eight women in the glyburide group ( 4 percent ) required insulin therapy . There were no significant differences between the glyburide and insulin groups in the percentage of infants who were large for gestational age ( 12 percent and 13 percent , respectively ) ; who had macrosomia , defined as a birth weight of 4000 g or more ( 7 percent and 4 percent ) ; who had lung complications ( 8 percent and 6 percent ) ; who had hypoglycemia ( 9 percent and 6 percent ) ; who were admitted to a neonatal intensive care unit ( 6 percent and 7 percent ) ; or who had fetal anomalies ( 2 percent and 2 percent ) . The cord-serum insulin concentrations were similar in the two groups , and glyburide was not detected in the cord serum of any infant in the glyburide group . CONCLUSIONS In women with gestational diabetes , glyburide is a clinical ly effective alternative to insulin therapy [18058723] INTRODUCTION Nutrition therapy is an integral part of the management of gestational diabetes mellitus ( GDM ) . Most women with GDM are treated by nutritional management alone . The goal of our study was to compare low and high carbohydrate diets in their effectiveness , safety and tolerability in women with GDM . MATERIAL AND METHODS The study group consisted of 30 Caucasian women newly diagnosed with GDM , with a mean age of 28.7 + /- 3.7 years and pregnancy duration of 29.2 + /- 5.4 weeks . The patients were r and omised into two groups : those on a low and those on a high carbohydrate diet ( 45 % vs. 65 % respectively of energy supply coming from carbohydrates ) . The presence of urine ketones was controlled every day . After two weeks daily glucose profiles and compliance with the recommended diets were analysed . RESULTS Glucose concentration before implementation of the diet regimen did not differ between groups . No changes in fasting blood glucose were noticed in the group that had followed a low carbohydrate diet , although a significant decrease in glucose concentration was observed after breakfast ( 102 + /- 16 vs. 94 + /- 11 mg/dl ) , lunch ( 105 + /- 12 vs. 99 + /- 9 mg/dl ) and dinner ( 112 + /- 16 vs. 103 + /- 13 mg/dl ) ( p < 0.05 ) . In the high carbohydrate diet group fasting and after-breakfast glucose concentration did not change . A significant decrease in glycaemia was noticed after lunch ( 106 + /- 15 vs. 96 + /- 7 mg/dl ) and dinner ( 107 + /- 12 vs. 97 + /- 7 mg/dl ) ( p < 0.05 ) . Ketonuria was not observed in either group . Obstetrical outcomes did not differ between groups . CONCLUSIONS Both high and low carbohydrate diets are effective and safe . A diet with carbohydrate limitation should be recommended to women who experience the highest glycaemia levels after breakfast [23524173] OBJECTIVE To evaluate glycemic control in women receiving metformin or insulin for gestational diabetes , and to identify factors predicting the need for supplemental insulin in women initially treated with metformin . STUDY DESIGN Women with gestational diabetes who failed to achieve glycemic control with diet and exercise were r and omized to receive metformin ( n = 47 ) or insulin ( n = 47 ) . Criteria for inclusion were singleton pregnancy , diet , and exercise for a minimum period of 1 week without satisfactory glycemic control , absence of risk factors for lactic acidosis , and absence of anatomic and /or chromosome anomalies of the conceptus . Patients who were lost to prenatal follow-up were excluded . RESULTS Comparison of mean pretreatment glucose levels showed no significant difference between groups ( P = .790 ) . After introduction of the drug , lower mean glucose levels were observed in the metformin group ( P = .020 ) , mainly because of lower levels after dinner ( P = .042 ) . Women using metformin presented less weight gain ( P = .002 ) and a lower frequency of neonatal hypoglycemia ( P = .032 ) . Twelve women in the metformin group ( 26.08 % ) required supplemental insulin for glycemic control . Early gestational age at diagnosis ( odds ratio , 0.71 ; 95 % confidence interval , 0.52 - 0.97 ; P = .032 ) and mean pretreatment glucose level ( odds ratio , 1.061 ; 95 % confidence interval , 1.001 - 1.124 ; P = .046 ) were identified as predictors of the need for insulin . CONCLUSION Metformin was found to provide adequate glycemic control with lower mean glucose levels throughout the day , less weight gain and a lower frequency of neonatal hypoglycemia . Logistic regression analysis showed that gestational age at diagnosis and mean pretreatment glucose level were predictors of the need for supplemental insulin therapy in women initially treated with metformin [23271384] OBJECTIVE To assess the relationship between a low 50-g 1-hour glucose loading test ( GLT ) and maternal and neonatal outcomes in women without diabetes . STUDY DESIGN This was a secondary analysis of a multicenter observational cohort from a r and omized trial of treatment for mild gestational diabetes . Maternal and neonatal outcomes were compared between women with GLT values < 90 mg/dL and those with results 90 to 119 mg/dL. RESULTS Of 436 enrolled women , 297 ( 68.1 % ) had a GLT result of 90 to 119 mg/dL and 139 ( 31.9 % ) had a result of < 90 mg/dL. There was a lower incidence of neonatal hypoglycemia in those with a GLT < 90 mg/dL ( 5.7 % versus 16.5 % , p = 0.006 ) . Other outcomes were not associated with test results . CONCLUSION A GLT result < 90 mg/dL compared with 90 to 119 mg/dL is associated with a lower risk of neonatal hypoglycemia , but no other significant findings [25706240] CONTEXT Gestational diabetes ( GDM ) confers a high risk of type 2 diabetes . In the Diabetes Prevention Program ( DPP ) , intensive lifestyle ( ILS ) and metformin prevented or delayed diabetes in women with a history of GDM . OBJECTIVE The objective of the study was to evaluate the impact of ILS and metformin intervention over 10 years in women with and without a history of GDM in the DPP/Diabetes Prevention Program Outcomes Study . DESIGN This was a r and omized controlled clinical trial with an observational follow-up . SETTING The study was conducted at 27 clinical centers . PARTICIPANTS Three hundred fifty women with a history of GDM and 1416 women with previous live births but no history of GDM participated in the study . The participants had an elevated body mass index and fasting glucose and impaired glucose tolerance at study entry . INTERVENTIONS Interventions included placebo , ILS , or metformin . OUTCOMES MEASURE Outcomes measure was diabetes mellitus . RESULTS Over 10 years , women with a history of GDM assigned to placebo had a 48 % higher risk of developing diabetes compared with women without a history of GDM . In women with a history of GDM , ILS and metformin reduced progression to diabetes compared with placebo by 35 % and 40 % , respectively . Among women without a history of GDM , ILS reduced the progression to diabetes by 30 % , and metformin did not reduce the progression to diabetes . CONCLUSIONS Women with a history of GDM are at an increased risk of developing diabetes . In women with a history of GDM in the DPP/Diabetes Prevention Program Outcomes Study , both lifestyle and metformin were highly effective in reducing progression to diabetes during a 10-year follow-up period . Among women without a history of GDM , lifestyle but not metformin reduced progression to diabetes [10097921] OBJECTIVE To estimate the percentage of pregnant women who would not be screened and the percentage of women with gestational diabetes mellitus ( GDM ) who would possibly remain undiagnosed if the American Diabetes Association 's ( ADA 's ) new selective screening recommendations are used rather than universal screening for GDM . RESEARCH DESIGN AND METHODS Since 1987 , the University of Michigan Health System has performed universal screening for GDM . In 1997 , the ADA recommended that women having all four of the following characteristics need not be screened : age < 25 years , not members of an ethnic/racial group with a high prevalence of diabetes , normal body weight , and no family history of diabetes . We studied a r and om sample of the 25,118 deliveries at the University of Michigan between 1987 and 1997 to determine the prevalence of these four characteristics in our obstetric population . We also studied the prevalence of these four characteristics in 200 women who were diagnosed with GDM in the Endocrine Testing Unit and delivered at the University of Michigan between 1987 and 1997 . RESULTS Approximately 10 - 11 % of women who delivered possessed all four low-risk characteristics and would not have been screened for GDM according to the new ADA recommendations . Only 4 % of women ( 5 of 141 ) with GDM who delivered and for whom data on all four characteristics were reported possessed all four low-risk characteristics and would not have been screened . CONCLUSIONS If the new ADA selective screening recommendations are used , few women with GDM will be missed ( 4 % ) but approximately 90 % of pregnant women will still need to be screened for GDM [24646172] The benefits of exercise and behavioural recommendations in gestational diabetes mellitus ( GDM ) are controversial . In a r and omized trial with a 2 × 2 factorial design , we examined the effect of exercise and behavioural recommendations on metabolic variables , and maternal/neonatal outcomes in 200 GDM patients . All women were given the same diet : group D received dietary recommendations only ; group E was advised to briskly walk 20‐min/day ; group B received behavioural dietary recommendations ; group BE was prescribed the same as B + E. Dietary habits improved in all groups . In a multivariable regression model , fasting glucose did not change . Exercise , but not behavioural recommendations , was associated with the reduction of postpr and ial glucose ( p < 0001 ) , glycated haemoglobin ( HbA1c ; p < 0.001 ) , triglycerides ( p = 0.02 ) and C‐reactive protein ( CRP ; p < 0.001 ) and reduced any maternal/neonatal complications ( OR = 0.50 ; 95%CI=0.28–0.89;p = 0.02 ) . In GDM patients a simple exercise programme reduced maternal postpr and ial glucose , HbA1c , CRP , triglycerides and any maternal/neonatal complications , but not fasting glucose values [18300849] Objective The objective of this study was to investigate early influences of postnatal growth on blood pressure ( BP ) in healthy , British-born South Asian and European origin infants . We tested the hypotheses that South Asian infants would be smaller in all body dimensions ( length and weight ) with higher relative truncal skinfold thickness at birth , and that increased ( central ) adiposity and accelerated growth up to 1 year would be associated with higher BP in both ethnic groups . Patients and methods Five hundred and sixty infants were followed prospect ively from birth to 3 and /or 12 months with measures of anthropometry and resting BP , compared against a UK 1990 growth reference , and analysed using regression methods . Results Marked differences in birth size persisted , as expected , between European and South Asian babies , but with a sexual dichotomy : South Asian boys were smaller in all anthropometric parameters ( P < 0.001 ) , including skinfolds ( P < 0.05 ) , than European boys , but South Asian girls , although smaller in length and weight , had similar skinfolds to European girls and thus a slightly larger subscapular skinfold thickness relative to birth weight [ 1.3 versus 1.2 , mean difference 0.07 , 95 % confidence interval ( CI ) 0.0009–0.14 , P = 0.047 ] . The dichotomy persisted postnatally ; South Asian boys showed a striking early increase in weight and length compared with European boys , associated with significant accrual of subscapular fat ( 6.1 versus 5.3 mm , mean difference 0.8 , 95 % CI 0.3–1.3 , P = 0.003 ) . In gender and ethnicity adjusted regression models , infants with the largest weight st and ard deviation score ( SDS ) increases in the first 3 months had the highest 12-month systolic BP ( β = 2.4 , 95 % CI 0.5–4.2 , P = 0.01 ) , while those with the greatest birth length ( β = 0.7 , 95 % CI 0.05–1.4 , P = 0.04 ) but the smallest changes in length over 3–12 months ( β = −0.57 , 95 % CI −0.95 to −0.19 , P = 0.004 ) had the highest diastolic BP . Conclusions Ethnic and gender differences in growth and adiposity present in early infancy include truncal fat preservation in South Asian girls from birth , which in boys is related to rapid early weight gain . Weight gain during the first 3 months appears to drive the rise in systolic BP to 1 year , itself a likely driver of later BP [23718748] AIM The aim of this study was to assess the efficacy of glyburide in the treatment of gestational diabetes mellitus and to compare the maternal and fetal outcome between two groups treated either with insulin or glyburide . MATERIAL AND METHODS Women with gestational diabetes not responding to diet control were r and omized into two groups : ( i ) the control group receiving insulin ( n = 32 ) ; and ( ii ) the study group receiving glyburide ( n = 32 ) . Primary outcome was assessed in terms of achievement of glycemic control and secondary outcome was assessed by the incidence of maternal and fetal complications in the insulin and glyburide treated groups . RESULTS The achievement of glycemic control between the insulin and the glyburide treated groups showed no significant difference ( 97.1 % , 93.8 % ) . The occurrence of maternal complications ( P = 0.87 ) and fetal complications ( P = 0.32 ) were comparable between the insulin and glyburide treated groups . CONCLUSION Glyburide was found to be as efficacious as insulin in achieving euglycemia in the treatment of gestational diabetic women who require treatment beyond diet control [23046401] OBJECTIVE This study identified the impact of intensive therapy on neonatal outcomes in women with gestational diabetes mellitus ( GDM ) and determined the effects on the postpartum metabolic status of the mothers . RESEARCH DESIGN AND METHODS In total , 127 pregnant women with GDM were r and omly selected to receive an intensive treatment regimen , which included one-to-one education , lifestyle intervention , scheduled clinic visits , strict glucose control , and frequent glucose self-monitoring . Meanwhile , 148 age-matched pregnant women with GDM were selected as controls and given the st and ard treatment regimen . Pregnancy outcomes including parameters related to the GDM mothers and to their neonates were comparatively analyzed between the two treatment groups . GDM patient follow-up ( range , 1 - 3 years after delivery ) included an oral glucose tolerance test and measurements of lipid concentration and insulin secretion . The insulinogenic index ( ΔInsulin(30 min)/ΔBlood glucose(30 min ) ) and homeostasis model assessment index of β-cell function and insulin resistance were calculated . The patients ' demographic and anthropometric data were also recorded for comparative analysis . RESULTS Compared with GDM patients receiving st and ard treatment , GDM patients receiving intensive treatment had lower instances of premature delivery ( 2.4 % vs. 8.3 % , P<0.05 ) and neonatal care unit admission ( 21.3 % vs. 33.3 % , P<0.05 ) and lower neonatal birth weight ( 3.26±0.53 vs. 3.45±0.55 kg , P<0.0001 ) . At follow-up , GDM patients from the intensive treatment group had a smaller waist circumference ( 75.83±3.11 vs. 78.34±4.20 cm , P<0.01 ) , lower 30-min glucose levels after a 75-g glucose load ( 8.26±1.85 vs. 9.46±2.74 mmol/L , P<0.05 ) , and higher high-density lipoprotein levels ( 1.30±0.24 vs. 1.18±0.23 mmol/L , P<0.05 ) . CONCLUSIONS The intensive GDM treatment regimen led to healthier outcomes for the women , the neonates , and the birth event and was associated with better maternal metabolic situations in the months and years after delivery [22468861] A r and omized , open-label , parallel study was conducted to assess the efficacy and safety of premixed insulin aspart 30 ( biphasic insulin aspart [ BIAsp ] 30 ) in managing gestational diabetes mellitus ( GDM ) . A total of 323 women with GDM registered at a single center in India were r and omly assigned to receive 6 U of either BIAsp 30 ( Group A ) or premixed human insulin ( biphasic human insulin [ BHI ] 30 ; Group B ) in a 1:1 ratio . Subjects performed home glucose monitoring and visited their care provider twice a month . The primary outcome was the degree of neonatal macrosomia ( neonatal birth weight > 90th percentile ) . Groups A and B were demographically comparable at study entry . Before labor onset , Groups A and B achieved similar degrees of fasting plasma glucose and postpr and ial plasma glucose control ( 92.97 ± 14.44 vs. 95.43 ± 18.96 and 127.59 ± 28.99 vs. 126.98 ± 29.89 , respectively ; both p = NS ) . Neonatal macrosomia frequency was 6.3 % in Group A and 6.9 % in Group B ; however , this difference was not statistically significant . By last visit , the required insulin dose was significantly lower for Group A than Group B ( 19.83 ± 15.75 IU vs. 26.34 ± 23.15 IU , respectively ; p = 0.006 ) . BIAsp 30 was noninferior to BHI 30 , producing comparable fetal outcomes when administered during pregnancy . Based on final doses , BIAsp 30 may offer greater treat-to-target potential for pregnant women

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### Context: [15512142] We set out to reevaluate the hypothesis that high normal ( negative ) results of 50 g oral glucose challenge test or high normal glucose level on 100 g oral glucose tolerance test are associated with complications of pregnancy and delivery . This was a prospect i ve study involving 735 nondiabetic women . The first group ( n=352 ) was made up of pregnant women with normal 50 g oral glucose challenge test without previous history of diabetes mellitus or gestational diabetes . The second group ( n=383 ) was made up of pregnant women without previous history of diabetes mellitus or gestational diabetes with an abnormal 50 g oral glucose challenge test and with normal 100 g oral glucose tolerance test and not more than one previous delivery . In nondiabetic women , we demonstrated a positive correlation between high normal 50 g glucose challenge test values and the incidence of preeclampsia , caesarean section rate , macrosomia , neonatal hyperlipidaemia and minor congenital abnormalities . We failed to confirm any relationship to any pregnancy complication in pregnant women with 2-hour glucose levels in the range 6.7 - 9.1 mmol/l on the 100 g oral glucose tolerance test . We have demonstrated a positive relationship between the incidence of premature rupture of membranes and 1-hour glucose level , caesarean section rate and maternal 1-hour glucose level or 1-hour glucose level minus fasting glucose level of 4.2 mmol/l , instrumental delivery rate and maternal 3-hour glucose level , incidence of neonatal macrosomia and 1-hour glucose level , and incidence of neonatal hyperlipidaemia and at least one high but normal glucose level on the 100 g oral glucose tolerance test . With regard to pregnancy and delivery complications there were no significant difference if the high normal value is on the 50 g glucose challenge test or on the 100 g oral glucose tolerance test . It is concluded that one high normal 100 g oral glucose tolerance test or high normal 50 g glucose challenge test are associated with adverse pregnancy and delivery outcome . Nondiabetic women with 50 g glucose challenge test value of 6.1 mmol/l and /or 100 g oral glucose tolerance test values of 5 mmol/l have a favourable pregnancy and delivery outcome [2571044] OBJECTIVE —We investigated the effects of normal variations in maternal glycemia on birth size and other birth outcomes . RESEARCH DESIGN AND METHODS —Women in two unselected birth cohorts , one retrospective ( n = 3,158 ) and one prospect i ve ( n = 668 ) , underwent an oral glucose challenge at 28 weeks of gestation . In the retrospective study , glycemia was linked to routine birth records . In the prospect i ve study , offspring adiposity was assessed by skinfold thickness from birth to age 24 months . RESULTS —In the retrospective study , within the nondiabetic range ( 2.1–7.8 mmol/l ) , each 1 mmol/l rise in the mother 's 60-min glucose level was associated with a ( mean ± SEM ) 2.1 ± 0.8 % ( P = 0.006 ) rise in absolute risk of assisted vaginal delivery , a 3.4 ± 0.8 % ( P < 0.0001 ) rise in emergency cesarean delivery , a 3.1 ± 0.7 % ( P < 0.0001 ) rise in elective cesarean delivery , and a 46 ± 8 g ( P < 0.0001 ) increase in offspring birth weight . In the prospect i ve study , fetal macrosomia ( birth weight > 90th centile ) was independently related to the mother 's fasting glucose ( odds ratio 2.61 per + 1 mmol/l [ 95 % CI 1.15–5.93 ] ) and prepregnancy BMI ( 1.10 per + 1 kg/m2 [ 1.04–1.18 ] ) . The mother 's higher fasting glycemia ( P = 0.004 ) , lower insulin sensitivity ( P = 0.01 ) , and lower insulin secretion ( P = 0.02 ) were independently related to greater offspring adiposity at birth . During postnatal follow-up , the correlation between the mother 's glycemia and offspring adiposity disappeared by 3 months , whereas prepregnancy BMI was associated with offspring adiposity that was only apparent at 12 and 24 months ( both P < 0.05 ) . CONCLUSIONS —Prepregnancy BMI , pregnancy glycemia , insulin sensitivity , and insulin secretion all contribute to offspring adiposity and macrosomia and may be separate targets for intervention to optimize birth outcomes and later offspring health [4218974] Aims /hypothesisTo determine the extent to which gestational fasting and postload levels of glucose explain differences in infant fat mass between UK-born Pakistani and white British infants . Methods Analyses were undertaken in a prospect i ve pregnancy cohort study of 1,415 women and their singleton live-born infants ( 629 white British and 786 Pakistani ) . Infant fat mass was assessed by cord-blood leptin levels and fetal insulin secretion by cord-blood insulin levels . Maternal OGTTs were completed at 26–28 weeks of gestation . Results Pakistani women had higher fasting and postload glucose levels and greater incidence of gestational diabetes than white British women . Higher fasting and postload glucose levels were associated with higher cord-blood levels of insulin and leptin in all participants , irrespective of ethnicity . Cord-blood leptin levels were 16 % ( 95 % CI 6 , 26 ) higher in Pakistani than in white British infants . After adjustment for fasting glucose levels , this difference attenuated to 7 % ( −3 , 16 ) , and with additional adjustment for cord-blood insulin levels it attenuated further to 5 % ( −4 , 14 ) . Path analyses supported the hypothesis that fasting glucose levels mediate the relationship of Pakistani ethnicity to greater fat mass at birth , as measured by cord-blood leptin levels ; on average , 19 % of this mediation involved fetal insulin secretion . Postload glucose levels did not act as an important mediator of ethnic differences in cord-blood leptin levels . Results were very similar when 130 women with gestational diabetes were removed . Conclusions /interpretationThese novel findings suggest a role of maternal pregnancy glycaemia in mediating differences in fat mass between Pakistani and white British infants [4526580] Aims /hypothesisGestational diabetes mellitus ( GDM ) is associated with increased risks to mother and child , but globally agreed diagnostic criteria remain elusive . Identification of women with GDM is important , as treatment reduces adverse outcomes such as perinatal death , shoulder dystocia and neonatal hypoglycaemia . Recently , the UK ’s National Institute for Health and Care Excellence ( NICE ) recommended new diagnostic thresholds for GDM which are different from the International Association of the Diabetes and Pregnancy Study Groups ( IADPSG ) criteria endorsed by the WHO . The study aim was to assess neonatal and obstetric outcomes among women who would test positive for the IADPSG criteria but negative for the NICE 2015 criteria . Methods Data from 25,543 consecutive singleton live births ( 2004–2008 ) were obtained retrospectively from hospital records . Women were screened with a r and om plasma glucose ( RPG ; 12–16 weeks ) and a 50 g glucose challenge test ( GCT ; 26–28 weeks ) . If RPG > 7.0 mmol/l , GCT > 7.7 mmol/l or symptoms were present , a 75 g OGTT was offered ( n = 3,848 ) . Results In this study , GDM prevalence was 4.13 % ( NICE 2015 ) and 4.62 % ( IADPSG ) . Women who ‘ fell through the net ’ , testing NICE-negative but IADPSG-positive ( n = 387 ) , had a higher risk of having a large-for-gestational-age ( LGA ) infant ( birthweight > 90th percentile for gestational age ; adjusted OR [ 95 % CI ] 3.12 [ 2.44 , 3.98 ] ) , Caesarean delivery ( 1.44 [ 1.15 , 1.81 ] ) and polyhydramnios ( 6.90 [ 3.94 , 12.08 ] ) compared with women with negative screening results and no OGTT ( n = 21,695 ) . LGA risk was highest among women with fasting plasma glucose 5.1–5.5 mmol/l ( n = 167 ) : the mean birthweight was 350 g above that of the reference population and 37.7 % of infants were LGA . Conclusions /interpretationThe IADPSG criteria identify women at substantial risk of complications who would not be identified by the NICE 2015 criteria [21220735] Background — Maternal diabetes mellitus in pregnancy results in greater offspring adiposity at birth . It is unclear whether it is associated with greater adiposity into adulthood , and if so , whether this is via intrauterine mechanisms or shared familial characteristics . Methods and Results — A record-linkage prospect i ve cohort study of 280 866 singleton-born Swedish men from 248 293 families was used to explore the intrauterine effect of maternal diabetes mellitus on offspring body mass index ( BMI ) in early adulthood . Maternal diabetes mellitus during pregnancy was associated with greater mean BMI at age 18 in their sons . The difference in BMI was similar within brothers and between nonsiblings . BMI of men whose mothers had diabetes mellitus during their pregnancy was on average 0.94 kg/m2 greater ( 95 % confidence interval [ CI ] , 0.35 to 1.52 ) than in their brothers born before their mother was diagnosed with diabetes , after adjustment for birth year , maternal age , parity and education , birth weight , gestational age , and age at assessment of BMI . Early-pregnancy BMI was positively associated with son 's BMI between nonsiblings , but there was no association within brothers . Adjustment of the maternal diabetes-offspring BMI association for maternal BMI did not alter the association either within brothers or between nonsiblings . Results were also robust to sensitivity analyses restricting the within-sibling analyses to siblings born within 3 years of each other . Conclusion — Maternal diabetes mellitus has long-term consequences for greater BMI in offspring ; this association is likely to be via intrauterine mechanisms , and is independent of maternal BMI in early pregnancy [21083860] Please cite this paper as : Ijäs H , Vääräsmäki M , Morin‐Papunen L , Keravuo R , Ebeling T , Saarela T , Raudaskoski T. Metformin should be considered in the treatment of gestational diabetes : a prospect i ve r and omised study . BJOG 2011;118:880–885 [17684614] OBJECTIVES To study glibenclamide as a treatment for gestational diabetes mellitus ( GDM ) and its impact on newborn birth weight and neonatal glycemia as compared to insulin . METHODS A r and omized and open-label clinical trial , conducted from October 1st , 2003 to March 8 , 2005 . Seventy-two pregnant women with gestational diabetes mellitus requiring drug therapy were r and omized and allocated into two groups -- insulin and glibenclamide . RESULTS The general characteristics in both groups were similar , except for the results of the 75 g OGTT , which were higher in the glibenclamide group ( p= 0.02 ) . Maternal fasting and postpr and ial glucose levels presented no difference . Six ( 18.75 % ) pregnant women received the maximum dose of glibenclamide with no glycemic control . The birth weight was higher in the group treated with glibenclamide ( p= 0.01 ) , and the incidence of macrosomic newborns statistically different ( p= 0.01 ) . Neonatal hypoglycemia was more frequent ( p= 0.01 ) in newborns of glibenclamide group , with one single case of persistent hypoglycemia . CONCLUSION Glibenclamide can be the first line drug for glycemic control in most GDM patients . The birth weight and incidence of hypoglycemia were higher in the glibenclamide group , but with one single case of persistent hypoglycemia that required intravenous infusion of glucose [21494772] Aims /hypothesisNew diagnostic criteria for gestational diabetes mellitus ( GDM ) have recently been published . We wished to evaluate what impact these new criteria would have on GDM prevalence and outcomes in a predominantly European population . Methods The Atlantic Diabetes In Pregnancy ( DIP ) programme performed screening for GDM in 5,500 women with an oral glucose tolerance test at 24–28 weeks . GDM was defined according to the new International Association of Diabetes and Pregnancy Study Groups ( IADPSG ) criteria and compared with previous WHO criteria ; maternal and neonatal adverse outcomes were prospect ively recorded . Results Of the participants , 12.4 % and 9.4 % were diagnosed with GDM using IADPSG and WHO criteria , respectively . IADPSG GDM pregnancies were associated with a statistically significant increased incidence of adverse maternal outcomes ( gestational hypertension , polyhydramnios and Caesarean section ) and neonatal outcomes ( prematurity , large for gestational age , neonatal unit admission , neonatal hypoglycaemia and respiratory distress ) . The odds ratio for the development of these adverse outcomes remained significant after adjustment for maternal age , body mass index and non-European ethnicity . Those women who were classified as having normal glucose tolerance by WHO criteria but as having GDM by IADPSG criteria also had significant adverse pregnancy outcomes . Conclusions /interpretationGDM prevalence is higher when using newer IADPSG , compared with WHO , criteria , and these women and their offspring experience significant adverse pregnancy outcomes . Higher rates of GDM pose a challenge to healthcare systems , but improved screening provides an opportunity to attempt to reduce the associated morbidity for mother and child [22505499] Abstract Objective : To evaluate the perinatal impact of metformin and glyburide in the treatment of gestational diabetes mellitus ( GDM ) . Methods : A r and omized clinical trial conducted from July 2008 until September 2010 studied 200 pregnant women with GDM who required adjunctive therapy to diet and physical activity . Patients were r and omized to use metformin ( n=104 ) or glyburide ( n=96 ) . The drugs were replaced by insulin when they reached the maximum dose without glycemic control . Assessed outcomes : weight and neonatal blood glucose . Results : : No difference was found ( P>0.05 ) between the groups regarding maternal age , gestational age at inclusion , body mass index , glucose levels in oral glucose tolerance test ( OGTT ) 75 g and glycemic control . Difference was found in the number of previous pregnancies ( 2.84 vs. 2.47 , P=0.04 ) and weight gain during pregnancy ( 7.78 vs. 9.84 , P=0.04 ) in the metformin group and glyburide respectively . The perinatal results showed no difference ( P>0.05 ) in the percentage of cesarean deliveries , gestational age at delivery , number of newborns large for gestational age ( LGA ) , neonatal hypoglycemia , admission to intensive care unit and perinatal death . We found differences in weight ( 3193 g vs. 3387 g , P=0.01 ) and ponderal index ( 2.87 vs. 2.96 , P=0.05 ) of newborns , and in neonatal blood glucose levels at the 1st ( 59.78 vs. 54.08 , P=0.01 ) and 3rd h ( 61.53 vs. 55.89 , P=0.01 ) after birth between the metformin and glyburide groups respectively . Conclusions : Weight and ponderal index were lower in the newborns of the metformin group ; glucose levels ( 1st and 3rd h after birth ) were lower in the glyburide group [7631672] OBJECTIVE Our purpose was to assess maternal-fetal outcomes in patients with increasing carbohydrate intolerance not meeting the current criteria for the diagnosis of gestational diabetes . STUDY DESIGN We conducted a prospect i ve analytic cohort study in which nondiabetic women aged > or = 24 years , receiving prenatal care in three Toronto teaching hospitals , were eligible for enrollment . A glucose challenge test and an oral glucose tolerance test were administered at 26 and 28 weeks ' gestation , respectively ; risk factors for unfavorable maternal-fetal outcomes were recorded . Caregivers and patients were blinded to glucose values except when test results met the current criteria for gestational diabetes . RESULTS Of 4274 patients screened , 3836 ( 90 % ) continued to the diagnostic oral glucose tolerance test . The study cohort was formed by the 3637 ( 95 % ) patients without gestational diabetes , carrying singleton fetuses . Increasing carbohydrate intolerance in women without overt gestational diabetes was associated with a significantly increased incidence of cesarean sections , preeclampsia , macrosomia , and need for phototherapy , as well as an increased length of maternal and neonatal hospital stay . Multivariate analysis showed that increasing carbohydrate intolerance is an independent predictor for various unfavorable outcomes . CONCLUSION Increasing maternal carbohydrate intolerance in pregnant women without gestational diabetes is associated with a grade d increase in adverse maternal-fetal outcomes [11597616] OBJECTIVES To assess the prevalence and association of frequently used screening risk factors for gestational diabetes mellitus ( GDM ) and to compare the validity and cost of universal screening with risk factor screening . METHOD A cross-sectional survey of 768 pregnant women at > or = 24 weeks ' gestation who were attending the antenatal clinic at the Hospital Universiti Kebangsaan Malaysia ( HUKM ) was made . Risk factors were determined using a question naire . An abnormal oral glucose tolerance test was defined as a 2-h post-pr and ial blood sugar level of > or = 7.8 mmol/l . RESULTS A total of 191 pregnant mothers ( 24.9 % ) had GDM . The most commonly identified screening factors were positive family history of diabetes mellitus ( 31.4 % ) , history of spontaneous abortion ( 17.8 % ) , vaginal discharge and pruritus vulvae in current pregnancy ( 16.0 % ) , and maternal age greater than 35 years ( 14.7 % ) . Five hundred and thirteen mothers ( 66.8 % ) had at least one risk factor . All screening risk factors , except past history of diabetes mellitus in previous pregnancy and maternal age , were not significantly associated with abnormal glucose tolerance ( GT ) . Risk factor screening gave a sensitivity of 72.2 % and a specificity of 35.0 % . Universal screening would cost RM 12.06 while traditional risk factor screening would cost RM 11.15 per identified case and will have missed 53 of the 191 cases . CONCLUSIONS Risk factor screening scored poorly in predicting GDM . Cost analysis of universal compared with traditional risk factor screening showed a negligible difference . Thus universal screening appears to be the most reliable method of diagnosing GDM [18826999] CONTEXT A past history of gestational diabetes mellitus ( GDM ) confers a very high risk of postpartum development of diabetes , particularly type 2 diabetes . OBJECTIVE The Diabetes Prevention Program ( DPP ) sought to identify individuals with impaired glucose tolerance ( IGT ) and intervene in an effort to prevent or delay their progression to diabetes . This analysis examined the differences between women enrolled in DPP with and without a reported history of GDM . DESIGN The DPP was a r and omized , controlled clinical trial . SETTING The study was a multicenter , National Institutes of Health-sponsored trial carried out at 27 centers including academic and Indian Health Services sites . PATIENTS A total of 2190 women were r and omized into the DPP and provided information for past history of GDM . This analysis addressed the differences between those 350 women providing a past history of GDM and those 1416 women with a previous live birth but no history of GDM . INTERVENTIONS Subjects were r and omized to either st and ard lifestyle and placebo or metformin therapy or to an intensive lifestyle intervention . MAIN OUTCOMES The primary outcome was the time to development of diabetes ascertained by semiannual fasting plasma glucose and annual oral glucose tolerance testing . Assessment s of insulin secretion and insulin sensitivity were also performed . RESULTS Whereas entering the study with similar glucose levels , women with a history of GDM r and omized to placebo had a crude incidence rate of diabetes 71 % higher than that of women without such a history . Among women reporting a history of GDM , both intensive lifestyle and metformin therapy reduced the incidence of diabetes by approximately 50 % compared with the placebo group , whereas this reduction was 49 and 14 % , respectively in parous women without GDM . These data suggest that metformin may be more effective in women with a GDM history as compared with those without . CONCLUSIONS Progression to diabetes is more common in women with a history of GDM compared with those without GDM history despite equivalent degrees of IGT at baseline . Both intensive lifestyle and metformin are highly effective in delaying or preventing diabetes in women with IGT and a history of GDM [20809381] Aims /hypothesisThe cost-effectiveness of eight strategies for screening for gestational diabetes ( including no screening ) was estimated with respect to the level of individual patient risk . Methods Cost – utility analysis using a decision analytic model populated with efficacy evidence pooled from recent r and omised controlled trials , from the funding perspective of the National Health Service in Engl and and Wales . Seven screening strategies using various combinations of screening and diagnostic tests were tested in addition to no screening . The primary outcome measure was the incremental cost per quality -adjusted life-year ( QALY ) over a lifetime . Results The strategy that has the greatest likelihood of being cost-effective is dependent on the risk of gestational diabetes mellitus for each individual woman . When gestational diabetes mellitus risk is < 1 % then the no screening/treatment strategy is cost-effective ; where risk is between 1.0 % and 4.2 % fasting plasma glucose followed by OGTT is most likely to be cost-effective ; and where risk is > 4.2 % , universal OGTT is most likely to be cost-effective . However , acceptability of the test alters the most cost-effective strategy . Conclusions /interpretationScreening for gestational diabetes can be cost-effective . The best strategy is dependent on the underlying risk of each individual and the acceptability of the tests used . The current study suggests that if a woman ’s individual risk of gestational diabetes could be accurately predicted , then healthcare re source allocation could be improved by providing an individualised screening strategy [24424076] Background / Objectives : The current study was performed to investigate the effects of the Dietary Approaches to Stop Hypertension ( DASH ) eating plan on pregnancy outcomes in pregnant women with gestational diabetes mellitus (GDM).Subjects/ Methods : This r and omized controlled clinical trial was performed among 52 women diagnosed with GDM . Participants were r and omly assigned to consume either the control ( n=26 ) or the DASH diet ( n=26 ) for 4 weeks . The control diet was design ed to contain 45–55 % carbohydrates , 15–20 % protein and 25–30 % total fat . The DASH diet was rich in fruits , vegetables , whole grains and low-fat dairy products , and contained lower amounts of saturated fats , cholesterol and refined grains with a total of 2400 mg/day sodium . The numbers of women who commenced insulin therapy after dietary intervention , the mode of delivery and prevalence of polyhydramnios were assessed . The length , weight and head circumference of infants were measured during the first 24 h after birth . Results : Whereas 46.2 % of women in the DASH diet needed to have a cesarean section , this percentage for the control group was 80.8 % ( P=0.01 ) . The percentage of those who needed to commence insulin therapy after intervention was also significantly different between the two groups ( 23 % for DASH vs 73 % for control group , P<0.0001 ) . Infants born to mothers on the DASH diet had significantly lower weight ( 3222.7 vs 3818.8 g , P<0.0001 ) , head circumference ( 34.2 vs 35.1 cm , P=0.01 ) and ponderal index ( 2.50 vs 2.87 kg/m3 , P<0.0001 ) compared with those born to mothers on the control diet . Conclusions : In conclusion , consumption of DASH diet for 4 weeks among pregnant women with GDM result ed in improved pregnancy outcomes [20827864] OBJECTIVE To determine if pregnancies with an abnormal glucose challenge test ( GCT ) but a normal ( GTT ) are at increased risk for fetal macrosomia or an adverse pregnancy outcome . STUDY DESIGN This prospect i ve observational study matched women with an abnormal glucose challenge test and a normal GTT with the next patient with a normal GCT . RESULTS Over 12 months , 107 women with abnormal GCT were matched with 107 women with normal GCT . Women with an abnormal GCT were older ( 27.3 vs. 24.7 , p = 0.001 ) and less likely to be African-American ( OR = 2.2 , 95 % CI 1.06 - 4.49 ) but no more likely to have an adverse pregnancy outcome . ROC curves could not differentiate between macrosomic vs non-macrosomic newborns using GCT values . CONCLUSION Women with an abnormal GCT but a normal GTT are more likely to be older , less likely to be African-American , but no more likely to have an adverse pregnancy outcome or a macrosomic fetus [24243635] CONTEXT Gestational hyperglycemia increases the risk of obesity and diabetes in offspring later in life . OBJECTIVE We examined the relationship between gestational glycemia and neonatal adiposity in a multiethnic cohort of Singaporean neonates . DESIGN A prospect i ve mother-offspring cohort study recruited 1247 pregnant mothers ( 57.2 % Chinese , 25.5 % Malay , 17.3 % Indian ) and performed 75-g , 2-hour oral glucose tolerance tests at 26 - 28 weeks ' gestation ; glucose levels were available for 1081 participants . Neonatal anthropometry ( birth weight , length , triceps , and subscapular skinfolds ) was measured , and percentage body fat ( % BF ) was derived using our published equation . Associations of maternal glucose with excessive neonatal adiposity [ large for gestational age ; % BF ; and sum of skinfolds (∑SFT)>90th centile ] were assessed using multiple logistic regression analyses . RESULTS Adjusting for potential confounders we observed strong positive continuous associations across the range of maternal fasting and 2-hour glucose in relation to excessive neonatal adiposity ; each 1 SD increase in fasting glucose was associated with 1.31 [ 95 % confidence interval ( CI ) 1.10 - 1.55 ] , 1.72 ( 95 % CI 1.31 - 2.27 ) and 1.64 ( 95 % CI 1.32 - 2.03 ) increases in odds ratios for large for gestational age and % BF and ∑SFT greater than the 90th centile , respectively . Corresponding odds ratios for 2-hour glucose were 1.11 ( 95 % CI 0.92 - 1.33 ) , 1.55 ( 95 % CI 1.10 - 2.20 ) , and 1.40 ( 95 % CI 1.10 - 1.79 ) , respectively . The influence of high maternal fasting glucose on neonatal ∑SFT was less pronounced in Indians compared with Chinese ( interaction P=.005 ) . CONCLUSIONS A continuous relationship between maternal glycemia and excessive neonatal adiposity extends across the range of maternal glycemia . Compared with Chinese infants , Indian infants may be less susceptible to excessive adiposity from high maternal glucose levels [3831638] The data for medical decision analyses are often unreliable . Traditional sensitivity analysis --varying one or more probability or utility estimates from baseline values to see if the optimal strategy changes -- is cumbersome if more than two values are allowed to vary concurrently . This paper describes a practical method for probabilistic sensitivity analysis , in which uncertainties in all values are considered simultaneously . The uncertainty in each probability and utility is assumed to possess a probability distribution . For ease of application we have used a parametric model that permits each distribution to be specified by two values : the baseline estimate and a bound ( upper or lower ) of the 95 percent confidence interval . Following multiple simulations of the decision tree in which each probability and utility is r and omly assigned a value within its distribution , the following results are recorded : ( a ) the mean and st and ard deviation of the expected utility of each strategy ; ( b ) the frequency with which each strategy is optimal ; ( c ) the frequency with which each strategy " buys " or " costs " a specified amount of utility relative to the remaining strategies . As illustrated by an application to a previously published decision analysis , this technique is easy to use and can be a valuable addition to the armamentarium of the decision analyst [15449338] Mixed treatment comparison ( MTC ) meta- analysis is a generalization of st and ard pairwise meta- analysis for A vs B trials , to data structures that include , for example , A vs B , B vs C , and A vs C trials . There are two roles for MTC : one is to strengthen inference concerning the relative efficacy of two treatments , by including both ' direct ' and ' indirect ' comparisons . The other is to facilitate simultaneous inference regarding all treatments , in order for example to select the best treatment . In this paper , we present a range of Bayesian hierarchical models using the Markov chain Monte Carlo software WinBUGS . These are multivariate r and om effects models that allow for variation in true treatment effects across trials . We consider models where the between-trials variance is homogeneous across treatment comparisons as well as heterogeneous variance models . We also compare models with fixed ( unconstrained ) baseline study effects with models with r and om baselines drawn from a common distribution . These models are applied to an illustrative data set and posterior parameter distributions are compared . We discuss model critique and model selection , illustrating the role of Bayesian deviance analysis , and node-based model criticism . The assumptions underlying the MTC models and their parameterization are also discussed [4673084] Summary Background Diagnosis of gestational diabetes predicts risk of infants who are large for gestational age ( LGA ) and with high adiposity , which in turn aims to predict a future risk of obesity in the offspring . South Asian women have higher risk of gestational diabetes , lower risk of LGA , and on average give birth to infants with greater adiposity than do white European women . Whether the same diagnostic criteria for gestational diabetes should apply to both groups of women is unclear . We aim ed to assess the association between maternal glucose and adverse perinatal outcomes to ascertain whether thresholds used to diagnose gestational diabetes should differ between south Asian and white British women . We also aim ed to assess whether ethnic origin affected prevalence of gestational diabetes irrespective of criteria used . Methods We used data ( including results of a 26–28 week gestation oral glucose tolerance test ) of women from the Born in Bradford study , a prospect i ve study that recruited women attending the antenatal clinic at the Bradford Royal Infirmary , UK , between 2007 and 2011 and who intended to give birth to their infant in that hospital . We studied the association between fasting and 2 h post-load glucose and three primary outcomes ( LGA [ defined as birthweight > 90th percentile for gestational age ] , high infant adiposity [ sum of skinfolds > 90th percentile for gestational age ] , and caesarean section ) . We calculated adjusted odds ratios ( ORs ) and their 95 % confidence intervals ( CIs ) for a 1 SD increase in fasting and post-load glucose . We established fasting and post-load glucose thresholds that equated to an OR of 1·75 for LGA and high infant adiposity in each group of women to identify ethnic-specific criteria for diagnosis of gestational diabetes . Findings Of 13 773 pregnancies , 3420 were excluded from analyses . Of 10 353 eligible pregnancies , 4088 women were white British , 5408 were south Asian , and 857 were of other ethnic origin . The adjusted ORs of LGA per 1 SD fasting glucose were 1·22 ( 95 % CI 1·08–1·38 ) in white British women and 1·43 ( 1·23–1·67 ) in south Asian women ( pinteraction with ethnicity = 0·39 ) . Results for high infant adiposity were 1·35 ( 1·23–1·49 ) and 1·35 ( 1·18–1·54 ; pinteraction with ethnicity=0·98 ) , and for caesarean section they were 1·06 ( 0·97–1·16 ) and 1·11 ( 1·02–1·20 ; pinteraction with ethnicity=0·47 ) . Associations between post-load glucose and the three primary outcomes were weaker than for fasting glucose . A fasting glucose concentration of 5·4 mmol/L or a 2 h post-load level of 7·5 mmol/L identified white British women with 75 % or higher relative risk of LGA or high infant adiposity ; in south Asian women , the cutoffs were 5·2 mmol/L or 7·2 mml/L ; in the whole cohort , the cutoffs were 5·3 mmol/L or 7·5 mml/L. The prevalence of gestational diabetes in our cohort ranged from 1·2 % to 8·7 % in white British women and 4 % to 24 % in south Asian women using six different criteria . Compared with the application of our whole-cohort criteria , use of our ethnic-specific criteria increased the prevalence of gestational diabetes in south Asian women from 17·4 % ( 95 % CI 16·4–18·4 ) to 24·2 % ( 23·1–25·3 ) . Interpretation Our data support the use of lower fasting and post-load glucose thresholds to diagnose gestational diabetes in south Asian than white British women . They also suggest that diagnostic criteria for gestational diabetes recommended by UK NICE might underestimate the prevalence of gestational diabetes compared with our criteria or those recommended by the International Association of Diabetes and Pregnancy Study Groups and WHO , especially in south Asian women . Funding The National Institute for Health Research [9240606] OBJECTIVES The purpose of this study was to determine whether strict maternal glycemic control for the treatment of gestational diabetes lessened the risk of fetal macrosomia , birth trauma , neonatal hypoglycemia , and operative delivery . The aim of the pilot study was to prepare for a multicenter trial by assessing patient acceptance of the study , by determining realistic accrual rates , and by detecting any major adverse outcomes in the control group that received routine obstetric care . STUDY DESIGN The study was a prospect i ve r and omized controlled trial comparing fetal-neonatal and maternal outcomes in 300 women with gestational diabetes . Women r and omized to the treatment arm were managed by strict glycemic control and tertiary level obstetric care , and women in the control arm received routine obstetric care . RESULTS Three hundred women with gestational diabetes mellitus were studied . There was no difference in maternal age , weight , or length of gestation between groups . The treatment mean birth weight was 3437 + /- 575 gm compared with 3544 + /- 601 gm in the control group , a difference of 107 gm ( not significant ) . Macrosomia rates were similar . There was no birth trauma in either group . The frequency of neonatal hypoglycemia and other metabolic complications was the same . The mode of delivery also showed similar patterns . The treatment group had significantly lower prepr and ial and postpr and ial glucose levels by 32 weeks ' gestation , which continued to term . CONCLUSION This pilot study suggests that intensive treatment of gestational diabetes mellitus may have little effect on birth weight , birth trauma , operative delivery , or neonatal metabolic disorders . It has demonstrated the safety of proceeding to a multicenter trial of sufficient sample size to confirm these findings [23001377] Aims /hypothesisIt is currently not clear how to construct a time- and cost-effective screening strategy for gestational diabetes mellitus ( GDM ) . Thus , we elaborated a simple screening algorithm combining ( 1 ) fasting plasma glucose ( FPG ) measurement ; and ( 2 ) a multivariable risk estimation model focused on individuals with normal FPG levels to decide if a further OGTT is indicated . Methods A total of 1,336 women were prospect ively screened for several risk factors for GDM within a multicentre study conducted in Austria . Of 714 women ( 53.4 % ) who developed GDM using recent diagnostic guidelines , 461 were sufficiently screened with FPG . A risk prediction score was finally developed using data from the remaining 253 women with GDM and 622 healthy women . The screening algorithm was vali date d with a further 258 pregnant women . Results A risk estimation model including history of GDM , glycosuria , family history of diabetes , age , preconception dyslipidaemia and ethnic origin , in addition to FPG , was accurate for detecting GDM in participants with normal FPG . Including an FPG pretest , the receiver operating characteristic AUC of the screening algorithm was 0.90 ( 95 % CI 0.88 , 0.91 ) . A cut-off value of 0.20 was able to differentiate between low and intermediate risk for GDM with a high sensitivity . Comparable results were seen with the validation cohort . Moreover , we demonstrated an independent association between values derived from the risk estimation and macrosomia in offspring ( OR 3.03 , 95 % CI 1.79 , 5.19 , p < 0.001 ) . Conclusions /interpretationThis study demonstrates a new concept for accurate but cheap GDM screening . This approach should be further evaluated in different population s to ensure an optimised diagnostic algorithm [15951574] BACKGROUND We conducted a r and omized clinical trial to determine whether treatment of women with gestational diabetes mellitus reduced the risk of perinatal complications . METHODS We r and omly assigned women between 24 and 34 weeks ' gestation who had gestational diabetes to receive dietary advice , blood glucose monitoring , and insulin therapy as needed ( the intervention group ) or routine care . Primary outcomes included serious perinatal complications ( defined as death , shoulder dystocia , bone fracture , and nerve palsy ) , admission to the neonatal nursery , jaundice requiring phototherapy , induction of labor , cesarean birth , and maternal anxiety , depression , and health status . RESULTS The rate of serious perinatal complications was significantly lower among the infants of the 490 women in the intervention group than among the infants of the 510 women in the routine-care group ( 1 percent vs. 4 percent ; relative risk adjusted for maternal age , race or ethnic group , and parity , 0.33 ; 95 percent confidence interval , 0.14 to 0.75 ; P=0.01 ) . However , more infants of women in the intervention group were admitted to the neonatal nursery ( 71 percent vs. 61 percent ; adjusted relative risk , 1.13 ; 95 percent confidence interval , 1.03 to 1.23 ; P=0.01 ) . Women in the intervention group had a higher rate of induction of labor than the women in the routine-care group ( 39 percent vs. 29 percent ; adjusted relative risk , 1.36 ; 95 percent confidence interval , 1.15 to 1.62 ; P<0.001 ) , although the rates of cesarean delivery were similar ( 31 percent and 32 percent , respectively ; adjusted relative risk , 0.97 ; 95 percent confidence interval , 0.81 to 1.16 ; P=0.73 ) . At three months post partum , data on the women 's mood and quality of life , available for 573 women , revealed lower rates of depression and higher scores , consistent with improved health status , in the intervention group . CONCLUSIONS Treatment of gestational diabetes reduces serious perinatal morbidity and may also improve the woman 's health-related quality of life [19841891] Aims /hypothesisThe aim of the study was to examine the association of existing diabetes ( i.e. already diagnosed prior to pregnancy ) , gestational diabetes and glycosuria ( both diagnosed and ascertained during pregnancy ) with birthweight and future offspring BMI , waist circumference and fat mass ( assessed by dual x-ray emission absorptiometry ) . Methods A prospect i ve pregnancy/birth cohort study was performed using data from the Avon Longitudinal Study of Parents and Children . Results Among 10,591 mother – offspring pairs included in analyses with birth size , women with existing diabetes ( n = 40 ) , those diagnosed with gestational diabetes ( n = 53 ) and those with at least two episodes of + + glycosuria ( n = 372 ) had greater mean birthweight and odds for macrosomia ( birthweight > 4,000 g ) than women with none of these . Adjusted odds ratios for macrosomia were 3.56 ( 95 % CI 1.53–8.28 ) , 5.50 ( 95 % CI 1.18–10.30 ) and 1.58 ( 95 % CI 1.18–2.12 ) for existing diabetes , gestational diabetes and glycosuria , respectively . Among 6,842 mother – offspring pairs with anthropometric measurements at age 9–11 years , maternal gestational diabetes and glycosuria ( but not existing diabetes ) were associated with increased offspring odds of general or central overweight/obesity . For gestational diabetes , these associations attenuated towards the null with adjustment for maternal prepregnancy BMI , but independent associations remained for glycosuria . The adjusted odds ratio for general overweight/obesity when comparing women with at least two episodes of + + glycosuria with those with no evidence of diabetes or glycosuria was 1.35 ( 95 % CI 1.00–1.82 ) and that for central obesity ( top 10 % waist circumference vs all others ) was 1.31 ( 95 % CI 1.00–1.72 ) . Conclusions /interpretationThese results provide some evidence for a long-term effect of maternal glycaemia in pregnancy on offspring obesity risk [23020608] AIMS We compared metformin with insulin as treatment of gestational diabetes mellitus ( GDM ) . Furthermore , we aim ed to characterize metformin-treated patients needing additional insulin to achieve prespecified glucose targets . METHODS We conducted a single centre r and omized controlled study with non-inferiority design comparing metformin and insulin in the treatment of 217 GDM patients having birth weight as primary outcome variable . RESULTS There were no significant differences in mean birth weight expressed in grams [ + 15 ( 90 % confidence interval ( CI ) : -121 to 89 ) ] or SD units [ + 0.04 ( 90 % CI : -0.27 to 0.18 ) ] between the metformin and insulin groups . There were no significant differences in neonatal or maternal data between the groups . Only 23 ( 20.9 % ) of the 110 patients in the metformin group needed additional insulin . Compared with the patients on metformin only , those needing additional insulin were older ( p = 0.04 ) , their oral glucose tolerance test had been performed earlier and diabetes therapy started earlier in gestation ( p = 0.01 and p = 0.004 , respectively ) . The risk for additional insulin was 4.6-fold in women with baseline serum fructosamine concentration above median compared with those below median . CONCLUSIONS Metformin is an effective alternative to insulin in the treatment of GDM patients . Serum fructosamine may help in predicting the adequacy of metformin treatment alone [18161398] OBJECTIVE To compare glycemic control and neonatal outcomes in women with gestational diabetes mellitus ( GDM ) treated with metformin vs. insulin . STUDY DESIGN Women with GDM not controlled with diet and exercise were r and omized to metformin ( n = 32 ) or insulin ( n = 31 ) . The levels of glycemic control as well as maternal/neonatal complications were evaluated . RESULTS The mean ( + /- SD ) fasting and 2-hour postpr and ial blood glucose did not differ statistically between the 2 treatment groups . No patient failed metformin and required insulin . The majority ( 27/32 ) were easily controlled on the initial dosage ( 500 mg twice a day ) . Gestational age at entry and delivery ( p = 0.077 , 0.412 ) were similar . The difference in the rate of cesarean delivery was not statistically significant between the 2 groups ( p = 0.102 ) . Neonatal statistics were also not different between the metformin and insulin groups : birth weight , Apgar score at 5 minutes , respiratory distress syndrome , hyperbilirubinemia , neonatal hypoglycemia and neonatal intensive care unit admission ( p = 0.144 - 0.373 ) . CONCLUSION Based on these preliminary data , metformin appears to be an effective alternative to insulin in the treatment of GDM [19477547] AIM A prediction rule for gestational diabetes mellitus ( GDM ) could be helpful in early detection and increased efficiency of screening . A prediction rule by means of a clinical scoring system is available , but has never been vali date d externally . The aim of this study was to vali date the scoring system . METHODS We used data from a prospect i ve cohort study . Women were assigned a score based on age , BMI and ethnicity . Performance of the scoring system was evaluated in terms of discrimination and calibration ( agreement between clinical score and observed probability of GDM ) . We compared the efficiency of a screening strategy derived from the scoring system with conventional screening . RESULTS We studied 1266 women . Forty-seven women had GDM ( 3.7 % ) . The scoring system discriminated moderately ( area under the curve=0.64 ( 95 % CI 0.56 - 0.72 ) ) . Calibration was limited ( chi(2)=8.89 , p=0.06 ) . The screening strategy derived from the scoring system reduced the number of women needed to be screened with 25 % for a comparable detection rate to universal screening . CONCLUSION Despite moderate discriminative capacity and calibration of the scoring system , the screening strategy based on the scoring system appears clinical ly useful . There is need for better prediction models for GDM [3634172] Background : Few studies have been done on the use of metformin in pregnancy and their results were not similar , therefore this research is performed to compare neonatal outcomes of metformin and insulin in the treatment of gestational diabetes . Methods : In this prospect i ve r and omized trial , 200 pregnant women within their 24th to 34th weeks of gestation with gestational diabetes , single fetus pregnancy , and in need of hyperglycemia treatment were entered and grouped as either metformin or insulin . Data related to maternal and neonatal outcomes were recorded and analyzed . Results : Considering data recorded of HbA1c at the beginning of pregnancy , pregnancy induced hypertension , preeclampsia , birth weight , dystocia , first and 5th min APGAR , neonatal sepsis , rout of delivery , liver function tests of neonate , hypoglycemia , anomaly , and still birth , there were no significant statistical differences between groups . The end pregnancy HbA1c , maternal weight gain during pregnancy , preterm labor , neonatal jaundice , respiratory distress and hospitalization of infants were higher in insulin group . Conclusions : Considering data from this study , metformin is efficient to control hyperglycemia in pregnancy . It is suggested performing more studies to evaluate long term side effects of metformin in pregnancy with higher sample size and longer follow-up of newborns [3791414] Objective : To describe how maternal obesity prevalence varies by established international and South Asian specific body mass index ( BMI ) cut-offs in women of Pakistani origin and investigate whether different BMI thresholds can help to identify women at risk of adverse pregnancy and birth outcomes . Design : Prospect i ve bi-ethnic birth cohort study ( the Born in Bradford ( BiB ) cohort ) . Setting : Bradford , a deprived city in the North of the UK . Participants : A total of 8478 South Asian and White British pregnant women participated in the BiB cohort study .Main outcome measures : Maternal obesity prevalence ; prevalence of known obesity-related adverse pregnancy outcomes : mode of birth , hypertensive disorders of pregnancy ( HDP ) , gestational diabetes , macrosomia and pre-term births . Results : Application of South Asian BMI cut-offs increased prevalence of obesity in Pakistani women from 18.8 ( 95 % confidence interval ( CI ) 17.6–19.9 ) to 30.9 % ( 95 % CI 29.5–32.2 ) . With the exception of pre-term births , there was a positive linear relationship between BMI and prevalence of adverse pregnancy and birth outcomes , across almost the whole BMI distribution . Risk of gestational diabetes and HDP increased more sharply in Pakistani women after a BMI threshold of at least 30 kg m−2 , but there was no evidence of a sharp increase in any risk factors at the new , lower thresholds suggested for use in South Asian women . BMI was a good single predictor of outcomes ( area under the receiver operating curve : 0.596–0.685 for different outcomes ) ; prediction was more discriminatory and accurate with BMI as a continuous variable than as a binary variable for any possible cut-off point . Conclusion : Applying the new South Asian threshold to pregnant women would markedly increase those who were referred for monitoring and lifestyle advice . However , our results suggest that lowering the BMI threshold in South Asian women would not improve the predictive ability for identifying those who were at risk of adverse pregnancy outcomes [21268030] OBJECTIVE To develop a model for the prediction of gestational diabetes mellitus ( GDM ) from maternal characteristics and biochemical markers at 11 to 13 weeks ' gestation . METHODS A prospect i ve screening study on early prediction of pregnancy complications ( n = 11 , 464 ) , including 297 ( 2.6 % ) cases of GDM was used to create the predictive model of GDM based on maternal characteristics . Maternal serum concentrations of adiponectin , follistatin-like-3 ( FSTL3 ) and sex hormone-binding globulin ( SHBG ) were measured in a case-control study of 80 women who developed GDM and 300 controls . RESULTS In the screening study , maternal age , body mass index , racial origin , previous history of GDM and macrosomic neonate were significant independent predictors of future GDM . In the GDM group , compared to controls , the median multiple of the normal median adiponectin ( 0.66 ; IQR : 0.5 - 0.9 vs 1.02 ; IQR : 0.7 - 1.29 ) and SHBG ( 0.81 ; IQR : 0.6 - 1.04 vs 1.02 ; IQR : 0.8 - 1.2 ) was lower ( p < 0.05 ) , but FSTL3 was not significantly different . In screening for GDM by maternal characteristics , the detection rate was 61.6 % at a false-positive rate of 20 % and the detection increased to 74.1 % by the addition of adiponectin and SHBG . CONCLUSION First-trimester screening for GDM can be provided by a combination of maternal characteristics and biomarkers [11679455] OBJECTIVE To compare management based on maternal glycemic criteria with management based on relaxed glycemic criteria and fetal abdominal circumference ( AC ) measurements in order to select patients for insulin treatment of gestational diabetes mellitus ( GDM ) with fasting hyperglycemia . RESEARCH DESIGN AND METHODS In a pilot study , 98 women with fasting plasma glucose ( FPG ) concentrations of 105 - 120 mg/dl were r and omized . The st and ard group received insulin treatment . The experimental group received insulin if the AC , measured monthly , was > or = 70th percentile and /or if any venous FPG measurement was > 120 mg/dl . Power was projected to detect a 250-g difference in birth weights . RESULTS Gestational ages , maternal glycemia , and AC percentiles were similar at r and omization . After initiation of protocol , venous FPG ( P = 0.003 ) and capillary blood glucose levels ( P = 0.049 ) were significantly lower in the st and ard group . Birth weights ( 3,271 + /- 458 vs. 3,369 + /- 461 g ) , frequencies of birth weights > 90th percentile ( 6.3 vs 8.3 % ) , and neonatal morbidity ( 25 vs. 25 % ) did not differ significantly between the st and ard and experimental groups , respectively . The cesarean delivery rate was significantly lower ( 14.6 vs. 33.3 % , P = 0.03 ) in the st and ard group ; this difference was not explained by birth weights . In the experimental group , infants of women who did not receive insulin had lower birth weights than infants of mothers treated with insulin ( 3,180 + /- 425 vs. 3,482 + /- 451 g , P = 0.03 ) . CONCLUSIONS In women with GDM and fasting hyperglycemia , glucose plus fetal AC measurements identified pregnancies at low risk for macrosomia and result ed in the avoidance of insulin therapy in 38 % of patients without increasing rates of neonatal morbidity [23508404] This paper is concerned with whether mothers who are more adipose or have higher glucose levels during pregnancy may overfeed their developing infants in utero and in doing so may set them on a pathway to greater adiposity throughout their lives . If this is the case , then the more adipose daughters of these mothers may also subsequently overfeed their infants in utero , thereby perpetuating the risk of greater adiposity across generations . I begin with the historical context of how gestational diabetes was first recognized and early evidence that diabetes in pregnancy results in increased birth size and adiposity . I then consider four questions , which are the main focus of the paper . Each of the four questions involves an exposure during pregnancy and evidence concerned with whether the exposure is causally related to offspring adiposity via intra-uterine mechanisms . The four related exposures are : ( i ) pregnancy diabetes ; ( ii ) extreme maternal pregnancy obesity ( 440 kg/m or meeting criteria for bariatric surgery ) ; ( iii ) incrementally greater pre-/early pregnancy adiposity across the whole distribution seen in pregnant women ; and ( iv ) gestational weight gain . Since r and omized controlled trial evidence is not available I focus on methods that can provide the best causal evidence from observational data such as negative control studies , family comparisons and using genetic variants as instrumental variables ( i.e. Mendelian r and omization studies ) . Having addressed these four questions I go on to briefly discuss the possible role of epigenetic modification mediating any effects of maternal exposures on offspring outcomes . I conclude with a discussion about the future research and policy implication s of evidence to date in this field [2858199] OBJECTIVE Gestational diabetes mellitus ( GDM ) may cause obesity in the offspring . The objective was to assess the effect of treatment for mild GDM on the BMI of 4- to 5-year-old children . RESEARCH DESIGN AND METHODS Participants were 199 mothers who participated in a r and omized controlled trial of the treatment of mild GDM during pregnancy and their children . Trained nurses measured the height and weight of the children at preschool visits in a state-wide surveillance program in the state of South Australia . The main outcome measure was age- and sex-specific BMI Z score based on st and ards of the International Obesity Task Force . RESULTS At birth , prevalence of macrosomia ( birth weight ≥4,000 g ) was 5.3 % among the 94 children whose mothers were in the intervention group , and 21.9 % among the 105 children in the routine care control group . At 4- to 5-years-old , mean ( SD ) BMI Z score was 0.49 ( 1.20 ) in intervention children and 0.41 ( 1.40 ) among controls . The difference between treatment groups was 0.08 ( 95 % CI −0.29 to 0.44 ) , an estimate minimally changed by adjustment for maternal race , parity , age , and socio-economic index ( 0.08 [ −0.29 to 0.45 ] ) . Evaluating BMI ≥85th percentile rather than continuous BMI Z score gave similarly null results . CONCLUSIONS Although treatment of GDM substantially reduced macrosomia at birth , it did not result in a change in BMI at age 4- to 5-years-old [2188182] One hundred eight gestational diabetics were r and omized to receive either diet alone or diet plus insulin ( 20 units NPH and 10 units regular ) for glycemic control . Blood glucose levels were evaluated weekly in a high-risk clinic where medical and nutritional support and counseling were provided . Among 68 women successfully treated for a minimum of 6 weeks , the mean birth weight , macrosomia rate , and ponderal index were reduced significantly in the insulin- treated group . Insulin reduced birth weights significantly in women with a delivery weight of 200 lb or more ( 4060 ± 342 versus 3397 ± 640 g ) and in those with a delivery weight less than 200 lb ( 3324 ± 448 versus 3047 ± 394 g ) . No patient with good glucose control and a maternal delivery weight under 200 lb had a newborn over 4000 g. Patients failing glycemic control were at greatest risk ( 30 % ) for fetal overgrowth whether initially receiving insulin or not . Maternal obesity or failure to achieve glycemic control should alert the clinician to a substantially increased risk of macrosomia [20542272] OBJECTIVE To assess blood glucose control and neonatal outcomes when women with gestational diabetes mellitus ( GDM ) were treated with metformin or glyburide . METHODS When an appropriate diet was insufficient to control their blood glucose levels , women with GDM were r and omized to a glyburide or a metformin treatment group . If the maximum dose was reached , the assessed drug was replaced by insulin . The primary outcome measures analyzed were maternal glucose levels during pregnancy , birth weight , and neonatal glucose levels . RESULTS The only significant difference in outcome between the 2 treatment drugs was that maternal weight gain during pregnancy was less in the metformin ( n=40 ) than in the glyburide group ( n=32 ) ( 10.3 kg vs 7.6 kg ; P=0.02 ) . No differences were found in treatment failure , mean level of fasting or postpr and ial plasma glucose , rate of participants with glycated hemoglobin , birth weight , rate of large-for-gestational-age newborns , or newborns with hypoglycemia . CONCLUSION The treatment of GDM with metformin or glyburide was found to be equivalent for both women and newborns [16572914] OBJECTIVE To estimate the prevalence of and associated factors in gestational diabetes mellitus ( GDM ) and its seasonal variation . STUDY DESIGN A clinic-based , prospect i ve , case register study was conducted from January 1996 to December 1997 . A total of 4,942 consecutive Caucasian , pregnant women aged 15 - 46 years , free of a history of diabetes mellitus , underwent r and om plasma glucose screening and a 75-g , 2-hour oral glucose tolerance test in Plymouth , U.K. The mean ( SD ) age of the women was 28.2 ( 5.5 ) years . Women with and without GDM were compared . RESULTS The prevalence of GDM among the subjects was 1.8 % ( 95 % CI 1.4,2.2 ) . The prevalence of GDM increased with the mother 's age and r and om plasma glucose level and decreased with the duration of pregnancy . Using a stepwise binary logistic regression model , older age ( relative prevalence [ RP ] 1.08 [ 95 % CI 1.04 , 1.12 ] ) and higher r and om plasma glucose ( RP 2.99 [ 95 % CI 2.51 , 3.551 ) were significant predictors of GDM . The monthly prevalence of GDM ranged from 2.9 % ( 95 % CI 1.5 , 5.0 ) in June to 1.1 % ( 95 % CI 0.3,2.8 ) in November . The seasonal GDM rate ranged from 2.3 % ( 95 % CI 1.5 , 3.2 ) in spring to 1.4 % ( 95 % CI 0.8 , 2.3 ) in winter . The differences were not statistically significant for either the month ( p = 0.82 ) or season ( p = 0.41 ) . CONCLUSION The prevalence ( 1.8 % ) of GDM in this representative sample of Caucasian pregnant women was lower than the 3 - 5 % typically reported in other European and North American studies , and there was no seasonal pattern [7660761] Objective . To evaluate the accuracy of diagnosing gestational diabetes mellitus ( GDM ) by a 2‐h blood glucose value ≥9.0 mmol/l in the 75 g oral glucose tolerance test ( OGTT ) . The maternal and neonatal outcome in women with a 2‐h blood glucose value just below this limit , 8.0–8.9 mmol/l , is analyzed . The outcome is compared to a r and omly selected control group [15804783] Objective : To evaluate the association between obesity , glucose challenge test ( GCT ) and pregnancy outcome . Methods : A prospect i ve cohort study of 6854 consecutive gravid patients screened for gestational diabetes ( GDM ) using 50-gram GCT , at 24–28 weeks ' gestation was performed . A screening value ⩾ 130 mg/dl was followed by 100 gr oral GTT . Patients who were diagnosed with GDM were excluded . For purpose of analysis patients were categorized by prepregnancy BMI and by different GCT thresholds . Maternal outcome was defined by rate of preeclampsia , gestational age at delivery , cesarean section ( CS ) rate and the need for labor induction . Neonatal outcome was defined by fetal size ( macrosomia/LGA ) , arterial cord pH , respiratory complications and neonatal intensive care unit ( NICU ) admission . Results : Overall , a positive GCT result ( GCT ⩾ 130 mg/dl ) was identified in 2541/6854 ( 37 % ) women . GDM was further diagnosed in 464/6854 ( 6.8 % ) of subjects . In both groups of screening results ( > 130 mg/dl and < 130 mg/dl ) , the obese women were significantly older , gained more weight during pregnancy and had a lower rate of nulliparity in comparison to the non obese women . The obese women had higher rates of macrosomia , LGA and induction of labor . No difference was found in mean birth weight , the total rate of cesarean section , preterm delivery , 5 minute Apgar score ⩽ 7 , mean arterial cord pH , NICU admission and a need for respiratory support in comparison to non obese women in both groups of screening results . A gradual increase in the rate of macrosomia , LGA and cesarean section was identified in both obese and non-obese women in relation to increasing GCT severity categories . Conclusion : Fetal size and cesarean section rate are associated with the degree of carbohydrate intolerance ( screening results ) . Furthermore , obesity remains the main contributor impacting fetal size [19375570] OBJECTIVE We hypothesized that body composition would be similar among neonates of women with gestational diabetes ( GDM ) treated with glyburide or insulin . STUDY DESIGN Women with GDM requiring medical therapy were r and omized to insulin or glyburide . The primary outcome was percent neonatal fat mass measured by total body electrical conductivity . Secondary outcomes included anthropometrics , glycemic control , and biomarkers . Statistical analysis included Student t test , chi(2 ) , and regression modeling . RESULTS Eighty-two neonates underwent postnatal measurements . Baseline factors were not different by group . Neonatal percent fat mass did not differ between treatment groups ( 11.2 + /- 4.2 vs 12.8 + /- 5.7 ) . Fat mass , body mass index , ponderal index , skinfold sum , and arm fat area were not different when analyzed by intent to treat or actual treatment group . Cord concentrations of biomarkers were also similar . CONCLUSION There was no difference in neonatal adiposity in infants of women treated for GDM with glyburide or insulin [22542118] OBJECTIVE We evaluated whether improvements in pregnancy outcomes after treatment of mild gestational diabetes mellitus differed in magnitude on the basis of fetal gender . STUDY DESIGN This is a secondary analysis of a masked r and omized controlled trial of treatment for mild gestational diabetes mellitus . The results included preeclampsia or gestational hypertension , birthweight , neonatal fat mass , and composite adverse outcomes for both neonate ( preterm birth , small for gestational age , or neonatal intensive care unit admission ) and mother ( labor induction , cesarean delivery , preeclampsia , or gestational hypertension ) . After stratification according to fetal gender , the interaction of gender with treatment status was estimated for these outcomes . RESULTS Of the 469 pregnancies with male fetuses , 244 pregnancies were assigned r and omly to treatment , and 225 pregnancies were assigned r and omly to routine care . Of the 463 pregnancies with female fetuses , 233 pregnancies were assigned r and omly to treatment , and 230 pregnancies were assigned r and omly to routine care . The interaction of gender with treatment status was significant for fat mass ( P = .04 ) and birthweight percentile ( P = .02 ) . Among women who were assigned to the treatment group , male offspring were significantly more likely to have both a lower birthweight percentile ( 50.7 ± 29.2 vs 62.5 ± 30.2 percentile ; P < .0001 ) and less neonatal fat mass ( 487 ± 229.6 g vs 416.6 ± 172.8 g ; P = .0005 , ) whereas these differences were not significant among female offspring . There was no interaction between fetal gender and treatment group with regard to other outcomes . CONCLUSION The magnitude of the reduction of a newborn 's birthweight percentile and neonatal fat mass that were related to the treatment of mild gestational diabetes mellitus appears greater for male neonates [20653150] OBJECTIVE The objective of the study was to compare premixed insulin aspart 30 ( BIAsp 30 ) vs premixed human insulin 30 ( BHI 30 ) on efficacy , safety , fetal and perinatal outcomes in pregnancies associated with gestational diabetes mellitus [ GDM ] . This was the first r and omized study to use pre mixed insulin analogue [ BIAsp ] in GDM . METHODS The study population consisted of 76 GDM women assigned to BIAsp 30 ( group A ) and an equal number to BHI 30 ( group B ) . RESULTS There was no statistically significant difference between the age , BMI , gestational weeks and glycemic level at entry between the group A and group B women ( p > 0.05 ) . There was no statistical difference between the two groups in glycemic control or insulin dose ( p > 0.05 ) before confinement . The frequency of birth weight of new born above 90 percentile was 6.8 % in Group 1 and 9.2 % in Group 2 . The proportion of macrosomia was higher in Group 2 when compared to Group 1 , however the difference was not statistically significant ( P = 0.819 ) . CONCLUSION BIAsp was safe during pregnancy and pregnant women found it convenient due to meal time dosing . Fetal outcome using BIAsp was also comparable with BHI 30 [2992182] OBJECTIVE To examine the association between levels of hyperglycemia , determined by each prenatal oral glucose tolerance test ( OGTT ) value ( fasting , 1 and 2 h ) , and maternal and perinatal outcomes and to determine whether the risk for these outcomes differs for women whose value(s ) equaled or exceeded the thresholds for gestational diabetes mellitus ( GDM ) established by the International Association of Diabetes in Pregnancy Study Groups ( IADPSG ) . RESEARCH DESIGN AND METHODS This article discusses a retrospective study of 8,711 women , delivering at ≥20 weeks ' gestation , who had a prenatal 2-h 75-g OGTT without a prior 50-g challenge and were not treated with insulin , glyburide , diet , and /or exercise during pregnancy . Associations between adverse outcomes and elevated OGTT values are reported . RESULTS After excluding treated women , 19.4 % of the remaining women had IADPSG-defined GDM . Continuous fasting , 1- and 2-h OGTT measures , and GDM ( yes/no ) were significantly associated with most adverse outcomes . However , the magnitude and significance of risk for these outcomes differed by various combinations of abnormal glucose values . Women with normal fasting and elevated postload values were at higher risk for preterm delivery , gestational hypertension , and having an infant with hyperbilirubinema , whereas women with elevated fasting and normal postload values were at higher risk of having a large-for-gestational-age infant , compared with women without GDM . CONCLUSIONS Risks for different adverse outcomes vary depending on which single or combined IADPSG-defined OGTT thresholds are equaled or exceeded . Prospect i ve studies are needed to determine whether changing pre- and postpr and ial glucose targets during pregnancy will more uniformly reduce adverse outcomes [14634573] OBJECTIVE This study was performed to prospect ively evaluate a screening model for gestational diabetes mellitus on the basis of clinical risk indicators . STUDY DESIGN In a prospect i ve multicenter study with 5235 consecutive pregnant women , diagnostic testing with a 2-hour 75-g oral glucose tolerance test was routinely performed in women with risk indicators and offered to women without risk indicators as part of the study . RESULTS Forty-four percent of the women underwent testing , 43 % declined participation , 6 % did not speak Danish , and 7 % could not be contacted . By extrapolation of the results from tested women to the whole group in question , a 2.4 % prevalence of gestational diabetes mellitus was calculated . Sensitivity and specificity of the model was 80.6 ( 73.7 - 87.6 ) and 64.8 ( 63.5 - 66.1 ) , respectively ( 95 % CIs ) . CONCLUSION Under ideal conditions , sensitivity of the model was comparable with universal screening by fasting glucose or a 1-hour 50-g glucose challenge test . Both screening and diagnostic testing could be avoided in two thirds of all pregnant women [18211656] RATIONALE , AIMS AND OBJECTIVE To investigate whether the introduction of a programme of optimising drug treatment , intensive education and self-monitoring of patients diagnosed with gestational diabetes mellitus ( GDM ) at an early stage ( < 20 gestational weeks ) , will improve management outcomes as determined by objective measures of patient knowledge about diabetes , glycaemia control , maternal/neonatal complications , and health-related quality of life . METHODS The study was a r and omized , controlled , longitudinal , prospect i ve clinical trial performed at Al-Ain Hospital , Al-Ain , United Arab Emirates . Over an 18-month period , patients diagnosed with GDM were recruited and were r and omly assigned to either an intervention or a control group , in a ratio of 3:2 . Intervention patients received a structured pharmaceutical care service ( including education and introduction of intensive self-monitoring ) while control patients received traditional services . Patients were followed up from time of recruitment until 6 months postnatally at scheduled outpatient clinics . A range of clinical and humanistic outcome measures , including maternal and neonatal complications , were used to assess the impact of the intervention . RESULTS A total of 165 patients ( 99 intervention , 66 control ) completed the study . The intervention patients exhibited a range of benefits from the provision of the programme when compared with control group patients . Statistically significant ( P < 0.05 ) improvements were shown in the intervention group for knowledge of diabetes , health-related quality of life ( as determined by the SF36 ) , control of plasma glucose and HbA(1c ) , maternal complications [ e.g. decreased incidence of pre-eclampsia ( 5.1 % vs. 16.7 % ) , eclampsia ( 1.0 % vs. 7.6 % ) , episodes of severe hyperglycaemia ( 3.0 % vs. 19.7 % ) and need for Caesarean section ( 7.1 % vs. 18.2 % ) ] , and neonatal complications [ e.g. decreased incidence of neonatal hypoglycaemia ( 2.0 % vs. 10.6 % ) , respiratory distress at birth ( 4.0 % vs. 15.2 % ) , hyperbilirubinaemia ( 1.0 % vs. 12.1 % ) and large for gestational age ( 9.0 % vs. 22.7 % ) ] . CONCLUSION The research provides clear evidence that provision of pharmaceutical care adds value to the management of GDM as exemplified by improved maternal and neonatal outcomes [11194427] Summary : A r and omised controlled trial was design ed to determine the effect of moderate 30 % maternal dietary energy restriction on the requirement for maternal insulin therapy and the incidence of macrosomia in gestational diabetes . Although the control group restricted their intake to a level similar to that of the intervention group ( 6845 kiloJoules ( kJ ) versus 6579 kJ ) , the result ing cohort could not identify any adverse effect of energy restriction in pregnancy . Energy restriction did not alter the frequency of insulin therapy ( 17.5 % in the intervention group and 16.9 % in the control group ) . Mean birth weight ( 3461 g in the intervention group and 3267 g in the control group ) was not affected . There was a trend in the intervention group towards later gestational age at commencement of insulin therapy ( 33 weeks versus 31 weeks ) and lower maximum daily insulin dose ( 23 units versus 60 units ) which did not reach statistical significance . Energy restriction did not cause an increase in ketonemia [3921038] A cost analysis of glucose screening was studied prospect ively in 434 patients . All patients underwent a 50-gm oral glucose load followed by a 1-hour plasma glucose screen test at 28 weeks ( + /- 2 weeks ) . Patients with a screen test greater than or equal to 130 mg/dl plasma glucose were further tested with an oral glucose tolerance test . Also , previously described clinical risk factors for diabetes were documented on all patients . A 3.3 % prevalence of gestational diabetes was found in 178 patients with risk factors , compared with 2.4 % of 256 patients without risk factors , not a significant difference . Ten of the 12 gestational diabetics were at least 24 years old , so that screening only this subgroup would still retain a good sensitivity ( 83 % ) but at half the cost of universal screening . Screening on the basis of risk factors other than age is inefficient . Though testing only patients who are 24 years of age or older is more cost effective than universal screening , an individual decision must be made regarding its reduced sensitivity [17972060] Aims /hypothesisThe aim of this study was to investigate whether the higher prevalence of insulin resistance and glucose intolerance in urban compared with rural Indian men is related to their higher adiposity ( percentage body fat ) and the associated inflammatory state . Methods We studied 149 rural , 142 urban slum and 150 urban middle-class male residents ( age 30–50 years ) , who were selected by stratified r and om sampling . We measured body fat ( bioimpedance ) , waist circumference , glucose tolerance ( 75 g OGTT ) , insulin resistance [ homeostasis model assessment ( HOMA-IR ) ] , beta cell function ( insulinogenic index ) and inflammatory markers ( total leucocyte count , IL-6 , TNF-α and C-reactive protein ) . Results Adiposity , waist circumference , HOMA-IR , insulinogenic index and both fasting and 120 min plasma glucose concentrations increased progressively from rural through to urban slum and urban middle-class men . Inflammatory markers were higher in urban than in rural men . Adiposity was strongly related to HOMA-IR ( r = 0.57 , p < 0.001 ) and to insulinogenic index and glycaemic parameters ( r = 0.25 , p < 0.001 for both ) . Adiposity explained approximately two thirds of the difference in HOMA-IR between the urban middle-class men and the rural and slum residents , but its contribution to the difference in insulinogenic index and 120 min plasma glucose concentration was not significant . Inclusion of C-reactive protein , IL-6 and total leucocyte count in the models did not further explain these results , nor did the inclusion of waist circumference . There was a significant residual difference after these adjustments . Conclusions /interpretationAdiposity is a major contributor to the difference in insulin resistance between rural and urban Indian men ; there was no additional contribution from inflammation or central obesity . Other unmeasured factors also seem to contribute to the metabolic differences between rural and urban men [23068960] AIMS To evaluate the effect of metformin and insulin in glycemic control and compare pregnancy outcome in women with gestational diabetes mellitus ( GDM ) . METHODS This r and omized controlled trial was conducted in GDM women with singleton pregnancy and gestational age between 20 and 34 weeks who did not achieve glycemic control on diet were assigned r and omly to receive either metformin ( n=80 ) or insulin ( n=80 ) . The primary outcomes were maternal glycemic control and birth weight . The secondary outcomes were neonatal and obstetric complications . RESULTS Two groups were comparable regarding the maternal characteristics . Two groups were similar in mean FBS ( P=0.68 ) and postpr and ial measurements ( P=0.87 ) throughout GDM treatment . The neonates of metformin group had less rate of birth weight centile > 90 than insulin group ( RR : 0.5 , 95 % CI : 0.3 - 0.9 , P=0.012 ) . Maternal weight gain was reduced in the metformin group ( P<0.001 ) . Two groups were comparable according to neonatal and obstetric complications ( P>0.05 ) . In metformin group 14 % of women needed to supplemental insulin to achieve euglycemia . CONCLUSION Metformin is an effective and safe alternative treatment to insulin for women with GDM . This study does not show significant risk of maternal or neonatal adverse outcome with the use of metformin [8053871] Summary : We determined in nondiabetic women , the relationship of plasma glucose values obtained 2 hours after a 75 g oral glucose challenge test ( GCT ) at 16–20 weeks ' gestation , with the incidence of macrosomia in term deliveries ( 37–41 weeks ' gestation ) . From 1988–1990 , in a systematic screening programme data collected prospect ively from 1,331 women were analysed retrospectively . Women with gestational diabetes or impaired glucose tolerance ( n = 53 ) were excluded . The rest ( n = 1,278 ) had no evidence of glucose intolerance including 1,215 women with normal plasma glucose by GCT ( < 7.8 mmol/L 2 hours after 75 g oral glucose load ) and 63 women with abnormal GCT but no abnormal value at a glucose tolerance test . The GCT values were divided into 5 groups : Group A ( < 4.5 mmol/L ) , B ( 4.5‐5.5 mmol/L ) , C ( 5.6‐6.6 mmol/L ) , D ( 6.7‐7.7 mmol/L ) and E ( > 7.8 mmol/L ) . The variables studied were age , parity , gestational age at delivery and incidence of macrosomia [5936737] The purpose of this study was to examine pregnancy outcome in women with abnormal oral glucose tolerance tests , in relation to treatment with diet and insulin . Glucose tolerance tests , done because of well-known historical risk factors , were considered abnormal if two or more readings exceeded the following : fasting , 110 ; 1 hour , 170 ; 2 hours , 120 ; and 3 hours , 110 ( all in mg/100 mL , measured as total reducing substances in whole venous blood ) . Those with positive tests were divided r and omly into a “ positive-control ” group ( n 308 ) that received st and ard prenatal care or a “ positive-treated ” group ( n 307 ) that received dietary instructions ( 30 kcal/kg ideal body weight , 40 % as carbohydrate , and 1.5–2 g protein/kg body weight ) and insulin ( initial dose 10 U per day of intermediate-acting insulin , adjusted subsequently as directed by blood and urine studies ) , beginning at usually about 32 weeks . A third group ( n 328 ) , termed “ negative controls , ” had exhibited normal glucose tolerance testing . The three groups were similar , except that those with abnormal glucose tolerance tended to be older and heavier , as expected . With respect to outcome , infants with birth weights exceeding 9 lb were three times as frequent in positive-control subjects as in either positive-treated subjects or negative controls ( 13.1 % , 4.3 % , and 3.7 % , respectively ) . Perinatal deaths ( 28 weeks ’ gestation through 14 days after birth ) were similar in the two positive groups ( 4.9 % in control and 4.3 % in treated ) and significantly higher than in negative controls ( 1.9 % ) , with the increase involving both fetal and neonatal components . The conclusions were 1 ) abnormal glucose tolerance during pregnancy leads to larger infants and higher perinatal mortality and 2 ) treatment with diet and insulin ameliorates the former but not the latter . This study concerned what O’Sullivan called potential diabetes and others at the time termed latent or chemical diabetes or prediabetes , but what today we refer to as gestational diabetes . Acceptance of it as a pathologic entity was far from unanimous in 1966 . O’Sullivan resolved the controversy with this large , well- design ed , and well-analyzed clinical trial . The immediate influence was two-fold . In the first place , it settled the existing disagreement as to whether or not impaired glucose tolerance adversely influences pregnancy outcome ; large infants occurred three times as frequently and perinatal deaths were more than doubled in women with abnormal carbohydrate metabolism . Second , the findings of the intervention trial indicated clearly that treatment of gestational diabetes with diet and insulin in late gestation normalizes birth weight ( although it did not seem to influence perinatal mortality ) , a finding confirmed a number of times by subsequent investigators . Incidentally , the frequencies of both fetal and neonatal deaths may seem high , but it needs to be remembered that this experience ante date d the advent of modern fetal surveillance and neonatal intensive care . John B. O’Sullivan , a pioneer in clinical research in gestational diabetes , was an internist . He defined st and ards for the oral glucose tolerance test in pregnancy that , though modified slightly by subsequent investigators , are basically those in use today . Born in 1926 , he received his medical education in his native Irel and before immigrating to the United States in 1955 . After further training in internal medicine at the Lahey Clinic , he took a faculty position at the Boston University School of Medicine , where he did his original work on early diabetes as medical director of the Prenatal Metabolism Clinic at Boston City Hospital and chief of medicine at St. Margaret ’s Hospital . In addition to his position as Associate Professor at Boston University , he also served on the faculties of the Harvard and Yale medical schools . Later he was director of employee health for the Liberty Mutual Insurance Company . He died of cancer in August 2001 [10691156] Aims Gestational diabetes mellitus ( GDM ) is associated with adverse maternal and fetal outcome . Screening for GDM is therefore recommended but the best screening method remains controversial . This prospect i ve , r and omized study compared a risk factor‐based screening programme with a universally based one [1748256] Forty-one patients with gestational diabetes requiring insulin were enrolled in a r and omized study to investigate the efficacy of an exercise program in normalizing glucose tolerance . Seventeen of 21 patients completed the exercise program while maintaining normoglycemia and obviating insulin therapy . Maternal and neonatal complications did not differ between the study and control groups . The type of program described appears to be safe and can serve as a model for exercise prescription for pregnant diabetic women to attain improved glucose tolerance [15995269] OBJECTIVES Muscle-thin but adipose ( ' thin-fat ' ) body composition of south Asian adults contributes to their high risk of type 2 diabetes . Studies in Pune , India showed that this phenotype is present at birth . We aim ed to determine if south Indian babies have a ' thin-fat ' phenotype and if this persists in childhood . DESIGN Prospect i ve cohort study . SETTING Holdsworth Memorial Hospital , Mysore , India . SUBJECTS Children ( n = 663 ) whose mothers were recruited from the antenatal clinics . METHODS Weight , length , head , mid-upper-arm , abdominal circumferences ; triceps and subscapular skinfolds were measured at birth , one and four years , and compared with white Caucasian babies born in Southampton , UK ( birth ) , and UK and Dutch growth st and ards ( one and four years ) . RESULTS Mysore babies were lighter ( 2983 g vs 3472 g ; -1.10 SD , CI -1.16 , -1.02 ) and smaller in all body measurements than UK neonates ( P < 0.001 ) . The deficit was greatest for mid-upper-arm ( -1.07 SD ) , head ( -0.89 SD ) and abdominal circumferences ( -0.73 SD ) , and least for length ( -0.25 SD ) and subscapular skinfold thickness ( -0.19 SD ) . Predictors of skinfold thickness were maternal body mass index ( P < 0.001 ) and socio-economic status ( P = 0.05 ) . At four years , subscapular skinfold thickness was larger than UK ( + 0.18 SD , CI + 0.11 , + 0.25 ; P < 0.001 ) and Dutch st and ards ( + 0.61 SD , CI + 0.51 , + 0.71 ; P < 0.001 ) , despite all other body measurements remaining smaller . Predictors of 4-year skinfold thickness were neonatal skinfold thickness ( P = 0.001 ) and maternal insulin concentrations ( P = 0.05 ) . CONCLUSIONS Mysore newborns have a ' thin-fat ' phenotype . This may reflect the action of genes and /or the ' maternal environment ' . The phenotype persists in childhood , and may be the forerunner of a diabetogenic adult phenotype [10586979] Infant macrosomia is a serious medical concern . Pregnant women who do not meet the specific diagnosis for gestational diabetes may still have glucose-mediated macrosomia . In Santa Barbara County all pregnant women are screened for gestational diabetes at 24 - 28 weeks with a 50-g , 1-hr glucose challenge test ( GCT ) . All patients who fail this test are placed on a st and ard euglycemic diet ( 40 % carbohydrate , 20 % protein , 40 % fat ) and perform home glucose monitoring of fasting and postpr and ial glucose levels . The objective of this study was to examine the effectiveness of this treatment program in decreasing infant macrosomia , maternal and infant morbidity , maternal complications , and operative delivery . We studied 103 women who had a positive GCT , but a negative 100-g , 3-hr oral glucose tolerance test ( OGTT ) . The women were r and omly assigned to either experimental or control groups with experimental women receiving dietary counseling and home glucose monitoring instruction ( HBGM ) . HBGM diaries were review ed weekly by clinic nurses . All women had hemoglobin A1c ( HbA1c ) tests at 28 and 32 weeks . Maternal and fetal charts were review ed to determine delivery type and complications , indications for cesarean section ( C-section ) , and infant gestational age , gender , Apgar scores , birth weight , morbidities , and congenital anomalies . Of the 103 women , 5 women required insulin treatment , 1 woman had an abortion , and 14 women were indeterminate regarding compliance or were control women who received diet counseling and HBGM . The results are based on 83 women--48 control and 35 experimental . There were no significant differences between the groups for age , parity , or weight at 28 - 30 weeks or 37 weeks to delivery , or HbA1c at 28 weeks . HbA1c was significantly higher in control women at 32 weeks . Birth weight expressed in grams or as a percentile specific for gender , ethnicity , and gestational age was significantly higher in control infants . Birth weight was significantly correlated with maternal intake weight , weight at 28 - 30 weeks , and weight at delivery and with HbA1c at 32 weeks ' gestation . There were no significant differences between groups for maternal complications . Groups were significantly different for mode of delivery with experimental women having more induced vaginal deliveries but fewer repeat C-sections than control women . Groups were not different for primary C-sections . Women who fail the GCT , but not the OGTT and thus do not receive the diagnosis of GDM are still at risk for delivering a macrosomic infant and operative delivery . Our program of treatment for all women who fail the GCT improves outcome by reducing infant birth weight and the number of cesarean sections [1992702] This prospect i ve investigation evaluated the reproducibility of the 100 gm oral glucose tolerance test . Sixty-four obstetric patients with greater than or equal to 135 mg/dl on the 50 gm oral glucose screening test were scheduled for the 100 gm test . All patients repeated the oral glucose tolerance test in 1 to 2 weeks . Both tests included a preparatory diet , and testing conditions were identical . There were no significant differences in the mean test values at each testing interval when the entire study population was considered . Patients were then divided into four groups according to the outcome of the two tests . Forty-eight of 64 ( 75 % ) had normal results at each testing period ( group 1 ) ; 11 of 64 ( 17 % ) had initially normal results and abnormal results on retest ( group 2 ) ; 3 of 64 ( 5 % ) had initially abnormal results and normal results on retest ( group 3 ) ; 2 of 64 ( 3 % ) had abnormal results at both testing phases ( group 4 ) . There were no significant differences between oral glucose tolerance test results within groups 1 and 4 . However , significant differences occurred within groups 2 and 3 between the two tests . Group 2 patients had a greater frequency of an abnormal 1-hour value on the test than group 1 patients ( p = 0.001 ) . Overall , the reproducibility of the oral glucose tolerance test was 78 % ( 50 of 64 ) . We recommend the oral glucose tolerance test be repeated when the 1-hour value is abnormal or when the fasting blood sugar , 1-hour , and 2-hour values are near the upper end of the normal range [11036118] BACKGROUND Women with gestational diabetes mellitus are rarely treated with a sulfonylurea drug , because of concern about teratogenicity and neonatal hypoglycemia . There is little information about the efficacy of these drugs in this group of women . METHODS We studied 404 women with singleton pregnancies and gestational diabetes that required treatment . The women were r and omly assigned between 11 and 33 weeks of gestation to receive glyburide or insulin according to an intensified treatment protocol . The primary end point was achievement of the desired level of glycemic control . Secondary end points included maternal and neonatal complications . RESULTS The mean ( + /-SD ) pretreatment blood glucose concentration as measured at home for one week was 114+/-19 mg per deciliter ( 6.4+/-1.1 mmol per liter ) in the glyburide group and 116+/-22 mg per deciliter ( 6.5+/-1.2 mmol per liter ) in the insulin group ( P=0.33 ) . The mean concentrations during treatment were 105+/-16 mg per deciliter ( 5.9+/-0.9 mmol per liter ) in the glyburide group and 105+/-18 mg per deciliter ( 5.9+/-1.0 mmol per liter ) in the insulin group ( P=0.99 ) . Eight women in the glyburide group ( 4 percent ) required insulin therapy . There were no significant differences between the glyburide and insulin groups in the percentage of infants who were large for gestational age ( 12 percent and 13 percent , respectively ) ; who had macrosomia , defined as a birth weight of 4000 g or more ( 7 percent and 4 percent ) ; who had lung complications ( 8 percent and 6 percent ) ; who had hypoglycemia ( 9 percent and 6 percent ) ; who were admitted to a neonatal intensive care unit ( 6 percent and 7 percent ) ; or who had fetal anomalies ( 2 percent and 2 percent ) . The cord-serum insulin concentrations were similar in the two groups , and glyburide was not detected in the cord serum of any infant in the glyburide group . CONCLUSIONS In women with gestational diabetes , glyburide is a clinical ly effective alternative to insulin therapy [18058723] INTRODUCTION Nutrition therapy is an integral part of the management of gestational diabetes mellitus ( GDM ) . Most women with GDM are treated by nutritional management alone . The goal of our study was to compare low and high carbohydrate diets in their effectiveness , safety and tolerability in women with GDM . MATERIAL AND METHODS The study group consisted of 30 Caucasian women newly diagnosed with GDM , with a mean age of 28.7 + /- 3.7 years and pregnancy duration of 29.2 + /- 5.4 weeks . The patients were r and omised into two groups : those on a low and those on a high carbohydrate diet ( 45 % vs. 65 % respectively of energy supply coming from carbohydrates ) . The presence of urine ketones was controlled every day . After two weeks daily glucose profiles and compliance with the recommended diets were analysed . RESULTS Glucose concentration before implementation of the diet regimen did not differ between groups . No changes in fasting blood glucose were noticed in the group that had followed a low carbohydrate diet , although a significant decrease in glucose concentration was observed after breakfast ( 102 + /- 16 vs. 94 + /- 11 mg/dl ) , lunch ( 105 + /- 12 vs. 99 + /- 9 mg/dl ) and dinner ( 112 + /- 16 vs. 103 + /- 13 mg/dl ) ( p < 0.05 ) . In the high carbohydrate diet group fasting and after-breakfast glucose concentration did not change . A significant decrease in glycaemia was noticed after lunch ( 106 + /- 15 vs. 96 + /- 7 mg/dl ) and dinner ( 107 + /- 12 vs. 97 + /- 7 mg/dl ) ( p < 0.05 ) . Ketonuria was not observed in either group . Obstetrical outcomes did not differ between groups . CONCLUSIONS Both high and low carbohydrate diets are effective and safe . A diet with carbohydrate limitation should be recommended to women who experience the highest glycaemia levels after breakfast [23524173] OBJECTIVE To evaluate glycemic control in women receiving metformin or insulin for gestational diabetes , and to identify factors predicting the need for supplemental insulin in women initially treated with metformin . STUDY DESIGN Women with gestational diabetes who failed to achieve glycemic control with diet and exercise were r and omized to receive metformin ( n = 47 ) or insulin ( n = 47 ) . Criteria for inclusion were singleton pregnancy , diet , and exercise for a minimum period of 1 week without satisfactory glycemic control , absence of risk factors for lactic acidosis , and absence of anatomic and /or chromosome anomalies of the conceptus . Patients who were lost to prenatal follow-up were excluded . RESULTS Comparison of mean pretreatment glucose levels showed no significant difference between groups ( P = .790 ) . After introduction of the drug , lower mean glucose levels were observed in the metformin group ( P = .020 ) , mainly because of lower levels after dinner ( P = .042 ) . Women using metformin presented less weight gain ( P = .002 ) and a lower frequency of neonatal hypoglycemia ( P = .032 ) . Twelve women in the metformin group ( 26.08 % ) required supplemental insulin for glycemic control . Early gestational age at diagnosis ( odds ratio , 0.71 ; 95 % confidence interval , 0.52 - 0.97 ; P = .032 ) and mean pretreatment glucose level ( odds ratio , 1.061 ; 95 % confidence interval , 1.001 - 1.124 ; P = .046 ) were identified as predictors of the need for insulin . CONCLUSION Metformin was found to provide adequate glycemic control with lower mean glucose levels throughout the day , less weight gain and a lower frequency of neonatal hypoglycemia . Logistic regression analysis showed that gestational age at diagnosis and mean pretreatment glucose level were predictors of the need for supplemental insulin therapy in women initially treated with metformin [23271384] OBJECTIVE To assess the relationship between a low 50-g 1-hour glucose loading test ( GLT ) and maternal and neonatal outcomes in women without diabetes . STUDY DESIGN This was a secondary analysis of a multicenter observational cohort from a r and omized trial of treatment for mild gestational diabetes . Maternal and neonatal outcomes were compared between women with GLT values < 90 mg/dL and those with results 90 to 119 mg/dL. RESULTS Of 436 enrolled women , 297 ( 68.1 % ) had a GLT result of 90 to 119 mg/dL and 139 ( 31.9 % ) had a result of < 90 mg/dL. There was a lower incidence of neonatal hypoglycemia in those with a GLT < 90 mg/dL ( 5.7 % versus 16.5 % , p = 0.006 ) . Other outcomes were not associated with test results . CONCLUSION A GLT result < 90 mg/dL compared with 90 to 119 mg/dL is associated with a lower risk of neonatal hypoglycemia , but no other significant findings [25706240] CONTEXT Gestational diabetes ( GDM ) confers a high risk of type 2 diabetes . In the Diabetes Prevention Program ( DPP ) , intensive lifestyle ( ILS ) and metformin prevented or delayed diabetes in women with a history of GDM . OBJECTIVE The objective of the study was to evaluate the impact of ILS and metformin intervention over 10 years in women with and without a history of GDM in the DPP/Diabetes Prevention Program Outcomes Study . DESIGN This was a r and omized controlled clinical trial with an observational follow-up . SETTING The study was conducted at 27 clinical centers . PARTICIPANTS Three hundred fifty women with a history of GDM and 1416 women with previous live births but no history of GDM participated in the study . The participants had an elevated body mass index and fasting glucose and impaired glucose tolerance at study entry . INTERVENTIONS Interventions included placebo , ILS , or metformin . OUTCOMES MEASURE Outcomes measure was diabetes mellitus . RESULTS Over 10 years , women with a history of GDM assigned to placebo had a 48 % higher risk of developing diabetes compared with women without a history of GDM . In women with a history of GDM , ILS and metformin reduced progression to diabetes compared with placebo by 35 % and 40 % , respectively . Among women without a history of GDM , ILS reduced the progression to diabetes by 30 % , and metformin did not reduce the progression to diabetes . CONCLUSIONS Women with a history of GDM are at an increased risk of developing diabetes . In women with a history of GDM in the DPP/Diabetes Prevention Program Outcomes Study , both lifestyle and metformin were highly effective in reducing progression to diabetes during a 10-year follow-up period . Among women without a history of GDM , lifestyle but not metformin reduced progression to diabetes [10097921] OBJECTIVE To estimate the percentage of pregnant women who would not be screened and the percentage of women with gestational diabetes mellitus ( GDM ) who would possibly remain undiagnosed if the American Diabetes Association 's ( ADA 's ) new selective screening recommendations are used rather than universal screening for GDM . RESEARCH DESIGN AND METHODS Since 1987 , the University of Michigan Health System has performed universal screening for GDM . In 1997 , the ADA recommended that women having all four of the following characteristics need not be screened : age < 25 years , not members of an ethnic/racial group with a high prevalence of diabetes , normal body weight , and no family history of diabetes . We studied a r and om sample of the 25,118 deliveries at the University of Michigan between 1987 and 1997 to determine the prevalence of these four characteristics in our obstetric population . We also studied the prevalence of these four characteristics in 200 women who were diagnosed with GDM in the Endocrine Testing Unit and delivered at the University of Michigan between 1987 and 1997 . RESULTS Approximately 10 - 11 % of women who delivered possessed all four low-risk characteristics and would not have been screened for GDM according to the new ADA recommendations . Only 4 % of women ( 5 of 141 ) with GDM who delivered and for whom data on all four characteristics were reported possessed all four low-risk characteristics and would not have been screened . CONCLUSIONS If the new ADA selective screening recommendations are used , few women with GDM will be missed ( 4 % ) but approximately 90 % of pregnant women will still need to be screened for GDM [24646172] The benefits of exercise and behavioural recommendations in gestational diabetes mellitus ( GDM ) are controversial . In a r and omized trial with a 2 × 2 factorial design , we examined the effect of exercise and behavioural recommendations on metabolic variables , and maternal/neonatal outcomes in 200 GDM patients . All women were given the same diet : group D received dietary recommendations only ; group E was advised to briskly walk 20‐min/day ; group B received behavioural dietary recommendations ; group BE was prescribed the same as B + E. Dietary habits improved in all groups . In a multivariable regression model , fasting glucose did not change . Exercise , but not behavioural recommendations , was associated with the reduction of postpr and ial glucose ( p < 0001 ) , glycated haemoglobin ( HbA1c ; p < 0.001 ) , triglycerides ( p = 0.02 ) and C‐reactive protein ( CRP ; p < 0.001 ) and reduced any maternal/neonatal complications ( OR = 0.50 ; 95%CI=0.28–0.89;p = 0.02 ) . In GDM patients a simple exercise programme reduced maternal postpr and ial glucose , HbA1c , CRP , triglycerides and any maternal/neonatal complications , but not fasting glucose values [18300849] Objective The objective of this study was to investigate early influences of postnatal growth on blood pressure ( BP ) in healthy , British-born South Asian and European origin infants . We tested the hypotheses that South Asian infants would be smaller in all body dimensions ( length and weight ) with higher relative truncal skinfold thickness at birth , and that increased ( central ) adiposity and accelerated growth up to 1 year would be associated with higher BP in both ethnic groups . Patients and methods Five hundred and sixty infants were followed prospect ively from birth to 3 and /or 12 months with measures of anthropometry and resting BP , compared against a UK 1990 growth reference , and analysed using regression methods . Results Marked differences in birth size persisted , as expected , between European and South Asian babies , but with a sexual dichotomy : South Asian boys were smaller in all anthropometric parameters ( P < 0.001 ) , including skinfolds ( P < 0.05 ) , than European boys , but South Asian girls , although smaller in length and weight , had similar skinfolds to European girls and thus a slightly larger subscapular skinfold thickness relative to birth weight [ 1.3 versus 1.2 , mean difference 0.07 , 95 % confidence interval ( CI ) 0.0009–0.14 , P = 0.047 ] . The dichotomy persisted postnatally ; South Asian boys showed a striking early increase in weight and length compared with European boys , associated with significant accrual of subscapular fat ( 6.1 versus 5.3 mm , mean difference 0.8 , 95 % CI 0.3–1.3 , P = 0.003 ) . In gender and ethnicity adjusted regression models , infants with the largest weight st and ard deviation score ( SDS ) increases in the first 3 months had the highest 12-month systolic BP ( β = 2.4 , 95 % CI 0.5–4.2 , P = 0.01 ) , while those with the greatest birth length ( β = 0.7 , 95 % CI 0.05–1.4 , P = 0.04 ) but the smallest changes in length over 3–12 months ( β = −0.57 , 95 % CI −0.95 to −0.19 , P = 0.004 ) had the highest diastolic BP . Conclusions Ethnic and gender differences in growth and adiposity present in early infancy include truncal fat preservation in South Asian girls from birth , which in boys is related to rapid early weight gain . Weight gain during the first 3 months appears to drive the rise in systolic BP to 1 year , itself a likely driver of later BP [23718748] AIM The aim of this study was to assess the efficacy of glyburide in the treatment of gestational diabetes mellitus and to compare the maternal and fetal outcome between two groups treated either with insulin or glyburide . MATERIAL AND METHODS Women with gestational diabetes not responding to diet control were r and omized into two groups : ( i ) the control group receiving insulin ( n = 32 ) ; and ( ii ) the study group receiving glyburide ( n = 32 ) . Primary outcome was assessed in terms of achievement of glycemic control and secondary outcome was assessed by the incidence of maternal and fetal complications in the insulin and glyburide treated groups . RESULTS The achievement of glycemic control between the insulin and the glyburide treated groups showed no significant difference ( 97.1 % , 93.8 % ) . The occurrence of maternal complications ( P = 0.87 ) and fetal complications ( P = 0.32 ) were comparable between the insulin and glyburide treated groups . CONCLUSION Glyburide was found to be as efficacious as insulin in achieving euglycemia in the treatment of gestational diabetic women who require treatment beyond diet control [23046401] OBJECTIVE This study identified the impact of intensive therapy on neonatal outcomes in women with gestational diabetes mellitus ( GDM ) and determined the effects on the postpartum metabolic status of the mothers . RESEARCH DESIGN AND METHODS In total , 127 pregnant women with GDM were r and omly selected to receive an intensive treatment regimen , which included one-to-one education , lifestyle intervention , scheduled clinic visits , strict glucose control , and frequent glucose self-monitoring . Meanwhile , 148 age-matched pregnant women with GDM were selected as controls and given the st and ard treatment regimen . Pregnancy outcomes including parameters related to the GDM mothers and to their neonates were comparatively analyzed between the two treatment groups . GDM patient follow-up ( range , 1 - 3 years after delivery ) included an oral glucose tolerance test and measurements of lipid concentration and insulin secretion . The insulinogenic index ( ΔInsulin(30 min)/ΔBlood glucose(30 min ) ) and homeostasis model assessment index of β-cell function and insulin resistance were calculated . The patients ' demographic and anthropometric data were also recorded for comparative analysis . RESULTS Compared with GDM patients receiving st and ard treatment , GDM patients receiving intensive treatment had lower instances of premature delivery ( 2.4 % vs. 8.3 % , P<0.05 ) and neonatal care unit admission ( 21.3 % vs. 33.3 % , P<0.05 ) and lower neonatal birth weight ( 3.26±0.53 vs. 3.45±0.55 kg , P<0.0001 ) . At follow-up , GDM patients from the intensive treatment group had a smaller waist circumference ( 75.83±3.11 vs. 78.34±4.20 cm , P<0.01 ) , lower 30-min glucose levels after a 75-g glucose load ( 8.26±1.85 vs. 9.46±2.74 mmol/L , P<0.05 ) , and higher high-density lipoprotein levels ( 1.30±0.24 vs. 1.18±0.23 mmol/L , P<0.05 ) . CONCLUSIONS The intensive GDM treatment regimen led to healthier outcomes for the women , the neonates , and the birth event and was associated with better maternal metabolic situations in the months and years after delivery [22468861] A r and omized , open-label , parallel study was conducted to assess the efficacy and safety of premixed insulin aspart 30 ( biphasic insulin aspart [ BIAsp ] 30 ) in managing gestational diabetes mellitus ( GDM ) . A total of 323 women with GDM registered at a single center in India were r and omly assigned to receive 6 U of either BIAsp 30 ( Group A ) or premixed human insulin ( biphasic human insulin [ BHI ] 30 ; Group B ) in a 1:1 ratio . Subjects performed home glucose monitoring and visited their care provider twice a month . The primary outcome was the degree of neonatal macrosomia ( neonatal birth weight > 90th percentile ) . Groups A and B were demographically comparable at study entry . Before labor onset , Groups A and B achieved similar degrees of fasting plasma glucose and postpr and ial plasma glucose control ( 92.97 ± 14.44 vs. 95.43 ± 18.96 and 127.59 ± 28.99 vs. 126.98 ± 29.89 , respectively ; both p = NS ) . Neonatal macrosomia frequency was 6.3 % in Group A and 6.9 % in Group B ; however , this difference was not statistically significant . By last visit , the required insulin dose was significantly lower for Group A than Group B ( 19.83 ± 15.75 IU vs. 26.34 ± 23.15 IU , respectively ; p = 0.006 ) . BIAsp 30 was noninferior to BHI 30 , producing comparable fetal outcomes when administered during pregnancy . Based on final doses , BIAsp 30 may offer greater treat-to-target potential for pregnant women Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Gestational diabetes ( GDM ) affects 3 % to 6 % of all pregnancies . Women are often intensively managed with increased obstetric monitoring , dietary regulation , and insulin . However , there has been no sound evidence base to support intensive treatment . The key issue for clinicians and consumers is whether treatment of GDM improves perinatal outcome . OBJECTIVES To compare the effect of alternative treatment policies for GDM on both maternal and infant outcomes . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

27471137

[17893311] BACKGROUND To our knowledge , verum acupuncture has never been directly compared with sham acupuncture and guideline -based conventional therapy in patients with chronic low back pain . METHODS A patient- and observer-blinded r and omized controlled trial conducted in Germany involving 340 outpatient practice s , including 1162 patients aged 18 to 86 years ( mean + /- SD age , 50 + /- 15 years ) with a history of chronic low back pain for a mean of 8 years . Patients underwent ten 30-minute sessions , generally 2 sessions per week , of verum acupuncture ( n = 387 ) according to principles of traditional Chinese medicine ; sham acupuncture ( n = 387 ) consisting of superficial needling at nonacupuncture points ; or conventional therapy , a combination of drugs , physical therapy , and exercise ( n = 388 ) . Five additional sessions were offered to patients who had a partial response to treatment ( 10%-50 % reduction in pain intensity ) . Primary outcome was response after 6 months , defined as 33 % improvement or better on 3 pain-related items on the Von Korff Chronic Pain Grade Scale question naire or 12 % improvement or better on the back-specific Hanover Functional Ability Question naire . Patients who were unblinded or had recourse to other than permitted concomitant therapies during follow-up were classified as nonresponders regardless of symptom improvement . RESULTS At 6 months , response rate was 47.6 % in the verum acupuncture group , 44.2 % in the sham acupuncture group , and 27.4 % in the conventional therapy group . Differences among groups were as follows : verum vs sham , 3.4 % ( 95 % confidence interval , -3.7 % to 10.3 % ; P = .39 ) ; verum vs conventional therapy , 20.2 % ( 95 % confidence interval , 13.4 % to 26.7 % ; P < .001 ) ; and sham vs conventional therapy , 16.8 % ( 95 % confidence interval , 10.1 % to 23.4 % ; P < .001 . CONCLUSIONS Low back pain improved after acupuncture treatment for at least 6 months . Effectiveness of acupuncture , either verum or sham , was almost twice that of conventional therapy [12067088] To evaluate the efficacy of Chinese medicine ( CM ) acupuncture for chronic neck pain ( CNP ) , a single blind , controlled , crossover , clinical trial was undertaken . Twenty-nine volunteers with CNP were r and omly recruited into two groups . Both groups received two phases of treatment with a washout period between the two phases . Group A ( 14 volunteers ) received CM acupuncture in the first phase and sham acupuncture in the second , while Group B ( 15 volunteers ) received sham in the first and real in the second . CM acupuncture was individualized and consisted of nine sessions on both local and distal points . Manual twisting of the needle was applied on all points plus strong electrical stimulation of distal points in CM acupuncture . Sham acupoints ( lateral to the real ) and sham ( weak ) electrical stimulation was used in the control group . Comparison of subjective and objective measures between the two groups was made at different periods , including baseline , after each phase of treatment , after washout , and after the 16th week follow-up . The subjective measures included pain intensity , duration per day , analgesic medication count , visual analogue scales ( VAS ) and neck disability index ( NDI ) . The objective measures consisted of neck range of motion ( ROM ) and pain threshold ( PT ) . Both the real and sham treatments significantly reduced subjective pain , without significant differences between groups for most subjective measures . Objective measures showed no significant change for either group before and after each period or by inter-groups analysis . A minimum 16-week effect of both real and sham acupuncture was found for subjective measures in the follow-up periods . Further study is recommended with an increased sample size , a longer washout period , and a longer baseline period [17989918] We evaluated the efficacy of acupuncture as a useful adjuvant treatment in the management of rheumatoid arthritis ( RA ) . A pilot , r and omized , double-blind , and controlled clinical trial was conducted . Forty RA patients with active disease despite stable therapy for at least the preceding 1 month were r and omized to receive a st and ard protocol of acupuncture ( AC ) or superficial acupuncture at non-acupuncture points ( controlAC ) for 9 weeks . The primary outcome was achievement of 20 % improvement according to the American College of Rheumatology ( ACR ) 20 criteria after five and ten treatment sessions and after 1 month of follow-up . Secondary measures included Disease Assessment Scale ( DAS ) , tender and swollen joint count , morning stiffness , Health Assessment Question naire ( HAQ ) , visual analogue scale ( VAS ) of pain , physician global assessment of activity disease , physician and patient global assessment of treatment , and inflammatory markers ( erythrocyte sedimentation rate and C-reactive protein ) . There was not significant difference between the groups regarding the number of patients that reached ACR20 at the end of the treatment ( p = 0.479 ) . However , after 1 month of follow-up , there was a trend in favor of the AC group , with p = 0,068 . Compared with the controlAC , the AC group also demonstrated significant improvement in the patient and physician global assessment of treatment and physician global assessment of disease activity , but there was no difference on other clinical and laboratorial measures . On the other h and , only the AC patients had within group improvement on the variables DAS , HAQ , morning stiffness , patient and physician global assessment of treatment , and physician global assessment of disease activity in comparison to baseline visit . Despite the improvement of some studied variables , there was no significant difference in the proportion of patients that reached ACR20 between the AC and controlAC groups . This negative result can be related to the small sample size , selection of patients , type of acupuncture protocol applied , and difficulties in establishing an innocuous and trustworthy placebo group to studies involving acupuncture [18591906] Objectives To compare the effect of acupuncture ( manual and electroacupuncture ) with that of a non-penetrating sham ( ‘ placebo ’ needle ) in patients with osteoarthritic knee pain and disability who are blind to the treatment allocation . Methods Acupuncture naive patients with symptomatic and radiological evidence of osteoarthritis of the knee were r and omly allocated to a course of either acupuncture or non-penetrating sham acupuncture using a sheathed ‘ placebo ’ needle system . Acupuncture points for pain and stiffness were selected according to acupuncture theory for treating Bi syndrome . Both manual and electrical stimulation were used . Response was assessed using the WOMAC index for osteoarthritis of the knee , self reported pain scale , the EuroQol score and plasma β-endorphin . The effectiveness of blinding was assessed . Results There were 34 patients in each group . The primary end point was the change in WOMAC pain score after the course of treatment . Comparison between the two treatment groups found a significantly greater improvement with acupuncture ( mean difference 60 , 95 % CI 5 to 116 , P=0.035 ) than with sham . Within the acupuncture group there was a significant improvement in pain ( baseline 294 , mean change 95 , 95 % CI 60 to 130 , P<0.001 ) which was not seen by those who had sham acupuncture ( baseline 261 , mean change 35 , 95 % CI-10 to 80 , P=0.12 ) . Similar effects within group , but not between groups , were seen with the secondary end points of WOMAC stiffness , WOMAC function , and self reported pain . One month after treatment the between group pain difference had been lost ( mean difference 46 ; 95 % CI −9 to 100 , P=0.10 ) although the acupuncture group was still benefiting compared to baseline ( mean difference 59 ; 95 % CI 16 to 102 , P=0.009 ) . The EuroQol score , a generic measure of health related quality of life , was not altered by the treatments . A minority of patients correctly guessed their treatment group ( 41 % in the acupuncture group and 44 % in the control group ) . Plasma β-endorphin levels were not affected by either treatment . Conclusions Acupuncture gives symptomatic improvement for patients with osteoarthritis of the knee , and is significantly superior to non-penetrating sham acupuncture . The study did not confirm earlier reports of release of plasma β-endorphin during acupuncture [19766392] ABSTRACT Neurobiological mechanisms invoking the release of endogenous opioids and depression of stress hormone release are believed to be the basis of acupuncture analgesia . This study compared plasma β‐endorphin and cortisol levels with self assessment scores of intensity of pain , before and after 10 days of electro‐acupuncture treatment in patients suffering from chronic pain as a result of osteoarthritis knees . Forty patients of either sex over 40 years with primary osteoarthritis knee were recruited into a single‐blinded , sham‐controlled study . For electro‐acupuncture group the points were selected according to the Traditional Chinese Medicine Meridian Theory . In the sham group needles were inserted at r and om points away from true acupoints and no current was passed . Both groups were treated for 10 days with one session every day lasting for 20–25 min . Pre‐ and post‐treatment Western Ontario and McMaster Universities ( WOMAC ) index of osteoarthritis knee and Visual Analogue Scale ( VAS ) for pain were recorded and blood sample s were taken for the measurement of plasma cortisol and β‐endorphin levels . Following electro‐acupuncture treatment there was a significant improvement in WOMAC index and VAS ( p = 0.001 ) , a significant rise in plasma β‐endorphin ( p = 0.001 ) , and a significant fall in plasma cortisol ( p = 0.016 ) . In conclusion electro‐acupuncture result ed in an improvement in pain , stiffness and disability . Of clinical importance is that an improvement in objective measures of pain and stress/pain associated biomarkers was shown above that of a sham treatment ; hence demonstrating acupuncture associated physiological changes beyond that of the placebo effects [20580303] Clinicians cl aim that myofascial trigger points ( MTrPs ) are a primary cause of pain in whiplash injured patients . Pain from MTrPs is often treated by needling , with or without injection . We conducted a placebo controlled study to test the feasibility of a phase III r and omised controlled trial investigating the efficacy of MTrP needling in patients with whiplash associated pain . Forty-one patients referred for physiotherapy with a recent whiplash injury , were recruited . Patients were r and omised to receive st and ardised physiotherapy plus either acupuncture or a sham needle control . A trial was judged feasible if : i ) the majority of eligible patients were willing to participate ; ii ) the majority of patients had MTrPs ; iii ) at least 75 % of patients provided completed self- assessment data ; iv ) no serious adverse events were reported and v ) the end of treatment attrition rate was less than 20 % . 70 % of those patients eligible to participate volunteered to do so ; all participants had clinical ly identified MTrPs ; a 100 % completion rate was achieved for recorded self- assessment data ; no serious adverse events were reported as a result of either intervention ; and the end of treatment attrition rate was 17 % . A phase III study is both feasible and clinical ly relevant . This study is currently being planned [16005336] BACKGROUND Acupuncture is widely used by patients with chronic pain although there is little evidence of its effectiveness . We investigated the efficacy of acupuncture compared with minimal acupuncture and with no acupuncture in patients with osteoarthritis of the knee . METHODS Patients with chronic osteoarthritis of the knee ( Kellgren grade < or = 2 ) were r and omly assigned to acupuncture ( n=150 ) , minimal acupuncture ( superficial needling at non-acupuncture points ; n=76 ) , or a waiting list control ( n=74 ) . Specialised physicians , in 28 outpatient centres , administered acupuncture and minimal acupuncture in 12 sessions over 8 weeks . Patients completed st and ard question naires at baseline and after 8 weeks , 26 weeks , and 52 weeks . The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis ( WOMAC ) index at the end of week 8 ( adjusted for baseline score ) . All main analyses were by intention to treat . RESULTS 294 patients were enrolled from March 6 , 2002 , to January 17 , 2003 ; eight patients were lost to follow-up after r and omisation , but were included in the final analysis . The mean baseline-adjusted WOMAC index at week 8 was 26.9 ( SE 1.4 ) in the acupuncture group , 35.8 ( 1.9 ) in the minimal acupuncture group , and 49.6 ( 2.0 ) in the waiting list group ( treatment difference acupuncture vs minimal acupuncture -8.8 , [ 95 % CI -13.5 to -4.2 ] , p=0.0002 ; acupuncture vs waiting list -22.7 [ -27.5 to -17.9 ] , p<0.0001 ) . After 52 weeks the difference between the acupuncture and minimal acupuncture groups was no longer significant ( p=0.08 ) . INTERPRETATION After 8 weeks of treatment , pain and joint function are improved more with acupuncture than with minimal acupuncture or no acupuncture in patients with osteoarthritis of the knee . However , this benefit decreases over time [9758075] OBJECTIVE This article examines the specific and nonspecific effects of Japanese acupuncture on chronic myofascial neck pain in a r and omized single-blind trial . DESIGN Forty-six patients were r and omly assigned to receive relevant acupuncture , irrelevant acupuncture , or no-acupuncture control treatment consisting of nonsteroidal anti-inflammatory medication . The two acupuncture groups underwent comparable light shallow needling . The irrelevant acupuncture group received acupuncture at specific sites not relevant for cervical pain . OUTCOME MEASURES The study measures included the McGill Pain Question naire-Short Form ( SF-MPQ ) , the Short-Form Health Survey ( SF-36 ) , the Symptom Checklist 90-Revised ( SCL-90-R ) , medication diary , and physiologic measures . The factors examined as predictors of outcome pain ratings were experience with , beliefs about , and knowledge of acupuncture before treatment ; perceived efficacy , credibility , and logic of acupuncture ; perceived competence of the acupuncturist ; and painfulness of acupuncture . RESULTS No differences were found among the three groups at baseline , except that the relevant acupuncture group reported having had more previous acupuncture treatments . No significant differences in terms of perceived credibility or perceived effectiveness of treatment were found between the two acupuncture groups . The relevant acupuncture group had significantly greater pre-/posttreatment differences in pain than the irrelevant acupuncture and control groups ( p < .05 ) . The nonspecific effects of confidence in the acupuncturist , willingness to try any treatment , mood , and physiologic effect of needling were not predictive of treatment outcome , whereas confidence in the treatment and past experiences with acupuncture did correlate significantly with a decrease in pain . CONCLUSIONS Relevant acupuncture with heat contributes to modest pain reduction in persons with myofascial neck pain . Previous experience with and confidence in treatment help to predict benefit . Measurement of nonspecific effects of alternative therapy is recommended in future clinical trials [20655660] & NA ; The German R and omized Acupuncture Trial for chronic shoulder pain ( GRASP ) comprised 424 out patients with chronic shoulder pain ( CSP ) ≥6 weeks and an average pain score of VAS ≥50 mm , who were r and omly assigned to receive Chinese acupuncture ( verum ) , sham acupuncture ( sham ) or conventional conservative orthopaedic treatment ( COT ) . The patients were blinded to the type of acupuncture and treated by 31 office‐based orthopaedists trained in acupuncture ; all received 15 treatments over 6 weeks . The 50 % responder rate for pain was measured on a VAS 3 months after the end of treatment ( primary endpoint ) and directly after the end of the treatment ( secondary endpoint ) . Results : In the ITT ( n = 424 ) analysis , percentages of responders for the primary endpoint were verum 65 % ( 95 % CI 56–74 % ) ( n = 100 ) , sham 24 % ( 95 % CI 9–39 % ) ( n = 32 ) , and COT 37 % ( 95 % CI 24–50 % ) ( n = 50 ) ; secondary endpoint : verum 68 % ( 95 % CI 58–77 % ) ( n = 92 ) , sham 40 % ( 95 % CI 27–53 % ) ( n = 53 ) , and COT 28 % ( 95 % CI 14–42 % ) ( n = 38 ) . The results are significant for verum over sham and verum over COT ( p < 0.01 ) for both the primary and secondary endpoints . The PPP analysis of the primary ( n = 308 ) and secondary endpoints ( n = 360 ) yields similar responder results for verum over sham and verum over COT ( p < 0.01 ) . Descriptive statistics showed greater improvement of shoulder mobility ( abduction and arm‐above‐head test ) for the verum group versus the control group immediately after treatment and after 3 months . The trial indicates that Chinese acupuncture is an effective alternative to conventional orthopaedic treatment for CSP [7818567] OBJECTIVE To determine the prevalence and characteristics of fibromyalgia in the general population . METHODS A r and om sample of 3,006 persons in Wichita , KS , were characterized according to the presence of no pain , non-widespread pain , and widespread pain . A sub sample of 391 persons , including 193 with widespread pain , were examined and interviewed in detail . RESULTS The prevalence of fibromyalgia was 2.0 % ( 95 % confidence interval [ 95 % CI ] 1.4 , 2.7 ) for both sexes , 3.4 % ( 95 % CI 2.3 , 4.6 ) for women , and 0.5 % ( 95 % CI 0.0 , 1.0 ) for men . The prevalence of the syndrome increased with age , with highest values attained between 60 and 79 years ( > 7.0 % in women ) . Demographic , psychological , dolorimetry , and symptom factors were associated with fibromyalgia . CONCLUSION Fibromyalgia is common in the population , and occurs often in older persons . Characteristic features of fibromyalgia -- pain threshold and symptoms -- are similar in community and clinic population s , but overall severity , pain , and functional disability are more severe in the clinic population [16505266] BACKGROUND Acupuncture is widely used by patients with low back pain , although its effectiveness is unclear . We investigated the efficacy of acupuncture compared with minimal acupuncture and with no acupuncture in patients with chronic low back pain . METHODS Patients were r and omized to treatment with acupuncture , minimal acupuncture ( superficial needling at nonacupuncture points ) , or a waiting list control . Acupuncture and minimal acupuncture were administered by specialized acupuncture physicians in 30 outpatient centers , and consisted of 12 sessions per patient over 8 weeks . Patients completed st and ardized question naires at baseline and at 8 , 26 , and 52 weeks after r and omization . The primary outcome variable was the change in low back pain intensity from baseline to the end of week 8 , as determined on a visual analog scale ( range , 0 - 100 mm ) . RESULTS A total of 298 patients ( 67.8 % female ; mean + /- SD age , 59 + /- 9 years ) were included . Between baseline and week 8 , pain intensity decreased by a mean + /- SD of 28.7 + /- 30.3 mm in the acupuncture group , 23.6 + /- 31.0 mm in the minimal acupuncture group , and 6.9 + /- 22.0 mm in the waiting list group . The difference for the acupuncture vs minimal acupuncture group was 5.1 mm ( 95 % confidence interval , -3.7 to 13.9 mm ; P = .26 ) , and the difference for the acupuncture vs waiting list group was 21.7 mm ( 95 % confidence interval , 13.9 - 30.0 mm ; P<.001 ) . Also , at 26 ( P=.96 ) and 52 ( P=.61 ) weeks , pain did not differ significantly between the acupuncture and the minimal acupuncture groups . CONCLUSION Acupuncture was more effective in improving pain than no acupuncture treatment in patients with chronic low back pain , whereas there were no significant differences between acupuncture and minimal acupuncture [16770975] OBJECTIVE To test the hypothesis that acupuncture improves symptoms of fibromyalgia . PATIENTS AND METHODS We conducted a prospect i ve , partially blinded , controlled , r and omized clinical trial of patients receiving true acupuncture compared with a control group of patients who received simulated acupuncture . All patients met American College of Rheumatology criteria for fibromyalgia and had tried conservative symptomatic treatments other than acupuncture . We measured symptoms with the Fibromyalgia Impact Question naire ( FIQ ) and the Multidimensional Pain Inventory at baseline , immediately after treatment , and at 1 month and 7 months after treatment . The trial was conducted from May 28 , 2002 , to August 18 , 2003 . RESULTS Fifty patients participated in the study : 25 in the acupuncture group and 25 in the control group . Total fibromyalgia symptoms , as measured by the FIQ , were significantly improved in the acupuncture group compared with the control group during the study period ( P = .01 ) . The largest difference in mean FIQ total scores was observed at 1 month ( 42.2 vs 34.8 in the control and acupuncture groups , respectively ; P = .007 ) . Fatigue and anxiety were the most significantly improved symptoms during the follow-up period . However , activity and physical function levels did not change . Acupuncture was well tolerated , with minimal adverse effects . CONCLUSION This study paradigm allows for controlled and blinded clinical trials of acupuncture . We found that acupuncture significantly improved symptoms of fibromyalgia . Symptomatic improvement was not restricted to pain relief and was most significant for fatigue and anxiety [19480864] OBJECTIVE To investigate the remote effect of acupuncture on the pain intensity and the endplate noise ( EPN ) recorded from a myofascial trigger point ( MTrP ) of the upper trapezius muscle . DESIGN R and omized controlled trial . SETTING University hospital . PARTICIPANTS Patients ( N=20 ) with active MTrPs in upper trapezius muscles and no experience in acupuncture therapy . INTERVENTIONS Patients were divided into 2 groups . Those in the control group received sham acupuncture , and those in the acupuncture group received modified acupuncture therapy with needle insertion into multiple loci to elicit local twitch responses . The acupuncture points of Wai-guan and Qu-chi were treated . MAIN OUTCOME MEASURES Subjective pain intensity ( numerical pain rating scale ) and mean EPN amplitude in the MTrP of the upper trapezius muscle . RESULTS The pain intensity in the MTrP was significantly reduced after remote acupuncture ( from 7.4+/-0.8 to 3.3+/-1.1 ; P<.001 ) , but not after sham acupuncture ( from 7.4+/-0.8 to 7.1+/-0.9 ; P>.05 ) . The mean EPN amplitude was significantly lower than the pretreatment level after acupuncture treatment ( from 21.3+/-9.5 microV to 9.5+/-3.5 microV ; P<.01 ) , but not after sham acupuncture treatment ( from 19.6+/-7.6 microV to 19.3+/-7.8 microV ; P>.05 ) . The change in the pain intensity was significantly correlated with the change of EPN amplitude ( r=0.685 ) . CONCLUSIONS Both subjective changes in the pain intensity and objective changes of the EPN amplitude in the MTrP region of the upper trapezius muscle were found during and after acupuncture treatment at the remote ipsilateral acupuncture points . This study may further clarify the physiological basis of the remote effectiveness of acupuncture therapy for pain control [9656906] In patients with myofascial pain , painful trigger points are often treated using dry needling and local anesthetic injections . However , the therapeutic effect of these treatments has been poorly quantified , and the mechanism underlying the effect is poorly understood . In a r and omized , double-blind , double-placebo clinical trial , a pressure algometer was used to measure pain-pressure thresholds in the masseter and temporalis muscles of 30 subjects aged 23 to 53 years with myofascial pain in the jaws , before and after a series of dry needling treatments , local anesthetic injections , and simulated dry needling and local anesthetic treatments ( treatment group A : Procaine + simulated dry needling ; treatment group B : dry needling + simulated local anesthetic ; control group C : simulated local anesthetic + simulated dry needling ) . Subjects rated pain intensity and unpleasantness using visual analogue scales , and the data were analyzed using analysis of variance . Pain pressure thresholds increased slightly after treatment , irrespective of the treatment modality . Pain intensity and unpleasantness scores decreased significantly at the end of treatment in all groups . There were no statistically significant between-group differences in pain pressure thresholds and visual analogue scale scores at the end of treatment . The findings suggest that the general improvement in pain symptoms was the result of nonspecific , placebo-related factors rather than a true treatment effect . Thus , the therapeutic value of dry needling and Procaine in the management of myofascial pain in the jaw muscles is question able [11932074] & NA ; There is some evidence for the efficacy of acupuncture in chronic low‐back pain ( LBP ) , but it remains unclear whether acupuncture is superior to placebo . In a r and omized , blinded , placebo‐controlled trial , we evaluated the effect of traditional acupuncture in chronic LBP . A total of 131 consecutive out‐ patients of the Department of Orthopaedics , University Goettingen , Germany , ( age=48.1 years , 58.5 % female , duration of pain : 9.6 years ) with non‐radiating LBP for at least 6 months and a normal neurological examination were r and omized to one of three groups over 12 weeks . Each group received active physiotherapy over 12 weeks . The control group ( n=46 ) received no further treatment , the acupuncture group ( n=40 ) received 20 sessions of traditional acupuncture and the sham‐acupuncture group ( n=45 ) 20 sessions of minimal acupuncture . Changes from baseline to the end of treatment and to 9‐month follow‐up were assessed in pain intensity and in pain disability , and secondary in psychological distress and in spine flexion , compared by intervention groups . Acupuncture was superior to the control condition ( physiotherapy ) regarding pain intensity ( P=0.000 ) , pain disability ( P=0.000 ) , and psychological distress ( P=0.020 ) at the end of treatment . Compared to sham‐acupuncture , acupuncture reduced psychological distress ( P=0.040 ) only . At 9‐month follow‐up , the superiority of acupuncture compared to the control condition became less and acupuncture was not different to sham‐acupuncture . We found a significant improvement by traditional acupuncture in chronic LBP compared to routine care ( physiotherapy ) but not compared to sham‐acupuncture . The trial demonstrated a placebo effect of traditional acupuncture in chronic LBP [19433697] BACKGROUND Acupuncture is a popular complementary and alternative treatment for chronic back pain . Recent European trials suggest similar short-term benefits from real and sham acupuncture needling . This trial addresses the importance of needle placement and skin penetration in eliciting acupuncture effects for patients with chronic low back pain . METHODS A total of 638 adults with chronic mechanical low back pain were r and omized to individualized acupuncture , st and ardized acupuncture , simulated acupuncture , or usual care . Ten treatments were provided over 7 weeks by experienced acupuncturists . The primary outcomes were back-related dysfunction ( Rol and -Morris Disability Question naire score ; range , 0 - 23 ) and symptom bothersomeness ( 0 - 10 scale ) . Outcomes were assessed at baseline and after 8 , 26 , and 52 weeks . RESULTS At 8 weeks , mean dysfunction scores for the individualized , st and ardized , and simulated acupuncture groups improved by 4.4 , 4.5 , and 4.4 points , respectively , compared with 2.1 points for those receiving usual care ( P < .001 ) . Participants receiving real or simulated acupuncture were more likely than those receiving usual care to experience clinical ly meaningful improvements on the dysfunction scale ( 60 % vs 39 % ; P < .001 ) . Symptoms improved by 1.6 to 1.9 points in the treatment groups compared with 0.7 points in the usual care group ( P < .001 ) . After 1 year , participants in the treatment groups were more likely than those receiving usual care to experience clinical ly meaningful improvements in dysfunction ( 59 % to 65 % vs 50 % , respectively ; P = .02 ) but not in symptoms ( P > .05 ) . CONCLUSIONS Although acupuncture was found effective for chronic low back pain , tailoring needling sites to each patient and penetration of the skin appear to be unimportant in eliciting therapeutic benefits . These findings raise questions about acupuncture 's purported mechanisms of action . It remains unclear whether acupuncture or our simulated method of acupuncture provide physiologically important stimulation or represent placebo or nonspecific effects [2174514] Background In planning a r and omized controlled trial of acupuncture , we conducted a pilot study using vali date d outcome measures to assess the feasibility of the protocol , and to obtain preliminary data on efficacy and tolerability of 3 different forms of acupuncture treatment as an adjunct for the treatment of chronic pain in patients with Rheumatoid arthritis ( RA ) . Methods The study employs a r and omized , prospect i ve , double-blind , placebo-controlled trial to evaluate the effect of electroacupuncture ( EA ) , traditional Chinese acupuncture ( TCA ) and sham acupuncture ( Sham ) in patients with RA . All patients received 20 sessions over a period of 10 weeks . Six acupuncture points were chosen . Primary outcome is the changes in the pain score . Secondary outcomes included the changes in the ACR core disease measures , DAS 28 score and the number of patients who achieved ACR 20 at week 10 . Results From 80 eligible patients , 36 patients with mean age of 58 ± 10 years and disease duration of 9.3 ± 6.4 years were recruited . Twelve patients were r and omized to each group . Twelve , 10 and 7 patients from the EA , TCA and Sham group respectively completed the study at 20 weeks ( p < 0.03 ) ; all except one of the premature dropouts were due to lack of efficacy . At week 10 , the pain score remained unchanged in all 3 groups . The number of tender joints was significantly reduced for the EA and TCA groups . Physician 's global score was significantly reduced for the EA group and patient 's global score was significantly reduced for the TCA group . All the outcomes except patient 's global score remained unchanged in the Sham group . Conclusion This pilot study has allowed a number of recommendations to be made to facilitate the design of a large-scale trial , which in turn will help to clarify the existing evidence base on acupuncture for RA.Trial registration Clinical Trials.gov [20178876] OBJECTIVES To examine Australian acupuncturists ' perspectives of : chronic low back pain outcome domains ; their use of outcome measures to assess chronic low back pain ; and their attitudes and perceptions of barriers to using the existing measures to evaluate acupuncture care for chronic low back pain . DESIGN A postal question naire was used in a cross-sectional survey . PARTICIPANTS 359 r and omly selected Australian acupuncturists . RESULTS 139 question naires were returned ( response rate : 38.7 % ) . The respondents ' demographic characteristics were similar to Australian Bureau of Statistics acupuncturist demographic data . Overall , acupuncturists endorsed a broad approach to assessing acupuncture care for chronic low back pain . However , they had typically used pain severity measures but generally did not use other types of measures . Acupuncturists tended to hold positive attitudes towards using outcome measures . The principal barriers acupuncturists perceived to using outcome measures concerned doubts about whether the concepts which underpin acupuncture practice had been explicitly articulated and whether the available measures capture the specific context and particular outcomes of acupuncture care for chronic low back pain . IMPLICATION S The findings of this study suggest that a broad range of outcome measures are required to adequately assess chronic low back pain acupuncture care outcomes . While numerous outcome measures have been developed that are relevant to chronic low back pain care , whether these measures are appropriate for use by acupuncturists is unclear . Further studies are warranted to explore if established outcome measures are useful to evaluate chronic low back acupuncture care [11829164] Acupuncture is increasingly used , so it is important to establish whether its benefits outweigh its risks . Numerous case reports of adverse events show that acupuncture is not free of risk , but accurate data from prospect i ve investigations is scarce . A prospect i ve survey was undertaken using intensive event monitoring . Forms were developed for reporting minor events each month and significant events as they occurred . The sample size was calculated to identify any adverse events that occurred more frequently than once in 10,000 consultations . Acupuncturists were recruited from two professional organisations in the UK . Seventy-eight acupuncturists , all doctors or physiotherapists , reported a total of 2178 events occurring in 31,822 consultations , an incidence of 684 per 10,000 consultations . The most common minor adverse events were bleeding , needling pain , and aggravation of symptoms ; aggravation was followed by resolution of symptoms in 70 % of cases . There were 43 significant minor adverse events reported , a rate of 14 per 10,000 , of which 13 ( 30 % ) interfered with daily activities . One patient suffered a seizure ( probably reflex anoxic ) during acupuncture , but no adverse event was classified as serious . Avoidable events included forgotten patients , needles left in patients , cellulitis and moxa burns . In conclusion , the incidence of adverse events following acupuncture performed by doctors and physiotherapists can be classified as minimal ; some avoidable events do occur . Acupuncture seems , in skilled h and s , one of the safer forms of medical intervention [17908569] OBJECTIVE To determine the efficacy of acupuncture in the treatment of chronic musculoskeletal shoulder pain in subjects with spinal cord injury ( SCI ) . DESIGN R and omized , double blind ( participants , evaluator ) , placebo ( invasive sham ) controlled trial . SETTING Clinical research center . PARTICIPANTS Seventeen manual wheelchair-using subjects with chronic SCI and chronic musculoskeletal shoulder pain . INTERVENTIONS Participants were r and omly assigned to receive 10 treatments of either acupuncture or invasive sham acupuncture ( light needling of nonacupuncture points ) . MAIN OUTCOME MEASURE Changes in shoulder pain intensity were measured using the Wheelchair User 's Shoulder Pain Index . RESULTS Shoulder pain decreased significantly over time in both the acupuncture and the sham acupuncture groups ( P=.005 ) , with decreases of 66 % and 43 % , respectively . There was no significant difference between the 2 groups ( P=.364 ) . There was , however , a medium effect size associated with the acupuncture treatment . CONCLUSIONS There appears to be an analgesic effect or a powerful placebo effect associated with both acupuncture and sham acupuncture . There was a medium treatment effect associated with the acupuncture , which suggests that it may be superior to sham acupuncture . This observation , along with the limited power , indicates that a larger , more definitive r and omized controlled trial using a similar design is warranted [20466596] UNLABELLED The equivalency of behavioral interventions has led to the consideration of whether patient-related factors influence clinical trial outcomes . The primary purpose of this secondary analysis was to determine if treatment preference and patient expectation were predictors of trial outcomes and if selected patient-satisfaction items were appropriate as outcome measures . Perceived effectiveness , treatment preference , and patient expectation were assessed before r and om assignment , and patient satisfaction was assessed 6 months later . Patient preference was associated with perceived effectiveness for those with no treatment preference and those preferring grade d exposure . Higher patient expectation was associated with higher perceived effectiveness ratings for all treatments in the clinical trial . Patients with no strong treatment preferences had larger 6-month improvements in pain intensity and disability , while patients with higher expectations had lower disability at baseline , 4 weeks , and 6 months . Patient satisfaction rates did not differ based on treatment received . Patient satisfaction was highest with treatment delivery and much lower with treatment effect . Patient satisfaction was uniformly associated with expectations being met , but only satisfaction with treatment effect was associated with lower pain and disability scores . These data support assessment of treatment preference and patient expectation as predictors and patient satisfaction as an outcome measure in low back pain ( LBP ) clinical trials . PERSPECTIVE These data indicate treatment preference potentially impacts rate of improvement for patients with low back pain . Patient expectation did not impact rate of improvement , but those with higher expectations had lower pain and disability scores throughout the trial . Optimal assessment of patient satisfaction should include items that separately consider treatment delivery and effect [15103431] The cerebral activation pattern due to acupuncture is not completely understood . Although the effect of acupuncture on cerebral haemodynamics has been studied , no previous report has focused on different puncture and stimulation methods . We used functional MRI ( fMRI ) in 15 healthy subjects to investigate cortical activation during stimulation of two real acupoints ( Liv3 and G40 ) and one sham point , needled in a r and om and , for the subjects , blinded order employing rotating and non-rotating methods , using a blocked paradigm on a 1.5 tesla imager . Compared to the non-rotating stimulation method , during rotating stimulation of the real acupoints , we observed an increase in activation in both secondary somatosensory cortical areas , frontal areas , the right side of the thalamus and the left side of the cerebellum ; no such effects of the needling technique were seen while stimulating the sham point . The observation that rotating the needle strengthened the effects of acupuncture only at real acupoints suggests that , as cl aim ed in Chinese traditional medicine , stimulation of these acupoints has a specific effect on cortical neuronal activity , absent with sham acupoints . These specific cerebral activation patterns might explain the therapeutic effects of acupuncture in certain subjects [24316509] Objective To assess the efficacy of Yamamoto 's acupuncture method on pain , drug intake , functional capacity and quality of life for the treatment of acute non-specific low back pain ( ANLBP ) . Methods A prospect i ve , r and omised , parallel-group , double-blind , placebo-controlled trial was performed in 80 men and women with ANLBP who were r and omly assigned to five acupuncture sessions ( intervention group ( IG ) , n=40 ) and to five non-penetrating acupuncture sessions ( sham group ( SG ) , n=40 ) . Patients were evaluated at baseline and at 3 , 7 , 14 , 21 and 28 days . The measurements used were : visual analogue scale ( VAS ) for cumulative pain ( before intervention , VAS1 ) and immediate pain ( after intervention , VAS2 ) ; function ( Rol and –Morris Disability Question naire ( RM ) ) ; quality of life ( SF-36 ) ; improvement rating ; and number of anti-inflammatory tablets taken . The primary endpoint was a decrease of at least 2 cm in VAS1 . Results Pain VAS improved significantly in the IG from day 14 onwards compared with the SG , but the difference did not reach the prespecified clinical ly relevant value of 2 cm . The IG was significantly superior to the SG in the following outcomes : cumulative pain , function , pain ( SF-36 ) and vitality ( SF-36 ) at days 14 , 21 and 28 ( p<0.05 ) ; limitation in physical aspects ( SF-36 ) at all times ( p=0.007 and p=0.02 ) ; and functional capacity ( SF-36 ) at days 21 and 28 ( p<0.05 ) . The IG also took significantly fewer anti-inflammatory tablets than the SG ( p=0.004 ) at all evaluation times and the improvement rating was better than the SG ( p<0.001 ) . Conclusions Yamamoto 's new scalp acupuncture was more effective than sham treatment with regard to decrease in pain and anti-inflammatory intake as well as improving functional status and quality of life for patients with ANLBP . Clinical Trials.gov NCT 01124955 [7727550] OBJECTIVE The purpose of this study was to determine whether acupuncture was more effective than sham acupuncture in the reduction of pain in persons with osteoarthritis ( OA ) of the knee . METHODS Forty subjects ( 20 men , 20 women ) with radiographic evidence of OA of the knee were stratified by gender and r and omly assigned to either the experimental ( real acupuncture ) or control ( sham acupuncture ) groups . Subjects were treated three times per week for 3 weeks and evaluated at three test sessions . Outcome measures were : 1 ) the Pain Rating Index of the McGill Pain Question naire , 2 ) the Western Ontario and McMaster Universities ( WOMAC ) Osteoarthritis Index , and 3 ) pain threshold at four sites at the knee . RESULTS The analyses of variance showed that both real and sham acupuncture significantly reduced pain , stiffness , and physical disability in the OA knee , but that there were no significant differences between groups . CONCLUSIONS Acupuncture is not more effective than sham acupuncture in the treatment of OA pain [1097921] Forty patients , r and omly assigned to an experimental and a control group , participated in a double-blind study to assess the effectiveness of acupuncture in reducing chronic pain associated with osteoarthritis . The experimental group received treatment at st and ard acupuncture points , and the control group at placebo points . Analysis before and after treatment showed a significant ( P less than 0.05 ) improvement in tenderness and subjective report of pain in both groups as evaluated by two independent observers and in activity by one observer . Comparison of responses to treatment between the two groups showed no significant ( P greater than 0.05 ) difference . Thus , both experimental and control groups showed a reduction in pain after the treatments . These results may reflect the natural course of illness , and various attitudinal and social factors [18534326] OBJECTIVE A pilot study to assess the feasibility of a trial to investigate the efficacy of acupuncture compared to placebo needling for the treatment of acute low back pain ( LBP ) . As part of this , the study was design ed to establish the credibility of the placebo control , and to provide data to inform a power analysis to determine numbers for a future trial . STUDY DESIGN A pilot patient and assessor blinded r and omized controlled trial . SETTING Primary care health centre facility , South and East Belfast Trust , Northern Irel and . PATIENTS Patients from the physiotherapy waiting list ( n=48 ) with LBP of less than 12 weeks duration . OUTCOME MEASURES Rol and and Morris Disability Question naire ( RMDQ ) , Visual Analogue Scale ( VAS ) , medication use and an exit question naire were completed at baseline , end of treatment , and at 3 months follow up . RESULTS Ninety-four percent ( 45/48 ) of patients completed assigned treatment , 83 % ( 40/48 ) completed 3 months follow-up . The sham needle used here proved to be credible : 91.7 % in the placebo group believed they had received acupuncture , compared to 95.8 % in the verum acupuncture group . Differences in baseline characteristics were accounted for using ANCOVA . There was no significant difference between groups on the RMDQ over time . For pain , the only statistically significant difference was at the 3 months follow up ( worst VAS , point estimate , 18.7 , 95 % CI 1.5 - 36.0 , p=0.034 ) . The majority of patients were taking some form of analgesic medication for LBP at the start of treatment ( n=44 ; 92 % ) , and at the end of treatment the verum acupuncture group were taking significantly fewer tablets of pain control medication ( mean ( S.D. ) : 1.0+/-0.3 ) than the placebo group ( mean ( S.D. ) : 4.2+/-0.6 , p<0.05 ) . Based upon these data , power analysis ( power=90 % , alpha=0.05 , minimal clinical ly important difference ( MCID ) for RMDQ=2.5 points ) indicated that 120 participants ( 60 per group ) would be needed to complete an adequately powered r and omized controlled trial . CONCLUSIONS This study has demonstrated the feasibility of a r and omized controlled trial of penetrating needle acupuncture compared to a non-penetrating sham for the treatment of acute LBP in primary care ; 120 participants would be required in a fully powered trial . The placebo needle used in this study proved to be a credible form of control [20578644] The aim of this study was to compare the efficacy of electroacupuncture and sham acupuncture in the treatment of patients with chronic neck pain . 31 patients with chronic neck pain were included in a r and omised , controlled trial . Electric stimulation was given for 30 minutes at low frequency ( 1 - 4Hz ) , pulse width of 200 micros , interrupted wave form . Of the 29 patients who completed the therapy , 13 were assigned to conventional acupuncture and 16 to sham acupuncture groups , receiving 3 sessions a week for a total of 10 sessions , each lasting for 30 minutes . Patients were evaluated before and after therapy and 3 months later by Visual Analogue Scale ( VAS ) and the bodily pain subscale of the Short Form Health Survey-36 scale . The treating physician was different from the evaluating physician who , like the patient , was blinded . VAS scores in both groups significantly reduced after therapy and at 3 months post-therapy , but the difference between groups was not significant . In respect of bodily pain , there was a significant improvement in the acupuncture group after therapy ( P<0.01 ) . Stimulation of conventional acupuncture points was not generally superior to needling ofnonspecific points on the neck , and both treatments were associated with improvement of symptoms . Needles inserted into the neck are likely to be an inappropriate sham control for acupuncture [23138883] The objective of this study was to test the hypothesis that dry needling is more effective than sham dry needling in the treatment of myofascial pain syndrome ( MPS ) . This was a prospect i ve , double-blinded , r and omized-controlled study conducted in an outpatient clinic . Thirty-nine subjects with established myofascial trigger points were r and omized into two groups : study group ( N = 22 ) and placebo group ( N = 17 ) . Dry needling was applied using acupuncture needles , and sham dry needling was applied in the placebo group . The treatment was composed of six sessions which were performed in 4 weeks ; the first four sessions were performed twice a week ( for 2 weeks ) and the last two , once a week ( for 2 weeks ) . The visual analog scale ( VAS ) and Short Form-36 ( SF-36 ) were used . When compared with the initial values , VAS scores of the dry needling group following the first and sixth sessions were significantly lower ( p = 0.000 and p < 0.000 , respectively ) . When VAS scores were compared between the groups , the first assessment scores were found to be similar , but the second and third assessment scores were found to be significantly lower in the dry needling group ( p = 0.034 and p < 0.001 , respectively ) . When SF-36 scores of the groups were compared , both the physical and mental component scores were found to be significantly increased in the dry needling group , whereas only those of vitality scores were found to be increased significantly in the placebo ( sham needling ) group . The present study shows that the dry needling treatment is effective in relieving the pain and in improving the quality of life of patients with MPS [15157691] & NA ; The study was carried out to examine whether acupuncture treatment can reduce chronic pain in the neck and shoulders and related headache , and also to examine whether possible effects are long‐lasting . Therefore , 24 female office workers ( 47±9 years old , mean±SD ) who had had neck and shoulder pain for 12±9 years were r and omly assigned to a test group ( TG ) or a control group ( CG ) . Acupuncture was applied 10 times during 3–4 weeks either at presumed anti‐pain acupoints ( TG ) or at placebo‐points ( CG ) . A physician measured the pain threshold ( PPT ) in the neck and shoulder regions with algometry before the first treatment , and after the last one and six months after the treatments . Question naires on muscle pain and headache were answered at the same occasions and again 3 years after the last treatment . The intensity and frequency of pain fell more for TG than for CG ( Pb≤0.04 ) during the treatment period . Three years after the treatments TG still reported less pain than before the treatments ( Pw<0.001 ) , contrary to what CG did ( Pb<0.04 ) . The degree of headache fell during the treatment period for both groups , but more for TG than for CG ( Pb=0.02 ) . Three years after the treatments the effect still lasted for TG ( Pw<0.001 ) while the degree of headache for CG was back to the pre‐treatment level ( Pb<0.001 ) . PPT of some muscles rose during the treatments for TG and remained higher 6 months after the treatments ( Pw<0.05 ) , which contrasts the situation for CG . Adequate acupuncture treatment may reduce chronic pain in the neck and shoulders and related headache . The effect lasted for 3 years [23220812] BACKGROUND AND OBJECTIVES To test the hypothesis that dry needling is more effective than sham dry needling in relieving myofascial pain of the temporom and ibular muscles . MATERIAL AND METHOD Fifty-two subjects with established myofascial trigger points were r and omized into two groups ; study group ( N : 26 ) and placebo group ( N : 26 ) . Dry needling was applied using acupuncture needles . Sham dry needling was applied to the placebo group . Pain pressure threshold was measured with pressure algometry , pain intensity was rated using a 10-cm visual analog scale ( VAS ) and the unassisted jaw opening without pain measurement was performed . Evaluations were done by a physician blinded to the data . RESULTS Of 52 patients assigned , 50 completed the study . Mean algometric values were significantly higher in the study group when compared to the placebo group ( p values being less than 0.05 ) . There were no differences between the two groups in terms of VAS and unassisted jaw-opening without pain values . CONCLUSION Dry needling appears to be an effective treatment method in relieving the pain and tenderness of myofascial trigger points [15998750] Context A substantial number of patients use acupuncture to treat the symptoms of fibromyalgia , but previous r and omized trials of this intervention are inconclusive , in part because of control groups that did not permit adequate blinding of the patients . Contribution This study r and omly assigned 100 patients with fibromyalgia to 12 weeks of either true acupuncture treatment or one of 3 types of sham acupuncture . No differences in pain were identified between acupuncture and sham acupuncture . Caution s The study had too few patients to detect small differences between the groups . Patients could use other fibromyalgia therapies , so this study evaluates acupuncture as adjunctive treatment . The Editors Fibromyalgia is a condition of unknown cause that is characterized by chronic , diffuse pain and tenderness to palpation at specific musculoskeletal sites ( 1 ) . It is the second most common rheumatologic condition after osteoarthritis , afflicting 2 % to 4 % of the U.S. population ( 2 ) . Most r and omized , controlled trials of allopathic interventions have not demonstrated sustained benefit , and use of complementary and alternative medicine for fibromyalgia is common ( 3 ) . For example , 60 % to 90 % of patients with fibromyalgia report using 1 or more complementary or alternative treatments ( 4 , 5 ) , and 22 % of these patients have tried acupuncture ( 6 ) . Despite skepticism in western cultures , the literature suggests that acupuncture may alleviate chronic pain ( 7 ) . R and omized , controlled trials of acupuncture face many method ologic challenges , including the identification of appropriate treatment and control groups , blinding of study participants , and the inability to blind practitioners ( 8) . Needle placement and the extent to which needle insertion and stimulation is necessary are also controversial ( 7 - 9 ) . In the only rigorous r and omized , controlled trial of acupuncture for fibromyalgia , 7 of 8 outcome measures significantly improved after 3 weeks of treatment with electroacupuncture ( 10 ) . However , because blinding was not assessed and electroacupuncture involves perceptible current , these promising results could reflect a lack of blinding to treatment condition . Moreover , the study followed patients only during treatment . Because fibromyalgia is a chronic condition , longer-term outcomes should be examined . To address these method ologic problems , we performed a r and omized , controlled trial of acupuncture to treat fibromyalgia that included 3 sham acupuncture treatments to account for the effects of needle insertion and placement . The adequacy of participant blinding was carefully evaluated . We sought to determine whether directed acupuncture that is design ed to treat fibromyalgia relieves pain better than does sham acupuncture in adults with fibromyalgia . On the basis of the scant literature and our clinical experience , we hypothesized a priori that directed acupuncture would result in the greatest clinical improvement . Methods Participants Participants were recruited from the greater Seattle , Washington , metropolitan area between January 2001 and September 2002 . Recruitment strategies included dissemination of information on the study through newspapers , television , advertisements , signs posted at university-affiliated hospitals , and letters to local fibromyalgia support groups and health care providers with large caseloads of patients with fibromyalgia . Potential participants were told that they had an equal chance of being assigned to 1 of 4 acupuncture interventions , none of which have been proven but 1 of which was believed to have the most potential to improve the symptoms of fibromyalgia . The institutional review boards at the participating institutions approved the study , and participants provided written informed consent . Eligible participants were English-speaking adults 18 years of age or older in whom fibromyalgia was diagnosed by a physician and who had a prer and omization global pain score of 4 or greater on a visual analogue scale ( 0 = no pain , 10 = worst pain ever ) . Participants agreed to undergo r and omization and kept use of any fibromyalgia-related pharmacologic and nonpharmacologic therapies constant throughout the study . At the baseline evaluation before r and omization , a research coordinator trained in tender-point examination confirmed the diagnosis of fibromyalgia by using the 1990 criteria of the American College of Rheumatology ( 1 ) . Participants were excluded if they reported other pain-related medical conditions or potential contraindications to acupuncture treatment ( such as bleeding disorders or severe needle phobia ) , were pregnant or breastfeeding , used narcotics ( which could blunt the effects of acupuncture ) , were involved in litigation related to fibromyalgia ( which might reduce their incentive for improvement ) , or had previously received acupuncture ( to maximize blinding ) . R and omization Procedure A research coordinator screened and enrolled participants at an academic research center . After participants completed a baseline evaluation , another research coordinator who was uninvolved with data collection r and omly assigned them to 1 of 4 treatment groups by using a computer-generated , blocked r and om-allocation sequence with a block size of 4 . This research coordinator informed the acupuncture clinic of the treatment assignment . Intervention Eight U.S.-trained and licensed acupuncturists with a median of 10 years of experience ( range , 4 to 18 years ) provided study treatments in their private offices . One investigator trained the acupuncturists in the study procedures to increase their comfort with delivering all 4 treatments and monitored compliance with the protocol throughout the study . Participants were assigned an acupuncturist according to geographic convenience and schedule availability , and every effort was made to have them treated by the same acupuncturist for the entire 12 weeks . The primary acupuncturist was defined as the practitioner from whom a participant received the most treatments . In all groups , participants were asked to attend treatment sessions twice weekly for 12 weeks ( 24 treatments ) . We considered participants who attended 80 % or more ( 19 of 24 ) of acupuncture appointments to have completed a full course of treatment . Outcome measures were collected at regularly scheduled time points from participants who discontinued treatment . Participants received directed acupuncture design ed to treat fibromyalgia according to the practice of Traditional Chinese Medicine or 1 of 3 sham acupuncture treatments . One sham intervention , a control for acupoint specificity , involved acupuncture typically used to treat irregular menses or early menses due to Blood Heat ( an unrelated condition ) according to Traditional Chinese Medicine . Another sham intervention , which was also a control for acupoint specificity , used body locations not recognized as true acupoints or meridians for needling ( sham needling ) . The third sham treatment , a control for needle insertion , consisted of noninsertive simulated acupuncture at the same acupoints used in directed acupuncture ( simulated acupuncture ) . This technique , in which a toothpick in a needle guide-tube is used to mimic needle insertion and withdrawal , has been shown to be indistinguishable from true acupuncture in acupuncture-nave patients with back pain ( 9 ) . Simulated acupuncture more closely duplicates the needle insertion experience than do techniques using placebo needles that require placing adhesive or plastic foam on the skin ( 11 , 12 ) . Acupoints and sham points ( Appendix Figure ) were chosen by a study acupuncturist with 15 years of experience in treating fibromyalgia and were approved by 3 other senior acupuncturists . In all groups that underwent needle insertion , needles were retained at st and ard depths ( 13 ) for 30 minutes at each acupoint . Disposable Chinese , Japanese , or Korean needles ( 34 to 40 gauge ) were used , depending on the practitioner 's preference . In the simulated acupuncture group , participants remained on the table for 30 minutes after simulated insertion and then underwent simulated needle withdrawal . Efforts were made to imitate the sounds of opening needle packs and needle disposal . Acupuncturists were not blinded to the treatments they delivered . To maximize participant blinding , we included only acupuncture-nave persons who could not compare their treatment with previous experiences with acupuncture , limited contact among study participants , restricted conversation between acupuncturists and participants , and blindfolded participants during treatment . All research personnel who collected or analyzed data were unaware of treatment group . At the end of 12 weeks , we collected data to assess the adequacy of blinding . Outcome Measures Demographic measures collected at the baseline evaluation included age , sex , race , education , marital status , and duration of pain and diagnosis of fibromyalgia . Participants also listed the types of therapies they had previously tried for their pain . We grouped this information into manual therapies ( physical , ergonometric , chiropractic , or massage therapy ) , mental health therapies ( psychotherapy or cognitive behavioral therapy ) , dietary changes , or other therapies ( nerve blocks , hypnosis , or biofeedback ) . Outcome measures were collected at baseline ; after 1 , 4 , 8 , and 12 weeks of acupuncture treatment ; and 3 and 6 months after completion of treatment ( weeks 24 and 36 ) . The primary outcome was subjective pain , as measured by a st and ard 10-cm visual analogue scale ( 0 = no pain , 10 = worst pain ever ) . Other outcomes measured by using a visual analogue scale were intensity of fatigue ( 0 = none , 10 = worst ever ) , sleep quality ( 0 = worst ever , 10 = best ever ) , and overall well-being ( 0 = worst ever , 10 = best ever ) . We assessed physical and mental functioning by using the Medical Outcomes Study 36-item Short-Form Health Survey ( 14 ) , which has high reliability and validity in many patient groups , including [16618043] Introduction There is some evidence for the efficacy of acupuncture , but it remains unclear whether trigger point acupuncture is effective . Our objective was to evaluate the effects of trigger point acupuncture on pain and quality of life in chronic low back pain patients compared with sham acupuncture . Methods Twenty-six consecutive out- patients ( 17 women , 9 men ; age range : 65–91 years ) from the Department of Orthopaedic Surgery , Meiji University of Oriental Medicine , with non-radiating low back pain for at least six months and normal neurological examination , were r and omised to two groups . Each group received one phase of trigger point acupuncture and one of sham acupuncture with a three week washout period between them , over 12 weeks . Group A ( n=13 ) received trigger point acupuncture in the first phase and sham acupuncture in the second . Group B ( n=13 ) received the same interventions in the reverse order . Outcome measures were pain intensity ( visual analogue scale , VAS ) and Rol and Morris Question naire . Results Nineteen patients were included in the analysis . At the end of the first treatment phase , group A receiving trigger point acupuncture scored significantly lower VAS ( P<0.001 ) and Rol and Morris Question naire scores ( P<0.01 ) than the sham control group . There were significant within-group reductions in pain in both groups during the trigger point acupuncture phase but not in the sham treatment phase . However , the beneficial effects were not sustained . Conclusion These results suggest that trigger point acupuncture may have greater short term effects on low back pain in elderly patients than sham acupuncture [21195294] OBJECTIVES This study aim ed to determine whether a non-penetrating sham needle can serve as an adequate sham control . DESIGN We conducted a r and omised , subject-blind , sham-controlled trial in both acupuncture-naïve and experienced healthy volunteers . SETTING AND INTERVENTIONS Participants were r and omly allocated to receive either real acupuncture ( n=39 ) or non-penetrating sham acupuncture ( n=40 ) on the h and ( LI4 ) , abdomen ( CV12 ) and leg ( ST36 ) . The procedures were st and ardised and identical for both groups . MAIN OUTCOME MEASURES Participants rated acupuncture sensations on a 10-point scale . A blinding index was calculated based on the participants ' guesses on the type of acupuncture they had received ( real , sham or do not know ) for each acupuncture point . The association of knowledge about and experience in acupuncture with correct guessing was also examined . RESULTS The subjects in both groups were similar with respect to age , gender , experience or knowledge about acupuncture . The sham needle tended to produce less penetration , pain and soreness only at LI4 . Blinding appeared to be successfully achieved for ST36 . Although 41 % of participants in the real acupuncture group made correct guesses for LI4 , 31 % guessed incorrectly for CV12 , beyond chance level . People with more experience and knowledge about acupuncture were more likely to correctly guess the type of needle they received at ST36 only , compared to that at the other points . CONCLUSIONS A non-penetrating sham needle may successfully blind participants and thus , may be a credible sham control . However , the small sample size , the different needle sensations , and the degree and direction of unblinding across acupuncture points warrant further studies in Korea as well as other countries to confirm our finding . Our results also justify the incorporation of formal testing of the use of sham controls in clinical trials of acupuncture [22727499] Summary Acupuncture is a useful and safe adjunctive therapy to pharmacological treatment in the short term management of knee osteoarthritis . Abstract The efficacy of acupuncture as an adjunctive therapy to pharmacological treatment of chronic pain due to knee osteoarthritis was studied with a 3‐armed , single‐blind , r and omized , sham‐controlled trial ; it compared acupuncture combined with pharmacological treatment , sham acupuncture including pharmacological treatment , and pharmacological treatment alone . A total of 120 patients with knee osteoarthritis were r and omly allocated to 3 groups : group I was treated with acupuncture and etoricoxib , group II with sham acupuncture and etoricoxib , and group III with etoricoxib . The primary efficacy variable was the Western Ontario and McMaster Universities ( WOMAC ) index and its subscales at the end of treatment at week 8 . Secondary efficacy variables included the WOMAC index at the end of weeks 4 and 12 , a visual analogue scale ( VAS ) at the end of weeks 4 , 8 , and 12 , and the Short Form 36 version 2 ( SF‐36v2 ) health survey at the end of week 8 . An algometer was used to determine changes in a predetermined unique fixed trigger point for every patient at the end of weeks 4 , 8 , and 12 . Group I exhibited statistically significant improvements in primary and secondary outcome measures , except for Short Form mental component , compared with the other treatment groups . We conclude that acupuncture with etoricoxib is more effective than sham acupuncture with etoricoxib , or etoricoxib alone for the treatment of knee osteoarthritis [19404189] Tsai C-T , Hsieh L-F , Kuan T-S , Kao MJ , Chou L-W , Hong C-Z : Remote effects of dry needling on the irritability of the myofascial trigger point in the upper trapezius muscle . Objective : To investigate the remote effect of dry needling on the irritability of a myofascial trigger point in the upper trapezius muscle . Design : Thirty-five patients with active myofascial trigger points in upper trapezius muscles were r and omly divided into two groups : 18 patients in the control group received sham needling , and 17 patients in the dry-needling group received dry needling into the myofascial trigger point in the extensor carpi radialis longus muscle . The subjective pain intensity , pressure pain threshold , and range of motion of the neck were assessed before and immediately after the treatment . Results : Immediately after dry needling in the experimental group , the mean pain intensity was significantly reduced , but the mean pressure threshold and the mean range of motion of cervical spine were significantly increased . There were significantly larger changes in all three parameters of measurement in the dry-needling group than that in the control group . Conclusions : This study demonstrated the remote effectiveness of dry needling . Dry needling of a distal myofascial trigger point can provide a remote effect to reduce the irritability of a proximal myofascial trigger point [17257756] Abstract In a pooled analysis of four r and omized controlled trials of acupuncture in patients with migraine , tension‐type headache , chronic low back pain , and osteoarthritis of the knee we investigated the influence of expectations on clinical outcome . The 864 patients included in the analysis received either 12 sessions of acupuncture or minimal ( i.e. sham ) acupuncture ( superficial needling of non‐acupuncture points ) over an 8 week period . Patients were asked at baseline whether they considered acupuncture to be an effective therapy in general and what they personally expected from the treatment . After three acupuncture sessions patients were asked how confident they were that they would benefit from the treatment strategy they were receiving . Patients were classified as responders if the respective main outcome measure improved by at least fifty percent . Both univariate and multivariate analyses adjusted for potential confounders ( such as condition , intervention group , age , sex , duration of complaints , etc . ) consistently showed a significant influence of attitudes and expectations on outcome . After completion of treatment , the odds ratio for response between patients considering acupuncture an effective or highly effective therapy and patients who were more sceptical was 1.67 ( 95 % confidence interval 1.20–2.32 ) . For personal expectations and confidence after the third session , odds ratios were 2.03 ( 1.26–3.26 ) and 2.35 ( 1.68–3.30 ) , respectively . Results from the 6‐month follow‐up were similar . In conclusion , in our trials a significant association was shown between better improvement and higher outcome expectations [17013356] Background The purpose of this study was to examine the immediate effect of single acupuncture stimulation to the most painful point in patients with low back pain . Method A r and omised , evaluator-blinded , sham controlled clinical trial was conducted in which 31 patients with low back pain were r and omly allocated to either an acupuncture group ( n=15 ) or a sham acupuncture group ( n=16 ) . Both acupuncture and sham acupuncture were performed at the most painful point on the lower back of the subjects . For the acupuncture group , a stainless steel needle was inserted to a depth of 20 mm and manually stimulated ( sparrow pecking method ) for 20 seconds , while for the sham treatment a guide tube without a needle was placed at the point and tapped on the skin . Changes in low back pain were evaluated with a visual analogue scale ( VAS ) and the Schober test . Participants were also asked if they felt the needling sensation or not . The therapy and the evaluation were independently performed by two different acupuncturists . Results VAS score and the Schober test score showed significant improvement after treatment as compared with the sham group ( P=0.02 , 0.001 , respectively ) . There were no significant differences in the needling sensation between the acupuncture and sham group . Conclusion These results suggest that acupuncture at the most painful point gives immediate relief of low back pain [16131290] OBJECTIVES The objective of this study was to investigate whether typical acupuncture methods such as needle placement , needle stimulation , and treatment frequency were important factors in fibromyalgia symptom improvement . DESIGN / SETTING S/SUBJECTS : A single-site , single-blind , r and omized trial of 114 participants diagnosed with fibromyalgia for at least 1 year was performed . INTERVENTION Participants were r and omized to one of four treatment groups : ( 1 ) T/S needles placed in traditional sites with manual needle stimulation ( n = 29 ) : ( 2 ) T/0 traditional needle location without stimulation ( n = 30 ) ; ( 3 ) N/S needles inserted in nontraditional locations that were not thought to be acupuncture sites , with stimulation ( n = 28 ) ; and ( 4 ) N/0 nontraditional needle location without stimulation ( n = 2 7 ) . All groups received treatment once weekly , followed by twice weekly , and finally three times weekly , for a total of 18 treatments . Each increase in frequency was separated by a 2-week washout period . OUTCOME MEASURES Pain was assessed by a numerical rating scale , fatigue by the Multi-dimensional Fatigue Inventory , and physical function by the Short Form-36 . RESULTS Overall pain improvement was noted with 25%-35 % of subjects having a clinical ly significant decrease in pain ; however this was not dependent upon " correct " needle stimulation ( t = 1.03 ; p = 0.307 ) or location ( t = 0.76 ; p = 0.450 ) . An overall dose effect of treatment was observed , with three sessions weekly providing more analgesia than sessions once weekly ( t = 2.10 ; p = 0.039 ) . Among treatment responders , improvements in pain , fatigue , and physical function were highly codependent ( all p < or = 0.002 ) . CONCLUSIONS Although needle insertion led to analgesia and improvement in other somatic symptoms , correct needle location and stimulation were not crucial [20980765] Background and Objective : A recent Cochrane review on placebo interventions for all kinds of conditions found that ‘ physical placebos ’ ( which included sham acupuncture ) were associated with larger effects over no-treatment control groups than ‘ pharmacological placebos ’ . We re-analyzed the data from this review to investigate whether effects associated with sham acupuncture differed from those of other ‘ physical placebos ’ . Methods : All trials included in the Cochrane review as investigating ‘ physical placebos ’ were classified as investigating either ( sham ) acupuncture or other physical placebos . The latter group was further subclassified into groups of similar interventions . Data from the Cochrane review were re-entered into the RevMan 5 software for meta- analysis . The primary analysis was a r and om-effects analysis of trials reporting continuous outcomes of trials that used either sham acupuncture or other physical placebos . Results : Out of a total of 61 trials which reported a continuous outcome measure , 19 compared sham acupuncture and 42 compared other physical placebos with a notreatment control group . The trials re-analyzed were highly heterogeneous regarding patients , interventions and outcomes measured . The pooled st and ardized mean difference was –0.41 ( 95 % confidence interval –0.56 , –0.24 ) between sham acupuncture and no treatment and –0.26 ( 95 % CI –0.37 , –0.15 ) between other physical placebos and no treatment ( p value for subgroup differences = 0.007 ) . Significant differences were also observed between subgroups of other physical placebos . Conclusion : Due to the heterogeneity of the trials included and the indirect comparison our results must be interpreted with caution . Still , they suggest that sham acupuncture interventions might , on average , be associated with larger effects than pharmacological and other physical placebos [22770838] Summary Each of the acupuncture modalities ( true , sham , and placebo ) associated with conventional treatment achieved a clinical improvement after 3 weeks that was greater than that achieved by conventional treatment alone in patients with acute low back pain , although there were no significant differences among the different forms of stimulus . Abstract Review s of the efficacy of acupuncture as a treatment for acute low back pain have concluded that there is insufficient evidence for its efficacy and that more research is needed to evaluate it . A multicentre r and omized controlled trial was conducted at 4 primary ‐care centres in Spain to evaluate the effects of acupuncture in patients with acute nonspecific low back pain in the context of primary care . A total of 275 patients with nonspecific acute low back pain ( diagnosed by their general practitioner ) were recruited and assigned r and omly to 4 different groups : conventional treatment either alone or complemented by 5 sessions over a 2‐week period of true acupuncture , sham acupuncture , or placebo acupuncture per patient . Patients were treated from February 2006 to January 2008 . The primary outcome was the reduction in Rol and Morris Disability Question naire scores of 35 % or more after 2 weeks ’ treatment . The patients in the 3 types of acupuncture groups were blinded to the treatments , but those who received conventional treatment alone were not . In the analysis adjusted for the total sample ( true acupuncture relative risk 5.04 , 95 % confidence interval 2.24–11.32 ; sham acupuncture relative risk 5.02 , 95 % confidence interval 2.26–11.16 ; placebo acupuncture relative risk 2.57 95 % confidence interval 1.21–5.46 ) , as well as for the sub sample of occupationally active patients , all 3 modalities of acupuncture were better than conventional treatment alone , but there was no difference among the 3 acupuncture modalities , which implies that true acupuncture is not better than sham or placebo acupuncture [11532841] Recent reports have highlighted the importance of having good evidence on the safety of acupuncture . 1 2 Sound evidence on the risks associated with acupuncture is , however , scarce.3 Our primary aim , therefore , was to describe the type and frequency of adverse events after acupuncture . A secondary aim was to examine mild transient reactions associated with acupuncture , some of which may indicate a positive response to treatment . The study involved a prospect i ve postal audit of treatments undertaken during a four week period in 2000 . All 1848 professional acupuncturists who were members of the British Acupuncture Council and were practising in the United Kingdom were invited to record details of adverse events and mild transient reactions after treatment . St and ardised self report forms were used . Participating practitioners also provided information on themselves , including age , sex , length of training , and years of practice . To have a [12594972] OBJECTIVES To compare the effects of real acupuncture to tender points for neck and shoulder pain and stiffness ( Japanese : katakori ) with those of sham acupuncture . DESIGN R and omized-controlled trial . METHODS Thirty-four volunteers from an acupuncture school with complaints of chronic pain and stiffness , who had no arm symptoms and gave informed consent , were r and omly allocated to acupuncture or sham groups . Acupuncture or sham acupuncture was applied to the tender points once a week for 3 weeks . In the acupuncture group the acupuncture needle was inserted to the muscle , then the sparrow pecking technique was applied five times . Sham acupuncture was done without insertion of the needle . Dull pain and stiffness were evaluated by visual analog scale ( VAS ) before , and every 2 days after the first needling for 1 month . Pressure pain threshold on the tender points was measured before and after each treatment . RESULTS There was no statistical difference of VAS scores between acupuncture and sham groups 9 days after the last treatment . However , the acupuncture group showed significant reduction of VAS scores immediately after and /or 1 day after the real acupuncture treatments ( P<0.01 ) . The effect tended to be prolonged after repeated treatment . Pressure pain thresholds tended to increase after real acupuncture treatment but not after sham acupuncture . CONCLUSIONS Acupuncture applied to tender points appears to have short-term effects on neck and shoulder pain and stiffness , but this study was unable to demonstrate any long-term superiority over sham acupuncture [18356795] Background There is evidence for the efficacy of acupuncture treatment in knee osteoarthritis , but it remains unclear which acupuncture modes are most effective . We evaluated the effects of trigger point acupuncture on pain and quality of life in knee osteoarthritis patients , compared with acupuncture at st and ard points , and sham acupuncture . Methods Thirty patients ( 27 women , 3 men ; aged 61–82 years ) with non-radiating knee osteoarthritis pain for at least six months and normal neurological examination were r and omised to one of three groups for the study period of 21 weeks . Each group received five acupuncture treatment sessions . The st and ard acupuncture point group ( n=10 ) received treatment at traditional acupuncture points for knee pain ; the trigger point acupuncture group ( n=10 ) received treatment at trigger points ; and the third group ( n=10 ) received sham acupuncture treatment at the trigger points . Outcome measures were pain intensity ( visual analogue scale , VAS ) and WOMAC index ( Western Ontario and McMaster Universities Arthritis Index ) . The groups were compared by the area under the curve method . Results Five patients dropped out of the study because of lack of improvement , and one patient ( in the trigger point acupuncture group ) dropped out because of deterioration of symptoms ; the remaining 24 patients were included in the analysis . After treatment , the trigger point acupuncture group reported less pain intensity on VAS than the st and ard acupuncture or sham treatment group , but both the trigger point acupuncture and st and ard acupuncture groups reported improvement of function of knee . There was a significant reduction in pain intensity between pre-treatment and five weeks after treatment for the trigger point acupuncture ( P<0.01 ) and st and ard acupuncture groups ( P<0.01 ) included in the analysis , but not for the sham treatment group . Group comparison using the area under the curves demonstrated a significant difference only between trigger point acupuncture and sham treatment groups analysed ( P<0.025 for VAS , and P<0.031 for WOMAC ) . Conclusion These results suggest that trigger point acupuncture therapy may be more effective for osteoarthritis of the knee in some elderly patients than st and ard acupuncture therapy [19454879] Objectives Owing to a lack of a suitable needle procedure , it has been impossible to evaluate the efficacy of acupuncture in clinical studies using double-blind testing . We evaluated the applicability of a new kind of press needle ( Pyonex ) to a double-blind trial by comparing the press needle with a placebo ( lacking the needle element ) . Methods The purpose of the study consisted of 2 phases . In the phase 1 , to evaluate the applicability and efficacy of the press needles , 90 participants who had never been treated using acupuncture were r and omly assigned to receive either the press needle ( n=45 ) or a placebo ( n=45 ) . The applicability was measured using a question naire regarding the perception of penetration , and efficacy was measured using a visual analog scale of low back pain ( LBP ) . When the applicability and efficacy of the press needles were confirmed in phase 1 , the mechanism of LBP relief by the press needles was examined in phase 2 . Results In phase 1 , intergroup comparisons showed no significant differences concerning the perception of penetration . In addition , for patients with LBP , the press needles reduced the subjective evaluation of LBP compared with the placebo ( P<0.05 ) . In phase 2 , visual analog scale results indicated that LBP was reduced significantly more in the press needle group than in the local anesthesia group ( P<0.05 ) . Discussion The participants could not distinguish between the press needle and a placebo , and the data from the press needle group suggested a specific influence on patients with LBP . These findings imply that the press needle and a placebo provide an effective means of realizing a double-blind setting for clinical studies of acupuncture [18630538] OBJECTIVE To scientifically assess effectiveness and safety of mono-use fu-needle . METHODS Sixty cases of periarthritis of shoulder were r and omly divided into a fu-needle group and a routine acupuncture group . The fu-needle group were treated with fu-needle , and the routine acupuncture group were treated with a needle of 0.38 mm in diameter and 40 mm in length . The articular mobility of the most limited direction , soft tissue pain self-rating score and self-rating score of shoulder tenderness before and after treatment , stabbing times and degree at inserting the needle , scattering and during retention of the needle , and bleeding at withdrawing the needle were compared in the two groups . RESULTS The fu-needle group was better than the routine acupuncture group in improvement of mobility-related pain , tenderness , and the articular mobility of the most limited direction , indicating that the transient effect in the fu-needle group was better than the routine acupuncture group , and the stabbing times and degree at insertion of the needle were less than the routine acupuncture group . And there was no significant difference between the two groups in stabbing times and degree at scattering and retaining the needle and bleeding times in withdrawing the needle . CONCLUSION The superficial needling therapy with mono-use fu-needle is more effective and more safe than the routine acupuncture for treatment of periarthritis of shoulder [19489707] OBJECTIVES The aim of this study was to evaluate the efficacy of acupuncture as a treatment for chronic shoulder pain and to compare the efficacy of individualized acupuncture to fixed , st and ard point acupuncture treatment . DESIGN The study was a single-blind r and omized , controlled trial . SETTING S/LOCATION The study was conducted in an outpatient rheumatology clinic at the VA Medical Center of Philadelphia . SUBJECTS The participants were adults with shoulder pain for at least 8 weeks with a diagnosis of osteoarthritis or rotator cuff tendonitis and a total Shoulder Pain and Disability Index ( SPADI ) score of > or = 30 . INTERVENTIONS Thirty-one ( 31 ) subjects were r and omized to one of three treatment groups : individualized acupuncture points according to the approaches of Traditional Chinese Medicine ; fixed , st and ard acupuncture points conventionally used for shoulder pain ; and sham nonpenetrating acupuncture . Subjects received 12 treatments over 6 weeks and were reassessed using the SPADI at the end of the 6 weeks . OUTCOME MEASURES The primary outcome evaluated was the mean change in total SPADI score in each group from baseline to 6 weeks . RESULTS After 6 weeks of treatment , the mean total SPADI score improved in all three groups , but the change was clinical ly significant ( > or = 10 points ) only in groups 1 and 2 ( -20.3 and -20.4 , respectively , versus -6.5 in group 3 ) . The treatment effects of groups 1 and 2 compared to the sham acupuncture group were -13.8 ( 95 % confidence interval : -2.2 to -25.4 , p < 0.015 ) and -13.9 ( -2.0 to -25.8 , p < 0.013 ) , respectively . There was no difference between the individualized acupuncture and st and ardized acupuncture treatments . CONCLUSIONS Acupuncture may be an effective treatment for chronic shoulder pain . There may be no difference in efficacy between individualized and st and ardized acupuncture treatment . This suggests that the use of st and ard points may make treatment easier for patient care and for further research studies [16818924] BACKGROUND Despite the popularity of acupuncture , evidence of its efficacy for reducing pain remains equivocal . OBJECTIVE To assess the efficacy and safety of traditional Chinese acupuncture ( TCA ) compared with sham acupuncture ( needling at defined nonacupuncture points ) and conservative therapy in patients with chronic pain due to osteoarthritis of the knee . DESIGN R and omized , controlled trial . SETTING 315 primary care practice s staffed by 320 practitioners with at least 2 years ' experience in acupuncture . PATIENTS 1007 patients who had had chronic pain for at least 6 months due to osteoarthritis of the knee ( American College of Rheumatology [ ACR ] criteria and Kellgren-Lawrence score of 2 or 3 ) . INTERVENTIONS Up to 6 physiotherapy sessions and as-needed anti-inflammatory drugs plus 10 sessions of TCA , 10 sessions of sham acupuncture , or 10 physician visits within 6 weeks . Patients could request up to 5 additional sessions or visits if the initial treatment was viewed as being partially successful . MEASUREMENTS Success rate , as defined by at least 36 % improvement in Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) score at 26 weeks . Additional end points were WOMAC score and global patient assessment . RESULTS Success rates were 53.1 % for TCA , 51.0 % for sham acupuncture , and 29.1 % for conservative therapy . Acupuncture groups had higher success rates than conservative therapy groups ( relative risk for TCA compared with conservative therapy , 1.75 [ 95 % CI , 1.43 to 2.13 ] ; relative risk for sham acupuncture compared with conservative therapy , 1.73 [ CI , 1.42 to 2.11 ] ) . There was no difference between TCA and sham acupuncture ( relative risk , 1.01 [ CI , 0.87 to 1.17 ] ) . LIMITATIONS There was no blinding between acupuncture and traditional therapy and no monitoring of acupuncture compliance with study protocol . In general , practitioner-patient contacts were less intense in the conservative therapy group than in the TCA and sham acupuncture groups . CONCLUSIONS Compared with physiotherapy and as-needed anti-inflammatory drugs , addition of either TCA or sham acupuncture led to greater improvement in WOMAC score at 26 weeks . No statistically significant difference was observed between TCA and sham acupuncture , suggesting that the observed differences could be due to placebo effects , differences in intensity of provider contact , or a physiologic effect of needling regardless of whether it is done according to TCA principles [9717924] BACKGROUND A problem acupuncture research has to face is the concept of a control group . If , in control groups , non-acupoint needling is done , physiological acupuncture effects are implied . Therefore the effects shown in this group are often close to those shown in the acupuncture group . In other trials , control groups have received obviously different treatments , such as transcutaneous electrical nervous stimulation or TENS-laser treatment ; it is not clear if the effects of acupuncture are due only to the psychological effects of the treatment . METHODS We developed a placebo acupuncture needle , with which it should be possible to simulate an acupuncture procedure without penetrating the skin . In a cross-over experiment with 60 volunteers we tested whether needling with the placebo needle feels any different from real acupuncture . FINDINGS Of 60 volunteers , 54 felt a penetration with acupuncture ( mean visual analogue scale [ VAS ] 13.4 ; SD 10.58 ) and 47 felt it with placebo ( VAS 8.86 ; SD 10.55 ) , 34 felt a dull pain sensation ( DEQI ) with acupuncture and 13 with placebo . None of the volunteers suspected that the needle may not have penetrated the skin . INTERPRETATION The placebo needle is sufficiently credible to be used in investigations of the effects of acupuncture [17709062] INTRODUCTION There is some evidence for the efficacy of acupuncture in chronic neck pain ( CNP ) treatment , but it remains unclear which acupuncture modes are most effective . Objective was to evaluate the effects of trigger point acupuncture on pain and quality of life ( QOL ) in CNP patients compared to three other acupuncture treatments ( acupoints , non-trigger point and sham treatment ) . METHODS Forty out- patients ( 29 women , 11 men ; age range : 47 - 80 years ) from the Department of Orthopaedic Surgery , Meiji University of Oriental Medicine , with non-radiating CNP for at least 6 months and normal neurological examination were r and omised to one of four groups over 13 weeks . Each group received two phases of acupuncture treatment with an interval between them . The acupoint group ( st and ard acupuncture ; SA , n=10 ) received treatment at traditional acupoints for neck pain , the trigger point ( TrP , n=10 ) and non-trigger point ( non-TrP , n=10 ) groups received treatment at tenderness points for the same muscle , while the other acupuncture group received sham treatments on the trigger point ( SH , n=10 ) . Outcome measures were pain intensity ( visual analogue scale ; VAS 0 - 100 mm ) and disease specific question naire ( neck disability index ; NDI , 60-point scale ) . RESULTS After treatment , the TrP group reported less pain intensity and improved QOL compared to the SA or non-TrP group . There was significant reduction in pain intensity between the treatment and the interval for the TrP group ( p<0.01 , Dunnett 's multiple test ) , but not for the SA or non-TrP group . CONCLUSION These results suggest that trigger point acupuncture therapy may be more effective on chronic neck pain in aged patients than the st and ard acupuncture therapy [17604557] BACKGROUND This paper describes the experiences of 8 licensed acupuncturists in a placebo-controlled r and omized clinical trial ( RCT ) . This information is important to the design and conduct of high- quality trials . METHODS We conducted a RCT ( N=135 ) with a 2-week placebo run-in followed by 4 weeks of twice-weekly treatments comparing genuine to sham acupuncture ( using the Streitberger placebo needle ) in the treatment of arm pain caused by repetitive use . At the end of this study , we conducted written structured interviews with 8 participating acupuncturists . The acupuncturists were not aware of the study 's results at the time of these interviews . The questions focused on their experiences in the study , adherence to study protocol s , their thoughts about the technical and ethical issues involved in using a sham needling device , and their expectations of trial outcomes . The questions were motivated by expressions of concerns the acupuncturists raised in feedback groups during the course of the study , and our desire to improve further trials . RESULTS The acupuncturists differed widely in their comfort levels with the research methods used , their adherence to the study protocol , and their expectations of trial outcomes . CONCLUSIONS We conclude that careful monitoring of acupuncturists , including observation of treatments and frequent meetings to support them throughout the trial , is necessary to maintain a high degree of quality control [20082247] Objective To observe the clinical effect of acupuncture in treating cervical spondylosis with different syndrome types . Methods One hundred and seventeen patients were r and omized into the treated group : ( 59 cases ) , treated with normal acupuncture , and the control group ( 58 cases ) , treated with sham acupuncture , operated once every other day , 9 times in total ( in 18 days ) as one therapeutic course , and a succeeding 3-month follow-up study was carried out after terminating the therapy . The efficacy of treatment was evaluated with the Northwick Park Neck Pain Question naire ( NPQ ) and Visual Analogue Scale ( VAS ) , and the scores gained in patients with different syndrome types were analyzed with a general linear model . Results The NPQ and VAS : scores showed a linear decreasing tendency in both groups at the time of ending treatment and the 1st month of follow-up , but showed a secondary curve increasing tendency in the 3rd month of follow-up . Multivariate analysis showed the difference was of statistical significance ( P<0.05 ) . However , the analysis through lead-in of syndrome type as an individual influencing factor showed that syndrome type exerts a significant influence on VAS score ( P<0.05 ) , but has insignificant influence on the NPQ score ( P>0.05 ) . Conclusion Acupuncture shows : good immediate effect in treating cervical spondylosis , but its long-term effect is not satisfactory . The difference in syndrome type may have some impact on the effects of acupuncture in alleviating pain , but exerts no evident influence on the comprehensive effect [20506122] There is conflicting evidence on the efficacy of traditional Chinese acupuncture ( TCA ) , and the role of placebo effects elicited by acupuncturists ' behavior has not been eluci date d. We conducted a 3‐month r and omized clinical trial in patients with knee osteoarthritis to compare the efficacy of TCA with sham acupuncture and to examine the effects of acupuncturists ' communication styles [23629597] Background : There are different types and parameters of dry needling ( DN ) that can affect its efficacy in the treatment of pain that have not been assessed properly . Objective : To test the hypothesis that either multiple deep intramuscular stimulation therapy multiple deep intramuscular stimulation therapy ( MDIMST ) or TrP lidocaine injection ( LTrP-I ) is more effective than a placebo-sham for the treatment of myofascial pain syndrome ( MPS ) and that MDIMST is more effective than LTrP-I for improving pain relief , sleep quality , and the physical and mental state of the patient . Methods : Seventy-eight females aged 20 to 40 who were limited in their ability to perform active and routine activities due to MPS in the previous 3 months were recruited . The participants were r and omized into 1 of the 3 groups as follows : placebo-sham , LTrP-I , or MDIMST . The treatments were provided twice weekly over 4 weeks using st and ardized MDIMST and LTrP-I protocol s. Results : There was a significant interaction ( time vs. group ) for the main outcomes . Compared with the sham-treated group , MDIMST and LTrP-I administration improved pain scores based on a visual analog scale , the pain pressure threshold ( P<0.001 for all analyses ) , and analgesic use ( P<0.01 for all analyses ) . In addition , when comparing the active groups for these outcomes , MDIMST result ed in better improvement than LTrP-I ( P<0.01 for all analyses ) . In addition , both active treatments had a clinical effect , as assessed by a sleep diary and by the SF-12 physical and mental health scores . Conclusions : This study highlighted the greater efficacy of MDIMST over the placebo-sham and LTrP-I and indicated that both active treatments are more effective than placebo-sham for MPS associated with limitations in active and routine activities [23380214] OBJECTIVE The purpose of this preliminary study was to examine whether collateral meridian ( CM ) therapy was feasible in treating knee osteoarthritis ( OA ) pain . METHODS Twenty-eight patients with knee OA and knee pain were r and omly allocated to 2 groups . The CM group patients received CM therapy , whereas the control patients received placebo treatment for knee pain relief . Patients in the CM group received 2 CM treatments weekly for 3 weeks . The outcome measures were pain intensity on a visual analog scale , and knee function was determined using the Western Ontario and McMaster Universities Osteoarthritis Index . RESULTS In the CM group , the posttreatment visual analog scale and Western Ontario and McMaster Universities Osteoarthritis Index scores were lower than those of the control group ; a significant reduction in pain intensity ( P = .02 , P = .01 , respectively ) and improvement in knee function ( P = .04 , P = .03 , respectively ) were shown in the CM group at the second and third week . CONCLUSION Collateral meridian therapy may be feasible and effective for knee OA pain relief and knee function recovery . Therefore , additional r and omized control trials are warranted [19888488] AIMS To evaluate the effectiveness of acupuncture in treating symptoms associated with myofascial pain of the jaw muscles . METHODS Twenty-eight subjects over the age of 18 and diagnosed with chronic myofascial pain of the jaw muscles were r and omized to receive real ( n = 16 ) or sham ( n = 12 ) acupuncture . Prior to treatment , each subject clenched his or her teeth for 2 minutes . Acupuncture or sham acupuncture was then administered at the Hegu large intestine 4 ( LI4 ) acupoint for 15 minutes . Real acupuncture was given by penetrating the needle through a sticky foam pad at the acupoint . Sham acupuncture was conducted by pricking the skin , without penetration , with a shortened , blunted acupuncture needle through a foam pad placed away from the acupoint . General head and neck pain ratings were obtained before and after treatment on a numerical rating scale . A mechanical pain stimulus on the masseter muscle was given before and after treatment and rated on a visual analog scale to measure pain tolerance level . Paired t tests were performed to detect significant changes in pain levels . RESULTS Subjects receiving real acupuncture experienced a significant reduction in jaw pain ( P = .04 ) , jaw/face tightness ( P = .04 ) , and neck pain ( P = .04 ) , and a significant increase in pain tolerance of the masseter muscle ( P = .001 ) . Subjects were not able to determine whether they received real or sham acupuncture ( P = .69 ) . No significant pain reductions were observed in the sham acupuncture group . CONCLUSION A single acupuncture session using one acupoint at Hegu large intestine 4 significantly reduced most myofascial pain endpoints when compared to sham acupuncture [11886971] OBJECTIVE To evaluate the clinical efficacy of acupuncture in the treatment of chronic lateral epicondylitis . METHODS In a r and omized , investigator- and patient-blinded , controlled clinical study , 23 patients were treated with real acupuncture and 22 patients received sham acupuncture . Patients each received 10 treatments , with two treatments per week . The primary outcome variables were maximal strength , pain intensity ( verbal rating scale ) and disability scale ( Disabilities of the Arm , Shoulder and H and question naire ) . Patients were examined at baseline ( 1 week before the start of treatment ) and at follow-up 2 weeks and 2 months after the end of treatment . RESULTS There was no significant difference between the groups at baseline for any outcome parameter . Two weeks and 2 months after the end of treatment , there were significant reductions in pain intensity and improvements in the function of the arm and in maximal strength in both treatment groups . At the 2-week follow-up these differences were significantly greater for all outcome parameters in the group treated with real acupuncture . At 2 months the function of the arm was still better in this group than in the sham acupuncture group ; however , the differences in pain intensity and maximal strength between the groups were no longer significant . CONCLUSION In the treatment of chronic epicondylopathia lateralis humeri , acupuncture in which real acupuncture points were selected and stimulated was superior to non-specific acupuncture with respect to reduction in pain and improvement in the functioning of the arm . These changes are particularly marked at early follow-up [8000747] The immediate analgesic effect of a single non-segmental acupuncture stimulation treatment on chronic tennis elbow pain was studied in a placebo-controlled single-blind trial completed by 48 patients . Before and after treatment , all patients were examined physically by an unbiased independent examiner . Eleven-point box scales were used [ 13 ] for pain measurement . Patients in the verum group were treated at non-segmental distal points ( homolateral leg ) for elbow pain following Chinese acupuncture rules , whereas patients in the placebo group were treated with placebo acupuncture avoiding penetration of the skin with an acupuncture needle . Overall reduction in the pain score was 55.8 % ( S = 2.95 ) in the verum group and 15 % ( S = 2.77 ) in the placebo group . After one treatment 19 out of 24 patients in the verum group ( 79.2 % ) reported pain relief of at least 50 % ( placebo group : six patients out of 24 ) . The average duration of analgesia after one treatment was 20.2 h in the verum group ( S = 21.54 ) and 1.4 h ( S = 3.50 ) in the placebo group . The results are statistically significant ( P < 0.01 ) ; they show that non-segmental verum acupuncture has an intrinsic analgesic effect in the clinical treatment of tennis elbow pain which exceeds that of placebo acupuncture [16309103] OBJECTIVE To compare therapeutic effects of superficial needling and body acupuncture on knee joint pain . METHODS Ninety-six cases of knee joint pain were r and omly divided into a treatment group of 48 cases treated with superficial needling , and a control group of 48 cases treated with body acupuncture . RESULTS The cured rate was 66.7 % in the treatment group and 39.6 % in the control group with a significant difference between the two groups ( P<0.01 ) . The total effective rate was 100.0 % in both the two groups . The needed therapeutic times of superficial needling was significantly less than that of the body acupuncture ( P < 0.05 ) . CONCLUSION Superficial needling has a good therapeutic effect on knee joint pain with a shorter therapeutic course [20821817] Chronic neck myofascial pain syndrome ( MPS ) is a common disorder seen in clinics . There is no gold st and ard method to treat myofascial pain . We investigated the effects of acupuncture on patients with chronic neck MPS by a single-blind r and omized controlled trial . A total of 35 patients were r and omly allocated to an acupuncture group ( AG ) or a sham acupuncture group ( SG ) . Each subject received acupuncture treatment twice per week for three consecutive weeks . The primary outcome measure was quality of life as assessed with Short Form-36 , and secondary outcome measures were neck range of motion ( ROM ) , motion-related pain , and Short-Form McGill Pain Question naire ( SF-MPQ ) , as determined by a blinded investigator . The clinical assessment s were made before treatment ( BT ) and after six acupuncture treatments ( AT ) , as well as four weeks ( F1 ) and 12 weeks ( F2 ) after the end of the treatment . A total of 34 patients completed the trial . The results indicated that there is no significant difference in the ROM , motion-related pain , and SF-MPQ scores between AG and SG at AT , F1 and F2 ( all p > 0.05 ) . However , AG has greater improvement in physical functioning and role emotional of Short Form-36 quality of life at F2 . The results indicate that acupuncture may be used to improve the quality of life in patients with chronic neck MPS [6217745] Acupuncture treatment of chronic low back pain was studied in a placebo-controlled double-blind crossover trial completed by 77 patients . The patients had significantly increased depression , neuroticism , and hypochondriasis scores . Initial pain levels correlated with state-anxiety , depression , pain duration , and abnormal illness behavior measures , as well as with the intake of psychotropic but not analgesic medication . Overall reduction in pain score was 26 percent for acupuncture and 22 percent for placebo treatment ; the difference was not significant ( p greater than 0.6 ) . Analgesic drug intake was reduced to a similar extent in both groups . During the first phase of treatment , patients receiving acupuncture had a greater but not significantly different reduction in pain rating scores compared with those receiving placebo ( t = 0.52 ; p greater than 0.6 ) . This group showed significantly lower pain scores ( p less than 0.05 ) in the second phase of the trial while receiving placebo treatment . Overall reduction in individual patient 's pain score was best predicted by initial pain severity ( r = 0.43 ; p less than 0.001 ) and psychotropic drug intake ( r = 0.37 ; p less than 0.001 ) . None of the variables tested predicted which patients would specifically respond to acupuncture or placebo [17095133] OBJECTIVES To compare the effect of real acupuncture and sham acupuncture in the treatment of temporom and ibulat joint myofascial pain , in order to establish the true efficacy of acupuncture . METHODS A double blind r and omised controlled trial conducted in the TMD Clinic , at the School of Dentistry , The University of Manchester . Twenty-seven patients were assigned to one of two treatment groups . Group 1 received real acupuncture treatment whilst Group 2 received a sham acupuncture intervention . Both the assessor and the patient were blinded regarding the group allocation . Baseline assessment of the outcome variables was made prior to the first treatment session , and was repeated following the last treatment . RESULTS The results demonstrated that real acupuncture had a greater influence on clinical outcome measure of TMJ MP than those of sham acupuncture , and the majority of these reached a level of statistical significance . CONCLUSION Acupuncture had a positive influence on the signs and symptoms of TMJ MP . In addition , this study provides evidence that the Park Sham Device was a credible acupuncture control method for trials involving facial acupoints [21195292] OBJECTIVE This study is aim ed to assess the efficacy of traditional acupuncture for chronic neck pain in patients by comparing the differences in symptoms , dysfunctions and quality of life . METHODS The study used a two-arm , single-blinded , r and omised controlled design . The patients were r and omised to the study group and control group , who respectively received traditional acupuncture and placebo treatment . The Northwick Park Neck Pain Question naire ( NPQ ) , visual analogue scale ( VAS ) , Short Form ( 36 ) Health Survey ( SF-36 ) and doctor 's judgement were applied for measuring effectiveness . The patients ' effectiveness outcome was assessed , respectively , before the intervention , immediately after the intervention , at the end of the first month of follow-up and at the end of the third month of follow-up . The statistical analysis was done on Statistical Package for Social Sciences ( SPSS ) v13 , which included comparison of demographic and clinical homogeneity , the repeated measures approach based on the general linear model ( GLM ) for effectiveness assessment and the sum rank test for doctors ' subjective efficacy judgement . RESULTS Totally , 190 patients were recruited and 178 patients ( 88 in the study group and 90 in the control group ) completed the intervention and follow-up assessment . The scores of NPQ , VAS and SF-36 were improved after the intervention and during follow-up ( P<0.01 vs. before the intervention ) . The patients in the study group had better effectiveness outcome in NPQ , VAS and in the VT , SF and MH domains of SF-36 ( P<0.05 ) . CONCLUSION Traditional acupuncture can relieve pain intensity and improve the quality of daily life with a relative long-term clinical efficacy in patients with chronic neck pain [17699546] Objective To investigate the benefit of adding acupuncture to a course of advice and exercise delivered by physiotherapists for pain reduction in patients with osteoarthritis of the knee . Design Multicentre , r and omised controlled trial . Setting 37 physiotherapy centres accepting primary care patients referred from general practitioners in the Midl and s , United Kingdom . Participants 352 adults aged 50 or more with a clinical diagnosis of knee osteoarthritis . Interventions Advice and exercise ( n=116 ) , advice and exercise plus true acupuncture ( n=117 ) , and advice and exercise plus non-penetrating acupuncture ( n=119 ) . Main outcome measures The primary outcome was change in scores on the Western Ontario and McMaster Universities osteoarthritis index pain subscale at six months . Secondary outcomes included function , pain intensity , and unpleasantness of pain at two weeks , six weeks , six months , and 12 months . Results Follow-up rate at six months was 94 % . The mean ( SD ) baseline pain score was 9.2 ( 3.8 ) . At six months mean reductions in pain were 2.28 ( 3.8 ) for advice and exercise , 2.32 ( 3.6 ) for advice and exercise plus true acupuncture , and 2.53 ( 4.2 ) for advice and exercise plus non-penetrating acupuncture . Mean differences in change scores between advice and exercise alone and each acupuncture group were 0.08 ( 95 % confidence interval −1.0 to 0.9 ) for advice and exercise plus true acupuncture and 0.25 ( −0.8 to 1.3 ) for advice and exercise plus non-penetrating acupuncture . Similar non-significant differences were seen at other follow-up points . Compared with advice and exercise alone there were small , statistically significant improvements in pain intensity and unpleasantness at two and six weeks for true acupuncture and at all follow-up points for non-penetrating acupuncture . Conclusion The addition of acupuncture to a course of advice and exercise for osteoarthritis of the knee delivered by physiotherapists provided no additional improvement in pain scores . Small benefits in pain intensity and unpleasantness were observed in both acupuncture groups , making it unlikely that this was due to acupuncture needling effects . Trial registration Current Controlled Trials IS RCT N88597683 [11889662] AIMS To compare the effectiveness of dry needling in classically recognized acupuncture points ( " acupuncture " ) with dry needling in skin areas not recognized as acupuncture points ( " sham acupuncture " ) in reducing masseter muscle pain in a group of patients with myofascial pain of the jaw muscles . METHODS Eighteen patients were r and omly assigned to 1 of 2 experimental groups : Ten patients received acupuncture and 8 received sham acupuncture . A visual analog scale ( VAS ) was used to measure changes in masseter muscle pain evoked by mechanical stimulation of the masseter muscle before and after the experiment . RESULTS Both groups showed a statistically significant reduction in VAS pain scores ( P = .001 ) . Seven out of 10 acupuncture subjects had a 10 mm or greater VAS reduction in pain , while 4 out of 8 of the sham acupuncture subjects had that great a pain reduction . There was no significant difference between the 2 groups . CONCLUSION Both acupuncture and sham acupuncture reduced pain evoked by mechanical stimulation of the masseter muscles in myofascial pain patients . However , this reduction in pain was not dependent on whether the needling was performed in st and ard acupuncture points or in other areas of the skin . These results suggest that pain reduction result ing from a noxious stimulus ( i.e. , needling ) may not be specific to the location of the stimulus as predicted by the classical acupuncture literature [18287826] Objective To compare true and sham acupuncture in their abilities to relieve arm pain and improve arm function in individuals with arm pain due to repetitive use . Methods Participants with persistent arm pain ( N=123 ) were r and omly assigned to true or sham acupuncture groups and received 8 treatments over 4 weeks . The primary outcome was intensity of pain ( 10-point scale ) and secondary outcomes were arm symptoms , arm function , and grip strength . Outcomes were measured during treatment ( at 2 and 4 wk ) and 1 month after treatment ended . Results Arm pain scores improved in both groups during the treatment period , but improvements were significantly greater in the sham group than in the true acupuncture group . This difference disappeared by 1 month after treatment ended . The true acupuncture group experienced more side effects , predominately mild pain at time of treatments . Discussion Sham acupuncture reduced arm pain more than true acupuncture during treatment , but the difference did not persist after 1 month . Mild side effects from true acupuncture may have blunted any positive treatment effects . Overall , this study did not find evidence to support the effectiveness of true acupuncture in treatment of persistent arm pain due to repetitive use [20137365] BACKGROUND Acupuncture has been shown to be effective in pain relief and anesthesia , and has been suggested for treating various kinds of functional disabilities in traditional Chinese medicine , including knee osteoarthritis ( OA ) . The study aim ed to investigate the immediate effects of acupuncture on gait patterns in patients with knee OA . METHODS Twenty patients with bilateral medial knee OA were assigned evenly and r and omly to a sham group and an experimental group . During the experiment , the experimental group underwent a 30-minute formula electro-acupuncture treatment while the sham group received a sham treatment . Before and after treatment , each subject was evaluated for their knee pain using visual analog scales ( VAS ) and then their performance of level walking using gait analysis . For all the obtained variables , the independent t-test was used for between-group comparisons , while paired t-test was used to investigate the before and after changes . RESULTS All the measured data before acupuncture treatment between the groups were not significantly different . The VAS scores were decreased significantly after acupuncture in both groups , and the mean change of the VAS values of the experiment group was 2 times greater than that of the sham group . After formula acupuncture stimulation , while no significant changes were found in all the gait variables in the sham group , the experimental group had significant increases in the gait speed , step length , as well as in several components of the joint angles and moments . CONCLUSIONS The results of the study suggest that significantly improved gait performance in the experimental group may be associated with pain relief after treatment , but the relatively small decrease of pain in the sham group was not enough to induce significant improvements in gait patterns . Gait analysis combined with the VAS can be useful for the evaluation of the effect of acupuncture treatment for patients with neuromusculoskeletal diseases and movement disorder [11444887] OBJECTIVES The effectiveness of acupuncture treatment in patients with osteoarthritis of the hip was tested . DESIGN This is a prospect i ve , r and omized , controlled , patient- and investigator-blinded clinical trial . PATIENTS AND SETTING The study was performed at a university department for physical medicine and rehabilitation . Sixty-seven patients were separated into two treatment groups . INTERVENTIONS Group 1 ( treatment ) had traditional needle placement and manipulation , whereas in group 2 ( control ) needles were placed away from classic positions and not manipulated . In both groups needles were placed within the L2 to L5 dermatomes . Outcome parameters were : pain ( VAS ) , functional impairment ( hip score ) , activity in daily life ( ADL ) and overall satisfaction before treatment , and 2 weeks and 2 months after treatment . RESULTS For all parameters there was a significant improvement versus baseline in both groups 2 weeks and 2 months following treatment , but no significant difference between the two treatment groups . CONCLUSIONS We conclude from these results that needle placement in the area of the affected hip is associated with improvement in the symptoms of osteoarthritis . It appears to be less important to follow the rules of traditional acupuncture techniques [17714105] AIM Short-term pain reduction from acupuncture in chronic myofascial pain subjects was evaluated using an 11-point ( 0 to 10 ) numeric rating scale , visual analog scale ( VAS ) , and pain rating of mechanical pressure on the masseter muscle . METHODS A single-blind , r and omized , controlled , clinical trial with an independent observer was performed . Fifteen chronic myofascial pain subjects over the age of 18 were r and omly assigned into groups : nine subjects received real acupuncture ; six subjects received sham acupuncture . Each subject clenched his/her teeth for 2 minutes . Acupuncture or sham acupuncture was administered at the Hegu Large Intestine 4 acupoint . Sham acupuncture was conducted by lightly pricking the skin with a shortened , blunted acupuncture needle through a foam pad , without penetrating the skin . The foam pad visually conceals the needle 's point of the entry , so that the subject can not discern which technique is being used . The subjects rated their general pain on a numeric rating scale . A mechanical pain stimulus was applied with an algometer and the subject rated his/her pain on a VAS . Statistical analysis was performed using the repeated measures anova , paired t-tests , and Fisher 's exact test as appropriate . RESULTS There was a statistically significant difference in pain tolerance with acupuncture ( P = 0.027 ) . There was statistically significant reduction in face pain ( P = 0.003 ) , neck pain ( P = 0.011 ) , and headache ( P = 0.015 ) with perception of real acupuncture . CONCLUSION Pain tolerance in the masticatory muscles increased significantly more with acupuncture than sham acupuncture [12406534] & NA ; This prospect i ve , r and omised controlled trial , with three parallel groups , patient and observer blinded for verum and sham acupuncture and a follow up of 3 months raises the question : “ Does a combination of acupuncture and conservative orthopedic treatment improve conservative orthopedic treatment in chronic low back pain ( LBP ) . 186 in‐ patients of a LBP rehabilitation center with a history of LBP ≥6 weeks , VAS ≥50 mm , and no pending compensation cl aims , were selected ; for the three r and om group 4 weeks of treatment was applied . 174 patients met the protocol criteria and reported after treatment , 124 reported after 3 months follow up . Patients were assorted 4 strata : chronic LBP , ≤0.5 years , 0.5–2 years , 2–5 years , ≥5 years . Analysis was by intention to treat . Group 1 ( Verum+COT ) recieved 12 treatments of verum acupuncture and conservative orthopedic treatment ( COT ) . Group 2 ( Sham+COT ) recieved 12 treatments of non‐specific needling and COT . Group 3 ( nil+COT ) recieved COT alone . Verum‐ and Sham acupuncture were blinded against patient and examiner . The primary endpoints were pain reduction ≥50 % on VAS 3 months after the end of the treatment protocol . Secondary endpoints were pain reduction ≥50 % on VAS and treatment efficacy on a four‐point box scale directly after the end of the treatment protocol and treatment efficacy after 3 months . In the whole sample a pain relief of ≥50 % on VAS was reported directly after the end of treatment protocol : Verum+COT 65 % ( 95%CI 51–77 % ) , Sham+COT 34 % ( 95%ci 22–49 % ) , nil+COT 43 % ( 95%ci 29–58 % ) – results are significant for Verum+COT over Sham+COT ( P≤0.02 ) . The results after 3 months are : Verum+COT 77 % ( 95%ci 62–88 % ) , Sham+COT 29 % ( 95%ci 16–46 % ) , nil+Cot 14 % ( 95%ci 4–30 % ) – effects are significant for Verum+COT over Sham+COT ( P≤0.001 ) and for Verum+COT over nil+COT ( P<0.001 ) . No difference was found in the mobility of the patients nor in the intake of NSAID diclofenac . Our conclusion is that acupuncture can be an important supplement of conservative orthopedic treatment in the management of chronic LBP

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### Context: [17893311] BACKGROUND To our knowledge , verum acupuncture has never been directly compared with sham acupuncture and guideline -based conventional therapy in patients with chronic low back pain . METHODS A patient- and observer-blinded r and omized controlled trial conducted in Germany involving 340 outpatient practice s , including 1162 patients aged 18 to 86 years ( mean + /- SD age , 50 + /- 15 years ) with a history of chronic low back pain for a mean of 8 years . Patients underwent ten 30-minute sessions , generally 2 sessions per week , of verum acupuncture ( n = 387 ) according to principles of traditional Chinese medicine ; sham acupuncture ( n = 387 ) consisting of superficial needling at nonacupuncture points ; or conventional therapy , a combination of drugs , physical therapy , and exercise ( n = 388 ) . Five additional sessions were offered to patients who had a partial response to treatment ( 10%-50 % reduction in pain intensity ) . Primary outcome was response after 6 months , defined as 33 % improvement or better on 3 pain-related items on the Von Korff Chronic Pain Grade Scale question naire or 12 % improvement or better on the back-specific Hanover Functional Ability Question naire . Patients who were unblinded or had recourse to other than permitted concomitant therapies during follow-up were classified as nonresponders regardless of symptom improvement . RESULTS At 6 months , response rate was 47.6 % in the verum acupuncture group , 44.2 % in the sham acupuncture group , and 27.4 % in the conventional therapy group . Differences among groups were as follows : verum vs sham , 3.4 % ( 95 % confidence interval , -3.7 % to 10.3 % ; P = .39 ) ; verum vs conventional therapy , 20.2 % ( 95 % confidence interval , 13.4 % to 26.7 % ; P < .001 ) ; and sham vs conventional therapy , 16.8 % ( 95 % confidence interval , 10.1 % to 23.4 % ; P < .001 . CONCLUSIONS Low back pain improved after acupuncture treatment for at least 6 months . Effectiveness of acupuncture , either verum or sham , was almost twice that of conventional therapy [12067088] To evaluate the efficacy of Chinese medicine ( CM ) acupuncture for chronic neck pain ( CNP ) , a single blind , controlled , crossover , clinical trial was undertaken . Twenty-nine volunteers with CNP were r and omly recruited into two groups . Both groups received two phases of treatment with a washout period between the two phases . Group A ( 14 volunteers ) received CM acupuncture in the first phase and sham acupuncture in the second , while Group B ( 15 volunteers ) received sham in the first and real in the second . CM acupuncture was individualized and consisted of nine sessions on both local and distal points . Manual twisting of the needle was applied on all points plus strong electrical stimulation of distal points in CM acupuncture . Sham acupoints ( lateral to the real ) and sham ( weak ) electrical stimulation was used in the control group . Comparison of subjective and objective measures between the two groups was made at different periods , including baseline , after each phase of treatment , after washout , and after the 16th week follow-up . The subjective measures included pain intensity , duration per day , analgesic medication count , visual analogue scales ( VAS ) and neck disability index ( NDI ) . The objective measures consisted of neck range of motion ( ROM ) and pain threshold ( PT ) . Both the real and sham treatments significantly reduced subjective pain , without significant differences between groups for most subjective measures . Objective measures showed no significant change for either group before and after each period or by inter-groups analysis . A minimum 16-week effect of both real and sham acupuncture was found for subjective measures in the follow-up periods . Further study is recommended with an increased sample size , a longer washout period , and a longer baseline period [17989918] We evaluated the efficacy of acupuncture as a useful adjuvant treatment in the management of rheumatoid arthritis ( RA ) . A pilot , r and omized , double-blind , and controlled clinical trial was conducted . Forty RA patients with active disease despite stable therapy for at least the preceding 1 month were r and omized to receive a st and ard protocol of acupuncture ( AC ) or superficial acupuncture at non-acupuncture points ( controlAC ) for 9 weeks . The primary outcome was achievement of 20 % improvement according to the American College of Rheumatology ( ACR ) 20 criteria after five and ten treatment sessions and after 1 month of follow-up . Secondary measures included Disease Assessment Scale ( DAS ) , tender and swollen joint count , morning stiffness , Health Assessment Question naire ( HAQ ) , visual analogue scale ( VAS ) of pain , physician global assessment of activity disease , physician and patient global assessment of treatment , and inflammatory markers ( erythrocyte sedimentation rate and C-reactive protein ) . There was not significant difference between the groups regarding the number of patients that reached ACR20 at the end of the treatment ( p = 0.479 ) . However , after 1 month of follow-up , there was a trend in favor of the AC group , with p = 0,068 . Compared with the controlAC , the AC group also demonstrated significant improvement in the patient and physician global assessment of treatment and physician global assessment of disease activity , but there was no difference on other clinical and laboratorial measures . On the other h and , only the AC patients had within group improvement on the variables DAS , HAQ , morning stiffness , patient and physician global assessment of treatment , and physician global assessment of disease activity in comparison to baseline visit . Despite the improvement of some studied variables , there was no significant difference in the proportion of patients that reached ACR20 between the AC and controlAC groups . This negative result can be related to the small sample size , selection of patients , type of acupuncture protocol applied , and difficulties in establishing an innocuous and trustworthy placebo group to studies involving acupuncture [18591906] Objectives To compare the effect of acupuncture ( manual and electroacupuncture ) with that of a non-penetrating sham ( ‘ placebo ’ needle ) in patients with osteoarthritic knee pain and disability who are blind to the treatment allocation . Methods Acupuncture naive patients with symptomatic and radiological evidence of osteoarthritis of the knee were r and omly allocated to a course of either acupuncture or non-penetrating sham acupuncture using a sheathed ‘ placebo ’ needle system . Acupuncture points for pain and stiffness were selected according to acupuncture theory for treating Bi syndrome . Both manual and electrical stimulation were used . Response was assessed using the WOMAC index for osteoarthritis of the knee , self reported pain scale , the EuroQol score and plasma β-endorphin . The effectiveness of blinding was assessed . Results There were 34 patients in each group . The primary end point was the change in WOMAC pain score after the course of treatment . Comparison between the two treatment groups found a significantly greater improvement with acupuncture ( mean difference 60 , 95 % CI 5 to 116 , P=0.035 ) than with sham . Within the acupuncture group there was a significant improvement in pain ( baseline 294 , mean change 95 , 95 % CI 60 to 130 , P<0.001 ) which was not seen by those who had sham acupuncture ( baseline 261 , mean change 35 , 95 % CI-10 to 80 , P=0.12 ) . Similar effects within group , but not between groups , were seen with the secondary end points of WOMAC stiffness , WOMAC function , and self reported pain . One month after treatment the between group pain difference had been lost ( mean difference 46 ; 95 % CI −9 to 100 , P=0.10 ) although the acupuncture group was still benefiting compared to baseline ( mean difference 59 ; 95 % CI 16 to 102 , P=0.009 ) . The EuroQol score , a generic measure of health related quality of life , was not altered by the treatments . A minority of patients correctly guessed their treatment group ( 41 % in the acupuncture group and 44 % in the control group ) . Plasma β-endorphin levels were not affected by either treatment . Conclusions Acupuncture gives symptomatic improvement for patients with osteoarthritis of the knee , and is significantly superior to non-penetrating sham acupuncture . The study did not confirm earlier reports of release of plasma β-endorphin during acupuncture [19766392] ABSTRACT Neurobiological mechanisms invoking the release of endogenous opioids and depression of stress hormone release are believed to be the basis of acupuncture analgesia . This study compared plasma β‐endorphin and cortisol levels with self assessment scores of intensity of pain , before and after 10 days of electro‐acupuncture treatment in patients suffering from chronic pain as a result of osteoarthritis knees . Forty patients of either sex over 40 years with primary osteoarthritis knee were recruited into a single‐blinded , sham‐controlled study . For electro‐acupuncture group the points were selected according to the Traditional Chinese Medicine Meridian Theory . In the sham group needles were inserted at r and om points away from true acupoints and no current was passed . Both groups were treated for 10 days with one session every day lasting for 20–25 min . Pre‐ and post‐treatment Western Ontario and McMaster Universities ( WOMAC ) index of osteoarthritis knee and Visual Analogue Scale ( VAS ) for pain were recorded and blood sample s were taken for the measurement of plasma cortisol and β‐endorphin levels . Following electro‐acupuncture treatment there was a significant improvement in WOMAC index and VAS ( p = 0.001 ) , a significant rise in plasma β‐endorphin ( p = 0.001 ) , and a significant fall in plasma cortisol ( p = 0.016 ) . In conclusion electro‐acupuncture result ed in an improvement in pain , stiffness and disability . Of clinical importance is that an improvement in objective measures of pain and stress/pain associated biomarkers was shown above that of a sham treatment ; hence demonstrating acupuncture associated physiological changes beyond that of the placebo effects [20580303] Clinicians cl aim that myofascial trigger points ( MTrPs ) are a primary cause of pain in whiplash injured patients . Pain from MTrPs is often treated by needling , with or without injection . We conducted a placebo controlled study to test the feasibility of a phase III r and omised controlled trial investigating the efficacy of MTrP needling in patients with whiplash associated pain . Forty-one patients referred for physiotherapy with a recent whiplash injury , were recruited . Patients were r and omised to receive st and ardised physiotherapy plus either acupuncture or a sham needle control . A trial was judged feasible if : i ) the majority of eligible patients were willing to participate ; ii ) the majority of patients had MTrPs ; iii ) at least 75 % of patients provided completed self- assessment data ; iv ) no serious adverse events were reported and v ) the end of treatment attrition rate was less than 20 % . 70 % of those patients eligible to participate volunteered to do so ; all participants had clinical ly identified MTrPs ; a 100 % completion rate was achieved for recorded self- assessment data ; no serious adverse events were reported as a result of either intervention ; and the end of treatment attrition rate was 17 % . A phase III study is both feasible and clinical ly relevant . This study is currently being planned [16005336] BACKGROUND Acupuncture is widely used by patients with chronic pain although there is little evidence of its effectiveness . We investigated the efficacy of acupuncture compared with minimal acupuncture and with no acupuncture in patients with osteoarthritis of the knee . METHODS Patients with chronic osteoarthritis of the knee ( Kellgren grade < or = 2 ) were r and omly assigned to acupuncture ( n=150 ) , minimal acupuncture ( superficial needling at non-acupuncture points ; n=76 ) , or a waiting list control ( n=74 ) . Specialised physicians , in 28 outpatient centres , administered acupuncture and minimal acupuncture in 12 sessions over 8 weeks . Patients completed st and ard question naires at baseline and after 8 weeks , 26 weeks , and 52 weeks . The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis ( WOMAC ) index at the end of week 8 ( adjusted for baseline score ) . All main analyses were by intention to treat . RESULTS 294 patients were enrolled from March 6 , 2002 , to January 17 , 2003 ; eight patients were lost to follow-up after r and omisation , but were included in the final analysis . The mean baseline-adjusted WOMAC index at week 8 was 26.9 ( SE 1.4 ) in the acupuncture group , 35.8 ( 1.9 ) in the minimal acupuncture group , and 49.6 ( 2.0 ) in the waiting list group ( treatment difference acupuncture vs minimal acupuncture -8.8 , [ 95 % CI -13.5 to -4.2 ] , p=0.0002 ; acupuncture vs waiting list -22.7 [ -27.5 to -17.9 ] , p<0.0001 ) . After 52 weeks the difference between the acupuncture and minimal acupuncture groups was no longer significant ( p=0.08 ) . INTERPRETATION After 8 weeks of treatment , pain and joint function are improved more with acupuncture than with minimal acupuncture or no acupuncture in patients with osteoarthritis of the knee . However , this benefit decreases over time [9758075] OBJECTIVE This article examines the specific and nonspecific effects of Japanese acupuncture on chronic myofascial neck pain in a r and omized single-blind trial . DESIGN Forty-six patients were r and omly assigned to receive relevant acupuncture , irrelevant acupuncture , or no-acupuncture control treatment consisting of nonsteroidal anti-inflammatory medication . The two acupuncture groups underwent comparable light shallow needling . The irrelevant acupuncture group received acupuncture at specific sites not relevant for cervical pain . OUTCOME MEASURES The study measures included the McGill Pain Question naire-Short Form ( SF-MPQ ) , the Short-Form Health Survey ( SF-36 ) , the Symptom Checklist 90-Revised ( SCL-90-R ) , medication diary , and physiologic measures . The factors examined as predictors of outcome pain ratings were experience with , beliefs about , and knowledge of acupuncture before treatment ; perceived efficacy , credibility , and logic of acupuncture ; perceived competence of the acupuncturist ; and painfulness of acupuncture . RESULTS No differences were found among the three groups at baseline , except that the relevant acupuncture group reported having had more previous acupuncture treatments . No significant differences in terms of perceived credibility or perceived effectiveness of treatment were found between the two acupuncture groups . The relevant acupuncture group had significantly greater pre-/posttreatment differences in pain than the irrelevant acupuncture and control groups ( p < .05 ) . The nonspecific effects of confidence in the acupuncturist , willingness to try any treatment , mood , and physiologic effect of needling were not predictive of treatment outcome , whereas confidence in the treatment and past experiences with acupuncture did correlate significantly with a decrease in pain . CONCLUSIONS Relevant acupuncture with heat contributes to modest pain reduction in persons with myofascial neck pain . Previous experience with and confidence in treatment help to predict benefit . Measurement of nonspecific effects of alternative therapy is recommended in future clinical trials [20655660] & NA ; The German R and omized Acupuncture Trial for chronic shoulder pain ( GRASP ) comprised 424 out patients with chronic shoulder pain ( CSP ) ≥6 weeks and an average pain score of VAS ≥50 mm , who were r and omly assigned to receive Chinese acupuncture ( verum ) , sham acupuncture ( sham ) or conventional conservative orthopaedic treatment ( COT ) . The patients were blinded to the type of acupuncture and treated by 31 office‐based orthopaedists trained in acupuncture ; all received 15 treatments over 6 weeks . The 50 % responder rate for pain was measured on a VAS 3 months after the end of treatment ( primary endpoint ) and directly after the end of the treatment ( secondary endpoint ) . Results : In the ITT ( n = 424 ) analysis , percentages of responders for the primary endpoint were verum 65 % ( 95 % CI 56–74 % ) ( n = 100 ) , sham 24 % ( 95 % CI 9–39 % ) ( n = 32 ) , and COT 37 % ( 95 % CI 24–50 % ) ( n = 50 ) ; secondary endpoint : verum 68 % ( 95 % CI 58–77 % ) ( n = 92 ) , sham 40 % ( 95 % CI 27–53 % ) ( n = 53 ) , and COT 28 % ( 95 % CI 14–42 % ) ( n = 38 ) . The results are significant for verum over sham and verum over COT ( p < 0.01 ) for both the primary and secondary endpoints . The PPP analysis of the primary ( n = 308 ) and secondary endpoints ( n = 360 ) yields similar responder results for verum over sham and verum over COT ( p < 0.01 ) . Descriptive statistics showed greater improvement of shoulder mobility ( abduction and arm‐above‐head test ) for the verum group versus the control group immediately after treatment and after 3 months . The trial indicates that Chinese acupuncture is an effective alternative to conventional orthopaedic treatment for CSP [7818567] OBJECTIVE To determine the prevalence and characteristics of fibromyalgia in the general population . METHODS A r and om sample of 3,006 persons in Wichita , KS , were characterized according to the presence of no pain , non-widespread pain , and widespread pain . A sub sample of 391 persons , including 193 with widespread pain , were examined and interviewed in detail . RESULTS The prevalence of fibromyalgia was 2.0 % ( 95 % confidence interval [ 95 % CI ] 1.4 , 2.7 ) for both sexes , 3.4 % ( 95 % CI 2.3 , 4.6 ) for women , and 0.5 % ( 95 % CI 0.0 , 1.0 ) for men . The prevalence of the syndrome increased with age , with highest values attained between 60 and 79 years ( > 7.0 % in women ) . Demographic , psychological , dolorimetry , and symptom factors were associated with fibromyalgia . CONCLUSION Fibromyalgia is common in the population , and occurs often in older persons . Characteristic features of fibromyalgia -- pain threshold and symptoms -- are similar in community and clinic population s , but overall severity , pain , and functional disability are more severe in the clinic population [16505266] BACKGROUND Acupuncture is widely used by patients with low back pain , although its effectiveness is unclear . We investigated the efficacy of acupuncture compared with minimal acupuncture and with no acupuncture in patients with chronic low back pain . METHODS Patients were r and omized to treatment with acupuncture , minimal acupuncture ( superficial needling at nonacupuncture points ) , or a waiting list control . Acupuncture and minimal acupuncture were administered by specialized acupuncture physicians in 30 outpatient centers , and consisted of 12 sessions per patient over 8 weeks . Patients completed st and ardized question naires at baseline and at 8 , 26 , and 52 weeks after r and omization . The primary outcome variable was the change in low back pain intensity from baseline to the end of week 8 , as determined on a visual analog scale ( range , 0 - 100 mm ) . RESULTS A total of 298 patients ( 67.8 % female ; mean + /- SD age , 59 + /- 9 years ) were included . Between baseline and week 8 , pain intensity decreased by a mean + /- SD of 28.7 + /- 30.3 mm in the acupuncture group , 23.6 + /- 31.0 mm in the minimal acupuncture group , and 6.9 + /- 22.0 mm in the waiting list group . The difference for the acupuncture vs minimal acupuncture group was 5.1 mm ( 95 % confidence interval , -3.7 to 13.9 mm ; P = .26 ) , and the difference for the acupuncture vs waiting list group was 21.7 mm ( 95 % confidence interval , 13.9 - 30.0 mm ; P<.001 ) . Also , at 26 ( P=.96 ) and 52 ( P=.61 ) weeks , pain did not differ significantly between the acupuncture and the minimal acupuncture groups . CONCLUSION Acupuncture was more effective in improving pain than no acupuncture treatment in patients with chronic low back pain , whereas there were no significant differences between acupuncture and minimal acupuncture [16770975] OBJECTIVE To test the hypothesis that acupuncture improves symptoms of fibromyalgia . PATIENTS AND METHODS We conducted a prospect i ve , partially blinded , controlled , r and omized clinical trial of patients receiving true acupuncture compared with a control group of patients who received simulated acupuncture . All patients met American College of Rheumatology criteria for fibromyalgia and had tried conservative symptomatic treatments other than acupuncture . We measured symptoms with the Fibromyalgia Impact Question naire ( FIQ ) and the Multidimensional Pain Inventory at baseline , immediately after treatment , and at 1 month and 7 months after treatment . The trial was conducted from May 28 , 2002 , to August 18 , 2003 . RESULTS Fifty patients participated in the study : 25 in the acupuncture group and 25 in the control group . Total fibromyalgia symptoms , as measured by the FIQ , were significantly improved in the acupuncture group compared with the control group during the study period ( P = .01 ) . The largest difference in mean FIQ total scores was observed at 1 month ( 42.2 vs 34.8 in the control and acupuncture groups , respectively ; P = .007 ) . Fatigue and anxiety were the most significantly improved symptoms during the follow-up period . However , activity and physical function levels did not change . Acupuncture was well tolerated , with minimal adverse effects . CONCLUSION This study paradigm allows for controlled and blinded clinical trials of acupuncture . We found that acupuncture significantly improved symptoms of fibromyalgia . Symptomatic improvement was not restricted to pain relief and was most significant for fatigue and anxiety [19480864] OBJECTIVE To investigate the remote effect of acupuncture on the pain intensity and the endplate noise ( EPN ) recorded from a myofascial trigger point ( MTrP ) of the upper trapezius muscle . DESIGN R and omized controlled trial . SETTING University hospital . PARTICIPANTS Patients ( N=20 ) with active MTrPs in upper trapezius muscles and no experience in acupuncture therapy . INTERVENTIONS Patients were divided into 2 groups . Those in the control group received sham acupuncture , and those in the acupuncture group received modified acupuncture therapy with needle insertion into multiple loci to elicit local twitch responses . The acupuncture points of Wai-guan and Qu-chi were treated . MAIN OUTCOME MEASURES Subjective pain intensity ( numerical pain rating scale ) and mean EPN amplitude in the MTrP of the upper trapezius muscle . RESULTS The pain intensity in the MTrP was significantly reduced after remote acupuncture ( from 7.4+/-0.8 to 3.3+/-1.1 ; P<.001 ) , but not after sham acupuncture ( from 7.4+/-0.8 to 7.1+/-0.9 ; P>.05 ) . The mean EPN amplitude was significantly lower than the pretreatment level after acupuncture treatment ( from 21.3+/-9.5 microV to 9.5+/-3.5 microV ; P<.01 ) , but not after sham acupuncture treatment ( from 19.6+/-7.6 microV to 19.3+/-7.8 microV ; P>.05 ) . The change in the pain intensity was significantly correlated with the change of EPN amplitude ( r=0.685 ) . CONCLUSIONS Both subjective changes in the pain intensity and objective changes of the EPN amplitude in the MTrP region of the upper trapezius muscle were found during and after acupuncture treatment at the remote ipsilateral acupuncture points . This study may further clarify the physiological basis of the remote effectiveness of acupuncture therapy for pain control [9656906] In patients with myofascial pain , painful trigger points are often treated using dry needling and local anesthetic injections . However , the therapeutic effect of these treatments has been poorly quantified , and the mechanism underlying the effect is poorly understood . In a r and omized , double-blind , double-placebo clinical trial , a pressure algometer was used to measure pain-pressure thresholds in the masseter and temporalis muscles of 30 subjects aged 23 to 53 years with myofascial pain in the jaws , before and after a series of dry needling treatments , local anesthetic injections , and simulated dry needling and local anesthetic treatments ( treatment group A : Procaine + simulated dry needling ; treatment group B : dry needling + simulated local anesthetic ; control group C : simulated local anesthetic + simulated dry needling ) . Subjects rated pain intensity and unpleasantness using visual analogue scales , and the data were analyzed using analysis of variance . Pain pressure thresholds increased slightly after treatment , irrespective of the treatment modality . Pain intensity and unpleasantness scores decreased significantly at the end of treatment in all groups . There were no statistically significant between-group differences in pain pressure thresholds and visual analogue scale scores at the end of treatment . The findings suggest that the general improvement in pain symptoms was the result of nonspecific , placebo-related factors rather than a true treatment effect . Thus , the therapeutic value of dry needling and Procaine in the management of myofascial pain in the jaw muscles is question able [11932074] & NA ; There is some evidence for the efficacy of acupuncture in chronic low‐back pain ( LBP ) , but it remains unclear whether acupuncture is superior to placebo . In a r and omized , blinded , placebo‐controlled trial , we evaluated the effect of traditional acupuncture in chronic LBP . A total of 131 consecutive out‐ patients of the Department of Orthopaedics , University Goettingen , Germany , ( age=48.1 years , 58.5 % female , duration of pain : 9.6 years ) with non‐radiating LBP for at least 6 months and a normal neurological examination were r and omized to one of three groups over 12 weeks . Each group received active physiotherapy over 12 weeks . The control group ( n=46 ) received no further treatment , the acupuncture group ( n=40 ) received 20 sessions of traditional acupuncture and the sham‐acupuncture group ( n=45 ) 20 sessions of minimal acupuncture . Changes from baseline to the end of treatment and to 9‐month follow‐up were assessed in pain intensity and in pain disability , and secondary in psychological distress and in spine flexion , compared by intervention groups . Acupuncture was superior to the control condition ( physiotherapy ) regarding pain intensity ( P=0.000 ) , pain disability ( P=0.000 ) , and psychological distress ( P=0.020 ) at the end of treatment . Compared to sham‐acupuncture , acupuncture reduced psychological distress ( P=0.040 ) only . At 9‐month follow‐up , the superiority of acupuncture compared to the control condition became less and acupuncture was not different to sham‐acupuncture . We found a significant improvement by traditional acupuncture in chronic LBP compared to routine care ( physiotherapy ) but not compared to sham‐acupuncture . The trial demonstrated a placebo effect of traditional acupuncture in chronic LBP [19433697] BACKGROUND Acupuncture is a popular complementary and alternative treatment for chronic back pain . Recent European trials suggest similar short-term benefits from real and sham acupuncture needling . This trial addresses the importance of needle placement and skin penetration in eliciting acupuncture effects for patients with chronic low back pain . METHODS A total of 638 adults with chronic mechanical low back pain were r and omized to individualized acupuncture , st and ardized acupuncture , simulated acupuncture , or usual care . Ten treatments were provided over 7 weeks by experienced acupuncturists . The primary outcomes were back-related dysfunction ( Rol and -Morris Disability Question naire score ; range , 0 - 23 ) and symptom bothersomeness ( 0 - 10 scale ) . Outcomes were assessed at baseline and after 8 , 26 , and 52 weeks . RESULTS At 8 weeks , mean dysfunction scores for the individualized , st and ardized , and simulated acupuncture groups improved by 4.4 , 4.5 , and 4.4 points , respectively , compared with 2.1 points for those receiving usual care ( P < .001 ) . Participants receiving real or simulated acupuncture were more likely than those receiving usual care to experience clinical ly meaningful improvements on the dysfunction scale ( 60 % vs 39 % ; P < .001 ) . Symptoms improved by 1.6 to 1.9 points in the treatment groups compared with 0.7 points in the usual care group ( P < .001 ) . After 1 year , participants in the treatment groups were more likely than those receiving usual care to experience clinical ly meaningful improvements in dysfunction ( 59 % to 65 % vs 50 % , respectively ; P = .02 ) but not in symptoms ( P > .05 ) . CONCLUSIONS Although acupuncture was found effective for chronic low back pain , tailoring needling sites to each patient and penetration of the skin appear to be unimportant in eliciting therapeutic benefits . These findings raise questions about acupuncture 's purported mechanisms of action . It remains unclear whether acupuncture or our simulated method of acupuncture provide physiologically important stimulation or represent placebo or nonspecific effects [2174514] Background In planning a r and omized controlled trial of acupuncture , we conducted a pilot study using vali date d outcome measures to assess the feasibility of the protocol , and to obtain preliminary data on efficacy and tolerability of 3 different forms of acupuncture treatment as an adjunct for the treatment of chronic pain in patients with Rheumatoid arthritis ( RA ) . Methods The study employs a r and omized , prospect i ve , double-blind , placebo-controlled trial to evaluate the effect of electroacupuncture ( EA ) , traditional Chinese acupuncture ( TCA ) and sham acupuncture ( Sham ) in patients with RA . All patients received 20 sessions over a period of 10 weeks . Six acupuncture points were chosen . Primary outcome is the changes in the pain score . Secondary outcomes included the changes in the ACR core disease measures , DAS 28 score and the number of patients who achieved ACR 20 at week 10 . Results From 80 eligible patients , 36 patients with mean age of 58 ± 10 years and disease duration of 9.3 ± 6.4 years were recruited . Twelve patients were r and omized to each group . Twelve , 10 and 7 patients from the EA , TCA and Sham group respectively completed the study at 20 weeks ( p < 0.03 ) ; all except one of the premature dropouts were due to lack of efficacy . At week 10 , the pain score remained unchanged in all 3 groups . The number of tender joints was significantly reduced for the EA and TCA groups . Physician 's global score was significantly reduced for the EA group and patient 's global score was significantly reduced for the TCA group . All the outcomes except patient 's global score remained unchanged in the Sham group . Conclusion This pilot study has allowed a number of recommendations to be made to facilitate the design of a large-scale trial , which in turn will help to clarify the existing evidence base on acupuncture for RA.Trial registration Clinical Trials.gov [20178876] OBJECTIVES To examine Australian acupuncturists ' perspectives of : chronic low back pain outcome domains ; their use of outcome measures to assess chronic low back pain ; and their attitudes and perceptions of barriers to using the existing measures to evaluate acupuncture care for chronic low back pain . DESIGN A postal question naire was used in a cross-sectional survey . PARTICIPANTS 359 r and omly selected Australian acupuncturists . RESULTS 139 question naires were returned ( response rate : 38.7 % ) . The respondents ' demographic characteristics were similar to Australian Bureau of Statistics acupuncturist demographic data . Overall , acupuncturists endorsed a broad approach to assessing acupuncture care for chronic low back pain . However , they had typically used pain severity measures but generally did not use other types of measures . Acupuncturists tended to hold positive attitudes towards using outcome measures . The principal barriers acupuncturists perceived to using outcome measures concerned doubts about whether the concepts which underpin acupuncture practice had been explicitly articulated and whether the available measures capture the specific context and particular outcomes of acupuncture care for chronic low back pain . IMPLICATION S The findings of this study suggest that a broad range of outcome measures are required to adequately assess chronic low back pain acupuncture care outcomes . While numerous outcome measures have been developed that are relevant to chronic low back pain care , whether these measures are appropriate for use by acupuncturists is unclear . Further studies are warranted to explore if established outcome measures are useful to evaluate chronic low back acupuncture care [11829164] Acupuncture is increasingly used , so it is important to establish whether its benefits outweigh its risks . Numerous case reports of adverse events show that acupuncture is not free of risk , but accurate data from prospect i ve investigations is scarce . A prospect i ve survey was undertaken using intensive event monitoring . Forms were developed for reporting minor events each month and significant events as they occurred . The sample size was calculated to identify any adverse events that occurred more frequently than once in 10,000 consultations . Acupuncturists were recruited from two professional organisations in the UK . Seventy-eight acupuncturists , all doctors or physiotherapists , reported a total of 2178 events occurring in 31,822 consultations , an incidence of 684 per 10,000 consultations . The most common minor adverse events were bleeding , needling pain , and aggravation of symptoms ; aggravation was followed by resolution of symptoms in 70 % of cases . There were 43 significant minor adverse events reported , a rate of 14 per 10,000 , of which 13 ( 30 % ) interfered with daily activities . One patient suffered a seizure ( probably reflex anoxic ) during acupuncture , but no adverse event was classified as serious . Avoidable events included forgotten patients , needles left in patients , cellulitis and moxa burns . In conclusion , the incidence of adverse events following acupuncture performed by doctors and physiotherapists can be classified as minimal ; some avoidable events do occur . Acupuncture seems , in skilled h and s , one of the safer forms of medical intervention [17908569] OBJECTIVE To determine the efficacy of acupuncture in the treatment of chronic musculoskeletal shoulder pain in subjects with spinal cord injury ( SCI ) . DESIGN R and omized , double blind ( participants , evaluator ) , placebo ( invasive sham ) controlled trial . SETTING Clinical research center . PARTICIPANTS Seventeen manual wheelchair-using subjects with chronic SCI and chronic musculoskeletal shoulder pain . INTERVENTIONS Participants were r and omly assigned to receive 10 treatments of either acupuncture or invasive sham acupuncture ( light needling of nonacupuncture points ) . MAIN OUTCOME MEASURE Changes in shoulder pain intensity were measured using the Wheelchair User 's Shoulder Pain Index . RESULTS Shoulder pain decreased significantly over time in both the acupuncture and the sham acupuncture groups ( P=.005 ) , with decreases of 66 % and 43 % , respectively . There was no significant difference between the 2 groups ( P=.364 ) . There was , however , a medium effect size associated with the acupuncture treatment . CONCLUSIONS There appears to be an analgesic effect or a powerful placebo effect associated with both acupuncture and sham acupuncture . There was a medium treatment effect associated with the acupuncture , which suggests that it may be superior to sham acupuncture . This observation , along with the limited power , indicates that a larger , more definitive r and omized controlled trial using a similar design is warranted [20466596] UNLABELLED The equivalency of behavioral interventions has led to the consideration of whether patient-related factors influence clinical trial outcomes . The primary purpose of this secondary analysis was to determine if treatment preference and patient expectation were predictors of trial outcomes and if selected patient-satisfaction items were appropriate as outcome measures . Perceived effectiveness , treatment preference , and patient expectation were assessed before r and om assignment , and patient satisfaction was assessed 6 months later . Patient preference was associated with perceived effectiveness for those with no treatment preference and those preferring grade d exposure . Higher patient expectation was associated with higher perceived effectiveness ratings for all treatments in the clinical trial . Patients with no strong treatment preferences had larger 6-month improvements in pain intensity and disability , while patients with higher expectations had lower disability at baseline , 4 weeks , and 6 months . Patient satisfaction rates did not differ based on treatment received . Patient satisfaction was highest with treatment delivery and much lower with treatment effect . Patient satisfaction was uniformly associated with expectations being met , but only satisfaction with treatment effect was associated with lower pain and disability scores . These data support assessment of treatment preference and patient expectation as predictors and patient satisfaction as an outcome measure in low back pain ( LBP ) clinical trials . PERSPECTIVE These data indicate treatment preference potentially impacts rate of improvement for patients with low back pain . Patient expectation did not impact rate of improvement , but those with higher expectations had lower pain and disability scores throughout the trial . Optimal assessment of patient satisfaction should include items that separately consider treatment delivery and effect [15103431] The cerebral activation pattern due to acupuncture is not completely understood . Although the effect of acupuncture on cerebral haemodynamics has been studied , no previous report has focused on different puncture and stimulation methods . We used functional MRI ( fMRI ) in 15 healthy subjects to investigate cortical activation during stimulation of two real acupoints ( Liv3 and G40 ) and one sham point , needled in a r and om and , for the subjects , blinded order employing rotating and non-rotating methods , using a blocked paradigm on a 1.5 tesla imager . Compared to the non-rotating stimulation method , during rotating stimulation of the real acupoints , we observed an increase in activation in both secondary somatosensory cortical areas , frontal areas , the right side of the thalamus and the left side of the cerebellum ; no such effects of the needling technique were seen while stimulating the sham point . The observation that rotating the needle strengthened the effects of acupuncture only at real acupoints suggests that , as cl aim ed in Chinese traditional medicine , stimulation of these acupoints has a specific effect on cortical neuronal activity , absent with sham acupoints . These specific cerebral activation patterns might explain the therapeutic effects of acupuncture in certain subjects [24316509] Objective To assess the efficacy of Yamamoto 's acupuncture method on pain , drug intake , functional capacity and quality of life for the treatment of acute non-specific low back pain ( ANLBP ) . Methods A prospect i ve , r and omised , parallel-group , double-blind , placebo-controlled trial was performed in 80 men and women with ANLBP who were r and omly assigned to five acupuncture sessions ( intervention group ( IG ) , n=40 ) and to five non-penetrating acupuncture sessions ( sham group ( SG ) , n=40 ) . Patients were evaluated at baseline and at 3 , 7 , 14 , 21 and 28 days . The measurements used were : visual analogue scale ( VAS ) for cumulative pain ( before intervention , VAS1 ) and immediate pain ( after intervention , VAS2 ) ; function ( Rol and –Morris Disability Question naire ( RM ) ) ; quality of life ( SF-36 ) ; improvement rating ; and number of anti-inflammatory tablets taken . The primary endpoint was a decrease of at least 2 cm in VAS1 . Results Pain VAS improved significantly in the IG from day 14 onwards compared with the SG , but the difference did not reach the prespecified clinical ly relevant value of 2 cm . The IG was significantly superior to the SG in the following outcomes : cumulative pain , function , pain ( SF-36 ) and vitality ( SF-36 ) at days 14 , 21 and 28 ( p<0.05 ) ; limitation in physical aspects ( SF-36 ) at all times ( p=0.007 and p=0.02 ) ; and functional capacity ( SF-36 ) at days 21 and 28 ( p<0.05 ) . The IG also took significantly fewer anti-inflammatory tablets than the SG ( p=0.004 ) at all evaluation times and the improvement rating was better than the SG ( p<0.001 ) . Conclusions Yamamoto 's new scalp acupuncture was more effective than sham treatment with regard to decrease in pain and anti-inflammatory intake as well as improving functional status and quality of life for patients with ANLBP . Clinical Trials.gov NCT 01124955 [7727550] OBJECTIVE The purpose of this study was to determine whether acupuncture was more effective than sham acupuncture in the reduction of pain in persons with osteoarthritis ( OA ) of the knee . METHODS Forty subjects ( 20 men , 20 women ) with radiographic evidence of OA of the knee were stratified by gender and r and omly assigned to either the experimental ( real acupuncture ) or control ( sham acupuncture ) groups . Subjects were treated three times per week for 3 weeks and evaluated at three test sessions . Outcome measures were : 1 ) the Pain Rating Index of the McGill Pain Question naire , 2 ) the Western Ontario and McMaster Universities ( WOMAC ) Osteoarthritis Index , and 3 ) pain threshold at four sites at the knee . RESULTS The analyses of variance showed that both real and sham acupuncture significantly reduced pain , stiffness , and physical disability in the OA knee , but that there were no significant differences between groups . CONCLUSIONS Acupuncture is not more effective than sham acupuncture in the treatment of OA pain [1097921] Forty patients , r and omly assigned to an experimental and a control group , participated in a double-blind study to assess the effectiveness of acupuncture in reducing chronic pain associated with osteoarthritis . The experimental group received treatment at st and ard acupuncture points , and the control group at placebo points . Analysis before and after treatment showed a significant ( P less than 0.05 ) improvement in tenderness and subjective report of pain in both groups as evaluated by two independent observers and in activity by one observer . Comparison of responses to treatment between the two groups showed no significant ( P greater than 0.05 ) difference . Thus , both experimental and control groups showed a reduction in pain after the treatments . These results may reflect the natural course of illness , and various attitudinal and social factors [18534326] OBJECTIVE A pilot study to assess the feasibility of a trial to investigate the efficacy of acupuncture compared to placebo needling for the treatment of acute low back pain ( LBP ) . As part of this , the study was design ed to establish the credibility of the placebo control , and to provide data to inform a power analysis to determine numbers for a future trial . STUDY DESIGN A pilot patient and assessor blinded r and omized controlled trial . SETTING Primary care health centre facility , South and East Belfast Trust , Northern Irel and . PATIENTS Patients from the physiotherapy waiting list ( n=48 ) with LBP of less than 12 weeks duration . OUTCOME MEASURES Rol and and Morris Disability Question naire ( RMDQ ) , Visual Analogue Scale ( VAS ) , medication use and an exit question naire were completed at baseline , end of treatment , and at 3 months follow up . RESULTS Ninety-four percent ( 45/48 ) of patients completed assigned treatment , 83 % ( 40/48 ) completed 3 months follow-up . The sham needle used here proved to be credible : 91.7 % in the placebo group believed they had received acupuncture , compared to 95.8 % in the verum acupuncture group . Differences in baseline characteristics were accounted for using ANCOVA . There was no significant difference between groups on the RMDQ over time . For pain , the only statistically significant difference was at the 3 months follow up ( worst VAS , point estimate , 18.7 , 95 % CI 1.5 - 36.0 , p=0.034 ) . The majority of patients were taking some form of analgesic medication for LBP at the start of treatment ( n=44 ; 92 % ) , and at the end of treatment the verum acupuncture group were taking significantly fewer tablets of pain control medication ( mean ( S.D. ) : 1.0+/-0.3 ) than the placebo group ( mean ( S.D. ) : 4.2+/-0.6 , p<0.05 ) . Based upon these data , power analysis ( power=90 % , alpha=0.05 , minimal clinical ly important difference ( MCID ) for RMDQ=2.5 points ) indicated that 120 participants ( 60 per group ) would be needed to complete an adequately powered r and omized controlled trial . CONCLUSIONS This study has demonstrated the feasibility of a r and omized controlled trial of penetrating needle acupuncture compared to a non-penetrating sham for the treatment of acute LBP in primary care ; 120 participants would be required in a fully powered trial . The placebo needle used in this study proved to be a credible form of control [20578644] The aim of this study was to compare the efficacy of electroacupuncture and sham acupuncture in the treatment of patients with chronic neck pain . 31 patients with chronic neck pain were included in a r and omised , controlled trial . Electric stimulation was given for 30 minutes at low frequency ( 1 - 4Hz ) , pulse width of 200 micros , interrupted wave form . Of the 29 patients who completed the therapy , 13 were assigned to conventional acupuncture and 16 to sham acupuncture groups , receiving 3 sessions a week for a total of 10 sessions , each lasting for 30 minutes . Patients were evaluated before and after therapy and 3 months later by Visual Analogue Scale ( VAS ) and the bodily pain subscale of the Short Form Health Survey-36 scale . The treating physician was different from the evaluating physician who , like the patient , was blinded . VAS scores in both groups significantly reduced after therapy and at 3 months post-therapy , but the difference between groups was not significant . In respect of bodily pain , there was a significant improvement in the acupuncture group after therapy ( P<0.01 ) . Stimulation of conventional acupuncture points was not generally superior to needling ofnonspecific points on the neck , and both treatments were associated with improvement of symptoms . Needles inserted into the neck are likely to be an inappropriate sham control for acupuncture [23138883] The objective of this study was to test the hypothesis that dry needling is more effective than sham dry needling in the treatment of myofascial pain syndrome ( MPS ) . This was a prospect i ve , double-blinded , r and omized-controlled study conducted in an outpatient clinic . Thirty-nine subjects with established myofascial trigger points were r and omized into two groups : study group ( N = 22 ) and placebo group ( N = 17 ) . Dry needling was applied using acupuncture needles , and sham dry needling was applied in the placebo group . The treatment was composed of six sessions which were performed in 4 weeks ; the first four sessions were performed twice a week ( for 2 weeks ) and the last two , once a week ( for 2 weeks ) . The visual analog scale ( VAS ) and Short Form-36 ( SF-36 ) were used . When compared with the initial values , VAS scores of the dry needling group following the first and sixth sessions were significantly lower ( p = 0.000 and p < 0.000 , respectively ) . When VAS scores were compared between the groups , the first assessment scores were found to be similar , but the second and third assessment scores were found to be significantly lower in the dry needling group ( p = 0.034 and p < 0.001 , respectively ) . When SF-36 scores of the groups were compared , both the physical and mental component scores were found to be significantly increased in the dry needling group , whereas only those of vitality scores were found to be increased significantly in the placebo ( sham needling ) group . The present study shows that the dry needling treatment is effective in relieving the pain and in improving the quality of life of patients with MPS [15157691] & NA ; The study was carried out to examine whether acupuncture treatment can reduce chronic pain in the neck and shoulders and related headache , and also to examine whether possible effects are long‐lasting . Therefore , 24 female office workers ( 47±9 years old , mean±SD ) who had had neck and shoulder pain for 12±9 years were r and omly assigned to a test group ( TG ) or a control group ( CG ) . Acupuncture was applied 10 times during 3–4 weeks either at presumed anti‐pain acupoints ( TG ) or at placebo‐points ( CG ) . A physician measured the pain threshold ( PPT ) in the neck and shoulder regions with algometry before the first treatment , and after the last one and six months after the treatments . Question naires on muscle pain and headache were answered at the same occasions and again 3 years after the last treatment . The intensity and frequency of pain fell more for TG than for CG ( Pb≤0.04 ) during the treatment period . Three years after the treatments TG still reported less pain than before the treatments ( Pw<0.001 ) , contrary to what CG did ( Pb<0.04 ) . The degree of headache fell during the treatment period for both groups , but more for TG than for CG ( Pb=0.02 ) . Three years after the treatments the effect still lasted for TG ( Pw<0.001 ) while the degree of headache for CG was back to the pre‐treatment level ( Pb<0.001 ) . PPT of some muscles rose during the treatments for TG and remained higher 6 months after the treatments ( Pw<0.05 ) , which contrasts the situation for CG . Adequate acupuncture treatment may reduce chronic pain in the neck and shoulders and related headache . The effect lasted for 3 years [23220812] BACKGROUND AND OBJECTIVES To test the hypothesis that dry needling is more effective than sham dry needling in relieving myofascial pain of the temporom and ibular muscles . MATERIAL AND METHOD Fifty-two subjects with established myofascial trigger points were r and omized into two groups ; study group ( N : 26 ) and placebo group ( N : 26 ) . Dry needling was applied using acupuncture needles . Sham dry needling was applied to the placebo group . Pain pressure threshold was measured with pressure algometry , pain intensity was rated using a 10-cm visual analog scale ( VAS ) and the unassisted jaw opening without pain measurement was performed . Evaluations were done by a physician blinded to the data . RESULTS Of 52 patients assigned , 50 completed the study . Mean algometric values were significantly higher in the study group when compared to the placebo group ( p values being less than 0.05 ) . There were no differences between the two groups in terms of VAS and unassisted jaw-opening without pain values . CONCLUSION Dry needling appears to be an effective treatment method in relieving the pain and tenderness of myofascial trigger points [15998750] Context A substantial number of patients use acupuncture to treat the symptoms of fibromyalgia , but previous r and omized trials of this intervention are inconclusive , in part because of control groups that did not permit adequate blinding of the patients . Contribution This study r and omly assigned 100 patients with fibromyalgia to 12 weeks of either true acupuncture treatment or one of 3 types of sham acupuncture . No differences in pain were identified between acupuncture and sham acupuncture . Caution s The study had too few patients to detect small differences between the groups . Patients could use other fibromyalgia therapies , so this study evaluates acupuncture as adjunctive treatment . The Editors Fibromyalgia is a condition of unknown cause that is characterized by chronic , diffuse pain and tenderness to palpation at specific musculoskeletal sites ( 1 ) . It is the second most common rheumatologic condition after osteoarthritis , afflicting 2 % to 4 % of the U.S. population ( 2 ) . Most r and omized , controlled trials of allopathic interventions have not demonstrated sustained benefit , and use of complementary and alternative medicine for fibromyalgia is common ( 3 ) . For example , 60 % to 90 % of patients with fibromyalgia report using 1 or more complementary or alternative treatments ( 4 , 5 ) , and 22 % of these patients have tried acupuncture ( 6 ) . Despite skepticism in western cultures , the literature suggests that acupuncture may alleviate chronic pain ( 7 ) . R and omized , controlled trials of acupuncture face many method ologic challenges , including the identification of appropriate treatment and control groups , blinding of study participants , and the inability to blind practitioners ( 8) . Needle placement and the extent to which needle insertion and stimulation is necessary are also controversial ( 7 - 9 ) . In the only rigorous r and omized , controlled trial of acupuncture for fibromyalgia , 7 of 8 outcome measures significantly improved after 3 weeks of treatment with electroacupuncture ( 10 ) . However , because blinding was not assessed and electroacupuncture involves perceptible current , these promising results could reflect a lack of blinding to treatment condition . Moreover , the study followed patients only during treatment . Because fibromyalgia is a chronic condition , longer-term outcomes should be examined . To address these method ologic problems , we performed a r and omized , controlled trial of acupuncture to treat fibromyalgia that included 3 sham acupuncture treatments to account for the effects of needle insertion and placement . The adequacy of participant blinding was carefully evaluated . We sought to determine whether directed acupuncture that is design ed to treat fibromyalgia relieves pain better than does sham acupuncture in adults with fibromyalgia . On the basis of the scant literature and our clinical experience , we hypothesized a priori that directed acupuncture would result in the greatest clinical improvement . Methods Participants Participants were recruited from the greater Seattle , Washington , metropolitan area between January 2001 and September 2002 . Recruitment strategies included dissemination of information on the study through newspapers , television , advertisements , signs posted at university-affiliated hospitals , and letters to local fibromyalgia support groups and health care providers with large caseloads of patients with fibromyalgia . Potential participants were told that they had an equal chance of being assigned to 1 of 4 acupuncture interventions , none of which have been proven but 1 of which was believed to have the most potential to improve the symptoms of fibromyalgia . The institutional review boards at the participating institutions approved the study , and participants provided written informed consent . Eligible participants were English-speaking adults 18 years of age or older in whom fibromyalgia was diagnosed by a physician and who had a prer and omization global pain score of 4 or greater on a visual analogue scale ( 0 = no pain , 10 = worst pain ever ) . Participants agreed to undergo r and omization and kept use of any fibromyalgia-related pharmacologic and nonpharmacologic therapies constant throughout the study . At the baseline evaluation before r and omization , a research coordinator trained in tender-point examination confirmed the diagnosis of fibromyalgia by using the 1990 criteria of the American College of Rheumatology ( 1 ) . Participants were excluded if they reported other pain-related medical conditions or potential contraindications to acupuncture treatment ( such as bleeding disorders or severe needle phobia ) , were pregnant or breastfeeding , used narcotics ( which could blunt the effects of acupuncture ) , were involved in litigation related to fibromyalgia ( which might reduce their incentive for improvement ) , or had previously received acupuncture ( to maximize blinding ) . R and omization Procedure A research coordinator screened and enrolled participants at an academic research center . After participants completed a baseline evaluation , another research coordinator who was uninvolved with data collection r and omly assigned them to 1 of 4 treatment groups by using a computer-generated , blocked r and om-allocation sequence with a block size of 4 . This research coordinator informed the acupuncture clinic of the treatment assignment . Intervention Eight U.S.-trained and licensed acupuncturists with a median of 10 years of experience ( range , 4 to 18 years ) provided study treatments in their private offices . One investigator trained the acupuncturists in the study procedures to increase their comfort with delivering all 4 treatments and monitored compliance with the protocol throughout the study . Participants were assigned an acupuncturist according to geographic convenience and schedule availability , and every effort was made to have them treated by the same acupuncturist for the entire 12 weeks . The primary acupuncturist was defined as the practitioner from whom a participant received the most treatments . In all groups , participants were asked to attend treatment sessions twice weekly for 12 weeks ( 24 treatments ) . We considered participants who attended 80 % or more ( 19 of 24 ) of acupuncture appointments to have completed a full course of treatment . Outcome measures were collected at regularly scheduled time points from participants who discontinued treatment . Participants received directed acupuncture design ed to treat fibromyalgia according to the practice of Traditional Chinese Medicine or 1 of 3 sham acupuncture treatments . One sham intervention , a control for acupoint specificity , involved acupuncture typically used to treat irregular menses or early menses due to Blood Heat ( an unrelated condition ) according to Traditional Chinese Medicine . Another sham intervention , which was also a control for acupoint specificity , used body locations not recognized as true acupoints or meridians for needling ( sham needling ) . The third sham treatment , a control for needle insertion , consisted of noninsertive simulated acupuncture at the same acupoints used in directed acupuncture ( simulated acupuncture ) . This technique , in which a toothpick in a needle guide-tube is used to mimic needle insertion and withdrawal , has been shown to be indistinguishable from true acupuncture in acupuncture-nave patients with back pain ( 9 ) . Simulated acupuncture more closely duplicates the needle insertion experience than do techniques using placebo needles that require placing adhesive or plastic foam on the skin ( 11 , 12 ) . Acupoints and sham points ( Appendix Figure ) were chosen by a study acupuncturist with 15 years of experience in treating fibromyalgia and were approved by 3 other senior acupuncturists . In all groups that underwent needle insertion , needles were retained at st and ard depths ( 13 ) for 30 minutes at each acupoint . Disposable Chinese , Japanese , or Korean needles ( 34 to 40 gauge ) were used , depending on the practitioner 's preference . In the simulated acupuncture group , participants remained on the table for 30 minutes after simulated insertion and then underwent simulated needle withdrawal . Efforts were made to imitate the sounds of opening needle packs and needle disposal . Acupuncturists were not blinded to the treatments they delivered . To maximize participant blinding , we included only acupuncture-nave persons who could not compare their treatment with previous experiences with acupuncture , limited contact among study participants , restricted conversation between acupuncturists and participants , and blindfolded participants during treatment . All research personnel who collected or analyzed data were unaware of treatment group . At the end of 12 weeks , we collected data to assess the adequacy of blinding . Outcome Measures Demographic measures collected at the baseline evaluation included age , sex , race , education , marital status , and duration of pain and diagnosis of fibromyalgia . Participants also listed the types of therapies they had previously tried for their pain . We grouped this information into manual therapies ( physical , ergonometric , chiropractic , or massage therapy ) , mental health therapies ( psychotherapy or cognitive behavioral therapy ) , dietary changes , or other therapies ( nerve blocks , hypnosis , or biofeedback ) . Outcome measures were collected at baseline ; after 1 , 4 , 8 , and 12 weeks of acupuncture treatment ; and 3 and 6 months after completion of treatment ( weeks 24 and 36 ) . The primary outcome was subjective pain , as measured by a st and ard 10-cm visual analogue scale ( 0 = no pain , 10 = worst pain ever ) . Other outcomes measured by using a visual analogue scale were intensity of fatigue ( 0 = none , 10 = worst ever ) , sleep quality ( 0 = worst ever , 10 = best ever ) , and overall well-being ( 0 = worst ever , 10 = best ever ) . We assessed physical and mental functioning by using the Medical Outcomes Study 36-item Short-Form Health Survey ( 14 ) , which has high reliability and validity in many patient groups , including [16618043] Introduction There is some evidence for the efficacy of acupuncture , but it remains unclear whether trigger point acupuncture is effective . Our objective was to evaluate the effects of trigger point acupuncture on pain and quality of life in chronic low back pain patients compared with sham acupuncture . Methods Twenty-six consecutive out- patients ( 17 women , 9 men ; age range : 65–91 years ) from the Department of Orthopaedic Surgery , Meiji University of Oriental Medicine , with non-radiating low back pain for at least six months and normal neurological examination , were r and omised to two groups . Each group received one phase of trigger point acupuncture and one of sham acupuncture with a three week washout period between them , over 12 weeks . Group A ( n=13 ) received trigger point acupuncture in the first phase and sham acupuncture in the second . Group B ( n=13 ) received the same interventions in the reverse order . Outcome measures were pain intensity ( visual analogue scale , VAS ) and Rol and Morris Question naire . Results Nineteen patients were included in the analysis . At the end of the first treatment phase , group A receiving trigger point acupuncture scored significantly lower VAS ( P<0.001 ) and Rol and Morris Question naire scores ( P<0.01 ) than the sham control group . There were significant within-group reductions in pain in both groups during the trigger point acupuncture phase but not in the sham treatment phase . However , the beneficial effects were not sustained . Conclusion These results suggest that trigger point acupuncture may have greater short term effects on low back pain in elderly patients than sham acupuncture [21195294] OBJECTIVES This study aim ed to determine whether a non-penetrating sham needle can serve as an adequate sham control . DESIGN We conducted a r and omised , subject-blind , sham-controlled trial in both acupuncture-naïve and experienced healthy volunteers . SETTING AND INTERVENTIONS Participants were r and omly allocated to receive either real acupuncture ( n=39 ) or non-penetrating sham acupuncture ( n=40 ) on the h and ( LI4 ) , abdomen ( CV12 ) and leg ( ST36 ) . The procedures were st and ardised and identical for both groups . MAIN OUTCOME MEASURES Participants rated acupuncture sensations on a 10-point scale . A blinding index was calculated based on the participants ' guesses on the type of acupuncture they had received ( real , sham or do not know ) for each acupuncture point . The association of knowledge about and experience in acupuncture with correct guessing was also examined . RESULTS The subjects in both groups were similar with respect to age , gender , experience or knowledge about acupuncture . The sham needle tended to produce less penetration , pain and soreness only at LI4 . Blinding appeared to be successfully achieved for ST36 . Although 41 % of participants in the real acupuncture group made correct guesses for LI4 , 31 % guessed incorrectly for CV12 , beyond chance level . People with more experience and knowledge about acupuncture were more likely to correctly guess the type of needle they received at ST36 only , compared to that at the other points . CONCLUSIONS A non-penetrating sham needle may successfully blind participants and thus , may be a credible sham control . However , the small sample size , the different needle sensations , and the degree and direction of unblinding across acupuncture points warrant further studies in Korea as well as other countries to confirm our finding . Our results also justify the incorporation of formal testing of the use of sham controls in clinical trials of acupuncture [22727499] Summary Acupuncture is a useful and safe adjunctive therapy to pharmacological treatment in the short term management of knee osteoarthritis . Abstract The efficacy of acupuncture as an adjunctive therapy to pharmacological treatment of chronic pain due to knee osteoarthritis was studied with a 3‐armed , single‐blind , r and omized , sham‐controlled trial ; it compared acupuncture combined with pharmacological treatment , sham acupuncture including pharmacological treatment , and pharmacological treatment alone . A total of 120 patients with knee osteoarthritis were r and omly allocated to 3 groups : group I was treated with acupuncture and etoricoxib , group II with sham acupuncture and etoricoxib , and group III with etoricoxib . The primary efficacy variable was the Western Ontario and McMaster Universities ( WOMAC ) index and its subscales at the end of treatment at week 8 . Secondary efficacy variables included the WOMAC index at the end of weeks 4 and 12 , a visual analogue scale ( VAS ) at the end of weeks 4 , 8 , and 12 , and the Short Form 36 version 2 ( SF‐36v2 ) health survey at the end of week 8 . An algometer was used to determine changes in a predetermined unique fixed trigger point for every patient at the end of weeks 4 , 8 , and 12 . Group I exhibited statistically significant improvements in primary and secondary outcome measures , except for Short Form mental component , compared with the other treatment groups . We conclude that acupuncture with etoricoxib is more effective than sham acupuncture with etoricoxib , or etoricoxib alone for the treatment of knee osteoarthritis [19404189] Tsai C-T , Hsieh L-F , Kuan T-S , Kao MJ , Chou L-W , Hong C-Z : Remote effects of dry needling on the irritability of the myofascial trigger point in the upper trapezius muscle . Objective : To investigate the remote effect of dry needling on the irritability of a myofascial trigger point in the upper trapezius muscle . Design : Thirty-five patients with active myofascial trigger points in upper trapezius muscles were r and omly divided into two groups : 18 patients in the control group received sham needling , and 17 patients in the dry-needling group received dry needling into the myofascial trigger point in the extensor carpi radialis longus muscle . The subjective pain intensity , pressure pain threshold , and range of motion of the neck were assessed before and immediately after the treatment . Results : Immediately after dry needling in the experimental group , the mean pain intensity was significantly reduced , but the mean pressure threshold and the mean range of motion of cervical spine were significantly increased . There were significantly larger changes in all three parameters of measurement in the dry-needling group than that in the control group . Conclusions : This study demonstrated the remote effectiveness of dry needling . Dry needling of a distal myofascial trigger point can provide a remote effect to reduce the irritability of a proximal myofascial trigger point [17257756] Abstract In a pooled analysis of four r and omized controlled trials of acupuncture in patients with migraine , tension‐type headache , chronic low back pain , and osteoarthritis of the knee we investigated the influence of expectations on clinical outcome . The 864 patients included in the analysis received either 12 sessions of acupuncture or minimal ( i.e. sham ) acupuncture ( superficial needling of non‐acupuncture points ) over an 8 week period . Patients were asked at baseline whether they considered acupuncture to be an effective therapy in general and what they personally expected from the treatment . After three acupuncture sessions patients were asked how confident they were that they would benefit from the treatment strategy they were receiving . Patients were classified as responders if the respective main outcome measure improved by at least fifty percent . Both univariate and multivariate analyses adjusted for potential confounders ( such as condition , intervention group , age , sex , duration of complaints , etc . ) consistently showed a significant influence of attitudes and expectations on outcome . After completion of treatment , the odds ratio for response between patients considering acupuncture an effective or highly effective therapy and patients who were more sceptical was 1.67 ( 95 % confidence interval 1.20–2.32 ) . For personal expectations and confidence after the third session , odds ratios were 2.03 ( 1.26–3.26 ) and 2.35 ( 1.68–3.30 ) , respectively . Results from the 6‐month follow‐up were similar . In conclusion , in our trials a significant association was shown between better improvement and higher outcome expectations [17013356] Background The purpose of this study was to examine the immediate effect of single acupuncture stimulation to the most painful point in patients with low back pain . Method A r and omised , evaluator-blinded , sham controlled clinical trial was conducted in which 31 patients with low back pain were r and omly allocated to either an acupuncture group ( n=15 ) or a sham acupuncture group ( n=16 ) . Both acupuncture and sham acupuncture were performed at the most painful point on the lower back of the subjects . For the acupuncture group , a stainless steel needle was inserted to a depth of 20 mm and manually stimulated ( sparrow pecking method ) for 20 seconds , while for the sham treatment a guide tube without a needle was placed at the point and tapped on the skin . Changes in low back pain were evaluated with a visual analogue scale ( VAS ) and the Schober test . Participants were also asked if they felt the needling sensation or not . The therapy and the evaluation were independently performed by two different acupuncturists . Results VAS score and the Schober test score showed significant improvement after treatment as compared with the sham group ( P=0.02 , 0.001 , respectively ) . There were no significant differences in the needling sensation between the acupuncture and sham group . Conclusion These results suggest that acupuncture at the most painful point gives immediate relief of low back pain [16131290] OBJECTIVES The objective of this study was to investigate whether typical acupuncture methods such as needle placement , needle stimulation , and treatment frequency were important factors in fibromyalgia symptom improvement . DESIGN / SETTING S/SUBJECTS : A single-site , single-blind , r and omized trial of 114 participants diagnosed with fibromyalgia for at least 1 year was performed . INTERVENTION Participants were r and omized to one of four treatment groups : ( 1 ) T/S needles placed in traditional sites with manual needle stimulation ( n = 29 ) : ( 2 ) T/0 traditional needle location without stimulation ( n = 30 ) ; ( 3 ) N/S needles inserted in nontraditional locations that were not thought to be acupuncture sites , with stimulation ( n = 28 ) ; and ( 4 ) N/0 nontraditional needle location without stimulation ( n = 2 7 ) . All groups received treatment once weekly , followed by twice weekly , and finally three times weekly , for a total of 18 treatments . Each increase in frequency was separated by a 2-week washout period . OUTCOME MEASURES Pain was assessed by a numerical rating scale , fatigue by the Multi-dimensional Fatigue Inventory , and physical function by the Short Form-36 . RESULTS Overall pain improvement was noted with 25%-35 % of subjects having a clinical ly significant decrease in pain ; however this was not dependent upon " correct " needle stimulation ( t = 1.03 ; p = 0.307 ) or location ( t = 0.76 ; p = 0.450 ) . An overall dose effect of treatment was observed , with three sessions weekly providing more analgesia than sessions once weekly ( t = 2.10 ; p = 0.039 ) . Among treatment responders , improvements in pain , fatigue , and physical function were highly codependent ( all p < or = 0.002 ) . CONCLUSIONS Although needle insertion led to analgesia and improvement in other somatic symptoms , correct needle location and stimulation were not crucial [20980765] Background and Objective : A recent Cochrane review on placebo interventions for all kinds of conditions found that ‘ physical placebos ’ ( which included sham acupuncture ) were associated with larger effects over no-treatment control groups than ‘ pharmacological placebos ’ . We re-analyzed the data from this review to investigate whether effects associated with sham acupuncture differed from those of other ‘ physical placebos ’ . Methods : All trials included in the Cochrane review as investigating ‘ physical placebos ’ were classified as investigating either ( sham ) acupuncture or other physical placebos . The latter group was further subclassified into groups of similar interventions . Data from the Cochrane review were re-entered into the RevMan 5 software for meta- analysis . The primary analysis was a r and om-effects analysis of trials reporting continuous outcomes of trials that used either sham acupuncture or other physical placebos . Results : Out of a total of 61 trials which reported a continuous outcome measure , 19 compared sham acupuncture and 42 compared other physical placebos with a notreatment control group . The trials re-analyzed were highly heterogeneous regarding patients , interventions and outcomes measured . The pooled st and ardized mean difference was –0.41 ( 95 % confidence interval –0.56 , –0.24 ) between sham acupuncture and no treatment and –0.26 ( 95 % CI –0.37 , –0.15 ) between other physical placebos and no treatment ( p value for subgroup differences = 0.007 ) . Significant differences were also observed between subgroups of other physical placebos . Conclusion : Due to the heterogeneity of the trials included and the indirect comparison our results must be interpreted with caution . Still , they suggest that sham acupuncture interventions might , on average , be associated with larger effects than pharmacological and other physical placebos [22770838] Summary Each of the acupuncture modalities ( true , sham , and placebo ) associated with conventional treatment achieved a clinical improvement after 3 weeks that was greater than that achieved by conventional treatment alone in patients with acute low back pain , although there were no significant differences among the different forms of stimulus . Abstract Review s of the efficacy of acupuncture as a treatment for acute low back pain have concluded that there is insufficient evidence for its efficacy and that more research is needed to evaluate it . A multicentre r and omized controlled trial was conducted at 4 primary ‐care centres in Spain to evaluate the effects of acupuncture in patients with acute nonspecific low back pain in the context of primary care . A total of 275 patients with nonspecific acute low back pain ( diagnosed by their general practitioner ) were recruited and assigned r and omly to 4 different groups : conventional treatment either alone or complemented by 5 sessions over a 2‐week period of true acupuncture , sham acupuncture , or placebo acupuncture per patient . Patients were treated from February 2006 to January 2008 . The primary outcome was the reduction in Rol and Morris Disability Question naire scores of 35 % or more after 2 weeks ’ treatment . The patients in the 3 types of acupuncture groups were blinded to the treatments , but those who received conventional treatment alone were not . In the analysis adjusted for the total sample ( true acupuncture relative risk 5.04 , 95 % confidence interval 2.24–11.32 ; sham acupuncture relative risk 5.02 , 95 % confidence interval 2.26–11.16 ; placebo acupuncture relative risk 2.57 95 % confidence interval 1.21–5.46 ) , as well as for the sub sample of occupationally active patients , all 3 modalities of acupuncture were better than conventional treatment alone , but there was no difference among the 3 acupuncture modalities , which implies that true acupuncture is not better than sham or placebo acupuncture [11532841] Recent reports have highlighted the importance of having good evidence on the safety of acupuncture . 1 2 Sound evidence on the risks associated with acupuncture is , however , scarce.3 Our primary aim , therefore , was to describe the type and frequency of adverse events after acupuncture . A secondary aim was to examine mild transient reactions associated with acupuncture , some of which may indicate a positive response to treatment . The study involved a prospect i ve postal audit of treatments undertaken during a four week period in 2000 . All 1848 professional acupuncturists who were members of the British Acupuncture Council and were practising in the United Kingdom were invited to record details of adverse events and mild transient reactions after treatment . St and ardised self report forms were used . Participating practitioners also provided information on themselves , including age , sex , length of training , and years of practice . To have a [12594972] OBJECTIVES To compare the effects of real acupuncture to tender points for neck and shoulder pain and stiffness ( Japanese : katakori ) with those of sham acupuncture . DESIGN R and omized-controlled trial . METHODS Thirty-four volunteers from an acupuncture school with complaints of chronic pain and stiffness , who had no arm symptoms and gave informed consent , were r and omly allocated to acupuncture or sham groups . Acupuncture or sham acupuncture was applied to the tender points once a week for 3 weeks . In the acupuncture group the acupuncture needle was inserted to the muscle , then the sparrow pecking technique was applied five times . Sham acupuncture was done without insertion of the needle . Dull pain and stiffness were evaluated by visual analog scale ( VAS ) before , and every 2 days after the first needling for 1 month . Pressure pain threshold on the tender points was measured before and after each treatment . RESULTS There was no statistical difference of VAS scores between acupuncture and sham groups 9 days after the last treatment . However , the acupuncture group showed significant reduction of VAS scores immediately after and /or 1 day after the real acupuncture treatments ( P<0.01 ) . The effect tended to be prolonged after repeated treatment . Pressure pain thresholds tended to increase after real acupuncture treatment but not after sham acupuncture . CONCLUSIONS Acupuncture applied to tender points appears to have short-term effects on neck and shoulder pain and stiffness , but this study was unable to demonstrate any long-term superiority over sham acupuncture [18356795] Background There is evidence for the efficacy of acupuncture treatment in knee osteoarthritis , but it remains unclear which acupuncture modes are most effective . We evaluated the effects of trigger point acupuncture on pain and quality of life in knee osteoarthritis patients , compared with acupuncture at st and ard points , and sham acupuncture . Methods Thirty patients ( 27 women , 3 men ; aged 61–82 years ) with non-radiating knee osteoarthritis pain for at least six months and normal neurological examination were r and omised to one of three groups for the study period of 21 weeks . Each group received five acupuncture treatment sessions . The st and ard acupuncture point group ( n=10 ) received treatment at traditional acupuncture points for knee pain ; the trigger point acupuncture group ( n=10 ) received treatment at trigger points ; and the third group ( n=10 ) received sham acupuncture treatment at the trigger points . Outcome measures were pain intensity ( visual analogue scale , VAS ) and WOMAC index ( Western Ontario and McMaster Universities Arthritis Index ) . The groups were compared by the area under the curve method . Results Five patients dropped out of the study because of lack of improvement , and one patient ( in the trigger point acupuncture group ) dropped out because of deterioration of symptoms ; the remaining 24 patients were included in the analysis . After treatment , the trigger point acupuncture group reported less pain intensity on VAS than the st and ard acupuncture or sham treatment group , but both the trigger point acupuncture and st and ard acupuncture groups reported improvement of function of knee . There was a significant reduction in pain intensity between pre-treatment and five weeks after treatment for the trigger point acupuncture ( P<0.01 ) and st and ard acupuncture groups ( P<0.01 ) included in the analysis , but not for the sham treatment group . Group comparison using the area under the curves demonstrated a significant difference only between trigger point acupuncture and sham treatment groups analysed ( P<0.025 for VAS , and P<0.031 for WOMAC ) . Conclusion These results suggest that trigger point acupuncture therapy may be more effective for osteoarthritis of the knee in some elderly patients than st and ard acupuncture therapy [19454879] Objectives Owing to a lack of a suitable needle procedure , it has been impossible to evaluate the efficacy of acupuncture in clinical studies using double-blind testing . We evaluated the applicability of a new kind of press needle ( Pyonex ) to a double-blind trial by comparing the press needle with a placebo ( lacking the needle element ) . Methods The purpose of the study consisted of 2 phases . In the phase 1 , to evaluate the applicability and efficacy of the press needles , 90 participants who had never been treated using acupuncture were r and omly assigned to receive either the press needle ( n=45 ) or a placebo ( n=45 ) . The applicability was measured using a question naire regarding the perception of penetration , and efficacy was measured using a visual analog scale of low back pain ( LBP ) . When the applicability and efficacy of the press needles were confirmed in phase 1 , the mechanism of LBP relief by the press needles was examined in phase 2 . Results In phase 1 , intergroup comparisons showed no significant differences concerning the perception of penetration . In addition , for patients with LBP , the press needles reduced the subjective evaluation of LBP compared with the placebo ( P<0.05 ) . In phase 2 , visual analog scale results indicated that LBP was reduced significantly more in the press needle group than in the local anesthesia group ( P<0.05 ) . Discussion The participants could not distinguish between the press needle and a placebo , and the data from the press needle group suggested a specific influence on patients with LBP . These findings imply that the press needle and a placebo provide an effective means of realizing a double-blind setting for clinical studies of acupuncture [18630538] OBJECTIVE To scientifically assess effectiveness and safety of mono-use fu-needle . METHODS Sixty cases of periarthritis of shoulder were r and omly divided into a fu-needle group and a routine acupuncture group . The fu-needle group were treated with fu-needle , and the routine acupuncture group were treated with a needle of 0.38 mm in diameter and 40 mm in length . The articular mobility of the most limited direction , soft tissue pain self-rating score and self-rating score of shoulder tenderness before and after treatment , stabbing times and degree at inserting the needle , scattering and during retention of the needle , and bleeding at withdrawing the needle were compared in the two groups . RESULTS The fu-needle group was better than the routine acupuncture group in improvement of mobility-related pain , tenderness , and the articular mobility of the most limited direction , indicating that the transient effect in the fu-needle group was better than the routine acupuncture group , and the stabbing times and degree at insertion of the needle were less than the routine acupuncture group . And there was no significant difference between the two groups in stabbing times and degree at scattering and retaining the needle and bleeding times in withdrawing the needle . CONCLUSION The superficial needling therapy with mono-use fu-needle is more effective and more safe than the routine acupuncture for treatment of periarthritis of shoulder [19489707] OBJECTIVES The aim of this study was to evaluate the efficacy of acupuncture as a treatment for chronic shoulder pain and to compare the efficacy of individualized acupuncture to fixed , st and ard point acupuncture treatment . DESIGN The study was a single-blind r and omized , controlled trial . SETTING S/LOCATION The study was conducted in an outpatient rheumatology clinic at the VA Medical Center of Philadelphia . SUBJECTS The participants were adults with shoulder pain for at least 8 weeks with a diagnosis of osteoarthritis or rotator cuff tendonitis and a total Shoulder Pain and Disability Index ( SPADI ) score of > or = 30 . INTERVENTIONS Thirty-one ( 31 ) subjects were r and omized to one of three treatment groups : individualized acupuncture points according to the approaches of Traditional Chinese Medicine ; fixed , st and ard acupuncture points conventionally used for shoulder pain ; and sham nonpenetrating acupuncture . Subjects received 12 treatments over 6 weeks and were reassessed using the SPADI at the end of the 6 weeks . OUTCOME MEASURES The primary outcome evaluated was the mean change in total SPADI score in each group from baseline to 6 weeks . RESULTS After 6 weeks of treatment , the mean total SPADI score improved in all three groups , but the change was clinical ly significant ( > or = 10 points ) only in groups 1 and 2 ( -20.3 and -20.4 , respectively , versus -6.5 in group 3 ) . The treatment effects of groups 1 and 2 compared to the sham acupuncture group were -13.8 ( 95 % confidence interval : -2.2 to -25.4 , p < 0.015 ) and -13.9 ( -2.0 to -25.8 , p < 0.013 ) , respectively . There was no difference between the individualized acupuncture and st and ardized acupuncture treatments . CONCLUSIONS Acupuncture may be an effective treatment for chronic shoulder pain . There may be no difference in efficacy between individualized and st and ardized acupuncture treatment . This suggests that the use of st and ard points may make treatment easier for patient care and for further research studies [16818924] BACKGROUND Despite the popularity of acupuncture , evidence of its efficacy for reducing pain remains equivocal . OBJECTIVE To assess the efficacy and safety of traditional Chinese acupuncture ( TCA ) compared with sham acupuncture ( needling at defined nonacupuncture points ) and conservative therapy in patients with chronic pain due to osteoarthritis of the knee . DESIGN R and omized , controlled trial . SETTING 315 primary care practice s staffed by 320 practitioners with at least 2 years ' experience in acupuncture . PATIENTS 1007 patients who had had chronic pain for at least 6 months due to osteoarthritis of the knee ( American College of Rheumatology [ ACR ] criteria and Kellgren-Lawrence score of 2 or 3 ) . INTERVENTIONS Up to 6 physiotherapy sessions and as-needed anti-inflammatory drugs plus 10 sessions of TCA , 10 sessions of sham acupuncture , or 10 physician visits within 6 weeks . Patients could request up to 5 additional sessions or visits if the initial treatment was viewed as being partially successful . MEASUREMENTS Success rate , as defined by at least 36 % improvement in Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) score at 26 weeks . Additional end points were WOMAC score and global patient assessment . RESULTS Success rates were 53.1 % for TCA , 51.0 % for sham acupuncture , and 29.1 % for conservative therapy . Acupuncture groups had higher success rates than conservative therapy groups ( relative risk for TCA compared with conservative therapy , 1.75 [ 95 % CI , 1.43 to 2.13 ] ; relative risk for sham acupuncture compared with conservative therapy , 1.73 [ CI , 1.42 to 2.11 ] ) . There was no difference between TCA and sham acupuncture ( relative risk , 1.01 [ CI , 0.87 to 1.17 ] ) . LIMITATIONS There was no blinding between acupuncture and traditional therapy and no monitoring of acupuncture compliance with study protocol . In general , practitioner-patient contacts were less intense in the conservative therapy group than in the TCA and sham acupuncture groups . CONCLUSIONS Compared with physiotherapy and as-needed anti-inflammatory drugs , addition of either TCA or sham acupuncture led to greater improvement in WOMAC score at 26 weeks . No statistically significant difference was observed between TCA and sham acupuncture , suggesting that the observed differences could be due to placebo effects , differences in intensity of provider contact , or a physiologic effect of needling regardless of whether it is done according to TCA principles [9717924] BACKGROUND A problem acupuncture research has to face is the concept of a control group . If , in control groups , non-acupoint needling is done , physiological acupuncture effects are implied . Therefore the effects shown in this group are often close to those shown in the acupuncture group . In other trials , control groups have received obviously different treatments , such as transcutaneous electrical nervous stimulation or TENS-laser treatment ; it is not clear if the effects of acupuncture are due only to the psychological effects of the treatment . METHODS We developed a placebo acupuncture needle , with which it should be possible to simulate an acupuncture procedure without penetrating the skin . In a cross-over experiment with 60 volunteers we tested whether needling with the placebo needle feels any different from real acupuncture . FINDINGS Of 60 volunteers , 54 felt a penetration with acupuncture ( mean visual analogue scale [ VAS ] 13.4 ; SD 10.58 ) and 47 felt it with placebo ( VAS 8.86 ; SD 10.55 ) , 34 felt a dull pain sensation ( DEQI ) with acupuncture and 13 with placebo . None of the volunteers suspected that the needle may not have penetrated the skin . INTERPRETATION The placebo needle is sufficiently credible to be used in investigations of the effects of acupuncture [17709062] INTRODUCTION There is some evidence for the efficacy of acupuncture in chronic neck pain ( CNP ) treatment , but it remains unclear which acupuncture modes are most effective . Objective was to evaluate the effects of trigger point acupuncture on pain and quality of life ( QOL ) in CNP patients compared to three other acupuncture treatments ( acupoints , non-trigger point and sham treatment ) . METHODS Forty out- patients ( 29 women , 11 men ; age range : 47 - 80 years ) from the Department of Orthopaedic Surgery , Meiji University of Oriental Medicine , with non-radiating CNP for at least 6 months and normal neurological examination were r and omised to one of four groups over 13 weeks . Each group received two phases of acupuncture treatment with an interval between them . The acupoint group ( st and ard acupuncture ; SA , n=10 ) received treatment at traditional acupoints for neck pain , the trigger point ( TrP , n=10 ) and non-trigger point ( non-TrP , n=10 ) groups received treatment at tenderness points for the same muscle , while the other acupuncture group received sham treatments on the trigger point ( SH , n=10 ) . Outcome measures were pain intensity ( visual analogue scale ; VAS 0 - 100 mm ) and disease specific question naire ( neck disability index ; NDI , 60-point scale ) . RESULTS After treatment , the TrP group reported less pain intensity and improved QOL compared to the SA or non-TrP group . There was significant reduction in pain intensity between the treatment and the interval for the TrP group ( p<0.01 , Dunnett 's multiple test ) , but not for the SA or non-TrP group . CONCLUSION These results suggest that trigger point acupuncture therapy may be more effective on chronic neck pain in aged patients than the st and ard acupuncture therapy [17604557] BACKGROUND This paper describes the experiences of 8 licensed acupuncturists in a placebo-controlled r and omized clinical trial ( RCT ) . This information is important to the design and conduct of high- quality trials . METHODS We conducted a RCT ( N=135 ) with a 2-week placebo run-in followed by 4 weeks of twice-weekly treatments comparing genuine to sham acupuncture ( using the Streitberger placebo needle ) in the treatment of arm pain caused by repetitive use . At the end of this study , we conducted written structured interviews with 8 participating acupuncturists . The acupuncturists were not aware of the study 's results at the time of these interviews . The questions focused on their experiences in the study , adherence to study protocol s , their thoughts about the technical and ethical issues involved in using a sham needling device , and their expectations of trial outcomes . The questions were motivated by expressions of concerns the acupuncturists raised in feedback groups during the course of the study , and our desire to improve further trials . RESULTS The acupuncturists differed widely in their comfort levels with the research methods used , their adherence to the study protocol , and their expectations of trial outcomes . CONCLUSIONS We conclude that careful monitoring of acupuncturists , including observation of treatments and frequent meetings to support them throughout the trial , is necessary to maintain a high degree of quality control [20082247] Objective To observe the clinical effect of acupuncture in treating cervical spondylosis with different syndrome types . Methods One hundred and seventeen patients were r and omized into the treated group : ( 59 cases ) , treated with normal acupuncture , and the control group ( 58 cases ) , treated with sham acupuncture , operated once every other day , 9 times in total ( in 18 days ) as one therapeutic course , and a succeeding 3-month follow-up study was carried out after terminating the therapy . The efficacy of treatment was evaluated with the Northwick Park Neck Pain Question naire ( NPQ ) and Visual Analogue Scale ( VAS ) , and the scores gained in patients with different syndrome types were analyzed with a general linear model . Results The NPQ and VAS : scores showed a linear decreasing tendency in both groups at the time of ending treatment and the 1st month of follow-up , but showed a secondary curve increasing tendency in the 3rd month of follow-up . Multivariate analysis showed the difference was of statistical significance ( P<0.05 ) . However , the analysis through lead-in of syndrome type as an individual influencing factor showed that syndrome type exerts a significant influence on VAS score ( P<0.05 ) , but has insignificant influence on the NPQ score ( P>0.05 ) . Conclusion Acupuncture shows : good immediate effect in treating cervical spondylosis , but its long-term effect is not satisfactory . The difference in syndrome type may have some impact on the effects of acupuncture in alleviating pain , but exerts no evident influence on the comprehensive effect [20506122] There is conflicting evidence on the efficacy of traditional Chinese acupuncture ( TCA ) , and the role of placebo effects elicited by acupuncturists ' behavior has not been eluci date d. We conducted a 3‐month r and omized clinical trial in patients with knee osteoarthritis to compare the efficacy of TCA with sham acupuncture and to examine the effects of acupuncturists ' communication styles [23629597] Background : There are different types and parameters of dry needling ( DN ) that can affect its efficacy in the treatment of pain that have not been assessed properly . Objective : To test the hypothesis that either multiple deep intramuscular stimulation therapy multiple deep intramuscular stimulation therapy ( MDIMST ) or TrP lidocaine injection ( LTrP-I ) is more effective than a placebo-sham for the treatment of myofascial pain syndrome ( MPS ) and that MDIMST is more effective than LTrP-I for improving pain relief , sleep quality , and the physical and mental state of the patient . Methods : Seventy-eight females aged 20 to 40 who were limited in their ability to perform active and routine activities due to MPS in the previous 3 months were recruited . The participants were r and omized into 1 of the 3 groups as follows : placebo-sham , LTrP-I , or MDIMST . The treatments were provided twice weekly over 4 weeks using st and ardized MDIMST and LTrP-I protocol s. Results : There was a significant interaction ( time vs. group ) for the main outcomes . Compared with the sham-treated group , MDIMST and LTrP-I administration improved pain scores based on a visual analog scale , the pain pressure threshold ( P<0.001 for all analyses ) , and analgesic use ( P<0.01 for all analyses ) . In addition , when comparing the active groups for these outcomes , MDIMST result ed in better improvement than LTrP-I ( P<0.01 for all analyses ) . In addition , both active treatments had a clinical effect , as assessed by a sleep diary and by the SF-12 physical and mental health scores . Conclusions : This study highlighted the greater efficacy of MDIMST over the placebo-sham and LTrP-I and indicated that both active treatments are more effective than placebo-sham for MPS associated with limitations in active and routine activities [23380214] OBJECTIVE The purpose of this preliminary study was to examine whether collateral meridian ( CM ) therapy was feasible in treating knee osteoarthritis ( OA ) pain . METHODS Twenty-eight patients with knee OA and knee pain were r and omly allocated to 2 groups . The CM group patients received CM therapy , whereas the control patients received placebo treatment for knee pain relief . Patients in the CM group received 2 CM treatments weekly for 3 weeks . The outcome measures were pain intensity on a visual analog scale , and knee function was determined using the Western Ontario and McMaster Universities Osteoarthritis Index . RESULTS In the CM group , the posttreatment visual analog scale and Western Ontario and McMaster Universities Osteoarthritis Index scores were lower than those of the control group ; a significant reduction in pain intensity ( P = .02 , P = .01 , respectively ) and improvement in knee function ( P = .04 , P = .03 , respectively ) were shown in the CM group at the second and third week . CONCLUSION Collateral meridian therapy may be feasible and effective for knee OA pain relief and knee function recovery . Therefore , additional r and omized control trials are warranted [19888488] AIMS To evaluate the effectiveness of acupuncture in treating symptoms associated with myofascial pain of the jaw muscles . METHODS Twenty-eight subjects over the age of 18 and diagnosed with chronic myofascial pain of the jaw muscles were r and omized to receive real ( n = 16 ) or sham ( n = 12 ) acupuncture . Prior to treatment , each subject clenched his or her teeth for 2 minutes . Acupuncture or sham acupuncture was then administered at the Hegu large intestine 4 ( LI4 ) acupoint for 15 minutes . Real acupuncture was given by penetrating the needle through a sticky foam pad at the acupoint . Sham acupuncture was conducted by pricking the skin , without penetration , with a shortened , blunted acupuncture needle through a foam pad placed away from the acupoint . General head and neck pain ratings were obtained before and after treatment on a numerical rating scale . A mechanical pain stimulus on the masseter muscle was given before and after treatment and rated on a visual analog scale to measure pain tolerance level . Paired t tests were performed to detect significant changes in pain levels . RESULTS Subjects receiving real acupuncture experienced a significant reduction in jaw pain ( P = .04 ) , jaw/face tightness ( P = .04 ) , and neck pain ( P = .04 ) , and a significant increase in pain tolerance of the masseter muscle ( P = .001 ) . Subjects were not able to determine whether they received real or sham acupuncture ( P = .69 ) . No significant pain reductions were observed in the sham acupuncture group . CONCLUSION A single acupuncture session using one acupoint at Hegu large intestine 4 significantly reduced most myofascial pain endpoints when compared to sham acupuncture [11886971] OBJECTIVE To evaluate the clinical efficacy of acupuncture in the treatment of chronic lateral epicondylitis . METHODS In a r and omized , investigator- and patient-blinded , controlled clinical study , 23 patients were treated with real acupuncture and 22 patients received sham acupuncture . Patients each received 10 treatments , with two treatments per week . The primary outcome variables were maximal strength , pain intensity ( verbal rating scale ) and disability scale ( Disabilities of the Arm , Shoulder and H and question naire ) . Patients were examined at baseline ( 1 week before the start of treatment ) and at follow-up 2 weeks and 2 months after the end of treatment . RESULTS There was no significant difference between the groups at baseline for any outcome parameter . Two weeks and 2 months after the end of treatment , there were significant reductions in pain intensity and improvements in the function of the arm and in maximal strength in both treatment groups . At the 2-week follow-up these differences were significantly greater for all outcome parameters in the group treated with real acupuncture . At 2 months the function of the arm was still better in this group than in the sham acupuncture group ; however , the differences in pain intensity and maximal strength between the groups were no longer significant . CONCLUSION In the treatment of chronic epicondylopathia lateralis humeri , acupuncture in which real acupuncture points were selected and stimulated was superior to non-specific acupuncture with respect to reduction in pain and improvement in the functioning of the arm . These changes are particularly marked at early follow-up [8000747] The immediate analgesic effect of a single non-segmental acupuncture stimulation treatment on chronic tennis elbow pain was studied in a placebo-controlled single-blind trial completed by 48 patients . Before and after treatment , all patients were examined physically by an unbiased independent examiner . Eleven-point box scales were used [ 13 ] for pain measurement . Patients in the verum group were treated at non-segmental distal points ( homolateral leg ) for elbow pain following Chinese acupuncture rules , whereas patients in the placebo group were treated with placebo acupuncture avoiding penetration of the skin with an acupuncture needle . Overall reduction in the pain score was 55.8 % ( S = 2.95 ) in the verum group and 15 % ( S = 2.77 ) in the placebo group . After one treatment 19 out of 24 patients in the verum group ( 79.2 % ) reported pain relief of at least 50 % ( placebo group : six patients out of 24 ) . The average duration of analgesia after one treatment was 20.2 h in the verum group ( S = 21.54 ) and 1.4 h ( S = 3.50 ) in the placebo group . The results are statistically significant ( P < 0.01 ) ; they show that non-segmental verum acupuncture has an intrinsic analgesic effect in the clinical treatment of tennis elbow pain which exceeds that of placebo acupuncture [16309103] OBJECTIVE To compare therapeutic effects of superficial needling and body acupuncture on knee joint pain . METHODS Ninety-six cases of knee joint pain were r and omly divided into a treatment group of 48 cases treated with superficial needling , and a control group of 48 cases treated with body acupuncture . RESULTS The cured rate was 66.7 % in the treatment group and 39.6 % in the control group with a significant difference between the two groups ( P<0.01 ) . The total effective rate was 100.0 % in both the two groups . The needed therapeutic times of superficial needling was significantly less than that of the body acupuncture ( P < 0.05 ) . CONCLUSION Superficial needling has a good therapeutic effect on knee joint pain with a shorter therapeutic course [20821817] Chronic neck myofascial pain syndrome ( MPS ) is a common disorder seen in clinics . There is no gold st and ard method to treat myofascial pain . We investigated the effects of acupuncture on patients with chronic neck MPS by a single-blind r and omized controlled trial . A total of 35 patients were r and omly allocated to an acupuncture group ( AG ) or a sham acupuncture group ( SG ) . Each subject received acupuncture treatment twice per week for three consecutive weeks . The primary outcome measure was quality of life as assessed with Short Form-36 , and secondary outcome measures were neck range of motion ( ROM ) , motion-related pain , and Short-Form McGill Pain Question naire ( SF-MPQ ) , as determined by a blinded investigator . The clinical assessment s were made before treatment ( BT ) and after six acupuncture treatments ( AT ) , as well as four weeks ( F1 ) and 12 weeks ( F2 ) after the end of the treatment . A total of 34 patients completed the trial . The results indicated that there is no significant difference in the ROM , motion-related pain , and SF-MPQ scores between AG and SG at AT , F1 and F2 ( all p > 0.05 ) . However , AG has greater improvement in physical functioning and role emotional of Short Form-36 quality of life at F2 . The results indicate that acupuncture may be used to improve the quality of life in patients with chronic neck MPS [6217745] Acupuncture treatment of chronic low back pain was studied in a placebo-controlled double-blind crossover trial completed by 77 patients . The patients had significantly increased depression , neuroticism , and hypochondriasis scores . Initial pain levels correlated with state-anxiety , depression , pain duration , and abnormal illness behavior measures , as well as with the intake of psychotropic but not analgesic medication . Overall reduction in pain score was 26 percent for acupuncture and 22 percent for placebo treatment ; the difference was not significant ( p greater than 0.6 ) . Analgesic drug intake was reduced to a similar extent in both groups . During the first phase of treatment , patients receiving acupuncture had a greater but not significantly different reduction in pain rating scores compared with those receiving placebo ( t = 0.52 ; p greater than 0.6 ) . This group showed significantly lower pain scores ( p less than 0.05 ) in the second phase of the trial while receiving placebo treatment . Overall reduction in individual patient 's pain score was best predicted by initial pain severity ( r = 0.43 ; p less than 0.001 ) and psychotropic drug intake ( r = 0.37 ; p less than 0.001 ) . None of the variables tested predicted which patients would specifically respond to acupuncture or placebo [17095133] OBJECTIVES To compare the effect of real acupuncture and sham acupuncture in the treatment of temporom and ibulat joint myofascial pain , in order to establish the true efficacy of acupuncture . METHODS A double blind r and omised controlled trial conducted in the TMD Clinic , at the School of Dentistry , The University of Manchester . Twenty-seven patients were assigned to one of two treatment groups . Group 1 received real acupuncture treatment whilst Group 2 received a sham acupuncture intervention . Both the assessor and the patient were blinded regarding the group allocation . Baseline assessment of the outcome variables was made prior to the first treatment session , and was repeated following the last treatment . RESULTS The results demonstrated that real acupuncture had a greater influence on clinical outcome measure of TMJ MP than those of sham acupuncture , and the majority of these reached a level of statistical significance . CONCLUSION Acupuncture had a positive influence on the signs and symptoms of TMJ MP . In addition , this study provides evidence that the Park Sham Device was a credible acupuncture control method for trials involving facial acupoints [21195292] OBJECTIVE This study is aim ed to assess the efficacy of traditional acupuncture for chronic neck pain in patients by comparing the differences in symptoms , dysfunctions and quality of life . METHODS The study used a two-arm , single-blinded , r and omised controlled design . The patients were r and omised to the study group and control group , who respectively received traditional acupuncture and placebo treatment . The Northwick Park Neck Pain Question naire ( NPQ ) , visual analogue scale ( VAS ) , Short Form ( 36 ) Health Survey ( SF-36 ) and doctor 's judgement were applied for measuring effectiveness . The patients ' effectiveness outcome was assessed , respectively , before the intervention , immediately after the intervention , at the end of the first month of follow-up and at the end of the third month of follow-up . The statistical analysis was done on Statistical Package for Social Sciences ( SPSS ) v13 , which included comparison of demographic and clinical homogeneity , the repeated measures approach based on the general linear model ( GLM ) for effectiveness assessment and the sum rank test for doctors ' subjective efficacy judgement . RESULTS Totally , 190 patients were recruited and 178 patients ( 88 in the study group and 90 in the control group ) completed the intervention and follow-up assessment . The scores of NPQ , VAS and SF-36 were improved after the intervention and during follow-up ( P<0.01 vs. before the intervention ) . The patients in the study group had better effectiveness outcome in NPQ , VAS and in the VT , SF and MH domains of SF-36 ( P<0.05 ) . CONCLUSION Traditional acupuncture can relieve pain intensity and improve the quality of daily life with a relative long-term clinical efficacy in patients with chronic neck pain [17699546] Objective To investigate the benefit of adding acupuncture to a course of advice and exercise delivered by physiotherapists for pain reduction in patients with osteoarthritis of the knee . Design Multicentre , r and omised controlled trial . Setting 37 physiotherapy centres accepting primary care patients referred from general practitioners in the Midl and s , United Kingdom . Participants 352 adults aged 50 or more with a clinical diagnosis of knee osteoarthritis . Interventions Advice and exercise ( n=116 ) , advice and exercise plus true acupuncture ( n=117 ) , and advice and exercise plus non-penetrating acupuncture ( n=119 ) . Main outcome measures The primary outcome was change in scores on the Western Ontario and McMaster Universities osteoarthritis index pain subscale at six months . Secondary outcomes included function , pain intensity , and unpleasantness of pain at two weeks , six weeks , six months , and 12 months . Results Follow-up rate at six months was 94 % . The mean ( SD ) baseline pain score was 9.2 ( 3.8 ) . At six months mean reductions in pain were 2.28 ( 3.8 ) for advice and exercise , 2.32 ( 3.6 ) for advice and exercise plus true acupuncture , and 2.53 ( 4.2 ) for advice and exercise plus non-penetrating acupuncture . Mean differences in change scores between advice and exercise alone and each acupuncture group were 0.08 ( 95 % confidence interval −1.0 to 0.9 ) for advice and exercise plus true acupuncture and 0.25 ( −0.8 to 1.3 ) for advice and exercise plus non-penetrating acupuncture . Similar non-significant differences were seen at other follow-up points . Compared with advice and exercise alone there were small , statistically significant improvements in pain intensity and unpleasantness at two and six weeks for true acupuncture and at all follow-up points for non-penetrating acupuncture . Conclusion The addition of acupuncture to a course of advice and exercise for osteoarthritis of the knee delivered by physiotherapists provided no additional improvement in pain scores . Small benefits in pain intensity and unpleasantness were observed in both acupuncture groups , making it unlikely that this was due to acupuncture needling effects . Trial registration Current Controlled Trials IS RCT N88597683 [11889662] AIMS To compare the effectiveness of dry needling in classically recognized acupuncture points ( " acupuncture " ) with dry needling in skin areas not recognized as acupuncture points ( " sham acupuncture " ) in reducing masseter muscle pain in a group of patients with myofascial pain of the jaw muscles . METHODS Eighteen patients were r and omly assigned to 1 of 2 experimental groups : Ten patients received acupuncture and 8 received sham acupuncture . A visual analog scale ( VAS ) was used to measure changes in masseter muscle pain evoked by mechanical stimulation of the masseter muscle before and after the experiment . RESULTS Both groups showed a statistically significant reduction in VAS pain scores ( P = .001 ) . Seven out of 10 acupuncture subjects had a 10 mm or greater VAS reduction in pain , while 4 out of 8 of the sham acupuncture subjects had that great a pain reduction . There was no significant difference between the 2 groups . CONCLUSION Both acupuncture and sham acupuncture reduced pain evoked by mechanical stimulation of the masseter muscles in myofascial pain patients . However , this reduction in pain was not dependent on whether the needling was performed in st and ard acupuncture points or in other areas of the skin . These results suggest that pain reduction result ing from a noxious stimulus ( i.e. , needling ) may not be specific to the location of the stimulus as predicted by the classical acupuncture literature [18287826] Objective To compare true and sham acupuncture in their abilities to relieve arm pain and improve arm function in individuals with arm pain due to repetitive use . Methods Participants with persistent arm pain ( N=123 ) were r and omly assigned to true or sham acupuncture groups and received 8 treatments over 4 weeks . The primary outcome was intensity of pain ( 10-point scale ) and secondary outcomes were arm symptoms , arm function , and grip strength . Outcomes were measured during treatment ( at 2 and 4 wk ) and 1 month after treatment ended . Results Arm pain scores improved in both groups during the treatment period , but improvements were significantly greater in the sham group than in the true acupuncture group . This difference disappeared by 1 month after treatment ended . The true acupuncture group experienced more side effects , predominately mild pain at time of treatments . Discussion Sham acupuncture reduced arm pain more than true acupuncture during treatment , but the difference did not persist after 1 month . Mild side effects from true acupuncture may have blunted any positive treatment effects . Overall , this study did not find evidence to support the effectiveness of true acupuncture in treatment of persistent arm pain due to repetitive use [20137365] BACKGROUND Acupuncture has been shown to be effective in pain relief and anesthesia , and has been suggested for treating various kinds of functional disabilities in traditional Chinese medicine , including knee osteoarthritis ( OA ) . The study aim ed to investigate the immediate effects of acupuncture on gait patterns in patients with knee OA . METHODS Twenty patients with bilateral medial knee OA were assigned evenly and r and omly to a sham group and an experimental group . During the experiment , the experimental group underwent a 30-minute formula electro-acupuncture treatment while the sham group received a sham treatment . Before and after treatment , each subject was evaluated for their knee pain using visual analog scales ( VAS ) and then their performance of level walking using gait analysis . For all the obtained variables , the independent t-test was used for between-group comparisons , while paired t-test was used to investigate the before and after changes . RESULTS All the measured data before acupuncture treatment between the groups were not significantly different . The VAS scores were decreased significantly after acupuncture in both groups , and the mean change of the VAS values of the experiment group was 2 times greater than that of the sham group . After formula acupuncture stimulation , while no significant changes were found in all the gait variables in the sham group , the experimental group had significant increases in the gait speed , step length , as well as in several components of the joint angles and moments . CONCLUSIONS The results of the study suggest that significantly improved gait performance in the experimental group may be associated with pain relief after treatment , but the relatively small decrease of pain in the sham group was not enough to induce significant improvements in gait patterns . Gait analysis combined with the VAS can be useful for the evaluation of the effect of acupuncture treatment for patients with neuromusculoskeletal diseases and movement disorder [11444887] OBJECTIVES The effectiveness of acupuncture treatment in patients with osteoarthritis of the hip was tested . DESIGN This is a prospect i ve , r and omized , controlled , patient- and investigator-blinded clinical trial . PATIENTS AND SETTING The study was performed at a university department for physical medicine and rehabilitation . Sixty-seven patients were separated into two treatment groups . INTERVENTIONS Group 1 ( treatment ) had traditional needle placement and manipulation , whereas in group 2 ( control ) needles were placed away from classic positions and not manipulated . In both groups needles were placed within the L2 to L5 dermatomes . Outcome parameters were : pain ( VAS ) , functional impairment ( hip score ) , activity in daily life ( ADL ) and overall satisfaction before treatment , and 2 weeks and 2 months after treatment . RESULTS For all parameters there was a significant improvement versus baseline in both groups 2 weeks and 2 months following treatment , but no significant difference between the two treatment groups . CONCLUSIONS We conclude from these results that needle placement in the area of the affected hip is associated with improvement in the symptoms of osteoarthritis . It appears to be less important to follow the rules of traditional acupuncture techniques [17714105] AIM Short-term pain reduction from acupuncture in chronic myofascial pain subjects was evaluated using an 11-point ( 0 to 10 ) numeric rating scale , visual analog scale ( VAS ) , and pain rating of mechanical pressure on the masseter muscle . METHODS A single-blind , r and omized , controlled , clinical trial with an independent observer was performed . Fifteen chronic myofascial pain subjects over the age of 18 were r and omly assigned into groups : nine subjects received real acupuncture ; six subjects received sham acupuncture . Each subject clenched his/her teeth for 2 minutes . Acupuncture or sham acupuncture was administered at the Hegu Large Intestine 4 acupoint . Sham acupuncture was conducted by lightly pricking the skin with a shortened , blunted acupuncture needle through a foam pad , without penetrating the skin . The foam pad visually conceals the needle 's point of the entry , so that the subject can not discern which technique is being used . The subjects rated their general pain on a numeric rating scale . A mechanical pain stimulus was applied with an algometer and the subject rated his/her pain on a VAS . Statistical analysis was performed using the repeated measures anova , paired t-tests , and Fisher 's exact test as appropriate . RESULTS There was a statistically significant difference in pain tolerance with acupuncture ( P = 0.027 ) . There was statistically significant reduction in face pain ( P = 0.003 ) , neck pain ( P = 0.011 ) , and headache ( P = 0.015 ) with perception of real acupuncture . CONCLUSION Pain tolerance in the masticatory muscles increased significantly more with acupuncture than sham acupuncture [12406534] & NA ; This prospect i ve , r and omised controlled trial , with three parallel groups , patient and observer blinded for verum and sham acupuncture and a follow up of 3 months raises the question : “ Does a combination of acupuncture and conservative orthopedic treatment improve conservative orthopedic treatment in chronic low back pain ( LBP ) . 186 in‐ patients of a LBP rehabilitation center with a history of LBP ≥6 weeks , VAS ≥50 mm , and no pending compensation cl aims , were selected ; for the three r and om group 4 weeks of treatment was applied . 174 patients met the protocol criteria and reported after treatment , 124 reported after 3 months follow up . Patients were assorted 4 strata : chronic LBP , ≤0.5 years , 0.5–2 years , 2–5 years , ≥5 years . Analysis was by intention to treat . Group 1 ( Verum+COT ) recieved 12 treatments of verum acupuncture and conservative orthopedic treatment ( COT ) . Group 2 ( Sham+COT ) recieved 12 treatments of non‐specific needling and COT . Group 3 ( nil+COT ) recieved COT alone . Verum‐ and Sham acupuncture were blinded against patient and examiner . The primary endpoints were pain reduction ≥50 % on VAS 3 months after the end of the treatment protocol . Secondary endpoints were pain reduction ≥50 % on VAS and treatment efficacy on a four‐point box scale directly after the end of the treatment protocol and treatment efficacy after 3 months . In the whole sample a pain relief of ≥50 % on VAS was reported directly after the end of treatment protocol : Verum+COT 65 % ( 95%CI 51–77 % ) , Sham+COT 34 % ( 95%ci 22–49 % ) , nil+COT 43 % ( 95%ci 29–58 % ) – results are significant for Verum+COT over Sham+COT ( P≤0.02 ) . The results after 3 months are : Verum+COT 77 % ( 95%ci 62–88 % ) , Sham+COT 29 % ( 95%ci 16–46 % ) , nil+Cot 14 % ( 95%ci 4–30 % ) – effects are significant for Verum+COT over Sham+COT ( P≤0.001 ) and for Verum+COT over nil+COT ( P<0.001 ) . No difference was found in the mobility of the patients nor in the intake of NSAID diclofenac . Our conclusion is that acupuncture can be an important supplement of conservative orthopedic treatment in the management of chronic LBP Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Although acupuncture is widely used for chronic pain , there remains considerable controversy as to its value . We aim ed to determine the effect size of acupuncture for 4 chronic pain conditions : back and neck pain , osteoarthritis , chronic headache , and shoulder pain . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

22656072

[18260176] OBJECTIVE To determine whether patients with rheumatoid arthritis ( RA ) are at increased risk of hospitalized infection and whether the risk varies by RA treatment . METHODS A retrospective cohort study was conducted using data from a medical and pharmacy cl aims managed-care data base from 1999 to 2006 . A total of 24,530 patients were included in the RA cohort ; a r and om sample of non-RA patients served as a comparison cohort ( n = 500,000 ) . Rates of hospitalized infection were compared between the cohorts . A nested case-control analysis was performed within the RA cohort to assess the effect of current RA medication use on hospitalized infection risk . RESULTS A total of 1,993 patients with RA and 11,977 non-RA patients experienced a hospitalized infection . The rate of first hospitalized infection was higher in the RA cohort [ adjusted hazard ratio = 2.03 ; 95 % confidence interval ( CI ) 1.93 - 2.13 ] . In the case-control analysis , the current use of biological disease modifying antirheumatic drugs ( DMARD ) was associated with slightly increased risk of hospitalized infection [ rate ratio ( RR ) = 1.21 ; 95 % CI 1.02 - 1.43 ] . Methotrexate and hydroxychloroquine were associated with decreased risk . Oral corticosteroid use increased risk ( RR = 1.92 ; 95 % CI 1.67 - 2.21 ) , and there was a dose-related effect [ < or = 5 mg/day : RR = 1.32 ( 95 % CI 1.06 - 1.63 ) , 6 - 10 mg/day : RR = 1.94 ( 95 % CI 1.53 - 2.46 ) , > 10 mg/day : RR = 2.98 ( 95 % CI 2.41 - 3.69 ) ] . CONCLUSION These data confirm that individuals with RA are at increased risk of hospitalized infection compared to those without RA . Oral corticosteroid use was associated with a dose-related increase . Biological DMARD use was associated with slightly elevated risk ; however , this may reflect confounding and channeling bias [19644849] OBJECTIVE To assess the safety and efficacy of golimumab in methotrexate (MTX)-naive patients with active rheumatoid arthritis ( RA ) . METHODS MTX-naive patients with RA ( n = 637 ) were r and omized to receive placebo plus MTX ( group 1 ) , golimumab 100 mg plus placebo ( group 2 ) , golimumab 50 mg plus MTX ( group 3 ) , or golimumab 100 mg plus MTX ( group 4 ) . Subcutaneous injections of golimumab or placebo were administered every 4 weeks . The dosage of MTX/placebo capsules started at 10 mg/week and escalated to 20 mg/week . The primary end point , the proportion of patients meeting the American College of Rheumatology 50 % improvement criteria ( achieving an ACR50 response ) at week 24 , required significant differences between groups 3 and 4 combined ( combined group ) versus group 1 and significant differences in a pairwise comparison ( group 3 or group 4 versus group 1 ) . RESULTS An intent-to-treat ( ITT ) analysis of the ACR50 response at week 24 did not show a significant difference between the combined group and group 1 ( 38.4 % and 29.4 % , respectively ; P=0.053 ) , while a post hoc modified ITT analysis ( excluding 3 untreated patients ) of the ACR50 response showed statistically significant differences between the combined group and group 1 ( 38.5 % versus 29.4 % ; P=0.049 ) and between group 3 ( 40.5 % ; P=0.038 ) but not group 4 ( 36.5 % ; P=0.177 ) and group 1 . Group 2 was noninferior to group 1 for the ACR50 response at week 24 ( 33.1 % ; 95 % confidence interval lower bound -5.2 % ; predefined delta value for noninferiority -10 % ) . The combination of golimumab plus MTX demonstrated a significantly better response compared with placebo plus MTX in most other efficacy parameters , including response/remission according to the Disease Activity Score in 28 joints . Serious adverse events occurred in 7 % , 3 % , 6 % , and 6 % of patients in groups 1 , 2 , 3 , and 4 , respectively . CONCLUSION Although the primary end point was not met , the modified ITT analysis of the primary end point and other prespecified efficacy measures demonstrated that the efficacy of golimumab plus MTX is better than , and the efficacy of golimumab alone is similar to , the efficacy of MTX alone in reducing RA signs and symptoms in MTX-naive patients , with no unexpected safety concerns [12687534] OBJECTIVE To evaluate the safety of anakinra ( a recombinant human interleukin-1 receptor antagonist ) in a large population of patients with rheumatoid arthritis ( RA ) , typical of those seen in clinical practice . METHODS A total of 1,414 patients were r and omly assigned to treatment with 100 mg of anakinra or placebo , administered daily by subcutaneous injection . Background medications included disease-modifying antirheumatic drugs , corticosteroids , and nonsteroidal antiinflammatory drugs , alone or in combination . The primary end point was safety , which was evaluated by adverse events ( including infections ) , discontinuation from study due to adverse events , and death . RESULTS Safety was evaluated in 1,399 patients ( 1,116 in the anakinra group and 283 in the placebo group ; 15 patients were r and omized but did not receive any study drug ) during the initial 6-month , double-blind , placebo-controlled phase of this long-term safety study . Baseline demographics , disease characteristics , and concomitant medications were similar between the 2 groups . The study group included patients with numerous comorbid conditions and a wide range of RA disease activity . Serious adverse events occurred at a similar rate in the anakinra group and the placebo group ( 7.7 % and 7.8 % , respectively ) . Serious infectious episodes were observed more frequently in the anakinra group ( 2.1 % versus 0.4 % in the placebo group ) . The rate of withdrawal due to adverse events was 13.4 % in the anakinra group and 9.2 % in the placebo group . CONCLUSION Results from this large , placebo-controlled safety study demonstrate that anakinra is safe and well tolerated in a diverse population of patients with RA , including those with comorbid conditions and those using multiple combinations of concomitant therapies . Although the frequency of serious infection was slightly higher in the anakinra group , no infection was attributed to opportunistic microorganisms or result ed in death [2674556] Background : Certolizumab pegol is a PEGylated tumour necrosis factor inhibitor . Objective : To evaluate the efficacy and safety of certolizumab pegol versus placebo , plus methotrexate ( MTX ) , in patients with active rheumatoid arthritis ( RA ) . Methods : An international , multicentre , phase 3 , r and omised , double-blind , placebo-controlled study in active adult-onset RA . Patients ( n = 619 ) were r and omised 2:2:1 to subcutaneous certolizumab pegol ( liquid formulation ) 400 mg at weeks 0 , 2 and 4 followed by 200 mg or 400 mg plus MTX , or placebo plus MTX , every 2 weeks for 24 weeks . The primary end point was ACR20 response at week 24 . Secondary end points included ACR50 and ACR70 responses , change from baseline in modified Total Sharp Score , ACR core set variables and physical function . Results : Significantly more patients in the certolizumab pegol 200 mg and 400 mg groups achieved an ACR20 response versus placebo ( p⩽0.001 ) ; rates were 57.3 % , 57.6 % and 8.7 % , respectively . Certolizumab pegol 200 and 400 mg also significantly inhibited radiographic progression ; mean changes from baseline in mTSS at week 24 were 0.2 and −0.4 , respectively , versus 1.2 for placebo ( rank analysis p⩽0.01 ) . Certolizumab pegol-treated patients reported rapid and significant improvements in physical function versus placebo ; mean changes from baseline in HAQ-DI at week 24 were −0.50 and −0.50 , respectively , versus −0.14 for placebo ( p⩽0.001 ) . Most adverse events were mild or moderate , with low incidence of withdrawals due to adverse events . Five patients developed tuberculosis . Conclusion : Certolizumab pegol plus MTX was more efficacious than placebo plus MTX , rapidly and significantly improving signs and symptoms of RA and physical function and inhibiting radiographic progression . Trial registration number : [15140776] OBJECTIVES To compare budesonide , a locally acting glucocorticoid with minimal systemic exposure , with conventional glucocorticoid treatment and placebo in rheumatoid arthritis . METHODS A double blind , r and omised , controlled trial over 12 weeks in 143 patients with active rheumatoid arthritis , comparing budesonide 3 mg daily , budesonide 9 mg daily , prednisolone 7.5 mg daily , and placebo . Particular attention was paid to the pattern of clinical response and to changes in the four week period following discontinuation of treatment . RESULTS There were improvements in tender joint count and swollen joint count on budesonide 9 mg compared with placebo ( 28 % for tender and 34 % for swollen joint counts , p<0.05 ) . Prednisolone 7.5 mg gave similar results , while budesonide 3 mg was less effective . ACR20 response criteria were met by 25 % of patients on placebo , 22 % on budesonide 3 mg , 42 % on budesonide 9 mg , and 56 % on prednisolone 7.5 mg . A rapid and significant reduction in symptoms and signs in response to budesonide 9 mg and prednisolone 7.5 mg was evident by two weeks and maximal at eight weeks . There was no evidence that budesonide provided a different pattern of symptom control from prednisolone , or that symptoms became worse than placebo treatment levels after discontinuation of glucocorticoid treatment . Adverse effects attributable to glucocorticoids were equally common in all groups . CONCLUSIONS The symptomatic benefits of budesonide 9 mg and prednisolone 7.5 mg are achieved within a short time of initiating treatment , are maintained for three months , and are not associated with any rebound in symptoms after stopping treatment [16079172] Objective : To compare patient reported measures of function , health related quality of life ( QoL ) , and satisfaction with medication among patients with rheumatoid arthritis ( RA ) treated with methotrexate ( MTX ) , etanercept , or both for up to 1 year . Methods : In a 52 week , double blind , clinical trial , patients with active RA were r and omised to receive etanercept 25 mg twice weekly , methotrexate up to 20 mg weekly , or combination therapy . The Health Assessment Question naire ( HAQ ) disability index , EuroQoL health status visual analogue scale ( EQ-5D VAS ) , patient global assessment , and patient general health VAS were administered at baseline and weeks 2 , 4 , 8 , 12 , 16 , 20 , 24 , 32 , 40 , 48 , and 52 . Satisfaction with the medication was compared at 52 weeks . Results : Of 682 enrolled patients , 522 completed 52 weeks of treatment . Mean improvement from baseline in HAQ score was 0.65 , 0.70 , and 1.0 for MTX , etanercept , and the combination , respectively . The mean percentage and absolute improvement in the HAQ was significantly higher ( p<0.01 ) for combination therapy than for either of the monotherapies . Combination therapy produced significantly more rapid achievement of HAQ ⩽0.5 sustained for 6 months than either of the monotherapies ( p<0.01 ) . Compared with patients receiving monotherapy , those receiving combination therapy achieved a significantly better ( p<0.05 ) health state as measured by the EQ-5D VAS ( mean ( SD ) 63.7 ( 3.2 ) , 66.8 ( 3.2 ) , 72.7 ( 3.1 ) for MTX , etanercept , and the combination , respectively ) . Results were similar for other assessment s ( p<0.01 ) . Patients in combination and etanercept groups were significantly more likely ( p<0.0001 , p = 0.0009 , respectively ) to report satisfaction with the medication . Conclusions : Combination therapy with etanercept and methotrexate improved function , QoL , and satisfaction with the medication significantly more than monotherapy [18358926] BACKGROUND Interleukin 6 is involved in the pathogenesis of rheumatoid arthritis via its broad effects on immune and inflammatory responses . Our aim was to assess the therapeutic effects of blocking interleukin 6 by inhibition of the interleukin-6 receptor with tocilizumab in patients with rheumatoid arthritis . METHODS In this double-blind , r and omised , placebo-controlled , parallel group phase III study , 623 patients with moderate to severe active rheumatoid arthritis were r and omly assigned with an interactive voice response system , stratified by site with a r and omisation list provided by the study sponsor , to receive tocilizumab 8 mg/kg ( n=205 ) , tocilizumab 4 mg/kg ( 214 ) , or placebo ( 204 ) intravenously every 4 weeks , with methotrexate at stable pre- study doses ( 10 - 25 mg/week ) . Rescue therapy with tocilizumab 8 mg/kg was offered at week 16 to patients with less than 20 % improvement in both swollen and tender joint counts . The primary endpoint was the proportion of patients with 20 % improvement in signs and symptoms of rheumatoid arthritis according to American College of Rheumatology criteria ( ACR20 response ) at week 24 . Analyses were by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00106548 . FINDINGS The intention-to-treat analysis population consisted of 622 patients : one patient in the 4 mg/kg group did not receive study treatment and was thus excluded . At 24 weeks , ACR20 responses were seen in more patients receiving tocilizumab than in those receiving placebo ( 120 [ 59 % ] patients in the 8 mg/kg group , 102 [ 48 % ] in the 4 mg/kg group , 54 [ 26 % ] in the placebo group ; odds ratio 4.0 [ 95 % CI 2.6 - 6.1 ] , p<0.0001 for 8 mg/kg vs placebo ; and 2.6 [ 1.7 - 3.9 ] , p<0.0001 for 4 mg/kg vs placebo ) . More people receiving tocilizumab than those receiving placebo had at least one adverse event ( 143 [ 69 % ] in the 8 mg/kg group ; 151 [ 71 % ] in the 4 mg/kg group ; 129 [ 63 % ] in the placebo group ) . The most common serious adverse events were serious infections or infestations , reported by six patients in the 8 mg/kg group , three in the 4 mg/kg group , and two in the placebo group . INTERPRETATION Tocilizumab could be an effective therapeutic approach in patients with moderate to severe active rheumatoid arthritis . FUNDING F Hoffmann-La Roche , Chugai Pharmaceutical [15201414] BACKGROUND An open-label study indicated that selective depletion of B cells with the use of rituximab led to sustained clinical improvements for patients with rheumatoid arthritis . To confirm these observations , we conducted a r and omized , double-blind , controlled study . METHODS We r and omly assigned 161 patients who had active rheumatoid arthritis despite treatment with methotrexate to receive one of four treatments : oral methotrexate ( > or = 10 mg per week ) ( control ) ; rituximab ( 1000 mg on days 1 and 15 ) ; rituximab plus cyclophosphamide ( 750 mg on days 3 and 17 ) ; or rituximab plus methotrexate . Responses defined according to the criteria of the American College of Rheumatology ( ACR ) and the European League against Rheumatism ( EULAR ) were assessed at week 24 ( primary analyses ) and week 48 ( exploratory analyses ) . RESULTS At week 24 , the proportion of patients with 50 percent improvement in disease symptoms according to the ACR criteria , the primary end point , was significantly greater with the rituximab-methotrexate combination ( 43 percent , P=0.005 ) and the rituximab-cyclophosphamide combination ( 41 percent , P=0.005 ) than with methotrexate alone ( 13 percent ) . In all groups treated with rituximab , a significantly higher proportion of patients had a 20 percent improvement in disease symptoms according to the ACR criteria ( 65 to 76 percent vs. 38 percent , P < or = 0.025 ) or had EULAR responses ( 83 to 85 percent vs. 50 percent , P < or = 0.004 ) . All ACR responses were maintained at week 48 in the rituximab-methotrexate group . The majority of adverse events occurred with the first rituximab infusion : at 24 weeks , serious infections occurred in one patient ( 2.5 percent ) in the control group and in four patients ( 3.3 percent ) in the rituximab groups . Peripheral-blood immunoglobulin concentrations remained within normal ranges . CONCLUSIONS In patients with active rheumatoid arthritis despite methotrexate treatment , a single course of two infusions of rituximab , alone or in combination with either cyclophosphamide or continued methotrexate , provided significant improvement in disease symptoms at both weeks 24 and 48 [19224750] CONTEXT The risk of bacterial infection is increased in patients treated with drugs that inhibit tumor necrosis factor alpha ( TNF-alpha ) . Little is known about the reactivation of latent viral infections during treatment with TNF-alpha inhibitors . OBJECTIVE To investigate whether TNF-alpha inhibitors together as a class , or separately as either monoclonal anti-TNF-alpha antibodies ( adalimumab , infliximab ) or a fusion protein ( etanercept ) , are related to higher rates of herpes zoster in patients with rheumatoid arthritis . DESIGN , SETTING , AND PATIENTS Patients were enrolled in the German biologics register RABBIT , a prospect i ve cohort , between May 2001 and December 2006 at the initiation of treatment with infliximab , etanercept , adalimumab , or anakinra , or when they changed conventional disease-modifying antirheumatic drug ( DMARD ) . Treatment , clinical status , and adverse events were assessed by rheumatologists at fixed points during follow-up . MAIN OUTCOME MEASURES Hazard ratio ( HR ) of herpes zoster episodes following anti-TNF-alpha treatment . Study aims were to detect a clinical ly significant difference ( HR , 2.0 ) between TNF-alpha inhibitors as a class compared with DMARDs and to detect an HR of at least 2.5 for each of 2 types of TNF-alpha inhibitors , the monoclonal antibodies or the fusion protein , compared with conventional DMARDs . RESULTS Among 5040 patients receiving TNF-alpha inhibitors or conventional DMARDs , 86 episodes of herpes zoster occurred in 82 patients . Thirty-nine occurrences could be attributed to treatment with anti-TNF-alpha antibodies , 23 to etanercept , and 24 to conventional DMARDs . The crude incidence rate per 1000 patient-years was 11.1 ( 95 % confidence interval [ CI ] , 7.9 - 15.1 ) for the monoclonal antibodies , 8.9 ( 95 % CI , 5.6 - 13.3 ) for etanercept , and 5.6 ( 95 % CI , 3.6 - 8.3 ) for conventional DMARDs . Adjusted for age , rheumatoid arthritis severity , and glucocorticoid use , a significantly increased risk was observed for treatment with the monoclonal antibodies ( HR , 1.82 [ 95 % CI , 1.05 - 3.15 ] ) , although this risk was lower than the threshold for clinical significance . No significant associations were found for etanercept use ( HR , 1.36 [ 95 % CI , 0.73 - 2.55 ] ) or for anti-TNF-alpha treatment ( HR , 1.63 [ 95 % CI , 0.97 - 2.74 ] ) as a class . CONCLUSION Treatment with monoclonal anti-TNF-alpha antibodies may be associated with increased risk of herpes zoster , but this requires further study [16255010] OBJECTIVE To assess the efficacy of low-dose prednisolone on joint damage and disease activity in patients with early rheumatoid arthritis ( RA ) . METHODS At the start of their initial treatment with a disease-modifying antirheumatic drug ( DMARD ) , patients with early ( duration < or = 1 year ) active RA were r and omly assigned to receive either 7.5 mg/day prednisolone or no prednisolone for 2 years . Radiographs of the h and s and feet were obtained at baseline and after 1 and 2 years and scored according to the Sharp score as modified by van der Heijde . Remission was defined as a Disease Activity Score in 28 joints of < 2.6 . Bone mineral density was measured by dual x-ray absorptiometry at baseline and after 2 years . RESULTS Of the 250 patients included , 242 completed the study and 225 had radiographs available both at baseline and at 2 years . At 2 years , the median and interquartile range ( IQR ) change in total Sharp score was lower in the prednisolone group than in the no-prednisolone group ( 1.8 [ IQR 0.5 - 6.0 ] versus 3.5 [ IQR 0.5 - 10 ] ; P = 0.019 ) . In the prednisolone group , there were fewer newly eroded joints per patient after 2 years ( median 0.5 [ IQR 0 - 2 ] versus 1.25 [ IQR 0 - 3.25 ] ; P = 0.007 ) . In the prednisolone group , 25.9 % of patients had radiographic progression beyond the smallest detectable difference compared with 39.3 % of patients in the no-prednisolone group ( P = 0.033 ) . At 2 years , 55.5 % of patients in the prednisolone group had achieved disease remission , compared with 32.8 % of patients in the no-prednisolone group ( P = 0.0005 ) . There were few adverse events that led to withdrawal . Bone loss during the 2-year study was similar in the 2 treatment groups . CONCLUSION Prednisolone at 7.5 mg/day added to the initial DMARD retarded the progression of radiographic damage after 2 years in patients with early RA , provided a high remission rate , and was well tolerated . Therefore , the data support the use of low-dose prednisolone as an adjunct to DMARDs in early active RA [2770104] Objectives : To assess the efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis ( RA ) and poor prognostic factors . Methods : In this double-blind , phase IIIb study , patients with RA for 2 years or less were r and omly assigned 1 : 1 to receive abatacept ( ∼10 mg/kg ) plus methotrexate , or placebo plus methotrexate . Patients were methotrexate-naive and seropositive for rheumatoid factor ( RF ) , anti-cyclic citrullinated protein ( CCP ) type 2 or both and had radiographic evidence of joint erosions . The co- primary endpoints were the proportion of patients achieving disease activity score in 28 joints (DAS28)-defined remission ( C-reactive protein ) and joint damage progression ( Genant-modified Sharp total score ; TS ) at year 1 . Safety was monitored throughout . Results : At baseline , patients had a mean DAS28 of 6.3 , a mean TS of 7.1 and mean disease duration of 6.5 months ; 96.5 % and 89.0 % of patients were RF or anti-CCP2 seropositive , respectively . At year 1 , a significantly greater proportion of abatacept plus methotrexate-treated patients achieved remission ( 41.4 % vs 23.3 % ; p<0.001 ) and there was significantly less radiographic progression ( mean change in TS 0.63 vs 1.06 ; p = 0.040 ) versus methotrexate alone . Over 1 year , the frequency of adverse events ( 84.8 % vs 83.4 % ) , serious adverse events ( 7.8 % vs 7.9 % ) , serious infections ( 2.0 % vs 2.0 % ) , autoimmune disorders ( 2.3 % vs 2.0 % ) and malignancies ( 0.4 % vs 0 % ) was comparable for abatacept plus methotrexate versus methotrexate alone . Conclusions : In a methotrexate-naive population with early RA and poor prognostic factors , the combination of abatacept and methotrexate provided significantly better clinical and radiographic efficacy compared with methotrexate alone and had a comparable , favourable safety profile [10668523] The efficacy and safety of the novel DMARD leflunomide was compared to placebo and sulfasalazine in a r and omized , double-blind study . At Week 24 , leflunomide significantly reduced tender and swollen joint counts and physician and patient assessment scores compared to placebo ( P < 0.001 ) . Response rates with leflunomide were significantly greater than placebo : ACR 20 % ( 55 % vs 29 % , P = 0.0001 ) . Comparable response rates were observed with sulfasalazine ( ACR 20 % : 56 % ) . Leflunomide significantly improved HAQ scores compared to placebo or sulfasalazine ( P < 0.009 ) . The onset of action with leflunomide was rapid and was seen as early as Week 2 . Radiographic disease progression was significantly slower with leflunomide than placebo ( P < 0.01 ) . Leflunomide was well tolerated . No long-term safety issues were reported with leflunomide in patients who opted to continue treatment for up to 2 years . Efficacy of leflunomide in the treatment of RA was maintained at 2 years [15860509] Objective : To assess methods to calculate achieving and sustaining remission in a double blind r and omised trial in patients with RA who received etanercept , methotrexate , or an etanercept/methotrexate combination . Methods : Remission was defined as DAS < 1.6 , DAS28 < 2.6 , and ACR70 response . Sustaining remission was analysed in three ways : ( a ) analysis of sustained DAS remission , DAS28 remission , or ACR70 response continuously for 6 months ; ( b ) analysis of sustained remission appraised through a continuity rewarded scoring system , which is the weighted sum of all intervals in the study in which patients are in DAS or DAS28 remission ; or ( c ) longitudinal modelling of remission odds using generalised estimating equations . Results : Significantly more patients treated with the etanercept/methotrexate combination reached DAS remission ( 37 % ) than those treated with either methotrexate ( 14 % ) or etanercept ( 18 % ) alone ( p<0.01 ) . Results for DAS28 and for the ACR70 response were similar . Agreement between DAS remission and DAS28 remission was good , but agreement between either of these and the ACR70 response was less . Patients in DAS or DAS28 remission had a lower level of disease activity ( fewer active joints , lower ESR ) than those achieving ACR70 response ; the converse was seen using pain VAS . The three methods were comparable for sustainability of remission and showed significant advantage for combination therapy , which increased the number and durability of remission periods . Conclusions : DAS and DAS28 remission results were similar for assessing achieving and sustaining remission in RA , frequently differing from patients classified as ACR70 responders . The three methods of examining duration of remission produced comparable results [15708884] OBJECTIVE To compare drug continuation rates in patients with rheumatoid arthritis who start on a biological agent and in a control group of patients with a change in disease modifying antirheumatic drug ( DMARD ) treatment after previous DMARD failure . METHODS Patients with rheumatoid arthritis enrolled in the German biologics register between May 2001 and September 2003 were included in the study . Data were available for 511 patients treated with etanercept , 343 with infliximab , 70 with anakinra , and 599 controls . Propensity scores were used to select a sub sample of patients from the control group who were likely to be treated with biological agents because of their disease severity , as well as comparable infliximab and etanercept cases . RESULTS Treatment continuation after 12 months was similar for etanercept ( 68.6 % ( 95 % confidence interval , 62 % to 75 % ) ) and infliximab ( 65.4 % ( 58 % to 73 % ) ) but lower for anakinra ( 59 % ( 41 % to 77 % ) ) . Treatment continuation was more likely for patients on combinations of biological agents and DMARDs than for those on infliximab or etanercept alone . Patients treated with biological agents were more severely ill than those in the control group and had more previous DMARD failures . After adjustment for baseline differences , the continuation rates were higher in patients treated with biological agents than in comparable control patients treated with leflunomide or leflunomide/methotrexate . CONCLUSIONS Treatment continuation of biological agents in clinical practice is less likely than in r and omised clinical trials but more likely than in comparable controls treated with conventional DMARDs [2564802] Objectives : This double-blind trial evaluated the efficacy and safety of abatacept or infliximab vs placebo . The primary objective of this study was to evaluate the mean change from baseline in Disease Activity Score ( based on erythrocyte sedimentation rates ; DAS28 ( ESR ) ) for the abatacept vs placebo groups at day 197 . Methods : Patients with rheumatoid arthritis ( RA ) and an inadequate response to methotrexate ( MTX ) were r and omised 3:3:2 to abatacept ( ∼10 mg/kg every 4 weeks , n = 156 ) , infliximab ( 3 mg/kg every 8 weeks , n = 165 ) , or placebo ( every 4 weeks , n = 110 ) and background MTX . Safety and efficacy were assessed throughout the study . Results : Similar patient demographics and clinical characteristics were present at baseline between groups , with mean scores of ∼1.7 for HAQ-DI and 6.8 for DAS28 ( ESR ) . At 6 months , mean changes in DAS28 ( ESR ) were significantly greater for abatacept vs placebo ( –2.53 vs –1.48 , p<0.001 ) and infliximab vs placebo ( –2.25 vs –1.48 , p<0.001 ) . For abatacept vs infliximab treatment at day 365 , reductions in the DAS28 ( ESR ) were –2.88 vs –2.25 . At day 365 , the following response rates were observed for abatacept and infliximab , respectively : American College of Rheumatology ( ACR ) 20 , 72.4 and 55.8 % ; ACR 50 , 45.5 and 36.4 % ; ACR 70 , 26.3 and 20.6 % ; low disease activity score ( LDAS ) , 35.3 and 22.4 % ; DAS28-defined remission , 18.7 and 12.2 % ; good European League Against Rheumatism ( EULAR ) responses , 32.0 and 18.5 % ; and Health Assessment Question naire Disability Index ( HAQ-DI ) , 57.7 and 52.7 % . Mean changes in physical component summary ( PCS ) were 9.5 and 7.6 , and mental component summary ( MCS ) were 6.0 and 4.0 , for abatacept and infliximab , respectively . Over 1 year , adverse events ( AEs ) ( 89.1 vs 93.3 % ) , serious AEs ( SAEs ) ( 9.6 vs 18.2 % ) , serious infections ( 1.9 vs 8.5 % ) and discontinuations due to AEs ( 3.2 vs 7.3 % ) and SAEs ( 2.6 vs 3.6 % ) were lower with abatacept than infliximab . Conclusions : In this study , abatacept and infliximab ( 3 mg/kg every 8 weeks ) demonstrated similar efficacy . Overall , abatacept had a relatively more acceptable safety and tolerability profile , with fewer SAEs , serious infections , acute infusional events and discontinuations due to AEs than the infliximab group . Trial registration number : NCT00095147 [16874796] OBJECTIVE To assess the risk of acute myocardial infa rct ion ( AMI ) associated with the use of disease-modifying antirheumatic drugs ( DMARDs ) and other medications commonly used in rheumatoid arthritis ( RA ) . METHODS We conducted a nested case-control analysis within a cohort of subjects with RA , observed between 1999 and 2003 , identified from the PharMetrics cl aims data base . For each first AMI hospitalization identified during followup , 10 controls matched on sex , age , and time of study entry were r and omly selected from the cohort . Conditional logistic regression was used to estimate the rate ratio ( RR ) of AMI associated with the current use of anti-RA therapy , as measured from dispensed prescriptions , after adjustment for AMI risk factors . RESULTS The cohort included 107,908 subjects ( average age 54 years at cohort entry ) . During followup , 558 AMI cases occurred ( 3.4 per 1,000 per year ) . AMI rate was significantly decreased with the current use of any DMARD ( adjusted RR 0.80 , 95 % confidence interval [ 95 % CI ] 0.65 - 0.98 ) . This effect was consistent across all DMARDs , including methotrexate ( RR 0.81 , 95 % CI 0.60 - 1.08 ) , leflunomide ( RR 0.28 , 95 % CI 0.12 - 0.65 ) , and other traditional DMARDs ( RR 0.67 , 95 % CI 0.46 - 0.97 ) , but not biologic agents ( RR 1.30 , 95 % CI 0.92 - 1.83 ) . AMI rate increased with the use of glucocorticoids ( RR 1.32 , 95 % CI 1.02 - 1.72 ) but not with nonselective nonsteroidal antiinflammatory drugs ( RR 1.05 , 95 % CI 0.81 - 1.36 ) or cyclooxygenase 2 ( COX-2 ) inhibitors ( RR 1.11 , 95 % CI 0.87 - 1.43 ) . CONCLUSION DMARD use is associated with a reduction in AMI risk in patients with RA . No risk increase was found with the COX-2 inhibitors in this population [18662933] Objectives : To compare the occurrence of drug-free remission , functional ability and radiological damage after 4 years of response-driven treatment according to four different treatment strategies for rheumatoid arthritis ( RA ) . Methods : Patients with recent-onset , active RA ( n = 508 ) were r and omly assigned to four different treatment strategies : ( 1 ) sequential monotherapy ; ( 2 ) step-up combination therapy ; ( 3 ) initial combination therapy with prednisone and ( 4 ) initial combination therapy with infliximab . Treatment was adjusted based on 3-monthly disease activity score ( DAS ) assessment s , aim ing at a DAS ⩽2.4 . From the third year , patients with a sustained DAS < 1.6 discontinued treatment . Results : In total , 43 % of patients were in remission ( DAS < 1.6 ) at 4 years and 13 % were in drug-free remission : 14 % , 12 % , 8 % and 18 % of patients in groups 1–4 , respectively . The absence of anti-cyclic citrullinated peptide antibodies , male gender and short symptom duration were independently associated with drug-free remission . Functional ability and remission were maintained in all four groups with the continuation of DAS-driven treatment , without significant differences between the groups . Significant progression of joint damage was observed in 38 % and 31 % of patients in groups 3 and 4 versus 51 % and 54 % of patients in groups 1 and 2 ( p<0.05 , group 4 versus groups 1 and 2 , group 3 versus group 2 ) . Conclusions : In patients with recent-onset active RA , drug-free remission was achieved in up to 18 % of patients . DAS-driven treatment maintained clinical and functional improvement , independent of the treatment strategy . Joint damage progression remained significantly lower after initial combination therapy compared with initial monotherapy [18050184] OBJECTIVE To determine whether the incidence of herpes zoster is elevated in patients with rheumatoid arthritis ( RA ) and whether herpes zoster is associated with use of disease-modifying antirheumatic drugs ( DMARDs ) in patients with RA . METHODS Two retrospective cohort studies were conducted using data from a US integrated managed care data base ( PharMetrics cl aims data base ) from 1998 - 2002 and the UK General Practice Research Data base ( GPRD ) between 1990 - 2001 . Rates of herpes zoster among patients with RA and r and omly sample d non-RA patients were compared . A nested case-control analysis was performed within each RA cohort to examine the effect of current treatment on herpes zoster risk . RESULTS A total of 122,272 patients with RA from the PharMetrics data base and 38,621 from the GPRD were included . The adjusted hazard ratios of herpes zoster for patients with RA compared with non-RA patients were 1.91 ( 95 % confidence interval [ 95 % CI ] 1.80 - 2.03 ) in the PharMetrics data base and 1.65 ( 95 % CI 1.57 - 1.75 ) in the GPRD . In the PharMetrics data base , current use of biologic DMARDs alone was associated with herpes zoster ( odds ratio [ OR ] 1.54 , 95 % CI 1.04 - 2.29 ) , as was current use of traditional DMARDs alone ( OR 1.37 , 95 % CI 1.18 - 1.59 ) . In the GPRD , current use of traditional DMARDs was associated with herpes zoster ( OR 1.27 , 95 % CI 1.10 - 1.48 ) . In both data sources , use of oral corticosteroids was associated with herpes zoster regardless of concomitant therapies . CONCLUSION Data from 2 large data bases suggested that patients with RA are at increased risk of herpes zoster . Among patients with RA , DMARDs and /or use of oral corticosteroids appeared to be associated with herpes zoster [17666447] Objectives : This study assessed the relative efficacy of etanercept ( ETN ) or etanercept and methotrexate ( ETN+MTX ) for patients with rheumatoid arthritis ( RA ) who had an unsatisfactory response to MTX , using patient-reported outcomes ( PROs ) of function , pain , general health , disease activity and morning stiffness . Methods : The PROs were secondary assessment s in a 16-week , prospect i ve , r and omised , parallel-group study conducted at 60 European centres . Patients with RA were r and omly assigned either to monotherapy with ETN or combination therapy with ETN+MTX . PRO instruments administered included the Stanford Health Assessment Question naire , the pain visual analogue scale , the EuroQoL assessment of current health state ( EQ-5D ) , the EQ-5D visual analogue scale , a patient global assessment of disease activity and an assessment of morning stiffness . Treatment groups were compared by percentage of patients within clinical ly meaningful categories . The primary endpoint for all PROs was comparison of mean improvement from baseline to week 16 between ETN and ETN+MTX groups . Results : Three hundred and fifteen patients were r and omised to ETN or ETN+MTX . Both treatment arms had similar Health Assessment Question naire Disability Index DI , EQ-5D , patient global assessment of disease activity , pain or morning stiffness scores and improvement from baseline to week 16 . Conclusions : For patients with active RA and intolerance or unsatisfactory response to MTX , substituting ETN for MTX and adding ETN to MTX are both effective ways of reducing disability , pain , disease activity , morning stiffness , and improving general health [20187135] OBJECTIVE To evaluate how continuation of and alterations to initial year 1 combination etanercept-methotrexate ( MTX ) therapy and MTX monotherapy regimens affect long-term remission and radiographic progression in early , active rheumatoid arthritis . METHODS Subjects were r and omized at baseline for the entire 2-year period ; those who completed 1 year of treatment with combination or MTX monotherapy entered year 2 . The original combination group either continued combination therapy ( the EM/EM group ; n = 111 ) or received etanercept monotherapy ( the EM/E group ; n = 111 ) in year 2 ; the original MTX monotherapy group either received combination therapy ( the M/EM group ; n = 90 ) or continued monotherapy ( the M/M group ; n = 99 ) in year 2 . Efficacy end points included remission ( a Disease Activity Score in 28 joints [ DAS28 ] < 2.6 ) and radiographic nonprogression ( change in the modified Sharp/van der Heijde score < or = 0.5 ) at year 2 . A last observation carried forward analysis from the modified intention-to-treat population ( n = 398 ) and a post hoc nonresponder imputation ( NRI ) analysis ( n = 528 ) were performed for remission . RESULTS At year 2 , DAS28 remission was achieved by 62/108 , 54/108 , 51/88 , and 33/94 subjects in the EM/EM , EM/E , M/EM , and M/M groups , respectively ( P < 0.01 for the EM/EM and M/EM groups versus the M/M group ) . This effect was corroborated by a more conservative post hoc 2-year NRI analysis , with remission observed in 59/131 , 50/134 , 48/133 , and 29/130 of the same respective groups ( P < 0.05 for each of the EM/EM , EM/E , and M/EM groups versus the M/M group ) . The proportions of subjects achieving radiographic nonprogression ( n = 360 ) were 89/99 , 74/99 , 59/79 , and 56/83 in the EM/EM ( P < 0.01 versus each of the other groups ) , EM/E , M/EM , and M/M groups , respectively . No new safety signals or between-group differences in serious adverse events were seen . CONCLUSION Early sustained combination etanercept-MTX therapy was consistently superior to MTX monotherapy . Combination therapy result ed in important clinical and radiographic benefits over 2 study years , without significant additional safety risk [9251634] BACKGROUND The value of intensive combination therapy in early rheumatoid arthritis is unproven . In a multicentre , double-blind , r and omised trial ( COBRA ) , we compared the combination of sulphasalazine ( 2 g/day ) , methotrexate ( 7.5 mg/week ) , and prednisolone ( initially 60 mg/day , tapered in 6 weekly steps to 7.5 mg/day ) with sulphasalazine alone . METHODS 155 patients with early rheumatoid arthritis ( median duration 4 months ) were r and omly assigned combined treatment ( 76 ) or sulphasalazine alone ( 79 ) . Prednisolone and methotrexate were tapered and stopped after 28 and 40 weeks , respectively . The main outcomes were the pooled index ( a weighted change score of five disease activity measures ) and the Sharp/Van der Heijde radiographic damage score in h and s and feet . Independent health-care professionals assessed the main outcomes without knowledge of treatment allocation . FINDINGS At week 28 , the mean pooled index was 1.4 ( 95 % CI 1.2 - 1.6 ) in the combined treatment group and 0.8 ( 0.6 - 1.0 ) in the sulphasalazine group ( p < 0.0001 ) . At this time , 55 ( 72 % ) and 39 ( 49 % ) patients , respectively , were improved according to American College of Rheumatology criteria . The clinical difference between the groups decreased and was no longer significant after prednisolone was stopped , and there were no further changes after methotrexate was stopped . At 28 weeks , the radiographic damage score had increased by a median of 1 ( range 0 - 28 ) in the combined-therapy group and 4 ( 0 - 44 ) in the sulphasalazine group ( p < 0.0001 ) . The increases at week 56 ( 2 [ 0 - 43 ] vs 6 [ 0 - 54 ] , p = 0.004 ) , and at week 80 ( 4 [ 0 - 80 ] vs 12 [ 0 - 72 ] , p = 0.01 ) were also significant . Further analysis suggests that combined therapy immediately suppressed damage progression , whereas sulphasalazine did so less effectively and with a lag of 6 to 12 months . There were fewer withdrawals in the combined therapy than the sulphasalazine group ( 6 [ 8 % ] vs 23 [ 29 % ] ) , and they occurred later . INTERPRETATION This combined-therapy regimen offers additional disease control over and above that of sulphasalazine alone that persists for up to a year after corticosteroids are stopped . Although confirmatory studies and long-term follow-up are needed , this approach may prove useful in the treatment of early rheumatoid arthritis [10573044] CONTEXT Leflunomide is a reversible inhibitor of de novo pyrimidine synthesis shown to be effective in a phase 2 trial in 402 patients with active rheumatoid arthritis ( RA ) . OBJECTIVE To compare the efficacy and safety of leflunomide treatment with placebo and methotrexate treatment in patients with active RA . DESIGN R and omized , double-blind , placebo , and active-controlled 12-month study . SETTING Forty-seven university and private rheumatology practice s in the United States and Canada . PATIENTS Diagnosis of RA by the American College of Rheumatology ( ACR ) criteria for duration of 6 months or longer and no previous methotrexate treatment . INTERVENTION Leflunomide treatment ( 20 mg/d ) , placebo , or methotrexate treatment ( 7.5 - 15 mg/wk ) . MAIN OUTCOME MEASURES American College of Rheumatology success rate ( completed 52 weeks of treatment and met the ACR > or = 20 % response criteria ) , disease progression as assessed by x-ray films , and improvement in function and health-related quality of life using the intent-to-treat population . RESULTS The 482 patients studied were predominantly women ( mean age , 54 years ; mean disease duration , 6.7 years ) for whom a mean of 0.8 disease-modifying antirheumatic drugs had failed . The ACR response and success rates for patients receiving leflunomide treatment ( 52 % and 41 % , respectively ) and methotrexate treatment ( 46 % and 35 % , respectively ) were significantly higher than those for patients receiving placebo ( 26 % and 19 % , respectively ) ( P<.001 ) , and they were statistically equivalent , with mean time to initial response at 8.4 weeks for patients receiving leflunomide vs 9.5 weeks for patients receiving methotrexate therapy . X-ray analyses demonstrated less disease progression with leflunomide ( P=.001 ) and methotrexate ( P = .02 ) therapy than with placebo . Leflunomide and methotrexate treatment improved measures of physical function and health-related quality of life significantly more than placebo ( P<.001 and P<.05 , respectively ) . Common adverse events for patients receiving leflunomide treatment included gastrointestinal complaints , skin rash , and reversible alopecia . Asymptomatic transaminase elevations result ed in treatment discontinuations for 7.1 % of patients receiving leflunomide therapy , 1.7 % of patients receiving placebo , and 3.3 % of patients receiving methotrexate therapy . CONCLUSIONS Clinical responses following administration of leflunomide , a new therapeutic agent for the treatment of RA , were statistically superior to those with placebo and equivalent to those with methotrexate treatment . Both active treatments improved signs and symptoms of active RA , delayed disease progression as demonstrated by x-ray films , and improved function and health-related quality of life [17768173] Objective : Treating early active rheumatoid arthritis ( RA ) with disease modifying antirheumatic drug ( DMARD ) monotherapy achieves incomplete outcomes and intensive treatment seems preferable . As the relative benefits of combining two DMARDs , one DMARD with glucocorticoids and two DMARDs with glucocorticoids are uncertain we defined them in a factorial trial . Methods : A 2-year r and omised double-blind factorial trial in patients with RA within 2 years of diagnosis treated with methotrexate studied the benefits of added ciclosporin , 9 months intensive prednisolone or both ( triple therapy ) . The primary outcome was the number of patients with new erosions . Secondary outcomes included Larsen ’s x-ray scores , disability , quality of life and adverse events . Findings : 1391 patients were screened and 467 r and omised . Over 2 years 132 ( 28 % ) changed therapy and 88 ( 19 % ) were lost to follow-up . The number of patients with new erosions was reduced by nearly half by adding ciclosporin or prednisolone ( p = 0.01 and 0.03 ) ; both treatments reduced increases in Larsen ’s x-ray scores by over 2 units ( p = 0.008 and 0.003 ) . A further reduction in erosive damage was seen with combined use of both treatments . Their effects on erosive damage appeared independent . Triple therapy reduced disability and improved quality of life compared with methotrexate ; ciclosporin and prednisolone acted synergistically . More patients withdrew because of adverse events with triple therapy , without an increase in serious adverse effects . Conclusions : This study confirms the existence of a “ window of opportunity ” in early RA , when intensive combination therapy produces sustained benefits on damage and disability . Although methotrexate – prednisolone combinations reduce erosive damage , the synergistic effect of two DMARDs is needed to improve quality of life [3811149] Objectives : The phase III RADIATE study examined the efficacy and safety of tocilizumab , an anti-IL-6 receptor monoclonal antibody in patients with rheumatoid arthritis ( RA ) refractory to tumour necrosis factor ( TNF ) antagonist therapy . Methods : 499 patients with inadequate response to one or more TNF antagonists were r and omly assigned to receive 8 mg/kg or 4 mg/kg tocilizumab or placebo ( control ) intravenously every 4 weeks with stable methotrexate for 24 weeks . ACR20 responses , secondary efficacy and safety endpoints were assessed . Results : ACR20 was achieved at 24 weeks by 50.0 % , 30.4 % and 10.1 % of patients in the 8 mg/kg , 4 mg/kg and control groups , respectively ( less than p<0.001 both tocilizumab groups versus control ) . At week 4 more patients achieved ACR20 in 8 mg/kg tocilizumab versus controls ( less than p = 0.001 ) . Patients responded regardless of most recently failed anti-TNF or the number of failed treatments . DAS28 remission ( DAS28 < 2.6 ) rates at week 24 were clearly dose related , being achieved by 30.1 % , 7.6 % and 1.6 % of 8 mg/kg , 4 mg/kg and control groups ( less than p = 0.001 for 8 mg/kg and p = 0.053 for 4 mg/kg versus control ) . Most adverse events were mild or moderate with overall incidences of 84.0 % , 87.1 % and 80.6 % , respectively . The most common adverse events with higher incidence in tocilizumab groups were infections , gastrointestinal symptoms , rash and headache . The incidence of serious adverse events was higher in controls ( 11.3 % ) than in the 8 mg/kg ( 6.3 % ) and 4 mg/kg ( 7.4 % ) groups . Conclusion : Tocilizumab plus methotrexate is effective in achieving rapid and sustained improvements in signs and symptoms of RA in patients with inadequate response to TNF antagonists and has a manageable safety profile . Trial registration number : NCT00106522 [16439435] Objective : To assess the safety of adalimumab in global clinical trials and postmarketing surveillance among patients with rheumatoid arthritis ( RA ) . Methods : Safety data for adalimumab treated patients from r and omised controlled trials , open label extensions , and two phase IIIb open label trials were analysed . In addition , postmarketing spontaneous reports of adverse events in the United States were collected following Food and Drug Administration approval of adalimumab on 31 December 2002 . Results : As of 15 April 2005 , the RA clinical trial safety data base analysed covered 10 050 patients , representing 12 506 patient-years ( PYs ) of adalimumab exposure . The rate of serious infections , 5.1/100 PYs , was comparable to that reported on 31 August 2002 ( 4.9/100 PYs ) , and to published reports of RA population s naive to anti-tumour necrosis factor ( TNF ) therapy . Following implementation of tuberculosis ( TB ) screening in clinical trials , the rate of TB decreased . There were 34 cases of TB as of this analysis ( 0.27/100 PYs ) . The st and ardised incidence ratio for lymphoma was 3.19 ( 95 % CI 1.78 to 5.26 ) , consistent with the observed increased incidence in the general RA population . As of 30 June 2005 , there were an estimated 78 522 PYs of exposure to adalimumab in the US postmarketing period . Seventeen TB cases were spontaneously reported ( 0.02/100 PYs ) from the US . Rates of other postmarketing events of interest , such as congestive heart failure , systemic lupus erythematosus , opportunistic infections , blood dyscrasias , lymphomas , and demyelinating disease , support observations from clinical trials . Conclusion : Analyses of these data demonstrate that long term adalimumab treatment is generally safe and well tolerated in patients with RA [16606651] Objective : To compare the efficacy and safety of etanercept and sulfasalazine , alone and in combination , in patients with active rheumatoid arthritis despite sulfasalazine treatment . Methods : A double-blind , r and omised study in adult patients with active rheumatoid arthritis despite stable sulfasalazine ( 2–3 g/day ) treatment . The primary end point was a 20 % response by the American College of Rheumatology ( ACR ) criteria at 24 weeks . Results : At baseline , the three treatment groups ( sulfasalazine , n = 50 ; etanercept , n = 103 ; etanercept and sulfasalazine , n = 101 ) were comparable for demographic variables and disease activity . Lack of efficacy was the primary reason for discontinuation ( sulfasalazine , n = 12 ; etanercept , n = 1 ; etanercept and sulfasalazine , n = 4 ; p<0.001 ) . Significantly more patients receiving etanercept , alone or in combination ( 74 % for each ) , achieved ACR 20 responses at 24 weeks than those receiving sulfasalazine ( 28 % ; p<0.01 ) . Similarly , more patients in the etanercept groups achieved ACR 50 and ACR 70 responses than those in the sulfasalazine group ( p<0.01 ) . In the groups receiving etanercept , significant differences in the ACR core components were observed by week 2 compared with those receiving sulfasalazine alone ( p<0.01 ) . The incidences of several common adverse events ( headache , nausea , asthenia ) were lower with etanercept alone than with the combination ( p<0.05 ) , but infections and injection site reactions were higher with etanercept alone ( p<0.05 ) . The safety profiles of both etanercept treatment groups were comparable with previous experience of etanercept . Conclusions : For all efficacy variables assessed , etanercept alone or in combination with sulfasalazine result ed in substantial and similar improvement in disease activity from baseline to week 24 compared with sulfasalazine alone in patients with active rheumatoid arthritis despite their sulfasalazine treatment . All three treatments were generally well tolerated [16258899] OBJECTIVE Several treatment strategies have proven value in the amelioration of rheumatoid arthritis ( RA ) , but the optimal strategy for preventing long-term joint damage and functional decline is unclear . We undertook this study to compare clinical and radiographic outcomes of 4 different treatment strategies , with intense monitoring in all patients . METHODS In a multicenter , r and omized clinical trial , 508 patients were allocated to 1 of 4 treatment strategies : sequential disease-modifying antirheumatic drug monotherapy ( group 1 ) , step-up combination therapy ( group 2 ) , initial combination therapy with tapered high-dose prednisone ( group 3 ) , and initial combination therapy with the tumor necrosis factor antagonist infliximab ( group 4 ) . Treatment adjustments were made every 3 months in an effort to obtain low disease activity ( a Disease Activity Score in 44 joints of < or = 2.4 ) . RESULTS Initial combination therapy including either prednisone ( group 3 ) or infliximab ( group 4 ) result ed in earlier functional improvement than did sequential monotherapy ( group 1 ) and step-up combination therapy ( group 2 ) , with mean scores at 3 months on the Dutch version of the Health Assessment Question naire ( D-HAQ ) of 1.0 in groups 1 and 2 and 0.6 in groups 3 and 4 ( P < 0.001 ) . After 1 year , mean D-HAQ scores were 0.7 in groups 1 and 2 and 0.5 in groups 3 and 4 ( P = 0.009 ) . The median increases in total Sharp/Van der Heijde radiographic joint score were 2.0 , 2.5 , 1.0 , and 0.5 in groups 1 - 4 , respectively ( P < 0.001 ) . There were no significant differences in the number of adverse events and withdrawals between the groups . CONCLUSION In patients with early RA , initial combination therapy including either prednisone or infliximab result ed in earlier functional improvement and less radiographic damage after 1 year than did sequential monotherapy or step-up combination therapy [2638601] We investigated the clinical efficacy and safety of tocilizumab ( a humanized anti-IL-6 receptor antibody ) monotherapy in active rheumatoid arthritis ( RA ) patients with an inadequate response to low dose methotrexate ( MTX ) . In a multicenter , double-blind , r and omized , controlled trial , 125 patients were allocated to receive either tocilizumab 8 mg/kg every 4 weeks plus MTX placebo ( tocilizumab group ) or tocilizumab placebo plus MTX 8 mg/week ( control group ) for 24 weeks . The clinical responses were measured using the American College of Rheumatology ( ACR ) criteria and the Disease Activity Score in 28 joints . Serum vascular endothelial growth factor ( VEGF ) levels were also monitored . At week 24 , 25.0 % in the control group and 80.3 % in the tocilizumab group achieved ACR20 response . The tocilizumab group showed superior ACR response criteria over control at all time points . Additionally , serum VEGF levels were significantly decreased by tocilizumab treatment . The overall incidences of adverse events ( AEs ) were 72 and 92 % ( serious AEs : 4.7 and 6.6 % ; serious infections : 1.6 and 3.3 % ) in the control and the tocilizumab groups , respectively . All serious adverse events improved by adequate treatment . Tocilizumab monotherapy was well tolerated and provided an excellent clinical benefit in active RA patients with an inadequate response to low dose MTX [1526636] We investigated the frequency of remission according to the disease activity score ( DAS28 ) definition , modified American Rheumatology Association ( ARA ) criteria , and the frequency of an achievement of a functional status above defined thresholds ( ' functional remission ' , ' physical independence ' ) in rheumatoid arthritis ( RA ) patients treated with either biologics or conventional DMARDs . We used the data of a prospect i ve cohort study , the German biologics register RABBIT ( German acronym for Rheumatoid Arthritis – Observation of Biologic Therapy ) to investigate the outcomes in RA patients with two or more DMARD failures who received new treatment with biologics ( BIOL ; n = 818 ) or a conventional DMARD ( n = 265 ) . Logistic regression analysis was applied to adjust for differences in baseline risks . Taking risk indicators such as previous DMARD failures or baseline clinical status into account , we found that biologics doubled the chance of remission compared to conventional DMARD therapies ( DAS28 remission , adjusted odds ratio ( OR ) 1.95 ( 95 % confidenece interval ( CI ) 1.2–3.2 ) ) ; ARA remission , OR 2.05 ( 95 % CI 1.2–3.5 ) ) . High remission rates ( DAS28 remission , 30.6 % ; ARA remission , 16.9 % ) were observed in BIOL patients with a moderate disease activity ( DAS28 , 3.2 to 5.1 ) at the start of treatment . These rates decreased to 8.5 % in patients with DAS28 > 6 . Sustained remission at 6 and 12 months was achieved in < 10 % of the patients . Severely disabled patients ( ≤50 % of full function ) receiving biologic therapies were significantly more likely to achieve a status indicating physical independence ( ≥67 % of full function ) than controls ( OR 3.88 ( 95 % CI 1.7–8.8 ) ) . ' Functional remission ' ( ≥83 % of full function ) was more often achieved in BIOL than in controls ( OR 2.18 ( 95 % CI 1.04–4.6 ) ) . In conclusion , our study shows that biologics increase the chance to achieve clinical remission and a status of functional remission or at least physical independence . However , temporary or even sustained remission remain ambitious aims , which are achieved in a minority of patients only [19560810] BACKGROUND Tumour necrosis factor alpha ( TNFalpha ) inhibitors are frequently used to treat rheumatoid arthritis , but whether use of a different TNFalpha inhibitor can improve patient response is unknown . We assess the efficacy and safety of the TNFalpha inhibitor golimumab in patients with active rheumatoid arthritis who had previously received one or more TNFalpha inhibitors . METHODS 461 patients with active rheumatoid arthritis from 82 sites in 10 countries were r and omly allocated by interactive voice response system , stratified by study site and methotrexate use , to receive subcutaneous injections of placebo ( n=155 ) , 50 mg golimumab ( n=153 ) , or 100 mg golimumab ( n=153 ) every 4 weeks between Feb 21 , 2006 , and Sept 26 , 2007 . Allocation was double-blind . Eligible patients had been treated with at least one dose of a TNFalpha inhibitor previously . Patients continued stable doses of methotrexate , sulfasalazine , hydroxychloroquine , oral corticosteroids , and non-steroidal anti-inflammatory drugs . The primary endpoint was achievement at week 14 of 20 % or higher improvement in American College of Rheumatology criteria for assessment of rheumatoid arthritis ( ACR20 ) . At week 16 , patients who had less than 20 % improvement in tender and swollen joint counts were given rescue therapy and changed treatment from placebo to 50 mg golimumab , or from 50 mg to 100 mg golimumab . Drug efficacy was assessed by intention to treat and safety was assessed according to the study drug given . This study is registered with Clinical Trials.gov , number NCT00299546 . FINDINGS Patients had discontinued previous TNFalpha inhibitors because of lack of effectiveness ( 269 [ 58 % ] patients ) or reasons unrelated to effectiveness ( 246 [ 53 % ] patients ) , such as intolerance and accessibility issues . Patients had active disease , which was indicated by a median of 14.0 ( IQR 9.0 - 22.0 ) swollen and 26.0 ( 16.0 - 41.0 ) tender joints for the whole group . 28 ( 18 % ) patients on placebo , 54 ( 35 % ) patients on 50 mg golimumab ( odds ratio 2.5 [ 95 % CI 1.5 - 4.2 ] , p=0.0006 ) , and 58 ( 38 % ) patients on 100 mg golimumab ( 2.8 [ 1.6 - 4.7 ] , p=0.0001 ) achieved ACR20 at week 14 . Two patients were never treated , and 57 patients did not complete the study because of adverse events , unsatisfactory treatment effect , loss to follow-up , death , or other reasons . 155 patients on placebo , 153 on 50 mg golimumab , and 153 on 100 mg golimumab were assessed for drug efficacy . For weeks 1 - 16 , serious adverse events were recorded in 11 ( 7 % ) patients on placebo , 8 ( 5 % ) on 50 mg golimumab , and 4 ( 3 % ) on 100 mg golimumab . For weeks 1 - 24 , after some patients were given rescue therapy , serious adverse events were recorded in 15 ( 10 % ) patients on placebo , 14 ( 5 % ) on 50 mg golimumab , and 8 ( 4 % ) on 100 mg golimumab . INTERPRETATION Golimumab reduced the signs and symptoms of rheumatoid arthritis in patients with active disease who had previously received one or more TNFalpha inhibitors . FUNDING Centocor Research and Development and Schering-Plough Research Institute [17083767] AIM To evaluate the efficacy and safety of four different treatment strategies for patients with early rheumatoid arthritis ( RA ) . METHODS In the BeSt study , 508 patients with newly diagnosed ( < 2 years ) active RA were r and omised to be treated according to four treatment strategies : 1 . sequential monotherapy , 2 . step up to combination therapy ( both starting with methotrexate ) , 3 . initial combination therapy with methotrexate , sulphasalazine , and a tapered high dose of prednisone , and 4 . initial combination therapy with methotrexate and infliximab . Three-monthly therapy adjustments were dictated by calculation of the Disease Activity Score ( DAS ) , with the goal to achieve and maintain a DAS < or= 2.4 . Functional ability was measured every 3 months with the Health Assessment Question naire . Radiographs of h and s and feet were assessed yearly , blinded for patient identity and treatment , and in r and om order , to measure joint damage progression ( Sharp/van der Heijde score ) . RESULTS After 2 years of treatment , 80 % of all patients achieved the goal of DAS < or= 2.4 , and 42 % reached clinical remission ( DAS < 1.6 ) . Initial combination therapy , either with prednisone ( group 3 ) or with infliximab ( group 4 ) , result ed in earlier improvement in functional ability , more continuous clinical remission ( DAS < 1.6 ) , and less joint damage progression than initial monotherapy ( groups 1 and 2 ) . Patients in groups 1 and 2 needed more therapy adjustments , including introduction of combination therapy with prednisone or infliximab , to achieve a DAS < or= 2.4 , whereas many patients in groups 3 and 4 were able to taper their medication to sulphasalazine or methotrexate , respectively , monotherapy . The adverse events profile was comparable in all groups . The presence or absence of rheumatoid factor , HLA DR4 , or anti-CCP was not associated with radiologic damage progression . CONCLUSION In patients with early , active RA , remarkable clinical improvement and suppression of joint damage progression can be achieved with frequent , objective ly steered treatment adjustments . The best chance for an early clinical and radiologic response lies with initial combination therapy with either methotrexate , sulphasalazine and prednisone or with methotrexate and infliximab , which can be tapered to DMARD monotherapy once low disease activity is achieved [15529377] OBJECTIVE To compare the benefits of initiating treatment with methotrexate ( MTX ) and infliximab ( anti-tumor necrosis factor alpha [ anti-TNFalpha ] monoclonal antibody ) with those of MTX treatment alone in patients with rheumatoid arthritis ( RA ) of < or =3 years ' duration . METHODS RA patients were eligible if they had active disease and no prior treatment with MTX or a TNFalpha inhibitor . One thous and forty-nine patients were r and omly assigned in a 4:5:5 ratio to 3 treatment groups : MTX-placebo , MTX-3 mg/kg infliximab , and MTX-6 mg/kg infliximab . MTX dosages were rapidly escalated to 20 mg/week , and infliximab or placebo infusions were given at weeks 0 , 2 , and 6 , and every 8 weeks thereafter through week 46 . RESULTS At week 54 , the median percentage of American College of Rheumatology improvement ( ACR-N ) was higher for the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups than for the MTX-placebo group ( 38.9 % and 46.7 % versus 26.4 % , respectively ; P < 0.001 for both comparisons ) . Patients in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups also showed less radiographic progression than those receiving MTX alone ( mean + /- SD changes in van der Heijde modification of the total Sharp score at week 54 : 0.4 + /- 5.8 and 0.5 + /- 5.6 versus 3.7 + /- 9.6 , respectively ; P < 0.001 for each comparison ) . In addition , physical function improved significantly more in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups than in the MTX-placebo group . Infliximab therapy was associated with a significantly higher incidence of serious infections , especially pneumonia . CONCLUSION For patients with active RA in its early stages , combination therapy with MTX and infliximab provides greater clinical , radiographic , and functional benefits than treatment with MTX alone [11023558] Infliximab is a chimeric anti-tumour necrosis factor-alpha monoclonal antibody that has been studied for the treatment of Crohn 's disease and rheumatoid arthritis . In several placebo controlled , r and omized clinical trials and open trials , 771 patients have been given infliximab ( a further 192 received placebo ) . Follow-up for safety has included the time of study ( 12 weeks after the last infusion ) , plus three additional years . Acute infusion reactions ( headache , fever , chills , urticaria , chest pain ) were seen in 17 % of patients receiving infliximab compared with 7 % of those receiving placebo . While infections were reported more frequently overall in the patients given infliximab ( 26 % over 27 weeks of follow-up versus 16 % of placebo-treated patients over 20 weeks of follow-up ) , there was no increased risk of serious infections . There was no difference in the overall mortality rate between the groups . While low titres of autoantibodies developed in less than 10 % of patients , drug-induced lupus was seen in less than 1 % , with these cases resolving upon discontinuation of the drug . Overall , infliximab showed an acceptable safety profile [16947384] OBJECTIVE To assess the safety of abatacept , a selective costimulation modulator , in patients with active rheumatoid arthritis ( RA ) who had been receiving > or = 1 traditional nonbiologic and /or biologic disease-modifying antirheumatic drugs ( DMARDs ) approved for the treatment of RA for at least 3 months prior to entry into the study . METHODS This was a 1-year , multicenter , r and omized , double-blind , placebo-controlled trial . Patients were r and omized 2:1 to receive abatacept at a fixed dose approximating 10 mg/kg by weight range , or placebo . RESULTS The abatacept and placebo groups exhibited similar frequencies of adverse events ( 90 % and 87 % , respectively ) , serious adverse events ( 13 % and 12 % , respectively ) , and discontinuations due to adverse events ( 5 % and 4 % , respectively ) . Five patients ( 0.5 % ) in the abatacept group and 4 patients ( 0.8 % ) in the placebo group died during the study . Serious infections were more frequent in the abatacept group than in the placebo group ( 2.9 % versus 1.9 % ) . Fewer than 4 % of patients in either group experienced a severe or very severe infection . The incidence of neoplasms was 3.5 % in both groups . When evaluated according to background therapy , serious adverse events occurred more frequently in the subgroup receiving abatacept plus a biologic agent ( 22.3 % ) than in the other subgroups ( 11.7 - 12.5 % ) . CONCLUSION Abatacept in combination with synthetic DMARDs was well tolerated and improved physical function and physician- and patient-reported disease outcomes . However , abatacept in combination with biologic background therapies was associated with an increase in the rate of serious adverse events . Therefore , abatacept is not recommended for use in combination with biologic therapy [16358366] OBJECTIVE To prospect ively determine the efficacy and safety of etanercept in combination with sulfasalazine ( SSZ ) , hydroxychloroquine ( HCQ ) , and gold in the treatment of rheumatoid arthritis ( RA ) . METHODS A prospect i ve open-label study enrolled 119 patients with RA who had active disease despite stable therapy with SSZ ( n = 50 ) , HCQ ( n = 50 ) , or intramuscular gold ( n = 19 ) . Primary efficacy endpoints consisted of American College of Rheumatology responses at 24 and 48 weeks . Safety was established at regularly scheduled visits . RESULTS Patients in each etanercept combination showed significant improvement at both 24 and 48 weeks . Toxicity withdrawals by 48 weeks included gold ( n = 1 ) : proteinuria ; HCQ ( n = 5 ) : septic wrist and bilateral pneumonia , rash , optic neuritis , breast cancer , squamous cancer of the tongue ; and SSZ ( n = 5 ) : otitis media , elevated liver function indicators , pericarditis , rash , and gastroenteritis . The most common adverse events not requiring discontinuation from the study were injection site reactions ( 43 % of patients ) and upper respiratory type infections ( 34 % ) . CONCLUSION This study is the first to prospect ively evaluate the safety of etanercept in combination with SSZ , HCQ , and gold in patients with RA . Etanercept in combination with SSZ , HCQ , or gold was efficacious and well tolerated , with a discontinuation rate of 9 % ( 11/119 ) for adverse events at 48 weeks [10334255] BACKGROUND The treatment of rheumatoid arthritis should aim at clinical remission . This multicentre , r and omised trial with 2-year follow-up sought evidence on the efficacy and tolerability of combination therapy ( sulphasalazine , methotrexate , hydroxychloroquine , and prednisolone ) compared with treatment with a single disease-modifying antirheumatic drug , with or without prednisolone , in the treatment of early rheumatoid arthritis . METHODS 199 patients were r and omly assigned to two treatment groups . 195 started the treatment ( 97 received combination and 98 single drug therapy ) . Single-drug therapy in all patients started with sulphasalazine ; in 51 patients methotrexate was later substituted . Oral prednisolone was required by 63 patients . The primary outcome measure was induction of remission . Analyses were intention to treat . FINDINGS 87 patients in the combination group and 91 in the single-therapy group completed the trial . After a year , remission was achieved in 24 of 97 patients with combination therapy , and 11 of 98 with single-drug therapy ( p=0.011 ) . The remission frequencies at 2 years were 36 of 97 and 18 of 98 ( p=0.003 ) . Clinical improvement ( American College of Rheumatology criteria of 50 % clinical response ) was achieved after 1 year in 68 ( 75 % ) patients with combination therapy , and in 56 ( 60 % ) using single-drug therapy ( p=0.028 ) , while at the 2-year visit 69 and 57 respectively ( 71 % vs 58 % , p=0.058 ) had clinical ly improved . The frequencies of adverse events were similar in both treatment groups . INTERPRETATION Combination therapy was better and not more hazardous than single treatment in induction of remission in early rheumatoid arthritis . The combination strategy as an initial therapy seems to increase the efficacy of the treatment in at least a proportion of patients with early rheumatoid arthritis [15001324] BACKGROUND Etanercept and methotrexate are effective in the treatment of rheumatoid arthritis but no data exist on concurrent initiation or use of the combination compared with either drug alone . We aim ed to assess combination treatment with etanercept and methotrexate versus the monotherapies in patients with rheumatoid arthritis . METHODS In a double-blind , r and omised , clinical efficacy , safety , and radiographic study , 686 patients with active rheumatoid arthritis were r and omly allocated to treatment with etanercept 25 mg ( subcutaneously twice a week ) , oral methotrexate ( up to 20 mg every week ) , or the combination . Clinical response was assessed by criteria of the American College of Rheumatology ( ACR ) . The primary efficacy endpoint was the numeric index of the ACR response ( ACR-N ) area under the curve ( AUC ) over the first 24 weeks . The primary radiographic endpoint was change from baseline to week 52 in total joint damage and was assessed with the modified Sharp score . Analysis was by intention to treat . FINDINGS Four patients did not receive any drug ; thus 682 were studied . ACR-N AUC at 24 weeks was greater for the combination group compared with etanercept alone and methotrexate alone ( 18.3%-years [ 95 % CI 17.1 - 19.6 ] vs 14.7%-years [ 13.5 - 16.0 ] , p<0.0001 , and 12.2%-years [ 11.0 - 13.4 ] , p<0.0001 ; respectively ) . The mean difference in ACR-N AUC between combination and methotrexate alone was 6.1 ( 95 % CI 4.5 - 7.8 , p<0.0001 ) and between etanercept and methotrexate was 2.5 ( 0.8 - 4.2 , p=0.0034 ) . The combination was more efficacious than methotrexate or etanercept alone in retardation of joint damage ( mean total Sharp score -0.54 [ 95 % CI -1.00 to -0.07 ] vs 2.80 [ 1.08 to 4.51 ] , p<0.0001 , and 0.52 [ -0.10 to 1.15 ] , p=0.0006 ; respectively ) . The mean difference in total Sharp score between combination and methotrexate alone was -3.34 ( 95 % CI -4.86 to -1.81 , p<0.0001 ) and between etanercept and methotrexate was -27 ( -3.81 to -0.74 , p=0.0469 ) . The number of patients reporting infections or adverse events was similar in all groups . INTERPRETATION The combination of etanercept and methotrexate was significantly better in reduction of disease activity , improvement of functional disability , and retardation of radiographic progression compared with methotrexate or etanercept alone . These findings bring us closer to achievement of remission and repair of structural damage in rheumatoid arthritis [16868999] OBJECTIVE To determine whether the rate of serious infection is higher in anti-tumor necrosis factor (anti-TNF)-treated rheumatoid arthritis ( RA ) patients compared with RA patients treated with traditional disease-modifying antirheumatic drugs ( DMARDs ) . METHODS This was a national prospect i ve observational study of 7,664 anti-TNF-treated and 1,354 DMARD-treated patients with severe RA from the British Society for Rheumatology Biologics Register . All serious infections , stratified by site and organism , were included in the analysis . RESULTS Between December 2001 and September 2005 , there were 525 serious infections in the anti-TNF-treated cohort and 56 in the comparison cohort ( 9,868 and 1,352 person-years of followup , respectively ) . The incidence rate ratio ( IRR ) , adjusted for baseline risk , for the anti-TNF-treated cohort compared with the comparison cohort was 1.03 ( 95 % confidence interval 0.68 - 1.57 ) . However , the frequency of serious skin and soft tissue infections was increased in anti-TNF-treated patients , with an adjusted IRR of 4.28 ( 95 % confidence interval 1.06 - 17.17 ) . There was no difference in infection risk between the 3 main anti-TNF drugs . Nineteen serious bacterial intracellular infections occurred , exclusively in patients in the anti-TNF-treated cohort . CONCLUSION In patients with active RA , anti-TNF therapy was not associated with increased risk of overall serious infection compared with DMARD treatment , after adjustment for baseline risk . In contrast , the rate of serious skin and soft tissue infections was increased , suggesting an important physiologic role of TNF in host defense in the skin and soft tissues beyond that in other tissues [16572442] OBJECTIVE To assess the risk of serious infections following 22 weeks of infliximab therapy , and to further characterize the safety profile of infliximab in combination with background treatments during 1 year in patients with rheumatoid arthritis ( RA ) with various comorbidities . METHODS Patients with active RA despite receiving methotrexate ( MTX ) were r and omly assigned to receive infusions of placebo ( group 1 , n=363 ) , 3 mg/kg infliximab ( group 2 , n=360 ) , or 10 mg/kg infliximab ( group 3 , n=361 ) at weeks 0 , 2 , 6 , and 14 . At week 22 , patients in placebo group 1 began receiving 3 mg/kg infliximab , and patients in group 3 continued to receive an infliximab dose of 10 mg/kg . Patients in group 2 who failed to meet predefined response criteria received increasing doses of infliximab in increments of 1.5 mg/kg . RESULTS At week 22 , the relative risk of developing serious infections in groups 2 and 3 , compared with group 1 , was 1.0 ( 95 % confidence interval [ 95 % CI ] 0.3 - 3.1 , P=0.995 ) and 3.1 ( 95 % CI 1.2 - 7.9 , P=0.013 ) , respectively . The incidence of serious adverse events was 7.8 % in groups 2 and 3 compared with 7.5 % in group 1 . From week 22 to week 54 , 11.8 % , 9.9 % , and 10.3 % of patients in groups 1 , 2 , and 3 , respectively , reported occurrences of serious adverse events . Through week 54 , 1 patient in group 1 , 2 patients in group 2 , and 4 patients in group 3 developed active tuberculosis . CONCLUSION The risk of serious infections in patients receiving the approved infliximab dose of 3 mg/kg plus MTX was similar to that in patients receiving MTX alone . Patients receiving the unapproved induction regimen of 10 mg/kg infliximab plus MTX followed by a 10 mg/kg maintenance regimen had an increased risk of serious infections through week 22 [18635256] BACKGROUND Remission and radiographic non-progression are goals in the treatment of early rheumatoid arthritis . The aim of the combination of methotrexate and etanercept in active early rheumatoid arthritis ( COMET ) trial is to compare remission and radiographic non-progression in patients treated with methotrexate monotherapy or with methotrexate plus etanercept . METHODS 542 out patients who were methotrexate-naive and had had early moderate-to-severe rheumatoid arthritis for 3 - 24 months were r and omly assigned to receive either methotrexate alone titrated up from 7.5 mg a week to a maximum of 20 mg a week by week 8 or methotrexate ( same titration ) plus etanercept 50 mg a week . Co primary endpoints at 52 weeks were remission measured with the disease activity score in 28 joints ( DAS28 ) and radiographic non-progression measured with modified total Sharp score . Treatment was allocated with a computerised r and omisation and enrolment system , which masked both participants and carers . Analysis was done by modified intention to treat with last observation carried forward for missing data . This study is registered with Clinical Trials.gov , number NCT00195494 ) . FINDINGS 274 participants were r and omly assigned to receive combined treatment and 268 methotrexate alone . 132 of 265 ( 50 % , 95 % CI 44 - 56 % ) patients who took combined treatment and were available for assessment achieved clinical remission compared with 73 of 263 ( 28 % , 23 - 33 % ) taking methotrexate alone ( effect difference 22.05 % , 95%CI 13.96 - 30.15 % , p<0.0001 ) . 487 evaluable patients had severe disease ( DAS28>5.1 ) . 196 of 246 ( 80 % , 75 - 85 % ) and 135 of 230 ( 59 % , 53 - 65 % ) , respectively , achieved radiographic non-progression ( 20.98 % , 12.97 - 29.09 % , p<0.0001 ) . Serious adverse events were similar between groups . INTERPRETATION Both clinical remission and radiographic non-progression are achievable goals in patients with early severe rheumatoid arthritis within 1 year of combined treatment with etanercept plus methotrexate . FUNDING Wyeth Research [16464988] Objective : To evaluate the efficacy and safety of etanercept ( ETN ) monotherapy compared with combination ETN and methotrexate ( MTX ) treatment in patients with rheumatoid arthritis who had an inadequate response to MTX monotherapy . ( The response was defined by the presence of Disease Activity Score-28 joint count ( DAS28 ) ⩾3.2 or a combination of ⩾5 swollen joints , ⩾5 painful joints and erythrocyte sedimentation rate ⩾10 mm/h . ) Methods : Patients with active rheumatoid arthritis taking MTX ⩾12.5 mg/week for ⩾3 months were included in this 16 week , r and omised , open-label study . Patients were r and omly assigned to either ETN ( 25 mg subcutaneous injection twice weekly ) added to the baseline dose of MTX or ETN monotherapy . Results : 315 patients were r and omised to ETN ( n = 160 ) or ETN plus MTX ( n = 155 ) . The primary end point , DAS28 ( 4 ) improvement of > 1.2 units , was achieved by 72.8 % and 75.2 % of patients treated with ETN and those treated with ETN plus MTX , respectively , with no significant difference ( p = 0.658 ) between the two groups . The European League Against Rheumatism response criteria of good or moderate response was attained by 80.0 % of patients in the ETN group and by 82.4 % of patients in the ETN plus MTX group . American College of Rheumatology 20 % , 50 % and 70 % response rates achieved by both groups were also similar : 71.0 % v 67.1 % , 41.9 % v 40.1 % and 17.4 % v 18.4 % , respectively . The rates of adverse and serious adverse events were similar between the treatment groups . Conclusion : Both the addition of ETN to MTX and the substitution of ETN for MTX in patients with rheumatoid arthritis who had an inadequate response to MTX result ed in substantial improvements in clinical signs and symptoms and were generally well-tolerated treatment strategies for improving clinical signs and symptoms of rheumatoid arthritis [12176803] Objective : To explore the feasibility of prospect ively monitoring treatment efficacy and tolerability of infliximab , etanercept , and leflunomide over a two year period in patients with established rheumatoid arthritis ( RA ) in clinical practice using a structured protocol . Methods : All patients with RA at seven centres in southern Sweden , for whom at least two disease modifying antirheumatic drugs , including methotrexate , had failed or not been tolerated , who started treatment with either infliximab , etanercept , or leflunomide were included . They were evaluated at predefined times using a st and ardised protocol including items required for evaluating response to the American College of Rheumatology ( ACR ) or EULAR criteria . All adverse events were recorded using World Health Organisation terminology . Concomitant treatment and survival while receiving a drug were recorded . Results : During the study 166 patients were treated with etanercept , 135 with infliximab , and 103 with leflunomide . Treatment response as determined by the ACR and EULAR response criteria was similar for the tumour necrosis factor ( TNF ) blockers . The TNF blockers performed significantly better than leflunomide both as determined by the response criteria and by survival on drug analysis . Thus 79 % and 75 % continued to receive etanercept or infliximab compared with 22 % of patients who started leflunomide after 20 months . The spectrum of side effects did not differ from those previously reported in the clinical trials . The initial two year experience of a protocol for postmarketing surveillance of etanercept , infliximab , and leflunomide shows that a structured protocol with central data h and ling can be used in clinical practice for documenting the performance of newly introduced drugs . Conclusions : Efficacy data for the TNF blockers comply with results in clinical trials , whereas leflunomide appeared to perform worse than in clinical trials . Prolonged monitoring is required to identify possible rare side effects [11840436] OBJECTIVE The Combinatietherapie Bij Reumatoide Artritis ( COBRA ) trial demonstrated that step-down combination therapy with prednisolone , methotrexate , and sulfasalazine ( SSZ ) was superior to SSZ monotherapy for suppressing disease activity and radiologic progression of rheumatoid arthritis ( RA ) . The current study was conducted to investigate whether the benefits of COBRA therapy were sustained over time , and to determine which baseline factors could predict outcome . METHODS All patients had participated in the 56-week COBRA trial . During followup , they were seen by their own rheumatologists and were also assessed regularly by study nurses ; no treatment protocol was specified . Disease activity , radiologic damage , and functional ability were the primary outcome domains . Two independent assessors scored radiographs in sequence according to the Sharp/van der Heijde method . Outcomes were analyzed by generalized estimating equations on the basis of intent-to-treat , starting with data obtained at the last visit of the COBRA trial ( 56 weeks after baseline ) . RESULTS At the beginning of followup , patients in the COBRA group had a significantly lower mean time-averaged 28-joint disease activity score ( DAS28 ) and a significantly lower median radiologic damage ( Sharp ) score compared with those in the SSZ monotherapy group . The functional ability score ( Health Assessment Question naire [ HAQ ] ) was similar in both groups . During the 4 - 5 year followup period , the time-averaged DAS28 decreased 0.17 points per year in the SSZ group and 0.07 in the COBRA group . The Sharp progression rate was 8.6 points per year in the SSZ group and 5.6 in the COBRA group . After adjustment for differences in treatment and disease activity during followup , the between-group difference in the rate of radiologic progression was 3.7 points per year . The HAQ score did not change significantly over time . Independent baseline predictors of radiologic progression over time ( apart from treatment allocation ) were rheumatoid factor positivity , Sharp score , and DAS28 . CONCLUSION An initial 6-month cycle of intensive combination treatment that includes high-dose corticosteroids results in sustained suppression of the rate of radiologic progression in patients with early RA , independent of subsequent antirheumatic therapy [15146410] OBJECTIVE To determine the potential for additive or synergistic effects of combination therapy with the selective anti-tumor necrosis factor alpha agent etanercept and the anti-interleukin-1 agent anakinra . METHODS Two hundred forty-four patients in whom rheumatoid arthritis ( RA ) was active despite methotrexate therapy were treated with subcutaneous etanercept only ( 25 mg twice weekly ) , full-dosage etanercept ( 25 mg twice weekly ) plus anakinra ( 100 mg/day ) , or half-dosage etanercept ( 25 mg once weekly ) plus anakinra ( 100 mg/day ) for 6 months in a double-blind study at 41 centers in the US . Patients had never previously received anticytokine therapy . Patient response was measured with the American College of Rheumatology ( ACR ) core set criteria , a health-related quality -of-life question naire , and the Disease Activity Score . Safety was assessed by the number of adverse events and clinical laboratory values . Plasma concentrations of both agents and antibody formation against both agents were also assessed . RESULTS Combination therapy with etanercept plus anakinra provided no treatment benefit over etanercept alone , regardless of the regimen , but was associated with an increased safety risk . Thirty-one percent of the patients treated with full-dosage etanercept plus anakinra achieved an ACR 50 % response , compared with 41 % of the patients treated with etanercept only . This result was not statistically significant ( P = 0.914 ) . The incidence of serious infections ( 0 % for etanercept alone , 3.7 - 7.4 % for combination therapy ) , injection-site reactions , and neutropenia was increased with combination therapy . Combination therapy had no effect on the pharmacokinetics or immunogenicity of either agent . CONCLUSION Combination therapy with etanercept and anakinra provides no added benefit and an increased risk compared with etanercept alone and is not recommended for the treatment of patients with RA [17469098] OBJECTIVE Patients with rheumatoid arthritis ( RA ) in whom the response to anti-tumor necrosis factor ( anti-TNF ) therapy is inadequate have several therapeutic options , such as switching to an alternative anti-TNF agent or initiating B cell-depleting therapy with rituximab ( RTX ) . Although both therapeutic options have been proven effective in trials , no head-to-head comparisons are available . The aim of this study was to compare the effectiveness of RTX with that of an alternative anti-TNF agent in the management of patients with RA who had an inadequate response to anti-TNF therapy . METHODS This prospect i ve cohort study was nested within the Swiss Clinical Quality Management RA cohort and included all patients who had an inadequate response to at least 1 anti-TNF agent and subsequently received either 1 cycle of RTX or an alternative anti-TNF agent . The primary outcome was the evolution of RA disease activity ( as measured on the Disease Activity Score in 28 joints [ DAS28 ] ) , which was analyzed using multivariate regression models for longitudinal data . RESULTS One hundred sixteen patients with RA were included ; 50 patients received 1 cycle of RTX , and 66 patients were treated with a second or a third alternative anti-TNF agent . At baseline , there were no significant differences between the 2 groups in age , sex , disease duration , and disease activity . Evolution of the DAS28 was more favorable in the group that received RTX compared with the group that received an alternative anti-TNF agent ( P = 0.01 ) . At 6 months , the mean decrease in the DAS28 was -1.61 ( 95 % confidence interval [ 95 % CI ] -1.97 , -1.25 ) among patients receiving RTX and -0.98 ( 95 % CI -1.33 , -0.62 ) among those receiving subsequent anti-TNF therapy . CONCLUSION The results of this observational study suggest that treatment with RTX may be more effective than switching to an alternative anti-TNF agent in patients with RA in whom active disease persists despite anti-TNF therapy [16393444] ABSTRACT Objective : To evaluate the effectiveness of select biologics , methotrexate ( MTX ) , and other disease-modifying anti-rheumatic drugs ( DMARDs ) in the management of adult rheumatoid arthritis ( RA ) in routine clinical practice . Research design and methods : RADIUS ( Rheumatoid Arthritis DMARD Intervention and Utilization Study ) comprises two prospect i ve , 5‐year , observational registries of over 10 000 patients . Over 4600 patients who initiated MTX or a biologic regimen ( etanercept [ ETN ] , infliximab [ INF ] , ETN + MTX , and INF + MTX ) and who had at least one on-regimen , follow-up evaluation , were included in this analysis . Adalimumab was not included because it had not yet received FDA approval at RADIUS initiation . Other common DMARD regimens ( N = 762 ) were also compared with MTX . Patients who initiated less commonly used regimens , such as anakinra or cyclosporine , and those who did not have at least one on-regimen , follow-up evaluation , were not eligible for this analysis . Because ESR/CRP measurements were often not available , a modified ACR20 response ( mACR20 ) , defined as three out of four response criteria excluding ESR/CRP , was used to assess response at 12 months . Logistic regression analysis was performed to control for baseline covariates that may affect outcomes . Main outcome measures : The primary endpoint was the proportion of patients who achieved a mACR20 response at 12 months post-RADIUS entry . Results : After adjusting for baseline covariates , patients receiving either ETN + MTX or ETN monotherapy were more likely to achieve a mACR20 response at 12 months than patients receiving MTX alone ( odds ratio [ OR ] 1.29 , 95 % confidence interval [ CI ] 1.09–1.52 ; p < 0.01 and OR 1.23 , 95 % CI 1.02–1.47 ; p < 0.05 , respectively ) . Conversely , patients treated with MTX + leflunomide ( LEF ) were less likely to achieve a mACR20 response than those receiving MTX alone ( OR 0.68 , 95 % CI 0.48–0.96 ; p < 0.05 ) . Significant differences were not observed between patients receiving MTX alone and either INF + MTX , MTX + hydroxychloroquine , MTX + hydroxychloroquine + sulfasalazine , INF monotherapy , or LEF monotherapy . Conclusion : These data from routine rheumatology clinical practice setting s highlight the effectiveness of common biologic and DMARD therapies , and provide additional data beyond those of r and omized , controlled trials [17195186] OBJECTIVE Patients with rheumatoid arthritis ( RA ) who experience treatment failure with one anti-tumor necrosis factor ( anti-TNF ) agent , due to either inefficacy or toxicity , are frequently switched to a second anti-TNF agent , although the benefits of switching are unknown . The present study was undertaken to compare drug continuation rates between the first course and second course of anti-TNF therapy . METHODS The study involved a prospect i ve cohort of RA patients from a UK national register of new anti-TNF treatment starts ( n = 6,739 ; 876 starting adalimumab , 2,826 starting etanercept , and starting 3,037 infliximab ) . Over a mean 15 months of followup , 841 patients stopped taking the first drug due to inefficacy and 1,023 stopped the first drug due to toxicity , of whom 503 and 353 , respectively , were switched to a second anti-TNF agent . Kaplan-Meier survival curves were plotted to determine continuation rates for each course , and Cox regression was used to compare each course for the risk of stopping and the reason for stopping ( inefficacy or toxicity ) . RESULTS Overall , 73 % of patients who switched to a second anti-TNF agent remained on the new therapy by the end of followup . First drug discontinuation due to inefficacy was associated with an increased rate of second drug discontinuation due to inefficacy ( hazard ratio [ HR ] 2.7 , 95 % confidence interval [ 95 % CI ] 2.1 - 3.4 ) but not toxicity ( HR 1.1 , 95 % CI 0.9 - 1.5 ) . Similarly , first drug discontinuation due to toxicity was associated with an increased rate of second drug discontinuation due to toxicity ( HR 2.3 , 95 % CI 1.9 - 2.9 ) but not inefficacy ( HR 1.2 , 95 % CI 0.8 - 1.6 ) . CONCLUSION RA patients who are switched to a second anti-TNF drug have high rates of continuation , although among those who must discontinue treatment , the reasons for stopping a second drug are related to the reasons for stopping the first drug . This large data set from the UK provides the first estimates of the magnitude of these effects in patients with long-st and ing severe RA [21360490] OBJECTIVE To assess the efficacy and safety of tocilizumab plus methotrexate ( MTX ) versus MTX alone in preventing structural joint damage and improving physical function and disease activity in patients with moderate-to-severe rheumatoid arthritis and inadequate responses to MTX . METHODS A total of 1,196 patients were enrolled in a 2-year , r and omized , double-blind , placebo-controlled trial . Patients received tocilizumab ( 8 mg/kg or 4 mg/kg ) or placebo every 4 weeks plus MTX . Rescue treatment was available from week 16 . Results from year 1 are presented . RESULTS Mean change in the total Genant-modified Sharp score was 0.29 and 0.34 with tocilizumab 8 mg/kg plus MTX and 4 mg/kg plus MTX , respectively , versus 1.13 with placebo plus MTX ( P < 0.0001 for both comparisons ) . Analysis of variance of the area under the curve for change from baseline in the disability index of the Health Assessment Question naire showed greater decreases with tocilizumab 8 mg/kg and 4 mg/kg ( -144.1 and -128.4 units , respectively ) than with placebo ( -58.1 units ; P < 0.0001 for both comparisons ) . Proportions of patients with American College of Rheumatology 20 % , 50 % , and 70 % improvement and with Disease Activity Score in 28 joints remission were higher in those receiving 8 mg/kg tocilizumab than in those receiving placebo ( P < 0.0001 for all comparisons ) . The safety profile of tocilizumab was consistent with the profiles in previous studies . Infections were the most common adverse and serious adverse events . CONCLUSION The findings of this study show that tocilizumab plus MTX results in greater inhibition of joint damage and improvement in physical function than does MTX alone . Tocilizumab has a well-characterized safety profile [16447237] OBJECTIVE To describe the use of the LUNDEX , a new index for comparing the long-term efficacy and tolerability of biologic therapies in rheumatoid arthritis ( RA ) patients treated in clinical practice . METHODS Patients ( n = 949 ) with active RA that had not responded to at least 2 disease-modifying antirheumatic drugs ( DMARDs ) including methotrexate , in whom biologic therapy was being initiated , were included in a structured clinical followup protocol . The protocol included collection of data on diagnosis , disease duration , previous and ongoing DMARD treatment , and date s on which biologic treatment was started and terminated . In addition , data on efficacy measures used for calculating vali date d response criteria , i.e. , the European League Against Rheumatism and American College of Rheumatology response criteria , were collected at fixed time points . Data were prospect ively registered from March 1999 through January 2004 . The LUNDEX , a new index combining the proportion of patients fulfilling a selected response criteria set with the proportion of patients adhering to a particular therapy , was design ed to compare the efficacy of the different therapies . RESULTS Etanercept had higher overall LUNDEX values compared with infliximab , mostly because of a lower rate of adherence to therapy with infliximab . The relationship between the drugs was consistent irrespective of the response criteria used . CONCLUSION The LUNDEX is a valuable tool for evaluating drug efficacy in observational studies . It has the advantage of integrating clinical response as well as adherence to therapy in a composite value . Moreover , the LUNDEX has a practical and potentially universal application independent of diagnosis and response criteria [15082480] OBJECTIVE To evaluate the efficacy and safety of monotherapy with adalimumab in patients with RA for whom previous DMARD treatment has failed . METHODS In a 26 week , double blind , placebo controlled , phase III trial , 544 patients with RA were r and omised to monotherapy with adalimumab 20 mg every other week , 20 mg weekly , 40 mg every other week , 40 mg weekly , or placebo . The primary efficacy end point was > or = 20 % improvement in the ACR core criteria ( ACR20 response ) . Secondary efficacy end points included ACR50 , ACR70 , EULAR responses , and the Disability Index of the Health Assessment Question naire ( HAQ DI ) . RESULTS After 26 weeks , patients treated with adalimumab 20 mg every other week , 20 mg weekly , 40 mg every other week , and 40 mg weekly had significantly better response rates than those treated with placebo : ACR20 ( 35.8 % , 39.3 % , 46.0 % , 53.4 % , respectively v 19.1 % ; p < or = 0.01 ) ; ACR50 ( 18.9 % , 20.5 % , 22.1 % , 35.0 % v 8.2 % ; p < or = 0.05 ) ; ACR70 ( 8.5 % , 9.8 % , 12.4 % , 18.4 % v 1.8 % ; p < or = 0.05 ) . Moderate EULAR response rates were significantly greater with adalimumab than with placebo ( 41.5 % , 48.2 % , 55.8 % , 63.1 % v 26.4 % ; p < or = 0.05 ) . Patients treated with adalimumab achieved better improvements in mean HAQ DI than those receiving placebo ( -0.29 , -0.39 , -0.38 , -0.49 v -0.07 ; p < or = 0.01 ) . No significant differences were found between adalimumab and placebo treated patients for serious adverse events , serious infections , or malignancies . Injection site reaction occurred in 10.6 % and 0.9 % of adalimumab and placebo treated patients , respectively ( p < or = 0.05 ) . CONCLUSION Among patients with RA for whom previous DMARD treatment had failed , adalimumab monotherapy achieved significant , rapid , and sustained improvements in disease activity and improved physical function and was safe and well tolerated [12115219] OBJECTIVE To compare the efficacy of combination therapy with methotrexate ( MTX ) and hydroxychloroquine ( HCQ ) , MTX and sulfasalazine ( SSZ ) , and MTX , HCQ , and SSZ in patients with rheumatoid arthritis ( RA ) . METHODS RA patients ( n = 171 ) who had not previously been treated with combinations of the study medications were r and omized to receive 1 of the 3 treatment combinations in this 2-year , double-blind , placebo-controlled protocol . HCQ was given at a dosage of 200 mg twice a day . The dosage of MTX was accelerated from 7.5 mg/week to 17.5 mg/week in all patients who were not in remission . Similarly , the dosage of SSZ was escalated from 500 mg twice a day to 1 gm twice a day in patients who were not in remission . The primary end point of the study was the percentage of patients who had a 20 % response to therapy according to the American College of Rheumatology ( ACR ) criteria at 2 years . RESULTS Intent-to-treat analysis revealed that patients receiving the triple combination responded best , with 78 % achieving an ACR 20 % response at 2 years , compared with 60 % of those treated with MTX and HCQ ( P = 0.05 ) and 49 % of those treated with MTX and SSZ ( P = 0.002 ) . Similar trends were seen for the ACR 50 % response , with 55 % , 40 % , and 29 % of patients in the 3 treatment groups , respectively , achieving these results at 2 years ( P = 0.005 for the triple combination group versus the MTX and SSZ group ) . All combination treatments were well-tolerated . Fourteen patients ( evenly distributed among the 3 groups ) withdrew from the protocol because of symptoms that were potentially related to the study medication . CONCLUSION The triple combination of MTX , SSZ , and HCQ is well-tolerated , and its efficacy is superior to that of the double combination of MTX and SSZ and is marginally superior to that of the double combination of MTX and HCQ [19665644] BACKGROUND New treatment strategies for early rheumatoid arthritis are evolving rapidly . We aim ed to compare addition of conventional disease-modifying antirheumatic drugs ( sulfasalazine and hydroxychloroquine ) with addition of a tumour necrosis factor antagonist ( infliximab ) to methotrexate in patients with early rheumatoid arthritis . METHODS We undertook a r and omised trial in 15 rheumatology units in Sweden . We enrolled patients with early rheumatoid arthritis ( symptom duration < 1 year ) and administered methotrexate ( up to 20 mg per week ) . After 3 - 4 months , those who had not achieved low disease activity but who could tolerate methotrexate were r and omly allocated by computer addition of either sulfasalazine and hydroxychloroquine or infliximab . Primary outcome was achievement of a good response according to European League Against Rheumatism ( EULAR ) criteria at 12 months . Patients were followed up to 24 months ; here , we present findings at 12 months . Analysis was by intention to treat and we used non-responder imputation . The Swefot ( Swedish Pharmacotherapy ) study is registered in the WHO data base at the Karolinska University Hospital , number CT20080004 . FINDINGS 487 patients were initially enrolled . Of 258 who had not achieved low disease activity with methotrexate , 130 were allocated sulfasalazine and hydroxychloroquine and 128 were assigned infliximab . 32 of 130 ( 25 % ) patients allocated sulfasalazine and hydroxychloroquine achieved the primary outcome compared with 50 of 128 ( 39 % ) assigned infliximab ( risk ratio 1.59 [ 95 % CI 1.10 - 2.30 ] , p=0.0160 ) . Adverse events were balanced fairly well between the two groups and accorded with known adverse events of the drugs used . No deaths occurred in either group . INTERPRETATION In patients with early rheumatoid arthritis in whom methotrexate treatment failed , addition of a tumour necrosis factor antagonist to methotrexate monotherapy is clinical ly superior to addition of conventional disease-modifying antirheumatic drugs . FUNDING Swedish Rheumatism Association , Schering-Plough [16984942] Objective : To examine the impact of added abatacept treatment on health related quality of life ( HRQoL ) in patients with rheumatoid arthritis ( RA ) who have inadequate response to methotrexate ( MTX ) . Methods : The impact of abatacept treatment on HRQoL was examined in a longitudinal , r and omised double blind , placebo controlled clinical trial . Effects of treatment on HRQoL were examined using repeated measures analysis of covariance and comparing rates of change in HRQoL across treatment groups . The relationship between American College of Rheumatology ( ACR ) clinical markers and disease duration with changes in HRQoL indicators was also examined . Finally , a responder analysis was used to examine the percentage of patients who improved by 0.5 SD in 12 months or who reached the normative levels seen in the US general population . Results : Statistically significant improvements in the abatacept group relative to controls were observed across a range of HRQoL measures , including physical function , fatigue , all eight domains of the SF-36 , and the physical and mental component summaries ( PCS and MCS ) . Improvements were seen as early as day 29 for fatigue and for five out of eight SF-36 domains . By day 169 , all HRQoL measures were significantly better with abatacept than with placebo . HRQoL gains were associated with greater ACR clinical improvement , and the effects were consistent for patients with different disease duration . A significantly greater percentage of patients treated with abatacept reached normative levels of PCS , MCS , physical functioning , and fatigue compared with patients treated with MTX alone . Conclusion : Combined abatacept and MTX treatment produces significant improvements across a wide range of HRQoL domains in patients with RA [11096165] BACKGROUND Etanercept , which blocks the action of tumor necrosis factor , reduces disease activity in patients with long-st and ing rheumatoid arthritis . Its efficacy in reducing disease activity and preventing joint damage in patients with active early rheumatoid arthritis is unknown . METHODS We treated 632 patients with early rheumatoid arthritis with either twice-weekly subcutaneous etanercept ( 10 or 25 mg ) or weekly oral methotrexate ( mean , 19 mg per week ) for 12 months . Clinical response was defined as the percent improvement in disease activity according to the criteria of the American College of Rheumatology . Bone erosion and joint-space narrowing were measured radiographically and scored with use of the Sharp scale . On this scale , an increase of 1 point represents one new erosion or minimal narrowing . RESULTS As compared with patients who received methotrexate , patients who received the 25-mg dose of etanercept had a more rapid rate of improvement , with significantly more patients having 20 percent , 50 percent , and 70 percent improvement in disease activity during the first six months ( P<0.05 ) . The mean increase in the erosion score during the first 6 months was 0.30 in the group assigned to receive 25 mg of etanercept and 0.68 in the methotrexate group ( P= 0.001 ) , and the respective increases during the first 12 months were 0.47 and 1.03 ( P=0.002 ) . Among patients who received the 25-mg dose of etanercept , 72 percent had no increase in the erosion score , as compared with 60 percent of patients in the methotrexate group ( P=0.007 ) . This group of patients also had fewer adverse events ( P=0.02 ) and fewer infections ( P= 0.006 ) than the group that was treated with methotrexate . CONCLUSIONS As compared with oral methotrexate , subcutaneous [ corrected ] etanercept acted more rapidly to decrease symptoms and slow joint damage in patients with early active rheumatoid arthritis [16935912] Objective : To investigate the efficacy and safety of abatacept in combination with etanercept in patients with active rheumatoid arthritis during a 1-year , r and omised , placebo-controlled , double-blind phase , followed by an open-label , long-term extension ( LTE ) . Methods : Patients continued etanercept ( 25 mg twice weekly ) and were r and omised to receive abatacept 2 mg/kg ( n = 85 ) or placebo ( n = 36 ) . As the effective dose of abatacept was established as 10 mg/kg in a separate trial , all patients received abatacept 10 mg/kg and etanercept during the LTE . Results : A total of 121 patients were r and omised ; 80 completed double-blind treatment and entered the LTE . During double-blind treatment , the difference in the percentage of patients achieving the primary end point ( modified American College of Rheumatology ( ACR ) 20 response at 6 months ) was not significant between groups ( 48.2 % v 30.6 % ; p = 0.072 ) . At 1 year , no notable changes in modified ACR responses were observed . Subsequent to the dosing change , similar modified ACR responses were seen during the LTE . Significant improvements in quality of life were observed with abatacept and etanercept versus placebo and etanercept in five of the eight short-form 36 subscales at 1 year . More abatacept and etanercept-treated patients experienced serious adverse events ( SAEs ) at 1 year than patients receiving placebo and etanercept ( 16.5 % v 2.8 % ) , with 3.5 % v 0 % experiencing serious infections . Conclusion : The combination of abatacept ( at a dose of 2 mg/kg during the double-blind phase and 10 mg/kg during the LTE ) and etanercept was associated with an increase in SAEs , including serious infections , with limited clinical effect . On the basis of the limited efficacy findings and safety concerns , abatacept in combination with etanercept should not be used for rheumatoid arthritis treatment [15188350] OBJECTIVE To determine in a placebo-controlled , double-blind trial the safety profile of daily anakinra ( Kineret ) use in patients with active rheumatoid arthritis ( RA ) and concurrent comorbid conditions . METHODS In 169 centers in 9 countries , 1,414 patients with active RA were r and omly assigned to receive either anakinra ( 100 mg ) or placebo treatment ( 4:1 anakinra-to-placebo allocation ratio ) , with study drug administered by daily subcutaneous injection for 6 months . The current post hoc analysis assessed baseline comorbid conditions , and patients were considered at high risk for the occurrence of adverse events if they had a history of at least one of the following : cardiovascular event , pulmonary event , central nervous system-related event , infection , diabetes , malignancy , or renal impairment . Within each treatment group ( anakinra or placebo ) , incidence rates were summarized for serious adverse events , infectious events , and serious infectious events in high-risk patients and compared with these incidence rates in patients without comorbid conditions . RESULTS The majority of patients in the trial had one or more comorbid conditions . In these high-risk patients , there were no differences in the incidence of serious adverse events or infectious events between treatment groups . The incidence of serious infectious events with anakinra use was similar between high-risk patients ( 2.5 % ) and the entire study population ( 2.1 % ) and was not attributable to any single comorbidity . CONCLUSION Results of the analysis of adverse events in patients with active RA and coexisting comorbidities suggest that the favorable safety profile of anakinra is maintained in a high-risk patient population [12355476] OBJECTIVE Patients with rheumatoid arthritis ( RA ) have been shown to have an increased susceptibility to the development of infections . The exact causes of this increased risk are unknown , but may relate to immunologic disturbances associated with the disease or to the immunosuppressive effects of agents used in its treatment . This study was undertaken to identify predictors of serious infections among patients with RA . Identification of such factors is the necessary first step in reducing the excess risk of infection in RA . METHODS Members of a population -based incidence cohort of Rochester , Minnesota residents ages > or=18 years , who had been diagnosed with RA between 1955 and 1994 , were followed up longitudinally through their complete medical records until January 1 , 2000 . We examined potential risk factors for the development of all objective ly confirmed ( by microbiology or radiology ) infections and for infections requiring hospitalization . Potential risk factors included RA severity measures ( rheumatoid factor positivity , elevated erythrocyte sedimentation rate , extraarticular manifestations of RA , and functional status ) , comorbidities ( diabetes mellitus , alcoholism , and chronic lung disease ) , and other risk factors for infection ( presence of leukopenia , smoking ) . Predictors were identified using multivariate time-dependent Cox proportional hazards modeling . RESULTS The 609 RA patients in the cohort had a total followup time of 7,729.7 person-years ( mean 12.7 years per patient ) . A total of 389 patients ( 64 % ) had at least 1 infection with objective confirmation , and 290 ( 48 % ) had at least 1 infection requiring hospitalization . Increasing age , presence of extraarticular manifestations of RA , leukopenia , and comorbidities ( chronic lung disease , alcoholism , organic brain disease , and diabetes mellitus ) , as well as use of corticosteroids , were strong predictors of infection ( P < 0.004 ) in both univariate and multivariate analyses . Notably , use of disease-modifying antirheumatic drugs was not associated with increased risk of infection in multivariate analyses , after adjustment for demographic characteristics , comorbidities , and disease-related variables . CONCLUSION We identified a number of strong predictors of infections in a population -based cohort of patients with RA . These results can be used to prospect ively identify high-risk patients , who may benefit from closer followup and implementation of preventive strategies [15146409] OBJECTIVE Tumor necrosis factor ( TNF ) is an important proinflammatory cytokine that mediates inflammatory synovitis and articular matrix degradation in rheumatoid arthritis ( RA ) . We investigated the ability of adalimumab , a human anti-TNF monoclonal antibody , to inhibit the progression of structural joint damage , reduce the signs and symptoms , and improve physical function in patients with active RA receiving concomitant treatment with methotrexate ( MTX ) . METHODS In this multicenter , 52-week , double-blind , placebo-controlled study , 619 patients with active RA who had an inadequate response to MTX were r and omized to receive adalimumab 40 mg subcutaneously every other week ( n = 207 ) , adalimumab 20 mg subcutaneously every week ( n = 212 ) , or placebo ( n = 200 ) plus concomitant MTX . The primary efficacy end points were radiographic progression at week 52 ( total Sharp score by a modified method [ TSS ] ) , clinical response at week 24 ( improvements of at least 20 % in the American College of Rheumatology core criteria [ ACR20 ] ) , and physical function at week 52 ( disability index of the Health Assessment Question naire [ HAQ ] ) . RESULTS At week 52 , there was statistically significantly less radiographic progression , as measured by the change in TSS , in the patients receiving adalimumab either 40 mg every other week ( mean + /- SD change 0.1 + /- 4.8 ) or 20 mg weekly ( 0.8 + /- 4.9 ) as compared with that in the placebo group ( 2.7 + /- 6.8 ) ( P < or = 0.001 for each comparison ) . In addition , there were statistically significant changes in the components of the TSS . At week 24 , ACR20 responses were achieved by 63 % and 61 % of patients in the adalimumab 40 mg every other week and 20 mg weekly groups , respectively , versus 30 % of patients in the placebo group ( P < or = 0.001 for each comparison ) . At week 52 , ACR20 responses were achieved by 59 % and 55 % of patients taking adalimumab 40 mg every other week and 20 mg weekly , respectively , versus 24 % of patients taking placebo ( P < or = 0.001 for each comparison ) . At week 52 , physical function as measured by the HAQ demonstrated statistically significant improvement with adalimumab 40 mg every other week and 20 mg weekly compared with placebo ( mean change in HAQ score -0.59 and -0.61 , respectively , versus -0.25 ; P < or = 0.001 for each comparison ) . A total of 467 patients ( 75.4 % ) completed 52 weeks of treatment . Adalimumab was generally well tolerated . Discontinuations occurred in 22.0 % of adalimumab-treated patients and in 30.0 % of placebo-treated patients . The rate of adverse events ( both serious and nonserious ) was comparable in the adalimumab and placebo groups , although the proportion of patients reporting serious infections was higher in patients receiving adalimumab ( 3.8 % ) than in those receiving placebo ( 0.5 % ) ( P < or = 0.02 ) , and was highest in the patients receiving 40 mg every other week . CONCLUSION In this 52-week trial , adalimumab was more effective than placebo at inhibiting the progression of structural joint damage , reducing the signs and symptoms , and improving physical function in patients with active RA who had demonstrated an incomplete response to MTX [17985409] OBJECTIVE To evaluate the effectiveness and safety of anti-tumor necrosis factor ( anti-TNF ) therapies in rheumatoid arthritis ( RA ) , and to identify the factors involved in this response . METHODS Dynamic prospect i ve cohort study of patients with RA treated with anti-TNF under clinical practice conditions . Effectiveness was evaluated using Disease Activity Score ( DAS ) 28 , European League Against Rheumatism ( EULAR ) response , Health Assessment Question naire ( HAQ ) , and time to treatment failure . Prior adherence was evaluated retrospectively and safety was evaluated by adverse events ( AE ) . The analysis was restricted to anti-TNF-naive patients . RESULTS The study included 161 patients treated for RA during 6 years ( 60 infliximab , 79 etanercept , and 22 adalimumab ) . At 6 months , 15 % reached a good EULAR response and 38 % a moderate response . A mean decrease of -1.5 ( p < 0.0001 ) was observed in the DAS28 and of -0.34 in the HAQ ( p < 0.0001 ) ; however , women showed poorer progress in terms of DAS and HAQ . In the first year , 64.3 % did not experience treatment failure and this figure was 50.5 % after 2 years . In one-third , glucocorticoids were withdrawn and in the remainder the dose was reduced by 50 % . Adherence to treatment , selection of etanercept , and intensification of infliximab were associated with a lower probability of premature failure in the multivariate model . AE were similar to other those in studies and no outst and ing differences in safety were found between the 3 anti-TNF therapies . CONCLUSIONS Anti-TNF treatments are effective and safe , reducing the activity of the disease , disability , and the need for corticosteroids . Patients who displayed good adherence prior to the anti-TNF treatment and were treated with etanercept or with increasing doses of infliximab had the best chance of displaying a response [8609945] BACKGROUND Rheumatoid arthritis is a common disease that causes substantial morbidity and mortality . The responses of patients with rheumatoid arthritis to treatment with a single so-called disease-modifying drug , such as methotrexate , are often suboptimal . Despite limited data , many patients are treated with combinations of these drugs . METHODS We enrolled 102 patients with rheumatoid arthritis and poor responses to at least one disease-modifying drug in a two-year , double-blind , r and omized study of treatment with methotrexate alone ( 7.5 to 17.5 mg per week ) , the combination of sulfasalazine ( 500 mg twice daily ) and hydroxychloroquine ( 200 mg twice daily ) , or all three drugs . The dose of methotrexate was adjusted in an attempt to achieve remission in all patients . The primary and point of the study was the successful completion of two years of treatment with 50 percent improvement in composite symptoms of arthritis and no evidence of drug toxicity . RESULTS Fifty of the 102 patients had 50 percent improvement at nine months and maintained at least that degree of improvement for two years without evidence of major drug toxicity . Among them were 24 of 31 patients treated with all three drugs ( 77 percent ) , 12 of 36 patients treated with methotrexate alone ( 33 percent , P < 0.001 for the comparison with the three-drug group ) , and 14 of 35 patients treated with sulfasalazine and hydroxychloroquine ( 40 percent ) , P = 0.003 for the comparison with the three-drug group ) . Seven patients in the methotrexate group and three patients in each of the other two groups discontinued treatment because of drug toxicity . CONCLUSIONS In patients with rheumatoid arthritis , combination therapy with methotrexate , sulfasalazine , and hydroxychloroquine is more effective than either methotrexate alone or a combination of sulfasalazine , and hydroxychloroquine [16785475] Context Abatacept , an agent that selectively modulates the co-stimulatory signal required for T-cell activation , may benefit some patients with rheumatoid arthritis . Contribution This 1-year , r and omized , double-blind trial compared once-monthly infusions of abatacept with placebo in 652 patients with symptomatic rheumatoid arthritis despite ongoing methotrexate treatment . Compared with placebo recipients , patients who received abatacept more often had improved physical function , more frequently met st and ard response criteria , and less often had radiographic progression of joint damage . They also had serious infections ( 2.5 % vs. 0.9 % ) and infusion reactions more often . Implication s Adding abatacept can reduce disease activity in patients with rheumatoid arthritis and an inadequate response to methotrexate . The Editors Rheumatoid arthritis is characterized by synovial membrane hyperplasia and inflammatory cell infiltrate , including activated T cells ( 1 ) . T cells contribute to the initiation and perpetuation of rheumatoid arthritis immunopathology , leading to inflammation and , ultimately , joint destruction . Activated T cells proliferate and induce monocytes , macrophages , and synovial fibroblasts to produce proinflammatory cytokines , such as tumor necrosis factor- , interleukin-1 , and interleukin-6 ( 1 ) , and stimulate osteoclastogenesis and matrix metalloproteinase secretion ( 2 ) , as well as immunoglobulin production by B cells ( 3 ) . The central role of activated T cells in rheumatoid arthritis immunopathology makes T-cell activation a rational therapeutic target . T cells require 2 signals for full activation : an antigen-specific signal ( signal 1 ) and a co-stimulatory signal ( signal 2 ) ( 4 ) . One of the best-characterized co-stimulatory pathways is the engagement of CD80 or CD86 on antigen-presenting cells with CD28 on T cells ( 5 ) . In the normal immune response , endogenous cytotoxic T-lymphocyte antigen-4 ( CTLA-4 ) downregulates CD28-mediated T-cell activation by binding to CD80 or CD86 with higher avidity than CD28 ( 6 ) . Abatacept is a soluble , recombinant , fully human fusion protein , comprising the extracellular domain of CTLA-4 and the Fc portion of IgG1 , modified to prevent complement fixation . Abatacept is the first in a new class of agents for treating rheumatoid arthritis that selectively modulate the co-stimulatory signal required for full T-cell activation . A phase IIa study of patients with rheumatoid arthritis and an inadequate response to disease-modifying antirheumatic drugs showed the efficacy of abatacept as monotherapy ( 7 ) . In a phase IIb study of abatacept plus methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate , signs and symptoms of rheumatoid arthritis , physical function , and health-related quality of life statistically significantly improved over 1 year ( 8 , 9 ) . We present findings from the phase III , 1-year Abatacept in Inadequate Responders to Methotrexate ( AIM ) trial , which was design ed to further evaluate the safety and clinical efficacy of abatacept plus methotrexate and to assess the effects of abatacept on the radiographic progression of structural damage . Methods The institutional review boards or independent ethics committees approved a common clinical protocol for each site , and we performed the study in accordance with the ethical principles of the Declaration of Helsinki . All patients provided written informed consent to the study protocol before r and omization . Patients Eligible patients were at least 18 years of age , had had rheumatoid arthritis for at least 1 year , and met the American Rheumatism Association criteria for rheumatoid arthritis ( 10 ) . Rheumatoid arthritis was persistent and active despite methotrexate treatment . All patients must have been treated with methotrexate ( 15 mg/wk ) for 3 months or longer , with a stable dose for 28 days before enrollment . We required patients to undergo a washout of all other disease-modifying antirheumatic drugs at least 28 days before r and omization . We allowed corticosteroid use , with dosages equal to 10 mg of prednisone or less per day , stabilized for 25 days before r and omization . At r and omization , we required patients to have 10 or more swollen joints , 12 or more tender joints , and C-reactive protein levels of 10.0 mg/L or greater ( normal range , 1.0 mg/L to 4.0 mg/L ) while receiving methotrexate . We required tuberculin skin testing before r and omization . We excluded patients with a positive tuberculin skin test result unless they had completed treatment for latent tuberculosis before enrollment . Study Design Our 1-year , multicenter , multinational , r and omized , double-blind , placebo-controlled study aim ed to compare the efficacy and safety of abatacept versus placebo in combination with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate treatment . We used a central r and omization system , and the Drug Management Group within Bristol-Myers Squibb , Princeton , New Jersey , generated the r and omization schedule . Stratification per site was not performed . Patients were r and omly assigned in a 2:1 ratio to receive either a fixed dose of abatacept , approximately 10 mg/kg of body weight , or placebo . Patients weighing less than 60 kg , 60 to 100 kg , or more than 100 kg received 500 mg , 750 mg , or 1000 mg of abatacept , respectively . We administered study medication by 30-minute intravenous infusion on days 1 , 15 , and 29 and then every 28 days up to and including day 337 . No premedication was required . The protocol specified that all patients were to receive methotrexate , 15 mg or more per week , although methotrexate at 10 mg per week was acceptable if the patient had a history of toxicity . During the first 6 months , we did not allow adjustments in methotrexate dose , except in cases of toxicity . We permitted use of stable dosages of nonsteroidal anti-inflammatory drugs and corticosteroid dosages equal to 10 mg of prednisone or less per day . Between 6 and 12 months , we allowed the following adjustments , as the investigator deemed necessary : 1 ) adjustment in methotrexate dose , 2 ) addition of 1 other disease-modifying antirheumatic drug ( hydroxychloroquine , sulfasalazine , gold , or azathioprine ) , or 3 ) adjustment in corticosteroid dose equal to 10 mg of prednisone or less per day . However , investigators were blinded to treatment group assignment throughout the 1-year study . Clinical Efficacy Measures Our 3 primary objectives were to evaluate the proportion of patients in each group with a 20 % improvement in American College of Rheumatology ( ACR ) response criteria ( ACR 20 ) at 6 months , the proportion of patients in each group with clinical ly significant improvement ( 0.3 unit ) in the Health Assessment Question naire Disability Index ( HAQ-DI ) score ( 11 ) at 1 year , and the radiographic progression of joint erosions ( assessed by comparing changes from baseline in the Genant-modified Sharp score ) ( 12 , 13 ) at 1 year . Table 1 summarizes the outcome measures used to assess the response to treatment . Table 1 . Outcome Measures for Assessing Response to Treatment of Rheumatoid Arthritis * Secondary objectives included assessing ACR 50 and ACR 70 responses at 6 months and all ACR responses at 1 year . In addition , we determined the proportions of patients achieving a major clinical response and a protocol -defined extended major clinical response at 1 year . We also assessed changes in disease activity by using the Disease Activity Score 28 ( DAS28 ) ( 20 , 21 ) . We assessed improvements in physical function over 1 year by using the HAQ-DI , which measures physical function during daily activities ( 22 ) . We evaluated changes in health-related quality of life by using the Medical Outcomes Study Short Form-36 Health Survey ( SF-36 ) ( 17 ) , which evaluates physical and mental health status ( Table 1 ) ( 18 , 19 ) . Physicians blinded to treatment group assignment performed assessment s at enrollment and at every visit before treatment administration on days 1 , 15 , and 29 ; every 28 days up to and including day 169 ( 6 months ) ; and on days 225 , 281 , and 365 ( 1 year ) . Radiographic Evaluation We performed st and ardized radiography of the h and s or wrists and feet at baseline and at 1 year or upon early termination ( if applicable ) . Two independent expert readers who were blinded to treatment group assignment , chronological order of radiography , and patients ' clinical response assessed all radiographic images for changes in erosion and joint-space narrowing by using the Genant-modified Sharp scoring system . Safety and Immunogenicity We monitored all patients who received at least 1 dose of the study medication for adverse events , serious adverse events , infusion reactions , clinical laboratory test abnormalities , and clinical ly significant changes in vital signs . Adverse events were self-reported by the patient and elicited by general question ing and examination at each visit . We attributed an adverse event to the study treatment on the basis of the investigator 's opinion , and we deemed an event as serious by st and ard regulatory definition . An external safety advisory panel , consisting of 5 physicians ( 3 rheumatologists , 1 oncologist , and 1 infectious disease expert ) , assessed overall safety in a blinded fashion by using reports of adverse events and laboratory results on a quarterly basis . We obtained serum sample s before infusions on days 1 , 29 , 85 , 169 , 281 , and 365 or 28 days after the last dose of the study medication in patients who discontinued before 1 year . We assessed immunogenicity by immunoassay to measure the antibody response to the entire abatacept molecule and also specifically to the CTLA-4 portion of the molecule ( 7 ) . Statistical Analysis The protocol estimated that 680 patients would need to be enrolled to r and omly assign 540 patients . We based sample sizes on a 5 % level of significance ( 2-tailed ) . The study had 99 % power to detect a difference of 20 % in ACR 20 between the 2 groups . On the basis of the [18383539] OBJECTIVE To assess the efficacy , safety , and pharmacology of subcutaneous administration of golimumab in patients with active rheumatoid arthritis ( RA ) despite treatment with methotrexate ( MTX ) . METHODS Patients were r and omly assigned in a double-blinded manner to receive injections of placebo plus MTX or 50 mg or 100 mg golimumab every 2 or 4 weeks plus MTX through week 48 . Patients originally assigned to receive injections every 2 weeks had the interval increased to every 4 weeks starting at week 20 . The primary end point was the proportion of patients meeting the American College of Rheumatology 20 % improvement criteria ( achieving an ACR20 response ) at week 16 . The study was powered to detect a difference in the primary end point when the combined golimumab groups and at least 1 of the individual dose groups were compared with placebo . RESULTS The primary end point was attained . Sixty-one percent of patients in the combined golimumab plus MTX dose groups achieved an ACR20 response at week 16 compared with 37 % of patients in the placebo plus MTX group ( P=0.010 ) . In addition , 79 % of patients in the group receiving 100 mg golimumab every 2 weeks achieved an ACR20 response ( P<0.001 versus placebo ) . Through week 20 ( after which patients receiving placebo were switched to active infliximab therapy ) , serious adverse events were reported in 9 % of patients in the combined golimumab groups and in 6 % of patients in the placebo group . CONCLUSION Golimumab plus MTX effectively reduces the signs and symptoms of RA and is generally well tolerated in patients with an inadequate response to MTX [16508932] OBJECTIVE To evaluate the impact of infliximab therapy on the employment status of patients with early rheumatoid arthritis ( RA ) . METHODS Methotrexate (MTX)-naive patients with active early RA were r and omly allocated to receive MTX plus placebo or MTX plus infliximab ( 3 mg/kg or 6 mg/kg ) at weeks 0 , 2 , and 6 and then every 8 weeks through week 46 . Data for patients younger than age 65 years were included in the analyses . A patient was categorized as employable if he or she was employed or felt well enough to work if a job were available . RESULTS The change in actual employment was not significantly different between patients receiving MTX plus infliximab and those receiving MTX plus placebo ( 0.5 % versus 1.3 % ; P > 0.5 ) . However , the proportion of patients whose status changed from employable at baseline to unemployable at week 54 was smaller in the group receiving MTX plus infliximab compared with that in the group receiving MTX alone ( 8 % versus 14 % ; P = 0.05 ) . Patients who were treated with infliximab plus MTX had a significantly greater likelihood of improvement rather than deterioration in employability ( odds ratio 2.4 ; P < 0.001 ) ; this likelihood was not significantly greater in patients receiving MTX alone . The proportion of employed patients who lost workdays during the trial was smaller in the MTX plus infliximab group than in the MTX-alone group ( P = 0.010 ) . CONCLUSION The actual employment rates among patients in the 2 treatment groups were not different . However , patients with early RA who were treated with MTX plus infliximab had a higher probability of maintaining their employability compared with those who were treated with MTX alone [14719195] OBJECTIVE This study , known as STAR ( Safety Trial of Adalimumab in Rheumatoid Arthritis ) , evaluated the safety and efficacy of adalimumab ( Humira ) , a fully human monoclonal tumor necrosis factor-alpha ( TNF-a ) antibody , when given with st and ard antirheumatic therapy in patients with active rheumatoid arthritis ( RA ) not adequately responding to such therapies . St and ard antirheumatic therapy included traditional disease modifying antirheumatic drugs ( DMARD ) , low dose corticosteroids , nonsteroidal antiinflammatory drugs ( NSAID ) , and /or analgesics . METHODS In this 24-week , double-blind , placebo-controlled study , 636 patients with RA were r and omly assigned to receive adalimumab 40 mg subcutaneously ( sc ) every other week ( n = 318 ) or placebo ( n = 318 ) while continuing st and ard antirheumatic therapy . The frequencies of adverse events , serious adverse events , severe or life-threatening adverse events , adverse events leading to withdrawal , infection , or serious infection were the primary endpoints . Secondary endpoints were determined by American College of Rheumatology ( ACR ) response criteria . RESULTS During the study , the majority of patients received concomitant traditional DMARD ( 83.5 % ) and /or corticosteroids , NSAID , and /or analgesics ( 97.3 % ) . Overall , 56.0 % of patients continued treatment with one , 23.6 % with 2 , and 3.9 % with > or = 3 traditional DMARD . At 24 weeks , there were no statistically significant differences between the adalimumab and placebo groups in their respective rates of adverse events ( 86.5 % vs 82.7 % ) , serious adverse events ( 5.3 % vs 6.9 % ) , severe or life-threatening adverse events ( 11.9 % vs 15.4 % ) , or those leading to withdrawal ( 2.8 % vs 2.2 % ) . There were also no statistically significant differences in the rates of infections ( 52.2 % vs 49.4 % ) or serious infections ( 1.3 % vs 1.9 % ) between the groups . The incidence and types of adverse events did not vary between adalimumab- and placebo-treated patients by the number of concomitant traditional DMARD ( 0 , 1 , or 2 ) . Adalimumab-treated patients compared with placebo-treated patients achieved statistically superior ACR20 ( 52.8 % vs 34.9 % ) , ACR50 ( 28.9 % vs 11.3 % ) , and ACR70 ( 14.8 % vs 3.5 % ) response rates at Week 24 ( p < or = 0.001 ) . CONCLUSION This study demonstrated that addition of adalimumab 40 mg given sc every other week to concomitant st and ard antirheumatic therapy is well tolerated and provides significant improvements in signs and symptoms of RA . The data indicate that adalimumab is a safe and effective therapeutic option in patients with active RA who have an inadequate response to st and ard antirheumatic therapy , including one or more traditional DMARD , corticosteroids , NSAID , and analgesics [1794519] The objective of this work is to compare the adherence to therapy of patients receiving etanercept and infliximab during first tumour necrosis factor (TNF)-blocking treatment course in rheumatoid arthritis . Special emphasis is placed on potential predictors for treatment termination and the impact of concomitant methotrexate ( MTX ) or other disease-modifying antirheumatic drugs ( DMARDs ) . Patients ( n = 1,161 ) with active rheumatoid arthritis , not responding to at least two DMARDs including MTX starting etanercept or infliximab therapy for the first time , were included in a structured clinical follow-up protocol . Information on diagnosis , disease duration , previous and ongoing DMARDs , treatment start and termination , as well as cause of withdrawal was prospect ively collected during the period of March 1999 through December 2004 . Patients were divided into six groups according to TNF-blocking drugs and concomitant DMARDs . Five-year level ( one-year ) of adherence to therapy was 36 % ( 69 % ) for patients receiving infliximab in combination with MTX compared with 65 % ( 89 % ) for patients treated with etanercept and MTX ( p < 0.001 ) . Cox regression models showed that the risk for premature treatment termination of patients treated with infliximab was threefold higher than for etanercept ( p < 0.001 ) . Also , the regression analysis showed that patients receiving concomitant MTX had better treatment continuation than patients treated solely with TNF blockers ( p < 0.001 ) . Moreover , patients receiving concomitant MTX had superior drug survival than patients receiving other concomitant DMARDs ( p < 0.010 ) . The superior effect of MTX was associated primarily with fewer treatment terminations because of adverse events . In addition , the study identifies low C-reactive protein level , high age , elevated health assessment question naire score , and higher previous number of DMARDs as predictors of premature treatment termination . In summary , treatment with etanercept has higher adherence to therapy than treatment with infliximab . Concomitant MTX is associated with improved treatment continuation of biologics when compared with both TNF blockers as monotherapy and TNF blockers combined with other DMARDs

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### Context: [18260176] OBJECTIVE To determine whether patients with rheumatoid arthritis ( RA ) are at increased risk of hospitalized infection and whether the risk varies by RA treatment . METHODS A retrospective cohort study was conducted using data from a medical and pharmacy cl aims managed-care data base from 1999 to 2006 . A total of 24,530 patients were included in the RA cohort ; a r and om sample of non-RA patients served as a comparison cohort ( n = 500,000 ) . Rates of hospitalized infection were compared between the cohorts . A nested case-control analysis was performed within the RA cohort to assess the effect of current RA medication use on hospitalized infection risk . RESULTS A total of 1,993 patients with RA and 11,977 non-RA patients experienced a hospitalized infection . The rate of first hospitalized infection was higher in the RA cohort [ adjusted hazard ratio = 2.03 ; 95 % confidence interval ( CI ) 1.93 - 2.13 ] . In the case-control analysis , the current use of biological disease modifying antirheumatic drugs ( DMARD ) was associated with slightly increased risk of hospitalized infection [ rate ratio ( RR ) = 1.21 ; 95 % CI 1.02 - 1.43 ] . Methotrexate and hydroxychloroquine were associated with decreased risk . Oral corticosteroid use increased risk ( RR = 1.92 ; 95 % CI 1.67 - 2.21 ) , and there was a dose-related effect [ < or = 5 mg/day : RR = 1.32 ( 95 % CI 1.06 - 1.63 ) , 6 - 10 mg/day : RR = 1.94 ( 95 % CI 1.53 - 2.46 ) , > 10 mg/day : RR = 2.98 ( 95 % CI 2.41 - 3.69 ) ] . CONCLUSION These data confirm that individuals with RA are at increased risk of hospitalized infection compared to those without RA . Oral corticosteroid use was associated with a dose-related increase . Biological DMARD use was associated with slightly elevated risk ; however , this may reflect confounding and channeling bias [19644849] OBJECTIVE To assess the safety and efficacy of golimumab in methotrexate (MTX)-naive patients with active rheumatoid arthritis ( RA ) . METHODS MTX-naive patients with RA ( n = 637 ) were r and omized to receive placebo plus MTX ( group 1 ) , golimumab 100 mg plus placebo ( group 2 ) , golimumab 50 mg plus MTX ( group 3 ) , or golimumab 100 mg plus MTX ( group 4 ) . Subcutaneous injections of golimumab or placebo were administered every 4 weeks . The dosage of MTX/placebo capsules started at 10 mg/week and escalated to 20 mg/week . The primary end point , the proportion of patients meeting the American College of Rheumatology 50 % improvement criteria ( achieving an ACR50 response ) at week 24 , required significant differences between groups 3 and 4 combined ( combined group ) versus group 1 and significant differences in a pairwise comparison ( group 3 or group 4 versus group 1 ) . RESULTS An intent-to-treat ( ITT ) analysis of the ACR50 response at week 24 did not show a significant difference between the combined group and group 1 ( 38.4 % and 29.4 % , respectively ; P=0.053 ) , while a post hoc modified ITT analysis ( excluding 3 untreated patients ) of the ACR50 response showed statistically significant differences between the combined group and group 1 ( 38.5 % versus 29.4 % ; P=0.049 ) and between group 3 ( 40.5 % ; P=0.038 ) but not group 4 ( 36.5 % ; P=0.177 ) and group 1 . Group 2 was noninferior to group 1 for the ACR50 response at week 24 ( 33.1 % ; 95 % confidence interval lower bound -5.2 % ; predefined delta value for noninferiority -10 % ) . The combination of golimumab plus MTX demonstrated a significantly better response compared with placebo plus MTX in most other efficacy parameters , including response/remission according to the Disease Activity Score in 28 joints . Serious adverse events occurred in 7 % , 3 % , 6 % , and 6 % of patients in groups 1 , 2 , 3 , and 4 , respectively . CONCLUSION Although the primary end point was not met , the modified ITT analysis of the primary end point and other prespecified efficacy measures demonstrated that the efficacy of golimumab plus MTX is better than , and the efficacy of golimumab alone is similar to , the efficacy of MTX alone in reducing RA signs and symptoms in MTX-naive patients , with no unexpected safety concerns [12687534] OBJECTIVE To evaluate the safety of anakinra ( a recombinant human interleukin-1 receptor antagonist ) in a large population of patients with rheumatoid arthritis ( RA ) , typical of those seen in clinical practice . METHODS A total of 1,414 patients were r and omly assigned to treatment with 100 mg of anakinra or placebo , administered daily by subcutaneous injection . Background medications included disease-modifying antirheumatic drugs , corticosteroids , and nonsteroidal antiinflammatory drugs , alone or in combination . The primary end point was safety , which was evaluated by adverse events ( including infections ) , discontinuation from study due to adverse events , and death . RESULTS Safety was evaluated in 1,399 patients ( 1,116 in the anakinra group and 283 in the placebo group ; 15 patients were r and omized but did not receive any study drug ) during the initial 6-month , double-blind , placebo-controlled phase of this long-term safety study . Baseline demographics , disease characteristics , and concomitant medications were similar between the 2 groups . The study group included patients with numerous comorbid conditions and a wide range of RA disease activity . Serious adverse events occurred at a similar rate in the anakinra group and the placebo group ( 7.7 % and 7.8 % , respectively ) . Serious infectious episodes were observed more frequently in the anakinra group ( 2.1 % versus 0.4 % in the placebo group ) . The rate of withdrawal due to adverse events was 13.4 % in the anakinra group and 9.2 % in the placebo group . CONCLUSION Results from this large , placebo-controlled safety study demonstrate that anakinra is safe and well tolerated in a diverse population of patients with RA , including those with comorbid conditions and those using multiple combinations of concomitant therapies . Although the frequency of serious infection was slightly higher in the anakinra group , no infection was attributed to opportunistic microorganisms or result ed in death [2674556] Background : Certolizumab pegol is a PEGylated tumour necrosis factor inhibitor . Objective : To evaluate the efficacy and safety of certolizumab pegol versus placebo , plus methotrexate ( MTX ) , in patients with active rheumatoid arthritis ( RA ) . Methods : An international , multicentre , phase 3 , r and omised , double-blind , placebo-controlled study in active adult-onset RA . Patients ( n = 619 ) were r and omised 2:2:1 to subcutaneous certolizumab pegol ( liquid formulation ) 400 mg at weeks 0 , 2 and 4 followed by 200 mg or 400 mg plus MTX , or placebo plus MTX , every 2 weeks for 24 weeks . The primary end point was ACR20 response at week 24 . Secondary end points included ACR50 and ACR70 responses , change from baseline in modified Total Sharp Score , ACR core set variables and physical function . Results : Significantly more patients in the certolizumab pegol 200 mg and 400 mg groups achieved an ACR20 response versus placebo ( p⩽0.001 ) ; rates were 57.3 % , 57.6 % and 8.7 % , respectively . Certolizumab pegol 200 and 400 mg also significantly inhibited radiographic progression ; mean changes from baseline in mTSS at week 24 were 0.2 and −0.4 , respectively , versus 1.2 for placebo ( rank analysis p⩽0.01 ) . Certolizumab pegol-treated patients reported rapid and significant improvements in physical function versus placebo ; mean changes from baseline in HAQ-DI at week 24 were −0.50 and −0.50 , respectively , versus −0.14 for placebo ( p⩽0.001 ) . Most adverse events were mild or moderate , with low incidence of withdrawals due to adverse events . Five patients developed tuberculosis . Conclusion : Certolizumab pegol plus MTX was more efficacious than placebo plus MTX , rapidly and significantly improving signs and symptoms of RA and physical function and inhibiting radiographic progression . Trial registration number : [15140776] OBJECTIVES To compare budesonide , a locally acting glucocorticoid with minimal systemic exposure , with conventional glucocorticoid treatment and placebo in rheumatoid arthritis . METHODS A double blind , r and omised , controlled trial over 12 weeks in 143 patients with active rheumatoid arthritis , comparing budesonide 3 mg daily , budesonide 9 mg daily , prednisolone 7.5 mg daily , and placebo . Particular attention was paid to the pattern of clinical response and to changes in the four week period following discontinuation of treatment . RESULTS There were improvements in tender joint count and swollen joint count on budesonide 9 mg compared with placebo ( 28 % for tender and 34 % for swollen joint counts , p<0.05 ) . Prednisolone 7.5 mg gave similar results , while budesonide 3 mg was less effective . ACR20 response criteria were met by 25 % of patients on placebo , 22 % on budesonide 3 mg , 42 % on budesonide 9 mg , and 56 % on prednisolone 7.5 mg . A rapid and significant reduction in symptoms and signs in response to budesonide 9 mg and prednisolone 7.5 mg was evident by two weeks and maximal at eight weeks . There was no evidence that budesonide provided a different pattern of symptom control from prednisolone , or that symptoms became worse than placebo treatment levels after discontinuation of glucocorticoid treatment . Adverse effects attributable to glucocorticoids were equally common in all groups . CONCLUSIONS The symptomatic benefits of budesonide 9 mg and prednisolone 7.5 mg are achieved within a short time of initiating treatment , are maintained for three months , and are not associated with any rebound in symptoms after stopping treatment [16079172] Objective : To compare patient reported measures of function , health related quality of life ( QoL ) , and satisfaction with medication among patients with rheumatoid arthritis ( RA ) treated with methotrexate ( MTX ) , etanercept , or both for up to 1 year . Methods : In a 52 week , double blind , clinical trial , patients with active RA were r and omised to receive etanercept 25 mg twice weekly , methotrexate up to 20 mg weekly , or combination therapy . The Health Assessment Question naire ( HAQ ) disability index , EuroQoL health status visual analogue scale ( EQ-5D VAS ) , patient global assessment , and patient general health VAS were administered at baseline and weeks 2 , 4 , 8 , 12 , 16 , 20 , 24 , 32 , 40 , 48 , and 52 . Satisfaction with the medication was compared at 52 weeks . Results : Of 682 enrolled patients , 522 completed 52 weeks of treatment . Mean improvement from baseline in HAQ score was 0.65 , 0.70 , and 1.0 for MTX , etanercept , and the combination , respectively . The mean percentage and absolute improvement in the HAQ was significantly higher ( p<0.01 ) for combination therapy than for either of the monotherapies . Combination therapy produced significantly more rapid achievement of HAQ ⩽0.5 sustained for 6 months than either of the monotherapies ( p<0.01 ) . Compared with patients receiving monotherapy , those receiving combination therapy achieved a significantly better ( p<0.05 ) health state as measured by the EQ-5D VAS ( mean ( SD ) 63.7 ( 3.2 ) , 66.8 ( 3.2 ) , 72.7 ( 3.1 ) for MTX , etanercept , and the combination , respectively ) . Results were similar for other assessment s ( p<0.01 ) . Patients in combination and etanercept groups were significantly more likely ( p<0.0001 , p = 0.0009 , respectively ) to report satisfaction with the medication . Conclusions : Combination therapy with etanercept and methotrexate improved function , QoL , and satisfaction with the medication significantly more than monotherapy [18358926] BACKGROUND Interleukin 6 is involved in the pathogenesis of rheumatoid arthritis via its broad effects on immune and inflammatory responses . Our aim was to assess the therapeutic effects of blocking interleukin 6 by inhibition of the interleukin-6 receptor with tocilizumab in patients with rheumatoid arthritis . METHODS In this double-blind , r and omised , placebo-controlled , parallel group phase III study , 623 patients with moderate to severe active rheumatoid arthritis were r and omly assigned with an interactive voice response system , stratified by site with a r and omisation list provided by the study sponsor , to receive tocilizumab 8 mg/kg ( n=205 ) , tocilizumab 4 mg/kg ( 214 ) , or placebo ( 204 ) intravenously every 4 weeks , with methotrexate at stable pre- study doses ( 10 - 25 mg/week ) . Rescue therapy with tocilizumab 8 mg/kg was offered at week 16 to patients with less than 20 % improvement in both swollen and tender joint counts . The primary endpoint was the proportion of patients with 20 % improvement in signs and symptoms of rheumatoid arthritis according to American College of Rheumatology criteria ( ACR20 response ) at week 24 . Analyses were by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00106548 . FINDINGS The intention-to-treat analysis population consisted of 622 patients : one patient in the 4 mg/kg group did not receive study treatment and was thus excluded . At 24 weeks , ACR20 responses were seen in more patients receiving tocilizumab than in those receiving placebo ( 120 [ 59 % ] patients in the 8 mg/kg group , 102 [ 48 % ] in the 4 mg/kg group , 54 [ 26 % ] in the placebo group ; odds ratio 4.0 [ 95 % CI 2.6 - 6.1 ] , p<0.0001 for 8 mg/kg vs placebo ; and 2.6 [ 1.7 - 3.9 ] , p<0.0001 for 4 mg/kg vs placebo ) . More people receiving tocilizumab than those receiving placebo had at least one adverse event ( 143 [ 69 % ] in the 8 mg/kg group ; 151 [ 71 % ] in the 4 mg/kg group ; 129 [ 63 % ] in the placebo group ) . The most common serious adverse events were serious infections or infestations , reported by six patients in the 8 mg/kg group , three in the 4 mg/kg group , and two in the placebo group . INTERPRETATION Tocilizumab could be an effective therapeutic approach in patients with moderate to severe active rheumatoid arthritis . FUNDING F Hoffmann-La Roche , Chugai Pharmaceutical [15201414] BACKGROUND An open-label study indicated that selective depletion of B cells with the use of rituximab led to sustained clinical improvements for patients with rheumatoid arthritis . To confirm these observations , we conducted a r and omized , double-blind , controlled study . METHODS We r and omly assigned 161 patients who had active rheumatoid arthritis despite treatment with methotrexate to receive one of four treatments : oral methotrexate ( > or = 10 mg per week ) ( control ) ; rituximab ( 1000 mg on days 1 and 15 ) ; rituximab plus cyclophosphamide ( 750 mg on days 3 and 17 ) ; or rituximab plus methotrexate . Responses defined according to the criteria of the American College of Rheumatology ( ACR ) and the European League against Rheumatism ( EULAR ) were assessed at week 24 ( primary analyses ) and week 48 ( exploratory analyses ) . RESULTS At week 24 , the proportion of patients with 50 percent improvement in disease symptoms according to the ACR criteria , the primary end point , was significantly greater with the rituximab-methotrexate combination ( 43 percent , P=0.005 ) and the rituximab-cyclophosphamide combination ( 41 percent , P=0.005 ) than with methotrexate alone ( 13 percent ) . In all groups treated with rituximab , a significantly higher proportion of patients had a 20 percent improvement in disease symptoms according to the ACR criteria ( 65 to 76 percent vs. 38 percent , P < or = 0.025 ) or had EULAR responses ( 83 to 85 percent vs. 50 percent , P < or = 0.004 ) . All ACR responses were maintained at week 48 in the rituximab-methotrexate group . The majority of adverse events occurred with the first rituximab infusion : at 24 weeks , serious infections occurred in one patient ( 2.5 percent ) in the control group and in four patients ( 3.3 percent ) in the rituximab groups . Peripheral-blood immunoglobulin concentrations remained within normal ranges . CONCLUSIONS In patients with active rheumatoid arthritis despite methotrexate treatment , a single course of two infusions of rituximab , alone or in combination with either cyclophosphamide or continued methotrexate , provided significant improvement in disease symptoms at both weeks 24 and 48 [19224750] CONTEXT The risk of bacterial infection is increased in patients treated with drugs that inhibit tumor necrosis factor alpha ( TNF-alpha ) . Little is known about the reactivation of latent viral infections during treatment with TNF-alpha inhibitors . OBJECTIVE To investigate whether TNF-alpha inhibitors together as a class , or separately as either monoclonal anti-TNF-alpha antibodies ( adalimumab , infliximab ) or a fusion protein ( etanercept ) , are related to higher rates of herpes zoster in patients with rheumatoid arthritis . DESIGN , SETTING , AND PATIENTS Patients were enrolled in the German biologics register RABBIT , a prospect i ve cohort , between May 2001 and December 2006 at the initiation of treatment with infliximab , etanercept , adalimumab , or anakinra , or when they changed conventional disease-modifying antirheumatic drug ( DMARD ) . Treatment , clinical status , and adverse events were assessed by rheumatologists at fixed points during follow-up . MAIN OUTCOME MEASURES Hazard ratio ( HR ) of herpes zoster episodes following anti-TNF-alpha treatment . Study aims were to detect a clinical ly significant difference ( HR , 2.0 ) between TNF-alpha inhibitors as a class compared with DMARDs and to detect an HR of at least 2.5 for each of 2 types of TNF-alpha inhibitors , the monoclonal antibodies or the fusion protein , compared with conventional DMARDs . RESULTS Among 5040 patients receiving TNF-alpha inhibitors or conventional DMARDs , 86 episodes of herpes zoster occurred in 82 patients . Thirty-nine occurrences could be attributed to treatment with anti-TNF-alpha antibodies , 23 to etanercept , and 24 to conventional DMARDs . The crude incidence rate per 1000 patient-years was 11.1 ( 95 % confidence interval [ CI ] , 7.9 - 15.1 ) for the monoclonal antibodies , 8.9 ( 95 % CI , 5.6 - 13.3 ) for etanercept , and 5.6 ( 95 % CI , 3.6 - 8.3 ) for conventional DMARDs . Adjusted for age , rheumatoid arthritis severity , and glucocorticoid use , a significantly increased risk was observed for treatment with the monoclonal antibodies ( HR , 1.82 [ 95 % CI , 1.05 - 3.15 ] ) , although this risk was lower than the threshold for clinical significance . No significant associations were found for etanercept use ( HR , 1.36 [ 95 % CI , 0.73 - 2.55 ] ) or for anti-TNF-alpha treatment ( HR , 1.63 [ 95 % CI , 0.97 - 2.74 ] ) as a class . CONCLUSION Treatment with monoclonal anti-TNF-alpha antibodies may be associated with increased risk of herpes zoster , but this requires further study [16255010] OBJECTIVE To assess the efficacy of low-dose prednisolone on joint damage and disease activity in patients with early rheumatoid arthritis ( RA ) . METHODS At the start of their initial treatment with a disease-modifying antirheumatic drug ( DMARD ) , patients with early ( duration < or = 1 year ) active RA were r and omly assigned to receive either 7.5 mg/day prednisolone or no prednisolone for 2 years . Radiographs of the h and s and feet were obtained at baseline and after 1 and 2 years and scored according to the Sharp score as modified by van der Heijde . Remission was defined as a Disease Activity Score in 28 joints of < 2.6 . Bone mineral density was measured by dual x-ray absorptiometry at baseline and after 2 years . RESULTS Of the 250 patients included , 242 completed the study and 225 had radiographs available both at baseline and at 2 years . At 2 years , the median and interquartile range ( IQR ) change in total Sharp score was lower in the prednisolone group than in the no-prednisolone group ( 1.8 [ IQR 0.5 - 6.0 ] versus 3.5 [ IQR 0.5 - 10 ] ; P = 0.019 ) . In the prednisolone group , there were fewer newly eroded joints per patient after 2 years ( median 0.5 [ IQR 0 - 2 ] versus 1.25 [ IQR 0 - 3.25 ] ; P = 0.007 ) . In the prednisolone group , 25.9 % of patients had radiographic progression beyond the smallest detectable difference compared with 39.3 % of patients in the no-prednisolone group ( P = 0.033 ) . At 2 years , 55.5 % of patients in the prednisolone group had achieved disease remission , compared with 32.8 % of patients in the no-prednisolone group ( P = 0.0005 ) . There were few adverse events that led to withdrawal . Bone loss during the 2-year study was similar in the 2 treatment groups . CONCLUSION Prednisolone at 7.5 mg/day added to the initial DMARD retarded the progression of radiographic damage after 2 years in patients with early RA , provided a high remission rate , and was well tolerated . Therefore , the data support the use of low-dose prednisolone as an adjunct to DMARDs in early active RA [2770104] Objectives : To assess the efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis ( RA ) and poor prognostic factors . Methods : In this double-blind , phase IIIb study , patients with RA for 2 years or less were r and omly assigned 1 : 1 to receive abatacept ( ∼10 mg/kg ) plus methotrexate , or placebo plus methotrexate . Patients were methotrexate-naive and seropositive for rheumatoid factor ( RF ) , anti-cyclic citrullinated protein ( CCP ) type 2 or both and had radiographic evidence of joint erosions . The co- primary endpoints were the proportion of patients achieving disease activity score in 28 joints (DAS28)-defined remission ( C-reactive protein ) and joint damage progression ( Genant-modified Sharp total score ; TS ) at year 1 . Safety was monitored throughout . Results : At baseline , patients had a mean DAS28 of 6.3 , a mean TS of 7.1 and mean disease duration of 6.5 months ; 96.5 % and 89.0 % of patients were RF or anti-CCP2 seropositive , respectively . At year 1 , a significantly greater proportion of abatacept plus methotrexate-treated patients achieved remission ( 41.4 % vs 23.3 % ; p<0.001 ) and there was significantly less radiographic progression ( mean change in TS 0.63 vs 1.06 ; p = 0.040 ) versus methotrexate alone . Over 1 year , the frequency of adverse events ( 84.8 % vs 83.4 % ) , serious adverse events ( 7.8 % vs 7.9 % ) , serious infections ( 2.0 % vs 2.0 % ) , autoimmune disorders ( 2.3 % vs 2.0 % ) and malignancies ( 0.4 % vs 0 % ) was comparable for abatacept plus methotrexate versus methotrexate alone . Conclusions : In a methotrexate-naive population with early RA and poor prognostic factors , the combination of abatacept and methotrexate provided significantly better clinical and radiographic efficacy compared with methotrexate alone and had a comparable , favourable safety profile [10668523] The efficacy and safety of the novel DMARD leflunomide was compared to placebo and sulfasalazine in a r and omized , double-blind study . At Week 24 , leflunomide significantly reduced tender and swollen joint counts and physician and patient assessment scores compared to placebo ( P < 0.001 ) . Response rates with leflunomide were significantly greater than placebo : ACR 20 % ( 55 % vs 29 % , P = 0.0001 ) . Comparable response rates were observed with sulfasalazine ( ACR 20 % : 56 % ) . Leflunomide significantly improved HAQ scores compared to placebo or sulfasalazine ( P < 0.009 ) . The onset of action with leflunomide was rapid and was seen as early as Week 2 . Radiographic disease progression was significantly slower with leflunomide than placebo ( P < 0.01 ) . Leflunomide was well tolerated . No long-term safety issues were reported with leflunomide in patients who opted to continue treatment for up to 2 years . Efficacy of leflunomide in the treatment of RA was maintained at 2 years [15860509] Objective : To assess methods to calculate achieving and sustaining remission in a double blind r and omised trial in patients with RA who received etanercept , methotrexate , or an etanercept/methotrexate combination . Methods : Remission was defined as DAS < 1.6 , DAS28 < 2.6 , and ACR70 response . Sustaining remission was analysed in three ways : ( a ) analysis of sustained DAS remission , DAS28 remission , or ACR70 response continuously for 6 months ; ( b ) analysis of sustained remission appraised through a continuity rewarded scoring system , which is the weighted sum of all intervals in the study in which patients are in DAS or DAS28 remission ; or ( c ) longitudinal modelling of remission odds using generalised estimating equations . Results : Significantly more patients treated with the etanercept/methotrexate combination reached DAS remission ( 37 % ) than those treated with either methotrexate ( 14 % ) or etanercept ( 18 % ) alone ( p<0.01 ) . Results for DAS28 and for the ACR70 response were similar . Agreement between DAS remission and DAS28 remission was good , but agreement between either of these and the ACR70 response was less . Patients in DAS or DAS28 remission had a lower level of disease activity ( fewer active joints , lower ESR ) than those achieving ACR70 response ; the converse was seen using pain VAS . The three methods were comparable for sustainability of remission and showed significant advantage for combination therapy , which increased the number and durability of remission periods . Conclusions : DAS and DAS28 remission results were similar for assessing achieving and sustaining remission in RA , frequently differing from patients classified as ACR70 responders . The three methods of examining duration of remission produced comparable results [15708884] OBJECTIVE To compare drug continuation rates in patients with rheumatoid arthritis who start on a biological agent and in a control group of patients with a change in disease modifying antirheumatic drug ( DMARD ) treatment after previous DMARD failure . METHODS Patients with rheumatoid arthritis enrolled in the German biologics register between May 2001 and September 2003 were included in the study . Data were available for 511 patients treated with etanercept , 343 with infliximab , 70 with anakinra , and 599 controls . Propensity scores were used to select a sub sample of patients from the control group who were likely to be treated with biological agents because of their disease severity , as well as comparable infliximab and etanercept cases . RESULTS Treatment continuation after 12 months was similar for etanercept ( 68.6 % ( 95 % confidence interval , 62 % to 75 % ) ) and infliximab ( 65.4 % ( 58 % to 73 % ) ) but lower for anakinra ( 59 % ( 41 % to 77 % ) ) . Treatment continuation was more likely for patients on combinations of biological agents and DMARDs than for those on infliximab or etanercept alone . Patients treated with biological agents were more severely ill than those in the control group and had more previous DMARD failures . After adjustment for baseline differences , the continuation rates were higher in patients treated with biological agents than in comparable control patients treated with leflunomide or leflunomide/methotrexate . CONCLUSIONS Treatment continuation of biological agents in clinical practice is less likely than in r and omised clinical trials but more likely than in comparable controls treated with conventional DMARDs [2564802] Objectives : This double-blind trial evaluated the efficacy and safety of abatacept or infliximab vs placebo . The primary objective of this study was to evaluate the mean change from baseline in Disease Activity Score ( based on erythrocyte sedimentation rates ; DAS28 ( ESR ) ) for the abatacept vs placebo groups at day 197 . Methods : Patients with rheumatoid arthritis ( RA ) and an inadequate response to methotrexate ( MTX ) were r and omised 3:3:2 to abatacept ( ∼10 mg/kg every 4 weeks , n = 156 ) , infliximab ( 3 mg/kg every 8 weeks , n = 165 ) , or placebo ( every 4 weeks , n = 110 ) and background MTX . Safety and efficacy were assessed throughout the study . Results : Similar patient demographics and clinical characteristics were present at baseline between groups , with mean scores of ∼1.7 for HAQ-DI and 6.8 for DAS28 ( ESR ) . At 6 months , mean changes in DAS28 ( ESR ) were significantly greater for abatacept vs placebo ( –2.53 vs –1.48 , p<0.001 ) and infliximab vs placebo ( –2.25 vs –1.48 , p<0.001 ) . For abatacept vs infliximab treatment at day 365 , reductions in the DAS28 ( ESR ) were –2.88 vs –2.25 . At day 365 , the following response rates were observed for abatacept and infliximab , respectively : American College of Rheumatology ( ACR ) 20 , 72.4 and 55.8 % ; ACR 50 , 45.5 and 36.4 % ; ACR 70 , 26.3 and 20.6 % ; low disease activity score ( LDAS ) , 35.3 and 22.4 % ; DAS28-defined remission , 18.7 and 12.2 % ; good European League Against Rheumatism ( EULAR ) responses , 32.0 and 18.5 % ; and Health Assessment Question naire Disability Index ( HAQ-DI ) , 57.7 and 52.7 % . Mean changes in physical component summary ( PCS ) were 9.5 and 7.6 , and mental component summary ( MCS ) were 6.0 and 4.0 , for abatacept and infliximab , respectively . Over 1 year , adverse events ( AEs ) ( 89.1 vs 93.3 % ) , serious AEs ( SAEs ) ( 9.6 vs 18.2 % ) , serious infections ( 1.9 vs 8.5 % ) and discontinuations due to AEs ( 3.2 vs 7.3 % ) and SAEs ( 2.6 vs 3.6 % ) were lower with abatacept than infliximab . Conclusions : In this study , abatacept and infliximab ( 3 mg/kg every 8 weeks ) demonstrated similar efficacy . Overall , abatacept had a relatively more acceptable safety and tolerability profile , with fewer SAEs , serious infections , acute infusional events and discontinuations due to AEs than the infliximab group . Trial registration number : NCT00095147 [16874796] OBJECTIVE To assess the risk of acute myocardial infa rct ion ( AMI ) associated with the use of disease-modifying antirheumatic drugs ( DMARDs ) and other medications commonly used in rheumatoid arthritis ( RA ) . METHODS We conducted a nested case-control analysis within a cohort of subjects with RA , observed between 1999 and 2003 , identified from the PharMetrics cl aims data base . For each first AMI hospitalization identified during followup , 10 controls matched on sex , age , and time of study entry were r and omly selected from the cohort . Conditional logistic regression was used to estimate the rate ratio ( RR ) of AMI associated with the current use of anti-RA therapy , as measured from dispensed prescriptions , after adjustment for AMI risk factors . RESULTS The cohort included 107,908 subjects ( average age 54 years at cohort entry ) . During followup , 558 AMI cases occurred ( 3.4 per 1,000 per year ) . AMI rate was significantly decreased with the current use of any DMARD ( adjusted RR 0.80 , 95 % confidence interval [ 95 % CI ] 0.65 - 0.98 ) . This effect was consistent across all DMARDs , including methotrexate ( RR 0.81 , 95 % CI 0.60 - 1.08 ) , leflunomide ( RR 0.28 , 95 % CI 0.12 - 0.65 ) , and other traditional DMARDs ( RR 0.67 , 95 % CI 0.46 - 0.97 ) , but not biologic agents ( RR 1.30 , 95 % CI 0.92 - 1.83 ) . AMI rate increased with the use of glucocorticoids ( RR 1.32 , 95 % CI 1.02 - 1.72 ) but not with nonselective nonsteroidal antiinflammatory drugs ( RR 1.05 , 95 % CI 0.81 - 1.36 ) or cyclooxygenase 2 ( COX-2 ) inhibitors ( RR 1.11 , 95 % CI 0.87 - 1.43 ) . CONCLUSION DMARD use is associated with a reduction in AMI risk in patients with RA . No risk increase was found with the COX-2 inhibitors in this population [18662933] Objectives : To compare the occurrence of drug-free remission , functional ability and radiological damage after 4 years of response-driven treatment according to four different treatment strategies for rheumatoid arthritis ( RA ) . Methods : Patients with recent-onset , active RA ( n = 508 ) were r and omly assigned to four different treatment strategies : ( 1 ) sequential monotherapy ; ( 2 ) step-up combination therapy ; ( 3 ) initial combination therapy with prednisone and ( 4 ) initial combination therapy with infliximab . Treatment was adjusted based on 3-monthly disease activity score ( DAS ) assessment s , aim ing at a DAS ⩽2.4 . From the third year , patients with a sustained DAS < 1.6 discontinued treatment . Results : In total , 43 % of patients were in remission ( DAS < 1.6 ) at 4 years and 13 % were in drug-free remission : 14 % , 12 % , 8 % and 18 % of patients in groups 1–4 , respectively . The absence of anti-cyclic citrullinated peptide antibodies , male gender and short symptom duration were independently associated with drug-free remission . Functional ability and remission were maintained in all four groups with the continuation of DAS-driven treatment , without significant differences between the groups . Significant progression of joint damage was observed in 38 % and 31 % of patients in groups 3 and 4 versus 51 % and 54 % of patients in groups 1 and 2 ( p<0.05 , group 4 versus groups 1 and 2 , group 3 versus group 2 ) . Conclusions : In patients with recent-onset active RA , drug-free remission was achieved in up to 18 % of patients . DAS-driven treatment maintained clinical and functional improvement , independent of the treatment strategy . Joint damage progression remained significantly lower after initial combination therapy compared with initial monotherapy [18050184] OBJECTIVE To determine whether the incidence of herpes zoster is elevated in patients with rheumatoid arthritis ( RA ) and whether herpes zoster is associated with use of disease-modifying antirheumatic drugs ( DMARDs ) in patients with RA . METHODS Two retrospective cohort studies were conducted using data from a US integrated managed care data base ( PharMetrics cl aims data base ) from 1998 - 2002 and the UK General Practice Research Data base ( GPRD ) between 1990 - 2001 . Rates of herpes zoster among patients with RA and r and omly sample d non-RA patients were compared . A nested case-control analysis was performed within each RA cohort to examine the effect of current treatment on herpes zoster risk . RESULTS A total of 122,272 patients with RA from the PharMetrics data base and 38,621 from the GPRD were included . The adjusted hazard ratios of herpes zoster for patients with RA compared with non-RA patients were 1.91 ( 95 % confidence interval [ 95 % CI ] 1.80 - 2.03 ) in the PharMetrics data base and 1.65 ( 95 % CI 1.57 - 1.75 ) in the GPRD . In the PharMetrics data base , current use of biologic DMARDs alone was associated with herpes zoster ( odds ratio [ OR ] 1.54 , 95 % CI 1.04 - 2.29 ) , as was current use of traditional DMARDs alone ( OR 1.37 , 95 % CI 1.18 - 1.59 ) . In the GPRD , current use of traditional DMARDs was associated with herpes zoster ( OR 1.27 , 95 % CI 1.10 - 1.48 ) . In both data sources , use of oral corticosteroids was associated with herpes zoster regardless of concomitant therapies . CONCLUSION Data from 2 large data bases suggested that patients with RA are at increased risk of herpes zoster . Among patients with RA , DMARDs and /or use of oral corticosteroids appeared to be associated with herpes zoster [17666447] Objectives : This study assessed the relative efficacy of etanercept ( ETN ) or etanercept and methotrexate ( ETN+MTX ) for patients with rheumatoid arthritis ( RA ) who had an unsatisfactory response to MTX , using patient-reported outcomes ( PROs ) of function , pain , general health , disease activity and morning stiffness . Methods : The PROs were secondary assessment s in a 16-week , prospect i ve , r and omised , parallel-group study conducted at 60 European centres . Patients with RA were r and omly assigned either to monotherapy with ETN or combination therapy with ETN+MTX . PRO instruments administered included the Stanford Health Assessment Question naire , the pain visual analogue scale , the EuroQoL assessment of current health state ( EQ-5D ) , the EQ-5D visual analogue scale , a patient global assessment of disease activity and an assessment of morning stiffness . Treatment groups were compared by percentage of patients within clinical ly meaningful categories . The primary endpoint for all PROs was comparison of mean improvement from baseline to week 16 between ETN and ETN+MTX groups . Results : Three hundred and fifteen patients were r and omised to ETN or ETN+MTX . Both treatment arms had similar Health Assessment Question naire Disability Index DI , EQ-5D , patient global assessment of disease activity , pain or morning stiffness scores and improvement from baseline to week 16 . Conclusions : For patients with active RA and intolerance or unsatisfactory response to MTX , substituting ETN for MTX and adding ETN to MTX are both effective ways of reducing disability , pain , disease activity , morning stiffness , and improving general health [20187135] OBJECTIVE To evaluate how continuation of and alterations to initial year 1 combination etanercept-methotrexate ( MTX ) therapy and MTX monotherapy regimens affect long-term remission and radiographic progression in early , active rheumatoid arthritis . METHODS Subjects were r and omized at baseline for the entire 2-year period ; those who completed 1 year of treatment with combination or MTX monotherapy entered year 2 . The original combination group either continued combination therapy ( the EM/EM group ; n = 111 ) or received etanercept monotherapy ( the EM/E group ; n = 111 ) in year 2 ; the original MTX monotherapy group either received combination therapy ( the M/EM group ; n = 90 ) or continued monotherapy ( the M/M group ; n = 99 ) in year 2 . Efficacy end points included remission ( a Disease Activity Score in 28 joints [ DAS28 ] < 2.6 ) and radiographic nonprogression ( change in the modified Sharp/van der Heijde score < or = 0.5 ) at year 2 . A last observation carried forward analysis from the modified intention-to-treat population ( n = 398 ) and a post hoc nonresponder imputation ( NRI ) analysis ( n = 528 ) were performed for remission . RESULTS At year 2 , DAS28 remission was achieved by 62/108 , 54/108 , 51/88 , and 33/94 subjects in the EM/EM , EM/E , M/EM , and M/M groups , respectively ( P < 0.01 for the EM/EM and M/EM groups versus the M/M group ) . This effect was corroborated by a more conservative post hoc 2-year NRI analysis , with remission observed in 59/131 , 50/134 , 48/133 , and 29/130 of the same respective groups ( P < 0.05 for each of the EM/EM , EM/E , and M/EM groups versus the M/M group ) . The proportions of subjects achieving radiographic nonprogression ( n = 360 ) were 89/99 , 74/99 , 59/79 , and 56/83 in the EM/EM ( P < 0.01 versus each of the other groups ) , EM/E , M/EM , and M/M groups , respectively . No new safety signals or between-group differences in serious adverse events were seen . CONCLUSION Early sustained combination etanercept-MTX therapy was consistently superior to MTX monotherapy . Combination therapy result ed in important clinical and radiographic benefits over 2 study years , without significant additional safety risk [9251634] BACKGROUND The value of intensive combination therapy in early rheumatoid arthritis is unproven . In a multicentre , double-blind , r and omised trial ( COBRA ) , we compared the combination of sulphasalazine ( 2 g/day ) , methotrexate ( 7.5 mg/week ) , and prednisolone ( initially 60 mg/day , tapered in 6 weekly steps to 7.5 mg/day ) with sulphasalazine alone . METHODS 155 patients with early rheumatoid arthritis ( median duration 4 months ) were r and omly assigned combined treatment ( 76 ) or sulphasalazine alone ( 79 ) . Prednisolone and methotrexate were tapered and stopped after 28 and 40 weeks , respectively . The main outcomes were the pooled index ( a weighted change score of five disease activity measures ) and the Sharp/Van der Heijde radiographic damage score in h and s and feet . Independent health-care professionals assessed the main outcomes without knowledge of treatment allocation . FINDINGS At week 28 , the mean pooled index was 1.4 ( 95 % CI 1.2 - 1.6 ) in the combined treatment group and 0.8 ( 0.6 - 1.0 ) in the sulphasalazine group ( p < 0.0001 ) . At this time , 55 ( 72 % ) and 39 ( 49 % ) patients , respectively , were improved according to American College of Rheumatology criteria . The clinical difference between the groups decreased and was no longer significant after prednisolone was stopped , and there were no further changes after methotrexate was stopped . At 28 weeks , the radiographic damage score had increased by a median of 1 ( range 0 - 28 ) in the combined-therapy group and 4 ( 0 - 44 ) in the sulphasalazine group ( p < 0.0001 ) . The increases at week 56 ( 2 [ 0 - 43 ] vs 6 [ 0 - 54 ] , p = 0.004 ) , and at week 80 ( 4 [ 0 - 80 ] vs 12 [ 0 - 72 ] , p = 0.01 ) were also significant . Further analysis suggests that combined therapy immediately suppressed damage progression , whereas sulphasalazine did so less effectively and with a lag of 6 to 12 months . There were fewer withdrawals in the combined therapy than the sulphasalazine group ( 6 [ 8 % ] vs 23 [ 29 % ] ) , and they occurred later . INTERPRETATION This combined-therapy regimen offers additional disease control over and above that of sulphasalazine alone that persists for up to a year after corticosteroids are stopped . Although confirmatory studies and long-term follow-up are needed , this approach may prove useful in the treatment of early rheumatoid arthritis [10573044] CONTEXT Leflunomide is a reversible inhibitor of de novo pyrimidine synthesis shown to be effective in a phase 2 trial in 402 patients with active rheumatoid arthritis ( RA ) . OBJECTIVE To compare the efficacy and safety of leflunomide treatment with placebo and methotrexate treatment in patients with active RA . DESIGN R and omized , double-blind , placebo , and active-controlled 12-month study . SETTING Forty-seven university and private rheumatology practice s in the United States and Canada . PATIENTS Diagnosis of RA by the American College of Rheumatology ( ACR ) criteria for duration of 6 months or longer and no previous methotrexate treatment . INTERVENTION Leflunomide treatment ( 20 mg/d ) , placebo , or methotrexate treatment ( 7.5 - 15 mg/wk ) . MAIN OUTCOME MEASURES American College of Rheumatology success rate ( completed 52 weeks of treatment and met the ACR > or = 20 % response criteria ) , disease progression as assessed by x-ray films , and improvement in function and health-related quality of life using the intent-to-treat population . RESULTS The 482 patients studied were predominantly women ( mean age , 54 years ; mean disease duration , 6.7 years ) for whom a mean of 0.8 disease-modifying antirheumatic drugs had failed . The ACR response and success rates for patients receiving leflunomide treatment ( 52 % and 41 % , respectively ) and methotrexate treatment ( 46 % and 35 % , respectively ) were significantly higher than those for patients receiving placebo ( 26 % and 19 % , respectively ) ( P<.001 ) , and they were statistically equivalent , with mean time to initial response at 8.4 weeks for patients receiving leflunomide vs 9.5 weeks for patients receiving methotrexate therapy . X-ray analyses demonstrated less disease progression with leflunomide ( P=.001 ) and methotrexate ( P = .02 ) therapy than with placebo . Leflunomide and methotrexate treatment improved measures of physical function and health-related quality of life significantly more than placebo ( P<.001 and P<.05 , respectively ) . Common adverse events for patients receiving leflunomide treatment included gastrointestinal complaints , skin rash , and reversible alopecia . Asymptomatic transaminase elevations result ed in treatment discontinuations for 7.1 % of patients receiving leflunomide therapy , 1.7 % of patients receiving placebo , and 3.3 % of patients receiving methotrexate therapy . CONCLUSIONS Clinical responses following administration of leflunomide , a new therapeutic agent for the treatment of RA , were statistically superior to those with placebo and equivalent to those with methotrexate treatment . Both active treatments improved signs and symptoms of active RA , delayed disease progression as demonstrated by x-ray films , and improved function and health-related quality of life [17768173] Objective : Treating early active rheumatoid arthritis ( RA ) with disease modifying antirheumatic drug ( DMARD ) monotherapy achieves incomplete outcomes and intensive treatment seems preferable . As the relative benefits of combining two DMARDs , one DMARD with glucocorticoids and two DMARDs with glucocorticoids are uncertain we defined them in a factorial trial . Methods : A 2-year r and omised double-blind factorial trial in patients with RA within 2 years of diagnosis treated with methotrexate studied the benefits of added ciclosporin , 9 months intensive prednisolone or both ( triple therapy ) . The primary outcome was the number of patients with new erosions . Secondary outcomes included Larsen ’s x-ray scores , disability , quality of life and adverse events . Findings : 1391 patients were screened and 467 r and omised . Over 2 years 132 ( 28 % ) changed therapy and 88 ( 19 % ) were lost to follow-up . The number of patients with new erosions was reduced by nearly half by adding ciclosporin or prednisolone ( p = 0.01 and 0.03 ) ; both treatments reduced increases in Larsen ’s x-ray scores by over 2 units ( p = 0.008 and 0.003 ) . A further reduction in erosive damage was seen with combined use of both treatments . Their effects on erosive damage appeared independent . Triple therapy reduced disability and improved quality of life compared with methotrexate ; ciclosporin and prednisolone acted synergistically . More patients withdrew because of adverse events with triple therapy , without an increase in serious adverse effects . Conclusions : This study confirms the existence of a “ window of opportunity ” in early RA , when intensive combination therapy produces sustained benefits on damage and disability . Although methotrexate – prednisolone combinations reduce erosive damage , the synergistic effect of two DMARDs is needed to improve quality of life [3811149] Objectives : The phase III RADIATE study examined the efficacy and safety of tocilizumab , an anti-IL-6 receptor monoclonal antibody in patients with rheumatoid arthritis ( RA ) refractory to tumour necrosis factor ( TNF ) antagonist therapy . Methods : 499 patients with inadequate response to one or more TNF antagonists were r and omly assigned to receive 8 mg/kg or 4 mg/kg tocilizumab or placebo ( control ) intravenously every 4 weeks with stable methotrexate for 24 weeks . ACR20 responses , secondary efficacy and safety endpoints were assessed . Results : ACR20 was achieved at 24 weeks by 50.0 % , 30.4 % and 10.1 % of patients in the 8 mg/kg , 4 mg/kg and control groups , respectively ( less than p<0.001 both tocilizumab groups versus control ) . At week 4 more patients achieved ACR20 in 8 mg/kg tocilizumab versus controls ( less than p = 0.001 ) . Patients responded regardless of most recently failed anti-TNF or the number of failed treatments . DAS28 remission ( DAS28 < 2.6 ) rates at week 24 were clearly dose related , being achieved by 30.1 % , 7.6 % and 1.6 % of 8 mg/kg , 4 mg/kg and control groups ( less than p = 0.001 for 8 mg/kg and p = 0.053 for 4 mg/kg versus control ) . Most adverse events were mild or moderate with overall incidences of 84.0 % , 87.1 % and 80.6 % , respectively . The most common adverse events with higher incidence in tocilizumab groups were infections , gastrointestinal symptoms , rash and headache . The incidence of serious adverse events was higher in controls ( 11.3 % ) than in the 8 mg/kg ( 6.3 % ) and 4 mg/kg ( 7.4 % ) groups . Conclusion : Tocilizumab plus methotrexate is effective in achieving rapid and sustained improvements in signs and symptoms of RA in patients with inadequate response to TNF antagonists and has a manageable safety profile . Trial registration number : NCT00106522 [16439435] Objective : To assess the safety of adalimumab in global clinical trials and postmarketing surveillance among patients with rheumatoid arthritis ( RA ) . Methods : Safety data for adalimumab treated patients from r and omised controlled trials , open label extensions , and two phase IIIb open label trials were analysed . In addition , postmarketing spontaneous reports of adverse events in the United States were collected following Food and Drug Administration approval of adalimumab on 31 December 2002 . Results : As of 15 April 2005 , the RA clinical trial safety data base analysed covered 10 050 patients , representing 12 506 patient-years ( PYs ) of adalimumab exposure . The rate of serious infections , 5.1/100 PYs , was comparable to that reported on 31 August 2002 ( 4.9/100 PYs ) , and to published reports of RA population s naive to anti-tumour necrosis factor ( TNF ) therapy . Following implementation of tuberculosis ( TB ) screening in clinical trials , the rate of TB decreased . There were 34 cases of TB as of this analysis ( 0.27/100 PYs ) . The st and ardised incidence ratio for lymphoma was 3.19 ( 95 % CI 1.78 to 5.26 ) , consistent with the observed increased incidence in the general RA population . As of 30 June 2005 , there were an estimated 78 522 PYs of exposure to adalimumab in the US postmarketing period . Seventeen TB cases were spontaneously reported ( 0.02/100 PYs ) from the US . Rates of other postmarketing events of interest , such as congestive heart failure , systemic lupus erythematosus , opportunistic infections , blood dyscrasias , lymphomas , and demyelinating disease , support observations from clinical trials . Conclusion : Analyses of these data demonstrate that long term adalimumab treatment is generally safe and well tolerated in patients with RA [16606651] Objective : To compare the efficacy and safety of etanercept and sulfasalazine , alone and in combination , in patients with active rheumatoid arthritis despite sulfasalazine treatment . Methods : A double-blind , r and omised study in adult patients with active rheumatoid arthritis despite stable sulfasalazine ( 2–3 g/day ) treatment . The primary end point was a 20 % response by the American College of Rheumatology ( ACR ) criteria at 24 weeks . Results : At baseline , the three treatment groups ( sulfasalazine , n = 50 ; etanercept , n = 103 ; etanercept and sulfasalazine , n = 101 ) were comparable for demographic variables and disease activity . Lack of efficacy was the primary reason for discontinuation ( sulfasalazine , n = 12 ; etanercept , n = 1 ; etanercept and sulfasalazine , n = 4 ; p<0.001 ) . Significantly more patients receiving etanercept , alone or in combination ( 74 % for each ) , achieved ACR 20 responses at 24 weeks than those receiving sulfasalazine ( 28 % ; p<0.01 ) . Similarly , more patients in the etanercept groups achieved ACR 50 and ACR 70 responses than those in the sulfasalazine group ( p<0.01 ) . In the groups receiving etanercept , significant differences in the ACR core components were observed by week 2 compared with those receiving sulfasalazine alone ( p<0.01 ) . The incidences of several common adverse events ( headache , nausea , asthenia ) were lower with etanercept alone than with the combination ( p<0.05 ) , but infections and injection site reactions were higher with etanercept alone ( p<0.05 ) . The safety profiles of both etanercept treatment groups were comparable with previous experience of etanercept . Conclusions : For all efficacy variables assessed , etanercept alone or in combination with sulfasalazine result ed in substantial and similar improvement in disease activity from baseline to week 24 compared with sulfasalazine alone in patients with active rheumatoid arthritis despite their sulfasalazine treatment . All three treatments were generally well tolerated [16258899] OBJECTIVE Several treatment strategies have proven value in the amelioration of rheumatoid arthritis ( RA ) , but the optimal strategy for preventing long-term joint damage and functional decline is unclear . We undertook this study to compare clinical and radiographic outcomes of 4 different treatment strategies , with intense monitoring in all patients . METHODS In a multicenter , r and omized clinical trial , 508 patients were allocated to 1 of 4 treatment strategies : sequential disease-modifying antirheumatic drug monotherapy ( group 1 ) , step-up combination therapy ( group 2 ) , initial combination therapy with tapered high-dose prednisone ( group 3 ) , and initial combination therapy with the tumor necrosis factor antagonist infliximab ( group 4 ) . Treatment adjustments were made every 3 months in an effort to obtain low disease activity ( a Disease Activity Score in 44 joints of < or = 2.4 ) . RESULTS Initial combination therapy including either prednisone ( group 3 ) or infliximab ( group 4 ) result ed in earlier functional improvement than did sequential monotherapy ( group 1 ) and step-up combination therapy ( group 2 ) , with mean scores at 3 months on the Dutch version of the Health Assessment Question naire ( D-HAQ ) of 1.0 in groups 1 and 2 and 0.6 in groups 3 and 4 ( P < 0.001 ) . After 1 year , mean D-HAQ scores were 0.7 in groups 1 and 2 and 0.5 in groups 3 and 4 ( P = 0.009 ) . The median increases in total Sharp/Van der Heijde radiographic joint score were 2.0 , 2.5 , 1.0 , and 0.5 in groups 1 - 4 , respectively ( P < 0.001 ) . There were no significant differences in the number of adverse events and withdrawals between the groups . CONCLUSION In patients with early RA , initial combination therapy including either prednisone or infliximab result ed in earlier functional improvement and less radiographic damage after 1 year than did sequential monotherapy or step-up combination therapy [2638601] We investigated the clinical efficacy and safety of tocilizumab ( a humanized anti-IL-6 receptor antibody ) monotherapy in active rheumatoid arthritis ( RA ) patients with an inadequate response to low dose methotrexate ( MTX ) . In a multicenter , double-blind , r and omized , controlled trial , 125 patients were allocated to receive either tocilizumab 8 mg/kg every 4 weeks plus MTX placebo ( tocilizumab group ) or tocilizumab placebo plus MTX 8 mg/week ( control group ) for 24 weeks . The clinical responses were measured using the American College of Rheumatology ( ACR ) criteria and the Disease Activity Score in 28 joints . Serum vascular endothelial growth factor ( VEGF ) levels were also monitored . At week 24 , 25.0 % in the control group and 80.3 % in the tocilizumab group achieved ACR20 response . The tocilizumab group showed superior ACR response criteria over control at all time points . Additionally , serum VEGF levels were significantly decreased by tocilizumab treatment . The overall incidences of adverse events ( AEs ) were 72 and 92 % ( serious AEs : 4.7 and 6.6 % ; serious infections : 1.6 and 3.3 % ) in the control and the tocilizumab groups , respectively . All serious adverse events improved by adequate treatment . Tocilizumab monotherapy was well tolerated and provided an excellent clinical benefit in active RA patients with an inadequate response to low dose MTX [1526636] We investigated the frequency of remission according to the disease activity score ( DAS28 ) definition , modified American Rheumatology Association ( ARA ) criteria , and the frequency of an achievement of a functional status above defined thresholds ( ' functional remission ' , ' physical independence ' ) in rheumatoid arthritis ( RA ) patients treated with either biologics or conventional DMARDs . We used the data of a prospect i ve cohort study , the German biologics register RABBIT ( German acronym for Rheumatoid Arthritis – Observation of Biologic Therapy ) to investigate the outcomes in RA patients with two or more DMARD failures who received new treatment with biologics ( BIOL ; n = 818 ) or a conventional DMARD ( n = 265 ) . Logistic regression analysis was applied to adjust for differences in baseline risks . Taking risk indicators such as previous DMARD failures or baseline clinical status into account , we found that biologics doubled the chance of remission compared to conventional DMARD therapies ( DAS28 remission , adjusted odds ratio ( OR ) 1.95 ( 95 % confidenece interval ( CI ) 1.2–3.2 ) ) ; ARA remission , OR 2.05 ( 95 % CI 1.2–3.5 ) ) . High remission rates ( DAS28 remission , 30.6 % ; ARA remission , 16.9 % ) were observed in BIOL patients with a moderate disease activity ( DAS28 , 3.2 to 5.1 ) at the start of treatment . These rates decreased to 8.5 % in patients with DAS28 > 6 . Sustained remission at 6 and 12 months was achieved in < 10 % of the patients . Severely disabled patients ( ≤50 % of full function ) receiving biologic therapies were significantly more likely to achieve a status indicating physical independence ( ≥67 % of full function ) than controls ( OR 3.88 ( 95 % CI 1.7–8.8 ) ) . ' Functional remission ' ( ≥83 % of full function ) was more often achieved in BIOL than in controls ( OR 2.18 ( 95 % CI 1.04–4.6 ) ) . In conclusion , our study shows that biologics increase the chance to achieve clinical remission and a status of functional remission or at least physical independence . However , temporary or even sustained remission remain ambitious aims , which are achieved in a minority of patients only [19560810] BACKGROUND Tumour necrosis factor alpha ( TNFalpha ) inhibitors are frequently used to treat rheumatoid arthritis , but whether use of a different TNFalpha inhibitor can improve patient response is unknown . We assess the efficacy and safety of the TNFalpha inhibitor golimumab in patients with active rheumatoid arthritis who had previously received one or more TNFalpha inhibitors . METHODS 461 patients with active rheumatoid arthritis from 82 sites in 10 countries were r and omly allocated by interactive voice response system , stratified by study site and methotrexate use , to receive subcutaneous injections of placebo ( n=155 ) , 50 mg golimumab ( n=153 ) , or 100 mg golimumab ( n=153 ) every 4 weeks between Feb 21 , 2006 , and Sept 26 , 2007 . Allocation was double-blind . Eligible patients had been treated with at least one dose of a TNFalpha inhibitor previously . Patients continued stable doses of methotrexate , sulfasalazine , hydroxychloroquine , oral corticosteroids , and non-steroidal anti-inflammatory drugs . The primary endpoint was achievement at week 14 of 20 % or higher improvement in American College of Rheumatology criteria for assessment of rheumatoid arthritis ( ACR20 ) . At week 16 , patients who had less than 20 % improvement in tender and swollen joint counts were given rescue therapy and changed treatment from placebo to 50 mg golimumab , or from 50 mg to 100 mg golimumab . Drug efficacy was assessed by intention to treat and safety was assessed according to the study drug given . This study is registered with Clinical Trials.gov , number NCT00299546 . FINDINGS Patients had discontinued previous TNFalpha inhibitors because of lack of effectiveness ( 269 [ 58 % ] patients ) or reasons unrelated to effectiveness ( 246 [ 53 % ] patients ) , such as intolerance and accessibility issues . Patients had active disease , which was indicated by a median of 14.0 ( IQR 9.0 - 22.0 ) swollen and 26.0 ( 16.0 - 41.0 ) tender joints for the whole group . 28 ( 18 % ) patients on placebo , 54 ( 35 % ) patients on 50 mg golimumab ( odds ratio 2.5 [ 95 % CI 1.5 - 4.2 ] , p=0.0006 ) , and 58 ( 38 % ) patients on 100 mg golimumab ( 2.8 [ 1.6 - 4.7 ] , p=0.0001 ) achieved ACR20 at week 14 . Two patients were never treated , and 57 patients did not complete the study because of adverse events , unsatisfactory treatment effect , loss to follow-up , death , or other reasons . 155 patients on placebo , 153 on 50 mg golimumab , and 153 on 100 mg golimumab were assessed for drug efficacy . For weeks 1 - 16 , serious adverse events were recorded in 11 ( 7 % ) patients on placebo , 8 ( 5 % ) on 50 mg golimumab , and 4 ( 3 % ) on 100 mg golimumab . For weeks 1 - 24 , after some patients were given rescue therapy , serious adverse events were recorded in 15 ( 10 % ) patients on placebo , 14 ( 5 % ) on 50 mg golimumab , and 8 ( 4 % ) on 100 mg golimumab . INTERPRETATION Golimumab reduced the signs and symptoms of rheumatoid arthritis in patients with active disease who had previously received one or more TNFalpha inhibitors . FUNDING Centocor Research and Development and Schering-Plough Research Institute [17083767] AIM To evaluate the efficacy and safety of four different treatment strategies for patients with early rheumatoid arthritis ( RA ) . METHODS In the BeSt study , 508 patients with newly diagnosed ( < 2 years ) active RA were r and omised to be treated according to four treatment strategies : 1 . sequential monotherapy , 2 . step up to combination therapy ( both starting with methotrexate ) , 3 . initial combination therapy with methotrexate , sulphasalazine , and a tapered high dose of prednisone , and 4 . initial combination therapy with methotrexate and infliximab . Three-monthly therapy adjustments were dictated by calculation of the Disease Activity Score ( DAS ) , with the goal to achieve and maintain a DAS < or= 2.4 . Functional ability was measured every 3 months with the Health Assessment Question naire . Radiographs of h and s and feet were assessed yearly , blinded for patient identity and treatment , and in r and om order , to measure joint damage progression ( Sharp/van der Heijde score ) . RESULTS After 2 years of treatment , 80 % of all patients achieved the goal of DAS < or= 2.4 , and 42 % reached clinical remission ( DAS < 1.6 ) . Initial combination therapy , either with prednisone ( group 3 ) or with infliximab ( group 4 ) , result ed in earlier improvement in functional ability , more continuous clinical remission ( DAS < 1.6 ) , and less joint damage progression than initial monotherapy ( groups 1 and 2 ) . Patients in groups 1 and 2 needed more therapy adjustments , including introduction of combination therapy with prednisone or infliximab , to achieve a DAS < or= 2.4 , whereas many patients in groups 3 and 4 were able to taper their medication to sulphasalazine or methotrexate , respectively , monotherapy . The adverse events profile was comparable in all groups . The presence or absence of rheumatoid factor , HLA DR4 , or anti-CCP was not associated with radiologic damage progression . CONCLUSION In patients with early , active RA , remarkable clinical improvement and suppression of joint damage progression can be achieved with frequent , objective ly steered treatment adjustments . The best chance for an early clinical and radiologic response lies with initial combination therapy with either methotrexate , sulphasalazine and prednisone or with methotrexate and infliximab , which can be tapered to DMARD monotherapy once low disease activity is achieved [15529377] OBJECTIVE To compare the benefits of initiating treatment with methotrexate ( MTX ) and infliximab ( anti-tumor necrosis factor alpha [ anti-TNFalpha ] monoclonal antibody ) with those of MTX treatment alone in patients with rheumatoid arthritis ( RA ) of < or =3 years ' duration . METHODS RA patients were eligible if they had active disease and no prior treatment with MTX or a TNFalpha inhibitor . One thous and forty-nine patients were r and omly assigned in a 4:5:5 ratio to 3 treatment groups : MTX-placebo , MTX-3 mg/kg infliximab , and MTX-6 mg/kg infliximab . MTX dosages were rapidly escalated to 20 mg/week , and infliximab or placebo infusions were given at weeks 0 , 2 , and 6 , and every 8 weeks thereafter through week 46 . RESULTS At week 54 , the median percentage of American College of Rheumatology improvement ( ACR-N ) was higher for the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups than for the MTX-placebo group ( 38.9 % and 46.7 % versus 26.4 % , respectively ; P < 0.001 for both comparisons ) . Patients in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups also showed less radiographic progression than those receiving MTX alone ( mean + /- SD changes in van der Heijde modification of the total Sharp score at week 54 : 0.4 + /- 5.8 and 0.5 + /- 5.6 versus 3.7 + /- 9.6 , respectively ; P < 0.001 for each comparison ) . In addition , physical function improved significantly more in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups than in the MTX-placebo group . Infliximab therapy was associated with a significantly higher incidence of serious infections , especially pneumonia . CONCLUSION For patients with active RA in its early stages , combination therapy with MTX and infliximab provides greater clinical , radiographic , and functional benefits than treatment with MTX alone [11023558] Infliximab is a chimeric anti-tumour necrosis factor-alpha monoclonal antibody that has been studied for the treatment of Crohn 's disease and rheumatoid arthritis . In several placebo controlled , r and omized clinical trials and open trials , 771 patients have been given infliximab ( a further 192 received placebo ) . Follow-up for safety has included the time of study ( 12 weeks after the last infusion ) , plus three additional years . Acute infusion reactions ( headache , fever , chills , urticaria , chest pain ) were seen in 17 % of patients receiving infliximab compared with 7 % of those receiving placebo . While infections were reported more frequently overall in the patients given infliximab ( 26 % over 27 weeks of follow-up versus 16 % of placebo-treated patients over 20 weeks of follow-up ) , there was no increased risk of serious infections . There was no difference in the overall mortality rate between the groups . While low titres of autoantibodies developed in less than 10 % of patients , drug-induced lupus was seen in less than 1 % , with these cases resolving upon discontinuation of the drug . Overall , infliximab showed an acceptable safety profile [16947384] OBJECTIVE To assess the safety of abatacept , a selective costimulation modulator , in patients with active rheumatoid arthritis ( RA ) who had been receiving > or = 1 traditional nonbiologic and /or biologic disease-modifying antirheumatic drugs ( DMARDs ) approved for the treatment of RA for at least 3 months prior to entry into the study . METHODS This was a 1-year , multicenter , r and omized , double-blind , placebo-controlled trial . Patients were r and omized 2:1 to receive abatacept at a fixed dose approximating 10 mg/kg by weight range , or placebo . RESULTS The abatacept and placebo groups exhibited similar frequencies of adverse events ( 90 % and 87 % , respectively ) , serious adverse events ( 13 % and 12 % , respectively ) , and discontinuations due to adverse events ( 5 % and 4 % , respectively ) . Five patients ( 0.5 % ) in the abatacept group and 4 patients ( 0.8 % ) in the placebo group died during the study . Serious infections were more frequent in the abatacept group than in the placebo group ( 2.9 % versus 1.9 % ) . Fewer than 4 % of patients in either group experienced a severe or very severe infection . The incidence of neoplasms was 3.5 % in both groups . When evaluated according to background therapy , serious adverse events occurred more frequently in the subgroup receiving abatacept plus a biologic agent ( 22.3 % ) than in the other subgroups ( 11.7 - 12.5 % ) . CONCLUSION Abatacept in combination with synthetic DMARDs was well tolerated and improved physical function and physician- and patient-reported disease outcomes . However , abatacept in combination with biologic background therapies was associated with an increase in the rate of serious adverse events . Therefore , abatacept is not recommended for use in combination with biologic therapy [16358366] OBJECTIVE To prospect ively determine the efficacy and safety of etanercept in combination with sulfasalazine ( SSZ ) , hydroxychloroquine ( HCQ ) , and gold in the treatment of rheumatoid arthritis ( RA ) . METHODS A prospect i ve open-label study enrolled 119 patients with RA who had active disease despite stable therapy with SSZ ( n = 50 ) , HCQ ( n = 50 ) , or intramuscular gold ( n = 19 ) . Primary efficacy endpoints consisted of American College of Rheumatology responses at 24 and 48 weeks . Safety was established at regularly scheduled visits . RESULTS Patients in each etanercept combination showed significant improvement at both 24 and 48 weeks . Toxicity withdrawals by 48 weeks included gold ( n = 1 ) : proteinuria ; HCQ ( n = 5 ) : septic wrist and bilateral pneumonia , rash , optic neuritis , breast cancer , squamous cancer of the tongue ; and SSZ ( n = 5 ) : otitis media , elevated liver function indicators , pericarditis , rash , and gastroenteritis . The most common adverse events not requiring discontinuation from the study were injection site reactions ( 43 % of patients ) and upper respiratory type infections ( 34 % ) . CONCLUSION This study is the first to prospect ively evaluate the safety of etanercept in combination with SSZ , HCQ , and gold in patients with RA . Etanercept in combination with SSZ , HCQ , or gold was efficacious and well tolerated , with a discontinuation rate of 9 % ( 11/119 ) for adverse events at 48 weeks [10334255] BACKGROUND The treatment of rheumatoid arthritis should aim at clinical remission . This multicentre , r and omised trial with 2-year follow-up sought evidence on the efficacy and tolerability of combination therapy ( sulphasalazine , methotrexate , hydroxychloroquine , and prednisolone ) compared with treatment with a single disease-modifying antirheumatic drug , with or without prednisolone , in the treatment of early rheumatoid arthritis . METHODS 199 patients were r and omly assigned to two treatment groups . 195 started the treatment ( 97 received combination and 98 single drug therapy ) . Single-drug therapy in all patients started with sulphasalazine ; in 51 patients methotrexate was later substituted . Oral prednisolone was required by 63 patients . The primary outcome measure was induction of remission . Analyses were intention to treat . FINDINGS 87 patients in the combination group and 91 in the single-therapy group completed the trial . After a year , remission was achieved in 24 of 97 patients with combination therapy , and 11 of 98 with single-drug therapy ( p=0.011 ) . The remission frequencies at 2 years were 36 of 97 and 18 of 98 ( p=0.003 ) . Clinical improvement ( American College of Rheumatology criteria of 50 % clinical response ) was achieved after 1 year in 68 ( 75 % ) patients with combination therapy , and in 56 ( 60 % ) using single-drug therapy ( p=0.028 ) , while at the 2-year visit 69 and 57 respectively ( 71 % vs 58 % , p=0.058 ) had clinical ly improved . The frequencies of adverse events were similar in both treatment groups . INTERPRETATION Combination therapy was better and not more hazardous than single treatment in induction of remission in early rheumatoid arthritis . The combination strategy as an initial therapy seems to increase the efficacy of the treatment in at least a proportion of patients with early rheumatoid arthritis [15001324] BACKGROUND Etanercept and methotrexate are effective in the treatment of rheumatoid arthritis but no data exist on concurrent initiation or use of the combination compared with either drug alone . We aim ed to assess combination treatment with etanercept and methotrexate versus the monotherapies in patients with rheumatoid arthritis . METHODS In a double-blind , r and omised , clinical efficacy , safety , and radiographic study , 686 patients with active rheumatoid arthritis were r and omly allocated to treatment with etanercept 25 mg ( subcutaneously twice a week ) , oral methotrexate ( up to 20 mg every week ) , or the combination . Clinical response was assessed by criteria of the American College of Rheumatology ( ACR ) . The primary efficacy endpoint was the numeric index of the ACR response ( ACR-N ) area under the curve ( AUC ) over the first 24 weeks . The primary radiographic endpoint was change from baseline to week 52 in total joint damage and was assessed with the modified Sharp score . Analysis was by intention to treat . FINDINGS Four patients did not receive any drug ; thus 682 were studied . ACR-N AUC at 24 weeks was greater for the combination group compared with etanercept alone and methotrexate alone ( 18.3%-years [ 95 % CI 17.1 - 19.6 ] vs 14.7%-years [ 13.5 - 16.0 ] , p<0.0001 , and 12.2%-years [ 11.0 - 13.4 ] , p<0.0001 ; respectively ) . The mean difference in ACR-N AUC between combination and methotrexate alone was 6.1 ( 95 % CI 4.5 - 7.8 , p<0.0001 ) and between etanercept and methotrexate was 2.5 ( 0.8 - 4.2 , p=0.0034 ) . The combination was more efficacious than methotrexate or etanercept alone in retardation of joint damage ( mean total Sharp score -0.54 [ 95 % CI -1.00 to -0.07 ] vs 2.80 [ 1.08 to 4.51 ] , p<0.0001 , and 0.52 [ -0.10 to 1.15 ] , p=0.0006 ; respectively ) . The mean difference in total Sharp score between combination and methotrexate alone was -3.34 ( 95 % CI -4.86 to -1.81 , p<0.0001 ) and between etanercept and methotrexate was -27 ( -3.81 to -0.74 , p=0.0469 ) . The number of patients reporting infections or adverse events was similar in all groups . INTERPRETATION The combination of etanercept and methotrexate was significantly better in reduction of disease activity , improvement of functional disability , and retardation of radiographic progression compared with methotrexate or etanercept alone . These findings bring us closer to achievement of remission and repair of structural damage in rheumatoid arthritis [16868999] OBJECTIVE To determine whether the rate of serious infection is higher in anti-tumor necrosis factor (anti-TNF)-treated rheumatoid arthritis ( RA ) patients compared with RA patients treated with traditional disease-modifying antirheumatic drugs ( DMARDs ) . METHODS This was a national prospect i ve observational study of 7,664 anti-TNF-treated and 1,354 DMARD-treated patients with severe RA from the British Society for Rheumatology Biologics Register . All serious infections , stratified by site and organism , were included in the analysis . RESULTS Between December 2001 and September 2005 , there were 525 serious infections in the anti-TNF-treated cohort and 56 in the comparison cohort ( 9,868 and 1,352 person-years of followup , respectively ) . The incidence rate ratio ( IRR ) , adjusted for baseline risk , for the anti-TNF-treated cohort compared with the comparison cohort was 1.03 ( 95 % confidence interval 0.68 - 1.57 ) . However , the frequency of serious skin and soft tissue infections was increased in anti-TNF-treated patients , with an adjusted IRR of 4.28 ( 95 % confidence interval 1.06 - 17.17 ) . There was no difference in infection risk between the 3 main anti-TNF drugs . Nineteen serious bacterial intracellular infections occurred , exclusively in patients in the anti-TNF-treated cohort . CONCLUSION In patients with active RA , anti-TNF therapy was not associated with increased risk of overall serious infection compared with DMARD treatment , after adjustment for baseline risk . In contrast , the rate of serious skin and soft tissue infections was increased , suggesting an important physiologic role of TNF in host defense in the skin and soft tissues beyond that in other tissues [16572442] OBJECTIVE To assess the risk of serious infections following 22 weeks of infliximab therapy , and to further characterize the safety profile of infliximab in combination with background treatments during 1 year in patients with rheumatoid arthritis ( RA ) with various comorbidities . METHODS Patients with active RA despite receiving methotrexate ( MTX ) were r and omly assigned to receive infusions of placebo ( group 1 , n=363 ) , 3 mg/kg infliximab ( group 2 , n=360 ) , or 10 mg/kg infliximab ( group 3 , n=361 ) at weeks 0 , 2 , 6 , and 14 . At week 22 , patients in placebo group 1 began receiving 3 mg/kg infliximab , and patients in group 3 continued to receive an infliximab dose of 10 mg/kg . Patients in group 2 who failed to meet predefined response criteria received increasing doses of infliximab in increments of 1.5 mg/kg . RESULTS At week 22 , the relative risk of developing serious infections in groups 2 and 3 , compared with group 1 , was 1.0 ( 95 % confidence interval [ 95 % CI ] 0.3 - 3.1 , P=0.995 ) and 3.1 ( 95 % CI 1.2 - 7.9 , P=0.013 ) , respectively . The incidence of serious adverse events was 7.8 % in groups 2 and 3 compared with 7.5 % in group 1 . From week 22 to week 54 , 11.8 % , 9.9 % , and 10.3 % of patients in groups 1 , 2 , and 3 , respectively , reported occurrences of serious adverse events . Through week 54 , 1 patient in group 1 , 2 patients in group 2 , and 4 patients in group 3 developed active tuberculosis . CONCLUSION The risk of serious infections in patients receiving the approved infliximab dose of 3 mg/kg plus MTX was similar to that in patients receiving MTX alone . Patients receiving the unapproved induction regimen of 10 mg/kg infliximab plus MTX followed by a 10 mg/kg maintenance regimen had an increased risk of serious infections through week 22 [18635256] BACKGROUND Remission and radiographic non-progression are goals in the treatment of early rheumatoid arthritis . The aim of the combination of methotrexate and etanercept in active early rheumatoid arthritis ( COMET ) trial is to compare remission and radiographic non-progression in patients treated with methotrexate monotherapy or with methotrexate plus etanercept . METHODS 542 out patients who were methotrexate-naive and had had early moderate-to-severe rheumatoid arthritis for 3 - 24 months were r and omly assigned to receive either methotrexate alone titrated up from 7.5 mg a week to a maximum of 20 mg a week by week 8 or methotrexate ( same titration ) plus etanercept 50 mg a week . Co primary endpoints at 52 weeks were remission measured with the disease activity score in 28 joints ( DAS28 ) and radiographic non-progression measured with modified total Sharp score . Treatment was allocated with a computerised r and omisation and enrolment system , which masked both participants and carers . Analysis was done by modified intention to treat with last observation carried forward for missing data . This study is registered with Clinical Trials.gov , number NCT00195494 ) . FINDINGS 274 participants were r and omly assigned to receive combined treatment and 268 methotrexate alone . 132 of 265 ( 50 % , 95 % CI 44 - 56 % ) patients who took combined treatment and were available for assessment achieved clinical remission compared with 73 of 263 ( 28 % , 23 - 33 % ) taking methotrexate alone ( effect difference 22.05 % , 95%CI 13.96 - 30.15 % , p<0.0001 ) . 487 evaluable patients had severe disease ( DAS28>5.1 ) . 196 of 246 ( 80 % , 75 - 85 % ) and 135 of 230 ( 59 % , 53 - 65 % ) , respectively , achieved radiographic non-progression ( 20.98 % , 12.97 - 29.09 % , p<0.0001 ) . Serious adverse events were similar between groups . INTERPRETATION Both clinical remission and radiographic non-progression are achievable goals in patients with early severe rheumatoid arthritis within 1 year of combined treatment with etanercept plus methotrexate . FUNDING Wyeth Research [16464988] Objective : To evaluate the efficacy and safety of etanercept ( ETN ) monotherapy compared with combination ETN and methotrexate ( MTX ) treatment in patients with rheumatoid arthritis who had an inadequate response to MTX monotherapy . ( The response was defined by the presence of Disease Activity Score-28 joint count ( DAS28 ) ⩾3.2 or a combination of ⩾5 swollen joints , ⩾5 painful joints and erythrocyte sedimentation rate ⩾10 mm/h . ) Methods : Patients with active rheumatoid arthritis taking MTX ⩾12.5 mg/week for ⩾3 months were included in this 16 week , r and omised , open-label study . Patients were r and omly assigned to either ETN ( 25 mg subcutaneous injection twice weekly ) added to the baseline dose of MTX or ETN monotherapy . Results : 315 patients were r and omised to ETN ( n = 160 ) or ETN plus MTX ( n = 155 ) . The primary end point , DAS28 ( 4 ) improvement of > 1.2 units , was achieved by 72.8 % and 75.2 % of patients treated with ETN and those treated with ETN plus MTX , respectively , with no significant difference ( p = 0.658 ) between the two groups . The European League Against Rheumatism response criteria of good or moderate response was attained by 80.0 % of patients in the ETN group and by 82.4 % of patients in the ETN plus MTX group . American College of Rheumatology 20 % , 50 % and 70 % response rates achieved by both groups were also similar : 71.0 % v 67.1 % , 41.9 % v 40.1 % and 17.4 % v 18.4 % , respectively . The rates of adverse and serious adverse events were similar between the treatment groups . Conclusion : Both the addition of ETN to MTX and the substitution of ETN for MTX in patients with rheumatoid arthritis who had an inadequate response to MTX result ed in substantial improvements in clinical signs and symptoms and were generally well-tolerated treatment strategies for improving clinical signs and symptoms of rheumatoid arthritis [12176803] Objective : To explore the feasibility of prospect ively monitoring treatment efficacy and tolerability of infliximab , etanercept , and leflunomide over a two year period in patients with established rheumatoid arthritis ( RA ) in clinical practice using a structured protocol . Methods : All patients with RA at seven centres in southern Sweden , for whom at least two disease modifying antirheumatic drugs , including methotrexate , had failed or not been tolerated , who started treatment with either infliximab , etanercept , or leflunomide were included . They were evaluated at predefined times using a st and ardised protocol including items required for evaluating response to the American College of Rheumatology ( ACR ) or EULAR criteria . All adverse events were recorded using World Health Organisation terminology . Concomitant treatment and survival while receiving a drug were recorded . Results : During the study 166 patients were treated with etanercept , 135 with infliximab , and 103 with leflunomide . Treatment response as determined by the ACR and EULAR response criteria was similar for the tumour necrosis factor ( TNF ) blockers . The TNF blockers performed significantly better than leflunomide both as determined by the response criteria and by survival on drug analysis . Thus 79 % and 75 % continued to receive etanercept or infliximab compared with 22 % of patients who started leflunomide after 20 months . The spectrum of side effects did not differ from those previously reported in the clinical trials . The initial two year experience of a protocol for postmarketing surveillance of etanercept , infliximab , and leflunomide shows that a structured protocol with central data h and ling can be used in clinical practice for documenting the performance of newly introduced drugs . Conclusions : Efficacy data for the TNF blockers comply with results in clinical trials , whereas leflunomide appeared to perform worse than in clinical trials . Prolonged monitoring is required to identify possible rare side effects [11840436] OBJECTIVE The Combinatietherapie Bij Reumatoide Artritis ( COBRA ) trial demonstrated that step-down combination therapy with prednisolone , methotrexate , and sulfasalazine ( SSZ ) was superior to SSZ monotherapy for suppressing disease activity and radiologic progression of rheumatoid arthritis ( RA ) . The current study was conducted to investigate whether the benefits of COBRA therapy were sustained over time , and to determine which baseline factors could predict outcome . METHODS All patients had participated in the 56-week COBRA trial . During followup , they were seen by their own rheumatologists and were also assessed regularly by study nurses ; no treatment protocol was specified . Disease activity , radiologic damage , and functional ability were the primary outcome domains . Two independent assessors scored radiographs in sequence according to the Sharp/van der Heijde method . Outcomes were analyzed by generalized estimating equations on the basis of intent-to-treat , starting with data obtained at the last visit of the COBRA trial ( 56 weeks after baseline ) . RESULTS At the beginning of followup , patients in the COBRA group had a significantly lower mean time-averaged 28-joint disease activity score ( DAS28 ) and a significantly lower median radiologic damage ( Sharp ) score compared with those in the SSZ monotherapy group . The functional ability score ( Health Assessment Question naire [ HAQ ] ) was similar in both groups . During the 4 - 5 year followup period , the time-averaged DAS28 decreased 0.17 points per year in the SSZ group and 0.07 in the COBRA group . The Sharp progression rate was 8.6 points per year in the SSZ group and 5.6 in the COBRA group . After adjustment for differences in treatment and disease activity during followup , the between-group difference in the rate of radiologic progression was 3.7 points per year . The HAQ score did not change significantly over time . Independent baseline predictors of radiologic progression over time ( apart from treatment allocation ) were rheumatoid factor positivity , Sharp score , and DAS28 . CONCLUSION An initial 6-month cycle of intensive combination treatment that includes high-dose corticosteroids results in sustained suppression of the rate of radiologic progression in patients with early RA , independent of subsequent antirheumatic therapy [15146410] OBJECTIVE To determine the potential for additive or synergistic effects of combination therapy with the selective anti-tumor necrosis factor alpha agent etanercept and the anti-interleukin-1 agent anakinra . METHODS Two hundred forty-four patients in whom rheumatoid arthritis ( RA ) was active despite methotrexate therapy were treated with subcutaneous etanercept only ( 25 mg twice weekly ) , full-dosage etanercept ( 25 mg twice weekly ) plus anakinra ( 100 mg/day ) , or half-dosage etanercept ( 25 mg once weekly ) plus anakinra ( 100 mg/day ) for 6 months in a double-blind study at 41 centers in the US . Patients had never previously received anticytokine therapy . Patient response was measured with the American College of Rheumatology ( ACR ) core set criteria , a health-related quality -of-life question naire , and the Disease Activity Score . Safety was assessed by the number of adverse events and clinical laboratory values . Plasma concentrations of both agents and antibody formation against both agents were also assessed . RESULTS Combination therapy with etanercept plus anakinra provided no treatment benefit over etanercept alone , regardless of the regimen , but was associated with an increased safety risk . Thirty-one percent of the patients treated with full-dosage etanercept plus anakinra achieved an ACR 50 % response , compared with 41 % of the patients treated with etanercept only . This result was not statistically significant ( P = 0.914 ) . The incidence of serious infections ( 0 % for etanercept alone , 3.7 - 7.4 % for combination therapy ) , injection-site reactions , and neutropenia was increased with combination therapy . Combination therapy had no effect on the pharmacokinetics or immunogenicity of either agent . CONCLUSION Combination therapy with etanercept and anakinra provides no added benefit and an increased risk compared with etanercept alone and is not recommended for the treatment of patients with RA [17469098] OBJECTIVE Patients with rheumatoid arthritis ( RA ) in whom the response to anti-tumor necrosis factor ( anti-TNF ) therapy is inadequate have several therapeutic options , such as switching to an alternative anti-TNF agent or initiating B cell-depleting therapy with rituximab ( RTX ) . Although both therapeutic options have been proven effective in trials , no head-to-head comparisons are available . The aim of this study was to compare the effectiveness of RTX with that of an alternative anti-TNF agent in the management of patients with RA who had an inadequate response to anti-TNF therapy . METHODS This prospect i ve cohort study was nested within the Swiss Clinical Quality Management RA cohort and included all patients who had an inadequate response to at least 1 anti-TNF agent and subsequently received either 1 cycle of RTX or an alternative anti-TNF agent . The primary outcome was the evolution of RA disease activity ( as measured on the Disease Activity Score in 28 joints [ DAS28 ] ) , which was analyzed using multivariate regression models for longitudinal data . RESULTS One hundred sixteen patients with RA were included ; 50 patients received 1 cycle of RTX , and 66 patients were treated with a second or a third alternative anti-TNF agent . At baseline , there were no significant differences between the 2 groups in age , sex , disease duration , and disease activity . Evolution of the DAS28 was more favorable in the group that received RTX compared with the group that received an alternative anti-TNF agent ( P = 0.01 ) . At 6 months , the mean decrease in the DAS28 was -1.61 ( 95 % confidence interval [ 95 % CI ] -1.97 , -1.25 ) among patients receiving RTX and -0.98 ( 95 % CI -1.33 , -0.62 ) among those receiving subsequent anti-TNF therapy . CONCLUSION The results of this observational study suggest that treatment with RTX may be more effective than switching to an alternative anti-TNF agent in patients with RA in whom active disease persists despite anti-TNF therapy [16393444] ABSTRACT Objective : To evaluate the effectiveness of select biologics , methotrexate ( MTX ) , and other disease-modifying anti-rheumatic drugs ( DMARDs ) in the management of adult rheumatoid arthritis ( RA ) in routine clinical practice . Research design and methods : RADIUS ( Rheumatoid Arthritis DMARD Intervention and Utilization Study ) comprises two prospect i ve , 5‐year , observational registries of over 10 000 patients . Over 4600 patients who initiated MTX or a biologic regimen ( etanercept [ ETN ] , infliximab [ INF ] , ETN + MTX , and INF + MTX ) and who had at least one on-regimen , follow-up evaluation , were included in this analysis . Adalimumab was not included because it had not yet received FDA approval at RADIUS initiation . Other common DMARD regimens ( N = 762 ) were also compared with MTX . Patients who initiated less commonly used regimens , such as anakinra or cyclosporine , and those who did not have at least one on-regimen , follow-up evaluation , were not eligible for this analysis . Because ESR/CRP measurements were often not available , a modified ACR20 response ( mACR20 ) , defined as three out of four response criteria excluding ESR/CRP , was used to assess response at 12 months . Logistic regression analysis was performed to control for baseline covariates that may affect outcomes . Main outcome measures : The primary endpoint was the proportion of patients who achieved a mACR20 response at 12 months post-RADIUS entry . Results : After adjusting for baseline covariates , patients receiving either ETN + MTX or ETN monotherapy were more likely to achieve a mACR20 response at 12 months than patients receiving MTX alone ( odds ratio [ OR ] 1.29 , 95 % confidence interval [ CI ] 1.09–1.52 ; p < 0.01 and OR 1.23 , 95 % CI 1.02–1.47 ; p < 0.05 , respectively ) . Conversely , patients treated with MTX + leflunomide ( LEF ) were less likely to achieve a mACR20 response than those receiving MTX alone ( OR 0.68 , 95 % CI 0.48–0.96 ; p < 0.05 ) . Significant differences were not observed between patients receiving MTX alone and either INF + MTX , MTX + hydroxychloroquine , MTX + hydroxychloroquine + sulfasalazine , INF monotherapy , or LEF monotherapy . Conclusion : These data from routine rheumatology clinical practice setting s highlight the effectiveness of common biologic and DMARD therapies , and provide additional data beyond those of r and omized , controlled trials [17195186] OBJECTIVE Patients with rheumatoid arthritis ( RA ) who experience treatment failure with one anti-tumor necrosis factor ( anti-TNF ) agent , due to either inefficacy or toxicity , are frequently switched to a second anti-TNF agent , although the benefits of switching are unknown . The present study was undertaken to compare drug continuation rates between the first course and second course of anti-TNF therapy . METHODS The study involved a prospect i ve cohort of RA patients from a UK national register of new anti-TNF treatment starts ( n = 6,739 ; 876 starting adalimumab , 2,826 starting etanercept , and starting 3,037 infliximab ) . Over a mean 15 months of followup , 841 patients stopped taking the first drug due to inefficacy and 1,023 stopped the first drug due to toxicity , of whom 503 and 353 , respectively , were switched to a second anti-TNF agent . Kaplan-Meier survival curves were plotted to determine continuation rates for each course , and Cox regression was used to compare each course for the risk of stopping and the reason for stopping ( inefficacy or toxicity ) . RESULTS Overall , 73 % of patients who switched to a second anti-TNF agent remained on the new therapy by the end of followup . First drug discontinuation due to inefficacy was associated with an increased rate of second drug discontinuation due to inefficacy ( hazard ratio [ HR ] 2.7 , 95 % confidence interval [ 95 % CI ] 2.1 - 3.4 ) but not toxicity ( HR 1.1 , 95 % CI 0.9 - 1.5 ) . Similarly , first drug discontinuation due to toxicity was associated with an increased rate of second drug discontinuation due to toxicity ( HR 2.3 , 95 % CI 1.9 - 2.9 ) but not inefficacy ( HR 1.2 , 95 % CI 0.8 - 1.6 ) . CONCLUSION RA patients who are switched to a second anti-TNF drug have high rates of continuation , although among those who must discontinue treatment , the reasons for stopping a second drug are related to the reasons for stopping the first drug . This large data set from the UK provides the first estimates of the magnitude of these effects in patients with long-st and ing severe RA [21360490] OBJECTIVE To assess the efficacy and safety of tocilizumab plus methotrexate ( MTX ) versus MTX alone in preventing structural joint damage and improving physical function and disease activity in patients with moderate-to-severe rheumatoid arthritis and inadequate responses to MTX . METHODS A total of 1,196 patients were enrolled in a 2-year , r and omized , double-blind , placebo-controlled trial . Patients received tocilizumab ( 8 mg/kg or 4 mg/kg ) or placebo every 4 weeks plus MTX . Rescue treatment was available from week 16 . Results from year 1 are presented . RESULTS Mean change in the total Genant-modified Sharp score was 0.29 and 0.34 with tocilizumab 8 mg/kg plus MTX and 4 mg/kg plus MTX , respectively , versus 1.13 with placebo plus MTX ( P < 0.0001 for both comparisons ) . Analysis of variance of the area under the curve for change from baseline in the disability index of the Health Assessment Question naire showed greater decreases with tocilizumab 8 mg/kg and 4 mg/kg ( -144.1 and -128.4 units , respectively ) than with placebo ( -58.1 units ; P < 0.0001 for both comparisons ) . Proportions of patients with American College of Rheumatology 20 % , 50 % , and 70 % improvement and with Disease Activity Score in 28 joints remission were higher in those receiving 8 mg/kg tocilizumab than in those receiving placebo ( P < 0.0001 for all comparisons ) . The safety profile of tocilizumab was consistent with the profiles in previous studies . Infections were the most common adverse and serious adverse events . CONCLUSION The findings of this study show that tocilizumab plus MTX results in greater inhibition of joint damage and improvement in physical function than does MTX alone . Tocilizumab has a well-characterized safety profile [16447237] OBJECTIVE To describe the use of the LUNDEX , a new index for comparing the long-term efficacy and tolerability of biologic therapies in rheumatoid arthritis ( RA ) patients treated in clinical practice . METHODS Patients ( n = 949 ) with active RA that had not responded to at least 2 disease-modifying antirheumatic drugs ( DMARDs ) including methotrexate , in whom biologic therapy was being initiated , were included in a structured clinical followup protocol . The protocol included collection of data on diagnosis , disease duration , previous and ongoing DMARD treatment , and date s on which biologic treatment was started and terminated . In addition , data on efficacy measures used for calculating vali date d response criteria , i.e. , the European League Against Rheumatism and American College of Rheumatology response criteria , were collected at fixed time points . Data were prospect ively registered from March 1999 through January 2004 . The LUNDEX , a new index combining the proportion of patients fulfilling a selected response criteria set with the proportion of patients adhering to a particular therapy , was design ed to compare the efficacy of the different therapies . RESULTS Etanercept had higher overall LUNDEX values compared with infliximab , mostly because of a lower rate of adherence to therapy with infliximab . The relationship between the drugs was consistent irrespective of the response criteria used . CONCLUSION The LUNDEX is a valuable tool for evaluating drug efficacy in observational studies . It has the advantage of integrating clinical response as well as adherence to therapy in a composite value . Moreover , the LUNDEX has a practical and potentially universal application independent of diagnosis and response criteria [15082480] OBJECTIVE To evaluate the efficacy and safety of monotherapy with adalimumab in patients with RA for whom previous DMARD treatment has failed . METHODS In a 26 week , double blind , placebo controlled , phase III trial , 544 patients with RA were r and omised to monotherapy with adalimumab 20 mg every other week , 20 mg weekly , 40 mg every other week , 40 mg weekly , or placebo . The primary efficacy end point was > or = 20 % improvement in the ACR core criteria ( ACR20 response ) . Secondary efficacy end points included ACR50 , ACR70 , EULAR responses , and the Disability Index of the Health Assessment Question naire ( HAQ DI ) . RESULTS After 26 weeks , patients treated with adalimumab 20 mg every other week , 20 mg weekly , 40 mg every other week , and 40 mg weekly had significantly better response rates than those treated with placebo : ACR20 ( 35.8 % , 39.3 % , 46.0 % , 53.4 % , respectively v 19.1 % ; p < or = 0.01 ) ; ACR50 ( 18.9 % , 20.5 % , 22.1 % , 35.0 % v 8.2 % ; p < or = 0.05 ) ; ACR70 ( 8.5 % , 9.8 % , 12.4 % , 18.4 % v 1.8 % ; p < or = 0.05 ) . Moderate EULAR response rates were significantly greater with adalimumab than with placebo ( 41.5 % , 48.2 % , 55.8 % , 63.1 % v 26.4 % ; p < or = 0.05 ) . Patients treated with adalimumab achieved better improvements in mean HAQ DI than those receiving placebo ( -0.29 , -0.39 , -0.38 , -0.49 v -0.07 ; p < or = 0.01 ) . No significant differences were found between adalimumab and placebo treated patients for serious adverse events , serious infections , or malignancies . Injection site reaction occurred in 10.6 % and 0.9 % of adalimumab and placebo treated patients , respectively ( p < or = 0.05 ) . CONCLUSION Among patients with RA for whom previous DMARD treatment had failed , adalimumab monotherapy achieved significant , rapid , and sustained improvements in disease activity and improved physical function and was safe and well tolerated [12115219] OBJECTIVE To compare the efficacy of combination therapy with methotrexate ( MTX ) and hydroxychloroquine ( HCQ ) , MTX and sulfasalazine ( SSZ ) , and MTX , HCQ , and SSZ in patients with rheumatoid arthritis ( RA ) . METHODS RA patients ( n = 171 ) who had not previously been treated with combinations of the study medications were r and omized to receive 1 of the 3 treatment combinations in this 2-year , double-blind , placebo-controlled protocol . HCQ was given at a dosage of 200 mg twice a day . The dosage of MTX was accelerated from 7.5 mg/week to 17.5 mg/week in all patients who were not in remission . Similarly , the dosage of SSZ was escalated from 500 mg twice a day to 1 gm twice a day in patients who were not in remission . The primary end point of the study was the percentage of patients who had a 20 % response to therapy according to the American College of Rheumatology ( ACR ) criteria at 2 years . RESULTS Intent-to-treat analysis revealed that patients receiving the triple combination responded best , with 78 % achieving an ACR 20 % response at 2 years , compared with 60 % of those treated with MTX and HCQ ( P = 0.05 ) and 49 % of those treated with MTX and SSZ ( P = 0.002 ) . Similar trends were seen for the ACR 50 % response , with 55 % , 40 % , and 29 % of patients in the 3 treatment groups , respectively , achieving these results at 2 years ( P = 0.005 for the triple combination group versus the MTX and SSZ group ) . All combination treatments were well-tolerated . Fourteen patients ( evenly distributed among the 3 groups ) withdrew from the protocol because of symptoms that were potentially related to the study medication . CONCLUSION The triple combination of MTX , SSZ , and HCQ is well-tolerated , and its efficacy is superior to that of the double combination of MTX and SSZ and is marginally superior to that of the double combination of MTX and HCQ [19665644] BACKGROUND New treatment strategies for early rheumatoid arthritis are evolving rapidly . We aim ed to compare addition of conventional disease-modifying antirheumatic drugs ( sulfasalazine and hydroxychloroquine ) with addition of a tumour necrosis factor antagonist ( infliximab ) to methotrexate in patients with early rheumatoid arthritis . METHODS We undertook a r and omised trial in 15 rheumatology units in Sweden . We enrolled patients with early rheumatoid arthritis ( symptom duration < 1 year ) and administered methotrexate ( up to 20 mg per week ) . After 3 - 4 months , those who had not achieved low disease activity but who could tolerate methotrexate were r and omly allocated by computer addition of either sulfasalazine and hydroxychloroquine or infliximab . Primary outcome was achievement of a good response according to European League Against Rheumatism ( EULAR ) criteria at 12 months . Patients were followed up to 24 months ; here , we present findings at 12 months . Analysis was by intention to treat and we used non-responder imputation . The Swefot ( Swedish Pharmacotherapy ) study is registered in the WHO data base at the Karolinska University Hospital , number CT20080004 . FINDINGS 487 patients were initially enrolled . Of 258 who had not achieved low disease activity with methotrexate , 130 were allocated sulfasalazine and hydroxychloroquine and 128 were assigned infliximab . 32 of 130 ( 25 % ) patients allocated sulfasalazine and hydroxychloroquine achieved the primary outcome compared with 50 of 128 ( 39 % ) assigned infliximab ( risk ratio 1.59 [ 95 % CI 1.10 - 2.30 ] , p=0.0160 ) . Adverse events were balanced fairly well between the two groups and accorded with known adverse events of the drugs used . No deaths occurred in either group . INTERPRETATION In patients with early rheumatoid arthritis in whom methotrexate treatment failed , addition of a tumour necrosis factor antagonist to methotrexate monotherapy is clinical ly superior to addition of conventional disease-modifying antirheumatic drugs . FUNDING Swedish Rheumatism Association , Schering-Plough [16984942] Objective : To examine the impact of added abatacept treatment on health related quality of life ( HRQoL ) in patients with rheumatoid arthritis ( RA ) who have inadequate response to methotrexate ( MTX ) . Methods : The impact of abatacept treatment on HRQoL was examined in a longitudinal , r and omised double blind , placebo controlled clinical trial . Effects of treatment on HRQoL were examined using repeated measures analysis of covariance and comparing rates of change in HRQoL across treatment groups . The relationship between American College of Rheumatology ( ACR ) clinical markers and disease duration with changes in HRQoL indicators was also examined . Finally , a responder analysis was used to examine the percentage of patients who improved by 0.5 SD in 12 months or who reached the normative levels seen in the US general population . Results : Statistically significant improvements in the abatacept group relative to controls were observed across a range of HRQoL measures , including physical function , fatigue , all eight domains of the SF-36 , and the physical and mental component summaries ( PCS and MCS ) . Improvements were seen as early as day 29 for fatigue and for five out of eight SF-36 domains . By day 169 , all HRQoL measures were significantly better with abatacept than with placebo . HRQoL gains were associated with greater ACR clinical improvement , and the effects were consistent for patients with different disease duration . A significantly greater percentage of patients treated with abatacept reached normative levels of PCS , MCS , physical functioning , and fatigue compared with patients treated with MTX alone . Conclusion : Combined abatacept and MTX treatment produces significant improvements across a wide range of HRQoL domains in patients with RA [11096165] BACKGROUND Etanercept , which blocks the action of tumor necrosis factor , reduces disease activity in patients with long-st and ing rheumatoid arthritis . Its efficacy in reducing disease activity and preventing joint damage in patients with active early rheumatoid arthritis is unknown . METHODS We treated 632 patients with early rheumatoid arthritis with either twice-weekly subcutaneous etanercept ( 10 or 25 mg ) or weekly oral methotrexate ( mean , 19 mg per week ) for 12 months . Clinical response was defined as the percent improvement in disease activity according to the criteria of the American College of Rheumatology . Bone erosion and joint-space narrowing were measured radiographically and scored with use of the Sharp scale . On this scale , an increase of 1 point represents one new erosion or minimal narrowing . RESULTS As compared with patients who received methotrexate , patients who received the 25-mg dose of etanercept had a more rapid rate of improvement , with significantly more patients having 20 percent , 50 percent , and 70 percent improvement in disease activity during the first six months ( P<0.05 ) . The mean increase in the erosion score during the first 6 months was 0.30 in the group assigned to receive 25 mg of etanercept and 0.68 in the methotrexate group ( P= 0.001 ) , and the respective increases during the first 12 months were 0.47 and 1.03 ( P=0.002 ) . Among patients who received the 25-mg dose of etanercept , 72 percent had no increase in the erosion score , as compared with 60 percent of patients in the methotrexate group ( P=0.007 ) . This group of patients also had fewer adverse events ( P=0.02 ) and fewer infections ( P= 0.006 ) than the group that was treated with methotrexate . CONCLUSIONS As compared with oral methotrexate , subcutaneous [ corrected ] etanercept acted more rapidly to decrease symptoms and slow joint damage in patients with early active rheumatoid arthritis [16935912] Objective : To investigate the efficacy and safety of abatacept in combination with etanercept in patients with active rheumatoid arthritis during a 1-year , r and omised , placebo-controlled , double-blind phase , followed by an open-label , long-term extension ( LTE ) . Methods : Patients continued etanercept ( 25 mg twice weekly ) and were r and omised to receive abatacept 2 mg/kg ( n = 85 ) or placebo ( n = 36 ) . As the effective dose of abatacept was established as 10 mg/kg in a separate trial , all patients received abatacept 10 mg/kg and etanercept during the LTE . Results : A total of 121 patients were r and omised ; 80 completed double-blind treatment and entered the LTE . During double-blind treatment , the difference in the percentage of patients achieving the primary end point ( modified American College of Rheumatology ( ACR ) 20 response at 6 months ) was not significant between groups ( 48.2 % v 30.6 % ; p = 0.072 ) . At 1 year , no notable changes in modified ACR responses were observed . Subsequent to the dosing change , similar modified ACR responses were seen during the LTE . Significant improvements in quality of life were observed with abatacept and etanercept versus placebo and etanercept in five of the eight short-form 36 subscales at 1 year . More abatacept and etanercept-treated patients experienced serious adverse events ( SAEs ) at 1 year than patients receiving placebo and etanercept ( 16.5 % v 2.8 % ) , with 3.5 % v 0 % experiencing serious infections . Conclusion : The combination of abatacept ( at a dose of 2 mg/kg during the double-blind phase and 10 mg/kg during the LTE ) and etanercept was associated with an increase in SAEs , including serious infections , with limited clinical effect . On the basis of the limited efficacy findings and safety concerns , abatacept in combination with etanercept should not be used for rheumatoid arthritis treatment [15188350] OBJECTIVE To determine in a placebo-controlled , double-blind trial the safety profile of daily anakinra ( Kineret ) use in patients with active rheumatoid arthritis ( RA ) and concurrent comorbid conditions . METHODS In 169 centers in 9 countries , 1,414 patients with active RA were r and omly assigned to receive either anakinra ( 100 mg ) or placebo treatment ( 4:1 anakinra-to-placebo allocation ratio ) , with study drug administered by daily subcutaneous injection for 6 months . The current post hoc analysis assessed baseline comorbid conditions , and patients were considered at high risk for the occurrence of adverse events if they had a history of at least one of the following : cardiovascular event , pulmonary event , central nervous system-related event , infection , diabetes , malignancy , or renal impairment . Within each treatment group ( anakinra or placebo ) , incidence rates were summarized for serious adverse events , infectious events , and serious infectious events in high-risk patients and compared with these incidence rates in patients without comorbid conditions . RESULTS The majority of patients in the trial had one or more comorbid conditions . In these high-risk patients , there were no differences in the incidence of serious adverse events or infectious events between treatment groups . The incidence of serious infectious events with anakinra use was similar between high-risk patients ( 2.5 % ) and the entire study population ( 2.1 % ) and was not attributable to any single comorbidity . CONCLUSION Results of the analysis of adverse events in patients with active RA and coexisting comorbidities suggest that the favorable safety profile of anakinra is maintained in a high-risk patient population [12355476] OBJECTIVE Patients with rheumatoid arthritis ( RA ) have been shown to have an increased susceptibility to the development of infections . The exact causes of this increased risk are unknown , but may relate to immunologic disturbances associated with the disease or to the immunosuppressive effects of agents used in its treatment . This study was undertaken to identify predictors of serious infections among patients with RA . Identification of such factors is the necessary first step in reducing the excess risk of infection in RA . METHODS Members of a population -based incidence cohort of Rochester , Minnesota residents ages > or=18 years , who had been diagnosed with RA between 1955 and 1994 , were followed up longitudinally through their complete medical records until January 1 , 2000 . We examined potential risk factors for the development of all objective ly confirmed ( by microbiology or radiology ) infections and for infections requiring hospitalization . Potential risk factors included RA severity measures ( rheumatoid factor positivity , elevated erythrocyte sedimentation rate , extraarticular manifestations of RA , and functional status ) , comorbidities ( diabetes mellitus , alcoholism , and chronic lung disease ) , and other risk factors for infection ( presence of leukopenia , smoking ) . Predictors were identified using multivariate time-dependent Cox proportional hazards modeling . RESULTS The 609 RA patients in the cohort had a total followup time of 7,729.7 person-years ( mean 12.7 years per patient ) . A total of 389 patients ( 64 % ) had at least 1 infection with objective confirmation , and 290 ( 48 % ) had at least 1 infection requiring hospitalization . Increasing age , presence of extraarticular manifestations of RA , leukopenia , and comorbidities ( chronic lung disease , alcoholism , organic brain disease , and diabetes mellitus ) , as well as use of corticosteroids , were strong predictors of infection ( P < 0.004 ) in both univariate and multivariate analyses . Notably , use of disease-modifying antirheumatic drugs was not associated with increased risk of infection in multivariate analyses , after adjustment for demographic characteristics , comorbidities , and disease-related variables . CONCLUSION We identified a number of strong predictors of infections in a population -based cohort of patients with RA . These results can be used to prospect ively identify high-risk patients , who may benefit from closer followup and implementation of preventive strategies [15146409] OBJECTIVE Tumor necrosis factor ( TNF ) is an important proinflammatory cytokine that mediates inflammatory synovitis and articular matrix degradation in rheumatoid arthritis ( RA ) . We investigated the ability of adalimumab , a human anti-TNF monoclonal antibody , to inhibit the progression of structural joint damage , reduce the signs and symptoms , and improve physical function in patients with active RA receiving concomitant treatment with methotrexate ( MTX ) . METHODS In this multicenter , 52-week , double-blind , placebo-controlled study , 619 patients with active RA who had an inadequate response to MTX were r and omized to receive adalimumab 40 mg subcutaneously every other week ( n = 207 ) , adalimumab 20 mg subcutaneously every week ( n = 212 ) , or placebo ( n = 200 ) plus concomitant MTX . The primary efficacy end points were radiographic progression at week 52 ( total Sharp score by a modified method [ TSS ] ) , clinical response at week 24 ( improvements of at least 20 % in the American College of Rheumatology core criteria [ ACR20 ] ) , and physical function at week 52 ( disability index of the Health Assessment Question naire [ HAQ ] ) . RESULTS At week 52 , there was statistically significantly less radiographic progression , as measured by the change in TSS , in the patients receiving adalimumab either 40 mg every other week ( mean + /- SD change 0.1 + /- 4.8 ) or 20 mg weekly ( 0.8 + /- 4.9 ) as compared with that in the placebo group ( 2.7 + /- 6.8 ) ( P < or = 0.001 for each comparison ) . In addition , there were statistically significant changes in the components of the TSS . At week 24 , ACR20 responses were achieved by 63 % and 61 % of patients in the adalimumab 40 mg every other week and 20 mg weekly groups , respectively , versus 30 % of patients in the placebo group ( P < or = 0.001 for each comparison ) . At week 52 , ACR20 responses were achieved by 59 % and 55 % of patients taking adalimumab 40 mg every other week and 20 mg weekly , respectively , versus 24 % of patients taking placebo ( P < or = 0.001 for each comparison ) . At week 52 , physical function as measured by the HAQ demonstrated statistically significant improvement with adalimumab 40 mg every other week and 20 mg weekly compared with placebo ( mean change in HAQ score -0.59 and -0.61 , respectively , versus -0.25 ; P < or = 0.001 for each comparison ) . A total of 467 patients ( 75.4 % ) completed 52 weeks of treatment . Adalimumab was generally well tolerated . Discontinuations occurred in 22.0 % of adalimumab-treated patients and in 30.0 % of placebo-treated patients . The rate of adverse events ( both serious and nonserious ) was comparable in the adalimumab and placebo groups , although the proportion of patients reporting serious infections was higher in patients receiving adalimumab ( 3.8 % ) than in those receiving placebo ( 0.5 % ) ( P < or = 0.02 ) , and was highest in the patients receiving 40 mg every other week . CONCLUSION In this 52-week trial , adalimumab was more effective than placebo at inhibiting the progression of structural joint damage , reducing the signs and symptoms , and improving physical function in patients with active RA who had demonstrated an incomplete response to MTX [17985409] OBJECTIVE To evaluate the effectiveness and safety of anti-tumor necrosis factor ( anti-TNF ) therapies in rheumatoid arthritis ( RA ) , and to identify the factors involved in this response . METHODS Dynamic prospect i ve cohort study of patients with RA treated with anti-TNF under clinical practice conditions . Effectiveness was evaluated using Disease Activity Score ( DAS ) 28 , European League Against Rheumatism ( EULAR ) response , Health Assessment Question naire ( HAQ ) , and time to treatment failure . Prior adherence was evaluated retrospectively and safety was evaluated by adverse events ( AE ) . The analysis was restricted to anti-TNF-naive patients . RESULTS The study included 161 patients treated for RA during 6 years ( 60 infliximab , 79 etanercept , and 22 adalimumab ) . At 6 months , 15 % reached a good EULAR response and 38 % a moderate response . A mean decrease of -1.5 ( p < 0.0001 ) was observed in the DAS28 and of -0.34 in the HAQ ( p < 0.0001 ) ; however , women showed poorer progress in terms of DAS and HAQ . In the first year , 64.3 % did not experience treatment failure and this figure was 50.5 % after 2 years . In one-third , glucocorticoids were withdrawn and in the remainder the dose was reduced by 50 % . Adherence to treatment , selection of etanercept , and intensification of infliximab were associated with a lower probability of premature failure in the multivariate model . AE were similar to other those in studies and no outst and ing differences in safety were found between the 3 anti-TNF therapies . CONCLUSIONS Anti-TNF treatments are effective and safe , reducing the activity of the disease , disability , and the need for corticosteroids . Patients who displayed good adherence prior to the anti-TNF treatment and were treated with etanercept or with increasing doses of infliximab had the best chance of displaying a response [8609945] BACKGROUND Rheumatoid arthritis is a common disease that causes substantial morbidity and mortality . The responses of patients with rheumatoid arthritis to treatment with a single so-called disease-modifying drug , such as methotrexate , are often suboptimal . Despite limited data , many patients are treated with combinations of these drugs . METHODS We enrolled 102 patients with rheumatoid arthritis and poor responses to at least one disease-modifying drug in a two-year , double-blind , r and omized study of treatment with methotrexate alone ( 7.5 to 17.5 mg per week ) , the combination of sulfasalazine ( 500 mg twice daily ) and hydroxychloroquine ( 200 mg twice daily ) , or all three drugs . The dose of methotrexate was adjusted in an attempt to achieve remission in all patients . The primary and point of the study was the successful completion of two years of treatment with 50 percent improvement in composite symptoms of arthritis and no evidence of drug toxicity . RESULTS Fifty of the 102 patients had 50 percent improvement at nine months and maintained at least that degree of improvement for two years without evidence of major drug toxicity . Among them were 24 of 31 patients treated with all three drugs ( 77 percent ) , 12 of 36 patients treated with methotrexate alone ( 33 percent , P < 0.001 for the comparison with the three-drug group ) , and 14 of 35 patients treated with sulfasalazine and hydroxychloroquine ( 40 percent ) , P = 0.003 for the comparison with the three-drug group ) . Seven patients in the methotrexate group and three patients in each of the other two groups discontinued treatment because of drug toxicity . CONCLUSIONS In patients with rheumatoid arthritis , combination therapy with methotrexate , sulfasalazine , and hydroxychloroquine is more effective than either methotrexate alone or a combination of sulfasalazine , and hydroxychloroquine [16785475] Context Abatacept , an agent that selectively modulates the co-stimulatory signal required for T-cell activation , may benefit some patients with rheumatoid arthritis . Contribution This 1-year , r and omized , double-blind trial compared once-monthly infusions of abatacept with placebo in 652 patients with symptomatic rheumatoid arthritis despite ongoing methotrexate treatment . Compared with placebo recipients , patients who received abatacept more often had improved physical function , more frequently met st and ard response criteria , and less often had radiographic progression of joint damage . They also had serious infections ( 2.5 % vs. 0.9 % ) and infusion reactions more often . Implication s Adding abatacept can reduce disease activity in patients with rheumatoid arthritis and an inadequate response to methotrexate . The Editors Rheumatoid arthritis is characterized by synovial membrane hyperplasia and inflammatory cell infiltrate , including activated T cells ( 1 ) . T cells contribute to the initiation and perpetuation of rheumatoid arthritis immunopathology , leading to inflammation and , ultimately , joint destruction . Activated T cells proliferate and induce monocytes , macrophages , and synovial fibroblasts to produce proinflammatory cytokines , such as tumor necrosis factor- , interleukin-1 , and interleukin-6 ( 1 ) , and stimulate osteoclastogenesis and matrix metalloproteinase secretion ( 2 ) , as well as immunoglobulin production by B cells ( 3 ) . The central role of activated T cells in rheumatoid arthritis immunopathology makes T-cell activation a rational therapeutic target . T cells require 2 signals for full activation : an antigen-specific signal ( signal 1 ) and a co-stimulatory signal ( signal 2 ) ( 4 ) . One of the best-characterized co-stimulatory pathways is the engagement of CD80 or CD86 on antigen-presenting cells with CD28 on T cells ( 5 ) . In the normal immune response , endogenous cytotoxic T-lymphocyte antigen-4 ( CTLA-4 ) downregulates CD28-mediated T-cell activation by binding to CD80 or CD86 with higher avidity than CD28 ( 6 ) . Abatacept is a soluble , recombinant , fully human fusion protein , comprising the extracellular domain of CTLA-4 and the Fc portion of IgG1 , modified to prevent complement fixation . Abatacept is the first in a new class of agents for treating rheumatoid arthritis that selectively modulate the co-stimulatory signal required for full T-cell activation . A phase IIa study of patients with rheumatoid arthritis and an inadequate response to disease-modifying antirheumatic drugs showed the efficacy of abatacept as monotherapy ( 7 ) . In a phase IIb study of abatacept plus methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate , signs and symptoms of rheumatoid arthritis , physical function , and health-related quality of life statistically significantly improved over 1 year ( 8 , 9 ) . We present findings from the phase III , 1-year Abatacept in Inadequate Responders to Methotrexate ( AIM ) trial , which was design ed to further evaluate the safety and clinical efficacy of abatacept plus methotrexate and to assess the effects of abatacept on the radiographic progression of structural damage . Methods The institutional review boards or independent ethics committees approved a common clinical protocol for each site , and we performed the study in accordance with the ethical principles of the Declaration of Helsinki . All patients provided written informed consent to the study protocol before r and omization . Patients Eligible patients were at least 18 years of age , had had rheumatoid arthritis for at least 1 year , and met the American Rheumatism Association criteria for rheumatoid arthritis ( 10 ) . Rheumatoid arthritis was persistent and active despite methotrexate treatment . All patients must have been treated with methotrexate ( 15 mg/wk ) for 3 months or longer , with a stable dose for 28 days before enrollment . We required patients to undergo a washout of all other disease-modifying antirheumatic drugs at least 28 days before r and omization . We allowed corticosteroid use , with dosages equal to 10 mg of prednisone or less per day , stabilized for 25 days before r and omization . At r and omization , we required patients to have 10 or more swollen joints , 12 or more tender joints , and C-reactive protein levels of 10.0 mg/L or greater ( normal range , 1.0 mg/L to 4.0 mg/L ) while receiving methotrexate . We required tuberculin skin testing before r and omization . We excluded patients with a positive tuberculin skin test result unless they had completed treatment for latent tuberculosis before enrollment . Study Design Our 1-year , multicenter , multinational , r and omized , double-blind , placebo-controlled study aim ed to compare the efficacy and safety of abatacept versus placebo in combination with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate treatment . We used a central r and omization system , and the Drug Management Group within Bristol-Myers Squibb , Princeton , New Jersey , generated the r and omization schedule . Stratification per site was not performed . Patients were r and omly assigned in a 2:1 ratio to receive either a fixed dose of abatacept , approximately 10 mg/kg of body weight , or placebo . Patients weighing less than 60 kg , 60 to 100 kg , or more than 100 kg received 500 mg , 750 mg , or 1000 mg of abatacept , respectively . We administered study medication by 30-minute intravenous infusion on days 1 , 15 , and 29 and then every 28 days up to and including day 337 . No premedication was required . The protocol specified that all patients were to receive methotrexate , 15 mg or more per week , although methotrexate at 10 mg per week was acceptable if the patient had a history of toxicity . During the first 6 months , we did not allow adjustments in methotrexate dose , except in cases of toxicity . We permitted use of stable dosages of nonsteroidal anti-inflammatory drugs and corticosteroid dosages equal to 10 mg of prednisone or less per day . Between 6 and 12 months , we allowed the following adjustments , as the investigator deemed necessary : 1 ) adjustment in methotrexate dose , 2 ) addition of 1 other disease-modifying antirheumatic drug ( hydroxychloroquine , sulfasalazine , gold , or azathioprine ) , or 3 ) adjustment in corticosteroid dose equal to 10 mg of prednisone or less per day . However , investigators were blinded to treatment group assignment throughout the 1-year study . Clinical Efficacy Measures Our 3 primary objectives were to evaluate the proportion of patients in each group with a 20 % improvement in American College of Rheumatology ( ACR ) response criteria ( ACR 20 ) at 6 months , the proportion of patients in each group with clinical ly significant improvement ( 0.3 unit ) in the Health Assessment Question naire Disability Index ( HAQ-DI ) score ( 11 ) at 1 year , and the radiographic progression of joint erosions ( assessed by comparing changes from baseline in the Genant-modified Sharp score ) ( 12 , 13 ) at 1 year . Table 1 summarizes the outcome measures used to assess the response to treatment . Table 1 . Outcome Measures for Assessing Response to Treatment of Rheumatoid Arthritis * Secondary objectives included assessing ACR 50 and ACR 70 responses at 6 months and all ACR responses at 1 year . In addition , we determined the proportions of patients achieving a major clinical response and a protocol -defined extended major clinical response at 1 year . We also assessed changes in disease activity by using the Disease Activity Score 28 ( DAS28 ) ( 20 , 21 ) . We assessed improvements in physical function over 1 year by using the HAQ-DI , which measures physical function during daily activities ( 22 ) . We evaluated changes in health-related quality of life by using the Medical Outcomes Study Short Form-36 Health Survey ( SF-36 ) ( 17 ) , which evaluates physical and mental health status ( Table 1 ) ( 18 , 19 ) . Physicians blinded to treatment group assignment performed assessment s at enrollment and at every visit before treatment administration on days 1 , 15 , and 29 ; every 28 days up to and including day 169 ( 6 months ) ; and on days 225 , 281 , and 365 ( 1 year ) . Radiographic Evaluation We performed st and ardized radiography of the h and s or wrists and feet at baseline and at 1 year or upon early termination ( if applicable ) . Two independent expert readers who were blinded to treatment group assignment , chronological order of radiography , and patients ' clinical response assessed all radiographic images for changes in erosion and joint-space narrowing by using the Genant-modified Sharp scoring system . Safety and Immunogenicity We monitored all patients who received at least 1 dose of the study medication for adverse events , serious adverse events , infusion reactions , clinical laboratory test abnormalities , and clinical ly significant changes in vital signs . Adverse events were self-reported by the patient and elicited by general question ing and examination at each visit . We attributed an adverse event to the study treatment on the basis of the investigator 's opinion , and we deemed an event as serious by st and ard regulatory definition . An external safety advisory panel , consisting of 5 physicians ( 3 rheumatologists , 1 oncologist , and 1 infectious disease expert ) , assessed overall safety in a blinded fashion by using reports of adverse events and laboratory results on a quarterly basis . We obtained serum sample s before infusions on days 1 , 29 , 85 , 169 , 281 , and 365 or 28 days after the last dose of the study medication in patients who discontinued before 1 year . We assessed immunogenicity by immunoassay to measure the antibody response to the entire abatacept molecule and also specifically to the CTLA-4 portion of the molecule ( 7 ) . Statistical Analysis The protocol estimated that 680 patients would need to be enrolled to r and omly assign 540 patients . We based sample sizes on a 5 % level of significance ( 2-tailed ) . The study had 99 % power to detect a difference of 20 % in ACR 20 between the 2 groups . On the basis of the [18383539] OBJECTIVE To assess the efficacy , safety , and pharmacology of subcutaneous administration of golimumab in patients with active rheumatoid arthritis ( RA ) despite treatment with methotrexate ( MTX ) . METHODS Patients were r and omly assigned in a double-blinded manner to receive injections of placebo plus MTX or 50 mg or 100 mg golimumab every 2 or 4 weeks plus MTX through week 48 . Patients originally assigned to receive injections every 2 weeks had the interval increased to every 4 weeks starting at week 20 . The primary end point was the proportion of patients meeting the American College of Rheumatology 20 % improvement criteria ( achieving an ACR20 response ) at week 16 . The study was powered to detect a difference in the primary end point when the combined golimumab groups and at least 1 of the individual dose groups were compared with placebo . RESULTS The primary end point was attained . Sixty-one percent of patients in the combined golimumab plus MTX dose groups achieved an ACR20 response at week 16 compared with 37 % of patients in the placebo plus MTX group ( P=0.010 ) . In addition , 79 % of patients in the group receiving 100 mg golimumab every 2 weeks achieved an ACR20 response ( P<0.001 versus placebo ) . Through week 20 ( after which patients receiving placebo were switched to active infliximab therapy ) , serious adverse events were reported in 9 % of patients in the combined golimumab groups and in 6 % of patients in the placebo group . CONCLUSION Golimumab plus MTX effectively reduces the signs and symptoms of RA and is generally well tolerated in patients with an inadequate response to MTX [16508932] OBJECTIVE To evaluate the impact of infliximab therapy on the employment status of patients with early rheumatoid arthritis ( RA ) . METHODS Methotrexate (MTX)-naive patients with active early RA were r and omly allocated to receive MTX plus placebo or MTX plus infliximab ( 3 mg/kg or 6 mg/kg ) at weeks 0 , 2 , and 6 and then every 8 weeks through week 46 . Data for patients younger than age 65 years were included in the analyses . A patient was categorized as employable if he or she was employed or felt well enough to work if a job were available . RESULTS The change in actual employment was not significantly different between patients receiving MTX plus infliximab and those receiving MTX plus placebo ( 0.5 % versus 1.3 % ; P > 0.5 ) . However , the proportion of patients whose status changed from employable at baseline to unemployable at week 54 was smaller in the group receiving MTX plus infliximab compared with that in the group receiving MTX alone ( 8 % versus 14 % ; P = 0.05 ) . Patients who were treated with infliximab plus MTX had a significantly greater likelihood of improvement rather than deterioration in employability ( odds ratio 2.4 ; P < 0.001 ) ; this likelihood was not significantly greater in patients receiving MTX alone . The proportion of employed patients who lost workdays during the trial was smaller in the MTX plus infliximab group than in the MTX-alone group ( P = 0.010 ) . CONCLUSION The actual employment rates among patients in the 2 treatment groups were not different . However , patients with early RA who were treated with MTX plus infliximab had a higher probability of maintaining their employability compared with those who were treated with MTX alone [14719195] OBJECTIVE This study , known as STAR ( Safety Trial of Adalimumab in Rheumatoid Arthritis ) , evaluated the safety and efficacy of adalimumab ( Humira ) , a fully human monoclonal tumor necrosis factor-alpha ( TNF-a ) antibody , when given with st and ard antirheumatic therapy in patients with active rheumatoid arthritis ( RA ) not adequately responding to such therapies . St and ard antirheumatic therapy included traditional disease modifying antirheumatic drugs ( DMARD ) , low dose corticosteroids , nonsteroidal antiinflammatory drugs ( NSAID ) , and /or analgesics . METHODS In this 24-week , double-blind , placebo-controlled study , 636 patients with RA were r and omly assigned to receive adalimumab 40 mg subcutaneously ( sc ) every other week ( n = 318 ) or placebo ( n = 318 ) while continuing st and ard antirheumatic therapy . The frequencies of adverse events , serious adverse events , severe or life-threatening adverse events , adverse events leading to withdrawal , infection , or serious infection were the primary endpoints . Secondary endpoints were determined by American College of Rheumatology ( ACR ) response criteria . RESULTS During the study , the majority of patients received concomitant traditional DMARD ( 83.5 % ) and /or corticosteroids , NSAID , and /or analgesics ( 97.3 % ) . Overall , 56.0 % of patients continued treatment with one , 23.6 % with 2 , and 3.9 % with > or = 3 traditional DMARD . At 24 weeks , there were no statistically significant differences between the adalimumab and placebo groups in their respective rates of adverse events ( 86.5 % vs 82.7 % ) , serious adverse events ( 5.3 % vs 6.9 % ) , severe or life-threatening adverse events ( 11.9 % vs 15.4 % ) , or those leading to withdrawal ( 2.8 % vs 2.2 % ) . There were also no statistically significant differences in the rates of infections ( 52.2 % vs 49.4 % ) or serious infections ( 1.3 % vs 1.9 % ) between the groups . The incidence and types of adverse events did not vary between adalimumab- and placebo-treated patients by the number of concomitant traditional DMARD ( 0 , 1 , or 2 ) . Adalimumab-treated patients compared with placebo-treated patients achieved statistically superior ACR20 ( 52.8 % vs 34.9 % ) , ACR50 ( 28.9 % vs 11.3 % ) , and ACR70 ( 14.8 % vs 3.5 % ) response rates at Week 24 ( p < or = 0.001 ) . CONCLUSION This study demonstrated that addition of adalimumab 40 mg given sc every other week to concomitant st and ard antirheumatic therapy is well tolerated and provides significant improvements in signs and symptoms of RA . The data indicate that adalimumab is a safe and effective therapeutic option in patients with active RA who have an inadequate response to st and ard antirheumatic therapy , including one or more traditional DMARD , corticosteroids , NSAID , and analgesics [1794519] The objective of this work is to compare the adherence to therapy of patients receiving etanercept and infliximab during first tumour necrosis factor (TNF)-blocking treatment course in rheumatoid arthritis . Special emphasis is placed on potential predictors for treatment termination and the impact of concomitant methotrexate ( MTX ) or other disease-modifying antirheumatic drugs ( DMARDs ) . Patients ( n = 1,161 ) with active rheumatoid arthritis , not responding to at least two DMARDs including MTX starting etanercept or infliximab therapy for the first time , were included in a structured clinical follow-up protocol . Information on diagnosis , disease duration , previous and ongoing DMARDs , treatment start and termination , as well as cause of withdrawal was prospect ively collected during the period of March 1999 through December 2004 . Patients were divided into six groups according to TNF-blocking drugs and concomitant DMARDs . Five-year level ( one-year ) of adherence to therapy was 36 % ( 69 % ) for patients receiving infliximab in combination with MTX compared with 65 % ( 89 % ) for patients treated with etanercept and MTX ( p < 0.001 ) . Cox regression models showed that the risk for premature treatment termination of patients treated with infliximab was threefold higher than for etanercept ( p < 0.001 ) . Also , the regression analysis showed that patients receiving concomitant MTX had better treatment continuation than patients treated solely with TNF blockers ( p < 0.001 ) . Moreover , patients receiving concomitant MTX had superior drug survival than patients receiving other concomitant DMARDs ( p < 0.010 ) . The superior effect of MTX was associated primarily with fewer treatment terminations because of adverse events . In addition , the study identifies low C-reactive protein level , high age , elevated health assessment question naire score , and higher previous number of DMARDs as predictors of premature treatment termination . In summary , treatment with etanercept has higher adherence to therapy than treatment with infliximab . Concomitant MTX is associated with improved treatment continuation of biologics when compared with both TNF blockers as monotherapy and TNF blockers combined with other DMARDs Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: OBJECTIVES Rheumatoid arthritis ( RA ) is a chronic inflammatory disease associated with increasing disability , reduced quality of life and substantial costs ( as a result of both intervention acquisition and hospitalisation ) . The objective was to assess the clinical effectiveness and cost-effectiveness of seven biologic disease-modifying antirheumatic drugs ( bDMARDs ) compared with each other and conventional disease-modifying antirheumatic drugs ( cDMARDs ) . Sensitivity analyses were undertaken to explore the impact of including RCTs with a small proportion of bDMARD experienced patients and where MTX exposure was deemed insufficient . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

16625584

[407818] Ninety-five children with difficult to treat asthma were given cromolyn in double-blind , crossover studies . Of these , 70 were studied for the next five to six years by open trial cromolyn prophylaxis to determine decreasing dependency on bronchodilators or corticosteroids . Evaluated at two-month intervals , 28 children required prednisone and bronchodilators , 37 required round-the-clock bronchodilators only and five required neither . Peak expiratory flow rates were below 80 % of predicted normal in eight patients , the remaining 62 showed reversibility of airways obstruction . Exercise-induced asthma was reported by 44 during the first two years but persistent improvement in exercise tolerance occurred in 24 patients . IgE specific RAST indicated a continuing extrinsic element in the etiology of 38 of 45 patients tested . Cromolyn was an effective prophylaxis for children with chronic asthma ; however , it was difficult to evaluate in 17 steroid-dependent subjects . Attempts to reduce the need for and especially to discontinue steroids were not as successful as other reports indicate [12949315] OBJECTIVE To compare the effects of 2 nebulizable controller asthma medications on caregiver and pediatric quality of life . METHODS In this 52-week , r and omized trial , children aged 2 to 6 years with mild to moderate persistent asthma received budesonide inhalation suspension 0.5 mg ( total daily dose ) once or twice daily ( n = 168 ) or cromolyn sodium nebulizer solution 20 mg 4 times daily ( n = 167 ) for 8 weeks , with dosage adjustment thereafter at the investigators ' discretion . The Pediatric Asthma Caregiver 's Quality of Life Question naire ( PACQLQ ) , Compliance/Caregiver Satisfaction Question naire ( CCSQ ) , Modified Child Health Question naire-Parent Form 50 ( CHQ-PF50 ) , and Functional Status-II(R ) ( FS-II[R ] ) Question naire were administered at baseline and weeks 8 , 28 , and 52 . Global assessment s of ease of asthma management and child health status were obtained from caregivers and physicians at the end of the study . RESULTS Improvements from baseline in domain-specific ( activities and emotional function ) and total PACQLQ scores were greater at each time point ( weeks 8 , 28 , and 52 ) for caregivers of patients treated with budesonide compared with caregivers of patients receiving cromolyn sodium . Only the budesonide group met the criterion for a clinical ly important improvement ( > or=0.5 unit change ) in all PACQLQ domains by week 8 , which was maintained at weeks 28 and 52 . Moreover , improvements surpassed the criterion for moderate clinical importance ( 1.0 unit change ) in all PACQLQ domains for the budesonide group , but this level of improvement was only achieved in the activities domain ( at week 28 ) for the cromolyn sodium group . Based on the CCSQ , budesonide result ed in greater caregiver satisfaction , treatment convenience , ease of use , and compliance compared with cromolyn sodium . Thus , 90.7 % of caregivers in the budesonide group were " completely or very satisfied " compared with 53.4 % in the cromolyn sodium group . Over half ( 54.6 % ) of caregivers in the budesonide group rated budesonide " highly or very convenient " compared with 23 % for cromolyn sodium ; 77 % rated budesonide " extremely or very easy " to use compared with 47 % for cromolyn . Adherence with daily medication regimens was reported for 76 % of children in the budesonide group compared with 57 % in the cromolyn sodium group . Child health status , as indicated by mean FS-II(R ) scores , showed improvements from baseline in both groups at weeks 8 , 28 , and 52 . There was a trend for these improvements to be superior in the budesonide group . Additionally , budesonide was superior to cromolyn sodium in caregiver and physician global assessment s. At the end of the study , 76 % of caregivers of children receiving budesonide reported asthma management to be " a great deal easier " compared with the start of the study , and 74 % rated the overall health status of their child as " much better now than 1 year ago . " In contrast , only 29 % and 37 % of caregivers whose children received cromolyn sodium provided these respective ratings . CONCLUSIONS Budesonide inhalation suspension improved the quality of life for caregivers of children with asthma . Caregivers of children treated with budesonide had significantly fewer limitations in daily activities and emotional functioning compared with caregivers of children treated with cromolyn sodium nebulizer solution . The improvements in caregiver quality of life occurred earlier with budesonide compared with cromolyn sodium . Only caregivers in the budesonide group had a clinical ly important mean change from baseline in all PACQLQ domains by week 8 . These benefits were maintained at week 52 . Children treated with budesonide inhalation suspension and cromolyn sodium experienced improvements in health status , assessed using the FS-II(R ) . The greatest differences between treatments were seen in the disease-specific portion of the FS-II(R ) , which relates impairments in functional status to the child 's illness . Caregiver and physician global assessment indicated significantly better overall child health after 1 year of treatment with budesonide , supporting an improvement in health status . Clinical trials in children 4 to 16 years of age with asthma have demonstrated greater effectiveness of inhaled corticosteroids versus cromolyn sodium on several clinical measures of efficacy . Measures of asthma control in this study , reported in detail elsewhere [ Leflein et al. Pediatrics 2002;109:866 - 872 ] , also have shown greater improvements with budesonide therapy . Treatment with budesonide inhalation suspension result ed in a significantly lower mean rate of asthma exacerbations , significantly longer times to first asthma exacerbation , significantly longer times to first additional use of chronic asthma therapy , and significant improvements in asthma symptom scores and breakthrough medication use compared with cromolyn sodium therapy . Additionally , children receiving budesonide inhalation suspension experienced more symptom-free days and episode-free days compared with children receiving cromolyn sodium . Safety profiles were similar between the 2 treatment groups . Budesonide inhalation suspension was associated with significantly greater caregiver satisfaction , convenience , ease of use , and compliance compared with cromolyn sodium nebulizer solution . This greater caregiver satisfaction and quality of life may be related to the greater asthma control achieved in children treated with budesonide therapy compared with cromolyn sodium . In addition , the convenience of once- or twice-daily dosing with budesonide inhalation suspension , compared with 3- or 4-times-daily dosing of cromolyn sodium , may decrease caregiver burden and enhance the willingness of caregivers to adhere to treatment regimens prescribed for their young children with asthma . This effect on caregiver adherence could further improve treatment effectiveness . This is the first clinical trial comparing the effects of a nebulized corticosteroid with that of an alternative nebulized therapy on quality of life in young children with asthma and their families . Compared with nebulized cromolyn sodium , budesonide inhalation suspension not only provides better overall child health status and asthma management , but greater caregiver quality of life and greater caregiver satisfaction , convenience , ease of use , and compliance [8576655] The effect of single-dose inhaled terbutaline , sodium cromo-glycate and budesonide were compared with control in 11 exercise-induced asthma ( EIA ) patients , aged 9 - 14 years . Patients exercise for 6 minutes , 15 minutes after inhaling drugs . The FVC , FEV1 , PEFR and MMEF were recorded before exercise and after exercise at 5 minutes interval up to 25 minutes . After exercise , the mean ( SEM ) maximal percentage fall in FEV1 after placebo , 200 micrograms of terbutaline , 10 mg of sodium cromoglycate , and 100 micrograms of budesonide were 22.81 ( 3.45 ) , 4.05 ( 2.11 ) , 11.29 ( 1.18 ) , and 20.36 ( 2.33 ) respectively . It was concluded that single-dose inhaled terbutaline and sodium cromoglycate result ed in a significant protective effect on exerxide-induced asthma whereas budesonide did not [14572325] The objective of this study was to analyze data on parents ' adherence to their child 's prescribed nebulizer treatment regimen and compliance with the dem and s of the nebulizer and the face mask . Data on adherence and compliance were recorded in a 24-week double-blind , r and omized , parallel-group study with budesonide inhalation suspension in 125 young children with mild to moderate asthma . Budesonide was administered with an Adaptive Aerosol Delivery ( AAD ) system , which recorded adherence to treatment and compliance with the AAD system . A total of 35,481 treatments were recorded and analyzed . A study question naire regarding the parents ' and children 's acceptance of the AAD system has also been analyzed . The adherence to the treatment regimen was 91.3 % , and the compliance with the AAD system was 90.4 % . True adherence , the product of adherence and compliance , was 82.5 % . Approximately 90 % of the parents found the face mask easy to seal and the AAD equipment easy to use , and over 90 % of the children accepted it within 1 week . In conclusion , the results indicate that the AAD system could be of real clinical advantage for treatment of asthma in young children [4996164] Cromolyn sodium , a specific inhibitor of mediator release induced by antigen-antibody interaction , was studied for corticosteroid sparing effect and clinical usefulness in a double-blind double-crossover , and in a subsequent open trial in 30 corticosteroid-dependent adults with severe perennial asthma . Of 29 patients completing the trials , 19 had corticosteroid dose reduction while receiving cromolyn in the double-blind trial , and 22 had corticosteroid dose reduction in the open trial . Cromolyn was judged to be clinical ly useful for corticosteroid sparing effect or symptomatic improvement , however , in only ten patients . Corticosteroid sparing effect and clinical usefulness were noted in all types of asthmatics studied . One patient noted increased asthma following inhalation of either cromolyn or placebo and did not complete the trial ; no adverse effects of cromolyn per se were noted [9020413] We investigated whether sodium cromoglycate 10 mg three times daily , delivered as an aerosol via Nebuhaler ( in addition to terbutaline 0.5 mg three times daily ) , could replace inhaled steroid in children with mild‐to‐moderate asthma . Children ( mean age 10.3 years ) were r and omly allocated to 12‐week treatment with sodium cromoglycate 10 mg plus terbutaline 0.5 mg ( group A ; n= 30 ) or placebo plus terbutaline 0.5 mg ( group B ; n= 32 ) , both taken three times a day . The daily steroid dose was reduced by 50 μg/week for 4 weeks from a starting dose of 200 μg . Fewer patients withdrew owing to worsening asthma from group A ( n= 1 ) than group B ( n = 11 ) . Symptom scores , morning and evening peak flows , and additional β2‐agonist usage , recorded on diary cards , were better in group A than group B. Lung function measured at clinic visits was unchanged in either group . Overall opinions of efficacy favoured Group A. Adverse events were similar in the groups . Sodium cromoglycate plus terbutaline substituted effectively for inhaled steroid therapy [8036306] In a controlled prospect i ve study we have measured growth and pulmonary function in children with asthma during long-term treatment with inhaled budesonide and compared these findings with those obtained from children not treated with corticosteroids . Two hundred and sixteen children were followed at 6 monthly intervals for 1 - 2 years without inhaled budesonide and then for 3 - 6 years on inhaled budesonide . Sixty-two children treated with theophylline , beta 2-agonists and sodium-cromoglycate but not with inhaled steroids were also followed for 3 - 7 years ( controls ) . During the period of budesonide therapy the mean daily dose decreased from 710 to 430 micrograms ( P < 0.01 ) and no signs of tachyphylaxis to the treatment were seen . Budesonide treatment was associated with a significant reduction in the number of annual hospital admissions due to acute severe asthma ( from 0.03 to 0.004 per child , P < 0.001 ) . In patients not treated with budesonide an annual decrease in % predicted FEV1 of 1 - 3 % was seen . In contrast FEV1 improved significantly with time during budesonide treatment , both compared with the run-in period and with the control group ( P < 0.01 ) . Furthermore , there was a significant ( P = 0.01 ) relationship between the duration of asthma at the start of budesonide and the annual increase in FEV1 during budesonide therapy . After 3 years of treatment with budesonide , children who started this therapy later than 5 years after the onset of asthma had significantly lower FEV1 ( 96 % ) than the children who received budesonide within the first 2 years after the onset of asthma ( 101 % ) ( P < 0.05 ) . ( ABSTRACT TRUNCATED AT 250 WORDS [10213547] BACKGROUND Inhalation therapy with sodium cromoglycate is recommended as the first-line prophylactic treatment for moderate asthma in children . The availability of spacer devices with face-masks has extended the applicability of metered-dose inhalers to younger children . We studied the feasibility and effects of this therapy compared with placebo in children aged 1 - 4 years . METHODS 218 children aged 1 - 4 years with moderate asthma were recruited through 151 general practitioners between March , 1995 , and March , 1996 . They were r and omly assigned sodium cromoglycate ( 10 mg three times daily ) or placebo , given by inhaler with spacer device and face-mask for 5 months . Rescue medication ( ipratropium plus fenoterol aerosol ) was available during the baseline period of 1 month and the intervention period . Parents completed a daily symptom-score list . The primary outcome measure was the proportion of symptom-free days in months 2 to 5 . Analysis was by both intention to treat and on treatment . FINDINGS 167 ( 77 % ) children completed the trial . 131 ( 78 % ) of these children used at least 80 % of the recommended dose . Of the 51 children who stopped prematurely , 23 had difficulties with inhaled treatment . The mean proportion of symptom-free days for both groups was greater for the treatment period than for the baseline period ( 95 % CI for mean difference 5.1 to 17.5 cromoglycate , 11.9 to 23.3 placebo ) . However there were no differences between the sodium cromoglycate and placebo groups in the proportion of symptom-free days ( mean 65.7 [ SD 25.3 ] vs 64.3 [24.5]% ; 95 % CI for difference -8.46 to 5.70 ) or in any other outcome measure . INTERPRETATION Our study in a general practice setting shows that inhalation therapy with a spacer device and face-mask is feasible in a majority of children below the age of 4 years . However , long-term prophylactic therapy with inhaled sodium cromoglycate is not more effective than placebo in this age-group [2500361] Twenty two allergic patients with bronchial asthma completed this study . Effects of long-term treatment with inhaled cromoglycate 4 x 2 mg.day-1 were compared to the effects of inhaled budesonide 4 x 0.1 mg.day-1 on symptoms , additional beta 2-agonist use , lung function and bronchial hyperresponsiveness measured by the provocation concentration of histamine producing a 20 % fall in forced expiratory volume in one second ( FEV1 ) ( PC20 histamine ) and exercise-induced fall in FEV1 . The study was carried out in a double-blind way with a r and omized crossover design using a double-dummy technique . After a single-blind placebo period , the two active treatment periods of 6 weeks were separated by a single-blind placebo period . Symptom score and beta 2-agonist use decreased during both active treatment periods , which showed no mutual differences . Morning and evening peak expiratory flow rates were significantly higher during treatment with budesonide versus placebo ( p less than 0.01 and p less than 0.001 ) , and also versus cromoglycate ( p less than 0.02 and p less than 0.05 ) . FEV1 showed improvement after a 6 week treatment with budesonide versus placebo ( p less than 0.05 ) , although there was no significant difference between the two active treatments . PC20 histamine did not change during treatment with cromoglycate . Budesonide showed a significant increase in PC20 histamine versus placebo ( p less than 0.05 ) and was marginally significantly better than cromoglycate ( p = 0.05 ) . Exercise-induced fall in FEV1 was not changed by cromoglycate , but improved significantly during budesonide in comparison with placebo ( p less than 0.01 ) and also with cromoglycate ( p less than 0.001 ) . ( ABSTRACT TRUNCATED AT 250 WORDS [407559] A double-blind , cross-over study was undertaken to compare inhalation of betamethasone valerate ( BV , 800 microgram daily ) with sodium cromoglycate ( SCG , 80 mg daily ) in twenty children requiring bronchodilators for perennial asthma . Each treatment period lasted 4 weeks but statistical comparisons were made only in respect of the last 14 days of each therapy . When the children were using BV they required not only less of the bronchodilator drugs but had fewer symptoms and higher daily peak expiratory flow rates when taking SCG . Statistically , all these differences were highly significant . For 2 weeks before the main trial each child was given a placebo aerosol ( single-blind ) to assess severity of asthma . In comparison with this period , SCG was associated with a significantly increased peak expiratory flow rate a lower symptom score by day but not by night , but their usage of bronchodilators followed a similar pattern . When the BV period was compared with the placebo period , patients had an even more significant rise in peak expiratory flow rate , less day and night symptoms , and took hardly any bronchodilators . The response to the two drugs did seem to depend upon which was given first . No monilial infections were found , nor any measurable defect in adrenal response from either treatment . Betamethasone valerate is considered to be superior to sodium cromoglycate as a treatment for childhood asthma insufficiently controlled on bronchodilators [14754977] OBJECTIVE Our aim was to compare the 12-month safety and efficacy of fluticasone propionate ( FP ) and sodium cromoglycate ( SCG ) in children aged 1 to 3 years with mild to moderate recurrent wheeze . METHODS The study was a r and omized , parallel-group , open-label multicenter study of 625 children , aged 1 to 3 years , with recurrent wheeze r and omized in a 3:1 ratio to treatment for 52 weeks with FP ( 100 microg twice daily ) via metered-dose inhaler and Babyhaler spacer device or SCG ( 5 mg 4 times daily ) via metered-dose inhaler and Nebuhaler spacer device , respectively . RESULTS There was no significant difference in mean adjusted growth rates between the 2 groups : 84.0 mm/year in the FP group versus 86.4 mm/year in the SCG group ( difference FP-SCG : -2.4 mm/year ; 95 % confidence interval : -6.6 to 1.8 ) . Growth comparisons were independent of age , gender , previous use of steroid , or whether measured as length and /or height . Serum and urinary cortisol concentrations showed a statistically significant suppression of 10 % and 14 % , respectively , but the number of patients with serum cortisol levels below the lower normal limit was reduced during the trial . Both treatments were well tolerated . The most common drug-related adverse events were cough ( 2 % FP vs 1 % SCG ) and hoarseness ( 1 % FP vs 0 % SCG ) . One incident of cataract was observed at baseline and 1 after FP treatment ; the latter had resolved after 12 months . The efficacy of FP was superior to SCG with fewer cases of symptom worsening , exacerbations , and requirements for oral steroid treatment and more symptom-free days and days without use of rescue treatment . CONCLUSIONS Twelve months of treatment with inhaled FP ( 100 microg twice daily ) in preschool children aged 1 to 3 years with recurrent wheeze has no effect on growth and no other clinical ly important side effects but is more efficacious than SCG [406103] A double‐blind comparison of betamethasone valerate , sodium cromoglycate and the combination of these two treatments was carried out in twenty‐two adult patients with asthma . Regular fortnightly assessment s were made in the clinic throughout the study and adrenal function was monitored and found to be normal . All patients measured their peak expiratory flow rates in the morning and evening and monitored their symptoms daily on a record card as well as recording bronchodilator usage . Assessment using these parameters indicated that treatment with betamethasone valerate compared with sodium cromoglycate result ed in an improvement in the patients ’ asthma which was statistically significant ( P<0.001 ) . Overall the combined treatment produced a better response than sodium cromoglycate ( P<0.02 ) but a poorer response compared with the steroid aerosol given alone ( P>0.05 ) . In only two patients was the response to the combined therapy significantly greater than to either drug given alone [11379805] BACKGROUND Budesonide and sodium cromoglycate are both recommended as maintenance therapy for childhood asthma . OBJECTIVE To compare the cost-effectiveness of these two treatment strategies in clinical practice , in an open-label , pharmacoeconomic clinical trial . METHODS Health economics were evaluated in 138 children , ages 5 to 11 years , with unstable asthma not previously treated with corticosteroids or cromones . The asthma was stabilized during 4 to 6 weeks with budesonide 200 to 400 microg twice daily . The children were then r and omly allocated to one of the two treatment strategies aim ing at maintaining asthma control for 12 months ; budesonide 400 microg/day ( N = 69 ) or sodium cromoglycate 60 mg/day ( N = 69 ) . If asthma control was judged unsatisfactory , the doses were increased or the children were switched to the alternate treatment . RESULTS In children continuing on the same treatment , the degree of asthma control was similar in the two groups at study end . To maintain asthma control , 42 % of cromoglycate children switched to budesonide , and then experienced a 14 % increase in symptom-free days . No budesonide patient had to switch therapy because of lack of asthma control . Although not statistically significant , total annual cost per patient was 24 % ( Swedish kronor 4195 ; US $ 487 ; Euro 485 ) lower in the budesonide than the cromoglycate group , mainly due to a lower cost for asthma medication . CONCLUSIONS A budesonide strategy for continued maintenance treatment , after an initial period of stabilizing treatment with budesonide , result ed in lower costs and less drug switches than did a strategy with sodium cromoglycate [7653745] This study compared the efficacy and tolerability of sodium cromoglycate ( SC ) and beclomethasone dipropionate ( BDP ) in adult patients with bronchial asthma inadequately treated with bronchodilators alone . The study was a double‐blind , r and omized , double‐dummy , parallel‐group study . Patients with mild to moderate symptomatic asthma , inadequately treated with bronchodilators only , were , after a 2–week run‐in ( base‐line ) period , r and omized to 8 weeks of treatment with either SC 10 mg four times daily or BDP 100 μg four times daily . Salbutamol metered‐dose inhaler was given as relief medication . A total of 37 patients were r and omized for treatment , 19 patients in the SC group and 18 patients in the BD group . Efficacy and safety were determined by daily record card data : morning and evening peak‐expiratory‐flow rates ( PEER ) , daytime and nighttime asthma symptom scores , and rescue salbutamol use . At clinic visits , FEV1 and FVC were measured , as were the physician 's and the patient 's assessment of the medication at the end of the study . The safety and tolerability of the trial medication were assessed by monitoring adverse events throughout the study . A clinical ly and statistically significant improvement of the asthma in FEV1 , symptom scores , rescue medication , and global opinion of efficacy was observed , and both groups provided equivalent efficacy . The morning PEFR as well as the evening PEFR for both groups improved , but was statistically significant only for the BDP group ( M‐PEFR ) . Both drugs were well tolerated with only a few minor adverse events . This trial shows that SC and BDP are equally effective anti‐inflammatory treatments for mild to moderate bronchial asthma in adults [4197916] Cromolyn sodium is a new antiasthmatic drug which exerts its action by interfering with the release of the mediators of immediate hypersensitivity reactions from the sensitized mast cells lining the bronchial tree . In a double-blind crossover trial , 36 children with chronic intractable asthma , 23 of whom were corticosteroid dependent , inhaled cromolyn sodium or a placebo four times per day for two 4 week periods . Although clinical improvement with cromolyn therapy was not statistically superior to the placebo , 36 patients noted subjective improvement from the cromolyn sodium and entered a 12 month open-end clinical trial . Twenty-six patients completed this second study ; 19 of them showed clinical improvement . Of the 18 steroid-dependent patients who completed 12 months of cromolyn sodium therapy , 7 discontinued corticosteroids , 10 decreased their dosage , and one patient increased his corticosteroid requirement . Even though cromolyn sodium is not always clinical ly efficacious , it should be considered in the management of intractable asthma in children [12882461] Regular salbutamol use can exacerbate allergen-induced airway eosinophilia in asthmatics , but its effect on airway eosinophil chemokine responses is unknown . Asthmatic subjects ( n=14 ) were treated for 10 days with placebo or salbutamol in a double-blind , cross-over study , then given same-dose allergen challenges . Their sputa were then analysed 1 and 7 h later for a panel of eosinophil-related cytokines . Eosinophils from five test and three control subjects were tested for expression of CXCL8/interleukin (IL)‐8 , and its receptors and responsiveness to CCL11/eotaxin and CXCL8/IL‐8 . Sputum CXCL8/IL‐8 , but not IL‐5 , CCL5/regulated on activation , T‐cell expressed and secreted , CCL7/monocyte chemotactic protein‐3 , CCL11/eotaxin , granulocyte-macrophage colony-stimulating factor or tumour necrosis factor levels , were increased ( 42 % ) by the salbutamol treatments . The CXCL8/IL‐8 levels correlated with the proportions of sputum eosinophils and these cells , but not other sputum cells , stained strongly for CXCL8/IL‐8 . The circulating eosinophils of the tested subjects ( n=5 ) expressed CXCL8/IL‐8 receptors and secreted high levels of this chemokine . Neutralisation of sputum CXCL8/IL‐8 reduced eosinophil chemotactic responses to these sample s by 19±5 % . These data suggest that regular use of salbutamol can augment airway CXCL8/interleukin‐8 responses to allergen challenge and that this CXCL8/interleukin‐8 could contribute to the airway inflammatory response [3106449] Single-dose salbutamol ( 200 micrograms ) , beclomethasone dipropionate ( 200 micrograms ) , and sodium cromoglycate ( SCG ) ( 10 mg ) administered by inhalation 10 minutes before allergen challenge were examined with regard to inhibition of allergen-induced early ( EAR ) and late ( LAR ) asthmatic responses and allergen-induced increase in bronchial responsiveness to inhaled histamine . Ten atopic subjects with asthma participated in a blinded , crossover , placebo-controlled trial . The EAR was inhibited by salbutamol and SCG but not by beclomethasone dipropionate or placebo ( p less than 0.01 ) . The LAR ( p less than 0.01 ) and the allergen-induced increased bronchial responsiveness to histamine 7 hours ( p less than 0.01 ) and 30 hours ( p less than 0.05 and p less than 0.01 for various comparisons ) were inhibited by SCG and beclomethasone diproprionate but not by salbutamol or placebo . The allergen-induced LAR and associated increased responsiveness are now believed to be more important clinical ly than the EAR . The clinical relevance of these results is to stress the importance of the prophylactic nonbronchodilator drugs ( SCG and steroids ) and the potential inadequacy of bronchodilators used alone in the treatment of both perennial and seasonal allergic asthma [1955633] Although both cromolyn ( C ) and inhaled corticosteroids are anti-inflammatory therapies for childhood asthma , there are few controlled comparisons of these medications for asthma therapy in children . None were conducted in the United States , and none specifically study triamcinolone acetonide ( T ) versus C. This 12-week evaluation followed 31 youths , aged 8 to 18 years , with moderate asthma who were assigned to receive C or T according to a prer and omized and blinded code . Patients were instructed to take two inhalations from the study metered-dose inhaler ( active T or placebo ) and to inhale the contents of one study -provided ampule ( C , 20 mg , or placebo ) from a compressor-driven home nebulizer three times per day . Patients also used albuterol , two inhalations from a metered-dose inhaler , three times a day ( before study medication ) and , additionally , if needed . Patients maintained a daily diary , recording extra medication use , adverse experiences , peak flow rates morning and night , and asthma symptom scores . Laboratory assessment of pulmonary function was done at 1 , 4 , 8 , and 12 weeks . Cosyntropin challenge and methacholine bronchoprovocation challenge were performed at the beginning and end of the study . C and T provided similar , adequate asthma control . Symptoms of wheezing , cough , and chest tightness decreased , and daily peak expiratory flow rate increased with both regimens compared to during a 2-week baseline when patients received medication only as needed . There was no significant change in methacholine sensitivity and no change in endocrine function , as measured with fasting plasma control before and after administration of cosyntropin . ( ABSTRACT TRUNCATED AT 250 WORDS [6782146] Some patients with chronic asthma treated with beclomethasone aerosol ( BA ) derive significant symptom benefit , yet have persisting adrenal suppression due in part to their BA therapy . The daily dose of BA required is higher in patients with atopy . We therefore assessed the usefulness of ancillary treatment with cromolyn sodium ( CS ) , a drug known to inhibit atopic asthma , to try to improve the balance of risk vs benefit in such patients . Thirty asthmatics , well controlled on high-dose BA ( mean , 1,040 micrograms + /- 97 SE ) but with morning cortisol levels averaging approximately 10 micrograms/dl , were allocated r and omly to placebo or CS inhalant , used in addition to their regular BA and other asthma medications . After 4 wk , their BA dose was halved . Both groups were monitored for greater than 6 mo by daily symptom diaries and peak flows , and by spirograms and morning serum cortisol tests every 4 wk . Mean cortisol levels rose 27 % after BA dose reduction ( p less than 0.05 ) but asthma worsened . Risk-benefit assessment s 20 wk after reducing the BA showed a general tendency for higher cortisol values to be coupled with worsening of the asthma symptoms and FEF25%-75 % . The distributions of good , fair , and poor risk-benefit responses were the same in both CS and placebo-treated groups ( p = 0.20 ) . In other asthmatics who may have less associated bronchitis or small airways obstruction than these patients , CS might prove useful , but in these adult chronic asthmatics with this particular therapeutic problem , there was no discernible BA-sparing effect or other clinical advantage from adding CS to their established BA regimen [9330414] The aim of this study was to compare accurately measured growth over 12 months in asthmatic children treated with either fluticasone propionate ( FP ) 50 micrograms twice daily ( b.i.d . ) or sodium cromoglycate ( SCG ) 20 mg four times daily ( q.i.d . ) . After a 2-week run-in , asthmatic children aged 4 - 10 years from 15 UK centers were r and omized in a 3:4 ratio to open-label FP ( n = 52 ) or SCG ( n = 70 ) . After 8 weeks , those whose asthma was not adequately controlled were switched from SCG to FP or withdrawn . St and ing height was measured ( Holtain stadiometry ) at baseline , after 8 weeks and at 6 weeks intervals thereafter for 1 year . Morning peak flows ( PEFam ) were recorded by patients for 2 weeks during baseline , and 1 week before each visit during treatment . Urinary free cortisol ( 24 h ) was measured at baseline , 6 months , and 1 year . After 8 weeks , 22 patients were withdrawn from SCG group ( and were switched to FP ) , and five patients were withdrawn from the FP group due to poor asthma control . A further 21 and 11 patients were withdrawn from the SCG and FP groups , respectively , during the course of the study . There were no significant differences between patients who received FP and SCG for 1 year ( n = 34 and n = 26 , respectively ) in terms of height velocity adjusted for age and gender ( HV ) , or height velocity st and ard deviation scores adjusted for gender ( HVSDS ) . Mean HV ( mean HVSDS ) were 6.0 cm/yr ( 0.1 ) and 6.5 cm/yr ( 0.5 ) for FP and SCG , respectively . There were no treatment differences in mean 24 h urinary free cortisol levels at 6 and 12 months . Mean % predicted PEFam improved over 1 year in both groups but to a greater degree in the FP group . We concluded that growth was normal in mildly asthmatic children receiving FP ( 50 micrograms bid ) for 1 year . There were fewer withdrawals and lung function improved to a greater extent in FP treated patients than in patients receiving SCG [12847475] BACKGROUND Salmeterol ( SLM ) is a long-acting beta(2)-receptor agonist that produces bronchodilatation for 12 hours in asthmatic subjects . The effects of the regular use of long-acting beta(2)-agonists on airway inflammation are largely unknown . OBJECTIVES We examined the effects of 16 weeks of treatment with 50 microg SLM bid , 250 microg fluticasone propionate ( FP ) bid,5 mg disodium cromoglycate ( DSCG ) qid , or placebo on airway inflammation in bronchial mucosa . METHODS Airway inflammation was assessed in bronchial biopsy specimens before and after treatments and bronchial hyperresponsiveness ( BHR ) in 80 patients with newly diagnosed asthma . Inflammatory cells and tenascin in the basement membrane were studied with immunohistochemical methods . Peak expiratory flow rate ( PEF ) , symptoms , and need for rescue medication were recorded . RESULTS SLM , FP , and DSCG reduced symptoms and need for rescue medication ( P < .04 ) . Both SLM and FP improved PEF and increased PD15FEV(1 ) to histamine by 2.8 and 5.2 doubling dose units , respectively . Both compounds reduced BHR more than placebo ( P < .05 ) . Both SLM and placebo had no effect on any inflammatory cell type . In both FP-treated and DSCG-treated patients , the number of EG2-positive eosinophils in the airway mucosa decreased ( P = .002 and P < .05 , respectively ) . CONCLUSIONS SLM showed no anti-eosinophil properties in this study , but it provided good symptom control . FP provided the best anti-eosinophil properties and symptom relief of the studied compounds [12457002] Background and Objectives : To investigate the therapeutic equivalence of the two formulations of the glucocorticosteroid budesonide delivered either by the budesonide Novolizer ® , i.e. a multidose dry powder inhaler , or by the Pulmicort ® Turbuhaler ® in asthmatic patients in terms of efficacy , safety and tolerability during a 12-week treatment . Methods : A total of 315 patients were r and omised in this open , multicentre study . Inclusion criteria comprised previously diagnosed bronchial asthma of mild to moderate persistent intensity ( ranging from 60 % to a maximum of 90 % predicted FEV1 ) , need for anti-inflammatory therapy , inhalation of β2-sympathomimetics on an as needed to regular basis , reversibility of airway obstruction of > 12 % after inhalation of 2 actuations of 100 µg salbutamol . Primary variable was FEV1 , secondary were other pulmonary function test variables , PC20FEV1 for histamine challenge , morning and evening PEFR , salbutamol usage , asthma symptoms , reactions after inhalation , st and ard safety variables . Results : The comparison of the FEV1 at study endpoint indicated that the Novolizer ® was at least as efficacious as the Turbuhaler ® ( p < 0.001 ) . All other variables of the pulmonary function tests as well as the asthma symptoms , nocturnal awakenings , PEFR measurements , or salbutamol usage indicated no relevant difference . Only 1 patient ( Turbuhaler ® ) discontinued prematurely due to lack of efficacy . None of the other safety variables ( adverse events , laboratory variables , vital signs , etc . ) indicated any difference between the groups . Conclusions : The budesonide Novolizer ® is therapeutically equivalent to the Pulmicort ® Turbuhaler ® for the long-term treatment of patients with mild to moderate persistent asthma [2825567] To determine whether 4 drugs used in the treatment of asthma inhibit the late asthmatic reaction and the associated increase in airway responsiveness induced by toluene diisocyanate ( TDI ) , we studied 24 sensitized subjects divided into 4 groups . Beclomethasone aerosol ( 1 mg bid ) , slow-release theophylline ( 6.5 mg/kg bid ) , slow-release verapamil ( 120 mg bid ) , and cromolyn ( 20 mg qid via spinhaler ) , were administered for 7 days , respectively , to 1 of the 4 groups , according to a double-blind , crossover , placebo-controlled study design . When the subjects were treated with placebo , verapamil , or cromolyn , FEV1 markedly decreased and airway responsiveness increased after exposure to TDI . By contrast , beclomethasone prevented the late asthmatic reaction and the associated increase in airway responsiveness to methacholine induced by TDI . Slow-release theophylline partially inhibited both the immediate and the late asthmatic reactions but had no effect on airway hyperresponsiveness to methacholine . These results suggest that only high-dose inhaled steroids can completely block TDI-induced late asthmatic reactions [12672309] BACKGROUND Although inhaled glucocorticosteroids are recommended for persistent asthma , their long-term effect on recent onset , mild , persistent asthma has yet to be established . METHODS We did a r and omised , double-blind clinical trial in 7241 patients in 32 countries to assess the effects of budesonide in patients who had had mild persistent asthma for less than 2 years and who had not had previous regular treatment with glucocorticosteroids . Patients aged 5 - 66 years received either budesonide or placebo once daily for 3 years in addition to their usual asthma medications . The daily budesonide dose was 400 microg , or 200 microg for children younger than 11 years . The primary outcome was time to first severe asthma-related event , and analysis was by intention to treat . FINDINGS 198 of 3568 patients on placebo and 117 of 3597 on budesonide had at least one severe asthma exacerbation ; hazard ratio 0.56 ( 95 % CI 0.45 - 0.71 , p<0.0001 ) . Patients on budesonide had fewer courses of systemic corticosteroids and more symptom-free days than did those on placebo . Compared with placebo , budesonide increased postbronchodilator forced expiratory volume in 1 s ( FEV1 ) from baseline by 1.48 % ( p<0.0001 ) after 1 year and by 0.88 % ( p=0.0005 ) after 3 years ( expressed as percent of the predicted value ) . The corresponding increase in prebronchodilator FEV1 was 2.24 % after 1 year and 1.71 % after 3 years ( p<0.0001 at both timepoints ) . The effect of treatment on all outcome variables was independent of the baseline lung function ( prebronchodilator or postbronchodilator ) or baseline medication . In children younger than 11 years , 3-year growth was reduced in the budesonide group by 1.34 cm . The reduction was greatest in the first year of treatment ( 0.58 cm ) than years 2 and 3 ( 0.43 cm and 0.33 cm , respectively ) . INTERPRETATION Long-term , once-daily treatment with low-dose budesonide decreases the risk of severe exacerbations and improves asthma control in patients with mild persistent asthma of recent onset [14579993] Introduction . There are no available data on the safety of recommended schedules for the initiation of treatment with budesonide inhalation suspension in children with recurrent wheezing episodes . We compared the safety of high and low starting dose of budesonide by measuring their effect on plasma cortisol concentration . Methods . A r and omized double-blind , placebo-controlled design was used . Twenty-nine children ages 6 months to 3 years were divided into three groups : ( 1 ) high starting dose : 1 mg budesonide inhalation suspension twice daily followed by a stepwise decrease of 25 % every second day for 8 days ( n = 11 ) ; ( 2 ) low starting dose : 0.25 mg twice daily for 8 days ( n = 11 ) ; ( 3 ) placebo ( n = 7 ) . The 8 AM ( fasting ) and 1-hour post-ACTH stimulation plasma cortisol concentrations were measured before and 10 days after initiation of budesonide treatment . Results . Before treatment and after 8–10 days of treatment , there was no significant difference in mean serum cortisol concentration in the high starting dose , low-dose and placebo groups , either at 8 AM or at 1 hour after ACTH stimulation . Conclusion . The administration of nebulized suspension of budesonide at a high starting dose ( 2 mg/day for 2 days ) followed by a rapid stepwise decrease over 8 days was safe , causing similar changes in serum cortisol levels to low-dose budesonide suspension or placebo [3110248] After a run-in period of 2 weeks , receiving a regimen of inhaled beta 2-agonists and /or theophyllines , 38 atopic patients with asthma with perennial symptoms were r and omly allocated to receive an 8-week treatment of additional inhalation treatment with either sodium cromoglycate ( SCG ) , 2 mg four times daily , and placebo beclomethasone dipropionate ( BDP ) , or BDP , 200 micrograms twice daily , and placebo SCG . After crossover , each group received the opposite treatment for the final 8 weeks . FEV1 , FVC , and provocation concentration of histamine causing a 20 % fall in FEV1 ( PC20 ) were determined monthly and peak expiratory flow ( PEF ) daily throughout the study . A significant increase in FEV1 , FVC , and PEF ( p less than 0.01 ) was observed after BDP treatment was started , and likewise , in the second period , an increase in both FEV1 and PEF ( p less than 0.05 ) was observed . The total effect on logarithm-natural ( Ln ) ( PC20 ) , i.e. , the mean effects of the two periods , was also significant ( p less than 0.01 ) . SCG , however , was most effective when it was used as the first drug , indicated by a significant increase in FVC in the first period ( p less than 0.05 ) . Neither in the first nor in the second period did SCG treatment influence the Ln ( PC20 ) value positively , and the SCG treatment administered in the second period could not maintain the improvement in the pulmonary function ( i.e. , FEV1 , FVC , and PEF ) obtained initially with the BDP treatment . When the effect of BDP on FEV1 , FVC , PEF , and Ln ( PC20 ) was compared to the effect of SCG in the first 8-week treatment period , no significant difference was observed ( p greater than 0.1 ) . ( ABSTRACT TRUNCATED AT 250 WORDS [9671161] In school children with atopic asthma the beneficial effects of disodium cromoglycate ( DSCG ) and beclomethasone dipropionate ( BDP ) are well-established . In preschool children , wheezing is quite common , and in the majority of cases the symptoms are episodic and reported to be associated with viral infections rather than atopy . We compared the efficacy of regular treatment with DSCG and BDP for prevention of wheezing in preschool children . We were interested to establish whether regular treatment with inhaled anti-inflammatory drugs could lead to a decrease in bronchial responsiveness . In 15 patients ( median age , 56 months ; range , 43 - 66 months ) bronchial responsiveness was assessed by measuring specific airway resistance ( sRaw ) during a histamine provocation test . The concentration of histamine eliciting a 100 % increase in sRaw ( PC100his ) was determined . In a double-blind crossover study , patients inhaled either DSCG 10 mg three times a day or BDP 100 microg three times a day for 2 months . After a wash-out period , treatment was changed to BDP or DSCG , respectively . Daily peak flow measurements were carried out , and exacerbations were noted . PC100his was measured at the start and end of each treatment period . No significant decrease in bronchial responsiveness was seen ( PC100his DSCG : before 1.3 , after 1.66 mg/ml , Pvalue not significant ; BDP : before 1.1 after 1.22 mg/ml , Pvalue not significant ) . Significantly higher morning peak flows were observed on BDP therapy ( 160 on BDP vs. 150 L/min on DSCG , P < 0.03 ) . BDP treatment result ed in significantly fewer wheezing exacerbations ( 7 vs. 16 , P < 0.005 ) compared with DSCG therapy . We conclude that in preschool children with episodic virally induced wheezing , BDP therapy was superior to DSCG aerosol treatments for the prevention of exacerbations of wheezing , although no significant effect on bronchial responsiveness was noted during either treatment protocol [10513756] Stepwise selection methods are widely applied to identify covariables for inclusion in regression models . One of the problems of stepwise selection is biased estimation of the regression coefficients . We illustrate this " selection bias " with logistic regression in the GUSTO-I trial ( 40,830 patients with an acute myocardial infa rct ion ) . R and om sample s were drawn that included 3 , 5 , 10 , 20 , or 40 events per variable ( EPV ) . Backward stepwise selection was applied in models containing 8 or 16 pre-specified predictors of 30-day mortality . We found a considerable overestimation of regression coefficients of selected covariables . The selection bias decreased with increasing EPV . For EPV 3 , 10 , or 40 , the bias exceeded 25 % for 7 , 3 , and 1 in the 8-predictor model respectively , when a conventional selection criterion was used ( alpha = 0.05 ) . For these EPV values , the bias was less than 20 % for all covariables when no selection was applied . We conclude that stepwise selection may result in a substantial bias of estimated regression coefficients [8620234] OBJECTIVE To evaluate whether early anti-inflammatory therapy with nebulized cromolyn sodium or budesonide reduces wheezing after bronchiolitis . DESIGN AND SETTING A r and omized , controlled study in a university hospital that provides primary hospital care for all pediatric patients in a defined area . PATIENTS One hundred consecutive infants younger than 24 months treated in the hospital for acute bronchiolitis . INTERVENTIONS Thirty-four patients received cromolyn sodium , 20 mg four times a day for 8 weeks and 20 mg three times a day for 8 weeks , and 34 patients received budesonide , 500 micrograms twice a day for 8 weeks and 250 micrograms twice a day for 8 weeks , by a foot pump with a face mask ; 32 patients in the control group received no therapy . MAIN OUTCOME MEASURES Numbers of physician-diagnosed wheezing episodes , hospital admissions for bronchial obstructions , and symptomatic days recorded by the parents . RESULTS Children in the cromolyn sodium ( 19 % ) and budesonide ( 16 % ) groups had significantly fewer physician-diagnosed wheezing episodes than those in the control group ( 47 % ) during the second 8-week period ( P < .05 ) . A significant reduction in hospital admissions for bronchial obstructions was seen in the budesonide group and in the children with atopy in both treatment groups ( P < .05 ) . The children with atopy had significantly more subsequent wheezing episodes and hospital admissions than those without atopy ( P < .05 ) . The numbers of symptomatic days did not differ significantly among the three groups . CONCLUSIONS Early anti-inflammatory therapy with nebulized cromolyn sodium or budesonide reduces the number of wheezing episodes and hospital admissions after bronchiolitis . Children with atopy are at high risk of subsequent wheezing episodes , and they particularly benefit from anti-inflammatory therapy [11986448] OBJECTIVE The availability of antiinflammatory asthma medications for infants and young children has been limited . The objective of this study was to compare effects of nebulized budesonide inhalation suspension and cromolyn sodium nebulizer solution on asthma-related health outcomes in young children with asthma . METHODS We conducted a r and omized , parallel-group , 52-week , open-label study in 36 US clinical sites . Patients included 335 children who were 2 to 6 years of age and had persistent asthma that had been treated with at least 1 long-term control medication ; 287 children ( 86 % ) completed the study . Patients received budesonide inhalation suspension , 0.5 mg daily ( n = 168 ) , or cromolyn sodium nebulizer solution , 20 mg 4 times daily ( n = 167 ) , for 8 weeks , followed by dose titration at the investigator 's discretion . The main outcome measure was the rate of asthma exacerbations over 52 weeks . Secondary measures included times to first asthma exacerbation and first use of additional asthma therapy , asthma symptom scores , rescue medication use , and health care re source use . RESULTS The budesonide group had a mean ( median ) asthma exacerbation rate of 1.23 ( 0.99 ) per year compared with 2.41 ( 1.85 ) for the cromolyn group , significantly longer times to first exacerbation and first use of additional long-term asthma medication , greater improvements in asthma symptom scores , reduced use of rescue medication , and fewer urgent care visits . Both treatments were well tolerated . CONCLUSIONS Budesonide inhalation suspension was more effective than nebulized cromolyn sodium in young children with persistent asthma . Both treatments were well tolerated with similar adverse event profiles [4175489] Abstract A double-blind cross-over trial of disodium cromoglycate was undertaken in 28 patients with asthma . This differed from previous trials in that isoprenaline was not included in the active or in the placebo capsules . 10 of the 28 patients improved clinical ly whilst on cromoglycate . F.E.V. 1·0 , dyspnœa on exertion , and disturbance of sleep were all improved by cromoglycate [8777828] 1 . Perception of asthma by patients can be assessed from the relationship between symptom scores and peak expiratory flows . This study was design ed to investigate the possibility that medication can affect perception of the sensation of asthma independently of changes in lung function . 2 . Twelve subjects whose asthma was inadequately controlled by inhaled bronchodilator alone were studied during four different drug treatments over 3 months . Subjective self- assessment of asthma was scored on a 10 cm visual analogue scale and followed by three consecutive measurements of peak expiratory flow , using a coded electronic peak flow meter . This was recorded not less than three times daily on diary cards . Observations were recorded during the second week of each of four treatments : ( i ) a run-in period using only inhaled salbutamol as required , ( ii ) inhaled beclomethasone , ( iii ) inhaled cromoglycate and ( iv ) oral theophylline at a dose adjusted to achieve blood levels of 10 - 20 mg/l . Inhaled salbutamol was permitted during the other treatments as required . Changes in the slope and position of the regression lines of asthma scores on PEF were used to measure changes in perception of asthma on each treatment . Dynamic lung volumes were measured in the clinic before the study and after each treatment period . 3 . In the group as a whole , theophylline improved lung function ( mean peak flow and dynamic lung volumes ) without affecting mean visual analogue scores , beclomethasone improved mean visual analogue scores with much less effect on lung function , while cromoglycate had a small though consistent effect on both . 4 . Perception of asthma , measured by the relationship between peak flow rate and visual analogue scores , was unaffected by cromoglycate . On theophylline , perception of asthma was heightened in five subjects despite a definite improvement in their peak flow . On beclomethasone , perception of asthma was reduced in most subjects , often with no discernible improvement in mean peak flow or dynamic spirometry . 5 . Perception of bronchoconstriction in asthma can be affected by drugs independently of control of the condition . Theophylline may produce a paradoxical increase in awareness of asthma in some individuals . With beclomethasone therapy a reduction in symptoms of asthma may occur without any improvement in tests of air flow [6818164] The protective effect of a new inhaled steroid , fluocortin butyl ( FCB ) , was compared to that of disodium cromoglycate ( DSCG ) and beclomethasone dipropionate ( BDP ) in patients with extrinsic asthma by means of the allergen-inhalation challenge test . Three different groups of 12 patients each participated in the study . One group was treated with FCB and BDP , the two others with FCB and DSCG , all in a r and omized crossover study plan . After an initial allergen challenge ( FEV1 fall greater than 15 % ) , the patients were allocated to either treatment for 7 - 10 days . A second challenge test was then carried out , followed by a washout period of 4 days . The treatments were then crossed-over , and a third allergen challenge was carried out at the end of the second treatment period . With BDP 5 of 12 patients were protected ; with FCB , 6 of 12 in two groups and 8 of 12 patients in a third group . With DSCG 3 of 12 patients were protected in the group in which the last medication was given 12 h before challenge , and 8 of 12 patients in the second group in which medication was given 1 - 2 h before challenge . In the same groups on FCB no such time-dependent effect was observed . No statistically significant differences were found between either FCB and BDP , or FCB and DSCG in either group [2833881] Nedocromil sodium is a new antiasthmatic drug with properties similar to sodium cromoglycate . We examined the efficacy of nedocromil sodium compared to placebo in 71 asthmatic patients in a three-centre double-blind parallel group study over 12 weeks . During the study the patients ' maintenance inhaled corticosteroids were progressively withdrawn . Nedocromil sodium had an advantage over placebo in the number of withdrawals related to uncontrolled asthma , 14 and 24 respectively ( p = 0.03 ) . Changes in symptom scores , peak flow rates and bronchodilator use favoured nedocromil sodium occasionally during the study . The unusual taste of the active drug was reported frequently . Nedocromil sodium is more efficacious than placebo in asthma maintenance , but does not replace inhaled corticosteroids [6439430] In a double‐blind controlled crossover trial of inhaled disodium cromoglycate and beclomethasone dipropionate in juvenile asthma , beclomethasone produced higher therapeutic scores but significantly so in only two indices – wheeze‐free days and morning peak flow rates . Combined treatment offered no advantage over beclomethasone alone . No side‐effects were noted . The findings confirm other studies of cromoglycate and a steroid aerosol ( betamethasone 17‐valerate ) but disagree with the only other comparative trial of cromoglycate and beclomethasone , in which both were found equally effective [12704354] BACKGROUND Determining who responds to asthma therapies , particularly leukotriene modifiers , continues to be explored . OBJECTIVE We sought to identify patient characteristics predictive of response to montelukast . METHODS We used data from 2 clinical trials in which children with asthma received either montelukast or placebo . Symptoms , beta-agonist use , and unanticipated health re source use caused by asthma were recorded in vali date d daily diaries for children 2 to 5 ( n = 689 ) and 6 to 14 ( n = 336 ) years old . We defined primary end points of days without asthma in 2- to 5-year-old patients ( 24 hours without symptoms , beta-agonist use , or asthma attack ) and change in percent predicted FEV(1 ) in 6- to 14-year-old children . Asthma attack was defined by the use of rescue oral corticosteroids or by an unscheduled visit to a medical provider . Patients were grouped according to baseline characteristics , such as family history of asthma , personal history of allergy , frequency of asthma symptoms , eosinophilia , and concomitant use of inhaled corticosteroids or cromolyn . We examined the stratum-specific effects of montelukast on the percentage of days without asthma , change in percent predicted FEV(1 ) , asthma attack , and a variety of secondary symptom and FEV(1 ) end points . RESULTS We did not identify characteristics that predicted response to montelukast in either preschool or 6- to 14-year-old children . These findings were consistent across all symptom and FEV(1 ) outcomes . There was also no differential response to montelukast in either age group when asthma attack was the outcome . CONCLUSION The patient characteristics studied do not appear to provide an indication of who will benefit most from treatment with montelukast [8387933] To compare the effectiveness of nedocromil sodium ( NS ) and sodium cromoglycate ( SCG ) administered by metered dose inhaler ( MDI ) in preventing exercise-induced asthma ( EIA ) , 12 asthmatic children with EIA were studied in a r and omized , double-blind , cross-over , placebo-controlled study . NS and SCG were given by MDI alone , and by MDI with a 700 ml spacer device ( Fisonair , Fisons , UK ) , in order to assess the benefit of using such a device . Following a baseline exercise challenge , the protective effect of NS , SCG or placebo was evaluated in each subject . The percentage fall in forced expiratory volume in one second , and percentage protection were measured . NS and SCG provided a significant and comparable protection from EIA , and both were better than placebo . No further improvement was observed after drug administration via the spacer . Both NS and SCG are effective in preventing EIA in children , when administered at the recommended clinical dose , and the use of a spacer for administering the drug provides no advantage if the technique of inhalation is good [806293] Eleven children with severe perennial asthma and a poor clinical response to disodium cromoglycate were studied in a 4-month , double blind trial involving 1 month 's treatment with placebo , disodium cromoglycate , betamethasone 17 valerate , and both drugs combined according to a predetermined r and om design . Each drug apparently reduced symptoms and improved daily peak flow and fortnightly spirometric measurements compared with placebo , but the improvement after betamethasone 17 valerate was greater in part because of the way this group of patients was selected . There did not appear to be any additional benefit when both drugs were used together . Betamethasone 17 valerate was not compared with beclomethasone diproprionate aerosol and there is no reason to believe it may be superior . Corticosteroid aerosols have potential hazards which may prove to equal those of long-term systemic steroids , but they offer the prospect of satisfactory control of symptoms without the risk of growth suppression in children with severe asthma . Disodium cromoglycate remains the drug of choice in severe childhood asthma and the use of corticosteroid aerosols should be confined to those children who fail to respond satisfactorily to disodium cromoglycate [10690871] The aim of the present study was to evaluate the prevalence of adrenal suppression and growth retardation in children using moderate doses of budesonide or fluticasone propionate . Seventy-five asthmatic children were r and omly divided into three treatment groups : 30 to the fluticasone propionate ( FP ) , 30 to the budesonide ( BUD ) , and 15 to the cromone ( CROM ) group . FP doses were 500 microg/day during the first 2 months and 200 microg/day thereafter . The respective BUD doses were 800 and 400 microg/day . A low dose ACTH ( 0.5 microg/1.73 m2 ) test was performed before treatment and 2 , 4 , and 6 months later . The test was considered abnormal if the stimulated serum cortisol concentration was more than 2 SD lower than the pretreatment mean ( < 330 nmol/L ) . The low dose ACTH test was abnormal after both the high and low steroid doses in 23 % of the children . At the 4 month measurement there were more abnormal tests in the BUD ( n = 9 ) than in the FP ( n = 5 ) group ( P < 0.05 ) . At that time also the stimulated concentration of serum cortisol was lower in the BUD than in the CROM group ( P < 0.01 ) , whereas the difference between the FP and CROM groups was not significant . During the study year the mean decrease in height SD score was 0.23 in the children treated with BUD , 0.03 in the children treated with FP , and 0.09 in the children treated with CROM ; the difference between the BUD and FP groups was significant ( P < 0.05 ) . In conclusion , the low dose ACTH test revealed mild adrenal suppression in a quarter of the children using moderate doses of inhaled steroids . A FP dose of 200 microg/day caused less adrenal and growth suppression than did a BUD dose of 400 microg/day [7638372] Inhaled corticosteroids are highly effective in the treatment of asthma at all ages and their use in younger children is increasing . As concerns exist about the long-term systemic side-effects of high dose inhaled corticosteroids , current guidelines continue to recommend sodium cromoglycate ( SCG ) as first line regular medication for children with frequent symptoms . Few published studies have compared the safety and efficacy of inhaled corticosteroids with SCG in children . This study compares SCG with the new inhaled corticosteroid , fluticasone propionate ( FP ) , which has theoretical advantages over other currently available corticosteroids due to its negligible oral bioavailability . This was a r and omized , open , multi-centre , parallel group comparison of 50 micrograms FP twice daily and 20 mg SCG four times daily over 8 weeks , preceded by a 2-week baseline period . Sixty-two general practice s and two hospital centres enrolled 225 asthmatic children aged 4 - 12 years ( 110 received FP ; 115 received SCG ) . Outcome measures improved in both groups , with a significant difference in favour of FP for the key variables of mean morning and evening % predicted PEFR and % of symptom-free days and nights . No significant difference was observed for FEV1 , or relief medication use . Two children taking FP and 10 children taking SCG withdrew because of adverse events . This study showed that low dose FP was effective and superior to SCG in young children with mild-moderate asthma . Safety studies of longer duration are needed before changing the current recommendations for inhaled corticosteroid therapy [12117660] BACKGROUND Children with persistent mild to moderate bronchial asthma require anti-inflammatory therapy . According to current treatment guidelines both sodium cromoglycate ( SCG ) and inhaled corticosteroids can be used . If children remain symptomatic despite regular SCG therapy , corticosteroids are the next therapeutic option . AIMS To determine whether combined SCG and fluticasone ( inhaled corticosteroid ) therapy is of additional benefit in children who are symptomatic on SCG compared with simply switching to fluticasone . PATIENTS AND METHODS Children with mild or moderate persistent asthma aged 6 to 16 years who had been treated with inhaled SCG for at least 3 months prior to the study received either 2 mg SCG four times daily from a metered dose inhaler plus fluticasone propionate powder 50 microg b.i.d . from the Diskus inhaler ( group FS ) or fluticasone 50 microg b.i.d . only ( group F ) . The r and omised , controlled , parallel-group study had a 2 week run-in phase and an 8 week treatment period . Morning and evening peak expiratory flow rates ( PEFR ) were measured daily by patients and recorded in diaries . Asthma symptoms , use of rescue medication and spirometry were also documented . RESULTS Paediatricians from 21 study centres recruited 124 children with asthma , of whom 104 fulfilled r and omisation criteria and were allocated to study medication . Morning PEFR increased by 47 l/min and by 45 l/min after 8 weeks of treatment in groups F and FS , respectively . The adjusted difference between groups was 0.84 % of predicted ( 95 % CI , -7.3 to 5.6 , p=0.80 ) . Asthma symptoms and lung function also improved with no significant differences between treatment groups ( p>0.24 ) . Frequency and severity of adverse events was similar in both groups . CONCLUSION In children who are symptomatic while taking sodium cromoglycate four times daily , the combination of inhaled fluticasone and SCG is not superior to fluticasone alone . SCG can safely be withdrawn when commencing fluticasone , thus facilitating asthma treatment [10070568] Asthma is a chronic inflammatory disorder of the airways that is characterized by infiltration of many inflammatory cells into the bronchial mucosa . We compared the effects of ketotifen , disodium cromoglycate ( DSCG ) , and beclomethasone dipropionate ( BDP ) on inflammatory cells in the bronchial mucosa and on the asthma symptoms of patients with atopic asthma . In this 12-week parallel study , 32 patients were r and omly allocated to either the ketotifen group ( 2 mg day-1 , n = 13 ) , DSCG group ( 8 mg day-1 , n = 9 ) or BDP ( 400 micrograms day-1 , n = 10 ) . Each subject recorded daily asthma symptoms and peak expiratory flow ( PEF ) . Before and after treatment , pulmonary function and bronchial responsiveness to methacholine were evaluated , and fibreoptic bronchoscopy and biopsy were performed before and after treatment . Biopsy specimens were obtained by bronchoscopy . We performed immunohistochemistry using specific monoclonal antibodies for activated eosinophils ( EG2 ) , mast cells ( AA1 ) , and T cells ( CD3 , CD4 , and CD8 ) . Our clinical findings showed significant improvement in symptom score and bronchial responsiveness ( P < 0.01 ) each ) in all groups . Both the DSCG and the BDP groups had significantly better symptom scores than the ketotifen group ( P < 0.05 , both groups ) . PEF significantly increased in the DSCG group in comparison to the ketotifen ( P < 0.01 ) and BDP ( P < 0.05 ) groups , FEV1 % increased significantly in the DSCG ( P < 0.01 ) and BDP ( P < 0.05 ) groups in comparison to the ketotifen group . Compared with their baseline values , treatment significantly decreased EG2 + activated eosinophils , and CD3 + and CD4 + T cells , in each group ( P < 0.01 ) . Both the DSCG ( P < 0.05 ) and the BDP groups ( P < 0.01 ) exhibited significant decreases in AA1 + mast cell count , but this was not observed in the ketotifen group . Comparing before- and after-treatment values , only the DSCG group exhibited a significant decrease in the number of CD8 + T cells ( P < 0.01 ) . Ketotifen , DSCG , and BDP all showed anti-inflammatory activity as determined by examination of the bronchial mucosa of asthmatic patients ; and both the DSCG and BDP groups had better clinical responses than the ketotifen group [821577] Neonatal pneumothorax : survey and prevention H V PRICE ........................................................ 456 Relationship between mood disturbances and free and total plasma tryptophan in postpartum women GEORGE STEIN , FRANK MILTON , PENNY BEBBINGTON , KEITH WOOD , ALEC COPPEN .............................................. 457 Treatment of childhood asthma with sodium cromoglycate and beclomethasone dipropionate aerosol singly and in combination I MITCHELL , I C PATERSON , S J CAMERON . , I W B GRANT .................................................. [4948179] D i s o c l i u i n c r o i i i o o l y c a l c ' ( D S C G ) * is t h e ( h s o t l i u m s a l t 1 , 3 b i s ( 2 c a r h o x y c l i r ( ) n i ( ) n i ; y l ( ) x y ) i l i y d r o x y p i o p a i i e ( I ' l .Ul ) I t h a s b e e n c l e m o n s t i a t e d t h a t t h i s s u b s t a n c e w i l l r e d u c e t h e h i o n c h o c o i i s t n c t o n a l I ' c s p o i i s e a l t c i a e r o s o l a l l c i ' n e i i c h a l l e i i i ^ c i n p a t i e n t s s u l l e i ' i n ^ ' I r n n i b r o n c h i a l a s t h m a { .illotniydii 1 9 6 7 ) . Tn a d o u b l e b l i n d t r i a l i t s \ a l u e in t h e lono t e r m t r e a t m e n t o l a s t h m a M a s i n d i c a t e d { . l l l o i i i i Y / i i i & l l o . v c l l ] ( ) G j ) . T h e r e June now lieen repoi'ted a niimbeiol double bliiitl t r i a l s , and most investigators ha\'e re < j , istered a benelicial e f f e c t iVom DSCCi . Thei-c are , ho\\e\er , mai-ked dil lei'eiices in t h e decree ol improxement ni the groups sUidied , probably beeaLisc there has been contro\'ersy about the assessment ol t h e pat ient response [ ll'oolcork & Read i^fi " ? , Grant et al. 1 9 6 7 , Jloicrl & /Illoiinxdii 1 9 6 7 ) . O S C C i acts by prc-\-enti?iL ; ' the release ol histaniine , SRS-A a n d p e r h a p s o the r biologically ac t i \ e substances a l t e r the c o m b i n a t i o n ol r e a l m s wilh the specilic al lergen m t)'pe I a l l e r c^ i e react ion . Voy this i-cason one could expect a [2045618] Facilitated asthma-specialist care delivered by allergists was compared to generalist care on the rate of relapse of asthma emergency room ( ER ) visits and hospitalizations and on asthma control in a prospect i ve , controlled study of San Diego Kaiser Health Plan members with asthma . Subjects with asthma between the ages of 6 and 59 years presenting for acute ER care for asthma were systematic ally assigned by alternating , consecutively , the day of their ER visit to receive either ( 1 ) facilitated referral to an asthma specialist within the allergy department and concomitant comprehensive ongoing asthma care ( intervention group , n = 149 ) or ( 2 ) continued outpatient management from generalist physicians ( control group , n = 160 ) . The course of their asthma was evaluated blindly during the subsequent 6 months by review of medical records , initial and follow-up question naires , and spirometry . Compared to the control group , the intervention group noted ( 1 ) a 75 % reduction in the number of , and percent of , subjects with asthma awakenings per night ( p less than or equal to 0.0001 ) , ( 2 ) an almost 50 % reduction in asthma ER relapses ( p = 0.017 ) result ing from a reduction in the frequency of multiple relapse ( p = 0.005 ) , and ( 3 ) a greater use of inhaled corticosteroids ( p less than 0.00001 ) and cromolyn ( p = 0.002 ) . Thus , facilitated referral of subjects with asthma to specialists in asthma therapy after acute ER therapy appears to reduce asthma ER relapses and to improve asthma outcome [9727762] We investigated the 1-year outcome of children hospitalized for wheezing , paying special attention to the effect of early anti-inflammatory therapy . In addition , we identified risk factors for recurrent wheezing and asthma . Eighty-eight children under 2 years old treated in the hospital for wheezing were followed for 1 year . Nebulized anti-inflammatory therapy was given for 16 weeks : 31 patients received budesonide , 29 patients cromolyn sodium , and 28 control patients received no therapy . The number of subsequent physician-diagnosed wheezing episodes was recorded . Four months of anti-inflammatory therapy did not significantly decrease the occurrence of asthma 1 year later ; 45 % of patients in the cromolyn group , 42 % in the budesonide group , and 61 % in the control group had asthma , defined as at least two bronchial obstruction episodes during the 1-year period after the original hospitalization for wheezing . An age over 12 months at the time of the initial bronchial obstructing episode [ P=0.009 , risk ratio (RR)=5.4 , 95 % confidence interval (CI)=1.53 - 19.31 ] , failure to identify a viral cause ( P=0.0003 , RR=12.0 , CI=3.16 - 45.40 ) , history of wheezing ( P=0.02 , RR=14.6 , CI=1.59 - 132.10 ) , the presence of atopy ( P=0.01 , RR=5.3 , CI=1.47 - 19.21 ) , a family history of atopy ( P=0.03 , RR=3.6 , CI = 1.15 - 11.12 ) , and serum eosinophil cationic protein ( ECP ) > or = 16 microg/L ( P=0.005 ) were significant risk factors for asthma . We conclude that early anti-inflammatory therapy for 4 months does not significantly decrease the occurrence of asthma during the period of 1 year following hospitalization for the original episode of wheezing . Young children requiring hospital admission for wheezing during a respiratory tract infection are at increased risk of having subsequent asthma if they have wheezed previously , if they have atopy or a family history of atopy , if they have elevated serum ECP , if they are over 12 months of age at the original bronchial obstructive episode , and especially when viral studies are negative [4352726] Thirty-one chronic perennial asthmatics aged from 2½ to 16 years were treated with beclomethasone dipropionate pressurized aerosols for up to 20 months . Of these , 16 patients dependent on oral corticosteroid or corticotrophin for up to 11 years were successfully transferred to this treatment , with one exception . Steroid withdrawal symptoms were slight . Loss of weight , disappearance of Cushingoid features , and resumption of growth indicated lack of systemic side effects . Fifteen others inadequately controlled on bronchodilators or disodium cromoglycate , were also effectively treated , and no clinical evidence of adrenal suppression was noted [3105242] ABSTRACT . The efficacy of beclomethasone dipropionate ( BDP ) was compared with sodium cromoglycate ( SCG ) and placebo in a double‐blind parallel group study of 30 asthmatic children over a two‐month period . All the three treatment groups received salbutamol concomitantly . Lung volumes , airway mechanics and the nonspecific bronchial hyperreactivity to carbachol were measured at the beginning and the end of the study . Two patients were excluded because of unequal clinical conditions at the entry and the end of the study and three because of lack of co‐operation . Three patients ( 1 on SCG , 2 on placebo ) dropped out because of worsening clinical symptoms . The improvement in airway mechanics shown by the group treated with BDP ( n=7 ) was significantly greater ( p<0.01 ) than in the group treated with SCG ( n=8 ) . Nonspecific hyperreactivity to carbachol improved significantly in the BDP group ( factor 5.9 ) compared to the SCG group ( factor 1.9 ) . Childhood asthma seems to be better controlled by a combination of BDP and salbutamol , than by SCG and salbutamol [8281343] In this 8-week , double-blind , comparative trial of nedocromil sodium ( 4 mg q.i.d . ) versus placebo in 42 patients with chronic reversible obstructive airways disease , there was a trend in favor of nedocromil sodium compared to placebo in parameters assessed by patients ( nocturnal symptom scores , evening PEFR values ) and those assessed by clinicians ( asthma severity scores ) compared with baseline values . There was a statistically significant difference ( p < 0.05 ) in favor of nedocromil sodium in the inhaled bronchodilator requirements in the last 2 weeks of treatment . Both patients ' and clinicians ' evaluation of the overall efficacy of treatment was significant in favor of nedocromil sodium ( p < 0.01 and p < 0.05 , respectively ) . The treatments were well tolerated by the majority of patients . From these data , it can be concluded that nedocromil sodium ( 4 mg q.i.d . ) is of value in the preventive treatment of chronic reversible obstructive airways disease [1320287] 165 patients ( 106 males , 59 females ) entered an open group comparative study of a 12-week test treatment on bronchial hyperresponsiveness ( BHR ) determined by methacholine challenge . Patients were r and omly allocated to receive nedocromil sodium ( 4 mg q.i.d . ) , sodium cromoglycate ( 10 micrograms q.i.d . ) and beclomethasone dipropionate ( 500 micrograms t.i.d . ) . At the end of the study , an 2.25-fold increase of the PD20FEV1 was noted in all the treated patients . No significant difference was noted among the treatments

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### Context: [407818] Ninety-five children with difficult to treat asthma were given cromolyn in double-blind , crossover studies . Of these , 70 were studied for the next five to six years by open trial cromolyn prophylaxis to determine decreasing dependency on bronchodilators or corticosteroids . Evaluated at two-month intervals , 28 children required prednisone and bronchodilators , 37 required round-the-clock bronchodilators only and five required neither . Peak expiratory flow rates were below 80 % of predicted normal in eight patients , the remaining 62 showed reversibility of airways obstruction . Exercise-induced asthma was reported by 44 during the first two years but persistent improvement in exercise tolerance occurred in 24 patients . IgE specific RAST indicated a continuing extrinsic element in the etiology of 38 of 45 patients tested . Cromolyn was an effective prophylaxis for children with chronic asthma ; however , it was difficult to evaluate in 17 steroid-dependent subjects . Attempts to reduce the need for and especially to discontinue steroids were not as successful as other reports indicate [12949315] OBJECTIVE To compare the effects of 2 nebulizable controller asthma medications on caregiver and pediatric quality of life . METHODS In this 52-week , r and omized trial , children aged 2 to 6 years with mild to moderate persistent asthma received budesonide inhalation suspension 0.5 mg ( total daily dose ) once or twice daily ( n = 168 ) or cromolyn sodium nebulizer solution 20 mg 4 times daily ( n = 167 ) for 8 weeks , with dosage adjustment thereafter at the investigators ' discretion . The Pediatric Asthma Caregiver 's Quality of Life Question naire ( PACQLQ ) , Compliance/Caregiver Satisfaction Question naire ( CCSQ ) , Modified Child Health Question naire-Parent Form 50 ( CHQ-PF50 ) , and Functional Status-II(R ) ( FS-II[R ] ) Question naire were administered at baseline and weeks 8 , 28 , and 52 . Global assessment s of ease of asthma management and child health status were obtained from caregivers and physicians at the end of the study . RESULTS Improvements from baseline in domain-specific ( activities and emotional function ) and total PACQLQ scores were greater at each time point ( weeks 8 , 28 , and 52 ) for caregivers of patients treated with budesonide compared with caregivers of patients receiving cromolyn sodium . Only the budesonide group met the criterion for a clinical ly important improvement ( > or=0.5 unit change ) in all PACQLQ domains by week 8 , which was maintained at weeks 28 and 52 . Moreover , improvements surpassed the criterion for moderate clinical importance ( 1.0 unit change ) in all PACQLQ domains for the budesonide group , but this level of improvement was only achieved in the activities domain ( at week 28 ) for the cromolyn sodium group . Based on the CCSQ , budesonide result ed in greater caregiver satisfaction , treatment convenience , ease of use , and compliance compared with cromolyn sodium . Thus , 90.7 % of caregivers in the budesonide group were " completely or very satisfied " compared with 53.4 % in the cromolyn sodium group . Over half ( 54.6 % ) of caregivers in the budesonide group rated budesonide " highly or very convenient " compared with 23 % for cromolyn sodium ; 77 % rated budesonide " extremely or very easy " to use compared with 47 % for cromolyn . Adherence with daily medication regimens was reported for 76 % of children in the budesonide group compared with 57 % in the cromolyn sodium group . Child health status , as indicated by mean FS-II(R ) scores , showed improvements from baseline in both groups at weeks 8 , 28 , and 52 . There was a trend for these improvements to be superior in the budesonide group . Additionally , budesonide was superior to cromolyn sodium in caregiver and physician global assessment s. At the end of the study , 76 % of caregivers of children receiving budesonide reported asthma management to be " a great deal easier " compared with the start of the study , and 74 % rated the overall health status of their child as " much better now than 1 year ago . " In contrast , only 29 % and 37 % of caregivers whose children received cromolyn sodium provided these respective ratings . CONCLUSIONS Budesonide inhalation suspension improved the quality of life for caregivers of children with asthma . Caregivers of children treated with budesonide had significantly fewer limitations in daily activities and emotional functioning compared with caregivers of children treated with cromolyn sodium nebulizer solution . The improvements in caregiver quality of life occurred earlier with budesonide compared with cromolyn sodium . Only caregivers in the budesonide group had a clinical ly important mean change from baseline in all PACQLQ domains by week 8 . These benefits were maintained at week 52 . Children treated with budesonide inhalation suspension and cromolyn sodium experienced improvements in health status , assessed using the FS-II(R ) . The greatest differences between treatments were seen in the disease-specific portion of the FS-II(R ) , which relates impairments in functional status to the child 's illness . Caregiver and physician global assessment indicated significantly better overall child health after 1 year of treatment with budesonide , supporting an improvement in health status . Clinical trials in children 4 to 16 years of age with asthma have demonstrated greater effectiveness of inhaled corticosteroids versus cromolyn sodium on several clinical measures of efficacy . Measures of asthma control in this study , reported in detail elsewhere [ Leflein et al. Pediatrics 2002;109:866 - 872 ] , also have shown greater improvements with budesonide therapy . Treatment with budesonide inhalation suspension result ed in a significantly lower mean rate of asthma exacerbations , significantly longer times to first asthma exacerbation , significantly longer times to first additional use of chronic asthma therapy , and significant improvements in asthma symptom scores and breakthrough medication use compared with cromolyn sodium therapy . Additionally , children receiving budesonide inhalation suspension experienced more symptom-free days and episode-free days compared with children receiving cromolyn sodium . Safety profiles were similar between the 2 treatment groups . Budesonide inhalation suspension was associated with significantly greater caregiver satisfaction , convenience , ease of use , and compliance compared with cromolyn sodium nebulizer solution . This greater caregiver satisfaction and quality of life may be related to the greater asthma control achieved in children treated with budesonide therapy compared with cromolyn sodium . In addition , the convenience of once- or twice-daily dosing with budesonide inhalation suspension , compared with 3- or 4-times-daily dosing of cromolyn sodium , may decrease caregiver burden and enhance the willingness of caregivers to adhere to treatment regimens prescribed for their young children with asthma . This effect on caregiver adherence could further improve treatment effectiveness . This is the first clinical trial comparing the effects of a nebulized corticosteroid with that of an alternative nebulized therapy on quality of life in young children with asthma and their families . Compared with nebulized cromolyn sodium , budesonide inhalation suspension not only provides better overall child health status and asthma management , but greater caregiver quality of life and greater caregiver satisfaction , convenience , ease of use , and compliance [8576655] The effect of single-dose inhaled terbutaline , sodium cromo-glycate and budesonide were compared with control in 11 exercise-induced asthma ( EIA ) patients , aged 9 - 14 years . Patients exercise for 6 minutes , 15 minutes after inhaling drugs . The FVC , FEV1 , PEFR and MMEF were recorded before exercise and after exercise at 5 minutes interval up to 25 minutes . After exercise , the mean ( SEM ) maximal percentage fall in FEV1 after placebo , 200 micrograms of terbutaline , 10 mg of sodium cromoglycate , and 100 micrograms of budesonide were 22.81 ( 3.45 ) , 4.05 ( 2.11 ) , 11.29 ( 1.18 ) , and 20.36 ( 2.33 ) respectively . It was concluded that single-dose inhaled terbutaline and sodium cromoglycate result ed in a significant protective effect on exerxide-induced asthma whereas budesonide did not [14572325] The objective of this study was to analyze data on parents ' adherence to their child 's prescribed nebulizer treatment regimen and compliance with the dem and s of the nebulizer and the face mask . Data on adherence and compliance were recorded in a 24-week double-blind , r and omized , parallel-group study with budesonide inhalation suspension in 125 young children with mild to moderate asthma . Budesonide was administered with an Adaptive Aerosol Delivery ( AAD ) system , which recorded adherence to treatment and compliance with the AAD system . A total of 35,481 treatments were recorded and analyzed . A study question naire regarding the parents ' and children 's acceptance of the AAD system has also been analyzed . The adherence to the treatment regimen was 91.3 % , and the compliance with the AAD system was 90.4 % . True adherence , the product of adherence and compliance , was 82.5 % . Approximately 90 % of the parents found the face mask easy to seal and the AAD equipment easy to use , and over 90 % of the children accepted it within 1 week . In conclusion , the results indicate that the AAD system could be of real clinical advantage for treatment of asthma in young children [4996164] Cromolyn sodium , a specific inhibitor of mediator release induced by antigen-antibody interaction , was studied for corticosteroid sparing effect and clinical usefulness in a double-blind double-crossover , and in a subsequent open trial in 30 corticosteroid-dependent adults with severe perennial asthma . Of 29 patients completing the trials , 19 had corticosteroid dose reduction while receiving cromolyn in the double-blind trial , and 22 had corticosteroid dose reduction in the open trial . Cromolyn was judged to be clinical ly useful for corticosteroid sparing effect or symptomatic improvement , however , in only ten patients . Corticosteroid sparing effect and clinical usefulness were noted in all types of asthmatics studied . One patient noted increased asthma following inhalation of either cromolyn or placebo and did not complete the trial ; no adverse effects of cromolyn per se were noted [9020413] We investigated whether sodium cromoglycate 10 mg three times daily , delivered as an aerosol via Nebuhaler ( in addition to terbutaline 0.5 mg three times daily ) , could replace inhaled steroid in children with mild‐to‐moderate asthma . Children ( mean age 10.3 years ) were r and omly allocated to 12‐week treatment with sodium cromoglycate 10 mg plus terbutaline 0.5 mg ( group A ; n= 30 ) or placebo plus terbutaline 0.5 mg ( group B ; n= 32 ) , both taken three times a day . The daily steroid dose was reduced by 50 μg/week for 4 weeks from a starting dose of 200 μg . Fewer patients withdrew owing to worsening asthma from group A ( n= 1 ) than group B ( n = 11 ) . Symptom scores , morning and evening peak flows , and additional β2‐agonist usage , recorded on diary cards , were better in group A than group B. Lung function measured at clinic visits was unchanged in either group . Overall opinions of efficacy favoured Group A. Adverse events were similar in the groups . Sodium cromoglycate plus terbutaline substituted effectively for inhaled steroid therapy [8036306] In a controlled prospect i ve study we have measured growth and pulmonary function in children with asthma during long-term treatment with inhaled budesonide and compared these findings with those obtained from children not treated with corticosteroids . Two hundred and sixteen children were followed at 6 monthly intervals for 1 - 2 years without inhaled budesonide and then for 3 - 6 years on inhaled budesonide . Sixty-two children treated with theophylline , beta 2-agonists and sodium-cromoglycate but not with inhaled steroids were also followed for 3 - 7 years ( controls ) . During the period of budesonide therapy the mean daily dose decreased from 710 to 430 micrograms ( P < 0.01 ) and no signs of tachyphylaxis to the treatment were seen . Budesonide treatment was associated with a significant reduction in the number of annual hospital admissions due to acute severe asthma ( from 0.03 to 0.004 per child , P < 0.001 ) . In patients not treated with budesonide an annual decrease in % predicted FEV1 of 1 - 3 % was seen . In contrast FEV1 improved significantly with time during budesonide treatment , both compared with the run-in period and with the control group ( P < 0.01 ) . Furthermore , there was a significant ( P = 0.01 ) relationship between the duration of asthma at the start of budesonide and the annual increase in FEV1 during budesonide therapy . After 3 years of treatment with budesonide , children who started this therapy later than 5 years after the onset of asthma had significantly lower FEV1 ( 96 % ) than the children who received budesonide within the first 2 years after the onset of asthma ( 101 % ) ( P < 0.05 ) . ( ABSTRACT TRUNCATED AT 250 WORDS [10213547] BACKGROUND Inhalation therapy with sodium cromoglycate is recommended as the first-line prophylactic treatment for moderate asthma in children . The availability of spacer devices with face-masks has extended the applicability of metered-dose inhalers to younger children . We studied the feasibility and effects of this therapy compared with placebo in children aged 1 - 4 years . METHODS 218 children aged 1 - 4 years with moderate asthma were recruited through 151 general practitioners between March , 1995 , and March , 1996 . They were r and omly assigned sodium cromoglycate ( 10 mg three times daily ) or placebo , given by inhaler with spacer device and face-mask for 5 months . Rescue medication ( ipratropium plus fenoterol aerosol ) was available during the baseline period of 1 month and the intervention period . Parents completed a daily symptom-score list . The primary outcome measure was the proportion of symptom-free days in months 2 to 5 . Analysis was by both intention to treat and on treatment . FINDINGS 167 ( 77 % ) children completed the trial . 131 ( 78 % ) of these children used at least 80 % of the recommended dose . Of the 51 children who stopped prematurely , 23 had difficulties with inhaled treatment . The mean proportion of symptom-free days for both groups was greater for the treatment period than for the baseline period ( 95 % CI for mean difference 5.1 to 17.5 cromoglycate , 11.9 to 23.3 placebo ) . However there were no differences between the sodium cromoglycate and placebo groups in the proportion of symptom-free days ( mean 65.7 [ SD 25.3 ] vs 64.3 [24.5]% ; 95 % CI for difference -8.46 to 5.70 ) or in any other outcome measure . INTERPRETATION Our study in a general practice setting shows that inhalation therapy with a spacer device and face-mask is feasible in a majority of children below the age of 4 years . However , long-term prophylactic therapy with inhaled sodium cromoglycate is not more effective than placebo in this age-group [2500361] Twenty two allergic patients with bronchial asthma completed this study . Effects of long-term treatment with inhaled cromoglycate 4 x 2 mg.day-1 were compared to the effects of inhaled budesonide 4 x 0.1 mg.day-1 on symptoms , additional beta 2-agonist use , lung function and bronchial hyperresponsiveness measured by the provocation concentration of histamine producing a 20 % fall in forced expiratory volume in one second ( FEV1 ) ( PC20 histamine ) and exercise-induced fall in FEV1 . The study was carried out in a double-blind way with a r and omized crossover design using a double-dummy technique . After a single-blind placebo period , the two active treatment periods of 6 weeks were separated by a single-blind placebo period . Symptom score and beta 2-agonist use decreased during both active treatment periods , which showed no mutual differences . Morning and evening peak expiratory flow rates were significantly higher during treatment with budesonide versus placebo ( p less than 0.01 and p less than 0.001 ) , and also versus cromoglycate ( p less than 0.02 and p less than 0.05 ) . FEV1 showed improvement after a 6 week treatment with budesonide versus placebo ( p less than 0.05 ) , although there was no significant difference between the two active treatments . PC20 histamine did not change during treatment with cromoglycate . Budesonide showed a significant increase in PC20 histamine versus placebo ( p less than 0.05 ) and was marginally significantly better than cromoglycate ( p = 0.05 ) . Exercise-induced fall in FEV1 was not changed by cromoglycate , but improved significantly during budesonide in comparison with placebo ( p less than 0.01 ) and also with cromoglycate ( p less than 0.001 ) . ( ABSTRACT TRUNCATED AT 250 WORDS [407559] A double-blind , cross-over study was undertaken to compare inhalation of betamethasone valerate ( BV , 800 microgram daily ) with sodium cromoglycate ( SCG , 80 mg daily ) in twenty children requiring bronchodilators for perennial asthma . Each treatment period lasted 4 weeks but statistical comparisons were made only in respect of the last 14 days of each therapy . When the children were using BV they required not only less of the bronchodilator drugs but had fewer symptoms and higher daily peak expiratory flow rates when taking SCG . Statistically , all these differences were highly significant . For 2 weeks before the main trial each child was given a placebo aerosol ( single-blind ) to assess severity of asthma . In comparison with this period , SCG was associated with a significantly increased peak expiratory flow rate a lower symptom score by day but not by night , but their usage of bronchodilators followed a similar pattern . When the BV period was compared with the placebo period , patients had an even more significant rise in peak expiratory flow rate , less day and night symptoms , and took hardly any bronchodilators . The response to the two drugs did seem to depend upon which was given first . No monilial infections were found , nor any measurable defect in adrenal response from either treatment . Betamethasone valerate is considered to be superior to sodium cromoglycate as a treatment for childhood asthma insufficiently controlled on bronchodilators [14754977] OBJECTIVE Our aim was to compare the 12-month safety and efficacy of fluticasone propionate ( FP ) and sodium cromoglycate ( SCG ) in children aged 1 to 3 years with mild to moderate recurrent wheeze . METHODS The study was a r and omized , parallel-group , open-label multicenter study of 625 children , aged 1 to 3 years , with recurrent wheeze r and omized in a 3:1 ratio to treatment for 52 weeks with FP ( 100 microg twice daily ) via metered-dose inhaler and Babyhaler spacer device or SCG ( 5 mg 4 times daily ) via metered-dose inhaler and Nebuhaler spacer device , respectively . RESULTS There was no significant difference in mean adjusted growth rates between the 2 groups : 84.0 mm/year in the FP group versus 86.4 mm/year in the SCG group ( difference FP-SCG : -2.4 mm/year ; 95 % confidence interval : -6.6 to 1.8 ) . Growth comparisons were independent of age , gender , previous use of steroid , or whether measured as length and /or height . Serum and urinary cortisol concentrations showed a statistically significant suppression of 10 % and 14 % , respectively , but the number of patients with serum cortisol levels below the lower normal limit was reduced during the trial . Both treatments were well tolerated . The most common drug-related adverse events were cough ( 2 % FP vs 1 % SCG ) and hoarseness ( 1 % FP vs 0 % SCG ) . One incident of cataract was observed at baseline and 1 after FP treatment ; the latter had resolved after 12 months . The efficacy of FP was superior to SCG with fewer cases of symptom worsening , exacerbations , and requirements for oral steroid treatment and more symptom-free days and days without use of rescue treatment . CONCLUSIONS Twelve months of treatment with inhaled FP ( 100 microg twice daily ) in preschool children aged 1 to 3 years with recurrent wheeze has no effect on growth and no other clinical ly important side effects but is more efficacious than SCG [406103] A double‐blind comparison of betamethasone valerate , sodium cromoglycate and the combination of these two treatments was carried out in twenty‐two adult patients with asthma . Regular fortnightly assessment s were made in the clinic throughout the study and adrenal function was monitored and found to be normal . All patients measured their peak expiratory flow rates in the morning and evening and monitored their symptoms daily on a record card as well as recording bronchodilator usage . Assessment using these parameters indicated that treatment with betamethasone valerate compared with sodium cromoglycate result ed in an improvement in the patients ’ asthma which was statistically significant ( P<0.001 ) . Overall the combined treatment produced a better response than sodium cromoglycate ( P<0.02 ) but a poorer response compared with the steroid aerosol given alone ( P>0.05 ) . In only two patients was the response to the combined therapy significantly greater than to either drug given alone [11379805] BACKGROUND Budesonide and sodium cromoglycate are both recommended as maintenance therapy for childhood asthma . OBJECTIVE To compare the cost-effectiveness of these two treatment strategies in clinical practice , in an open-label , pharmacoeconomic clinical trial . METHODS Health economics were evaluated in 138 children , ages 5 to 11 years , with unstable asthma not previously treated with corticosteroids or cromones . The asthma was stabilized during 4 to 6 weeks with budesonide 200 to 400 microg twice daily . The children were then r and omly allocated to one of the two treatment strategies aim ing at maintaining asthma control for 12 months ; budesonide 400 microg/day ( N = 69 ) or sodium cromoglycate 60 mg/day ( N = 69 ) . If asthma control was judged unsatisfactory , the doses were increased or the children were switched to the alternate treatment . RESULTS In children continuing on the same treatment , the degree of asthma control was similar in the two groups at study end . To maintain asthma control , 42 % of cromoglycate children switched to budesonide , and then experienced a 14 % increase in symptom-free days . No budesonide patient had to switch therapy because of lack of asthma control . Although not statistically significant , total annual cost per patient was 24 % ( Swedish kronor 4195 ; US $ 487 ; Euro 485 ) lower in the budesonide than the cromoglycate group , mainly due to a lower cost for asthma medication . CONCLUSIONS A budesonide strategy for continued maintenance treatment , after an initial period of stabilizing treatment with budesonide , result ed in lower costs and less drug switches than did a strategy with sodium cromoglycate [7653745] This study compared the efficacy and tolerability of sodium cromoglycate ( SC ) and beclomethasone dipropionate ( BDP ) in adult patients with bronchial asthma inadequately treated with bronchodilators alone . The study was a double‐blind , r and omized , double‐dummy , parallel‐group study . Patients with mild to moderate symptomatic asthma , inadequately treated with bronchodilators only , were , after a 2–week run‐in ( base‐line ) period , r and omized to 8 weeks of treatment with either SC 10 mg four times daily or BDP 100 μg four times daily . Salbutamol metered‐dose inhaler was given as relief medication . A total of 37 patients were r and omized for treatment , 19 patients in the SC group and 18 patients in the BD group . Efficacy and safety were determined by daily record card data : morning and evening peak‐expiratory‐flow rates ( PEER ) , daytime and nighttime asthma symptom scores , and rescue salbutamol use . At clinic visits , FEV1 and FVC were measured , as were the physician 's and the patient 's assessment of the medication at the end of the study . The safety and tolerability of the trial medication were assessed by monitoring adverse events throughout the study . A clinical ly and statistically significant improvement of the asthma in FEV1 , symptom scores , rescue medication , and global opinion of efficacy was observed , and both groups provided equivalent efficacy . The morning PEFR as well as the evening PEFR for both groups improved , but was statistically significant only for the BDP group ( M‐PEFR ) . Both drugs were well tolerated with only a few minor adverse events . This trial shows that SC and BDP are equally effective anti‐inflammatory treatments for mild to moderate bronchial asthma in adults [4197916] Cromolyn sodium is a new antiasthmatic drug which exerts its action by interfering with the release of the mediators of immediate hypersensitivity reactions from the sensitized mast cells lining the bronchial tree . In a double-blind crossover trial , 36 children with chronic intractable asthma , 23 of whom were corticosteroid dependent , inhaled cromolyn sodium or a placebo four times per day for two 4 week periods . Although clinical improvement with cromolyn therapy was not statistically superior to the placebo , 36 patients noted subjective improvement from the cromolyn sodium and entered a 12 month open-end clinical trial . Twenty-six patients completed this second study ; 19 of them showed clinical improvement . Of the 18 steroid-dependent patients who completed 12 months of cromolyn sodium therapy , 7 discontinued corticosteroids , 10 decreased their dosage , and one patient increased his corticosteroid requirement . Even though cromolyn sodium is not always clinical ly efficacious , it should be considered in the management of intractable asthma in children [12882461] Regular salbutamol use can exacerbate allergen-induced airway eosinophilia in asthmatics , but its effect on airway eosinophil chemokine responses is unknown . Asthmatic subjects ( n=14 ) were treated for 10 days with placebo or salbutamol in a double-blind , cross-over study , then given same-dose allergen challenges . Their sputa were then analysed 1 and 7 h later for a panel of eosinophil-related cytokines . Eosinophils from five test and three control subjects were tested for expression of CXCL8/interleukin (IL)‐8 , and its receptors and responsiveness to CCL11/eotaxin and CXCL8/IL‐8 . Sputum CXCL8/IL‐8 , but not IL‐5 , CCL5/regulated on activation , T‐cell expressed and secreted , CCL7/monocyte chemotactic protein‐3 , CCL11/eotaxin , granulocyte-macrophage colony-stimulating factor or tumour necrosis factor levels , were increased ( 42 % ) by the salbutamol treatments . The CXCL8/IL‐8 levels correlated with the proportions of sputum eosinophils and these cells , but not other sputum cells , stained strongly for CXCL8/IL‐8 . The circulating eosinophils of the tested subjects ( n=5 ) expressed CXCL8/IL‐8 receptors and secreted high levels of this chemokine . Neutralisation of sputum CXCL8/IL‐8 reduced eosinophil chemotactic responses to these sample s by 19±5 % . These data suggest that regular use of salbutamol can augment airway CXCL8/interleukin‐8 responses to allergen challenge and that this CXCL8/interleukin‐8 could contribute to the airway inflammatory response [3106449] Single-dose salbutamol ( 200 micrograms ) , beclomethasone dipropionate ( 200 micrograms ) , and sodium cromoglycate ( SCG ) ( 10 mg ) administered by inhalation 10 minutes before allergen challenge were examined with regard to inhibition of allergen-induced early ( EAR ) and late ( LAR ) asthmatic responses and allergen-induced increase in bronchial responsiveness to inhaled histamine . Ten atopic subjects with asthma participated in a blinded , crossover , placebo-controlled trial . The EAR was inhibited by salbutamol and SCG but not by beclomethasone dipropionate or placebo ( p less than 0.01 ) . The LAR ( p less than 0.01 ) and the allergen-induced increased bronchial responsiveness to histamine 7 hours ( p less than 0.01 ) and 30 hours ( p less than 0.05 and p less than 0.01 for various comparisons ) were inhibited by SCG and beclomethasone diproprionate but not by salbutamol or placebo . The allergen-induced LAR and associated increased responsiveness are now believed to be more important clinical ly than the EAR . The clinical relevance of these results is to stress the importance of the prophylactic nonbronchodilator drugs ( SCG and steroids ) and the potential inadequacy of bronchodilators used alone in the treatment of both perennial and seasonal allergic asthma [1955633] Although both cromolyn ( C ) and inhaled corticosteroids are anti-inflammatory therapies for childhood asthma , there are few controlled comparisons of these medications for asthma therapy in children . None were conducted in the United States , and none specifically study triamcinolone acetonide ( T ) versus C. This 12-week evaluation followed 31 youths , aged 8 to 18 years , with moderate asthma who were assigned to receive C or T according to a prer and omized and blinded code . Patients were instructed to take two inhalations from the study metered-dose inhaler ( active T or placebo ) and to inhale the contents of one study -provided ampule ( C , 20 mg , or placebo ) from a compressor-driven home nebulizer three times per day . Patients also used albuterol , two inhalations from a metered-dose inhaler , three times a day ( before study medication ) and , additionally , if needed . Patients maintained a daily diary , recording extra medication use , adverse experiences , peak flow rates morning and night , and asthma symptom scores . Laboratory assessment of pulmonary function was done at 1 , 4 , 8 , and 12 weeks . Cosyntropin challenge and methacholine bronchoprovocation challenge were performed at the beginning and end of the study . C and T provided similar , adequate asthma control . Symptoms of wheezing , cough , and chest tightness decreased , and daily peak expiratory flow rate increased with both regimens compared to during a 2-week baseline when patients received medication only as needed . There was no significant change in methacholine sensitivity and no change in endocrine function , as measured with fasting plasma control before and after administration of cosyntropin . ( ABSTRACT TRUNCATED AT 250 WORDS [6782146] Some patients with chronic asthma treated with beclomethasone aerosol ( BA ) derive significant symptom benefit , yet have persisting adrenal suppression due in part to their BA therapy . The daily dose of BA required is higher in patients with atopy . We therefore assessed the usefulness of ancillary treatment with cromolyn sodium ( CS ) , a drug known to inhibit atopic asthma , to try to improve the balance of risk vs benefit in such patients . Thirty asthmatics , well controlled on high-dose BA ( mean , 1,040 micrograms + /- 97 SE ) but with morning cortisol levels averaging approximately 10 micrograms/dl , were allocated r and omly to placebo or CS inhalant , used in addition to their regular BA and other asthma medications . After 4 wk , their BA dose was halved . Both groups were monitored for greater than 6 mo by daily symptom diaries and peak flows , and by spirograms and morning serum cortisol tests every 4 wk . Mean cortisol levels rose 27 % after BA dose reduction ( p less than 0.05 ) but asthma worsened . Risk-benefit assessment s 20 wk after reducing the BA showed a general tendency for higher cortisol values to be coupled with worsening of the asthma symptoms and FEF25%-75 % . The distributions of good , fair , and poor risk-benefit responses were the same in both CS and placebo-treated groups ( p = 0.20 ) . In other asthmatics who may have less associated bronchitis or small airways obstruction than these patients , CS might prove useful , but in these adult chronic asthmatics with this particular therapeutic problem , there was no discernible BA-sparing effect or other clinical advantage from adding CS to their established BA regimen [9330414] The aim of this study was to compare accurately measured growth over 12 months in asthmatic children treated with either fluticasone propionate ( FP ) 50 micrograms twice daily ( b.i.d . ) or sodium cromoglycate ( SCG ) 20 mg four times daily ( q.i.d . ) . After a 2-week run-in , asthmatic children aged 4 - 10 years from 15 UK centers were r and omized in a 3:4 ratio to open-label FP ( n = 52 ) or SCG ( n = 70 ) . After 8 weeks , those whose asthma was not adequately controlled were switched from SCG to FP or withdrawn . St and ing height was measured ( Holtain stadiometry ) at baseline , after 8 weeks and at 6 weeks intervals thereafter for 1 year . Morning peak flows ( PEFam ) were recorded by patients for 2 weeks during baseline , and 1 week before each visit during treatment . Urinary free cortisol ( 24 h ) was measured at baseline , 6 months , and 1 year . After 8 weeks , 22 patients were withdrawn from SCG group ( and were switched to FP ) , and five patients were withdrawn from the FP group due to poor asthma control . A further 21 and 11 patients were withdrawn from the SCG and FP groups , respectively , during the course of the study . There were no significant differences between patients who received FP and SCG for 1 year ( n = 34 and n = 26 , respectively ) in terms of height velocity adjusted for age and gender ( HV ) , or height velocity st and ard deviation scores adjusted for gender ( HVSDS ) . Mean HV ( mean HVSDS ) were 6.0 cm/yr ( 0.1 ) and 6.5 cm/yr ( 0.5 ) for FP and SCG , respectively . There were no treatment differences in mean 24 h urinary free cortisol levels at 6 and 12 months . Mean % predicted PEFam improved over 1 year in both groups but to a greater degree in the FP group . We concluded that growth was normal in mildly asthmatic children receiving FP ( 50 micrograms bid ) for 1 year . There were fewer withdrawals and lung function improved to a greater extent in FP treated patients than in patients receiving SCG [12847475] BACKGROUND Salmeterol ( SLM ) is a long-acting beta(2)-receptor agonist that produces bronchodilatation for 12 hours in asthmatic subjects . The effects of the regular use of long-acting beta(2)-agonists on airway inflammation are largely unknown . OBJECTIVES We examined the effects of 16 weeks of treatment with 50 microg SLM bid , 250 microg fluticasone propionate ( FP ) bid,5 mg disodium cromoglycate ( DSCG ) qid , or placebo on airway inflammation in bronchial mucosa . METHODS Airway inflammation was assessed in bronchial biopsy specimens before and after treatments and bronchial hyperresponsiveness ( BHR ) in 80 patients with newly diagnosed asthma . Inflammatory cells and tenascin in the basement membrane were studied with immunohistochemical methods . Peak expiratory flow rate ( PEF ) , symptoms , and need for rescue medication were recorded . RESULTS SLM , FP , and DSCG reduced symptoms and need for rescue medication ( P < .04 ) . Both SLM and FP improved PEF and increased PD15FEV(1 ) to histamine by 2.8 and 5.2 doubling dose units , respectively . Both compounds reduced BHR more than placebo ( P < .05 ) . Both SLM and placebo had no effect on any inflammatory cell type . In both FP-treated and DSCG-treated patients , the number of EG2-positive eosinophils in the airway mucosa decreased ( P = .002 and P < .05 , respectively ) . CONCLUSIONS SLM showed no anti-eosinophil properties in this study , but it provided good symptom control . FP provided the best anti-eosinophil properties and symptom relief of the studied compounds [12457002] Background and Objectives : To investigate the therapeutic equivalence of the two formulations of the glucocorticosteroid budesonide delivered either by the budesonide Novolizer ® , i.e. a multidose dry powder inhaler , or by the Pulmicort ® Turbuhaler ® in asthmatic patients in terms of efficacy , safety and tolerability during a 12-week treatment . Methods : A total of 315 patients were r and omised in this open , multicentre study . Inclusion criteria comprised previously diagnosed bronchial asthma of mild to moderate persistent intensity ( ranging from 60 % to a maximum of 90 % predicted FEV1 ) , need for anti-inflammatory therapy , inhalation of β2-sympathomimetics on an as needed to regular basis , reversibility of airway obstruction of > 12 % after inhalation of 2 actuations of 100 µg salbutamol . Primary variable was FEV1 , secondary were other pulmonary function test variables , PC20FEV1 for histamine challenge , morning and evening PEFR , salbutamol usage , asthma symptoms , reactions after inhalation , st and ard safety variables . Results : The comparison of the FEV1 at study endpoint indicated that the Novolizer ® was at least as efficacious as the Turbuhaler ® ( p < 0.001 ) . All other variables of the pulmonary function tests as well as the asthma symptoms , nocturnal awakenings , PEFR measurements , or salbutamol usage indicated no relevant difference . Only 1 patient ( Turbuhaler ® ) discontinued prematurely due to lack of efficacy . None of the other safety variables ( adverse events , laboratory variables , vital signs , etc . ) indicated any difference between the groups . Conclusions : The budesonide Novolizer ® is therapeutically equivalent to the Pulmicort ® Turbuhaler ® for the long-term treatment of patients with mild to moderate persistent asthma [2825567] To determine whether 4 drugs used in the treatment of asthma inhibit the late asthmatic reaction and the associated increase in airway responsiveness induced by toluene diisocyanate ( TDI ) , we studied 24 sensitized subjects divided into 4 groups . Beclomethasone aerosol ( 1 mg bid ) , slow-release theophylline ( 6.5 mg/kg bid ) , slow-release verapamil ( 120 mg bid ) , and cromolyn ( 20 mg qid via spinhaler ) , were administered for 7 days , respectively , to 1 of the 4 groups , according to a double-blind , crossover , placebo-controlled study design . When the subjects were treated with placebo , verapamil , or cromolyn , FEV1 markedly decreased and airway responsiveness increased after exposure to TDI . By contrast , beclomethasone prevented the late asthmatic reaction and the associated increase in airway responsiveness to methacholine induced by TDI . Slow-release theophylline partially inhibited both the immediate and the late asthmatic reactions but had no effect on airway hyperresponsiveness to methacholine . These results suggest that only high-dose inhaled steroids can completely block TDI-induced late asthmatic reactions [12672309] BACKGROUND Although inhaled glucocorticosteroids are recommended for persistent asthma , their long-term effect on recent onset , mild , persistent asthma has yet to be established . METHODS We did a r and omised , double-blind clinical trial in 7241 patients in 32 countries to assess the effects of budesonide in patients who had had mild persistent asthma for less than 2 years and who had not had previous regular treatment with glucocorticosteroids . Patients aged 5 - 66 years received either budesonide or placebo once daily for 3 years in addition to their usual asthma medications . The daily budesonide dose was 400 microg , or 200 microg for children younger than 11 years . The primary outcome was time to first severe asthma-related event , and analysis was by intention to treat . FINDINGS 198 of 3568 patients on placebo and 117 of 3597 on budesonide had at least one severe asthma exacerbation ; hazard ratio 0.56 ( 95 % CI 0.45 - 0.71 , p<0.0001 ) . Patients on budesonide had fewer courses of systemic corticosteroids and more symptom-free days than did those on placebo . Compared with placebo , budesonide increased postbronchodilator forced expiratory volume in 1 s ( FEV1 ) from baseline by 1.48 % ( p<0.0001 ) after 1 year and by 0.88 % ( p=0.0005 ) after 3 years ( expressed as percent of the predicted value ) . The corresponding increase in prebronchodilator FEV1 was 2.24 % after 1 year and 1.71 % after 3 years ( p<0.0001 at both timepoints ) . The effect of treatment on all outcome variables was independent of the baseline lung function ( prebronchodilator or postbronchodilator ) or baseline medication . In children younger than 11 years , 3-year growth was reduced in the budesonide group by 1.34 cm . The reduction was greatest in the first year of treatment ( 0.58 cm ) than years 2 and 3 ( 0.43 cm and 0.33 cm , respectively ) . INTERPRETATION Long-term , once-daily treatment with low-dose budesonide decreases the risk of severe exacerbations and improves asthma control in patients with mild persistent asthma of recent onset [14579993] Introduction . There are no available data on the safety of recommended schedules for the initiation of treatment with budesonide inhalation suspension in children with recurrent wheezing episodes . We compared the safety of high and low starting dose of budesonide by measuring their effect on plasma cortisol concentration . Methods . A r and omized double-blind , placebo-controlled design was used . Twenty-nine children ages 6 months to 3 years were divided into three groups : ( 1 ) high starting dose : 1 mg budesonide inhalation suspension twice daily followed by a stepwise decrease of 25 % every second day for 8 days ( n = 11 ) ; ( 2 ) low starting dose : 0.25 mg twice daily for 8 days ( n = 11 ) ; ( 3 ) placebo ( n = 7 ) . The 8 AM ( fasting ) and 1-hour post-ACTH stimulation plasma cortisol concentrations were measured before and 10 days after initiation of budesonide treatment . Results . Before treatment and after 8–10 days of treatment , there was no significant difference in mean serum cortisol concentration in the high starting dose , low-dose and placebo groups , either at 8 AM or at 1 hour after ACTH stimulation . Conclusion . The administration of nebulized suspension of budesonide at a high starting dose ( 2 mg/day for 2 days ) followed by a rapid stepwise decrease over 8 days was safe , causing similar changes in serum cortisol levels to low-dose budesonide suspension or placebo [3110248] After a run-in period of 2 weeks , receiving a regimen of inhaled beta 2-agonists and /or theophyllines , 38 atopic patients with asthma with perennial symptoms were r and omly allocated to receive an 8-week treatment of additional inhalation treatment with either sodium cromoglycate ( SCG ) , 2 mg four times daily , and placebo beclomethasone dipropionate ( BDP ) , or BDP , 200 micrograms twice daily , and placebo SCG . After crossover , each group received the opposite treatment for the final 8 weeks . FEV1 , FVC , and provocation concentration of histamine causing a 20 % fall in FEV1 ( PC20 ) were determined monthly and peak expiratory flow ( PEF ) daily throughout the study . A significant increase in FEV1 , FVC , and PEF ( p less than 0.01 ) was observed after BDP treatment was started , and likewise , in the second period , an increase in both FEV1 and PEF ( p less than 0.05 ) was observed . The total effect on logarithm-natural ( Ln ) ( PC20 ) , i.e. , the mean effects of the two periods , was also significant ( p less than 0.01 ) . SCG , however , was most effective when it was used as the first drug , indicated by a significant increase in FVC in the first period ( p less than 0.05 ) . Neither in the first nor in the second period did SCG treatment influence the Ln ( PC20 ) value positively , and the SCG treatment administered in the second period could not maintain the improvement in the pulmonary function ( i.e. , FEV1 , FVC , and PEF ) obtained initially with the BDP treatment . When the effect of BDP on FEV1 , FVC , PEF , and Ln ( PC20 ) was compared to the effect of SCG in the first 8-week treatment period , no significant difference was observed ( p greater than 0.1 ) . ( ABSTRACT TRUNCATED AT 250 WORDS [9671161] In school children with atopic asthma the beneficial effects of disodium cromoglycate ( DSCG ) and beclomethasone dipropionate ( BDP ) are well-established . In preschool children , wheezing is quite common , and in the majority of cases the symptoms are episodic and reported to be associated with viral infections rather than atopy . We compared the efficacy of regular treatment with DSCG and BDP for prevention of wheezing in preschool children . We were interested to establish whether regular treatment with inhaled anti-inflammatory drugs could lead to a decrease in bronchial responsiveness . In 15 patients ( median age , 56 months ; range , 43 - 66 months ) bronchial responsiveness was assessed by measuring specific airway resistance ( sRaw ) during a histamine provocation test . The concentration of histamine eliciting a 100 % increase in sRaw ( PC100his ) was determined . In a double-blind crossover study , patients inhaled either DSCG 10 mg three times a day or BDP 100 microg three times a day for 2 months . After a wash-out period , treatment was changed to BDP or DSCG , respectively . Daily peak flow measurements were carried out , and exacerbations were noted . PC100his was measured at the start and end of each treatment period . No significant decrease in bronchial responsiveness was seen ( PC100his DSCG : before 1.3 , after 1.66 mg/ml , Pvalue not significant ; BDP : before 1.1 after 1.22 mg/ml , Pvalue not significant ) . Significantly higher morning peak flows were observed on BDP therapy ( 160 on BDP vs. 150 L/min on DSCG , P < 0.03 ) . BDP treatment result ed in significantly fewer wheezing exacerbations ( 7 vs. 16 , P < 0.005 ) compared with DSCG therapy . We conclude that in preschool children with episodic virally induced wheezing , BDP therapy was superior to DSCG aerosol treatments for the prevention of exacerbations of wheezing , although no significant effect on bronchial responsiveness was noted during either treatment protocol [10513756] Stepwise selection methods are widely applied to identify covariables for inclusion in regression models . One of the problems of stepwise selection is biased estimation of the regression coefficients . We illustrate this " selection bias " with logistic regression in the GUSTO-I trial ( 40,830 patients with an acute myocardial infa rct ion ) . R and om sample s were drawn that included 3 , 5 , 10 , 20 , or 40 events per variable ( EPV ) . Backward stepwise selection was applied in models containing 8 or 16 pre-specified predictors of 30-day mortality . We found a considerable overestimation of regression coefficients of selected covariables . The selection bias decreased with increasing EPV . For EPV 3 , 10 , or 40 , the bias exceeded 25 % for 7 , 3 , and 1 in the 8-predictor model respectively , when a conventional selection criterion was used ( alpha = 0.05 ) . For these EPV values , the bias was less than 20 % for all covariables when no selection was applied . We conclude that stepwise selection may result in a substantial bias of estimated regression coefficients [8620234] OBJECTIVE To evaluate whether early anti-inflammatory therapy with nebulized cromolyn sodium or budesonide reduces wheezing after bronchiolitis . DESIGN AND SETTING A r and omized , controlled study in a university hospital that provides primary hospital care for all pediatric patients in a defined area . PATIENTS One hundred consecutive infants younger than 24 months treated in the hospital for acute bronchiolitis . INTERVENTIONS Thirty-four patients received cromolyn sodium , 20 mg four times a day for 8 weeks and 20 mg three times a day for 8 weeks , and 34 patients received budesonide , 500 micrograms twice a day for 8 weeks and 250 micrograms twice a day for 8 weeks , by a foot pump with a face mask ; 32 patients in the control group received no therapy . MAIN OUTCOME MEASURES Numbers of physician-diagnosed wheezing episodes , hospital admissions for bronchial obstructions , and symptomatic days recorded by the parents . RESULTS Children in the cromolyn sodium ( 19 % ) and budesonide ( 16 % ) groups had significantly fewer physician-diagnosed wheezing episodes than those in the control group ( 47 % ) during the second 8-week period ( P < .05 ) . A significant reduction in hospital admissions for bronchial obstructions was seen in the budesonide group and in the children with atopy in both treatment groups ( P < .05 ) . The children with atopy had significantly more subsequent wheezing episodes and hospital admissions than those without atopy ( P < .05 ) . The numbers of symptomatic days did not differ significantly among the three groups . CONCLUSIONS Early anti-inflammatory therapy with nebulized cromolyn sodium or budesonide reduces the number of wheezing episodes and hospital admissions after bronchiolitis . Children with atopy are at high risk of subsequent wheezing episodes , and they particularly benefit from anti-inflammatory therapy [11986448] OBJECTIVE The availability of antiinflammatory asthma medications for infants and young children has been limited . The objective of this study was to compare effects of nebulized budesonide inhalation suspension and cromolyn sodium nebulizer solution on asthma-related health outcomes in young children with asthma . METHODS We conducted a r and omized , parallel-group , 52-week , open-label study in 36 US clinical sites . Patients included 335 children who were 2 to 6 years of age and had persistent asthma that had been treated with at least 1 long-term control medication ; 287 children ( 86 % ) completed the study . Patients received budesonide inhalation suspension , 0.5 mg daily ( n = 168 ) , or cromolyn sodium nebulizer solution , 20 mg 4 times daily ( n = 167 ) , for 8 weeks , followed by dose titration at the investigator 's discretion . The main outcome measure was the rate of asthma exacerbations over 52 weeks . Secondary measures included times to first asthma exacerbation and first use of additional asthma therapy , asthma symptom scores , rescue medication use , and health care re source use . RESULTS The budesonide group had a mean ( median ) asthma exacerbation rate of 1.23 ( 0.99 ) per year compared with 2.41 ( 1.85 ) for the cromolyn group , significantly longer times to first exacerbation and first use of additional long-term asthma medication , greater improvements in asthma symptom scores , reduced use of rescue medication , and fewer urgent care visits . Both treatments were well tolerated . CONCLUSIONS Budesonide inhalation suspension was more effective than nebulized cromolyn sodium in young children with persistent asthma . Both treatments were well tolerated with similar adverse event profiles [4175489] Abstract A double-blind cross-over trial of disodium cromoglycate was undertaken in 28 patients with asthma . This differed from previous trials in that isoprenaline was not included in the active or in the placebo capsules . 10 of the 28 patients improved clinical ly whilst on cromoglycate . F.E.V. 1·0 , dyspnœa on exertion , and disturbance of sleep were all improved by cromoglycate [8777828] 1 . Perception of asthma by patients can be assessed from the relationship between symptom scores and peak expiratory flows . This study was design ed to investigate the possibility that medication can affect perception of the sensation of asthma independently of changes in lung function . 2 . Twelve subjects whose asthma was inadequately controlled by inhaled bronchodilator alone were studied during four different drug treatments over 3 months . Subjective self- assessment of asthma was scored on a 10 cm visual analogue scale and followed by three consecutive measurements of peak expiratory flow , using a coded electronic peak flow meter . This was recorded not less than three times daily on diary cards . Observations were recorded during the second week of each of four treatments : ( i ) a run-in period using only inhaled salbutamol as required , ( ii ) inhaled beclomethasone , ( iii ) inhaled cromoglycate and ( iv ) oral theophylline at a dose adjusted to achieve blood levels of 10 - 20 mg/l . Inhaled salbutamol was permitted during the other treatments as required . Changes in the slope and position of the regression lines of asthma scores on PEF were used to measure changes in perception of asthma on each treatment . Dynamic lung volumes were measured in the clinic before the study and after each treatment period . 3 . In the group as a whole , theophylline improved lung function ( mean peak flow and dynamic lung volumes ) without affecting mean visual analogue scores , beclomethasone improved mean visual analogue scores with much less effect on lung function , while cromoglycate had a small though consistent effect on both . 4 . Perception of asthma , measured by the relationship between peak flow rate and visual analogue scores , was unaffected by cromoglycate . On theophylline , perception of asthma was heightened in five subjects despite a definite improvement in their peak flow . On beclomethasone , perception of asthma was reduced in most subjects , often with no discernible improvement in mean peak flow or dynamic spirometry . 5 . Perception of bronchoconstriction in asthma can be affected by drugs independently of control of the condition . Theophylline may produce a paradoxical increase in awareness of asthma in some individuals . With beclomethasone therapy a reduction in symptoms of asthma may occur without any improvement in tests of air flow [6818164] The protective effect of a new inhaled steroid , fluocortin butyl ( FCB ) , was compared to that of disodium cromoglycate ( DSCG ) and beclomethasone dipropionate ( BDP ) in patients with extrinsic asthma by means of the allergen-inhalation challenge test . Three different groups of 12 patients each participated in the study . One group was treated with FCB and BDP , the two others with FCB and DSCG , all in a r and omized crossover study plan . After an initial allergen challenge ( FEV1 fall greater than 15 % ) , the patients were allocated to either treatment for 7 - 10 days . A second challenge test was then carried out , followed by a washout period of 4 days . The treatments were then crossed-over , and a third allergen challenge was carried out at the end of the second treatment period . With BDP 5 of 12 patients were protected ; with FCB , 6 of 12 in two groups and 8 of 12 patients in a third group . With DSCG 3 of 12 patients were protected in the group in which the last medication was given 12 h before challenge , and 8 of 12 patients in the second group in which medication was given 1 - 2 h before challenge . In the same groups on FCB no such time-dependent effect was observed . No statistically significant differences were found between either FCB and BDP , or FCB and DSCG in either group [2833881] Nedocromil sodium is a new antiasthmatic drug with properties similar to sodium cromoglycate . We examined the efficacy of nedocromil sodium compared to placebo in 71 asthmatic patients in a three-centre double-blind parallel group study over 12 weeks . During the study the patients ' maintenance inhaled corticosteroids were progressively withdrawn . Nedocromil sodium had an advantage over placebo in the number of withdrawals related to uncontrolled asthma , 14 and 24 respectively ( p = 0.03 ) . Changes in symptom scores , peak flow rates and bronchodilator use favoured nedocromil sodium occasionally during the study . The unusual taste of the active drug was reported frequently . Nedocromil sodium is more efficacious than placebo in asthma maintenance , but does not replace inhaled corticosteroids [6439430] In a double‐blind controlled crossover trial of inhaled disodium cromoglycate and beclomethasone dipropionate in juvenile asthma , beclomethasone produced higher therapeutic scores but significantly so in only two indices – wheeze‐free days and morning peak flow rates . Combined treatment offered no advantage over beclomethasone alone . No side‐effects were noted . The findings confirm other studies of cromoglycate and a steroid aerosol ( betamethasone 17‐valerate ) but disagree with the only other comparative trial of cromoglycate and beclomethasone , in which both were found equally effective [12704354] BACKGROUND Determining who responds to asthma therapies , particularly leukotriene modifiers , continues to be explored . OBJECTIVE We sought to identify patient characteristics predictive of response to montelukast . METHODS We used data from 2 clinical trials in which children with asthma received either montelukast or placebo . Symptoms , beta-agonist use , and unanticipated health re source use caused by asthma were recorded in vali date d daily diaries for children 2 to 5 ( n = 689 ) and 6 to 14 ( n = 336 ) years old . We defined primary end points of days without asthma in 2- to 5-year-old patients ( 24 hours without symptoms , beta-agonist use , or asthma attack ) and change in percent predicted FEV(1 ) in 6- to 14-year-old children . Asthma attack was defined by the use of rescue oral corticosteroids or by an unscheduled visit to a medical provider . Patients were grouped according to baseline characteristics , such as family history of asthma , personal history of allergy , frequency of asthma symptoms , eosinophilia , and concomitant use of inhaled corticosteroids or cromolyn . We examined the stratum-specific effects of montelukast on the percentage of days without asthma , change in percent predicted FEV(1 ) , asthma attack , and a variety of secondary symptom and FEV(1 ) end points . RESULTS We did not identify characteristics that predicted response to montelukast in either preschool or 6- to 14-year-old children . These findings were consistent across all symptom and FEV(1 ) outcomes . There was also no differential response to montelukast in either age group when asthma attack was the outcome . CONCLUSION The patient characteristics studied do not appear to provide an indication of who will benefit most from treatment with montelukast [8387933] To compare the effectiveness of nedocromil sodium ( NS ) and sodium cromoglycate ( SCG ) administered by metered dose inhaler ( MDI ) in preventing exercise-induced asthma ( EIA ) , 12 asthmatic children with EIA were studied in a r and omized , double-blind , cross-over , placebo-controlled study . NS and SCG were given by MDI alone , and by MDI with a 700 ml spacer device ( Fisonair , Fisons , UK ) , in order to assess the benefit of using such a device . Following a baseline exercise challenge , the protective effect of NS , SCG or placebo was evaluated in each subject . The percentage fall in forced expiratory volume in one second , and percentage protection were measured . NS and SCG provided a significant and comparable protection from EIA , and both were better than placebo . No further improvement was observed after drug administration via the spacer . Both NS and SCG are effective in preventing EIA in children , when administered at the recommended clinical dose , and the use of a spacer for administering the drug provides no advantage if the technique of inhalation is good [806293] Eleven children with severe perennial asthma and a poor clinical response to disodium cromoglycate were studied in a 4-month , double blind trial involving 1 month 's treatment with placebo , disodium cromoglycate , betamethasone 17 valerate , and both drugs combined according to a predetermined r and om design . Each drug apparently reduced symptoms and improved daily peak flow and fortnightly spirometric measurements compared with placebo , but the improvement after betamethasone 17 valerate was greater in part because of the way this group of patients was selected . There did not appear to be any additional benefit when both drugs were used together . Betamethasone 17 valerate was not compared with beclomethasone diproprionate aerosol and there is no reason to believe it may be superior . Corticosteroid aerosols have potential hazards which may prove to equal those of long-term systemic steroids , but they offer the prospect of satisfactory control of symptoms without the risk of growth suppression in children with severe asthma . Disodium cromoglycate remains the drug of choice in severe childhood asthma and the use of corticosteroid aerosols should be confined to those children who fail to respond satisfactorily to disodium cromoglycate [10690871] The aim of the present study was to evaluate the prevalence of adrenal suppression and growth retardation in children using moderate doses of budesonide or fluticasone propionate . Seventy-five asthmatic children were r and omly divided into three treatment groups : 30 to the fluticasone propionate ( FP ) , 30 to the budesonide ( BUD ) , and 15 to the cromone ( CROM ) group . FP doses were 500 microg/day during the first 2 months and 200 microg/day thereafter . The respective BUD doses were 800 and 400 microg/day . A low dose ACTH ( 0.5 microg/1.73 m2 ) test was performed before treatment and 2 , 4 , and 6 months later . The test was considered abnormal if the stimulated serum cortisol concentration was more than 2 SD lower than the pretreatment mean ( < 330 nmol/L ) . The low dose ACTH test was abnormal after both the high and low steroid doses in 23 % of the children . At the 4 month measurement there were more abnormal tests in the BUD ( n = 9 ) than in the FP ( n = 5 ) group ( P < 0.05 ) . At that time also the stimulated concentration of serum cortisol was lower in the BUD than in the CROM group ( P < 0.01 ) , whereas the difference between the FP and CROM groups was not significant . During the study year the mean decrease in height SD score was 0.23 in the children treated with BUD , 0.03 in the children treated with FP , and 0.09 in the children treated with CROM ; the difference between the BUD and FP groups was significant ( P < 0.05 ) . In conclusion , the low dose ACTH test revealed mild adrenal suppression in a quarter of the children using moderate doses of inhaled steroids . A FP dose of 200 microg/day caused less adrenal and growth suppression than did a BUD dose of 400 microg/day [7638372] Inhaled corticosteroids are highly effective in the treatment of asthma at all ages and their use in younger children is increasing . As concerns exist about the long-term systemic side-effects of high dose inhaled corticosteroids , current guidelines continue to recommend sodium cromoglycate ( SCG ) as first line regular medication for children with frequent symptoms . Few published studies have compared the safety and efficacy of inhaled corticosteroids with SCG in children . This study compares SCG with the new inhaled corticosteroid , fluticasone propionate ( FP ) , which has theoretical advantages over other currently available corticosteroids due to its negligible oral bioavailability . This was a r and omized , open , multi-centre , parallel group comparison of 50 micrograms FP twice daily and 20 mg SCG four times daily over 8 weeks , preceded by a 2-week baseline period . Sixty-two general practice s and two hospital centres enrolled 225 asthmatic children aged 4 - 12 years ( 110 received FP ; 115 received SCG ) . Outcome measures improved in both groups , with a significant difference in favour of FP for the key variables of mean morning and evening % predicted PEFR and % of symptom-free days and nights . No significant difference was observed for FEV1 , or relief medication use . Two children taking FP and 10 children taking SCG withdrew because of adverse events . This study showed that low dose FP was effective and superior to SCG in young children with mild-moderate asthma . Safety studies of longer duration are needed before changing the current recommendations for inhaled corticosteroid therapy [12117660] BACKGROUND Children with persistent mild to moderate bronchial asthma require anti-inflammatory therapy . According to current treatment guidelines both sodium cromoglycate ( SCG ) and inhaled corticosteroids can be used . If children remain symptomatic despite regular SCG therapy , corticosteroids are the next therapeutic option . AIMS To determine whether combined SCG and fluticasone ( inhaled corticosteroid ) therapy is of additional benefit in children who are symptomatic on SCG compared with simply switching to fluticasone . PATIENTS AND METHODS Children with mild or moderate persistent asthma aged 6 to 16 years who had been treated with inhaled SCG for at least 3 months prior to the study received either 2 mg SCG four times daily from a metered dose inhaler plus fluticasone propionate powder 50 microg b.i.d . from the Diskus inhaler ( group FS ) or fluticasone 50 microg b.i.d . only ( group F ) . The r and omised , controlled , parallel-group study had a 2 week run-in phase and an 8 week treatment period . Morning and evening peak expiratory flow rates ( PEFR ) were measured daily by patients and recorded in diaries . Asthma symptoms , use of rescue medication and spirometry were also documented . RESULTS Paediatricians from 21 study centres recruited 124 children with asthma , of whom 104 fulfilled r and omisation criteria and were allocated to study medication . Morning PEFR increased by 47 l/min and by 45 l/min after 8 weeks of treatment in groups F and FS , respectively . The adjusted difference between groups was 0.84 % of predicted ( 95 % CI , -7.3 to 5.6 , p=0.80 ) . Asthma symptoms and lung function also improved with no significant differences between treatment groups ( p>0.24 ) . Frequency and severity of adverse events was similar in both groups . CONCLUSION In children who are symptomatic while taking sodium cromoglycate four times daily , the combination of inhaled fluticasone and SCG is not superior to fluticasone alone . SCG can safely be withdrawn when commencing fluticasone , thus facilitating asthma treatment [10070568] Asthma is a chronic inflammatory disorder of the airways that is characterized by infiltration of many inflammatory cells into the bronchial mucosa . We compared the effects of ketotifen , disodium cromoglycate ( DSCG ) , and beclomethasone dipropionate ( BDP ) on inflammatory cells in the bronchial mucosa and on the asthma symptoms of patients with atopic asthma . In this 12-week parallel study , 32 patients were r and omly allocated to either the ketotifen group ( 2 mg day-1 , n = 13 ) , DSCG group ( 8 mg day-1 , n = 9 ) or BDP ( 400 micrograms day-1 , n = 10 ) . Each subject recorded daily asthma symptoms and peak expiratory flow ( PEF ) . Before and after treatment , pulmonary function and bronchial responsiveness to methacholine were evaluated , and fibreoptic bronchoscopy and biopsy were performed before and after treatment . Biopsy specimens were obtained by bronchoscopy . We performed immunohistochemistry using specific monoclonal antibodies for activated eosinophils ( EG2 ) , mast cells ( AA1 ) , and T cells ( CD3 , CD4 , and CD8 ) . Our clinical findings showed significant improvement in symptom score and bronchial responsiveness ( P < 0.01 ) each ) in all groups . Both the DSCG and the BDP groups had significantly better symptom scores than the ketotifen group ( P < 0.05 , both groups ) . PEF significantly increased in the DSCG group in comparison to the ketotifen ( P < 0.01 ) and BDP ( P < 0.05 ) groups , FEV1 % increased significantly in the DSCG ( P < 0.01 ) and BDP ( P < 0.05 ) groups in comparison to the ketotifen group . Compared with their baseline values , treatment significantly decreased EG2 + activated eosinophils , and CD3 + and CD4 + T cells , in each group ( P < 0.01 ) . Both the DSCG ( P < 0.05 ) and the BDP groups ( P < 0.01 ) exhibited significant decreases in AA1 + mast cell count , but this was not observed in the ketotifen group . Comparing before- and after-treatment values , only the DSCG group exhibited a significant decrease in the number of CD8 + T cells ( P < 0.01 ) . Ketotifen , DSCG , and BDP all showed anti-inflammatory activity as determined by examination of the bronchial mucosa of asthmatic patients ; and both the DSCG and BDP groups had better clinical responses than the ketotifen group [821577] Neonatal pneumothorax : survey and prevention H V PRICE ........................................................ 456 Relationship between mood disturbances and free and total plasma tryptophan in postpartum women GEORGE STEIN , FRANK MILTON , PENNY BEBBINGTON , KEITH WOOD , ALEC COPPEN .............................................. 457 Treatment of childhood asthma with sodium cromoglycate and beclomethasone dipropionate aerosol singly and in combination I MITCHELL , I C PATERSON , S J CAMERON . , I W B GRANT .................................................. [4948179] D i s o c l i u i n c r o i i i o o l y c a l c ' ( D S C G ) * is t h e ( h s o t l i u m s a l t 1 , 3 b i s ( 2 c a r h o x y c l i r ( ) n i ( ) n i ; y l ( ) x y ) i l i y d r o x y p i o p a i i e ( I ' l .Ul ) I t h a s b e e n c l e m o n s t i a t e d t h a t t h i s s u b s t a n c e w i l l r e d u c e t h e h i o n c h o c o i i s t n c t o n a l I ' c s p o i i s e a l t c i a e r o s o l a l l c i ' n e i i c h a l l e i i i ^ c i n p a t i e n t s s u l l e i ' i n ^ ' I r n n i b r o n c h i a l a s t h m a { .illotniydii 1 9 6 7 ) . Tn a d o u b l e b l i n d t r i a l i t s \ a l u e in t h e lono t e r m t r e a t m e n t o l a s t h m a M a s i n d i c a t e d { . l l l o i i i i Y / i i i & l l o . v c l l ] ( ) G j ) . T h e r e June now lieen repoi'ted a niimbeiol double bliiitl t r i a l s , and most investigators ha\'e re < j , istered a benelicial e f f e c t iVom DSCCi . Thei-c are , ho\\e\er , mai-ked dil lei'eiices in t h e decree ol improxement ni the groups sUidied , probably beeaLisc there has been contro\'ersy about the assessment ol t h e pat ient response [ ll'oolcork & Read i^fi " ? , Grant et al. 1 9 6 7 , Jloicrl & /Illoiinxdii 1 9 6 7 ) . O S C C i acts by prc-\-enti?iL ; ' the release ol histaniine , SRS-A a n d p e r h a p s o the r biologically ac t i \ e substances a l t e r the c o m b i n a t i o n ol r e a l m s wilh the specilic al lergen m t)'pe I a l l e r c^ i e react ion . Voy this i-cason one could expect a [2045618] Facilitated asthma-specialist care delivered by allergists was compared to generalist care on the rate of relapse of asthma emergency room ( ER ) visits and hospitalizations and on asthma control in a prospect i ve , controlled study of San Diego Kaiser Health Plan members with asthma . Subjects with asthma between the ages of 6 and 59 years presenting for acute ER care for asthma were systematic ally assigned by alternating , consecutively , the day of their ER visit to receive either ( 1 ) facilitated referral to an asthma specialist within the allergy department and concomitant comprehensive ongoing asthma care ( intervention group , n = 149 ) or ( 2 ) continued outpatient management from generalist physicians ( control group , n = 160 ) . The course of their asthma was evaluated blindly during the subsequent 6 months by review of medical records , initial and follow-up question naires , and spirometry . Compared to the control group , the intervention group noted ( 1 ) a 75 % reduction in the number of , and percent of , subjects with asthma awakenings per night ( p less than or equal to 0.0001 ) , ( 2 ) an almost 50 % reduction in asthma ER relapses ( p = 0.017 ) result ing from a reduction in the frequency of multiple relapse ( p = 0.005 ) , and ( 3 ) a greater use of inhaled corticosteroids ( p less than 0.00001 ) and cromolyn ( p = 0.002 ) . Thus , facilitated referral of subjects with asthma to specialists in asthma therapy after acute ER therapy appears to reduce asthma ER relapses and to improve asthma outcome [9727762] We investigated the 1-year outcome of children hospitalized for wheezing , paying special attention to the effect of early anti-inflammatory therapy . In addition , we identified risk factors for recurrent wheezing and asthma . Eighty-eight children under 2 years old treated in the hospital for wheezing were followed for 1 year . Nebulized anti-inflammatory therapy was given for 16 weeks : 31 patients received budesonide , 29 patients cromolyn sodium , and 28 control patients received no therapy . The number of subsequent physician-diagnosed wheezing episodes was recorded . Four months of anti-inflammatory therapy did not significantly decrease the occurrence of asthma 1 year later ; 45 % of patients in the cromolyn group , 42 % in the budesonide group , and 61 % in the control group had asthma , defined as at least two bronchial obstruction episodes during the 1-year period after the original hospitalization for wheezing . An age over 12 months at the time of the initial bronchial obstructing episode [ P=0.009 , risk ratio (RR)=5.4 , 95 % confidence interval (CI)=1.53 - 19.31 ] , failure to identify a viral cause ( P=0.0003 , RR=12.0 , CI=3.16 - 45.40 ) , history of wheezing ( P=0.02 , RR=14.6 , CI=1.59 - 132.10 ) , the presence of atopy ( P=0.01 , RR=5.3 , CI=1.47 - 19.21 ) , a family history of atopy ( P=0.03 , RR=3.6 , CI = 1.15 - 11.12 ) , and serum eosinophil cationic protein ( ECP ) > or = 16 microg/L ( P=0.005 ) were significant risk factors for asthma . We conclude that early anti-inflammatory therapy for 4 months does not significantly decrease the occurrence of asthma during the period of 1 year following hospitalization for the original episode of wheezing . Young children requiring hospital admission for wheezing during a respiratory tract infection are at increased risk of having subsequent asthma if they have wheezed previously , if they have atopy or a family history of atopy , if they have elevated serum ECP , if they are over 12 months of age at the original bronchial obstructive episode , and especially when viral studies are negative [4352726] Thirty-one chronic perennial asthmatics aged from 2½ to 16 years were treated with beclomethasone dipropionate pressurized aerosols for up to 20 months . Of these , 16 patients dependent on oral corticosteroid or corticotrophin for up to 11 years were successfully transferred to this treatment , with one exception . Steroid withdrawal symptoms were slight . Loss of weight , disappearance of Cushingoid features , and resumption of growth indicated lack of systemic side effects . Fifteen others inadequately controlled on bronchodilators or disodium cromoglycate , were also effectively treated , and no clinical evidence of adrenal suppression was noted [3105242] ABSTRACT . The efficacy of beclomethasone dipropionate ( BDP ) was compared with sodium cromoglycate ( SCG ) and placebo in a double‐blind parallel group study of 30 asthmatic children over a two‐month period . All the three treatment groups received salbutamol concomitantly . Lung volumes , airway mechanics and the nonspecific bronchial hyperreactivity to carbachol were measured at the beginning and the end of the study . Two patients were excluded because of unequal clinical conditions at the entry and the end of the study and three because of lack of co‐operation . Three patients ( 1 on SCG , 2 on placebo ) dropped out because of worsening clinical symptoms . The improvement in airway mechanics shown by the group treated with BDP ( n=7 ) was significantly greater ( p<0.01 ) than in the group treated with SCG ( n=8 ) . Nonspecific hyperreactivity to carbachol improved significantly in the BDP group ( factor 5.9 ) compared to the SCG group ( factor 1.9 ) . Childhood asthma seems to be better controlled by a combination of BDP and salbutamol , than by SCG and salbutamol [8281343] In this 8-week , double-blind , comparative trial of nedocromil sodium ( 4 mg q.i.d . ) versus placebo in 42 patients with chronic reversible obstructive airways disease , there was a trend in favor of nedocromil sodium compared to placebo in parameters assessed by patients ( nocturnal symptom scores , evening PEFR values ) and those assessed by clinicians ( asthma severity scores ) compared with baseline values . There was a statistically significant difference ( p < 0.05 ) in favor of nedocromil sodium in the inhaled bronchodilator requirements in the last 2 weeks of treatment . Both patients ' and clinicians ' evaluation of the overall efficacy of treatment was significant in favor of nedocromil sodium ( p < 0.01 and p < 0.05 , respectively ) . The treatments were well tolerated by the majority of patients . From these data , it can be concluded that nedocromil sodium ( 4 mg q.i.d . ) is of value in the preventive treatment of chronic reversible obstructive airways disease [1320287] 165 patients ( 106 males , 59 females ) entered an open group comparative study of a 12-week test treatment on bronchial hyperresponsiveness ( BHR ) determined by methacholine challenge . Patients were r and omly allocated to receive nedocromil sodium ( 4 mg q.i.d . ) , sodium cromoglycate ( 10 micrograms q.i.d . ) and beclomethasone dipropionate ( 500 micrograms t.i.d . ) . At the end of the study , an 2.25-fold increase of the PD20FEV1 was noted in all the treated patients . No significant difference was noted among the treatments Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Treatment guidelines for asthma recommend inhaled corticosteroids ( ICS ) as first-line therapy for children with persistent asthma . Although ICS treatment is generally considered safe in children , the potential systemic adverse effects related to regular use of these drugs have been and continue to be a matter of concern , especially the effects on linear growth . OBJECTIVES To assess the impact of ICS on the linear growth of children with persistent asthma and to explore potential effect modifiers such as characteristics of available treatments ( molecule , dose , length of exposure , inhalation device ) and of treated children ( age , disease severity , compliance with treatment ) . However , additional studies are needed to better characterise the molecule dependency of growth suppression , particularly with newer molecules ( mometasone , ciclesonide ) , to specify the respective role of molecule , daily dose , inhalation device and patient age on the effect size of ICS , and to define the growth suppression effect of ICS treatment over a period of several years in children with persistent asthma . PLAIN LANGUAGE SUMMARY Do inhaled corticosteroids reduce growth in children with persistent asthma ? Review question : We review ed the evidence on whether inhaled corticosteroids ( ICS ) could affect growth in children with persistent asthma , that is , a more severe asthma that requires regular use of medications for control of symptoms . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

22592715

[14618287] It has been proposed that somatosensory stimulation in the form of electromyographically triggered neuromuscular electrical stimulation ( NMES ) to the peripheral nerve can influence functional measures of motor performance in subjects with stroke and can additionally produce changes in cortical excitability . Using a controlled , double-blind design , we studied the effects of intensive ( 60 h/3 weeks ) treatment at home with NMES compared with a sham treatment , applied to the extensor muscles of the hemiplegic forearm to facilitate h and opening in 16 chronic stroke subjects . We investigated improvement in functional use of the h and and change in cortical activation as measured by functional magnetic resonance imaging ( fMRI ) . Following treatment , subjects improved on measures of grasp and release of objects ( Box and Block Test and Jebsen Taylor H and Function Test [ JTHFT ] : small objects , stacking , heavy cans ) , isometric finger extension strength , and self-rated Motor Activity Log ( MAL ) : Amount of Use and How Well score . The sham subjects did not improve on any grasp and release measure or self-rated scale , but did improve on isometric finger extension strength . Importantly , however , following crossover , these subjects improved further in the measure of strength , grasp and release ( Box and Block [ JTHFT ] : page turning ) , and self-rated MAL : Amount of Use score and How Well score . Using fMRI and a finger-tracking task , an index of cortical intensity in the ipsilateral somatosensory cortex increased significantly from pre-test to post-test following treatment . Cortical activation , as measured by voxel count , did not change . These findings suggest that NMES may have an important role in stimulating cortical sensory areas allowing for improved motor function [7149946] Poor prognosis for upper limb recovery of stroke survivors has not changed in at least 28 years ; only 4 % to 5 % of patients regain arm function during or after the active rehabilitation phase . This pilot study included 37 patients r and omly assigned to either an integrated behavioral-physical therapy treatment program including electromyographic feedback ( experimental group ) or a st and ard exercise physical therapy program of like duration and intensity ( control group ) . Both groups showed clinical ly significant improvements that exceeded previously reported experience . The experimental technique appears to be more effective when upper limb involvement is not severe in a late case , or when treatment is started early ( within 3 months poststroke ) in a severe case . The rehabilitation community should quickly investigate the improved prospect s of restoring a greater number of useful upper limbs in this often neglected group of hemiplegic patients [16634340] Objective : ( 1 ) To evaluate constraint-induced movement therapy for chronic stroke patients modified into group practice to limit the dem and on therapist re sources . ( 2 ) To explore whether extended mitt use alone may enhance outcome . Design : A combined case-control and r and omized controlled study with pre- and post-treatment measures by blinded observers . Setting : A university hospital rehabilitation department . Participants : Sixteen stroke patients ( nine men and seven women ; mean age 56.7 years ; on average 28.9 months post stroke , five of whom were 6 - 9 months post stroke ) with moderate motor impairments in the contralateral upper limb . Intervention : Constraint-induced therapy ( mitt on the less affected h and 90 % of waking hours for 12 days ) with 2 - 3 patients per therapist and 6 h of group training per day . After the training period , the patients were r and omized either to using the mitt at home every other day for two-week periods for another three months ( in total 21 days ) or to no further treatment . Outcome measures : Modified Motor Assessment Scale , Sollerman H and Function Test , Two-Point Discrimination test and Motor Activity Log . Results : The mean motor performance improved significantly after two weeks of constraint-induced group therapy on Motor Assessment Scale ( 1.44 ( 95 % confidence interval ( 95 % CI ) 0.59 - 2.28 ) points ; P = 0.003 ) and on Sollerman H and Function Test ( 3.81 ( 95 % CI 0.26 - 7.36 ) points ; P = 0.037 ) but showed no sensory change in the Two-Point Discrimination Test ( P = 0.283 ) . The median difference in self-reported motor ability ( Motor Activity Log ) also improved ( P B=0.001 ) . However , no additional effect was seen from wearing a mitt for another three months . Conclusion : Constraint-induced group therapy , allowing several patients per therapist , seems to be a feasible alternative to improve upper limb motor function . The restraint alone , extended in time , did not enhance the treatment effect [11441212] Background and Purpose — The Wolf Motor Function Test ( WMFT ) is a new time-based method to evaluate upper extremity performance while providing insight into joint-specific and total limb movements . This study addresses selected psychometric attributes of the WMFT applied to a chronic stroke population . Methods — Nineteen individuals after stroke and with intact cognition and sitting balance were age- and sex-matched with 19 individuals without impairment . Subjects performed the WMFT and the upper extremity portion of the Fugl-Meyer Motor Assessment ( FMA ) on 2 occasions ( 12 to 16 days apart ) , with scoring performed independently by 2 r and om raters . Results — The WMFT and FMA demonstrated agreement ( P < 0.0001 ) between raters at each session . WMFT scores for the dominant and nondominant extremities of individuals without impairment were different ( P ≤0.05 ) from the more and less affected extremities of subjects after stroke . The FMA score for the more affected extremity of subjects after stroke was different ( P ≤0.05 ) from the dominant and nondominant extremities . However , the FMA score for the less affected upper extremity of individuals after stroke was not different ( P > 0.05 ) from the dominant and nondominant extremities of individuals without impairment . The WMFT and FMA scores were related ( P < 0.02 ) for the more affected extremity in individuals after stroke . Conclusions — The interrater reliability , construct validity , and criterion validity of the WMFT , as used in these subject sample s , are supported [18403742] Background and Purpose — Severe upper limb paresis is a major contributor to disability after stroke . This study investigated the efficacy of a new nonrobotic training device , the Sensorimotor Active Rehabilitation Training ( SMART ) Arm , that was used with or without electromyography-triggered electrical stimulation of triceps brachii to augment elbow extension , permitting stroke survivors with severe paresis to practice a constrained reaching task . Methods — A single-blind , r and omized clinical trial was conducted with 42 stroke survivors with severe and chronic paresis . Thirty-three participants completed the study , of whom 10 received training using the SMART Arm with electromyography-triggered electrical stimulation , 13 received training using the SMART Arm alone , and 10 received no intervention ( control ) . Training consisted of 12 1-hour sessions over 4 weeks . The primary outcome measure was “ upper arm function , ” item 6 of the Motor Assessment Scale . Secondary outcome measures included impairment measures ; triceps muscle strength , reaching force , modified Ashworth scale ; and activity measures : reaching distance and Motor Assessment Scale . Assessment s were administered before ( 0 weeks ) and after training ( 4 weeks ) and at 2 months follow-up ( 12 weeks ) . Results — Both SMART Arm groups demonstrated significant improvements in all impairment and activity measures after training and at follow-up . There was no significant difference between these 2 groups . There was no change in the control group . Conclusions — Our findings indicate that training of reaching using the SMART Arm can reduce impairment and improve activity in stroke survivors with severe and chronic upper limb paresis , highlighting the benefits of intensive task-oriented practice , even in the context of severe paresis [18633001] We conducted a pilot telerehabilitation study with post-stroke patients with arm motor impairment . We compared the degree of satisfaction of patients undergoing a virtual reality ( VR ) therapy programme at home ( Tele-VR group ) to satisfaction experienced by those undergoing the same VR therapy in a hospital setting ( VR-group ) . The rehabilitation equipment used a 3D motion tracking system to create a virtual environment in which the patient 's movement was represented . In tele-therapy , the patient equipment was installed in their homes , connected to the hospital by four ISDN lines at a total b and width of 512 kbit/s . Rehabilitation data were transmitted via one line and videoconferencing via the other three . Ten patients with mild to intermediate arm motor impairment due to an ischaemic stroke , were r and omized into VR or Tele-VR groups . A question naire was used at the end of treatment to measure each patient 's degree of satisfaction . Tele-VR treated patients showed median values equal to or higher than the VR group patients in all 12 items investigated , except one . In motor performance , the Tele-VR group improved significantly ( P ≤ 0.05 ) , while the VR group showed no significant change . Patients assigned to the Tele-VR group were able to engage in therapy at home and the videoconferencing system ensured a good relationship between the patient and the physical therapist whose physical proximity was not required [11022069] Background and Purpose Chronic upper extremity hemiparesis is a leading cause of functional disability after stroke . We investigated the hypothesis that bilateral arm training with rhythmic auditory cueing ( BATRAC ) will improve motor function in the hemiparetic arm of stroke patients . Methods In this single group pilot study we determined the effects of 6 weeks of BATRAC on 14 patients with chronic hemiparetic stroke ( median time after stroke , 30 months ) immediately after training and at 2 months after training . Four 5-minute periods per session ( 3 times per week ) of BATRAC were performed with the use of a custom- design ed arm training machine . Results The patients showed significant and potentially durable increases in the following : Fugl-Meyer Upper Extremity Motor Performance Test of impairment ( P < 0.0004 ) , Wolf Motor Function Test ( performance time measure , P < 0.02 ) , and University of Maryl and Arm Question naire for Stroke measuring daily use of the hemiparetic arm ( P < 0.002 ) . Isometric strength improved in elbow flexion ( P < 0.05 ) and wrist flexion ( P < 0.02 ) for the paretic arm and in elbow flexion ( P < 0.02 ) and wrist extension ( P < 0.02 ) for the nonparetic arm . Active range of motion improved for paretic-side shoulder extension ( P < 0.01 ) , wrist flexion ( P < 0.004 ) , and thumb opposition ( P < 0.002 ) , and passive range of motion improved for paretic wrist flexion ( P < 0.03 ) . Conclusions Six weeks of BATRAC improves functional motor performance of the paretic upper extremity as well as a few changes in isometric strength and range of motion . These benefits are largely sustained at 8 weeks after training cessation [12920254] BACKGROUND AND PURPOSE Rehabilitation care after stroke is highly variable and increasingly shorter in duration . The effect of therapeutic exercise on impairments and functional limitations after stroke is not clear . The objective of this study was to determine whether a structured , progressive , physiologically based exercise program for subacute stroke produces gains greater than those attributable to spontaneous recovery and usual care . METHODS This r and omized , controlled , single-blind clinical trial was conducted in a metropolitan area and 17 participating healthcare institutions . We included persons with stroke who were living in the community . One hundred patients ( mean age , 70 years ; mean Orpington score , 3.4 ) consented and were r and omized from a screened sample of 582 . Ninety-two subjects completed the trial . Intervention was a structured , progressive , physiologically based , therapist-supervised , in-home program of thirty-six 90-minute sessions over 12 weeks targeting flexibility , strength , balance , endurance , and upper-extremity function . Main outcome measures were postintervention strength ( ankle and knee isometric peak torque , grip strength ) , upper- and lower-extremity motor control ( Fugl Meyer ) , balance ( Berg and functional reach ) , endurance ( peak aerobic capacity and exercise duration ) , upper-extremity function ( Wolf Motor Function Test ) , and mobility ( timed 10-m walk and 6-minute walk distance ) . RESULTS In the intention-to-treat multivariate analysis of variance testing the overall effect , the intervention produced greater gains than usual care ( Wilk 's lambda=0.64 , P=0.0056 ) . Both intervention and usual care groups improved in strength , balance , upper- and lower-extremity motor control , upper-extremity function , and gait velocity . Gains for the intervention group exceeded those in the usual care group in balance , endurance , peak aerobic capacity , and mobility . Upper-extremity gains exceeded those in the usual care group only in patients with higher baseline function . CONCLUSIONS This structured , progressive program of therapeutic exercise in persons who had completed acute rehabilitation services produced gains in endurance , balance , and mobility beyond those attributable to spontaneous recovery and usual care [20400552] BACKGROUND Effective rehabilitative therapies are needed for patients with long-term deficits after stroke . METHODS In this multicenter , r and omized , controlled trial involving 127 patients with moderate-to-severe upper-limb impairment 6 months or more after a stroke , we r and omly assigned 49 patients to receive intensive robot-assisted therapy , 50 to receive intensive comparison therapy , and 28 to receive usual care . Therapy consisted of 36 1-hour sessions over a period of 12 weeks . The primary outcome was a change in motor function , as measured on the Fugl-Meyer Assessment of Sensorimotor Recovery after Stroke , at 12 weeks . Secondary outcomes were scores on the Wolf Motor Function Test and the Stroke Impact Scale . Secondary analyses assessed the treatment effect at 36 weeks . RESULTS At 12 weeks , the mean Fugl-Meyer score for patients receiving robot-assisted therapy was better than that for patients receiving usual care ( difference , 2.17 points ; 95 % confidence interval [ CI ] , -0.23 to 4.58 ) and worse than that for patients receiving intensive comparison therapy ( difference , -0.14 points ; 95 % CI , -2.94 to 2.65 ) , but the differences were not significant . The results on the Stroke Impact Scale were significantly better for patients receiving robot-assisted therapy than for those receiving usual care ( difference , 7.64 points ; 95 % CI , 2.03 to 13.24 ) . No other treatment comparisons were significant at 12 weeks . Secondary analyses showed that at 36 weeks , robot-assisted therapy significantly improved the Fugl-Meyer score ( difference , 2.88 points ; 95 % CI , 0.57 to 5.18 ) and the time on the Wolf Motor Function Test ( difference , -8.10 seconds ; 95 % CI , -13.61 to -2.60 ) as compared with usual care but not with intensive therapy . No serious adverse events were reported . CONCLUSIONS In patients with long-term upper-limb deficits after stroke , robot-assisted therapy did not significantly improve motor function at 12 weeks , as compared with usual care or intensive therapy . In secondary analyses , robot-assisted therapy improved outcomes over 36 weeks as compared with usual care but not with intensive therapy . ( Clinical Trials.gov number , NCT00372411 . [16040590] Background and Purpose — The ability of therapeutic exercise after stroke to improve daily functioning and quality of life ( QOL ) remains controversial . We examined treatment effects on these outcomes in a r and omized controlled trial ( RCT ) of exercise in subacute stroke survivors . Methods — This is a secondary analysis of a single-blind RCT of a 12-week program versus usual care . Baseline , post-treatment and 6-month post-treatment daily functioning and QOL were assessed by Barthel index , Functional Independence Measure , instrumental activities of daily living , Medical Outcomes Study short-form 36-item question naire ( SF-36 ) , and Stroke Impact Scale ( SIS ) . Results — Of 100 r and omized subjects , 93 completed the postintervention assessment , ( mean age 70 ; 54 % male ; 81 % white ; mean Orpington Prognostic Score 3.4 ) , and 80 had 6-month post-treatment assessment . Immediately after intervention , the intervention group improved more than usual care in SF-36 social function ( 14.0 points ; P=0.0051 ) and in SIS ( strength [ 9.2 points ; P=0.0003 ] , emotion [ 5.6 points ; P=0.0240 ] , social participation [ 6.6 points ; P=0.0488 ] , and physical function [ 5.0 points ; P=0.0145 ] ) . Treatment was marginally more effective on Barthel score ( 3.3 points ; P=0.0510 ) , SF-36 ( physical function [ 6.8 points ; P=0.0586 ] , physical role function [ 14.4 points ; P=0.0708 ] ) , and SIS upper extremity function ( 7.2 points ; P=0.0790 ) . Effects were diluted 6 months after treatment ended . Conclusion — This rehabilitation exercise program led to more rapid improvement in aspects of physical , social , and role function than usual care in persons with subacute stroke . Adherence interventions to promote continued exercise after treatment might be needed to continue benefit [19109444] Background . Functional training and muscle strength training may improve upper limb motor recovery after stroke . Combining these as functional strength training ( FST ) might enhance the benefit , but it is unclear whether this is better than conventional physical therapy ( CPT ) . Comparing FST with CPT is not straightforward . Objective . This study aim ed at assessing the feasibility of conducting a phase III trial comparing CPT with FST for upper limb recovery . Methods . R and omized , observer-blind , phase II trial . Subjects had upper limb weakness within 3 months of anterior circulation infa rct ion . Subjects were r and omized to CPT ( no extra therapy ) , CPT + CPT , and CPT + FST . Intervention lasted 6 weeks . Primary outcome measure was the Action Research Arm Test ( ARAT ) . Measurements were taken before treatment began , after 6 weeks of intervention , and 12 weeks thereafter . Attrition rate was calculated and differences between groups were interpreted using descriptive statistics . ARAT data were used to inform a power calculation . Results . Thirty subjects were recruited ( 8 % of people screened ) . Attrition rate was 6.7 % at outcome and 40 % at follow-up . At outcome the CPT + FST group showed the largest increase in ARAT score and this was above the clinical ly important level of 5.7 points . Median ( interquartile range ) increases were 11.5 ( 21.0 ) for CPT ; 8.0 ( 13.3 ) for CPT + CPT ; and 19.5 ( 22.0 ) for CPT + FST . The estimated sample size for an adequately powered subsequent phase III trial was 279 subjects at outcome . Conclusion . Further work toward a phase III clinical trial appears justifiable [18971385] Objective . The aim of this study was to establish the efficacy of a therapeutic intervention based on functional electrical stimulation ( FES ) therapy to improve reaching and grasping function after severe hemiplegia due to stroke . Methods . A total of 21 subjects with acute stroke were r and omized into 2 groups , FES plus conventional occupational and physiotherapy ( FES group ) or only conventional therapy ( control group ) 5 days a week for 12 to 16 weeks . A third group of 7 subjects with chronic hemiplegia ( at least 5 months poststroke ) received only FES therapy ( chronic group ) and pre — post training changes were compared . FES was applied to proximal and then distal muscle groups during specific motor tasks . At baseline and at the end of treatment , grasping function was assessed using the Rehabilitation Engineering Laboratory H and Function Test , along with more st and ard measures of rehabilitation outcome . Results . The FES group improved significantly more than the control group in terms of object manipulation , palmar grip torque , pinch grip pulling force , Barthel Index , Upper Extremity Fugl — Meyer scores , and Upper Extremity Chedoke — McMaster Stages of Motor Recovery . The chronic stroke subjects demonstrated improvements in most categories , but the changes were not statistically significant . Conclusions . FES therapy with upper extremity training may be an efficacious intervention in the rehabilitation of reaching and grasping function during acute stroke rehabilitation [14617717] Objective : To investigate progress toward motor recovery in patients with chronic hemiparesis ( mean time since stroke 3.2 years ) , comparing different types of practice schedules . Design : To increase voluntary control of the upper extremity , active neuromuscular stimulation was administered during blocked and r and om practice schedules as patients performed three specific movements : wrist/finger extension , elbow joint extension , and shoulder joint abduction . Methods : 34 stroke subjects volunteered to participate and were r and omly assigned to one of three treatment groups : blocked practice ( the same movement was repetitively performed on successive trials ) combined with active neuromuscular stimulation ; r and om practice ( different movements on successive trials ) along with active stimulation ; or no active stimulation assistance control group . Subjects completed two days of 90 minute training for each of two weeks with at least 24 hours of rest between sessions . A session was three sets of 30 successful active neuromuscular stimulation trials with the three movements executed 10 times/set . Results : Mixed design analyses on three categories of behavioural measures indicated motor improvements for the blocked and r and om practice /stimulation groups in comparison with the control group during the post-test period , with a larger number of blocks moved , faster premotor and motor reaction times , and less variability in the sustained muscular contraction task . Conclusions : Upper extremity rehabilitation intervention of active stimulation and blocked practice performed as well as stimulation/r and om practice . Moreover , these purpose ful voluntary movement findings support and extend sensorimotor integration theory to both practice schedules [15788330] OBJECTIVE Assess the effects of daily neuroprosthetic ( NESS H and master ) functional electrical stimulation in sub-acute stroke . DESIGN Controlled study , patients clinical ly stratified to 2 groups ; no active finger movement , and partial active finger movements , and then r and omized to control and neuroprosthesis groups . Observer blinded evaluations at baseline and completion of the 6-week study . SUBJECTS 22 patients with moderate to severe upper limb paresis 3 - 6 months post-onset . METHODS Patients in day hospital rehabilitation , receiving physical and occupational therapy 3 times weekly . The neuroprosthesis group used the device at home . RESULTS The neuroprosthesis group had significantly greater improvements in spasticity , active range of motion and scores on the functional h and tests ( those with partial active motion ) . Of the few patients with pain and oedema , there was improvement only among those in the neuroprosthesis group . There were no adverse reactions . CONCLUSION Supplementing st and ard outpatient rehabilitation with daily home neuroprosthetic activation improves upper limb outcomes [9756581] BACKGROUND AND PURPOSE Many stroke survivors have minimal to moderate neurological deficits but are physically deconditioned and have a high prevalence of cardiovascular problems ; all of these are potentially modifiable with exercise . The purpose s of this r and omized , controlled pilot study were ( 1 ) to develop a home-based balance , strength , and endurance program ; ( 2 ) to evaluate the ability to recruit and retain stroke subjects ; and ( 3 ) to assess the effects of the interventions used . METHODS Twenty minimally and moderately impaired stroke patients who had completed inpatient rehabilitation and who were 30 to 90 days after stroke onset were r and omized to a control group or to an experimental group that received a therapist-supervised , 8-week , 3-times-per-week , home-based exercise program . The control group received usual care as prescribed by the patients ' physicians . Baseline and postintervention assessment s included the Fugl-Meyer Motor Assessment , the Barthel Index of Activities of Daily Living ( ADL ) , the Lawton Scale of Instrumental ADL , and the Medical Outcomes Study -36 Health Status Measurement . Functional assessment s of balance and gait included a 10-m walk , 6-Minute Walk , and the Berg Balance Scale . Upper extremity function was evaluated by the Jebsen Test of H and Function . RESULTS Of 22 patients who met study criteria , 20 completed the study and 2 refused to participate . The experimental group tended to improve more than the control group in motor function ( Fugl-Meyer Upper Extremity : mean change in score , 8 . 4 versus 2.2 ; Fugl-Meyer Lower Extremity : 4.7 versus -0.9 ; gait velocity : median change , 0.25 versus .09 m/s ; 6-Minute Walk : 195 versus 114 ft ; Berg Balance Score : 7.8 versus 5 ; and Medical Outcomes Study -36 Health Status Measurement of Physical Function : 15 . 5 versus 9 ) . There were no trends in differences in change scores by the Jebsen Test of H and Function , Barthel Index , and Lawton Instrumental ADL Scale . CONCLUSIONS This study demonstrated that a r and omized , controlled clinical trial of a poststroke exercise program is feasible . Measures of neurological impairments and lower extremity function showed the most benefit . Effects of the intervention on upper extremity dexterity and functional health status were equivocal . The lasting effects of the intervention were not assessed [3093230] The objective of this study was to develop and examine the effectiveness of an individual home rehabilitation program for patients with ischemic stroke . This was a r and omized controlled trial in 60 patients with recent middle cerebral artery infa rct ion . After hospital discharge for acute stroke care , they were r and omly assigned to receive either a home rehabilitation program for three months ( intervention group ) or usual care ( control group ) . We collected outcome data over three months after their discharge from the hospital . The Barthel Index ( BI ) , the Modified Rankin Scale ( MRS ) , the health-related quality -of-life index ( EQ-5D ) , the Hospital Anxiety and Depression score ( HADs ) , and the Thai Mental State Examination ( TMSE ) were used to analyze the outcomes . In the intervention group , all outcomes were significantly better ( p<0.05 ) than in the control group , except in the case of TMSE . A favorable outcome , which was defined as minimal or no disability as measured by BI ( score 95–100 ) , was achieved by 93.33 % of patients in the intervention group , and 90 % had favorable scores ( 0 or 1 ) on the MRS . This showed a benefit in reducing disability , with two being the number of patients considered as needed-to-treat ( NNT ) ( 95 % CI , 1.0–1.2 ) . All dimensions of EQ-5D in the intervention group were significantly better for quality of life and generic health status than in the control group ( p=0.001 ) . Depression was found in one patient ( 3.33 % ) in the intervention group and in two patients ( 6.67 % ) in the control group . Dementia was found in three patients ( 10 % ) in the intervention group and in four patients ( 13.33 % ) in the control group . We concluded that an early home rehabilitation program for patients with ischemic stroke in the first three-month period provides significantly better outcomes in improving function , reducing disability , increasing quality of life , and reducing depression than a program of usual care does [2780376] Background About 80 % of all stroke survivors have an upper limb paresis immediately after stroke , only about a third of whom ( 30 to 40 % ) regain some dexterity within six months following conventional treatment programs . Of late , however , two recently developed interventions - constraint-induced movement therapy ( CIMT ) and bilateral arm training with rhythmic auditory cueing ( BATRAC ) - have shown promising results in the treatment of upper limb paresis in chronic stroke patients . The ULTRA-stroke ( acronym for Upper Limb TRaining After stroke ) program was conceived to assess the effectiveness of these interventions in subacute stroke patients and to examine how the observed changes in sensori-motor functioning relate to changes in stroke recovery mechanisms associated with peripheral stiffness , interlimb interactions , and cortical inter- and intrahemispheric networks . The present paper describes the design of this single-blinded r and omized clinical trial ( RCT ) , which has recently started and will take several years to complete . Methods / Design Sixty patients with a first ever stroke will be recruited . Patients will be stratified in terms of their remaining motor ability at the distal part of the arm ( i.e. , wrist and finger movements ) and r and omized over three intervention groups receiving modified CIMT , modified BATRAC , or an equally intensive ( i.e. , dose-matched ) conventional treatment program for 6 weeks . Primary outcome variable is the score on the Action Research Arm test ( ARAT ) , which will be assessed before , directly after , and 6 weeks after the intervention . During those test sessions all patients will also undergo measurements aim ed at investigating the associated recovery mechanisms using haptic robots and magneto-encephalography ( MEG ) . Discussion ULTRA-stroke is a 3-year translational research program which aims ( 1 ) to assess the relative effectiveness of the three interventions , on a group level but also as a function of patient characteristics , and ( 2 ) to delineate the functional and neurophysiological changes that are induced by those interventions .The outcome on the ARAT together with information about changes in the associated mechanisms will provide a better underst and ing of how specific therapies influence neurobiological changes , and which post-stroke conditions lend themselves to specific treatments . Trial Registration The ULTRA-stroke program is registered at the Netherl and s Trial Register ( NTR , http://www.trialregister.nl , number NTR1665 ) [16541932] Objective : To compare intensive with non-intensive home-based rehabilitation provision following stroke or hip fracture in old age ( 65 years ) . Design : Parallel single-blind r and omized control trial . Setting : Domiciliary provided multidisciplinary rehabilitation . Subjects : One hundred and sixty patients aged 65 or over recently discharged from hospital after suffering a stroke or hip fracture . Intervention : Patients assigned to receive six or more face-to-face contacts or three or less face-to-face contacts from members of a multidisciplinary rehabilitation team . Main measures : Patients assessed using the Barthel Index , Therapy Outcome Measure , Euroqol 5D ( EQ-5D ) , Hospital Anxiety and Depression Scale ( HADS ) and Frenchay Activities Index ( FAI ) at three months . All follow-up assessment s were conducted blind to allocation . Results : Subgroup analysis was conducted on the basis of incident condition ( stroke or hip fracture ) . Significant differences were detected for the stroke subgroup at three months [ Therapy Outcome Measure H and icap ( median difference 0.5 ( P < 0.05 ) ) and EQ-5D ( median difference 0.17 ( P < 0.05 ) ) ] and in change at three months [ Therapy Outcome Measure ( mean difference 0.52 ( SD 0.85 ) 95 % CI ( 0.16 , 0.88 ) ) and EQ-5D ( mean difference 0.15 ( SD 0.25 ) 95 % CI ( 0.05 , 0.26 ) ) ] . No significant differences were detected between the two arms of the study for the hip fracture subgroup . Conclusion : Following stroke older people who receive a more intensive communitybased multidisciplinary rehabilitation service may experience short-term benefit in relation to social participation and some aspects of health-related quality of life . A more intensive service after discharge from hospital following a hip fracture is unlikely to result in similar patient benefit [11128729] Objective : To assess the effectiveness of community-based rehabilitation for stroke patients who were not admitted to hospital in South London . Design : R and omized controlled trial . Setting : Patients ' homes in South London . Subjects : Stroke patients not admitted to hospital after a stroke . Intervention : Rehabilitation at home by rehabilitation team for up to three months or usual care . Main outcome measures : The primary outcome measure was the Barthel score . Secondary measures included the Motricity Index , Rivermead ADL , Hospital Anxiety and Depression score and Nottingham Health Profile . Results : Forty-three patients who remained at home were r and omized to rehabilitation team ( 23 ) or ‘ usual ’ care ( 20 ) . The mean number of physiotherapy sessions was three ( range 1–14 ) for the rehabilitation team group and two for the usual care group . Patients ( with a deficit ) in the rehabilitation arm of the trial were more likely to receive occupational , physical and speech therapy than those in the control arm ( p = 0.03 , 0.01 and 0.008 , respectively ) . For those patients actually receiving therapy , there was no evidence that the amount received differed between the groups . However , the number of patients in each of these comparisons was very small . The outcome for patients in the rehabilitation team arm of the trial was nonsignificantly higher ( 0.05 < p < 0.2 ) than for those in the control arm for the areas of Nottingham Health Profile , anxiety , depression , caregiver strain and the proportion of patients living at home . Based on the data observed here , a trial with approximately 150 patients in each arm would be needed to have adequate power to detect a 33 % difference between intervention and control groups in these outcomes . Conclusion : Community therapy support for patients not admitted to hospital is feasible but to determine whether it is cost- or clinical ly effective would require trials of adequate size [16888263] Background and Purpose — A pilot evaluation of an occupational therapy intervention to improve self-care independence for residents with stroke-related disability living in care homes was the basis of this study . Methods — A cluster r and omized controlled trial with care home as the unit of r and omization was undertaken in Oxfordshire , UK . Twelve homes ( 118 residents ) were r and omly allocated to either intervention ( 6 homes , 63 residents ) or control ( 6 homes , 55 residents ) . Occupational therapy was provided to individuals but included carer education . The control group received usual care . Assessment s were made at baseline , postintervention ( 3 months ) and at 6-months to estimate change using the Barthel Activity of Daily Living Index ( BI ) scores , “ poor global outcome ” , ( defined as deterioration in BI score , or death ) and the Rivermead Mobility Index . Results — At 3 months BI score in survivors had increased by 0.6 ( SD 3.9 ) in the intervention group and decreased by 0.9 ( 2.2 ) in the control group ; a difference of 1.5 ( 95 % CI allowing for cluster design , −0.5 to 3.5 ) . At 6 months the difference was 1.9 ( −0.7 to 4.4 ) . Global poor outcome was less common in the intervention group . At 3 months , 20/63 ( 32 % ) were worse/dead in the intervention group compared with 31/55 ( 56 % ) in the control group , difference −25 % ( −51 % to 1 % ) . At 6 months the difference was similar , −26 % ( −48 % to −3 % ) . Between-group changes in Rivermead Mobility Index scores were not significantly different . Conclusion — Residents who received an occupational therapy intervention were less likely to deteriorate in their ability to perform activities of daily living [19109542] Background and Purpose — Modified constraint-induced therapy ( mCIT ) is an outpatient therapy encouraging repetitive , task-specific practice with the affected arm . mCIT has shown efficacy in all stages poststroke . Given its efficacy when combined with other therapy regimens , the current study examined the efficacy of mental practice when combined with mCIT versus mCIT only using r and omized , controlled methods . Method — Ten patients with chronic stroke ( 7 males ; mean age , 61.4±3.02 years ; age range , 48 to 79 years ; mean time since stroke , 28.5 months ; range , 13 to 42 months ) exhibiting stable , affected arm motor deficits were administered mCIT , consisting of : ( 1 ) structured therapy emphasizing affected arm use in functional activities 3 days/week for 10 weeks ; and ( 2 ) less affected arm restraint 5 days/week for 5 hours . Both of these components were administered during a 10-week period . Subjects r and omly assigned to the mCIT+mental practice experimental condition also received 30-minute mental practice sessions provided directly after therapy sessions . These mental practice sessions required daily cognitive rehearsal of the activities of daily living practice d during mCIT clinical sessions . Results — No pre-existing differences were found between groups on any demographic variable or movement scale . All subjects exhibited marked reductions in affected arm impairment and functional limitation . However , subjects in the mCIT+mental practice group exhibited significantly larger changes on both movement measures after intervention : Action Research Arm Test , + 15.4-point change versus + 8.4-point change for mCIT only subjects ( P<0.001 ) ; Fugl-Meyer , + 7.8-point change versus + 4.1-point change for the mCIT only subjects ( P=0.01 ) . These changes were sustained 3 months after intervention . Conclusions — mCIT remains a promising motor intervention . However , its efficacy appears to be enhanced by use of mental practice provided directly after mCIT clinical sessions [10698876] Abstract Objective : To establish if a brief programme of domiciliary occupational therapy could improve the recovery of patients with stroke discharged from hospital . Design : Single blind r and omised controlled trial . Setting : Two hospital sites within a UK teaching hospital . Subjects : 138 patients with stroke with a definite plan for discharge home from hospital . Intervention : Six week domiciliary occupational therapy or routine follow up . Main outcome measures : Nottingham extended activities of daily living score and “ global outcome ” ( deterioration according to the Barthel activities of daily living index , or death ) . Results : By eight weeks the mean Nottingham extended activities of daily living score in the intervention group was 4.8 points ( 95 % confidence interval −0.5 to 10.0 , P=0.08 ) greater than that of the control group . Overall , 16 ( 24 % ) intervention patients had a poor global outcome compared with 30 ( 42 % ) control patients ( odds ratio 0.43 , 0.21 to 0.89 , P=0.02 ) . These patterns persisted at six months but were not statistically significant . Patients in the intervention group were more likely to report satisfaction with a range of aspects of services . Conclusion : The functional outcome and satisfaction of patients with stroke can be improved by a brief occupational therapy programme carried out in the patient 's home immediately after discharge . Major benefits may not , however , be sustained [11509308] OBJECTIVES To compare the effectiveness and costs of a new domiciliary rehabilitation service for elderly stroke patients with geriatric day-hospital care . DESIGN R and omized controlled trial . PARTICIPANTS Stroke patients aged 55 + who required further rehabilitation after hospital discharge or after referral to geriatricians from the community . SETTING Poole area , East Dorset , a mixed urban/rural area on the south coast of Engl and . MAIN OUTCOMES Primary -changes between hospital discharge and 6-month follow-up in physical function as measured by Barthel index . Secondary -changes over this period in Rivermead Mobility Index and mental state ( Philadelphia Geriatric Centre Morale Scale ) and differences in social activity ( Frenchay Activities Index ) and generic health status ( SF-36 ) . Health service and social service cost per patient were compared for the two groups . RESULTS 180 patients were eligible and 140 ( 78 % ) were r and omized . The groups were well balanced for age , sex , social class and initial Barthel index . We achieved follow-up in 88 % of subjects who were alive at 6 months . We detected no significant differences in patient outcomes , although there was a non-significant improvement in measures of physical function and social activity in the domiciliary group . Domiciliary patients had more physiotherapy time per session and more district nurse time , and made greater use of social service day centres and home helps . Total cost per patient did not differ significantly between the two groups , with reduced health service costs in the domiciliary arm offset by higher social service costs . CONCLUSION No significant differences were detected in the effectiveness of the two services . Neither service influenced patients ' mental state , and their social activity remained low . Total costs were similar . A mixed model of day-hospital and domiciliary care may be most cost-effective for community stroke rehabilitation , but this requires further evaluation [10797163] BACKGROUND AND PURPOSE About 50 % of stroke survivors are discharged to their homes with lasting disability . Knowledge , however , of the importance of follow-up services that targets these patients is sparse . The purpose of the present study was to evaluate 2 models of follow-up intervention after discharge . The study hypothesis was that intervention could reduce readmission rates and institutionalization and prevent functional decline . We report the results regarding readmission . METHODS This r and omized study included 155 stroke patients with persistent impairment and disability who , after the completion of inpatient rehabilitation , were discharged to their homes . The patients were r and omized to 1 of 2 follow-up interventions provided in addition to st and ard care or to st and ard aftercare . Fifty-four received follow-up home visits by a physician ( INT1-HVP ) , 53 were provided instructions by a physiotherapist in their home ( INT2-PI ) , and 48 received st and ard aftercare only ( controls ) . Baseline characteristics for the 3 groups were comparable . Six months after discharge , data were obtained on readmission and institutionalization . RESULTS The readmission rates within 6 months after discharge were significantly lower in the intervention groups than in the control group ( INT1-HVP 26 % , INT2-PI 34 % , controls 44 % ; P=0.028 ) . Multivariate analysis of readmission risk showed a significant favorable effect of intervention ( INT1-HVP or INT2-PI ) in interaction with length of hospital stay ( P=0.0332 ) , indicating that the effect of intervention was strongest for patients with a prolonged inpatient rehabilitation . CONCLUSIONS Readmission is common among disabled stroke survivors . Follow-up intervention after discharge seems to be a way of preventing readmission , especially for patients with long inpatient rehabilitation [19541918] Background . The study investigated whether passive splinting or active motor training as either individualized best conventional therapy or as st and ardized impairment-oriented training ( IOT ) would be superior in promoting motor recovery in subacute stroke patients with mildly or severely paretic arms . Methods . A total of 148 anterior circulation ischemic stroke patients were r and omly assigned to 45 minutes of additional daily arm therapy over 3 to 4 weeks as either ( a ) passive therapy with inflatable splints or active arm motor therapy as either ( b ) individualized best conventional therapy ( CONV ) or ( c ) st and ardized IOT , that is Arm BASIS training for severe paresis or Arm Ability training for mild paresis . Main outcome measures included the following : Fugl-Meyer arm motor score ( severely paretic arms ) and the TEMPA time scores ( mildly affected arms ) . Pre — post ( immediate effects ) and pre—4 weeks follow-up analyses ( long-term effects ) were performed . Results . Overall improvements were documented ( mean baseline and change scores efficacy : Fugl-Meyer , arm motor scores , 24.4 , + 9.1 points ; TEMPA , 119 , −26.6 seconds ; P < .0001 ) , but with no differential effects between splint therapy and the combined active motor rehabilitation groups . Both efficacy and effectiveness analyses indicated , however , bigger immediate motor improvements after IOT as compared with best conventional therapy ( Fugl-Meyer , arm motor scores : IOT + 12.3 , CONV + 9.2 points ; TEMPA : IOT −31.1 seconds , CONV −20.5 seconds ; P = .0363 ) ; for mildly affected patients long-term effects could also be substantiated . Conclusions . Specificity of active training seemed more important for motor recovery than intensity ( therapy time ) . The comprehensive modular IOT approach promoted motor recovery in patients with either severe or mild arm paresis [9472875] BACKGROUND AND PURPOSE Data on survival and functioning after stroke needs to be supplemented by measures emphasizing the patients ' subjective perception . We studied ( 1 ) subjective well-being ( SWB ) as a latent variable in a common-factor model with four items , ( 2 ) the reliability of these four items , and ( 3 ) variables related to SWB in stroke patients . METHODS Data on all stroke patients ( n=1417 ) and a r and om sub sample of stroke-free individuals of similar age ( n=1439 ) were collected from the Nord-Trøndelag Health Survey , a cross-sectional study of 74977 persons . Based on a two- sample factor analysis model , scores of SWB were calculated , and variables explaining SWB were studied in a regression model . RESULTS Four items were a priori believed to measure SWB as a latent variable ( " satisfaction , " " strength , " " calmness , " and " cheerfulness " ) . This was confirmed by factor analysis . The reliability of these items ( the proportion of the variance of the items that can be explained by the common factor ) was between .42 and .53 . Regression analyses showed a significant effect of having had a stroke , gender ( lower SWB in men ) , age ( increasing SWB with increasing age ) , perceived general health , nervousness , loneliness , sleep problems , social support , and use of analgesics . There was no statistical interaction between these variables and having had a stroke . CONCLUSIONS Higher SWB after stroke relates to female gender , older age , good general and mental health , and a firm social network [8410035] This study compared the functional ability and perceived health status of stroke patients treated by a domiciliary rehabilitation team or by routine hospital-based services after discharge from hospital . Patients discharged from two acute and three rehabilitation hospitals in Nottingham were r and omly allocated in three strata ( Health Care of the Elderly , General Medical and Stroke Unit ) to receive domiciliary or hospital-based care after discharge . Functional recovery was assessed by the Extended Activities of Daily Living ( ADL ) scale three and six months after discharge and perceived health at six months was measured by the Nottingham Health Profile . A total of 327 eligible patients of 1119 on a register of acute stroke admissions were recruited over 16 months . Overall there were no differences between the groups in their Extended ADL scores at three or six months , or their Nottingham Health Profile scores at six months . In the Stroke Unit stratum , patients treated by the domiciliary team had higher household ( p = 0.02 ) and leisure activity ( p = 0.04 ) scores at six months than those receiving routine care . In the Health Care of the Elderly stratum , death or a move into long-term institutional care at six months occurred less frequently in patients allocated to the routine service , about half of whom attended a geriatric day hospital . Overall there was no difference in the effectiveness of the domiciliary and hospital-based services , although younger stroke unit patients appeared to do better with home therapy while some frail elderly patients might have benefited from day hospital attendance [19841835] OBJECTIVE Telerehabilitation enables a remotely controlled programme to be used to treat motor deficits in post-stroke patients . The effects of this telerehabilitation approach were compared with traditional motor rehabilitation methods . DESIGN R and omized single-blind controlled trial . PATIENTS A total of 36 patients with mild arm motor impairments due to ischaemic stroke in the region of the middle cerebral artery . METHODS The experimental treatment was a virtual reality-based system delivered via the Internet , which provided motor tasks to the patients from a remote rehabilitation facility . The control group underwent traditional physical therapy for the upper limb . Both treatments were of 4 weeks duration . All patients were assessed one month prior to therapy , at the commencement and termination of therapies and one month post-therapy , with the Fugl-Meyer Upper Extremity , the ABILH AND and the Ashworth scales . RESULTS Both rehabilitative therapies significantly improved all outcome scores after treatment , but only the Fugl-Meyer Upper Extremity scale showed differences in the comparison between groups . CONCLUSION Both strategies were effective , but the experimental approach induced better outcomes in motor performance . These results may favour early discharge from hospital sustained by a telerehabilitation programme , with potential beneficial effects on the use of available re sources [17148515] Objective : To assess the effect of three weeks of rehabilitation in the home setting for younger patients with stroke with the aim of improving activity level . Design : A r and omized controlled study with blinded evaluations at discharge , three weeks , three months and one year after discharge . Setting : Home of the patient or the ordinary day rehabilitation clinic at the university hospital . Subjects : Fifty-eight patients ( median age 53 years ) consecutively discharged from inpatient rehabilitation with a first occurrence of stroke participated in training directly after discharge . Intervention : Rehabilitation was given for 9 hours/week over three weeks . The home group received individually tailored training , based on the patient 's needs and desires , with a focus on activities in their natural context . Support and information were also given . The intervention in the day clinic group was aim ed mainly at improved functions . Main measures : The main outcome was activity , assessed with the Assessment of Motor and Process Skill ( AMPS ) . The impairment level was also evaluated . Costs were estimated . Result : There were no significant differences between the groups on any of the four assessment s. However , there seemed to be an earlier improvement on some measures ( including AMPS ) for the home group . For both groups there was a greater improvement on the activity level than on the impairment level . The costs of the home group were less than half of the costs of the day clinic group . Conclusion : With the present results , both rehabilitation programmes could be recommended , however , further studies are needed to define patients who may specifically benefit from the home rehabilitation programme . Costs should be taken into consideration [17852312] Purpose . To assess the effects of daily power-assisted functional electrical stimulation ( FES ) home program therapy in chronic stroke . Methods . A total of 20 consecutively enrolled stroke patients with spastic upper-extremity impairments > 1 year after stroke were recruited for this non-blinded r and omized controlled trial . Subjects were assigned to control and FES groups and followed for 5 months . The FES group used a power-assisted FES device to induce greater muscle contraction by electrical stimulation in proportion to the integrated electromyography ( EMG ) signal picked up on surface electrodes . Target muscles were the extensor carpi radialis longus ( ECRL ) and extensor carpi radialis brevis ( ECRB ) , extensor digitorum communis ( EDC ) , extensor indicis proprius ( EIP ) , and deltoid ( Del ) . Patients underwent 30 ∼ 60 min FES sessions at home about 6 days/week . Root mean square ( RMS ) of ECRL , EDC and Del maximum voluntary EMGs , active range of motion ( ROM ) of wrist and finger extension and shoulder flexion , modified Ashworth scale ( MAS ) , and clinical tests were investigated before and after FES training . Results . The FES group displayed significantly greater improvements in RMS , active ROM , MAS and functional h and tests , and was able to smoothly perform activities of daily life using the hemiplegic upper extremities . Conclusions . Daily power-assisted FES home program therapy can effectively improve wrist and finger extension and shoulder flexion . Proprioceptional sensory feedback might play an important role in power-assisted FES therapy [18184932] Investigators have demonstrated that a variety of intensive movement training protocol s for persistent upper limb paralysis in patients with chronic stroke ( 6 months or more after stroke ) improve motor outcome . This r and omized controlled study determined in patients with upper limb motor impairment after chronic stroke whether movement therapy delivered by a robot or by a therapist using an intensive training protocol was superior . Robotic training ( n = 11 ) and an intensive movement protocol ( n = 10 ) improved the impairment measures of motor outcome significantly and comparably ; there were no significant changes in disability measures . Motor gains were maintained at the 3-month evaluation after training . These data contribute to the growing awareness that persistent impairments in those with chronic stroke may not reflect exhausted capacity for improvement . These new protocol s , rendered by either therapist or robot , can be st and ardized , tested , and replicated , and potentially will contribute to rational activity-based programs [11237160] Objective : To evaluate the effects of leisure therapy and conventional occupational therapy ( OT ) on the mood , leisure participation and independence in activities of daily living ( ADL ) of stroke patients 6 and 12 months after hospital discharge . Design : Multicentre r and omized controlled trial . Setting and participants : Four hundred and sixty-six stroke patients from five UK centres . Main outcome measures : The General Health Question naire ( 12 item ) , the Nottingham Extended ADL Scale and the Nottingham Leisure Question naire , assessed by post , with telephone clarification . Results : Four hundred and forty ( 94 % ) and 426 ( 91 % ) subjects were alive at 6 and 12 months , respectively . Three hundred and seventy-four ( 85 % of survivors ) and 311 ( 78 % of survivors ) responded at 6 and 12 month follow-up respectively . At six months and compared to the control group , those allocated to leisure therapy had nonsignificantly better GHQ scores ( –1.2 : 95 % CI –2.9 , + 0.5 ) , leisure scores ( + 0.7 , 95 % CI –1.1 , + 2.5 ) and Extended ADL scores ( + 0.4 : 95 % CI –3.8 , + 4.5 ) : the ADL group had nonsignificantly better GHQ scores ( –0.1 : 95 % CI –1.8 , + 1.7 ) and Extended ADL scores ( + 1.4 : 95 % CI –2.9 , + 5.6 ) and nonsignificantly worse leisure scores ( –0.3 : 95 % CI –2.1 , + 1.6 ) . The results at 12 months were similar . Conclusion : In contrast to the findings of previous smaller trials , neither of the additional OT treatments showed a clear beneficial effect on mood , leisure activity or independence in ADL measured at 6 or 12 months [10440303] BACKGROUND Patients who have a stroke are not always admitted to hospital , and 22 - 60 % remain in the community , frequently without coordinated rehabilitation . We aim ed to assess the efficacy of an occupational therapy intervention for patients with stroke who were not admitted to hospital . METHODS In this single-blind r and omised controlled trial , consecutive stroke patients on a UK community register in Nottingham and Derbyshire were allocated r and omly to up to 5 months of occupational therapy at home or to no intervention ( control group ) 1 month after their stroke . The aim of the occupational therapy was to encourage independence in personal and instrumental activities of daily living . Patients were assessed on outcome measures at baseline ( before r and omisation ) and at 6 months . The primary outcome measure was the score on the extended activities of daily living ( EADL ) scale at 6 months . Other outcome measures included the Barthel index , the general health question naire 28 , the carer strain index , and the London h and icap scale . All assessment s were done by an independent assessor who was unaware of treatment allocation . The analysis included only data from completed question naires . FINDINGS 185 patients were included : 94 in the occupational therapy group and 91 in the control group . 22 patients were not assessed at 6 months . At follow-up , patients who had occupational therapy had significantly higher median scores than the controls on : the EADL scale ( 16 vs 12 , p<0.01 , estimated difference 3 [ 95 % CI 1 to 4 ] ) ; the Barthel index ( 20 vs 18 , p<0.01 , difference 1 , [ 0 - 1 ] ) ; the carer strain index ( 1 vs 3 , p<0.05 , difference 1 [ 0 to 2 ] ) ; and the London h and icap scale ( 76 vs 65 , p<0.05 , difference 7 , [ 0.3 to 13.5 ] ) . There were no significant differences on the general health question naire between the patient or carer . INTERPRETATION Occupational therapy significantly reduced disability and h and icap in patients with stroke who were not admitted to hospital [12392333] Objective : To evaluate whether follow-up services for stroke survivors could improve functional outcome and reduce readmission rate . In this paper results of functional outcome are reported . Design : R and omized controlled trial allocating patients to one of three different types of aftercare : ( 1 ) follow-up home visits by a physician , ( 2 ) physiotherapist instruction in the patient 's home , or ( 3 ) st and ard aftercare . Subjects : Stroke patients with persisting impairment and disability who , after completing inpatient rehabilitation , were discharged to their homes . Outcome measures : Six months after discharge , functional outcome was assessed with Functional Quality of Movement , Barthel Index , Frenchay Activity Index and Index of Extended Activites of Daily Living . Results : One-hundred and fifty-five stroke patients were included in the study . Fifty-four received follow-up home visits by a physician , 53 were given instructions by a physiotherapist in their home and 48 received st and ard aftercare only . No statistically signi ca nt differences in functional outcome six months after discharge were demonstrated between the three groups . However , all measurements showed a tendency towards higher scores indicating better function in both interventions groups compared with the control group . Conclusion : Follow-up services after stroke may be a way of improving functional outcome . The results of the present study should be evaluated in future trials . More research in this eld is needed , especially studies of how to support stroke survivors to resume social and leisure activities [10327094] Objective : To assess the efficacy of a programme of continuing self-directed exercises for people discharged home after a stroke , supervised once a week by therapists . Design : A r and omized controlled trial of 100 patients discharged from hospital after a stroke , requiring ongoing therapy . The control group received outpatient or day hospital therapy ; the experimental group were visited once a week by an occupational and /or physiotherapist who prescribed a programme of exercises and activities for the following week . Subjects were studied for the first three months after discharge from hospital . Setting : A district general hospital , or the homes of subjects r and omized to the experimental group , in New Zeal and . Main outcome measures : ( 1 ) Characteristics of the groups , ( 2 ) gait speed , limb function , activities of daily living , ( 3 ) time with therapists , ( 4 ) mood of both subjects and caregivers , ( 5 ) anticipation of outcome at entry , compared with perceived outcome at exit . Results : No statistical differences between the control and experimental groups in characteristics , or in any outcomes measured , except that the contact time period , but not the number of visits , was longer in the experimental group ( p = 0.003 ) . Conclusions : A supervised home-based programme is as effective as outpatient or day hospital therapy [9366727] Abstract Objective : To assess the clinical effectiveness of an early discharge policy for patients with stroke by using a community based rehabilitation team . Design : R and omised controlled trial to compare conventional care with an early discharge policy . Setting : Two teaching hospitals in inner London . Subjects : 331 medically stable patients with stroke ( mean age 71 ) who lived alone and were able to transfer independently or who lived with a resident carer and were able to transfer with help . Interventions : 167 patients received specialist community rehabilitation for up to 3 months after r and omisation . 164 patients continued with conventional hospital and community care . Main outcome measures : Barthel score at 12 months . Secondary outcomes measured impairment with motoricity index , minimental state examination , and Frenchay aphasia screening test ; disability with the Rivermead activity of daily living scales , hospital anxiety and depression scale , and 5 m walk ; h and icap with the Nottingham health profile ; carer stress with caregiver strain index and patient and carer satisfaction . The main process measure was length of stay after r and omisation . Results : One year after r and omisation no significant differences in clinical outcomes were found apart from increased satisfaction with hospital care in the community therapy group . Length of stay after r and omisation in the community therapy group was significantly reduced ( 12 v 18 days ; P<0.0001 ) . Patients with impairments were more likely to receive treatment in the community therapy group . Conclusions : Early discharge with specialist community rehabilitation after stroke is feasible , as clinical ly effective as conventional care , and acceptable to patients . Considerable reductions in use of hospital beds are achievable . Key messages Early discharge from hospital after stroke with specialist rehabilitation at home is feasible without an increase in readmission rates or stress to carers This r and omised controlled trial shows this method to be as effective as conventional care when assessed with a range of measures of impairment , disability , h and icap , carer stress , and patient and carer satisfaction at 1 year Significant reductions in bed usage can be achieved by the provision of a community rehabilitation team with no significant increase in rehabilitation [15468020] OBJECTIVE To evaluate the effectiveness of 2 rehabilitative approaches for improving paretic limb reaching by chronic stroke subjects . DESIGN Pre- and posttest reaching to targets ipsilateral , midline , and contralateral to the impaired side . SETTING Training in subjects ' homes ; testing in a laboratory setting . PARTICIPANTS Twelve poststroke volunteers were matched using the Motor Assessment Scale ( MAS ) and then were r and omly assigned to 1 of 2 training conditions . Subjects were subsequently categorized as at a high or low functional level , using the reaching pretest movement time scores . INTERVENTIONS Training ( trunk unrestrained ) using the paretic limb was 4 weeks ( 12 sessions ) . Task-related training ( TRT ) involved reaching to objects placed across the workspace . Progressive resistive exercise ( PRE ) involved whole-arm pulling against resistive therapeutic tubing in planes and distances similar to that in TRT . Main outcome measures Kinematic analysis of arm trajectory and trunk motion using the Peak Performance System , as well as scores on the MAS and the Rivermead Motor Assessment ( RMA ) . RESULTS For low-level groups , TRT result ed in increased substitutive trunk use at the target ipsilateral to the moving arm , and for midline and contralateral targets after PRE . Only low-level , TRT subjects straightened h and paths , which suggested better coordination of elbow-shoulder motion , and improved on the RMA . High-level subjects decreased trunk use at ipsilateral target after PRE , which was not observed after TRT . No significant differences between training conditions were found for other kinematic variables . CONCLUSIONS Training benefits appear to depend on initial level of functioning . Although compensatory trunk use was evident , low-level subjects seemed to benefit most from TRT . High-level subjects , whose kinematics showed fairly normal movement organization , demonstrated less compensatory movement after PRE [19541917] Background . Chronic upper extremity impairment due to stroke has significant medical , psychosocial , and financial consequences , but few studies have examined the effectiveness of rehabilitation therapy during the chronic stroke period . Objective . To test the safety and efficacy of the MIT-Manus robotic device for chronic upper extremity impairment following stroke . Methods . The VA Cooperative Studies Program initiated a multicenter , r and omized , controlled trial in November 2006 ( VA ROBOTICS ) . Participants with upper extremity impairment ≥6 months poststroke were r and omized to robot-assisted therapy ( RT ) , intensive comparison therapy ( ICT ) , or usual care ( UC ) . RT and ICT consisted of three 1-hour treatment sessions per week for 12 weeks . The primary outcome was change in the Fugl-Meyer Assessment upper extremity motor function score at 12 weeks relative to baseline . Secondary outcomes included the Wolf Motor Function Test and the Stroke Impact Scale . Results . A total of 127 participants were r and omized : 49 to RT , 50 to ICT , and 28 to UC . The majority of participants were male ( 96 % ) , with a mean age of 65 years . The primary stroke type was ischemic ( 85 % ) , and 58 % of strokes occurred in the anterior circulation . Twenty percent of the participants reported a stroke in addition to their index stroke . The average time from the index stroke to enrollment was 56 months ( range , 6 months to 24 years ) . The mean Fugl-Meyer score at entry was 18.9 . Conclusions . VA ROBOTICS demonstrates the feasibility of conducting multicenter clinical trials to rigorously test new rehabilitative devices before their introduction to clinical practice . The results are expected in early 2010 [15481562] This study was a preliminary examination of the effect of low-intensity home-based physical therapy on the performance of activities of daily living ( ADL ) and motor function in patients more than 1 year after stroke . Twenty patients were recruited from a community stroke register in Nan-Tou County , Taiwan , to a r and omized , crossover trial comparing intervention by a physical therapist immediately after entry into the trial ( Group I ) or after a delay of 10 weeks ( Group II ) . The intervention consisted of home-based physical therapy once a week for 10 weeks . The Barthel Index ( BI ) and Stroke Rehabilitation Assessment of Movement ( STREAM ) were used as st and ard measures for ADL and motor function . At the first follow-up assessment at 11 weeks , Group I showed greater improvement in lower limb motor function than Group II . At the second follow-up assessment at 22 weeks , Group II showed improvement while Group I had declined . At 22 weeks , the motor function of upper limbs , mobility , and ADL performance in Group II had improved slightly more than in Group I , but the between-group differences were not significant . It appears that low-intensity home-based physical therapy can improve lower limb motor function in chronic stroke survivors . Further studies will be needed to confirm these findings [16250192] Objectives : ( 1 ) To determine the feasibility of a home-based electromyography triggered neuromuscular stimulation ( ETMS ) programme ; and ( 2 ) to determine ETMS efficacy in increasing affected wrist extension and reducing affected arm impairment . Design : R and omized , controlled , pre-lpost , cross-over design . Setting : Outpatient rehabilitation hospital . Patients : Twelve chronic stroke patients with palpable muscle contraction in their affected wrist extensors but no movement ( 7 males ; mean age=59.75 years , age range 44 - 75 years ; mean time since stroke=52.75 months , range 13 - 131 months ) . Intervention : Subjects were r and omly assigned to receive either : ( a ) ETMS use twice every weekday in 35-min increments during an eight-week period followed by an eight-week home exercise programme ( ETMS/home exercise programme ) ( n=8 ) ; or ( b ) an eight-week home exercise programme followed by use of ETMS twice every weekday in 35-min increments during an eight-week period ( home exercise programme ) ( n=4 ) . Main outcome measures : The Fugl-Meyer , Action Research Arm Test and goniometry . Results : After home exercise programme participation , subjects showed nominal or no changes on any of the outcome measures . After ETMS , patients showed modest impairment reductions , as shown by the Fugl-Meyer , and no Action Research Arm Test changes . However , both groups showed a 218 increase in active affected wrist extension after ETMS use . Conclusion : ETMS use is feasible in the home environment . Neither participation in a traditional home exercise programme nor ETMS use conveyed changes on the Fugl-Meyer or Action Research Arm Test . However , ETMS use increased active affected limb extension . This new movement may provide a potential pathway for subjects to participate in other interventions , such as modified constraint induced therapy [8010180] The DOMINO study compared domiciliary and hospital-based rehabilitation services for stroke patients after discharge from hospital , stratified by the hospital ward at discharge . No difference between the services had been found at 6 months , but home therapy was better than outpatient department therapy at improving household ability and leisure activity in the patients discharged from the Stroke Unit ( SU ) , and attendance at a day hospital may have been better than a domiciliary service at preventing death or institutionalization for patients discharged from Health Care of the Elderly ( HCE ) wards . We report the follow-up of the patients between 6 months and 1 year after discharge , during which time few patients received further treatment and little change in health or function occurred . Over this period the benefits of domiciliary rehabilitation in the SU group were lost , largely because the patients who had been treated in outpatient departments continued to improve . Between 6 months and 1 year the numbers of HCE patients in the two treatment groups who died or were institutionalized were similar , but the advantage of day hospital attendance was still evident at 1 year [14503438] Based on the principles of neuroplasticity , the purpose of this crossover study was to determine if improvement in upper extremity ( UE ) function and independence could be achieved in patients 6 months to 7 years poststroke following an outpatient rehabilitation program ( supervised 1.5 hours per week for 8 weeks reinforced with home gloving unaffected side and attended , grade d , repetitive sensory and motor training activities ) . Twenty-one subjects ( right or left hemiparesis ; able to walk 100 feet with or without a cane ; partially opened and closed the h and ; partially elevated the shoulder and elbow against gravity ) were r and omly assigned to Group A ( sensory training 4 weeks , motor training 4 weeks ) or Group B ( motor training 4 weeks , sensory training 4 weeks ) . Greater than 20 % ( P < 0.01 ) improvement was measured in functional independence and UE function ( fine motor , sensory discrimination , and musculoskeletal performance ) . Gains were hemispheric and training specific and maintained over 3 months . This study provides evidence documenting significant improvement in function in the late poststroke recovery period following 12 hours of supervised learning based sensory motor training [16719028] Objective : To evaluate the efficacy of a task-oriented intervention in enhancing arm function in people with stroke . Design : Two-centre , observer-blinded , stratified , block-r and omized controlled trial . Setting : General community . Patients : Ninety-one individuals within one year of a first or recurrent stroke consented to participate between May 2000 and February 2003 . Interventions : The experimental intervention involved practice of functional , unilateral and bilateral tasks that were design ed to improve gross and fine manual dexterity whereas the control intervention was composed of walking tasks . Members in both groups participated in three sessions a week for six weeks . Main outcome measure(s ) : The primary test of arm function was the Box and Block Test . Secondary tests included the Nine-Hole Peg Test , maximal grip strength , the Test d'Evaluation des Membres supé rieurs des Personnes Agées ( TEMPA ) and the Stroke Rehabilitation Assessment of Movement . Results : Results are for the more affected arm . Baseline performance on the Box and Block Test was an average of 26 blocks ( st and ard deviation ( SD=16 ) in the experimental group ( n=47 ) and 26 blocks ( Sd=18 ) in the control group ( n=44 ) . These values represent approximately 40 % of age-predicted values . Values for the postintervention evaluation were an average of 28 ( SD=17 ) and 28 ( SD=19 ) blocks for the experimental and control group respectively . No meaningful change on other measures of arm function was observed . Conclusions : A task-oriented intervention did not improve voluntary movement or manual dexterity of the affected arm in people with chronic stroke [17214754] AIM This paper reports an evaluation of a range-of-motion exercise programme aim ed at improving joint flexibility , activity function , perception of pain , and depressive symptoms in a sample of stroke survivors in long-term care facilities . BACKGROUND The benefits of physical rehabilitation for stroke survivors have been well established . There is , however , little empirical data on the effects of a simple nurse-led range-of-motion exercise programme in improving function for these people . METHOD A r and omized controlled trial was conducted in 1999 with 59 bedridden older stroke survivors in residential care . Participants were r and omly assigned to usual care or one of two intervention groups . The 4-week , twice-per-day , 6 days-per-week range-of-motion exercise protocol s were similar in both intervention groups , and consisted of full range-of-motion exercises of the upper and lower extremities . To test the effect of different degrees of staff involvement , in intervention group I , a Registered Nurse was present to supervise participants performing the exercises , while intervention group II involved a Registered Nurse physically assisting participants to achieve maximum range-of-motion within or beyond their present abilities . RESULTS Both intervention groups had statistically significant improvement in joint angles , activity function , perception of pain and depressive symptoms compared with the usual care group ( P < 0.05 ) . Post hoc comparison revealed that the joint angles in intervention group II were statistically significantly wider than in both the other groups ( P < 0.01 ) . CONCLUSIONS A simple nurse-led range-of-motion exercise programme can generate positive effects in enhancing physical and psychological function of bedridden older people with stroke . Further studies are needed to investigate the long-term effects of the programme in maximizing function , reducing care utilization and enhancing quality of life for this population [11588740] OBJECTIVE To compare outcomes in stroke survivors who received rehabilitation services in an acute inpatient rehabilitation setting ( multidisciplinary rehabilitation team ) with outcomes in survivors in a home-based setting ( family caregivers , limited team supervision ) . DESIGN R and omized clinical trial , with mean follow-up after 60 days . SETTING Inpatient rehabilitation setting and home-based setting s. PATIENTS Sixty patients ( age range , 43 - 80yr ) who had a stroke between 1996 and 1999 and had been referred after medical stabilization , r and omly divided into 2 groups : group 1 , inpatient rehabilitation ; group 2 , home-based rehabilitation . INTERVENTIONS Group 1 : therapeutical and neuromuscular exercises with occupational therapy with professional supervision ; group 2 : conventional exercises with family caregiver and limited professional supervision . MAIN OUTCOME MEASURES Spasticity was evaluated with the Ashworth Scale , motor status with Brunnstrom 's stages , functional status with the FIM instrument , and cognitive status with the Mini-Mental State Examination before and after rehabilitation . RESULTS Patients rehabilitated in acute inpatient setting s had better motor , functional , and cognitive outcomes ( p < .05 ) . Spasticity changes did not differ between the groups . CONCLUSION Intense inpatient rehabilitation services for stroke survivors provide significantly more favorable functional and cognitive outcomes with relatively low complications than did nonintense rehabilitation efforts in home setting [18806506] Hesse S , Werner C , Pohl M , Mehrholz J , Puzich U , Krebs HI : Mechanical arm trainer for the treatment of the severely affected arm after a stroke : a single-blinded r and omized trial in two centers . Am J Phys Med Rehabil 2008;87:779–788 . Objective : To test whether training with a new mechanical arm trainer leads to better outcomes than electrical stimulation of the paretic wrist extensors in subacute stroke patients with severe upper limb paresis . Electrical stimulation is a st and ard and reimbursable form of therapy in Germany . Design : R and omized controlled trial of 54 in patients enrolled 4–8 wks from stroke onset , mean upper-extremity subsection of Fugl-Meyer assessment ( 0–66 ) at admission less than 18 . In addition to st and ard care , all patients practice d 20–30 mins arm trainer or electrical stimulation every workday for 6 wks , totaling 30 sessions . Primary outcome was the Fugl-Meyer assessment , secondary outcomes were the Box and Block test , the Medical Research Council and the modified Ashworth scale , blindly assessed at enrollment , after 6 wks , and at 3-mo follow-up . Results : Both groups were homogeneous at study onset . Shoulder pain occurred in two arm trainer patients . The primary Fugl-Meyer assessment outcome improved for both groups over time ( P < 0.001 ) , but this improvement did not differ between groups . The initial ( terminal ) mean Fugl-Meyer assessment scores were 8.8 ± 4.8 ( 19.2 ± 14.5 ) for the arm trainer and 8.6 ± 3.5 ( 13.6 ± 7.9 ) for the electrical stimulation group . No patient could transport a block initially , but at completion significantly more arm trainer patients were able to transport at least three blocks ( five vs. zero , P = 0.023 ) . No significant differences were observed between the groups on the secondary Box and Block outcome at follow-up ( eight vs. four patients ) . All Box and Block responders had an initial Fugl-Meyer assessment ≥10 . Conclusions : Arm trainer training did not lead to a superior primary outcome over electrical stimulation training . However , “ good performers ” on the secondary outcome seemed to benefit more from the arm trainer training [19349340] Objective : To evaluate the effects of community-based rehabilitation therapy on neurological function deficit in stroke patients . Design : Prospect i ve , single-blind , r and omized controlled multicentre trial . Setting : At home , in Shanghai , China . Subjects : A total of 737 stroke patients in the community . Intervention : The rehabilitation group received additional st and ardized community-based rehabilitation therapy at home for five months . Main outcome measures : Patients were evaluated using the Clinical Neurological Function Deficit Scale before intervention and at the end of two and five months . Results : Although both the rehabilitation group and the control group improved over time , the rehabilitation group showed a greater improvement in Clinical Neurological Function Deficit Scale scores . The differences between the groups were significant . After five months , the Clinical Neurological Function Deficit Scale scores of the cerebral infa rct ion rehabilitation group improved by 6.77 ; the haemorrhage rehabilitation group by 7.99 ; the total rehabilitation group by 7.03 . In comparison , the Clinical Neurological Function Deficit Scale scores of the cerebral infa rct ion control group improved by 1.57 ; the haemorrhage control group by 5.34 ; the total control group by 2.43 . This implies a difference in improvement of 5.2 in the cerebral infa rct ion group , 2.65 in the haemorrhage group , and 4.6 in the total group in favour of the rehabilitation group between groups . Conclusion : St and ardized community-based rehabilitation therapy may help stroke patients to improve their neurological function [19729582] Background and objective . Botulinum toxin type A ( BtxA ) injection and modified constraint-induced movement therapy ( mCIMT ) are both promising approaches to enhance recovery after stroke . The combined application of these 2 promising modalities has rarely been studied . The aim was to investigate whether combined BtxA and mCIMT would improve spasticity and upper extremity motor function more than BtxA plus conventional rehabilitation in chronic stroke patients with upper extremity spasticity . Methods . In a prospect i ve , r and omized controlled , observer-blinded trial with 6-month follow-up , 32 patients ( ≥1 year after stroke ) with ability to actively extend > 10 ° at metacarpophalangeal and interphalangeal joints and 20 ° at wrist of the affected upper limb were r and omized to receive BtxA + mCIMT ( combination group ) or BtxA + conventional rehabilitation ( control group ) for 2 hours/day , 3 days/week for 3 months . The primary outcome assessed spasticity on the Modified Ashworth Scale . Secondary outcomes assessed real-world arm function ( Motor Activity Log ) , laboratory motor activity ( Action Research Arm Test ) , and patients ’ global satisfaction . Results . A total of 32 stroke patients were recruited , and 29 completed the study . Spasticity significantly improved in all subjects at 4 weeks and 3 months postinjection without between-group differences . The combination group showed significantly greater improvements in elbow , wrist , and finger spasticity ( P = .019 , P = .019 , and P < .001 , respectively ) , affected upper extremity real-world arm function ( P < .001 ) and laboratory motor activity ( P < .001 ) than the control group at 6-month postinjection . Patients reported considerable satisfaction and no serious adverse events occurred . Conclusions . Combining BtxA and mCIMT is an effective and safe intervention for improving spasticity and motor function in chronic stroke patients . The results are promising enough to justify further studies . We recommend future research to address the likely need for including rehabilitation with BtxA to improve function in patients with poststroke spasticity [8650505] A new method ( The Sødring Motor Evaluation of Stroke Patients ) has been developed for physiotherapists to evaluate motor function and activities in stroke patients . Its main characteristics are the assessment of motor activity without assisting the patient , and the use of a rating which reflects quantity as well as quality in motor performance . A hospitalised group of stroke patients ( n = 93 ) was assessed three times after the acute event , by means of SMES . The data were analysed regarding construct validity as well as concurrent validity against another assessment method . Factor analyses showed a reasonably stable three-factor pattern ( " arm " , " gross motor function " , and " leg " ) which explained 84 , 89 and 90 % , respectively , of the variance at the three study points , with Factor 1 ( " arm " ) as the dominant factor . The ordinality of the rating scale was assessed by means of linear regression analysis and found to be acceptable . The correlation coefficients were high between comparable parts of the new and the reference methods [8172497] Time course and degree of recovery of upper extremity ( UE ) function after stroke and the influence of initial UE paresis were studied prospect ively in a community-based population of 421 consecutive stroke patients admitted acutely during a 1-year period . UE function was assessed weekly , using the Barthel Index subscores for feeding and grooming . UE paresis was assessed by the Sc and inavian Stroke Scale subscores for h and and arm . The best possible UE function was achieved by 80 % of the patients within 3 weeks after stroke onset and by 95 % within 9 weeks ; in patients with mild UE paresis , function was achieved within 3 and 6 weeks , respectively , and in patients with severe UE paresis within 6 and 11 weeks , respectively . Full UE function was achieved by 79 % of patients with mild UE paresis and only by 18 % of patients with severe UE paresis . A valid prognosis of UE function can be made within 3 and 6 weeks in patients with mild and severe UE paresis , respectively . Further recovery of UE function should not be expected after 6 and 11 weeks respectively , in these groups of patients [16401430] OBJECTIVE To assess the effects of a community-based exercise program on motor recovery and functional abilities of the paretic upper extremity in persons with chronic stroke . DESIGN R and omized controlled trial . SETTING Rehabilitation research laboratory and a community hall . PARTICIPANTS A sample of 63 people ( > or = 50y ) with chronic deficits result ing from stroke ( onset > or = 1y ) . INTERVENTIONS The arm group underwent an exercise program design ed to improve upper-extremity function ( 1h/session , 3 sessions/wk for 19wk ) . The leg group underwent a lower-extremity exercise program . MAIN OUTCOME MEASURES The Wolf Motor Function Test ( WMFT ) , Fugl-Meyer Assessment ( FMA ) , h and -held dynamometry ( grip strength ) , and the Motor Activity Log . RESULTS Multivariate analysis showed a significant group by time interaction ( Wilks lambda=.726 , P=.017 ) , indicating that overall , the arm group had significantly more improvement than the leg group . Post hoc analysis demonstrated that gains in WMFT ( functional ability ) ( P=.001 ) and FMA ( P=.001 ) scores were significantly higher in the arm group . The amount of improvement was comparable to other novel treatment approaches such as constraint-induced movement therapy or robot-aided exercise training previously reported in chronic stroke . Participants with moderate arm impairment benefited more from the program . CONCLUSIONS The pilot study showed that a community-based exercise program can improve upper-extremity function in persons with chronic stroke . This outcome justifies a larger clinical trial to further assess efficacy and cost effectiveness [18996231] OBJECTIVE To determine whether acute exercise , using a body-weight-supported treadmill , improves performance on subsequent cognitive tests or an upper-extremity task in people with stroke . DESIGN The study was a within-subject , cross-over design in which 21 subjects received , r and omly , 2 different testing sequences separated by an interval of 7 to 10 days . SETTING Outpatient department of a rehabilitation hospital . PARTICIPANTS Of 72 potential participants in the convenience sample , 21 people with chronic stroke completed the study . They were 0.5 to 5 years after only 1 documented stroke , were able to walk with or without a cane , were able to grasp with the affected h and , and scored more than 24 on the Mini-Mental State Examination . INTERVENTIONS One session of body-weight-supported treadmill walking for 20 minutes at 70 % of estimated heart rate reserve or level 13 on the Borg rating of perceived exertion scale . The control condition consisted of a 20-minute review of a home exercise program with a physiotherapist . MAIN OUTCOME MEASURES Cognitive tests included Trail Making Tests Parts A and B , Symbol Digit Substitution Test , and Paced Auditory Serial Addition Test . The Action Research Arm Test ( ARAT ) measured hemiplegic upper-extremity motor skill . RESULTS Treadmill exercise improved movement of the hemiplegic upper extremity ( P=.04 ) but not cognitive performance . The improvement in the ARAT occurred without a change in strength ( measured by grip strength ) and was negatively correlated with maximum treadmill speed ( R(2)=.20 ; P=.04 ) . CONCLUSIONS These findings suggest that acute treadmill exercise improves subsequent skilled movement of the hemiplegic upper extremity that seems unrelated to attention , visuomotor processing , or strength . The etiology and duration of this enhancing effect are worth further study . The existence of an exercise-cognition relationship in people with stroke is an intriguing area of future research

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### Context: [14618287] It has been proposed that somatosensory stimulation in the form of electromyographically triggered neuromuscular electrical stimulation ( NMES ) to the peripheral nerve can influence functional measures of motor performance in subjects with stroke and can additionally produce changes in cortical excitability . Using a controlled , double-blind design , we studied the effects of intensive ( 60 h/3 weeks ) treatment at home with NMES compared with a sham treatment , applied to the extensor muscles of the hemiplegic forearm to facilitate h and opening in 16 chronic stroke subjects . We investigated improvement in functional use of the h and and change in cortical activation as measured by functional magnetic resonance imaging ( fMRI ) . Following treatment , subjects improved on measures of grasp and release of objects ( Box and Block Test and Jebsen Taylor H and Function Test [ JTHFT ] : small objects , stacking , heavy cans ) , isometric finger extension strength , and self-rated Motor Activity Log ( MAL ) : Amount of Use and How Well score . The sham subjects did not improve on any grasp and release measure or self-rated scale , but did improve on isometric finger extension strength . Importantly , however , following crossover , these subjects improved further in the measure of strength , grasp and release ( Box and Block [ JTHFT ] : page turning ) , and self-rated MAL : Amount of Use score and How Well score . Using fMRI and a finger-tracking task , an index of cortical intensity in the ipsilateral somatosensory cortex increased significantly from pre-test to post-test following treatment . Cortical activation , as measured by voxel count , did not change . These findings suggest that NMES may have an important role in stimulating cortical sensory areas allowing for improved motor function [7149946] Poor prognosis for upper limb recovery of stroke survivors has not changed in at least 28 years ; only 4 % to 5 % of patients regain arm function during or after the active rehabilitation phase . This pilot study included 37 patients r and omly assigned to either an integrated behavioral-physical therapy treatment program including electromyographic feedback ( experimental group ) or a st and ard exercise physical therapy program of like duration and intensity ( control group ) . Both groups showed clinical ly significant improvements that exceeded previously reported experience . The experimental technique appears to be more effective when upper limb involvement is not severe in a late case , or when treatment is started early ( within 3 months poststroke ) in a severe case . The rehabilitation community should quickly investigate the improved prospect s of restoring a greater number of useful upper limbs in this often neglected group of hemiplegic patients [16634340] Objective : ( 1 ) To evaluate constraint-induced movement therapy for chronic stroke patients modified into group practice to limit the dem and on therapist re sources . ( 2 ) To explore whether extended mitt use alone may enhance outcome . Design : A combined case-control and r and omized controlled study with pre- and post-treatment measures by blinded observers . Setting : A university hospital rehabilitation department . Participants : Sixteen stroke patients ( nine men and seven women ; mean age 56.7 years ; on average 28.9 months post stroke , five of whom were 6 - 9 months post stroke ) with moderate motor impairments in the contralateral upper limb . Intervention : Constraint-induced therapy ( mitt on the less affected h and 90 % of waking hours for 12 days ) with 2 - 3 patients per therapist and 6 h of group training per day . After the training period , the patients were r and omized either to using the mitt at home every other day for two-week periods for another three months ( in total 21 days ) or to no further treatment . Outcome measures : Modified Motor Assessment Scale , Sollerman H and Function Test , Two-Point Discrimination test and Motor Activity Log . Results : The mean motor performance improved significantly after two weeks of constraint-induced group therapy on Motor Assessment Scale ( 1.44 ( 95 % confidence interval ( 95 % CI ) 0.59 - 2.28 ) points ; P = 0.003 ) and on Sollerman H and Function Test ( 3.81 ( 95 % CI 0.26 - 7.36 ) points ; P = 0.037 ) but showed no sensory change in the Two-Point Discrimination Test ( P = 0.283 ) . The median difference in self-reported motor ability ( Motor Activity Log ) also improved ( P B=0.001 ) . However , no additional effect was seen from wearing a mitt for another three months . Conclusion : Constraint-induced group therapy , allowing several patients per therapist , seems to be a feasible alternative to improve upper limb motor function . The restraint alone , extended in time , did not enhance the treatment effect [11441212] Background and Purpose — The Wolf Motor Function Test ( WMFT ) is a new time-based method to evaluate upper extremity performance while providing insight into joint-specific and total limb movements . This study addresses selected psychometric attributes of the WMFT applied to a chronic stroke population . Methods — Nineteen individuals after stroke and with intact cognition and sitting balance were age- and sex-matched with 19 individuals without impairment . Subjects performed the WMFT and the upper extremity portion of the Fugl-Meyer Motor Assessment ( FMA ) on 2 occasions ( 12 to 16 days apart ) , with scoring performed independently by 2 r and om raters . Results — The WMFT and FMA demonstrated agreement ( P < 0.0001 ) between raters at each session . WMFT scores for the dominant and nondominant extremities of individuals without impairment were different ( P ≤0.05 ) from the more and less affected extremities of subjects after stroke . The FMA score for the more affected extremity of subjects after stroke was different ( P ≤0.05 ) from the dominant and nondominant extremities . However , the FMA score for the less affected upper extremity of individuals after stroke was not different ( P > 0.05 ) from the dominant and nondominant extremities of individuals without impairment . The WMFT and FMA scores were related ( P < 0.02 ) for the more affected extremity in individuals after stroke . Conclusions — The interrater reliability , construct validity , and criterion validity of the WMFT , as used in these subject sample s , are supported [18403742] Background and Purpose — Severe upper limb paresis is a major contributor to disability after stroke . This study investigated the efficacy of a new nonrobotic training device , the Sensorimotor Active Rehabilitation Training ( SMART ) Arm , that was used with or without electromyography-triggered electrical stimulation of triceps brachii to augment elbow extension , permitting stroke survivors with severe paresis to practice a constrained reaching task . Methods — A single-blind , r and omized clinical trial was conducted with 42 stroke survivors with severe and chronic paresis . Thirty-three participants completed the study , of whom 10 received training using the SMART Arm with electromyography-triggered electrical stimulation , 13 received training using the SMART Arm alone , and 10 received no intervention ( control ) . Training consisted of 12 1-hour sessions over 4 weeks . The primary outcome measure was “ upper arm function , ” item 6 of the Motor Assessment Scale . Secondary outcome measures included impairment measures ; triceps muscle strength , reaching force , modified Ashworth scale ; and activity measures : reaching distance and Motor Assessment Scale . Assessment s were administered before ( 0 weeks ) and after training ( 4 weeks ) and at 2 months follow-up ( 12 weeks ) . Results — Both SMART Arm groups demonstrated significant improvements in all impairment and activity measures after training and at follow-up . There was no significant difference between these 2 groups . There was no change in the control group . Conclusions — Our findings indicate that training of reaching using the SMART Arm can reduce impairment and improve activity in stroke survivors with severe and chronic upper limb paresis , highlighting the benefits of intensive task-oriented practice , even in the context of severe paresis [18633001] We conducted a pilot telerehabilitation study with post-stroke patients with arm motor impairment . We compared the degree of satisfaction of patients undergoing a virtual reality ( VR ) therapy programme at home ( Tele-VR group ) to satisfaction experienced by those undergoing the same VR therapy in a hospital setting ( VR-group ) . The rehabilitation equipment used a 3D motion tracking system to create a virtual environment in which the patient 's movement was represented . In tele-therapy , the patient equipment was installed in their homes , connected to the hospital by four ISDN lines at a total b and width of 512 kbit/s . Rehabilitation data were transmitted via one line and videoconferencing via the other three . Ten patients with mild to intermediate arm motor impairment due to an ischaemic stroke , were r and omized into VR or Tele-VR groups . A question naire was used at the end of treatment to measure each patient 's degree of satisfaction . Tele-VR treated patients showed median values equal to or higher than the VR group patients in all 12 items investigated , except one . In motor performance , the Tele-VR group improved significantly ( P ≤ 0.05 ) , while the VR group showed no significant change . Patients assigned to the Tele-VR group were able to engage in therapy at home and the videoconferencing system ensured a good relationship between the patient and the physical therapist whose physical proximity was not required [11022069] Background and Purpose Chronic upper extremity hemiparesis is a leading cause of functional disability after stroke . We investigated the hypothesis that bilateral arm training with rhythmic auditory cueing ( BATRAC ) will improve motor function in the hemiparetic arm of stroke patients . Methods In this single group pilot study we determined the effects of 6 weeks of BATRAC on 14 patients with chronic hemiparetic stroke ( median time after stroke , 30 months ) immediately after training and at 2 months after training . Four 5-minute periods per session ( 3 times per week ) of BATRAC were performed with the use of a custom- design ed arm training machine . Results The patients showed significant and potentially durable increases in the following : Fugl-Meyer Upper Extremity Motor Performance Test of impairment ( P < 0.0004 ) , Wolf Motor Function Test ( performance time measure , P < 0.02 ) , and University of Maryl and Arm Question naire for Stroke measuring daily use of the hemiparetic arm ( P < 0.002 ) . Isometric strength improved in elbow flexion ( P < 0.05 ) and wrist flexion ( P < 0.02 ) for the paretic arm and in elbow flexion ( P < 0.02 ) and wrist extension ( P < 0.02 ) for the nonparetic arm . Active range of motion improved for paretic-side shoulder extension ( P < 0.01 ) , wrist flexion ( P < 0.004 ) , and thumb opposition ( P < 0.002 ) , and passive range of motion improved for paretic wrist flexion ( P < 0.03 ) . Conclusions Six weeks of BATRAC improves functional motor performance of the paretic upper extremity as well as a few changes in isometric strength and range of motion . These benefits are largely sustained at 8 weeks after training cessation [12920254] BACKGROUND AND PURPOSE Rehabilitation care after stroke is highly variable and increasingly shorter in duration . The effect of therapeutic exercise on impairments and functional limitations after stroke is not clear . The objective of this study was to determine whether a structured , progressive , physiologically based exercise program for subacute stroke produces gains greater than those attributable to spontaneous recovery and usual care . METHODS This r and omized , controlled , single-blind clinical trial was conducted in a metropolitan area and 17 participating healthcare institutions . We included persons with stroke who were living in the community . One hundred patients ( mean age , 70 years ; mean Orpington score , 3.4 ) consented and were r and omized from a screened sample of 582 . Ninety-two subjects completed the trial . Intervention was a structured , progressive , physiologically based , therapist-supervised , in-home program of thirty-six 90-minute sessions over 12 weeks targeting flexibility , strength , balance , endurance , and upper-extremity function . Main outcome measures were postintervention strength ( ankle and knee isometric peak torque , grip strength ) , upper- and lower-extremity motor control ( Fugl Meyer ) , balance ( Berg and functional reach ) , endurance ( peak aerobic capacity and exercise duration ) , upper-extremity function ( Wolf Motor Function Test ) , and mobility ( timed 10-m walk and 6-minute walk distance ) . RESULTS In the intention-to-treat multivariate analysis of variance testing the overall effect , the intervention produced greater gains than usual care ( Wilk 's lambda=0.64 , P=0.0056 ) . Both intervention and usual care groups improved in strength , balance , upper- and lower-extremity motor control , upper-extremity function , and gait velocity . Gains for the intervention group exceeded those in the usual care group in balance , endurance , peak aerobic capacity , and mobility . Upper-extremity gains exceeded those in the usual care group only in patients with higher baseline function . CONCLUSIONS This structured , progressive program of therapeutic exercise in persons who had completed acute rehabilitation services produced gains in endurance , balance , and mobility beyond those attributable to spontaneous recovery and usual care [20400552] BACKGROUND Effective rehabilitative therapies are needed for patients with long-term deficits after stroke . METHODS In this multicenter , r and omized , controlled trial involving 127 patients with moderate-to-severe upper-limb impairment 6 months or more after a stroke , we r and omly assigned 49 patients to receive intensive robot-assisted therapy , 50 to receive intensive comparison therapy , and 28 to receive usual care . Therapy consisted of 36 1-hour sessions over a period of 12 weeks . The primary outcome was a change in motor function , as measured on the Fugl-Meyer Assessment of Sensorimotor Recovery after Stroke , at 12 weeks . Secondary outcomes were scores on the Wolf Motor Function Test and the Stroke Impact Scale . Secondary analyses assessed the treatment effect at 36 weeks . RESULTS At 12 weeks , the mean Fugl-Meyer score for patients receiving robot-assisted therapy was better than that for patients receiving usual care ( difference , 2.17 points ; 95 % confidence interval [ CI ] , -0.23 to 4.58 ) and worse than that for patients receiving intensive comparison therapy ( difference , -0.14 points ; 95 % CI , -2.94 to 2.65 ) , but the differences were not significant . The results on the Stroke Impact Scale were significantly better for patients receiving robot-assisted therapy than for those receiving usual care ( difference , 7.64 points ; 95 % CI , 2.03 to 13.24 ) . No other treatment comparisons were significant at 12 weeks . Secondary analyses showed that at 36 weeks , robot-assisted therapy significantly improved the Fugl-Meyer score ( difference , 2.88 points ; 95 % CI , 0.57 to 5.18 ) and the time on the Wolf Motor Function Test ( difference , -8.10 seconds ; 95 % CI , -13.61 to -2.60 ) as compared with usual care but not with intensive therapy . No serious adverse events were reported . CONCLUSIONS In patients with long-term upper-limb deficits after stroke , robot-assisted therapy did not significantly improve motor function at 12 weeks , as compared with usual care or intensive therapy . In secondary analyses , robot-assisted therapy improved outcomes over 36 weeks as compared with usual care but not with intensive therapy . ( Clinical Trials.gov number , NCT00372411 . [16040590] Background and Purpose — The ability of therapeutic exercise after stroke to improve daily functioning and quality of life ( QOL ) remains controversial . We examined treatment effects on these outcomes in a r and omized controlled trial ( RCT ) of exercise in subacute stroke survivors . Methods — This is a secondary analysis of a single-blind RCT of a 12-week program versus usual care . Baseline , post-treatment and 6-month post-treatment daily functioning and QOL were assessed by Barthel index , Functional Independence Measure , instrumental activities of daily living , Medical Outcomes Study short-form 36-item question naire ( SF-36 ) , and Stroke Impact Scale ( SIS ) . Results — Of 100 r and omized subjects , 93 completed the postintervention assessment , ( mean age 70 ; 54 % male ; 81 % white ; mean Orpington Prognostic Score 3.4 ) , and 80 had 6-month post-treatment assessment . Immediately after intervention , the intervention group improved more than usual care in SF-36 social function ( 14.0 points ; P=0.0051 ) and in SIS ( strength [ 9.2 points ; P=0.0003 ] , emotion [ 5.6 points ; P=0.0240 ] , social participation [ 6.6 points ; P=0.0488 ] , and physical function [ 5.0 points ; P=0.0145 ] ) . Treatment was marginally more effective on Barthel score ( 3.3 points ; P=0.0510 ) , SF-36 ( physical function [ 6.8 points ; P=0.0586 ] , physical role function [ 14.4 points ; P=0.0708 ] ) , and SIS upper extremity function ( 7.2 points ; P=0.0790 ) . Effects were diluted 6 months after treatment ended . Conclusion — This rehabilitation exercise program led to more rapid improvement in aspects of physical , social , and role function than usual care in persons with subacute stroke . Adherence interventions to promote continued exercise after treatment might be needed to continue benefit [19109444] Background . Functional training and muscle strength training may improve upper limb motor recovery after stroke . Combining these as functional strength training ( FST ) might enhance the benefit , but it is unclear whether this is better than conventional physical therapy ( CPT ) . Comparing FST with CPT is not straightforward . Objective . This study aim ed at assessing the feasibility of conducting a phase III trial comparing CPT with FST for upper limb recovery . Methods . R and omized , observer-blind , phase II trial . Subjects had upper limb weakness within 3 months of anterior circulation infa rct ion . Subjects were r and omized to CPT ( no extra therapy ) , CPT + CPT , and CPT + FST . Intervention lasted 6 weeks . Primary outcome measure was the Action Research Arm Test ( ARAT ) . Measurements were taken before treatment began , after 6 weeks of intervention , and 12 weeks thereafter . Attrition rate was calculated and differences between groups were interpreted using descriptive statistics . ARAT data were used to inform a power calculation . Results . Thirty subjects were recruited ( 8 % of people screened ) . Attrition rate was 6.7 % at outcome and 40 % at follow-up . At outcome the CPT + FST group showed the largest increase in ARAT score and this was above the clinical ly important level of 5.7 points . Median ( interquartile range ) increases were 11.5 ( 21.0 ) for CPT ; 8.0 ( 13.3 ) for CPT + CPT ; and 19.5 ( 22.0 ) for CPT + FST . The estimated sample size for an adequately powered subsequent phase III trial was 279 subjects at outcome . Conclusion . Further work toward a phase III clinical trial appears justifiable [18971385] Objective . The aim of this study was to establish the efficacy of a therapeutic intervention based on functional electrical stimulation ( FES ) therapy to improve reaching and grasping function after severe hemiplegia due to stroke . Methods . A total of 21 subjects with acute stroke were r and omized into 2 groups , FES plus conventional occupational and physiotherapy ( FES group ) or only conventional therapy ( control group ) 5 days a week for 12 to 16 weeks . A third group of 7 subjects with chronic hemiplegia ( at least 5 months poststroke ) received only FES therapy ( chronic group ) and pre — post training changes were compared . FES was applied to proximal and then distal muscle groups during specific motor tasks . At baseline and at the end of treatment , grasping function was assessed using the Rehabilitation Engineering Laboratory H and Function Test , along with more st and ard measures of rehabilitation outcome . Results . The FES group improved significantly more than the control group in terms of object manipulation , palmar grip torque , pinch grip pulling force , Barthel Index , Upper Extremity Fugl — Meyer scores , and Upper Extremity Chedoke — McMaster Stages of Motor Recovery . The chronic stroke subjects demonstrated improvements in most categories , but the changes were not statistically significant . Conclusions . FES therapy with upper extremity training may be an efficacious intervention in the rehabilitation of reaching and grasping function during acute stroke rehabilitation [14617717] Objective : To investigate progress toward motor recovery in patients with chronic hemiparesis ( mean time since stroke 3.2 years ) , comparing different types of practice schedules . Design : To increase voluntary control of the upper extremity , active neuromuscular stimulation was administered during blocked and r and om practice schedules as patients performed three specific movements : wrist/finger extension , elbow joint extension , and shoulder joint abduction . Methods : 34 stroke subjects volunteered to participate and were r and omly assigned to one of three treatment groups : blocked practice ( the same movement was repetitively performed on successive trials ) combined with active neuromuscular stimulation ; r and om practice ( different movements on successive trials ) along with active stimulation ; or no active stimulation assistance control group . Subjects completed two days of 90 minute training for each of two weeks with at least 24 hours of rest between sessions . A session was three sets of 30 successful active neuromuscular stimulation trials with the three movements executed 10 times/set . Results : Mixed design analyses on three categories of behavioural measures indicated motor improvements for the blocked and r and om practice /stimulation groups in comparison with the control group during the post-test period , with a larger number of blocks moved , faster premotor and motor reaction times , and less variability in the sustained muscular contraction task . Conclusions : Upper extremity rehabilitation intervention of active stimulation and blocked practice performed as well as stimulation/r and om practice . Moreover , these purpose ful voluntary movement findings support and extend sensorimotor integration theory to both practice schedules [15788330] OBJECTIVE Assess the effects of daily neuroprosthetic ( NESS H and master ) functional electrical stimulation in sub-acute stroke . DESIGN Controlled study , patients clinical ly stratified to 2 groups ; no active finger movement , and partial active finger movements , and then r and omized to control and neuroprosthesis groups . Observer blinded evaluations at baseline and completion of the 6-week study . SUBJECTS 22 patients with moderate to severe upper limb paresis 3 - 6 months post-onset . METHODS Patients in day hospital rehabilitation , receiving physical and occupational therapy 3 times weekly . The neuroprosthesis group used the device at home . RESULTS The neuroprosthesis group had significantly greater improvements in spasticity , active range of motion and scores on the functional h and tests ( those with partial active motion ) . Of the few patients with pain and oedema , there was improvement only among those in the neuroprosthesis group . There were no adverse reactions . CONCLUSION Supplementing st and ard outpatient rehabilitation with daily home neuroprosthetic activation improves upper limb outcomes [9756581] BACKGROUND AND PURPOSE Many stroke survivors have minimal to moderate neurological deficits but are physically deconditioned and have a high prevalence of cardiovascular problems ; all of these are potentially modifiable with exercise . The purpose s of this r and omized , controlled pilot study were ( 1 ) to develop a home-based balance , strength , and endurance program ; ( 2 ) to evaluate the ability to recruit and retain stroke subjects ; and ( 3 ) to assess the effects of the interventions used . METHODS Twenty minimally and moderately impaired stroke patients who had completed inpatient rehabilitation and who were 30 to 90 days after stroke onset were r and omized to a control group or to an experimental group that received a therapist-supervised , 8-week , 3-times-per-week , home-based exercise program . The control group received usual care as prescribed by the patients ' physicians . Baseline and postintervention assessment s included the Fugl-Meyer Motor Assessment , the Barthel Index of Activities of Daily Living ( ADL ) , the Lawton Scale of Instrumental ADL , and the Medical Outcomes Study -36 Health Status Measurement . Functional assessment s of balance and gait included a 10-m walk , 6-Minute Walk , and the Berg Balance Scale . Upper extremity function was evaluated by the Jebsen Test of H and Function . RESULTS Of 22 patients who met study criteria , 20 completed the study and 2 refused to participate . The experimental group tended to improve more than the control group in motor function ( Fugl-Meyer Upper Extremity : mean change in score , 8 . 4 versus 2.2 ; Fugl-Meyer Lower Extremity : 4.7 versus -0.9 ; gait velocity : median change , 0.25 versus .09 m/s ; 6-Minute Walk : 195 versus 114 ft ; Berg Balance Score : 7.8 versus 5 ; and Medical Outcomes Study -36 Health Status Measurement of Physical Function : 15 . 5 versus 9 ) . There were no trends in differences in change scores by the Jebsen Test of H and Function , Barthel Index , and Lawton Instrumental ADL Scale . CONCLUSIONS This study demonstrated that a r and omized , controlled clinical trial of a poststroke exercise program is feasible . Measures of neurological impairments and lower extremity function showed the most benefit . Effects of the intervention on upper extremity dexterity and functional health status were equivocal . The lasting effects of the intervention were not assessed [3093230] The objective of this study was to develop and examine the effectiveness of an individual home rehabilitation program for patients with ischemic stroke . This was a r and omized controlled trial in 60 patients with recent middle cerebral artery infa rct ion . After hospital discharge for acute stroke care , they were r and omly assigned to receive either a home rehabilitation program for three months ( intervention group ) or usual care ( control group ) . We collected outcome data over three months after their discharge from the hospital . The Barthel Index ( BI ) , the Modified Rankin Scale ( MRS ) , the health-related quality -of-life index ( EQ-5D ) , the Hospital Anxiety and Depression score ( HADs ) , and the Thai Mental State Examination ( TMSE ) were used to analyze the outcomes . In the intervention group , all outcomes were significantly better ( p<0.05 ) than in the control group , except in the case of TMSE . A favorable outcome , which was defined as minimal or no disability as measured by BI ( score 95–100 ) , was achieved by 93.33 % of patients in the intervention group , and 90 % had favorable scores ( 0 or 1 ) on the MRS . This showed a benefit in reducing disability , with two being the number of patients considered as needed-to-treat ( NNT ) ( 95 % CI , 1.0–1.2 ) . All dimensions of EQ-5D in the intervention group were significantly better for quality of life and generic health status than in the control group ( p=0.001 ) . Depression was found in one patient ( 3.33 % ) in the intervention group and in two patients ( 6.67 % ) in the control group . Dementia was found in three patients ( 10 % ) in the intervention group and in four patients ( 13.33 % ) in the control group . We concluded that an early home rehabilitation program for patients with ischemic stroke in the first three-month period provides significantly better outcomes in improving function , reducing disability , increasing quality of life , and reducing depression than a program of usual care does [2780376] Background About 80 % of all stroke survivors have an upper limb paresis immediately after stroke , only about a third of whom ( 30 to 40 % ) regain some dexterity within six months following conventional treatment programs . Of late , however , two recently developed interventions - constraint-induced movement therapy ( CIMT ) and bilateral arm training with rhythmic auditory cueing ( BATRAC ) - have shown promising results in the treatment of upper limb paresis in chronic stroke patients . The ULTRA-stroke ( acronym for Upper Limb TRaining After stroke ) program was conceived to assess the effectiveness of these interventions in subacute stroke patients and to examine how the observed changes in sensori-motor functioning relate to changes in stroke recovery mechanisms associated with peripheral stiffness , interlimb interactions , and cortical inter- and intrahemispheric networks . The present paper describes the design of this single-blinded r and omized clinical trial ( RCT ) , which has recently started and will take several years to complete . Methods / Design Sixty patients with a first ever stroke will be recruited . Patients will be stratified in terms of their remaining motor ability at the distal part of the arm ( i.e. , wrist and finger movements ) and r and omized over three intervention groups receiving modified CIMT , modified BATRAC , or an equally intensive ( i.e. , dose-matched ) conventional treatment program for 6 weeks . Primary outcome variable is the score on the Action Research Arm test ( ARAT ) , which will be assessed before , directly after , and 6 weeks after the intervention . During those test sessions all patients will also undergo measurements aim ed at investigating the associated recovery mechanisms using haptic robots and magneto-encephalography ( MEG ) . Discussion ULTRA-stroke is a 3-year translational research program which aims ( 1 ) to assess the relative effectiveness of the three interventions , on a group level but also as a function of patient characteristics , and ( 2 ) to delineate the functional and neurophysiological changes that are induced by those interventions .The outcome on the ARAT together with information about changes in the associated mechanisms will provide a better underst and ing of how specific therapies influence neurobiological changes , and which post-stroke conditions lend themselves to specific treatments . Trial Registration The ULTRA-stroke program is registered at the Netherl and s Trial Register ( NTR , http://www.trialregister.nl , number NTR1665 ) [16541932] Objective : To compare intensive with non-intensive home-based rehabilitation provision following stroke or hip fracture in old age ( 65 years ) . Design : Parallel single-blind r and omized control trial . Setting : Domiciliary provided multidisciplinary rehabilitation . Subjects : One hundred and sixty patients aged 65 or over recently discharged from hospital after suffering a stroke or hip fracture . Intervention : Patients assigned to receive six or more face-to-face contacts or three or less face-to-face contacts from members of a multidisciplinary rehabilitation team . Main measures : Patients assessed using the Barthel Index , Therapy Outcome Measure , Euroqol 5D ( EQ-5D ) , Hospital Anxiety and Depression Scale ( HADS ) and Frenchay Activities Index ( FAI ) at three months . All follow-up assessment s were conducted blind to allocation . Results : Subgroup analysis was conducted on the basis of incident condition ( stroke or hip fracture ) . Significant differences were detected for the stroke subgroup at three months [ Therapy Outcome Measure H and icap ( median difference 0.5 ( P < 0.05 ) ) and EQ-5D ( median difference 0.17 ( P < 0.05 ) ) ] and in change at three months [ Therapy Outcome Measure ( mean difference 0.52 ( SD 0.85 ) 95 % CI ( 0.16 , 0.88 ) ) and EQ-5D ( mean difference 0.15 ( SD 0.25 ) 95 % CI ( 0.05 , 0.26 ) ) ] . No significant differences were detected between the two arms of the study for the hip fracture subgroup . Conclusion : Following stroke older people who receive a more intensive communitybased multidisciplinary rehabilitation service may experience short-term benefit in relation to social participation and some aspects of health-related quality of life . A more intensive service after discharge from hospital following a hip fracture is unlikely to result in similar patient benefit [11128729] Objective : To assess the effectiveness of community-based rehabilitation for stroke patients who were not admitted to hospital in South London . Design : R and omized controlled trial . Setting : Patients ' homes in South London . Subjects : Stroke patients not admitted to hospital after a stroke . Intervention : Rehabilitation at home by rehabilitation team for up to three months or usual care . Main outcome measures : The primary outcome measure was the Barthel score . Secondary measures included the Motricity Index , Rivermead ADL , Hospital Anxiety and Depression score and Nottingham Health Profile . Results : Forty-three patients who remained at home were r and omized to rehabilitation team ( 23 ) or ‘ usual ’ care ( 20 ) . The mean number of physiotherapy sessions was three ( range 1–14 ) for the rehabilitation team group and two for the usual care group . Patients ( with a deficit ) in the rehabilitation arm of the trial were more likely to receive occupational , physical and speech therapy than those in the control arm ( p = 0.03 , 0.01 and 0.008 , respectively ) . For those patients actually receiving therapy , there was no evidence that the amount received differed between the groups . However , the number of patients in each of these comparisons was very small . The outcome for patients in the rehabilitation team arm of the trial was nonsignificantly higher ( 0.05 < p < 0.2 ) than for those in the control arm for the areas of Nottingham Health Profile , anxiety , depression , caregiver strain and the proportion of patients living at home . Based on the data observed here , a trial with approximately 150 patients in each arm would be needed to have adequate power to detect a 33 % difference between intervention and control groups in these outcomes . Conclusion : Community therapy support for patients not admitted to hospital is feasible but to determine whether it is cost- or clinical ly effective would require trials of adequate size [16888263] Background and Purpose — A pilot evaluation of an occupational therapy intervention to improve self-care independence for residents with stroke-related disability living in care homes was the basis of this study . Methods — A cluster r and omized controlled trial with care home as the unit of r and omization was undertaken in Oxfordshire , UK . Twelve homes ( 118 residents ) were r and omly allocated to either intervention ( 6 homes , 63 residents ) or control ( 6 homes , 55 residents ) . Occupational therapy was provided to individuals but included carer education . The control group received usual care . Assessment s were made at baseline , postintervention ( 3 months ) and at 6-months to estimate change using the Barthel Activity of Daily Living Index ( BI ) scores , “ poor global outcome ” , ( defined as deterioration in BI score , or death ) and the Rivermead Mobility Index . Results — At 3 months BI score in survivors had increased by 0.6 ( SD 3.9 ) in the intervention group and decreased by 0.9 ( 2.2 ) in the control group ; a difference of 1.5 ( 95 % CI allowing for cluster design , −0.5 to 3.5 ) . At 6 months the difference was 1.9 ( −0.7 to 4.4 ) . Global poor outcome was less common in the intervention group . At 3 months , 20/63 ( 32 % ) were worse/dead in the intervention group compared with 31/55 ( 56 % ) in the control group , difference −25 % ( −51 % to 1 % ) . At 6 months the difference was similar , −26 % ( −48 % to −3 % ) . Between-group changes in Rivermead Mobility Index scores were not significantly different . Conclusion — Residents who received an occupational therapy intervention were less likely to deteriorate in their ability to perform activities of daily living [19109542] Background and Purpose — Modified constraint-induced therapy ( mCIT ) is an outpatient therapy encouraging repetitive , task-specific practice with the affected arm . mCIT has shown efficacy in all stages poststroke . Given its efficacy when combined with other therapy regimens , the current study examined the efficacy of mental practice when combined with mCIT versus mCIT only using r and omized , controlled methods . Method — Ten patients with chronic stroke ( 7 males ; mean age , 61.4±3.02 years ; age range , 48 to 79 years ; mean time since stroke , 28.5 months ; range , 13 to 42 months ) exhibiting stable , affected arm motor deficits were administered mCIT , consisting of : ( 1 ) structured therapy emphasizing affected arm use in functional activities 3 days/week for 10 weeks ; and ( 2 ) less affected arm restraint 5 days/week for 5 hours . Both of these components were administered during a 10-week period . Subjects r and omly assigned to the mCIT+mental practice experimental condition also received 30-minute mental practice sessions provided directly after therapy sessions . These mental practice sessions required daily cognitive rehearsal of the activities of daily living practice d during mCIT clinical sessions . Results — No pre-existing differences were found between groups on any demographic variable or movement scale . All subjects exhibited marked reductions in affected arm impairment and functional limitation . However , subjects in the mCIT+mental practice group exhibited significantly larger changes on both movement measures after intervention : Action Research Arm Test , + 15.4-point change versus + 8.4-point change for mCIT only subjects ( P<0.001 ) ; Fugl-Meyer , + 7.8-point change versus + 4.1-point change for the mCIT only subjects ( P=0.01 ) . These changes were sustained 3 months after intervention . Conclusions — mCIT remains a promising motor intervention . However , its efficacy appears to be enhanced by use of mental practice provided directly after mCIT clinical sessions [10698876] Abstract Objective : To establish if a brief programme of domiciliary occupational therapy could improve the recovery of patients with stroke discharged from hospital . Design : Single blind r and omised controlled trial . Setting : Two hospital sites within a UK teaching hospital . Subjects : 138 patients with stroke with a definite plan for discharge home from hospital . Intervention : Six week domiciliary occupational therapy or routine follow up . Main outcome measures : Nottingham extended activities of daily living score and “ global outcome ” ( deterioration according to the Barthel activities of daily living index , or death ) . Results : By eight weeks the mean Nottingham extended activities of daily living score in the intervention group was 4.8 points ( 95 % confidence interval −0.5 to 10.0 , P=0.08 ) greater than that of the control group . Overall , 16 ( 24 % ) intervention patients had a poor global outcome compared with 30 ( 42 % ) control patients ( odds ratio 0.43 , 0.21 to 0.89 , P=0.02 ) . These patterns persisted at six months but were not statistically significant . Patients in the intervention group were more likely to report satisfaction with a range of aspects of services . Conclusion : The functional outcome and satisfaction of patients with stroke can be improved by a brief occupational therapy programme carried out in the patient 's home immediately after discharge . Major benefits may not , however , be sustained [11509308] OBJECTIVES To compare the effectiveness and costs of a new domiciliary rehabilitation service for elderly stroke patients with geriatric day-hospital care . DESIGN R and omized controlled trial . PARTICIPANTS Stroke patients aged 55 + who required further rehabilitation after hospital discharge or after referral to geriatricians from the community . SETTING Poole area , East Dorset , a mixed urban/rural area on the south coast of Engl and . MAIN OUTCOMES Primary -changes between hospital discharge and 6-month follow-up in physical function as measured by Barthel index . Secondary -changes over this period in Rivermead Mobility Index and mental state ( Philadelphia Geriatric Centre Morale Scale ) and differences in social activity ( Frenchay Activities Index ) and generic health status ( SF-36 ) . Health service and social service cost per patient were compared for the two groups . RESULTS 180 patients were eligible and 140 ( 78 % ) were r and omized . The groups were well balanced for age , sex , social class and initial Barthel index . We achieved follow-up in 88 % of subjects who were alive at 6 months . We detected no significant differences in patient outcomes , although there was a non-significant improvement in measures of physical function and social activity in the domiciliary group . Domiciliary patients had more physiotherapy time per session and more district nurse time , and made greater use of social service day centres and home helps . Total cost per patient did not differ significantly between the two groups , with reduced health service costs in the domiciliary arm offset by higher social service costs . CONCLUSION No significant differences were detected in the effectiveness of the two services . Neither service influenced patients ' mental state , and their social activity remained low . Total costs were similar . A mixed model of day-hospital and domiciliary care may be most cost-effective for community stroke rehabilitation , but this requires further evaluation [10797163] BACKGROUND AND PURPOSE About 50 % of stroke survivors are discharged to their homes with lasting disability . Knowledge , however , of the importance of follow-up services that targets these patients is sparse . The purpose of the present study was to evaluate 2 models of follow-up intervention after discharge . The study hypothesis was that intervention could reduce readmission rates and institutionalization and prevent functional decline . We report the results regarding readmission . METHODS This r and omized study included 155 stroke patients with persistent impairment and disability who , after the completion of inpatient rehabilitation , were discharged to their homes . The patients were r and omized to 1 of 2 follow-up interventions provided in addition to st and ard care or to st and ard aftercare . Fifty-four received follow-up home visits by a physician ( INT1-HVP ) , 53 were provided instructions by a physiotherapist in their home ( INT2-PI ) , and 48 received st and ard aftercare only ( controls ) . Baseline characteristics for the 3 groups were comparable . Six months after discharge , data were obtained on readmission and institutionalization . RESULTS The readmission rates within 6 months after discharge were significantly lower in the intervention groups than in the control group ( INT1-HVP 26 % , INT2-PI 34 % , controls 44 % ; P=0.028 ) . Multivariate analysis of readmission risk showed a significant favorable effect of intervention ( INT1-HVP or INT2-PI ) in interaction with length of hospital stay ( P=0.0332 ) , indicating that the effect of intervention was strongest for patients with a prolonged inpatient rehabilitation . CONCLUSIONS Readmission is common among disabled stroke survivors . Follow-up intervention after discharge seems to be a way of preventing readmission , especially for patients with long inpatient rehabilitation [19541918] Background . The study investigated whether passive splinting or active motor training as either individualized best conventional therapy or as st and ardized impairment-oriented training ( IOT ) would be superior in promoting motor recovery in subacute stroke patients with mildly or severely paretic arms . Methods . A total of 148 anterior circulation ischemic stroke patients were r and omly assigned to 45 minutes of additional daily arm therapy over 3 to 4 weeks as either ( a ) passive therapy with inflatable splints or active arm motor therapy as either ( b ) individualized best conventional therapy ( CONV ) or ( c ) st and ardized IOT , that is Arm BASIS training for severe paresis or Arm Ability training for mild paresis . Main outcome measures included the following : Fugl-Meyer arm motor score ( severely paretic arms ) and the TEMPA time scores ( mildly affected arms ) . Pre — post ( immediate effects ) and pre—4 weeks follow-up analyses ( long-term effects ) were performed . Results . Overall improvements were documented ( mean baseline and change scores efficacy : Fugl-Meyer , arm motor scores , 24.4 , + 9.1 points ; TEMPA , 119 , −26.6 seconds ; P < .0001 ) , but with no differential effects between splint therapy and the combined active motor rehabilitation groups . Both efficacy and effectiveness analyses indicated , however , bigger immediate motor improvements after IOT as compared with best conventional therapy ( Fugl-Meyer , arm motor scores : IOT + 12.3 , CONV + 9.2 points ; TEMPA : IOT −31.1 seconds , CONV −20.5 seconds ; P = .0363 ) ; for mildly affected patients long-term effects could also be substantiated . Conclusions . Specificity of active training seemed more important for motor recovery than intensity ( therapy time ) . The comprehensive modular IOT approach promoted motor recovery in patients with either severe or mild arm paresis [9472875] BACKGROUND AND PURPOSE Data on survival and functioning after stroke needs to be supplemented by measures emphasizing the patients ' subjective perception . We studied ( 1 ) subjective well-being ( SWB ) as a latent variable in a common-factor model with four items , ( 2 ) the reliability of these four items , and ( 3 ) variables related to SWB in stroke patients . METHODS Data on all stroke patients ( n=1417 ) and a r and om sub sample of stroke-free individuals of similar age ( n=1439 ) were collected from the Nord-Trøndelag Health Survey , a cross-sectional study of 74977 persons . Based on a two- sample factor analysis model , scores of SWB were calculated , and variables explaining SWB were studied in a regression model . RESULTS Four items were a priori believed to measure SWB as a latent variable ( " satisfaction , " " strength , " " calmness , " and " cheerfulness " ) . This was confirmed by factor analysis . The reliability of these items ( the proportion of the variance of the items that can be explained by the common factor ) was between .42 and .53 . Regression analyses showed a significant effect of having had a stroke , gender ( lower SWB in men ) , age ( increasing SWB with increasing age ) , perceived general health , nervousness , loneliness , sleep problems , social support , and use of analgesics . There was no statistical interaction between these variables and having had a stroke . CONCLUSIONS Higher SWB after stroke relates to female gender , older age , good general and mental health , and a firm social network [8410035] This study compared the functional ability and perceived health status of stroke patients treated by a domiciliary rehabilitation team or by routine hospital-based services after discharge from hospital . Patients discharged from two acute and three rehabilitation hospitals in Nottingham were r and omly allocated in three strata ( Health Care of the Elderly , General Medical and Stroke Unit ) to receive domiciliary or hospital-based care after discharge . Functional recovery was assessed by the Extended Activities of Daily Living ( ADL ) scale three and six months after discharge and perceived health at six months was measured by the Nottingham Health Profile . A total of 327 eligible patients of 1119 on a register of acute stroke admissions were recruited over 16 months . Overall there were no differences between the groups in their Extended ADL scores at three or six months , or their Nottingham Health Profile scores at six months . In the Stroke Unit stratum , patients treated by the domiciliary team had higher household ( p = 0.02 ) and leisure activity ( p = 0.04 ) scores at six months than those receiving routine care . In the Health Care of the Elderly stratum , death or a move into long-term institutional care at six months occurred less frequently in patients allocated to the routine service , about half of whom attended a geriatric day hospital . Overall there was no difference in the effectiveness of the domiciliary and hospital-based services , although younger stroke unit patients appeared to do better with home therapy while some frail elderly patients might have benefited from day hospital attendance [19841835] OBJECTIVE Telerehabilitation enables a remotely controlled programme to be used to treat motor deficits in post-stroke patients . The effects of this telerehabilitation approach were compared with traditional motor rehabilitation methods . DESIGN R and omized single-blind controlled trial . PATIENTS A total of 36 patients with mild arm motor impairments due to ischaemic stroke in the region of the middle cerebral artery . METHODS The experimental treatment was a virtual reality-based system delivered via the Internet , which provided motor tasks to the patients from a remote rehabilitation facility . The control group underwent traditional physical therapy for the upper limb . Both treatments were of 4 weeks duration . All patients were assessed one month prior to therapy , at the commencement and termination of therapies and one month post-therapy , with the Fugl-Meyer Upper Extremity , the ABILH AND and the Ashworth scales . RESULTS Both rehabilitative therapies significantly improved all outcome scores after treatment , but only the Fugl-Meyer Upper Extremity scale showed differences in the comparison between groups . CONCLUSION Both strategies were effective , but the experimental approach induced better outcomes in motor performance . These results may favour early discharge from hospital sustained by a telerehabilitation programme , with potential beneficial effects on the use of available re sources [17148515] Objective : To assess the effect of three weeks of rehabilitation in the home setting for younger patients with stroke with the aim of improving activity level . Design : A r and omized controlled study with blinded evaluations at discharge , three weeks , three months and one year after discharge . Setting : Home of the patient or the ordinary day rehabilitation clinic at the university hospital . Subjects : Fifty-eight patients ( median age 53 years ) consecutively discharged from inpatient rehabilitation with a first occurrence of stroke participated in training directly after discharge . Intervention : Rehabilitation was given for 9 hours/week over three weeks . The home group received individually tailored training , based on the patient 's needs and desires , with a focus on activities in their natural context . Support and information were also given . The intervention in the day clinic group was aim ed mainly at improved functions . Main measures : The main outcome was activity , assessed with the Assessment of Motor and Process Skill ( AMPS ) . The impairment level was also evaluated . Costs were estimated . Result : There were no significant differences between the groups on any of the four assessment s. However , there seemed to be an earlier improvement on some measures ( including AMPS ) for the home group . For both groups there was a greater improvement on the activity level than on the impairment level . The costs of the home group were less than half of the costs of the day clinic group . Conclusion : With the present results , both rehabilitation programmes could be recommended , however , further studies are needed to define patients who may specifically benefit from the home rehabilitation programme . Costs should be taken into consideration [17852312] Purpose . To assess the effects of daily power-assisted functional electrical stimulation ( FES ) home program therapy in chronic stroke . Methods . A total of 20 consecutively enrolled stroke patients with spastic upper-extremity impairments > 1 year after stroke were recruited for this non-blinded r and omized controlled trial . Subjects were assigned to control and FES groups and followed for 5 months . The FES group used a power-assisted FES device to induce greater muscle contraction by electrical stimulation in proportion to the integrated electromyography ( EMG ) signal picked up on surface electrodes . Target muscles were the extensor carpi radialis longus ( ECRL ) and extensor carpi radialis brevis ( ECRB ) , extensor digitorum communis ( EDC ) , extensor indicis proprius ( EIP ) , and deltoid ( Del ) . Patients underwent 30 ∼ 60 min FES sessions at home about 6 days/week . Root mean square ( RMS ) of ECRL , EDC and Del maximum voluntary EMGs , active range of motion ( ROM ) of wrist and finger extension and shoulder flexion , modified Ashworth scale ( MAS ) , and clinical tests were investigated before and after FES training . Results . The FES group displayed significantly greater improvements in RMS , active ROM , MAS and functional h and tests , and was able to smoothly perform activities of daily life using the hemiplegic upper extremities . Conclusions . Daily power-assisted FES home program therapy can effectively improve wrist and finger extension and shoulder flexion . Proprioceptional sensory feedback might play an important role in power-assisted FES therapy [18184932] Investigators have demonstrated that a variety of intensive movement training protocol s for persistent upper limb paralysis in patients with chronic stroke ( 6 months or more after stroke ) improve motor outcome . This r and omized controlled study determined in patients with upper limb motor impairment after chronic stroke whether movement therapy delivered by a robot or by a therapist using an intensive training protocol was superior . Robotic training ( n = 11 ) and an intensive movement protocol ( n = 10 ) improved the impairment measures of motor outcome significantly and comparably ; there were no significant changes in disability measures . Motor gains were maintained at the 3-month evaluation after training . These data contribute to the growing awareness that persistent impairments in those with chronic stroke may not reflect exhausted capacity for improvement . These new protocol s , rendered by either therapist or robot , can be st and ardized , tested , and replicated , and potentially will contribute to rational activity-based programs [11237160] Objective : To evaluate the effects of leisure therapy and conventional occupational therapy ( OT ) on the mood , leisure participation and independence in activities of daily living ( ADL ) of stroke patients 6 and 12 months after hospital discharge . Design : Multicentre r and omized controlled trial . Setting and participants : Four hundred and sixty-six stroke patients from five UK centres . Main outcome measures : The General Health Question naire ( 12 item ) , the Nottingham Extended ADL Scale and the Nottingham Leisure Question naire , assessed by post , with telephone clarification . Results : Four hundred and forty ( 94 % ) and 426 ( 91 % ) subjects were alive at 6 and 12 months , respectively . Three hundred and seventy-four ( 85 % of survivors ) and 311 ( 78 % of survivors ) responded at 6 and 12 month follow-up respectively . At six months and compared to the control group , those allocated to leisure therapy had nonsignificantly better GHQ scores ( –1.2 : 95 % CI –2.9 , + 0.5 ) , leisure scores ( + 0.7 , 95 % CI –1.1 , + 2.5 ) and Extended ADL scores ( + 0.4 : 95 % CI –3.8 , + 4.5 ) : the ADL group had nonsignificantly better GHQ scores ( –0.1 : 95 % CI –1.8 , + 1.7 ) and Extended ADL scores ( + 1.4 : 95 % CI –2.9 , + 5.6 ) and nonsignificantly worse leisure scores ( –0.3 : 95 % CI –2.1 , + 1.6 ) . The results at 12 months were similar . Conclusion : In contrast to the findings of previous smaller trials , neither of the additional OT treatments showed a clear beneficial effect on mood , leisure activity or independence in ADL measured at 6 or 12 months [10440303] BACKGROUND Patients who have a stroke are not always admitted to hospital , and 22 - 60 % remain in the community , frequently without coordinated rehabilitation . We aim ed to assess the efficacy of an occupational therapy intervention for patients with stroke who were not admitted to hospital . METHODS In this single-blind r and omised controlled trial , consecutive stroke patients on a UK community register in Nottingham and Derbyshire were allocated r and omly to up to 5 months of occupational therapy at home or to no intervention ( control group ) 1 month after their stroke . The aim of the occupational therapy was to encourage independence in personal and instrumental activities of daily living . Patients were assessed on outcome measures at baseline ( before r and omisation ) and at 6 months . The primary outcome measure was the score on the extended activities of daily living ( EADL ) scale at 6 months . Other outcome measures included the Barthel index , the general health question naire 28 , the carer strain index , and the London h and icap scale . All assessment s were done by an independent assessor who was unaware of treatment allocation . The analysis included only data from completed question naires . FINDINGS 185 patients were included : 94 in the occupational therapy group and 91 in the control group . 22 patients were not assessed at 6 months . At follow-up , patients who had occupational therapy had significantly higher median scores than the controls on : the EADL scale ( 16 vs 12 , p<0.01 , estimated difference 3 [ 95 % CI 1 to 4 ] ) ; the Barthel index ( 20 vs 18 , p<0.01 , difference 1 , [ 0 - 1 ] ) ; the carer strain index ( 1 vs 3 , p<0.05 , difference 1 [ 0 to 2 ] ) ; and the London h and icap scale ( 76 vs 65 , p<0.05 , difference 7 , [ 0.3 to 13.5 ] ) . There were no significant differences on the general health question naire between the patient or carer . INTERPRETATION Occupational therapy significantly reduced disability and h and icap in patients with stroke who were not admitted to hospital [12392333] Objective : To evaluate whether follow-up services for stroke survivors could improve functional outcome and reduce readmission rate . In this paper results of functional outcome are reported . Design : R and omized controlled trial allocating patients to one of three different types of aftercare : ( 1 ) follow-up home visits by a physician , ( 2 ) physiotherapist instruction in the patient 's home , or ( 3 ) st and ard aftercare . Subjects : Stroke patients with persisting impairment and disability who , after completing inpatient rehabilitation , were discharged to their homes . Outcome measures : Six months after discharge , functional outcome was assessed with Functional Quality of Movement , Barthel Index , Frenchay Activity Index and Index of Extended Activites of Daily Living . Results : One-hundred and fifty-five stroke patients were included in the study . Fifty-four received follow-up home visits by a physician , 53 were given instructions by a physiotherapist in their home and 48 received st and ard aftercare only . No statistically signi ca nt differences in functional outcome six months after discharge were demonstrated between the three groups . However , all measurements showed a tendency towards higher scores indicating better function in both interventions groups compared with the control group . Conclusion : Follow-up services after stroke may be a way of improving functional outcome . The results of the present study should be evaluated in future trials . More research in this eld is needed , especially studies of how to support stroke survivors to resume social and leisure activities [10327094] Objective : To assess the efficacy of a programme of continuing self-directed exercises for people discharged home after a stroke , supervised once a week by therapists . Design : A r and omized controlled trial of 100 patients discharged from hospital after a stroke , requiring ongoing therapy . The control group received outpatient or day hospital therapy ; the experimental group were visited once a week by an occupational and /or physiotherapist who prescribed a programme of exercises and activities for the following week . Subjects were studied for the first three months after discharge from hospital . Setting : A district general hospital , or the homes of subjects r and omized to the experimental group , in New Zeal and . Main outcome measures : ( 1 ) Characteristics of the groups , ( 2 ) gait speed , limb function , activities of daily living , ( 3 ) time with therapists , ( 4 ) mood of both subjects and caregivers , ( 5 ) anticipation of outcome at entry , compared with perceived outcome at exit . Results : No statistical differences between the control and experimental groups in characteristics , or in any outcomes measured , except that the contact time period , but not the number of visits , was longer in the experimental group ( p = 0.003 ) . Conclusions : A supervised home-based programme is as effective as outpatient or day hospital therapy [9366727] Abstract Objective : To assess the clinical effectiveness of an early discharge policy for patients with stroke by using a community based rehabilitation team . Design : R and omised controlled trial to compare conventional care with an early discharge policy . Setting : Two teaching hospitals in inner London . Subjects : 331 medically stable patients with stroke ( mean age 71 ) who lived alone and were able to transfer independently or who lived with a resident carer and were able to transfer with help . Interventions : 167 patients received specialist community rehabilitation for up to 3 months after r and omisation . 164 patients continued with conventional hospital and community care . Main outcome measures : Barthel score at 12 months . Secondary outcomes measured impairment with motoricity index , minimental state examination , and Frenchay aphasia screening test ; disability with the Rivermead activity of daily living scales , hospital anxiety and depression scale , and 5 m walk ; h and icap with the Nottingham health profile ; carer stress with caregiver strain index and patient and carer satisfaction . The main process measure was length of stay after r and omisation . Results : One year after r and omisation no significant differences in clinical outcomes were found apart from increased satisfaction with hospital care in the community therapy group . Length of stay after r and omisation in the community therapy group was significantly reduced ( 12 v 18 days ; P<0.0001 ) . Patients with impairments were more likely to receive treatment in the community therapy group . Conclusions : Early discharge with specialist community rehabilitation after stroke is feasible , as clinical ly effective as conventional care , and acceptable to patients . Considerable reductions in use of hospital beds are achievable . Key messages Early discharge from hospital after stroke with specialist rehabilitation at home is feasible without an increase in readmission rates or stress to carers This r and omised controlled trial shows this method to be as effective as conventional care when assessed with a range of measures of impairment , disability , h and icap , carer stress , and patient and carer satisfaction at 1 year Significant reductions in bed usage can be achieved by the provision of a community rehabilitation team with no significant increase in rehabilitation [15468020] OBJECTIVE To evaluate the effectiveness of 2 rehabilitative approaches for improving paretic limb reaching by chronic stroke subjects . DESIGN Pre- and posttest reaching to targets ipsilateral , midline , and contralateral to the impaired side . SETTING Training in subjects ' homes ; testing in a laboratory setting . PARTICIPANTS Twelve poststroke volunteers were matched using the Motor Assessment Scale ( MAS ) and then were r and omly assigned to 1 of 2 training conditions . Subjects were subsequently categorized as at a high or low functional level , using the reaching pretest movement time scores . INTERVENTIONS Training ( trunk unrestrained ) using the paretic limb was 4 weeks ( 12 sessions ) . Task-related training ( TRT ) involved reaching to objects placed across the workspace . Progressive resistive exercise ( PRE ) involved whole-arm pulling against resistive therapeutic tubing in planes and distances similar to that in TRT . Main outcome measures Kinematic analysis of arm trajectory and trunk motion using the Peak Performance System , as well as scores on the MAS and the Rivermead Motor Assessment ( RMA ) . RESULTS For low-level groups , TRT result ed in increased substitutive trunk use at the target ipsilateral to the moving arm , and for midline and contralateral targets after PRE . Only low-level , TRT subjects straightened h and paths , which suggested better coordination of elbow-shoulder motion , and improved on the RMA . High-level subjects decreased trunk use at ipsilateral target after PRE , which was not observed after TRT . No significant differences between training conditions were found for other kinematic variables . CONCLUSIONS Training benefits appear to depend on initial level of functioning . Although compensatory trunk use was evident , low-level subjects seemed to benefit most from TRT . High-level subjects , whose kinematics showed fairly normal movement organization , demonstrated less compensatory movement after PRE [19541917] Background . Chronic upper extremity impairment due to stroke has significant medical , psychosocial , and financial consequences , but few studies have examined the effectiveness of rehabilitation therapy during the chronic stroke period . Objective . To test the safety and efficacy of the MIT-Manus robotic device for chronic upper extremity impairment following stroke . Methods . The VA Cooperative Studies Program initiated a multicenter , r and omized , controlled trial in November 2006 ( VA ROBOTICS ) . Participants with upper extremity impairment ≥6 months poststroke were r and omized to robot-assisted therapy ( RT ) , intensive comparison therapy ( ICT ) , or usual care ( UC ) . RT and ICT consisted of three 1-hour treatment sessions per week for 12 weeks . The primary outcome was change in the Fugl-Meyer Assessment upper extremity motor function score at 12 weeks relative to baseline . Secondary outcomes included the Wolf Motor Function Test and the Stroke Impact Scale . Results . A total of 127 participants were r and omized : 49 to RT , 50 to ICT , and 28 to UC . The majority of participants were male ( 96 % ) , with a mean age of 65 years . The primary stroke type was ischemic ( 85 % ) , and 58 % of strokes occurred in the anterior circulation . Twenty percent of the participants reported a stroke in addition to their index stroke . The average time from the index stroke to enrollment was 56 months ( range , 6 months to 24 years ) . The mean Fugl-Meyer score at entry was 18.9 . Conclusions . VA ROBOTICS demonstrates the feasibility of conducting multicenter clinical trials to rigorously test new rehabilitative devices before their introduction to clinical practice . The results are expected in early 2010 [15481562] This study was a preliminary examination of the effect of low-intensity home-based physical therapy on the performance of activities of daily living ( ADL ) and motor function in patients more than 1 year after stroke . Twenty patients were recruited from a community stroke register in Nan-Tou County , Taiwan , to a r and omized , crossover trial comparing intervention by a physical therapist immediately after entry into the trial ( Group I ) or after a delay of 10 weeks ( Group II ) . The intervention consisted of home-based physical therapy once a week for 10 weeks . The Barthel Index ( BI ) and Stroke Rehabilitation Assessment of Movement ( STREAM ) were used as st and ard measures for ADL and motor function . At the first follow-up assessment at 11 weeks , Group I showed greater improvement in lower limb motor function than Group II . At the second follow-up assessment at 22 weeks , Group II showed improvement while Group I had declined . At 22 weeks , the motor function of upper limbs , mobility , and ADL performance in Group II had improved slightly more than in Group I , but the between-group differences were not significant . It appears that low-intensity home-based physical therapy can improve lower limb motor function in chronic stroke survivors . Further studies will be needed to confirm these findings [16250192] Objectives : ( 1 ) To determine the feasibility of a home-based electromyography triggered neuromuscular stimulation ( ETMS ) programme ; and ( 2 ) to determine ETMS efficacy in increasing affected wrist extension and reducing affected arm impairment . Design : R and omized , controlled , pre-lpost , cross-over design . Setting : Outpatient rehabilitation hospital . Patients : Twelve chronic stroke patients with palpable muscle contraction in their affected wrist extensors but no movement ( 7 males ; mean age=59.75 years , age range 44 - 75 years ; mean time since stroke=52.75 months , range 13 - 131 months ) . Intervention : Subjects were r and omly assigned to receive either : ( a ) ETMS use twice every weekday in 35-min increments during an eight-week period followed by an eight-week home exercise programme ( ETMS/home exercise programme ) ( n=8 ) ; or ( b ) an eight-week home exercise programme followed by use of ETMS twice every weekday in 35-min increments during an eight-week period ( home exercise programme ) ( n=4 ) . Main outcome measures : The Fugl-Meyer , Action Research Arm Test and goniometry . Results : After home exercise programme participation , subjects showed nominal or no changes on any of the outcome measures . After ETMS , patients showed modest impairment reductions , as shown by the Fugl-Meyer , and no Action Research Arm Test changes . However , both groups showed a 218 increase in active affected wrist extension after ETMS use . Conclusion : ETMS use is feasible in the home environment . Neither participation in a traditional home exercise programme nor ETMS use conveyed changes on the Fugl-Meyer or Action Research Arm Test . However , ETMS use increased active affected limb extension . This new movement may provide a potential pathway for subjects to participate in other interventions , such as modified constraint induced therapy [8010180] The DOMINO study compared domiciliary and hospital-based rehabilitation services for stroke patients after discharge from hospital , stratified by the hospital ward at discharge . No difference between the services had been found at 6 months , but home therapy was better than outpatient department therapy at improving household ability and leisure activity in the patients discharged from the Stroke Unit ( SU ) , and attendance at a day hospital may have been better than a domiciliary service at preventing death or institutionalization for patients discharged from Health Care of the Elderly ( HCE ) wards . We report the follow-up of the patients between 6 months and 1 year after discharge , during which time few patients received further treatment and little change in health or function occurred . Over this period the benefits of domiciliary rehabilitation in the SU group were lost , largely because the patients who had been treated in outpatient departments continued to improve . Between 6 months and 1 year the numbers of HCE patients in the two treatment groups who died or were institutionalized were similar , but the advantage of day hospital attendance was still evident at 1 year [14503438] Based on the principles of neuroplasticity , the purpose of this crossover study was to determine if improvement in upper extremity ( UE ) function and independence could be achieved in patients 6 months to 7 years poststroke following an outpatient rehabilitation program ( supervised 1.5 hours per week for 8 weeks reinforced with home gloving unaffected side and attended , grade d , repetitive sensory and motor training activities ) . Twenty-one subjects ( right or left hemiparesis ; able to walk 100 feet with or without a cane ; partially opened and closed the h and ; partially elevated the shoulder and elbow against gravity ) were r and omly assigned to Group A ( sensory training 4 weeks , motor training 4 weeks ) or Group B ( motor training 4 weeks , sensory training 4 weeks ) . Greater than 20 % ( P < 0.01 ) improvement was measured in functional independence and UE function ( fine motor , sensory discrimination , and musculoskeletal performance ) . Gains were hemispheric and training specific and maintained over 3 months . This study provides evidence documenting significant improvement in function in the late poststroke recovery period following 12 hours of supervised learning based sensory motor training [16719028] Objective : To evaluate the efficacy of a task-oriented intervention in enhancing arm function in people with stroke . Design : Two-centre , observer-blinded , stratified , block-r and omized controlled trial . Setting : General community . Patients : Ninety-one individuals within one year of a first or recurrent stroke consented to participate between May 2000 and February 2003 . Interventions : The experimental intervention involved practice of functional , unilateral and bilateral tasks that were design ed to improve gross and fine manual dexterity whereas the control intervention was composed of walking tasks . Members in both groups participated in three sessions a week for six weeks . Main outcome measure(s ) : The primary test of arm function was the Box and Block Test . Secondary tests included the Nine-Hole Peg Test , maximal grip strength , the Test d'Evaluation des Membres supé rieurs des Personnes Agées ( TEMPA ) and the Stroke Rehabilitation Assessment of Movement . Results : Results are for the more affected arm . Baseline performance on the Box and Block Test was an average of 26 blocks ( st and ard deviation ( SD=16 ) in the experimental group ( n=47 ) and 26 blocks ( Sd=18 ) in the control group ( n=44 ) . These values represent approximately 40 % of age-predicted values . Values for the postintervention evaluation were an average of 28 ( SD=17 ) and 28 ( SD=19 ) blocks for the experimental and control group respectively . No meaningful change on other measures of arm function was observed . Conclusions : A task-oriented intervention did not improve voluntary movement or manual dexterity of the affected arm in people with chronic stroke [17214754] AIM This paper reports an evaluation of a range-of-motion exercise programme aim ed at improving joint flexibility , activity function , perception of pain , and depressive symptoms in a sample of stroke survivors in long-term care facilities . BACKGROUND The benefits of physical rehabilitation for stroke survivors have been well established . There is , however , little empirical data on the effects of a simple nurse-led range-of-motion exercise programme in improving function for these people . METHOD A r and omized controlled trial was conducted in 1999 with 59 bedridden older stroke survivors in residential care . Participants were r and omly assigned to usual care or one of two intervention groups . The 4-week , twice-per-day , 6 days-per-week range-of-motion exercise protocol s were similar in both intervention groups , and consisted of full range-of-motion exercises of the upper and lower extremities . To test the effect of different degrees of staff involvement , in intervention group I , a Registered Nurse was present to supervise participants performing the exercises , while intervention group II involved a Registered Nurse physically assisting participants to achieve maximum range-of-motion within or beyond their present abilities . RESULTS Both intervention groups had statistically significant improvement in joint angles , activity function , perception of pain and depressive symptoms compared with the usual care group ( P < 0.05 ) . Post hoc comparison revealed that the joint angles in intervention group II were statistically significantly wider than in both the other groups ( P < 0.01 ) . CONCLUSIONS A simple nurse-led range-of-motion exercise programme can generate positive effects in enhancing physical and psychological function of bedridden older people with stroke . Further studies are needed to investigate the long-term effects of the programme in maximizing function , reducing care utilization and enhancing quality of life for this population [11588740] OBJECTIVE To compare outcomes in stroke survivors who received rehabilitation services in an acute inpatient rehabilitation setting ( multidisciplinary rehabilitation team ) with outcomes in survivors in a home-based setting ( family caregivers , limited team supervision ) . DESIGN R and omized clinical trial , with mean follow-up after 60 days . SETTING Inpatient rehabilitation setting and home-based setting s. PATIENTS Sixty patients ( age range , 43 - 80yr ) who had a stroke between 1996 and 1999 and had been referred after medical stabilization , r and omly divided into 2 groups : group 1 , inpatient rehabilitation ; group 2 , home-based rehabilitation . INTERVENTIONS Group 1 : therapeutical and neuromuscular exercises with occupational therapy with professional supervision ; group 2 : conventional exercises with family caregiver and limited professional supervision . MAIN OUTCOME MEASURES Spasticity was evaluated with the Ashworth Scale , motor status with Brunnstrom 's stages , functional status with the FIM instrument , and cognitive status with the Mini-Mental State Examination before and after rehabilitation . RESULTS Patients rehabilitated in acute inpatient setting s had better motor , functional , and cognitive outcomes ( p < .05 ) . Spasticity changes did not differ between the groups . CONCLUSION Intense inpatient rehabilitation services for stroke survivors provide significantly more favorable functional and cognitive outcomes with relatively low complications than did nonintense rehabilitation efforts in home setting [18806506] Hesse S , Werner C , Pohl M , Mehrholz J , Puzich U , Krebs HI : Mechanical arm trainer for the treatment of the severely affected arm after a stroke : a single-blinded r and omized trial in two centers . Am J Phys Med Rehabil 2008;87:779–788 . Objective : To test whether training with a new mechanical arm trainer leads to better outcomes than electrical stimulation of the paretic wrist extensors in subacute stroke patients with severe upper limb paresis . Electrical stimulation is a st and ard and reimbursable form of therapy in Germany . Design : R and omized controlled trial of 54 in patients enrolled 4–8 wks from stroke onset , mean upper-extremity subsection of Fugl-Meyer assessment ( 0–66 ) at admission less than 18 . In addition to st and ard care , all patients practice d 20–30 mins arm trainer or electrical stimulation every workday for 6 wks , totaling 30 sessions . Primary outcome was the Fugl-Meyer assessment , secondary outcomes were the Box and Block test , the Medical Research Council and the modified Ashworth scale , blindly assessed at enrollment , after 6 wks , and at 3-mo follow-up . Results : Both groups were homogeneous at study onset . Shoulder pain occurred in two arm trainer patients . The primary Fugl-Meyer assessment outcome improved for both groups over time ( P < 0.001 ) , but this improvement did not differ between groups . The initial ( terminal ) mean Fugl-Meyer assessment scores were 8.8 ± 4.8 ( 19.2 ± 14.5 ) for the arm trainer and 8.6 ± 3.5 ( 13.6 ± 7.9 ) for the electrical stimulation group . No patient could transport a block initially , but at completion significantly more arm trainer patients were able to transport at least three blocks ( five vs. zero , P = 0.023 ) . No significant differences were observed between the groups on the secondary Box and Block outcome at follow-up ( eight vs. four patients ) . All Box and Block responders had an initial Fugl-Meyer assessment ≥10 . Conclusions : Arm trainer training did not lead to a superior primary outcome over electrical stimulation training . However , “ good performers ” on the secondary outcome seemed to benefit more from the arm trainer training [19349340] Objective : To evaluate the effects of community-based rehabilitation therapy on neurological function deficit in stroke patients . Design : Prospect i ve , single-blind , r and omized controlled multicentre trial . Setting : At home , in Shanghai , China . Subjects : A total of 737 stroke patients in the community . Intervention : The rehabilitation group received additional st and ardized community-based rehabilitation therapy at home for five months . Main outcome measures : Patients were evaluated using the Clinical Neurological Function Deficit Scale before intervention and at the end of two and five months . Results : Although both the rehabilitation group and the control group improved over time , the rehabilitation group showed a greater improvement in Clinical Neurological Function Deficit Scale scores . The differences between the groups were significant . After five months , the Clinical Neurological Function Deficit Scale scores of the cerebral infa rct ion rehabilitation group improved by 6.77 ; the haemorrhage rehabilitation group by 7.99 ; the total rehabilitation group by 7.03 . In comparison , the Clinical Neurological Function Deficit Scale scores of the cerebral infa rct ion control group improved by 1.57 ; the haemorrhage control group by 5.34 ; the total control group by 2.43 . This implies a difference in improvement of 5.2 in the cerebral infa rct ion group , 2.65 in the haemorrhage group , and 4.6 in the total group in favour of the rehabilitation group between groups . Conclusion : St and ardized community-based rehabilitation therapy may help stroke patients to improve their neurological function [19729582] Background and objective . Botulinum toxin type A ( BtxA ) injection and modified constraint-induced movement therapy ( mCIMT ) are both promising approaches to enhance recovery after stroke . The combined application of these 2 promising modalities has rarely been studied . The aim was to investigate whether combined BtxA and mCIMT would improve spasticity and upper extremity motor function more than BtxA plus conventional rehabilitation in chronic stroke patients with upper extremity spasticity . Methods . In a prospect i ve , r and omized controlled , observer-blinded trial with 6-month follow-up , 32 patients ( ≥1 year after stroke ) with ability to actively extend > 10 ° at metacarpophalangeal and interphalangeal joints and 20 ° at wrist of the affected upper limb were r and omized to receive BtxA + mCIMT ( combination group ) or BtxA + conventional rehabilitation ( control group ) for 2 hours/day , 3 days/week for 3 months . The primary outcome assessed spasticity on the Modified Ashworth Scale . Secondary outcomes assessed real-world arm function ( Motor Activity Log ) , laboratory motor activity ( Action Research Arm Test ) , and patients ’ global satisfaction . Results . A total of 32 stroke patients were recruited , and 29 completed the study . Spasticity significantly improved in all subjects at 4 weeks and 3 months postinjection without between-group differences . The combination group showed significantly greater improvements in elbow , wrist , and finger spasticity ( P = .019 , P = .019 , and P < .001 , respectively ) , affected upper extremity real-world arm function ( P < .001 ) and laboratory motor activity ( P < .001 ) than the control group at 6-month postinjection . Patients reported considerable satisfaction and no serious adverse events occurred . Conclusions . Combining BtxA and mCIMT is an effective and safe intervention for improving spasticity and motor function in chronic stroke patients . The results are promising enough to justify further studies . We recommend future research to address the likely need for including rehabilitation with BtxA to improve function in patients with poststroke spasticity [8650505] A new method ( The Sødring Motor Evaluation of Stroke Patients ) has been developed for physiotherapists to evaluate motor function and activities in stroke patients . Its main characteristics are the assessment of motor activity without assisting the patient , and the use of a rating which reflects quantity as well as quality in motor performance . A hospitalised group of stroke patients ( n = 93 ) was assessed three times after the acute event , by means of SMES . The data were analysed regarding construct validity as well as concurrent validity against another assessment method . Factor analyses showed a reasonably stable three-factor pattern ( " arm " , " gross motor function " , and " leg " ) which explained 84 , 89 and 90 % , respectively , of the variance at the three study points , with Factor 1 ( " arm " ) as the dominant factor . The ordinality of the rating scale was assessed by means of linear regression analysis and found to be acceptable . The correlation coefficients were high between comparable parts of the new and the reference methods [8172497] Time course and degree of recovery of upper extremity ( UE ) function after stroke and the influence of initial UE paresis were studied prospect ively in a community-based population of 421 consecutive stroke patients admitted acutely during a 1-year period . UE function was assessed weekly , using the Barthel Index subscores for feeding and grooming . UE paresis was assessed by the Sc and inavian Stroke Scale subscores for h and and arm . The best possible UE function was achieved by 80 % of the patients within 3 weeks after stroke onset and by 95 % within 9 weeks ; in patients with mild UE paresis , function was achieved within 3 and 6 weeks , respectively , and in patients with severe UE paresis within 6 and 11 weeks , respectively . Full UE function was achieved by 79 % of patients with mild UE paresis and only by 18 % of patients with severe UE paresis . A valid prognosis of UE function can be made within 3 and 6 weeks in patients with mild and severe UE paresis , respectively . Further recovery of UE function should not be expected after 6 and 11 weeks respectively , in these groups of patients [16401430] OBJECTIVE To assess the effects of a community-based exercise program on motor recovery and functional abilities of the paretic upper extremity in persons with chronic stroke . DESIGN R and omized controlled trial . SETTING Rehabilitation research laboratory and a community hall . PARTICIPANTS A sample of 63 people ( > or = 50y ) with chronic deficits result ing from stroke ( onset > or = 1y ) . INTERVENTIONS The arm group underwent an exercise program design ed to improve upper-extremity function ( 1h/session , 3 sessions/wk for 19wk ) . The leg group underwent a lower-extremity exercise program . MAIN OUTCOME MEASURES The Wolf Motor Function Test ( WMFT ) , Fugl-Meyer Assessment ( FMA ) , h and -held dynamometry ( grip strength ) , and the Motor Activity Log . RESULTS Multivariate analysis showed a significant group by time interaction ( Wilks lambda=.726 , P=.017 ) , indicating that overall , the arm group had significantly more improvement than the leg group . Post hoc analysis demonstrated that gains in WMFT ( functional ability ) ( P=.001 ) and FMA ( P=.001 ) scores were significantly higher in the arm group . The amount of improvement was comparable to other novel treatment approaches such as constraint-induced movement therapy or robot-aided exercise training previously reported in chronic stroke . Participants with moderate arm impairment benefited more from the program . CONCLUSIONS The pilot study showed that a community-based exercise program can improve upper-extremity function in persons with chronic stroke . This outcome justifies a larger clinical trial to further assess efficacy and cost effectiveness [18996231] OBJECTIVE To determine whether acute exercise , using a body-weight-supported treadmill , improves performance on subsequent cognitive tests or an upper-extremity task in people with stroke . DESIGN The study was a within-subject , cross-over design in which 21 subjects received , r and omly , 2 different testing sequences separated by an interval of 7 to 10 days . SETTING Outpatient department of a rehabilitation hospital . PARTICIPANTS Of 72 potential participants in the convenience sample , 21 people with chronic stroke completed the study . They were 0.5 to 5 years after only 1 documented stroke , were able to walk with or without a cane , were able to grasp with the affected h and , and scored more than 24 on the Mini-Mental State Examination . INTERVENTIONS One session of body-weight-supported treadmill walking for 20 minutes at 70 % of estimated heart rate reserve or level 13 on the Borg rating of perceived exertion scale . The control condition consisted of a 20-minute review of a home exercise program with a physiotherapist . MAIN OUTCOME MEASURES Cognitive tests included Trail Making Tests Parts A and B , Symbol Digit Substitution Test , and Paced Auditory Serial Addition Test . The Action Research Arm Test ( ARAT ) measured hemiplegic upper-extremity motor skill . RESULTS Treadmill exercise improved movement of the hemiplegic upper extremity ( P=.04 ) but not cognitive performance . The improvement in the ARAT occurred without a change in strength ( measured by grip strength ) and was negatively correlated with maximum treadmill speed ( R(2)=.20 ; P=.04 ) . CONCLUSIONS These findings suggest that acute treadmill exercise improves subsequent skilled movement of the hemiplegic upper extremity that seems unrelated to attention , visuomotor processing , or strength . The etiology and duration of this enhancing effect are worth further study . The existence of an exercise-cognition relationship in people with stroke is an intriguing area of future research Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: Objective : To determine the evidence for physical therapy interventions aim ed at improving functional outcome after stroke . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

27839531

[23780458] IMPORTANCE Tissue verification of noncaseating granulomas is recommended for the diagnosis of sarcoidosis . Bronchoscopy with transbronchial lung biopsies , the current diagnostic st and ard , has moderate sensitivity in assessing granulomas . Endosonography with intrathoracic nodal aspiration appears to be a promising diagnostic technique . OBJECTIVE To evaluate the diagnostic yield of bronchoscopy vs endosonography in the diagnosis of stage I/II sarcoidosis . DESIGN , SETTING , AND PATIENTS R and omized clinical multicenter trial ( 14 centers in 6 countries ) between March 2009 and November 2011 of 304 consecutive patients with suspected pulmonary sarcoidosis ( stage I/II ) in whom tissue confirmation of noncaseating granulomas was indicated . INTERVENTIONS Either bronchoscopy with transbronchial and endobronchial lung biopsies or endosonography ( esophageal or endobronchial ultrasonography ) with aspiration of intrathoracic lymph nodes . All patients also underwent bronchoalveolar lavage . MAIN OUTCOMES AND MEASURES The primary outcome was the diagnostic yield for detecting noncaseating granulomas in patients with a final diagnosis of sarcoidosis . The diagnosis was based on final clinical judgment by the treating physician , according to all available information ( including findings from initial bronchoscopy or endosonography ) . Secondary outcomes were the complication rate in both groups and sensitivity and specificity of bronchoalveolar lavage in the diagnosis of sarcoidosis . RESULTS A total of 149 patients were r and omized to bronchoscopy and 155 to endosonography . Significantly more granulomas were detected at endosonography vs bronchoscopy ( 114 vs 72 patients ; 74 % vs 48 % ; P < .001 ) . Diagnostic yield to detect granulomas for endosonography was 80 % ( 95 % CI , 73%-86 % ) ; for bronchoscopy , 53 % ( 95 % CI , 45%-61 % ) ( P < .001 ) . Two serious adverse events occurred in the bronchoscopy group and 1 in the endosonography group ; all patients recovered completely . Sensitivity of the bronchoalveolar lavage for sarcoidosis based on CD4/CD8 ratio was 54 % ( 95 % CI , 46%-62 % ) for flow cytometry and 24 % ( 95 % CI , 16%-34 % ) for cytospin analysis . CONCLUSION AND RELEVANCE Among patients with suspected stage I/II pulmonary sarcoidosis undergoing tissue confirmation , the use of endosonographic nodal aspiration compared with bronchoscopic biopsy result ed in greater diagnostic yield . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00872612 [1516390] A patient 's tolerance of fiberoptic bronchoscopy depends on the effectiveness of local anesthesia . This study compares the three different methods of local anesthesia in common use After sedation , patients ( n = 53 ) received either 4 ml of 2.5 percent cocaine by intratracheal injection ( TI ) ( n = 18 ) , by bronchoscopic injection ( BI ) ( n = 19 ) , or had 4 ml of 4 percent lidocaine delivered by nebulizer 20 min before the procedure ( NEB ) ( n = 16 ) . Patients and bronchoscopists scored the procedure using visual analog ( VAS ) and severity scales . Objective measurements of cough counts and episodes of stridor were recorded by phonopneumography . Patients ' VAS scores showed a clear preference for the transtracheal method compared with either bronchoscopically injected cocaine ( p less than 0.001 ) or nebulized lidocaine ( p less than 0.001 ) . Patients also reported that the TI method produced less cough during intubation of the larynx and inspection of the airways ( BI and NEB , p less than 0.01 ) . The TI method was also preferred by the bronchoscopists ( BI and NEB , p less than 0.001 ) ; they reported less cough and easier tracheal intubation . The mean cough count was significantly lower for the TI group , 49 ( 43 ) compared with 95 ( 52 ) for BI ( p less than 0.01 ) , and 81 ( 43 ) for the NEB group ( p less than 0.05 ) . Patients ' and bronchoscopists ' VAS showed significant correlation with cough ( r = 0.63 - 69 , p less than 0.01 ) . Stridor occurred in only two patients after TI , compared with 15 in the other two groups . Extra local anesthesia was required by 16 patients after BI , by all the NEB group , but by only one patient after TI . Subjective and objective measurement shows that 4 ml of 2.5 percent cocaine injected into the trachea produced excellent local anesthesia for fiberoptic bronchoscopy , there were no extra complications , and it was the method preferred by both patients and bronchoscopists [15786902] OBJECTIVE The route of bronchoscope insertion varies between centres , without a firm rationale based on well- design ed studies . We therefore compared nasal and oral insertion of a flexible bronchoscope and evaluated efficacy and patient satisfaction . DESIGN Prospect i ve r and omised study of patients who underwent flexible bronchoscopy from May to September 2003 and who were r and omly assigned to nasal and oral insertion approaches . RESULTS Clinical characteristics , factors related to the procedure and patient satisfaction were analysed . In total , 307 patients were r and omly assigned to the nasal ( n = 158 ) or oral insertion groups ( n = 149 ) . No difference in baseline characteristics was identified between the groups . Insertion by the oral route was associated with a smaller amount of lidocaine use during the procedure ( P = 0.04 ) and less frequent insertion site bleeding ( P = 0.005 ) . Patients assigned to oral insertion reported less discomfort during anaesthesia ( P = 0.01 ) and scope insertion ( P < 0.001 ) , as well as less dyspnoea ( P = 0.04 ) and coughing ( P = 0.03 ) . CONCLUSION Oral insertion of a flexible bronchoscope was associated with less discomfort for patients than nasal insertion , although the route of insertion had no significant effect on outcome [20804674] BACKGROUND Conscious sedation for patients undergoing flexible bronchoscopy ( FB ) is suggested to alleviate discomfort and improve satisfaction despite controversy regarding its benefits . In Taiwan , the general FB practice involves local anesthesia only . This study aim ed to assess the benefits and risks of conscious sedation in diagnostic FB . METHODS This prospect i ve case control study enrolled 44 non-se date d and 44 se date d patients who underwent diagnostic FB . All received the st and ard upper airway preparation , while se date d patients received clinical ly judged increments of midazolam and alfentanil for conscious sedation . Patient discomforts and the operator 's opinions during FB were assessed using the verbal analogue score ( VAS , 0 - 10 scale ) . Willingness to return was assessed as five scales to monitor patient satisfaction . Safety profiles throughout the procedures were also assessed . RESULTS Compared to non-se date d patients , se date d ones expressed less discomfort , with lower VAS scores regarding scope insertion ( 3.5 [ 0 - 10 ] vs. 0 [ 0 - 5 ] , p < 0.001 ) , cough ( 5 [ 0 - 10 ] vs. 0 [ 0 - 5 ] , p < 0.001 ) , dyspnea ( 3 [ 0 - 10 ] vs. 0 [ 0 - 8 ] , p < 0.001 ) , pain ( 3 [ 0 - 10 ] vs. 0 [ 0 - 5 ] , p < 0.001 ) , and global tolerance of the procedures ( 5 [ 1 - 10 ] vs. 0 [ 0 - 9 ] , p < 0.001 ) . More se date d patients expressed willingness to return ( 70.5 % vs. 36.4 % , p = 0.001 ) . The bronchoscopist also rated lower VAS scores on cough and dyspnea in se date d patients . Se date d patients had less hypertension but more hypoxemic episodes during the procedure , which were all transient and not life-threatening . CONCLUSIONS Conscious sedation with clinical ly judged midazolam and alfentanil reduces discomforts , improves satisfaction , and carries slight , but manageable , hypoxemia risks in patients undergoing FB [24602973] Background : The clinical benefits associated with the use of the bispectral index ( BIS ) to monitor the depth of sedation during flexible fiberoptic bronchoscopy ( FFB ) are question able . Objectives : To evaluate the added value in terms of procedural safety and patients ' awareness of monitoring sedation depth using the BIS compared to conventional clinical judgment alone in patients undergoing FFB under propofol sedation . Methods : The cohort included 81 patients undergoing diagnostic or therapeutic bronchoscopy under propofol sedation that were prospect ively r and omized to guide the depth of sedation by BIS monitoring ( BIS group ; n = 40 ) or conventional monitoring ( control group ; n = 41 ) . Results : The mean duration s of the procedure were 18 and 19 min in the BIS and control groups , respectively . No significant difference was noted in the dosage of propofol used between the BIS and control groups ( 168.7 vs. 167.3 mg , respectively ) . Average sedation-related oxygen saturation drop and transcutaneous CO2 rise were not significantly different between groups . There was also no significant difference in the percentage of patients that required either hemodynamic support ( 5 vs. 7.5 % , respectively ) , oxygen supplementation by 100 % O2 mask ( 67.5 vs. 82.5 % , respectively ) or Ambu face mask manual ventilation ( 2.5 vs. 5 % , respectively ) between the groups . No significant difference was noted in terms of patients ' awareness during the procedure , which was assessed following recovery by a structured Brice interview . Conclusion : Using BIS to guide the depth of sedation during propofol sedation in patients undergoing FFB of relatively short duration offers no clinical ly significant advantages over conventional monitoring [16506681] Optimisation of topical anaesthesia for flexible fibreoptic bronchoscopy ( FOB ) is becoming increasingly important as a wider range of more complex , and thereby more prolonged , interventional endoscopic procedures are becoming available . Lignocaine is the most commonly used topical anaesthetic agent for bronchoscopy , but there is variability in current practice as to its optimum mode of administration . In this prospect i ve , r and omised , placebo-controlled , blinded study , we examine whether there was enhanced effectiveness of additional nebulised lignocaine as compared to our current regime utilising two visual analogue scales as markers of efficacy . Treatment groups were matched in terms of age ( p = 0.39 ) , gender , concomitant sedation ( p = 0.51 midazolam ; p = 0.12 fentanyl ) and dose of background administered lignocaine ( 290 mg ) . We found no significant additional differences between any of the treatment groups in terms of general ease of procedure ( p = 0.09 ) or in cough severity ( p = 0.12 ) . We conclude that this study does not support the hypothesis that additional nebulised lignocaine confers any additional benefit to the ease of procedure or cough severity in patients undergoing fibreoptic bronchoscopy . We suggest that preparation regimes for bronchoscopic examinations need optimization [12377879] STUDY OBJECTIVES The present study was performed to determine whether the risk of bleeding after transbronchial lung biopsy is increased in patients taking aspirin . DESIGN Prospect i ve cohort study . PATIENTS AND INTERVENTIONS After excluding patients with other coagulation problems , 1,217 patients who had undergone transbronchial lung biopsy during a prospect i ve 1.5-year study period were included in this study . The use of aspirin was not discontinued before the procedure . Two hundred eighty-five patients ( 23 % ) had consumed aspirin within 24 h of the procedure , and most of them ( 82 % ) used aspirin on a daily basis . Transbronchial biopsies were performed , and the bleeding incidence was compared between the groups . RESULTS A total of 57 patients ( 4.7 % ) experienced procedure-related bleeding . Minor bleeding occurred in 5 of 285 patients ( 1.8 % ) taking aspirin and in 27 of 932 control patients ( 2.9 % ; not significant ) . Moderate bleeding was seen in 3 of 285 patients ( 1.1 % ) in the aspirin group and in 13 of 932 patients ( 1.4 % ) in the control group ( not significant ) . Major bleeding occurred in only 9 patients , 2 of 285 ( 0.9 % ) in the aspirin group and 7 of 932 ( 0.8 % ) in the control group ( not significant ) . All bleeding was controlled by endoscopic means , and there were no fatalities and no need for blood transfusions . CONCLUSIONS We conclude that the risk of severe bleeding after transbronchial lung biopsy is small ( ie , < 1 % ) and that the use of aspirin is not associated with any increased risk of bleeding [25811287] BACKGROUND The optimal concentration of lignocaine to be used during flexible bronchoscopy ( FB ) remains unknown . This r and omized controlled trial compared the efficacy and safety of 1 % and 2 % lignocaine solution for topical anesthesia during FB . METHODS Consecutive patients were r and omized to receive either 1 % or 2 % lignocaine solution through the bronchoscope by the " spray-as-you-go " technique . The primary outcome of the study was the assessment of cough by the operator and the patient using the visual analog scale ( VAS ) and pain assessment using the faces pain rating scale . The secondary outcomes included total lignocaine dose , oxygenation status , adverse reactions related to lignocaine , and others . RESULTS Five hundred patients were r and omized ( median age , 51 years ; 71 % men ) 1:1 to either group . The median operator VAS score for cough was significantly higher ( 25 vs 21 , P = .015 ) in the 1 % group ; however , the patient VAS score was not significantly different ( 32 vs 27 , P = .065 ) . The pain rating was similar between the two groups . The median cumulative dose of lignocaine was significantly higher in the 2 % group ( 397 mg vs 312 mg , P = .0001 ; 7.1 mg/kg vs 5.7 mg/kg , P = .0001 ) . About 28 % of patients in the 2 % group exceeded the maximum recommended dose ( > 8.2 mg/kg ) of lignocaine . No adverse event related to lignocaine overdose was seen in either group . CONCLUSIONS One percent lignocaine was found to be as effective as 2 % solution for topical anesthesia during FB , albeit at a significantly lower dose as the latter . Thus , 1 % lignocaine should be the preferred concentration for topical anesthesia during FB . TRIAL REGISTRY Clinical Trials.gov ; No. : NCT01955824 ; URL : www . clinical trials.gov [17284894] Background : Coughing is increased during bronchoscopy and may last for several hours after the procedure . Also prior to the procedure patients show high levels of anxiety due to fear of the pain and breathing difficulties that they might experience during the procedure . Objectives : To evaluate the antitussive , anxiolytic and sedative effect of dextromethorphan ( DM ) premedication on the amount of intravenous midazolam during bronchoscopic procedures . Methods : Sixty consecutive patients undergoing scheduled bronchoscopy were r and omly allocated in a double-blind , placebo-controlled study . Half received 90 mg DM and half placebo . Local anesthesia with 2 ml of repeated intratracheal instillation of 1 % lidocaine as needed during bronchoscopy was applied . Midazolam 1 mg ( maximum of 5 mg ) was administered intravenously until a satisfactory sedation was achieved . Results : Heart rate , systolic and diastolic pressure and SpO2 were assessed before and during bronchoscopy . A visual analog score ( VAS ) for pain , cough , communication , cooperation , emotional state , complaints , expectoration , level of information about the procedure , feeling of unpleasantness and stress level assessed before and after the examination by the patient and the physician was used . There were no significant differences in the reported degrees of difficulty in undergoing bronchoscopic procedures . DM patients needed significantly fewer lidocaine instillations and lower midazolam dosage , achieved better analgesia , had lower emotion and complaint scores , significantly less coughing , significantly less stress , were significantly more cooperative , found that the procedure was much less unpleasant than they had expected , and produced less sputum at end of the procedure . Conclusions : DM is an effective bronchoscopic premedication in combination with midazolam and improves the overall well-being of the patients [2392794] Local anaesthesia for fibreoptic bronchoscopy should be given by a safe technique that is not unpleasant to the patient and should provide acceptable conditions for the bronchoscopist . Single injection transcricoid local anaesthesia was compared with the " spray as you go " technique in patients having day case fibreoptic bronchoscopy . Patients were r and omised to receive either 100 mg lignocaine by a single cricothyroid puncture or 240 mg lignocaine instilled through the bronchoscope under direct vision . Further doses were given by the operator to both groups as required . The 30 patients receiving transcricoid lignocaine coughed less ( 3.56 ( SD 3.1 ) coughs/min ) than the 32 patients receiving lignocaine through the bronchoscope ( 5.89 (4.8)/min ) despite receiving a lower total dose of lignocaine ( 322 ( 25.9 ) v 451 ( 20.9 ) mg ) . Cricothyroid puncture was not associated with any complications and was not unpleasant for the patients [18641105] BACKGROUND Fospropofol disodium is a water-soluble prodrug of propofol with unique pharmacokinetic/pharmacodynamic properties . This r and omized , double-blind , multicenter study evaluated the use of fospropofol in patients undergoing flexible bronchoscopy . METHODS Patients > or= 18 years of age were r and omized ( 2:3 ) to receive fospropofol , 2 mg/kg or 6.5 mg/kg , after pretreatment with fentanyl , 50 microg . Supplemental doses of each were given per protocol . The primary end point was sedation success , which was defined as follows : three consecutive Modified Observer 's Assessment of Alertness/Sedation scores of < or= 4 plus procedure completion without alternative sedative medication and /or mechanical ventilation . Other end points included treatment success , patient/physician satisfaction , and safety . RESULTS Of 252 patients , 150 were r and omized to receive 6.5 mg/kg fospropofol ; 102 were r and omized to receive 2 mg/kg fospropofol . Sedation success rates were 88.7 % and 27.5 % , respectively ( p < 0.0001 ) . Treatment successes ( 91.3 % vs 41.2 % , respectively ; p < 0.001 ) , willingness to be treated again ( 94.6 % vs 78.2 % , respectively ; p < 0.001 ) , and absence of procedural recall ( 83.3 % vs 55.4 % , respectively ; p < 0.001 ) were significantly better with the administration of 6.5 mg/kg fospropofol . The median time to full alertness was slightly longer for the 6.5 mg/kg dose ( 5.5 vs 3.0 min , respectively ) . The proportion of patients requiring supplemental therapy with analgesics ( 16.7 % vs 37.3 % , respectively ) and the use of alternative sedative medications ( 8.0 % vs 58.8 % , respectively ) were lower for patients in the 6.5 mg/kg dose group ( all comparisons , p < 0.001 ) . The most frequent adverse events ( AEs ) were transient and self-limited paresthesias and pruritus of mild-to-moderate severity . Hypoxemia ( predominantly mild-to-moderate ) was the most common sedation-related AE , and occurred in 15.4 % and 12.6 % of patients , respectively , in the 6.5 and 2 mg/kg fospropofol dose groups . CONCLUSIONS Fospropofol provided safe and effective sedation for patients undergoing flexible bronchoscopy . TRIAL REGISTRATION Clinical Trials.gov Identifier : NCT00306722 [14769756] STUDY OBJECTIVE To study the diagnostic role of flexible bronchoscopy ( FB ) in immunocompromised patients with pulmonary infiltrates . DESIGN Prospect i ve , observational study . SETTING Tertiary care hospital . PATIENTS A total of 104 consecutive non-HIV-infected immunocompromised patients with lung infiltrates in whom FB was performed . METHODS The primary outcome measure was the diagnostic yield of FB , which was derived as the number of the diagnoses made using FB results divided by all final diagnoses . Final diagnoses were established using data from FB , surgical lung biopsy ( SLB ) , and microbiology and serology testing , and by the clinical response to empiric therapy . We also studied the diagnostic yields of individual sampling procedures such as BAL , transbronchial biopsy ( TBB ) , and protected-specimen brush ( PSB ) sampling . RESULTS Overall , 128 diagnoses were made in 104 patients . The overall diagnostic yield of FB was 56.2 % ( 95 % confidence interval [ CI ] , 47 to 64 % ) . FB provided at least one diagnosis in 53 of 104 patients ( 51 % ; 95 % CI , 40 to 62 % ) . FB was more likely to establish the diagnosis when the lung infiltrate was due to an infectious agent ( 81 % ; 95 % CI , 67 to 90 % ) than to a noninfectious process ( 56 % ; 95 % CI , 43 to 67 % ; p = 0.011 ) . The diagnostic yields of BAL ( 38 % ; 95 % CI , 30 to 47 % ) and TBB ( 38 % ; 95 % CI , 27 to 51 % ) were similar ( p = 0.94 ) . The diagnostic yield of PSB sampling was lower ( 13 % ; 95 % CI 6 to 24 % ; p = 0.001 ) than that of BAL . The combined diagnostic yield of BAL and TBB ( 70 % ; 95 % CI , 57 to 80 % ) was higher than that of BAL alone ( p < 0.001 ) . Finally , the diagnostic yield of FB with PSB sampling , BAL , and TBB was similar to that of FB with BAL and TBB . The complication rate from FB was 21 % ( 95 % CI , 15 to 31 % ) . Minor bleeding ( 13 % ) and pneumothorax ( 4 % ) were the most common complications . CONCLUSIONS FB has a high diagnostic yield in immunocompromised patients with pulmonary infiltrates . Based on our results , we recommend performing TBB in these patients , whenever possible [21852332] Forceps , brushes or needles are currently the st and ard tools used during flexible bronchoscopy when diagnosing endobronchial malignancies . The new biopsy technique of cryobiopsy appears to provide better diagnostic sample s. The aim of this study was to evaluate cryobiopsy over conventional endobronchial sampling . A total of 600 patients in eight centres with suspected endobronchial tumours were included in a prospect i ve , r and omised , single-blinded multicentre study . Patients were r and omised to either sampling using forceps or the cryoprobe . After obtaining biopsy sample s , a blinded histological evaluation was performed . According to the definitive clinical diagnosis , the diagnostic yield for malignancy was evaluated by a Chi-squared test . A total of 593 patients were r and omised , of whom 563 had a final diagnosis of cancer . 281 patients were r and omised to receive endobronchial biopsies using forceps and 282 had biopsies performed using a flexible cryoprobe . A definitive diagnosis was achieved in 85.1 % of patients r and omised to conventional forceps biopsy and 95.0 % of patients who underwent cryobiopsy ( p<0.001 ) . Importantly , there was no difference in the incidence of significant bleeding . Endobronchial cryobiopsy is a safe technique with superior diagnostic yield in comparison with conventional forceps biopsy [16023336] Bronchoalveolar lavage ( BAL ) is a widely used clinical and research tool even though certain steps in the procedure have not been st and arized . One step that is subject to variation is the technique used to instill and recover BAL fluid . Our aim was to assess whether attaching a plastic tube between the syringe and the working channel of the flexible bronchoscope allowed recovery of more fluid in comparison with recovery using only a syringe , and whether tubing had a favorable impact on diagnostic yield and complications . A r and omized multicenter study was performed in eleven public hospitals in Catalonia ( Spain ) . Patients scheduled for BAL were r and omly assigned to tubing ( n=140 ) or no-tubing groups ( n=155 ) . Flexible bronchoscopy and a 150 mL BAL in three 50 mL aliquots with or without tubing attached to the syringe . In the group with tubing , 8 % more fluid was recovered . The difference was both statistically significant and clinical ly relevant given that 17.4 % more diagnoses , 6.9 % fewer complications , and 8.8 % fewer technical failures were recorded . Based on these results , we recommend performing BAL using plastic tubing between the 50 mL syringe and the working channel of the flexible bronchoscope when carrying out manual instillation and suction [9151514] Endobronchial forceps biopsy ( FB ) specimens of lung carcinoma are not uncommonly interpreted as nondiagnostic owing to extensive crush artefact , necrosis , or insufficient tissue . FB can not be performed in some endobronchial lung cancers ( EBLCs ) with massive bleeding tendency due to fragility and friability . Cytological studies from the brushings and washings may also be unproductive , increasing the bronchoscopist 's frustration . The aim of this study was to compare the diagnostic yield and complications of endobronchial needle aspiration ( EBNA ) with those of FB and brush biopsy ( BB ) in EBLCs examined by fibreoptic bronchoscopy . A prospect i ve sequential study was carried out on 151 in- patients with EBLC . Bronchial aspiration ( BA ) , EBNA and BB were performed in the patients with respiratory distress and with accompanying tumours of high bleeding tendency , completely obstructing main bronchi ( Group 1 : 68 patients ) . BA , EBNA and FB were performed in those with either central or peripheral EBLCs but without respiratory distress and /or significant bleeding tendency ( Group 2 : 83 patients ) . In Group 1 , the diagnostic yield of EBNA was found to be 90 % , whereas that of BB was 66 % ( p < 0.05 ) . In the same group , EBNA provided cell types in 95 % , compared with 88 % by BB ( p > 0.05 ) . EBNA was diagnostic in 92 % of Group 2 patients , while FB established diagnosis in 78 % of patients ( p > 0.05 ) . In determining cell type , no significant difference was found between EBNA ( 95 % ) and FB ( 97 % ) ( p > 0.05 ) . Regarding complications ( only bleeding ) , there was no significant difference ( p > 0.05 ) between EBNA ( 7 % ) and BB ( 13 % ) , or between EBNA ( 4 % ) and FB ( 17 % ) . We conclude that in endobronchial lung cancers : 1 ) the diagnostic yield of endobronchial needle aspiration is higher than brush biopsy ; 2 ) endobronchial needle aspiration increases the yield of brush biopsy when forceps biopsy can not be performed owing to significant bleeding ; 3 ) endobronchial needle aspiration increases the diagnostic yield when a forceps biopsy specimen is inadequate because of crush artefact , necrosis , or tissue resistance ; and 4 ) endobronchial needle aspiration is as safe as brush biopsy and forceps biopsy [16924893] BACKGROUND Oxygen desaturation is not uncommon during bronchoscopy . We sought to identify factors predictive of desaturation during flexible bronchoscopy . METHODS Over eight months , we enrolled 137 r and omly selected patients who were undergoing fiberoptic bronchoscopy at our medical center . The patients ' oxygen saturation was monitored on their arrival and during the procedure by finger pulse oximetry . Desaturation was defined as an overall saturation nadir of < 90 % or an episode of decreased saturation of 5 % from the baseline regardless of whether the patient was receiving supplemental oxygen . RESULTS The need for oxygen supplementation before the procedure was predictive of a higher rate of desaturation episodes ( 73.9 % vs. 50 % , p = 0.036 ) . Although all interventional procedures or their complications can cause desaturation , the specific type of procedure was the most important predictor of desaturation ( lavage , 88.9 % ; washing , 43.8 % ; brushing , 15.2 % ; biopsy , 10 % ) . A low peak expiratory flow rate before the procedure seemed to be predictive of a high desaturation rate in patients undergoing lavage or washing during bronchoscopy . CONCLUSION Our study suggested that age , sex and baseline oxygen saturation were not predictors of desaturation . We should be reminded of the possibility of desaturation during every procedure , especially in patients who need supplemental oxygen before bronchoscopy [12628899] STUDY OBJECTIVES To determine whether distraction therapy with nature sights and sounds during flexible bronchoscopy ( FB ) reduces pain and anxiety . DESIGN R and omized controlled trial . SETTING Teaching hospital in Baltimore , MD . PATIENTS Consecutive adult patients ( n = 80 ) undergoing FB with conscious sedation . INTERVENTION Nature scene murals were placed at the bedside , and patients were provided a tape of nature sounds to listen to before , during , and after the procedure . Patients assigned to the control group were not offered either the nature scene or the sounds . MEASUREMENTS AND RESULTS The primary outcomes were patient ratings of pain control ( a 5-point scale ranging from poor to excellent ) and anxiety . In a multivariate ordinal logistic regression model , the odds of better pain control were greater in the intervention patients than in the control patients ( odds ratio [ OR ] , 4.76 ; 95 % confidence interval [ CI ] , 1.35 to 16.7 ) , after adjustment for age , gender , race , education , health status , and dose of narcotic medication . Older patients and patients with better health status reported significantly less pain . There was no difference in patient-reported anxiety between the two groups ( OR , 0.87 ; 95 % CI , 0.39 to 1.96 ) . CONCLUSIONS Distraction therapy with nature sights and sounds significantly reduces pain in patients undergoing FB . Although the precise mechanism of this beneficial effect requires further investigation , clinicians should consider this nonintrusive strategy in addition to st and ard analgesic medications in patients undergoing painful , invasive procedures [24853014] BACKGROUND Newer more advanced techniques in bronchoscopy may require longer procedure times , although a st and ard protocol for sedation during prolonged bronchoscopy has not yet been defined . METHODS We design ed a prospect i ve , non-r and omized , single-arm study ( UMIN trial number 000003971 ) using patient question naires and vital sign monitoring to assess the efficacy and safety of a st and ardized midazolam dosing protocol based on gender and age for use during bronchoscopy . The loading dose of midazolam was 0.075mg/kg for men ≤65 years old and women ≤70 and 0.05mg/kg for men ≥66 years and women ≥71 years , with subsequent doses of one-half the loading dose to be administered every 20min . The primary endpoint was tolerability and secondary endpoints included anxiety and recall of procedure , willingness to undergo repeat procedure , and complications . Safety was evaluated in terms of monitored changes in blood pressures , ECG , oxygen saturation , and CO2 content in expiration during the procedure . RESULTS A total of 204 patients were included in the study . Overall , 163 patients ( 79.9 % ) reported " no distress " during the procedure , 185 patients ( 90.7 % ) reported " no anxiety , " and 175 ( 85.8 % ) replied that they would accept a repeat procedure , if necessary . The mean minimum oxygen saturation was 90.2 % and the mean maximum expiratory CO2 level was 37.7mmHg . There were no serious complications related to the protocol . CONCLUSIONS The midazolam dosing protocol examined in this study was safe and effective . It is simple , and it could easily be translated to routine clinical practice [16162784] OBJECTIVE Topical anesthesia for flexible bronchoscopy can be administered via transcricoid injection , nebulizer , or directly through the bronchoscope in a " spray as you go " fashion . We performed a prospect i ve , r and omized , double-blind , placebo-controlled trial to evaluate whether nebulized lidocaine provides additional benefit and reduces the total anesthetic dose required during bronchoscopy . SETTING Tertiary care university hospital . METHODS One hundred fifty patients ( 93 men ; age , 20 to 89 years ) undergoing diagnostic flexible bronchoscopy were r and omized to receive either 4 mL of 4 % lidocaine ( 160 mg ) or 4 mL of saline solution as placebo via nebulization . Combined sedation was achieved using 5 mg of IV hydrocodone and midazolam boluses . Supplemental lidocaine doses and total midazolam required as judged by the bronchoscopist were recorded for each patient . After the procedure , both bronchoscopists and patients charted their perception of cough on a 10-cm visual analog scale ( VAS ) . Similarly , patients recorded their discomfort related to the procedure on a 10-cm VAS . RESULTS The most common procedures were BAL in 77 cases ( 51 % ) , transbronchial biopsy in 40 cases ( 27 % ) , and transbronchial needle aspiration in 34 cases ( 23 % ) . Outcome parameters , including hemodynamic findings , duration of the procedure , cough scores for physicians and patients , discomfort score for patients , midazolam doses , and supplemental lidocaine doses , were similar in both groups . Mean total lidocaine dose required in the lidocaine group was 318 + /- 41 mg and was significantly higher than the total dose required in the placebo group ( 157 + /- 44 mg [ + /- SD ] ) [ p < 0.001 ] . CONCLUSION Additional nebulized lidocaine can not be recommended for flexible bronchoscopy performed under combined sedation [21870301] BACKGROUND Propofol is a sedative-hypnotic with a rapid onset of action . There are only limited data evaluating propofol for flexible bronchoscopy . We analysed the feasibility and safety of propofol for bronchoscopy in a high output tertiary care centre . METHODS Prospect i ve data on patients undergoing flexible bronchoscopy at the University Hospital Basel , Switzerl and , were analysed . Patient demographics , ASA class , Mallampati class , indication for bronchoscopy , bronchoscopic procedures , duration of examination , medication requirements , minor and major adverse events , haemodynamic parameters , as well as cough scores during the procedure were documented . Patients were followed up to discharge from the bronchoscopy suite . RESULTS Data from 440 patients with a mean age 60 years ( ±15.5 , 260 male ) were analysed . The main indication for bronchoscopy was a suspicion of malignancy . The most common diagnostic procedures were bronchoalveolar lavage in 253 cases ( 31.5 % ) and bronchial washing in 174 cases ( 21.7 % ) . The mean duration of the procedure was 19.6 min ( ±12.08 ) . The mean propofol dose was 200 mg ( ±107.5 ) corresponding to 2.89 mg/kg ( ±1.70 ) . Minor adverse events included oxygen desaturation in 72 ( 16.4 % ) , hypotension in 68 ( 15.4 % ) and minor bleeding in 11 ( 2.5 % ) patients . No major adverse events were recorded . The median decline in systolic blood pressure after initiation of sedation was 14 mm Hg ( 3 - 28 ) . A drop in systolic blood pressure greater than 20 mm Hg was observed in 166 of the 440 patients ( 37 % ) . CONCLUSION Propofol sedation for flexible bronchoscopy is feasible and safe [1426224] We compared the efficacy of nebulized ( N ) and sprayed ( S ) topical anaesthesia prior to fibreoptic bronchoscopy in a blinded study involving 54 patients aged 57 + /- 26 yrs ( mean + /- SD ) . Cough frequency , recorded on cassette tape , was the index of efficacy . All patients received 100 mg lignocaine sprayed into the pharynx , or nebulized in r and om order prior to bronchoscopy , and all received intravenous diazepam sedation . Each patient received a further 100 mg of lignocaine solution through the bronchoscope onto the vocal cords and major airways during the procedure . No significant difference was found in overall cough frequency between N and S groups ( 8.7 + /- 6.9 coughs.min-1 N vs 10.5 + /- 6.0 S ) , and cough frequency was also similar between N and S during the periods above and below the vocal cords . Furthermore , no differences were found in cough frequency between N and S among smokers , patients with asthma and COPD , and patients who had a biopsy procedure , although a trend was seen in all comparisons towards a lower cough frequency with the nebulized route . Most patients in the S group found the spray unpleasant , whereas only one in the N group complained . We conclude that nebulized and sprayed lignocaine have similar efficacy as topical anaesthetics in fibreoptic bronchoscopy , but patient preference favours the nebulized route [23900984] Propofol has been established as a reliable method for sedation in flexible bronchoscopy . There are no data comparing propofol administered as intravenous boluses versus continuous infusion . 702 consecutive patients undergoing flexible bronchoscopy were r and omly allocated to receive intravenous propofol using either an intermittent bolus technique or a continuous infusion . The primary end-point was the number of adverse events assessed at the end of flexible bronchoscopy and at 24 h. The number of any adverse event was similar in both r and omised groups ( 219 versus 211 , p=0.810 ) . There were complications in eight cases ( seven major bleedings , one respiratory failure ) . As compared with the bolus group , the amount of propofol required was significantly higher in the infusion group ( 226 ±147 mg versus 308±204.8 mg , p<0.0001 ) . In a multivariate regression model , this difference remained significant independent of the duration and the interventions performed during the procedure . The duration of bronchoscopy was significantly longer in the infusion group ( median 14 ( interquartile range 9–24 ) versus 17 ( 12–27 ) min , p<0.0001 ) . Propofol continuous infusion is as safe as bolus administration ; however , it is associated with higher propofol requirements and a longer duration of the bronchoscopy . Propofol continuous infusion is as safe as bolus administration , but has higher requirements and longer bronchoscopy [3223212] Objectives There are safety issues associated with propofol use for flexible bronchoscopy ( FB ) . The bispectral index ( BIS ) correlates well with the level of consciousness . The aim of this study was to show that BIS-guided propofol infusion is safe and may provide better sedation , benefiting the patients and bronchoscopists . Methods After administering alfentanil bolus , 500 patients were r and omized to either propofol infusion titrated to a BIS level of 65 - 75 ( study group ) or incremental midazolam bolus based on clinical judgment to achieve moderate sedation . The primary endpoint was safety , while the secondary endpoints were recovery time , patient tolerance , and cooperation . Results The proportion of patients with hypoxemia or hypotensive events were not different in the 2 groups ( study vs. control groups : 39.9 % vs. 35.7 % , p = 0.340 ; 7.4 % vs. 4.4 % , p = 0.159 , respectively ) . The mean lowest blood pressure was lower in the study group . Logistic regression revealed male gender , higher American Society of Anesthesiologists physical status , and electrocautery were associated with hypoxemia , whereas lower propofol dose for induction was associated with hypotension in the study group . The study group had better global tolerance ( p<0.001 ) , less procedural interference by movement or cough ( 13.6 % vs. 36.1 % , p<0.001 ; 30.0 % vs. 44.2 % , p = 0.001 , respectively ) , and shorter time to orientation and ambulation ( 11.7±10.2 min vs. 29.7±26.8 min , p<0.001 ; 30.0±18.2 min vs. 55.7±40.6 min , p<0.001 , respectively ) compared to the control group . Conclusions BIS-guided propofol infusion combined with alfentanil for FB sedation provides excellent patient tolerance , with fast recovery and less procedure interference . Trial Registration Clinical Trials . gov [8882070] BACKGROUND : Concerns remain about the safety of bronchoscopy in asthma and there are few data on the effect of this procedure on asthma control in the days or weeks following bronchoscopy . METHODS : In an initial study of bronchoalveolar lavage and bronchial biopsies in asthmatic and control subjects , data on peak expiratory flow rates ( PEFR ) collected prospect ively before and after the procedure were available from 21 of the 29 asthmatic subjects studied . These showed a median 23 % fall in PEFR from baseline after bronchoscopy ( range 3 - 58 % ) . To determine whether this fall in PEFR following bronchoscopy reflected bronchospasm or the effect of sedation , PEFR and spirometric tests were performed during the two hours following bronchoscopy in a further study of 15 symptomatic asthmatic subjects and 20 non-asthmatic controls . To examine the effect on asthma control , asthmatic patients recorded PEFR , symptom scores , and medication use for two weeks before and after bronchoscopy . RESULTS : After bronchoscopy with bronchial biopsies there was no difference between the median maximal fall in either PEFR or arterial oxygen saturation between the 15 asthmatic patients ( 10.4 % and 4 % , respectively ) and 20 controls ( 12 % and 3 % ) . Moreover , there were no significant changes in PEFR , symptom score , or medication use by the asthmatic subjects in the two weeks after bronchoscopy when compared with the two weeks before bronchoscopy . CONCLUSIONS : Fibreoptic bronchoscopy is well tolerated in asthmatic subjects . Falls in PEFR in both asthmatic and non-asthmatic subjects after bronchial biopsy may reflect the effects of sedation rather than bronchospasm . Additional bronchoalveolar lavage may cause bronchoconstriction . Careful monitoring is therefore essential . Peak flow monitoring up to two weeks after bronchoscopy with bronchial biopsy revealed no delayed effects on asthma control [20980720] Background : Although electrocoagulation at time of endobronchial biopsy can potentially reduce procedure-related bleeding during fiberoptic bronchoscopy ( FOB ) , it can also impair quality of tissue specimen ; credible data for either are lacking . Objective : To evaluate the impact of hot biopsy on the quality of tissue sample s and to quantify the amount of procedure-related bleeding during endobronchial biopsy . Methods : In this single-center , prospect i ve , single-blind , r and omized controlled study we included adult patients referred for FOB and having endobronchial lesions . Patients were r and omized to bronchial biopsy using an electrocoagulation-enabled biopsy forceps , with ( EC+ group ) or without ( EC– group ) application of electrocoagulation current ( 40 W for 10 s in a monopolar mode ) . Procedure-related bleeding was semi-quantified by observer description , as well as through a visual analogue scale . Overall quality of biopsy specimen and tissue damage were assessed and grade d by a pulmonary pathologist blinded to FOB details . Result : 160 patients were r and omized to endobronchial biopsy with ( n = 81 ) or without ( n = 79 ) the application of electrocoagulation . There were no severe bleeding episodes in either group , and severity of bleeding in the EC+ and EC– groups was similar ( median visual analogue scale scores of 14 and 16 , respectively ) . Histopathological diagnosis was similar in the EC+ and EC– groups ( 77.8 % and 82.3 % , respectively ) . There was no significant difference in tissue quality between the two groups . Conclusion : Use of electrocoagulation-enabled endobronchial biopsy does not alter specimen quality and does not result in any significant reduction in procedure-related bleeding [2247670] In a double-blind study of 60 patients undergoing fibreoptic bronchoscopy we have compared the local anaesthetic effects of intratracheal injections of cocaine ( 4 ml , 2.5 % ) and lignocaine ( 4 ml , 4 % ) . The two local anaesthetics were equally effective in terms of cough suppression , requirement for extra local anaesthetic , patient discomfort and operator acceptability [15333854] Background : Current British Thoracic Society guidelines do not recommend routinely the combined use of a benzodiazepine and opiate during flexible bronchoscopy ( FB ) . A r and omised , placebo controlled , double blind study was undertaken to determine whether hydrocodone in combination with midazolan improves cough suppression during FB without increasing the risk of desaturation . Methods : 120 patients were r and omised to receive midazolam and 5 mg IV hydrocodone or midazolam and placebo with topical anaesthesia . Pulse oximetry was recorded continuously during FB . Bronchoscopists and nurses charted their perception of cough and the patients rated their discomfort during the procedure on a 10 cm visual analogue scale ( VAS ) . Results : There was no significant difference between the two groups with regard to the indication for FB , duration of procedure ( 21 ( 11 ) min v 22 ( 10 ) min , p = 0.570 ) , doses of supplemental lignocaine ( 171 ( 60 ) mg v 173 ( 66 ) mg , p = 0.766 ) and midazolam ( 4.5 ( 2.3 ) mg v 4.9 ( 2.7 ) mg , p = 0.309 ) , lowest oxygen saturation ( 94.8 ( 2.7 ) v 94.9 ( 2.7 ) , p = 0.433 ) , and desaturations ⩽90 % . Perception of cough by both the bronchoscopist and the nurse was significantly lower in the hydrocodone group ( 3 ( 0–10 ) and 3 ( 0–10 ) ) than in the placebo group ( 6 ( 0–10 ) and 6 ( 0–10 ) ) , respectively ( p = 0.001 ) . According to the VAS scale , patients ’ tolerance was also significantly better with hydrocodone than with placebo ( 2 ( 0–8 ) v 3 ( 0–9 ) , p = 0.043 ) . Conclusion : The combination of midazolam and hydrocodone markedly reduces cough during FB without causing significant desaturation , especially when invasive diagnostic procedures are performed [19174601] Background : Patients with pulmonary hypertension ( PH ) are considered to be at risk for complications associated with flexible bronchoscopy ( FB ) . Although previous reports suggest that transbronchial biopsies increase the risk for hemorrhage in this population , data are limited to survey analyses and isolated reports . Objectives : It was the aim of this study to describe our experience with FB and to determine if bronchoscopic procedures are associated with adverse events in this population . Methods : We conducted a retrospective review of patients with diagnosis of PH who underwent FB at the Clevel and Clinic between 2002 and 2005 . Patients without PH who underwent FB by the same pulmonary physician were used as controls . Results : A total of 90 patients , PH ( n = 45 ) versus controls ( n = 45 ) , were included . The mean systolic pulmonary artery pressure in patients with PH was 58 ± 7 mm Hg . Patients with PH had higher oxygen requirements at baseline ( FiO2 0.42 vs. 0.3 % ; p = 0.01 ) . The total number of procedures was similar between the groups ( 95 vs. 102 ) . Procedures performed were bronchoalveolar lavage ( 21 vs. 13 ) , transbronchial biopsies ( 24 vs. 32 ) and transbronchial needle aspiration ( 7 vs. 6 ) . There were no hemodynamic complications or episodes of respiratory failure associated with the procedures . None of the patients had significant hemorrhage and only 2 developed mild bleeding which resolved spontaneously . Similarly , none required hospitalization or transfer to an intensive care unit . Conclusions : FB can be performed safely in patients with mild to moderate PH . Transbronchial biopsies are not associated with worsening hypoxemia or an increased risk of hemorrhage . Prospect i ve studies with hemodynamic measurements are necessary to confirm these findings [12117048] The tolerability of 57 non-smoking asthma patients inhaling salbutamol as needed ( ATS , 18 - -60 years , 60 % < or = FEV1 < or = 100 % , PD15FEV1 < 0.4 mg histamine ) to fibreoptic bronchoscopy ( FOB ) and endobronchial biopsy was studied . The FOB was done in local Lignocaine anaesthesia , and from five to eight biopsy specimens were taken from the bronchial mucosa of the right lung . The tolerability was measured as cough/bronchospasm during the procedure ( from 0 = normal to 3 = interrupted procedure ) , success of the procedure , and untoward occurrences . Twenty-seven of the 57 patients ( 48 % ) had no cough or bronchospasm during the FOB ( score 0 ) . Few coughs of no importance ( score 1 ) were documented in 23 patients ( 40 % ) . Seven patients ( 12 % ) had cough and /or bronchospasm interfering with the FOB procedure ( score 2 ) . The FOB procedure was not interrupted because of cough and /or bronchospasm ( score 3 ) in any patient . Scores of cough and /or bronchospasm diminished progressively with the increase of PD15FEV1 histamine . The success of the procedure was 100 % . Two patients had untoward medical occurrences requiring additional rescue medication ( 3.5 % ) . In conclusion , we found that hyperreactivity predicts cough and /or bronchospasm during the FOB . Cough and /or bronchospasm are frequently observed during the bronchial procedure , but they are mild and of minor clinical importance . An investigational endobronchial procedure can be successfully performed in mildly or moderately obstructive asthmatic patients , even in cases with severe bronchial hyperreactivity [15715190] INTRODUCTION Older patients are the most prevalent age cohort requiring bronchoscopy . Prior sedation should be offered to improve patient comfort and operator technical ease . Older patients have increased sensitivity to central ly acting drugs increasing the procedural risk . This perceived risk may limit access to bronchoscopy in older patients . There have been no systematic prospect i ve placebo-controlled studies in older patients . We compared a novel premedication regimen-oral temazepam plus nebulised Lignocaine ( new treatment ) to an established regimen of intravenous alfentanyl ( control ) . METHODS Consecutive patients 75 years and older referred for bronchoscopy were considered . Twenty-five patients were r and omly assigned to each group . The primary outcome measure was the lowest oxygen saturation recorded from the administration of IV drugs and for 30 min post-bronchoscopy . RESULTS The lowest mean oxygen saturation in the new treatment group was 92.2 % ( 90.3 - 94.2 ) and in the control group 91.1 % ( 89.2 - 93.1 ) . This was not statistically different ( P = 0.370 ) . There were no adverse events . CONCLUSION This is the largest prospect i ve study to date on an older population undergoing bronchoscopy supporting previous retrospective findings regarding the safety of this procedure . Determined by oxygen saturations there is no difference in safety between premedication regimens comprising oral temazepam/nebulised lignocaine or intravenous alfentanyl [1657538] To further improve the diagnostic value of bronchoscopy in the immunosuppressed population presenting with diffuse pulmonary infiltrates , we prospect ively investigated the utility of bilateral bronchoalveolar lavage ( BAL ) . We performed 62 bronchoscopies on 52 immunosuppressed patients . Of the 52 patients , 33 had pulmonary infections . The yield for Pneumocystis carinii pneumonia on bilateral BAL was 94 percent ( 31/33 ) , compared to the 84 percent ( 51/61 ) previously obtained with unilateral BAL in our institution . The recovery of P carinii was unilateral in four of five patients without AIDS and in four of 26 patients with AIDS . Transbronchial biopsy gave a yield of 85 percent ( 11/13 ) . In ten patients with definitive cytomegalovirus ( CMV ) pneumonia , recovery of CMV by combined culture and cytology was 100 percent . Of nine bronchoscopies with positive cytology for CMV , five showed cytopathologic changes in the BAL from both sides and four in the BAL from one side only . No complications were seen in the 14 patients with thrombocytopenia or the five patients receiving mechanical ventilation . Our findings indicate that bilateral BAL significantly increases the yield for recovery of P carinii ( p less than 0.02 ) and CMV ( p less than 0.001 ) in immunosuppressed patients [11578889] STUDY OBJECTIVE To determine the optimal solution to use when anesthetizing the airway by aspiration of lidocaine . DESIGN R and omized , double-blind clinical study . SETTING University hospital . PATIENTS 96 adult ASA physical status 1,II , and III patients , scheduled for diagnostic flexible bronchoscopy . INTERVENTIONS Patients were r and omized to receive one of 5 solutions of lidocaine : Group A ( n = 16 ) : 1 % lidocaine , 0.2 mL. kg(-1 ) ; Group B ( n = 16 ) : 1.5 % 0.2 mL. kg(-1 ) ; Group C ( n = 32 ) : 2 % 0.2 mL. kg(-1 ) ; Group D ( n = 16 ) : 1 % 0.3 mL. kg(-1 ) , and Group E ( n = 16 ) : 2 % 0.3 mL. kg(-1 ) . Fiberoptic bronchoscopy was performed after the airway was anesthetized with this aspiration technique , using the assigned lidocaine solution . The scope was manipulated in the trachea to test for anesthesia . MEASUREMENTS AND MAIN RESULTS Successful airway anesthesia was determined by tolerance to bronchoscopy without sustained coughing , and also by the number of lidocaine supplements , if any , that were given via the bronchoscope . Arterial plasma concentrations of lidocaine were measured in 33 patients from Groups C , D , and E. All solutions provided equally effective anesthesia of the airway . All patients tolerated endoscopy through the vocal cords , and 94 patients required no supplementary anesthesia , or only one dose of lidocaine , during bronchoscopy to the carina . The highest peak plasma concentrations of lidocaine were 5.02 and 6.28 microg . mL. No patient had signs of toxicity . CONCLUSIONS This technique produced anesthesia of the airway to the carina , safely , suitable for awake intubation , in 94 of 95 patients . The use of 1 % lidocaine , 0.2 to 0.3 mL. kg(-1 ) , so that the volume is 10 to 20 mL , is recommended [8266157] Lignocaine spray for anaesthetising the nasal mucosa for fibreoptic bronchoscopy often causes discomfort to the patient . We compared two techniques of applying nasal topical anaesthesia using either lignocaine spray ( group A : 25 patients ) or gel ( group B : 30 patients ) to assess patients ' tolerance to the procedure . Both groups received 100 mg of lignocaine in the nostril , 40 - 50 mg to oropharynx , 120 mg to vocal cords and 40 - 100 mg to trachea and bronchi . Throat anaesthesia was the most common unpleasant part experienced by both groups of patients ( 34.5 % ) , followed by examination of bronchi ( 30.6 % ) and nasal anaesthesia ( 21.8 % ) . Significantly more patients in group A experienced discomfort or pain during nasal anaesthesia as compared to group B ( p < 0.001 ) . Patients ' tolerance to the bronchoscopy was similar in both groups and the examination was performed satisfactorily in all patients . Thus , lignocaine gel is a simple technique , effective and less irritating as compared to lignocaine spray for topical nasal anaesthesia [22174346] BACKGROUND The safety profiles and efficacies of remifentanil and dexmedetomidine ( a sedative-analgesic without respiratory depression ) for sedation during flexible bronchoscopy were investigated . METHODS Seventy-two patients undergoing elective flexible bronchoscopy were r and omly assigned to a propofol-remifentanil group ( Group PR , n=36 ) or a propofol-dexmedetomidine group ( Group PD , n=36 ) . The primary outcome was the incidence of oxygen desaturation . Haemodynamic variables , adverse events , need of oral cavity suction , cough scores , satisfaction scores of patients and bronchoscopists , levels of sedation , and recovery times were also compared . RESULTS The incidence of oxygen desaturation was significantly lower in the PD group than in the PR group ( P=0.01 ) . There were no significant differences between groups in terms of level of sedation , oxygen saturation , mean arterial pressure , heart rate over time , cough scores , or patient satisfaction scores ( P>0.05 ) . However , cough scores and bronchoscopist satisfaction scores ( P<0.01 ) were lower in the PD group . In addition , topical anaesthesia ( P<0.01 ) was required more frequently and recovery time ( P=0.00 ) was significantly longer in the PD group . However , oral suction ( P=0.03 ) was required less frequently in the PD group . CONCLUSIONS Dexmedetomidine was associated with fewer incidents of oxygen desaturation and a reduced need for oral cavity suction than remifentanil during flexible bronchoscopy . However , dexmedetomidine was associated with a longer recovery time and poorer bronchoscopist satisfaction score [20492004] BACKGROUND Flexible fibre-optic bronchoscopy has become an essential investigation and is widely regarded as safe , but wider published prospect i ve data regarding delayed complications are limited . There is continuing debate concerning the safety of proceduralist-administered sedation . We evaluated complication rates of bronchoscopy and proceduralist-administered sedation at our tertiary institution , and their clinical significance . METHODS Prospect i ve evaluation of all patients undergoing bronchoscopy over a 12-month period at a tertiary referral centre . Immediate minor and major complications were documented within 4 h of bronchoscopy , delayed complications at 48 h , case notes and bronchoscopy records were review ed 1 month later . RESULTS Five hundred and fifty-eight flexible fibre-optic bronchoscopies were performed , 216 with transbronchial biopsy or nodal aspiration , 19 had therapeutic airways intervention . The minor complication rate at 4 h was 4.12 % ( 23 ) , rising to 26 % ( 145 ) at 48 h. All 2.2 % ( 12 ) major complications occurred exclusively within 4 h of bronchoscopy . No complications could be attributed to proceduralist-administered sedation . DISCUSSION Complication rates at 4 h were comparable with previously reported data . Delayed minor complications were greater than expected , and did not require additional medical input . There were no complications from proceduralist-administered sedation . Flexible fibre-optic bronchoscopy and proceduralist-administered sedation within our institution 's guidelines are safe [16696751] OBJECTIVES To assess the frequency of fever and pneumonia after fiberoptic bronchoscopy ( FOB ) in older people and to evaluate increased risk for these two adverse events with increasing age . DESIGN Prospect i ve study . SETTING University hospital system . PARTICIPANTS Three hundred fifty-eight patients , with 165 ( 46.1 % ) patients aged 70 and older , undergoing bronchoscopy . MEASUREMENTS Indications , abnormal bronchoscopic findings , sampling procedures , final diagnosis , and fever and pneumonia after bronchoscopy . RESULTS With regard to the indication for bronchoscopy and abnormal bronchoscopic findings , there was no statistical difference between elderly patients ( > or = 70 ) and younger patients ( < 70 ) . Procedures such as forceps biopsy , brushing , and curetting were not performed more often in elderly patients , although final diagnosis of lung cancer was significantly more common in the elderly group ( P=.002 ) . The overall incidence of fever after FOB was 6.7 % , and that of pneumonia after FOB was 5.6 % . The patients aged 70 and older had an incidence of fever after FOB of 3.6 % and an incidence of pneumonia of 4.2 % , which were not higher than those in patients younger than 70 . CONCLUSION Increasing age is not associated with increasing fever and pneumonia after FOB , and chronological age should not be considered a limiting factor in the decision of whether to perform FOB when it is clinical ly indicated [21310875] Propofol and the combination of a benzodiazepine and an opiate have been established for sedation in flexible bronchoscopy . It is as yet unknown whether propofol in combination with an opiate is superior to propofol alone to suppress cough during the procedure . 300 consecutive patients undergoing flexible bronchoscopy at a tertiary care university hospital were r and omly allocated to receive either the combination propofol and hydrocodone or propofol alone in a double-blind fashion . The primary end-point was the cough score during the procedure as estimated by the physician using a visual analogue scale . Demographics were similar in both groups . Compared with propofol alone , median ( interquartile range ) cough scores assessed by physicians , nurses and patients were significantly lower in the group r and omised to the combination propofol and hydrocodone ( 2.5 ( 1.5–4.0 ) versus 2.0 ( 1.0–3.0 ) , respectively , p=0.011 ) . Additionally , patients receiving the combination required significantly lower doses of propofol than those receiving propofol alone ( 200 mg ( 140–280 ) versus 260 mg ( 180–350 ) , p<0.0001 ) . Complex examinations , including bronchoalveolar lavage or transbronchial biopsy , benefited more from additional opiate . The duration of the procedure , time to discharge and complication rate were similar in both groups . The combination of propofol and hydrocodone is safe and superior to propofol alone for cough suppression in flexible bronchoscopy [7708981] Most current sedative regimens for fibre optic bronchoscopy use an opioid , a benzodiazepine or a combination of both . This study compares midazolam ( M ) ( a benzodiazepine ) , alfentanil ( A ) ( an opioid ) and a combination of both drugs ( M+A ) . One hundred and three patients were r and omized in double-blind manner into groups M(35 ) , A(33 ) and M+A(35 ) . The number of coughs , number of additional aliquots of lignocaine and duration of the procedures were recorded along with oxygen desaturation . The patient 's level of discomfort was assessed by patient and bronchoscopist and expressed as a visual analogue score . There were significantly fewer coughs per minute in Group A compared with Group M ( P = 0.0053 ) , and significantly less lignocaine was required in Group A ( P = 0.005 ) and in Groups M+A ( P < 0.002 ) compared with Group M. There was no significant difference in the assessment of discomfort between the groups . There was a trend for Group M+A to desaturate more than the other two with a significant difference between desaturation in Group M+A and Group A ( P = 0.033 ) . Alfentanil is a more effective anti-tussive agent than midazolam for outpatient fibre optic bronchoscopy . The combination of alfentanil and midazolam does not provide any better anti-tussive effect and may have the risk of a greater degree of desaturation secondary to increased sedation [10334165] STUDY OBJECTIVE Bronchoscopic technique is not st and ardized . Controversies exist with regard to premedication with sedatives before the test . To evaluate safety and efficacy of conscious sedation , we studied 100 r and omized patients undergoing diagnostic bronchoscopy ; patients received premedication with lidocaine spray and atropine sulfate i.m . ( nonsedation group ; 50 patients ) or lidocaine spray , atropine i.m . and diazepam i.v . ( sedation group ; 50 patients ) . METHODS AND RESULTS Monitoring during flexible fiberoptic bronchoscopy included continuous ECG and pulse oximetry . The procedure could not be completed in six patients . None received premedication with diazepam ; among the patients who ended the examination , tolerance to the examination ( visual analogue scale , 0 to 100 ; 0 = excellent ; 100 = unbearable ) was better in the sedation group . Low anxiety , male sex , but not age were also associated with improved patient tolerance to the test . Oxygen desaturation occurred in 17 % of patients , and it was not more frequent after diazepam treatment . CONCLUSIONS In our study , sedation had a beneficial effect on patient tolerance and rarely induced significant alterations in cardiorespiratory monitoring parameters [9596324] OBJECTIVE Atropine premedication is widely used for fiberoptic bronchoscopy and may help by drying secretions , producing bronchodilatation , or preventing vasovagal reactions . The objective of this study was to see whether atropine premedication is really of practical benefit when patients are se date d with i.v . midazolam . DESIGN In a double-blind study , patients were r and omly allocated to receive i.m . atropine ( 0.6 mg ) or saline placebo ( 1 mL ) as premedication 30 to 60 minutes before they were se date d with progressive doses of i.v . midazolam until judged to be lightly asleep . SETTING A District General Hospital in Engl and . PARTICIPANTS One hundred consecutive patients referred for bronchoscopy . MEASUREMENTS AND RESULTS Sample s taken during the procedure were washings for microbiology and cytology and brushings for cytology and biopsy , but no transbronchial biopsies . Peak flow readings were recorded before premedication and before the start of the procedure . During the procedure an estimate was made of pharyngeal and tracheobronchial secretions , bleeding , use of saline to wash out secretions , and local anesthetic needed to control coughing . Patients were monitored for saturation and cardiac rhythm . There was no significant bronchodilatation after premedication in either group , nor were there differences in secretions , use of saline , tracheobronchial bleeding , desaturation , and arrhythmias . More local anesthetic was needed to control coughing in the placebo group ( mean 357 mg vs 331 mg in the atropine group , p=0.02 ) , but this was not of practical significance . CONCLUSION When intravenous midazolam sedation is used for bronchoscopy , atropine premedication is not of benefit [1479636] A prospect i ve study was performed to detect oxygen saturation ( SaO2 ) during and following fiberoptic bronchoscopy ( FOB ) in 50 patients . Twenty-five patients ( group 1 ) underwent the procedure without and 25 ( group 2 ) with supplemental oxygen . The SaO2 declined from the baseline value of 96.4 % to 92.08 % in group 1 and to 94.88 % in group 2 after bronchoscopy alone . The decline was also noted when biopsy and broncho-alveolar lavage ( BAL ) were performed , the lowest values being recorded during BAL . The result showed that the fall in SaO2 in group 2 was significantly less than that in group 1 ( P < 0.05 ) . SaO2 returned to baseline values after a mean time of 4.9 minutes in group 1 and 2.4 minutes in group 2 , demonstrating the benefit of supplemental oxygen [18971092] BACKGROUND Long-term survival of lung transplant ( LT ) recipients is limited by the development of the bronchiolitis obliterans syndrome ( BOS ) . A number of risk factors for BOS have been identified , which can be detected using bronchoscopy with transbronchial biopsy ( TBB ) . Many LT units perform routine surveillance bronchoscopy ( SB ) to detect problems such as : acute rejection ( AR ) ; infection , particularly with cytomegalovirus ( CMV ) ; and lymphocytic bronchiolitis . This study aim ed to assess the safety and efficacy of surveillance bronchoscopy in lung transplant recipients ( LTRs ) , including TBB and bronchoalveolar lavage ( BAL ) . METHODS All bronchoscopy procedures , including SB and clinical ly indicated ( CB ) procedures performed on LTRs in one calendar year , were audited prospect ively . Complications and clinical utility were recorded to determine the clinical utility both early ( 3 months and 3 to 12 months ) and late ( > 12 months ) post-LT . RESULTS In one calendar year , 353 procedures ( 232 SBs and 121 CBs ) were performed on 124 LTRs , with 246 performed < 1 year post-LT . The complication rates were similar to those reported previously , except for an increased rate of sedation-related complications , particularly up to 3 months post-LT . SBs showed high rates of acute rejection , particularly in the first year post-LT ( p = 0.01 ) . The rate of asymptomatic infection diagnosed on BAL remained high regardless of time post-transplant . CONCLUSIONS This study confirms that SB can frequently detect clinical ly significant infection and rejection with very low complication rates . The data support SB with TBB up to 12 months post-LT , and ongoing use of SB with BAL ( only ) to detect clinical ly silent infection beyond 1 year post-LT [2019163] We evaluated nasal anesthesia regimens by comparing , in seven normal men , four drug regimens : 1 ) 1 percent phenylephrine ; 2 ) 4 percent lidocaine ; 3 ) 1 percent phenylephrine + 4 percent lidocaine ; and 4 ) 5 percent cocaine . After spraying each drug into the anterior nares , vasoconstriction , decongestion , and nasal anesthesia ( measured as transnasal depth of nasogastric ( NG ) tube insertion before discomfort ) were assessed . There were no significant differences in NG tube insertion depth between the regimens ( p = 0.54 ) . Insertion depth was significantly increased after 10 ml of 2 percent viscous lidocaine were sniffed ( p less than 0.004 ) , but again , differences between regimens were not significant ( p = 0.051 ) . One hundred bronchoscoped patients received one of the following sprayed into the nose : 1 ) placebo ( P ) ; 2 ) 1 percent phenylephrine + P ; 3 ) 1 percent phenylephrine + 4 percent lidocaine ; or 4 ) 5 percent cocaine + P. Each patient then sniffed viscous lidocaine . There were no significant differences between regimens for any of the following : 1 ) nasal resistance to bronchoscope insertion , 2 ) patient 's nasal discomfort , or 3 ) bronchoscopist 's perception of patient discomfort . We conclude that sprayed anesthetics contribute little to nasal anesthesia and any regimen appears acceptable when viscous lidocaine is used [1147384] The frequencies of fever , parenchymal infiltration , and bacteremia were studied prospect ively after 100 flexible fiberoptic bronchoscopies performed transnasally under topical anesthesia . Fever occurred after 16 per cent , and parenchymal infiltration , after 6 per cent of the procedures . Most complications were mild and transient ; however , one patient developed rapidly progressive pneumonia and died . No organisms were isolated from cultures of blood drawn at the time of the procedure or during complications . The organisms most commonly isolated from the sputum of the patients who developed pneumonia were the aerobic and anaerobic bacteria normally found in the mouth . Isolation of a significant pathogen before the procedure did not predispose to development of a complication . Advanced age ( greater than 60 years ) and the endoscopic findings of abnormalities were significant predisposing factors . Bronchial brushing , but not bronchial biopsy or bronchial washing , was associated with significantly higher complication rates in patients with bronchial carcinomas than in those without a neoplasm . The mechanism of the fever and parenchymal infiltration is thought to be related to obstructive atelectasis and infection produced by organisms present in the airways at the time of the procedures [10027438] STUDY OBJECTIVE To determine whether recipients of lung transplants have a higher risk of bleeding from fiberoptic bronchoscopy ( FOB ) than other patients who undergo the procedure . DESIGN Prospect i ve cohort study . SETTING Bronchoscopy services of Johns Hopkins Hospital , a tertiary referral center and Johns Hopkins Bayview Medical Center , a community hospital . PATIENTS All adult patients ( 18 years ) who underwent FOB between July 1 , 1996 and June 30 , 1997 by the full-time pulmonary medicine staff were included . A total of 720 procedures were performed , including 38 in lung transplant recipients . MEASUREMENTS Bleeding was assessed by review ing physician reports of bloody drainage after the procedure and whether the procedure was terminated early for bleeding . Patient reports of hemoptysis were assessed using question naires administered pre- and post-FOB . Predictor variables included patient demographics , bleeding parameters ( platelets , prothrombin time , and activated partial thromboplastin time ) , immunosuppressive medications , aspirin use , use of transbronchial biopsy , and the time length of the procedure . RESULTS Lung transplant recipients were significantly more likely to have used aspirin prior to FOB ( 18.4 vs 7.2 % , p < 0.05 ) and to undergo transbronchial biopsy ( 64.9 vs 26.8 % , p < 0.001 ) . Lung transplant patients were more likely to have new or worsened hemoptysis ( 53.8 vs 24.6 % , p < 0.001 ) , to have > 25 mL of blood loss ( 44.5 vs 17.5 % , p < 0.001 ) and to have the procedure terminated early for bleeding ( 5.4 vs 1.0 % , p < 0.05 ) . In multivariate analysis , predictors of new or worsened hemoptysis included lung transplant , longer procedure time , and older patient age . Independent predictors of greater blood loss included lung transplant , performance of transbronchial biopsy , longer procedure time , and older patient age . CONCLUSIONS Lung transplant recipients are at higher risk of bleeding from bronchoscopy than are other patients . This propensity to bleed is independent of coagulation parameters , platelet count , immunosuppressive medication use , aspirin use , or performance of transbronchial biopsy . The higher risk of bleeding should be considered when assessing the risks and benefits of bronchoscopy in lung transplant recipients [23455477] INTRODUCTION Pulmonary infiltrates are common within the hematopoietic stem cell transplant ( HSCT ) population and unfortunately portend an increased mortality . Bronchoscopy is often utilized as an initial diagnostic tool , but the literature supporting its diagnostic utility and effect on clinical management varies significantly . The aim of this study was to investigate the diagnostic ability , complication rate , and clinical impact of flexible bronchoscopy ( FB ) in evaluating pulmonary infiltrates in a large HSCT population . PATIENTS AND METHOD Retrospective review of all patients undergoing FB after HSCT in the Bone Marrow Transplant Unit from 1996 to 2009 . RESULTS FB was performed 162times in 144 patients with pulmonary infiltrates yielding positive results in 52.5 % . The most common positive results were bacterial pneumonia ( 31 % ) , fungal pneumonia ( 15 % ) , and alveolar hemorrhage ( 11 % ) . Treatment changes occurred in 44 % of patients after FB . Treatment changes included antibiotic modification ( 59 % ) , addition of corticosteroids ( 21 % ) , antifungal modification ( 12 % ) , and antiviral modification ( 7 % ) . The overall complication rate associated with FB was 30 % , although 84 % of these complications were considered minor . CONCLUSIONS FB in patients with pulmonary infiltrates after HSCT should still be considered a valuable tool in the evaluation and management of pulmonary infiltrates in the HSCT population . Future prospect i ve , multicenter r and omized studies are needed to evaluate the overall clinical impact that bronchoscopic results and management changes have in this unique population [25686147] SETTING Diagnostic flexible bronchoscopy performed in hospitalised and ambulatory patients in a tertiary care academic hospital in Monterrey , Mexico . OBJECTIVE To determine the effect of the route of insertion of the bronchoscope ( oral or nasal ) on patient comfort , vocal cord visualisation , local anaesthetic and sedation requirements and possible complications . DESIGN Prospect i ve study carried out in patients aged ⩾ 18 years with an indication for flexible bronchoscopy . The route of insertion was r and omly assigned . Symptoms related to the procedure were evaluated using a question naire . RESULTS Sixty-three patients were included : 32 in the oral insertion group and 31 in the nasal insertion group . There was no statistically significant difference in patient discomfort ( 1.91 ± 2.95 vs. 2.39 ± 3.56 points on a scale of 1 to 10 , P = 0.74 ) or procedural complications ( 4 vs. 0 events , P = 0.12 ) between study groups . Oral insertion was associated with less time to vocal cord visualisation ( 25.5 ± 156 s vs. 56 ± 61 s , P < 0.01 ) , lower requirement for lidocaine ( 15 ± 7.50 vs. 16 ± 4 ml , P = 0.01 ) and fewer insertion failures ( 0 vs. 6 cases , P < 0.01 ) . CONCLUSIONS With intravenous sedoanalgesia , route of insertion did not affect patient comfort . However , the oral route was associated with faster vocal cord visualisation , less use of lidocaine and no insertion failure [21058940] Background : Propofol is an excellent sedative agent for use in patients undergoing bronchoscopy . The addition of an opioid to propofol can be advantageous because of the antitussive effect of the opioid and the possible improvement in sedation quality . However , it may increase the risk of hypoxaemia . To investigate the effect of the addition of alfentanil to propofol , we performed a prospect i ve study to compare propofol‐only sedation with propofol – alfentanil combination sedation in patients undergoing bronchoscopy

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### Context: [23780458] IMPORTANCE Tissue verification of noncaseating granulomas is recommended for the diagnosis of sarcoidosis . Bronchoscopy with transbronchial lung biopsies , the current diagnostic st and ard , has moderate sensitivity in assessing granulomas . Endosonography with intrathoracic nodal aspiration appears to be a promising diagnostic technique . OBJECTIVE To evaluate the diagnostic yield of bronchoscopy vs endosonography in the diagnosis of stage I/II sarcoidosis . DESIGN , SETTING , AND PATIENTS R and omized clinical multicenter trial ( 14 centers in 6 countries ) between March 2009 and November 2011 of 304 consecutive patients with suspected pulmonary sarcoidosis ( stage I/II ) in whom tissue confirmation of noncaseating granulomas was indicated . INTERVENTIONS Either bronchoscopy with transbronchial and endobronchial lung biopsies or endosonography ( esophageal or endobronchial ultrasonography ) with aspiration of intrathoracic lymph nodes . All patients also underwent bronchoalveolar lavage . MAIN OUTCOMES AND MEASURES The primary outcome was the diagnostic yield for detecting noncaseating granulomas in patients with a final diagnosis of sarcoidosis . The diagnosis was based on final clinical judgment by the treating physician , according to all available information ( including findings from initial bronchoscopy or endosonography ) . Secondary outcomes were the complication rate in both groups and sensitivity and specificity of bronchoalveolar lavage in the diagnosis of sarcoidosis . RESULTS A total of 149 patients were r and omized to bronchoscopy and 155 to endosonography . Significantly more granulomas were detected at endosonography vs bronchoscopy ( 114 vs 72 patients ; 74 % vs 48 % ; P < .001 ) . Diagnostic yield to detect granulomas for endosonography was 80 % ( 95 % CI , 73%-86 % ) ; for bronchoscopy , 53 % ( 95 % CI , 45%-61 % ) ( P < .001 ) . Two serious adverse events occurred in the bronchoscopy group and 1 in the endosonography group ; all patients recovered completely . Sensitivity of the bronchoalveolar lavage for sarcoidosis based on CD4/CD8 ratio was 54 % ( 95 % CI , 46%-62 % ) for flow cytometry and 24 % ( 95 % CI , 16%-34 % ) for cytospin analysis . CONCLUSION AND RELEVANCE Among patients with suspected stage I/II pulmonary sarcoidosis undergoing tissue confirmation , the use of endosonographic nodal aspiration compared with bronchoscopic biopsy result ed in greater diagnostic yield . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00872612 [1516390] A patient 's tolerance of fiberoptic bronchoscopy depends on the effectiveness of local anesthesia . This study compares the three different methods of local anesthesia in common use After sedation , patients ( n = 53 ) received either 4 ml of 2.5 percent cocaine by intratracheal injection ( TI ) ( n = 18 ) , by bronchoscopic injection ( BI ) ( n = 19 ) , or had 4 ml of 4 percent lidocaine delivered by nebulizer 20 min before the procedure ( NEB ) ( n = 16 ) . Patients and bronchoscopists scored the procedure using visual analog ( VAS ) and severity scales . Objective measurements of cough counts and episodes of stridor were recorded by phonopneumography . Patients ' VAS scores showed a clear preference for the transtracheal method compared with either bronchoscopically injected cocaine ( p less than 0.001 ) or nebulized lidocaine ( p less than 0.001 ) . Patients also reported that the TI method produced less cough during intubation of the larynx and inspection of the airways ( BI and NEB , p less than 0.01 ) . The TI method was also preferred by the bronchoscopists ( BI and NEB , p less than 0.001 ) ; they reported less cough and easier tracheal intubation . The mean cough count was significantly lower for the TI group , 49 ( 43 ) compared with 95 ( 52 ) for BI ( p less than 0.01 ) , and 81 ( 43 ) for the NEB group ( p less than 0.05 ) . Patients ' and bronchoscopists ' VAS showed significant correlation with cough ( r = 0.63 - 69 , p less than 0.01 ) . Stridor occurred in only two patients after TI , compared with 15 in the other two groups . Extra local anesthesia was required by 16 patients after BI , by all the NEB group , but by only one patient after TI . Subjective and objective measurement shows that 4 ml of 2.5 percent cocaine injected into the trachea produced excellent local anesthesia for fiberoptic bronchoscopy , there were no extra complications , and it was the method preferred by both patients and bronchoscopists [15786902] OBJECTIVE The route of bronchoscope insertion varies between centres , without a firm rationale based on well- design ed studies . We therefore compared nasal and oral insertion of a flexible bronchoscope and evaluated efficacy and patient satisfaction . DESIGN Prospect i ve r and omised study of patients who underwent flexible bronchoscopy from May to September 2003 and who were r and omly assigned to nasal and oral insertion approaches . RESULTS Clinical characteristics , factors related to the procedure and patient satisfaction were analysed . In total , 307 patients were r and omly assigned to the nasal ( n = 158 ) or oral insertion groups ( n = 149 ) . No difference in baseline characteristics was identified between the groups . Insertion by the oral route was associated with a smaller amount of lidocaine use during the procedure ( P = 0.04 ) and less frequent insertion site bleeding ( P = 0.005 ) . Patients assigned to oral insertion reported less discomfort during anaesthesia ( P = 0.01 ) and scope insertion ( P < 0.001 ) , as well as less dyspnoea ( P = 0.04 ) and coughing ( P = 0.03 ) . CONCLUSION Oral insertion of a flexible bronchoscope was associated with less discomfort for patients than nasal insertion , although the route of insertion had no significant effect on outcome [20804674] BACKGROUND Conscious sedation for patients undergoing flexible bronchoscopy ( FB ) is suggested to alleviate discomfort and improve satisfaction despite controversy regarding its benefits . In Taiwan , the general FB practice involves local anesthesia only . This study aim ed to assess the benefits and risks of conscious sedation in diagnostic FB . METHODS This prospect i ve case control study enrolled 44 non-se date d and 44 se date d patients who underwent diagnostic FB . All received the st and ard upper airway preparation , while se date d patients received clinical ly judged increments of midazolam and alfentanil for conscious sedation . Patient discomforts and the operator 's opinions during FB were assessed using the verbal analogue score ( VAS , 0 - 10 scale ) . Willingness to return was assessed as five scales to monitor patient satisfaction . Safety profiles throughout the procedures were also assessed . RESULTS Compared to non-se date d patients , se date d ones expressed less discomfort , with lower VAS scores regarding scope insertion ( 3.5 [ 0 - 10 ] vs. 0 [ 0 - 5 ] , p < 0.001 ) , cough ( 5 [ 0 - 10 ] vs. 0 [ 0 - 5 ] , p < 0.001 ) , dyspnea ( 3 [ 0 - 10 ] vs. 0 [ 0 - 8 ] , p < 0.001 ) , pain ( 3 [ 0 - 10 ] vs. 0 [ 0 - 5 ] , p < 0.001 ) , and global tolerance of the procedures ( 5 [ 1 - 10 ] vs. 0 [ 0 - 9 ] , p < 0.001 ) . More se date d patients expressed willingness to return ( 70.5 % vs. 36.4 % , p = 0.001 ) . The bronchoscopist also rated lower VAS scores on cough and dyspnea in se date d patients . Se date d patients had less hypertension but more hypoxemic episodes during the procedure , which were all transient and not life-threatening . CONCLUSIONS Conscious sedation with clinical ly judged midazolam and alfentanil reduces discomforts , improves satisfaction , and carries slight , but manageable , hypoxemia risks in patients undergoing FB [24602973] Background : The clinical benefits associated with the use of the bispectral index ( BIS ) to monitor the depth of sedation during flexible fiberoptic bronchoscopy ( FFB ) are question able . Objectives : To evaluate the added value in terms of procedural safety and patients ' awareness of monitoring sedation depth using the BIS compared to conventional clinical judgment alone in patients undergoing FFB under propofol sedation . Methods : The cohort included 81 patients undergoing diagnostic or therapeutic bronchoscopy under propofol sedation that were prospect ively r and omized to guide the depth of sedation by BIS monitoring ( BIS group ; n = 40 ) or conventional monitoring ( control group ; n = 41 ) . Results : The mean duration s of the procedure were 18 and 19 min in the BIS and control groups , respectively . No significant difference was noted in the dosage of propofol used between the BIS and control groups ( 168.7 vs. 167.3 mg , respectively ) . Average sedation-related oxygen saturation drop and transcutaneous CO2 rise were not significantly different between groups . There was also no significant difference in the percentage of patients that required either hemodynamic support ( 5 vs. 7.5 % , respectively ) , oxygen supplementation by 100 % O2 mask ( 67.5 vs. 82.5 % , respectively ) or Ambu face mask manual ventilation ( 2.5 vs. 5 % , respectively ) between the groups . No significant difference was noted in terms of patients ' awareness during the procedure , which was assessed following recovery by a structured Brice interview . Conclusion : Using BIS to guide the depth of sedation during propofol sedation in patients undergoing FFB of relatively short duration offers no clinical ly significant advantages over conventional monitoring [16506681] Optimisation of topical anaesthesia for flexible fibreoptic bronchoscopy ( FOB ) is becoming increasingly important as a wider range of more complex , and thereby more prolonged , interventional endoscopic procedures are becoming available . Lignocaine is the most commonly used topical anaesthetic agent for bronchoscopy , but there is variability in current practice as to its optimum mode of administration . In this prospect i ve , r and omised , placebo-controlled , blinded study , we examine whether there was enhanced effectiveness of additional nebulised lignocaine as compared to our current regime utilising two visual analogue scales as markers of efficacy . Treatment groups were matched in terms of age ( p = 0.39 ) , gender , concomitant sedation ( p = 0.51 midazolam ; p = 0.12 fentanyl ) and dose of background administered lignocaine ( 290 mg ) . We found no significant additional differences between any of the treatment groups in terms of general ease of procedure ( p = 0.09 ) or in cough severity ( p = 0.12 ) . We conclude that this study does not support the hypothesis that additional nebulised lignocaine confers any additional benefit to the ease of procedure or cough severity in patients undergoing fibreoptic bronchoscopy . We suggest that preparation regimes for bronchoscopic examinations need optimization [12377879] STUDY OBJECTIVES The present study was performed to determine whether the risk of bleeding after transbronchial lung biopsy is increased in patients taking aspirin . DESIGN Prospect i ve cohort study . PATIENTS AND INTERVENTIONS After excluding patients with other coagulation problems , 1,217 patients who had undergone transbronchial lung biopsy during a prospect i ve 1.5-year study period were included in this study . The use of aspirin was not discontinued before the procedure . Two hundred eighty-five patients ( 23 % ) had consumed aspirin within 24 h of the procedure , and most of them ( 82 % ) used aspirin on a daily basis . Transbronchial biopsies were performed , and the bleeding incidence was compared between the groups . RESULTS A total of 57 patients ( 4.7 % ) experienced procedure-related bleeding . Minor bleeding occurred in 5 of 285 patients ( 1.8 % ) taking aspirin and in 27 of 932 control patients ( 2.9 % ; not significant ) . Moderate bleeding was seen in 3 of 285 patients ( 1.1 % ) in the aspirin group and in 13 of 932 patients ( 1.4 % ) in the control group ( not significant ) . Major bleeding occurred in only 9 patients , 2 of 285 ( 0.9 % ) in the aspirin group and 7 of 932 ( 0.8 % ) in the control group ( not significant ) . All bleeding was controlled by endoscopic means , and there were no fatalities and no need for blood transfusions . CONCLUSIONS We conclude that the risk of severe bleeding after transbronchial lung biopsy is small ( ie , < 1 % ) and that the use of aspirin is not associated with any increased risk of bleeding [25811287] BACKGROUND The optimal concentration of lignocaine to be used during flexible bronchoscopy ( FB ) remains unknown . This r and omized controlled trial compared the efficacy and safety of 1 % and 2 % lignocaine solution for topical anesthesia during FB . METHODS Consecutive patients were r and omized to receive either 1 % or 2 % lignocaine solution through the bronchoscope by the " spray-as-you-go " technique . The primary outcome of the study was the assessment of cough by the operator and the patient using the visual analog scale ( VAS ) and pain assessment using the faces pain rating scale . The secondary outcomes included total lignocaine dose , oxygenation status , adverse reactions related to lignocaine , and others . RESULTS Five hundred patients were r and omized ( median age , 51 years ; 71 % men ) 1:1 to either group . The median operator VAS score for cough was significantly higher ( 25 vs 21 , P = .015 ) in the 1 % group ; however , the patient VAS score was not significantly different ( 32 vs 27 , P = .065 ) . The pain rating was similar between the two groups . The median cumulative dose of lignocaine was significantly higher in the 2 % group ( 397 mg vs 312 mg , P = .0001 ; 7.1 mg/kg vs 5.7 mg/kg , P = .0001 ) . About 28 % of patients in the 2 % group exceeded the maximum recommended dose ( > 8.2 mg/kg ) of lignocaine . No adverse event related to lignocaine overdose was seen in either group . CONCLUSIONS One percent lignocaine was found to be as effective as 2 % solution for topical anesthesia during FB , albeit at a significantly lower dose as the latter . Thus , 1 % lignocaine should be the preferred concentration for topical anesthesia during FB . TRIAL REGISTRY Clinical Trials.gov ; No. : NCT01955824 ; URL : www . clinical trials.gov [17284894] Background : Coughing is increased during bronchoscopy and may last for several hours after the procedure . Also prior to the procedure patients show high levels of anxiety due to fear of the pain and breathing difficulties that they might experience during the procedure . Objectives : To evaluate the antitussive , anxiolytic and sedative effect of dextromethorphan ( DM ) premedication on the amount of intravenous midazolam during bronchoscopic procedures . Methods : Sixty consecutive patients undergoing scheduled bronchoscopy were r and omly allocated in a double-blind , placebo-controlled study . Half received 90 mg DM and half placebo . Local anesthesia with 2 ml of repeated intratracheal instillation of 1 % lidocaine as needed during bronchoscopy was applied . Midazolam 1 mg ( maximum of 5 mg ) was administered intravenously until a satisfactory sedation was achieved . Results : Heart rate , systolic and diastolic pressure and SpO2 were assessed before and during bronchoscopy . A visual analog score ( VAS ) for pain , cough , communication , cooperation , emotional state , complaints , expectoration , level of information about the procedure , feeling of unpleasantness and stress level assessed before and after the examination by the patient and the physician was used . There were no significant differences in the reported degrees of difficulty in undergoing bronchoscopic procedures . DM patients needed significantly fewer lidocaine instillations and lower midazolam dosage , achieved better analgesia , had lower emotion and complaint scores , significantly less coughing , significantly less stress , were significantly more cooperative , found that the procedure was much less unpleasant than they had expected , and produced less sputum at end of the procedure . Conclusions : DM is an effective bronchoscopic premedication in combination with midazolam and improves the overall well-being of the patients [2392794] Local anaesthesia for fibreoptic bronchoscopy should be given by a safe technique that is not unpleasant to the patient and should provide acceptable conditions for the bronchoscopist . Single injection transcricoid local anaesthesia was compared with the " spray as you go " technique in patients having day case fibreoptic bronchoscopy . Patients were r and omised to receive either 100 mg lignocaine by a single cricothyroid puncture or 240 mg lignocaine instilled through the bronchoscope under direct vision . Further doses were given by the operator to both groups as required . The 30 patients receiving transcricoid lignocaine coughed less ( 3.56 ( SD 3.1 ) coughs/min ) than the 32 patients receiving lignocaine through the bronchoscope ( 5.89 (4.8)/min ) despite receiving a lower total dose of lignocaine ( 322 ( 25.9 ) v 451 ( 20.9 ) mg ) . Cricothyroid puncture was not associated with any complications and was not unpleasant for the patients [18641105] BACKGROUND Fospropofol disodium is a water-soluble prodrug of propofol with unique pharmacokinetic/pharmacodynamic properties . This r and omized , double-blind , multicenter study evaluated the use of fospropofol in patients undergoing flexible bronchoscopy . METHODS Patients > or= 18 years of age were r and omized ( 2:3 ) to receive fospropofol , 2 mg/kg or 6.5 mg/kg , after pretreatment with fentanyl , 50 microg . Supplemental doses of each were given per protocol . The primary end point was sedation success , which was defined as follows : three consecutive Modified Observer 's Assessment of Alertness/Sedation scores of < or= 4 plus procedure completion without alternative sedative medication and /or mechanical ventilation . Other end points included treatment success , patient/physician satisfaction , and safety . RESULTS Of 252 patients , 150 were r and omized to receive 6.5 mg/kg fospropofol ; 102 were r and omized to receive 2 mg/kg fospropofol . Sedation success rates were 88.7 % and 27.5 % , respectively ( p < 0.0001 ) . Treatment successes ( 91.3 % vs 41.2 % , respectively ; p < 0.001 ) , willingness to be treated again ( 94.6 % vs 78.2 % , respectively ; p < 0.001 ) , and absence of procedural recall ( 83.3 % vs 55.4 % , respectively ; p < 0.001 ) were significantly better with the administration of 6.5 mg/kg fospropofol . The median time to full alertness was slightly longer for the 6.5 mg/kg dose ( 5.5 vs 3.0 min , respectively ) . The proportion of patients requiring supplemental therapy with analgesics ( 16.7 % vs 37.3 % , respectively ) and the use of alternative sedative medications ( 8.0 % vs 58.8 % , respectively ) were lower for patients in the 6.5 mg/kg dose group ( all comparisons , p < 0.001 ) . The most frequent adverse events ( AEs ) were transient and self-limited paresthesias and pruritus of mild-to-moderate severity . Hypoxemia ( predominantly mild-to-moderate ) was the most common sedation-related AE , and occurred in 15.4 % and 12.6 % of patients , respectively , in the 6.5 and 2 mg/kg fospropofol dose groups . CONCLUSIONS Fospropofol provided safe and effective sedation for patients undergoing flexible bronchoscopy . TRIAL REGISTRATION Clinical Trials.gov Identifier : NCT00306722 [14769756] STUDY OBJECTIVE To study the diagnostic role of flexible bronchoscopy ( FB ) in immunocompromised patients with pulmonary infiltrates . DESIGN Prospect i ve , observational study . SETTING Tertiary care hospital . PATIENTS A total of 104 consecutive non-HIV-infected immunocompromised patients with lung infiltrates in whom FB was performed . METHODS The primary outcome measure was the diagnostic yield of FB , which was derived as the number of the diagnoses made using FB results divided by all final diagnoses . Final diagnoses were established using data from FB , surgical lung biopsy ( SLB ) , and microbiology and serology testing , and by the clinical response to empiric therapy . We also studied the diagnostic yields of individual sampling procedures such as BAL , transbronchial biopsy ( TBB ) , and protected-specimen brush ( PSB ) sampling . RESULTS Overall , 128 diagnoses were made in 104 patients . The overall diagnostic yield of FB was 56.2 % ( 95 % confidence interval [ CI ] , 47 to 64 % ) . FB provided at least one diagnosis in 53 of 104 patients ( 51 % ; 95 % CI , 40 to 62 % ) . FB was more likely to establish the diagnosis when the lung infiltrate was due to an infectious agent ( 81 % ; 95 % CI , 67 to 90 % ) than to a noninfectious process ( 56 % ; 95 % CI , 43 to 67 % ; p = 0.011 ) . The diagnostic yields of BAL ( 38 % ; 95 % CI , 30 to 47 % ) and TBB ( 38 % ; 95 % CI , 27 to 51 % ) were similar ( p = 0.94 ) . The diagnostic yield of PSB sampling was lower ( 13 % ; 95 % CI 6 to 24 % ; p = 0.001 ) than that of BAL . The combined diagnostic yield of BAL and TBB ( 70 % ; 95 % CI , 57 to 80 % ) was higher than that of BAL alone ( p < 0.001 ) . Finally , the diagnostic yield of FB with PSB sampling , BAL , and TBB was similar to that of FB with BAL and TBB . The complication rate from FB was 21 % ( 95 % CI , 15 to 31 % ) . Minor bleeding ( 13 % ) and pneumothorax ( 4 % ) were the most common complications . CONCLUSIONS FB has a high diagnostic yield in immunocompromised patients with pulmonary infiltrates . Based on our results , we recommend performing TBB in these patients , whenever possible [21852332] Forceps , brushes or needles are currently the st and ard tools used during flexible bronchoscopy when diagnosing endobronchial malignancies . The new biopsy technique of cryobiopsy appears to provide better diagnostic sample s. The aim of this study was to evaluate cryobiopsy over conventional endobronchial sampling . A total of 600 patients in eight centres with suspected endobronchial tumours were included in a prospect i ve , r and omised , single-blinded multicentre study . Patients were r and omised to either sampling using forceps or the cryoprobe . After obtaining biopsy sample s , a blinded histological evaluation was performed . According to the definitive clinical diagnosis , the diagnostic yield for malignancy was evaluated by a Chi-squared test . A total of 593 patients were r and omised , of whom 563 had a final diagnosis of cancer . 281 patients were r and omised to receive endobronchial biopsies using forceps and 282 had biopsies performed using a flexible cryoprobe . A definitive diagnosis was achieved in 85.1 % of patients r and omised to conventional forceps biopsy and 95.0 % of patients who underwent cryobiopsy ( p<0.001 ) . Importantly , there was no difference in the incidence of significant bleeding . Endobronchial cryobiopsy is a safe technique with superior diagnostic yield in comparison with conventional forceps biopsy [16023336] Bronchoalveolar lavage ( BAL ) is a widely used clinical and research tool even though certain steps in the procedure have not been st and arized . One step that is subject to variation is the technique used to instill and recover BAL fluid . Our aim was to assess whether attaching a plastic tube between the syringe and the working channel of the flexible bronchoscope allowed recovery of more fluid in comparison with recovery using only a syringe , and whether tubing had a favorable impact on diagnostic yield and complications . A r and omized multicenter study was performed in eleven public hospitals in Catalonia ( Spain ) . Patients scheduled for BAL were r and omly assigned to tubing ( n=140 ) or no-tubing groups ( n=155 ) . Flexible bronchoscopy and a 150 mL BAL in three 50 mL aliquots with or without tubing attached to the syringe . In the group with tubing , 8 % more fluid was recovered . The difference was both statistically significant and clinical ly relevant given that 17.4 % more diagnoses , 6.9 % fewer complications , and 8.8 % fewer technical failures were recorded . Based on these results , we recommend performing BAL using plastic tubing between the 50 mL syringe and the working channel of the flexible bronchoscope when carrying out manual instillation and suction [9151514] Endobronchial forceps biopsy ( FB ) specimens of lung carcinoma are not uncommonly interpreted as nondiagnostic owing to extensive crush artefact , necrosis , or insufficient tissue . FB can not be performed in some endobronchial lung cancers ( EBLCs ) with massive bleeding tendency due to fragility and friability . Cytological studies from the brushings and washings may also be unproductive , increasing the bronchoscopist 's frustration . The aim of this study was to compare the diagnostic yield and complications of endobronchial needle aspiration ( EBNA ) with those of FB and brush biopsy ( BB ) in EBLCs examined by fibreoptic bronchoscopy . A prospect i ve sequential study was carried out on 151 in- patients with EBLC . Bronchial aspiration ( BA ) , EBNA and BB were performed in the patients with respiratory distress and with accompanying tumours of high bleeding tendency , completely obstructing main bronchi ( Group 1 : 68 patients ) . BA , EBNA and FB were performed in those with either central or peripheral EBLCs but without respiratory distress and /or significant bleeding tendency ( Group 2 : 83 patients ) . In Group 1 , the diagnostic yield of EBNA was found to be 90 % , whereas that of BB was 66 % ( p < 0.05 ) . In the same group , EBNA provided cell types in 95 % , compared with 88 % by BB ( p > 0.05 ) . EBNA was diagnostic in 92 % of Group 2 patients , while FB established diagnosis in 78 % of patients ( p > 0.05 ) . In determining cell type , no significant difference was found between EBNA ( 95 % ) and FB ( 97 % ) ( p > 0.05 ) . Regarding complications ( only bleeding ) , there was no significant difference ( p > 0.05 ) between EBNA ( 7 % ) and BB ( 13 % ) , or between EBNA ( 4 % ) and FB ( 17 % ) . We conclude that in endobronchial lung cancers : 1 ) the diagnostic yield of endobronchial needle aspiration is higher than brush biopsy ; 2 ) endobronchial needle aspiration increases the yield of brush biopsy when forceps biopsy can not be performed owing to significant bleeding ; 3 ) endobronchial needle aspiration increases the diagnostic yield when a forceps biopsy specimen is inadequate because of crush artefact , necrosis , or tissue resistance ; and 4 ) endobronchial needle aspiration is as safe as brush biopsy and forceps biopsy [16924893] BACKGROUND Oxygen desaturation is not uncommon during bronchoscopy . We sought to identify factors predictive of desaturation during flexible bronchoscopy . METHODS Over eight months , we enrolled 137 r and omly selected patients who were undergoing fiberoptic bronchoscopy at our medical center . The patients ' oxygen saturation was monitored on their arrival and during the procedure by finger pulse oximetry . Desaturation was defined as an overall saturation nadir of < 90 % or an episode of decreased saturation of 5 % from the baseline regardless of whether the patient was receiving supplemental oxygen . RESULTS The need for oxygen supplementation before the procedure was predictive of a higher rate of desaturation episodes ( 73.9 % vs. 50 % , p = 0.036 ) . Although all interventional procedures or their complications can cause desaturation , the specific type of procedure was the most important predictor of desaturation ( lavage , 88.9 % ; washing , 43.8 % ; brushing , 15.2 % ; biopsy , 10 % ) . A low peak expiratory flow rate before the procedure seemed to be predictive of a high desaturation rate in patients undergoing lavage or washing during bronchoscopy . CONCLUSION Our study suggested that age , sex and baseline oxygen saturation were not predictors of desaturation . We should be reminded of the possibility of desaturation during every procedure , especially in patients who need supplemental oxygen before bronchoscopy [12628899] STUDY OBJECTIVES To determine whether distraction therapy with nature sights and sounds during flexible bronchoscopy ( FB ) reduces pain and anxiety . DESIGN R and omized controlled trial . SETTING Teaching hospital in Baltimore , MD . PATIENTS Consecutive adult patients ( n = 80 ) undergoing FB with conscious sedation . INTERVENTION Nature scene murals were placed at the bedside , and patients were provided a tape of nature sounds to listen to before , during , and after the procedure . Patients assigned to the control group were not offered either the nature scene or the sounds . MEASUREMENTS AND RESULTS The primary outcomes were patient ratings of pain control ( a 5-point scale ranging from poor to excellent ) and anxiety . In a multivariate ordinal logistic regression model , the odds of better pain control were greater in the intervention patients than in the control patients ( odds ratio [ OR ] , 4.76 ; 95 % confidence interval [ CI ] , 1.35 to 16.7 ) , after adjustment for age , gender , race , education , health status , and dose of narcotic medication . Older patients and patients with better health status reported significantly less pain . There was no difference in patient-reported anxiety between the two groups ( OR , 0.87 ; 95 % CI , 0.39 to 1.96 ) . CONCLUSIONS Distraction therapy with nature sights and sounds significantly reduces pain in patients undergoing FB . Although the precise mechanism of this beneficial effect requires further investigation , clinicians should consider this nonintrusive strategy in addition to st and ard analgesic medications in patients undergoing painful , invasive procedures [24853014] BACKGROUND Newer more advanced techniques in bronchoscopy may require longer procedure times , although a st and ard protocol for sedation during prolonged bronchoscopy has not yet been defined . METHODS We design ed a prospect i ve , non-r and omized , single-arm study ( UMIN trial number 000003971 ) using patient question naires and vital sign monitoring to assess the efficacy and safety of a st and ardized midazolam dosing protocol based on gender and age for use during bronchoscopy . The loading dose of midazolam was 0.075mg/kg for men ≤65 years old and women ≤70 and 0.05mg/kg for men ≥66 years and women ≥71 years , with subsequent doses of one-half the loading dose to be administered every 20min . The primary endpoint was tolerability and secondary endpoints included anxiety and recall of procedure , willingness to undergo repeat procedure , and complications . Safety was evaluated in terms of monitored changes in blood pressures , ECG , oxygen saturation , and CO2 content in expiration during the procedure . RESULTS A total of 204 patients were included in the study . Overall , 163 patients ( 79.9 % ) reported " no distress " during the procedure , 185 patients ( 90.7 % ) reported " no anxiety , " and 175 ( 85.8 % ) replied that they would accept a repeat procedure , if necessary . The mean minimum oxygen saturation was 90.2 % and the mean maximum expiratory CO2 level was 37.7mmHg . There were no serious complications related to the protocol . CONCLUSIONS The midazolam dosing protocol examined in this study was safe and effective . It is simple , and it could easily be translated to routine clinical practice [16162784] OBJECTIVE Topical anesthesia for flexible bronchoscopy can be administered via transcricoid injection , nebulizer , or directly through the bronchoscope in a " spray as you go " fashion . We performed a prospect i ve , r and omized , double-blind , placebo-controlled trial to evaluate whether nebulized lidocaine provides additional benefit and reduces the total anesthetic dose required during bronchoscopy . SETTING Tertiary care university hospital . METHODS One hundred fifty patients ( 93 men ; age , 20 to 89 years ) undergoing diagnostic flexible bronchoscopy were r and omized to receive either 4 mL of 4 % lidocaine ( 160 mg ) or 4 mL of saline solution as placebo via nebulization . Combined sedation was achieved using 5 mg of IV hydrocodone and midazolam boluses . Supplemental lidocaine doses and total midazolam required as judged by the bronchoscopist were recorded for each patient . After the procedure , both bronchoscopists and patients charted their perception of cough on a 10-cm visual analog scale ( VAS ) . Similarly , patients recorded their discomfort related to the procedure on a 10-cm VAS . RESULTS The most common procedures were BAL in 77 cases ( 51 % ) , transbronchial biopsy in 40 cases ( 27 % ) , and transbronchial needle aspiration in 34 cases ( 23 % ) . Outcome parameters , including hemodynamic findings , duration of the procedure , cough scores for physicians and patients , discomfort score for patients , midazolam doses , and supplemental lidocaine doses , were similar in both groups . Mean total lidocaine dose required in the lidocaine group was 318 + /- 41 mg and was significantly higher than the total dose required in the placebo group ( 157 + /- 44 mg [ + /- SD ] ) [ p < 0.001 ] . CONCLUSION Additional nebulized lidocaine can not be recommended for flexible bronchoscopy performed under combined sedation [21870301] BACKGROUND Propofol is a sedative-hypnotic with a rapid onset of action . There are only limited data evaluating propofol for flexible bronchoscopy . We analysed the feasibility and safety of propofol for bronchoscopy in a high output tertiary care centre . METHODS Prospect i ve data on patients undergoing flexible bronchoscopy at the University Hospital Basel , Switzerl and , were analysed . Patient demographics , ASA class , Mallampati class , indication for bronchoscopy , bronchoscopic procedures , duration of examination , medication requirements , minor and major adverse events , haemodynamic parameters , as well as cough scores during the procedure were documented . Patients were followed up to discharge from the bronchoscopy suite . RESULTS Data from 440 patients with a mean age 60 years ( ±15.5 , 260 male ) were analysed . The main indication for bronchoscopy was a suspicion of malignancy . The most common diagnostic procedures were bronchoalveolar lavage in 253 cases ( 31.5 % ) and bronchial washing in 174 cases ( 21.7 % ) . The mean duration of the procedure was 19.6 min ( ±12.08 ) . The mean propofol dose was 200 mg ( ±107.5 ) corresponding to 2.89 mg/kg ( ±1.70 ) . Minor adverse events included oxygen desaturation in 72 ( 16.4 % ) , hypotension in 68 ( 15.4 % ) and minor bleeding in 11 ( 2.5 % ) patients . No major adverse events were recorded . The median decline in systolic blood pressure after initiation of sedation was 14 mm Hg ( 3 - 28 ) . A drop in systolic blood pressure greater than 20 mm Hg was observed in 166 of the 440 patients ( 37 % ) . CONCLUSION Propofol sedation for flexible bronchoscopy is feasible and safe [1426224] We compared the efficacy of nebulized ( N ) and sprayed ( S ) topical anaesthesia prior to fibreoptic bronchoscopy in a blinded study involving 54 patients aged 57 + /- 26 yrs ( mean + /- SD ) . Cough frequency , recorded on cassette tape , was the index of efficacy . All patients received 100 mg lignocaine sprayed into the pharynx , or nebulized in r and om order prior to bronchoscopy , and all received intravenous diazepam sedation . Each patient received a further 100 mg of lignocaine solution through the bronchoscope onto the vocal cords and major airways during the procedure . No significant difference was found in overall cough frequency between N and S groups ( 8.7 + /- 6.9 coughs.min-1 N vs 10.5 + /- 6.0 S ) , and cough frequency was also similar between N and S during the periods above and below the vocal cords . Furthermore , no differences were found in cough frequency between N and S among smokers , patients with asthma and COPD , and patients who had a biopsy procedure , although a trend was seen in all comparisons towards a lower cough frequency with the nebulized route . Most patients in the S group found the spray unpleasant , whereas only one in the N group complained . We conclude that nebulized and sprayed lignocaine have similar efficacy as topical anaesthetics in fibreoptic bronchoscopy , but patient preference favours the nebulized route [23900984] Propofol has been established as a reliable method for sedation in flexible bronchoscopy . There are no data comparing propofol administered as intravenous boluses versus continuous infusion . 702 consecutive patients undergoing flexible bronchoscopy were r and omly allocated to receive intravenous propofol using either an intermittent bolus technique or a continuous infusion . The primary end-point was the number of adverse events assessed at the end of flexible bronchoscopy and at 24 h. The number of any adverse event was similar in both r and omised groups ( 219 versus 211 , p=0.810 ) . There were complications in eight cases ( seven major bleedings , one respiratory failure ) . As compared with the bolus group , the amount of propofol required was significantly higher in the infusion group ( 226 ±147 mg versus 308±204.8 mg , p<0.0001 ) . In a multivariate regression model , this difference remained significant independent of the duration and the interventions performed during the procedure . The duration of bronchoscopy was significantly longer in the infusion group ( median 14 ( interquartile range 9–24 ) versus 17 ( 12–27 ) min , p<0.0001 ) . Propofol continuous infusion is as safe as bolus administration ; however , it is associated with higher propofol requirements and a longer duration of the bronchoscopy . Propofol continuous infusion is as safe as bolus administration , but has higher requirements and longer bronchoscopy [3223212] Objectives There are safety issues associated with propofol use for flexible bronchoscopy ( FB ) . The bispectral index ( BIS ) correlates well with the level of consciousness . The aim of this study was to show that BIS-guided propofol infusion is safe and may provide better sedation , benefiting the patients and bronchoscopists . Methods After administering alfentanil bolus , 500 patients were r and omized to either propofol infusion titrated to a BIS level of 65 - 75 ( study group ) or incremental midazolam bolus based on clinical judgment to achieve moderate sedation . The primary endpoint was safety , while the secondary endpoints were recovery time , patient tolerance , and cooperation . Results The proportion of patients with hypoxemia or hypotensive events were not different in the 2 groups ( study vs. control groups : 39.9 % vs. 35.7 % , p = 0.340 ; 7.4 % vs. 4.4 % , p = 0.159 , respectively ) . The mean lowest blood pressure was lower in the study group . Logistic regression revealed male gender , higher American Society of Anesthesiologists physical status , and electrocautery were associated with hypoxemia , whereas lower propofol dose for induction was associated with hypotension in the study group . The study group had better global tolerance ( p<0.001 ) , less procedural interference by movement or cough ( 13.6 % vs. 36.1 % , p<0.001 ; 30.0 % vs. 44.2 % , p = 0.001 , respectively ) , and shorter time to orientation and ambulation ( 11.7±10.2 min vs. 29.7±26.8 min , p<0.001 ; 30.0±18.2 min vs. 55.7±40.6 min , p<0.001 , respectively ) compared to the control group . Conclusions BIS-guided propofol infusion combined with alfentanil for FB sedation provides excellent patient tolerance , with fast recovery and less procedure interference . Trial Registration Clinical Trials . gov [8882070] BACKGROUND : Concerns remain about the safety of bronchoscopy in asthma and there are few data on the effect of this procedure on asthma control in the days or weeks following bronchoscopy . METHODS : In an initial study of bronchoalveolar lavage and bronchial biopsies in asthmatic and control subjects , data on peak expiratory flow rates ( PEFR ) collected prospect ively before and after the procedure were available from 21 of the 29 asthmatic subjects studied . These showed a median 23 % fall in PEFR from baseline after bronchoscopy ( range 3 - 58 % ) . To determine whether this fall in PEFR following bronchoscopy reflected bronchospasm or the effect of sedation , PEFR and spirometric tests were performed during the two hours following bronchoscopy in a further study of 15 symptomatic asthmatic subjects and 20 non-asthmatic controls . To examine the effect on asthma control , asthmatic patients recorded PEFR , symptom scores , and medication use for two weeks before and after bronchoscopy . RESULTS : After bronchoscopy with bronchial biopsies there was no difference between the median maximal fall in either PEFR or arterial oxygen saturation between the 15 asthmatic patients ( 10.4 % and 4 % , respectively ) and 20 controls ( 12 % and 3 % ) . Moreover , there were no significant changes in PEFR , symptom score , or medication use by the asthmatic subjects in the two weeks after bronchoscopy when compared with the two weeks before bronchoscopy . CONCLUSIONS : Fibreoptic bronchoscopy is well tolerated in asthmatic subjects . Falls in PEFR in both asthmatic and non-asthmatic subjects after bronchial biopsy may reflect the effects of sedation rather than bronchospasm . Additional bronchoalveolar lavage may cause bronchoconstriction . Careful monitoring is therefore essential . Peak flow monitoring up to two weeks after bronchoscopy with bronchial biopsy revealed no delayed effects on asthma control [20980720] Background : Although electrocoagulation at time of endobronchial biopsy can potentially reduce procedure-related bleeding during fiberoptic bronchoscopy ( FOB ) , it can also impair quality of tissue specimen ; credible data for either are lacking . Objective : To evaluate the impact of hot biopsy on the quality of tissue sample s and to quantify the amount of procedure-related bleeding during endobronchial biopsy . Methods : In this single-center , prospect i ve , single-blind , r and omized controlled study we included adult patients referred for FOB and having endobronchial lesions . Patients were r and omized to bronchial biopsy using an electrocoagulation-enabled biopsy forceps , with ( EC+ group ) or without ( EC– group ) application of electrocoagulation current ( 40 W for 10 s in a monopolar mode ) . Procedure-related bleeding was semi-quantified by observer description , as well as through a visual analogue scale . Overall quality of biopsy specimen and tissue damage were assessed and grade d by a pulmonary pathologist blinded to FOB details . Result : 160 patients were r and omized to endobronchial biopsy with ( n = 81 ) or without ( n = 79 ) the application of electrocoagulation . There were no severe bleeding episodes in either group , and severity of bleeding in the EC+ and EC– groups was similar ( median visual analogue scale scores of 14 and 16 , respectively ) . Histopathological diagnosis was similar in the EC+ and EC– groups ( 77.8 % and 82.3 % , respectively ) . There was no significant difference in tissue quality between the two groups . Conclusion : Use of electrocoagulation-enabled endobronchial biopsy does not alter specimen quality and does not result in any significant reduction in procedure-related bleeding [2247670] In a double-blind study of 60 patients undergoing fibreoptic bronchoscopy we have compared the local anaesthetic effects of intratracheal injections of cocaine ( 4 ml , 2.5 % ) and lignocaine ( 4 ml , 4 % ) . The two local anaesthetics were equally effective in terms of cough suppression , requirement for extra local anaesthetic , patient discomfort and operator acceptability [15333854] Background : Current British Thoracic Society guidelines do not recommend routinely the combined use of a benzodiazepine and opiate during flexible bronchoscopy ( FB ) . A r and omised , placebo controlled , double blind study was undertaken to determine whether hydrocodone in combination with midazolan improves cough suppression during FB without increasing the risk of desaturation . Methods : 120 patients were r and omised to receive midazolam and 5 mg IV hydrocodone or midazolam and placebo with topical anaesthesia . Pulse oximetry was recorded continuously during FB . Bronchoscopists and nurses charted their perception of cough and the patients rated their discomfort during the procedure on a 10 cm visual analogue scale ( VAS ) . Results : There was no significant difference between the two groups with regard to the indication for FB , duration of procedure ( 21 ( 11 ) min v 22 ( 10 ) min , p = 0.570 ) , doses of supplemental lignocaine ( 171 ( 60 ) mg v 173 ( 66 ) mg , p = 0.766 ) and midazolam ( 4.5 ( 2.3 ) mg v 4.9 ( 2.7 ) mg , p = 0.309 ) , lowest oxygen saturation ( 94.8 ( 2.7 ) v 94.9 ( 2.7 ) , p = 0.433 ) , and desaturations ⩽90 % . Perception of cough by both the bronchoscopist and the nurse was significantly lower in the hydrocodone group ( 3 ( 0–10 ) and 3 ( 0–10 ) ) than in the placebo group ( 6 ( 0–10 ) and 6 ( 0–10 ) ) , respectively ( p = 0.001 ) . According to the VAS scale , patients ’ tolerance was also significantly better with hydrocodone than with placebo ( 2 ( 0–8 ) v 3 ( 0–9 ) , p = 0.043 ) . Conclusion : The combination of midazolam and hydrocodone markedly reduces cough during FB without causing significant desaturation , especially when invasive diagnostic procedures are performed [19174601] Background : Patients with pulmonary hypertension ( PH ) are considered to be at risk for complications associated with flexible bronchoscopy ( FB ) . Although previous reports suggest that transbronchial biopsies increase the risk for hemorrhage in this population , data are limited to survey analyses and isolated reports . Objectives : It was the aim of this study to describe our experience with FB and to determine if bronchoscopic procedures are associated with adverse events in this population . Methods : We conducted a retrospective review of patients with diagnosis of PH who underwent FB at the Clevel and Clinic between 2002 and 2005 . Patients without PH who underwent FB by the same pulmonary physician were used as controls . Results : A total of 90 patients , PH ( n = 45 ) versus controls ( n = 45 ) , were included . The mean systolic pulmonary artery pressure in patients with PH was 58 ± 7 mm Hg . Patients with PH had higher oxygen requirements at baseline ( FiO2 0.42 vs. 0.3 % ; p = 0.01 ) . The total number of procedures was similar between the groups ( 95 vs. 102 ) . Procedures performed were bronchoalveolar lavage ( 21 vs. 13 ) , transbronchial biopsies ( 24 vs. 32 ) and transbronchial needle aspiration ( 7 vs. 6 ) . There were no hemodynamic complications or episodes of respiratory failure associated with the procedures . None of the patients had significant hemorrhage and only 2 developed mild bleeding which resolved spontaneously . Similarly , none required hospitalization or transfer to an intensive care unit . Conclusions : FB can be performed safely in patients with mild to moderate PH . Transbronchial biopsies are not associated with worsening hypoxemia or an increased risk of hemorrhage . Prospect i ve studies with hemodynamic measurements are necessary to confirm these findings [12117048] The tolerability of 57 non-smoking asthma patients inhaling salbutamol as needed ( ATS , 18 - -60 years , 60 % < or = FEV1 < or = 100 % , PD15FEV1 < 0.4 mg histamine ) to fibreoptic bronchoscopy ( FOB ) and endobronchial biopsy was studied . The FOB was done in local Lignocaine anaesthesia , and from five to eight biopsy specimens were taken from the bronchial mucosa of the right lung . The tolerability was measured as cough/bronchospasm during the procedure ( from 0 = normal to 3 = interrupted procedure ) , success of the procedure , and untoward occurrences . Twenty-seven of the 57 patients ( 48 % ) had no cough or bronchospasm during the FOB ( score 0 ) . Few coughs of no importance ( score 1 ) were documented in 23 patients ( 40 % ) . Seven patients ( 12 % ) had cough and /or bronchospasm interfering with the FOB procedure ( score 2 ) . The FOB procedure was not interrupted because of cough and /or bronchospasm ( score 3 ) in any patient . Scores of cough and /or bronchospasm diminished progressively with the increase of PD15FEV1 histamine . The success of the procedure was 100 % . Two patients had untoward medical occurrences requiring additional rescue medication ( 3.5 % ) . In conclusion , we found that hyperreactivity predicts cough and /or bronchospasm during the FOB . Cough and /or bronchospasm are frequently observed during the bronchial procedure , but they are mild and of minor clinical importance . An investigational endobronchial procedure can be successfully performed in mildly or moderately obstructive asthmatic patients , even in cases with severe bronchial hyperreactivity [15715190] INTRODUCTION Older patients are the most prevalent age cohort requiring bronchoscopy . Prior sedation should be offered to improve patient comfort and operator technical ease . Older patients have increased sensitivity to central ly acting drugs increasing the procedural risk . This perceived risk may limit access to bronchoscopy in older patients . There have been no systematic prospect i ve placebo-controlled studies in older patients . We compared a novel premedication regimen-oral temazepam plus nebulised Lignocaine ( new treatment ) to an established regimen of intravenous alfentanyl ( control ) . METHODS Consecutive patients 75 years and older referred for bronchoscopy were considered . Twenty-five patients were r and omly assigned to each group . The primary outcome measure was the lowest oxygen saturation recorded from the administration of IV drugs and for 30 min post-bronchoscopy . RESULTS The lowest mean oxygen saturation in the new treatment group was 92.2 % ( 90.3 - 94.2 ) and in the control group 91.1 % ( 89.2 - 93.1 ) . This was not statistically different ( P = 0.370 ) . There were no adverse events . CONCLUSION This is the largest prospect i ve study to date on an older population undergoing bronchoscopy supporting previous retrospective findings regarding the safety of this procedure . Determined by oxygen saturations there is no difference in safety between premedication regimens comprising oral temazepam/nebulised lignocaine or intravenous alfentanyl [1657538] To further improve the diagnostic value of bronchoscopy in the immunosuppressed population presenting with diffuse pulmonary infiltrates , we prospect ively investigated the utility of bilateral bronchoalveolar lavage ( BAL ) . We performed 62 bronchoscopies on 52 immunosuppressed patients . Of the 52 patients , 33 had pulmonary infections . The yield for Pneumocystis carinii pneumonia on bilateral BAL was 94 percent ( 31/33 ) , compared to the 84 percent ( 51/61 ) previously obtained with unilateral BAL in our institution . The recovery of P carinii was unilateral in four of five patients without AIDS and in four of 26 patients with AIDS . Transbronchial biopsy gave a yield of 85 percent ( 11/13 ) . In ten patients with definitive cytomegalovirus ( CMV ) pneumonia , recovery of CMV by combined culture and cytology was 100 percent . Of nine bronchoscopies with positive cytology for CMV , five showed cytopathologic changes in the BAL from both sides and four in the BAL from one side only . No complications were seen in the 14 patients with thrombocytopenia or the five patients receiving mechanical ventilation . Our findings indicate that bilateral BAL significantly increases the yield for recovery of P carinii ( p less than 0.02 ) and CMV ( p less than 0.001 ) in immunosuppressed patients [11578889] STUDY OBJECTIVE To determine the optimal solution to use when anesthetizing the airway by aspiration of lidocaine . DESIGN R and omized , double-blind clinical study . SETTING University hospital . PATIENTS 96 adult ASA physical status 1,II , and III patients , scheduled for diagnostic flexible bronchoscopy . INTERVENTIONS Patients were r and omized to receive one of 5 solutions of lidocaine : Group A ( n = 16 ) : 1 % lidocaine , 0.2 mL. kg(-1 ) ; Group B ( n = 16 ) : 1.5 % 0.2 mL. kg(-1 ) ; Group C ( n = 32 ) : 2 % 0.2 mL. kg(-1 ) ; Group D ( n = 16 ) : 1 % 0.3 mL. kg(-1 ) , and Group E ( n = 16 ) : 2 % 0.3 mL. kg(-1 ) . Fiberoptic bronchoscopy was performed after the airway was anesthetized with this aspiration technique , using the assigned lidocaine solution . The scope was manipulated in the trachea to test for anesthesia . MEASUREMENTS AND MAIN RESULTS Successful airway anesthesia was determined by tolerance to bronchoscopy without sustained coughing , and also by the number of lidocaine supplements , if any , that were given via the bronchoscope . Arterial plasma concentrations of lidocaine were measured in 33 patients from Groups C , D , and E. All solutions provided equally effective anesthesia of the airway . All patients tolerated endoscopy through the vocal cords , and 94 patients required no supplementary anesthesia , or only one dose of lidocaine , during bronchoscopy to the carina . The highest peak plasma concentrations of lidocaine were 5.02 and 6.28 microg . mL. No patient had signs of toxicity . CONCLUSIONS This technique produced anesthesia of the airway to the carina , safely , suitable for awake intubation , in 94 of 95 patients . The use of 1 % lidocaine , 0.2 to 0.3 mL. kg(-1 ) , so that the volume is 10 to 20 mL , is recommended [8266157] Lignocaine spray for anaesthetising the nasal mucosa for fibreoptic bronchoscopy often causes discomfort to the patient . We compared two techniques of applying nasal topical anaesthesia using either lignocaine spray ( group A : 25 patients ) or gel ( group B : 30 patients ) to assess patients ' tolerance to the procedure . Both groups received 100 mg of lignocaine in the nostril , 40 - 50 mg to oropharynx , 120 mg to vocal cords and 40 - 100 mg to trachea and bronchi . Throat anaesthesia was the most common unpleasant part experienced by both groups of patients ( 34.5 % ) , followed by examination of bronchi ( 30.6 % ) and nasal anaesthesia ( 21.8 % ) . Significantly more patients in group A experienced discomfort or pain during nasal anaesthesia as compared to group B ( p < 0.001 ) . Patients ' tolerance to the bronchoscopy was similar in both groups and the examination was performed satisfactorily in all patients . Thus , lignocaine gel is a simple technique , effective and less irritating as compared to lignocaine spray for topical nasal anaesthesia [22174346] BACKGROUND The safety profiles and efficacies of remifentanil and dexmedetomidine ( a sedative-analgesic without respiratory depression ) for sedation during flexible bronchoscopy were investigated . METHODS Seventy-two patients undergoing elective flexible bronchoscopy were r and omly assigned to a propofol-remifentanil group ( Group PR , n=36 ) or a propofol-dexmedetomidine group ( Group PD , n=36 ) . The primary outcome was the incidence of oxygen desaturation . Haemodynamic variables , adverse events , need of oral cavity suction , cough scores , satisfaction scores of patients and bronchoscopists , levels of sedation , and recovery times were also compared . RESULTS The incidence of oxygen desaturation was significantly lower in the PD group than in the PR group ( P=0.01 ) . There were no significant differences between groups in terms of level of sedation , oxygen saturation , mean arterial pressure , heart rate over time , cough scores , or patient satisfaction scores ( P>0.05 ) . However , cough scores and bronchoscopist satisfaction scores ( P<0.01 ) were lower in the PD group . In addition , topical anaesthesia ( P<0.01 ) was required more frequently and recovery time ( P=0.00 ) was significantly longer in the PD group . However , oral suction ( P=0.03 ) was required less frequently in the PD group . CONCLUSIONS Dexmedetomidine was associated with fewer incidents of oxygen desaturation and a reduced need for oral cavity suction than remifentanil during flexible bronchoscopy . However , dexmedetomidine was associated with a longer recovery time and poorer bronchoscopist satisfaction score [20492004] BACKGROUND Flexible fibre-optic bronchoscopy has become an essential investigation and is widely regarded as safe , but wider published prospect i ve data regarding delayed complications are limited . There is continuing debate concerning the safety of proceduralist-administered sedation . We evaluated complication rates of bronchoscopy and proceduralist-administered sedation at our tertiary institution , and their clinical significance . METHODS Prospect i ve evaluation of all patients undergoing bronchoscopy over a 12-month period at a tertiary referral centre . Immediate minor and major complications were documented within 4 h of bronchoscopy , delayed complications at 48 h , case notes and bronchoscopy records were review ed 1 month later . RESULTS Five hundred and fifty-eight flexible fibre-optic bronchoscopies were performed , 216 with transbronchial biopsy or nodal aspiration , 19 had therapeutic airways intervention . The minor complication rate at 4 h was 4.12 % ( 23 ) , rising to 26 % ( 145 ) at 48 h. All 2.2 % ( 12 ) major complications occurred exclusively within 4 h of bronchoscopy . No complications could be attributed to proceduralist-administered sedation . DISCUSSION Complication rates at 4 h were comparable with previously reported data . Delayed minor complications were greater than expected , and did not require additional medical input . There were no complications from proceduralist-administered sedation . Flexible fibre-optic bronchoscopy and proceduralist-administered sedation within our institution 's guidelines are safe [16696751] OBJECTIVES To assess the frequency of fever and pneumonia after fiberoptic bronchoscopy ( FOB ) in older people and to evaluate increased risk for these two adverse events with increasing age . DESIGN Prospect i ve study . SETTING University hospital system . PARTICIPANTS Three hundred fifty-eight patients , with 165 ( 46.1 % ) patients aged 70 and older , undergoing bronchoscopy . MEASUREMENTS Indications , abnormal bronchoscopic findings , sampling procedures , final diagnosis , and fever and pneumonia after bronchoscopy . RESULTS With regard to the indication for bronchoscopy and abnormal bronchoscopic findings , there was no statistical difference between elderly patients ( > or = 70 ) and younger patients ( < 70 ) . Procedures such as forceps biopsy , brushing , and curetting were not performed more often in elderly patients , although final diagnosis of lung cancer was significantly more common in the elderly group ( P=.002 ) . The overall incidence of fever after FOB was 6.7 % , and that of pneumonia after FOB was 5.6 % . The patients aged 70 and older had an incidence of fever after FOB of 3.6 % and an incidence of pneumonia of 4.2 % , which were not higher than those in patients younger than 70 . CONCLUSION Increasing age is not associated with increasing fever and pneumonia after FOB , and chronological age should not be considered a limiting factor in the decision of whether to perform FOB when it is clinical ly indicated [21310875] Propofol and the combination of a benzodiazepine and an opiate have been established for sedation in flexible bronchoscopy . It is as yet unknown whether propofol in combination with an opiate is superior to propofol alone to suppress cough during the procedure . 300 consecutive patients undergoing flexible bronchoscopy at a tertiary care university hospital were r and omly allocated to receive either the combination propofol and hydrocodone or propofol alone in a double-blind fashion . The primary end-point was the cough score during the procedure as estimated by the physician using a visual analogue scale . Demographics were similar in both groups . Compared with propofol alone , median ( interquartile range ) cough scores assessed by physicians , nurses and patients were significantly lower in the group r and omised to the combination propofol and hydrocodone ( 2.5 ( 1.5–4.0 ) versus 2.0 ( 1.0–3.0 ) , respectively , p=0.011 ) . Additionally , patients receiving the combination required significantly lower doses of propofol than those receiving propofol alone ( 200 mg ( 140–280 ) versus 260 mg ( 180–350 ) , p<0.0001 ) . Complex examinations , including bronchoalveolar lavage or transbronchial biopsy , benefited more from additional opiate . The duration of the procedure , time to discharge and complication rate were similar in both groups . The combination of propofol and hydrocodone is safe and superior to propofol alone for cough suppression in flexible bronchoscopy [7708981] Most current sedative regimens for fibre optic bronchoscopy use an opioid , a benzodiazepine or a combination of both . This study compares midazolam ( M ) ( a benzodiazepine ) , alfentanil ( A ) ( an opioid ) and a combination of both drugs ( M+A ) . One hundred and three patients were r and omized in double-blind manner into groups M(35 ) , A(33 ) and M+A(35 ) . The number of coughs , number of additional aliquots of lignocaine and duration of the procedures were recorded along with oxygen desaturation . The patient 's level of discomfort was assessed by patient and bronchoscopist and expressed as a visual analogue score . There were significantly fewer coughs per minute in Group A compared with Group M ( P = 0.0053 ) , and significantly less lignocaine was required in Group A ( P = 0.005 ) and in Groups M+A ( P < 0.002 ) compared with Group M. There was no significant difference in the assessment of discomfort between the groups . There was a trend for Group M+A to desaturate more than the other two with a significant difference between desaturation in Group M+A and Group A ( P = 0.033 ) . Alfentanil is a more effective anti-tussive agent than midazolam for outpatient fibre optic bronchoscopy . The combination of alfentanil and midazolam does not provide any better anti-tussive effect and may have the risk of a greater degree of desaturation secondary to increased sedation [10334165] STUDY OBJECTIVE Bronchoscopic technique is not st and ardized . Controversies exist with regard to premedication with sedatives before the test . To evaluate safety and efficacy of conscious sedation , we studied 100 r and omized patients undergoing diagnostic bronchoscopy ; patients received premedication with lidocaine spray and atropine sulfate i.m . ( nonsedation group ; 50 patients ) or lidocaine spray , atropine i.m . and diazepam i.v . ( sedation group ; 50 patients ) . METHODS AND RESULTS Monitoring during flexible fiberoptic bronchoscopy included continuous ECG and pulse oximetry . The procedure could not be completed in six patients . None received premedication with diazepam ; among the patients who ended the examination , tolerance to the examination ( visual analogue scale , 0 to 100 ; 0 = excellent ; 100 = unbearable ) was better in the sedation group . Low anxiety , male sex , but not age were also associated with improved patient tolerance to the test . Oxygen desaturation occurred in 17 % of patients , and it was not more frequent after diazepam treatment . CONCLUSIONS In our study , sedation had a beneficial effect on patient tolerance and rarely induced significant alterations in cardiorespiratory monitoring parameters [9596324] OBJECTIVE Atropine premedication is widely used for fiberoptic bronchoscopy and may help by drying secretions , producing bronchodilatation , or preventing vasovagal reactions . The objective of this study was to see whether atropine premedication is really of practical benefit when patients are se date d with i.v . midazolam . DESIGN In a double-blind study , patients were r and omly allocated to receive i.m . atropine ( 0.6 mg ) or saline placebo ( 1 mL ) as premedication 30 to 60 minutes before they were se date d with progressive doses of i.v . midazolam until judged to be lightly asleep . SETTING A District General Hospital in Engl and . PARTICIPANTS One hundred consecutive patients referred for bronchoscopy . MEASUREMENTS AND RESULTS Sample s taken during the procedure were washings for microbiology and cytology and brushings for cytology and biopsy , but no transbronchial biopsies . Peak flow readings were recorded before premedication and before the start of the procedure . During the procedure an estimate was made of pharyngeal and tracheobronchial secretions , bleeding , use of saline to wash out secretions , and local anesthetic needed to control coughing . Patients were monitored for saturation and cardiac rhythm . There was no significant bronchodilatation after premedication in either group , nor were there differences in secretions , use of saline , tracheobronchial bleeding , desaturation , and arrhythmias . More local anesthetic was needed to control coughing in the placebo group ( mean 357 mg vs 331 mg in the atropine group , p=0.02 ) , but this was not of practical significance . CONCLUSION When intravenous midazolam sedation is used for bronchoscopy , atropine premedication is not of benefit [1479636] A prospect i ve study was performed to detect oxygen saturation ( SaO2 ) during and following fiberoptic bronchoscopy ( FOB ) in 50 patients . Twenty-five patients ( group 1 ) underwent the procedure without and 25 ( group 2 ) with supplemental oxygen . The SaO2 declined from the baseline value of 96.4 % to 92.08 % in group 1 and to 94.88 % in group 2 after bronchoscopy alone . The decline was also noted when biopsy and broncho-alveolar lavage ( BAL ) were performed , the lowest values being recorded during BAL . The result showed that the fall in SaO2 in group 2 was significantly less than that in group 1 ( P < 0.05 ) . SaO2 returned to baseline values after a mean time of 4.9 minutes in group 1 and 2.4 minutes in group 2 , demonstrating the benefit of supplemental oxygen [18971092] BACKGROUND Long-term survival of lung transplant ( LT ) recipients is limited by the development of the bronchiolitis obliterans syndrome ( BOS ) . A number of risk factors for BOS have been identified , which can be detected using bronchoscopy with transbronchial biopsy ( TBB ) . Many LT units perform routine surveillance bronchoscopy ( SB ) to detect problems such as : acute rejection ( AR ) ; infection , particularly with cytomegalovirus ( CMV ) ; and lymphocytic bronchiolitis . This study aim ed to assess the safety and efficacy of surveillance bronchoscopy in lung transplant recipients ( LTRs ) , including TBB and bronchoalveolar lavage ( BAL ) . METHODS All bronchoscopy procedures , including SB and clinical ly indicated ( CB ) procedures performed on LTRs in one calendar year , were audited prospect ively . Complications and clinical utility were recorded to determine the clinical utility both early ( 3 months and 3 to 12 months ) and late ( > 12 months ) post-LT . RESULTS In one calendar year , 353 procedures ( 232 SBs and 121 CBs ) were performed on 124 LTRs , with 246 performed < 1 year post-LT . The complication rates were similar to those reported previously , except for an increased rate of sedation-related complications , particularly up to 3 months post-LT . SBs showed high rates of acute rejection , particularly in the first year post-LT ( p = 0.01 ) . The rate of asymptomatic infection diagnosed on BAL remained high regardless of time post-transplant . CONCLUSIONS This study confirms that SB can frequently detect clinical ly significant infection and rejection with very low complication rates . The data support SB with TBB up to 12 months post-LT , and ongoing use of SB with BAL ( only ) to detect clinical ly silent infection beyond 1 year post-LT [2019163] We evaluated nasal anesthesia regimens by comparing , in seven normal men , four drug regimens : 1 ) 1 percent phenylephrine ; 2 ) 4 percent lidocaine ; 3 ) 1 percent phenylephrine + 4 percent lidocaine ; and 4 ) 5 percent cocaine . After spraying each drug into the anterior nares , vasoconstriction , decongestion , and nasal anesthesia ( measured as transnasal depth of nasogastric ( NG ) tube insertion before discomfort ) were assessed . There were no significant differences in NG tube insertion depth between the regimens ( p = 0.54 ) . Insertion depth was significantly increased after 10 ml of 2 percent viscous lidocaine were sniffed ( p less than 0.004 ) , but again , differences between regimens were not significant ( p = 0.051 ) . One hundred bronchoscoped patients received one of the following sprayed into the nose : 1 ) placebo ( P ) ; 2 ) 1 percent phenylephrine + P ; 3 ) 1 percent phenylephrine + 4 percent lidocaine ; or 4 ) 5 percent cocaine + P. Each patient then sniffed viscous lidocaine . There were no significant differences between regimens for any of the following : 1 ) nasal resistance to bronchoscope insertion , 2 ) patient 's nasal discomfort , or 3 ) bronchoscopist 's perception of patient discomfort . We conclude that sprayed anesthetics contribute little to nasal anesthesia and any regimen appears acceptable when viscous lidocaine is used [1147384] The frequencies of fever , parenchymal infiltration , and bacteremia were studied prospect ively after 100 flexible fiberoptic bronchoscopies performed transnasally under topical anesthesia . Fever occurred after 16 per cent , and parenchymal infiltration , after 6 per cent of the procedures . Most complications were mild and transient ; however , one patient developed rapidly progressive pneumonia and died . No organisms were isolated from cultures of blood drawn at the time of the procedure or during complications . The organisms most commonly isolated from the sputum of the patients who developed pneumonia were the aerobic and anaerobic bacteria normally found in the mouth . Isolation of a significant pathogen before the procedure did not predispose to development of a complication . Advanced age ( greater than 60 years ) and the endoscopic findings of abnormalities were significant predisposing factors . Bronchial brushing , but not bronchial biopsy or bronchial washing , was associated with significantly higher complication rates in patients with bronchial carcinomas than in those without a neoplasm . The mechanism of the fever and parenchymal infiltration is thought to be related to obstructive atelectasis and infection produced by organisms present in the airways at the time of the procedures [10027438] STUDY OBJECTIVE To determine whether recipients of lung transplants have a higher risk of bleeding from fiberoptic bronchoscopy ( FOB ) than other patients who undergo the procedure . DESIGN Prospect i ve cohort study . SETTING Bronchoscopy services of Johns Hopkins Hospital , a tertiary referral center and Johns Hopkins Bayview Medical Center , a community hospital . PATIENTS All adult patients ( 18 years ) who underwent FOB between July 1 , 1996 and June 30 , 1997 by the full-time pulmonary medicine staff were included . A total of 720 procedures were performed , including 38 in lung transplant recipients . MEASUREMENTS Bleeding was assessed by review ing physician reports of bloody drainage after the procedure and whether the procedure was terminated early for bleeding . Patient reports of hemoptysis were assessed using question naires administered pre- and post-FOB . Predictor variables included patient demographics , bleeding parameters ( platelets , prothrombin time , and activated partial thromboplastin time ) , immunosuppressive medications , aspirin use , use of transbronchial biopsy , and the time length of the procedure . RESULTS Lung transplant recipients were significantly more likely to have used aspirin prior to FOB ( 18.4 vs 7.2 % , p < 0.05 ) and to undergo transbronchial biopsy ( 64.9 vs 26.8 % , p < 0.001 ) . Lung transplant patients were more likely to have new or worsened hemoptysis ( 53.8 vs 24.6 % , p < 0.001 ) , to have > 25 mL of blood loss ( 44.5 vs 17.5 % , p < 0.001 ) and to have the procedure terminated early for bleeding ( 5.4 vs 1.0 % , p < 0.05 ) . In multivariate analysis , predictors of new or worsened hemoptysis included lung transplant , longer procedure time , and older patient age . Independent predictors of greater blood loss included lung transplant , performance of transbronchial biopsy , longer procedure time , and older patient age . CONCLUSIONS Lung transplant recipients are at higher risk of bleeding from bronchoscopy than are other patients . This propensity to bleed is independent of coagulation parameters , platelet count , immunosuppressive medication use , aspirin use , or performance of transbronchial biopsy . The higher risk of bleeding should be considered when assessing the risks and benefits of bronchoscopy in lung transplant recipients [23455477] INTRODUCTION Pulmonary infiltrates are common within the hematopoietic stem cell transplant ( HSCT ) population and unfortunately portend an increased mortality . Bronchoscopy is often utilized as an initial diagnostic tool , but the literature supporting its diagnostic utility and effect on clinical management varies significantly . The aim of this study was to investigate the diagnostic ability , complication rate , and clinical impact of flexible bronchoscopy ( FB ) in evaluating pulmonary infiltrates in a large HSCT population . PATIENTS AND METHOD Retrospective review of all patients undergoing FB after HSCT in the Bone Marrow Transplant Unit from 1996 to 2009 . RESULTS FB was performed 162times in 144 patients with pulmonary infiltrates yielding positive results in 52.5 % . The most common positive results were bacterial pneumonia ( 31 % ) , fungal pneumonia ( 15 % ) , and alveolar hemorrhage ( 11 % ) . Treatment changes occurred in 44 % of patients after FB . Treatment changes included antibiotic modification ( 59 % ) , addition of corticosteroids ( 21 % ) , antifungal modification ( 12 % ) , and antiviral modification ( 7 % ) . The overall complication rate associated with FB was 30 % , although 84 % of these complications were considered minor . CONCLUSIONS FB in patients with pulmonary infiltrates after HSCT should still be considered a valuable tool in the evaluation and management of pulmonary infiltrates in the HSCT population . Future prospect i ve , multicenter r and omized studies are needed to evaluate the overall clinical impact that bronchoscopic results and management changes have in this unique population [25686147] SETTING Diagnostic flexible bronchoscopy performed in hospitalised and ambulatory patients in a tertiary care academic hospital in Monterrey , Mexico . OBJECTIVE To determine the effect of the route of insertion of the bronchoscope ( oral or nasal ) on patient comfort , vocal cord visualisation , local anaesthetic and sedation requirements and possible complications . DESIGN Prospect i ve study carried out in patients aged ⩾ 18 years with an indication for flexible bronchoscopy . The route of insertion was r and omly assigned . Symptoms related to the procedure were evaluated using a question naire . RESULTS Sixty-three patients were included : 32 in the oral insertion group and 31 in the nasal insertion group . There was no statistically significant difference in patient discomfort ( 1.91 ± 2.95 vs. 2.39 ± 3.56 points on a scale of 1 to 10 , P = 0.74 ) or procedural complications ( 4 vs. 0 events , P = 0.12 ) between study groups . Oral insertion was associated with less time to vocal cord visualisation ( 25.5 ± 156 s vs. 56 ± 61 s , P < 0.01 ) , lower requirement for lidocaine ( 15 ± 7.50 vs. 16 ± 4 ml , P = 0.01 ) and fewer insertion failures ( 0 vs. 6 cases , P < 0.01 ) . CONCLUSIONS With intravenous sedoanalgesia , route of insertion did not affect patient comfort . However , the oral route was associated with faster vocal cord visualisation , less use of lidocaine and no insertion failure [21058940] Background : Propofol is an excellent sedative agent for use in patients undergoing bronchoscopy . The addition of an opioid to propofol can be advantageous because of the antitussive effect of the opioid and the possible improvement in sedation quality . However , it may increase the risk of hypoxaemia . To investigate the effect of the addition of alfentanil to propofol , we performed a prospect i ve study to compare propofol‐only sedation with propofol – alfentanil combination sedation in patients undergoing bronchoscopy Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: OBJECTIVES The aim of this review was to search existing literature to identify comfort interventions that can be used to assist an adult patient to undergo complex radiotherapy requiring positional stability for periods greater than 10 min . The objectives of this review were to ; 1 ) identify comfort interventions used for clinical procedures that involve sustained inactivity similar to radiotherapy ; 2 ) define characteristics of comfort interventions for future practice ; and 3 ) determine the effectiveness of identified comfort interventions . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

31090070

[4672709] Abstract The treatment of uncomplicated severe acute malnutrition ( SAM ) requires substantial amounts of ready‐to‐use therapeutic food ( RUTF ) . In 2009 , Action Contre la F aim anticipated a shortfall of RUTF for their nutrition programme in Myanmar . A low‐dose RUTF protocol to treat children with uncomplicated SAM was adopted . In this protocol , RUTF was dosed according to beneficiary 's body weight , until the child reached a Weight‐for‐Height z‐score of ≥−3 and mid‐upper arm circumference ≥110 mm . From this point , the child received a fixed quantity of RUTF per day , independent of body weight until discharge . Specific measures were implemented as part of this low‐dose RUTF protocol in order to improve service quality and beneficiary support . We analysed individual records of 3083 children treated from July 2009 to January 2010 . Up to 90.2 % of children recovered , 2.0 % defaulted and 0.9 % were classified as non‐responders . No deaths were recorded . Among children who recovered , median [ IQR ] length of stay and weight gain were 42 days [ 28 ; 56 ] and 4.0 g kg–1 day–1 [ 3.0 ; 5.7 ] , respectively . Multivariable logistic regression showed that children older than 48 months had higher odds of non‐response to treatment than younger children ( adjusted odds ratio : 3.51 , 95 % CI : 1.67–7.42 ) . Our results indicate that a low‐dose RUTF protocol , combined with specific measures to ensure good service quality and beneficiary support , was successful in treating uncomplicated SAM in this setting . This programmatic experience should be vali date d by r and omised studies aim ing to test , quantify and attribute the effect of the protocol adaptation and programme improvements presented here [4407555] Background Ready-to-use therapeutic foods ( RUTF ) are lipid-based pastes widely used in the treatment of acute malnutrition . Current specifications for RUTF permit a high n-6 polyunsaturated fatty acid ( PUFA ) content and low n-3 PUFA , with no stipulated requirements for preformed long-chain n-3 PUFA . The objective of this study was to develop an RUTF with elevated short-chain n-3 PUFA and measure its impact , with and without fish oil supplementation , on children ’s PUFA status during treatment of severe acute malnutrition . Methods This r and omized controlled trial in children with severe acute malnutrition in rural Kenya included 60 children aged 6 to 50 months who were r and omized to receive i ) RUTF with st and ard composition ; ii ) RUTF with elevated short chain n-3 PUFA ; or iii ) RUTF with elevated short chain n-3 PUFA plus fish oil capsules . Participants were followed-up for 3 months . The primary outcome was erythrocyte PUFA composition . Results Erythrocyte docosahexaenoic acid ( DHA ) content declined from baseline in the two arms not receiving fish oil . Erythrocyte long-chain n-3 PUFA content following treatment was significantly higher for participants in the arm receiving fish oil than for those in the arms receiving RUTF with elevated short chain n-3 PUFA or st and ard RUTF alone : 3 months after enrolment , DHA content was 6.3 % ( interquartile range 6.0–7.3 ) , 4.5 % ( 3.9–4.9 ) , and 3.9 % ( 2.4–5.7 ) of total erythrocyte fatty acids ( P < 0.001 ) , respectively , while eicosapentaenoic acid ( EPA ) content was 2.0 % ( 1.5–2.6 ) , 0.7 % ( 0.6–0.8 ) , and 0.4 % ( 0.3–0.5 ) ( P < 0.001 ) . RUTF with elevated short chain n-3 PUFA and fish oil capsules were acceptable to participants and carers , and there were no significant differences in safety outcomes . Conclusions PUFA requirements of children with SAM are not met by current formulations of RUTF , or by an RUTF with elevated short-chain n-3 PUFA without additional preformed long-chain n-3 PUFA . Clinical and growth implication s of revised formulations need to be addressed in large clinical trials . Trial registration Clinical trials.gov NCT01593969 . Registered 4 May 2012 [17030533] To measure the success rate of three different strategies used in Médecins Sans Frontières large-scale therapeutic nutritional rehabilitation programme in Niger , we analysed three cohorts of severely malnourished patients in terms of daily weight gain , length of stay , recovery , case fatality and defaulting . A total of 1937 children aged 6 - 59 months were followed prospect ively from 15 August 2002 to 21 October 2003 . For the three cohorts , 660 children were maintained in the therapeutic feeding centre ( TFC ) during the entire treatment , 937 children were initially treated at the TFC and completed treatment at home and 340 children were exclusively treated at home . For all cohorts , average time in the programme and average weight gain met the international st and ards ( 30 - 40 days , > 8 g/kg/day ) . Default rates were 28.1 , 16.8 and 5.6 % for TFC only , TFC plus home-based and home-based alone strategies , respectively . The overall case fatality rate for the entire programme was 6.8 % . Case fatality rates were 18.9 % for TFC only and 1.7 % for home-based alone . No deaths were recorded in children transferred to rehabilitation at home . This study suggests that satisfactory results for the treatment of severe malnutrition can be achieved using a combination of home and hospital-based strategies [19591885] The aim of this study was to test the ability of two new products , an instant infant flour and a food supplement containing amylases , to increase energy and micronutrient intakes of infants older than 6 months . Three groups of 48 infants were r and omly constituted . Infants in groups 1 and 2 consumed at least twice a day gruel made either from the instant flour or from the food supplement . Infants from the control group received complementary foods prepared in the usual way . Each infant was surveyed during a whole day in order to measure feeding frequencies and characteristics as well as amounts of the different types of complementary foods consumed . Foods consumed by infants in the two experimental groups differed considerably in energy , micronutrient density and in consistency from the home-made complementary foods . Due to the incorporation of amylases , gruels made from the food supplement had a higher energy density , a more appropriate consistency and result ed in higher intakes per meal than gruels made from instant flour . In comparison with home-made complementary foods , both experimental products result ed in significantly higher energy and nutrient intakes . The two experimental products appeared to increase sufficiently both energy and nutrient intakes of infants to complement their breastmilk intake [5833365] The number of published systematic review s of studies of healthcare interventions has increased rapidly and these are used extensively for clinical and policy decisions . Systematic review s are subject to a range of biases and increasingly include non-r and omised studies of interventions . It is important that users can distinguish high quality review s. Many instruments have been design ed to evaluate different aspects of review s , but there are few comprehensive critical appraisal instruments . AMSTAR was developed to evaluate systematic review s of r and omised trials . In this paper , we report on the updating of AMSTAR and its adaptation to enable more detailed assessment of systematic review s that include r and omised or non-r and omised studies of healthcare interventions , or both . With moves to base more decisions on real world observational evidence we believe that AMSTAR 2 will assist decision makers in the identification of high quality systematic review s , including those based on non-r and omised studies of healthcare interventions [5841493] Trial design Three feeding regimens— central ly produced ready-to-use therapeutic food , locally produced ready-to-use therapeutic food , and augmented , energy-dense , home-prepared food — were provided in a community setting for children with severe acute malnutrition ( SAM ) in the age group of 6–59 months in an individually r and omised multicentre trial that enrolled 906 children . Foods , counselling , feeding support and treatment for mild illnesses were provided until recovery or 16 weeks . Methods Costs were estimated for 371 children enrolled in Delhi in a semiurban location after active survey and identification , enrolment , diagnosis and treatment for mild illnesses , and finally treatment with one of the three regimens , both under the research and government setting . Direct costs were estimated for human re sources using a price times quantity approach , based on their salaries and average time taken for each activity . The cost per week per child for food , medicines and other consumables was estimated based on the total expenditure over the period and children covered . Indirect costs for programme management including training , transport , non-consumables , infrastructure and equipment were estimated per week per child based on total expenditures for research study and making suitable adjustments for estimations under government setting . Results No significant difference in costs was found across the three regimens per covered or per treated child . The average cost per treated child in the government setting was estimated at US$ 56 ( < 3500 rupees ) . Conclusion Home-based management of SAM with a locally produced ready-to-use therapeutic food is feasible , acceptable , affordable and very cost-effective in terms of the disability-adjusted life years saved and gross national income per capita of the country . The treatment of SAM at home needs serious attention and integration into the existing health system , along with actions to prevent SAM . Trial registration number NCT01705769 ; Pre- results [15817865] BACKGROUND Childhood malnutrition is common in Malawi , and the st and ard treatment , which follows international guidelines , results in poor recovery rates . Higher recovery rates have been seen in pilot studies of home-based therapy with ready-to-use therapeutic food ( RUTF ) . OBJECTIVE The objective was to compare the recovery rates among children with moderate and severe wasting , kwashiorkor , or both receiving either home-based therapy with RUTF or st and ard inpatient therapy . DESIGN A controlled , comparative , clinical effectiveness trial was conducted in southern Malawi with 1178 malnourished children . Children were systematic ally allocated to either st and ard therapy ( 186 children ) or home-based therapy with RUTF ( 992 children ) according to a stepped wedge design to control for bias introduced by the season of the year . Recovery , defined as reaching a weight-for-height z score > -2 , and relapse or death were the primary outcomes . The rate of weight gain and the prevalence of fever , cough , and diarrhea were the secondary outcomes . RESULTS Children who received home-based therapy with RUTF were more likely to achieve a weight-for-height z score > -2 than were those who received st and ard therapy ( 79 % compared with 46 % ; P < 0.001 ) and were less likely to relapse or die ( 8.7 % compared with 16.7 % ; P < 0.001 ) . Children who received home-based therapy with RUTF had greater rates of weight gain ( 3.5 compared with 2.0 g . kg(-1 ) . d(-1 ) ; difference : 1.5 ; 95 % CI : 1.0 , 2.0 g . kg(-1 ) . d(-1 ) ) and a lower prevalence of fever , cough , and diarrhea than did children who received st and ard therapy . CONCLUSION Home-based therapy with RUTF is associated with better outcomes for childhood malnutrition than is st and ard therapy [18287372] Poor complementary feeding practice s are associated with stunting and growth faltering throughout the developing world . The objective was to compare the effect of using peanut-/soy-based fortified spread ( FS ) and corn porridge fortified with fish powder ( FP ) as complementary foods on growth in rural Malawian children . A total of 240 children were enrolled at the age of 6 mo and r and omized to receive FS or FP . Both complementary foods provided 836 kJ/d from 6 to 9 mo of age and 1254 kJ/d from 9 to 18 mo of age . Children were followed monthly for anthropometry and fortnightly for the symptoms of fever , cough , or diarrhea until they were 18 mo old . Zn and Se status were assessed at 6 and 12 mo . The primary outcomes were the rates of weight and length gain from 6 - 12 mo and from 12 - 18 mo . Children who received FS gained 110 g more ( 95 % CI 220 to 10 ) from 6 - 12 mo of age than children receiving FP . Weight gain did not differ between children receiving FS and FP between 12 and 18 mo of age , nor did statural growth from 6 to 12 mo or 12 to 18 mo . A total of 23 % of all children were Zn deficient at 6 mo of age and this increased to 37 % at 12 mo of age . Neither FS nor FP was associated with significantly improved Zn status . FS was associated with better weight gain from 6 - 12 mo of age and may be useful in conjunction with additional interventions to improve infant growth in the developing world [15447908] BACKGROUND Multiple micronutrient deficiencies are often the basic causative factor in stunting and anemia , 2 conditions that affect entire generations of children in deprived population s. No generally accepted recommendations for micronutrient intakes for recovery from stunting are available . OBJECTIVE The objective was to assess the effect of a highly nutrient-dense spread fortified with vitamins and minerals , with or without antiparasitic metronidazole treatment , in correcting retarded linear growth and reducing anemia in stunted children . DESIGN Saharawi refugee children ( n = 374 ) aged 3 - 6 y with initial height-for-age z scores < -2 were assigned to 1 of 5 groups : fortified spread ( FS ) , fortified spread plus metronidazole ( FS+M ) , unfortified spread ( US ) , unfortified spread plus metronidazole ( US+M ) , or control . Supervised supplementation was given daily for 6 mo . Weight , height , knee-heel length , hematologic indexes , parasitic infections , and morbidity were assessed at 0 , 3 , and 6 mo . RESULTS Linear growth of children fed FS was 30 % faster at 3 mo than in US and control groups , after which height-for-age z scores increased only slightly in the FS group and remained unchanged in the other groups . No additional benefits from metronidazole were observed . Increase in hemoglobin concentrations in the FS group at 6 mo was twofold that in the US and control groups ( 37 + /- 40 , 19 + /- 15 , and 16 + /- 17 g/L , respectively ; P < 0.0001 ) , and anemia was reduced by nearly 90 % . CONCLUSIONS FS , and not US , induces catch-up growth in stunted children whose diets are poor in micronutrients . Our trial provides support for delivering multiple micronutrients to reverse stunting and reduce anemia in children up to age 6 [12885713] BACKGROUND The World Health Organization recommends a liquid , milk-based diet ( F100 ) during the rehabilitation phase of the treatment of severe malnutrition . A dry , solid , ready-to-use food ( RTUF ) that can be eaten without adding water has been proposed to eliminate the risk of bacterial contamination from added water . The efficacies of RTUF and F100 have not been compared . OBJECTIVE The objective was to compare the efficacy of RTUF and F100 in promoting weight gain in malnourished children . DESIGN In an open-labeled , r and omized trial , 70 severely malnourished Senegalese children aged 6 - 36 mo were r and omly allocated to receive 3 meals containing either F100 ( n = 35 ) or RTUF ( n = 35 ) in addition to the local diet . The data from 30 children in each group were analyzed . RESULTS The mean ( + /- SD ) daily energy intake in the RTUF group was 808 + /- 280 ( 95 % CI : 703.8 , 912.9 ) kJ x kg body wt(-1 ) x d(-1 ) , and that in the F100 group was 573 + /- 201 ( 95 % CI : 497.9 , 648.7 ) kJ. kg body wt(-1 ) x d(-1 ) ( P < 0.001 ) . The average weight gains in the RTUF and F100 groups were 15.6 ( 95 % CI : 13.4 , 17.8 ) and 10.1 ( 95 % CI : 8.7 , 11.4 ) g x kg body wt(-1 ) x d(-1 ) , respectively ( P < 0.001 ) . The difference in weight gain was greater in the most wasted children ( P < 0.05 ) . The average duration of rehabilitation was 17.3 ( 95 % CI : 15.6 , 19.0 ) d in the F100 group and was 13.4 ( 95 % CI : 12.1 , 14.7 ) d in the RTUF group ( P < 0.001 ) . CONCLUSIONS This study indicated that RTUF can be used efficiently for the rehabilitation of severely malnourished children [5932190] Summary Background In sub-Saharan Africa , severely immunocompromised HIV-infected individuals have a high risk of mortality during the first few months after starting antiretroviral therapy ( ART ) . We hypothesise that universally providing ready-to-use supplementary food ( RUSF ) would increase early weight gain , thereby reducing early mortality compared with current guidelines recommending ready-to-use therapeutic food ( RUTF ) for severely malnourished individuals only . Methods We did a 2 × 2 × 2 factorial , open-label , parallel-group trial at inpatient and outpatient facilities in eight urban or periurban regional hospitals in Kenya , Malawi , Ug and a , and Zimbabwe . Eligible participants were ART-naive adults and children aged at least 5 years with confirmed HIV infection and a CD4 cell count of fewer than 100 cells per μL , who were initiating ART at the facilities . We r and omly assigned participants ( 1:1 ) to initiate ART either with ( RUSF ) or without ( no-RUSF ) 12 weeks ' of peanut-based RUSF containing 1000 kcal per day and micronutrients , given as two 92 g packets per day for adults and one packet ( 500 kcal per day ) for children aged 5–12 years , regardless of nutritional status . In both groups , individuals received supplementation with RUTF only when severely malnourished ( ie , body-mass index [ BMI ] < 16–18 kg/m2 or BMI -for-age Z scores < –3 for children ) . We did the r and omisation with computer-generated , sequentially numbered tables with different block sizes incorporated within an online data base . R and omisation was stratified by centre , age , and two other factorial r and omisations , to 12 week adjunctive raltegravir and enhanced anti-infection prophylaxis ( reported elsewhere ) . Clinic visits were scheduled at weeks 2 , 4 , 8 , 12 , 18 , 24 , 36 , and 48 , and included nurse assessment of vital status and symptoms and dispensing of all medication including ART and RUSF . The primary outcome was mortality at week 24 , analysed by intention to treat . Secondary outcomes included absolute changes in weight , BMI , and mid-upper-arm circumference ( MUAC ) . Safety was analysed in all r and omly assigned participants . Follow-up was 48 weeks . This trial is registered with Clinical Trials.gov ( NCT01825031 ) and the IS RCT N registry ( 43622374 ) . Findings Between June 18 , 2013 , and April 10 , 2015 , we r and omly assigned 1805 participants to treatment : 897 to RUSF and 908 to no-RUSF . 56 ( 3 % ) were lost-to-follow-up . 96 ( 10·9 % , 95 % CI 9·0–13·1 ) participants allocated to RUSF and 92 ( 10·3 % , 8·5–12·5 ) to no-RUSF died within 24 weeks ( hazard ratio 1·05 , 95 % CI 0·79–1·40 ; log-rank p=0·75 ) , with no evidence of interaction with the other r and omisations ( both p>0·7 ) . Through 48 weeks , adults and adolescents aged 13 years and older in the RUSF group had significantly greater gains in weight , BMI , and MUAC than the no-RUSF group ( p=0·004 , 0·004 , and 0·03 , respectively ) . The most common type of serious adverse event was specific infections , occurring in 90 ( 10 % ) of 897 participants assigned RUSF and 87 ( 10 % ) of 908 assigned no-RUSF . By week 48 , 205 participants had serious adverse events in both groups ( p=0·81 ) , and 181 had grade 4 adverse events in the RUSF group compared with 172 in the non-RUSF group ( p=0·45 ) . Interpretation In severely immunocompromised HIV-infected individuals , providing RUSF universally at ART initiation , compared with providing RUTF to severely malnourished individuals only , improved short-term weight gain but not mortality . A change in policy to provide nutritional supplementation to all severely immunocompromised HIV-infected individuals starting ART is therefore not warranted at present . Funding Joint Global Health Trials Scheme ( UK Medical Research Council , UK Department for International Development , and Wellcome Trust ) [15981758] Aim : To determine if home‐based nutritional therapy will benefit a significant fraction of malnourished , HIV‐infected Malawian children , and to determine if ready‐to‐use therapeutic food ( RUTF ) is more effective in home‐based nutritional therapy than traditional foods . Methods : 93 HIV‐positive children > 1 y old discharged from the nutrition unit in Blantyre , Malawi were systematic ally allocated to one of three dietary regimens : RUTF , RUTF supplement or blended maize/soy flour . RUTF and maize/soy flour provided 730 kJ·kg−1·d−1 , while the RUTF supplement provided a fixed amount of energy , 2100 kJ/d . These children did not receive antiretroviral chemotherapy . Children were followed fortnightly . Children completed the study when they reached 100 % weight‐for‐height , relapsed or died . Outcomes were compared using regression modeling to account for differences in the severity of malnutrition between the dietary groups . Results : 52/93 ( 56 % ) of all children reached 100 % weight‐for‐height . Regression modeling found that the children receiving RUTF gained weight more rapidly and were more likely to reach 100 % weight‐for‐height than the other two dietary groups ( p<0.05 ) [15155403] Background : The st and ard treatment of severe malnutrition in Malawi often utilises prolonged inpatient care , and after discharge results in high rates of relapse . Aims : To test the hypothesis that the recovery rate , defined as catch-up growth such that weight-for-height z score > 0 ( WHZ , based on initial height ) for ready-to-use food ( RTUF ) is greater than two other home based dietary regimens in the treatment of malnutrition . Methods : HIV negative children > 1 year old discharged from the nutrition unit in Blantyre , Malawi were systematic ally allocated to one of three dietary regimens : RTUF , RTUF supplement , or blended maize/soy flour . RTUF and maize/soy flour provided 730 kJ/kg/day , while the RTUF supplement provided a fixed amount of energy , 2100 kJ/day . Children were followed fortnightly . Children completed the study when they reached WHZ > 0 , relapsed , or died . Outcomes were compared using a time-event model . Results : A total of 282 children were enrolled . Children receiving RTUF were more likely to reach WHZ > 0 than those receiving RTUF supplement or maize/soy flour ( 95 % v 78 % , RR 1.2 , 95 % CI 1.1 to 1.3 ) . The average weight gain was 5.2 g/kg/day in the RTUF group compared to 3.1 g/kg/day for the maize/soy and RTUF supplement groups . Six months later , 96 % of all children that reached WHZ > 0 were not wasted . Conclusions : Home based therapy of malnutrition with RTUF was successful ; further operational work is needed to implement this promising therapy [19595348] BACKGROUND Severe acute malnutrition affects 13 million children worldwide and causes 1 - 2 million deaths every year . Our aim was to assess the clinical and nutritional efficacy of a probiotic and prebiotic functional food for the treatment of severe acute malnutrition in a HIV-prevalent setting . METHODS We recruited 795 Malawian children ( age range 5 to 168 months [ median 22 , IQR 15 to 32 ] ) from July 12 , 2006 , to March 7 , 2007 , into a double-blind , r and omised , placebo-controlled efficacy trial . For generalisability , all admissions for severe acute malnutrition treatment were eligible for recruitment . After stabilisation with milk feeds , children were r and omly assigned to ready-to-use therapeutic food either with ( n=399 ) or without ( n=396 ) Synbiotic2000 Forte . Average prescribed Synbiotic dose was 10(10 ) colony-forming units or more of lactic acid bacteria per day for the duration of treatment ( median 33 days ) . Primary outcome was nutritional cure ( weight-for-height > 80 % of National Center for Health Statistics median on two consecutive outpatient visits ) . Secondary outcomes included death , weight gain , time to cure , and prevalence of clinical symptoms ( diarrhoea , fever , and respiratory problems ) . Analysis was on an intention-to-treat basis . This trial is registered as an International St and ard R and omised Controlled Trial , number IS RCT N19364765 . FINDINGS Nutritional cure was similar in both Synbiotic and control groups ( 53.9 % [ 215 of 399 ] and 51.3 % [ 203 of 396 ] ; p=0.40 ) . Secondary outcomes were also similar between groups . HIV seropositivity was associated with worse outcomes overall , but did not modify or confound the negative results . Subgroup analyses showed possible trends towards reduced outpatient mortality in the Synbiotic group ( p=0.06 ) . INTERPRETATION In Malawi , Synbiotic2000 Forte did not improve severe acute malnutrition outcomes . The observation of reduced outpatient mortality might be caused by bias , confounding , or chance , but is biologically plausible , has potential for public health impact , and should be explored in future studies . FUNDING Department for International Development ( DfID ) [26121696] Background : Ready-to-use therapeutic food ( RUTF ) has been found effective in treating severe acute malnutrition . Vietnam ’s National Institute of Nutrition ( NIN ) , the Institut de Recherche pour le Développement ( IRD ) , and UNICEF collaborated to formulate a local RUTF called High-Energy Bar for Integrated Management of Acute Malnutrition ( HEBI ) . RUTF might be useful to address malnutrition in HIV patients . Objective : To compare the acceptability of the local RUTF and an imported RUTF among malnourished people with HIV in Vietnam Methods : The acceptability of HEBI and Plumpy’Nut was studied among 80 HIV-positive children and 80 HIV-positive adults . In a crossover design , participants were r and omly assigned to receive either Plumpy’Nut or HEBI for 2 weeks and were switched to the other product for the subsequent 2 weeks . A third ( control ) group of about 40 HIV-positive participants in each study was r and omly assigned to receive no RUTF . Nurses took anthropometric measurements weekly , and the subjects or their caregivers monitored daily RUTF intake . Results : Children consumed 69 % of HEBI and 65 % of Plumpy’Nut ( p = .13 ) . Adults consumed 91 % of HEBI and 81 % of Plumpy’Nut ( p = .059 ) . Both children ( p = .058 ) and adults ( p ≤ .0001 ) preferred HEBI . Significant gains were observed in percent weight ( p = .035 ) , weight-for-age ( p = .014 ) , and body mass index ( BMI ) -for-age ( p = .036 ) in children who received RUTF and in percent weight ( p = .017 ) and BMI ( p = .0048 ) in adults who received RUTF compared with the control groups . Conclusions : In this study in Vietnam , both HEBI and Plumpy’Nut were found acceptable by people with HIV [15269617] Objectives : To determine the efficacy of home-based therapy with ready-to-use food ( RTUF ) in producing catch-up growth in malnourished children and to compare locally produced RTUF with imported RTUF for this purpose . Methods : After a brief inpatient stabilization , 260 children with severe malnutrition were enrolled and systematic ally allocated to receive home therapy with either imported , commercially produced RTUF or locally produced RTUF . Each child received 730 kJ/kg/day and was followed up fortnightly . Children completed the study when they reached a weight-for-height Z score > −0.5 ( WHZ ) , relapsed , died , or failed to achieve WHZ > −0.5 after 16 weeks . Analyses were stratified by human immunodeficiency virus ( HIV ) status . Results : 78 % of all children reached WHZ > −0.5 , 95 % of those with HIV-negative status and 59 % of those with HIV-positive status . Eighty percent of those receiving locally produced RTUF and 75 % of those receiving imported RTUF reached WHZ > −0.5 . The difference between recovery rates was 5 % ( 95 % confidence interval [ CI ] , −5–15 % ) . The rate of weight gain was 0.4 g/kg/day ( 95 % CI , −0.6 , 1.4 ) greater among children receiving locally produced RTUF . The prevalence of diarrhea reported by mothers was 3.7 % for locally produced RTUF and 4.3 % for imported RTUF . After completion of home therapy and resumption of habitual diet for 6 months , 91 % of all children maintained a normal WHZ . Conclusions : Home-based therapy with RTUF was successful in affecting complete catch-up growth . In this study , locally produced and imported RTUF were similar in efficacy in treating of severe childhood malnutrition [5345228] Background Children in third world countries suffer from severe acute malnutrition ( SAM ) in an extent of public health important . SAM management protocol available this time brought the approach from facility-based to community-based by Outpatient Therapeutic Program ( OTP ) . But , little was known about the treatment outcomes of the program in Ethiopia . Thus , this study was aim ed to assess treatment outcomes of SAM and identify factors associated among children treated at OTP in Wolaita Zone . Methods A retrospective facility-based cross-sectional study was conducted in OTP records of 794 children , treated at 24 health posts retrieved from January to December 2014 . Population proportion to size ( PPS ) was used to allocate sample for each selected district and OTP sites within district . Individual cards of children were selected by systematic r and om sampling . Data were entered , thoroughly cleaned , and analyzed in SPSS version 20 . Results The recovery rate was revealed as 64.9 % at 95 % CI ( 61 , 68 ) . Death rate , default rate , weight gain , and length of stay were 1.2 % , 2.2 % , 4.2 g/kg/day , and 6.8 weeks respectively . Children living in < 25 min were with 1.53 times higher odds of recovery than children residing in ≥25 min ( AOR = 1.53 at 95 % CI ( 1.11 , 2.12 ) ) . The likelihood of recovery was 2.6 times higher for children with kwashiorkor than for those with marasmus ( AOR = 2.62 at 95 % CI ( 1.77 , 3.89 ) ) . Likewise , children provided with amoxicillin were 1.52 times more likely to recover compared to their counterparts ( AOR = 1.52 at 95 % CI ( 1.09 , 2.11 ) ) . Conclusions The recovery rate and weight gain were lower than sphere st and ard . Distance from OTP , provision of amoxicillin , and type of malnutrition were factors identified as significantly associated with treatment outcome of SAM . Building capacity of OTP service providers and regular monitoring of service provision based on the management protocol were recommended [20332221] St and ard nutritional treatment of moderate acute malnutrition ( MAM ) relies on fortified blended flours though their importance to treat this condition is a matter of discussion . With the newly introduced World Health Organization growth st and ards , more children at an early stage of malnutrition will be treated following the dietary protocol s as for severe acute malnutrition , including ready-to-use therapeutic food ( RUTF ) . We compared the effectiveness of RUTF and a corn/soy-blend (CSB)-based pre-mix for the treatment of MAM in the supplementary feeding programmes ( SFPs ) supported by Médecins Sans Frontières , located in the Zinder region ( south of Niger ) . Children measuring 65 to < 110 cm , newly admitted with MAM [ weight-for-height ( WHM% ) between 70 % and < 80 % of the NCHS median ] were r and omly allocated to receive either RUTF ( Plumpy'Nut ® , 1000 kcal day(-1 ) ) or a CSB pre-mix ( 1231 kcal day(-1 ) ) . Other interventions were similar in both groups ( e.g. weekly family ration and ration at discharge ) . Children were followed weekly up to recovery ( WHM% ≥ 85 % for 2 consecutive weeks ) . In total , 215 children were recruited in the RUTF group and 236 children in the CSB pre-mix group with an overall recovery rate of 79.1 and 64.4 % , respectively ( p < 0.001 ) . There was no evidence for a difference between death , defaulter and non-responder rates . More transfers to the inpatient Therapeutic Feeding Centre ( I-TFC ) were observed in the CSB pre-mix group ( 19.1 % ) compared to the RUTF group ( 9.3 % ) ( p = 0.003 ) . The average weight gain up to discharge was 1.08 g kg(-1 ) day(-1 ) higher in the RUTF group [ 95 % confidence interval : 0.46 - 1.70 ] and the length of stay was 2 weeks shorter in the RUTF group ( p < 0.001 ) . For the treatment of childhood MAM in Niger , RUTF result ed in a higher weight gain , a higher recovery rate , a shorter length of stay and a lower transfer rate to the I-TFC compared to a CSB pre-mix . This might have important implication s on the efficacy and the quality of SFPs [28125907] Background : Severe acute malnutrition ( SAM ) is a salient health problem in India . Federation of Indian Chamber of Commerce and Industry ( FICCI ) Research and Analysis Centre , New Delhi , prepared nutreal equivalent to ready-to-use therapeutic food by World Health Organization ( WHO ) for the management of SAM and defined food like homemade diet . Objective : To compare acceptability and efficacy of nutreal over defined food for the management of SAM . Methods : One hundred twelve children aged less than 5 years with SAM were enrolled as per the st and ard of WHO . Children were r and omized into 2 groups to receive nutreal ( n = 56 ) and defined food ( n = 56 ) in unlimited amounts for 42 consecutive days and extended by 2 weeks as per dem and . Calorie and protein intake , weight , and mid-upper arm circumference ( MUAC ) were recorded daily . Results : Age range was 8 to 45 months . Ninety-three percent of children eagerly accepted nutreal but 7 % does not . Whereas in the defined food group , 68 % accepted eagerly , 30 % did not accept eagerly , and 1.8 % accepted poorly ( P = .004 ) . At enrollment , mean weight in the nutreal group was 6.44 ± 1.60 kg and in the defined food group was 8.69 ± 1.76 kg , with MUAC in the nutreal group being 11.12 ± 0.47 cm and in the defined food group being 11.54 ± 0.34 cm . Mean weight in the nutreal and defined food groups at eighth week of intervention was 7.97 ± 1.8 kg and 9.71 ± 1.8 kg ( P < .001 ) , respectively . Mid-upper arm circumference at eighth week was 12.10 ± 0.29 cm in the nutreal group and 12.49 ± 0.50 cm in the defined group ( P < .001 ) . Conclusion : Acceptability , mean weight gain , and MUAC in the nutreal group are greater than the defined food [6860310] Abstract The cost of ready‐to‐use therapeutic food ( RUTF ) used in community‐based management of acute malnutrition has been a major obstacle to the scale up of this important child survival strategy . The current st and ard recipe for RUTF [ peanut‐based RUTF ( P‐RUTF ) ] is made from peanut paste , milk powder , oil , sugar , and minerals and vitamins . Milk powder forms about 30 % of the ingredients and may represent over half the cost of the final product . The quality of whey protein concentrates 34 % ( WPC34 ) is similar to that of dried skimmed milk ( DSM ) used in the st and ard recipe and can be 25–33 % cheaper . This blinded , parallel group , r and omised , controlled non‐inferiority clinical trial tested the effectiveness in treating severe acute malnutrition ( SAM ) of a new RUTF formulation WPC‐RUTF in which WPC34 was used to replace DSM . Average weight gain ( non‐inferiority margin Δ = −1.2 g kg−1 day−1 ) and recovery rate ( Δ = −10 % ) were the primary outcomes , and length of stay ( LOS ) was the secondary outcome ( Δ = + 14 days ) . Both per‐ protocol ( PP ) and intention‐to‐treat ( ITT ) analyses showed that WPC‐RUTF was not inferior to P‐RUTF for recovery rate [ difference and its 95 % confidence interval ( CI ) of 0.5 % ( 95 % CI –2.7 , 3.7 ) in PP analysis and 0.6 % ( 95 % CI –5.2 , 6.3 ) in ITT analysis ] for average weight gain [ 0.2 ( −0.5 ; 0.9 ) for both analyses ] and LOS [ −1.6 days ( 95 % CI , −4.6 , 1.4 days ) in PP analysis and −1.9 days ( 95 % CI , −4.6 , 0.8 days ) for ITT analysis ] . In conclusion , whey protein‐based RUTF is an effective cheaper alternative to the st and ard milk‐based RUTF for the treatment of SAM [5916722] Background Acute malnutrition is currently divided into severe ( SAM ) and moderate ( MAM ) based on level of wasting . SAM and MAM currently have separate treatment protocol s and products , managed by separate international agencies . For SAM , the dose of treatment is allocated by the child ’s weight . A combined and simplified protocol for SAM and MAM , with a st and ardised dose of ready-to-use therapeutic food ( RUTF ) , is being trialled for non-inferior recovery rates and may be more cost-effective than the current st and ard protocol s for treating SAM and MAM . Method This is the protocol for the economic evaluation of the ComPAS trial , a cluster-r and omised controlled , non-inferiority trial that compares a novel combined protocol for treating uncomplicated acute malnutrition compared to the current st and ard protocol in South Sudan and Kenya . We will calculate the total economic costs of both protocol s from a societal perspective , using accounting data , interviews and survey question naires . The incremental cost of implementing the combined protocol will be estimated , and all costs and outcomes will be presented as a cost-consequence analysis . Incremental cost-effectiveness ratio will be calculated for primary and secondary outcome , if statistically significant . Discussion We hypothesise that implementing the combined protocol will be cost-effective due to streamlined logistics at clinic level , reduced length of treatment , especially for MAM , and reduced dosages of RUTF . The findings of this economic evaluation will be important for policymakers , especially given the hypothesised non-inferiority of the main health outcomes . The publication of this protocol aims to improve rigour of conduct and transparency of data collection and analysis . It is also intended to promote inclusion of economic evaluation in other nutrition intervention studies , especially for MAM , and improve comparability with other studies .Trial Registration IS RCT N 30393230 , date : 16/03/2017 [5978994] Background Acute malnutrition is a continuum condition , but severe and moderate forms are treated separately , with different protocol s and therapeutic products , managed by separate United Nations agencies . The Combined Protocol for Acute Malnutrition Study ( ComPAS ) aims to simplify and unify the treatment of uncomplicated severe and moderate acute malnutrition ( SAM and MAM ) for children 6–59 months into one protocol in order to improve the global coverage , quality , continuity of care and cost-effectiveness of acute malnutrition treatment in re source -constrained setting s. Methods / design This study is a multi-site , cluster r and omized non-inferiority trial with 12 clusters in Kenya and 12 clusters in South Sudan . Participants are 3600 children aged 6–59 months with uncomplicated acute malnutrition . This study will evaluate the impact of a simplified and combined protocol for the treatment of SAM and MAM compared to the st and ard protocol , which is the national treatment protocol in each country . We will assess recovery rate as a primary outcome and coverage , defaulting , death , length of stay , average weekly weight gain and average weekly mid-upper arm circumference ( MUAC ) gain as secondary outcomes . Recovery rate is defined across both treatment arms as MUAC ≥125 mm and no oedema for two consecutive visits . Per- protocol and intention-to-treat analyses will be conducted . Discussion If the combined protocol is shown to be non-inferior to the st and ard protocol , updating guidelines to use the combined protocol would eliminate the need for separate products , re sources and procedures for MAM treatment . This would likely be more cost-effective , increase availability of services , enable earlier case finding and treatment before deterioration of MAM into SAM , promote better continuity of care and improve community perceptions of the programme . Trial registration IS RCT N , IS RCT N30393230 . Registered on 16 March 2017 [1386687] Background Malnutrition constitutes a public health problem throughout the world and particularly in developing countries . Aims The objective of the study is to assess the impact of an elementary integrator composed of Spiruline ( Spirulina platensis ) and Misola ( millet , soja , peanut ) produced at the Centre Medical St Camille ( CMSC ) of Ouagadougou , Burkina Faso , on the nutritional status of undernourished children . Material s and methods 550 undernourished children of less than 5 years old were enrolled in this study , 455 showed severe marasma , 57 marasma of medium severity and 38 kwashiorkor plus marasma . We divided the children r and omly into four groups : 170 were given Misola ( 731 ± 7 kcal/day ) , 170 were given Spiruline plus traditional meals ( 748 ± 6 kcal/day ) , 170 were given Spiruline plus Misola ( 767 ± 5 kcal/day ) . Forty children received only traditional meals ( 722 ± 8 kcal/day ) and functioned as the control group . The duration of this study was eight weeks . Results and Discussion Anthropometrics and haematological parameters allowed us to appreciate both the nutritional and biological evolution of these children . The rehabilitation with Spiruline plus Misola ( this association gave an energy intake of 767 ± 5 kcal/day with a protein assumption of 33.3 ± 1.2 g a day ) , both greater than Misola or Spiruline alone , seems to correct weight loss more quickly . Conclusion Our results indicate that Misola , Spiruline plus traditional meals or Spiruline plus Misola are all a good food supplement for undernourished children , but the rehabilitation by Spiruline plus Misola seems synergically favour the nutrition rehabilitation better than the simple addition of protein and energy intake [23751252] A r and omized controlled trial was conducted in Ch and igarh , India ( 2011 ) , to determine the effectiveness of indigenous ready-to-use therapeutic food ( RUTF ) in community-based management of uncomplicated severe acute malnutrition ( SAM ) . Intervention was through outpatient therapeutic program site ( OTP ) . Study and control group children ( 6 months-5 years ) were followed up weekly for 12 weeks , in OTP and at home . All children received supplementary nutrition through anganwadis under integrated child development scheme . Study children , in addition , received therapeutic dose of RUTF in OTP . Primary outcome , 115 % of baseline weight , was attained in 6 of 13 ( 46.2 % ) and 1 of 13 ( 7.7 % ) children among study and control group , respectively [ odds ratio : 10.28 , 95 % confidence interval ( CI ) : 1.02 - 103.95 ] . Compared with control group , addition of RUTF in study group result ed in average additional increase in weight by 13 g/kg of baseline weight/week/child ( 95 % CI : 2 - 23 ) . Indigenous RUTF was effective in community-based management of uncomplicated SAM [18606932] OBJECTIVE To compare growth and incidence of malnutrition in infants receiving long-term dietary supplementation with ready-to-use fortified spread ( FS ) or micronutrient-fortified maize-soy flour ( likuni phala [ LP ] ) . DESIGN R and omized , controlled , single-blind trial . SETTING Rural Malawi . PARTICIPANTS A total of 182 six-month-old infants . INTERVENTION Participants were r and omized to receive 1 year of daily supplementation with 71 g of LP ( 282 kcal ) , 50 g of FS ( FS50 ) ( 256 kcal ) , or 25 g of FS ( FS25 ) ( 130 [ corrected ] kcal ) . OUTCOME MEASURES Weight and length gains and the incidences of severe stunting , underweight , and wasting . RESULTS Mean weight and length gains in the LP , FS50 , and FS25 groups were 2.37 , 2.47 , and 2.37 kg ( P = .66 ) and 12.7 , 13.5 , and 13.2 cm ( P = .23 ) , respectively . In the same groups , the cumulative 12-month incidence of severe stunting was 13.3 % , 0.0 % , and 3.5 % ( P = .01 ) , of severe underweight was 15.0 % , 22.5 % , and 16.9 % ( P = .71 ) , and of severe wasting was 1.8 % , 1.9 % , and 1.8 % ( P > .99 ) . Compared with LP-supplemented infants , those given FS50 gained a mean of 100 g more weight and 0.8 cm more length . There was a significant interaction between baseline length and intervention ( P = .04 ) ; in children with below-median length at enrollment , those given FS50 gained a mean of 1.9 cm more than individuals receiving LP . CONCLUSION One-year-long complementary feeding with FS does not have a significantly larger effect than LP on mean weight gain in all infants , but it is likely to boost linear growth in the most disadvantaged individuals and , hence , decrease the incidence of severe stunting [20972285] Objective To evaluate the effectiveness of a locally made ready-to-use therapeutic food ( RUTF ) in decreasing mild to moderate malnutrition . Design A r and omized open label , controlled trial . Setting Pre-schools run by the Department of Community Health in Kaniyambadi administrative block , Vellore , India ; duration of follow-up - 3 months from the date of recruitment . Participants Pupils aged 18–60 months with Weight-for-Age ≤2 SD . Interventions A locally produced energy-dense supplement ( RUTF ) , and the current st and ard of care [ teaching caregivers how to make a fortified cereal-milk supplement called High Calorie Cereal Milk (HCCM)].Main outcome measures Increase in weight-for-age status ; increase in levels of plasma zinc , vitamin B12 , serum albumin and haemoglobin . Results The Mean ( SD ) weight gain at 3 months was higher in the RUTF group : RUTF ( n=51 ) : 0.54 kg ; ( SE = 0.05 ; 95 % CI = 0.44–0.65 ) vs HCCM ( n=45 ) : 0.38 kg ; ( SE = 0.06 ; 95 % CI = 0.25–0.51 ) , P = 0.047 . The weight gain per kilogram of body weight was directly proportional to the severity of malnutrition . Conclusions Community-based treatment showed weight gain in both groups , the gain being higher with RUTF [20861218] Although widely used , there is little information concerning the efficacy of corn-soy blend ( CSB ) supplementation in the treatment of moderate underweight in African children . Lipid-based nutrient supplements ( LNS ) , which have proven to be beneficial treatment for severely wasted children , could offer benefits to less severely affected individuals . We conducted a clinical r and omized trial to determine whether LNS or CSB supplementation improves weight gain of moderately underweight children . A total of 182 underweight [ weight-for-age Z-score ( WAZ ) < -2 ] 6- to 15-mo-old children were r and omized to receive for 12 wk a ration of 43 g/d LNS or 71 g/d CSB , providing 1189 and 921 kJ , respectively , or no supplementation ( control ) . The primary outcome was weight change ; secondary outcomes included changes in anthropometric indices , hemoglobin levels , and morbidity . The body weight increases ( mean ± SD ) did not differ and were 620 ± 470 , 510 ± 350 , and 470 ± 350 g in the LNS , CSB , and control groups , respectively ( P = 0.11 ) . Compared with controls , infants and children in the LNS group gained more weight [ mean ( 95 % CI ) = 150 g ( 0 - 300 g ) ; P = 0.05 ] and had a greater increase in WAZ [ 0.33 ( -0.02 - 0.65 ) ; P = 0.04 ] . Weight and WAZ changes did not differ between the control and CSB groups . In exploratory stratified analysis , the weight increase was higher in the LNS group compared with the control group among those with lower initial WAZ [ 250 g ( 60 - 430 g ; P = 0.01 ] . Supplementation with LNS but not CSB modestly increases weight gain among moderately underweight children and the effect appears most pronounced among those with a lower initial WAZ [23782554] Community-based Management of Acute Malnutrition using ready-to-use therapeutic food ( RUTF ) has revolutionised the treatment of severe acute malnutrition ( SAM ) . However , 25 % milk content in st and ard peanut-based RUTF ( P-RUTF ) makes it too expensive . The effectiveness of milk-free RUTF has not been reported hitherto . This non-blinded , parallel group , cluster r and omised , controlled , equivalence trial that compares the effectiveness of a milk-free soy-maize-sorghum-based RUTF ( SMS-RUTF ) with P-RUTF in treatment of children with SAM , closes the gap . A statistician r and omly assigned health centres ( HC ) either to the SMS-RUTF ( n = 12 ; 824 enrolled ) or P-RUTF ( n = 12 ; 1103 enrolled ) arms . All SAM children admitted at the participating HCs were enrolled . All the outcomes were measured at individual level . Recovery rate was the primary outcome . The recovery rates for SMS-RUTF and P-RUTF were 53.3 % and 60.8 % for the intention-to-treat ( ITT ) analysis and 77.9 % and 81.8 % for per protocol ( PP ) analyses , respectively . The corresponding adjusted risk difference ( ARD ) and 95 % confidence interval , were -7.6 % ( -14.9 , 0.6 % ) and -3.5 % ( -9,6 . , 2.7 % ) for ITT ( P = 0.034 ) and PP analyses ( P = 0.257 ) , respectively . An unanticipated interaction ( interaction P < 0.001 for ITT analyses and 0.0683 for PP analyses ) between the study arm and age group was observed . The ARDs were -10.0 ( -17.7 to -2.3)% for ITT ( P = 0.013 ) and -4.7 ( -10.0 to 0.7 ) for PP ( P = 0.083 ) analyses for the < 24 months age group and 2.1 (-10.3,14.6)% for ITT ( P = 0.726 ) and -0.6 ( -16.1 , 14.5 ) for PP ( P = 0.939 ) for the ≥24 months age group . In conclusion , the study did not confirm our hypothesis of equivalence between SMS-RUTF and P-RUTF in SAM management [19225128] Moderate childhood wasting is defined as having a weight-for-height Z-score ( WHZ ) < -2 , but > or = -3 . These children are typically given fortified corn/soy blended flour ( CSB ) , but this intervention has shown limited effectiveness . Fortified spreads ( FS ) can be used as supplementary foods instead ; they are energy-dense , lipid-based pastes with added powdered micronutrients . In this r and omized clinical effectiveness trial , the recovery rates were compared among children with moderate wasting who received either milk/peanut FS , soy/peanut FS , or CSB . Children received isoenergetic quantities of food , 314 kJ x kg(-1 ) x d(-1 ) , for up to 8 wk with biweekly follow-up . The primary outcome was recovery , defined as having a WHZ > -2 . Time-event analysis was used to compare the recovery rate . A total of 1362 children were enrolled in the study . Children receiving soy/peanut FS had a similar recovery rate to those receiving milk/peanut FS and children in either FS group were more likely to recover than those receiving CSB ( 80 % in both FS groups vs. 72 % in the CSB group ; P < 0.01 ) . The rate of weight gain in the first 2 wk was greater among children receiving milk/peanut FS ( 2.6 g x kg(-1 ) x d(-1 ) , n = 465 ) or children receiving soy/peanut FS ( 2.4 g x kg(-1 ) x d(-1 ) , n = 450 ) than among children receiving CSB ( 2.0 g x kg(-1 ) x d(-1 ) , n = 447 ; P < 0.05 ) . Rates of length gain did not differ among the 3 groups . A total of 8 % of children in each feeding group developed edema , indicative of severe malnutrition , while receiving supplemental feeding . We conclude that FS are superior supplementary foods to CSB for moderately wasted Malawian children [16599106] The study was a controlled , comparative clinical effectiveness trial of two supplementary feeding regimens in children at risk of malnutrition from seven centres in rural Malawi . Being at risk of malnutrition was defined as weight-for-height < 85 % , but > 80 % of the international st and ard . A stepped-wedge design with systematic allocation was used for assigning children to receive either ready-to-use therapeutic food ( RUTF ) ( n=331 ) or micronutrient-fortified corn/soy-blend ( n=41 ) for up to eight weeks . The primary outcomes were recovery , defined as weight-for-height > 90 % , and the rate of weight gain . Children receiving RUTF were more likely to recover ( 58 % vs 22 % ; difference 36 % ; 95 % confidence interval [ CI ] 20 - 52 ) and had greater rates of weight gain ( 3.1 g/kg.d vs 1.4 g/kg x d ; difference 1.7 ; 95 % CI 0.8 - 2.6 ) than children receiving corn/soy-blend . The results of this preliminary work suggest that supplementary feeding with RUTF promotes better growth in children at risk of malnutrition than the st and ard fortified cereal/legume-blended food [14734876] Objective Maize and soy flour mixes are often used in the treatment of moderate malnutrition in Malawi . Their efficacy has not been formally evaluated . A recently developed ready-to-use food ( RTUF ) effectively promotes growth among severely malnourished children . The authors compared the effect of maize and soy flour with that of RTUF in the home treatment of moderately malnourished children . Methods Sixty-one underweight , stunted children 42 to 60 months of age were recruited in rural Malawi , in southeastern Africa . They received either RTUF or maize and soy flour for 12 weeks . Both supplements provided 2 MJ ( 500Kcal ) of energy daily but had different energy and nutrient densities . Outcome variables were weight and height gain and dietary intake . Results Before intervention , the mean dietary intake and weight and height gain were similar in the two groups . During the supplementation phase , the consumption of staple food fell among children receiving maize and soy flour but not among those receiving RTUF . There was thus higher intake of energy , fat , iron , and zinc in the RTUF group . Both supplements result ed in modest weight gain , but the effect lasted longer after RTUF supplementation . Height gain was not affected in either group . Periodic 24-hour dietary recalls suggested that the children received only 30 % and 43 % , respectively , of the supplementary RTUF and maize and soy flour provided . Conclusions RTUF is an acceptable alternative to maize and soy flour for dietary supplementation of moderately malnourished children . Approaches aim ed at increasing the consumption of supplementary food by the selected recipients are needed [20522296] Abstract Background : Typical treatment of moderate acute malnutrition , simple wasting , in sub-Saharan Africa consists of dietary counselling and /or general or targeted distribution of corn/soy-blended flour ( CSB ) . A r and omised clinical effectiveness trial in 2007 showed CSB to be less effective than ready-to-use supplementary food ( RUSF ) . Aim : To determine the operational effectiveness of treating moderate acute malnutrition with RUSF . Methods : Children aged 6–59 months were recruited in rural southern Malawi . Each child received 65 kcal/kg/d of locally produced soy/peanut RUSF , a product that provided about 1 RDA of each micronutrient . Anthropometric measurements were taken every 2 weeks and additional rations of RUSF were distributed at this time if the child remained wasted . Study participation lasted up to 8 weeks . Results : Of the 2417 children enrolled , 80 % recovered , 4 % defaulted , 0.4 % died , 12 % remained moderately wasted and 3 % developed severe acute malnutrition . Weight , length and MUAC gain were 2.6 g/kg/d , 0.2 mm/d and 0.1 mm/d respectively . Cost per child treated was $ 5.39 . Conclusions : This intervention proved to be robust , maintaining high recovery rates and low default rates when instituted without the additional supervision and beneficiary incentives of a research setting [28096555] Malnutrition is a major public health problem especially in the developing countries . The objective of the study was to compare WHO/UNICEF recommended therapeutic food with home based therapeutic food in the management of severe acute malnutrition . It was a r and omized controlled trial at tertiary care level hospital with nutritional rehabilitation centre . Children ( 6 month to 5 years ) having severe acute malnutrition were included in the study . Group A ( n=74 children ) was given WHO recommended therapeutic food and group B ( n=75 children ) was given home based therapeutic food . The mean rate of weight gain , gain in height and increase in mid-upper arm circumference were significantly higher ( p<0.05 ) in the group received home based therapeutic food . Mean duration to achieve target weight was 21.44±3.33 days in group A and 16.28±2.11 days in group B ( p < o.ooo1 ) . Group B children had higher rate of increase in urinary creatinine ( p<0.0001 ) . Affordability ( p<0.0001 ) , Feasibility ( p=0.027 ) and Average frequency of feeding per day ( p<0.0001 ) was found significantly higher in group B. Difficulty in making therapeutic food was significantly low in group B ( p<0.05 ) . Both kinds of therapeutic food were effective for the management of severe acute malnutrition , but the home based therapeutic food was found to be more effective . This could be explained by better acceptability in terms of better palatability , more affordability , increased frequency of feeding , and having less difficulty in making [22170366] BACKGROUND Children with moderate acute malnutrition ( MAM ) are often treated with fortified blended flours , most commonly a corn-soy blend ( CSB ) . However , recovery rates remain < 75 % , lower than the rate achieved with peanut paste-based ready-to-use supplementary foods ( RUSFs ) . To bridge this gap , a novel CSB recipe fortified with oil and dry skim milk , " CSB++ , " has been developed . OBJECTIVE In this trial we compared CSB++ with 2 RUSF products for the treatment of MAM to test the hypothesis that the recovery rate achieved with CSB++ will not be > 5 % worse than that achieved with either RUSF . DESIGN We conducted a prospect i ve , r and omized , investigator-blinded , controlled noninferiority trial involving rural Malawian children aged 6 - 59 mo with MAM . Children received 75 kcal CSB++ · kg(-1 ) · d(-1 ) , locally produced soy RUSF , or an imported soy/whey RUSF for ≤12 wk . RESULTS The recovery rate for CSB++ ( n = 763 of 888 ; 85.9 % ) was similar to that for soy RUSF ( 795 of 806 , 87.7 % ; risk difference : -1.82 % ; 95 % CI : -4.95 % , 1.30 % ) and soy/whey RUSF ( 807 of 918 , 87.9 % ; risk difference : -1.99 % ; 95 % CI : -5.10 % , 1.13 % ) . On average , children who received CSB++ required 2 d longer to recover , and the rate of weight gain was less than that with either RUSF , although height gain was the same among all 3 foods studied . CONCLUSIONS A novel , locally produced , fortified blended flour ( CSB++ ) was not inferior to a locally produced soy RUSF and an imported soy/whey RUSF in facilitating recovery from MAM . The recovery rate observed for CSB++ was higher than that for any other fortified blended flour tested previously . This trial is registered at clinical trials.gov as NCT00998517 [19155454] CONTEXT Ready-to-use therapeutic foods ( RUTFs ) are an important component of effective outpatient treatment of severe wasting . However , their effectiveness in the population -based prevention of moderate and severe wasting has not been evaluated . OBJECTIVE To evaluate the effect of a 3-month distribution of RUTF on the nutritional status , mortality , and morbidity of children aged 6 to 60 months in Niger . DESIGN , SETTING , AND PARTICIPANTS A cluster r and omized trial of 12 villages in Maradi , Niger . Six villages were r and omized to intervention and 6 to no intervention . All children in the study villages aged 6 to 60 months were eligible for recruitment . INTERVENTION Children with weight-for-height 80 % or more of the National Center for Health Statistics reference median in the 6 intervention villages received a monthly distribution of 1 packet per day of RUTF ( 92 g [ 500 kcal/d ] ) from August to October 2006 . Children in the 6 nonintervention villages received no preventive supplementation . Active surveillance for conditions requiring medical or nutritional treatment was conducted monthly in all 12 study villages from August 2006 to March 2007 . MAIN OUTCOME MEASURES Changes in weight-for-height z score ( WHZ ) according to the World Health Organization Child Growth St and ards and incidence of wasting ( WHZ < -2 ) over 8 months of follow-up . RESULTS The number of children with height and weight measurements in August , October , December , and February was 3166 , 3110 , 2936 , and 3026 , respectively . The WHZ difference between the intervention and nonintervention groups was -0.10 z ( 95 % confidence interval [ CI ] , -0.23 to 0.03 ) at baseline and 0.12 z ( 95 % CI , 0.02 to 0.21 ) after 8 months of follow-up . The adjusted effect of the intervention on WHZ from baseline to the end of follow-up was thus 0.22 z ( 95 % CI , 0.13 to 0.30 ) . The absolute rate of wasting and severe wasting , respectively , was 0.17 events per child-year ( 140 events/841 child-years ) and 0.03 events per child-year ( 29 events/943 child-years ) in the intervention villages , compared with 0.26 events per child-year ( 233 events/895 child-years ) and 0.07 events per child-year ( 71 events/1029 child-years ) in the nonintervention villages . The intervention thus result ed in a 36 % ( 95 % CI , 17 % to 50 % ; P < .001 ) reduction in the incidence of wasting and a 58 % ( 95 % CI , 43 % to 68 % ; P < .001 ) reduction in the incidence of severe wasting . There was no reduction in mortality , with a mortality rate of 0.007 deaths per child-year ( 7 deaths/986 child-years ) in the intervention villages and 0.016 deaths per child-year ( 18 deaths/1099 child-years ) in the nonintervention villages ( adjusted hazard ratio , 0.51 ; 95 % CI , 0.25 to 1.05 ) . CONCLUSION Short-term supplementation of nonmalnourished children with RUTF reduced the decline in WHZ and the incidence of wasting and severe wasting over 8 months . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00682708 [17033528] Objectives : Nutritional rehabilitation in Africa relies mainly on imported skim milk enriched with a sugar and salt mixture . We evaluated whether milk plus porridge made from local ingredients improves the outcome of childhood nutritional rehabilitation versus milk alone . Patients and Methods : This study was conducted in a nutritional unit in Lacor ( Northern Ug and a ) . The porridge , made from cheap locally available ingredients ( maize flour , dried fish or meat , peanut butter and oil ) supplemented with proteins and fats , provides 1.1 energy units , 4.4 kJ/g . We r and omly sample d the files of 100 cases discharged in October , November and December 2001 ( preintervention ) , in 2002 ( soon after intervention onset ) and in 2003 ( more than 1 year after intervention onset ) . We recorded the average hospital days and average oedema-free weight gain at discharge in the 3 groups . Results : Average oedema-free weight gain increased from 21 g/d ( 95 % confidence interval [ CI ] , 12 - 29 ) in 2001 to 35 g/d ( 95 % CI , 25 - 45 ) in 2002 and reached 59 g/d ( 95 % CI , 51 - 65 ) in 2003 . Mortality decreased from 22 % to 7.8 % , and nutritional failures ( insufficient weight gain ) decreased by greater than 50 % . Conclusions : The low-cost porridge supplement ( & U20AC;2640/yr per 100 children ) was effective in treating malnutrition . Widespread use of the porridge , which result ed in better outcomes than milk alone , could produce a savings in the medium- to long-term , thereby releasing re sources for other uses . A high-energy porridge that is made from locally available ingredients and does not require imported foods seems to be appropriate for supplementary feeding after mother 's milk in this setting [25633498] Objectives : Ready-to-use therapeutic food ( RUTF ) is the preferred treatment for uncomplicated severe acute malnutrition . It contains large amounts of linoleic acid and little & agr;-linolenic acid , which may reduce the availability of docosahexaenoic acid ( DHA ) and eicosapentaenoic acid ( EPA ) to the recovering child . A novel high-oleic RUTF ( HO-RUTF ) was developed with less linoleic acid to determine its effect on DHA and EPA status . Methods : We conducted a prospect i ve , r and omized , double-blind clinical effectiveness trial treating rural Malawian children with severe acute malnutrition . Children were treated with either HO-RUTF or st and ard RUTF . Plasma phospholipid fatty acid status was measured on enrollment and after 4 weeks and compared between the 2 intervention groups . Results : Among the 141 children enrolled , 48 of 71 receiving HO-RUTF and 50 of 70 receiving RUTF recovered . Plasma phospholipid sample s were analyzed from 43 children consuming HO-RUTF and 35 children consuming RUTF . The change in DHA content during the first 4 weeks was + 4 % and −25 % in the HO-RUTF and RUTF groups , respectively ( P = 0.04 ) . For EPA , the change in content was 63 % and −24 % in the HO-RUTF and RUTF groups , respectively ( P < 0.001 ) . For arachidonic acid , the change in content was −3 % and 13 % in the HO-RUTF and RUTF groups , respectively ( P < 0.009 ) . Conclusions : The changes in DHA and EPA seen in the children treated with HO-RUTF warrant further investigation because they suggest that HO-RUTF support improved polyunsaturated fatty acid status , necessary for neural development and recovery [17033530] Objective : Fortified spreads ( FSs ) have proven effective in the rehabilitation of severely malnourished children . We examined acceptability , growth and change in blood haemoglobin ( Hb ) concentration among moderately underweight ambulatory infants given FS . Methods : This was a r and omised , controlled , parallel-group , investigator-blind clinical trial in rural Malawi . Six- to 17-month-old underweight infants ( weight for age < −2 ) , whose weight was greater than 5.5 kg and weight-for-height z score greater than −3 received for 12 weeks at home 1 of 8 food supplementation schemes : nothing , 5 , 25 , 50 , or 75 g/day milk-based FS or 25 , 50 , or 75 g/day soy-based FS . Outcome measures included change in weight , length and blood Hb concentration . Results : A total of 126 infants started and 125 completed the intervention . All infants accepted the spread well , and no intolerance was recorded . Average weight and length gains were higher among infants receiving daily 25 to 75 g FS than among those receiving only 0 to 5 g FS . Mean Hb concentration remained unchanged among unsupplemented controls but increased by 10 to 17 g/L among infants receiving any FS . All average gains were largest among infants receiving 50 g of FS daily : mean difference ( 95 % confidence interval ) in the 12-week gain between infants in 50 g milk-based FS group and the unsupplemented group was 290 g ( range , −130 to 700 g ) , 0.9 cm ( range , −0.3 to 2.2 cm ) , and 17 g/L ( range , 0 to 34 g/L ) for weight , length and blood Hb concentration , respectively . In soy- vs milk-based FS groups , average outcomes were comparable . Conclusions : Supplementation with 25 to 75 g/day of highly fortified spread is feasible and may promote growth and alleviate anaemia among moderately malnourished infants . Further trials should test this hypothesis [26984485] BACKGROUND The cost of current st and ard ready-to-use therapeutic food ( RUTF ) is among the major obstacles to scaling up community-based management of acute malnutrition ( CMAM ) , an important child survival strategy . Identifying a cheaper alternative is a global public health priority . OBJECTIVE We sought to compare the efficacy of soya-maize-sorghum RUTF ( SMS-RUTF ) with that of st and ard peanut paste-based RUTF ( P-RUTF ) . DESIGN We used a nonblinded , parallel-group , simple r and omized controlled trial along with a day care approach that enrolled 2 groups of children aged 6 - 23 and 24 - 59 mo , respectively , with severe acute malnutrition ( SAM ) . RESULTS Intention-to-treat ( ITT ) and per- protocol ( PP ) analyses showed noninferiority of SMS-RUTF compared with P-RUTF for the recovery rate [ ITT : Δ = -2.0 % ( 95 % CI : -7.6 % , 3.6 % ) ; PP : -1.9 % ( 95 % CI : -5.3 % , 1.4 % ) ] , weight gain [ Δ = -0.7 g · kg(-1 ) · d(-1)(95 % CI : -1.3 , 0.0 g · kg(-1 ) · d(-1 ) ) ] , and length of stay [ Δ = 2.0 d ( 95 % CI : -1.7 , 5.8 d ) ] in children ≥24 mo of age . In children ≤23 mo of age , the recovery rate of SMS-RUTF was inferior to that of P-RUTF [ ITT : Δ = -20.8 % ( 95 % CI : -29.9 % , -11.7 % ) ; PP : -17.2 % ( 95 % CI : -25.6 % , -8.7 % ) ] . Treatment with SMS-RUTF result ed in a greater increase in hemoglobin [ 0.670 g/dL ( 95 % CI : 0.420 , 0.921 g/dL);P < 0.001 ] . Treatment with both RUTFs result ed in the replenishment of all of the amino acids tested except for methionine . There were no differences at discharge between RUTF groups in fat mass [ Δ = 0.3 kg ( 95 % CI : -0.6 , 1.6 kg);P= 0.341 ] or fat mass index [ Δ = 0.4 kg/m(2)(95 % CI : -0.3 , 1.1 kg/m(2));P= 0.262 ] . By contrast , comparisons of fat-free mass indicated lower concentrations than the community controls after treatment with either of the 2 RUTFs [ Δ = -1.3 kg ( 95 % CI : -2.4 , -0.1 kg ) and P= 0.034 for comparison between community controls and the SMS-RUTF group ; Δ = -1.8 kg ( 95 % CI : -2.9 , -0.6 kg ) and P= 0.003 for comparison between community controls and the P-RUTF group ] . CONCLUSION SMS-RUTF can be used to treat SAM in children aged ≥24 mo to reduce the costs of CMAM programs . More research is required to optimize SMS-RUTF for younger children . This trial was registered in the Pan African Clinical Trial Registry as PACTR201303000475166 [28729459] The importance of adequate intervention descriptions in minimising research waste and improving research usability and reproducibility has gained attention in the past few years . Nearly all focus to date has been on intervention reporting in r and omised trials . Yet clinicians are encouraged to use systematic review s , whenever available , rather than single trials to inform their practice . This article explores the problem and implication s of incomplete intervention details during the planning , conduct , and reporting of systematic review s and makes recommendations for review authors , peer review ers , and journal [26423737] BACKGROUND Global acute malnutrition ( GAM ) is the sum of moderate acute malnutrition ( MAM ) and severe acute malnutrition ( SAM ) . The use of different foods and protocol s for MAM and SAM treatment can be cumbersome in emergency setting s. OBJECTIVE Our objective was to determine the recovery and coverage rates for GAM of an integrated protocol with a single food product , ready-to-use therapeutic food ( RUTF ) , compared with st and ard management . METHODS This was a cluster-r and omized controlled trial in Sierra Leone conducted in 10 centers treating GAM in children aged 6 - 59 mo . The integrated protocol used midupper arm circumference ( MUAC ) as the criterion for admission and discharge , with a MUAC < 12.5 cm defining malnutrition . The protocol included a decreasing ration of RUTF and health maintenance messages delivered by peers . St and ard therapy treated MAM with a fortified blended flour and SAM with RUTF and used weight-for-height to determine admission to the treatment program . Coverage rates were the number of children who received treatment/number of children in the community eligible for treatment . RESULTS Most of the children receiving integrated management had MAM ( 774 of 1100 ; 70 % ) , whereas among those receiving st and ard management , SAM predominated ( 537 of 857 ; 63 % ; P = 0.0001 ) . Coverage was 71 % in the communities served by integrated management and 55 % in the communities served by st and ard care ( P = 0.0005 ) . GAM recovery in the integrated management protocol was 910 of 1100 ( 83 % ) children and was 682 of 857 ( 79 % ) children in the st and ard therapy protocol . CONCLUSION Integrated management of GAM in children is an acceptable alternative to st and ard management and provides greater community coverage . This trial was registered at clinical trials.gov as NCT01785680 [6073612] Cambodia continues to have a high prevalence of acute malnutrition . Low acceptability has been found for st and ard ready-to-use-therapeutic-food ( RUTF ) products . Therefore , NumTrey , a locally-produced fish-based RUTF , was developed . The objective was to evaluate the effectiveness of NumTrey compared to an imported milk-based RUTF for weight gain among children aged 6–59 months in the home-treatment for acute malnutrition . Effectiveness was tested in a single-blinded r and omized controlled trial with weight gain as the primary outcome . Anthropometry was assessed at baseline and bi-weekly follow-ups until endline at Week 8 . In total , 121 patients were r and omized into BP-100TM ( n = 61 ) or NumTrey ( n = 60 ) . There was no statistical difference in mean weight gain between the groups ( 1.06 g/kg/day ; 95 % CI ( 0.72 , 1.41 ) and 1.08 g/kg/day ; 95 % CI ( 0.75 , 1.41 ) for BP-100 ™ and NumTrey , respectively ) . In addition , no statistically significant differences in secondary outcomes were found . Although the ability to draw conclusions was limited by lower weight gain than the desired 4 g/kg/day in both groups , no superiority was found for eitherRUTF . A locally produced RUTF is highly relevant to improve nutrition interventions in Cambodia . A locally produced fish-based RUTF is a relevant alternative to imported milk-based RUTF for the treatment of SAM in Cambodia [6086422] Background Ready-to-use therapeutic food ( RUTF ) is used to treat children suffering from severe acute malnutrition ( SAM ) . St and ard RUTF uses milk as the primary protein source , which makes the product expensive , and given the high worldwide SAM burden , having a less expensive effective alternative is a public health priority . Objective The objective of this study was to evaluate whether newly developed amino acid-enriched milk-free RUTF ( FSMS-RUTF ) or amino acid-enriched low-milk RUTF ( MSMS-RUTF ) treatment could replenish plasma amino acids to levels comparable to those following st and ard peanut-milk RUTF ( PM-RUTF ) treatment and to improve underst and ing of the effects of treatment on anthropometric measurements . A secondary analysis was performed to test the noninferiority hypothesis of plasma essential amino acid ( EAA ) levels . Methods Plasma EAA levels were measured in a nonblinded , 3-arm , parallel-group simple r and omized controlled trial conducted in Malawi to examine the efficacy of FSMS-RUTF , MSMS-RUTF and PM-RUTF in the treatment of SAM in 2 groups of children aged 6–23 and 24–59 months ( mo ) . Sample size calculations were performed based on the previous our study . A noninferiority margin was set at -25 % of the PM-RUTF arm at discharge . Results The relative values of the differences ( 95 % CI ) in plasma EAA levels between PM-RUTF treatment and FSMS-RUTF and MSMS-RUTF treatments at discharge were -7.9 % ( -18.6 , 2.8 ) and 9.8 % ( 0.2 , 19.5 ) , respectively , in children aged 6–23 mo , while in those aged 24–59 mo , the difference values were 17.8 % ( 1.6 , 34.1 ) and 13.6 % ( -2.8 , 29.9 ) , respectively . Conclusion At discharge , the plasma EAA concentrations in 6 - 59-mo-old SAM children treated with FSMS-RUTF and MSMS-RUTF were not less than those of children treated with PM-RUTF . These findings indicate that treatment with either of the 3 RUTFs was associated with adequate protein synthesis and that all the formulations provided sufficient functional metabolites of plasma amino acids to support nutritional recovery from SAM [20980648] St and ard therapy for severe acute malnutrition ( SAM ) is home-based therapy with ready-to-use therapeutic food ( RUTF ) containing 25 % milk . In an effort to lower the cost of RUTF and increase availability , some have suggested that a portion of milk be replaced with soy . This trial was design ed to determine whether treating children with SAM with 10 % milk RUTF containing soy would result in a similar recovery rate compared with the 25 % milk RUTF . This was a r and omized , double-blind , controlled , clinical , quasi-effectiveness trial of isoenergetic amounts of 2 locally produced RUTF to treat SAM in Malawi among children aged 6 - 59 mo . A total of 1874 children were enrolled . Children were assessed every fortnight and participated in the study until they clinical ly recovered or received 8 wk of treatment . The primary outcome was recovery ( weight-for-height Z score > -2 and no edema ) . Secondary outcomes were rates of weight and height gain . Survival analysis was used to compare the recovery rates . Recovery among children receiving 25 % milk RUTF was greater than children receiving 10 % milk RUTF , 64 % compared with 57 % after 4 wk , and 84 % compared with 81 % after 8 wk ( P < 0.001 ) . Children receiving 25 % milk RUTF also had higher rates of weight and height gain compared with children receiving 10 % milk RUTF . Treating children with SAM with 10 % milk RUTF is less effective compared with treatment with the st and ard 25 % milk RUTF . These findings also emphasize that clinical evidence should be examined before recommending any changes to the formulation of RUTF

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### Context: [4672709] Abstract The treatment of uncomplicated severe acute malnutrition ( SAM ) requires substantial amounts of ready‐to‐use therapeutic food ( RUTF ) . In 2009 , Action Contre la F aim anticipated a shortfall of RUTF for their nutrition programme in Myanmar . A low‐dose RUTF protocol to treat children with uncomplicated SAM was adopted . In this protocol , RUTF was dosed according to beneficiary 's body weight , until the child reached a Weight‐for‐Height z‐score of ≥−3 and mid‐upper arm circumference ≥110 mm . From this point , the child received a fixed quantity of RUTF per day , independent of body weight until discharge . Specific measures were implemented as part of this low‐dose RUTF protocol in order to improve service quality and beneficiary support . We analysed individual records of 3083 children treated from July 2009 to January 2010 . Up to 90.2 % of children recovered , 2.0 % defaulted and 0.9 % were classified as non‐responders . No deaths were recorded . Among children who recovered , median [ IQR ] length of stay and weight gain were 42 days [ 28 ; 56 ] and 4.0 g kg–1 day–1 [ 3.0 ; 5.7 ] , respectively . Multivariable logistic regression showed that children older than 48 months had higher odds of non‐response to treatment than younger children ( adjusted odds ratio : 3.51 , 95 % CI : 1.67–7.42 ) . Our results indicate that a low‐dose RUTF protocol , combined with specific measures to ensure good service quality and beneficiary support , was successful in treating uncomplicated SAM in this setting . This programmatic experience should be vali date d by r and omised studies aim ing to test , quantify and attribute the effect of the protocol adaptation and programme improvements presented here [4407555] Background Ready-to-use therapeutic foods ( RUTF ) are lipid-based pastes widely used in the treatment of acute malnutrition . Current specifications for RUTF permit a high n-6 polyunsaturated fatty acid ( PUFA ) content and low n-3 PUFA , with no stipulated requirements for preformed long-chain n-3 PUFA . The objective of this study was to develop an RUTF with elevated short-chain n-3 PUFA and measure its impact , with and without fish oil supplementation , on children ’s PUFA status during treatment of severe acute malnutrition . Methods This r and omized controlled trial in children with severe acute malnutrition in rural Kenya included 60 children aged 6 to 50 months who were r and omized to receive i ) RUTF with st and ard composition ; ii ) RUTF with elevated short chain n-3 PUFA ; or iii ) RUTF with elevated short chain n-3 PUFA plus fish oil capsules . Participants were followed-up for 3 months . The primary outcome was erythrocyte PUFA composition . Results Erythrocyte docosahexaenoic acid ( DHA ) content declined from baseline in the two arms not receiving fish oil . Erythrocyte long-chain n-3 PUFA content following treatment was significantly higher for participants in the arm receiving fish oil than for those in the arms receiving RUTF with elevated short chain n-3 PUFA or st and ard RUTF alone : 3 months after enrolment , DHA content was 6.3 % ( interquartile range 6.0–7.3 ) , 4.5 % ( 3.9–4.9 ) , and 3.9 % ( 2.4–5.7 ) of total erythrocyte fatty acids ( P < 0.001 ) , respectively , while eicosapentaenoic acid ( EPA ) content was 2.0 % ( 1.5–2.6 ) , 0.7 % ( 0.6–0.8 ) , and 0.4 % ( 0.3–0.5 ) ( P < 0.001 ) . RUTF with elevated short chain n-3 PUFA and fish oil capsules were acceptable to participants and carers , and there were no significant differences in safety outcomes . Conclusions PUFA requirements of children with SAM are not met by current formulations of RUTF , or by an RUTF with elevated short-chain n-3 PUFA without additional preformed long-chain n-3 PUFA . Clinical and growth implication s of revised formulations need to be addressed in large clinical trials . Trial registration Clinical trials.gov NCT01593969 . Registered 4 May 2012 [17030533] To measure the success rate of three different strategies used in Médecins Sans Frontières large-scale therapeutic nutritional rehabilitation programme in Niger , we analysed three cohorts of severely malnourished patients in terms of daily weight gain , length of stay , recovery , case fatality and defaulting . A total of 1937 children aged 6 - 59 months were followed prospect ively from 15 August 2002 to 21 October 2003 . For the three cohorts , 660 children were maintained in the therapeutic feeding centre ( TFC ) during the entire treatment , 937 children were initially treated at the TFC and completed treatment at home and 340 children were exclusively treated at home . For all cohorts , average time in the programme and average weight gain met the international st and ards ( 30 - 40 days , > 8 g/kg/day ) . Default rates were 28.1 , 16.8 and 5.6 % for TFC only , TFC plus home-based and home-based alone strategies , respectively . The overall case fatality rate for the entire programme was 6.8 % . Case fatality rates were 18.9 % for TFC only and 1.7 % for home-based alone . No deaths were recorded in children transferred to rehabilitation at home . This study suggests that satisfactory results for the treatment of severe malnutrition can be achieved using a combination of home and hospital-based strategies [19591885] The aim of this study was to test the ability of two new products , an instant infant flour and a food supplement containing amylases , to increase energy and micronutrient intakes of infants older than 6 months . Three groups of 48 infants were r and omly constituted . Infants in groups 1 and 2 consumed at least twice a day gruel made either from the instant flour or from the food supplement . Infants from the control group received complementary foods prepared in the usual way . Each infant was surveyed during a whole day in order to measure feeding frequencies and characteristics as well as amounts of the different types of complementary foods consumed . Foods consumed by infants in the two experimental groups differed considerably in energy , micronutrient density and in consistency from the home-made complementary foods . Due to the incorporation of amylases , gruels made from the food supplement had a higher energy density , a more appropriate consistency and result ed in higher intakes per meal than gruels made from instant flour . In comparison with home-made complementary foods , both experimental products result ed in significantly higher energy and nutrient intakes . The two experimental products appeared to increase sufficiently both energy and nutrient intakes of infants to complement their breastmilk intake [5833365] The number of published systematic review s of studies of healthcare interventions has increased rapidly and these are used extensively for clinical and policy decisions . Systematic review s are subject to a range of biases and increasingly include non-r and omised studies of interventions . It is important that users can distinguish high quality review s. Many instruments have been design ed to evaluate different aspects of review s , but there are few comprehensive critical appraisal instruments . AMSTAR was developed to evaluate systematic review s of r and omised trials . In this paper , we report on the updating of AMSTAR and its adaptation to enable more detailed assessment of systematic review s that include r and omised or non-r and omised studies of healthcare interventions , or both . With moves to base more decisions on real world observational evidence we believe that AMSTAR 2 will assist decision makers in the identification of high quality systematic review s , including those based on non-r and omised studies of healthcare interventions [5841493] Trial design Three feeding regimens— central ly produced ready-to-use therapeutic food , locally produced ready-to-use therapeutic food , and augmented , energy-dense , home-prepared food — were provided in a community setting for children with severe acute malnutrition ( SAM ) in the age group of 6–59 months in an individually r and omised multicentre trial that enrolled 906 children . Foods , counselling , feeding support and treatment for mild illnesses were provided until recovery or 16 weeks . Methods Costs were estimated for 371 children enrolled in Delhi in a semiurban location after active survey and identification , enrolment , diagnosis and treatment for mild illnesses , and finally treatment with one of the three regimens , both under the research and government setting . Direct costs were estimated for human re sources using a price times quantity approach , based on their salaries and average time taken for each activity . The cost per week per child for food , medicines and other consumables was estimated based on the total expenditure over the period and children covered . Indirect costs for programme management including training , transport , non-consumables , infrastructure and equipment were estimated per week per child based on total expenditures for research study and making suitable adjustments for estimations under government setting . Results No significant difference in costs was found across the three regimens per covered or per treated child . The average cost per treated child in the government setting was estimated at US$ 56 ( < 3500 rupees ) . Conclusion Home-based management of SAM with a locally produced ready-to-use therapeutic food is feasible , acceptable , affordable and very cost-effective in terms of the disability-adjusted life years saved and gross national income per capita of the country . The treatment of SAM at home needs serious attention and integration into the existing health system , along with actions to prevent SAM . Trial registration number NCT01705769 ; Pre- results [15817865] BACKGROUND Childhood malnutrition is common in Malawi , and the st and ard treatment , which follows international guidelines , results in poor recovery rates . Higher recovery rates have been seen in pilot studies of home-based therapy with ready-to-use therapeutic food ( RUTF ) . OBJECTIVE The objective was to compare the recovery rates among children with moderate and severe wasting , kwashiorkor , or both receiving either home-based therapy with RUTF or st and ard inpatient therapy . DESIGN A controlled , comparative , clinical effectiveness trial was conducted in southern Malawi with 1178 malnourished children . Children were systematic ally allocated to either st and ard therapy ( 186 children ) or home-based therapy with RUTF ( 992 children ) according to a stepped wedge design to control for bias introduced by the season of the year . Recovery , defined as reaching a weight-for-height z score > -2 , and relapse or death were the primary outcomes . The rate of weight gain and the prevalence of fever , cough , and diarrhea were the secondary outcomes . RESULTS Children who received home-based therapy with RUTF were more likely to achieve a weight-for-height z score > -2 than were those who received st and ard therapy ( 79 % compared with 46 % ; P < 0.001 ) and were less likely to relapse or die ( 8.7 % compared with 16.7 % ; P < 0.001 ) . Children who received home-based therapy with RUTF had greater rates of weight gain ( 3.5 compared with 2.0 g . kg(-1 ) . d(-1 ) ; difference : 1.5 ; 95 % CI : 1.0 , 2.0 g . kg(-1 ) . d(-1 ) ) and a lower prevalence of fever , cough , and diarrhea than did children who received st and ard therapy . CONCLUSION Home-based therapy with RUTF is associated with better outcomes for childhood malnutrition than is st and ard therapy [18287372] Poor complementary feeding practice s are associated with stunting and growth faltering throughout the developing world . The objective was to compare the effect of using peanut-/soy-based fortified spread ( FS ) and corn porridge fortified with fish powder ( FP ) as complementary foods on growth in rural Malawian children . A total of 240 children were enrolled at the age of 6 mo and r and omized to receive FS or FP . Both complementary foods provided 836 kJ/d from 6 to 9 mo of age and 1254 kJ/d from 9 to 18 mo of age . Children were followed monthly for anthropometry and fortnightly for the symptoms of fever , cough , or diarrhea until they were 18 mo old . Zn and Se status were assessed at 6 and 12 mo . The primary outcomes were the rates of weight and length gain from 6 - 12 mo and from 12 - 18 mo . Children who received FS gained 110 g more ( 95 % CI 220 to 10 ) from 6 - 12 mo of age than children receiving FP . Weight gain did not differ between children receiving FS and FP between 12 and 18 mo of age , nor did statural growth from 6 to 12 mo or 12 to 18 mo . A total of 23 % of all children were Zn deficient at 6 mo of age and this increased to 37 % at 12 mo of age . Neither FS nor FP was associated with significantly improved Zn status . FS was associated with better weight gain from 6 - 12 mo of age and may be useful in conjunction with additional interventions to improve infant growth in the developing world [15447908] BACKGROUND Multiple micronutrient deficiencies are often the basic causative factor in stunting and anemia , 2 conditions that affect entire generations of children in deprived population s. No generally accepted recommendations for micronutrient intakes for recovery from stunting are available . OBJECTIVE The objective was to assess the effect of a highly nutrient-dense spread fortified with vitamins and minerals , with or without antiparasitic metronidazole treatment , in correcting retarded linear growth and reducing anemia in stunted children . DESIGN Saharawi refugee children ( n = 374 ) aged 3 - 6 y with initial height-for-age z scores < -2 were assigned to 1 of 5 groups : fortified spread ( FS ) , fortified spread plus metronidazole ( FS+M ) , unfortified spread ( US ) , unfortified spread plus metronidazole ( US+M ) , or control . Supervised supplementation was given daily for 6 mo . Weight , height , knee-heel length , hematologic indexes , parasitic infections , and morbidity were assessed at 0 , 3 , and 6 mo . RESULTS Linear growth of children fed FS was 30 % faster at 3 mo than in US and control groups , after which height-for-age z scores increased only slightly in the FS group and remained unchanged in the other groups . No additional benefits from metronidazole were observed . Increase in hemoglobin concentrations in the FS group at 6 mo was twofold that in the US and control groups ( 37 + /- 40 , 19 + /- 15 , and 16 + /- 17 g/L , respectively ; P < 0.0001 ) , and anemia was reduced by nearly 90 % . CONCLUSIONS FS , and not US , induces catch-up growth in stunted children whose diets are poor in micronutrients . Our trial provides support for delivering multiple micronutrients to reverse stunting and reduce anemia in children up to age 6 [12885713] BACKGROUND The World Health Organization recommends a liquid , milk-based diet ( F100 ) during the rehabilitation phase of the treatment of severe malnutrition . A dry , solid , ready-to-use food ( RTUF ) that can be eaten without adding water has been proposed to eliminate the risk of bacterial contamination from added water . The efficacies of RTUF and F100 have not been compared . OBJECTIVE The objective was to compare the efficacy of RTUF and F100 in promoting weight gain in malnourished children . DESIGN In an open-labeled , r and omized trial , 70 severely malnourished Senegalese children aged 6 - 36 mo were r and omly allocated to receive 3 meals containing either F100 ( n = 35 ) or RTUF ( n = 35 ) in addition to the local diet . The data from 30 children in each group were analyzed . RESULTS The mean ( + /- SD ) daily energy intake in the RTUF group was 808 + /- 280 ( 95 % CI : 703.8 , 912.9 ) kJ x kg body wt(-1 ) x d(-1 ) , and that in the F100 group was 573 + /- 201 ( 95 % CI : 497.9 , 648.7 ) kJ. kg body wt(-1 ) x d(-1 ) ( P < 0.001 ) . The average weight gains in the RTUF and F100 groups were 15.6 ( 95 % CI : 13.4 , 17.8 ) and 10.1 ( 95 % CI : 8.7 , 11.4 ) g x kg body wt(-1 ) x d(-1 ) , respectively ( P < 0.001 ) . The difference in weight gain was greater in the most wasted children ( P < 0.05 ) . The average duration of rehabilitation was 17.3 ( 95 % CI : 15.6 , 19.0 ) d in the F100 group and was 13.4 ( 95 % CI : 12.1 , 14.7 ) d in the RTUF group ( P < 0.001 ) . CONCLUSIONS This study indicated that RTUF can be used efficiently for the rehabilitation of severely malnourished children [5932190] Summary Background In sub-Saharan Africa , severely immunocompromised HIV-infected individuals have a high risk of mortality during the first few months after starting antiretroviral therapy ( ART ) . We hypothesise that universally providing ready-to-use supplementary food ( RUSF ) would increase early weight gain , thereby reducing early mortality compared with current guidelines recommending ready-to-use therapeutic food ( RUTF ) for severely malnourished individuals only . Methods We did a 2 × 2 × 2 factorial , open-label , parallel-group trial at inpatient and outpatient facilities in eight urban or periurban regional hospitals in Kenya , Malawi , Ug and a , and Zimbabwe . Eligible participants were ART-naive adults and children aged at least 5 years with confirmed HIV infection and a CD4 cell count of fewer than 100 cells per μL , who were initiating ART at the facilities . We r and omly assigned participants ( 1:1 ) to initiate ART either with ( RUSF ) or without ( no-RUSF ) 12 weeks ' of peanut-based RUSF containing 1000 kcal per day and micronutrients , given as two 92 g packets per day for adults and one packet ( 500 kcal per day ) for children aged 5–12 years , regardless of nutritional status . In both groups , individuals received supplementation with RUTF only when severely malnourished ( ie , body-mass index [ BMI ] < 16–18 kg/m2 or BMI -for-age Z scores < –3 for children ) . We did the r and omisation with computer-generated , sequentially numbered tables with different block sizes incorporated within an online data base . R and omisation was stratified by centre , age , and two other factorial r and omisations , to 12 week adjunctive raltegravir and enhanced anti-infection prophylaxis ( reported elsewhere ) . Clinic visits were scheduled at weeks 2 , 4 , 8 , 12 , 18 , 24 , 36 , and 48 , and included nurse assessment of vital status and symptoms and dispensing of all medication including ART and RUSF . The primary outcome was mortality at week 24 , analysed by intention to treat . Secondary outcomes included absolute changes in weight , BMI , and mid-upper-arm circumference ( MUAC ) . Safety was analysed in all r and omly assigned participants . Follow-up was 48 weeks . This trial is registered with Clinical Trials.gov ( NCT01825031 ) and the IS RCT N registry ( 43622374 ) . Findings Between June 18 , 2013 , and April 10 , 2015 , we r and omly assigned 1805 participants to treatment : 897 to RUSF and 908 to no-RUSF . 56 ( 3 % ) were lost-to-follow-up . 96 ( 10·9 % , 95 % CI 9·0–13·1 ) participants allocated to RUSF and 92 ( 10·3 % , 8·5–12·5 ) to no-RUSF died within 24 weeks ( hazard ratio 1·05 , 95 % CI 0·79–1·40 ; log-rank p=0·75 ) , with no evidence of interaction with the other r and omisations ( both p>0·7 ) . Through 48 weeks , adults and adolescents aged 13 years and older in the RUSF group had significantly greater gains in weight , BMI , and MUAC than the no-RUSF group ( p=0·004 , 0·004 , and 0·03 , respectively ) . The most common type of serious adverse event was specific infections , occurring in 90 ( 10 % ) of 897 participants assigned RUSF and 87 ( 10 % ) of 908 assigned no-RUSF . By week 48 , 205 participants had serious adverse events in both groups ( p=0·81 ) , and 181 had grade 4 adverse events in the RUSF group compared with 172 in the non-RUSF group ( p=0·45 ) . Interpretation In severely immunocompromised HIV-infected individuals , providing RUSF universally at ART initiation , compared with providing RUTF to severely malnourished individuals only , improved short-term weight gain but not mortality . A change in policy to provide nutritional supplementation to all severely immunocompromised HIV-infected individuals starting ART is therefore not warranted at present . Funding Joint Global Health Trials Scheme ( UK Medical Research Council , UK Department for International Development , and Wellcome Trust ) [15981758] Aim : To determine if home‐based nutritional therapy will benefit a significant fraction of malnourished , HIV‐infected Malawian children , and to determine if ready‐to‐use therapeutic food ( RUTF ) is more effective in home‐based nutritional therapy than traditional foods . Methods : 93 HIV‐positive children > 1 y old discharged from the nutrition unit in Blantyre , Malawi were systematic ally allocated to one of three dietary regimens : RUTF , RUTF supplement or blended maize/soy flour . RUTF and maize/soy flour provided 730 kJ·kg−1·d−1 , while the RUTF supplement provided a fixed amount of energy , 2100 kJ/d . These children did not receive antiretroviral chemotherapy . Children were followed fortnightly . Children completed the study when they reached 100 % weight‐for‐height , relapsed or died . Outcomes were compared using regression modeling to account for differences in the severity of malnutrition between the dietary groups . Results : 52/93 ( 56 % ) of all children reached 100 % weight‐for‐height . Regression modeling found that the children receiving RUTF gained weight more rapidly and were more likely to reach 100 % weight‐for‐height than the other two dietary groups ( p<0.05 ) [15155403] Background : The st and ard treatment of severe malnutrition in Malawi often utilises prolonged inpatient care , and after discharge results in high rates of relapse . Aims : To test the hypothesis that the recovery rate , defined as catch-up growth such that weight-for-height z score > 0 ( WHZ , based on initial height ) for ready-to-use food ( RTUF ) is greater than two other home based dietary regimens in the treatment of malnutrition . Methods : HIV negative children > 1 year old discharged from the nutrition unit in Blantyre , Malawi were systematic ally allocated to one of three dietary regimens : RTUF , RTUF supplement , or blended maize/soy flour . RTUF and maize/soy flour provided 730 kJ/kg/day , while the RTUF supplement provided a fixed amount of energy , 2100 kJ/day . Children were followed fortnightly . Children completed the study when they reached WHZ > 0 , relapsed , or died . Outcomes were compared using a time-event model . Results : A total of 282 children were enrolled . Children receiving RTUF were more likely to reach WHZ > 0 than those receiving RTUF supplement or maize/soy flour ( 95 % v 78 % , RR 1.2 , 95 % CI 1.1 to 1.3 ) . The average weight gain was 5.2 g/kg/day in the RTUF group compared to 3.1 g/kg/day for the maize/soy and RTUF supplement groups . Six months later , 96 % of all children that reached WHZ > 0 were not wasted . Conclusions : Home based therapy of malnutrition with RTUF was successful ; further operational work is needed to implement this promising therapy [19595348] BACKGROUND Severe acute malnutrition affects 13 million children worldwide and causes 1 - 2 million deaths every year . Our aim was to assess the clinical and nutritional efficacy of a probiotic and prebiotic functional food for the treatment of severe acute malnutrition in a HIV-prevalent setting . METHODS We recruited 795 Malawian children ( age range 5 to 168 months [ median 22 , IQR 15 to 32 ] ) from July 12 , 2006 , to March 7 , 2007 , into a double-blind , r and omised , placebo-controlled efficacy trial . For generalisability , all admissions for severe acute malnutrition treatment were eligible for recruitment . After stabilisation with milk feeds , children were r and omly assigned to ready-to-use therapeutic food either with ( n=399 ) or without ( n=396 ) Synbiotic2000 Forte . Average prescribed Synbiotic dose was 10(10 ) colony-forming units or more of lactic acid bacteria per day for the duration of treatment ( median 33 days ) . Primary outcome was nutritional cure ( weight-for-height > 80 % of National Center for Health Statistics median on two consecutive outpatient visits ) . Secondary outcomes included death , weight gain , time to cure , and prevalence of clinical symptoms ( diarrhoea , fever , and respiratory problems ) . Analysis was on an intention-to-treat basis . This trial is registered as an International St and ard R and omised Controlled Trial , number IS RCT N19364765 . FINDINGS Nutritional cure was similar in both Synbiotic and control groups ( 53.9 % [ 215 of 399 ] and 51.3 % [ 203 of 396 ] ; p=0.40 ) . Secondary outcomes were also similar between groups . HIV seropositivity was associated with worse outcomes overall , but did not modify or confound the negative results . Subgroup analyses showed possible trends towards reduced outpatient mortality in the Synbiotic group ( p=0.06 ) . INTERPRETATION In Malawi , Synbiotic2000 Forte did not improve severe acute malnutrition outcomes . The observation of reduced outpatient mortality might be caused by bias , confounding , or chance , but is biologically plausible , has potential for public health impact , and should be explored in future studies . FUNDING Department for International Development ( DfID ) [26121696] Background : Ready-to-use therapeutic food ( RUTF ) has been found effective in treating severe acute malnutrition . Vietnam ’s National Institute of Nutrition ( NIN ) , the Institut de Recherche pour le Développement ( IRD ) , and UNICEF collaborated to formulate a local RUTF called High-Energy Bar for Integrated Management of Acute Malnutrition ( HEBI ) . RUTF might be useful to address malnutrition in HIV patients . Objective : To compare the acceptability of the local RUTF and an imported RUTF among malnourished people with HIV in Vietnam Methods : The acceptability of HEBI and Plumpy’Nut was studied among 80 HIV-positive children and 80 HIV-positive adults . In a crossover design , participants were r and omly assigned to receive either Plumpy’Nut or HEBI for 2 weeks and were switched to the other product for the subsequent 2 weeks . A third ( control ) group of about 40 HIV-positive participants in each study was r and omly assigned to receive no RUTF . Nurses took anthropometric measurements weekly , and the subjects or their caregivers monitored daily RUTF intake . Results : Children consumed 69 % of HEBI and 65 % of Plumpy’Nut ( p = .13 ) . Adults consumed 91 % of HEBI and 81 % of Plumpy’Nut ( p = .059 ) . Both children ( p = .058 ) and adults ( p ≤ .0001 ) preferred HEBI . Significant gains were observed in percent weight ( p = .035 ) , weight-for-age ( p = .014 ) , and body mass index ( BMI ) -for-age ( p = .036 ) in children who received RUTF and in percent weight ( p = .017 ) and BMI ( p = .0048 ) in adults who received RUTF compared with the control groups . Conclusions : In this study in Vietnam , both HEBI and Plumpy’Nut were found acceptable by people with HIV [15269617] Objectives : To determine the efficacy of home-based therapy with ready-to-use food ( RTUF ) in producing catch-up growth in malnourished children and to compare locally produced RTUF with imported RTUF for this purpose . Methods : After a brief inpatient stabilization , 260 children with severe malnutrition were enrolled and systematic ally allocated to receive home therapy with either imported , commercially produced RTUF or locally produced RTUF . Each child received 730 kJ/kg/day and was followed up fortnightly . Children completed the study when they reached a weight-for-height Z score > −0.5 ( WHZ ) , relapsed , died , or failed to achieve WHZ > −0.5 after 16 weeks . Analyses were stratified by human immunodeficiency virus ( HIV ) status . Results : 78 % of all children reached WHZ > −0.5 , 95 % of those with HIV-negative status and 59 % of those with HIV-positive status . Eighty percent of those receiving locally produced RTUF and 75 % of those receiving imported RTUF reached WHZ > −0.5 . The difference between recovery rates was 5 % ( 95 % confidence interval [ CI ] , −5–15 % ) . The rate of weight gain was 0.4 g/kg/day ( 95 % CI , −0.6 , 1.4 ) greater among children receiving locally produced RTUF . The prevalence of diarrhea reported by mothers was 3.7 % for locally produced RTUF and 4.3 % for imported RTUF . After completion of home therapy and resumption of habitual diet for 6 months , 91 % of all children maintained a normal WHZ . Conclusions : Home-based therapy with RTUF was successful in affecting complete catch-up growth . In this study , locally produced and imported RTUF were similar in efficacy in treating of severe childhood malnutrition [5345228] Background Children in third world countries suffer from severe acute malnutrition ( SAM ) in an extent of public health important . SAM management protocol available this time brought the approach from facility-based to community-based by Outpatient Therapeutic Program ( OTP ) . But , little was known about the treatment outcomes of the program in Ethiopia . Thus , this study was aim ed to assess treatment outcomes of SAM and identify factors associated among children treated at OTP in Wolaita Zone . Methods A retrospective facility-based cross-sectional study was conducted in OTP records of 794 children , treated at 24 health posts retrieved from January to December 2014 . Population proportion to size ( PPS ) was used to allocate sample for each selected district and OTP sites within district . Individual cards of children were selected by systematic r and om sampling . Data were entered , thoroughly cleaned , and analyzed in SPSS version 20 . Results The recovery rate was revealed as 64.9 % at 95 % CI ( 61 , 68 ) . Death rate , default rate , weight gain , and length of stay were 1.2 % , 2.2 % , 4.2 g/kg/day , and 6.8 weeks respectively . Children living in < 25 min were with 1.53 times higher odds of recovery than children residing in ≥25 min ( AOR = 1.53 at 95 % CI ( 1.11 , 2.12 ) ) . The likelihood of recovery was 2.6 times higher for children with kwashiorkor than for those with marasmus ( AOR = 2.62 at 95 % CI ( 1.77 , 3.89 ) ) . Likewise , children provided with amoxicillin were 1.52 times more likely to recover compared to their counterparts ( AOR = 1.52 at 95 % CI ( 1.09 , 2.11 ) ) . Conclusions The recovery rate and weight gain were lower than sphere st and ard . Distance from OTP , provision of amoxicillin , and type of malnutrition were factors identified as significantly associated with treatment outcome of SAM . Building capacity of OTP service providers and regular monitoring of service provision based on the management protocol were recommended [20332221] St and ard nutritional treatment of moderate acute malnutrition ( MAM ) relies on fortified blended flours though their importance to treat this condition is a matter of discussion . With the newly introduced World Health Organization growth st and ards , more children at an early stage of malnutrition will be treated following the dietary protocol s as for severe acute malnutrition , including ready-to-use therapeutic food ( RUTF ) . We compared the effectiveness of RUTF and a corn/soy-blend (CSB)-based pre-mix for the treatment of MAM in the supplementary feeding programmes ( SFPs ) supported by Médecins Sans Frontières , located in the Zinder region ( south of Niger ) . Children measuring 65 to < 110 cm , newly admitted with MAM [ weight-for-height ( WHM% ) between 70 % and < 80 % of the NCHS median ] were r and omly allocated to receive either RUTF ( Plumpy'Nut ® , 1000 kcal day(-1 ) ) or a CSB pre-mix ( 1231 kcal day(-1 ) ) . Other interventions were similar in both groups ( e.g. weekly family ration and ration at discharge ) . Children were followed weekly up to recovery ( WHM% ≥ 85 % for 2 consecutive weeks ) . In total , 215 children were recruited in the RUTF group and 236 children in the CSB pre-mix group with an overall recovery rate of 79.1 and 64.4 % , respectively ( p < 0.001 ) . There was no evidence for a difference between death , defaulter and non-responder rates . More transfers to the inpatient Therapeutic Feeding Centre ( I-TFC ) were observed in the CSB pre-mix group ( 19.1 % ) compared to the RUTF group ( 9.3 % ) ( p = 0.003 ) . The average weight gain up to discharge was 1.08 g kg(-1 ) day(-1 ) higher in the RUTF group [ 95 % confidence interval : 0.46 - 1.70 ] and the length of stay was 2 weeks shorter in the RUTF group ( p < 0.001 ) . For the treatment of childhood MAM in Niger , RUTF result ed in a higher weight gain , a higher recovery rate , a shorter length of stay and a lower transfer rate to the I-TFC compared to a CSB pre-mix . This might have important implication s on the efficacy and the quality of SFPs [28125907] Background : Severe acute malnutrition ( SAM ) is a salient health problem in India . Federation of Indian Chamber of Commerce and Industry ( FICCI ) Research and Analysis Centre , New Delhi , prepared nutreal equivalent to ready-to-use therapeutic food by World Health Organization ( WHO ) for the management of SAM and defined food like homemade diet . Objective : To compare acceptability and efficacy of nutreal over defined food for the management of SAM . Methods : One hundred twelve children aged less than 5 years with SAM were enrolled as per the st and ard of WHO . Children were r and omized into 2 groups to receive nutreal ( n = 56 ) and defined food ( n = 56 ) in unlimited amounts for 42 consecutive days and extended by 2 weeks as per dem and . Calorie and protein intake , weight , and mid-upper arm circumference ( MUAC ) were recorded daily . Results : Age range was 8 to 45 months . Ninety-three percent of children eagerly accepted nutreal but 7 % does not . Whereas in the defined food group , 68 % accepted eagerly , 30 % did not accept eagerly , and 1.8 % accepted poorly ( P = .004 ) . At enrollment , mean weight in the nutreal group was 6.44 ± 1.60 kg and in the defined food group was 8.69 ± 1.76 kg , with MUAC in the nutreal group being 11.12 ± 0.47 cm and in the defined food group being 11.54 ± 0.34 cm . Mean weight in the nutreal and defined food groups at eighth week of intervention was 7.97 ± 1.8 kg and 9.71 ± 1.8 kg ( P < .001 ) , respectively . Mid-upper arm circumference at eighth week was 12.10 ± 0.29 cm in the nutreal group and 12.49 ± 0.50 cm in the defined group ( P < .001 ) . Conclusion : Acceptability , mean weight gain , and MUAC in the nutreal group are greater than the defined food [6860310] Abstract The cost of ready‐to‐use therapeutic food ( RUTF ) used in community‐based management of acute malnutrition has been a major obstacle to the scale up of this important child survival strategy . The current st and ard recipe for RUTF [ peanut‐based RUTF ( P‐RUTF ) ] is made from peanut paste , milk powder , oil , sugar , and minerals and vitamins . Milk powder forms about 30 % of the ingredients and may represent over half the cost of the final product . The quality of whey protein concentrates 34 % ( WPC34 ) is similar to that of dried skimmed milk ( DSM ) used in the st and ard recipe and can be 25–33 % cheaper . This blinded , parallel group , r and omised , controlled non‐inferiority clinical trial tested the effectiveness in treating severe acute malnutrition ( SAM ) of a new RUTF formulation WPC‐RUTF in which WPC34 was used to replace DSM . Average weight gain ( non‐inferiority margin Δ = −1.2 g kg−1 day−1 ) and recovery rate ( Δ = −10 % ) were the primary outcomes , and length of stay ( LOS ) was the secondary outcome ( Δ = + 14 days ) . Both per‐ protocol ( PP ) and intention‐to‐treat ( ITT ) analyses showed that WPC‐RUTF was not inferior to P‐RUTF for recovery rate [ difference and its 95 % confidence interval ( CI ) of 0.5 % ( 95 % CI –2.7 , 3.7 ) in PP analysis and 0.6 % ( 95 % CI –5.2 , 6.3 ) in ITT analysis ] for average weight gain [ 0.2 ( −0.5 ; 0.9 ) for both analyses ] and LOS [ −1.6 days ( 95 % CI , −4.6 , 1.4 days ) in PP analysis and −1.9 days ( 95 % CI , −4.6 , 0.8 days ) for ITT analysis ] . In conclusion , whey protein‐based RUTF is an effective cheaper alternative to the st and ard milk‐based RUTF for the treatment of SAM [5916722] Background Acute malnutrition is currently divided into severe ( SAM ) and moderate ( MAM ) based on level of wasting . SAM and MAM currently have separate treatment protocol s and products , managed by separate international agencies . For SAM , the dose of treatment is allocated by the child ’s weight . A combined and simplified protocol for SAM and MAM , with a st and ardised dose of ready-to-use therapeutic food ( RUTF ) , is being trialled for non-inferior recovery rates and may be more cost-effective than the current st and ard protocol s for treating SAM and MAM . Method This is the protocol for the economic evaluation of the ComPAS trial , a cluster-r and omised controlled , non-inferiority trial that compares a novel combined protocol for treating uncomplicated acute malnutrition compared to the current st and ard protocol in South Sudan and Kenya . We will calculate the total economic costs of both protocol s from a societal perspective , using accounting data , interviews and survey question naires . The incremental cost of implementing the combined protocol will be estimated , and all costs and outcomes will be presented as a cost-consequence analysis . Incremental cost-effectiveness ratio will be calculated for primary and secondary outcome , if statistically significant . Discussion We hypothesise that implementing the combined protocol will be cost-effective due to streamlined logistics at clinic level , reduced length of treatment , especially for MAM , and reduced dosages of RUTF . The findings of this economic evaluation will be important for policymakers , especially given the hypothesised non-inferiority of the main health outcomes . The publication of this protocol aims to improve rigour of conduct and transparency of data collection and analysis . It is also intended to promote inclusion of economic evaluation in other nutrition intervention studies , especially for MAM , and improve comparability with other studies .Trial Registration IS RCT N 30393230 , date : 16/03/2017 [5978994] Background Acute malnutrition is a continuum condition , but severe and moderate forms are treated separately , with different protocol s and therapeutic products , managed by separate United Nations agencies . The Combined Protocol for Acute Malnutrition Study ( ComPAS ) aims to simplify and unify the treatment of uncomplicated severe and moderate acute malnutrition ( SAM and MAM ) for children 6–59 months into one protocol in order to improve the global coverage , quality , continuity of care and cost-effectiveness of acute malnutrition treatment in re source -constrained setting s. Methods / design This study is a multi-site , cluster r and omized non-inferiority trial with 12 clusters in Kenya and 12 clusters in South Sudan . Participants are 3600 children aged 6–59 months with uncomplicated acute malnutrition . This study will evaluate the impact of a simplified and combined protocol for the treatment of SAM and MAM compared to the st and ard protocol , which is the national treatment protocol in each country . We will assess recovery rate as a primary outcome and coverage , defaulting , death , length of stay , average weekly weight gain and average weekly mid-upper arm circumference ( MUAC ) gain as secondary outcomes . Recovery rate is defined across both treatment arms as MUAC ≥125 mm and no oedema for two consecutive visits . Per- protocol and intention-to-treat analyses will be conducted . Discussion If the combined protocol is shown to be non-inferior to the st and ard protocol , updating guidelines to use the combined protocol would eliminate the need for separate products , re sources and procedures for MAM treatment . This would likely be more cost-effective , increase availability of services , enable earlier case finding and treatment before deterioration of MAM into SAM , promote better continuity of care and improve community perceptions of the programme . Trial registration IS RCT N , IS RCT N30393230 . Registered on 16 March 2017 [1386687] Background Malnutrition constitutes a public health problem throughout the world and particularly in developing countries . Aims The objective of the study is to assess the impact of an elementary integrator composed of Spiruline ( Spirulina platensis ) and Misola ( millet , soja , peanut ) produced at the Centre Medical St Camille ( CMSC ) of Ouagadougou , Burkina Faso , on the nutritional status of undernourished children . Material s and methods 550 undernourished children of less than 5 years old were enrolled in this study , 455 showed severe marasma , 57 marasma of medium severity and 38 kwashiorkor plus marasma . We divided the children r and omly into four groups : 170 were given Misola ( 731 ± 7 kcal/day ) , 170 were given Spiruline plus traditional meals ( 748 ± 6 kcal/day ) , 170 were given Spiruline plus Misola ( 767 ± 5 kcal/day ) . Forty children received only traditional meals ( 722 ± 8 kcal/day ) and functioned as the control group . The duration of this study was eight weeks . Results and Discussion Anthropometrics and haematological parameters allowed us to appreciate both the nutritional and biological evolution of these children . The rehabilitation with Spiruline plus Misola ( this association gave an energy intake of 767 ± 5 kcal/day with a protein assumption of 33.3 ± 1.2 g a day ) , both greater than Misola or Spiruline alone , seems to correct weight loss more quickly . Conclusion Our results indicate that Misola , Spiruline plus traditional meals or Spiruline plus Misola are all a good food supplement for undernourished children , but the rehabilitation by Spiruline plus Misola seems synergically favour the nutrition rehabilitation better than the simple addition of protein and energy intake [23751252] A r and omized controlled trial was conducted in Ch and igarh , India ( 2011 ) , to determine the effectiveness of indigenous ready-to-use therapeutic food ( RUTF ) in community-based management of uncomplicated severe acute malnutrition ( SAM ) . Intervention was through outpatient therapeutic program site ( OTP ) . Study and control group children ( 6 months-5 years ) were followed up weekly for 12 weeks , in OTP and at home . All children received supplementary nutrition through anganwadis under integrated child development scheme . Study children , in addition , received therapeutic dose of RUTF in OTP . Primary outcome , 115 % of baseline weight , was attained in 6 of 13 ( 46.2 % ) and 1 of 13 ( 7.7 % ) children among study and control group , respectively [ odds ratio : 10.28 , 95 % confidence interval ( CI ) : 1.02 - 103.95 ] . Compared with control group , addition of RUTF in study group result ed in average additional increase in weight by 13 g/kg of baseline weight/week/child ( 95 % CI : 2 - 23 ) . Indigenous RUTF was effective in community-based management of uncomplicated SAM [18606932] OBJECTIVE To compare growth and incidence of malnutrition in infants receiving long-term dietary supplementation with ready-to-use fortified spread ( FS ) or micronutrient-fortified maize-soy flour ( likuni phala [ LP ] ) . DESIGN R and omized , controlled , single-blind trial . SETTING Rural Malawi . PARTICIPANTS A total of 182 six-month-old infants . INTERVENTION Participants were r and omized to receive 1 year of daily supplementation with 71 g of LP ( 282 kcal ) , 50 g of FS ( FS50 ) ( 256 kcal ) , or 25 g of FS ( FS25 ) ( 130 [ corrected ] kcal ) . OUTCOME MEASURES Weight and length gains and the incidences of severe stunting , underweight , and wasting . RESULTS Mean weight and length gains in the LP , FS50 , and FS25 groups were 2.37 , 2.47 , and 2.37 kg ( P = .66 ) and 12.7 , 13.5 , and 13.2 cm ( P = .23 ) , respectively . In the same groups , the cumulative 12-month incidence of severe stunting was 13.3 % , 0.0 % , and 3.5 % ( P = .01 ) , of severe underweight was 15.0 % , 22.5 % , and 16.9 % ( P = .71 ) , and of severe wasting was 1.8 % , 1.9 % , and 1.8 % ( P > .99 ) . Compared with LP-supplemented infants , those given FS50 gained a mean of 100 g more weight and 0.8 cm more length . There was a significant interaction between baseline length and intervention ( P = .04 ) ; in children with below-median length at enrollment , those given FS50 gained a mean of 1.9 cm more than individuals receiving LP . CONCLUSION One-year-long complementary feeding with FS does not have a significantly larger effect than LP on mean weight gain in all infants , but it is likely to boost linear growth in the most disadvantaged individuals and , hence , decrease the incidence of severe stunting [20972285] Objective To evaluate the effectiveness of a locally made ready-to-use therapeutic food ( RUTF ) in decreasing mild to moderate malnutrition . Design A r and omized open label , controlled trial . Setting Pre-schools run by the Department of Community Health in Kaniyambadi administrative block , Vellore , India ; duration of follow-up - 3 months from the date of recruitment . Participants Pupils aged 18–60 months with Weight-for-Age ≤2 SD . Interventions A locally produced energy-dense supplement ( RUTF ) , and the current st and ard of care [ teaching caregivers how to make a fortified cereal-milk supplement called High Calorie Cereal Milk (HCCM)].Main outcome measures Increase in weight-for-age status ; increase in levels of plasma zinc , vitamin B12 , serum albumin and haemoglobin . Results The Mean ( SD ) weight gain at 3 months was higher in the RUTF group : RUTF ( n=51 ) : 0.54 kg ; ( SE = 0.05 ; 95 % CI = 0.44–0.65 ) vs HCCM ( n=45 ) : 0.38 kg ; ( SE = 0.06 ; 95 % CI = 0.25–0.51 ) , P = 0.047 . The weight gain per kilogram of body weight was directly proportional to the severity of malnutrition . Conclusions Community-based treatment showed weight gain in both groups , the gain being higher with RUTF [20861218] Although widely used , there is little information concerning the efficacy of corn-soy blend ( CSB ) supplementation in the treatment of moderate underweight in African children . Lipid-based nutrient supplements ( LNS ) , which have proven to be beneficial treatment for severely wasted children , could offer benefits to less severely affected individuals . We conducted a clinical r and omized trial to determine whether LNS or CSB supplementation improves weight gain of moderately underweight children . A total of 182 underweight [ weight-for-age Z-score ( WAZ ) < -2 ] 6- to 15-mo-old children were r and omized to receive for 12 wk a ration of 43 g/d LNS or 71 g/d CSB , providing 1189 and 921 kJ , respectively , or no supplementation ( control ) . The primary outcome was weight change ; secondary outcomes included changes in anthropometric indices , hemoglobin levels , and morbidity . The body weight increases ( mean ± SD ) did not differ and were 620 ± 470 , 510 ± 350 , and 470 ± 350 g in the LNS , CSB , and control groups , respectively ( P = 0.11 ) . Compared with controls , infants and children in the LNS group gained more weight [ mean ( 95 % CI ) = 150 g ( 0 - 300 g ) ; P = 0.05 ] and had a greater increase in WAZ [ 0.33 ( -0.02 - 0.65 ) ; P = 0.04 ] . Weight and WAZ changes did not differ between the control and CSB groups . In exploratory stratified analysis , the weight increase was higher in the LNS group compared with the control group among those with lower initial WAZ [ 250 g ( 60 - 430 g ; P = 0.01 ] . Supplementation with LNS but not CSB modestly increases weight gain among moderately underweight children and the effect appears most pronounced among those with a lower initial WAZ [23782554] Community-based Management of Acute Malnutrition using ready-to-use therapeutic food ( RUTF ) has revolutionised the treatment of severe acute malnutrition ( SAM ) . However , 25 % milk content in st and ard peanut-based RUTF ( P-RUTF ) makes it too expensive . The effectiveness of milk-free RUTF has not been reported hitherto . This non-blinded , parallel group , cluster r and omised , controlled , equivalence trial that compares the effectiveness of a milk-free soy-maize-sorghum-based RUTF ( SMS-RUTF ) with P-RUTF in treatment of children with SAM , closes the gap . A statistician r and omly assigned health centres ( HC ) either to the SMS-RUTF ( n = 12 ; 824 enrolled ) or P-RUTF ( n = 12 ; 1103 enrolled ) arms . All SAM children admitted at the participating HCs were enrolled . All the outcomes were measured at individual level . Recovery rate was the primary outcome . The recovery rates for SMS-RUTF and P-RUTF were 53.3 % and 60.8 % for the intention-to-treat ( ITT ) analysis and 77.9 % and 81.8 % for per protocol ( PP ) analyses , respectively . The corresponding adjusted risk difference ( ARD ) and 95 % confidence interval , were -7.6 % ( -14.9 , 0.6 % ) and -3.5 % ( -9,6 . , 2.7 % ) for ITT ( P = 0.034 ) and PP analyses ( P = 0.257 ) , respectively . An unanticipated interaction ( interaction P < 0.001 for ITT analyses and 0.0683 for PP analyses ) between the study arm and age group was observed . The ARDs were -10.0 ( -17.7 to -2.3)% for ITT ( P = 0.013 ) and -4.7 ( -10.0 to 0.7 ) for PP ( P = 0.083 ) analyses for the < 24 months age group and 2.1 (-10.3,14.6)% for ITT ( P = 0.726 ) and -0.6 ( -16.1 , 14.5 ) for PP ( P = 0.939 ) for the ≥24 months age group . In conclusion , the study did not confirm our hypothesis of equivalence between SMS-RUTF and P-RUTF in SAM management [19225128] Moderate childhood wasting is defined as having a weight-for-height Z-score ( WHZ ) < -2 , but > or = -3 . These children are typically given fortified corn/soy blended flour ( CSB ) , but this intervention has shown limited effectiveness . Fortified spreads ( FS ) can be used as supplementary foods instead ; they are energy-dense , lipid-based pastes with added powdered micronutrients . In this r and omized clinical effectiveness trial , the recovery rates were compared among children with moderate wasting who received either milk/peanut FS , soy/peanut FS , or CSB . Children received isoenergetic quantities of food , 314 kJ x kg(-1 ) x d(-1 ) , for up to 8 wk with biweekly follow-up . The primary outcome was recovery , defined as having a WHZ > -2 . Time-event analysis was used to compare the recovery rate . A total of 1362 children were enrolled in the study . Children receiving soy/peanut FS had a similar recovery rate to those receiving milk/peanut FS and children in either FS group were more likely to recover than those receiving CSB ( 80 % in both FS groups vs. 72 % in the CSB group ; P < 0.01 ) . The rate of weight gain in the first 2 wk was greater among children receiving milk/peanut FS ( 2.6 g x kg(-1 ) x d(-1 ) , n = 465 ) or children receiving soy/peanut FS ( 2.4 g x kg(-1 ) x d(-1 ) , n = 450 ) than among children receiving CSB ( 2.0 g x kg(-1 ) x d(-1 ) , n = 447 ; P < 0.05 ) . Rates of length gain did not differ among the 3 groups . A total of 8 % of children in each feeding group developed edema , indicative of severe malnutrition , while receiving supplemental feeding . We conclude that FS are superior supplementary foods to CSB for moderately wasted Malawian children [16599106] The study was a controlled , comparative clinical effectiveness trial of two supplementary feeding regimens in children at risk of malnutrition from seven centres in rural Malawi . Being at risk of malnutrition was defined as weight-for-height < 85 % , but > 80 % of the international st and ard . A stepped-wedge design with systematic allocation was used for assigning children to receive either ready-to-use therapeutic food ( RUTF ) ( n=331 ) or micronutrient-fortified corn/soy-blend ( n=41 ) for up to eight weeks . The primary outcomes were recovery , defined as weight-for-height > 90 % , and the rate of weight gain . Children receiving RUTF were more likely to recover ( 58 % vs 22 % ; difference 36 % ; 95 % confidence interval [ CI ] 20 - 52 ) and had greater rates of weight gain ( 3.1 g/kg.d vs 1.4 g/kg x d ; difference 1.7 ; 95 % CI 0.8 - 2.6 ) than children receiving corn/soy-blend . The results of this preliminary work suggest that supplementary feeding with RUTF promotes better growth in children at risk of malnutrition than the st and ard fortified cereal/legume-blended food [14734876] Objective Maize and soy flour mixes are often used in the treatment of moderate malnutrition in Malawi . Their efficacy has not been formally evaluated . A recently developed ready-to-use food ( RTUF ) effectively promotes growth among severely malnourished children . The authors compared the effect of maize and soy flour with that of RTUF in the home treatment of moderately malnourished children . Methods Sixty-one underweight , stunted children 42 to 60 months of age were recruited in rural Malawi , in southeastern Africa . They received either RTUF or maize and soy flour for 12 weeks . Both supplements provided 2 MJ ( 500Kcal ) of energy daily but had different energy and nutrient densities . Outcome variables were weight and height gain and dietary intake . Results Before intervention , the mean dietary intake and weight and height gain were similar in the two groups . During the supplementation phase , the consumption of staple food fell among children receiving maize and soy flour but not among those receiving RTUF . There was thus higher intake of energy , fat , iron , and zinc in the RTUF group . Both supplements result ed in modest weight gain , but the effect lasted longer after RTUF supplementation . Height gain was not affected in either group . Periodic 24-hour dietary recalls suggested that the children received only 30 % and 43 % , respectively , of the supplementary RTUF and maize and soy flour provided . Conclusions RTUF is an acceptable alternative to maize and soy flour for dietary supplementation of moderately malnourished children . Approaches aim ed at increasing the consumption of supplementary food by the selected recipients are needed [20522296] Abstract Background : Typical treatment of moderate acute malnutrition , simple wasting , in sub-Saharan Africa consists of dietary counselling and /or general or targeted distribution of corn/soy-blended flour ( CSB ) . A r and omised clinical effectiveness trial in 2007 showed CSB to be less effective than ready-to-use supplementary food ( RUSF ) . Aim : To determine the operational effectiveness of treating moderate acute malnutrition with RUSF . Methods : Children aged 6–59 months were recruited in rural southern Malawi . Each child received 65 kcal/kg/d of locally produced soy/peanut RUSF , a product that provided about 1 RDA of each micronutrient . Anthropometric measurements were taken every 2 weeks and additional rations of RUSF were distributed at this time if the child remained wasted . Study participation lasted up to 8 weeks . Results : Of the 2417 children enrolled , 80 % recovered , 4 % defaulted , 0.4 % died , 12 % remained moderately wasted and 3 % developed severe acute malnutrition . Weight , length and MUAC gain were 2.6 g/kg/d , 0.2 mm/d and 0.1 mm/d respectively . Cost per child treated was $ 5.39 . Conclusions : This intervention proved to be robust , maintaining high recovery rates and low default rates when instituted without the additional supervision and beneficiary incentives of a research setting [28096555] Malnutrition is a major public health problem especially in the developing countries . The objective of the study was to compare WHO/UNICEF recommended therapeutic food with home based therapeutic food in the management of severe acute malnutrition . It was a r and omized controlled trial at tertiary care level hospital with nutritional rehabilitation centre . Children ( 6 month to 5 years ) having severe acute malnutrition were included in the study . Group A ( n=74 children ) was given WHO recommended therapeutic food and group B ( n=75 children ) was given home based therapeutic food . The mean rate of weight gain , gain in height and increase in mid-upper arm circumference were significantly higher ( p<0.05 ) in the group received home based therapeutic food . Mean duration to achieve target weight was 21.44±3.33 days in group A and 16.28±2.11 days in group B ( p < o.ooo1 ) . Group B children had higher rate of increase in urinary creatinine ( p<0.0001 ) . Affordability ( p<0.0001 ) , Feasibility ( p=0.027 ) and Average frequency of feeding per day ( p<0.0001 ) was found significantly higher in group B. Difficulty in making therapeutic food was significantly low in group B ( p<0.05 ) . Both kinds of therapeutic food were effective for the management of severe acute malnutrition , but the home based therapeutic food was found to be more effective . This could be explained by better acceptability in terms of better palatability , more affordability , increased frequency of feeding , and having less difficulty in making [22170366] BACKGROUND Children with moderate acute malnutrition ( MAM ) are often treated with fortified blended flours , most commonly a corn-soy blend ( CSB ) . However , recovery rates remain < 75 % , lower than the rate achieved with peanut paste-based ready-to-use supplementary foods ( RUSFs ) . To bridge this gap , a novel CSB recipe fortified with oil and dry skim milk , " CSB++ , " has been developed . OBJECTIVE In this trial we compared CSB++ with 2 RUSF products for the treatment of MAM to test the hypothesis that the recovery rate achieved with CSB++ will not be > 5 % worse than that achieved with either RUSF . DESIGN We conducted a prospect i ve , r and omized , investigator-blinded , controlled noninferiority trial involving rural Malawian children aged 6 - 59 mo with MAM . Children received 75 kcal CSB++ · kg(-1 ) · d(-1 ) , locally produced soy RUSF , or an imported soy/whey RUSF for ≤12 wk . RESULTS The recovery rate for CSB++ ( n = 763 of 888 ; 85.9 % ) was similar to that for soy RUSF ( 795 of 806 , 87.7 % ; risk difference : -1.82 % ; 95 % CI : -4.95 % , 1.30 % ) and soy/whey RUSF ( 807 of 918 , 87.9 % ; risk difference : -1.99 % ; 95 % CI : -5.10 % , 1.13 % ) . On average , children who received CSB++ required 2 d longer to recover , and the rate of weight gain was less than that with either RUSF , although height gain was the same among all 3 foods studied . CONCLUSIONS A novel , locally produced , fortified blended flour ( CSB++ ) was not inferior to a locally produced soy RUSF and an imported soy/whey RUSF in facilitating recovery from MAM . The recovery rate observed for CSB++ was higher than that for any other fortified blended flour tested previously . This trial is registered at clinical trials.gov as NCT00998517 [19155454] CONTEXT Ready-to-use therapeutic foods ( RUTFs ) are an important component of effective outpatient treatment of severe wasting . However , their effectiveness in the population -based prevention of moderate and severe wasting has not been evaluated . OBJECTIVE To evaluate the effect of a 3-month distribution of RUTF on the nutritional status , mortality , and morbidity of children aged 6 to 60 months in Niger . DESIGN , SETTING , AND PARTICIPANTS A cluster r and omized trial of 12 villages in Maradi , Niger . Six villages were r and omized to intervention and 6 to no intervention . All children in the study villages aged 6 to 60 months were eligible for recruitment . INTERVENTION Children with weight-for-height 80 % or more of the National Center for Health Statistics reference median in the 6 intervention villages received a monthly distribution of 1 packet per day of RUTF ( 92 g [ 500 kcal/d ] ) from August to October 2006 . Children in the 6 nonintervention villages received no preventive supplementation . Active surveillance for conditions requiring medical or nutritional treatment was conducted monthly in all 12 study villages from August 2006 to March 2007 . MAIN OUTCOME MEASURES Changes in weight-for-height z score ( WHZ ) according to the World Health Organization Child Growth St and ards and incidence of wasting ( WHZ < -2 ) over 8 months of follow-up . RESULTS The number of children with height and weight measurements in August , October , December , and February was 3166 , 3110 , 2936 , and 3026 , respectively . The WHZ difference between the intervention and nonintervention groups was -0.10 z ( 95 % confidence interval [ CI ] , -0.23 to 0.03 ) at baseline and 0.12 z ( 95 % CI , 0.02 to 0.21 ) after 8 months of follow-up . The adjusted effect of the intervention on WHZ from baseline to the end of follow-up was thus 0.22 z ( 95 % CI , 0.13 to 0.30 ) . The absolute rate of wasting and severe wasting , respectively , was 0.17 events per child-year ( 140 events/841 child-years ) and 0.03 events per child-year ( 29 events/943 child-years ) in the intervention villages , compared with 0.26 events per child-year ( 233 events/895 child-years ) and 0.07 events per child-year ( 71 events/1029 child-years ) in the nonintervention villages . The intervention thus result ed in a 36 % ( 95 % CI , 17 % to 50 % ; P < .001 ) reduction in the incidence of wasting and a 58 % ( 95 % CI , 43 % to 68 % ; P < .001 ) reduction in the incidence of severe wasting . There was no reduction in mortality , with a mortality rate of 0.007 deaths per child-year ( 7 deaths/986 child-years ) in the intervention villages and 0.016 deaths per child-year ( 18 deaths/1099 child-years ) in the nonintervention villages ( adjusted hazard ratio , 0.51 ; 95 % CI , 0.25 to 1.05 ) . CONCLUSION Short-term supplementation of nonmalnourished children with RUTF reduced the decline in WHZ and the incidence of wasting and severe wasting over 8 months . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00682708 [17033528] Objectives : Nutritional rehabilitation in Africa relies mainly on imported skim milk enriched with a sugar and salt mixture . We evaluated whether milk plus porridge made from local ingredients improves the outcome of childhood nutritional rehabilitation versus milk alone . Patients and Methods : This study was conducted in a nutritional unit in Lacor ( Northern Ug and a ) . The porridge , made from cheap locally available ingredients ( maize flour , dried fish or meat , peanut butter and oil ) supplemented with proteins and fats , provides 1.1 energy units , 4.4 kJ/g . We r and omly sample d the files of 100 cases discharged in October , November and December 2001 ( preintervention ) , in 2002 ( soon after intervention onset ) and in 2003 ( more than 1 year after intervention onset ) . We recorded the average hospital days and average oedema-free weight gain at discharge in the 3 groups . Results : Average oedema-free weight gain increased from 21 g/d ( 95 % confidence interval [ CI ] , 12 - 29 ) in 2001 to 35 g/d ( 95 % CI , 25 - 45 ) in 2002 and reached 59 g/d ( 95 % CI , 51 - 65 ) in 2003 . Mortality decreased from 22 % to 7.8 % , and nutritional failures ( insufficient weight gain ) decreased by greater than 50 % . Conclusions : The low-cost porridge supplement ( & U20AC;2640/yr per 100 children ) was effective in treating malnutrition . Widespread use of the porridge , which result ed in better outcomes than milk alone , could produce a savings in the medium- to long-term , thereby releasing re sources for other uses . A high-energy porridge that is made from locally available ingredients and does not require imported foods seems to be appropriate for supplementary feeding after mother 's milk in this setting [25633498] Objectives : Ready-to-use therapeutic food ( RUTF ) is the preferred treatment for uncomplicated severe acute malnutrition . It contains large amounts of linoleic acid and little & agr;-linolenic acid , which may reduce the availability of docosahexaenoic acid ( DHA ) and eicosapentaenoic acid ( EPA ) to the recovering child . A novel high-oleic RUTF ( HO-RUTF ) was developed with less linoleic acid to determine its effect on DHA and EPA status . Methods : We conducted a prospect i ve , r and omized , double-blind clinical effectiveness trial treating rural Malawian children with severe acute malnutrition . Children were treated with either HO-RUTF or st and ard RUTF . Plasma phospholipid fatty acid status was measured on enrollment and after 4 weeks and compared between the 2 intervention groups . Results : Among the 141 children enrolled , 48 of 71 receiving HO-RUTF and 50 of 70 receiving RUTF recovered . Plasma phospholipid sample s were analyzed from 43 children consuming HO-RUTF and 35 children consuming RUTF . The change in DHA content during the first 4 weeks was + 4 % and −25 % in the HO-RUTF and RUTF groups , respectively ( P = 0.04 ) . For EPA , the change in content was 63 % and −24 % in the HO-RUTF and RUTF groups , respectively ( P < 0.001 ) . For arachidonic acid , the change in content was −3 % and 13 % in the HO-RUTF and RUTF groups , respectively ( P < 0.009 ) . Conclusions : The changes in DHA and EPA seen in the children treated with HO-RUTF warrant further investigation because they suggest that HO-RUTF support improved polyunsaturated fatty acid status , necessary for neural development and recovery [17033530] Objective : Fortified spreads ( FSs ) have proven effective in the rehabilitation of severely malnourished children . We examined acceptability , growth and change in blood haemoglobin ( Hb ) concentration among moderately underweight ambulatory infants given FS . Methods : This was a r and omised , controlled , parallel-group , investigator-blind clinical trial in rural Malawi . Six- to 17-month-old underweight infants ( weight for age < −2 ) , whose weight was greater than 5.5 kg and weight-for-height z score greater than −3 received for 12 weeks at home 1 of 8 food supplementation schemes : nothing , 5 , 25 , 50 , or 75 g/day milk-based FS or 25 , 50 , or 75 g/day soy-based FS . Outcome measures included change in weight , length and blood Hb concentration . Results : A total of 126 infants started and 125 completed the intervention . All infants accepted the spread well , and no intolerance was recorded . Average weight and length gains were higher among infants receiving daily 25 to 75 g FS than among those receiving only 0 to 5 g FS . Mean Hb concentration remained unchanged among unsupplemented controls but increased by 10 to 17 g/L among infants receiving any FS . All average gains were largest among infants receiving 50 g of FS daily : mean difference ( 95 % confidence interval ) in the 12-week gain between infants in 50 g milk-based FS group and the unsupplemented group was 290 g ( range , −130 to 700 g ) , 0.9 cm ( range , −0.3 to 2.2 cm ) , and 17 g/L ( range , 0 to 34 g/L ) for weight , length and blood Hb concentration , respectively . In soy- vs milk-based FS groups , average outcomes were comparable . Conclusions : Supplementation with 25 to 75 g/day of highly fortified spread is feasible and may promote growth and alleviate anaemia among moderately malnourished infants . Further trials should test this hypothesis [26984485] BACKGROUND The cost of current st and ard ready-to-use therapeutic food ( RUTF ) is among the major obstacles to scaling up community-based management of acute malnutrition ( CMAM ) , an important child survival strategy . Identifying a cheaper alternative is a global public health priority . OBJECTIVE We sought to compare the efficacy of soya-maize-sorghum RUTF ( SMS-RUTF ) with that of st and ard peanut paste-based RUTF ( P-RUTF ) . DESIGN We used a nonblinded , parallel-group , simple r and omized controlled trial along with a day care approach that enrolled 2 groups of children aged 6 - 23 and 24 - 59 mo , respectively , with severe acute malnutrition ( SAM ) . RESULTS Intention-to-treat ( ITT ) and per- protocol ( PP ) analyses showed noninferiority of SMS-RUTF compared with P-RUTF for the recovery rate [ ITT : Δ = -2.0 % ( 95 % CI : -7.6 % , 3.6 % ) ; PP : -1.9 % ( 95 % CI : -5.3 % , 1.4 % ) ] , weight gain [ Δ = -0.7 g · kg(-1 ) · d(-1)(95 % CI : -1.3 , 0.0 g · kg(-1 ) · d(-1 ) ) ] , and length of stay [ Δ = 2.0 d ( 95 % CI : -1.7 , 5.8 d ) ] in children ≥24 mo of age . In children ≤23 mo of age , the recovery rate of SMS-RUTF was inferior to that of P-RUTF [ ITT : Δ = -20.8 % ( 95 % CI : -29.9 % , -11.7 % ) ; PP : -17.2 % ( 95 % CI : -25.6 % , -8.7 % ) ] . Treatment with SMS-RUTF result ed in a greater increase in hemoglobin [ 0.670 g/dL ( 95 % CI : 0.420 , 0.921 g/dL);P < 0.001 ] . Treatment with both RUTFs result ed in the replenishment of all of the amino acids tested except for methionine . There were no differences at discharge between RUTF groups in fat mass [ Δ = 0.3 kg ( 95 % CI : -0.6 , 1.6 kg);P= 0.341 ] or fat mass index [ Δ = 0.4 kg/m(2)(95 % CI : -0.3 , 1.1 kg/m(2));P= 0.262 ] . By contrast , comparisons of fat-free mass indicated lower concentrations than the community controls after treatment with either of the 2 RUTFs [ Δ = -1.3 kg ( 95 % CI : -2.4 , -0.1 kg ) and P= 0.034 for comparison between community controls and the SMS-RUTF group ; Δ = -1.8 kg ( 95 % CI : -2.9 , -0.6 kg ) and P= 0.003 for comparison between community controls and the P-RUTF group ] . CONCLUSION SMS-RUTF can be used to treat SAM in children aged ≥24 mo to reduce the costs of CMAM programs . More research is required to optimize SMS-RUTF for younger children . This trial was registered in the Pan African Clinical Trial Registry as PACTR201303000475166 [28729459] The importance of adequate intervention descriptions in minimising research waste and improving research usability and reproducibility has gained attention in the past few years . Nearly all focus to date has been on intervention reporting in r and omised trials . Yet clinicians are encouraged to use systematic review s , whenever available , rather than single trials to inform their practice . This article explores the problem and implication s of incomplete intervention details during the planning , conduct , and reporting of systematic review s and makes recommendations for review authors , peer review ers , and journal [26423737] BACKGROUND Global acute malnutrition ( GAM ) is the sum of moderate acute malnutrition ( MAM ) and severe acute malnutrition ( SAM ) . The use of different foods and protocol s for MAM and SAM treatment can be cumbersome in emergency setting s. OBJECTIVE Our objective was to determine the recovery and coverage rates for GAM of an integrated protocol with a single food product , ready-to-use therapeutic food ( RUTF ) , compared with st and ard management . METHODS This was a cluster-r and omized controlled trial in Sierra Leone conducted in 10 centers treating GAM in children aged 6 - 59 mo . The integrated protocol used midupper arm circumference ( MUAC ) as the criterion for admission and discharge , with a MUAC < 12.5 cm defining malnutrition . The protocol included a decreasing ration of RUTF and health maintenance messages delivered by peers . St and ard therapy treated MAM with a fortified blended flour and SAM with RUTF and used weight-for-height to determine admission to the treatment program . Coverage rates were the number of children who received treatment/number of children in the community eligible for treatment . RESULTS Most of the children receiving integrated management had MAM ( 774 of 1100 ; 70 % ) , whereas among those receiving st and ard management , SAM predominated ( 537 of 857 ; 63 % ; P = 0.0001 ) . Coverage was 71 % in the communities served by integrated management and 55 % in the communities served by st and ard care ( P = 0.0005 ) . GAM recovery in the integrated management protocol was 910 of 1100 ( 83 % ) children and was 682 of 857 ( 79 % ) children in the st and ard therapy protocol . CONCLUSION Integrated management of GAM in children is an acceptable alternative to st and ard management and provides greater community coverage . This trial was registered at clinical trials.gov as NCT01785680 [6073612] Cambodia continues to have a high prevalence of acute malnutrition . Low acceptability has been found for st and ard ready-to-use-therapeutic-food ( RUTF ) products . Therefore , NumTrey , a locally-produced fish-based RUTF , was developed . The objective was to evaluate the effectiveness of NumTrey compared to an imported milk-based RUTF for weight gain among children aged 6–59 months in the home-treatment for acute malnutrition . Effectiveness was tested in a single-blinded r and omized controlled trial with weight gain as the primary outcome . Anthropometry was assessed at baseline and bi-weekly follow-ups until endline at Week 8 . In total , 121 patients were r and omized into BP-100TM ( n = 61 ) or NumTrey ( n = 60 ) . There was no statistical difference in mean weight gain between the groups ( 1.06 g/kg/day ; 95 % CI ( 0.72 , 1.41 ) and 1.08 g/kg/day ; 95 % CI ( 0.75 , 1.41 ) for BP-100 ™ and NumTrey , respectively ) . In addition , no statistically significant differences in secondary outcomes were found . Although the ability to draw conclusions was limited by lower weight gain than the desired 4 g/kg/day in both groups , no superiority was found for eitherRUTF . A locally produced RUTF is highly relevant to improve nutrition interventions in Cambodia . A locally produced fish-based RUTF is a relevant alternative to imported milk-based RUTF for the treatment of SAM in Cambodia [6086422] Background Ready-to-use therapeutic food ( RUTF ) is used to treat children suffering from severe acute malnutrition ( SAM ) . St and ard RUTF uses milk as the primary protein source , which makes the product expensive , and given the high worldwide SAM burden , having a less expensive effective alternative is a public health priority . Objective The objective of this study was to evaluate whether newly developed amino acid-enriched milk-free RUTF ( FSMS-RUTF ) or amino acid-enriched low-milk RUTF ( MSMS-RUTF ) treatment could replenish plasma amino acids to levels comparable to those following st and ard peanut-milk RUTF ( PM-RUTF ) treatment and to improve underst and ing of the effects of treatment on anthropometric measurements . A secondary analysis was performed to test the noninferiority hypothesis of plasma essential amino acid ( EAA ) levels . Methods Plasma EAA levels were measured in a nonblinded , 3-arm , parallel-group simple r and omized controlled trial conducted in Malawi to examine the efficacy of FSMS-RUTF , MSMS-RUTF and PM-RUTF in the treatment of SAM in 2 groups of children aged 6–23 and 24–59 months ( mo ) . Sample size calculations were performed based on the previous our study . A noninferiority margin was set at -25 % of the PM-RUTF arm at discharge . Results The relative values of the differences ( 95 % CI ) in plasma EAA levels between PM-RUTF treatment and FSMS-RUTF and MSMS-RUTF treatments at discharge were -7.9 % ( -18.6 , 2.8 ) and 9.8 % ( 0.2 , 19.5 ) , respectively , in children aged 6–23 mo , while in those aged 24–59 mo , the difference values were 17.8 % ( 1.6 , 34.1 ) and 13.6 % ( -2.8 , 29.9 ) , respectively . Conclusion At discharge , the plasma EAA concentrations in 6 - 59-mo-old SAM children treated with FSMS-RUTF and MSMS-RUTF were not less than those of children treated with PM-RUTF . These findings indicate that treatment with either of the 3 RUTFs was associated with adequate protein synthesis and that all the formulations provided sufficient functional metabolites of plasma amino acids to support nutritional recovery from SAM [20980648] St and ard therapy for severe acute malnutrition ( SAM ) is home-based therapy with ready-to-use therapeutic food ( RUTF ) containing 25 % milk . In an effort to lower the cost of RUTF and increase availability , some have suggested that a portion of milk be replaced with soy . This trial was design ed to determine whether treating children with SAM with 10 % milk RUTF containing soy would result in a similar recovery rate compared with the 25 % milk RUTF . This was a r and omized , double-blind , controlled , clinical , quasi-effectiveness trial of isoenergetic amounts of 2 locally produced RUTF to treat SAM in Malawi among children aged 6 - 59 mo . A total of 1874 children were enrolled . Children were assessed every fortnight and participated in the study until they clinical ly recovered or received 8 wk of treatment . The primary outcome was recovery ( weight-for-height Z score > -2 and no edema ) . Secondary outcomes were rates of weight and height gain . Survival analysis was used to compare the recovery rates . Recovery among children receiving 25 % milk RUTF was greater than children receiving 10 % milk RUTF , 64 % compared with 57 % after 4 wk , and 84 % compared with 81 % after 8 wk ( P < 0.001 ) . Children receiving 25 % milk RUTF also had higher rates of weight and height gain compared with children receiving 10 % milk RUTF . Treating children with SAM with 10 % milk RUTF is less effective compared with treatment with the st and ard 25 % milk RUTF . These findings also emphasize that clinical evidence should be examined before recommending any changes to the formulation of RUTF Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Moderate acute malnutrition , also called moderate wasting , affects around 10 % of children under five years of age in low- and middle-income countries . There are different approaches to addressing malnutrition with prepared foods in these setting s ; for example , providing lipid-based nutrient supplements or blended foods , either a full daily dose or in a low dose as a complement to the usual diet . There is no definitive consensus on the most effective way to treat children with moderate acute malnutrition . OBJECTIVES To evaluate the safety and effectiveness of different types of specially formulated foods for children with moderate acute malnutrition in low- and middle-income countries , and to assess whether foods complying or not complying with specific nutritional compositions , such as the WHO technical specifications , are safe and effective . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

22777099

[10808574] Vaccine " Grippol "-- has been developed at the State Research Center -- Institute of Immunology . The preparation belongs to new generation vaccines and is a trivalent polymer-subunit vaccine containing the sterile conjugate of influenza virus surface proteins , types A and B , bound with copolymer polyoxidonium . The administration of " Grippol " to children of school age ( 6 - 18 years ) demonstrated low reactogenicity of the vaccine , its safety and sufficient prophylactic effectiveness . During observations on total morbidity ( with the exception of influenza and acute respiratory diseases ) no side effects produced by " Grippol " were registered . At the same time the fact that the morbidity rate of upper respiratory tract disease in the group of children immunized with the vaccine decreased in comparison with the control group ( by 2.4 times ) can not be disregarded [8160445] Production lots of a live influenza vaccine made of strains A/47/T ( N1H1 ) , A/47/6/2 ( H3N2 ) , and B/60/32 were used for vaccination of 3663 children aged from 5 to 14 years inoculated twice with monovaccines , a trivaccine made of the above strains , or placebo . Both mono- and polyvaccine were practically areactogenic . An average per cent of subjects with a significant rise in antibody titres to the respective three antigens was 60 % . The efficacy of the vaccination was 31.0 - 42.8 % for monopreparations and 36.3 % for the trivaccine . The studies showed the possibility and expedience of using for children the live influenza vaccine in the form of a polyvalent preparation including current influenza type A and B viruses [12271721] In Russia for prevention of influenza in children , aged from 3 to 14 years , the children 's live influenza vaccine ( LIV ) , based upon A/Leningrad/134/47/57(H2N2 ) master strain ( LIVI ) is used . The need for double immunization appears to be one out of the faulties of this preparation . The study was aim ed to comparing the safety , immunogenic activity and prevention of influenza by LIV for adults ( LIVII ) ( A/Leningrad/134/17/57(H2N2 master strain ) and LIVI in children aged from 7 to 17 years under similar administration schedule . The safety , the preventive efficacy , humoral and secretory immunity were studied . In total 2486 persons , including 539 children , twice inoculated with LIVI , 971 persons once inoculated with LIVII , and 840 treated by placebo were obserbed . From the data of the clinical observations during 7 days after immunization both vaccines appeared to be low reactogenic . The LIVII advantages in induction of the humoral and secretory antibodies in comparison with children 's vaccine had been revealed . Both vaccines were highly efficacious , the efficiency of both preparations was more pronounced after serologic correction of the diagnosis . The results obtained permit to recommend the single immunization by the variant of LIV at the base on A/Leningrad/134/17/57/(H2N2 ) master strain for prevention of influenza in school children [10930686] The immunogenicity and efficacy of Russian live attenuated and US inactivated trivalent influenza vaccines administered alone or in three different combinations were evaluated in a r and omized , placebo-controlled , double-blinded study of 614 elderly or chronically ill nursing home residents in St. Petersburg , Russia during the 1996 - 97 influenza season . Postvaccination serum antibody responses were more frequent among individuals administered the combination vaccines than among those vaccinated with live or inactivated vaccine alone . Only individuals who received live vaccine , alone or in combination with inactivated vaccine , achieved significant postvaccination increases in virus-specific nasal IgA. Efficacy in preventing laboratory-confirmed influenza in vaccinated versus nonvaccinated individuals was 67 % ( 95%CI , 36 - 81 % ) for recipients of a combination of the vaccines compared with 51 % ( 95%CI , -17 - 79 % ) for recipients of live vaccine alone and 50 % ( 95%CI , -26 - 80 % ) for recipients of inactivated vaccine alone . These results suggest that administration of a combination of influenza vaccines may provide a strategy for improved influenza vaccination of elderly people [19395948] Background : We investigated the efficacy and safety of 1 versus 2 doses of live attenuated influenza vaccine ( LAIV ) in influenza vaccine – naive children aged 6 to < 36 months . Patients / Methods : Subjects were r and omized to 1 of 4 regimens in year 1 : 2 doses LAIV , 1 dose LAIV , excipient placebo , or saline placebo . In year 2 , LAIV recipients were to receive 1 dose of LAIV and placebo recipients were to receive saline placebo . Because of an unintended treatment allocation error in year 2 , 1 block of subjects who were r and omized to LAIV received saline placebo and 1 block who were r and omized to placebo received LAIV . Results : In year 1 , vaccine efficacy versus placebo among recipients of 2 and 1 doses of LAIV was 73.5 % and 57.7 % , respectively , against antigenically similar strains . In year 2 , absolute efficacy of a single dose of LAIV was 73.6 % and 65.2 % , respectively , in recipients of 2 and 1 doses of LAIV in year 1 . Year 2 efficacy was 57.0 % in subjects who received 2 doses of LAIV in year 1 and placebo in year 2 . Safety and tolerability of LAIV were consistent with previous studies . Reactogenicity was similar between placebo groups . Seroconversion rates were significantly higher in the 2-dose versus the 1-dose LAIV group in year 1 and in both LAIV groups versus placebo in years 1 and 2 . Conclusions : One dose of LAIV provided clinical ly significant protection against influenza in young children previously unvaccinated against influenza ; 2 doses provided additional protection . Protection after 2 doses in year 1 persisted through a second season without revaccination . LAIV excipients were not a major contributor to reactogenicity . These benefits provide support for increased use of LAIV in children ≥2 years of age [10078487] CONTEXT Data are limited and conflicting regarding the effectiveness of influenza vaccine in health care professionals . OBJECTIVE To determine the effectiveness of trivalent influenza vaccine in reducing infection , illness , and absence from work in young , healthy health care professionals . DESIGN R and omized , prospect i ve , double-blind , controlled trial over 3 consecutive years , from 1992 - 1993 to 1994 - 1995 . SETTING Two large teaching hospitals in Baltimore , Md. PARTICIPANTS Two hundred sixty-four hospital-based health care professionals without chronic medical problems were recruited ; 49 participated for 2 seasons ; 24 participated for 3 seasons . The mean age was 28.4 years , 75 % were resident physicians , and 57 % were women . INTERVENTION Participants were r and omly assigned to receive either an influenza vaccine or a control ( meningococcal vaccine , pneumococcal vaccine , or placebo ) . Serum sample s for antibody assays were collected at the time of vaccination , 1 month after vaccination , and at the end of the influenza season . Active weekly surveillance for illness was conducted during each influenza epidemic period . MAIN OUTCOME MEASURES Serologically defined influenza infection ( 4-fold increase in hemagglutination-inhibiting antibodies ) , days of febrile respiratory illness , and days absent from work . RESULTS We conducted 359 person-winters of serologic surveillance ( 99.4 % follow-up ) and 4746 person-weeks of illness surveillance ( 100 % follow-up ) . Twenty-four(13.4 % ) of 179 control subjects and 3 ( 1.7 % ) of 180 influenza vaccine recipients had serologic evidence of influenza type A or B infection during the study period . Vaccine efficacy against serologically defined infection was 88 % for influenza A ( 95 % confidence interval [ CI ] , 47%-97 % ; P=.001 ) and 89 % for influenza B ( 95 % CI , 14%-99 % ; P=.03 ) . Among influenza vaccinees , cumulative days of reported febrile respiratory illness were 28.7 per 100 subjects compared with 40.6 per 100 subjects in controls ( P=.57 ) and days of absence were 9.9 per 100 subjects vs 21.1 per 100 subjects in controls ( P=.41 ) . CONCLUSIONS Influenza vaccine is effective in preventing infection by influenza A and B in health care professionals and may reduce reported days of work absence and febrile respiratory illness . These data support a policy of annual influenza vaccination of health care professionals [12234038] BACKGROUND Approximately 10 % of the general population worldwide acquires influenza infection every year . Airline crews run a particularly high risk of contracting influenza and influenza-like viruses because they come in contact with hundreds of potentially infected individuals every day . Respiratory diseases are the most frequent cause of absenteeism among flight crews in airline companies . Several studies have shown the efficacy of influenza vaccination in the workplace of healthy , working adults leading to increased productivity and lower absenteeism . We conducted a double blind , r and omized , placebo-controlled study on flight crews of an airline company in order to determine the safety and efficacy of a trivalent inactivated influenza vaccine in reducing illness and absences from work . METHODS The 813 healthy members of a Brazilian airline company were r and omly assigned to receive injections of either an influenza vaccine or a placebo , with a follow-up period of 7 mo after vaccination . Primary outcomes included influenza-like illness episodes and absenteeism from work due to such episodes . RESULTS Demographic characteristics were similar in the two groups . No significant side-effects occurred in either group . Compared to the placebo group , individuals receiving the vaccine showed 39.5 % fewer episodes of flu-like illness ( p < 0.001 ) and 26 % fewer days of work lost ( p = 0.03 ) . The vaccinated group developed 33 % fewer episodes of any severe flu-like illness ( p < 0.01 ) . CONCLUSION The data indicates that influenza vaccination is safe in airline flight crews and may produce health-related benefits including reduced absenteeism [7054318] A live , attenuated influenza B virus vaccine was evaluated in a group of students . The virus , cold-recombinant ( CR ) 7 , was produced by recombining the attenuated cold-adapted parent , B/Ann Arbor/1/66 , with a wild strain , B/Hong Kong/8/73 . In ferrets , the wild strain produced histopathologic lesions in the lungs , whereas the CR strain and the attenuated parent did not . A total of 306 individuals was inoculated intranasally with either the CR virus or a placebo . After inoculation , only one symptom was significantly more common in the vaccinees than in the control subjects . That symptom , sore throat , occurred briefly in 26 % of the vaccine recipients and in 10.5 % of the placebo recipients . An outbreak of influenza B occurred three months after vaccination . When serologic infection rates in the two groups were compared , it was found that the vaccine had been significantly effective ( P less than 0.01 ) in preventing infection [11893153] OBJECTIVE To evaluate the effectiveness of influenza vaccines against influenza-like illness ( ILI ) among nursing home residents . DESIGN Prospect i ve , nonr and omized , cohort study . SETTING Nine nursing homes during the 1998 - 1999 influenza season and 11 nursing homes during the 1999 - 2000 influenza season in Niigata Prefecture , Japan . PARTICIPANTS Six hundred ninety-nine residents and 440 healthcare workers ( HCWs ) during the first season , and 930 residents and 517 HCWs during the second season , with vaccination rates ranging from 0 % to 97.7 % . RESULTS Overall , ILI decreased from 24.3 % during the 1998 - 1999 season to 8.8 % during the 1999 - 2000 season . Multivariate analysis adjusted for several factors , including gender , age , underlying diseases , and resident and HCW vaccination rates , failed to demonstrate clear individual protection of residents ( relative risk [ RR ] , 1.42 ; P = .2 for the first season ; RR , 0.95 ; P = .9 for the second season ) . However , vaccination rates of 60 % or greater for residents and HCWs reduced the risk of ILI , and also could prevent outbreaks during the 2 seasons . Highly impaired activities of daily living and chronic respiratory diseases were significantly associated with increased ILI . CONCLUSIONS A high vaccination rate for both residents and HCWs may reduce the risk of ILI and institutional outbreaks in nursing homes [19366887] When the first edition of A Dictionary of Epidemiology was launched in 1983 , its principal aim was to facilitate communication among health professionals . The field was relatively young and comprised complex interdisciplinary relations ranging from the biomedical sciences to statistics and the social sciences . The International Epidemiological Association ( IEA ) co-sponsored the project with the aim of developing certain st and ards for teaching , research reports and communication of epidemiological findings to the public . This is a well-known history : John M Last , the emeritus professor of epidemiology and community medicine from the University of Ottawa , Canada , was appointed as the editor of A Dictionary ... , and kept ahead of the task during the subsequent decades . The original slim pocket book grew substantially with each re-edit , keeping pace with the remarkable developments in the discipline . When the fourth edition was launched in 2001 , John Last told me with a smile that he would die soon , supposedly to increase the value of the signature he had just h and written in my book . Fortunately , he did not , and his love for dictionary-making allowed him to produce his A Dictionary of Public Health , and to collaborate in the recently launched fifth edition of A Dictionary ... , now edited by Miquel Porta , professor of preventive medicine and public health from the Universitat Autònoma de Barcelona , senior scientist of the Institut Municipal d’Investigació Mèdica in Barcelona , Spain , and collaborator in the previous editions . If he had to limit his professional bookcase to a single volume , Professor Charles du V Florey , the former president of the IEA , would choose to keep A Dictionary .... I argue that anybody among us — epidemiologists and would-be epidemiologists ( hopefully with a larger shelf)—should also have a copy of this book at h and for frequent consultation . The collective effort gathered in its making is impressive . Miquel Porta has built over the previously crafted editions , and has relied on the support of a wide network of professionals to up date each entry and to exp and the selection of subjects . The Journal of Epidemiology and Community Health joined the initiative by publishing a call for su bmi ssions . Items already selected from the previous edition have been revised and up date d ; several new items have been added . As a result , the fifth edition of A Dictionary ... performs normative and informative functions : you will be informed on important matters and instructed on how to proceed in the epidemiological field . Readers with different needs and anxieties with knowledge will find straightforward writing , authoritative definitions and pertinent bibliographical references . How to differentiate a rate from a ratio , incidence from prevalence , confounding from intervening variables , type I from type II error ? How to appraise emerging themes in the epidemiological literature such as genetic polymorphisms and Bayesian statistics ? Key method ological issues such as meta- analysis , multilevel analysis and regression models : the list solely enrols a small sample of possible search es . The selection of issues was broad in scope ; intelligent and synthetic writing contemplated from the easier to the more intricate subjects . You may want to up date conceptual and method ological issues relevant to your teaching and research activities , to resolve doubts or to confirm an impression . You may want to check on terminology , fulfil curiosities or learn about topics unrelated to your preferential themes . You may be a professional applied to other health specialities , an undergraduate or a high school student . Several users will meet their needs by consulting A Dictionary ... ; even those who aim lessly scan the text may find some valuable insight . While it will not resolve all your needs in the epidemiological field , it surely provides enough substance to build on — a very good start or ammunition for more comprehensive search es . Miquel Porta dealt with the challenge of preparing reader-friendly texts on a wide range of subjects , which will satisfy both a beginner and an experienced epidemiologist . He seems to have transposed Occam ’s razor ( see the correspondent entry : ‘ ‘ the philosophical principle of parsimony ... assumptions to explain a phenomenon must not be multiplied beyond necessity ... ’ ’ ) to the writing of the book . If I may indulge in selftestimony , I found my teenage daughter consulting the book and it motivated a conversation on subjects so dear to me .... Arousing the interest of the young for a speciality admittedly perceived as difficult by adolescents ; as goes the popular saying , this is priceless ! ‘ ‘ Epidemiology is the study of the occurrence and distribution of healthrelated states or events in specified population s , including the study of the determinants influencing such states , and the application of this knowledge to control the health problems ’ ’ . The definition has matured over the years and presents slight modifications from its previous formulation in the fourth edition . The entry for ‘ ‘ Epidemiology ’ ’ exp and s the conceptualisation of terms comprised in the definition and includes historical aspects . In subsequent years , this definition will be the benchmark of the discipline , until Miquel Porta and his collaborators eventually prepare a further edition to meet the new needs that the future may bring forth . I dare to guess that the prospect i ve sixth edition of A Dictionary ... will have an online dynamic interface interacting with the hard copy . I also dare to guess that it will include a new entry for A Dictionary of Epidemiology , whose importance to the professional field will surely have earned it [7080769] To evaluate the safety , reactogenicity and immunogenicity of inactivated chromatographic influenza vaccine A(H3N2 ) produced by the Pasteur Research Institute of Epidemiology and Microbiology in Leningrad , children aged 7 - 15 years received the vaccine intradermally in doses of 114 - 228 IU , and 152 children received placebo . In this study inactivated influenza vaccine introduced parenterally to children aged 11 - 15 years in a dose of 228 IU proved to be nonreactogenic . The reactogenicity index of the preparation injected in a dose of 114 IU to children aged 7 - 10 years was 0.6 % . Immunization in a single injection was accompanied by significant seroconversions in 87.5%-96.0 % of children with the highly pronounced growth of antibody titers ( 21.1 - 34.6 times ) . The complex of clinico-laboratory tests showed the safety of this preparation for both age groups [18522501] BACKGROUND The efficacy of influenza vaccines may vary annually . In 2004 - 2005 , when antigenically drifted viruses were circulating , a r and omized , placebo-controlled trial involving healthy adults showed that inactivated vaccine appeared to be efficacious , whereas live attenuated vaccine appeared to be less so . METHODS In 2005 - 2006 , we continued our trial , examining the absolute and relative efficacies of the live attenuated and inactivated vaccines in preventing laboratory-confirmed symptomatic influenza . RESULTS A total of 2058 persons were vaccinated in October and November 2005 . Study wide influenza activity was prolonged but of low intensity ; type A ( H3N2 ) virus was circulating , which was antigenically similar to the vaccine strain . The absolute efficacy of the inactivated vaccine was 16 % ( 95 % confidence interval [ CI ] , -171 % to 70 % ) for the virus identification end point ( virus isolation in cell culture or identification through polymerase chain reaction ) and 54 % ( 95 % CI , 4%-77 % ) for the primary end point ( virus isolation or increase in serum antibody titer ) . The absolute efficacies of the live attenuated vaccine for these end points were 8 % ( 95 % CI , -194 % to 67 % ) and 43 % ( 95 % CI , -15 % to 71 % ) , respectively . CONCLUSIONS With serologic end points included , efficacy was demonstrated for the inactivated vaccine in a year with low influenza attack rates . The efficacy of the live attenuated vaccine was slightly less than that of the inactivated vaccine , but not statistically greater than that of the placebo [6531951] A trial with a trivalent influenza subunit vaccine prepared with sodium deoxycholate was carried out in 88 volunteers between May and November 1981 . Each haemagglutinin antigen was present at 7 micrograms per dose . Fourfold or greater haemagglutination inhibition antibody ( HI ) responses to the H1N1 virus A/Brazil/11/78 occurred in 70 % of volunteers following a single dose . For the H3N2 virus A/Bangkok/1/79 and B/Singapore/222/79 these figures were 52 and 11 % , respectively . No increase in the antibody titre was noted to any of the antigens following a second vaccination dose . Antibody levels remained relatively constant six months after vaccination . A response to B/Singapore/222/79 , comparable with the HI response for the influenza A antigens , was noted when serum titres were estimated by a plaque reduction procedure . No neuraminidase inhibition antibody could be detected in response to either A/Brazil/11/78 or A/Bangkok/1/79 . No reactions specifically attributable to the vaccine occurred after either injection . A lower HI response to A/Brazil/11/78 was noted in volunteers 52 years of age and older , who also showed less evidence of earlier priming to this virus . Levels of nasal wash neutralizing antibodies to A/Brazil/11/78 were proportional to those detected in sera by HI tests , but were present in smaller amounts [16645502] Objective : The objective of this study was to evaluate the effectiveness of inactivated influenza vaccine in preventing acute otitis media ( AOM ) and otitis media with effusion ( OME ) in children aged 6 to 60 months who attend day care . Study Design : This prospect i ve , single-blind study was conducted in 8 day care centers in Ankara , Turkey . One hundred nineteen ( 61 vaccinated and 58 unvaccinated against influenza ) healthy children were examined at study entry and at 6-week intervals for 6 months by the same 2 otorhinolaryngologists who were blinded about the vaccination status of the children . The frequency of AOM and OME is compared between the 2 groups and the effect of influenza season on frequency of episodes was evaluated . Based on national influenza laboratory data , the influenza season was determined to be the period between December 15 , 2003 , and January 31 , 2004 . Result : The frequencies of AOM , OME and total otitis media episodes in vaccinated children were 2.3 % , 22.8 % and 25.2 % , respectively , and these frequencies were 5.2 % , 31.1 % and 36.3 % in the unvaccinated group . The difference was statistically significant ( P < 0.01 ) . This difference was especially prominent in the influenza season ( P < 0.05 ) . Conclusion : Influenza vaccine is effective in reducing AOM and OME episodes in 6- to 60-month-old day care children , especially during influenza season [5819227] Monovalent adjuvant and aqueous influenza vaccines were evaluated in a retirement community from 1964 to 1966 . In the second year of investigation , an epidemic of A2 influenza provided opportunity to study the protective value of immunization . Vaccine efficacy was shown to be related to the pattern of vaccination . Individuals who had received single doses of A2 vaccine in both years of the study were considerably better protected than those who had received vaccine in only one of the years . The rate of febrile illnesses in the former group was more than 90 % below that of vaccinated control . Those given one dose were only about half as well protected . Monovalent adjuvant A2 vaccine given more than a year before the outbreak appeared to protect as well as , if not slightly better than , monovalent aqueous vaccine administered several months before the epidemic [17142512] OBJECTIVE . The goal was to evaluate the safety , tolerability , and efficacy of an investigational , refrigerator-stable formulation of live attenuated influenza vaccine ( cold-adapted influenza vaccine-trivalent ) against culture-confirmed influenza , acute otitis media , and effectiveness outcomes in young children in day care over 2 consecutive influenza seasons . METHODS . Children 6 to < 36 months of age who were attending day care were assigned r and omly in year 1 to receive 2 doses of vaccine or placebo intranasally , 35 ± 7 days apart . In year 2 , subjects received 1 dose of the same treatment as in year 1 . RESULTS . A total of 1616 subjects ( vaccine : 951 subjects ; placebo : 665 subjects ) in year 1 and 1090 subjects ( vaccine : 640 subjects ; placebo : 450 subjects ) in year 2 were able to be evaluated for efficacy . The mean age at first vaccination was 23.4 ± 7.9 months . In year 1 , the overall efficacy of the vaccine against influenza subtypes similar to the vaccine was 85.4 % ; efficacy was 91.8 % against A/H1N1 and 72.6 % against B. In year 2 , the overall efficacy was 88.7 % ; efficacy was 90.0 % against H1N1 , 90.3 % against A/H3N2 , and 81.7 % against B. Efficacy against all episodes of acute otitis media associated with culture-confirmed influenza was 90.6 % in year 1 and 97.0 % in year 2 . Runny nose or nasal discharge after dose 1 in year 1 was the only reactogenicity event that was significantly more frequent with cold-adapted influenza vaccine-trivalent ( 82.3 % ) than placebo ( 75.4 % ) . CONCLUSIONS . Cold-adapted influenza vaccine-trivalent was well tolerated and effective in preventing culture-confirmed influenza illness in children as young as 6 months of age who attended day care [4984268] Influenza A2 vaccine containing 300 chick-cell agglutination ( CCA ) units per dose of the Hong Kong variant provided a high degree of protection during an outbreak of respiratory illnesses in military personnel in December 1968 and January 1969 . This inactivated chicken embryo-propagated virus vaccine stimulated hemagglutination-inhibition antibody responses that were equivalent to natural infection . Polyvalent vaccine , 1967 formula , was not without some contribution in preventing disease in those who did not receive Hong Kong influenza vaccine . Influenza A2 comprised 56 % of all respiratory illnesses during the outbreak . Virus was isolated in rhesus monkey kidney cultures from pharyngeal washings of a third of the individuals with serologic evidence of infection by influenza A2 [17167134] BACKGROUND The efficacy of influenza vaccines may decline during years when the circulating viruses have antigenically drifted from those included in the vaccine . METHODS We carried out a r and omized , double-blind , placebo-controlled trial of inactivated and live attenuated influenza vaccines in healthy adults during the 2004 - 2005 influenza season and estimated both absolute and relative efficacies . RESULTS A total of 1247 persons were vaccinated between October and December 2004 . Influenza activity in Michigan began in January 2005 with the circulation of an antigenically drifted type A ( H3N2 ) virus , the A/California/07/2004-like strain , and of type B viruses from two lineages . The absolute efficacy of the inactivated vaccine against both types of virus was 77 % ( 95 % confidence interval [ CI ] , 37 to 92 ) as measured by isolating the virus in cell culture , 75 % ( 95 % CI , 42 to 90 ) as measured by either isolating the virus in cell culture or identifying it through real-time polymerase chain reaction , and 67 % ( 95 % CI , 16 to 87 ) as measured by either isolating the virus or observing a rise in the serum antibody titer . The absolute efficacies of the live attenuated vaccine were 57 % ( 95 % CI , -3 to 82 ) , 48 % ( 95 % CI , -7 to 74 ) , and 30 % ( 95 % CI , -57 to 67 ) , respectively . The difference in efficacy between the two vaccines appeared to be related mainly to reduced protection of the live attenuated vaccine against type B viruses . CONCLUSIONS In the 2004 - 2005 season , in which most circulating viruses were dissimilar to those included in the vaccine , the inactivated vaccine was efficacious in preventing laboratory-confirmed symptomatic illnesses from influenza in healthy adults . The live attenuated vaccine also prevented influenza illnesses but was less efficacious . ( Clinical Trials.gov number , NCT00133523 . [20868284] BACKGROUND More efficient methods are needed to manufacture influenza vaccines . This trial compared the efficacy of cell culture-derived influenza vaccine ( CCIV ) and egg-derived trivalent inactivated vaccine ( TIV ) with placebo against laboratory-confirmed influenza illness in healthy adults in the United States , Finl and , and Pol and during the 2007 - 2008 influenza season . METHODS A total of 11,404 study participants aged 18 - 49 years were r and omized equally to receive CCIV ( Optaflu ; n = 3828 ) , TIV ( Agrippal ; n = 3676 ) , or placebo ( n = 3900 ) . Each participant was observed during a 6-month study surveillance period . Nasal and throat swabs for virus isolation and characterization were collected from all patients with influenza-like illness . Vaccine immunogenicity was evaluated in a subset of 1045 participants . RESULTS Efficacy of CCIV and TIV against vaccine-like ( 83.8 % [ 1-sided 97.5 % confidence interval [ CI ] lower limit , 61.0 % ] and 78.4 % [ 1-sided 97.5 % CI lower limit , 52.1 % ] , respectively ) and all circulating influenza virus strains ( 69.5 % [ 1-sided 97.5 % CI lower limit , 55.0 % ] and 63.0 % [ 1-sided 97.5 % lower limit , 46.7 % ] , respectively ) exceeded the Center for Biologics Evaluation and Research efficacy criteria . Immunogenicity of both vaccines exceeded the Center for Biologics Evaluation and Research licensing criteria . Both vaccines were well tolerated , with similar safety profiles . Most solicited reactions were mild to moderate in severity and transient . No vaccination-related serious adverse events were reported ; no withdrawals result ed from vaccine-related adverse events . CONCLUSIONS Both CCIV and TIV were effective in preventing influenza caused by vaccine-like and by all circulating influenza virus strains , were well tolerated , and had good safety profiles . Both vaccines can be considered for annual influenza vaccination campaigns . CLINICAL TRIALS REGISTRATION NCT00630331 [3123619] Although current guidelines target hospital employees who contact high-risk patients as a high priority for influenza immunization , there are few data to support or refute this recommendation . Therefore , the authors enrolled 179 hospital employees in a r and omized double-blind placebo-controlled clinical trial during the 1985–1986 influenza season . Influenza immunization was performed without serious adverse reactions and there was no increase in absenteeism attributable to the vaccination . Among those who developed clinical influenza , there was a trend toward fewer days of illness in the vaccinated group compared with the placebo group ( 6.0 vs. 8.0 , p=0.07 ) . There were no statistically significant differences between subjects receiving influenza vaccine and those receiving the placebo when comparing incidences of influenza-like illness , severities of illness , and sick absenteeism . Influenza immunization of hospital employees was performed at minimal cost and risk but provided little benefit , most likely because of an unexpected drift of the prevalent influenza strain away from the vaccine type [12087523] To evaluate the efficacy of an intranasal , inactivated , virosomal subunit influenza vaccine for prevention of new episodes of acute otitis media ( AOM ) in children with recurrent AOM , 133 children aged 1 - 5 years were r and omized to receive the vaccine ( n=67 ) or no vaccination ( n=66 ) . During a 6-month period , 24 ( 35.8 % ) vaccine recipients had 32 episodes of AOM ; 42 ( 63.6 % ) control subjects had 64 episodes . The overall efficacy of vaccination in preventing AOM was 43.7 % ( 95 % confidence interval , 18.6 - 61.1 ; P=.002 ) . Children vaccinated before influenza season had a significantly better outcome than did those vaccinated after the onset of influenza season . The cumulative duration of middle ear effusion was significantly less in vaccinated children than in control subjects . Data suggest that the intranasal virosomal influenza vaccine might be considered among the options for the prevention of AOM in children < 5 years old with recurrent AOM [2639595] Background Our aim was to determine the efficacy of a trivalent inactivated split virus influenza vaccine ( TIV ) against culture-confirmed influenza A and /or B in adults 18 to 64 years of age during the 2005/2006 season in the Czech Republic . Methods 6203 subjects were r and omized to receive TIV ( N = 4137 ) or placebo ( N = 2066 ) . The sample size was based on an assumed attack rate of 4 % which provided 90 % power to reject the hypothesis that vaccine efficacy ( VE ) was ≥ 45 % . Cases of influenza like illness ( defined as fever ( oral temperature ≥37.8 ° C ) plus cough and /or sore throat ) were identified both by active ( biweekly phone contact ) and passive ( self reporting ) surveillance and nasal and throat swabs were collected from subjects for viral culture . Results TIV was well tolerated and induced a good immune response . The 2005/2006 influenza season was exceptionally mild in the study area , as it was throughout Europe , and only 46 culture-confirmed cases were found in the study cohort ( 10 influenza A and 36 influenza B ) . Furthermore among the B isolates , 35 were identified as B/Hong Kong 330/2001-like ( B/Victoria/2/87 lineage ) which is antigenically unrelated to the vaccine B strain ( B/Yamagata/16/88 lineage ) . The attack rate in the vaccine group ( 0.7 % ) was not statistically significantly different from the attack rate in the placebo group ( 0.9 % ) . Conclusion Due to the atypical nature of the influenza season during this study we were unable to assess TIV efficacy . This experience illustrates the challenge of conducting a prospect i ve influenza vaccine efficacy trial during a single season when influenza attack rates and drift in circulating strains or B virus lineage match can be difficult to estimate in advance . Trial Registration Clinical trial registery : NCT00197223 [3229554] Background R and omized evidence for vaccine immunogenicity and safety is urgently needed in the setting of p and emics with new emerging infectious agents . We carried out an observational survey to evaluate how many r and omized controlled trials testing 2009 H1N1 vaccines were published among those registered , and what was the time lag from their start to publication and from their completion to publication . Methods PubMed , EMBASE and 9 clinical trial registries were search ed for eligible r and omized controlled trials . The units of the analysis were single r and omized trials on any individual receiving influenza vaccines in any setting . Results 73 eligible trials were identified that had been registered in 2009–2010 . By June 30 , 2011 only 21 ( 29 % ) of these trials had been published , representing 38 % of the r and omized sample size ( 19905 of 52765 ) . Trials starting later were published less rapidly ( hazard ratio 0.42 per month ; 95 % Confidence Interval : 0.27 to 0.64 ; p<0.001 ) . Similarly , trials completed later were published less rapidly ( hazard ratio 0.43 per month ; 95 % CI : 0.27 to 0.67 ; p<0.001 ) . R and omized controlled trials were completed promptly ( median , 5 months from start to completion ) , but only a minority were subsequently published . Conclusions Most registered r and omized trials on vaccines for the H1N1 p and emic are not published in the peer- review ed literature [3256242] Please cite this paper as : Ambrose et al. ( 2011 ) An integrated , multi study analysis of the safety of Ann Arbor strain live attenuated influenza vaccine in children aged 2–17 years . Influenza and Other Respiratory Viruses 5(6 ) , 389–397 . Background Trivalent , Ann Arbor strain , live attenuated influenza vaccine ( LAIV ) is approved in several countries for use in eligible children aged ≥2 years . Objective To describe the safety of Ann Arbor strain LAIV in children aged 2–17 years . Methods An integrated analysis of r and omized , controlled trials of LAIV . Results A total of 4245 and 10 693 children received ≥1 dose of LAIV in year 1 of 6 trivalent inactivated influenza vaccine (TIV)‐controlled and 14 placebo‐controlled studies , respectively ; 3212 children were revaccinated in year 2 of 4 placebo‐controlled studies . Compared with placebo for days 0–10 post‐vaccination , LAIV recipients exhibited increased runny/stuffy nose ( + 7 % ) , headache ( + 7 % ) , and tiredness/decreased activity ( + 2 % ) after dose 1 ; and a higher rate of decreased appetite ( + 4 % ) after year 2 revaccination . Compared with TIV , only runny/stuffy nose was increased ( dose 1 , + 12 % ; dose 2 , + 4 % ) . Compared with initial vaccination , LAIV reactogenicity was lower after dose 2 in year 1 and revaccination in year 2 . Unsolicited adverse events ( AEs ) increased with LAIV in some comparisons were headache , nasal congestion/rhinorrhea , rhinitis , and pyrexia ; ear pain and lower respiratory illness were decreased . There was no evidence of an increase in any potential vaccine‐related serious AE in LAIV recipients . Among children aged 2–17 years and specifically aged 24–35 months , there was no evidence that lower respiratory illness or wheezing illness occurred at a higher rate in LAIV recipients . Conclusion This analysis supports the safety of Ann Arbor strain LAIV in children aged 2–17 years and provides a consensus assessment of events expected after vaccination [831465] The reactogenicity , immunogenicity and protection effecacy of a serum inhibitor-resistant live attenuated influenza A/B ( " Alice"/R-75 ) vaccine was determined in a group of health young volunteers . The influenza A component was derived from A/Engl and /42/72 ( H3N2 ) strain , and the B component from B/Hong Kong/5/72 strain . Sixty-eight subjects had hemagglutination inhibition ( HAI ) antibody titers to influenza A hemagglutinin ( HA ) antigen of less than or equal to 1:8 ( " low A " group ) and 75 had similarly low antibody titers to B HA antigen ( " low B " group ) . Two inocula given 14 days apart consisted of vaccine in two doses ( VV ) ; one dose of vaccine followed by placebo ( VP ) ; or two doses of placebo ( PP ) . The reactogenicity of the vaccine was low , with approximately 25 % of subjects in both the immunized and placebo categories having symptoms mainly of respiratory nature . The A component of the vaccine was immunogenic with 90.9 % of the subjects in the low A group VV category showing seroconversion . By contrast , only 20 % of VV subjects in the low B group seroconverted to B antigen . The vaccine afforded significant protection againndergone a slight antigenic drift . There was no difference in protection afforded either by one or two doses of the vaccine . Thus the overall protection efficacy following at least one dose of the vaccine was 80.0 % ( p = .01 ) , and in the low A group subjects it was 85.5 % ( p = .01 ) [9580647] BACKGROUND Influenzavirus vaccine is used infrequently in healthy children , even though the rates of influenza in this group are high . We conducted a multicenter , double-blind , placebo-controlled trial of a live attenuated , cold-adapted , trivalent influenzavirus vaccine in children 15 to 71 months old . METHODS Two hundred eighty-eight children were assigned to receive one dose of vaccine or placebo given by intranasal spray , and 1314 were assigned to receive two doses approximately 60 days apart . The strains included in the vaccine were antigenically equivalent to those in the inactivated influenzavirus vaccine in use at the time . The subjects were monitored with viral cultures for influenza during the subsequent influenza season . A case of influenza was defined as an illness associated with the isolation of wild-type influenzavirus from respiratory secretions . RESULTS The intranasal vaccine was accepted and well tolerated . Among children who were initially seronegative , antibody titers increased by a factor of four in 61 to 96 percent , depending on the influenza strain . Culture-positive influenza was significantly less common in the vaccine group ( 14 cases among 1070 subjects ) than the placebo group ( 95 cases among 532 subjects ) . The vaccine efficacy was 93 percent ( 95 percent confidence interval , 88 to 96 percent ) against culture-confirmed influenza . Both the one-dose regimen ( 89 percent efficacy ) and the two-dose regimen ( 94 percent efficacy ) were efficacious , and the vaccine was efficacious against both strains of influenza circulating in 1996 - 1997 , A(H3N2 ) and B. The vaccinated children had significantly fewer febrile illnesses , including 30 percent fewer episodes of febrile otitis media ( 95 percent confidence interval , 18 to 45 percent ; P<0.001 ) . CONCLUSIONS A live attenuated , cold-adapted influenzavirus vaccine was safe , immunogenic , and effective against influenza A(H3N2 ) and B in healthy children [12449696] The formation of immunity and epidemiological effectiveness of inactivated influenza vaccines in children , regularly immunized against influenza for three years , were evaluated . The study revealed that a year after each immunization the number of children having antibodies in liters regarded as protective decreased 2 - 2.5 times . At the periods of epidemics morbidity rate among the vaccines dynamically decreased in these years 1.3 , 2.0 and 2.8 times . Considering that a year after the second immunization a high immune stratum ( 60 - 78 % ) was retained in the group under study , we propose that annual immunization of the same children be limited by a period of three years , followed by an interval of one year [17596805] Background : This study was design ed to evaluate the efficacy and safety of cold-adapted influenza vaccine , trivalent ( CAIV-T ) against culture-confirmed influenza in children 12 to < 36 months of age during 2 consecutive influenza seasons at multiple sites in Asia . Methods : In year 1 , 3174 children 12 to < 36 months of age were r and omized to receive 2 doses of CAIV-T ( n = 1900 ) or placebo ( n = 1274 ) intranasally ≥28 days apart . In year 2 , 2947 subjects were rer and omized to receive 1 dose of CAIV-T or placebo . Results : Mean age at enrollment was 23.5 ± 7.4 months . In year 1 , efficacy of CAIV-T compared with placebo was 72.9 % [ 95 % confidence interval ( CI ) : 62.8–80.5 % ] against antigenically similar influenza subtypes , and 70.1 % ( 95 % CI : 60.9–77.3 % ) against any strain . In year 2 , revaccination with CAIV-T demonstrated significant efficacy against antigenically similar ( 84.3 % ; 95 % CI : 70.1–92.4 % ) and any ( 64.2 % ; 95 % CI : 44.2–77.3 % ) influenza strains . In year 1 , fever , runny nose/nasal congestion , decreased activity and appetite , and use of fever medication were more frequent with CAIV-T after dose 1 . Runny nose/nasal congestion after dose 2 ( year 1 ) and dose 3 ( year 2 ) and use of fever medication after dose 3 ( year 2 ) were the only other events reported significantly more frequently in CAIV-T recipients . Conclusions : CAIV-T was well tolerated and effective in preventing culture-confirmed influenza illness over multiple and complex influenza seasons in young children in Asia [8653819] Reported is a study of live , cold-adapted ( CA ) reassortant mono- , di- , and trivalent influenza type A and B vaccines in a series of controlled clinical and epidemiological investigations involving nearly 130 000 children aged 3 - 15 years . The results of clinical , immunological , and morbidity investigations of the vaccinees and a control group over 6-months ' follow-up indicated that the vaccines were completely attenuated by the children . Transient febrile reactions occurred in < 1 % of the children after vaccination , including double seronegative individuals with low antibody titres . The type A reisolates examined were genetically stable . The reassortants did not suppress each other after simultaneous inoculation of children and stimulated antibody response to influenza virus strains A1 , A3 , and B. The incidence of influenza-like diseases was approximately 30 - 40 % lower among the vaccinated group than among the control group . The study demonstrates , for the first time , the efficacy of CA vaccine against infections caused by influenza B virus [19909082] BACKGROUND A new trivalent inactivated split-virus influenza vaccine ( TIV ) was recently introduced in the United States . We assessed the efficacy of TIV against culture-confirmed influenza A and /or B. METHODS In this double-blind trial conducted from September 2006 to May 2007 in the Czech Republic and Finl and , participants aged 18 - 64 years were r and omized to receive 1 dose of TIV ( n = 5103 ) or placebo ( n = 2549 ) . Influenza-like illnesses ( ILI ) ( defined as at least 1 systemic symptom [ fever { oral temperature , > or = 37.8 degrees C } and /or myalgia ] and at least 1 respiratory symptom [ cough and /or sore throat ] ) were identified by both active ( biweekly phone contact ) and passive surveillance . Nasal and throat swab specimens were collected for viral culture . RESULTS The attack rate for culture-confirmed ILI was 3.2 % in the placebo group , with most strains identified as influenza A ( all except 1 were H3N2 ) matching the vaccine strain . There were 6 cases of influenza B , all of which were of a different lineage ( Yamagata ) than the vaccine strain . Vaccine efficacy against culture-confirmed influenza A and /or B due to strains antigenically matched to the vaccine was 66.9 % ( 95 % confidence interval [ CI ] , 51.9%-77.4 % ; P < .001 ) and to any strain was 61.6 % ( 95 % CI , 46.0%-72.8 % ; P < .001 ) . CONCLUSION TIV is efficacious against culture-confirmed influenza in healthy adults . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT00363870 [8376833] Children aged 7 - 14 years in Novgorod , Russia , were given Russian live cold-adapted or inactivated influenza vaccines or placebo over a 2-year period . Schools were r and omly assigned as a whole to one of the preparations . In the first year , the vaccines were bivalent , containing types A ( H3N2 ) and A ( H1N1 ) components . In the second year , the vaccines also contained a type B component . In the first year , all viruses isolated were type A ( H3N2 ) ; in the second , about three-quarters of the isolates were type B and the rest type A ( H1N1 ) . During both years , the vaccines protected the vaccinated children . Where significant differences existed , the live attenuated vaccine was more protective than the inactivated . Vaccination rates in schools in which live attenuated vaccines had been used were inversely related to illness rates of staff and unvaccinated children , suggesting that viral transmission had been reduced by the vaccine [3337087] Inactivated influenza virus vaccine efficacy after annual revaccination has been reported to be less than that after first vaccination in boarding school children . We prospect ively examined the immunogenicity and efficacy of this vaccine in healthy 30- to 60-year-old volunteers in Houston , Texas , over two epidemic seasons ( 1983 - 1985 ) encompassing outbreaks due to influenza A ( H3N2 and H1N1 ) and influenza B viruses . A placebo group that had never ( or not in recent years ) received inactivated influenza virus vaccine , a group that received the vaccine for the first time ( first vac ) , and a group given two or more recent vaccinations ( multivac ) were evaluated in a double-blind fashion each year . Vaccination induced higher frequencies of rise in serum antibody titer to vaccine components in first vac than in multivac volunteers , but mean postvaccination titers were similar . Clinical and virologic evaluations of illnesses during both epidemics and of influenza infections diagnosed serologically over the epidemic seasons revealed no overall reduction in illness from that in the placebo group for either vaccine group ; modest reductions in influenza infection-related illness that were significant only for the multivac group against A/H3N2-related illness ( 55 % ; p less than 0.04 ) ; reduction in moderate-to-severe lower respiratory and /or systemic illness due to influenza for multivac ( 73 % , p less than 0.025 ) but not first vac ( 15 % , p greater than 0.10 ) volunteers during the A/H3N2 epidemic ; reduction in influenza virus shedding in the multivac ( 54 % , p less than 0.05 ) but not the first vac ( 16 % , p greater than 0.10 ) group when compared with the placebo group for both years ; and overall 63 - 81 % reductions in documented infections with each influenza virus for both vaccine groups with the exception of A/H1N1 for the first vac group ( 24 % , p greater than 0.10 ) and type B for the multivac group ( 58 % , p = 0.067 ) . Vaccine efficacy was only modest in these studies , but in contrast to the earlier report in boarding school children , efficacy appeared to be somewhat greater after repeated annual vaccination than after first administration [4605401] The appearance of the p and emic A/Hong Kong/1/68 ( H3N2 ) influenzavirus strain provided an opportunity for a clinical field trial of influenza vaccines in Canada during the winter of 1968 - 69 . As by November 1968 there were reports of influenza B activity and as supplies of A2/HK/68 vaccines were limited , it was decided to make a series of strictly r and omized double-blind trials comparing A2/HK/68 vaccines not only with B/Mass/66 vaccines but also with a bivalent vaccine that was already in production and contained B/Mass/66 and A2/Mtl/68 , the latter a strain isolated in Canada during January 1968 . In 4 trials , a total of 13 729 military personnel and 4 795 primary schoolchildren were vaccinated . Reported vaccine reactions were less than 0.1 % with zonally-purified vaccines and 2.6 % with the " st and ard " aqueous killed bivalent vaccine . Three children had serious reactions . Surveillance detected an outbreak of influenza in the first two trials on the military . The 3 vaccines containing A2 strains gave similar clinical protection conservatively estimated at 42 - 55 % but probably about 80 % . The effectiveness of the A2/Mtl/68 vaccine , which was in production before the Hong Kong variant had been isolated , was unexpected . In the absence of a vaccine specific to a new p and emic strain , it should not be assumed that a vaccine made from another recent strain could not be useful [396336] Three groups of children were immunized with an inactivated Port Chalmers ( H3ChN2Ch ) influenza vaccine ( group A ) , a neuraminidase-specific ( Heq1N2Ch ) influenza vaccine ( group B ) , or a placebo . Immunization induced seroconversion for H3Ch and N2Ch-specific antibody in group A and for N2Ch antibody in group B. The protective efficacies observed against naturally acquired illness with the Port Chalmers strain of influneza A virus were 68.7 % and 37.4 % in groups A and B , respectively , in comparison to the placebo group , and those against illness produced by the subsequent outbreak of the Victoria strain were 80.0 % and 72.7 % . These data support the role of neuraminidase-specific immunization in protection against influenza . Although the degree of protection after vaccination with the Heq1N2Ch vaccine was less than that provided by the biphasic H3ChN2Ch vaccine against the Port Chalmers strain , it appeared to be similar in the two vaccine study groups against the Victoria strain [11319482] BACKGROUND Studies of influenza vaccination in healthy children have not definitely answered the question of their efficacy . METHODS We have carried out a r and omized trial in a well selected population of healthy preschool children in Sardinia , Italy . During October 1995 , 344 children aged 1 to 6 years , were r and omly assigned to receive influenza vaccine ( n=177 ) or no treatment ( n=167 ) . Two doses of a trivalent subvirion vaccine , containing 15 mg of highly purified surface antigens from the component strains A/Johannesburg/33/94-like , A/Singapore/6/86-like and B/ Beijing/184/ 93-like were administered . Follow-up data were collected from December 1 , 1995 through April 30 , 1996 . RESULTS Seroconversion was documented in 17 out of 17 children . No specific systemic symptoms or severe local reactions were observed after vaccination . Influenza-like episodes , defined by the presence of fever and cough or sore throat that lasted at least 72 hours , occurred in 63 ( 37.7 % ) of unvaccinated children and in 22 ( 12.4 % ) of vaccinated ones . The corresponding reduction in disease incidence was 67 % ( 95 % CI : 0.59 - 0.74 ) . Three episodes of otitis were observed among children in the control group versus zero among vaccinated children ( p=0.07 ) . Mean duration of day care center absenteism was significantly reduced by vaccination ( 2.3 days in unvaccinated and 0.5 day in vaccinated children , p<0.001 ) CONCLUSIONS Influenza vaccine is safe and effective in healthy preschool children . However the favourable implication s of vaccination on disease rate in subsequent years have to be evaluated [4555773] A placebo-controlled influenza vaccination trial was carried out on 374 children in the winter of 1967 - 68 . The children were r and omly vaccinated with 300 CCA of A2/Engl and /1/1966 , 300 CCA of A/equine 2/Miami/1963 , or with a placebo . During this winter an influenza outbreak occurred , caused by A2/Nederl and /1968 . The A2 vaccine yielded a protection rate of 58 % ( P = 0.02 ) and the A/equine 2 vaccine a rate of 19 % ( P = 0.33 ) . Serological data revealed that all influenza infections occurred in subjects who had a pre-epidemic haemagglutination inhibition titre below 150 . The antibody response against various human influenza A2 viruses and against the horse strain ( A/equine 2 ) is discussed [15542184] The aim of this study was to determine the cost effectiveness of influenza vaccination for healthy people aged 65 - 74 years living in the UK . People without risk factors for influenza ( chronic heart , lung or renal disease , diabetic , immunosuppressed or those living in an institution ) were identified from 20 general practitioner ( GP ) practice s in Liverpool in September 1999 . 729/5875 ( 12.4 % ) eligible individuals were recruited and r and omised to receive either influenza vaccine or placebo ( ratio 3:1 ) , with all participants receiving 23-valent-pneumococcal polysaccharide vaccine unless already administered . The primary analysis was the frequency of influenza as recorded by a GP diagnosis of pneumonia or influenza like illness . In 2000 , the UK vaccination policy was changed with influenza vaccine becoming available for all people aged 65 years and over irrespective of risk . As a consequence of this policy change , the study had to be fundamentally restructured and only results obtained over a one rather than the originally planned two-year r and omised controlled trial framework were used . Results from 1999/2000 demonstrated no significant difference between groups for the primary outcome ( relative risk 0.8 , 95 % CI 0.16 - 4.1 ) . In addition , there were no deaths or hospitalisations for influenza associated respiratory illness in either group . The subsequent analysis , using both national and local sources of evidence , estimated the following cost effectiveness indicators : ( 1 ) incremental NHS cost per GP consultation avoided = 2000 pound sterling ; ( 2 ) incremental NHS cost per hospital admission avoided = 61,000 pound sterling ; ( 3 ) incremental NHS cost per death avoided = 1,900,000 pound sterling and ( 4 ) incremental NHS cost per QALY gained = 304,000 pound sterling . The analysis suggested that influenza vaccination in this population would not be cost effective [10411194] CONTEXT Influenza virus is a major cause of illness , disruption to daily life , and increased use of health care in all age groups . OBJECTIVE To assess the safety and effectiveness of intranasally administered trivalent , live , attenuated influenza virus ( LAIV ) vaccine for reducing illness , absenteeism , and health care use among healthy , working adults . DESIGN R and omized , double-blind , placebo-controlled trial conducted from September 1997 through March 1998 . SETTING Thirteen centers across the United States . PARTICIPANTS A total of 4561 healthy , working adults aged 18 to 64 years recruited through health insurance plans , at work sites , and from the general population . INTERVENTION Participants were r and omized 2:1 to receive intranasally administered trivalent LAIV vaccine ( n = 3041 ) or placebo ( n = 1520 ) in the fall of 1997 . MAIN OUTCOME MEASURES Episodes of febrile illness , severe febrile illness , febrile upper respiratory tract illness , work loss , and health care use during the peak and total influenza outbreak periods , and adverse events . RESULTS Recipients of LAIV vaccine were as likely to experience 1 or more febrile illnesses as placebo recipients during peak outbreak periods ( 13.2 % for vaccine vs 14.6 % for placebo ; P=.19 ) . However , vaccination significantly reduced the numbers of severe febrile illnesses ( 18.8 % reduction ; 95 % confidence interval [ CI ] , 7.4%-28.8 % ) and febrile upper respiratory tract illnesses ( 23.6 % reduction ; 95 % CI , 12.7%-33.2 % ) . Vaccination also led to fewer days of illness across all illness syndromes ( 22.9 % reduction for febrile illnesses ; 27.3 % reduction for severe febrile illnesses ) , fewer days of work lost ( 17.9 % reduction for severe febrile illnesses ; 28.4 % reduction for febrile upper respiratory tract illnesses ) , and fewer days with health care provider visits ( 24.8 % reduction for severe febrile illnesses ; 40.9 % reduction for febrile upper respiratory tract illnesses ) . Use of prescription antibiotics and over-the-counter medications was also reduced across all illness syndromes . Vaccine recipients were more likely to experience runny nose or sore throat during the first 7 days after vaccination , but serious adverse events between the groups were not significantly different . The match between the type A(H3N2 ) vaccine strain and the predominant circulating virus strain ( A/Sydney/05/97[H3N2 ] ) for the 1997 - 1998 season was poor , suggesting that LAIV provided substantial cross-protection against this variant influenza A virus strain . CONCLUSION Intranasal trivalent LAIV vaccine was safe and effective in healthy , working adults in a year in which a drifted influenza A virus predominated [2968738] Controlled epidemiological surveillance covering the total number of 13,355 schoolchildren aged 11 - 14 years and adolescents was carried out with a view to compare the efficacies of inactivated influenza vaccines . The children were immunized intradermally in a single injection with inactivated influenza vaccines containing A ( H3N2 ) and A ( H1N1 ) hemagglutinins , 3.5 micrograms per 0.2 ml of the preparation each . The studies demonstrated the safety and low reactogenicity of these vaccines , as well as their high antigenic potency . In 1984 during mixed influenza B + A ( H1N1 ) epidemic the preparations produced a pronounced prophylactic effect : the efficacy indices were 1.6 - 1.9 ( p less than 0.001 ) . The results obtained in these studies made it possible to recommend two inactivated influenza vaccines ( chromatographic and centrifugal ) for practical medicine with the aim of protecting children aged 11 years and over from influenza [7666874] BACKGROUND Although influenza causes substantial morbidity and mortality in all age groups , current recommendations emphasize annual immunization for people at high risk for complications of influenza . We conducted a double-blind , placebo-controlled trial of vaccination against influenza in healthy , working adults . METHODS In the fall of 1994 , we recruited working adults from 18 to 64 years of age from in and around the Minneapolis-St . Paul area and r and omly assigned them to receive either influenza vaccine or placebo injections . The primary study outcomes included upper respiratory illnesses , absenteeism from work because of upper respiratory illnesses , and visits to physicians ' offices for upper respiratory illnesses . The economic benefits of vaccination were analyzed by estimating the direct and indirect costs associated with immunization and with upper respiratory illnesses . RESULTS We enrolled a total of 849 subjects . Baseline characteristics were similar in the two groups . During the follow-up period , consisting of the 1994 - 1995 influenza season ( December 1 , 1994 , through March 31 , 1995 ) , those who received the vaccine reported 25 percent fewer episodes of upper respiratory illness than those who received the placebo ( 105 vs. 140 episodes per 100 subjects , P < 0.001 ) , 43 percent fewer days of sick leave from work due to upper respiratory illness ( 70 vs. 122 days per 100 subjects , P = 0.001 ) , and 44 percent fewer visits to physicians ' offices for upper respiratory illnesses ( 31 vs. 55 visits per 100 subjects , P = 0.004 ) . The cost savings were estimated to be $ 46.85 per person vaccinated . CONCLUSIONS Vaccination against influenza has substantial health-related and economic benefits for healthy , working adults [9382404] A quantitative systematic review , or meta- analysis , uses statistical methods to combine the results of multiple studies . Meta-analyses have been done for systematic review s of therapeutic trials , diagnostic test evaluations , and epidemiologic studies . Although the statistical methods involved may at first appear to be mathematically complex , their purpose is simple : They are trying to answer four basic questions . Are the results of the different studies similar ? To the extent that they are similar , what is the best overall estimate ? How precise and robust is this estimate ? Finally , can dissimilarities be explained ? This article provides some guidance in underst and ing the key technical aspects of the quantitative approach to these questions . We have avoided using equations and statistical notations ; interested readers will find implementations of the described methods in the listed references . We focus here on the quantitative synthesis of reports of r and omized , controlled , therapeutic trials because far more meta-analyses on therapeutic studies than on other types of studies have been published . For practical reasons , we present a stepwise description of the tasks that are performed when statistical methods are used to combine data . These tasks are 1 ) deciding whether to combine data and defining what to combine , 2 ) evaluating the statistical heterogeneity of the data , 3 ) estimating a common effect , 4 ) exploring and explaining heterogeneity , 5 ) assessing the potential for bias , and 6 ) presenting the results . Deciding Whether To Combine Data and Defining What To Combine By the time one performs a quantitative synthesis , certain decisions should already have been made about the formulation of the question and the selection of included studies . These topics were discussed in two previous articles in this series [ 1 , 2 ] . Statistical tests can not compensate for lack of common sense , clinical acumen , and biological plausibility in the design of the protocol of a meta- analysis . Thus , a reader of a systematic review should always address these issues before evaluating the statistical methods that have been used and the results that have been generated . Combining poor- quality data , overly biased data , or data that do not make sense can easily produce unreliable results . The data to be combined in a meta- analysis are usually either binary or continuous . Binary data involve a yes/no categorization ( for example , death or survival ) . Continuous data take a range of values ( for example , change in diastolic blood pressure after antihypertensive treatment , measured in mm Hg ) . When one is comparing groups of patients , binary data can be summarized by using several measures of treatment effect that were discussed earlier in this series [ 3 ] . These measures include the risk ratio ; the odds ratio ; the risk difference ; and , when study duration is important , the incidence rate . Another useful clinical measure , the number needed to treat ( NNT ) , is derived from the inverse of the risk difference [ 3 ] . Treatment effect measures , such as the risk ratio and the odds ratio , provide an estimate of the relative efficacy of an intervention , whereas the risk difference describes the intervention 's absolute benefit . The various measures of treatment effect offer complementary information , and all should be examined [ 4 ] . Continuous data can be summarized by the raw mean difference between the treatment and control groups when the treatment effect is measured on the same scale ( for example , diastolic blood pressure in mm Hg ) , by the st and ardized mean difference when different scales are used to measure the same treatment effect ( for example , different pain scales being combined ) , or by the correlation coefficients between two continuous variables [ 5 ] . The st and ardized mean difference , also called the effect size , is obtained by dividing the difference between the mean in the treatment group and the mean in the control group by the SD in the control group . Evaluating the Statistical Heterogeneity of the Data This step is intended to answer the question , Are the results of the different studies similar ( homogeneous ) ? It is important to answer this question before combining any data . To do this , one must calculate the magnitude of the statistical diversity ( heterogeneity ) of the treatment effect that exists among the different sets of data . Statistical diversity can be thought of as attributable to one or both of two causes . First , study results can differ because of r and om sampling error . Even if the true effect is the same in each study , the results of different studies would be expected to vary r and omly around the true common fixed effect . This diversity is called the within- study variance . Second , each study may have been drawn from a different population , depending on the particular patients chosen and the interventions and conditions unique to the study . Therefore , even if each study enrolled a large patient sample , the treatment effect would be expected to differ . These differences , called r and om effects , describe the between- study variation with regard to an overall mean of the effects of all of the studies that could be undertaken . The test most commonly used to assess the statistical significance of between- study heterogeneity is based on the chi-square distribution [ 6 ] . It provides a measure of the sum of the squared differences between the results observed and the results expected in each study , under the assumption that each study estimates the same common treatment effect . A large total deviation indicates that a single common treatment effect is unlikely . Any pooled estimate calculated must account for the between- study heterogeneity . In practice , this test has low sensitivity for detecting heterogeneity , and it has been suggested that a liberal significance level , such as 0.1 , should be used [ 6 ] . Estimating a Common Effect The questions that this step tries to answers are , 1 ) To the extent that data are similar , what is their best common point estimate of a therapeutic effect , and 2 ) how precise is this estimate ? The mathematical process involved in this step generally involves combining ( pooling ) the results of different studies into an overall estimate . Compared with the results of individual studies , pooled results can increase statistical power and lead to more precise estimates of treatment effect . Each study is given a weight according to the precision of its results . The rationale is that studies with narrow CIs should be weighted more heavily than studies with greater uncertainty . The precision is generally expressed by the inverse of the variance of the estimate of each study . The variance has two components : the variance of the individual study and the variance between different studies . When the between- study variance is found to be or assumed to be zero , each study is simply weighted by the inverse of its own variance , which is a function of the study size and the number of events in the study . This approach characterizes a fixed-effects model , as exemplified by the Mantel-Haenszel method [ 7 , 8 ] or the Peto method [ 9 ] for dichotomous data . The Peto method has been particularly popular in the past . It has the advantage of simple calculation ; however , although it is appropriate in most cases , it may introduce large biases if the data are unbalanced [ 10 , 11 ] . On the other h and , r and om-effects models also add the between- study variance to the within- study variance of each individual study when the pooled mean of the r and om effects is calculated . The r and om-effects model most commonly used for dichotomous data is the DerSimonian and Laird estimate of the between- study variance [ 12 ] . Fixed- and r and om-effects models for continuous data have also been described [ 13 ] . Pooled results are generally reported as a point estimate and CI , typically a 95 % CI . Other quantitative techniques for combining data , such as the Confidence Profile Method [ 14 ] , use Bayesian methods to calculate posterior probability distributions for effects of interest . Bayesian statistics are based on the principle that each observation or set of observations should be viewed in conjunction with a prior probability describing the prior knowledge about the phenomenon of interest [ 15 ] . The new observations alter this prior probability to generate a posterior probability . Traditional meta- analysis assumes that nothing is known about the magnitude of the treatment effect before r and omized trials are performed . In Bayesian terms , the prior probability distribution is noninformative . Bayesian approaches may also allow the incorporation of indirect evidence in generating prior distributions [ 14 ] and may be particularly helpful in situations in which few data from r and omized studies exist [ 16 ] . Bayesian analyses may also be used to account for the uncertainty introduced by estimating the between- study variance in the r and om-effects model , leading to more appropriate estimates and predictions of treatment efficacy [ 17 ] . Exploring and Explaining Heterogeneity The next important issue is whether the common estimate obtained in the previous step is robust . Sensitivity analyses determine whether the common estimate is influenced by changes in the assumptions and in the protocol for combining the data . A comparison of the results of fixed- and r and om-effects models is one such sensitivity analysis [ 18 ] . Generally , the r and om-effects model produces wider CIs than does the fixed-effects model , and the level of statistical significance may therefore be different depending on the model used . The pooled point estimate per se is less likely to be affected , although exceptions are possible [ 19 ] . Other sensitivity analyses may include the examination of the residuals and the chi-square components [ 13 ] and assessment of the effect of deleting each study in turn . Statistically significant results that depend on a single study may require further exploration . Cumulative Meta- Analysis [20935591] Background : Acute otitis media ( AOM ) is a frequent complication of influenza in young children . Influenza vaccination is known to protect against AOM by preventing influenza illness . We sought to determine the efficacy of the live attenuated influenza vaccine ( LAIV ) against influenza-associated AOM compared with placebo and trivalent inactivated influenza vaccine ( TIV ) . LAIV is approved for eligible children aged ≥2 years in the United States and in several other countries . Methods : AOM incidence data from 6 r and omized , double-blind , placebo-controlled trials and 2 r and omized , double-blind , TIV-controlled trials in children 6 to 83 months of age were pooled and analyzed . Results : A total of 290 cases of AOM were identified in 24,046 study subjects . LAIV efficacy against influenza-associated AOM was 85.0 % ( 95 % confidence interval [ CI ] , 78.3%–89.8 % ) compared with placebo and 54.0 % ( 95 % CI , 27.0%–71.7 % ) compared with TIV . Efficacy trended higher in those ≥24 months of age compared with those aged 6 to 23 months . In placebo-controlled trials , among children who acquired influenza despite vaccination , AOM was diagnosed in 10.3 % of LAIV recipients and 16.8 % of placebo recipients , representing a 38.2 % ( 95 % CI , 11.0%–58.2 % ) relative reduction in the development of AOM . In TIV-controlled studies , among subjects with breakthrough influenza illness , the proportions of LAIV and TIV recipients who developed AOM were similar . Conclusions : Children receiving LAIV had a high level of protection against influenza-associated AOM when compared with placebo or TIV . This was most evident in children older than 2 years , for whom LAIV is indicated . LAIV recipients who contracted breakthrough influenza illness despite vaccination developed AOM at a significantly lower rate than did unvaccinated children who developed influenza [10979921] A r and omized , blinded , pilot study of influenza vaccine administered to children attending day care centers was conducted during the 1996 - 1997 winter . Vaccine efficacy in preventing serologically proven influenza virus infection was 0.45 ( 95 % confidence limit [ CL ] : -0.02 , 0.69 ) for influenza B and 0.31 ( 95 % CL : -0.95 , 0.73 ) for influenza A(H3N2 ) . For both influenza A(H3N2 ) and B , children without preexisting hemagglutination inhibition ( HI ) antibody to these antigens had lower antibody responses to vaccine , were less likely to develop a serological response , and were more likely to develop serological evidence of influenza infection . Although there were no reductions in respiratory or febrile respiratory illnesses among all vaccinated children , there was a trend for reductions in such illnesses among vaccinated children with preexisting HI antibodies to influenza A(H3N2 ) and B. Therefore , immunologic priming in young children may be important for vaccine response and for protection against infection . Larger studies are needed in other influenza seasons to assess vaccine efficacy and clinical effectiveness [11015795] CONTEXT Although the cost-effectiveness and cost-benefit of influenza vaccination are well established for persons aged 65 years or older , the benefits for healthy adults younger than 65 years are less clear . OBJECTIVE To evaluate the effectiveness and cost-benefit of influenza vaccine in preventing influenza-like illness ( ILI ) and reducing societal costs of ILI among healthy working adults . DESIGN Double-blind , r and omized , placebo-controlled trial conducted during 2 influenza seasons . SETTING AND PARTICIPANTS Healthy adults aged 18 to 64 years and employed full-time by a US manufacturing company ( for 1997 - 1998 season , n = 1184 ; for 1998 - 1999 season , n = 1191 ) . INTERVENTIONS For each season , participants were r and omly assigned to receive either trivalent inactivated influenza vaccine ( n = 595 in 1997 - 1998 and n = 587 in 1998 - 1999 ) or sterile saline injection ( placebo ; n = 589 in 1997 - 1998 and n = 604 in 1998 - 1999 ) . Participants in 1997 - 1998 were rer and omized if they participated in 1998 - 1999 . MAIN OUTCOME MEASURES Influenza-like illnesses and associated physician visits and work absenteeism reported in biweekly question naires by all participants , and serologically confirmed influenza illness among 23 % of participants in each year ( n = 275 in 1997 - 1998 ; n = 278 in 1998 - 1999 ) ; societal cost of ILI per vaccinated vs unvaccinated person . RESULTS For 1997 - 1998 and 1998 - 1999 , respectively , 95 % ( 1130/1184 ) and 99 % ( 1178/1191 ) of participants had complete follow-up , and 23 % in each year had serologic testing . In 1997 - 1998 , when the vaccine virus differed from the predominant circulating viruses , vaccine efficacy against serologically confirmed influenza illness was 50 % ( P = .33 ) . In this season , vaccination did not reduce ILI , physician visits , or lost workdays ; the net societal cost was $ 65.59 per person compared with no vaccination . In 1998 - 1999 , the vaccine and predominant circulating viruses were well matched . Vaccine efficacy was 86 % ( P = .001 ) , and vaccination reduced ILI , physician visits , and lost workdays by 34 % , 42 % , and 32 % , respectively . However , vaccination result ed in a net societal cost of $ 11.17 per person compared with no vaccination . CONCLUSION Influenza vaccination of healthy working adults younger than 65 years can reduce the rates of ILI , lost workdays , and physician visits during years when the vaccine and circulating viruses are similar , but vaccination may not provide overall economic benefits in most years . JAMA . 2000;284:1655 - 1663 [2180233] A reassortant cold-adapted ( ca ) influenza B experimental live attenuated intranasal vaccine was evaluated for safety and immunogenicity in children by means of a blind , placebo controlled study . The vaccine contained the haemagglutinin and neuraminidase genes , and the gene for its non-structural proteins from wild-type ( wt ) B/Ann Arbor/1/86 virus , the contemporary strain at the time of the study . Other genes were derived from ca B/Leningrad/14/55 virus . No increase in illness rates was seen in the children from ages 3 - 15 years given vaccine at maximum potency ( a one in two dilution of infectious allantoic fluid , having a titre of 10(7.0 ) EID50 ) compared to children given placebo . About 60 % of seronegative children , ages 3 - 7 years , exhibited a detectible antibody response following one dose of intranasal vaccine , with the seroresponse rate rising to greater than 70 % after two doses of vaccine . Immunogenicity was lowest in seropositive children age 8 - 15 years , reaching a maximum of 36 % after two doses . Results indicated that the vaccine was highly attenuated , and probably of adequate immunogenicity for kindergarten age children . The lower immunogenicity in older children suggests the vaccine might be overly attenuated for use in school-age children who are more likely to have a history of prior natural infection with influenza B virus . Further clinical and epidemiological studies of protection are needed to fully assess this [1803766] This study was carried out to compare reactogenicity , immunogenicity , and efficacy of live attenuated and inactivated influenza vaccines prepared from influenza A/Philippines/2/82-like virus strains . Schoolchildren of a boarding school of Moscow were r and omly divided into three groups : ( 1 ) vaccinated with a live attenuated vaccine , ( 2 ) vaccinated with inactivated influenza vaccine , and ( 3 ) given placebo . Both vaccines were well tolerated by the children , with practically no severe general or local reactions . The inactivated vaccine was found to be superior to the live one in its capacity to stimulate humoral immunity studied by HI , EIA , and microneutralization tests . In 69.7 % of the children given the inactivated vaccine , seroconversion to the vaccine strain was detected by two or three methods of antibody titration used . Only 35.4 % seroconversions were demonstrated in children immunized with the live influenza vaccine . Enzyme immunoassay was found to be a more sensitive but less specific method for antibody titration as compared with HI test whereas microneutralization proved to be more specific but less sensitive for titration of antibodies to influenza A ( H3N2 ) viruses [4124042] Abstract A trial of inactivated influenza vaccine containing the A/Hong Kong/68 strain was made in 800 boys in a boarding-school starting in 1970 . The boys had serum sample s withdrawn for antibody estimations and were allocated at r and om to vaccine and control groups . During an outbreak of influenza A due to the A/Engl and /42/72 strain , all boys with clinical influenza reported to the medical officer and the diagnosis was confirmed by laboratory examination . The vaccine was shown to confer substantial protection against the new virus strain . The presence of haemagglutinating ( H.I. ) antibody to either strain 6 weeks before the outbreak was associated with protection against influenza . In boys with H.I. antibody to A/Hong Kong/68 virus the attack-rate was 6 % , compared with 25 % in boys with no H.I. antibody to either virus strain . No influenza occurred in boys known to have H.I. antibody to the A/Engl and /42/72 strain . Three-quarters of the boys in whom A/Hong Kong/68 H.I. antibody had been naturally acquired developed A/Engl and / 42/72 H.I. antibody after vaccination . In contrast , the development of A/Engl and /42/72 H.I. antibody was less frequent after revaccination of boys in whom the A/Hong Kong/68 H.I. antibody had been induced by vaccination . A vaccine prepared from the A/Hong Kong/68 strain conferred substantial protection despite the recent antigenic shift of the influenza virus [5115671] Albert Leibovitz , * Raymond L. Coultrip , Edwin D. Kilbourne , Llewellyn J. Legters , Creed D. Smith , James Chin , and Jerome L. Schulman From the Sixth U.S. Army Medical Laboratory , Fort Baker , California ; Preventive Medicine Division , Office of the Surgeon , Fort Ord , California ; Department of Microbiology , Mount Sinai School of Medicine , City University of New York , New York ; and the Infectious Disease Element , California State Department of Public Health , Berkeley , [7769297] This study evaluated the safety , immunogenicity , and protective efficacy of vaccines containing purified recombinant uncleaved hemagglutinin ( rHA0 ) from influenza A/Beijing/32/92 ( H3N2 ) virus . In a r and omized , double-blinded trial , 127 adult volunteers were immunized with 15 micrograms of rHA0 , 15 micrograms of rHA0 plus alum , 90 micrograms of rHA0 , licensed subvirion vaccine , or saline placebo . The rHA0 vaccines caused fewer local adverse reactions than did the commercial subvirion preparation . Neutralizing hemagglutinin-specific antibody responses to 15 micrograms of rHA0 were comparable to those elicited by licensed vaccine , not enhanced by the addition of alum , and significantly increased by raising the rHA0 dose from 15 to 90 micrograms . Compared with placebo recipients , rHA0-vaccinated subjects had significantly lower rates of influenza A ( H3N2 ) virus infection and illness during the epidemic winter season . These results suggest that influenza vaccines containing purified rHA0 may offer an advantage over licensed preparations containing egg-grown antigens by inducing equivalent protective immune responses while being potentially less reactogenic [9269055] Some reports have suggested that influenza virus vaccine is less effective in persons that have received prior annual vaccination(s ) than in those receiving it for the first time . This issue was addressed by evaluating the efficacy of annual influenza vaccinations over a 5 year period in healthy adults employing commercially-available , inactivated whole-virus vaccine . Influenza vaccination had minimal effects on overall respiratory illnesses during epidemic periods . However , it reduced influenza virus shedding by an average of 38.8 % and conferred protection against influenza virus infection during each epidemic . Some variation in infection rates were noted between vaccine groups given one or more than one annual immunization , and between years , but no consistent pattern of differences was noted in relation to number of successive years of vaccination . These results suggest that the current recommendation for annual influenza vaccination of persons at special risk of serious disease and complications is appropriate , but that continued efforts to improve the effectiveness of our prophylactic measures against influenza are needed [2330929] In 1985 , we enrolled 189 school-age children by family in a double-blind study to determine protection against influenza by a single dose of cold-recombinant bivalent A vaccine or commercial trivalent inactivated vaccine compared with placebo . All children in school or day care , 3 to 18 years of age , in an enrolled family received the same preparation . Following vaccination , 60 % and 21 % of cold-recombinant bivalent A vaccine recipients and 73 % and 83 % of trivalent inactivated vaccine recipients demonstrated fourfold or greater response in hemagglutination-inhibition antibody titer to A/H1N1 and A/H3N2 , respectively . Sixty-seven percent of all trivalent inactivated vaccine recipients demonstrated a fourfold or greater serologic response to H1N1 , H3N2 , and influenza B following a single dose of vaccine . During the 1985 - 1986 influenza B/Ann Arbor epidemic , heterotypic protection afforded by the influenza B/USSR component of trivalent inactivated vaccine was 62 % compared with placebo . A single dose of trivalent inactivated vaccine protected school-age children , 6 to 19 years of age , from influenza B infection ; the rate of protection was 64 % against infection and 73 % against febrile illness [4559743] The purpose of this field trial on influenza vaccine , which was done with a population of university students , was to compare the aerosol route with the subcutaneous route of vaccine administration and the Hong Kong influenza vaccine with the older A2 influenza vaccine ( " bivalent " vaccine ) . Side-effects of the vaccines were significantly higher in the groups that received the vaccine subcutaneously . There were no more side-effects in those who received vaccine by aerosol . There was a significant reduction in the rate of illness in all groups vaccinated except for the group given bivalent vaccine subcutaneously . Recipents of Hong Kong vaccine had significantly greater protection than did recipients of the bivalent vaccine . Recipients of aerosol vaccine had significantly better protection than did those who received vaccine by the subcutaneous route . The data suggest that protection was closely related to the ability of the vaccine to stimulate nasalsecretion antibody to the A2 Hong Kong influenza virus [18370460] Summary Currently three different inactivated influenza vaccine types are available : whole virus ( WV ) , split ( SPL ) and subunit ( SU ) vaccines . Physicians and patients at risk for influenza complications may wonder whether there are important differences between the vaccine types with respect to antibody induction ( serology ) and adverse effects ( reactogenicity ) . A literature review ( 1975 to 1995 ) was performed to evaluate the serology and reactogenicity of SU vaccines in comparison with either split or whole virus vaccines . 22 publications with r and omised allocation were identified describing a total of 5416 serological observations , 2858 observations of local reactions , and 2990 observations of systemic reactions . Subjects included those from all age groups from children to the elderly . Absolute protection and reaction rate differences ( RD ) were calculated for the comparisons SU vs SPL or SU vs WV vaccine . These were subjected to a method of meta- analysis , result ing in pooled rate differences and their 95 % confidence intervals . With the exception of the comparison SU vs WV vaccine in subjects born after 1957 and unexposed to the reappearing H1N1 subtype after 1977 , no evidence was found to suggest relevant differences in seroresponse among the three currently available inactivated influenza vaccine types . Although insufficient data were available in the meta- analysis for vaccines in children for whom specific recommendations concerning these vaccines exist , adverse events after administration of any of the three vaccine types were generally mild and transitory ; however , SU vaccines were associated with a lower frequency of local and systemic reactions [3905983] We report the safety and antigenicity of influenza A vaccines in seronegative children one to seven years of age . A natural H1N1 challenge that occurred shortly after completion of the vaccination program permitted an evaluation of efficacy . Twenty-eight subjects were inoculated with live cold-adapted ( ca ) influenza A/Washington/897/80 ( H3N2 ) , 29 with ca influenza A/California/10/78 ( H1N1 ) , 24 with inactivated whole-virus influenza A/Bangkok/79 ( H3N2 ) , and 30 with a placebo . The ca vaccines were well tolerated , whereas the inactivated vaccine caused adverse reactions in about one-third of the children . Fifty-seven percent of the ca H1N1 recipients showed serological responses , contrasted with 84 % and 100 % of subjects receiving the ca or inactivated H3N2 vaccines , respectively . None of the 16 children with induced H1N1 antibody developed clinical ly apparent influenza-like illness , compared with eleven of the 51 initially seronegative children who did not receive the ca H1N1 vaccine and with four of the 12 who failed to respond . Results of the efficacy field trial suggest protection against infection and symptomatic illness in children inoculated with ca H1N1 , despite its failure to stimulate high levels of hemagglutinin-inhibiting antibody [8447161] The performance of two doses of cold-adapted live attenuated vaccine versus one dose of whole-virus inactivated vaccine was compared in 8 - 15-year-old schoolchildren in two schools in Moscow , Russia , during the winter of 1987/88 . Both vaccines gave rise to low frequencies of associated febrile or systemic reactions , but the inactivated vaccine , delivered by jet injector , did cause small local reactions in about half of the children . Immunogenicity was higher for both vaccines in antibody-free children , and higher levels of serum antibody were detected following use of inactivated vaccine . During the winter , influenza A ( H3N2 ) and influenza B viruses circulated in Moscow . A clear outbreak of ( H3N2 ) virus occurred in both schools , and infections with type B virus also occurred in one school . The influenza A/Philippines/2/82 ( H3N2 ) component of both vaccines exhibited protective efficacy of about 40 % ( p < 0.05 ) against serologically proven infection caused by the antigenically drifted A/Sichuan/2/87 (H3N2)-like epidemic viruses in one school . In another school where illnesses associated with antibody rise were documented , efficacy was seen for both vaccines in reduction of illnesses , and of illnesses with serological evidence of infection , but statistical significance was not achieved [8091754] Schoolchildren of 30 to 34 schools of Novgorod were vaccinated over a three-year period with Russian live cold-adapted attenuated vaccine for children and whole-virus inactivated vaccines and placebo for comparative field study of the vaccines properties and efficacy . In control trials both bi- and trivalent live attenuated vaccines were well tolerated and areactogenic . A whole-virus inactivated trivalent vaccine induced mild and moderate fever and local reactions in 2 - 4 % of the vaccinees . Special observations are necessary to establish the possibility of use and to determine a dose of this inactivated vaccine for immunization of children , especially those of 7 - 10 years of age . All the vaccines induced HI antibody production in 50 - 80 % and antineuraminidase in 50 - 70 % of seronegative children . The pattern of the results was similar to that in revaccinated children with preexisting antibody at a level of 1:20 , but much lower in children with the initial titre above 1:20 . After the 3rd year of vaccination the immune response of the vaccinees was similar , most of the results depending on the initial antibody titre and also on the change of vaccine strains . This raises a question of the expediency of annual influenza revaccination of the same person after 2 years of successful immunization and of the necessity of vaccine strains replacement after 2 - 3 years of use [11734733] Background . Influenza is a common and potentially serious infection in children . Although there is interest in broadening the use of influenza vaccine in healthy children , there are few large , r and omized , controlled trials that evaluate the safety and efficacy of inactivated vaccine in the pediatric population . Methods . From 1985 through 1990 a r and omized , controlled trial of cold-adapted and inactivated vaccines for the prevention of influenza A disease was conducted at V and erbilt University , and the cumulative results from this trial in patients of all ages have been previously published . We reanalyzed the data from this trial in the subset of patients who were younger than 16 years at the time of their participation . We determined vaccine safety , immunogenicity and efficacy , based on culture-positive illness and seroconversion , in this subset of patients . Results . During the 5 years of the study , 791 children younger than 16 years received 1809 doses of either inactivated or cold-adapted vaccine or placebo . The vaccines were well-tolerated , and there were no serious reactions . Inactivated trivalent influenza vaccines were 91.4 and 77.3 % efficacious in preventing symptomatic , culture-positive influenza A H1N1 and H3N2 illness , respectively . The efficacy of the inactivated vaccine based on hemagglutination inhibition assay seroconversion was 67.1 and 65.5 % , respectively , for H1N1 and H3N2 serotypes . Conclusions . Inactivated trivalent influenza A vaccines are well-tolerated and efficacious in the prevention of influenza A disease in children 1 to 16 years old [3354254] Forty-three school children from 8 to 11 years old were vaccinated intranasally with two doses of a paediatric attenuated influenza vaccine developed by reassortment between cold-adapted A/Leningrad/134/57(H2N2 ) and an A/Brazil/11/78(H1N1)-like strain . Two vaccine doses were administered 1 month apart in a r and omized , blind , placebo-controlled study . Although the first vaccine dose had a low infectivity titre , overall 65 % of children who received two doses of vaccine showed serological evidence of infection by HI tests . Serum IgA antibody responses against the vaccine strain were detected in nearly 50 % of the vaccines and serum IgG antibody responses were detected in approximately equal to 40 % by an enzyme immunoassay [4608708] A trial of influenza A vaccines in general practice is described . Five hundred and seven subjects were vaccinated with either inactivated monovalent A/Hong Kong vaccine , A/Engl and vaccine or influenza B vaccine as control . Local reactions were noted in 24 % and general reactions in 12 % of patients . Antibody titres in serum were measured by haemagglutination inhibition ( HI ) and complement fixation ( CF ) tests in 465 subjects . The influenza vaccines produced substantial increases in both homologous and heterologous antibodies as measured by the HI test and a comparatively poor response as measured by the CF test . Although clinical influenza was confirmed in only a few cases , there was serological evidence of significant sub clinical infection in the control group [3524050] Live cold-adapted recombinant bivalent vaccine of influenza type A was studied in a controlled field trial in 1982 - 1983 among nearly 30,000 children 3 - 15 years old . The bivalent vaccine consisted of recombinants 47/25/1 ( H1N1 ) and 47/7/2 ( H3N2 ) of wild-type viruses A/Brazil/11/78 ( H1N1 ) and A/Bangkok/1/79 ( H3N2 ) with cold-adapted donor A/Leningrad/134/47/57 ( H2N2 ) . The recombinants which received mutant nonglycoprotein genes from cold-adapted donor did not suppress each other after simultaneous inoculation of children and stimulated antibody response to both strains . The bivalent vaccine was completely attenuated for children . It caused less than 1 % transient febrile reactions during five days after the first vaccination , including double seronegative individuals with low antibody titres to both vaccinal strains . The cold-adapted bivalent vaccine tested proved to be safe for children according to the analysis of morbidity studies among vaccines and a control group performed during the five days and the following six months after the first immunization . There is a similar distribution of non-influenza illnesses and a statistically significant decrease in influenza-like diseases among vaccines compared to the control group . In the four months after the immunization programme was completed , epidemics of influenza A H1N1 and H3N2 occurred . The incidence of influenza-like diseases was approximately 50 % less in the vaccinated than in the control groups . This is the first evidence of safety and protective efficacy of recombinant live influenza vaccine for children 3 - 15 years of age [1988512] Children ( n = 192 ) aged 3 - 19 years from 98 families completed this double-blind , placebo-controlled study comparing the efficacy of a bivalent attenuated ( CR ) vaccine with trivalent inactivated ( TI ) vaccine . Both vaccines contained A/Chile/83 (H1N1)-like antigens . After vaccination the geometric mean titer to A/Taiwan/86 ( H1N1 ) was 1:36 in the CR group , 1:92 in the TI group , and 1:5 in the placebo group . During the influenza A/Taiwan/86 ( H1N1 ) epidemic , 21.4 % of CR recipients , 16.7 % of TI recipients , and 43.9 % of placebo recipients were infected with influenza A/Taiwan . TI vaccine provided better heterotypic protection than did CR vaccine for children aged 10 - 18 years ( infection rate , 0 vs. 24 % , respectively ; P less than .025 ) ; in contrast , in the younger children ( 3 - 9 years ) , CR vaccine tended to be more protective ( 19 % vs. 26 % for TI ) [3515812] In the trial of the trivalent subunit influenza vaccine Grippovac CE-AK observations on children aged 3 - 6 years were made . The preparation showed insignificant reactogenicity and moderate antigenic potency . The trial established that at the period of the epidemic rise of influenza B morbidity the vaccine showed , according to the data of the clinical diagnosis of influenza , insignificant effectiveness , its index of effectiveness ( IE ) being 1.08 ; according to the data of the serological diagnosis of influenza , only the A ( H1N1 ) component of the vaccine was found to have IE equal to 1.58 [9854114] BACKGROUND The number of reports of influenza-vaccine-associated Guillain-Barré syndrome to the national Vaccine Adverse Event Reporting System increased from 37 in 1992 - 1993 to 74 in 1993 - 1994 , arousing concern about a possible increase in vaccine-associated risk . METHODS Patients given a diagnosis of the Guillain-Barré syndrome in the 1992 - 1993 and 1993 - 1994 influenza-vaccination seasons were identified in the hospital-discharge data bases of four states . Vaccination histories were obtained by telephone interviews during 1995 - 1996 and were confirmed by the vaccine providers . Disease with an onset within six weeks after vaccination was defined as vaccine-associated . Vaccine coverage in the population was measured through a r and om-digit-dialing telephone survey . RESULTS We interviewed 180 of 273 adults with the Guillain-Barré syndrome ; 15 declined to participate , and the remaining 78 could not be contacted . The vaccine providers confirmed influenza vaccination in the six weeks before the onset of Guillain-Barré syndrome for 19 patients . The relative risk of the Guillain-Barré syndrome associated with vaccination , adjusted for age , sex , and vaccine season , was 1.7 ( 95 percent confidence interval , 1.0 to 2.8 ; P=0.04 ) . The adjusted relative risks were 2.0 for the 1992 - 1993 season ( 95 percent confidence interval , 1.0 to 4.3 ) and 1.5 for the 1993 - 1994 season ( 95 percent confidence interval , 0.8 to 2.9 ) . In 9 of the 19 vaccine-associated cases , the onset was in the second week after vaccination , all between day 9 and day 12 . CONCLUSIONS There was no increase in the risk of vaccine-associated Guillain-Barré syndrome from 1992 - 1993 to 1993 - 1994 . For the two seasons combined , the adjusted relative risk of 1.7 suggests slightly more than one additional case of Guillain-Barré syndrome per million persons vaccinated against influenza [7550814] OBJECTIVE To determine if the use of influenza vaccine in children in day care decreases the incidence of otitis media during the influenza season . DESIGN Prospect i ve cohort study . SETTING Eight day-care centers in North Carolina . PARTICIPANTS One hundred eighty-six children aged 6 to 30 months . INTERVENTION Half the participants received trivalent subvirion influenza virus vaccine . MEASUREMENTS Acute otitis media ( AOM ) and serous otitis media ( SOM ) were assessed biweekly from mid-November 1993 to mid-March 1994 by visual and tympanometric examinations performed by " blinded " observers . The winter season was divided into three periods-before , during , and after influenza season-- and the number of children with AOM or SOM during each period was determined . Unadjusted and adjusted odds ratios ( ORs ) were computed , while controlling for race and sex using logistic regression methods . RESULTS Influenza vaccine was protective against AOM ( OR = 0.69 , 95 % CI , 0.49 - 0.98 ) during the influenza season . Although there may have been some protection against SOM ( OR = 0.75 , 95 % CI , 0.54 - 1.02 ) statistical significance was not achieved . Myringotomy tubes were also significantly protective against AOM and SOM during all three time periods , with ORs between 0.34 and 0.52 , but the greatest protection was seen during the influenza period . CONCLUSIONS Influenza vaccination of 6- to 30-month-old children in day care was associated with a decreased incidence of otitis media during the influenza season . Myringotomy tubes protected against AOM and SOM during all 16 weeks monitored [8277200] A double-blind , r and omized controlled trial over 5 years compared the safety , immunogenicity , and efficacy of cold-adapted and inactivated influenza A vaccines in 5210 normal subjects . Both vaccines were well tolerated . Inactivated vaccine significantly increased hemagglutination inhibition antibody titers . Significant titer rises were also noted after cold-adapted vaccine but of lesser magnitude than with inactivated vaccine . The efficacy of inactivated vaccine in preventing culture-positive influenza was 76 % ( 95 % confidence interval [ CI ] , 58%-87 % ) for H1N1 disease and 74 % ( 95 % CI , 52%-86 % ) for H3N2 ; for cold-adapted vaccine , 85 % ( 95 % CI , 70%-92 % ) and 58 % ( 95 % CI , 29%-75 % ) , respectively . The efficacy of inactivated vaccine in preventing a four-fold rise in antibody titer over the influenza season was 69 % ( 95 % CI , 61%-76 % ) for H1N1 and 73 % ( 95 % CI , 65%-79 % ) for H3N2 ; for cold-adapted vaccine , 54 % ( 95 % CI , 44%-62 % ) and 32 % ( 95 % CI , 17%-44 % ) , respectively . Cold-adapted and inactivated influenza vaccines are safe and effective for preventing influenza A disease [3300032] During the autumn-winter epidemic of influenza-like diseases in December , 1983 - -first quarter , 1984 , in Moscow commissioned coded observations on the effectiveness of prophylactic vaccination against influenza of 3 - 7-year-old children with a preparation " Grippovak SE-AZh " were carried out in day-care centers . In the previous large-scale trials , 1981 - 1984 , the " Grippovak " had been evaluated positively as a completely harmless , serologically and immunologically active preparation reducing 3 - 3.5-fold the number of laboratory-verified cases of viral type A and B influenza in the vaccinees . In 1986 , however , the " Journal of Microbiology , Epidemiology , Immunology " ( JMEI , 2 : 49 - 54 ) published a paper whose authors , on behalf of the Commission which had checked the preparation in the day-care centers ( Z.A. Bashliaeva , A.A. Sumarokov , et al. ) , came to a conclusion that " Grippovak " was ineffective in children . Other members of the above Commission disagreeing with this conclusion made a repeat analysis of the decoded material s of the observations in the day-care centers using computer methods and demonstrated that because of significant prevalence of non-influenza ARD cases and recurrent ( up to 44 % ) ARD cases in children in the 4 months of observation , it was impossible to judge the effectiveness of the vaccine by comparison of the total incidence of influenza and ARD from the clinical data alone in the vaccinees and controls . ( ABSTRACT TRUNCATED AT 250 WORDS [12271720] The study of the based on the A/Leningrad/134/17/57/(H2N2 ) attenuated adult live influenza vaccine ( LIV ) investigated features for immunization of the children , aged 3 - 6 years . During autumn , 1999 , out of 256 children , aged 3 - 6 years , residents of the Leningrad region , who attended the kindergarten , 184 children were immunized with 1 or 2 doses of the live influenza vaccine , and 72 ones were given placebo . There were no any moderate or strong temperature reactions revealed after the inoculation . The LIV was shown to be genetically stable . After a single dose of the vaccine seroconversion to influenza type A virus and to influenza type B virus was observed respectively in 58 % and in 39 % of seronegative 3 - 6 year old vaccinees . The twofold LIV administration failed to give any advantages in stimulation of the immune response . During 6 months after immunization the morbidity rate in vaccinees did not exceed the morbidity rate in unvaccinated children . Thus LIV for adults proved safe and immunogenic and can be recommended for single dose immunization both of adults and children [1803767] A limited controlled comparative study for the evaluation of the epidemiological efficacy of live recombinant and inactivated virion vaccines from A/Philippines/2/82-like strains of influenza A ( H3N2 ) virus was carried out in schoolchildren of 8 to 15 years of age . During the influenza epidemic of 1987 - 1988 caused by influenza A/Sichuan/2/87 (H3N2)-like strains and by influenza B virus in 8.2 - 17 % of cases , a statistically significant efficacy index for live influenza vaccine was 1.8 for the laboratory confirmed A ( H3N2 ) cases . In the group vaccinated with the inactivated vaccine the number of serologically diagnosed A ( H3N2 ) cases was 1.6 times lower than in the group receiving placebo , this difference being statistically significant . Thus , under the conditions of significant difference in the antigenic structure of the vaccine and epidemic A ( H3N2 ) strains , both vaccines produced some diminished but statistically significant preventive effect in vaccinated children although its level was below the optimal . Revaccination of some children with a live influenza vaccine from a new A/Sichuan/2/87-like variant of A ( H3N2 ) virus in the autumn of 1988 with reisolation of the vaccine strain also revealed the presence of some , though weak , resistance to this strain in the children vaccinated with both vaccines [4908340] A field study was undertaken in Tampa , Fla. , to assess the efficacy of subcutaneous and aerosol methods of administering vaccine , and to compare the protection afforded by bivalent ( A2 and B ) influenza virus vaccine and by A2/Hong Kong/68 virus vaccine . Further objectives of the study included a comparison of the effectiveness of single-dose and 2-dose immunization . Approximately 2100 volunteers received , in a double-blind manner , both an injection and an aerosol administration on 2 occasions 3 weeks apart . The results showed that aerosol administration gave a lower over-all protection rate , although the booster dose seemed to have a marked effect . The protection afforded by A2/Hong Kong/68 virus vaccine was considerably greater than that afforded by the bivalent vaccine , particularly when administration was subcutaneous . Results are also given on the occurrence of side-effects and on the correlation between cigarette smoking and the occurrence of influenza-like illness [11715169] OBJECTIVE To determine if a vaccine against influenza significantly decreases episodes of acute upper respiratory infection ( AURI ) and work absenteeism caused by AURI , in healthy adult employees of a banking entity in the city of Medellín , Colombia . METHODS This was a double-blind r and omized placebo-controlled study with 493 volunteers . The volunteers were r and omly assigned to two groups , an experimental group and a control group , with 247 and 246 employees , respectively . The experimental group participants received a dose of 0.5 mL of an influenza vaccine containing surface antigens of the strains recommended by the World Health Organization for the 1996 - 1997 period , with subtypes A/Wuhan/359/95 ( H3N2 ) , A/Texas/36/91 ( H1N1 ) , and B/Beijing/184/93 . An illness was considered an episode of AURI when a participant reported having a sore throat , fever , and a cough lasting more than 24 hours . Evaluations were made every 2 weeks over a 6-month period ; the severity of the episodes was assessed in terms of lost workdays due to AURI ( defined according to the ninth revision of the International Classification of Diseases , or ICD-9 ) , through monthly evaluations of incapacitating work absences certified by the Colombian Social Security system , over the period of a year . RESULTS Side effects associated with the vaccine were erythema ( relative risk ( RR ) = 8.0 ; P = 0.02 ) and local edema ( RR = 4.5 ; P = 0.03 ) . The proportion of the annual cumulative incidence of episodes of AURI was 78.5 % for the vaccinated persons and 91.5 % for those in the placebo group , with a reduction of 14 % , with values between 7 % and 20 % ( RR = 0.86 ; 95 % confidence interval ( CI ) = 0.80 - 0.93 ) . The annual cumulative incidence of incapacitating AURI was 15.8 % in those vaccinated , with a reduction of 31 % in comparison to the placebo group ( 22.8 % ) , with values between 0 % and 52 % ( RR = 0.69 ; 95 % CI = 0.48 - 1.0 ) . These levels of protection , both against more mildly symptomatic forms of AURI and those causing lost workdays , increased significantly ( between 62 % and 89 % ) in the months of May and October , when outbreaks caused by the influenza virus were confirmed in Colombia . CONCLUSIONS The results demonstrated that the influenza vaccination strategy decreased the AURI episodes as well as the number of work absences due to AURI in the healthy adult employees of a banking entity in the city of Medellín , Colombia . The impact that influenza has on this population group is small , and the effect of this vaccination measure is greater then the influenza virus is in circulation [8568310] In a blinded , placebo-controlled study , the reactogenicity , immunogenicity , and clinical efficacy of single doses of US inactivated split-virus and Russian live attenuated , cold-adapted influenza vaccines were compared in 555 schoolchildren in Vologda , Russia . Serial serum sample s were collected and school absenteeism was assessed . Systemic reactions were rare , but local reactions ( primarily erythema at the injection site ) were observed in 27 % of the inactivated vaccine group , and coryza ( 12 % ) and sore throat ( 8 % ) were observed in the attenuated vaccine group . At 4 weeks after vaccination a > or = 4-fold rise in titer of hemagglutination inhibition antibody to A ( H1N1 ) , A ( H3N2 ) , and B was noted , respectively , among 78 % , 88 % , and 53 % of children who received inactivated vaccine and among 55 % , 79 % , and 30 % of children who received attenuated vaccine . The vaccine efficacy for preventing school absenteeism due to respiratory illness during the period of peak influenza activity was 56 % for inactivated vaccine and 47 % for attenuated vaccine [351351] Immunization with an influenza subunit vaccine given in one dose about 1 month to 2 months before onset of an epidemic of influenza afforded from 80 % to 90 % protection in a double-blind clinical trial which was supported by isolation of virus and serological studies . In the vaccinated group , 20 % failed to develop antibodies to the vaccine . Either serology tests or attempted isolation of virus alone would have failed to detect some of the cases [18448618] ABSTRACT The highly sensitive gamma interferon ( IFN-γ ) enzyme-linked immunosorbent spot ( ELISPOT ) assay permits the investigation of the role of cell-mediated immunity ( CMI ) in the protection of young children against influenza . Preliminary studies of young children confirmed that the IFN-γ ELISPOT assay was a more sensitive measure of influenza memory immune responses than serum antibody and that among seronegative children aged 6 to < 36 months , an intranasal dose of 107 fluorescent focus units ( FFU ) of a live attenuated influenza virus vaccine ( CAIV-T ) elicited substantial CMI responses . A commercial inactivated influenza virus vaccine elicited CMI responses only in children with some previous exposure to related influenza viruses as determined by detectable antibody levels prevaccination . The role of CMI in actual protection against community-acquired , culture-confirmed clinical influenza by CAIV-T was investigated in a large r and omized , double-blind , placebo-controlled dose-ranging efficacy trial with 2,172 children aged 6 to < 36 months in the Philippines and Thail and . The estimated protection curve indicated that the majority of infants and young children with ≥100 spot-forming cells/106 peripheral blood mononuclear cells were protected against clinical influenza , establishing a possible target level of CMI for future influenza vaccine development . The ELISPOT assay for IFN-γ is a sensitive and reproducible measure of CMI and memory immune responses and contributes to establishing requirements for the future development of vaccines against influenza , especially those used for children [19776407] BACKGROUND The efficacy of influenza vaccines may vary from year to year , depending on a variety of factors , and may differ for inactivated and live attenuated vaccines . METHODS We carried out a r and omized , double-blind , placebo-controlled trial of licensed inactivated and live attenuated influenza vaccines in healthy adults during the 2007 - 2008 influenza season and estimated the absolute and relative efficacies of the two vaccines . RESULTS A total of 1952 subjects were enrolled and received study vaccines in the fall of 2007 . Influenza activity occurred from January through April 2008 , with the circulation of influenza types A ( H3N2 ) ( about 90 % ) and B ( about 9 % ) . Absolute efficacy against both types of influenza , as measured by isolating the virus in culture , identifying it on real-time polymerase-chain-reaction assay , or both , was 68 % ( 95 % confidence interval [ CI ] , 46 to 81 ) for the inactivated vaccine and 36 % ( 95 % CI , 0 to 59 ) for the live attenuated vaccine . In terms of relative efficacy , there was a 50 % ( 95 % CI , 20 to 69 ) reduction in laboratory-confirmed influenza among subjects who received inactivated vaccine as compared with those given live attenuated vaccine . The absolute efficacy against the influenza A virus was 72 % ( 95 % CI , 49 to 84 ) for the inactivated vaccine and 29 % ( 95 % CI , -14 to 55 ) for the live attenuated vaccine , with a relative efficacy of 60 % ( 95 % CI , 33 to 77 ) for the inactivated vaccine . CONCLUSIONS In the 2007 - 2008 season , the inactivated vaccine was efficacious in preventing laboratory-confirmed symptomatic influenza A ( predominately H3N2 ) in healthy adults . The live attenuated vaccine also prevented influenza illnesses but was less efficacious . ( Clinical Trials.gov number , NCT00538512 . [19931952] A cluster-r and omised controlled trial of antiviral treatment to control influenza outbreaks in aged-care facilities ( ACFs ) provided an opportunity to assess VE in the frail , institutionalised elderly . Data were pooled from five influenza outbreaks in 2007 . Rapid testing methods for influenza were used to confirm outbreaks and /or identify further cases . Vaccination coverage among ACF residents ranged from 59 % to 100 % , whereas it was consistently low in staff ( 11 - 33 % ) . The attack rates for laboratory-confirmed influenza in residents ranged from 9 % to 24 % , with the predominate strain determined to be influenza A. Sequencing of the hemagglutinin gene from a sub- sample demonstrated an incomplete match with the 2007 southern hemisphere influenza vaccine . Influenza VE was estimated to be 61 % ( 95%CI 6 % , 84 % ) against laboratory-confirmed influenza , 51 % ( 95%CI -16 % , 79 % ) against influenza-like illness , 82 % ( 95%CI 27 % , 96 % ) against pneumonia-related and influenza-related hospitalisations and 71 % ( 95%CI -28 % , 95 % ) against death from all causes . This supports the continued policy of targeted vaccination of the institutionalised , frail elderly . There is also reassurance that influenza vaccine can be effective against disease and severe outcomes , despite an incomplete vaccine match . This benefit is additional to protection from antivirals [2845585] Background Seasonal influenza imposes a substantial personal morbidity and societal cost burden . Vaccination is the major strategy for influenza prevention ; however , because antigenically drifted influenza A and B viruses circulate annually , influenza vaccines must be up date d to provide protection against the predicted prevalent strains for the next influenza season . The aim of this study was to assess the efficacy , safety , reactogenicity , and immunogenicity of a trivalent inactivated split virion influenza vaccine ( TIV ) in healthy adults over two influenza seasons in the US . Methods The primary endpoint of this double-blind , r and omized study was the average efficacy of TIV versus placebo for the prevention of vaccine-matched , culture-confirmed influenza ( VMCCI ) across the 2005 - 2006 and 2006 - 2007 influenza seasons . Secondary endpoints included the prevention of laboratory-confirmed ( defined by culture and /or serology ) influenza , as well as safety , reactogenicity , immunogenicity , and consistency between three consecutive vaccine lots . Participants were assessed actively during both influenza seasons , and nasopharyngeal swabs were collected for viral culture from individuals with influenza-like illness . Blood specimens were obtained for serology one month after vaccination and at the end of each influenza season 's surveillance period . Results Although the point estimate for efficacy in the prevention of all laboratory-confirmed influenza was 63.2 % ( 97.5 % confidence interval [ CI ] lower bound of 48.2 % ) , the point estimate for the primary endpoint , efficacy of TIV against VMCCI across both influenza seasons , was 46.3 % with a 97.5 % CI lower bound of 9.8 % . This did not satisfy the pre-specified success criterion of a one-sided 97.5 % CI lower bound of > 35 % for vaccine efficacy . The VMCCI attack rates were very low overall at 0.6 % and 1.2 % in the TIV and placebo groups , respectively . Apart from a mismatch for influenza B virus lineage in 2005 - 2006 , there was a good match between TIV and the circulating strains . TIV was highly immunogenic , and immune responses were consistent between three different TIV lots . The most common reactogenicity events and spontaneous adverse events were associated with the injection site , and were mild in severity . Conclusions Despite a good immune response , and an average efficacy over two influenza seasons against laboratory-confirmed influenza of 63.2 % , the pre-specified target ( lower one-sided 97.5 % confidence bound for efficacy > 35 % ) for the primary efficacy endpoint , the prevention of VMCCI , was not met . However , the results should be interpreted with caution in view of the very low attack rates we observed at the study sites in the 2005 - 2006 and 2006 - 2007 , which corresponded to relatively mild influenza seasons in the US . Overall , the results showed that TIV has an acceptable safety profile and offered clinical benefit that exceeded risk . Trial registration

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### Context: [10808574] Vaccine " Grippol "-- has been developed at the State Research Center -- Institute of Immunology . The preparation belongs to new generation vaccines and is a trivalent polymer-subunit vaccine containing the sterile conjugate of influenza virus surface proteins , types A and B , bound with copolymer polyoxidonium . The administration of " Grippol " to children of school age ( 6 - 18 years ) demonstrated low reactogenicity of the vaccine , its safety and sufficient prophylactic effectiveness . During observations on total morbidity ( with the exception of influenza and acute respiratory diseases ) no side effects produced by " Grippol " were registered . At the same time the fact that the morbidity rate of upper respiratory tract disease in the group of children immunized with the vaccine decreased in comparison with the control group ( by 2.4 times ) can not be disregarded [8160445] Production lots of a live influenza vaccine made of strains A/47/T ( N1H1 ) , A/47/6/2 ( H3N2 ) , and B/60/32 were used for vaccination of 3663 children aged from 5 to 14 years inoculated twice with monovaccines , a trivaccine made of the above strains , or placebo . Both mono- and polyvaccine were practically areactogenic . An average per cent of subjects with a significant rise in antibody titres to the respective three antigens was 60 % . The efficacy of the vaccination was 31.0 - 42.8 % for monopreparations and 36.3 % for the trivaccine . The studies showed the possibility and expedience of using for children the live influenza vaccine in the form of a polyvalent preparation including current influenza type A and B viruses [12271721] In Russia for prevention of influenza in children , aged from 3 to 14 years , the children 's live influenza vaccine ( LIV ) , based upon A/Leningrad/134/47/57(H2N2 ) master strain ( LIVI ) is used . The need for double immunization appears to be one out of the faulties of this preparation . The study was aim ed to comparing the safety , immunogenic activity and prevention of influenza by LIV for adults ( LIVII ) ( A/Leningrad/134/17/57(H2N2 master strain ) and LIVI in children aged from 7 to 17 years under similar administration schedule . The safety , the preventive efficacy , humoral and secretory immunity were studied . In total 2486 persons , including 539 children , twice inoculated with LIVI , 971 persons once inoculated with LIVII , and 840 treated by placebo were obserbed . From the data of the clinical observations during 7 days after immunization both vaccines appeared to be low reactogenic . The LIVII advantages in induction of the humoral and secretory antibodies in comparison with children 's vaccine had been revealed . Both vaccines were highly efficacious , the efficiency of both preparations was more pronounced after serologic correction of the diagnosis . The results obtained permit to recommend the single immunization by the variant of LIV at the base on A/Leningrad/134/17/57/(H2N2 ) master strain for prevention of influenza in school children [10930686] The immunogenicity and efficacy of Russian live attenuated and US inactivated trivalent influenza vaccines administered alone or in three different combinations were evaluated in a r and omized , placebo-controlled , double-blinded study of 614 elderly or chronically ill nursing home residents in St. Petersburg , Russia during the 1996 - 97 influenza season . Postvaccination serum antibody responses were more frequent among individuals administered the combination vaccines than among those vaccinated with live or inactivated vaccine alone . Only individuals who received live vaccine , alone or in combination with inactivated vaccine , achieved significant postvaccination increases in virus-specific nasal IgA. Efficacy in preventing laboratory-confirmed influenza in vaccinated versus nonvaccinated individuals was 67 % ( 95%CI , 36 - 81 % ) for recipients of a combination of the vaccines compared with 51 % ( 95%CI , -17 - 79 % ) for recipients of live vaccine alone and 50 % ( 95%CI , -26 - 80 % ) for recipients of inactivated vaccine alone . These results suggest that administration of a combination of influenza vaccines may provide a strategy for improved influenza vaccination of elderly people [19395948] Background : We investigated the efficacy and safety of 1 versus 2 doses of live attenuated influenza vaccine ( LAIV ) in influenza vaccine – naive children aged 6 to < 36 months . Patients / Methods : Subjects were r and omized to 1 of 4 regimens in year 1 : 2 doses LAIV , 1 dose LAIV , excipient placebo , or saline placebo . In year 2 , LAIV recipients were to receive 1 dose of LAIV and placebo recipients were to receive saline placebo . Because of an unintended treatment allocation error in year 2 , 1 block of subjects who were r and omized to LAIV received saline placebo and 1 block who were r and omized to placebo received LAIV . Results : In year 1 , vaccine efficacy versus placebo among recipients of 2 and 1 doses of LAIV was 73.5 % and 57.7 % , respectively , against antigenically similar strains . In year 2 , absolute efficacy of a single dose of LAIV was 73.6 % and 65.2 % , respectively , in recipients of 2 and 1 doses of LAIV in year 1 . Year 2 efficacy was 57.0 % in subjects who received 2 doses of LAIV in year 1 and placebo in year 2 . Safety and tolerability of LAIV were consistent with previous studies . Reactogenicity was similar between placebo groups . Seroconversion rates were significantly higher in the 2-dose versus the 1-dose LAIV group in year 1 and in both LAIV groups versus placebo in years 1 and 2 . Conclusions : One dose of LAIV provided clinical ly significant protection against influenza in young children previously unvaccinated against influenza ; 2 doses provided additional protection . Protection after 2 doses in year 1 persisted through a second season without revaccination . LAIV excipients were not a major contributor to reactogenicity . These benefits provide support for increased use of LAIV in children ≥2 years of age [10078487] CONTEXT Data are limited and conflicting regarding the effectiveness of influenza vaccine in health care professionals . OBJECTIVE To determine the effectiveness of trivalent influenza vaccine in reducing infection , illness , and absence from work in young , healthy health care professionals . DESIGN R and omized , prospect i ve , double-blind , controlled trial over 3 consecutive years , from 1992 - 1993 to 1994 - 1995 . SETTING Two large teaching hospitals in Baltimore , Md. PARTICIPANTS Two hundred sixty-four hospital-based health care professionals without chronic medical problems were recruited ; 49 participated for 2 seasons ; 24 participated for 3 seasons . The mean age was 28.4 years , 75 % were resident physicians , and 57 % were women . INTERVENTION Participants were r and omly assigned to receive either an influenza vaccine or a control ( meningococcal vaccine , pneumococcal vaccine , or placebo ) . Serum sample s for antibody assays were collected at the time of vaccination , 1 month after vaccination , and at the end of the influenza season . Active weekly surveillance for illness was conducted during each influenza epidemic period . MAIN OUTCOME MEASURES Serologically defined influenza infection ( 4-fold increase in hemagglutination-inhibiting antibodies ) , days of febrile respiratory illness , and days absent from work . RESULTS We conducted 359 person-winters of serologic surveillance ( 99.4 % follow-up ) and 4746 person-weeks of illness surveillance ( 100 % follow-up ) . Twenty-four(13.4 % ) of 179 control subjects and 3 ( 1.7 % ) of 180 influenza vaccine recipients had serologic evidence of influenza type A or B infection during the study period . Vaccine efficacy against serologically defined infection was 88 % for influenza A ( 95 % confidence interval [ CI ] , 47%-97 % ; P=.001 ) and 89 % for influenza B ( 95 % CI , 14%-99 % ; P=.03 ) . Among influenza vaccinees , cumulative days of reported febrile respiratory illness were 28.7 per 100 subjects compared with 40.6 per 100 subjects in controls ( P=.57 ) and days of absence were 9.9 per 100 subjects vs 21.1 per 100 subjects in controls ( P=.41 ) . CONCLUSIONS Influenza vaccine is effective in preventing infection by influenza A and B in health care professionals and may reduce reported days of work absence and febrile respiratory illness . These data support a policy of annual influenza vaccination of health care professionals [12234038] BACKGROUND Approximately 10 % of the general population worldwide acquires influenza infection every year . Airline crews run a particularly high risk of contracting influenza and influenza-like viruses because they come in contact with hundreds of potentially infected individuals every day . Respiratory diseases are the most frequent cause of absenteeism among flight crews in airline companies . Several studies have shown the efficacy of influenza vaccination in the workplace of healthy , working adults leading to increased productivity and lower absenteeism . We conducted a double blind , r and omized , placebo-controlled study on flight crews of an airline company in order to determine the safety and efficacy of a trivalent inactivated influenza vaccine in reducing illness and absences from work . METHODS The 813 healthy members of a Brazilian airline company were r and omly assigned to receive injections of either an influenza vaccine or a placebo , with a follow-up period of 7 mo after vaccination . Primary outcomes included influenza-like illness episodes and absenteeism from work due to such episodes . RESULTS Demographic characteristics were similar in the two groups . No significant side-effects occurred in either group . Compared to the placebo group , individuals receiving the vaccine showed 39.5 % fewer episodes of flu-like illness ( p < 0.001 ) and 26 % fewer days of work lost ( p = 0.03 ) . The vaccinated group developed 33 % fewer episodes of any severe flu-like illness ( p < 0.01 ) . CONCLUSION The data indicates that influenza vaccination is safe in airline flight crews and may produce health-related benefits including reduced absenteeism [7054318] A live , attenuated influenza B virus vaccine was evaluated in a group of students . The virus , cold-recombinant ( CR ) 7 , was produced by recombining the attenuated cold-adapted parent , B/Ann Arbor/1/66 , with a wild strain , B/Hong Kong/8/73 . In ferrets , the wild strain produced histopathologic lesions in the lungs , whereas the CR strain and the attenuated parent did not . A total of 306 individuals was inoculated intranasally with either the CR virus or a placebo . After inoculation , only one symptom was significantly more common in the vaccinees than in the control subjects . That symptom , sore throat , occurred briefly in 26 % of the vaccine recipients and in 10.5 % of the placebo recipients . An outbreak of influenza B occurred three months after vaccination . When serologic infection rates in the two groups were compared , it was found that the vaccine had been significantly effective ( P less than 0.01 ) in preventing infection [11893153] OBJECTIVE To evaluate the effectiveness of influenza vaccines against influenza-like illness ( ILI ) among nursing home residents . DESIGN Prospect i ve , nonr and omized , cohort study . SETTING Nine nursing homes during the 1998 - 1999 influenza season and 11 nursing homes during the 1999 - 2000 influenza season in Niigata Prefecture , Japan . PARTICIPANTS Six hundred ninety-nine residents and 440 healthcare workers ( HCWs ) during the first season , and 930 residents and 517 HCWs during the second season , with vaccination rates ranging from 0 % to 97.7 % . RESULTS Overall , ILI decreased from 24.3 % during the 1998 - 1999 season to 8.8 % during the 1999 - 2000 season . Multivariate analysis adjusted for several factors , including gender , age , underlying diseases , and resident and HCW vaccination rates , failed to demonstrate clear individual protection of residents ( relative risk [ RR ] , 1.42 ; P = .2 for the first season ; RR , 0.95 ; P = .9 for the second season ) . However , vaccination rates of 60 % or greater for residents and HCWs reduced the risk of ILI , and also could prevent outbreaks during the 2 seasons . Highly impaired activities of daily living and chronic respiratory diseases were significantly associated with increased ILI . CONCLUSIONS A high vaccination rate for both residents and HCWs may reduce the risk of ILI and institutional outbreaks in nursing homes [19366887] When the first edition of A Dictionary of Epidemiology was launched in 1983 , its principal aim was to facilitate communication among health professionals . The field was relatively young and comprised complex interdisciplinary relations ranging from the biomedical sciences to statistics and the social sciences . The International Epidemiological Association ( IEA ) co-sponsored the project with the aim of developing certain st and ards for teaching , research reports and communication of epidemiological findings to the public . This is a well-known history : John M Last , the emeritus professor of epidemiology and community medicine from the University of Ottawa , Canada , was appointed as the editor of A Dictionary ... , and kept ahead of the task during the subsequent decades . The original slim pocket book grew substantially with each re-edit , keeping pace with the remarkable developments in the discipline . When the fourth edition was launched in 2001 , John Last told me with a smile that he would die soon , supposedly to increase the value of the signature he had just h and written in my book . Fortunately , he did not , and his love for dictionary-making allowed him to produce his A Dictionary of Public Health , and to collaborate in the recently launched fifth edition of A Dictionary ... , now edited by Miquel Porta , professor of preventive medicine and public health from the Universitat Autònoma de Barcelona , senior scientist of the Institut Municipal d’Investigació Mèdica in Barcelona , Spain , and collaborator in the previous editions . If he had to limit his professional bookcase to a single volume , Professor Charles du V Florey , the former president of the IEA , would choose to keep A Dictionary .... I argue that anybody among us — epidemiologists and would-be epidemiologists ( hopefully with a larger shelf)—should also have a copy of this book at h and for frequent consultation . The collective effort gathered in its making is impressive . Miquel Porta has built over the previously crafted editions , and has relied on the support of a wide network of professionals to up date each entry and to exp and the selection of subjects . The Journal of Epidemiology and Community Health joined the initiative by publishing a call for su bmi ssions . Items already selected from the previous edition have been revised and up date d ; several new items have been added . As a result , the fifth edition of A Dictionary ... performs normative and informative functions : you will be informed on important matters and instructed on how to proceed in the epidemiological field . Readers with different needs and anxieties with knowledge will find straightforward writing , authoritative definitions and pertinent bibliographical references . How to differentiate a rate from a ratio , incidence from prevalence , confounding from intervening variables , type I from type II error ? How to appraise emerging themes in the epidemiological literature such as genetic polymorphisms and Bayesian statistics ? Key method ological issues such as meta- analysis , multilevel analysis and regression models : the list solely enrols a small sample of possible search es . The selection of issues was broad in scope ; intelligent and synthetic writing contemplated from the easier to the more intricate subjects . You may want to up date conceptual and method ological issues relevant to your teaching and research activities , to resolve doubts or to confirm an impression . You may want to check on terminology , fulfil curiosities or learn about topics unrelated to your preferential themes . You may be a professional applied to other health specialities , an undergraduate or a high school student . Several users will meet their needs by consulting A Dictionary ... ; even those who aim lessly scan the text may find some valuable insight . While it will not resolve all your needs in the epidemiological field , it surely provides enough substance to build on — a very good start or ammunition for more comprehensive search es . Miquel Porta dealt with the challenge of preparing reader-friendly texts on a wide range of subjects , which will satisfy both a beginner and an experienced epidemiologist . He seems to have transposed Occam ’s razor ( see the correspondent entry : ‘ ‘ the philosophical principle of parsimony ... assumptions to explain a phenomenon must not be multiplied beyond necessity ... ’ ’ ) to the writing of the book . If I may indulge in selftestimony , I found my teenage daughter consulting the book and it motivated a conversation on subjects so dear to me .... Arousing the interest of the young for a speciality admittedly perceived as difficult by adolescents ; as goes the popular saying , this is priceless ! ‘ ‘ Epidemiology is the study of the occurrence and distribution of healthrelated states or events in specified population s , including the study of the determinants influencing such states , and the application of this knowledge to control the health problems ’ ’ . The definition has matured over the years and presents slight modifications from its previous formulation in the fourth edition . The entry for ‘ ‘ Epidemiology ’ ’ exp and s the conceptualisation of terms comprised in the definition and includes historical aspects . In subsequent years , this definition will be the benchmark of the discipline , until Miquel Porta and his collaborators eventually prepare a further edition to meet the new needs that the future may bring forth . I dare to guess that the prospect i ve sixth edition of A Dictionary ... will have an online dynamic interface interacting with the hard copy . I also dare to guess that it will include a new entry for A Dictionary of Epidemiology , whose importance to the professional field will surely have earned it [7080769] To evaluate the safety , reactogenicity and immunogenicity of inactivated chromatographic influenza vaccine A(H3N2 ) produced by the Pasteur Research Institute of Epidemiology and Microbiology in Leningrad , children aged 7 - 15 years received the vaccine intradermally in doses of 114 - 228 IU , and 152 children received placebo . In this study inactivated influenza vaccine introduced parenterally to children aged 11 - 15 years in a dose of 228 IU proved to be nonreactogenic . The reactogenicity index of the preparation injected in a dose of 114 IU to children aged 7 - 10 years was 0.6 % . Immunization in a single injection was accompanied by significant seroconversions in 87.5%-96.0 % of children with the highly pronounced growth of antibody titers ( 21.1 - 34.6 times ) . The complex of clinico-laboratory tests showed the safety of this preparation for both age groups [18522501] BACKGROUND The efficacy of influenza vaccines may vary annually . In 2004 - 2005 , when antigenically drifted viruses were circulating , a r and omized , placebo-controlled trial involving healthy adults showed that inactivated vaccine appeared to be efficacious , whereas live attenuated vaccine appeared to be less so . METHODS In 2005 - 2006 , we continued our trial , examining the absolute and relative efficacies of the live attenuated and inactivated vaccines in preventing laboratory-confirmed symptomatic influenza . RESULTS A total of 2058 persons were vaccinated in October and November 2005 . Study wide influenza activity was prolonged but of low intensity ; type A ( H3N2 ) virus was circulating , which was antigenically similar to the vaccine strain . The absolute efficacy of the inactivated vaccine was 16 % ( 95 % confidence interval [ CI ] , -171 % to 70 % ) for the virus identification end point ( virus isolation in cell culture or identification through polymerase chain reaction ) and 54 % ( 95 % CI , 4%-77 % ) for the primary end point ( virus isolation or increase in serum antibody titer ) . The absolute efficacies of the live attenuated vaccine for these end points were 8 % ( 95 % CI , -194 % to 67 % ) and 43 % ( 95 % CI , -15 % to 71 % ) , respectively . CONCLUSIONS With serologic end points included , efficacy was demonstrated for the inactivated vaccine in a year with low influenza attack rates . The efficacy of the live attenuated vaccine was slightly less than that of the inactivated vaccine , but not statistically greater than that of the placebo [6531951] A trial with a trivalent influenza subunit vaccine prepared with sodium deoxycholate was carried out in 88 volunteers between May and November 1981 . Each haemagglutinin antigen was present at 7 micrograms per dose . Fourfold or greater haemagglutination inhibition antibody ( HI ) responses to the H1N1 virus A/Brazil/11/78 occurred in 70 % of volunteers following a single dose . For the H3N2 virus A/Bangkok/1/79 and B/Singapore/222/79 these figures were 52 and 11 % , respectively . No increase in the antibody titre was noted to any of the antigens following a second vaccination dose . Antibody levels remained relatively constant six months after vaccination . A response to B/Singapore/222/79 , comparable with the HI response for the influenza A antigens , was noted when serum titres were estimated by a plaque reduction procedure . No neuraminidase inhibition antibody could be detected in response to either A/Brazil/11/78 or A/Bangkok/1/79 . No reactions specifically attributable to the vaccine occurred after either injection . A lower HI response to A/Brazil/11/78 was noted in volunteers 52 years of age and older , who also showed less evidence of earlier priming to this virus . Levels of nasal wash neutralizing antibodies to A/Brazil/11/78 were proportional to those detected in sera by HI tests , but were present in smaller amounts [16645502] Objective : The objective of this study was to evaluate the effectiveness of inactivated influenza vaccine in preventing acute otitis media ( AOM ) and otitis media with effusion ( OME ) in children aged 6 to 60 months who attend day care . Study Design : This prospect i ve , single-blind study was conducted in 8 day care centers in Ankara , Turkey . One hundred nineteen ( 61 vaccinated and 58 unvaccinated against influenza ) healthy children were examined at study entry and at 6-week intervals for 6 months by the same 2 otorhinolaryngologists who were blinded about the vaccination status of the children . The frequency of AOM and OME is compared between the 2 groups and the effect of influenza season on frequency of episodes was evaluated . Based on national influenza laboratory data , the influenza season was determined to be the period between December 15 , 2003 , and January 31 , 2004 . Result : The frequencies of AOM , OME and total otitis media episodes in vaccinated children were 2.3 % , 22.8 % and 25.2 % , respectively , and these frequencies were 5.2 % , 31.1 % and 36.3 % in the unvaccinated group . The difference was statistically significant ( P < 0.01 ) . This difference was especially prominent in the influenza season ( P < 0.05 ) . Conclusion : Influenza vaccine is effective in reducing AOM and OME episodes in 6- to 60-month-old day care children , especially during influenza season [5819227] Monovalent adjuvant and aqueous influenza vaccines were evaluated in a retirement community from 1964 to 1966 . In the second year of investigation , an epidemic of A2 influenza provided opportunity to study the protective value of immunization . Vaccine efficacy was shown to be related to the pattern of vaccination . Individuals who had received single doses of A2 vaccine in both years of the study were considerably better protected than those who had received vaccine in only one of the years . The rate of febrile illnesses in the former group was more than 90 % below that of vaccinated control . Those given one dose were only about half as well protected . Monovalent adjuvant A2 vaccine given more than a year before the outbreak appeared to protect as well as , if not slightly better than , monovalent aqueous vaccine administered several months before the epidemic [17142512] OBJECTIVE . The goal was to evaluate the safety , tolerability , and efficacy of an investigational , refrigerator-stable formulation of live attenuated influenza vaccine ( cold-adapted influenza vaccine-trivalent ) against culture-confirmed influenza , acute otitis media , and effectiveness outcomes in young children in day care over 2 consecutive influenza seasons . METHODS . Children 6 to < 36 months of age who were attending day care were assigned r and omly in year 1 to receive 2 doses of vaccine or placebo intranasally , 35 ± 7 days apart . In year 2 , subjects received 1 dose of the same treatment as in year 1 . RESULTS . A total of 1616 subjects ( vaccine : 951 subjects ; placebo : 665 subjects ) in year 1 and 1090 subjects ( vaccine : 640 subjects ; placebo : 450 subjects ) in year 2 were able to be evaluated for efficacy . The mean age at first vaccination was 23.4 ± 7.9 months . In year 1 , the overall efficacy of the vaccine against influenza subtypes similar to the vaccine was 85.4 % ; efficacy was 91.8 % against A/H1N1 and 72.6 % against B. In year 2 , the overall efficacy was 88.7 % ; efficacy was 90.0 % against H1N1 , 90.3 % against A/H3N2 , and 81.7 % against B. Efficacy against all episodes of acute otitis media associated with culture-confirmed influenza was 90.6 % in year 1 and 97.0 % in year 2 . Runny nose or nasal discharge after dose 1 in year 1 was the only reactogenicity event that was significantly more frequent with cold-adapted influenza vaccine-trivalent ( 82.3 % ) than placebo ( 75.4 % ) . CONCLUSIONS . Cold-adapted influenza vaccine-trivalent was well tolerated and effective in preventing culture-confirmed influenza illness in children as young as 6 months of age who attended day care [4984268] Influenza A2 vaccine containing 300 chick-cell agglutination ( CCA ) units per dose of the Hong Kong variant provided a high degree of protection during an outbreak of respiratory illnesses in military personnel in December 1968 and January 1969 . This inactivated chicken embryo-propagated virus vaccine stimulated hemagglutination-inhibition antibody responses that were equivalent to natural infection . Polyvalent vaccine , 1967 formula , was not without some contribution in preventing disease in those who did not receive Hong Kong influenza vaccine . Influenza A2 comprised 56 % of all respiratory illnesses during the outbreak . Virus was isolated in rhesus monkey kidney cultures from pharyngeal washings of a third of the individuals with serologic evidence of infection by influenza A2 [17167134] BACKGROUND The efficacy of influenza vaccines may decline during years when the circulating viruses have antigenically drifted from those included in the vaccine . METHODS We carried out a r and omized , double-blind , placebo-controlled trial of inactivated and live attenuated influenza vaccines in healthy adults during the 2004 - 2005 influenza season and estimated both absolute and relative efficacies . RESULTS A total of 1247 persons were vaccinated between October and December 2004 . Influenza activity in Michigan began in January 2005 with the circulation of an antigenically drifted type A ( H3N2 ) virus , the A/California/07/2004-like strain , and of type B viruses from two lineages . The absolute efficacy of the inactivated vaccine against both types of virus was 77 % ( 95 % confidence interval [ CI ] , 37 to 92 ) as measured by isolating the virus in cell culture , 75 % ( 95 % CI , 42 to 90 ) as measured by either isolating the virus in cell culture or identifying it through real-time polymerase chain reaction , and 67 % ( 95 % CI , 16 to 87 ) as measured by either isolating the virus or observing a rise in the serum antibody titer . The absolute efficacies of the live attenuated vaccine were 57 % ( 95 % CI , -3 to 82 ) , 48 % ( 95 % CI , -7 to 74 ) , and 30 % ( 95 % CI , -57 to 67 ) , respectively . The difference in efficacy between the two vaccines appeared to be related mainly to reduced protection of the live attenuated vaccine against type B viruses . CONCLUSIONS In the 2004 - 2005 season , in which most circulating viruses were dissimilar to those included in the vaccine , the inactivated vaccine was efficacious in preventing laboratory-confirmed symptomatic illnesses from influenza in healthy adults . The live attenuated vaccine also prevented influenza illnesses but was less efficacious . ( Clinical Trials.gov number , NCT00133523 . [20868284] BACKGROUND More efficient methods are needed to manufacture influenza vaccines . This trial compared the efficacy of cell culture-derived influenza vaccine ( CCIV ) and egg-derived trivalent inactivated vaccine ( TIV ) with placebo against laboratory-confirmed influenza illness in healthy adults in the United States , Finl and , and Pol and during the 2007 - 2008 influenza season . METHODS A total of 11,404 study participants aged 18 - 49 years were r and omized equally to receive CCIV ( Optaflu ; n = 3828 ) , TIV ( Agrippal ; n = 3676 ) , or placebo ( n = 3900 ) . Each participant was observed during a 6-month study surveillance period . Nasal and throat swabs for virus isolation and characterization were collected from all patients with influenza-like illness . Vaccine immunogenicity was evaluated in a subset of 1045 participants . RESULTS Efficacy of CCIV and TIV against vaccine-like ( 83.8 % [ 1-sided 97.5 % confidence interval [ CI ] lower limit , 61.0 % ] and 78.4 % [ 1-sided 97.5 % CI lower limit , 52.1 % ] , respectively ) and all circulating influenza virus strains ( 69.5 % [ 1-sided 97.5 % CI lower limit , 55.0 % ] and 63.0 % [ 1-sided 97.5 % lower limit , 46.7 % ] , respectively ) exceeded the Center for Biologics Evaluation and Research efficacy criteria . Immunogenicity of both vaccines exceeded the Center for Biologics Evaluation and Research licensing criteria . Both vaccines were well tolerated , with similar safety profiles . Most solicited reactions were mild to moderate in severity and transient . No vaccination-related serious adverse events were reported ; no withdrawals result ed from vaccine-related adverse events . CONCLUSIONS Both CCIV and TIV were effective in preventing influenza caused by vaccine-like and by all circulating influenza virus strains , were well tolerated , and had good safety profiles . Both vaccines can be considered for annual influenza vaccination campaigns . CLINICAL TRIALS REGISTRATION NCT00630331 [3123619] Although current guidelines target hospital employees who contact high-risk patients as a high priority for influenza immunization , there are few data to support or refute this recommendation . Therefore , the authors enrolled 179 hospital employees in a r and omized double-blind placebo-controlled clinical trial during the 1985–1986 influenza season . Influenza immunization was performed without serious adverse reactions and there was no increase in absenteeism attributable to the vaccination . Among those who developed clinical influenza , there was a trend toward fewer days of illness in the vaccinated group compared with the placebo group ( 6.0 vs. 8.0 , p=0.07 ) . There were no statistically significant differences between subjects receiving influenza vaccine and those receiving the placebo when comparing incidences of influenza-like illness , severities of illness , and sick absenteeism . Influenza immunization of hospital employees was performed at minimal cost and risk but provided little benefit , most likely because of an unexpected drift of the prevalent influenza strain away from the vaccine type [12087523] To evaluate the efficacy of an intranasal , inactivated , virosomal subunit influenza vaccine for prevention of new episodes of acute otitis media ( AOM ) in children with recurrent AOM , 133 children aged 1 - 5 years were r and omized to receive the vaccine ( n=67 ) or no vaccination ( n=66 ) . During a 6-month period , 24 ( 35.8 % ) vaccine recipients had 32 episodes of AOM ; 42 ( 63.6 % ) control subjects had 64 episodes . The overall efficacy of vaccination in preventing AOM was 43.7 % ( 95 % confidence interval , 18.6 - 61.1 ; P=.002 ) . Children vaccinated before influenza season had a significantly better outcome than did those vaccinated after the onset of influenza season . The cumulative duration of middle ear effusion was significantly less in vaccinated children than in control subjects . Data suggest that the intranasal virosomal influenza vaccine might be considered among the options for the prevention of AOM in children < 5 years old with recurrent AOM [2639595] Background Our aim was to determine the efficacy of a trivalent inactivated split virus influenza vaccine ( TIV ) against culture-confirmed influenza A and /or B in adults 18 to 64 years of age during the 2005/2006 season in the Czech Republic . Methods 6203 subjects were r and omized to receive TIV ( N = 4137 ) or placebo ( N = 2066 ) . The sample size was based on an assumed attack rate of 4 % which provided 90 % power to reject the hypothesis that vaccine efficacy ( VE ) was ≥ 45 % . Cases of influenza like illness ( defined as fever ( oral temperature ≥37.8 ° C ) plus cough and /or sore throat ) were identified both by active ( biweekly phone contact ) and passive ( self reporting ) surveillance and nasal and throat swabs were collected from subjects for viral culture . Results TIV was well tolerated and induced a good immune response . The 2005/2006 influenza season was exceptionally mild in the study area , as it was throughout Europe , and only 46 culture-confirmed cases were found in the study cohort ( 10 influenza A and 36 influenza B ) . Furthermore among the B isolates , 35 were identified as B/Hong Kong 330/2001-like ( B/Victoria/2/87 lineage ) which is antigenically unrelated to the vaccine B strain ( B/Yamagata/16/88 lineage ) . The attack rate in the vaccine group ( 0.7 % ) was not statistically significantly different from the attack rate in the placebo group ( 0.9 % ) . Conclusion Due to the atypical nature of the influenza season during this study we were unable to assess TIV efficacy . This experience illustrates the challenge of conducting a prospect i ve influenza vaccine efficacy trial during a single season when influenza attack rates and drift in circulating strains or B virus lineage match can be difficult to estimate in advance . Trial Registration Clinical trial registery : NCT00197223 [3229554] Background R and omized evidence for vaccine immunogenicity and safety is urgently needed in the setting of p and emics with new emerging infectious agents . We carried out an observational survey to evaluate how many r and omized controlled trials testing 2009 H1N1 vaccines were published among those registered , and what was the time lag from their start to publication and from their completion to publication . Methods PubMed , EMBASE and 9 clinical trial registries were search ed for eligible r and omized controlled trials . The units of the analysis were single r and omized trials on any individual receiving influenza vaccines in any setting . Results 73 eligible trials were identified that had been registered in 2009–2010 . By June 30 , 2011 only 21 ( 29 % ) of these trials had been published , representing 38 % of the r and omized sample size ( 19905 of 52765 ) . Trials starting later were published less rapidly ( hazard ratio 0.42 per month ; 95 % Confidence Interval : 0.27 to 0.64 ; p<0.001 ) . Similarly , trials completed later were published less rapidly ( hazard ratio 0.43 per month ; 95 % CI : 0.27 to 0.67 ; p<0.001 ) . R and omized controlled trials were completed promptly ( median , 5 months from start to completion ) , but only a minority were subsequently published . Conclusions Most registered r and omized trials on vaccines for the H1N1 p and emic are not published in the peer- review ed literature [3256242] Please cite this paper as : Ambrose et al. ( 2011 ) An integrated , multi study analysis of the safety of Ann Arbor strain live attenuated influenza vaccine in children aged 2–17 years . Influenza and Other Respiratory Viruses 5(6 ) , 389–397 . Background Trivalent , Ann Arbor strain , live attenuated influenza vaccine ( LAIV ) is approved in several countries for use in eligible children aged ≥2 years . Objective To describe the safety of Ann Arbor strain LAIV in children aged 2–17 years . Methods An integrated analysis of r and omized , controlled trials of LAIV . Results A total of 4245 and 10 693 children received ≥1 dose of LAIV in year 1 of 6 trivalent inactivated influenza vaccine (TIV)‐controlled and 14 placebo‐controlled studies , respectively ; 3212 children were revaccinated in year 2 of 4 placebo‐controlled studies . Compared with placebo for days 0–10 post‐vaccination , LAIV recipients exhibited increased runny/stuffy nose ( + 7 % ) , headache ( + 7 % ) , and tiredness/decreased activity ( + 2 % ) after dose 1 ; and a higher rate of decreased appetite ( + 4 % ) after year 2 revaccination . Compared with TIV , only runny/stuffy nose was increased ( dose 1 , + 12 % ; dose 2 , + 4 % ) . Compared with initial vaccination , LAIV reactogenicity was lower after dose 2 in year 1 and revaccination in year 2 . Unsolicited adverse events ( AEs ) increased with LAIV in some comparisons were headache , nasal congestion/rhinorrhea , rhinitis , and pyrexia ; ear pain and lower respiratory illness were decreased . There was no evidence of an increase in any potential vaccine‐related serious AE in LAIV recipients . Among children aged 2–17 years and specifically aged 24–35 months , there was no evidence that lower respiratory illness or wheezing illness occurred at a higher rate in LAIV recipients . Conclusion This analysis supports the safety of Ann Arbor strain LAIV in children aged 2–17 years and provides a consensus assessment of events expected after vaccination [831465] The reactogenicity , immunogenicity and protection effecacy of a serum inhibitor-resistant live attenuated influenza A/B ( " Alice"/R-75 ) vaccine was determined in a group of health young volunteers . The influenza A component was derived from A/Engl and /42/72 ( H3N2 ) strain , and the B component from B/Hong Kong/5/72 strain . Sixty-eight subjects had hemagglutination inhibition ( HAI ) antibody titers to influenza A hemagglutinin ( HA ) antigen of less than or equal to 1:8 ( " low A " group ) and 75 had similarly low antibody titers to B HA antigen ( " low B " group ) . Two inocula given 14 days apart consisted of vaccine in two doses ( VV ) ; one dose of vaccine followed by placebo ( VP ) ; or two doses of placebo ( PP ) . The reactogenicity of the vaccine was low , with approximately 25 % of subjects in both the immunized and placebo categories having symptoms mainly of respiratory nature . The A component of the vaccine was immunogenic with 90.9 % of the subjects in the low A group VV category showing seroconversion . By contrast , only 20 % of VV subjects in the low B group seroconverted to B antigen . The vaccine afforded significant protection againndergone a slight antigenic drift . There was no difference in protection afforded either by one or two doses of the vaccine . Thus the overall protection efficacy following at least one dose of the vaccine was 80.0 % ( p = .01 ) , and in the low A group subjects it was 85.5 % ( p = .01 ) [9580647] BACKGROUND Influenzavirus vaccine is used infrequently in healthy children , even though the rates of influenza in this group are high . We conducted a multicenter , double-blind , placebo-controlled trial of a live attenuated , cold-adapted , trivalent influenzavirus vaccine in children 15 to 71 months old . METHODS Two hundred eighty-eight children were assigned to receive one dose of vaccine or placebo given by intranasal spray , and 1314 were assigned to receive two doses approximately 60 days apart . The strains included in the vaccine were antigenically equivalent to those in the inactivated influenzavirus vaccine in use at the time . The subjects were monitored with viral cultures for influenza during the subsequent influenza season . A case of influenza was defined as an illness associated with the isolation of wild-type influenzavirus from respiratory secretions . RESULTS The intranasal vaccine was accepted and well tolerated . Among children who were initially seronegative , antibody titers increased by a factor of four in 61 to 96 percent , depending on the influenza strain . Culture-positive influenza was significantly less common in the vaccine group ( 14 cases among 1070 subjects ) than the placebo group ( 95 cases among 532 subjects ) . The vaccine efficacy was 93 percent ( 95 percent confidence interval , 88 to 96 percent ) against culture-confirmed influenza . Both the one-dose regimen ( 89 percent efficacy ) and the two-dose regimen ( 94 percent efficacy ) were efficacious , and the vaccine was efficacious against both strains of influenza circulating in 1996 - 1997 , A(H3N2 ) and B. The vaccinated children had significantly fewer febrile illnesses , including 30 percent fewer episodes of febrile otitis media ( 95 percent confidence interval , 18 to 45 percent ; P<0.001 ) . CONCLUSIONS A live attenuated , cold-adapted influenzavirus vaccine was safe , immunogenic , and effective against influenza A(H3N2 ) and B in healthy children [12449696] The formation of immunity and epidemiological effectiveness of inactivated influenza vaccines in children , regularly immunized against influenza for three years , were evaluated . The study revealed that a year after each immunization the number of children having antibodies in liters regarded as protective decreased 2 - 2.5 times . At the periods of epidemics morbidity rate among the vaccines dynamically decreased in these years 1.3 , 2.0 and 2.8 times . Considering that a year after the second immunization a high immune stratum ( 60 - 78 % ) was retained in the group under study , we propose that annual immunization of the same children be limited by a period of three years , followed by an interval of one year [17596805] Background : This study was design ed to evaluate the efficacy and safety of cold-adapted influenza vaccine , trivalent ( CAIV-T ) against culture-confirmed influenza in children 12 to < 36 months of age during 2 consecutive influenza seasons at multiple sites in Asia . Methods : In year 1 , 3174 children 12 to < 36 months of age were r and omized to receive 2 doses of CAIV-T ( n = 1900 ) or placebo ( n = 1274 ) intranasally ≥28 days apart . In year 2 , 2947 subjects were rer and omized to receive 1 dose of CAIV-T or placebo . Results : Mean age at enrollment was 23.5 ± 7.4 months . In year 1 , efficacy of CAIV-T compared with placebo was 72.9 % [ 95 % confidence interval ( CI ) : 62.8–80.5 % ] against antigenically similar influenza subtypes , and 70.1 % ( 95 % CI : 60.9–77.3 % ) against any strain . In year 2 , revaccination with CAIV-T demonstrated significant efficacy against antigenically similar ( 84.3 % ; 95 % CI : 70.1–92.4 % ) and any ( 64.2 % ; 95 % CI : 44.2–77.3 % ) influenza strains . In year 1 , fever , runny nose/nasal congestion , decreased activity and appetite , and use of fever medication were more frequent with CAIV-T after dose 1 . Runny nose/nasal congestion after dose 2 ( year 1 ) and dose 3 ( year 2 ) and use of fever medication after dose 3 ( year 2 ) were the only other events reported significantly more frequently in CAIV-T recipients . Conclusions : CAIV-T was well tolerated and effective in preventing culture-confirmed influenza illness over multiple and complex influenza seasons in young children in Asia [8653819] Reported is a study of live , cold-adapted ( CA ) reassortant mono- , di- , and trivalent influenza type A and B vaccines in a series of controlled clinical and epidemiological investigations involving nearly 130 000 children aged 3 - 15 years . The results of clinical , immunological , and morbidity investigations of the vaccinees and a control group over 6-months ' follow-up indicated that the vaccines were completely attenuated by the children . Transient febrile reactions occurred in < 1 % of the children after vaccination , including double seronegative individuals with low antibody titres . The type A reisolates examined were genetically stable . The reassortants did not suppress each other after simultaneous inoculation of children and stimulated antibody response to influenza virus strains A1 , A3 , and B. The incidence of influenza-like diseases was approximately 30 - 40 % lower among the vaccinated group than among the control group . The study demonstrates , for the first time , the efficacy of CA vaccine against infections caused by influenza B virus [19909082] BACKGROUND A new trivalent inactivated split-virus influenza vaccine ( TIV ) was recently introduced in the United States . We assessed the efficacy of TIV against culture-confirmed influenza A and /or B. METHODS In this double-blind trial conducted from September 2006 to May 2007 in the Czech Republic and Finl and , participants aged 18 - 64 years were r and omized to receive 1 dose of TIV ( n = 5103 ) or placebo ( n = 2549 ) . Influenza-like illnesses ( ILI ) ( defined as at least 1 systemic symptom [ fever { oral temperature , > or = 37.8 degrees C } and /or myalgia ] and at least 1 respiratory symptom [ cough and /or sore throat ] ) were identified by both active ( biweekly phone contact ) and passive surveillance . Nasal and throat swab specimens were collected for viral culture . RESULTS The attack rate for culture-confirmed ILI was 3.2 % in the placebo group , with most strains identified as influenza A ( all except 1 were H3N2 ) matching the vaccine strain . There were 6 cases of influenza B , all of which were of a different lineage ( Yamagata ) than the vaccine strain . Vaccine efficacy against culture-confirmed influenza A and /or B due to strains antigenically matched to the vaccine was 66.9 % ( 95 % confidence interval [ CI ] , 51.9%-77.4 % ; P < .001 ) and to any strain was 61.6 % ( 95 % CI , 46.0%-72.8 % ; P < .001 ) . CONCLUSION TIV is efficacious against culture-confirmed influenza in healthy adults . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT00363870 [8376833] Children aged 7 - 14 years in Novgorod , Russia , were given Russian live cold-adapted or inactivated influenza vaccines or placebo over a 2-year period . Schools were r and omly assigned as a whole to one of the preparations . In the first year , the vaccines were bivalent , containing types A ( H3N2 ) and A ( H1N1 ) components . In the second year , the vaccines also contained a type B component . In the first year , all viruses isolated were type A ( H3N2 ) ; in the second , about three-quarters of the isolates were type B and the rest type A ( H1N1 ) . During both years , the vaccines protected the vaccinated children . Where significant differences existed , the live attenuated vaccine was more protective than the inactivated . Vaccination rates in schools in which live attenuated vaccines had been used were inversely related to illness rates of staff and unvaccinated children , suggesting that viral transmission had been reduced by the vaccine [3337087] Inactivated influenza virus vaccine efficacy after annual revaccination has been reported to be less than that after first vaccination in boarding school children . We prospect ively examined the immunogenicity and efficacy of this vaccine in healthy 30- to 60-year-old volunteers in Houston , Texas , over two epidemic seasons ( 1983 - 1985 ) encompassing outbreaks due to influenza A ( H3N2 and H1N1 ) and influenza B viruses . A placebo group that had never ( or not in recent years ) received inactivated influenza virus vaccine , a group that received the vaccine for the first time ( first vac ) , and a group given two or more recent vaccinations ( multivac ) were evaluated in a double-blind fashion each year . Vaccination induced higher frequencies of rise in serum antibody titer to vaccine components in first vac than in multivac volunteers , but mean postvaccination titers were similar . Clinical and virologic evaluations of illnesses during both epidemics and of influenza infections diagnosed serologically over the epidemic seasons revealed no overall reduction in illness from that in the placebo group for either vaccine group ; modest reductions in influenza infection-related illness that were significant only for the multivac group against A/H3N2-related illness ( 55 % ; p less than 0.04 ) ; reduction in moderate-to-severe lower respiratory and /or systemic illness due to influenza for multivac ( 73 % , p less than 0.025 ) but not first vac ( 15 % , p greater than 0.10 ) volunteers during the A/H3N2 epidemic ; reduction in influenza virus shedding in the multivac ( 54 % , p less than 0.05 ) but not the first vac ( 16 % , p greater than 0.10 ) group when compared with the placebo group for both years ; and overall 63 - 81 % reductions in documented infections with each influenza virus for both vaccine groups with the exception of A/H1N1 for the first vac group ( 24 % , p greater than 0.10 ) and type B for the multivac group ( 58 % , p = 0.067 ) . Vaccine efficacy was only modest in these studies , but in contrast to the earlier report in boarding school children , efficacy appeared to be somewhat greater after repeated annual vaccination than after first administration [4605401] The appearance of the p and emic A/Hong Kong/1/68 ( H3N2 ) influenzavirus strain provided an opportunity for a clinical field trial of influenza vaccines in Canada during the winter of 1968 - 69 . As by November 1968 there were reports of influenza B activity and as supplies of A2/HK/68 vaccines were limited , it was decided to make a series of strictly r and omized double-blind trials comparing A2/HK/68 vaccines not only with B/Mass/66 vaccines but also with a bivalent vaccine that was already in production and contained B/Mass/66 and A2/Mtl/68 , the latter a strain isolated in Canada during January 1968 . In 4 trials , a total of 13 729 military personnel and 4 795 primary schoolchildren were vaccinated . Reported vaccine reactions were less than 0.1 % with zonally-purified vaccines and 2.6 % with the " st and ard " aqueous killed bivalent vaccine . Three children had serious reactions . Surveillance detected an outbreak of influenza in the first two trials on the military . The 3 vaccines containing A2 strains gave similar clinical protection conservatively estimated at 42 - 55 % but probably about 80 % . The effectiveness of the A2/Mtl/68 vaccine , which was in production before the Hong Kong variant had been isolated , was unexpected . In the absence of a vaccine specific to a new p and emic strain , it should not be assumed that a vaccine made from another recent strain could not be useful [396336] Three groups of children were immunized with an inactivated Port Chalmers ( H3ChN2Ch ) influenza vaccine ( group A ) , a neuraminidase-specific ( Heq1N2Ch ) influenza vaccine ( group B ) , or a placebo . Immunization induced seroconversion for H3Ch and N2Ch-specific antibody in group A and for N2Ch antibody in group B. The protective efficacies observed against naturally acquired illness with the Port Chalmers strain of influneza A virus were 68.7 % and 37.4 % in groups A and B , respectively , in comparison to the placebo group , and those against illness produced by the subsequent outbreak of the Victoria strain were 80.0 % and 72.7 % . These data support the role of neuraminidase-specific immunization in protection against influenza . Although the degree of protection after vaccination with the Heq1N2Ch vaccine was less than that provided by the biphasic H3ChN2Ch vaccine against the Port Chalmers strain , it appeared to be similar in the two vaccine study groups against the Victoria strain [11319482] BACKGROUND Studies of influenza vaccination in healthy children have not definitely answered the question of their efficacy . METHODS We have carried out a r and omized trial in a well selected population of healthy preschool children in Sardinia , Italy . During October 1995 , 344 children aged 1 to 6 years , were r and omly assigned to receive influenza vaccine ( n=177 ) or no treatment ( n=167 ) . Two doses of a trivalent subvirion vaccine , containing 15 mg of highly purified surface antigens from the component strains A/Johannesburg/33/94-like , A/Singapore/6/86-like and B/ Beijing/184/ 93-like were administered . Follow-up data were collected from December 1 , 1995 through April 30 , 1996 . RESULTS Seroconversion was documented in 17 out of 17 children . No specific systemic symptoms or severe local reactions were observed after vaccination . Influenza-like episodes , defined by the presence of fever and cough or sore throat that lasted at least 72 hours , occurred in 63 ( 37.7 % ) of unvaccinated children and in 22 ( 12.4 % ) of vaccinated ones . The corresponding reduction in disease incidence was 67 % ( 95 % CI : 0.59 - 0.74 ) . Three episodes of otitis were observed among children in the control group versus zero among vaccinated children ( p=0.07 ) . Mean duration of day care center absenteism was significantly reduced by vaccination ( 2.3 days in unvaccinated and 0.5 day in vaccinated children , p<0.001 ) CONCLUSIONS Influenza vaccine is safe and effective in healthy preschool children . However the favourable implication s of vaccination on disease rate in subsequent years have to be evaluated [4555773] A placebo-controlled influenza vaccination trial was carried out on 374 children in the winter of 1967 - 68 . The children were r and omly vaccinated with 300 CCA of A2/Engl and /1/1966 , 300 CCA of A/equine 2/Miami/1963 , or with a placebo . During this winter an influenza outbreak occurred , caused by A2/Nederl and /1968 . The A2 vaccine yielded a protection rate of 58 % ( P = 0.02 ) and the A/equine 2 vaccine a rate of 19 % ( P = 0.33 ) . Serological data revealed that all influenza infections occurred in subjects who had a pre-epidemic haemagglutination inhibition titre below 150 . The antibody response against various human influenza A2 viruses and against the horse strain ( A/equine 2 ) is discussed [15542184] The aim of this study was to determine the cost effectiveness of influenza vaccination for healthy people aged 65 - 74 years living in the UK . People without risk factors for influenza ( chronic heart , lung or renal disease , diabetic , immunosuppressed or those living in an institution ) were identified from 20 general practitioner ( GP ) practice s in Liverpool in September 1999 . 729/5875 ( 12.4 % ) eligible individuals were recruited and r and omised to receive either influenza vaccine or placebo ( ratio 3:1 ) , with all participants receiving 23-valent-pneumococcal polysaccharide vaccine unless already administered . The primary analysis was the frequency of influenza as recorded by a GP diagnosis of pneumonia or influenza like illness . In 2000 , the UK vaccination policy was changed with influenza vaccine becoming available for all people aged 65 years and over irrespective of risk . As a consequence of this policy change , the study had to be fundamentally restructured and only results obtained over a one rather than the originally planned two-year r and omised controlled trial framework were used . Results from 1999/2000 demonstrated no significant difference between groups for the primary outcome ( relative risk 0.8 , 95 % CI 0.16 - 4.1 ) . In addition , there were no deaths or hospitalisations for influenza associated respiratory illness in either group . The subsequent analysis , using both national and local sources of evidence , estimated the following cost effectiveness indicators : ( 1 ) incremental NHS cost per GP consultation avoided = 2000 pound sterling ; ( 2 ) incremental NHS cost per hospital admission avoided = 61,000 pound sterling ; ( 3 ) incremental NHS cost per death avoided = 1,900,000 pound sterling and ( 4 ) incremental NHS cost per QALY gained = 304,000 pound sterling . The analysis suggested that influenza vaccination in this population would not be cost effective [10411194] CONTEXT Influenza virus is a major cause of illness , disruption to daily life , and increased use of health care in all age groups . OBJECTIVE To assess the safety and effectiveness of intranasally administered trivalent , live , attenuated influenza virus ( LAIV ) vaccine for reducing illness , absenteeism , and health care use among healthy , working adults . DESIGN R and omized , double-blind , placebo-controlled trial conducted from September 1997 through March 1998 . SETTING Thirteen centers across the United States . PARTICIPANTS A total of 4561 healthy , working adults aged 18 to 64 years recruited through health insurance plans , at work sites , and from the general population . INTERVENTION Participants were r and omized 2:1 to receive intranasally administered trivalent LAIV vaccine ( n = 3041 ) or placebo ( n = 1520 ) in the fall of 1997 . MAIN OUTCOME MEASURES Episodes of febrile illness , severe febrile illness , febrile upper respiratory tract illness , work loss , and health care use during the peak and total influenza outbreak periods , and adverse events . RESULTS Recipients of LAIV vaccine were as likely to experience 1 or more febrile illnesses as placebo recipients during peak outbreak periods ( 13.2 % for vaccine vs 14.6 % for placebo ; P=.19 ) . However , vaccination significantly reduced the numbers of severe febrile illnesses ( 18.8 % reduction ; 95 % confidence interval [ CI ] , 7.4%-28.8 % ) and febrile upper respiratory tract illnesses ( 23.6 % reduction ; 95 % CI , 12.7%-33.2 % ) . Vaccination also led to fewer days of illness across all illness syndromes ( 22.9 % reduction for febrile illnesses ; 27.3 % reduction for severe febrile illnesses ) , fewer days of work lost ( 17.9 % reduction for severe febrile illnesses ; 28.4 % reduction for febrile upper respiratory tract illnesses ) , and fewer days with health care provider visits ( 24.8 % reduction for severe febrile illnesses ; 40.9 % reduction for febrile upper respiratory tract illnesses ) . Use of prescription antibiotics and over-the-counter medications was also reduced across all illness syndromes . Vaccine recipients were more likely to experience runny nose or sore throat during the first 7 days after vaccination , but serious adverse events between the groups were not significantly different . The match between the type A(H3N2 ) vaccine strain and the predominant circulating virus strain ( A/Sydney/05/97[H3N2 ] ) for the 1997 - 1998 season was poor , suggesting that LAIV provided substantial cross-protection against this variant influenza A virus strain . CONCLUSION Intranasal trivalent LAIV vaccine was safe and effective in healthy , working adults in a year in which a drifted influenza A virus predominated [2968738] Controlled epidemiological surveillance covering the total number of 13,355 schoolchildren aged 11 - 14 years and adolescents was carried out with a view to compare the efficacies of inactivated influenza vaccines . The children were immunized intradermally in a single injection with inactivated influenza vaccines containing A ( H3N2 ) and A ( H1N1 ) hemagglutinins , 3.5 micrograms per 0.2 ml of the preparation each . The studies demonstrated the safety and low reactogenicity of these vaccines , as well as their high antigenic potency . In 1984 during mixed influenza B + A ( H1N1 ) epidemic the preparations produced a pronounced prophylactic effect : the efficacy indices were 1.6 - 1.9 ( p less than 0.001 ) . The results obtained in these studies made it possible to recommend two inactivated influenza vaccines ( chromatographic and centrifugal ) for practical medicine with the aim of protecting children aged 11 years and over from influenza [7666874] BACKGROUND Although influenza causes substantial morbidity and mortality in all age groups , current recommendations emphasize annual immunization for people at high risk for complications of influenza . We conducted a double-blind , placebo-controlled trial of vaccination against influenza in healthy , working adults . METHODS In the fall of 1994 , we recruited working adults from 18 to 64 years of age from in and around the Minneapolis-St . Paul area and r and omly assigned them to receive either influenza vaccine or placebo injections . The primary study outcomes included upper respiratory illnesses , absenteeism from work because of upper respiratory illnesses , and visits to physicians ' offices for upper respiratory illnesses . The economic benefits of vaccination were analyzed by estimating the direct and indirect costs associated with immunization and with upper respiratory illnesses . RESULTS We enrolled a total of 849 subjects . Baseline characteristics were similar in the two groups . During the follow-up period , consisting of the 1994 - 1995 influenza season ( December 1 , 1994 , through March 31 , 1995 ) , those who received the vaccine reported 25 percent fewer episodes of upper respiratory illness than those who received the placebo ( 105 vs. 140 episodes per 100 subjects , P < 0.001 ) , 43 percent fewer days of sick leave from work due to upper respiratory illness ( 70 vs. 122 days per 100 subjects , P = 0.001 ) , and 44 percent fewer visits to physicians ' offices for upper respiratory illnesses ( 31 vs. 55 visits per 100 subjects , P = 0.004 ) . The cost savings were estimated to be $ 46.85 per person vaccinated . CONCLUSIONS Vaccination against influenza has substantial health-related and economic benefits for healthy , working adults [9382404] A quantitative systematic review , or meta- analysis , uses statistical methods to combine the results of multiple studies . Meta-analyses have been done for systematic review s of therapeutic trials , diagnostic test evaluations , and epidemiologic studies . Although the statistical methods involved may at first appear to be mathematically complex , their purpose is simple : They are trying to answer four basic questions . Are the results of the different studies similar ? To the extent that they are similar , what is the best overall estimate ? How precise and robust is this estimate ? Finally , can dissimilarities be explained ? This article provides some guidance in underst and ing the key technical aspects of the quantitative approach to these questions . We have avoided using equations and statistical notations ; interested readers will find implementations of the described methods in the listed references . We focus here on the quantitative synthesis of reports of r and omized , controlled , therapeutic trials because far more meta-analyses on therapeutic studies than on other types of studies have been published . For practical reasons , we present a stepwise description of the tasks that are performed when statistical methods are used to combine data . These tasks are 1 ) deciding whether to combine data and defining what to combine , 2 ) evaluating the statistical heterogeneity of the data , 3 ) estimating a common effect , 4 ) exploring and explaining heterogeneity , 5 ) assessing the potential for bias , and 6 ) presenting the results . Deciding Whether To Combine Data and Defining What To Combine By the time one performs a quantitative synthesis , certain decisions should already have been made about the formulation of the question and the selection of included studies . These topics were discussed in two previous articles in this series [ 1 , 2 ] . Statistical tests can not compensate for lack of common sense , clinical acumen , and biological plausibility in the design of the protocol of a meta- analysis . Thus , a reader of a systematic review should always address these issues before evaluating the statistical methods that have been used and the results that have been generated . Combining poor- quality data , overly biased data , or data that do not make sense can easily produce unreliable results . The data to be combined in a meta- analysis are usually either binary or continuous . Binary data involve a yes/no categorization ( for example , death or survival ) . Continuous data take a range of values ( for example , change in diastolic blood pressure after antihypertensive treatment , measured in mm Hg ) . When one is comparing groups of patients , binary data can be summarized by using several measures of treatment effect that were discussed earlier in this series [ 3 ] . These measures include the risk ratio ; the odds ratio ; the risk difference ; and , when study duration is important , the incidence rate . Another useful clinical measure , the number needed to treat ( NNT ) , is derived from the inverse of the risk difference [ 3 ] . Treatment effect measures , such as the risk ratio and the odds ratio , provide an estimate of the relative efficacy of an intervention , whereas the risk difference describes the intervention 's absolute benefit . The various measures of treatment effect offer complementary information , and all should be examined [ 4 ] . Continuous data can be summarized by the raw mean difference between the treatment and control groups when the treatment effect is measured on the same scale ( for example , diastolic blood pressure in mm Hg ) , by the st and ardized mean difference when different scales are used to measure the same treatment effect ( for example , different pain scales being combined ) , or by the correlation coefficients between two continuous variables [ 5 ] . The st and ardized mean difference , also called the effect size , is obtained by dividing the difference between the mean in the treatment group and the mean in the control group by the SD in the control group . Evaluating the Statistical Heterogeneity of the Data This step is intended to answer the question , Are the results of the different studies similar ( homogeneous ) ? It is important to answer this question before combining any data . To do this , one must calculate the magnitude of the statistical diversity ( heterogeneity ) of the treatment effect that exists among the different sets of data . Statistical diversity can be thought of as attributable to one or both of two causes . First , study results can differ because of r and om sampling error . Even if the true effect is the same in each study , the results of different studies would be expected to vary r and omly around the true common fixed effect . This diversity is called the within- study variance . Second , each study may have been drawn from a different population , depending on the particular patients chosen and the interventions and conditions unique to the study . Therefore , even if each study enrolled a large patient sample , the treatment effect would be expected to differ . These differences , called r and om effects , describe the between- study variation with regard to an overall mean of the effects of all of the studies that could be undertaken . The test most commonly used to assess the statistical significance of between- study heterogeneity is based on the chi-square distribution [ 6 ] . It provides a measure of the sum of the squared differences between the results observed and the results expected in each study , under the assumption that each study estimates the same common treatment effect . A large total deviation indicates that a single common treatment effect is unlikely . Any pooled estimate calculated must account for the between- study heterogeneity . In practice , this test has low sensitivity for detecting heterogeneity , and it has been suggested that a liberal significance level , such as 0.1 , should be used [ 6 ] . Estimating a Common Effect The questions that this step tries to answers are , 1 ) To the extent that data are similar , what is their best common point estimate of a therapeutic effect , and 2 ) how precise is this estimate ? The mathematical process involved in this step generally involves combining ( pooling ) the results of different studies into an overall estimate . Compared with the results of individual studies , pooled results can increase statistical power and lead to more precise estimates of treatment effect . Each study is given a weight according to the precision of its results . The rationale is that studies with narrow CIs should be weighted more heavily than studies with greater uncertainty . The precision is generally expressed by the inverse of the variance of the estimate of each study . The variance has two components : the variance of the individual study and the variance between different studies . When the between- study variance is found to be or assumed to be zero , each study is simply weighted by the inverse of its own variance , which is a function of the study size and the number of events in the study . This approach characterizes a fixed-effects model , as exemplified by the Mantel-Haenszel method [ 7 , 8 ] or the Peto method [ 9 ] for dichotomous data . The Peto method has been particularly popular in the past . It has the advantage of simple calculation ; however , although it is appropriate in most cases , it may introduce large biases if the data are unbalanced [ 10 , 11 ] . On the other h and , r and om-effects models also add the between- study variance to the within- study variance of each individual study when the pooled mean of the r and om effects is calculated . The r and om-effects model most commonly used for dichotomous data is the DerSimonian and Laird estimate of the between- study variance [ 12 ] . Fixed- and r and om-effects models for continuous data have also been described [ 13 ] . Pooled results are generally reported as a point estimate and CI , typically a 95 % CI . Other quantitative techniques for combining data , such as the Confidence Profile Method [ 14 ] , use Bayesian methods to calculate posterior probability distributions for effects of interest . Bayesian statistics are based on the principle that each observation or set of observations should be viewed in conjunction with a prior probability describing the prior knowledge about the phenomenon of interest [ 15 ] . The new observations alter this prior probability to generate a posterior probability . Traditional meta- analysis assumes that nothing is known about the magnitude of the treatment effect before r and omized trials are performed . In Bayesian terms , the prior probability distribution is noninformative . Bayesian approaches may also allow the incorporation of indirect evidence in generating prior distributions [ 14 ] and may be particularly helpful in situations in which few data from r and omized studies exist [ 16 ] . Bayesian analyses may also be used to account for the uncertainty introduced by estimating the between- study variance in the r and om-effects model , leading to more appropriate estimates and predictions of treatment efficacy [ 17 ] . Exploring and Explaining Heterogeneity The next important issue is whether the common estimate obtained in the previous step is robust . Sensitivity analyses determine whether the common estimate is influenced by changes in the assumptions and in the protocol for combining the data . A comparison of the results of fixed- and r and om-effects models is one such sensitivity analysis [ 18 ] . Generally , the r and om-effects model produces wider CIs than does the fixed-effects model , and the level of statistical significance may therefore be different depending on the model used . The pooled point estimate per se is less likely to be affected , although exceptions are possible [ 19 ] . Other sensitivity analyses may include the examination of the residuals and the chi-square components [ 13 ] and assessment of the effect of deleting each study in turn . Statistically significant results that depend on a single study may require further exploration . Cumulative Meta- Analysis [20935591] Background : Acute otitis media ( AOM ) is a frequent complication of influenza in young children . Influenza vaccination is known to protect against AOM by preventing influenza illness . We sought to determine the efficacy of the live attenuated influenza vaccine ( LAIV ) against influenza-associated AOM compared with placebo and trivalent inactivated influenza vaccine ( TIV ) . LAIV is approved for eligible children aged ≥2 years in the United States and in several other countries . Methods : AOM incidence data from 6 r and omized , double-blind , placebo-controlled trials and 2 r and omized , double-blind , TIV-controlled trials in children 6 to 83 months of age were pooled and analyzed . Results : A total of 290 cases of AOM were identified in 24,046 study subjects . LAIV efficacy against influenza-associated AOM was 85.0 % ( 95 % confidence interval [ CI ] , 78.3%–89.8 % ) compared with placebo and 54.0 % ( 95 % CI , 27.0%–71.7 % ) compared with TIV . Efficacy trended higher in those ≥24 months of age compared with those aged 6 to 23 months . In placebo-controlled trials , among children who acquired influenza despite vaccination , AOM was diagnosed in 10.3 % of LAIV recipients and 16.8 % of placebo recipients , representing a 38.2 % ( 95 % CI , 11.0%–58.2 % ) relative reduction in the development of AOM . In TIV-controlled studies , among subjects with breakthrough influenza illness , the proportions of LAIV and TIV recipients who developed AOM were similar . Conclusions : Children receiving LAIV had a high level of protection against influenza-associated AOM when compared with placebo or TIV . This was most evident in children older than 2 years , for whom LAIV is indicated . LAIV recipients who contracted breakthrough influenza illness despite vaccination developed AOM at a significantly lower rate than did unvaccinated children who developed influenza [10979921] A r and omized , blinded , pilot study of influenza vaccine administered to children attending day care centers was conducted during the 1996 - 1997 winter . Vaccine efficacy in preventing serologically proven influenza virus infection was 0.45 ( 95 % confidence limit [ CL ] : -0.02 , 0.69 ) for influenza B and 0.31 ( 95 % CL : -0.95 , 0.73 ) for influenza A(H3N2 ) . For both influenza A(H3N2 ) and B , children without preexisting hemagglutination inhibition ( HI ) antibody to these antigens had lower antibody responses to vaccine , were less likely to develop a serological response , and were more likely to develop serological evidence of influenza infection . Although there were no reductions in respiratory or febrile respiratory illnesses among all vaccinated children , there was a trend for reductions in such illnesses among vaccinated children with preexisting HI antibodies to influenza A(H3N2 ) and B. Therefore , immunologic priming in young children may be important for vaccine response and for protection against infection . Larger studies are needed in other influenza seasons to assess vaccine efficacy and clinical effectiveness [11015795] CONTEXT Although the cost-effectiveness and cost-benefit of influenza vaccination are well established for persons aged 65 years or older , the benefits for healthy adults younger than 65 years are less clear . OBJECTIVE To evaluate the effectiveness and cost-benefit of influenza vaccine in preventing influenza-like illness ( ILI ) and reducing societal costs of ILI among healthy working adults . DESIGN Double-blind , r and omized , placebo-controlled trial conducted during 2 influenza seasons . SETTING AND PARTICIPANTS Healthy adults aged 18 to 64 years and employed full-time by a US manufacturing company ( for 1997 - 1998 season , n = 1184 ; for 1998 - 1999 season , n = 1191 ) . INTERVENTIONS For each season , participants were r and omly assigned to receive either trivalent inactivated influenza vaccine ( n = 595 in 1997 - 1998 and n = 587 in 1998 - 1999 ) or sterile saline injection ( placebo ; n = 589 in 1997 - 1998 and n = 604 in 1998 - 1999 ) . Participants in 1997 - 1998 were rer and omized if they participated in 1998 - 1999 . MAIN OUTCOME MEASURES Influenza-like illnesses and associated physician visits and work absenteeism reported in biweekly question naires by all participants , and serologically confirmed influenza illness among 23 % of participants in each year ( n = 275 in 1997 - 1998 ; n = 278 in 1998 - 1999 ) ; societal cost of ILI per vaccinated vs unvaccinated person . RESULTS For 1997 - 1998 and 1998 - 1999 , respectively , 95 % ( 1130/1184 ) and 99 % ( 1178/1191 ) of participants had complete follow-up , and 23 % in each year had serologic testing . In 1997 - 1998 , when the vaccine virus differed from the predominant circulating viruses , vaccine efficacy against serologically confirmed influenza illness was 50 % ( P = .33 ) . In this season , vaccination did not reduce ILI , physician visits , or lost workdays ; the net societal cost was $ 65.59 per person compared with no vaccination . In 1998 - 1999 , the vaccine and predominant circulating viruses were well matched . Vaccine efficacy was 86 % ( P = .001 ) , and vaccination reduced ILI , physician visits , and lost workdays by 34 % , 42 % , and 32 % , respectively . However , vaccination result ed in a net societal cost of $ 11.17 per person compared with no vaccination . CONCLUSION Influenza vaccination of healthy working adults younger than 65 years can reduce the rates of ILI , lost workdays , and physician visits during years when the vaccine and circulating viruses are similar , but vaccination may not provide overall economic benefits in most years . JAMA . 2000;284:1655 - 1663 [2180233] A reassortant cold-adapted ( ca ) influenza B experimental live attenuated intranasal vaccine was evaluated for safety and immunogenicity in children by means of a blind , placebo controlled study . The vaccine contained the haemagglutinin and neuraminidase genes , and the gene for its non-structural proteins from wild-type ( wt ) B/Ann Arbor/1/86 virus , the contemporary strain at the time of the study . Other genes were derived from ca B/Leningrad/14/55 virus . No increase in illness rates was seen in the children from ages 3 - 15 years given vaccine at maximum potency ( a one in two dilution of infectious allantoic fluid , having a titre of 10(7.0 ) EID50 ) compared to children given placebo . About 60 % of seronegative children , ages 3 - 7 years , exhibited a detectible antibody response following one dose of intranasal vaccine , with the seroresponse rate rising to greater than 70 % after two doses of vaccine . Immunogenicity was lowest in seropositive children age 8 - 15 years , reaching a maximum of 36 % after two doses . Results indicated that the vaccine was highly attenuated , and probably of adequate immunogenicity for kindergarten age children . The lower immunogenicity in older children suggests the vaccine might be overly attenuated for use in school-age children who are more likely to have a history of prior natural infection with influenza B virus . Further clinical and epidemiological studies of protection are needed to fully assess this [1803766] This study was carried out to compare reactogenicity , immunogenicity , and efficacy of live attenuated and inactivated influenza vaccines prepared from influenza A/Philippines/2/82-like virus strains . Schoolchildren of a boarding school of Moscow were r and omly divided into three groups : ( 1 ) vaccinated with a live attenuated vaccine , ( 2 ) vaccinated with inactivated influenza vaccine , and ( 3 ) given placebo . Both vaccines were well tolerated by the children , with practically no severe general or local reactions . The inactivated vaccine was found to be superior to the live one in its capacity to stimulate humoral immunity studied by HI , EIA , and microneutralization tests . In 69.7 % of the children given the inactivated vaccine , seroconversion to the vaccine strain was detected by two or three methods of antibody titration used . Only 35.4 % seroconversions were demonstrated in children immunized with the live influenza vaccine . Enzyme immunoassay was found to be a more sensitive but less specific method for antibody titration as compared with HI test whereas microneutralization proved to be more specific but less sensitive for titration of antibodies to influenza A ( H3N2 ) viruses [4124042] Abstract A trial of inactivated influenza vaccine containing the A/Hong Kong/68 strain was made in 800 boys in a boarding-school starting in 1970 . The boys had serum sample s withdrawn for antibody estimations and were allocated at r and om to vaccine and control groups . During an outbreak of influenza A due to the A/Engl and /42/72 strain , all boys with clinical influenza reported to the medical officer and the diagnosis was confirmed by laboratory examination . The vaccine was shown to confer substantial protection against the new virus strain . The presence of haemagglutinating ( H.I. ) antibody to either strain 6 weeks before the outbreak was associated with protection against influenza . In boys with H.I. antibody to A/Hong Kong/68 virus the attack-rate was 6 % , compared with 25 % in boys with no H.I. antibody to either virus strain . No influenza occurred in boys known to have H.I. antibody to the A/Engl and /42/72 strain . Three-quarters of the boys in whom A/Hong Kong/68 H.I. antibody had been naturally acquired developed A/Engl and / 42/72 H.I. antibody after vaccination . In contrast , the development of A/Engl and /42/72 H.I. antibody was less frequent after revaccination of boys in whom the A/Hong Kong/68 H.I. antibody had been induced by vaccination . A vaccine prepared from the A/Hong Kong/68 strain conferred substantial protection despite the recent antigenic shift of the influenza virus [5115671] Albert Leibovitz , * Raymond L. Coultrip , Edwin D. Kilbourne , Llewellyn J. Legters , Creed D. Smith , James Chin , and Jerome L. Schulman From the Sixth U.S. Army Medical Laboratory , Fort Baker , California ; Preventive Medicine Division , Office of the Surgeon , Fort Ord , California ; Department of Microbiology , Mount Sinai School of Medicine , City University of New York , New York ; and the Infectious Disease Element , California State Department of Public Health , Berkeley , [7769297] This study evaluated the safety , immunogenicity , and protective efficacy of vaccines containing purified recombinant uncleaved hemagglutinin ( rHA0 ) from influenza A/Beijing/32/92 ( H3N2 ) virus . In a r and omized , double-blinded trial , 127 adult volunteers were immunized with 15 micrograms of rHA0 , 15 micrograms of rHA0 plus alum , 90 micrograms of rHA0 , licensed subvirion vaccine , or saline placebo . The rHA0 vaccines caused fewer local adverse reactions than did the commercial subvirion preparation . Neutralizing hemagglutinin-specific antibody responses to 15 micrograms of rHA0 were comparable to those elicited by licensed vaccine , not enhanced by the addition of alum , and significantly increased by raising the rHA0 dose from 15 to 90 micrograms . Compared with placebo recipients , rHA0-vaccinated subjects had significantly lower rates of influenza A ( H3N2 ) virus infection and illness during the epidemic winter season . These results suggest that influenza vaccines containing purified rHA0 may offer an advantage over licensed preparations containing egg-grown antigens by inducing equivalent protective immune responses while being potentially less reactogenic [9269055] Some reports have suggested that influenza virus vaccine is less effective in persons that have received prior annual vaccination(s ) than in those receiving it for the first time . This issue was addressed by evaluating the efficacy of annual influenza vaccinations over a 5 year period in healthy adults employing commercially-available , inactivated whole-virus vaccine . Influenza vaccination had minimal effects on overall respiratory illnesses during epidemic periods . However , it reduced influenza virus shedding by an average of 38.8 % and conferred protection against influenza virus infection during each epidemic . Some variation in infection rates were noted between vaccine groups given one or more than one annual immunization , and between years , but no consistent pattern of differences was noted in relation to number of successive years of vaccination . These results suggest that the current recommendation for annual influenza vaccination of persons at special risk of serious disease and complications is appropriate , but that continued efforts to improve the effectiveness of our prophylactic measures against influenza are needed [2330929] In 1985 , we enrolled 189 school-age children by family in a double-blind study to determine protection against influenza by a single dose of cold-recombinant bivalent A vaccine or commercial trivalent inactivated vaccine compared with placebo . All children in school or day care , 3 to 18 years of age , in an enrolled family received the same preparation . Following vaccination , 60 % and 21 % of cold-recombinant bivalent A vaccine recipients and 73 % and 83 % of trivalent inactivated vaccine recipients demonstrated fourfold or greater response in hemagglutination-inhibition antibody titer to A/H1N1 and A/H3N2 , respectively . Sixty-seven percent of all trivalent inactivated vaccine recipients demonstrated a fourfold or greater serologic response to H1N1 , H3N2 , and influenza B following a single dose of vaccine . During the 1985 - 1986 influenza B/Ann Arbor epidemic , heterotypic protection afforded by the influenza B/USSR component of trivalent inactivated vaccine was 62 % compared with placebo . A single dose of trivalent inactivated vaccine protected school-age children , 6 to 19 years of age , from influenza B infection ; the rate of protection was 64 % against infection and 73 % against febrile illness [4559743] The purpose of this field trial on influenza vaccine , which was done with a population of university students , was to compare the aerosol route with the subcutaneous route of vaccine administration and the Hong Kong influenza vaccine with the older A2 influenza vaccine ( " bivalent " vaccine ) . Side-effects of the vaccines were significantly higher in the groups that received the vaccine subcutaneously . There were no more side-effects in those who received vaccine by aerosol . There was a significant reduction in the rate of illness in all groups vaccinated except for the group given bivalent vaccine subcutaneously . Recipents of Hong Kong vaccine had significantly greater protection than did recipients of the bivalent vaccine . Recipients of aerosol vaccine had significantly better protection than did those who received vaccine by the subcutaneous route . The data suggest that protection was closely related to the ability of the vaccine to stimulate nasalsecretion antibody to the A2 Hong Kong influenza virus [18370460] Summary Currently three different inactivated influenza vaccine types are available : whole virus ( WV ) , split ( SPL ) and subunit ( SU ) vaccines . Physicians and patients at risk for influenza complications may wonder whether there are important differences between the vaccine types with respect to antibody induction ( serology ) and adverse effects ( reactogenicity ) . A literature review ( 1975 to 1995 ) was performed to evaluate the serology and reactogenicity of SU vaccines in comparison with either split or whole virus vaccines . 22 publications with r and omised allocation were identified describing a total of 5416 serological observations , 2858 observations of local reactions , and 2990 observations of systemic reactions . Subjects included those from all age groups from children to the elderly . Absolute protection and reaction rate differences ( RD ) were calculated for the comparisons SU vs SPL or SU vs WV vaccine . These were subjected to a method of meta- analysis , result ing in pooled rate differences and their 95 % confidence intervals . With the exception of the comparison SU vs WV vaccine in subjects born after 1957 and unexposed to the reappearing H1N1 subtype after 1977 , no evidence was found to suggest relevant differences in seroresponse among the three currently available inactivated influenza vaccine types . Although insufficient data were available in the meta- analysis for vaccines in children for whom specific recommendations concerning these vaccines exist , adverse events after administration of any of the three vaccine types were generally mild and transitory ; however , SU vaccines were associated with a lower frequency of local and systemic reactions [3905983] We report the safety and antigenicity of influenza A vaccines in seronegative children one to seven years of age . A natural H1N1 challenge that occurred shortly after completion of the vaccination program permitted an evaluation of efficacy . Twenty-eight subjects were inoculated with live cold-adapted ( ca ) influenza A/Washington/897/80 ( H3N2 ) , 29 with ca influenza A/California/10/78 ( H1N1 ) , 24 with inactivated whole-virus influenza A/Bangkok/79 ( H3N2 ) , and 30 with a placebo . The ca vaccines were well tolerated , whereas the inactivated vaccine caused adverse reactions in about one-third of the children . Fifty-seven percent of the ca H1N1 recipients showed serological responses , contrasted with 84 % and 100 % of subjects receiving the ca or inactivated H3N2 vaccines , respectively . None of the 16 children with induced H1N1 antibody developed clinical ly apparent influenza-like illness , compared with eleven of the 51 initially seronegative children who did not receive the ca H1N1 vaccine and with four of the 12 who failed to respond . Results of the efficacy field trial suggest protection against infection and symptomatic illness in children inoculated with ca H1N1 , despite its failure to stimulate high levels of hemagglutinin-inhibiting antibody [8447161] The performance of two doses of cold-adapted live attenuated vaccine versus one dose of whole-virus inactivated vaccine was compared in 8 - 15-year-old schoolchildren in two schools in Moscow , Russia , during the winter of 1987/88 . Both vaccines gave rise to low frequencies of associated febrile or systemic reactions , but the inactivated vaccine , delivered by jet injector , did cause small local reactions in about half of the children . Immunogenicity was higher for both vaccines in antibody-free children , and higher levels of serum antibody were detected following use of inactivated vaccine . During the winter , influenza A ( H3N2 ) and influenza B viruses circulated in Moscow . A clear outbreak of ( H3N2 ) virus occurred in both schools , and infections with type B virus also occurred in one school . The influenza A/Philippines/2/82 ( H3N2 ) component of both vaccines exhibited protective efficacy of about 40 % ( p < 0.05 ) against serologically proven infection caused by the antigenically drifted A/Sichuan/2/87 (H3N2)-like epidemic viruses in one school . In another school where illnesses associated with antibody rise were documented , efficacy was seen for both vaccines in reduction of illnesses , and of illnesses with serological evidence of infection , but statistical significance was not achieved [8091754] Schoolchildren of 30 to 34 schools of Novgorod were vaccinated over a three-year period with Russian live cold-adapted attenuated vaccine for children and whole-virus inactivated vaccines and placebo for comparative field study of the vaccines properties and efficacy . In control trials both bi- and trivalent live attenuated vaccines were well tolerated and areactogenic . A whole-virus inactivated trivalent vaccine induced mild and moderate fever and local reactions in 2 - 4 % of the vaccinees . Special observations are necessary to establish the possibility of use and to determine a dose of this inactivated vaccine for immunization of children , especially those of 7 - 10 years of age . All the vaccines induced HI antibody production in 50 - 80 % and antineuraminidase in 50 - 70 % of seronegative children . The pattern of the results was similar to that in revaccinated children with preexisting antibody at a level of 1:20 , but much lower in children with the initial titre above 1:20 . After the 3rd year of vaccination the immune response of the vaccinees was similar , most of the results depending on the initial antibody titre and also on the change of vaccine strains . This raises a question of the expediency of annual influenza revaccination of the same person after 2 years of successful immunization and of the necessity of vaccine strains replacement after 2 - 3 years of use [11734733] Background . Influenza is a common and potentially serious infection in children . Although there is interest in broadening the use of influenza vaccine in healthy children , there are few large , r and omized , controlled trials that evaluate the safety and efficacy of inactivated vaccine in the pediatric population . Methods . From 1985 through 1990 a r and omized , controlled trial of cold-adapted and inactivated vaccines for the prevention of influenza A disease was conducted at V and erbilt University , and the cumulative results from this trial in patients of all ages have been previously published . We reanalyzed the data from this trial in the subset of patients who were younger than 16 years at the time of their participation . We determined vaccine safety , immunogenicity and efficacy , based on culture-positive illness and seroconversion , in this subset of patients . Results . During the 5 years of the study , 791 children younger than 16 years received 1809 doses of either inactivated or cold-adapted vaccine or placebo . The vaccines were well-tolerated , and there were no serious reactions . Inactivated trivalent influenza vaccines were 91.4 and 77.3 % efficacious in preventing symptomatic , culture-positive influenza A H1N1 and H3N2 illness , respectively . The efficacy of the inactivated vaccine based on hemagglutination inhibition assay seroconversion was 67.1 and 65.5 % , respectively , for H1N1 and H3N2 serotypes . Conclusions . Inactivated trivalent influenza A vaccines are well-tolerated and efficacious in the prevention of influenza A disease in children 1 to 16 years old [3354254] Forty-three school children from 8 to 11 years old were vaccinated intranasally with two doses of a paediatric attenuated influenza vaccine developed by reassortment between cold-adapted A/Leningrad/134/57(H2N2 ) and an A/Brazil/11/78(H1N1)-like strain . Two vaccine doses were administered 1 month apart in a r and omized , blind , placebo-controlled study . Although the first vaccine dose had a low infectivity titre , overall 65 % of children who received two doses of vaccine showed serological evidence of infection by HI tests . Serum IgA antibody responses against the vaccine strain were detected in nearly 50 % of the vaccines and serum IgG antibody responses were detected in approximately equal to 40 % by an enzyme immunoassay [4608708] A trial of influenza A vaccines in general practice is described . Five hundred and seven subjects were vaccinated with either inactivated monovalent A/Hong Kong vaccine , A/Engl and vaccine or influenza B vaccine as control . Local reactions were noted in 24 % and general reactions in 12 % of patients . Antibody titres in serum were measured by haemagglutination inhibition ( HI ) and complement fixation ( CF ) tests in 465 subjects . The influenza vaccines produced substantial increases in both homologous and heterologous antibodies as measured by the HI test and a comparatively poor response as measured by the CF test . Although clinical influenza was confirmed in only a few cases , there was serological evidence of significant sub clinical infection in the control group [3524050] Live cold-adapted recombinant bivalent vaccine of influenza type A was studied in a controlled field trial in 1982 - 1983 among nearly 30,000 children 3 - 15 years old . The bivalent vaccine consisted of recombinants 47/25/1 ( H1N1 ) and 47/7/2 ( H3N2 ) of wild-type viruses A/Brazil/11/78 ( H1N1 ) and A/Bangkok/1/79 ( H3N2 ) with cold-adapted donor A/Leningrad/134/47/57 ( H2N2 ) . The recombinants which received mutant nonglycoprotein genes from cold-adapted donor did not suppress each other after simultaneous inoculation of children and stimulated antibody response to both strains . The bivalent vaccine was completely attenuated for children . It caused less than 1 % transient febrile reactions during five days after the first vaccination , including double seronegative individuals with low antibody titres to both vaccinal strains . The cold-adapted bivalent vaccine tested proved to be safe for children according to the analysis of morbidity studies among vaccines and a control group performed during the five days and the following six months after the first immunization . There is a similar distribution of non-influenza illnesses and a statistically significant decrease in influenza-like diseases among vaccines compared to the control group . In the four months after the immunization programme was completed , epidemics of influenza A H1N1 and H3N2 occurred . The incidence of influenza-like diseases was approximately 50 % less in the vaccinated than in the control groups . This is the first evidence of safety and protective efficacy of recombinant live influenza vaccine for children 3 - 15 years of age [1988512] Children ( n = 192 ) aged 3 - 19 years from 98 families completed this double-blind , placebo-controlled study comparing the efficacy of a bivalent attenuated ( CR ) vaccine with trivalent inactivated ( TI ) vaccine . Both vaccines contained A/Chile/83 (H1N1)-like antigens . After vaccination the geometric mean titer to A/Taiwan/86 ( H1N1 ) was 1:36 in the CR group , 1:92 in the TI group , and 1:5 in the placebo group . During the influenza A/Taiwan/86 ( H1N1 ) epidemic , 21.4 % of CR recipients , 16.7 % of TI recipients , and 43.9 % of placebo recipients were infected with influenza A/Taiwan . TI vaccine provided better heterotypic protection than did CR vaccine for children aged 10 - 18 years ( infection rate , 0 vs. 24 % , respectively ; P less than .025 ) ; in contrast , in the younger children ( 3 - 9 years ) , CR vaccine tended to be more protective ( 19 % vs. 26 % for TI ) [3515812] In the trial of the trivalent subunit influenza vaccine Grippovac CE-AK observations on children aged 3 - 6 years were made . The preparation showed insignificant reactogenicity and moderate antigenic potency . The trial established that at the period of the epidemic rise of influenza B morbidity the vaccine showed , according to the data of the clinical diagnosis of influenza , insignificant effectiveness , its index of effectiveness ( IE ) being 1.08 ; according to the data of the serological diagnosis of influenza , only the A ( H1N1 ) component of the vaccine was found to have IE equal to 1.58 [9854114] BACKGROUND The number of reports of influenza-vaccine-associated Guillain-Barré syndrome to the national Vaccine Adverse Event Reporting System increased from 37 in 1992 - 1993 to 74 in 1993 - 1994 , arousing concern about a possible increase in vaccine-associated risk . METHODS Patients given a diagnosis of the Guillain-Barré syndrome in the 1992 - 1993 and 1993 - 1994 influenza-vaccination seasons were identified in the hospital-discharge data bases of four states . Vaccination histories were obtained by telephone interviews during 1995 - 1996 and were confirmed by the vaccine providers . Disease with an onset within six weeks after vaccination was defined as vaccine-associated . Vaccine coverage in the population was measured through a r and om-digit-dialing telephone survey . RESULTS We interviewed 180 of 273 adults with the Guillain-Barré syndrome ; 15 declined to participate , and the remaining 78 could not be contacted . The vaccine providers confirmed influenza vaccination in the six weeks before the onset of Guillain-Barré syndrome for 19 patients . The relative risk of the Guillain-Barré syndrome associated with vaccination , adjusted for age , sex , and vaccine season , was 1.7 ( 95 percent confidence interval , 1.0 to 2.8 ; P=0.04 ) . The adjusted relative risks were 2.0 for the 1992 - 1993 season ( 95 percent confidence interval , 1.0 to 4.3 ) and 1.5 for the 1993 - 1994 season ( 95 percent confidence interval , 0.8 to 2.9 ) . In 9 of the 19 vaccine-associated cases , the onset was in the second week after vaccination , all between day 9 and day 12 . CONCLUSIONS There was no increase in the risk of vaccine-associated Guillain-Barré syndrome from 1992 - 1993 to 1993 - 1994 . For the two seasons combined , the adjusted relative risk of 1.7 suggests slightly more than one additional case of Guillain-Barré syndrome per million persons vaccinated against influenza [7550814] OBJECTIVE To determine if the use of influenza vaccine in children in day care decreases the incidence of otitis media during the influenza season . DESIGN Prospect i ve cohort study . SETTING Eight day-care centers in North Carolina . PARTICIPANTS One hundred eighty-six children aged 6 to 30 months . INTERVENTION Half the participants received trivalent subvirion influenza virus vaccine . MEASUREMENTS Acute otitis media ( AOM ) and serous otitis media ( SOM ) were assessed biweekly from mid-November 1993 to mid-March 1994 by visual and tympanometric examinations performed by " blinded " observers . The winter season was divided into three periods-before , during , and after influenza season-- and the number of children with AOM or SOM during each period was determined . Unadjusted and adjusted odds ratios ( ORs ) were computed , while controlling for race and sex using logistic regression methods . RESULTS Influenza vaccine was protective against AOM ( OR = 0.69 , 95 % CI , 0.49 - 0.98 ) during the influenza season . Although there may have been some protection against SOM ( OR = 0.75 , 95 % CI , 0.54 - 1.02 ) statistical significance was not achieved . Myringotomy tubes were also significantly protective against AOM and SOM during all three time periods , with ORs between 0.34 and 0.52 , but the greatest protection was seen during the influenza period . CONCLUSIONS Influenza vaccination of 6- to 30-month-old children in day care was associated with a decreased incidence of otitis media during the influenza season . Myringotomy tubes protected against AOM and SOM during all 16 weeks monitored [8277200] A double-blind , r and omized controlled trial over 5 years compared the safety , immunogenicity , and efficacy of cold-adapted and inactivated influenza A vaccines in 5210 normal subjects . Both vaccines were well tolerated . Inactivated vaccine significantly increased hemagglutination inhibition antibody titers . Significant titer rises were also noted after cold-adapted vaccine but of lesser magnitude than with inactivated vaccine . The efficacy of inactivated vaccine in preventing culture-positive influenza was 76 % ( 95 % confidence interval [ CI ] , 58%-87 % ) for H1N1 disease and 74 % ( 95 % CI , 52%-86 % ) for H3N2 ; for cold-adapted vaccine , 85 % ( 95 % CI , 70%-92 % ) and 58 % ( 95 % CI , 29%-75 % ) , respectively . The efficacy of inactivated vaccine in preventing a four-fold rise in antibody titer over the influenza season was 69 % ( 95 % CI , 61%-76 % ) for H1N1 and 73 % ( 95 % CI , 65%-79 % ) for H3N2 ; for cold-adapted vaccine , 54 % ( 95 % CI , 44%-62 % ) and 32 % ( 95 % CI , 17%-44 % ) , respectively . Cold-adapted and inactivated influenza vaccines are safe and effective for preventing influenza A disease [3300032] During the autumn-winter epidemic of influenza-like diseases in December , 1983 - -first quarter , 1984 , in Moscow commissioned coded observations on the effectiveness of prophylactic vaccination against influenza of 3 - 7-year-old children with a preparation " Grippovak SE-AZh " were carried out in day-care centers . In the previous large-scale trials , 1981 - 1984 , the " Grippovak " had been evaluated positively as a completely harmless , serologically and immunologically active preparation reducing 3 - 3.5-fold the number of laboratory-verified cases of viral type A and B influenza in the vaccinees . In 1986 , however , the " Journal of Microbiology , Epidemiology , Immunology " ( JMEI , 2 : 49 - 54 ) published a paper whose authors , on behalf of the Commission which had checked the preparation in the day-care centers ( Z.A. Bashliaeva , A.A. Sumarokov , et al. ) , came to a conclusion that " Grippovak " was ineffective in children . Other members of the above Commission disagreeing with this conclusion made a repeat analysis of the decoded material s of the observations in the day-care centers using computer methods and demonstrated that because of significant prevalence of non-influenza ARD cases and recurrent ( up to 44 % ) ARD cases in children in the 4 months of observation , it was impossible to judge the effectiveness of the vaccine by comparison of the total incidence of influenza and ARD from the clinical data alone in the vaccinees and controls . ( ABSTRACT TRUNCATED AT 250 WORDS [12271720] The study of the based on the A/Leningrad/134/17/57/(H2N2 ) attenuated adult live influenza vaccine ( LIV ) investigated features for immunization of the children , aged 3 - 6 years . During autumn , 1999 , out of 256 children , aged 3 - 6 years , residents of the Leningrad region , who attended the kindergarten , 184 children were immunized with 1 or 2 doses of the live influenza vaccine , and 72 ones were given placebo . There were no any moderate or strong temperature reactions revealed after the inoculation . The LIV was shown to be genetically stable . After a single dose of the vaccine seroconversion to influenza type A virus and to influenza type B virus was observed respectively in 58 % and in 39 % of seronegative 3 - 6 year old vaccinees . The twofold LIV administration failed to give any advantages in stimulation of the immune response . During 6 months after immunization the morbidity rate in vaccinees did not exceed the morbidity rate in unvaccinated children . Thus LIV for adults proved safe and immunogenic and can be recommended for single dose immunization both of adults and children [1803767] A limited controlled comparative study for the evaluation of the epidemiological efficacy of live recombinant and inactivated virion vaccines from A/Philippines/2/82-like strains of influenza A ( H3N2 ) virus was carried out in schoolchildren of 8 to 15 years of age . During the influenza epidemic of 1987 - 1988 caused by influenza A/Sichuan/2/87 (H3N2)-like strains and by influenza B virus in 8.2 - 17 % of cases , a statistically significant efficacy index for live influenza vaccine was 1.8 for the laboratory confirmed A ( H3N2 ) cases . In the group vaccinated with the inactivated vaccine the number of serologically diagnosed A ( H3N2 ) cases was 1.6 times lower than in the group receiving placebo , this difference being statistically significant . Thus , under the conditions of significant difference in the antigenic structure of the vaccine and epidemic A ( H3N2 ) strains , both vaccines produced some diminished but statistically significant preventive effect in vaccinated children although its level was below the optimal . Revaccination of some children with a live influenza vaccine from a new A/Sichuan/2/87-like variant of A ( H3N2 ) virus in the autumn of 1988 with reisolation of the vaccine strain also revealed the presence of some , though weak , resistance to this strain in the children vaccinated with both vaccines [4908340] A field study was undertaken in Tampa , Fla. , to assess the efficacy of subcutaneous and aerosol methods of administering vaccine , and to compare the protection afforded by bivalent ( A2 and B ) influenza virus vaccine and by A2/Hong Kong/68 virus vaccine . Further objectives of the study included a comparison of the effectiveness of single-dose and 2-dose immunization . Approximately 2100 volunteers received , in a double-blind manner , both an injection and an aerosol administration on 2 occasions 3 weeks apart . The results showed that aerosol administration gave a lower over-all protection rate , although the booster dose seemed to have a marked effect . The protection afforded by A2/Hong Kong/68 virus vaccine was considerably greater than that afforded by the bivalent vaccine , particularly when administration was subcutaneous . Results are also given on the occurrence of side-effects and on the correlation between cigarette smoking and the occurrence of influenza-like illness [11715169] OBJECTIVE To determine if a vaccine against influenza significantly decreases episodes of acute upper respiratory infection ( AURI ) and work absenteeism caused by AURI , in healthy adult employees of a banking entity in the city of Medellín , Colombia . METHODS This was a double-blind r and omized placebo-controlled study with 493 volunteers . The volunteers were r and omly assigned to two groups , an experimental group and a control group , with 247 and 246 employees , respectively . The experimental group participants received a dose of 0.5 mL of an influenza vaccine containing surface antigens of the strains recommended by the World Health Organization for the 1996 - 1997 period , with subtypes A/Wuhan/359/95 ( H3N2 ) , A/Texas/36/91 ( H1N1 ) , and B/Beijing/184/93 . An illness was considered an episode of AURI when a participant reported having a sore throat , fever , and a cough lasting more than 24 hours . Evaluations were made every 2 weeks over a 6-month period ; the severity of the episodes was assessed in terms of lost workdays due to AURI ( defined according to the ninth revision of the International Classification of Diseases , or ICD-9 ) , through monthly evaluations of incapacitating work absences certified by the Colombian Social Security system , over the period of a year . RESULTS Side effects associated with the vaccine were erythema ( relative risk ( RR ) = 8.0 ; P = 0.02 ) and local edema ( RR = 4.5 ; P = 0.03 ) . The proportion of the annual cumulative incidence of episodes of AURI was 78.5 % for the vaccinated persons and 91.5 % for those in the placebo group , with a reduction of 14 % , with values between 7 % and 20 % ( RR = 0.86 ; 95 % confidence interval ( CI ) = 0.80 - 0.93 ) . The annual cumulative incidence of incapacitating AURI was 15.8 % in those vaccinated , with a reduction of 31 % in comparison to the placebo group ( 22.8 % ) , with values between 0 % and 52 % ( RR = 0.69 ; 95 % CI = 0.48 - 1.0 ) . These levels of protection , both against more mildly symptomatic forms of AURI and those causing lost workdays , increased significantly ( between 62 % and 89 % ) in the months of May and October , when outbreaks caused by the influenza virus were confirmed in Colombia . CONCLUSIONS The results demonstrated that the influenza vaccination strategy decreased the AURI episodes as well as the number of work absences due to AURI in the healthy adult employees of a banking entity in the city of Medellín , Colombia . The impact that influenza has on this population group is small , and the effect of this vaccination measure is greater then the influenza virus is in circulation [8568310] In a blinded , placebo-controlled study , the reactogenicity , immunogenicity , and clinical efficacy of single doses of US inactivated split-virus and Russian live attenuated , cold-adapted influenza vaccines were compared in 555 schoolchildren in Vologda , Russia . Serial serum sample s were collected and school absenteeism was assessed . Systemic reactions were rare , but local reactions ( primarily erythema at the injection site ) were observed in 27 % of the inactivated vaccine group , and coryza ( 12 % ) and sore throat ( 8 % ) were observed in the attenuated vaccine group . At 4 weeks after vaccination a > or = 4-fold rise in titer of hemagglutination inhibition antibody to A ( H1N1 ) , A ( H3N2 ) , and B was noted , respectively , among 78 % , 88 % , and 53 % of children who received inactivated vaccine and among 55 % , 79 % , and 30 % of children who received attenuated vaccine . The vaccine efficacy for preventing school absenteeism due to respiratory illness during the period of peak influenza activity was 56 % for inactivated vaccine and 47 % for attenuated vaccine [351351] Immunization with an influenza subunit vaccine given in one dose about 1 month to 2 months before onset of an epidemic of influenza afforded from 80 % to 90 % protection in a double-blind clinical trial which was supported by isolation of virus and serological studies . In the vaccinated group , 20 % failed to develop antibodies to the vaccine . Either serology tests or attempted isolation of virus alone would have failed to detect some of the cases [18448618] ABSTRACT The highly sensitive gamma interferon ( IFN-γ ) enzyme-linked immunosorbent spot ( ELISPOT ) assay permits the investigation of the role of cell-mediated immunity ( CMI ) in the protection of young children against influenza . Preliminary studies of young children confirmed that the IFN-γ ELISPOT assay was a more sensitive measure of influenza memory immune responses than serum antibody and that among seronegative children aged 6 to < 36 months , an intranasal dose of 107 fluorescent focus units ( FFU ) of a live attenuated influenza virus vaccine ( CAIV-T ) elicited substantial CMI responses . A commercial inactivated influenza virus vaccine elicited CMI responses only in children with some previous exposure to related influenza viruses as determined by detectable antibody levels prevaccination . The role of CMI in actual protection against community-acquired , culture-confirmed clinical influenza by CAIV-T was investigated in a large r and omized , double-blind , placebo-controlled dose-ranging efficacy trial with 2,172 children aged 6 to < 36 months in the Philippines and Thail and . The estimated protection curve indicated that the majority of infants and young children with ≥100 spot-forming cells/106 peripheral blood mononuclear cells were protected against clinical influenza , establishing a possible target level of CMI for future influenza vaccine development . The ELISPOT assay for IFN-γ is a sensitive and reproducible measure of CMI and memory immune responses and contributes to establishing requirements for the future development of vaccines against influenza , especially those used for children [19776407] BACKGROUND The efficacy of influenza vaccines may vary from year to year , depending on a variety of factors , and may differ for inactivated and live attenuated vaccines . METHODS We carried out a r and omized , double-blind , placebo-controlled trial of licensed inactivated and live attenuated influenza vaccines in healthy adults during the 2007 - 2008 influenza season and estimated the absolute and relative efficacies of the two vaccines . RESULTS A total of 1952 subjects were enrolled and received study vaccines in the fall of 2007 . Influenza activity occurred from January through April 2008 , with the circulation of influenza types A ( H3N2 ) ( about 90 % ) and B ( about 9 % ) . Absolute efficacy against both types of influenza , as measured by isolating the virus in culture , identifying it on real-time polymerase-chain-reaction assay , or both , was 68 % ( 95 % confidence interval [ CI ] , 46 to 81 ) for the inactivated vaccine and 36 % ( 95 % CI , 0 to 59 ) for the live attenuated vaccine . In terms of relative efficacy , there was a 50 % ( 95 % CI , 20 to 69 ) reduction in laboratory-confirmed influenza among subjects who received inactivated vaccine as compared with those given live attenuated vaccine . The absolute efficacy against the influenza A virus was 72 % ( 95 % CI , 49 to 84 ) for the inactivated vaccine and 29 % ( 95 % CI , -14 to 55 ) for the live attenuated vaccine , with a relative efficacy of 60 % ( 95 % CI , 33 to 77 ) for the inactivated vaccine . CONCLUSIONS In the 2007 - 2008 season , the inactivated vaccine was efficacious in preventing laboratory-confirmed symptomatic influenza A ( predominately H3N2 ) in healthy adults . The live attenuated vaccine also prevented influenza illnesses but was less efficacious . ( Clinical Trials.gov number , NCT00538512 . [19931952] A cluster-r and omised controlled trial of antiviral treatment to control influenza outbreaks in aged-care facilities ( ACFs ) provided an opportunity to assess VE in the frail , institutionalised elderly . Data were pooled from five influenza outbreaks in 2007 . Rapid testing methods for influenza were used to confirm outbreaks and /or identify further cases . Vaccination coverage among ACF residents ranged from 59 % to 100 % , whereas it was consistently low in staff ( 11 - 33 % ) . The attack rates for laboratory-confirmed influenza in residents ranged from 9 % to 24 % , with the predominate strain determined to be influenza A. Sequencing of the hemagglutinin gene from a sub- sample demonstrated an incomplete match with the 2007 southern hemisphere influenza vaccine . Influenza VE was estimated to be 61 % ( 95%CI 6 % , 84 % ) against laboratory-confirmed influenza , 51 % ( 95%CI -16 % , 79 % ) against influenza-like illness , 82 % ( 95%CI 27 % , 96 % ) against pneumonia-related and influenza-related hospitalisations and 71 % ( 95%CI -28 % , 95 % ) against death from all causes . This supports the continued policy of targeted vaccination of the institutionalised , frail elderly . There is also reassurance that influenza vaccine can be effective against disease and severe outcomes , despite an incomplete vaccine match . This benefit is additional to protection from antivirals [2845585] Background Seasonal influenza imposes a substantial personal morbidity and societal cost burden . Vaccination is the major strategy for influenza prevention ; however , because antigenically drifted influenza A and B viruses circulate annually , influenza vaccines must be up date d to provide protection against the predicted prevalent strains for the next influenza season . The aim of this study was to assess the efficacy , safety , reactogenicity , and immunogenicity of a trivalent inactivated split virion influenza vaccine ( TIV ) in healthy adults over two influenza seasons in the US . Methods The primary endpoint of this double-blind , r and omized study was the average efficacy of TIV versus placebo for the prevention of vaccine-matched , culture-confirmed influenza ( VMCCI ) across the 2005 - 2006 and 2006 - 2007 influenza seasons . Secondary endpoints included the prevention of laboratory-confirmed ( defined by culture and /or serology ) influenza , as well as safety , reactogenicity , immunogenicity , and consistency between three consecutive vaccine lots . Participants were assessed actively during both influenza seasons , and nasopharyngeal swabs were collected for viral culture from individuals with influenza-like illness . Blood specimens were obtained for serology one month after vaccination and at the end of each influenza season 's surveillance period . Results Although the point estimate for efficacy in the prevention of all laboratory-confirmed influenza was 63.2 % ( 97.5 % confidence interval [ CI ] lower bound of 48.2 % ) , the point estimate for the primary endpoint , efficacy of TIV against VMCCI across both influenza seasons , was 46.3 % with a 97.5 % CI lower bound of 9.8 % . This did not satisfy the pre-specified success criterion of a one-sided 97.5 % CI lower bound of > 35 % for vaccine efficacy . The VMCCI attack rates were very low overall at 0.6 % and 1.2 % in the TIV and placebo groups , respectively . Apart from a mismatch for influenza B virus lineage in 2005 - 2006 , there was a good match between TIV and the circulating strains . TIV was highly immunogenic , and immune responses were consistent between three different TIV lots . The most common reactogenicity events and spontaneous adverse events were associated with the injection site , and were mild in severity . Conclusions Despite a good immune response , and an average efficacy over two influenza seasons against laboratory-confirmed influenza of 63.2 % , the pre-specified target ( lower one-sided 97.5 % confidence bound for efficacy > 35 % ) for the primary efficacy endpoint , the prevention of VMCCI , was not met . However , the results should be interpreted with caution in view of the very low attack rates we observed at the study sites in the 2005 - 2006 and 2006 - 2007 , which corresponded to relatively mild influenza seasons in the US . Overall , the results showed that TIV has an acceptable safety profile and offered clinical benefit that exceeded risk . Trial registration Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND In children and adults the consequences of influenza are mainly absences from school and work , however the risk of complications is greatest in children and people over 65 years old . OBJECTIVES To appraise all comparative studies evaluating the effects of influenza vaccines in healthy children ; assess vaccine efficacy ( prevention of confirmed influenza ) and effectiveness ( prevention of influenza-like illness ) and document adverse events associated with receiving influenza vaccines . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

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[3844137] We investigated the efficacy and safety of dual bronchodilation with QVA149 versus its monocomponents indacaterol and glycopyrronium , tiotropium and placebo in patients with moderate-to-severe chronic obstructive pulmonary disease ( COPD ) . This was a multicentre , r and omised , double-blind , placebo- and active-controlled , 26-week trial . Patients ( n = 2144 ) were r and omised ( 2:2:2:2:1 ) to receive once-daily QVA149 ( indacaterol 110 & mgr;g/glycopyrronium 50 & mgr;g ) , indacaterol 150 & mgr;g , glycopyrronium 50 & mgr;g , open-label tiotropium 18 & mgr;g or placebo . The primary end-point was trough forced expiratory volume in 1 s ( FEV1 ) at week 26 for QVA149 versus its monocomponents . Secondary end-points included dyspnoea , health status , rescue medication use and safety . Trough FEV1 at week 26 was significantly improved ( p<0.001 ) with QVA149 compared with indacaterol and glycopyrronium ( least squares mean ( LSM ) differences 0.07 L and 0.09 L , respectively ) , tiotropium and placebo ( LSM differences 0.08 L and 0.20 L , respectively ) ; these beneficial effects were sustained throughout the 26-week study . QVA149 significantly improved dyspnoea and health status versus placebo ( p<0.001 and p = 0.002 , respectively ) and tiotropium ( p = 0.007 and p = 0.009 , respectively ) at week 26 . All treatments were well tolerated . Dual bronchodilation with once-daily QVA149 demonstrated superior and clinical ly meaningful outcomes versus placebo and superiority versus treatment with a single bronchodilator , with a safety and tolerability profile similar to placebo , supporting the concept of fixed-dose long-acting muscarinic antagonist/long-acting & bgr;2-agonist combinations for the treatment of COPD . Dual indacaterol/glycopyrronium therapy was safe and more efficacious than monotherapy in moderate-to-severe COPD [4869636] Background The combination of the inhaled muscarinic antagonist umeclidinium ( UMEC ) with the long-acting β2-agonist vilanterol ( VI ) has been shown to provide significant improvements in lung function compared with UMEC , VI , or placebo ( PBO ) in patients with chronic obstructive pulmonary disease ( COPD ) . This study was specifically design ed to support these findings by assessing health-related quality of life and symptomatic outcomes in a similar population . Methods This was a 12-week multicenter , r and omized , double-blind , parallel-group , placebo-controlled study . Eligible patients were r and omized 1:1 to receive once-daily UMEC/VI 62.5/25 μg ( via ELLIPTA ® dry powder inhaler ) or PBO for 12 weeks . The primary endpoint was St George ’s Respiratory Question naire ( SGRQ ) total score at day 84 . Secondary efficacy endpoints included rescue albuterol use ( puffs/day ) over weeks 1–12 and trough forced expiratory volume in 1 second on day 84 . Adverse events were also assessed . Results A total of 496 patients were included in the intent-to-treat population in the UMEC/VI ( n=248 ) and PBO ( n=248 ) treatment groups . UMEC/VI 62.5/25 μg provided a significant and clinical ly meaningful improvement in SGRQ total score at day 84 versus PBO ( difference between treatments in SGRQ total score change from baseline : −4.03 [ 95 % confidence interval { CI } : −6.28 , −1.79 ] ; P<0.001 ) . UMEC/VI 62.5/25 μg result ed in a statistically significant reduction in rescue albuterol use versus PBO ( −0.7 puffs/day [ 95 % CI : −1.1 , −0.4 ] ; P<0.001 ) . UMEC/VI 62.5/25 μg provided a significant and clinical ly meaningful improvement in trough forced expiratory volume in 1 second on day 84 versus PBO ( 122 mL [ 95 % CI : 71 , 172 ] ; P<0.001 ) . The incidence of adverse events was similar between treatments ( 32 % and 30 % of patients in the UMEC/VI 62.5/25 μg and PBO groups , respectively ) . Conclusion The results of this study demonstrate that treatment with UMEC/VI 62.5/25 μg provides clinical ly important improvements in SGRQ and rescue medication use versus PBO in patients with moderate-to-very-severe COPD [3266210] Background NVA237 is a once-daily dry-powder formulation of the long-acting muscarinic antagonist glycopyrronium bromide in development for the treatment of chronic obstructive pulmonary disease ( COPD ) . The glycopyrronium bromide in COPD airways clinical study 1 ( GLOW1 ) evaluated the efficacy , safety and tolerability of NVA237 in patients with moderate-to-severe COPD . Methods Patients with COPD with a smoking history of ≥ 10 pack-years , post-bronchodilator forced expiratory volume in 1 second ( FEV1 ) < 80 % and ≥ 30 % predicted normal and FEV1/forced vital capacity < 0.70 were enrolled . Patients were r and omized to double-blind treatment with NVA237 50 μg once daily or placebo for 26 weeks with inhaled/intranasal corticosteroids or H1 antagonists permitted in patients stabilized on them prior to study entry . The primary outcome measure was trough FEV1 at Week 12 . Results A total of 822 patients were r and omized to NVA237 ( n = 552 ) or placebo ( n = 270 ) . Least squares mean ( ± st and ard error ) trough FEV1 at Week 12 was significantly higher in patients receiving NVA237 ( 1.408 ± 0.0105 L ) , versus placebo ( 1.301 ± 0.0137 L ; treatment difference 108 ± 14.8 mL , p < 0.001 ) . Significant improvements in trough FEV1 were apparent at the end of Day 1 and sustained through Week 26 . FEV1 was significantly improved in the NVA237 group versus placebo throughout the 24-hour periods on Day 1 and at Weeks 12 and 26 , and at all other visits and timepoints . Transition dyspnoea index focal scores and St. George 's Respiratory Question naire scores were significantly improved with NVA237 versus placebo at Week 26 , with treatment differences of 1.04 ( p < 0.001 ) and -2.81 ( p = 0.004 ) , respectively . NVA237 significantly reduced the risk of first moderate/severe COPD exacerbation by 31 % ( p = 0.023 ) and use of rescue medication by 0.46 puffs per day ( p = 0.005 ) , versus placebo . NVA237 was well tolerated and had an acceptable safety profile , with a low frequency of cardiac and typical antimuscarinic adverse effects . Conclusions Once-daily NVA237 was safe and well tolerated and provided rapid , sustained improvements in lung function , improvements in dyspnoea , and health-related quality of life , and reduced the risk of exacerbations and the use of rescue medication . Trial registration Clinical Trials.gov : [18836213] BACKGROUND Previous studies showing that tiotropium improves multiple end points in patients with chronic obstructive pulmonary disease ( COPD ) led us to examine the long-term effects of tiotropium therapy . METHODS In this r and omized , double-blind trial , we compared 4 years of therapy with either tiotropium or placebo in patients with COPD who were permitted to use all respiratory medications except inhaled anticholinergic drugs . The patients were at least 40 years of age , with a forced expiratory volume in 1 second ( FEV(1 ) ) of 70 % or less after bronchodilation and a ratio of FEV(1 ) to forced vital capacity ( FVC ) of 70 % or less . Co primary end points were the rate of decline in the mean FEV(1 ) before and after bronchodilation beginning on day 30 . Secondary end points included measures of FVC , changes in response on St. George 's Respiratory Question naire ( SGRQ ) , exacerbations of COPD , and mortality . RESULTS Of a total of 5993 patients ( mean age , 65+/-8 years ) with a mean FEV(1 ) of 1.32+/-0.44 liters after bronchodilation ( 48 % of predicted value ) , we r and omly assigned 2987 to the tiotropium group and 3006 to the placebo group . Mean absolute improvements in FEV(1 ) in the tiotropium group were maintained throughout the trial ( ranging from 87 to 103 ml before bronchodilation and from 47 to 65 ml after bronchodilation ) , as compared with the placebo group ( P<0.001 ) . After day 30 , the differences between the two groups in the rate of decline in the mean FEV(1 ) before and after bronchodilation were not significant . The mean absolute total score on the SGRQ was improved ( lower ) in the tiotropium group , as compared with the placebo group , at each time point throughout the 4-year period ( ranging from 2.3 to 3.3 units , P<0.001 ) . At 4 years and 30 days , tiotropium was associated with a reduction in the risks of exacerbations , related hospitalizations , and respiratory failure . CONCLUSIONS In patients with COPD , therapy with tiotropium was associated with improvements in lung function , quality of life , and exacerbations during a 4-year period but did not significantly reduce the rate of decline in FEV(1 ) . ( Clinical Trials.gov number , NCT00144339 . [4778540] Abstract The novel long-acting β2-agonist olo date rol demonstrated an acceptable safety profile in short-term phase II clinical studies . This analysis of four r and omized , double-blind , placebo-controlled , parallel-group , phase III studies ( 1222.11 , NCT00782210 ; 1222.12 , NCT00782509 ; 1222.13 , NCT00793624 ; 1222.14 , NCT00796653 ) evaluated the long-term safety of olo date rol once daily ( QD ) in a large cohort of patients with moderate to very severe ( Global initiative for chronic Obstructive Lung Disease 2–4 ) chronic obstructive pulmonary disease ( COPD ) . The studies compared olo date rol ( 5 or 10 μg ) QD via Respimat ® , formoterol 12 μg twice daily ( BID ) via Aerolizer ® ( 1222.13 and 1222.14 ) , and placebo for 48 weeks . Patients continued receiving background maintenance therapy , with ∼60 % receiving concomitant cardiovascular therapy and 25 % having a history of concomitant cardiac disease . Pre-specified analyses of pooled data assessed the adverse events ( AEs ) and serious AEs in the whole population , and in subgroups with cardiac disease , along with in-depth electrocardiogram and Holter monitoring . In total , 3104 patients were included in the safety analysis : 876 received olo date rol 5 μg , 883 received olo date rol 10 μg , 885 received placebos , and 460 received formoterol 12 μg BID . Overall incidence of on-treatment AEs ( 71.2 % ) , serious AEs ( 16.1 % ) , and deaths ( 1.7 % ) were balanced across treatment groups . Respiratory and cardiovascular AEs , including major adverse cardiac events , were reported at similar frequencies in placebo and active treatment groups . The safety profiles of both olo date rol 5 μg ( marketed and registered dose ) and 10 μg QD delivered via Respimat ® are comparable to placebo and formoterol BID in this population , with no safety signals identified [4213545] Background Combining two long-acting bronchodilators with complementary mechanisms of action may provide treatment benefits to patients with chronic obstructive pulmonary disease ( COPD ) that are greater than those derived from either treatment alone . The efficacy and safety of a fixed-dose combination ( FDC ) of aclidinium bromide , a long-acting muscarinic antagonist , and formoterol fumarate , a long-acting β2-agonist , in patients with moderate to severe COPD are presented . Methods In this 24-week double-blind study , 1692 patients with stable COPD were equally r and omized to twice-daily treatment with FDC aclidinium 400μg/formoterol 12μg ( ACL400/FOR12 FDC ) , FDC aclidinium 400μg/formoterol 6μg ( ACL400/FOR6 FDC ) , aclidinium 400μg , formoterol 12μg , or placebo administered by a multidose dry powder inhaler (Genuair ® /Pressair ® )*. Co primary endpoints were change from baseline to week 24 in 1-hour morning postdose FEV1 ( FDCs versus aclidinium ) and change from baseline to week 24 in morning predose ( trough ) FEV1 ( FDCs versus formoterol ) . Secondary endpoints were change from baseline in St. George ’s Respiratory Question naire ( SGRQ ) total score and improvement in Transition Dyspnea Index ( TDI ) focal score at week 24 . Safety and tolerability were also assessed . Results At study end , improvements from baseline in 1-hour postdose FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC or ACL400/FOR6 FDC compared with aclidinium ( 108 mL and 87 mL , respectively ; p < 0.0001 ) . Improvements in trough FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC versus formoterol ( 45 mL ; p = 0.0102 ) , a numerical improvement of 26 mL in trough FEV1 over formoterol was observed with ACL400/FOR6 FDC . Significant improvements in both SGRQ total and TDI focal scores were observed in the ACL400/FOR12 FDC group at study end ( p < 0.0001 ) , with differences over placebo exceeding the minimal clinical ly important difference of ≥4 points and ≥1 unit , respectively . All treatments were well tolerated , with safety profiles of the FDCs similar to those of the monotherapies . Conclusions Treatment with twice-daily aclidinium 400μg/formoterol 12μg FDC provided rapid and sustained bronchodilation that was greater than either monotherapy ; clinical ly significant improvements in dyspnea and health status were evident compared with placebo . Aclidinium/formoterol FDC may be an effective and well tolerated new treatment option for patients with COPD .Trial registration Clinical trials.gov NCT01437397.*Registered trademarks of Almirall S.A. , Barcelona , Spain ; for use within the US as Pressair ® and Genuair ® within all other licensed territories [20693243] Indacaterol is a novel , inhaled , once-daily , ultra-long-acting & bgr;2-agonist bronchodilator recently approved in Europe for the treatment of chronic obstructive pulmonary disease ( COPD ) . The aim of the present study was to investigate the efficacy and safety of indacaterol compared with placebo and the twice-daily & bgr;2-agonist , salmeterol , as an active control . Patients with moderate-to-severe COPD were r and omised to 6 months double-blind treatment with indacaterol ( 150 & mgr;g once daily ) , salmeterol ( 50 & mgr;g twice daily ) or placebo . The primary efficacy end-point was trough ( 24 h post-dose ) forced expiratory volume in 1 s ( FEV1 ) after 12 weeks . 1,002 patients were r and omised and 838 ( 84 % ) completed the study . Indacaterol increased trough FEV1 at week 12 by 170 mL over placebo ( p<0.001 ) and by 60 mL over salmeterol ( p<0.001 ) . Both active treatments improved health status ( St George 's Respiratory Question naire ) and dyspnoea ( transition dyspnoea index ) compared with placebo , with differences between them favouring indacaterol . Safety profiles were similar across the treatment groups , and both indacaterol and salmeterol were well tolerated . Once-daily treatment with 150 & mgr;g indacaterol had a significant and clinical ly relevant bronchodilator effect over 24 h post-dose and improved health status and dyspnoea to a greater extent than twice-daily 50 & mgr;g salmeterol . Indacaterol should prove a useful additional treatment for patients with COPD [2848004] Background Indacaterol is a novel , once-daily ( o.d . ) inhaled , long-acting β2-agonist in development for chronic obstructive pulmonary disease ( COPD ) . This 12-week , double-blind study compared the efficacy , safety , and tolerability of indacaterol to that of placebo in patients with moderate-to-severe COPD . Methods Efficacy variables included 24-h trough FEV1 ( mean of 23 h 10 min and 23 h 45 min post-dose ) at Week 12 ( primary endpoint ) and after Day 1 , and the percentage of COPD days with poor control ( i.e. , worsening symptoms ) . Safety was assessed by adverse events ( AEs ) , mean serum potassium and blood glucose , QTc ( Fridericia ) , and vital signs . Results Patients were r and omised ( n = 416 , mean age 63 years ) to receive either indacaterol 150 μg o.d . ( n = 211 ) or placebo ( n = 205 ) via a single-dose dry-powder inhaler ; 87.5 % completed the study . Trough FEV1 ( LSM ± SEM ) at Week 12 was 1.48 ± 0.018 L for indacaterol and 1.35 ± 0.019 L for placebo , a clinical ly relevant difference of 130 ± 24 mL ( p < 0.001 ) . Trough FEV1 after one dose was significantly higher with indacaterol than placebo ( p < 0.001 ) . Indacaterol demonstrated significantly higher peak FEV1 than placebo , both on Day 1 and at Week 12 , with indacaterol-placebo differences ( LSM ± SEM ) of 190 ± 28 ( p < 0.001 ) and 160 ± 28 mL ( p < 0.001 ) , respectively . St and ardised AUC measurements for FEV1 ( between 5 min and 4 h , 5 min and 1 h , and 1 and 4 h post-dose ) at Week 12 were all significantly greater with indacaterol than placebo ( p < 0.001 ) , with LSM ( ± SEM ) differences of 170 ± 24 , 180 ± 24 , and 170 ± 24 mL , respectively . Indacaterol significantly reduced the percentage of days of poor control versus placebo by 22.5 % ( p < 0.001 ) and was also associated with significantly reduced use of rescue medication ( p < 0.001 ) . The overall rates of AEs were comparable between the groups ( indacaterol 49.3 % , placebo 46.8 % ) , with the most common AEs being COPD worsening ( indacaterol 8.5 % , placebo 12.2 % ) and cough ( indacaterol 6.2 % , placebo 7.3 % ) . One patient died in the placebo group . Serum potassium and blood glucose levels did not differ significantly between the two groups , and no patient had QTc > 500 ms . Conclusions Indacaterol 150 μg o.d . provided clinical ly significant and sustained bronchodilation , reduced rescue medication use , and had a safety and tolerability profile similar to placebo . Trial registration [5629944] Objectives Cardiovascular disease ( CVD ) and chronic obstructive pulmonary disease ( COPD ) often coexist . We assessed the effect of inhaled COPD treatments on CVD outcomes and safety in patients with COPD and at heightened CVD risk . Methods The SUMMIT ( Study to Underst and Mortality and MorbidITy ) was a multicentre , r and omised , double-blind , placebo-controlled , event-driven trial in 16 485 patients with moderate COPD who had or were at high risk of CVD . Here , we assessed the prespecified secondary endpoint of time to first on-treatment composite CVD event ( CVD death , myocardial infa rct ion , stroke , unstable angina or transient ischaemic attack ( TIA ) ) by Cox regression and by clinician-reported CVD adverse events across the four groups : once-daily inhaled placebo ( n=4111 ) , long-acting beta2-agonist ( vilanterol ( VI ) 25 µg ; n=4118 ) , corticosteroid ( fluticasone furoate ( FF ) 100 µg ; n=4135 ) and combination therapy ( FF/VI ; n=4121 ) . Results Participants were predominantly middle-aged ( mean 65 ( SD 8) years ) men ( 75 % ) with overt CVD ( 66 % ) . The composite CVD endpoint occurred in 688 patients ( first event : sudden death ( 35 % ) , acute coronary syndrome ( 37 % ) and stroke or TIA ( 23 % ) , and was not reduced in any treatment group versus placebo : VI ( HR 0.99 , 95 % CI 0.80 to 1.22 ) , FF ( HR 0.90 , 95 % CI 0.72 to 1.11 ) and their combination ( HR 0.93 , 95 % CI 0.75 to 1.14 ) . Outcomes were similar among all subgroups . Adverse events , including palpitations and arrhythmias , did not differ by treatment . Conclusions In patients with COPD with moderate airflow limitation and heightened CVD risk , treatment with inhaled VI , FF or their combination has an excellent safety profile and does not impact CVD outcomes . Trial registration number NCT01313676 [11948033] STUDY OBJECTIVE To compare the efficacy , tolerability , and safety of therapy with formoterol and oral slow-release theophylline ( THEO ) in patients with COPD . DESIGN A r and omized , parallel-group study , with double-blind arms for formoterol and placebo ( PL ) and an open arm for oral slow-release THEO administered in individual doses on the basis of plasma concentrations . SETTING Eighty-one centers worldwide . PATIENTS Eight hundred fifty-four patients with symptomatic COPD . INTERVENTION Comparison of twice-daily inhaled formoterol dry powder ( 12 or 24 microg ) , PL , and THEO ( individualized doses ) over 12 months . MEASUREMENTS AND RESULTS Compared to PL , doses of formoterol and THEO both significantly improved the area under the curve for FEV(1 ) measured over a period of 12 h following the morning dose of study medication at 3 and 12 months ( p < 0.001 for all comparisons ) . Therapy with formoterol , 12 microg , was significantly more effective than that with THEO ( p < or = 0.026 ) . Formoterol significantly reduced the percentage of " bad days " ( i.e. , days with at least two individual symptom scores > or = 2 and /or a reduction in peak expiratory flow from a baseline of > 20 % ; p < or = 0.035 vs. PL and THEO ) , and the use of salbutamol rescue medication ( p < or = 0.003 vs PL ) over the whole treatment period , while the effect of THEO was similar to that of PL . Therapy with formoterol and THEO was more effective than PL at improving quality of life for > 12 months ( p < or = 0.030 ) . Treatment-related adverse events and discontinuations were more frequent among patients receiving THEO than among those receiving formoterol . CONCLUSIONS Long-term treatment with inhaled formoterol dry powder is more effective and better tolerated than treatment with therapeutically appropriate doses of oral slow-release THEO in symptomatic patients with COPD [20522841] Background Indacaterol is a long-acting inhaled β2-agonist ( LABA ) for the treatment of chronic obstructive pulmonary disease ( COPD ) . In previous studies , indacaterol provided 24 h bronchodilation on once-daily dosing with a fast onset of action . This study compared the efficacy and safety of indacaterol with the twice-daily LABA formoterol and placebo over 1 year . Methods Patients with moderate to severe COPD were r and omised to receive once-daily indacaterol 300 μg ( n=437 ) or 600 μg ( n=428 ) , twice-daily formoterol 12 μg ( n=435 ) or placebo ( n=432 ) for 52 weeks in a double-blind double-dummy parallel group study . The primary efficacy variable was forced expiratory volume in 1 s ( FEV1 ) measured 24 h postdose after 12 weeks ( indacaterol vs placebo ) . Other outcomes included dyspnoea ( transition dyspnoea index , TDI ) , use of as-needed salbutamol , symptom-based measures recorded on diary cards , exacerbations , health status ( St George 's Respiratory Question naire ) , BODE index ( body mass index , obstruction , dyspnoea , exercise ) , safety and tolerability . Results Indacaterol increased 24 h postdose FEV1 after 12 weeks by 170 ml ( both doses ) versus placebo and by 100 ml versus formoterol ( all p<0.001 ) . These significant differences were maintained at 52 weeks . Symptomatic outcomes were improved compared with placebo with all active treatments , and indacaterol was more effective than formoterol in improving TDI score and reducing the need for as-needed salbutamol . Indacaterol was well tolerated and had a good overall safety profile , including minimal impact on QTc interval and systemic β2-mediated events . Conclusions Once-daily indacaterol is an effective 24 h bronchodilator that improves symptoms and health status and confers clinical improvements over a twice-daily 12 h LABA as a treatment for patients with moderate to severe COPD . Trial registration number NCT 00393458 [2629970] Clinical manifestations of chronic obstructive pulmonary disease ( COPD ) , including airflow limitation , dyspnea , and activity limitation , ultimately lead to impaired health-related quality of life ( HRQoL ) . This 9-month , r and omized , double-blind , multicenter study compared the effect of once-daily tiotropium 18 μg and placebo on HRQoL , spirometric parameters , and exacerbations in 554 patients with moderate-to-severe COPD . HRQoL was assessed using the St. George ’s Respiratory Question naire ( SGRQ ) and the new 8-item Visual Simplified Respiratory Question naire ( VSRQ ) , which is currently being vali date d. The primary efficacy endpoint was the proportion of patients achieving a reduction of at least 4 units in the SGRQ total score at study end ( Month 9 ) . Mean ± SD baseline SGRQ total score was 47.4 ± 18.1 . Significantly more tiotropium-treated patients achieved a reduction of at least 4 units in the SGRQ score vs placebo at study end ( 59.1 % vs 48.2 % , respectively ; p = 0.029 ) . Tiotropium significantly improved spirometric parameters ( forced expiratory volume in 1 second [ FEV1 ] : 0.11 ± 0.02 L vs 0.01 ± 0.02 L ; between-group difference : 0.10 ± 0.03 L , p = 0.0001 ) and reduced exacerbations vs placebo . Maintenance treatment with tiotropium provided significant and clinical ly relevant improvements in HRQoL , as measured by the SGRQ [23352226] BACKGROUND Fluticasone furoate (FF)/vilanterol ( VI ) is a novel once-daily inhaled corticosteroid/long-acting β2-agonist combination therapy for COPD . We aim ed to assess the efficacy and safety of two strengths of FF/VI ( 100/25 μg ; 50/25 μg ) vs. individual components ( FF 100 μg , VI 25 μg ) and placebo over 24 weeks . METHODS Multicentre , r and omised , placebo-controlled , double-blind , parallel-group study of patients ( N = 1030 ) with moderate-to-severe COPD . All medication was administered once daily in the morning . Co- primary efficacy endpoints were : ( 1 ) weighted mean ( wm ) FEV1 ( 0 - 4 h post-dose on day 168 ) to assess acute lung function effects ; and ( 2 ) trough FEV1 ( 23 - 24 h post-dose on day 169 ) to assess long-lasting effects . Symptom-related outcomes were analysed and adverse events ( AEs ) assessed . RESULTS Main findings were : ( 1 ) the combination of FF/VI at a strength of 100/25 μg significantly ( p < 0.001 ) improved wm FEV1 ( 173 ml ) and trough FEV1 ( 115 ml ) vs. placebo . Similar effects were observed with FF/VI 50/25 μg ; ( 2 ) no significant difference was seen between FF/VI 100/25 μg and VI 25 μg for trough FEV1 ( 48 ml , p = 0.082 ) , while an effect was observed between FF/VI 100/25 μg and FF 100 μg for wm FEV1 ( 120 ml , p < 0.001 ) ; ( 3 ) VI 25 μg over 24 weeks improved lung function vs. placebo significantly for wm FEV1 ( 103 ml , p < 0.001 ) and trough FEV1 ( 67 ml , p = 0.017 ) ; and ( 4 ) no safety signal was observed . CONCLUSIONS In subjects with moderate-to-severe COPD , FF/VI 100/25 μg provides rapid and significant sustained bronchodilation at 24 weeks . Lung function is improved to a similar extent with FF/VI 50/25 μg and to a somewhat lesser extent with VI 25 μg . All treatments were well tolerated . GSK study number : HZC112206 . Clinical Trials.gov : NCT01053988 [4562726] Background Combination of the inhaled long-acting muscarinic antagonist umeclidinium ( UMEC ; GSK573719 ) with the long-acting β2-agonist vilanterol ( VI ) is an approved maintenance treatment for COPD in the US and EU . We compared the efficacy and safety of UMEC/VI with placebo in patients with COPD of Asian ancestry . Patients and methods In this 24-week , Phase III , multicenter , r and omized , double-blind , placebo-controlled , parallel-group study , patients were r and omized 1:1:1 to UMEC/VI 125/25 μg , UMEC/VI 62.5/25 μg , or placebo . The primary efficacy end point was trough forced expiratory volume in 1 second ( FEV1 ) on day 169 ; secondary end points were Transition Dyspnea Index ( TDI ) focal score at week 24 and weighted mean ( WM ) FEV1 over 0–6 hours postdose on day 1 . Additional end points and safety were also assessed . Results Both UMEC/VI 125/25 μg and UMEC/VI 62.5/25 μg statistically significantly improved trough FEV1 at day 169 versus placebo ( UMEC/VI 125/25 μg , 0.216 L , [ 95 % confidence interval [ CI ] 0.175–0.257 ] ; UMEC/VI 62.5/25 μg , 0.151 L , 95 % CI 0.110–0.191 ; both P<0.001 ) . Statistically significant improvements in TDI score were observed for both UMEC/VI groups versus placebo ( UMEC/VI 125/25 μg , 0.9 , 95 % CI 0.3–1.4 , P=0.002 ; UMEC/VI 62.5/25 μg , 0.7 , 95 % CI 0.1–1.2 , P=0.016 ) . On day 1 , both UMEC/VI groups improved 0–6-hour WM FEV1 versus placebo ( UMEC/VI 125/25 μg , 0.182 L 95 % CI 0.161–0.203 ; UMEC/VI 62.5/25 μg , 0.160 L , 95 % CI 0.139–0.181 ; both P<0.001 ) . Statistically significant improvements for UMEC/VI groups versus placebo were observed for rescue albuterol use at weeks 1–24 ( puffs/day , both P<0.001 ) . The incidence of adverse events was similar across groups . Conclusion In Asian patients with COPD , once-daily UMEC/VI 125/25 μg and UMEC 62.5/25 μg result ed in clinical ly meaningful and statistically significant improvements in lung-function end points versus placebo . Symptomatic and quality of life measures also improved . The safety profile of UMEC/VI was consistent with previous studies [4273456] Background Aclidinium/formoterol is a twice-daily ( BID ) fixed-dose combination ( FDC ) in development for chronic obstructive pulmonary disease ( COPD ) . The efficacy and safety of aclidinium/formoterol versus monotherapy and placebo in patients with COPD was assessed . Methods In this 24-week double-blind , parallel-group , active- and placebo-controlled , multicentre Phase III study , patients ( ≥40 years , post-bronchodilator forced expiratory volume in 1 second [FEV1]/forced vital capacity < 70 % and FEV1 ≥30 % but < 80 % predicted normal ) were r and omised 2:2:2:2:1 to aclidinium/formoterol 400/12 μg ( n = 385 ) or 400/6 μg ( n = 381 ) , aclidinium 400 μg ( n = 385 ) , formoterol 12 μg ( n = 384 ) or placebo ( n = 194 ) BID via Genuair ® /Pressair ® a . Results At Week 24 , aclidinium/formoterol 400/12 μg and 400/6 μg lead to significant improvements from baseline in 1-hour post-dose FEV1 versus aclidinium ( 125 mL [ 95 % CI : 90 , 160 ; p < 0 · 001 ] and 69 mL [ 95 % CI : 34 , 105 ; p < 0.001 ] , respectively ) and trough FEV1 versus formoterol ( 85 mL [ 95 % CI : 51 , 119 ; p < 0.001 ] and 53 mL [ 95 % CI : 19 , 87 ; p < 0.01 ] , respectively ; co- primary endpoints ) . Additionally , aclidinium/formoterol 400/12 μg and 400/6 μg provided significant improvements in Transition Dyspnoea Index ( TDI ) focal score versus placebo ( 1.29 units [ 95 % CI : 0.73 , 1.86 ; p < 0.001 ] and 1.16 units [ 95 % CI : 0.59 , 1.73 ; p < 0.001 ] , respectively ; secondary endpoint ) . All treatments were well tolerated , with safety profiles of the FDCs similar to those of placebo and monotherapy . Conclusions Both aclidinium/formoterol BID doses significantly improved bronchodilation versus monotherapy , and dyspnoea versus placebo , with no increase in safety risk . Aclidinium/formoterol may be an effective treatment for patients with COPD .Trial registration Clinical Trials.gov : NCT01462942 [20685748] Background Previous studies have suggested that long-term use of β agonists to treat chronic obstructive pulmonary disease ( COPD ) may increase the risk of cardiovascular adverse events . In this post hoc analysis , data from the TOwards a Revolution in COPD Health ( TORCH ) study were used to investigate whether use of the long-acting β2 agonist salmeterol over 3 years increased the risk of cardiovascular adverse events in patients with moderate to severe COPD . Methods TORCH was a r and omised , double-blind , placebo controlled study conducted at 444 centres in 42 countries . Patients ( n=6184 ; safety population ) received twice daily combined salmeterol 50 μg plus fluticasone propionate 500 μg ( SFC ) , either component alone , or placebo . Adverse events were recorded every 12 weeks for 3 years . Results The probability of having a cardiovascular adverse event by 3 years was 24.2 % for placebo , 22.7 % for salmeterol , 24.3 % for fluticasone propionate and 20.8 % for SFC . Although a history of myocardial infa rct ion doubled the probability of cardiovascular adverse events , the event rates remained similar across treatment groups . Conclusion Post hoc analysis of the 3-year TORCH data set showed that salmeterol alone or in combination ( SFC ) did not increase the risk of cardiovascular events in patients with moderate to severe COPD [4064950] Background Olo date rol is a long-acting β2-agonist with a 24-hour bronchodilator profile . Two replicate , r and omized , double-blind , placebo-controlled , parallel-group , Phase III trials were performed as part of a comprehensive clinical program to investigate the long-term safety and efficacy of olo date rol in patients with moderate to very severe chronic obstructive pulmonary disease ( COPD ) receiving usual-care background therapy . Methods Patients received olo date rol 5 μg or 10 μg or placebo once daily for 48 weeks . Co primary end points were forced expiratory volume in 1 second ( FEV1 ) area under the curve from 0 to 3 hours ( AUC0–3 ) response ( change from baseline ) , and trough FEV1 response at 12 weeks . Secondary end points included additional lung function assessment s , use of rescue medications , FEV1 AUC response from 0 to 12 hours , and Patient Global Rating over 48 weeks . Results Overall , 624 and 642 patients were evaluated in studies 1222.11 and 1222.12 , respectively . In both studies , olo date rol 5 μg and 10 μg significantly improved the FEV1 AUC0–3 response ( P<0.0001 ) and trough FEV1 ( study 1222.11 , P<0.0001 ; study 1222.12 , P<0.05 , post hoc ) at week 12 , with an incidence of adverse events comparable with that of placebo . Secondary end points supported the efficacy of olo date rol . Conclusion These studies demonstrate the long-term efficacy and safety of once-daily olo date rol 5 μg and 10 μg in patients with moderate to very severe COPD continuing with usual-care maintenance therapy [20463178] RATIONALE Indacaterol is the first once-daily , long-acting inhaled beta(2)-agonist bronchodilator studied in patients with chronic obstructive pulmonary disease ( COPD ) . OBJECTIVES To demonstrate greater efficacy of indacaterol versus placebo on FEV(1 ) at 24 hours post dose ( trough ) after 12 weeks , to compare efficacy with placebo and tiotropium , and to evaluate safety and tolerability over 26 weeks . MEASUREMENTS Patients with moderate-to-severe COPD were r and omized to double-blind indacaterol 150 or 300 microg or placebo , or open-label tiotropium 18 microg , all once daily , for 26 weeks . The primary efficacy outcome was trough FEV(1 ) at 12 weeks . Additional analyses ( not adjusted for multiplicity ) included transition dyspnea index ( TDI ) , health status ( St George 's Respiratory Question naire [ SGRQ ] ) , and exacerbations . Serum potassium , blood glucose , and QTc interval were measured . RESULTS A total of 1,683 patients ( age , 63.3 yr ; post-bronchodilator FEV(1 ) , 56 % predicted ; FEV(1)/FVC , 0.53 ) were r and omized to the four treatment arms . Trough FEV(1 ) at Week 12 increased versus placebo by 180 ml with both indacaterol doses and by 140 ml with tiotropium ( all P < 0.001 vs. placebo ) . At Week 26 , for indacaterol 150/300 microg , respectively , versus placebo , TDI increased ( 1.00/1.18 , P < 0.001 ) and SGRQ total score decreased ( -3.3/-2.4 , P < 0.01 ) ; corresponding results with tiotropium were 0.87 ( P < 0.001 ) for TDI and ( -1.0 , P = not significant ) for SGRQ total score . The incidence of adverse events , low serum potassium , high blood glucose , and prolonged QTc interval was similar across treatments . CONCLUSIONS Indacaterol was an effective once-daily bronchodilator and was at least as effective as tiotropium in improving clinical outcomes for patients with COPD . Clinical trial registered with clinical trials.gov ( NCT 00463567 ) [20080201] BACKGROUND The drug development process can be streamlined by combining the traditionally separate stages of dose-finding ( Phase IIb ) and confirmation of efficacy and safety ( Phase III ) using an adaptive seamless design . This approach was used in a clinical study of indacaterol , a novel once-daily ( od ) inhaled long-acting beta(2)-adrenoreceptor agonist bronchodilator for the treatment of COPD ( chronic obstructive pulmonary disease ) . METHODS The study comprised a dose-finding stage with dose selection after 14 days of treatment , and a second stage evaluating efficacy and safety during 26 weeks of treatment . The dose-finding stage included seven r and omized treatment arms : double-blind indacaterol 75 microg , 150 microg , 300 microg or 600 microg od , the beta(2)-adrenoceptor agonist formoterol 12 microg twice-daily or placebo , or the anticholinergic tiotropium 18 microg od open-label . An independent data monitoring committee selected two indacaterol doses based on unblinded results of an interim analysis performed by an independent statistician . The sponsor , investigators and patients remained blinded to the results . The indacaterol doses were selected using pre-set efficacy criteria for trough ( 24-h post-dose ) and early ( 1 - 4 h post-dose ) bronchodilator effect after 14 days , and all safety data . To qualify for selection , the doses had to exceed a threshold for clinical relevance or be superior to either tiotropium or formoterol , whichever was the highest value . Selected doses were continued into the second , 26-week stage . The two other indacaterol doses not selected , and formoterol , were discontinued following dose selection . RESULTS 801 patients with moderate-to-severe COPD were evaluated . Indacaterol 150 microg was the lowest effective dose , exceeding criteria for trough FEV(1 ) ( reference value 140 mL vs placebo ) and FEV(1 ) AUC(1 - 4 h ) ( reference value 220 mL vs placebo ) . No safety signal was observed with any dose of indacaterol . Thus , indacaterol 150 and 300 microg were selected to continue into the second , 26-week stage . CONCLUSION The adaptive seamless design is a novel and efficient way to combine dose selection with efficacy evaluation and safety confirmation in a single trial [27916620] Background : Long‐acting muscarinic antagonist (LAMA)/long‐acting & bgr;2‐agonist ( LABA ) combinations are a treatment option for patients with COPD who continue to have symptoms despite treatment with a LAMA or a LABA alone . The Efficacy and Safety of PT003 , PT005 , and PT001 in Subjects with Moderate‐to‐Very Severe COPD ( PINNACLE‐1 ) ( NCT01854645 ) and the Multi‐Center Study to Assess the Efficacy and Safety of PT003 , PT005 , and PT001 in Subjects with Moderate‐to‐Very Severe COPD ( PINNACLE‐2 ) ( NCT01854658 ) trials investigated the efficacy and safety of a novel glycopyrrolate [GP]/formoterol [ FF ] 18/9.6‐&mgr;g ( GFF ) metered dose inhaler ( MDI ) formulated using the Co‐Suspension Delivery Technology in patients with moderate‐to‐very severe COPD . Methods : These two phase III trials took place over 24 weeks and were r and omized , double blind , and placebo controlled ; 2,103 and 1,615 patients ( 40–80 years of age ) , respectively , were r and omized . Patients received GFF MDI , GP MDI 18 & mgr;g , FF MDI 9.6 & mgr;g , or placebo MDI ( all twice daily ) , or tiotropium 18 & mgr;g dry powder inhaler ( once daily in PINNACLE‐1 only [ open‐label active comparator ] ) . Efficacy and safety were assessed . Results : At week 24 , differences in change from baseline in the morning predose trough FEV1 for GFF MDI vs placebo MDI , GP MDI , and FF MDI were 150 mL , 59 mL , and 64 mL in PINNACLE‐1 ( all P < .0001 ) and 103 mL , 54 mL , and 56 mL in PINNACLE‐2 ( all P < .001 ) , respectively . There were no significant safety findings ( incidence of adverse events was similar between treatment arms ) . Conclusions : We conclude that GFF MDI 18/9.6 & mgr;g demonstrated superiority over placebo and monocomponent MDIs and was well tolerated , thus providing an additional treatment option for patients with moderate‐to‐very severe COPD . Trial Registry : Clinical Trials.gov ; No. : NCT01854645 and No. NCT01854658 ; URL : www . clinical trials.gov [26177074] RATIONALE Current Global Initiative for Chronic Obstructive Lung Disease ( GOLD ) strategy recommends the combination of two long-acting bronchodilators of different pharmacologic classes for the management of chronic obstructive pulmonary disease ( COPD ) if symptoms are not adequately controlled by a single bronchodilator . OBJECTIVES The FLIGHT1 and FLIGHT2 studies evaluated the efficacy and safety of QVA149 ( indacaterol/glycopyrrolate ) , a fixed-dose combination of a long-acting β2-agonist ( indacaterol ) and a long-acting muscarinic antagonist ( glycopyrrolate ) , compared with its monocomponents and placebo in patients with moderate-to-severe COPD . METHODS FLIGHT1 and FLIGHT2 were 12-week , identical , multicenter , r and omized , double-blind , parallel-group , placebo- and active-controlled studies . Patients were r and omized ( 1:1:1:1 ) to indacaterol/glycopyrrolate ( 27.5/15.6 μg twice daily ) , indacaterol ( 27.5 μg twice daily ) , glycopyrrolate ( 15.6 μg twice daily ) , or placebo , all delivered via the Neohaler device . The primary objective was to demonstrate the superiority of indacaterol/glycopyrrolate versus its monocomponents for st and ardized area under the curve from 0 - 12 hours for FEV1 at Week 12 . Secondary objectives included St. George 's Respiratory Question naire total score and transition dyspnea index total score and reduction in daily rescue medication use with indacaterol/glycopyrrolate versus placebo . MEASUREMENTS AND MAIN RESULTS In total , 2,038 patients were included in the pooled analysis . Indacaterol/glycopyrrolate was statistically superior in terms of FEV1 area under the curve from 0 - 12 hours compared with its monocomponents ( P < 0.001 ) . Statistically and clinical ly meaningful improvements in St. George 's Respiratory Question naire total score , transition dyspnea index total score , and reduction in rescue medication use were observed with indacaterol/glycopyrrolate compared with placebo ( P < 0.001 ) . The safety profile was comparable across the treatment groups . CONCLUSIONS Indacaterol/glycopyrrolate twice daily can be an alternative treatment option for the management of symptomatic patients with moderate-to-severe COPD . Clinical trial registered with www . clinical trials.gov ( NCT 01727141 and NCT 0171251 ) [18042473] BACKGROUND Recently , there have been concerns about the tolerability of long-acting (2)-agonists , including possible adverse cardiovascular effects-a particular concern in patients with chronic obstructive pulmonary disease ( COPD ) , who are at elevated risk for cardiovascular disease . OBJECTIVE The aim of this study was to assess the cardiac safety profile of nebulized formoterol fumarate inhalation solution . METHODS Cardiac safety was assessed as part of a 12-week , r and omized , double-blind , double-dummy , placebo- and active-controlled trial that was conducted at 38 centers across the United States . Male and female patients aged > /=40 years with COPD and without other significant disease were enrolled . After a 4- to 14-day , single-blind placebo run-in period , patients with COPD were r and omly assigned to receive formoterol fumarate inhalation solution 20 microg BID via nebulizer ( FFIS group ) , formoterol fumarate 12 microg BID via dry powder inhaler ( FA group ) , or placebo . Cardiac effects-measured by changes in heart rate ( HR ) and ventricular premature beats ; incidence of proarrhythmic events ; change in corrected QT ( QTc ) interval ; and incidence of maximum mean change in QTc > /=60 ms-were assessed using 24-hour Holter monitoring at baseline and 12 weeks ; 12-lead electrocardiography at screening and weeks 4 , 8 , and 12 ; and patient diary cards . RESULTS A total of 351 patients with COPD were r and omized ( mean age , 62.8 years ; 56.1 % male ; mean postbronchodilator forced expiratory volume in 1 second , 1.5 L ) . Holter monitoring found no clinical ly meaningful effects of FFIS or FA treatment on mean or maximum HR , ventricular premature beats , or inci dence of arrhythmic events compared with placebo . At week 12 , mean ( SD ) changes from baseline in mean HR were -0.6 ( 10.9 ) , + 0.1 ( 11.6 ) , and -1.4 ( 9.4 ) bpm in the FFIS , FA , and placebo groups , respectively . The incidence of mean maximum changes in QTc > /=60 ms at any time during the 12-week treatment period were 1.6 % , 1.8 % , and 1.8 % with FFIS , FA , and placebo , respectively . Treatment-emergent cardiac adverse events ( AEs ) occurred in 4.1 % , 3.5 % , and 4.4 % of patients in the FFIS , FA , and placebo groups ; withdrawals due to possible cardiac AEs occurred in 1 patient per treatment group . No deaths or serious cardiac AEs occurred during the treatment period . CONCLUSION In this COPD population , no clinical ly significant cardiac effects were found with twicedaily treatment with nebulized formoterol fumarate inhalation solution [22177371] BACKGROUND Indacaterol is the first once-daily , long-acting , inhaled β(2)-agonist bronchodilator for maintenance treatment of chronic obstructive pulmonary disease ( COPD ) . Two studies ( previously reported in a Congress abstract ) were performed in 2010 to provide efficacy and tolerability data to support the application for approval in the United States of indacaterol 75 μg once daily , a dose lower than that previously investigated in most studies . OBJECTIVE The primary objective was to evaluate the efficacy of indacaterol 75 μg once daily in terms of 24-hour post-dose ( " trough " ) forced expiratory volume in the first second of respiration ( FEV(1 ) ) compared with placebo after 12 weeks of treatment . METHODS Patients with moderate to severe COPD were r and omized to receive double-blind treatment with indacaterol 75 μg once daily ( n = 163 and 159 ) or placebo ( n = 160 and 159 ) for 12 weeks . In addition to trough FEV(1 ) after 12 weeks , rescue albuterol use , health status ( St. George 's Respiratory Question naire [ SGRQ ] ) , and tolerability were evaluated . Clinical ly relevant differences between active and placebo treatments were defined as ≥120 mL for trough FEV(1 ) and a decrease of ≥4 units in SGRQ total score . RESULTS Of patients enrolled in the 2 studies , 54 % were men , and 90 % and 94 % were white , with mean age 64 and 61 years . Mean duration of COPD was 7 years ; smoking history was 52 pack-years ; and 45 % and 37 % of patients were receiving inhaled corticosteroid therapy . At week 12 , indacaterol demonstrated clinical ly relevant bronchodilator efficacy , increasing trough FEV(1 ) by ≥120 mL versus placebo ( P < 0.001 ) , with significant bronchodilation maintained at all time points from 5 minutes to 24 hours post-dose . Over 12 weeks , relative to placebo , in patients receiving indacaterol therapy , rescue albuterol use was reduced by 1.2 and 0.7 puffs per day ( P < 0.01 ) , and the percentage of rescue-free days was increased by 13.7 and 8.4 ( P < 0.01 ) . At week 12 , the SGRQ total score differed in the indacaterol group versus the placebo group by -3.8 and -3.6 , respectively ( P ≤ 0.01 ) . Adverse events were reported for 49 % and 45 % of patients receiving indacaterol therapy , and for 46 % and 41 % receiving placebo . CONCLUSIONS Compared with placebo , indacaterol 75 μg once daily provided statistically significant and clinical ly relevant 24-hour bronchodilation and was well tolerated . In patients receiving indacaterol , the reduction in rescue albuterol use was statistically significant . Changes in health status also were statistically significant compared with placebo , although the differences of 3.6 and 3.8 units were below the predefined 4-unit level of clinical relevance . The results of these studies suggest that indacaterol 75 μg once daily is an effective maintenance treatment in patients with moderate to severe COPD . Clinical Trials.gov identifiers : NCT01072448 and NCT01068600 [20620037] In this r and omised double-blind study , patients > or=40 years old with COPD , a smoking history of > or=10 pack-years , a pre-bronchodilator FEV(1 ) of < or=60 % predicted and an FEV(1)/FVC of < or=70 % received tiotropium 5 microg or placebo via Respimat inhaler once daily for 48 weeks . Other medications were permitted except inhaled anticholinergics . Co- primary endpoints were trough FEV(1 ) and the time to first exacerbation . Adverse events were followed and vital status regularly assessed . In all , 3991 patients ( mean age , 65 years [ SD , 9 years ] ) were evaluable . Mean baseline FEV(1 ) was 1.11 L ( 0.40 L ) or 40 % ( 12 % ) of predicted normal . Adjusted mean differences in trough FEV(1 ) and trough FVC at Week 48 ( tiotropium minus placebo ) were 102 and 168 ml respectively ( p < 0.0001 , both ) . Tiotropium delayed time to first exacerbation relative to placebo ( hazard ratio [ HR ] , 0.69 [ 95 % CI , 0.63 - 0.77 ] ) and time to first hospital-treated exacerbation ( HR , 0.73 [ 0.59 - 0.90 ] ) . SGRQ score at Week 48 was 2.9 units lower with tiotropium ( p < 0.0001 ) . Adverse and serious adverse events were balanced across treatment groups and similar in profile to previous tiotropium trials . The rate ratio for a major adverse cardiovascular event during the treatment period + 30 days was 1.12 ( 0.67 - 1.86 ) . By the end of planned treatment ( Day 337 ) 52 patients on tiotropium ( incidence rate per 100 years , 2.94 ) and 38 on placebo ( 2.13 ) had died ( HR = 1.38 [ 0.91 - 2.10 ] ; p = 0.13 ) . Lung function , exacerbations and quality of life were improved by tiotropium 5 microg Respimat but a numerical imbalance was seen in all-cause mortality . The protocol is registered on the European Clinical Trials Data base as trial number 2006 - 001009 - 27 and in the Clinical Trials.gov data base as NCT00387088 [22561964] RATIONALE Patients with chronic obstructive pulmonary disease ( COPD ) are afflicted by comorbidities . Few studies have prospect ively evaluated COPD comorbidities and mortality risk . OBJECTIVES To prospect ively evaluate COPD comorbidities and mortality risk . METHODS We followed 1,664 patients with COPD in five centers for a median of 51 months . Systematic ally , 79 comorbidities were recorded . We calculated mortality risk using Cox proportional hazard , and developed a graphic representation of the prevalence and strength of association to mortality in the form of a " comorbidome " . A COPD comorbidity index ( COPD specific comorbidity test [ COTE ] ) was constructed based on the comorbidities that increase mortality risk using a multivariate analysis . We tested the COTE index as predictor of mortality and explored whether the COTE index added predictive information when used with the vali date d BODE index . MEASUREMENTS AND MAIN RESULTS Fifteen of 79 comorbidities differed in prevalence between survivors and nonsurvivors . Of those , 12 predicted mortality and were integrated into the COTE index . Increases in the COTE index were associated with an increased risk of death from COPD -related ( hazard ratio [ HR ] , 1.13 ; 95 % confidence interval , 1.08 - 1.18 ; P < 0.001 ) and non- COPD -related causes ( HR , 1.18 ; 95 % confidence interval , 1.15 - 1.21 ; P < 0.001 ) . Further , increases in the BODE and COTE were independently associated with increased risk of death . A COTE score of greater than or equal to 4 points increased by 2.2-fold the risk of death ( HR , 2.26 - 2.68 ; P < 0.001 ) in all BODE quartile . CONCLUSIONS Comorbidities are frequent in COPD and 12 of them negatively influence survival . A simple disease-specific comorbidities index ( COTE ) helps assess mortality risk in patients with COPD [23332861] BACKGROUND Once-daily combination treatment is an attractive maintenance therapy for COPD . However , the dose of inhaled corticosteroid to use in a once-daily combination is unknown . We compared two strengths of fluticasone furoate ( FF ) plus vilanterol ( VI ) , the same strengths of the individual components , and placebo . METHODS Multicentre , r and omised , 24-week , double-blind , placebo-controlled , parallel-group study in stable , moderate-to-severe COPD subjects ( N = 1224 ) . Subjects were r and omised to FF/VI ( 200/25 μg ; 100/25 μg ) , FF ( 200 μg ; 100 μg ) , VI 25 μg , or placebo , once daily in the morning . Co- primary efficacy endpoints ; 0 - 4 h weighted mean ( wm ) FEV(1 ) on day 168 , and change from baseline in trough ( 23 - 24 h post-dose ) FEV(1 ) on day 169 . The primary safety objective was adverse events ( AEs ) . RESULTS There was a statistically significant ( p < 0.001 ) increase in wm FEV(1 ) ( 209 ml ) and trough FEV(1 ) ( 131 ml ) for FF/VI 200/25 μg vs. placebo ; similar changes were seen for FF/VI 100/25 μg vs. placebo . Whereas the difference between FF/VI 200/25 μg and VI 25 μg in change from baseline trough FEV(1 ) ( 32 ml ) was not statistically significant ( p = 0.224 ) , the difference between FF/VI 200/25 μg and FF 200 μg for wm FEV(1 ) ( 168 ml ) was significantly different ( p < 0.001 ) . VI 25 μg significantly improved wm and trough FEV(1 ) vs. placebo ( 185 ml and 100 ml , [ corrected ] respectively ) . No increase was seen in on-treatment AEs or serious AEs ( SAEs ) , with active therapy vs. placebo . CONCLUSIONS FF/VI provides rapid and significant sustained improvement in FEV(1 ) in subjects with moderate-to-severe COPD , which was not influenced by the dose of FF . These data suggest that FF/VI may offer clinical efficacy in COPD and warrants additional study . GSK study number : HZC112207 . Clinical Trials.gov : NCT01054885 [24383720] BACKGROUND AND OBJECTIVE This study , in a predominantly Chinese population , investigated the efficacy and safety of a once-daily ( o.d . ) inhaled ultra-long-acting β2 -agonist indacaterol for the treatment of moderate-to-severe chronic obstructive pulmonary disease ( COPD ) . METHODS This is a 26-week , double-blind study on r and omized patients who received indacaterol 150 μg or 300 μg or placebo o.d . The primary variable was trough forced expiratory volume in 1 s ( FEV1 , average of 23 h 10 min and 23 h 45 min post-dose values ) at Week 12 . Health status ( St George 's Respiratory Question naire , SGRQ ) , dyspnoea ( transition dyspnoea index , TDI ) and safety were evaluated over 26 weeks . RESULTS Of the 563 patients r and omized , 561 ( 89.8 % Chinese ) received treatment and 482 completed . At Week 12 , trough FEV1 improved significantly for indacaterol 150 and 300 μg versus placebo ( 1.32 , 1.29 vs 1.17 ; P < 0.001 for both comparisons ) , with differences exceeding the pre-specified minimal clinical ly important difference of 0.12 L. At Week 26 , TDI score was superior to placebo for indacaterol 150 and 300 μg ( 0.82 , 1.15 ; P < 0.01 ) , as was the percentage of patients with a clinical ly relevant improvement ( ≥1 point ) ( 74.1 % , 78.6 % vs 55.5 % ; P < 0.05 ) . Both doses provided ≥4-point improvements from baseline in SGRQ score at Week 26 that were numerically greater than placebo ( unadjusted means : -9.6 , -8.8 vs -7.0 ) , with a similar pattern in percentage of patients with clinical ly relevant improvements in SGRQ score ( 65.0 % , 61.5 % vs 60.6 % ) . Incidences of adverse events were comparable across treatment groups . CONCLUSIONS Indacaterol delivered effective bronchodilation with significant improvements in breathlessness and health status in this predominantly Chinese population [16144890] Context Tiotropium , a new once-daily inhaled anticholinergic bronchodilator , has been shown to improve lung function in patients with chronic obstructive pulmonary disease ( COPD ) . Previous studies have suggested that it may also decrease the frequency of exacerbations and hospitalizations in these patients . Contribution This r and omized , parallel-group , double-blind , placebo-controlled study in patients with moderate to severe COPD showed a small but statistically significant decrease in the exacerbation rate during the 6-month study period . Caution s The study period was relatively short , and the beneficial effects were modest . The Editors Exacerbations of chronic obstructive pulmonary disease ( COPD ) can lead to costly and clinical ly significant consequences . Proven treatments for exacerbations are only modestly effective ( 1 , 2 ) . Recovery from even mild exacerbations may be protracted ( 3 ) . Frequent exacerbations are associated with impaired quality of life and a more rapid decline in lung function over time ( 4 , 5 ) . Patients with severe exacerbations commonly seek care in emergency departments , and many of these patients are hospitalized . In 2000 , COPD was responsible for 1.5 million emergency department visits and 726000 hospitalizations in the United States ( 6 ) . Economic analyses suggest that hospitalization alone consumes up to 70 % of all medical expenses for patients with COPD ( 7 , 8) . Interventions that reduce the frequency or severity of exacerbations are a highly desirable but poorly met medical need . An expert panel convened by the National Heart , Lung , and Blood Institute assigned a high priority to clinical research that might improve the management of COPD exacerbations ( 9 ) . Tiotropium is a newly developed , once-daily inhaled anticholinergic bronchodilator . Because of its very slow dissociation from muscarinic M3 receptors , 1 inhaled dose produces sustained bronchodilation for at least 24 hours ( 10 ) . In controlled clinical trials , compared with placebo or the short-acting anticholinergic bronchodilator ipratropium , tiotropium improved lung function , dyspnea , and health-related quality of life in patients with COPD ( 11 , 12 ) . An analysis of adverse event reports su bmi tted during those studies suggested that tiotropium might also reduce exacerbation and COPD -related hospitalization rates . Therefore , we design ed a clinical trial to prospect ively test the hypothesis that tiotropium reduces exacerbations and hospitalizations due to COPD . Methods Study Design Our study was a parallel-group , r and omized , double-blind , placebo-controlled trial in patients with moderate to severe COPD conducted at 26 Veterans Affairs medical centers in the United States . The sole intervention was tiotropium given by inhalation once daily . The principal outcomes were the percentage of patients experiencing at least 1 exacerbation and the percentage of patients with at least 1 hospitalization due to a COPD exacerbation during a 6-month treatment period . The protocol is consistent with the principles of Helsinki . The institutional review boards of participating medical centers approved the study . All trial participants provided written informed consent . Patients All men and women receiving medical care at participating Veterans Affairs medical centers were potential study participants . We enrolled enough participants to ensure a minimum of 1800 r and omly assigned patients . Eligibility criteria included an age of 40 years or older , a cigarette smoking history of 10 pack-years or more , a clinical diagnosis of COPD , and an FEV1 of 60 % predicted or less and 70 % or less of the FVC . Exclusion criteria were a clinical diagnosis of asthma , a myocardial infa rct ion within the previous 6 months , a serious cardiac arrhythmia or hospitalization for heart failure within the previous year , known moderate to severe renal impairment , moderate to severe symptomatic prostatic hypertrophy or bladder-neck obstruction , narrow-angle glaucoma , current radiation or chemotherapy for a malignant condition , or inability to give informed consent . We also excluded patients who took systemic corticosteroids at unstable doses , or in regular daily doses of 20 mg or more of prednisone ( or equivalent ) , or who had not fully recovered from an exacerbation for at least 30 days before the first study visit . We gathered baseline data on respiratory disease and other relevant medical history by question naire . Procedures We allocated eligible patients in equal numbers to receive tiotropium or placebo according to a central ly generated blocked r and omization list . We generated a single r and omization and assigned blocks to centers . We provided r and omly assigned patients with training and detailed instructions on the use of the dry powder inhalation device ( H and iHaler , Boehringer Ingelheim Pharma GmbH & Co. KG , Biberach , Germany ) ( 13 ) . Blinding of supplies was performed at Boehringer Ingelheim before distribution to investigational sites . The double-blind remained in place until all patients were clinical ly complete or until a serious adverse event required unblinding . Each morning during the trial , patients inhaled 1 capsule of tiotropium ( 18 g ) or 1 identical placebo capsule . Participants otherwise received usual medical care , except that they could not take any open-label anticholinergic bronchodilator . They continued taking all other respiratory medications ( including inhaled corticosteroids and long-acting -agonists ) , and primary providers were allowed to prescribe additional medications according to medical need . Primary providers also prescribed antibiotics and systemic steroid prescriptions for exacerbations without restrictions . For purpose s of recall , patients kept a daily diary throughout the treatment period , recording information about specific respiratory symptoms , medications taken for exacerbations , clinic visits , and hospitalizations . We collected information about exacerbations and health care utilization by interviews when patients made site visits at 3 and 6 months and by telephone calls at 1-month intervals between visits . We assessed study drug adherence by query and by counting returned capsules . Participants performed spirometry before and 90 minutes after inhalation of study drug at baseline and again at the 3-month and 6-month visits . We encouraged patients to complete study visits and to provide all requested medical information even if they prematurely discontinued the study drug therapy . However , patients who discontinued the study drug therapy did not have 90-minute postinhalation spirometry testing at subsequent study visits . All open-label bronchodilators and the study drug were withheld overnight before spirometry . Study sites performed spirometry by using a common predictive nomogram with equipment and methods that conformed to American Thoracic Society recommendations ( 14 , 15 ) . Objectives We aim ed to determine whether tiotropium decreased COPD exacerbations and hospitalizations due to exacerbations . Outcome Measures The co primary outcomes were the percentage of patients with a COPD exacerbation and the percentage of patients with a hospitalization due to COPD exacerbation . We defined an exacerbation as a complex of respiratory symptoms ( increase or new-onset ) of more than 1 of the following : cough , sputum , wheezing , dyspnea , or chest tightness with a duration of at least 3 days requiring treatment with antibiotics or systemic steroids , hospitalization , or both . The study team at each site requested discharge summaries for all hospitalizations , wherever they occurred . We identified hospitalizations due to COPD exacerbations from events on case report forms that met the protocol definition of an exacerbation and where review of discharge summaries and other available medical records indicated that the event result ed in a hospitalization . We also considered an event to be a hospitalization if a patient was held and treated for an acute respiratory condition in an urgent care department or in an observation unit for longer than 24 hours . Admissions to nursing homes or other extended care facilities were not considered hospitalizations . Secondary outcomes included time to first COPD exacerbation and time to first hospitalization due to COPD exacerbation , the frequencies of exacerbations and of exacerbation-related health care utilization ( hospitalizations , hospitalization days , unscheduled clinic visits , antibiotic treatment days , and systemic corticosteroid treatment days ) , the frequencies of all-cause hospitalizations and hospitalization days , and results of spirometry . Statistical Analysis We analyzed the data by using a modified intention-to-treat principle . Therefore , we included all available data for the patients with any follow-up contact who took at least 1 capsule of study drug in the analysis up to their first event ( for the time-to-event end points ) or their withdrawal from the trial . For the time-to-event end points , we censored patients without an event at the end of their participation in the trial . Although we intended to follow all patients for the full 6 months , some patients were lost to follow-up . We h and led missing data by using longitudinal data analysis methods ( spirometry ) , analysis of observed data only ( number of events ) , or analysis methods for censored data ( time-to-event data ) . For the percentage of patients with an event , we considered that patients who discontinued the study drug therapy before having an event did not have an event . We analyzed the co primary end points by using a CochranMantelHaenszel test with center as a stratum . We used a stepwise procedure to test the percentage of patients with an exacerbation and , if rejected , to test percentage of patients with a hospitalization due to COPD exacerbation , each at a 2-sided level of 0.05 . Because of the prespecified closed testing procedure , no adjustment for multiplicity was required . We calculated that a sample size of 1800 patients would have 80 % power to [17472819] OBJECTIVE The aim of this study was to assess the efficacy and tolerability of nebulized arformoterol tartrate ( a selective , long-acting beta(2)-adrenergic agonist that is the [ R , R ] isomer of formoterol ) and salmeterol xinafoate versus placebo in patients with chronic obstructive pulmonary disease ( COPD ) . METHODS This 12-week , multicenter , r and omized , double-blind , double-dummy , placebo- and active-controlled trial was conducted at 60 centers across the United States . Male and female patients aged > or=35 years with physician-diagnosed COPD received arformoterol ( 15 microg BID , 25 microg BID , or 50 microg QD via nebulizer ) , salmeterol ( 42 microg BID via metered dose inhaler ) , or placebo . Pulmonary function was assessed by spirometry ; dyspnea , by the Transitional Dyspnea Index ( TDI ) ; and health status , by the St. George 's Respiratory Question naire ( SGRQ ) . Adverse events ( AEs ) were assessed by site personnel at all clinic visits ( screening , first dose at week 0 , and at weeks 3 , 6 , 9 , 12 , and follow-up ) . COPD exacerbations were defined as worsening respiratory status requiring a change in medication or an unscheduled provider visit . RESULTS A total of 717 patients received study medication . The demographic composition of all treatment arms was similar . The mean age was 62.9 years , 58 % were men , and mean baseline forced expiratory volume in 1 second ( FEV(1 ) ) was 1.2 L ( 41 % predicted ) . Mean improvement in trough FEV(1 ) over 12 weeks was significantly greater with all 3 arformoterol doses ( 15 microg BID , + 16.9 % ; 25 microg BID , + 18.9 % ; 50 microg QD , + 14.9 % ) and for salmeterol ( + 17.4 % ) relative to placebo ( + 6.0 % ; P < 0.001 ) . There were significantly greater improvements in the mean percentage change in FEV(1 ) AUC(0 - 12h ) from the predose value over 12 weeks ( 15 microg BID , 12.7 % , 25 microg BID , 13.9 % , 50 microg QD , 18.9 % ; salmeterol , 9.8 % ) versus placebo ( 2.7 % ; P < or= 0.001 ) ; all doses of arformoterol were statistically different from salmeterol for this end point ( P < or= 0.024 ) . At week 12 , TDI focal scores were significantly greater with all arformoterol doses compared with placebo ( mean [ 95 % CI ] : 15 microg BID , 0.97 [ 0.25 - 1.69 ] ; 25 microg BID , 1.08 [ 0.3 - 1.86 ] ; 50 microg QD , 1.04 [ 0.32 - 1.771 ) , suggesting treatment-associated improvement in dyspnea , however , the difference between salmeterol and placebo was not statistically significant ( 0.36 [ -0.40 to 1.12 ] ) . Improvements in health status , as measured using SGRQ total scores , were -2.6 to -3.6 U in the arformoterol groups , -4.4 U for salmeterol , and -1.2 U for placebo ; 95 % CI of differences versus placebo suggested significant improvement for the arformoterol 25 microg BID and salmeterol groups . There was a similar frequency of AEs and COPD exacerbations across all groups , including placebo . CONCLUSIONS In this trial , patients with moderate to severe COPD administered nebulized arformoterol over 12 weeks were observed to have significant and sustained improvements in airway function and dyspnea compared with placebo . The results also suggest that all doses of arformoterol , including the lowest dose ( 15 microg BID ) , were effective . Overall , nebulized arformoterol was well tolerated [30077810] BACKGROUND Cardiovascular comorbidities are common in chronic obstructive pulmonary disease ( COPD ) , and elevated heart rate reflects increased cardiovascular risk over time , which is associated with unfavourable neurohumoral activation . Long-acting β2-agonists ( LABAs ) are established treatments in COPD , but potentially increase heart rate . We report a post hoc pooled analysis of the effect of olo date rol ( 5 or 10 μg ) or formoterol ( 12 μg ) on heart rate and blood pressure ( BP ) in Global Initiative for Chronic Obstructive Lung Disease Stage 2 - 4 COPD patients . METHODS Four r and omised , double-blind , placebo-controlled , Phase III studies were analysed . Changes in heart rate and systolic/diastolic BP were measured before and after dosing with the study medication at each visit . RESULTS At each study visit , the increase in pre-dose heart rate was numerically lower with both LABAs compared with placebo . Systolic and diastolic BP were decreased with all treatments . Short-term ( pre-dose to 40 min post-dose ) effects of drug administration on heart rate were small and similar for all treatment arms ( between -3 and + 1 beats per minute ) . CONCLUSION Heart rate and BP were not adversely influenced in this study involving long-term administration of olo date rol or formoterol in patients with moderate-to-severe COPD . This supports the cardiovascular safety of LABAs in COPD maintenance treatment [6157543] Background Phase III studies demonstrated efficacy and safety of nebulized glycopyrrolate inhalation solution ( GLY ) in subjects with COPD . Secondary analyses were performed to examine the effect of background long-acting beta2-agonist ( LABA ) use on the efficacy and safety of nebulized GLY . Methods In two 12-week placebo-controlled studies ( GOLDEN 3 and GOLDEN 4 ) and one 48-week , open-label active-controlled study ( GOLDEN 5 ) , a total of 2,379 subjects were stratified by background LABA use ( LABA-yes : n=861 ; LABA-no : n=1,518 ) and r and omized to placebo vs GLY 25 or 50 µg twice daily , or GLY 50 µg twice daily vs tiotropium ( TIO ) 18 µg once daily . Lung function , patient-reported outcomes , exacerbations , and safety were assessed . Results Compared with placebo , pooled data from the 12-week studies showed significant improvements from baseline with GLY 25 and 50 µg across LABA subgroups in trough FEV1 ( LABA-yes : 0.101 and 0.110 L ; LABA-no : 0.092 and 0.101 L , respectively ; P<0.001 ) and St George ’s Respiratory Question naire total score ( SGRQ ; LABA-yes : −2.957 and −3.888 ; LABA-no : −3.301 and −2.073 , respectively ; P<0.05 ) . Incidence of treatment-emergent adverse events ( TEAEs ) was similar in LABA subgroups , and lower in GLY 25 µg vs placebo . In the 48-week active-controlled study , GLY and TIO both showed improvement from baseline across LABA subgroups in FEV1 ( LABA-yes : 0.106 and 0.092 L ; LABA-no : 0.096 and 0.096 L , respectively ) and in SGRQ total score ( LABA-yes : −5.190 and −3.094 ; LABA-no : −4.368 and −4.821 , respectively ) . Incidence of TEAEs was similar between GLY and TIO , and across LABA subgroups . Exacerbation rates were similar across treatments and LABA subgroups , and cardiovascular events of special interest were more frequent in the LABA-no subgroup . Nebulized GLY , combined with LABA , did not generate any additional safety signals . Conclusion Nebulized GLY demonstrated efficacy and was well tolerated up to 48 weeks in subjects with COPD with/without background LABA [23867808] BACKGROUND QVA149 is an inhaled , once-daily fixed-dose dual bronchodilator combination of the long-acting β2-agonist indacaterol and long-acting muscarinic antagonist glycopyrronium ( NVA237 ) for the treatment of chronic obstructive pulmonary disease ( COPD ) . We investigated the safety and efficacy of QVA149 over 52 weeks . METHODS This 52-week , multicenter , double-blind , parallel-group , placebo-controlled study r and omized ( 2:1 ) patients with moderate-to-severe COPD to once-daily QVA149 ( 110 μg indacaterol/50 μg glycopyrronium ) or placebo delivered via the Breezhaler device . Primary endpoint was safety and tolerability for treatment-emergent adverse events ( AEs ) . Secondary endpoints included safety based on vital signs , electrocardiograms ( ECGs ) , laboratory evaluations , and pre-dose forced expiratory volume in 1 s ( FEV1 ) . RESULTS Of 339 patients r and omized , QVA149 [ n = 226 ] , placebo [ n = 113 ] ; 76.9 % male , mean age : 62.6 years , post-bronchodilator FEV1 : 57.4 % predicted , 83.5 % completed study . A smaller percentage of patients discontinued in the QVA149 group ( 14.2 % ) compared with placebo ( 21.2 % ) . Overall incidence of AEs was similar in the QVA149 ( 57.8 % ) and placebo ( 56.6 % ) groups , with most AEs being mild to moderate in severity . The numerical differences in some AEs observed could be at least in part explained by differences in baseline patient characteristics . No clinical ly relevant differences were observed between treatment groups for vital signs or ECG parameters . The five deaths reported were unrelated to study medication ( QVA149 , n = 4 [ 1.8 % ] ; placebo , n = 1 [ 0.9 % ] ) . QVA149 demonstrated rapid and clinical ly meaningful bronchodilation sustained over 52 weeks versus placebo . CONCLUSION QVA149 demonstrated a good safety and tolerability profile , providing rapid and sustained bronchodilation over 52 weeks in patients with moderate-to-severe COPD . Clinical Trials.gov identifier : NCT01120717 [27203508] BACKGROUND Chronic obstructive pulmonary disease ( COPD ) often coexists with cardiovascular disease . Treatments for airflow limitation might improve survival and both respiratory and cardiovascular outcomes . The aim of this study was to assess whether inhaled treatment with a combined treatment of the corticosteroid , fluticasone furoate , and the long-acting β agonist , vilanterol could improve survival compared with placebo in patients with moderate COPD and heightened cardiovascular risk . METHODS In this double-blind r and omised controlled trial ( SUMMIT ) done in 1368 centres in 43 countries , eligible patients were aged 40 - 80 years and had a post-bronchodilator forced expiratory volume in 1 s ( FEV1 ) between 50 % and 70 % of the predicted value , a ratio of post-bronchodilator FEV1 to forced vital capacity ( FVC ) of 0·70 or less , a smoking history of at least 10 pack-years , and a score of 2 or greater on the modified Medical Research Council dyspnoea scale . Patients had to have a history , or be at increased risk , of cardiovascular disease . Enrolled patients were r and omly assigned ( 1:1:1:1 ) through a central ised r and omisation service in permuted blocks to receive once daily inhaled placebo , fluticasone furoate ( 100 μg ) , vilanterol ( 25 μg ) , or the combination of fluticasone furoate ( 100 μg ) and vilanterol ( 25 μg ) . The primary outcome was all-cause mortality , and secondary outcomes were on-treatment rate of decline in forced expiratory volume in 1 s ( FEV1 ) and a composite of cardiovascular events . Safety analyses were performed on the safety population ( all patients who took at least one dose of study drug ) and efficacy analyses were performed on the intention-to-treat population ( safety population minus sites excluded with Good Clinical Practice violations ) . This study is registered with Clinical Trials.gov , number NCT01313676 . FINDINGS Between Jan 24 , 2011 , and March 12 , 2014 , 23 835 patients were screened , of whom 16 590 were r and omised . 16 485 patients were included in the intention-to-treat efficacy population ; 4111 in the placebo group , 4135 in the fluticasone furoate group , 4118 in the vilanterol group , and 4121 in the combination group . Compared with placebo , all-cause mortality was unaffected by combination therapy ( hazard ratio [ HR ] 0·88 [ 95 % CI 0·74 - 1·04 ] ; 12 % relative reduction ; p=0·137 ) or the components ( fluticasone furoate , HR 0·91 [ 0·77 - 1·08 ] ; p=0·284 ; vilanterol , 0·96 [ 0·81 - 1·14 ] ; p=0·655 ) , and therefore secondary outcomes should be interpreted with caution . Rate of decline in FEV1 was reduced by combination therapy ( 38 mL per year [ SE 2·4 ] vs 46 mL per year [ 2·5 ] for placebo , difference 8 mL per year [ 95 % CI 1 - 15 ] ) with similar findings for fluticasone furoate ( difference 8 mL per year [ 95 % CI 1 - 14 ] ) , but not vilanterol ( difference -2 mL per year [ 95 % CI -8 to 5 ] ) . Combination therapy had no effect on composite cardiovascular events ( HR 0·93 [ 95 % CI 0·75 - 1·14 ] ) with similar findings for fluticasone furoate ( 0·90 [ 0·72 - 1·11 ] ) and vilanterol ( 0·99 [ 0·80 - 1·22 ] ) . All treatments reduced the rate of moderate and severe exacerbation . No reported excess risks of pneumonia ( 5 % in the placebo group , 6 % in the combination group , 5 % in the fluticasone furoate group , and 4 % in the vilanterol group ) or adverse cardiac events ( 17 % in the placebo group , 18 % in the combination group , and 17 % in the fluticasone furoate group , and 17 % in the vilanterol group ) were noted in the treatment groups . INTERPRETATION In patients with moderate COPD and heightened cardiovascular risk , treatment with fluticasone furoate and vilanterol did not affect mortality or cardiovascular outcomes , reduced exacerbations , and was well tolerated . Fluticasone furoate , alone or in combination with vilanterol , seemed to reduce FEV1 decline . FUNDING GlaxoSmithKline

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### Context: [3844137] We investigated the efficacy and safety of dual bronchodilation with QVA149 versus its monocomponents indacaterol and glycopyrronium , tiotropium and placebo in patients with moderate-to-severe chronic obstructive pulmonary disease ( COPD ) . This was a multicentre , r and omised , double-blind , placebo- and active-controlled , 26-week trial . Patients ( n = 2144 ) were r and omised ( 2:2:2:2:1 ) to receive once-daily QVA149 ( indacaterol 110 & mgr;g/glycopyrronium 50 & mgr;g ) , indacaterol 150 & mgr;g , glycopyrronium 50 & mgr;g , open-label tiotropium 18 & mgr;g or placebo . The primary end-point was trough forced expiratory volume in 1 s ( FEV1 ) at week 26 for QVA149 versus its monocomponents . Secondary end-points included dyspnoea , health status , rescue medication use and safety . Trough FEV1 at week 26 was significantly improved ( p<0.001 ) with QVA149 compared with indacaterol and glycopyrronium ( least squares mean ( LSM ) differences 0.07 L and 0.09 L , respectively ) , tiotropium and placebo ( LSM differences 0.08 L and 0.20 L , respectively ) ; these beneficial effects were sustained throughout the 26-week study . QVA149 significantly improved dyspnoea and health status versus placebo ( p<0.001 and p = 0.002 , respectively ) and tiotropium ( p = 0.007 and p = 0.009 , respectively ) at week 26 . All treatments were well tolerated . Dual bronchodilation with once-daily QVA149 demonstrated superior and clinical ly meaningful outcomes versus placebo and superiority versus treatment with a single bronchodilator , with a safety and tolerability profile similar to placebo , supporting the concept of fixed-dose long-acting muscarinic antagonist/long-acting & bgr;2-agonist combinations for the treatment of COPD . Dual indacaterol/glycopyrronium therapy was safe and more efficacious than monotherapy in moderate-to-severe COPD [4869636] Background The combination of the inhaled muscarinic antagonist umeclidinium ( UMEC ) with the long-acting β2-agonist vilanterol ( VI ) has been shown to provide significant improvements in lung function compared with UMEC , VI , or placebo ( PBO ) in patients with chronic obstructive pulmonary disease ( COPD ) . This study was specifically design ed to support these findings by assessing health-related quality of life and symptomatic outcomes in a similar population . Methods This was a 12-week multicenter , r and omized , double-blind , parallel-group , placebo-controlled study . Eligible patients were r and omized 1:1 to receive once-daily UMEC/VI 62.5/25 μg ( via ELLIPTA ® dry powder inhaler ) or PBO for 12 weeks . The primary endpoint was St George ’s Respiratory Question naire ( SGRQ ) total score at day 84 . Secondary efficacy endpoints included rescue albuterol use ( puffs/day ) over weeks 1–12 and trough forced expiratory volume in 1 second on day 84 . Adverse events were also assessed . Results A total of 496 patients were included in the intent-to-treat population in the UMEC/VI ( n=248 ) and PBO ( n=248 ) treatment groups . UMEC/VI 62.5/25 μg provided a significant and clinical ly meaningful improvement in SGRQ total score at day 84 versus PBO ( difference between treatments in SGRQ total score change from baseline : −4.03 [ 95 % confidence interval { CI } : −6.28 , −1.79 ] ; P<0.001 ) . UMEC/VI 62.5/25 μg result ed in a statistically significant reduction in rescue albuterol use versus PBO ( −0.7 puffs/day [ 95 % CI : −1.1 , −0.4 ] ; P<0.001 ) . UMEC/VI 62.5/25 μg provided a significant and clinical ly meaningful improvement in trough forced expiratory volume in 1 second on day 84 versus PBO ( 122 mL [ 95 % CI : 71 , 172 ] ; P<0.001 ) . The incidence of adverse events was similar between treatments ( 32 % and 30 % of patients in the UMEC/VI 62.5/25 μg and PBO groups , respectively ) . Conclusion The results of this study demonstrate that treatment with UMEC/VI 62.5/25 μg provides clinical ly important improvements in SGRQ and rescue medication use versus PBO in patients with moderate-to-very-severe COPD [3266210] Background NVA237 is a once-daily dry-powder formulation of the long-acting muscarinic antagonist glycopyrronium bromide in development for the treatment of chronic obstructive pulmonary disease ( COPD ) . The glycopyrronium bromide in COPD airways clinical study 1 ( GLOW1 ) evaluated the efficacy , safety and tolerability of NVA237 in patients with moderate-to-severe COPD . Methods Patients with COPD with a smoking history of ≥ 10 pack-years , post-bronchodilator forced expiratory volume in 1 second ( FEV1 ) < 80 % and ≥ 30 % predicted normal and FEV1/forced vital capacity < 0.70 were enrolled . Patients were r and omized to double-blind treatment with NVA237 50 μg once daily or placebo for 26 weeks with inhaled/intranasal corticosteroids or H1 antagonists permitted in patients stabilized on them prior to study entry . The primary outcome measure was trough FEV1 at Week 12 . Results A total of 822 patients were r and omized to NVA237 ( n = 552 ) or placebo ( n = 270 ) . Least squares mean ( ± st and ard error ) trough FEV1 at Week 12 was significantly higher in patients receiving NVA237 ( 1.408 ± 0.0105 L ) , versus placebo ( 1.301 ± 0.0137 L ; treatment difference 108 ± 14.8 mL , p < 0.001 ) . Significant improvements in trough FEV1 were apparent at the end of Day 1 and sustained through Week 26 . FEV1 was significantly improved in the NVA237 group versus placebo throughout the 24-hour periods on Day 1 and at Weeks 12 and 26 , and at all other visits and timepoints . Transition dyspnoea index focal scores and St. George 's Respiratory Question naire scores were significantly improved with NVA237 versus placebo at Week 26 , with treatment differences of 1.04 ( p < 0.001 ) and -2.81 ( p = 0.004 ) , respectively . NVA237 significantly reduced the risk of first moderate/severe COPD exacerbation by 31 % ( p = 0.023 ) and use of rescue medication by 0.46 puffs per day ( p = 0.005 ) , versus placebo . NVA237 was well tolerated and had an acceptable safety profile , with a low frequency of cardiac and typical antimuscarinic adverse effects . Conclusions Once-daily NVA237 was safe and well tolerated and provided rapid , sustained improvements in lung function , improvements in dyspnoea , and health-related quality of life , and reduced the risk of exacerbations and the use of rescue medication . Trial registration Clinical Trials.gov : [18836213] BACKGROUND Previous studies showing that tiotropium improves multiple end points in patients with chronic obstructive pulmonary disease ( COPD ) led us to examine the long-term effects of tiotropium therapy . METHODS In this r and omized , double-blind trial , we compared 4 years of therapy with either tiotropium or placebo in patients with COPD who were permitted to use all respiratory medications except inhaled anticholinergic drugs . The patients were at least 40 years of age , with a forced expiratory volume in 1 second ( FEV(1 ) ) of 70 % or less after bronchodilation and a ratio of FEV(1 ) to forced vital capacity ( FVC ) of 70 % or less . Co primary end points were the rate of decline in the mean FEV(1 ) before and after bronchodilation beginning on day 30 . Secondary end points included measures of FVC , changes in response on St. George 's Respiratory Question naire ( SGRQ ) , exacerbations of COPD , and mortality . RESULTS Of a total of 5993 patients ( mean age , 65+/-8 years ) with a mean FEV(1 ) of 1.32+/-0.44 liters after bronchodilation ( 48 % of predicted value ) , we r and omly assigned 2987 to the tiotropium group and 3006 to the placebo group . Mean absolute improvements in FEV(1 ) in the tiotropium group were maintained throughout the trial ( ranging from 87 to 103 ml before bronchodilation and from 47 to 65 ml after bronchodilation ) , as compared with the placebo group ( P<0.001 ) . After day 30 , the differences between the two groups in the rate of decline in the mean FEV(1 ) before and after bronchodilation were not significant . The mean absolute total score on the SGRQ was improved ( lower ) in the tiotropium group , as compared with the placebo group , at each time point throughout the 4-year period ( ranging from 2.3 to 3.3 units , P<0.001 ) . At 4 years and 30 days , tiotropium was associated with a reduction in the risks of exacerbations , related hospitalizations , and respiratory failure . CONCLUSIONS In patients with COPD , therapy with tiotropium was associated with improvements in lung function , quality of life , and exacerbations during a 4-year period but did not significantly reduce the rate of decline in FEV(1 ) . ( Clinical Trials.gov number , NCT00144339 . [4778540] Abstract The novel long-acting β2-agonist olo date rol demonstrated an acceptable safety profile in short-term phase II clinical studies . This analysis of four r and omized , double-blind , placebo-controlled , parallel-group , phase III studies ( 1222.11 , NCT00782210 ; 1222.12 , NCT00782509 ; 1222.13 , NCT00793624 ; 1222.14 , NCT00796653 ) evaluated the long-term safety of olo date rol once daily ( QD ) in a large cohort of patients with moderate to very severe ( Global initiative for chronic Obstructive Lung Disease 2–4 ) chronic obstructive pulmonary disease ( COPD ) . The studies compared olo date rol ( 5 or 10 μg ) QD via Respimat ® , formoterol 12 μg twice daily ( BID ) via Aerolizer ® ( 1222.13 and 1222.14 ) , and placebo for 48 weeks . Patients continued receiving background maintenance therapy , with ∼60 % receiving concomitant cardiovascular therapy and 25 % having a history of concomitant cardiac disease . Pre-specified analyses of pooled data assessed the adverse events ( AEs ) and serious AEs in the whole population , and in subgroups with cardiac disease , along with in-depth electrocardiogram and Holter monitoring . In total , 3104 patients were included in the safety analysis : 876 received olo date rol 5 μg , 883 received olo date rol 10 μg , 885 received placebos , and 460 received formoterol 12 μg BID . Overall incidence of on-treatment AEs ( 71.2 % ) , serious AEs ( 16.1 % ) , and deaths ( 1.7 % ) were balanced across treatment groups . Respiratory and cardiovascular AEs , including major adverse cardiac events , were reported at similar frequencies in placebo and active treatment groups . The safety profiles of both olo date rol 5 μg ( marketed and registered dose ) and 10 μg QD delivered via Respimat ® are comparable to placebo and formoterol BID in this population , with no safety signals identified [4213545] Background Combining two long-acting bronchodilators with complementary mechanisms of action may provide treatment benefits to patients with chronic obstructive pulmonary disease ( COPD ) that are greater than those derived from either treatment alone . The efficacy and safety of a fixed-dose combination ( FDC ) of aclidinium bromide , a long-acting muscarinic antagonist , and formoterol fumarate , a long-acting β2-agonist , in patients with moderate to severe COPD are presented . Methods In this 24-week double-blind study , 1692 patients with stable COPD were equally r and omized to twice-daily treatment with FDC aclidinium 400μg/formoterol 12μg ( ACL400/FOR12 FDC ) , FDC aclidinium 400μg/formoterol 6μg ( ACL400/FOR6 FDC ) , aclidinium 400μg , formoterol 12μg , or placebo administered by a multidose dry powder inhaler (Genuair ® /Pressair ® )*. Co primary endpoints were change from baseline to week 24 in 1-hour morning postdose FEV1 ( FDCs versus aclidinium ) and change from baseline to week 24 in morning predose ( trough ) FEV1 ( FDCs versus formoterol ) . Secondary endpoints were change from baseline in St. George ’s Respiratory Question naire ( SGRQ ) total score and improvement in Transition Dyspnea Index ( TDI ) focal score at week 24 . Safety and tolerability were also assessed . Results At study end , improvements from baseline in 1-hour postdose FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC or ACL400/FOR6 FDC compared with aclidinium ( 108 mL and 87 mL , respectively ; p < 0.0001 ) . Improvements in trough FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC versus formoterol ( 45 mL ; p = 0.0102 ) , a numerical improvement of 26 mL in trough FEV1 over formoterol was observed with ACL400/FOR6 FDC . Significant improvements in both SGRQ total and TDI focal scores were observed in the ACL400/FOR12 FDC group at study end ( p < 0.0001 ) , with differences over placebo exceeding the minimal clinical ly important difference of ≥4 points and ≥1 unit , respectively . All treatments were well tolerated , with safety profiles of the FDCs similar to those of the monotherapies . Conclusions Treatment with twice-daily aclidinium 400μg/formoterol 12μg FDC provided rapid and sustained bronchodilation that was greater than either monotherapy ; clinical ly significant improvements in dyspnea and health status were evident compared with placebo . Aclidinium/formoterol FDC may be an effective and well tolerated new treatment option for patients with COPD .Trial registration Clinical trials.gov NCT01437397.*Registered trademarks of Almirall S.A. , Barcelona , Spain ; for use within the US as Pressair ® and Genuair ® within all other licensed territories [20693243] Indacaterol is a novel , inhaled , once-daily , ultra-long-acting & bgr;2-agonist bronchodilator recently approved in Europe for the treatment of chronic obstructive pulmonary disease ( COPD ) . The aim of the present study was to investigate the efficacy and safety of indacaterol compared with placebo and the twice-daily & bgr;2-agonist , salmeterol , as an active control . Patients with moderate-to-severe COPD were r and omised to 6 months double-blind treatment with indacaterol ( 150 & mgr;g once daily ) , salmeterol ( 50 & mgr;g twice daily ) or placebo . The primary efficacy end-point was trough ( 24 h post-dose ) forced expiratory volume in 1 s ( FEV1 ) after 12 weeks . 1,002 patients were r and omised and 838 ( 84 % ) completed the study . Indacaterol increased trough FEV1 at week 12 by 170 mL over placebo ( p<0.001 ) and by 60 mL over salmeterol ( p<0.001 ) . Both active treatments improved health status ( St George 's Respiratory Question naire ) and dyspnoea ( transition dyspnoea index ) compared with placebo , with differences between them favouring indacaterol . Safety profiles were similar across the treatment groups , and both indacaterol and salmeterol were well tolerated . Once-daily treatment with 150 & mgr;g indacaterol had a significant and clinical ly relevant bronchodilator effect over 24 h post-dose and improved health status and dyspnoea to a greater extent than twice-daily 50 & mgr;g salmeterol . Indacaterol should prove a useful additional treatment for patients with COPD [2848004] Background Indacaterol is a novel , once-daily ( o.d . ) inhaled , long-acting β2-agonist in development for chronic obstructive pulmonary disease ( COPD ) . This 12-week , double-blind study compared the efficacy , safety , and tolerability of indacaterol to that of placebo in patients with moderate-to-severe COPD . Methods Efficacy variables included 24-h trough FEV1 ( mean of 23 h 10 min and 23 h 45 min post-dose ) at Week 12 ( primary endpoint ) and after Day 1 , and the percentage of COPD days with poor control ( i.e. , worsening symptoms ) . Safety was assessed by adverse events ( AEs ) , mean serum potassium and blood glucose , QTc ( Fridericia ) , and vital signs . Results Patients were r and omised ( n = 416 , mean age 63 years ) to receive either indacaterol 150 μg o.d . ( n = 211 ) or placebo ( n = 205 ) via a single-dose dry-powder inhaler ; 87.5 % completed the study . Trough FEV1 ( LSM ± SEM ) at Week 12 was 1.48 ± 0.018 L for indacaterol and 1.35 ± 0.019 L for placebo , a clinical ly relevant difference of 130 ± 24 mL ( p < 0.001 ) . Trough FEV1 after one dose was significantly higher with indacaterol than placebo ( p < 0.001 ) . Indacaterol demonstrated significantly higher peak FEV1 than placebo , both on Day 1 and at Week 12 , with indacaterol-placebo differences ( LSM ± SEM ) of 190 ± 28 ( p < 0.001 ) and 160 ± 28 mL ( p < 0.001 ) , respectively . St and ardised AUC measurements for FEV1 ( between 5 min and 4 h , 5 min and 1 h , and 1 and 4 h post-dose ) at Week 12 were all significantly greater with indacaterol than placebo ( p < 0.001 ) , with LSM ( ± SEM ) differences of 170 ± 24 , 180 ± 24 , and 170 ± 24 mL , respectively . Indacaterol significantly reduced the percentage of days of poor control versus placebo by 22.5 % ( p < 0.001 ) and was also associated with significantly reduced use of rescue medication ( p < 0.001 ) . The overall rates of AEs were comparable between the groups ( indacaterol 49.3 % , placebo 46.8 % ) , with the most common AEs being COPD worsening ( indacaterol 8.5 % , placebo 12.2 % ) and cough ( indacaterol 6.2 % , placebo 7.3 % ) . One patient died in the placebo group . Serum potassium and blood glucose levels did not differ significantly between the two groups , and no patient had QTc > 500 ms . Conclusions Indacaterol 150 μg o.d . provided clinical ly significant and sustained bronchodilation , reduced rescue medication use , and had a safety and tolerability profile similar to placebo . Trial registration [5629944] Objectives Cardiovascular disease ( CVD ) and chronic obstructive pulmonary disease ( COPD ) often coexist . We assessed the effect of inhaled COPD treatments on CVD outcomes and safety in patients with COPD and at heightened CVD risk . Methods The SUMMIT ( Study to Underst and Mortality and MorbidITy ) was a multicentre , r and omised , double-blind , placebo-controlled , event-driven trial in 16 485 patients with moderate COPD who had or were at high risk of CVD . Here , we assessed the prespecified secondary endpoint of time to first on-treatment composite CVD event ( CVD death , myocardial infa rct ion , stroke , unstable angina or transient ischaemic attack ( TIA ) ) by Cox regression and by clinician-reported CVD adverse events across the four groups : once-daily inhaled placebo ( n=4111 ) , long-acting beta2-agonist ( vilanterol ( VI ) 25 µg ; n=4118 ) , corticosteroid ( fluticasone furoate ( FF ) 100 µg ; n=4135 ) and combination therapy ( FF/VI ; n=4121 ) . Results Participants were predominantly middle-aged ( mean 65 ( SD 8) years ) men ( 75 % ) with overt CVD ( 66 % ) . The composite CVD endpoint occurred in 688 patients ( first event : sudden death ( 35 % ) , acute coronary syndrome ( 37 % ) and stroke or TIA ( 23 % ) , and was not reduced in any treatment group versus placebo : VI ( HR 0.99 , 95 % CI 0.80 to 1.22 ) , FF ( HR 0.90 , 95 % CI 0.72 to 1.11 ) and their combination ( HR 0.93 , 95 % CI 0.75 to 1.14 ) . Outcomes were similar among all subgroups . Adverse events , including palpitations and arrhythmias , did not differ by treatment . Conclusions In patients with COPD with moderate airflow limitation and heightened CVD risk , treatment with inhaled VI , FF or their combination has an excellent safety profile and does not impact CVD outcomes . Trial registration number NCT01313676 [11948033] STUDY OBJECTIVE To compare the efficacy , tolerability , and safety of therapy with formoterol and oral slow-release theophylline ( THEO ) in patients with COPD . DESIGN A r and omized , parallel-group study , with double-blind arms for formoterol and placebo ( PL ) and an open arm for oral slow-release THEO administered in individual doses on the basis of plasma concentrations . SETTING Eighty-one centers worldwide . PATIENTS Eight hundred fifty-four patients with symptomatic COPD . INTERVENTION Comparison of twice-daily inhaled formoterol dry powder ( 12 or 24 microg ) , PL , and THEO ( individualized doses ) over 12 months . MEASUREMENTS AND RESULTS Compared to PL , doses of formoterol and THEO both significantly improved the area under the curve for FEV(1 ) measured over a period of 12 h following the morning dose of study medication at 3 and 12 months ( p < 0.001 for all comparisons ) . Therapy with formoterol , 12 microg , was significantly more effective than that with THEO ( p < or = 0.026 ) . Formoterol significantly reduced the percentage of " bad days " ( i.e. , days with at least two individual symptom scores > or = 2 and /or a reduction in peak expiratory flow from a baseline of > 20 % ; p < or = 0.035 vs. PL and THEO ) , and the use of salbutamol rescue medication ( p < or = 0.003 vs PL ) over the whole treatment period , while the effect of THEO was similar to that of PL . Therapy with formoterol and THEO was more effective than PL at improving quality of life for > 12 months ( p < or = 0.030 ) . Treatment-related adverse events and discontinuations were more frequent among patients receiving THEO than among those receiving formoterol . CONCLUSIONS Long-term treatment with inhaled formoterol dry powder is more effective and better tolerated than treatment with therapeutically appropriate doses of oral slow-release THEO in symptomatic patients with COPD [20522841] Background Indacaterol is a long-acting inhaled β2-agonist ( LABA ) for the treatment of chronic obstructive pulmonary disease ( COPD ) . In previous studies , indacaterol provided 24 h bronchodilation on once-daily dosing with a fast onset of action . This study compared the efficacy and safety of indacaterol with the twice-daily LABA formoterol and placebo over 1 year . Methods Patients with moderate to severe COPD were r and omised to receive once-daily indacaterol 300 μg ( n=437 ) or 600 μg ( n=428 ) , twice-daily formoterol 12 μg ( n=435 ) or placebo ( n=432 ) for 52 weeks in a double-blind double-dummy parallel group study . The primary efficacy variable was forced expiratory volume in 1 s ( FEV1 ) measured 24 h postdose after 12 weeks ( indacaterol vs placebo ) . Other outcomes included dyspnoea ( transition dyspnoea index , TDI ) , use of as-needed salbutamol , symptom-based measures recorded on diary cards , exacerbations , health status ( St George 's Respiratory Question naire ) , BODE index ( body mass index , obstruction , dyspnoea , exercise ) , safety and tolerability . Results Indacaterol increased 24 h postdose FEV1 after 12 weeks by 170 ml ( both doses ) versus placebo and by 100 ml versus formoterol ( all p<0.001 ) . These significant differences were maintained at 52 weeks . Symptomatic outcomes were improved compared with placebo with all active treatments , and indacaterol was more effective than formoterol in improving TDI score and reducing the need for as-needed salbutamol . Indacaterol was well tolerated and had a good overall safety profile , including minimal impact on QTc interval and systemic β2-mediated events . Conclusions Once-daily indacaterol is an effective 24 h bronchodilator that improves symptoms and health status and confers clinical improvements over a twice-daily 12 h LABA as a treatment for patients with moderate to severe COPD . Trial registration number NCT 00393458 [2629970] Clinical manifestations of chronic obstructive pulmonary disease ( COPD ) , including airflow limitation , dyspnea , and activity limitation , ultimately lead to impaired health-related quality of life ( HRQoL ) . This 9-month , r and omized , double-blind , multicenter study compared the effect of once-daily tiotropium 18 μg and placebo on HRQoL , spirometric parameters , and exacerbations in 554 patients with moderate-to-severe COPD . HRQoL was assessed using the St. George ’s Respiratory Question naire ( SGRQ ) and the new 8-item Visual Simplified Respiratory Question naire ( VSRQ ) , which is currently being vali date d. The primary efficacy endpoint was the proportion of patients achieving a reduction of at least 4 units in the SGRQ total score at study end ( Month 9 ) . Mean ± SD baseline SGRQ total score was 47.4 ± 18.1 . Significantly more tiotropium-treated patients achieved a reduction of at least 4 units in the SGRQ score vs placebo at study end ( 59.1 % vs 48.2 % , respectively ; p = 0.029 ) . Tiotropium significantly improved spirometric parameters ( forced expiratory volume in 1 second [ FEV1 ] : 0.11 ± 0.02 L vs 0.01 ± 0.02 L ; between-group difference : 0.10 ± 0.03 L , p = 0.0001 ) and reduced exacerbations vs placebo . Maintenance treatment with tiotropium provided significant and clinical ly relevant improvements in HRQoL , as measured by the SGRQ [23352226] BACKGROUND Fluticasone furoate (FF)/vilanterol ( VI ) is a novel once-daily inhaled corticosteroid/long-acting β2-agonist combination therapy for COPD . We aim ed to assess the efficacy and safety of two strengths of FF/VI ( 100/25 μg ; 50/25 μg ) vs. individual components ( FF 100 μg , VI 25 μg ) and placebo over 24 weeks . METHODS Multicentre , r and omised , placebo-controlled , double-blind , parallel-group study of patients ( N = 1030 ) with moderate-to-severe COPD . All medication was administered once daily in the morning . Co- primary efficacy endpoints were : ( 1 ) weighted mean ( wm ) FEV1 ( 0 - 4 h post-dose on day 168 ) to assess acute lung function effects ; and ( 2 ) trough FEV1 ( 23 - 24 h post-dose on day 169 ) to assess long-lasting effects . Symptom-related outcomes were analysed and adverse events ( AEs ) assessed . RESULTS Main findings were : ( 1 ) the combination of FF/VI at a strength of 100/25 μg significantly ( p < 0.001 ) improved wm FEV1 ( 173 ml ) and trough FEV1 ( 115 ml ) vs. placebo . Similar effects were observed with FF/VI 50/25 μg ; ( 2 ) no significant difference was seen between FF/VI 100/25 μg and VI 25 μg for trough FEV1 ( 48 ml , p = 0.082 ) , while an effect was observed between FF/VI 100/25 μg and FF 100 μg for wm FEV1 ( 120 ml , p < 0.001 ) ; ( 3 ) VI 25 μg over 24 weeks improved lung function vs. placebo significantly for wm FEV1 ( 103 ml , p < 0.001 ) and trough FEV1 ( 67 ml , p = 0.017 ) ; and ( 4 ) no safety signal was observed . CONCLUSIONS In subjects with moderate-to-severe COPD , FF/VI 100/25 μg provides rapid and significant sustained bronchodilation at 24 weeks . Lung function is improved to a similar extent with FF/VI 50/25 μg and to a somewhat lesser extent with VI 25 μg . All treatments were well tolerated . GSK study number : HZC112206 . Clinical Trials.gov : NCT01053988 [4562726] Background Combination of the inhaled long-acting muscarinic antagonist umeclidinium ( UMEC ; GSK573719 ) with the long-acting β2-agonist vilanterol ( VI ) is an approved maintenance treatment for COPD in the US and EU . We compared the efficacy and safety of UMEC/VI with placebo in patients with COPD of Asian ancestry . Patients and methods In this 24-week , Phase III , multicenter , r and omized , double-blind , placebo-controlled , parallel-group study , patients were r and omized 1:1:1 to UMEC/VI 125/25 μg , UMEC/VI 62.5/25 μg , or placebo . The primary efficacy end point was trough forced expiratory volume in 1 second ( FEV1 ) on day 169 ; secondary end points were Transition Dyspnea Index ( TDI ) focal score at week 24 and weighted mean ( WM ) FEV1 over 0–6 hours postdose on day 1 . Additional end points and safety were also assessed . Results Both UMEC/VI 125/25 μg and UMEC/VI 62.5/25 μg statistically significantly improved trough FEV1 at day 169 versus placebo ( UMEC/VI 125/25 μg , 0.216 L , [ 95 % confidence interval [ CI ] 0.175–0.257 ] ; UMEC/VI 62.5/25 μg , 0.151 L , 95 % CI 0.110–0.191 ; both P<0.001 ) . Statistically significant improvements in TDI score were observed for both UMEC/VI groups versus placebo ( UMEC/VI 125/25 μg , 0.9 , 95 % CI 0.3–1.4 , P=0.002 ; UMEC/VI 62.5/25 μg , 0.7 , 95 % CI 0.1–1.2 , P=0.016 ) . On day 1 , both UMEC/VI groups improved 0–6-hour WM FEV1 versus placebo ( UMEC/VI 125/25 μg , 0.182 L 95 % CI 0.161–0.203 ; UMEC/VI 62.5/25 μg , 0.160 L , 95 % CI 0.139–0.181 ; both P<0.001 ) . Statistically significant improvements for UMEC/VI groups versus placebo were observed for rescue albuterol use at weeks 1–24 ( puffs/day , both P<0.001 ) . The incidence of adverse events was similar across groups . Conclusion In Asian patients with COPD , once-daily UMEC/VI 125/25 μg and UMEC 62.5/25 μg result ed in clinical ly meaningful and statistically significant improvements in lung-function end points versus placebo . Symptomatic and quality of life measures also improved . The safety profile of UMEC/VI was consistent with previous studies [4273456] Background Aclidinium/formoterol is a twice-daily ( BID ) fixed-dose combination ( FDC ) in development for chronic obstructive pulmonary disease ( COPD ) . The efficacy and safety of aclidinium/formoterol versus monotherapy and placebo in patients with COPD was assessed . Methods In this 24-week double-blind , parallel-group , active- and placebo-controlled , multicentre Phase III study , patients ( ≥40 years , post-bronchodilator forced expiratory volume in 1 second [FEV1]/forced vital capacity < 70 % and FEV1 ≥30 % but < 80 % predicted normal ) were r and omised 2:2:2:2:1 to aclidinium/formoterol 400/12 μg ( n = 385 ) or 400/6 μg ( n = 381 ) , aclidinium 400 μg ( n = 385 ) , formoterol 12 μg ( n = 384 ) or placebo ( n = 194 ) BID via Genuair ® /Pressair ® a . Results At Week 24 , aclidinium/formoterol 400/12 μg and 400/6 μg lead to significant improvements from baseline in 1-hour post-dose FEV1 versus aclidinium ( 125 mL [ 95 % CI : 90 , 160 ; p < 0 · 001 ] and 69 mL [ 95 % CI : 34 , 105 ; p < 0.001 ] , respectively ) and trough FEV1 versus formoterol ( 85 mL [ 95 % CI : 51 , 119 ; p < 0.001 ] and 53 mL [ 95 % CI : 19 , 87 ; p < 0.01 ] , respectively ; co- primary endpoints ) . Additionally , aclidinium/formoterol 400/12 μg and 400/6 μg provided significant improvements in Transition Dyspnoea Index ( TDI ) focal score versus placebo ( 1.29 units [ 95 % CI : 0.73 , 1.86 ; p < 0.001 ] and 1.16 units [ 95 % CI : 0.59 , 1.73 ; p < 0.001 ] , respectively ; secondary endpoint ) . All treatments were well tolerated , with safety profiles of the FDCs similar to those of placebo and monotherapy . Conclusions Both aclidinium/formoterol BID doses significantly improved bronchodilation versus monotherapy , and dyspnoea versus placebo , with no increase in safety risk . Aclidinium/formoterol may be an effective treatment for patients with COPD .Trial registration Clinical Trials.gov : NCT01462942 [20685748] Background Previous studies have suggested that long-term use of β agonists to treat chronic obstructive pulmonary disease ( COPD ) may increase the risk of cardiovascular adverse events . In this post hoc analysis , data from the TOwards a Revolution in COPD Health ( TORCH ) study were used to investigate whether use of the long-acting β2 agonist salmeterol over 3 years increased the risk of cardiovascular adverse events in patients with moderate to severe COPD . Methods TORCH was a r and omised , double-blind , placebo controlled study conducted at 444 centres in 42 countries . Patients ( n=6184 ; safety population ) received twice daily combined salmeterol 50 μg plus fluticasone propionate 500 μg ( SFC ) , either component alone , or placebo . Adverse events were recorded every 12 weeks for 3 years . Results The probability of having a cardiovascular adverse event by 3 years was 24.2 % for placebo , 22.7 % for salmeterol , 24.3 % for fluticasone propionate and 20.8 % for SFC . Although a history of myocardial infa rct ion doubled the probability of cardiovascular adverse events , the event rates remained similar across treatment groups . Conclusion Post hoc analysis of the 3-year TORCH data set showed that salmeterol alone or in combination ( SFC ) did not increase the risk of cardiovascular events in patients with moderate to severe COPD [4064950] Background Olo date rol is a long-acting β2-agonist with a 24-hour bronchodilator profile . Two replicate , r and omized , double-blind , placebo-controlled , parallel-group , Phase III trials were performed as part of a comprehensive clinical program to investigate the long-term safety and efficacy of olo date rol in patients with moderate to very severe chronic obstructive pulmonary disease ( COPD ) receiving usual-care background therapy . Methods Patients received olo date rol 5 μg or 10 μg or placebo once daily for 48 weeks . Co primary end points were forced expiratory volume in 1 second ( FEV1 ) area under the curve from 0 to 3 hours ( AUC0–3 ) response ( change from baseline ) , and trough FEV1 response at 12 weeks . Secondary end points included additional lung function assessment s , use of rescue medications , FEV1 AUC response from 0 to 12 hours , and Patient Global Rating over 48 weeks . Results Overall , 624 and 642 patients were evaluated in studies 1222.11 and 1222.12 , respectively . In both studies , olo date rol 5 μg and 10 μg significantly improved the FEV1 AUC0–3 response ( P<0.0001 ) and trough FEV1 ( study 1222.11 , P<0.0001 ; study 1222.12 , P<0.05 , post hoc ) at week 12 , with an incidence of adverse events comparable with that of placebo . Secondary end points supported the efficacy of olo date rol . Conclusion These studies demonstrate the long-term efficacy and safety of once-daily olo date rol 5 μg and 10 μg in patients with moderate to very severe COPD continuing with usual-care maintenance therapy [20463178] RATIONALE Indacaterol is the first once-daily , long-acting inhaled beta(2)-agonist bronchodilator studied in patients with chronic obstructive pulmonary disease ( COPD ) . OBJECTIVES To demonstrate greater efficacy of indacaterol versus placebo on FEV(1 ) at 24 hours post dose ( trough ) after 12 weeks , to compare efficacy with placebo and tiotropium , and to evaluate safety and tolerability over 26 weeks . MEASUREMENTS Patients with moderate-to-severe COPD were r and omized to double-blind indacaterol 150 or 300 microg or placebo , or open-label tiotropium 18 microg , all once daily , for 26 weeks . The primary efficacy outcome was trough FEV(1 ) at 12 weeks . Additional analyses ( not adjusted for multiplicity ) included transition dyspnea index ( TDI ) , health status ( St George 's Respiratory Question naire [ SGRQ ] ) , and exacerbations . Serum potassium , blood glucose , and QTc interval were measured . RESULTS A total of 1,683 patients ( age , 63.3 yr ; post-bronchodilator FEV(1 ) , 56 % predicted ; FEV(1)/FVC , 0.53 ) were r and omized to the four treatment arms . Trough FEV(1 ) at Week 12 increased versus placebo by 180 ml with both indacaterol doses and by 140 ml with tiotropium ( all P < 0.001 vs. placebo ) . At Week 26 , for indacaterol 150/300 microg , respectively , versus placebo , TDI increased ( 1.00/1.18 , P < 0.001 ) and SGRQ total score decreased ( -3.3/-2.4 , P < 0.01 ) ; corresponding results with tiotropium were 0.87 ( P < 0.001 ) for TDI and ( -1.0 , P = not significant ) for SGRQ total score . The incidence of adverse events , low serum potassium , high blood glucose , and prolonged QTc interval was similar across treatments . CONCLUSIONS Indacaterol was an effective once-daily bronchodilator and was at least as effective as tiotropium in improving clinical outcomes for patients with COPD . Clinical trial registered with clinical trials.gov ( NCT 00463567 ) [20080201] BACKGROUND The drug development process can be streamlined by combining the traditionally separate stages of dose-finding ( Phase IIb ) and confirmation of efficacy and safety ( Phase III ) using an adaptive seamless design . This approach was used in a clinical study of indacaterol , a novel once-daily ( od ) inhaled long-acting beta(2)-adrenoreceptor agonist bronchodilator for the treatment of COPD ( chronic obstructive pulmonary disease ) . METHODS The study comprised a dose-finding stage with dose selection after 14 days of treatment , and a second stage evaluating efficacy and safety during 26 weeks of treatment . The dose-finding stage included seven r and omized treatment arms : double-blind indacaterol 75 microg , 150 microg , 300 microg or 600 microg od , the beta(2)-adrenoceptor agonist formoterol 12 microg twice-daily or placebo , or the anticholinergic tiotropium 18 microg od open-label . An independent data monitoring committee selected two indacaterol doses based on unblinded results of an interim analysis performed by an independent statistician . The sponsor , investigators and patients remained blinded to the results . The indacaterol doses were selected using pre-set efficacy criteria for trough ( 24-h post-dose ) and early ( 1 - 4 h post-dose ) bronchodilator effect after 14 days , and all safety data . To qualify for selection , the doses had to exceed a threshold for clinical relevance or be superior to either tiotropium or formoterol , whichever was the highest value . Selected doses were continued into the second , 26-week stage . The two other indacaterol doses not selected , and formoterol , were discontinued following dose selection . RESULTS 801 patients with moderate-to-severe COPD were evaluated . Indacaterol 150 microg was the lowest effective dose , exceeding criteria for trough FEV(1 ) ( reference value 140 mL vs placebo ) and FEV(1 ) AUC(1 - 4 h ) ( reference value 220 mL vs placebo ) . No safety signal was observed with any dose of indacaterol . Thus , indacaterol 150 and 300 microg were selected to continue into the second , 26-week stage . CONCLUSION The adaptive seamless design is a novel and efficient way to combine dose selection with efficacy evaluation and safety confirmation in a single trial [27916620] Background : Long‐acting muscarinic antagonist (LAMA)/long‐acting & bgr;2‐agonist ( LABA ) combinations are a treatment option for patients with COPD who continue to have symptoms despite treatment with a LAMA or a LABA alone . The Efficacy and Safety of PT003 , PT005 , and PT001 in Subjects with Moderate‐to‐Very Severe COPD ( PINNACLE‐1 ) ( NCT01854645 ) and the Multi‐Center Study to Assess the Efficacy and Safety of PT003 , PT005 , and PT001 in Subjects with Moderate‐to‐Very Severe COPD ( PINNACLE‐2 ) ( NCT01854658 ) trials investigated the efficacy and safety of a novel glycopyrrolate [GP]/formoterol [ FF ] 18/9.6‐&mgr;g ( GFF ) metered dose inhaler ( MDI ) formulated using the Co‐Suspension Delivery Technology in patients with moderate‐to‐very severe COPD . Methods : These two phase III trials took place over 24 weeks and were r and omized , double blind , and placebo controlled ; 2,103 and 1,615 patients ( 40–80 years of age ) , respectively , were r and omized . Patients received GFF MDI , GP MDI 18 & mgr;g , FF MDI 9.6 & mgr;g , or placebo MDI ( all twice daily ) , or tiotropium 18 & mgr;g dry powder inhaler ( once daily in PINNACLE‐1 only [ open‐label active comparator ] ) . Efficacy and safety were assessed . Results : At week 24 , differences in change from baseline in the morning predose trough FEV1 for GFF MDI vs placebo MDI , GP MDI , and FF MDI were 150 mL , 59 mL , and 64 mL in PINNACLE‐1 ( all P < .0001 ) and 103 mL , 54 mL , and 56 mL in PINNACLE‐2 ( all P < .001 ) , respectively . There were no significant safety findings ( incidence of adverse events was similar between treatment arms ) . Conclusions : We conclude that GFF MDI 18/9.6 & mgr;g demonstrated superiority over placebo and monocomponent MDIs and was well tolerated , thus providing an additional treatment option for patients with moderate‐to‐very severe COPD . Trial Registry : Clinical Trials.gov ; No. : NCT01854645 and No. NCT01854658 ; URL : www . clinical trials.gov [26177074] RATIONALE Current Global Initiative for Chronic Obstructive Lung Disease ( GOLD ) strategy recommends the combination of two long-acting bronchodilators of different pharmacologic classes for the management of chronic obstructive pulmonary disease ( COPD ) if symptoms are not adequately controlled by a single bronchodilator . OBJECTIVES The FLIGHT1 and FLIGHT2 studies evaluated the efficacy and safety of QVA149 ( indacaterol/glycopyrrolate ) , a fixed-dose combination of a long-acting β2-agonist ( indacaterol ) and a long-acting muscarinic antagonist ( glycopyrrolate ) , compared with its monocomponents and placebo in patients with moderate-to-severe COPD . METHODS FLIGHT1 and FLIGHT2 were 12-week , identical , multicenter , r and omized , double-blind , parallel-group , placebo- and active-controlled studies . Patients were r and omized ( 1:1:1:1 ) to indacaterol/glycopyrrolate ( 27.5/15.6 μg twice daily ) , indacaterol ( 27.5 μg twice daily ) , glycopyrrolate ( 15.6 μg twice daily ) , or placebo , all delivered via the Neohaler device . The primary objective was to demonstrate the superiority of indacaterol/glycopyrrolate versus its monocomponents for st and ardized area under the curve from 0 - 12 hours for FEV1 at Week 12 . Secondary objectives included St. George 's Respiratory Question naire total score and transition dyspnea index total score and reduction in daily rescue medication use with indacaterol/glycopyrrolate versus placebo . MEASUREMENTS AND MAIN RESULTS In total , 2,038 patients were included in the pooled analysis . Indacaterol/glycopyrrolate was statistically superior in terms of FEV1 area under the curve from 0 - 12 hours compared with its monocomponents ( P < 0.001 ) . Statistically and clinical ly meaningful improvements in St. George 's Respiratory Question naire total score , transition dyspnea index total score , and reduction in rescue medication use were observed with indacaterol/glycopyrrolate compared with placebo ( P < 0.001 ) . The safety profile was comparable across the treatment groups . CONCLUSIONS Indacaterol/glycopyrrolate twice daily can be an alternative treatment option for the management of symptomatic patients with moderate-to-severe COPD . Clinical trial registered with www . clinical trials.gov ( NCT 01727141 and NCT 0171251 ) [18042473] BACKGROUND Recently , there have been concerns about the tolerability of long-acting (2)-agonists , including possible adverse cardiovascular effects-a particular concern in patients with chronic obstructive pulmonary disease ( COPD ) , who are at elevated risk for cardiovascular disease . OBJECTIVE The aim of this study was to assess the cardiac safety profile of nebulized formoterol fumarate inhalation solution . METHODS Cardiac safety was assessed as part of a 12-week , r and omized , double-blind , double-dummy , placebo- and active-controlled trial that was conducted at 38 centers across the United States . Male and female patients aged > /=40 years with COPD and without other significant disease were enrolled . After a 4- to 14-day , single-blind placebo run-in period , patients with COPD were r and omly assigned to receive formoterol fumarate inhalation solution 20 microg BID via nebulizer ( FFIS group ) , formoterol fumarate 12 microg BID via dry powder inhaler ( FA group ) , or placebo . Cardiac effects-measured by changes in heart rate ( HR ) and ventricular premature beats ; incidence of proarrhythmic events ; change in corrected QT ( QTc ) interval ; and incidence of maximum mean change in QTc > /=60 ms-were assessed using 24-hour Holter monitoring at baseline and 12 weeks ; 12-lead electrocardiography at screening and weeks 4 , 8 , and 12 ; and patient diary cards . RESULTS A total of 351 patients with COPD were r and omized ( mean age , 62.8 years ; 56.1 % male ; mean postbronchodilator forced expiratory volume in 1 second , 1.5 L ) . Holter monitoring found no clinical ly meaningful effects of FFIS or FA treatment on mean or maximum HR , ventricular premature beats , or inci dence of arrhythmic events compared with placebo . At week 12 , mean ( SD ) changes from baseline in mean HR were -0.6 ( 10.9 ) , + 0.1 ( 11.6 ) , and -1.4 ( 9.4 ) bpm in the FFIS , FA , and placebo groups , respectively . The incidence of mean maximum changes in QTc > /=60 ms at any time during the 12-week treatment period were 1.6 % , 1.8 % , and 1.8 % with FFIS , FA , and placebo , respectively . Treatment-emergent cardiac adverse events ( AEs ) occurred in 4.1 % , 3.5 % , and 4.4 % of patients in the FFIS , FA , and placebo groups ; withdrawals due to possible cardiac AEs occurred in 1 patient per treatment group . No deaths or serious cardiac AEs occurred during the treatment period . CONCLUSION In this COPD population , no clinical ly significant cardiac effects were found with twicedaily treatment with nebulized formoterol fumarate inhalation solution [22177371] BACKGROUND Indacaterol is the first once-daily , long-acting , inhaled β(2)-agonist bronchodilator for maintenance treatment of chronic obstructive pulmonary disease ( COPD ) . Two studies ( previously reported in a Congress abstract ) were performed in 2010 to provide efficacy and tolerability data to support the application for approval in the United States of indacaterol 75 μg once daily , a dose lower than that previously investigated in most studies . OBJECTIVE The primary objective was to evaluate the efficacy of indacaterol 75 μg once daily in terms of 24-hour post-dose ( " trough " ) forced expiratory volume in the first second of respiration ( FEV(1 ) ) compared with placebo after 12 weeks of treatment . METHODS Patients with moderate to severe COPD were r and omized to receive double-blind treatment with indacaterol 75 μg once daily ( n = 163 and 159 ) or placebo ( n = 160 and 159 ) for 12 weeks . In addition to trough FEV(1 ) after 12 weeks , rescue albuterol use , health status ( St. George 's Respiratory Question naire [ SGRQ ] ) , and tolerability were evaluated . Clinical ly relevant differences between active and placebo treatments were defined as ≥120 mL for trough FEV(1 ) and a decrease of ≥4 units in SGRQ total score . RESULTS Of patients enrolled in the 2 studies , 54 % were men , and 90 % and 94 % were white , with mean age 64 and 61 years . Mean duration of COPD was 7 years ; smoking history was 52 pack-years ; and 45 % and 37 % of patients were receiving inhaled corticosteroid therapy . At week 12 , indacaterol demonstrated clinical ly relevant bronchodilator efficacy , increasing trough FEV(1 ) by ≥120 mL versus placebo ( P < 0.001 ) , with significant bronchodilation maintained at all time points from 5 minutes to 24 hours post-dose . Over 12 weeks , relative to placebo , in patients receiving indacaterol therapy , rescue albuterol use was reduced by 1.2 and 0.7 puffs per day ( P < 0.01 ) , and the percentage of rescue-free days was increased by 13.7 and 8.4 ( P < 0.01 ) . At week 12 , the SGRQ total score differed in the indacaterol group versus the placebo group by -3.8 and -3.6 , respectively ( P ≤ 0.01 ) . Adverse events were reported for 49 % and 45 % of patients receiving indacaterol therapy , and for 46 % and 41 % receiving placebo . CONCLUSIONS Compared with placebo , indacaterol 75 μg once daily provided statistically significant and clinical ly relevant 24-hour bronchodilation and was well tolerated . In patients receiving indacaterol , the reduction in rescue albuterol use was statistically significant . Changes in health status also were statistically significant compared with placebo , although the differences of 3.6 and 3.8 units were below the predefined 4-unit level of clinical relevance . The results of these studies suggest that indacaterol 75 μg once daily is an effective maintenance treatment in patients with moderate to severe COPD . Clinical Trials.gov identifiers : NCT01072448 and NCT01068600 [20620037] In this r and omised double-blind study , patients > or=40 years old with COPD , a smoking history of > or=10 pack-years , a pre-bronchodilator FEV(1 ) of < or=60 % predicted and an FEV(1)/FVC of < or=70 % received tiotropium 5 microg or placebo via Respimat inhaler once daily for 48 weeks . Other medications were permitted except inhaled anticholinergics . Co- primary endpoints were trough FEV(1 ) and the time to first exacerbation . Adverse events were followed and vital status regularly assessed . In all , 3991 patients ( mean age , 65 years [ SD , 9 years ] ) were evaluable . Mean baseline FEV(1 ) was 1.11 L ( 0.40 L ) or 40 % ( 12 % ) of predicted normal . Adjusted mean differences in trough FEV(1 ) and trough FVC at Week 48 ( tiotropium minus placebo ) were 102 and 168 ml respectively ( p < 0.0001 , both ) . Tiotropium delayed time to first exacerbation relative to placebo ( hazard ratio [ HR ] , 0.69 [ 95 % CI , 0.63 - 0.77 ] ) and time to first hospital-treated exacerbation ( HR , 0.73 [ 0.59 - 0.90 ] ) . SGRQ score at Week 48 was 2.9 units lower with tiotropium ( p < 0.0001 ) . Adverse and serious adverse events were balanced across treatment groups and similar in profile to previous tiotropium trials . The rate ratio for a major adverse cardiovascular event during the treatment period + 30 days was 1.12 ( 0.67 - 1.86 ) . By the end of planned treatment ( Day 337 ) 52 patients on tiotropium ( incidence rate per 100 years , 2.94 ) and 38 on placebo ( 2.13 ) had died ( HR = 1.38 [ 0.91 - 2.10 ] ; p = 0.13 ) . Lung function , exacerbations and quality of life were improved by tiotropium 5 microg Respimat but a numerical imbalance was seen in all-cause mortality . The protocol is registered on the European Clinical Trials Data base as trial number 2006 - 001009 - 27 and in the Clinical Trials.gov data base as NCT00387088 [22561964] RATIONALE Patients with chronic obstructive pulmonary disease ( COPD ) are afflicted by comorbidities . Few studies have prospect ively evaluated COPD comorbidities and mortality risk . OBJECTIVES To prospect ively evaluate COPD comorbidities and mortality risk . METHODS We followed 1,664 patients with COPD in five centers for a median of 51 months . Systematic ally , 79 comorbidities were recorded . We calculated mortality risk using Cox proportional hazard , and developed a graphic representation of the prevalence and strength of association to mortality in the form of a " comorbidome " . A COPD comorbidity index ( COPD specific comorbidity test [ COTE ] ) was constructed based on the comorbidities that increase mortality risk using a multivariate analysis . We tested the COTE index as predictor of mortality and explored whether the COTE index added predictive information when used with the vali date d BODE index . MEASUREMENTS AND MAIN RESULTS Fifteen of 79 comorbidities differed in prevalence between survivors and nonsurvivors . Of those , 12 predicted mortality and were integrated into the COTE index . Increases in the COTE index were associated with an increased risk of death from COPD -related ( hazard ratio [ HR ] , 1.13 ; 95 % confidence interval , 1.08 - 1.18 ; P < 0.001 ) and non- COPD -related causes ( HR , 1.18 ; 95 % confidence interval , 1.15 - 1.21 ; P < 0.001 ) . Further , increases in the BODE and COTE were independently associated with increased risk of death . A COTE score of greater than or equal to 4 points increased by 2.2-fold the risk of death ( HR , 2.26 - 2.68 ; P < 0.001 ) in all BODE quartile . CONCLUSIONS Comorbidities are frequent in COPD and 12 of them negatively influence survival . A simple disease-specific comorbidities index ( COTE ) helps assess mortality risk in patients with COPD [23332861] BACKGROUND Once-daily combination treatment is an attractive maintenance therapy for COPD . However , the dose of inhaled corticosteroid to use in a once-daily combination is unknown . We compared two strengths of fluticasone furoate ( FF ) plus vilanterol ( VI ) , the same strengths of the individual components , and placebo . METHODS Multicentre , r and omised , 24-week , double-blind , placebo-controlled , parallel-group study in stable , moderate-to-severe COPD subjects ( N = 1224 ) . Subjects were r and omised to FF/VI ( 200/25 μg ; 100/25 μg ) , FF ( 200 μg ; 100 μg ) , VI 25 μg , or placebo , once daily in the morning . Co- primary efficacy endpoints ; 0 - 4 h weighted mean ( wm ) FEV(1 ) on day 168 , and change from baseline in trough ( 23 - 24 h post-dose ) FEV(1 ) on day 169 . The primary safety objective was adverse events ( AEs ) . RESULTS There was a statistically significant ( p < 0.001 ) increase in wm FEV(1 ) ( 209 ml ) and trough FEV(1 ) ( 131 ml ) for FF/VI 200/25 μg vs. placebo ; similar changes were seen for FF/VI 100/25 μg vs. placebo . Whereas the difference between FF/VI 200/25 μg and VI 25 μg in change from baseline trough FEV(1 ) ( 32 ml ) was not statistically significant ( p = 0.224 ) , the difference between FF/VI 200/25 μg and FF 200 μg for wm FEV(1 ) ( 168 ml ) was significantly different ( p < 0.001 ) . VI 25 μg significantly improved wm and trough FEV(1 ) vs. placebo ( 185 ml and 100 ml , [ corrected ] respectively ) . No increase was seen in on-treatment AEs or serious AEs ( SAEs ) , with active therapy vs. placebo . CONCLUSIONS FF/VI provides rapid and significant sustained improvement in FEV(1 ) in subjects with moderate-to-severe COPD , which was not influenced by the dose of FF . These data suggest that FF/VI may offer clinical efficacy in COPD and warrants additional study . GSK study number : HZC112207 . Clinical Trials.gov : NCT01054885 [24383720] BACKGROUND AND OBJECTIVE This study , in a predominantly Chinese population , investigated the efficacy and safety of a once-daily ( o.d . ) inhaled ultra-long-acting β2 -agonist indacaterol for the treatment of moderate-to-severe chronic obstructive pulmonary disease ( COPD ) . METHODS This is a 26-week , double-blind study on r and omized patients who received indacaterol 150 μg or 300 μg or placebo o.d . The primary variable was trough forced expiratory volume in 1 s ( FEV1 , average of 23 h 10 min and 23 h 45 min post-dose values ) at Week 12 . Health status ( St George 's Respiratory Question naire , SGRQ ) , dyspnoea ( transition dyspnoea index , TDI ) and safety were evaluated over 26 weeks . RESULTS Of the 563 patients r and omized , 561 ( 89.8 % Chinese ) received treatment and 482 completed . At Week 12 , trough FEV1 improved significantly for indacaterol 150 and 300 μg versus placebo ( 1.32 , 1.29 vs 1.17 ; P < 0.001 for both comparisons ) , with differences exceeding the pre-specified minimal clinical ly important difference of 0.12 L. At Week 26 , TDI score was superior to placebo for indacaterol 150 and 300 μg ( 0.82 , 1.15 ; P < 0.01 ) , as was the percentage of patients with a clinical ly relevant improvement ( ≥1 point ) ( 74.1 % , 78.6 % vs 55.5 % ; P < 0.05 ) . Both doses provided ≥4-point improvements from baseline in SGRQ score at Week 26 that were numerically greater than placebo ( unadjusted means : -9.6 , -8.8 vs -7.0 ) , with a similar pattern in percentage of patients with clinical ly relevant improvements in SGRQ score ( 65.0 % , 61.5 % vs 60.6 % ) . Incidences of adverse events were comparable across treatment groups . CONCLUSIONS Indacaterol delivered effective bronchodilation with significant improvements in breathlessness and health status in this predominantly Chinese population [16144890] Context Tiotropium , a new once-daily inhaled anticholinergic bronchodilator , has been shown to improve lung function in patients with chronic obstructive pulmonary disease ( COPD ) . Previous studies have suggested that it may also decrease the frequency of exacerbations and hospitalizations in these patients . Contribution This r and omized , parallel-group , double-blind , placebo-controlled study in patients with moderate to severe COPD showed a small but statistically significant decrease in the exacerbation rate during the 6-month study period . Caution s The study period was relatively short , and the beneficial effects were modest . The Editors Exacerbations of chronic obstructive pulmonary disease ( COPD ) can lead to costly and clinical ly significant consequences . Proven treatments for exacerbations are only modestly effective ( 1 , 2 ) . Recovery from even mild exacerbations may be protracted ( 3 ) . Frequent exacerbations are associated with impaired quality of life and a more rapid decline in lung function over time ( 4 , 5 ) . Patients with severe exacerbations commonly seek care in emergency departments , and many of these patients are hospitalized . In 2000 , COPD was responsible for 1.5 million emergency department visits and 726000 hospitalizations in the United States ( 6 ) . Economic analyses suggest that hospitalization alone consumes up to 70 % of all medical expenses for patients with COPD ( 7 , 8) . Interventions that reduce the frequency or severity of exacerbations are a highly desirable but poorly met medical need . An expert panel convened by the National Heart , Lung , and Blood Institute assigned a high priority to clinical research that might improve the management of COPD exacerbations ( 9 ) . Tiotropium is a newly developed , once-daily inhaled anticholinergic bronchodilator . Because of its very slow dissociation from muscarinic M3 receptors , 1 inhaled dose produces sustained bronchodilation for at least 24 hours ( 10 ) . In controlled clinical trials , compared with placebo or the short-acting anticholinergic bronchodilator ipratropium , tiotropium improved lung function , dyspnea , and health-related quality of life in patients with COPD ( 11 , 12 ) . An analysis of adverse event reports su bmi tted during those studies suggested that tiotropium might also reduce exacerbation and COPD -related hospitalization rates . Therefore , we design ed a clinical trial to prospect ively test the hypothesis that tiotropium reduces exacerbations and hospitalizations due to COPD . Methods Study Design Our study was a parallel-group , r and omized , double-blind , placebo-controlled trial in patients with moderate to severe COPD conducted at 26 Veterans Affairs medical centers in the United States . The sole intervention was tiotropium given by inhalation once daily . The principal outcomes were the percentage of patients experiencing at least 1 exacerbation and the percentage of patients with at least 1 hospitalization due to a COPD exacerbation during a 6-month treatment period . The protocol is consistent with the principles of Helsinki . The institutional review boards of participating medical centers approved the study . All trial participants provided written informed consent . Patients All men and women receiving medical care at participating Veterans Affairs medical centers were potential study participants . We enrolled enough participants to ensure a minimum of 1800 r and omly assigned patients . Eligibility criteria included an age of 40 years or older , a cigarette smoking history of 10 pack-years or more , a clinical diagnosis of COPD , and an FEV1 of 60 % predicted or less and 70 % or less of the FVC . Exclusion criteria were a clinical diagnosis of asthma , a myocardial infa rct ion within the previous 6 months , a serious cardiac arrhythmia or hospitalization for heart failure within the previous year , known moderate to severe renal impairment , moderate to severe symptomatic prostatic hypertrophy or bladder-neck obstruction , narrow-angle glaucoma , current radiation or chemotherapy for a malignant condition , or inability to give informed consent . We also excluded patients who took systemic corticosteroids at unstable doses , or in regular daily doses of 20 mg or more of prednisone ( or equivalent ) , or who had not fully recovered from an exacerbation for at least 30 days before the first study visit . We gathered baseline data on respiratory disease and other relevant medical history by question naire . Procedures We allocated eligible patients in equal numbers to receive tiotropium or placebo according to a central ly generated blocked r and omization list . We generated a single r and omization and assigned blocks to centers . We provided r and omly assigned patients with training and detailed instructions on the use of the dry powder inhalation device ( H and iHaler , Boehringer Ingelheim Pharma GmbH & Co. KG , Biberach , Germany ) ( 13 ) . Blinding of supplies was performed at Boehringer Ingelheim before distribution to investigational sites . The double-blind remained in place until all patients were clinical ly complete or until a serious adverse event required unblinding . Each morning during the trial , patients inhaled 1 capsule of tiotropium ( 18 g ) or 1 identical placebo capsule . Participants otherwise received usual medical care , except that they could not take any open-label anticholinergic bronchodilator . They continued taking all other respiratory medications ( including inhaled corticosteroids and long-acting -agonists ) , and primary providers were allowed to prescribe additional medications according to medical need . Primary providers also prescribed antibiotics and systemic steroid prescriptions for exacerbations without restrictions . For purpose s of recall , patients kept a daily diary throughout the treatment period , recording information about specific respiratory symptoms , medications taken for exacerbations , clinic visits , and hospitalizations . We collected information about exacerbations and health care utilization by interviews when patients made site visits at 3 and 6 months and by telephone calls at 1-month intervals between visits . We assessed study drug adherence by query and by counting returned capsules . Participants performed spirometry before and 90 minutes after inhalation of study drug at baseline and again at the 3-month and 6-month visits . We encouraged patients to complete study visits and to provide all requested medical information even if they prematurely discontinued the study drug therapy . However , patients who discontinued the study drug therapy did not have 90-minute postinhalation spirometry testing at subsequent study visits . All open-label bronchodilators and the study drug were withheld overnight before spirometry . Study sites performed spirometry by using a common predictive nomogram with equipment and methods that conformed to American Thoracic Society recommendations ( 14 , 15 ) . Objectives We aim ed to determine whether tiotropium decreased COPD exacerbations and hospitalizations due to exacerbations . Outcome Measures The co primary outcomes were the percentage of patients with a COPD exacerbation and the percentage of patients with a hospitalization due to COPD exacerbation . We defined an exacerbation as a complex of respiratory symptoms ( increase or new-onset ) of more than 1 of the following : cough , sputum , wheezing , dyspnea , or chest tightness with a duration of at least 3 days requiring treatment with antibiotics or systemic steroids , hospitalization , or both . The study team at each site requested discharge summaries for all hospitalizations , wherever they occurred . We identified hospitalizations due to COPD exacerbations from events on case report forms that met the protocol definition of an exacerbation and where review of discharge summaries and other available medical records indicated that the event result ed in a hospitalization . We also considered an event to be a hospitalization if a patient was held and treated for an acute respiratory condition in an urgent care department or in an observation unit for longer than 24 hours . Admissions to nursing homes or other extended care facilities were not considered hospitalizations . Secondary outcomes included time to first COPD exacerbation and time to first hospitalization due to COPD exacerbation , the frequencies of exacerbations and of exacerbation-related health care utilization ( hospitalizations , hospitalization days , unscheduled clinic visits , antibiotic treatment days , and systemic corticosteroid treatment days ) , the frequencies of all-cause hospitalizations and hospitalization days , and results of spirometry . Statistical Analysis We analyzed the data by using a modified intention-to-treat principle . Therefore , we included all available data for the patients with any follow-up contact who took at least 1 capsule of study drug in the analysis up to their first event ( for the time-to-event end points ) or their withdrawal from the trial . For the time-to-event end points , we censored patients without an event at the end of their participation in the trial . Although we intended to follow all patients for the full 6 months , some patients were lost to follow-up . We h and led missing data by using longitudinal data analysis methods ( spirometry ) , analysis of observed data only ( number of events ) , or analysis methods for censored data ( time-to-event data ) . For the percentage of patients with an event , we considered that patients who discontinued the study drug therapy before having an event did not have an event . We analyzed the co primary end points by using a CochranMantelHaenszel test with center as a stratum . We used a stepwise procedure to test the percentage of patients with an exacerbation and , if rejected , to test percentage of patients with a hospitalization due to COPD exacerbation , each at a 2-sided level of 0.05 . Because of the prespecified closed testing procedure , no adjustment for multiplicity was required . We calculated that a sample size of 1800 patients would have 80 % power to [17472819] OBJECTIVE The aim of this study was to assess the efficacy and tolerability of nebulized arformoterol tartrate ( a selective , long-acting beta(2)-adrenergic agonist that is the [ R , R ] isomer of formoterol ) and salmeterol xinafoate versus placebo in patients with chronic obstructive pulmonary disease ( COPD ) . METHODS This 12-week , multicenter , r and omized , double-blind , double-dummy , placebo- and active-controlled trial was conducted at 60 centers across the United States . Male and female patients aged > or=35 years with physician-diagnosed COPD received arformoterol ( 15 microg BID , 25 microg BID , or 50 microg QD via nebulizer ) , salmeterol ( 42 microg BID via metered dose inhaler ) , or placebo . Pulmonary function was assessed by spirometry ; dyspnea , by the Transitional Dyspnea Index ( TDI ) ; and health status , by the St. George 's Respiratory Question naire ( SGRQ ) . Adverse events ( AEs ) were assessed by site personnel at all clinic visits ( screening , first dose at week 0 , and at weeks 3 , 6 , 9 , 12 , and follow-up ) . COPD exacerbations were defined as worsening respiratory status requiring a change in medication or an unscheduled provider visit . RESULTS A total of 717 patients received study medication . The demographic composition of all treatment arms was similar . The mean age was 62.9 years , 58 % were men , and mean baseline forced expiratory volume in 1 second ( FEV(1 ) ) was 1.2 L ( 41 % predicted ) . Mean improvement in trough FEV(1 ) over 12 weeks was significantly greater with all 3 arformoterol doses ( 15 microg BID , + 16.9 % ; 25 microg BID , + 18.9 % ; 50 microg QD , + 14.9 % ) and for salmeterol ( + 17.4 % ) relative to placebo ( + 6.0 % ; P < 0.001 ) . There were significantly greater improvements in the mean percentage change in FEV(1 ) AUC(0 - 12h ) from the predose value over 12 weeks ( 15 microg BID , 12.7 % , 25 microg BID , 13.9 % , 50 microg QD , 18.9 % ; salmeterol , 9.8 % ) versus placebo ( 2.7 % ; P < or= 0.001 ) ; all doses of arformoterol were statistically different from salmeterol for this end point ( P < or= 0.024 ) . At week 12 , TDI focal scores were significantly greater with all arformoterol doses compared with placebo ( mean [ 95 % CI ] : 15 microg BID , 0.97 [ 0.25 - 1.69 ] ; 25 microg BID , 1.08 [ 0.3 - 1.86 ] ; 50 microg QD , 1.04 [ 0.32 - 1.771 ) , suggesting treatment-associated improvement in dyspnea , however , the difference between salmeterol and placebo was not statistically significant ( 0.36 [ -0.40 to 1.12 ] ) . Improvements in health status , as measured using SGRQ total scores , were -2.6 to -3.6 U in the arformoterol groups , -4.4 U for salmeterol , and -1.2 U for placebo ; 95 % CI of differences versus placebo suggested significant improvement for the arformoterol 25 microg BID and salmeterol groups . There was a similar frequency of AEs and COPD exacerbations across all groups , including placebo . CONCLUSIONS In this trial , patients with moderate to severe COPD administered nebulized arformoterol over 12 weeks were observed to have significant and sustained improvements in airway function and dyspnea compared with placebo . The results also suggest that all doses of arformoterol , including the lowest dose ( 15 microg BID ) , were effective . Overall , nebulized arformoterol was well tolerated [30077810] BACKGROUND Cardiovascular comorbidities are common in chronic obstructive pulmonary disease ( COPD ) , and elevated heart rate reflects increased cardiovascular risk over time , which is associated with unfavourable neurohumoral activation . Long-acting β2-agonists ( LABAs ) are established treatments in COPD , but potentially increase heart rate . We report a post hoc pooled analysis of the effect of olo date rol ( 5 or 10 μg ) or formoterol ( 12 μg ) on heart rate and blood pressure ( BP ) in Global Initiative for Chronic Obstructive Lung Disease Stage 2 - 4 COPD patients . METHODS Four r and omised , double-blind , placebo-controlled , Phase III studies were analysed . Changes in heart rate and systolic/diastolic BP were measured before and after dosing with the study medication at each visit . RESULTS At each study visit , the increase in pre-dose heart rate was numerically lower with both LABAs compared with placebo . Systolic and diastolic BP were decreased with all treatments . Short-term ( pre-dose to 40 min post-dose ) effects of drug administration on heart rate were small and similar for all treatment arms ( between -3 and + 1 beats per minute ) . CONCLUSION Heart rate and BP were not adversely influenced in this study involving long-term administration of olo date rol or formoterol in patients with moderate-to-severe COPD . This supports the cardiovascular safety of LABAs in COPD maintenance treatment [6157543] Background Phase III studies demonstrated efficacy and safety of nebulized glycopyrrolate inhalation solution ( GLY ) in subjects with COPD . Secondary analyses were performed to examine the effect of background long-acting beta2-agonist ( LABA ) use on the efficacy and safety of nebulized GLY . Methods In two 12-week placebo-controlled studies ( GOLDEN 3 and GOLDEN 4 ) and one 48-week , open-label active-controlled study ( GOLDEN 5 ) , a total of 2,379 subjects were stratified by background LABA use ( LABA-yes : n=861 ; LABA-no : n=1,518 ) and r and omized to placebo vs GLY 25 or 50 µg twice daily , or GLY 50 µg twice daily vs tiotropium ( TIO ) 18 µg once daily . Lung function , patient-reported outcomes , exacerbations , and safety were assessed . Results Compared with placebo , pooled data from the 12-week studies showed significant improvements from baseline with GLY 25 and 50 µg across LABA subgroups in trough FEV1 ( LABA-yes : 0.101 and 0.110 L ; LABA-no : 0.092 and 0.101 L , respectively ; P<0.001 ) and St George ’s Respiratory Question naire total score ( SGRQ ; LABA-yes : −2.957 and −3.888 ; LABA-no : −3.301 and −2.073 , respectively ; P<0.05 ) . Incidence of treatment-emergent adverse events ( TEAEs ) was similar in LABA subgroups , and lower in GLY 25 µg vs placebo . In the 48-week active-controlled study , GLY and TIO both showed improvement from baseline across LABA subgroups in FEV1 ( LABA-yes : 0.106 and 0.092 L ; LABA-no : 0.096 and 0.096 L , respectively ) and in SGRQ total score ( LABA-yes : −5.190 and −3.094 ; LABA-no : −4.368 and −4.821 , respectively ) . Incidence of TEAEs was similar between GLY and TIO , and across LABA subgroups . Exacerbation rates were similar across treatments and LABA subgroups , and cardiovascular events of special interest were more frequent in the LABA-no subgroup . Nebulized GLY , combined with LABA , did not generate any additional safety signals . Conclusion Nebulized GLY demonstrated efficacy and was well tolerated up to 48 weeks in subjects with COPD with/without background LABA [23867808] BACKGROUND QVA149 is an inhaled , once-daily fixed-dose dual bronchodilator combination of the long-acting β2-agonist indacaterol and long-acting muscarinic antagonist glycopyrronium ( NVA237 ) for the treatment of chronic obstructive pulmonary disease ( COPD ) . We investigated the safety and efficacy of QVA149 over 52 weeks . METHODS This 52-week , multicenter , double-blind , parallel-group , placebo-controlled study r and omized ( 2:1 ) patients with moderate-to-severe COPD to once-daily QVA149 ( 110 μg indacaterol/50 μg glycopyrronium ) or placebo delivered via the Breezhaler device . Primary endpoint was safety and tolerability for treatment-emergent adverse events ( AEs ) . Secondary endpoints included safety based on vital signs , electrocardiograms ( ECGs ) , laboratory evaluations , and pre-dose forced expiratory volume in 1 s ( FEV1 ) . RESULTS Of 339 patients r and omized , QVA149 [ n = 226 ] , placebo [ n = 113 ] ; 76.9 % male , mean age : 62.6 years , post-bronchodilator FEV1 : 57.4 % predicted , 83.5 % completed study . A smaller percentage of patients discontinued in the QVA149 group ( 14.2 % ) compared with placebo ( 21.2 % ) . Overall incidence of AEs was similar in the QVA149 ( 57.8 % ) and placebo ( 56.6 % ) groups , with most AEs being mild to moderate in severity . The numerical differences in some AEs observed could be at least in part explained by differences in baseline patient characteristics . No clinical ly relevant differences were observed between treatment groups for vital signs or ECG parameters . The five deaths reported were unrelated to study medication ( QVA149 , n = 4 [ 1.8 % ] ; placebo , n = 1 [ 0.9 % ] ) . QVA149 demonstrated rapid and clinical ly meaningful bronchodilation sustained over 52 weeks versus placebo . CONCLUSION QVA149 demonstrated a good safety and tolerability profile , providing rapid and sustained bronchodilation over 52 weeks in patients with moderate-to-severe COPD . Clinical Trials.gov identifier : NCT01120717 [27203508] BACKGROUND Chronic obstructive pulmonary disease ( COPD ) often coexists with cardiovascular disease . Treatments for airflow limitation might improve survival and both respiratory and cardiovascular outcomes . The aim of this study was to assess whether inhaled treatment with a combined treatment of the corticosteroid , fluticasone furoate , and the long-acting β agonist , vilanterol could improve survival compared with placebo in patients with moderate COPD and heightened cardiovascular risk . METHODS In this double-blind r and omised controlled trial ( SUMMIT ) done in 1368 centres in 43 countries , eligible patients were aged 40 - 80 years and had a post-bronchodilator forced expiratory volume in 1 s ( FEV1 ) between 50 % and 70 % of the predicted value , a ratio of post-bronchodilator FEV1 to forced vital capacity ( FVC ) of 0·70 or less , a smoking history of at least 10 pack-years , and a score of 2 or greater on the modified Medical Research Council dyspnoea scale . Patients had to have a history , or be at increased risk , of cardiovascular disease . Enrolled patients were r and omly assigned ( 1:1:1:1 ) through a central ised r and omisation service in permuted blocks to receive once daily inhaled placebo , fluticasone furoate ( 100 μg ) , vilanterol ( 25 μg ) , or the combination of fluticasone furoate ( 100 μg ) and vilanterol ( 25 μg ) . The primary outcome was all-cause mortality , and secondary outcomes were on-treatment rate of decline in forced expiratory volume in 1 s ( FEV1 ) and a composite of cardiovascular events . Safety analyses were performed on the safety population ( all patients who took at least one dose of study drug ) and efficacy analyses were performed on the intention-to-treat population ( safety population minus sites excluded with Good Clinical Practice violations ) . This study is registered with Clinical Trials.gov , number NCT01313676 . FINDINGS Between Jan 24 , 2011 , and March 12 , 2014 , 23 835 patients were screened , of whom 16 590 were r and omised . 16 485 patients were included in the intention-to-treat efficacy population ; 4111 in the placebo group , 4135 in the fluticasone furoate group , 4118 in the vilanterol group , and 4121 in the combination group . Compared with placebo , all-cause mortality was unaffected by combination therapy ( hazard ratio [ HR ] 0·88 [ 95 % CI 0·74 - 1·04 ] ; 12 % relative reduction ; p=0·137 ) or the components ( fluticasone furoate , HR 0·91 [ 0·77 - 1·08 ] ; p=0·284 ; vilanterol , 0·96 [ 0·81 - 1·14 ] ; p=0·655 ) , and therefore secondary outcomes should be interpreted with caution . Rate of decline in FEV1 was reduced by combination therapy ( 38 mL per year [ SE 2·4 ] vs 46 mL per year [ 2·5 ] for placebo , difference 8 mL per year [ 95 % CI 1 - 15 ] ) with similar findings for fluticasone furoate ( difference 8 mL per year [ 95 % CI 1 - 14 ] ) , but not vilanterol ( difference -2 mL per year [ 95 % CI -8 to 5 ] ) . Combination therapy had no effect on composite cardiovascular events ( HR 0·93 [ 95 % CI 0·75 - 1·14 ] ) with similar findings for fluticasone furoate ( 0·90 [ 0·72 - 1·11 ] ) and vilanterol ( 0·99 [ 0·80 - 1·22 ] ) . All treatments reduced the rate of moderate and severe exacerbation . No reported excess risks of pneumonia ( 5 % in the placebo group , 6 % in the combination group , 5 % in the fluticasone furoate group , and 4 % in the vilanterol group ) or adverse cardiac events ( 17 % in the placebo group , 18 % in the combination group , and 17 % in the fluticasone furoate group , and 17 % in the vilanterol group ) were noted in the treatment groups . INTERPRETATION In patients with moderate COPD and heightened cardiovascular risk , treatment with fluticasone furoate and vilanterol did not affect mortality or cardiovascular outcomes , reduced exacerbations , and was well tolerated . Fluticasone furoate , alone or in combination with vilanterol , seemed to reduce FEV1 decline . FUNDING GlaxoSmithKline Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Pharmacological therapy for chronic obstructive pulmonary disease ( COPD ) is aim ed at relieving symptoms , improving quality of life and preventing or treating exacerbations . Treatment tends to begin with one inhaler , and additional therapies are introduced as necessary . For persistent or worsening symptoms , long-acting inhaled therapies taken once or twice daily are preferred over short-acting inhalers . Several Cochrane review s have looked at the risks and benefits of specific long-acting inhaled therapies compared with placebo or other treatments . However for patients and clinicians , it is important to underst and the merits of these treatments relative to each other , and whether a particular class of inhaled therapies is more beneficial than the others . OBJECTIVES To assess the efficacy of treatment options for patients whose chronic obstructive pulmonary disease can not be controlled by short-acting therapies alone . The review will not look at combination therapies usually considered later in the course of the disease . How does long-term efficacy compare between different pharmacological treatments for COPD ? 2 . Are there limitations in the current evidence base that may compromise the conclusions drawn by this network meta- analysis ? If so , what are the implication s for future research ? AUTHORS ' CONCLUSIONS This network meta- analysis compares four different classes of long-acting inhalers for people with COPD who need more than short-acting bronchodilators . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

26031211

[3862451] Background : The long-term impact of early malnutrition on human capital outcomes remains unclear , and existing evidence has come largely from observational studies . Objective : We compared the impact of a nutritional supplement given during pregnancy or lactation in rural Gambia on educational performance and cognitive ability in offspring at their maturity . Design : This study was a follow-up of a r and omized trial of prenatal high protein and energy supplementation conducted between 1989 and 1994 . Subjects were 16–22 y of age at follow-up , and information was collected on schooling achievement and cognitive ability by using the Raven 's progressive matrices test , Mill Hill vocabulary test , and forward and backward digit-span tests . Results : A total of 1459 individuals were traced and interviewed and represented 71 % of the original cohort and 81 % of the surviving cohort . There was no difference in cognitive ability or educational attainment between treatment groups by using any of the methods of assessment . Conclusion : We have shown little evidence to support a long-term effect of prenatal protein-energy supplementation compared with supplementation during lactation on cognitive development in rural Gambians . This trial was registered at http://www.controlled-trials.com as IS RCT N72582014 [18458209] CONTEXT The evidence that breastfeeding improves cognitive development is based almost entirely on observational studies and is thus prone to confounding by subtle behavioral differences in the breastfeeding mother 's behavior or her interaction with the infant . OBJECTIVE To assess whether prolonged and exclusive breastfeeding improves children 's cognitive ability at age 6.5 years . DESIGN Cluster-r and omized trial , with enrollment from June 17 , 1996 , to December 31 , 1997 , and follow-up from December 21 , 2002 , to April 27 , 2005 . SETTING Thirty-one Belarussian maternity hospitals and their affiliated polyclinics . PARTICIPANTS A total of 17,046 healthy breastfeeding infants were enrolled , of whom 13,889 ( 81.5 % ) were followed up at age 6.5 years . INTERVENTION Breastfeeding promotion intervention modeled on the Baby-Friendly Hospital Initiative by the World Health Organization and UNICEF . MAIN OUTCOME MEASURES Subtest and IQ scores on the Wechsler Abbreviated Scales of Intelligence , and teacher evaluations of academic performance in reading , writing , mathematics , and other subjects . RESULTS The experimental intervention led to a large increase in exclusive breastfeeding at age 3 months ( 43.3 % for the experimental group vs 6.4 % for the control group ; P < .001 ) and a significantly higher prevalence of any breastfeeding at all ages up to and including 12 months . The experimental group had higher means on all of the Wechsler Abbreviated Scales of Intelligence measures , with cluster-adjusted mean differences ( 95 % confidence intervals ) of + 7.5 ( + 0.8 to + 14.3 ) for verbal IQ , + 2.9 ( -3.3 to + 9.1 ) for performance IQ , and + 5.9 ( -1.0 to + 12.8 ) for full-scale IQ . Teachers ' academic ratings were significantly higher in the experimental group for both reading and writing . CONCLUSION These results , based on the largest r and omized trial ever conducted in the area of human lactation , provide strong evidence that prolonged and exclusive breastfeeding improves children 's cognitive development . TRIAL REGISTRATION is rct n.org Identifier : IS RCT N37687716 [4000057] Background Research directed to optimizing maternal nutrition commencing prior to conception remains very limited , despite suggestive evidence of its importance in addition to ensuring an optimal nutrition environment in the periconceptional period and throughout the first trimester of pregnancy . Methods / Study design This is an individually r and omized controlled trial of the impact on birth length ( primary outcome ) of the time at which a maternal nutrition intervention is commenced : Arm 1 : ≥ 3 mo preconception vs. Arm 2 : 12 - 14 wk gestation vs. Arm 3 : none.192 ( derived from 480 ) r and omized mothers and living offspring in each arm in each of four research sites ( Guatemala , India , Pakistan , Democratic Republic of the Congo ) . The intervention is a daily 20 g lipid-based ( 118 kcal ) multi-micronutient ( MMN ) supplement . Women r and omized to receive this intervention with body mass index ( BMI ) < 20 or whose gestational weight gain is low will receive an additional 300 kcal/d as a balanced energy-protein supplement . Research ers will visit homes biweekly to deliver intervention and monitor compliance , pregnancy status and morbidity ; ensure prenatal and delivery care ; and promote breast feeding . The primary outcome is birth length . Secondary outcomes include : fetal length at 12 and 34 wk ; incidence of low birth weight ( LBW ) ; neonatal/infant anthropometry 0 - 6 mo of age ; infectious disease morbidity ; maternal , fetal , newborn , and infant epigenetics ; maternal and infant nutritional status ; maternal and infant microbiome ; gut inflammatory biomarkers and bioactive and nutritive compounds in breast milk . The primary analysis will compare birth Length-for-Age Z-score ( LAZ ) among trial arms ( independently for each site , estimated effect size : 0.35 ) . Additional statistical analyses will examine the secondary outcomes and a pooled analysis of data from all sites . Discussion Positive results of this trial will support a paradigm shift in attention to nutrition of all females of child-bearing age . Trial registration Clinical Trials.gov NCT01883193 [3313975] Background Previous studies suggest that over-nutrition in early infancy may programme long-term susceptibility to insulin resistance . Objective To assess the association of breast milk and quantity of infant formula and cows ' milk intake during infancy with insulin resistance measures in early adulthood . Design Long-term follow-up of the Barry Caerphilly Growth cohort , into which mothers and their offspring had originally been r and omly assigned , between 1972–1974 , to receive milk supplementation or not . Participants were the offspring , aged 23–27 years at follow-up ( n = 679 ) . Breastfeeding and formula/cows ' milk intake was recorded prospect ively by nurses . The main outcomes were insulin sensitivity ( ISI0 ) and insulin secretion ( CIR30 ) . Results 573 ( 84 % ) individuals had valid glucose and insulin results and complete covariate information . There was little evidence of associations of breastfeeding versus any formula/cows ' milk feeding or of increasing quartiles of formula/cows ' milk consumption during infancy ( <3 months ) with any outcome measure in young adulthood . In fully adjusted models , the differences in outcomes between breastfeeding versus formula/cows ' milk feeding at 3 months were : fasting glucose ( −0.07 mmol/l ; 95 % CI : −0.19 , 0.05 ) ; fasting insulin ( 8.0 % ; −8.7 , 27.6 ) ; ISI0 ( −6.1 % ; −11.3 , 12.1 ) and CIR30 ( 3.8 % ; −19.0 , 32.8 ) . There was also little evidence that increasing intakes of formula/cows ' milk at 3 months were associated with fasting glucose ( increase per quartile of formula/cows ' milk intake = 0.00 mmol/l ; −0.03 , 0.03 ) ; fasting insulin ( 0.8 % ; −3.2 , 5.1 ) ; ISI 0 ( −0.9 % ; −5.1 , 3.5 ) and CIR30 ( −2.6 % ; −8.4 , 3.6 ) . Conclusions We found no evidence that increasing consumption of formula/cows ' milk in early infancy was associated with insulin resistance in young adulthood [3616846] Background Nutritionists advise pregnant women to eat fish to obtain adequate docosahexaenoic acid ( DHA ) , an essential nutrient important for optimal brain development . However , concern exists that this advice will lead to excess intake of methylmercury , a developmental neurotoxicant . Objective Conduct a pilot intervention to increase consumption of high-DHA , low-mercury fish in pregnancy . Methods In April-October 2010 we recruited 61 women in the greater Boston , MA area at 12–22 weeks gestation who consumed < = 2 fish servings/month , and obtained outcome data from 55 . We r and omized participants to 3 arms : Advice to consume low-mercury/high-DHA fish ( n=18 ) ; Advice + grocery store gift cards ( GC ) to purchase fish ( n=17 ) ; or Control messages ( n=20 ) . At baseline and 12-week follow-up we estimated intake of fish , DHA and mercury using a 1-month fish intake food frequency question naire , and measured plasma DHA and blood and hair total mercury . Results Baseline characteristics and mean ( range ) intakes of fish [ 21 ( 0–125 ) g/day ] and DHA from fish [ 91 ( 0–554 ) mg/d ] were similar in all 3 arms . From baseline to follow-up , intake of fish [ Advice : 12 g/day ( 95 % CI : -5 , 29 ) , Advice+GC : 22 g/day ( 5 , 39 ) ] and DHA [ Advice : 70 mg/d ( 3 , 137 ) , Advice+GC : 161 mg/d ( 93 , 229 ) ] increased in both intervention groups , compared with controls . At follow-up , no control women consumed > = 200mg/d of DHA from fish , compared with 33 % in the Advice arm ( p=0.005 ) and 53 % in the Advice+GC arm ( p=0.0002 ) . We did not detect any differences in mercury intake or in biomarker levels of mercury and DHA between groups . Conclusions An educational intervention increased consumption of fish and DHA but not mercury . Future studies are needed to determine intervention effects on pregnancy and childhood health outcomes .Trial registration Registered on clinical trials.gov as [4124499] Background The in utero environment is known to affect fetal development however many of the mechanisms by which this occurs remain unknown . The aim of this study was to examine the association between maternal dietary macronutrient intake and lifestyle throughout pregnancy and neonatal weight and adiposity . Methods This was an analysis of 542 mother and infant pairs from the ROLO study ( R and omised cOntrol trial of LOw glycaemic index diet versus no dietary intervention to prevent recurrence of fetal macrosomia ) . Food diaries as well as food frequency and lifestyle and physical activity question naires were completed during pregnancy . Maternal anthropometry was measured throughout pregnancy and neonatal anthropometry was measured at birth . Results Multiple linear regression analysis revealed the main maternal factor associated with increased birth weight was greater gestational weight gain R2adj23.3 % ( F = 11.547 , p < 0.001 ) . The main maternal factor associated with increased birth length was non-smoking status R2adj27.8 % ( F = 6.193 , p < 0.001 ) . Neonatal central adiposity ( determined using waist : length ratio ) was negatively associated with maternal age , and positively associated with the following parameters : smoking status , maternal pre-pregnancy arm circumference , percentage energy from saturated fat in late pregnancy , postpr and ial glucose at 28 weeks gestation and membership of the control group with a positive trend towards association with trimester 2 glycaemic load R2adj 38.1 % ( F = 8.000 , p < 0.001 ) . Conclusions Several maternal diet and lifestyle factors were associated with neonatal anthropometry . Low glycaemic index dietary intervention in pregnancy was found to have a beneficial effect on neonatal central adiposity . Additionally , central adiposity was positively associated with maternal dietary fat intake and postpr and ial glucose highlighting the important role of healthy diet in pregnancy in promoting normal neonatal adiposity . Trial registration Current Controlled Trials IS RCT N54392969 [19017418] Balanced glucose metabolism ensures optimal fetal growth with long-term health implication s conferred on both mother and child . We examined whether supplementation of probiotics with dietary counselling affects glucose metabolism in normoglycaemic pregnant women . At the first trimester of pregnancy 256 women were r and omised to receive nutrition counselling to modify dietary intake according to current recommendations or as controls ; the dietary intervention group was further r and omised to receive probiotics ( Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12 ; diet/probiotics ) or placebo ( diet/placebo ) in a double-blind manner , whilst the control group received placebo ( control/placebo ) . Blood glucose concentrations were lowest in the diet/probiotics group during pregnancy ( baseline-adjusted means 4.45 , 4.60 and 4.56 mmol/l in diet/probiotics , diet/placebo and control/placebo , respectively ; P = 0.025 ) and over the 12 months ' postpartum period ( baseline-adjusted means 4.87 , 5.01 and 5.02 mmol/l ; P = 0.025 ) . Better glucose tolerance in the diet/probiotics group was confirmed by a reduced risk of elevated glucose concentration compared with the control/placebo group ( OR 0.31 ( 95 % CI 0.12 , 0.78 ) ; P = 0.013 ) as well as by the lowest insulin concentration ( adjusted means 7.55 , 9.32 and 9.27 mU/l ; P = 0.032 ) and homeostasis model assessment ( adjusted means 1.49 , 1.90 and 1.88 ; P = 0.028 ) and the highest quantitative insulin sensitivity check index ( adjusted means 0.37 , 0.35 and 0.35 ; P = 0.028 ) during the last trimester of pregnancy . The effects observed extended over the 12-month postpartum period . The present study demonstrated that improved blood glucose control can be achieved by dietary counselling with probiotics even in a normoglycaemic population and thus may provide potential novel means for the prophylactic and therapeutic management of glucose disorders [3431285] Objective To determine if a low glycaemic index diet in pregnancy could reduce the incidence of macrosomia in an at risk group . Design R and omised controlled trial . Setting Maternity hospital in Dublin , Irel and . Participants 800 women without diabetes , all in their second pregnancy between January 2007 to January 2011 , having previously delivered an infant weighing greater than 4 kg . Intervention Women were r and omised to receive no dietary intervention or start on a low glycaemic index diet from early pregnancy . Main outcomes The primary outcome measure was difference in birth weight . The secondary outcome measure was difference in gestational weight gain . Results No significant difference was seen between the two groups in absolute birth weight , birthweight centile , or ponderal index . Significantly less gestational weight gain occurred in women in the intervention arm ( 12.2 v 13.7 kg ; mean difference −1.3 , 95 % confidence interval −2.4 to −0.2 ; P=0.01 ) . The rate of glucose intolerance was also lower in the intervention arm : 21 % ( 67/320 ) compared with 28 % ( 100/352 ) of controls had a fasting glucose of 5.1 mmol/L or greater or a 1 hour glucose challenge test result of greater than 7.8 mmol/L ( P=0.02 ) . Conclusion A low glycaemic index diet in pregnancy did not reduce the incidence of large for gestational age infants in a group at risk of fetal macrosomia . It did , however , have a significant positive effect on gestational weight gain and maternal glucose intolerance . Trial registration Current Controlled Trials IS RCT N54392969 [23535609] In developing countries , prenatal lipid-based nutrient supplements ( LNSs ) were shown to increase birth size ; however , the mechanism of this effect remains unknown . Cord blood hormone concentrations are strongly associated with birth size . Therefore , we hypothesize that LNSs increase birth size through a change in the endocrine regulation of fetal development . We compared the effect of daily prenatal LNSs with multiple micronutrient tablets on cord blood hormone concentrations using a r and omized , controlled design including 197 pregnant women from rural Burkina Faso . Insulin-like growth factors ( IGF ) I and II , their binding proteins IGFBP-1 and IGFBP-3 , leptin , cortisol , and insulin were quantified in cord sera using immunoassays . LNS was associated with higher cord blood leptin mainly in primigravidae ( + 57 % ; P = 0.02 ) and women from the highest tertile of BMI at study inclusion ( + 41 % ; P = 0.02 ) . We did not find any significant LNS effects on other measured cord hormones . The observed increase in cord leptin was associated with a significantly higher birth weight . Cord sera from small-for-gestational age newborns had lower median IGF-I ( -9 μg/L ; P = 0.003 ) , IGF-II ( -79 μg/L ; P = 0.003 ) , IGFBP-3 ( -0.7 μg/L ; P = 0.007 ) , and leptin ( -1.0 μg/L ; P = 0.016 ) concentrations but higher median cortisol ( + 18 μg/L ; P = 0.037 ) concentrations compared with normally grown newborns . Prenatal LNS result ed in increased cord leptin concentrations in primigravidae and mothers with higher BMI at study inclusion . The elevated leptin concentrations could point toward a higher neonatal fat mass [4196482] Background : Low birth weight ( LBW ) is an important public health problem in undernourished population s. Objective : We tested whether improving women 's dietary micronutrient quality before conception and throughout pregnancy increases birth weight in a high-risk Indian population . Design : The study was a nonblinded , individually r and omized controlled trial . The intervention was a daily snack made from green leafy vegetables , fruit , and milk ( treatment group ) or low-micronutrient vegetables ( potato and onion ) ( control group ) from ≥90 d before pregnancy until delivery in addition to the usual diet . Treatment snacks contained 0.69 MJ of energy ( controls : 0.37 MJ ) and 10–23 % of WHO Reference Nutrient Intakes of β-carotene , riboflavin , folate , vitamin B-12 , calcium , and iron ( controls : 0–7 % ) . The primary outcome was birth weight . Results : Of 6513 women r and omly assigned , 2291 women became pregnant , 1962 women delivered live singleton newborns , and 1360 newborns were measured . In an intention-to-treat analysis , there was no overall increase in birth weight in the treatment group ( + 26 g ; 95 % CI : −15 , 68 g ; P = 0.22 ) . There was an interaction ( P < 0.001 ) between the allocation group and maternal prepregnant body mass index ( BMI ; in kg/m2 ) [ birth-weight effect : −23 , + 34 , and + 96 g in lowest ( < 18.6 ) , middle ( 18.6–21.8 ) , and highest ( > 21.8 ) thirds of BMI , respectively ] . In 1094 newborns whose mothers started supplementation ≥90 d before pregnancy ( per- protocol analysis ) , birth weight was higher in the treatment group ( + 48 g ; 95 % CI : 1 , 96 g ; P = 0.046 ) . Again , the effect increased with maternal BMI ( −8 , + 79 , and + 113 g ; P-interaction = 0.001 ) . There were similar results for LBW ( intention-to-treat OR : 0.83 ; 95 % CI : 0.66 , 1.05 ; P = 0.10 ; per- protocol OR = 0.76 ; 95 % CI : 0.59 , 0.98 ; P = 0.03 ) but no effect on gestational age in either analysis . Conclusions : A daily snack providing additional green leafy vegetables , fruit , and milk before conception and throughout pregnancy had no overall effect on birth weight . Per- protocol and subgroup analyses indicated a possible increase in birth weight if the mother was supplemented ≥3 mo before conception and was not underweight . This trial was registered at www.controlled-trials.com/is rct n/ as IS RCT N62811278 [2239797] The effect of prenatal energy supplementation on maternal anthropometry was assessed in a controlled , r and omized trial in Madura , East Java . At 26 - 28 wk of gestation women were either given 465 kcal/d ( HE group ) or 52 kcal/d ( LE group ) . Two hundred seventy-six women were enrolled in the HE group and 266 women , in the LE group . Supplement intake was variable . Testing of effect by treatment and compliance was thus done by subcategories ( HE 1 - 3 and LE 1 - 3 , corresponding to less than 45 , 45 - 89 , and greater than or equal to 90 packets of supplement consumed ) . Analysis of variance did not show significant differences among the six subcategories in third-trimester weight gain , sum of skinfold thicknesses , 4-wk postpartum weight , or body mass index . In this population energy supplementation for the short duration of the last 90 - 110 d of pregnancy was not sufficient to improve maternal nutrition as judged by anthropometry [6372428] We related the macroscopic and microscopic morphology and the histomorphometry of the placenta to prenatal nutritional supplementation . In the Prenatal Project , a controlled clinical trial , three dietary treatments ( supplement , a high-protein beverage ; complement , a balanced protein-calorie beverage , or routine vitamin and mineral tablets ) were r and omly allocated to poor Black pregnant women , and the outcome was assessed . Herein we report the effects on placental morphology and histomorphometry . There were significantly fewer preterm deliveries in the complement group , and this was reflected by an increase in the size of decidual cells , an index associated with placental aging . Several other characteristics of the placentas of the complement group may have been more directly associated with improved perinatal outcome : decreased intervillous fibrin , lower incidence of gross surface infa rct , and smaller ( and presumably less edematous ) cells of the villous stroma , may have mediated increased placental perfusion . There was no evidence of any placental change associated with the increase in very preterm delivery and the highly significant depressed birth weight among preterm deliveries in the supplement group . The significantly lower incidence of meconium staining of Wharton 's jelly among controls seems likely to have been a chance finding . While there were several other indices that reflected placental aging , the significantly increased chorioamnionitis , acute funisitis , and acute decidual inflammation among placentas of those who delivered prematurely [ the former two associated with very early delivery ( less than 35 wk gestation ) ] were likely to have been involved as causes of premature delivery [3279745] The effects on pregnancy outcome and maternal iron status of powdered milk ( PUR ) and a milk-based fortified product ( V-N ) were compared in a group of underweight gravidas . These take-home products were distributed during regular prenatal visits . Women in the V-N group had greater weight gain ( 12.29 vs 11.31 kg , p less than 0.05 ) and mean birth weights ( 3178 vs 3105 g , p less than 0.05 ) than those in the PUR group . Values for various indicators of maternal Fe status were also higher in the V-N group . Compared with self-selected noncompliers , similar in all control variables to compliers , children of women who consumed powdered milk or the milk-based fortified product had mean birth weights that were higher by 258 and 335 g , respectively . Data indicate a beneficial effect of the fortified product on both maternal nutritional status and fetal growth [3521254] To improve maternal nutritional status and to ameliorate protein-energy malnutrition in pregnant women and infants , supplementary foods for rural pregnant women were formulated and evaluated . Six formulas with protein and energy contents of 16 - 22 g and 350 - 500 kcal/100 g food , respectively , were developed from locally available raw material s. A field evaluation of formulas I and V was conducted at the regional MCH Center at Rajchaburi , about 120 km from Bangkok . Formulas providing 13 g protein and 350 kcal per day were given to two groups of mothers in the first or second pregnancy , starting at 28 + /- 2 wk of gestation . A third group , unsupplemented , served as controls . Maternal weight gain and left mid-arm circumference were measured every 2 wk . Birth weight , length , head and chest circumferences of newborns , and placental weight were significantly higher in both supplemented groups . These findings suggest that among undernourished mothers , supplementation of as little as 13 g protein and 350 kcal daily during the last trimester can significantly improve maternal weight gain and birth weight of newborns [11722967] BACKGROUND We previously showed that mortality from infectious diseases among young adults in rural Gambia is strongly correlated with the season of their birth . This suggests that early life insults that involve fetal malnutrition , exposure to natural toxins , or highly seasonal infections affecting the infant or pregnant mother cause permanent damage to the immune system . Excess mortality begins after puberty and has a maximal odds ratio of > 10 for deaths between ages 25 and 50 y. OBJECTIVE We investigated the immune function of children according to birth weight , season of birth , and exposure to maternal dietary supplementation during pregnancy . DESIGN Immune function was measured in 472 prepubertal children aged 6.5 - 9.5 y from 28 villages in rural Gambia . The mothers of these children had been r and omly assigned to a high-energy prenatal supplementation program , which significantly increased birth weight . This permitted supplementation status , birth weight , and season of birth to be investigated as exposure variables . The outcome variables tested were naive responses to rabies and pneumococcus vaccines , delayed-type hypersensitivity skin reactions , and mucosal defense ( secretory immunoglobulin A and dual-sugar permeability ) . RESULTS Immune responses were strongly related to current age and sex , suggesting a high level of sensitivity , but were not consistently related to birth weight , season of birth , or maternal supplementation ( control compared with intervention ) . CONCLUSION Events in early life did not predict a measurable defect in immune response within this cohort of rural Gambian children . It is possible that the early programming of immune function may be mediated through a defect in immunologic memory or early senescence rather than through impairment of early responses [12816786] BACKGROUND The secular increase in height is assumed to result from long-term improvements in nutritional intakes and reductions in infectious disease burdens . Nutritional supplementation in early life reduces stunting in chronically undernourished population s. It is unknown whether these improvements can be transmitted to subsequent generations . OBJECTIVE Our objective was to estimate the intergenerational effect on offspring length of improved nutrition in the mother 's childhood . DESIGN We studied 263 children born in 1996 - 1999 to 231 women who had received nutritional supplementation , ie , atole ( high-protein , moderate-energy drink ) or fresco ( nonprotein , low-energy drink ) , prenatally and up to age 7 y as part of a community trial in Guatemala between 1969 and 1977 . Child length was measured at different times to age 36 mo . RESULTS Children born to women who received the enhanced supplement were taller ( age-adjusted difference : 0.80 cm ; 95 % CI : 0.16 , 1.44 cm ) than were children whose mothers received the low-energy supplement . This increment was independent of the children 's birth weight or socioeconomic status but was substantially attenuated and no longer significant after adjustment for maternal height ( adjusted difference : 0.43 cm ; 95 % CI : -0.10 , 0.96 cm ; P > 0.10 ) . The effect of maternal nutritional supplementation was more pronounced in boys than in girls ( P for interaction < 0.10 ) and in children born to women who received supplements at ages 3 - 7 y than in children born to women who received supplements at ages 0 - 3 y ( P for interaction < 0.01 ) . CONCLUSION Nutritional supplementation in childhood has positive effects on both the supplemented persons and on the subsequent generation [2816804] An intervention program was undertaken to assess dietary habits and the impact of nutrition education among pregnant women in the rural county of Florina , northern Greece . Analysis of dietary habits , nutrient intake , hemoglobin , and serum vitamin concentrations in an intervention and control group indicated that the population was adequately nourished although nutrient intake was below recommended levels for pregnant women . Nutrition counseling was associated with improvements in dietary intake and significantly greater maternal weight gain ( p less than 0.05 ) . Mean birth weight was slightly higher in the intervention group but so was the incidence of low birth weight ( 4.5 % vs 3.9 % ) . The prematurity rate was marginally lower in the intervention group ( p less than 0.04 ) , as was the number of perinatal deaths ( 9 vs 11 ) . The results indicate that nutrition counseling during pregnancy can improve dietary intake and maternal weight gain but the mediating influence on low frequency pregnancy outcomes is indeterminate in a population that is not nutritionally at risk [6179410] Protein and nucleic acid content , and RNase levels were measured in placentas collected at birth in a r and omized controlled trial of prenatal nutritional supplementation in New York City . These biochemical indices were explored to underst and better the effects of nutritional supplementation . ( With high-protein supplements , gross measures had shown no improvement in outcome at birth and adverse effects on fetal growth , prematurity , and newborn survival ; with balanced protein-calorie supplements , there was a nonsignificant rise in birth weight and longer gestation . ) The biochemical indices were in general somewhat weakly related to fetal growth measures . Significant effects of nutritional treatment on the indices were minimal , and added no information that could account for gross effects observed in the fetus [2756913] Breast-milk output was measured in women who during the last trimester of pregnancy consumed a high- or low-energy supplement ( 53 and 55 women , respectively ) . Infant and mother pairs were enrolled at 2 or 6 wk postpartum . Test weighings were done four times at 8-wk intervals . Mean breast-milk output ranged from 682 to 744 g/d in the age period of 2 wk to 7 mo . There was no difference in milk output between the two experimental groups . In all cohorts , breast-feeding frequency influenced milk output positively . Only at age 18 - 22 wk did the mothers ' prepregnancy or 4-wk postpartum body mass index play an additional role . The results confirm that breast-milk output of mildly undernourished women is comparable with that of well-nourished women . Short-term energy supplementation during pregnancy did not increase breast-milk output , probably because the sample studied was not at nutritional risk [7282613] The effect of food supplementation on physical growth during the last trimester of pregnancy and the first 3 yr of life was studied in a sample of families at risk of malnutrition living in the urban slums of Bogota , Colombia . Families in which the mother was pregnant and at least one-half of the children under 5 yr of age were below 85 % of weight for age were selected for the study . All were provided with free obstetrical and pediatric care . The families were then r and omly assigned to control and supplemented groups . The supplemented families received a daily allotment of 600 cal or 30 g of protein per capita for home consumption from the onset of the 3rd trimester of pregnancy until the subject children reached the age of 3 yr . Calorie consumption from the supplement by the study children ( offspring of the target pregnancy ) was 458 ± 249 calories at age 18 months and 363 ± 283 cal at age 36 months . Protein consumption at those ages was 34 . 1 ± 20.6 and 23.6 ± 19.7 g,'day . However , substitution of the supplement for foods from the regular diet result ed in net supplementation of approximately 200 cal and 22 g of protein per day . There were significant differences in weight between supplemented and control groups beginning at age 3 months and in length beginning at age 6 months . Supplementation reduced the total prevalence of malnutrition ( Gomez classification ) only slightly ; at 36 months of age , 72 % of the supplemented group and 77.8 % of the control group were malnourished . On the other h and , the prevalence of moderate and severe malnutrition ( Gomez II and III ) , was significantly reduced by supplementation . At 36 months , 20.6 % of the control group and 8.8 % of the supplemented group fell into those categories . Despite improved physical growth in the supplemented group , their height and weight remained substantially below those of the high socioeconomic Colombian st and ards . The failure of supplementation to close the gap between low and high socioeconomic groups was attributed , in part , to the high incidence of diarrheal disease among subjects of the study . It is postulated that simple provision of food supplements , without effective prevention of diarrheal disease , is likely to have limited effects on physical growth among disadvantaged children . Am . J. Clin . Nutr . 34 : 1885 - 1892 , 1981 [3993611] Of 824 women screened , 410 were enrolled at midpregnancy in a prospect i ve , r and omized , controlled nutrition intervention study . Of these , 226 were predicted as likely to have small or large babies , 184 to have average-sized babies . Two hundred thirty eight mothers received USDA Women , Infants and Children ( WIC ) Food Supplementation vouchers from midpregnancy , 172 did not . Leukocyte protein synthesis ( as a cell model ) was significantly higher ( p = 0.009 ) by 36 weeks gestation in supplemented mothers . Mean birth weight of their babies was greater , 3254 vs 3163 g , ( + 91 g ) p = 0.039 , adjusted for sex , gestational age , prenatal visits , pregnancy interval , smoking , and previous low birth weight infants . Controlling for entry weight obviated the significance of the difference , except for WIC supplemented smokers ( greater than 10 cigarettes/day ) whose babies were significantly heavier by + 168 g ( p = 0.017 ) than those of unsupplemented smokers . WIC partially protects fetal growth in smokers [3993612] In a double blind controlled intervention , two groups of nutritionally at-risk rural Taiwanese women were given a nutrient-rich dietary supplement ( group A , n = 114 ) or a placebo ( group B , n = 111 ) beginning after the birth of one child and continuing through the lactation period for a subsequent child . Outcome variables assessed include infant birth measurements postnatal physical growth , motor , mental , and dental development , morbidity , and maternal weight and skinfold changes during pregnancy and lactation . While few A-B differences in mean values of outcome variables were found , there were significant responses in subgroups of the sample . Comparisons of infants born after a nutrient-supplemented pregnancy ( A2 ) versus an unsupplemented pregnancy ( A1 ) showed that A2 male infants weighed more than A1 males at birth , and A1-A2 sibling correlations in birth measurements , especially Rohrer 's index ( wt/l3 ) were significantly reduced . Important mediators of supplement effects included sex of the offspring , season of birth , maternal body size , and birth of a previous infant characterized by dysmorphic prenatal growth . The limited effects of supplementation on the population as a whole may reflect the operation of long term adaptations which allow women to maintain reproductive success despite their apparent marginal nutritional status [15051843] Cardiovascular disease and diabetes may be programmed early in life by abnormal development associated with undernutrition . We investigated whether maternal nutritional status ( MNS ; height , pregnancy weight gain , nonpregnant BMI , and prenatal supplementation ) or childhood nutritional status ( CNS ; birth weight , length , ponderal index , height-for-age Z-score at 24 mo , and supplementation from 0 to 24 mo ) were related to fasting plasma glucose levels in rural-born Guatemalan adults . We studied 209 men and 220 women ( mean age 24.4 y ) who were involved in a r and omized trial of nutritional supplementation of their mothers during pregnancy and during their early childhoods , conducted from 1969 to 1977 . In 2 villages , residents were offered Atole ( 3.8 MJ and 64 g protein/L ) ; 2 other villages were offered Fresco ( 1.4 MJ/L , no protein ) . No associations were observed between anthropometric measures of MNS or CNS and fasting plasma glucose levels . In subgroup analyses , inverse associations ( all P < 0.15 ) with birth size were found among women born to fatter mothers , women with low supplement intake , men born to short mothers , and men more severely stunted at 24 mo . Prenatal supplementation was inversely associated with fasting plasma glucose among women [ -0.40 + /- 0.17 mmol/(L. MJ . d ) , P = 0.02 ] . Among men , postnatal intake of supplementation of 0.10 to 0.20 MJ/d was associated with up to a 0.56 mmol/L reduction in fasting plasma glucose ( P = 0.03 ) , but intake in excess of 0.20 MJ/d provided no added benefit . Among women , the benefit of postnatal supplementation was restricted to those born thin ( test for interaction P = 0.10 ) . Improving the nutritional status of undernourished women and children may have positive long-term consequences [6816061] Protein-energy malnutrition in synergism with infection is a major problem for most developing countries , and inadequate food consumption is a critical factor in its development . Food supplementation programs can improve nutrient consumption but may also have unintended consequences . Changes in consumption of foods as well as nutrients need to be identified and evaluated . The effects of a food supplementation program on family diet patterns and protein-energy intake were investigated using data from nutritionally at risk families in Bogota , Colombia . Because food supplements are income transfers they need to substitute for purchases of similar food items . However , the results of our investigation reveal that food supplementation based on familiar foods that are part of the usual family diet are consumed in substantial quantities and result in net nutrient consumption increases . The food supplementation program increases consumption of preferred food items and introduces greater diversity into the family diet . These effects are enhanced when combined with a home education program [420135] Colombian women at risk of malnutrition were enrolled in a health care program and r and omly assigned to supplementation and control groups at the beginning of the third trimester of pregnancy . The net dietary intake increments result ing from supplementation amounted to 155 cal and 20 g of protein per day . Supplementation had a significant effect on the mean birth weight of male infants , but not that of female infants ; the mechanisms responsible for the sex differences remain to be eluci date d. The r and omized trial design of the experiment and the documented similarity between the experimental and control groups at the onset permit the conclusion that the observed differences were caused by the food supplementation program . The effect of supplementation on maternal weight gain and the association of the latter with birth weight strongly suggest that improved maternal nutrition mediated the effect on birth weight [1274890] Low-income pregnant women of Mexican descent were studied to determine whether their food habits could be improved by nutrition education . Biochemical indices of nutritional status were also investigated . Twenty-four-hour dietary recalls were obtained at an initial interview and again at a final interview after a nutrition education program , which was offered to a r and omly selected treatment group . At the initial interview , the mean nutrient intakes that were most often below two-thirds of the Recommended Dietary Allowance ( RDA ) were iron , vitamin A , thiamin , and calcium . The mean energy value of the diets was also frequently below the RDA . At the final intakes , although the mean energy values and the calcium and carbohydrate of both the control and treatment groups increased significantly , the following improvements in dietary intakes were seen only within the treatment group : 1 ) there were significant increases in the mean intake of protein , ascorbic acid , niacin , riboflavin , and thiamin , 2 ) there were significant decreases in the percentage of intakes below two-thirds of the RDA for ascorbic acid and riboflavin , and 3 ) there was a significant decrease in the incidence of multiple low nutrient intakes . These dietary improvements , which occurred only in the treatment group , suggest the effectiveness of the nutrition education program . The most common biochemical deficiencies were of folic acid , thiamin , and riboflavin . Except for an improvement in mean serum folate levels , the biochemical indices for the treatment group did not appear to be influenced by the nutrition education . It is possible that the vitamin and mineral supplements which were taken by 80 % of the women could have obscured improvements in biochemical indices which may have been due to the education program [7027780] This study is a r and omized controlled double-blind trial on the effects of nutrition supplement of pregnant and lactating women on their offspring . The study was conducted by the late Dr. Bacon Chow in 14 villages in Sui-Lin township , a farming area about 180 miles from Taipei , Taiwan . Two hundred ninety-four women were r and omly assigned to one of two treatment groups . The daily supplement for one group provided 800 kcal and 40 g of protein/day ; for the other group it only provided 80 kcal/day . Supplementation began after 3 wk of the delivery of a first study infant , continued throughout lactation , and through the pregnancy and lactation of a second study infant . Between group comparisons on the birth weight , number of low birth weight infants , or incidence of fetal deaths showed no statistically significant findings . However , the birth weight of the second study infant was statistically different and higher than that of the first study infant in the high supplement group . Moreover , in the low supplement group there was a correlation of 0.22 ( p = 0.06 ) between the change scores for birth weight from the first to the second study infant and the quantity of supplements consumed during the last trimester of pregnancy . There was also in this same group a significant slope in a linear regression of birth weight on total daily caloric intake during the 3rd trimester of pregnancy for the male second study infants . These findings are partly in agreement with findings from three other large supplementation studies in Colombia , Guatemala , and New York . In this study the findings indicate that caloric supplementation does result in a small yet statistically meaningful increment in birth weight within a population which is not nutritionally at risk [2375294] In many regions of the world , women breastfeed one child while pregnant with the next . Among rural Guatemalan women participating in a nutrition-supplementation trial , lactation overlapped with pregnancy in 253 of 504 ( 50.2 % ) of the pregnancies . For cases where overlap occurred , 41.4 % continued to breast-feed into the second trimester and 3.2 % , in the third trimester . The maternal and fetal responses to the energetic stresses of overlap and of the duration of the recuperative ( nonpregnant , nonlactating ) interval were assessed . Overlap result ed in increased supplement intake . Short recuperative periods ( less than 6 mo ) result ed in increased supplement intake and reduced maternal fat stores . The energetic stresses of overlap and short recuperative periods did not significantly affect fetal growth . The mother appears to buffer the energetic stress , protecting fetal growth . This research demonstrates that evidence of depletion of maternal nutrient stores caused by a dem and ing reproductive history is found when reproductive stress is characterized adequately [24045792] Background / Objectives : The mother is an important mediator to the infant of polyunsaturated fatty acids ( PUFA ) , the essential constituents of membranes particularly in the brain and retina . We here aim ed in a prospect i ve study initiated in early pregnancy to establish whether serum fatty acid ( FA ) compositions and concentrations in the mother can be modified by dietary means emphasizing counseling on a recommended diet . Subjects/ Methods : Ninety women in the first trimester of pregnancy were r and omized into intervention ( n=45 ) or control ( n=45 ) groups . The intervention comprised individual dietary counseling advocating choice of foods that will increase the intake of unsaturated and reduce that of saturated FA . To support this , appropriate products , including spreads , were provided for consumption at home . Dietary intakes were measured from food records and serum phospholipids , cholesteryl esters and triacylglycerols FA were analyzed by gas chromatography . Results : Dietary counseling result ed in lower intake of saturated and higher intake of unsaturated FA compared with the controls . These changes were reflected in higher proportions of serum phospholipid PUFA ( mean difference between groups 0.61 % ( 95 % confidence interval , CI 0.05–1.17 ) , P=0.03 ) , docosahexaenoic acid ( 0.5 % ( 0.15–0.85 ) , P=0.01 ) , sum of n-3 FA ( 0.61 % ( 0.07–1.15 ) , P=0.03 ) and lower ratio of n-6/n-3 FA ( −0.42 % ( −0.81–0.03 ) , P=0.03 ) in the intervention group at the third trimester of pregnancy but not at 1 month postpartum . Similar changes were seen in the FA of cholesteryl esters and triacylglycerols . Conclusion : Maternal serum n-3 FA status during pregnancy can be improved by dietary means emphasizing the importance of dietary advice [6365516] The effect of maternal supplementation during both gestation and lactation on infant growth from birth to 12 mth was investigated in the double-blind , r and omly allocated control trial conducted in Taiwan by the late Bacon F. Chow . The supplement was a milk-based formula providing 800 kcal and 40 g protein daily . The placebo provided less than 40 kcal per diem but resembled the supplement in appearance . Supplementation was limited to mothers and began after birth of one infant and continued without interruption until weaning of a second infant . Supplement effects were tested by comparing both supplement and placebo groups and first- and second-infant groups with respect to weight , length and head circumference . Both comparisons of growth curves and analyses of variance were carried out . Both strategies agreed in failing to detect differences in growth between supplement and placebo groups . However , differences were found between first and second infants in the supplement group [6819029] Unselective dietary protein energy supplementation of Asian mothers at Sorrento Maternity Hospital did not enhance intrauterine growth . The effect of selective supplementation was therefore studied . Forty-five mothers who at 28 weeks were known to be nutritionally at risk ( triceps increment less than or equal to 20 microns/week between 18 and 28 weeks ) received one of three supplements during the third trimester : ( a ) vitamins only -- a multivitamin sachet daily containing vitamins A , B , C , and D ; ( b ) energy--42 - 125 MJ ( 10 000 - 30 000 kcal ) , all from carbohydrate , plus vitamins ; ( c ) protein energy -- energy and vitamins as before , but with 5 - 10 % of energy from milk protein . Eighty-three mothers regarded as adequately nourished at 28 weeks also received one of the three supplements . In the nutritionally at-risk mothers the protein energy supplement was associated with a heavier crude birth weight and heavier weight for gestational age . Supplementation did not lead to improved intrauterine growth in those mothers who were adequately nourished . The differential effect of supplementation depending on the mothers ' nutritional state during the second trimester may explain apparently conflicting results of other studies where some have shown a substantial effect of supplementation and others only a small effect . This effect of intervention is further evidence that " poor nutrition " contributes to poor intrauterine growth in selected mothers , even in developed countries [19812173] BACKGROUND Prenatal multiple micronutrient ( MMN ) or balanced energy and protein supplementation has a limited effect on birth size of the offspring . OBJECTIVE The objective was to determine whether a prenatal MMN-fortified food supplement ( FFS ) improves anthropometric measures at birth compared with supplementation with an MMN pill alone . DESIGN We conducted a nonblinded , individually r and omized controlled trial in 1296 pregnant women in 2 villages in rural Burkina Faso . Supplements were provided on a daily basis , and compliance was closely verified by using a community-based network of home visitors . RESULTS Anthropometric measures at birth were available for analysis for 87 % of the 1175 live singleton deliveries enrolled . After adjustment for gestational age at birth , the FFS group had a significantly higher birth length ( + 4.6 mm ; P = 0.001 ) . FFS supplementation result ed in a modestly higher birth weight ( + 31 g ; P = 0.197 ) . Subgroup analyses showed clinical ly important treatment effects on birth length ( + 12.0 mm ; P = 0.005 ) and on birth weight ( + 111 g ; P = 0.133 ) for underweight [ body mass index ( in kg/m(2 ) ) < 18.5 ] pregnant women . Women with early pregnancy anemia who received FFS gave birth to longer newborns ( + 7.3 mm ; P = 0.002 ) than did those who received MMN supplementation . CONCLUSIONS The provision of FFS to pregnant women result ed in higher birth length than did MMN supplementation . For women with a suboptimal prepregnancy nutritional status , MMN supplementation should be complemented with a balanced energy and protein supplement to produce a clinical effect on birth size . The trial was registered at clinical trials.gov as NCT00909974 [19022974] Fetal nutrition is thought to be an important determinant of later disease risk , although evidence from r and omized-controlled trials in humans is lacking . We followed children born during a protein-energy supplementation trial to investigate to what extent this maternal supplement , which improved birth weight , influenced offspring body composition in adolescence . Subjects were 1270 Gambian children ( 659 boys , 611 girls ) aged 11 - 17 y whose mothers had participated in the original cluster-r and omized trial and had received the supplement during pregnancy ( intervention ) or postpartum ( control ) . Basic anthropometry was measured using st and ard techniques and fatness was assessed by bioelectrical impedance analysis and population -specific prediction equations . For boys , mean body fat was 12.6 % for both intervention and control groups . Mean trunk fat was 11.9 % in the intervention group and 12.0 % in the control . Intervention girls had a mean body fat of 19.5 % and trunk fat of 15.2 % ; for control girls , it was 19.3 and 14.8 % , respectively . BMI , body fat , trunk fat , fat mass index , and fat-free mass index did not differ for either sex when analyzed with generalized estimating equations adjusted for age , maternal height , maternal parity , location , season of birth , and menarche in females . Neither infant-attained size nor the onset of menarche were affected by maternal supplementation . These findings suggest that protein-energy supplements to pregnant women , compared with lactating women , do not affect offspring body composition during adolescence [24169456] Background / Objective : Well-being has been linked to the quality of diet and lifestyle in adults ; however , there is a paucity of data in pregnancy . The aim of this study was to examine the relationship between well-being and socioeconomic status , diet and lifestyle during pregnancy and to consider the effect of intervention with low glycaemic index ( GI ) diet on well-being . Subjects/ Methods : This was a cohort analysis of 619 participants of the ROLO study ( R and omised cOntrol trial of LOw GI diet versus no dietary intervention to prevent recurrence of fetal macrosomia ) . The following data were collected : educational attainment , dietary intakes ( food frequency question naire ) , physical activity ( self-reported ) and well-being ( WHO-5-Item Wellbeing Index — expressed as a percentage ) . Results : Well-being was positively associated with education and physical activity . Third-level education was associated with a 3.07-point higher well-being percentage score , and each day that an individual achieved > 30 min walking per week was associated with a 1.10-point increase in percentage well-being score , Radj2 2.4 % ( F=7.260 , P=0.001 ) . The intervention low GI group had a significantly lower percentage well-being score than the usual diet group ( 56.3 % vs 59.9 % , P=0.015 ) . No correlation was noted between well-being and GI status calculated from food diaries ( P=0.469 ) . Well-being was not associated with micronutrient intake . Conclusions : Well-being in pregnancy was independently and positively associated with education and physical activity and negatively associated with low GI dietary intervention . These findings have significance not only for women at risk of low mood but also for healthcare professionals when counselling women about the importance of healthy lifestyle in pregnancy [4221449] ABSTRACT Ready-to-eat ( RTE ) snacks are routinely distributed to pregnant women in India . These provide protein and calories but are low in micronutrients . We investigated whether RTE snacks fortified with leaf concentrate ( LC ) could improve pregnancy outcomes , including maternal haemoglobin ( Hb ) concentrations and infants ’ birthweight . This r and omized controlled two-arm trial was conducted over 18 months : control ( sRTE ) group received st and ard 120 g RTE snack ( 102 g wheat flour , 18 g soya flour ) ; intervention ( lcRTE ) group received the same snack fortified with 7 g LC . The study was conducted in Jaipur , Rajasthan , India . One hundred and five pregnant women aged 18 - 35 years were studied . Among the 105 women r and omized to the two arms of the trial , 2 ( 1.9 % ) were severely anaemic ( Hb ≤6.0 g/dL ) ; 55 ( 53.4 % ) were moderately anaemic ( Hb 6.0 - 8.0 g/dL ) ; 34 ( 33.0 % ) were mildly anaemic ( Hb 8.6 - 10.9 g/dL ) ; and 12 ( 11.7 % ) were not anaemic ( Hb ≥11.0 g/dL ) . In the final month of pregnancy , 83.0 % ( 39/47 ) of women in the sRTE group had Hb ≤8.5 g/dL compared to 37.8 % ( 17/45 ) in the lcRTE group ( p<0.001 ) . After adjustment for age and baseline Hb concentration , the difference in Hb concentrations due to LC fortification was 0.94 g/dL ( 95 % CI 6.8 - 12.0 ; p<0.001 ) . Mean live birthweight in the lcRTE group was 2,695 g ( SD 325 g ) compared to 2,545 g ( 297 g ) in the sRTE group ( p=0.02 ) . The lcRTE snacks increased infants ’ birthweight by 133.7 g ( 95 % CI 7.3 - 260.2 ; p=0.04 ) compared to sRTE snacks . Leaf concentrate fortification of antenatal protein-calorie snacks in a low-income setting in India protected against declining maternal haemoglobin concentrations and increased infants ’ birthweight when compared with unfortified snacks . These findings require replication in a larger trial [15894592] BACKGROUND Low birth weight and subsequent rapid child growth are associated with later blood pressure levels . The role of maternal and child nutrition in this association remains unclear . METHODS We studied 450 men and women ( ages 21 - 29 years ) born during a r and omized trial of protein-energy supplementation ( Atole ) vs low energy/no protein supplementation ( Fresco ) in pregnancy and early childhood in four rural Guatemalan villages from 1969 to 1977 . RESULTS Protein-energy supplementation was not associated with differences in blood pressure in adulthood ( diastolic blood pressure ( DBP ) : beta = 0.69 mm Hg , 95 % confidence internal ( CI ) ( 20.82 - 2.19 ) ; P = 0.37 ; systolic blood pressure ( SBP ) : beta = 0.17 mm Hg , 95 % CI ( 21.68 - 2.02 ) ; P = 0.86 ) . Within the Atole group , maternal height was associated with later SBP ( 0.22 mm Hg/cm , 95 % CI ( 20.002 - 0.45 ) ; P = 0.05 ) . No other associations between maternal nutritional status , birth size , child growth , or supplement intake were observed for adult blood pressure . CONCLUSIONS Our data do not support the role of maternal nutrition during pregnancy , birth size , or early child growth in programming adult blood pressure . Likewise , we found no effect of protein-energy supplementation in pregnancy or in early childhood on blood pressure in young adults [2681032] OBJECTIVE A low – glycemic index diet is effective as a treatment for individuals with diabetes and has been shown to improve pregnancy outcomes when used from the first trimester . A low – glycemic index diet is commonly advised as treatment for women with gestational diabetes mellitus ( GDM ) . However , the efficacy of this advice and associated pregnancy outcomes have not been systematic ally examined . The purpose of this study was to determine whether prescribing a low – glycemic index diet for women with GDM could reduce the number of women requiring insulin without compromise of pregnancy outcomes . RESEARCH DESIGN AND METHODS All women with GDM seen over a 12-month period were considered for inclusion in the study . Women ( n = 63 ) were r and omly assigned to receive either a low – glycemic index diet or a conventional high-fiber ( and higher glycemic index ) diet . RESULTS Of the 31 women r and omly assigned to a low – glycemic index diet , 9 ( 29 % ) required insulin . Of the women r and omly assigned to a higher – glycemic index diet , a significantly higher proportion , 19 of 32 ( 59 % ) , met the criteria to commence insulin treatment ( P = 0.023 ) . However , 9 of these 19 women were able to avoid insulin use by changing to a low – glycemic index diet . Key obstetric and fetal outcomes were not significantly different . CONCLUSIONS Using a low – glycemic index diet for women with GDM effectively halved the number needing to use insulin , with no compromise of obstetric or fetal outcomes [4292819] Background Fish and meat intake may affect gestational weight gain , body composition and serum fatty acids . We aim ed to determine whether a longitudinal dietary intervention during pregnancy could increase fish intake , affect serum phospholipid fatty acids , gestational weight gain and body composition changes during pregnancy in women of normal weight participating in the Pregnancy Obesity Nutrition and Child Health study . A second aim was to study possible effects in early pregnancy of fish intake and meat intake , respectively , on serum phospholipid fatty acids , gestational weight gain , and body composition changes during pregnancy . Methods In this prospect i ve , r and omized controlled study , women were allocated to a control group or to a dietary counseling group that focused on increasing fish intake . Fat mass and fat-free mass were measured by air-displacement plethysmography . Reported intake of fish and meat was collected from a baseline population and from a subgroup of women who participated in each trimester of their pregnancies . Serum levels of phospholipid arachidonic acid ( s-ARA ) , eicosapentaenoic acid ( s-EPA ) , and docosahexaenoic acid ( s-DHA ) were measured during each trimester . Results Weekly fish intake increased only in the intervention group ( n = 18 ) from the first to the second trimester ( median difference 113 g , p = 0.03 ) and from the first to the third trimester ( median difference 75 g , p = 0.01 ) . In the first trimester , fish intake correlated with s-EPA ( r = 0.36 , p = 0.002 , n = 69 ) and s-DHA ( r = 0.34 , p = 0.005 , n = 69 ) , and meat intake correlated with s-ARA ( r = 0.28 , p = 0.02 , n = 69 ) . Fat-free mass gain correlated with reported meat intake in the first trimester ( r = 0.39 , p = 0.01 , n = 45 ) . Conclusions Dietary counseling throughout pregnancy could help women increase their fish intake . Intake of meat in early pregnancy may increase the gain in fat-free mass during pregnancy [18154905] OBJECTIVES To evaluate the impact of maternal nutrition during pregnancy on infant blood pressure . STUDY DESIGN Pregnant women ( n = 256 ) were r and omized into 3 groups : modified dietary intake according to current recommendations and probiotics ( diet/probiotics ) , placebo ( diet/placebo ) , and a control/placebo group . In the infants born to these women , blood pressure was recorded at age 6 months using an automated oscillometric DINAMAP R. RESULTS Despite significant differences in maternal dietary intakes between the study groups , the intervention focusing on maternal fat intake showed no direct impact on infants ' blood pressure . Instead , a complex U-shaped interrelationship was uncovered ; the highest and lowest quartiles of intakes of specific nutrients , carbohydrate ( P = .006 for systolic pressure and P = .015 for diastolic pressure ) , and monounsaturated fatty acids ( P = .029 for diastolic pressure ) compared with the middle quartiles result ed in higher blood pressure at age 6 months . The pattern between maternal carbohydrate intake during pregnancy and infants ' blood pressure remained significant even after adjustment for breastfeeding and body length . A reverse U-shaped trend again was observed between maternal intake of fruits and infants ' systolic blood pressure ( P = .077 ) . CONCLUSION With a view toward programming blood pressure to adulthood , our results suggest an opportunity for dietary counseling to promote child health [3534399] Background Recent observational research indicates that immune development may be programmed by nutritional exposures early in life . Such findings require replication from trials specifically design ed to assess the impact of nutritional intervention during pregnancy on infant immune development . The current trial seeks to establish : ( a ) which combination of protein-energy ( PE ) and multiple-micronutrient ( MMN ) supplements would be most effective ; and ( b ) the most critical periods for intervention in pregnancy and infancy , for optimal immune development in infancy . Methods / Design The ENID Trial is a 2 x 2 x 2 factorial r and omized , partially blind trial to assess whether nutritional supplementation to pregnant women ( from < 20 weeks gestation to term ) and their infants ( from 6 to 12 months of age ) can enhance infant immune development . Eligible pregnant women from the West Kiang region of The Gambia ( pregnancy date d by ultrasound examination ) are r and omized on entry to 4 intervention groups ( Iron-folate ( FeFol = st and ard care ) , multiple micronutrients ( MMN ) , protein-energy ( PE ) , PE + MMN ) . Women are visited at home weekly for supplement administration and morbidity assessment and seen at MRC Keneba at 20 and 30 weeks gestation for a detailed antenatal examination , including ultrasound . At delivery , cord blood and placental sample s are collected , with detailed infant anthropometry collected within 72 hours . Infants are visited weekly thereafter for a morbidity question naire . From 6 to 12 months of age , infants are further r and omized to a lipid-based nutritional supplement , with or without additional MMN . The primary outcome measures of this study are thymic development during infancy , and antibody response to vaccination . Measures of cellular markers of immunity will be made in a selected sub-cohort . Subsidiary studies to the main trial will additionally assess the impact of supplementation on infant growth and development to 24 months of age . Discussion The proposed trial is design ed to test whether nutritional repletion can enhance early immune development and , if so , to help determine the most efficacious form of nutritional support . Where there is evidence of benefit from a specific intervention/combination of interventions , future research should focus on refining the supplements to achieve the optimal , most cost-effective balance of interventions for improved health outcomes .Trial registration IS RCT [17018700] To study the role of nutrition in the association of birth size and childhood growth with development of cardiovascular disease , the authors in 2002 - 2004 surveyed 665 men and 790 women aged 25 - 42 years who had been exposed as children to a community-r and omized nutrition supplementation intervention in four villages in eastern Guatemala . Exposure was associated with a lower fasting glucose level ( 7.0 mg/dl , 95 % confidence interval ( CI ) : 0.5 , 13.5 ) for exposure at ages 36 - 72 months ; lower systolic blood pressure ( 3.0 mmHg , 95 % CI : 0.4 , 5.6 ) for exposure at ages 24 - 60 months ; and a lower triglyceride level ( sex-adjusted ; 22.2 mg/dl , 95 % CI : 0.4 , 44.1 ) and higher high density lipoprotein cholesterol level ( males only ; 4.7 mg/dl , 95 % CI : 1.5 , 7.9 ) for exposure prior to age 36 months . Improved nutrition at any age prior to 7 years was not associated with diastolic blood pressure , total or low density lipoprotein cholesterol level , or prevalence of the metabolic syndrome . Interventions design ed to address nutrient deficiencies and ameliorate stunting that are targeted at pregnant women and young children are unlikely to increase cardiovascular disease risk later in life and may instead lower the risk [21346924] OBJECTIVE To examine the association between gestational weight gain and maternal body mass index ( BMI ) among Vietnamese women and the risk of delivering an infant too small or too large for gestational age . METHODS A prospect i ve health-facility-based study of 2989 pregnant Vietnamese women was conducted in the city of Nha Trang in 2007 - 2008 . Cubic logistic regression was used to investigate the association of interest . Infants were classified into weight-for-gestational-age categories according to weight centiles for the Asian population . Gestational age was based on the date of last menstrual period and adjusted by the results of first-trimester ultrasound . FINDINGS BMI was low ( < 18.5 ) , normal ( 18.5 - 22.9 ) and high ( ≥ 23.0 ) in 26.1 % , 65.4 % and 8.5 % of the women , respectively . In each of these BMI categories , the percentage of women who delivered infants too small for gestational age was 18.1 , 10.0 and 9.4 , respectively , and the mean gestational weight gain was 12.5 kg ( st and ard deviation , SD : ± 3.6 ) , 12.2 kg ( SD : ± 3.8 ) and 11.5 kg ( SD : ± 4.7 ) , respectively . Among women with low BMI , the risk of delivering an infant too small for gestational age ranged from approximately 40 % if the gestational weight gain was < 5 kg to 20 % if it was 5 - 10 kg . CONCLUSION Having a low BMI , commonly found in Viet Nam , puts women at risk of delivering an infant too small for gestational age , especially when total maternal gestational weight gain is < 10 kg [20053938] Knowledge about the impact of maternal food and micronutrient supplementation on infant micronutrient status is limited . We examined the effect of maternal food and micronutrient supplementation on infant micronutrient status in the Maternal and Infant Nutrition Interventions in Matlab Trial . Pregnant women ( n = 4436 ) were r and omized to Early or Usual promotion of enrollment in a food supplementation program . In addition , they were r and omly allocated to 1 of the following 3 types of daily micronutrient supplements provided from wk 14 of gestation to 3 mo postpartum : 1 ) folic acid and 30 mg iron ( Fe30Fol ) ; 2 ) folic acid and 60 mg iron ; or 3 ) a multiple micronutrient including folic acid and 30 mg iron ( MMS ) . At 6 mo , infant blood sample s ( n = 1066 ) were collected and analyzed for hemoglobin and plasma ferritin , zinc , retinol , vitamin B-12 , and folate . The vitamin B-12 concentration differed between the micronutrient supplementation groups ( P = 0.049 ) . The prevalence of vitamin B-12 deficiency was lower in the MMS group ( 26.1 % ) than in the Fe30Fol group ( 36.5 % ) ( P = 0.003 ) . The prevalence of zinc deficiency was lower in the Usual food supplementation group ( 54.1 % ) than in the Early group ( 60.2 % ) ( P = 0.046 ) . There were no other differential effects according to food or micronutrient supplementation groups . We conclude that maternal multiple micronutrient supplementation may have a beneficial effect on vitamin B-12 status in infancy [4176103] Background Maternal diet is known to impact pregnancy outcome . Following a low glycemic index ( GI ) diet during pregnancy has been shown to improve maternal glycemia and reduce infant birthweight and may be associated with a higher fibre intake . We assessed the impact of a low GI dietary intervention on maternal GI , nutritional intake and gestational weight gain ( GWG ) during pregnancy . Compliance and acceptability of the low GI diet was also examined . Method Eight hundred women were r and omised in early pregnancy to receive low GI and healthy eating dietary advice or to receive st and ard maternity care . The intervention group received dietary advice at a group education session before 22 weeks gestation . All women completed a 3 day food diary during each trimester of pregnancy . Two hundred and thirty five women from the intervention arm and 285 women from the control arm returned complete 3x3d FDs and were included in the present analysis . Results Maternal GI was significantly reduced in the intervention group at trimester 2 and 3 . The numbers of women within the lowest quartile of GI increased from 37 % in trimester 1 to 52 % in trimester 3 ( P < 0.001 ) among the intervention group . The intervention group had significantly lower energy intake ( P < 0.05 ) , higher protein ( % TE ) ( P < 0.01 ) and higher dietary fibre intake ( P < 0.01 ) post intervention . Consumption of food groups with known high GI values were significantly reduced among the intervention group . Women in the intervention low GI group were less likely to exceed the Institute of Medicine ’s GWG goals . Conclusion A dietary intervention in early pregnancy had a positive influence on maternal GI , food and nutrient intakes and GWG . Following a low GI diet may be particularly beneficial for women at risk of exceeding the GWG goals for pregnancy . Trial registration Current Controlled Trials Registration Number : IS RCT N54392969 [20128938] The perinatal nutritional environment impacts upon the health and well-being of mother and child also in the long term . The aim of the present study was to determine the safety and efficacy of perinatal probiotic-supplemented dietary counselling by evaluating pregnancy outcome and fetal and infant growth during the 24 months ' follow-up . Altogether , 256 women were r and omised at their first trimester of pregnancy into a control and a dietary intervention group . The intervention group received intensive dietary counselling provided by a nutritionist and were further r and omised , double-blind to receive probiotics ( Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12 ; diet/probiotics ) or placebo ( diet/placebo ) . Firstly , probiotic intervention reduced the frequency of gestational diabetes mellitus ( GDM ) ; 13 % ( diet/probiotics ) v. 36 % ( diet/placebo ) and 34 % ( control ) ; P = 0.003 . Secondly , the safety of this approach was attested by normal duration of pregnancies with no adverse events in mothers or children . No significant differences in prenatal or postnatal growth rates among the study groups were detected . Thirdly , distinctive effects of the two interventions were detected ; probiotic intervention reduced the risk of GDM and dietary intervention diminished the risk of larger birth size in affected cases ; P = 0.035 for birth weight and P = 0.028 for birth length . The results of the present study show that probiotic-supplemented perinatal dietary counselling could be a safe and cost-effective tool in addressing the metabolic epidemic . In view of the fact that birth size is a risk marker for later obesity , the present results are of significance for public health in demonstrating that this risk is modifiable [21729487] OBJECTIVE Increasing the consumption of Fe-rich foods and thus improving Fe bioavailability without significantly increasing diet cost is the most sustainable intervention for improving Fe intake . We assessed the effect of supplementary food consisting of fermented soyabean ( tempeh ) and vitamin C-rich fruit consumed during pregnancy on maternal iron deficiency ( ID ) . DESIGN Pregnant women were r and omly allocated by village into optimized diet and control groups . Supplementary food was given 6 d/week at home . The average weekly food provided comprised 600 g of tempeh , 30 g of meat , 350 g of guava , 300 g of papaya and 100 g of orange . Hb , ferritin and transferrin receptor ( TfR ) concentrations were measured at 12 - 20 and at 32 - 36 weeks of gestation . SETTING Thirty-nine villages in Indonesia . SUBJECTS Pregnant women ( 12 - 20 weeks of gestation , n 252 ) . RESULTS At baseline , mean Hb , ferritin and TfR concentrations and body Fe concentration were within the normal range and did not differ between groups . At near term , mean Hb , ferritin and body Fe decreased , whereas mean TfR increased significantly in both groups . The mean changes in Fe status were similar in both groups . In Fe-deficient women , consumption of an optimized diet was associated with smaller decreases in Hb ( 1·02 ( 95 % CI 0·98 , 1·07 ) g/l ; P = 0·058 ) , ferritin ( 1·42 ( 95 % CI 1·16 , 1·75 ) μg/l ; P = 0·046 ) and body Fe ( 2·57 ( 95 % CI 1·71 , 3·43 ) mg/kg ; P = 0·073 ) concentrations , compared with a state of no intervention . Fe-deficient women at baseline benefited more from supplementary food compared with Fe-replete women . CONCLUSIONS Daily supplementary food containing tempeh and vitamin C-rich fruits during pregnancy might have positive effects on maternal ID [2639364] Background Birthweight , and by inference maternal nutrition during pregnancy , is thought to be an important determinant of offspring blood pressure but the evidence base for this in humans is lacking data from r and omized controlled trials . Methods The offspring from a maternal prenatal protein-energy supplementation trial were enrolled into a follow-up study of chronic disease risk factors including blood pressure . Subjects were 11–17 years of age and blood pressure was measured in triplicate using an automated monitor ( Omron 705IT ) . One-thous and two-hundred sixty seven individuals ( 71 % of potential participants ) were included in the analysis . Results There was no difference in blood pressure between those whose mothers had consumed protein-energy biscuits during pregnancy and those whose mothers had consumed the same supplement post-partum . For systolic blood pressure the intention-to-treat regression coefficient was 0.46 ( 95 % CI : –1.12 , 2.04 ) . Mean systolic blood pressure for control children was 110.2 ( SD ± 9.3 ) mmHg and for intervention children was 110.8 ( SD ± 8.8 ) mmHg . Mean diastolic blood pressure for control children was 64.7 ( SD ± 7.7 ) mmHg and for intervention children was 64.6 ( SD ± 7.6 ) mmHg . Conclusions We have found no association between maternal prenatal protein-energy supplementation and offspring blood pressure in adolescence amongst rural Gambians . We found some evidence to suggest that offspring body composition may interact with the effect of maternal supplementation on blood pressure [21561932] BACKGROUND Relative leg length is frequently used as a biomarker of childhood nutrition in epidemiological studies , but evidence is lacking . We examined the association between supplemental nutrition in pregnancy and childhood and relative proportions of components of height in adolescence . METHODS In a community trial of nutritional supplementation , villages from adjacent administrative areas were selected to serve as intervention ( n = 15 ) and control ( n = 14 ) arms . In the intervention villages , balanced protein-calorie supplementation ( 2.51 MJ , 20 g protein ) was offered daily to pregnant women and their offspring until the age of 6 years . Children born in the trial were re-examined 15 years later to assess components of height . RESULTS A total of 1165 adolescents ( intervention : 654 , 49 % of trial participants ; control : 511 , 41 % of trial participants ) aged 13 - 18 years were examined . Supplemented children were 10 mm taller [ 95 % confidence interval ( CI ) : 1.4 to 18.7 mm ] , but almost all of the increase was in trunk length ( 9 mm , 95 % CI : 2.6 to 15.4 mm ) . The age- and gender-adjusted β-coefficients for the association of nutritional supplementation with relative trunk , leg and lower leg lengths ( expressed as st and ard deviation scores ) were 0.26 ( 95 % CI : 0.11 to 0.42 ) , 0.08 ( 95 % CI : -0.03 to 0.19 ) and 0.03 ( 95 % CI : -0.08 to 0.15 ) respectively , thereby unsupportive of cephalocaudal gradient in growth . CONCLUSIONS In this nutritional supplementation trial in an undernourished population , we were unable to confirm relative leg length as a biomarker of childhood nutrition . Alternative explanations may underlie the reported associations between childhood conditions and relative leg length [19955397] BACKGROUND Maternal obesity and excessive gestational weight gain ( GWG ) are major short- and long-term risk factors for maternal and fetal complications . OBJECTIVE The objective was to study whether a lifestyle intervention based on a brochure or on active education can improve dietary habits , increase physical activity ( PA ) , and reduce GWG in obese pregnant women . DESIGN In this r and omized controlled trial , 195 white , obese pregnant women [ age : 29 + or - 4 y ; body mass index ( in kg/m(2 ) ) ; 33.6 + or - 4.2 ] were r and omly assigned into 3 groups : a group that received nutritional advice from a brochure , a group that received the brochure and lifestyle education by a nutritionist , and a control group . Nutritional habits were evaluated every trimester through 7-d food records . PA was evaluated with the Baecke question naire . RESULTS Energy intake did not change during pregnancy and was comparable in all groups . Fat intake , specifically saturated fat intake , decreased and protein intake increased from the first to the third trimester in the passive and active groups compared with an opposite change in the control group . Calcium intake and vegetable consumption increased during pregnancy in all groups . PA decreased in all groups , especially in the third trimester . No significant differences in GWG and obstetrical or neonatal outcome could be observed between the groups . CONCLUSIONS Both lifestyle interventions improved the nutritional habits of obese women during pregnancy . Neither PA nor GWG was affected [3847473] The current study attempts to identify the effects of an individual prescription for protein and kilocalorie requirements during pregnancy on subsequent maternal and infant outcomes . This study was a replication of Agnes Higgins ' Intervention Method for Nutritional Rehabilitation During Pregnancy developed at the Montreal Diet Dispensary , Montreal , Canada . The present study was a r and omized clinical trial using an experimental control group design . There were 47 subjects in phases 1 and 2 of a multiphase study . Total food intake data was available for 43 subjects with singleton live births . The Higgins method was found to have a significant impact on increasing the amount of protein but not calories consumed by the experimental group . A significant increase in maternal weight and infant birth weight was found in those underweight and normal weight women , who gained at least 10 lb ( 4.5 kg ) in the first 20 weeks of their pregnancy and who consumed an adequate amount of their prescriptions of both protein and kilocalories . All the women with premature labor and pregnancy-induced hypertension were in the group with an inadequate early pregnancy weight gain and inadequate nutrition intake . Data collection to increase sample size is ongoing [24896237] The present study is a secondary analysis of the ROLO study , a r and omised control trial of a low-glycaemic index ( GI ) diet in pregnancy to prevent the recurrence of fetal macrosomia . The objectives of the present study were to identify which women are most likely to respond to a low-GI dietary intervention in pregnancy with respect to three outcome measures : birth weight ; maternal glucose intolerance ; gestational weight gain ( GWG ) . In early pregnancy , 372 women had their mid-upper arm circumference recorded and BMI calculated . Concentrations of glucose , insulin and leptin were measured in early pregnancy and at 28 weeks . At delivery , infant birth weight was recorded and fetal glucose , C-peptide and leptin concentrations were measured in the cord blood . Women who benefited in terms of infant birth weight were shorter , with a lower education level . Those who maintained weight gain within the GWG guidelines were less overweight in both their first and second pregnancies , with no difference being observed in maternal height . Women who at 28 weeks of gestation developed glucose intolerance , despite the low-GI diet , had a higher BMI and higher glucose concentrations in early pregnancy with more insulin resistance . They also had significantly higher-interval pregnancy weight gain . For each analysis , women who responded to the intervention had lower leptin concentrations in early pregnancy than those who did not . These findings suggest that the maternal metabolic environment in early pregnancy is important in determining later risks of excessive weight gain and metabolic disturbance , whereas birth weight is mediated more by genetic factors . It highlights key areas , which warrant further interrogation before future pregnancy intervention studies , in particular , maternal education level and inter-pregnancy weight gain [9345173] Abstract Objective : To test the efficacy in terms of birth weight and infant survival of a diet supplement programme in pregnant African women through a primary healthcare system . Design : 5 year controlled trial of all pregnant women in 28 villages r and omised to daily supplementation with high energy groundnut biscuits ( 4.3MJ/day ) for about 20 weeks before delivery ( intervention ) or after delivery ( control ) . Setting : Rural Gambia . Subjects : Chronically undernourished women ( twin bearers excluded ) , yielding 2047 singleton live births and 35 stillbirths . Main outcome measures : Birth weight ; prevalence of low birth weight ( < 2500 g ) ; head circumference ; birth length ; gestational age ; prevalence of stillbirths ; neonatal and postneonatal mortality . Results : Supplementation increased weight gain in pregnancy and significantly increased birth weight , particularly during the nutritionally debilitating hungry season ( June to October ) . Weight gain increased by 201 g ( P<0.001 ) in the hungry season , by 94 g ( P<0.01 ) in the harvest season ( November to May ) , and by 136 g ( P<0.001 ) over the whole year . The odds ratio for low birthweight babies in supplemented women was 0.61 ( 95 % confidence interval 0.47 to 0.79 , P<0.001 ) . Head circumference was significantly increased ( P<0.01 ) , but by only 3.1 mm . Birth length and duration of gestation were not affected . Supplementation significantly reduced perinatal mortality : the odds ratio was 0.47 ( 0.23 to 0.99 , P<0.05 ) for stillbirths and 0.54 ( 0.35 to 0.85 , P<0.01 ) for all deaths in first week of life . Mortality after 7 days was unaffected . Conclusion : Prenatal dietary supplementation reduced retardation in intrauterine growth when effectively targeted at genuinely at-risk mothers . This was associated with a substantial reduction in the prevalence of stillbirths and in early neonatal mortality . The intervention can be successfully delivered through a primary healthcare system . Key messages In developing countries chronic maternal undernutrition is a prime contributor to the birth of over 25 million low birthweight babies annually and to high rates of neonatal mortality . An absence of well design ed field trials has created uncertainty about the potential efficacy of maternal feeding programmes This large scale r and omised controlled trial shows that dietary supplementation in pregnancy can be highly effective in reducing the proportion of low birthweight babies and perinatal mortality Incorporating supplementary feeding into a rural primary healthcare system is feasible Late pregnancy is the period most amenable to [6988785] This r and omized controlled trial of nutritional supplementation in pregnancy , in a poor black urban population in the United States , aim ed to increase the birth weight and influence the postnatal development of the offspring of mothers at high risk of having low birth weight infants . The execution of the research design and adherence to the treatment regimen among the experimental population appeared adequate for a reasonable test of the treatments . At birth , the only significant favorable effect of supplementation observed was the prevention of depressed birth weight among the offspring of mothers who smoked heavily . With balanced protein-calorie supplementation , length of gestation was increased , the proportion of low-birth-weight infants reduced , and mean birth weight raised by 41 gm ( not statistically significant ) . With high protein supplementation , there was an excess of very early premature births and associated neonatal deaths , and there was significant growth retardation up to 37 weeks of gestation . At 1 year of age , significant effects of high protein supplement were found on three psychological measures : visual habituation , visual dishabituation , and mean length of free play episodes . These measures were unrelated to measures of growth at birth and at 1 year of age . There were no detectable residual adverse effects of high protein supplementation at 1 year of age [18242415] BACKGROUND Substantial , but indirect , evidence suggests that improving nutrition in early childhood in developing countries is a long-term economic investment . We investigated the direct effect of a nutrition intervention in early childhood on adult economic productivity . METHODS We obtained economic data from 1424 Guatemalan individuals ( aged 25 - 42 years ) between 2002 and 2004 . They accounted for 60 % of the 2392 children ( aged 0 - 7 years ) who had been enrolled in a nutrition intervention study during 1969 - 77 . In this initial study , two villages were r and omly assigned a nutritious supplement ( atole ) for all children and two villages a less nutritious one ( fresco ) . We estimated annual income , hours worked , and average hourly wages from all economic activities . We used linear regression models , adjusting for potentially confounding factors , to assess the relation between economic variables and exposure to atole or fresco at specific ages between birth and 7 years . FINDINGS Exposure to atole before , but not after , age 3 years was associated with higher hourly wages , but only for men . For exposure to atole from 0 to 2 years , the increase was US$ 0.67 per hour ( 95 % CI 0.16 - 1.17 ) , which meant a 46 % increase in average wages . There was a non-significant tendency for hours worked to be reduced and for annual incomes to be greater for those exposed to atole from 0 to 2 years . INTERPRETATION Improving nutrition in early childhood led to substantial increases in wage rates for men , which suggests that investments in early childhood nutrition can be long-term drivers of economic growth [23432806] Leptin regulates energy homeostasis and immune and metabolic functions . Highly elevated leptin concentrations during pregnancy may be associated with aberrations in maternal metabolism and long-term health consequences both in women and children . The objective of the present study was to evaluate whether dietary counselling , probiotic supplementation , maternal characteristics or dietary intake during pregnancy has an impact on serum leptin concentrations in women , cord blood or in children . A total of 256 pregnant women were r and omised to a control group ( n 85 ) or to receive dietary counselling with probiotics ( n 85 ) or placebo ( n 86 ) . Dietary counselling aim ed at affecting the type of fat used and to increase the amount of fibre in the women 's diet . Women 's dietary intake and serum leptin concentrations were analysed at the first and third trimesters of pregnancy and at 1 month postpartum . Furthermore , leptin concentrations were measured from the cord blood and from children 's serum at 1 and 6 months of age . Weight status and dietary composition were the key determinants of leptin concentrations . Specifically , high dietary fibre and low SFA intakes were related to low serum leptin concentrations in women . Female sex and birth weight were associated with higher infant leptin , whereas cord blood leptin was additionally affected by maternal leptin concentration and protein intake . Probiotics or dietary counselling did not affect leptin concentrations . Weight control to recommended levels and modification of diet towards higher fibre and lower SFA intakes during pregnancy may through leptin concentrations provide health benefits to both women and children [25639126] Background Maternal malnutrition and poor gestational weight gain are the most important causes of low birthweight and infant mortality in Bangladesh . Objective To assess the effect of short-term nutrition education on weight gain in the third trimester of pregnancy , birth outcomes , and breastfeeding . Methods Three hundred pregnant women participated in this r and omized , controlled trial during a 3-month intervention period . The study was conducted in two antenatal clinics in urban Dhaka . One group of women was given monthly education sessions during the third trimester of pregnancy to promote consumption of khichuri , while the control group received only routine services from the health facilities . Birthweight was recorded within 24 hours after delivery . Breastfeeding practice s were observed for 1 month after delivery . Results In the intervention group , maternal weight gain in the third trimester was 60 % higher ( 8.60 vs. 5.38 kg , p = .011 ) , mean birthweight was 20 % higher ( 2.98 vs. 2.49 kg , p < .001 ) , the rate of low birth-weight was 94 % lower ( 2.7 % vs. 44.7 % , p < .001 ) , and the rate of initiation of breastfeeding within 1 hour after birth was 52 % higher ( 86.0 % vs. 56.7 % , p < .001 ) , in comparison with the control group . Birthweight was associated with frequency of intake of khichuri ( p < 0.001 ) . Conclusions Nutrition education with a focus on promoting consumption of khichuri during the third trimester of pregnancy significantly reduced the rate of low birthweight and increased maternal weight gain [6761102] A r and omized controlled double-blind study of nutrition supplementation of pregnant and lactating women was conducted in Suilin township , Taiwan . Pregnant mothers were r and omly assigned to one of two treatment groups consisting of either a high ( 800 kcal and 40 g protein ) calorie daily supplement or a placebo . For each mother treatment began following the delivery of her first study infant , continued throughout the lactation period ; and through the pregnancy and lactation of her second study infant . Comparisons of sibling-sibling anthropometric correlations at birth between groups show that among the placebo group the sibling correlations are statistically significant and of the same magnitude seen in previous studies ( approximately 0.5 ) , while among high calorie siblings correlations are unusually low and often not significant . This is particularly true for male fetuses , suggesting that the latter are more sensitive to nutritional environmental variations in utero , than are female fetuses . Reduction in familial correlations , presumed measures of genetic influence , in nutritionally stressed population s , will occur when the environment of relatives differ , but are not due to malnutrition per se [1676083] There is little unequivocal evidence that nutritional supplementation of undernourished children has a beneficial effect on their mental development . The effects of nutritional supplementation , with or without psychosocial stimulation , of growth-retarded ( stunted ) children aged 9 - 24 months were assessed in a study in Kingston , Jamaica . 129 children from poor neighbourhoods were r and omly assigned to four groups -- control , supplemented only , stimulated only , and supplemented plus stimulated . A group of matched non-stunted children ( n = 32 ) was also included . The supplement comprised 1 kg milk-based formula per week for 2 years , and the stimulation weekly play sessions at home with a community health aide . The children 's development ( DQ ) was assessed on the Griffiths mental development scales . Initially the stunted groups ' DQs were lower than those of the non-stunted group , and those of the control group declined during the study , increasing their deficit . Stimulation and supplementation had significant independent beneficial effects on the children 's development . Estimates of the supplementation effect ranged from 2.2 ( 95 % confidence limits-1.4 , 5.7 ) for the h and and eye subscale to 12.4 ( 5.4 , 19.5 ) for the locomotor subscale and those for the stimulation effect from 6.4 ( 2.8 , 10.0 ) for h and and eye to 10.3 ( 3.3 , 17.3 ) for locomotor . The treatment effects were additive , and combined interventions were significantly more effective than either alone . These findings suggest that poor mental development in stunted children is at least partly attributable to undernutrition [3048373] Summary . The effect of two levels of energy supplementation in the last trimester of pregnancy on birthweight was tested in a controlled r and omized trial in three villages in Madura , East Java . The high and low energy supplements provided 1·95 MJ ( 465 kcal ) and 218 kj ( 52 kcal ) per day respectively . In the baseline period the home diet provided on average 6·28 MJ ( 1500 kcal ) ( SD 2·1 MJ ( 499 kcal ) ) and 41g(SD 13 g ) of protein . The mean birthweight was 2835 g and the rate of low birth‐weight 12·2 % . In the experimental period the home diet was better . The average intake ranged from 6·45 to 7·19 MJ ( 1541–1717 kcal ) and 41·4–44·2 g per day , depending on the degree of compliance . Mean birth‐weight increased by 100 g and the rate of low birthweight dropped to 9·5 % . There was no difference between the high and low energy supplemented group as a whole , probably due to the masking effect of the better home diet in the experimental period . It is likely that a positive effect of energy supplementation on birthweight was restricted to the group of pregnant women with the lowest home dietary intake and /or a low prepregnant weight . In this community targeting of supplementation to lean seasons and /or to women with a low prepregnant weight may be cost‐effective [2424471] We related cigarette smoking during pregnancy to the macroscopic and microscopic morphology , histomorphometry , and biochemistry of the placenta among participants in The Prenatal Project , a r and omized , controlled trial of nutritional supplementation during pregnancy . The aim was to ascertain if the harmful effects of cigarette smoking on the fetus were reflected , and possibly mediated , by changes in the placenta , and whether such changes might be modified by the nutritional supplements , parallel to the nutritional reversal of birthweight depression among heavy smokers . Maternal smoking was associated with increased alkaline ribonuclease ( RNase ) levels , possibly result ing in disturbed protein synthesis . More smokers had placentas with villous hyperplasia on histologic examination . This was accompanied by biochemical evidence of significantly increased cellularity ( increased DNA/gm of placental mass and decreased protein/DNA ratios ) and ( nonsignificant ) trends to reduced syncytial villous cell size on histomorphometry . There were joint effects of cigarette smoking and use of either form of nutritional supplementation on the fibrin and stoma components of the villi , but such changes are not necessarily pathologic . The significant reduction in pathology of the stem villi among smokers was confined to those who were nutritionally supplemented , particularly heavy smokers . This change may thus have reflected the protective effects of supplementation on the birthweight of the offspring of these heavy smokers [24351875] BACKGROUND Eating carbohydrate foods with a high glycemic index ( GI ) has been postulated to result in fetoplacental overgrowth and higher infant body fat . A diet with a low glycemic index ( LGI ) has been shown to reduce birth percentiles and the ponderal index ( PI ) . OBJECTIVES We investigated whether offering LGI dietary advice at the first antenatal visit would result in a lower fetal birth weight , birth percentile , and PI than providing healthy eating ( HE ) advice . This advice had to be presented within the re sources of routine antenatal care . DESIGN The Pregnancy and Glycemic Index Outcomes study was a 2-arm , parallel- design , r and omized , controlled trial that compared the effects of LGI dietary advice with HE advice on pregnancy outcomes . Eligible volunteers who attended for routine antenatal care at < 20 wk of gestation were r and omly assigned to either group . RESULTS A total of 691 women were enrolled , and 576 women had final data considered . In the LGI group , the GI was reduced from a mean ( ± SEM ) of 56 ± 0.3 at enrollment to 52 ± 0.3 ( P < 0.001 ) at the final assessment . There were no significant differences in primary outcomes of fetal birth weight , birth percentile , or PI . In a multivariate regression analysis , the glycemic load was the only significant dietary predictor ( P = 0.046 ) of primary outcomes but explained < 1 % of all variation . CONCLUSION A low-intensity dietary intervention with an LGI diet compared with an HE diet in pregnancy did not result in any significant differences in birth weight , fetal percentile , or PI [15894699] Objective : Insulin-like growth factors ( IGF ) are increasingly recognized as important determinants of adult health , in particular risk of certain cancers . However , little is known about the determinants of adult IGFs and to what degree they may be programmed by early life influences . Design : R and omized controlled trial of prenatal and postnatal milk supplementation among 951 subjects born in 1972 to 1974 in South Wales . Main outcome measure : Measures of IGF-I , IGF binding protein 3 , and the molar ratio . Results : Data on adult IGFs were available from 663 subjects at a mean age of 25 years . Subjects in the intervention arm had lower IGF-I ( −8.5 ng/mL ; 95 % confidence interval , −15.1 to −1.8 , P = 0.01 ) and ratio ( −1.20 ; 95 % confidence interval , −2.33 to −0.04 , P = 0.04 ) . These differences could not be explained by follow-up bias or confounding factors . Conclusions : These results provide experimental data on the role of early life programming either in the intrauterine or postnatal period that may have long-term influences on the IGF axis , with potential implication s for disease risk [17181885] The aim of this study was to assess the impact of dietary counselling combined with the provision of food products on food and nutrient intake in pregnant women . We carried out a prospect i ve cohort study of healthy and atopic pregnant women ( n 209 ) , who were r and omized into dietary intervention and control groups . The intervention group received dietary counselling and food products to modify the fat composition of their diet to meet current recommendations . Three-day food records were collected during each trimester of pregnancy . Women in the intervention group consumed more vegetables , fruits , soft margarines and vegetable oils and less butter than those in the control group during the course of pregnancy ( P<0.05 ) . The main distinction between the groups in nutrient intake over the pregnancy was attributable to a higher energy intake ( % energy ) of PUFA by 0.5%energy ( 95 % CI 0.1 , 0.8 ) and to a lower intake of SFA by 0.8 % energy ( 95 % CI -1.4 , -0.4 ) in the intervention group . Dietary intake of vitamin E was 1.4 mg ( 95 % CI 0.6 , 2.2 ) , folate 20.9 microg ( 95 % CI 0.8 , 41.0 ) and ascorbic acid 19.8 mg ( 95 % CI 3.5 , 36.0 ) higher in the intervention group compared to the controls , while no differences in other nutrients were detected . Dietary counselling combined with the provision of food products during pregnancy is of importance in modifying food and nutrient intake , with potential health benefits [7030223] Twelve hundred and fifty-one pregnant women were contacted and their infants followed to age 5 years . Nine hundred and fifty-one ( 76 % ) children completed the trial . Measurements were made of birthweight , length , head circumference , and triceps skinfold at 10 days , and of weight , height , head circumference , and triceps at 5 years . Throughout the entire period of the study half the families , selected at r and om , were supplied with milk tokens entitling the mother , while pregnant , and all children under age 5 years , to 1 pint of milk a day at half its current price . The tokens led to a small increase in milk purchases by the families and to a small increase in milk drunk by the children . However no effect was detected in any growth measurement either in the total group , or in a more " vulnerable " group of children from the largest families [420136] Colombian women at risk of mild-to-moderate malnutrition were enrolled in a health care program and r and omly assigned into nutritional supplementation and control groups at the beginning of the third trimester of preganancy . One hundred unsupplemented and 144 supplemented infants were tested at 15 days of age : a 2X2 checkerboard was presented eight times followed by a single presentation of a 6X6 checkerboard . Unsupplemented infants showed less initial attention followed by slower habituation and higher levels of movement than the supplemented infants . The observed effect of maternal nutritional supplementation during the last trimester of pregnancy on new-born attention was interpreted to be maturational in nature [1096930] A 1200 calorie diet or cyclopenthiazide with potassium was given to two groups of 51 high weight gain primigravidae and baby weight and the incidence of pre‐eclampsia were compared with those in a matched control group . There was no difference in the development of pre‐eclampsia , but the weight of babies in the control group was higher than in the treated groups . The body fat was reduced in the diet group and the total body water in the diuretic group [7223696] Infants born to families at risk of malnutrition were studied prospect ively from the beginning of the 3rd trimester of the mother 's pregnancy until the child reached 3 yr of age to ascertain the effects of nutritional supplementation and /or a maternal education program on their cognitive development . Four hundred thirty-three families were assigned r and omly to six groups : group A served as a control ; group B received the supplement from the age of 6 months to 3 yr ; group C received the supplement during the 3rd trimester of pregnancy and the first 6 months of the child 's life ; and group D received the supplement throughout the entire study period . In addition , group A1 was enrolled in a maternal education program but received no nutritional supplement and group B1 received both treatments . The Griffiths test of infant development was administered at 4 , 6 , 12 , 18 , 24 , and 36 months of age , and the Corman-Escalona Einstein scale was administered at each age up to 18 months . Children who received food supplementation performed better than those who did not , especially on subtests that were primarily motoric . The effect of food supplementation on behavior appeared to be contemporaneous . In addition , the treatment effects were more pronounced for girls than for boys in this sample . Although these interventions reduced the gap in cognitive performance between lower and upper socioeconomic classes , a disparity nevertheless remained by the end of the study [6722081] Effects of a feeding programme on maternal weight , triceps and subscapular skinfolds during pregnancy and lactation were assessed in a marginally undernourished population of rural Taiwan . Mothers participated during two pregnancy and lactation periods . At 3 weeks after the delivery of the first infant , one group of 114 mothers began consuming a nutrient-dense supplement ( A ) , while another group of 111 received a placebo ( B ) . There was no significant A-B difference in pregnancy weight gain ( A 7.52 kg , B 7.75 kg ) or in mean maternal weight , triceps or subscapular skinfolds at any time during pregnancy or lactation . Despite a general trend toward moderate weight loss during lactation , one-third of mothers in both groups gained weight . Highly significant increases in weight and skinfold thicknesses from one lactation period to the next characterized both groups . The absence of demonstrable supplement-effects on maternal anthropometry concomitant with increments in infant birth weight supports the notion that infants can benefit from maternal supplementation without changes in maternal nutritional status [20399406] OBJECTIVE Examine the impact of providing yogurt to women enrolled in the Special Supplemental Nutrition Program for Women , Infants , and Children ( WIC ) . DESIGN R and omized , controlled intervention trial . SETTING Two California WIC local agency sites . PARTICIPANTS 511 pregnant , breast-feeding , or postpartum women . INTERVENTION Substitution of part of the WIC milk allowance with yogurt accompanied with educational material s. MAIN OUTCOME MEASURES Participants ' consumption and attitudes regarding yogurt provision . ANALYSIS Chi-square , Fisher exact , and Student t test to compare pre- versus post-intervention responses . Nonparametric Wilcoxon , chi-square , and t test to compare changes in response in intervention versus controls . Analysis of covariance models to test the influence of language preference on outcomes . RESULTS Over 86 % of women wanted to substitute some of their milk vouchers with yogurt . Among these , 62 % reported preferring yogurt to milk . The majority ( 89 % ) redeemed the yogurt coupons . Compared to controls , intervention women reported a trend ( P = .09 ) toward an increase in yogurt intake of 1.0 fl oz/day while not decreasing other dairy consumption . Those in the intervention group with the lowest tertile of yogurt intake at baseline increased yogurt consumption by 2.8 fl oz/day ( P = .003 ) relative to controls with lowest intake . CONCLUSIONS Yogurt is likely to be a popular substitute for milk and could contribute to increased dairy intake among women if it were an option in WIC [21677054] BACKGROUND Maternal nutritional intake during pregnancy may have important consequences for long-term health in offspring . OBJECTIVE The objective was to follow up the offspring in 2 r and omized trials of nutrient supplementation during pregnancy to investigate the effect on cardiovascular disease ( CVD ) risk in offspring . DESIGN We recruited offspring born during 2 trials in The Gambia , West Africa . One trial provided protein-energy-dense food supplements ( 1015 kcal and 22 g protein/d ) to pregnant ( intervention , from 20 wk gestation until delivery ) or lactating ( control , for 20 wk from birth ) women and was r and omized at the village level . The second was a double-blind , individually r and omized , placebo-controlled trial of calcium supplementation ( 1.5 g/d ) , which was also provided from 20 wk gestation until delivery . RESULTS Sixty-two percent ( n = 1267 ) of children ( aged 11 - 17 y ) born during the protein-energy trial were recruited and included in the analysis , and 64 % ( n = 350 ) of children ( aged 5 - 10 y ) born during the calcium trial were recruited and included in the analysis . Fasted plasma glucose was marginally lower in children born to mothers receiving protein-energy supplements during pregnancy than in those children of the lactating group ( adjusted mean difference : -0.05 mmol/L ; 95 % CI : -0.10 , -0.001 mmol/L ) . There were no other differences in CVD risk factors , including blood pressure , body composition , and cholesterol , between children born to intervention and control women from the protein-energy trial . Maternal calcium supplementation during pregnancy was unrelated to offspring blood pressure . CONCLUSION These data suggest that providing supplements to pregnant women in the second half of pregnancy may have little effect on the CVD risk of their offspring , at least in this setting and at the ages studied here . This trial was registered at www.controlled-trials.com as IS RCT N96502494 [2985353] The study attempted to determine if the bulk of dietary supplements given to pregnant women after midgestation affects fetal growth . 127 Zulu women were r and omly assigned to four groups , two of which received daily food supplements design ed to raise their energy , protein and vitamin intakes to levels recommended by the U.S. Food and Nutrition Board . One of these supplements had a high bulk , the other a low bulk . The third supplement contained only zinc and the fourth a placebo . Women in all four groups had a similar weight gain and length of gestation . Birth weights were from 6.5 to 9.5 % greater with the low bulk than with the other supplements [6499715] Studies on nutritional supplementation of pregnant mothers have observed small but sometimes significant effects on fetal growth . Previously we also reported significant changes in physical resemblance of siblings at birth due to this kind of supplementation , using data collected by the late Dr. Bacon Chow and associates . This suggested that components of variation in physical growth may change as a result of supplementation . To explore this further , we sought the effects of nutritional supplementation on somatic growth , holding constant the birth measurements of a previous ( unsupplemented ) sibling . Only head circumference at birth came close to showing a statistically significant ( P less than 0.06 ) supplement effect on its mean ( + 0.36 cm ) when the measurement of the first infant was held constant . Both increases and decreases in weight for length as assessed by Rohrer 's Index ( wt/l3 ) occurred with supplementation . Increases in the index occurred by a significant ( P less than 0.01 ) gain in birth weight ( 238 g ) between 1st and 2nd siblings in the supplement group but not in the placebo group . Decreases in this index result ed from a significant gain in birth length ( 1.3 cm ) in supplemented families with a previous ( untreated ) sibling having a below average length for average weight . These non-linear effects on somatic growth suggest that responses to maternal nutritional supplementation may be more effective in a subgroup of the population where the normal adaptive responses to low energy protein intakes may have failed or where nutritional conditions over pregnancy may have varied considerably [13244366] THE Nutrition Study carried on at the Pennsylvania Hos­ pital from 1947 to 1952 was design ed to investigate the effect of the addition of protein and vitamin supple­ ments to the diets of pregnant women upon the outcome of their pregnancy and upon the physical status of their infants . The previous reports from the Study have dealt primarily with the first of these two questions , and it is with the second , the relationship between supplementation of the maternal diet and the physical status of the baby , that this report is concerned . Under the plan of the study , women coming to the Clinic of the Hospital during the first 16 weeks of pregnancy were re­ ferred to the Nutrition Clinic . There they were assigned to one of four groups , on a r and om basis controlled for race , age , and gravida . One group was design ated as the control and was given no nutritional supplement , a second group was given vitamins only , the third group a protein supplement only , and the fourth group was given both vitamins and the protein sup­ plement.4 Uniform diet instructions were given to the [7358235] Pregnant women at risk of malnutrition were enrolled in a health care programme in Colombia , South America , and were r and omly assigned to a group receiving supplementary food or to a control group at the beginning of the third trimester of pregnancy . There were no differences between the groups in social or nutritional variables [25516314] Many studies have demonstrated the efficacy of folic acid ( FA ) supplementation in prevention of neural tube defects ( NTDs ) , although the extent of NTDs varies among individuals of different races and ethnic origin . China is a multi-ethnic country with no st and ard practice for FA-fortified food . Milk is consumed by women , but little is known about the effects of milk on folate concentration in maternal blood and neonatal umbilical cord blood in Han and Mongolian women after stopping taking the supplement for a month and five month , respectively . The objective of this study was to determine whether only daily consumption of liquid milk can increase the blood folate concentration in pregnant women and whether there are differences in blood folate concentrations between Han and Mongolian women after cessation of FA supplementation . Of the 4052 women enrolled in the parallel group design study . Three thous and five hundred and twenty-six women had confirmed pregnancies and were r and omized to receive liquid milk or not until delivery . Women who consumed the liquid milk had significantly increased serum folate concentrations at 16 and 32 weeks of gestation as well as cord blood at birth compared to control groups in both ethnic groups . Infants born to women drinking milk also had better the term birth weight and height , which may be related to the increased concentration of folate . In conclusion , daily consumption of milk can increase the serum folate concentration in pregnant Han and Mongolian women in China ( differences in the efficacy of FA and milk supplementation ) and may enhance birth outcomes [6726837] This study assesses the effect of supplementation of energy and protein to meet the nutrient requirements of pregnant women in India on the basis of lactation performance and the nutritional status of the infant . 20 pregnant women between the ages of 20 - 23 belonging to a low socioeconomic group who were in their last trimester of pregnancy were selected . Out of 20 10 women were supplemented while the other 10 served as controls . The results reveal that the mean milk yield of supplemented women did not increase significantly ( P<0.05 ) when compared to that of control women during the 1st month of lactation suggesting that lactation potential may be the same in all women in the 1st month irrespective of inadequacies in food intake during the last trimester of pregnancy . The milk yield was significantly higher ( 307 g ) in supplemented women than that of controls in the 3rd month of lactation . Although no difference in weight gain was observed due to supplementation in pregnancy additional food intake supported lactation for a longer period . The birth weight and length of infants born to women who received the supplement were higher by 264 g and 1.81 cm respectively suggesting the effect of supplementary food . Supplementation also brought about a significant increase ( P<0.05 ) in hemoglobin levels which may be attributed to the contribution of iron and protein contained in the supplement . A comparison of length weight and arm circumference of infants in the present study during the 1st 3 months of infancy with those of Harvard st and ards revealed that the increments in these measurements were equal to those of the st and ards though the actual values were 90 - 95 % of Harvard st and ards in the case of the supplemented group and 80 - 85 % in the control group . From the investigation it can be concluded that dietary supplementation during the last trimester of pregnancy has beneficial effects on maternal hemoglobin levels and on morbidity lactation performance birth weight and the physical development of the infant [15345867] Objective : This study investigated the influence of modifying the maternal dietary fat on the serum lipids of infants at birth and at one year of age . Methods : This single-blind r and omized clinical trial was done on 180 4-month-pregnant women . All subjects proved to have a fat-unmodified diet through a 4-day food record dietary question naire . They were divided r and omly into two groups . The intervention group was kept on a fat-modified diet including saturated fatty acid ( SFA ) < 10 % , monounsaturated fatty acids : ( MUFA ) 10 - 5 % , polyunsaturated fatty acid ( PUFA ) upto 10 % and cholesterol < 300 mg/day with dietary advice for the pregnancy period . The control group was given only the latter advice . All subjects were followed up monthly . The serum lipids including total cholesterol ( T.cho ) , triglyceride ( TG ) , and HDL cholesterol ( HDL-C ) were analyzed through enzymatic methods . The level of LDL-cholesterol ( LDL-C ) was calculated by Friedewald formula . The comparison of mean cord and one-year-old infant serum lipids were done through unpaired T-test in two groups . Results : The mean level of T.cho in the intervention and control group was ( 70.3±15.9 , vs 81.4±17.2 , P<0.009 ) , TG ( 85.3 ± 16.7 vs 97.5 ± 18.2 , P<0.007 ) , LDL-C ( 27.8 ± 15.2 vs 34.8 ±17.1 , P<0.04 ) and non-HDL-C ( 44.5±7.2 vs 54.5 ± 8.1 , P<0.02 ) and in one year old infant the comparison of serum lipids were as follows . T.cho ( 145.7 ± 51.4 vs 161.4 + 56.2 , P<0.003 ) , TG ( 90.1 ± 31.8 vs 98.3 ± 33.1 , P<0.02 ) , LDL-C ( 85.6 ± 20.4 vs 92.3 ± 19.6 , P<0,05 ) and non-HDL-C ( 113.6 ± 30.2 vs 128.8 ± 34.8 , P<0.04 ) . However , there was no significant difference in HDL-C of both groups . Conclusion : There is a significant decrease of T.cho , TG , LDL-C and non-HDL-C levels with no significant increase of HDL-C in the intervention group with the fat-modified diet . Maternal fatmodified diet could be suitable way to prevent cardiovascular disease among infants from the beginning of the life [19793851] BACKGROUND Better early childhood nutrition improves schooling , adult health , skills , and wages , but there is little evidence regarding its effect on the next generation . OBJECTIVE We assessed whether nutritional supplementation in children aged < 7 to 15 y affected their children 's nutritional status 29 - 38 y later . DESIGN We studied 791 children 0 - 12 y who were offspring of 401 Guatemalan women who had participated as children in a nutritional supplementation trial in which 2 villages were r and omly assigned to receive a nutritious supplement ( atole ) and 2 were assigned to receive a less-nutritious supplement ( fresco ) . We compared anthropometric indicators between the offspring of mothers exposed to atole and the offspring of mothers exposed to fresco . RESULTS Compared with the offspring of women exposed to fresco , the offspring of women exposed to atole had a 116-g ( 95 % CI : 17 , 215 g ) higher birth weight , were 1.3-cm ( 0.4 , 2.2 cm ) taller , had a 0.6-cm ( 0.4 , 0.9 cm ) greater head circumference , had a 0.26 ( 0.09 , 0.43 ) greater height-for-age z score , and had a 0.20 ( 0.02 , 0.39 ) greater weight-for-age z score . The association for height differed by offspring sex . Sons of women exposed to atole were 2.0-cm ( 95 % CI : 1.0 , 3.1 cm ) taller than the sons of women exposed to fresco . Supplementation was not associated with 6 other offspring anthropometric indicators that reflect measures of adiposity . Supplementation in boys did not affect their children 's anthropometric measures . CONCLUSION Nutritional supplementation in girls is associated with substantial increases in their offsprings ' ( more for sons ) birth weight , height , head circumference , height-for-age z score , and weight-for-age z score

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### Context: [3862451] Background : The long-term impact of early malnutrition on human capital outcomes remains unclear , and existing evidence has come largely from observational studies . Objective : We compared the impact of a nutritional supplement given during pregnancy or lactation in rural Gambia on educational performance and cognitive ability in offspring at their maturity . Design : This study was a follow-up of a r and omized trial of prenatal high protein and energy supplementation conducted between 1989 and 1994 . Subjects were 16–22 y of age at follow-up , and information was collected on schooling achievement and cognitive ability by using the Raven 's progressive matrices test , Mill Hill vocabulary test , and forward and backward digit-span tests . Results : A total of 1459 individuals were traced and interviewed and represented 71 % of the original cohort and 81 % of the surviving cohort . There was no difference in cognitive ability or educational attainment between treatment groups by using any of the methods of assessment . Conclusion : We have shown little evidence to support a long-term effect of prenatal protein-energy supplementation compared with supplementation during lactation on cognitive development in rural Gambians . This trial was registered at http://www.controlled-trials.com as IS RCT N72582014 [18458209] CONTEXT The evidence that breastfeeding improves cognitive development is based almost entirely on observational studies and is thus prone to confounding by subtle behavioral differences in the breastfeeding mother 's behavior or her interaction with the infant . OBJECTIVE To assess whether prolonged and exclusive breastfeeding improves children 's cognitive ability at age 6.5 years . DESIGN Cluster-r and omized trial , with enrollment from June 17 , 1996 , to December 31 , 1997 , and follow-up from December 21 , 2002 , to April 27 , 2005 . SETTING Thirty-one Belarussian maternity hospitals and their affiliated polyclinics . PARTICIPANTS A total of 17,046 healthy breastfeeding infants were enrolled , of whom 13,889 ( 81.5 % ) were followed up at age 6.5 years . INTERVENTION Breastfeeding promotion intervention modeled on the Baby-Friendly Hospital Initiative by the World Health Organization and UNICEF . MAIN OUTCOME MEASURES Subtest and IQ scores on the Wechsler Abbreviated Scales of Intelligence , and teacher evaluations of academic performance in reading , writing , mathematics , and other subjects . RESULTS The experimental intervention led to a large increase in exclusive breastfeeding at age 3 months ( 43.3 % for the experimental group vs 6.4 % for the control group ; P < .001 ) and a significantly higher prevalence of any breastfeeding at all ages up to and including 12 months . The experimental group had higher means on all of the Wechsler Abbreviated Scales of Intelligence measures , with cluster-adjusted mean differences ( 95 % confidence intervals ) of + 7.5 ( + 0.8 to + 14.3 ) for verbal IQ , + 2.9 ( -3.3 to + 9.1 ) for performance IQ , and + 5.9 ( -1.0 to + 12.8 ) for full-scale IQ . Teachers ' academic ratings were significantly higher in the experimental group for both reading and writing . CONCLUSION These results , based on the largest r and omized trial ever conducted in the area of human lactation , provide strong evidence that prolonged and exclusive breastfeeding improves children 's cognitive development . TRIAL REGISTRATION is rct n.org Identifier : IS RCT N37687716 [4000057] Background Research directed to optimizing maternal nutrition commencing prior to conception remains very limited , despite suggestive evidence of its importance in addition to ensuring an optimal nutrition environment in the periconceptional period and throughout the first trimester of pregnancy . Methods / Study design This is an individually r and omized controlled trial of the impact on birth length ( primary outcome ) of the time at which a maternal nutrition intervention is commenced : Arm 1 : ≥ 3 mo preconception vs. Arm 2 : 12 - 14 wk gestation vs. Arm 3 : none.192 ( derived from 480 ) r and omized mothers and living offspring in each arm in each of four research sites ( Guatemala , India , Pakistan , Democratic Republic of the Congo ) . The intervention is a daily 20 g lipid-based ( 118 kcal ) multi-micronutient ( MMN ) supplement . Women r and omized to receive this intervention with body mass index ( BMI ) < 20 or whose gestational weight gain is low will receive an additional 300 kcal/d as a balanced energy-protein supplement . Research ers will visit homes biweekly to deliver intervention and monitor compliance , pregnancy status and morbidity ; ensure prenatal and delivery care ; and promote breast feeding . The primary outcome is birth length . Secondary outcomes include : fetal length at 12 and 34 wk ; incidence of low birth weight ( LBW ) ; neonatal/infant anthropometry 0 - 6 mo of age ; infectious disease morbidity ; maternal , fetal , newborn , and infant epigenetics ; maternal and infant nutritional status ; maternal and infant microbiome ; gut inflammatory biomarkers and bioactive and nutritive compounds in breast milk . The primary analysis will compare birth Length-for-Age Z-score ( LAZ ) among trial arms ( independently for each site , estimated effect size : 0.35 ) . Additional statistical analyses will examine the secondary outcomes and a pooled analysis of data from all sites . Discussion Positive results of this trial will support a paradigm shift in attention to nutrition of all females of child-bearing age . Trial registration Clinical Trials.gov NCT01883193 [3313975] Background Previous studies suggest that over-nutrition in early infancy may programme long-term susceptibility to insulin resistance . Objective To assess the association of breast milk and quantity of infant formula and cows ' milk intake during infancy with insulin resistance measures in early adulthood . Design Long-term follow-up of the Barry Caerphilly Growth cohort , into which mothers and their offspring had originally been r and omly assigned , between 1972–1974 , to receive milk supplementation or not . Participants were the offspring , aged 23–27 years at follow-up ( n = 679 ) . Breastfeeding and formula/cows ' milk intake was recorded prospect ively by nurses . The main outcomes were insulin sensitivity ( ISI0 ) and insulin secretion ( CIR30 ) . Results 573 ( 84 % ) individuals had valid glucose and insulin results and complete covariate information . There was little evidence of associations of breastfeeding versus any formula/cows ' milk feeding or of increasing quartiles of formula/cows ' milk consumption during infancy ( <3 months ) with any outcome measure in young adulthood . In fully adjusted models , the differences in outcomes between breastfeeding versus formula/cows ' milk feeding at 3 months were : fasting glucose ( −0.07 mmol/l ; 95 % CI : −0.19 , 0.05 ) ; fasting insulin ( 8.0 % ; −8.7 , 27.6 ) ; ISI0 ( −6.1 % ; −11.3 , 12.1 ) and CIR30 ( 3.8 % ; −19.0 , 32.8 ) . There was also little evidence that increasing intakes of formula/cows ' milk at 3 months were associated with fasting glucose ( increase per quartile of formula/cows ' milk intake = 0.00 mmol/l ; −0.03 , 0.03 ) ; fasting insulin ( 0.8 % ; −3.2 , 5.1 ) ; ISI 0 ( −0.9 % ; −5.1 , 3.5 ) and CIR30 ( −2.6 % ; −8.4 , 3.6 ) . Conclusions We found no evidence that increasing consumption of formula/cows ' milk in early infancy was associated with insulin resistance in young adulthood [3616846] Background Nutritionists advise pregnant women to eat fish to obtain adequate docosahexaenoic acid ( DHA ) , an essential nutrient important for optimal brain development . However , concern exists that this advice will lead to excess intake of methylmercury , a developmental neurotoxicant . Objective Conduct a pilot intervention to increase consumption of high-DHA , low-mercury fish in pregnancy . Methods In April-October 2010 we recruited 61 women in the greater Boston , MA area at 12–22 weeks gestation who consumed < = 2 fish servings/month , and obtained outcome data from 55 . We r and omized participants to 3 arms : Advice to consume low-mercury/high-DHA fish ( n=18 ) ; Advice + grocery store gift cards ( GC ) to purchase fish ( n=17 ) ; or Control messages ( n=20 ) . At baseline and 12-week follow-up we estimated intake of fish , DHA and mercury using a 1-month fish intake food frequency question naire , and measured plasma DHA and blood and hair total mercury . Results Baseline characteristics and mean ( range ) intakes of fish [ 21 ( 0–125 ) g/day ] and DHA from fish [ 91 ( 0–554 ) mg/d ] were similar in all 3 arms . From baseline to follow-up , intake of fish [ Advice : 12 g/day ( 95 % CI : -5 , 29 ) , Advice+GC : 22 g/day ( 5 , 39 ) ] and DHA [ Advice : 70 mg/d ( 3 , 137 ) , Advice+GC : 161 mg/d ( 93 , 229 ) ] increased in both intervention groups , compared with controls . At follow-up , no control women consumed > = 200mg/d of DHA from fish , compared with 33 % in the Advice arm ( p=0.005 ) and 53 % in the Advice+GC arm ( p=0.0002 ) . We did not detect any differences in mercury intake or in biomarker levels of mercury and DHA between groups . Conclusions An educational intervention increased consumption of fish and DHA but not mercury . Future studies are needed to determine intervention effects on pregnancy and childhood health outcomes .Trial registration Registered on clinical trials.gov as [4124499] Background The in utero environment is known to affect fetal development however many of the mechanisms by which this occurs remain unknown . The aim of this study was to examine the association between maternal dietary macronutrient intake and lifestyle throughout pregnancy and neonatal weight and adiposity . Methods This was an analysis of 542 mother and infant pairs from the ROLO study ( R and omised cOntrol trial of LOw glycaemic index diet versus no dietary intervention to prevent recurrence of fetal macrosomia ) . Food diaries as well as food frequency and lifestyle and physical activity question naires were completed during pregnancy . Maternal anthropometry was measured throughout pregnancy and neonatal anthropometry was measured at birth . Results Multiple linear regression analysis revealed the main maternal factor associated with increased birth weight was greater gestational weight gain R2adj23.3 % ( F = 11.547 , p < 0.001 ) . The main maternal factor associated with increased birth length was non-smoking status R2adj27.8 % ( F = 6.193 , p < 0.001 ) . Neonatal central adiposity ( determined using waist : length ratio ) was negatively associated with maternal age , and positively associated with the following parameters : smoking status , maternal pre-pregnancy arm circumference , percentage energy from saturated fat in late pregnancy , postpr and ial glucose at 28 weeks gestation and membership of the control group with a positive trend towards association with trimester 2 glycaemic load R2adj 38.1 % ( F = 8.000 , p < 0.001 ) . Conclusions Several maternal diet and lifestyle factors were associated with neonatal anthropometry . Low glycaemic index dietary intervention in pregnancy was found to have a beneficial effect on neonatal central adiposity . Additionally , central adiposity was positively associated with maternal dietary fat intake and postpr and ial glucose highlighting the important role of healthy diet in pregnancy in promoting normal neonatal adiposity . Trial registration Current Controlled Trials IS RCT N54392969 [19017418] Balanced glucose metabolism ensures optimal fetal growth with long-term health implication s conferred on both mother and child . We examined whether supplementation of probiotics with dietary counselling affects glucose metabolism in normoglycaemic pregnant women . At the first trimester of pregnancy 256 women were r and omised to receive nutrition counselling to modify dietary intake according to current recommendations or as controls ; the dietary intervention group was further r and omised to receive probiotics ( Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12 ; diet/probiotics ) or placebo ( diet/placebo ) in a double-blind manner , whilst the control group received placebo ( control/placebo ) . Blood glucose concentrations were lowest in the diet/probiotics group during pregnancy ( baseline-adjusted means 4.45 , 4.60 and 4.56 mmol/l in diet/probiotics , diet/placebo and control/placebo , respectively ; P = 0.025 ) and over the 12 months ' postpartum period ( baseline-adjusted means 4.87 , 5.01 and 5.02 mmol/l ; P = 0.025 ) . Better glucose tolerance in the diet/probiotics group was confirmed by a reduced risk of elevated glucose concentration compared with the control/placebo group ( OR 0.31 ( 95 % CI 0.12 , 0.78 ) ; P = 0.013 ) as well as by the lowest insulin concentration ( adjusted means 7.55 , 9.32 and 9.27 mU/l ; P = 0.032 ) and homeostasis model assessment ( adjusted means 1.49 , 1.90 and 1.88 ; P = 0.028 ) and the highest quantitative insulin sensitivity check index ( adjusted means 0.37 , 0.35 and 0.35 ; P = 0.028 ) during the last trimester of pregnancy . The effects observed extended over the 12-month postpartum period . The present study demonstrated that improved blood glucose control can be achieved by dietary counselling with probiotics even in a normoglycaemic population and thus may provide potential novel means for the prophylactic and therapeutic management of glucose disorders [3431285] Objective To determine if a low glycaemic index diet in pregnancy could reduce the incidence of macrosomia in an at risk group . Design R and omised controlled trial . Setting Maternity hospital in Dublin , Irel and . Participants 800 women without diabetes , all in their second pregnancy between January 2007 to January 2011 , having previously delivered an infant weighing greater than 4 kg . Intervention Women were r and omised to receive no dietary intervention or start on a low glycaemic index diet from early pregnancy . Main outcomes The primary outcome measure was difference in birth weight . The secondary outcome measure was difference in gestational weight gain . Results No significant difference was seen between the two groups in absolute birth weight , birthweight centile , or ponderal index . Significantly less gestational weight gain occurred in women in the intervention arm ( 12.2 v 13.7 kg ; mean difference −1.3 , 95 % confidence interval −2.4 to −0.2 ; P=0.01 ) . The rate of glucose intolerance was also lower in the intervention arm : 21 % ( 67/320 ) compared with 28 % ( 100/352 ) of controls had a fasting glucose of 5.1 mmol/L or greater or a 1 hour glucose challenge test result of greater than 7.8 mmol/L ( P=0.02 ) . Conclusion A low glycaemic index diet in pregnancy did not reduce the incidence of large for gestational age infants in a group at risk of fetal macrosomia . It did , however , have a significant positive effect on gestational weight gain and maternal glucose intolerance . Trial registration Current Controlled Trials IS RCT N54392969 [23535609] In developing countries , prenatal lipid-based nutrient supplements ( LNSs ) were shown to increase birth size ; however , the mechanism of this effect remains unknown . Cord blood hormone concentrations are strongly associated with birth size . Therefore , we hypothesize that LNSs increase birth size through a change in the endocrine regulation of fetal development . We compared the effect of daily prenatal LNSs with multiple micronutrient tablets on cord blood hormone concentrations using a r and omized , controlled design including 197 pregnant women from rural Burkina Faso . Insulin-like growth factors ( IGF ) I and II , their binding proteins IGFBP-1 and IGFBP-3 , leptin , cortisol , and insulin were quantified in cord sera using immunoassays . LNS was associated with higher cord blood leptin mainly in primigravidae ( + 57 % ; P = 0.02 ) and women from the highest tertile of BMI at study inclusion ( + 41 % ; P = 0.02 ) . We did not find any significant LNS effects on other measured cord hormones . The observed increase in cord leptin was associated with a significantly higher birth weight . Cord sera from small-for-gestational age newborns had lower median IGF-I ( -9 μg/L ; P = 0.003 ) , IGF-II ( -79 μg/L ; P = 0.003 ) , IGFBP-3 ( -0.7 μg/L ; P = 0.007 ) , and leptin ( -1.0 μg/L ; P = 0.016 ) concentrations but higher median cortisol ( + 18 μg/L ; P = 0.037 ) concentrations compared with normally grown newborns . Prenatal LNS result ed in increased cord leptin concentrations in primigravidae and mothers with higher BMI at study inclusion . The elevated leptin concentrations could point toward a higher neonatal fat mass [4196482] Background : Low birth weight ( LBW ) is an important public health problem in undernourished population s. Objective : We tested whether improving women 's dietary micronutrient quality before conception and throughout pregnancy increases birth weight in a high-risk Indian population . Design : The study was a nonblinded , individually r and omized controlled trial . The intervention was a daily snack made from green leafy vegetables , fruit , and milk ( treatment group ) or low-micronutrient vegetables ( potato and onion ) ( control group ) from ≥90 d before pregnancy until delivery in addition to the usual diet . Treatment snacks contained 0.69 MJ of energy ( controls : 0.37 MJ ) and 10–23 % of WHO Reference Nutrient Intakes of β-carotene , riboflavin , folate , vitamin B-12 , calcium , and iron ( controls : 0–7 % ) . The primary outcome was birth weight . Results : Of 6513 women r and omly assigned , 2291 women became pregnant , 1962 women delivered live singleton newborns , and 1360 newborns were measured . In an intention-to-treat analysis , there was no overall increase in birth weight in the treatment group ( + 26 g ; 95 % CI : −15 , 68 g ; P = 0.22 ) . There was an interaction ( P < 0.001 ) between the allocation group and maternal prepregnant body mass index ( BMI ; in kg/m2 ) [ birth-weight effect : −23 , + 34 , and + 96 g in lowest ( < 18.6 ) , middle ( 18.6–21.8 ) , and highest ( > 21.8 ) thirds of BMI , respectively ] . In 1094 newborns whose mothers started supplementation ≥90 d before pregnancy ( per- protocol analysis ) , birth weight was higher in the treatment group ( + 48 g ; 95 % CI : 1 , 96 g ; P = 0.046 ) . Again , the effect increased with maternal BMI ( −8 , + 79 , and + 113 g ; P-interaction = 0.001 ) . There were similar results for LBW ( intention-to-treat OR : 0.83 ; 95 % CI : 0.66 , 1.05 ; P = 0.10 ; per- protocol OR = 0.76 ; 95 % CI : 0.59 , 0.98 ; P = 0.03 ) but no effect on gestational age in either analysis . Conclusions : A daily snack providing additional green leafy vegetables , fruit , and milk before conception and throughout pregnancy had no overall effect on birth weight . Per- protocol and subgroup analyses indicated a possible increase in birth weight if the mother was supplemented ≥3 mo before conception and was not underweight . This trial was registered at www.controlled-trials.com/is rct n/ as IS RCT N62811278 [2239797] The effect of prenatal energy supplementation on maternal anthropometry was assessed in a controlled , r and omized trial in Madura , East Java . At 26 - 28 wk of gestation women were either given 465 kcal/d ( HE group ) or 52 kcal/d ( LE group ) . Two hundred seventy-six women were enrolled in the HE group and 266 women , in the LE group . Supplement intake was variable . Testing of effect by treatment and compliance was thus done by subcategories ( HE 1 - 3 and LE 1 - 3 , corresponding to less than 45 , 45 - 89 , and greater than or equal to 90 packets of supplement consumed ) . Analysis of variance did not show significant differences among the six subcategories in third-trimester weight gain , sum of skinfold thicknesses , 4-wk postpartum weight , or body mass index . In this population energy supplementation for the short duration of the last 90 - 110 d of pregnancy was not sufficient to improve maternal nutrition as judged by anthropometry [6372428] We related the macroscopic and microscopic morphology and the histomorphometry of the placenta to prenatal nutritional supplementation . In the Prenatal Project , a controlled clinical trial , three dietary treatments ( supplement , a high-protein beverage ; complement , a balanced protein-calorie beverage , or routine vitamin and mineral tablets ) were r and omly allocated to poor Black pregnant women , and the outcome was assessed . Herein we report the effects on placental morphology and histomorphometry . There were significantly fewer preterm deliveries in the complement group , and this was reflected by an increase in the size of decidual cells , an index associated with placental aging . Several other characteristics of the placentas of the complement group may have been more directly associated with improved perinatal outcome : decreased intervillous fibrin , lower incidence of gross surface infa rct , and smaller ( and presumably less edematous ) cells of the villous stroma , may have mediated increased placental perfusion . There was no evidence of any placental change associated with the increase in very preterm delivery and the highly significant depressed birth weight among preterm deliveries in the supplement group . The significantly lower incidence of meconium staining of Wharton 's jelly among controls seems likely to have been a chance finding . While there were several other indices that reflected placental aging , the significantly increased chorioamnionitis , acute funisitis , and acute decidual inflammation among placentas of those who delivered prematurely [ the former two associated with very early delivery ( less than 35 wk gestation ) ] were likely to have been involved as causes of premature delivery [3279745] The effects on pregnancy outcome and maternal iron status of powdered milk ( PUR ) and a milk-based fortified product ( V-N ) were compared in a group of underweight gravidas . These take-home products were distributed during regular prenatal visits . Women in the V-N group had greater weight gain ( 12.29 vs 11.31 kg , p less than 0.05 ) and mean birth weights ( 3178 vs 3105 g , p less than 0.05 ) than those in the PUR group . Values for various indicators of maternal Fe status were also higher in the V-N group . Compared with self-selected noncompliers , similar in all control variables to compliers , children of women who consumed powdered milk or the milk-based fortified product had mean birth weights that were higher by 258 and 335 g , respectively . Data indicate a beneficial effect of the fortified product on both maternal nutritional status and fetal growth [3521254] To improve maternal nutritional status and to ameliorate protein-energy malnutrition in pregnant women and infants , supplementary foods for rural pregnant women were formulated and evaluated . Six formulas with protein and energy contents of 16 - 22 g and 350 - 500 kcal/100 g food , respectively , were developed from locally available raw material s. A field evaluation of formulas I and V was conducted at the regional MCH Center at Rajchaburi , about 120 km from Bangkok . Formulas providing 13 g protein and 350 kcal per day were given to two groups of mothers in the first or second pregnancy , starting at 28 + /- 2 wk of gestation . A third group , unsupplemented , served as controls . Maternal weight gain and left mid-arm circumference were measured every 2 wk . Birth weight , length , head and chest circumferences of newborns , and placental weight were significantly higher in both supplemented groups . These findings suggest that among undernourished mothers , supplementation of as little as 13 g protein and 350 kcal daily during the last trimester can significantly improve maternal weight gain and birth weight of newborns [11722967] BACKGROUND We previously showed that mortality from infectious diseases among young adults in rural Gambia is strongly correlated with the season of their birth . This suggests that early life insults that involve fetal malnutrition , exposure to natural toxins , or highly seasonal infections affecting the infant or pregnant mother cause permanent damage to the immune system . Excess mortality begins after puberty and has a maximal odds ratio of > 10 for deaths between ages 25 and 50 y. OBJECTIVE We investigated the immune function of children according to birth weight , season of birth , and exposure to maternal dietary supplementation during pregnancy . DESIGN Immune function was measured in 472 prepubertal children aged 6.5 - 9.5 y from 28 villages in rural Gambia . The mothers of these children had been r and omly assigned to a high-energy prenatal supplementation program , which significantly increased birth weight . This permitted supplementation status , birth weight , and season of birth to be investigated as exposure variables . The outcome variables tested were naive responses to rabies and pneumococcus vaccines , delayed-type hypersensitivity skin reactions , and mucosal defense ( secretory immunoglobulin A and dual-sugar permeability ) . RESULTS Immune responses were strongly related to current age and sex , suggesting a high level of sensitivity , but were not consistently related to birth weight , season of birth , or maternal supplementation ( control compared with intervention ) . CONCLUSION Events in early life did not predict a measurable defect in immune response within this cohort of rural Gambian children . It is possible that the early programming of immune function may be mediated through a defect in immunologic memory or early senescence rather than through impairment of early responses [12816786] BACKGROUND The secular increase in height is assumed to result from long-term improvements in nutritional intakes and reductions in infectious disease burdens . Nutritional supplementation in early life reduces stunting in chronically undernourished population s. It is unknown whether these improvements can be transmitted to subsequent generations . OBJECTIVE Our objective was to estimate the intergenerational effect on offspring length of improved nutrition in the mother 's childhood . DESIGN We studied 263 children born in 1996 - 1999 to 231 women who had received nutritional supplementation , ie , atole ( high-protein , moderate-energy drink ) or fresco ( nonprotein , low-energy drink ) , prenatally and up to age 7 y as part of a community trial in Guatemala between 1969 and 1977 . Child length was measured at different times to age 36 mo . RESULTS Children born to women who received the enhanced supplement were taller ( age-adjusted difference : 0.80 cm ; 95 % CI : 0.16 , 1.44 cm ) than were children whose mothers received the low-energy supplement . This increment was independent of the children 's birth weight or socioeconomic status but was substantially attenuated and no longer significant after adjustment for maternal height ( adjusted difference : 0.43 cm ; 95 % CI : -0.10 , 0.96 cm ; P > 0.10 ) . The effect of maternal nutritional supplementation was more pronounced in boys than in girls ( P for interaction < 0.10 ) and in children born to women who received supplements at ages 3 - 7 y than in children born to women who received supplements at ages 0 - 3 y ( P for interaction < 0.01 ) . CONCLUSION Nutritional supplementation in childhood has positive effects on both the supplemented persons and on the subsequent generation [2816804] An intervention program was undertaken to assess dietary habits and the impact of nutrition education among pregnant women in the rural county of Florina , northern Greece . Analysis of dietary habits , nutrient intake , hemoglobin , and serum vitamin concentrations in an intervention and control group indicated that the population was adequately nourished although nutrient intake was below recommended levels for pregnant women . Nutrition counseling was associated with improvements in dietary intake and significantly greater maternal weight gain ( p less than 0.05 ) . Mean birth weight was slightly higher in the intervention group but so was the incidence of low birth weight ( 4.5 % vs 3.9 % ) . The prematurity rate was marginally lower in the intervention group ( p less than 0.04 ) , as was the number of perinatal deaths ( 9 vs 11 ) . The results indicate that nutrition counseling during pregnancy can improve dietary intake and maternal weight gain but the mediating influence on low frequency pregnancy outcomes is indeterminate in a population that is not nutritionally at risk [6179410] Protein and nucleic acid content , and RNase levels were measured in placentas collected at birth in a r and omized controlled trial of prenatal nutritional supplementation in New York City . These biochemical indices were explored to underst and better the effects of nutritional supplementation . ( With high-protein supplements , gross measures had shown no improvement in outcome at birth and adverse effects on fetal growth , prematurity , and newborn survival ; with balanced protein-calorie supplements , there was a nonsignificant rise in birth weight and longer gestation . ) The biochemical indices were in general somewhat weakly related to fetal growth measures . Significant effects of nutritional treatment on the indices were minimal , and added no information that could account for gross effects observed in the fetus [2756913] Breast-milk output was measured in women who during the last trimester of pregnancy consumed a high- or low-energy supplement ( 53 and 55 women , respectively ) . Infant and mother pairs were enrolled at 2 or 6 wk postpartum . Test weighings were done four times at 8-wk intervals . Mean breast-milk output ranged from 682 to 744 g/d in the age period of 2 wk to 7 mo . There was no difference in milk output between the two experimental groups . In all cohorts , breast-feeding frequency influenced milk output positively . Only at age 18 - 22 wk did the mothers ' prepregnancy or 4-wk postpartum body mass index play an additional role . The results confirm that breast-milk output of mildly undernourished women is comparable with that of well-nourished women . Short-term energy supplementation during pregnancy did not increase breast-milk output , probably because the sample studied was not at nutritional risk [7282613] The effect of food supplementation on physical growth during the last trimester of pregnancy and the first 3 yr of life was studied in a sample of families at risk of malnutrition living in the urban slums of Bogota , Colombia . Families in which the mother was pregnant and at least one-half of the children under 5 yr of age were below 85 % of weight for age were selected for the study . All were provided with free obstetrical and pediatric care . The families were then r and omly assigned to control and supplemented groups . The supplemented families received a daily allotment of 600 cal or 30 g of protein per capita for home consumption from the onset of the 3rd trimester of pregnancy until the subject children reached the age of 3 yr . Calorie consumption from the supplement by the study children ( offspring of the target pregnancy ) was 458 ± 249 calories at age 18 months and 363 ± 283 cal at age 36 months . Protein consumption at those ages was 34 . 1 ± 20.6 and 23.6 ± 19.7 g,'day . However , substitution of the supplement for foods from the regular diet result ed in net supplementation of approximately 200 cal and 22 g of protein per day . There were significant differences in weight between supplemented and control groups beginning at age 3 months and in length beginning at age 6 months . Supplementation reduced the total prevalence of malnutrition ( Gomez classification ) only slightly ; at 36 months of age , 72 % of the supplemented group and 77.8 % of the control group were malnourished . On the other h and , the prevalence of moderate and severe malnutrition ( Gomez II and III ) , was significantly reduced by supplementation . At 36 months , 20.6 % of the control group and 8.8 % of the supplemented group fell into those categories . Despite improved physical growth in the supplemented group , their height and weight remained substantially below those of the high socioeconomic Colombian st and ards . The failure of supplementation to close the gap between low and high socioeconomic groups was attributed , in part , to the high incidence of diarrheal disease among subjects of the study . It is postulated that simple provision of food supplements , without effective prevention of diarrheal disease , is likely to have limited effects on physical growth among disadvantaged children . Am . J. Clin . Nutr . 34 : 1885 - 1892 , 1981 [3993611] Of 824 women screened , 410 were enrolled at midpregnancy in a prospect i ve , r and omized , controlled nutrition intervention study . Of these , 226 were predicted as likely to have small or large babies , 184 to have average-sized babies . Two hundred thirty eight mothers received USDA Women , Infants and Children ( WIC ) Food Supplementation vouchers from midpregnancy , 172 did not . Leukocyte protein synthesis ( as a cell model ) was significantly higher ( p = 0.009 ) by 36 weeks gestation in supplemented mothers . Mean birth weight of their babies was greater , 3254 vs 3163 g , ( + 91 g ) p = 0.039 , adjusted for sex , gestational age , prenatal visits , pregnancy interval , smoking , and previous low birth weight infants . Controlling for entry weight obviated the significance of the difference , except for WIC supplemented smokers ( greater than 10 cigarettes/day ) whose babies were significantly heavier by + 168 g ( p = 0.017 ) than those of unsupplemented smokers . WIC partially protects fetal growth in smokers [3993612] In a double blind controlled intervention , two groups of nutritionally at-risk rural Taiwanese women were given a nutrient-rich dietary supplement ( group A , n = 114 ) or a placebo ( group B , n = 111 ) beginning after the birth of one child and continuing through the lactation period for a subsequent child . Outcome variables assessed include infant birth measurements postnatal physical growth , motor , mental , and dental development , morbidity , and maternal weight and skinfold changes during pregnancy and lactation . While few A-B differences in mean values of outcome variables were found , there were significant responses in subgroups of the sample . Comparisons of infants born after a nutrient-supplemented pregnancy ( A2 ) versus an unsupplemented pregnancy ( A1 ) showed that A2 male infants weighed more than A1 males at birth , and A1-A2 sibling correlations in birth measurements , especially Rohrer 's index ( wt/l3 ) were significantly reduced . Important mediators of supplement effects included sex of the offspring , season of birth , maternal body size , and birth of a previous infant characterized by dysmorphic prenatal growth . The limited effects of supplementation on the population as a whole may reflect the operation of long term adaptations which allow women to maintain reproductive success despite their apparent marginal nutritional status [15051843] Cardiovascular disease and diabetes may be programmed early in life by abnormal development associated with undernutrition . We investigated whether maternal nutritional status ( MNS ; height , pregnancy weight gain , nonpregnant BMI , and prenatal supplementation ) or childhood nutritional status ( CNS ; birth weight , length , ponderal index , height-for-age Z-score at 24 mo , and supplementation from 0 to 24 mo ) were related to fasting plasma glucose levels in rural-born Guatemalan adults . We studied 209 men and 220 women ( mean age 24.4 y ) who were involved in a r and omized trial of nutritional supplementation of their mothers during pregnancy and during their early childhoods , conducted from 1969 to 1977 . In 2 villages , residents were offered Atole ( 3.8 MJ and 64 g protein/L ) ; 2 other villages were offered Fresco ( 1.4 MJ/L , no protein ) . No associations were observed between anthropometric measures of MNS or CNS and fasting plasma glucose levels . In subgroup analyses , inverse associations ( all P < 0.15 ) with birth size were found among women born to fatter mothers , women with low supplement intake , men born to short mothers , and men more severely stunted at 24 mo . Prenatal supplementation was inversely associated with fasting plasma glucose among women [ -0.40 + /- 0.17 mmol/(L. MJ . d ) , P = 0.02 ] . Among men , postnatal intake of supplementation of 0.10 to 0.20 MJ/d was associated with up to a 0.56 mmol/L reduction in fasting plasma glucose ( P = 0.03 ) , but intake in excess of 0.20 MJ/d provided no added benefit . Among women , the benefit of postnatal supplementation was restricted to those born thin ( test for interaction P = 0.10 ) . Improving the nutritional status of undernourished women and children may have positive long-term consequences [6816061] Protein-energy malnutrition in synergism with infection is a major problem for most developing countries , and inadequate food consumption is a critical factor in its development . Food supplementation programs can improve nutrient consumption but may also have unintended consequences . Changes in consumption of foods as well as nutrients need to be identified and evaluated . The effects of a food supplementation program on family diet patterns and protein-energy intake were investigated using data from nutritionally at risk families in Bogota , Colombia . Because food supplements are income transfers they need to substitute for purchases of similar food items . However , the results of our investigation reveal that food supplementation based on familiar foods that are part of the usual family diet are consumed in substantial quantities and result in net nutrient consumption increases . The food supplementation program increases consumption of preferred food items and introduces greater diversity into the family diet . These effects are enhanced when combined with a home education program [420135] Colombian women at risk of malnutrition were enrolled in a health care program and r and omly assigned to supplementation and control groups at the beginning of the third trimester of pregnancy . The net dietary intake increments result ing from supplementation amounted to 155 cal and 20 g of protein per day . Supplementation had a significant effect on the mean birth weight of male infants , but not that of female infants ; the mechanisms responsible for the sex differences remain to be eluci date d. The r and omized trial design of the experiment and the documented similarity between the experimental and control groups at the onset permit the conclusion that the observed differences were caused by the food supplementation program . The effect of supplementation on maternal weight gain and the association of the latter with birth weight strongly suggest that improved maternal nutrition mediated the effect on birth weight [1274890] Low-income pregnant women of Mexican descent were studied to determine whether their food habits could be improved by nutrition education . Biochemical indices of nutritional status were also investigated . Twenty-four-hour dietary recalls were obtained at an initial interview and again at a final interview after a nutrition education program , which was offered to a r and omly selected treatment group . At the initial interview , the mean nutrient intakes that were most often below two-thirds of the Recommended Dietary Allowance ( RDA ) were iron , vitamin A , thiamin , and calcium . The mean energy value of the diets was also frequently below the RDA . At the final intakes , although the mean energy values and the calcium and carbohydrate of both the control and treatment groups increased significantly , the following improvements in dietary intakes were seen only within the treatment group : 1 ) there were significant increases in the mean intake of protein , ascorbic acid , niacin , riboflavin , and thiamin , 2 ) there were significant decreases in the percentage of intakes below two-thirds of the RDA for ascorbic acid and riboflavin , and 3 ) there was a significant decrease in the incidence of multiple low nutrient intakes . These dietary improvements , which occurred only in the treatment group , suggest the effectiveness of the nutrition education program . The most common biochemical deficiencies were of folic acid , thiamin , and riboflavin . Except for an improvement in mean serum folate levels , the biochemical indices for the treatment group did not appear to be influenced by the nutrition education . It is possible that the vitamin and mineral supplements which were taken by 80 % of the women could have obscured improvements in biochemical indices which may have been due to the education program [7027780] This study is a r and omized controlled double-blind trial on the effects of nutrition supplement of pregnant and lactating women on their offspring . The study was conducted by the late Dr. Bacon Chow in 14 villages in Sui-Lin township , a farming area about 180 miles from Taipei , Taiwan . Two hundred ninety-four women were r and omly assigned to one of two treatment groups . The daily supplement for one group provided 800 kcal and 40 g of protein/day ; for the other group it only provided 80 kcal/day . Supplementation began after 3 wk of the delivery of a first study infant , continued throughout lactation , and through the pregnancy and lactation of a second study infant . Between group comparisons on the birth weight , number of low birth weight infants , or incidence of fetal deaths showed no statistically significant findings . However , the birth weight of the second study infant was statistically different and higher than that of the first study infant in the high supplement group . Moreover , in the low supplement group there was a correlation of 0.22 ( p = 0.06 ) between the change scores for birth weight from the first to the second study infant and the quantity of supplements consumed during the last trimester of pregnancy . There was also in this same group a significant slope in a linear regression of birth weight on total daily caloric intake during the 3rd trimester of pregnancy for the male second study infants . These findings are partly in agreement with findings from three other large supplementation studies in Colombia , Guatemala , and New York . In this study the findings indicate that caloric supplementation does result in a small yet statistically meaningful increment in birth weight within a population which is not nutritionally at risk [2375294] In many regions of the world , women breastfeed one child while pregnant with the next . Among rural Guatemalan women participating in a nutrition-supplementation trial , lactation overlapped with pregnancy in 253 of 504 ( 50.2 % ) of the pregnancies . For cases where overlap occurred , 41.4 % continued to breast-feed into the second trimester and 3.2 % , in the third trimester . The maternal and fetal responses to the energetic stresses of overlap and of the duration of the recuperative ( nonpregnant , nonlactating ) interval were assessed . Overlap result ed in increased supplement intake . Short recuperative periods ( less than 6 mo ) result ed in increased supplement intake and reduced maternal fat stores . The energetic stresses of overlap and short recuperative periods did not significantly affect fetal growth . The mother appears to buffer the energetic stress , protecting fetal growth . This research demonstrates that evidence of depletion of maternal nutrient stores caused by a dem and ing reproductive history is found when reproductive stress is characterized adequately [24045792] Background / Objectives : The mother is an important mediator to the infant of polyunsaturated fatty acids ( PUFA ) , the essential constituents of membranes particularly in the brain and retina . We here aim ed in a prospect i ve study initiated in early pregnancy to establish whether serum fatty acid ( FA ) compositions and concentrations in the mother can be modified by dietary means emphasizing counseling on a recommended diet . Subjects/ Methods : Ninety women in the first trimester of pregnancy were r and omized into intervention ( n=45 ) or control ( n=45 ) groups . The intervention comprised individual dietary counseling advocating choice of foods that will increase the intake of unsaturated and reduce that of saturated FA . To support this , appropriate products , including spreads , were provided for consumption at home . Dietary intakes were measured from food records and serum phospholipids , cholesteryl esters and triacylglycerols FA were analyzed by gas chromatography . Results : Dietary counseling result ed in lower intake of saturated and higher intake of unsaturated FA compared with the controls . These changes were reflected in higher proportions of serum phospholipid PUFA ( mean difference between groups 0.61 % ( 95 % confidence interval , CI 0.05–1.17 ) , P=0.03 ) , docosahexaenoic acid ( 0.5 % ( 0.15–0.85 ) , P=0.01 ) , sum of n-3 FA ( 0.61 % ( 0.07–1.15 ) , P=0.03 ) and lower ratio of n-6/n-3 FA ( −0.42 % ( −0.81–0.03 ) , P=0.03 ) in the intervention group at the third trimester of pregnancy but not at 1 month postpartum . Similar changes were seen in the FA of cholesteryl esters and triacylglycerols . Conclusion : Maternal serum n-3 FA status during pregnancy can be improved by dietary means emphasizing the importance of dietary advice [6365516] The effect of maternal supplementation during both gestation and lactation on infant growth from birth to 12 mth was investigated in the double-blind , r and omly allocated control trial conducted in Taiwan by the late Bacon F. Chow . The supplement was a milk-based formula providing 800 kcal and 40 g protein daily . The placebo provided less than 40 kcal per diem but resembled the supplement in appearance . Supplementation was limited to mothers and began after birth of one infant and continued without interruption until weaning of a second infant . Supplement effects were tested by comparing both supplement and placebo groups and first- and second-infant groups with respect to weight , length and head circumference . Both comparisons of growth curves and analyses of variance were carried out . Both strategies agreed in failing to detect differences in growth between supplement and placebo groups . However , differences were found between first and second infants in the supplement group [6819029] Unselective dietary protein energy supplementation of Asian mothers at Sorrento Maternity Hospital did not enhance intrauterine growth . The effect of selective supplementation was therefore studied . Forty-five mothers who at 28 weeks were known to be nutritionally at risk ( triceps increment less than or equal to 20 microns/week between 18 and 28 weeks ) received one of three supplements during the third trimester : ( a ) vitamins only -- a multivitamin sachet daily containing vitamins A , B , C , and D ; ( b ) energy--42 - 125 MJ ( 10 000 - 30 000 kcal ) , all from carbohydrate , plus vitamins ; ( c ) protein energy -- energy and vitamins as before , but with 5 - 10 % of energy from milk protein . Eighty-three mothers regarded as adequately nourished at 28 weeks also received one of the three supplements . In the nutritionally at-risk mothers the protein energy supplement was associated with a heavier crude birth weight and heavier weight for gestational age . Supplementation did not lead to improved intrauterine growth in those mothers who were adequately nourished . The differential effect of supplementation depending on the mothers ' nutritional state during the second trimester may explain apparently conflicting results of other studies where some have shown a substantial effect of supplementation and others only a small effect . This effect of intervention is further evidence that " poor nutrition " contributes to poor intrauterine growth in selected mothers , even in developed countries [19812173] BACKGROUND Prenatal multiple micronutrient ( MMN ) or balanced energy and protein supplementation has a limited effect on birth size of the offspring . OBJECTIVE The objective was to determine whether a prenatal MMN-fortified food supplement ( FFS ) improves anthropometric measures at birth compared with supplementation with an MMN pill alone . DESIGN We conducted a nonblinded , individually r and omized controlled trial in 1296 pregnant women in 2 villages in rural Burkina Faso . Supplements were provided on a daily basis , and compliance was closely verified by using a community-based network of home visitors . RESULTS Anthropometric measures at birth were available for analysis for 87 % of the 1175 live singleton deliveries enrolled . After adjustment for gestational age at birth , the FFS group had a significantly higher birth length ( + 4.6 mm ; P = 0.001 ) . FFS supplementation result ed in a modestly higher birth weight ( + 31 g ; P = 0.197 ) . Subgroup analyses showed clinical ly important treatment effects on birth length ( + 12.0 mm ; P = 0.005 ) and on birth weight ( + 111 g ; P = 0.133 ) for underweight [ body mass index ( in kg/m(2 ) ) < 18.5 ] pregnant women . Women with early pregnancy anemia who received FFS gave birth to longer newborns ( + 7.3 mm ; P = 0.002 ) than did those who received MMN supplementation . CONCLUSIONS The provision of FFS to pregnant women result ed in higher birth length than did MMN supplementation . For women with a suboptimal prepregnancy nutritional status , MMN supplementation should be complemented with a balanced energy and protein supplement to produce a clinical effect on birth size . The trial was registered at clinical trials.gov as NCT00909974 [19022974] Fetal nutrition is thought to be an important determinant of later disease risk , although evidence from r and omized-controlled trials in humans is lacking . We followed children born during a protein-energy supplementation trial to investigate to what extent this maternal supplement , which improved birth weight , influenced offspring body composition in adolescence . Subjects were 1270 Gambian children ( 659 boys , 611 girls ) aged 11 - 17 y whose mothers had participated in the original cluster-r and omized trial and had received the supplement during pregnancy ( intervention ) or postpartum ( control ) . Basic anthropometry was measured using st and ard techniques and fatness was assessed by bioelectrical impedance analysis and population -specific prediction equations . For boys , mean body fat was 12.6 % for both intervention and control groups . Mean trunk fat was 11.9 % in the intervention group and 12.0 % in the control . Intervention girls had a mean body fat of 19.5 % and trunk fat of 15.2 % ; for control girls , it was 19.3 and 14.8 % , respectively . BMI , body fat , trunk fat , fat mass index , and fat-free mass index did not differ for either sex when analyzed with generalized estimating equations adjusted for age , maternal height , maternal parity , location , season of birth , and menarche in females . Neither infant-attained size nor the onset of menarche were affected by maternal supplementation . These findings suggest that protein-energy supplements to pregnant women , compared with lactating women , do not affect offspring body composition during adolescence [24169456] Background / Objective : Well-being has been linked to the quality of diet and lifestyle in adults ; however , there is a paucity of data in pregnancy . The aim of this study was to examine the relationship between well-being and socioeconomic status , diet and lifestyle during pregnancy and to consider the effect of intervention with low glycaemic index ( GI ) diet on well-being . Subjects/ Methods : This was a cohort analysis of 619 participants of the ROLO study ( R and omised cOntrol trial of LOw GI diet versus no dietary intervention to prevent recurrence of fetal macrosomia ) . The following data were collected : educational attainment , dietary intakes ( food frequency question naire ) , physical activity ( self-reported ) and well-being ( WHO-5-Item Wellbeing Index — expressed as a percentage ) . Results : Well-being was positively associated with education and physical activity . Third-level education was associated with a 3.07-point higher well-being percentage score , and each day that an individual achieved > 30 min walking per week was associated with a 1.10-point increase in percentage well-being score , Radj2 2.4 % ( F=7.260 , P=0.001 ) . The intervention low GI group had a significantly lower percentage well-being score than the usual diet group ( 56.3 % vs 59.9 % , P=0.015 ) . No correlation was noted between well-being and GI status calculated from food diaries ( P=0.469 ) . Well-being was not associated with micronutrient intake . Conclusions : Well-being in pregnancy was independently and positively associated with education and physical activity and negatively associated with low GI dietary intervention . These findings have significance not only for women at risk of low mood but also for healthcare professionals when counselling women about the importance of healthy lifestyle in pregnancy [4221449] ABSTRACT Ready-to-eat ( RTE ) snacks are routinely distributed to pregnant women in India . These provide protein and calories but are low in micronutrients . We investigated whether RTE snacks fortified with leaf concentrate ( LC ) could improve pregnancy outcomes , including maternal haemoglobin ( Hb ) concentrations and infants ’ birthweight . This r and omized controlled two-arm trial was conducted over 18 months : control ( sRTE ) group received st and ard 120 g RTE snack ( 102 g wheat flour , 18 g soya flour ) ; intervention ( lcRTE ) group received the same snack fortified with 7 g LC . The study was conducted in Jaipur , Rajasthan , India . One hundred and five pregnant women aged 18 - 35 years were studied . Among the 105 women r and omized to the two arms of the trial , 2 ( 1.9 % ) were severely anaemic ( Hb ≤6.0 g/dL ) ; 55 ( 53.4 % ) were moderately anaemic ( Hb 6.0 - 8.0 g/dL ) ; 34 ( 33.0 % ) were mildly anaemic ( Hb 8.6 - 10.9 g/dL ) ; and 12 ( 11.7 % ) were not anaemic ( Hb ≥11.0 g/dL ) . In the final month of pregnancy , 83.0 % ( 39/47 ) of women in the sRTE group had Hb ≤8.5 g/dL compared to 37.8 % ( 17/45 ) in the lcRTE group ( p<0.001 ) . After adjustment for age and baseline Hb concentration , the difference in Hb concentrations due to LC fortification was 0.94 g/dL ( 95 % CI 6.8 - 12.0 ; p<0.001 ) . Mean live birthweight in the lcRTE group was 2,695 g ( SD 325 g ) compared to 2,545 g ( 297 g ) in the sRTE group ( p=0.02 ) . The lcRTE snacks increased infants ’ birthweight by 133.7 g ( 95 % CI 7.3 - 260.2 ; p=0.04 ) compared to sRTE snacks . Leaf concentrate fortification of antenatal protein-calorie snacks in a low-income setting in India protected against declining maternal haemoglobin concentrations and increased infants ’ birthweight when compared with unfortified snacks . These findings require replication in a larger trial [15894592] BACKGROUND Low birth weight and subsequent rapid child growth are associated with later blood pressure levels . The role of maternal and child nutrition in this association remains unclear . METHODS We studied 450 men and women ( ages 21 - 29 years ) born during a r and omized trial of protein-energy supplementation ( Atole ) vs low energy/no protein supplementation ( Fresco ) in pregnancy and early childhood in four rural Guatemalan villages from 1969 to 1977 . RESULTS Protein-energy supplementation was not associated with differences in blood pressure in adulthood ( diastolic blood pressure ( DBP ) : beta = 0.69 mm Hg , 95 % confidence internal ( CI ) ( 20.82 - 2.19 ) ; P = 0.37 ; systolic blood pressure ( SBP ) : beta = 0.17 mm Hg , 95 % CI ( 21.68 - 2.02 ) ; P = 0.86 ) . Within the Atole group , maternal height was associated with later SBP ( 0.22 mm Hg/cm , 95 % CI ( 20.002 - 0.45 ) ; P = 0.05 ) . No other associations between maternal nutritional status , birth size , child growth , or supplement intake were observed for adult blood pressure . CONCLUSIONS Our data do not support the role of maternal nutrition during pregnancy , birth size , or early child growth in programming adult blood pressure . Likewise , we found no effect of protein-energy supplementation in pregnancy or in early childhood on blood pressure in young adults [2681032] OBJECTIVE A low – glycemic index diet is effective as a treatment for individuals with diabetes and has been shown to improve pregnancy outcomes when used from the first trimester . A low – glycemic index diet is commonly advised as treatment for women with gestational diabetes mellitus ( GDM ) . However , the efficacy of this advice and associated pregnancy outcomes have not been systematic ally examined . The purpose of this study was to determine whether prescribing a low – glycemic index diet for women with GDM could reduce the number of women requiring insulin without compromise of pregnancy outcomes . RESEARCH DESIGN AND METHODS All women with GDM seen over a 12-month period were considered for inclusion in the study . Women ( n = 63 ) were r and omly assigned to receive either a low – glycemic index diet or a conventional high-fiber ( and higher glycemic index ) diet . RESULTS Of the 31 women r and omly assigned to a low – glycemic index diet , 9 ( 29 % ) required insulin . Of the women r and omly assigned to a higher – glycemic index diet , a significantly higher proportion , 19 of 32 ( 59 % ) , met the criteria to commence insulin treatment ( P = 0.023 ) . However , 9 of these 19 women were able to avoid insulin use by changing to a low – glycemic index diet . Key obstetric and fetal outcomes were not significantly different . CONCLUSIONS Using a low – glycemic index diet for women with GDM effectively halved the number needing to use insulin , with no compromise of obstetric or fetal outcomes [4292819] Background Fish and meat intake may affect gestational weight gain , body composition and serum fatty acids . We aim ed to determine whether a longitudinal dietary intervention during pregnancy could increase fish intake , affect serum phospholipid fatty acids , gestational weight gain and body composition changes during pregnancy in women of normal weight participating in the Pregnancy Obesity Nutrition and Child Health study . A second aim was to study possible effects in early pregnancy of fish intake and meat intake , respectively , on serum phospholipid fatty acids , gestational weight gain , and body composition changes during pregnancy . Methods In this prospect i ve , r and omized controlled study , women were allocated to a control group or to a dietary counseling group that focused on increasing fish intake . Fat mass and fat-free mass were measured by air-displacement plethysmography . Reported intake of fish and meat was collected from a baseline population and from a subgroup of women who participated in each trimester of their pregnancies . Serum levels of phospholipid arachidonic acid ( s-ARA ) , eicosapentaenoic acid ( s-EPA ) , and docosahexaenoic acid ( s-DHA ) were measured during each trimester . Results Weekly fish intake increased only in the intervention group ( n = 18 ) from the first to the second trimester ( median difference 113 g , p = 0.03 ) and from the first to the third trimester ( median difference 75 g , p = 0.01 ) . In the first trimester , fish intake correlated with s-EPA ( r = 0.36 , p = 0.002 , n = 69 ) and s-DHA ( r = 0.34 , p = 0.005 , n = 69 ) , and meat intake correlated with s-ARA ( r = 0.28 , p = 0.02 , n = 69 ) . Fat-free mass gain correlated with reported meat intake in the first trimester ( r = 0.39 , p = 0.01 , n = 45 ) . Conclusions Dietary counseling throughout pregnancy could help women increase their fish intake . Intake of meat in early pregnancy may increase the gain in fat-free mass during pregnancy [18154905] OBJECTIVES To evaluate the impact of maternal nutrition during pregnancy on infant blood pressure . STUDY DESIGN Pregnant women ( n = 256 ) were r and omized into 3 groups : modified dietary intake according to current recommendations and probiotics ( diet/probiotics ) , placebo ( diet/placebo ) , and a control/placebo group . In the infants born to these women , blood pressure was recorded at age 6 months using an automated oscillometric DINAMAP R. RESULTS Despite significant differences in maternal dietary intakes between the study groups , the intervention focusing on maternal fat intake showed no direct impact on infants ' blood pressure . Instead , a complex U-shaped interrelationship was uncovered ; the highest and lowest quartiles of intakes of specific nutrients , carbohydrate ( P = .006 for systolic pressure and P = .015 for diastolic pressure ) , and monounsaturated fatty acids ( P = .029 for diastolic pressure ) compared with the middle quartiles result ed in higher blood pressure at age 6 months . The pattern between maternal carbohydrate intake during pregnancy and infants ' blood pressure remained significant even after adjustment for breastfeeding and body length . A reverse U-shaped trend again was observed between maternal intake of fruits and infants ' systolic blood pressure ( P = .077 ) . CONCLUSION With a view toward programming blood pressure to adulthood , our results suggest an opportunity for dietary counseling to promote child health [3534399] Background Recent observational research indicates that immune development may be programmed by nutritional exposures early in life . Such findings require replication from trials specifically design ed to assess the impact of nutritional intervention during pregnancy on infant immune development . The current trial seeks to establish : ( a ) which combination of protein-energy ( PE ) and multiple-micronutrient ( MMN ) supplements would be most effective ; and ( b ) the most critical periods for intervention in pregnancy and infancy , for optimal immune development in infancy . Methods / Design The ENID Trial is a 2 x 2 x 2 factorial r and omized , partially blind trial to assess whether nutritional supplementation to pregnant women ( from < 20 weeks gestation to term ) and their infants ( from 6 to 12 months of age ) can enhance infant immune development . Eligible pregnant women from the West Kiang region of The Gambia ( pregnancy date d by ultrasound examination ) are r and omized on entry to 4 intervention groups ( Iron-folate ( FeFol = st and ard care ) , multiple micronutrients ( MMN ) , protein-energy ( PE ) , PE + MMN ) . Women are visited at home weekly for supplement administration and morbidity assessment and seen at MRC Keneba at 20 and 30 weeks gestation for a detailed antenatal examination , including ultrasound . At delivery , cord blood and placental sample s are collected , with detailed infant anthropometry collected within 72 hours . Infants are visited weekly thereafter for a morbidity question naire . From 6 to 12 months of age , infants are further r and omized to a lipid-based nutritional supplement , with or without additional MMN . The primary outcome measures of this study are thymic development during infancy , and antibody response to vaccination . Measures of cellular markers of immunity will be made in a selected sub-cohort . Subsidiary studies to the main trial will additionally assess the impact of supplementation on infant growth and development to 24 months of age . Discussion The proposed trial is design ed to test whether nutritional repletion can enhance early immune development and , if so , to help determine the most efficacious form of nutritional support . Where there is evidence of benefit from a specific intervention/combination of interventions , future research should focus on refining the supplements to achieve the optimal , most cost-effective balance of interventions for improved health outcomes .Trial registration IS RCT [17018700] To study the role of nutrition in the association of birth size and childhood growth with development of cardiovascular disease , the authors in 2002 - 2004 surveyed 665 men and 790 women aged 25 - 42 years who had been exposed as children to a community-r and omized nutrition supplementation intervention in four villages in eastern Guatemala . Exposure was associated with a lower fasting glucose level ( 7.0 mg/dl , 95 % confidence interval ( CI ) : 0.5 , 13.5 ) for exposure at ages 36 - 72 months ; lower systolic blood pressure ( 3.0 mmHg , 95 % CI : 0.4 , 5.6 ) for exposure at ages 24 - 60 months ; and a lower triglyceride level ( sex-adjusted ; 22.2 mg/dl , 95 % CI : 0.4 , 44.1 ) and higher high density lipoprotein cholesterol level ( males only ; 4.7 mg/dl , 95 % CI : 1.5 , 7.9 ) for exposure prior to age 36 months . Improved nutrition at any age prior to 7 years was not associated with diastolic blood pressure , total or low density lipoprotein cholesterol level , or prevalence of the metabolic syndrome . Interventions design ed to address nutrient deficiencies and ameliorate stunting that are targeted at pregnant women and young children are unlikely to increase cardiovascular disease risk later in life and may instead lower the risk [21346924] OBJECTIVE To examine the association between gestational weight gain and maternal body mass index ( BMI ) among Vietnamese women and the risk of delivering an infant too small or too large for gestational age . METHODS A prospect i ve health-facility-based study of 2989 pregnant Vietnamese women was conducted in the city of Nha Trang in 2007 - 2008 . Cubic logistic regression was used to investigate the association of interest . Infants were classified into weight-for-gestational-age categories according to weight centiles for the Asian population . Gestational age was based on the date of last menstrual period and adjusted by the results of first-trimester ultrasound . FINDINGS BMI was low ( < 18.5 ) , normal ( 18.5 - 22.9 ) and high ( ≥ 23.0 ) in 26.1 % , 65.4 % and 8.5 % of the women , respectively . In each of these BMI categories , the percentage of women who delivered infants too small for gestational age was 18.1 , 10.0 and 9.4 , respectively , and the mean gestational weight gain was 12.5 kg ( st and ard deviation , SD : ± 3.6 ) , 12.2 kg ( SD : ± 3.8 ) and 11.5 kg ( SD : ± 4.7 ) , respectively . Among women with low BMI , the risk of delivering an infant too small for gestational age ranged from approximately 40 % if the gestational weight gain was < 5 kg to 20 % if it was 5 - 10 kg . CONCLUSION Having a low BMI , commonly found in Viet Nam , puts women at risk of delivering an infant too small for gestational age , especially when total maternal gestational weight gain is < 10 kg [20053938] Knowledge about the impact of maternal food and micronutrient supplementation on infant micronutrient status is limited . We examined the effect of maternal food and micronutrient supplementation on infant micronutrient status in the Maternal and Infant Nutrition Interventions in Matlab Trial . Pregnant women ( n = 4436 ) were r and omized to Early or Usual promotion of enrollment in a food supplementation program . In addition , they were r and omly allocated to 1 of the following 3 types of daily micronutrient supplements provided from wk 14 of gestation to 3 mo postpartum : 1 ) folic acid and 30 mg iron ( Fe30Fol ) ; 2 ) folic acid and 60 mg iron ; or 3 ) a multiple micronutrient including folic acid and 30 mg iron ( MMS ) . At 6 mo , infant blood sample s ( n = 1066 ) were collected and analyzed for hemoglobin and plasma ferritin , zinc , retinol , vitamin B-12 , and folate . The vitamin B-12 concentration differed between the micronutrient supplementation groups ( P = 0.049 ) . The prevalence of vitamin B-12 deficiency was lower in the MMS group ( 26.1 % ) than in the Fe30Fol group ( 36.5 % ) ( P = 0.003 ) . The prevalence of zinc deficiency was lower in the Usual food supplementation group ( 54.1 % ) than in the Early group ( 60.2 % ) ( P = 0.046 ) . There were no other differential effects according to food or micronutrient supplementation groups . We conclude that maternal multiple micronutrient supplementation may have a beneficial effect on vitamin B-12 status in infancy [4176103] Background Maternal diet is known to impact pregnancy outcome . Following a low glycemic index ( GI ) diet during pregnancy has been shown to improve maternal glycemia and reduce infant birthweight and may be associated with a higher fibre intake . We assessed the impact of a low GI dietary intervention on maternal GI , nutritional intake and gestational weight gain ( GWG ) during pregnancy . Compliance and acceptability of the low GI diet was also examined . Method Eight hundred women were r and omised in early pregnancy to receive low GI and healthy eating dietary advice or to receive st and ard maternity care . The intervention group received dietary advice at a group education session before 22 weeks gestation . All women completed a 3 day food diary during each trimester of pregnancy . Two hundred and thirty five women from the intervention arm and 285 women from the control arm returned complete 3x3d FDs and were included in the present analysis . Results Maternal GI was significantly reduced in the intervention group at trimester 2 and 3 . The numbers of women within the lowest quartile of GI increased from 37 % in trimester 1 to 52 % in trimester 3 ( P < 0.001 ) among the intervention group . The intervention group had significantly lower energy intake ( P < 0.05 ) , higher protein ( % TE ) ( P < 0.01 ) and higher dietary fibre intake ( P < 0.01 ) post intervention . Consumption of food groups with known high GI values were significantly reduced among the intervention group . Women in the intervention low GI group were less likely to exceed the Institute of Medicine ’s GWG goals . Conclusion A dietary intervention in early pregnancy had a positive influence on maternal GI , food and nutrient intakes and GWG . Following a low GI diet may be particularly beneficial for women at risk of exceeding the GWG goals for pregnancy . Trial registration Current Controlled Trials Registration Number : IS RCT N54392969 [20128938] The perinatal nutritional environment impacts upon the health and well-being of mother and child also in the long term . The aim of the present study was to determine the safety and efficacy of perinatal probiotic-supplemented dietary counselling by evaluating pregnancy outcome and fetal and infant growth during the 24 months ' follow-up . Altogether , 256 women were r and omised at their first trimester of pregnancy into a control and a dietary intervention group . The intervention group received intensive dietary counselling provided by a nutritionist and were further r and omised , double-blind to receive probiotics ( Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12 ; diet/probiotics ) or placebo ( diet/placebo ) . Firstly , probiotic intervention reduced the frequency of gestational diabetes mellitus ( GDM ) ; 13 % ( diet/probiotics ) v. 36 % ( diet/placebo ) and 34 % ( control ) ; P = 0.003 . Secondly , the safety of this approach was attested by normal duration of pregnancies with no adverse events in mothers or children . No significant differences in prenatal or postnatal growth rates among the study groups were detected . Thirdly , distinctive effects of the two interventions were detected ; probiotic intervention reduced the risk of GDM and dietary intervention diminished the risk of larger birth size in affected cases ; P = 0.035 for birth weight and P = 0.028 for birth length . The results of the present study show that probiotic-supplemented perinatal dietary counselling could be a safe and cost-effective tool in addressing the metabolic epidemic . In view of the fact that birth size is a risk marker for later obesity , the present results are of significance for public health in demonstrating that this risk is modifiable [21729487] OBJECTIVE Increasing the consumption of Fe-rich foods and thus improving Fe bioavailability without significantly increasing diet cost is the most sustainable intervention for improving Fe intake . We assessed the effect of supplementary food consisting of fermented soyabean ( tempeh ) and vitamin C-rich fruit consumed during pregnancy on maternal iron deficiency ( ID ) . DESIGN Pregnant women were r and omly allocated by village into optimized diet and control groups . Supplementary food was given 6 d/week at home . The average weekly food provided comprised 600 g of tempeh , 30 g of meat , 350 g of guava , 300 g of papaya and 100 g of orange . Hb , ferritin and transferrin receptor ( TfR ) concentrations were measured at 12 - 20 and at 32 - 36 weeks of gestation . SETTING Thirty-nine villages in Indonesia . SUBJECTS Pregnant women ( 12 - 20 weeks of gestation , n 252 ) . RESULTS At baseline , mean Hb , ferritin and TfR concentrations and body Fe concentration were within the normal range and did not differ between groups . At near term , mean Hb , ferritin and body Fe decreased , whereas mean TfR increased significantly in both groups . The mean changes in Fe status were similar in both groups . In Fe-deficient women , consumption of an optimized diet was associated with smaller decreases in Hb ( 1·02 ( 95 % CI 0·98 , 1·07 ) g/l ; P = 0·058 ) , ferritin ( 1·42 ( 95 % CI 1·16 , 1·75 ) μg/l ; P = 0·046 ) and body Fe ( 2·57 ( 95 % CI 1·71 , 3·43 ) mg/kg ; P = 0·073 ) concentrations , compared with a state of no intervention . Fe-deficient women at baseline benefited more from supplementary food compared with Fe-replete women . CONCLUSIONS Daily supplementary food containing tempeh and vitamin C-rich fruits during pregnancy might have positive effects on maternal ID [2639364] Background Birthweight , and by inference maternal nutrition during pregnancy , is thought to be an important determinant of offspring blood pressure but the evidence base for this in humans is lacking data from r and omized controlled trials . Methods The offspring from a maternal prenatal protein-energy supplementation trial were enrolled into a follow-up study of chronic disease risk factors including blood pressure . Subjects were 11–17 years of age and blood pressure was measured in triplicate using an automated monitor ( Omron 705IT ) . One-thous and two-hundred sixty seven individuals ( 71 % of potential participants ) were included in the analysis . Results There was no difference in blood pressure between those whose mothers had consumed protein-energy biscuits during pregnancy and those whose mothers had consumed the same supplement post-partum . For systolic blood pressure the intention-to-treat regression coefficient was 0.46 ( 95 % CI : –1.12 , 2.04 ) . Mean systolic blood pressure for control children was 110.2 ( SD ± 9.3 ) mmHg and for intervention children was 110.8 ( SD ± 8.8 ) mmHg . Mean diastolic blood pressure for control children was 64.7 ( SD ± 7.7 ) mmHg and for intervention children was 64.6 ( SD ± 7.6 ) mmHg . Conclusions We have found no association between maternal prenatal protein-energy supplementation and offspring blood pressure in adolescence amongst rural Gambians . We found some evidence to suggest that offspring body composition may interact with the effect of maternal supplementation on blood pressure [21561932] BACKGROUND Relative leg length is frequently used as a biomarker of childhood nutrition in epidemiological studies , but evidence is lacking . We examined the association between supplemental nutrition in pregnancy and childhood and relative proportions of components of height in adolescence . METHODS In a community trial of nutritional supplementation , villages from adjacent administrative areas were selected to serve as intervention ( n = 15 ) and control ( n = 14 ) arms . In the intervention villages , balanced protein-calorie supplementation ( 2.51 MJ , 20 g protein ) was offered daily to pregnant women and their offspring until the age of 6 years . Children born in the trial were re-examined 15 years later to assess components of height . RESULTS A total of 1165 adolescents ( intervention : 654 , 49 % of trial participants ; control : 511 , 41 % of trial participants ) aged 13 - 18 years were examined . Supplemented children were 10 mm taller [ 95 % confidence interval ( CI ) : 1.4 to 18.7 mm ] , but almost all of the increase was in trunk length ( 9 mm , 95 % CI : 2.6 to 15.4 mm ) . The age- and gender-adjusted β-coefficients for the association of nutritional supplementation with relative trunk , leg and lower leg lengths ( expressed as st and ard deviation scores ) were 0.26 ( 95 % CI : 0.11 to 0.42 ) , 0.08 ( 95 % CI : -0.03 to 0.19 ) and 0.03 ( 95 % CI : -0.08 to 0.15 ) respectively , thereby unsupportive of cephalocaudal gradient in growth . CONCLUSIONS In this nutritional supplementation trial in an undernourished population , we were unable to confirm relative leg length as a biomarker of childhood nutrition . Alternative explanations may underlie the reported associations between childhood conditions and relative leg length [19955397] BACKGROUND Maternal obesity and excessive gestational weight gain ( GWG ) are major short- and long-term risk factors for maternal and fetal complications . OBJECTIVE The objective was to study whether a lifestyle intervention based on a brochure or on active education can improve dietary habits , increase physical activity ( PA ) , and reduce GWG in obese pregnant women . DESIGN In this r and omized controlled trial , 195 white , obese pregnant women [ age : 29 + or - 4 y ; body mass index ( in kg/m(2 ) ) ; 33.6 + or - 4.2 ] were r and omly assigned into 3 groups : a group that received nutritional advice from a brochure , a group that received the brochure and lifestyle education by a nutritionist , and a control group . Nutritional habits were evaluated every trimester through 7-d food records . PA was evaluated with the Baecke question naire . RESULTS Energy intake did not change during pregnancy and was comparable in all groups . Fat intake , specifically saturated fat intake , decreased and protein intake increased from the first to the third trimester in the passive and active groups compared with an opposite change in the control group . Calcium intake and vegetable consumption increased during pregnancy in all groups . PA decreased in all groups , especially in the third trimester . No significant differences in GWG and obstetrical or neonatal outcome could be observed between the groups . CONCLUSIONS Both lifestyle interventions improved the nutritional habits of obese women during pregnancy . Neither PA nor GWG was affected [3847473] The current study attempts to identify the effects of an individual prescription for protein and kilocalorie requirements during pregnancy on subsequent maternal and infant outcomes . This study was a replication of Agnes Higgins ' Intervention Method for Nutritional Rehabilitation During Pregnancy developed at the Montreal Diet Dispensary , Montreal , Canada . The present study was a r and omized clinical trial using an experimental control group design . There were 47 subjects in phases 1 and 2 of a multiphase study . Total food intake data was available for 43 subjects with singleton live births . The Higgins method was found to have a significant impact on increasing the amount of protein but not calories consumed by the experimental group . A significant increase in maternal weight and infant birth weight was found in those underweight and normal weight women , who gained at least 10 lb ( 4.5 kg ) in the first 20 weeks of their pregnancy and who consumed an adequate amount of their prescriptions of both protein and kilocalories . All the women with premature labor and pregnancy-induced hypertension were in the group with an inadequate early pregnancy weight gain and inadequate nutrition intake . Data collection to increase sample size is ongoing [24896237] The present study is a secondary analysis of the ROLO study , a r and omised control trial of a low-glycaemic index ( GI ) diet in pregnancy to prevent the recurrence of fetal macrosomia . The objectives of the present study were to identify which women are most likely to respond to a low-GI dietary intervention in pregnancy with respect to three outcome measures : birth weight ; maternal glucose intolerance ; gestational weight gain ( GWG ) . In early pregnancy , 372 women had their mid-upper arm circumference recorded and BMI calculated . Concentrations of glucose , insulin and leptin were measured in early pregnancy and at 28 weeks . At delivery , infant birth weight was recorded and fetal glucose , C-peptide and leptin concentrations were measured in the cord blood . Women who benefited in terms of infant birth weight were shorter , with a lower education level . Those who maintained weight gain within the GWG guidelines were less overweight in both their first and second pregnancies , with no difference being observed in maternal height . Women who at 28 weeks of gestation developed glucose intolerance , despite the low-GI diet , had a higher BMI and higher glucose concentrations in early pregnancy with more insulin resistance . They also had significantly higher-interval pregnancy weight gain . For each analysis , women who responded to the intervention had lower leptin concentrations in early pregnancy than those who did not . These findings suggest that the maternal metabolic environment in early pregnancy is important in determining later risks of excessive weight gain and metabolic disturbance , whereas birth weight is mediated more by genetic factors . It highlights key areas , which warrant further interrogation before future pregnancy intervention studies , in particular , maternal education level and inter-pregnancy weight gain [9345173] Abstract Objective : To test the efficacy in terms of birth weight and infant survival of a diet supplement programme in pregnant African women through a primary healthcare system . Design : 5 year controlled trial of all pregnant women in 28 villages r and omised to daily supplementation with high energy groundnut biscuits ( 4.3MJ/day ) for about 20 weeks before delivery ( intervention ) or after delivery ( control ) . Setting : Rural Gambia . Subjects : Chronically undernourished women ( twin bearers excluded ) , yielding 2047 singleton live births and 35 stillbirths . Main outcome measures : Birth weight ; prevalence of low birth weight ( < 2500 g ) ; head circumference ; birth length ; gestational age ; prevalence of stillbirths ; neonatal and postneonatal mortality . Results : Supplementation increased weight gain in pregnancy and significantly increased birth weight , particularly during the nutritionally debilitating hungry season ( June to October ) . Weight gain increased by 201 g ( P<0.001 ) in the hungry season , by 94 g ( P<0.01 ) in the harvest season ( November to May ) , and by 136 g ( P<0.001 ) over the whole year . The odds ratio for low birthweight babies in supplemented women was 0.61 ( 95 % confidence interval 0.47 to 0.79 , P<0.001 ) . Head circumference was significantly increased ( P<0.01 ) , but by only 3.1 mm . Birth length and duration of gestation were not affected . Supplementation significantly reduced perinatal mortality : the odds ratio was 0.47 ( 0.23 to 0.99 , P<0.05 ) for stillbirths and 0.54 ( 0.35 to 0.85 , P<0.01 ) for all deaths in first week of life . Mortality after 7 days was unaffected . Conclusion : Prenatal dietary supplementation reduced retardation in intrauterine growth when effectively targeted at genuinely at-risk mothers . This was associated with a substantial reduction in the prevalence of stillbirths and in early neonatal mortality . The intervention can be successfully delivered through a primary healthcare system . Key messages In developing countries chronic maternal undernutrition is a prime contributor to the birth of over 25 million low birthweight babies annually and to high rates of neonatal mortality . An absence of well design ed field trials has created uncertainty about the potential efficacy of maternal feeding programmes This large scale r and omised controlled trial shows that dietary supplementation in pregnancy can be highly effective in reducing the proportion of low birthweight babies and perinatal mortality Incorporating supplementary feeding into a rural primary healthcare system is feasible Late pregnancy is the period most amenable to [6988785] This r and omized controlled trial of nutritional supplementation in pregnancy , in a poor black urban population in the United States , aim ed to increase the birth weight and influence the postnatal development of the offspring of mothers at high risk of having low birth weight infants . The execution of the research design and adherence to the treatment regimen among the experimental population appeared adequate for a reasonable test of the treatments . At birth , the only significant favorable effect of supplementation observed was the prevention of depressed birth weight among the offspring of mothers who smoked heavily . With balanced protein-calorie supplementation , length of gestation was increased , the proportion of low-birth-weight infants reduced , and mean birth weight raised by 41 gm ( not statistically significant ) . With high protein supplementation , there was an excess of very early premature births and associated neonatal deaths , and there was significant growth retardation up to 37 weeks of gestation . At 1 year of age , significant effects of high protein supplement were found on three psychological measures : visual habituation , visual dishabituation , and mean length of free play episodes . These measures were unrelated to measures of growth at birth and at 1 year of age . There were no detectable residual adverse effects of high protein supplementation at 1 year of age [18242415] BACKGROUND Substantial , but indirect , evidence suggests that improving nutrition in early childhood in developing countries is a long-term economic investment . We investigated the direct effect of a nutrition intervention in early childhood on adult economic productivity . METHODS We obtained economic data from 1424 Guatemalan individuals ( aged 25 - 42 years ) between 2002 and 2004 . They accounted for 60 % of the 2392 children ( aged 0 - 7 years ) who had been enrolled in a nutrition intervention study during 1969 - 77 . In this initial study , two villages were r and omly assigned a nutritious supplement ( atole ) for all children and two villages a less nutritious one ( fresco ) . We estimated annual income , hours worked , and average hourly wages from all economic activities . We used linear regression models , adjusting for potentially confounding factors , to assess the relation between economic variables and exposure to atole or fresco at specific ages between birth and 7 years . FINDINGS Exposure to atole before , but not after , age 3 years was associated with higher hourly wages , but only for men . For exposure to atole from 0 to 2 years , the increase was US$ 0.67 per hour ( 95 % CI 0.16 - 1.17 ) , which meant a 46 % increase in average wages . There was a non-significant tendency for hours worked to be reduced and for annual incomes to be greater for those exposed to atole from 0 to 2 years . INTERPRETATION Improving nutrition in early childhood led to substantial increases in wage rates for men , which suggests that investments in early childhood nutrition can be long-term drivers of economic growth [23432806] Leptin regulates energy homeostasis and immune and metabolic functions . Highly elevated leptin concentrations during pregnancy may be associated with aberrations in maternal metabolism and long-term health consequences both in women and children . The objective of the present study was to evaluate whether dietary counselling , probiotic supplementation , maternal characteristics or dietary intake during pregnancy has an impact on serum leptin concentrations in women , cord blood or in children . A total of 256 pregnant women were r and omised to a control group ( n 85 ) or to receive dietary counselling with probiotics ( n 85 ) or placebo ( n 86 ) . Dietary counselling aim ed at affecting the type of fat used and to increase the amount of fibre in the women 's diet . Women 's dietary intake and serum leptin concentrations were analysed at the first and third trimesters of pregnancy and at 1 month postpartum . Furthermore , leptin concentrations were measured from the cord blood and from children 's serum at 1 and 6 months of age . Weight status and dietary composition were the key determinants of leptin concentrations . Specifically , high dietary fibre and low SFA intakes were related to low serum leptin concentrations in women . Female sex and birth weight were associated with higher infant leptin , whereas cord blood leptin was additionally affected by maternal leptin concentration and protein intake . Probiotics or dietary counselling did not affect leptin concentrations . Weight control to recommended levels and modification of diet towards higher fibre and lower SFA intakes during pregnancy may through leptin concentrations provide health benefits to both women and children [25639126] Background Maternal malnutrition and poor gestational weight gain are the most important causes of low birthweight and infant mortality in Bangladesh . Objective To assess the effect of short-term nutrition education on weight gain in the third trimester of pregnancy , birth outcomes , and breastfeeding . Methods Three hundred pregnant women participated in this r and omized , controlled trial during a 3-month intervention period . The study was conducted in two antenatal clinics in urban Dhaka . One group of women was given monthly education sessions during the third trimester of pregnancy to promote consumption of khichuri , while the control group received only routine services from the health facilities . Birthweight was recorded within 24 hours after delivery . Breastfeeding practice s were observed for 1 month after delivery . Results In the intervention group , maternal weight gain in the third trimester was 60 % higher ( 8.60 vs. 5.38 kg , p = .011 ) , mean birthweight was 20 % higher ( 2.98 vs. 2.49 kg , p < .001 ) , the rate of low birth-weight was 94 % lower ( 2.7 % vs. 44.7 % , p < .001 ) , and the rate of initiation of breastfeeding within 1 hour after birth was 52 % higher ( 86.0 % vs. 56.7 % , p < .001 ) , in comparison with the control group . Birthweight was associated with frequency of intake of khichuri ( p < 0.001 ) . Conclusions Nutrition education with a focus on promoting consumption of khichuri during the third trimester of pregnancy significantly reduced the rate of low birthweight and increased maternal weight gain [6761102] A r and omized controlled double-blind study of nutrition supplementation of pregnant and lactating women was conducted in Suilin township , Taiwan . Pregnant mothers were r and omly assigned to one of two treatment groups consisting of either a high ( 800 kcal and 40 g protein ) calorie daily supplement or a placebo . For each mother treatment began following the delivery of her first study infant , continued throughout the lactation period ; and through the pregnancy and lactation of her second study infant . Comparisons of sibling-sibling anthropometric correlations at birth between groups show that among the placebo group the sibling correlations are statistically significant and of the same magnitude seen in previous studies ( approximately 0.5 ) , while among high calorie siblings correlations are unusually low and often not significant . This is particularly true for male fetuses , suggesting that the latter are more sensitive to nutritional environmental variations in utero , than are female fetuses . Reduction in familial correlations , presumed measures of genetic influence , in nutritionally stressed population s , will occur when the environment of relatives differ , but are not due to malnutrition per se [1676083] There is little unequivocal evidence that nutritional supplementation of undernourished children has a beneficial effect on their mental development . The effects of nutritional supplementation , with or without psychosocial stimulation , of growth-retarded ( stunted ) children aged 9 - 24 months were assessed in a study in Kingston , Jamaica . 129 children from poor neighbourhoods were r and omly assigned to four groups -- control , supplemented only , stimulated only , and supplemented plus stimulated . A group of matched non-stunted children ( n = 32 ) was also included . The supplement comprised 1 kg milk-based formula per week for 2 years , and the stimulation weekly play sessions at home with a community health aide . The children 's development ( DQ ) was assessed on the Griffiths mental development scales . Initially the stunted groups ' DQs were lower than those of the non-stunted group , and those of the control group declined during the study , increasing their deficit . Stimulation and supplementation had significant independent beneficial effects on the children 's development . Estimates of the supplementation effect ranged from 2.2 ( 95 % confidence limits-1.4 , 5.7 ) for the h and and eye subscale to 12.4 ( 5.4 , 19.5 ) for the locomotor subscale and those for the stimulation effect from 6.4 ( 2.8 , 10.0 ) for h and and eye to 10.3 ( 3.3 , 17.3 ) for locomotor . The treatment effects were additive , and combined interventions were significantly more effective than either alone . These findings suggest that poor mental development in stunted children is at least partly attributable to undernutrition [3048373] Summary . The effect of two levels of energy supplementation in the last trimester of pregnancy on birthweight was tested in a controlled r and omized trial in three villages in Madura , East Java . The high and low energy supplements provided 1·95 MJ ( 465 kcal ) and 218 kj ( 52 kcal ) per day respectively . In the baseline period the home diet provided on average 6·28 MJ ( 1500 kcal ) ( SD 2·1 MJ ( 499 kcal ) ) and 41g(SD 13 g ) of protein . The mean birthweight was 2835 g and the rate of low birth‐weight 12·2 % . In the experimental period the home diet was better . The average intake ranged from 6·45 to 7·19 MJ ( 1541–1717 kcal ) and 41·4–44·2 g per day , depending on the degree of compliance . Mean birth‐weight increased by 100 g and the rate of low birthweight dropped to 9·5 % . There was no difference between the high and low energy supplemented group as a whole , probably due to the masking effect of the better home diet in the experimental period . It is likely that a positive effect of energy supplementation on birthweight was restricted to the group of pregnant women with the lowest home dietary intake and /or a low prepregnant weight . In this community targeting of supplementation to lean seasons and /or to women with a low prepregnant weight may be cost‐effective [2424471] We related cigarette smoking during pregnancy to the macroscopic and microscopic morphology , histomorphometry , and biochemistry of the placenta among participants in The Prenatal Project , a r and omized , controlled trial of nutritional supplementation during pregnancy . The aim was to ascertain if the harmful effects of cigarette smoking on the fetus were reflected , and possibly mediated , by changes in the placenta , and whether such changes might be modified by the nutritional supplements , parallel to the nutritional reversal of birthweight depression among heavy smokers . Maternal smoking was associated with increased alkaline ribonuclease ( RNase ) levels , possibly result ing in disturbed protein synthesis . More smokers had placentas with villous hyperplasia on histologic examination . This was accompanied by biochemical evidence of significantly increased cellularity ( increased DNA/gm of placental mass and decreased protein/DNA ratios ) and ( nonsignificant ) trends to reduced syncytial villous cell size on histomorphometry . There were joint effects of cigarette smoking and use of either form of nutritional supplementation on the fibrin and stoma components of the villi , but such changes are not necessarily pathologic . The significant reduction in pathology of the stem villi among smokers was confined to those who were nutritionally supplemented , particularly heavy smokers . This change may thus have reflected the protective effects of supplementation on the birthweight of the offspring of these heavy smokers [24351875] BACKGROUND Eating carbohydrate foods with a high glycemic index ( GI ) has been postulated to result in fetoplacental overgrowth and higher infant body fat . A diet with a low glycemic index ( LGI ) has been shown to reduce birth percentiles and the ponderal index ( PI ) . OBJECTIVES We investigated whether offering LGI dietary advice at the first antenatal visit would result in a lower fetal birth weight , birth percentile , and PI than providing healthy eating ( HE ) advice . This advice had to be presented within the re sources of routine antenatal care . DESIGN The Pregnancy and Glycemic Index Outcomes study was a 2-arm , parallel- design , r and omized , controlled trial that compared the effects of LGI dietary advice with HE advice on pregnancy outcomes . Eligible volunteers who attended for routine antenatal care at < 20 wk of gestation were r and omly assigned to either group . RESULTS A total of 691 women were enrolled , and 576 women had final data considered . In the LGI group , the GI was reduced from a mean ( ± SEM ) of 56 ± 0.3 at enrollment to 52 ± 0.3 ( P < 0.001 ) at the final assessment . There were no significant differences in primary outcomes of fetal birth weight , birth percentile , or PI . In a multivariate regression analysis , the glycemic load was the only significant dietary predictor ( P = 0.046 ) of primary outcomes but explained < 1 % of all variation . CONCLUSION A low-intensity dietary intervention with an LGI diet compared with an HE diet in pregnancy did not result in any significant differences in birth weight , fetal percentile , or PI [15894699] Objective : Insulin-like growth factors ( IGF ) are increasingly recognized as important determinants of adult health , in particular risk of certain cancers . However , little is known about the determinants of adult IGFs and to what degree they may be programmed by early life influences . Design : R and omized controlled trial of prenatal and postnatal milk supplementation among 951 subjects born in 1972 to 1974 in South Wales . Main outcome measure : Measures of IGF-I , IGF binding protein 3 , and the molar ratio . Results : Data on adult IGFs were available from 663 subjects at a mean age of 25 years . Subjects in the intervention arm had lower IGF-I ( −8.5 ng/mL ; 95 % confidence interval , −15.1 to −1.8 , P = 0.01 ) and ratio ( −1.20 ; 95 % confidence interval , −2.33 to −0.04 , P = 0.04 ) . These differences could not be explained by follow-up bias or confounding factors . Conclusions : These results provide experimental data on the role of early life programming either in the intrauterine or postnatal period that may have long-term influences on the IGF axis , with potential implication s for disease risk [17181885] The aim of this study was to assess the impact of dietary counselling combined with the provision of food products on food and nutrient intake in pregnant women . We carried out a prospect i ve cohort study of healthy and atopic pregnant women ( n 209 ) , who were r and omized into dietary intervention and control groups . The intervention group received dietary counselling and food products to modify the fat composition of their diet to meet current recommendations . Three-day food records were collected during each trimester of pregnancy . Women in the intervention group consumed more vegetables , fruits , soft margarines and vegetable oils and less butter than those in the control group during the course of pregnancy ( P<0.05 ) . The main distinction between the groups in nutrient intake over the pregnancy was attributable to a higher energy intake ( % energy ) of PUFA by 0.5%energy ( 95 % CI 0.1 , 0.8 ) and to a lower intake of SFA by 0.8 % energy ( 95 % CI -1.4 , -0.4 ) in the intervention group . Dietary intake of vitamin E was 1.4 mg ( 95 % CI 0.6 , 2.2 ) , folate 20.9 microg ( 95 % CI 0.8 , 41.0 ) and ascorbic acid 19.8 mg ( 95 % CI 3.5 , 36.0 ) higher in the intervention group compared to the controls , while no differences in other nutrients were detected . Dietary counselling combined with the provision of food products during pregnancy is of importance in modifying food and nutrient intake , with potential health benefits [7030223] Twelve hundred and fifty-one pregnant women were contacted and their infants followed to age 5 years . Nine hundred and fifty-one ( 76 % ) children completed the trial . Measurements were made of birthweight , length , head circumference , and triceps skinfold at 10 days , and of weight , height , head circumference , and triceps at 5 years . Throughout the entire period of the study half the families , selected at r and om , were supplied with milk tokens entitling the mother , while pregnant , and all children under age 5 years , to 1 pint of milk a day at half its current price . The tokens led to a small increase in milk purchases by the families and to a small increase in milk drunk by the children . However no effect was detected in any growth measurement either in the total group , or in a more " vulnerable " group of children from the largest families [420136] Colombian women at risk of mild-to-moderate malnutrition were enrolled in a health care program and r and omly assigned into nutritional supplementation and control groups at the beginning of the third trimester of preganancy . One hundred unsupplemented and 144 supplemented infants were tested at 15 days of age : a 2X2 checkerboard was presented eight times followed by a single presentation of a 6X6 checkerboard . Unsupplemented infants showed less initial attention followed by slower habituation and higher levels of movement than the supplemented infants . The observed effect of maternal nutritional supplementation during the last trimester of pregnancy on new-born attention was interpreted to be maturational in nature [1096930] A 1200 calorie diet or cyclopenthiazide with potassium was given to two groups of 51 high weight gain primigravidae and baby weight and the incidence of pre‐eclampsia were compared with those in a matched control group . There was no difference in the development of pre‐eclampsia , but the weight of babies in the control group was higher than in the treated groups . The body fat was reduced in the diet group and the total body water in the diuretic group [7223696] Infants born to families at risk of malnutrition were studied prospect ively from the beginning of the 3rd trimester of the mother 's pregnancy until the child reached 3 yr of age to ascertain the effects of nutritional supplementation and /or a maternal education program on their cognitive development . Four hundred thirty-three families were assigned r and omly to six groups : group A served as a control ; group B received the supplement from the age of 6 months to 3 yr ; group C received the supplement during the 3rd trimester of pregnancy and the first 6 months of the child 's life ; and group D received the supplement throughout the entire study period . In addition , group A1 was enrolled in a maternal education program but received no nutritional supplement and group B1 received both treatments . The Griffiths test of infant development was administered at 4 , 6 , 12 , 18 , 24 , and 36 months of age , and the Corman-Escalona Einstein scale was administered at each age up to 18 months . Children who received food supplementation performed better than those who did not , especially on subtests that were primarily motoric . The effect of food supplementation on behavior appeared to be contemporaneous . In addition , the treatment effects were more pronounced for girls than for boys in this sample . Although these interventions reduced the gap in cognitive performance between lower and upper socioeconomic classes , a disparity nevertheless remained by the end of the study [6722081] Effects of a feeding programme on maternal weight , triceps and subscapular skinfolds during pregnancy and lactation were assessed in a marginally undernourished population of rural Taiwan . Mothers participated during two pregnancy and lactation periods . At 3 weeks after the delivery of the first infant , one group of 114 mothers began consuming a nutrient-dense supplement ( A ) , while another group of 111 received a placebo ( B ) . There was no significant A-B difference in pregnancy weight gain ( A 7.52 kg , B 7.75 kg ) or in mean maternal weight , triceps or subscapular skinfolds at any time during pregnancy or lactation . Despite a general trend toward moderate weight loss during lactation , one-third of mothers in both groups gained weight . Highly significant increases in weight and skinfold thicknesses from one lactation period to the next characterized both groups . The absence of demonstrable supplement-effects on maternal anthropometry concomitant with increments in infant birth weight supports the notion that infants can benefit from maternal supplementation without changes in maternal nutritional status [20399406] OBJECTIVE Examine the impact of providing yogurt to women enrolled in the Special Supplemental Nutrition Program for Women , Infants , and Children ( WIC ) . DESIGN R and omized , controlled intervention trial . SETTING Two California WIC local agency sites . PARTICIPANTS 511 pregnant , breast-feeding , or postpartum women . INTERVENTION Substitution of part of the WIC milk allowance with yogurt accompanied with educational material s. MAIN OUTCOME MEASURES Participants ' consumption and attitudes regarding yogurt provision . ANALYSIS Chi-square , Fisher exact , and Student t test to compare pre- versus post-intervention responses . Nonparametric Wilcoxon , chi-square , and t test to compare changes in response in intervention versus controls . Analysis of covariance models to test the influence of language preference on outcomes . RESULTS Over 86 % of women wanted to substitute some of their milk vouchers with yogurt . Among these , 62 % reported preferring yogurt to milk . The majority ( 89 % ) redeemed the yogurt coupons . Compared to controls , intervention women reported a trend ( P = .09 ) toward an increase in yogurt intake of 1.0 fl oz/day while not decreasing other dairy consumption . Those in the intervention group with the lowest tertile of yogurt intake at baseline increased yogurt consumption by 2.8 fl oz/day ( P = .003 ) relative to controls with lowest intake . CONCLUSIONS Yogurt is likely to be a popular substitute for milk and could contribute to increased dairy intake among women if it were an option in WIC [21677054] BACKGROUND Maternal nutritional intake during pregnancy may have important consequences for long-term health in offspring . OBJECTIVE The objective was to follow up the offspring in 2 r and omized trials of nutrient supplementation during pregnancy to investigate the effect on cardiovascular disease ( CVD ) risk in offspring . DESIGN We recruited offspring born during 2 trials in The Gambia , West Africa . One trial provided protein-energy-dense food supplements ( 1015 kcal and 22 g protein/d ) to pregnant ( intervention , from 20 wk gestation until delivery ) or lactating ( control , for 20 wk from birth ) women and was r and omized at the village level . The second was a double-blind , individually r and omized , placebo-controlled trial of calcium supplementation ( 1.5 g/d ) , which was also provided from 20 wk gestation until delivery . RESULTS Sixty-two percent ( n = 1267 ) of children ( aged 11 - 17 y ) born during the protein-energy trial were recruited and included in the analysis , and 64 % ( n = 350 ) of children ( aged 5 - 10 y ) born during the calcium trial were recruited and included in the analysis . Fasted plasma glucose was marginally lower in children born to mothers receiving protein-energy supplements during pregnancy than in those children of the lactating group ( adjusted mean difference : -0.05 mmol/L ; 95 % CI : -0.10 , -0.001 mmol/L ) . There were no other differences in CVD risk factors , including blood pressure , body composition , and cholesterol , between children born to intervention and control women from the protein-energy trial . Maternal calcium supplementation during pregnancy was unrelated to offspring blood pressure . CONCLUSION These data suggest that providing supplements to pregnant women in the second half of pregnancy may have little effect on the CVD risk of their offspring , at least in this setting and at the ages studied here . This trial was registered at www.controlled-trials.com as IS RCT N96502494 [2985353] The study attempted to determine if the bulk of dietary supplements given to pregnant women after midgestation affects fetal growth . 127 Zulu women were r and omly assigned to four groups , two of which received daily food supplements design ed to raise their energy , protein and vitamin intakes to levels recommended by the U.S. Food and Nutrition Board . One of these supplements had a high bulk , the other a low bulk . The third supplement contained only zinc and the fourth a placebo . Women in all four groups had a similar weight gain and length of gestation . Birth weights were from 6.5 to 9.5 % greater with the low bulk than with the other supplements [6499715] Studies on nutritional supplementation of pregnant mothers have observed small but sometimes significant effects on fetal growth . Previously we also reported significant changes in physical resemblance of siblings at birth due to this kind of supplementation , using data collected by the late Dr. Bacon Chow and associates . This suggested that components of variation in physical growth may change as a result of supplementation . To explore this further , we sought the effects of nutritional supplementation on somatic growth , holding constant the birth measurements of a previous ( unsupplemented ) sibling . Only head circumference at birth came close to showing a statistically significant ( P less than 0.06 ) supplement effect on its mean ( + 0.36 cm ) when the measurement of the first infant was held constant . Both increases and decreases in weight for length as assessed by Rohrer 's Index ( wt/l3 ) occurred with supplementation . Increases in the index occurred by a significant ( P less than 0.01 ) gain in birth weight ( 238 g ) between 1st and 2nd siblings in the supplement group but not in the placebo group . Decreases in this index result ed from a significant gain in birth length ( 1.3 cm ) in supplemented families with a previous ( untreated ) sibling having a below average length for average weight . These non-linear effects on somatic growth suggest that responses to maternal nutritional supplementation may be more effective in a subgroup of the population where the normal adaptive responses to low energy protein intakes may have failed or where nutritional conditions over pregnancy may have varied considerably [13244366] THE Nutrition Study carried on at the Pennsylvania Hos­ pital from 1947 to 1952 was design ed to investigate the effect of the addition of protein and vitamin supple­ ments to the diets of pregnant women upon the outcome of their pregnancy and upon the physical status of their infants . The previous reports from the Study have dealt primarily with the first of these two questions , and it is with the second , the relationship between supplementation of the maternal diet and the physical status of the baby , that this report is concerned . Under the plan of the study , women coming to the Clinic of the Hospital during the first 16 weeks of pregnancy were re­ ferred to the Nutrition Clinic . There they were assigned to one of four groups , on a r and om basis controlled for race , age , and gravida . One group was design ated as the control and was given no nutritional supplement , a second group was given vitamins only , the third group a protein supplement only , and the fourth group was given both vitamins and the protein sup­ plement.4 Uniform diet instructions were given to the [7358235] Pregnant women at risk of malnutrition were enrolled in a health care programme in Colombia , South America , and were r and omly assigned to a group receiving supplementary food or to a control group at the beginning of the third trimester of pregnancy . There were no differences between the groups in social or nutritional variables [25516314] Many studies have demonstrated the efficacy of folic acid ( FA ) supplementation in prevention of neural tube defects ( NTDs ) , although the extent of NTDs varies among individuals of different races and ethnic origin . China is a multi-ethnic country with no st and ard practice for FA-fortified food . Milk is consumed by women , but little is known about the effects of milk on folate concentration in maternal blood and neonatal umbilical cord blood in Han and Mongolian women after stopping taking the supplement for a month and five month , respectively . The objective of this study was to determine whether only daily consumption of liquid milk can increase the blood folate concentration in pregnant women and whether there are differences in blood folate concentrations between Han and Mongolian women after cessation of FA supplementation . Of the 4052 women enrolled in the parallel group design study . Three thous and five hundred and twenty-six women had confirmed pregnancies and were r and omized to receive liquid milk or not until delivery . Women who consumed the liquid milk had significantly increased serum folate concentrations at 16 and 32 weeks of gestation as well as cord blood at birth compared to control groups in both ethnic groups . Infants born to women drinking milk also had better the term birth weight and height , which may be related to the increased concentration of folate . In conclusion , daily consumption of milk can increase the serum folate concentration in pregnant Han and Mongolian women in China ( differences in the efficacy of FA and milk supplementation ) and may enhance birth outcomes [6726837] This study assesses the effect of supplementation of energy and protein to meet the nutrient requirements of pregnant women in India on the basis of lactation performance and the nutritional status of the infant . 20 pregnant women between the ages of 20 - 23 belonging to a low socioeconomic group who were in their last trimester of pregnancy were selected . Out of 20 10 women were supplemented while the other 10 served as controls . The results reveal that the mean milk yield of supplemented women did not increase significantly ( P<0.05 ) when compared to that of control women during the 1st month of lactation suggesting that lactation potential may be the same in all women in the 1st month irrespective of inadequacies in food intake during the last trimester of pregnancy . The milk yield was significantly higher ( 307 g ) in supplemented women than that of controls in the 3rd month of lactation . Although no difference in weight gain was observed due to supplementation in pregnancy additional food intake supported lactation for a longer period . The birth weight and length of infants born to women who received the supplement were higher by 264 g and 1.81 cm respectively suggesting the effect of supplementary food . Supplementation also brought about a significant increase ( P<0.05 ) in hemoglobin levels which may be attributed to the contribution of iron and protein contained in the supplement . A comparison of length weight and arm circumference of infants in the present study during the 1st 3 months of infancy with those of Harvard st and ards revealed that the increments in these measurements were equal to those of the st and ards though the actual values were 90 - 95 % of Harvard st and ards in the case of the supplemented group and 80 - 85 % in the control group . From the investigation it can be concluded that dietary supplementation during the last trimester of pregnancy has beneficial effects on maternal hemoglobin levels and on morbidity lactation performance birth weight and the physical development of the infant [15345867] Objective : This study investigated the influence of modifying the maternal dietary fat on the serum lipids of infants at birth and at one year of age . Methods : This single-blind r and omized clinical trial was done on 180 4-month-pregnant women . All subjects proved to have a fat-unmodified diet through a 4-day food record dietary question naire . They were divided r and omly into two groups . The intervention group was kept on a fat-modified diet including saturated fatty acid ( SFA ) < 10 % , monounsaturated fatty acids : ( MUFA ) 10 - 5 % , polyunsaturated fatty acid ( PUFA ) upto 10 % and cholesterol < 300 mg/day with dietary advice for the pregnancy period . The control group was given only the latter advice . All subjects were followed up monthly . The serum lipids including total cholesterol ( T.cho ) , triglyceride ( TG ) , and HDL cholesterol ( HDL-C ) were analyzed through enzymatic methods . The level of LDL-cholesterol ( LDL-C ) was calculated by Friedewald formula . The comparison of mean cord and one-year-old infant serum lipids were done through unpaired T-test in two groups . Results : The mean level of T.cho in the intervention and control group was ( 70.3±15.9 , vs 81.4±17.2 , P<0.009 ) , TG ( 85.3 ± 16.7 vs 97.5 ± 18.2 , P<0.007 ) , LDL-C ( 27.8 ± 15.2 vs 34.8 ±17.1 , P<0.04 ) and non-HDL-C ( 44.5±7.2 vs 54.5 ± 8.1 , P<0.02 ) and in one year old infant the comparison of serum lipids were as follows . T.cho ( 145.7 ± 51.4 vs 161.4 + 56.2 , P<0.003 ) , TG ( 90.1 ± 31.8 vs 98.3 ± 33.1 , P<0.02 ) , LDL-C ( 85.6 ± 20.4 vs 92.3 ± 19.6 , P<0,05 ) and non-HDL-C ( 113.6 ± 30.2 vs 128.8 ± 34.8 , P<0.04 ) . However , there was no significant difference in HDL-C of both groups . Conclusion : There is a significant decrease of T.cho , TG , LDL-C and non-HDL-C levels with no significant increase of HDL-C in the intervention group with the fat-modified diet . Maternal fatmodified diet could be suitable way to prevent cardiovascular disease among infants from the beginning of the life [19793851] BACKGROUND Better early childhood nutrition improves schooling , adult health , skills , and wages , but there is little evidence regarding its effect on the next generation . OBJECTIVE We assessed whether nutritional supplementation in children aged < 7 to 15 y affected their children 's nutritional status 29 - 38 y later . DESIGN We studied 791 children 0 - 12 y who were offspring of 401 Guatemalan women who had participated as children in a nutritional supplementation trial in which 2 villages were r and omly assigned to receive a nutritious supplement ( atole ) and 2 were assigned to receive a less-nutritious supplement ( fresco ) . We compared anthropometric indicators between the offspring of mothers exposed to atole and the offspring of mothers exposed to fresco . RESULTS Compared with the offspring of women exposed to fresco , the offspring of women exposed to atole had a 116-g ( 95 % CI : 17 , 215 g ) higher birth weight , were 1.3-cm ( 0.4 , 2.2 cm ) taller , had a 0.6-cm ( 0.4 , 0.9 cm ) greater head circumference , had a 0.26 ( 0.09 , 0.43 ) greater height-for-age z score , and had a 0.20 ( 0.02 , 0.39 ) greater weight-for-age z score . The association for height differed by offspring sex . Sons of women exposed to atole were 2.0-cm ( 95 % CI : 1.0 , 3.1 cm ) taller than the sons of women exposed to fresco . Supplementation was not associated with 6 other offspring anthropometric indicators that reflect measures of adiposity . Supplementation in boys did not affect their children 's anthropometric measures . CONCLUSION Nutritional supplementation in girls is associated with substantial increases in their offsprings ' ( more for sons ) birth weight , height , head circumference , height-for-age z score , and weight-for-age z score Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND This is an up date of a Cochrane review first published in 2012 , Issue 4 . Excessive weight gain during pregnancy is associated with poor maternal and neonatal outcomes including gestational diabetes , hypertension , caesarean section , macrosomia , and stillbirth . Diet or exercise interventions , or both , may reduce excessive gestational weight gain ( GWG ) and associated poor outcomes ; however , evidence from the original review was inconclusive . OBJECTIVES To evaluate the effectiveness of diet or exercise , or both , interventions for preventing excessive weight gain during pregnancy and associated pregnancy complications . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

19057432

[16714767] BACKGROUND Optimal fluid management in patients with acute lung injury is unknown . Diuresis or fluid restriction may improve lung function but could jeopardize extrapulmonary-organ perfusion . METHODS In a r and omized study , we compared a conservative and a liberal strategy of fluid management using explicit protocol s applied for seven days in 1000 patients with acute lung injury . The primary end point was death at 60 days . Secondary end points included the number of ventilator-free days and organ-failure-free days and measures of lung physiology . RESULTS The rate of death at 60 days was 25.5 percent in the conservative- strategy group and 28.4 percent in the liberal- strategy group ( P=0.30 ; 95 percent confidence interval for the difference , -2.6 to 8.4 percent ) . The mean ( + /-SE ) cumulative fluid balance during the first seven days was -136+/-491 ml in the conservative- strategy group and 6992+/-502 ml in the liberal- strategy group ( P<0.001 ) . As compared with the liberal strategy , the conservative strategy improved the oxygenation index ( [ mean airway pressure x the ratio of the fraction of inspired oxygen to the partial pressure of arterial oxygen]x100 ) and the lung injury score and increased the number of ventilator-free days ( 14.6+/-0.5 vs. 12.1+/-0.5 , P<0.001 ) and days not spent in the intensive care unit ( 13.4+/-0.4 vs. 11.2+/-0.4 , P<0.001 ) during the first 28 days but did not increase the incidence or prevalence of shock during the study or the use of dialysis during the first 60 days ( 10 percent vs. 14 percent , P=0.06 ) . CONCLUSIONS Although there was no significant difference in the primary outcome of 60-day mortality , the conservative strategy of fluid management improved lung function and shortened the duration of mechanical ventilation and intensive care without increasing nonpulmonary-organ failures . These results support the use of a conservative strategy of fluid management in patients with acute lung injury . ( Clinical Trials.gov number , NCT00281268 [ Clinical Trials.gov ] . ) [8874303] OBJECTIVE To determine whether dexamethasone prevents postextubation airway obstruction in young children . DESIGN Prospect i ve , r and omized , double-blind , placebo-controlled study . SETTING Pediatric intensive care unit of a university teaching hospital . PATIENTS Sixty-six children , < 5 yrs of age , intubated and mechanically ventilated for > 48 hrs . INTERVENTIONS Patients were r and omized to receive intravenous dexamethasone ( 0.5 mg/kg , maximum dose 10 mg ) or saline , every 6 hrs for six doses , beginning 6 to 12 hrs before elective extubation . MEASUREMENTS AND MAIN RESULTS Dependent variables included the presence of stridor , Croup Score , and pulsus paradoxus at 10 mins , 6 , 12 , and 24 hrs after extubation ; need for aerosolized racemic epinephrine and reintubation . The dexamethasone and placebo groups were similar in age ( median 3 months [ range 1 to 57 ] vs. 4 months [ range 1 to 59 ] , p = .6 ) , frequency of underlying airway anomalies ( 3/33 vs. 3/33 , p = 1.0 ) , and duration of mechanical ventilation ( median 3.3 days [ range 2.1 to 39 ] vs. 3.5 days [ range 2.1 to 15 ] , p = .7 ) . The dexamethasone group had a lower frequency of stridor , Croup Score , and pulsus paradoxus measurement at 10 mins and at 6 and 12 hrs after extubation . Fewer dexamethasone-treated patients required epinephrine aerosol ( 4/31 vs. 22/32 , p < .0001 ) and reintubation ( 0/31 vs. 7/32 , p < .01 ) . Three patients exited the study early-one patient in the dexamethasone group had occult gastrointestinal hemorrhage and one patient in each group had hypertension . CONCLUSION Pretreatment with dexamethasone decreases the frequency of postextubation airway obstruction in children [9279224] A 2-h T-tube trial of spontaneous breathing was used in selecting patients ready for extubation and discontinuation of mechanical ventilation . However , some doubt remains as to whether it is the most appropriate method of performing a spontaneous breathing trial . We carried out a prospect i ve , r and omized , multicenter study involving patients who had received mechanical ventilation for more than 48 h and who were considered by their physicians to be ready for weaning according to clinical criteria and st and ard weaning parameters . Patients were r and omly assigned to undergo a 2-h trial of spontaneous breathing in one of two ways : with a T-tube system or with pressure support ventilation of 7 cm H2O . If a patient had signs of poor tolerance at any time during the trial , mechanical ventilation was reinstituted . Patients without these features at the end of the trial were extubated . Of the 246 patients assigned to the T-tube group , 192 successfully completed the trial and were extubated ; 36 of them required reintubation . Of the 238 patients in the group receiving pressure support ventilation , 205 were extubated and 38 of them required reintubation . The percentage of patients who remained extubated after 48 h was not different between the two groups ( 63 % T-tube , 70 % pressure support ventilation , p = 0.14 ) . The percentage of patients falling the trial was significantly higher when the T-tube was used ( 22 versus 14 % , p = 0.03 ) . Clinical evolution during the trial was not different in patients reintubated and successfully extubated . ICU mortality among reintubated patients was significantly higher than in successfully extubated patients ( 27 versus 2.6 % , p < 0.001 ) . Spontaneous breathing trials with pressure support or T-tube are suitable methods for successful discontinuation of ventilator support in patients without problems to resume spontaneous breathing [8727443] Objective To evaluate the accuracy of the initial negative inspiratory pressure ( PI ) to maximal negative inspiratory pressure ( PImax ) ratio in predicting extubation outcome for intubated infants and children . Design A prospect i ve study . Setting : Pediatric intensive care unit . Patients A sample of 50 stable intubated pediatric patients who were judged clinical ly ready for extubation . Methods Using a one-way valve , PI and PImax were measured in all patients , after which the ≦ ratioPI/PImax was calculated and its accuracy in predicting extubation outcome evaluated . Measurements and results A total of 39 patients ( 78 % ) were successfully extubated and 11 patients ( 22 % ) were not . The meanPI/PImax ratio was not significantly different between extubation successes ( 0.36±0.14 ) and failures ( 0.45±0.1 ) ( P>0.05 ) . The cut-off value of 0.3 forPI/PImax identified in adult patients did not discriminate between extubation success and failure in children . Furthermore , a discriminatory cut-off value other than 0.3 could not be identified for infants and children . Conclusion ThePI/PImax ratio can not be used to predict extubation outcome in pediatric patients . Indices that predict extubation outcome in adults should not be extrapolated to infants and children before testing and validation [12107682] Abstract Objective . To assess the accuracy of traditional weaning indices in predicting extubation failure , and to compare their accuracy when indices are measured at the onset of a breathing trial ( SBT ) and at the end of the SBT before extubation . Design . Prospect i ve study . Setting . Medical-surgical intensive care unit at a tertiary care hospital . Patients . Four hundred eighteen consecutive infants and children who received mechanical ventilation for at least 48 h and were deemed ready to undergo a SBT by their primary physician . Interventions . Respiratory frequency ( RR ) , tidal volume ( VT ) , maximal inspiratory pressure ( Pimax ) and frequency-to-tidal volume ratio ( f/VT ) were obtained within the first 5 min of breathing through a T-piece . The primary physicians were unaware of those measurements and the decision to extubate a patient was made by them . RR , VT , f/VT were remeasured before extubation by the respiratory therapists . Extubation failure was defined as needing re intubation within 48 h after extubation . The area under the receiver operating characteristic ( ROC ) curve was calculated for each index as a measure of the accuracy in predicting extubation outcome . Measurements and main results . Three hundred twenty-three patients successfully underwent the SBT and were extubated , but 48 of them ( 14 % ) required re-intubation . The ROC curve for VT , RR , Pimax and f/VT measured within the first 5 min of breathing were 0.54 , 0.56 , 0.57 and 0.57 , respectively . The ROC curve did not increase significantly when the above indices were remeasured before extubation . Conclusions . In a population which had passed SBT , the ability of the traditional weaning indices to discriminate between children successfully extubated and children re-intubated is very poor [10793162] BACKGROUND Traditional approaches to mechanical ventilation use tidal volumes of 10 to 15 ml per kilogram of body weight and may cause stretch-induced lung injury in patients with acute lung injury and the acute respiratory distress syndrome . We therefore conducted a trial to determine whether ventilation with lower tidal volumes would improve the clinical outcomes in these patients . METHODS Patients with acute lung injury and the acute respiratory distress syndrome were enrolled in a multicenter , r and omized trial . The trial compared traditional ventilation treatment , which involved an initial tidal volume of 12 ml per kilogram of predicted body weight and an airway pressure measured after a 0.5-second pause at the end of inspiration ( plateau pressure ) of 50 cm of water or less , with ventilation with a lower tidal volume , which involved an initial tidal volume of 6 ml per kilogram of predicted body weight and a plateau pressure of 30 cm of water or less . The primary outcomes were death before a patient was discharged home and was breathing without assistance and the number of days without ventilator use from day 1 to day 28 . RESULTS The trial was stopped after the enrollment of 861 patients because mortality was lower in the group treated with lower tidal volumes than in the group treated with traditional tidal volumes ( 31.0 percent vs. 39.8 percent , P=0.007 ) , and the number of days without ventilator use during the first 28 days after r and omization was greater in this group ( mean [ + /-SD ] , 12+/-11 vs. 10+/-11 ; P=0.007 ) . The mean tidal volumes on days 1 to 3 were 6.2+/-0.8 and 11.8+/-0.8 ml per kilogram of predicted body weight ( P<0.001 ) , respectively , and the mean plateau pressures were 25+/-6 and 33+/-8 cm of water ( P<0.001 ) , respectively . CONCLUSIONS In patients with acute lung injury and the acute respiratory distress syndrome , mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use [15671432] CONTEXT Despite evidence that patients with acute lung injury ( ALI ) have pulmonary surfactant dysfunction , trials of several surfactant preparations to treat adults with ALI have not been successful . Preliminary studies in children with ALI have shown that instillation of a natural lung surfactant ( calfactant ) containing high levels of surfactant-specific protein B may be beneficial . OBJECTIVE To determine if endotracheal instillation of calfactant in infants , children , and adolescents with ALI would shorten the course of respiratory failure . DESIGN , SETTING , AND PATIENTS A multicenter , r and omized , blinded trial of calfactant compared with placebo in 153 infants , children , and adolescents with respiratory failure from ALI conducted from July 2000 to July 2003 . Twenty-one tertiary care pediatric intensive care units participated . Entry criteria included age 1 week to 21 years , enrollment within 48 hours of endotracheal intubation , radiological evidence of bilateral lung disease , and an oxygenation index higher than 7 . Premature infants and children with preexisting lung , cardiac , or central nervous system disease were excluded . INTERVENTION Treatment with intratracheal instillation of 2 doses of 80 mL/m2 calfactant or an equal volume of air placebo administered 12 hours apart . MAIN OUTCOME MEASURES Ventilator-free days and mortality ; secondary outcome measures were hospital course , adverse events , and failure of conventional mechanical ventilation . RESULTS The calfactant group experienced an acute mean ( SD ) decrease in oxygenation index from 20 ( 12.9 ) to 13.9 ( 9.6 ) after 12 hours compared with the placebo group 's decrease from 20.5 ( 14.7 ) to 15.1 ( 9.0 ) ( P = .01 ) . Mortality was significantly greater in the placebo group compared with the calfactant group ( 27/75 vs 15/77 ; odds ratio , 2.32 ; 95 % confidence interval , 1.15 - 4.85 ) , although ventilator-free days were not different . More patients in the placebo group did not respond to conventional mechanical ventilation . There were no differences in long-term complications . CONCLUSIONS Calfactant acutely improved oxygenation and significantly decreased mortality in infants , children , and adolescents with ALI although no significant decrease in the course of respiratory failure measured by duration of ventilator therapy , intensive care unit , or hospital stay was observed [1356176] Many studies have attempted to find out whether steroid treatment is beneficial in children with croup , but the results have been inconclusive . We have done a prospect i ve placebo-controlled study of the effect of prednisolone on two clinical endpoints -- the duration of intubation and the need for reintubation . Reasons for exclusion were age under 6 months , congenital airway anomalies , and previous intubation . 70 eligible children were r and omly assigned treatment with prednisolone 1 mg/kg ( n = 38 ) or placebo ( n = 32 ) every 12 h given by nasogastric tube until 24 h after extubation . 11 ( 34 % ) placebo-treated and only 2 ( 5 % ) prednisolone-treated patients required reintubation after accidental or elective extubation ( p = 0.004 , Fisher 's exact test ; odds ratio 8.9 , 95 % confidence interval 1.7 - 59.3 ) . Survival analysis with log-normal regression showed that the duration of intubation was shorter with steroid therapy ( p less than 0.003 ) and increasing age ( p less than 0.02 ) , but was not influenced by endotracheal tube size or abnormality on chest radiograph . The median duration of intubation was 138 ( 95 % CI 118 - 160 ) h in children who received placebo and 98 ( 85 - 113 ) h in the prednisolone group . Steroid therapy reduces the duration of intubation and the need for reintubation in children intubated for croup [16446601] Objective : To develop and test the reliability and validity of the State Behavioral Scale for use in describing sedation/agitation levels in young intubated patients supported on mechanical ventilation . Design : In this prospect i ve , psychometric evaluation , pairs of trained pediatric critical care nurse evaluators simultaneously and independently assessed a convenience sample of pediatric intensive care unit patients along eight state/behavioral dimensions and a numeric rating scale ( NRS ) of 0 ( extremely se date d ) to 10 ( extremely agitated ) . The eight dimensions were derived from the sedation/agitation literature and expert opinion and included respiratory drive , response to ventilation , coughing , best response to stimulation , attentiveness to careprovider , tolerance to care , consolability , and movement after consoled , each with 3–5 levels . Setting : An 18-bed pediatric medical – surgical intensive care unit and 26-bed pediatric cardiovascular intensive care unit in a university-affiliated academic children ’s hospital . Patients : A total of 91 intubated mechanically ventilated patients 6 wks to 6 yrs of age provided a median of two observations ( interquartile range , 1–3 ) for a total of 198 sets of observations . Excluded were postoperative patients or those receiving neuromuscular blockade . Interventions : Patients were observed for 1 min , and then incremental levels of stimulation were applied until patient response . After 2 mins of consoling , the state behavioral assessment and NRS were completed . Measurements : Weighted kappa and intraclass coefficients were generated to assess interrater reliability of the eight dimension and NRS ratings . Distinct state behavior profiles were empirically identified from the dimension ratings using hierarchical cluster analysis using a squared Euclidean distance measure and between-groups linkage . Construct validity of these profiles was assessed by comparing group mean NRS scores using one-way analysis of variance . Main Results : Weighted kappa scores for all 198 dimension ratings ranged from .44 to .76 , indicating moderate to good interrater reliability . The intraclass coefficient of .79 was high for NRS ratings . Cluster analysis revealed five distinct state profiles , with mean NRS ratings of 1.1 , 2.5 , 4.0 , 5.3 , and 7.6 , all of which differed significantly from each other ( F = 75.8 , p < .001 ) , supporting the profiles ’ construct validity . Conclusions : Based on empirically derived state behavior profiles , we have constructed the State Behavioral Scale to allow systematic description of the sedation – agitation continuum in young pediatric patients supported on mechanical ventilation . Further studies including prospect i ve validation and describing the effect of State Behavioral Scale implementation on clinical outcomes , including the quality of sedation and length of mechanical ventilation , are warranted [15673313] BACKGROUND Critical illness leading to multi-organ dysfunction syndrome ( MODS ) and associated acute renal failure ( ARF ) is less common in children compared to adult patients . As a result , many issues plague the pediatric ARF outcome literature , including a relative lack of prospect i ve study , a lack of modality stratification in subject population s and inconsistent controls for patient illness severity in outcome analysis . METHODS We now report data from the first multicenter study to assess the outcome of pediatric patients with MODS receiving continuous renal replacement therapy ( CRRT ) . One hundred twenty of 157 Registry patients ( 63 male/57 female ) experienced MODS during their course . RESULTS One hundred sixteen patients had complete data available for analysis . The most common causes leading to CRRT were sepsis ( N= 47 ; 39.2 % ) and cardiogenic shock ( N= 24 ; 20 % ) . Overall survival was 51.7 % . Pediatric Risk of Mortality ( PRISM 2 ) score , central venous pressure ( CVP ) , and % fluid overload ( % FO ) at CRRT initiation were significantly lower for survivors versus nonsurvivors . Multivariate analysis controlling for severity of illness using PRISM 2 at CRRT initiation revealed that%FO was still significantly lower for survivors versus nonsurvivors ( P < 0.05 ) even for patients receiving both mechanical ventilation and vasoactive pressors . We speculate that increased fluid administration from PICU admission to CRRT initiation is an independent risk factor for mortality in pediatric patients with MODS receiving CRRT . CONCLUSION We suggest that after initial resuscitative efforts , an increased emphasis should be placed on early initiation of CRRT and inotropic agent use over fluid administration to maintain acceptable blood pressure [11046212] Background Patient-triggered ventilation ( PTV ) is commonly used in adults to avoid dyssynchrony between patient and ventilator . However , few investigations have examined the effects of PTV in infants . Our objective was to determine if pressure-control PTV reduces infants ’ respiratory workloads in proportion to the level of pressure control . We also explored which level of pressure control provided respiratory workloads similar to those after the extubation of the trachea . Methods When seven post – cardiac surgery infants , aged 1 to 11 months , were to be weaned with the pressure-control PTV , we r and omly applied five levels of pressure control : 0 , 4 , 8 , 12 , and 16 cm H2O . All patients were ventilated with assist – control mode , triggering sensitivity of 1 l/min , and positive end-expiratory pressure of 3 cm H2O . After establishing steady state conditions at each level of pressure control , arterial blood gases were analyzed and esophageal pressure ( Pes ) , airway pressure , and airflow were measured . Inspiratory work of breathing ( WOB ) was calculated using a Campbell diagram . A modified pressure – time product ( PTPmod ) and the negative deflection of Pes were calculated from the Pes tracing below the baseline . The measurement was repeated after extubation . Results Pressure-control PTV supported every spontaneous breath . By decreasing the level of pressure control , respiratory rate increased , tidal volume decreased , and as a result , minute ventilation and arterial carbon dioxide partial pressure were maintained stable . The WOB , PTPmod , and negative deflection of Pes increased as pressure control level was decreased . The WOB and PTPmod at 4 cm H2O pressure control and 0 cm H2O pressure control and after extubation were significantly greater than those at the pressure control of 16 , 12 , and 8 cm H2O ( P < 0.05 ) . The WOB and PTPmod were almost equivalent after extubation and at 4 cm H2O pressure control . Conclusions Work of breathing and PTPmod were changed according to the pressure control level in post – cardiac surgery infants . PTV may be feasible in infants as well as in adults [8162750] This prospect i ve study compared two weaning modalities in COPD patients requiring mechanical ventilation ( MV ) for acute respiratory failure . Nineteen patients with COPD were studied when their precipitating illness was controlled . Although they satisfied the conventional bedside weaning criteria , they could not tolerate any reduction in the respirator rate below 10 cycles/min . At this time , patients were r and omized into two groups receiving either synchronized intermittent m and atory ventilation ( SIMV ) with pressure support ventilation ( PSV ) ( group 1 ) or SIMV alone ( group 2 ) . The volumetric support of ventilation ( SIMV rate ) was progressively decreased in both groups according to the patient 's tolerance with a concurrent decrease in the barometric support of ventilation ( PSV levels from 15 cm H2O to 6 cm H2O ) . At each step of SIMV rate , we found no difference between group 1 and group 2 in arterial blood gases , blood pressure , heart rate , airway occlusion pressure , maximal inspiratory pressure , and oxygen cost of breathing ( OCB ) . At each step , however , group 1 patients showed significantly higher spontaneous tidal volume and lower spontaneous breathing frequency than did group 2 patients . We found a slight but not significant tendency to a shorter weaning period with than without PSV , but no difference in the weaning success . We concluded that ( 1 ) conventional weaning criteria might be inaccurate in COPD patients , ( 2 ) SIMV appeared very useful in weaning COPD patients from MV , ( 3 ) PSV marginally reduced the weaning period when added to SIMV , and ( 4 ) the OCB was not significantly improved with PSV [11463367] OBJECTIVE Compare outcomes between physician-directed and protocol -directed weaning from mechanical ventilation in pediatric patients . DESIGN Prospect ive-r and omized . SETTING Pediatric and cardiac intensive care units in a 307-bed tertiary referral hospital for children . INTERVENTIONS The control group ( physician-directed ) was weaned according to individual physician order for reduction in minute ventilation , positive end-expiratory pressure , and ordered oxygen saturation parameters for reduction in fraction of inspired oxygen ( F(IO)(2 ) ) . The study group ( protocol -directed ) was weaned according to a predetermined algorithm developed for the purpose of this investigation . METHODS The study enrolled 223 patients ( 116 physician-directed , 107 protocol -directed ) . All patients were monitored for hemodynamics , ventilator parameters , arterial blood gas values when available , oxygen saturation , weaning time , pre-weaning time , extubation time , and time on F(IO)(2 ) > or = 0.40 . We also monitored the incidence of reintubation , subglottic stenosis , tracheitis , and pneumonia . The protocol -directed group had additional measurements of actual versus predicted minute volume , comparisons of respiratory rate ( actual versus predicted for age ) , and presence of spontaneous breathing effort for 10 consecutive minutes . Data analysis was done according to intent to treat . RESULTS There was no significant difference in 12-hour and 24-hour pediatric risk of mortality ( PRISM III ) scores between groups . The protocol -directed group overall had shorter total ventilation time , weaning time , pre-weaning time , time to extubation , and time on F(IO)(2 ) > 0.40 , although after stratification for respiratory diagnosis , only the difference in weaning time remained significant . There was no difference in the incidence of reintubation , new-onset tracheitis , subglottic stenosis , or pneumonia . CONCLUSIONS Protocol -directed weaning result ed in a shorter weaning time than physician-directed weaning in these pediatric patients [10390384] Prolonged duration of endotracheal mechanical ventilation ( ETMV ) is associated with an increased morbidity and mortality in intensive care unit ( ICU ) patients . The aim of this study was to assess the usefulness of noninvasive ventilation ( NIV ) as a systematic extubation and weaning technique to reduce the duration of ETMV in acute-on-chronic respiratory failure ( ACRF ) . Among 53 consecutively intubated patients admitted for ACRF , we conducted a prospect i ve , r and omized controlled trial of weaning in 33 patients who failed a 2-h T-piece weaning trial ( 2 h-WT ) although they met simple criteria for weaning . Conventional invasive pressure support ventilation ( IPSV ) was used as the control weaning technique in 16 patients ( IPSV group ) , and NIV was applied immediately after extubation in 17 patients ( NIV group ) . The two weaning groups were similar for type of chronic respiratory failure ( CRF ) , pulmonary function data , age , Simplified Acute Physiology Score ( SAPS II ) , and severity of ACRF on admission . The characteristics of the two groups were also similar at r and omization . In the IPSV group , 12 of 16 patients ( 75 % ) were successfully weaned and extubated , versus 13 of 17 ( 76.5 % ) in the NIV group ( p = NS ) . NIV like IPSV significantly and similarly improved gas exchange in relation to that achieved during 2 h-WT ( p < 0.05 ) . The duration of ETMV was significantly shorter in the NIV ( 4.56 + /- 1.85 d ) than in the IPSV group ( 7.69 + /- 3.79 d ) ( p = 0 . 004 ) . NIV also reduced the mean period of daily ventilatory support , but increased the total duration of ventilatory support related to weaning ( 3.46 + /- 1.42 d , versus 11.54 + /- 5.24 d with NIV ; p = 0 . 0001 ) . Most patients in the IPSV group developed complications related to ETMV and /or the weaning process , but the difference was not significant ( nine of 16 versus six of 17 ) . The duration s of ICU and hospital stays and the 3-mo survival were similar in the two groups . In conclusion , NIV permits earlier removal of the endotracheal tube than with conventional IPSV , and reduces the duration of daily ventilatory support without increasing the risk of weaning failures . NIV should be considered as a new and useful systematic approach to weaning in patients with ACRF who are difficult to wean [16014597] CONTEXT In uncontrolled clinical studies , prone positioning appeared to be safe and to improve oxygenation in pediatric patients with acute lung injury . However , the effect of prone positioning on clinical outcomes in children is not known . OBJECTIVE To test the hypothesis that at the end of 28 days infants and children with acute lung injury treated with prone positioning would have more ventilator-free days than those treated with supine positioning . DESIGN , SETTING , AND PATIENTS Multicenter , r and omized , controlled clinical trial conducted from August 28 , 2001 , to April 23 , 2004 , of 102 pediatric patients from 7 US pediatric intensive care units aged 2 weeks to 18 years who were treated with supine vs prone positioning . R and omization was concealed and group assignment was not blinded . INTERVENTION Patients were r and omized to either supine or prone positioning within 48 hours of meeting acute lung injury criteria , with those patients in the prone group being positioned within 4 hours of r and omization and remaining prone for 20 hours each day during the acute phase of their illness for a maximum of 7 days , after which they were positioned supine . Both groups were treated using lung protective ventilator and sedation protocol s , extubation readiness testing , and hemodynamic , nutrition , and skin care guidelines . MAIN OUTCOME MEASURE Ventilator-free days to day 28 . RESULTS The trial was stopped at the planned interim analysis on the basis of the prespecified futility stopping rule . There were no differences in the number of ventilator-free days between the 2 groups ( mean [ SD ] , 15.8 [ 8.5 ] supine vs 15.6 [ 8.6 ] prone ; mean difference , -0.2 days ; 95 % CI , -3.6 to 3.2 ; P = .91 ) . After controlling for age , Pediatric Risk of Mortality III score , direct vs indirect acute lung injury , and mode of mechanical ventilation at enrollment , the adjusted difference in ventilator-free days was 0.3 days ( 95 % CI , -3.0 to 3.5 ; P = .87 ) . There were no differences in the secondary end points , including proportion alive and ventilator-free on day 28 ( P = .45 ) , mortality from all causes ( P>.99 ) , the time to recovery of lung injury ( P = .78 ) , organ-failure-free days ( P = .88 ) , and cognitive impairment ( P = .16 ) or overall functional health ( P = .12 ) at hospital discharge or on day 28 . CONCLUSION Prone positioning does not significantly reduce ventilator-free days or improve other clinical outcomes in pediatric patients with acute lung injury [16228176] Objective To compare the pressure-rate products and phase angles of children during minimal support ventilation and after extubation . Design and setting Prospect i ve , r and omized single-center trial in a pediatric intensive care unit in a tertiary children ’s hospital . Methods Seventeen endotracheally intubated , mechanically ventilated children were placed on T-piece , T-piece with heliox , continuous positive airway pressure , and pressure support in r and om order . Esophageal pressure swings , phase angles , respiratory mechanics , and physiological parameters were measured on these modes and after extubation . Measurements and results Pressure-rate product postextubation was significantly higher than on support modes . For each mode and after extubation they were : pressure support 198±31 , continuous positive airway pressure 237±30 , T-piece 323±47 , T-piece/heliox 308±61 , and extubation 378±43 cmH2O/min . Phase angles were significantly higher during T-piece ventilation than pressure support but not did not differ significantly from postextubation . Conclusions Assessment of effort of breathing during even minimal mechanical ventilation may underestimate postextubation effort in children . Postextubation pressure-rate product and hence “ effort of breathing ” in children is best approximated by T-piece ventilation [10556121] Objective criteria to predict extubation outcome in mechanically ventilated children are not available . Our goal was to study factors associated with extubation success and to evaluate the usefulness of the rapid shallow breathing index ( RSBI ) and the compliance , resistance , oxygenation , and pressure index ( CROP index ) in children . Data were prospect ively collected on 227 mechanically ventilated children . Patients successfully extubated had significantly better lung compliance ( Cdyn : 0.59 + /- 0.91 versus 0.39 + /- 0.14 ml/kg/cm H(2)O ) , higher Pa(O(2))/FI(O(2 ) ) ratio ( 382.4 + /- 181.2 versus 279.8 + /- 93.9 ) , and lower Pa(CO(2 ) ) ( 41.3 + /- 6.7 versus 47.3 + /- 8.5 mm Hg ) . Spontaneous breathing parameters showed significantly lower respiratory rates ( RR ) ( 36.6 + /- 17.9 versus 52.8 + /- 23 breaths/min ) , larger tidal volumes ( VT ) ( 7.3 + /- 2.6 versus 4.9 + /- 1.8 ml/kg ) , and greater muscle strength ( negative inspiratory force [ NIF ] : 41.8 + /- 15.4 versus 35.1 + /- 12.5 cm H(2)O ) in successfully extubated children . Extubation failures had higher RSBIs and lower CROP index values . A RSBI value of < /= 8 breaths/ml/kg had a sensitivity of 74 % and specificity of 74 % , whereas a CROP value of > /= 0.15 ml/kg/breaths/min had a sensitivity of 83 % and specificity of 53 % for extubation success . Children failing extubation demonstrate abnormalities of respiratory function . The RSBI and CROP index are useful to predict pediatric extubation success [10890660] Objective Using a modification of the Bohr equation , single-breath carbon dioxide capnography is a noninvasive technology for calculating physiologic dead space ( Vd/Vt ) . The objective of this study was to identify a minimal Vd/Vt value for predicting successful extubation from mechanical ventilation in pediatric patients . Design Prospect i ve , blinded , clinical study . Setting Medical and surgical pediatric intensive care unit of a university hospital . Patients Intubated children ranging in age from 1 wk to 18 yrs . Interventions None . Measurements and Main Results Forty-five patients were identified by the pediatric intensive care unit clinical team as meeting criteria for extubation . Thirty minutes before the planned extubation , each patient was begun on pressure support ventilation set to deliver an exhaled tidal volume of 6 mL/kg . After 20 mins on pressure support ventilation , an arterial blood gas was obtained , Vd/Vt was calculated , and the patient was extubated . Over the next 48 hrs , the clinical team managed the patient without knowledge of the preextubation Vd/Vt value . Of the 45 patients studied , 25 had Vd/Vt ≤0.50 . Of these patients , 24 of 25 ( 96 % ) were successfully extubated without needing additional ventilatory support . In an intermediate group of patients with Vd/Vt between 0.50 and 0.65 , six of ten patients ( 60 % ) successfully extubated from mechanical ventilation . However , only two of ten patients ( 20 % ) with a Vd/Vt ≥0.65 were successfully extubated . Logistic regression analysis revealed a significant association between lower Vd/Vt and successful extubation . Conclusions A Vd/Vt ≤0.50 reliably predicts successful extubation , whereas a Vd/Vt > 0.65 identifies patients at risk for respiratory failure following extubation . There appears to be an intermediate Vd/Vt range ( 0.51–0.65 ) that is less predictive of successful extubation . Routine Vd/Vt monitoring of pediatric patients may permit earlier extubation and reduce unexpected extubation failures [14605539] Objective To determine a contemporary failed extubation rate , risk factors , and consequences of extubation failure in pediatric intensive care units ( PICUs ) . Three hypotheses were investigated : a ) Extubation failure is in part disease specific ; b ) preexisting respiratory conditions predispose to extubation failure ; and c ) admission acuity scoring does not affect extubation failure . Design Twelve-month prospect i ve , observational , clinical study . Setting Sixteen diverse PICUs in the United States . Patients Patients were 2,794 patients from the newborn period to 18 yrs of age experiencing a planned extubation trial . Interventions None . Measurements and Main Results A descriptive statistical analysis was performed , and outcome differences of the failed extubation population were determined . The extubation failure rate was 6.2 % ( 174 of 2,794 ; 95 % confidence interval , 5.3–7.1 ) . Patient features associated with extubation failure ( p < .05 ) included age ≤24 months ; dysgenetic condition ; syndromic condition ; chronic respiratory disorder ; chronic neurologic condition ; medical or surgical airway condition ; chronic noninvasive positive pressure ventilation ; the need to replace the endotracheal tube on admission to the PICU ; and the use of racemic epinephrine , steroids , helium-oxygen therapy ( heliox ) , or noninvasive positive pressure ventilation within 24 hrs of extubation . Patients failing extubation had longer pre-extubation intubation time ( failed , 148.7 hrs , sd ± 207.8 vs. success , 107.9 hrs , sd ± 171.3 ; p < .001 ) , longer PICU length of stay ( 17.5 days , sd ± 15.6 vs. 7.6 days , sd ± 11.1 ; p < .001 ) , and a higher mortality rate than patients not failing extubation ( 4.0 % vs. 0.8 % ; p < .001 ) . Failure was found to be in part disease specific , and preexisting respiratory conditions were found to predispose to failure whereas admission acuity did not . Conclusion A variety of patient features are associated with an increase in extubation failure rate , and serious outcome consequences characterize the extubation failure population in PICUs [12209275] Abstract Objective . Laryngeal edema secondary to endotracheal intubation may require early re-intubation . Prior to extubation the absence of leak around an endotracheal tube may predict laryngeal edema after extubation . We evaluated the usefulness of a quantitative assessment of such a leak to identify the patients who will require early re-intubation for laryngeal edema . Methods . This prospect i ve study included 76 patients with endotracheal intubation for more than 12 h. The leak , in percent , was defined as the difference between expired tidal volume measured just before extubation , in volume-controlled mode , with the cuff inflated and then deflated . The best cut-off value to predict the need for re-intubation for significant laryngeal edema was determined and the patients were divided into two groups , according to this cut-off value . Results . Eight of the 76 patients ( 11 % ) needed re-intubation for laryngeal edema . Patients requiring re-intubation had a smaller leak than the other patients [ 9 ( 3–18 ) vs 35 (13–53)% , p<0.01 ] . The best cut-off value for gas leak was 15.5 % . The high leak group included 51 patients , of whom only two patients ( 3 % ) required re-intubation . The low leak group included 25 patients , among whom six patients ( 24 % ) required re-intubation ( p<0.01 ) . The sensitivity of this test was 75 % , the specificity 72.1 % , the positive predictive value 25 % , the negative predictive value 96.1 % and the percent of correct classification 72.4 % . Conclusions . A gas leak around the endotracheal tube greater than 15.5 % can be used as a screening test to limit the risk of re-intubation for laryngeal edema [10936141] STUDY OBJECTIVES ( 1 ) To determine the effect of a single ventilator management protocol ( VMP ) used in medical and surgical ICUs on the duration of mechanical ventilation . ( 2 ) To determine the effect of a VMP on the incidence of ventilator-associated pneumonia ( VAP ) . DESIGN Prospect i ve , r and omized , controlled study . SETTING : University medical center . PATIENTS Three hundred eighty-five patients receiving mechanical ventilation between June 1997 and May 1998 . INTERVENTIONS A respiratory care practitioner- and registered nurse-driven VMP . RESULTS Intervention and control groups were comparable with respect to age , sex , severity of illness and injury , and duration of respiratory failure at the time of r and omization . The duration of mechanical ventilation for patients was decreased from a median of 124 h for the control group to 68 h in the VMP group ( p = 0.0001 ) . Thirty-one total instances of VAP were noted . Twelve patients in the surgical control group had VAP , compared with 5 in the surgical VMP group ( p = 0.061 ) . The impact of the VMP on VAP frequency was less for medical patients . Mortality and ventilator discontinuation failure rates were similar between control and VMP groups . CONCLUSIONS A VMP design ed for multidisciplinary use was effective in reducing duration of mechanical ventilatory support without any adverse effects on patient outcome . The VMP was also associated with a decrease in incidence of VAP in trauma patients . These results , in conjunction with prior studies , suggest that VMPs are highly effective means of improving care , even in university ICUs [9840242] Objective : The development of weaning predictors in mechanically ventilated children has not been sufficiently investigated . The purpose of this study was to evaluate the accuracy of some weaning indices in predicting weaning failure . Design : Prospect i ve , interventional study . Setting : University-affiliated children 's hospital with a 19-bed intensive care unit . Patients : 84 consecutive infants and children requiring mechanical ventilation for at least 48 h and judged ready to wean by their primary physicians . Interventions : Patients who met the criteria to start weaning underwent a trial of spontaneous breathing lasting up to 2 h. Bedside measurements of respiratory function were obtained immediately before discontinuation of mechanical ventilation and within the first 5 min of spontaneous breathing . The primary physicians were blinded to those measurements , and the decision to extubate a patient at the end of the spontaneous breathing trial or reinstitute mechanical ventilation was made by them . Failure to wean was defined as the requirement for mechanical ventilation at any time during the trial of spontaneous breathing ( trial failure ) or needing reintubation within 48 h of extubation ( extubation failure ) . Measurements and main results : Seventy-five patients had neither signs of respiratory distress nor deterioration in gas exchange during the trial and were extubated . Twelve patients required reintubation within 48 h. In 9 patients , mechanical ventilation was reinstituted after a median duration of the spontaneous breathing trial of 35 min . The only independent predictor of trial failure was tidal volume indexed to body weight [ odds ratio 2.60 , 95 % confidence interval ( CI ) 1.40 to 24.9 ] . The only independent predictor of extubation failure was frequency-to-tidal volume ratio indexed to body weight ( odds ratio 1.23 , 95 % CI 1.11 to 1.36 ) . The sensitivity , specificity , and positive and negative predictive values to predict weaning failure were calculated for each of the above variables . These values were 0.48 , 0.86 , 0.53 , and 0.83 , respectively , for a frequency-to-tidal volume ratio higher than 11 breaths/min per ml per kg and 0.43 , 0.94 , 0.69 , and 0.83 , respectively , for a tidal volume lower than 4 ml/kg . Conclusions : Three-quarters of ventilated children can be successfully weaned after a trial of spontaneous breathing lasting 2 h. Both tidal volume and frequency-to-tidal volume ratio indexed to body weight were poor predictors of weaning failure in the study population [11093984] Work of breathing ( WOB ) increases during general anesthesia in adults , but such information has been limited in pediatric patients . We studied WOB in 24 healthy children ( mean age 2 ± 1.9 yrs ) , during elective urogenital surgery under 1 minimum alveolar anesthetic concentration halothane-nitrous oxide anesthesia with a caudal block while breathing spontaneously . WOB was measured with an esophageal balloon , miniature flowmeter , and a computerized ( Bicore ) system . In each patient , WOB was computed under four conditions : a mask without oral airway ( -AW ) , a mask with oral airway ( + AW ) , a laryngeal mask airway ( LMA ) , and an endotracheal tube ( ETT ) . With each apparatus WOB was studied both with continuous positive airway pressure ( CPAP ) ( 5–6 cm H2O ) and without CPAP ( or zero end-expiratory pressure [ ZEEP ] ) . Under ZEEP , WOB ( g · cm/kg ) among the four apparatus were ( mean ± sem ) : mask ( -AW ) ( 64 ± 19.2 ) > mask ( + AW ) ( 44 ± 17.2 ) , LMA ( 42 ± 15.6 ) > ETT ( 25.4 ± 12.4 ) ( P < 0.05 ) . WOB with CPAP significantly ( P < 0.05 ) decreased from WOB with ZEEP in three groups ( mask [ -AW ] , mask [ + AW ] , and LMA ) , but not in the ETT group . Tidal volume ( both ZEEP and CPAP ) and end-tidal Pco2 ( with CPAP only ) were significantly ( P < 0.05 ) decreased only in the ETT group , whereas no significant difference was found in respiratory rate or minute volume among the four airway apparatus groups , either with or without CPAP . The reduction in WOB , when breathing through ETT was primarily attributable to decreases in tidal volume and volume work . The finding that WOB decreases with CPAP in all groups except for the ETT group suggests that the decrease is a result of improved patency of the upper airway rather than of increases in functional residual capacity and lung compliance . Implication s We studied work of breathing ( WOB ) measured with four airway devices , with and without application of continuous positive airway pressure ( CPAP ) . Laryngeal mask airway and mask with oral airway decrease WOB compared with mask alone . CPAP decreases WOB with all devices except the endotracheal tube . Increased WOB appears mostly because of soft tissue upper airway obstruction [7823995] BACKGROUND Weaning patients from mechanical ventilation is an important problem in intensive care units . Weaning is usually conducted in an empirical manner , and a st and ardized approach has not been developed . METHODS We carried out a prospect i ve , r and omized , multicenter study involving 546 patients who had received mechanical ventilation for a mean ( + /- SD ) of 7.5 + /- 6.1 days and who were considered by their physicians to be ready for weaning . One hundred thirty patients had respiratory distress during a two-hour trial of spontaneous breathing . These patients were r and omly assigned to undergo one of four weaning techniques : intermittent m and atory ventilation , in which the ventilator rate was initially set at a mean ( + /- SD ) of 10.0 + /- 2.2 breaths per minute and then decreased , if possible , at least twice a day , usually by 2 to 4 breaths per minute ( 29 patients ) ; pressure-support ventilation , in which pressure support was initially set at 18.0 + /- 6.1 cm of water and then reduced , if possible , by 2 to 4 cm of water at least twice a day ( 37 patients ) ; intermittent trials of spontaneous breathing , conducted two or more times a day if possible ( 33 patients ) ; or a once-daily trail of spontaneous breathing ( 31 patients ) . St and ardized protocol s were followed for each technique . RESULTS The median duration of weaning was 5 days for intermittent m and atory ventilation ( first quartile , 3 days ; third quartile , 11 days ) , 4 days for pressure-support ventilation ( 2 and 12 days , respectively ) , 3 days for intermittent ( multiple ) trials of spontaneous breathing ( 2 and 6 days , respectively ) , and 3 days for a once-daily trial of spontaneous breathing ( 1 and 6 days , respectively ) . After adjustment for other covariates , the rate of successful weaning was higher with a once-daily trial of spontaneous breathing than with intermittent m and atory ventilation ( rate ratio , 2.83 ; 95 percent confidence interval , 1.36 to 5.89 ; P < 0.006 ) or pressure-support ventilation ( rate ratio , 2.05 ; 95 percent confidence interval , 1.04 to 4.04 ; P < 0.04 ) . There was no significant difference in the rate of success between once-daily trials and multiple trials of spontaneous breathing . CONCLUSIONS A once-daily trial of spontaneous breathing led to extubation about three times more quickly than intermittent m and atory ventilation and about twice as quickly as pressure-support ventilation . Multiple daily trials of spontaneous breathing were equally successful [8131469] The purpose of this study was to determine if a computer-directed weaning system could wean patients with complex medical problems from mechanical ventilation and appropriately respond to signs of respiratory failure more effectively than traditional physician-directed weaning methods . In a prospect i ve , r and omized , controlled study , we tested the system in 15 patients who had required prolonged mechanical ventilation and met predetermined weaning tests . Patients were r and omly assigned to one of two groups : ( 1 ) automatic , computer-directed weaning or ( 2 ) physician-controlled weaning . The computer-directed system decreased or increased the synchronized intermittent m and atory ventilation rate and pressure support ( PS ) based on predetermined limits of patient respiratory rate ( RR ) and tidal volume ( TV ) . Pulse oximeter oxygen saturation was monitored , and alarms were triggered by an oxygen saturation of < 90 percent . In the physician control group , weaning progressed with SIMV rate and PS reduction , as judged appropriate by the physician . Nine patients were assigned to the computer group ; six patients were assigned to the control group . The average patient age was 64.8 + /- 14.9 years for the computer group , 65.2 + /- 22.7 years for the control group . The average time on mechanical ventilation prior to weaning was 13.4 + /- 7.8 days for the computer group and 14.5 + /- 11.1 days for the control group . Seven of the nine computer group patients weaned within 48 h of the study , with an average time to wean of 18.7 + /- 5.9 h. All seven were breathing spontaneously 48 h after weaning . Two of the six control group patients weaned within 48 h of the study , with an average time of 25.6 + /- 5.6 h. Both patients who weaned were placed back on mechanical ventilation within 30 h. The number of arterial blood gas sample s drawn during the study was 1.4 + /- 0.7 for the computer group , 7.2 + /- 4.3 for the control group . The number of minutes per hour outside acceptable limits of RR > 30 , RR < 8 , or TV < 5 ml/kg was 3.2 + /- 2.8 min for the computer group and 6.6 + /- 4.1 min for the control group . The study suggests that use of the computer-directed weaning system results in fewer arterial blood gas sample s , shorter weaning times , and less time spent outside acceptable RR and TV parameters [17398307] BACKGROUND The efficacy of corticosteroids in reducing the incidence of postextubation laryngeal oedema is controversial . We aim ed to test our hypothesis that methylprednisolone started 12 h before a planned extubation could prevent postextubation laryngeal oedema . METHODS We did a placebo-controlled , double-blind multicentre trial in 761 adults in intensive-care units . Patients who were ventilated for more than 36 h and underwent a planned extubation received intravenous 20 mg methylprednisolone ( n=380 ) or placebo ( 381 ) 12 h before extubation and every 4 h until tube removal . The primary endpoint was occurrence of laryngeal oedema within 24 h of extubation . Laryngeal oedema was clinical ly diagnosed and deemed serious if tracheal reintubation was needed . Analyses were done on a per protocol and intention-to-treat basis . This trial is registered at Clinical Trials.gov , number NCT00199576 . FINDINGS 63 patients could not be assessed , mainly because of self-extubation ( n=16 ) or cancelled extubation ( 44 ) between r and omisation and planned extubation . 698 patients were analysed ( 343 in placebo group , 355 in methylprednisolone group ) . Methylprednisolone significantly reduced the incidence of postextubation laryngeal oedema ( 11 of 355 , 3%vs 76 of 343 , 22 % , p<0.0001 ) , the global incidence of reintubations ( 13 of 355 , 4%vs 26 of 343 , 8 % , p=0.02 ) , and the proportion of reintubations secondary to laryngeal oedema ( one of 13 , 8 % vs 14 of 26 , 54 % , p=0.005 ) . One patient in each group died after extubation , and atelectasia occurred in one patient given methylprednisolone . INTERPRETATION Methylprednisolone started 12 h before a planned extubation substantially reduced the incidence of postextubation laryngeal oedema and reintubation . Such pretreatment should be considered in adult patients before a planned extubation that follows a tracheal intubation of more than 36 [11685307] Abstract . Objective : To compare the percentage of infants and children successfully extubated after a trial of breathing performed with either pressure support or T-piece . Design : Prospect i ve and r and omized study . Setting : Three medical-surgical pediatric intensive care units ( PICUs ) . Patients : Two hundred fifty-seven consecutive infants and children who received mechanical ventilation for at least 48 h and were deemed ready to undergo a breathing trial by their primary physician . Interventions : Patients were r and omly assigned to undergo a trial of breathing in one of two ways : pressure support of 10 cmH2O or T-piece . Bedside measurements of respiratory function were obtained immediately before discontinuation of mechanical ventilation and within the first 5 min of breathing through a T-piece . The primary physicians were unaware of those measurements , and the decision to extubate a patient at the end of the breathing trial was made by them . Measurements and main results : Of the 125 patients in the pressure support group , 99 ( 79.2 % ) completed the breathing trial and were extubated , but 15 of them ( 15.1 % ) required reintubation within 48 h. Of the 132 patients in the T-piece group , 102 ( 77.5 % ) completed the breathing trial and were extubated , but 13 of them ( 12.7 % ) required reintubation within 48 h. The percentage of patients who remained extubated for 48 h after the breathing trial did not differ in the pressure support and T-piece groups ( 67.2 % versus 67.4 % , p=0.97 ) . Conclusions : In infants and children mechanically ventilated , successful extubation was achieved equally effectively after a first breathing trial performed with pressure support of 10 cmH2O or a T-piece [15269312] BACKGROUND Most patients requiring mechanical ventilation for acute lung injury and the acute respiratory distress syndrome ( ARDS ) receive positive end-expiratory pressure ( PEEP ) of 5 to 12 cm of water . Higher PEEP levels may improve oxygenation and reduce ventilator-induced lung injury but may also cause circulatory depression and lung injury from overdistention . We conducted this trial to compare the effects of higher and lower PEEP levels on clinical outcomes in these patients . METHODS We r and omly assigned 549 patients with acute lung injury and ARDS to receive mechanical ventilation with either lower or higher PEEP levels , which were set according to different tables of predetermined combinations of PEEP and fraction of inspired oxygen . RESULTS Mean ( + /-SD ) PEEP values on days 1 through 4 were 8.3+/-3.2 cm of water in the lower-PEEP group and 13.2+/-3.5 cm of water in the higher-PEEP group ( P<0.001 ) . The rates of death before hospital discharge were 24.9 percent and 27.5 percent , respectively ( P=0.48 ; 95 percent confidence interval for the difference between groups , -10.0 to 4.7 percent ) . From day 1 to day 28 , breathing was unassisted for a mean of 14.5+/-10.4 days in the lower-PEEP group and 13.8+/-10.6 days in the higher-PEEP group ( P=0.50 ) . CONCLUSIONS These results suggest that in patients with acute lung injury and ARDS who receive mechanical ventilation with a tidal-volume goal of 6 ml per kilogram of predicted body weight and an end-inspiratory plateau-pressure limit of 30 cm of water , clinical outcomes are similar whether lower or higher PEEP levels are used [9927366] The duration of spontaneous breathing trials before extubation has been set at 2 h in research studies , but the optimal duration is not known . We conducted a prospect i ve , multicenter study involving 526 ventilator-supported patients considered ready for weaning , to compare clinical outcomes for trials of spontaneous breathing with target duration s of 30 and 120 min . Of the 270 and 256 patients in the 30- and 120-min trial groups , respectively , 237 ( 87.8 % ) and 216 ( 84.8 % ) , respectively , completed the trial without distress and were extubated ( p = 0.32 ) ; 32 ( 13.5 % ) and 29 ( 13.4 % ) , respectively , of these patients required reintubation within 48 h. The percentage of patients who remained extubated for 48 h after a spontaneous breathing trial did not differ in the 30- and 120-min trial groups ( 75.9 % versus 73.0 % , respectively , p = 0.43 ) . The 30- and 120-min trial groups had similar within-unit mortality rates ( 13 and 9 % , respectively ) and in-hospital mortality rates ( 19 and 18 % , respectively ) . Reintubation was required in 61 ( 13.5 % ) patients , and these patients had a higher mortality ( 20 of 61 , 32.8 % ) than did patients who tolerated extubation ( 18 of 392 , 4.6 % ) ( p < 0.001 ) . Neither measurements of respiratory frequency , heart rate , systolic blood pressure , and oxygen saturation during the trial , nor other functional measurements before the trial discriminated between patients who required reintubation from those who tolerated extubation . In conclusion , after a first trial of spontaneous breathing , successful extubation was achieved equally effectively with trials targeted to last 30 and 120 min [9407568] Objective criteria for ending mechanical ventilation have not been established for infants and children . A recent study in adult patients developed two new indexes , the Rapid Shallow Breathing Index ( RSB ) and the CROP Index for predicting success or failure of extubation . We decided to evaluate the applicability of these indices to intubated , mechanically ventilated pediatric patients . For this evaluation the indices were adapted to the physiology of infants and children . A pneumotachograph was used to measure spontaneous tidal volume , respiratory rate and dynamic compliance . The tidal volume and the dynamic compliance were corrected for the patient 's body weight . Based on the data collected a cutoff value for each index was determined . Of 47 sets of patient data , 38 ( 81 % ) were collected during successful extubations , 9 ( 19 % ) during failed extubations . A modified CROP index value of > or = 0.1 ml x mmHg/bpm/kg and a modified RSB index value of < or = 11 bpm/mlkg were identified as predictive of successful extubation . The modified CROP cutoff value produced a sensitivity and specificity of 1.0 ; respective values for the modified RSB cutoff value are 0.79 and 0.78 . Cutoff values of > or = 0.1 and < or = 11 for the modified CROP index and RSB index , respectively , appear to be predictive of successful extubation in the pediatric population . Our data identifies the modified CROP index as a superior discriminator between successful and unsuccessful extubation [8797633] OBJECTIVE To predict extubation success and failure in mechanically ventilated infants and children using bedside measures of respiratory function . DESIGN Prospect i ve collection of data . SETTING A university-affiliated children 's hospital with a 51-bed critical care unit . PATIENTS All infants and children who were mechanically ventilated for at least 24 hrs , except neonates < or = 37 wks gestation and patients with neuromuscular disease . INTERVENTIONS Bedside measurements of cardiorespiratory function were obtained immediately before extubation . MEASUREMENTS AND MAIN RESULTS Extubation failure was defined as reintubation within 48 hrs of extubation in the absence of upper airway obstruction . Failure rates were calculated for different ranges ( selected a priori ) of preextubation measures of breathing effort , ventilatory support , respiratory mechanics , central inspiratory drive , and integrated indices useful in adults . Effort of spontaneous breathing was assessed by the respiratory rate st and ardized to age , the presence of retractions and paradoxical breathing , inspiratory pressure , maximal negative inspiratory pressure ( maximal negative inspiratory pressure ) , inspiratory pressure/maximal negative inspiratory pressure ratio , and tidal volume indexed to body weight of a spontaneous breath . Ventilatory support was measured by the fraction of inspired oxygen ( F10(2 ) ) , mean airway pressure , oxygenation index , and the fraction of total minute ventilation provided by the ventilator . Respiratory mechanics were assessed by determination of peak ventilatory inspiratory pressure and dynamic compliance . Central inspiratory drive was assessed by mean inspiratory flow . Frequency to tidal volume ratio and the compliance , rate , oxygenation , and pressure indexed to body weight , the integrated indices useful in predicting extubation failure in adults , were also calculated . Thirty-four of the 208 patients who were studied were reintubated for an overall failure rate of 16.3 % ( 95 % confidence interval 11.3 % to 21.4 % ) . The reasons for reintubation were poor effort ( n = 8) , excessive effort ( n = 14 ) , altered mental status or absent airway reflexes ( n = 2 ) , cardiovascular instability ( n = 3 ) , inadequate oxygenation ( n = 3 ) , respiratory acidosis ( n = 3 ) , and undocumented ( n = 1 ) . Extubation failure increased significantly with decreasing tidal volume indexed to body weight of a spontaneous breath , increasing F10(2 ) , increasing mean airway pressure , increasing oxygenation index , increasing fraction of total minute ventilation provided by the ventilator , increasing peak ventilatory inspiratory pressure , or decreasing mean inspiratory flow ( p < .05 ) . Dynamic compliance showed a trend of increasing failure rate with decreasing dynamic compliance but did not reach statistical significance ( p = .116 ) . Respiratory rate st and ardized to age , inspiratory pressure , maximal negative inspiratory pressure , inspiratory pressure/maximal negative inspiratory pressure ratio , frequency to tidal volume ratio , and compliance , rate , oxygenation , and pressure did not show any trend in failure rate with increasing or decreasing values . Threshold values that defined a low risk ( < or = 10 % ) and a high risk ( > or = 25 % ) of extubation failure could be determined for tidal volume indexed to body weight of a spontaneous breath , F10(2 ) , mean airway pressure , oxygenation index , fraction of total minute ventilation provided by the ventilator , peak ventilatory inspiratory pressure , dynamic compliance , and mean inspiratory flow . Neither a low nor a high risk of failure could be defined for frequency to tidal volume ratio or the compliance , rate , oxygenation , and pressure ( CROP ) index . CONCLUSIONS Bedside measurements of respiratory function can predict extubation success and failure in infants and children . Both a low risk and a high risk of failure can be determined using these measures . Integrated indices useful in adults do not reliably predict extubation success or failure [15857531] Objectives : To evaluate the hypotheses that children requiring reintubation are at an increased risk of prolonged hospitalizations , congenital heart disease , and death compared with age- and disease-severity-matched control patients . Design : Prospect i ve decision to evaluate all children undergoing extubation over a 5-yr time interval ( 1997–2001 ) with retrospective analysis of all failed extubation patients . Setting : A large multidisciplinary , dual-site , single-system pediatric intensive care unit caring for critically ill and injured children . Patients : All children intubated and ventilated during the study period ( 1997–2001 ) . Interventions : None . Measurements and Main Results : Failed extubation was defined as the unanticipated requirement to replace an endotracheal tube within 48 hrs of extubation . One hundred thirty children of 3,193 pediatric intensive care unit patients failed extubation ( 4.1 % ) . The median age of children who failed extubation was 6.5 months , compared with a median age of 21.3 months in the control population . The median age of failed extubation in children with cardiac disease was 9.3 months . Failed extubation patients had lengthier hospital and pediatric intensive care unit stays , longer duration of mechanical ventilation , and a higher rate of tracheostomy placement than nonfailed extubation patients ( p < .001 ) . Children with congenital heart disease who failed extubation had the longest duration of hospitalization ( 40.0 ± 5.4 days ) . Conversely , cardiac patients who did not fail extubation had the shortest length of stay ( 11.2 ± 0.4 days ) . Conclusions : In the present trial , 4.1 % of mechanically ventilated children failed extubation . Pediatric intensive care unit patients with failed extubation have longer hospital , pediatric intensive care unit , and ventilator courses but are not at increased risk of death relative to nonfailed extubation patients [1993963] To assess whether there is any advantage in the use of corticosteroid to prevent postextubation stridor in children , we conducted a prospect i ve , r and omized , double-blind trial of dexamethasone versus saline solution . The patients were evaluated and then r and omly selected to receive either dexamethasone or saline solution according to a stratification based on risk factors for postextubation stridor : age , duration of intubation , upper airway trauma , circulatory compromise , and tracheitis . Dexamethasone , 0.5 mg/kg , was given every 6 hours for a total of six doses beginning 6 to 12 hours before and continuing after endotracheal extubation in a pediatric intensive care setting . There was no statistical difference in incidence of postextubation stridor in the two groups ; 23 of 77 children in the placebo group and 16 of 76 in the dexamethasone group had stridor requiring therapy ( p = 0.21 ) . We conclude that the routine use of corticosteroids for the prevention of postextubation stridor during uncomplicated pediatric intensive care airway management is unwarranted [12163791] Objective Trials of potential new therapies in acute lung injury are difficult and expensive to conduct . This article is design ed to determine the utility , behavior , and statistical properties of a new primary end point for such trials , ventilator-free days , defined as days alive and free from mechanical ventilation . Describing the nuances of this outcome measure is particularly important because using it , while ignoring mortality , could result in misleading conclusions . Design To develop a model for the duration of ventilation and mortality and fit the model by using data from a recently completed clinical trial . To determine the appropriate test statistic for the new measure and derive a formula for power . To determine a formula for the probability that the test statistic will reject the null hypothesis and mortality will simultaneously show improvement . To plot power curves for the test statistic and determine sample sizes for reasonable alternative hypotheses . Setting Intensive care units . Patients Patients with acute respiratory distress syndrome or acute lung injury as defined by the American-European Consensus Conference . Main Results The proposed model fit the clinical data . Ventilator-free days were improved by lower tidal volume ventilation , but the improvement was mostly caused by the improved mortality rate , so trials that expected similar effects would only have modest increase in power if they used ventilator-free days as their primary end point rather than 28-day mortality . Similar results were obtained using the model in two groups segregated by low or high Acute Physiology and Chronic Health Evaluation score . On the other h and , if patients are divided into two groups on the basis of the lung injury score , both the duration of ventilation and mortality are lower in the low lung injury score group . A trial of a treatment that had a similar clinical effect would have a large increase in power , allowing for a reduction in the required sample size . Conclusions Use of ventilator-free days as a trial end point allows smaller sample sizes if it is assumed that the treatment being tested simultaneously reduces the duration of ventilation and improves mortality . It is unlikely that a treatment that led to higher mortality could lead to a statistically significant improvement in ventilator-free days . This would be especially true if the treatment were also required to produce a nominal improvement in mortality [15730603] Objective : To describe the incidence of extubation failure and its associated risk factors among mechanically ventilated children . Method : Prospect i ve cohort study . Children who were mechanically ventilated for longer than 12 hrs were followed up to 48 hrs after extubation . Cases of upper airway obstruction , accidental extubation , tracheostomy , or death before extubation were excluded . Extubation failure was defined as reintubation within 48 hrs after extubation . Student ’s t-test , Mann-Whitney , and chi-squared tests , odds ratio with 95 % confidence interval , and multivariate analysis were used for data analysis . Results : Extubation failure rate was 10.5 % ( 13 of 124 patients ) . Variables associated with extubation failure were age between 1 and 3 mos ( odds ratio [ OR ] = 5.68 ; 95 % confidence interval [ CI ] = 1.58–20.42 ) , mechanical ventilation > 15 days ( OR = 6.36 ; 95 % CI = 1.32–30.61 ) , mean oxygenation index ( OI ) > 5 ( OR = 4.08 ; 95 % CI = 1.25–13.30 ) , mean airway pressure 24 hrs before extubation lower than 5 cm H2O ( OR = 6.03 ; 95 % CI = 1.48–24.60 ) , continuous positive airway pressure ( CPAP ) ( OR = 4.71 ; 95 % CI = 1.34–16.58 ) , dopamine and dobutamine use ( OR = 3.71 ; 95 % CI = 1.08–12.78 ) , intravenous sedation > 10 days ( OR = 6.60 ; 95 % CI = 1.62–26.90 ) , tachypnea and subcostal retractions ( relative risk [ RR ] = 3.68 ; 95 % CI = 1.14–11.93 ) , and inspired fraction of oxygen (Fio2)>0.4 after extubation ( RR = 3.63 ; 95 % CI = 1.21–10.88 ) . After multiple logistic regression analysis , age between 1 and 3 mos , mean OI > 5 , CPAP and mechanical ventilation > 15 days remained associated with extubation failure . Conclusion : Extubation failure was more frequent among young infants who received prolonged ventilatory support and intravenous sedation , used CPAP , had impaired lung oxygenation , and required inotropic therapy [7921460] Several modalities of ventilatory support have been proposed to gradually withdraw patients from mechanical ventilation , but their respective effects on the outcome of weaning from mechanical ventilation are not known . We conducted a r and omized trial in three intensive care units in mechanically ventilated patients who met st and ard weaning criteria . Those who could not sustain 2 h of spontaneous breathing were r and omly assigned to be weaned with T-piece trials , with synchronized intermittent m and atory ventilation ( SIMV ) , or with pressure support ventilation ( PSV ) . Specific criteria for performing tracheal extubation were defined for each modality . The number of patients who could not be separated from the ventilator at 21 d ( i.e. , who failed to wean ) was compared between the groups . Patients in whom tracheal intubation was required in a 48-h period following extubation were also classified as failures . Among 456 mechanically ventilated patients who met weaning criteria , 109 entered into the study ( 35 with T piece , 43 with SIMV , and 31 with PSV ) . The three groups were comparable in terms of etiology of disease or characteristics at entry in the study . When all causes for weaning failure were considered , a lower number of failures was found with PSV than with the other two modes , with the difference just reaching the level of significance ( 23 % for PSV , 43 % for T piece , 42 % for SIMV ; p = 0.05 ) . After excluding patients whose weaning was terminated for complications unrelated to the weaning process , the difference became highly significant ( 8 % for PSV versus 33 % and 39 % , p < 0.025 ) . ( ABSTRACT TRUNCATED AT 250 WORDS [16738500] Objective : To assess the value of a spontaneous breathing trial ( SBT ) using a flow-inflating bag in predicting extubation success . Secondary goals were to evaluate the positive and negative predictive accuracy of a 15-min SBT . Design : Prospect i ve , blinded , clinical study . Setting : Pediatric intensive care unit ( ICU ) of a university hospital Patients : Infants and children intubated for ≥24 hrs . Interventions : Patients who met defined criteria for extubation underwent a 15-min SBT connected to a flow-inflating bag set to provide 5 cm H2O continuous positive airway pressure . Measurements and Main Results : Seventy patients underwent the SBT . Respiratory rate , heart rate , blood pressure , and pulse oxygen saturations were recorded at baseline and at 5 and 15 mins into the SBT . The ICU physicians were blinded to the results of the SBT , and all patients were extubated at the end of the trial . Patients were observed for the next 24 hrs , and the need for noninvasive ventilation or reintubation ( i.e. , extubation failure ) was recorded . Sixty-four patients ( 91 % ) passed the SBT with a subsequent extubation failure rate of 7.8 % ( only 1.6 % required reintubation ) . Six of the 70 ( 9 % ) patients enrolled failed the trial , but half were extubated successfully . Successful completion of the SBT has a 95 % sensitivity for predicting successful extubation with a positive predictive value of 92 % and an odds ratio of 12 ( 95 % confidence interval , 1.3 , 53.7 ) . The specificity of the SBT was 37 % with a negative predictive value of 50 % . Logistic regression analysis revealed a significant association between passing the SBT and extubation success ( p = .017 ) . Conclusions : A 15-min flow-inflating bag SBT represents a practical , reliable bedside test that has 95 % sensitivity for predicting extubation success in pediatric ICU patients . A trial failure is associated with but does not accurately predict extubation failure [2023603] BACKGROUND The traditional predictors of the outcome of weaning from mechanical ventilation -- minute ventilation ( VE ) and maximal inspiratory pressure (Plmax)--are frequently inaccurate . We developed two new indexes : the first quantitates rapid shallow breathing as the ratio of respiratory frequency to tidal volume ( f/VT ) , and the second is termed CROP , because it integrates thoracic compliance , respiratory rate , arterial oxygenation , and Plmax . METHODS The threshold values for each index that discriminated best between a successful and an unsuccessful outcome of weaning were determined in 36 patients , and the predictive accuracy of these values was then tested prospect ively in an additional 64 patients . Sensitivity and specificity were calculated , and the data were also analyzed with receiver-operating-characteristic ( ROC ) curves , in which the proportions of true positive results and false positive results are plotted against each other for a number of threshold values of an index ; the area under the curve reflects the accuracy of the index . RESULTS Sensitivity was highest for Plmax ( 1.00 ) , followed closely by the f/VT ratio ( 0.97 ) . Specificity was highest for the f/VT ratio ( 0.64 ) and lowest for Plmax ( 0.11 ) . The f/VT ratio was the best predictor of successful weaning , and Plmax and the f/VT ratio were the best predictors of failure . The area under the ROC curve for the f/VT ratio ( 0.89 ) was larger than that under the curves for the CROP index ( 0.78 , P less than 0.05 ) , Plmax ( 0.61 , P less than 0.001 ) , and VE ( 0.40 , P less than 0.001 ) . CONCLUSIONS Rapid shallow breathing , as reflected by the f/VT ratio , was the most accurate predictor of failure , and its absence the most accurate predictor of success , in weaning patients from mechanical ventilation [14697111] Objective Children undergoing congenital heart surgery require mechanical ventilation . We sought to identify pre- and intraoperative factors ( PrO , IO ) associated with successful early extubation < 24 hrs . Design and Patients We performed a retrospective chart review of children < 36 months old who underwent congenital heart surgery from January 1998 to July 1999 . Setting Pediatric intensive care unit in a children ’s hospital . Measurements Generalized Estimating Equation models were fit to assess the association between PrO and IO and early extubation while accounting for the correlation between surgeries performed on the same patient . Estimated odds ratios ( EOR ) and 95 % confidence intervals were calculated . Multivariable models were constructed using a forward selection process with inclusion criteria of p < .05 . Multivariable models , which included PrO and IO variables , were adjusted for procedure group . The area under the receiver operating characteristic curve was computed for each model . Results A total of 203 children underwent 219 surgeries ; 103 ( 47 % ) children were extubated in < 24 hrs , with only one ( 1 % ) failed extubation . PrO variables associated with successful early extubation included age > 6 months ( EOR , 6.1 ) , absence of pulmonary hypertension ( EOR , 9.1 ) , gestational age > 36 wks ( EOR , 4.6 ) , and absence of congestive heart failure ( EOR , 2.4 ) . IO variables were less likely to be associated with successful early extubation . Our model of PrO variables with multiple factors showed that presence of two factors was associated with an EOR of 4.2 for successful early extubation compared with children with zero or one factor . Presence of three and four factors was associated with an EOR of 18.0 and 76.5 , respectively . The area under the receiver operating characteristic curve for this model is 0.816 . Incision type , complex vs. simple procedure , and palliative vs. complete repair were not associated with success of early extubation . Conclusions Early extubation is possible in many very young children undergoing congenital heart surgery , with a low rate of failed extubation . The model would be improved by prospect i ve validation with larger numbers at multiple institutions [15286557] Objective : Continuous venovenous hemofiltration ( CVVH ) is used for renal replacement and fluid management in critically ill children . A previous small study suggested that survival was associated with less percent fluid overload ( % FO ) in the intensive care unit ( ICU ) before hemofiltration . We review ed our experience with a large series of pediatric CVVH patients to evaluate factors associated with outcome . Design : Retrospective chart review . Setting : Tertiary children ’s hospital . Patients : CVVH pediatric ICU patients from November 1997 to January 2003 . Interventions : None . Measurements and Main Results : % FO was defined as total fluid input minus output ( up to 7 days before CVVH for both hospital stay and ICU stay ) divided by body weight . One hundred thirteen patients received CVVH ; 69 survived ( 61 % ) . Multiple organ dysfunction syndrome ( MODS ) was present in 103 patients ; 59 survived ( 57 % ) . Median patient age was 9.6 yrs ( 25th , 75th percentile : 2.5 , 14.3 ) . Median % FO was significantly lower in survivors vs. nonsurvivors for all patients ( 7.8 % [ 2.0 , 16.7 ] vs. 15.1 % [ 4.9 , 25.9 ] ; p = .02 ] and in patients with ≥3-organ MODS ( 9.2 % [ 5.1,16.7 ] vs. 15.5 % [ 8.3 , 28.6 ] ; p = .01 ) . The Pediatric Risk of Mortality Score III at CVVH initiation also was associated with survival in these groups , but by multivariate analysis , % FO was independently associated with survival in patients with ≥3-organ MODS ( p = .01 ) . Conclusions : Survival in critically ill children receiving CVVH in this large series was higher than in previous reports . CVVH survival may be associated with less % FO in patients with ≥3-organ MODS . Prospect i ve studies are necessary to determine whether earlier use of CVVH to control fluid overload in critically ill children can improve survival [17693913] Objective : To evaluate the applicability , tolerance , and efficacy of a closed-loop protocol to wean children from mechanical ventilation . Design : Prospect i ve single-center pilot study . Setting : Tertiary care university hospital . Patients : Twenty mechanically ventilated children aged between 1 and 17 yrs , with a body weight ≥10 kg , no inotropes , and no heavy sedation . Interventions : Patients were weaned in pressure support mode by a closed-loop computerized protocol ( closed-loop protocol ) that interprets clinical data in real time and controls pressure support levels . Measurements and Main Results : The closed-loop protocol applicability and tolerance were evaluated . The efficacy of this protocol was evaluated by comparing the duration of mechanical ventilation with a historical group of 20 patients weaned with a clinician-decision protocol . The closed-loop protocol successfully decreased pressure support ventilation in 16 children , recommended separation from the ventilator in 14 children , and did not cause any serious adverse events . Mechanical ventilation duration was 5.1 ± 4.2 days in the closed-loop group and 6.7 ± 11.5 days ( mean ± sd ) in the clinician-decision group ( p = .33 ) with no difference in the need for reintubation or noninvasive mechanical ventilation ( one of 20 and four of 20 , respectively ; p = .20 ) . Conclusions : A closed-loop protocol was successfully used to wean children from mechanical ventilation . Further studies are required to assess the impact of this novel therapeutic strategy on the length of mechanical ventilation [15764727] Several variables are recommended for identifying if a patient is ready for a trial of weaning from mechanical ventilation , but there is no agreement as to whether monitoring any variable during the trial enhances patient management . To determine whether repeated measurements of esophageal pressure throughout a trial are more reliable than measurements of esophageal pressure or frequency-to-VT ratio during the first minute of the trial , we studied 60 patients . A trend index that quantified esophageal pressure swings over time was more reliable than the first-minute measurements : sensitivity , 0.91 , and specificity , 0.89 . Area under receiver operating characteristic curve for trend index ( 0.94 ) was greater than for first-minute measurement of esophageal pressure ( 0.44 , p < 0.05 ) and tended to be greater than that for frequency-to-VT ratio ( 0.78 , p = 0.13 ) . The likelihood ratio was highest for the trend index ( 8.2 , p < 0.05 ) . The advantage of the trend index may be related to the progressive increase in esophageal pressure throughout a failed weaning trial , whereas breathing pattern changed little after 2 minutes of spontaneous breathing . In conclusion , continuous monitoring of esophageal pressure swings during a spontaneous breathing trial provides additional guidance in patient management over tests used for deciding when to initiate weaning [11265020] BACKGROUND Variability and logistic complexity of mechanical ventilatory support of acute respiratory distress syndrome , and need to st and ardize care among all clinicians and patients , led University of Utah/LDS Hospital physicians , nurses , and engineers to develop a comprehensive computerized protocol . This bedside decision support system was the basis of a multicenter clinical trial ( 1993 - 1998 ) that showed ability to export a computerized protocol to other sites and improved efficacy with computer- versus physician-directed ventilatory support . The Memorial Hermann Hospital Shock Trauma intensive care unit ( ICU ) ( Houston , TX ; a Level I trauma center and teaching affiliate of The University of Texas Houston Medical School ) served as one of the 10 trial sites and recruited two thirds of the trauma patients . Results from the trauma patient subgroup at this site are reported to answer three questions : Can a computerized protocol be successfully exported to a trauma ICU ? Was ventilator management different between study groups ? Was patient outcome affected ? METHODS Sixty-seven trauma patients were r and omized at the Memorial Hermann Shock Trauma ICU site . " Protocol " assigned patients had ventilatory support directed by the bedside respiratory therapist using the computerized protocol . " Non protocol " patients were managed by physician orders . RESULTS Of the 67 trauma patients r and omized , 33 were protocol ( age 40 + /- 3 ; Injury Severity Score [ ISS ] 26 + /- 3 ; 73 % blunt ) and 34 were non protocol ( age 38 + /- 2 ; ISS 25 + /- 2 ; 76 % blunt ) . For the protocol group , the computerized protocol was used 96 % of the time of ventilatory support and 95 % of computer-generated instructions were followed by the bedside respiratory therapist . Outcome measures ( i.e. , survival , ICU length of stay , morbidity , and barotrauma ) were not significantly different between groups . Fio2 > or = 0.6 and Pplateau > or = 35 cm H2O exposures were less for the protocol group . CONCLUSION A computerized protocol for bedside decision support was successfully exported to a trauma center , and effectively st and ardized mechanical ventilatory support of trauma-induced acute respiratory distress syndrome without adverse effect on patient outcome [6377071] Previous studies have suggested that the early application of positive end-expiratory pressure ( PEEP ) reduces the incidence of the adult respiratory-distress syndrome . We r and omly assigned 92 patients with a known risk for this syndrome to receive mechanical ventilation either without PEEP ( control ) or with early PEEP at 8 cm H2O . These therapies continued for 72 hours unless respiratory distress developed or arterial oxygen tension was above 140 ( fractional inspired oxygen concentration , 0.5 ) at 24 hours or later and remained at that level after removal of PEEP . The study was design ed to have an 80 per cent probability of detecting a 60 per cent reduction in the incidence of the syndrome . The treatment groups were comparable in age , severity of injury , number and type of risk factors for adult respiratory-distress syndrome , and initial oxygenation . The syndrome developed in 11 of 44 patients given early PEEP ( 25 per cent ) and in 13 of 48 control patients ( 27 per cent ) . The incidence of atelectasis , pneumonia , and barotrauma was the same in both groups , as was mortality . We found that the early application of PEEP at 8 cm H2O in high-risk patients had no effect on the incidence of the adult respiratory-distress syndrome or other , associated complications [15001938] OBJECTIVE To report our experience with cuffed endotracheal tubes ( ETT ) in a large cohort of critically ill children . Study design We prospect ively collected data over a 1-year period concerning long-term intubation on 860 critically ill children admitted to our intensive care unit . Tube sizes were dictated by the modified Cole formula for uncuffed ETT ( age [y]/4 + 4 mm ID ) and chosen one-half size less for cuffed ETT . Cuff pressure was regularly monitored to maintain a small leak at peak inspiratory pressure . The choice of ETT was made by the physician responsible for the initial airway management . RESULTS There were 597 patients in the first 5 years of life , with 210 having cuffed ETT . There were no significant differences in the use of racemic epinephrine for postextubation subglottic edema , the rate of successful extubation or the need for tracheotomy between those with cuffed and uncuffed ETT in any age group . CONCLUSIONS Our data suggest that the traditional teaching in pediatric anesthesia and intensive care , including current pediatric life support recommendations , need to be review ed for children to benefit from the advantages of modern low-pressure cuffed ETT during critical illnesses [2298007] All patients intubated in the neonatal ( NICU ) and pediatric ( PICU ) ICUs over a 3-yr period were evaluated prospect ively to determine the incidence of accidental extubation ( AE ) and contributing factors . Two thous and two hundred patients ( age range 26 wk gestation to 18 yr ) were intubated for a total of 21,222 days . In the PICU and NICU , a total of 153 patients experienced 195 AE . The PICU had 113 AE in 1,388 subunit for a rate of 1.15 AE/100 intubated days . The NICU had 82 AE in 812 intubated patients , a rate of 0.72 AE/100 intubated days . A review of factors contributing to AE showed the most critical to be : sedation not administered in the 2 h before AE ( 65 % ) , the lack of two-point or more restraints ( 58 % ) , and the performance of a patient procedure at the bedside ( 49 % ) . One death occurred as an indirect consequence of AE . The data are being reported as a function of number of days intubated in an attempt to st and ardize reporting techniques . The use of st and ardized reporting and the identification of high-risk factors may be useful for education and modification of patient care practice s. ( Crit Care Med 1990 ; 18:163 [10966284] Objective To vali date predictors of extubation success and failure in mechanically ventilated infants and children by using bedside measures of respiratory function . Design Prospect i ve , descriptive study . Setting A university-affiliated children ’s hospital with a 51-bed critical care area . Patients All infants and children who were mechanically ventilated for ≥24 hrs except neonates ≤37 wks gestation and patients with neuromuscular disease . Interventions None . Measurements and Methods Extubation failure was defined as reintubation within 48 hrs of extubation in the absence of upper airway obstruction . Failure rates were calculated for different ranges ( selected a priori ) of preextubation measures of breathing effort , ventilator support , respiratory mechanics , central inspiratory drive , and integrated indices useful in adults . Effort of spontaneous breathing was assessed by the respiratory rate st and ardized to age , the presence of retractions and paradoxic breathing , inspiratory pressure , maximal negative inspiratory pressure , ratio of inspiratory pressure to maximal negative inspiratory pressure , and tidal volume indexed to body weight of a spontaneous breath . Ventilator support was measured by Fio2 , mean airway pressure , oxygenation index , and the fraction of total minute ventilation provided by the ventilator . Respiratory mechanics was assessed by peak ventilatory inspiratory pressure and dynamic compliance . Central inspiratory drive was assessed by mean inspiratory flow . Frequency to tidal volume ratio and the CROP ( compliance , rate , oxygenation , and pressure ) indexed to body weight , the integrated indices useful in predicting extubation failure in adults , were also calculated . A regression test for a linear trend in proportions was performed with preselected ranges and the corresponding failure rates . The failure rates from this study ( validation group ) were compared to those published previously ( prediction group ) by the chi-square test for proportions . The distribution of categorical variables between groups was analyzed by using the chi-square test or the Fisher ’s exact test , and p < .05 was considered significant . Main Results The study involved 312 patients . There were no differences in any of the clinical characteristics between the prediction and validation groups . The reasons for reintubation were similar in both groups . Preextubation data were also similar between the two groups . There were no differences between the prediction and the validation groups in failure rates with different ranges . There were no differences in the failure rates for any of the cutoff values for peak ventilatory inspiratory pressure , mean airway pressure , Fio2 , oxygenation index , dynamic compliance , tidal volume indexed to body weight of a spontaneous breath , fraction of total minute ventilation provided by the ventilator , and mean inspiratory flow . Conclusions Bedside measures of respiratory function can predict extubation success and failure in infants and children . Both a low risk and a high risk of failure can be determined by using these measures . Integrated indices useful in adults do not reliably predict extubation success or failure in infants and children . Our study vali date s our previously published study [12780985] Background Most children who undergo congenital heart surgery require postoperative mechanical ventilation . Failed extubation ( FE ) may result in physiologic instability , delay , or set back of the weaning process . FE is statistically associated with prolonged mechanical ventilation . Purpose We sought to identify frequency , pathogenesis , and risk factors for FE after congenital heart surgery in young children . Setting Pediatric intensive care unit . Patients Children ≤36 months of age who underwent congenital heart surgery in the period between January 1998 and July 1999 at our children ’s hospital . Measurements and Statistical Methods We performed a retrospective chart review . We defined reintubation within 24 hrs as an FE . Demographic , preoperative , intraoperative , and postoperative data were collected . A modified version of logistic regression , which accounts for lack of independence in data with multiple records per subject , was used to assess the impact of risk factors for FE . A forward selection process was used with p < .05 as the criterion for entry into the model . Estimated odds ratios ( EORs ) are reported with 95 % confidence intervals ( CI ) . The predictive ability of the final model was assessed by using area under the receiver operating characteristic curve . Main Results A total of 212 children ≤36 months of age underwent 230 congenital heart operations . Eleven children ( 5.2 % ) died perioperatively . After excluding patients who died , there were 219 surgeries among 202 patients ; 25.9 % ( 51 of 197 ) , 51.8 % ( 102 of 197 ) , and 72.6 % ( 143 of 197 ) of patients were successfully extubated by 12 , 24 , and 48 hrs , respectively . There were 22 cases in which an initial attempt at extubation failed at a median of 67.8 hrs ( range , 2.4–335.5 hrs ) . Five patients failed a subsequent attempt at extubation at a median of 189.5 hrs ( range , 115.8–602.5 hrs ) . The most common causes of initial FE were cardiac dysfunction ( n = 6 ) , lung disease ( n = 6 ) , and airway edema ( n = 3 ) . Risk factors for FE included pulmonary hypertension ( EOR , 38.7 ; 95 % CI , 2.9–25.8;p < .001 ) , Down syndrome ( EOR , 4.6 ; 95 % CI , 1.8–11.8;p = .002 ) , and deep hypothermic circulatory arrest ( EOR , 4.5 ; 95 % CI , 1.3–17.5;p = .018 ) . All were independent predictors of FE ( area under the curve , 0.837 ) . The strongest predictor was pulmonary hypertension , which when used alone to predict FE provided a sensitivity of 0.83 ( 95 % CI , 0.59–0.94 ) and a specificity of 0.75 ( 95 % CI , 0.68–0.80 ) . Conclusions Extubation fails after approximately 10 % of congenital heart surgery in young patients . Causes of FE are diverse . In our population , preoperative pulmonary hypertension , presence of a congenital syndrome , and intraoperative circulatory arrest are risk factors for FE . Prospect i ve validation of our predictive model with larger numbers and at multiple institutions would improve its utility [12813282] Objective Unsuccessful extubation from mechanical ventilation increases mortality and morbidity . Therefore , the identification of an accurate predictor of successful extubation is desirable . This study was design ed to determine whether the results of easily performed respiratory measurements , particularly if reported as “ combined extubation ” indices , were better predictors of extubation failure in a pediatric population than were readily available clinical data . Design Prospect i ve observational study . Setting Tertiary pediatric intensive care unit . Patients All children who required mechanical ventilation for ≥24 hrs during a 12-month period and whose parents gave informed written consent . Interventions Respiratory function measurements were made ( on average ) 7 hrs ( range , 0.2–25.0 hrs ) before extubation . Arterial blood gas results were obtained immediately before extubation . The values of each predictor associated with maximum sensitivity and specificity were determined , and the areas under receiver operator characteristic curves were compared to determine the most accurate predictor of successful extubation . Measurements and Main Results A total of 47 children ( mean age , 3.90 yrs ; range , 0.10–17.3 yrs ) were studied ; extubation failed in 7 . A low tidal volume ( < 7.5 mL/kg ) and a low minute volume ( < 250 mL/kg ) had the highest sensitivities ( 86 % and 71 % , respectively ) and specificities ( 61 % and 71 % , respectively ) in predicting extubation failure . The a/A ratio performed least well in predicting extubation failure ( area under the receiver operating characteristic curve , 0.51 ) . Conclusions Volume measurements during pediatric mechanical ventilation may facilitate successful extubation [9228375] OBJECTIVE To examine medical outcomes associated with reintubation for extubation failure after discontinuation of mechanical ventilation . DESIGN Prospect i ve cohort study of consecutive intubated medical ICU patients who underwent a trial of extubation at a tertiary-care teaching hospital . The failed extubation group consisted of all patients reintubated within 72 h or within 7 days ( if continuous ICU care had been required ) of extubation . All others were considered to be successfully extubated . Study end points included hospital death vs survival , the number of days spent in the ICU and in the hospital after the onset of mechanical ventilation , the likelihood of requiring > or = 7 or > or = 14 days of ICU care after extubation , and the need for transfer to either a long-term care or rehabilitation facility among the survivors . RESULTS Of 289 intubated patients , 247 ( 85 % ) were successfully extubated , and 42 ( 15 % ) required reintubation for failed extubation ( time to reintubation 1.5+/-0.2 days ) . Reintubation for extubation failure result ed in 12 additional days of mechanical ventilation . When compared with successfully extubated patients , reintubated patients were more likely to die in the hospital ( 43 % vs 12 % ; p<0.0001 ) , spend more time in the ICU ( 21.2+/-2.8 days vs 4.5+/-0.6 days ; p<0.001 ) and in the hospital ( 30.5+/-3.3 days vs 16.3+/-1.2 days ; p<0.001 ) after extubation , and require transfer to a long-term care or rehabilitation facility ( 38 % vs 21 % ; p<0.05 ) . Using multiple logistic regression , extubation failure was an independent predictor for death and the need for transfer to a long-term care facility . Compared with those successfully extubated , patients who failed extubation were seven times ( p<0.0001 ) more likely to die , 31 times ( p<0.0001 ) more likely to spend > or = 14 days in the ICU after extubation , and six times ( p<0.001 ) more likely to need transfer to a long-term care or rehabilitation facility if they survived . CONCLUSION After adjusting for severity of illness and comorbid conditions , extubation failure had a significant independent association with increased risk for death , prolonged ICU stay , and transfer to a long-term care or rehabilitation facility . Extubation failure may serve as an additional independent marker of severity of illness . Alternatively , poor outcomes may be etiologically related to extubation failure . If the latter proves to be the case , identifying patients at risk for poor outcomes from extubation failure and instituting alternative care practice s may reduce mortality , duration of ICU stay , and need for transfer to a long-term care facility

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### Context: [16714767] BACKGROUND Optimal fluid management in patients with acute lung injury is unknown . Diuresis or fluid restriction may improve lung function but could jeopardize extrapulmonary-organ perfusion . METHODS In a r and omized study , we compared a conservative and a liberal strategy of fluid management using explicit protocol s applied for seven days in 1000 patients with acute lung injury . The primary end point was death at 60 days . Secondary end points included the number of ventilator-free days and organ-failure-free days and measures of lung physiology . RESULTS The rate of death at 60 days was 25.5 percent in the conservative- strategy group and 28.4 percent in the liberal- strategy group ( P=0.30 ; 95 percent confidence interval for the difference , -2.6 to 8.4 percent ) . The mean ( + /-SE ) cumulative fluid balance during the first seven days was -136+/-491 ml in the conservative- strategy group and 6992+/-502 ml in the liberal- strategy group ( P<0.001 ) . As compared with the liberal strategy , the conservative strategy improved the oxygenation index ( [ mean airway pressure x the ratio of the fraction of inspired oxygen to the partial pressure of arterial oxygen]x100 ) and the lung injury score and increased the number of ventilator-free days ( 14.6+/-0.5 vs. 12.1+/-0.5 , P<0.001 ) and days not spent in the intensive care unit ( 13.4+/-0.4 vs. 11.2+/-0.4 , P<0.001 ) during the first 28 days but did not increase the incidence or prevalence of shock during the study or the use of dialysis during the first 60 days ( 10 percent vs. 14 percent , P=0.06 ) . CONCLUSIONS Although there was no significant difference in the primary outcome of 60-day mortality , the conservative strategy of fluid management improved lung function and shortened the duration of mechanical ventilation and intensive care without increasing nonpulmonary-organ failures . These results support the use of a conservative strategy of fluid management in patients with acute lung injury . ( Clinical Trials.gov number , NCT00281268 [ Clinical Trials.gov ] . ) [8874303] OBJECTIVE To determine whether dexamethasone prevents postextubation airway obstruction in young children . DESIGN Prospect i ve , r and omized , double-blind , placebo-controlled study . SETTING Pediatric intensive care unit of a university teaching hospital . PATIENTS Sixty-six children , < 5 yrs of age , intubated and mechanically ventilated for > 48 hrs . INTERVENTIONS Patients were r and omized to receive intravenous dexamethasone ( 0.5 mg/kg , maximum dose 10 mg ) or saline , every 6 hrs for six doses , beginning 6 to 12 hrs before elective extubation . MEASUREMENTS AND MAIN RESULTS Dependent variables included the presence of stridor , Croup Score , and pulsus paradoxus at 10 mins , 6 , 12 , and 24 hrs after extubation ; need for aerosolized racemic epinephrine and reintubation . The dexamethasone and placebo groups were similar in age ( median 3 months [ range 1 to 57 ] vs. 4 months [ range 1 to 59 ] , p = .6 ) , frequency of underlying airway anomalies ( 3/33 vs. 3/33 , p = 1.0 ) , and duration of mechanical ventilation ( median 3.3 days [ range 2.1 to 39 ] vs. 3.5 days [ range 2.1 to 15 ] , p = .7 ) . The dexamethasone group had a lower frequency of stridor , Croup Score , and pulsus paradoxus measurement at 10 mins and at 6 and 12 hrs after extubation . Fewer dexamethasone-treated patients required epinephrine aerosol ( 4/31 vs. 22/32 , p < .0001 ) and reintubation ( 0/31 vs. 7/32 , p < .01 ) . Three patients exited the study early-one patient in the dexamethasone group had occult gastrointestinal hemorrhage and one patient in each group had hypertension . CONCLUSION Pretreatment with dexamethasone decreases the frequency of postextubation airway obstruction in children [9279224] A 2-h T-tube trial of spontaneous breathing was used in selecting patients ready for extubation and discontinuation of mechanical ventilation . However , some doubt remains as to whether it is the most appropriate method of performing a spontaneous breathing trial . We carried out a prospect i ve , r and omized , multicenter study involving patients who had received mechanical ventilation for more than 48 h and who were considered by their physicians to be ready for weaning according to clinical criteria and st and ard weaning parameters . Patients were r and omly assigned to undergo a 2-h trial of spontaneous breathing in one of two ways : with a T-tube system or with pressure support ventilation of 7 cm H2O . If a patient had signs of poor tolerance at any time during the trial , mechanical ventilation was reinstituted . Patients without these features at the end of the trial were extubated . Of the 246 patients assigned to the T-tube group , 192 successfully completed the trial and were extubated ; 36 of them required reintubation . Of the 238 patients in the group receiving pressure support ventilation , 205 were extubated and 38 of them required reintubation . The percentage of patients who remained extubated after 48 h was not different between the two groups ( 63 % T-tube , 70 % pressure support ventilation , p = 0.14 ) . The percentage of patients falling the trial was significantly higher when the T-tube was used ( 22 versus 14 % , p = 0.03 ) . Clinical evolution during the trial was not different in patients reintubated and successfully extubated . ICU mortality among reintubated patients was significantly higher than in successfully extubated patients ( 27 versus 2.6 % , p < 0.001 ) . Spontaneous breathing trials with pressure support or T-tube are suitable methods for successful discontinuation of ventilator support in patients without problems to resume spontaneous breathing [8727443] Objective To evaluate the accuracy of the initial negative inspiratory pressure ( PI ) to maximal negative inspiratory pressure ( PImax ) ratio in predicting extubation outcome for intubated infants and children . Design A prospect i ve study . Setting : Pediatric intensive care unit . Patients A sample of 50 stable intubated pediatric patients who were judged clinical ly ready for extubation . Methods Using a one-way valve , PI and PImax were measured in all patients , after which the ≦ ratioPI/PImax was calculated and its accuracy in predicting extubation outcome evaluated . Measurements and results A total of 39 patients ( 78 % ) were successfully extubated and 11 patients ( 22 % ) were not . The meanPI/PImax ratio was not significantly different between extubation successes ( 0.36±0.14 ) and failures ( 0.45±0.1 ) ( P>0.05 ) . The cut-off value of 0.3 forPI/PImax identified in adult patients did not discriminate between extubation success and failure in children . Furthermore , a discriminatory cut-off value other than 0.3 could not be identified for infants and children . Conclusion ThePI/PImax ratio can not be used to predict extubation outcome in pediatric patients . Indices that predict extubation outcome in adults should not be extrapolated to infants and children before testing and validation [12107682] Abstract Objective . To assess the accuracy of traditional weaning indices in predicting extubation failure , and to compare their accuracy when indices are measured at the onset of a breathing trial ( SBT ) and at the end of the SBT before extubation . Design . Prospect i ve study . Setting . Medical-surgical intensive care unit at a tertiary care hospital . Patients . Four hundred eighteen consecutive infants and children who received mechanical ventilation for at least 48 h and were deemed ready to undergo a SBT by their primary physician . Interventions . Respiratory frequency ( RR ) , tidal volume ( VT ) , maximal inspiratory pressure ( Pimax ) and frequency-to-tidal volume ratio ( f/VT ) were obtained within the first 5 min of breathing through a T-piece . The primary physicians were unaware of those measurements and the decision to extubate a patient was made by them . RR , VT , f/VT were remeasured before extubation by the respiratory therapists . Extubation failure was defined as needing re intubation within 48 h after extubation . The area under the receiver operating characteristic ( ROC ) curve was calculated for each index as a measure of the accuracy in predicting extubation outcome . Measurements and main results . Three hundred twenty-three patients successfully underwent the SBT and were extubated , but 48 of them ( 14 % ) required re-intubation . The ROC curve for VT , RR , Pimax and f/VT measured within the first 5 min of breathing were 0.54 , 0.56 , 0.57 and 0.57 , respectively . The ROC curve did not increase significantly when the above indices were remeasured before extubation . Conclusions . In a population which had passed SBT , the ability of the traditional weaning indices to discriminate between children successfully extubated and children re-intubated is very poor [10793162] BACKGROUND Traditional approaches to mechanical ventilation use tidal volumes of 10 to 15 ml per kilogram of body weight and may cause stretch-induced lung injury in patients with acute lung injury and the acute respiratory distress syndrome . We therefore conducted a trial to determine whether ventilation with lower tidal volumes would improve the clinical outcomes in these patients . METHODS Patients with acute lung injury and the acute respiratory distress syndrome were enrolled in a multicenter , r and omized trial . The trial compared traditional ventilation treatment , which involved an initial tidal volume of 12 ml per kilogram of predicted body weight and an airway pressure measured after a 0.5-second pause at the end of inspiration ( plateau pressure ) of 50 cm of water or less , with ventilation with a lower tidal volume , which involved an initial tidal volume of 6 ml per kilogram of predicted body weight and a plateau pressure of 30 cm of water or less . The primary outcomes were death before a patient was discharged home and was breathing without assistance and the number of days without ventilator use from day 1 to day 28 . RESULTS The trial was stopped after the enrollment of 861 patients because mortality was lower in the group treated with lower tidal volumes than in the group treated with traditional tidal volumes ( 31.0 percent vs. 39.8 percent , P=0.007 ) , and the number of days without ventilator use during the first 28 days after r and omization was greater in this group ( mean [ + /-SD ] , 12+/-11 vs. 10+/-11 ; P=0.007 ) . The mean tidal volumes on days 1 to 3 were 6.2+/-0.8 and 11.8+/-0.8 ml per kilogram of predicted body weight ( P<0.001 ) , respectively , and the mean plateau pressures were 25+/-6 and 33+/-8 cm of water ( P<0.001 ) , respectively . CONCLUSIONS In patients with acute lung injury and the acute respiratory distress syndrome , mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use [15671432] CONTEXT Despite evidence that patients with acute lung injury ( ALI ) have pulmonary surfactant dysfunction , trials of several surfactant preparations to treat adults with ALI have not been successful . Preliminary studies in children with ALI have shown that instillation of a natural lung surfactant ( calfactant ) containing high levels of surfactant-specific protein B may be beneficial . OBJECTIVE To determine if endotracheal instillation of calfactant in infants , children , and adolescents with ALI would shorten the course of respiratory failure . DESIGN , SETTING , AND PATIENTS A multicenter , r and omized , blinded trial of calfactant compared with placebo in 153 infants , children , and adolescents with respiratory failure from ALI conducted from July 2000 to July 2003 . Twenty-one tertiary care pediatric intensive care units participated . Entry criteria included age 1 week to 21 years , enrollment within 48 hours of endotracheal intubation , radiological evidence of bilateral lung disease , and an oxygenation index higher than 7 . Premature infants and children with preexisting lung , cardiac , or central nervous system disease were excluded . INTERVENTION Treatment with intratracheal instillation of 2 doses of 80 mL/m2 calfactant or an equal volume of air placebo administered 12 hours apart . MAIN OUTCOME MEASURES Ventilator-free days and mortality ; secondary outcome measures were hospital course , adverse events , and failure of conventional mechanical ventilation . RESULTS The calfactant group experienced an acute mean ( SD ) decrease in oxygenation index from 20 ( 12.9 ) to 13.9 ( 9.6 ) after 12 hours compared with the placebo group 's decrease from 20.5 ( 14.7 ) to 15.1 ( 9.0 ) ( P = .01 ) . Mortality was significantly greater in the placebo group compared with the calfactant group ( 27/75 vs 15/77 ; odds ratio , 2.32 ; 95 % confidence interval , 1.15 - 4.85 ) , although ventilator-free days were not different . More patients in the placebo group did not respond to conventional mechanical ventilation . There were no differences in long-term complications . CONCLUSIONS Calfactant acutely improved oxygenation and significantly decreased mortality in infants , children , and adolescents with ALI although no significant decrease in the course of respiratory failure measured by duration of ventilator therapy , intensive care unit , or hospital stay was observed [1356176] Many studies have attempted to find out whether steroid treatment is beneficial in children with croup , but the results have been inconclusive . We have done a prospect i ve placebo-controlled study of the effect of prednisolone on two clinical endpoints -- the duration of intubation and the need for reintubation . Reasons for exclusion were age under 6 months , congenital airway anomalies , and previous intubation . 70 eligible children were r and omly assigned treatment with prednisolone 1 mg/kg ( n = 38 ) or placebo ( n = 32 ) every 12 h given by nasogastric tube until 24 h after extubation . 11 ( 34 % ) placebo-treated and only 2 ( 5 % ) prednisolone-treated patients required reintubation after accidental or elective extubation ( p = 0.004 , Fisher 's exact test ; odds ratio 8.9 , 95 % confidence interval 1.7 - 59.3 ) . Survival analysis with log-normal regression showed that the duration of intubation was shorter with steroid therapy ( p less than 0.003 ) and increasing age ( p less than 0.02 ) , but was not influenced by endotracheal tube size or abnormality on chest radiograph . The median duration of intubation was 138 ( 95 % CI 118 - 160 ) h in children who received placebo and 98 ( 85 - 113 ) h in the prednisolone group . Steroid therapy reduces the duration of intubation and the need for reintubation in children intubated for croup [16446601] Objective : To develop and test the reliability and validity of the State Behavioral Scale for use in describing sedation/agitation levels in young intubated patients supported on mechanical ventilation . Design : In this prospect i ve , psychometric evaluation , pairs of trained pediatric critical care nurse evaluators simultaneously and independently assessed a convenience sample of pediatric intensive care unit patients along eight state/behavioral dimensions and a numeric rating scale ( NRS ) of 0 ( extremely se date d ) to 10 ( extremely agitated ) . The eight dimensions were derived from the sedation/agitation literature and expert opinion and included respiratory drive , response to ventilation , coughing , best response to stimulation , attentiveness to careprovider , tolerance to care , consolability , and movement after consoled , each with 3–5 levels . Setting : An 18-bed pediatric medical – surgical intensive care unit and 26-bed pediatric cardiovascular intensive care unit in a university-affiliated academic children ’s hospital . Patients : A total of 91 intubated mechanically ventilated patients 6 wks to 6 yrs of age provided a median of two observations ( interquartile range , 1–3 ) for a total of 198 sets of observations . Excluded were postoperative patients or those receiving neuromuscular blockade . Interventions : Patients were observed for 1 min , and then incremental levels of stimulation were applied until patient response . After 2 mins of consoling , the state behavioral assessment and NRS were completed . Measurements : Weighted kappa and intraclass coefficients were generated to assess interrater reliability of the eight dimension and NRS ratings . Distinct state behavior profiles were empirically identified from the dimension ratings using hierarchical cluster analysis using a squared Euclidean distance measure and between-groups linkage . Construct validity of these profiles was assessed by comparing group mean NRS scores using one-way analysis of variance . Main Results : Weighted kappa scores for all 198 dimension ratings ranged from .44 to .76 , indicating moderate to good interrater reliability . The intraclass coefficient of .79 was high for NRS ratings . Cluster analysis revealed five distinct state profiles , with mean NRS ratings of 1.1 , 2.5 , 4.0 , 5.3 , and 7.6 , all of which differed significantly from each other ( F = 75.8 , p < .001 ) , supporting the profiles ’ construct validity . Conclusions : Based on empirically derived state behavior profiles , we have constructed the State Behavioral Scale to allow systematic description of the sedation – agitation continuum in young pediatric patients supported on mechanical ventilation . Further studies including prospect i ve validation and describing the effect of State Behavioral Scale implementation on clinical outcomes , including the quality of sedation and length of mechanical ventilation , are warranted [15673313] BACKGROUND Critical illness leading to multi-organ dysfunction syndrome ( MODS ) and associated acute renal failure ( ARF ) is less common in children compared to adult patients . As a result , many issues plague the pediatric ARF outcome literature , including a relative lack of prospect i ve study , a lack of modality stratification in subject population s and inconsistent controls for patient illness severity in outcome analysis . METHODS We now report data from the first multicenter study to assess the outcome of pediatric patients with MODS receiving continuous renal replacement therapy ( CRRT ) . One hundred twenty of 157 Registry patients ( 63 male/57 female ) experienced MODS during their course . RESULTS One hundred sixteen patients had complete data available for analysis . The most common causes leading to CRRT were sepsis ( N= 47 ; 39.2 % ) and cardiogenic shock ( N= 24 ; 20 % ) . Overall survival was 51.7 % . Pediatric Risk of Mortality ( PRISM 2 ) score , central venous pressure ( CVP ) , and % fluid overload ( % FO ) at CRRT initiation were significantly lower for survivors versus nonsurvivors . Multivariate analysis controlling for severity of illness using PRISM 2 at CRRT initiation revealed that%FO was still significantly lower for survivors versus nonsurvivors ( P < 0.05 ) even for patients receiving both mechanical ventilation and vasoactive pressors . We speculate that increased fluid administration from PICU admission to CRRT initiation is an independent risk factor for mortality in pediatric patients with MODS receiving CRRT . CONCLUSION We suggest that after initial resuscitative efforts , an increased emphasis should be placed on early initiation of CRRT and inotropic agent use over fluid administration to maintain acceptable blood pressure [11046212] Background Patient-triggered ventilation ( PTV ) is commonly used in adults to avoid dyssynchrony between patient and ventilator . However , few investigations have examined the effects of PTV in infants . Our objective was to determine if pressure-control PTV reduces infants ’ respiratory workloads in proportion to the level of pressure control . We also explored which level of pressure control provided respiratory workloads similar to those after the extubation of the trachea . Methods When seven post – cardiac surgery infants , aged 1 to 11 months , were to be weaned with the pressure-control PTV , we r and omly applied five levels of pressure control : 0 , 4 , 8 , 12 , and 16 cm H2O . All patients were ventilated with assist – control mode , triggering sensitivity of 1 l/min , and positive end-expiratory pressure of 3 cm H2O . After establishing steady state conditions at each level of pressure control , arterial blood gases were analyzed and esophageal pressure ( Pes ) , airway pressure , and airflow were measured . Inspiratory work of breathing ( WOB ) was calculated using a Campbell diagram . A modified pressure – time product ( PTPmod ) and the negative deflection of Pes were calculated from the Pes tracing below the baseline . The measurement was repeated after extubation . Results Pressure-control PTV supported every spontaneous breath . By decreasing the level of pressure control , respiratory rate increased , tidal volume decreased , and as a result , minute ventilation and arterial carbon dioxide partial pressure were maintained stable . The WOB , PTPmod , and negative deflection of Pes increased as pressure control level was decreased . The WOB and PTPmod at 4 cm H2O pressure control and 0 cm H2O pressure control and after extubation were significantly greater than those at the pressure control of 16 , 12 , and 8 cm H2O ( P < 0.05 ) . The WOB and PTPmod were almost equivalent after extubation and at 4 cm H2O pressure control . Conclusions Work of breathing and PTPmod were changed according to the pressure control level in post – cardiac surgery infants . PTV may be feasible in infants as well as in adults [8162750] This prospect i ve study compared two weaning modalities in COPD patients requiring mechanical ventilation ( MV ) for acute respiratory failure . Nineteen patients with COPD were studied when their precipitating illness was controlled . Although they satisfied the conventional bedside weaning criteria , they could not tolerate any reduction in the respirator rate below 10 cycles/min . At this time , patients were r and omized into two groups receiving either synchronized intermittent m and atory ventilation ( SIMV ) with pressure support ventilation ( PSV ) ( group 1 ) or SIMV alone ( group 2 ) . The volumetric support of ventilation ( SIMV rate ) was progressively decreased in both groups according to the patient 's tolerance with a concurrent decrease in the barometric support of ventilation ( PSV levels from 15 cm H2O to 6 cm H2O ) . At each step of SIMV rate , we found no difference between group 1 and group 2 in arterial blood gases , blood pressure , heart rate , airway occlusion pressure , maximal inspiratory pressure , and oxygen cost of breathing ( OCB ) . At each step , however , group 1 patients showed significantly higher spontaneous tidal volume and lower spontaneous breathing frequency than did group 2 patients . We found a slight but not significant tendency to a shorter weaning period with than without PSV , but no difference in the weaning success . We concluded that ( 1 ) conventional weaning criteria might be inaccurate in COPD patients , ( 2 ) SIMV appeared very useful in weaning COPD patients from MV , ( 3 ) PSV marginally reduced the weaning period when added to SIMV , and ( 4 ) the OCB was not significantly improved with PSV [11463367] OBJECTIVE Compare outcomes between physician-directed and protocol -directed weaning from mechanical ventilation in pediatric patients . DESIGN Prospect ive-r and omized . SETTING Pediatric and cardiac intensive care units in a 307-bed tertiary referral hospital for children . INTERVENTIONS The control group ( physician-directed ) was weaned according to individual physician order for reduction in minute ventilation , positive end-expiratory pressure , and ordered oxygen saturation parameters for reduction in fraction of inspired oxygen ( F(IO)(2 ) ) . The study group ( protocol -directed ) was weaned according to a predetermined algorithm developed for the purpose of this investigation . METHODS The study enrolled 223 patients ( 116 physician-directed , 107 protocol -directed ) . All patients were monitored for hemodynamics , ventilator parameters , arterial blood gas values when available , oxygen saturation , weaning time , pre-weaning time , extubation time , and time on F(IO)(2 ) > or = 0.40 . We also monitored the incidence of reintubation , subglottic stenosis , tracheitis , and pneumonia . The protocol -directed group had additional measurements of actual versus predicted minute volume , comparisons of respiratory rate ( actual versus predicted for age ) , and presence of spontaneous breathing effort for 10 consecutive minutes . Data analysis was done according to intent to treat . RESULTS There was no significant difference in 12-hour and 24-hour pediatric risk of mortality ( PRISM III ) scores between groups . The protocol -directed group overall had shorter total ventilation time , weaning time , pre-weaning time , time to extubation , and time on F(IO)(2 ) > 0.40 , although after stratification for respiratory diagnosis , only the difference in weaning time remained significant . There was no difference in the incidence of reintubation , new-onset tracheitis , subglottic stenosis , or pneumonia . CONCLUSIONS Protocol -directed weaning result ed in a shorter weaning time than physician-directed weaning in these pediatric patients [10390384] Prolonged duration of endotracheal mechanical ventilation ( ETMV ) is associated with an increased morbidity and mortality in intensive care unit ( ICU ) patients . The aim of this study was to assess the usefulness of noninvasive ventilation ( NIV ) as a systematic extubation and weaning technique to reduce the duration of ETMV in acute-on-chronic respiratory failure ( ACRF ) . Among 53 consecutively intubated patients admitted for ACRF , we conducted a prospect i ve , r and omized controlled trial of weaning in 33 patients who failed a 2-h T-piece weaning trial ( 2 h-WT ) although they met simple criteria for weaning . Conventional invasive pressure support ventilation ( IPSV ) was used as the control weaning technique in 16 patients ( IPSV group ) , and NIV was applied immediately after extubation in 17 patients ( NIV group ) . The two weaning groups were similar for type of chronic respiratory failure ( CRF ) , pulmonary function data , age , Simplified Acute Physiology Score ( SAPS II ) , and severity of ACRF on admission . The characteristics of the two groups were also similar at r and omization . In the IPSV group , 12 of 16 patients ( 75 % ) were successfully weaned and extubated , versus 13 of 17 ( 76.5 % ) in the NIV group ( p = NS ) . NIV like IPSV significantly and similarly improved gas exchange in relation to that achieved during 2 h-WT ( p < 0.05 ) . The duration of ETMV was significantly shorter in the NIV ( 4.56 + /- 1.85 d ) than in the IPSV group ( 7.69 + /- 3.79 d ) ( p = 0 . 004 ) . NIV also reduced the mean period of daily ventilatory support , but increased the total duration of ventilatory support related to weaning ( 3.46 + /- 1.42 d , versus 11.54 + /- 5.24 d with NIV ; p = 0 . 0001 ) . Most patients in the IPSV group developed complications related to ETMV and /or the weaning process , but the difference was not significant ( nine of 16 versus six of 17 ) . The duration s of ICU and hospital stays and the 3-mo survival were similar in the two groups . In conclusion , NIV permits earlier removal of the endotracheal tube than with conventional IPSV , and reduces the duration of daily ventilatory support without increasing the risk of weaning failures . NIV should be considered as a new and useful systematic approach to weaning in patients with ACRF who are difficult to wean [16014597] CONTEXT In uncontrolled clinical studies , prone positioning appeared to be safe and to improve oxygenation in pediatric patients with acute lung injury . However , the effect of prone positioning on clinical outcomes in children is not known . OBJECTIVE To test the hypothesis that at the end of 28 days infants and children with acute lung injury treated with prone positioning would have more ventilator-free days than those treated with supine positioning . DESIGN , SETTING , AND PATIENTS Multicenter , r and omized , controlled clinical trial conducted from August 28 , 2001 , to April 23 , 2004 , of 102 pediatric patients from 7 US pediatric intensive care units aged 2 weeks to 18 years who were treated with supine vs prone positioning . R and omization was concealed and group assignment was not blinded . INTERVENTION Patients were r and omized to either supine or prone positioning within 48 hours of meeting acute lung injury criteria , with those patients in the prone group being positioned within 4 hours of r and omization and remaining prone for 20 hours each day during the acute phase of their illness for a maximum of 7 days , after which they were positioned supine . Both groups were treated using lung protective ventilator and sedation protocol s , extubation readiness testing , and hemodynamic , nutrition , and skin care guidelines . MAIN OUTCOME MEASURE Ventilator-free days to day 28 . RESULTS The trial was stopped at the planned interim analysis on the basis of the prespecified futility stopping rule . There were no differences in the number of ventilator-free days between the 2 groups ( mean [ SD ] , 15.8 [ 8.5 ] supine vs 15.6 [ 8.6 ] prone ; mean difference , -0.2 days ; 95 % CI , -3.6 to 3.2 ; P = .91 ) . After controlling for age , Pediatric Risk of Mortality III score , direct vs indirect acute lung injury , and mode of mechanical ventilation at enrollment , the adjusted difference in ventilator-free days was 0.3 days ( 95 % CI , -3.0 to 3.5 ; P = .87 ) . There were no differences in the secondary end points , including proportion alive and ventilator-free on day 28 ( P = .45 ) , mortality from all causes ( P>.99 ) , the time to recovery of lung injury ( P = .78 ) , organ-failure-free days ( P = .88 ) , and cognitive impairment ( P = .16 ) or overall functional health ( P = .12 ) at hospital discharge or on day 28 . CONCLUSION Prone positioning does not significantly reduce ventilator-free days or improve other clinical outcomes in pediatric patients with acute lung injury [16228176] Objective To compare the pressure-rate products and phase angles of children during minimal support ventilation and after extubation . Design and setting Prospect i ve , r and omized single-center trial in a pediatric intensive care unit in a tertiary children ’s hospital . Methods Seventeen endotracheally intubated , mechanically ventilated children were placed on T-piece , T-piece with heliox , continuous positive airway pressure , and pressure support in r and om order . Esophageal pressure swings , phase angles , respiratory mechanics , and physiological parameters were measured on these modes and after extubation . Measurements and results Pressure-rate product postextubation was significantly higher than on support modes . For each mode and after extubation they were : pressure support 198±31 , continuous positive airway pressure 237±30 , T-piece 323±47 , T-piece/heliox 308±61 , and extubation 378±43 cmH2O/min . Phase angles were significantly higher during T-piece ventilation than pressure support but not did not differ significantly from postextubation . Conclusions Assessment of effort of breathing during even minimal mechanical ventilation may underestimate postextubation effort in children . Postextubation pressure-rate product and hence “ effort of breathing ” in children is best approximated by T-piece ventilation [10556121] Objective criteria to predict extubation outcome in mechanically ventilated children are not available . Our goal was to study factors associated with extubation success and to evaluate the usefulness of the rapid shallow breathing index ( RSBI ) and the compliance , resistance , oxygenation , and pressure index ( CROP index ) in children . Data were prospect ively collected on 227 mechanically ventilated children . Patients successfully extubated had significantly better lung compliance ( Cdyn : 0.59 + /- 0.91 versus 0.39 + /- 0.14 ml/kg/cm H(2)O ) , higher Pa(O(2))/FI(O(2 ) ) ratio ( 382.4 + /- 181.2 versus 279.8 + /- 93.9 ) , and lower Pa(CO(2 ) ) ( 41.3 + /- 6.7 versus 47.3 + /- 8.5 mm Hg ) . Spontaneous breathing parameters showed significantly lower respiratory rates ( RR ) ( 36.6 + /- 17.9 versus 52.8 + /- 23 breaths/min ) , larger tidal volumes ( VT ) ( 7.3 + /- 2.6 versus 4.9 + /- 1.8 ml/kg ) , and greater muscle strength ( negative inspiratory force [ NIF ] : 41.8 + /- 15.4 versus 35.1 + /- 12.5 cm H(2)O ) in successfully extubated children . Extubation failures had higher RSBIs and lower CROP index values . A RSBI value of < /= 8 breaths/ml/kg had a sensitivity of 74 % and specificity of 74 % , whereas a CROP value of > /= 0.15 ml/kg/breaths/min had a sensitivity of 83 % and specificity of 53 % for extubation success . Children failing extubation demonstrate abnormalities of respiratory function . The RSBI and CROP index are useful to predict pediatric extubation success [10890660] Objective Using a modification of the Bohr equation , single-breath carbon dioxide capnography is a noninvasive technology for calculating physiologic dead space ( Vd/Vt ) . The objective of this study was to identify a minimal Vd/Vt value for predicting successful extubation from mechanical ventilation in pediatric patients . Design Prospect i ve , blinded , clinical study . Setting Medical and surgical pediatric intensive care unit of a university hospital . Patients Intubated children ranging in age from 1 wk to 18 yrs . Interventions None . Measurements and Main Results Forty-five patients were identified by the pediatric intensive care unit clinical team as meeting criteria for extubation . Thirty minutes before the planned extubation , each patient was begun on pressure support ventilation set to deliver an exhaled tidal volume of 6 mL/kg . After 20 mins on pressure support ventilation , an arterial blood gas was obtained , Vd/Vt was calculated , and the patient was extubated . Over the next 48 hrs , the clinical team managed the patient without knowledge of the preextubation Vd/Vt value . Of the 45 patients studied , 25 had Vd/Vt ≤0.50 . Of these patients , 24 of 25 ( 96 % ) were successfully extubated without needing additional ventilatory support . In an intermediate group of patients with Vd/Vt between 0.50 and 0.65 , six of ten patients ( 60 % ) successfully extubated from mechanical ventilation . However , only two of ten patients ( 20 % ) with a Vd/Vt ≥0.65 were successfully extubated . Logistic regression analysis revealed a significant association between lower Vd/Vt and successful extubation . Conclusions A Vd/Vt ≤0.50 reliably predicts successful extubation , whereas a Vd/Vt > 0.65 identifies patients at risk for respiratory failure following extubation . There appears to be an intermediate Vd/Vt range ( 0.51–0.65 ) that is less predictive of successful extubation . Routine Vd/Vt monitoring of pediatric patients may permit earlier extubation and reduce unexpected extubation failures [14605539] Objective To determine a contemporary failed extubation rate , risk factors , and consequences of extubation failure in pediatric intensive care units ( PICUs ) . Three hypotheses were investigated : a ) Extubation failure is in part disease specific ; b ) preexisting respiratory conditions predispose to extubation failure ; and c ) admission acuity scoring does not affect extubation failure . Design Twelve-month prospect i ve , observational , clinical study . Setting Sixteen diverse PICUs in the United States . Patients Patients were 2,794 patients from the newborn period to 18 yrs of age experiencing a planned extubation trial . Interventions None . Measurements and Main Results A descriptive statistical analysis was performed , and outcome differences of the failed extubation population were determined . The extubation failure rate was 6.2 % ( 174 of 2,794 ; 95 % confidence interval , 5.3–7.1 ) . Patient features associated with extubation failure ( p < .05 ) included age ≤24 months ; dysgenetic condition ; syndromic condition ; chronic respiratory disorder ; chronic neurologic condition ; medical or surgical airway condition ; chronic noninvasive positive pressure ventilation ; the need to replace the endotracheal tube on admission to the PICU ; and the use of racemic epinephrine , steroids , helium-oxygen therapy ( heliox ) , or noninvasive positive pressure ventilation within 24 hrs of extubation . Patients failing extubation had longer pre-extubation intubation time ( failed , 148.7 hrs , sd ± 207.8 vs. success , 107.9 hrs , sd ± 171.3 ; p < .001 ) , longer PICU length of stay ( 17.5 days , sd ± 15.6 vs. 7.6 days , sd ± 11.1 ; p < .001 ) , and a higher mortality rate than patients not failing extubation ( 4.0 % vs. 0.8 % ; p < .001 ) . Failure was found to be in part disease specific , and preexisting respiratory conditions were found to predispose to failure whereas admission acuity did not . Conclusion A variety of patient features are associated with an increase in extubation failure rate , and serious outcome consequences characterize the extubation failure population in PICUs [12209275] Abstract Objective . Laryngeal edema secondary to endotracheal intubation may require early re-intubation . Prior to extubation the absence of leak around an endotracheal tube may predict laryngeal edema after extubation . We evaluated the usefulness of a quantitative assessment of such a leak to identify the patients who will require early re-intubation for laryngeal edema . Methods . This prospect i ve study included 76 patients with endotracheal intubation for more than 12 h. The leak , in percent , was defined as the difference between expired tidal volume measured just before extubation , in volume-controlled mode , with the cuff inflated and then deflated . The best cut-off value to predict the need for re-intubation for significant laryngeal edema was determined and the patients were divided into two groups , according to this cut-off value . Results . Eight of the 76 patients ( 11 % ) needed re-intubation for laryngeal edema . Patients requiring re-intubation had a smaller leak than the other patients [ 9 ( 3–18 ) vs 35 (13–53)% , p<0.01 ] . The best cut-off value for gas leak was 15.5 % . The high leak group included 51 patients , of whom only two patients ( 3 % ) required re-intubation . The low leak group included 25 patients , among whom six patients ( 24 % ) required re-intubation ( p<0.01 ) . The sensitivity of this test was 75 % , the specificity 72.1 % , the positive predictive value 25 % , the negative predictive value 96.1 % and the percent of correct classification 72.4 % . Conclusions . A gas leak around the endotracheal tube greater than 15.5 % can be used as a screening test to limit the risk of re-intubation for laryngeal edema [10936141] STUDY OBJECTIVES ( 1 ) To determine the effect of a single ventilator management protocol ( VMP ) used in medical and surgical ICUs on the duration of mechanical ventilation . ( 2 ) To determine the effect of a VMP on the incidence of ventilator-associated pneumonia ( VAP ) . DESIGN Prospect i ve , r and omized , controlled study . SETTING : University medical center . PATIENTS Three hundred eighty-five patients receiving mechanical ventilation between June 1997 and May 1998 . INTERVENTIONS A respiratory care practitioner- and registered nurse-driven VMP . RESULTS Intervention and control groups were comparable with respect to age , sex , severity of illness and injury , and duration of respiratory failure at the time of r and omization . The duration of mechanical ventilation for patients was decreased from a median of 124 h for the control group to 68 h in the VMP group ( p = 0.0001 ) . Thirty-one total instances of VAP were noted . Twelve patients in the surgical control group had VAP , compared with 5 in the surgical VMP group ( p = 0.061 ) . The impact of the VMP on VAP frequency was less for medical patients . Mortality and ventilator discontinuation failure rates were similar between control and VMP groups . CONCLUSIONS A VMP design ed for multidisciplinary use was effective in reducing duration of mechanical ventilatory support without any adverse effects on patient outcome . The VMP was also associated with a decrease in incidence of VAP in trauma patients . These results , in conjunction with prior studies , suggest that VMPs are highly effective means of improving care , even in university ICUs [9840242] Objective : The development of weaning predictors in mechanically ventilated children has not been sufficiently investigated . The purpose of this study was to evaluate the accuracy of some weaning indices in predicting weaning failure . Design : Prospect i ve , interventional study . Setting : University-affiliated children 's hospital with a 19-bed intensive care unit . Patients : 84 consecutive infants and children requiring mechanical ventilation for at least 48 h and judged ready to wean by their primary physicians . Interventions : Patients who met the criteria to start weaning underwent a trial of spontaneous breathing lasting up to 2 h. Bedside measurements of respiratory function were obtained immediately before discontinuation of mechanical ventilation and within the first 5 min of spontaneous breathing . The primary physicians were blinded to those measurements , and the decision to extubate a patient at the end of the spontaneous breathing trial or reinstitute mechanical ventilation was made by them . Failure to wean was defined as the requirement for mechanical ventilation at any time during the trial of spontaneous breathing ( trial failure ) or needing reintubation within 48 h of extubation ( extubation failure ) . Measurements and main results : Seventy-five patients had neither signs of respiratory distress nor deterioration in gas exchange during the trial and were extubated . Twelve patients required reintubation within 48 h. In 9 patients , mechanical ventilation was reinstituted after a median duration of the spontaneous breathing trial of 35 min . The only independent predictor of trial failure was tidal volume indexed to body weight [ odds ratio 2.60 , 95 % confidence interval ( CI ) 1.40 to 24.9 ] . The only independent predictor of extubation failure was frequency-to-tidal volume ratio indexed to body weight ( odds ratio 1.23 , 95 % CI 1.11 to 1.36 ) . The sensitivity , specificity , and positive and negative predictive values to predict weaning failure were calculated for each of the above variables . These values were 0.48 , 0.86 , 0.53 , and 0.83 , respectively , for a frequency-to-tidal volume ratio higher than 11 breaths/min per ml per kg and 0.43 , 0.94 , 0.69 , and 0.83 , respectively , for a tidal volume lower than 4 ml/kg . Conclusions : Three-quarters of ventilated children can be successfully weaned after a trial of spontaneous breathing lasting 2 h. Both tidal volume and frequency-to-tidal volume ratio indexed to body weight were poor predictors of weaning failure in the study population [11093984] Work of breathing ( WOB ) increases during general anesthesia in adults , but such information has been limited in pediatric patients . We studied WOB in 24 healthy children ( mean age 2 ± 1.9 yrs ) , during elective urogenital surgery under 1 minimum alveolar anesthetic concentration halothane-nitrous oxide anesthesia with a caudal block while breathing spontaneously . WOB was measured with an esophageal balloon , miniature flowmeter , and a computerized ( Bicore ) system . In each patient , WOB was computed under four conditions : a mask without oral airway ( -AW ) , a mask with oral airway ( + AW ) , a laryngeal mask airway ( LMA ) , and an endotracheal tube ( ETT ) . With each apparatus WOB was studied both with continuous positive airway pressure ( CPAP ) ( 5–6 cm H2O ) and without CPAP ( or zero end-expiratory pressure [ ZEEP ] ) . Under ZEEP , WOB ( g · cm/kg ) among the four apparatus were ( mean ± sem ) : mask ( -AW ) ( 64 ± 19.2 ) > mask ( + AW ) ( 44 ± 17.2 ) , LMA ( 42 ± 15.6 ) > ETT ( 25.4 ± 12.4 ) ( P < 0.05 ) . WOB with CPAP significantly ( P < 0.05 ) decreased from WOB with ZEEP in three groups ( mask [ -AW ] , mask [ + AW ] , and LMA ) , but not in the ETT group . Tidal volume ( both ZEEP and CPAP ) and end-tidal Pco2 ( with CPAP only ) were significantly ( P < 0.05 ) decreased only in the ETT group , whereas no significant difference was found in respiratory rate or minute volume among the four airway apparatus groups , either with or without CPAP . The reduction in WOB , when breathing through ETT was primarily attributable to decreases in tidal volume and volume work . The finding that WOB decreases with CPAP in all groups except for the ETT group suggests that the decrease is a result of improved patency of the upper airway rather than of increases in functional residual capacity and lung compliance . Implication s We studied work of breathing ( WOB ) measured with four airway devices , with and without application of continuous positive airway pressure ( CPAP ) . Laryngeal mask airway and mask with oral airway decrease WOB compared with mask alone . CPAP decreases WOB with all devices except the endotracheal tube . Increased WOB appears mostly because of soft tissue upper airway obstruction [7823995] BACKGROUND Weaning patients from mechanical ventilation is an important problem in intensive care units . Weaning is usually conducted in an empirical manner , and a st and ardized approach has not been developed . METHODS We carried out a prospect i ve , r and omized , multicenter study involving 546 patients who had received mechanical ventilation for a mean ( + /- SD ) of 7.5 + /- 6.1 days and who were considered by their physicians to be ready for weaning . One hundred thirty patients had respiratory distress during a two-hour trial of spontaneous breathing . These patients were r and omly assigned to undergo one of four weaning techniques : intermittent m and atory ventilation , in which the ventilator rate was initially set at a mean ( + /- SD ) of 10.0 + /- 2.2 breaths per minute and then decreased , if possible , at least twice a day , usually by 2 to 4 breaths per minute ( 29 patients ) ; pressure-support ventilation , in which pressure support was initially set at 18.0 + /- 6.1 cm of water and then reduced , if possible , by 2 to 4 cm of water at least twice a day ( 37 patients ) ; intermittent trials of spontaneous breathing , conducted two or more times a day if possible ( 33 patients ) ; or a once-daily trail of spontaneous breathing ( 31 patients ) . St and ardized protocol s were followed for each technique . RESULTS The median duration of weaning was 5 days for intermittent m and atory ventilation ( first quartile , 3 days ; third quartile , 11 days ) , 4 days for pressure-support ventilation ( 2 and 12 days , respectively ) , 3 days for intermittent ( multiple ) trials of spontaneous breathing ( 2 and 6 days , respectively ) , and 3 days for a once-daily trial of spontaneous breathing ( 1 and 6 days , respectively ) . After adjustment for other covariates , the rate of successful weaning was higher with a once-daily trial of spontaneous breathing than with intermittent m and atory ventilation ( rate ratio , 2.83 ; 95 percent confidence interval , 1.36 to 5.89 ; P < 0.006 ) or pressure-support ventilation ( rate ratio , 2.05 ; 95 percent confidence interval , 1.04 to 4.04 ; P < 0.04 ) . There was no significant difference in the rate of success between once-daily trials and multiple trials of spontaneous breathing . CONCLUSIONS A once-daily trial of spontaneous breathing led to extubation about three times more quickly than intermittent m and atory ventilation and about twice as quickly as pressure-support ventilation . Multiple daily trials of spontaneous breathing were equally successful [8131469] The purpose of this study was to determine if a computer-directed weaning system could wean patients with complex medical problems from mechanical ventilation and appropriately respond to signs of respiratory failure more effectively than traditional physician-directed weaning methods . In a prospect i ve , r and omized , controlled study , we tested the system in 15 patients who had required prolonged mechanical ventilation and met predetermined weaning tests . Patients were r and omly assigned to one of two groups : ( 1 ) automatic , computer-directed weaning or ( 2 ) physician-controlled weaning . The computer-directed system decreased or increased the synchronized intermittent m and atory ventilation rate and pressure support ( PS ) based on predetermined limits of patient respiratory rate ( RR ) and tidal volume ( TV ) . Pulse oximeter oxygen saturation was monitored , and alarms were triggered by an oxygen saturation of < 90 percent . In the physician control group , weaning progressed with SIMV rate and PS reduction , as judged appropriate by the physician . Nine patients were assigned to the computer group ; six patients were assigned to the control group . The average patient age was 64.8 + /- 14.9 years for the computer group , 65.2 + /- 22.7 years for the control group . The average time on mechanical ventilation prior to weaning was 13.4 + /- 7.8 days for the computer group and 14.5 + /- 11.1 days for the control group . Seven of the nine computer group patients weaned within 48 h of the study , with an average time to wean of 18.7 + /- 5.9 h. All seven were breathing spontaneously 48 h after weaning . Two of the six control group patients weaned within 48 h of the study , with an average time of 25.6 + /- 5.6 h. Both patients who weaned were placed back on mechanical ventilation within 30 h. The number of arterial blood gas sample s drawn during the study was 1.4 + /- 0.7 for the computer group , 7.2 + /- 4.3 for the control group . The number of minutes per hour outside acceptable limits of RR > 30 , RR < 8 , or TV < 5 ml/kg was 3.2 + /- 2.8 min for the computer group and 6.6 + /- 4.1 min for the control group . The study suggests that use of the computer-directed weaning system results in fewer arterial blood gas sample s , shorter weaning times , and less time spent outside acceptable RR and TV parameters [17398307] BACKGROUND The efficacy of corticosteroids in reducing the incidence of postextubation laryngeal oedema is controversial . We aim ed to test our hypothesis that methylprednisolone started 12 h before a planned extubation could prevent postextubation laryngeal oedema . METHODS We did a placebo-controlled , double-blind multicentre trial in 761 adults in intensive-care units . Patients who were ventilated for more than 36 h and underwent a planned extubation received intravenous 20 mg methylprednisolone ( n=380 ) or placebo ( 381 ) 12 h before extubation and every 4 h until tube removal . The primary endpoint was occurrence of laryngeal oedema within 24 h of extubation . Laryngeal oedema was clinical ly diagnosed and deemed serious if tracheal reintubation was needed . Analyses were done on a per protocol and intention-to-treat basis . This trial is registered at Clinical Trials.gov , number NCT00199576 . FINDINGS 63 patients could not be assessed , mainly because of self-extubation ( n=16 ) or cancelled extubation ( 44 ) between r and omisation and planned extubation . 698 patients were analysed ( 343 in placebo group , 355 in methylprednisolone group ) . Methylprednisolone significantly reduced the incidence of postextubation laryngeal oedema ( 11 of 355 , 3%vs 76 of 343 , 22 % , p<0.0001 ) , the global incidence of reintubations ( 13 of 355 , 4%vs 26 of 343 , 8 % , p=0.02 ) , and the proportion of reintubations secondary to laryngeal oedema ( one of 13 , 8 % vs 14 of 26 , 54 % , p=0.005 ) . One patient in each group died after extubation , and atelectasia occurred in one patient given methylprednisolone . INTERPRETATION Methylprednisolone started 12 h before a planned extubation substantially reduced the incidence of postextubation laryngeal oedema and reintubation . Such pretreatment should be considered in adult patients before a planned extubation that follows a tracheal intubation of more than 36 [11685307] Abstract . Objective : To compare the percentage of infants and children successfully extubated after a trial of breathing performed with either pressure support or T-piece . Design : Prospect i ve and r and omized study . Setting : Three medical-surgical pediatric intensive care units ( PICUs ) . Patients : Two hundred fifty-seven consecutive infants and children who received mechanical ventilation for at least 48 h and were deemed ready to undergo a breathing trial by their primary physician . Interventions : Patients were r and omly assigned to undergo a trial of breathing in one of two ways : pressure support of 10 cmH2O or T-piece . Bedside measurements of respiratory function were obtained immediately before discontinuation of mechanical ventilation and within the first 5 min of breathing through a T-piece . The primary physicians were unaware of those measurements , and the decision to extubate a patient at the end of the breathing trial was made by them . Measurements and main results : Of the 125 patients in the pressure support group , 99 ( 79.2 % ) completed the breathing trial and were extubated , but 15 of them ( 15.1 % ) required reintubation within 48 h. Of the 132 patients in the T-piece group , 102 ( 77.5 % ) completed the breathing trial and were extubated , but 13 of them ( 12.7 % ) required reintubation within 48 h. The percentage of patients who remained extubated for 48 h after the breathing trial did not differ in the pressure support and T-piece groups ( 67.2 % versus 67.4 % , p=0.97 ) . Conclusions : In infants and children mechanically ventilated , successful extubation was achieved equally effectively after a first breathing trial performed with pressure support of 10 cmH2O or a T-piece [15269312] BACKGROUND Most patients requiring mechanical ventilation for acute lung injury and the acute respiratory distress syndrome ( ARDS ) receive positive end-expiratory pressure ( PEEP ) of 5 to 12 cm of water . Higher PEEP levels may improve oxygenation and reduce ventilator-induced lung injury but may also cause circulatory depression and lung injury from overdistention . We conducted this trial to compare the effects of higher and lower PEEP levels on clinical outcomes in these patients . METHODS We r and omly assigned 549 patients with acute lung injury and ARDS to receive mechanical ventilation with either lower or higher PEEP levels , which were set according to different tables of predetermined combinations of PEEP and fraction of inspired oxygen . RESULTS Mean ( + /-SD ) PEEP values on days 1 through 4 were 8.3+/-3.2 cm of water in the lower-PEEP group and 13.2+/-3.5 cm of water in the higher-PEEP group ( P<0.001 ) . The rates of death before hospital discharge were 24.9 percent and 27.5 percent , respectively ( P=0.48 ; 95 percent confidence interval for the difference between groups , -10.0 to 4.7 percent ) . From day 1 to day 28 , breathing was unassisted for a mean of 14.5+/-10.4 days in the lower-PEEP group and 13.8+/-10.6 days in the higher-PEEP group ( P=0.50 ) . CONCLUSIONS These results suggest that in patients with acute lung injury and ARDS who receive mechanical ventilation with a tidal-volume goal of 6 ml per kilogram of predicted body weight and an end-inspiratory plateau-pressure limit of 30 cm of water , clinical outcomes are similar whether lower or higher PEEP levels are used [9927366] The duration of spontaneous breathing trials before extubation has been set at 2 h in research studies , but the optimal duration is not known . We conducted a prospect i ve , multicenter study involving 526 ventilator-supported patients considered ready for weaning , to compare clinical outcomes for trials of spontaneous breathing with target duration s of 30 and 120 min . Of the 270 and 256 patients in the 30- and 120-min trial groups , respectively , 237 ( 87.8 % ) and 216 ( 84.8 % ) , respectively , completed the trial without distress and were extubated ( p = 0.32 ) ; 32 ( 13.5 % ) and 29 ( 13.4 % ) , respectively , of these patients required reintubation within 48 h. The percentage of patients who remained extubated for 48 h after a spontaneous breathing trial did not differ in the 30- and 120-min trial groups ( 75.9 % versus 73.0 % , respectively , p = 0.43 ) . The 30- and 120-min trial groups had similar within-unit mortality rates ( 13 and 9 % , respectively ) and in-hospital mortality rates ( 19 and 18 % , respectively ) . Reintubation was required in 61 ( 13.5 % ) patients , and these patients had a higher mortality ( 20 of 61 , 32.8 % ) than did patients who tolerated extubation ( 18 of 392 , 4.6 % ) ( p < 0.001 ) . Neither measurements of respiratory frequency , heart rate , systolic blood pressure , and oxygen saturation during the trial , nor other functional measurements before the trial discriminated between patients who required reintubation from those who tolerated extubation . In conclusion , after a first trial of spontaneous breathing , successful extubation was achieved equally effectively with trials targeted to last 30 and 120 min [9407568] Objective criteria for ending mechanical ventilation have not been established for infants and children . A recent study in adult patients developed two new indexes , the Rapid Shallow Breathing Index ( RSB ) and the CROP Index for predicting success or failure of extubation . We decided to evaluate the applicability of these indices to intubated , mechanically ventilated pediatric patients . For this evaluation the indices were adapted to the physiology of infants and children . A pneumotachograph was used to measure spontaneous tidal volume , respiratory rate and dynamic compliance . The tidal volume and the dynamic compliance were corrected for the patient 's body weight . Based on the data collected a cutoff value for each index was determined . Of 47 sets of patient data , 38 ( 81 % ) were collected during successful extubations , 9 ( 19 % ) during failed extubations . A modified CROP index value of > or = 0.1 ml x mmHg/bpm/kg and a modified RSB index value of < or = 11 bpm/mlkg were identified as predictive of successful extubation . The modified CROP cutoff value produced a sensitivity and specificity of 1.0 ; respective values for the modified RSB cutoff value are 0.79 and 0.78 . Cutoff values of > or = 0.1 and < or = 11 for the modified CROP index and RSB index , respectively , appear to be predictive of successful extubation in the pediatric population . Our data identifies the modified CROP index as a superior discriminator between successful and unsuccessful extubation [8797633] OBJECTIVE To predict extubation success and failure in mechanically ventilated infants and children using bedside measures of respiratory function . DESIGN Prospect i ve collection of data . SETTING A university-affiliated children 's hospital with a 51-bed critical care unit . PATIENTS All infants and children who were mechanically ventilated for at least 24 hrs , except neonates < or = 37 wks gestation and patients with neuromuscular disease . INTERVENTIONS Bedside measurements of cardiorespiratory function were obtained immediately before extubation . MEASUREMENTS AND MAIN RESULTS Extubation failure was defined as reintubation within 48 hrs of extubation in the absence of upper airway obstruction . Failure rates were calculated for different ranges ( selected a priori ) of preextubation measures of breathing effort , ventilatory support , respiratory mechanics , central inspiratory drive , and integrated indices useful in adults . Effort of spontaneous breathing was assessed by the respiratory rate st and ardized to age , the presence of retractions and paradoxical breathing , inspiratory pressure , maximal negative inspiratory pressure ( maximal negative inspiratory pressure ) , inspiratory pressure/maximal negative inspiratory pressure ratio , and tidal volume indexed to body weight of a spontaneous breath . Ventilatory support was measured by the fraction of inspired oxygen ( F10(2 ) ) , mean airway pressure , oxygenation index , and the fraction of total minute ventilation provided by the ventilator . Respiratory mechanics were assessed by determination of peak ventilatory inspiratory pressure and dynamic compliance . Central inspiratory drive was assessed by mean inspiratory flow . Frequency to tidal volume ratio and the compliance , rate , oxygenation , and pressure indexed to body weight , the integrated indices useful in predicting extubation failure in adults , were also calculated . Thirty-four of the 208 patients who were studied were reintubated for an overall failure rate of 16.3 % ( 95 % confidence interval 11.3 % to 21.4 % ) . The reasons for reintubation were poor effort ( n = 8) , excessive effort ( n = 14 ) , altered mental status or absent airway reflexes ( n = 2 ) , cardiovascular instability ( n = 3 ) , inadequate oxygenation ( n = 3 ) , respiratory acidosis ( n = 3 ) , and undocumented ( n = 1 ) . Extubation failure increased significantly with decreasing tidal volume indexed to body weight of a spontaneous breath , increasing F10(2 ) , increasing mean airway pressure , increasing oxygenation index , increasing fraction of total minute ventilation provided by the ventilator , increasing peak ventilatory inspiratory pressure , or decreasing mean inspiratory flow ( p < .05 ) . Dynamic compliance showed a trend of increasing failure rate with decreasing dynamic compliance but did not reach statistical significance ( p = .116 ) . Respiratory rate st and ardized to age , inspiratory pressure , maximal negative inspiratory pressure , inspiratory pressure/maximal negative inspiratory pressure ratio , frequency to tidal volume ratio , and compliance , rate , oxygenation , and pressure did not show any trend in failure rate with increasing or decreasing values . Threshold values that defined a low risk ( < or = 10 % ) and a high risk ( > or = 25 % ) of extubation failure could be determined for tidal volume indexed to body weight of a spontaneous breath , F10(2 ) , mean airway pressure , oxygenation index , fraction of total minute ventilation provided by the ventilator , peak ventilatory inspiratory pressure , dynamic compliance , and mean inspiratory flow . Neither a low nor a high risk of failure could be defined for frequency to tidal volume ratio or the compliance , rate , oxygenation , and pressure ( CROP ) index . CONCLUSIONS Bedside measurements of respiratory function can predict extubation success and failure in infants and children . Both a low risk and a high risk of failure can be determined using these measures . Integrated indices useful in adults do not reliably predict extubation success or failure [15857531] Objectives : To evaluate the hypotheses that children requiring reintubation are at an increased risk of prolonged hospitalizations , congenital heart disease , and death compared with age- and disease-severity-matched control patients . Design : Prospect i ve decision to evaluate all children undergoing extubation over a 5-yr time interval ( 1997–2001 ) with retrospective analysis of all failed extubation patients . Setting : A large multidisciplinary , dual-site , single-system pediatric intensive care unit caring for critically ill and injured children . Patients : All children intubated and ventilated during the study period ( 1997–2001 ) . Interventions : None . Measurements and Main Results : Failed extubation was defined as the unanticipated requirement to replace an endotracheal tube within 48 hrs of extubation . One hundred thirty children of 3,193 pediatric intensive care unit patients failed extubation ( 4.1 % ) . The median age of children who failed extubation was 6.5 months , compared with a median age of 21.3 months in the control population . The median age of failed extubation in children with cardiac disease was 9.3 months . Failed extubation patients had lengthier hospital and pediatric intensive care unit stays , longer duration of mechanical ventilation , and a higher rate of tracheostomy placement than nonfailed extubation patients ( p < .001 ) . Children with congenital heart disease who failed extubation had the longest duration of hospitalization ( 40.0 ± 5.4 days ) . Conversely , cardiac patients who did not fail extubation had the shortest length of stay ( 11.2 ± 0.4 days ) . Conclusions : In the present trial , 4.1 % of mechanically ventilated children failed extubation . Pediatric intensive care unit patients with failed extubation have longer hospital , pediatric intensive care unit , and ventilator courses but are not at increased risk of death relative to nonfailed extubation patients [1993963] To assess whether there is any advantage in the use of corticosteroid to prevent postextubation stridor in children , we conducted a prospect i ve , r and omized , double-blind trial of dexamethasone versus saline solution . The patients were evaluated and then r and omly selected to receive either dexamethasone or saline solution according to a stratification based on risk factors for postextubation stridor : age , duration of intubation , upper airway trauma , circulatory compromise , and tracheitis . Dexamethasone , 0.5 mg/kg , was given every 6 hours for a total of six doses beginning 6 to 12 hours before and continuing after endotracheal extubation in a pediatric intensive care setting . There was no statistical difference in incidence of postextubation stridor in the two groups ; 23 of 77 children in the placebo group and 16 of 76 in the dexamethasone group had stridor requiring therapy ( p = 0.21 ) . We conclude that the routine use of corticosteroids for the prevention of postextubation stridor during uncomplicated pediatric intensive care airway management is unwarranted [12163791] Objective Trials of potential new therapies in acute lung injury are difficult and expensive to conduct . This article is design ed to determine the utility , behavior , and statistical properties of a new primary end point for such trials , ventilator-free days , defined as days alive and free from mechanical ventilation . Describing the nuances of this outcome measure is particularly important because using it , while ignoring mortality , could result in misleading conclusions . Design To develop a model for the duration of ventilation and mortality and fit the model by using data from a recently completed clinical trial . To determine the appropriate test statistic for the new measure and derive a formula for power . To determine a formula for the probability that the test statistic will reject the null hypothesis and mortality will simultaneously show improvement . To plot power curves for the test statistic and determine sample sizes for reasonable alternative hypotheses . Setting Intensive care units . Patients Patients with acute respiratory distress syndrome or acute lung injury as defined by the American-European Consensus Conference . Main Results The proposed model fit the clinical data . Ventilator-free days were improved by lower tidal volume ventilation , but the improvement was mostly caused by the improved mortality rate , so trials that expected similar effects would only have modest increase in power if they used ventilator-free days as their primary end point rather than 28-day mortality . Similar results were obtained using the model in two groups segregated by low or high Acute Physiology and Chronic Health Evaluation score . On the other h and , if patients are divided into two groups on the basis of the lung injury score , both the duration of ventilation and mortality are lower in the low lung injury score group . A trial of a treatment that had a similar clinical effect would have a large increase in power , allowing for a reduction in the required sample size . Conclusions Use of ventilator-free days as a trial end point allows smaller sample sizes if it is assumed that the treatment being tested simultaneously reduces the duration of ventilation and improves mortality . It is unlikely that a treatment that led to higher mortality could lead to a statistically significant improvement in ventilator-free days . This would be especially true if the treatment were also required to produce a nominal improvement in mortality [15730603] Objective : To describe the incidence of extubation failure and its associated risk factors among mechanically ventilated children . Method : Prospect i ve cohort study . Children who were mechanically ventilated for longer than 12 hrs were followed up to 48 hrs after extubation . Cases of upper airway obstruction , accidental extubation , tracheostomy , or death before extubation were excluded . Extubation failure was defined as reintubation within 48 hrs after extubation . Student ’s t-test , Mann-Whitney , and chi-squared tests , odds ratio with 95 % confidence interval , and multivariate analysis were used for data analysis . Results : Extubation failure rate was 10.5 % ( 13 of 124 patients ) . Variables associated with extubation failure were age between 1 and 3 mos ( odds ratio [ OR ] = 5.68 ; 95 % confidence interval [ CI ] = 1.58–20.42 ) , mechanical ventilation > 15 days ( OR = 6.36 ; 95 % CI = 1.32–30.61 ) , mean oxygenation index ( OI ) > 5 ( OR = 4.08 ; 95 % CI = 1.25–13.30 ) , mean airway pressure 24 hrs before extubation lower than 5 cm H2O ( OR = 6.03 ; 95 % CI = 1.48–24.60 ) , continuous positive airway pressure ( CPAP ) ( OR = 4.71 ; 95 % CI = 1.34–16.58 ) , dopamine and dobutamine use ( OR = 3.71 ; 95 % CI = 1.08–12.78 ) , intravenous sedation > 10 days ( OR = 6.60 ; 95 % CI = 1.62–26.90 ) , tachypnea and subcostal retractions ( relative risk [ RR ] = 3.68 ; 95 % CI = 1.14–11.93 ) , and inspired fraction of oxygen (Fio2)>0.4 after extubation ( RR = 3.63 ; 95 % CI = 1.21–10.88 ) . After multiple logistic regression analysis , age between 1 and 3 mos , mean OI > 5 , CPAP and mechanical ventilation > 15 days remained associated with extubation failure . Conclusion : Extubation failure was more frequent among young infants who received prolonged ventilatory support and intravenous sedation , used CPAP , had impaired lung oxygenation , and required inotropic therapy [7921460] Several modalities of ventilatory support have been proposed to gradually withdraw patients from mechanical ventilation , but their respective effects on the outcome of weaning from mechanical ventilation are not known . We conducted a r and omized trial in three intensive care units in mechanically ventilated patients who met st and ard weaning criteria . Those who could not sustain 2 h of spontaneous breathing were r and omly assigned to be weaned with T-piece trials , with synchronized intermittent m and atory ventilation ( SIMV ) , or with pressure support ventilation ( PSV ) . Specific criteria for performing tracheal extubation were defined for each modality . The number of patients who could not be separated from the ventilator at 21 d ( i.e. , who failed to wean ) was compared between the groups . Patients in whom tracheal intubation was required in a 48-h period following extubation were also classified as failures . Among 456 mechanically ventilated patients who met weaning criteria , 109 entered into the study ( 35 with T piece , 43 with SIMV , and 31 with PSV ) . The three groups were comparable in terms of etiology of disease or characteristics at entry in the study . When all causes for weaning failure were considered , a lower number of failures was found with PSV than with the other two modes , with the difference just reaching the level of significance ( 23 % for PSV , 43 % for T piece , 42 % for SIMV ; p = 0.05 ) . After excluding patients whose weaning was terminated for complications unrelated to the weaning process , the difference became highly significant ( 8 % for PSV versus 33 % and 39 % , p < 0.025 ) . ( ABSTRACT TRUNCATED AT 250 WORDS [16738500] Objective : To assess the value of a spontaneous breathing trial ( SBT ) using a flow-inflating bag in predicting extubation success . Secondary goals were to evaluate the positive and negative predictive accuracy of a 15-min SBT . Design : Prospect i ve , blinded , clinical study . Setting : Pediatric intensive care unit ( ICU ) of a university hospital Patients : Infants and children intubated for ≥24 hrs . Interventions : Patients who met defined criteria for extubation underwent a 15-min SBT connected to a flow-inflating bag set to provide 5 cm H2O continuous positive airway pressure . Measurements and Main Results : Seventy patients underwent the SBT . Respiratory rate , heart rate , blood pressure , and pulse oxygen saturations were recorded at baseline and at 5 and 15 mins into the SBT . The ICU physicians were blinded to the results of the SBT , and all patients were extubated at the end of the trial . Patients were observed for the next 24 hrs , and the need for noninvasive ventilation or reintubation ( i.e. , extubation failure ) was recorded . Sixty-four patients ( 91 % ) passed the SBT with a subsequent extubation failure rate of 7.8 % ( only 1.6 % required reintubation ) . Six of the 70 ( 9 % ) patients enrolled failed the trial , but half were extubated successfully . Successful completion of the SBT has a 95 % sensitivity for predicting successful extubation with a positive predictive value of 92 % and an odds ratio of 12 ( 95 % confidence interval , 1.3 , 53.7 ) . The specificity of the SBT was 37 % with a negative predictive value of 50 % . Logistic regression analysis revealed a significant association between passing the SBT and extubation success ( p = .017 ) . Conclusions : A 15-min flow-inflating bag SBT represents a practical , reliable bedside test that has 95 % sensitivity for predicting extubation success in pediatric ICU patients . A trial failure is associated with but does not accurately predict extubation failure [2023603] BACKGROUND The traditional predictors of the outcome of weaning from mechanical ventilation -- minute ventilation ( VE ) and maximal inspiratory pressure (Plmax)--are frequently inaccurate . We developed two new indexes : the first quantitates rapid shallow breathing as the ratio of respiratory frequency to tidal volume ( f/VT ) , and the second is termed CROP , because it integrates thoracic compliance , respiratory rate , arterial oxygenation , and Plmax . METHODS The threshold values for each index that discriminated best between a successful and an unsuccessful outcome of weaning were determined in 36 patients , and the predictive accuracy of these values was then tested prospect ively in an additional 64 patients . Sensitivity and specificity were calculated , and the data were also analyzed with receiver-operating-characteristic ( ROC ) curves , in which the proportions of true positive results and false positive results are plotted against each other for a number of threshold values of an index ; the area under the curve reflects the accuracy of the index . RESULTS Sensitivity was highest for Plmax ( 1.00 ) , followed closely by the f/VT ratio ( 0.97 ) . Specificity was highest for the f/VT ratio ( 0.64 ) and lowest for Plmax ( 0.11 ) . The f/VT ratio was the best predictor of successful weaning , and Plmax and the f/VT ratio were the best predictors of failure . The area under the ROC curve for the f/VT ratio ( 0.89 ) was larger than that under the curves for the CROP index ( 0.78 , P less than 0.05 ) , Plmax ( 0.61 , P less than 0.001 ) , and VE ( 0.40 , P less than 0.001 ) . CONCLUSIONS Rapid shallow breathing , as reflected by the f/VT ratio , was the most accurate predictor of failure , and its absence the most accurate predictor of success , in weaning patients from mechanical ventilation [14697111] Objective Children undergoing congenital heart surgery require mechanical ventilation . We sought to identify pre- and intraoperative factors ( PrO , IO ) associated with successful early extubation < 24 hrs . Design and Patients We performed a retrospective chart review of children < 36 months old who underwent congenital heart surgery from January 1998 to July 1999 . Setting Pediatric intensive care unit in a children ’s hospital . Measurements Generalized Estimating Equation models were fit to assess the association between PrO and IO and early extubation while accounting for the correlation between surgeries performed on the same patient . Estimated odds ratios ( EOR ) and 95 % confidence intervals were calculated . Multivariable models were constructed using a forward selection process with inclusion criteria of p < .05 . Multivariable models , which included PrO and IO variables , were adjusted for procedure group . The area under the receiver operating characteristic curve was computed for each model . Results A total of 203 children underwent 219 surgeries ; 103 ( 47 % ) children were extubated in < 24 hrs , with only one ( 1 % ) failed extubation . PrO variables associated with successful early extubation included age > 6 months ( EOR , 6.1 ) , absence of pulmonary hypertension ( EOR , 9.1 ) , gestational age > 36 wks ( EOR , 4.6 ) , and absence of congestive heart failure ( EOR , 2.4 ) . IO variables were less likely to be associated with successful early extubation . Our model of PrO variables with multiple factors showed that presence of two factors was associated with an EOR of 4.2 for successful early extubation compared with children with zero or one factor . Presence of three and four factors was associated with an EOR of 18.0 and 76.5 , respectively . The area under the receiver operating characteristic curve for this model is 0.816 . Incision type , complex vs. simple procedure , and palliative vs. complete repair were not associated with success of early extubation . Conclusions Early extubation is possible in many very young children undergoing congenital heart surgery , with a low rate of failed extubation . The model would be improved by prospect i ve validation with larger numbers at multiple institutions [15286557] Objective : Continuous venovenous hemofiltration ( CVVH ) is used for renal replacement and fluid management in critically ill children . A previous small study suggested that survival was associated with less percent fluid overload ( % FO ) in the intensive care unit ( ICU ) before hemofiltration . We review ed our experience with a large series of pediatric CVVH patients to evaluate factors associated with outcome . Design : Retrospective chart review . Setting : Tertiary children ’s hospital . Patients : CVVH pediatric ICU patients from November 1997 to January 2003 . Interventions : None . Measurements and Main Results : % FO was defined as total fluid input minus output ( up to 7 days before CVVH for both hospital stay and ICU stay ) divided by body weight . One hundred thirteen patients received CVVH ; 69 survived ( 61 % ) . Multiple organ dysfunction syndrome ( MODS ) was present in 103 patients ; 59 survived ( 57 % ) . Median patient age was 9.6 yrs ( 25th , 75th percentile : 2.5 , 14.3 ) . Median % FO was significantly lower in survivors vs. nonsurvivors for all patients ( 7.8 % [ 2.0 , 16.7 ] vs. 15.1 % [ 4.9 , 25.9 ] ; p = .02 ] and in patients with ≥3-organ MODS ( 9.2 % [ 5.1,16.7 ] vs. 15.5 % [ 8.3 , 28.6 ] ; p = .01 ) . The Pediatric Risk of Mortality Score III at CVVH initiation also was associated with survival in these groups , but by multivariate analysis , % FO was independently associated with survival in patients with ≥3-organ MODS ( p = .01 ) . Conclusions : Survival in critically ill children receiving CVVH in this large series was higher than in previous reports . CVVH survival may be associated with less % FO in patients with ≥3-organ MODS . Prospect i ve studies are necessary to determine whether earlier use of CVVH to control fluid overload in critically ill children can improve survival [17693913] Objective : To evaluate the applicability , tolerance , and efficacy of a closed-loop protocol to wean children from mechanical ventilation . Design : Prospect i ve single-center pilot study . Setting : Tertiary care university hospital . Patients : Twenty mechanically ventilated children aged between 1 and 17 yrs , with a body weight ≥10 kg , no inotropes , and no heavy sedation . Interventions : Patients were weaned in pressure support mode by a closed-loop computerized protocol ( closed-loop protocol ) that interprets clinical data in real time and controls pressure support levels . Measurements and Main Results : The closed-loop protocol applicability and tolerance were evaluated . The efficacy of this protocol was evaluated by comparing the duration of mechanical ventilation with a historical group of 20 patients weaned with a clinician-decision protocol . The closed-loop protocol successfully decreased pressure support ventilation in 16 children , recommended separation from the ventilator in 14 children , and did not cause any serious adverse events . Mechanical ventilation duration was 5.1 ± 4.2 days in the closed-loop group and 6.7 ± 11.5 days ( mean ± sd ) in the clinician-decision group ( p = .33 ) with no difference in the need for reintubation or noninvasive mechanical ventilation ( one of 20 and four of 20 , respectively ; p = .20 ) . Conclusions : A closed-loop protocol was successfully used to wean children from mechanical ventilation . Further studies are required to assess the impact of this novel therapeutic strategy on the length of mechanical ventilation [15764727] Several variables are recommended for identifying if a patient is ready for a trial of weaning from mechanical ventilation , but there is no agreement as to whether monitoring any variable during the trial enhances patient management . To determine whether repeated measurements of esophageal pressure throughout a trial are more reliable than measurements of esophageal pressure or frequency-to-VT ratio during the first minute of the trial , we studied 60 patients . A trend index that quantified esophageal pressure swings over time was more reliable than the first-minute measurements : sensitivity , 0.91 , and specificity , 0.89 . Area under receiver operating characteristic curve for trend index ( 0.94 ) was greater than for first-minute measurement of esophageal pressure ( 0.44 , p < 0.05 ) and tended to be greater than that for frequency-to-VT ratio ( 0.78 , p = 0.13 ) . The likelihood ratio was highest for the trend index ( 8.2 , p < 0.05 ) . The advantage of the trend index may be related to the progressive increase in esophageal pressure throughout a failed weaning trial , whereas breathing pattern changed little after 2 minutes of spontaneous breathing . In conclusion , continuous monitoring of esophageal pressure swings during a spontaneous breathing trial provides additional guidance in patient management over tests used for deciding when to initiate weaning [11265020] BACKGROUND Variability and logistic complexity of mechanical ventilatory support of acute respiratory distress syndrome , and need to st and ardize care among all clinicians and patients , led University of Utah/LDS Hospital physicians , nurses , and engineers to develop a comprehensive computerized protocol . This bedside decision support system was the basis of a multicenter clinical trial ( 1993 - 1998 ) that showed ability to export a computerized protocol to other sites and improved efficacy with computer- versus physician-directed ventilatory support . The Memorial Hermann Hospital Shock Trauma intensive care unit ( ICU ) ( Houston , TX ; a Level I trauma center and teaching affiliate of The University of Texas Houston Medical School ) served as one of the 10 trial sites and recruited two thirds of the trauma patients . Results from the trauma patient subgroup at this site are reported to answer three questions : Can a computerized protocol be successfully exported to a trauma ICU ? Was ventilator management different between study groups ? Was patient outcome affected ? METHODS Sixty-seven trauma patients were r and omized at the Memorial Hermann Shock Trauma ICU site . " Protocol " assigned patients had ventilatory support directed by the bedside respiratory therapist using the computerized protocol . " Non protocol " patients were managed by physician orders . RESULTS Of the 67 trauma patients r and omized , 33 were protocol ( age 40 + /- 3 ; Injury Severity Score [ ISS ] 26 + /- 3 ; 73 % blunt ) and 34 were non protocol ( age 38 + /- 2 ; ISS 25 + /- 2 ; 76 % blunt ) . For the protocol group , the computerized protocol was used 96 % of the time of ventilatory support and 95 % of computer-generated instructions were followed by the bedside respiratory therapist . Outcome measures ( i.e. , survival , ICU length of stay , morbidity , and barotrauma ) were not significantly different between groups . Fio2 > or = 0.6 and Pplateau > or = 35 cm H2O exposures were less for the protocol group . CONCLUSION A computerized protocol for bedside decision support was successfully exported to a trauma center , and effectively st and ardized mechanical ventilatory support of trauma-induced acute respiratory distress syndrome without adverse effect on patient outcome [6377071] Previous studies have suggested that the early application of positive end-expiratory pressure ( PEEP ) reduces the incidence of the adult respiratory-distress syndrome . We r and omly assigned 92 patients with a known risk for this syndrome to receive mechanical ventilation either without PEEP ( control ) or with early PEEP at 8 cm H2O . These therapies continued for 72 hours unless respiratory distress developed or arterial oxygen tension was above 140 ( fractional inspired oxygen concentration , 0.5 ) at 24 hours or later and remained at that level after removal of PEEP . The study was design ed to have an 80 per cent probability of detecting a 60 per cent reduction in the incidence of the syndrome . The treatment groups were comparable in age , severity of injury , number and type of risk factors for adult respiratory-distress syndrome , and initial oxygenation . The syndrome developed in 11 of 44 patients given early PEEP ( 25 per cent ) and in 13 of 48 control patients ( 27 per cent ) . The incidence of atelectasis , pneumonia , and barotrauma was the same in both groups , as was mortality . We found that the early application of PEEP at 8 cm H2O in high-risk patients had no effect on the incidence of the adult respiratory-distress syndrome or other , associated complications [15001938] OBJECTIVE To report our experience with cuffed endotracheal tubes ( ETT ) in a large cohort of critically ill children . Study design We prospect ively collected data over a 1-year period concerning long-term intubation on 860 critically ill children admitted to our intensive care unit . Tube sizes were dictated by the modified Cole formula for uncuffed ETT ( age [y]/4 + 4 mm ID ) and chosen one-half size less for cuffed ETT . Cuff pressure was regularly monitored to maintain a small leak at peak inspiratory pressure . The choice of ETT was made by the physician responsible for the initial airway management . RESULTS There were 597 patients in the first 5 years of life , with 210 having cuffed ETT . There were no significant differences in the use of racemic epinephrine for postextubation subglottic edema , the rate of successful extubation or the need for tracheotomy between those with cuffed and uncuffed ETT in any age group . CONCLUSIONS Our data suggest that the traditional teaching in pediatric anesthesia and intensive care , including current pediatric life support recommendations , need to be review ed for children to benefit from the advantages of modern low-pressure cuffed ETT during critical illnesses [2298007] All patients intubated in the neonatal ( NICU ) and pediatric ( PICU ) ICUs over a 3-yr period were evaluated prospect ively to determine the incidence of accidental extubation ( AE ) and contributing factors . Two thous and two hundred patients ( age range 26 wk gestation to 18 yr ) were intubated for a total of 21,222 days . In the PICU and NICU , a total of 153 patients experienced 195 AE . The PICU had 113 AE in 1,388 subunit for a rate of 1.15 AE/100 intubated days . The NICU had 82 AE in 812 intubated patients , a rate of 0.72 AE/100 intubated days . A review of factors contributing to AE showed the most critical to be : sedation not administered in the 2 h before AE ( 65 % ) , the lack of two-point or more restraints ( 58 % ) , and the performance of a patient procedure at the bedside ( 49 % ) . One death occurred as an indirect consequence of AE . The data are being reported as a function of number of days intubated in an attempt to st and ardize reporting techniques . The use of st and ardized reporting and the identification of high-risk factors may be useful for education and modification of patient care practice s. ( Crit Care Med 1990 ; 18:163 [10966284] Objective To vali date predictors of extubation success and failure in mechanically ventilated infants and children by using bedside measures of respiratory function . Design Prospect i ve , descriptive study . Setting A university-affiliated children ’s hospital with a 51-bed critical care area . Patients All infants and children who were mechanically ventilated for ≥24 hrs except neonates ≤37 wks gestation and patients with neuromuscular disease . Interventions None . Measurements and Methods Extubation failure was defined as reintubation within 48 hrs of extubation in the absence of upper airway obstruction . Failure rates were calculated for different ranges ( selected a priori ) of preextubation measures of breathing effort , ventilator support , respiratory mechanics , central inspiratory drive , and integrated indices useful in adults . Effort of spontaneous breathing was assessed by the respiratory rate st and ardized to age , the presence of retractions and paradoxic breathing , inspiratory pressure , maximal negative inspiratory pressure , ratio of inspiratory pressure to maximal negative inspiratory pressure , and tidal volume indexed to body weight of a spontaneous breath . Ventilator support was measured by Fio2 , mean airway pressure , oxygenation index , and the fraction of total minute ventilation provided by the ventilator . Respiratory mechanics was assessed by peak ventilatory inspiratory pressure and dynamic compliance . Central inspiratory drive was assessed by mean inspiratory flow . Frequency to tidal volume ratio and the CROP ( compliance , rate , oxygenation , and pressure ) indexed to body weight , the integrated indices useful in predicting extubation failure in adults , were also calculated . A regression test for a linear trend in proportions was performed with preselected ranges and the corresponding failure rates . The failure rates from this study ( validation group ) were compared to those published previously ( prediction group ) by the chi-square test for proportions . The distribution of categorical variables between groups was analyzed by using the chi-square test or the Fisher ’s exact test , and p < .05 was considered significant . Main Results The study involved 312 patients . There were no differences in any of the clinical characteristics between the prediction and validation groups . The reasons for reintubation were similar in both groups . Preextubation data were also similar between the two groups . There were no differences between the prediction and the validation groups in failure rates with different ranges . There were no differences in the failure rates for any of the cutoff values for peak ventilatory inspiratory pressure , mean airway pressure , Fio2 , oxygenation index , dynamic compliance , tidal volume indexed to body weight of a spontaneous breath , fraction of total minute ventilation provided by the ventilator , and mean inspiratory flow . Conclusions Bedside measures of respiratory function can predict extubation success and failure in infants and children . Both a low risk and a high risk of failure can be determined by using these measures . Integrated indices useful in adults do not reliably predict extubation success or failure in infants and children . Our study vali date s our previously published study [12780985] Background Most children who undergo congenital heart surgery require postoperative mechanical ventilation . Failed extubation ( FE ) may result in physiologic instability , delay , or set back of the weaning process . FE is statistically associated with prolonged mechanical ventilation . Purpose We sought to identify frequency , pathogenesis , and risk factors for FE after congenital heart surgery in young children . Setting Pediatric intensive care unit . Patients Children ≤36 months of age who underwent congenital heart surgery in the period between January 1998 and July 1999 at our children ’s hospital . Measurements and Statistical Methods We performed a retrospective chart review . We defined reintubation within 24 hrs as an FE . Demographic , preoperative , intraoperative , and postoperative data were collected . A modified version of logistic regression , which accounts for lack of independence in data with multiple records per subject , was used to assess the impact of risk factors for FE . A forward selection process was used with p < .05 as the criterion for entry into the model . Estimated odds ratios ( EORs ) are reported with 95 % confidence intervals ( CI ) . The predictive ability of the final model was assessed by using area under the receiver operating characteristic curve . Main Results A total of 212 children ≤36 months of age underwent 230 congenital heart operations . Eleven children ( 5.2 % ) died perioperatively . After excluding patients who died , there were 219 surgeries among 202 patients ; 25.9 % ( 51 of 197 ) , 51.8 % ( 102 of 197 ) , and 72.6 % ( 143 of 197 ) of patients were successfully extubated by 12 , 24 , and 48 hrs , respectively . There were 22 cases in which an initial attempt at extubation failed at a median of 67.8 hrs ( range , 2.4–335.5 hrs ) . Five patients failed a subsequent attempt at extubation at a median of 189.5 hrs ( range , 115.8–602.5 hrs ) . The most common causes of initial FE were cardiac dysfunction ( n = 6 ) , lung disease ( n = 6 ) , and airway edema ( n = 3 ) . Risk factors for FE included pulmonary hypertension ( EOR , 38.7 ; 95 % CI , 2.9–25.8;p < .001 ) , Down syndrome ( EOR , 4.6 ; 95 % CI , 1.8–11.8;p = .002 ) , and deep hypothermic circulatory arrest ( EOR , 4.5 ; 95 % CI , 1.3–17.5;p = .018 ) . All were independent predictors of FE ( area under the curve , 0.837 ) . The strongest predictor was pulmonary hypertension , which when used alone to predict FE provided a sensitivity of 0.83 ( 95 % CI , 0.59–0.94 ) and a specificity of 0.75 ( 95 % CI , 0.68–0.80 ) . Conclusions Extubation fails after approximately 10 % of congenital heart surgery in young patients . Causes of FE are diverse . In our population , preoperative pulmonary hypertension , presence of a congenital syndrome , and intraoperative circulatory arrest are risk factors for FE . Prospect i ve validation of our predictive model with larger numbers and at multiple institutions would improve its utility [12813282] Objective Unsuccessful extubation from mechanical ventilation increases mortality and morbidity . Therefore , the identification of an accurate predictor of successful extubation is desirable . This study was design ed to determine whether the results of easily performed respiratory measurements , particularly if reported as “ combined extubation ” indices , were better predictors of extubation failure in a pediatric population than were readily available clinical data . Design Prospect i ve observational study . Setting Tertiary pediatric intensive care unit . Patients All children who required mechanical ventilation for ≥24 hrs during a 12-month period and whose parents gave informed written consent . Interventions Respiratory function measurements were made ( on average ) 7 hrs ( range , 0.2–25.0 hrs ) before extubation . Arterial blood gas results were obtained immediately before extubation . The values of each predictor associated with maximum sensitivity and specificity were determined , and the areas under receiver operator characteristic curves were compared to determine the most accurate predictor of successful extubation . Measurements and Main Results A total of 47 children ( mean age , 3.90 yrs ; range , 0.10–17.3 yrs ) were studied ; extubation failed in 7 . A low tidal volume ( < 7.5 mL/kg ) and a low minute volume ( < 250 mL/kg ) had the highest sensitivities ( 86 % and 71 % , respectively ) and specificities ( 61 % and 71 % , respectively ) in predicting extubation failure . The a/A ratio performed least well in predicting extubation failure ( area under the receiver operating characteristic curve , 0.51 ) . Conclusions Volume measurements during pediatric mechanical ventilation may facilitate successful extubation [9228375] OBJECTIVE To examine medical outcomes associated with reintubation for extubation failure after discontinuation of mechanical ventilation . DESIGN Prospect i ve cohort study of consecutive intubated medical ICU patients who underwent a trial of extubation at a tertiary-care teaching hospital . The failed extubation group consisted of all patients reintubated within 72 h or within 7 days ( if continuous ICU care had been required ) of extubation . All others were considered to be successfully extubated . Study end points included hospital death vs survival , the number of days spent in the ICU and in the hospital after the onset of mechanical ventilation , the likelihood of requiring > or = 7 or > or = 14 days of ICU care after extubation , and the need for transfer to either a long-term care or rehabilitation facility among the survivors . RESULTS Of 289 intubated patients , 247 ( 85 % ) were successfully extubated , and 42 ( 15 % ) required reintubation for failed extubation ( time to reintubation 1.5+/-0.2 days ) . Reintubation for extubation failure result ed in 12 additional days of mechanical ventilation . When compared with successfully extubated patients , reintubated patients were more likely to die in the hospital ( 43 % vs 12 % ; p<0.0001 ) , spend more time in the ICU ( 21.2+/-2.8 days vs 4.5+/-0.6 days ; p<0.001 ) and in the hospital ( 30.5+/-3.3 days vs 16.3+/-1.2 days ; p<0.001 ) after extubation , and require transfer to a long-term care or rehabilitation facility ( 38 % vs 21 % ; p<0.05 ) . Using multiple logistic regression , extubation failure was an independent predictor for death and the need for transfer to a long-term care facility . Compared with those successfully extubated , patients who failed extubation were seven times ( p<0.0001 ) more likely to die , 31 times ( p<0.0001 ) more likely to spend > or = 14 days in the ICU after extubation , and six times ( p<0.001 ) more likely to need transfer to a long-term care or rehabilitation facility if they survived . CONCLUSION After adjusting for severity of illness and comorbid conditions , extubation failure had a significant independent association with increased risk for death , prolonged ICU stay , and transfer to a long-term care or rehabilitation facility . Extubation failure may serve as an additional independent marker of severity of illness . Alternatively , poor outcomes may be etiologically related to extubation failure . If the latter proves to be the case , identifying patients at risk for poor outcomes from extubation failure and instituting alternative care practice s may reduce mortality , duration of ICU stay , and need for transfer to a long-term care facility Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Multiple pharmacologic treatments have been studied for acute lung injury ( ALI ) and acute respiratory distress syndrome ( ARDS ) . OBJECTIVES Our objective was to determine the effects of pharmacologic treatments on clinical outcomes in adults with ALI or ARDS . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

22965186

[17893311] BACKGROUND To our knowledge , verum acupuncture has never been directly compared with sham acupuncture and guideline -based conventional therapy in patients with chronic low back pain . METHODS A patient- and observer-blinded r and omized controlled trial conducted in Germany involving 340 outpatient practice s , including 1162 patients aged 18 to 86 years ( mean + /- SD age , 50 + /- 15 years ) with a history of chronic low back pain for a mean of 8 years . Patients underwent ten 30-minute sessions , generally 2 sessions per week , of verum acupuncture ( n = 387 ) according to principles of traditional Chinese medicine ; sham acupuncture ( n = 387 ) consisting of superficial needling at nonacupuncture points ; or conventional therapy , a combination of drugs , physical therapy , and exercise ( n = 388 ) . Five additional sessions were offered to patients who had a partial response to treatment ( 10%-50 % reduction in pain intensity ) . Primary outcome was response after 6 months , defined as 33 % improvement or better on 3 pain-related items on the Von Korff Chronic Pain Grade Scale question naire or 12 % improvement or better on the back-specific Hanover Functional Ability Question naire . Patients who were unblinded or had recourse to other than permitted concomitant therapies during follow-up were classified as nonresponders regardless of symptom improvement . RESULTS At 6 months , response rate was 47.6 % in the verum acupuncture group , 44.2 % in the sham acupuncture group , and 27.4 % in the conventional therapy group . Differences among groups were as follows : verum vs sham , 3.4 % ( 95 % confidence interval , -3.7 % to 10.3 % ; P = .39 ) ; verum vs conventional therapy , 20.2 % ( 95 % confidence interval , 13.4 % to 26.7 % ; P < .001 ) ; and sham vs conventional therapy , 16.8 % ( 95 % confidence interval , 10.1 % to 23.4 % ; P < .001 . CONCLUSIONS Low back pain improved after acupuncture treatment for at least 6 months . Effectiveness of acupuncture , either verum or sham , was almost twice that of conventional therapy [12890859] OBJECTIVE To determine if acupuncture is an effective , safe adjunctive treatment to st and ard therapy for chronic low back pain ( LBP ) in older patients . METHODS The inclusion criteria for subjects were : ( i ) LBP > or = 12 weeks and ( ii ) age > or = 60 yr ; the exclusion criteria were ( i ) spinal tumour , infection or fracture and ( ii ) associated neurological symptoms . The subjects were r and omized to two groups . The control group of subjects continued their usual care as directed by their physicians , i.e. NSAIDs , muscle relaxants , paracetamol and back exercises . Subjects in the acupuncture group in addition received biweekly acupuncture with electrical stimulation for 5 weeks . Outcome was measured by the modified Rol and Disability Question naire ( RDQ ) at weeks 0 , 2 , 6 and 9 . The primary outcome measure was change in RDQ score between weeks 0 and 6 . RESULTS Fifty-five patients were enrolled , with eight drop-outs . Twenty-four subjects were r and omized to the acupuncture group and 23 were r and omized to the control group . Acupuncture subjects had a significant decrease in RDQ score of 4.1 + /- 3.9 at week 6 , compared with a mean decrease of 0.7 + /- 2.8 in the control group ( P = 0.001 ) . This effect was maintained for up to 4 weeks after treatment at week 9 , with a decrease in RDQ of 3.5 + /- 4.4 from baseline , compared with 0.43 + /- 2.7 in the control group ( P = 0.007 ) . The mean global transition score was higher in the acupuncture group , 3.7 + /- 1.2 , indicating greater improvement , compared with the score in the control group , 2.5 + /- 0.9 ( P < 0.001 ) . Fewer acupuncture subjects had medication-related side-effects compared with the control group . CONCLUSIONS Acupuncture is an effective , safe adjunctive treatment for chronic LBP in older patients [18591906] Objectives To compare the effect of acupuncture ( manual and electroacupuncture ) with that of a non-penetrating sham ( ‘ placebo ’ needle ) in patients with osteoarthritic knee pain and disability who are blind to the treatment allocation . Methods Acupuncture naive patients with symptomatic and radiological evidence of osteoarthritis of the knee were r and omly allocated to a course of either acupuncture or non-penetrating sham acupuncture using a sheathed ‘ placebo ’ needle system . Acupuncture points for pain and stiffness were selected according to acupuncture theory for treating Bi syndrome . Both manual and electrical stimulation were used . Response was assessed using the WOMAC index for osteoarthritis of the knee , self reported pain scale , the EuroQol score and plasma β-endorphin . The effectiveness of blinding was assessed . Results There were 34 patients in each group . The primary end point was the change in WOMAC pain score after the course of treatment . Comparison between the two treatment groups found a significantly greater improvement with acupuncture ( mean difference 60 , 95 % CI 5 to 116 , P=0.035 ) than with sham . Within the acupuncture group there was a significant improvement in pain ( baseline 294 , mean change 95 , 95 % CI 60 to 130 , P<0.001 ) which was not seen by those who had sham acupuncture ( baseline 261 , mean change 35 , 95 % CI-10 to 80 , P=0.12 ) . Similar effects within group , but not between groups , were seen with the secondary end points of WOMAC stiffness , WOMAC function , and self reported pain . One month after treatment the between group pain difference had been lost ( mean difference 46 ; 95 % CI −9 to 100 , P=0.10 ) although the acupuncture group was still benefiting compared to baseline ( mean difference 59 ; 95 % CI 16 to 102 , P=0.009 ) . The EuroQol score , a generic measure of health related quality of life , was not altered by the treatments . A minority of patients correctly guessed their treatment group ( 41 % in the acupuncture group and 44 % in the control group ) . Plasma β-endorphin levels were not affected by either treatment . Conclusions Acupuncture gives symptomatic improvement for patients with osteoarthritis of the knee , and is significantly superior to non-penetrating sham acupuncture . The study did not confirm earlier reports of release of plasma β-endorphin during acupuncture [15077933] Background Using an open r and omised controlled study , we examined the effectiveness of manual and electroacupuncture on symptom relief for patients with osteoarthritis of the knee . Methods Patients with symptomatic osteoarthritis of the knee were r and omised to one of three treatment groups . Group A had acupuncture alone , group B had acupuncture but continued on their symptomatic medication , and group C used their symptomatic medication for the first five weeks and then had a course of acupuncture added . Patients receiving acupuncture were treated twice weekly over five weeks . Needles were inserted ( with manual and electrical stimulation ) in acupuncture points for pain and stiffness , selected according to traditional acupuncture theory for treating Bi syndrome . Patients were assessed by a blinded observer before treatment , after five weeks ’ treatment and at one month follow up , using a visual analogue pain scale ( VAS ) and the Western Ontario McMaster ( WOMAC ) question naire for osteoarthritis of the knee . Results The 30 patients in our study were well matched for age , body mass index , disease duration , baseline VAS pain score and baseline WOMAC scores . Repeated measure analyses gave a highly significant improvement in pain ( VAS ) after the courses of acupuncture in groups A ( P=0.012 ) and B ( P=0.001 ) ; there was no change in group C until after the course of acupuncture , when the improvement was significant ( P=0.001 ) . Similarly significant changes were seen with the WOMAC pain and stiffness scores . These benefits were maintained during the one month after the course of acupuncture . Patients ’ rating of global assessment was higher than that of the acupuncturist . Conclusion We conclude that manual and electroacupuncture causes a significant improvement in the symptoms of osteoarthritis of the knee , either on its own or as an adjunct therapy , with no loss of benefit after one month [1713236] Background Acupuncture is increasingly being used for many conditions including chronic neck pain . However the evidence remains inconclusive , indicating the need for further well- design ed research . The aim of this study was to conduct a pilot r and omised controlled parallel arm trial , to establish key features required for the design and implementation of a large-scale trial on acupuncture for chronic neck pain . Methods Patients whose GPs had diagnosed neck pain were recruited from one general practice , and r and omised to receive usual GP care only , or acupuncture ( up to 10 treatments over 3 months ) as an adjunctive treatment to usual GP care . The primary outcome measure was the Northwick Park Neck Pain Question naire ( NPQ ) at 3 months . The primary analysis was to determine the sample size for the full scale study . Results Of the 227 patients with neck pain identified from the GP data base , 28 ( 12.3 % ) consenting patients were eligible to participate in the pilot and 24 ( 10.5 % ) were recruited to the trial . Ten patients were r and omised to acupuncture , receiving an average of eight treatments from one of four acupuncturists , and 14 were r and omised to usual GP care alone . The sample size for the full scale trial was calculated from a clinical ly meaningful difference of 5 % on the NPQ and , from this pilot , an adjusted st and ard deviation of 15.3 % . Assuming 90 % power at the 5 % significance level , a sample size of 229 would be required in each arm in a large-scale trial when allowing for a loss to follow-up rate of 14 % . In order to achieve this sample , one would need to identify patients from data bases of GP practice s with a total population of 230,000 patients , or approximately 15 GP practice s roughly equal in size to the one involved in this study ( i.e. 15,694 patients ) . Conclusion This pilot study has allowed a number of recommendations to be made to facilitate the design of a large-scale trial , which in turn will help to clarify the existing evidence base on acupuncture for neck pain [16781068] & NA ; Acupuncture is widely used by patients with neck pain , but there is a lack of information about its effectiveness in routine medical care . The aim was to investigate the effectiveness of acupuncture in addition to routine care in patients with chronic neck pain compared to treatment with routine care alone . We performed a r and omized controlled multicentre trial plus non‐r and omized cohort in general practice s in Germany . 14,161 patients with chronic neck pain ( duration > 6 months ) . Patients were r and omly allocated to an acupuncture group or a control group receiving no acupuncture . Patients in the acupuncture group received up to 15 acupuncture sessions over three months . Patients who did not consent to r and omization received acupuncture treatment . All subjects were allowed to receive usual medical care in addition to study treatment . Neck pain and disability ( NPAD Scale by Wheeler ) after three months . Of 14,161 patients ( mean age 50.9 ± 13.1 years , 68 % female ) 1880 were r and omized to acupuncture and 1886 to control , and 10,395 included into the non‐r and omized acupuncture group . At three months , neck pain and disability improved by 16.2 ( SE : 0.4 ) to 38.3 ( SE : 0.4 ) ; and by 3.9 ( SE : 0.4 ) to 50.5 ( SE : 0.4 ) , difference 12.3 ( p < 0.001 ) in the acupuncture and control group , respectively . Treatment success was essentially maintained through six months . Non‐r and omized patients had more severe symptoms at baseline and showed higher neck pain and disability improvement compared to r and omized patients . Treatment with acupuncture added to routine care in patients with chronic neck pain was associated with improvements in neck pain and disability compared to treatment with routine care alone [10378713] OBJECTIVE The purpose of this study was to investigate the efficacy of acupuncture as an adjunctive therapy to st and ard care for the relief of pain and dysfunction in elderly patients with osteoarthritis ( OA ) of the knee . METHODS Seventy-three patients with symptomatic OA of the knee were r and omly assigned to treatment ( acupuncture ) or st and ard care ( control ) . Analysis was performed on last score carried forward to account for patients who dropped out before completion . Patients self-scored Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) and Lequesne indices at baseline and at 4 , 8 and 12 weeks . Patients in the control group were offered acupuncture treatment after 12 weeks . The data for these patients are pooled with those from the original acupuncture group for within-group analysis . RESULTS Patients r and omized to acupuncture improved on both WOMAC and Lequesne indices compared to those who received st and ard treatment alone . Significant differences on total WOMAC Scale were seen at 4 and 8 weeks . There appears to be a slight decline in effect at 4 weeks after cessation of treatment ( 12 weeks after first treatment ) . No adverse effects of acupuncture were reported . CONCLUSION These data suggest that acupuncture is an effective and safe adjunctive therapy to conventional care for patients with OA of the knee [16005336] BACKGROUND Acupuncture is widely used by patients with chronic pain although there is little evidence of its effectiveness . We investigated the efficacy of acupuncture compared with minimal acupuncture and with no acupuncture in patients with osteoarthritis of the knee . METHODS Patients with chronic osteoarthritis of the knee ( Kellgren grade < or = 2 ) were r and omly assigned to acupuncture ( n=150 ) , minimal acupuncture ( superficial needling at non-acupuncture points ; n=76 ) , or a waiting list control ( n=74 ) . Specialised physicians , in 28 outpatient centres , administered acupuncture and minimal acupuncture in 12 sessions over 8 weeks . Patients completed st and ard question naires at baseline and after 8 weeks , 26 weeks , and 52 weeks . The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis ( WOMAC ) index at the end of week 8 ( adjusted for baseline score ) . All main analyses were by intention to treat . RESULTS 294 patients were enrolled from March 6 , 2002 , to January 17 , 2003 ; eight patients were lost to follow-up after r and omisation , but were included in the final analysis . The mean baseline-adjusted WOMAC index at week 8 was 26.9 ( SE 1.4 ) in the acupuncture group , 35.8 ( 1.9 ) in the minimal acupuncture group , and 49.6 ( 2.0 ) in the waiting list group ( treatment difference acupuncture vs minimal acupuncture -8.8 , [ 95 % CI -13.5 to -4.2 ] , p=0.0002 ; acupuncture vs waiting list -22.7 [ -27.5 to -17.9 ] , p<0.0001 ) . After 52 weeks the difference between the acupuncture and minimal acupuncture groups was no longer significant ( p=0.08 ) . INTERPRETATION After 8 weeks of treatment , pain and joint function are improved more with acupuncture than with minimal acupuncture or no acupuncture in patients with osteoarthritis of the knee . However , this benefit decreases over time [12865832] Study Design . A r and omized controlled clinical trial was conducted . Objective . To compare medication , needle acupuncture , and spinal manipulation for managing chronic ( > 13 weeks duration ) spinal pain because the value of medicinal and popular forms of alternative care for chronic spinal pain syndromes is uncertain . Summary of Background Data . Between February 1999 and October 2001 , 115 patients without contraindication for the three treatment regimens were enrolled at the public hospital ’s multidisciplinary spinal pain unit . Methods . One of three separate intervention protocol s was used : medication , needle acupuncture , or chiropractic spinal manipulation . Patients were assessed before treatment by a sports medical physician for exclusion criteria and by a research assistant using the Oswestry Back Pain Disability Index ( Oswestry ) , the Neck Disability Index ( NDI ) , the Short-Form-36 Health Survey question naire ( SF-36 ) , visual analog scales ( VAS ) of pain intensity and ranges of movement . These instruments were administered again at 2 , 5 , and 9 weeks after the beginning of treatment . Results . R and omization proved to be successful . The highest proportion of early ( asymptomatic status ) recovery was found for manipulation ( 27.3 % ) , followed by acupuncture ( 9.4 % ) and medication ( 5 % ) . Manipulation achieved the best overall results , with improvements of 50 % ( P = 0.01 ) on the Oswestry scale , 38 % ( P = 0.08 ) on the NDI , 47 % ( P < 0.001 ) on the SF-36 , and 50 % ( P < 0.01 ) on the VAS for back pain , 38 % ( P < 0.001 ) for lumbar st and ing flexion , 20 % ( P < 0.001 ) for lumbar sitting flexion , 25 % ( P = 0.1 ) for cervical sitting flexion , and 18 % ( P = 0.02 ) for cervical sitting extension . However , on the VAS for neck pain , acupuncture showed a better result than manipulation ( 50%vs 42 % ) . Conclusions . The consistency of the results provides , despite some discussed shortcomings of this study , evidence that in patients with chronic spinal pain , manipulation , if not contraindicated , results in greater short-term improvement than acupuncture or medication . However , the data do not strongly support the use of only manipulation , only acupuncture , or only nonsteroidal antiinflammatory drugs for the treatment of chronic spinal pain . The results from this exploratory study need confirmation from future larger studies [3476149] Acupuncture treatment is frequently sought for tension-type headache ( TTH ) , but there is conflicting evidence as to its effectiveness . This r and omised , controlled , multicentre , patient- and observer-blinded trial was carried out in 122 outpatient practice s in Germany on 409 patients with TTH , defined as ≥0 headache days per month of which ≤1 included migraine symptoms . Interventions were verum acupuncture according to the practice of traditional Chinese medicine or sham acupuncture consisting of superficial needling at nonacupuncture points . Acupuncture was administered by physicians with specialist acupuncture training . Ten 30-min sessions were given over a six-week period , with additional sessions available for partial response . Response was defined as > 50 % reduction in headache days/month at six months and no use of excluded concomitant medication or other therapies . In the intent-to-treat analysis ( all 409 patients ) , 33 % of verum patients and 27 % of sham controls ( p=0.18 ) were classed as responders . Verum was superior to sham for most secondary endpoints , including headache days ( 1.8 fewer ; 95 % CI 0.6 , 3.0 ; p=0.004 ) and the International Headache Society response criterion ( 66 % vs. 55 % response , risk difference 12 % , 95 % CI : 2%-21 % ; p=0.024 ) . ) . The relative risk on the primary and secondary response criterion was very similar ( ∼0.8 ) ; the difference in statistical significance may be due to differences in event rate . TTH improves after acupuncture treatment . However , the degree to which treatment benefits depend on psychological compared to physiological effects and the degree to which any physiological effects depend on needle placement and insertion depth are unclear [17604311] OBJECTIVE To evaluate the effects of st and ardized western acupuncture and physiotherapy on pain and functional ability in patients with severe osteoarthritic knee pain awaiting knee arthroplasty . METHODS Three-arm , assessor-blind , r and omized controlled trial . PARTICIPANTS 181 patients awaiting knee arthroplasty . INTERVENTIONS acupuncture for 6 weeks ; physiotherapy for 6 weeks ; st and ardized advice . MAIN OUTCOME MEASURES Oxford Knee Score question naire ( OKS ) ( primary ) ; 50 m timed walk , and duration of hospital stay following knee arthroplasty . RESULTS There was no baseline difference between groups . At 7 weeks , there was a 10 % reduction in OKS in the acupuncture group which was a significant difference between the acupuncture and the control group : Mean ( s.d . ) acupuncture 36.8 ( 7.20 ) ; physiotherapy 39.2 ( 8.22 ) ; control 40.3 ( 8.48 ) ( P = 0.0497 ) . These effects were no longer present at 12 weeks . There was a trend ( P = 0.0984 ) towards a shorter in-patient stay of 1 day for the physiotherapy group [ mean 6.50 days ( s.d . 2.0 ) ] compared with the acupuncture group [ mean 7.77 days ( s.d . 3.96 ) ] . CONCLUSIONS We have demonstrated that patients with severe knee osteoarthritis can achieve a short-term reduction in OKS when treated with acupuncture . However , we failed to demonstrate any other clinical ly or statically significant effects between the groups . Both interventions can be delivered effectively in an out-patient group setting at a district general hospital . Further study is needed to evaluate the combined effects of these treatments [20655660] & NA ; The German R and omized Acupuncture Trial for chronic shoulder pain ( GRASP ) comprised 424 out patients with chronic shoulder pain ( CSP ) ≥6 weeks and an average pain score of VAS ≥50 mm , who were r and omly assigned to receive Chinese acupuncture ( verum ) , sham acupuncture ( sham ) or conventional conservative orthopaedic treatment ( COT ) . The patients were blinded to the type of acupuncture and treated by 31 office‐based orthopaedists trained in acupuncture ; all received 15 treatments over 6 weeks . The 50 % responder rate for pain was measured on a VAS 3 months after the end of treatment ( primary endpoint ) and directly after the end of the treatment ( secondary endpoint ) . Results : In the ITT ( n = 424 ) analysis , percentages of responders for the primary endpoint were verum 65 % ( 95 % CI 56–74 % ) ( n = 100 ) , sham 24 % ( 95 % CI 9–39 % ) ( n = 32 ) , and COT 37 % ( 95 % CI 24–50 % ) ( n = 50 ) ; secondary endpoint : verum 68 % ( 95 % CI 58–77 % ) ( n = 92 ) , sham 40 % ( 95 % CI 27–53 % ) ( n = 53 ) , and COT 28 % ( 95 % CI 14–42 % ) ( n = 38 ) . The results are significant for verum over sham and verum over COT ( p < 0.01 ) for both the primary and secondary endpoints . The PPP analysis of the primary ( n = 308 ) and secondary endpoints ( n = 360 ) yields similar responder results for verum over sham and verum over COT ( p < 0.01 ) . Descriptive statistics showed greater improvement of shoulder mobility ( abduction and arm‐above‐head test ) for the verum group versus the control group immediately after treatment and after 3 months . The trial indicates that Chinese acupuncture is an effective alternative to conventional orthopaedic treatment for CSP [2268695] Background The present study tests whether a combined treatment of acupuncture and transcutaneous electrical nerve stimulation ( TENS ) is more effective than acupuncture or TENS alone for treating knee osteoarthritis ( OA ) . Methods Thirty-two patients with knee OA were r and omly allocated to four groups . The acupuncture group ( ACP ) received only acupuncture treatment at selected acupoints for knee pain ; the TENS group ( TENS ) received only TENS treatment at pain areas ; the acupuncture and TENS group ( A&T ) received both acupuncture and TENS treatments ; the control group ( CT ) received topical poultice ( only when necessary ) . Each group received specific weekly treatment five times during the study . Outcome measures were pain intensity in a visual analogue scale ( VAS ) and knee function in terms of the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) . Results The ACP , TENS and A&T groups reported lower VAS and WOMAC scores than the control group . Significant reduction in pain intensity ( P = 0.039 ) and significant improvement in knee function ( P = 0.008 ) were shown in the A&T group . Conclusion Combined acupuncture and TENS treatment was effective in pain relief and knee function improvement for the sample d patients suffering from knee OA [15611487] Context Previous studies of acupuncture for osteoarthritis have had conflicting results . This may have occurred because most studies have included small sample s , a limited number of treatment sessions , or other limitations . Contribution This r and omized , controlled trial compared 24 acupuncture sessions over 26 weeks with sham acupuncture or arthritis education in 570 patients with osteoarthritis of the knee . Acupuncture led to greater improvements in function but not pain after 8 weeks and in both pain and function after 26 weeks . No adverse effects were associated with acupuncture . Caution s Many participants dropped out of the study , so readers should interpret the findings at 26 weeks with caution . The Editors Osteoarthritis is the most common form of arthritis and is a major cause of morbidity , limitation of activity , and health care utilization , especially in elderly patients ( 1 , 2 ) . Pain and functional limitation are the primary clinical manifestations of osteoarthritis of the knee . Current recommendations for managing osteoarthritis , including guidelines published by the American College of Rheumatology ( 3 ) and European League of Associations of Rheumatology ( 4 ) , focus on relieving pain and stiffness and maintaining or improving physical function as important goals of therapy . No curative therapies exist for osteoarthritis ; thus , both pharmacologic and nonpharmacologic management focus on controlling pain and reducing functional limitation ( 5 ) . Nonpharmacologic therapy , which includes patient education , social support , physical and occupational therapy , aerobic and resistive exercises , and weight loss , is the cornerstone of a multidisciplinary approach to osteoarthritis patient management ( 3 ) . Pharmacologic therapies include nonopioid analgesics ( such as acetaminophen ) , nonsteroidal anti-inflammatory drugs ( NSAIDs ) ( including cyclooxygenase-2 [ COX-2 ] enzyme selective inhibitors ) , topical analgesics ( capsaicin cream ) , opioid analgesics , and intra-articular steroid and hyaluronate injections . Often , these agents are used in combination for additive analgesic efficacy ( 6 ) . Pharmacologic management of osteoarthritis is often ineffective , and agents such as NSAIDs may cause unwanted and dangerous side effects ( 7 , 8) . Complementary and alternative medicine is another approach to treating osteoarthritis ( 9 - 12 ) , particularly in Asian societies ( 13 ) . Many U.S. patients with osteoarthritis also use complementary and alternative medical therapies ( 14 ) . A systematic review of acupuncture and knee osteoarthritis ( 15 ) identified 7 small r and omized , controlled trials published in English . Within the method ologic limitations of the studies , the evidence suggested that acupuncture seemed to alleviate knee pain and function compared with sham acupuncture controls , although 2 trials comparing acupuncture with an active , nonpharmacologic treatment ( physical therapy ) did not indicate such an effect ( 16 , 17 ) . Before conducting our large-scale trial , we completed both a pilot study ( 18 ) and a r and omized , single-blind trial ( 19 ) of the effect of acupuncture on osteoarthritis of the knee . Participants in the uncontrolled pilot study ( n= 12 ) showed statistically significant improvement in both self-reported pain and physical function , as well as performance measures of physical function after 8 weeks of acupuncture treatment and at 12-week follow-up as compared with their baseline ( 18 ) . In our larger r and omized , single-blind trial ( n= 73 ) , which examined the benefit of acupuncture added to st and ard management with NSAIDs , the acupuncture treatment group experienced statistically significant improvements in self-reported pain and disability scores compared with a st and ard-care control group as late as 4 weeks after the end of treatment ( 19 ) . However , this effect diminished within 18 weeks ( 26 weeks after the beginning of the trial ) after the final acupuncture treatment . Together , however , the previously conducted trials ( both our preliminary studies [ 18 , 19 ] and those referenced in the systematic review [ 15 ] ) have 3 method ologic limitations : lack of credible controls for the placebo effect , inadequate assessment of long-term treatment benefits , and insufficient sample sizes . We tested the hypothesis that an 8-week intensive acupuncture treatment regimen , followed by an 18-week tapering regimen , reduces pain and improves function among patients with knee osteoarthritis as compared with both sham acupuncture and education control groups . Methods Patient Recruitment We recruited patients for this multisite , placebo-controlled trial from March 2000 through December 2003 , primarily through print and radio advertisements . The 3 sites were the Integrative Medicine Clinic of the University of Maryl and School of Medicine , Baltimore , Maryl and ; the Innovative Medical Research Center ( a private research firm ) , Towson , Maryl and ; and the Hospital for Special Surgery , New York City , New York . The institutional review boards of the 3 sites approved the study . We determined the sample size ( n= 570 ) by a power analysis based on our r and omized pilot study ( 19 ) , adjusted by the estimated decrease in effect size result ing from the inclusion of a sham acupuncture group design ed to control for placebo effects . Patients met the following inclusion criteria : age 50 years or older , a diagnosis of osteoarthritis of the knee , radiographic evidence of at least 1 osteophyte at the tibiofemoral joint ( KellgrenLawrence grade 2 ) , moderate or greater clinical ly significant knee pain on most days during the past month , and willingness to be r and omly assigned . Exclusion criteria were the presence of serious medical conditions that precluded participation in study , bleeding disorders that might contraindicate acupuncture , intra-articular corticosteroid or hyaluronate injections ( as well as any knee surgeries or concomitant use of topical capsaicin cream ) during the past 6 months , previous experience with acupuncture , or any planned events ( including total knee replacement ) that would interfere with participation in the study during the following 26 weeks . After a brief telephone screening , patients were scheduled to visit 1 of the 3 participating sites to sign an informed consent statement and undergo a brief rheumatologic examination ( including radiographic examination of affected knees ) by a physician or a nurse practitioner . Because the education course was a group activity , patients were recruited until a cohort of 12 to 21 patients was formed , at which point each cohort at each site was r and omly assigned to 1 of 3 groups by a computer-generated process using r and omly selected blocks of 3 , 6 , and 9 . We assured allocation concealment by using disguised letter codes that were generated and sent to the site coordinators by a central statistical core . We used this procedure to ensure that approximately equal numbers of participants were in each treatment group across the course of the study , to ensure that each cohort would have participants assigned to all 3 treatment groups , and to make the breaking of the group assignment process more difficult . The research assistants who collected assessment s from participants , the participants themselves ( in the true acupuncture and sham acupuncture groups ) , and the statistician were blinded to group assignment . Assessment s were conducted at baseline and 4 , 8 , 14 , and 26 weeks after r and omization . Study Interventions We developed and modified the acupuncture treatment and sham control protocol s from previously reported and vali date d procedures ( 18 - 21 ) . During the trial , 7 acupuncturists were used : 3 at the Integrative Medicine Clinic , 3 at the Innovative Medical Research Center , and 1 at the Hospital for Special Surgery . In general , acupuncturists were assigned to the same participants throughout the 26-week treatment schedule , except for vacation conflicts and staff turnover , and provided approximately the same proportions of true versus sham procedures . All acupuncturists were state-licensed and had at least 2 years of clinical experience . The study 's principal acupuncturist trained and supervised the acupuncturists in performing true or sham procedures and avoiding interactions that could inadvertently communicate group assignment . True Acupuncture The true acupuncture ( experimental ) group underwent 26 weeks of gradually tapering treatment according to the following schedule : 8 weeks of 2 treatments per week followed by 2 weeks of 1 treatment per week , 4 weeks of 1 treatment every other week , and 12 weeks of 1 treatment per month . We based the acupuncture point selection s on Traditional Chinese Medicine meridian theory to treat knee joint pain , known as the Bi syndrome . These points consisted of 5 local points ( Yanglinquan [ gall bladder meridian point 34 ] , Yinlinquan [ spleen meridian point 9 ] , Zhusanli [ stomach meridian point 36 ] , Dubi [ stomach meridian point 35 ] , and extra point Xiyan ) and 4 distal points ( Kunlun [ urinarybladder , meridian point 60 ] , Xuanzhong [ gall bladder meridian point 39 ] , Sanyinjiao [ spleen meridian point 6 ] , and Taixi [ kidney meridian point 3 ] ) on meridians that traverse the area of pain ( 22 , 23 ) . The same points were treated for each affected leg . If both knees were affected , 9 needles were inserted in each leg . ( The outcome measures were not specifically targeted to whether the patient had osteoarthritis in 1 or both knees , and we observed no differential effects on the basis of the number of knees treated . ) The acupuncturists inserted 1.5-inch ( for local points ) and 1-inch ( for distal points ) 32-gauge ( 0.25-mm diameter ) acupuncture needles to a conventional depth of approximately 0.3 to 1.0 inch , depending on point location . All participants in the treatment group achieved the De-Qi sensation , a local sensation of heaviness , numbness , soreness , or paresthesia that accompanies the insertion and manipulation of needles during acupuncture , at these 9 points . Acupuncturists applied electrical [16505266] BACKGROUND Acupuncture is widely used by patients with low back pain , although its effectiveness is unclear . We investigated the efficacy of acupuncture compared with minimal acupuncture and with no acupuncture in patients with chronic low back pain . METHODS Patients were r and omized to treatment with acupuncture , minimal acupuncture ( superficial needling at nonacupuncture points ) , or a waiting list control . Acupuncture and minimal acupuncture were administered by specialized acupuncture physicians in 30 outpatient centers , and consisted of 12 sessions per patient over 8 weeks . Patients completed st and ardized question naires at baseline and at 8 , 26 , and 52 weeks after r and omization . The primary outcome variable was the change in low back pain intensity from baseline to the end of week 8 , as determined on a visual analog scale ( range , 0 - 100 mm ) . RESULTS A total of 298 patients ( 67.8 % female ; mean + /- SD age , 59 + /- 9 years ) were included . Between baseline and week 8 , pain intensity decreased by a mean + /- SD of 28.7 + /- 30.3 mm in the acupuncture group , 23.6 + /- 31.0 mm in the minimal acupuncture group , and 6.9 + /- 22.0 mm in the waiting list group . The difference for the acupuncture vs minimal acupuncture group was 5.1 mm ( 95 % confidence interval , -3.7 to 13.9 mm ; P = .26 ) , and the difference for the acupuncture vs waiting list group was 21.7 mm ( 95 % confidence interval , 13.9 - 30.0 mm ; P<.001 ) . Also , at 26 ( P=.96 ) and 52 ( P=.61 ) weeks , pain did not differ significantly between the acupuncture and the minimal acupuncture groups . CONCLUSION Acupuncture was more effective in improving pain than no acupuncture treatment in patients with chronic low back pain , whereas there were no significant differences between acupuncture and minimal acupuncture [16798792] In a r and omized controlled trial plus a nonr and omized cohort , the authors investigated the effectiveness and costs of acupuncture in addition to routine care in the treatment of chronic low back pain and assessed whether the effects of acupuncture differed in r and omized and nonr and omized patients . In 2001 , German patients with chronic low back pain were allocated to an acupuncture group or a no-acupuncture control group . Persons who did not consent to r and omization were included in a nonr and omized acupuncture group . All patients were allowed to receive routine medical care in addition to study treatment . Back function ( Hannover Functional Ability Question naire ) , pain , and quality of life were assessed at baseline and after 3 and 6 months , and cost-effectiveness was analyzed . Of 11,630 patients ( mean age=52.9 years ( st and ard deviation , 13.7 ) ; 59 % female ) , 1,549 were r and omized to the acupuncture group and 1,544 to the control group ; 8,537 were included in the nonr and omized acupuncture group . At 3 months , back function improved by 12.1 ( st and ard error ( SE ) , 0.4 ) to 74.5 ( SE , 0.4 ) points in the acupuncture group and by 2.7 ( SE , 0.4 ) to 65.1 ( SE , 0.4 ) points among controls ( difference=9.4 points ( 95 % confidence interval 8.3 , 10.5 ) ; p<0.001 ) . Nonr and omized patients had more severe symptoms at baseline and showed improvements in back function similar to those seen in r and omized patients . The incremental cost-effectiveness ratio was euro10,526 ( euros ) per quality -adjusted life year . Acupuncture plus routine care was associated with marked clinical improvements in these patients and was relatively cost-effective [11431299] Abstract Objectives : To compare the efficacy of acupuncture and conventional massage for the treatment of chronic neck pain . Design : Prospect i ve , r and omised , placebo controlled trial . Setting : Three outpatient departments in Germany . Participants : 177 patients aged 18–85 years with chronic neck pain . Interventions : Patients were r and omly allocated to five treatments over three weeks with acupuncture ( 56 ) , massage ( 60 ) , or “ sham ” laser acupuncture ( 61 ) . Main outcome measures : Primary outcome measure : maximum pain related to motion ( visual analogue scale ) irrespective of direction of movement one week after treatment . Secondary outcome measures : range of motion ( 3D ultrasound real time motion analyser ) , pain related to movement in six directions ( visual analogue scale ) , pressure pain threshold ( pressure algometer ) , changes of spontaneous pain , motion related pain , global complaints ( seven point scale ) , and quality of life ( SF-36 ) . Assessment s were performed before , during , and one week and three months after treatment . Patients ' beliefs in treatment were assessed . Results : One week after five treatments the acupuncture group showed a significantly greater improvement in motion related pain compared with massage ( difference 24.22 ( 95 % confidence interval 16.5 to 31.9 ) , P=0.0052 ) but not compared with sham laser ( 17.28 ( 10.0 to 24.6 ) , P=0.327 ) . Differences between acupuncture and massage or sham laser were greater in the subgroup who had had pain for longer than five years ( n=75 ) and in patients with myofascial pain syndrome ( n=129 ) . The acupuncture group had the best results in most secondary outcome measures . There were no differences in patients ' beliefs in treatment . Conclusions : Acupuncture is an effective short term treatment for patients with chronic neck pain , but there is only limited evidence for long term effects after five treatments . What is already known on this topic Acupuncture is a widespread complementary treatment Evidence from trials have given conflicting results on its use in the treatment of neck pain because of method ological shortcomings and because effects were compared either with alternative treatments or with different sham procedures imitating acupuncture , but not both What this study adds Compared with sham laser acupuncture and massage , needle acupuncture has beneficial effects on mobility and pain related to motion in patients with chronic neck pain Acupuncture was clearly more effective than massage , but differences were not always significant compared with sham laser acupuncture Acupuncture was the best treatment for patients with the myofascial syndrome and those who had had pain for longer than five [14629842] OBJECTIVES To examine the relative effectiveness of electro-acupuncture ( EA ) and transcutaneous electrical nerve stimulation ( TENS ) in alleviating osteoarthritic (OA)-induced knee pain . DESIGN Single-blinded , r and omized controlled study . SUBJECTS Twenty-four ( 24 ) subjects ( 23 women and 1 man ) , mean age 85 , were recruited from eight subsidized Care & Attention Homes for the elderly . INTERVENTIONS Subjects were r and omly assigned to the EA , TENS , or control groups . Subjects in the EA group ( n = 8) received low-frequency EA ( 2 Hz ) on two acupuncture points ( ST-35 , Dubi and EX-LE-4 , Neixiyan ) of the painful knee for 20 minutes . Subjects in the TENS group ( n = 8) received low-frequency TENS of 2 Hz and pulse width of 200 micros on the same acupuncture points for 20 minutes . In both treatment groups , electrical treatment was carried out for a total of eight sessions in 2 weeks . Eight subjects received osteoarthritic knee care and education only in a control group . All subjects were evaluated before the first treatment , after the last treatment , and at 2-week follow-up periods . RESULTS After eight sessions of treatment , there was significant reduction of knee pain in both EA group and TENS group , as measured by the Numeric Rating Scale ( NRS ) of pain ( p < 0.01 ) . Prolonged analgesic effect was maintained in the EA and the TENS groups at a 2-week follow-up evaluation . The Timed Up- and -Go Test ( TUGT ) score of the EA group was significantly lower than that of the control group ( p < 0.05 ) , but such change was not observed in the TENS group . CONCLUSIONS Both EA and TENS treatments were effective in reducing OA-induced knee pain . EA had the additional advantage of enhancing the TUGT results as opposed to TENS treatment or no treatment , which did not produce such corollary effect [11932074] & NA ; There is some evidence for the efficacy of acupuncture in chronic low‐back pain ( LBP ) , but it remains unclear whether acupuncture is superior to placebo . In a r and omized , blinded , placebo‐controlled trial , we evaluated the effect of traditional acupuncture in chronic LBP . A total of 131 consecutive out‐ patients of the Department of Orthopaedics , University Goettingen , Germany , ( age=48.1 years , 58.5 % female , duration of pain : 9.6 years ) with non‐radiating LBP for at least 6 months and a normal neurological examination were r and omized to one of three groups over 12 weeks . Each group received active physiotherapy over 12 weeks . The control group ( n=46 ) received no further treatment , the acupuncture group ( n=40 ) received 20 sessions of traditional acupuncture and the sham‐acupuncture group ( n=45 ) 20 sessions of minimal acupuncture . Changes from baseline to the end of treatment and to 9‐month follow‐up were assessed in pain intensity and in pain disability , and secondary in psychological distress and in spine flexion , compared by intervention groups . Acupuncture was superior to the control condition ( physiotherapy ) regarding pain intensity ( P=0.000 ) , pain disability ( P=0.000 ) , and psychological distress ( P=0.020 ) at the end of treatment . Compared to sham‐acupuncture , acupuncture reduced psychological distress ( P=0.040 ) only . At 9‐month follow‐up , the superiority of acupuncture compared to the control condition became less and acupuncture was not different to sham‐acupuncture . We found a significant improvement by traditional acupuncture in chronic LBP compared to routine care ( physiotherapy ) but not compared to sham‐acupuncture . The trial demonstrated a placebo effect of traditional acupuncture in chronic LBP [16452103] Abstract Objective To investigate whether a sham device ( a vali date d sham acupuncture needle ) has a greater placebo effect than an inert pill in patients with persistent arm pain . Design A single blind r and omised controlled trial created from the two week placebo run-in periods for two nested trials that compared acupuncture and amitriptyline with their respective placebo controls . Comparison of participants who remained on placebo continued beyond the run-in period to the end of the study . Setting Academic medical centre . Participants 270 adults with arm pain due to repetitive use that had lasted at least three months despite treatment and who scored ≥3 on a 10 point pain scale . Interventions Acupuncture with sham device twice a week for six weeks or placebo pill once a day for eight weeks . Main outcome measures Arm pain measured on a 10 point pain scale . Secondary outcomes were symptoms measured by the Levine symptom severity scale , function measured by Pransky 's upper extremity function scale , and grip strength . Results Pain decreased during the two week placebo run-in period in both the sham device and placebo pill groups , but changes were not different between the groups ( −0.14 , 95 % confidence interval −0.52 to 0.25 , P = 0.49 ) . Changes in severity scores for arm symptoms and grip strength were similar between groups , but arm function improved more in the placebo pill group ( 2.0 , 0.06 to 3.92 , P = 0.04 ) . Longitudinal regression analyses that followed participants throughout the treatment period showed significantly greater downward slopes per week on the 10 point arm pain scale in the sham device group than in the placebo pill group ( −0.33 ( −0.40 to −0.26 ) v −0.15 ( −0.21 to −0.09 ) , P = 0.0001 ) and on the symptom severity scale ( −0.07 ( −0.09 to −0.05 ) v −0.05 ( −0.06 to −0.03 ) , P = 0.02 ) . Differences were not significant , however , on the function scale or for grip strength . Reported adverse effects were different in the two groups . Conclusions The sham device had greater effects than the placebo pill on self reported pain and severity of symptoms over the entire course of treatment but not during the two week placebo run in . Placebo effects seem to be malleable and depend on the behaviours embedded in medical rituals [16934402] & NA ; Chronic neck pain is highly prevalent . To determine the efficacy and safety of acupuncture , in comparison with transcutaneous nerve stimulation‐placebo ( TENS‐placebo ) in the treatment of chronic uncomplicated neck pain , a single blind prospect i ve study was design ed , to be carried out at a Primary Healthcare Centre , with r and om assignment to two parallel groups and with evaluation and analysis by independent evaluators . A r and om assignment was made from 123 patients of the 149 initially recruited . These patients had been diagnosed with uncomplicated neck pain and experienced neck motion‐related pain intensity equal to or exceeding 30 on a visual analogue scale ( VAS ) from 0 to 100 mm . The treatment with acupuncture was compared with TENS‐placebo , applied over 5 sessions in three weeks . The primary endpoint was the change in maximum pain intensity related to motion of the neck , one week after the final treatment . Sensitivity was analysed per protocol ( PP ) and variant analyses were by intention to treat ( ITT ) . Adjustment was made for confounders by multiple linear regression , including baseline values and rescue therapy . By ITT analysis , the change in the pain‐VAS variable was greater among the experimental group ( 28.1 ( 95 % CI 21.4–34.7 ) ) . The improvements in quality of life ( physical aspect ) , active neck mobility and reduced rescue medication were clinical ly and statistically significant . In the treatment of the intensity of chronic neck pain , acupuncture is more effective than the placebo treatment and presents a safety profile making it suitable for routine use in clinical practice [15322438] Objectives : Acupuncture has been promoted for the treatment of chronic pain . Though many r and omized trials have been conducted , these have been criticized for deficiencies of methodology , acupuncture technique , and sample size . Somewhat less emphasis has been placed on methods of statistical analysis . This paper describes 4 recent r and omized trials of acupuncture for musculoskeletal or headache pain . Each trial used statistical methods that did not adjust for baseline pain scores and were thus of suboptimal power . The objective of this study is to reanalyze the trials using analysis of covariance ( ANCOVA ) . Methods : Raw data for the 4 trials were obtained from the original authors . Data were reanalyzed by ANCOVA . Results : For 2 trials — acupuncture versus placebo for chronic headache and acupuncture versus transcutaneous electric nerve stimulation for back pain — re analysis did not change the conclusion of no difference between groups , but showed that clinical ly significant differences between groups could not ruled out . Re analysis of a trial of acupuncture versus placebo for shoulder pain slightly strengthened the evidence of acupuncture effectiveness . Re analysis of the fourth trial , which compared acupuncture to placebo acupuncture and massage for neck pain , reversed the results of the original paper : re analysis found acupuncture to be effective and that its effectiveness could not be ascribed to a placebo effect . Discussion : Future trials of acupuncture and other modalities for pain should use efficient statistical methods . ANCOVA is more efficient than unadjusted analysis where used appropriately [15023828] Abstract Objective To determine the effects of a policy of “ use acupuncture ” on headache , health status , days off sick , and use of re sources in patients with chronic headache compared with a policy of “ avoid acupuncture . ” Design R and omised , controlled trial . Setting General practice s in Engl and and Wales . Participants 401 patients with chronic headache , predominantly migraine . Interventions Patients were r and omly allocated to receive up to 12 acupuncture treatments over three months or to a control intervention offering usual care . Main outcome measures Headache score , SF-36 health status , and use of medication were assessed at baseline , three , and 12 months . Use of re sources was assessed every three months . Results Headache score at 12 months , the primary end point , was lower in the acupuncture group ( 16.2 , SD 13.7 , n = 161 , 34 % reduction from baseline ) than in controls ( 22.3 , SD 17.0 , n = 140 , 16 % reduction from baseline ) . The adjusted difference between means is 4.6 ( 95 % confidence interval 2.2 to 7.0 ; P = 0.0002 ) . This result is robust to sensitivity analysis incorporating imputation for missing data . Patients in the acupuncture group experienced the equivalent of 22 fewer days of headache per year ( 8 to 38 ) . SF-36 data favoured acupuncture , although differences reached significance only for physical role functioning , energy , and change in health . Compared with controls , patients r and omised to acupuncture used 15 % less medication ( P = 0.02 ) , made 25 % fewer visits to general practitioners ( P = 0.10 ) , and took 15 % fewer days off sick ( P = 0.2 ) . Conclusions Acupuncture leads to persisting , clinical ly relevant benefits for primary care patients with chronic headache , particularly migraine . Expansion of NHS acupuncture services should be considered [16055451] Abstract Objective To investigate the effectiveness of acupuncture compared with minimal acupuncture and with no acupuncture in patients with tension-type headache . Design Three armed r and omised controlled multicentre trial . Setting 28 outpatient centres in Germany . Participants 270 patients ( 74 % women , mean age 43 ( SD 13 ) years ) with episodic or chronic tension-type headache . Interventions Acupuncture , minimal acupuncture ( superficial needling at non-acupuncture points ) , or waiting list control . Acupuncture and minimal acupuncture were administered by specialised physicians and consisted of 12 sessions per patient over eight weeks . Main outcome measure Difference in numbers of days with headache between the four weeks before r and omisation and weeks 9 - 12 after r and omisation , as recorded by participants in headache diaries . Results The number of days with headache decreased by 7.2 ( SD 6.5 ) days in the acupuncture group compared with 6.6 ( SD 6.0 ) days in the minimal acupuncture group and 1.5 ( SD 3.7 ) days in the waiting list group ( difference : acupuncture v minimal acupuncture , 0.6 days , 95 % confidence interval -1.5 to 2.6 days , P = 0.58 ; acupuncture v waiting list , 5.7 days , 3.9 to 7.5 days , P < 0.001 ) . The proportion of responders ( at least 50 % reduction in days with headache ) was 46 % in the acupuncture group , 35 % in the minimal acupuncture group , and 4 % in the waiting list group . Conclusions The acupuncture intervention investigated in this trial was more effective than no treatment but not significantly more effective than minimal acupuncture for the treatment of tension-type headache . Trial registration number IS RCT N9737659 [2775018] Background There is some evidence that acupuncture for pain and osteoarthritis ( OA ) of the knee is more than a placebo , and short term clinical benefits have been observed when acupuncture is compared to usual care . However there is insufficient evidence on whether clinical benefits of acupuncture are sustained over the longer term . In this study our key objectives are to inform the design parameters for a fully powered pragmatic r and omised controlled trial . These objectives include establishing potential recruitment rates , appropriate vali date d outcome measures , attendance levels for acupuncture treatment , loss to follow up and the sample size for a full scale trial . Methods Potential participants aged over 50 with pain and osteoarthritis of the knee were identified from a GP data base . Eligible patients were r and omised to either ' acupuncture plus usual care ' and ' usual care ' alone , with allocation appropriately concealed . Acupuncture consisted of up to 10 sessions usually weekly . Outcome measures included Western Ontario and McMaster Universities ( WOMAC ) index with the sample size for a full scale trial determined from the variance . Results From the GP data base of 15,927 patients , 335 potential trial participants were identified and invited to participate . After screening responses , 78 ( 23 % ) were identified as eligible and 30 patients who responded most promptly were r and omised to ' acupuncture plus usual care ' ( 15 patients ) and ' usual care ' alone ( 15 patients ) . Attendance for acupuncture appointments was high at 90 % of the maximum . Although the trial was not powered to detect significant changes in outcome , the WOMAC pain index showed a statistically significant reduction at 3 months in the acupuncture group compared to usual care . This was not sustained at 12 months . The sample size for a fully powered two-arm trial was estimated to be 350 . Conclusion This pilot study provided the evidence that a fully powered study to explore the longer term impact of acupuncture would be worthwhile , and relevant design features for such a trial were determined . Trial registration numberIS RCT N25134802 [15726029] OBJECTIVE To assess the long-term benefits of medication , needle acupuncture , and spinal manipulation as exclusive and st and ardized treatment regimens in patients with chronic ( > 13 weeks ) spinal pain syndromes . STUDY DESIGN Extended follow-up ( > 1 year ) of a r and omized clinical trial was conducted at the multidisciplinary spinal pain unit of Townsville 's General Hospital between February 1999 and October 2001 . PATIENTS AND METHODS Of the 115 patients originally r and omized , 69 had exclusively been treated with the r and omly allocated treatment during the 9-week treatment period ( results at 9 weeks were reported earlier ) . These patients were followed up and assessed again 1 year after inception into the study reapplying the same instruments ( ie , Oswestry Back Pain Index , Neck Disability Index , Short-Form-36 , and Visual Analogue Scales ) . Question naires were obtained from 62 patients reflecting a retention proportion of 90 % . The main analysis was restricted to 40 patients who had received exclusively the r and omly allocated treatment for the whole observation period since r and omization . RESULTS Comparisons of initial and extended follow-up question naires to assess absolute efficacy showed that only the application of spinal manipulation revealed broad-based long-term benefit : 5 of the 7 main outcome measures showed significant improvements compared with only 1 item in each of the acupuncture and the medication groups . CONCLUSIONS In patients with chronic spinal pain syndromes , spinal manipulation , if not contraindicated , may be the only treatment modality of the assessed regimens that provides broad and significant long-term benefit [15023830] Abstract Objective To evaluate the cost effectiveness of acupuncture in the management of chronic headache . Design Cost effectiveness analysis of a r and omised controlled trial . Setting General practice s in Engl and and Wales . Participants 401 patients with chronic headache , predominantly migraine . Interventions Patients were r and omly allocated to receive up to 12 acupuncture treatments over three months from appropriately trained physiotherapists , or to usual care alone . Main outcome measure Incremental cost per quality adjusted life year ( QALY ) gained . Results Total costs during the one year period of the study were on average higher for the acupuncture group ( £ 403 ; $ 768;€598 ) than for controls ( £ 217 ) because of the acupuncture practitioners ' costs . The mean health gain from acupuncture during the one year of the trial was 0.021 quality adjusted life years ( QALYs ) , leading to a base case estimate of £ 9180 per QALY gained . This result was robust to sensitivity analysis . Cost per QALY dropped substantially when the analysis incorporated likely QALY differences for the years after the trial . Conclusions Acupuncture for chronic headache improves health related quality of life at a small additional cost ; it is relatively cost effective compared with a number of other interventions provided by the NHS [19433697] BACKGROUND Acupuncture is a popular complementary and alternative treatment for chronic back pain . Recent European trials suggest similar short-term benefits from real and sham acupuncture needling . This trial addresses the importance of needle placement and skin penetration in eliciting acupuncture effects for patients with chronic low back pain . METHODS A total of 638 adults with chronic mechanical low back pain were r and omized to individualized acupuncture , st and ardized acupuncture , simulated acupuncture , or usual care . Ten treatments were provided over 7 weeks by experienced acupuncturists . The primary outcomes were back-related dysfunction ( Rol and -Morris Disability Question naire score ; range , 0 - 23 ) and symptom bothersomeness ( 0 - 10 scale ) . Outcomes were assessed at baseline and after 8 , 26 , and 52 weeks . RESULTS At 8 weeks , mean dysfunction scores for the individualized , st and ardized , and simulated acupuncture groups improved by 4.4 , 4.5 , and 4.4 points , respectively , compared with 2.1 points for those receiving usual care ( P < .001 ) . Participants receiving real or simulated acupuncture were more likely than those receiving usual care to experience clinical ly meaningful improvements on the dysfunction scale ( 60 % vs 39 % ; P < .001 ) . Symptoms improved by 1.6 to 1.9 points in the treatment groups compared with 0.7 points in the usual care group ( P < .001 ) . After 1 year , participants in the treatment groups were more likely than those receiving usual care to experience clinical ly meaningful improvements in dysfunction ( 59 % to 65 % vs 50 % , respectively ; P = .02 ) but not in symptoms ( P > .05 ) . CONCLUSIONS Although acupuncture was found effective for chronic low back pain , tailoring needling sites to each patient and penetration of the skin appear to be unimportant in eliciting therapeutic benefits . These findings raise questions about acupuncture 's purported mechanisms of action . It remains unclear whether acupuncture or our simulated method of acupuncture provide physiologically important stimulation or represent placebo or nonspecific effects [16980316] Abstract Objective To determine whether a short course of traditional acupuncture improves longer term outcomes for patients with persistent non-specific low back pain in primary care . Design Pragmatic , open , r and omised controlled trial . Setting Three private acupuncture clinics and 18 general practice s in York , Engl and . Participants 241 adults aged 18 - 65 with non-specific low back pain of 4 - 52 weeks ' duration . Interventions 10 individualised acupuncture treatments from one of six qualified acupuncturists ( 160 patients ) or usual care only ( 81 patients ) . Main outcome measures The primary outcome was SF-36 bodily pain , measured at 12 and 24 months . Other outcomes included reported use of analgesics , scores on the Oswestry pain disability index , safety , and patient satisfaction . Results 39 general practitioners referred 289 patients of whom 241 were r and omised . At 12 months average SF-36 pain scores increased by 33.2 to 64.0 in the acupuncture group and by 27.9 to 58.3 in the control group . Adjusting for baseline score and for any clustering by acupuncturist , the estimated intervention effect was 5.6 points ( 95 % confidence interval −0.2 to 11.4 ) at 12 months ( n = 213 ) and 8.0 points ( 2.8 to 13.2 ) at 24 months ( n = 182 ) . The magnitude of the difference between the groups was about 10%-15 % of the final pain score in the control group . Functional disability was not improved . No serious or life threatening events were reported . Conclusions Weak evidence was found of an effect of acupuncture on persistent non-specific low back pain at 12 months , but stronger evidence of a small benefit at 24 months . Referral to a qualified traditional acupuncturist for a short course of treatment seems safe and acceptable to patients with low back pain . Trial registration IS RCT N80764175 [ controlled-trials.com ] [18209514] Objective To assess the efficacy of acupuncture in migraine prophylaxis . Methods Thirty-seven patients with migraine were enrolled in a r and omized control trial at the Headache clinic located in a University Hospital . Real and sham acupuncture groups received 16 acupuncture sessions over 3 months . Treatment was individualized in the real acupuncture group and minimal acupuncture was used in the sham group . The primary end point was the percentage of patients with a ≥50 % reduction in their migraine attack frequency in the second , third , fourth , fifth , and sixth ( months ) compared with the first one ( baseline period ) . Primary and secondary end points were measured comparing headache diaries . Results Real acupuncture group showed improvement with significant differences compared with the sham acupuncture group in the primary efficacy end point ( P=0.021 ) at the second month of the treatment . Differences also appeared in 2 secondary end points : number of days with migraine per month ( P=0.007 ) in the second month and the percentage of patients with ≥40 % reduction in migraine attack frequency in the first ( P=0.044 ) and second months ( P=0.004 ) of the treatment . These differences disappeared in the third ( last ) month of the treatment as a consequence of the high improvement of the sham acupuncture group . Comparisons within each group showed that several migraine parameters evaluated improved significantly in both groups . Conclusions Individualized treatment based on traditional Chinese medicine plays a role in preventing migraine attacks . Nevertheless , sham acupuncture had similar effects . Major conclusions were limited by the small sample sizes however the observed trends may contribute to design future trials [12542558] OBJECTIVES To investigate whether acupuncture is superior to placebo and equivalent to sumatriptan for the early treatment of an acute migraine attack . DESIGN R and omized , partly double-blind ( sumatriptan versus placebo ) trial . SETTING Two hospitals in Germany ( one specialized in traditional Chinese medicine and one in the treatment of headache ) . SUBJECTS A total of 179 migraineurs experiencing the first symptoms of a developing migraine attack . INTERVENTIONS Traditional Chinese acupuncture , sumatriptan ( 6 mg subcutaneously ) or placebo injection . MAIN OUTCOME MEASURE Number of patients in whom a full migraine attack ( defined as severe migraine headache ) within 48 h was prevented . In patients who developed a migraine attack in spite of early treatment , acupuncture and sumatriptan were applied a second time , whilst patients initially r and omized to placebo received sumatriptan . RESULTS A full migraine attack was prevented in 21 of 60 ( 35 % ) patients receiving acupuncture , 21 of 58 ( 36 % ) patients receiving sumatriptan and 11 of 61 ( 18 % ) patients receiving placebo ( relative risk of having a full attack 0.79 ( 95 % CI , 0.64 - 0.99 ) for acupuncture versus placebo , and 0.78 ( 95 % CI , 0.62 - 0.98 ) for sumatriptan versus placebo ) . Response to the second intervention in patients who developed a full attack was better with sumatriptan ( 17/31 patients who received sumatriptan twice and 37/46 patients who had had placebo first ) than with acupuncture ( 4/31 ) . The number of patients reporting side-effects was 14 in the acupuncture group , 23 in the sumatriptan group and 10 in the placebo group . CONCLUSIONS In this trial acupuncture and sumatriptan were more effective than a placebo injection in the early treatment of an acute migraine attack . When an attack could not be prevented , sumatriptan was more effective than acupuncture at relieving headache [18624803] We aim ed to investigate the effectiveness of acupuncture in addition to routine care in patients with primary headache ( > 12 months , two or more headaches/month ) compared with treatment with routine care alone and whether the effects of acupuncture differ in r and omized and non-r and omized patients . In a r and omized controlled trial plus non-r and omized cohort , patients with headache were allocated to receive up to 15 acupuncture sessions over 3 months or to a control group receiving no acupuncture during the first 3 months . Patients who did not consent to r and omization received acupuncture treatment immediately . All subjects were allowed usual medical care in addition to study treatment . Number of days with headache , intensity of pain and health-related quality of life ( SF-36 ) were assessed at baseline , and after 3 and 6 months using st and ardized question naires . Of 15 056 headache patients ( mean age 44.1 ± 12.8 years , 77 % female ) , 1613 were r and omized to acupuncture and 1569 to control , and 11 874 included in the non-r and omized acupuncture group . At 3 months , the number of days with headache decreased from 8.4 ± 7.2 ( estimated mean ± S.E. ) to 4.7 ± 5.6 in the acupuncture group and from 8.1 ± 6.8 to 7.5 ± 6.3 in the control group ( P < 0.001 ) . Similarly , intensity of pain and quality of life improvements were more pronounced in the acupuncture vs. control group ( P < 0.001 ) . Treatment success was maintained through 6 months . The outcome changes in non-r and omized patients were similar to those in r and omized patients . Acupuncture plus routine care in patients with headache was associated with marked clinical improvements compared with routine care alone [18765182] OBJECTIVE To evaluate the effect of acupuncture combined with physiotherapy in comparison with acupuncture and physiotherapy performed alone in different parameters ; pain intensity , muscle tension , functional disability and muscle strength in the treatment of tension neck syndrome ( TNS ) . DESIGN A prospect i ve , comparative clinical trial . SETTING Acupuncture and Rehabilitation Department . BACKGROUND TNS can occur in computer users . Acupuncture has been one alternative treatment in physiotherapeutic rehabilitation of musculoskeletal disorders . SUBJECTS Forty-six patients with TNS . INTERVENTIONS Patients were allocated into three groups : Group-1 received physiotherapy ( therapeutic exercises ) combined with acupuncture ; Group-2 , acupuncture alone , and Group-3 , physiotherapy alone ; over a period of 10 weeks , with one or two sessions weekly . OUTCOME ASSESSMENT All patients had completed the protocol s and were assessed using a visual analogue scale for pain intensity ( VASpain ) and muscle tension ( VASmt ) , the Neck Disability Index : Brazilian Portuguese version for functional disability , and the cranio-cervical Flexion Test for isometric neck muscle strength ( INMS ) ; in the periods before treatment ( baseline ) , after 10 weeks of treatment , and after 6 months of follow-up . RESULTS All groups showed significant improvement ( p < 0.001 ) in these parameters after 10 weeks of treatment and after 6 months of follow-up . Group-1 was superior to Group-3 in pain and functional disability improvements ( p<0.05 ) ; and Group-1 was superior to both Group-2 ( p < 0.01 ) and Group-3 ( p < 0.05 ) in INMS . After 6 months of follow-up , the improvements of all groups were maintained ( p < 0.05 ) . CONCLUSION The data suggested that acupuncture effect may facilitate and /or enhance physiotherapy performance in musculoskeletal rehabilitation for tension neck syndrome [6446852] The acupuncture treatment situation was beneficial to the majority of people with low back pain . This was shown by the use of short-term controls and long-term controls , although the latter were not intended in the study design . After acupuncture , there was a 51 % pain reduction in the average pain score in the Immediate Treatment Group . The short-term controls , the Delayed Treatment Group , had no reduction whatsoever in their pain scores at the comparable followup period . Later , the Delayed Treatment Group bere also treated by acupuncturists , and reported 62 % less pain . When these two treatment groups were compared at 40 weeks with long-term controls ( Inadequate Treatment Group ) , the Inadequate Treatment Group still had the same pain scores , on the average , as when they enrolled in the study . Both treatment groups , on the average , had 30 % lower pain scores . Furthermore , 58 % of the treatment groups felt that they were definitely improved at 40 weeks , while only 11 % of the Inadequate Treatment Group felt definitely improved at 40 weeks [15870415] CONTEXT Acupuncture is widely used to prevent migraine attacks , but the available evidence of its benefit is scarce . OBJECTIVE To investigate the effectiveness of acupuncture compared with sham acupuncture and with no acupuncture in patients with migraine . DESIGN , SETTING , AND PATIENTS Three-group , r and omized , controlled trial ( April 2002-January 2003 ) involving 302 patients ( 88 % women ) , mean ( SD ) age of 43 ( 11 ) years , with migraine headaches , based on International Headache Society criteria . Patients were treated at 18 outpatient centers in Germany . INTERVENTIONS Acupuncture , sham acupuncture , or waiting list control . Acupuncture and sham acupuncture were administered by specialized physicians and consisted of 12 sessions per patient over 8 weeks . Patients completed headache diaries from 4 weeks before to 12 weeks after r and omization and from week 21 to 24 after r and omization . MAIN OUTCOME MEASURES Difference in headache days of moderate or severe intensity between the 4 weeks before and weeks 9 to 12 after r and omization . RESULTS Between baseline and weeks 9 to 12 , the mean ( SD ) number of days with headache of moderate or severe intensity decreased by 2.2 ( 2.7 ) days from a baseline of 5.2 ( 2.5 ) days in the acupuncture group compared with a decrease to 2.2 ( 2.7 ) days from a baseline of 5.0 ( 2.4 ) days in the sham acupuncture group , and by 0.8 ( 2.0 ) days from a baseline if 5.4 ( 3.0 ) days in the waiting list group . No difference was detected between the acupuncture and the sham acupuncture groups ( 0.0 days , 95 % confidence interval , -0.7 to 0.7 days ; P = .96 ) while there was a difference between the acupuncture group compared with the waiting list group ( 1.4 days ; 95 % confidence interval ; 0.8 - 2.1 days ; P<.001 ) . The proportion of responders ( reduction in headache days by at least 50 % ) was 51 % in the acupuncture group , 53 % in the sham acupuncture group , and 15 % in the waiting list group . CONCLUSION Acupuncture was no more effective than sham acupuncture in reducing migraine headaches although both interventions were more effective than a waiting list control [16178942] BACKGROUND Approximately 4 % of adults experience headaches nearly every day . Nonpharmacologic interventions for frequent headaches may be appropriate because medical management alone is often ineffective . OBJECTIVE To assess the efficacy of acupuncture as an adjunct to medical management for chronic daily headache ( CDH ) . METHODS We conducted a r and omized , controlled trial of 74 patients with CDH that compared medical management provided by neurologists to medical management plus 10 acupuncture treatments . Primary outcome measures were daily pain severity and headache-related quality of life ( QoL ) . RESULTS Patients who received only medical management did not demonstrate improvement in any of the st and ardized measures . Daily pain severity scores trended downward but did not differ between treatment groups ( P= .60 ) . Relative to medical management only , medical management plus acupuncture was associated with an improvement of 3.0 points ( 95 % CI , 1.0 to 4.9 ) on the Headache Impact Test and an increase of 8 or more points on the role limitations due to physical problems , social functioning , and general mental health domains of the Short Form 36 Health Survey . Patients who received acupuncture were 3.7 times more likely ( CI , 1.7 to 8.1 ) to report less suffering from headaches at 6 weeks ( absolute risk reduction 46 % ; number needed to treat 2 ) . CONCLUSION Headache-specialty medical management alone was not associated with improved clinical outcomes among our study population . Supplementing medical management with acupuncture , however , result ed in improvements in health-related QoL and the perception by patients that they suffered less from headaches [16545747] BACKGROUND Our aim was to assess the efficacy of a part-st and ardised verum acupuncture procedure , in accordance with the rules of traditional Chinese medicine , compared with that of part-st and ardised sham acupuncture and st and ard migraine prophylaxis with beta blockers , calcium-channel blockers , or antiepileptic drugs in the reduction of migraine days 26 weeks after the start of treatment . METHODS This study was a prospect i ve , r and omised , multicentre , double-blind , parallel-group , controlled , clinical trial , undertaken between April 2002 and July 2005 . Patients who had two to six migraine attacks per month were r and omly assigned verum acupuncture ( n=313 ) , sham acupuncture ( n=339 ) , or st and ard therapy ( n=308 ) . Patients received ten sessions of acupuncture treatment in 6 weeks or continuous prophylaxis with drugs . Primary outcome was the difference in migraine days between 4 weeks before r and omisation and weeks 23 - 26 after r and omisation . This study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N52683557 . FINDINGS Of 1295 patients screened , 960 were r and omly assigned to a treatment group . Immediately after r and omisation , 125 patients ( 106 from the st and ard group ) withdrew their consent to study participation . 794 patients were analysed in the intention-to-treat popoulation and 443 in the per- protocol population . The primary outcome showed a mean reduction of 2 .3 days ( 95 % CI 1.9 - 2.7 ) in the verum acupuncture group , 1.5 days ( 1.1 - 2.0 ) in the sham acupuncture group , and 2.1 days ( 1.5 - 2.7 ) in the st and ard therapy group . These differences were statistically significant compared with baseline ( p<0.0001 ) , but not across the treatment groups ( p=0.09 ) . The proportion of responders , defined as patients with a reduction of migraine days by at least 50 % , 26 weeks after r and omisation , was 47 % in the verum group , 39 % in the sham acupuncture group , and 40 % in the st and ard group ( p=0.133 ) . INTERPRETATION Treatment outcomes for migraine do not differ between patients treated with sham acupuncture , verum acupuncture , or st and ard therapy [15105215] Acupuncture is an established adjuvant analgesic modality for the treatment of chronic pain . Electrical stimulation of acupuncture points is considered to increase acupuncture analgesia . In this prospect i ve , r and omized , double-blind , controlled study we tested the hypothesis that auricular electroacupuncture ( EA ) relieves pain more effectively than conventional manual auricular acupuncture ( CO ) in chronic low back pain patients with insufficient pain relief ( visual analogue scale [ VAS ] ≥5 ) treated with st and ardized analgesic therapy . Disposable acupuncture needles were inserted in the auricular acupuncture points 29 , 40 , and 55 of the dominant side and connected to a newly developed battery-powered miniaturized stimulator worn behind the ear . Patients were r and omized into group EA ( n = 31 ) with continuous low-frequency auricular EA ( 1 Hz biphasic constant current of 2 mA ) and group CO ( n = 30 ) without electrical stimulation ( sham-electroacupuncture ) . Treatment was performed once weekly for 6 wk , and in each group needles were withdrawn 48 h after insertion . During the study period and a 3-mo follow-up , patients were asked to complete the McGill question naire . Psychological well being , activity level , quality of sleep , and pain intensity were assessed by means of VAS ; moreover , analgesic drug consumption was documented . Pain relief was significantly better in group EA during the study and the follow-up period as compared with group CO . Similarly , psychological well-being , activity , and sleep were significantly improved in group EA versus group CO , the consumption of analgesic rescue medication was less , and more patients returned to full-time employment . Neuropathic pain in particular improved in patients treated with EA . There were no adverse side effects . These results are the first to demonstrate that continuous EA stimulation of auricular acupuncture points improves the treatment of chronic low back pain in an outpatient population [7727550] OBJECTIVE The purpose of this study was to determine whether acupuncture was more effective than sham acupuncture in the reduction of pain in persons with osteoarthritis ( OA ) of the knee . METHODS Forty subjects ( 20 men , 20 women ) with radiographic evidence of OA of the knee were stratified by gender and r and omly assigned to either the experimental ( real acupuncture ) or control ( sham acupuncture ) groups . Subjects were treated three times per week for 3 weeks and evaluated at three test sessions . Outcome measures were : 1 ) the Pain Rating Index of the McGill Pain Question naire , 2 ) the Western Ontario and McMaster Universities ( WOMAC ) Osteoarthritis Index , and 3 ) pain threshold at four sites at the knee . RESULTS The analyses of variance showed that both real and sham acupuncture significantly reduced pain , stiffness , and physical disability in the OA knee , but that there were no significant differences between groups . CONCLUSIONS Acupuncture is not more effective than sham acupuncture in the treatment of OA pain [18534326] OBJECTIVE A pilot study to assess the feasibility of a trial to investigate the efficacy of acupuncture compared to placebo needling for the treatment of acute low back pain ( LBP ) . As part of this , the study was design ed to establish the credibility of the placebo control , and to provide data to inform a power analysis to determine numbers for a future trial . STUDY DESIGN A pilot patient and assessor blinded r and omized controlled trial . SETTING Primary care health centre facility , South and East Belfast Trust , Northern Irel and . PATIENTS Patients from the physiotherapy waiting list ( n=48 ) with LBP of less than 12 weeks duration . OUTCOME MEASURES Rol and and Morris Disability Question naire ( RMDQ ) , Visual Analogue Scale ( VAS ) , medication use and an exit question naire were completed at baseline , end of treatment , and at 3 months follow up . RESULTS Ninety-four percent ( 45/48 ) of patients completed assigned treatment , 83 % ( 40/48 ) completed 3 months follow-up . The sham needle used here proved to be credible : 91.7 % in the placebo group believed they had received acupuncture , compared to 95.8 % in the verum acupuncture group . Differences in baseline characteristics were accounted for using ANCOVA . There was no significant difference between groups on the RMDQ over time . For pain , the only statistically significant difference was at the 3 months follow up ( worst VAS , point estimate , 18.7 , 95 % CI 1.5 - 36.0 , p=0.034 ) . The majority of patients were taking some form of analgesic medication for LBP at the start of treatment ( n=44 ; 92 % ) , and at the end of treatment the verum acupuncture group were taking significantly fewer tablets of pain control medication ( mean ( S.D. ) : 1.0+/-0.3 ) than the placebo group ( mean ( S.D. ) : 4.2+/-0.6 , p<0.05 ) . Based upon these data , power analysis ( power=90 % , alpha=0.05 , minimal clinical ly important difference ( MCID ) for RMDQ=2.5 points ) indicated that 120 participants ( 60 per group ) would be needed to complete an adequately powered r and omized controlled trial . CONCLUSIONS This study has demonstrated the feasibility of a r and omized controlled trial of penetrating needle acupuncture compared to a non-penetrating sham for the treatment of acute LBP in primary care ; 120 participants would be required in a fully powered trial . The placebo needle used in this study proved to be a credible form of control [14600536] Objective To assess the efficacy of acupuncture in the treatment of chronic low back pain . Methods Patients ( n = 60 ) with chronic low back pain were recruited and r and omly allocated to either Acupuncture therapy or Placebo transcutaneous electrical nerve stimulation ( TENS ) groups . Patients were treated weekly for 6 weeks , and blinded assessment s were carried out pre- and post-treatment using the McGill Pain Question naire ( MPQ ) and visual analog scales ( VAS ) for pain , the Short-form 36 quality -of-life question naire , and a simple range of motion measurement . A total of 46 patients completed the trial and were followed up at 6 months . Results Analysis of results using t tests showed that in both groups there were significant pre-post improvements for all scores , except for MPQ scores in the Placebo-TENS group . There was no significant difference between the 2 groups for any of the outcome measures at the end of treatment . Results from the 6-month follow-up would suggest that the response was better in the acupuncture group . Discussion Further research is necessary to fully assess the efficacy of this treatment in combating chronic low back pain using larger sample sizes or alternative control groups [15798042] PURPOSE This study provides basic information about the training and practice s of licensed acupuncturists . METHODS R and omly selected licensed acupuncturists in Massachusetts and Washington state were interviewed and asked to record information on 20 consecutive patient visits . RESULTS Most acupuncturists in both states had 3 or 4 years of academic acupuncture training and had received additional “ postgraduate ” training as well . Acupuncturists treated a wide range of conditions , including musculoskeletal problems ( usually back , neck , and shoulder ) ( 33 % in Massachusetts and 47 % in Washington ) , general body symptoms ( 12 % and 9 % , respectively ) such as fatigue , neurological problems ( 10 % and 12 % , respectively ) ( eg , headaches ) , and psychological complaints ( 10 % and 8 % , respectively ) ( especially anxiety and depression ) . Traditional Chinese medicine ( TCM ) was the predominant style of acupuncture used in both states ( 79 % and 86 % , respectively ) . Most visits included a traditional diagnostic assessment ( more than 99 % ) , regular body acupuncture ( 95 % and 93 % , respectively ) , and additional treatment modalities ( 79 % and 77 % , respectively ) . These included heat and lifestyle advice ( 66 % and 65 % , respectively ) , most commonly dietary advice and exercise recommendations . Chinese herbs were used in about one third of visits . Although most patients self-referred to acupuncture , about one half received concomitant care from a physician . Acupuncturists rarely communicated with the physicians of their patients who were providing care for the same problem . CONCLUSIONS This study contributes new information about acupuncturists and the care they provide that should be useful to clinicians interested in becoming more knowledgeable about complementary or alternative medical therapies available to their patients [11322842] BACKGROUND Because the value of popular forms of alternative care for chronic back pain remains uncertain , we compared the effectiveness of acupuncture , therapeutic massage , and self-care education for persistent back pain . METHODS We r and omized 262 patients aged 20 to 70 years who had persistent back pain to receive Traditional Chinese Medical acupuncture ( n = 94 ) , therapeutic massage ( n = 78 ) , or self-care educational material s ( n = 90 ) . Up to 10 massage or acupuncture visits were permitted over 10 weeks . Symptoms ( 0 - 10 scale ) and dysfunction ( 0 - 23 scale ) were assessed by telephone interviewers masked to treatment group . Follow-up was available for 95 % of patients after 4 , 10 , and 52 weeks , and none withdrew for adverse effects . RESULTS Treatment groups were compared after adjustment for prer and omization covariates using an intent-to-treat analysis . At 10 weeks , massage was superior to self-care on the symptom scale ( 3.41 vs 4.71 , respectively ; P = .01 ) and the disability scale ( 5.88 vs 8.92 , respectively ; P<.001 ) . Massage was also superior to acupuncture on the disability scale ( 5.89 vs 8.25 , respectively ; P = .01 ) . After 1 year , massage was not better than self-care but was better than acupuncture ( symptom scale : 3.08 vs 4.74 , respectively ; P = .002 ; dysfunction scale : 6.29 vs 8.21 , respectively ; P = .05 ) . The massage group used the least medications ( P<.05 ) and had the lowest costs of subsequent care . CONCLUSIONS Therapeutic massage was effective for persistent low back pain , apparently providing long-lasting benefits . Traditional Chinese Medical acupuncture was relatively ineffective . Massage might be an effective alternative to conventional medical care for persistent back pain [11841108] The principle aim of the present work is the evaluation of the importance of the variable " depth " of needle insertion in the determination of acupuncture 's therapeutic results . A r and omized clinical trial carried out on 44 patients belonging to two groups of 22 each , suffering from shoulder myofascial pain : group A : superficial acupuncture ; group B : deep acupuncture . All of them subjected to the same model of treatment with 13 needles and the treatment of the most painful 4 trigger points ( TP ) found in the shoulder 's area . In the group A patients , the needles were introduced in the skin at a depth of 2 mm , on the TP . In the group B patients , the needles were placed deeply both in the muscular acupuncture points and in the TP . The treatment was planned for a cycle of 8 sessions , the first 4 to be performed twice a week , the last 4 weekly . The intensity of pain was evaluated with the McGill Pain Question naire before beginning the therapy , at the end of the therapy , and at the follow-up after 1 and 3 months . Both techniques had efficacy in controlling pain . A statistically significant difference rose between the two needling techniques at the end of the treatment and at the follow up after one and three months . Deep acupuncture shows to be better at all times and this underlines the importance of the muscular afferences in acupunctural stimulation in the control of pain [15157691] & NA ; The study was carried out to examine whether acupuncture treatment can reduce chronic pain in the neck and shoulders and related headache , and also to examine whether possible effects are long‐lasting . Therefore , 24 female office workers ( 47±9 years old , mean±SD ) who had had neck and shoulder pain for 12±9 years were r and omly assigned to a test group ( TG ) or a control group ( CG ) . Acupuncture was applied 10 times during 3–4 weeks either at presumed anti‐pain acupoints ( TG ) or at placebo‐points ( CG ) . A physician measured the pain threshold ( PPT ) in the neck and shoulder regions with algometry before the first treatment , and after the last one and six months after the treatments . Question naires on muscle pain and headache were answered at the same occasions and again 3 years after the last treatment . The intensity and frequency of pain fell more for TG than for CG ( Pb≤0.04 ) during the treatment period . Three years after the treatments TG still reported less pain than before the treatments ( Pw<0.001 ) , contrary to what CG did ( Pb<0.04 ) . The degree of headache fell during the treatment period for both groups , but more for TG than for CG ( Pb=0.02 ) . Three years after the treatments the effect still lasted for TG ( Pw<0.001 ) while the degree of headache for CG was back to the pre‐treatment level ( Pb<0.001 ) . PPT of some muscles rose during the treatments for TG and remained higher 6 months after the treatments ( Pw<0.05 ) , which contrasts the situation for CG . Adequate acupuncture treatment may reduce chronic pain in the neck and shoulders and related headache . The effect lasted for 3 years [1514335] Purpose : Acupuncture treatment of patients waiting for arthroplasty surgery . Methods : 29 patients with a total of 42 osteoarthritic knees were r and omized to two groups . Group A was treated while Group B served as a no‐treatment control group . After 9 weeks Group B was treated too . Analgesic consumption , pain and objective measurements were registered . All objective measures were done by investigators who were “ blinded ” as to Group A & B. In the second part of the study 17 patients ( 26 knees ) continued with treatments once a month . Registration of analgesic consumption , pain and objective measurements continued . Total study period 49 weeks . Results : Comparing Group A to B there was a significant reduction in pain , analgesic consumption and in most objective measures . In Group A + B combined there was an 80 % subjective improvement , and a significantly increased knee range movement – an increase mainly in the worst knees . Results were significantly better in those who had not been ill for a long time . In the second part of the study , it was shown that it was possible to maintain the improvements . Conclusions : Acupuncture can ease the discomfort while waiting for an operation and perhaps even serve as an alternative to surgery . Seven patients have responded so well that at present they do not want an operation . ( USD 9000 saved per operation ) [11531895] A study with needle acupuncture was performed in tension-type headache employing a new placebo acupuncture method . Sixty-nine patients ( mean age 48.1 years , sd = 14.1 ) fulfilling the International Headache Society criteria for tension-type headache were r and omly assigned to verum or placebo condition . No significant differences between placebo and verum with respect to visual analogue scale and frequency of headache attacks could be observed immediately , 6 weeks and 5 months after the end of treatment . There was a significant but weak improvement in quality of life parameters ( clinical global impressions , Nottingham Health Profile ) after verum treatment . In decision tree analyses , the changes in clinical global impressions and headache frequency depended significantly on primary headache frequency with a limit value of 24.5 days headache per month . High values in the von Zerssen Depression Score result ed in high mean visual analogue scale values [10422654] Sixty patients aged 60 or over with back pain for at least 6 months were recruited from General Practitioner referrals and r and omized to 4 weeks of treatment with acupuncture or transcutaneous electrical nerve stimulation ( TENS ) . All treatments were administered by the same physiotherapist and both groups had the same contact with him . The following were measured at baseline , completion and at a 3-month follow-up by an independent observer blinded to treatment received : ( 1 ) pain severity on visual analogue scale ( VAS ) ; ( 2 ) pain subscale of Nottingham Health Profile ( NHP ) ; ( 3 ) number of analgesic tablets consumed in previous week ; ( 4 ) spinal flexion from C7 to S1 . Thirty-two patients were r and omized to acupuncture and 28 to TENS ; only three withdrew ( two from acupuncture , one from TENS ) . Significant improvements were shown on VAS ( P < 0.001 ) , NHP ( P < 0.001 ) and tablet count ( P < 0.05 ) between baseline and completion in both groups , these improvements remaining significant comparing baseline with follow-up with a further non-significant improvement in VAS and NHP in the acupuncture group . The acupuncture but not the TENS patients showed a small but statistically significant improvement ( P < 0.05 ) in mean spinal flexion between baseline and completion which was not maintained at follow-up . Thus in these elderly patients with chronic back pain both acupuncture and TENS had demonstrable benefits which outlasted the treatment period . Acupuncture may improve spinal flexion . This trial can not exclude the possibility that both treatments are ' placebos ' [16618043] Introduction There is some evidence for the efficacy of acupuncture , but it remains unclear whether trigger point acupuncture is effective . Our objective was to evaluate the effects of trigger point acupuncture on pain and quality of life in chronic low back pain patients compared with sham acupuncture . Methods Twenty-six consecutive out- patients ( 17 women , 9 men ; age range : 65–91 years ) from the Department of Orthopaedic Surgery , Meiji University of Oriental Medicine , with non-radiating low back pain for at least six months and normal neurological examination , were r and omised to two groups . Each group received one phase of trigger point acupuncture and one of sham acupuncture with a three week washout period between them , over 12 weeks . Group A ( n=13 ) received trigger point acupuncture in the first phase and sham acupuncture in the second . Group B ( n=13 ) received the same interventions in the reverse order . Outcome measures were pain intensity ( visual analogue scale , VAS ) and Rol and Morris Question naire . Results Nineteen patients were included in the analysis . At the end of the first treatment phase , group A receiving trigger point acupuncture scored significantly lower VAS ( P<0.001 ) and Rol and Morris Question naire scores ( P<0.01 ) than the sham control group . There were significant within-group reductions in pain in both groups during the trigger point acupuncture phase but not in the sham treatment phase . However , the beneficial effects were not sustained . Conclusion These results suggest that trigger point acupuncture may have greater short term effects on low back pain in elderly patients than sham acupuncture [15561516] OBJECTIVE To investigate the effectiveness of a clinical treatment program with traditional Chinese medicine for migraine and tension-type headache . METHODS Ninety-one patients with migraine , episodic or chronic tension-type headache according to the criteria of the International Headache Society were r and omised into an experimental or a waiting list control group . Patients in the experimental group were treated 4 weeks in a hospital for traditional Chinese medicine after a baseline period of one month . Patients in the waiting list group continued their previous headache treatment . Main outcome measure was the difference in the number of days with headache of at least moderate intensity during baseline ( month 1 ) and month 7 . RESULTS The difference in the number of days with headache of at least moderate intensity was 5.6 ( S.D. , 6.1 ) days in the experimental group and 1.2 ( S.D. , 4.5 ) days in the waiting list group ( P < 0.001 ) . A reduction of more than 50 % in headache days was observed in 52 % of the patients in the experimental group and 16 % in the waiting list group . Patients with migraine and a combination of migraine and episodic tension-type headaches improved more than patients with other headaches . CONCLUSION The results of this study indicate that treatment in the hospital for traditional Chinese medicine in Kotzting is associated with lasting improvements in the majority of patients [15650469] DESIGN Forty-two ( 42 ) subjects suffering from chronic low-back pain were matched with the nature of their occupations and then r and omly allocated into : ( 1 ) an electroacupuncture group ( EA ) ; ( 2 ) an electrical heat acupuncture ( EH ) group or ; ( 3 ) a control group . INTERVENTIONS Subjects in the EA group and the EH group received treatment for 20 minutes on a total of 6 acupuncture points . Treatment was delivered twice per week for 4 weeks ( a total of 8 sessions ) . Back exercise was taught to all subjects including the control group as a home program . OUTCOMES MEASURES A numerical rating scale of pain ( NPRS ) , straight leg raise ( SLR ) , and Rol and Morris Disability Question naire ( RMDQ ) were recorded . RESULTS There were significant reduction of NPRS within the EA ( p = 0.000 ) , EH ( p = 0.000 ) , and control ( p = 0.013 ) groups across sessions . Significant between-group differences were shown in session 4 ( p = 0.006 ) , session 8 ( p = 0.001 ) , and 1-month follow-up sessions ( p = 0.001 ) . Posthoc tests showed that the NPRS of the EH group was significantly lower than that of the EA group and the control group by session 4 ( p = 0.004 ) . After session 8 , the NPRS of both the EA group ( p = 0.003 ) and the EH group ( p = 0.001 ) were significantly lower than that of the control group . Such a difference was maintained at least up to the 1-month follow-up . Only the EA group had significant improvement in the measurement of SLR across sessions ( p = 0.000 ) . The between-group difference reached significance level in session 8 ( p = 0.001 ) and at 1-month follow-up ( p = 0.002 ) . Posthoc tests showed that EA group had significantly greater gain than the EH group and the control group . For the RMDQ score , the improvement was statistically significant within each of the three groups over time ( p = 0.000 ) . However , the between-group difference did not reach statistical significance . CONCLUSIONS Our findings suggest that 4 sessions of EH treatment over 2 weeks produced significantly greater reduction in the NPRS than that of the EA or the control . However , EA produced greater improvement in SLR and reduction in RMDQ score than that of the EH and the control [18403402] OBJECTIVE Evaluate the efficacy of acupuncture associated with physiotherapy for patients with painful shoulder . METHODS In a multicentre controlled r and omized study , participants were recruited with a clinical diagnosis of unilateral subacromial syndrome from six rehabilitation medicine departments belonging to the Public Health System in two Spanish regions . All participants received 15 sessions of physiotherapy during the 3 weeks that the treatment lasted and were r and omized to additionally receive , once a week , acupuncture or mock TENS ( transcutaneous electrical nerve stimulation ) . The primary outcome measure was the change in the Constant-Murley Score ( CMS ) for functional assessment of the shoulder , at 4 weeks after r and omization . This study is registered as an International St and ard R and omized Controlled Trial , number IS RCT N28687220 . RESULTS A total of 425 patients were recruited . The mean score ( s.d . ) on the CMS had increased by 16.6 ( 15.6 ) points among the acupuncture group , compared with 10.6 ( 13.5 ) points in the control group , and the mean difference between the two groups was statistically significant ( 6.0 points ; 95 % CI 3.2 , 8.8 points ; P < 0.001 ) . By the end of the treatment , 53 % of the patients in the acupuncture group had decreased their consumption of analgesics , compared with a corresponding 30 % among the control group ( P < 0.001 ) . CONCLUSIONS Single-point acupuncture in association with physiotherapy improves shoulder function and alleviates pain , compared with physiotherapy as the sole treatment . This improvement is accompanied by a reduction in the consumption of analgesic medicaments [15628774] Objective There is some evidence for the efficacy of acupuncture in chronic low back pain , but it remains unclear which acupuncture modes are most effective . Our objective was to evaluate the effects of two different modes of trigger point acupuncture on pain and quality of life in chronic low back pain patients compared to st and ard acupuncture treatment . Methods Thirty five consecutive out- patients ( 25 women , 10 men ; age range : 65–81 years ) from the Department of Orthopaedic Surgery , Meiji University of Oriental Medicine , with non-radiating low back pain for at least six months and normal neurological examination , were r and omised to one of three groups over 12 weeks . Each group received two phases of acupuncture treatment with an interval between them . Nine patients dropped out during the course of the study . The st and ard acupuncture group ( n=9 ) received treatment at traditional acupuncture points for low back pain , while the other acupuncture groups received superficial ( n=9 ) or deep ( n=9 ) treatments on trigger points . Outcome measures were VAS pain intensity and Rol and Morris Question naire . Results After treatment , the group that received deep needling to trigger points reported less pain intensity and improved quality of life compared to the st and ard acupuncture group or the group that received superficial needling to trigger points , but the differences were not statistically significant . There was a significant reduction in pain intensity between the treatment and interval in the group that received deep needling to trigger points ( P<0.01 ) , but not in the st and ard acupuncture group or the group that received superficial needling to trigger points . Conclusion These results suggest that deep needling to trigger points may be more effective in the treatment of low back pain in elderly patients than either st and ard acupuncture therapy , or superficial needling to trigger points [18035566] Opioid-like medications ( OLM ) are commonly used by patients with various types of chronic pain , but their long-term benefit is question able . Electroacupuncture ( EA ) has been previously shown beneficial in reducing post-operative acute OLM consumption . In this pilot r and omized controlled trial , the effect of EA on OLM usage and associated side effects in chronic pain patients was evaluated . After a two-week baseline assessment , participants using OLM for their non-malignant chronic pain were r and omly assigned to receive either real EA ( REA , n=17 ) or sham EA ( SEA , n=18 ) treatment twice weekly for 6 weeks before entering a 12-week follow-up . Pain , OLM consumption and their side effects were recorded daily . Participants also completed the McGill Pain Question naire ( MPQ ) , SF-36 and Beck Depression Inventory ( BDI ) at baseline , and at the 5th , 8th , 12th , 16th and 20th week . Nine participants withdrew during the treatment period with another three during the follow-up period . Intention to treat analysis was applied . At the end of treatment period , reductions of OLM consumption in REA and SEA were 39 % and 25 % , respectively ( p=0.056 ) , but this effect did not last more than 8 weeks after treatment . There was no difference between the two groups with respect to reduction of side effects and pain and the improvement of depression and quality of life . In conclusion , REA demonstrates promising short-term reduction of OLM for participants with chronic non-malignant pain , but such effect needs to be confirmed by trials with adequate sample sizes [17013356] Background The purpose of this study was to examine the immediate effect of single acupuncture stimulation to the most painful point in patients with low back pain . Method A r and omised , evaluator-blinded , sham controlled clinical trial was conducted in which 31 patients with low back pain were r and omly allocated to either an acupuncture group ( n=15 ) or a sham acupuncture group ( n=16 ) . Both acupuncture and sham acupuncture were performed at the most painful point on the lower back of the subjects . For the acupuncture group , a stainless steel needle was inserted to a depth of 20 mm and manually stimulated ( sparrow pecking method ) for 20 seconds , while for the sham treatment a guide tube without a needle was placed at the point and tapped on the skin . Changes in low back pain were evaluated with a visual analogue scale ( VAS ) and the Schober test . Participants were also asked if they felt the needling sensation or not . The therapy and the evaluation were independently performed by two different acupuncturists . Results VAS score and the Schober test score showed significant improvement after treatment as compared with the sham group ( P=0.02 , 0.001 , respectively ) . There were no significant differences in the needling sensation between the acupuncture and sham group . Conclusion These results suggest that acupuncture at the most painful point gives immediate relief of low back pain [17868354] OBJECTIVE To check the effectiveness of a true acupuncture treatment according to traditional Chinese medicine ( TCM ) in migraine without aura , comparing it to a st and ard mock acupuncture protocol , an accurate mock acupuncture healing ritual , and untreated controls . BACKGROUND Migraine prevalence is high and affects a relevant rate of adults in the productive phase of their life . Acupuncture has been increasingly advocated and used in Western countries for migraine treatment , but the evidence of its effectiveness still remains weak . A large variability of treatments is present in published studies and no acupoint selection according to TCM has been investigated so far ; therefore , the low level of evidence of acupuncture effectiveness might partly depend on inappropriate treatment . DESIGN AND METHODS A prospect i ve , r and omized , controlled study was performed in 160 patients suffering from migraine without aura , assessed according to the ICD-10 classification . The patients were divided into the following 4 groups : ( 1 ) group TA , treated with true acupuncture ( according to TCM ) plus Rizatriptan ; ( 2 ) group RMA , treated with ritualized mock acupuncture plus Rizatriptan ; ( 3 ) group SMA , treated with st and ard mock acupuncture plus Rizatriptan ; ( 4 ) group R , without prophylactic treatment with relief therapy only ( Rizatriptan ) . The MIDAS Question naire was administered before treatment ( T0 ) , at 3 ( T1 ) and 6 months ( T2 ) from the beginning of treatment , and the MIDAS Index ( MI ) was calculated . Rizatriptan intake was also checked in all groups of patients at T0 , T1 , and T2 . Group TA and RMA were evaluated according to TCM as well ; then , the former was su bmi tted to true acupuncture and the latter to mock acupuncture treatment resembling the same as TA . The statistical analysis was conducted with factorial ANOVA and multiple tests with a Bonferroni adjustment . RESULTS A total of 127 patients completed the study ( 33 dropouts ) : 32 belonged to group TA , 30 to group RMA , 31 to group SMA , and 34 to group R. Before treatment the MI ( T(0 ) ) was moderate to severe with no significant intergroup differences . All groups underwent a decrease of MI at T(1 ) and T(2 ) , with a significant group difference at both T(1 ) and T(2 ) compared to T(0 ) ( P < .0001 ) . Only TA provided a significant improvement at both T(1 ) and T(2 ) compared to R ( P < .0001 ) . RMA underwent a transient improvement of MI at T(1 ) . The Rizatriptan intake paralleled the MI in all groups . CONCLUSIONS TA was the only treatment able to provide a steady outcome improvement in comparison to the use of only Rizatriptan , while RMA showed a transient placebo effect at T1 [20980765] Background and Objective : A recent Cochrane review on placebo interventions for all kinds of conditions found that ‘ physical placebos ’ ( which included sham acupuncture ) were associated with larger effects over no-treatment control groups than ‘ pharmacological placebos ’ . We re-analyzed the data from this review to investigate whether effects associated with sham acupuncture differed from those of other ‘ physical placebos ’ . Methods : All trials included in the Cochrane review as investigating ‘ physical placebos ’ were classified as investigating either ( sham ) acupuncture or other physical placebos . The latter group was further subclassified into groups of similar interventions . Data from the Cochrane review were re-entered into the RevMan 5 software for meta- analysis . The primary analysis was a r and om-effects analysis of trials reporting continuous outcomes of trials that used either sham acupuncture or other physical placebos . Results : Out of a total of 61 trials which reported a continuous outcome measure , 19 compared sham acupuncture and 42 compared other physical placebos with a notreatment control group . The trials re-analyzed were highly heterogeneous regarding patients , interventions and outcomes measured . The pooled st and ardized mean difference was –0.41 ( 95 % confidence interval –0.56 , –0.24 ) between sham acupuncture and no treatment and –0.26 ( 95 % CI –0.37 , –0.15 ) between other physical placebos and no treatment ( p value for subgroup differences = 0.007 ) . Significant differences were also observed between subgroups of other physical placebos . Conclusion : Due to the heterogeneity of the trials included and the indirect comparison our results must be interpreted with caution . Still , they suggest that sham acupuncture interventions might , on average , be associated with larger effects than pharmacological and other physical placebos [15921471] BACKGROUND AND PURPOSE There is no definitive evidence for the efficacy of the physical therapy interventions used for patients with impingement syndrome . The purpose of this study was to compare manual acupuncture and continuous ultrasound , both applied in addition to home exercises , for patients diagnosed with impingement syndrome . SUBJECTS AND METHODS Eighty-five patients with clinical signs of impingement syndrome were r and omly assigned to either a group that received acupuncture ( n=44 ) or a group that received ultrasound ( n=41 ) . Both interventions were given by physical therapists twice a week for 5 weeks in addition to a home exercise program . Scores from 3 shoulder disability measures , combined in the analysis , measured change during a period of 12 months . RESULTS Both groups improved , but the acupuncture group had a larger improvement in the combined score . DISCUSSION AND CONCLUSION The results suggest that acupuncture is more efficacious than ultrasound when applied in addition to home exercises [11128820] A multicentre , r and omized clinical trial was undertaken to test the hypothesis that acupuncture is more efficacious than sham control procedure in the prevention of episodic tension-type headache . Fifty subjects were r and omized to receive a course of treatment with either brief acupuncture or a sham procedure . Subjects were followed up for 3 months . Changes in headache were assessed by daily diary , the primary outcome measure being the number of days with headache . No significant differences were found between the changes in the two groups for any measure at any time point . Results also show that patient blinding was successful . In conclusion , this study does not provide evidence that this form of acupuncture is effective in the prevention of episodic tension-type headache [12594972] OBJECTIVES To compare the effects of real acupuncture to tender points for neck and shoulder pain and stiffness ( Japanese : katakori ) with those of sham acupuncture . DESIGN R and omized-controlled trial . METHODS Thirty-four volunteers from an acupuncture school with complaints of chronic pain and stiffness , who had no arm symptoms and gave informed consent , were r and omly allocated to acupuncture or sham groups . Acupuncture or sham acupuncture was applied to the tender points once a week for 3 weeks . In the acupuncture group the acupuncture needle was inserted to the muscle , then the sparrow pecking technique was applied five times . Sham acupuncture was done without insertion of the needle . Dull pain and stiffness were evaluated by visual analog scale ( VAS ) before , and every 2 days after the first needling for 1 month . Pressure pain threshold on the tender points was measured before and after each treatment . RESULTS There was no statistical difference of VAS scores between acupuncture and sham groups 9 days after the last treatment . However , the acupuncture group showed significant reduction of VAS scores immediately after and /or 1 day after the real acupuncture treatments ( P<0.01 ) . The effect tended to be prolonged after repeated treatment . Pressure pain thresholds tended to increase after real acupuncture treatment but not after sham acupuncture . CONCLUSIONS Acupuncture applied to tender points appears to have short-term effects on neck and shoulder pain and stiffness , but this study was unable to demonstrate any long-term superiority over sham acupuncture [18356795] Background There is evidence for the efficacy of acupuncture treatment in knee osteoarthritis , but it remains unclear which acupuncture modes are most effective . We evaluated the effects of trigger point acupuncture on pain and quality of life in knee osteoarthritis patients , compared with acupuncture at st and ard points , and sham acupuncture . Methods Thirty patients ( 27 women , 3 men ; aged 61–82 years ) with non-radiating knee osteoarthritis pain for at least six months and normal neurological examination were r and omised to one of three groups for the study period of 21 weeks . Each group received five acupuncture treatment sessions . The st and ard acupuncture point group ( n=10 ) received treatment at traditional acupuncture points for knee pain ; the trigger point acupuncture group ( n=10 ) received treatment at trigger points ; and the third group ( n=10 ) received sham acupuncture treatment at the trigger points . Outcome measures were pain intensity ( visual analogue scale , VAS ) and WOMAC index ( Western Ontario and McMaster Universities Arthritis Index ) . The groups were compared by the area under the curve method . Results Five patients dropped out of the study because of lack of improvement , and one patient ( in the trigger point acupuncture group ) dropped out because of deterioration of symptoms ; the remaining 24 patients were included in the analysis . After treatment , the trigger point acupuncture group reported less pain intensity on VAS than the st and ard acupuncture or sham treatment group , but both the trigger point acupuncture and st and ard acupuncture groups reported improvement of function of knee . There was a significant reduction in pain intensity between pre-treatment and five weeks after treatment for the trigger point acupuncture ( P<0.01 ) and st and ard acupuncture groups ( P<0.01 ) included in the analysis , but not for the sham treatment group . Group comparison using the area under the curves demonstrated a significant difference only between trigger point acupuncture and sham treatment groups analysed ( P<0.025 for VAS , and P<0.031 for WOMAC ) . Conclusion These results suggest that trigger point acupuncture therapy may be more effective for osteoarthritis of the knee in some elderly patients than st and ard acupuncture therapy [17075849] OBJECTIVE To investigate the effectiveness of acupuncture in addition to routine care , compared with routine care alone , in the treatment of patients with chronic pain due to osteoarthritis ( OA ) of the knee or hip . METHODS In a r and omized , controlled trial , patients with chronic pain due to OA of the knee or hip were r and omly allocated to undergo up to 15 sessions of acupuncture in a 3-month period or to a control group receiving no acupuncture . Another group of patients who did not consent to r and omization underwent acupuncture treatment . All patients were allowed to receive usual medical care in addition to the study treatment . Clinical OA severity ( Western Ontario and McMaster Universities Osteoarthritis Index [ WOMAC ] ) and health-related quality of life ( Short Form 36 ) were assessed at baseline and after 3 months and 6 months . RESULTS Of 3,633 patients ( mean + /- SD age 61.8 + /- 10.8 years ; 61 % female ) , 357 were r and omized to the acupuncture group and 355 to the control group , and 2,921 were included in the nonr and omized acupuncture group . At 3 months , the WOMAC had improved by a mean + /- SEM of 17.6 + /- 1.0 in the acupuncture group and 0.9 + /- 1.0 in the control group ( 3-month scores 30.5 + /- 1.0 and 47.3 + /- 1.0 , respectively [ difference in improvement 16.7 + /- 1.4 ; P < 0.001 ] ) . Similarly , quality of life improvements were more pronounced in the acupuncture group versus the control group ( P < 0.001 ) . Treatment success was maintained through 6 months . The changes in outcome in nonr and omized patients were comparable with those in r and omized patients who received acupuncture . CONCLUSION These results indicate that acupuncture plus routine care is associated with marked clinical improvement in patients with chronic OA-associated pain of the knee or hip [9717924] BACKGROUND A problem acupuncture research has to face is the concept of a control group . If , in control groups , non-acupoint needling is done , physiological acupuncture effects are implied . Therefore the effects shown in this group are often close to those shown in the acupuncture group . In other trials , control groups have received obviously different treatments , such as transcutaneous electrical nervous stimulation or TENS-laser treatment ; it is not clear if the effects of acupuncture are due only to the psychological effects of the treatment . METHODS We developed a placebo acupuncture needle , with which it should be possible to simulate an acupuncture procedure without penetrating the skin . In a cross-over experiment with 60 volunteers we tested whether needling with the placebo needle feels any different from real acupuncture . FINDINGS Of 60 volunteers , 54 felt a penetration with acupuncture ( mean visual analogue scale [ VAS ] 13.4 ; SD 10.58 ) and 47 felt it with placebo ( VAS 8.86 ; SD 10.55 ) , 34 felt a dull pain sensation ( DEQI ) with acupuncture and 13 with placebo . None of the volunteers suspected that the needle may not have penetrated the skin . INTERPRETATION The placebo needle is sufficiently credible to be used in investigations of the effects of acupuncture [17709062] INTRODUCTION There is some evidence for the efficacy of acupuncture in chronic neck pain ( CNP ) treatment , but it remains unclear which acupuncture modes are most effective . Objective was to evaluate the effects of trigger point acupuncture on pain and quality of life ( QOL ) in CNP patients compared to three other acupuncture treatments ( acupoints , non-trigger point and sham treatment ) . METHODS Forty out- patients ( 29 women , 11 men ; age range : 47 - 80 years ) from the Department of Orthopaedic Surgery , Meiji University of Oriental Medicine , with non-radiating CNP for at least 6 months and normal neurological examination were r and omised to one of four groups over 13 weeks . Each group received two phases of acupuncture treatment with an interval between them . The acupoint group ( st and ard acupuncture ; SA , n=10 ) received treatment at traditional acupoints for neck pain , the trigger point ( TrP , n=10 ) and non-trigger point ( non-TrP , n=10 ) groups received treatment at tenderness points for the same muscle , while the other acupuncture group received sham treatments on the trigger point ( SH , n=10 ) . Outcome measures were pain intensity ( visual analogue scale ; VAS 0 - 100 mm ) and disease specific question naire ( neck disability index ; NDI , 60-point scale ) . RESULTS After treatment , the TrP group reported less pain intensity and improved QOL compared to the SA or non-TrP group . There was significant reduction in pain intensity between the treatment and the interval for the TrP group ( p<0.01 , Dunnett 's multiple test ) , but not for the SA or non-TrP group . CONCLUSION These results suggest that trigger point acupuncture therapy may be more effective on chronic neck pain in aged patients than the st and ard acupuncture therapy [17115982] OBJECTIVES In a r and omized controlled multicenter trial extending over 24 weeks , we investigated whether acupuncture is as effective and safe as metoprolol in the prophylactic treatment of migraine under conditions similar to routine care . METHODS One hundred fourteen migraine patients could be r and omized to treatment over 12 weeks either with acupuncture ( 8 to 15 sessions ) or metoprolol ( 100 to 200 mg daily ) . Main outcome measure was the difference in the number of migraine days between baseline and the weeks 9 to 12 after r and omization ( derived from a headache diary ) . RESULTS Two of 59 patients r and omized to acupuncture withdrew prematurely from the study compared to 18 of 55 r and omized to metoprolol . The number of migraine days decreased by 2.5 + /- 2.9 days ( baseline 5.8 + /- 2.5 days ) in the acupuncture group compared to 2.2 + /- 2.7 days ( baseline 5.8 + /- 2.9 days ) in the metoprolol group ( P= .721 ) . The proportion of responders ( reduction of migraine attacks by > or = 50 % ) was 61 % for acupuncture and 49 % for metoprolol . Both physicians and patients reported fewer adverse effects in the acupuncture group . CONCLUSIONS Due to missing the recruitment target ( 480 patients ) and the high drop-out in the metoprolol group the results must be interpreted with caution . Still , they suggest that acupuncture might be an effective and safe treatment option for patients unwilling or unable to use drug prophylaxis [20506122] There is conflicting evidence on the efficacy of traditional Chinese acupuncture ( TCA ) , and the role of placebo effects elicited by acupuncturists ' behavior has not been eluci date d. We conducted a 3‐month r and omized clinical trial in patients with knee osteoarthritis to compare the efficacy of TCA with sham acupuncture and to examine the effects of acupuncturists ' communication styles [15606569] The objectives were to introduce a new method for controlled trials of acupuncture in the field of headache research and to examine the role of needling per se . Women with menstrually related migraine were r and omized to three months of treatment with verum or placebo needles . Three st and ard size casts were moulded to secure the placebo needles in the head . No significant differences were found between the verum group ( n = 15 ) and the placebo group ( n = 13 ) during treatment or follow up three and six months later , either in the attack frequency or in the number of days per month with migraine , headache intensity or drug-use . The casts held the needles exactly in place despite movements of the head , and are vali date d as practical , hygienic and extremely durable . This method is satisfactory for controlled studies of acupuncture in headache . It is possible that the positive results in earlier clinical trials on acupuncture in migraine are attributable to other mechanisms than needling of subcutaneous tissue [17908057] OBJECTIVES To examine the efficacy of periosteal stimulation therapy ( PST , osteopuncture ) for the treatment of chronic pain associated with advanced knee osteoarthritis . DESIGN R and omized , controlled clinical trial . SETTING Outpatient pain clinic . PARTICIPANTS Eighty-eight community-dwelling older adults with moderate knee pain or greater for 3 months or longer and Kellgren-Lawrence ( K-L ) grade 2 through 4 radiographic severity ( 80 % had K-L 4 ) . INTERVENTION Participants were r and omized to receive PST or control PST once a week for 6 weeks . MEASUREMENTS Pain severity and self-reported function ( Western Ontario and McMasters University Osteoarthritis Index ( WOMAC ) ) and physical performance ( Short Physical Performance Battery ( SPPB ) ) were assessed at baseline , after the last PST session ( post ) , and 3 months later ( follow-up ) . Pain severity was also assessed monthly using the multidimensional pain inventory short form . RESULTS Pain was reduced significantly more in the PST group than in the control PST group at post ( P=.003 ; mean WOMAC pain subscale baseline 9.4 vs 6.4 ) and 1 month later ( P<.001 ) , but by 2 months , pain levels had regressed to pre-intervention levels . The group-by-time interaction for the WOMAC function scale was significant at post ( P=.04 ) but not at follow-up ( P=.63 ) . No significant group differences were found for the SPPB . Neither analgesic use nor global improvement differed between groups . There were four treatment dropouts . CONCLUSION PST affords short-term modest pain reduction for older adults with advanced knee OA . Future research should test the effectiveness of booster treatments in sustaining analgesic benefits and of combining PST with therapeutic exercise in ameliorating disability risk [18160923] Aim To compare the efficacy of acupuncture needling and 0.5 % lidocaine injection of trigger points in myofascial pain syndrome of elderly patients . Methods Thirty nine participants with myofascial pain syndrome of one or both upper trapezius muscles were r and omised to treatment with either acupuncture needling ( n=18 ) or 0.5 % lidocaine injection ( n=21 ) at all the trigger points on days 0 , 7 and 14 , in a single-blinded study . Pain scores , range of neck movement , pressure pain intensity and depression were measured up to four weeks from the first treatment . Results Local twitch responses were elicited at least once in 94.9 % of all subjects . Both groups improved , but there was no significant difference in reduction of pain in the two groups at any time point up to one month . Overall , the range of cervical movement improved in both groups , apart from extension in the acupuncture needling group . Changes in depression showed only trends . Conclusion There was no significant difference between acupuncture needling and 0.5 % lidocaine injection of trigger points for treating myofascial pain syndrome in elderly patients [12048416] Objective The aim of the study was to compare the therapeutic effect of the superficial and in-depth insertion of acupuncture needles in the treatment of patients with chronic lumbar myofascial pain . Design A prospect i ve r and omized double-blind study of superficial and deep acupuncture was conducted . Setting The study was conducted in the Pain Service Unit of the University of Padova . Patients The study comprised 42 patients with lumbar myofascial pain who were divided into two equal groups ( A and B ) . InterventionIn group A , the needle was introduced in the skin at a depth of 2 mm , whereas in group B the needle was placed deeply into muscular tissue . The treatment was planned for a cycle of eight sessions . Outcome Measures The intensity of pain was evaluated with the McGill Pain Question naire before and after treatment and at the 3-month follow-up examination . Results Although at the end of the treatment there was no evidence of significant statistical differences between the two different groups , pain reduction was greater in the group treated with deep acupuncture . A statistical difference existed between the two groups at the 3-month follow up , with a better result in the deeply stimulated group . Conclusions Clinical results show that deep stimulation has a better analgesic effect when compared with superficial stimulation [14499023] OBJECTIVES To determine the effect of a series of electro-acupuncture ( EA ) treatment in conjunction with exercise on the pain , disability , and functional improvement scores of patients with chronic low-back pain ( LBP ) . DESIGN A blinded prospect i ve r and omized controlled study . SUBJECTS AND INTERVENTIONS A total of 52 patients were r and omly allocated to an exercise group ( n = 26 ) or an exercise plus EA group ( n = 26 ) and treated for 12 sessions . OUTCOME MEASURES Numerical Rating Scale ( NRS ) , Aberdeen LBP scale , lumbar spinal active range of movement ( AROM ) , and the isokinetic strength were assessed by a blinded observer . Repeated measures analysis of variance ( R-ANOVA ) with factors of group and time was used to compare the outcomes between the two groups at baseline ( before treatment ) , immediately after treatment , 1-month follow-up , and 3-month follow-up . The level of significance was set at p = 0.05 . RESULTS Significantly better scores in the NRS and Aberdeen LBP scale were found in the exercise plus EA group immediately after treatment and at 1-month follow-up . Higher scores were also seen at 3-month follow-up . No significant differences were observed in spinal AROM and isokinetic trunk concentric strength between the two groups at any stage of follow-up . CONCLUSIONS This study provides additional data on the potential role of EA in the treatment of LBP , and indicates that the combination of EA and back exercise might be an effective option in the treatment of pain and disability associated with chronic LBP [11783809] Objective The authors sought to determine whether a series of needle acupuncture treatments produced long-term relief of chronic low back pain . Design A blinded placebo-controlled study with an independent observer . The patients were r and omized to receive manual acupuncture , electroacupuncture , or active placebo ( mock transcutaneous electrical nerve stimulation ) . Subjects were examined and monitored by an investigator who was blinded to the treatment given . Setting A tertiary-level pain clinic at a Swedish university hospital . Patients Fifty consecutive patients ( 33 women , 17 men ; mean age , 49.8 years ) with chronic low back pain ( mean pain duration , 9.5 years ) and without rhizopathy or history of acupuncture treatment were included in the study . Interventions Treatments were given once per week for 8 weeks . Two further treatments were given during the follow-up assessment period of 6 months or longer . Outcome Measures The independent observer made a global assessment of the patients 1 , 3 , and 6 months after treatment . The patients kept pain diaries to score pain intensity twice daily , analgesic intake , and quality of sleep daily , and activity level weekly . Results At the 1-month independent assessment , 16 of 34 patients in the acupuncture groups and 2 of 16 patients in the placebo group showed improvement ( p < 0.05 ) . At the 6-month follow-up assessment , 14 of 34 patients in the acupuncture groups and 2 of 16 patients in the placebo group showed improvement ( p < 0.05 ) . A significant decrease in pain intensities occurred at 1 and 3 months in the acupuncture groups compared with the placebo group . There was a significant improvement in return to work , quality of sleep , and analgesic intake in subjects treated with acupuncture . Conclusions The authors found a long-term pain-relieving effect of needle acupuncture compared with true placebo in some patients with chronic nociceptive low back pain [11773673] This r and omised controlled trial was undertaken to evaluate the effectiveness of acupuncture as a treatment for frozen shoulder . Thirty-five patients with a diagnosis of frozen shoulder were r and omly allocated to an exercise group or an exercise plus acupuncture group and treated for a period of 6 weeks . Functional mobility , power , and pain were assessed by a blinded assessor using the Constant Shoulder Assessment , at baseline , 6 weeks and 20 weeks . Analysis was based on the intention-to-treat principle . Compared with the exercise group , the exercise plus acupuncture group experienced significantly greater improvement with treatment . Improvements in scores by 39.8 % ( st and ard deviation , 27.1 ) and 76.4 % ( 55.0 ) were seen for the exercise and the exercise plus acupuncture groups , respectively at 6 weeks ( P=0.048 ) , and were sustained at the 20-week re- assessment ( 40.3 % [ 26.7 ] and 77.2 % [ 54.0 ] , respectively ; P=0.025 ) . We conclude that the combination of acupuncture with shoulder exercise may offer effective treatment for frozen shoulder [15609842] Objective : To compare the effect of acupuncture with placebo transcutaneous electrical nerve stimulation ( TENS ) when added to the exercise treatment of rotator cuff tendinitis with respect to pain , shoulder movements and function . Design : Prospect i ve alternate allocation controlled trial . Setting : Outpatient department . Patients : Thirty-three patients ( 12 women and 21 men ) were included in the study . All had clinical ly diagnosed rotator cuff tendinitis . Intervention : Both groups underwent a st and ardized training programme . Each patient received in addition either 10 treatments with acupuncture or placebo TENS , 1 - 2 times per week . Main outcome measures : The parameters investigated were intensity of pain ( measured with visual analogue scale ) , active , passive as well as functional movements in the shoulder ( h and in neck ( HIN ) and pour out of a pot ( POP ) ) . Patients were tested before treatment , after treatment and at a six-month follow-up . Medicine intake , ability to lie on the affected side and sleep disturbances were evaluated . A subjective assessment was made after the treatment and at follow-up . Results : Sixteen patients had acupuncture , 17 placebo TENS . Eight patients endured pain at rest in the placebo TENS group , and 10 in the acupuncture group . After treatment both groups improved , the improvement persisted at the six-month follow-up . Both groups increased range of movement . Except for the functional test HIN in the acupuncture group , there were no differences between the groups regarding other parameters investigated directly after treatment or at six-month follow-up . Conclusion : There is no difference between the effect of additional acupuncture treatment and placebo TENS in the treatment of rotator cuff tendinitis [9825752] OBJECTIVE To evaluate the effectiveness of acupuncture , as compared with physiotherapy , in the management of chronic neck pain . DESIGN Seventy adult patients with non-inflammatory neck pain of > 6 weeks duration and with no abnormal neurology were r and omly assigned to receive either of the treatments . Thirty-five patients were included in each group . OUTCOME MEASURES Pain by visual analogue scale and neck pain question naire , improvement in range of movement of neck relative to baseline , and well-being ( general health question naire ) . Measurements were recorded at the start of treatment , at 6 weeks and at 6 months . RESULTS Both treatment groups improved in all criteria . Acupuncture was slightly more effective in patients who had higher baseline pain scores . CONCLUSIONS Both acupuncture and physiotherapy are effective forms of treatment . Since an untreated control group was not part of the study design , the magnitude of this improvement can not be quantified [769630] One half of 42 subjects treated for painful shoulders received classic acupuncture , and one half received a placebo in which the needles did not penetrate the skin . Half of each of these groups was treated in a positive setting to encourage the subject , and half in a negative setting design ed to keep encouragement at a minimum . All patients were independently rated for susceptibility to hypnosis . Although range of motion did not improve , the majority of patients reported significant improvement in shoulder discomfort to a blind evaluator after treatment ; placebo and acupuncture groups did not differ in this respect , however . The positive and negative setting s did not affect treatment outcome . In all groups , those who were not rated as highly susceptible to hypnosis tended to fail to achieve the highest levels of relief , but such differences were not statistically significant [17699546] Objective To investigate the benefit of adding acupuncture to a course of advice and exercise delivered by physiotherapists for pain reduction in patients with osteoarthritis of the knee . Design Multicentre , r and omised controlled trial . Setting 37 physiotherapy centres accepting primary care patients referred from general practitioners in the Midl and s , United Kingdom . Participants 352 adults aged 50 or more with a clinical diagnosis of knee osteoarthritis . Interventions Advice and exercise ( n=116 ) , advice and exercise plus true acupuncture ( n=117 ) , and advice and exercise plus non-penetrating acupuncture ( n=119 ) . Main outcome measures The primary outcome was change in scores on the Western Ontario and McMaster Universities osteoarthritis index pain subscale at six months . Secondary outcomes included function , pain intensity , and unpleasantness of pain at two weeks , six weeks , six months , and 12 months . Results Follow-up rate at six months was 94 % . The mean ( SD ) baseline pain score was 9.2 ( 3.8 ) . At six months mean reductions in pain were 2.28 ( 3.8 ) for advice and exercise , 2.32 ( 3.6 ) for advice and exercise plus true acupuncture , and 2.53 ( 4.2 ) for advice and exercise plus non-penetrating acupuncture . Mean differences in change scores between advice and exercise alone and each acupuncture group were 0.08 ( 95 % confidence interval −1.0 to 0.9 ) for advice and exercise plus true acupuncture and 0.25 ( −0.8 to 1.3 ) for advice and exercise plus non-penetrating acupuncture . Similar non-significant differences were seen at other follow-up points . Compared with advice and exercise alone there were small , statistically significant improvements in pain intensity and unpleasantness at two and six weeks for true acupuncture and at all follow-up points for non-penetrating acupuncture . Conclusion The addition of acupuncture to a course of advice and exercise for osteoarthritis of the knee delivered by physiotherapists provided no additional improvement in pain scores . Small benefits in pain intensity and unpleasantness were observed in both acupuncture groups , making it unlikely that this was due to acupuncture needling effects . Trial registration Current Controlled Trials IS RCT N88597683 [12406534] & NA ; This prospect i ve , r and omised controlled trial , with three parallel groups , patient and observer blinded for verum and sham acupuncture and a follow up of 3 months raises the question : “ Does a combination of acupuncture and conservative orthopedic treatment improve conservative orthopedic treatment in chronic low back pain ( LBP ) . 186 in‐ patients of a LBP rehabilitation center with a history of LBP ≥6 weeks , VAS ≥50 mm , and no pending compensation cl aims , were selected ; for the three r and om group 4 weeks of treatment was applied . 174 patients met the protocol criteria and reported after treatment , 124 reported after 3 months follow up . Patients were assorted 4 strata : chronic LBP , ≤0.5 years , 0.5–2 years , 2–5 years , ≥5 years . Analysis was by intention to treat . Group 1 ( Verum+COT ) recieved 12 treatments of verum acupuncture and conservative orthopedic treatment ( COT ) . Group 2 ( Sham+COT ) recieved 12 treatments of non‐specific needling and COT . Group 3 ( nil+COT ) recieved COT alone . Verum‐ and Sham acupuncture were blinded against patient and examiner . The primary endpoints were pain reduction ≥50 % on VAS 3 months after the end of the treatment protocol . Secondary endpoints were pain reduction ≥50 % on VAS and treatment efficacy on a four‐point box scale directly after the end of the treatment protocol and treatment efficacy after 3 months . In the whole sample a pain relief of ≥50 % on VAS was reported directly after the end of treatment protocol : Verum+COT 65 % ( 95%CI 51–77 % ) , Sham+COT 34 % ( 95%ci 22–49 % ) , nil+COT 43 % ( 95%ci 29–58 % ) – results are significant for Verum+COT over Sham+COT ( P≤0.02 ) . The results after 3 months are : Verum+COT 77 % ( 95%ci 62–88 % ) , Sham+COT 29 % ( 95%ci 16–46 % ) , nil+Cot 14 % ( 95%ci 4–30 % ) – effects are significant for Verum+COT over Sham+COT ( P≤0.001 ) and for Verum+COT over nil+COT ( P<0.001 ) . No difference was found in the mobility of the patients nor in the intake of NSAID diclofenac . Our conclusion is that acupuncture can be an important supplement of conservative orthopedic treatment in the management of chronic LBP [7053030] Thirty patients with cervical spine pain syndromes persisting a mean of 8 years were assigned r and omly into equal treatment and control groups . After 12 weeks , 12 of 15 ( 80 % ) of the treated group felt improved , some dramatically , with a mean 40 % reduction of pain score , 54 % reduction of pain pills , 68 % reduction of pain hours per day and 32 % less limitation of activity . Two of 15 ( 13 % ) of the control group reported slight improvement after 12.8 weeks . The control group had a mean 2 % worsening of the pain score , 10 % reduction in pain pills , no lessening of pain hours and 12 % less limitation of activity [10534595] Acupuncture has gained increasing attention in the treatment of chronic pain . The lack of a satisfying placebo method has made it impossible to show whether needling is an important part of the method or whether the improvement felt by the patient is due to the therapeutic setting and psychological phenomena . Also , the effectiveness of acupuncture has not been demonstrated sufficiently . We treated 52 sportsmen with rotator cuff tendinitis in a r and omised single-blind clinical trial using a new placebo-needle as control . Patients were treated for 4 weeks . The primary endpoint of the trial was the change in the modified Constant-Murley-score from the baseline . Assessment of the treatment outcome was made by experienced orthopaedists not informed of the treatment allocation . Acupuncture with penetration of the skin was shown to be more effective than a similar therapeutic setting with placebo needling in the treatment of pain . The acupuncture-group improved 19.2 Constant-Murley-score points ( SD 16.1 , range from -13 to 50 ) , the control-group improved 8.37 points ( SD 14.56 , range from -20 to 41 ) , ( P=0.014 ; C.I. 2.3;19.4 ) . This study showed that needling is an important part of the acupuncture effect in the treatment of chronic shoulder pain in athletes . No conclusions can be derived from this study concerning the importance of choosing points and the rules of Traditional Chinese Medicine . Using the new placebo method as control for other ailments could improve the evidence of specific acupuncture effects beyond pain treatment [15100594] Objectives : The aim of the study was to evaluate the therapeutic effect of electro-acupuncture ( EA ) and hydrotherapy , both in combination with patient education or with patient education alone , in the treatment of osteoarthritis in the hip . Methods : Forty-five patients , aged 42–86 years , with radiographic changes consistent with osteoarthritis in the hip , pain related to motion , pain on load , and ache were chosen . They were r and omly allocated to EA , hydrotherapy , both in combination with patient education , or patient education alone . Outcome measures were the disability rating index ( DRI ) , global self-rating index ( GSI ) , and visual analogue scale ( VAS ) . Assessment s were done before the intervention and immediately after the last treatment and 1 , 3 , and 6 months after the last treatment . Results : Pain related to motion and pain on load was reduced up to 3 months after last the treatment in the hydrotherapy group and up to 6 months in the EA group . Ache during the day was significantly improved in both the EA and hydrotherapy group up to 3 months after the last treatment . Ache during the night was reduced in the hydrotherapy group up to 3 months after the last treatment and in the EA group up to 6 months after . Disability in functional activities was improved in EA and hydrotherapy groups up to 6 months after the last treatment . Quality of life was also improved in EA and hydrotherapy groups up to 3 months after the last treatment . There were no changes in the education group alone . Discussion : In conclusion , EA and hydrotherapy , both in combination with patient education , induce long-lasting effects , shown by reduced pain and ache and by increased functional activity and quality of life , as demonstrated by differences in the pre- and post-treatment assessment

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### Context: [17893311] BACKGROUND To our knowledge , verum acupuncture has never been directly compared with sham acupuncture and guideline -based conventional therapy in patients with chronic low back pain . METHODS A patient- and observer-blinded r and omized controlled trial conducted in Germany involving 340 outpatient practice s , including 1162 patients aged 18 to 86 years ( mean + /- SD age , 50 + /- 15 years ) with a history of chronic low back pain for a mean of 8 years . Patients underwent ten 30-minute sessions , generally 2 sessions per week , of verum acupuncture ( n = 387 ) according to principles of traditional Chinese medicine ; sham acupuncture ( n = 387 ) consisting of superficial needling at nonacupuncture points ; or conventional therapy , a combination of drugs , physical therapy , and exercise ( n = 388 ) . Five additional sessions were offered to patients who had a partial response to treatment ( 10%-50 % reduction in pain intensity ) . Primary outcome was response after 6 months , defined as 33 % improvement or better on 3 pain-related items on the Von Korff Chronic Pain Grade Scale question naire or 12 % improvement or better on the back-specific Hanover Functional Ability Question naire . Patients who were unblinded or had recourse to other than permitted concomitant therapies during follow-up were classified as nonresponders regardless of symptom improvement . RESULTS At 6 months , response rate was 47.6 % in the verum acupuncture group , 44.2 % in the sham acupuncture group , and 27.4 % in the conventional therapy group . Differences among groups were as follows : verum vs sham , 3.4 % ( 95 % confidence interval , -3.7 % to 10.3 % ; P = .39 ) ; verum vs conventional therapy , 20.2 % ( 95 % confidence interval , 13.4 % to 26.7 % ; P < .001 ) ; and sham vs conventional therapy , 16.8 % ( 95 % confidence interval , 10.1 % to 23.4 % ; P < .001 . CONCLUSIONS Low back pain improved after acupuncture treatment for at least 6 months . Effectiveness of acupuncture , either verum or sham , was almost twice that of conventional therapy [12890859] OBJECTIVE To determine if acupuncture is an effective , safe adjunctive treatment to st and ard therapy for chronic low back pain ( LBP ) in older patients . METHODS The inclusion criteria for subjects were : ( i ) LBP > or = 12 weeks and ( ii ) age > or = 60 yr ; the exclusion criteria were ( i ) spinal tumour , infection or fracture and ( ii ) associated neurological symptoms . The subjects were r and omized to two groups . The control group of subjects continued their usual care as directed by their physicians , i.e. NSAIDs , muscle relaxants , paracetamol and back exercises . Subjects in the acupuncture group in addition received biweekly acupuncture with electrical stimulation for 5 weeks . Outcome was measured by the modified Rol and Disability Question naire ( RDQ ) at weeks 0 , 2 , 6 and 9 . The primary outcome measure was change in RDQ score between weeks 0 and 6 . RESULTS Fifty-five patients were enrolled , with eight drop-outs . Twenty-four subjects were r and omized to the acupuncture group and 23 were r and omized to the control group . Acupuncture subjects had a significant decrease in RDQ score of 4.1 + /- 3.9 at week 6 , compared with a mean decrease of 0.7 + /- 2.8 in the control group ( P = 0.001 ) . This effect was maintained for up to 4 weeks after treatment at week 9 , with a decrease in RDQ of 3.5 + /- 4.4 from baseline , compared with 0.43 + /- 2.7 in the control group ( P = 0.007 ) . The mean global transition score was higher in the acupuncture group , 3.7 + /- 1.2 , indicating greater improvement , compared with the score in the control group , 2.5 + /- 0.9 ( P < 0.001 ) . Fewer acupuncture subjects had medication-related side-effects compared with the control group . CONCLUSIONS Acupuncture is an effective , safe adjunctive treatment for chronic LBP in older patients [18591906] Objectives To compare the effect of acupuncture ( manual and electroacupuncture ) with that of a non-penetrating sham ( ‘ placebo ’ needle ) in patients with osteoarthritic knee pain and disability who are blind to the treatment allocation . Methods Acupuncture naive patients with symptomatic and radiological evidence of osteoarthritis of the knee were r and omly allocated to a course of either acupuncture or non-penetrating sham acupuncture using a sheathed ‘ placebo ’ needle system . Acupuncture points for pain and stiffness were selected according to acupuncture theory for treating Bi syndrome . Both manual and electrical stimulation were used . Response was assessed using the WOMAC index for osteoarthritis of the knee , self reported pain scale , the EuroQol score and plasma β-endorphin . The effectiveness of blinding was assessed . Results There were 34 patients in each group . The primary end point was the change in WOMAC pain score after the course of treatment . Comparison between the two treatment groups found a significantly greater improvement with acupuncture ( mean difference 60 , 95 % CI 5 to 116 , P=0.035 ) than with sham . Within the acupuncture group there was a significant improvement in pain ( baseline 294 , mean change 95 , 95 % CI 60 to 130 , P<0.001 ) which was not seen by those who had sham acupuncture ( baseline 261 , mean change 35 , 95 % CI-10 to 80 , P=0.12 ) . Similar effects within group , but not between groups , were seen with the secondary end points of WOMAC stiffness , WOMAC function , and self reported pain . One month after treatment the between group pain difference had been lost ( mean difference 46 ; 95 % CI −9 to 100 , P=0.10 ) although the acupuncture group was still benefiting compared to baseline ( mean difference 59 ; 95 % CI 16 to 102 , P=0.009 ) . The EuroQol score , a generic measure of health related quality of life , was not altered by the treatments . A minority of patients correctly guessed their treatment group ( 41 % in the acupuncture group and 44 % in the control group ) . Plasma β-endorphin levels were not affected by either treatment . Conclusions Acupuncture gives symptomatic improvement for patients with osteoarthritis of the knee , and is significantly superior to non-penetrating sham acupuncture . The study did not confirm earlier reports of release of plasma β-endorphin during acupuncture [15077933] Background Using an open r and omised controlled study , we examined the effectiveness of manual and electroacupuncture on symptom relief for patients with osteoarthritis of the knee . Methods Patients with symptomatic osteoarthritis of the knee were r and omised to one of three treatment groups . Group A had acupuncture alone , group B had acupuncture but continued on their symptomatic medication , and group C used their symptomatic medication for the first five weeks and then had a course of acupuncture added . Patients receiving acupuncture were treated twice weekly over five weeks . Needles were inserted ( with manual and electrical stimulation ) in acupuncture points for pain and stiffness , selected according to traditional acupuncture theory for treating Bi syndrome . Patients were assessed by a blinded observer before treatment , after five weeks ’ treatment and at one month follow up , using a visual analogue pain scale ( VAS ) and the Western Ontario McMaster ( WOMAC ) question naire for osteoarthritis of the knee . Results The 30 patients in our study were well matched for age , body mass index , disease duration , baseline VAS pain score and baseline WOMAC scores . Repeated measure analyses gave a highly significant improvement in pain ( VAS ) after the courses of acupuncture in groups A ( P=0.012 ) and B ( P=0.001 ) ; there was no change in group C until after the course of acupuncture , when the improvement was significant ( P=0.001 ) . Similarly significant changes were seen with the WOMAC pain and stiffness scores . These benefits were maintained during the one month after the course of acupuncture . Patients ’ rating of global assessment was higher than that of the acupuncturist . Conclusion We conclude that manual and electroacupuncture causes a significant improvement in the symptoms of osteoarthritis of the knee , either on its own or as an adjunct therapy , with no loss of benefit after one month [1713236] Background Acupuncture is increasingly being used for many conditions including chronic neck pain . However the evidence remains inconclusive , indicating the need for further well- design ed research . The aim of this study was to conduct a pilot r and omised controlled parallel arm trial , to establish key features required for the design and implementation of a large-scale trial on acupuncture for chronic neck pain . Methods Patients whose GPs had diagnosed neck pain were recruited from one general practice , and r and omised to receive usual GP care only , or acupuncture ( up to 10 treatments over 3 months ) as an adjunctive treatment to usual GP care . The primary outcome measure was the Northwick Park Neck Pain Question naire ( NPQ ) at 3 months . The primary analysis was to determine the sample size for the full scale study . Results Of the 227 patients with neck pain identified from the GP data base , 28 ( 12.3 % ) consenting patients were eligible to participate in the pilot and 24 ( 10.5 % ) were recruited to the trial . Ten patients were r and omised to acupuncture , receiving an average of eight treatments from one of four acupuncturists , and 14 were r and omised to usual GP care alone . The sample size for the full scale trial was calculated from a clinical ly meaningful difference of 5 % on the NPQ and , from this pilot , an adjusted st and ard deviation of 15.3 % . Assuming 90 % power at the 5 % significance level , a sample size of 229 would be required in each arm in a large-scale trial when allowing for a loss to follow-up rate of 14 % . In order to achieve this sample , one would need to identify patients from data bases of GP practice s with a total population of 230,000 patients , or approximately 15 GP practice s roughly equal in size to the one involved in this study ( i.e. 15,694 patients ) . Conclusion This pilot study has allowed a number of recommendations to be made to facilitate the design of a large-scale trial , which in turn will help to clarify the existing evidence base on acupuncture for neck pain [16781068] & NA ; Acupuncture is widely used by patients with neck pain , but there is a lack of information about its effectiveness in routine medical care . The aim was to investigate the effectiveness of acupuncture in addition to routine care in patients with chronic neck pain compared to treatment with routine care alone . We performed a r and omized controlled multicentre trial plus non‐r and omized cohort in general practice s in Germany . 14,161 patients with chronic neck pain ( duration > 6 months ) . Patients were r and omly allocated to an acupuncture group or a control group receiving no acupuncture . Patients in the acupuncture group received up to 15 acupuncture sessions over three months . Patients who did not consent to r and omization received acupuncture treatment . All subjects were allowed to receive usual medical care in addition to study treatment . Neck pain and disability ( NPAD Scale by Wheeler ) after three months . Of 14,161 patients ( mean age 50.9 ± 13.1 years , 68 % female ) 1880 were r and omized to acupuncture and 1886 to control , and 10,395 included into the non‐r and omized acupuncture group . At three months , neck pain and disability improved by 16.2 ( SE : 0.4 ) to 38.3 ( SE : 0.4 ) ; and by 3.9 ( SE : 0.4 ) to 50.5 ( SE : 0.4 ) , difference 12.3 ( p < 0.001 ) in the acupuncture and control group , respectively . Treatment success was essentially maintained through six months . Non‐r and omized patients had more severe symptoms at baseline and showed higher neck pain and disability improvement compared to r and omized patients . Treatment with acupuncture added to routine care in patients with chronic neck pain was associated with improvements in neck pain and disability compared to treatment with routine care alone [10378713] OBJECTIVE The purpose of this study was to investigate the efficacy of acupuncture as an adjunctive therapy to st and ard care for the relief of pain and dysfunction in elderly patients with osteoarthritis ( OA ) of the knee . METHODS Seventy-three patients with symptomatic OA of the knee were r and omly assigned to treatment ( acupuncture ) or st and ard care ( control ) . Analysis was performed on last score carried forward to account for patients who dropped out before completion . Patients self-scored Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) and Lequesne indices at baseline and at 4 , 8 and 12 weeks . Patients in the control group were offered acupuncture treatment after 12 weeks . The data for these patients are pooled with those from the original acupuncture group for within-group analysis . RESULTS Patients r and omized to acupuncture improved on both WOMAC and Lequesne indices compared to those who received st and ard treatment alone . Significant differences on total WOMAC Scale were seen at 4 and 8 weeks . There appears to be a slight decline in effect at 4 weeks after cessation of treatment ( 12 weeks after first treatment ) . No adverse effects of acupuncture were reported . CONCLUSION These data suggest that acupuncture is an effective and safe adjunctive therapy to conventional care for patients with OA of the knee [16005336] BACKGROUND Acupuncture is widely used by patients with chronic pain although there is little evidence of its effectiveness . We investigated the efficacy of acupuncture compared with minimal acupuncture and with no acupuncture in patients with osteoarthritis of the knee . METHODS Patients with chronic osteoarthritis of the knee ( Kellgren grade < or = 2 ) were r and omly assigned to acupuncture ( n=150 ) , minimal acupuncture ( superficial needling at non-acupuncture points ; n=76 ) , or a waiting list control ( n=74 ) . Specialised physicians , in 28 outpatient centres , administered acupuncture and minimal acupuncture in 12 sessions over 8 weeks . Patients completed st and ard question naires at baseline and after 8 weeks , 26 weeks , and 52 weeks . The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis ( WOMAC ) index at the end of week 8 ( adjusted for baseline score ) . All main analyses were by intention to treat . RESULTS 294 patients were enrolled from March 6 , 2002 , to January 17 , 2003 ; eight patients were lost to follow-up after r and omisation , but were included in the final analysis . The mean baseline-adjusted WOMAC index at week 8 was 26.9 ( SE 1.4 ) in the acupuncture group , 35.8 ( 1.9 ) in the minimal acupuncture group , and 49.6 ( 2.0 ) in the waiting list group ( treatment difference acupuncture vs minimal acupuncture -8.8 , [ 95 % CI -13.5 to -4.2 ] , p=0.0002 ; acupuncture vs waiting list -22.7 [ -27.5 to -17.9 ] , p<0.0001 ) . After 52 weeks the difference between the acupuncture and minimal acupuncture groups was no longer significant ( p=0.08 ) . INTERPRETATION After 8 weeks of treatment , pain and joint function are improved more with acupuncture than with minimal acupuncture or no acupuncture in patients with osteoarthritis of the knee . However , this benefit decreases over time [12865832] Study Design . A r and omized controlled clinical trial was conducted . Objective . To compare medication , needle acupuncture , and spinal manipulation for managing chronic ( > 13 weeks duration ) spinal pain because the value of medicinal and popular forms of alternative care for chronic spinal pain syndromes is uncertain . Summary of Background Data . Between February 1999 and October 2001 , 115 patients without contraindication for the three treatment regimens were enrolled at the public hospital ’s multidisciplinary spinal pain unit . Methods . One of three separate intervention protocol s was used : medication , needle acupuncture , or chiropractic spinal manipulation . Patients were assessed before treatment by a sports medical physician for exclusion criteria and by a research assistant using the Oswestry Back Pain Disability Index ( Oswestry ) , the Neck Disability Index ( NDI ) , the Short-Form-36 Health Survey question naire ( SF-36 ) , visual analog scales ( VAS ) of pain intensity and ranges of movement . These instruments were administered again at 2 , 5 , and 9 weeks after the beginning of treatment . Results . R and omization proved to be successful . The highest proportion of early ( asymptomatic status ) recovery was found for manipulation ( 27.3 % ) , followed by acupuncture ( 9.4 % ) and medication ( 5 % ) . Manipulation achieved the best overall results , with improvements of 50 % ( P = 0.01 ) on the Oswestry scale , 38 % ( P = 0.08 ) on the NDI , 47 % ( P < 0.001 ) on the SF-36 , and 50 % ( P < 0.01 ) on the VAS for back pain , 38 % ( P < 0.001 ) for lumbar st and ing flexion , 20 % ( P < 0.001 ) for lumbar sitting flexion , 25 % ( P = 0.1 ) for cervical sitting flexion , and 18 % ( P = 0.02 ) for cervical sitting extension . However , on the VAS for neck pain , acupuncture showed a better result than manipulation ( 50%vs 42 % ) . Conclusions . The consistency of the results provides , despite some discussed shortcomings of this study , evidence that in patients with chronic spinal pain , manipulation , if not contraindicated , results in greater short-term improvement than acupuncture or medication . However , the data do not strongly support the use of only manipulation , only acupuncture , or only nonsteroidal antiinflammatory drugs for the treatment of chronic spinal pain . The results from this exploratory study need confirmation from future larger studies [3476149] Acupuncture treatment is frequently sought for tension-type headache ( TTH ) , but there is conflicting evidence as to its effectiveness . This r and omised , controlled , multicentre , patient- and observer-blinded trial was carried out in 122 outpatient practice s in Germany on 409 patients with TTH , defined as ≥0 headache days per month of which ≤1 included migraine symptoms . Interventions were verum acupuncture according to the practice of traditional Chinese medicine or sham acupuncture consisting of superficial needling at nonacupuncture points . Acupuncture was administered by physicians with specialist acupuncture training . Ten 30-min sessions were given over a six-week period , with additional sessions available for partial response . Response was defined as > 50 % reduction in headache days/month at six months and no use of excluded concomitant medication or other therapies . In the intent-to-treat analysis ( all 409 patients ) , 33 % of verum patients and 27 % of sham controls ( p=0.18 ) were classed as responders . Verum was superior to sham for most secondary endpoints , including headache days ( 1.8 fewer ; 95 % CI 0.6 , 3.0 ; p=0.004 ) and the International Headache Society response criterion ( 66 % vs. 55 % response , risk difference 12 % , 95 % CI : 2%-21 % ; p=0.024 ) . ) . The relative risk on the primary and secondary response criterion was very similar ( ∼0.8 ) ; the difference in statistical significance may be due to differences in event rate . TTH improves after acupuncture treatment . However , the degree to which treatment benefits depend on psychological compared to physiological effects and the degree to which any physiological effects depend on needle placement and insertion depth are unclear [17604311] OBJECTIVE To evaluate the effects of st and ardized western acupuncture and physiotherapy on pain and functional ability in patients with severe osteoarthritic knee pain awaiting knee arthroplasty . METHODS Three-arm , assessor-blind , r and omized controlled trial . PARTICIPANTS 181 patients awaiting knee arthroplasty . INTERVENTIONS acupuncture for 6 weeks ; physiotherapy for 6 weeks ; st and ardized advice . MAIN OUTCOME MEASURES Oxford Knee Score question naire ( OKS ) ( primary ) ; 50 m timed walk , and duration of hospital stay following knee arthroplasty . RESULTS There was no baseline difference between groups . At 7 weeks , there was a 10 % reduction in OKS in the acupuncture group which was a significant difference between the acupuncture and the control group : Mean ( s.d . ) acupuncture 36.8 ( 7.20 ) ; physiotherapy 39.2 ( 8.22 ) ; control 40.3 ( 8.48 ) ( P = 0.0497 ) . These effects were no longer present at 12 weeks . There was a trend ( P = 0.0984 ) towards a shorter in-patient stay of 1 day for the physiotherapy group [ mean 6.50 days ( s.d . 2.0 ) ] compared with the acupuncture group [ mean 7.77 days ( s.d . 3.96 ) ] . CONCLUSIONS We have demonstrated that patients with severe knee osteoarthritis can achieve a short-term reduction in OKS when treated with acupuncture . However , we failed to demonstrate any other clinical ly or statically significant effects between the groups . Both interventions can be delivered effectively in an out-patient group setting at a district general hospital . Further study is needed to evaluate the combined effects of these treatments [20655660] & NA ; The German R and omized Acupuncture Trial for chronic shoulder pain ( GRASP ) comprised 424 out patients with chronic shoulder pain ( CSP ) ≥6 weeks and an average pain score of VAS ≥50 mm , who were r and omly assigned to receive Chinese acupuncture ( verum ) , sham acupuncture ( sham ) or conventional conservative orthopaedic treatment ( COT ) . The patients were blinded to the type of acupuncture and treated by 31 office‐based orthopaedists trained in acupuncture ; all received 15 treatments over 6 weeks . The 50 % responder rate for pain was measured on a VAS 3 months after the end of treatment ( primary endpoint ) and directly after the end of the treatment ( secondary endpoint ) . Results : In the ITT ( n = 424 ) analysis , percentages of responders for the primary endpoint were verum 65 % ( 95 % CI 56–74 % ) ( n = 100 ) , sham 24 % ( 95 % CI 9–39 % ) ( n = 32 ) , and COT 37 % ( 95 % CI 24–50 % ) ( n = 50 ) ; secondary endpoint : verum 68 % ( 95 % CI 58–77 % ) ( n = 92 ) , sham 40 % ( 95 % CI 27–53 % ) ( n = 53 ) , and COT 28 % ( 95 % CI 14–42 % ) ( n = 38 ) . The results are significant for verum over sham and verum over COT ( p < 0.01 ) for both the primary and secondary endpoints . The PPP analysis of the primary ( n = 308 ) and secondary endpoints ( n = 360 ) yields similar responder results for verum over sham and verum over COT ( p < 0.01 ) . Descriptive statistics showed greater improvement of shoulder mobility ( abduction and arm‐above‐head test ) for the verum group versus the control group immediately after treatment and after 3 months . The trial indicates that Chinese acupuncture is an effective alternative to conventional orthopaedic treatment for CSP [2268695] Background The present study tests whether a combined treatment of acupuncture and transcutaneous electrical nerve stimulation ( TENS ) is more effective than acupuncture or TENS alone for treating knee osteoarthritis ( OA ) . Methods Thirty-two patients with knee OA were r and omly allocated to four groups . The acupuncture group ( ACP ) received only acupuncture treatment at selected acupoints for knee pain ; the TENS group ( TENS ) received only TENS treatment at pain areas ; the acupuncture and TENS group ( A&T ) received both acupuncture and TENS treatments ; the control group ( CT ) received topical poultice ( only when necessary ) . Each group received specific weekly treatment five times during the study . Outcome measures were pain intensity in a visual analogue scale ( VAS ) and knee function in terms of the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) . Results The ACP , TENS and A&T groups reported lower VAS and WOMAC scores than the control group . Significant reduction in pain intensity ( P = 0.039 ) and significant improvement in knee function ( P = 0.008 ) were shown in the A&T group . Conclusion Combined acupuncture and TENS treatment was effective in pain relief and knee function improvement for the sample d patients suffering from knee OA [15611487] Context Previous studies of acupuncture for osteoarthritis have had conflicting results . This may have occurred because most studies have included small sample s , a limited number of treatment sessions , or other limitations . Contribution This r and omized , controlled trial compared 24 acupuncture sessions over 26 weeks with sham acupuncture or arthritis education in 570 patients with osteoarthritis of the knee . Acupuncture led to greater improvements in function but not pain after 8 weeks and in both pain and function after 26 weeks . No adverse effects were associated with acupuncture . Caution s Many participants dropped out of the study , so readers should interpret the findings at 26 weeks with caution . The Editors Osteoarthritis is the most common form of arthritis and is a major cause of morbidity , limitation of activity , and health care utilization , especially in elderly patients ( 1 , 2 ) . Pain and functional limitation are the primary clinical manifestations of osteoarthritis of the knee . Current recommendations for managing osteoarthritis , including guidelines published by the American College of Rheumatology ( 3 ) and European League of Associations of Rheumatology ( 4 ) , focus on relieving pain and stiffness and maintaining or improving physical function as important goals of therapy . No curative therapies exist for osteoarthritis ; thus , both pharmacologic and nonpharmacologic management focus on controlling pain and reducing functional limitation ( 5 ) . Nonpharmacologic therapy , which includes patient education , social support , physical and occupational therapy , aerobic and resistive exercises , and weight loss , is the cornerstone of a multidisciplinary approach to osteoarthritis patient management ( 3 ) . Pharmacologic therapies include nonopioid analgesics ( such as acetaminophen ) , nonsteroidal anti-inflammatory drugs ( NSAIDs ) ( including cyclooxygenase-2 [ COX-2 ] enzyme selective inhibitors ) , topical analgesics ( capsaicin cream ) , opioid analgesics , and intra-articular steroid and hyaluronate injections . Often , these agents are used in combination for additive analgesic efficacy ( 6 ) . Pharmacologic management of osteoarthritis is often ineffective , and agents such as NSAIDs may cause unwanted and dangerous side effects ( 7 , 8) . Complementary and alternative medicine is another approach to treating osteoarthritis ( 9 - 12 ) , particularly in Asian societies ( 13 ) . Many U.S. patients with osteoarthritis also use complementary and alternative medical therapies ( 14 ) . A systematic review of acupuncture and knee osteoarthritis ( 15 ) identified 7 small r and omized , controlled trials published in English . Within the method ologic limitations of the studies , the evidence suggested that acupuncture seemed to alleviate knee pain and function compared with sham acupuncture controls , although 2 trials comparing acupuncture with an active , nonpharmacologic treatment ( physical therapy ) did not indicate such an effect ( 16 , 17 ) . Before conducting our large-scale trial , we completed both a pilot study ( 18 ) and a r and omized , single-blind trial ( 19 ) of the effect of acupuncture on osteoarthritis of the knee . Participants in the uncontrolled pilot study ( n= 12 ) showed statistically significant improvement in both self-reported pain and physical function , as well as performance measures of physical function after 8 weeks of acupuncture treatment and at 12-week follow-up as compared with their baseline ( 18 ) . In our larger r and omized , single-blind trial ( n= 73 ) , which examined the benefit of acupuncture added to st and ard management with NSAIDs , the acupuncture treatment group experienced statistically significant improvements in self-reported pain and disability scores compared with a st and ard-care control group as late as 4 weeks after the end of treatment ( 19 ) . However , this effect diminished within 18 weeks ( 26 weeks after the beginning of the trial ) after the final acupuncture treatment . Together , however , the previously conducted trials ( both our preliminary studies [ 18 , 19 ] and those referenced in the systematic review [ 15 ] ) have 3 method ologic limitations : lack of credible controls for the placebo effect , inadequate assessment of long-term treatment benefits , and insufficient sample sizes . We tested the hypothesis that an 8-week intensive acupuncture treatment regimen , followed by an 18-week tapering regimen , reduces pain and improves function among patients with knee osteoarthritis as compared with both sham acupuncture and education control groups . Methods Patient Recruitment We recruited patients for this multisite , placebo-controlled trial from March 2000 through December 2003 , primarily through print and radio advertisements . The 3 sites were the Integrative Medicine Clinic of the University of Maryl and School of Medicine , Baltimore , Maryl and ; the Innovative Medical Research Center ( a private research firm ) , Towson , Maryl and ; and the Hospital for Special Surgery , New York City , New York . The institutional review boards of the 3 sites approved the study . We determined the sample size ( n= 570 ) by a power analysis based on our r and omized pilot study ( 19 ) , adjusted by the estimated decrease in effect size result ing from the inclusion of a sham acupuncture group design ed to control for placebo effects . Patients met the following inclusion criteria : age 50 years or older , a diagnosis of osteoarthritis of the knee , radiographic evidence of at least 1 osteophyte at the tibiofemoral joint ( KellgrenLawrence grade 2 ) , moderate or greater clinical ly significant knee pain on most days during the past month , and willingness to be r and omly assigned . Exclusion criteria were the presence of serious medical conditions that precluded participation in study , bleeding disorders that might contraindicate acupuncture , intra-articular corticosteroid or hyaluronate injections ( as well as any knee surgeries or concomitant use of topical capsaicin cream ) during the past 6 months , previous experience with acupuncture , or any planned events ( including total knee replacement ) that would interfere with participation in the study during the following 26 weeks . After a brief telephone screening , patients were scheduled to visit 1 of the 3 participating sites to sign an informed consent statement and undergo a brief rheumatologic examination ( including radiographic examination of affected knees ) by a physician or a nurse practitioner . Because the education course was a group activity , patients were recruited until a cohort of 12 to 21 patients was formed , at which point each cohort at each site was r and omly assigned to 1 of 3 groups by a computer-generated process using r and omly selected blocks of 3 , 6 , and 9 . We assured allocation concealment by using disguised letter codes that were generated and sent to the site coordinators by a central statistical core . We used this procedure to ensure that approximately equal numbers of participants were in each treatment group across the course of the study , to ensure that each cohort would have participants assigned to all 3 treatment groups , and to make the breaking of the group assignment process more difficult . The research assistants who collected assessment s from participants , the participants themselves ( in the true acupuncture and sham acupuncture groups ) , and the statistician were blinded to group assignment . Assessment s were conducted at baseline and 4 , 8 , 14 , and 26 weeks after r and omization . Study Interventions We developed and modified the acupuncture treatment and sham control protocol s from previously reported and vali date d procedures ( 18 - 21 ) . During the trial , 7 acupuncturists were used : 3 at the Integrative Medicine Clinic , 3 at the Innovative Medical Research Center , and 1 at the Hospital for Special Surgery . In general , acupuncturists were assigned to the same participants throughout the 26-week treatment schedule , except for vacation conflicts and staff turnover , and provided approximately the same proportions of true versus sham procedures . All acupuncturists were state-licensed and had at least 2 years of clinical experience . The study 's principal acupuncturist trained and supervised the acupuncturists in performing true or sham procedures and avoiding interactions that could inadvertently communicate group assignment . True Acupuncture The true acupuncture ( experimental ) group underwent 26 weeks of gradually tapering treatment according to the following schedule : 8 weeks of 2 treatments per week followed by 2 weeks of 1 treatment per week , 4 weeks of 1 treatment every other week , and 12 weeks of 1 treatment per month . We based the acupuncture point selection s on Traditional Chinese Medicine meridian theory to treat knee joint pain , known as the Bi syndrome . These points consisted of 5 local points ( Yanglinquan [ gall bladder meridian point 34 ] , Yinlinquan [ spleen meridian point 9 ] , Zhusanli [ stomach meridian point 36 ] , Dubi [ stomach meridian point 35 ] , and extra point Xiyan ) and 4 distal points ( Kunlun [ urinarybladder , meridian point 60 ] , Xuanzhong [ gall bladder meridian point 39 ] , Sanyinjiao [ spleen meridian point 6 ] , and Taixi [ kidney meridian point 3 ] ) on meridians that traverse the area of pain ( 22 , 23 ) . The same points were treated for each affected leg . If both knees were affected , 9 needles were inserted in each leg . ( The outcome measures were not specifically targeted to whether the patient had osteoarthritis in 1 or both knees , and we observed no differential effects on the basis of the number of knees treated . ) The acupuncturists inserted 1.5-inch ( for local points ) and 1-inch ( for distal points ) 32-gauge ( 0.25-mm diameter ) acupuncture needles to a conventional depth of approximately 0.3 to 1.0 inch , depending on point location . All participants in the treatment group achieved the De-Qi sensation , a local sensation of heaviness , numbness , soreness , or paresthesia that accompanies the insertion and manipulation of needles during acupuncture , at these 9 points . Acupuncturists applied electrical [16505266] BACKGROUND Acupuncture is widely used by patients with low back pain , although its effectiveness is unclear . We investigated the efficacy of acupuncture compared with minimal acupuncture and with no acupuncture in patients with chronic low back pain . METHODS Patients were r and omized to treatment with acupuncture , minimal acupuncture ( superficial needling at nonacupuncture points ) , or a waiting list control . Acupuncture and minimal acupuncture were administered by specialized acupuncture physicians in 30 outpatient centers , and consisted of 12 sessions per patient over 8 weeks . Patients completed st and ardized question naires at baseline and at 8 , 26 , and 52 weeks after r and omization . The primary outcome variable was the change in low back pain intensity from baseline to the end of week 8 , as determined on a visual analog scale ( range , 0 - 100 mm ) . RESULTS A total of 298 patients ( 67.8 % female ; mean + /- SD age , 59 + /- 9 years ) were included . Between baseline and week 8 , pain intensity decreased by a mean + /- SD of 28.7 + /- 30.3 mm in the acupuncture group , 23.6 + /- 31.0 mm in the minimal acupuncture group , and 6.9 + /- 22.0 mm in the waiting list group . The difference for the acupuncture vs minimal acupuncture group was 5.1 mm ( 95 % confidence interval , -3.7 to 13.9 mm ; P = .26 ) , and the difference for the acupuncture vs waiting list group was 21.7 mm ( 95 % confidence interval , 13.9 - 30.0 mm ; P<.001 ) . Also , at 26 ( P=.96 ) and 52 ( P=.61 ) weeks , pain did not differ significantly between the acupuncture and the minimal acupuncture groups . CONCLUSION Acupuncture was more effective in improving pain than no acupuncture treatment in patients with chronic low back pain , whereas there were no significant differences between acupuncture and minimal acupuncture [16798792] In a r and omized controlled trial plus a nonr and omized cohort , the authors investigated the effectiveness and costs of acupuncture in addition to routine care in the treatment of chronic low back pain and assessed whether the effects of acupuncture differed in r and omized and nonr and omized patients . In 2001 , German patients with chronic low back pain were allocated to an acupuncture group or a no-acupuncture control group . Persons who did not consent to r and omization were included in a nonr and omized acupuncture group . All patients were allowed to receive routine medical care in addition to study treatment . Back function ( Hannover Functional Ability Question naire ) , pain , and quality of life were assessed at baseline and after 3 and 6 months , and cost-effectiveness was analyzed . Of 11,630 patients ( mean age=52.9 years ( st and ard deviation , 13.7 ) ; 59 % female ) , 1,549 were r and omized to the acupuncture group and 1,544 to the control group ; 8,537 were included in the nonr and omized acupuncture group . At 3 months , back function improved by 12.1 ( st and ard error ( SE ) , 0.4 ) to 74.5 ( SE , 0.4 ) points in the acupuncture group and by 2.7 ( SE , 0.4 ) to 65.1 ( SE , 0.4 ) points among controls ( difference=9.4 points ( 95 % confidence interval 8.3 , 10.5 ) ; p<0.001 ) . Nonr and omized patients had more severe symptoms at baseline and showed improvements in back function similar to those seen in r and omized patients . The incremental cost-effectiveness ratio was euro10,526 ( euros ) per quality -adjusted life year . Acupuncture plus routine care was associated with marked clinical improvements in these patients and was relatively cost-effective [11431299] Abstract Objectives : To compare the efficacy of acupuncture and conventional massage for the treatment of chronic neck pain . Design : Prospect i ve , r and omised , placebo controlled trial . Setting : Three outpatient departments in Germany . Participants : 177 patients aged 18–85 years with chronic neck pain . Interventions : Patients were r and omly allocated to five treatments over three weeks with acupuncture ( 56 ) , massage ( 60 ) , or “ sham ” laser acupuncture ( 61 ) . Main outcome measures : Primary outcome measure : maximum pain related to motion ( visual analogue scale ) irrespective of direction of movement one week after treatment . Secondary outcome measures : range of motion ( 3D ultrasound real time motion analyser ) , pain related to movement in six directions ( visual analogue scale ) , pressure pain threshold ( pressure algometer ) , changes of spontaneous pain , motion related pain , global complaints ( seven point scale ) , and quality of life ( SF-36 ) . Assessment s were performed before , during , and one week and three months after treatment . Patients ' beliefs in treatment were assessed . Results : One week after five treatments the acupuncture group showed a significantly greater improvement in motion related pain compared with massage ( difference 24.22 ( 95 % confidence interval 16.5 to 31.9 ) , P=0.0052 ) but not compared with sham laser ( 17.28 ( 10.0 to 24.6 ) , P=0.327 ) . Differences between acupuncture and massage or sham laser were greater in the subgroup who had had pain for longer than five years ( n=75 ) and in patients with myofascial pain syndrome ( n=129 ) . The acupuncture group had the best results in most secondary outcome measures . There were no differences in patients ' beliefs in treatment . Conclusions : Acupuncture is an effective short term treatment for patients with chronic neck pain , but there is only limited evidence for long term effects after five treatments . What is already known on this topic Acupuncture is a widespread complementary treatment Evidence from trials have given conflicting results on its use in the treatment of neck pain because of method ological shortcomings and because effects were compared either with alternative treatments or with different sham procedures imitating acupuncture , but not both What this study adds Compared with sham laser acupuncture and massage , needle acupuncture has beneficial effects on mobility and pain related to motion in patients with chronic neck pain Acupuncture was clearly more effective than massage , but differences were not always significant compared with sham laser acupuncture Acupuncture was the best treatment for patients with the myofascial syndrome and those who had had pain for longer than five [14629842] OBJECTIVES To examine the relative effectiveness of electro-acupuncture ( EA ) and transcutaneous electrical nerve stimulation ( TENS ) in alleviating osteoarthritic (OA)-induced knee pain . DESIGN Single-blinded , r and omized controlled study . SUBJECTS Twenty-four ( 24 ) subjects ( 23 women and 1 man ) , mean age 85 , were recruited from eight subsidized Care & Attention Homes for the elderly . INTERVENTIONS Subjects were r and omly assigned to the EA , TENS , or control groups . Subjects in the EA group ( n = 8) received low-frequency EA ( 2 Hz ) on two acupuncture points ( ST-35 , Dubi and EX-LE-4 , Neixiyan ) of the painful knee for 20 minutes . Subjects in the TENS group ( n = 8) received low-frequency TENS of 2 Hz and pulse width of 200 micros on the same acupuncture points for 20 minutes . In both treatment groups , electrical treatment was carried out for a total of eight sessions in 2 weeks . Eight subjects received osteoarthritic knee care and education only in a control group . All subjects were evaluated before the first treatment , after the last treatment , and at 2-week follow-up periods . RESULTS After eight sessions of treatment , there was significant reduction of knee pain in both EA group and TENS group , as measured by the Numeric Rating Scale ( NRS ) of pain ( p < 0.01 ) . Prolonged analgesic effect was maintained in the EA and the TENS groups at a 2-week follow-up evaluation . The Timed Up- and -Go Test ( TUGT ) score of the EA group was significantly lower than that of the control group ( p < 0.05 ) , but such change was not observed in the TENS group . CONCLUSIONS Both EA and TENS treatments were effective in reducing OA-induced knee pain . EA had the additional advantage of enhancing the TUGT results as opposed to TENS treatment or no treatment , which did not produce such corollary effect [11932074] & NA ; There is some evidence for the efficacy of acupuncture in chronic low‐back pain ( LBP ) , but it remains unclear whether acupuncture is superior to placebo . In a r and omized , blinded , placebo‐controlled trial , we evaluated the effect of traditional acupuncture in chronic LBP . A total of 131 consecutive out‐ patients of the Department of Orthopaedics , University Goettingen , Germany , ( age=48.1 years , 58.5 % female , duration of pain : 9.6 years ) with non‐radiating LBP for at least 6 months and a normal neurological examination were r and omized to one of three groups over 12 weeks . Each group received active physiotherapy over 12 weeks . The control group ( n=46 ) received no further treatment , the acupuncture group ( n=40 ) received 20 sessions of traditional acupuncture and the sham‐acupuncture group ( n=45 ) 20 sessions of minimal acupuncture . Changes from baseline to the end of treatment and to 9‐month follow‐up were assessed in pain intensity and in pain disability , and secondary in psychological distress and in spine flexion , compared by intervention groups . Acupuncture was superior to the control condition ( physiotherapy ) regarding pain intensity ( P=0.000 ) , pain disability ( P=0.000 ) , and psychological distress ( P=0.020 ) at the end of treatment . Compared to sham‐acupuncture , acupuncture reduced psychological distress ( P=0.040 ) only . At 9‐month follow‐up , the superiority of acupuncture compared to the control condition became less and acupuncture was not different to sham‐acupuncture . We found a significant improvement by traditional acupuncture in chronic LBP compared to routine care ( physiotherapy ) but not compared to sham‐acupuncture . The trial demonstrated a placebo effect of traditional acupuncture in chronic LBP [16452103] Abstract Objective To investigate whether a sham device ( a vali date d sham acupuncture needle ) has a greater placebo effect than an inert pill in patients with persistent arm pain . Design A single blind r and omised controlled trial created from the two week placebo run-in periods for two nested trials that compared acupuncture and amitriptyline with their respective placebo controls . Comparison of participants who remained on placebo continued beyond the run-in period to the end of the study . Setting Academic medical centre . Participants 270 adults with arm pain due to repetitive use that had lasted at least three months despite treatment and who scored ≥3 on a 10 point pain scale . Interventions Acupuncture with sham device twice a week for six weeks or placebo pill once a day for eight weeks . Main outcome measures Arm pain measured on a 10 point pain scale . Secondary outcomes were symptoms measured by the Levine symptom severity scale , function measured by Pransky 's upper extremity function scale , and grip strength . Results Pain decreased during the two week placebo run-in period in both the sham device and placebo pill groups , but changes were not different between the groups ( −0.14 , 95 % confidence interval −0.52 to 0.25 , P = 0.49 ) . Changes in severity scores for arm symptoms and grip strength were similar between groups , but arm function improved more in the placebo pill group ( 2.0 , 0.06 to 3.92 , P = 0.04 ) . Longitudinal regression analyses that followed participants throughout the treatment period showed significantly greater downward slopes per week on the 10 point arm pain scale in the sham device group than in the placebo pill group ( −0.33 ( −0.40 to −0.26 ) v −0.15 ( −0.21 to −0.09 ) , P = 0.0001 ) and on the symptom severity scale ( −0.07 ( −0.09 to −0.05 ) v −0.05 ( −0.06 to −0.03 ) , P = 0.02 ) . Differences were not significant , however , on the function scale or for grip strength . Reported adverse effects were different in the two groups . Conclusions The sham device had greater effects than the placebo pill on self reported pain and severity of symptoms over the entire course of treatment but not during the two week placebo run in . Placebo effects seem to be malleable and depend on the behaviours embedded in medical rituals [16934402] & NA ; Chronic neck pain is highly prevalent . To determine the efficacy and safety of acupuncture , in comparison with transcutaneous nerve stimulation‐placebo ( TENS‐placebo ) in the treatment of chronic uncomplicated neck pain , a single blind prospect i ve study was design ed , to be carried out at a Primary Healthcare Centre , with r and om assignment to two parallel groups and with evaluation and analysis by independent evaluators . A r and om assignment was made from 123 patients of the 149 initially recruited . These patients had been diagnosed with uncomplicated neck pain and experienced neck motion‐related pain intensity equal to or exceeding 30 on a visual analogue scale ( VAS ) from 0 to 100 mm . The treatment with acupuncture was compared with TENS‐placebo , applied over 5 sessions in three weeks . The primary endpoint was the change in maximum pain intensity related to motion of the neck , one week after the final treatment . Sensitivity was analysed per protocol ( PP ) and variant analyses were by intention to treat ( ITT ) . Adjustment was made for confounders by multiple linear regression , including baseline values and rescue therapy . By ITT analysis , the change in the pain‐VAS variable was greater among the experimental group ( 28.1 ( 95 % CI 21.4–34.7 ) ) . The improvements in quality of life ( physical aspect ) , active neck mobility and reduced rescue medication were clinical ly and statistically significant . In the treatment of the intensity of chronic neck pain , acupuncture is more effective than the placebo treatment and presents a safety profile making it suitable for routine use in clinical practice [15322438] Objectives : Acupuncture has been promoted for the treatment of chronic pain . Though many r and omized trials have been conducted , these have been criticized for deficiencies of methodology , acupuncture technique , and sample size . Somewhat less emphasis has been placed on methods of statistical analysis . This paper describes 4 recent r and omized trials of acupuncture for musculoskeletal or headache pain . Each trial used statistical methods that did not adjust for baseline pain scores and were thus of suboptimal power . The objective of this study is to reanalyze the trials using analysis of covariance ( ANCOVA ) . Methods : Raw data for the 4 trials were obtained from the original authors . Data were reanalyzed by ANCOVA . Results : For 2 trials — acupuncture versus placebo for chronic headache and acupuncture versus transcutaneous electric nerve stimulation for back pain — re analysis did not change the conclusion of no difference between groups , but showed that clinical ly significant differences between groups could not ruled out . Re analysis of a trial of acupuncture versus placebo for shoulder pain slightly strengthened the evidence of acupuncture effectiveness . Re analysis of the fourth trial , which compared acupuncture to placebo acupuncture and massage for neck pain , reversed the results of the original paper : re analysis found acupuncture to be effective and that its effectiveness could not be ascribed to a placebo effect . Discussion : Future trials of acupuncture and other modalities for pain should use efficient statistical methods . ANCOVA is more efficient than unadjusted analysis where used appropriately [15023828] Abstract Objective To determine the effects of a policy of “ use acupuncture ” on headache , health status , days off sick , and use of re sources in patients with chronic headache compared with a policy of “ avoid acupuncture . ” Design R and omised , controlled trial . Setting General practice s in Engl and and Wales . Participants 401 patients with chronic headache , predominantly migraine . Interventions Patients were r and omly allocated to receive up to 12 acupuncture treatments over three months or to a control intervention offering usual care . Main outcome measures Headache score , SF-36 health status , and use of medication were assessed at baseline , three , and 12 months . Use of re sources was assessed every three months . Results Headache score at 12 months , the primary end point , was lower in the acupuncture group ( 16.2 , SD 13.7 , n = 161 , 34 % reduction from baseline ) than in controls ( 22.3 , SD 17.0 , n = 140 , 16 % reduction from baseline ) . The adjusted difference between means is 4.6 ( 95 % confidence interval 2.2 to 7.0 ; P = 0.0002 ) . This result is robust to sensitivity analysis incorporating imputation for missing data . Patients in the acupuncture group experienced the equivalent of 22 fewer days of headache per year ( 8 to 38 ) . SF-36 data favoured acupuncture , although differences reached significance only for physical role functioning , energy , and change in health . Compared with controls , patients r and omised to acupuncture used 15 % less medication ( P = 0.02 ) , made 25 % fewer visits to general practitioners ( P = 0.10 ) , and took 15 % fewer days off sick ( P = 0.2 ) . Conclusions Acupuncture leads to persisting , clinical ly relevant benefits for primary care patients with chronic headache , particularly migraine . Expansion of NHS acupuncture services should be considered [16055451] Abstract Objective To investigate the effectiveness of acupuncture compared with minimal acupuncture and with no acupuncture in patients with tension-type headache . Design Three armed r and omised controlled multicentre trial . Setting 28 outpatient centres in Germany . Participants 270 patients ( 74 % women , mean age 43 ( SD 13 ) years ) with episodic or chronic tension-type headache . Interventions Acupuncture , minimal acupuncture ( superficial needling at non-acupuncture points ) , or waiting list control . Acupuncture and minimal acupuncture were administered by specialised physicians and consisted of 12 sessions per patient over eight weeks . Main outcome measure Difference in numbers of days with headache between the four weeks before r and omisation and weeks 9 - 12 after r and omisation , as recorded by participants in headache diaries . Results The number of days with headache decreased by 7.2 ( SD 6.5 ) days in the acupuncture group compared with 6.6 ( SD 6.0 ) days in the minimal acupuncture group and 1.5 ( SD 3.7 ) days in the waiting list group ( difference : acupuncture v minimal acupuncture , 0.6 days , 95 % confidence interval -1.5 to 2.6 days , P = 0.58 ; acupuncture v waiting list , 5.7 days , 3.9 to 7.5 days , P < 0.001 ) . The proportion of responders ( at least 50 % reduction in days with headache ) was 46 % in the acupuncture group , 35 % in the minimal acupuncture group , and 4 % in the waiting list group . Conclusions The acupuncture intervention investigated in this trial was more effective than no treatment but not significantly more effective than minimal acupuncture for the treatment of tension-type headache . Trial registration number IS RCT N9737659 [2775018] Background There is some evidence that acupuncture for pain and osteoarthritis ( OA ) of the knee is more than a placebo , and short term clinical benefits have been observed when acupuncture is compared to usual care . However there is insufficient evidence on whether clinical benefits of acupuncture are sustained over the longer term . In this study our key objectives are to inform the design parameters for a fully powered pragmatic r and omised controlled trial . These objectives include establishing potential recruitment rates , appropriate vali date d outcome measures , attendance levels for acupuncture treatment , loss to follow up and the sample size for a full scale trial . Methods Potential participants aged over 50 with pain and osteoarthritis of the knee were identified from a GP data base . Eligible patients were r and omised to either ' acupuncture plus usual care ' and ' usual care ' alone , with allocation appropriately concealed . Acupuncture consisted of up to 10 sessions usually weekly . Outcome measures included Western Ontario and McMaster Universities ( WOMAC ) index with the sample size for a full scale trial determined from the variance . Results From the GP data base of 15,927 patients , 335 potential trial participants were identified and invited to participate . After screening responses , 78 ( 23 % ) were identified as eligible and 30 patients who responded most promptly were r and omised to ' acupuncture plus usual care ' ( 15 patients ) and ' usual care ' alone ( 15 patients ) . Attendance for acupuncture appointments was high at 90 % of the maximum . Although the trial was not powered to detect significant changes in outcome , the WOMAC pain index showed a statistically significant reduction at 3 months in the acupuncture group compared to usual care . This was not sustained at 12 months . The sample size for a fully powered two-arm trial was estimated to be 350 . Conclusion This pilot study provided the evidence that a fully powered study to explore the longer term impact of acupuncture would be worthwhile , and relevant design features for such a trial were determined . Trial registration numberIS RCT N25134802 [15726029] OBJECTIVE To assess the long-term benefits of medication , needle acupuncture , and spinal manipulation as exclusive and st and ardized treatment regimens in patients with chronic ( > 13 weeks ) spinal pain syndromes . STUDY DESIGN Extended follow-up ( > 1 year ) of a r and omized clinical trial was conducted at the multidisciplinary spinal pain unit of Townsville 's General Hospital between February 1999 and October 2001 . PATIENTS AND METHODS Of the 115 patients originally r and omized , 69 had exclusively been treated with the r and omly allocated treatment during the 9-week treatment period ( results at 9 weeks were reported earlier ) . These patients were followed up and assessed again 1 year after inception into the study reapplying the same instruments ( ie , Oswestry Back Pain Index , Neck Disability Index , Short-Form-36 , and Visual Analogue Scales ) . Question naires were obtained from 62 patients reflecting a retention proportion of 90 % . The main analysis was restricted to 40 patients who had received exclusively the r and omly allocated treatment for the whole observation period since r and omization . RESULTS Comparisons of initial and extended follow-up question naires to assess absolute efficacy showed that only the application of spinal manipulation revealed broad-based long-term benefit : 5 of the 7 main outcome measures showed significant improvements compared with only 1 item in each of the acupuncture and the medication groups . CONCLUSIONS In patients with chronic spinal pain syndromes , spinal manipulation , if not contraindicated , may be the only treatment modality of the assessed regimens that provides broad and significant long-term benefit [15023830] Abstract Objective To evaluate the cost effectiveness of acupuncture in the management of chronic headache . Design Cost effectiveness analysis of a r and omised controlled trial . Setting General practice s in Engl and and Wales . Participants 401 patients with chronic headache , predominantly migraine . Interventions Patients were r and omly allocated to receive up to 12 acupuncture treatments over three months from appropriately trained physiotherapists , or to usual care alone . Main outcome measure Incremental cost per quality adjusted life year ( QALY ) gained . Results Total costs during the one year period of the study were on average higher for the acupuncture group ( £ 403 ; $ 768;€598 ) than for controls ( £ 217 ) because of the acupuncture practitioners ' costs . The mean health gain from acupuncture during the one year of the trial was 0.021 quality adjusted life years ( QALYs ) , leading to a base case estimate of £ 9180 per QALY gained . This result was robust to sensitivity analysis . Cost per QALY dropped substantially when the analysis incorporated likely QALY differences for the years after the trial . Conclusions Acupuncture for chronic headache improves health related quality of life at a small additional cost ; it is relatively cost effective compared with a number of other interventions provided by the NHS [19433697] BACKGROUND Acupuncture is a popular complementary and alternative treatment for chronic back pain . Recent European trials suggest similar short-term benefits from real and sham acupuncture needling . This trial addresses the importance of needle placement and skin penetration in eliciting acupuncture effects for patients with chronic low back pain . METHODS A total of 638 adults with chronic mechanical low back pain were r and omized to individualized acupuncture , st and ardized acupuncture , simulated acupuncture , or usual care . Ten treatments were provided over 7 weeks by experienced acupuncturists . The primary outcomes were back-related dysfunction ( Rol and -Morris Disability Question naire score ; range , 0 - 23 ) and symptom bothersomeness ( 0 - 10 scale ) . Outcomes were assessed at baseline and after 8 , 26 , and 52 weeks . RESULTS At 8 weeks , mean dysfunction scores for the individualized , st and ardized , and simulated acupuncture groups improved by 4.4 , 4.5 , and 4.4 points , respectively , compared with 2.1 points for those receiving usual care ( P < .001 ) . Participants receiving real or simulated acupuncture were more likely than those receiving usual care to experience clinical ly meaningful improvements on the dysfunction scale ( 60 % vs 39 % ; P < .001 ) . Symptoms improved by 1.6 to 1.9 points in the treatment groups compared with 0.7 points in the usual care group ( P < .001 ) . After 1 year , participants in the treatment groups were more likely than those receiving usual care to experience clinical ly meaningful improvements in dysfunction ( 59 % to 65 % vs 50 % , respectively ; P = .02 ) but not in symptoms ( P > .05 ) . CONCLUSIONS Although acupuncture was found effective for chronic low back pain , tailoring needling sites to each patient and penetration of the skin appear to be unimportant in eliciting therapeutic benefits . These findings raise questions about acupuncture 's purported mechanisms of action . It remains unclear whether acupuncture or our simulated method of acupuncture provide physiologically important stimulation or represent placebo or nonspecific effects [16980316] Abstract Objective To determine whether a short course of traditional acupuncture improves longer term outcomes for patients with persistent non-specific low back pain in primary care . Design Pragmatic , open , r and omised controlled trial . Setting Three private acupuncture clinics and 18 general practice s in York , Engl and . Participants 241 adults aged 18 - 65 with non-specific low back pain of 4 - 52 weeks ' duration . Interventions 10 individualised acupuncture treatments from one of six qualified acupuncturists ( 160 patients ) or usual care only ( 81 patients ) . Main outcome measures The primary outcome was SF-36 bodily pain , measured at 12 and 24 months . Other outcomes included reported use of analgesics , scores on the Oswestry pain disability index , safety , and patient satisfaction . Results 39 general practitioners referred 289 patients of whom 241 were r and omised . At 12 months average SF-36 pain scores increased by 33.2 to 64.0 in the acupuncture group and by 27.9 to 58.3 in the control group . Adjusting for baseline score and for any clustering by acupuncturist , the estimated intervention effect was 5.6 points ( 95 % confidence interval −0.2 to 11.4 ) at 12 months ( n = 213 ) and 8.0 points ( 2.8 to 13.2 ) at 24 months ( n = 182 ) . The magnitude of the difference between the groups was about 10%-15 % of the final pain score in the control group . Functional disability was not improved . No serious or life threatening events were reported . Conclusions Weak evidence was found of an effect of acupuncture on persistent non-specific low back pain at 12 months , but stronger evidence of a small benefit at 24 months . Referral to a qualified traditional acupuncturist for a short course of treatment seems safe and acceptable to patients with low back pain . Trial registration IS RCT N80764175 [ controlled-trials.com ] [18209514] Objective To assess the efficacy of acupuncture in migraine prophylaxis . Methods Thirty-seven patients with migraine were enrolled in a r and omized control trial at the Headache clinic located in a University Hospital . Real and sham acupuncture groups received 16 acupuncture sessions over 3 months . Treatment was individualized in the real acupuncture group and minimal acupuncture was used in the sham group . The primary end point was the percentage of patients with a ≥50 % reduction in their migraine attack frequency in the second , third , fourth , fifth , and sixth ( months ) compared with the first one ( baseline period ) . Primary and secondary end points were measured comparing headache diaries . Results Real acupuncture group showed improvement with significant differences compared with the sham acupuncture group in the primary efficacy end point ( P=0.021 ) at the second month of the treatment . Differences also appeared in 2 secondary end points : number of days with migraine per month ( P=0.007 ) in the second month and the percentage of patients with ≥40 % reduction in migraine attack frequency in the first ( P=0.044 ) and second months ( P=0.004 ) of the treatment . These differences disappeared in the third ( last ) month of the treatment as a consequence of the high improvement of the sham acupuncture group . Comparisons within each group showed that several migraine parameters evaluated improved significantly in both groups . Conclusions Individualized treatment based on traditional Chinese medicine plays a role in preventing migraine attacks . Nevertheless , sham acupuncture had similar effects . Major conclusions were limited by the small sample sizes however the observed trends may contribute to design future trials [12542558] OBJECTIVES To investigate whether acupuncture is superior to placebo and equivalent to sumatriptan for the early treatment of an acute migraine attack . DESIGN R and omized , partly double-blind ( sumatriptan versus placebo ) trial . SETTING Two hospitals in Germany ( one specialized in traditional Chinese medicine and one in the treatment of headache ) . SUBJECTS A total of 179 migraineurs experiencing the first symptoms of a developing migraine attack . INTERVENTIONS Traditional Chinese acupuncture , sumatriptan ( 6 mg subcutaneously ) or placebo injection . MAIN OUTCOME MEASURE Number of patients in whom a full migraine attack ( defined as severe migraine headache ) within 48 h was prevented . In patients who developed a migraine attack in spite of early treatment , acupuncture and sumatriptan were applied a second time , whilst patients initially r and omized to placebo received sumatriptan . RESULTS A full migraine attack was prevented in 21 of 60 ( 35 % ) patients receiving acupuncture , 21 of 58 ( 36 % ) patients receiving sumatriptan and 11 of 61 ( 18 % ) patients receiving placebo ( relative risk of having a full attack 0.79 ( 95 % CI , 0.64 - 0.99 ) for acupuncture versus placebo , and 0.78 ( 95 % CI , 0.62 - 0.98 ) for sumatriptan versus placebo ) . Response to the second intervention in patients who developed a full attack was better with sumatriptan ( 17/31 patients who received sumatriptan twice and 37/46 patients who had had placebo first ) than with acupuncture ( 4/31 ) . The number of patients reporting side-effects was 14 in the acupuncture group , 23 in the sumatriptan group and 10 in the placebo group . CONCLUSIONS In this trial acupuncture and sumatriptan were more effective than a placebo injection in the early treatment of an acute migraine attack . When an attack could not be prevented , sumatriptan was more effective than acupuncture at relieving headache [18624803] We aim ed to investigate the effectiveness of acupuncture in addition to routine care in patients with primary headache ( > 12 months , two or more headaches/month ) compared with treatment with routine care alone and whether the effects of acupuncture differ in r and omized and non-r and omized patients . In a r and omized controlled trial plus non-r and omized cohort , patients with headache were allocated to receive up to 15 acupuncture sessions over 3 months or to a control group receiving no acupuncture during the first 3 months . Patients who did not consent to r and omization received acupuncture treatment immediately . All subjects were allowed usual medical care in addition to study treatment . Number of days with headache , intensity of pain and health-related quality of life ( SF-36 ) were assessed at baseline , and after 3 and 6 months using st and ardized question naires . Of 15 056 headache patients ( mean age 44.1 ± 12.8 years , 77 % female ) , 1613 were r and omized to acupuncture and 1569 to control , and 11 874 included in the non-r and omized acupuncture group . At 3 months , the number of days with headache decreased from 8.4 ± 7.2 ( estimated mean ± S.E. ) to 4.7 ± 5.6 in the acupuncture group and from 8.1 ± 6.8 to 7.5 ± 6.3 in the control group ( P < 0.001 ) . Similarly , intensity of pain and quality of life improvements were more pronounced in the acupuncture vs. control group ( P < 0.001 ) . Treatment success was maintained through 6 months . The outcome changes in non-r and omized patients were similar to those in r and omized patients . Acupuncture plus routine care in patients with headache was associated with marked clinical improvements compared with routine care alone [18765182] OBJECTIVE To evaluate the effect of acupuncture combined with physiotherapy in comparison with acupuncture and physiotherapy performed alone in different parameters ; pain intensity , muscle tension , functional disability and muscle strength in the treatment of tension neck syndrome ( TNS ) . DESIGN A prospect i ve , comparative clinical trial . SETTING Acupuncture and Rehabilitation Department . BACKGROUND TNS can occur in computer users . Acupuncture has been one alternative treatment in physiotherapeutic rehabilitation of musculoskeletal disorders . SUBJECTS Forty-six patients with TNS . INTERVENTIONS Patients were allocated into three groups : Group-1 received physiotherapy ( therapeutic exercises ) combined with acupuncture ; Group-2 , acupuncture alone , and Group-3 , physiotherapy alone ; over a period of 10 weeks , with one or two sessions weekly . OUTCOME ASSESSMENT All patients had completed the protocol s and were assessed using a visual analogue scale for pain intensity ( VASpain ) and muscle tension ( VASmt ) , the Neck Disability Index : Brazilian Portuguese version for functional disability , and the cranio-cervical Flexion Test for isometric neck muscle strength ( INMS ) ; in the periods before treatment ( baseline ) , after 10 weeks of treatment , and after 6 months of follow-up . RESULTS All groups showed significant improvement ( p < 0.001 ) in these parameters after 10 weeks of treatment and after 6 months of follow-up . Group-1 was superior to Group-3 in pain and functional disability improvements ( p<0.05 ) ; and Group-1 was superior to both Group-2 ( p < 0.01 ) and Group-3 ( p < 0.05 ) in INMS . After 6 months of follow-up , the improvements of all groups were maintained ( p < 0.05 ) . CONCLUSION The data suggested that acupuncture effect may facilitate and /or enhance physiotherapy performance in musculoskeletal rehabilitation for tension neck syndrome [6446852] The acupuncture treatment situation was beneficial to the majority of people with low back pain . This was shown by the use of short-term controls and long-term controls , although the latter were not intended in the study design . After acupuncture , there was a 51 % pain reduction in the average pain score in the Immediate Treatment Group . The short-term controls , the Delayed Treatment Group , had no reduction whatsoever in their pain scores at the comparable followup period . Later , the Delayed Treatment Group bere also treated by acupuncturists , and reported 62 % less pain . When these two treatment groups were compared at 40 weeks with long-term controls ( Inadequate Treatment Group ) , the Inadequate Treatment Group still had the same pain scores , on the average , as when they enrolled in the study . Both treatment groups , on the average , had 30 % lower pain scores . Furthermore , 58 % of the treatment groups felt that they were definitely improved at 40 weeks , while only 11 % of the Inadequate Treatment Group felt definitely improved at 40 weeks [15870415] CONTEXT Acupuncture is widely used to prevent migraine attacks , but the available evidence of its benefit is scarce . OBJECTIVE To investigate the effectiveness of acupuncture compared with sham acupuncture and with no acupuncture in patients with migraine . DESIGN , SETTING , AND PATIENTS Three-group , r and omized , controlled trial ( April 2002-January 2003 ) involving 302 patients ( 88 % women ) , mean ( SD ) age of 43 ( 11 ) years , with migraine headaches , based on International Headache Society criteria . Patients were treated at 18 outpatient centers in Germany . INTERVENTIONS Acupuncture , sham acupuncture , or waiting list control . Acupuncture and sham acupuncture were administered by specialized physicians and consisted of 12 sessions per patient over 8 weeks . Patients completed headache diaries from 4 weeks before to 12 weeks after r and omization and from week 21 to 24 after r and omization . MAIN OUTCOME MEASURES Difference in headache days of moderate or severe intensity between the 4 weeks before and weeks 9 to 12 after r and omization . RESULTS Between baseline and weeks 9 to 12 , the mean ( SD ) number of days with headache of moderate or severe intensity decreased by 2.2 ( 2.7 ) days from a baseline of 5.2 ( 2.5 ) days in the acupuncture group compared with a decrease to 2.2 ( 2.7 ) days from a baseline of 5.0 ( 2.4 ) days in the sham acupuncture group , and by 0.8 ( 2.0 ) days from a baseline if 5.4 ( 3.0 ) days in the waiting list group . No difference was detected between the acupuncture and the sham acupuncture groups ( 0.0 days , 95 % confidence interval , -0.7 to 0.7 days ; P = .96 ) while there was a difference between the acupuncture group compared with the waiting list group ( 1.4 days ; 95 % confidence interval ; 0.8 - 2.1 days ; P<.001 ) . The proportion of responders ( reduction in headache days by at least 50 % ) was 51 % in the acupuncture group , 53 % in the sham acupuncture group , and 15 % in the waiting list group . CONCLUSION Acupuncture was no more effective than sham acupuncture in reducing migraine headaches although both interventions were more effective than a waiting list control [16178942] BACKGROUND Approximately 4 % of adults experience headaches nearly every day . Nonpharmacologic interventions for frequent headaches may be appropriate because medical management alone is often ineffective . OBJECTIVE To assess the efficacy of acupuncture as an adjunct to medical management for chronic daily headache ( CDH ) . METHODS We conducted a r and omized , controlled trial of 74 patients with CDH that compared medical management provided by neurologists to medical management plus 10 acupuncture treatments . Primary outcome measures were daily pain severity and headache-related quality of life ( QoL ) . RESULTS Patients who received only medical management did not demonstrate improvement in any of the st and ardized measures . Daily pain severity scores trended downward but did not differ between treatment groups ( P= .60 ) . Relative to medical management only , medical management plus acupuncture was associated with an improvement of 3.0 points ( 95 % CI , 1.0 to 4.9 ) on the Headache Impact Test and an increase of 8 or more points on the role limitations due to physical problems , social functioning , and general mental health domains of the Short Form 36 Health Survey . Patients who received acupuncture were 3.7 times more likely ( CI , 1.7 to 8.1 ) to report less suffering from headaches at 6 weeks ( absolute risk reduction 46 % ; number needed to treat 2 ) . CONCLUSION Headache-specialty medical management alone was not associated with improved clinical outcomes among our study population . Supplementing medical management with acupuncture , however , result ed in improvements in health-related QoL and the perception by patients that they suffered less from headaches [16545747] BACKGROUND Our aim was to assess the efficacy of a part-st and ardised verum acupuncture procedure , in accordance with the rules of traditional Chinese medicine , compared with that of part-st and ardised sham acupuncture and st and ard migraine prophylaxis with beta blockers , calcium-channel blockers , or antiepileptic drugs in the reduction of migraine days 26 weeks after the start of treatment . METHODS This study was a prospect i ve , r and omised , multicentre , double-blind , parallel-group , controlled , clinical trial , undertaken between April 2002 and July 2005 . Patients who had two to six migraine attacks per month were r and omly assigned verum acupuncture ( n=313 ) , sham acupuncture ( n=339 ) , or st and ard therapy ( n=308 ) . Patients received ten sessions of acupuncture treatment in 6 weeks or continuous prophylaxis with drugs . Primary outcome was the difference in migraine days between 4 weeks before r and omisation and weeks 23 - 26 after r and omisation . This study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N52683557 . FINDINGS Of 1295 patients screened , 960 were r and omly assigned to a treatment group . Immediately after r and omisation , 125 patients ( 106 from the st and ard group ) withdrew their consent to study participation . 794 patients were analysed in the intention-to-treat popoulation and 443 in the per- protocol population . The primary outcome showed a mean reduction of 2 .3 days ( 95 % CI 1.9 - 2.7 ) in the verum acupuncture group , 1.5 days ( 1.1 - 2.0 ) in the sham acupuncture group , and 2.1 days ( 1.5 - 2.7 ) in the st and ard therapy group . These differences were statistically significant compared with baseline ( p<0.0001 ) , but not across the treatment groups ( p=0.09 ) . The proportion of responders , defined as patients with a reduction of migraine days by at least 50 % , 26 weeks after r and omisation , was 47 % in the verum group , 39 % in the sham acupuncture group , and 40 % in the st and ard group ( p=0.133 ) . INTERPRETATION Treatment outcomes for migraine do not differ between patients treated with sham acupuncture , verum acupuncture , or st and ard therapy [15105215] Acupuncture is an established adjuvant analgesic modality for the treatment of chronic pain . Electrical stimulation of acupuncture points is considered to increase acupuncture analgesia . In this prospect i ve , r and omized , double-blind , controlled study we tested the hypothesis that auricular electroacupuncture ( EA ) relieves pain more effectively than conventional manual auricular acupuncture ( CO ) in chronic low back pain patients with insufficient pain relief ( visual analogue scale [ VAS ] ≥5 ) treated with st and ardized analgesic therapy . Disposable acupuncture needles were inserted in the auricular acupuncture points 29 , 40 , and 55 of the dominant side and connected to a newly developed battery-powered miniaturized stimulator worn behind the ear . Patients were r and omized into group EA ( n = 31 ) with continuous low-frequency auricular EA ( 1 Hz biphasic constant current of 2 mA ) and group CO ( n = 30 ) without electrical stimulation ( sham-electroacupuncture ) . Treatment was performed once weekly for 6 wk , and in each group needles were withdrawn 48 h after insertion . During the study period and a 3-mo follow-up , patients were asked to complete the McGill question naire . Psychological well being , activity level , quality of sleep , and pain intensity were assessed by means of VAS ; moreover , analgesic drug consumption was documented . Pain relief was significantly better in group EA during the study and the follow-up period as compared with group CO . Similarly , psychological well-being , activity , and sleep were significantly improved in group EA versus group CO , the consumption of analgesic rescue medication was less , and more patients returned to full-time employment . Neuropathic pain in particular improved in patients treated with EA . There were no adverse side effects . These results are the first to demonstrate that continuous EA stimulation of auricular acupuncture points improves the treatment of chronic low back pain in an outpatient population [7727550] OBJECTIVE The purpose of this study was to determine whether acupuncture was more effective than sham acupuncture in the reduction of pain in persons with osteoarthritis ( OA ) of the knee . METHODS Forty subjects ( 20 men , 20 women ) with radiographic evidence of OA of the knee were stratified by gender and r and omly assigned to either the experimental ( real acupuncture ) or control ( sham acupuncture ) groups . Subjects were treated three times per week for 3 weeks and evaluated at three test sessions . Outcome measures were : 1 ) the Pain Rating Index of the McGill Pain Question naire , 2 ) the Western Ontario and McMaster Universities ( WOMAC ) Osteoarthritis Index , and 3 ) pain threshold at four sites at the knee . RESULTS The analyses of variance showed that both real and sham acupuncture significantly reduced pain , stiffness , and physical disability in the OA knee , but that there were no significant differences between groups . CONCLUSIONS Acupuncture is not more effective than sham acupuncture in the treatment of OA pain [18534326] OBJECTIVE A pilot study to assess the feasibility of a trial to investigate the efficacy of acupuncture compared to placebo needling for the treatment of acute low back pain ( LBP ) . As part of this , the study was design ed to establish the credibility of the placebo control , and to provide data to inform a power analysis to determine numbers for a future trial . STUDY DESIGN A pilot patient and assessor blinded r and omized controlled trial . SETTING Primary care health centre facility , South and East Belfast Trust , Northern Irel and . PATIENTS Patients from the physiotherapy waiting list ( n=48 ) with LBP of less than 12 weeks duration . OUTCOME MEASURES Rol and and Morris Disability Question naire ( RMDQ ) , Visual Analogue Scale ( VAS ) , medication use and an exit question naire were completed at baseline , end of treatment , and at 3 months follow up . RESULTS Ninety-four percent ( 45/48 ) of patients completed assigned treatment , 83 % ( 40/48 ) completed 3 months follow-up . The sham needle used here proved to be credible : 91.7 % in the placebo group believed they had received acupuncture , compared to 95.8 % in the verum acupuncture group . Differences in baseline characteristics were accounted for using ANCOVA . There was no significant difference between groups on the RMDQ over time . For pain , the only statistically significant difference was at the 3 months follow up ( worst VAS , point estimate , 18.7 , 95 % CI 1.5 - 36.0 , p=0.034 ) . The majority of patients were taking some form of analgesic medication for LBP at the start of treatment ( n=44 ; 92 % ) , and at the end of treatment the verum acupuncture group were taking significantly fewer tablets of pain control medication ( mean ( S.D. ) : 1.0+/-0.3 ) than the placebo group ( mean ( S.D. ) : 4.2+/-0.6 , p<0.05 ) . Based upon these data , power analysis ( power=90 % , alpha=0.05 , minimal clinical ly important difference ( MCID ) for RMDQ=2.5 points ) indicated that 120 participants ( 60 per group ) would be needed to complete an adequately powered r and omized controlled trial . CONCLUSIONS This study has demonstrated the feasibility of a r and omized controlled trial of penetrating needle acupuncture compared to a non-penetrating sham for the treatment of acute LBP in primary care ; 120 participants would be required in a fully powered trial . The placebo needle used in this study proved to be a credible form of control [14600536] Objective To assess the efficacy of acupuncture in the treatment of chronic low back pain . Methods Patients ( n = 60 ) with chronic low back pain were recruited and r and omly allocated to either Acupuncture therapy or Placebo transcutaneous electrical nerve stimulation ( TENS ) groups . Patients were treated weekly for 6 weeks , and blinded assessment s were carried out pre- and post-treatment using the McGill Pain Question naire ( MPQ ) and visual analog scales ( VAS ) for pain , the Short-form 36 quality -of-life question naire , and a simple range of motion measurement . A total of 46 patients completed the trial and were followed up at 6 months . Results Analysis of results using t tests showed that in both groups there were significant pre-post improvements for all scores , except for MPQ scores in the Placebo-TENS group . There was no significant difference between the 2 groups for any of the outcome measures at the end of treatment . Results from the 6-month follow-up would suggest that the response was better in the acupuncture group . Discussion Further research is necessary to fully assess the efficacy of this treatment in combating chronic low back pain using larger sample sizes or alternative control groups [15798042] PURPOSE This study provides basic information about the training and practice s of licensed acupuncturists . METHODS R and omly selected licensed acupuncturists in Massachusetts and Washington state were interviewed and asked to record information on 20 consecutive patient visits . RESULTS Most acupuncturists in both states had 3 or 4 years of academic acupuncture training and had received additional “ postgraduate ” training as well . Acupuncturists treated a wide range of conditions , including musculoskeletal problems ( usually back , neck , and shoulder ) ( 33 % in Massachusetts and 47 % in Washington ) , general body symptoms ( 12 % and 9 % , respectively ) such as fatigue , neurological problems ( 10 % and 12 % , respectively ) ( eg , headaches ) , and psychological complaints ( 10 % and 8 % , respectively ) ( especially anxiety and depression ) . Traditional Chinese medicine ( TCM ) was the predominant style of acupuncture used in both states ( 79 % and 86 % , respectively ) . Most visits included a traditional diagnostic assessment ( more than 99 % ) , regular body acupuncture ( 95 % and 93 % , respectively ) , and additional treatment modalities ( 79 % and 77 % , respectively ) . These included heat and lifestyle advice ( 66 % and 65 % , respectively ) , most commonly dietary advice and exercise recommendations . Chinese herbs were used in about one third of visits . Although most patients self-referred to acupuncture , about one half received concomitant care from a physician . Acupuncturists rarely communicated with the physicians of their patients who were providing care for the same problem . CONCLUSIONS This study contributes new information about acupuncturists and the care they provide that should be useful to clinicians interested in becoming more knowledgeable about complementary or alternative medical therapies available to their patients [11322842] BACKGROUND Because the value of popular forms of alternative care for chronic back pain remains uncertain , we compared the effectiveness of acupuncture , therapeutic massage , and self-care education for persistent back pain . METHODS We r and omized 262 patients aged 20 to 70 years who had persistent back pain to receive Traditional Chinese Medical acupuncture ( n = 94 ) , therapeutic massage ( n = 78 ) , or self-care educational material s ( n = 90 ) . Up to 10 massage or acupuncture visits were permitted over 10 weeks . Symptoms ( 0 - 10 scale ) and dysfunction ( 0 - 23 scale ) were assessed by telephone interviewers masked to treatment group . Follow-up was available for 95 % of patients after 4 , 10 , and 52 weeks , and none withdrew for adverse effects . RESULTS Treatment groups were compared after adjustment for prer and omization covariates using an intent-to-treat analysis . At 10 weeks , massage was superior to self-care on the symptom scale ( 3.41 vs 4.71 , respectively ; P = .01 ) and the disability scale ( 5.88 vs 8.92 , respectively ; P<.001 ) . Massage was also superior to acupuncture on the disability scale ( 5.89 vs 8.25 , respectively ; P = .01 ) . After 1 year , massage was not better than self-care but was better than acupuncture ( symptom scale : 3.08 vs 4.74 , respectively ; P = .002 ; dysfunction scale : 6.29 vs 8.21 , respectively ; P = .05 ) . The massage group used the least medications ( P<.05 ) and had the lowest costs of subsequent care . CONCLUSIONS Therapeutic massage was effective for persistent low back pain , apparently providing long-lasting benefits . Traditional Chinese Medical acupuncture was relatively ineffective . Massage might be an effective alternative to conventional medical care for persistent back pain [11841108] The principle aim of the present work is the evaluation of the importance of the variable " depth " of needle insertion in the determination of acupuncture 's therapeutic results . A r and omized clinical trial carried out on 44 patients belonging to two groups of 22 each , suffering from shoulder myofascial pain : group A : superficial acupuncture ; group B : deep acupuncture . All of them subjected to the same model of treatment with 13 needles and the treatment of the most painful 4 trigger points ( TP ) found in the shoulder 's area . In the group A patients , the needles were introduced in the skin at a depth of 2 mm , on the TP . In the group B patients , the needles were placed deeply both in the muscular acupuncture points and in the TP . The treatment was planned for a cycle of 8 sessions , the first 4 to be performed twice a week , the last 4 weekly . The intensity of pain was evaluated with the McGill Pain Question naire before beginning the therapy , at the end of the therapy , and at the follow-up after 1 and 3 months . Both techniques had efficacy in controlling pain . A statistically significant difference rose between the two needling techniques at the end of the treatment and at the follow up after one and three months . Deep acupuncture shows to be better at all times and this underlines the importance of the muscular afferences in acupunctural stimulation in the control of pain [15157691] & NA ; The study was carried out to examine whether acupuncture treatment can reduce chronic pain in the neck and shoulders and related headache , and also to examine whether possible effects are long‐lasting . Therefore , 24 female office workers ( 47±9 years old , mean±SD ) who had had neck and shoulder pain for 12±9 years were r and omly assigned to a test group ( TG ) or a control group ( CG ) . Acupuncture was applied 10 times during 3–4 weeks either at presumed anti‐pain acupoints ( TG ) or at placebo‐points ( CG ) . A physician measured the pain threshold ( PPT ) in the neck and shoulder regions with algometry before the first treatment , and after the last one and six months after the treatments . Question naires on muscle pain and headache were answered at the same occasions and again 3 years after the last treatment . The intensity and frequency of pain fell more for TG than for CG ( Pb≤0.04 ) during the treatment period . Three years after the treatments TG still reported less pain than before the treatments ( Pw<0.001 ) , contrary to what CG did ( Pb<0.04 ) . The degree of headache fell during the treatment period for both groups , but more for TG than for CG ( Pb=0.02 ) . Three years after the treatments the effect still lasted for TG ( Pw<0.001 ) while the degree of headache for CG was back to the pre‐treatment level ( Pb<0.001 ) . PPT of some muscles rose during the treatments for TG and remained higher 6 months after the treatments ( Pw<0.05 ) , which contrasts the situation for CG . Adequate acupuncture treatment may reduce chronic pain in the neck and shoulders and related headache . The effect lasted for 3 years [1514335] Purpose : Acupuncture treatment of patients waiting for arthroplasty surgery . Methods : 29 patients with a total of 42 osteoarthritic knees were r and omized to two groups . Group A was treated while Group B served as a no‐treatment control group . After 9 weeks Group B was treated too . Analgesic consumption , pain and objective measurements were registered . All objective measures were done by investigators who were “ blinded ” as to Group A & B. In the second part of the study 17 patients ( 26 knees ) continued with treatments once a month . Registration of analgesic consumption , pain and objective measurements continued . Total study period 49 weeks . Results : Comparing Group A to B there was a significant reduction in pain , analgesic consumption and in most objective measures . In Group A + B combined there was an 80 % subjective improvement , and a significantly increased knee range movement – an increase mainly in the worst knees . Results were significantly better in those who had not been ill for a long time . In the second part of the study , it was shown that it was possible to maintain the improvements . Conclusions : Acupuncture can ease the discomfort while waiting for an operation and perhaps even serve as an alternative to surgery . Seven patients have responded so well that at present they do not want an operation . ( USD 9000 saved per operation ) [11531895] A study with needle acupuncture was performed in tension-type headache employing a new placebo acupuncture method . Sixty-nine patients ( mean age 48.1 years , sd = 14.1 ) fulfilling the International Headache Society criteria for tension-type headache were r and omly assigned to verum or placebo condition . No significant differences between placebo and verum with respect to visual analogue scale and frequency of headache attacks could be observed immediately , 6 weeks and 5 months after the end of treatment . There was a significant but weak improvement in quality of life parameters ( clinical global impressions , Nottingham Health Profile ) after verum treatment . In decision tree analyses , the changes in clinical global impressions and headache frequency depended significantly on primary headache frequency with a limit value of 24.5 days headache per month . High values in the von Zerssen Depression Score result ed in high mean visual analogue scale values [10422654] Sixty patients aged 60 or over with back pain for at least 6 months were recruited from General Practitioner referrals and r and omized to 4 weeks of treatment with acupuncture or transcutaneous electrical nerve stimulation ( TENS ) . All treatments were administered by the same physiotherapist and both groups had the same contact with him . The following were measured at baseline , completion and at a 3-month follow-up by an independent observer blinded to treatment received : ( 1 ) pain severity on visual analogue scale ( VAS ) ; ( 2 ) pain subscale of Nottingham Health Profile ( NHP ) ; ( 3 ) number of analgesic tablets consumed in previous week ; ( 4 ) spinal flexion from C7 to S1 . Thirty-two patients were r and omized to acupuncture and 28 to TENS ; only three withdrew ( two from acupuncture , one from TENS ) . Significant improvements were shown on VAS ( P < 0.001 ) , NHP ( P < 0.001 ) and tablet count ( P < 0.05 ) between baseline and completion in both groups , these improvements remaining significant comparing baseline with follow-up with a further non-significant improvement in VAS and NHP in the acupuncture group . The acupuncture but not the TENS patients showed a small but statistically significant improvement ( P < 0.05 ) in mean spinal flexion between baseline and completion which was not maintained at follow-up . Thus in these elderly patients with chronic back pain both acupuncture and TENS had demonstrable benefits which outlasted the treatment period . Acupuncture may improve spinal flexion . This trial can not exclude the possibility that both treatments are ' placebos ' [16618043] Introduction There is some evidence for the efficacy of acupuncture , but it remains unclear whether trigger point acupuncture is effective . Our objective was to evaluate the effects of trigger point acupuncture on pain and quality of life in chronic low back pain patients compared with sham acupuncture . Methods Twenty-six consecutive out- patients ( 17 women , 9 men ; age range : 65–91 years ) from the Department of Orthopaedic Surgery , Meiji University of Oriental Medicine , with non-radiating low back pain for at least six months and normal neurological examination , were r and omised to two groups . Each group received one phase of trigger point acupuncture and one of sham acupuncture with a three week washout period between them , over 12 weeks . Group A ( n=13 ) received trigger point acupuncture in the first phase and sham acupuncture in the second . Group B ( n=13 ) received the same interventions in the reverse order . Outcome measures were pain intensity ( visual analogue scale , VAS ) and Rol and Morris Question naire . Results Nineteen patients were included in the analysis . At the end of the first treatment phase , group A receiving trigger point acupuncture scored significantly lower VAS ( P<0.001 ) and Rol and Morris Question naire scores ( P<0.01 ) than the sham control group . There were significant within-group reductions in pain in both groups during the trigger point acupuncture phase but not in the sham treatment phase . However , the beneficial effects were not sustained . Conclusion These results suggest that trigger point acupuncture may have greater short term effects on low back pain in elderly patients than sham acupuncture [15561516] OBJECTIVE To investigate the effectiveness of a clinical treatment program with traditional Chinese medicine for migraine and tension-type headache . METHODS Ninety-one patients with migraine , episodic or chronic tension-type headache according to the criteria of the International Headache Society were r and omised into an experimental or a waiting list control group . Patients in the experimental group were treated 4 weeks in a hospital for traditional Chinese medicine after a baseline period of one month . Patients in the waiting list group continued their previous headache treatment . Main outcome measure was the difference in the number of days with headache of at least moderate intensity during baseline ( month 1 ) and month 7 . RESULTS The difference in the number of days with headache of at least moderate intensity was 5.6 ( S.D. , 6.1 ) days in the experimental group and 1.2 ( S.D. , 4.5 ) days in the waiting list group ( P < 0.001 ) . A reduction of more than 50 % in headache days was observed in 52 % of the patients in the experimental group and 16 % in the waiting list group . Patients with migraine and a combination of migraine and episodic tension-type headaches improved more than patients with other headaches . CONCLUSION The results of this study indicate that treatment in the hospital for traditional Chinese medicine in Kotzting is associated with lasting improvements in the majority of patients [15650469] DESIGN Forty-two ( 42 ) subjects suffering from chronic low-back pain were matched with the nature of their occupations and then r and omly allocated into : ( 1 ) an electroacupuncture group ( EA ) ; ( 2 ) an electrical heat acupuncture ( EH ) group or ; ( 3 ) a control group . INTERVENTIONS Subjects in the EA group and the EH group received treatment for 20 minutes on a total of 6 acupuncture points . Treatment was delivered twice per week for 4 weeks ( a total of 8 sessions ) . Back exercise was taught to all subjects including the control group as a home program . OUTCOMES MEASURES A numerical rating scale of pain ( NPRS ) , straight leg raise ( SLR ) , and Rol and Morris Disability Question naire ( RMDQ ) were recorded . RESULTS There were significant reduction of NPRS within the EA ( p = 0.000 ) , EH ( p = 0.000 ) , and control ( p = 0.013 ) groups across sessions . Significant between-group differences were shown in session 4 ( p = 0.006 ) , session 8 ( p = 0.001 ) , and 1-month follow-up sessions ( p = 0.001 ) . Posthoc tests showed that the NPRS of the EH group was significantly lower than that of the EA group and the control group by session 4 ( p = 0.004 ) . After session 8 , the NPRS of both the EA group ( p = 0.003 ) and the EH group ( p = 0.001 ) were significantly lower than that of the control group . Such a difference was maintained at least up to the 1-month follow-up . Only the EA group had significant improvement in the measurement of SLR across sessions ( p = 0.000 ) . The between-group difference reached significance level in session 8 ( p = 0.001 ) and at 1-month follow-up ( p = 0.002 ) . Posthoc tests showed that EA group had significantly greater gain than the EH group and the control group . For the RMDQ score , the improvement was statistically significant within each of the three groups over time ( p = 0.000 ) . However , the between-group difference did not reach statistical significance . CONCLUSIONS Our findings suggest that 4 sessions of EH treatment over 2 weeks produced significantly greater reduction in the NPRS than that of the EA or the control . However , EA produced greater improvement in SLR and reduction in RMDQ score than that of the EH and the control [18403402] OBJECTIVE Evaluate the efficacy of acupuncture associated with physiotherapy for patients with painful shoulder . METHODS In a multicentre controlled r and omized study , participants were recruited with a clinical diagnosis of unilateral subacromial syndrome from six rehabilitation medicine departments belonging to the Public Health System in two Spanish regions . All participants received 15 sessions of physiotherapy during the 3 weeks that the treatment lasted and were r and omized to additionally receive , once a week , acupuncture or mock TENS ( transcutaneous electrical nerve stimulation ) . The primary outcome measure was the change in the Constant-Murley Score ( CMS ) for functional assessment of the shoulder , at 4 weeks after r and omization . This study is registered as an International St and ard R and omized Controlled Trial , number IS RCT N28687220 . RESULTS A total of 425 patients were recruited . The mean score ( s.d . ) on the CMS had increased by 16.6 ( 15.6 ) points among the acupuncture group , compared with 10.6 ( 13.5 ) points in the control group , and the mean difference between the two groups was statistically significant ( 6.0 points ; 95 % CI 3.2 , 8.8 points ; P < 0.001 ) . By the end of the treatment , 53 % of the patients in the acupuncture group had decreased their consumption of analgesics , compared with a corresponding 30 % among the control group ( P < 0.001 ) . CONCLUSIONS Single-point acupuncture in association with physiotherapy improves shoulder function and alleviates pain , compared with physiotherapy as the sole treatment . This improvement is accompanied by a reduction in the consumption of analgesic medicaments [15628774] Objective There is some evidence for the efficacy of acupuncture in chronic low back pain , but it remains unclear which acupuncture modes are most effective . Our objective was to evaluate the effects of two different modes of trigger point acupuncture on pain and quality of life in chronic low back pain patients compared to st and ard acupuncture treatment . Methods Thirty five consecutive out- patients ( 25 women , 10 men ; age range : 65–81 years ) from the Department of Orthopaedic Surgery , Meiji University of Oriental Medicine , with non-radiating low back pain for at least six months and normal neurological examination , were r and omised to one of three groups over 12 weeks . Each group received two phases of acupuncture treatment with an interval between them . Nine patients dropped out during the course of the study . The st and ard acupuncture group ( n=9 ) received treatment at traditional acupuncture points for low back pain , while the other acupuncture groups received superficial ( n=9 ) or deep ( n=9 ) treatments on trigger points . Outcome measures were VAS pain intensity and Rol and Morris Question naire . Results After treatment , the group that received deep needling to trigger points reported less pain intensity and improved quality of life compared to the st and ard acupuncture group or the group that received superficial needling to trigger points , but the differences were not statistically significant . There was a significant reduction in pain intensity between the treatment and interval in the group that received deep needling to trigger points ( P<0.01 ) , but not in the st and ard acupuncture group or the group that received superficial needling to trigger points . Conclusion These results suggest that deep needling to trigger points may be more effective in the treatment of low back pain in elderly patients than either st and ard acupuncture therapy , or superficial needling to trigger points [18035566] Opioid-like medications ( OLM ) are commonly used by patients with various types of chronic pain , but their long-term benefit is question able . Electroacupuncture ( EA ) has been previously shown beneficial in reducing post-operative acute OLM consumption . In this pilot r and omized controlled trial , the effect of EA on OLM usage and associated side effects in chronic pain patients was evaluated . After a two-week baseline assessment , participants using OLM for their non-malignant chronic pain were r and omly assigned to receive either real EA ( REA , n=17 ) or sham EA ( SEA , n=18 ) treatment twice weekly for 6 weeks before entering a 12-week follow-up . Pain , OLM consumption and their side effects were recorded daily . Participants also completed the McGill Pain Question naire ( MPQ ) , SF-36 and Beck Depression Inventory ( BDI ) at baseline , and at the 5th , 8th , 12th , 16th and 20th week . Nine participants withdrew during the treatment period with another three during the follow-up period . Intention to treat analysis was applied . At the end of treatment period , reductions of OLM consumption in REA and SEA were 39 % and 25 % , respectively ( p=0.056 ) , but this effect did not last more than 8 weeks after treatment . There was no difference between the two groups with respect to reduction of side effects and pain and the improvement of depression and quality of life . In conclusion , REA demonstrates promising short-term reduction of OLM for participants with chronic non-malignant pain , but such effect needs to be confirmed by trials with adequate sample sizes [17013356] Background The purpose of this study was to examine the immediate effect of single acupuncture stimulation to the most painful point in patients with low back pain . Method A r and omised , evaluator-blinded , sham controlled clinical trial was conducted in which 31 patients with low back pain were r and omly allocated to either an acupuncture group ( n=15 ) or a sham acupuncture group ( n=16 ) . Both acupuncture and sham acupuncture were performed at the most painful point on the lower back of the subjects . For the acupuncture group , a stainless steel needle was inserted to a depth of 20 mm and manually stimulated ( sparrow pecking method ) for 20 seconds , while for the sham treatment a guide tube without a needle was placed at the point and tapped on the skin . Changes in low back pain were evaluated with a visual analogue scale ( VAS ) and the Schober test . Participants were also asked if they felt the needling sensation or not . The therapy and the evaluation were independently performed by two different acupuncturists . Results VAS score and the Schober test score showed significant improvement after treatment as compared with the sham group ( P=0.02 , 0.001 , respectively ) . There were no significant differences in the needling sensation between the acupuncture and sham group . Conclusion These results suggest that acupuncture at the most painful point gives immediate relief of low back pain [17868354] OBJECTIVE To check the effectiveness of a true acupuncture treatment according to traditional Chinese medicine ( TCM ) in migraine without aura , comparing it to a st and ard mock acupuncture protocol , an accurate mock acupuncture healing ritual , and untreated controls . BACKGROUND Migraine prevalence is high and affects a relevant rate of adults in the productive phase of their life . Acupuncture has been increasingly advocated and used in Western countries for migraine treatment , but the evidence of its effectiveness still remains weak . A large variability of treatments is present in published studies and no acupoint selection according to TCM has been investigated so far ; therefore , the low level of evidence of acupuncture effectiveness might partly depend on inappropriate treatment . DESIGN AND METHODS A prospect i ve , r and omized , controlled study was performed in 160 patients suffering from migraine without aura , assessed according to the ICD-10 classification . The patients were divided into the following 4 groups : ( 1 ) group TA , treated with true acupuncture ( according to TCM ) plus Rizatriptan ; ( 2 ) group RMA , treated with ritualized mock acupuncture plus Rizatriptan ; ( 3 ) group SMA , treated with st and ard mock acupuncture plus Rizatriptan ; ( 4 ) group R , without prophylactic treatment with relief therapy only ( Rizatriptan ) . The MIDAS Question naire was administered before treatment ( T0 ) , at 3 ( T1 ) and 6 months ( T2 ) from the beginning of treatment , and the MIDAS Index ( MI ) was calculated . Rizatriptan intake was also checked in all groups of patients at T0 , T1 , and T2 . Group TA and RMA were evaluated according to TCM as well ; then , the former was su bmi tted to true acupuncture and the latter to mock acupuncture treatment resembling the same as TA . The statistical analysis was conducted with factorial ANOVA and multiple tests with a Bonferroni adjustment . RESULTS A total of 127 patients completed the study ( 33 dropouts ) : 32 belonged to group TA , 30 to group RMA , 31 to group SMA , and 34 to group R. Before treatment the MI ( T(0 ) ) was moderate to severe with no significant intergroup differences . All groups underwent a decrease of MI at T(1 ) and T(2 ) , with a significant group difference at both T(1 ) and T(2 ) compared to T(0 ) ( P < .0001 ) . Only TA provided a significant improvement at both T(1 ) and T(2 ) compared to R ( P < .0001 ) . RMA underwent a transient improvement of MI at T(1 ) . The Rizatriptan intake paralleled the MI in all groups . CONCLUSIONS TA was the only treatment able to provide a steady outcome improvement in comparison to the use of only Rizatriptan , while RMA showed a transient placebo effect at T1 [20980765] Background and Objective : A recent Cochrane review on placebo interventions for all kinds of conditions found that ‘ physical placebos ’ ( which included sham acupuncture ) were associated with larger effects over no-treatment control groups than ‘ pharmacological placebos ’ . We re-analyzed the data from this review to investigate whether effects associated with sham acupuncture differed from those of other ‘ physical placebos ’ . Methods : All trials included in the Cochrane review as investigating ‘ physical placebos ’ were classified as investigating either ( sham ) acupuncture or other physical placebos . The latter group was further subclassified into groups of similar interventions . Data from the Cochrane review were re-entered into the RevMan 5 software for meta- analysis . The primary analysis was a r and om-effects analysis of trials reporting continuous outcomes of trials that used either sham acupuncture or other physical placebos . Results : Out of a total of 61 trials which reported a continuous outcome measure , 19 compared sham acupuncture and 42 compared other physical placebos with a notreatment control group . The trials re-analyzed were highly heterogeneous regarding patients , interventions and outcomes measured . The pooled st and ardized mean difference was –0.41 ( 95 % confidence interval –0.56 , –0.24 ) between sham acupuncture and no treatment and –0.26 ( 95 % CI –0.37 , –0.15 ) between other physical placebos and no treatment ( p value for subgroup differences = 0.007 ) . Significant differences were also observed between subgroups of other physical placebos . Conclusion : Due to the heterogeneity of the trials included and the indirect comparison our results must be interpreted with caution . Still , they suggest that sham acupuncture interventions might , on average , be associated with larger effects than pharmacological and other physical placebos [15921471] BACKGROUND AND PURPOSE There is no definitive evidence for the efficacy of the physical therapy interventions used for patients with impingement syndrome . The purpose of this study was to compare manual acupuncture and continuous ultrasound , both applied in addition to home exercises , for patients diagnosed with impingement syndrome . SUBJECTS AND METHODS Eighty-five patients with clinical signs of impingement syndrome were r and omly assigned to either a group that received acupuncture ( n=44 ) or a group that received ultrasound ( n=41 ) . Both interventions were given by physical therapists twice a week for 5 weeks in addition to a home exercise program . Scores from 3 shoulder disability measures , combined in the analysis , measured change during a period of 12 months . RESULTS Both groups improved , but the acupuncture group had a larger improvement in the combined score . DISCUSSION AND CONCLUSION The results suggest that acupuncture is more efficacious than ultrasound when applied in addition to home exercises [11128820] A multicentre , r and omized clinical trial was undertaken to test the hypothesis that acupuncture is more efficacious than sham control procedure in the prevention of episodic tension-type headache . Fifty subjects were r and omized to receive a course of treatment with either brief acupuncture or a sham procedure . Subjects were followed up for 3 months . Changes in headache were assessed by daily diary , the primary outcome measure being the number of days with headache . No significant differences were found between the changes in the two groups for any measure at any time point . Results also show that patient blinding was successful . In conclusion , this study does not provide evidence that this form of acupuncture is effective in the prevention of episodic tension-type headache [12594972] OBJECTIVES To compare the effects of real acupuncture to tender points for neck and shoulder pain and stiffness ( Japanese : katakori ) with those of sham acupuncture . DESIGN R and omized-controlled trial . METHODS Thirty-four volunteers from an acupuncture school with complaints of chronic pain and stiffness , who had no arm symptoms and gave informed consent , were r and omly allocated to acupuncture or sham groups . Acupuncture or sham acupuncture was applied to the tender points once a week for 3 weeks . In the acupuncture group the acupuncture needle was inserted to the muscle , then the sparrow pecking technique was applied five times . Sham acupuncture was done without insertion of the needle . Dull pain and stiffness were evaluated by visual analog scale ( VAS ) before , and every 2 days after the first needling for 1 month . Pressure pain threshold on the tender points was measured before and after each treatment . RESULTS There was no statistical difference of VAS scores between acupuncture and sham groups 9 days after the last treatment . However , the acupuncture group showed significant reduction of VAS scores immediately after and /or 1 day after the real acupuncture treatments ( P<0.01 ) . The effect tended to be prolonged after repeated treatment . Pressure pain thresholds tended to increase after real acupuncture treatment but not after sham acupuncture . CONCLUSIONS Acupuncture applied to tender points appears to have short-term effects on neck and shoulder pain and stiffness , but this study was unable to demonstrate any long-term superiority over sham acupuncture [18356795] Background There is evidence for the efficacy of acupuncture treatment in knee osteoarthritis , but it remains unclear which acupuncture modes are most effective . We evaluated the effects of trigger point acupuncture on pain and quality of life in knee osteoarthritis patients , compared with acupuncture at st and ard points , and sham acupuncture . Methods Thirty patients ( 27 women , 3 men ; aged 61–82 years ) with non-radiating knee osteoarthritis pain for at least six months and normal neurological examination were r and omised to one of three groups for the study period of 21 weeks . Each group received five acupuncture treatment sessions . The st and ard acupuncture point group ( n=10 ) received treatment at traditional acupuncture points for knee pain ; the trigger point acupuncture group ( n=10 ) received treatment at trigger points ; and the third group ( n=10 ) received sham acupuncture treatment at the trigger points . Outcome measures were pain intensity ( visual analogue scale , VAS ) and WOMAC index ( Western Ontario and McMaster Universities Arthritis Index ) . The groups were compared by the area under the curve method . Results Five patients dropped out of the study because of lack of improvement , and one patient ( in the trigger point acupuncture group ) dropped out because of deterioration of symptoms ; the remaining 24 patients were included in the analysis . After treatment , the trigger point acupuncture group reported less pain intensity on VAS than the st and ard acupuncture or sham treatment group , but both the trigger point acupuncture and st and ard acupuncture groups reported improvement of function of knee . There was a significant reduction in pain intensity between pre-treatment and five weeks after treatment for the trigger point acupuncture ( P<0.01 ) and st and ard acupuncture groups ( P<0.01 ) included in the analysis , but not for the sham treatment group . Group comparison using the area under the curves demonstrated a significant difference only between trigger point acupuncture and sham treatment groups analysed ( P<0.025 for VAS , and P<0.031 for WOMAC ) . Conclusion These results suggest that trigger point acupuncture therapy may be more effective for osteoarthritis of the knee in some elderly patients than st and ard acupuncture therapy [17075849] OBJECTIVE To investigate the effectiveness of acupuncture in addition to routine care , compared with routine care alone , in the treatment of patients with chronic pain due to osteoarthritis ( OA ) of the knee or hip . METHODS In a r and omized , controlled trial , patients with chronic pain due to OA of the knee or hip were r and omly allocated to undergo up to 15 sessions of acupuncture in a 3-month period or to a control group receiving no acupuncture . Another group of patients who did not consent to r and omization underwent acupuncture treatment . All patients were allowed to receive usual medical care in addition to the study treatment . Clinical OA severity ( Western Ontario and McMaster Universities Osteoarthritis Index [ WOMAC ] ) and health-related quality of life ( Short Form 36 ) were assessed at baseline and after 3 months and 6 months . RESULTS Of 3,633 patients ( mean + /- SD age 61.8 + /- 10.8 years ; 61 % female ) , 357 were r and omized to the acupuncture group and 355 to the control group , and 2,921 were included in the nonr and omized acupuncture group . At 3 months , the WOMAC had improved by a mean + /- SEM of 17.6 + /- 1.0 in the acupuncture group and 0.9 + /- 1.0 in the control group ( 3-month scores 30.5 + /- 1.0 and 47.3 + /- 1.0 , respectively [ difference in improvement 16.7 + /- 1.4 ; P < 0.001 ] ) . Similarly , quality of life improvements were more pronounced in the acupuncture group versus the control group ( P < 0.001 ) . Treatment success was maintained through 6 months . The changes in outcome in nonr and omized patients were comparable with those in r and omized patients who received acupuncture . CONCLUSION These results indicate that acupuncture plus routine care is associated with marked clinical improvement in patients with chronic OA-associated pain of the knee or hip [9717924] BACKGROUND A problem acupuncture research has to face is the concept of a control group . If , in control groups , non-acupoint needling is done , physiological acupuncture effects are implied . Therefore the effects shown in this group are often close to those shown in the acupuncture group . In other trials , control groups have received obviously different treatments , such as transcutaneous electrical nervous stimulation or TENS-laser treatment ; it is not clear if the effects of acupuncture are due only to the psychological effects of the treatment . METHODS We developed a placebo acupuncture needle , with which it should be possible to simulate an acupuncture procedure without penetrating the skin . In a cross-over experiment with 60 volunteers we tested whether needling with the placebo needle feels any different from real acupuncture . FINDINGS Of 60 volunteers , 54 felt a penetration with acupuncture ( mean visual analogue scale [ VAS ] 13.4 ; SD 10.58 ) and 47 felt it with placebo ( VAS 8.86 ; SD 10.55 ) , 34 felt a dull pain sensation ( DEQI ) with acupuncture and 13 with placebo . None of the volunteers suspected that the needle may not have penetrated the skin . INTERPRETATION The placebo needle is sufficiently credible to be used in investigations of the effects of acupuncture [17709062] INTRODUCTION There is some evidence for the efficacy of acupuncture in chronic neck pain ( CNP ) treatment , but it remains unclear which acupuncture modes are most effective . Objective was to evaluate the effects of trigger point acupuncture on pain and quality of life ( QOL ) in CNP patients compared to three other acupuncture treatments ( acupoints , non-trigger point and sham treatment ) . METHODS Forty out- patients ( 29 women , 11 men ; age range : 47 - 80 years ) from the Department of Orthopaedic Surgery , Meiji University of Oriental Medicine , with non-radiating CNP for at least 6 months and normal neurological examination were r and omised to one of four groups over 13 weeks . Each group received two phases of acupuncture treatment with an interval between them . The acupoint group ( st and ard acupuncture ; SA , n=10 ) received treatment at traditional acupoints for neck pain , the trigger point ( TrP , n=10 ) and non-trigger point ( non-TrP , n=10 ) groups received treatment at tenderness points for the same muscle , while the other acupuncture group received sham treatments on the trigger point ( SH , n=10 ) . Outcome measures were pain intensity ( visual analogue scale ; VAS 0 - 100 mm ) and disease specific question naire ( neck disability index ; NDI , 60-point scale ) . RESULTS After treatment , the TrP group reported less pain intensity and improved QOL compared to the SA or non-TrP group . There was significant reduction in pain intensity between the treatment and the interval for the TrP group ( p<0.01 , Dunnett 's multiple test ) , but not for the SA or non-TrP group . CONCLUSION These results suggest that trigger point acupuncture therapy may be more effective on chronic neck pain in aged patients than the st and ard acupuncture therapy [17115982] OBJECTIVES In a r and omized controlled multicenter trial extending over 24 weeks , we investigated whether acupuncture is as effective and safe as metoprolol in the prophylactic treatment of migraine under conditions similar to routine care . METHODS One hundred fourteen migraine patients could be r and omized to treatment over 12 weeks either with acupuncture ( 8 to 15 sessions ) or metoprolol ( 100 to 200 mg daily ) . Main outcome measure was the difference in the number of migraine days between baseline and the weeks 9 to 12 after r and omization ( derived from a headache diary ) . RESULTS Two of 59 patients r and omized to acupuncture withdrew prematurely from the study compared to 18 of 55 r and omized to metoprolol . The number of migraine days decreased by 2.5 + /- 2.9 days ( baseline 5.8 + /- 2.5 days ) in the acupuncture group compared to 2.2 + /- 2.7 days ( baseline 5.8 + /- 2.9 days ) in the metoprolol group ( P= .721 ) . The proportion of responders ( reduction of migraine attacks by > or = 50 % ) was 61 % for acupuncture and 49 % for metoprolol . Both physicians and patients reported fewer adverse effects in the acupuncture group . CONCLUSIONS Due to missing the recruitment target ( 480 patients ) and the high drop-out in the metoprolol group the results must be interpreted with caution . Still , they suggest that acupuncture might be an effective and safe treatment option for patients unwilling or unable to use drug prophylaxis [20506122] There is conflicting evidence on the efficacy of traditional Chinese acupuncture ( TCA ) , and the role of placebo effects elicited by acupuncturists ' behavior has not been eluci date d. We conducted a 3‐month r and omized clinical trial in patients with knee osteoarthritis to compare the efficacy of TCA with sham acupuncture and to examine the effects of acupuncturists ' communication styles [15606569] The objectives were to introduce a new method for controlled trials of acupuncture in the field of headache research and to examine the role of needling per se . Women with menstrually related migraine were r and omized to three months of treatment with verum or placebo needles . Three st and ard size casts were moulded to secure the placebo needles in the head . No significant differences were found between the verum group ( n = 15 ) and the placebo group ( n = 13 ) during treatment or follow up three and six months later , either in the attack frequency or in the number of days per month with migraine , headache intensity or drug-use . The casts held the needles exactly in place despite movements of the head , and are vali date d as practical , hygienic and extremely durable . This method is satisfactory for controlled studies of acupuncture in headache . It is possible that the positive results in earlier clinical trials on acupuncture in migraine are attributable to other mechanisms than needling of subcutaneous tissue [17908057] OBJECTIVES To examine the efficacy of periosteal stimulation therapy ( PST , osteopuncture ) for the treatment of chronic pain associated with advanced knee osteoarthritis . DESIGN R and omized , controlled clinical trial . SETTING Outpatient pain clinic . PARTICIPANTS Eighty-eight community-dwelling older adults with moderate knee pain or greater for 3 months or longer and Kellgren-Lawrence ( K-L ) grade 2 through 4 radiographic severity ( 80 % had K-L 4 ) . INTERVENTION Participants were r and omized to receive PST or control PST once a week for 6 weeks . MEASUREMENTS Pain severity and self-reported function ( Western Ontario and McMasters University Osteoarthritis Index ( WOMAC ) ) and physical performance ( Short Physical Performance Battery ( SPPB ) ) were assessed at baseline , after the last PST session ( post ) , and 3 months later ( follow-up ) . Pain severity was also assessed monthly using the multidimensional pain inventory short form . RESULTS Pain was reduced significantly more in the PST group than in the control PST group at post ( P=.003 ; mean WOMAC pain subscale baseline 9.4 vs 6.4 ) and 1 month later ( P<.001 ) , but by 2 months , pain levels had regressed to pre-intervention levels . The group-by-time interaction for the WOMAC function scale was significant at post ( P=.04 ) but not at follow-up ( P=.63 ) . No significant group differences were found for the SPPB . Neither analgesic use nor global improvement differed between groups . There were four treatment dropouts . CONCLUSION PST affords short-term modest pain reduction for older adults with advanced knee OA . Future research should test the effectiveness of booster treatments in sustaining analgesic benefits and of combining PST with therapeutic exercise in ameliorating disability risk [18160923] Aim To compare the efficacy of acupuncture needling and 0.5 % lidocaine injection of trigger points in myofascial pain syndrome of elderly patients . Methods Thirty nine participants with myofascial pain syndrome of one or both upper trapezius muscles were r and omised to treatment with either acupuncture needling ( n=18 ) or 0.5 % lidocaine injection ( n=21 ) at all the trigger points on days 0 , 7 and 14 , in a single-blinded study . Pain scores , range of neck movement , pressure pain intensity and depression were measured up to four weeks from the first treatment . Results Local twitch responses were elicited at least once in 94.9 % of all subjects . Both groups improved , but there was no significant difference in reduction of pain in the two groups at any time point up to one month . Overall , the range of cervical movement improved in both groups , apart from extension in the acupuncture needling group . Changes in depression showed only trends . Conclusion There was no significant difference between acupuncture needling and 0.5 % lidocaine injection of trigger points for treating myofascial pain syndrome in elderly patients [12048416] Objective The aim of the study was to compare the therapeutic effect of the superficial and in-depth insertion of acupuncture needles in the treatment of patients with chronic lumbar myofascial pain . Design A prospect i ve r and omized double-blind study of superficial and deep acupuncture was conducted . Setting The study was conducted in the Pain Service Unit of the University of Padova . Patients The study comprised 42 patients with lumbar myofascial pain who were divided into two equal groups ( A and B ) . InterventionIn group A , the needle was introduced in the skin at a depth of 2 mm , whereas in group B the needle was placed deeply into muscular tissue . The treatment was planned for a cycle of eight sessions . Outcome Measures The intensity of pain was evaluated with the McGill Pain Question naire before and after treatment and at the 3-month follow-up examination . Results Although at the end of the treatment there was no evidence of significant statistical differences between the two different groups , pain reduction was greater in the group treated with deep acupuncture . A statistical difference existed between the two groups at the 3-month follow up , with a better result in the deeply stimulated group . Conclusions Clinical results show that deep stimulation has a better analgesic effect when compared with superficial stimulation [14499023] OBJECTIVES To determine the effect of a series of electro-acupuncture ( EA ) treatment in conjunction with exercise on the pain , disability , and functional improvement scores of patients with chronic low-back pain ( LBP ) . DESIGN A blinded prospect i ve r and omized controlled study . SUBJECTS AND INTERVENTIONS A total of 52 patients were r and omly allocated to an exercise group ( n = 26 ) or an exercise plus EA group ( n = 26 ) and treated for 12 sessions . OUTCOME MEASURES Numerical Rating Scale ( NRS ) , Aberdeen LBP scale , lumbar spinal active range of movement ( AROM ) , and the isokinetic strength were assessed by a blinded observer . Repeated measures analysis of variance ( R-ANOVA ) with factors of group and time was used to compare the outcomes between the two groups at baseline ( before treatment ) , immediately after treatment , 1-month follow-up , and 3-month follow-up . The level of significance was set at p = 0.05 . RESULTS Significantly better scores in the NRS and Aberdeen LBP scale were found in the exercise plus EA group immediately after treatment and at 1-month follow-up . Higher scores were also seen at 3-month follow-up . No significant differences were observed in spinal AROM and isokinetic trunk concentric strength between the two groups at any stage of follow-up . CONCLUSIONS This study provides additional data on the potential role of EA in the treatment of LBP , and indicates that the combination of EA and back exercise might be an effective option in the treatment of pain and disability associated with chronic LBP [11783809] Objective The authors sought to determine whether a series of needle acupuncture treatments produced long-term relief of chronic low back pain . Design A blinded placebo-controlled study with an independent observer . The patients were r and omized to receive manual acupuncture , electroacupuncture , or active placebo ( mock transcutaneous electrical nerve stimulation ) . Subjects were examined and monitored by an investigator who was blinded to the treatment given . Setting A tertiary-level pain clinic at a Swedish university hospital . Patients Fifty consecutive patients ( 33 women , 17 men ; mean age , 49.8 years ) with chronic low back pain ( mean pain duration , 9.5 years ) and without rhizopathy or history of acupuncture treatment were included in the study . Interventions Treatments were given once per week for 8 weeks . Two further treatments were given during the follow-up assessment period of 6 months or longer . Outcome Measures The independent observer made a global assessment of the patients 1 , 3 , and 6 months after treatment . The patients kept pain diaries to score pain intensity twice daily , analgesic intake , and quality of sleep daily , and activity level weekly . Results At the 1-month independent assessment , 16 of 34 patients in the acupuncture groups and 2 of 16 patients in the placebo group showed improvement ( p < 0.05 ) . At the 6-month follow-up assessment , 14 of 34 patients in the acupuncture groups and 2 of 16 patients in the placebo group showed improvement ( p < 0.05 ) . A significant decrease in pain intensities occurred at 1 and 3 months in the acupuncture groups compared with the placebo group . There was a significant improvement in return to work , quality of sleep , and analgesic intake in subjects treated with acupuncture . Conclusions The authors found a long-term pain-relieving effect of needle acupuncture compared with true placebo in some patients with chronic nociceptive low back pain [11773673] This r and omised controlled trial was undertaken to evaluate the effectiveness of acupuncture as a treatment for frozen shoulder . Thirty-five patients with a diagnosis of frozen shoulder were r and omly allocated to an exercise group or an exercise plus acupuncture group and treated for a period of 6 weeks . Functional mobility , power , and pain were assessed by a blinded assessor using the Constant Shoulder Assessment , at baseline , 6 weeks and 20 weeks . Analysis was based on the intention-to-treat principle . Compared with the exercise group , the exercise plus acupuncture group experienced significantly greater improvement with treatment . Improvements in scores by 39.8 % ( st and ard deviation , 27.1 ) and 76.4 % ( 55.0 ) were seen for the exercise and the exercise plus acupuncture groups , respectively at 6 weeks ( P=0.048 ) , and were sustained at the 20-week re- assessment ( 40.3 % [ 26.7 ] and 77.2 % [ 54.0 ] , respectively ; P=0.025 ) . We conclude that the combination of acupuncture with shoulder exercise may offer effective treatment for frozen shoulder [15609842] Objective : To compare the effect of acupuncture with placebo transcutaneous electrical nerve stimulation ( TENS ) when added to the exercise treatment of rotator cuff tendinitis with respect to pain , shoulder movements and function . Design : Prospect i ve alternate allocation controlled trial . Setting : Outpatient department . Patients : Thirty-three patients ( 12 women and 21 men ) were included in the study . All had clinical ly diagnosed rotator cuff tendinitis . Intervention : Both groups underwent a st and ardized training programme . Each patient received in addition either 10 treatments with acupuncture or placebo TENS , 1 - 2 times per week . Main outcome measures : The parameters investigated were intensity of pain ( measured with visual analogue scale ) , active , passive as well as functional movements in the shoulder ( h and in neck ( HIN ) and pour out of a pot ( POP ) ) . Patients were tested before treatment , after treatment and at a six-month follow-up . Medicine intake , ability to lie on the affected side and sleep disturbances were evaluated . A subjective assessment was made after the treatment and at follow-up . Results : Sixteen patients had acupuncture , 17 placebo TENS . Eight patients endured pain at rest in the placebo TENS group , and 10 in the acupuncture group . After treatment both groups improved , the improvement persisted at the six-month follow-up . Both groups increased range of movement . Except for the functional test HIN in the acupuncture group , there were no differences between the groups regarding other parameters investigated directly after treatment or at six-month follow-up . Conclusion : There is no difference between the effect of additional acupuncture treatment and placebo TENS in the treatment of rotator cuff tendinitis [9825752] OBJECTIVE To evaluate the effectiveness of acupuncture , as compared with physiotherapy , in the management of chronic neck pain . DESIGN Seventy adult patients with non-inflammatory neck pain of > 6 weeks duration and with no abnormal neurology were r and omly assigned to receive either of the treatments . Thirty-five patients were included in each group . OUTCOME MEASURES Pain by visual analogue scale and neck pain question naire , improvement in range of movement of neck relative to baseline , and well-being ( general health question naire ) . Measurements were recorded at the start of treatment , at 6 weeks and at 6 months . RESULTS Both treatment groups improved in all criteria . Acupuncture was slightly more effective in patients who had higher baseline pain scores . CONCLUSIONS Both acupuncture and physiotherapy are effective forms of treatment . Since an untreated control group was not part of the study design , the magnitude of this improvement can not be quantified [769630] One half of 42 subjects treated for painful shoulders received classic acupuncture , and one half received a placebo in which the needles did not penetrate the skin . Half of each of these groups was treated in a positive setting to encourage the subject , and half in a negative setting design ed to keep encouragement at a minimum . All patients were independently rated for susceptibility to hypnosis . Although range of motion did not improve , the majority of patients reported significant improvement in shoulder discomfort to a blind evaluator after treatment ; placebo and acupuncture groups did not differ in this respect , however . The positive and negative setting s did not affect treatment outcome . In all groups , those who were not rated as highly susceptible to hypnosis tended to fail to achieve the highest levels of relief , but such differences were not statistically significant [17699546] Objective To investigate the benefit of adding acupuncture to a course of advice and exercise delivered by physiotherapists for pain reduction in patients with osteoarthritis of the knee . Design Multicentre , r and omised controlled trial . Setting 37 physiotherapy centres accepting primary care patients referred from general practitioners in the Midl and s , United Kingdom . Participants 352 adults aged 50 or more with a clinical diagnosis of knee osteoarthritis . Interventions Advice and exercise ( n=116 ) , advice and exercise plus true acupuncture ( n=117 ) , and advice and exercise plus non-penetrating acupuncture ( n=119 ) . Main outcome measures The primary outcome was change in scores on the Western Ontario and McMaster Universities osteoarthritis index pain subscale at six months . Secondary outcomes included function , pain intensity , and unpleasantness of pain at two weeks , six weeks , six months , and 12 months . Results Follow-up rate at six months was 94 % . The mean ( SD ) baseline pain score was 9.2 ( 3.8 ) . At six months mean reductions in pain were 2.28 ( 3.8 ) for advice and exercise , 2.32 ( 3.6 ) for advice and exercise plus true acupuncture , and 2.53 ( 4.2 ) for advice and exercise plus non-penetrating acupuncture . Mean differences in change scores between advice and exercise alone and each acupuncture group were 0.08 ( 95 % confidence interval −1.0 to 0.9 ) for advice and exercise plus true acupuncture and 0.25 ( −0.8 to 1.3 ) for advice and exercise plus non-penetrating acupuncture . Similar non-significant differences were seen at other follow-up points . Compared with advice and exercise alone there were small , statistically significant improvements in pain intensity and unpleasantness at two and six weeks for true acupuncture and at all follow-up points for non-penetrating acupuncture . Conclusion The addition of acupuncture to a course of advice and exercise for osteoarthritis of the knee delivered by physiotherapists provided no additional improvement in pain scores . Small benefits in pain intensity and unpleasantness were observed in both acupuncture groups , making it unlikely that this was due to acupuncture needling effects . Trial registration Current Controlled Trials IS RCT N88597683 [12406534] & NA ; This prospect i ve , r and omised controlled trial , with three parallel groups , patient and observer blinded for verum and sham acupuncture and a follow up of 3 months raises the question : “ Does a combination of acupuncture and conservative orthopedic treatment improve conservative orthopedic treatment in chronic low back pain ( LBP ) . 186 in‐ patients of a LBP rehabilitation center with a history of LBP ≥6 weeks , VAS ≥50 mm , and no pending compensation cl aims , were selected ; for the three r and om group 4 weeks of treatment was applied . 174 patients met the protocol criteria and reported after treatment , 124 reported after 3 months follow up . Patients were assorted 4 strata : chronic LBP , ≤0.5 years , 0.5–2 years , 2–5 years , ≥5 years . Analysis was by intention to treat . Group 1 ( Verum+COT ) recieved 12 treatments of verum acupuncture and conservative orthopedic treatment ( COT ) . Group 2 ( Sham+COT ) recieved 12 treatments of non‐specific needling and COT . Group 3 ( nil+COT ) recieved COT alone . Verum‐ and Sham acupuncture were blinded against patient and examiner . The primary endpoints were pain reduction ≥50 % on VAS 3 months after the end of the treatment protocol . Secondary endpoints were pain reduction ≥50 % on VAS and treatment efficacy on a four‐point box scale directly after the end of the treatment protocol and treatment efficacy after 3 months . In the whole sample a pain relief of ≥50 % on VAS was reported directly after the end of treatment protocol : Verum+COT 65 % ( 95%CI 51–77 % ) , Sham+COT 34 % ( 95%ci 22–49 % ) , nil+COT 43 % ( 95%ci 29–58 % ) – results are significant for Verum+COT over Sham+COT ( P≤0.02 ) . The results after 3 months are : Verum+COT 77 % ( 95%ci 62–88 % ) , Sham+COT 29 % ( 95%ci 16–46 % ) , nil+Cot 14 % ( 95%ci 4–30 % ) – effects are significant for Verum+COT over Sham+COT ( P≤0.001 ) and for Verum+COT over nil+COT ( P<0.001 ) . No difference was found in the mobility of the patients nor in the intake of NSAID diclofenac . Our conclusion is that acupuncture can be an important supplement of conservative orthopedic treatment in the management of chronic LBP [7053030] Thirty patients with cervical spine pain syndromes persisting a mean of 8 years were assigned r and omly into equal treatment and control groups . After 12 weeks , 12 of 15 ( 80 % ) of the treated group felt improved , some dramatically , with a mean 40 % reduction of pain score , 54 % reduction of pain pills , 68 % reduction of pain hours per day and 32 % less limitation of activity . Two of 15 ( 13 % ) of the control group reported slight improvement after 12.8 weeks . The control group had a mean 2 % worsening of the pain score , 10 % reduction in pain pills , no lessening of pain hours and 12 % less limitation of activity [10534595] Acupuncture has gained increasing attention in the treatment of chronic pain . The lack of a satisfying placebo method has made it impossible to show whether needling is an important part of the method or whether the improvement felt by the patient is due to the therapeutic setting and psychological phenomena . Also , the effectiveness of acupuncture has not been demonstrated sufficiently . We treated 52 sportsmen with rotator cuff tendinitis in a r and omised single-blind clinical trial using a new placebo-needle as control . Patients were treated for 4 weeks . The primary endpoint of the trial was the change in the modified Constant-Murley-score from the baseline . Assessment of the treatment outcome was made by experienced orthopaedists not informed of the treatment allocation . Acupuncture with penetration of the skin was shown to be more effective than a similar therapeutic setting with placebo needling in the treatment of pain . The acupuncture-group improved 19.2 Constant-Murley-score points ( SD 16.1 , range from -13 to 50 ) , the control-group improved 8.37 points ( SD 14.56 , range from -20 to 41 ) , ( P=0.014 ; C.I. 2.3;19.4 ) . This study showed that needling is an important part of the acupuncture effect in the treatment of chronic shoulder pain in athletes . No conclusions can be derived from this study concerning the importance of choosing points and the rules of Traditional Chinese Medicine . Using the new placebo method as control for other ailments could improve the evidence of specific acupuncture effects beyond pain treatment [15100594] Objectives : The aim of the study was to evaluate the therapeutic effect of electro-acupuncture ( EA ) and hydrotherapy , both in combination with patient education or with patient education alone , in the treatment of osteoarthritis in the hip . Methods : Forty-five patients , aged 42–86 years , with radiographic changes consistent with osteoarthritis in the hip , pain related to motion , pain on load , and ache were chosen . They were r and omly allocated to EA , hydrotherapy , both in combination with patient education , or patient education alone . Outcome measures were the disability rating index ( DRI ) , global self-rating index ( GSI ) , and visual analogue scale ( VAS ) . Assessment s were done before the intervention and immediately after the last treatment and 1 , 3 , and 6 months after the last treatment . Results : Pain related to motion and pain on load was reduced up to 3 months after last the treatment in the hydrotherapy group and up to 6 months in the EA group . Ache during the day was significantly improved in both the EA and hydrotherapy group up to 3 months after the last treatment . Ache during the night was reduced in the hydrotherapy group up to 3 months after the last treatment and in the EA group up to 6 months after . Disability in functional activities was improved in EA and hydrotherapy groups up to 6 months after the last treatment . Quality of life was also improved in EA and hydrotherapy groups up to 3 months after the last treatment . There were no changes in the education group alone . Discussion : In conclusion , EA and hydrotherapy , both in combination with patient education , induce long-lasting effects , shown by reduced pain and ache and by increased functional activity and quality of life , as demonstrated by differences in the pre- and post-treatment assessment Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: nan Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

27922724

[16304074] CONTEXT Lactation is associated with improved glucose and insulin homeostasis , independent of weight change . OBJECTIVE To evaluate the association between lactation history and incidence of type 2 diabetes . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve observational cohort study of 83,585 parous women in the Nurses ' Health Study ( NHS ) and retrospective observational cohort study of 73,418 parous women in the Nurses ' Health Study II ( NHS II ) . MAIN OUTCOME MEASURE Incident cases of type 2 diabetes mellitus . RESULTS In the NHS , 5145 cases of type 2 diabetes were diagnosed during 1,239,709 person-years of follow-up between 1986 and 2002 , and in the NHS II , 1132 cases were diagnosed during 778,876 person-years of follow-up between 1989 and 2001 . Among parous women , increasing duration of lactation was associated with a reduced risk of type 2 diabetes . For each additional year of lactation , women with a birth in the prior 15 years had a decrease in the risk of diabetes of 15 % ( 95 % confidence interval , 1%-27 % ) among NHS participants and of 14 % ( 95 % confidence interval , 7%-21 % ) among NHS II participants , controlling for current body mass index and other relevant risk factors for type 2 diabetes . CONCLUSIONS Longer duration of breastfeeding was associated with reduced incidence of type 2 diabetes in 2 large US cohorts of women . Lactation may reduce risk of type 2 diabetes in young and middle-aged women by improving glucose homeostasis [9543954] We evaluated the single and combined effects of introducing a motivational video and peer counseling into four matched WIC clinics on breastfeeding initiation and continuation at 7 - 10 days among African-American WIC participants . Of the 242 women with complete data , 48 % initiated breastfeeding , but only 31 % were still breastfeeding at 7 - 10 days . Initiation was associated with cesarean delivery , infant feeding instruction , no artificial milk discharge pack , attending the peer counselor only-intervention site , and intention to breastfeed . Continuation was influenced by infant feeding instruction , no artificial milk discharge pack , and intention to breastfeed . Overall , trends toward a positive impact of the breastfeeding promotion activities were evident but weak , and largely gone by 7 - 10 days postpartum [25193602] Background : Whereas breastfeeding initiation rates have risen in all groups throughout the country , rates of breastfeeding duration have changed more slowly . Peer counseling has had some success in sustaining breastfeeding , but with intensive programs and variable effects . Objectives : We aim ed to improve rates of any and exclusive breastfeeding at 1 and 6 months using a low-intensity peer counseling intervention beginning prenatally . We also planned to study the interaction of breastfeeding attitude and self-efficacy with the intervention . Methods : One hundred twenty prenatal women underwent stratified r and omization based on breastfeeding attitude , measured by the Iowa Infant Feeding Attitude Scale ( IIFAS ) . The peer counselor contacted the intervention group by telephone or in clinic up to 4 months postdelivery . Study groups were compared on breastfeeding outcomes , adjusting for IIFAS strata , and on interactions with self-efficacy . Results : One hundred three women were followed to at least 1 month . Women with positive attitudes had significantly higher rates of initiation ( 93 % vs 61 % ) and breastfeeding at 1 and 6 months ( 79 % vs 25 % and 12 % vs 0 % , respectively ) than those with negative attitudes , regardless of intervention . After adjusting for self-efficacy , women who received peer counseling had significantly higher breastfeeding rates at 1 month ( odds ratio = 3.2 ; 95 % confidence interval , 1.02 - 9.8 ) . The intervention group was marginally more likely to achieve their breastfeeding goal ( 43 % vs 22 % , P = .073 ) . Conclusion : Breastfeeding rates in all women improved during the study period . Breastfeeding attitude was more strongly associated with breastfeeding behavior than peer support . Peer counseling supported women with low self-efficacy and helped women achieve their breastfeeding goals [22018394] OBJECTIVE to assess the effect of an antenatal training programme on knowledge , self-efficacy and problems related to breast feeding and on breast-feeding duration . DESIGN a r and omised controlled trial . SETTING the Aarhus Midwifery Clinic , a large clinic connected to a Danish university hospital in an urban area of Denmark . PARTICIPANTS a total of 1193 nulliparous women were recruited before week 21 + 6 days of gestation , 603 were r and omised to the intervention group , and 590 to the reference group . INTERVENTION we compared a structured antenatal training programme attended in mid-pregnancy with usual practice . MEASUREMENTS data were collected through self-reported question naires sent to the women 's e-mail addresses and analysed according to the intention to treat principle . The primary outcomes were duration of full and any breast feeding collected 6 weeks post partum ( any ) and 1 year post partum ( full and any ) . FINDINGS no differences were found between groups according to duration of breast feeding , self-efficacy score , or breast-feeding problems , but after participation in the course in week 36 of gestation women in the intervention group reported a higher level of confidence ( p=0.05 ) , and 6 weeks after birth they reported to have obtained sufficient knowledge about breast feeding ( p=0.02 ) . Supplemental analysis in the intervention group revealed that women with sufficient knowledge breast fed significantly longer than women without sufficient knowledge ( HR=0.74 CI : 0.58 - 0.97 ) . This association was not found in the reference group ( HR=1.12 CI : 0.89 - 1.41 ) . KEY CONCLUSIONS AND IMPLICATION S FOR PRACTICE antenatal training can increase confidence of breast feeding in pregnancy and provide women with sufficient knowledge about breast feeding after birth . Antenatal training may therefore be an important low-technology health promotion tool that can be provided at low costs in most setting s. The antenatal training programme needs to be followed by postnatal breast-feeding support as it is not sufficient in itself to increase the duration of breast feeding or reduce breast-feeding problems [24812071] In northern Nigeria , interventions are urgently needed to narrow the large gap between international breastfeeding recommendations and actual breastfeeding practice s. Studies of integrated microcredit and community health interventions documented success in modifying health behaviors but typically had uncontrolled design s. We conducted a cluster-r and omized controlled trial in Bauchi State , Nigeria , with the aim of increasing early breastfeeding initiation and exclusive breastfeeding among female microcredit clients . The intervention had 3 components . Trained credit officers led monthly breastfeeding learning sessions during regularly scheduled microcredit meetings for 10 mo . Text and voice messages were sent out weekly to a cell phone provided to small groups of microcredit clients ( 5 - 7 women ) . The small groups prepared songs or dramas about the messages and presented them at the monthly microcredit meetings . The control arm continued with the regular microcredit program . R and omization occurred at the level of the monthly meeting groups . Pregnant clients were recruited at baseline and interviewed again when their infants were aged ≥6 mo . Logistic regression models accounting for clustering were used to estimate the odds of performing recommended behaviors . Among the clients who completed the final survey ( n = 390 ) , the odds of exclusive breastfeeding to 6 mo ( OR : 2.4 ; 95 % CI : 1.4 , 4.0 ) and timely breastfeeding initiation ( OR : 2.6 ; 95 % CI : 1.6 , 4.1 ) were increased in the intervention vs. control arm . Delayed introduction of water explained most of the increase in exclusive breastfeeding among clients receiving the intervention . In conclusion , a breastfeeding promotion intervention integrated into microcredit increased the likelihood that women adopted recommended breastfeeding practice s. This intervention could be scaled up in Nigeria , where local organizations provide microcredit to > 500,000 clients . Furthermore , the intervention could be adopted more widely given that > 150 million women , many of childbearing age , are involved in microfinance globally [15987851] Exclusive breast-feeding ( EBF ) rates remain low despite numerous health benefits associated with this behavior . We conducted a r and omized trial on the effect of lactation counseling on EBF , which controlled for the Hawthorne effect while also varying the timing of the intervention . Pregnant women attending prenatal clinics in Tema were r and omly assigned to 1 of 2 intervention groups ( IG ) or to a control group ( C ) , as follows : 1 ) EBF support given pre- , peri- , and postnatally ( IG1 ; n = 43 ) ; 2 ) EBF support given only peri- and postnatally ( IG2 ; n = 44 ) ; or 3 ) nonbreast-feeding health educational support ( C ; n = 49 ) that had an equal amount of contact with lactation counselors . Two educational sessions were provided prenatally , and 9 home follow-up visits were provided in the 6-mo postpartum period . Infant feeding data were collected monthly at the participant 's home . The 3 groups did not differ in sociodemographic characteristics . At 6 mo postpartum , 90.0 % in IG1 and 74.4 % in IG2 had exclusively breast-fed during the previous month . By contrast , only 47.7 % in C were doing so ( P = 0.008 ) . Similarly , the percentage of EBF during the 6 mo was significantly higher ( P = 0.02 ) among IG1 and IG2 ( 39.5 % ) than among C ( 19.6 % ) . The 100 % increase in EBF rates can be attributed to the lactation counseling provided . Additional prenatal EBF support may not be needed within a context of strong routine prenatal EBF education [17413108] BACKGROUND The World Health Organization recommends exclusive breastfeeding until age 6 mo . Studies relying on mothers ' self-reported behaviors have shown that lactation counseling increases both the rate and duration of exclusive breastfeeding . OBJECTIVE We aim ed to vali date reported infant feeding practice s in rural Bangladesh ; intakes of breast milk and nonbreast-milk water were measured by the dose-given-to-the mother deuterium dilution technique . DESIGN Subjects were drawn from the large-scale Maternal and Infant Nutrition Interventions , Matlab , study of combined interventions to improve maternal and infant health , in which women were r and omly assigned to receive either exclusive breastfeeding counseling or st and ard health care messages . Data on infant feeding practice s were collected by question naire at monthly visits . Intakes of breast milk and nonbreast-milk water were measured in a sub sample of 98 mother-infant pairs ( mean infant age : 14.3 wk ) and compared with question naire data reporting feeding practice s. RESULTS Seventy-five of the 98 subjects reported exclusive breastfeeding . Mean ( + /-SD ) breast milk intake was 884 + /- 163 mL/d in that group and 791 + /- 180 mL/d in the group reported as nonexclusively breastfed ( P = 0.0267 ) . Intakes of nonbreast-milk water were 40 + /- 80.6 and 166 + /- 214 mL/d ( P < 0.0001 ) , respectively . Objective cross-validation using deuterium dilution data showed good accuracy in reporting of feeding practice s , although apparent misreporting was widely present in both groups . CONCLUSIONS The dose-given-to-the-mother deuterium dilution technique can be applied to vali date reported feeding behaviors . Whereas this technique shows that the reports of feeding practice s were accurate at the group level , it is not adequate to distinguish between feeding practice s in individual infants [11120550] CONTEXT Promotion of breastfeeding in Brazilian maternity hospitals . OBJECTIVE To quantify changes in the breastfeeding duration among mothers served by hospitals exposed to the Wellstart-SLC course , comparing them with changes among mothers attended by institutions not exposed to this course . DESIGN R and omized Institutional Trial . SETTING The effects of training on breastfeeding duration was assessed in eight Brazilian hospitals assigned at r and om to either an exposed group ( staff attending the Wellstart-SLC course ) or a control group . SAMPLE For each of the eight study hospitals , two cohorts of about 50 children were visited at home at one and six months after birth . The first cohort ( n = 494 ) was composed of babies born in the month prior to exposure to the Wellstart-SLC course , and the second cohort ( n = 476 ) was composed of babies born six months subsequent to this exposure . MAIN MEASUREMENTS Kaplan-Meier curves were plotted to describe the weaning process and log-rank tests were used to assess statistical differences among survival curves . Hazard ratio ( HR ) estimates were calculated by fitting Cox proportional hazard regression models to the data . RESULTS The increases in estimated , adjusted rates for children born in hospitals with trained personnel were 29 % ( HR = 0.71 ) and 20 % ( HR = 0.80 ) for exclusive and full breastfeeding , respectively . No changes were identified for total breastfeeding . CONCLUSION This r and omized trial supports a growing body of evidence that training hospital health professionals in breastfeeding promotion and protection results in an increase in breastfeeding duration [9233202] The effect of prenatal breastfeeding education on breastfeeding incidence and duration was determined among 31 prenatal WIC participants . The subjects , assigned to a control group ( n= 17 ) or experimental group ( n= 14 ) , received prenatal nutrition education through the WIC program . The experimental group received at least one breastfeeding education class . There was no significant difference in breastfeeding incidence between the groups , however , there was a significant difference in breastfeeding incidence by parity ( p<0.05 ) . There was a significantly higher percentage of women still breastfeeding at 3 and 4 months postpartum in the experimental versus the control group ( p<0.05 ) . The control group breastfed for 29.5 + 43.6 days , while the experimental group breastfed for 76 days + 104.3 ( p=.05 ) . Multiparous women who had bottle-fed previous children breastfed for a shorter duration ( 18 + 22 days ) than primiparous women ( 60 87 days ) ( p<.07 ) [2636685] Objective To assess the effectiveness of an antenatal service using community based breastfeeding peer support workers on initiation of breast feeding . Design Cluster r and omised controlled trial . Setting Community antenatal clinics in one primary care trust in a multiethnic , deprived population . Participants 66 antenatal clinics with 2511 pregnant women : 33 clinics including 1140 women were r and omised to receive the peer support worker service and 33 clinics including 1371 women were r and omised to receive st and ard care . Intervention An antenatal peer support worker service planned to comprise a minimum of two contacts with women to provide advice , information , and support from approximately 24 weeks ’ gestation within the antenatal clinic or at home . The trained peer support workers were of similar ethnic and sociodemographic background s to their clinic population . Main outcome measure Initiation of breast feeding obtained from computerised maternity records of the hospitals where women from the primary care trust delivered . Results The sample was multiethnic , with only 9.4 % of women being white British , and 70 % were in the lowest 10th for deprivation . Most of the contacts with peer support workers took place in the antenatal clinics . Data on initiation of breast feeding were obtained for 2398 of 2511 ( 95.5 % ) women ( 1083/1140 intervention and 1315/1371 controls ) . The groups did not differ for initiation of breast feeding : 69.0 % ( 747/1083 ) in the intervention group and 68.1 % ( 896/1315 ) in the control groups ; cluster adjusted odds ratio 1.11 ( 95 % confidence interval 0.87 to 1.43 ) . Ethnicity , parity , and mode of delivery independently predicted initiation of breast feeding , but r and omisation to the peer support worker service did not . Conclusion A universal service for initiation of breast feeding using peer support workers provided within antenatal clinics serving a multiethnic , deprived population was ineffective in increasing initiation rates . Trial registration Current Controlled Trials IS RCT N16126175 [201032] Background It has proven difficult to reach World Health Organization ( WHO ) recommendations that infants be exclusively breastfed from birth to six months of age [ 1 , 2 ] , yet there is limited knowledge about interventions that are effective in increasing breastfeeding initiation and duration . Particularly lacking is evidence about how to maintain breastfeeding rates in countries which already have a high initiation of breastfeeding . This study aims to determine whether mid-pregnancy breastfeeding education , with a focus on either attitudes to breastfeeding or on technical aspects of breastfeeding , has an effect on rates of breastfeeding initiation and duration . Secondary aims of the study are to : explore what factors might affect the duration of breastfeeding and evaluate the interventions from the participant and childbirth facilitator perspectives . Methods / Design A r and omised controlled trial ( RCT ) design will be used . Women having their first baby , and planning to give birth as public patients at the Royal Women 's Hospital ( RWH ) , Melbourne , will be approached at 18–20 weeks of pregnancy and invited to participate in the study . Participants will be r and omly allocated to a control group or one of two group interventions : a previously design ed and trialled tool to teach practical aspects of breastfeeding or an exploration of family attitudes to breastfeeding . The latter was developed and piloted by the investigators in conjunction with the group facilitators , prior to trial commencement . The interventions are planned to take place at 20–25 weeks . Data will be collected by question naire at recruitment , at interview in hospital after the birth and by telephone interview six months later . Medical/obstetric outcomes will be obtained from the medical record . The sample size ( 972 ) was calculated to identify an increase in breastfeeding initiation from 75 to 85 % and an increase from 40 to 50 % in breastfeeding at six months [23209111] OBJECTIVE : To evaluate a specialized breastfeeding peer counseling ( SBFPC ) intervention promoting exclusive breastfeeding ( EBF ) among overweight/obese , low-income women . METHODS : We recruited 206 pregnant , overweight/obese , low-income women and r and omly assigned them to receive SBFPC or st and ard care ( controls ) at a Baby-Friendly hospital . SBFPC included 3 prenatal visits , daily in-hospital support , and up to 11 postpartum home visits promoting EBF and addressing potential obesity-related breastfeeding barriers . St and ard care involved routine access to breastfeeding support from hospital personnel , including staff peer counselors . Data collection included an in-hospital interview , medical record review , and monthly telephone calls through 6 months postpartum to assess infant feeding practice s , demographics , and health outcomes . Bivariate and logistic regression analyses were conducted . RESULTS : The intervention had no impact on EBF or breastfeeding continuation at 1 , 3 , or 6 months postpartum . In adjusted posthoc analyses , at 2 weeks postpartum the intervention group had significantly greater odds of continuing any breastfeeding ( adjusted odds ratio [ aOR ] : 3.76 [ 95 % confidence interval ( CI ) : 1.07–13.22 ] ) , and giving at least 50 % of feedings as breast milk ( aOR : 4.47 [ 95 % CI : 1.38–14.5 ] ) , compared with controls . Infants in the intervention group had significantly lower odds of hospitalization during the first 6 months after birth ( aOR : 0.24 [ 95 % CI : 0.07–0.86 ] ) . CONCLUSIONS : In a Baby-Friendly hospital setting , SBFPC targeting overweight/obese women did not impact EBF practice s but was associated with increased rates of any breastfeeding and breastfeeding intensity at 2 weeks postpartum and decreased rates of infant hospitalization in the first 6 months after birth [16958717] OBJECTIVE To determine the effects of a prenatal breastfeeding workshop on maternal breastfeeding self-efficacy and breastfeeding duration . DESIGN R and omized controlled trial . SETTING Large tertiary hospital in Ontario , Canada . PARTICIPANTS 110 primiparous women expecting a single child , an uncomplicated birth , and planning to breastfeed . INTERVENTION 2.5-hour prenatal breastfeeding workshop based on adult learning principles and self-efficacy theory . MAIN OUTCOME MEASURE Maternal breastfeeding self-efficacy and the numbers of days and amount of breastfeeding were measured at four and eight weeks postpartum . RESULTS / DATA ANALYSIS : Over time , maternal breastfeeding self-efficacy scores increased in both groups . Women who attended the workshop had higher self-efficacy scores and a higher proportion were exclusively breastfeeding compared to women who did not attend the workshop . There was little difference in the average number of days of breastfeeding , but the intervention group had less weaning . CONCLUSIONS The workshop increased maternal breastfeeding self-efficacy and exclusive breastfeeding [24187119] OBJECTIVES : Despite recent efforts to increase breastfeeding , young African American mothers continue to breastfeed at low rates , and commonly introduce complementary foods earlier than recommended . This study examines the effects of a community doula home visiting intervention on infant feeding practice s among young mothers . METHODS : Low-income , African American mothers ( n = 248 ) under age 22 years participated in a r and omized trial of a community doula intervention . Intervention-group mothers received services from paraprofessional doulas : specialized home visitors trained as childbirth educators and lactation counselors . Doulas provided home visits from pregnancy through 3 months postpartum , and support during childbirth . Control-group mothers received usual prenatal care . Data were obtained from medical records and maternal interviews at birth and 4 months postpartum . RESULTS : Intent-to-treat analyses showed that doula-group mothers attempted breastfeeding at a higher rate than control-group mothers ( 64 % vs 50 % ; P = .02 ) and were more likely to breastfeed longer than 6 weeks ( 29 % vs 17 % ; P = .04 ) , although few mothers still breastfed at 4 months . The intervention also impacted mothers ’ cereal/solid food introduction ( P = .008 ) : fewer doula-group mothers introduced complementary foods before 6 weeks of age ( 6 % vs 18 % ) , while more waited until at least 4 months ( 21 % vs 13 % ) compared with control-group mothers . CONCLUSIONS : Community doulas may be effective in helping young mothers meet breastfeeding and healthy feeding guidelines . The intervention ’s success may lie in the relationship that develops between doula and mother based on shared cultural background and months of prenatal home visiting , and the doula ’s presence at the birth , where she supports early breastfeeding experiences [1635041] Background Despite high levels of breastfeeding initiation in Australia , only 47 percent of women are breastfeeding ( exclusively or partially ) six months later , with marked differences between social groups . It is important to identify women who are at increased risk of early cessation of breastfeeding . Methods Data from the three arms of a r and omised controlled trial were pooled and analysed as a cohort using logistic regression to identify which factors predicted women continuing to feed any breast milk at six months postpartum . The original trial included 981 primiparous women attending a public , tertiary , women 's hospital in Melbourne , Australia in 1999–2001 . The trial evaluated the effect of two mid-pregnancy educational interventions on breastfeeding initiation and duration . In the 889 women with six month outcomes available , neither intervention increased breastfeeding initiation nor duration compared to st and ard care . Independent variables were included in the predictive model based on the literature and discussion with peers and were each tested individually against the dependent variable ( any breastfeeding at six months ) . Results Thirty-three independent variables of interest were identified , of which 25 qualified for inclusion in the preliminary regression model ; 764 observations had complete data available . Factors remaining in the final model that were positively associated with breastfeeding any breast milk at six months were : a very strong desire to breastfeed ; having been breastfed oneself as a baby ; being born in an Asian country ; and older maternal age . There was an increasing association with increasing age . Factors negatively associated with feeding any breast milk at six months were : a woman having no intention to breastfeed six months or more ; smoking 20 or more cigarettes per day pre-pregnancy ; not attending childbirth education ; maternal obesity ; having self-reported depression in the six months after birth ; and the baby receiving infant formula while in hospital . Conclusion In addition to the factors commonly reported as being associated with breastfeeding in previous work , this study found a negative association between breastfeeding outcomes and giving babies infant formula in hospital , a high maternal body mass index , and self-reported maternal depression or anxiety in the six months after the baby was born . Interventions that seek to increase breastfeeding should consider focusing on women who wish to breastfeed but are at high risk of early discontinuation [4587817] Background Interventions promoting optimal infant and young child nutrition could prevent a fifth of under-5 deaths in countries with high mortality . Poor infant and young child feeding practice s are widely documented in Kenya , with potential detrimental effects on child growth , health and survival . Effective strategies to improve these practice s are needed . This study aims to pilot implementation of the Baby Friendly Community Initiative ( BFCI ) , a global initiative aim ed at promoting optimal infant and young child feeding practice s , to determine its feasibility and effectiveness with regards to infant feeding practice s , nutrition and health outcomes in a rural setting in Kenya . Methods The study , employing a cluster-r and omized trial design , will be conducted in rural Kenya . A total of 12 clusters , constituting community units within the government ’s Community Health Strategy , will be r and omized , with half allocated to the intervention and the other half to the control arm . A total of 812 pregnant women and their respective children will be recruited into the study . The mother-child pairs will be followed up until the child is 6 months old . Recruitment will last approximately 1 year from January 2015 , and the study will run for 3 years , from 2014 to 2016 . The intervention will involve regular counseling and support of mothers by trained community health workers and health professionals on maternal , infant and young child nutrition . Regular assessment of knowledge , attitudes and practice s on maternal , infant and young child nutrition will be done , coupled with assessment of nutritional status of the mother-child pairs and morbidity for the children . Statistical methods will include analysis of covariance , multinomial logistic regression and multilevel modeling . The study is funded by the NIH and USAID through the Program for Enhanced Research ( PEER ) Health . Discussion Findings from the study outlined in this protocol will inform potential feasibility and effectiveness of a community-based intervention aim ed at promoting optimal breastfeeding and other infant feeding practice s. The intervention , if proved feasible and effective , will inform policy and practice in Kenya and similar setting s , particularly regarding implementation of the baby friendly community initiative . Trial registration IS RCT N03467700 ; Date of Registration : 24 September [19454915] OBJECTIVE To evaluate the efficacy of a paraprofessional-delivered , home-visiting intervention among young , reservation-based American Indian ( AI ) mothers on parenting knowledge , involvement , and maternal and infant outcomes . METHOD From 2002 to 2004 , expectant AI women aged 12 to 22 years ( n = 167 ) were r and omized ( 1:1 ) to one of two paraprofessional-delivered , home-visiting interventions : the 25-visit " Family Spirit " intervention addressing prenatal and newborn care and maternal life skills ( treatment ) or a 23-visit breast-feeding/nutrition education intervention ( active control ) . The interventions began during pregnancy and continued to 6 months postpartum . Mothers and children were evaluated at baseline and 2 , 6 , and 12 months postpartum . Primary outcomes included changes in mothers ' parenting knowledge and involvement . Secondary outcomes included infants ' social and emotional behavior ; the home environment ; and mothers ' stress , social support , depression , and substance use . RESULTS Participants were mostly teenaged , first-time , unmarried mothers living in reservation communities . At 6 and 12 months postpartum , treatment mothers compared with control mothers had greater parenting knowledge gains , 13.5 ( p < .0001 ) and 13.9 ( p < .0001 ) points higher , respectively ( 100-point scale ) . At 12 months postpartum , treatment mothers reported their infants to have significantly lower scores on the externalizing domain ( beta = -.17 , p < .05 ) and less separation distress in the internalizing domain ( beta = -.17 , p < .05 ) . No between-group differences were found for maternal involvement , home environment , or mothers ' stress , social support , depression , or substance use . CONCLUSIONS This study supports the efficacy of the paraprofessional-delivered Family Spirit home-visiting intervention for young AI mothers on maternal knowledge and infant behavior outcomes . A longer , larger study is needed to replicate results and evaluate the durability of child behavior outcomes [9310540] OBJECTIVE We followed a cohort ( N = 306 ) of infants at well-baby visits in two suburban pediatric practice s to assess the relation of exclusive breastfeeding , and other environmental exposures , to episodes of acute otitis media ( AOM ) and otitis media with effusion ( OME ) . METHODS Detailed prospect i ve information about the exclusiveness of breastfeeding , parental smoking , day care attendance , and family history was obtained at scheduled clinic visits . Tympanometric and otoscopic examinations were used in the diagnosis of otitis media ( OM ) . Nasopharyngeal cultures were performed at 1 - 6 months , and at 8 , 10 , 12 , 15 , 18 , and 24 months of age to detect colonization with middle-ear pathogens . RESULTS Between 6 and 12 months of age , cumulative incidence of first OM episodes increased from 25 % to 51 % in infants exclusively breastfed and from 54 % to 76 % in infants formula-fed from birth . Peak incidence of AOM and OME episodes was inversely related to rates of breastfeeding beyond 3 months of age . A twofold elevated risk of first episodes of AOM or OME was observed in exclusively formula-fed infants compared with infants exclusively breast-fed for 6 months . In the logistic regression analysis , formula-feeding was the most significant predictor of AOM and OME episodes , although age at colonization with middle-ear pathogens and day care ( outside the home ) were significant competing risk factors . A hazard health model suggested additionally that breastfeeding , even for short duration s ( 3 months ) , reduced onset of OM episodes in infancy . CONCLUSIONS Modifiable factors in the onset of AOM and OME episodes during the first 2 years of life include early age at colonization ( < /=3 months of age ) , day care outside the home , and not being breastfed [21787375] We sought to assess the relationship between acculturative type and breastfeeding outcomes among low-income Latinas , utilising a multidimensional assessment of acculturation . We analysed data derived from a breastfeeding peer counselling r and omised trial . Acculturation was assessed during pregnancy using a modified Acculturation Rating Scale for Mexican Americans scale . Analyses were restricted to Latinas who completed the acculturation scale and had post-partum breastfeeding data ( n = 114 ) . Cox survival analyses were conducted to evaluate differences in breastfeeding continuation and exclusivity by acculturative type . Participants were classified as integrated-high ( 23.7 % , n = 27 ) , traditional Hispanic ( 36.8 % , n = 42 ) , integrated-low ( 12.3 % , n = 14 ) and assimilated ( 27.2 % , n = 31 ) . The integrated-low group was significantly more likely to continue breastfeeding than the traditional Hispanic , assimilated , and integrated-high groups ( P < 0.05 , P < 0.05 , and P < 0.01 , respectively ) . The traditional Hispanic group was marginally more likely to continue breastfeeding than the integrated-high group ( P = 0.06 ) . Breastfeeding continuation rates vary significantly between acculturative types in this multinational , low-income Latina sample . Multidimensional assessment s of acculturation may prove useful in better tailoring future breastfeeding promotion interventions [4522088] Background Very few Australian infants are exclusively breastfed to 6 months as recommended by the World Health Organization . There is strong empirical evidence that fathers have a major impact on their partner ’s decision to breastfeed and continuation of breastfeeding . Fathers want to participate in the breastfeeding decision making process and to know how they can support their partner to achieve their breastfeeding goals . The aim of the Parent Infant Feeding Initiative ( PIFI ) is to evaluate the effect on duration of any and exclusive breastfeeding of three breastfeeding promotion interventions of differing intensity and duration , targeted at couples but channelled through the male partner . The study will also undertake a cost-effectiveness evaluation of the interventions . Methods / design The PIFI study is a factorial r and omised controlled trial . Participants will be mothers and their male partners attending antenatal classes at selected public and private hospitals with maternity departments in Perth , Western Australia . Fathers will be r and omly allocated to either the usual care control group ( CG ) , one of two medium intensity ( MI1 and MI2 ) interventions , or a high intensity ( HI ) intervention . MI1 will include a specialised antenatal breastfeeding education session for fathers with supporting print material s. MI2 will involve the delivery of an antenatal and postnatal social support intervention delivered via a smartphone application and HI will include both the specialised antenatal class and the social support intervention . Outcome data will be collected from couples at baseline and at six and 26 weeks postnatally . A total of 1600 couples will be recruited . This takes into account a 25 % attrition rate , and will detect at least a 10 % difference in the proportion of mothers breastfeeding between any two of the groups at 26 weeks at 80 % power and 5 % level of significance , using a Log-rank survival test . Multivariable survival and logistic regression analyses will be used to assess the effect of the treatment groups on the outcomes after adjusting for covariates . Discussion The PIFI study will be the first Australian study to provide Level II evidence of the impact on breastfeeding duration of a comprehensive , multi-level , male-partner-focused breastfeeding intervention . Unique features of the intervention include its large sample size , delivery of two of the interventions by mobile device technology , a rigorous assessment of intervention fidelity and a cost-effectiveness evaluation . Trial registration Australian New Zeal and Clinical Trials Registry ACTRN12614000605695 . Registered 6 June [8568022] This study was undertaken to determine the effects of a partner-support , incentive-baed educational program on breast feeding knowledge , attitudes and support and to examine the relationship between feeding intentions and feeding behavior among low-income women . Women who expressed a willingness to participate in the intervention were r and omly assigned to “ intervention ” and “ usual breast feeding ” ( control ) groups . Sixty-eight primipara women , with expected due date s between May and December , 1992 , volunteered to participate in the study . Of these , 34 were r and omly assigned to each of the two groups . Approximately 81 percent of the women completed the study , leaving n=29 in the control group and n-26 in the intervention group . The intervention consisted of special incentives ( prizes ) for women and their partners to participate in several breast feeding education and promotion activities . Intervention group women and their partners experienced positive changes in breast feeding knowledge and attitudes . Furthermore , the intervention seemed to have influenced more women in the treatment group to breast feed despite their prenatal feeding intentions . In addition , the partners of intervention group women were perceived to be more supportive of , breast feeding than control group partners . These findings suggest that incentives , such as donated prizes , can be used to attract lower socioeconomic group women and their partners to breast feeding promotion interventions . Participation in such interventions can produce positive changes in breast feeding knowledge , attitudes , and support , and can have a dramatic effect in promoting breast feeding [3879433] Background Nutrition in the first 1,000 days of life ( during pregnancy and the first two years ) is critical for child growth and survival . Poor maternal , infant and young child nutrition ( MIYCN ) practice s are widely documented in Kenya , with potential detrimental effects on child growth and survival . This is particularly a problem in slums , where most urban residents live . For example , exclusive breastfeeding for the first six months is only about two per cent . Innovative strategies to reach slum residents are therefore needed . Strategies like the Baby Friendly Hospital Initiative have proven effective in some setting s but their effectiveness in re source -limited setting s , including slums where many women do not deliver in hospital , is question able . We propose to test the effectiveness of a home-based intervention on infant feeding practice s , nutrition and health outcomes of infants born in two slums in Nairobi , Kenya . Methods / Design The study , employing a cluster-r and omised study design , will be conducted in two slums in Nairobi : Korogocho and Viw and ani where 14 community units ( defined by the Government ’s health care system ) will form the unit of r and omization . A total of 780 pregnant women and their respective child will be recruited into the study . The mother-child pair will be followed up until the child is one year old . Recruitment will last approximately one year and three months from September 2012 to December 2013 . The mothers will receive regular , personalised , home-based counselling by trained Community Health Workers on MIYCN . Regular assessment of knowledge , attitudes and practice s on MIYCN will be done , coupled with assessment s of nutritional status of the mother-child pairs and diarrhea morbidity for the children . Statistical methods will include analysis of covariance and multinomial logistic regression . Additionally , cost-effectiveness analysis will be done . The study is funded by the Wellcome Trust and will run from March 2012 to February 2015 . Discussion Interventions aim ed at promoting optimal breastfeeding and complementary feeding practice s are considered to have high impact and could prevent a fifth of the under-five deaths in countries with high mortality rates . This study will inform policy and practice in Kenya and similar setting s regarding delivery mechanisms for such high-impact interventions , particularly among urban poor population s . Trial registration IS RCT [14703543] Abstract Objective To investigate whether offering volunteer support from counsellors in breast feeding would result in more women breast feeding . Design R and omised controlled trial . Setting 32 general practice s in London and south Essex . Participants 720 women considering breast feeding . Main outcome measures Primary outcome was prevalence of any breast feeding at six weeks . Secondary outcomes were the proportion of women giving any breast feeds , or bottle feeds at four months , duration of any breast feeding , time to introduction of bottle feeds , and satisfaction with breast feeding . Results Offering support in breast feeding did not significantly increase the prevalence of any breast feeding to six weeks ( 65 % ( 218/336 ) in the intervention group and 63 % ( 213/336 ) in the control group ; relative risk 1.02 , 95 % confidence interval 0.84 to 1.24 ) . Survival analysis up to four months confirmed that neither duration of breast feeding nor time to introduction of formula feeds differed significantly between control and intervention groups . Not all women in the intervention group contacted counsellors postnatally , but 73 % ( 123/179 ) of those who did rated them as very helpful . More women in the intervention group than in the control group said that their most helpful advice came from counsellors rather than from other sources . Conclusions Women valued the support of a counsellor in breast feeding , but the intervention did not significantly increase breastfeeding rates , perhaps because some women did not ask for help [17088511] OBJECTIVE To assess the impact of a paraprofessional-delivered home-visiting intervention to promote child care knowledge , skills , and involvement among pregnant American Indian adolescents . DESIGN R and omized controlled trial comparing a family-strengthening intervention with a breastfeeding education program . SETTING One Apache and 3 Navajo communities . PARTICIPANTS Fifty-three pregnant American Indian adolescents were r and omly assigned to intervention ( n = 28 ) or control ( n = 25 ) groups . Follow-up data were available for 19 intervention and 22 control participants . Intervention Paraprofessionals delivered 41 prenatal and infant care lessons in participants ' homes from 28 weeks ' gestation to 6 months post partum . MAIN OUTCOME MEASURES Child care knowledge , skills , and involvement . RESULTS Mothers in the intervention compared with the control group had significantly higher parent knowledge scores at 2 months ( adjusted mean difference [ AMD ] , + 14.9 [ 95 % confidence interval ( CI ) , + 7.5 to + 22.4 ] ) and 6 months post partum ( AMD , + 15.3 [ 95 % CI , + 5.9 to + 24.7 ] ) . Intervention group mothers scored significantly higher on maternal involvement scales at 2 months post partum ( AMD , + 1.5 [ 95 % CI , -0.02 to + 3.02 ] ) , and scores approached significance at 6 months post partum ( AMD , + 1.1 [ 95 % CI , -0.06 to + 2.2 ] ) . No between-group differences were found for child care skills . CONCLUSIONS A paraprofessional-delivered , family-strengthening home-visiting program significantly increased mothers ' child care knowledge and involvement . A longer and larger trial is needed to underst and the intervention 's potential to improve adolescent parenting and related child outcomes in American Indian communities [23039968] OBJECTIVE To determine the impact of facility-based semi-intensive and home-based intensive counselling in improving exclusive breast-feeding ( EBF ) in a low-re source urban setting in Kenya . DESIGN A cluster r and omized controlled trial in which nine villages were assigned on a 1:1:1 ratio , by computer , to two intervention groups and a control group . The home-based intensive counselling group ( HBICG ) received seven counselling sessions at home by trained peers , one prenatally and six postnatally . The facility-based semi-intensive counselling group ( FBSICG ) received only one counselling session prenatally . The control group ( CG ) received no counselling from the research team . Information on infant feeding practice s was collected monthly for 6 months after delivery . The data -gathering team was blinded to the intervention allocation . The outcome was EBF prevalence at 6 months . SETTING Kibera slum , Nairobi . SUBJECTS A total of 360 HIV-negative women , 34 - 36 weeks pregnant , were selected from an antenatal clinic in Kibera ; 120 per study group . RESULTS Of the 360 women enrolled , 265 completed the study and were included in the analysis ( CG n 89 ; FBSICG n 87 ; HBICG n 89 ) . Analysis was by intention to treat . The prevalence of EBF at 6 months was 23.6 % in HBICG , 9.2 % in FBSICG and 5.6 % in CG . HBICG mothers had four times increased likelihood to practise EBF compared with those in the CG ( adjusted relative risk = 4.01 ; 95 % CI 2.30 , 7.01 ; P=0.001 ) . There was no significant difference between EBF rates in FBSICG and CG . CONCLUSIONS EBF can be promoted in low socio-economic conditions using home-based intensive counselling . One session of facility-based counselling is not sufficient to sustain EBF [7554017] Assessed is a breast-feeding training course that was attended by health professionals at the Santos Lactation Center ( SLC ) , Santos , São Paulo , Brazil , as well as its impact on the implementation of breast-feeding programmes in maternity hospitals . Eight maternity hospitals were studied -- four were r and omly allocated to the experimental group and sent three health professionals to attend an 18-day course at SLC ; the remaining four institutions constituted the control group . The compliance of all eight hospitals with WHO/UNICEF 's " Ten steps for successful breast-feeding " was determined using scores obtained before and 6 months after the training course . Institutions in the experimental group had an improved score , but those in the control group did not . The SLC training course was efficient since it enabled the participants to promote breast-feeding practice s. However , in order to succeed in implementing breast-feeding programmes , health professionals require also to develop skills to apply the knowledge they acquire in the course , as well as to involve the whole maternity unit team in the activities [16143742] OBJECTIVE To assess the efficacy of peer counseling to promote exclusive breastfeeding ( EBF ) among low-income inner-city women in Hartford , Conn. DESIGN Participants recruited prenatally were r and omly assigned to either receive support for EBF from a peer counselor plus conventional breastfeeding support ( peer counseling group [ PC ] ) or only conventional breastfeeding support ( control group [ CG ] ) and followed through 3 months post partum . SETTING Low-income predominantly Latina community . PARTICIPANTS Expectant mothers , less than 32 weeks gestation and considering breastfeeding ( N = 162 ) . Intervention Exclusive breastfeeding peer counseling support offering 3 prenatal home visits , daily perinatal visits , 9 postpartum home visits , and telephone counseling as needed . MAIN OUTCOME MEASURES Exclusive breastfeeding rates at hospital discharge , 1 , 2 , and 3 months post partum ( n = 135 ) . RESULTS At hospital discharge , 24 % in the CG compared with 9 % in the PC had not initiated breastfeeding , with 56 % and 41 % , respectively , nonexclusively breastfeeding . At 3 months , 97 % in the CG and 73 % in the PC had not exclusively breastfed ( relative risk [ RR ] = 1.33 ; 95 % CI , 1.14 - 1.56 ) during the previous 24 hours . The likelihood of nonexclusive breastfeeding throughout the first 3 months was significantly higher for the CG than the PC ( 99 % vs 79 % ; RR = 1.24 ; 95 % CI , 1.09 - 1.41 ) . Mothers in the CG were less likely than their PC counterparts to remain amenorrheic at 3 months ( 33 % vs 52 % ; RR = 0.64 ; 95 % CI , 0.43 - 0.95 ) . The likelihood of having 1 or more diarrheal episode in infants was cut in half in the PC ( 18 % vs 38 % ; RR = 2.15 ; 95 % CI , 1.16 - 3.97 ) . CONCLUSION Well-structured , intensive breastfeeding support provided by hospital and community-based peer counselors is effective in improving exclusive breastfeeding rates among low-income , inner-city women in the United States [25437725] OBJECTIVE : To evaluate the effectiveness of a professional one-to-one antenatal breastfeeding support and education intervention on the exclusivity and duration of breastfeeding . METHODS : A total of 469 primiparous women who attended the antenatal clinics of two geographically distributed public hospitals in Hong Kong were r and omized to receive either st and ard antenatal care or a one-to-one antenatal breastfeeding support and education session . The primary outcome was the prevalence of exclusive breastfeeding at 6 weeks postpartum . Secondary outcomes were the prevalence of exclusive breastfeeding at 3 and 6 months postpartum as well as the overall duration of any and exclusive breastfeeding across the first 6 months postpartum . RESULTS : The exclusive breastfeeding rate in the intervention group was 37.8 % at 6 weeks postpartum compared with 36.4 % in the st and ard care group ( P=.77 ; 95 % confidence interval [ CI ] −0.08 to 0.11 ) . There were no significant differences between the two treatment groups in exclusive breastfeeding rates at 3 and 6 months or in the overall duration of any ( hazard ratio [ HR ] 1.11 , 95 % CI 0.88–1.40 ] or exclusive breastfeeding ( HR 0.96 , 95 % CI 0.79–1.17 ) . The study had a least 80 % power to detect a 50 % increase in the rate of exclusive breastfeeding at 6 weeks postpartum . CONCLUSION : In a setting with a high breastfeeding initiation rate , one-to-one antenatal breastfeeding support and education did not increase the exclusivity or duration of breastfeeding . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT01648114 . LEVEL OF EVIDENCE : [16045516] Objective To evaluate the affect of an antenatal educational breastfeeding intervention on women 's breastfeeding duration [15351756] BACKGROUND Breastfeeding peer counseling has improved breastfeeding rates in developing countries ; however , its impact in this country has not been adequately evaluated . OBJECTIVE To evaluate the effectiveness of an existing , breastfeeding peer counseling program within the United States . DESIGN R and omized , prospect i ve , controlled trial in which participants were recruited prenatally and r and omly assigned to receive either routine breastfeeding education or routine breastfeeding education plus peer counseling . SETTING An urban hospital serving a large population of low-income Latinas . PARTICIPANTS Pregnant women ( < or = 26 weeks ' gestation ) were recruited from the hospital 's prenatal clinic . Inclusion criteria specified that participants be low income , be considering breastfeeding , have delivered a healthy , full-term singleton , and have access to a telephone . Intervention Breastfeeding peer counseling services included 1 prenatal home visit , daily perinatal visits , 3 postpartum home visits , and telephone contact as needed . MAIN OUTCOME MEASURES Breastfeeding rates at birth and 1 , 3 , and 6 months postpartum . RESULTS The proportion not initiating breastfeeding was significantly lower in the intervention group than among controls ( 8/90 [ 9 % ] vs 17/75 [ 23 % ] ; relative risk , 0.39 ; 95 % confidence interval , 0.18 - 0.86 ) . The probability of stopping breastfeeding also tended to be lower in the intervention group at both 1 month ( 36 % vs 49 % ; relative risk , 0.72 ; 95 % confidence interval , 0.50 - 1.05 ) and 3 months ( 56 % vs 71 % ; relative risk , 0.78 ; 95 % confidence interval , 0.61 - 1.00 ) . CONCLUSION These findings demonstrate that , in the United States , peer counselors can significantly improve breastfeeding initiation rates and have an impact on breastfeeding rates at 1 and 3 months post partum [23329167] Mothers need consistent , sustained information and support to develop and meet personal breastfeeding goals , but often receive insufficient assistance and conflicting and incorrect advice . The use of technology may be helpful in supplementing existing health care professional breastfeeding education and support efforts . We developed and evaluated a computer-based animated , interactive agent design ed to provide breastfeeding information and support to mothers interested in breastfeeding . A r and omized controlled study of a first-generation system was conducted to determine the feasibility of ( 1 ) use of the Computer Agent ; ( 2 ) the recruitment plan ; and ( 3 ) the planned outcome evaluation ( assessing the impact of the intervention on intent to breastfeed , attitudes towards breastfeeding , and breastfeeding self-efficacy ) . The pilot study ( N = 15 ) showed that the use of the Computer Agent , the recruitment plan , and the planned outcome evaluation were all feasible . Mothers who used the Computer Agent had greater intentions to exclusively breastfeed after exposure to the Agent ( intent to exclusively breastfeed for 6 months 1–7 scale score of 6.14 ( post ) vs. 5.14 ( pre ) ; p < 0.05 ) . Non-statistically significant trends in improvement with use of the Computer Agent breastfeeding support system were also seen in the between subjects analyses of intent to breastfeed and breastfeeding self-efficacy . The pilot study demonstrated the feasibility of using a Computer Agent to support breastfeeding mothers and informed the design of a larger r and omized clinical trial . An interactive Computer Agent may be helpful in improving rates of exclusive breastfeeding , particularly when there is not adequate health care professional support [24262719] OBJECTIVE The purpose of this study was to compare breastfeeding duration in mothers after delivery who were assigned r and omly to a behavioral educational intervention vs enhanced usual care . STUDY DESIGN We conducted a r and omized trial . Self-identified black and Latina mothers early after delivery were assigned r and omly to receive a behavioral educational intervention or enhanced usual care . The 2-step intervention aim ed to prepare and educate mothers about postpartum symptoms and experiences ( including tips on breastfeeding and breast/nipple pain ) and to bolster social support and self-management skills . Enhanced usual care participants received a list of community re sources and received a 2-week control call . Intention-to-treat analyses examined breastfeeding duration ( measured in weeks ) for up to 6 months of observation . This study was registered with clinical trial.gov ( NCT01312883 ) . RESULTS Five hundred forty mothers were assigned r and omly to the intervention ( n = 270 ) vs control subjects ( n = 270 ) . Mean age was 28 years ( range , 18 - 46 years ) ; 62 % of the women were Latina , and 38 % were black . Baseline sociodemographic , clinical , psychosocial , and breastfeeding characteristics were similar among intervention vs control subjects . Mothers in the intervention arm breastfed for a longer duration than did the control subjects ( median , 12.0 vs 6.5 weeks , respectively ; P = .02 ) Mothers in the intervention arm were less likely to quit breastfeeding over the first 6 months after delivery ( hazard ratio , 0.79 ; 95 % confidence interval , 0.65 - 0.97 ) . CONCLUSION A behavioral educational intervention increased breastfeeding duration among low-income , self-identified black and Latina mothers during the 6-month postpartum period [16113021] The factors that influence the actual initiation and duration of breastfeeding were studied among low-income women followed by the Canada Prenatal Nutrition Program ( CPNP ) . A group of 196 pregnant women were selected at r and om from a sample of 6223 pregnant women who registered with the CPNP . Two 24-hour recalls and information regarding lifestyle habits , peer support , and infant-feeding practice s were obtained between 26 and 34 weeks of gestation and 21 days and 6 months after birth . Women who received a university education ( completed or not completed ) versus women with [ .lessequal ] high school education ( odds ratio [ OR ] , 8.40 ; 95 % confidence interval [ CI ] , 1.02 - 69.50 ) , women born outside Canada ( OR,8.81 ; 95 % CI , 3.34 - 23.19 ) , and women of low birth weight infants ( OR , 0.39 ; 95 % CI , 0.16 - 0.96 ) were more likely to initiate breastfeeding . Late introduction of solid foods ( P = .004 ) , nonsmoking ( P = .005 ) , multiparity ( P = .012 ) , and a higher level of education ( P = .049 ) were positively associated with the duration of breastfeeding among initiators . Underst and ing factors associated with initiation and duration of breastfeeding among low-income women is critical to better target breastfeeding promotion [26289058] Background : Guidelines recommend prenatal education to improve breastfeeding rates ; however , effective educational interventions targeted at low-income , minority population s are needed as they remain less likely to breastfeed . Objective : To determine whether a low-cost prenatal education video improves hospital rates of breastfeeding initiation and exclusivity in a low-income population . Methods : A total of 522 low-income women were r and omized during a prenatal care visit occurring in the third trimester to view an educational video on either breastfeeding or prenatal nutrition and exercise . Using multivariable analyses , breastfeeding initiation rates and exclusivity during the hospital stay were compared . Results : Exposure to the intervention did not affect breastfeeding initiation rates or duration during the hospital stay . The lack of an effect on breastfeeding initiation persisted even after controlling for partner , parent , or other living at home and infant complications ( adjusted odds ratio [ OR ] = 1.05 , 95 % CI , 0.70 - 1.56 ) . In addition , breastfeeding exclusivity rates during the hospital stay did not differ between the groups ( P = .87 ) . Conclusion : This study suggests that an educational breastfeeding video alone is ineffective in improving the hospital breastfeeding practice s of low-income women . Increasing breastfeeding rates in this at-risk population likely requires a multipronged effort begun early in pregnancy or preconception [12449049] The objective of this study was to prospect ively explore the influence ofwomen ’s experiences in preparing for and establishing breastfeeding on the duration of breastfeeding . A cohort of 490 women was surveyed at intervals during pregnancy and after giving birth . Data were collected on breastfeeding outcomes and experiences and analyzed using multiple logistic regression . After controlling for sociodemographic variables , women were less likely to be still fully breastfeeding at 6 to 10 weeks postpartum if they believed they needed more breastfeeding information prior to delivery or had experienced breastfeeding problems . Women were less likely to be fully breastfeeding at 4 months postpartum if they had experienced breastfeeding problems . This prospect i ve study demonstrated the influence ofwomen ’s preparedness for breastfeeding and their experiences in establishing breastfeeding on breastfeeding duration . Improvements in prenatal education about breastfeeding and management of breastfeeding problems are likely to increase breastfeeding duration [15330879] BACKGROUND Despite high levels of breastfeeding initiation in Australia , only 46 percent of women are still breastfeeding ( exclusively or partially ) 6 months later , with marked differences between social groups . This study aim ed to determine the influence of mid-pregnancy breastfeeding education on the proportions of women breastfeeding at hospital discharge , and on the duration of breastfeeding . METHODS A r and omized controlled trial to compare two strategies for increasing the initiation and duration of breastfeeding was conducted , in which 981 primiparas who attended a public , tertiary women 's hospital in Melbourne , Australia , were r and omized to one of two interventions or to st and ard care ( 327 in each group ) . The interventions were a 1.5-hour class on practical aspects of breastfeeding using a previously tested tool ( Practical Skills ) , and two 1-hour classes exploring family and community attitudes toward , and experiences of , breastfeeding ( Attitudes ) . Both interventions took place in interactive small groups when women were in mid-pregnancy . Breastfeeding initiation was ascertained by interview 2 to 4 days after birth , and breastfeeding duration was assessed by telephone interview 6 months after birth . RESULTS Neither intervention increased breastfeeding initiation or duration compared with st and ard care . Rates at initiation were 97 percent ( 296/306 ) for the Practical Skills intervention , 95 percent ( 291/308 ) for the Attitudes intervention , and 96 percent ( 297/310 ) for st and ard care . Rates at 6 months were , respectively , 55 percent ( 162/297 ) , 50 percent ( 146/293 ) , and 54 percent ( 162/299 ) . CONCLUSIONS In setting s where breastfeeding initiation is already high , neither study intervention could be recommended as an effective strategy to increase breastfeeding initiation or duration [7860944] OBJECTIVE To determine the effects of a partner-supported , incentive-based educational program on rates and duration of breast-feeding among low-income women . DESIGN Women who expressed a willingness to participate in the breast-feeding educational program were r and omly assigned to one of two groups : an intervention group and a control group who received usual breast-feeding education . SETTING Clinics of the Special Supplemental Food Program for Women , Infants , and Children in Flagstaff , Ariz. SUBJECTS Sixty-eight primiparous pregnant women with expected due date s between May 1992 and December 1992 were willing to participate in the study . Of these , 34 were r and omly assigned to the intervention group and 34 to the control group . Approximately 81 % of the women completed the study : 29 in the control group and 26 in the intervention group . INTERVENTION The intervention consisted of special incentives ( prizes ) for women and their partners to participate in a breast-feeding class for expectant couples and an educational series on childbirth . Women were also encouraged to use a breast-feeding support program in which peers serve as role models . MAIN OUTCOME MEASURES The primary outcome measure was infant feeding method . Data were collected from mothers in both groups at the time of discharge from the hospital and at 2 weeks , 6 weeks , and 3 months postpartum . STATISTICAL ANALYSES PERFORMED Binomial proportional analyses of the feeding data were performed . RESULTS Women in the intervention group reported a higher percentage of breast-feeding at all measurement times . APPLICATIONS These findings suggest that incentives , such as donated prizes , can be used to attract primiparous women from lower socioeconomic groups , along with their partners , to participate in educational interventions design ed to promote breast-feeding . Participation by couples in breast-feeding promotion activities can dramatically increase the rate and duration of breast-feeding [9183091] Breast feeding rates in Irel and have stagnated at around 33 % over the past 10 years . We aim ed to assess the effect of a simple intervention in late pregnancy on breast feeding rates . The study was r and omised and prospect i ve . In the intervention group a sheet illustrating eight positive aspects of breast feeding was presented to mothers at their 36 week antenatal visit . This information was reinforced with a question naire on the topic of breast feeding . The control group received a routine antenatal care . There were 98 mothers in the intervention group and 95 controls . A similar percentage in each group had medical cards . On discharge from hospital 31.5 % of controls and 43.9 % of the test group were breast feeding . This difference just failed to reach statistical significance ( P = 0.07 ) . The intervention , which took just three minutes of a medical student 's time , appeared to result in an improved breast feeding rate . Though the difference did not reach statistical significance , this reflects , in part , the small numbers in the study . About half of the women in the study indicated that no doctor had offered any advice on the choice of feeding . Since this minor intervention produced a good response , it would seem appropriate to adopt a more positive attitude in the promotion of breast feeding [15530582] BACKGROUND In the Netherl and s , the initiation rate of breast-feeding ( BF ) was 80 % in 2002 , but only 35 % of the mothers continued to breast-feed for 3 months . This study examined the effectiveness of a breast-feeding promotion program to increase the continuation of breast-feeding . METHODS A cluster-r and omized intervention trial was used . Ten child health care centers in three regions of the home health care were r and omly allocated to the program or usual care . Elements in the program were health counseling , measures to enhance cooperation , early signaling of breast-feeding problems and continuity of care , and lactation consultancy . Pregnant mothers who applied for home health care in the intervention or usual care regions were enrolled and were followed up from pregnancy until 6 months postpartum ( n = 683 ) . The primary outcome measure was the continuation of breast-feeding until at least 3 months . RESULTS The 3-month breast-feeding rate was 32 % in the intervention and 38 % in the control groups ( OR = 0.79 , 95 % CI = 0.58 - 1.08 ) . CONCLUSION The program was not effective . We discuss possible explanations from the design and execution of the trial and give some points for improvement of our program , such as the categories of caregivers involved and the number and duration of contacts after parturition [2235229] Many factors are associated with low breast-feeding rates among black low-income women . This study examines whether , despite such factors , health professionals ' prenatal education of black poor women is associated with increased breast-feeding rates . Black women born in the United States who attended a midwives prenatal clinic ( N = 159 ) were r and omly assigned to two types of prenatal education or were followed up in a control group . All women were interviewed on entry into the study and after delivery of their infants . Women assigned to group classes attended at least one session discussing myths , problems , and benefits of breast-feeding . Women assigned to individual prenatal counseling spoke with a pediatrician or nurse practitioner , who discussed breast-feeding topics similar to those covered in the classes . Women in the control group received no additional prenatal education . The three study groups had significantly different percentages of women who breast-fed ( controls 22 % , classes 46 % , individual sessions 53 % ) . Higher percentages of women in the study groups carried out their prenatal plans to breast-feed ( controls 50 % , classes 86 % , individual sessions 62 % ) or breast-fed despite prenatal plans to bottle-feed ( controls 10 % , classes 26 % , individual sessions 48 % ) . After multivariable analysis controlling for age , prenatal plans to breast-feed , prior breast-feeding experience , perceived support for breast-feeding , education , gravidity , and employment plans , women in intervention groups had a higher likelihood of breast-feeding than control subjects . These findings suggest that an increase in relatively simple , not-too-time-consuming educational efforts in institutions and offices serving black low-income women might yield significant narrowing of the gap in breast-feeding rates between white affluent women and black low-income women [16128971] BACKGROUND Breastfeeding conveys many benefits , but women often encounter difficulties in the first few weeks . The objective of this study was to examine women 's perspectives on the information , advice , and support they receive with breastfeeding . METHODS A qualitative analysis was conducted of women 's responses to open questions about their experiences of breastfeeding support . Participants were recruited as part of a r and omized controlled trial of additional support from volunteer breastfeeding counselors , and they completed question naires when their babies were 6 weeks old . RESULTS Of the 720 women recruited to the trial , 654 began breastfeeding and completed postnatal question naires ; 492 ( 75 % ) participants were first-time mothers and 200 ( 31 % ) were of minority ethnic origin . At 6 weeks , 249 ( 38 % ) women were exclusively breastfeeding , 183 ( 28 % ) were both breastfeeding and bottle-feeding , whereas 222 ( 34 % ) were exclusively bottle-feeding . Although many women commented positively on their experiences , others thought they did not receive the information and support they needed . Thematic analysis of women 's responses to open questions identified five components of the support that women wanted : information about breastfeeding and what to expect , practical help with positioning the baby to breastfeed , effective advice and suggestions , acknowledgment of mothers ' experiences and feelings , and reassurance and encouragement . CONCLUSIONS Maternity services should address the components identified by the study findings as constituting good breastfeeding support . Guidance and information for family members and training for those involved in peer or professional initiatives should take into account women 's views on what support they want , together with when and how they want it provided [10217083] BACKGROUND Exclusive breastfeeding is recommended worldwide but not commonly practised . We undertook a r and omised controlled study of the efficacy of home-based peer counselling to increase the proportion of exclusive breastfeeding among mothers and infants residing in periurban Mexico City . METHODS Two intervention groups with different counselling frequencies , six visits ( 44 ) and three visits ( 52 ) , were compared with a control group ( 34 ) that had no intervention . From March , 1995 , to September , 1996 , 170 pregnant women were identified by census and invited to participate in the study . Home visits were made during pregnancy and early post partum by peer counsellors recruited from the same community and trained by La Leche League . Data were collected by independent interview . Exclusive breastfeeding was defined by WHO criteria . FINDINGS 130 women participated in the study . Only 12 women refused participation . Study groups did not differ in baseline factors . At 3 months post partum , exclusive breastfeeding was practised by 67 % of six-visit , 50 % of three-visit , and 12 % of control mothers ( intervention groups vs controls , p<0.001 ; six-visit vs three-visit , p=0.02 ) . Duration of breastfeeding was significantly ( p=0.02 ) longer in intervention groups than in controls , and fewer intervention than control infants had an episode of diarrhoea ( 12 % vs 26 % , p=0.03 ) . INTERPRETATION This is the first reported community-based r and omised trial of breastfeeding promotion . Early and repeated contact with peer counsellors was associated with a significant increase in breastfeeding exclusivity and duration . The two-fold decrease in diarrhoea demonstrates the importance of breastfeeding promotion to infant health [15063960] OBJECTIVE To assess the impact of experiential learning method ologies in primiparous women on their choice and maintenance of an infant feeding method . STUDY DESIGN A prospect i ve controlled study into experiential learning methods applied to patients with four months ' follow up . Seventy-three primiparous women attending the antenatal clinic at the West Suffolk Hospital for their 32 weeks check were allocated to two groups on the basis of date of attendance . Multiple pregnancy and serious illness were excluded . Thirty-three women attended a two hour seminar on breast feeding using experiential techniques . Forty had routine antenatal care and acted as controls . Breast feeding rates of the two groups were recorded at various stages . Assessment also included comments from question naires . RESULTS The two groups did not differ significantly in the number of women proposing to breast feed their infants ( Z = -0.0490 , P = 0.9609 ) nor in the numbers of women breast feeding on day one ( Z = -0.6203 , P = 0.5350 ) . There were proportionally more women breast feeding their infants at two weeks ( Z = -1.4944 , P = 0.1351 ) in the subject group , but this was not statistically significant . However , the difference at four months was significant , ( Z = -2.5784 , P = 0.0099 ) , more than double the percentage of controls maintaining some breast feeding to four months in the subject group . CONCLUSIONS Experiential learning was associated with increased rates of prolonged breast feeding , possibly due to increased patient confidence in their choice . This learning approach could be applied to other areas of patient health education [16322166] Objective . To determine whether an individualized , prenatal and postnatal , lactation consultant intervention result ed in increased cumulative intensity of breastfeeding up to 52 weeks . Design . The r and omized , nonblinded , controlled trial recruited women from prenatal care . Baseline prenatal interviews covered demographic data and breastfeeding experience , intention , and knowledge . Interviews at 1 , 2 , 3 , 4 , 6 , 8 , 10 , and 12 months after birth collected data on weekly feeding patterns , infant illness , and infant health care use . Setting . Two community health centers serving low-income , primarily Hispanic and /or black women . Participants . The analytic sample included 304 women ( intervention : n = 145 ; control : n = 159 ) with ≥1 postnatal interview . Intervention . Study lactation consultants attempted 2 prenatal meetings , a postpartum hospital visit , and /or home visits and telephone calls . Control subjects received the st and ard of care . Outcome Measures . Cumulative breastfeeding intensity at 13 and 52 weeks , based on self-reports of weekly feeding , on a 7-level scale . Results . The intervention group was more likely to breastfeed through week 20 ( 53.0 % vs 39.3 % ) . Exclusive breastfeeding rates were low and did not differ according to group . In multivariate analyses , control subjects had lower breastfeeding intensity at 13 weeks ( odds ratio [ OR ] : 1.90 ; 95 % confidence interval [ CI ] : 1.13–3.20 ) and 52 weeks ( OR : 2.50 ; 95 % CI : 1.48–4.21 ) . US-born control subjects had lowest breastfeeding intensity at 13 weeks ( OR : 5.22 ; 95 % CI : 2.43–11.22 ) and 52 weeks ( OR : 5.25 ; 95 % CI : 2.44–11.29 ) . There were no significant differences in breastfeeding intensity among the US-born intervention , foreign-born intervention , and foreign-born control groups . Conclusions . This “ best- practice s ” intervention was effective in increasing breastfeeding duration and intensity . Breastfeeding promotion should focus on US-born women and exclusive breastfeeding [15467529] OBJECTIVE Recognizing that an expectant father may influence a mother 's decision to breast- or formula-feed , we tested the effectiveness of a simple , educational intervention that was design ed to encourage fathers to advocate for breastfeeding and to assist his partner if she chooses to breastfeed . STUDY DESIGN We conducted a r and omized controlled trial in which expectant fathers ( n = 59 ) were assigned r and omly to attend either a 2-hour intervention class on infant care and breastfeeding promotion ( intervention ) or a class on infant care only ( control group ) . The classes , which were led by a peer-educator , were interactive and informal and utilized different media to create an accessible environment for participants . Couples were recruited during the second trimester from a university obstetrics practice . RESULTS Overall , breastfeeding was initiated by 74 % of women whose partners attended the intervention class , as compared with 41 % of women whose partners attended the control class ( P = .02 ) . CONCLUSION Expectant fathers can be influential advocates for breastfeeding , playing a critical role in encouraging a woman to breastfeed her newborn infant [16581077] BACKGROUND The study documented Australian primigravidas ' perceptions about breastfeeding . OBJECTIVES To examine women 's perspectives of their breastfeeding experiences during the first 12 weeks postpartum . DESIGN A Journal was introduced to an intervention group ( n=149 ) attending prenatal classes at a private hospital at 36 antenatal weeks . Using quantitative data at two days and 12 weeks postpartum , the intervention group was compared with a control group ( n=154 ) that delivered at the same hospital . Qualitative data were also collected about the women 's perceptions about breastfeeding to further illuminate their experience . Qualitative data from 203 women at two days postpartum and 252 women at 12 weeks postpartum represented the combined comments from the intervention and control groups . PARTICIPANTS Participants were recruited as part of a r and omised controlled trial of the effects of a Breastfeeding Journal on breastfeeding prevalence , self-efficacy , support , and influence from conflicting advice . The convenience sample of middle class , well-educated primiparous women from a Western Australian hospital had given birth to a singleton infant that was greater than 34 weeks gestation . METHODS An open-ended question on a question naire sought mothers ' comments about their breastfeeding experiences . Data were analysed using inductive content analysis . FINDINGS These mothers described trying to ' get breastfeeding right ' . Getting it right included enhancing factors , factors with mixed effect , and negative factors . CONCLUSIONS Middle class mothers share breastfeeding perceptions with women in more vulnerable groups , including encountering conflicting and unhelpful advice and feeding pressures from health care professionals , family , and community members [19239405] OBJECTIVE To evaluate the effectiveness of a breastfeeding promotion program in the Women , Infant and Children ( WIC ) Supplemental Nutrition Program participants . STUDY DESIGN This r and omized clinical trial included 52 women in the intervention group who received one-to-one pre- and postnatal breastfeeding education and support from a lactation consultant . Women ( n = 52 ) r and omized to controls received st and ard breastfeeding services . Data regarding their infants ' feeding ( classified as exclusive , partial , and bottle ) during the first 7 days , 1 , 2 , and 3 months of age were compared . Additionally , the mothers were surveyed to assess their knowledge , attitude , and beliefs regarding breastfeeding . RESULTS Among the 104 enrolled women , 91 ( 87.5 % ) were Hispanic . Almost all the pregnant women had planned to breastfeed their infants . Although the majority of women reported breastfeeding their infants , 45.6 % in the intervention group and 28.9 % of controls practice d exclusive breastfeeding during the first 7 days . By 3 months , the rate of exclusive breastfeeding in the intervention and control groups had dropped to 13.9 % and 10.5 % , respectively . Parity , mode of delivery , previous experience with breastfeeding , rooming in , and return to work did not significantly affect the exclusive breastfeeding rate . Maternal knowledge , attitude , and beliefs regarding breastfeeding were comparable between the study groups at the baseline stage as well as 3 months postpartum . CONCLUSIONS Participation in the proposed breastfeeding promotion program by the low-income mothers was associated with an insignificant increase in the exclusive breastfeeding rate during the first 3 postpartum months [17670909] Objective To investigate whether antenatal breast feeding education alone or postnatal lactation support alone improves rates of exclusive breast feeding compared with routine hospital care . Design R and omised controlled trial . Setting A tertiary hospital in Singapore . Participants 450 women with uncomplicated pregnancies . Main outcome measures Primary outcomes were rates of exclusive breast feeding at discharge from hospital and two weeks , six weeks , three months , and six months after delivery . Secondary outcomes were rates of any breast feeding . Results Compared with women who received routine care , women in the postnatal support group were more likely to breastfeed exclusively at two weeks ( relative risk 1.82 , 95 % confidence interval 1.14 to 2.90 ) , six weeks ( 1.85 , 1.11 to 3.09 ) , three months ( 1.87 , 1.03 to 3.41 ) , and six months ( 2.12 , 1.03 to 4.37 ) postnatally . Women receiving antenatal education were more likely to breast feed exclusively at six weeks ( 1.73 , 1.04 to 2.90 ) , three months ( 1.92 , 1.07 to 3.48 ) , and six months ( 2.16 , 1.05 to 4.43 ) postnatally . The numbers needed to treat to achieve one woman exclusively breast feeding at six months were 11 ( 6 to 80 ) for postnatal support and 10 ( 6 to 60 ) for antenatal education . Women who received postnatal support were more likely to exclusively or predominantly breast feed two weeks after delivery compared with women who received antenatal education ( 1.53 , 1.01 to 2.31 ) . The rate of any breastfeeding six weeks after delivery was also higher in the postnatal support group compared with women who received routine care ( 1.16 , 1.02 to 1.31 ) . Conclusions Antenatal breast feeding education and postnatal lactation support , as single interventions based in hospital both significantly improve rates of exclusive breast feeding up to six months after delivery . Postnatal support was marginally more effective than antenatal education . Trial registration Clinical Trials NCT00270920 [16536959] BACKGROUND Peer support may improve breastfeeding rates but the evidence is inconclusive . Previous studies and review s recommend trials in different healthcare setting s. AIM To test if a specified programme of peer support affects the initiation and /or the duration of breastfeeding . DESIGN OF STUDY A two-group r and omised controlled trial of peer support for breastfeeding with evaluation of breastfeeding initiation and duration on an intention-to-treat basis . SETTING General practice in Ayrshire , Scotl and . METHOD Following informed consent , 225 women at 28 weeks gestation were allocated to control or peer support group by post-recruitment concealed allocation . All peer support and control group mothers received normal professional breastfeeding support . Additionally , those in the peer support group still breastfeeding on return home from hospital had peer support until 16 weeks . RESULTS Thirty-five of the 112 ( 31 % ) women in the peer support group were breastfeeding at 6 weeks compared to 33/113 ( 29 % ) in the control group , a difference of 2 % ( 95 % confidence interval = -10 % to 14 % ) . The median breastfeeding duration for all women in the peer support group was 2 days compared to 1 day for the control group and the Kaplan-Meier survival plot shows the peer support group overall breastfeeding slightly longer than the control group , with no statistically significant difference by logrank test ( P = 0.5 ) . The median breastfeeding duration among primagravidae in the peer support group was 7 days , compared to 3 days for the control group . Among women who started to breastfeed the medians were 72 days in the peer support group and 56 days in the control group . These differences were not statistically significant . CONCLUSIONS Peer support did not increase breastfeeding in this population by a statistically significant amount [15296584] This study compared breastfeeding attitudes , intention , and initiation among low-income women exposed or not exposed to the Best Start program . A between- ( experimental vs control group ) and within-factor ( pretest vs posttest ) repeated measures design was employed . A nonprobability sample of 54 subjects was r and omly assigned to a control group ( n = 28 ) or an experimental group ( n = 26 ) . Using the Breastfeeding Attrition Prediction Tool , statistically significant group by time interaction effects were found for negative breastfeeding sentiment , positive breastfeeding sentiment , and breastfeeding control scales . Compared to the control group , the experimental group had significantly increased positive breastfeeding sentiment ( P < .01 ) , decreased negative breastfeeding sentiment ( P < .01 ) , and increased breastfeeding control ( P < .01 ) from pretest to posttest . Following exposure to the Best Start program , subjects in the experimental group showed statistically significantly higher breastfeeding intention and initiation than did those in the control group . Practical implication s are discussed . J Hum Lact . 20(3):300 - 305 [16881913] We interviewed women who participated in a breast-feeding promotion intervention study about whether and how participation affected their infant feeding choices , and if they would recommend such an intervention to others . The larger study , a r and omized controlled trial ( RCT ) of an individualized , pre- and post-natal lactation consultant ( LC ) intervention , enrolled 382 low-income primarily Black and Hispanic women in New York City . Twenty-one women completed qualitative exit interviews for this study ( 11 from the Intervention group and 10 Controls ) . Several of the Controls stated that the post-partum study interviews were a source of support , and made them more conscious of how they fed their infant . The Intervention Group was asked about contacts with the study ' Mother-Baby specialist ' ( i.e. LC ) , including what was and was n't helpful . The Intervention Group participants described the Mother-Baby Specialist as key in their decision to initiate and maintain breastfeeding . They credit her direct skills and positive reinforcement with their confidence and perseverance to breastfeed . The success of the intervention is attributed to technical assistance from a trained lactation consultant within the context of a relationship built on encouragement , guidance and support [7740378] Despite the vast number of risk factors that apparently predispose to the development of osteoporosis ( OP ) , they have not been accurately identified and given relative priority . In order to analyse possible risk factors prospect ively in a local patient population with overt OP ( histomorphometrically confirmed and characterised ) and compare it with an appropriately matched non-OP control group ( with normal bone mass on dual-energy X-ray absorptiometry ) , a detailed general history , risk factor analysis , dietary history and anthropometric data were obtained from 56 OP and 125 non-OP subjects . In females a positive family history of OP ( P = 0.002 ) , a fair complexion ( P = 0.009 ) , lower body mass ( P = 0.02 ) and height ( P = 0.03 ) , no breast-feeding of babies ( P = 0.006 ) , a history of smoking ( P = 0.001 ) and fat distribution around the waist ( P = 0.009 ) were identified as risk factors . In males lack of exercise ( P = 0.008 ) , a history of smoking ( P = 0.01 ) , lower body mass ( P = 0.04 ) and height ( P = 0.04 ) , a preference for salty food ( P = 0.02 ) and fat distribution around the waist ( P = 0.002 ) appeared to predispose . Dietary calcium , phosphorus , protein and caffeine intakes were similar in OP and control subjects , but alcohol consumption was clearly higher in both OP males ( P = 0.001 ) and females ( P = 0.01 ) [17197590] OBJECTIVE : To address the impact of simple antenatal educational interventions on breastfeeding practice . METHODS : A r and omized controlled trial was carried out in a tertiary referral center from May 2002 to December 2004 . A r and om sample of eligible low-risk antenatal patients was recruited from clinics in the National University Hospital , Singapore . Group A received breastfeeding educational material and individual coaching from a lactation counselor . Group B received breastfeeding educational material with no counseling . Group C received routine antenatal care only . RESULTS : A total of 401 women were recruited . Mothers receiving individual counseling and educational material practice d exclusive and predominant breastfeeding more often than mothers receiving routine care alone at 3 months ( odds ratio [ OR ] 2.6 , 95 % confidence interval [ CI ] 1.2–5.4 ) and 6 months ( OR 2.4 , 95 % CI 1.0–5.7 ) postpartum . More mothers practice d exclusive and predominant breastfeeding at 6 months among women receiving individual counseling compared with women exposed to educational material alone ( OR 2.5 , 95 % CI 1.0–6.3 ) . CONCLUSION : Where breastfeeding practice s are suboptimal , simple one-encounter antenatal education and counseling significantly improve breastfeeding practice up to 3 months after delivery . Provision of printed or audiovisual educational material is not enough . Health care workers should make every effort to have one face-to-face encounter to discuss breastfeeding with expectant mothers before they deliver . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT002770192 LEVEL OF EVIDENCE : [7795772] OBJECTIVE To evaluate the efficacy of an intervention program to increase breast-feeding in a low-income , inner-city population . DESIGN A r and omized , nonblinded clinical control trial . Patients were followed up through pregnancy , delivery , and the first year of the infant 's life or until the time of weaning from the breast , whichever came first . SETTING The ambulatory care center for prenatal and pediatric care and the inpatient maternity unit of a primary care center that serves a low-income , inner-city population . PATIENTS There were a total of 108 patients : 51 were r and omized to the intervention group that received prenatal and postnatal lactation instruction from a lactation consultant , and 57 were r and omized to the control group that received the st and ard of care at the institution . Patients in the control group were not seen by the lactation consultant . The two groups were similar demographically . INTERVENTION This program consisted of individual prenatal lactation consultation , daily rounds by the lactation consultant on the postpartum unit , and outpatient follow-up at 48 hours after discharge , at the time that the infant was 1 week of age , and at all future health supervision visits for infants up to 1 year of age . MAIN OUTCOME MEASURES The incidence and duration of breast-feeding . RESULTS There was a markedly higher incidence of breast-feeding in the intervention group , as compared with that of the control group ( 61 % vs 32 % , respectively ; P = .002 ) . The duration of breast-feeding was also significantly longer in the intervention group ( P = .005 ) . CONCLUSIONS This lactation program increased the incidence and duration of breast-feeding in our low-income cohort . We suggest that similar efforts that are applied to analogous population s may increase the incidence and duration of breast-feeding in low-income population s in the United States [16953019] OBJECTIVE To determine whether infants of women r and omized to a prenatal and postpartum lactation support intervention incur fewer otitis media- , respiratory tract- , or gastrointestinal-related visits than controls . DESIGN R and omized , unmasked controlled trial recruiting women from prenatal care setting s. Breastfeeding sensitive ( BFS ) illness visits for otitis media or respiratory tract or gastrointestinal complaints were obtained up to 12 months . SETTING Two urban community health centers . PARTICIPANTS Analytic sample of 338 low-income , primarily Hispanic and /or black mother-infant dyads ( n = 163 for the intervention group and n = 175 for the control group ) . INTERVENTION Study lactation consultants attempted 2 prenatal meetings , 1 postpartum hospital and /or home visit , and telephone calls as needed . Controls received the st and ard of care . MAIN OUTCOME MEASURES Combined outpatient and emergency department visits with illness and BFS illness diagnoses . RESULTS There was a significant interaction between treatment and Medicaid ; among those not receiving Medicaid , the number of otitis media visits was higher among controls ( P</=.03 ) . Visits for any illness and BFS , gastrointestinal , or respiratory tract illnesses did not differ by treatment group . Intervention group infants received more breast milk than controls , but exclusive breastfeeding rates remained low and did not differ between groups at any point . CONCLUSIONS Only the number of otitis media visits was reduced , in a subset of the intervention group . The intervention did not reduce visits for respiratory tract or gastrointestinal illness . Limited intervention contact and low exclusive breastfeeding rates may have attenuated intervention effects . Future interventions design ed to yield markedly increased breastfeeding rates may show greater effects in low-income multiethnic sample s. Health coverage for visits may moderate intervention effects [20873071] BACKGROUND Although there are many benefits to breastfeeding , its prevalence and duration in many countries is still lower than the international recommendation for 6-month exclusive breastfeeding . The objective of the present study was to investigate whether a knowledge sharing practice s with empowerment strategies ( KSPES ) program on antenatal education and postnatal support strategies improves the rates of 6-month exclusive breastfeeding during the first six months postpartum compared with a st and ard knowledge of breastfeeding techniques . MATERIAL AND METHOD A r and omized controlled trial was conducted . Pregnant women of more than 32 weeks ' gestation were r and omly assigned to receive a routine st and ard knowledge of breastfeeding techniques alone ( control group ) or with KSPES on antenatal education and postnatal support strategies ( study group ) . The primary outcome was the rate of exclusive breastfeeding at 6-month postpartum . The secondary outcomes were rates at 7 days , 14 days , 1 , 2 , 3 , 4 , and 5 months postpartum . RESULTS Rates of exclusive breastfeeding in the study group were significantly higher when compared with those in the control group at 14 days ( 82.5 % vs. 52.6 % , p = 0.005 ) , 1 month ( 77.5 % vs. 52.6 % , p = 0.021 ) , 2 months ( 62.5 % vs. 368 % , p = 0.023 ) , 4 months ( 35.0 % vs. 7.9 % , p = 0.008 ) , 5 months ( 25.0 % vs. 2.6 % , p = 0.012 ) , and 6 months postpartum ( 20.0 % vs. 0 % , p = 0.005 ) . CONCLUSION KSPES on antenatal education and postnatal support strategies significantly improve rates of exclusive breastfeeding at 6-month postpartum . These strategies also significantly improve rates of exclusive breastfeeding at 14 days , 1 , 2 , 4 , 5 , and 6 months postpartum [8951255] BACKGROUND Prenatal pediatric visits have been recommended by the American Academy of Pediatrics to allow the pediatrician to counsel parents on infant care issues , establish a supportive relationship , and provide pediatric practice information to parents . We hypothesized that prenatal pediatric visits would have an impact on breastfeeding decisions , health care behaviors , health care utilization , and the doctor-patient relationship . METHODS We conducted a r and omized controlled trial of prenatal pediatric visits for urban , low-income families to measure the impact on breastfeeding decisions , infant car safety seat use , circumcision , health maintenance , and emergency room visits and the pediatrician 's perception that he/she would know the mother better . Pregnant women were recruited prenatally from the obstetrics clinic . Outcomes were measured by maternal interview prenatally and when the infant was 2 months old , in addition to review of the nursery record . Physicians were interviewed after the 2-month visit . Health care utilization was measured by chart review at 7 months . RESULTS A total of 156 pregnant women were enrolled and r and omized , 81 to the intervention group and 75 to the control group . Of mothers who breastfed , 45 % in the intervention group changed their mind in favor of breastfeeding after enrollment compared with 14 % in the control group . Mothers in the intervention group compared with the control group were more likely to make fewer emergency room visits , 0.58 compared with 1.0 . Pediatricians were more likely to think that they knew mothers in the intervention group well , 54 % versus 29 % in the control group , yet 67 % of mothers in both groups agreed their pediatrician knew them well . There were no differences between groups in initiation or duration of breastfeeding at 30 or 60 days , infant car safety seat use , circumcision , or health maintenance visits . CONCLUSIONS Prenatal pediatric visits have potential impact on a variety of health care outcomes . Among urban , low-income mothers , we found beneficial effects on breastfeeding decisions , a decrease in emergency department visits , and an initial impact on the doctor-patient relationship . We suggest urban practice s actively promote prenatal pediatric visits [11598600] OBJECTIVE To determine whether docosahexaenoic acid ( DHA ) is related to visual and neural development in term breast-fed infants . DESIGN A prospect i ve study of 83 infants who were exclusively breast-fed for at least 3 months . We determined red blood cell and plasma fatty acids at 2 months , visual acuity at 2 , 4 , 6 , and 12 months , speech perception and an object search task at 9 months , Bayley 's mental development index and psychomotor development index at 6 and 12 months , and novelty pReference at 6 and 9 months . RESULTS The infant red blood cell phosphatidylethanolamine DHA was significantly related to visual acuity at 2 months of age ( r = 0.32 , P = .01 ) and 12 months of age ( r = 0.30 , P = .03 ) . The ability to discriminate nonnative retroflex and phonetic contrasts at 9 months of age was related to the plasma phospholipid DHA ( r = 0.48 , P < .02 ) and red blood cell phosphatidylethanolamine DHA ( r = 0.26 , P = .02 ) at 2 months of age after adjusting for covariates . CONCLUSION DHA may influence the development of visual acuity and neural pathways associated with the developmental progression of language acquisition in term breast-fed infants . The extent to which our results can be attributed solely to DHA from maternal sources through breast milk or in gestation or other confounding factors remains to be determined [4442197] Background Promotion of healthy eating and physical activity in early childhood is recommended as a global chronic disease prevention strategy . Centre-based childcare services represent a promising setting to provide children with opportunities to improve healthy eating and physical activity . Evidence to inform implementation of childcare obesity prevention guidelines into routine practice in childcare , however , is lacking . This study aims to assess the effectiveness of an intervention , delivered to childcare staff , aim ing to increasing service implementation of healthy eating and physical activity-promoting policies and practice s. Methods and analysis A pragmatic parallel group r and omised controlled trial will be undertaken with 165 childcare services in the Hunter New Engl and region of New South Wales , Australia . Services will be r and omised to receive either a 10-month evidence -based performance review intervention with other re sources to support practice change , or to a waitlist control group . The primary trial outcome is the proportion of services implementing all of the following recommended healthy eating and physical activity promoting practice s : written nutrition , physical activity and small screen recreation policies ; providing information to families regarding healthy eating ( including breastfeeding ) , physical activity and small screen time ; providing twice weekly healthy eating learning experiences to children ; providing water and only plain milk to children ; providing fundamental movement skills activities for children every day ; and limiting and using electronic screen time more for educational purpose s and learning experiences . Effectiveness will be assessed using a telephone interview of practice implementation with childcare staff at baseline and 12 months following baseline . Ethics and dissemination The study was approved by the Hunter New Engl and Human Research Ethics Committee and the University of Newcastle Human Research Ethics Committee . Study findings will be disseminated widely through peer- review ed publications and conference presentations . Trial registration number Australian New Zeal and Clinical Trials Registry ACTRN12614000972628 [9511686] OBJECTIVE To assess whether an antenatal teaching session on position and attachment of the baby on the breast had an effect on postnatal nipple pain , nipple trauma and breast feeding duration . The study was planned as a pilot study to allow an adequate sample size to be calculated for a larger study . DESIGN An observer blind experimental design was used . Women were r and omly assigned to either the experimental group teaching session or the control group . SETTING One public hospital in Western Australia . PARTICIPANTS 70 primiparae who intended to breast feed their baby were recruited from the antenatal clinic of the study hospital at 36 weeks ' gestation . INTERVENTION Antenatal group sessions on position and attachment of the baby on the breast were conducted by a lactation consultant . MEASUREMENTS AND FINDINGS During the first four postnatal days , position and attachment was measured by LATCH ( Latch on , Audible swallow , Type of nipple , Comfort and Help ) ( Jensen et al 1994 ) , nipple pain was measured by the Visual Analogue Scale ( VAS ) and nipple trauma was measured by the Nipple Trauma Index ( NTI ) . The analysis of variance ( ANOVA ) results indicated that the women in the experimental group were better able to attach the baby on the breast and had significantly less nipple pain and trauma than the control group . At six weeks postnatally , 31 of the 35 women in the experimental group were breast feeding compared to 10 of the 35 in the control group . CONCLUSIONS AND IMPLICATION S These initial findings suggest that midwives can make the best use of decreasing re sources by using practical ' h and s on ' antenatal group teaching as an effective strategy to increase breast feeding rates [2040509] Educational intervention programs in Florin , Greece , a mountainous rural area with a low ( 15 - 20 % ) attendance at prenatal clinics , were conducted to reduce perinatal and infant morbidity and mortality and to promote physical and psychomotor development . Prior community diagnostic surveys had identified low income , poor living conditions , and illiteracy as very closely linked with poor hygiene , poor nutrition , nonutilization of services , frequent infections and high perinatal and infant mortality . The objectives of the intervention were to assess the effects of health education on breast feeding practice s and use of available medical services . 300 pregnant women participants were r and omly identified by the clinic as the intervention group and 200 as controls . Both groups were similar with predominantly low socioeconomic status ( 69 - 73 % ) and peasant farmers . There were few basic housing amenities ( 13.1 with interventions and 12.7 for controls ) . 70 % of the women lived in extended families . The intervention involved home visits on nutrition , general hygiene , breast feeding , and newborn care . Visits were scheduled every 2 weeks in the 1st 2 months of pregnancy and every month until the infant was 12 months old . It was found that nutrition counseling was positively associated with maternal weight between interventions and controls ( 11.33 vs. 10.30 p.05 ) but not on low birth weight . Prematurity was reduced ( 3.7 % intervention vs. 8.3 % controls , p.04 ) . The perinatal mortality was 31 % for interventions vs. 41 % for controls , but there were a significantly higher number of fetal deaths ( 28 weeks ) for interventions . There was no discernible impact on breast feeding practice s except for dem and feeding ( 61 % interventions vs. 38 % controls ) perhaps because both groups considered breast milk the best . Overfeeding was affected by health counseling , but was reflected only after the 1st year ( 12.1 % control vs. 6.7 % intervention in the 90th percentile ) . The presence of anemia followed a similar pattern with intervention impact after the 1st year . There was no measurable impact in psychomotor development . Reported illness days had a significant lower mean 1 year for interventions . Illness reports checked against clinic visits showed underreporting for both groups . Colds , otitis , and gastroenteritis were the most common ailments . Both showed greater illness between 8 and 12 months with a slightly higher incidence of feverish episodes , gastroenteritis and otitis among controls . Hospitalizations were not significantly different . Both groups used the clinic for infant illness ; home visits depressed the use of free routine checkups for interventions from 0 to 4 months . 5 neonatal deaths occurred among controls and interventions . It was anticipated that mortality is also affected by linkages to the community and improvement in medical services . The results were mixed but the program was partly successful [7882806] OBJECTIVE To identify environmental factors involved in the etiology of insulin-dependent diabetes mellitus ( IDDM ) . RESEARCH DESIGN AND METHODS An estimated 90 % of all incident cases of IDDM in patients 0–14 years of age in New South Wales , Australia , were ascertained over 18 months . For each IDDM patient , two age- and sex-matched control subjects were r and omly selected from the population . Past environmental exposures were determined with a question naire completed by the parents . Response rates were 92 % for the IDDM patients ( 217 of 235 ) and 55 % for the control subjects ( 258 of 470 ) . The relative risk associated with each exposure was estimated with the odds ratio ( OR ) adjusted for confounding factors using multiple logistic regression . RESULTS The introduction of cow 's milk-based infant formula into the diet before 3 months of age was associated with an increased risk ( OR 1.52 , 95 % confidence interval [ CI ] 1.04–2.24 ) . Exclusive breast-feeding for ≥3 months was associated with a protective effect ( OR 0.66 , 95 % CI 0.45–0.97 ) . High dietary intake of cow 's milk protein in the 12 months before the onset of diabetic symptoms was also associated with an increased risk ( OR 1.84 , 95 % CI 1.12–3.00 ) . A recent infection ( during the 3 months before onset of diabetic symptoms ) was more common in the patients than the control subjects ( OR 2.92 , 95 % CI 1.96–4.35 ) , as was day care attendance before the age of 3 ( OR 1.73 , 95 % CI 1.00–3.00 ) . When two age-groups , defined by the median age at onset of diabetes , were compared , the associations with early infant-feeding were stronger among the younger group ( < 9.2 years ) , and associations with recent diet and recent infection were stronger among the older group ( ≥9.2 years ) . CONCLUSIONS These results indicate an increased risk of IDDM associated with early dietary exposure to cow 's milk-containing formula , short duration of exclusive breast-feeding , high intake of cow 's milk protein in the recent diet , recent infection , and early attendance at day care [10655814] OBJECTIVE Although improving mothers ' knowledge about breastfeeding can increase rates and duration of breastfeeding , little is known about the influence of fathers ' knowledge . The purpose of this study was to assess the knowledge of mothers and fathers about breastfeeding before and after receiving postpartum advice and its relationship to the frequency of breastfeeding . METHODS A clinical trial was performed with mothers and fathers of normal children born at the Hospital de Clínicas de Porto Alegre , Brazil , between July 1994 and March 1995 . The study intervention consisted of postpartum advice supplied by means of a video film discussing basic topics of breastfeeding , an explanatory leaflet , and open discussion after viewing the video . The first 208 couples comprised the control group , the next 197 comprised experimental group 1 , and the remaining 196 comprised experimental group 2 . Immediately after delivery , mothers and fathers in the three groups answered a test on breastfeeding knowledge ; they completed the same test at the end of the first month . All families received home visits at the end of the first , second , fourth , and sixth months , or until breastfeeding ceased . Logistic regression was used to evaluate the association between the mothers ' and fathers ' knowledge and frequency of breastfeeding . RESULTS Postpartum advice increased the breastfeeding knowledge of mothers and fathers . The mothers with the highest level of knowledge had a 6.5 times higher chance of exclusively breastfeeding at the end of the third month , and 1.97 times higher chance of continuing breastfeeding to the end of the sixth month compared with other mothers . The fathers ' knowledge also significantly influenced breastfeeding rates . The children whose fathers knew more had a 1.76 higher chance of being exclusively breastfed at the end of the first month , and 1.91 higher chance of receiving maternal milk at the end of the third month . CONCLUSION A simple , inexpensive strategy can increase the level of breastfeeding knowledge of mothers and fathers and , consequently , have a positive impact on the frequency of breastfeeding [16732777] BACKGROUND Social support has been shown to be greatly important for breastfeeding success . The objective of this study was to investigate if mothers who were attended by midwives and nurses specially trained in breastfeeding counseling perceived better continuity of care and emotional and informative breastfeeding support than mothers who received only routine care . METHOD Ten municipalities , each with an antenatal center and child health center , in southwest Sweden were r and omized either to intervention or control municipalities . The intervention included a process-oriented training in breastfeeding counseling and continuity of care at the antenatal and child health centers . Primiparas were asked to evaluate the care given , and those living in the control municipalities were divided into control groups A and B. Data collection took place at different points in time for the two control groups . The 540 mothers responded to 3 question naires at 3 days and at 3 and 9 months postpartum . The perception of support provided by the health professionals and from the family classes was rated on Likert scales . RESULTS Intervention group mothers rated the breastfeeding information given during the family class as significantly better during pregnancy than both control groups , and better than control group B mothers at 3 months postpartum ; compared with both control groups , intervention group mothers perceived that they received significantly better overall support and that postnatal nurses provided better information about breastfeeding and the baby 's needs . At 9 months , intervention group mothers were more satisfied with knowledge about social rights , information about the baby 's needs , and their social network than control group B mothers . Both intervention group and control group B mothers perceived better overall support than control group A during pregnancy . At 3 and 9 months , intervention group mothers perceived that postnatal nurses were more sensitive and underst and ing compared with both control groups . CONCLUSIONS After implementation of a process-oriented breastfeeding training program for antenatal midwives and postnatal nurses that included an intervention guaranteeing continuity of care , the mothers were more satisfied with emotional and informative support during the first 9 months postpartum . The results lend support to family classes incorporating continuity of care [7928125] The rate of breastfeeding among immigrant Vietnamese women in Western countries is low compared to those in Vietnam . To counteract this trend , a language and culture specific education program was developed . An experimental design was used to test the effectiveness of this program . The sample consisted of 182 prenatal Vietnamese women . Data collection included question naires and interviews . Results suggested that the education program had significant effects on knowledge , attitudes , planned and actual behaviour towards breastfeeding . However , the effect did not sustain until 6 months postpartum . Implication s for nursing practice and further research are discussed [14685550] OBJECTIVES : To assess the implementation and the impact of the Breastfeeding Counselling Course WHO/UNICEF on knowledge and skills of health workers . METHODOLOGY : The implementation of the course was assessed by participant observation ; the impact on participants was assessed with an experimental controlled study where 20 health workers were r and omly allocated as course participants ( Exposed Group-EG ) and 40 as non participants ( Control Group -CG ) . Impact on knowledge was verified with pre and post evaluations , with multiple choice questions ; clinical and counselling skills were assessed through pre and post tests , observing participants in clinical consults with mother and baby pairs in rooming-in before and after the course . Kruskal-Wallis test of variance of means was used in analysis . RESULTS : In the post test of knowledge , the mean of the EG was 8.35 and that of the CG was 5.54 ( p=0,0000 ) . In clinical and counselling skills , the means of the EG were higher when compared with the CG in all items observed ( p < 0,05 ) . Some difficulties were found in breastfeeding history and in breastfeeding observation . Counselling skills were the most incorporated aspects . CONCLUSION : The course may be implemented as proposed ; participants acquired counselling skills , but clinical management should be reinforced ; participants shoud have continued support to put what they learned in practice [19487705] A r and omized controlled trial study design was used to investigate the effectiveness of a Healthy Families America model prenatal intervention for increasing breastfeeding rates among Latina immigrants residing in an impoverished New York City community . Exposure to the intervention did not affect mother report of any breastfeeding ( ABF ) during the first week postpartum , but it did affect mother report of exclusive breastfeeding ( EBF ) . Thirty-two percent ( 44/137 ) of mothers exposed to the intervention reported EBF during the first week postpartum compared to 20 % ( 20/101 ) of mothers not exposed to the intervention ( odds ratio 1.92 ; 95 % confidence interval 1.05 - 3.52 ) . This positive effect of the intervention on EBF remained statistically significant after controlling for the negative effect of household income on EBF ( adjusted odds ratio , 1.89 ; 95 % confidence interval , 1.02 - 3.50 ) . Additional research is needed on the effectiveness of breastfeeding promotion programs targeting low-income Latinas . J Hum Lact . 25(4):404 - 411

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### Context: [16304074] CONTEXT Lactation is associated with improved glucose and insulin homeostasis , independent of weight change . OBJECTIVE To evaluate the association between lactation history and incidence of type 2 diabetes . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve observational cohort study of 83,585 parous women in the Nurses ' Health Study ( NHS ) and retrospective observational cohort study of 73,418 parous women in the Nurses ' Health Study II ( NHS II ) . MAIN OUTCOME MEASURE Incident cases of type 2 diabetes mellitus . RESULTS In the NHS , 5145 cases of type 2 diabetes were diagnosed during 1,239,709 person-years of follow-up between 1986 and 2002 , and in the NHS II , 1132 cases were diagnosed during 778,876 person-years of follow-up between 1989 and 2001 . Among parous women , increasing duration of lactation was associated with a reduced risk of type 2 diabetes . For each additional year of lactation , women with a birth in the prior 15 years had a decrease in the risk of diabetes of 15 % ( 95 % confidence interval , 1%-27 % ) among NHS participants and of 14 % ( 95 % confidence interval , 7%-21 % ) among NHS II participants , controlling for current body mass index and other relevant risk factors for type 2 diabetes . CONCLUSIONS Longer duration of breastfeeding was associated with reduced incidence of type 2 diabetes in 2 large US cohorts of women . Lactation may reduce risk of type 2 diabetes in young and middle-aged women by improving glucose homeostasis [9543954] We evaluated the single and combined effects of introducing a motivational video and peer counseling into four matched WIC clinics on breastfeeding initiation and continuation at 7 - 10 days among African-American WIC participants . Of the 242 women with complete data , 48 % initiated breastfeeding , but only 31 % were still breastfeeding at 7 - 10 days . Initiation was associated with cesarean delivery , infant feeding instruction , no artificial milk discharge pack , attending the peer counselor only-intervention site , and intention to breastfeed . Continuation was influenced by infant feeding instruction , no artificial milk discharge pack , and intention to breastfeed . Overall , trends toward a positive impact of the breastfeeding promotion activities were evident but weak , and largely gone by 7 - 10 days postpartum [25193602] Background : Whereas breastfeeding initiation rates have risen in all groups throughout the country , rates of breastfeeding duration have changed more slowly . Peer counseling has had some success in sustaining breastfeeding , but with intensive programs and variable effects . Objectives : We aim ed to improve rates of any and exclusive breastfeeding at 1 and 6 months using a low-intensity peer counseling intervention beginning prenatally . We also planned to study the interaction of breastfeeding attitude and self-efficacy with the intervention . Methods : One hundred twenty prenatal women underwent stratified r and omization based on breastfeeding attitude , measured by the Iowa Infant Feeding Attitude Scale ( IIFAS ) . The peer counselor contacted the intervention group by telephone or in clinic up to 4 months postdelivery . Study groups were compared on breastfeeding outcomes , adjusting for IIFAS strata , and on interactions with self-efficacy . Results : One hundred three women were followed to at least 1 month . Women with positive attitudes had significantly higher rates of initiation ( 93 % vs 61 % ) and breastfeeding at 1 and 6 months ( 79 % vs 25 % and 12 % vs 0 % , respectively ) than those with negative attitudes , regardless of intervention . After adjusting for self-efficacy , women who received peer counseling had significantly higher breastfeeding rates at 1 month ( odds ratio = 3.2 ; 95 % confidence interval , 1.02 - 9.8 ) . The intervention group was marginally more likely to achieve their breastfeeding goal ( 43 % vs 22 % , P = .073 ) . Conclusion : Breastfeeding rates in all women improved during the study period . Breastfeeding attitude was more strongly associated with breastfeeding behavior than peer support . Peer counseling supported women with low self-efficacy and helped women achieve their breastfeeding goals [22018394] OBJECTIVE to assess the effect of an antenatal training programme on knowledge , self-efficacy and problems related to breast feeding and on breast-feeding duration . DESIGN a r and omised controlled trial . SETTING the Aarhus Midwifery Clinic , a large clinic connected to a Danish university hospital in an urban area of Denmark . PARTICIPANTS a total of 1193 nulliparous women were recruited before week 21 + 6 days of gestation , 603 were r and omised to the intervention group , and 590 to the reference group . INTERVENTION we compared a structured antenatal training programme attended in mid-pregnancy with usual practice . MEASUREMENTS data were collected through self-reported question naires sent to the women 's e-mail addresses and analysed according to the intention to treat principle . The primary outcomes were duration of full and any breast feeding collected 6 weeks post partum ( any ) and 1 year post partum ( full and any ) . FINDINGS no differences were found between groups according to duration of breast feeding , self-efficacy score , or breast-feeding problems , but after participation in the course in week 36 of gestation women in the intervention group reported a higher level of confidence ( p=0.05 ) , and 6 weeks after birth they reported to have obtained sufficient knowledge about breast feeding ( p=0.02 ) . Supplemental analysis in the intervention group revealed that women with sufficient knowledge breast fed significantly longer than women without sufficient knowledge ( HR=0.74 CI : 0.58 - 0.97 ) . This association was not found in the reference group ( HR=1.12 CI : 0.89 - 1.41 ) . KEY CONCLUSIONS AND IMPLICATION S FOR PRACTICE antenatal training can increase confidence of breast feeding in pregnancy and provide women with sufficient knowledge about breast feeding after birth . Antenatal training may therefore be an important low-technology health promotion tool that can be provided at low costs in most setting s. The antenatal training programme needs to be followed by postnatal breast-feeding support as it is not sufficient in itself to increase the duration of breast feeding or reduce breast-feeding problems [24812071] In northern Nigeria , interventions are urgently needed to narrow the large gap between international breastfeeding recommendations and actual breastfeeding practice s. Studies of integrated microcredit and community health interventions documented success in modifying health behaviors but typically had uncontrolled design s. We conducted a cluster-r and omized controlled trial in Bauchi State , Nigeria , with the aim of increasing early breastfeeding initiation and exclusive breastfeeding among female microcredit clients . The intervention had 3 components . Trained credit officers led monthly breastfeeding learning sessions during regularly scheduled microcredit meetings for 10 mo . Text and voice messages were sent out weekly to a cell phone provided to small groups of microcredit clients ( 5 - 7 women ) . The small groups prepared songs or dramas about the messages and presented them at the monthly microcredit meetings . The control arm continued with the regular microcredit program . R and omization occurred at the level of the monthly meeting groups . Pregnant clients were recruited at baseline and interviewed again when their infants were aged ≥6 mo . Logistic regression models accounting for clustering were used to estimate the odds of performing recommended behaviors . Among the clients who completed the final survey ( n = 390 ) , the odds of exclusive breastfeeding to 6 mo ( OR : 2.4 ; 95 % CI : 1.4 , 4.0 ) and timely breastfeeding initiation ( OR : 2.6 ; 95 % CI : 1.6 , 4.1 ) were increased in the intervention vs. control arm . Delayed introduction of water explained most of the increase in exclusive breastfeeding among clients receiving the intervention . In conclusion , a breastfeeding promotion intervention integrated into microcredit increased the likelihood that women adopted recommended breastfeeding practice s. This intervention could be scaled up in Nigeria , where local organizations provide microcredit to > 500,000 clients . Furthermore , the intervention could be adopted more widely given that > 150 million women , many of childbearing age , are involved in microfinance globally [15987851] Exclusive breast-feeding ( EBF ) rates remain low despite numerous health benefits associated with this behavior . We conducted a r and omized trial on the effect of lactation counseling on EBF , which controlled for the Hawthorne effect while also varying the timing of the intervention . Pregnant women attending prenatal clinics in Tema were r and omly assigned to 1 of 2 intervention groups ( IG ) or to a control group ( C ) , as follows : 1 ) EBF support given pre- , peri- , and postnatally ( IG1 ; n = 43 ) ; 2 ) EBF support given only peri- and postnatally ( IG2 ; n = 44 ) ; or 3 ) nonbreast-feeding health educational support ( C ; n = 49 ) that had an equal amount of contact with lactation counselors . Two educational sessions were provided prenatally , and 9 home follow-up visits were provided in the 6-mo postpartum period . Infant feeding data were collected monthly at the participant 's home . The 3 groups did not differ in sociodemographic characteristics . At 6 mo postpartum , 90.0 % in IG1 and 74.4 % in IG2 had exclusively breast-fed during the previous month . By contrast , only 47.7 % in C were doing so ( P = 0.008 ) . Similarly , the percentage of EBF during the 6 mo was significantly higher ( P = 0.02 ) among IG1 and IG2 ( 39.5 % ) than among C ( 19.6 % ) . The 100 % increase in EBF rates can be attributed to the lactation counseling provided . Additional prenatal EBF support may not be needed within a context of strong routine prenatal EBF education [17413108] BACKGROUND The World Health Organization recommends exclusive breastfeeding until age 6 mo . Studies relying on mothers ' self-reported behaviors have shown that lactation counseling increases both the rate and duration of exclusive breastfeeding . OBJECTIVE We aim ed to vali date reported infant feeding practice s in rural Bangladesh ; intakes of breast milk and nonbreast-milk water were measured by the dose-given-to-the mother deuterium dilution technique . DESIGN Subjects were drawn from the large-scale Maternal and Infant Nutrition Interventions , Matlab , study of combined interventions to improve maternal and infant health , in which women were r and omly assigned to receive either exclusive breastfeeding counseling or st and ard health care messages . Data on infant feeding practice s were collected by question naire at monthly visits . Intakes of breast milk and nonbreast-milk water were measured in a sub sample of 98 mother-infant pairs ( mean infant age : 14.3 wk ) and compared with question naire data reporting feeding practice s. RESULTS Seventy-five of the 98 subjects reported exclusive breastfeeding . Mean ( + /-SD ) breast milk intake was 884 + /- 163 mL/d in that group and 791 + /- 180 mL/d in the group reported as nonexclusively breastfed ( P = 0.0267 ) . Intakes of nonbreast-milk water were 40 + /- 80.6 and 166 + /- 214 mL/d ( P < 0.0001 ) , respectively . Objective cross-validation using deuterium dilution data showed good accuracy in reporting of feeding practice s , although apparent misreporting was widely present in both groups . CONCLUSIONS The dose-given-to-the-mother deuterium dilution technique can be applied to vali date reported feeding behaviors . Whereas this technique shows that the reports of feeding practice s were accurate at the group level , it is not adequate to distinguish between feeding practice s in individual infants [11120550] CONTEXT Promotion of breastfeeding in Brazilian maternity hospitals . OBJECTIVE To quantify changes in the breastfeeding duration among mothers served by hospitals exposed to the Wellstart-SLC course , comparing them with changes among mothers attended by institutions not exposed to this course . DESIGN R and omized Institutional Trial . SETTING The effects of training on breastfeeding duration was assessed in eight Brazilian hospitals assigned at r and om to either an exposed group ( staff attending the Wellstart-SLC course ) or a control group . SAMPLE For each of the eight study hospitals , two cohorts of about 50 children were visited at home at one and six months after birth . The first cohort ( n = 494 ) was composed of babies born in the month prior to exposure to the Wellstart-SLC course , and the second cohort ( n = 476 ) was composed of babies born six months subsequent to this exposure . MAIN MEASUREMENTS Kaplan-Meier curves were plotted to describe the weaning process and log-rank tests were used to assess statistical differences among survival curves . Hazard ratio ( HR ) estimates were calculated by fitting Cox proportional hazard regression models to the data . RESULTS The increases in estimated , adjusted rates for children born in hospitals with trained personnel were 29 % ( HR = 0.71 ) and 20 % ( HR = 0.80 ) for exclusive and full breastfeeding , respectively . No changes were identified for total breastfeeding . CONCLUSION This r and omized trial supports a growing body of evidence that training hospital health professionals in breastfeeding promotion and protection results in an increase in breastfeeding duration [9233202] The effect of prenatal breastfeeding education on breastfeeding incidence and duration was determined among 31 prenatal WIC participants . The subjects , assigned to a control group ( n= 17 ) or experimental group ( n= 14 ) , received prenatal nutrition education through the WIC program . The experimental group received at least one breastfeeding education class . There was no significant difference in breastfeeding incidence between the groups , however , there was a significant difference in breastfeeding incidence by parity ( p<0.05 ) . There was a significantly higher percentage of women still breastfeeding at 3 and 4 months postpartum in the experimental versus the control group ( p<0.05 ) . The control group breastfed for 29.5 + 43.6 days , while the experimental group breastfed for 76 days + 104.3 ( p=.05 ) . Multiparous women who had bottle-fed previous children breastfed for a shorter duration ( 18 + 22 days ) than primiparous women ( 60 87 days ) ( p<.07 ) [2636685] Objective To assess the effectiveness of an antenatal service using community based breastfeeding peer support workers on initiation of breast feeding . Design Cluster r and omised controlled trial . Setting Community antenatal clinics in one primary care trust in a multiethnic , deprived population . Participants 66 antenatal clinics with 2511 pregnant women : 33 clinics including 1140 women were r and omised to receive the peer support worker service and 33 clinics including 1371 women were r and omised to receive st and ard care . Intervention An antenatal peer support worker service planned to comprise a minimum of two contacts with women to provide advice , information , and support from approximately 24 weeks ’ gestation within the antenatal clinic or at home . The trained peer support workers were of similar ethnic and sociodemographic background s to their clinic population . Main outcome measure Initiation of breast feeding obtained from computerised maternity records of the hospitals where women from the primary care trust delivered . Results The sample was multiethnic , with only 9.4 % of women being white British , and 70 % were in the lowest 10th for deprivation . Most of the contacts with peer support workers took place in the antenatal clinics . Data on initiation of breast feeding were obtained for 2398 of 2511 ( 95.5 % ) women ( 1083/1140 intervention and 1315/1371 controls ) . The groups did not differ for initiation of breast feeding : 69.0 % ( 747/1083 ) in the intervention group and 68.1 % ( 896/1315 ) in the control groups ; cluster adjusted odds ratio 1.11 ( 95 % confidence interval 0.87 to 1.43 ) . Ethnicity , parity , and mode of delivery independently predicted initiation of breast feeding , but r and omisation to the peer support worker service did not . Conclusion A universal service for initiation of breast feeding using peer support workers provided within antenatal clinics serving a multiethnic , deprived population was ineffective in increasing initiation rates . Trial registration Current Controlled Trials IS RCT N16126175 [201032] Background It has proven difficult to reach World Health Organization ( WHO ) recommendations that infants be exclusively breastfed from birth to six months of age [ 1 , 2 ] , yet there is limited knowledge about interventions that are effective in increasing breastfeeding initiation and duration . Particularly lacking is evidence about how to maintain breastfeeding rates in countries which already have a high initiation of breastfeeding . This study aims to determine whether mid-pregnancy breastfeeding education , with a focus on either attitudes to breastfeeding or on technical aspects of breastfeeding , has an effect on rates of breastfeeding initiation and duration . Secondary aims of the study are to : explore what factors might affect the duration of breastfeeding and evaluate the interventions from the participant and childbirth facilitator perspectives . Methods / Design A r and omised controlled trial ( RCT ) design will be used . Women having their first baby , and planning to give birth as public patients at the Royal Women 's Hospital ( RWH ) , Melbourne , will be approached at 18–20 weeks of pregnancy and invited to participate in the study . Participants will be r and omly allocated to a control group or one of two group interventions : a previously design ed and trialled tool to teach practical aspects of breastfeeding or an exploration of family attitudes to breastfeeding . The latter was developed and piloted by the investigators in conjunction with the group facilitators , prior to trial commencement . The interventions are planned to take place at 20–25 weeks . Data will be collected by question naire at recruitment , at interview in hospital after the birth and by telephone interview six months later . Medical/obstetric outcomes will be obtained from the medical record . The sample size ( 972 ) was calculated to identify an increase in breastfeeding initiation from 75 to 85 % and an increase from 40 to 50 % in breastfeeding at six months [23209111] OBJECTIVE : To evaluate a specialized breastfeeding peer counseling ( SBFPC ) intervention promoting exclusive breastfeeding ( EBF ) among overweight/obese , low-income women . METHODS : We recruited 206 pregnant , overweight/obese , low-income women and r and omly assigned them to receive SBFPC or st and ard care ( controls ) at a Baby-Friendly hospital . SBFPC included 3 prenatal visits , daily in-hospital support , and up to 11 postpartum home visits promoting EBF and addressing potential obesity-related breastfeeding barriers . St and ard care involved routine access to breastfeeding support from hospital personnel , including staff peer counselors . Data collection included an in-hospital interview , medical record review , and monthly telephone calls through 6 months postpartum to assess infant feeding practice s , demographics , and health outcomes . Bivariate and logistic regression analyses were conducted . RESULTS : The intervention had no impact on EBF or breastfeeding continuation at 1 , 3 , or 6 months postpartum . In adjusted posthoc analyses , at 2 weeks postpartum the intervention group had significantly greater odds of continuing any breastfeeding ( adjusted odds ratio [ aOR ] : 3.76 [ 95 % confidence interval ( CI ) : 1.07–13.22 ] ) , and giving at least 50 % of feedings as breast milk ( aOR : 4.47 [ 95 % CI : 1.38–14.5 ] ) , compared with controls . Infants in the intervention group had significantly lower odds of hospitalization during the first 6 months after birth ( aOR : 0.24 [ 95 % CI : 0.07–0.86 ] ) . CONCLUSIONS : In a Baby-Friendly hospital setting , SBFPC targeting overweight/obese women did not impact EBF practice s but was associated with increased rates of any breastfeeding and breastfeeding intensity at 2 weeks postpartum and decreased rates of infant hospitalization in the first 6 months after birth [16958717] OBJECTIVE To determine the effects of a prenatal breastfeeding workshop on maternal breastfeeding self-efficacy and breastfeeding duration . DESIGN R and omized controlled trial . SETTING Large tertiary hospital in Ontario , Canada . PARTICIPANTS 110 primiparous women expecting a single child , an uncomplicated birth , and planning to breastfeed . INTERVENTION 2.5-hour prenatal breastfeeding workshop based on adult learning principles and self-efficacy theory . MAIN OUTCOME MEASURE Maternal breastfeeding self-efficacy and the numbers of days and amount of breastfeeding were measured at four and eight weeks postpartum . RESULTS / DATA ANALYSIS : Over time , maternal breastfeeding self-efficacy scores increased in both groups . Women who attended the workshop had higher self-efficacy scores and a higher proportion were exclusively breastfeeding compared to women who did not attend the workshop . There was little difference in the average number of days of breastfeeding , but the intervention group had less weaning . CONCLUSIONS The workshop increased maternal breastfeeding self-efficacy and exclusive breastfeeding [24187119] OBJECTIVES : Despite recent efforts to increase breastfeeding , young African American mothers continue to breastfeed at low rates , and commonly introduce complementary foods earlier than recommended . This study examines the effects of a community doula home visiting intervention on infant feeding practice s among young mothers . METHODS : Low-income , African American mothers ( n = 248 ) under age 22 years participated in a r and omized trial of a community doula intervention . Intervention-group mothers received services from paraprofessional doulas : specialized home visitors trained as childbirth educators and lactation counselors . Doulas provided home visits from pregnancy through 3 months postpartum , and support during childbirth . Control-group mothers received usual prenatal care . Data were obtained from medical records and maternal interviews at birth and 4 months postpartum . RESULTS : Intent-to-treat analyses showed that doula-group mothers attempted breastfeeding at a higher rate than control-group mothers ( 64 % vs 50 % ; P = .02 ) and were more likely to breastfeed longer than 6 weeks ( 29 % vs 17 % ; P = .04 ) , although few mothers still breastfed at 4 months . The intervention also impacted mothers ’ cereal/solid food introduction ( P = .008 ) : fewer doula-group mothers introduced complementary foods before 6 weeks of age ( 6 % vs 18 % ) , while more waited until at least 4 months ( 21 % vs 13 % ) compared with control-group mothers . CONCLUSIONS : Community doulas may be effective in helping young mothers meet breastfeeding and healthy feeding guidelines . The intervention ’s success may lie in the relationship that develops between doula and mother based on shared cultural background and months of prenatal home visiting , and the doula ’s presence at the birth , where she supports early breastfeeding experiences [1635041] Background Despite high levels of breastfeeding initiation in Australia , only 47 percent of women are breastfeeding ( exclusively or partially ) six months later , with marked differences between social groups . It is important to identify women who are at increased risk of early cessation of breastfeeding . Methods Data from the three arms of a r and omised controlled trial were pooled and analysed as a cohort using logistic regression to identify which factors predicted women continuing to feed any breast milk at six months postpartum . The original trial included 981 primiparous women attending a public , tertiary , women 's hospital in Melbourne , Australia in 1999–2001 . The trial evaluated the effect of two mid-pregnancy educational interventions on breastfeeding initiation and duration . In the 889 women with six month outcomes available , neither intervention increased breastfeeding initiation nor duration compared to st and ard care . Independent variables were included in the predictive model based on the literature and discussion with peers and were each tested individually against the dependent variable ( any breastfeeding at six months ) . Results Thirty-three independent variables of interest were identified , of which 25 qualified for inclusion in the preliminary regression model ; 764 observations had complete data available . Factors remaining in the final model that were positively associated with breastfeeding any breast milk at six months were : a very strong desire to breastfeed ; having been breastfed oneself as a baby ; being born in an Asian country ; and older maternal age . There was an increasing association with increasing age . Factors negatively associated with feeding any breast milk at six months were : a woman having no intention to breastfeed six months or more ; smoking 20 or more cigarettes per day pre-pregnancy ; not attending childbirth education ; maternal obesity ; having self-reported depression in the six months after birth ; and the baby receiving infant formula while in hospital . Conclusion In addition to the factors commonly reported as being associated with breastfeeding in previous work , this study found a negative association between breastfeeding outcomes and giving babies infant formula in hospital , a high maternal body mass index , and self-reported maternal depression or anxiety in the six months after the baby was born . Interventions that seek to increase breastfeeding should consider focusing on women who wish to breastfeed but are at high risk of early discontinuation [4587817] Background Interventions promoting optimal infant and young child nutrition could prevent a fifth of under-5 deaths in countries with high mortality . Poor infant and young child feeding practice s are widely documented in Kenya , with potential detrimental effects on child growth , health and survival . Effective strategies to improve these practice s are needed . This study aims to pilot implementation of the Baby Friendly Community Initiative ( BFCI ) , a global initiative aim ed at promoting optimal infant and young child feeding practice s , to determine its feasibility and effectiveness with regards to infant feeding practice s , nutrition and health outcomes in a rural setting in Kenya . Methods The study , employing a cluster-r and omized trial design , will be conducted in rural Kenya . A total of 12 clusters , constituting community units within the government ’s Community Health Strategy , will be r and omized , with half allocated to the intervention and the other half to the control arm . A total of 812 pregnant women and their respective children will be recruited into the study . The mother-child pairs will be followed up until the child is 6 months old . Recruitment will last approximately 1 year from January 2015 , and the study will run for 3 years , from 2014 to 2016 . The intervention will involve regular counseling and support of mothers by trained community health workers and health professionals on maternal , infant and young child nutrition . Regular assessment of knowledge , attitudes and practice s on maternal , infant and young child nutrition will be done , coupled with assessment of nutritional status of the mother-child pairs and morbidity for the children . Statistical methods will include analysis of covariance , multinomial logistic regression and multilevel modeling . The study is funded by the NIH and USAID through the Program for Enhanced Research ( PEER ) Health . Discussion Findings from the study outlined in this protocol will inform potential feasibility and effectiveness of a community-based intervention aim ed at promoting optimal breastfeeding and other infant feeding practice s. The intervention , if proved feasible and effective , will inform policy and practice in Kenya and similar setting s , particularly regarding implementation of the baby friendly community initiative . Trial registration IS RCT N03467700 ; Date of Registration : 24 September [19454915] OBJECTIVE To evaluate the efficacy of a paraprofessional-delivered , home-visiting intervention among young , reservation-based American Indian ( AI ) mothers on parenting knowledge , involvement , and maternal and infant outcomes . METHOD From 2002 to 2004 , expectant AI women aged 12 to 22 years ( n = 167 ) were r and omized ( 1:1 ) to one of two paraprofessional-delivered , home-visiting interventions : the 25-visit " Family Spirit " intervention addressing prenatal and newborn care and maternal life skills ( treatment ) or a 23-visit breast-feeding/nutrition education intervention ( active control ) . The interventions began during pregnancy and continued to 6 months postpartum . Mothers and children were evaluated at baseline and 2 , 6 , and 12 months postpartum . Primary outcomes included changes in mothers ' parenting knowledge and involvement . Secondary outcomes included infants ' social and emotional behavior ; the home environment ; and mothers ' stress , social support , depression , and substance use . RESULTS Participants were mostly teenaged , first-time , unmarried mothers living in reservation communities . At 6 and 12 months postpartum , treatment mothers compared with control mothers had greater parenting knowledge gains , 13.5 ( p < .0001 ) and 13.9 ( p < .0001 ) points higher , respectively ( 100-point scale ) . At 12 months postpartum , treatment mothers reported their infants to have significantly lower scores on the externalizing domain ( beta = -.17 , p < .05 ) and less separation distress in the internalizing domain ( beta = -.17 , p < .05 ) . No between-group differences were found for maternal involvement , home environment , or mothers ' stress , social support , depression , or substance use . CONCLUSIONS This study supports the efficacy of the paraprofessional-delivered Family Spirit home-visiting intervention for young AI mothers on maternal knowledge and infant behavior outcomes . A longer , larger study is needed to replicate results and evaluate the durability of child behavior outcomes [9310540] OBJECTIVE We followed a cohort ( N = 306 ) of infants at well-baby visits in two suburban pediatric practice s to assess the relation of exclusive breastfeeding , and other environmental exposures , to episodes of acute otitis media ( AOM ) and otitis media with effusion ( OME ) . METHODS Detailed prospect i ve information about the exclusiveness of breastfeeding , parental smoking , day care attendance , and family history was obtained at scheduled clinic visits . Tympanometric and otoscopic examinations were used in the diagnosis of otitis media ( OM ) . Nasopharyngeal cultures were performed at 1 - 6 months , and at 8 , 10 , 12 , 15 , 18 , and 24 months of age to detect colonization with middle-ear pathogens . RESULTS Between 6 and 12 months of age , cumulative incidence of first OM episodes increased from 25 % to 51 % in infants exclusively breastfed and from 54 % to 76 % in infants formula-fed from birth . Peak incidence of AOM and OME episodes was inversely related to rates of breastfeeding beyond 3 months of age . A twofold elevated risk of first episodes of AOM or OME was observed in exclusively formula-fed infants compared with infants exclusively breast-fed for 6 months . In the logistic regression analysis , formula-feeding was the most significant predictor of AOM and OME episodes , although age at colonization with middle-ear pathogens and day care ( outside the home ) were significant competing risk factors . A hazard health model suggested additionally that breastfeeding , even for short duration s ( 3 months ) , reduced onset of OM episodes in infancy . CONCLUSIONS Modifiable factors in the onset of AOM and OME episodes during the first 2 years of life include early age at colonization ( < /=3 months of age ) , day care outside the home , and not being breastfed [21787375] We sought to assess the relationship between acculturative type and breastfeeding outcomes among low-income Latinas , utilising a multidimensional assessment of acculturation . We analysed data derived from a breastfeeding peer counselling r and omised trial . Acculturation was assessed during pregnancy using a modified Acculturation Rating Scale for Mexican Americans scale . Analyses were restricted to Latinas who completed the acculturation scale and had post-partum breastfeeding data ( n = 114 ) . Cox survival analyses were conducted to evaluate differences in breastfeeding continuation and exclusivity by acculturative type . Participants were classified as integrated-high ( 23.7 % , n = 27 ) , traditional Hispanic ( 36.8 % , n = 42 ) , integrated-low ( 12.3 % , n = 14 ) and assimilated ( 27.2 % , n = 31 ) . The integrated-low group was significantly more likely to continue breastfeeding than the traditional Hispanic , assimilated , and integrated-high groups ( P < 0.05 , P < 0.05 , and P < 0.01 , respectively ) . The traditional Hispanic group was marginally more likely to continue breastfeeding than the integrated-high group ( P = 0.06 ) . Breastfeeding continuation rates vary significantly between acculturative types in this multinational , low-income Latina sample . Multidimensional assessment s of acculturation may prove useful in better tailoring future breastfeeding promotion interventions [4522088] Background Very few Australian infants are exclusively breastfed to 6 months as recommended by the World Health Organization . There is strong empirical evidence that fathers have a major impact on their partner ’s decision to breastfeed and continuation of breastfeeding . Fathers want to participate in the breastfeeding decision making process and to know how they can support their partner to achieve their breastfeeding goals . The aim of the Parent Infant Feeding Initiative ( PIFI ) is to evaluate the effect on duration of any and exclusive breastfeeding of three breastfeeding promotion interventions of differing intensity and duration , targeted at couples but channelled through the male partner . The study will also undertake a cost-effectiveness evaluation of the interventions . Methods / design The PIFI study is a factorial r and omised controlled trial . Participants will be mothers and their male partners attending antenatal classes at selected public and private hospitals with maternity departments in Perth , Western Australia . Fathers will be r and omly allocated to either the usual care control group ( CG ) , one of two medium intensity ( MI1 and MI2 ) interventions , or a high intensity ( HI ) intervention . MI1 will include a specialised antenatal breastfeeding education session for fathers with supporting print material s. MI2 will involve the delivery of an antenatal and postnatal social support intervention delivered via a smartphone application and HI will include both the specialised antenatal class and the social support intervention . Outcome data will be collected from couples at baseline and at six and 26 weeks postnatally . A total of 1600 couples will be recruited . This takes into account a 25 % attrition rate , and will detect at least a 10 % difference in the proportion of mothers breastfeeding between any two of the groups at 26 weeks at 80 % power and 5 % level of significance , using a Log-rank survival test . Multivariable survival and logistic regression analyses will be used to assess the effect of the treatment groups on the outcomes after adjusting for covariates . Discussion The PIFI study will be the first Australian study to provide Level II evidence of the impact on breastfeeding duration of a comprehensive , multi-level , male-partner-focused breastfeeding intervention . Unique features of the intervention include its large sample size , delivery of two of the interventions by mobile device technology , a rigorous assessment of intervention fidelity and a cost-effectiveness evaluation . Trial registration Australian New Zeal and Clinical Trials Registry ACTRN12614000605695 . Registered 6 June [8568022] This study was undertaken to determine the effects of a partner-support , incentive-baed educational program on breast feeding knowledge , attitudes and support and to examine the relationship between feeding intentions and feeding behavior among low-income women . Women who expressed a willingness to participate in the intervention were r and omly assigned to “ intervention ” and “ usual breast feeding ” ( control ) groups . Sixty-eight primipara women , with expected due date s between May and December , 1992 , volunteered to participate in the study . Of these , 34 were r and omly assigned to each of the two groups . Approximately 81 percent of the women completed the study , leaving n=29 in the control group and n-26 in the intervention group . The intervention consisted of special incentives ( prizes ) for women and their partners to participate in several breast feeding education and promotion activities . Intervention group women and their partners experienced positive changes in breast feeding knowledge and attitudes . Furthermore , the intervention seemed to have influenced more women in the treatment group to breast feed despite their prenatal feeding intentions . In addition , the partners of intervention group women were perceived to be more supportive of , breast feeding than control group partners . These findings suggest that incentives , such as donated prizes , can be used to attract lower socioeconomic group women and their partners to breast feeding promotion interventions . Participation in such interventions can produce positive changes in breast feeding knowledge , attitudes , and support , and can have a dramatic effect in promoting breast feeding [3879433] Background Nutrition in the first 1,000 days of life ( during pregnancy and the first two years ) is critical for child growth and survival . Poor maternal , infant and young child nutrition ( MIYCN ) practice s are widely documented in Kenya , with potential detrimental effects on child growth and survival . This is particularly a problem in slums , where most urban residents live . For example , exclusive breastfeeding for the first six months is only about two per cent . Innovative strategies to reach slum residents are therefore needed . Strategies like the Baby Friendly Hospital Initiative have proven effective in some setting s but their effectiveness in re source -limited setting s , including slums where many women do not deliver in hospital , is question able . We propose to test the effectiveness of a home-based intervention on infant feeding practice s , nutrition and health outcomes of infants born in two slums in Nairobi , Kenya . Methods / Design The study , employing a cluster-r and omised study design , will be conducted in two slums in Nairobi : Korogocho and Viw and ani where 14 community units ( defined by the Government ’s health care system ) will form the unit of r and omization . A total of 780 pregnant women and their respective child will be recruited into the study . The mother-child pair will be followed up until the child is one year old . Recruitment will last approximately one year and three months from September 2012 to December 2013 . The mothers will receive regular , personalised , home-based counselling by trained Community Health Workers on MIYCN . Regular assessment of knowledge , attitudes and practice s on MIYCN will be done , coupled with assessment s of nutritional status of the mother-child pairs and diarrhea morbidity for the children . Statistical methods will include analysis of covariance and multinomial logistic regression . Additionally , cost-effectiveness analysis will be done . The study is funded by the Wellcome Trust and will run from March 2012 to February 2015 . Discussion Interventions aim ed at promoting optimal breastfeeding and complementary feeding practice s are considered to have high impact and could prevent a fifth of the under-five deaths in countries with high mortality rates . This study will inform policy and practice in Kenya and similar setting s regarding delivery mechanisms for such high-impact interventions , particularly among urban poor population s . Trial registration IS RCT [14703543] Abstract Objective To investigate whether offering volunteer support from counsellors in breast feeding would result in more women breast feeding . Design R and omised controlled trial . Setting 32 general practice s in London and south Essex . Participants 720 women considering breast feeding . Main outcome measures Primary outcome was prevalence of any breast feeding at six weeks . Secondary outcomes were the proportion of women giving any breast feeds , or bottle feeds at four months , duration of any breast feeding , time to introduction of bottle feeds , and satisfaction with breast feeding . Results Offering support in breast feeding did not significantly increase the prevalence of any breast feeding to six weeks ( 65 % ( 218/336 ) in the intervention group and 63 % ( 213/336 ) in the control group ; relative risk 1.02 , 95 % confidence interval 0.84 to 1.24 ) . Survival analysis up to four months confirmed that neither duration of breast feeding nor time to introduction of formula feeds differed significantly between control and intervention groups . Not all women in the intervention group contacted counsellors postnatally , but 73 % ( 123/179 ) of those who did rated them as very helpful . More women in the intervention group than in the control group said that their most helpful advice came from counsellors rather than from other sources . Conclusions Women valued the support of a counsellor in breast feeding , but the intervention did not significantly increase breastfeeding rates , perhaps because some women did not ask for help [17088511] OBJECTIVE To assess the impact of a paraprofessional-delivered home-visiting intervention to promote child care knowledge , skills , and involvement among pregnant American Indian adolescents . DESIGN R and omized controlled trial comparing a family-strengthening intervention with a breastfeeding education program . SETTING One Apache and 3 Navajo communities . PARTICIPANTS Fifty-three pregnant American Indian adolescents were r and omly assigned to intervention ( n = 28 ) or control ( n = 25 ) groups . Follow-up data were available for 19 intervention and 22 control participants . Intervention Paraprofessionals delivered 41 prenatal and infant care lessons in participants ' homes from 28 weeks ' gestation to 6 months post partum . MAIN OUTCOME MEASURES Child care knowledge , skills , and involvement . RESULTS Mothers in the intervention compared with the control group had significantly higher parent knowledge scores at 2 months ( adjusted mean difference [ AMD ] , + 14.9 [ 95 % confidence interval ( CI ) , + 7.5 to + 22.4 ] ) and 6 months post partum ( AMD , + 15.3 [ 95 % CI , + 5.9 to + 24.7 ] ) . Intervention group mothers scored significantly higher on maternal involvement scales at 2 months post partum ( AMD , + 1.5 [ 95 % CI , -0.02 to + 3.02 ] ) , and scores approached significance at 6 months post partum ( AMD , + 1.1 [ 95 % CI , -0.06 to + 2.2 ] ) . No between-group differences were found for child care skills . CONCLUSIONS A paraprofessional-delivered , family-strengthening home-visiting program significantly increased mothers ' child care knowledge and involvement . A longer and larger trial is needed to underst and the intervention 's potential to improve adolescent parenting and related child outcomes in American Indian communities [23039968] OBJECTIVE To determine the impact of facility-based semi-intensive and home-based intensive counselling in improving exclusive breast-feeding ( EBF ) in a low-re source urban setting in Kenya . DESIGN A cluster r and omized controlled trial in which nine villages were assigned on a 1:1:1 ratio , by computer , to two intervention groups and a control group . The home-based intensive counselling group ( HBICG ) received seven counselling sessions at home by trained peers , one prenatally and six postnatally . The facility-based semi-intensive counselling group ( FBSICG ) received only one counselling session prenatally . The control group ( CG ) received no counselling from the research team . Information on infant feeding practice s was collected monthly for 6 months after delivery . The data -gathering team was blinded to the intervention allocation . The outcome was EBF prevalence at 6 months . SETTING Kibera slum , Nairobi . SUBJECTS A total of 360 HIV-negative women , 34 - 36 weeks pregnant , were selected from an antenatal clinic in Kibera ; 120 per study group . RESULTS Of the 360 women enrolled , 265 completed the study and were included in the analysis ( CG n 89 ; FBSICG n 87 ; HBICG n 89 ) . Analysis was by intention to treat . The prevalence of EBF at 6 months was 23.6 % in HBICG , 9.2 % in FBSICG and 5.6 % in CG . HBICG mothers had four times increased likelihood to practise EBF compared with those in the CG ( adjusted relative risk = 4.01 ; 95 % CI 2.30 , 7.01 ; P=0.001 ) . There was no significant difference between EBF rates in FBSICG and CG . CONCLUSIONS EBF can be promoted in low socio-economic conditions using home-based intensive counselling . One session of facility-based counselling is not sufficient to sustain EBF [7554017] Assessed is a breast-feeding training course that was attended by health professionals at the Santos Lactation Center ( SLC ) , Santos , São Paulo , Brazil , as well as its impact on the implementation of breast-feeding programmes in maternity hospitals . Eight maternity hospitals were studied -- four were r and omly allocated to the experimental group and sent three health professionals to attend an 18-day course at SLC ; the remaining four institutions constituted the control group . The compliance of all eight hospitals with WHO/UNICEF 's " Ten steps for successful breast-feeding " was determined using scores obtained before and 6 months after the training course . Institutions in the experimental group had an improved score , but those in the control group did not . The SLC training course was efficient since it enabled the participants to promote breast-feeding practice s. However , in order to succeed in implementing breast-feeding programmes , health professionals require also to develop skills to apply the knowledge they acquire in the course , as well as to involve the whole maternity unit team in the activities [16143742] OBJECTIVE To assess the efficacy of peer counseling to promote exclusive breastfeeding ( EBF ) among low-income inner-city women in Hartford , Conn. DESIGN Participants recruited prenatally were r and omly assigned to either receive support for EBF from a peer counselor plus conventional breastfeeding support ( peer counseling group [ PC ] ) or only conventional breastfeeding support ( control group [ CG ] ) and followed through 3 months post partum . SETTING Low-income predominantly Latina community . PARTICIPANTS Expectant mothers , less than 32 weeks gestation and considering breastfeeding ( N = 162 ) . Intervention Exclusive breastfeeding peer counseling support offering 3 prenatal home visits , daily perinatal visits , 9 postpartum home visits , and telephone counseling as needed . MAIN OUTCOME MEASURES Exclusive breastfeeding rates at hospital discharge , 1 , 2 , and 3 months post partum ( n = 135 ) . RESULTS At hospital discharge , 24 % in the CG compared with 9 % in the PC had not initiated breastfeeding , with 56 % and 41 % , respectively , nonexclusively breastfeeding . At 3 months , 97 % in the CG and 73 % in the PC had not exclusively breastfed ( relative risk [ RR ] = 1.33 ; 95 % CI , 1.14 - 1.56 ) during the previous 24 hours . The likelihood of nonexclusive breastfeeding throughout the first 3 months was significantly higher for the CG than the PC ( 99 % vs 79 % ; RR = 1.24 ; 95 % CI , 1.09 - 1.41 ) . Mothers in the CG were less likely than their PC counterparts to remain amenorrheic at 3 months ( 33 % vs 52 % ; RR = 0.64 ; 95 % CI , 0.43 - 0.95 ) . The likelihood of having 1 or more diarrheal episode in infants was cut in half in the PC ( 18 % vs 38 % ; RR = 2.15 ; 95 % CI , 1.16 - 3.97 ) . CONCLUSION Well-structured , intensive breastfeeding support provided by hospital and community-based peer counselors is effective in improving exclusive breastfeeding rates among low-income , inner-city women in the United States [25437725] OBJECTIVE : To evaluate the effectiveness of a professional one-to-one antenatal breastfeeding support and education intervention on the exclusivity and duration of breastfeeding . METHODS : A total of 469 primiparous women who attended the antenatal clinics of two geographically distributed public hospitals in Hong Kong were r and omized to receive either st and ard antenatal care or a one-to-one antenatal breastfeeding support and education session . The primary outcome was the prevalence of exclusive breastfeeding at 6 weeks postpartum . Secondary outcomes were the prevalence of exclusive breastfeeding at 3 and 6 months postpartum as well as the overall duration of any and exclusive breastfeeding across the first 6 months postpartum . RESULTS : The exclusive breastfeeding rate in the intervention group was 37.8 % at 6 weeks postpartum compared with 36.4 % in the st and ard care group ( P=.77 ; 95 % confidence interval [ CI ] −0.08 to 0.11 ) . There were no significant differences between the two treatment groups in exclusive breastfeeding rates at 3 and 6 months or in the overall duration of any ( hazard ratio [ HR ] 1.11 , 95 % CI 0.88–1.40 ] or exclusive breastfeeding ( HR 0.96 , 95 % CI 0.79–1.17 ) . The study had a least 80 % power to detect a 50 % increase in the rate of exclusive breastfeeding at 6 weeks postpartum . CONCLUSION : In a setting with a high breastfeeding initiation rate , one-to-one antenatal breastfeeding support and education did not increase the exclusivity or duration of breastfeeding . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT01648114 . LEVEL OF EVIDENCE : [16045516] Objective To evaluate the affect of an antenatal educational breastfeeding intervention on women 's breastfeeding duration [15351756] BACKGROUND Breastfeeding peer counseling has improved breastfeeding rates in developing countries ; however , its impact in this country has not been adequately evaluated . OBJECTIVE To evaluate the effectiveness of an existing , breastfeeding peer counseling program within the United States . DESIGN R and omized , prospect i ve , controlled trial in which participants were recruited prenatally and r and omly assigned to receive either routine breastfeeding education or routine breastfeeding education plus peer counseling . SETTING An urban hospital serving a large population of low-income Latinas . PARTICIPANTS Pregnant women ( < or = 26 weeks ' gestation ) were recruited from the hospital 's prenatal clinic . Inclusion criteria specified that participants be low income , be considering breastfeeding , have delivered a healthy , full-term singleton , and have access to a telephone . Intervention Breastfeeding peer counseling services included 1 prenatal home visit , daily perinatal visits , 3 postpartum home visits , and telephone contact as needed . MAIN OUTCOME MEASURES Breastfeeding rates at birth and 1 , 3 , and 6 months postpartum . RESULTS The proportion not initiating breastfeeding was significantly lower in the intervention group than among controls ( 8/90 [ 9 % ] vs 17/75 [ 23 % ] ; relative risk , 0.39 ; 95 % confidence interval , 0.18 - 0.86 ) . The probability of stopping breastfeeding also tended to be lower in the intervention group at both 1 month ( 36 % vs 49 % ; relative risk , 0.72 ; 95 % confidence interval , 0.50 - 1.05 ) and 3 months ( 56 % vs 71 % ; relative risk , 0.78 ; 95 % confidence interval , 0.61 - 1.00 ) . CONCLUSION These findings demonstrate that , in the United States , peer counselors can significantly improve breastfeeding initiation rates and have an impact on breastfeeding rates at 1 and 3 months post partum [23329167] Mothers need consistent , sustained information and support to develop and meet personal breastfeeding goals , but often receive insufficient assistance and conflicting and incorrect advice . The use of technology may be helpful in supplementing existing health care professional breastfeeding education and support efforts . We developed and evaluated a computer-based animated , interactive agent design ed to provide breastfeeding information and support to mothers interested in breastfeeding . A r and omized controlled study of a first-generation system was conducted to determine the feasibility of ( 1 ) use of the Computer Agent ; ( 2 ) the recruitment plan ; and ( 3 ) the planned outcome evaluation ( assessing the impact of the intervention on intent to breastfeed , attitudes towards breastfeeding , and breastfeeding self-efficacy ) . The pilot study ( N = 15 ) showed that the use of the Computer Agent , the recruitment plan , and the planned outcome evaluation were all feasible . Mothers who used the Computer Agent had greater intentions to exclusively breastfeed after exposure to the Agent ( intent to exclusively breastfeed for 6 months 1–7 scale score of 6.14 ( post ) vs. 5.14 ( pre ) ; p < 0.05 ) . Non-statistically significant trends in improvement with use of the Computer Agent breastfeeding support system were also seen in the between subjects analyses of intent to breastfeed and breastfeeding self-efficacy . The pilot study demonstrated the feasibility of using a Computer Agent to support breastfeeding mothers and informed the design of a larger r and omized clinical trial . An interactive Computer Agent may be helpful in improving rates of exclusive breastfeeding , particularly when there is not adequate health care professional support [24262719] OBJECTIVE The purpose of this study was to compare breastfeeding duration in mothers after delivery who were assigned r and omly to a behavioral educational intervention vs enhanced usual care . STUDY DESIGN We conducted a r and omized trial . Self-identified black and Latina mothers early after delivery were assigned r and omly to receive a behavioral educational intervention or enhanced usual care . The 2-step intervention aim ed to prepare and educate mothers about postpartum symptoms and experiences ( including tips on breastfeeding and breast/nipple pain ) and to bolster social support and self-management skills . Enhanced usual care participants received a list of community re sources and received a 2-week control call . Intention-to-treat analyses examined breastfeeding duration ( measured in weeks ) for up to 6 months of observation . This study was registered with clinical trial.gov ( NCT01312883 ) . RESULTS Five hundred forty mothers were assigned r and omly to the intervention ( n = 270 ) vs control subjects ( n = 270 ) . Mean age was 28 years ( range , 18 - 46 years ) ; 62 % of the women were Latina , and 38 % were black . Baseline sociodemographic , clinical , psychosocial , and breastfeeding characteristics were similar among intervention vs control subjects . Mothers in the intervention arm breastfed for a longer duration than did the control subjects ( median , 12.0 vs 6.5 weeks , respectively ; P = .02 ) Mothers in the intervention arm were less likely to quit breastfeeding over the first 6 months after delivery ( hazard ratio , 0.79 ; 95 % confidence interval , 0.65 - 0.97 ) . CONCLUSION A behavioral educational intervention increased breastfeeding duration among low-income , self-identified black and Latina mothers during the 6-month postpartum period [16113021] The factors that influence the actual initiation and duration of breastfeeding were studied among low-income women followed by the Canada Prenatal Nutrition Program ( CPNP ) . A group of 196 pregnant women were selected at r and om from a sample of 6223 pregnant women who registered with the CPNP . Two 24-hour recalls and information regarding lifestyle habits , peer support , and infant-feeding practice s were obtained between 26 and 34 weeks of gestation and 21 days and 6 months after birth . Women who received a university education ( completed or not completed ) versus women with [ .lessequal ] high school education ( odds ratio [ OR ] , 8.40 ; 95 % confidence interval [ CI ] , 1.02 - 69.50 ) , women born outside Canada ( OR,8.81 ; 95 % CI , 3.34 - 23.19 ) , and women of low birth weight infants ( OR , 0.39 ; 95 % CI , 0.16 - 0.96 ) were more likely to initiate breastfeeding . Late introduction of solid foods ( P = .004 ) , nonsmoking ( P = .005 ) , multiparity ( P = .012 ) , and a higher level of education ( P = .049 ) were positively associated with the duration of breastfeeding among initiators . Underst and ing factors associated with initiation and duration of breastfeeding among low-income women is critical to better target breastfeeding promotion [26289058] Background : Guidelines recommend prenatal education to improve breastfeeding rates ; however , effective educational interventions targeted at low-income , minority population s are needed as they remain less likely to breastfeed . Objective : To determine whether a low-cost prenatal education video improves hospital rates of breastfeeding initiation and exclusivity in a low-income population . Methods : A total of 522 low-income women were r and omized during a prenatal care visit occurring in the third trimester to view an educational video on either breastfeeding or prenatal nutrition and exercise . Using multivariable analyses , breastfeeding initiation rates and exclusivity during the hospital stay were compared . Results : Exposure to the intervention did not affect breastfeeding initiation rates or duration during the hospital stay . The lack of an effect on breastfeeding initiation persisted even after controlling for partner , parent , or other living at home and infant complications ( adjusted odds ratio [ OR ] = 1.05 , 95 % CI , 0.70 - 1.56 ) . In addition , breastfeeding exclusivity rates during the hospital stay did not differ between the groups ( P = .87 ) . Conclusion : This study suggests that an educational breastfeeding video alone is ineffective in improving the hospital breastfeeding practice s of low-income women . Increasing breastfeeding rates in this at-risk population likely requires a multipronged effort begun early in pregnancy or preconception [12449049] The objective of this study was to prospect ively explore the influence ofwomen ’s experiences in preparing for and establishing breastfeeding on the duration of breastfeeding . A cohort of 490 women was surveyed at intervals during pregnancy and after giving birth . Data were collected on breastfeeding outcomes and experiences and analyzed using multiple logistic regression . After controlling for sociodemographic variables , women were less likely to be still fully breastfeeding at 6 to 10 weeks postpartum if they believed they needed more breastfeeding information prior to delivery or had experienced breastfeeding problems . Women were less likely to be fully breastfeeding at 4 months postpartum if they had experienced breastfeeding problems . This prospect i ve study demonstrated the influence ofwomen ’s preparedness for breastfeeding and their experiences in establishing breastfeeding on breastfeeding duration . Improvements in prenatal education about breastfeeding and management of breastfeeding problems are likely to increase breastfeeding duration [15330879] BACKGROUND Despite high levels of breastfeeding initiation in Australia , only 46 percent of women are still breastfeeding ( exclusively or partially ) 6 months later , with marked differences between social groups . This study aim ed to determine the influence of mid-pregnancy breastfeeding education on the proportions of women breastfeeding at hospital discharge , and on the duration of breastfeeding . METHODS A r and omized controlled trial to compare two strategies for increasing the initiation and duration of breastfeeding was conducted , in which 981 primiparas who attended a public , tertiary women 's hospital in Melbourne , Australia , were r and omized to one of two interventions or to st and ard care ( 327 in each group ) . The interventions were a 1.5-hour class on practical aspects of breastfeeding using a previously tested tool ( Practical Skills ) , and two 1-hour classes exploring family and community attitudes toward , and experiences of , breastfeeding ( Attitudes ) . Both interventions took place in interactive small groups when women were in mid-pregnancy . Breastfeeding initiation was ascertained by interview 2 to 4 days after birth , and breastfeeding duration was assessed by telephone interview 6 months after birth . RESULTS Neither intervention increased breastfeeding initiation or duration compared with st and ard care . Rates at initiation were 97 percent ( 296/306 ) for the Practical Skills intervention , 95 percent ( 291/308 ) for the Attitudes intervention , and 96 percent ( 297/310 ) for st and ard care . Rates at 6 months were , respectively , 55 percent ( 162/297 ) , 50 percent ( 146/293 ) , and 54 percent ( 162/299 ) . CONCLUSIONS In setting s where breastfeeding initiation is already high , neither study intervention could be recommended as an effective strategy to increase breastfeeding initiation or duration [7860944] OBJECTIVE To determine the effects of a partner-supported , incentive-based educational program on rates and duration of breast-feeding among low-income women . DESIGN Women who expressed a willingness to participate in the breast-feeding educational program were r and omly assigned to one of two groups : an intervention group and a control group who received usual breast-feeding education . SETTING Clinics of the Special Supplemental Food Program for Women , Infants , and Children in Flagstaff , Ariz. SUBJECTS Sixty-eight primiparous pregnant women with expected due date s between May 1992 and December 1992 were willing to participate in the study . Of these , 34 were r and omly assigned to the intervention group and 34 to the control group . Approximately 81 % of the women completed the study : 29 in the control group and 26 in the intervention group . INTERVENTION The intervention consisted of special incentives ( prizes ) for women and their partners to participate in a breast-feeding class for expectant couples and an educational series on childbirth . Women were also encouraged to use a breast-feeding support program in which peers serve as role models . MAIN OUTCOME MEASURES The primary outcome measure was infant feeding method . Data were collected from mothers in both groups at the time of discharge from the hospital and at 2 weeks , 6 weeks , and 3 months postpartum . STATISTICAL ANALYSES PERFORMED Binomial proportional analyses of the feeding data were performed . RESULTS Women in the intervention group reported a higher percentage of breast-feeding at all measurement times . APPLICATIONS These findings suggest that incentives , such as donated prizes , can be used to attract primiparous women from lower socioeconomic groups , along with their partners , to participate in educational interventions design ed to promote breast-feeding . Participation by couples in breast-feeding promotion activities can dramatically increase the rate and duration of breast-feeding [9183091] Breast feeding rates in Irel and have stagnated at around 33 % over the past 10 years . We aim ed to assess the effect of a simple intervention in late pregnancy on breast feeding rates . The study was r and omised and prospect i ve . In the intervention group a sheet illustrating eight positive aspects of breast feeding was presented to mothers at their 36 week antenatal visit . This information was reinforced with a question naire on the topic of breast feeding . The control group received a routine antenatal care . There were 98 mothers in the intervention group and 95 controls . A similar percentage in each group had medical cards . On discharge from hospital 31.5 % of controls and 43.9 % of the test group were breast feeding . This difference just failed to reach statistical significance ( P = 0.07 ) . The intervention , which took just three minutes of a medical student 's time , appeared to result in an improved breast feeding rate . Though the difference did not reach statistical significance , this reflects , in part , the small numbers in the study . About half of the women in the study indicated that no doctor had offered any advice on the choice of feeding . Since this minor intervention produced a good response , it would seem appropriate to adopt a more positive attitude in the promotion of breast feeding [15530582] BACKGROUND In the Netherl and s , the initiation rate of breast-feeding ( BF ) was 80 % in 2002 , but only 35 % of the mothers continued to breast-feed for 3 months . This study examined the effectiveness of a breast-feeding promotion program to increase the continuation of breast-feeding . METHODS A cluster-r and omized intervention trial was used . Ten child health care centers in three regions of the home health care were r and omly allocated to the program or usual care . Elements in the program were health counseling , measures to enhance cooperation , early signaling of breast-feeding problems and continuity of care , and lactation consultancy . Pregnant mothers who applied for home health care in the intervention or usual care regions were enrolled and were followed up from pregnancy until 6 months postpartum ( n = 683 ) . The primary outcome measure was the continuation of breast-feeding until at least 3 months . RESULTS The 3-month breast-feeding rate was 32 % in the intervention and 38 % in the control groups ( OR = 0.79 , 95 % CI = 0.58 - 1.08 ) . CONCLUSION The program was not effective . We discuss possible explanations from the design and execution of the trial and give some points for improvement of our program , such as the categories of caregivers involved and the number and duration of contacts after parturition [2235229] Many factors are associated with low breast-feeding rates among black low-income women . This study examines whether , despite such factors , health professionals ' prenatal education of black poor women is associated with increased breast-feeding rates . Black women born in the United States who attended a midwives prenatal clinic ( N = 159 ) were r and omly assigned to two types of prenatal education or were followed up in a control group . All women were interviewed on entry into the study and after delivery of their infants . Women assigned to group classes attended at least one session discussing myths , problems , and benefits of breast-feeding . Women assigned to individual prenatal counseling spoke with a pediatrician or nurse practitioner , who discussed breast-feeding topics similar to those covered in the classes . Women in the control group received no additional prenatal education . The three study groups had significantly different percentages of women who breast-fed ( controls 22 % , classes 46 % , individual sessions 53 % ) . Higher percentages of women in the study groups carried out their prenatal plans to breast-feed ( controls 50 % , classes 86 % , individual sessions 62 % ) or breast-fed despite prenatal plans to bottle-feed ( controls 10 % , classes 26 % , individual sessions 48 % ) . After multivariable analysis controlling for age , prenatal plans to breast-feed , prior breast-feeding experience , perceived support for breast-feeding , education , gravidity , and employment plans , women in intervention groups had a higher likelihood of breast-feeding than control subjects . These findings suggest that an increase in relatively simple , not-too-time-consuming educational efforts in institutions and offices serving black low-income women might yield significant narrowing of the gap in breast-feeding rates between white affluent women and black low-income women [16128971] BACKGROUND Breastfeeding conveys many benefits , but women often encounter difficulties in the first few weeks . The objective of this study was to examine women 's perspectives on the information , advice , and support they receive with breastfeeding . METHODS A qualitative analysis was conducted of women 's responses to open questions about their experiences of breastfeeding support . Participants were recruited as part of a r and omized controlled trial of additional support from volunteer breastfeeding counselors , and they completed question naires when their babies were 6 weeks old . RESULTS Of the 720 women recruited to the trial , 654 began breastfeeding and completed postnatal question naires ; 492 ( 75 % ) participants were first-time mothers and 200 ( 31 % ) were of minority ethnic origin . At 6 weeks , 249 ( 38 % ) women were exclusively breastfeeding , 183 ( 28 % ) were both breastfeeding and bottle-feeding , whereas 222 ( 34 % ) were exclusively bottle-feeding . Although many women commented positively on their experiences , others thought they did not receive the information and support they needed . Thematic analysis of women 's responses to open questions identified five components of the support that women wanted : information about breastfeeding and what to expect , practical help with positioning the baby to breastfeed , effective advice and suggestions , acknowledgment of mothers ' experiences and feelings , and reassurance and encouragement . CONCLUSIONS Maternity services should address the components identified by the study findings as constituting good breastfeeding support . Guidance and information for family members and training for those involved in peer or professional initiatives should take into account women 's views on what support they want , together with when and how they want it provided [10217083] BACKGROUND Exclusive breastfeeding is recommended worldwide but not commonly practised . We undertook a r and omised controlled study of the efficacy of home-based peer counselling to increase the proportion of exclusive breastfeeding among mothers and infants residing in periurban Mexico City . METHODS Two intervention groups with different counselling frequencies , six visits ( 44 ) and three visits ( 52 ) , were compared with a control group ( 34 ) that had no intervention . From March , 1995 , to September , 1996 , 170 pregnant women were identified by census and invited to participate in the study . Home visits were made during pregnancy and early post partum by peer counsellors recruited from the same community and trained by La Leche League . Data were collected by independent interview . Exclusive breastfeeding was defined by WHO criteria . FINDINGS 130 women participated in the study . Only 12 women refused participation . Study groups did not differ in baseline factors . At 3 months post partum , exclusive breastfeeding was practised by 67 % of six-visit , 50 % of three-visit , and 12 % of control mothers ( intervention groups vs controls , p<0.001 ; six-visit vs three-visit , p=0.02 ) . Duration of breastfeeding was significantly ( p=0.02 ) longer in intervention groups than in controls , and fewer intervention than control infants had an episode of diarrhoea ( 12 % vs 26 % , p=0.03 ) . INTERPRETATION This is the first reported community-based r and omised trial of breastfeeding promotion . Early and repeated contact with peer counsellors was associated with a significant increase in breastfeeding exclusivity and duration . The two-fold decrease in diarrhoea demonstrates the importance of breastfeeding promotion to infant health [15063960] OBJECTIVE To assess the impact of experiential learning method ologies in primiparous women on their choice and maintenance of an infant feeding method . STUDY DESIGN A prospect i ve controlled study into experiential learning methods applied to patients with four months ' follow up . Seventy-three primiparous women attending the antenatal clinic at the West Suffolk Hospital for their 32 weeks check were allocated to two groups on the basis of date of attendance . Multiple pregnancy and serious illness were excluded . Thirty-three women attended a two hour seminar on breast feeding using experiential techniques . Forty had routine antenatal care and acted as controls . Breast feeding rates of the two groups were recorded at various stages . Assessment also included comments from question naires . RESULTS The two groups did not differ significantly in the number of women proposing to breast feed their infants ( Z = -0.0490 , P = 0.9609 ) nor in the numbers of women breast feeding on day one ( Z = -0.6203 , P = 0.5350 ) . There were proportionally more women breast feeding their infants at two weeks ( Z = -1.4944 , P = 0.1351 ) in the subject group , but this was not statistically significant . However , the difference at four months was significant , ( Z = -2.5784 , P = 0.0099 ) , more than double the percentage of controls maintaining some breast feeding to four months in the subject group . CONCLUSIONS Experiential learning was associated with increased rates of prolonged breast feeding , possibly due to increased patient confidence in their choice . This learning approach could be applied to other areas of patient health education [16322166] Objective . To determine whether an individualized , prenatal and postnatal , lactation consultant intervention result ed in increased cumulative intensity of breastfeeding up to 52 weeks . Design . The r and omized , nonblinded , controlled trial recruited women from prenatal care . Baseline prenatal interviews covered demographic data and breastfeeding experience , intention , and knowledge . Interviews at 1 , 2 , 3 , 4 , 6 , 8 , 10 , and 12 months after birth collected data on weekly feeding patterns , infant illness , and infant health care use . Setting . Two community health centers serving low-income , primarily Hispanic and /or black women . Participants . The analytic sample included 304 women ( intervention : n = 145 ; control : n = 159 ) with ≥1 postnatal interview . Intervention . Study lactation consultants attempted 2 prenatal meetings , a postpartum hospital visit , and /or home visits and telephone calls . Control subjects received the st and ard of care . Outcome Measures . Cumulative breastfeeding intensity at 13 and 52 weeks , based on self-reports of weekly feeding , on a 7-level scale . Results . The intervention group was more likely to breastfeed through week 20 ( 53.0 % vs 39.3 % ) . Exclusive breastfeeding rates were low and did not differ according to group . In multivariate analyses , control subjects had lower breastfeeding intensity at 13 weeks ( odds ratio [ OR ] : 1.90 ; 95 % confidence interval [ CI ] : 1.13–3.20 ) and 52 weeks ( OR : 2.50 ; 95 % CI : 1.48–4.21 ) . US-born control subjects had lowest breastfeeding intensity at 13 weeks ( OR : 5.22 ; 95 % CI : 2.43–11.22 ) and 52 weeks ( OR : 5.25 ; 95 % CI : 2.44–11.29 ) . There were no significant differences in breastfeeding intensity among the US-born intervention , foreign-born intervention , and foreign-born control groups . Conclusions . This “ best- practice s ” intervention was effective in increasing breastfeeding duration and intensity . Breastfeeding promotion should focus on US-born women and exclusive breastfeeding [15467529] OBJECTIVE Recognizing that an expectant father may influence a mother 's decision to breast- or formula-feed , we tested the effectiveness of a simple , educational intervention that was design ed to encourage fathers to advocate for breastfeeding and to assist his partner if she chooses to breastfeed . STUDY DESIGN We conducted a r and omized controlled trial in which expectant fathers ( n = 59 ) were assigned r and omly to attend either a 2-hour intervention class on infant care and breastfeeding promotion ( intervention ) or a class on infant care only ( control group ) . The classes , which were led by a peer-educator , were interactive and informal and utilized different media to create an accessible environment for participants . Couples were recruited during the second trimester from a university obstetrics practice . RESULTS Overall , breastfeeding was initiated by 74 % of women whose partners attended the intervention class , as compared with 41 % of women whose partners attended the control class ( P = .02 ) . CONCLUSION Expectant fathers can be influential advocates for breastfeeding , playing a critical role in encouraging a woman to breastfeed her newborn infant [16581077] BACKGROUND The study documented Australian primigravidas ' perceptions about breastfeeding . OBJECTIVES To examine women 's perspectives of their breastfeeding experiences during the first 12 weeks postpartum . DESIGN A Journal was introduced to an intervention group ( n=149 ) attending prenatal classes at a private hospital at 36 antenatal weeks . Using quantitative data at two days and 12 weeks postpartum , the intervention group was compared with a control group ( n=154 ) that delivered at the same hospital . Qualitative data were also collected about the women 's perceptions about breastfeeding to further illuminate their experience . Qualitative data from 203 women at two days postpartum and 252 women at 12 weeks postpartum represented the combined comments from the intervention and control groups . PARTICIPANTS Participants were recruited as part of a r and omised controlled trial of the effects of a Breastfeeding Journal on breastfeeding prevalence , self-efficacy , support , and influence from conflicting advice . The convenience sample of middle class , well-educated primiparous women from a Western Australian hospital had given birth to a singleton infant that was greater than 34 weeks gestation . METHODS An open-ended question on a question naire sought mothers ' comments about their breastfeeding experiences . Data were analysed using inductive content analysis . FINDINGS These mothers described trying to ' get breastfeeding right ' . Getting it right included enhancing factors , factors with mixed effect , and negative factors . CONCLUSIONS Middle class mothers share breastfeeding perceptions with women in more vulnerable groups , including encountering conflicting and unhelpful advice and feeding pressures from health care professionals , family , and community members [19239405] OBJECTIVE To evaluate the effectiveness of a breastfeeding promotion program in the Women , Infant and Children ( WIC ) Supplemental Nutrition Program participants . STUDY DESIGN This r and omized clinical trial included 52 women in the intervention group who received one-to-one pre- and postnatal breastfeeding education and support from a lactation consultant . Women ( n = 52 ) r and omized to controls received st and ard breastfeeding services . Data regarding their infants ' feeding ( classified as exclusive , partial , and bottle ) during the first 7 days , 1 , 2 , and 3 months of age were compared . Additionally , the mothers were surveyed to assess their knowledge , attitude , and beliefs regarding breastfeeding . RESULTS Among the 104 enrolled women , 91 ( 87.5 % ) were Hispanic . Almost all the pregnant women had planned to breastfeed their infants . Although the majority of women reported breastfeeding their infants , 45.6 % in the intervention group and 28.9 % of controls practice d exclusive breastfeeding during the first 7 days . By 3 months , the rate of exclusive breastfeeding in the intervention and control groups had dropped to 13.9 % and 10.5 % , respectively . Parity , mode of delivery , previous experience with breastfeeding , rooming in , and return to work did not significantly affect the exclusive breastfeeding rate . Maternal knowledge , attitude , and beliefs regarding breastfeeding were comparable between the study groups at the baseline stage as well as 3 months postpartum . CONCLUSIONS Participation in the proposed breastfeeding promotion program by the low-income mothers was associated with an insignificant increase in the exclusive breastfeeding rate during the first 3 postpartum months [17670909] Objective To investigate whether antenatal breast feeding education alone or postnatal lactation support alone improves rates of exclusive breast feeding compared with routine hospital care . Design R and omised controlled trial . Setting A tertiary hospital in Singapore . Participants 450 women with uncomplicated pregnancies . Main outcome measures Primary outcomes were rates of exclusive breast feeding at discharge from hospital and two weeks , six weeks , three months , and six months after delivery . Secondary outcomes were rates of any breast feeding . Results Compared with women who received routine care , women in the postnatal support group were more likely to breastfeed exclusively at two weeks ( relative risk 1.82 , 95 % confidence interval 1.14 to 2.90 ) , six weeks ( 1.85 , 1.11 to 3.09 ) , three months ( 1.87 , 1.03 to 3.41 ) , and six months ( 2.12 , 1.03 to 4.37 ) postnatally . Women receiving antenatal education were more likely to breast feed exclusively at six weeks ( 1.73 , 1.04 to 2.90 ) , three months ( 1.92 , 1.07 to 3.48 ) , and six months ( 2.16 , 1.05 to 4.43 ) postnatally . The numbers needed to treat to achieve one woman exclusively breast feeding at six months were 11 ( 6 to 80 ) for postnatal support and 10 ( 6 to 60 ) for antenatal education . Women who received postnatal support were more likely to exclusively or predominantly breast feed two weeks after delivery compared with women who received antenatal education ( 1.53 , 1.01 to 2.31 ) . The rate of any breastfeeding six weeks after delivery was also higher in the postnatal support group compared with women who received routine care ( 1.16 , 1.02 to 1.31 ) . Conclusions Antenatal breast feeding education and postnatal lactation support , as single interventions based in hospital both significantly improve rates of exclusive breast feeding up to six months after delivery . Postnatal support was marginally more effective than antenatal education . Trial registration Clinical Trials NCT00270920 [16536959] BACKGROUND Peer support may improve breastfeeding rates but the evidence is inconclusive . Previous studies and review s recommend trials in different healthcare setting s. AIM To test if a specified programme of peer support affects the initiation and /or the duration of breastfeeding . DESIGN OF STUDY A two-group r and omised controlled trial of peer support for breastfeeding with evaluation of breastfeeding initiation and duration on an intention-to-treat basis . SETTING General practice in Ayrshire , Scotl and . METHOD Following informed consent , 225 women at 28 weeks gestation were allocated to control or peer support group by post-recruitment concealed allocation . All peer support and control group mothers received normal professional breastfeeding support . Additionally , those in the peer support group still breastfeeding on return home from hospital had peer support until 16 weeks . RESULTS Thirty-five of the 112 ( 31 % ) women in the peer support group were breastfeeding at 6 weeks compared to 33/113 ( 29 % ) in the control group , a difference of 2 % ( 95 % confidence interval = -10 % to 14 % ) . The median breastfeeding duration for all women in the peer support group was 2 days compared to 1 day for the control group and the Kaplan-Meier survival plot shows the peer support group overall breastfeeding slightly longer than the control group , with no statistically significant difference by logrank test ( P = 0.5 ) . The median breastfeeding duration among primagravidae in the peer support group was 7 days , compared to 3 days for the control group . Among women who started to breastfeed the medians were 72 days in the peer support group and 56 days in the control group . These differences were not statistically significant . CONCLUSIONS Peer support did not increase breastfeeding in this population by a statistically significant amount [15296584] This study compared breastfeeding attitudes , intention , and initiation among low-income women exposed or not exposed to the Best Start program . A between- ( experimental vs control group ) and within-factor ( pretest vs posttest ) repeated measures design was employed . A nonprobability sample of 54 subjects was r and omly assigned to a control group ( n = 28 ) or an experimental group ( n = 26 ) . Using the Breastfeeding Attrition Prediction Tool , statistically significant group by time interaction effects were found for negative breastfeeding sentiment , positive breastfeeding sentiment , and breastfeeding control scales . Compared to the control group , the experimental group had significantly increased positive breastfeeding sentiment ( P < .01 ) , decreased negative breastfeeding sentiment ( P < .01 ) , and increased breastfeeding control ( P < .01 ) from pretest to posttest . Following exposure to the Best Start program , subjects in the experimental group showed statistically significantly higher breastfeeding intention and initiation than did those in the control group . Practical implication s are discussed . J Hum Lact . 20(3):300 - 305 [16881913] We interviewed women who participated in a breast-feeding promotion intervention study about whether and how participation affected their infant feeding choices , and if they would recommend such an intervention to others . The larger study , a r and omized controlled trial ( RCT ) of an individualized , pre- and post-natal lactation consultant ( LC ) intervention , enrolled 382 low-income primarily Black and Hispanic women in New York City . Twenty-one women completed qualitative exit interviews for this study ( 11 from the Intervention group and 10 Controls ) . Several of the Controls stated that the post-partum study interviews were a source of support , and made them more conscious of how they fed their infant . The Intervention Group was asked about contacts with the study ' Mother-Baby specialist ' ( i.e. LC ) , including what was and was n't helpful . The Intervention Group participants described the Mother-Baby Specialist as key in their decision to initiate and maintain breastfeeding . They credit her direct skills and positive reinforcement with their confidence and perseverance to breastfeed . The success of the intervention is attributed to technical assistance from a trained lactation consultant within the context of a relationship built on encouragement , guidance and support [7740378] Despite the vast number of risk factors that apparently predispose to the development of osteoporosis ( OP ) , they have not been accurately identified and given relative priority . In order to analyse possible risk factors prospect ively in a local patient population with overt OP ( histomorphometrically confirmed and characterised ) and compare it with an appropriately matched non-OP control group ( with normal bone mass on dual-energy X-ray absorptiometry ) , a detailed general history , risk factor analysis , dietary history and anthropometric data were obtained from 56 OP and 125 non-OP subjects . In females a positive family history of OP ( P = 0.002 ) , a fair complexion ( P = 0.009 ) , lower body mass ( P = 0.02 ) and height ( P = 0.03 ) , no breast-feeding of babies ( P = 0.006 ) , a history of smoking ( P = 0.001 ) and fat distribution around the waist ( P = 0.009 ) were identified as risk factors . In males lack of exercise ( P = 0.008 ) , a history of smoking ( P = 0.01 ) , lower body mass ( P = 0.04 ) and height ( P = 0.04 ) , a preference for salty food ( P = 0.02 ) and fat distribution around the waist ( P = 0.002 ) appeared to predispose . Dietary calcium , phosphorus , protein and caffeine intakes were similar in OP and control subjects , but alcohol consumption was clearly higher in both OP males ( P = 0.001 ) and females ( P = 0.01 ) [17197590] OBJECTIVE : To address the impact of simple antenatal educational interventions on breastfeeding practice . METHODS : A r and omized controlled trial was carried out in a tertiary referral center from May 2002 to December 2004 . A r and om sample of eligible low-risk antenatal patients was recruited from clinics in the National University Hospital , Singapore . Group A received breastfeeding educational material and individual coaching from a lactation counselor . Group B received breastfeeding educational material with no counseling . Group C received routine antenatal care only . RESULTS : A total of 401 women were recruited . Mothers receiving individual counseling and educational material practice d exclusive and predominant breastfeeding more often than mothers receiving routine care alone at 3 months ( odds ratio [ OR ] 2.6 , 95 % confidence interval [ CI ] 1.2–5.4 ) and 6 months ( OR 2.4 , 95 % CI 1.0–5.7 ) postpartum . More mothers practice d exclusive and predominant breastfeeding at 6 months among women receiving individual counseling compared with women exposed to educational material alone ( OR 2.5 , 95 % CI 1.0–6.3 ) . CONCLUSION : Where breastfeeding practice s are suboptimal , simple one-encounter antenatal education and counseling significantly improve breastfeeding practice up to 3 months after delivery . Provision of printed or audiovisual educational material is not enough . Health care workers should make every effort to have one face-to-face encounter to discuss breastfeeding with expectant mothers before they deliver . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT002770192 LEVEL OF EVIDENCE : [7795772] OBJECTIVE To evaluate the efficacy of an intervention program to increase breast-feeding in a low-income , inner-city population . DESIGN A r and omized , nonblinded clinical control trial . Patients were followed up through pregnancy , delivery , and the first year of the infant 's life or until the time of weaning from the breast , whichever came first . SETTING The ambulatory care center for prenatal and pediatric care and the inpatient maternity unit of a primary care center that serves a low-income , inner-city population . PATIENTS There were a total of 108 patients : 51 were r and omized to the intervention group that received prenatal and postnatal lactation instruction from a lactation consultant , and 57 were r and omized to the control group that received the st and ard of care at the institution . Patients in the control group were not seen by the lactation consultant . The two groups were similar demographically . INTERVENTION This program consisted of individual prenatal lactation consultation , daily rounds by the lactation consultant on the postpartum unit , and outpatient follow-up at 48 hours after discharge , at the time that the infant was 1 week of age , and at all future health supervision visits for infants up to 1 year of age . MAIN OUTCOME MEASURES The incidence and duration of breast-feeding . RESULTS There was a markedly higher incidence of breast-feeding in the intervention group , as compared with that of the control group ( 61 % vs 32 % , respectively ; P = .002 ) . The duration of breast-feeding was also significantly longer in the intervention group ( P = .005 ) . CONCLUSIONS This lactation program increased the incidence and duration of breast-feeding in our low-income cohort . We suggest that similar efforts that are applied to analogous population s may increase the incidence and duration of breast-feeding in low-income population s in the United States [16953019] OBJECTIVE To determine whether infants of women r and omized to a prenatal and postpartum lactation support intervention incur fewer otitis media- , respiratory tract- , or gastrointestinal-related visits than controls . DESIGN R and omized , unmasked controlled trial recruiting women from prenatal care setting s. Breastfeeding sensitive ( BFS ) illness visits for otitis media or respiratory tract or gastrointestinal complaints were obtained up to 12 months . SETTING Two urban community health centers . PARTICIPANTS Analytic sample of 338 low-income , primarily Hispanic and /or black mother-infant dyads ( n = 163 for the intervention group and n = 175 for the control group ) . INTERVENTION Study lactation consultants attempted 2 prenatal meetings , 1 postpartum hospital and /or home visit , and telephone calls as needed . Controls received the st and ard of care . MAIN OUTCOME MEASURES Combined outpatient and emergency department visits with illness and BFS illness diagnoses . RESULTS There was a significant interaction between treatment and Medicaid ; among those not receiving Medicaid , the number of otitis media visits was higher among controls ( P</=.03 ) . Visits for any illness and BFS , gastrointestinal , or respiratory tract illnesses did not differ by treatment group . Intervention group infants received more breast milk than controls , but exclusive breastfeeding rates remained low and did not differ between groups at any point . CONCLUSIONS Only the number of otitis media visits was reduced , in a subset of the intervention group . The intervention did not reduce visits for respiratory tract or gastrointestinal illness . Limited intervention contact and low exclusive breastfeeding rates may have attenuated intervention effects . Future interventions design ed to yield markedly increased breastfeeding rates may show greater effects in low-income multiethnic sample s. Health coverage for visits may moderate intervention effects [20873071] BACKGROUND Although there are many benefits to breastfeeding , its prevalence and duration in many countries is still lower than the international recommendation for 6-month exclusive breastfeeding . The objective of the present study was to investigate whether a knowledge sharing practice s with empowerment strategies ( KSPES ) program on antenatal education and postnatal support strategies improves the rates of 6-month exclusive breastfeeding during the first six months postpartum compared with a st and ard knowledge of breastfeeding techniques . MATERIAL AND METHOD A r and omized controlled trial was conducted . Pregnant women of more than 32 weeks ' gestation were r and omly assigned to receive a routine st and ard knowledge of breastfeeding techniques alone ( control group ) or with KSPES on antenatal education and postnatal support strategies ( study group ) . The primary outcome was the rate of exclusive breastfeeding at 6-month postpartum . The secondary outcomes were rates at 7 days , 14 days , 1 , 2 , 3 , 4 , and 5 months postpartum . RESULTS Rates of exclusive breastfeeding in the study group were significantly higher when compared with those in the control group at 14 days ( 82.5 % vs. 52.6 % , p = 0.005 ) , 1 month ( 77.5 % vs. 52.6 % , p = 0.021 ) , 2 months ( 62.5 % vs. 368 % , p = 0.023 ) , 4 months ( 35.0 % vs. 7.9 % , p = 0.008 ) , 5 months ( 25.0 % vs. 2.6 % , p = 0.012 ) , and 6 months postpartum ( 20.0 % vs. 0 % , p = 0.005 ) . CONCLUSION KSPES on antenatal education and postnatal support strategies significantly improve rates of exclusive breastfeeding at 6-month postpartum . These strategies also significantly improve rates of exclusive breastfeeding at 14 days , 1 , 2 , 4 , 5 , and 6 months postpartum [8951255] BACKGROUND Prenatal pediatric visits have been recommended by the American Academy of Pediatrics to allow the pediatrician to counsel parents on infant care issues , establish a supportive relationship , and provide pediatric practice information to parents . We hypothesized that prenatal pediatric visits would have an impact on breastfeeding decisions , health care behaviors , health care utilization , and the doctor-patient relationship . METHODS We conducted a r and omized controlled trial of prenatal pediatric visits for urban , low-income families to measure the impact on breastfeeding decisions , infant car safety seat use , circumcision , health maintenance , and emergency room visits and the pediatrician 's perception that he/she would know the mother better . Pregnant women were recruited prenatally from the obstetrics clinic . Outcomes were measured by maternal interview prenatally and when the infant was 2 months old , in addition to review of the nursery record . Physicians were interviewed after the 2-month visit . Health care utilization was measured by chart review at 7 months . RESULTS A total of 156 pregnant women were enrolled and r and omized , 81 to the intervention group and 75 to the control group . Of mothers who breastfed , 45 % in the intervention group changed their mind in favor of breastfeeding after enrollment compared with 14 % in the control group . Mothers in the intervention group compared with the control group were more likely to make fewer emergency room visits , 0.58 compared with 1.0 . Pediatricians were more likely to think that they knew mothers in the intervention group well , 54 % versus 29 % in the control group , yet 67 % of mothers in both groups agreed their pediatrician knew them well . There were no differences between groups in initiation or duration of breastfeeding at 30 or 60 days , infant car safety seat use , circumcision , or health maintenance visits . CONCLUSIONS Prenatal pediatric visits have potential impact on a variety of health care outcomes . Among urban , low-income mothers , we found beneficial effects on breastfeeding decisions , a decrease in emergency department visits , and an initial impact on the doctor-patient relationship . We suggest urban practice s actively promote prenatal pediatric visits [11598600] OBJECTIVE To determine whether docosahexaenoic acid ( DHA ) is related to visual and neural development in term breast-fed infants . DESIGN A prospect i ve study of 83 infants who were exclusively breast-fed for at least 3 months . We determined red blood cell and plasma fatty acids at 2 months , visual acuity at 2 , 4 , 6 , and 12 months , speech perception and an object search task at 9 months , Bayley 's mental development index and psychomotor development index at 6 and 12 months , and novelty pReference at 6 and 9 months . RESULTS The infant red blood cell phosphatidylethanolamine DHA was significantly related to visual acuity at 2 months of age ( r = 0.32 , P = .01 ) and 12 months of age ( r = 0.30 , P = .03 ) . The ability to discriminate nonnative retroflex and phonetic contrasts at 9 months of age was related to the plasma phospholipid DHA ( r = 0.48 , P < .02 ) and red blood cell phosphatidylethanolamine DHA ( r = 0.26 , P = .02 ) at 2 months of age after adjusting for covariates . CONCLUSION DHA may influence the development of visual acuity and neural pathways associated with the developmental progression of language acquisition in term breast-fed infants . The extent to which our results can be attributed solely to DHA from maternal sources through breast milk or in gestation or other confounding factors remains to be determined [4442197] Background Promotion of healthy eating and physical activity in early childhood is recommended as a global chronic disease prevention strategy . Centre-based childcare services represent a promising setting to provide children with opportunities to improve healthy eating and physical activity . Evidence to inform implementation of childcare obesity prevention guidelines into routine practice in childcare , however , is lacking . This study aims to assess the effectiveness of an intervention , delivered to childcare staff , aim ing to increasing service implementation of healthy eating and physical activity-promoting policies and practice s. Methods and analysis A pragmatic parallel group r and omised controlled trial will be undertaken with 165 childcare services in the Hunter New Engl and region of New South Wales , Australia . Services will be r and omised to receive either a 10-month evidence -based performance review intervention with other re sources to support practice change , or to a waitlist control group . The primary trial outcome is the proportion of services implementing all of the following recommended healthy eating and physical activity promoting practice s : written nutrition , physical activity and small screen recreation policies ; providing information to families regarding healthy eating ( including breastfeeding ) , physical activity and small screen time ; providing twice weekly healthy eating learning experiences to children ; providing water and only plain milk to children ; providing fundamental movement skills activities for children every day ; and limiting and using electronic screen time more for educational purpose s and learning experiences . Effectiveness will be assessed using a telephone interview of practice implementation with childcare staff at baseline and 12 months following baseline . Ethics and dissemination The study was approved by the Hunter New Engl and Human Research Ethics Committee and the University of Newcastle Human Research Ethics Committee . Study findings will be disseminated widely through peer- review ed publications and conference presentations . Trial registration number Australian New Zeal and Clinical Trials Registry ACTRN12614000972628 [9511686] OBJECTIVE To assess whether an antenatal teaching session on position and attachment of the baby on the breast had an effect on postnatal nipple pain , nipple trauma and breast feeding duration . The study was planned as a pilot study to allow an adequate sample size to be calculated for a larger study . DESIGN An observer blind experimental design was used . Women were r and omly assigned to either the experimental group teaching session or the control group . SETTING One public hospital in Western Australia . PARTICIPANTS 70 primiparae who intended to breast feed their baby were recruited from the antenatal clinic of the study hospital at 36 weeks ' gestation . INTERVENTION Antenatal group sessions on position and attachment of the baby on the breast were conducted by a lactation consultant . MEASUREMENTS AND FINDINGS During the first four postnatal days , position and attachment was measured by LATCH ( Latch on , Audible swallow , Type of nipple , Comfort and Help ) ( Jensen et al 1994 ) , nipple pain was measured by the Visual Analogue Scale ( VAS ) and nipple trauma was measured by the Nipple Trauma Index ( NTI ) . The analysis of variance ( ANOVA ) results indicated that the women in the experimental group were better able to attach the baby on the breast and had significantly less nipple pain and trauma than the control group . At six weeks postnatally , 31 of the 35 women in the experimental group were breast feeding compared to 10 of the 35 in the control group . CONCLUSIONS AND IMPLICATION S These initial findings suggest that midwives can make the best use of decreasing re sources by using practical ' h and s on ' antenatal group teaching as an effective strategy to increase breast feeding rates [2040509] Educational intervention programs in Florin , Greece , a mountainous rural area with a low ( 15 - 20 % ) attendance at prenatal clinics , were conducted to reduce perinatal and infant morbidity and mortality and to promote physical and psychomotor development . Prior community diagnostic surveys had identified low income , poor living conditions , and illiteracy as very closely linked with poor hygiene , poor nutrition , nonutilization of services , frequent infections and high perinatal and infant mortality . The objectives of the intervention were to assess the effects of health education on breast feeding practice s and use of available medical services . 300 pregnant women participants were r and omly identified by the clinic as the intervention group and 200 as controls . Both groups were similar with predominantly low socioeconomic status ( 69 - 73 % ) and peasant farmers . There were few basic housing amenities ( 13.1 with interventions and 12.7 for controls ) . 70 % of the women lived in extended families . The intervention involved home visits on nutrition , general hygiene , breast feeding , and newborn care . Visits were scheduled every 2 weeks in the 1st 2 months of pregnancy and every month until the infant was 12 months old . It was found that nutrition counseling was positively associated with maternal weight between interventions and controls ( 11.33 vs. 10.30 p.05 ) but not on low birth weight . Prematurity was reduced ( 3.7 % intervention vs. 8.3 % controls , p.04 ) . The perinatal mortality was 31 % for interventions vs. 41 % for controls , but there were a significantly higher number of fetal deaths ( 28 weeks ) for interventions . There was no discernible impact on breast feeding practice s except for dem and feeding ( 61 % interventions vs. 38 % controls ) perhaps because both groups considered breast milk the best . Overfeeding was affected by health counseling , but was reflected only after the 1st year ( 12.1 % control vs. 6.7 % intervention in the 90th percentile ) . The presence of anemia followed a similar pattern with intervention impact after the 1st year . There was no measurable impact in psychomotor development . Reported illness days had a significant lower mean 1 year for interventions . Illness reports checked against clinic visits showed underreporting for both groups . Colds , otitis , and gastroenteritis were the most common ailments . Both showed greater illness between 8 and 12 months with a slightly higher incidence of feverish episodes , gastroenteritis and otitis among controls . Hospitalizations were not significantly different . Both groups used the clinic for infant illness ; home visits depressed the use of free routine checkups for interventions from 0 to 4 months . 5 neonatal deaths occurred among controls and interventions . It was anticipated that mortality is also affected by linkages to the community and improvement in medical services . The results were mixed but the program was partly successful [7882806] OBJECTIVE To identify environmental factors involved in the etiology of insulin-dependent diabetes mellitus ( IDDM ) . RESEARCH DESIGN AND METHODS An estimated 90 % of all incident cases of IDDM in patients 0–14 years of age in New South Wales , Australia , were ascertained over 18 months . For each IDDM patient , two age- and sex-matched control subjects were r and omly selected from the population . Past environmental exposures were determined with a question naire completed by the parents . Response rates were 92 % for the IDDM patients ( 217 of 235 ) and 55 % for the control subjects ( 258 of 470 ) . The relative risk associated with each exposure was estimated with the odds ratio ( OR ) adjusted for confounding factors using multiple logistic regression . RESULTS The introduction of cow 's milk-based infant formula into the diet before 3 months of age was associated with an increased risk ( OR 1.52 , 95 % confidence interval [ CI ] 1.04–2.24 ) . Exclusive breast-feeding for ≥3 months was associated with a protective effect ( OR 0.66 , 95 % CI 0.45–0.97 ) . High dietary intake of cow 's milk protein in the 12 months before the onset of diabetic symptoms was also associated with an increased risk ( OR 1.84 , 95 % CI 1.12–3.00 ) . A recent infection ( during the 3 months before onset of diabetic symptoms ) was more common in the patients than the control subjects ( OR 2.92 , 95 % CI 1.96–4.35 ) , as was day care attendance before the age of 3 ( OR 1.73 , 95 % CI 1.00–3.00 ) . When two age-groups , defined by the median age at onset of diabetes , were compared , the associations with early infant-feeding were stronger among the younger group ( < 9.2 years ) , and associations with recent diet and recent infection were stronger among the older group ( ≥9.2 years ) . CONCLUSIONS These results indicate an increased risk of IDDM associated with early dietary exposure to cow 's milk-containing formula , short duration of exclusive breast-feeding , high intake of cow 's milk protein in the recent diet , recent infection , and early attendance at day care [10655814] OBJECTIVE Although improving mothers ' knowledge about breastfeeding can increase rates and duration of breastfeeding , little is known about the influence of fathers ' knowledge . The purpose of this study was to assess the knowledge of mothers and fathers about breastfeeding before and after receiving postpartum advice and its relationship to the frequency of breastfeeding . METHODS A clinical trial was performed with mothers and fathers of normal children born at the Hospital de Clínicas de Porto Alegre , Brazil , between July 1994 and March 1995 . The study intervention consisted of postpartum advice supplied by means of a video film discussing basic topics of breastfeeding , an explanatory leaflet , and open discussion after viewing the video . The first 208 couples comprised the control group , the next 197 comprised experimental group 1 , and the remaining 196 comprised experimental group 2 . Immediately after delivery , mothers and fathers in the three groups answered a test on breastfeeding knowledge ; they completed the same test at the end of the first month . All families received home visits at the end of the first , second , fourth , and sixth months , or until breastfeeding ceased . Logistic regression was used to evaluate the association between the mothers ' and fathers ' knowledge and frequency of breastfeeding . RESULTS Postpartum advice increased the breastfeeding knowledge of mothers and fathers . The mothers with the highest level of knowledge had a 6.5 times higher chance of exclusively breastfeeding at the end of the third month , and 1.97 times higher chance of continuing breastfeeding to the end of the sixth month compared with other mothers . The fathers ' knowledge also significantly influenced breastfeeding rates . The children whose fathers knew more had a 1.76 higher chance of being exclusively breastfed at the end of the first month , and 1.91 higher chance of receiving maternal milk at the end of the third month . CONCLUSION A simple , inexpensive strategy can increase the level of breastfeeding knowledge of mothers and fathers and , consequently , have a positive impact on the frequency of breastfeeding [16732777] BACKGROUND Social support has been shown to be greatly important for breastfeeding success . The objective of this study was to investigate if mothers who were attended by midwives and nurses specially trained in breastfeeding counseling perceived better continuity of care and emotional and informative breastfeeding support than mothers who received only routine care . METHOD Ten municipalities , each with an antenatal center and child health center , in southwest Sweden were r and omized either to intervention or control municipalities . The intervention included a process-oriented training in breastfeeding counseling and continuity of care at the antenatal and child health centers . Primiparas were asked to evaluate the care given , and those living in the control municipalities were divided into control groups A and B. Data collection took place at different points in time for the two control groups . The 540 mothers responded to 3 question naires at 3 days and at 3 and 9 months postpartum . The perception of support provided by the health professionals and from the family classes was rated on Likert scales . RESULTS Intervention group mothers rated the breastfeeding information given during the family class as significantly better during pregnancy than both control groups , and better than control group B mothers at 3 months postpartum ; compared with both control groups , intervention group mothers perceived that they received significantly better overall support and that postnatal nurses provided better information about breastfeeding and the baby 's needs . At 9 months , intervention group mothers were more satisfied with knowledge about social rights , information about the baby 's needs , and their social network than control group B mothers . Both intervention group and control group B mothers perceived better overall support than control group A during pregnancy . At 3 and 9 months , intervention group mothers perceived that postnatal nurses were more sensitive and underst and ing compared with both control groups . CONCLUSIONS After implementation of a process-oriented breastfeeding training program for antenatal midwives and postnatal nurses that included an intervention guaranteeing continuity of care , the mothers were more satisfied with emotional and informative support during the first 9 months postpartum . The results lend support to family classes incorporating continuity of care [7928125] The rate of breastfeeding among immigrant Vietnamese women in Western countries is low compared to those in Vietnam . To counteract this trend , a language and culture specific education program was developed . An experimental design was used to test the effectiveness of this program . The sample consisted of 182 prenatal Vietnamese women . Data collection included question naires and interviews . Results suggested that the education program had significant effects on knowledge , attitudes , planned and actual behaviour towards breastfeeding . However , the effect did not sustain until 6 months postpartum . Implication s for nursing practice and further research are discussed [14685550] OBJECTIVES : To assess the implementation and the impact of the Breastfeeding Counselling Course WHO/UNICEF on knowledge and skills of health workers . METHODOLOGY : The implementation of the course was assessed by participant observation ; the impact on participants was assessed with an experimental controlled study where 20 health workers were r and omly allocated as course participants ( Exposed Group-EG ) and 40 as non participants ( Control Group -CG ) . Impact on knowledge was verified with pre and post evaluations , with multiple choice questions ; clinical and counselling skills were assessed through pre and post tests , observing participants in clinical consults with mother and baby pairs in rooming-in before and after the course . Kruskal-Wallis test of variance of means was used in analysis . RESULTS : In the post test of knowledge , the mean of the EG was 8.35 and that of the CG was 5.54 ( p=0,0000 ) . In clinical and counselling skills , the means of the EG were higher when compared with the CG in all items observed ( p < 0,05 ) . Some difficulties were found in breastfeeding history and in breastfeeding observation . Counselling skills were the most incorporated aspects . CONCLUSION : The course may be implemented as proposed ; participants acquired counselling skills , but clinical management should be reinforced ; participants shoud have continued support to put what they learned in practice [19487705] A r and omized controlled trial study design was used to investigate the effectiveness of a Healthy Families America model prenatal intervention for increasing breastfeeding rates among Latina immigrants residing in an impoverished New York City community . Exposure to the intervention did not affect mother report of any breastfeeding ( ABF ) during the first week postpartum , but it did affect mother report of exclusive breastfeeding ( EBF ) . Thirty-two percent ( 44/137 ) of mothers exposed to the intervention reported EBF during the first week postpartum compared to 20 % ( 20/101 ) of mothers not exposed to the intervention ( odds ratio 1.92 ; 95 % confidence interval 1.05 - 3.52 ) . This positive effect of the intervention on EBF remained statistically significant after controlling for the negative effect of household income on EBF ( adjusted odds ratio , 1.89 ; 95 % confidence interval , 1.02 - 3.50 ) . Additional research is needed on the effectiveness of breastfeeding promotion programs targeting low-income Latinas . J Hum Lact . 25(4):404 - 411 Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND There is extensive evidence of important health risks for infants and mothers related to not breastfeeding . In 2003 , the World Health Organization recommended that infants be breastfed exclusively until six months of age , with breastfeeding continuing as an important part of the infant 's diet until at least two years of age . However , current breastfeeding rates in many countries do not reflect this recommendation . OBJECTIVES To describe forms of breastfeeding support which have been evaluated in controlled studies , the timing of the interventions and the setting s in which they have been used . To examine the effectiveness of different modes of offering similar supportive interventions ( for example , whether the support offered was proactive or reactive , face-to-face or over the telephone ) , and whether interventions containing both antenatal and postnatal elements were more effective than those taking place in the postnatal period alone . To examine the effectiveness of different care providers and ( where information was available ) training . To explore the interaction between background breastfeeding rates and effectiveness of support . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

26177378

[24978062] Background : Postoperative nausea and vomiting ( PONV ) is a multifactorial problem after general anesthesia . Despite antiemetic prophylaxis and improved anesthetic techniques , PONV still occurs frequently after craniotomies . P6 stimulation is described as an alternative method for preventing PONV . The primary aim of this study was to determine whether P6 acupressure with Sea-B and could reduce postoperative nausea after elective craniotomy . Secondary aims were to investigate whether the frequency of vomiting and the need for antiemetics could be reduced . Methods : In this r and omized , double-blinded , placebo-controlled study , patients were r and omized into either a P6 acupressure group ( n=43 ) or a sham group ( n=52 ) . B and s were applied unilaterally at the end of surgery , and all patients were administered prophylactic ondansetron . Postoperative nausea was evaluated with a Numerical Rating Scale , 0 to10 , and the frequency of vomiting was recorded for 48 hours . Results : We found no significant effect from P6 acupressure with Sea-B and on postoperative nausea or vomiting in patients undergoing craniotomy . Nor was there any difference in the need for rescue antiemetics . Altogether , 67 % experienced PONV , and this was especially an issue at > 24 hours in patients recovering from infratentorial surgery compared with supratentorial surgery ( 55 % vs. 26 % ; P=0.014 ) . Conclusions : Unilateral P6 acupressure with Sea-B and applied at the end of surgery together with prophylactic ondansetron did not significantly reduce PONV or the need for rescue antiemetics in patients undergoing craniotomy . Our study confirmed that PONV is a common issue after craniotomy , especially after infratentorial surgery [20178877] OBJECTIVES Acupressure , a complementary and alternative medicine ( CAM ) treatment , uses fingertips , rather than needles , to stimulate acupoints on the skin and has been implicated as a successful treatment for a variety of medical disorders . However , acupressure 's underlying mechanisms remain unclear . One theory is that acupoint stimulation modulates autonomic nervous system activity . Previous studies have suggested that acupressure may positively affect heart rate and blood pressure . The current study investigated the effects of a type of acupressure , Jin Shin , on cardiovascular function in stroke survivors , a population that could especially benefit from a treatment promoting cardiovascular health . The study tested the hypothesis that active acupressure treatments would reduce heart rate and blood pressure ( i.e. , induce a greater relaxation response ) above and beyond that seen during placebo acupressure treatments . METHODS A r and omised , placebo-controlled , single-blind crossover design was utilised , in which 16 participants received 8 weeks of either active or placebo acupressure followed by washout and crossover into the opposite treatment condition . Heart rate and blood pressure measurements were taken throughout treatments . RESULTS Active acupressure treatments were associated with a significantly greater ( p=.043 , eta(2)=.30 ) and faster ( p=.002 , eta(2)=.76 ) reduction in heart rate compared to that seen during placebo treatments . No treatment effect on blood pressure was found . CONCLUSIONS Active acupressure reduced heart rate significantly more than did placebo acupressure during treatments . Although no treatment effect on blood pressure was found , this could be due to 67 % of participants taking antihypertensive medications during the study [22504214] BACKGROUND : There is still controversy regarding the optimal strategy for managing postoperative nausea and vomiting ( PONV ) in high-risk surgical population s. Although acustimulation at the P6 acupoint has been demonstrated to be effective in preventing PONV , the effect of this nonpharmacologic therapy on the patient 's recovery with respect to resumption of normal activities of daily living has not been previously assessed when it is used as part of a multimodal antiemetic regimen . Therefore , we design ed this r and omized , sham-controlled , and double-blind study to assess the efficacy of a disposable acupressure device ( Pressure Right ® ; Pressure Point Inc. , Gr and Rapids , MI ) on the incidence of emetic episodes and quality of recovery when used in combination with ondansetron and dexamethasone for antiemetic prophylaxis . METHODS : One hundred ASA physical status I and II patients undergoing major laparoscopic procedures were r and omly assigned to either a control group ( n = 50 ) receiving a “ sham ” acustimulation device or an acupressure group ( n = 50 ) receiving a disposable Pressure Right device placed bilaterally at the P6 point 30 to 60 minutes before induction of anesthesia . All patients received a st and ardized general anesthetic . A combination of ondansetron , 4 mg IV , and dexamethasone , 4 mg IV , was administered during surgery for antiemetic prophylaxis in both study groups . The incidence of nausea and vomiting and the need for “ rescue ” antiemetic therapy were assessed at specific time intervals for up to 72 hours after surgery . The recovery profiles and quality of recovery question naires were evaluated at 48 hours and 72 hours after surgery . Patient satisfaction with the management of their PONV was assessed at the end of the 72-hour study period . RESULTS : The 2 study groups did not differ in their demographic characteristics or risk factors for PONV . The incidence of vomiting at 24 hours was significantly decreased in the acupressure group ( 10 % vs 26 % , P = 0.04 , 95 % confidence interval for absolute risk reduction 1%–31 % ) . The overall incidence of vomiting from 0 to 72 hours after surgery was also significantly decreased from 30 % to 12 % in the acupressure group ( P = 0.03 , 95 % confidence interval 2%–33 % ) . Furthermore , adjunctive use of the acupressure device seemed to enhance patient satisfaction with their PONV management and quality of recovery at 48 hours after surgery . However , the recovery times to hospital discharge , resumption of normal physical activities , and return to work did not differ significantly between the 2 study groups . CONCLUSION : Use of the Pressure Right acupressure device in combination with antiemetic drugs provided a reduction in the incidence of vomiting from 0 to 72 hours after surgery with an associated improvement in patient satisfaction with their PONV management . However , recovery and outcome variables failed to demonstrate any improvement with the addition of the acupressure device [20979460] Acupressure is a complementary and alternative medicine ( CAM ) treatment using fingertips to stimulate acupoints on the skin . Although suggested to improve cognitive function , acupressure has not been previously investigated with a controlled design in traumatic brain injury ( TBI ) survivors , who could particularly benefit from a non-pharmacological intervention for cognitive impairment . A r and omized , placebo-controlled , single-blind design assessed the effects of acupressure ( eight treatments over 4 weeks ) on cognitive impairment and state of being following TBI , including assessment of event-related potentials ( ERPs ) during Stroop and auditory oddball tasks . It was hypothesized that active acupressure treatments would confer greater cognitive improvement than placebo treatments , perhaps because of enhanced relaxation response induction and result ing stress reduction . Significant treatment effects were found comparing pre- to post-treatment change between groups . During the Stroop task , the active-treatment group showed greater reduction in both P300 latency ( p = 0.010 , partial η² = 0.26 ) and amplitude ( p = 0.011 , partial η² = 0.26 ) , as well as a reduced Stroop effect on accuracy ( p = 0.008 , partial η² = 0.21 ) than did the placebo group . Additionally , the active-treatment group improved more than did the placebo group on the digit span test ( p = 0.043 , Cohen 's d = 0.68 ) . Together , these results suggest an enhancement in working memory function associated with active treatments . Because acupressure emphasizes self-care and can be taught to novice individuals , it warrants further study as an adjunct treatment for TBI [19757334] Introduction . The reduction of the duration and pain of the active phase of labor is a very important issue and therefore always under serious investigation . Objective . The purpose of the present study is to evaluate the effect of acupressure at the Sanyinjiao point ( SP6 ) on the duration and pain of the active phase of labor in nulliparas women . Method . A single blind r and omized clinical trial was performed on 120 eligible nulliparas women who were at the beginning of active phase of labor ( 3 - 4 cm dilatation of cervix plus proper uterine contractions ) . The women were r and omly assigned into two groups . The case group ( n = 60 ) , received acupressure at Sanyinjiao point ( above the ankle ) , for 30 min during contractions . In the control group ( n = 60 ) , simply a touch at this point without massage was performed . Two hours later a second pelvic examination was performed and in the absence of good forceful contractions oxytocin in the classical form was infused . Finally , duration of active phase , severity of pain ( using the Visual Analogue Scale ) , the amount of necessary oxytocin and necessity to administer oxytocin and the route of delivery were compared between the two groups and statistical analyses were performed using SPSS 15 . Results . The mean duration of active phase was shorter in the case group ( 252.37 + /- 108.50 min vs. 441.38 + /- 155.88 , p = 0.0001 ) . Six patients ( 10 % ) in the case group and 25 patients ( 41.7 % ) in the control group delivered via cesarean section ( p = 0.0001 ) . The severity of pain in the case group was less than the control group ( 5.87 + /- 1.77 vs. 6.79 + /- 1.52 , p = 0.003 ) . Twenty-five women ( 41.7 % ) in the case group and 38 women ( 63.3 % ) in the control group needed oxytocin ( p = 0.017 ) The amount of necessary oxytocin in the case group was less than the control group ( 73.33 + /- 97.19 ml vs. 126.6 + /- 97.19 ml , p = 0.003 ) . Conclusion . Acupressure at Sanyinjiao point ( SP6 ) reduced the duration and severity of pain of the active phase of labor , cesarean section rates , and necessity and amount of oxytocin [8623811] OBJECTIVE Our purpose was to investigate the efficacy of P6 acupressure in reducing or relieving symptoms of nausea with or without vomiting and retching during pregnancy . STUDY DESIGN Symptomatic pregnant volunteers ( n=161 ) participated in a 7-day community-based clinical trial . All participants were assigned to one of three groups ( i.e. , P6 acupressure , placebo [ acupressure b and s inappropriately placed ] , or control ) on the basis of a process of blocked r and omization . Data were analyzed by error bar charts and analysis of variance of difference scores . RESULTS Of 161 women , 149 ( 92.5 % ) completed the protocol . Irrespective of group assignment , participants reported significant decreases in nausea ( p<0.0009 ) and vomiting or retching ( p<0.0009 ) . However , there was no differential treatment effect as a result of acupressure . CONCLUSION There was no apparent medical benefit from the use of P6 acupressure . Our findings differ from other recently published studies that did not include a control group [17388769] OBJECTIVES The onset of depression is often triggered by breathlessness in persons with chronic obstructive pulmonary disease ( COPD ) . It is hypothesized that these are the psychologic consequences of chronic dyspnea . Lessening dyspnea might alleviate depressive symptoms . Acupressure has been shown in other studies to produce relaxation . The aim of this study was to determine if it would lessen dyspnea and reduce depression in patients with COPD . SUBJECTS AND DESIGN Subjects diagnosed with COPD were chosen from one medical center and three regional hospitals in Taipei , Taiwan . A r and omized , block experimental design was used , with subjects and the data collector blinded . Using age , gender , pulmonary function , smoking , and steroid use as matching factors , 44 subjects were r and omly assigned to either the true acupressure or the sham acupressure groups . The true acupressure group received a program of acupressure using appropriate acupoints that promote relaxation and relieve dyspnea . The sham acupressure group received acupressure using sham acupoints different from the meridians and ganglionic sections of the true acupressure group . Both acupressure programs lasted 4 weeks , with five sessions per week that lasted 16 minutes per session . OUTCOME MEASURES The Geriatric Depression Scale ( GDS ) and Dyspnea Visual Analogue Scale ( DVAS ) were administered prior to the program as a baseline , and again following the completion of the 4-week program . Oxygen saturation and other physiological indicators were measured before and after each session . RESULTS The results of this study showed that the GDS scores , DVAS scores , oxygen saturation , and physiological indicators of the true acupressure group were significantly improved , compared to those of the sham acupressure group . CONCLUSIONS These findings provide health professionals with an evidence -based intervention to use with persons with COPD . Applying this acupressure program in clinical practice , communities , and long-term care units may lessen chronic dyspnea and depression in persons with COPD [25276718] INTRODUCTION Most women have experienced child birth and its pain , which is inevitable . If this pain is not controlled it leads to prolonged labor and injury to the mother and fetus . This study was conducted to identify the effect of acupressure on sanyinjiao and hugo points on delivery pain in nulliparous women . METHODS This was a r and omized controlled clinical trial on 84 nulliparous women in hospitals of Ardebil , Iran . The participants were divided by r and omized blocks of 4 and 6 into two groups . The intervention was in the form of applying pressure at sanyinjiao and hugo points based on different dilatations . The intensity of the pain before and after the intervention was recorded by visual scale of pain assessment . To determine the effect of pressure on the intensity of labor pain , analytical descriptive test was conducted in SPSS ( version 13 ) . RESULTS There was a significant decrease in mean intensity of pain after each intervention in the experimental group with different dilatations ( 4 , 6 , 8 , and 10 cm ) . Moreover , the Student 's independent t-test results indicated that the mean intensity of pain in the experimental group after the intervention in all four dilatations was significantly lower than the control group . Repeated measures ANOVA test indicated that in both experimental and control groups in four time periods , there was a statistically significant difference . CONCLUSION Acupressure on sanyinjiao and hugo points decreases the labor pain . Therefore , this method can be used effectively in the labor process [3818617] Background : The Le7 acupoint had been known as an acupoint for reducing pain of appendicitis . However , no study on the effect of its acupressure on post-appendectomy pain is available . The objective of this study was to evaluate the effects of acupressure of Le7 acupoint on pain , nausea , and vomiting after appendectomy . Material s and Methods : A single-blind r and omized controlled trial was conducted on 70 post-appendectomy patients in a general surgical ward . Patients with inclusion criteria were selected consecutively and were r and omly assigned into two groups . The intervention group received acupressure to the Le7 acupoint and the second group was the control group . The severity of post-operative pain , nausea , and vomiting measured hourly till the seventh post-operative hour . T-test was used to compare the mean of pain and nausea severity of two groups . Paired t-test was used to compare the mean of pain intensity of each group before and total mean of pain at post-intervention hours . Chi-squared test and Fisher exact test were used for nominal data . Results : The mean of pain intensity in the intervention group was 5.10 ± 3.52 before intervention and decreased to 3.53 ± 0.75 in the post-operative hours ( P = 0.018 ) . The mean of pain intensity in the control group was 4.45 ± 3.16 before intervention and changed to 4.01 ± 0.92 in the post-operative hours ( P = 0.32 ) . However , the mean of pain intensity in the intervention group was less than the control group till 6th h after the surgery . No significant differences were observed between the two groups in terms of nausea and vomiting ( P = 0.74 ) . Conclusion : Acupressure on Le7 acupoint was effective on post-appendectomy pain but did not affect nausea and vomiting . Further investigations are suggested with starting acupressure at the onset of pain or nausea and vomiting [3851943] Background Nested qualitative studies within clinical trials provide data on patients ’ experiences of receiving trial interventions and can inform and improve trial design s. The present study explored patients ’ experiences of participating in a r and omised controlled trial of acupressure wristb and s for chemotherapy related nausea . Methods A r and omised three-group sham-controlled trial was carried out to evaluate the effectiveness of acupressure wristb and s in the management of chemotherapy-related nausea . A convenience sample of 26 patients volunteered to participate in a qualitative study to explore their experiences of using acupressure wristb and s , and taking part in the clinical trial . Participants were recruited from each of the three UK geographical sites from which the trial was conducted : Manchester , Liverpool and Plymouth . In-depth semi-structured interviews were conducted with the participants in their own homes or other location convenient for participating patients . Interviews were audio-taped , transcribed verbatim and analysed using Framework methodology . Results The main motivational factors influencing participants to take part in the trial were a desire to ' give something back ’ and limit their own experience of nausea . Participants were largely satisfied with the organisation and running of the acupressure wristb and trial . Many participants experienced positive outcomes as a result of taking part in the trial . Lapses in memory , or poor health as a result of their chemotherapy treatment , led to some participants failing to complete trial paperwork on design ated days . Two sham wristb and participants reported wearing the b and s inappropriately result ing in pressure being applied to the acupoint . Almost all of the participants interviewed had only experienced mild nausea or vomiting during the trial . Participants were pragmatic on the extent to which the wristb and s were responsible for this lack of nausea and vomiting during the trial . However , many participants , including some patients receiving sham acupressure , believed the wristb and s to have had a positive impact on their nausea and vomiting ; there was a perception that the wristb and s were , at least in part , responsible for the lack of nausea and vomiting they had experienced . Conclusions Participants perceive acupressure wristb and s as reducing the level of nausea and vomiting experienced during chemotherapy treatment . Reports that some participants wore wristb and s inappropriately , and /or delayed completion of trial paperwork could represent confounding variables and have implication s for the trial results , and the design of clinical trials within the field of cancer [12705488] OBJECTIVE To evaluate the effectiveness of acupressure applied at meridian P6 point for prevention of nausea and vomiting in patients undergoing laparoscopic cholecystectomy . METHODOLOGY A r and omized double blind study was performed in 50 ASA I and II patients scheduled for laparoscopic cholecystectomy . Patients were divided into two groups ; control and placebo . In the control group acupressure was applied at P6 point half an hour before surgery while in the placebo group the acupressure b and was tied on meridian P6 point but the plastic bead was placed on the dosum of right forearm away from meridian P6 point . Patients were assessed for nausea and vomiting for six hours after surgery . Anaesthetic technique and postoperative analgesia were st and ardized for all patients . RESULTS Results showed that the incidence of postoperative nausea and vomiting was 36 % in the treatment group and 40 % in placebo group , which is statistically insignificant . CONCLUSION Application of acupressure at P6 point half an hour before induction of anaesthesia does not significantly alter the incidence of postoperative nausea and /or vomiting within 6 hours after surgery [16522418] OBJECTIVE The purpose of this study was to evaluate the efficacy of acupressure at the P6 point for the in-patient treatment of severe nausea and vomiting in early pregnancy . STUDY DESIGN This was a prospect i ve single-blind r and omized control trial that involved 80 patients with nausea and vomiting plus ketonuria before 14 weeks of gestation . RESULTS There was no difference between length of stay , amount of medication , or fluid required between the acupressure and placebo groups , although acupressure reduced the number of patients who stayed > or = 4 nights in the hospital . Acupressure was well tolerated and not associated with an increase in perinatal morbidity or death . CONCLUSION The use of acupressure at the P6 point does not reduce the amount of antiemetic medication that is required , the requirement for intravenous fluid , and median duration of in-patient stay more than the use of placebo . A small reduction was seen in the number of women who required > or = 4 days in the hospital [21306863] CONTEXT Bone marrow aspiration and biopsy ( BMAB ) is a frequently performed and painful procedure . OBJECTIVES To evaluate the efficacy of magnetic acupressure in reducing pain in cancer patients undergoing BMAB . METHODS Cancer patients without previous acupuncture or acupressure experience were stratified by the number of prior BMAB and r and omized to having magnetic acupressure delivered to either the large intestine 4 ( LI4 ) acupoint or a sham site . The primary study endpoint was the patient 's pain intensity rating during the procedure using a visual analogue scale ( VAS ) . RESULTS Seventy-seven eligible patients received magnetic acupressure : 37 were r and omized to treatment at the LI4 site arm and 40 at the design ated sham site arm . There was no significant difference between the median pain scores of patients treated at the LI4 site and the sham site ( P=0.87 ) . However , severe pain ( VAS ≥ 7 ) was reported in only one patient ( 2.7 % ) treated at the LI4 site compared with eight patients ( 20 % ) at the sham site ( P=0.03 ) . No patients experienced significant magnetic acupressure-related toxicities . CONCLUSION Magnetic acupressure at the LI4 acupoint requires minimal training and expense and is well tolerated . Although its use did not significantly reduce median pain scores in patients undergoing BMAB , it does appear to reduce the proportion of patients with severe pain associated with this invasive procedure [8041539] Objective : To evaluate the effectiveness of acupressure in reducing nausea and vomiting of pregnancy . Methods : Symptomatic pregnant women were r and omized to one of two acupressure groups : one treatment group using an acupressure point ( PC-6 ) and one sham control group using a placebo point . Subjects were blind to the group assignment . Each evening for 10 consecutive days , the subjects completed an assessment scale describing the severity and frequency of symptoms that occurred . Data from the first 3 days were used as pre-treatment scores . Beginning on the morning of the fourth day , each subject used acupressure at her assigned point for 10 minutes four times a day . Data from day 4 were discarded to allow 24 hours for the treatment to take effect . Data from days 5 - 7 were used to measure treatment effect . Results : Sixty women completed the study . There were no differences between groups in attrition , parity , fetal number , maternal age , gestational age at entry , or pre-treatment nausea and emesis scores . Analysis of variance indicated that both groups improved significantly over time , but that nausea improved significantly more in the treatment group than in the sham control group ( F1,58=10.4 , P = .0021 ) . There were no differences in the severity or frequency of emesis between the groups . There was a significant positive correlation ( r=0.261 , P = .044 ) between maternal age and severity of nausea . Conclusion : Our results indicate that acupressure at the PC-6 anatomical site is effective in reducing symptoms of nausea but not frequency of vomiting in pregnant women [16492848] Nausea and vomiting are major adverse effects during spinal anesthesia for cesarean delivery . Stimulation of the P6 ( Neiguan ) acupoint is a traditional Chinese acupuncture technique used for effective antiemetic purpose s. In this study , we evaluated the antiemetic effect of P6 acupressure in parturients during spinal anesthesia for cesarean delivery . In a r and omized , double-blind , controlled trial , 110 parturients scheduled for elective cesarean delivery were enrolled in the study . Thirty minutes before initiation of spinal anesthesia , parturients were r and omized to acupressure b and s or placebo b and s bilaterally on the P6 acupoint and nausea and vomiting were observed over the study period . There were no statistically significant differences in maternal characteristics . Incidence rates for intraoperative nausea were 64 % ( acupressure group ) and 71 % ( control group ) ( P = 0.416 ) , with an incidence of intraoperative vomiting of 22 % ( acupressure group ) and 27 % ( control group ) ( P = 0.506 ) . The results suggest that prophylactic use of acupressure b and s bilaterally on the P6 acupoint failed to prevent nausea and vomiting during spinal anesthesia for cesarean delivery [10823097] The efficacy of acupressure at the P6 point in the prevention of nausea and vomiting during and after Caesarean section was studied . A double-blind , r and omized controlled study of acupressure vs placebo was design ed . Ninety-four patients scheduled for Caesarean section were included . The anaesthetic technique and postoperative analgesia were st and ardized . The use of acupressure reduced the incidence of nausea or vomiting from 53 % to 23 % compared with placebo ( 95 % confidence interval ( CI ) 0.34 - 0.25 ; P = 0.002 ) during the operation and from 66 % to 36 % compared with placebo ( 95 % CI 0.34 - 0.19 ; P = 0.003 ) after the operation . Other variables were similar between the groups [2818640] Background The results of many clinical trials and experimental studies regarding acupoint specificity are contradictory . This review aims to investigate whether a difference in efficacy exists between ordinary acupuncture on specific acupoints and sham acupuncture controls on non-acupoints or on irrelevant acupoints . Methods Data bases including Medline , Embase , AMED and Chinese Biomedical Data base were search ed to identify r and omized controlled trials published between 1998 and 2009 that compared traditional body acupuncture on acupoints with sham acupuncture controls on irrelevant acupoints or non-acupoints with the same needling depth . The Cochrane Collaboration 's tool for assessing risk of bias was employed to address the quality of the included trials . Results Twelve acupuncture clinical trials with sham acupuncture controls were identified and included in the review . The conditions treated varied . Half of the included trials had positive results on the primary outcomes and demonstrated acupoint specificity . However , among those six trials ( total sample size : 985 ) with low risk of bias , five trials ( sample size : 940 ) showed no statistically significant difference between proper and sham acupuncture treatments . Conclusion This review did not demonstrate the existence of acupoint specificity . Further clinical trials with larger sample sizes , optimal acupuncture treatment protocol s and appropriate sham acupuncture controls are required to resolve this important issue [3139519] R and omized , placebo-controlled clinical trials are recommended for evaluation of a treatment 's efficacy with the goal of separating the specific effects ( verum ) from the non-specific ones ( placebo ) . In order to be able to carry out placebo-controlled acupuncture trials , minimal/sham acupuncture procedures and a sham acupuncture needle has been used with the intention of being inert . However , clinical and experimental results suggest that sham/minimal acupuncture is not inert since it is reported that both verum acupuncture and sham/minimal acupuncture induce a significant alleviation of pain . This alleviation is as pronounced as the alleviation obtained with st and ard treatment and more obvious than the one obtained with placebo medication or by the use of waiting list controls . These results also suggest that sham acupuncture needles evoke a physiological response . In healthy individuals sham acupuncture results in activation of limbic structures , whereas a deactivation is seen in patients with pain , i.e. results from healthy individuals do not reflect what is seen in clinical conditions . Also , depending on the etiology of pain ( or any under clinical condition under investigation ) , the response to sham acupuncture is varying . The acupuncture ritual may also be seen as an emotional focused therapy allowing for psychological re-orientation . Sham needling in such context may be as powerful as verum acupuncture . We recommend that the evaluated effects of acupuncture could be compared with those of st and ard treatment , also taking the individual response into consideration , before its use or non-use is established [21168112] OBJECTIVE The current study was conducted to evaluate the effect of acupressure on primary dysmenorrhea in Iranian medical sciences students . DESIGN A r and omized controlled pre and post-test design was employed to verify the effects of SP6 acupressure on dysmenorrhea . SETTING A total of 30 young college female students with primary dysmenorrhea were r and omly allocated to intervention ( n = 15 ) and control ( n = 15 ) groups . INTERVENTION The intervention group received SP6 acupressure during menstruation cycle and the control group received light touch on the SP6 acupoint . Using a Visual Analog Scale , the severity of dysmenorrhea was assessed prior to and immediately , 30 min , 1 , 2 , and 3 h following treatment . MAIN OUTCOME MEASURES Data were analyzed using X(2 ) , t-test and ANOVA statistical tests . RESULTS Significant differences were observed in the scores of dysmenorrhea between the two groups immediately after ( 3.50 ± 1.42 vs. 5.06 ± 1.43 , p = 0.004 ) and also 3 h after treatment ( 1.66 ± 1.98 vs. 4.80 ± 1.37 , p = 0.000 ) . CONCLUSIONS Acupressure on the SP6 meridian can be an effective non-invasive nursing intervention for alleviating primary dysmenorrhea and its effects last for 3 h post-treatment [14608559] The purpose of this study was to evaluate the effectiveness of acupressure b and s , droperidol , and the combined modalities , administered preoperatively , in reducing PONV in inpatient gynecologic patients . One hundred and forty-three patients were r and omized to one of four groups : droperidol and acupressure b and s , droperidol and placebo b and s , placebo drug and acupressure b and s , or placebo drug and placebo b and s. Overall , during their hospital stay , 69 % of the women experienced PONV and 45 % experienced vomiting at some time . Although droperidol was most effective the day of surgery , neither acupressure b and s or droperidol were effective in reducing PONV [11303547] OBJECTIVE To find out whether acupressure wristb and can alleviate nausea and vomiting in early pregnancy . DESIGN Double-blind , placebo-controlled study . SUBJECTS 97 women with mean gestational length completed 8 - 12 weeks . MAIN OUTCOME MEASURES Symptoms were recorded according to intensity , duration and nature of complaints . RESULTS 71 % of women in the intervention group reported both less intensive morning sickness and reduced duration of symptoms . The same tendency was seen in the placebo group , with 59 % reporting less intensity and 63 % shorter duration of symptoms . However , a significance level of 5 % was reached only in the case of duration of symptoms , which was reduced by 2.74 hours in the intervention group compared to 0.85 hours in the placebo group ( p = 0.018 ) . CONCLUSIONS Acupressure wristb and might be an alternative therapy for morning sickness in early pregnancy , especially before pharmaceutical treatment is considered [15870415] CONTEXT Acupuncture is widely used to prevent migraine attacks , but the available evidence of its benefit is scarce . OBJECTIVE To investigate the effectiveness of acupuncture compared with sham acupuncture and with no acupuncture in patients with migraine . DESIGN , SETTING , AND PATIENTS Three-group , r and omized , controlled trial ( April 2002-January 2003 ) involving 302 patients ( 88 % women ) , mean ( SD ) age of 43 ( 11 ) years , with migraine headaches , based on International Headache Society criteria . Patients were treated at 18 outpatient centers in Germany . INTERVENTIONS Acupuncture , sham acupuncture , or waiting list control . Acupuncture and sham acupuncture were administered by specialized physicians and consisted of 12 sessions per patient over 8 weeks . Patients completed headache diaries from 4 weeks before to 12 weeks after r and omization and from week 21 to 24 after r and omization . MAIN OUTCOME MEASURES Difference in headache days of moderate or severe intensity between the 4 weeks before and weeks 9 to 12 after r and omization . RESULTS Between baseline and weeks 9 to 12 , the mean ( SD ) number of days with headache of moderate or severe intensity decreased by 2.2 ( 2.7 ) days from a baseline of 5.2 ( 2.5 ) days in the acupuncture group compared with a decrease to 2.2 ( 2.7 ) days from a baseline of 5.0 ( 2.4 ) days in the sham acupuncture group , and by 0.8 ( 2.0 ) days from a baseline if 5.4 ( 3.0 ) days in the waiting list group . No difference was detected between the acupuncture and the sham acupuncture groups ( 0.0 days , 95 % confidence interval , -0.7 to 0.7 days ; P = .96 ) while there was a difference between the acupuncture group compared with the waiting list group ( 1.4 days ; 95 % confidence interval ; 0.8 - 2.1 days ; P<.001 ) . The proportion of responders ( reduction in headache days by at least 50 % ) was 51 % in the acupuncture group , 53 % in the sham acupuncture group , and 15 % in the waiting list group . CONCLUSION Acupuncture was no more effective than sham acupuncture in reducing migraine headaches although both interventions were more effective than a waiting list control [22950829] OBJECTIVES The purpose of this study was to evaluate the effectiveness of P6 acupressure on vertigo and neurovegetative symptoms , its possible interference with vestibular-ocular reflex ( VOR ) , and its clinical usefulness during acute vertigo . MATERIAL S AND METHODS Two hundred and four patients , either affected by acute vertigo ( n=124 ) or undergoing labyrinth stimulation ( n=80 ) , were r and omly divided in two homogeneous groups : an experimental group A and a placebo group B. Each patient rated severity of vertigo and neurovegetative symptoms on a visuo-analogue scale ranging from 0 to 10 , before and after bilateral placement of a P6 device . The latter was placed on the P6 acupressure point ( appropriate placement ) in Group A patients or on the dorsal part of the carpus ( inappropriate placement ) in the Group B patients . Furthermore , qualitative and quantitative nystagmus parameters were collected via recorded video-oculoscopy and electronystagmography . RESULTS Eighty-five percent of Group A patients reported improvement of symptoms , which was significant for neurovegetative symptoms , but not for vertigo . In contrast , only 11 % of the Group B patients reported improvement . VOR analysis did not show any significant variation of qualitative and quantitative nystagmus variables . CONCLUSIONS This study demonstrated that the P6 device is effective in improving neurovegetative symptoms in patients affected by spontaneous and provoked vertigo , without any interference with VOR . Given the low cost and lack of side-effects of the P6 device , its routine application is suggested for acute vertigo and during labyrinth stimulation [22579428] OBJECTIVES Identifying a non-pharmacological intervention to reduce the stress response could be particularly beneficial to college students , a group prone to considerable stress . Acupressure has shown some efficacy in reducing stress in adults following stroke or traumatic brain injury ( TBI ) , but multiple treatments were required . Results from single treatments in healthy population s have been mixed . DESIGN The current study used a r and omised , placebo-controlled , single-blind design to investigate the use of a single acupressure treatment for stress reduction in healthy college students ( n=109 ) during a stressor . INTERVENTIONS Participants were r and omly assigned to one of three single , 40-min interventions : active acupressure , placebo acupressure , or a relaxation CD control . A math task stressor administered before and after the intervention assessed intervention effects on stressor responsivity . MAIN OUTCOME MEASURES Stress responses were measured by physiological ( heart rate ( HR ) , heart rate variability ( HRV ) , skin conductance response ( SCR ) ) and subjective measures ( State Anxiety Inventory , nine-item Psychological Stress Measure ) of anxiety and stress . RESULTS All interventions were associated with the following changes during the post-intervention stressor compared to the pre-intervention stressor : reduced HR ( p<0.001 ) , increased HRV ( p<0.024 ) , reduced SCR ( p<0.001 ) , reduced subjective stress scores ( p<0.001 ) , and increased correct answers ( p<0.001 ) . Although all groups demonstrated stress reduction , there were no significant group differences after a single treatment . CONCLUSIONS All interventions significantly reduced the stress response , although not differently . The lack of active acupressure-associated treatment effects appears to be due to insufficient dosing [22432484] INTRODUCTION Complementary and alternative medicines have been used to decrease labor pain for many years . Despite reports that some of these methods reduce pain , increase maternal satisfaction , and improve other obstetric outcomes , they have received limited attention in the US medical literature . The purpose of this study was to evaluate the effects of LI4 acupressure on labor pain in the first stage of labor , on labor duration , and on patient satisfaction . METHODS A single , blind , r and omized clinical trial was performed with eligible women ( N = 100 ) who were at the beginning of the active phase of labor ( 3 - 4 cm dilatation of cervix with regular uterine contractions ) . The women in the acupressure group ( n = 50 ) received LI4 acupressure at the onset of the active phase for the duration of each uterine contraction over a period of 20 minutes , and the women in the control group ( n = 50 ) received a touch on this point without massage . Labor pain was measured using a structured question naire of a subjective labor pain scale ( visual analogue scale ) before the intervention , immediately after the intervention , 20 and 60 minutes after the intervention , and then every hour . RESULTS There were significant differences between the groups in subjective labor pain scores immediately and 20 , 60 , and 120 minutes after intervention ( P ≤ .001 ) . Active phase duration ( 3 - 4 cm dilatation to full dilatation ) and second stage duration ( full dilatation to birth ) were shorter in the acupressure group . The women in the acupressure group reported greater satisfaction . DISCUSSION LI4 acupressure was effective at decreasing pain and duration of labor . The participants were satisfied , and no adverse effects were noted [15321185] In this r and omized double-blind trial we investigated the effect of acupressure on the incidence of nausea and vomiting after caesarean section under spinal anaesthesia with added intrathecal morphine . Parturients wore either acupressure or placebo wristb and s during surgery and postoperatively for at least 10 h. There was no significant difference overall between the two groups in the incidence of intra- or postoperative nausea or vomiting/retching . Dem and for antiemetic medication was also similar in the two groups . However , in the sub-group of parturients who gave a previous history of postoperative nausea or vomiting , there was a statistically significant reduction in both postoperative nausea and vomiting/retching in the acupressure group . Further investigations are needed to see whether acupressure may be an effective non-pharmacological , non-invasive treatment for a common problem in this sub-group of patients [16895618] Background and objectives : To evaluate the effectiveness of acupressure in preventing nausea and vomiting in patients undergoing gynaecological operations and receiving a patient‐controlled analgesia device . Methods : Patients aged between 40 and 65 yr were included . Exclusion criteria were obesity , diabetes mellitus , and history of motion sickness , postoperative nausea and vomiting , or smoking . Patients were r and omized into one of two groups , acupressure and control . In the acupressure group , acupressure b and s were placed on both wrists with the plastic bead positioned at the P6 point . In controls , beads were placed at a non‐acupoint site . All patients received a st and ard general anaesthetic . Postoperatively , patients were connected to a patient‐controlled analgesia device with morphine ( loading dose 5 mg , background infusion 1 mg h−1 , bolus dose 1 mg and lock‐out time 10 min ) . Pain and sedation scores , respiratory rate , heart rate , arterial pressure and oxygen saturation were recorded for 24 h. Metoclopramide 10 mg was administered intravenously as a rescue antiemetic . Results : Fifty patients received acupressure and 50 were controls . In the acupressure group , 33 % of patients had nausea compared with 63 % controls . The cumulative incidence of vomiting at 24 h was 25 % with acupressure and 61 % in controls . The incidence of nausea , vomiting and antiemetic use was significantly lower with acupressure . Conclusions : Acupressure at the P6 meridian point is an effective alternative for the prevention of nausea and vomiting in patients receiving patient‐controlled analgesia with morphine after gynaecological surgery [23448746] PURPOSE / OBJECTIVES To evaluate the effectiveness of ST-36 ( Zusanli ) acupressure on recovery of postoperative gastrointestinal function in patients with colorectal cancer . DESIGN A longitudinal , r and omized , controlled trial design . SETTING An urban medical center in Taiwan . SAMPLE 60 patients with colorectal cancer who had undergone abdominal surgery . METHODS Patients were r and omly assigned to two groups , the ST-36 acupressure group ( n = 30 ) and a sham acupressure group ( n = 30 ) . Patients in the ST-36 group received an acupressure procedure in a three-minute cycle performed three times per day during the five days after surgery . Patients in the control group received routine postoperative care and sham acupressure . Generalized estimating equations ( GEEs ) were used to gauge longitudinal effects of the two groups of patients . MAIN RESEARCH VARIABLES Frequency of bowel sounds , the time to first flatus passage , first liquid intake , solid intake , and defecation . FINDINGS Patients who received acupressure had significantly earlier flatus passage and time to liquid intake as compared to patients in the control group . Other main variables , including the first time to solid intake and defecation , did not show significant difference between the two groups . The GEE method revealed that all patients had increasing bowel sounds over time , and the experimental group had greater improvement of bowel motility than the control group within the period of 2 - 3 days postoperatively . CONCLUSIONS ST-36 acupressure was able to shorten the time to first flatus passage , oral liquid intake , and improve gastrointestinal function in patients after abdominal surgery . IMPLICATION S FOR NURSING ST-36 acupressure can be integrated into postoperative adjunct nursing care to assist patients ' postoperative gastrointestinal function . KNOWLEDGE TRANSLATION Few studies have explored the effectiveness of acupressure techniques on promoting bowel sounds . Evidence from this study suggests stimulation of the ST-36 acupressure point can increase bowel sound frequency for patients with colorectal cancer in the first three days after surgery . Application of this technique may improve a patient 's comfort after surgery [14720242] BACKGROUND Patients with chronic obstructive pulmonary disease ( COPD ) suffer from dyspnoea in their daily life and this may be increased by anxiety . Acupressure may promote relaxation and relieve dyspnoea . Thus , it is appropriate to explore the effectiveness of acupressure on dyspnoea in patients with COPD . AIMS To compare outcomes of acupressure using sham acupoints on different meridians and ganglionic sections with that using true acupoints , in patients with COPD who are living at home . METHODS Patients diagnosed with COPD were selected from a medical centre and three regional hospitals in Taipei . A r and omized block experimental design was used . Using age , sex , pulmonary function , smoking , and steroid use as matching factors , 44 patients were r and omly assigned either to a true acupoint acupressure or a sham group . The true acupoint acupressure group received a programme to decrease dyspnoea . Those in the sham group received acupressure using sham pressure points . Both acupressure programmes consisted of five sessions per week lasting 16 minutes per session , extending over 4 weeks for a total of 20 sessions . Before acupressure was initiated and at the conclusion of the 20th session , the Pulmonary Functional Status and Dyspnoea Question naire-modified scale and the Spielberger State Anxiety scale were administered , and a 6-minute walking distance test was performed . Physiological indicators of oxygen saturation and respiratory rate were measured before and after every session . RESULTS The results of this study showed that the pulmonary function and dyspnoea scores , 6-minute walking distance measurements , state anxiety scale scores , and physiological indicators of the true acupoint acupressure group improved significantly compared with those of the sham group . CONCLUSIONS The findings suggest that acupressure can be used as a nursing intervention to improve dyspnoea in patients with COPD [20056221] BACKGROUND Acupressure on the Shenmen point ( indexed as HT7 ) can improve insomnia , but there has been no longitudinal study to evaluate its efficacy for residents of long-term care facilities . No evidence from the existing literature indicates how long its efficacy can be maintained after stopping acupressure . OBJECTIVE The aim of this study was to evaluate the effectiveness of acupressure on the Shenmen point for residents of long-term care facilities with insomnia . METHODS Fifty residents with insomnia in long-term care facilities were enrolled in a r and omized controlled trial , with 25 participants allocated to the experimental group and 25 participants to the control group . For a 5-week period , the experimental group received st and ard acupressure on the HT7 points of both wrists , whereas the control group received only light touch on the same places . Insomnia was measured with the Athens Insomnia Scale-Taiwan form ( AIS-T ) . Participants ' self-reported scores were done at baseline , during the 5-week period , and after intervention . This study was analyzed on an intention-to-treat procedure . RESULTS The experimental group has significantly better scores on the AIS-T compared to the control group , not only during the intervention period , but also extending after intervention , as shown by generalized estimating equations ( p<0.05 ) . CONCLUSIONS Offering acupressure on a regular basis has the potential to improve insomnia in residents of long-term care facilities . Acupressure on the HT7 point may improve insomnia for up to 2 weeks after the intervention [10081532] Background : Acupuncture and acupressure have previously been reported to possess antiemetic effect . We wanted to investigate the “ true ” and placebo effect of acupressure in prevention of postoperative nausea and vomiting ( PONV ) [22082432] OBJECTIVES This study 's objective was to examine the effectiveness of Sanyinjiao point ( SP6 ) acupressure on women 's general health . DESIGN This was a r and omized , single-blind clinical trial . SETTING The setting for this trial was at Medical University , Bojnoord University of Medical Science , Bojnoord , Iran . MATERIAL S AND METHODS Eighty-six ( 86 ) university students were recruited for this study . Their demographic characteristics were gathered before the intervention commenced . Participants completed General Health Question naires ( GHQ ) prior to participation . Next , they were r and omly assigned to either the acupressure-receiving group or the sham-pressure-receiving group . The study group received acupressure at the Sanyinjiao point , while the control group received sham pressure . OUTCOME MEASURES Both groups completed GHQ after both the first and second months of intervention . Data analysis was carried out using SPSS version 13.5 for Windows . RESULTS The mean age of those who completed the study was 20.84±1.64 years . Mean scores of GHQs were similar between groups before intervention ( p>0.05 ) . The general health of participants in both groups improved after intervention , and the amelioration in four domains was significant in the groups ( p<0.05 within group ) . It was found that acupressure was more effective than sham pressure . In addition , there was a statistically significant difference between the two groups in the four domains of their general heath after the first month of the intervention ( p<0.0001 ) . Furthermore , the general health status of the participants changed much more after the second month in both the acupressure intervention and the sham pressure groups ; nevertheless , acupressure was more effective than sham pressure ( p<0.05 ) . CONCLUSIONS Both acupressure and sham pressure were effective in promoting women 's general health ; nevertheless , the efficacy of acupressure was more than that of sham pressure . SP6 acupressure could be regarded as a self-manageable approach to improve women 's general health [12801491] OBJECTIVES To assess the effectiveness of continuous PC6 acupressure as an adjunct to antiemetic drug therapy in the prevention and control of nausea and vomiting in the first 24h after myocardial infa rct ion ( MI ) . DESIGN Partially r and omised , partially blinded placebo-controlled , exploratory clinical study . SETTING Coronary Care Unit , Torbay Hospital , Torquay , Devon . PARTICIPANTS A total of 301 consecutive patients ( 205 males , 96 females ) admitted following acute MI . INTERVENTION The first 125 patients recruited received no additional intervention . Subsequent patients were r and omised to receive either continuous PC6 acupressure or placebo acupressure . OUTCOME MEASURES ( 1 ) Incidence of post-MI nausea and /or vomiting , ( 2 ) severity of symptoms , ( 3 ) use of antiemetic drugs , over 24h . RESULTS There were no significant differences between the groups for the whole 24-h treatment period . However , the PC6 acupressure group experienced significantly lower incidence of nausea and /or vomiting during the last 20h ( 18 % ) , compared with the placebo ( 32 % ) or control ( 43 % ) groups ( P<0.05 ) . The severity of symptoms and the need for antiemetic drugs were also reduced in the acupressure group , but these differences were not statistically significant . CONCLUSIONS Continuous 24-h PC6 acupressure therapy as an adjunct to st and ard antiemetic medication for post-MI nausea and vomiting is feasible and is well accepted and tolerated by patients . In view of its benefits , further studies are worthwhile using earlier onset of treatment [17920972] BACKGROUND Pain during transportation is a common phenomenon in emergency medicine . As acupressure has been deemed effective for pain management by the National Institutes of Health , we conducted a study to evaluate its effectiveness in prehospital patients with isolated distal radial fracture . METHODS This was a prospect i ve , r and omized , double-blind study . Thirty-two patients were enrolled . Acupressure was performed either at " true " points or at " sham " points . Vital signs and pain and anxiety scores were recorded before and after the acupressure treatment . Normally distributed values were compared using the Student t test . RESULTS Pretreatment scores for pain and anxiety were similar in the 2 groups ( 47.6 + /- 8.9 vs 51.2 + /- 8.7 visual analog scale [ VAS ] score for pain , 52.4 + /- 6.0 vs 47.5 + /- 9.3 VAS score for anxiety ) . At the hospital , patients in the true-points group had significantly lower pain ( 36.6 + /- 11.0 vs 56.0 + /- 13.3 VAS score , P < .001 ) and anxiety scores ( 34.9 + /- 22.2 vs 53.4 + /- 19.7 VAS score , P = .022 ) . CONCLUSION Acupressure in the prehospital setting effectively reduces pain and anxiety in patients with distal radial trauma [12198060] Untreated pain during the transportation of patients after minor trauma is a common problem in emergency medicine . Because paramedics usually are not allowed to perform invasive procedures or to give drugs for pain treatment , a noninvasive , nondrug-based method would be helpful . Acupressure is a traditional Chinese treatment for pain that is based on pain relief followed by a short mechanical stimulation of specific points . Consequently , we tested the hypothesis that effective pain therapy is possible by paramedics who are trained in acupressure . In a double-blinded trial we included 60 trauma patients . We r and omly assigned them into three groups ( “ true points , ” “ sham-points , ” and “ no acupressure ” ) . An independent observer , blinded to the treatment assignment , recorded vital variables and visual analog scales for pain and anxiety before and after treatment . At the end of transport , we asked for ratings of overall satisfaction . For statistical evaluation , one-way analysis of variance and the Scheffé F test were used . P < 0.05 was considered statistically significant . Morphometric and demographic data and potential confounding factors such as age , sex , pain , anxiety , blood pressure , and heart rate before treatment did not differ among the groups . At the end of transport we found significantly less pain , anxiety , and heart rate and a greater satisfaction in the “ true points ” groups ( P < 0.01 ) . Our results show that acupressure is an effective and simple-to-learn treatment of pain in emergency trauma care and leads to an improvement of the quality of care in emergency transport . We suggest that this technique is easy to learn and risk free and may improve paramedic-based rescue systems [16618043] Introduction There is some evidence for the efficacy of acupuncture , but it remains unclear whether trigger point acupuncture is effective . Our objective was to evaluate the effects of trigger point acupuncture on pain and quality of life in chronic low back pain patients compared with sham acupuncture . Methods Twenty-six consecutive out- patients ( 17 women , 9 men ; age range : 65–91 years ) from the Department of Orthopaedic Surgery , Meiji University of Oriental Medicine , with non-radiating low back pain for at least six months and normal neurological examination , were r and omised to two groups . Each group received one phase of trigger point acupuncture and one of sham acupuncture with a three week washout period between them , over 12 weeks . Group A ( n=13 ) received trigger point acupuncture in the first phase and sham acupuncture in the second . Group B ( n=13 ) received the same interventions in the reverse order . Outcome measures were pain intensity ( visual analogue scale , VAS ) and Rol and Morris Question naire . Results Nineteen patients were included in the analysis . At the end of the first treatment phase , group A receiving trigger point acupuncture scored significantly lower VAS ( P<0.001 ) and Rol and Morris Question naire scores ( P<0.01 ) than the sham control group . There were significant within-group reductions in pain in both groups during the trigger point acupuncture phase but not in the sham treatment phase . However , the beneficial effects were not sustained . Conclusion These results suggest that trigger point acupuncture may have greater short term effects on low back pain in elderly patients than sham acupuncture [22083987] The efficacy of acupressure therapy in managing urodynamic stress incontinence has not been fully investigated . This study evaluates the effects of a vali date d acupressure protocol for treating women with urodynamic stress incontinence . A r and omized , single-blinded , placebo-controlled trial with a before- and -after study design was conducted . Eighty-one women aged between 18 and 60 were recruited at a urogynecology clinic in an acute hospital in Hong Kong . Participants were r and omly assigned to an intervention ( acupressure ) group , a sham group , or a usual care ( control ) group . A vali date d acupressure protocol was employed in the intervention group . The intervention comprised three weekly sessions of 30 minutes each for a total of thirty sessions . Outcome measures included pelvic floor muscle strength , number of episodes of urine leakage over four days , self-reported severity of urine leakage , and responses on the Chinese version of the King 's Health Question naire . No adverse effects were reported . Five percent of the participants dropped out of the study . Intention-to-treat analysis was conducted , the results indicated significant differences in pelvic floor muscle strength across the three groups ( H = 7.05 , p = 0.03 ) and in self-reported severity of urine leakage between the intervention and control groups ( Z = -2.48 , p = 0.01 ) . Significant improvement in all domains of the Chinese version of the King 's Health Question naire was evident in the intervention group . Acupressure is a simple and non-invasive intervention that appears to have positive physiological and psychological effects on women with urodynamic stress incontinence . The findings support acupressure as an intervention option for managing urodynamic stress incontinence in women [14696681] The purpose of this study was to evaluate the effectiveness of acupressure on gastrointestinal ( GI ) motility in women after trans-abdominal hysterectomy ( TAH ) . Patients were r and omly assigned into two groups of 21 and 20 patients each . The experimental group received acupressure for 3 minutes at each of three meridian points : Neiguan ( PC-6 ) , Zusanli ( ST-36 ) and Sanyinjiao ( SP-6 ) . The control group received 3 minutes of acupressure on sham points . Acupressure was performed twice a day . A question naire was used to determine patients ' satisfaction prior to and after afternoon acupressure . GI contractions were measured with a multifunctional stethoscope before and after acupressure . Acupressure of these three meridian points significantly ( p < 0.05 ) increased GI motility in the experimental group , but there was little change in the control group ( p > 0.05 ) . Our conclusions are that non-invasive acupressure of these meridian points can significantly improve GI motility and can be incorporated into the technical curriculum and clinical education program of nursing schools . Patients and their family members can be taught to continue this procedure at home to enhance GI motility in patients who have undergone TAH [20347838] INTRODUCTION Sleep disturbances are very common in elderly people and Traditional Chinese acupressure a noninvasive technique that promotes health and comfort recently has been used in this regard . The purpose of the present study was to evaluate the potential beneficial effects of acupressure on a group of institutionalized elders experiencing sleep disturbances . METHOD A r and omized controlled clinical trial was conducted to test the effectiveness of acupressure on quality of sleep of elderly residing in a Nursing home . The Pittsburgh Sleep Quality index ( PSQI ) question naire was used as a screening tool to select 90 residents with moderate to marked sleep disturbances . The elders were r and omly assigned to an acupressure group , a sham acupressure group and a control group by Balanced r and omization method . RESULTS There were significant differences between the acupressure group and the control group in subjective sleep quality , sleep latency , sleep duration , habitual sleep efficiency and sleep disturbance . But no significant differences were found in sleep indices between the sham acupressure group and the control group . Sleep log data showed a significant decrease in nocturnal awakenings in acupressure group compared to other two groups . CONCLUSION The findings of this study indicated that acupressure has an effect on improvement of sleep quality and endorsed it as a non-pharmacological and complementary therapy for sleep-disturbed elderly people [12477673] Purpose To investigate the effect of sensory stimulation of the P6 point on postoperative nausea and vomiting ( PONV ) after gynecological surgery in the everyday clinical setting ( effectiveness study ) . Methods Four hundred and ten women undergoing general anesthesia for elective gynecological surgery were included in a prospect i ve , consecutive , r and omized , multicentre , placebo-controlled , double-blind clinical trial with a reference group . One group was given bilateral P6 acupressure ( n = 135 ) , a second group similar pressure on bilateral non-acupressure points ( n = 139 ) , and a third group ( n = 136 ) served as reference group . Nausea ( scale 0–6 ) , vomiting , pain , and satisfaction with the treatment were recorded . Primary outcome was complete response , i.e. , no nausea , vomiting or rescue medication for 24 hr . Results were analyzed by applying logistic regression with indicators of treatments , type of operation and risk score for PONV as explanatory variables . Results Complete response was more frequent in the P6 acupressure group than in the reference group ( P = 0.0194 ) Conversely , the incidence of PONV was 46 % in the reference group , 38 % after pressure on a non-acupoint and 33 % after P6 acupressure . The decrease from 46 % to 33 % was statistically significant . When considering vaginal cases separately , the decrease in PONV was from 36 % to 20 % ( P = 0.0168 ) . The corresponding decrease from 59 % to 55 % in the laparoscopic surgery group was not statistically significant . Conclusion P6 acupressure is a non-invasive method that may have a place as prophylactic antiemetic therapy during gynecological surgery . RésuméObjectifRechercher l’effet d’une stimulation sensorielle acupressive en P6 sur les nausées et vomissements postopératoires ( NVPO ) à la suite d’une intervention chirurgicale gynécologique dans un cadre clinique normal ( étude d’efficacité).MéthodeUn essai clinique prospect if , r and omisé , multicentrique , en double aveugle contre placebo et comportant un groupe de référence a été réalisé auprès de 410 femmes qui se sont présentées successivement pour une intervention gynécologique non urgente sous anesthésie générale . Les patientes d’un premier groupe ont reçu de l’acupression en P6 ( n = 135 ) , celles d’un second groupe ont reçu une pression semblable sur des points bilatéraux , non d’acupression , ( n = 139 ) et un troisième groupe ( n = 136 ) a servi de référence . Les nausées ( échelle de 0–6 ) , les vomissements , la douleur et la satisfaction face au traitement ont été notés . Le premier résultat était une réponse complète , donc absence de nausées , de vomissements ou de médication de secours pendant 24 h. Les résultats ont été analysés par régression logistique avec des indicateurs de traitements , le type d’intervention et le taux de risque de NVPO comme variables explicatives . RésultatsLa réponse complète a été plus fréquente avec l’acupression en P6 que chez les patientes témoins ( P = 0,0194 ) . Inversement , l’incidence de NVPO a été de 46 % dans le groupe de référence , 38 % après une pression de points non acupresseurs et 33 % après l’acupression en P6 . La diminution de 46 % à 33 % était significative . L’examen séparé des cas d’intervention vaginale indique une baisse des NVPO de 36 % à 20 % ( P = 0,0168 ) . La baisse correspondante de 59 % à 55 % dans les cas d’intervention laparoscopique n’était pas significative . Conclusion L’acupression en P6 représente une méthode non effractive de traitement antiémétique prophylactique qui peut avoir sa place pendant une intervention gynécologique [21544020] Background and objective Postoperative nausea and vomiting causes discomfort in many patients despite both antiemetic prophylactics and improved anaesthetic techniques . Stimulation of acupoint P6 is described as an alternative method for prophylaxis of postoperative nausea and vomiting . In a r and omised , double-blinded study , we aim ed to investigate the effect of P6 acupoint stimulation on the incidence of postoperative nausea and vomiting within 24 h postoperatively with an acupressure wristb and : Vital-B and . Methods One hundred and thirty-four healthy , non-smoking women scheduled for breast surgery were r and omised either to P6 stimulation or to sham control . Wristb and s were applied and covered with a dressing before induction of anaesthesia . Follow-up was carried out three times within 24 h postoperatively . Primary outcomes were postoperative nausea and /or vomiting . Results One hundred and twelve patients completed the study . There were no statistically significant differences in the incidence of nausea [ P6 stimulation , 35.1 % ( 95 % confidence interval , CI 22.7–47.5 % ) versus sham control , 43.1 % ( 95 % CI 29.5–56.7 % ; P = 0.433 ) ] or vomiting [ P6 stimulation , 25.9 % ( 95 % CI 14.6–37.2 % ) versus sham control , 26.9 % ( 95 % CI 14.8–39.0 % ; P = 1.000 ) ] . Approximately , one third of the patients reported side effects caused by the wristb and , for example , redness , swelling and tenderness . Conclusion We did not find the Vital-B and effective in preventing either nausea or vomiting after operation in women undergoing breast surgery [20980765] Background and Objective : A recent Cochrane review on placebo interventions for all kinds of conditions found that ‘ physical placebos ’ ( which included sham acupuncture ) were associated with larger effects over no-treatment control groups than ‘ pharmacological placebos ’ . We re-analyzed the data from this review to investigate whether effects associated with sham acupuncture differed from those of other ‘ physical placebos ’ . Methods : All trials included in the Cochrane review as investigating ‘ physical placebos ’ were classified as investigating either ( sham ) acupuncture or other physical placebos . The latter group was further subclassified into groups of similar interventions . Data from the Cochrane review were re-entered into the RevMan 5 software for meta- analysis . The primary analysis was a r and om-effects analysis of trials reporting continuous outcomes of trials that used either sham acupuncture or other physical placebos . Results : Out of a total of 61 trials which reported a continuous outcome measure , 19 compared sham acupuncture and 42 compared other physical placebos with a notreatment control group . The trials re-analyzed were highly heterogeneous regarding patients , interventions and outcomes measured . The pooled st and ardized mean difference was –0.41 ( 95 % confidence interval –0.56 , –0.24 ) between sham acupuncture and no treatment and –0.26 ( 95 % CI –0.37 , –0.15 ) between other physical placebos and no treatment ( p value for subgroup differences = 0.007 ) . Significant differences were also observed between subgroups of other physical placebos . Conclusion : Due to the heterogeneity of the trials included and the indirect comparison our results must be interpreted with caution . Still , they suggest that sham acupuncture interventions might , on average , be associated with larger effects than pharmacological and other physical placebos [21713729] To compare the efficacy of acupressure wrist b and s , ondansetron , metoclopramide and placebo in the prevention of vomiting and nausea after strabismus surgery . Two hundred patients , ASA physical status I or II , aged between 10 and 60 years , undergoing strabismus surgery in Farabi Hospital in 2007 - 2008 years , were included in this r and omized , prospect i ve , double-blind and placebo-controlled study . Group I was the Control , group II received metoclopramide 0.2 mg/kg , group III received ondansetron 0.15 mg/kg iv just before induction , in Group IV acupressure wristb and s were applied at the P6 points . Acupressure wrist b and s were placed inappropriately in Groups I , II and III . The acupressure wrist b and s were applied 30 min prior to the induction of anesthesia and removed six hours after surgery . Postoperative nausea and vomiting ( PONV ) was evaluated within 0 - 2 hours and 2 - 24 hours after surgery by a blinded observer . Results were analyzed by X(2 ) test . A P value of < 0.05 was taken as significant . The incidence of PONV was not significantly different in acupressure , metoclopramide and ondansetron during the 24 hours . Acupressure at P6 causes a significant reduction in the incidence of PONV 24 hours after strabismus surgery as well as metoclopramide 0.2 mg/kg and ondansetron 0.15 mg/kg iv for patients aged 10 or more [22828022] Preoperative anxiety , as an emotional reaction , is common among patients undergoing surgery . The purpose of this study was to examine the effect of acupressure on preoperative anxiety before abdominal surgery . The 70 subjects of this clinical trial were r and omly assigned into the acupressure group ( n=35 ) , which received acupressure at the true points , or the placebo group ( n=35 ) , which received acupressure at sham ( false ) points . Preoperative anxiety and vital signs before and after the intervention were measured in both groups . The findings demonstrated a reduction in the level of preoperative anxiety for both groups ( P<.001 ) . Furthermore , they showed a statistically significant difference between the mean of vital signs before and after the intervention in the acupressure group ( P<.001 ) and only statistically significant results for cardiovascular ( P=.016 ) and respiratory rates ( P=.007 ) in the placebo group . Overall , findings revealed that acupressure at true points ( third eye and Shen men ) can reduce higher preoperative anxiety of patients before abdominal surgery and that it has had a more clinical ly beneficial effect than sham points [16115972] In this r and omized sham-controlled study we examined the anxiolytic and sedative effects of acupressure on parents in the preoperative holding area before their children ’s surgery . Sixty-one parents received acupressure either at the Yintang point ( midpoint between the two eyebrows ) or at a sham point . Anxiety ( as measured by the Stait-Trait Anxiety Inventory ) , arterial blood pressure , and heart rate were assessed before and after the intervention and a Bispectral Index monitor was used to continuously monitor hypnotic sedation levels . Repeated- measures analysis of variance showed that parents in the acupressure group reported significantly less anxiety at 20 min postintervention as compared with parents in the sham group ( 37 ± 10 versus 45 ± 13 , P = 0.03 ) . Bispectral Index values , heart rate , and arterial blood pressure , however , did not differ between the two study groups ( P = not significant ) . We conclude that acupressure at the Yintang point may be used as a treatment for parental preoperative anxiety . Future studies are needed to quantify the magnitude and duration of the anxiolytic effect [17402962] AIMS AND OBJECTIVES To examine and compare the effects of acupressure on the perceived health-related quality of life of the participants with bronchiectasis . BACKGROUND In an attempt to offer comfort , pain control and symptom management , nursing is becoming increasingly involved in offering complementary-alternative medicine as part of its caring-healing focus in comprehensive patient care . Acupressure is one such modality that is being increasingly used by both medical and nursing professionals . While acupressure has been reported to have beneficial effects in patients with respiratory disease , the benefits to bronchiectasis patients have remained uncertain . DESIGN A r and omized , partially blinded study consisting of three groups . METHODS Thirty-five out- patients of both genders , aged 59.46 SD 11.52 years , who were suffering from bronchiectasis , were r and omly split into one of three groups : st and ard care with supplemental acupressure for eight weeks ( 11 participants ) ; st and ard care with supplemental sham acupressure for eight weeks ( 11 participants ) ; and st and ard care alone ( 13 participants ) . Outcomes were determined by changes in daily sputum amounts , sputum self- assessment , six-minute walking distance , breathing difficulty ( measured on the dyspnea visual analogue scale ) and health-related quality of life ( measured by the Saint George Respiratory Question naire ) . RESULTS The sputum self- assessment score improved over time for the sham acupressure participants ( P = 0.03 ) , when compared with the controls . For acupressure participants , the Saint George respiratory question naire activity component scores also improved over time , compared with controls ( P = 0.01 ) after adjustment for covariates ( treatment , time , age , sex and baseline values ) . Other variables did not differ between the st and ard care alone group and the other two groups . CONCLUSIONS Eight weeks of self-administered acupressure could be useful in reducing the effects of bronchiectasis on a patient 's daily activities . RELEVANCE TO CLINICAL PRACTICE Acupressure may be regarded as a viable nursing intervention [11277163] OBJECTIVE To determine the effect of continuous acupressure at P6 applied by Sea-B and s with acupressure buttons on the frequency and severity of nausea and vomiting of pregnancy during the 1 st trimester . DESIGN A two-group , quasi-experimental , posttest-only and posttest-repeated measure . SETTING Seventeen medical clinics or offices in southern Michigan . PARTICIPANTS Convenience sample of English-speaking , healthy pregnant women in their 1 st trimester , who had at least one episode of nausea , vomiting , or both before their prenatal clinic/office visit where they were recruited . After being accepted for the study , the women were r and omly assigned to treatment or placebo groups . INTERVENTION Treatment group 1 applied SeaB and s with acupressure buttons to both wrists for 4 days and removed the Sea-B and s for 3 subsequent days . Placebo group 2 applied the Sea-B and s without acupressure buttons to both wrists on the same time schedule as group 1 . MAIN OUTCOME MEASURE Self-report daily diaries of the number of times per day that participants experienced nausea , the severity of nausea , the number of vomiting episodes per day , and the severity of vomiting . RESULTS Mann-Whitney U procedures revealed that the treatment group had significantly less frequency and severity of nausea and vomiting of pregnancy while wearing the Sea-B and s than did the placebo group . The treatment group also had significantly less frequency and severity of nausea and vomiting of pregnancy while wearing the SeaB and s than when not wearing the Sea-B and s. CONCLUSIONS Sea-B and s with acupressure buttons are a noninvasive , inexpensive , safe , and effective treatment for the nausea and vomiting of pregnancy [15673989] OBJECTIVE The purpose of this study was to evaluate the effects of SP6 acupressure on labor pain and delivery time in women in labor . DESIGN R and omized clinical trial . SETTING /LOCATION Delivery room in a university hospital . PARTICIPANTS Seventy-five ( 75 ) women in labor were r and omly assigned to either the SP6 acupressure ( n = 36 ) or SP6 touch control ( n = 39 ) group . The participants were matched according to parity , cervical dilation , labor stage , rupture of amniotic membrane , and husb and 's presence during labor . There were no additional oxytocin augmentation or administration of analgesics during the study period . INTERVENTION The 30-minute acupressure or touch on SP6 acupoint was performed . OUTCOME MEASURES Labor pain was measured four times using a structured question naire , a subjective labor pain scale ( visual-analogue scale [ VAS ] ) : before intervention , immediately after the intervention , and 30 and 60 minutes after the intervention . Length of delivery time was calculated in two stages : from 3 cm cervical dilation to full cervical dilatation , and full cervical dilatation to the delivery . RESULTS There were significant differences between the groups in subjective labor pain scores at all time points following the intervention : immediately after the intervention ( p = 0.012 ) ; 30 minutes after the intervention ( p = 0.021 ) ; and 60 minutes after the intervention ( p = 0.012 ) . The total labor time ( 3 cm dilatation to delivery ) was significantly shorter in the SP6 acupressure intervention group than in the control group ( p = 0.006 ) . CONCLUSIONS These findings showed that SP6 acupressure was effective for decreasing labor pain and shortening the length of delivery time . SP6 acupressure can be an effective nursing management for women in labor [16818924] BACKGROUND Despite the popularity of acupuncture , evidence of its efficacy for reducing pain remains equivocal . OBJECTIVE To assess the efficacy and safety of traditional Chinese acupuncture ( TCA ) compared with sham acupuncture ( needling at defined nonacupuncture points ) and conservative therapy in patients with chronic pain due to osteoarthritis of the knee . DESIGN R and omized , controlled trial . SETTING 315 primary care practice s staffed by 320 practitioners with at least 2 years ' experience in acupuncture . PATIENTS 1007 patients who had had chronic pain for at least 6 months due to osteoarthritis of the knee ( American College of Rheumatology [ ACR ] criteria and Kellgren-Lawrence score of 2 or 3 ) . INTERVENTIONS Up to 6 physiotherapy sessions and as-needed anti-inflammatory drugs plus 10 sessions of TCA , 10 sessions of sham acupuncture , or 10 physician visits within 6 weeks . Patients could request up to 5 additional sessions or visits if the initial treatment was viewed as being partially successful . MEASUREMENTS Success rate , as defined by at least 36 % improvement in Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) score at 26 weeks . Additional end points were WOMAC score and global patient assessment . RESULTS Success rates were 53.1 % for TCA , 51.0 % for sham acupuncture , and 29.1 % for conservative therapy . Acupuncture groups had higher success rates than conservative therapy groups ( relative risk for TCA compared with conservative therapy , 1.75 [ 95 % CI , 1.43 to 2.13 ] ; relative risk for sham acupuncture compared with conservative therapy , 1.73 [ CI , 1.42 to 2.11 ] ) . There was no difference between TCA and sham acupuncture ( relative risk , 1.01 [ CI , 0.87 to 1.17 ] ) . LIMITATIONS There was no blinding between acupuncture and traditional therapy and no monitoring of acupuncture compliance with study protocol . In general , practitioner-patient contacts were less intense in the conservative therapy group than in the TCA and sham acupuncture groups . CONCLUSIONS Compared with physiotherapy and as-needed anti-inflammatory drugs , addition of either TCA or sham acupuncture led to greater improvement in WOMAC score at 26 weeks . No statistically significant difference was observed between TCA and sham acupuncture , suggesting that the observed differences could be due to placebo effects , differences in intensity of provider contact , or a physiologic effect of needling regardless of whether it is done according to TCA principles [12550145] The purpose of the study is to test the effectiveness of acupressure on sleep quality of end-stage renal disease patients . The study was a r and omized controlled trial ; qualified patients in the dialysis centers of four major hospitals were r and omly assigned into an acupressure group , a sham acupressure group , and a control group . A total of 98 participants were included in the study . The main outcomes measured were the Pittsburgh sleep quality index ( PSQI ) and the sleep log . Data were collected at pretreatment and following treatment . Primary statistical analysis was by means of Analysis of Covariance , the Kruskal-Wallis Test and repeated measure ANOVA . The results indicated that PSQI scores of the acupressure group have a significantly greater improvement ( p < 0.01 ) than the control group . However , there were no differences between the acupressure group and the sham group or the sham group and the control group ( p > 0.05 ) . Subscales of PSQI were further analyzed . Results demonstrated significant differences between the acupressure group and the control group in subjective sleep quality ( p = 0.009 ) , sleep duration ( p = 0.004 ) , habitual sleep efficiency ( p = 0.001 ) , and sleep sufficiency ( p = 0.004 ) . Significant differences in the subscale of subjective sleep quality ( p = 0.003 ) between the sham acupressure group and the control group were also observed . Sleep log data showed that the acupressure group significantly decreased awake time and improved quality of sleep over time more than the control group ( p < 0.01 ) . The improvement could be seen as soon as the acupoints massage was implemented , and it was maintained through the post intervention [8969878] Our objective was to study the analgesic effect of acupoint pressure on postoperative pain in a controlled single-blind study . Forty patients undergoing knee arthroscopy in an ambulatory surgery unit in a university-affiliated hospital were r and omized to receive either an active stimulation ( AS ) or a placebo stimulation ( PS ) 30 min after awakening from anesthesia . We stimulated 15 classical acupoints in the AS group , on the side contralateral to surgery , with a firm pressure and a gliding movement across the acupoint . In the PS group , 15 nonacupoints were subjected to light pressure in the same areas as the acupoints in the AS group . We assessed pain using a 100-mm visual analog scale ( VAS ) before sensory stimulation , after 30 and 60 min , and after 24 h. We recorded heart rate , systolic arterial pressure , and skin temperature before stimulation and after 30 and 60 min . We assessed skin blood flow with laser Doppler before stimulation and after 1 and 30 min . Sixty minutes and 24 h after AS , VAS pain scores were lower than in the placebo group ( p < 0.05 and 0.0001 , respectively ) . There were no significant changes in the autonomic variables . The results indicate that pressure on acupoints can decrease postoperative pain [14973803] OBJECTIVE To determine whether the application of acupressure b and s would lead to a reduction in postoperative nausea and vomiting after cardiac surgery . DESIGN Prospect i ve , r and omized , double-blind clinical trial . SETTING University-affiliated tertiary care teaching hospital . PARTICIPANTS Adult patients undergoing cardiac surgery . INTERVENTIONS One hundred fifty-two patients were enrolled to receive either acupressure treatment ( n = 75 ) or placebo ( n = 77 ) . All patients had acupressure b and s placed on both wrists before induction of anesthesia ; those in the treatment group had a bead placed in contact with the P6 point on the forearm . MEASUREMENTS AND MAIN RESULTS Patients were assessed for nausea , vomiting , and pain scores during the first 24 hours of the postoperative period . The incidences of nausea , vomiting , pain scores , and analgesic and antiemetic requirements were similar between the 2 groups . A subgroup analysis by gender implied that acupressure treatment may be effective only in female patients . CONCLUSION Acupressure treatment did not lead to a reduction in nausea , vomiting , or antiemetic requirements in patients after cardiac surgery [8189280] To evaluate the reported benefit of ipsilateral single-application ophthalmic anesthetic eyedrops in patients with typical trigeminal neuralgia , a r and omized double-blind placebo-controlled trial was performed . Forty-seven patients were r and omly assigned to receive two drops of either proparacaine ( 25 cases ) or saline placebo ( 22 cases ) . The experimental and placebo groups were equivalent in regard to patient age , distribution of trigeminal neuralgia pain , duration of pain , current medication regimens , and number of prior procedures performed . Pain response was assessed at 3 , 10 , and 30 days after instillation using two pain rating scales and a measure of pain frequency . Treatment failure was defined in advance as any of the following : a lack of clinical response , the need for an increase in medication , or the need for surgery . No significant difference in outcomes was found between the two groups either when using a verbal pain rating scale ( p = 0.24 ) or when comparing overall pain status ( unchanged , improved throughout the study period , or temporarily improved ) ( p = 0.98 ) . No difference in the frequency of trigeminal neuralgia attacks between the two treatment groups ( scaled within five levels of pain frequency ) was detected ( p = 0.09 ) . During follow-up monitoring , 11 patients in the test drug group and 14 in the placebo group required surgery because of persistent pain ( p = 0.24 ) . The results of this study indicate that single-application topical ophthalmic anesthesia reduces neither the severity nor the frequency of pain in comparison to placebo administration . Although a simple and safe treatment , the single application of topical ophthalmic eyedrops provides no short- or long-term benefit to patients with trigeminal neuralgia [17645494] AIM This paper is a report of a study to examine the effect of Nei-Guan point acupressure on nausea , vomiting and ketonuria levels in women diagnosed with hyperemesis gravidarum . BACKGROUND Previous studies have shown that acupressure application on the Nei-Guan point is effective in relieving nausea and vomiting associated with pregnancy and surgery . However , no findings have been supported by physiological data . METHOD A r and omized control group pretest-post-test design was implemented from 1 April 2003 to 30 April 2004 using three groups : a Nei-Guan point acupressure group , a placebo group and a control group which received only conventional intravenous treatment . The participants were 66 women admitted to two general hospitals in Korea with hyperemesis gravidarum . RESULTS The degree of nausea and vomiting was statistically significantly lower in the Nei-Guan point acupressure group in comparison with the placebo and control groups . Ketonuria levels were reduced over time and , on days three and four of hospitalization , levels in the treatment group were statistically significantly lower than in the placebo or control groups ( P < 0.05 ) . CONCLUSION Nei-Guan point acupressure is a useful treatment for relieving symptoms experienced by women with hyperemesis gravidarum [25440382] OBJECTIVES In clinical trials where participants are likely to be able to distinguish between true and sham interventions , informing participants that they may receive a sham intervention increases the likelihood of participants ' breaking the blind ' and invalidating trial findings . The present study explored participants ' perceptions of the consent process in a sham controlled acupressure trial which did not explicitly indicate participants may receive a sham intervention . DESIGN Nested qualitative study within a r and omised sham controlled trial of acupressure wristb and s for chemotherapy-related nausea . Convenience sample of 26 patients participated in semi-structured interviews . Interviews were audio-recorded and transcribed verbatim . Transcripts analysed thematically using framework analysis . SETTING Study conducted within three geographical sites in the UK : Manchester , Liverpool , and Plymouth . RESULTS All participants indicated that they believed they were fully informed when providing written consent to participate in the trial . Participants ' perceived it was acceptable to employ a sham intervention within the trial of acupressure wristb and s without informing potential participants that they may receive a sham treatment . Despite the fact that participants were not informed that one of the treatment arms was a sham intervention the majority indicated they assumed one of the treatment arms would be placebo . CONCLUSIONS Many trials of acupuncture and acupressure do not inform participants they may receive a sham intervention . The current study indicates patients ' perceive this approach to the consent process as acceptable . However , the fact participants assume one treatment may be placebo threatens the method ological basis for utilising this approach to the consent process [18713889] BACKGROUND : Acupuncture and related techniques have been used as adjuncts for perioperative anesthesia management . We examined whether acupressure in the Extra-1 ( Yin-Tang ) point would result in decreased preprocedural anxiety and reduced intraprocedural propofol requirements in a group of children undergoing endoscopic procedures . METHODS : Fifty-two children were r and omized to receive acupressure bead intervention either at the Extra-1 acupuncture point or at a sham point . A Bispectral Index ( BIS ) monitor was applied to all children before the onset of the intervention . Anxiety was assessed at baseline and before entrance to the operating room . Anesthetic techniques were st and ardized and maintained with IV propofol infusion titrated to keep BIS values of 40–60 . RESULTS : We found that after the intervention , children in the Extra-1 group experienced reduced anxiety whereas children in the sham group experienced increased anxiety ( −9 % [ −3 to −15 ] vs 2 % [ −6 to 7.4 ] , P = 0.012 ) . In contrast , no significant changes in BIS values were observed in the preprocedural waiting period between groups ( P = ns ) . We also found that total intraprocedural propofol requirements did not differ between the two study groups ( 214 ± 76 & mgr;g · kg−1 · min−1 vs 229 ± 95 & mgr;g · kg−1 · min−1 , P = 0.52 ) . CONCLUSIONS : We conclude that acupressure bead intervention at Extra-1 acupoint reduces preprocedural anxiety in children undergoing endoscopic procedures . This intervention , however , has no impact on BIS values or intraprocedural propofol requirements [23803562] BACKGROUND Chemotherapy-induced nausea and vomiting remain difficult symptoms to manage in clinical practice . As st and ard antiemetic drugs do not fully eliminate these symptoms , it is important to explore the adjuvant role of non-pharmacological and complementary therapies in antiemetic management approaches . Acupressure is one such treatment showing highly suggestive evidence so far of a positive effect , meriting further investigation . OBJECTIVES The primary objective was to assess the effectiveness and cost-effectiveness of self-acupressure using wristb and s compared with sham acupressure wristb and s and st and ard care alone in the management of chemotherapy-induced nausea . Secondary objectives included assessment of the effectiveness and cost-effectiveness of the wristb and s in relation to vomiting and quality of life and exploration of any age , gender and emetogenic risk effects . DESIGN R and omised three-arm sham-controlled trial ( Assessment of Nausea in Chemotherapy Research or ANCHoR ) with an economic evaluation . Arms include the wristb and arm , the sham wristb and arm and the st and ard care only arm . R and omisation consisted of minimisation with a r and om element balancing for gender , age ( 16 - 24 , > 24 - 50 , > 50 years ) and three levels of emetogenic chemotherapy ( low , moderate and high ) . Qualitative interviews were incorporated to shed more light on the quantitative findings . SETTING Outpatient chemotherapy clinics in three regions in the UK involving 14 different cancer units/centres . PARTICIPANTS Chemotherapy-naive cancer patients receiving chemotherapy of low , moderate and high emetogenic risk . INTERVENTION The intervention was acupressure wristb and s pressing the P6 point ( anterior surface of the forearm ) . MAIN OUTCOME MEASURES The Rhodes Index for Nausea/Vomiting , the Multinational Association of Supportive Care in Cancer ( MASCC ) Antiemesis Tool and the Functional Assessment of Cancer Therapy - General ( FACT-G ) . At baseline participants completed measures of anxiety/depression , nausea/vomiting expectation and expectations from using the wristb and s. RESULTS In total , 500 patients were r and omised in the study arms ( 166 st and ard care , 166 sham acupressure and 168 acupressure ) and data were available for 361 participants for the primary outcome . The primary outcome analysis ( nausea in cycle 1 ) revealed no statistically significant differences between the three arms , although the median nausea experience in patients using wristb and s ( both real and sham ones ) was somewhat lower than that in the antiemetics only group ( median nausea experience scores for the four cycles : st and ard care arm 1.43 , 1.71 , 1.14 , 1.14 ; sham acupressure arm 0.57 , 0.71 , 0.71 , 0.43 ; acupressure arm 1.00 , 0.93 , 0.43 , 0 ) . A gender effect was evident ( p= 0.002 ) , with women responding more favourably to the use of sham acupressure wristb and s than men ( odds ratio 0.35 for men and 2.02 for women in the sham acupressure group ; 1.27 for men and 1.17 for women in the acupressure group ) . This suggests a placebo effect . No significant differences were detected in relation to vomiting outcomes , anxiety and quality of life . Some transient adverse effects were reported , including tightness in the area of the wristb and s , feeling uncomfortable when wearing them and minor swelling in the wristb and area ( n= 6).There were no statistically significant cost differences associated with the use of real acupressure b and s ( £ 70.66 for the acupressure group , £ 111.13 for the st and ard care group and £ 161.92 for the sham acupressure group ) . In total , 26 subjects took part in qualitative interviews . The qualitative data suggested that participants perceived the wristb and s ( both real and sham ) as effective and helpful in managing their nausea during chemotherapy . CONCLUSIONS There were no statistically significant differences between the three arms in terms of nausea , vomiting and quality of life , although apparent re source use was less in both the real acupressure arm and the sham acupressure arm compared with st and ard care only ; therefore ; no clear conclusions can be drawn about the use of acupressure wristb and s in the management of chemotherapy-related nausea and vomiting . However , the study provided encouraging evidence in relation to an improved nausea experience and some indications of possible cost savings to warrant further consideration of acupressure both in practice and in further clinical trials . TRIAL REGISTRATION IS RCT N87604299 . SOURCE OF FUNDING This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol . 17 , No. 26 . See the HTA programme website for further project information [24673069] R and omized controlled trials ( RCT ) is the source of the raw data of evidence -based medicine . Blind method is adopted in most of the high- quality RCT . Sham acupuncture is the main form of blinded in acupuncture clinical trial . In order to improve the quality of acupuncture clinical trail , based on the necessity of sham acupuncture in clinical research , the current situation as well as the existing problems of sham acupuncture , suggestions were put forward from the aspects of new way and new design ation method which can be adopted as reference , and factors which have to be considered during the process of implementing . Various subjective and objective factors involving in the process of trial should be considered , and used of the current international st and ards , try to be quantification , and carry out strict quality monitoring [19034253] AIM Insomnia is a major problem which decreases life quality . Many causes are involved with it and anxiety is often associated . The underlying mechanism is not completely understood , even though different factors seem to be associated . Among them melatonin and its circadian rhythm is thought to have an important role . In addition , acupressure and acupuncture are known to ameliorate insomnia and anxiety , when a specific wrist point is stimulated ( HT 7 Shenmen ) . With these bases , the aim of the present study has been to evaluate the efficacy of an acupressure device , ' ' H7-insomnia control ' ' , positioned on HT 7 points , during the night , in terms of general health and anxiety levels , together with the evaluation of sleep quality and the urinary melatonin metabolite 6-hydroxymelatonin sulphate determination , in a number of insomniacs . METHODS Forty patients with insomnia were divided into two groups and r and omly received either the H7 or placebo treatments , in a double-blind protocol , for 20 nights . Before and after treatments every subject answered a series of question naires ( General Health Question naire 28 items ; State-Trait Anxiety Inventory ; Pittsburgh Sleep Quality Index ) and collected 24 h urines , divided into two sample s of 12 h each . Urinary melatonin metabolite was then determined using a RIA method . RESULTS Data obtained indicate that the device H7-insomnia control is efficacious to ameliorate quality of sleep and reduce anxiety levels in insomniacs , at a higher extent than in the placebo group . In addition , the 24 hours urinary melatonin metabolite rhythm , obtained at the end of treatment , was considered as being normal in a higher percentage of H7-treated patients , with respect to the placebo group . CONCLUSION It is plausible to hypothesize that the wrist acupressure device might be considered a valid tool , without adverse effects since it does not contain pharmaceutical products , that is able to naturally ameliorate sleep quality in insomniacs , acting through a not jet completely clarified mechanism , that may involve melatonin [25146059] BACKGROUND This study explored the effects of acupressure on fatigue of lung cancer patients undergoing chemotherapy . PATIENTS AND METHODS For this experimental study , 57 subjects were r and omly assigned to three groups : acupressure with essential oils ( n=17 ) , acupressure only ( n=24 ) , and sham acupressure ( n=16 ) . Acupoints were Hegu ( LI4 ) , Zusanli ( ST36 ) , and Sanyingjiao ( SP6 ) . All subjects received acupressure once every morning for 5 months , with each acupoint pressed for 1 min . Fatigue , functional status , anxiety , depression , and sleep quality were measured before initial chemotherapy ( T0 ) , on Day 1 of third chemotherapy ( T1 ) , and on Day 1 of sixth chemotherapy ( T2 ) . Outcome differences between groups were analyzed at T0 , T1 , and T2 by general estimating equations . RESULTS After controlling for baseline outcome values , age , and adherence to acupressure , subjects who received acupressure with essential oils and acupressure had significantly less fatigue in daily living activities and sleep better quality at T1 than subjects who received sham acupressure . Subjects who received acupressure with essential oils had significantly better sleep quality at T2 than the sham acupressure group . Subjects who received acupressure with or without essential oils had greater odds of better functional status at T1 than the sham group . CONCLUSION It is plausible that acupressure with or without essential oils helps lung cancer patients undergoing chemotherapy reduce cancer-related fatigue and increase activity level . Further study is wanted to test this hypothesis [9085965] Postoperative nausea and vomiting are still common problems after general anesthesia , especially in ambulatory surgery . Drug therapy is often complicated with central nervous system symptoms . We studied a nonpharmacological method of therapy-acupressure-at the Pericardium 6 ( P.6 ) ( Nei-Guan ) meridian point . Two hundred consecutive healthy patients undergoing a variety of short surgical procedures were included in a r and omized , double-blind study : 108 patients were in the acupressure group ( Group 1 ) and 92 patients were in the control group ( Group 2 ) . Spherical beads of acupressure b and s were placed at the P.6 points in the anterior surface of both forearms in Group 1 patients , while in Group 2 they were placed inappropriately on the posterior surface . The acupressure b and s were placed before induction of anesthesia and were removed 6 h postoperatively . They were covered with a soft cotton wrapping to conceal them from the blinded observer who evaluated the patients for presence of nausea and vomiting and checked the order sheet for any antiemetics prescribed . In both groups , the age , gender , height , weight , and type and duration of surgical procedures were all comparable without significant statistical difference . In Group 1 , only 25 of 108 patients ( 23 % ) had nausea and vomiting as compared to Group 2 , in which 38 of 92 patients ( 41 % ) had nausea and vomiting ( P = 0.0058 ) . We concluded that acupressure at the P.6 ( Nei-Guan ) point is an effective prophylaxis for postsurgical nausea and vomiting and therefore a good alternative to conventional antiemetic treatment . ( Anesth Analg 1997;84:821 - 5 [10434821] The efficacy of currently available antiemetics remains poor . Concern with their side effects and the high cost of the newer drugs has led to renewed interest in non-pharmacological methods of treatment . We have studied the efficacy of acupressure at the P6 point in the prevention of nausea and vomiting after laparoscopy , in a double-blind , r and omized , controlled study of acupressure vs placebo . We studied 104 patients undergoing laparoscopy and dye investigation . The anaesthetic technique and postoperative analgesia were st and ardized . Failure of treatment was defined as the occurrence of nausea and /or vomiting within the first 24 h after anaesthesia . The use of acupressure reduced the incidence of nausea or vomiting from 42 % to 19 % compared with placebo , with an adjusted risk ratio of 0.24 ( 95 % CI 0.08 - 0.62 ; P = 0.005 ) . Other variables were similar between groups [1859764] A prospect i ve , double-blind study was conducted to compare the effect of pressure at the P6 ( Neikuan ) point with placebo as an antiemetic in children . Sixty-six patients , ages 3 - 12 yr , undergoing outpatient surgery for correction of strabismus , were allocated r and omly to receive either bilateral P6 acupressure or placebo during the perioperative period . The study was design ed to detect a 50 % difference in the incidence of postoperative vomiting between the two groups , with a 90 % power of achieving a statistically significant result at the 5 % level ( two-tailed ) . The incidence of postoperative vomiting for the placebo group was 58 % before discharge from hospital , 73 % at home and 82 % in the first 24 h after surgery . The corresponding results for the acupressure group were 58 % before discharge , 71 % at home and 94 % in the first 24 h. These differences were not significant ; P6 acupressure did not reduce the incidence of postoperative vomiting in children undergoing strabismus surgery [22201663] PURPOSE / OBJECTIVES To evaluate the effects of pericardium 6 ( P6 ) acupressure and nurse-provided counseling on chemotherapy-induced nausea and vomiting ( CINV ) in patients with breast cancer . DESIGN R and omized , controlled trial . SETTING A university cancer center in Seoul , South Korea . SAMPLE 120 women who were beginning their second cycle of adjuvant chemotherapy after definitive surgery for breast cancer and who had more than mild levels of nausea and vomiting with the first cycle of chemotherapy . METHODS Participants were assigned r and omly into four groups : control ( placebo on SI3 ) , counseling only , P6 acupressure only , and P6 acupressure plus nurse-provided counseling . The experiences of upper-gastrointestinal distress were measured by the Rhodes Index of Nausea , Vomiting , and Retching for acute ( day 1 ) and delayed ( day 2 to day 5 ) CINV . MAIN RESEARCH VARIABLES Nausea , retching , vomiting , P6 acupressure , and counseling . FINDINGS No significant differences were found in the demographic and disease-related variables among the four groups . The levels of CINV were significantly different among the groups from day 2 to day 5 . The CINV differences were attributed mainly to the difference between the control group and the group with P6 acupressure plus nurse-provided counseling . The effects of acupressure were proven from day 2 to day 5 , and the effects of nurse-provided counseling were proven on day 4 and were close to significance level on day 5 . CONCLUSIONS Synergic effects of P6 acupressure with nurse-provided counseling appeared to be effective in reducing CINV in patients with breast cancer . IMPLICATION S FOR NURSING P6 acupressure combined with counseling by nurses is a safe and easy-to-apply tool in CINV management in practice [23605600] Postoperative nausea and vomiting ( PONV ) is one of the most common postoperative complications . Aside from pharmacological interventions , other complementary healing modalities have been introduced to assist patients in decreasing PONV and improving postoperative outcomes . This study examined acupressure as a safe complement to the more traditional approach of using drugs to prevent and /or relieve nausea and vomiting in the Cesarean section ( C/S ) under spinal anesthesia . In a prospect i ve r and omized clinical trial , 152 patients who were c and i date for elective C/S under spinal anesthesia were evaluated in two groups ( acupressure vs control groups ) . Subjects in the acupressure group received constant pressure by a specific wrist elastic b and ( without puncture of the skin ) on the Nei-Guan acupuncture point , 30 min prior to spinal anesthesia . The incidence of PONV was assessed during the surgery , at recovery room and at 1st , 2nd and 3rd two hours after the surgery . Significant differences in the incidence of the post-operative nausea and vomiting were found between the acupressure and control groups , with a reduction in the incidence rate of nausea from 35.5 % to 13.2 % . The amount of vomitus and the degree of discomfort were , respectively , less and lower in the study group . In view of the total absence of side-effects in acupressure , its application is worthy . Our study confirmed the effectiveness of acupressure in preventing post-operative nausea and vomiting , when applied 30 minutes prior to surgery [10764175] Purpose : To evaluate the efficacy of acupressure wristb and s in the prevention of postoperative nausea and vomiting ( PONV ) . Methods : Two hundred ASAI - II patients undergoing elective endoscopic urological procedures were included in a r and omized , prospect i ve , double blind , placebo-controlled study . Spherical beads of acupressure wristb and s were placed at the P6 points in the anterior surface of both forearms in Group 1 patients ( acupressure group , n=100 ) whereas , in Group 2(control group , n=100 ) they were placed inappropriately on the posterior surface . The acupressure wristb and s were applied 30 min before induction of anesthesia and were removed six hours postoperatively . Anesthesia was induced with thiopental and maintained with nitrous oxide and oxygen , fentanly , isoflurane and vecuronium . The tracheas were extubated on the operation table after patients received neostigmine and atropine . Post operative nausea and vomiting were evaluated separately as none , mild , moderate or severe at the time of patient ’s arrival in PACU , then at six hours and twenty-four hours after surgery by a blinded observer . Results : In the acupressure group , 25 patients had PONV compared with 29 patients in the control group ( P = NS ) . Conclusion : Application of acupressure wristb and s at the P6 of both forearms 30 min before induction of anesthesia did not decrease the incidence of PONV in patients undergoing endoscopic urological procedures .RésuméObjectif : Évaluer l’efficacité de bracelets d’acupression utilisés pour la prévention des nausées et des vomissements postopératoires (NVPO).Méthode : Deux cents patients , ASA I – II , devant subir une intervention urologique endoscopique planifiée ont participé à l’étude r and omisée , prospect i ve et à double insu contre placebo . Des bracelets de billes d’acupression ont été placés aux points P6 de la face antérieure des deux avant-bras des patients du Groupe 1 ( groupe d’acupression , n=100 ) t and is que dans le Groupe 2 , ( groupe témoin , n=100 ) , ils l’ont été , de façon inappropriée , sur la face postérieure . On les a appliqués 30 min avant l’induction de l’anesthésie et retirés six heures après l’opération . L’anesthésie comportait du thiopental , à l’induction , et du protoxyde d’azote , de l’oxygène , du fentanyl , de l’isoflurane et du vécuronium . L’extubation trachéale a eu lieu à la salle d’opération après l’administration de néostigmine et d’atropine . Un observateur objectif a évalué les nausées et les vomissements postopératoires comme absents , légers , modérés ou sévères au moment où le patient est arrivé à la salle de réveil , puis six et vingt-quatre heures après l’opération . Résultats : Dans le groupe d’acupression , 25 patients ont eu des NVPO , comparativement à 29 patients du groupe témoin ( P = NS ) . Conclusion : L’application de bracelets d’acupression en P6 aux deux avant-bras , 30 min avant l’induction de l’anesthésie , n’a pas diminué l’incidence de NVPO chez des patients qui subissent une intervention urologique endoscopique [21194921] INTRODUCTION Approximately 50 % of women experience nausea or vomiting during labour . P6 acupoint stimulation reduces postoperative nausea and vomiting in early pregnancy and after chemotherapy . The aim of this r and omised , double-blinded , placebo-controlled trial was to determine whether P6 acupressure prevented nausea and vomiting during labour and delivery . METHODS After ethical approval and informed consent , women admitted for induction of labour , or in spontaneous labour , were r and omised to receive either acupressure b and s ( Pressure Right ) ( Group A ) or sham placebo b and s ( Group P ) applied to each wrist . Exclusions included recent nausea or vomiting . RESULTS We consented 365 women and r and omised 340 ( 170 per group ) . The groups had similar patient and labour characteristics . The incidence of nausea and /or vomiting did not significantly differ ( Group A 53 % vs. Group P 50 % , P=0.58 ) . There was no significant difference between groups ( A vs. P , respectively ) in the incidence of nausea ( 52 % vs. 45 % ) , vomiting ( 27 % vs. 28 % ) , rescue antiemetic treatment ( 27 % in both ) , severity of nausea or vomiting , satisfaction with control of nausea or ratings of inconvenience or discomfort from the b and s ( 10 % vs. 11 % ) . Factors significantly associated with emetic symptoms were smoking ( OR 2.16 , 95 % CI 1.07 - 4.37 ) , opioid analgesia ( OR 1.95 , 95 % CI 1.06 - 3.59 ) , history of motion-induced or postoperative nausea and vomiting ( OR 1.85 , 95 % CI 1.17 - 2.94 ) and higher body mass index ( OR 1.07 , 95 % CI 1.01 - 1.12 ) . CONCLUSION In this study acupressure wristb and s applied bilaterally did not reduce the incidence of nausea and vomiting during labour and delivery

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### Context: [24978062] Background : Postoperative nausea and vomiting ( PONV ) is a multifactorial problem after general anesthesia . Despite antiemetic prophylaxis and improved anesthetic techniques , PONV still occurs frequently after craniotomies . P6 stimulation is described as an alternative method for preventing PONV . The primary aim of this study was to determine whether P6 acupressure with Sea-B and could reduce postoperative nausea after elective craniotomy . Secondary aims were to investigate whether the frequency of vomiting and the need for antiemetics could be reduced . Methods : In this r and omized , double-blinded , placebo-controlled study , patients were r and omized into either a P6 acupressure group ( n=43 ) or a sham group ( n=52 ) . B and s were applied unilaterally at the end of surgery , and all patients were administered prophylactic ondansetron . Postoperative nausea was evaluated with a Numerical Rating Scale , 0 to10 , and the frequency of vomiting was recorded for 48 hours . Results : We found no significant effect from P6 acupressure with Sea-B and on postoperative nausea or vomiting in patients undergoing craniotomy . Nor was there any difference in the need for rescue antiemetics . Altogether , 67 % experienced PONV , and this was especially an issue at > 24 hours in patients recovering from infratentorial surgery compared with supratentorial surgery ( 55 % vs. 26 % ; P=0.014 ) . Conclusions : Unilateral P6 acupressure with Sea-B and applied at the end of surgery together with prophylactic ondansetron did not significantly reduce PONV or the need for rescue antiemetics in patients undergoing craniotomy . Our study confirmed that PONV is a common issue after craniotomy , especially after infratentorial surgery [20178877] OBJECTIVES Acupressure , a complementary and alternative medicine ( CAM ) treatment , uses fingertips , rather than needles , to stimulate acupoints on the skin and has been implicated as a successful treatment for a variety of medical disorders . However , acupressure 's underlying mechanisms remain unclear . One theory is that acupoint stimulation modulates autonomic nervous system activity . Previous studies have suggested that acupressure may positively affect heart rate and blood pressure . The current study investigated the effects of a type of acupressure , Jin Shin , on cardiovascular function in stroke survivors , a population that could especially benefit from a treatment promoting cardiovascular health . The study tested the hypothesis that active acupressure treatments would reduce heart rate and blood pressure ( i.e. , induce a greater relaxation response ) above and beyond that seen during placebo acupressure treatments . METHODS A r and omised , placebo-controlled , single-blind crossover design was utilised , in which 16 participants received 8 weeks of either active or placebo acupressure followed by washout and crossover into the opposite treatment condition . Heart rate and blood pressure measurements were taken throughout treatments . RESULTS Active acupressure treatments were associated with a significantly greater ( p=.043 , eta(2)=.30 ) and faster ( p=.002 , eta(2)=.76 ) reduction in heart rate compared to that seen during placebo treatments . No treatment effect on blood pressure was found . CONCLUSIONS Active acupressure reduced heart rate significantly more than did placebo acupressure during treatments . Although no treatment effect on blood pressure was found , this could be due to 67 % of participants taking antihypertensive medications during the study [22504214] BACKGROUND : There is still controversy regarding the optimal strategy for managing postoperative nausea and vomiting ( PONV ) in high-risk surgical population s. Although acustimulation at the P6 acupoint has been demonstrated to be effective in preventing PONV , the effect of this nonpharmacologic therapy on the patient 's recovery with respect to resumption of normal activities of daily living has not been previously assessed when it is used as part of a multimodal antiemetic regimen . Therefore , we design ed this r and omized , sham-controlled , and double-blind study to assess the efficacy of a disposable acupressure device ( Pressure Right ® ; Pressure Point Inc. , Gr and Rapids , MI ) on the incidence of emetic episodes and quality of recovery when used in combination with ondansetron and dexamethasone for antiemetic prophylaxis . METHODS : One hundred ASA physical status I and II patients undergoing major laparoscopic procedures were r and omly assigned to either a control group ( n = 50 ) receiving a “ sham ” acustimulation device or an acupressure group ( n = 50 ) receiving a disposable Pressure Right device placed bilaterally at the P6 point 30 to 60 minutes before induction of anesthesia . All patients received a st and ardized general anesthetic . A combination of ondansetron , 4 mg IV , and dexamethasone , 4 mg IV , was administered during surgery for antiemetic prophylaxis in both study groups . The incidence of nausea and vomiting and the need for “ rescue ” antiemetic therapy were assessed at specific time intervals for up to 72 hours after surgery . The recovery profiles and quality of recovery question naires were evaluated at 48 hours and 72 hours after surgery . Patient satisfaction with the management of their PONV was assessed at the end of the 72-hour study period . RESULTS : The 2 study groups did not differ in their demographic characteristics or risk factors for PONV . The incidence of vomiting at 24 hours was significantly decreased in the acupressure group ( 10 % vs 26 % , P = 0.04 , 95 % confidence interval for absolute risk reduction 1%–31 % ) . The overall incidence of vomiting from 0 to 72 hours after surgery was also significantly decreased from 30 % to 12 % in the acupressure group ( P = 0.03 , 95 % confidence interval 2%–33 % ) . Furthermore , adjunctive use of the acupressure device seemed to enhance patient satisfaction with their PONV management and quality of recovery at 48 hours after surgery . However , the recovery times to hospital discharge , resumption of normal physical activities , and return to work did not differ significantly between the 2 study groups . CONCLUSION : Use of the Pressure Right acupressure device in combination with antiemetic drugs provided a reduction in the incidence of vomiting from 0 to 72 hours after surgery with an associated improvement in patient satisfaction with their PONV management . However , recovery and outcome variables failed to demonstrate any improvement with the addition of the acupressure device [20979460] Acupressure is a complementary and alternative medicine ( CAM ) treatment using fingertips to stimulate acupoints on the skin . Although suggested to improve cognitive function , acupressure has not been previously investigated with a controlled design in traumatic brain injury ( TBI ) survivors , who could particularly benefit from a non-pharmacological intervention for cognitive impairment . A r and omized , placebo-controlled , single-blind design assessed the effects of acupressure ( eight treatments over 4 weeks ) on cognitive impairment and state of being following TBI , including assessment of event-related potentials ( ERPs ) during Stroop and auditory oddball tasks . It was hypothesized that active acupressure treatments would confer greater cognitive improvement than placebo treatments , perhaps because of enhanced relaxation response induction and result ing stress reduction . Significant treatment effects were found comparing pre- to post-treatment change between groups . During the Stroop task , the active-treatment group showed greater reduction in both P300 latency ( p = 0.010 , partial η² = 0.26 ) and amplitude ( p = 0.011 , partial η² = 0.26 ) , as well as a reduced Stroop effect on accuracy ( p = 0.008 , partial η² = 0.21 ) than did the placebo group . Additionally , the active-treatment group improved more than did the placebo group on the digit span test ( p = 0.043 , Cohen 's d = 0.68 ) . Together , these results suggest an enhancement in working memory function associated with active treatments . Because acupressure emphasizes self-care and can be taught to novice individuals , it warrants further study as an adjunct treatment for TBI [19757334] Introduction . The reduction of the duration and pain of the active phase of labor is a very important issue and therefore always under serious investigation . Objective . The purpose of the present study is to evaluate the effect of acupressure at the Sanyinjiao point ( SP6 ) on the duration and pain of the active phase of labor in nulliparas women . Method . A single blind r and omized clinical trial was performed on 120 eligible nulliparas women who were at the beginning of active phase of labor ( 3 - 4 cm dilatation of cervix plus proper uterine contractions ) . The women were r and omly assigned into two groups . The case group ( n = 60 ) , received acupressure at Sanyinjiao point ( above the ankle ) , for 30 min during contractions . In the control group ( n = 60 ) , simply a touch at this point without massage was performed . Two hours later a second pelvic examination was performed and in the absence of good forceful contractions oxytocin in the classical form was infused . Finally , duration of active phase , severity of pain ( using the Visual Analogue Scale ) , the amount of necessary oxytocin and necessity to administer oxytocin and the route of delivery were compared between the two groups and statistical analyses were performed using SPSS 15 . Results . The mean duration of active phase was shorter in the case group ( 252.37 + /- 108.50 min vs. 441.38 + /- 155.88 , p = 0.0001 ) . Six patients ( 10 % ) in the case group and 25 patients ( 41.7 % ) in the control group delivered via cesarean section ( p = 0.0001 ) . The severity of pain in the case group was less than the control group ( 5.87 + /- 1.77 vs. 6.79 + /- 1.52 , p = 0.003 ) . Twenty-five women ( 41.7 % ) in the case group and 38 women ( 63.3 % ) in the control group needed oxytocin ( p = 0.017 ) The amount of necessary oxytocin in the case group was less than the control group ( 73.33 + /- 97.19 ml vs. 126.6 + /- 97.19 ml , p = 0.003 ) . Conclusion . Acupressure at Sanyinjiao point ( SP6 ) reduced the duration and severity of pain of the active phase of labor , cesarean section rates , and necessity and amount of oxytocin [8623811] OBJECTIVE Our purpose was to investigate the efficacy of P6 acupressure in reducing or relieving symptoms of nausea with or without vomiting and retching during pregnancy . STUDY DESIGN Symptomatic pregnant volunteers ( n=161 ) participated in a 7-day community-based clinical trial . All participants were assigned to one of three groups ( i.e. , P6 acupressure , placebo [ acupressure b and s inappropriately placed ] , or control ) on the basis of a process of blocked r and omization . Data were analyzed by error bar charts and analysis of variance of difference scores . RESULTS Of 161 women , 149 ( 92.5 % ) completed the protocol . Irrespective of group assignment , participants reported significant decreases in nausea ( p<0.0009 ) and vomiting or retching ( p<0.0009 ) . However , there was no differential treatment effect as a result of acupressure . CONCLUSION There was no apparent medical benefit from the use of P6 acupressure . Our findings differ from other recently published studies that did not include a control group [17388769] OBJECTIVES The onset of depression is often triggered by breathlessness in persons with chronic obstructive pulmonary disease ( COPD ) . It is hypothesized that these are the psychologic consequences of chronic dyspnea . Lessening dyspnea might alleviate depressive symptoms . Acupressure has been shown in other studies to produce relaxation . The aim of this study was to determine if it would lessen dyspnea and reduce depression in patients with COPD . SUBJECTS AND DESIGN Subjects diagnosed with COPD were chosen from one medical center and three regional hospitals in Taipei , Taiwan . A r and omized , block experimental design was used , with subjects and the data collector blinded . Using age , gender , pulmonary function , smoking , and steroid use as matching factors , 44 subjects were r and omly assigned to either the true acupressure or the sham acupressure groups . The true acupressure group received a program of acupressure using appropriate acupoints that promote relaxation and relieve dyspnea . The sham acupressure group received acupressure using sham acupoints different from the meridians and ganglionic sections of the true acupressure group . Both acupressure programs lasted 4 weeks , with five sessions per week that lasted 16 minutes per session . OUTCOME MEASURES The Geriatric Depression Scale ( GDS ) and Dyspnea Visual Analogue Scale ( DVAS ) were administered prior to the program as a baseline , and again following the completion of the 4-week program . Oxygen saturation and other physiological indicators were measured before and after each session . RESULTS The results of this study showed that the GDS scores , DVAS scores , oxygen saturation , and physiological indicators of the true acupressure group were significantly improved , compared to those of the sham acupressure group . CONCLUSIONS These findings provide health professionals with an evidence -based intervention to use with persons with COPD . Applying this acupressure program in clinical practice , communities , and long-term care units may lessen chronic dyspnea and depression in persons with COPD [25276718] INTRODUCTION Most women have experienced child birth and its pain , which is inevitable . If this pain is not controlled it leads to prolonged labor and injury to the mother and fetus . This study was conducted to identify the effect of acupressure on sanyinjiao and hugo points on delivery pain in nulliparous women . METHODS This was a r and omized controlled clinical trial on 84 nulliparous women in hospitals of Ardebil , Iran . The participants were divided by r and omized blocks of 4 and 6 into two groups . The intervention was in the form of applying pressure at sanyinjiao and hugo points based on different dilatations . The intensity of the pain before and after the intervention was recorded by visual scale of pain assessment . To determine the effect of pressure on the intensity of labor pain , analytical descriptive test was conducted in SPSS ( version 13 ) . RESULTS There was a significant decrease in mean intensity of pain after each intervention in the experimental group with different dilatations ( 4 , 6 , 8 , and 10 cm ) . Moreover , the Student 's independent t-test results indicated that the mean intensity of pain in the experimental group after the intervention in all four dilatations was significantly lower than the control group . Repeated measures ANOVA test indicated that in both experimental and control groups in four time periods , there was a statistically significant difference . CONCLUSION Acupressure on sanyinjiao and hugo points decreases the labor pain . Therefore , this method can be used effectively in the labor process [3818617] Background : The Le7 acupoint had been known as an acupoint for reducing pain of appendicitis . However , no study on the effect of its acupressure on post-appendectomy pain is available . The objective of this study was to evaluate the effects of acupressure of Le7 acupoint on pain , nausea , and vomiting after appendectomy . Material s and Methods : A single-blind r and omized controlled trial was conducted on 70 post-appendectomy patients in a general surgical ward . Patients with inclusion criteria were selected consecutively and were r and omly assigned into two groups . The intervention group received acupressure to the Le7 acupoint and the second group was the control group . The severity of post-operative pain , nausea , and vomiting measured hourly till the seventh post-operative hour . T-test was used to compare the mean of pain and nausea severity of two groups . Paired t-test was used to compare the mean of pain intensity of each group before and total mean of pain at post-intervention hours . Chi-squared test and Fisher exact test were used for nominal data . Results : The mean of pain intensity in the intervention group was 5.10 ± 3.52 before intervention and decreased to 3.53 ± 0.75 in the post-operative hours ( P = 0.018 ) . The mean of pain intensity in the control group was 4.45 ± 3.16 before intervention and changed to 4.01 ± 0.92 in the post-operative hours ( P = 0.32 ) . However , the mean of pain intensity in the intervention group was less than the control group till 6th h after the surgery . No significant differences were observed between the two groups in terms of nausea and vomiting ( P = 0.74 ) . Conclusion : Acupressure on Le7 acupoint was effective on post-appendectomy pain but did not affect nausea and vomiting . Further investigations are suggested with starting acupressure at the onset of pain or nausea and vomiting [3851943] Background Nested qualitative studies within clinical trials provide data on patients ’ experiences of receiving trial interventions and can inform and improve trial design s. The present study explored patients ’ experiences of participating in a r and omised controlled trial of acupressure wristb and s for chemotherapy related nausea . Methods A r and omised three-group sham-controlled trial was carried out to evaluate the effectiveness of acupressure wristb and s in the management of chemotherapy-related nausea . A convenience sample of 26 patients volunteered to participate in a qualitative study to explore their experiences of using acupressure wristb and s , and taking part in the clinical trial . Participants were recruited from each of the three UK geographical sites from which the trial was conducted : Manchester , Liverpool and Plymouth . In-depth semi-structured interviews were conducted with the participants in their own homes or other location convenient for participating patients . Interviews were audio-taped , transcribed verbatim and analysed using Framework methodology . Results The main motivational factors influencing participants to take part in the trial were a desire to ' give something back ’ and limit their own experience of nausea . Participants were largely satisfied with the organisation and running of the acupressure wristb and trial . Many participants experienced positive outcomes as a result of taking part in the trial . Lapses in memory , or poor health as a result of their chemotherapy treatment , led to some participants failing to complete trial paperwork on design ated days . Two sham wristb and participants reported wearing the b and s inappropriately result ing in pressure being applied to the acupoint . Almost all of the participants interviewed had only experienced mild nausea or vomiting during the trial . Participants were pragmatic on the extent to which the wristb and s were responsible for this lack of nausea and vomiting during the trial . However , many participants , including some patients receiving sham acupressure , believed the wristb and s to have had a positive impact on their nausea and vomiting ; there was a perception that the wristb and s were , at least in part , responsible for the lack of nausea and vomiting they had experienced . Conclusions Participants perceive acupressure wristb and s as reducing the level of nausea and vomiting experienced during chemotherapy treatment . Reports that some participants wore wristb and s inappropriately , and /or delayed completion of trial paperwork could represent confounding variables and have implication s for the trial results , and the design of clinical trials within the field of cancer [12705488] OBJECTIVE To evaluate the effectiveness of acupressure applied at meridian P6 point for prevention of nausea and vomiting in patients undergoing laparoscopic cholecystectomy . METHODOLOGY A r and omized double blind study was performed in 50 ASA I and II patients scheduled for laparoscopic cholecystectomy . Patients were divided into two groups ; control and placebo . In the control group acupressure was applied at P6 point half an hour before surgery while in the placebo group the acupressure b and was tied on meridian P6 point but the plastic bead was placed on the dosum of right forearm away from meridian P6 point . Patients were assessed for nausea and vomiting for six hours after surgery . Anaesthetic technique and postoperative analgesia were st and ardized for all patients . RESULTS Results showed that the incidence of postoperative nausea and vomiting was 36 % in the treatment group and 40 % in placebo group , which is statistically insignificant . CONCLUSION Application of acupressure at P6 point half an hour before induction of anaesthesia does not significantly alter the incidence of postoperative nausea and /or vomiting within 6 hours after surgery [16522418] OBJECTIVE The purpose of this study was to evaluate the efficacy of acupressure at the P6 point for the in-patient treatment of severe nausea and vomiting in early pregnancy . STUDY DESIGN This was a prospect i ve single-blind r and omized control trial that involved 80 patients with nausea and vomiting plus ketonuria before 14 weeks of gestation . RESULTS There was no difference between length of stay , amount of medication , or fluid required between the acupressure and placebo groups , although acupressure reduced the number of patients who stayed > or = 4 nights in the hospital . Acupressure was well tolerated and not associated with an increase in perinatal morbidity or death . CONCLUSION The use of acupressure at the P6 point does not reduce the amount of antiemetic medication that is required , the requirement for intravenous fluid , and median duration of in-patient stay more than the use of placebo . A small reduction was seen in the number of women who required > or = 4 days in the hospital [21306863] CONTEXT Bone marrow aspiration and biopsy ( BMAB ) is a frequently performed and painful procedure . OBJECTIVES To evaluate the efficacy of magnetic acupressure in reducing pain in cancer patients undergoing BMAB . METHODS Cancer patients without previous acupuncture or acupressure experience were stratified by the number of prior BMAB and r and omized to having magnetic acupressure delivered to either the large intestine 4 ( LI4 ) acupoint or a sham site . The primary study endpoint was the patient 's pain intensity rating during the procedure using a visual analogue scale ( VAS ) . RESULTS Seventy-seven eligible patients received magnetic acupressure : 37 were r and omized to treatment at the LI4 site arm and 40 at the design ated sham site arm . There was no significant difference between the median pain scores of patients treated at the LI4 site and the sham site ( P=0.87 ) . However , severe pain ( VAS ≥ 7 ) was reported in only one patient ( 2.7 % ) treated at the LI4 site compared with eight patients ( 20 % ) at the sham site ( P=0.03 ) . No patients experienced significant magnetic acupressure-related toxicities . CONCLUSION Magnetic acupressure at the LI4 acupoint requires minimal training and expense and is well tolerated . Although its use did not significantly reduce median pain scores in patients undergoing BMAB , it does appear to reduce the proportion of patients with severe pain associated with this invasive procedure [8041539] Objective : To evaluate the effectiveness of acupressure in reducing nausea and vomiting of pregnancy . Methods : Symptomatic pregnant women were r and omized to one of two acupressure groups : one treatment group using an acupressure point ( PC-6 ) and one sham control group using a placebo point . Subjects were blind to the group assignment . Each evening for 10 consecutive days , the subjects completed an assessment scale describing the severity and frequency of symptoms that occurred . Data from the first 3 days were used as pre-treatment scores . Beginning on the morning of the fourth day , each subject used acupressure at her assigned point for 10 minutes four times a day . Data from day 4 were discarded to allow 24 hours for the treatment to take effect . Data from days 5 - 7 were used to measure treatment effect . Results : Sixty women completed the study . There were no differences between groups in attrition , parity , fetal number , maternal age , gestational age at entry , or pre-treatment nausea and emesis scores . Analysis of variance indicated that both groups improved significantly over time , but that nausea improved significantly more in the treatment group than in the sham control group ( F1,58=10.4 , P = .0021 ) . There were no differences in the severity or frequency of emesis between the groups . There was a significant positive correlation ( r=0.261 , P = .044 ) between maternal age and severity of nausea . Conclusion : Our results indicate that acupressure at the PC-6 anatomical site is effective in reducing symptoms of nausea but not frequency of vomiting in pregnant women [16492848] Nausea and vomiting are major adverse effects during spinal anesthesia for cesarean delivery . Stimulation of the P6 ( Neiguan ) acupoint is a traditional Chinese acupuncture technique used for effective antiemetic purpose s. In this study , we evaluated the antiemetic effect of P6 acupressure in parturients during spinal anesthesia for cesarean delivery . In a r and omized , double-blind , controlled trial , 110 parturients scheduled for elective cesarean delivery were enrolled in the study . Thirty minutes before initiation of spinal anesthesia , parturients were r and omized to acupressure b and s or placebo b and s bilaterally on the P6 acupoint and nausea and vomiting were observed over the study period . There were no statistically significant differences in maternal characteristics . Incidence rates for intraoperative nausea were 64 % ( acupressure group ) and 71 % ( control group ) ( P = 0.416 ) , with an incidence of intraoperative vomiting of 22 % ( acupressure group ) and 27 % ( control group ) ( P = 0.506 ) . The results suggest that prophylactic use of acupressure b and s bilaterally on the P6 acupoint failed to prevent nausea and vomiting during spinal anesthesia for cesarean delivery [10823097] The efficacy of acupressure at the P6 point in the prevention of nausea and vomiting during and after Caesarean section was studied . A double-blind , r and omized controlled study of acupressure vs placebo was design ed . Ninety-four patients scheduled for Caesarean section were included . The anaesthetic technique and postoperative analgesia were st and ardized . The use of acupressure reduced the incidence of nausea or vomiting from 53 % to 23 % compared with placebo ( 95 % confidence interval ( CI ) 0.34 - 0.25 ; P = 0.002 ) during the operation and from 66 % to 36 % compared with placebo ( 95 % CI 0.34 - 0.19 ; P = 0.003 ) after the operation . Other variables were similar between the groups [2818640] Background The results of many clinical trials and experimental studies regarding acupoint specificity are contradictory . This review aims to investigate whether a difference in efficacy exists between ordinary acupuncture on specific acupoints and sham acupuncture controls on non-acupoints or on irrelevant acupoints . Methods Data bases including Medline , Embase , AMED and Chinese Biomedical Data base were search ed to identify r and omized controlled trials published between 1998 and 2009 that compared traditional body acupuncture on acupoints with sham acupuncture controls on irrelevant acupoints or non-acupoints with the same needling depth . The Cochrane Collaboration 's tool for assessing risk of bias was employed to address the quality of the included trials . Results Twelve acupuncture clinical trials with sham acupuncture controls were identified and included in the review . The conditions treated varied . Half of the included trials had positive results on the primary outcomes and demonstrated acupoint specificity . However , among those six trials ( total sample size : 985 ) with low risk of bias , five trials ( sample size : 940 ) showed no statistically significant difference between proper and sham acupuncture treatments . Conclusion This review did not demonstrate the existence of acupoint specificity . Further clinical trials with larger sample sizes , optimal acupuncture treatment protocol s and appropriate sham acupuncture controls are required to resolve this important issue [3139519] R and omized , placebo-controlled clinical trials are recommended for evaluation of a treatment 's efficacy with the goal of separating the specific effects ( verum ) from the non-specific ones ( placebo ) . In order to be able to carry out placebo-controlled acupuncture trials , minimal/sham acupuncture procedures and a sham acupuncture needle has been used with the intention of being inert . However , clinical and experimental results suggest that sham/minimal acupuncture is not inert since it is reported that both verum acupuncture and sham/minimal acupuncture induce a significant alleviation of pain . This alleviation is as pronounced as the alleviation obtained with st and ard treatment and more obvious than the one obtained with placebo medication or by the use of waiting list controls . These results also suggest that sham acupuncture needles evoke a physiological response . In healthy individuals sham acupuncture results in activation of limbic structures , whereas a deactivation is seen in patients with pain , i.e. results from healthy individuals do not reflect what is seen in clinical conditions . Also , depending on the etiology of pain ( or any under clinical condition under investigation ) , the response to sham acupuncture is varying . The acupuncture ritual may also be seen as an emotional focused therapy allowing for psychological re-orientation . Sham needling in such context may be as powerful as verum acupuncture . We recommend that the evaluated effects of acupuncture could be compared with those of st and ard treatment , also taking the individual response into consideration , before its use or non-use is established [21168112] OBJECTIVE The current study was conducted to evaluate the effect of acupressure on primary dysmenorrhea in Iranian medical sciences students . DESIGN A r and omized controlled pre and post-test design was employed to verify the effects of SP6 acupressure on dysmenorrhea . SETTING A total of 30 young college female students with primary dysmenorrhea were r and omly allocated to intervention ( n = 15 ) and control ( n = 15 ) groups . INTERVENTION The intervention group received SP6 acupressure during menstruation cycle and the control group received light touch on the SP6 acupoint . Using a Visual Analog Scale , the severity of dysmenorrhea was assessed prior to and immediately , 30 min , 1 , 2 , and 3 h following treatment . MAIN OUTCOME MEASURES Data were analyzed using X(2 ) , t-test and ANOVA statistical tests . RESULTS Significant differences were observed in the scores of dysmenorrhea between the two groups immediately after ( 3.50 ± 1.42 vs. 5.06 ± 1.43 , p = 0.004 ) and also 3 h after treatment ( 1.66 ± 1.98 vs. 4.80 ± 1.37 , p = 0.000 ) . CONCLUSIONS Acupressure on the SP6 meridian can be an effective non-invasive nursing intervention for alleviating primary dysmenorrhea and its effects last for 3 h post-treatment [14608559] The purpose of this study was to evaluate the effectiveness of acupressure b and s , droperidol , and the combined modalities , administered preoperatively , in reducing PONV in inpatient gynecologic patients . One hundred and forty-three patients were r and omized to one of four groups : droperidol and acupressure b and s , droperidol and placebo b and s , placebo drug and acupressure b and s , or placebo drug and placebo b and s. Overall , during their hospital stay , 69 % of the women experienced PONV and 45 % experienced vomiting at some time . Although droperidol was most effective the day of surgery , neither acupressure b and s or droperidol were effective in reducing PONV [11303547] OBJECTIVE To find out whether acupressure wristb and can alleviate nausea and vomiting in early pregnancy . DESIGN Double-blind , placebo-controlled study . SUBJECTS 97 women with mean gestational length completed 8 - 12 weeks . MAIN OUTCOME MEASURES Symptoms were recorded according to intensity , duration and nature of complaints . RESULTS 71 % of women in the intervention group reported both less intensive morning sickness and reduced duration of symptoms . The same tendency was seen in the placebo group , with 59 % reporting less intensity and 63 % shorter duration of symptoms . However , a significance level of 5 % was reached only in the case of duration of symptoms , which was reduced by 2.74 hours in the intervention group compared to 0.85 hours in the placebo group ( p = 0.018 ) . CONCLUSIONS Acupressure wristb and might be an alternative therapy for morning sickness in early pregnancy , especially before pharmaceutical treatment is considered [15870415] CONTEXT Acupuncture is widely used to prevent migraine attacks , but the available evidence of its benefit is scarce . OBJECTIVE To investigate the effectiveness of acupuncture compared with sham acupuncture and with no acupuncture in patients with migraine . DESIGN , SETTING , AND PATIENTS Three-group , r and omized , controlled trial ( April 2002-January 2003 ) involving 302 patients ( 88 % women ) , mean ( SD ) age of 43 ( 11 ) years , with migraine headaches , based on International Headache Society criteria . Patients were treated at 18 outpatient centers in Germany . INTERVENTIONS Acupuncture , sham acupuncture , or waiting list control . Acupuncture and sham acupuncture were administered by specialized physicians and consisted of 12 sessions per patient over 8 weeks . Patients completed headache diaries from 4 weeks before to 12 weeks after r and omization and from week 21 to 24 after r and omization . MAIN OUTCOME MEASURES Difference in headache days of moderate or severe intensity between the 4 weeks before and weeks 9 to 12 after r and omization . RESULTS Between baseline and weeks 9 to 12 , the mean ( SD ) number of days with headache of moderate or severe intensity decreased by 2.2 ( 2.7 ) days from a baseline of 5.2 ( 2.5 ) days in the acupuncture group compared with a decrease to 2.2 ( 2.7 ) days from a baseline of 5.0 ( 2.4 ) days in the sham acupuncture group , and by 0.8 ( 2.0 ) days from a baseline if 5.4 ( 3.0 ) days in the waiting list group . No difference was detected between the acupuncture and the sham acupuncture groups ( 0.0 days , 95 % confidence interval , -0.7 to 0.7 days ; P = .96 ) while there was a difference between the acupuncture group compared with the waiting list group ( 1.4 days ; 95 % confidence interval ; 0.8 - 2.1 days ; P<.001 ) . The proportion of responders ( reduction in headache days by at least 50 % ) was 51 % in the acupuncture group , 53 % in the sham acupuncture group , and 15 % in the waiting list group . CONCLUSION Acupuncture was no more effective than sham acupuncture in reducing migraine headaches although both interventions were more effective than a waiting list control [22950829] OBJECTIVES The purpose of this study was to evaluate the effectiveness of P6 acupressure on vertigo and neurovegetative symptoms , its possible interference with vestibular-ocular reflex ( VOR ) , and its clinical usefulness during acute vertigo . MATERIAL S AND METHODS Two hundred and four patients , either affected by acute vertigo ( n=124 ) or undergoing labyrinth stimulation ( n=80 ) , were r and omly divided in two homogeneous groups : an experimental group A and a placebo group B. Each patient rated severity of vertigo and neurovegetative symptoms on a visuo-analogue scale ranging from 0 to 10 , before and after bilateral placement of a P6 device . The latter was placed on the P6 acupressure point ( appropriate placement ) in Group A patients or on the dorsal part of the carpus ( inappropriate placement ) in the Group B patients . Furthermore , qualitative and quantitative nystagmus parameters were collected via recorded video-oculoscopy and electronystagmography . RESULTS Eighty-five percent of Group A patients reported improvement of symptoms , which was significant for neurovegetative symptoms , but not for vertigo . In contrast , only 11 % of the Group B patients reported improvement . VOR analysis did not show any significant variation of qualitative and quantitative nystagmus variables . CONCLUSIONS This study demonstrated that the P6 device is effective in improving neurovegetative symptoms in patients affected by spontaneous and provoked vertigo , without any interference with VOR . Given the low cost and lack of side-effects of the P6 device , its routine application is suggested for acute vertigo and during labyrinth stimulation [22579428] OBJECTIVES Identifying a non-pharmacological intervention to reduce the stress response could be particularly beneficial to college students , a group prone to considerable stress . Acupressure has shown some efficacy in reducing stress in adults following stroke or traumatic brain injury ( TBI ) , but multiple treatments were required . Results from single treatments in healthy population s have been mixed . DESIGN The current study used a r and omised , placebo-controlled , single-blind design to investigate the use of a single acupressure treatment for stress reduction in healthy college students ( n=109 ) during a stressor . INTERVENTIONS Participants were r and omly assigned to one of three single , 40-min interventions : active acupressure , placebo acupressure , or a relaxation CD control . A math task stressor administered before and after the intervention assessed intervention effects on stressor responsivity . MAIN OUTCOME MEASURES Stress responses were measured by physiological ( heart rate ( HR ) , heart rate variability ( HRV ) , skin conductance response ( SCR ) ) and subjective measures ( State Anxiety Inventory , nine-item Psychological Stress Measure ) of anxiety and stress . RESULTS All interventions were associated with the following changes during the post-intervention stressor compared to the pre-intervention stressor : reduced HR ( p<0.001 ) , increased HRV ( p<0.024 ) , reduced SCR ( p<0.001 ) , reduced subjective stress scores ( p<0.001 ) , and increased correct answers ( p<0.001 ) . Although all groups demonstrated stress reduction , there were no significant group differences after a single treatment . CONCLUSIONS All interventions significantly reduced the stress response , although not differently . The lack of active acupressure-associated treatment effects appears to be due to insufficient dosing [22432484] INTRODUCTION Complementary and alternative medicines have been used to decrease labor pain for many years . Despite reports that some of these methods reduce pain , increase maternal satisfaction , and improve other obstetric outcomes , they have received limited attention in the US medical literature . The purpose of this study was to evaluate the effects of LI4 acupressure on labor pain in the first stage of labor , on labor duration , and on patient satisfaction . METHODS A single , blind , r and omized clinical trial was performed with eligible women ( N = 100 ) who were at the beginning of the active phase of labor ( 3 - 4 cm dilatation of cervix with regular uterine contractions ) . The women in the acupressure group ( n = 50 ) received LI4 acupressure at the onset of the active phase for the duration of each uterine contraction over a period of 20 minutes , and the women in the control group ( n = 50 ) received a touch on this point without massage . Labor pain was measured using a structured question naire of a subjective labor pain scale ( visual analogue scale ) before the intervention , immediately after the intervention , 20 and 60 minutes after the intervention , and then every hour . RESULTS There were significant differences between the groups in subjective labor pain scores immediately and 20 , 60 , and 120 minutes after intervention ( P ≤ .001 ) . Active phase duration ( 3 - 4 cm dilatation to full dilatation ) and second stage duration ( full dilatation to birth ) were shorter in the acupressure group . The women in the acupressure group reported greater satisfaction . DISCUSSION LI4 acupressure was effective at decreasing pain and duration of labor . The participants were satisfied , and no adverse effects were noted [15321185] In this r and omized double-blind trial we investigated the effect of acupressure on the incidence of nausea and vomiting after caesarean section under spinal anaesthesia with added intrathecal morphine . Parturients wore either acupressure or placebo wristb and s during surgery and postoperatively for at least 10 h. There was no significant difference overall between the two groups in the incidence of intra- or postoperative nausea or vomiting/retching . Dem and for antiemetic medication was also similar in the two groups . However , in the sub-group of parturients who gave a previous history of postoperative nausea or vomiting , there was a statistically significant reduction in both postoperative nausea and vomiting/retching in the acupressure group . Further investigations are needed to see whether acupressure may be an effective non-pharmacological , non-invasive treatment for a common problem in this sub-group of patients [16895618] Background and objectives : To evaluate the effectiveness of acupressure in preventing nausea and vomiting in patients undergoing gynaecological operations and receiving a patient‐controlled analgesia device . Methods : Patients aged between 40 and 65 yr were included . Exclusion criteria were obesity , diabetes mellitus , and history of motion sickness , postoperative nausea and vomiting , or smoking . Patients were r and omized into one of two groups , acupressure and control . In the acupressure group , acupressure b and s were placed on both wrists with the plastic bead positioned at the P6 point . In controls , beads were placed at a non‐acupoint site . All patients received a st and ard general anaesthetic . Postoperatively , patients were connected to a patient‐controlled analgesia device with morphine ( loading dose 5 mg , background infusion 1 mg h−1 , bolus dose 1 mg and lock‐out time 10 min ) . Pain and sedation scores , respiratory rate , heart rate , arterial pressure and oxygen saturation were recorded for 24 h. Metoclopramide 10 mg was administered intravenously as a rescue antiemetic . Results : Fifty patients received acupressure and 50 were controls . In the acupressure group , 33 % of patients had nausea compared with 63 % controls . The cumulative incidence of vomiting at 24 h was 25 % with acupressure and 61 % in controls . The incidence of nausea , vomiting and antiemetic use was significantly lower with acupressure . Conclusions : Acupressure at the P6 meridian point is an effective alternative for the prevention of nausea and vomiting in patients receiving patient‐controlled analgesia with morphine after gynaecological surgery [23448746] PURPOSE / OBJECTIVES To evaluate the effectiveness of ST-36 ( Zusanli ) acupressure on recovery of postoperative gastrointestinal function in patients with colorectal cancer . DESIGN A longitudinal , r and omized , controlled trial design . SETTING An urban medical center in Taiwan . SAMPLE 60 patients with colorectal cancer who had undergone abdominal surgery . METHODS Patients were r and omly assigned to two groups , the ST-36 acupressure group ( n = 30 ) and a sham acupressure group ( n = 30 ) . Patients in the ST-36 group received an acupressure procedure in a three-minute cycle performed three times per day during the five days after surgery . Patients in the control group received routine postoperative care and sham acupressure . Generalized estimating equations ( GEEs ) were used to gauge longitudinal effects of the two groups of patients . MAIN RESEARCH VARIABLES Frequency of bowel sounds , the time to first flatus passage , first liquid intake , solid intake , and defecation . FINDINGS Patients who received acupressure had significantly earlier flatus passage and time to liquid intake as compared to patients in the control group . Other main variables , including the first time to solid intake and defecation , did not show significant difference between the two groups . The GEE method revealed that all patients had increasing bowel sounds over time , and the experimental group had greater improvement of bowel motility than the control group within the period of 2 - 3 days postoperatively . CONCLUSIONS ST-36 acupressure was able to shorten the time to first flatus passage , oral liquid intake , and improve gastrointestinal function in patients after abdominal surgery . IMPLICATION S FOR NURSING ST-36 acupressure can be integrated into postoperative adjunct nursing care to assist patients ' postoperative gastrointestinal function . KNOWLEDGE TRANSLATION Few studies have explored the effectiveness of acupressure techniques on promoting bowel sounds . Evidence from this study suggests stimulation of the ST-36 acupressure point can increase bowel sound frequency for patients with colorectal cancer in the first three days after surgery . Application of this technique may improve a patient 's comfort after surgery [14720242] BACKGROUND Patients with chronic obstructive pulmonary disease ( COPD ) suffer from dyspnoea in their daily life and this may be increased by anxiety . Acupressure may promote relaxation and relieve dyspnoea . Thus , it is appropriate to explore the effectiveness of acupressure on dyspnoea in patients with COPD . AIMS To compare outcomes of acupressure using sham acupoints on different meridians and ganglionic sections with that using true acupoints , in patients with COPD who are living at home . METHODS Patients diagnosed with COPD were selected from a medical centre and three regional hospitals in Taipei . A r and omized block experimental design was used . Using age , sex , pulmonary function , smoking , and steroid use as matching factors , 44 patients were r and omly assigned either to a true acupoint acupressure or a sham group . The true acupoint acupressure group received a programme to decrease dyspnoea . Those in the sham group received acupressure using sham pressure points . Both acupressure programmes consisted of five sessions per week lasting 16 minutes per session , extending over 4 weeks for a total of 20 sessions . Before acupressure was initiated and at the conclusion of the 20th session , the Pulmonary Functional Status and Dyspnoea Question naire-modified scale and the Spielberger State Anxiety scale were administered , and a 6-minute walking distance test was performed . Physiological indicators of oxygen saturation and respiratory rate were measured before and after every session . RESULTS The results of this study showed that the pulmonary function and dyspnoea scores , 6-minute walking distance measurements , state anxiety scale scores , and physiological indicators of the true acupoint acupressure group improved significantly compared with those of the sham group . CONCLUSIONS The findings suggest that acupressure can be used as a nursing intervention to improve dyspnoea in patients with COPD [20056221] BACKGROUND Acupressure on the Shenmen point ( indexed as HT7 ) can improve insomnia , but there has been no longitudinal study to evaluate its efficacy for residents of long-term care facilities . No evidence from the existing literature indicates how long its efficacy can be maintained after stopping acupressure . OBJECTIVE The aim of this study was to evaluate the effectiveness of acupressure on the Shenmen point for residents of long-term care facilities with insomnia . METHODS Fifty residents with insomnia in long-term care facilities were enrolled in a r and omized controlled trial , with 25 participants allocated to the experimental group and 25 participants to the control group . For a 5-week period , the experimental group received st and ard acupressure on the HT7 points of both wrists , whereas the control group received only light touch on the same places . Insomnia was measured with the Athens Insomnia Scale-Taiwan form ( AIS-T ) . Participants ' self-reported scores were done at baseline , during the 5-week period , and after intervention . This study was analyzed on an intention-to-treat procedure . RESULTS The experimental group has significantly better scores on the AIS-T compared to the control group , not only during the intervention period , but also extending after intervention , as shown by generalized estimating equations ( p<0.05 ) . CONCLUSIONS Offering acupressure on a regular basis has the potential to improve insomnia in residents of long-term care facilities . Acupressure on the HT7 point may improve insomnia for up to 2 weeks after the intervention [10081532] Background : Acupuncture and acupressure have previously been reported to possess antiemetic effect . We wanted to investigate the “ true ” and placebo effect of acupressure in prevention of postoperative nausea and vomiting ( PONV ) [22082432] OBJECTIVES This study 's objective was to examine the effectiveness of Sanyinjiao point ( SP6 ) acupressure on women 's general health . DESIGN This was a r and omized , single-blind clinical trial . SETTING The setting for this trial was at Medical University , Bojnoord University of Medical Science , Bojnoord , Iran . MATERIAL S AND METHODS Eighty-six ( 86 ) university students were recruited for this study . Their demographic characteristics were gathered before the intervention commenced . Participants completed General Health Question naires ( GHQ ) prior to participation . Next , they were r and omly assigned to either the acupressure-receiving group or the sham-pressure-receiving group . The study group received acupressure at the Sanyinjiao point , while the control group received sham pressure . OUTCOME MEASURES Both groups completed GHQ after both the first and second months of intervention . Data analysis was carried out using SPSS version 13.5 for Windows . RESULTS The mean age of those who completed the study was 20.84±1.64 years . Mean scores of GHQs were similar between groups before intervention ( p>0.05 ) . The general health of participants in both groups improved after intervention , and the amelioration in four domains was significant in the groups ( p<0.05 within group ) . It was found that acupressure was more effective than sham pressure . In addition , there was a statistically significant difference between the two groups in the four domains of their general heath after the first month of the intervention ( p<0.0001 ) . Furthermore , the general health status of the participants changed much more after the second month in both the acupressure intervention and the sham pressure groups ; nevertheless , acupressure was more effective than sham pressure ( p<0.05 ) . CONCLUSIONS Both acupressure and sham pressure were effective in promoting women 's general health ; nevertheless , the efficacy of acupressure was more than that of sham pressure . SP6 acupressure could be regarded as a self-manageable approach to improve women 's general health [12801491] OBJECTIVES To assess the effectiveness of continuous PC6 acupressure as an adjunct to antiemetic drug therapy in the prevention and control of nausea and vomiting in the first 24h after myocardial infa rct ion ( MI ) . DESIGN Partially r and omised , partially blinded placebo-controlled , exploratory clinical study . SETTING Coronary Care Unit , Torbay Hospital , Torquay , Devon . PARTICIPANTS A total of 301 consecutive patients ( 205 males , 96 females ) admitted following acute MI . INTERVENTION The first 125 patients recruited received no additional intervention . Subsequent patients were r and omised to receive either continuous PC6 acupressure or placebo acupressure . OUTCOME MEASURES ( 1 ) Incidence of post-MI nausea and /or vomiting , ( 2 ) severity of symptoms , ( 3 ) use of antiemetic drugs , over 24h . RESULTS There were no significant differences between the groups for the whole 24-h treatment period . However , the PC6 acupressure group experienced significantly lower incidence of nausea and /or vomiting during the last 20h ( 18 % ) , compared with the placebo ( 32 % ) or control ( 43 % ) groups ( P<0.05 ) . The severity of symptoms and the need for antiemetic drugs were also reduced in the acupressure group , but these differences were not statistically significant . CONCLUSIONS Continuous 24-h PC6 acupressure therapy as an adjunct to st and ard antiemetic medication for post-MI nausea and vomiting is feasible and is well accepted and tolerated by patients . In view of its benefits , further studies are worthwhile using earlier onset of treatment [17920972] BACKGROUND Pain during transportation is a common phenomenon in emergency medicine . As acupressure has been deemed effective for pain management by the National Institutes of Health , we conducted a study to evaluate its effectiveness in prehospital patients with isolated distal radial fracture . METHODS This was a prospect i ve , r and omized , double-blind study . Thirty-two patients were enrolled . Acupressure was performed either at " true " points or at " sham " points . Vital signs and pain and anxiety scores were recorded before and after the acupressure treatment . Normally distributed values were compared using the Student t test . RESULTS Pretreatment scores for pain and anxiety were similar in the 2 groups ( 47.6 + /- 8.9 vs 51.2 + /- 8.7 visual analog scale [ VAS ] score for pain , 52.4 + /- 6.0 vs 47.5 + /- 9.3 VAS score for anxiety ) . At the hospital , patients in the true-points group had significantly lower pain ( 36.6 + /- 11.0 vs 56.0 + /- 13.3 VAS score , P < .001 ) and anxiety scores ( 34.9 + /- 22.2 vs 53.4 + /- 19.7 VAS score , P = .022 ) . CONCLUSION Acupressure in the prehospital setting effectively reduces pain and anxiety in patients with distal radial trauma [12198060] Untreated pain during the transportation of patients after minor trauma is a common problem in emergency medicine . Because paramedics usually are not allowed to perform invasive procedures or to give drugs for pain treatment , a noninvasive , nondrug-based method would be helpful . Acupressure is a traditional Chinese treatment for pain that is based on pain relief followed by a short mechanical stimulation of specific points . Consequently , we tested the hypothesis that effective pain therapy is possible by paramedics who are trained in acupressure . In a double-blinded trial we included 60 trauma patients . We r and omly assigned them into three groups ( “ true points , ” “ sham-points , ” and “ no acupressure ” ) . An independent observer , blinded to the treatment assignment , recorded vital variables and visual analog scales for pain and anxiety before and after treatment . At the end of transport , we asked for ratings of overall satisfaction . For statistical evaluation , one-way analysis of variance and the Scheffé F test were used . P < 0.05 was considered statistically significant . Morphometric and demographic data and potential confounding factors such as age , sex , pain , anxiety , blood pressure , and heart rate before treatment did not differ among the groups . At the end of transport we found significantly less pain , anxiety , and heart rate and a greater satisfaction in the “ true points ” groups ( P < 0.01 ) . Our results show that acupressure is an effective and simple-to-learn treatment of pain in emergency trauma care and leads to an improvement of the quality of care in emergency transport . We suggest that this technique is easy to learn and risk free and may improve paramedic-based rescue systems [16618043] Introduction There is some evidence for the efficacy of acupuncture , but it remains unclear whether trigger point acupuncture is effective . Our objective was to evaluate the effects of trigger point acupuncture on pain and quality of life in chronic low back pain patients compared with sham acupuncture . Methods Twenty-six consecutive out- patients ( 17 women , 9 men ; age range : 65–91 years ) from the Department of Orthopaedic Surgery , Meiji University of Oriental Medicine , with non-radiating low back pain for at least six months and normal neurological examination , were r and omised to two groups . Each group received one phase of trigger point acupuncture and one of sham acupuncture with a three week washout period between them , over 12 weeks . Group A ( n=13 ) received trigger point acupuncture in the first phase and sham acupuncture in the second . Group B ( n=13 ) received the same interventions in the reverse order . Outcome measures were pain intensity ( visual analogue scale , VAS ) and Rol and Morris Question naire . Results Nineteen patients were included in the analysis . At the end of the first treatment phase , group A receiving trigger point acupuncture scored significantly lower VAS ( P<0.001 ) and Rol and Morris Question naire scores ( P<0.01 ) than the sham control group . There were significant within-group reductions in pain in both groups during the trigger point acupuncture phase but not in the sham treatment phase . However , the beneficial effects were not sustained . Conclusion These results suggest that trigger point acupuncture may have greater short term effects on low back pain in elderly patients than sham acupuncture [22083987] The efficacy of acupressure therapy in managing urodynamic stress incontinence has not been fully investigated . This study evaluates the effects of a vali date d acupressure protocol for treating women with urodynamic stress incontinence . A r and omized , single-blinded , placebo-controlled trial with a before- and -after study design was conducted . Eighty-one women aged between 18 and 60 were recruited at a urogynecology clinic in an acute hospital in Hong Kong . Participants were r and omly assigned to an intervention ( acupressure ) group , a sham group , or a usual care ( control ) group . A vali date d acupressure protocol was employed in the intervention group . The intervention comprised three weekly sessions of 30 minutes each for a total of thirty sessions . Outcome measures included pelvic floor muscle strength , number of episodes of urine leakage over four days , self-reported severity of urine leakage , and responses on the Chinese version of the King 's Health Question naire . No adverse effects were reported . Five percent of the participants dropped out of the study . Intention-to-treat analysis was conducted , the results indicated significant differences in pelvic floor muscle strength across the three groups ( H = 7.05 , p = 0.03 ) and in self-reported severity of urine leakage between the intervention and control groups ( Z = -2.48 , p = 0.01 ) . Significant improvement in all domains of the Chinese version of the King 's Health Question naire was evident in the intervention group . Acupressure is a simple and non-invasive intervention that appears to have positive physiological and psychological effects on women with urodynamic stress incontinence . The findings support acupressure as an intervention option for managing urodynamic stress incontinence in women [14696681] The purpose of this study was to evaluate the effectiveness of acupressure on gastrointestinal ( GI ) motility in women after trans-abdominal hysterectomy ( TAH ) . Patients were r and omly assigned into two groups of 21 and 20 patients each . The experimental group received acupressure for 3 minutes at each of three meridian points : Neiguan ( PC-6 ) , Zusanli ( ST-36 ) and Sanyinjiao ( SP-6 ) . The control group received 3 minutes of acupressure on sham points . Acupressure was performed twice a day . A question naire was used to determine patients ' satisfaction prior to and after afternoon acupressure . GI contractions were measured with a multifunctional stethoscope before and after acupressure . Acupressure of these three meridian points significantly ( p < 0.05 ) increased GI motility in the experimental group , but there was little change in the control group ( p > 0.05 ) . Our conclusions are that non-invasive acupressure of these meridian points can significantly improve GI motility and can be incorporated into the technical curriculum and clinical education program of nursing schools . Patients and their family members can be taught to continue this procedure at home to enhance GI motility in patients who have undergone TAH [20347838] INTRODUCTION Sleep disturbances are very common in elderly people and Traditional Chinese acupressure a noninvasive technique that promotes health and comfort recently has been used in this regard . The purpose of the present study was to evaluate the potential beneficial effects of acupressure on a group of institutionalized elders experiencing sleep disturbances . METHOD A r and omized controlled clinical trial was conducted to test the effectiveness of acupressure on quality of sleep of elderly residing in a Nursing home . The Pittsburgh Sleep Quality index ( PSQI ) question naire was used as a screening tool to select 90 residents with moderate to marked sleep disturbances . The elders were r and omly assigned to an acupressure group , a sham acupressure group and a control group by Balanced r and omization method . RESULTS There were significant differences between the acupressure group and the control group in subjective sleep quality , sleep latency , sleep duration , habitual sleep efficiency and sleep disturbance . But no significant differences were found in sleep indices between the sham acupressure group and the control group . Sleep log data showed a significant decrease in nocturnal awakenings in acupressure group compared to other two groups . CONCLUSION The findings of this study indicated that acupressure has an effect on improvement of sleep quality and endorsed it as a non-pharmacological and complementary therapy for sleep-disturbed elderly people [12477673] Purpose To investigate the effect of sensory stimulation of the P6 point on postoperative nausea and vomiting ( PONV ) after gynecological surgery in the everyday clinical setting ( effectiveness study ) . Methods Four hundred and ten women undergoing general anesthesia for elective gynecological surgery were included in a prospect i ve , consecutive , r and omized , multicentre , placebo-controlled , double-blind clinical trial with a reference group . One group was given bilateral P6 acupressure ( n = 135 ) , a second group similar pressure on bilateral non-acupressure points ( n = 139 ) , and a third group ( n = 136 ) served as reference group . Nausea ( scale 0–6 ) , vomiting , pain , and satisfaction with the treatment were recorded . Primary outcome was complete response , i.e. , no nausea , vomiting or rescue medication for 24 hr . Results were analyzed by applying logistic regression with indicators of treatments , type of operation and risk score for PONV as explanatory variables . Results Complete response was more frequent in the P6 acupressure group than in the reference group ( P = 0.0194 ) Conversely , the incidence of PONV was 46 % in the reference group , 38 % after pressure on a non-acupoint and 33 % after P6 acupressure . The decrease from 46 % to 33 % was statistically significant . When considering vaginal cases separately , the decrease in PONV was from 36 % to 20 % ( P = 0.0168 ) . The corresponding decrease from 59 % to 55 % in the laparoscopic surgery group was not statistically significant . Conclusion P6 acupressure is a non-invasive method that may have a place as prophylactic antiemetic therapy during gynecological surgery . RésuméObjectifRechercher l’effet d’une stimulation sensorielle acupressive en P6 sur les nausées et vomissements postopératoires ( NVPO ) à la suite d’une intervention chirurgicale gynécologique dans un cadre clinique normal ( étude d’efficacité).MéthodeUn essai clinique prospect if , r and omisé , multicentrique , en double aveugle contre placebo et comportant un groupe de référence a été réalisé auprès de 410 femmes qui se sont présentées successivement pour une intervention gynécologique non urgente sous anesthésie générale . Les patientes d’un premier groupe ont reçu de l’acupression en P6 ( n = 135 ) , celles d’un second groupe ont reçu une pression semblable sur des points bilatéraux , non d’acupression , ( n = 139 ) et un troisième groupe ( n = 136 ) a servi de référence . Les nausées ( échelle de 0–6 ) , les vomissements , la douleur et la satisfaction face au traitement ont été notés . Le premier résultat était une réponse complète , donc absence de nausées , de vomissements ou de médication de secours pendant 24 h. Les résultats ont été analysés par régression logistique avec des indicateurs de traitements , le type d’intervention et le taux de risque de NVPO comme variables explicatives . RésultatsLa réponse complète a été plus fréquente avec l’acupression en P6 que chez les patientes témoins ( P = 0,0194 ) . Inversement , l’incidence de NVPO a été de 46 % dans le groupe de référence , 38 % après une pression de points non acupresseurs et 33 % après l’acupression en P6 . La diminution de 46 % à 33 % était significative . L’examen séparé des cas d’intervention vaginale indique une baisse des NVPO de 36 % à 20 % ( P = 0,0168 ) . La baisse correspondante de 59 % à 55 % dans les cas d’intervention laparoscopique n’était pas significative . Conclusion L’acupression en P6 représente une méthode non effractive de traitement antiémétique prophylactique qui peut avoir sa place pendant une intervention gynécologique [21544020] Background and objective Postoperative nausea and vomiting causes discomfort in many patients despite both antiemetic prophylactics and improved anaesthetic techniques . Stimulation of acupoint P6 is described as an alternative method for prophylaxis of postoperative nausea and vomiting . In a r and omised , double-blinded study , we aim ed to investigate the effect of P6 acupoint stimulation on the incidence of postoperative nausea and vomiting within 24 h postoperatively with an acupressure wristb and : Vital-B and . Methods One hundred and thirty-four healthy , non-smoking women scheduled for breast surgery were r and omised either to P6 stimulation or to sham control . Wristb and s were applied and covered with a dressing before induction of anaesthesia . Follow-up was carried out three times within 24 h postoperatively . Primary outcomes were postoperative nausea and /or vomiting . Results One hundred and twelve patients completed the study . There were no statistically significant differences in the incidence of nausea [ P6 stimulation , 35.1 % ( 95 % confidence interval , CI 22.7–47.5 % ) versus sham control , 43.1 % ( 95 % CI 29.5–56.7 % ; P = 0.433 ) ] or vomiting [ P6 stimulation , 25.9 % ( 95 % CI 14.6–37.2 % ) versus sham control , 26.9 % ( 95 % CI 14.8–39.0 % ; P = 1.000 ) ] . Approximately , one third of the patients reported side effects caused by the wristb and , for example , redness , swelling and tenderness . Conclusion We did not find the Vital-B and effective in preventing either nausea or vomiting after operation in women undergoing breast surgery [20980765] Background and Objective : A recent Cochrane review on placebo interventions for all kinds of conditions found that ‘ physical placebos ’ ( which included sham acupuncture ) were associated with larger effects over no-treatment control groups than ‘ pharmacological placebos ’ . We re-analyzed the data from this review to investigate whether effects associated with sham acupuncture differed from those of other ‘ physical placebos ’ . Methods : All trials included in the Cochrane review as investigating ‘ physical placebos ’ were classified as investigating either ( sham ) acupuncture or other physical placebos . The latter group was further subclassified into groups of similar interventions . Data from the Cochrane review were re-entered into the RevMan 5 software for meta- analysis . The primary analysis was a r and om-effects analysis of trials reporting continuous outcomes of trials that used either sham acupuncture or other physical placebos . Results : Out of a total of 61 trials which reported a continuous outcome measure , 19 compared sham acupuncture and 42 compared other physical placebos with a notreatment control group . The trials re-analyzed were highly heterogeneous regarding patients , interventions and outcomes measured . The pooled st and ardized mean difference was –0.41 ( 95 % confidence interval –0.56 , –0.24 ) between sham acupuncture and no treatment and –0.26 ( 95 % CI –0.37 , –0.15 ) between other physical placebos and no treatment ( p value for subgroup differences = 0.007 ) . Significant differences were also observed between subgroups of other physical placebos . Conclusion : Due to the heterogeneity of the trials included and the indirect comparison our results must be interpreted with caution . Still , they suggest that sham acupuncture interventions might , on average , be associated with larger effects than pharmacological and other physical placebos [21713729] To compare the efficacy of acupressure wrist b and s , ondansetron , metoclopramide and placebo in the prevention of vomiting and nausea after strabismus surgery . Two hundred patients , ASA physical status I or II , aged between 10 and 60 years , undergoing strabismus surgery in Farabi Hospital in 2007 - 2008 years , were included in this r and omized , prospect i ve , double-blind and placebo-controlled study . Group I was the Control , group II received metoclopramide 0.2 mg/kg , group III received ondansetron 0.15 mg/kg iv just before induction , in Group IV acupressure wristb and s were applied at the P6 points . Acupressure wrist b and s were placed inappropriately in Groups I , II and III . The acupressure wrist b and s were applied 30 min prior to the induction of anesthesia and removed six hours after surgery . Postoperative nausea and vomiting ( PONV ) was evaluated within 0 - 2 hours and 2 - 24 hours after surgery by a blinded observer . Results were analyzed by X(2 ) test . A P value of < 0.05 was taken as significant . The incidence of PONV was not significantly different in acupressure , metoclopramide and ondansetron during the 24 hours . Acupressure at P6 causes a significant reduction in the incidence of PONV 24 hours after strabismus surgery as well as metoclopramide 0.2 mg/kg and ondansetron 0.15 mg/kg iv for patients aged 10 or more [22828022] Preoperative anxiety , as an emotional reaction , is common among patients undergoing surgery . The purpose of this study was to examine the effect of acupressure on preoperative anxiety before abdominal surgery . The 70 subjects of this clinical trial were r and omly assigned into the acupressure group ( n=35 ) , which received acupressure at the true points , or the placebo group ( n=35 ) , which received acupressure at sham ( false ) points . Preoperative anxiety and vital signs before and after the intervention were measured in both groups . The findings demonstrated a reduction in the level of preoperative anxiety for both groups ( P<.001 ) . Furthermore , they showed a statistically significant difference between the mean of vital signs before and after the intervention in the acupressure group ( P<.001 ) and only statistically significant results for cardiovascular ( P=.016 ) and respiratory rates ( P=.007 ) in the placebo group . Overall , findings revealed that acupressure at true points ( third eye and Shen men ) can reduce higher preoperative anxiety of patients before abdominal surgery and that it has had a more clinical ly beneficial effect than sham points [16115972] In this r and omized sham-controlled study we examined the anxiolytic and sedative effects of acupressure on parents in the preoperative holding area before their children ’s surgery . Sixty-one parents received acupressure either at the Yintang point ( midpoint between the two eyebrows ) or at a sham point . Anxiety ( as measured by the Stait-Trait Anxiety Inventory ) , arterial blood pressure , and heart rate were assessed before and after the intervention and a Bispectral Index monitor was used to continuously monitor hypnotic sedation levels . Repeated- measures analysis of variance showed that parents in the acupressure group reported significantly less anxiety at 20 min postintervention as compared with parents in the sham group ( 37 ± 10 versus 45 ± 13 , P = 0.03 ) . Bispectral Index values , heart rate , and arterial blood pressure , however , did not differ between the two study groups ( P = not significant ) . We conclude that acupressure at the Yintang point may be used as a treatment for parental preoperative anxiety . Future studies are needed to quantify the magnitude and duration of the anxiolytic effect [17402962] AIMS AND OBJECTIVES To examine and compare the effects of acupressure on the perceived health-related quality of life of the participants with bronchiectasis . BACKGROUND In an attempt to offer comfort , pain control and symptom management , nursing is becoming increasingly involved in offering complementary-alternative medicine as part of its caring-healing focus in comprehensive patient care . Acupressure is one such modality that is being increasingly used by both medical and nursing professionals . While acupressure has been reported to have beneficial effects in patients with respiratory disease , the benefits to bronchiectasis patients have remained uncertain . DESIGN A r and omized , partially blinded study consisting of three groups . METHODS Thirty-five out- patients of both genders , aged 59.46 SD 11.52 years , who were suffering from bronchiectasis , were r and omly split into one of three groups : st and ard care with supplemental acupressure for eight weeks ( 11 participants ) ; st and ard care with supplemental sham acupressure for eight weeks ( 11 participants ) ; and st and ard care alone ( 13 participants ) . Outcomes were determined by changes in daily sputum amounts , sputum self- assessment , six-minute walking distance , breathing difficulty ( measured on the dyspnea visual analogue scale ) and health-related quality of life ( measured by the Saint George Respiratory Question naire ) . RESULTS The sputum self- assessment score improved over time for the sham acupressure participants ( P = 0.03 ) , when compared with the controls . For acupressure participants , the Saint George respiratory question naire activity component scores also improved over time , compared with controls ( P = 0.01 ) after adjustment for covariates ( treatment , time , age , sex and baseline values ) . Other variables did not differ between the st and ard care alone group and the other two groups . CONCLUSIONS Eight weeks of self-administered acupressure could be useful in reducing the effects of bronchiectasis on a patient 's daily activities . RELEVANCE TO CLINICAL PRACTICE Acupressure may be regarded as a viable nursing intervention [11277163] OBJECTIVE To determine the effect of continuous acupressure at P6 applied by Sea-B and s with acupressure buttons on the frequency and severity of nausea and vomiting of pregnancy during the 1 st trimester . DESIGN A two-group , quasi-experimental , posttest-only and posttest-repeated measure . SETTING Seventeen medical clinics or offices in southern Michigan . PARTICIPANTS Convenience sample of English-speaking , healthy pregnant women in their 1 st trimester , who had at least one episode of nausea , vomiting , or both before their prenatal clinic/office visit where they were recruited . After being accepted for the study , the women were r and omly assigned to treatment or placebo groups . INTERVENTION Treatment group 1 applied SeaB and s with acupressure buttons to both wrists for 4 days and removed the Sea-B and s for 3 subsequent days . Placebo group 2 applied the Sea-B and s without acupressure buttons to both wrists on the same time schedule as group 1 . MAIN OUTCOME MEASURE Self-report daily diaries of the number of times per day that participants experienced nausea , the severity of nausea , the number of vomiting episodes per day , and the severity of vomiting . RESULTS Mann-Whitney U procedures revealed that the treatment group had significantly less frequency and severity of nausea and vomiting of pregnancy while wearing the Sea-B and s than did the placebo group . The treatment group also had significantly less frequency and severity of nausea and vomiting of pregnancy while wearing the SeaB and s than when not wearing the Sea-B and s. CONCLUSIONS Sea-B and s with acupressure buttons are a noninvasive , inexpensive , safe , and effective treatment for the nausea and vomiting of pregnancy [15673989] OBJECTIVE The purpose of this study was to evaluate the effects of SP6 acupressure on labor pain and delivery time in women in labor . DESIGN R and omized clinical trial . SETTING /LOCATION Delivery room in a university hospital . PARTICIPANTS Seventy-five ( 75 ) women in labor were r and omly assigned to either the SP6 acupressure ( n = 36 ) or SP6 touch control ( n = 39 ) group . The participants were matched according to parity , cervical dilation , labor stage , rupture of amniotic membrane , and husb and 's presence during labor . There were no additional oxytocin augmentation or administration of analgesics during the study period . INTERVENTION The 30-minute acupressure or touch on SP6 acupoint was performed . OUTCOME MEASURES Labor pain was measured four times using a structured question naire , a subjective labor pain scale ( visual-analogue scale [ VAS ] ) : before intervention , immediately after the intervention , and 30 and 60 minutes after the intervention . Length of delivery time was calculated in two stages : from 3 cm cervical dilation to full cervical dilatation , and full cervical dilatation to the delivery . RESULTS There were significant differences between the groups in subjective labor pain scores at all time points following the intervention : immediately after the intervention ( p = 0.012 ) ; 30 minutes after the intervention ( p = 0.021 ) ; and 60 minutes after the intervention ( p = 0.012 ) . The total labor time ( 3 cm dilatation to delivery ) was significantly shorter in the SP6 acupressure intervention group than in the control group ( p = 0.006 ) . CONCLUSIONS These findings showed that SP6 acupressure was effective for decreasing labor pain and shortening the length of delivery time . SP6 acupressure can be an effective nursing management for women in labor [16818924] BACKGROUND Despite the popularity of acupuncture , evidence of its efficacy for reducing pain remains equivocal . OBJECTIVE To assess the efficacy and safety of traditional Chinese acupuncture ( TCA ) compared with sham acupuncture ( needling at defined nonacupuncture points ) and conservative therapy in patients with chronic pain due to osteoarthritis of the knee . DESIGN R and omized , controlled trial . SETTING 315 primary care practice s staffed by 320 practitioners with at least 2 years ' experience in acupuncture . PATIENTS 1007 patients who had had chronic pain for at least 6 months due to osteoarthritis of the knee ( American College of Rheumatology [ ACR ] criteria and Kellgren-Lawrence score of 2 or 3 ) . INTERVENTIONS Up to 6 physiotherapy sessions and as-needed anti-inflammatory drugs plus 10 sessions of TCA , 10 sessions of sham acupuncture , or 10 physician visits within 6 weeks . Patients could request up to 5 additional sessions or visits if the initial treatment was viewed as being partially successful . MEASUREMENTS Success rate , as defined by at least 36 % improvement in Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) score at 26 weeks . Additional end points were WOMAC score and global patient assessment . RESULTS Success rates were 53.1 % for TCA , 51.0 % for sham acupuncture , and 29.1 % for conservative therapy . Acupuncture groups had higher success rates than conservative therapy groups ( relative risk for TCA compared with conservative therapy , 1.75 [ 95 % CI , 1.43 to 2.13 ] ; relative risk for sham acupuncture compared with conservative therapy , 1.73 [ CI , 1.42 to 2.11 ] ) . There was no difference between TCA and sham acupuncture ( relative risk , 1.01 [ CI , 0.87 to 1.17 ] ) . LIMITATIONS There was no blinding between acupuncture and traditional therapy and no monitoring of acupuncture compliance with study protocol . In general , practitioner-patient contacts were less intense in the conservative therapy group than in the TCA and sham acupuncture groups . CONCLUSIONS Compared with physiotherapy and as-needed anti-inflammatory drugs , addition of either TCA or sham acupuncture led to greater improvement in WOMAC score at 26 weeks . No statistically significant difference was observed between TCA and sham acupuncture , suggesting that the observed differences could be due to placebo effects , differences in intensity of provider contact , or a physiologic effect of needling regardless of whether it is done according to TCA principles [12550145] The purpose of the study is to test the effectiveness of acupressure on sleep quality of end-stage renal disease patients . The study was a r and omized controlled trial ; qualified patients in the dialysis centers of four major hospitals were r and omly assigned into an acupressure group , a sham acupressure group , and a control group . A total of 98 participants were included in the study . The main outcomes measured were the Pittsburgh sleep quality index ( PSQI ) and the sleep log . Data were collected at pretreatment and following treatment . Primary statistical analysis was by means of Analysis of Covariance , the Kruskal-Wallis Test and repeated measure ANOVA . The results indicated that PSQI scores of the acupressure group have a significantly greater improvement ( p < 0.01 ) than the control group . However , there were no differences between the acupressure group and the sham group or the sham group and the control group ( p > 0.05 ) . Subscales of PSQI were further analyzed . Results demonstrated significant differences between the acupressure group and the control group in subjective sleep quality ( p = 0.009 ) , sleep duration ( p = 0.004 ) , habitual sleep efficiency ( p = 0.001 ) , and sleep sufficiency ( p = 0.004 ) . Significant differences in the subscale of subjective sleep quality ( p = 0.003 ) between the sham acupressure group and the control group were also observed . Sleep log data showed that the acupressure group significantly decreased awake time and improved quality of sleep over time more than the control group ( p < 0.01 ) . The improvement could be seen as soon as the acupoints massage was implemented , and it was maintained through the post intervention [8969878] Our objective was to study the analgesic effect of acupoint pressure on postoperative pain in a controlled single-blind study . Forty patients undergoing knee arthroscopy in an ambulatory surgery unit in a university-affiliated hospital were r and omized to receive either an active stimulation ( AS ) or a placebo stimulation ( PS ) 30 min after awakening from anesthesia . We stimulated 15 classical acupoints in the AS group , on the side contralateral to surgery , with a firm pressure and a gliding movement across the acupoint . In the PS group , 15 nonacupoints were subjected to light pressure in the same areas as the acupoints in the AS group . We assessed pain using a 100-mm visual analog scale ( VAS ) before sensory stimulation , after 30 and 60 min , and after 24 h. We recorded heart rate , systolic arterial pressure , and skin temperature before stimulation and after 30 and 60 min . We assessed skin blood flow with laser Doppler before stimulation and after 1 and 30 min . Sixty minutes and 24 h after AS , VAS pain scores were lower than in the placebo group ( p < 0.05 and 0.0001 , respectively ) . There were no significant changes in the autonomic variables . The results indicate that pressure on acupoints can decrease postoperative pain [14973803] OBJECTIVE To determine whether the application of acupressure b and s would lead to a reduction in postoperative nausea and vomiting after cardiac surgery . DESIGN Prospect i ve , r and omized , double-blind clinical trial . SETTING University-affiliated tertiary care teaching hospital . PARTICIPANTS Adult patients undergoing cardiac surgery . INTERVENTIONS One hundred fifty-two patients were enrolled to receive either acupressure treatment ( n = 75 ) or placebo ( n = 77 ) . All patients had acupressure b and s placed on both wrists before induction of anesthesia ; those in the treatment group had a bead placed in contact with the P6 point on the forearm . MEASUREMENTS AND MAIN RESULTS Patients were assessed for nausea , vomiting , and pain scores during the first 24 hours of the postoperative period . The incidences of nausea , vomiting , pain scores , and analgesic and antiemetic requirements were similar between the 2 groups . A subgroup analysis by gender implied that acupressure treatment may be effective only in female patients . CONCLUSION Acupressure treatment did not lead to a reduction in nausea , vomiting , or antiemetic requirements in patients after cardiac surgery [8189280] To evaluate the reported benefit of ipsilateral single-application ophthalmic anesthetic eyedrops in patients with typical trigeminal neuralgia , a r and omized double-blind placebo-controlled trial was performed . Forty-seven patients were r and omly assigned to receive two drops of either proparacaine ( 25 cases ) or saline placebo ( 22 cases ) . The experimental and placebo groups were equivalent in regard to patient age , distribution of trigeminal neuralgia pain , duration of pain , current medication regimens , and number of prior procedures performed . Pain response was assessed at 3 , 10 , and 30 days after instillation using two pain rating scales and a measure of pain frequency . Treatment failure was defined in advance as any of the following : a lack of clinical response , the need for an increase in medication , or the need for surgery . No significant difference in outcomes was found between the two groups either when using a verbal pain rating scale ( p = 0.24 ) or when comparing overall pain status ( unchanged , improved throughout the study period , or temporarily improved ) ( p = 0.98 ) . No difference in the frequency of trigeminal neuralgia attacks between the two treatment groups ( scaled within five levels of pain frequency ) was detected ( p = 0.09 ) . During follow-up monitoring , 11 patients in the test drug group and 14 in the placebo group required surgery because of persistent pain ( p = 0.24 ) . The results of this study indicate that single-application topical ophthalmic anesthesia reduces neither the severity nor the frequency of pain in comparison to placebo administration . Although a simple and safe treatment , the single application of topical ophthalmic eyedrops provides no short- or long-term benefit to patients with trigeminal neuralgia [17645494] AIM This paper is a report of a study to examine the effect of Nei-Guan point acupressure on nausea , vomiting and ketonuria levels in women diagnosed with hyperemesis gravidarum . BACKGROUND Previous studies have shown that acupressure application on the Nei-Guan point is effective in relieving nausea and vomiting associated with pregnancy and surgery . However , no findings have been supported by physiological data . METHOD A r and omized control group pretest-post-test design was implemented from 1 April 2003 to 30 April 2004 using three groups : a Nei-Guan point acupressure group , a placebo group and a control group which received only conventional intravenous treatment . The participants were 66 women admitted to two general hospitals in Korea with hyperemesis gravidarum . RESULTS The degree of nausea and vomiting was statistically significantly lower in the Nei-Guan point acupressure group in comparison with the placebo and control groups . Ketonuria levels were reduced over time and , on days three and four of hospitalization , levels in the treatment group were statistically significantly lower than in the placebo or control groups ( P < 0.05 ) . CONCLUSION Nei-Guan point acupressure is a useful treatment for relieving symptoms experienced by women with hyperemesis gravidarum [25440382] OBJECTIVES In clinical trials where participants are likely to be able to distinguish between true and sham interventions , informing participants that they may receive a sham intervention increases the likelihood of participants ' breaking the blind ' and invalidating trial findings . The present study explored participants ' perceptions of the consent process in a sham controlled acupressure trial which did not explicitly indicate participants may receive a sham intervention . DESIGN Nested qualitative study within a r and omised sham controlled trial of acupressure wristb and s for chemotherapy-related nausea . Convenience sample of 26 patients participated in semi-structured interviews . Interviews were audio-recorded and transcribed verbatim . Transcripts analysed thematically using framework analysis . SETTING Study conducted within three geographical sites in the UK : Manchester , Liverpool , and Plymouth . RESULTS All participants indicated that they believed they were fully informed when providing written consent to participate in the trial . Participants ' perceived it was acceptable to employ a sham intervention within the trial of acupressure wristb and s without informing potential participants that they may receive a sham treatment . Despite the fact that participants were not informed that one of the treatment arms was a sham intervention the majority indicated they assumed one of the treatment arms would be placebo . CONCLUSIONS Many trials of acupuncture and acupressure do not inform participants they may receive a sham intervention . The current study indicates patients ' perceive this approach to the consent process as acceptable . However , the fact participants assume one treatment may be placebo threatens the method ological basis for utilising this approach to the consent process [18713889] BACKGROUND : Acupuncture and related techniques have been used as adjuncts for perioperative anesthesia management . We examined whether acupressure in the Extra-1 ( Yin-Tang ) point would result in decreased preprocedural anxiety and reduced intraprocedural propofol requirements in a group of children undergoing endoscopic procedures . METHODS : Fifty-two children were r and omized to receive acupressure bead intervention either at the Extra-1 acupuncture point or at a sham point . A Bispectral Index ( BIS ) monitor was applied to all children before the onset of the intervention . Anxiety was assessed at baseline and before entrance to the operating room . Anesthetic techniques were st and ardized and maintained with IV propofol infusion titrated to keep BIS values of 40–60 . RESULTS : We found that after the intervention , children in the Extra-1 group experienced reduced anxiety whereas children in the sham group experienced increased anxiety ( −9 % [ −3 to −15 ] vs 2 % [ −6 to 7.4 ] , P = 0.012 ) . In contrast , no significant changes in BIS values were observed in the preprocedural waiting period between groups ( P = ns ) . We also found that total intraprocedural propofol requirements did not differ between the two study groups ( 214 ± 76 & mgr;g · kg−1 · min−1 vs 229 ± 95 & mgr;g · kg−1 · min−1 , P = 0.52 ) . CONCLUSIONS : We conclude that acupressure bead intervention at Extra-1 acupoint reduces preprocedural anxiety in children undergoing endoscopic procedures . This intervention , however , has no impact on BIS values or intraprocedural propofol requirements [23803562] BACKGROUND Chemotherapy-induced nausea and vomiting remain difficult symptoms to manage in clinical practice . As st and ard antiemetic drugs do not fully eliminate these symptoms , it is important to explore the adjuvant role of non-pharmacological and complementary therapies in antiemetic management approaches . Acupressure is one such treatment showing highly suggestive evidence so far of a positive effect , meriting further investigation . OBJECTIVES The primary objective was to assess the effectiveness and cost-effectiveness of self-acupressure using wristb and s compared with sham acupressure wristb and s and st and ard care alone in the management of chemotherapy-induced nausea . Secondary objectives included assessment of the effectiveness and cost-effectiveness of the wristb and s in relation to vomiting and quality of life and exploration of any age , gender and emetogenic risk effects . DESIGN R and omised three-arm sham-controlled trial ( Assessment of Nausea in Chemotherapy Research or ANCHoR ) with an economic evaluation . Arms include the wristb and arm , the sham wristb and arm and the st and ard care only arm . R and omisation consisted of minimisation with a r and om element balancing for gender , age ( 16 - 24 , > 24 - 50 , > 50 years ) and three levels of emetogenic chemotherapy ( low , moderate and high ) . Qualitative interviews were incorporated to shed more light on the quantitative findings . SETTING Outpatient chemotherapy clinics in three regions in the UK involving 14 different cancer units/centres . PARTICIPANTS Chemotherapy-naive cancer patients receiving chemotherapy of low , moderate and high emetogenic risk . INTERVENTION The intervention was acupressure wristb and s pressing the P6 point ( anterior surface of the forearm ) . MAIN OUTCOME MEASURES The Rhodes Index for Nausea/Vomiting , the Multinational Association of Supportive Care in Cancer ( MASCC ) Antiemesis Tool and the Functional Assessment of Cancer Therapy - General ( FACT-G ) . At baseline participants completed measures of anxiety/depression , nausea/vomiting expectation and expectations from using the wristb and s. RESULTS In total , 500 patients were r and omised in the study arms ( 166 st and ard care , 166 sham acupressure and 168 acupressure ) and data were available for 361 participants for the primary outcome . The primary outcome analysis ( nausea in cycle 1 ) revealed no statistically significant differences between the three arms , although the median nausea experience in patients using wristb and s ( both real and sham ones ) was somewhat lower than that in the antiemetics only group ( median nausea experience scores for the four cycles : st and ard care arm 1.43 , 1.71 , 1.14 , 1.14 ; sham acupressure arm 0.57 , 0.71 , 0.71 , 0.43 ; acupressure arm 1.00 , 0.93 , 0.43 , 0 ) . A gender effect was evident ( p= 0.002 ) , with women responding more favourably to the use of sham acupressure wristb and s than men ( odds ratio 0.35 for men and 2.02 for women in the sham acupressure group ; 1.27 for men and 1.17 for women in the acupressure group ) . This suggests a placebo effect . No significant differences were detected in relation to vomiting outcomes , anxiety and quality of life . Some transient adverse effects were reported , including tightness in the area of the wristb and s , feeling uncomfortable when wearing them and minor swelling in the wristb and area ( n= 6).There were no statistically significant cost differences associated with the use of real acupressure b and s ( £ 70.66 for the acupressure group , £ 111.13 for the st and ard care group and £ 161.92 for the sham acupressure group ) . In total , 26 subjects took part in qualitative interviews . The qualitative data suggested that participants perceived the wristb and s ( both real and sham ) as effective and helpful in managing their nausea during chemotherapy . CONCLUSIONS There were no statistically significant differences between the three arms in terms of nausea , vomiting and quality of life , although apparent re source use was less in both the real acupressure arm and the sham acupressure arm compared with st and ard care only ; therefore ; no clear conclusions can be drawn about the use of acupressure wristb and s in the management of chemotherapy-related nausea and vomiting . However , the study provided encouraging evidence in relation to an improved nausea experience and some indications of possible cost savings to warrant further consideration of acupressure both in practice and in further clinical trials . TRIAL REGISTRATION IS RCT N87604299 . SOURCE OF FUNDING This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol . 17 , No. 26 . See the HTA programme website for further project information [24673069] R and omized controlled trials ( RCT ) is the source of the raw data of evidence -based medicine . Blind method is adopted in most of the high- quality RCT . Sham acupuncture is the main form of blinded in acupuncture clinical trial . In order to improve the quality of acupuncture clinical trail , based on the necessity of sham acupuncture in clinical research , the current situation as well as the existing problems of sham acupuncture , suggestions were put forward from the aspects of new way and new design ation method which can be adopted as reference , and factors which have to be considered during the process of implementing . Various subjective and objective factors involving in the process of trial should be considered , and used of the current international st and ards , try to be quantification , and carry out strict quality monitoring [19034253] AIM Insomnia is a major problem which decreases life quality . Many causes are involved with it and anxiety is often associated . The underlying mechanism is not completely understood , even though different factors seem to be associated . Among them melatonin and its circadian rhythm is thought to have an important role . In addition , acupressure and acupuncture are known to ameliorate insomnia and anxiety , when a specific wrist point is stimulated ( HT 7 Shenmen ) . With these bases , the aim of the present study has been to evaluate the efficacy of an acupressure device , ' ' H7-insomnia control ' ' , positioned on HT 7 points , during the night , in terms of general health and anxiety levels , together with the evaluation of sleep quality and the urinary melatonin metabolite 6-hydroxymelatonin sulphate determination , in a number of insomniacs . METHODS Forty patients with insomnia were divided into two groups and r and omly received either the H7 or placebo treatments , in a double-blind protocol , for 20 nights . Before and after treatments every subject answered a series of question naires ( General Health Question naire 28 items ; State-Trait Anxiety Inventory ; Pittsburgh Sleep Quality Index ) and collected 24 h urines , divided into two sample s of 12 h each . Urinary melatonin metabolite was then determined using a RIA method . RESULTS Data obtained indicate that the device H7-insomnia control is efficacious to ameliorate quality of sleep and reduce anxiety levels in insomniacs , at a higher extent than in the placebo group . In addition , the 24 hours urinary melatonin metabolite rhythm , obtained at the end of treatment , was considered as being normal in a higher percentage of H7-treated patients , with respect to the placebo group . CONCLUSION It is plausible to hypothesize that the wrist acupressure device might be considered a valid tool , without adverse effects since it does not contain pharmaceutical products , that is able to naturally ameliorate sleep quality in insomniacs , acting through a not jet completely clarified mechanism , that may involve melatonin [25146059] BACKGROUND This study explored the effects of acupressure on fatigue of lung cancer patients undergoing chemotherapy . PATIENTS AND METHODS For this experimental study , 57 subjects were r and omly assigned to three groups : acupressure with essential oils ( n=17 ) , acupressure only ( n=24 ) , and sham acupressure ( n=16 ) . Acupoints were Hegu ( LI4 ) , Zusanli ( ST36 ) , and Sanyingjiao ( SP6 ) . All subjects received acupressure once every morning for 5 months , with each acupoint pressed for 1 min . Fatigue , functional status , anxiety , depression , and sleep quality were measured before initial chemotherapy ( T0 ) , on Day 1 of third chemotherapy ( T1 ) , and on Day 1 of sixth chemotherapy ( T2 ) . Outcome differences between groups were analyzed at T0 , T1 , and T2 by general estimating equations . RESULTS After controlling for baseline outcome values , age , and adherence to acupressure , subjects who received acupressure with essential oils and acupressure had significantly less fatigue in daily living activities and sleep better quality at T1 than subjects who received sham acupressure . Subjects who received acupressure with essential oils had significantly better sleep quality at T2 than the sham acupressure group . Subjects who received acupressure with or without essential oils had greater odds of better functional status at T1 than the sham group . CONCLUSION It is plausible that acupressure with or without essential oils helps lung cancer patients undergoing chemotherapy reduce cancer-related fatigue and increase activity level . Further study is wanted to test this hypothesis [9085965] Postoperative nausea and vomiting are still common problems after general anesthesia , especially in ambulatory surgery . Drug therapy is often complicated with central nervous system symptoms . We studied a nonpharmacological method of therapy-acupressure-at the Pericardium 6 ( P.6 ) ( Nei-Guan ) meridian point . Two hundred consecutive healthy patients undergoing a variety of short surgical procedures were included in a r and omized , double-blind study : 108 patients were in the acupressure group ( Group 1 ) and 92 patients were in the control group ( Group 2 ) . Spherical beads of acupressure b and s were placed at the P.6 points in the anterior surface of both forearms in Group 1 patients , while in Group 2 they were placed inappropriately on the posterior surface . The acupressure b and s were placed before induction of anesthesia and were removed 6 h postoperatively . They were covered with a soft cotton wrapping to conceal them from the blinded observer who evaluated the patients for presence of nausea and vomiting and checked the order sheet for any antiemetics prescribed . In both groups , the age , gender , height , weight , and type and duration of surgical procedures were all comparable without significant statistical difference . In Group 1 , only 25 of 108 patients ( 23 % ) had nausea and vomiting as compared to Group 2 , in which 38 of 92 patients ( 41 % ) had nausea and vomiting ( P = 0.0058 ) . We concluded that acupressure at the P.6 ( Nei-Guan ) point is an effective prophylaxis for postsurgical nausea and vomiting and therefore a good alternative to conventional antiemetic treatment . ( Anesth Analg 1997;84:821 - 5 [10434821] The efficacy of currently available antiemetics remains poor . Concern with their side effects and the high cost of the newer drugs has led to renewed interest in non-pharmacological methods of treatment . We have studied the efficacy of acupressure at the P6 point in the prevention of nausea and vomiting after laparoscopy , in a double-blind , r and omized , controlled study of acupressure vs placebo . We studied 104 patients undergoing laparoscopy and dye investigation . The anaesthetic technique and postoperative analgesia were st and ardized . Failure of treatment was defined as the occurrence of nausea and /or vomiting within the first 24 h after anaesthesia . The use of acupressure reduced the incidence of nausea or vomiting from 42 % to 19 % compared with placebo , with an adjusted risk ratio of 0.24 ( 95 % CI 0.08 - 0.62 ; P = 0.005 ) . Other variables were similar between groups [1859764] A prospect i ve , double-blind study was conducted to compare the effect of pressure at the P6 ( Neikuan ) point with placebo as an antiemetic in children . Sixty-six patients , ages 3 - 12 yr , undergoing outpatient surgery for correction of strabismus , were allocated r and omly to receive either bilateral P6 acupressure or placebo during the perioperative period . The study was design ed to detect a 50 % difference in the incidence of postoperative vomiting between the two groups , with a 90 % power of achieving a statistically significant result at the 5 % level ( two-tailed ) . The incidence of postoperative vomiting for the placebo group was 58 % before discharge from hospital , 73 % at home and 82 % in the first 24 h after surgery . The corresponding results for the acupressure group were 58 % before discharge , 71 % at home and 94 % in the first 24 h. These differences were not significant ; P6 acupressure did not reduce the incidence of postoperative vomiting in children undergoing strabismus surgery [22201663] PURPOSE / OBJECTIVES To evaluate the effects of pericardium 6 ( P6 ) acupressure and nurse-provided counseling on chemotherapy-induced nausea and vomiting ( CINV ) in patients with breast cancer . DESIGN R and omized , controlled trial . SETTING A university cancer center in Seoul , South Korea . SAMPLE 120 women who were beginning their second cycle of adjuvant chemotherapy after definitive surgery for breast cancer and who had more than mild levels of nausea and vomiting with the first cycle of chemotherapy . METHODS Participants were assigned r and omly into four groups : control ( placebo on SI3 ) , counseling only , P6 acupressure only , and P6 acupressure plus nurse-provided counseling . The experiences of upper-gastrointestinal distress were measured by the Rhodes Index of Nausea , Vomiting , and Retching for acute ( day 1 ) and delayed ( day 2 to day 5 ) CINV . MAIN RESEARCH VARIABLES Nausea , retching , vomiting , P6 acupressure , and counseling . FINDINGS No significant differences were found in the demographic and disease-related variables among the four groups . The levels of CINV were significantly different among the groups from day 2 to day 5 . The CINV differences were attributed mainly to the difference between the control group and the group with P6 acupressure plus nurse-provided counseling . The effects of acupressure were proven from day 2 to day 5 , and the effects of nurse-provided counseling were proven on day 4 and were close to significance level on day 5 . CONCLUSIONS Synergic effects of P6 acupressure with nurse-provided counseling appeared to be effective in reducing CINV in patients with breast cancer . IMPLICATION S FOR NURSING P6 acupressure combined with counseling by nurses is a safe and easy-to-apply tool in CINV management in practice [23605600] Postoperative nausea and vomiting ( PONV ) is one of the most common postoperative complications . Aside from pharmacological interventions , other complementary healing modalities have been introduced to assist patients in decreasing PONV and improving postoperative outcomes . This study examined acupressure as a safe complement to the more traditional approach of using drugs to prevent and /or relieve nausea and vomiting in the Cesarean section ( C/S ) under spinal anesthesia . In a prospect i ve r and omized clinical trial , 152 patients who were c and i date for elective C/S under spinal anesthesia were evaluated in two groups ( acupressure vs control groups ) . Subjects in the acupressure group received constant pressure by a specific wrist elastic b and ( without puncture of the skin ) on the Nei-Guan acupuncture point , 30 min prior to spinal anesthesia . The incidence of PONV was assessed during the surgery , at recovery room and at 1st , 2nd and 3rd two hours after the surgery . Significant differences in the incidence of the post-operative nausea and vomiting were found between the acupressure and control groups , with a reduction in the incidence rate of nausea from 35.5 % to 13.2 % . The amount of vomitus and the degree of discomfort were , respectively , less and lower in the study group . In view of the total absence of side-effects in acupressure , its application is worthy . Our study confirmed the effectiveness of acupressure in preventing post-operative nausea and vomiting , when applied 30 minutes prior to surgery [10764175] Purpose : To evaluate the efficacy of acupressure wristb and s in the prevention of postoperative nausea and vomiting ( PONV ) . Methods : Two hundred ASAI - II patients undergoing elective endoscopic urological procedures were included in a r and omized , prospect i ve , double blind , placebo-controlled study . Spherical beads of acupressure wristb and s were placed at the P6 points in the anterior surface of both forearms in Group 1 patients ( acupressure group , n=100 ) whereas , in Group 2(control group , n=100 ) they were placed inappropriately on the posterior surface . The acupressure wristb and s were applied 30 min before induction of anesthesia and were removed six hours postoperatively . Anesthesia was induced with thiopental and maintained with nitrous oxide and oxygen , fentanly , isoflurane and vecuronium . The tracheas were extubated on the operation table after patients received neostigmine and atropine . Post operative nausea and vomiting were evaluated separately as none , mild , moderate or severe at the time of patient ’s arrival in PACU , then at six hours and twenty-four hours after surgery by a blinded observer . Results : In the acupressure group , 25 patients had PONV compared with 29 patients in the control group ( P = NS ) . Conclusion : Application of acupressure wristb and s at the P6 of both forearms 30 min before induction of anesthesia did not decrease the incidence of PONV in patients undergoing endoscopic urological procedures .RésuméObjectif : Évaluer l’efficacité de bracelets d’acupression utilisés pour la prévention des nausées et des vomissements postopératoires (NVPO).Méthode : Deux cents patients , ASA I – II , devant subir une intervention urologique endoscopique planifiée ont participé à l’étude r and omisée , prospect i ve et à double insu contre placebo . Des bracelets de billes d’acupression ont été placés aux points P6 de la face antérieure des deux avant-bras des patients du Groupe 1 ( groupe d’acupression , n=100 ) t and is que dans le Groupe 2 , ( groupe témoin , n=100 ) , ils l’ont été , de façon inappropriée , sur la face postérieure . On les a appliqués 30 min avant l’induction de l’anesthésie et retirés six heures après l’opération . L’anesthésie comportait du thiopental , à l’induction , et du protoxyde d’azote , de l’oxygène , du fentanyl , de l’isoflurane et du vécuronium . L’extubation trachéale a eu lieu à la salle d’opération après l’administration de néostigmine et d’atropine . Un observateur objectif a évalué les nausées et les vomissements postopératoires comme absents , légers , modérés ou sévères au moment où le patient est arrivé à la salle de réveil , puis six et vingt-quatre heures après l’opération . Résultats : Dans le groupe d’acupression , 25 patients ont eu des NVPO , comparativement à 29 patients du groupe témoin ( P = NS ) . Conclusion : L’application de bracelets d’acupression en P6 aux deux avant-bras , 30 min avant l’induction de l’anesthésie , n’a pas diminué l’incidence de NVPO chez des patients qui subissent une intervention urologique endoscopique [21194921] INTRODUCTION Approximately 50 % of women experience nausea or vomiting during labour . P6 acupoint stimulation reduces postoperative nausea and vomiting in early pregnancy and after chemotherapy . The aim of this r and omised , double-blinded , placebo-controlled trial was to determine whether P6 acupressure prevented nausea and vomiting during labour and delivery . METHODS After ethical approval and informed consent , women admitted for induction of labour , or in spontaneous labour , were r and omised to receive either acupressure b and s ( Pressure Right ) ( Group A ) or sham placebo b and s ( Group P ) applied to each wrist . Exclusions included recent nausea or vomiting . RESULTS We consented 365 women and r and omised 340 ( 170 per group ) . The groups had similar patient and labour characteristics . The incidence of nausea and /or vomiting did not significantly differ ( Group A 53 % vs. Group P 50 % , P=0.58 ) . There was no significant difference between groups ( A vs. P , respectively ) in the incidence of nausea ( 52 % vs. 45 % ) , vomiting ( 27 % vs. 28 % ) , rescue antiemetic treatment ( 27 % in both ) , severity of nausea or vomiting , satisfaction with control of nausea or ratings of inconvenience or discomfort from the b and s ( 10 % vs. 11 % ) . Factors significantly associated with emetic symptoms were smoking ( OR 2.16 , 95 % CI 1.07 - 4.37 ) , opioid analgesia ( OR 1.95 , 95 % CI 1.06 - 3.59 ) , history of motion-induced or postoperative nausea and vomiting ( OR 1.85 , 95 % CI 1.17 - 2.94 ) and higher body mass index ( OR 1.07 , 95 % CI 1.01 - 1.12 ) . CONCLUSION In this study acupressure wristb and s applied bilaterally did not reduce the incidence of nausea and vomiting during labour and delivery Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: CONTEXT Acupressure is a noninvasive strategy used to manage various symptoms . OBJECTIVES The purpose of this article was to review r and omized controlled trials that investigated the efficacy of acupressure for the management of symptoms . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

32245711

[12719743] PURPOSE / OBJECTIVES To test the hypotheses that the effects of a music intervention are greater than those of simple distraction and that either intervention is better at controlling procedural pain and anxiety than treatment as usual . DESIGN R and omized , controlled experiment . SETTING A midwestern comprehensive cancer center . SAMPLE 60 people with cancer having noxious medical procedures such as tissue biopsy or port placement or removal ; 58 provided usable data . METHODS Participants completed measures of pain and anxiety before and after their medical procedures and provided a rating of perceived control over pain and anxiety after the procedure . MAIN RESEARCH VARIABLES Procedural pain , state anxiety , and perceived control over pain and anxiety . FINDINGS Contrary to hypotheses , outcomes achieved with music did not differ from those achieved with simple distraction . Moreover , outcomes achieved under treatment as usual were not significantly different from those obtained with music or distraction interventions . Some patients found that the interventions were bothersome and reported that they wanted to attend to the activities of the surgeon and the medical procedure itself . CONCLUSIONS The effects of music , distraction , and treatment as usual are equivocal . In addition , patients have individual preferences for use of distraction during painful or anxiety-provoking procedures . IMPLICATION S FOR NURSING Patients having noxious medical procedures should be asked about their desire to be distracted before and during the procedure and offered a strategy that is consistent with their preferences [23364361] Colonoscopy is a procedure often experienced as uncomfortable and worrying . Music has been reported to reduce discomfort during colonoscopy ; however , no study in a Swedish setting has been found . The purpose of this r and omized controlled trial was to analyze the effects of sedative music on patients ' experience of anxiety , pain , relaxation , and well-being during colonoscopy . Prior to colonoscopy , adult patients ( n = 120 ) , aged 18–80 years , were r and omly assigned to either an intervention group ( n = 60 ) who listened to sedative instrumental music with 60–80 beats per minute during the colonoscopy or a control group . After the colonoscopy , both groups completed a question naire on anxiety , the State Trait Anxiety Inventory , and an anxiety Visual Analogue Scale . Pain , relaxation , and well-being were also measured with Visual Analogue Scales . Women in the intervention group had a lower level of anxiety during the colonoscopy than those in the control group ( p = .007 ) and well-being was significantly higher in the intervention group , especially among men , than in the controls ( p = .006 and p = .025 , respectively ) . Men in the intervention group were more relaxed during the colonoscopy than those in the control group ( p = .065 ) . Listening to sedative music decreased anxiety among women and increased well-being among men during colonoscopy [4019638] Objectives To test the inter-rater reliability of the RoB tool applied to Physical Therapy ( PT ) trials by comparing ratings from Cochrane review authors with those of blinded external review ers . Methods R and omized controlled trials ( RCTs ) in PT were identified by search ing the Cochrane Data base of Systematic Review s for meta- analysis of PT interventions . RoB assessment s were conducted independently by 2 review ers blinded to the RoB ratings reported in the Cochrane review s. Data on RoB assessment s from Cochrane review s and other characteristics of review s and trials were extracted . Consensus assessment s between the two review ers were then compared with the RoB ratings from the Cochrane review s. Agreement between Cochrane and blinded external review ers was assessed using weighted kappa ( κ ) . Results In total , 109 trials included in 17 Cochrane review s were assessed . Inter-rater reliability on the overall RoB assessment between Cochrane review authors and blinded external review ers was poor ( κ = 0.02 , 95%CI : −0.06 , 0.06 ] ) . Inter-rater reliability on individual domains of the RoB tool was poor ( median κ = 0.19 ) , ranging from κ = −0.04 ( “ Other bias ” ) to κ = 0.62 ( “ Sequence generation ” ) . There was also no agreement ( κ = −0.29 , 95%CI : −0.81 , 0.35 ] ) in the overall RoB assessment at the meta- analysis level . Conclusions Risk of bias assessment s of RCTs using the RoB tool are not consistent across different research groups . Poor agreement was not only demonstrated at the trial level but also at the meta- analysis level . Results have implication s for decision making since different recommendations can be reached depending on the group analyzing the evidence . Improved guidelines to consistently apply the RoB tool and revisions to the tool for different health areas are needed [26817929] Abstract Objectives To evaluate the heart rate lowering effect of relaxation music in patients undergoing coronary CT angiography ( CCTA ) , pulmonary vein CT ( PVCT ) and coronary calcium score CT ( CCS ) . Methods Patients were r and omised to a control group ( i.e. st and ard of care protocol ) or to a relaxation music group ( ie . st and ard of care protocol with music ) . The groups were compared for heart rate , radiation dose , image quality and dose of IV metoprolol . Both groups completed State-Trait Anxiety Inventory anxiety question naires to assess patient experience . Results One hundred and ninety-seven patients were recruited ( 61.9 % males ) ; mean age 56y ( 19 - 86 y ) ; 127 CCTA , 17 PVCT , 53 CCS . No significant difference in heart rate , radiation dose , image quality , metoprolol dose and anxiety scores . 86 % of patients enjoyed the music . 90 % of patients in the music group expressed a strong preference to have music for future examinations . The patient cohort demonstrated low anxiety levels prior to CT . Conclusion Relaxation music in CCTA , PVCT and CCS does not reduce heart rate or IV metoprolol use . Patients showed low levels of anxiety indicating that anxiolytics may not have a significant role in lowering heart rate . Music can be used in cardiac CT to improve patient experience . Key Points• Relaxation music does not reduce heart rate in cardiac CT • Relaxation music does not reduce beta-blocker use in cardiac CT • Relaxation music has no effect on cardiac CT image quality • Low levels of anxiety are present in patients prior to cardiac CT • Patients enjoyed the relaxation music and this results in improved patient [24021347] BACKGROUND AND PURPOSE Optimizing communication between radiotherapy team members and patients and between colleagues requires training . This study applies a r and omized controlled design to assess the efficacy of a 38-h communication skills training program . MATERIAL AND METHODS Four radiotherapy teams were r and omly assigned either to a training program or to a waiting list . Team members ' communication skills and their self-efficacy to communicate in the context of an encounter with a simulated patient were the primary endpoints . These encounters were scheduled at the baseline and after training for the training group , and at the baseline and four months later for the waiting list group . Encounters were audiotaped and transcribed . Transcripts were analyzed with content analysis software ( LaComm ) and by an independent rater . RESULTS Eighty team members were included in the study . Compared to untrained team members , trained team members used more turns of speech with content oriented toward available re sources in the team ( relative rate [RR]=1.38 ; p=0.023 ) , more assessment utterances ( RR=1.69 ; p<0.001 ) , more empathy ( RR=4.05 ; p=0.037 ) , more negotiation ( RR=2.34 ; p=0.021 ) and more emotional words ( RR=1.32 ; p=0.030 ) , and their self-efficacy to communicate increased ( p=0.024 and p=0.008 , respectively ) . CONCLUSIONS The training program was effective in improving team members ' communication skills and their self-efficacy to communicate in the context of an encounter with a simulated patient . Future study should assess the effect of this training program on communication with actual patients and their satisfaction . Moreover a cost-benefit analysis is needed , before implementing such an intensive training program on a broader scale [19226611] Breast cancer radiotherapy can be an emotionally difficult experience . Despite this , few studies have examined the effectiveness of psychological interventions to reduce negative affect , and none to date have explicitly examined interventions to improve positive affect among breast cancer radiotherapy patients . The present study examined the effectiveness of a multimodal psychotherapeutic approach , combining cognitive-behavioral therapy and hypnosis ( CBTH ) , to reduce negative affect and increase positive affect in 40 women undergoing breast cancer radiotherapy . Participants were r and omly assigned to receive either CBTH or st and ard care . Participants completed weekly self-report measures of positive and negative affect . Repeated and univariate analyses of variance revealed that the CBTH approach reduced levels of negative affect [ F(1 , 38)=13.49 ; p=.0007 , omega(2)=.56 ] , and increased levels of positive affect [ F(1 , 38)=9.67 ; p=.0035 , omega(2)=.48 ] , during the course of radiotherapy . Additionally , relative to the control group , the CBTH group demonstrated significantly more intense positive affect [ F(1 , 38)=7.09 ; p=.0113 , d=.71 ] and significantly less intense negative affect [ F(1 , 38)=10.30 ; p=.0027 , d=.90 ] during radiotherapy . The CBTH group also had a significantly higher frequency of days where positive affect was greater than negative affect ( 85 % of days assessed for the CBTH group versus 43 % of the Control group ) [ F(1 , 38)=18.16 ; p=.0001 , d=1.16 ] . Therefore , the CBTH intervention has the potential to improve the affective experience of women undergoing breast cancer radiotherapy [28570305] The objective of this study was to evaluate the effect of immersive virtual reality ( IVR ) distraction therapy during painful wound care procedures in adults on the amount of opioid medications required to manage pain . A convenience sample of consenting , adult in patients requiring recurrent painful wound care procedures was studied . Using a within-subject , r and omized controlled trial study design , 2 sequential wound procedures were compared , 1 with IVR distraction therapy and 1 without IVR . Total opioid medications administered before and during the wound procedures were recorded and pain and anxiety were rated before and after the 2 wound procedures . The IVR intervention included the wearing of virtual reality goggles and participation in an immersive , computer generated , interactive , 3-dimensional virtual world program . Data were analyzed with Student 's t test and chi-square analysis , with P < 0.05 considered significant . A total of 18 patients were studied , with 12 completing both study wound procedures and 6 completing a single wound procedure . The amount of opioid administered before each of the 2 wound procedures was similar with and without IVR . Total opioid administration during the dressing procedures with IVR was significantly less than when no IVR was used , 17.9 ± 6.0 and 29.2 ± 4.5 mcg/kg fentanyl , respectively ( t = -2.7 ; df = 14 ; P = 0.02 ) . Two of 15 patients ( 11 % ) requested more than 1 opioid rescue dose with IVR and 9 of 15 patients ( 60 % ) requested more than 1 rescue dose without IVR . Seventy-five percentage of participants stated that they would want to use IVR with future dressing changes . Pain and anxiety scores were similar for the wound procedures with and without IVR ( P > 0.05 ) . IVR significantly reduced the amount of opioid medication administered during painful wound care procedures when IVR was used compared with no IVR . Since pain scores were similar before and after the wound procedures with IVR and without IVR , the 39 % reduction in opioid medication during IVR supports its use as a pain distraction therapy during painful procedures [29149455] AIMS AND OBJECTIVES To evaluate the effect of video information given before cardiovascular magnetic resonance imaging on patient anxiety and to compare patient experiences of cardiovascular magnetic resonance imaging versus myocardial perfusion scintigraphy . To evaluate whether additional information has an impact on motion artefacts . BACKGROUND Cardiovascular magnetic resonance imaging and myocardial perfusion scintigraphy are technically advanced methods for the evaluation of heart diseases . Although cardiovascular magnetic resonance imaging is considered to be painless , patients may experience anxiety due to the closed environment . DESIGN A prospect i ve r and omised intervention study , not registered . METHODS The sample ( n = 148 ) consisted of 97 patients referred for cardiovascular magnetic resonance imaging , r and omised to receive either video information in addition to st and ard text-information ( CMR-video/n = 49 ) or st and ard text-information alone ( CMR-st and ard/n = 48 ) . A third group undergoing myocardial perfusion scintigraphy ( n = 51 ) was compared with the cardiovascular magnetic resonance imaging-st and ard group . Anxiety was evaluated before , immediately after the procedure and 1 week later . Five question naires were used : Cardiac Anxiety Question naire , State-Trait Anxiety Inventory , Hospital Anxiety and Depression scale , MRI Fear Survey Schedule and the MRI-Anxiety Question naire . Motion artefacts were evaluated by three observers , blinded to the information given . Data were collected between April 2015-April 2016 . The study followed the CONSORT guidelines . RESULT The CMR-video group scored lower ( better ) than the cardiovascular magnetic resonance imaging-st and ard group in the factor Relaxation ( p = .039 ) but not in the factor Anxiety . Anxiety levels were lower during scintigraphic examinations compared to the CMR-st and ard group ( p < .001 ) . No difference was found regarding motion artefacts between CMR-video and CMR-st and ard . CONCLUSION Patient ability to relax during cardiovascular magnetic resonance imaging increased by adding video information prior the exam , which is important in relation to perceived quality in nursing . No effect was seen on motion artefacts . RELEVANCE TO CLINICAL PRACTICE Video information prior to examinations can be an easy and time effective method to help patients cooperate in imaging procedures [28917370] BACKGROUND AND AIMS Colonoscopy can be painful and uncomfortable . Aromatherapy is often used for the relief of anxiety or discomfort . Recently , it has been reported that olfactory stimulation induces various physiological effects . We investigated the effects of aromatherapy on anxiety and abdominal discomfort during colonoscopy . METHODS The investigation was carried out using a r and omized controlled study . Aromatherapy was performed by vapor diffusion , and each patient was given one of the following treatments : no inhalation ( control group ) , essential-oil-less vapor ( vehicle group ) , lavender oil ( lavender group ) , grapefruit oil ( grapefruit group ) , or Osmanthus fragrans oil ( Osmanthus fragrans group ) . Following total colonoscopy procedures , each patient estimated their anxiety and abdominal discomfort using the Numeric Rating Scale . RESULTS Total colonoscopy was performed on 361 patients . No complications caused by colonoscopy or aromatherapy were experienced . In the Osmanthus fragrans group , anxiety was significantly attenuated . The abdominal discomfort of patients who reported strong anxiety during colonoscopy was significantly attenuated in the grapefruit group and the Osmanthus fragrans group . CONCLUSION Aromatherapies using Osmanthus fragrans oil and grapefruit oil are effective complementary treatments for anxious patients undergoing colonoscopy [24372795] AIMS AND OBJECTIVES To evaluate the effectiveness of an accessibility-enhanced multimedia informational educational programme in reducing anxiety and increasing satisfaction with the information and material s received by patients undergoing cardiac catheterisation . BACKGROUND Cardiac catheterisation is one of the most anxiety-provoking invasive procedures for patients . However , informational education using multimedia to inform patients undergoing cardiac catheterisation has not been extensively explored . DESIGN A r and omised experimental design with three-cohort prospect i ve comparisons . METHODS In total , 123 consecutive patients were r and omly assigned to one of three groups : regular education ; ( group 1 ) , accessibility-enhanced multimedia informational education ( group 2 ) and instructional digital videodisc education ( group 3 ) . Anxiety was measured with Spielberger 's State Anxiety Inventory , which was administered at four time intervals : before education ( T0 ) , immediately after education ( T1 ) , before cardiac catheterisation ( T2 ) and one day after cardiac catheterisation ( T3 ) . A satisfaction question naire was administrated one day after cardiac catheterisation . Data were collected from May 2009-September 2010 and analysed using descriptive statistics , chi-squared tests , one-way analysis of variance , Scheffe 's post hoc test and generalised estimating equations . RESULTS All patients experienced moderate anxiety at T0 to low anxiety at T3 . Accessibility-enhanced multimedia informational education patients had significantly lower anxiety levels and felt the most satisfied with the information and material s received compared with patients in groups 1 and 3 . A statistically significant difference in anxiety levels was only found at T2 among the three groups ( p = 0·004 ) . CONCLUSIONS The findings demonstrate that the accessibility-enhanced multimedia informational education was the most effective informational educational module for informing patients about their upcoming cardiac catheterisation , to reduce anxiety and improve satisfaction with the information and material s received compared with the regular education and instructional digital videodisc education . RELEVANCE TO CLINICAL PRACTICE As the accessibility-enhanced multimedia informational education reduced patient anxiety and improved satisfaction with the information and material s received , it can be adapted to complement patient education in future regular cardiac care [25641687] BACKGROUND High levels of anxiety during surgery are associated with poorer post-surgical outcomes . This prospect i ve , non-blinded r and omized controlled trial aim ed to compare the effectiveness of four intraoperative distraction interventions for anxiety and pain management during minimally invasive venous surgery under local anaesthetic . METHODS 407 patients presenting with varicose veins at a private clinic , were r and omized to one of four intraoperative distraction interventions or treatment as usual . All participants received endovenous thermoablation and /or phlebectomies of varicose veins . After losses to follow-up , 398 participants were entered into the analysis . Participants were r and omly allocated to one of the following intraoperative distraction techniques : patient selected music ( n = 85 ) , patient selected DVD ( n = 85 ) , interaction with nurses ( n = 81 ) , touch ( stress balls ) ( n = 80 ) or treatment as usual ( TAU , n = 76 ) . The state scale of the STAI , the Short-form McGill pain question naire and numeric rating scales were used to assess intraoperative pain and anxiety . RESULTS Intraoperative anxiety ratings were significantly lower when participants interacted with nurses , used stress balls or watched a DVD during surgery compared to treatment as usual . Intraoperative pain ratings were significantly lower than treatment as usual when participants interacted with nurses or used stress balls during surgery . Patients ' satisfaction was not significantly impacted by intraoperative distractions . CONCLUSIONS The use of simple intraoperative distraction techniques , particularly interacting with nurses , using stress balls or watching a DVD during surgery conducted under local anaesthetic can significantly improve patients ' experiences [23860442] BACKGROUND Anxiety is a relevant but still underscored perioperative problem . The Visual Analogue Scale for Anxiety ( VAS-A ) seems to be effective , fast and manageable , but has not been fully vali date d yet . The aim of this study is to vali date VAS-A comparing it to , Corah 's Dental Anxiety Scale ( CDAS ) Spielberger 's State Trait Anxiety Inventory ( STAI ) and Beck Depression Inventory ( BDI ) . METHODS One hundred consecutive patients ( 38 males and 62 females , median age 49 years ) su bmi tted to oral surgery filled out the VAS-A , CDAS , STAI forms Y1 and Y2 , and BDI at preoperative examination ; the order of administration of tests was r and omized . RESULTS VAS-A score was significantly correlated to CDAS ( P<0.0001 ) , STAI-Y1 ( P<0.0001 ) , STAI-Y2 ( P<0.002 ) but not to BDI ( P=0.18 ) . ROC curve analysis suggested VAS-A equal to 46 mm as threshold for anxiety when using STAI Y1 equal to 40 as reference cutoff . CONCLUSION Our study confirms that VAS-A is a reliable indicator of preoperative anxiety and may detect patients with depressive symptoms also . Values of VAS-A around 50 mm are a reliable threshold for a clinical ly meaningful level of preoperative anxiety [25102532] OBJECTIVE Assessment of virtual reality ( VR ) distraction for alleviating pain and anxiety during flexible cystoscopy . Cystoscopy is a common ambulatory procedure performed in Urology and can be associated with moderate pain and anxiety . Sophisticated distraction techniques are not used with cystoscopy and VR has not been studied for this procedure . We design ed a prospect i ve , r and omized , controlled trial assessing the efficacy of VR for alleviating pain and anxiety during flexible cystoscopy . METHODS Adult men referred for cystoscopy were r and omized into a control or VR group . Subjects were given preprocedure and postprocedure question naires addressing anxiety , pain , and time spent thinking about pain . Vitals signs and galvanic skin monitors were used as objective measures . The control group underwent routine cystoscopy and the VR group underwent cystoscopy with VR . Physicians answered a postprocedure question naire assessing the difficulty of the exam . All question naires used a visual analog score for assessment . RESULTS 23 patients enrolled in the control group and 22 in the VR group . Mean scores and Student 's t-test were employed to analyze the data . No data endpoints showed a statistically significant difference between the 2 groups . CONCLUSIONS We concluded no benefit to VR distraction mitigating pain in male patients during cystoscopy [4015863] Background Thresholds for statistical significance are insufficiently demonstrated by 95 % confidence intervals or P-values when assessing results from r and omised clinical trials . First , a P-value only shows the probability of getting a result assuming that the null hypothesis is true and does not reflect the probability of getting a result assuming an alternative hypothesis to the null hypothesis is true . Second , a confidence interval or a P-value showing significance may be caused by multiplicity . Third , statistical significance does not necessarily result in clinical significance . Therefore , assessment of intervention effects in r and omised clinical trials deserves more rigour in order to become more valid . Methods Several method ologies for assessing the statistical and clinical significance of intervention effects in r and omised clinical trials were considered . Balancing simplicity and comprehensiveness , a simple five-step procedure was developed . Results For a more valid assessment of results from a r and omised clinical trial we propose the following five-steps : ( 1 ) report the confidence intervals and the exact P-values ; ( 2 ) report Bayes factor for the primary outcome , being the ratio of the probability that a given trial result is compatible with a ‘ null ’ effect ( corresponding to the P-value ) divided by the probability that the trial result is compatible with the intervention effect hypothesised in the sample size calculation ; ( 3 ) adjust the confidence intervals and the statistical significance threshold if the trial is stopped early or if interim analyses have been conducted ; ( 4 ) adjust the confidence intervals and the P-values for multiplicity due to number of outcome comparisons ; and ( 5 ) assess clinical significance of the trial results . Conclusions If the proposed five-step procedure is followed , this may increase the validity of assessment s of intervention effects in r and omised clinical trials [12628899] STUDY OBJECTIVES To determine whether distraction therapy with nature sights and sounds during flexible bronchoscopy ( FB ) reduces pain and anxiety . DESIGN R and omized controlled trial . SETTING Teaching hospital in Baltimore , MD . PATIENTS Consecutive adult patients ( n = 80 ) undergoing FB with conscious sedation . INTERVENTION Nature scene murals were placed at the bedside , and patients were provided a tape of nature sounds to listen to before , during , and after the procedure . Patients assigned to the control group were not offered either the nature scene or the sounds . MEASUREMENTS AND RESULTS The primary outcomes were patient ratings of pain control ( a 5-point scale ranging from poor to excellent ) and anxiety . In a multivariate ordinal logistic regression model , the odds of better pain control were greater in the intervention patients than in the control patients ( odds ratio [ OR ] , 4.76 ; 95 % confidence interval [ CI ] , 1.35 to 16.7 ) , after adjustment for age , gender , race , education , health status , and dose of narcotic medication . Older patients and patients with better health status reported significantly less pain . There was no difference in patient-reported anxiety between the two groups ( OR , 0.87 ; 95 % CI , 0.39 to 1.96 ) . CONCLUSIONS Distraction therapy with nature sights and sounds significantly reduces pain in patients undergoing FB . Although the precise mechanism of this beneficial effect requires further investigation , clinicians should consider this nonintrusive strategy in addition to st and ard analgesic medications in patients undergoing painful , invasive procedures [5547864] Background : A high level of preoperative anxiety is common among patients undergoing medical and surgical procedures . Anxiety impacts of gastroenterological procedures on psychological and physiological responses are worth consideration . Aims and Objectives : To analyze the effect of listening to Vedic chants and Indian classical instrumental music on anxiety levels and on blood pressure ( BP ) , heart rate ( HR ) , and oxygen saturation in patients undergoing upper gastrointestinal ( GI ) endoscopy . Material s and Methods : A prospect i ve , r and omized controlled trial was done on 199 patients undergoing upper GI endoscopy . On arrival , their anxiety levels were assessed using state and trait scores and various physiological parameters such as HR , BP , and SpO2 . Patients were r and omly divided into three groups : Group I of 67 patients who were made to listen prerecorded Vedic chants for 10 min , Group II consisting of 66 patients who listened to Indian classical instrumental music for 10 min , and Group III of 66 controls who remained seated for same period in the same environment . Thereafter , their anxiety state scores and physiological parameters were reassessed . Results : A significant reduction in anxiety state scores was observed in the patients in Group I ( from 40.4 ± 8.9 to 38.5 ± 10.7 ; P < 0.05 ) and Group II ( from 41.8 ± 9.9 to 38.0 ± 8.6 ; P < 0.001 ) while Group III controls showed no significant change in the anxiety scores . A significant decrease in systolic BP ( P < 0.001 ) , diastolic BP ( P < 0.05 ) , and SpO2 ( P < 0.05 was also observed in Group II . Conclusion : Listening to Vedic chants and Indian classical instrumental music has beneficial effects on alleviating anxiety levels induced by apprehension of invasive procedures and can be of therapeutic use [29705448] OBJECTIVE The purpose of this study was to determine effect of three different types of music on patients ' preoperative anxiety . METHOD This r and omized controlled trial included 180 patients who were r and omly divided into four groups . While the control group did n't listen to music , the experimental groups respectively listened to natural sounds , Classical Turkish or Western Music for 30 min . The State Anxiety Inventory ( STAI-S ) , systolic blood pressure ( SBP ) , diastolic blood pressure ( DBP ) , heart rate ( HR ) and cortisol levels were checked . FINDINGS The post-music STAI-S , SBP , DBP , HR and cortisol levels of the patients in music groups were significantly lower than pre-music time . All types of music decreased STAI-S , SBP , and cortisol levels ; additionally natural sounds reduced DBP ; Classical Turkish Music also decreased DBP , and HR . CONCLUSIONS All types of music had an effect on reducing patients ' preoperative anxiety , and listening to Classical Turkish Music was particularly the most effective one [5292140] Background Breast cancer is the most common cancer in women , and the second leading cause of cancer deaths . The detection and treatment of this cancer may create mental pressure and lower mood levels , causing anxiety , depression , stress , and pain for the patients . Objectives The aim of this study was to determine the effects of Swedish massage on mood disorders in breast cancer patients undergoing radiotherapy at the cancer institute of the Imam Khomeini hospital at the Tehran University of Medical Sciences . Patients and Methods This study consisted of a clinical trial including 100 patients with breast cancer . The participants were chosen r and omly , with their consent , by the use of polling , to be included in the intervention group ( which received a Swedish massage three times a week , for 30 minutes , over five weeks ) and control group ( which received routine care ) . At the beginning of the intervention and after 5 weeks , the mood disorders of the patients , including anger , anxiety , depression , and any positive affect , were assessed using the affective control scale ( ACS ) question naire . Results Before the intervention , there was no significant difference in the average of the overall scale between the intervention and control groups in the subscales of anger , anxiety , depression , and positive affect ( P = 0.469 ) . The average of the overall scale in the Swedish massage group decreased from 3.52 ± 0.65 to 2.42 ± 0.76 when compared to the pre-intervention conditions , and to ( P < 0.001 ) after the intervention . Moreover , the values for the control group were 3.41 ± 0.94 for the pre-intervention and 3.38 ± 0.9 after the intervention ( P = 0.620 ) . Conclusions When compared to the control group , the Swedish massage showed an improvement in the mood disorders of women with breast cancer [6030513] Machine learning ( ML ) algorithms have proven highly accurate for identifying R and omized Controlled Trials ( RCTs ) but are not used much in practice , in part because the best way to make use of the technology in a typical workflow is unclear . In this work , we evaluate ML models for RCT classification ( support vector machines , convolutional neural networks , and ensemble approaches ) . We trained and optimized support vector machine and convolutional neural network models on the titles and abstract s of the Cochrane Crowd RCT set . We evaluated the models on an external data set ( Clinical Hedges ) , allowing direct comparison with traditional data base search filters . We estimated area under receiver operating characteristics ( AUROC ) using the Clinical Hedges data set . We demonstrate that ML approaches better discriminate between RCTs and non‐ RCTs than widely used traditional data base search filters at all sensitivity levels ; our best‐performing model also achieved the best results to date for ML in this task ( AUROC 0.987 , 95 % CI , 0.984‐0.989 ) . We provide practical guidance on the role of ML in ( 1 ) systematic review s ( high‐sensitivity strategies ) and ( 2 ) rapid review s and clinical question answering ( high‐precision strategies ) together with recommended probability cutoffs for each use case . Finally , we provide open‐ source software to enable these approaches to be used in practice [29709434] OBJECTIVE To investigate the effect of ambient music on anxiety and pain in men undergoing prostate biopsies . MATERIAL S AND METHODS Between September 2015 and June 2016 , men undergoing office transrectal prostate biopsy at our institution were r and omly assigned to music ( n = 85 ) or control ( n = 97 ) groups . We examined clinical characteristics , pathologic variables , and baseline anxiety using the Trait Instrument of State-Trait Anxiety Inventory . Primary outcomes included anxiety assessed by State Instrument of STAI ( STAI-S ) and pain using a visual analog scale . RESULTS There were no significant differences in baseline characteristics between the music and control groups , including median age , prostate-specific antigen , use of magnetic resonance imaging-guided biopsies , or Trait Instrument of State-Trait Anxiety Inventory . The majority ( 93 % ) of patients indicated they desired music in their prebiopsy survey . There were no significant differences in STAI-S ( 33.7 ± 8.9 vs 34.4 ± 9.9 , P = .6 ) , pain score ( 2.3 ± 2.1 vs 2.0 ± 2.1 , P = .3 ) , or vital signs between the music and control groups , respectively . There were also no differences in STAI-S , visual analog scale , or vital signs between groups when stratified by age , prostate-specific antigen , or number of previous biopsies . Men who received music were more likely to request music for future prostate biopsy , compared to men who did not ( 93 % vs 83 % , P = .07 , respectively ) . CONCLUSION This r and omized study showed no difference in anxiety or pain scores for patients who had ambient music during transrectal prostate biopsy . Future studies are needed to discern the influence of details including method of music delivery , music type , and utilization of adjunct relaxation tools [23953858] OBJECTIVE The purpose of this study was to investigate the music therapy ( MT ) effect in levels of intraoperative anxiety in patients undergoing crossectomy with stripping of the great saphenous vein and to assess the efficacy , safety , and feasibility of this alternative therapy as a complement of st and ard intraoperative care . MATERIAL AND METHODS The study is a simple blind , controlled , parallel groups , prospect i ve r and omized clinical trial . Patients were allocated by means of r and omized controlled sampling . The study was performed in the surgery room of Getafe University Hospital in Madrid . The study was carried out in 40 patients , 20 r and omized to the experimental group and 20 r and omized to the control group , with an age range from 27 to 70 years . The control group was given intraoperative routine attention , and the experimental group was given an MT passive intervention that consisted of audition of musical fragments during varicose veins surgery . These pieces previously showed relaxing actions on the cardiovascular system . The anxiety levels were measured by means of pre- and postsurgical question naires by a blinded investigator for the study arm to which the patients had been r and omized . Heart rate and systolic and diastolic blood pressures were determined during the intervention , and adrenaline and noradrenaline plasma levels were determined before and after the surgical procedure . RESULTS The majority of the patients in the MT group ( 95 % ) and st and ard care group ( 90 % ) completed the study . There were no statistical differences between the control and experimental groups in heart rate gradient or systolic and diastolic blood pressures measured after the intervention . The anxiety state and the stress feeling scale score after surgery were significantly inferior in the MT group ( 94.7 % vs 57.9 % decrease in anxiety levels , P < .05 , and stress score of 1.31 vs 2.36 , P < .05 , respectively ) . The adverse events ratio was low and occurred with similar frequency in both groups . CONCLUSIONS The MT intervention was easily implemented in the context of nursing care received during varicose vein surgery and was positively accepted and valued by the majority of the patients . MT is a safe procedure that is proved to reduce anxiety and stress in the study patients [9921569] PURPOSE / OBJECTIVES To measure the effectiveness of customized guided imagery for increasing comfort in women with early stage breast cancer . DESIGN Experimental longitudinal , r and om assignment to groups . SETTING Two urban radiation oncology departments . SAMPLE 53 women ( 26 in the experimental group , 27 in the control group ) aged 37 - 81 ; 80 % European and 10 % African American with stage I or II breast cancer about to begin radiation therapy . METHODS The experimental group was to listen to a guided imagery audiotape once a day for the duration of the study . The Radiation Therapy Comfort Question naire was self-administered at three time points : prior to the introduction of intervention and the beginning of radiation therapy ( Time 1 ) , three weeks later ( Time 2 ) , and three weeks after completing radiation therapy ( Time 3 ) . The State Anxiety Inventory was administered at Time 1 only . MAIN RESEARCH VARIABLES The effect of use of guided imagery on comfort with anxiety as a control variable . FINDINGS Pooled data indicated a significant overall increase in differences in comfort between the treatment and control group , with the treatment group having higher comfort over time . The data also revealed a significant linear trend in differences between groups . No significant interaction of group and time existed . CONCLUSIONS Guided imagery is an effective intervention for enhancing comfort of women undergoing radiation therapy for early stage breast cancer . The intervention was especially salient in the first three weeks of therapy . IMPLICATION S FOR NURSING PRACTICE Guided imagery audiotapes specifically design ed for this population were re source effective in terms of cost , personnel , and time [26626861] PURPOSE To evaluate the clinical efficacy , safety , and feasibility of implementing video glasses in a variety of interventional radiologic ( IR ) procedures . MATERIAL S AND METHODS Between August 2012 and August 2013 , 83 patients undergoing outpatient IR procedures were r and omized to a control group ( n = 44 ) or an experimental group outfitted with video glasses ( n = 39 ) . State-Trait Anxiety Inventory ( STAI ) scores , sedation and analgesia doses , mean arterial pressure ( MAP ) , heart rate ( HR ) , respiratory rate ( RR ) , pain scores , and procedure times were obtained . Complications and adverse events related to the use of video glasses were recorded . Postprocedural staff surveys and patient satisfaction surveys were completed . RESULTS Women had greater preprocedural anxiety than men ( P = .0056 ) , and patients undergoing vascular interventions had greater preprocedural anxiety than those undergoing nonvascular interventions ( P = .0396 ) . When assessed after the procedure , patients who wore video glasses had significantly reduced levels of anxiety ( -7.7 vs -4.4 , respectively ; P = .0335 ) and average MAP ( -6.3 vs 2.1 , respectively ; P = .0486 ) compared with control patients . There was no significant difference in amount of sedation and analgesia , HR , RR , pain score , or procedure time between groups . No significant adverse events related to the use of video glasses were observed . Postprocedural surveys showed that video glasses were not distracting and did not interfere or pose a safety issue during procedures . Patients enjoyed using the video glasses and would use them again for a future procedure . CONCLUSIONS Video glasses can be safely implemented during IR procedures to reduce anxiety and improve a patient 's overall experience [16371522] PURPOSE To assess how patients ' underlying anxiety affects their experience of distress , use of re sources , and responsiveness toward nonpharmacologic analgesia adjunct therapies during invasive procedures . MATERIAL S AND METHODS Two hundred thirty-six patients undergoing vascular and renal interventions , who had been r and omized to receive during st and ard care treatment , structured empathic attention , or self-hypnotic relaxation , were divided into two groups : those with low state anxiety scores on the State-Trait Anxiety Inventory ( STAI , scores < 43 ; n = 116 ) and those with high state anxiety scores ( > or = 43 ; n = 120 ) . All had access to patient-controlled analgesia with fentanyl and midazolam . Every 15 minutes during the procedure , patients rated their anxiety and pain on a scale of 0 - 10 ( 0 , no pain/anxiety at all ; 10 , worst possible pain/anxiety ) . Effects were assessed by analysis of variance and repeated- measures analysis . RESULTS Patients with high state anxiety levels required significantly greater procedure time and medication . Empathic attention as well as hypnosis treatment reduced procedure time and medication use for all patients . These nonpharmacologic analgesia adjunct treatments also provided significantly better pain control than st and ard care for patients with low anxiety levels . Anxiety decreased over the time of the procedure ; patients with high state anxiety levels experienced the most significant decreases in anxiety with nonpharmacologic adjuncts whereas patients with low state anxiety levels coped relatively well under all conditions . CONCLUSION Patients ' state anxiety level is a predictor of trends in procedural pain and anxiety , need for medication , and procedure duration . Low and high state anxiety groups profit from the use of nonpharmacologic analgesia adjuncts but those with high state anxiety levels have the most to gain [21410035] BACKGROUND / AIMS Colonoscopy is generally tolerated , some patients regarding the procedure as unpleasant and painful and generally performed with the patient se date d and receiving analgesics . The effect of sedation and analgesia for colonoscopy is limited . Aromatherapy is also applied to gastrointestinal endoscopy to reduce procedural anxiety . There is lack of information about aromatherapy specific for colonoscopy . In this study , we aim ed to performed a r and omized controlled study to investigate the effect of aromatherapy on relieve anxiety , stress and physiological parameters of colonoscopy . METHODOLOGY A r and omized controlled trail was carried out and collected in 2009 and 2010 . The participants were r and omized in two groups . Aromatherapy was then carried out by inhalation of Sunflower oil ( control group ) and Neroli oil ( Experimental group ) . The anxiety index was evaluated by State Trait Anxiety Inventory-state ( STAI-S ) score before aromatherapy and after colonoscopy as well as the pain index for post-procedural by visual analogue scale ( VAS ) . Physiological indicators , such as blood pressure ( systolic and diastolic blood pressure ) , heart rate and respiratory rate were evaluated before and after aromatherapy . RESULTS Participates in this study were 27 subjects , 13 in control group and 14 in Neroli group with average age 52.26 + /- 17.79 years . There was no significance of procedural anxiety by STAI-S score and procedural pain by VAS . The physiological parameters showed a significant lower pre- and post-procedural systolic blood pressure in Neroli group than control group . CONCLUSIONS Aromatic care for colonoscopy , although with no significant effect on procedural anxiety , is an inexpensive , effective and safe pre-procedural technique that could decrease systolic blood pressure [12920428] Patients scheduled for gastrointestinal procedures such as colonoscopy or esophagogastroduodenoscopy are often anxious and frightened . High levels of anxiety may result in more difficult and painful procedures . Past research has reported education , coping skills , relaxation techniques , and combinations of these including music , have decreased anxiety in patients across many setting s. Self-selected music therapy for preprocedural anxiety has not been studied . A r and omized controlled trial of 198 patients was undertaken to determine whether 15 minutes of self-selected music reduced preprocedure anxiety . The State Trait Anxiety Inventory was used to measure patients ’ anxiety . One-hundred ninety-three men and 5 women comprised the sample with an average age of 61 ( SD 10.5 ) . Patients who listened to music ( n = 100 ) reduced their anxiety score from 36.7 ( SD 9.1 ) to 32.3 ( SD 10.4 ) , while those who did not listen to music ( n = 98 ) reduced their anxiety score from 36.1 ( SD 8.3 ) to 34.6 ( SD 11.5 ) . These differences were statistically significant ( F = 7.5 , p = .007 ) after controlling for trait anxiety . There were no significant vital sign changes premusic and postmusic . Music is a noninvasive nursing intervention that can significantly reduce patients ’ anxiety prior to gastrointestinal procedures . Further research should address using music to reduce anxiety in other procedure areas and testing effectiveness of self-selected versus investigator-selected music in reducing anxiety [10801169] BACKGROUND Non-pharmacological behavioural adjuncts have been suggested as efficient safe means in reducing discomfort and adverse effects during medical procedures . We tested this assumption for patients undergoing percutaneous vascular and renal procedures in a prospect i ve , r and omised , single-centre study . METHODS 241 patients were r and omised to receive intraoperatively st and ard care ( n=79 ) , structured attention ( n=80 ) , or self-hypnotic relaxation ( n=82 ) . All had access to patient-controlled intravenous analgesia with fentanyl and midazolam . Patients rated their pain and anxiety on 0 - 10 scales before , every 15 min during and after the procedures . FINDINGS Pain increased linearly with procedure time in the st and ard group ( slope 0.09 in pain score/15 min , p<0.0001 ) , and the attention group ( slope 0.04/15 min ; p=0.0425 ) , but remained flat in the hypnosis group . Anxiety decreased over time in all three groups with slopes of -0.04 ( st and ard ) , -0.07 ( attention ) , and -0.11 ( hypnosis ) . Drug use in the st and ard group ( 1.9 units ) was significantly higher than in the attention and hypnosis groups ( 0.8 and 0.9 units , respectively ) . One hypnosis patient became haemodynamically unstable compared with ten attention patients ( p=0.0041 ) , and 12 st and ard patients ( p=0.0009 ) . Procedure times were significantly shorter in the hypnosis group ( 61 min ) than in the st and ard group ( 78 min , p=0.0016 ) with procedure duration of the attention group in between ( 67 min ) . INTERPRETATION Structured attention and self-hypnotic relaxation proved beneficial during invasive medical procedures . Hypnosis had more pronounced effects on pain and anxiety reduction , and is superior , in that it also improves haemodynamic stability [16897144] Summary Background Intracardiac catheterization is a routine physical examination . Due to psychological strains , several psychosocial interventions , including music therapy , have been proposed . The aim of the present study was to examine whether the preventive or adjuvant use of music therapy results in a reduction in both subjective and objective anxiety and thus leads to a reduction in sedative medication . Methods of assessment N=83 patients ( 48 male , 35 female , 66±11 yrs ) waiting for scheduled cardiac catheterization were r and omly allocated to one of three groups : control group ( st and ard care ) , exposure group ( music stimulation during the procedure ) , or coaching group ( additional music therapeutic coaching ) . Target variables were subjective anxiety and physiological parameters . Results Music intervention did effectively reduce subjective anxiety ( STAI-S reduction pre-post : exposure 11 pt , coaching : 4 pt , control : 6 pt ; p=0.033 ) . Physiological values and medication did not differ between groups . Conclusion The use of music stimulation during the catheterization has a relaxing and calming effect on patients . It seems to be especially beneficial in a subgroup of patients with higher-than-average psychological strains [15693467] This research study evaluates the effectiveness of distraction interventions on subject perceptions of discomfort or pain and anxiety during the ocular anesthetic injection prior to cataract surgery . Eighty subjects received either usual care , usual care with massage , usual care with verbal coaching and slow breathing , or usual care with massage and verbal coaching and slow breathing combined as different types of distraction interventions . After the ocular anesthetic injection(s ) , the subjects rated their level of experienced discomfort or pain and anxiety on a Likert scale of 0 to 10 . The statistical analyses revealed a significant reduction of discomfort or pain and anxiety when the distraction interventions were implemented during the ocular anesthetic injections . Because the different distraction interventions are effective , inexpensive , and easy to implement , routine use during ocular anesthetic injections , prior to cataract surgery , is recommended [24183068] OBJECTIVE This paper describes a r and omized controlled single blind study testing the effects of a patient education intervention combined with positive therapeutic suggestions on anxiety for cataract surgery patients . METHODS 84 patients participated in the study . Physiological and behavioral indicators of anxiety were compared between a regularly treated control and an intervention group receiving an audio CD containing information , relaxation , and positive imagery . RESULTS We found that the intervention group was calmer throughout the four measurement points of the study ( p=.004 ; d=0.71 ) and they were more cooperative ( p=.01 ; d=0.60 ) during the operation . The groups did not differ in sleep quality before the day of the operation , heart rate during the procedure , and subjective Well-being . CONCLUSION Findings indicate that preoperative information combined with positive suggestions and anxiety management techniques might reduce patient anxiety in the perioperative period of cataract surgery , but further research is needed to investigate the benefits of such interventions and to uncover the underlying mechanisms . PRACTICE IMPLICATION S Patient education interventions providing additional anxiety management techniques are recommended for use prior to cataract surgery [26377497] Abstract Introduction Several studies evaluating the tolerance of transrectal ultrasound (TRUS)-guided needle biopsies showed that moderate-to-severe pain was associated with the procedure . Additionally , prebiopsy anxiety or rebiopsy as a result of a prior biopsy procedure is mentioned as factors predisposing to higher pain intensity . Thus , in this study , we investigated the effects of hypnotherapy during transrectal ultrasound-guided prostate needle biopsy for pain and anxiety . Material s and methods Sixty-four patients presenting for TRUS-guided prostate needle biopsy were r and omly assigned to receive either 10-min presurgery hypnosis session ( n = 32 , mean age 63.5 ± 6.1 , p = 0.289 ) or a presurgery control session ( n = 32 , mean age 61.8 ± 6.8 , p = 0.289 ) . The hypnosis session involved suggestions for increased relaxation and decreased anxiety . Presurgery pain and anxiety were measured using visual analog scales ( VAS ) , Beck Anxiety Inventory ( BAI ) , and Hamilton Anxiety Scale ( HAS ) , respectively . In our statistics , p < 0.05 was considered statistically significant . Results Postintervention , and before surgery , patients in the hypnosis group had significantly lower mean values for presurgery VAS [ mean 1 ( 0–8 ) ; p = 0.011 ] , BAI ( 6.0 vs 2.0 ; p < 0.001 ) , and HAS ( 11.0 vs 6.0 ; p < 0.001 ) . Conclusion The study results indicate that a brief presurgery hypnosis intervention can be an effective means of controlling presurgical anxiety , and therefore pain , in patients awaiting diagnostic prostate cancer surgery [16952777] Patients scheduled for vascular angiography are often anxious and frightened . High levels of anxiety may result in more difficult and painful procedures . Past research has reported mixed results for anxiety reduction techniques in other procedures setting s , such as education , cognitive-behavioral skills , coping and relaxation skills , combinations of techniques , and music . Music as an intervention for pre-procedural anxiety prior to vascular angiography has not been studied . A r and omized controlled trial of 170 patients was undertaken to determine whether 15 minutes of self-selected music reduced pre-procedure anxiety . The State Trait Anxiety Inventory was used to measure patients ' anxiety . One-hundred sixty-six men and 4 women comprised the sample with an average age of 66.8 years ( SD 9.95 , range 37 to 85 years ) . Patients who listened to music ( n=89 ) reduced their anxiety score from 38.57 ( SD 10.46 ) to 35.2 ( SD 9.7 ) , while those who did not listen to music ( n=81 ) reduced their anxiety score from 36.23 ( SD 10.54 ) to 35.1 ( SD 10.59 ) ; the difference between the groups was statistically significant ( t=1.95 , df 161 , p=0.05 ) . Pulse achieved a statistically significant reduction in the music group ( t=2.45 , df 167 , p=0.02 ) . Music is a noninvasive nursing intervention that patients enjoy and reduces their anxiety and their pulse rate . Further research should address using music to reduce anxiety in other interventional vascular angiography setting s with equal numbers of men and women and comparing self-selected versus investigator-selected music [28395396] BACKGROUND Aromatherapy has been used to reduce anxiety in a variety of setting s , but usefulness associated with breast biopsies has not been documented . AIMS This study was conducted in women undergoing image-guided breast biopsy . We explored the use of two different aromatherapy scents , compared to placebo , aim ed at reducing anxiety with the intent of generating new knowledge . METHODS This was a r and omized , placebo-controlled study of two different types of external aromatherapy tabs ( lavender-s and alwood and orange-peppermint ) compared with a matched placebo-control delivery system . Anxiety was self-reported before and after undergoing a breast biopsy using the Spielberger State Anxiety Inventory Scale . RESULTS AND FINDINGS Eighty-seven women participated in this study . There was a statistically significant reduction in self-reported anxiety with the use of the lavender-s and alwood aromatherapy tab compared with the placebo group ( p = .032 ) . Aromatherapy tabs reduced anxiety during image-guided breast biopsy . LINKING EVIDENCE TO ACTION The completion of the biopsy provided some relief from anxiety in all groups . The use of aromatherapy tabs offers an evidence -based nursing intervention to improve adaptation and reduce anxiety for women undergoing breast biopsy . Lavender-s and alwood aromatherapy reduced anxiety and promoted adaptation more than orange-peppermint aromatherapy or placebo [21095634] The purpose was to investigate if women with high pre-procedural anxiety reported higher degree of relaxation and comfort if listening to music during coronary angiographic procedures . A prospect i ve r and omized controlled trial was used included 68 patients undergoing coronary angiography and /or PCI . The women were allocated to receive calming music and st and ard care or st and ard care only . Relaxation , environmental sound and discomfort associated with lying still were assessed . There was significantly more positive impression of the sound environment and less discomfort associated with lying still in women listening to music in comparison to women who received only st and ard care . No effect in relaxation was found [15036850] BACKGROUND AND PURPOSE The optimal treatment position for patients receiving radical radiation therapy for prostate cancer has been a source of controversy . To resolve this issue , we conducted a r and omized trial to evaluate the effects of supine and prone positioning on organ motion , positioning errors , and dose to critical organs during escalated dose conformal irradiation for localized prostate cancer and patient and therapist satisfaction with setup technique . PATIENTS AND METHODS Twenty eight patients were r and omized to commence treatment immobilized in the supine or prone position and were subsequently changed to the alternate positioning for the latter half of their treatment . Patients underwent CT simulation and conformal radiotherapy planning and treatment in both positions . The clinical target volume encompassed the prostate gl and . Alternate day lateral port films were compared to corresponding simulator radiographs to measure the isocentre positioning errors ( IPE ) . Prostate motion ( PM ) and total positioning error ( TPE ) were measured from the same films by the displacements of three implanted fiducial markers . Dose volume histograms ( DVHs ) for the two treatment positions were compared at the 95 , 80 and 50 % dose ( D% ) levels . The patients and radiation therapists completed weekly question naires regarding patient comfort and ease of setup . RESULTS Seven patients , who started in the supine position , subsequently refused prone position and received their whole treatment supine . Small bowel in the treatment volume , not present in the supine position , prevented one patient from being treated prone . PM in anterior posterior direction was statistically significantly less in the supine position ( P<0.05 ) . There was no significant difference in superior inferior PM for the two treatment positions . No statistically significant difference between supine and prone positioning was observed in isocentre positioning error ( IPE ) or total positioning error ( TPE ) due to a policy of daily pre-treatment correction . However , more pre-treatment corrections were required for patients in the prone position . The DVH analysis demonstrated larger volumes of the bladder wall , rectal wall and small bowel within the D95 , D80 and D50 % when comparing the planning target volumes ( PTVs ) actually treated for prone positioning . When the prone PTV was exp and ed to account for the greater PM encountered in that position , a statistically significant difference ( P<0.007 ) was observed in favour of the supine position at all dose levels . In the prone position , four patients had small bowel within the 60 Gray ( Gy ) isodose and in the supine position , no patients had small bowel in the 60 or 38Gy volumes . Supine position was significantly more comfortable for the patients and setup was significantly easier for the radiation therapists . The median patient comfort score was 0.79 ( St and ard deviation ( SD ) 0.03 ) supine and 0.45 ( SD 0.05 ) prone ( P<0.001 ) The therapist convenience of setup was 0.80 ( SD 0.016 ) supine and 0.54 ( SD 0.025 ) prone ( P<0.005 ) . No statistically significant difference was seen for the other parameters studied . CONCLUSIONS We demonstrated significantly less PM in the supine treatment position . There was no difference for either treatment position in IPE or TPE , however , more pre-treatment corrections were required in the prone position . Prone position required a larger PTV with result ing increased dose to critical organs . There were statistically significant improvements at all dose levels for small bowel , rectal wall and bladder wall doses in the supine position once corrections were made for differences in organ motion . Linear analogue scores of patient comfort and radiation therapist convenience demonstrated statistically significant improvement in favour of the supine position . Supine positioning has been adopted as the st and ard for conformal prostatic irradiation at our centre [20685168] Background : A cardiac catheterization laboratory can be a frightening environment and music can be a supportive source of environmental sound that stimulates and maintains relaxation . Aim : To test the effects of patient focused music versus loudspeaker music versus st and ard sound on patient 's experiences of anxiety and well-being during coronary angiographic procedures . Methods : A prospect i ve , r and omized , controlled trial of 98 subjects undergoing elective coronary angiogram and /or percutaneous coronary intervention . The subjects were r and omly allocated to three different groups of sound environments : a control group ( the usual sound environment ) , a patient focused music group ( audio pillow ) or to a loudspeaker music group . Results : Anxiety decreased significantly and well-being increased significantly in the two music groups compared to the control group . There was a significantly more positive impression of the sound environment in the patient focused music group compared to the two other groups . Conclusion : This study showed that the use of a specially design ed music reduced anxiety and increased well-being in patients during coronary angiographic procedures . However , patient focused music seemed to be more preferable . The sound environment was rated more positively by the subjects listening to music via audio pillow . The music delivered via loudspeakers seemed to distract the staff during the examination at the cardiac catheterization laboratory [17661855] OBJECTIVE To determine whether therapeutic touch administered at the time of stereotactic core biopsy of suspicious breast lesions results in a reduction in anxiety and pain . DESIGN R and omized , patient-blinded , controlled trial of either Krieger-Kunz therapeutic touch administered by a trained practitioner or a sham intervention mimicking therapeutic touch delivered during core biopsy . SETTING Stereotactic breast biopsy unit of a comprehensive breast center . PATIENTS Women with mammographically detected , nonpalpable breast lesions requiring biopsy . OUTCOME MEASURES Changes in pain and anxiety measured by visual analog scales immediately before and after stereotactic core biopsy . RESULTS A total of 82 patients were accrued : 42 received actual therapeutic touch and 40 sham therapeutic touch . No significant differences were found between the arms for age , ethnicity , educational background , or other demographic data . The sham arm had a preponderance of left breast biopsies ( 48 % vs 58 % ; P = 0.07 ) and received a slightly higher volume of epinephrine-containing local anesthetic ( 6.5 + /- 6.1 vs 4.5 + /- 4.5 mL ; P = 0.09 ) . Therapeutic touch patients were more likely to have an upper breast lesion location ( 57 % vs 53 % ; P = 0.022 ) . No significant differences between the arms were seen regarding postbiopsy pain ( P = 0.95 ) , anxiety ( P = 0.66 ) , fearfulness , or physiological parameters . Similarly , no differences were seen between the arms when change in parameters from prebiopsy to postbiopsy was considered for any of the psychological or physiological variables measured . These findings persisted when confounding variables were controlled for . CONCLUSIONS Women undergoing stereotactic core breast biopsy received no significant benefit from therapeutic touch administered during the procedure . Therapeutic touch can not be routinely recommended for patients in this setting [23679113] Abstract Many patients experience some degree of anxiety during dermatologic procedures . A prospect i ve , r and omized-control trial of hypnotic induction followed by self-guided imagery was conducted with patients in 3 groups : live induction , recorded induction , or control . By 20 minutes into the procedure , there was significantly reduced anxiety reported in the live-induction group compared with the control , whereas reported anxiety in the recorded-induction group was similar to that of the control group . All 13 in the live induction , 11 of the 13 in the recorded induction , and none of the 13 in the control group imagined scenes . The findings of this study suggest that live hypnotic induction followed by self-guided imagery can help to reduce anxiety experienced by many patients during dermatologic procedures [25198487] OBJECTIVES To determine the impact of music intervention on endothelial function , hemodynamics , and patient anxiety before , during , and after cardiac catheterization . BACKGROUND The effect of music therapy during cardiac catheterization on endothelial function and patient satisfaction has received limited study . METHODS Seventy patients undergoing elective cardiac catheterization were r and omized to music therapy ( n=36 ) or no music therapy ( n=34 ) . Peripheral arterial tonometry was performed before and after catheterization . A 6 item ( 24-point scale ) question naire evaluating patient anxiety and discomfort levels was also administered after the procedure . RESULTS Both study groups had similar baseline characteristics , fluoroscopy time , and contrast administration . Reactive hyperemia index ( RHI ) change was 0.14 ± 0.72 in the music group and 0.30 ± 0.58 in the control group ( P=.35 ) . Systolic and diastolic blood pressure ( BP ) changes did not significantly differ between the two groups ( systolic BP change -3.3 ± 17.3 mm Hg vs -2.3 ± 19.4 mm Hg ; P=.83 and diastolic BP change -1.9 ± 12.2 mm Hg vs. 2.0 ± 13.4 mm Hg ; P=.23 ) . Heart rate changes were also comparable between the two groups ( -1 ± 6 beats/ min vs -1 ± 7 beats/min ; P=.22 ) . Patient satisfaction question naire measurements were found to be similar in patients with and without music therapy ( 8 [ 7 - 11 ] vs 9 [ 8 - 12 ] ; P=.36 ) . CONCLUSIONS In this study , music intervention did not elicit a vasodilator response , did not lower blood pressure or heart rate , and did not relieve anxiety or stress discomfort in patients who underwent coronary angiography [19186107] Several studies have evaluated music interventions prior and after coronary angiography and percutaneous coronary intervention ( PCI ) , but there is no clear evidence showing that music has an effect on patients during these procedures . The purpose was to investigate the effects of music on anxiety , angina , pain , relaxation , and comfort in patients during angiographic procedures and to evaluate gender differences . The study was a four-armed , prospect i ve r and omized controlled trial included 240 patients undergoing coronary angiography and /or PCI . Patients were allocated to receive relaxing music , MusiCure ® or st and ard care during the procedure . Outcome measures were ; puncture pain and the discomfort related to it , angina and the discomfort related to it , anxiety , experience of the sound environment , discomfort of lying still , and the doses of anxiolytics and analgesics during the procedure . No differences were found between the music and control groups regarding any of the trial endpoints or gender-related differences . The overall rating of the sound environment and feeling of relaxation was high . In conclusion , music intervention in patients undergoing angiographic procedures was highly feasible , but not effective in this study though the delivery of music went smoothly and did not disturb the examination and patients and staff alike looked favorably on it [11310081] Screening flexible sigmoidoscopy ( FS ) is an effective tool for the detection of colon cancer . Nonetheless , persons are reluctant to undergo FS for a variety of reasons such as anxiety , discomfort , and the possibility of abnormal findings . Nurses caring for FS patients can implement interventions to allay anxiety and promote comfort in an effort to enhance satisfaction and future compliance . Music therapy is one nonpharmacologic intervention that has been shown to be effective in allaying anxiety , reducing discomfort , and promoting satisfaction in other patient population s. A two-group pretest , posttest experimental design with repeated measures study recruited 64 subjects undergoing FS from one Midwestern tertiary care center . Subjects were r and omly assigned to a control condition of usual procedural care or to an experimental condition of music therapy during the examination . State and trait anxieties were measured at pretest . State anxiety , discomfort , satisfaction , and perceived compliance with future screening were measured after the procedure . Subjects in the music group reported less anxiety and discomfort than subjects in the control group . There were no differences on satisfaction ratings or perceived compliance with screening guidelines . Nurses caring for patients undergoing screening FS can offer music therapy as one nonpharmacologic intervention to ameliorate anxiety and reduce discomfort [20307440] BACKGROUND Minor surgery for ingrown toenails can provoke anxiety and the anaesthetic injection can be acutely painful . Distraction techniques may reduce the associated pain and anxiety . OBJECTIVE To investigate an audiovisual distraction ( Bedscapes ) on pain and anxiety during minor surgery for the correction of ingrown toenail . METHOD In a r and omised controlled trial , patients ( N=152 ) with ingrown toenails requiring surgical correction under local anaesthesia were allocated to receive Bedscapes+st and ard care or st and ard care alone . Pain levels due to local anaesthetic injection were assessed post-procedure , and anxiety levels were assessed pre- and post-procedure in both groups . Follow-up focus groups were conducted with 14 patients allocated to the Bedscapes group , and one-to-one interviews were held with four podiatrists . RESULTS Participants with high pre-procedure anxiety scores experienced greater pain on injection , and older patients reported lower pain than younger patients , regardless of group allocation . Bedscapes did not reduce pain or anxiety , and was apparently no more effective than interpersonal interaction between podiatry staff and the patient . CONCLUSIONS Pain of injected anaesthesia correlates closely with pre-operative anxiety . Formal audiovisual distraction has no added benefit over interpersonal interaction in the alleviation of pain and anxiety in patients undergoing nail surgery [27764835] Background : Patients undergoing flexible bronchoscopy usually experience anxiety before and during the procedure . Objectives : We performed this study to investigate whether verbal empathy and intentional touch from a bronchoscopist could reduce anxiety in patients undergoing flexible bronchoscopy . Methods : We conducted a prospect i ve r and omized trial in a university-affiliated hospital . Participants were r and omly assigned to one of the following groups : a control group , a verbal empathy group , or a verbal empathy and touch group . The staff pulmonologist performing bronchoscopy expressed verbal empathy and used touch by speaking to the patient ( using predefined short statements ) and making eye contact , and by laying his/her left h and on the patient 's right shoulder . We assessed the level of patient anxiety with a visual analog scale before and after the intervention . Results : Participants were 267 patients with a median age of 65 years ; 62.2 % were men . Although there were no differences in changes in anxiety between the three groups , subgroup analysis of the visual analog scale including participants with higher baseline anxiety ( empathy and touch group participants with anxiety ≥60 mm ; empathy group and empathy and touch group participants with anxiety ≥70 mm ) showed a larger reduction in anxiety than the control group . Conclusions : Verbal empathy and touch given by a bronchoscopist before bronchoscopy reduced anxiety in patients with high baseline anxiety levels [23341418] CONTEXT Despite major advances in cancer treatment , many patients undergo painful procedures during treatment and suffer debilitating side effects as well as report a decrease in quality of life ( QOL ) . This problem is exacerbated for low-income , racial , and ethnic minorities with cancer . Minority cancer patients often enter care with larger tumors and with a more aggressive disease , increasing the risk of debilitating symptoms , such as pain and anxiety . Research ers have never assessed the feasibility and effectiveness of offering massage therapy for low-income , underserved cancer patients who are undergoing port insertion . OBJECTIVE This study examined the feasibility of conducting a r and omized , controlled trial ( RCT ) that would assess the use of massage therapy to reduce pain and anxiety in urban patients with cancer who undergo surgical placement of a vascular access device ( port ) . The study also assessed the effectiveness of the intervention in reducing perioperative pain and anxiety . DESIGN The research team conducted a 9-month RC T of 60 cancer patients undergoing port placement . The research team r and omly assigned patients in a 2:1 ratio to usual care with massage therapy ( intervention group ) versus usual care with structured attention ( control group ) . SETTING The study took place at Boston Medical Center ( BMC ) , which is an urban , tertiary-referral , safety-net hospital . PARTICIPANTS Participants were cancer patients undergoing port placement . Sixty-seven percent were racial or ethnic minorities , and the majority were female and unemployed , with annual household incomes < $ 30 000 and publicly funded health insurance coverage . INTERVENTION For the intervention , an expert panel developed a reproducible , st and ardized massage therapy intended for individuals undergoing surgical port insertion . Both groups received 20-minute interventions immediately pre- and postsurgery . The research team collected data on pain and anxiety before and after the preoperative and postoperative interventions as well as 1 day after the surgery . OUTCOME MEASURES With respect to feasibility , the study examined ( 1 ) data about recruitment -- time to complete enrollment and proportion of racial and ethnic minorities enrolled ; ( 2 ) participants ' retention ; and ( 3 ) adherence to treatment allocation . The efficacy outcomes included measuring ( 1 ) participants ' average pain level using an 11-point numerical rating scale ( 0 = no pain to 10 = worst possible pain ) and ( 2 ) participants ' situational anxiety using the State-Trait Anxiety Inventory ( STAI ) . RESULTS The research team assigned the 60 patients to the groups over 53 weeks . Sixty-seven percent of the participants were racial or ethnic minorities . A majority were female and unemployed , with annual household incomes < $ 30 000 and publicly funded health insurance coverage . Of the 40 patients allocated to massage therapy , the majority ( n = 33 ) received both the pre- and postoperative interventions . Massage therapy participants had a statistically significant , greater reduction in anxiety after the first intervention compared with individuals receiving structured attention ( -10.27 vs -5.21 , P = .0037 ) . CONCLUSIONS Recruitment of low-income , minority patients into an RCT of massage therapy for perioperative pain and anxiety is feasible . Both massage therapy and structured attention proved beneficial for alleviating preoperative anxiety in cancer patients undergoing port placement [6745384] Abstract Introduction Distress related to wearing an immobilisation mask for radiotherapy treatment ( RT ) is a common experience for the person undergoing RT for head and neck cancer ( HNC ) . Described as ‘ mask anxiety ’ , there is little known about the patterns of this distress through the course of the treatment or what strategies are being used by people to help alleviate mask anxiety . Methods The study used a prospect i ve cohort design to examine the patterns of patient – reported mask anxiety during the course of RT , using a modified Distress Thermometer ( DT ) and a survey to explore strategies patients used to assist their mask anxiety . Results Thirty‐five participants , who identified as experiencing mask anxiety , were followed throughout RT treatment . At baseline , females were more likely to experience higher mask anxiety ( P = 0.03 ) . Across the course of treatment , mask anxiety significantly ( P < 0.001 ) reduced within the total cohort . In 72 % of participants , the level of initial distress was found to reduce over time . Only 22 % experienced mask anxiety that remained constant . Few ( 6 % ) experienced an increase in mask anxiety across the course of RT . Participants reported relying on intervention from health professionals , self – taught strategies , music , visualisation and medication to manage their mask anxiety . Conclusions Due to its high prevalence and variable patterns over time , it is recommended that routine screening for mask anxiety be implemented as st and ard care throughout the course of RT for HNC . Multiple , diverse strategies are being used by patients and studies are needed to develop effective interventions for managing mask anxiety [22571244] Pain and anxiety are closely associated with bone marrow aspirates and biopsies . To determine whether hypnosis administered concurrently with the procedure can ameliorate these morbidities , the authors r and omly assigned 80 cancer patients undergoing bone marrow aspirates and biopsies to either hypnosis or st and ard of care . The hypnosis intervention reduced the anxiety associated with procedure , but the difference in pain scores between the two groups was not statistically significant . The authors conclude that brief hypnosis concurrently administered reduces patient anxiety during bone marrow aspirates and biopsies but may not adequately control pain . The authors explain this latter finding as indicating that the sensory component of a patient 's pain experience may be of lesser importance than the affective component . The authors describe future studies to clarify their results and address the limitations of this study [20510947] Bone marrow biopsy and aspiration are commonly used for diagnosing , treating , and following up after treatment for blood disorders and solid tumors . For adults , the infiltration of local anesthesia at the biopsy site has been used as the principal form of analgesia for bone marrow biopsy and aspiration . Pain relief during these procedures is often incomplete , especially during aspiration of the bone marrow , and pain is likely to contribute to patient anxiety . Research ers at the Tabriz Hematology and Oncology Center in Iran conducted a study to quantify and evaluate the effectiveness of music therapy interventions on pain and anxiety control for 100 patients undergoing bone marrow biopsy and aspiration . Participants in the study were r and omly assigned to one of two groups : one group listened to music during the procedure , and the other did not . Patients completed the Spielberger State-Trait Anxiety Inventory both before and after the procedure and reported pain severity by using a visual analog scale . Results showed that participants who listened to music had lower state anxiety and pain levels than those who did not listen to music [25636013] The aim of this study was to test the effects of visual and audiovisual distraction on pain , anxiety , and procedure tolerance among patients undergoing colonoscopy . A prospect i ve , r and omized , controlled design was used with 180 consecutive patients who underwent colonoscopy . Subjects were r and omly allocated into 3 groups : Group A received visual distraction , Group B received audiovisual distraction , Group C with routine care . Outcome variables included pain , anxiety , and willingness to undergo colonoscopy again if the procedure was to be repeated . No significant difference was found on the pain scores of the 3 groups . However , when groups A and B were further divided into groups A1 , A2 , A3 ( low- , middle- , high-involvement groups ) , and B1 , B2 , B3 ( low- , middle- , high-involvement groups ) according to the level of distraction involvement , significant differences in pain scores were found between 7 groups ( A1 and A3 , A2 and A3 , A1 and B3 , A2 and B3 , A3 and C , B1 and B3 , B3 and C ) . The pain score of Group A3 was significantly lower than those of groups A1 , A2 , and C , and the pain score of Group B3 was significantly lower than those of groups B1 and C. The reduction of anxiety levels after procedure was insignificant between the 2 intervention groups and control group . The rates of willingness to undergo colonoscopy again if the procedure was to be repeated of the 2 intervention groups were significantly higher than that of the control group . Visual and audiovisual distraction is effective in promoting pain control for patients undergoing colonoscopy and improving their tolerance of the procedure [23962572] STUDY OBJECTIVE To investigate the effects of music on anxiety and perception of pain during office hysteroscopy . DESIGN Prospect i ve r and omized trial ( Canadian Task Force classification I ) . SETTING Major university medical center . INTERVENTIONS Three hundred fifty-six patients were enrolled between July 2012 and January 2013 . Hysteroscopy was performed in a dedicated ambulatory room , using vaginoscopy and without any type of anesthesia . A Bettocchi hysteroscope 5 mm in diameter was used . All procedures were performed by the same surgeon , a gynecologist with special interest in hysteroscopy . MEASUREMENTS AND MAIN RESULTS Data collected included age , body mass index , number of vaginal deliveries , educational achievement level , and history of endometrial surgery ( curettage and /or hysteroscopy ) . For each patient , vital parameters such as blood pressure , heart rate , and respiratory rate were recorded 15 minutes before the procedure and during hysteroscopy after traversing the cervix . Wait time before surgery and the duration of the procedure were also recorded . A completed Italian version of the state anxiety question naire ( State-Trait Anxiety Inventory ) and a visual analog scale ( VAS ) were administered to each patient before and after the procedure . The t test and Mann-Whitney U test was used when appropriate to compare the 2 groups . Statistical significance was accepted at p = .05 . During surgery , systolic blood pressure and heart rate were significantly lower in the music group compared with the no music group . Women in the music group experienced significantly lower anxiety after hysteroscopy and less pain during the procedure , and a significant decrease in both anxiety and pain scores after hysteroscopy . Postoperative State-Trait Anxiety Inventory form Y1 and VAS scores were significantly lower in the music group . CONCLUSION Music can be useful as a complementary method to control anxiety and reduce perception of pain . The patient is more relaxed and experiences less discomfort [27897034] OBJECTIVE This study examines the effects of listening to meditative music on state anxiety and heart rate variability ( HRV ) of patients during the uptake phase before positron emission tomography ( PET ) scans . METHODS A two-group r and omized experimental design was used . Eligible patients were r and omly assigned to either the experimental or control group . All patients received baseline assessment s of state anxiety using Spielberger State-Trait Anxiety Inventory ( STAI-S ) and HRV before receiving an intravenous injection of radiopharmaceutical fluorine-18 fludeoxyglucose in the uptake room . The experimental group ( n = 35 ) listened individually to 30 min of meditative music , integrating Chinese " Chi " and western frequency resonation in the uptake room . The control group ( n = 37 ) lay on bed quietly for 40 min in the uptake room without music . All patients were assessed for their anxiety level and HRV again , before receiving PET scanning as post-test . RESULTS The results indicated that patients in the experimental group showed a significant reduction in state anxiety and heart rate , and increase on high frequency norm of HRV ( p < 0.001 ) . There was a statistically significant reduction on anxiety level ( p < 0.001 ) , heart rate ( p < 0.001 ) and high frequency norm ( p = 0.001 ) in the experimental group compared with those of the control group . CONCLUSION Listening to meditative music as a non-invasive and cost-effective strategy can help maximize efforts to promote comfort and relaxation for patients awaiting stressful procedures , such as PET scans . Meditative music can be effective in alleviating state anxiety of patients during the uptake phase before PET scans . Advances in knowledge : The study provides scientific evidence of the effects of listening to meditative music for reducing state anxiety in patients during the uptake phase before PET scans . It may have the potential to lower the risk of unwanted false-positive fluorine-18 fludeoxyglucose uptake in normal organs and to further improve image quality and image interpretation . Listening to meditative music is a safe and inexpensive intervention which can be incorporated into routine procedures to reduce anxiety of patients undergoing PET scans [25739317] PURPOSE To compare mean heart and left anterior descending coronary artery ( LAD ) doses ( NTDmean ) and positional reproducibility in larger-breasted women receiving left breast radiotherapy using supine voluntary deep-inspiratory breath-hold ( VBH ) and free-breathing prone techniques . MATERIAL S AND METHODS Following surgery for early breast cancer , patients with estimated breast volumes > 750 cm(3 ) underwent planning-CT scans in supine VBH and free-breathing prone positions . Radiotherapy treatment plans were prepared , and mean heart and LAD doses were calculated . Patients were r and omised to receive one technique for fractions 1 - 7 , before switching techniques for fractions 8 - 15 ( 40 Gy/15 fractions total ) . Daily electronic portal imaging and alternate-day cone-beam CT ( CBCT ) imaging were performed . The primary endpoint was the difference in mean LAD NTDmean between techniques . Population systematic ( Σ ) and r and om errors ( σ ) were estimated . Within-patient comparisons between techniques used Wilcoxon signed-rank tests . RESULTS 34 patients were recruited , with complete dosimetric data available for 28 . Mean heart and LAD NTDmean doses for VBH and prone treatments respectively were 0.4 and 0.7 ( p<0.001 ) and 2.9 and 7.8 ( p<0.001 ) . Clip-based CBCT errors for VBH and prone respectively were ⩽3.0 mm and ⩽6.5 mm ( Σ ) and ⩽3.5 mm and ⩽5.4 mm ( σ ) . CONCLUSIONS In larger-breasted women , supine VBH provided superior cardiac sparing and reproducibility than a free-breathing prone position

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### Context: [12719743] PURPOSE / OBJECTIVES To test the hypotheses that the effects of a music intervention are greater than those of simple distraction and that either intervention is better at controlling procedural pain and anxiety than treatment as usual . DESIGN R and omized , controlled experiment . SETTING A midwestern comprehensive cancer center . SAMPLE 60 people with cancer having noxious medical procedures such as tissue biopsy or port placement or removal ; 58 provided usable data . METHODS Participants completed measures of pain and anxiety before and after their medical procedures and provided a rating of perceived control over pain and anxiety after the procedure . MAIN RESEARCH VARIABLES Procedural pain , state anxiety , and perceived control over pain and anxiety . FINDINGS Contrary to hypotheses , outcomes achieved with music did not differ from those achieved with simple distraction . Moreover , outcomes achieved under treatment as usual were not significantly different from those obtained with music or distraction interventions . Some patients found that the interventions were bothersome and reported that they wanted to attend to the activities of the surgeon and the medical procedure itself . CONCLUSIONS The effects of music , distraction , and treatment as usual are equivocal . In addition , patients have individual preferences for use of distraction during painful or anxiety-provoking procedures . IMPLICATION S FOR NURSING Patients having noxious medical procedures should be asked about their desire to be distracted before and during the procedure and offered a strategy that is consistent with their preferences [23364361] Colonoscopy is a procedure often experienced as uncomfortable and worrying . Music has been reported to reduce discomfort during colonoscopy ; however , no study in a Swedish setting has been found . The purpose of this r and omized controlled trial was to analyze the effects of sedative music on patients ' experience of anxiety , pain , relaxation , and well-being during colonoscopy . Prior to colonoscopy , adult patients ( n = 120 ) , aged 18–80 years , were r and omly assigned to either an intervention group ( n = 60 ) who listened to sedative instrumental music with 60–80 beats per minute during the colonoscopy or a control group . After the colonoscopy , both groups completed a question naire on anxiety , the State Trait Anxiety Inventory , and an anxiety Visual Analogue Scale . Pain , relaxation , and well-being were also measured with Visual Analogue Scales . Women in the intervention group had a lower level of anxiety during the colonoscopy than those in the control group ( p = .007 ) and well-being was significantly higher in the intervention group , especially among men , than in the controls ( p = .006 and p = .025 , respectively ) . Men in the intervention group were more relaxed during the colonoscopy than those in the control group ( p = .065 ) . Listening to sedative music decreased anxiety among women and increased well-being among men during colonoscopy [4019638] Objectives To test the inter-rater reliability of the RoB tool applied to Physical Therapy ( PT ) trials by comparing ratings from Cochrane review authors with those of blinded external review ers . Methods R and omized controlled trials ( RCTs ) in PT were identified by search ing the Cochrane Data base of Systematic Review s for meta- analysis of PT interventions . RoB assessment s were conducted independently by 2 review ers blinded to the RoB ratings reported in the Cochrane review s. Data on RoB assessment s from Cochrane review s and other characteristics of review s and trials were extracted . Consensus assessment s between the two review ers were then compared with the RoB ratings from the Cochrane review s. Agreement between Cochrane and blinded external review ers was assessed using weighted kappa ( κ ) . Results In total , 109 trials included in 17 Cochrane review s were assessed . Inter-rater reliability on the overall RoB assessment between Cochrane review authors and blinded external review ers was poor ( κ = 0.02 , 95%CI : −0.06 , 0.06 ] ) . Inter-rater reliability on individual domains of the RoB tool was poor ( median κ = 0.19 ) , ranging from κ = −0.04 ( “ Other bias ” ) to κ = 0.62 ( “ Sequence generation ” ) . There was also no agreement ( κ = −0.29 , 95%CI : −0.81 , 0.35 ] ) in the overall RoB assessment at the meta- analysis level . Conclusions Risk of bias assessment s of RCTs using the RoB tool are not consistent across different research groups . Poor agreement was not only demonstrated at the trial level but also at the meta- analysis level . Results have implication s for decision making since different recommendations can be reached depending on the group analyzing the evidence . Improved guidelines to consistently apply the RoB tool and revisions to the tool for different health areas are needed [26817929] Abstract Objectives To evaluate the heart rate lowering effect of relaxation music in patients undergoing coronary CT angiography ( CCTA ) , pulmonary vein CT ( PVCT ) and coronary calcium score CT ( CCS ) . Methods Patients were r and omised to a control group ( i.e. st and ard of care protocol ) or to a relaxation music group ( ie . st and ard of care protocol with music ) . The groups were compared for heart rate , radiation dose , image quality and dose of IV metoprolol . Both groups completed State-Trait Anxiety Inventory anxiety question naires to assess patient experience . Results One hundred and ninety-seven patients were recruited ( 61.9 % males ) ; mean age 56y ( 19 - 86 y ) ; 127 CCTA , 17 PVCT , 53 CCS . No significant difference in heart rate , radiation dose , image quality , metoprolol dose and anxiety scores . 86 % of patients enjoyed the music . 90 % of patients in the music group expressed a strong preference to have music for future examinations . The patient cohort demonstrated low anxiety levels prior to CT . Conclusion Relaxation music in CCTA , PVCT and CCS does not reduce heart rate or IV metoprolol use . Patients showed low levels of anxiety indicating that anxiolytics may not have a significant role in lowering heart rate . Music can be used in cardiac CT to improve patient experience . Key Points• Relaxation music does not reduce heart rate in cardiac CT • Relaxation music does not reduce beta-blocker use in cardiac CT • Relaxation music has no effect on cardiac CT image quality • Low levels of anxiety are present in patients prior to cardiac CT • Patients enjoyed the relaxation music and this results in improved patient [24021347] BACKGROUND AND PURPOSE Optimizing communication between radiotherapy team members and patients and between colleagues requires training . This study applies a r and omized controlled design to assess the efficacy of a 38-h communication skills training program . MATERIAL AND METHODS Four radiotherapy teams were r and omly assigned either to a training program or to a waiting list . Team members ' communication skills and their self-efficacy to communicate in the context of an encounter with a simulated patient were the primary endpoints . These encounters were scheduled at the baseline and after training for the training group , and at the baseline and four months later for the waiting list group . Encounters were audiotaped and transcribed . Transcripts were analyzed with content analysis software ( LaComm ) and by an independent rater . RESULTS Eighty team members were included in the study . Compared to untrained team members , trained team members used more turns of speech with content oriented toward available re sources in the team ( relative rate [RR]=1.38 ; p=0.023 ) , more assessment utterances ( RR=1.69 ; p<0.001 ) , more empathy ( RR=4.05 ; p=0.037 ) , more negotiation ( RR=2.34 ; p=0.021 ) and more emotional words ( RR=1.32 ; p=0.030 ) , and their self-efficacy to communicate increased ( p=0.024 and p=0.008 , respectively ) . CONCLUSIONS The training program was effective in improving team members ' communication skills and their self-efficacy to communicate in the context of an encounter with a simulated patient . Future study should assess the effect of this training program on communication with actual patients and their satisfaction . Moreover a cost-benefit analysis is needed , before implementing such an intensive training program on a broader scale [19226611] Breast cancer radiotherapy can be an emotionally difficult experience . Despite this , few studies have examined the effectiveness of psychological interventions to reduce negative affect , and none to date have explicitly examined interventions to improve positive affect among breast cancer radiotherapy patients . The present study examined the effectiveness of a multimodal psychotherapeutic approach , combining cognitive-behavioral therapy and hypnosis ( CBTH ) , to reduce negative affect and increase positive affect in 40 women undergoing breast cancer radiotherapy . Participants were r and omly assigned to receive either CBTH or st and ard care . Participants completed weekly self-report measures of positive and negative affect . Repeated and univariate analyses of variance revealed that the CBTH approach reduced levels of negative affect [ F(1 , 38)=13.49 ; p=.0007 , omega(2)=.56 ] , and increased levels of positive affect [ F(1 , 38)=9.67 ; p=.0035 , omega(2)=.48 ] , during the course of radiotherapy . Additionally , relative to the control group , the CBTH group demonstrated significantly more intense positive affect [ F(1 , 38)=7.09 ; p=.0113 , d=.71 ] and significantly less intense negative affect [ F(1 , 38)=10.30 ; p=.0027 , d=.90 ] during radiotherapy . The CBTH group also had a significantly higher frequency of days where positive affect was greater than negative affect ( 85 % of days assessed for the CBTH group versus 43 % of the Control group ) [ F(1 , 38)=18.16 ; p=.0001 , d=1.16 ] . Therefore , the CBTH intervention has the potential to improve the affective experience of women undergoing breast cancer radiotherapy [28570305] The objective of this study was to evaluate the effect of immersive virtual reality ( IVR ) distraction therapy during painful wound care procedures in adults on the amount of opioid medications required to manage pain . A convenience sample of consenting , adult in patients requiring recurrent painful wound care procedures was studied . Using a within-subject , r and omized controlled trial study design , 2 sequential wound procedures were compared , 1 with IVR distraction therapy and 1 without IVR . Total opioid medications administered before and during the wound procedures were recorded and pain and anxiety were rated before and after the 2 wound procedures . The IVR intervention included the wearing of virtual reality goggles and participation in an immersive , computer generated , interactive , 3-dimensional virtual world program . Data were analyzed with Student 's t test and chi-square analysis , with P < 0.05 considered significant . A total of 18 patients were studied , with 12 completing both study wound procedures and 6 completing a single wound procedure . The amount of opioid administered before each of the 2 wound procedures was similar with and without IVR . Total opioid administration during the dressing procedures with IVR was significantly less than when no IVR was used , 17.9 ± 6.0 and 29.2 ± 4.5 mcg/kg fentanyl , respectively ( t = -2.7 ; df = 14 ; P = 0.02 ) . Two of 15 patients ( 11 % ) requested more than 1 opioid rescue dose with IVR and 9 of 15 patients ( 60 % ) requested more than 1 rescue dose without IVR . Seventy-five percentage of participants stated that they would want to use IVR with future dressing changes . Pain and anxiety scores were similar for the wound procedures with and without IVR ( P > 0.05 ) . IVR significantly reduced the amount of opioid medication administered during painful wound care procedures when IVR was used compared with no IVR . Since pain scores were similar before and after the wound procedures with IVR and without IVR , the 39 % reduction in opioid medication during IVR supports its use as a pain distraction therapy during painful procedures [29149455] AIMS AND OBJECTIVES To evaluate the effect of video information given before cardiovascular magnetic resonance imaging on patient anxiety and to compare patient experiences of cardiovascular magnetic resonance imaging versus myocardial perfusion scintigraphy . To evaluate whether additional information has an impact on motion artefacts . BACKGROUND Cardiovascular magnetic resonance imaging and myocardial perfusion scintigraphy are technically advanced methods for the evaluation of heart diseases . Although cardiovascular magnetic resonance imaging is considered to be painless , patients may experience anxiety due to the closed environment . DESIGN A prospect i ve r and omised intervention study , not registered . METHODS The sample ( n = 148 ) consisted of 97 patients referred for cardiovascular magnetic resonance imaging , r and omised to receive either video information in addition to st and ard text-information ( CMR-video/n = 49 ) or st and ard text-information alone ( CMR-st and ard/n = 48 ) . A third group undergoing myocardial perfusion scintigraphy ( n = 51 ) was compared with the cardiovascular magnetic resonance imaging-st and ard group . Anxiety was evaluated before , immediately after the procedure and 1 week later . Five question naires were used : Cardiac Anxiety Question naire , State-Trait Anxiety Inventory , Hospital Anxiety and Depression scale , MRI Fear Survey Schedule and the MRI-Anxiety Question naire . Motion artefacts were evaluated by three observers , blinded to the information given . Data were collected between April 2015-April 2016 . The study followed the CONSORT guidelines . RESULT The CMR-video group scored lower ( better ) than the cardiovascular magnetic resonance imaging-st and ard group in the factor Relaxation ( p = .039 ) but not in the factor Anxiety . Anxiety levels were lower during scintigraphic examinations compared to the CMR-st and ard group ( p < .001 ) . No difference was found regarding motion artefacts between CMR-video and CMR-st and ard . CONCLUSION Patient ability to relax during cardiovascular magnetic resonance imaging increased by adding video information prior the exam , which is important in relation to perceived quality in nursing . No effect was seen on motion artefacts . RELEVANCE TO CLINICAL PRACTICE Video information prior to examinations can be an easy and time effective method to help patients cooperate in imaging procedures [28917370] BACKGROUND AND AIMS Colonoscopy can be painful and uncomfortable . Aromatherapy is often used for the relief of anxiety or discomfort . Recently , it has been reported that olfactory stimulation induces various physiological effects . We investigated the effects of aromatherapy on anxiety and abdominal discomfort during colonoscopy . METHODS The investigation was carried out using a r and omized controlled study . Aromatherapy was performed by vapor diffusion , and each patient was given one of the following treatments : no inhalation ( control group ) , essential-oil-less vapor ( vehicle group ) , lavender oil ( lavender group ) , grapefruit oil ( grapefruit group ) , or Osmanthus fragrans oil ( Osmanthus fragrans group ) . Following total colonoscopy procedures , each patient estimated their anxiety and abdominal discomfort using the Numeric Rating Scale . RESULTS Total colonoscopy was performed on 361 patients . No complications caused by colonoscopy or aromatherapy were experienced . In the Osmanthus fragrans group , anxiety was significantly attenuated . The abdominal discomfort of patients who reported strong anxiety during colonoscopy was significantly attenuated in the grapefruit group and the Osmanthus fragrans group . CONCLUSION Aromatherapies using Osmanthus fragrans oil and grapefruit oil are effective complementary treatments for anxious patients undergoing colonoscopy [24372795] AIMS AND OBJECTIVES To evaluate the effectiveness of an accessibility-enhanced multimedia informational educational programme in reducing anxiety and increasing satisfaction with the information and material s received by patients undergoing cardiac catheterisation . BACKGROUND Cardiac catheterisation is one of the most anxiety-provoking invasive procedures for patients . However , informational education using multimedia to inform patients undergoing cardiac catheterisation has not been extensively explored . DESIGN A r and omised experimental design with three-cohort prospect i ve comparisons . METHODS In total , 123 consecutive patients were r and omly assigned to one of three groups : regular education ; ( group 1 ) , accessibility-enhanced multimedia informational education ( group 2 ) and instructional digital videodisc education ( group 3 ) . Anxiety was measured with Spielberger 's State Anxiety Inventory , which was administered at four time intervals : before education ( T0 ) , immediately after education ( T1 ) , before cardiac catheterisation ( T2 ) and one day after cardiac catheterisation ( T3 ) . A satisfaction question naire was administrated one day after cardiac catheterisation . Data were collected from May 2009-September 2010 and analysed using descriptive statistics , chi-squared tests , one-way analysis of variance , Scheffe 's post hoc test and generalised estimating equations . RESULTS All patients experienced moderate anxiety at T0 to low anxiety at T3 . Accessibility-enhanced multimedia informational education patients had significantly lower anxiety levels and felt the most satisfied with the information and material s received compared with patients in groups 1 and 3 . A statistically significant difference in anxiety levels was only found at T2 among the three groups ( p = 0·004 ) . CONCLUSIONS The findings demonstrate that the accessibility-enhanced multimedia informational education was the most effective informational educational module for informing patients about their upcoming cardiac catheterisation , to reduce anxiety and improve satisfaction with the information and material s received compared with the regular education and instructional digital videodisc education . RELEVANCE TO CLINICAL PRACTICE As the accessibility-enhanced multimedia informational education reduced patient anxiety and improved satisfaction with the information and material s received , it can be adapted to complement patient education in future regular cardiac care [25641687] BACKGROUND High levels of anxiety during surgery are associated with poorer post-surgical outcomes . This prospect i ve , non-blinded r and omized controlled trial aim ed to compare the effectiveness of four intraoperative distraction interventions for anxiety and pain management during minimally invasive venous surgery under local anaesthetic . METHODS 407 patients presenting with varicose veins at a private clinic , were r and omized to one of four intraoperative distraction interventions or treatment as usual . All participants received endovenous thermoablation and /or phlebectomies of varicose veins . After losses to follow-up , 398 participants were entered into the analysis . Participants were r and omly allocated to one of the following intraoperative distraction techniques : patient selected music ( n = 85 ) , patient selected DVD ( n = 85 ) , interaction with nurses ( n = 81 ) , touch ( stress balls ) ( n = 80 ) or treatment as usual ( TAU , n = 76 ) . The state scale of the STAI , the Short-form McGill pain question naire and numeric rating scales were used to assess intraoperative pain and anxiety . RESULTS Intraoperative anxiety ratings were significantly lower when participants interacted with nurses , used stress balls or watched a DVD during surgery compared to treatment as usual . Intraoperative pain ratings were significantly lower than treatment as usual when participants interacted with nurses or used stress balls during surgery . Patients ' satisfaction was not significantly impacted by intraoperative distractions . CONCLUSIONS The use of simple intraoperative distraction techniques , particularly interacting with nurses , using stress balls or watching a DVD during surgery conducted under local anaesthetic can significantly improve patients ' experiences [23860442] BACKGROUND Anxiety is a relevant but still underscored perioperative problem . The Visual Analogue Scale for Anxiety ( VAS-A ) seems to be effective , fast and manageable , but has not been fully vali date d yet . The aim of this study is to vali date VAS-A comparing it to , Corah 's Dental Anxiety Scale ( CDAS ) Spielberger 's State Trait Anxiety Inventory ( STAI ) and Beck Depression Inventory ( BDI ) . METHODS One hundred consecutive patients ( 38 males and 62 females , median age 49 years ) su bmi tted to oral surgery filled out the VAS-A , CDAS , STAI forms Y1 and Y2 , and BDI at preoperative examination ; the order of administration of tests was r and omized . RESULTS VAS-A score was significantly correlated to CDAS ( P<0.0001 ) , STAI-Y1 ( P<0.0001 ) , STAI-Y2 ( P<0.002 ) but not to BDI ( P=0.18 ) . ROC curve analysis suggested VAS-A equal to 46 mm as threshold for anxiety when using STAI Y1 equal to 40 as reference cutoff . CONCLUSION Our study confirms that VAS-A is a reliable indicator of preoperative anxiety and may detect patients with depressive symptoms also . Values of VAS-A around 50 mm are a reliable threshold for a clinical ly meaningful level of preoperative anxiety [25102532] OBJECTIVE Assessment of virtual reality ( VR ) distraction for alleviating pain and anxiety during flexible cystoscopy . Cystoscopy is a common ambulatory procedure performed in Urology and can be associated with moderate pain and anxiety . Sophisticated distraction techniques are not used with cystoscopy and VR has not been studied for this procedure . We design ed a prospect i ve , r and omized , controlled trial assessing the efficacy of VR for alleviating pain and anxiety during flexible cystoscopy . METHODS Adult men referred for cystoscopy were r and omized into a control or VR group . Subjects were given preprocedure and postprocedure question naires addressing anxiety , pain , and time spent thinking about pain . Vitals signs and galvanic skin monitors were used as objective measures . The control group underwent routine cystoscopy and the VR group underwent cystoscopy with VR . Physicians answered a postprocedure question naire assessing the difficulty of the exam . All question naires used a visual analog score for assessment . RESULTS 23 patients enrolled in the control group and 22 in the VR group . Mean scores and Student 's t-test were employed to analyze the data . No data endpoints showed a statistically significant difference between the 2 groups . CONCLUSIONS We concluded no benefit to VR distraction mitigating pain in male patients during cystoscopy [4015863] Background Thresholds for statistical significance are insufficiently demonstrated by 95 % confidence intervals or P-values when assessing results from r and omised clinical trials . First , a P-value only shows the probability of getting a result assuming that the null hypothesis is true and does not reflect the probability of getting a result assuming an alternative hypothesis to the null hypothesis is true . Second , a confidence interval or a P-value showing significance may be caused by multiplicity . Third , statistical significance does not necessarily result in clinical significance . Therefore , assessment of intervention effects in r and omised clinical trials deserves more rigour in order to become more valid . Methods Several method ologies for assessing the statistical and clinical significance of intervention effects in r and omised clinical trials were considered . Balancing simplicity and comprehensiveness , a simple five-step procedure was developed . Results For a more valid assessment of results from a r and omised clinical trial we propose the following five-steps : ( 1 ) report the confidence intervals and the exact P-values ; ( 2 ) report Bayes factor for the primary outcome , being the ratio of the probability that a given trial result is compatible with a ‘ null ’ effect ( corresponding to the P-value ) divided by the probability that the trial result is compatible with the intervention effect hypothesised in the sample size calculation ; ( 3 ) adjust the confidence intervals and the statistical significance threshold if the trial is stopped early or if interim analyses have been conducted ; ( 4 ) adjust the confidence intervals and the P-values for multiplicity due to number of outcome comparisons ; and ( 5 ) assess clinical significance of the trial results . Conclusions If the proposed five-step procedure is followed , this may increase the validity of assessment s of intervention effects in r and omised clinical trials [12628899] STUDY OBJECTIVES To determine whether distraction therapy with nature sights and sounds during flexible bronchoscopy ( FB ) reduces pain and anxiety . DESIGN R and omized controlled trial . SETTING Teaching hospital in Baltimore , MD . PATIENTS Consecutive adult patients ( n = 80 ) undergoing FB with conscious sedation . INTERVENTION Nature scene murals were placed at the bedside , and patients were provided a tape of nature sounds to listen to before , during , and after the procedure . Patients assigned to the control group were not offered either the nature scene or the sounds . MEASUREMENTS AND RESULTS The primary outcomes were patient ratings of pain control ( a 5-point scale ranging from poor to excellent ) and anxiety . In a multivariate ordinal logistic regression model , the odds of better pain control were greater in the intervention patients than in the control patients ( odds ratio [ OR ] , 4.76 ; 95 % confidence interval [ CI ] , 1.35 to 16.7 ) , after adjustment for age , gender , race , education , health status , and dose of narcotic medication . Older patients and patients with better health status reported significantly less pain . There was no difference in patient-reported anxiety between the two groups ( OR , 0.87 ; 95 % CI , 0.39 to 1.96 ) . CONCLUSIONS Distraction therapy with nature sights and sounds significantly reduces pain in patients undergoing FB . Although the precise mechanism of this beneficial effect requires further investigation , clinicians should consider this nonintrusive strategy in addition to st and ard analgesic medications in patients undergoing painful , invasive procedures [5547864] Background : A high level of preoperative anxiety is common among patients undergoing medical and surgical procedures . Anxiety impacts of gastroenterological procedures on psychological and physiological responses are worth consideration . Aims and Objectives : To analyze the effect of listening to Vedic chants and Indian classical instrumental music on anxiety levels and on blood pressure ( BP ) , heart rate ( HR ) , and oxygen saturation in patients undergoing upper gastrointestinal ( GI ) endoscopy . Material s and Methods : A prospect i ve , r and omized controlled trial was done on 199 patients undergoing upper GI endoscopy . On arrival , their anxiety levels were assessed using state and trait scores and various physiological parameters such as HR , BP , and SpO2 . Patients were r and omly divided into three groups : Group I of 67 patients who were made to listen prerecorded Vedic chants for 10 min , Group II consisting of 66 patients who listened to Indian classical instrumental music for 10 min , and Group III of 66 controls who remained seated for same period in the same environment . Thereafter , their anxiety state scores and physiological parameters were reassessed . Results : A significant reduction in anxiety state scores was observed in the patients in Group I ( from 40.4 ± 8.9 to 38.5 ± 10.7 ; P < 0.05 ) and Group II ( from 41.8 ± 9.9 to 38.0 ± 8.6 ; P < 0.001 ) while Group III controls showed no significant change in the anxiety scores . A significant decrease in systolic BP ( P < 0.001 ) , diastolic BP ( P < 0.05 ) , and SpO2 ( P < 0.05 was also observed in Group II . Conclusion : Listening to Vedic chants and Indian classical instrumental music has beneficial effects on alleviating anxiety levels induced by apprehension of invasive procedures and can be of therapeutic use [29705448] OBJECTIVE The purpose of this study was to determine effect of three different types of music on patients ' preoperative anxiety . METHOD This r and omized controlled trial included 180 patients who were r and omly divided into four groups . While the control group did n't listen to music , the experimental groups respectively listened to natural sounds , Classical Turkish or Western Music for 30 min . The State Anxiety Inventory ( STAI-S ) , systolic blood pressure ( SBP ) , diastolic blood pressure ( DBP ) , heart rate ( HR ) and cortisol levels were checked . FINDINGS The post-music STAI-S , SBP , DBP , HR and cortisol levels of the patients in music groups were significantly lower than pre-music time . All types of music decreased STAI-S , SBP , and cortisol levels ; additionally natural sounds reduced DBP ; Classical Turkish Music also decreased DBP , and HR . CONCLUSIONS All types of music had an effect on reducing patients ' preoperative anxiety , and listening to Classical Turkish Music was particularly the most effective one [5292140] Background Breast cancer is the most common cancer in women , and the second leading cause of cancer deaths . The detection and treatment of this cancer may create mental pressure and lower mood levels , causing anxiety , depression , stress , and pain for the patients . Objectives The aim of this study was to determine the effects of Swedish massage on mood disorders in breast cancer patients undergoing radiotherapy at the cancer institute of the Imam Khomeini hospital at the Tehran University of Medical Sciences . Patients and Methods This study consisted of a clinical trial including 100 patients with breast cancer . The participants were chosen r and omly , with their consent , by the use of polling , to be included in the intervention group ( which received a Swedish massage three times a week , for 30 minutes , over five weeks ) and control group ( which received routine care ) . At the beginning of the intervention and after 5 weeks , the mood disorders of the patients , including anger , anxiety , depression , and any positive affect , were assessed using the affective control scale ( ACS ) question naire . Results Before the intervention , there was no significant difference in the average of the overall scale between the intervention and control groups in the subscales of anger , anxiety , depression , and positive affect ( P = 0.469 ) . The average of the overall scale in the Swedish massage group decreased from 3.52 ± 0.65 to 2.42 ± 0.76 when compared to the pre-intervention conditions , and to ( P < 0.001 ) after the intervention . Moreover , the values for the control group were 3.41 ± 0.94 for the pre-intervention and 3.38 ± 0.9 after the intervention ( P = 0.620 ) . Conclusions When compared to the control group , the Swedish massage showed an improvement in the mood disorders of women with breast cancer [6030513] Machine learning ( ML ) algorithms have proven highly accurate for identifying R and omized Controlled Trials ( RCTs ) but are not used much in practice , in part because the best way to make use of the technology in a typical workflow is unclear . In this work , we evaluate ML models for RCT classification ( support vector machines , convolutional neural networks , and ensemble approaches ) . We trained and optimized support vector machine and convolutional neural network models on the titles and abstract s of the Cochrane Crowd RCT set . We evaluated the models on an external data set ( Clinical Hedges ) , allowing direct comparison with traditional data base search filters . We estimated area under receiver operating characteristics ( AUROC ) using the Clinical Hedges data set . We demonstrate that ML approaches better discriminate between RCTs and non‐ RCTs than widely used traditional data base search filters at all sensitivity levels ; our best‐performing model also achieved the best results to date for ML in this task ( AUROC 0.987 , 95 % CI , 0.984‐0.989 ) . We provide practical guidance on the role of ML in ( 1 ) systematic review s ( high‐sensitivity strategies ) and ( 2 ) rapid review s and clinical question answering ( high‐precision strategies ) together with recommended probability cutoffs for each use case . Finally , we provide open‐ source software to enable these approaches to be used in practice [29709434] OBJECTIVE To investigate the effect of ambient music on anxiety and pain in men undergoing prostate biopsies . MATERIAL S AND METHODS Between September 2015 and June 2016 , men undergoing office transrectal prostate biopsy at our institution were r and omly assigned to music ( n = 85 ) or control ( n = 97 ) groups . We examined clinical characteristics , pathologic variables , and baseline anxiety using the Trait Instrument of State-Trait Anxiety Inventory . Primary outcomes included anxiety assessed by State Instrument of STAI ( STAI-S ) and pain using a visual analog scale . RESULTS There were no significant differences in baseline characteristics between the music and control groups , including median age , prostate-specific antigen , use of magnetic resonance imaging-guided biopsies , or Trait Instrument of State-Trait Anxiety Inventory . The majority ( 93 % ) of patients indicated they desired music in their prebiopsy survey . There were no significant differences in STAI-S ( 33.7 ± 8.9 vs 34.4 ± 9.9 , P = .6 ) , pain score ( 2.3 ± 2.1 vs 2.0 ± 2.1 , P = .3 ) , or vital signs between the music and control groups , respectively . There were also no differences in STAI-S , visual analog scale , or vital signs between groups when stratified by age , prostate-specific antigen , or number of previous biopsies . Men who received music were more likely to request music for future prostate biopsy , compared to men who did not ( 93 % vs 83 % , P = .07 , respectively ) . CONCLUSION This r and omized study showed no difference in anxiety or pain scores for patients who had ambient music during transrectal prostate biopsy . Future studies are needed to discern the influence of details including method of music delivery , music type , and utilization of adjunct relaxation tools [23953858] OBJECTIVE The purpose of this study was to investigate the music therapy ( MT ) effect in levels of intraoperative anxiety in patients undergoing crossectomy with stripping of the great saphenous vein and to assess the efficacy , safety , and feasibility of this alternative therapy as a complement of st and ard intraoperative care . MATERIAL AND METHODS The study is a simple blind , controlled , parallel groups , prospect i ve r and omized clinical trial . Patients were allocated by means of r and omized controlled sampling . The study was performed in the surgery room of Getafe University Hospital in Madrid . The study was carried out in 40 patients , 20 r and omized to the experimental group and 20 r and omized to the control group , with an age range from 27 to 70 years . The control group was given intraoperative routine attention , and the experimental group was given an MT passive intervention that consisted of audition of musical fragments during varicose veins surgery . These pieces previously showed relaxing actions on the cardiovascular system . The anxiety levels were measured by means of pre- and postsurgical question naires by a blinded investigator for the study arm to which the patients had been r and omized . Heart rate and systolic and diastolic blood pressures were determined during the intervention , and adrenaline and noradrenaline plasma levels were determined before and after the surgical procedure . RESULTS The majority of the patients in the MT group ( 95 % ) and st and ard care group ( 90 % ) completed the study . There were no statistical differences between the control and experimental groups in heart rate gradient or systolic and diastolic blood pressures measured after the intervention . The anxiety state and the stress feeling scale score after surgery were significantly inferior in the MT group ( 94.7 % vs 57.9 % decrease in anxiety levels , P < .05 , and stress score of 1.31 vs 2.36 , P < .05 , respectively ) . The adverse events ratio was low and occurred with similar frequency in both groups . CONCLUSIONS The MT intervention was easily implemented in the context of nursing care received during varicose vein surgery and was positively accepted and valued by the majority of the patients . MT is a safe procedure that is proved to reduce anxiety and stress in the study patients [9921569] PURPOSE / OBJECTIVES To measure the effectiveness of customized guided imagery for increasing comfort in women with early stage breast cancer . DESIGN Experimental longitudinal , r and om assignment to groups . SETTING Two urban radiation oncology departments . SAMPLE 53 women ( 26 in the experimental group , 27 in the control group ) aged 37 - 81 ; 80 % European and 10 % African American with stage I or II breast cancer about to begin radiation therapy . METHODS The experimental group was to listen to a guided imagery audiotape once a day for the duration of the study . The Radiation Therapy Comfort Question naire was self-administered at three time points : prior to the introduction of intervention and the beginning of radiation therapy ( Time 1 ) , three weeks later ( Time 2 ) , and three weeks after completing radiation therapy ( Time 3 ) . The State Anxiety Inventory was administered at Time 1 only . MAIN RESEARCH VARIABLES The effect of use of guided imagery on comfort with anxiety as a control variable . FINDINGS Pooled data indicated a significant overall increase in differences in comfort between the treatment and control group , with the treatment group having higher comfort over time . The data also revealed a significant linear trend in differences between groups . No significant interaction of group and time existed . CONCLUSIONS Guided imagery is an effective intervention for enhancing comfort of women undergoing radiation therapy for early stage breast cancer . The intervention was especially salient in the first three weeks of therapy . IMPLICATION S FOR NURSING PRACTICE Guided imagery audiotapes specifically design ed for this population were re source effective in terms of cost , personnel , and time [26626861] PURPOSE To evaluate the clinical efficacy , safety , and feasibility of implementing video glasses in a variety of interventional radiologic ( IR ) procedures . MATERIAL S AND METHODS Between August 2012 and August 2013 , 83 patients undergoing outpatient IR procedures were r and omized to a control group ( n = 44 ) or an experimental group outfitted with video glasses ( n = 39 ) . State-Trait Anxiety Inventory ( STAI ) scores , sedation and analgesia doses , mean arterial pressure ( MAP ) , heart rate ( HR ) , respiratory rate ( RR ) , pain scores , and procedure times were obtained . Complications and adverse events related to the use of video glasses were recorded . Postprocedural staff surveys and patient satisfaction surveys were completed . RESULTS Women had greater preprocedural anxiety than men ( P = .0056 ) , and patients undergoing vascular interventions had greater preprocedural anxiety than those undergoing nonvascular interventions ( P = .0396 ) . When assessed after the procedure , patients who wore video glasses had significantly reduced levels of anxiety ( -7.7 vs -4.4 , respectively ; P = .0335 ) and average MAP ( -6.3 vs 2.1 , respectively ; P = .0486 ) compared with control patients . There was no significant difference in amount of sedation and analgesia , HR , RR , pain score , or procedure time between groups . No significant adverse events related to the use of video glasses were observed . Postprocedural surveys showed that video glasses were not distracting and did not interfere or pose a safety issue during procedures . Patients enjoyed using the video glasses and would use them again for a future procedure . CONCLUSIONS Video glasses can be safely implemented during IR procedures to reduce anxiety and improve a patient 's overall experience [16371522] PURPOSE To assess how patients ' underlying anxiety affects their experience of distress , use of re sources , and responsiveness toward nonpharmacologic analgesia adjunct therapies during invasive procedures . MATERIAL S AND METHODS Two hundred thirty-six patients undergoing vascular and renal interventions , who had been r and omized to receive during st and ard care treatment , structured empathic attention , or self-hypnotic relaxation , were divided into two groups : those with low state anxiety scores on the State-Trait Anxiety Inventory ( STAI , scores < 43 ; n = 116 ) and those with high state anxiety scores ( > or = 43 ; n = 120 ) . All had access to patient-controlled analgesia with fentanyl and midazolam . Every 15 minutes during the procedure , patients rated their anxiety and pain on a scale of 0 - 10 ( 0 , no pain/anxiety at all ; 10 , worst possible pain/anxiety ) . Effects were assessed by analysis of variance and repeated- measures analysis . RESULTS Patients with high state anxiety levels required significantly greater procedure time and medication . Empathic attention as well as hypnosis treatment reduced procedure time and medication use for all patients . These nonpharmacologic analgesia adjunct treatments also provided significantly better pain control than st and ard care for patients with low anxiety levels . Anxiety decreased over the time of the procedure ; patients with high state anxiety levels experienced the most significant decreases in anxiety with nonpharmacologic adjuncts whereas patients with low state anxiety levels coped relatively well under all conditions . CONCLUSION Patients ' state anxiety level is a predictor of trends in procedural pain and anxiety , need for medication , and procedure duration . Low and high state anxiety groups profit from the use of nonpharmacologic analgesia adjuncts but those with high state anxiety levels have the most to gain [21410035] BACKGROUND / AIMS Colonoscopy is generally tolerated , some patients regarding the procedure as unpleasant and painful and generally performed with the patient se date d and receiving analgesics . The effect of sedation and analgesia for colonoscopy is limited . Aromatherapy is also applied to gastrointestinal endoscopy to reduce procedural anxiety . There is lack of information about aromatherapy specific for colonoscopy . In this study , we aim ed to performed a r and omized controlled study to investigate the effect of aromatherapy on relieve anxiety , stress and physiological parameters of colonoscopy . METHODOLOGY A r and omized controlled trail was carried out and collected in 2009 and 2010 . The participants were r and omized in two groups . Aromatherapy was then carried out by inhalation of Sunflower oil ( control group ) and Neroli oil ( Experimental group ) . The anxiety index was evaluated by State Trait Anxiety Inventory-state ( STAI-S ) score before aromatherapy and after colonoscopy as well as the pain index for post-procedural by visual analogue scale ( VAS ) . Physiological indicators , such as blood pressure ( systolic and diastolic blood pressure ) , heart rate and respiratory rate were evaluated before and after aromatherapy . RESULTS Participates in this study were 27 subjects , 13 in control group and 14 in Neroli group with average age 52.26 + /- 17.79 years . There was no significance of procedural anxiety by STAI-S score and procedural pain by VAS . The physiological parameters showed a significant lower pre- and post-procedural systolic blood pressure in Neroli group than control group . CONCLUSIONS Aromatic care for colonoscopy , although with no significant effect on procedural anxiety , is an inexpensive , effective and safe pre-procedural technique that could decrease systolic blood pressure [12920428] Patients scheduled for gastrointestinal procedures such as colonoscopy or esophagogastroduodenoscopy are often anxious and frightened . High levels of anxiety may result in more difficult and painful procedures . Past research has reported education , coping skills , relaxation techniques , and combinations of these including music , have decreased anxiety in patients across many setting s. Self-selected music therapy for preprocedural anxiety has not been studied . A r and omized controlled trial of 198 patients was undertaken to determine whether 15 minutes of self-selected music reduced preprocedure anxiety . The State Trait Anxiety Inventory was used to measure patients ’ anxiety . One-hundred ninety-three men and 5 women comprised the sample with an average age of 61 ( SD 10.5 ) . Patients who listened to music ( n = 100 ) reduced their anxiety score from 36.7 ( SD 9.1 ) to 32.3 ( SD 10.4 ) , while those who did not listen to music ( n = 98 ) reduced their anxiety score from 36.1 ( SD 8.3 ) to 34.6 ( SD 11.5 ) . These differences were statistically significant ( F = 7.5 , p = .007 ) after controlling for trait anxiety . There were no significant vital sign changes premusic and postmusic . Music is a noninvasive nursing intervention that can significantly reduce patients ’ anxiety prior to gastrointestinal procedures . Further research should address using music to reduce anxiety in other procedure areas and testing effectiveness of self-selected versus investigator-selected music in reducing anxiety [10801169] BACKGROUND Non-pharmacological behavioural adjuncts have been suggested as efficient safe means in reducing discomfort and adverse effects during medical procedures . We tested this assumption for patients undergoing percutaneous vascular and renal procedures in a prospect i ve , r and omised , single-centre study . METHODS 241 patients were r and omised to receive intraoperatively st and ard care ( n=79 ) , structured attention ( n=80 ) , or self-hypnotic relaxation ( n=82 ) . All had access to patient-controlled intravenous analgesia with fentanyl and midazolam . Patients rated their pain and anxiety on 0 - 10 scales before , every 15 min during and after the procedures . FINDINGS Pain increased linearly with procedure time in the st and ard group ( slope 0.09 in pain score/15 min , p<0.0001 ) , and the attention group ( slope 0.04/15 min ; p=0.0425 ) , but remained flat in the hypnosis group . Anxiety decreased over time in all three groups with slopes of -0.04 ( st and ard ) , -0.07 ( attention ) , and -0.11 ( hypnosis ) . Drug use in the st and ard group ( 1.9 units ) was significantly higher than in the attention and hypnosis groups ( 0.8 and 0.9 units , respectively ) . One hypnosis patient became haemodynamically unstable compared with ten attention patients ( p=0.0041 ) , and 12 st and ard patients ( p=0.0009 ) . Procedure times were significantly shorter in the hypnosis group ( 61 min ) than in the st and ard group ( 78 min , p=0.0016 ) with procedure duration of the attention group in between ( 67 min ) . INTERPRETATION Structured attention and self-hypnotic relaxation proved beneficial during invasive medical procedures . Hypnosis had more pronounced effects on pain and anxiety reduction , and is superior , in that it also improves haemodynamic stability [16897144] Summary Background Intracardiac catheterization is a routine physical examination . Due to psychological strains , several psychosocial interventions , including music therapy , have been proposed . The aim of the present study was to examine whether the preventive or adjuvant use of music therapy results in a reduction in both subjective and objective anxiety and thus leads to a reduction in sedative medication . Methods of assessment N=83 patients ( 48 male , 35 female , 66±11 yrs ) waiting for scheduled cardiac catheterization were r and omly allocated to one of three groups : control group ( st and ard care ) , exposure group ( music stimulation during the procedure ) , or coaching group ( additional music therapeutic coaching ) . Target variables were subjective anxiety and physiological parameters . Results Music intervention did effectively reduce subjective anxiety ( STAI-S reduction pre-post : exposure 11 pt , coaching : 4 pt , control : 6 pt ; p=0.033 ) . Physiological values and medication did not differ between groups . Conclusion The use of music stimulation during the catheterization has a relaxing and calming effect on patients . It seems to be especially beneficial in a subgroup of patients with higher-than-average psychological strains [15693467] This research study evaluates the effectiveness of distraction interventions on subject perceptions of discomfort or pain and anxiety during the ocular anesthetic injection prior to cataract surgery . Eighty subjects received either usual care , usual care with massage , usual care with verbal coaching and slow breathing , or usual care with massage and verbal coaching and slow breathing combined as different types of distraction interventions . After the ocular anesthetic injection(s ) , the subjects rated their level of experienced discomfort or pain and anxiety on a Likert scale of 0 to 10 . The statistical analyses revealed a significant reduction of discomfort or pain and anxiety when the distraction interventions were implemented during the ocular anesthetic injections . Because the different distraction interventions are effective , inexpensive , and easy to implement , routine use during ocular anesthetic injections , prior to cataract surgery , is recommended [24183068] OBJECTIVE This paper describes a r and omized controlled single blind study testing the effects of a patient education intervention combined with positive therapeutic suggestions on anxiety for cataract surgery patients . METHODS 84 patients participated in the study . Physiological and behavioral indicators of anxiety were compared between a regularly treated control and an intervention group receiving an audio CD containing information , relaxation , and positive imagery . RESULTS We found that the intervention group was calmer throughout the four measurement points of the study ( p=.004 ; d=0.71 ) and they were more cooperative ( p=.01 ; d=0.60 ) during the operation . The groups did not differ in sleep quality before the day of the operation , heart rate during the procedure , and subjective Well-being . CONCLUSION Findings indicate that preoperative information combined with positive suggestions and anxiety management techniques might reduce patient anxiety in the perioperative period of cataract surgery , but further research is needed to investigate the benefits of such interventions and to uncover the underlying mechanisms . PRACTICE IMPLICATION S Patient education interventions providing additional anxiety management techniques are recommended for use prior to cataract surgery [26377497] Abstract Introduction Several studies evaluating the tolerance of transrectal ultrasound (TRUS)-guided needle biopsies showed that moderate-to-severe pain was associated with the procedure . Additionally , prebiopsy anxiety or rebiopsy as a result of a prior biopsy procedure is mentioned as factors predisposing to higher pain intensity . Thus , in this study , we investigated the effects of hypnotherapy during transrectal ultrasound-guided prostate needle biopsy for pain and anxiety . Material s and methods Sixty-four patients presenting for TRUS-guided prostate needle biopsy were r and omly assigned to receive either 10-min presurgery hypnosis session ( n = 32 , mean age 63.5 ± 6.1 , p = 0.289 ) or a presurgery control session ( n = 32 , mean age 61.8 ± 6.8 , p = 0.289 ) . The hypnosis session involved suggestions for increased relaxation and decreased anxiety . Presurgery pain and anxiety were measured using visual analog scales ( VAS ) , Beck Anxiety Inventory ( BAI ) , and Hamilton Anxiety Scale ( HAS ) , respectively . In our statistics , p < 0.05 was considered statistically significant . Results Postintervention , and before surgery , patients in the hypnosis group had significantly lower mean values for presurgery VAS [ mean 1 ( 0–8 ) ; p = 0.011 ] , BAI ( 6.0 vs 2.0 ; p < 0.001 ) , and HAS ( 11.0 vs 6.0 ; p < 0.001 ) . Conclusion The study results indicate that a brief presurgery hypnosis intervention can be an effective means of controlling presurgical anxiety , and therefore pain , in patients awaiting diagnostic prostate cancer surgery [16952777] Patients scheduled for vascular angiography are often anxious and frightened . High levels of anxiety may result in more difficult and painful procedures . Past research has reported mixed results for anxiety reduction techniques in other procedures setting s , such as education , cognitive-behavioral skills , coping and relaxation skills , combinations of techniques , and music . Music as an intervention for pre-procedural anxiety prior to vascular angiography has not been studied . A r and omized controlled trial of 170 patients was undertaken to determine whether 15 minutes of self-selected music reduced pre-procedure anxiety . The State Trait Anxiety Inventory was used to measure patients ' anxiety . One-hundred sixty-six men and 4 women comprised the sample with an average age of 66.8 years ( SD 9.95 , range 37 to 85 years ) . Patients who listened to music ( n=89 ) reduced their anxiety score from 38.57 ( SD 10.46 ) to 35.2 ( SD 9.7 ) , while those who did not listen to music ( n=81 ) reduced their anxiety score from 36.23 ( SD 10.54 ) to 35.1 ( SD 10.59 ) ; the difference between the groups was statistically significant ( t=1.95 , df 161 , p=0.05 ) . Pulse achieved a statistically significant reduction in the music group ( t=2.45 , df 167 , p=0.02 ) . Music is a noninvasive nursing intervention that patients enjoy and reduces their anxiety and their pulse rate . Further research should address using music to reduce anxiety in other interventional vascular angiography setting s with equal numbers of men and women and comparing self-selected versus investigator-selected music [28395396] BACKGROUND Aromatherapy has been used to reduce anxiety in a variety of setting s , but usefulness associated with breast biopsies has not been documented . AIMS This study was conducted in women undergoing image-guided breast biopsy . We explored the use of two different aromatherapy scents , compared to placebo , aim ed at reducing anxiety with the intent of generating new knowledge . METHODS This was a r and omized , placebo-controlled study of two different types of external aromatherapy tabs ( lavender-s and alwood and orange-peppermint ) compared with a matched placebo-control delivery system . Anxiety was self-reported before and after undergoing a breast biopsy using the Spielberger State Anxiety Inventory Scale . RESULTS AND FINDINGS Eighty-seven women participated in this study . There was a statistically significant reduction in self-reported anxiety with the use of the lavender-s and alwood aromatherapy tab compared with the placebo group ( p = .032 ) . Aromatherapy tabs reduced anxiety during image-guided breast biopsy . LINKING EVIDENCE TO ACTION The completion of the biopsy provided some relief from anxiety in all groups . The use of aromatherapy tabs offers an evidence -based nursing intervention to improve adaptation and reduce anxiety for women undergoing breast biopsy . Lavender-s and alwood aromatherapy reduced anxiety and promoted adaptation more than orange-peppermint aromatherapy or placebo [21095634] The purpose was to investigate if women with high pre-procedural anxiety reported higher degree of relaxation and comfort if listening to music during coronary angiographic procedures . A prospect i ve r and omized controlled trial was used included 68 patients undergoing coronary angiography and /or PCI . The women were allocated to receive calming music and st and ard care or st and ard care only . Relaxation , environmental sound and discomfort associated with lying still were assessed . There was significantly more positive impression of the sound environment and less discomfort associated with lying still in women listening to music in comparison to women who received only st and ard care . No effect in relaxation was found [15036850] BACKGROUND AND PURPOSE The optimal treatment position for patients receiving radical radiation therapy for prostate cancer has been a source of controversy . To resolve this issue , we conducted a r and omized trial to evaluate the effects of supine and prone positioning on organ motion , positioning errors , and dose to critical organs during escalated dose conformal irradiation for localized prostate cancer and patient and therapist satisfaction with setup technique . PATIENTS AND METHODS Twenty eight patients were r and omized to commence treatment immobilized in the supine or prone position and were subsequently changed to the alternate positioning for the latter half of their treatment . Patients underwent CT simulation and conformal radiotherapy planning and treatment in both positions . The clinical target volume encompassed the prostate gl and . Alternate day lateral port films were compared to corresponding simulator radiographs to measure the isocentre positioning errors ( IPE ) . Prostate motion ( PM ) and total positioning error ( TPE ) were measured from the same films by the displacements of three implanted fiducial markers . Dose volume histograms ( DVHs ) for the two treatment positions were compared at the 95 , 80 and 50 % dose ( D% ) levels . The patients and radiation therapists completed weekly question naires regarding patient comfort and ease of setup . RESULTS Seven patients , who started in the supine position , subsequently refused prone position and received their whole treatment supine . Small bowel in the treatment volume , not present in the supine position , prevented one patient from being treated prone . PM in anterior posterior direction was statistically significantly less in the supine position ( P<0.05 ) . There was no significant difference in superior inferior PM for the two treatment positions . No statistically significant difference between supine and prone positioning was observed in isocentre positioning error ( IPE ) or total positioning error ( TPE ) due to a policy of daily pre-treatment correction . However , more pre-treatment corrections were required for patients in the prone position . The DVH analysis demonstrated larger volumes of the bladder wall , rectal wall and small bowel within the D95 , D80 and D50 % when comparing the planning target volumes ( PTVs ) actually treated for prone positioning . When the prone PTV was exp and ed to account for the greater PM encountered in that position , a statistically significant difference ( P<0.007 ) was observed in favour of the supine position at all dose levels . In the prone position , four patients had small bowel within the 60 Gray ( Gy ) isodose and in the supine position , no patients had small bowel in the 60 or 38Gy volumes . Supine position was significantly more comfortable for the patients and setup was significantly easier for the radiation therapists . The median patient comfort score was 0.79 ( St and ard deviation ( SD ) 0.03 ) supine and 0.45 ( SD 0.05 ) prone ( P<0.001 ) The therapist convenience of setup was 0.80 ( SD 0.016 ) supine and 0.54 ( SD 0.025 ) prone ( P<0.005 ) . No statistically significant difference was seen for the other parameters studied . CONCLUSIONS We demonstrated significantly less PM in the supine treatment position . There was no difference for either treatment position in IPE or TPE , however , more pre-treatment corrections were required in the prone position . Prone position required a larger PTV with result ing increased dose to critical organs . There were statistically significant improvements at all dose levels for small bowel , rectal wall and bladder wall doses in the supine position once corrections were made for differences in organ motion . Linear analogue scores of patient comfort and radiation therapist convenience demonstrated statistically significant improvement in favour of the supine position . Supine positioning has been adopted as the st and ard for conformal prostatic irradiation at our centre [20685168] Background : A cardiac catheterization laboratory can be a frightening environment and music can be a supportive source of environmental sound that stimulates and maintains relaxation . Aim : To test the effects of patient focused music versus loudspeaker music versus st and ard sound on patient 's experiences of anxiety and well-being during coronary angiographic procedures . Methods : A prospect i ve , r and omized , controlled trial of 98 subjects undergoing elective coronary angiogram and /or percutaneous coronary intervention . The subjects were r and omly allocated to three different groups of sound environments : a control group ( the usual sound environment ) , a patient focused music group ( audio pillow ) or to a loudspeaker music group . Results : Anxiety decreased significantly and well-being increased significantly in the two music groups compared to the control group . There was a significantly more positive impression of the sound environment in the patient focused music group compared to the two other groups . Conclusion : This study showed that the use of a specially design ed music reduced anxiety and increased well-being in patients during coronary angiographic procedures . However , patient focused music seemed to be more preferable . The sound environment was rated more positively by the subjects listening to music via audio pillow . The music delivered via loudspeakers seemed to distract the staff during the examination at the cardiac catheterization laboratory [17661855] OBJECTIVE To determine whether therapeutic touch administered at the time of stereotactic core biopsy of suspicious breast lesions results in a reduction in anxiety and pain . DESIGN R and omized , patient-blinded , controlled trial of either Krieger-Kunz therapeutic touch administered by a trained practitioner or a sham intervention mimicking therapeutic touch delivered during core biopsy . SETTING Stereotactic breast biopsy unit of a comprehensive breast center . PATIENTS Women with mammographically detected , nonpalpable breast lesions requiring biopsy . OUTCOME MEASURES Changes in pain and anxiety measured by visual analog scales immediately before and after stereotactic core biopsy . RESULTS A total of 82 patients were accrued : 42 received actual therapeutic touch and 40 sham therapeutic touch . No significant differences were found between the arms for age , ethnicity , educational background , or other demographic data . The sham arm had a preponderance of left breast biopsies ( 48 % vs 58 % ; P = 0.07 ) and received a slightly higher volume of epinephrine-containing local anesthetic ( 6.5 + /- 6.1 vs 4.5 + /- 4.5 mL ; P = 0.09 ) . Therapeutic touch patients were more likely to have an upper breast lesion location ( 57 % vs 53 % ; P = 0.022 ) . No significant differences between the arms were seen regarding postbiopsy pain ( P = 0.95 ) , anxiety ( P = 0.66 ) , fearfulness , or physiological parameters . Similarly , no differences were seen between the arms when change in parameters from prebiopsy to postbiopsy was considered for any of the psychological or physiological variables measured . These findings persisted when confounding variables were controlled for . CONCLUSIONS Women undergoing stereotactic core breast biopsy received no significant benefit from therapeutic touch administered during the procedure . Therapeutic touch can not be routinely recommended for patients in this setting [23679113] Abstract Many patients experience some degree of anxiety during dermatologic procedures . A prospect i ve , r and omized-control trial of hypnotic induction followed by self-guided imagery was conducted with patients in 3 groups : live induction , recorded induction , or control . By 20 minutes into the procedure , there was significantly reduced anxiety reported in the live-induction group compared with the control , whereas reported anxiety in the recorded-induction group was similar to that of the control group . All 13 in the live induction , 11 of the 13 in the recorded induction , and none of the 13 in the control group imagined scenes . The findings of this study suggest that live hypnotic induction followed by self-guided imagery can help to reduce anxiety experienced by many patients during dermatologic procedures [25198487] OBJECTIVES To determine the impact of music intervention on endothelial function , hemodynamics , and patient anxiety before , during , and after cardiac catheterization . BACKGROUND The effect of music therapy during cardiac catheterization on endothelial function and patient satisfaction has received limited study . METHODS Seventy patients undergoing elective cardiac catheterization were r and omized to music therapy ( n=36 ) or no music therapy ( n=34 ) . Peripheral arterial tonometry was performed before and after catheterization . A 6 item ( 24-point scale ) question naire evaluating patient anxiety and discomfort levels was also administered after the procedure . RESULTS Both study groups had similar baseline characteristics , fluoroscopy time , and contrast administration . Reactive hyperemia index ( RHI ) change was 0.14 ± 0.72 in the music group and 0.30 ± 0.58 in the control group ( P=.35 ) . Systolic and diastolic blood pressure ( BP ) changes did not significantly differ between the two groups ( systolic BP change -3.3 ± 17.3 mm Hg vs -2.3 ± 19.4 mm Hg ; P=.83 and diastolic BP change -1.9 ± 12.2 mm Hg vs. 2.0 ± 13.4 mm Hg ; P=.23 ) . Heart rate changes were also comparable between the two groups ( -1 ± 6 beats/ min vs -1 ± 7 beats/min ; P=.22 ) . Patient satisfaction question naire measurements were found to be similar in patients with and without music therapy ( 8 [ 7 - 11 ] vs 9 [ 8 - 12 ] ; P=.36 ) . CONCLUSIONS In this study , music intervention did not elicit a vasodilator response , did not lower blood pressure or heart rate , and did not relieve anxiety or stress discomfort in patients who underwent coronary angiography [19186107] Several studies have evaluated music interventions prior and after coronary angiography and percutaneous coronary intervention ( PCI ) , but there is no clear evidence showing that music has an effect on patients during these procedures . The purpose was to investigate the effects of music on anxiety , angina , pain , relaxation , and comfort in patients during angiographic procedures and to evaluate gender differences . The study was a four-armed , prospect i ve r and omized controlled trial included 240 patients undergoing coronary angiography and /or PCI . Patients were allocated to receive relaxing music , MusiCure ® or st and ard care during the procedure . Outcome measures were ; puncture pain and the discomfort related to it , angina and the discomfort related to it , anxiety , experience of the sound environment , discomfort of lying still , and the doses of anxiolytics and analgesics during the procedure . No differences were found between the music and control groups regarding any of the trial endpoints or gender-related differences . The overall rating of the sound environment and feeling of relaxation was high . In conclusion , music intervention in patients undergoing angiographic procedures was highly feasible , but not effective in this study though the delivery of music went smoothly and did not disturb the examination and patients and staff alike looked favorably on it [11310081] Screening flexible sigmoidoscopy ( FS ) is an effective tool for the detection of colon cancer . Nonetheless , persons are reluctant to undergo FS for a variety of reasons such as anxiety , discomfort , and the possibility of abnormal findings . Nurses caring for FS patients can implement interventions to allay anxiety and promote comfort in an effort to enhance satisfaction and future compliance . Music therapy is one nonpharmacologic intervention that has been shown to be effective in allaying anxiety , reducing discomfort , and promoting satisfaction in other patient population s. A two-group pretest , posttest experimental design with repeated measures study recruited 64 subjects undergoing FS from one Midwestern tertiary care center . Subjects were r and omly assigned to a control condition of usual procedural care or to an experimental condition of music therapy during the examination . State and trait anxieties were measured at pretest . State anxiety , discomfort , satisfaction , and perceived compliance with future screening were measured after the procedure . Subjects in the music group reported less anxiety and discomfort than subjects in the control group . There were no differences on satisfaction ratings or perceived compliance with screening guidelines . Nurses caring for patients undergoing screening FS can offer music therapy as one nonpharmacologic intervention to ameliorate anxiety and reduce discomfort [20307440] BACKGROUND Minor surgery for ingrown toenails can provoke anxiety and the anaesthetic injection can be acutely painful . Distraction techniques may reduce the associated pain and anxiety . OBJECTIVE To investigate an audiovisual distraction ( Bedscapes ) on pain and anxiety during minor surgery for the correction of ingrown toenail . METHOD In a r and omised controlled trial , patients ( N=152 ) with ingrown toenails requiring surgical correction under local anaesthesia were allocated to receive Bedscapes+st and ard care or st and ard care alone . Pain levels due to local anaesthetic injection were assessed post-procedure , and anxiety levels were assessed pre- and post-procedure in both groups . Follow-up focus groups were conducted with 14 patients allocated to the Bedscapes group , and one-to-one interviews were held with four podiatrists . RESULTS Participants with high pre-procedure anxiety scores experienced greater pain on injection , and older patients reported lower pain than younger patients , regardless of group allocation . Bedscapes did not reduce pain or anxiety , and was apparently no more effective than interpersonal interaction between podiatry staff and the patient . CONCLUSIONS Pain of injected anaesthesia correlates closely with pre-operative anxiety . Formal audiovisual distraction has no added benefit over interpersonal interaction in the alleviation of pain and anxiety in patients undergoing nail surgery [27764835] Background : Patients undergoing flexible bronchoscopy usually experience anxiety before and during the procedure . Objectives : We performed this study to investigate whether verbal empathy and intentional touch from a bronchoscopist could reduce anxiety in patients undergoing flexible bronchoscopy . Methods : We conducted a prospect i ve r and omized trial in a university-affiliated hospital . Participants were r and omly assigned to one of the following groups : a control group , a verbal empathy group , or a verbal empathy and touch group . The staff pulmonologist performing bronchoscopy expressed verbal empathy and used touch by speaking to the patient ( using predefined short statements ) and making eye contact , and by laying his/her left h and on the patient 's right shoulder . We assessed the level of patient anxiety with a visual analog scale before and after the intervention . Results : Participants were 267 patients with a median age of 65 years ; 62.2 % were men . Although there were no differences in changes in anxiety between the three groups , subgroup analysis of the visual analog scale including participants with higher baseline anxiety ( empathy and touch group participants with anxiety ≥60 mm ; empathy group and empathy and touch group participants with anxiety ≥70 mm ) showed a larger reduction in anxiety than the control group . Conclusions : Verbal empathy and touch given by a bronchoscopist before bronchoscopy reduced anxiety in patients with high baseline anxiety levels [23341418] CONTEXT Despite major advances in cancer treatment , many patients undergo painful procedures during treatment and suffer debilitating side effects as well as report a decrease in quality of life ( QOL ) . This problem is exacerbated for low-income , racial , and ethnic minorities with cancer . Minority cancer patients often enter care with larger tumors and with a more aggressive disease , increasing the risk of debilitating symptoms , such as pain and anxiety . Research ers have never assessed the feasibility and effectiveness of offering massage therapy for low-income , underserved cancer patients who are undergoing port insertion . OBJECTIVE This study examined the feasibility of conducting a r and omized , controlled trial ( RCT ) that would assess the use of massage therapy to reduce pain and anxiety in urban patients with cancer who undergo surgical placement of a vascular access device ( port ) . The study also assessed the effectiveness of the intervention in reducing perioperative pain and anxiety . DESIGN The research team conducted a 9-month RC T of 60 cancer patients undergoing port placement . The research team r and omly assigned patients in a 2:1 ratio to usual care with massage therapy ( intervention group ) versus usual care with structured attention ( control group ) . SETTING The study took place at Boston Medical Center ( BMC ) , which is an urban , tertiary-referral , safety-net hospital . PARTICIPANTS Participants were cancer patients undergoing port placement . Sixty-seven percent were racial or ethnic minorities , and the majority were female and unemployed , with annual household incomes < $ 30 000 and publicly funded health insurance coverage . INTERVENTION For the intervention , an expert panel developed a reproducible , st and ardized massage therapy intended for individuals undergoing surgical port insertion . Both groups received 20-minute interventions immediately pre- and postsurgery . The research team collected data on pain and anxiety before and after the preoperative and postoperative interventions as well as 1 day after the surgery . OUTCOME MEASURES With respect to feasibility , the study examined ( 1 ) data about recruitment -- time to complete enrollment and proportion of racial and ethnic minorities enrolled ; ( 2 ) participants ' retention ; and ( 3 ) adherence to treatment allocation . The efficacy outcomes included measuring ( 1 ) participants ' average pain level using an 11-point numerical rating scale ( 0 = no pain to 10 = worst possible pain ) and ( 2 ) participants ' situational anxiety using the State-Trait Anxiety Inventory ( STAI ) . RESULTS The research team assigned the 60 patients to the groups over 53 weeks . Sixty-seven percent of the participants were racial or ethnic minorities . A majority were female and unemployed , with annual household incomes < $ 30 000 and publicly funded health insurance coverage . Of the 40 patients allocated to massage therapy , the majority ( n = 33 ) received both the pre- and postoperative interventions . Massage therapy participants had a statistically significant , greater reduction in anxiety after the first intervention compared with individuals receiving structured attention ( -10.27 vs -5.21 , P = .0037 ) . CONCLUSIONS Recruitment of low-income , minority patients into an RCT of massage therapy for perioperative pain and anxiety is feasible . Both massage therapy and structured attention proved beneficial for alleviating preoperative anxiety in cancer patients undergoing port placement [6745384] Abstract Introduction Distress related to wearing an immobilisation mask for radiotherapy treatment ( RT ) is a common experience for the person undergoing RT for head and neck cancer ( HNC ) . Described as ‘ mask anxiety ’ , there is little known about the patterns of this distress through the course of the treatment or what strategies are being used by people to help alleviate mask anxiety . Methods The study used a prospect i ve cohort design to examine the patterns of patient – reported mask anxiety during the course of RT , using a modified Distress Thermometer ( DT ) and a survey to explore strategies patients used to assist their mask anxiety . Results Thirty‐five participants , who identified as experiencing mask anxiety , were followed throughout RT treatment . At baseline , females were more likely to experience higher mask anxiety ( P = 0.03 ) . Across the course of treatment , mask anxiety significantly ( P < 0.001 ) reduced within the total cohort . In 72 % of participants , the level of initial distress was found to reduce over time . Only 22 % experienced mask anxiety that remained constant . Few ( 6 % ) experienced an increase in mask anxiety across the course of RT . Participants reported relying on intervention from health professionals , self – taught strategies , music , visualisation and medication to manage their mask anxiety . Conclusions Due to its high prevalence and variable patterns over time , it is recommended that routine screening for mask anxiety be implemented as st and ard care throughout the course of RT for HNC . Multiple , diverse strategies are being used by patients and studies are needed to develop effective interventions for managing mask anxiety [22571244] Pain and anxiety are closely associated with bone marrow aspirates and biopsies . To determine whether hypnosis administered concurrently with the procedure can ameliorate these morbidities , the authors r and omly assigned 80 cancer patients undergoing bone marrow aspirates and biopsies to either hypnosis or st and ard of care . The hypnosis intervention reduced the anxiety associated with procedure , but the difference in pain scores between the two groups was not statistically significant . The authors conclude that brief hypnosis concurrently administered reduces patient anxiety during bone marrow aspirates and biopsies but may not adequately control pain . The authors explain this latter finding as indicating that the sensory component of a patient 's pain experience may be of lesser importance than the affective component . The authors describe future studies to clarify their results and address the limitations of this study [20510947] Bone marrow biopsy and aspiration are commonly used for diagnosing , treating , and following up after treatment for blood disorders and solid tumors . For adults , the infiltration of local anesthesia at the biopsy site has been used as the principal form of analgesia for bone marrow biopsy and aspiration . Pain relief during these procedures is often incomplete , especially during aspiration of the bone marrow , and pain is likely to contribute to patient anxiety . Research ers at the Tabriz Hematology and Oncology Center in Iran conducted a study to quantify and evaluate the effectiveness of music therapy interventions on pain and anxiety control for 100 patients undergoing bone marrow biopsy and aspiration . Participants in the study were r and omly assigned to one of two groups : one group listened to music during the procedure , and the other did not . Patients completed the Spielberger State-Trait Anxiety Inventory both before and after the procedure and reported pain severity by using a visual analog scale . Results showed that participants who listened to music had lower state anxiety and pain levels than those who did not listen to music [25636013] The aim of this study was to test the effects of visual and audiovisual distraction on pain , anxiety , and procedure tolerance among patients undergoing colonoscopy . A prospect i ve , r and omized , controlled design was used with 180 consecutive patients who underwent colonoscopy . Subjects were r and omly allocated into 3 groups : Group A received visual distraction , Group B received audiovisual distraction , Group C with routine care . Outcome variables included pain , anxiety , and willingness to undergo colonoscopy again if the procedure was to be repeated . No significant difference was found on the pain scores of the 3 groups . However , when groups A and B were further divided into groups A1 , A2 , A3 ( low- , middle- , high-involvement groups ) , and B1 , B2 , B3 ( low- , middle- , high-involvement groups ) according to the level of distraction involvement , significant differences in pain scores were found between 7 groups ( A1 and A3 , A2 and A3 , A1 and B3 , A2 and B3 , A3 and C , B1 and B3 , B3 and C ) . The pain score of Group A3 was significantly lower than those of groups A1 , A2 , and C , and the pain score of Group B3 was significantly lower than those of groups B1 and C. The reduction of anxiety levels after procedure was insignificant between the 2 intervention groups and control group . The rates of willingness to undergo colonoscopy again if the procedure was to be repeated of the 2 intervention groups were significantly higher than that of the control group . Visual and audiovisual distraction is effective in promoting pain control for patients undergoing colonoscopy and improving their tolerance of the procedure [23962572] STUDY OBJECTIVE To investigate the effects of music on anxiety and perception of pain during office hysteroscopy . DESIGN Prospect i ve r and omized trial ( Canadian Task Force classification I ) . SETTING Major university medical center . INTERVENTIONS Three hundred fifty-six patients were enrolled between July 2012 and January 2013 . Hysteroscopy was performed in a dedicated ambulatory room , using vaginoscopy and without any type of anesthesia . A Bettocchi hysteroscope 5 mm in diameter was used . All procedures were performed by the same surgeon , a gynecologist with special interest in hysteroscopy . MEASUREMENTS AND MAIN RESULTS Data collected included age , body mass index , number of vaginal deliveries , educational achievement level , and history of endometrial surgery ( curettage and /or hysteroscopy ) . For each patient , vital parameters such as blood pressure , heart rate , and respiratory rate were recorded 15 minutes before the procedure and during hysteroscopy after traversing the cervix . Wait time before surgery and the duration of the procedure were also recorded . A completed Italian version of the state anxiety question naire ( State-Trait Anxiety Inventory ) and a visual analog scale ( VAS ) were administered to each patient before and after the procedure . The t test and Mann-Whitney U test was used when appropriate to compare the 2 groups . Statistical significance was accepted at p = .05 . During surgery , systolic blood pressure and heart rate were significantly lower in the music group compared with the no music group . Women in the music group experienced significantly lower anxiety after hysteroscopy and less pain during the procedure , and a significant decrease in both anxiety and pain scores after hysteroscopy . Postoperative State-Trait Anxiety Inventory form Y1 and VAS scores were significantly lower in the music group . CONCLUSION Music can be useful as a complementary method to control anxiety and reduce perception of pain . The patient is more relaxed and experiences less discomfort [27897034] OBJECTIVE This study examines the effects of listening to meditative music on state anxiety and heart rate variability ( HRV ) of patients during the uptake phase before positron emission tomography ( PET ) scans . METHODS A two-group r and omized experimental design was used . Eligible patients were r and omly assigned to either the experimental or control group . All patients received baseline assessment s of state anxiety using Spielberger State-Trait Anxiety Inventory ( STAI-S ) and HRV before receiving an intravenous injection of radiopharmaceutical fluorine-18 fludeoxyglucose in the uptake room . The experimental group ( n = 35 ) listened individually to 30 min of meditative music , integrating Chinese " Chi " and western frequency resonation in the uptake room . The control group ( n = 37 ) lay on bed quietly for 40 min in the uptake room without music . All patients were assessed for their anxiety level and HRV again , before receiving PET scanning as post-test . RESULTS The results indicated that patients in the experimental group showed a significant reduction in state anxiety and heart rate , and increase on high frequency norm of HRV ( p < 0.001 ) . There was a statistically significant reduction on anxiety level ( p < 0.001 ) , heart rate ( p < 0.001 ) and high frequency norm ( p = 0.001 ) in the experimental group compared with those of the control group . CONCLUSION Listening to meditative music as a non-invasive and cost-effective strategy can help maximize efforts to promote comfort and relaxation for patients awaiting stressful procedures , such as PET scans . Meditative music can be effective in alleviating state anxiety of patients during the uptake phase before PET scans . Advances in knowledge : The study provides scientific evidence of the effects of listening to meditative music for reducing state anxiety in patients during the uptake phase before PET scans . It may have the potential to lower the risk of unwanted false-positive fluorine-18 fludeoxyglucose uptake in normal organs and to further improve image quality and image interpretation . Listening to meditative music is a safe and inexpensive intervention which can be incorporated into routine procedures to reduce anxiety of patients undergoing PET scans [25739317] PURPOSE To compare mean heart and left anterior descending coronary artery ( LAD ) doses ( NTDmean ) and positional reproducibility in larger-breasted women receiving left breast radiotherapy using supine voluntary deep-inspiratory breath-hold ( VBH ) and free-breathing prone techniques . MATERIAL S AND METHODS Following surgery for early breast cancer , patients with estimated breast volumes > 750 cm(3 ) underwent planning-CT scans in supine VBH and free-breathing prone positions . Radiotherapy treatment plans were prepared , and mean heart and LAD doses were calculated . Patients were r and omised to receive one technique for fractions 1 - 7 , before switching techniques for fractions 8 - 15 ( 40 Gy/15 fractions total ) . Daily electronic portal imaging and alternate-day cone-beam CT ( CBCT ) imaging were performed . The primary endpoint was the difference in mean LAD NTDmean between techniques . Population systematic ( Σ ) and r and om errors ( σ ) were estimated . Within-patient comparisons between techniques used Wilcoxon signed-rank tests . RESULTS 34 patients were recruited , with complete dosimetric data available for 28 . Mean heart and LAD NTDmean doses for VBH and prone treatments respectively were 0.4 and 0.7 ( p<0.001 ) and 2.9 and 7.8 ( p<0.001 ) . Clip-based CBCT errors for VBH and prone respectively were ⩽3.0 mm and ⩽6.5 mm ( Σ ) and ⩽3.5 mm and ⩽5.4 mm ( σ ) . CONCLUSIONS In larger-breasted women , supine VBH provided superior cardiac sparing and reproducibility than a free-breathing prone position Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: nan Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

20393970

[7912633] Sulphasalazine ( SASP ) and methotrexate ( MTX ) are well-established treatments for RA but the use of these drugs in combination has been avoided as both have antifolate activity . In this paper we report our experience with 32 patients treated with the combination MTX/SASP and compare the toxicity and tolerability of the combination with 63 patients treated with MTX alone . The median duration of exposure to the combination was 23 months . Nineteen patients have continued this regime for over 18 months . Five patients on MTX/SASP combination discontinued MTX , in four cases due to toxicity and in one because MTX/SASP was ineffective . In 17 patients on MTX alone , the drug was withdrawn permanently . In seven cases the cause was toxicity including two patients with severe reactions . In patients known to tolerate SASP alone , the combination of MTX/SASP is also well tolerated . In our experience of 48 patient-years of such combination therapy , there is no increase in toxicity compared to therapy with MTX alone in RA [8633829] In recent years , therapeutic strategies for patients with rheumatoid arthritis have been discussed in detail [ 1 - 8 ] . Traditional therapy , usually referred to as the pyramid model , begins with nonsteroidal anti-inflammatory drugs ( NSAIDs ) . If these are insufficiently effective , they are later replaced or supplemented with second-line antirheumatic drugs , which are distinguished from NSAIDs primarily by their assumed disease-modifying potential and delayed onset of action . These second-line drugs are also referred to as slow-acting antirheumatic drugs ( SAARDs ) or disease-modifying antirheumatic drugs ( DMARDs ) . Traditionally , the SAARDs of first choice have been hydroxychloroquine or intramuscular gold followed by D-penicillamine , methotrexate , or azathioprine . The traditional therapeutic pyramid is based on the principle of primum non nocere : Because of their potential toxicity , SAARDs should only be given when milder therapies have failed . Recently , the beneficial effects of the pyramid strategy have been question ed because the long-term outcome of rheumatoid arthritis continues to be disappointing . Patients with rheumatoid arthritis have increased mortality [ 9 , 10 ] , and their quality of life is seriously affected by functional impairment and loss of employment [ 11 , 12 ] . The pyramid model might be undesirable because administering SAARDs only after milder regimens prove to be insufficiently effective delays the suppression of inflammation . It is preferable that the disease process be controlled as soon as possible , because radiologic abnormalities appear in the joints early in the course of the disease [ 13 , 14 ] and are related to the extent of inflammation [ 15 , 16 ] . Toxicity indices for NSAIDs and most SAARDs have recently been shown to be similar ; thus , exposure of patients to possible adverse reactions is probably not in itself a reason to withhold treatment with SAARDs [ 17 ] . However , the ability of SAARDs to modify the course of disease and prevent radiologic damage is often question ed [ 18 , 19 ] . The poor long-term outcome of rheumatoid arthritis might be caused not by a delay in effective treatment but by the low disease-modifying power of both first- and second-line drugs . The short courses of SAARDs ( short because of adverse reactions or impatience with a delay in effect ) might also play a role [ 20 , 21 ] . Combinations of SAARDs have not been shown to be superior to single drugs [ 21 , 22 ] . Current clinical practice is shifting toward the earlier introduction of second-line treatment for rheumatoid arthritis , but thus far no clinical trials have shown this strategy to be beneficial . We investigated the consequences of ignoring the treatment pyramid for patients with recent-onset rheumatoid arthritis . In this report , we describe the first-year results of a r and omized clinical trial in which the delayed and the immediate introduction of SAARDs were compared . Effectiveness was measured by disease activity and progression of radiologic abnormalities . The various SAARDs are considered as a single group in this report ; comparisons among the second-line therapies will be reported in detail later . Methods Patients As of January 1990 , all patients with recent-onset rheumatoid arthritis ( diagnosed according to the 1987 American College of Rheumatology criteria [ [ 23 ] ] from six rheumatologic centers in the region of Utrecht , the Netherl and s , were asked to participate in a r and omized , prospect i ve clinical trial . Disease duration had to have been less than 1 year , and most patients were enrolled shortly after diagnosis . The following exclusion criteria were applied : 1 ) age younger than 17 years , 2 ) comorbid conditions that might interfere with one of the therapeutic strategies , 3 ) previous or current treatment with any SAARDs , glucocorticosteroids , or cytotoxic or immunosuppressive therapy , 4 ) the possibility of pregnancy or breast feeding , and 5 ) psychiatric or mental disturbances that would make adherence to the study protocol unlikely . All patients gave informed consent before study entry and were told that the study was intended to compare the unsure outcome of treatment with NSAIDs alone with that of treatment with NSAIDs and a SAARD for rheumatoid arthritis at an early stage . The study design was approved by the ethical committees of all participating hospitals . The baseline characteristics of patients who were eligible for the study but who objected to r and omization were compared with those of r and omly assigned patients to determine whether any selection bias had occurred . Treatment Patients entering the study were r and omly assigned to one of two therapeutic groups . All r and omization procedures were done by drawing sealed envelopes from blocks of 100 with equal numbers of patients for each of the four treatments per hospital ; the person doing the procedures was blinded to treatment assignments . This method was used because eligible patients were not distributed equally among the centers . The assigned therapeutic strategy was continued for at least 1 year . In the non-SAARD group , patients began receiving NSAID therapy , the dose and type of which could be modified at any time . For this group , initiation of SAARD treatment during the study was regarded as discontinuation of the therapeutic strategy . In the SAARD group , patients were r and omly assigned ( by persons blinded to treatment assignments ) to treatment with one of the following SAARDs : hydroxychloroquine ( 400 mg/d ) , intramuscular gold ( aurothioglucose , 50 mg/wk ) , or oral methotrexate ( 7.5 to 15 mg/wk ) . Therapy with the initial SAARD was continued for 12 months unless adverse reactions necessitated discontinuation ; if this occurred , another SAARD was given . Hydroxychloroquine was followed by auranofin ( 6 to 9 mg/d ) ; intramuscular gold was followed by D-penicillamine ( 500 to 750 mg/d ) ; and methotrexate was followed by sulfasalazine ( 2000 to 3000 mg/d ) . Discontinuation of therapy with the second SAARD was regarded as discontinuation of the therapeutic strategy . Use of NSAIDs was allowed in the SAARD group ; as in the non-SAARD group , the dose and type could be changed at any time . Patients were assigned to the non-SAARD group and the SAARD group in a ratio of 1:3 , and power calculations for the primary end point disability ( equals 0.05 ; equals 0.20 ; difference to be detected , 25 % ) indicated that group sizes of 40 and 120 , respectively , would be sufficient . The ratio of 1:3 was chosen to enable later comparisons of results within the SAARD group , which were thought to be similar . The use of analgesics was allowed in both groups ; the use of oral glucocorticosteroids was avoided if possible ; and intraarticular injections were not allowed within 2 months of a scheduled visit . Criteria for discontinuation or dose adjustment of a SAARD because of adverse reactions were described in detail in the study protocol . Discontinuation of any treatment because of sustained disease activity was done only if the patient and the attending physician ( who had to discuss the patient with a colleague ) judged it to be unavoidable . Primary End Points Assessment s were done at the start of the trial and were repeated every 3 months . Clinical variables were assessed by the same physician or research nurse for each patient on each occasion . Primary end points were functional disability , pain , joint score , erythrocyte sedimentation rate , and radiologic abnormalities [ 24 ] . Radiologic abnormalities and erythrocyte sedimentation rate were determined by persons blinded to treatment assignments ; functional disability and pain were self-assessed scores ; and determination of the joint score was not blinded to treatment . Functional disability was assessed using a vali date d Dutch version of the Health Assessment Question naire Disability Score [ 25 - 27 ] . The question naire scores range from 0 to 3 ; 0 is the best score ( no problems ) , and 3 is the worst . Pain was measured on two horizontal visual analog scales of 100 mm ; the mean of the scores for pain during the night and pain during the morning was calculated . The joint score according to Thompson and colleagues [ 28 , 29 ] assessed the simultaneous presence of joint tenderness and swelling in a selection of joints weighed for joint size ( range , 0 to 534 ) [ 28 , 29 ] . Erythrocyte sedimentation rate ( mm/h ) was measured using Westergren method . Radiography of h and s and feet was done at the start of the study and at 12 months . A modified version of the method of Sharp and coworkers [ 30 , 31 ] was used to score radiologic abnormalities . According to this method , erosions and joint space narrowing in h and and foot joints are scored and added together to obtain a total radiologic damage score ( range , 0 to 448 ) . All radiographs were evaluated by two investigators who were blinded to treatment assignments . The scores of the first investigator were used in the analyses , and the scores of the second investigator were used to vali date the scores of the first . Correlation between the two sets of scores was satisfactory ( Spearman correlation coefficients for scores at baseline and at 12 months were 0.84 for both ) ; the second investigator was found to have given lower scores ( means at baseline were 4.2 and 3.4 , respectively ; means at 12 months were 11.2 and 9.7 , respectively ) . Therefore , in individual cases , differences in total scores of 25 % or more were discussed until an agreement was reached on the appropriate score . That score was then used in the analyses . Additional Assessment s Secondary end points were grip strength ( mean of three measurements of each h and with a vigorimeter [ Martin , Tuttlingen , Germany ] in kPa ) , duration of morning stiffness ( maximum , 720 min ) , and general well-being ( horizontal visual analog scale of 100 mm ) . Additional laboratory variables were serum level of C-reactive protein ( mg/L ) , hemoglobin concentration ( mmol/L ) , and platelet count ( times 109/L ) . Rheumatoid factor status was determined to be positive or negative , as indicated by either the [15290730] OBJECTIVE To obtain additional safety and efficacy data on leflunomide ( LEF ) treatment in combination with methotrexate ( MTX ) therapy in an open-label extension study in patients with rheumatoid arthritis ( RA ) . METHODS Following a 24 week , r and omized , double-blind trial of adding placebo ( PLA ) or LEF to stable MTX therapy , patients could enter a 24 week extension . Subjects r and omized to LEF and MTX continued treatment [ ( LEF/LEF ) + MTX ] . Subjects r and omized to PLA and MTX switched to LEF ( 10 mg/day , no loading dose ) and MTX [ ( PLA/LEF ) + MTX ] . The double-blind regarding initial r and omization was maintained . RESULTS For subjects in the extension phase , American College of Rheumatology 20 % ( ACR20 ) responder rates for the ( LEF/LEF ) + MTX group were maintained from Week 24 ( 57/96 , 59.4 % ) to Week 48 ( 53/96 , 55.2 % ) . ACR20 responder rates improved in patients switched to LEF from PLA at Week 24 [ ( PLA/LEF ) + MTX ] from 25.0 % ( 24/96 ) at Week 24 to 57.3 % ( 55/96 ) at Week 48 . Patients in the extension who switched from PLA to LEF without a loading dose exhibited a lower incidence of elevated transaminases compared to patients initially r and omized to LEF . Diarrhea and nausea were less frequent during the open-label extension in patients who did not receive a LEF loading dose . CONCLUSION Response to therapy was maintained to 48 weeks of treatment in patients who continued to receive LEF and MTX during the extension . Importantly , ACR20 response rates after 24 weeks of LEF therapy were similar between patients switched from PLA to LEF without loading dose , and those who received a loading does of LEF ( 100 mg/day x 2 days ) at r and omization . Fewer adverse events were reported in patients switched to LEF without a loading dose [9712088] OBJECTIVE To evaluate tolerability and efficacy of combination therapy with methotrexate (MTX)/parenteral gold or MTX/other disease modifying antirheumatic drug ( DMARD , d-penicillamine or chloroquine ) in comparison with MTX monotherapy in patients with longst and ing destructive active rheumatoid arthritis ( RA ) . METHODS In an open prospect i ve trial all consecutive MTX-naive patients with active RA starting MTX treatment alone or in combination between January 1980 and December 1987 , after failing one or more DMARD , were followed at regular intervals up to 108 months . Evaluations included the number of swollen joints ( 0 - 32 ) , grip strength , patient assessment of pain and mobility , erythrocyte sedimentation rate ( ESR ) , C-reactive protein ( CRP ) , and hemoglobin . Group 1 , treated with MTX monotherapy ( n = 97 ) , was compared with Group 2 , with combination therapy MTX/parenteral gold ( n = 126 ) and Group 3 with MTX + other DMARD ( n = 48 ) . RESULTS There were no significant differences between the groups in mean age ( 59/57/56 yrs ) , disease duration ( 9.6/7.7/8.3 yrs ) , seropositivity ( 80/88/82 % ) , or ACR anatomical disease stage ( 2/3 in stage III and IV ) . The number of swollen joints ( 16.8/19.3/16.1 of 32 ) and the CRP ( 4.4/5.1/4.7 mg/dl ) was significantly greater in Group 2 ; other disease activity variables were not significantly different . The mean MTX dose at baseline ( mostly parenteral ) was 16.8/17.0/12.8 mg and could be reduced to around 12 mg ( predominantly oral ) in the 3 groups . Frequency of adverse events ( 80/83/88 % ) , nature of clinical ( nausea , hair loss , stomatitis ) and laboratory ( liver enzyme elevation , slight proteinuria ) side effects , and withdrawal rate for side effects ( 20.6/15.0/12.5 % ) were not significantly different between the groups . After 5 years 54/54/80 % of patients continued their treatment . All efficacy variables improved significantly ( p < 0.001 ) in all groups without significant intergroup difference . Improvement > 50 % in the ESR was achieved in 63/68/41 % and in the swollen joint count in 70/85/48 % of patients after 3 years . The number of patients taking oral steroids decreased from 63/59/65 % to 22/31/48 % after 3 years . In half the patients hemoglobin increased by at least 1 g/dl . CONCLUSION Combination therapy of MTX with parenteral gold or other DMARD is effective in reducing clinical and biochemical disease activity in patients with longst and ing destructive RA with no greater risk of toxicity compared with MTX alone ; our study however , did not show clear advantages of combination therapy versus monotherapy for effectiveness [7973475] To compare the efficacy of the combination therapy Methotrexate ( MTX ) and Chloroquine ( CHLO ) with MTX and Placebo ( PLA ) in the treatment of Rheumatoid Arthritis . A total of 82 patients with Rheumatoid Arthritis ( RA ) , diagnosed according to the American College of Rheumatology criteria , received orally either MTX 7.5 mg/week and CHLO 250 mg/day or MTX 7.5 mg/week and PLA 1 tablet/day . Adverse effects ( AE ) were monitored monthly and disease activity was assessed at 0 , 2 , 4 and 6 months . Sixty-eight patients completed the study . All outcome measures improved significantly in both treatment groups . Patients receiving MTX/CHLO ended the study with a significantly lower joint count , greater grip strength and better functional ability the patients in the MTX/PLA group , respectively ; 4.5 vs 7.5 ( P < 0.05 ) , 113.3 vs 89.1 ( P < 0.05 ) and 0.636 vs 0.811 ( P < 0.05 ) . Mild AE were more frequently observed in the MTX/CHLO , 17 events in 15 patients , compared to 9 events in 8 patients in the MTX/PLA group ( NS ) . These data indicate that MTX/CHLO is slightly more efficacious and toxic than is MTX/PLA in the treatment of RA [17183623] OBJECTIVE To study sustainability of remission and good treatment response , and the association of both with radiographic progression , in early rheumatoid arthritis ( RA ) in the Finnish Rheumatoid Arthritis Combination Therapy trial ( FIN-RACo ) . METHODS Patients were r and omized to receive either a combination of disease modifying antirheumatic drugs ( DMARD ; COMBI , n = 97 ) or a single DMARD ( SINGLE , n = 98 ) . Remission was defined according to modified American College of Rheumatology ( ACR ) remission criteria and Disease Activity Score 28 joint count ( DAS28 ) < or = 2.6 , and sustained remission as presence of remission at 6 , 12 , and 24 months . Good treatment response was defined as DAS28 ( 3/4 ) 3.2 and decrease of DAS28 > 1.2 . RESULTS In 169 patients with complete data , 33 ( 42 % ) COMBI and 18 ( 20 % ) SINGLE patients achieved modified ACR remission at 2 years , which was sustained in 11 ( 14 % ) COMBI and 3 ( 3 % ) SINGLE patients . Fifty-four ( 68 % ) COMBI and 37 ( 41 % ) SINGLE patients were in DAS28 remission at 2 years , which was sustained in 40 ( 51 % ) COMBI and 14 ( 16 % ) SINGLE patients . Good treatment response was sustained in 67 % of COMBI and 27 % of SINGLE patients . Over 2 years , the Larsen score increased by a median of 1 ( 95 % CI 0 - 2 ) in patients in sustained DAS28 remission compared to 4 ( 95 % CI 2 - 16 ) in patients who were in DAS28 remission at 6 months but lost it later ; and by 6 ( 95 % CI 2 - 10 ) in patients who were not in remission at 6 months . CONCLUSION A remarkable proportion of patients with early RA treated with combinations of DMARD were in remission at 2 years , and remission was more often sustained compared to patients treated with a single DMARD . Sustained remission protects against radiographic joint damage [16645967] OBJECTIVE To investigate whether disease control can be achieved in early active rheumatoid arthritis ( RA ) by treatment with methotrexate and intraarticular betamethasone , and whether the addition of cyclosporine to the regimen has any additional effect . METHODS Patients ( n = 160 ) were r and omized to receive methotrexate 7.5 mg/week plus cyclosporine 2.5 mg/kg of body weight/day ( combination therapy ) or methotrexate plus placebo-cyclosporine ( monotherapy ) . At weeks 0 , 2 , 4 , 6 , and 8 and every 4 weeks thereafter , betamethasone was injected into swollen joints ( maximum 4 joints or 4 ml per visit ) . Beginning at week 8 , if synovitis was present , the methotrexate dosage was increased stepwise up to 20 mg/week , with a subsequent stepwise increase in the cyclosporine or placebo-cyclosporine dosage up to 4 mg/kg . RESULTS At 52 weeks , 20 % improvement according to the American College of Rheumatology criteria ( ACR20 ) was achieved in 85 % of the combination therapy group versus 68 % of the monotherapy group ( P = 0.02 ) . The median individual overall ACR response ( ACR-N ) in the 2 groups was 80.0 % ( interquartile range 40.1 - 91.8 % ) and 54.5 % ( interquartile range 2.4 - 87.8 % ) , respectively ( P = 0.025 ) . At 48 and 52 weeks , ACR remission criteria were met in 35 % of the combination therapy group and 28 % of the monotherapy group . Progression in the Larsen score at 52 weeks was -0.2 + /- 6.5 and 0.4 + /- 6.9 ( mean + /- SD ) in the combination therapy and monotherapy groups , respectively . Serum creatinine levels increased by 7 % , and hypertrichosis was more prevalent , in the combination therapy group . CONCLUSION Combined treatment with methotrexate and intraarticular glucocorticoid showed excellent disease control and stopped the progression of erosions in patients with early active RA , who had a poor prognosis . Addition of cyclosporine improved the ACR20 and ACR-N responses , whereas the ACR50 and ACR70 responses , remission rates , and radiographic changes did not differ between the 2 study groups [8546736] OBJECTIVE To vali date the European League Against Rheumatism ( EULAR ) , the American College of Rheumatology ( ACR ) , and the World Health Organization (WHO)/International League Against Rheumatism ( ILAR ) response criteria for rheumatoid arthritis ( RA ) . METHODS EULAR response criteria were developed combining change from baseline and level of disease activity attained during follow up . In a trial comparing hydroxychloroquine and sulfasalazine , we studied construct ( radiographic progression ) , criterion ( functional capacity ) , and discriminant validity . RESULTS EULAR response criteria had good construct , criterion , and discriminant validity , ACR and WHO/ILAR criteria showed only good criterion validity . CONCLUSION EULAR response criteria showed better construct and discriminant validity than did the ACR and the WHO/ILAR response criteria for RA [10609068] OBJECTIVE The response to single disease modifying antirheumatic drug ( DMARD ) is often suboptimal in patients with rheumatoid arthritis ( RA ) . Thus , despite the limited data on the therapeutic efficacy of combination therapies , many patients are currently treated with a combination of DMARDs . METHODS We studied prospect ively the efficacy of combination therapy with DMARDs . The study was design ed as a r and omized trial and a single DMARD or two or three DMARD combinations were administered to 180 consecutive , age- and sex-matched patients with active RA , each of whom was followed up for a period of 2 years under treatment . Patients were divided into 3 groups which did not differ with regard to demographic , clinical and laboratory parameters . Patients in group I were treated with a single DMARD [ methotrexate ( MTX ) 7.5 - 15 mg/week or sulfasalazine ( SSZ ) 1 - 2 g/day or hydroxychloroquine ( HCQ ) 200 mg/day ] , group II with MTX + SSZ or MTX + HCQ , and group III with a combination of all three drugs . Patients were re-evaluated at regular intervals by means of clinical and biochemical tests design ed to detect specific rheumatic activity . Radiological assessment s were also performed and scored according to Larsen by the same radiologist who was blinded to the treatment groups . RESULTS At the end of the trial there were significant improvements in the clinical and laboratory parameters in all 3 groups . However , improvements were greater and much more significant in the patients who were given combination therapies . The combination of MTX + SSZ + HCQ was more effective than both monotherapy and the two-drug combinations . CONCLUSION In conclusion , we suggest that patients with RA should be treated with combinations of DMARDs [10364900] OBJECTIVES To investigate the potential clinical benefit of a combination therapy . METHODS 205 patients fulfilling the ACR criteria for rheumatoid arthritis ( RA ) , not treated with disease modifying anti-rheumatoid drugs previously , with an early ( ⩽1 year duration ) , active ( Disease Activity Score ( DAS ) > 3.0 ) , rheumatoid factor and /or HLA DR 1/4 positive disease were r and omised between sulphasalazine ( SASP ) 2000 ( maximum 3000 ) mg daily ( n = 68 ) , or methotrexate ( MTX ) 7.5 ( maximum 15 ) mg weekly ( n = 69 ) or the combination ( SASP + MTX ) of both ( n = 68 ) . RESULTS The mean changes in the DAS during the one year follow up of the study was −1.15 , −0.87 , −1.26 in the SASP , MTX , and SASP + MTX group respectively ( p = 0.019 ) . However , there was no statistically significant difference in terms of either EULAR good responders 34 % , 38 % , 38 % or ACR criteria responders 59 % , 59 % , 65 % in the SASP , MTX , and SASP + MTX group respectively . Radiological progression evaluated by the modified Sharp score was very modest in the three groups : mean changes in erosion score : + 2.4 , + 2.4 , + 1.9 , in narrowing score : + 2.3 , + 2.1 , + 1.6 and in total damage score : + 4.6 , + 4.5 , + 3.5 , in the SASP , MTX , and SASP + MTX groups respectively . Adverse events occurred more frequently in the SASP + MTX group 91 % versus 75 % in the SASP and MTX group ( p = 0.025 ) . Nausea was the most frequent side effect : 32 % , 23 % , 49 % in the SASP , MTX , and SASP + MTX groups respectively ( p = 0.007 ) . CONCLUSION This study suggests that an early initiation therapy of disease modifying drug seems to be of benefit . However , this study was unable to demonstrate a clinical ly relevant superiority of the combination therapy although several outcomes were in favour of this observation . The tolerability of the three treatment modalities seems acceptable [16258899] OBJECTIVE Several treatment strategies have proven value in the amelioration of rheumatoid arthritis ( RA ) , but the optimal strategy for preventing long-term joint damage and functional decline is unclear . We undertook this study to compare clinical and radiographic outcomes of 4 different treatment strategies , with intense monitoring in all patients . METHODS In a multicenter , r and omized clinical trial , 508 patients were allocated to 1 of 4 treatment strategies : sequential disease-modifying antirheumatic drug monotherapy ( group 1 ) , step-up combination therapy ( group 2 ) , initial combination therapy with tapered high-dose prednisone ( group 3 ) , and initial combination therapy with the tumor necrosis factor antagonist infliximab ( group 4 ) . Treatment adjustments were made every 3 months in an effort to obtain low disease activity ( a Disease Activity Score in 44 joints of < or = 2.4 ) . RESULTS Initial combination therapy including either prednisone ( group 3 ) or infliximab ( group 4 ) result ed in earlier functional improvement than did sequential monotherapy ( group 1 ) and step-up combination therapy ( group 2 ) , with mean scores at 3 months on the Dutch version of the Health Assessment Question naire ( D-HAQ ) of 1.0 in groups 1 and 2 and 0.6 in groups 3 and 4 ( P < 0.001 ) . After 1 year , mean D-HAQ scores were 0.7 in groups 1 and 2 and 0.5 in groups 3 and 4 ( P = 0.009 ) . The median increases in total Sharp/Van der Heijde radiographic joint score were 2.0 , 2.5 , 1.0 , and 0.5 in groups 1 - 4 , respectively ( P < 0.001 ) . There were no significant differences in the number of adverse events and withdrawals between the groups . CONCLUSION In patients with early RA , initial combination therapy including either prednisone or infliximab result ed in earlier functional improvement and less radiographic damage after 1 year than did sequential monotherapy or step-up combination therapy [12810924] OBJECTIVE To determine whether patients with early rheumatoid arthritis ( RA ) treated with cyclosporin A ( CsA ) and methotrexate ( MTX ) in combination for 12 months show a lower rate of radiographic deterioration than those treated with MTX alone . METHODS In this controlled and r and omized single-blind trial , 61 consecutive patients with untreated RA of less than 2 yr duration were treated with either CsA + MTX combination therapy ( n = 30 ) or MTX alone ( n = 31 ) . The primary end-point was radiographic progression after 12 months , measured using the damage score ( DS ) of the Sharp and van der Heijde method . RESULTS Although there was a significant difference between the mean baseline and 12-month DS in both treatment groups ( MTX/CsA , 1.93 + /- 0.90 ; MTX , 7.47 + /- 2.03 ) , it was significantly less in the combination arm ( P = 0.018 ) . Of the 30 evaluable CsA + MTX patients , 16 ( 53 % ) were ACR20 responders , 15 ( 50 % ) ACR50 and 14 ( 47 % ) ACR70 ; the corresponding figures in the MTX arm were 19 ( 61 % ) , 13 ( 44 % ) and 6 ( 19 % ) . Toxicity was acceptable in both groups . CONCLUSIONS In patients with early RA , CsA + MTX combination therapy led to a significantly lower rate of 12-month radiographic progression , was effective on inflammatory articular symptoms , and was well tolerated [1642652] OBJECTIVE To compare the relative safety and efficacy of azathioprine ( AZA ) , methotrexate ( MTX ) , and the combination of both in the treatment of active rheumatoid arthritis ( RA ) . METHODS Two hundred twelve patients with active RA were entered into a 24-week prospect i ve , controlled , double-blind , multicenter trial and were r and omly assigned to 1 of 3 treatment groups . RESULTS One hundred fifty-eight patients finished 24 weeks of the study . There were no remissions seen but response rates were greater than 30 % for all outcome measures . Combination therapy was not statistically superior to MTX therapy alone , but both combination therapy and MTX alone were superior to AZA alone when patients were analyzed by intent-to-treat and with withdrawals treated as therapy failures . If only patients who continued taking the therapy were analyzed , the mean improvement was greater for AZA therapy than for MTX , while the combination remained the most active . Adverse effects on the gastrointestinal tract and elevations of liver enzyme levels were the most frequent causes for discontinuations . CONCLUSION Both combination therapy and MTX alone were superior to therapy with AZA alone for active RA but were not statistically different in their effect on outcome assessment [16870092] OBJECTIVE To evaluate the effectiveness of disease-modifying antirheumatic drugs , namely , methotrexate ( MTX ) , sulfasalazine ( SSZ ) and bucillamine ( BUC ) at low-doses ( 4 , 6 or 8 mg MTX , 500 or 1,000 mg SSZ , and 100 or 200 mg BUC ) in 1,358 patients with a follow-up of at least 12 months and more than 120 months . METHODS Clinical assessment s were based on the number of painful joints ( NPJ ) and that of swollen joints ( NSJ ) , CRP level , erythrocyte sedimentation rate , rheumatoid factor level and morning stiffness before and after treatment . Results were evaluated on the basis of the duration of treatment for each drug with inefficacy or inadequate efficacy as one endpoint for discontinuation and adverse drug reactions ( ADRs ) as the other in single agent and combination therapy . The incidence and nature of ADRs in single and combination treatment are described . RESULTS The effects of MTX , SSZ and BUC on clinical parameters were monitored over the first three months , and in particular , NPJs and NSJs were found to decrease significantly during single agent MTX or BUC treatment over 108 months . CRP levels remained significantly improved for more than 120 months with MTX . In the single and combination long-term treatments , continuation rate with inefficacy or inadequate efficacy as the end point achieved for each of the treatments were 83.1 % for MTX , 76.0 % for BUC , 68.5 % for SSZ , and in the case of the combination treatments , these rates were 83.3 % for MTX + BUC and 71.0 % for MTX+SSZ . Continuation rates using ADRs as the end point were 88 % for SSZ , 79.6 % for BUC and 79.4 % for MTX . The incidences of ADRs for the various treatments were : MTX 22.2 % , SSZ 11.0 % , BUC 20.6 % , MTX + BUC 30.0 % and MTX + SSZ 31.2 % . CONCLUSION MTX showed the highest efficacy even though it was administrated at a low dose ( 6 - 8 mg ) , as a single agent or in combination with other treatment . However , in combination treatments , the continuous duration of treatment ending in ADRs as the end point were lower than those in single treatments with MTX , SSZ and BUC [8833056] To assess the relative efficacy of methotrexate ( MTX ) , azathioprine ( AZA ) , and their combination in the treatment of rheumatoid arthritis ( RA ) , a double blind , prospect i ve , multicenter , controlled trial was carried out . Two hundred nine patients with active RA were treated with escalating doses of MTX ( 5 - 15 mg/week ) , AZA ( 50 - 150 mg/day ) , or combination ( 5/50 - 7.5/100 ) with opportunity to increase dosage at 6 week intervals . Patients were evaluated for clinical and laboratory improvement and assessed for radiologic progression at 48 weeks . One hundred ten patients remained on the initial , r and omly assigned therapy . Response was defined as 30 % or greater improvement in at least 3 of 4 variables , and occurred in the following : 38 % on the combination arm , 26 % on AZA , and 45 % on MTX ( p = 0.06 ) . A trend for decreased radiologic progression was seen in the MTX group . Adverse experiences and treatment termination occurred more frequently in the combination and AZA arms relative to the MTX group . The most frequent causes for treatment discontinuations were lack of effectiveness , gastrointestinal adverse effects and liver enzyme elevation . This study establishes that the combination of MTX and AZA in the dosages employed is not associated with more toxicity than treatment with single agents , but enhanced efficacy is not seen . A trend toward decreased radiographic progression was noted in the MTX treated patients [8849352] OBJECTIVE To assess the relative efficacy of methotrexate ( MTX ) , azathioprine ( AZA ) , and their combination in the treatment of rheumatoid arthritis ( RA ) in a double-blind , prospect i ve , multicenter , controlled trial . METHODS Two hundred nine patients with active RA were treated with escalating doses of MTX ( 5 - 15 mg/week ) , AZA ( 50 - 150 mg/day ) , or combination ( 5 mg MTX/week plus 50 mg AZA/day-7.5 mg MTX/week plus 100 mg AZA/day ) , with opportunity to increase the dosage at 6-week intervals . The patients were evaluated for significant clinical and laboratory improvement and assessed for radiologic progression at 48 weeks . RESULTS One hundred ten patients remained on the initial , r and omly assigned therapeutic regimen . The percentage of patients who were responders , defined as those who had 30 % or greater improvement in at least 3 of 4 variables , was 38 % for the combination treatment , 26 % for AZA , and 45 % for MTX ( P = 0.06 ) . A trend toward decreased radiologic progression was seen in the MTX-treated patients . Termination of treatment due to adverse experience occurred more frequently with combination and AZA treatments than with MTX treatment . Lack of effectiveness , adverse gastrointestinal effects , and liver enzyme elevation were the most frequent causes of treatment discontinuation . CONCLUSION This study establishes that the combination of MTX and AZA in the dosages utilized is not associated with more toxicity than treatment with single agents ; however , enhanced efficacy is also not seen . There is a trend toward decreased radiologic progression in patients treated with MTX [10334255] BACKGROUND The treatment of rheumatoid arthritis should aim at clinical remission . This multicentre , r and omised trial with 2-year follow-up sought evidence on the efficacy and tolerability of combination therapy ( sulphasalazine , methotrexate , hydroxychloroquine , and prednisolone ) compared with treatment with a single disease-modifying antirheumatic drug , with or without prednisolone , in the treatment of early rheumatoid arthritis . METHODS 199 patients were r and omly assigned to two treatment groups . 195 started the treatment ( 97 received combination and 98 single drug therapy ) . Single-drug therapy in all patients started with sulphasalazine ; in 51 patients methotrexate was later substituted . Oral prednisolone was required by 63 patients . The primary outcome measure was induction of remission . Analyses were intention to treat . FINDINGS 87 patients in the combination group and 91 in the single-therapy group completed the trial . After a year , remission was achieved in 24 of 97 patients with combination therapy , and 11 of 98 with single-drug therapy ( p=0.011 ) . The remission frequencies at 2 years were 36 of 97 and 18 of 98 ( p=0.003 ) . Clinical improvement ( American College of Rheumatology criteria of 50 % clinical response ) was achieved after 1 year in 68 ( 75 % ) patients with combination therapy , and in 56 ( 60 % ) using single-drug therapy ( p=0.028 ) , while at the 2-year visit 69 and 57 respectively ( 71 % vs 58 % , p=0.058 ) had clinical ly improved . The frequencies of adverse events were similar in both treatment groups . INTERPRETATION Combination therapy was better and not more hazardous than single treatment in induction of remission in early rheumatoid arthritis . The combination strategy as an initial therapy seems to increase the efficacy of the treatment in at least a proportion of patients with early rheumatoid arthritis [9330929] OBJECTIVE To evaluate the ability of hydroxychloroquine sulfate ( HCQ ) to extend the response to combination therapy with HCQ and methotrexate ( MTX ) and the safety of longterm HCQ maintenance therapy in patients with active rheumatoid arthritis ( RA ) . METHODS Two-part study consisting of an open label segment evaluating combination HCQ/MTX therapy followed by a double blind segment evaluating maintenance therapy for a total of 60 weeks . First , all patients were treated with HCQ 400 mg/day and MTX 7.5 to 15 mg/week for 24 weeks . Then , responders were r and omized into 3 groups : ( 1 ) HCQ with MTX as needed for disease flare ( n = 40 ) , ( 2 ) HCQ 400 mg/day ( n = 41 ) , or ( 3 ) placebo with MTX as needed for disease flare ( n = 40 ) , each for 36 weeks . RESULTS Clinical disease and laboratory variables improved significantly during initial combination therapy with HCQ and MTX . After MTX withdrawal , HCQ-containing maintenance regimens delayed the onset of disease flare ( p = 0.023 ) . There were no unexpected adverse events at any time or between-group differences in the distribution of adverse events during the double blind segment . CONCLUSION Combination of HCQ and MTX appeared to be effective and well tolerated for 24 weeks . After withdrawal of MTX , HCQ extended the response seen with combination therapy and was well tolerated for 36 weeks . Initial therapy with HCQ and MTX , followed by maintenance HCQ , may be a useful alternative for the treatment of RA [8833058] Rheumatoid arthritis ( RA ) has a profound effect on patients , producing significant morbidity and in some cases mortality . Because of this , most rheumatologists are moving to disease modifying antirheumatic drug ( DMARD ) therapy earlier in the course of RA . Methotrexate ( MTX ) has become the initial DMARD of choice for most rheumatologists . Unfortunately , treatment of RA with a single DMARD , including MTX , often results in a suboptimal response . Therefore , most rheumatologists are now using combinations of DMARD to treat patients with RA who have had incomplete responses to single DMARD therapy . The Rheumatoid Arthritis Investigational Network ( RAIN ) reported the results of a double blind , controlled comparison of triple drug therapy ( MTX-sulfasalazine-hydroxychloroquine ) against MTX alone , and against the combination of hydroxychloroquine and sulfasalazine . Twenty-eight patients who had suboptimal responses to MTX or the combination of sulfasalazine and hydroxychloroquine were then treated with triple therapy in an open label study . Fourteen had previously failed MTX therapy , and 14 had previously failed combination therapy with sulfasalazine and hydroxychloroquine . Both groups had statistically significant improvements in sedimentation rates , morning stiffness , swollen joint scores , tender joint scores , patient global status assessment , and physician global status assessment . Statistical significance was reached for all these variables for patients in both groups , but improvement was greater for the patients in the sulfasalazine-hydroxychloroquine group . Patients with RA who have had suboptimal responses to MTX , or to the combination of sulfasalazine-hydroxychloroquine , show both statistical and clinical ly significant improvement in multiple clinical variables when treated with the combination of MTX 17.5 mg/week , sulfasalazine 500 mg bid , and hydroxychloroquine 200 mg bid [7981992] To compare efficacy , toxicity , and the pharmacokinetics of the combination of sulphasalazine ( SASP ) and methotrexate ( MTX ) vs MTX alone in the treatment of SASP-resistant RA we conducted a controlled open clinical trial . Forty RA patients with active arthritis despite adequate SASP therapy , were allocated r and omly to regimes of either SASP+MTX or MTX alone . The patients were evaluated openly by a single observer for 24 weeks . In the first 15 patients using the combination , pharmacokinetics of MTX without and with SASP were studied . Thirty-eight patients completed the trial . The mean decrease in the disease activity score in the group of patients receiving the combination was significantly greater than in the MTX group ( -2.6 vs -1.3 respectively ) . The same pattern was seen concerning the other efficacy variables . There was no difference in the occurrence of toxicity . SASP had no influence on the pharmacokinetics of MTX . In conclusion in this open study the efficacy of the combination of MTX and SASP seems to be superior to MTX alone , the toxicity of both therapies was similar . This effect was not explained by the pharmacokinetics of MTX which were not altered by concomitant SASP administration [16645968] OBJECTIVE Bisphosphonates inhibit osteoclast activity , which is central to the development of bone damage in rheumatoid arthritis ( RA ) . The aim of this study was to assess whether treatment with zoledronic acid , compared with placebo , could achieve a > or = 50 % reduction in the development of new erosions on magnetic resonance imaging ( MRI ) in patients with early RA . METHODS In this proof-of-concept study , 39 patients with early RA and clinical synovitis of the h and /wrist were r and omized to receive infusions with either zoledronic acid ( 5 mg ) or placebo , administered at baseline and week 13 . Patients in both groups received methotrexate ( MTX ) at a dosage of 7.5 - 20 mg/week . MRI and plain radiography were performed at baseline and week 26 . RESULTS At week 26 , the mean + /- SD change in MRI h and and wrist erosions was 61 % lower in the zoledronic acid group compared with the placebo group ( 0.9 + /- 1.63 versus 2.3 + /- 3.09 ; P = 0.176 ) . The mean + /- SD increase in the number of h and and wrist bones with erosions was 0.3 + /- 0.75 for zoledronic acid compared with 1.4 + /- 1.77 for placebo ( P = 0.029 ) . The proportion of patients in whom new MRI-visualized bone edema developed was smaller in the zoledronic acid group compared with the placebo group ( 33 % versus 58 % ; P = 0.121 ) . The zoledronic acid group had a mean change in the number of radiographic erosions of 0.1 compared with 0.5 for the placebo group ( P = 0.677 ) . The safety profile of zoledronic acid was similar to that of placebo . CONCLUSION The results of this study suggest a structural benefit associated with zoledronic acid therapy in patients with RA , as demonstrated by consistent results in structural end points in favor of zoledronic acid plus MTX compared with MTX alone [10589360] An open-label , one-year study was conducted to evaluate the safety and clinical response to leflunomide and methotrexate combination therapy for rheumatoid arthritis . Study results revealed tolerable safety , no significant pharmacokinetic interactions between methotrexate and leflunomide , and suggested improved clinical response with combination therapy [8259721] The aim of the study was to compare the efficacy of hydroxychloroquine ( HCQ ) alone and in combination with methotrexate ( MTX ) in a r and omized placebo-controlled study lasting 6 months . Forty patients with rheumatoid arthritis participated in the study and were r and omly assigned to two groups--20 patients were treated with HCQ ( 200 mg daily ) and placebo , 20 patients with HCQ and MTX ( 7.5 mg ) once a week . Patients were assessed at regular intervals of 1 month up to 6 months using six clinical and five laboratory tests and one radiological measure . All six clinical variables and two laboratory variables were favorably influenced by combination therapy during the 6-month period . HCQ alone significantly influenced only three clinical variables and none of the laboratory parameters . There was a greater number of patients without radiological progression in the combination group . There was one drop-out in combination group due to general allergic reaction ; otherwise the treatment was well tolerated . The results suggest that a combination of HCQ and MTX is more potent than HCQ alone [16447240] OBJECTIVE To compare the efficacy of doxycycline plus methotrexate ( MTX ) versus MTX alone in the treatment of early seropositive rheumatoid arthritis ( RA ) , and to attempt to differentiate the antibacterial and antimetalloproteinase effects of doxycycline . METHODS Sixty-six patients with seropositive RA of < 1 year 's duration who had not been previously treated with disease-modifying antirheumatic drugs were r and omized to receive 100 mg of doxycycline twice daily with MTX ( high-dose doxycycline group ) , 20 mg of doxycycline twice daily with MTX ( low-dose doxycycline group ) , or placebo with MTX ( placebo group ) , in a 2-year double-blind study . Treatment was started with an MTX dosage of 7.5 mg/week , which was titrated every 3 months until remission was reached ( maximum dosage of 17.5 mg/week ) . The primary end point was an American College of Rheumatology 50 % improvement ( ACR50 ) response at 2 years . RESULTS ACR50 responses were observed in 41.6 % of patients in the high-dose doxycycline group , 38.9 % of those in the low-dose doxycycline group , and 12.5 % of patients in the placebo group . Results of chi-square analysis of the ACR50 response in the high-dose doxycycline group versus that in the placebo group were significantly different ( P = 0.02 ) . Trend analysis revealed that the ACR20 response and the ACR50 response were significantly different between groups ( P = 0.04 and P = 0.03 , respectively ) . MTX doses at 2 years were not different among groups . Four patients in the high-dose doxycycline group , 2 patients in the low-dose doxycycline group , and 2 patients in the placebo group were withdrawn because of toxic reactions . CONCLUSION In patients with early seropositive RA , initial therapy with MTX plus doxycycline was superior ( based on an ACR50 response ) to treatment with MTX alone . The therapeutic responses to low-dose and high-dose doxycycline were similar , suggesting that the antimetalloproteinase effects were more important than the antibacterial effects . Further studies to evaluate the mechanism of action of tetracyclines in RA are indicated [11192489] Early intervention with slow acting anti-rheumatic drugs ( SAARDs ) has led to improvement in substantial proportion of rheumatoid arthritis ( RA ) patients . The present open , controlled study was design ed to assess whether a combination of SAARDs offer any added benefit . Fifty-four adult RA patients were r and omly allocated to methotrexate ( MTX ) ( n = 27 ) and MTX plus sulphasalazine ( SSZ ) ( n = 27 ) groups . The subjects were followed-up fortnightly for four weeks then monthly for six months . The disease activity was assessed with the help of 10 clinical and four laboratory indices . The improvement was grade d as : minor , mild decreases in indices , non-steroidal anti-inflammatory drugs ( NSAIDs ) continued , physician 's global assessment ( PGA ) decreased by one ; marked , acceptable decreases in indices , NSAIDs being taken sparingly , PGA decreased by at least 2 , and complete , all indices normalised and patients discontinued NSAIDs completely . The improvement was considered clinical ly important when marked or complete improvement occurred . Adverse drug reactions result ed in withdrawal of 4 subjects from the MTX + SSZ group and 1 from the control groups . Four and three subjects in the combined and MTX groups respectively were lost to follow-up . Subjects in both groups showed significant decline in all indices except hemoglobin and neutrophil count . The differences between the two groups in the pre-treatment and post-treatment values were insignificant . Complete , marked , minor and no improvement occurred in 4 ( 21 % ) , 12 ( 63 % ) , 3 ( 16 % ) & 0 in the MTX and in 11 ( 48 % ) , 7 ( 30 % ) , 4 ( 17 % ) & 1 ( 4 % ) in MTX + SSZ groups respectively . The differences in the rates of complete and clinical ly important improvement between the two groups were insignificant ( P 0.1398 and 0.7092 ) . The incidence of side effects was insignificantly higher in the MTX + SSZ group . Most of them were mild and transient . The combination of SAARDs offered little added advantage in RA . However , the higher rate of complete improvement in the combination group justifies trials including larger sample [8609945] BACKGROUND Rheumatoid arthritis is a common disease that causes substantial morbidity and mortality . The responses of patients with rheumatoid arthritis to treatment with a single so-called disease-modifying drug , such as methotrexate , are often suboptimal . Despite limited data , many patients are treated with combinations of these drugs . METHODS We enrolled 102 patients with rheumatoid arthritis and poor responses to at least one disease-modifying drug in a two-year , double-blind , r and omized study of treatment with methotrexate alone ( 7.5 to 17.5 mg per week ) , the combination of sulfasalazine ( 500 mg twice daily ) and hydroxychloroquine ( 200 mg twice daily ) , or all three drugs . The dose of methotrexate was adjusted in an attempt to achieve remission in all patients . The primary and point of the study was the successful completion of two years of treatment with 50 percent improvement in composite symptoms of arthritis and no evidence of drug toxicity . RESULTS Fifty of the 102 patients had 50 percent improvement at nine months and maintained at least that degree of improvement for two years without evidence of major drug toxicity . Among them were 24 of 31 patients treated with all three drugs ( 77 percent ) , 12 of 36 patients treated with methotrexate alone ( 33 percent , P < 0.001 for the comparison with the three-drug group ) , and 14 of 35 patients treated with sulfasalazine and hydroxychloroquine ( 40 percent ) , P = 0.003 for the comparison with the three-drug group ) . Seven patients in the methotrexate group and three patients in each of the other two groups discontinued treatment because of drug toxicity . CONCLUSIONS In patients with rheumatoid arthritis , combination therapy with methotrexate , sulfasalazine , and hydroxychloroquine is more effective than either methotrexate alone or a combination of sulfasalazine , and hydroxychloroquine [12416946] Context Several disease-modifying antirheumatic drugs ( DMARDs ) slow disease progression in patients with rheumatoid arthritis . Many experts prefer methotrexate , although trials do not uniformly show that it is superior to other DMARDs . It is not known whether combining methotrexate with a second DMARD is better than prescribing methotrexate alone . Contribution This 24-week , r and omized , double-blind , placebo-controlled trial shows that leflunomide added to ongoing stable-dose methotrexate therapy in patients with persistently active rheumatoid arthritis improves clinical outcomes compared with methotrexate alone . Caution s Some adverse effects , such as diarrhea , were more common with combination therapy . All patients receiving DMARD therapy need close monitoring for toxicities . The Editors Rheumatoid arthritis has considerable societal costs ( 1 - 5 ) . Many patients with rheumatoid arthritis become disabled within a few years of disease onset ( 4 , 5 ) . Methotrexate is the st and ard treatment for rheumatoid arthritis . During the past several years , investigators have found that some disease-modifying antirheumatic drugs can increase the efficacy of methotrexate monotherapy ( 6 - 9 ) . Methotrexate is an antimetabolite and immunomodulator that affects many intracellular metabolic pathways of purine metabolism ( 10 ) . The precise intracellular biochemical pathway responsible for the observed clinical benefits of methotrexate in the treatment of rheumatoid arthritis is still the subject of some debate ( 11 ) , but methotrexate is thought to act primarily on purine pathways of cellular metabolism ( 10 ) . Leflunomide ( Arava , Aventis Pharmaceuticals , Bridgewater , New Jersey ) also has antimetabolic effects , inhibiting pyrimidine intracellular pathways ( 12 ) . Leflunomide has been shown to be effective for rheumatoid arthritis in double-blind , placebo-controlled trials ( 13 , 14 ) . Given the diverse intracellular pathways affected by both drugs , the combination of leflunomide and methotrexate has the potential for biochemical synergy . The possibility of increased benefits should be weighed against the possible toxicities of this combination . Abnormal aminotransferase levels have been seen with both methotrexate ( 15 ) and leflunomide ( 14 ) monotherapy in patients with rheumatoid arthritis . In a small open study , we previously observed that the combination of methotrexate and leflunomide led to considerable clinical improvements and reversible elevations in aminotransferase levels ( 16 ) . We therefore sought to determine whether similar results could be achieved in a large , double-blind investigation of the combination of these two antimetabolic agents . Methods Patients The study sample consisted of 263 patients who had rheumatoid arthritis as defined by American College of Rheumatology ( ACR ) criteria ( 17 ) . Patients were 18 to 75 years of age and were receiving stable dosages of methotrexate ( 15 to 20 mg/wk , or 10 to 15 mg/wk if this was the maximum tolerated dose ) . Patients were recruited from active outpatient practice centers , and study participants were approached without a particular schema . Eligible patients had active rheumatoid arthritis despite at least 6 months of methotrexate therapy , including stable dosage for at least 8 weeks . Patients with active rheumatoid arthritis were defined as meeting three of the following criteria on two different evaluations , 7 to 21 days apart : at least nine tender joints , at least six swollen joints , at least 45 minutes of morning stiffness , and an erythrocyte sedimentation rate of at least 28 mm/h . Previous disease-modifying antirheumatic drugs , not including ongoing methotrexate , had failed in 11 patients . Patients receiving corticosteroids were required to have been taking a stable daily dose of 10 mg or less for at least 30 days before study drug administration , and the corticosteroid dose was required to remain constant throughout the study . Complete exclusion criteria are listed in Appendix Table 1 . Study Design The 24-week , r and omized , double-blind , placebo-controlled study , with evaluations occurring at 4-week intervals ( Figure 1 ) , was conducted in 20 centers in the United States and Canada between September 1998 and June 2000 . The primary objective was to evaluate the efficacy and safety of adding leflunomide or placebo to stable methotrexate therapy in patients with active rheumatoid arthritis . All participants provided written consent , and the institutional review board at each center approved the protocol . Figure 1 . Patient eligibility , r and omization , assignment , and discontinuation . Include no wish to continue in study , poor adherence to treatment , protocol violation , and moving away from the study area . A r and omization schedule , generated by and stored with Quintiles , Inc. , Kansas City , Missouri , was used to assign sequential numbers to r and omly allocated treatment codes . R and omization was done by using the Aventis st and ard r and om-code generator . Investigators allocated numbers to patients , beginning with the lowest available number . Quintiles , Inc. , packaged and labeled the study medication . The r and omization code used was concealed from investigators and patients throughout the study . R and omization was stratified by center . A set of 500 r and om numbers was generated , with treatment groups r and omly assigned in a balanced manner ( 1:1 ratio ) within each block of four consecutive r and om numbers ( block size , 4 ) . A set of these blocks was then sent to each investigative center . This method is identical to stratification by center because centers are balanced with respect to treatment assignment . Patients were r and omly assigned to receive leflunomide , 100 mg/d , for 2 days followed by 10 mg/d or matching placebo . If substantial adverse events occurred , this dose could be reduced to 10 mg every other day . If 10 mg/d was tolerated but active disease , as defined earlier , was still present at week 8 or thereafter , an increase to 20 mg of leflunomide or matching placebo per day was required . If substantial adverse events occurred while the patient was taking 20 mg of the study drug per day , a one-time dose reduction to 10 mg/d was allowed at the discretion of the investigator . At least 1 mg of folate supplementation per day was m and ated by the protocol . Adherence to study medication , assessed at each visit by tablet counts ( actual number of tablets returned compared with number expected to be returned ) , was similar in the two groups . The mean adherence for all patients in the intention-to-treat sample was 98.0 % ( 98.5 % for those receiving placebo and 97.4 % for those receiving leflunomide ) . In the placebo group and leflunomide group , respectively , 90.2 % ( 120 of 133 patients ) and 87.7 % ( 114 of 130 patients ) had adherence rates of 80 % to 120 % . Measurement of Efficacy The primary efficacy variable was the rate at which the intention-to-treat sample achieved 20 % improvement in ACR criteria ( ACR20 ) at the end of the study . To be classified as having achieved ACR20 , patients were required to complete 24 weeks of treatment and meet ACR20 response criteria at end of the study ( 13 ) . The ACR20 criteria were developed to define improvement in rheumatoid arthritis ( 18 ) . Clinical improvement is indicated by 20 % improvement in tender and swollen joint counts and 20 % improvement in three of the following five criteria : patient global assessment , physician global assessment , pain intensity , physical function or disability measure , and level of acute-phase reactant ( 19 ) . All ACR assessment s were performed by the investigators , and the same assessor performed all analyses throughout the study whenever possible to increase the reliability of the assessment . Patients who discontinued therapy before the end of week 24 or for whom data were insufficient to assess ACR20 response at week 24 were classified as nonresponders for the primary analysis . Count of tender joints was based on 68 joint assessment s , and count of swollen joints was based on 66 joint assessment s. Percentage changes in tender joint and swollen joint counts were based on the number of evaluable joints at a visit . Joints that had been replaced or had been injected with corticosteroids within 4 weeks before the assessment were considered nonevaluable . Secondary outcomes included ACR50 and ACR70 responder rates at week 24 ( analyses of responders at study end for the non primary efficacy measures ) . The ACR50 and ACR70 were defined as at least 50 % and 70 % improvement , respectively , in the same criteria used to calculate ACR20 response . Secondary efficacy variables also included change from baseline to end point in each of the individual components of the ACR response criteria and change from baseline to week 24 in levels of rheumatoid factor . Mean changes from baseline in individual efficacy measures are shown in Appendix Table 2 . Measurement of Safety Safety was evaluated by adverse event reports ; laboratory assays for changes in hematologic characteristics , blood chemistry , urinalysis , and liver function ; and physical examination . Potential adverse events were assessed by using open-ended questions at each study visit . The assessor was blinded to reported toxicities and to any additional information obtained at the visit . The study protocol provided recommendations for dosage change and discontinuation of drug therapy , without unblinding , when patients were found to have alanine aminotransferase ( ALT ) and aspartate aminotransferase ( AST ) values greater than two times the upper limit of normal . Investigators decreased the dose of the study medication if , on repeated analysis at 72 hours , test values remained greater than two times but less than or equal to five times the upper limit of normal ; only one dose adjustment was allowed before discontinuation of therapy with the study drug . Therapy with the study drug was also discontinued in patients with persistent elevations of aminotransferase enzyme levels to more than two times the upper limit of normal on repeated [16926184] Background : Optimal use of disease-modifying antirheumatic drugs ( DMARDs ) in rheumatoid arthritis is vital if progression of disease is to be reduced . Methotrexate ( MTX ) and sulfasalazine ( SASP ) are widely used inexpensive DMARDs , recently often combined despite no firm evidence of benefit from previous studies . Aim : To establish whether a combination of SASP and MTX is superior to either drug alone in patients with rheumatoid arthritis with a suboptimal response to 6 months of SASP . Methods : A r and omised controlled study of step-up DMARD treatment in early rheumatoid arthritis . In phase I , 687 patients received SASP for 6 months . Those with a disease activity score ( DAS ) ⩾2.4 were offered additional treatment in phase II ( SASP alone , MTX alone or a combination of the two ) . The primary outcome measure was change in DAS . Results : At 6 months , 191 ( 28 % ) patients had a DAS < 2.4 , 123 ( 18 % ) were eligible but did not wish to enter phase II , 130 ( 19 % ) stopped SASP because of reversible adverse events and 165 ( 24 % ) entered phase II . DAS at 18 months was significantly lower in those who received combination treatment compared with those who received either SASP or MTX : monotherapy arms did not differ . Improvement in European League Against Rheumatism and American College of Rheumatology 20 , 50 and 70 scores favoured combination therapy . Conclusions : In this “ true-to-life ” study , an inexpensive combination of DMARDs proved more effective than monotherapy in patients with rheumatoid arthritis with a suboptimal response to SASP . There was no increase in toxicity . These results provide an evidence base for the use of this combination as a component of tight control strategies [15880810] OBJECTIVE To evaluate the efficacy and safety of adding intramuscular ( IM ) gold to the treatment regimen of patients with rheumatoid arthritis ( RA ) who have a suboptimal response to methotrexate ( MTX ) . METHODS A r and omized , double-blind , double-observer , placebo-controlled multicenter trial of 48 weeks was conducted . Sixty-five RA patients who had a suboptimal response to > /=12 weeks of MTX therapy were r and omly assigned to receive weekly IM gold or placebo in addition to MTX . Gold was administered according to a st and ard protocol developed for the study . The primary outcome measure was the percentage of patients who met the American College of Rheumatology ( ACR ) 20 % improvement criteria ( achieved an ACR20 response ) at week 48 . Secondary outcomes included the percentages of patients achieving ACR50 and ACR70 responses , the individual criteria that make up the primary outcome , quality of life , direct and indirect health care costs , intraarticular steroid use , and adverse events , among other measures . Statistical analyses were based on an intent-to-treat strategy . RESULTS Sixty-one percent of patients receiving gold achieved an ACR20 response compared with 30 % of patients receiving placebo ( chi(2 ) = 6.04 , P = 0.014 ; logistic regression odds ratio 3.64 [ 95 % confidence interval 1.3 , 10.4 ] , P = 0.016 ) . Twenty-six percent of patients receiving gold achieved an ACR50 response compared with 4 % of patients receiving placebo ( P = 0.017 ) , and 21 % of patients receiving gold achieved an ACR70 response compared with 0 % of patients receiving placebo ( P = 0.011 ) . From both clinical and cost-effectiveness perspectives , gold was the preferred and dominant strategy . Study treatment was discontinued in 23 patients ( 14 in the placebo group compared with 9 in the gold group ; P = 0.022 ) due to loss to followup , adverse events , or lack of efficacy . CONCLUSION In RA patients with a suboptimal response to MTX , adding weekly IM gold causes significant clinical improvement . Adverse events were minor , and IM gold-related adverse events led to discontinuation in only 11 % of the gold group over 48 weeks [17330681] Background : Sulfasalazine and tetracyclines are effective against rheumatoid arthritis ( RA ) . Levofloxacin , the bacteriologically active isomer of ofloxacin , is used in the treatment of infections caused by periodontopathic bacteria and facultative anaerobic bacteria . The aim of this study is to evaluate the clinical efficacy , safety , and tolerability of levofloxacin in patients with rheumatoid arthritis . Methods : In a 6-month , double-blind trial , we r and omly assigned 76 patients with persistently active rheumatoid arthritis despite at least 6 months of methotrexate therapy at a stable dose of 15 to 25 mg per week to receive either levofloxacin ( 500 mg ) or placebo orally once daily while continuing to receive methotrexate . The change from baseline to six months in the swollen-joint count and tender-joint count was the primary measure of efficacy . Secondary endpoints included pain , quality of life , duration of morning stiffness , erythrocyte sedimentation rate , C-reactive protein level , and physician ’s and patient ’s global assessment s. The data were also analyzed to determine the number of patients meeting American College of Rheumatology criteria for 20 , 50 , and 70 % improvement . Results : The levofloxacin plus methotrexate was associated with the greatest reduction in the number of swollen or tender joints ( P < 0.001 ) . The levofloxacin plus methotrexate group also had significant improvement in many of the secondary outcome measures ( P < 0.001 ) . Levofloxacin was well tolerated . There were no dose-limiting toxic effects . Conclusion : In patients with active rheumatoid arthritis who received methotrexate , treatment with levofloxacin significantly improved the signs and symptoms of rheumatoid arthritis [17371885] Context First-year results of the BeSt study showed that initial combination therapy for rheumatoid arthritis produced more rapid clinical improvement and less radiologic evidence of progression of joint damage than did initial monotherapy . Contribution The investigators assessed clinical and radiologic outcomes during year 2 while following a scheduled program of step-up and step-down medication adjustment based on disease activity score . All treatment groups achieved similar disease activity after 2 years , although initial monotherapy was often converted to combination therapy during follow-up . Implication s Although all regimens were equally effective in eventually controlling disease activity , the rapid control produced by initial combination therapy may translate into decreased joint damage . The Editors Over the past few years , the outcome for patients with rheumatoid arthritis has improved considerably ( 1 ) . Combinations of disease-modifying antirheumatic drugs ( DMARDs ) with corticosteroids and DMARDs with the new tumor necrosis factor antagonists seem to suppress the inflammatory process more effectively than single-drug therapy in patients with early ( 210 ) and established ( 1115 ) disease . This results in less progression of radiographic joint damage and better preservation of physical function compared with single-drug therapy . More recently , tight control of disease activity has been shown to improve outcome ( 16 ) , and there are indications that outcome is related to adherence to treatment guidelines ( 17 ) . Whether combination therapy with DMARDs , corticosteroids , or tumor necrosis factor antagonists should be considered for initial treatment in all patients with rheumatoid arthritis or whether such therapy should be reserved for patients who do not respond to monotherapy is unknown . Therefore , the BeSt study ( 9 ) evaluated the efficacy of 4 of the most frequently used treatment strategies in a head-to-head comparison : sequential monotherapy ( group 1 ) , step-up combination therapy ( group 2 ) , initial combination therapy with tapered high-dose prednisone ( group 3 ) , and initial combination therapy with infliximab ( group 4 ) . Treatment adjustments were made every 3 months in patients with an insufficient response or a continued good response . During the first year of treatment , initial combination therapy for groups 3 and 4 result ed in more rapid clinical improvement and less progression of joint damage compared with initial monotherapy for groups 1 and 2 . In the second year , response to therapy continued to be tightly monitored . Treatment adjustments were made according to the protocol . We evaluated whether the initial clinical and radiologic outcomes could be maintained and what treatment adjustments were needed in each group . Methods Patients Rheumatologists participating in the Foundation for Applied Rheumatology Research in 18 peripheral and 2 university hospitals in the western part of the Netherl and s design ed and conducted the BeSt study . Between April 2000 and August 2002 , we recruited patients with early rheumatoid arthritis who fulfilled the American College of Rheumatology ( ACR ) 1987 criteria for rheumatoid arthritis ( 18 ) . Patients were 18 years of age or older ; had a disease duration of 2 years or less ; had active disease with at least 6 of 66 swollen joints and at least 6 of 68 tender joints ; and had an erythrocyte sedimentation rate of 28 mm/h or greater or a global health score of 20 mm or more ( on a visual analogue scale of 0 mm [ best ] to 100 mm [ worst ] ) . Patient enrollment criteria have been described in detail previously ( 9 ) . The medical ethics committee at each participating center approved the study protocol , and all patients gave written informed consent before study inclusion . Treatment Protocol Patients were allocated to 1 of 4 treatment groups by variable block r and omization ( 913 ) , which was stratified per center . Treatment groups were sequential monotherapy ( group 1 ) , step-up combination therapy ( group 2 ) , initial combination therapy with tapered high-dose prednisone ( group 3 ) , and initial combination therapy with infliximab ( group 4 ) . For patients who did not respond to medication , the protocol prescribed many subsequent steps . The decision of whether to adjust medication was made every 3 months on the basis of disease activity score ( 19 ) , a continuous measure consisting of the Ritchie articular index and number of swollen joints in a 44-joint count , erythrocyte sedimentation rate , and global health as measured on a visual analogue scale . A disease activity score of 2.4 or less indicates low disease activity ( 20 ) . A research nurse who remained blinded to the allocated treatment group during the study period calculated the score . If the disease activity score was greater than 2.4 ( insufficient response ) , the treating physician immediately adjusted therapy by proceeding to the next step in the allocated treatment group . If the disease activity score was 2.4 or less for at least 6 months , medication was gradually withdrawn until 1 drug remained in a maintenance dosage . Patients in group 1 started with methotrexate , followed subsequently by sulfasalazine , leflunomide , methotrexate with infliximab , gold with methylprednisolone ( intramuscular ) , methotrexate with cyclosporine and prednisone , and azathioprine with prednisone . Patients in group 2 started with methotrexate , followed subsequently by methotrexate with sulfasalazine , methotrexate with sulfasalazine and hydroxychloroquine , methotrexate with sulfasalazine , hydroxychloroquine and prednisone , methotrexate with infliximab , methotrexate with cyclosporine and prednisone , leflunomide , and azathioprine with prednisone . Patients in group 3 started with the combination of methotrexate , sulfasalazine , and tapered high-dose prednisone ( 2 ) , followed subsequently by methotrexate with cyclosporine and prednisone , methotrexate with infliximab , leflunomide , gold with methylprednisolone , and azathioprine with prednisone . Patients in group 4 started with the combination of methotrexate and infliximab , followed subsequently by sulfasalazine , leflunomide , methotrexate with cyclosporine and prednisone , gold with methylprednisolone , and azathioprine with prednisone . In addition to the regular trimonthly assessment s , we calculated additional disease activity scores every 8 weeks in all patients who were treated with infliximab in the week before infusion . On the basis of these scores , we decided whether to increase or taper the dosage . The treatment protocol and dose regimen have been described in detail previously ( 9 ) . We permitted concomitant treatment with nonsteroidal anti-inflammatory drugs and intra-articular injections with corticosteroids and did not allow other parenteral corticosteroids . We allowed DMARDs or oral corticosteroids only as dictated by the treatment protocol . All patients received folic acid , 1 mg per day , during treatment with methotrexate . Study End Points and Assessment s The primary efficacy end point was functional ability , as measured by the Dutch Health Assessment Question naire . Higher scores indicated more severe loss of physical function ( 21 ) . Secondary efficacy end points were 20 % and 70 % improvement according to the ACR ( ACR20 and ACR70 , respectively ) response criteria ( 22 ) and clinical remission , defined as a disease activity score less than 1.6 ( 23 ) . Assessment s were done every 3 months by blinded research nurses , who were trained at study onset and every 6 months thereafter to maintain consistency . Two study physicians ensured adherence to the protocol every 3 months . All protocol deviations were recorded . Patients were not informed about study outcomes until the end of the second year of follow-up . The primary radiographic end point was the change in the total Sharpvan der Heijde score for joint damage , which ranged from 0 to 448 , over 2 years ( 24 ) . Two trained readers independently scored the radiographs of h and s , wrists , and feet at baseline and at the 2-year follow-up . The patient 's identity , treatment group , and sequence of the films in sets were masked to the readers . We used the mean score of the 2 readers for the analysis . The intraobserver coefficients were 0.90 and 0.91 , and the interobserver coefficient was 0.94 . Erosive disease was defined as a mean erosion score greater than 0.5 . Toxicity We performed physical examination and laboratory tests and recorded all adverse events at all visits . If necessary , the treating physician adjusted the patient 's medication as outlined previously . Serious adverse events were defined as an adverse reaction result ing in any of the following outcomes : a life-threatening condition or death , substantial or permanent disability , malignant disease , hospitalization or prolongation of hospitalization , or a congenital abnormality or birth defect . Before beginning infliximab therapy , all patients were evaluated for tuberculosis with a purified protein derivative skin test and chest radiography . In the beginning of 2002 , congestive heart failure was added as a contraindication for treatment with infliximab . Treatment was discontinued for previously enrolled patients with functional classes I , II , III , and IV concomitant congestive heart failure , as defined by the New York Heart Association ( 25 ) . These patients ' conditions seemed to be worsening with infliximab therapy . Worsening was defined as every transition to a higher functional class . Statistical Analysis We needed a sample size of 468 patients ( 117 per group ) to ascertain 80 % power to detect a difference of at least 0.2 in the Health Assessment Question naire score . This was set as a clinical ly relevant difference with a 5 % significance level and adjustment for multiple comparisons between groups , assuming an SD of 0.45 . The sample size also ensured greater than 80 % power to detect a difference of 20 % or greater in the change in score for radiologic joint damage . We performed intention-to-treat analyses . When appropriate , we [12860733] Objective : To evaluate whether early combined therapy with methotrexate ( MTX ) and sulfasalazine ( SSZ ) during the first year in early rheumatoid arthritis ( RA ) induces long term beneficial effects , compared with monotherapy , when the further treatment strategy is a free choice . Methods : Study design : five year multicentre prospect i ve longitudinal trial . Participants : 146/205 patients with RA previously included in a one year prospect i ve r and omised trial comparing the effects of treatment with MTX , SSZ , or a combination of both . Criteria for inclusion : patients with early RA ( ⩽1 year duration ) . Follow up : between the end of years 1 and 5 , patients were followed up and treated by their own rheumatologist , who was allowed to indicate any treatment . Outcome measures : disease activity score ( DAS ) , health assessment question naire ( HAQ ) , and Sharp/van der Heijde radiological score at baseline and after five years of follow up . Analysis : comparison of the five year follow up DAS , HAQ , and radiological scores in patients given combined and single treatment during the first year . Results : At the end of the five years of follow up , the patients primarily receiving single or combined treatment had similar mean DAS , HAQ , and radiographic scores . Conclusion : Treatment of patients with early RA using combined therapy with MTX and SSZ during the first year did not influence the long term inflammatory status , or disability , or structural changes , compared with single disease modifying antirheumatic drug treatment [7791814] BACKGROUND Patients with severe rheumatoid arthritis who are treated with methotrexate frequently have only partial improvement . METHODS In a six-month r and omized , double-blind trial , we compared combination therapy with cyclosporine ( 2.5 to 5 mg per kilogram of body weight per day in two divided doses at 12-hour intervals ) and methotrexate ( at the maximal tolerated dose ) with methotrexate and placebo in 148 patients with rheumatoid arthritis who had residual inflammation and disability despite partial but substantial responses to prior methotrexate treatment . The primary outcome measure was the change in the number of tender joints . RESULTS The mean ( + /- SD ) dose of cyclosporine at the final treatment was 2.97 + /- 1.02 mg per kilogram per day . As compared with the placebo group , the patients in the treatment group had a net improvement in the tender-joint count of 25 percent , or 4.8 joints ( 95 percent confidence interval , 0.7 to 8.9 ; P = 0.02 ) , and in the swollen-joint count of 25 percent , or 3.8 joints ( 95 percent confidence interval , 1.3 to 6.3 ; P = 0.005 ) ; improvement in overall disease activity as assessed by the physician ( 19 percent , P < 0.001 ) and the patient ( 21 percent , P < 0.001 ) ; and improvement in joint pain ( 23 percent , P = 0.04 ) and in the degree of disability ( 26 percent , P < 0.001 ) . The mean erythrocyte sedimentation rate increased by 4.2 mm per hour in the cyclosporine group and decreased by 4.8 mm per hour in the placebo group ( P = 0.006 ) . Thirty-six patients ( 48 percent ) in the cyclosporine group and 12 patients ( 16 percent ) in the placebo group ( P < 0.001 ) met the 1993 criteria for improvement of the American College of Rheumatology ( more than 20 percent improvement in the numbers of both swollen and tender joints and improvement in three of five other variables ) . Seventeen patients in the cyclosporine group and 12 patients in the placebo group were withdrawn from the study ; 2 patients in the cyclosporine group died , 1 from viral pneumonia and the other in a motor vehicle accident . Serum creatinine concentrations increased by a mean of 0.14 + /- 0.27 mg per deciliter ( 12 + /- 24 mmol per liter ) in the cyclosporine group and by 0.05 + /- 0.19 mg per deciliter ( 4 + /- 17 mmol per liter ) in the placebo group ( P = 0.02 ) . CONCLUSIONS In a six-month study , patients with severe rheumatoid arthritis and only partial responses to methotrexate had clinical ly important improvement after combination therapy with cyclosporine and methotrexate . Side effects were not substantially increased . Long-term follow-up of patients treated with this combination is needed [9374925] To compare the efficacy of sulphasalazine , methotrexate , and the combination of both in patients with early rheumatoid arthritis ( RA ) , not treated with disease-modifying anti-rheumatic drugs previously , we conducted a double-blind , double-dummy , controlled , clinical trial . One hundred and five patients with active , early RA , rheumatoid factor and /or HLA DR1/4 positive were r and omized between sulphasalazine ( SSZ ) 2000 ( maximum 3000 ) mg daily , or methotrexate ( MTX ) 7.5 ( maximum 15 ) mg weekly , or the combination ( COMBI ) of both , and were followed up by a single observer for 52 weeks . The mean change over time per patient , including all visits , in Disease Activity Score ( DAS ) was : SSZ : -1.6 ( 95 % CI -2.0 to -1.2 ) ; MTX : -1.7 ( -2.0 to -1.4 ) ; COMBI : -1.9 ( -2.2 to -1.6 ) ; the difference week 0-week 52 ( SSZ , MTX , COMBI respectively ) ; DAS : -1.8 , -2.0 , -2.3 , Ritchie articular index : -9.2 , -9.5 , -10.6 , swollen joints : -9.2 , -12.4 , -14.3 , erythrocyte sedimentation rate : -17 , -21 , -28 . Nausea occurred significantly more in the COMBI group . The numbers of drop-outs due to toxicity were SSZ 9 , MTX 2 , COMBI 5 . In conclusion , there were no significant differences in efficacy between combination and single therapy , only a modest trend favouring COMBI . The results of MTX and SSZ were very comparable . Nausea occurred more often in the COMBI group : the number of withdrawals due to adverse events did not differ significantly

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### Context: [7912633] Sulphasalazine ( SASP ) and methotrexate ( MTX ) are well-established treatments for RA but the use of these drugs in combination has been avoided as both have antifolate activity . In this paper we report our experience with 32 patients treated with the combination MTX/SASP and compare the toxicity and tolerability of the combination with 63 patients treated with MTX alone . The median duration of exposure to the combination was 23 months . Nineteen patients have continued this regime for over 18 months . Five patients on MTX/SASP combination discontinued MTX , in four cases due to toxicity and in one because MTX/SASP was ineffective . In 17 patients on MTX alone , the drug was withdrawn permanently . In seven cases the cause was toxicity including two patients with severe reactions . In patients known to tolerate SASP alone , the combination of MTX/SASP is also well tolerated . In our experience of 48 patient-years of such combination therapy , there is no increase in toxicity compared to therapy with MTX alone in RA [8633829] In recent years , therapeutic strategies for patients with rheumatoid arthritis have been discussed in detail [ 1 - 8 ] . Traditional therapy , usually referred to as the pyramid model , begins with nonsteroidal anti-inflammatory drugs ( NSAIDs ) . If these are insufficiently effective , they are later replaced or supplemented with second-line antirheumatic drugs , which are distinguished from NSAIDs primarily by their assumed disease-modifying potential and delayed onset of action . These second-line drugs are also referred to as slow-acting antirheumatic drugs ( SAARDs ) or disease-modifying antirheumatic drugs ( DMARDs ) . Traditionally , the SAARDs of first choice have been hydroxychloroquine or intramuscular gold followed by D-penicillamine , methotrexate , or azathioprine . The traditional therapeutic pyramid is based on the principle of primum non nocere : Because of their potential toxicity , SAARDs should only be given when milder therapies have failed . Recently , the beneficial effects of the pyramid strategy have been question ed because the long-term outcome of rheumatoid arthritis continues to be disappointing . Patients with rheumatoid arthritis have increased mortality [ 9 , 10 ] , and their quality of life is seriously affected by functional impairment and loss of employment [ 11 , 12 ] . The pyramid model might be undesirable because administering SAARDs only after milder regimens prove to be insufficiently effective delays the suppression of inflammation . It is preferable that the disease process be controlled as soon as possible , because radiologic abnormalities appear in the joints early in the course of the disease [ 13 , 14 ] and are related to the extent of inflammation [ 15 , 16 ] . Toxicity indices for NSAIDs and most SAARDs have recently been shown to be similar ; thus , exposure of patients to possible adverse reactions is probably not in itself a reason to withhold treatment with SAARDs [ 17 ] . However , the ability of SAARDs to modify the course of disease and prevent radiologic damage is often question ed [ 18 , 19 ] . The poor long-term outcome of rheumatoid arthritis might be caused not by a delay in effective treatment but by the low disease-modifying power of both first- and second-line drugs . The short courses of SAARDs ( short because of adverse reactions or impatience with a delay in effect ) might also play a role [ 20 , 21 ] . Combinations of SAARDs have not been shown to be superior to single drugs [ 21 , 22 ] . Current clinical practice is shifting toward the earlier introduction of second-line treatment for rheumatoid arthritis , but thus far no clinical trials have shown this strategy to be beneficial . We investigated the consequences of ignoring the treatment pyramid for patients with recent-onset rheumatoid arthritis . In this report , we describe the first-year results of a r and omized clinical trial in which the delayed and the immediate introduction of SAARDs were compared . Effectiveness was measured by disease activity and progression of radiologic abnormalities . The various SAARDs are considered as a single group in this report ; comparisons among the second-line therapies will be reported in detail later . Methods Patients As of January 1990 , all patients with recent-onset rheumatoid arthritis ( diagnosed according to the 1987 American College of Rheumatology criteria [ [ 23 ] ] from six rheumatologic centers in the region of Utrecht , the Netherl and s , were asked to participate in a r and omized , prospect i ve clinical trial . Disease duration had to have been less than 1 year , and most patients were enrolled shortly after diagnosis . The following exclusion criteria were applied : 1 ) age younger than 17 years , 2 ) comorbid conditions that might interfere with one of the therapeutic strategies , 3 ) previous or current treatment with any SAARDs , glucocorticosteroids , or cytotoxic or immunosuppressive therapy , 4 ) the possibility of pregnancy or breast feeding , and 5 ) psychiatric or mental disturbances that would make adherence to the study protocol unlikely . All patients gave informed consent before study entry and were told that the study was intended to compare the unsure outcome of treatment with NSAIDs alone with that of treatment with NSAIDs and a SAARD for rheumatoid arthritis at an early stage . The study design was approved by the ethical committees of all participating hospitals . The baseline characteristics of patients who were eligible for the study but who objected to r and omization were compared with those of r and omly assigned patients to determine whether any selection bias had occurred . Treatment Patients entering the study were r and omly assigned to one of two therapeutic groups . All r and omization procedures were done by drawing sealed envelopes from blocks of 100 with equal numbers of patients for each of the four treatments per hospital ; the person doing the procedures was blinded to treatment assignments . This method was used because eligible patients were not distributed equally among the centers . The assigned therapeutic strategy was continued for at least 1 year . In the non-SAARD group , patients began receiving NSAID therapy , the dose and type of which could be modified at any time . For this group , initiation of SAARD treatment during the study was regarded as discontinuation of the therapeutic strategy . In the SAARD group , patients were r and omly assigned ( by persons blinded to treatment assignments ) to treatment with one of the following SAARDs : hydroxychloroquine ( 400 mg/d ) , intramuscular gold ( aurothioglucose , 50 mg/wk ) , or oral methotrexate ( 7.5 to 15 mg/wk ) . Therapy with the initial SAARD was continued for 12 months unless adverse reactions necessitated discontinuation ; if this occurred , another SAARD was given . Hydroxychloroquine was followed by auranofin ( 6 to 9 mg/d ) ; intramuscular gold was followed by D-penicillamine ( 500 to 750 mg/d ) ; and methotrexate was followed by sulfasalazine ( 2000 to 3000 mg/d ) . Discontinuation of therapy with the second SAARD was regarded as discontinuation of the therapeutic strategy . Use of NSAIDs was allowed in the SAARD group ; as in the non-SAARD group , the dose and type could be changed at any time . Patients were assigned to the non-SAARD group and the SAARD group in a ratio of 1:3 , and power calculations for the primary end point disability ( equals 0.05 ; equals 0.20 ; difference to be detected , 25 % ) indicated that group sizes of 40 and 120 , respectively , would be sufficient . The ratio of 1:3 was chosen to enable later comparisons of results within the SAARD group , which were thought to be similar . The use of analgesics was allowed in both groups ; the use of oral glucocorticosteroids was avoided if possible ; and intraarticular injections were not allowed within 2 months of a scheduled visit . Criteria for discontinuation or dose adjustment of a SAARD because of adverse reactions were described in detail in the study protocol . Discontinuation of any treatment because of sustained disease activity was done only if the patient and the attending physician ( who had to discuss the patient with a colleague ) judged it to be unavoidable . Primary End Points Assessment s were done at the start of the trial and were repeated every 3 months . Clinical variables were assessed by the same physician or research nurse for each patient on each occasion . Primary end points were functional disability , pain , joint score , erythrocyte sedimentation rate , and radiologic abnormalities [ 24 ] . Radiologic abnormalities and erythrocyte sedimentation rate were determined by persons blinded to treatment assignments ; functional disability and pain were self-assessed scores ; and determination of the joint score was not blinded to treatment . Functional disability was assessed using a vali date d Dutch version of the Health Assessment Question naire Disability Score [ 25 - 27 ] . The question naire scores range from 0 to 3 ; 0 is the best score ( no problems ) , and 3 is the worst . Pain was measured on two horizontal visual analog scales of 100 mm ; the mean of the scores for pain during the night and pain during the morning was calculated . The joint score according to Thompson and colleagues [ 28 , 29 ] assessed the simultaneous presence of joint tenderness and swelling in a selection of joints weighed for joint size ( range , 0 to 534 ) [ 28 , 29 ] . Erythrocyte sedimentation rate ( mm/h ) was measured using Westergren method . Radiography of h and s and feet was done at the start of the study and at 12 months . A modified version of the method of Sharp and coworkers [ 30 , 31 ] was used to score radiologic abnormalities . According to this method , erosions and joint space narrowing in h and and foot joints are scored and added together to obtain a total radiologic damage score ( range , 0 to 448 ) . All radiographs were evaluated by two investigators who were blinded to treatment assignments . The scores of the first investigator were used in the analyses , and the scores of the second investigator were used to vali date the scores of the first . Correlation between the two sets of scores was satisfactory ( Spearman correlation coefficients for scores at baseline and at 12 months were 0.84 for both ) ; the second investigator was found to have given lower scores ( means at baseline were 4.2 and 3.4 , respectively ; means at 12 months were 11.2 and 9.7 , respectively ) . Therefore , in individual cases , differences in total scores of 25 % or more were discussed until an agreement was reached on the appropriate score . That score was then used in the analyses . Additional Assessment s Secondary end points were grip strength ( mean of three measurements of each h and with a vigorimeter [ Martin , Tuttlingen , Germany ] in kPa ) , duration of morning stiffness ( maximum , 720 min ) , and general well-being ( horizontal visual analog scale of 100 mm ) . Additional laboratory variables were serum level of C-reactive protein ( mg/L ) , hemoglobin concentration ( mmol/L ) , and platelet count ( times 109/L ) . Rheumatoid factor status was determined to be positive or negative , as indicated by either the [15290730] OBJECTIVE To obtain additional safety and efficacy data on leflunomide ( LEF ) treatment in combination with methotrexate ( MTX ) therapy in an open-label extension study in patients with rheumatoid arthritis ( RA ) . METHODS Following a 24 week , r and omized , double-blind trial of adding placebo ( PLA ) or LEF to stable MTX therapy , patients could enter a 24 week extension . Subjects r and omized to LEF and MTX continued treatment [ ( LEF/LEF ) + MTX ] . Subjects r and omized to PLA and MTX switched to LEF ( 10 mg/day , no loading dose ) and MTX [ ( PLA/LEF ) + MTX ] . The double-blind regarding initial r and omization was maintained . RESULTS For subjects in the extension phase , American College of Rheumatology 20 % ( ACR20 ) responder rates for the ( LEF/LEF ) + MTX group were maintained from Week 24 ( 57/96 , 59.4 % ) to Week 48 ( 53/96 , 55.2 % ) . ACR20 responder rates improved in patients switched to LEF from PLA at Week 24 [ ( PLA/LEF ) + MTX ] from 25.0 % ( 24/96 ) at Week 24 to 57.3 % ( 55/96 ) at Week 48 . Patients in the extension who switched from PLA to LEF without a loading dose exhibited a lower incidence of elevated transaminases compared to patients initially r and omized to LEF . Diarrhea and nausea were less frequent during the open-label extension in patients who did not receive a LEF loading dose . CONCLUSION Response to therapy was maintained to 48 weeks of treatment in patients who continued to receive LEF and MTX during the extension . Importantly , ACR20 response rates after 24 weeks of LEF therapy were similar between patients switched from PLA to LEF without loading dose , and those who received a loading does of LEF ( 100 mg/day x 2 days ) at r and omization . Fewer adverse events were reported in patients switched to LEF without a loading dose [9712088] OBJECTIVE To evaluate tolerability and efficacy of combination therapy with methotrexate (MTX)/parenteral gold or MTX/other disease modifying antirheumatic drug ( DMARD , d-penicillamine or chloroquine ) in comparison with MTX monotherapy in patients with longst and ing destructive active rheumatoid arthritis ( RA ) . METHODS In an open prospect i ve trial all consecutive MTX-naive patients with active RA starting MTX treatment alone or in combination between January 1980 and December 1987 , after failing one or more DMARD , were followed at regular intervals up to 108 months . Evaluations included the number of swollen joints ( 0 - 32 ) , grip strength , patient assessment of pain and mobility , erythrocyte sedimentation rate ( ESR ) , C-reactive protein ( CRP ) , and hemoglobin . Group 1 , treated with MTX monotherapy ( n = 97 ) , was compared with Group 2 , with combination therapy MTX/parenteral gold ( n = 126 ) and Group 3 with MTX + other DMARD ( n = 48 ) . RESULTS There were no significant differences between the groups in mean age ( 59/57/56 yrs ) , disease duration ( 9.6/7.7/8.3 yrs ) , seropositivity ( 80/88/82 % ) , or ACR anatomical disease stage ( 2/3 in stage III and IV ) . The number of swollen joints ( 16.8/19.3/16.1 of 32 ) and the CRP ( 4.4/5.1/4.7 mg/dl ) was significantly greater in Group 2 ; other disease activity variables were not significantly different . The mean MTX dose at baseline ( mostly parenteral ) was 16.8/17.0/12.8 mg and could be reduced to around 12 mg ( predominantly oral ) in the 3 groups . Frequency of adverse events ( 80/83/88 % ) , nature of clinical ( nausea , hair loss , stomatitis ) and laboratory ( liver enzyme elevation , slight proteinuria ) side effects , and withdrawal rate for side effects ( 20.6/15.0/12.5 % ) were not significantly different between the groups . After 5 years 54/54/80 % of patients continued their treatment . All efficacy variables improved significantly ( p < 0.001 ) in all groups without significant intergroup difference . Improvement > 50 % in the ESR was achieved in 63/68/41 % and in the swollen joint count in 70/85/48 % of patients after 3 years . The number of patients taking oral steroids decreased from 63/59/65 % to 22/31/48 % after 3 years . In half the patients hemoglobin increased by at least 1 g/dl . CONCLUSION Combination therapy of MTX with parenteral gold or other DMARD is effective in reducing clinical and biochemical disease activity in patients with longst and ing destructive RA with no greater risk of toxicity compared with MTX alone ; our study however , did not show clear advantages of combination therapy versus monotherapy for effectiveness [7973475] To compare the efficacy of the combination therapy Methotrexate ( MTX ) and Chloroquine ( CHLO ) with MTX and Placebo ( PLA ) in the treatment of Rheumatoid Arthritis . A total of 82 patients with Rheumatoid Arthritis ( RA ) , diagnosed according to the American College of Rheumatology criteria , received orally either MTX 7.5 mg/week and CHLO 250 mg/day or MTX 7.5 mg/week and PLA 1 tablet/day . Adverse effects ( AE ) were monitored monthly and disease activity was assessed at 0 , 2 , 4 and 6 months . Sixty-eight patients completed the study . All outcome measures improved significantly in both treatment groups . Patients receiving MTX/CHLO ended the study with a significantly lower joint count , greater grip strength and better functional ability the patients in the MTX/PLA group , respectively ; 4.5 vs 7.5 ( P < 0.05 ) , 113.3 vs 89.1 ( P < 0.05 ) and 0.636 vs 0.811 ( P < 0.05 ) . Mild AE were more frequently observed in the MTX/CHLO , 17 events in 15 patients , compared to 9 events in 8 patients in the MTX/PLA group ( NS ) . These data indicate that MTX/CHLO is slightly more efficacious and toxic than is MTX/PLA in the treatment of RA [17183623] OBJECTIVE To study sustainability of remission and good treatment response , and the association of both with radiographic progression , in early rheumatoid arthritis ( RA ) in the Finnish Rheumatoid Arthritis Combination Therapy trial ( FIN-RACo ) . METHODS Patients were r and omized to receive either a combination of disease modifying antirheumatic drugs ( DMARD ; COMBI , n = 97 ) or a single DMARD ( SINGLE , n = 98 ) . Remission was defined according to modified American College of Rheumatology ( ACR ) remission criteria and Disease Activity Score 28 joint count ( DAS28 ) < or = 2.6 , and sustained remission as presence of remission at 6 , 12 , and 24 months . Good treatment response was defined as DAS28 ( 3/4 ) 3.2 and decrease of DAS28 > 1.2 . RESULTS In 169 patients with complete data , 33 ( 42 % ) COMBI and 18 ( 20 % ) SINGLE patients achieved modified ACR remission at 2 years , which was sustained in 11 ( 14 % ) COMBI and 3 ( 3 % ) SINGLE patients . Fifty-four ( 68 % ) COMBI and 37 ( 41 % ) SINGLE patients were in DAS28 remission at 2 years , which was sustained in 40 ( 51 % ) COMBI and 14 ( 16 % ) SINGLE patients . Good treatment response was sustained in 67 % of COMBI and 27 % of SINGLE patients . Over 2 years , the Larsen score increased by a median of 1 ( 95 % CI 0 - 2 ) in patients in sustained DAS28 remission compared to 4 ( 95 % CI 2 - 16 ) in patients who were in DAS28 remission at 6 months but lost it later ; and by 6 ( 95 % CI 2 - 10 ) in patients who were not in remission at 6 months . CONCLUSION A remarkable proportion of patients with early RA treated with combinations of DMARD were in remission at 2 years , and remission was more often sustained compared to patients treated with a single DMARD . Sustained remission protects against radiographic joint damage [16645967] OBJECTIVE To investigate whether disease control can be achieved in early active rheumatoid arthritis ( RA ) by treatment with methotrexate and intraarticular betamethasone , and whether the addition of cyclosporine to the regimen has any additional effect . METHODS Patients ( n = 160 ) were r and omized to receive methotrexate 7.5 mg/week plus cyclosporine 2.5 mg/kg of body weight/day ( combination therapy ) or methotrexate plus placebo-cyclosporine ( monotherapy ) . At weeks 0 , 2 , 4 , 6 , and 8 and every 4 weeks thereafter , betamethasone was injected into swollen joints ( maximum 4 joints or 4 ml per visit ) . Beginning at week 8 , if synovitis was present , the methotrexate dosage was increased stepwise up to 20 mg/week , with a subsequent stepwise increase in the cyclosporine or placebo-cyclosporine dosage up to 4 mg/kg . RESULTS At 52 weeks , 20 % improvement according to the American College of Rheumatology criteria ( ACR20 ) was achieved in 85 % of the combination therapy group versus 68 % of the monotherapy group ( P = 0.02 ) . The median individual overall ACR response ( ACR-N ) in the 2 groups was 80.0 % ( interquartile range 40.1 - 91.8 % ) and 54.5 % ( interquartile range 2.4 - 87.8 % ) , respectively ( P = 0.025 ) . At 48 and 52 weeks , ACR remission criteria were met in 35 % of the combination therapy group and 28 % of the monotherapy group . Progression in the Larsen score at 52 weeks was -0.2 + /- 6.5 and 0.4 + /- 6.9 ( mean + /- SD ) in the combination therapy and monotherapy groups , respectively . Serum creatinine levels increased by 7 % , and hypertrichosis was more prevalent , in the combination therapy group . CONCLUSION Combined treatment with methotrexate and intraarticular glucocorticoid showed excellent disease control and stopped the progression of erosions in patients with early active RA , who had a poor prognosis . Addition of cyclosporine improved the ACR20 and ACR-N responses , whereas the ACR50 and ACR70 responses , remission rates , and radiographic changes did not differ between the 2 study groups [8546736] OBJECTIVE To vali date the European League Against Rheumatism ( EULAR ) , the American College of Rheumatology ( ACR ) , and the World Health Organization (WHO)/International League Against Rheumatism ( ILAR ) response criteria for rheumatoid arthritis ( RA ) . METHODS EULAR response criteria were developed combining change from baseline and level of disease activity attained during follow up . In a trial comparing hydroxychloroquine and sulfasalazine , we studied construct ( radiographic progression ) , criterion ( functional capacity ) , and discriminant validity . RESULTS EULAR response criteria had good construct , criterion , and discriminant validity , ACR and WHO/ILAR criteria showed only good criterion validity . CONCLUSION EULAR response criteria showed better construct and discriminant validity than did the ACR and the WHO/ILAR response criteria for RA [10609068] OBJECTIVE The response to single disease modifying antirheumatic drug ( DMARD ) is often suboptimal in patients with rheumatoid arthritis ( RA ) . Thus , despite the limited data on the therapeutic efficacy of combination therapies , many patients are currently treated with a combination of DMARDs . METHODS We studied prospect ively the efficacy of combination therapy with DMARDs . The study was design ed as a r and omized trial and a single DMARD or two or three DMARD combinations were administered to 180 consecutive , age- and sex-matched patients with active RA , each of whom was followed up for a period of 2 years under treatment . Patients were divided into 3 groups which did not differ with regard to demographic , clinical and laboratory parameters . Patients in group I were treated with a single DMARD [ methotrexate ( MTX ) 7.5 - 15 mg/week or sulfasalazine ( SSZ ) 1 - 2 g/day or hydroxychloroquine ( HCQ ) 200 mg/day ] , group II with MTX + SSZ or MTX + HCQ , and group III with a combination of all three drugs . Patients were re-evaluated at regular intervals by means of clinical and biochemical tests design ed to detect specific rheumatic activity . Radiological assessment s were also performed and scored according to Larsen by the same radiologist who was blinded to the treatment groups . RESULTS At the end of the trial there were significant improvements in the clinical and laboratory parameters in all 3 groups . However , improvements were greater and much more significant in the patients who were given combination therapies . The combination of MTX + SSZ + HCQ was more effective than both monotherapy and the two-drug combinations . CONCLUSION In conclusion , we suggest that patients with RA should be treated with combinations of DMARDs [10364900] OBJECTIVES To investigate the potential clinical benefit of a combination therapy . METHODS 205 patients fulfilling the ACR criteria for rheumatoid arthritis ( RA ) , not treated with disease modifying anti-rheumatoid drugs previously , with an early ( ⩽1 year duration ) , active ( Disease Activity Score ( DAS ) > 3.0 ) , rheumatoid factor and /or HLA DR 1/4 positive disease were r and omised between sulphasalazine ( SASP ) 2000 ( maximum 3000 ) mg daily ( n = 68 ) , or methotrexate ( MTX ) 7.5 ( maximum 15 ) mg weekly ( n = 69 ) or the combination ( SASP + MTX ) of both ( n = 68 ) . RESULTS The mean changes in the DAS during the one year follow up of the study was −1.15 , −0.87 , −1.26 in the SASP , MTX , and SASP + MTX group respectively ( p = 0.019 ) . However , there was no statistically significant difference in terms of either EULAR good responders 34 % , 38 % , 38 % or ACR criteria responders 59 % , 59 % , 65 % in the SASP , MTX , and SASP + MTX group respectively . Radiological progression evaluated by the modified Sharp score was very modest in the three groups : mean changes in erosion score : + 2.4 , + 2.4 , + 1.9 , in narrowing score : + 2.3 , + 2.1 , + 1.6 and in total damage score : + 4.6 , + 4.5 , + 3.5 , in the SASP , MTX , and SASP + MTX groups respectively . Adverse events occurred more frequently in the SASP + MTX group 91 % versus 75 % in the SASP and MTX group ( p = 0.025 ) . Nausea was the most frequent side effect : 32 % , 23 % , 49 % in the SASP , MTX , and SASP + MTX groups respectively ( p = 0.007 ) . CONCLUSION This study suggests that an early initiation therapy of disease modifying drug seems to be of benefit . However , this study was unable to demonstrate a clinical ly relevant superiority of the combination therapy although several outcomes were in favour of this observation . The tolerability of the three treatment modalities seems acceptable [16258899] OBJECTIVE Several treatment strategies have proven value in the amelioration of rheumatoid arthritis ( RA ) , but the optimal strategy for preventing long-term joint damage and functional decline is unclear . We undertook this study to compare clinical and radiographic outcomes of 4 different treatment strategies , with intense monitoring in all patients . METHODS In a multicenter , r and omized clinical trial , 508 patients were allocated to 1 of 4 treatment strategies : sequential disease-modifying antirheumatic drug monotherapy ( group 1 ) , step-up combination therapy ( group 2 ) , initial combination therapy with tapered high-dose prednisone ( group 3 ) , and initial combination therapy with the tumor necrosis factor antagonist infliximab ( group 4 ) . Treatment adjustments were made every 3 months in an effort to obtain low disease activity ( a Disease Activity Score in 44 joints of < or = 2.4 ) . RESULTS Initial combination therapy including either prednisone ( group 3 ) or infliximab ( group 4 ) result ed in earlier functional improvement than did sequential monotherapy ( group 1 ) and step-up combination therapy ( group 2 ) , with mean scores at 3 months on the Dutch version of the Health Assessment Question naire ( D-HAQ ) of 1.0 in groups 1 and 2 and 0.6 in groups 3 and 4 ( P < 0.001 ) . After 1 year , mean D-HAQ scores were 0.7 in groups 1 and 2 and 0.5 in groups 3 and 4 ( P = 0.009 ) . The median increases in total Sharp/Van der Heijde radiographic joint score were 2.0 , 2.5 , 1.0 , and 0.5 in groups 1 - 4 , respectively ( P < 0.001 ) . There were no significant differences in the number of adverse events and withdrawals between the groups . CONCLUSION In patients with early RA , initial combination therapy including either prednisone or infliximab result ed in earlier functional improvement and less radiographic damage after 1 year than did sequential monotherapy or step-up combination therapy [12810924] OBJECTIVE To determine whether patients with early rheumatoid arthritis ( RA ) treated with cyclosporin A ( CsA ) and methotrexate ( MTX ) in combination for 12 months show a lower rate of radiographic deterioration than those treated with MTX alone . METHODS In this controlled and r and omized single-blind trial , 61 consecutive patients with untreated RA of less than 2 yr duration were treated with either CsA + MTX combination therapy ( n = 30 ) or MTX alone ( n = 31 ) . The primary end-point was radiographic progression after 12 months , measured using the damage score ( DS ) of the Sharp and van der Heijde method . RESULTS Although there was a significant difference between the mean baseline and 12-month DS in both treatment groups ( MTX/CsA , 1.93 + /- 0.90 ; MTX , 7.47 + /- 2.03 ) , it was significantly less in the combination arm ( P = 0.018 ) . Of the 30 evaluable CsA + MTX patients , 16 ( 53 % ) were ACR20 responders , 15 ( 50 % ) ACR50 and 14 ( 47 % ) ACR70 ; the corresponding figures in the MTX arm were 19 ( 61 % ) , 13 ( 44 % ) and 6 ( 19 % ) . Toxicity was acceptable in both groups . CONCLUSIONS In patients with early RA , CsA + MTX combination therapy led to a significantly lower rate of 12-month radiographic progression , was effective on inflammatory articular symptoms , and was well tolerated [1642652] OBJECTIVE To compare the relative safety and efficacy of azathioprine ( AZA ) , methotrexate ( MTX ) , and the combination of both in the treatment of active rheumatoid arthritis ( RA ) . METHODS Two hundred twelve patients with active RA were entered into a 24-week prospect i ve , controlled , double-blind , multicenter trial and were r and omly assigned to 1 of 3 treatment groups . RESULTS One hundred fifty-eight patients finished 24 weeks of the study . There were no remissions seen but response rates were greater than 30 % for all outcome measures . Combination therapy was not statistically superior to MTX therapy alone , but both combination therapy and MTX alone were superior to AZA alone when patients were analyzed by intent-to-treat and with withdrawals treated as therapy failures . If only patients who continued taking the therapy were analyzed , the mean improvement was greater for AZA therapy than for MTX , while the combination remained the most active . Adverse effects on the gastrointestinal tract and elevations of liver enzyme levels were the most frequent causes for discontinuations . CONCLUSION Both combination therapy and MTX alone were superior to therapy with AZA alone for active RA but were not statistically different in their effect on outcome assessment [16870092] OBJECTIVE To evaluate the effectiveness of disease-modifying antirheumatic drugs , namely , methotrexate ( MTX ) , sulfasalazine ( SSZ ) and bucillamine ( BUC ) at low-doses ( 4 , 6 or 8 mg MTX , 500 or 1,000 mg SSZ , and 100 or 200 mg BUC ) in 1,358 patients with a follow-up of at least 12 months and more than 120 months . METHODS Clinical assessment s were based on the number of painful joints ( NPJ ) and that of swollen joints ( NSJ ) , CRP level , erythrocyte sedimentation rate , rheumatoid factor level and morning stiffness before and after treatment . Results were evaluated on the basis of the duration of treatment for each drug with inefficacy or inadequate efficacy as one endpoint for discontinuation and adverse drug reactions ( ADRs ) as the other in single agent and combination therapy . The incidence and nature of ADRs in single and combination treatment are described . RESULTS The effects of MTX , SSZ and BUC on clinical parameters were monitored over the first three months , and in particular , NPJs and NSJs were found to decrease significantly during single agent MTX or BUC treatment over 108 months . CRP levels remained significantly improved for more than 120 months with MTX . In the single and combination long-term treatments , continuation rate with inefficacy or inadequate efficacy as the end point achieved for each of the treatments were 83.1 % for MTX , 76.0 % for BUC , 68.5 % for SSZ , and in the case of the combination treatments , these rates were 83.3 % for MTX + BUC and 71.0 % for MTX+SSZ . Continuation rates using ADRs as the end point were 88 % for SSZ , 79.6 % for BUC and 79.4 % for MTX . The incidences of ADRs for the various treatments were : MTX 22.2 % , SSZ 11.0 % , BUC 20.6 % , MTX + BUC 30.0 % and MTX + SSZ 31.2 % . CONCLUSION MTX showed the highest efficacy even though it was administrated at a low dose ( 6 - 8 mg ) , as a single agent or in combination with other treatment . However , in combination treatments , the continuous duration of treatment ending in ADRs as the end point were lower than those in single treatments with MTX , SSZ and BUC [8833056] To assess the relative efficacy of methotrexate ( MTX ) , azathioprine ( AZA ) , and their combination in the treatment of rheumatoid arthritis ( RA ) , a double blind , prospect i ve , multicenter , controlled trial was carried out . Two hundred nine patients with active RA were treated with escalating doses of MTX ( 5 - 15 mg/week ) , AZA ( 50 - 150 mg/day ) , or combination ( 5/50 - 7.5/100 ) with opportunity to increase dosage at 6 week intervals . Patients were evaluated for clinical and laboratory improvement and assessed for radiologic progression at 48 weeks . One hundred ten patients remained on the initial , r and omly assigned therapy . Response was defined as 30 % or greater improvement in at least 3 of 4 variables , and occurred in the following : 38 % on the combination arm , 26 % on AZA , and 45 % on MTX ( p = 0.06 ) . A trend for decreased radiologic progression was seen in the MTX group . Adverse experiences and treatment termination occurred more frequently in the combination and AZA arms relative to the MTX group . The most frequent causes for treatment discontinuations were lack of effectiveness , gastrointestinal adverse effects and liver enzyme elevation . This study establishes that the combination of MTX and AZA in the dosages employed is not associated with more toxicity than treatment with single agents , but enhanced efficacy is not seen . A trend toward decreased radiographic progression was noted in the MTX treated patients [8849352] OBJECTIVE To assess the relative efficacy of methotrexate ( MTX ) , azathioprine ( AZA ) , and their combination in the treatment of rheumatoid arthritis ( RA ) in a double-blind , prospect i ve , multicenter , controlled trial . METHODS Two hundred nine patients with active RA were treated with escalating doses of MTX ( 5 - 15 mg/week ) , AZA ( 50 - 150 mg/day ) , or combination ( 5 mg MTX/week plus 50 mg AZA/day-7.5 mg MTX/week plus 100 mg AZA/day ) , with opportunity to increase the dosage at 6-week intervals . The patients were evaluated for significant clinical and laboratory improvement and assessed for radiologic progression at 48 weeks . RESULTS One hundred ten patients remained on the initial , r and omly assigned therapeutic regimen . The percentage of patients who were responders , defined as those who had 30 % or greater improvement in at least 3 of 4 variables , was 38 % for the combination treatment , 26 % for AZA , and 45 % for MTX ( P = 0.06 ) . A trend toward decreased radiologic progression was seen in the MTX-treated patients . Termination of treatment due to adverse experience occurred more frequently with combination and AZA treatments than with MTX treatment . Lack of effectiveness , adverse gastrointestinal effects , and liver enzyme elevation were the most frequent causes of treatment discontinuation . CONCLUSION This study establishes that the combination of MTX and AZA in the dosages utilized is not associated with more toxicity than treatment with single agents ; however , enhanced efficacy is also not seen . There is a trend toward decreased radiologic progression in patients treated with MTX [10334255] BACKGROUND The treatment of rheumatoid arthritis should aim at clinical remission . This multicentre , r and omised trial with 2-year follow-up sought evidence on the efficacy and tolerability of combination therapy ( sulphasalazine , methotrexate , hydroxychloroquine , and prednisolone ) compared with treatment with a single disease-modifying antirheumatic drug , with or without prednisolone , in the treatment of early rheumatoid arthritis . METHODS 199 patients were r and omly assigned to two treatment groups . 195 started the treatment ( 97 received combination and 98 single drug therapy ) . Single-drug therapy in all patients started with sulphasalazine ; in 51 patients methotrexate was later substituted . Oral prednisolone was required by 63 patients . The primary outcome measure was induction of remission . Analyses were intention to treat . FINDINGS 87 patients in the combination group and 91 in the single-therapy group completed the trial . After a year , remission was achieved in 24 of 97 patients with combination therapy , and 11 of 98 with single-drug therapy ( p=0.011 ) . The remission frequencies at 2 years were 36 of 97 and 18 of 98 ( p=0.003 ) . Clinical improvement ( American College of Rheumatology criteria of 50 % clinical response ) was achieved after 1 year in 68 ( 75 % ) patients with combination therapy , and in 56 ( 60 % ) using single-drug therapy ( p=0.028 ) , while at the 2-year visit 69 and 57 respectively ( 71 % vs 58 % , p=0.058 ) had clinical ly improved . The frequencies of adverse events were similar in both treatment groups . INTERPRETATION Combination therapy was better and not more hazardous than single treatment in induction of remission in early rheumatoid arthritis . The combination strategy as an initial therapy seems to increase the efficacy of the treatment in at least a proportion of patients with early rheumatoid arthritis [9330929] OBJECTIVE To evaluate the ability of hydroxychloroquine sulfate ( HCQ ) to extend the response to combination therapy with HCQ and methotrexate ( MTX ) and the safety of longterm HCQ maintenance therapy in patients with active rheumatoid arthritis ( RA ) . METHODS Two-part study consisting of an open label segment evaluating combination HCQ/MTX therapy followed by a double blind segment evaluating maintenance therapy for a total of 60 weeks . First , all patients were treated with HCQ 400 mg/day and MTX 7.5 to 15 mg/week for 24 weeks . Then , responders were r and omized into 3 groups : ( 1 ) HCQ with MTX as needed for disease flare ( n = 40 ) , ( 2 ) HCQ 400 mg/day ( n = 41 ) , or ( 3 ) placebo with MTX as needed for disease flare ( n = 40 ) , each for 36 weeks . RESULTS Clinical disease and laboratory variables improved significantly during initial combination therapy with HCQ and MTX . After MTX withdrawal , HCQ-containing maintenance regimens delayed the onset of disease flare ( p = 0.023 ) . There were no unexpected adverse events at any time or between-group differences in the distribution of adverse events during the double blind segment . CONCLUSION Combination of HCQ and MTX appeared to be effective and well tolerated for 24 weeks . After withdrawal of MTX , HCQ extended the response seen with combination therapy and was well tolerated for 36 weeks . Initial therapy with HCQ and MTX , followed by maintenance HCQ , may be a useful alternative for the treatment of RA [8833058] Rheumatoid arthritis ( RA ) has a profound effect on patients , producing significant morbidity and in some cases mortality . Because of this , most rheumatologists are moving to disease modifying antirheumatic drug ( DMARD ) therapy earlier in the course of RA . Methotrexate ( MTX ) has become the initial DMARD of choice for most rheumatologists . Unfortunately , treatment of RA with a single DMARD , including MTX , often results in a suboptimal response . Therefore , most rheumatologists are now using combinations of DMARD to treat patients with RA who have had incomplete responses to single DMARD therapy . The Rheumatoid Arthritis Investigational Network ( RAIN ) reported the results of a double blind , controlled comparison of triple drug therapy ( MTX-sulfasalazine-hydroxychloroquine ) against MTX alone , and against the combination of hydroxychloroquine and sulfasalazine . Twenty-eight patients who had suboptimal responses to MTX or the combination of sulfasalazine and hydroxychloroquine were then treated with triple therapy in an open label study . Fourteen had previously failed MTX therapy , and 14 had previously failed combination therapy with sulfasalazine and hydroxychloroquine . Both groups had statistically significant improvements in sedimentation rates , morning stiffness , swollen joint scores , tender joint scores , patient global status assessment , and physician global status assessment . Statistical significance was reached for all these variables for patients in both groups , but improvement was greater for the patients in the sulfasalazine-hydroxychloroquine group . Patients with RA who have had suboptimal responses to MTX , or to the combination of sulfasalazine-hydroxychloroquine , show both statistical and clinical ly significant improvement in multiple clinical variables when treated with the combination of MTX 17.5 mg/week , sulfasalazine 500 mg bid , and hydroxychloroquine 200 mg bid [7981992] To compare efficacy , toxicity , and the pharmacokinetics of the combination of sulphasalazine ( SASP ) and methotrexate ( MTX ) vs MTX alone in the treatment of SASP-resistant RA we conducted a controlled open clinical trial . Forty RA patients with active arthritis despite adequate SASP therapy , were allocated r and omly to regimes of either SASP+MTX or MTX alone . The patients were evaluated openly by a single observer for 24 weeks . In the first 15 patients using the combination , pharmacokinetics of MTX without and with SASP were studied . Thirty-eight patients completed the trial . The mean decrease in the disease activity score in the group of patients receiving the combination was significantly greater than in the MTX group ( -2.6 vs -1.3 respectively ) . The same pattern was seen concerning the other efficacy variables . There was no difference in the occurrence of toxicity . SASP had no influence on the pharmacokinetics of MTX . In conclusion in this open study the efficacy of the combination of MTX and SASP seems to be superior to MTX alone , the toxicity of both therapies was similar . This effect was not explained by the pharmacokinetics of MTX which were not altered by concomitant SASP administration [16645968] OBJECTIVE Bisphosphonates inhibit osteoclast activity , which is central to the development of bone damage in rheumatoid arthritis ( RA ) . The aim of this study was to assess whether treatment with zoledronic acid , compared with placebo , could achieve a > or = 50 % reduction in the development of new erosions on magnetic resonance imaging ( MRI ) in patients with early RA . METHODS In this proof-of-concept study , 39 patients with early RA and clinical synovitis of the h and /wrist were r and omized to receive infusions with either zoledronic acid ( 5 mg ) or placebo , administered at baseline and week 13 . Patients in both groups received methotrexate ( MTX ) at a dosage of 7.5 - 20 mg/week . MRI and plain radiography were performed at baseline and week 26 . RESULTS At week 26 , the mean + /- SD change in MRI h and and wrist erosions was 61 % lower in the zoledronic acid group compared with the placebo group ( 0.9 + /- 1.63 versus 2.3 + /- 3.09 ; P = 0.176 ) . The mean + /- SD increase in the number of h and and wrist bones with erosions was 0.3 + /- 0.75 for zoledronic acid compared with 1.4 + /- 1.77 for placebo ( P = 0.029 ) . The proportion of patients in whom new MRI-visualized bone edema developed was smaller in the zoledronic acid group compared with the placebo group ( 33 % versus 58 % ; P = 0.121 ) . The zoledronic acid group had a mean change in the number of radiographic erosions of 0.1 compared with 0.5 for the placebo group ( P = 0.677 ) . The safety profile of zoledronic acid was similar to that of placebo . CONCLUSION The results of this study suggest a structural benefit associated with zoledronic acid therapy in patients with RA , as demonstrated by consistent results in structural end points in favor of zoledronic acid plus MTX compared with MTX alone [10589360] An open-label , one-year study was conducted to evaluate the safety and clinical response to leflunomide and methotrexate combination therapy for rheumatoid arthritis . Study results revealed tolerable safety , no significant pharmacokinetic interactions between methotrexate and leflunomide , and suggested improved clinical response with combination therapy [8259721] The aim of the study was to compare the efficacy of hydroxychloroquine ( HCQ ) alone and in combination with methotrexate ( MTX ) in a r and omized placebo-controlled study lasting 6 months . Forty patients with rheumatoid arthritis participated in the study and were r and omly assigned to two groups--20 patients were treated with HCQ ( 200 mg daily ) and placebo , 20 patients with HCQ and MTX ( 7.5 mg ) once a week . Patients were assessed at regular intervals of 1 month up to 6 months using six clinical and five laboratory tests and one radiological measure . All six clinical variables and two laboratory variables were favorably influenced by combination therapy during the 6-month period . HCQ alone significantly influenced only three clinical variables and none of the laboratory parameters . There was a greater number of patients without radiological progression in the combination group . There was one drop-out in combination group due to general allergic reaction ; otherwise the treatment was well tolerated . The results suggest that a combination of HCQ and MTX is more potent than HCQ alone [16447240] OBJECTIVE To compare the efficacy of doxycycline plus methotrexate ( MTX ) versus MTX alone in the treatment of early seropositive rheumatoid arthritis ( RA ) , and to attempt to differentiate the antibacterial and antimetalloproteinase effects of doxycycline . METHODS Sixty-six patients with seropositive RA of < 1 year 's duration who had not been previously treated with disease-modifying antirheumatic drugs were r and omized to receive 100 mg of doxycycline twice daily with MTX ( high-dose doxycycline group ) , 20 mg of doxycycline twice daily with MTX ( low-dose doxycycline group ) , or placebo with MTX ( placebo group ) , in a 2-year double-blind study . Treatment was started with an MTX dosage of 7.5 mg/week , which was titrated every 3 months until remission was reached ( maximum dosage of 17.5 mg/week ) . The primary end point was an American College of Rheumatology 50 % improvement ( ACR50 ) response at 2 years . RESULTS ACR50 responses were observed in 41.6 % of patients in the high-dose doxycycline group , 38.9 % of those in the low-dose doxycycline group , and 12.5 % of patients in the placebo group . Results of chi-square analysis of the ACR50 response in the high-dose doxycycline group versus that in the placebo group were significantly different ( P = 0.02 ) . Trend analysis revealed that the ACR20 response and the ACR50 response were significantly different between groups ( P = 0.04 and P = 0.03 , respectively ) . MTX doses at 2 years were not different among groups . Four patients in the high-dose doxycycline group , 2 patients in the low-dose doxycycline group , and 2 patients in the placebo group were withdrawn because of toxic reactions . CONCLUSION In patients with early seropositive RA , initial therapy with MTX plus doxycycline was superior ( based on an ACR50 response ) to treatment with MTX alone . The therapeutic responses to low-dose and high-dose doxycycline were similar , suggesting that the antimetalloproteinase effects were more important than the antibacterial effects . Further studies to evaluate the mechanism of action of tetracyclines in RA are indicated [11192489] Early intervention with slow acting anti-rheumatic drugs ( SAARDs ) has led to improvement in substantial proportion of rheumatoid arthritis ( RA ) patients . The present open , controlled study was design ed to assess whether a combination of SAARDs offer any added benefit . Fifty-four adult RA patients were r and omly allocated to methotrexate ( MTX ) ( n = 27 ) and MTX plus sulphasalazine ( SSZ ) ( n = 27 ) groups . The subjects were followed-up fortnightly for four weeks then monthly for six months . The disease activity was assessed with the help of 10 clinical and four laboratory indices . The improvement was grade d as : minor , mild decreases in indices , non-steroidal anti-inflammatory drugs ( NSAIDs ) continued , physician 's global assessment ( PGA ) decreased by one ; marked , acceptable decreases in indices , NSAIDs being taken sparingly , PGA decreased by at least 2 , and complete , all indices normalised and patients discontinued NSAIDs completely . The improvement was considered clinical ly important when marked or complete improvement occurred . Adverse drug reactions result ed in withdrawal of 4 subjects from the MTX + SSZ group and 1 from the control groups . Four and three subjects in the combined and MTX groups respectively were lost to follow-up . Subjects in both groups showed significant decline in all indices except hemoglobin and neutrophil count . The differences between the two groups in the pre-treatment and post-treatment values were insignificant . Complete , marked , minor and no improvement occurred in 4 ( 21 % ) , 12 ( 63 % ) , 3 ( 16 % ) & 0 in the MTX and in 11 ( 48 % ) , 7 ( 30 % ) , 4 ( 17 % ) & 1 ( 4 % ) in MTX + SSZ groups respectively . The differences in the rates of complete and clinical ly important improvement between the two groups were insignificant ( P 0.1398 and 0.7092 ) . The incidence of side effects was insignificantly higher in the MTX + SSZ group . Most of them were mild and transient . The combination of SAARDs offered little added advantage in RA . However , the higher rate of complete improvement in the combination group justifies trials including larger sample [8609945] BACKGROUND Rheumatoid arthritis is a common disease that causes substantial morbidity and mortality . The responses of patients with rheumatoid arthritis to treatment with a single so-called disease-modifying drug , such as methotrexate , are often suboptimal . Despite limited data , many patients are treated with combinations of these drugs . METHODS We enrolled 102 patients with rheumatoid arthritis and poor responses to at least one disease-modifying drug in a two-year , double-blind , r and omized study of treatment with methotrexate alone ( 7.5 to 17.5 mg per week ) , the combination of sulfasalazine ( 500 mg twice daily ) and hydroxychloroquine ( 200 mg twice daily ) , or all three drugs . The dose of methotrexate was adjusted in an attempt to achieve remission in all patients . The primary and point of the study was the successful completion of two years of treatment with 50 percent improvement in composite symptoms of arthritis and no evidence of drug toxicity . RESULTS Fifty of the 102 patients had 50 percent improvement at nine months and maintained at least that degree of improvement for two years without evidence of major drug toxicity . Among them were 24 of 31 patients treated with all three drugs ( 77 percent ) , 12 of 36 patients treated with methotrexate alone ( 33 percent , P < 0.001 for the comparison with the three-drug group ) , and 14 of 35 patients treated with sulfasalazine and hydroxychloroquine ( 40 percent ) , P = 0.003 for the comparison with the three-drug group ) . Seven patients in the methotrexate group and three patients in each of the other two groups discontinued treatment because of drug toxicity . CONCLUSIONS In patients with rheumatoid arthritis , combination therapy with methotrexate , sulfasalazine , and hydroxychloroquine is more effective than either methotrexate alone or a combination of sulfasalazine , and hydroxychloroquine [12416946] Context Several disease-modifying antirheumatic drugs ( DMARDs ) slow disease progression in patients with rheumatoid arthritis . Many experts prefer methotrexate , although trials do not uniformly show that it is superior to other DMARDs . It is not known whether combining methotrexate with a second DMARD is better than prescribing methotrexate alone . Contribution This 24-week , r and omized , double-blind , placebo-controlled trial shows that leflunomide added to ongoing stable-dose methotrexate therapy in patients with persistently active rheumatoid arthritis improves clinical outcomes compared with methotrexate alone . Caution s Some adverse effects , such as diarrhea , were more common with combination therapy . All patients receiving DMARD therapy need close monitoring for toxicities . The Editors Rheumatoid arthritis has considerable societal costs ( 1 - 5 ) . Many patients with rheumatoid arthritis become disabled within a few years of disease onset ( 4 , 5 ) . Methotrexate is the st and ard treatment for rheumatoid arthritis . During the past several years , investigators have found that some disease-modifying antirheumatic drugs can increase the efficacy of methotrexate monotherapy ( 6 - 9 ) . Methotrexate is an antimetabolite and immunomodulator that affects many intracellular metabolic pathways of purine metabolism ( 10 ) . The precise intracellular biochemical pathway responsible for the observed clinical benefits of methotrexate in the treatment of rheumatoid arthritis is still the subject of some debate ( 11 ) , but methotrexate is thought to act primarily on purine pathways of cellular metabolism ( 10 ) . Leflunomide ( Arava , Aventis Pharmaceuticals , Bridgewater , New Jersey ) also has antimetabolic effects , inhibiting pyrimidine intracellular pathways ( 12 ) . Leflunomide has been shown to be effective for rheumatoid arthritis in double-blind , placebo-controlled trials ( 13 , 14 ) . Given the diverse intracellular pathways affected by both drugs , the combination of leflunomide and methotrexate has the potential for biochemical synergy . The possibility of increased benefits should be weighed against the possible toxicities of this combination . Abnormal aminotransferase levels have been seen with both methotrexate ( 15 ) and leflunomide ( 14 ) monotherapy in patients with rheumatoid arthritis . In a small open study , we previously observed that the combination of methotrexate and leflunomide led to considerable clinical improvements and reversible elevations in aminotransferase levels ( 16 ) . We therefore sought to determine whether similar results could be achieved in a large , double-blind investigation of the combination of these two antimetabolic agents . Methods Patients The study sample consisted of 263 patients who had rheumatoid arthritis as defined by American College of Rheumatology ( ACR ) criteria ( 17 ) . Patients were 18 to 75 years of age and were receiving stable dosages of methotrexate ( 15 to 20 mg/wk , or 10 to 15 mg/wk if this was the maximum tolerated dose ) . Patients were recruited from active outpatient practice centers , and study participants were approached without a particular schema . Eligible patients had active rheumatoid arthritis despite at least 6 months of methotrexate therapy , including stable dosage for at least 8 weeks . Patients with active rheumatoid arthritis were defined as meeting three of the following criteria on two different evaluations , 7 to 21 days apart : at least nine tender joints , at least six swollen joints , at least 45 minutes of morning stiffness , and an erythrocyte sedimentation rate of at least 28 mm/h . Previous disease-modifying antirheumatic drugs , not including ongoing methotrexate , had failed in 11 patients . Patients receiving corticosteroids were required to have been taking a stable daily dose of 10 mg or less for at least 30 days before study drug administration , and the corticosteroid dose was required to remain constant throughout the study . Complete exclusion criteria are listed in Appendix Table 1 . Study Design The 24-week , r and omized , double-blind , placebo-controlled study , with evaluations occurring at 4-week intervals ( Figure 1 ) , was conducted in 20 centers in the United States and Canada between September 1998 and June 2000 . The primary objective was to evaluate the efficacy and safety of adding leflunomide or placebo to stable methotrexate therapy in patients with active rheumatoid arthritis . All participants provided written consent , and the institutional review board at each center approved the protocol . Figure 1 . Patient eligibility , r and omization , assignment , and discontinuation . Include no wish to continue in study , poor adherence to treatment , protocol violation , and moving away from the study area . A r and omization schedule , generated by and stored with Quintiles , Inc. , Kansas City , Missouri , was used to assign sequential numbers to r and omly allocated treatment codes . R and omization was done by using the Aventis st and ard r and om-code generator . Investigators allocated numbers to patients , beginning with the lowest available number . Quintiles , Inc. , packaged and labeled the study medication . The r and omization code used was concealed from investigators and patients throughout the study . R and omization was stratified by center . A set of 500 r and om numbers was generated , with treatment groups r and omly assigned in a balanced manner ( 1:1 ratio ) within each block of four consecutive r and om numbers ( block size , 4 ) . A set of these blocks was then sent to each investigative center . This method is identical to stratification by center because centers are balanced with respect to treatment assignment . Patients were r and omly assigned to receive leflunomide , 100 mg/d , for 2 days followed by 10 mg/d or matching placebo . If substantial adverse events occurred , this dose could be reduced to 10 mg every other day . If 10 mg/d was tolerated but active disease , as defined earlier , was still present at week 8 or thereafter , an increase to 20 mg of leflunomide or matching placebo per day was required . If substantial adverse events occurred while the patient was taking 20 mg of the study drug per day , a one-time dose reduction to 10 mg/d was allowed at the discretion of the investigator . At least 1 mg of folate supplementation per day was m and ated by the protocol . Adherence to study medication , assessed at each visit by tablet counts ( actual number of tablets returned compared with number expected to be returned ) , was similar in the two groups . The mean adherence for all patients in the intention-to-treat sample was 98.0 % ( 98.5 % for those receiving placebo and 97.4 % for those receiving leflunomide ) . In the placebo group and leflunomide group , respectively , 90.2 % ( 120 of 133 patients ) and 87.7 % ( 114 of 130 patients ) had adherence rates of 80 % to 120 % . Measurement of Efficacy The primary efficacy variable was the rate at which the intention-to-treat sample achieved 20 % improvement in ACR criteria ( ACR20 ) at the end of the study . To be classified as having achieved ACR20 , patients were required to complete 24 weeks of treatment and meet ACR20 response criteria at end of the study ( 13 ) . The ACR20 criteria were developed to define improvement in rheumatoid arthritis ( 18 ) . Clinical improvement is indicated by 20 % improvement in tender and swollen joint counts and 20 % improvement in three of the following five criteria : patient global assessment , physician global assessment , pain intensity , physical function or disability measure , and level of acute-phase reactant ( 19 ) . All ACR assessment s were performed by the investigators , and the same assessor performed all analyses throughout the study whenever possible to increase the reliability of the assessment . Patients who discontinued therapy before the end of week 24 or for whom data were insufficient to assess ACR20 response at week 24 were classified as nonresponders for the primary analysis . Count of tender joints was based on 68 joint assessment s , and count of swollen joints was based on 66 joint assessment s. Percentage changes in tender joint and swollen joint counts were based on the number of evaluable joints at a visit . Joints that had been replaced or had been injected with corticosteroids within 4 weeks before the assessment were considered nonevaluable . Secondary outcomes included ACR50 and ACR70 responder rates at week 24 ( analyses of responders at study end for the non primary efficacy measures ) . The ACR50 and ACR70 were defined as at least 50 % and 70 % improvement , respectively , in the same criteria used to calculate ACR20 response . Secondary efficacy variables also included change from baseline to end point in each of the individual components of the ACR response criteria and change from baseline to week 24 in levels of rheumatoid factor . Mean changes from baseline in individual efficacy measures are shown in Appendix Table 2 . Measurement of Safety Safety was evaluated by adverse event reports ; laboratory assays for changes in hematologic characteristics , blood chemistry , urinalysis , and liver function ; and physical examination . Potential adverse events were assessed by using open-ended questions at each study visit . The assessor was blinded to reported toxicities and to any additional information obtained at the visit . The study protocol provided recommendations for dosage change and discontinuation of drug therapy , without unblinding , when patients were found to have alanine aminotransferase ( ALT ) and aspartate aminotransferase ( AST ) values greater than two times the upper limit of normal . Investigators decreased the dose of the study medication if , on repeated analysis at 72 hours , test values remained greater than two times but less than or equal to five times the upper limit of normal ; only one dose adjustment was allowed before discontinuation of therapy with the study drug . Therapy with the study drug was also discontinued in patients with persistent elevations of aminotransferase enzyme levels to more than two times the upper limit of normal on repeated [16926184] Background : Optimal use of disease-modifying antirheumatic drugs ( DMARDs ) in rheumatoid arthritis is vital if progression of disease is to be reduced . Methotrexate ( MTX ) and sulfasalazine ( SASP ) are widely used inexpensive DMARDs , recently often combined despite no firm evidence of benefit from previous studies . Aim : To establish whether a combination of SASP and MTX is superior to either drug alone in patients with rheumatoid arthritis with a suboptimal response to 6 months of SASP . Methods : A r and omised controlled study of step-up DMARD treatment in early rheumatoid arthritis . In phase I , 687 patients received SASP for 6 months . Those with a disease activity score ( DAS ) ⩾2.4 were offered additional treatment in phase II ( SASP alone , MTX alone or a combination of the two ) . The primary outcome measure was change in DAS . Results : At 6 months , 191 ( 28 % ) patients had a DAS < 2.4 , 123 ( 18 % ) were eligible but did not wish to enter phase II , 130 ( 19 % ) stopped SASP because of reversible adverse events and 165 ( 24 % ) entered phase II . DAS at 18 months was significantly lower in those who received combination treatment compared with those who received either SASP or MTX : monotherapy arms did not differ . Improvement in European League Against Rheumatism and American College of Rheumatology 20 , 50 and 70 scores favoured combination therapy . Conclusions : In this “ true-to-life ” study , an inexpensive combination of DMARDs proved more effective than monotherapy in patients with rheumatoid arthritis with a suboptimal response to SASP . There was no increase in toxicity . These results provide an evidence base for the use of this combination as a component of tight control strategies [15880810] OBJECTIVE To evaluate the efficacy and safety of adding intramuscular ( IM ) gold to the treatment regimen of patients with rheumatoid arthritis ( RA ) who have a suboptimal response to methotrexate ( MTX ) . METHODS A r and omized , double-blind , double-observer , placebo-controlled multicenter trial of 48 weeks was conducted . Sixty-five RA patients who had a suboptimal response to > /=12 weeks of MTX therapy were r and omly assigned to receive weekly IM gold or placebo in addition to MTX . Gold was administered according to a st and ard protocol developed for the study . The primary outcome measure was the percentage of patients who met the American College of Rheumatology ( ACR ) 20 % improvement criteria ( achieved an ACR20 response ) at week 48 . Secondary outcomes included the percentages of patients achieving ACR50 and ACR70 responses , the individual criteria that make up the primary outcome , quality of life , direct and indirect health care costs , intraarticular steroid use , and adverse events , among other measures . Statistical analyses were based on an intent-to-treat strategy . RESULTS Sixty-one percent of patients receiving gold achieved an ACR20 response compared with 30 % of patients receiving placebo ( chi(2 ) = 6.04 , P = 0.014 ; logistic regression odds ratio 3.64 [ 95 % confidence interval 1.3 , 10.4 ] , P = 0.016 ) . Twenty-six percent of patients receiving gold achieved an ACR50 response compared with 4 % of patients receiving placebo ( P = 0.017 ) , and 21 % of patients receiving gold achieved an ACR70 response compared with 0 % of patients receiving placebo ( P = 0.011 ) . From both clinical and cost-effectiveness perspectives , gold was the preferred and dominant strategy . Study treatment was discontinued in 23 patients ( 14 in the placebo group compared with 9 in the gold group ; P = 0.022 ) due to loss to followup , adverse events , or lack of efficacy . CONCLUSION In RA patients with a suboptimal response to MTX , adding weekly IM gold causes significant clinical improvement . Adverse events were minor , and IM gold-related adverse events led to discontinuation in only 11 % of the gold group over 48 weeks [17330681] Background : Sulfasalazine and tetracyclines are effective against rheumatoid arthritis ( RA ) . Levofloxacin , the bacteriologically active isomer of ofloxacin , is used in the treatment of infections caused by periodontopathic bacteria and facultative anaerobic bacteria . The aim of this study is to evaluate the clinical efficacy , safety , and tolerability of levofloxacin in patients with rheumatoid arthritis . Methods : In a 6-month , double-blind trial , we r and omly assigned 76 patients with persistently active rheumatoid arthritis despite at least 6 months of methotrexate therapy at a stable dose of 15 to 25 mg per week to receive either levofloxacin ( 500 mg ) or placebo orally once daily while continuing to receive methotrexate . The change from baseline to six months in the swollen-joint count and tender-joint count was the primary measure of efficacy . Secondary endpoints included pain , quality of life , duration of morning stiffness , erythrocyte sedimentation rate , C-reactive protein level , and physician ’s and patient ’s global assessment s. The data were also analyzed to determine the number of patients meeting American College of Rheumatology criteria for 20 , 50 , and 70 % improvement . Results : The levofloxacin plus methotrexate was associated with the greatest reduction in the number of swollen or tender joints ( P < 0.001 ) . The levofloxacin plus methotrexate group also had significant improvement in many of the secondary outcome measures ( P < 0.001 ) . Levofloxacin was well tolerated . There were no dose-limiting toxic effects . Conclusion : In patients with active rheumatoid arthritis who received methotrexate , treatment with levofloxacin significantly improved the signs and symptoms of rheumatoid arthritis [17371885] Context First-year results of the BeSt study showed that initial combination therapy for rheumatoid arthritis produced more rapid clinical improvement and less radiologic evidence of progression of joint damage than did initial monotherapy . Contribution The investigators assessed clinical and radiologic outcomes during year 2 while following a scheduled program of step-up and step-down medication adjustment based on disease activity score . All treatment groups achieved similar disease activity after 2 years , although initial monotherapy was often converted to combination therapy during follow-up . Implication s Although all regimens were equally effective in eventually controlling disease activity , the rapid control produced by initial combination therapy may translate into decreased joint damage . The Editors Over the past few years , the outcome for patients with rheumatoid arthritis has improved considerably ( 1 ) . Combinations of disease-modifying antirheumatic drugs ( DMARDs ) with corticosteroids and DMARDs with the new tumor necrosis factor antagonists seem to suppress the inflammatory process more effectively than single-drug therapy in patients with early ( 210 ) and established ( 1115 ) disease . This results in less progression of radiographic joint damage and better preservation of physical function compared with single-drug therapy . More recently , tight control of disease activity has been shown to improve outcome ( 16 ) , and there are indications that outcome is related to adherence to treatment guidelines ( 17 ) . Whether combination therapy with DMARDs , corticosteroids , or tumor necrosis factor antagonists should be considered for initial treatment in all patients with rheumatoid arthritis or whether such therapy should be reserved for patients who do not respond to monotherapy is unknown . Therefore , the BeSt study ( 9 ) evaluated the efficacy of 4 of the most frequently used treatment strategies in a head-to-head comparison : sequential monotherapy ( group 1 ) , step-up combination therapy ( group 2 ) , initial combination therapy with tapered high-dose prednisone ( group 3 ) , and initial combination therapy with infliximab ( group 4 ) . Treatment adjustments were made every 3 months in patients with an insufficient response or a continued good response . During the first year of treatment , initial combination therapy for groups 3 and 4 result ed in more rapid clinical improvement and less progression of joint damage compared with initial monotherapy for groups 1 and 2 . In the second year , response to therapy continued to be tightly monitored . Treatment adjustments were made according to the protocol . We evaluated whether the initial clinical and radiologic outcomes could be maintained and what treatment adjustments were needed in each group . Methods Patients Rheumatologists participating in the Foundation for Applied Rheumatology Research in 18 peripheral and 2 university hospitals in the western part of the Netherl and s design ed and conducted the BeSt study . Between April 2000 and August 2002 , we recruited patients with early rheumatoid arthritis who fulfilled the American College of Rheumatology ( ACR ) 1987 criteria for rheumatoid arthritis ( 18 ) . Patients were 18 years of age or older ; had a disease duration of 2 years or less ; had active disease with at least 6 of 66 swollen joints and at least 6 of 68 tender joints ; and had an erythrocyte sedimentation rate of 28 mm/h or greater or a global health score of 20 mm or more ( on a visual analogue scale of 0 mm [ best ] to 100 mm [ worst ] ) . Patient enrollment criteria have been described in detail previously ( 9 ) . The medical ethics committee at each participating center approved the study protocol , and all patients gave written informed consent before study inclusion . Treatment Protocol Patients were allocated to 1 of 4 treatment groups by variable block r and omization ( 913 ) , which was stratified per center . Treatment groups were sequential monotherapy ( group 1 ) , step-up combination therapy ( group 2 ) , initial combination therapy with tapered high-dose prednisone ( group 3 ) , and initial combination therapy with infliximab ( group 4 ) . For patients who did not respond to medication , the protocol prescribed many subsequent steps . The decision of whether to adjust medication was made every 3 months on the basis of disease activity score ( 19 ) , a continuous measure consisting of the Ritchie articular index and number of swollen joints in a 44-joint count , erythrocyte sedimentation rate , and global health as measured on a visual analogue scale . A disease activity score of 2.4 or less indicates low disease activity ( 20 ) . A research nurse who remained blinded to the allocated treatment group during the study period calculated the score . If the disease activity score was greater than 2.4 ( insufficient response ) , the treating physician immediately adjusted therapy by proceeding to the next step in the allocated treatment group . If the disease activity score was 2.4 or less for at least 6 months , medication was gradually withdrawn until 1 drug remained in a maintenance dosage . Patients in group 1 started with methotrexate , followed subsequently by sulfasalazine , leflunomide , methotrexate with infliximab , gold with methylprednisolone ( intramuscular ) , methotrexate with cyclosporine and prednisone , and azathioprine with prednisone . Patients in group 2 started with methotrexate , followed subsequently by methotrexate with sulfasalazine , methotrexate with sulfasalazine and hydroxychloroquine , methotrexate with sulfasalazine , hydroxychloroquine and prednisone , methotrexate with infliximab , methotrexate with cyclosporine and prednisone , leflunomide , and azathioprine with prednisone . Patients in group 3 started with the combination of methotrexate , sulfasalazine , and tapered high-dose prednisone ( 2 ) , followed subsequently by methotrexate with cyclosporine and prednisone , methotrexate with infliximab , leflunomide , gold with methylprednisolone , and azathioprine with prednisone . Patients in group 4 started with the combination of methotrexate and infliximab , followed subsequently by sulfasalazine , leflunomide , methotrexate with cyclosporine and prednisone , gold with methylprednisolone , and azathioprine with prednisone . In addition to the regular trimonthly assessment s , we calculated additional disease activity scores every 8 weeks in all patients who were treated with infliximab in the week before infusion . On the basis of these scores , we decided whether to increase or taper the dosage . The treatment protocol and dose regimen have been described in detail previously ( 9 ) . We permitted concomitant treatment with nonsteroidal anti-inflammatory drugs and intra-articular injections with corticosteroids and did not allow other parenteral corticosteroids . We allowed DMARDs or oral corticosteroids only as dictated by the treatment protocol . All patients received folic acid , 1 mg per day , during treatment with methotrexate . Study End Points and Assessment s The primary efficacy end point was functional ability , as measured by the Dutch Health Assessment Question naire . Higher scores indicated more severe loss of physical function ( 21 ) . Secondary efficacy end points were 20 % and 70 % improvement according to the ACR ( ACR20 and ACR70 , respectively ) response criteria ( 22 ) and clinical remission , defined as a disease activity score less than 1.6 ( 23 ) . Assessment s were done every 3 months by blinded research nurses , who were trained at study onset and every 6 months thereafter to maintain consistency . Two study physicians ensured adherence to the protocol every 3 months . All protocol deviations were recorded . Patients were not informed about study outcomes until the end of the second year of follow-up . The primary radiographic end point was the change in the total Sharpvan der Heijde score for joint damage , which ranged from 0 to 448 , over 2 years ( 24 ) . Two trained readers independently scored the radiographs of h and s , wrists , and feet at baseline and at the 2-year follow-up . The patient 's identity , treatment group , and sequence of the films in sets were masked to the readers . We used the mean score of the 2 readers for the analysis . The intraobserver coefficients were 0.90 and 0.91 , and the interobserver coefficient was 0.94 . Erosive disease was defined as a mean erosion score greater than 0.5 . Toxicity We performed physical examination and laboratory tests and recorded all adverse events at all visits . If necessary , the treating physician adjusted the patient 's medication as outlined previously . Serious adverse events were defined as an adverse reaction result ing in any of the following outcomes : a life-threatening condition or death , substantial or permanent disability , malignant disease , hospitalization or prolongation of hospitalization , or a congenital abnormality or birth defect . Before beginning infliximab therapy , all patients were evaluated for tuberculosis with a purified protein derivative skin test and chest radiography . In the beginning of 2002 , congestive heart failure was added as a contraindication for treatment with infliximab . Treatment was discontinued for previously enrolled patients with functional classes I , II , III , and IV concomitant congestive heart failure , as defined by the New York Heart Association ( 25 ) . These patients ' conditions seemed to be worsening with infliximab therapy . Worsening was defined as every transition to a higher functional class . Statistical Analysis We needed a sample size of 468 patients ( 117 per group ) to ascertain 80 % power to detect a difference of at least 0.2 in the Health Assessment Question naire score . This was set as a clinical ly relevant difference with a 5 % significance level and adjustment for multiple comparisons between groups , assuming an SD of 0.45 . The sample size also ensured greater than 80 % power to detect a difference of 20 % or greater in the change in score for radiologic joint damage . We performed intention-to-treat analyses . When appropriate , we [12860733] Objective : To evaluate whether early combined therapy with methotrexate ( MTX ) and sulfasalazine ( SSZ ) during the first year in early rheumatoid arthritis ( RA ) induces long term beneficial effects , compared with monotherapy , when the further treatment strategy is a free choice . Methods : Study design : five year multicentre prospect i ve longitudinal trial . Participants : 146/205 patients with RA previously included in a one year prospect i ve r and omised trial comparing the effects of treatment with MTX , SSZ , or a combination of both . Criteria for inclusion : patients with early RA ( ⩽1 year duration ) . Follow up : between the end of years 1 and 5 , patients were followed up and treated by their own rheumatologist , who was allowed to indicate any treatment . Outcome measures : disease activity score ( DAS ) , health assessment question naire ( HAQ ) , and Sharp/van der Heijde radiological score at baseline and after five years of follow up . Analysis : comparison of the five year follow up DAS , HAQ , and radiological scores in patients given combined and single treatment during the first year . Results : At the end of the five years of follow up , the patients primarily receiving single or combined treatment had similar mean DAS , HAQ , and radiographic scores . Conclusion : Treatment of patients with early RA using combined therapy with MTX and SSZ during the first year did not influence the long term inflammatory status , or disability , or structural changes , compared with single disease modifying antirheumatic drug treatment [7791814] BACKGROUND Patients with severe rheumatoid arthritis who are treated with methotrexate frequently have only partial improvement . METHODS In a six-month r and omized , double-blind trial , we compared combination therapy with cyclosporine ( 2.5 to 5 mg per kilogram of body weight per day in two divided doses at 12-hour intervals ) and methotrexate ( at the maximal tolerated dose ) with methotrexate and placebo in 148 patients with rheumatoid arthritis who had residual inflammation and disability despite partial but substantial responses to prior methotrexate treatment . The primary outcome measure was the change in the number of tender joints . RESULTS The mean ( + /- SD ) dose of cyclosporine at the final treatment was 2.97 + /- 1.02 mg per kilogram per day . As compared with the placebo group , the patients in the treatment group had a net improvement in the tender-joint count of 25 percent , or 4.8 joints ( 95 percent confidence interval , 0.7 to 8.9 ; P = 0.02 ) , and in the swollen-joint count of 25 percent , or 3.8 joints ( 95 percent confidence interval , 1.3 to 6.3 ; P = 0.005 ) ; improvement in overall disease activity as assessed by the physician ( 19 percent , P < 0.001 ) and the patient ( 21 percent , P < 0.001 ) ; and improvement in joint pain ( 23 percent , P = 0.04 ) and in the degree of disability ( 26 percent , P < 0.001 ) . The mean erythrocyte sedimentation rate increased by 4.2 mm per hour in the cyclosporine group and decreased by 4.8 mm per hour in the placebo group ( P = 0.006 ) . Thirty-six patients ( 48 percent ) in the cyclosporine group and 12 patients ( 16 percent ) in the placebo group ( P < 0.001 ) met the 1993 criteria for improvement of the American College of Rheumatology ( more than 20 percent improvement in the numbers of both swollen and tender joints and improvement in three of five other variables ) . Seventeen patients in the cyclosporine group and 12 patients in the placebo group were withdrawn from the study ; 2 patients in the cyclosporine group died , 1 from viral pneumonia and the other in a motor vehicle accident . Serum creatinine concentrations increased by a mean of 0.14 + /- 0.27 mg per deciliter ( 12 + /- 24 mmol per liter ) in the cyclosporine group and by 0.05 + /- 0.19 mg per deciliter ( 4 + /- 17 mmol per liter ) in the placebo group ( P = 0.02 ) . CONCLUSIONS In a six-month study , patients with severe rheumatoid arthritis and only partial responses to methotrexate had clinical ly important improvement after combination therapy with cyclosporine and methotrexate . Side effects were not substantially increased . Long-term follow-up of patients treated with this combination is needed [9374925] To compare the efficacy of sulphasalazine , methotrexate , and the combination of both in patients with early rheumatoid arthritis ( RA ) , not treated with disease-modifying anti-rheumatic drugs previously , we conducted a double-blind , double-dummy , controlled , clinical trial . One hundred and five patients with active , early RA , rheumatoid factor and /or HLA DR1/4 positive were r and omized between sulphasalazine ( SSZ ) 2000 ( maximum 3000 ) mg daily , or methotrexate ( MTX ) 7.5 ( maximum 15 ) mg weekly , or the combination ( COMBI ) of both , and were followed up by a single observer for 52 weeks . The mean change over time per patient , including all visits , in Disease Activity Score ( DAS ) was : SSZ : -1.6 ( 95 % CI -2.0 to -1.2 ) ; MTX : -1.7 ( -2.0 to -1.4 ) ; COMBI : -1.9 ( -2.2 to -1.6 ) ; the difference week 0-week 52 ( SSZ , MTX , COMBI respectively ) ; DAS : -1.8 , -2.0 , -2.3 , Ritchie articular index : -9.2 , -9.5 , -10.6 , swollen joints : -9.2 , -12.4 , -14.3 , erythrocyte sedimentation rate : -17 , -21 , -28 . Nausea occurred significantly more in the COMBI group . The numbers of drop-outs due to toxicity were SSZ 9 , MTX 2 , COMBI 5 . In conclusion , there were no significant differences in efficacy between combination and single therapy , only a modest trend favouring COMBI . The results of MTX and SSZ were very comparable . Nausea occurred more often in the COMBI group : the number of withdrawals due to adverse events did not differ significantly Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Rheumatoid arthritis ( RA ) is initially treated with methotrexate and other disease-modifying antirheumatic drugs ( DMARDs ) . Active RA patients who fail such treatments can receive tumour necrosis factor inhibitors ( TNFis ) , which are effective but expensive . OBJECTIVE We assessed whether or not combination DMARDs ( cDMARDs ) give equivalent clinical benefits at lower costs in RA patients eligible for TNFis . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

28453622

[3042101] Objective Research suggests that physical activity is associated with improved breast cancer survival , yet no studies have examined the association between post-diagnosis changes in physical activity and breast cancer outcomes . The aim of this study was to determine whether baseline activity and 1-year change in activity are associated with breast cancer events or mortality . Methods A total of 2,361 post-treatment breast cancer survivors ( Stage I – III ) enrolled in a r and omized controlled trial of dietary change completed physical activity measures at baseline and one year . Physical activity variables ( total , moderate – vigorous , and adherence to guidelines ) were calculated for each time point . Median follow-up was 7.1 years . Outcomes were invasive breast cancer events and all-cause mortality . Results Those who were most active at baseline had a 53 % lower mortality risk compared to the least active women ( HR = 0.47 ; 95 % CI : 0.26 , 0.84 ; p = .01 ) . Adherence to activity guidelines was associated with a 35 % lower mortality risk ( HR = 0.65 , 95 % CI : 0.47 , 0.91 ; p < .01 ) . Neither baseline nor 1-year change in activity was associated with additional breast cancer events . Conclusions Higher baseline ( post-treatment ) physical activity was associated with improved survival . However , change in activity over the following year was not associated with outcomes . These data suggest that long-term physical activity levels are important for breast cancer prognosis [22749425] OBJECTIVE To examine the changes from a combined exercise intervention after radical prostatectomy ( RP ) in elderly patients with prostate cancer , because r and omized controlled trials addressing exercise intervention after RP have been lacking . METHODS From May 2009 to May 2010 , all patients who underwent laparoscopic RP were assessed for eligibility . A total of 66 patients were r and omized to an exercise or a control group . The exercise group received a combined exercise intervention ( resistance , flexibility , and Kegel exercises ) twice a week for 12 weeks , and the control group received only Kegel exercises . The primary outcome was physical function , and the secondary outcomes were continence status and quality of life after the exercise intervention . RESULTS A total of 49 patients completed follow-up to the end of study . After the 12-week exercise intervention , except for grip strength , all physical functions were better in the exercise group than in the control group . The 24-hour pad test results ( 12.2 g in the exercise group , 46.2 g in the control group ) and continence rate ( 73.1 % in exercise group , 43.5 % in the control group ) recovered more promptly in the exercise group . On a question naire study using the International Consultation on Incontinence question naire , Beck Depression Inventory , and Medical Outcomes Study 36-item short-form health survey , only the exercise group showed improvement at the last follow-up visit . CONCLUSION A 12-week combined exercise intervention after RP results in improvement of physical function , continence rate , and quality of life . These results could help with prompt recovery of daily activities [19723652] Purpose : Physical activity in colon cancer survivors has been associated with lower cancer recurrences and improved survival . Whether molecular features of the tumor portend more or less likelihood for benefit from exercise is unknown . Experimental Design : Using two large prospect i ve cohort studies with physical activity assessment s after colon cancer diagnosis , we examined expression of fatty acid synthase , p53 , p21 , and p27 and mutational status of K-ras and phosphatidylinositol 3-kinase(PI3KCA ) . We calculated hazard ratios ( HR ) of colon cancer – specific mortality , adjusted for tumor and patient characteristics , and tested for molecular interactions with exercise . Results : In a cohort of 484 men and women with stage I to III colon cancer , patients who engaged in at least 18 metabolic equivalent task (MET)–hours per week after diagnosis had an adjusted HR for colon cancer – specific mortality of 0.64 [ 95 % confidence interval ( 95 % CI ) , 0.33 - 1.23 ] and for overall mortality of 0.60 ( 95 % CI , 0.41 - 0.86 ) . A statistically significant interaction was detected based on p27 expression ( P = 0.03 ) . For tumors with loss of p27 ( n = 195 ) , physical activity of ≥18 MET-hours/week led to a HR for colon cancer mortality of 1.40 ( 95 % CI , 0.41 - 4.72 ) , compared with those with < 18 MET-hours/week . However , for tumors with expression of p27 ( n = 251 ) , the adjusted HR was 0.33 ( 95 % CI , 0.12 - 0.85 ) . Molecular status of fatty acid synthase , K-ras , p53 , p21 , and PI3KCA did not influence the association between exercise and colon cancer – specific or overall mortality . Conclusion : The benefit of physical activity on outcomes in patients with stage I to III colon cancer may be influenced by p27 status . Further studies are warranted to confirm these findings . ( Clin Cancer Res 2009;15(18):5931–6 [23045575] PURPOSE The purpose of our study was to evaluate the effect of cognitive behavioral therapy ( CBT ) , physical exercise ( PE ) , and of these two interventions combined ( CBT/PE ) on menopausal symptoms ( primary outcome ) , body image , sexual functioning , psychological well-being , and health-related quality of life ( secondary outcomes ) in patients with breast cancer experiencing treatment-induced menopause . PATIENTS AND METHODS Patients with breast cancer reporting treatment-induced menopausal symptoms ( N=422 ) were r and omly assigned to CBT ( n=109 ) , PE ( n=104 ) , CBT/PE ( n=106 ) , or to a waiting list control group ( n=103 ) . Self-report question naires were completed at baseline , 12 weeks , and 6 months . Multilevel procedures were used to compare the intervention groups with the control group over time . RESULTS Compared with the control group , the intervention groups had a significant decrease in levels of endocrine symptoms ( Functional Assessment of Cancer Therapy-Endocrine Symptoms ; P<.001 ; effect size , 0.31 - 0.52 ) and urinary symptoms ( Bristol Female Lower Urinary Tract Symptoms Question naire ; P=.002 ; effect size , 0.29 - 0.33 ) , and they showed an improvement in physical functioning ( 36-Item Short Form Health Survey physical functioning subscale ; P=.002 ; effect size , 0.37 - 0.46 ) . The groups that included CBT also showed a significant decrease in the perceived burden of hot flashes and night sweats ( problem rating scale of the Hot Flush Rating Scale ; P<.001 ; effect size , 0.39 - 0.56 ) and an increase in sexual activity ( Sexual Activity Question naire habit subscale ; P=.027 ; effect size , 0.65 ) . Most of these effects were observed at both the 12-week and 6-month follow-ups . CONCLUSION CBT and PE can have salutary effects on endocrine symptoms and , to a lesser degree , on sexuality and physical functioning of patients with breast cancer experiencing treatment-induced menopause . Future work is needed to improve the design and the planning of these interventions to improve program adherence [21610110] Vigorous activity after diagnosis was recently reported to be inversely associated with prostate cancer-specific mortality . However , men with metastatic disease may decrease their activity due to their disease ; thus , a causal interpretation is uncertain . We therefore prospect ively examined vigorous activity and brisk walking after diagnosis in relation to risk of prostate cancer progression , an outcome less susceptible to reverse causation , among 1,455 men diagnosed with clinical ly localized prostate cancer . Cox proportional hazards regression was used to examine vigorous activity , nonvigorous activity , walking duration , and walking pace after diagnosis and risk of prostate cancer progression . We observed 117 events ( 45 biochemical recurrences , 66 secondary treatments , 3 bone metastases , 3 prostate cancer deaths ) during 2,750 person-years . Walking accounted for nearly half of all activity . Men who walked briskly for 3 h/wk or more had a 57 % lower rate of progression than men who walked at an easy pace for less than 3 h/wk ( HR = 0.43 ; 95 % CI : 0.21 - 0.91 ; P = 0.03 ) . Walking pace was associated with decreased risk of progression independent of duration ( HR brisk vs. easy pace = 0.52 ; 95 % CI : 0.29 - 0.91 ; P(trend ) = 0.01 ) . Few men engaged in vigorous activity , but there was a suggestive inverse association ( HR ≥3 h/wk vs. none = 0.63 ; 95 % CI : 0.32 - 1.23 ; P(trend ) = 0.17 ) . Walking duration and total nonvigorous activity were not associated with risk of progression independent of pace or vigorous activity , respectively . Brisk walking after diagnosis may inhibit or delay prostate cancer progression among men diagnosed with clinical ly localized prostate cancer [22286332] The aim of this study was to determine whether an exercise program , commencing 4–6 weeks post-operatively , reduces upper limb impairments in women treated for early breast cancer . Women ( n = 160 ) were r and omized to either an 8-week exercise program ( n = 81 ) or to a control group ( n = 79 ) following stratification for axillary surgery . The exercise program comprised a weekly session and home program of passive stretching and progressive resistance training for shoulder muscles . The control group attended fortnightly assessment s but no exercises were provided . The primary outcome was self-reported arm symptoms derived from the EORTC breast cancer-specific question naire ( BR23 ) , scored out of 100 with a low score indicative of fewer symptoms . The secondary outcomes included physical measures of shoulder range of motion , strength , and swelling ( i.e. , lymphedema ) . Women were assessed immediately following the intervention and at 6 months post-intervention . The change in symptoms from baseline was not significantly different between groups immediately following the intervention or at 6 m post-intervention . The between group difference immediately following the intervention was 4 ( 95 % CI −1 to 9 ) and 6 months post-intervention was 4 ( −2 to 10 ) . However , the change in range of motion for flexion and abduction was significantly greater in the exercise group immediately following the intervention , as was change in shoulder abductor strength . In conclusion , a supervised exercise program provided some , albeit small , additional benefit at 6 months post-intervention to women who had been provided with written information and reminders to use their arm . Both the groups reported few impairments including swelling immediately following the intervention and 6 months post-intervention . Notably , resistance training in the post-operative period did not precipitate lymphedema [25096607] BACKGROUND Exercise has been reported to decrease cancer-related fatigue and to increase quality of life ( QoL ) in various breast cancer ( BC ) population s. However , studies investigating exercise during radiotherapy or resistance training are scarce . We conducted a r and omized , controlled trial ( BEST study ) to assess the efficacy of 12-week resistance training on fatigue beyond possible psychosocial effects of a group-based intervention . PATIENTS AND METHODS One hundred sixty patients with BC stage 0-III were r and omly assigned to a 12-week progressive resistance training ( 2 times/week ) or a 12-week relaxation control ( RC , 2 times/week ) . Both interventions were group-based . The primary end point fatigue was assessed with a 20-item multidimensional question naire , QoL with EORTC question naires . Statistical analyses were based on analysis of covariance models for the individual changes from baseline to week 13 . RESULTS Adherence to the intervention program as well as the completion rate ( 97 % ) for the primary outcome variable fatigue was high . In intention-to-treat analyses for the N = 155 patients , significant between-group mean differences ( MD ) favoring the exercise group ( EX ) were observed for general fatigue ( P = 0.044 ) , especially for the subscale physical fatigue [ MD = -0.8 ; 95 % confidence interval -1.5 to -0.2 , P = 0.013 ] , but not for affective ( P = 0.91 ) or cognitive fatigue ( P = 0.65 ) . For QoL , significantly larger improvements regarding the role function ( P = 0.035 ) and pain ( P = 0.040 ) were noted among exercisers compared with RCs . Future perspective improved significantly stronger in the RC group compared with the EX group ( P = 0.047 ) . CONCLUSIONS The 12-week resistance training program was a safe , feasible and efficacious strategy to improve cancer-related fatigue and components of QoL in BC patients during adjuvant radiotherapy . As exercise was compared with another group-based intervention , results indicate that resistance training effects on fatigue and QoL go beyond psychosocial benefits , and that the clinical ly relevant overall benefit of resistance exercise compared with usual care can be assumed to be higher . TRIAL REGISTRATION Clinical Trials.gov NCT01468766 [22996743] Summary Our r and omized controlled trial in prematurely menopausal breast cancer survivors showed that impact + resistance training prevented increases in percentage of body fat compared with controls and also improved BMD at the hip and prevented BMD loss at the spine among exercise-trained women who were menopausal for > 1 year . Introduction Cancer treatment-related menopause worsens bone health and body composition in breast cancer survivors ( BCS ) . We investigated whether impact + resistance training could improve bone mineral density ( BMD ) , reduce bone turnover , build muscle , and decrease fat mass in BCS with premature menopause . Methods We conducted a r and omized controlled trial in 71 BCS ( mean age , 46.5 years ) within 5 years of treatment-related menopause . Women were r and omly assigned to one of two groups : ( 1 ) impact + resistance training ( prevent osteoporosis with impact + resistance ( POWIR ) ) or ( 2 ) exercise placebo ( FLEX ) 3 × /week for 1 year . Outcomes were hip and spine BMD ( in grams per square centimeter ) and body composition ( percent body fat ( % BF ) and lean and fat mass ( in kilograms ) ) by DXA and bone turnover markers ( serum osteocalcin ( in nanograms per milliliter ) and urinary deoxypryrodinoline ( in nanomoles per milliliter ) . Results There were no significant group × time interactions for bone outcomes when using an intent-to-treat approach on the full sample . In analyses restricted to BCS who were menopausal for ≥1 year , POWIR increased BMD at the hip and slowed BMD loss at the spine compared with FLEX ( femoral neck — POWIR , 0.004 ± 0.093 g/cm2 vs. FLEX , −0.010 ± 0.089 g/cm2 ; p < 0.01 ; spine — POWIR , −0.003 ± 0.114 g/cm2 vs. FLEX , −0.020 ± 0.110 g/cm2 ; p = 0.03 ) . POWIR prevented increases in % BF ( POWIR , 0.01 % vs. FLEX , 1.3 % ; p < 0.04 ) . Women with attendance to POWIR at ≥64 % had better improvements in % BF than women attending less often ( p < 0.03 ) . Conclusion Impact + resistance training may effectively combat bone loss and worsening body composition from premature menopause in BCS [17638108] Objective With increases in cancer survival , promotion of healthy lifestyle behaviors among survivors is receiving considerable attention . This study compared health behaviors among a large sample of Australian adult cancer survivors with an age- and sex-matched cohort of people with no cancer history . Methods Using the Australian National Health Survey , 968 cancer survivors were identified , and r and omly matched by age and sex to 5,808 respondents without a history of cancer . Six health behaviors were compared ( smoking , physical activity , servings of vegetables , servings of fruit , alcohol use , skin checks ) , along with overweight and obesity , using polytomous logistic regression analyses controlling for selected chronic conditions . Models were applied across both groups and by tumor site . Results Compared to the non-cancer comparison group , cancer survivors were significantly more likely to be current ( OR = 1.35 ) smokers , particularly those under 40 years ( OR = 1.69 ) , and more likely to have regular skin checks ( OR = 1.76 ) . Although not significant , there was consistent evidence that cancer survivors were slightly more likely to be overweight or obese ( p = 0.065 ) and have higher levels of alcohol consumption ( p = 0.088 ) . There was no evidence of differences between survivors and controls for levels of physical inactivity , vegetable consumption or fruit consumption . Women with a history of gynecological cancers were much more likely to be current smokers ( OR = 2.37 ) , while other differences by sex and cancer site were consistent with overall patterns . Cancer survivors were also significantly more likely to report having a range of co-morbid chronic medical conditions . Conclusion Given their increased risk of second cancers and co-morbid chronic conditions , the lack of difference in behavioral risk factors confirms the need for a focus on improving the health behaviors of cancer survivors . Collaborative chronic disease management models may be particularly appropriate in this regard [24460069] Abstract Background . Physical activity during chemotherapy has been shown in several studies to reduce fatigue , improve symptoms and impact positively on health-related quality of life ( HRQoL ) . Challenges associated with intervention studies on physical activity during cancer treatment relate to consistent adherence . The primary objective was to study feasibility and adherence of physical activity intervention among patients with cancer during adjuvant chemotherapy treatment . The secondary objective was to investigate the effects of physical activity on health aspects , including HRQoL , symptoms and surrogate markers for cardiovascular disease . Material and methods . This r and omized controlled trial included patients with breast cancer ( BRCA ) and colorectal cancer ( CRC ) during adjuvant chemotherapy . The intervention continued for 10 weeks and included daily walks of 10 000 steps and a weekly supervised group walk . Adherence was assessed by a pedometer and the number of participants who reported step counts every week and percentage of participants who achieved the target steps every week . Results . Adherence average reached 91 % during the intervention period ; in total 74 % completed the exercise intervention . The majority of the participants achieved an average of 83 % of the target of 10 000 steps per day for 10 weeks . There was a significant increase in daily physical activity ( p = 0.016 ) in the intervention group . Significant differences were also found for some breast cancer-specific symptoms [ swelling , mobility and pain ( p = 0.045 ) ] . The study showed a relatively small weight gain an average of 0.9 kg in the intervention group and 1.3 kg in the control group . Conclusion . Physical activity in the form of walking is feasible during adjuvant chemotherapy treatment despite increasing symptoms . The physical activity increased in the intervention group during the study time and had a positive impact on breast symptoms and the weight gain was lower in comparison to previous studies [25491935] Purpose Few r and omized controlled trials in exercise oncology have examined survival outcomes . Here , we report an exploratory follow-up of progression-free survival ( PFS ) from the Healthy Exercise for Lymphoma Patients ( HELP ) Trial . Methods The HELP Trial r and omized 122 lymphoma patients between 2005 and 2008 to either control ( n = 62 ) or 12 weeks of supervised aerobic exercise ( n = 60 ) . PFS events were abstract ed from medical records in 2013 . In addition to the r and omized comparison , we explored the effects of exercise adherence ( < 80 % vs. ≥80 % ) and control group crossover ( no vs. yes ) . Results After a median follow-up of 61 months ( interquartile range 36–67 ) , the adjusted 5-year PFS was 64.8 % for the exercise group compared with 65.0 % for the control group ( Hazard ratio [ HR ] 1.01 , 95 % CI 0.51–2.01 , p = 0.98 ) . In the secondary analysis , the adjusted 5-year PFS was 59.0 % in the control group without crossover compared with 69.2 % for the control group with crossover ( HR 0.68 , 95 % CI 0.22–2.06 , p = 0.49 ) , 67.7 % for the exercise group with < 80 % adherence ( HR 0.72 , 95 % CI 0.28–1.85 , p = 0.50 ) , and 68.4 % for the exercise group with ≥80 % adherence ( HR 0.70 , 95 % CI 0.32–1.56 , p = 0.39 ) . In a post hoc analysis combining the three groups that received supervised exercise , the adjusted 5-year PFS for the supervised exercise groups was 68.5 % compared with 59.0 % for the group that received no supervised exercise ( HR 0.70 , 95 % CI 0.35–1.39 , p = 0.31 ) . Conclusions This exploratory follow-up of the HELP Trial suggests that supervised aerobic exercise may be associated with improved PFS in lymphoma patients . Larger trials design ed to answer this question are needed [3196245] Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more [25060288] BACKGROUND Participation in physical activity can improve the health outcomes of breast cancer survivors . To impact public health , broad-reaching sustainable interventions that promote physical activity are needed . PURPOSE To evaluate the efficacy of two distance-based interventions for promoting physical activity among breast cancer survivors compared with a st and ard recommendation control . METHODS Breast cancer survivors who had finished ' active ' cancer treatment were eligible to participate . Participants ( n = 330 ) were r and omly assigned to receive one of the following mail-delivered interventions : three computer-tailored newsletters , a previously developed breast cancer-specific physical activity booklet or a pamphlet detailing the public health recommendations for physical activity ( control ) . Primary outcomes were self-reported moderate to vigorous aerobic activity and participant 's self-reported resistance training activity at 4 months post-baseline . Secondary outcomes were pedometer step counts , whether or not participants were meeting the physical activity guidelines , time spent in sedentary behaviour , fatigue and health-related quality of life . RESULTS Participants r and omised into the tailored-print intervention group were three times more likely to commence resistance training and meet the resistance-training guidelines immediately after the intervention than participants allocated to the control group . There were no other significant intervention effects . CONCLUSION Computer-tailored newsletters may be an effective strategy for enhancing resistance-based physical activity among breast cancer survivors . The null findings relating to other outcomes may be due to ceiling effects ( in the case of aerobic activity , fatigue and health-related quality of life ) or the sensitivity of the measure used ( in the case of sitting time ) . These issues require further exploration [15914748] CONTEXT Physical activity has been shown to decrease the incidence of breast cancer , but the effect on recurrence or survival after a breast cancer diagnosis is not known . OBJECTIVE To determine whether physical activity among women with breast cancer decreases their risk of death from breast cancer compared with more sedentary women . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve observational study based on responses from 2987 female registered nurses in the Nurses ' Health Study who were diagnosed with stage I , II , or III breast cancer between 1984 and 1998 and who were followed up until death or June 2002 , whichever came first . MAIN OUTCOME MEASURE Breast cancer mortality risk according to physical activity category ( <3 , 3 - 8.9 , 9 - 14.9 , 15 - 23.9 , or > or = 24 metabolic equivalent task [ MET ] hours per week ) . RESULTS Compared with women who engaged in less than 3 MET-hours per week of physical activity , the adjusted relative risk ( RR ) of death from breast cancer was 0.80 ( 95 % confidence interval [ CI ] , 0.60 - 1.06 ) for 3 to 8.9 MET-hours per week ; 0.50 ( 95 % CI , 0.31 - 0.82 ) for 9 to 14.9 MET-hours per week ; 0.56 ( 95 % CI , 0.38 - 0.84 ) for 15 to 23.9 MET-hours per week ; and 0.60 ( 95 % CI , 0.40 - 0.89 ) for 24 or more MET-hours per week ( P for trend = .004 ) . Three MET-hours is equivalent to walking at average pace of 2 to 2.9 mph for 1 hour . The benefit of physical activity was particularly apparent among women with hormone-responsive tumors . The RR of breast cancer death for women with hormone-responsive tumors who engaged in 9 or more MET-hours per week of activity compared with women with hormone-responsive tumors who engaged in less than 9 MET-hours per week was 0.50 ( 95 % CI , 0.34 - 0.74 ) . Compared with women who engaged in less than 3 MET-hours per week of activity , the absolute unadjusted mortality risk reduction was 6 % at 10 years for women who engaged in 9 or more MET-hours per week . CONCLUSIONS Physical activity after a breast cancer diagnosis may reduce the risk of death from this disease . The greatest benefit occurred in women who performed the equivalent of walking 3 to 5 hours per week at an average pace , with little evidence of a correlation between increased benefit and greater energy expenditure . Women with breast cancer who follow US physical activity recommendations may improve their survival [24532471] OBJECTIVE We conducted this study with the aim of demonstrating the feasibility and efficacy of speed-feedback therapy with a bicycle ergometer on cognitive function in elderly cancer patients . METHODS The subjects were patients with breast or prostate cancer who were 65 years of age or over . Among 146 patients , 78 were r and omly assigned to the intervention group ( n = 38 ) or the control group ( n = 40 ) . The intervention group received speed-feedback therapy with a bicycle ergometer once a week for four successive weeks . The control group was advised to spend the 4-week period engaged in their routine activities . Evaluations were carried out at the baseline and 4 weeks after the baseline ( week 4 ) using the Frontal Assessment Battery , the Barthel Index , the Lawton and Brody Instrumental Activities of Daily Living , and the Functional Assessment of Cancer Therapy-General ver.4 . Data were analyzed by a two-way repeated- measures analysis of variance . RESULTS The mean score of Frontal Assessment Battery for the intervention group was higher than that for the control group at week 4 . In addition to significant main effects of time and group , we also found a significant interaction between the two groups ( p = 0.006 ) . Moreover , all of the subjects in the intervention group could complete all the four sessions of therapy without any pain or distress . CONCLUSION These results suggest that speed-feedback therapy with a bicycle ergometer may be feasible as well as effective for improving the cognitive function in elderly cancer patients [23017985] OBJECTIVE To investigate the effectiveness of an 8-week aquatic program on cancer-related fatigue , as well as physical and psychological outcomes in breast cancer survivors . DESIGN A r and omized controlled trial . SETTING Outpatient clinic , urban , academic medical center , and a sport university swimming pool . PARTICIPANTS Breast cancer survivors ( N=68 ) were r and omly assigned to either an experimental ( aquatic exercise group in deep water pool ) group or a control ( usual care ) group . INTERVENTIONS The intervention group attended aquatic exercise sessions 3 times per week for 8 weeks in a heated deep swimming pool . Sessions lasted 60 minutes in duration : 10 minutes of warm-up , 40 minutes of aerobic and endurance exercises , and 10 minutes of cool-down exercises . Patients allocated to the usual care group followed the oncologist 's recommendations in relation to a healthy lifestyle . MAIN OUTCOME MEASURES Values for fatigue ( Piper Fatigue Scale ) , mood state ( Profile of Mood States ) , and abdominal ( trunk curl static endurance test ) and leg ( multiple sit-to-st and test ) strength were collected at baseline , after the last treatment session , and at a 6-month follow-up . RESULTS Immediately after discharge , the aquatic exercise group showed a large effect size in total fatigue score ( d=.87 ; 95 % confidence interval , .48 - 1.26 ) , trunk curl endurance ( d=.92 ; 95 % confidence interval , 1.97 - 3.83 ) , and leg strength ( d=1.10 ; .55 - 2.76 ) , but negligible effects in vigor , confusion , and disturbance of mood ( d<.25 ) . At the 6-month follow-up period , the aquatic exercise group maintained large to small effect sizes in fatigue scores , multiple sit-to-st and test , and trunk curl static endurance ( .25>d>.90 ) and negligible effects for the fatigue-severity dimension and different scales of the Profile of Mood States ( d<.25 ) . CONCLUSION An aquatic exercise program conducted in deep water was effective for improving cancer-related fatigue and strength in breast cancer survivors [24390808] Purpose This study aim ed to determine whether the Physical Activity and Lymphedema ( PAL ) trial weight training program for breast cancer survivors at risk of or with breast cancer-related lymphedema provided skeletal benefits . Methods Of the 295 participants in the r and omized controlled PAL trial , 258 ( weight training ; N = 128 ; control , N = 130 ) had complete measures of bone mineral density ( BMD ( in grams per square centimeter ) ) of the proximal femur and lumbar spine and were also categorized by T scores . Women in the weight training group performed slowly progressive weight training 2 days/week for 12 months compared to women in the control group who maintained their usual physical activities . Results There were no significant differences in the rate of BMD change at any skeletal site between weight training and control groups , regardless of menopausal status . Distribution of bone health categories was not significantly different between groups at baseline , but became different at 12 months ( p < 0.03 ) among postmenopausal women due to an increase in the percentage of controls who became osteopenic ( 35 to 44 % ) compared to stable bone health in weight lifters . Conclusions The PAL weight training program that increased muscle strength without exacerbating or causing lymphedema among breast cancer survivors was not as efficacious at improving skeletal health . The skeletal loads produced from the PAL program may be insufficient to notably shift BMD , but may have a subtle osteogenic effect . Implication s for cancer survivorsThe safety and efficacy of rigorous weight training programs for improving skeletal health in women at risk for or with breast cancer-related lymphedema remain to be determined [17785708] PURPOSE Breast cancer chemotherapy may cause unfavorable changes in physical functioning , body composition , psychosocial functioning , and quality of life ( QOL ) . We evaluated the relative merits of aerobic and resistance exercise in blunting these effects . PATIENTS AND METHODS We conducted a multicenter r and omized controlled trial in Canada between 2003 and 2005 that r and omly assigned 242 breast cancer patients initiating adjuvant chemotherapy to usual care ( n = 82 ) , supervised resistance exercise ( n = 82 ) , or supervised aerobic exercise ( n = 78 ) for the duration of their chemotherapy ( median , 17 weeks ; 95 % CI , 9 to 24 weeks ) . Our primary end point was cancer-specific QOL assessed by the Functional Assessment of Cancer Therapy-Anemia scale . Secondary end points were fatigue , psychosocial functioning , physical fitness , body composition , chemotherapy completion rate , and lymphedema . RESULTS The follow-up assessment rate for our primary end point was 92.1 % , and adherence to the supervised exercise was 70.2 % . Unadjusted and adjusted mixed-model analyses indicated that aerobic exercise was superior to usual care for improving self-esteem ( P = .015 ) , aerobic fitness ( P = .006 ) , and percent body fat ( adjusted P = .076 ) . Resistance exercise was superior to usual care for improving self-esteem ( P = .018 ) , muscular strength ( P < .001 ) , lean body mass ( P = .015 ) , and chemotherapy completion rate ( P = .033 ) . Changes in cancer-specific QOL , fatigue , depression , and anxiety favored the exercise groups but did not reach statistical significance . Exercise did not cause lymphedema or adverse events . CONCLUSION Neither aerobic nor resistance exercise significantly improved cancer-specific QOL in breast cancer patients receiving chemotherapy , but they did improve self-esteem , physical fitness , body composition , and chemotherapy completion rate without causing lymphedema or significant adverse events [19124485] Introduction : Identifying modifiable factors that reduce the risk of recurrence and improve survival in breast cancer survivors is a pressing concern . The purpose of this study was to examine the association of physical activity following diagnosis and treatment with the risk of breast cancer recurrence and mortality and all-cause mortality in women with early-stage breast cancer . Material s and Methods : The sample consisted of 1,970 women from the Life After Cancer Epidemiology study , a prospect i ve investigation of behavioral risk factors and health outcomes . Self-reported frequency and duration of work-related , household and caregiving , recreational , and transportation-related activities during the six months prior to enrollment were assessed . Outcomes were ascertained from electronic or paper medical charts . Hazard ratios and 95 % confidence intervals were estimated from delayed entry Cox proportional hazards models . Results : Although age-adjusted results suggested that higher levels of physical activity were associated with reduced risk of recurrence and breast cancer mortality ( P for trend = 0.05 and 0.07 , respectively for highest versus lowest level of hours per week of moderate physical activity ) , these associations were attenuated after adjustment for prognostic factors and other confounding variables ( P for trend = 0.36 and 0.26 ) . In contrast , a statistically significant protective association between physical activity and all-cause mortality remained in multivariable analyses ( hazard ratio , 0.66 ; 95 % confidence interval , 0.42 - 1.03 ; P for trend = 0.04 ) . Conclusions : These findings do not support a protective effect of physical activity on breast cancer recurrence or mortality but do suggest that regular physical activity is beneficial for breast cancer survivors in terms of total mortality . ( Cancer Epidemiol Biomarkers Prev 2009;18(1):87–95 [23053793] Background and purpose Previous studies have shown that physical inactivity and obesity are risk factors for the development of colorectal cancer . However , controversy exists regarding the influence of these factors on survival in colorectal cancer patients . We evaluated the impact of recreational physical activity and body mass index ( BMI ) before and after colorectal cancer diagnosis on disease-specific mortality and all-cause mortality . Patients and methods This prospect i ve cohort study included 1,339 women enrolled in the Women ’s Health Initiative study who were diagnosed with colorectal cancer subsequent to study enrollment . BMI and recreational physical activity were measured before cancer diagnosis at study entry ( pre-diagnostic ) and after diagnosis at study follow-up interviews ( post-diagnostic ) . We used Cox regression to estimate the association between pre- and post-diagnostic exposures and survival after colorectal cancer diagnosis . Results Among women diagnosed with colorectal cancer , 265 ( 13 % ) deaths occurred during a median study follow-up of 11.9 years , of which 171 ( 65 % ) were attributed to colorectal cancer . Compared with women reporting no pre-diagnostic recreational physical activity , those reporting activity levels of ≥18 MET-h/week had significantly lower colorectal cancer-specific mortality ( hazard ratio ( HR ) = 0.68 ; 95 % confidence interval ( CI ) : 0.41–1.13 ) and all-cause mortality ( HR = 0.63 ; 95 % CI : 0.42–0.96 ) . Similar inverse associations were seen for post-diagnostic recreational physical activity . Neither pre- nor post-diagnostic BMI were associated with mortality after colorectal cancer diagnosis . Conclusion Recreational physical activity before and after colorectal cancer diagnosis , but not BMI , is associated with more favorable survival [18250341] Previous studies suggest that increased physical activity may lower the risk of breast cancer incidence , but less is known about whether levels of physical activity after breast cancer diagnosis can influence survival . We prospect ively examined the relation between postdiagnosis recreational physical activity and risk of breast cancer death in women who had a previous invasive breast cancer diagnosed between 1988 and 2001 ( at ages 20 - 79 years ) . All women completed a question naire on recent postdiagnosis physical activity and other lifestyle factors . Among 4,482 women without history of recurrence at the time of completing the question naire , 109 died from breast cancer within 6 years of enrollment . Physical activity was expressed as metabolic equivalent task-hours per week ( MET-h/wk ) ; hazard ratios ( HR ) and 95 % confidence intervals ( 95 % CI ) were estimated using Cox proportional hazards regression . After adjusting for age at diagnosis , stage of disease , state of residence , interval between diagnosis and physical activity assessment , body mass index , menopausal status , hormone therapy use , energy intake , education , family history of breast cancer , and treatment modality compared with women expending < 2.8 MET-h/wk in physical activity , women who engaged in greater levels of activity had a significantly lower risk of dying from breast cancer ( HR , 0.65 ; 95 % CI , 0.39 - 1.08 for 2.8 - 7.9 MET-h/wk ; HR , 0.59 ; 95 % CI , 0.35 - 1.01 for 8.0 - 20.9 MET-h/wk ; and HR , 0.51 ; 95 % CI , 0.29 - 0.89 for ≥21.0 MET-h/wk ; P for trend = 0.05 ) . Results were similar for overall survival ( HR , 0.44 ; 95 % CI , 0.32 - 0.60 for ≥21.0 versus < 2.8 MET-h/wk ; P for trend < 0.001 ) and were similar regardless of a woman ’s age , stage of disease , and body mass index . This study provides support for reduced overall mortality and mortality from breast cancer among women who engage in physical activity after breast cancer diagnosis . ( Cancer Epidemiol Biomarkers Prev 2008;17(2):379–86 [26360370] Background : Very little is known about the effect of modifiable lifestyle factors on outcomes of triple-negative breast cancer . We examined this association in a population -based prospect i ve cohort study of patients with triple-negative breast cancer . Methods : A total of 518 women with confirmed triple-negative breast cancer , recruited by the Shanghai Breast Cancer Survival Study , completed 6- , 18- , 36- , and 60-month postdiagnosis surveys . We applied Cox proportional hazard models to evaluate the associations . Results : The mean age at diagnosis was 53.4 ( st and ard deviation = 10.6 ) years old . After a median follow-up of 9.1 years ( range : 0.6–11.8 ) , 128 deaths and 112 recurrences were documented . Exercise during the first 60 months postdiagnosis was inversely associated with total mortality and recurrence/disease-specific mortality with adjusted hazard ratios ( HRs ) of 0.67 ( 95 % confidence interval [ CI ] = 0.46 , 0.96 ) and 0.58 ( 95 % CI = 0.39 , 0.86 ) , respectively . Women with higher exercise-metabolic equivalent scores ( ≥7.6 metabolic equivalent-hours/week ) and longer duration of exercise ( ≥2.5 hours/week ) had lower risk of total and recurrence/disease-specific mortality than did nonexercisers . Compared with nontea drinkers , survival was better among women who were regular tea drinkers during the first 60 months for all cause ( HR = 0.57 , 95 % CI = 0.34 , 0.93 ) and recurrence/disease-specific mortality ( HR = 0.54 , 95 % CI = 0.31 , 0.96 ) . There was no dose – response pattern for tea consumption . No interactions were observed for body mass index , menopausal status , and comorbidity . Conclusions : These findings show that postdiagnosis exercise and tea intake were associated with improved survival among women with triple-negative breast cancer [26606746] Lifestyle factors have been well studied in relation to breast cancer prognosis overall ; however , associations of lifestyle and late outcomes ( > 5 years after diagnosis ) have been much less studied , and no studies have focused on estrogen receptor-positive ( ER+ ) breast cancer survivors , who may have high risk of late recurrence and mortality . We utilized a large prospect i ve pooling study to evaluate the associations of lifestyle factors with late recurrence and all-cause mortality among 6,295 5-year ER+ Stage I-III breast cancer survivors . Pooled and harmonized data were available on clinical factors and lifestyle factors ( pre- to post-diagnosis weight change , body mass index ( BMI ) ( kg/m(2 ) ) , recreational physical activity , alcohol intake and smoking history ) , measured on average 2.1 years after diagnosis . Up date d information for weight only was available . Study heterogeneity was evaluated by the Q-statistic . Multivariable Cox regression models were stratified by study . Adjusting for clinical factors and potential confounders , ≥ 10 % weight gain and obesity ( BMI , 30 - 34.99 and ≥ 35 ) were associated with increased risk of late recurrence ( hazard ratios ( 95 % confidence intervals ) : 1.24 ( 1.00 - 1.53 ) , 1.40 ( 1.05 - 1.86 ) and 1.41 ( 1.02 - 1.93 ) , respectively ) . Daily alcohol intake was associated with late recurrence , 1.28 ( 1.01 - 1.62 ) . Physical activity was inversely associated with late all-cause mortality ( 0.81 ( 0.71 - 0.93 ) and 0.71 ( 0.61 - 0.82 ) for 4.9 to < 17.4 and ≥ 17.4 metabolic equivalent-hr/week ) . A U-shaped association was observed for late all-cause mortality and BMI using up date d weight ( 1.42 ( 1.15 - 1.74 ) and 1.40 ( 1.09 - 1.81 ) , < 21.5 and ≥ 35 , respectively ) . Smoking was associated with increased risk of late outcomes . In this large prospect i ve pooling project , modifiable lifestyle factors were associated with late outcomes among long-term ER+ breast cancer survivors [26774959] BACKGROUND Despite the high global prevalence of prostate cancer ( PCa ) , few epidemiologic studies have assessed physical activity in relation to PCa survival . OBJECTIVE To evaluate different types , intensities , and timing of physical activity relative to PCa survival . DESIGN , SETTING , AND PARTICIPANTS A prospect i ve study was conducted in Alberta , Canada , in a cohort of 830 stage II-IV incident PCa cases diagnosed between 1997 and 2000 with follow-up to 2014 ( up to 17 yr ) . Prediagnosis lifetime activity was self-reported at diagnosis . Postdiagnosis activity was self-reported up to three times during follow-up . OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Cox proportional hazards models related physical activity to all-cause and PCa-specific deaths and to first recurrence/progression of PCa . RESULTS AND LIMITATIONS A total of 458 deaths , 170 PCa-specific deaths , and , after first follow-up , 239 first recurrences/progressions occurred . Postdiagnosis total activity ( > 119 vs ≤42 metabolic equivalent [MET]-hours/week per year ) was associated with a significantly lower all-cause mortality risk ( hazard ratio [ HR ] : 0.58 ; 95 % confidence interval [ CI ] , 0.42 - 0.79 ; p value for trend < 0.01 ) . Postdiagnosis recreational activity ( > 26 vs ≤4 MET-hours/week per year ) was associated with a significantly lower PCa-specific mortality risk ( HR : 0.56 ; 95 % CI , 0.35 - 0.90 ; p value for trend = 0.01 ) . Sustained recreational activity before and after diagnosis ( > 18 - 20 vs < 7 - 8 MET-hours/week per year ) was associated with a lower risk of all-cause mortality ( HR : 0.66 ; 95 % CI , 0.49 - 0.88 ) . Limitations included generalisability to healthier cases and an observational study design . CONCLUSIONS These findings support emerging recommendations to increase physical activity after the diagnosis of PCa and would inform a future exercise intervention trial examining PCa outcomes . PATIENT SUMMARY In a 17-yr prostate cancer ( PCa ) survival study , men who survived at least 2 yr who were more physically active postdiagnosis or performed more recreational physical activity before and after diagnosis survived longer . Recreational physical activity after diagnosis was associated with a lower risk of PCa death [23318529] Background : Previous research has shown exercise to be an effective method to mitigate many adverse treatment-related effects of and rogen suppression therapy ( AST ) but the potential impact of exercise on sexual activity remains unknown . The purpose of this investigation was to report the effect of a 12-week exercise program on sexual activity in prostate cancer patients undergoing AST . Methods : Fifty-seven prostate cancer patients undergoing AST were r and omly assigned to an exercise program ( resistance and aerobic modes ; n=29 ) or usual care control ( n=28 ) . Sexual activity was assessed by the European Organization for Research and Treatment of Cancer prostate cancer-specific quality of life question naire ( QLQ-PR25 ) . Results : QLQ-PR25 data were log transformed and analysis of covariance was used to compare sexual activity between groups following the intervention adjusted for baseline activity . No differences in sexual activity were observed between the exercise and control groups before the intervention . There was a significant ( P=0.045 ) adjusted group difference in sexual activity following the 12-week intervention . Patients undergoing usual care decreased sexual activity while patients in the exercise program maintained their level of sexual activity . At baseline , 20.6 and 22.2 % of participants in the exercise and control groups reported a major interest in sex ( that is , high libido ) . Following the intervention , the exercise group had a significantly higher percentage of participants reporting a major interest in sex ( exercise=17.2 % vs control=0 % ; P=0.024 ) . Conclusions : Participation in a short-term exercise program result ed in the maintenance of sexual activity in prostate cancer patients undergoing AST [21424279] Targeted exercise training could reduce risk factors for fracture and obesity-related diseases that increase from breast cancer treatment , but has not been sufficiently tested . We hypothesized that progressive , moderate-intensity resistance + impact training would increase or maintain hip and spine bone mass , lean mass and fat mass and reduce bone turnover compared to controls who participated in a low-intensity , non-weight bearing stretching program . We conducted a r and omized , controlled trial in 106 women with early stage breast cancer who were > 1 year post-radiation and /or chemotherapy , ≥50 years of age at diagnosis and postmenopausal , free from osteoporosis and medications for bone loss , resistance and impact exercise naïve , and cleared to exercise by a physician . Women were r and omly assigned to participate in 1 year of thrice-weekly progressive , moderate-intensity resistance + impact ( jump ) exercise or in a similar frequency and length control program of progressive , low-intensity stretching . Primary endpoints were bone mineral density ( BMD ; g/cm2 ) of the hip and spine and whole body bone-free lean and fat mass ( kg ) determined by DXA and biomarkers of bone turnover — serum osteocalcin ( ng/ml ) and urinary deoxypyrodiniline cross-links ( nmol/mmolCr ) . Women in the resistance + impact training program preserved BMD at the lumbar spine ( 0.47 vs. −2.13 % ; P = 0.001 ) compared to controls . The resistance + impact group had a smaller increase in osteocalcin ( 7.0 vs. 27 % , P = 0.03 ) and a larger decrease in deoxypyrodinoline ( −49.9 vs. −32.6 % , P = 0.06 ) than controls . Increases in lean mass from resistance + impact training were greatest among women currently taking aromatase inhibitors compared to controls not on this therapy ( P = 0.01 ) . Our combined program of resistance + impact exercise reduced risk factors for fracture among postmenopausal breast cancer survivors ( BCS ) and may be particularly relevant for BCS on aromatase inhibitors ( AIs ) because of the additional benefit of exercise on muscle mass that could reduce falls [16822843] PURPOSE Regular physical activity reduces the risk of developing colon cancer , however , its influence on patients with established disease is unknown . PATIENTS AND METHODS We conducted a prospect i ve observational study of 832 patients with stage III colon cancer enrolled in a r and omized adjuvant chemotherapy trial . Patients reported on various recreational physical activities approximately 6 months after completion of therapy and were observed for recurrence or death . To minimize bias by occult recurrence , we excluded patients who experienced recurrence or died within 90 days of their physical activity assessment . RESULTS Compared with patients engaged in less than three metabolic equivalent task ( MET ) -hours per week of physical activity , the adjusted hazard ratio for disease-free survival was 0.51 ( 95 % CI , 0.26 to 0.97 ) for 18 to 26.9 MET-hours per week and 0.55 ( 95 % CI , 0.33 to 0.91 ) for 27 or more MET-hours per week . The adjusted P for trend was .01 . Postdiagnosis activity was associated with similar improvements in recurrence-free survival ( P for trend = .03 ) and overall survival ( P for trend = .01 ) . The benefit associated with physical activity was not significantly modified by sex , body mass index , number of positive lymph nodes , age , baseline performance status , or chemotherapy received . Moreover , the benefit remained unchanged even after excluding participants who developed cancer recurrence or died within 6 months of activity assessment . CONCLUSION Beyond surgical resection and postoperative adjuvant chemotherapy for stage III colon cancer , for patients who survive and are recurrence free approximately 6 months after adjuvant chemotherapy , physical activity appears to reduce the risk of cancer recurrence and mortality [21892676] Summary The ability of combined step aerobic- and circuit-training to prevent bone loss after breast cancer treatments was related to skeletal site and patients ’ menopausal status . Among premenopausal breast cancer survivors , a 12-month exercise intervention completely prevented bone loss at the femoral neck , whereas no exercise effect was seen at lumbar spine or at neither site in postmenopausal women . Introduction The primary objective of this r and omised clinical trial was to determine the preventive effect of supervised weight-bearing jumping exercises and circuit training on bone loss among breast cancer patients . Methods Of 573 breast cancer survivors aged 35–68 years r and omly allocated into exercise or control group after adjuvant treatments , 498 ( 87 % ) were included in the final analysis . The 12-month exercise intervention comprised weekly supervised step aerobic- and circuit-exercises and similar home training . Bone mineral density ( BMD ) at lumbar spine and femoral neck were measured by dual-energy X-ray absorptiometry . Physical performance was assessed by 2-km walking and figure-8 running tests , and the amount of physical activity was estimated in metabolic equivalent-hours/week . Results In premenopausal women , bone loss at the femoral neck was prevented by exercise , the mean BMD changes being −0.2 % among the trainees vs. −1.4 % among the controls ( p = 0.01 ) . Lumbar bone loss could not be prevented ( −1.9 % vs. −2.2 % ) . In postmenopausal women , no significant exercise-effect on BMD was found either at the lumbar spine ( −1.6 % vs. −2.1 % ) or femoral neck ( −1.1 % vs. −1.1 % ) . Conclusions This 12-month aerobic jumping and circuit training intervention completely prevented femoral neck bone loss in premenopausal breast cancer patients , whereas no effect on BMD was seen in postmenopausal women [21837478] The study was conducted to determine the effect of physical activity on DNA methylation and to predict the consequence of this effect concerning gene expression and breast cancer survival . Blood sample s , collected from 12 breast cancer patients who participated in a r and omized clinical trial of exercise , were examined for exercise-related changes in DNA methylation using a methylation microarray . Tumor sample s of 348 breast cancer patients were analyzed with qRT-PCR and qMSP to determine gene expression and methylation identified in the microarray analysis . Cox regression models were developed to predict survival outcomes in association with gene expression and methylation . After 6 months of moderate-intensity aerobic exercise , changes in DNA methylation ( P < 5 × 10−5 ) in peripheral blood leukocytes were detected in 43 genes from a panel of 14 495 . Based on the list , we analyzed gene expression in association with overall survival in breast tumors and found three genes whose methylation was reduced after exercise were favorably in association with overall survival , i.e. , higher expression associated with better survival . Of the three genes , L3MBTL1 was a putative tumor suppressor gene with known function to repress chromatin for transcription , which is activated mainly in germline stem cells . Further analyses of tumor features among patients indicated that high expression of L3MBTL1 was associated with low grade and hormone receptor – positive tumors , as well as low risk of disease recurrence and breast cancer death . In conclusion , the study suggests that increasing physical activity after a breast cancer diagnosis may affect epigenetic regulation of tumor suppressor genes , which have favorable impacts on survival outcomes of breast cancer patients [23629521] Background : Higher levels of physical activity are associated with lower colorectal carcinoma incidence and mortality , perhaps through influencing energy balance , cellular prosta7 systemic inflammation . Although evidence suggests interactive effects of energetics , sedentary lifestyle , and tumor CTNNB1 ( β-catenin ) or CDKN1B ( p27 ) status on colon cancer prognosis , interactive effects of physical activity and tumor PTGS2 ( the official symbol for COX-2 ) status on clinical outcome remain unknown . Methods : Using molecular pathological epidemiology data base of 605 stage I – III colon and rectal cancers in two prospect i ve cohort studies ( the Nurse 's Health Study and the Health Professionals Follow-up Study ) , we examined patient survival according to postdiagnosis physical activity and tumor PTGS2 status ( with 382 PTGS2-positive and 223 PTGS2-negative tumors by immunohistochemistry ) . Cox proportional hazards models were used to calculate colorectal cancer-specific mortality HR , adjusting for clinical and other tumor variables including microsatellite instability status . Results : Among PTGS2-positive cases , compared with the least active first quartile , the multivariate HRs ( 95 % confidence interval ) were 0.30 ( 0.14–0.62 ) for the second , 0.38 ( 0.20–0.71 ) for the third , and 0.18 ( 0.08–0.41 ) for the fourth quartile of physical activity level ( Ptrend = 0.0002 ) . In contrast , among PTGS2-negative cases , physical activity level was not significantly associated with survival ( Ptrend = 0.84 ; Pinteraction = 0.024 , between physical activity and tumor PTGS2 status ) . Conclusions : Postdiagnosis physical activity is associated with better survival among patients with PTGS2-positive tumors but not among patients with PTGS2-negative tumors . Impact : Immunohistochemical PTGS2 expression in colorectal carcinoma may serve as a predictive biomarker in pathology practice , which may predict stronger benefit from exercise . Cancer Epidemiol Biomarkers Prev ; 22(6 ) ; 1142–52 . © 2013 AACR [24151326] BACKGROUND Exercise improves physical functioning and symptom management during breast cancer chemotherapy , but the effects of different doses and types of exercise are unknown . METHODS A multicenter trial in Canada r and omized 301 breast cancer patients to thrice-weekly supervised exercise during chemotherapy consisting of either a st and ard dose of 25 to 30 minutes of aerobic exercise ( STAN ; n = 96 ) , a higher dose of 50 to 60 minutes of aerobic exercise ( HIGH ; n = 101 ) , or a combined dose of 50 to 60 minutes of aerobic and resistance exercise ( COMB ; n = 104 ) . The primary endpoint was physical functioning assessed by the Medical Outcomes Survey-Short Form (SF)-36 . Secondary endpoints were other physical functioning scales , symptoms , fitness , and chemotherapy completion . All statistical tests were linear mixed model analyses , and the P values were two-sided . RESULTS Follow-up assessment of patient-reported outcomes was 99.0 % . Adjusted linear mixed-model analyses showed that neither HIGH ( + 0.8 ; 95 % confidence interval [ CI ] = -0.8 to 2.4 ; P = .30 ) nor COMB ( + 0.5 ; 95 % CI = -1.1 to 2.1 ; P = .52 ] were superior to STAN for the primary outcome . In secondary analyses not adjusted for multiple comparisons , HIGH was superior to STAN for the SF-36 physical component summary ( P = .04 ) , SF-36 bodily pain ( P = .02 ) , and endocrine symptoms ( P = .02 ) . COMB was superior to STAN for endocrine symptoms ( P = .009 ) and superior to STAN ( P < .001 ) and HIGH ( P < .001 ) for muscular strength . HIGH was superior to COMB for the SF-36 bodily pain ( P = .04 ) and aerobic fitness ( P = .03 ) . No differences emerged for body composition or chemotherapy completion . CONCLUSIONS A higher volume of aerobic or combined exercise is achievable and safe during breast cancer chemotherapy and may manage declines in physical functioning and worsening symptoms better than st and ard volumes [16822844] PURPOSE Physically active individuals have a lower risk of developing colorectal cancer but the influence of exercise on cancer survival is unknown . PATIENTS AND METHODS By a prospect i ve , observational study of 573 women with stage I to III colorectal cancer , we studied colorectal cancer-specific and overall mortality according to predefined physical activity categories before and after diagnosis and by change in activity after diagnosis . To minimize bias by occult recurrences , we excluded women who died within 6 months of their postdiagnosis physical activity assessment . RESULTS Increasing levels of exercise after diagnosis of nonmetastatic colorectal cancer reduced cancer-specific mortality ( P for trend = .008 ) and overall mortality ( P for trend = .003 ) . Compared with women who engaged in less than 3 metabolic equivalent task [ MET ] -hours per week of physical activity , those engaging in at least 18 MET-hours per week had an adjusted hazard ratio for colorectal cancer-specific mortality of 0.39 ( 95 % CI , 0.18 to 0.82 ) and an adjusted hazard ratio for overall mortality of 0.43 ( 95 % CI , 0.25 to 0.74 ) . These results remained unchanged even after excluding women who died within 12 and 24 months of activity assessment . Prediagnosis physical activity was not predictive of mortality . Women who increased their activity ( when comparing prediagnosis to postdiagnosis values ) had a hazard ratio of 0.48 ( 95 % CI , 0.24 to 0.97 ) for colorectal cancer deaths and a hazard ratio of 0.51 ( 95 % CI , 0.30 to 0.85 ) for any-cause death , compared with those with no change in activity . CONCLUSION Recreational physical activity after the diagnosis of stages I to III colorectal cancer may reduce the risk of colorectal cancer-specific and overall mortality [18711185] PURPOSE To investigate the association between pre- and postdiagnosis physical activity ( as well as change in prediagnosis to postdiagnosis physical activity ) and mortality among women with breast cancer . PATIENTS AND METHODS This was a prospect i ve observational study of 933 women enrolled onto the Health , Eating , Activity , and Lifestyle Study who were diagnosed with local or regional breast cancer between 1995 and 1998 and observed until death or September 2004 , whichever came first . The primary outcomes measured were total deaths and breast cancer deaths . The primary exposures were physical activity in the year before and 2 years after diagnosis and the pre- to postdiagnosis change in physical activity . RESULTS Compared with inactive women , the multivariable hazard ratios ( HRs ) for total deaths for women expending at least 9 metabolic equivalent hours per week ( approximately 2 to 3 h/wk of brisk walking ) were 0.69 ( 95 % CI , 0.45 to 1.06 ; P = .045 ) for those active in the year before diagnosis and 0.33 ( 95 % CI , 0.15 to 0.73 ; P = .046 ) for those active 2 years after diagnosis . Compared with women who were inactive both before and after diagnosis , women who increased physical activity after diagnosis had a 45 % lower risk of death ( HR = 0.55 ; 95 % CI , 0.22 to 1.38 ) , and women who decreased physical activity after diagnosis had a four-fold greater risk of death ( HR = 3.95 ; 95 % CI , 1.45 to 10.50 ) . CONCLUSION Moderate-intensity physical activity after a diagnosis of breast cancer may improve prognosis [23225299] Summary We evaluated whether age moderated the effect of impact + resistance exercise on hip BMD in older post-menopausal breast cancer survivors ( BCS ) . Exercise was more beneficial among younger than older women within our sample , suggesting that much older BCS may require different training programs to improve hip health . Purpose Previously , we reported that a program of resistance + impact training stopped bone loss at the spine in older , post-menopausal BCS but had no effect on bone mineral density ( BMD ) at the hip . Aging may blunt the responsiveness of the hip to mechanical loading , so we conducted a secondary data analysis to evaluate whether age moderated the effect of exercise on hip BMD . Methods We analyzed data from our r and omized , controlled trial in older ( ≥ 50 years of age at diagnosis ) , post-menopausal , post-adjuvant treatment BCS ( n = 106 ) comparing women assigned to impact + resistance exercise ( POWIR ) or to a control program of low-intensity stretching ( FLEX ) . We examined effect modification by age on BMD at three hip sites ( greater trochanter , femoral neck , and total hip ) using hierarchical linear modeling adjusting for time since diagnosis and use of adjuvant hormone therapy . Results Age moderated the effect of exercise on total hip BMD such that younger women in POWIR were more likely to see a positive net benefit than FLEX compared to older women where there was little difference between groups ( p = 0.02 ) . Conclusions The skeletal response to loading at the hip within post-menopausal BCS diminishes with age . Whether more vigorous exercise programs and /or longer training periods are required to favorably change hip health in older BCS will require future study and careful thought about the risks and benefits of tougher training programs [26061092] Observational studies have suggested that physical activity may be associated with improved survival after cancer treatment . However , data from controlled clinical trials are required . We analyzed survival data of 103 patients from a previously published r and omized controlled trial in allogeneic stem cell transplant patients who were r and omized to either an exercise intervention ( EX ) or to a social contact control group . EX patients trained prior to hospital admission , during inpatient treatment , and for 6 - 8 weeks after discharge . Survival analyses were used to compare both total mortality ( TM ) and non-relapse mortality ( NRM ) after discharge and transplantation during an observation period of 2 years after transplantation . Analyses were corroborated with Cox and Fine & Gray regression models adjusting for potential confounders . After discharge , EX patients had a significantly lower TM rate than controls ( 12.0 vs. 28.3 % , p = 0.030 ) and a numerically lower NRM rate ( 4.0 vs. 13.5 % , p = 0.086 ) . When the inpatient period was included , absolute risk reductions were similar but not significantly different ( TM : 34.0 vs. 50.9 % , p = 0.112 ; NRM : 26.0 vs. 36.5 % , p = 0.293 ) . The number needed to treat ( NNT ) to prevent one death with EX was about 6 . Furthermore , regression analyses revealed that baseline fitness was protective against mortality . The data suggest that exercise might improve survival in patients undergoing allo-HCT . However , the results should be interpreted with caution as the study was not design ed to detect differences in survival rates , and as no stratification on relevant prognostic factors was carried out [20861399] Background : Aerobic exercise training ( AET ) is known to increase RBC production ; however , this has not been evaluated in breast cancer patients undergoing adjuvant chemotherapy . The purpose of this study was to examine the changes in hemoglobin ( Hb ) levels in the Supervised Trial of Aerobic versus Resistance Training ( START ) and to determine its association with changes in VO2peak . Methods : Two hundred and forty-two breast cancer patients initiating chemotherapy were r and omized to usual care ( n = 82 ) , resistance exercise ( RET , n = 82 ) , or AET ( n = 78 ) groups for the duration of their chemotherapy ( median , 17 weeks ) . Supervised exercise was thrice weekly based on st and ard AET and RET prescriptions . Aerobic fitness ( VO2peak ) and Hb concentration were measured at baseline and end of chemotherapy . Results : Regardless of the exercise group , Hb declined over the course of chemotherapy ( 13.4 ± 10.0 to 11.8 ± 11.5 g/dL , P < 0.01 ) . Both AET and RET groups had significant , moderate correlations between the change in VO2peak and Hb ( AET : r = 0.49 , P < 0.001 ; RET : r = 0.39 , P = 0.001 ) . Conclusion : The results indicate that regular exercise does not protect against the decline in Hb associated with chemotherapy in breast cancer patients , but result ed in a stronger association between Hb and VO2peak . Impact : Even with the chemotherapy-induced decline in Hb , breast cancer patients can maintain their aerobic capacity by participating in regular aerobic exercise . Further studies are required to determine safe intensity levels that may stimulate the maintenance of Hb levels in breast cancer patients . Cancer Epidemiol Biomarkers Prev ; 19(11 ) ; 2826–32 . © 2010 AACR [24500540] INTRODUCTION And rogen deprivation therapy ( ADT ) is associated with significant bone loss and an increase in fracture risk among prostate cancer survivors ( PCS ) . We investigated whether impact + resistance training could stop ADT-related declines in bone mineral density ( BMD ) among PCS on ADT . METHODS We r and omized 51 PCS ( mean age , 70.2 yr ) currently prescribed ADT to participate in 1 yr of impact + resistance training ( Prevent Osteoporosis with Impact + Resistance ( POWIR ) ) or in an exercise placebo program of stretching exercise ( FLEX ) . Outcomes were proximal femur ( total hip , femoral neck , and greater trochanter ) and spine ( L1-L4 ) BMD ( g·cm ) and bone turnover markers ( serum osteocalcin ( ng·mL ) and urinary deoxypyrodinoline cross-links ( nmol·mmol Cr ) ) . RESULTS Retention in the 1-yr study was 84 % and median attendance to supervised classes was 84 % in POWIR and 74 % in FLEX . No study -related injuries were reported . There were no significant differences between groups for average L1-L4 BMD or for BMD at any hip site . When examining individual vertebrae , POWIR has a significant effect on preservation of BMD ( -0.4 % ) at the L4 vertebrae compared with losses ( -3.1 % ) in FLEX ( P = 0.03 ) . CONCLUSION Impact + resistance training was a safe and acceptable form of exercise for older PCS on ADT . Among our limited sample , POWIR did not appear to have a clinical ly meaningful effect on hip or spine BMD , but some evidence of skeletal adaptation to resistance + impact training in an and rogen-deprived state was apparent . Future studies need to be conducted on a larger sample of patients and should consider modifications to POWIR that could further enhance loading across the spine and at the hip to preserve BMD at these clinical ly relevant sites [22993332] AIM The study aim ed at determining whether physical exercise training improves the quality of life ( QoL ) and physical fitness of breast cancer survivors . PATIENTS AND METHODS A total of 573 breast cancer survivors were r and omized into an exercise or a control group , 12-months after adjuvant treatments . EORTC QLQ-C30 and BR-23 question naires were used for evaluation of QoL , FACIT-F for fatigue and the Finnish modified version of Beck 's 13-item depression scale ( RBDI ) for depression . Physical fitness was assessed by a 2-km walking test , and a figure-8 running test and physical activity ( PA ) by metabolic equivalent ( MET ) hours per week ( MET-h/wk ) . RESULTS Figure-8 running time improved significantly among the patients of the intervention group compared with the controls ( p<0.001 ) . No significant between-group differences were observed in 2-km walking time , in PA , EORTC-QLQ-C30 , BR-23 , FACIT-F or BDI . However , there was a linear relationship between increased PA and improved QoL ( p=0.006 ) , irrespective of the intervention . CONCLUSION Increase in physical activity was associated with improved QoL , but no effect of the exercise intervention was observed [25927504] Background . And rogen deprivation therapy ( ADT ) increases survival rates in prostate cancer ( PCa ) patients with locally advanced disease , but is associated with side effects that may impair daily function . Strength training may counteract several side effects of ADT , such as changes in body composition and physical functioning , which in turn may affect health-related quality of life ( HRQOL ) . However , additional r and omised controlled trials are needed to exp and this knowledge . Material and methods . Fifty-eight PCa patients on ADT were r and omised to either 16 weeks of high-load strength training ( n = 28 ) or usual care ( n = 30 ) . The primary outcome was change in total lean body mass ( LBM ) assessed by dual x-ray absorptiometry ( DXA ) . Secondary outcomes were changes in regional LBM , fat mass , and areal bone mineral density ( aBMD ) measured by DXA ; physical functioning assessed by 1-repetition maximum ( 1RM ) tests , sit-to-st and test , stair climbing test and Shuttle walk test ; and HRQOL as measured by the European Organization for the Research and Treatment of Cancer Quality of Life Question naire Core 30 . Results and Conclusion . No statistically significant effect of high-load strength training was demonstrated on total LBM ( p = 0.16 ) , but significant effects were found on LBM in the lower and upper extremities ( 0.49 kg , p < 0.01 and 0.15 kg , p < 0.05 , respectively ) . Compared to usual care , high-load strength training showed no effect on fat mass , aBMD or HRQOL , but beneficial effects were observed in all 1RM tests , sit-to-st and test and stair climbing tests . Adherence to the training program was 88 % for lower body exercises and 84 % for upper body exercises . In summary , high-load strength training improved LBM in extremities and physical functioning , but had no effect on fat mass , aBMD , or HRQOL in PCa patients on ADT [23766391] Background . Chronic fatigue is one of the most restricting symptoms following primary breast cancer treatment , but clinical studies on symptom management are rare . The objective was to evaluate the impact of a multimodal mind – body program ( MMMT ) , including moderate physical activity as compared with a walking intervention alone , on chronic fatigue symptoms of women with stage I to IIIA breast cancer . Patients and Methods . Sixty-four women ( mean age = 56.7 years ) suffering from chronic fatigue after active tumor treatment were r and omly assigned to either an experimental or a control ( n = 32 each ) intervention ( 10 weeks ) . Fatigue , quality of life ( QoL ) , functional well-being , anxiety , and depression were measured with st and ard question naires at baseline , after 10 weeks , and after 3 months . Results . Compared with baseline , both groups had reduced fatigue scores after treatment without any significant difference between groups ( posttreatment , Δ = −0.3 , confidence interval = −1.6 to 1.0 , P = .678 ; follow-up , Δ = −0.4 , confidence interval = −1.8 to 0.9 , P = .510 ) . All patients also improved regarding QoL and general functional well-being . Conclusion . Since both interventions reduced fatigue symptoms and enhanced QoL to a similar extent , we observed no verifiable add-on effect of the MMMT regarding fatigue symptoms . Considering the higher costs with additional expenditure related to MMMT , home-based walking intervention is recommended [23250326] BACKGROUND The number of cancer survivors is increasing rapidly ; however , little is known about whether engaging in physical activity after a cancer diagnosis is associated with lower mortality rates in men . METHODS We conducted a prospect i ve cohort study of 1021 men ( mean age , 71.3 years ) who were diagnosed with cancer ( other than nonmelanoma skin cancer ) . Men reported their physical activities ( walking , stair climbing , and participation in sports and recreational activities ) on question naires in 1988 , a median of 6 years after their cancer diagnosis . Physical activity was up date d in 1993 and men were followed until 2008 , with mortality follow-up > 99 % complete , during which 777 men died ( 337 from cancer , 190 from cardiovascular disease ) . RESULTS In multivariate analyses , the relative risks for all-cause mortality associated with expending < 2100 , 2100 - 4199 , 4200 - 8399 , 8400 - 12,599 , and ≥ 12,600 kJ/week in physical activity were 1.00 ( referent ) , 0.77 , 0.74 , 0.76 , and 0.52 , respectively ( P-trend < 0.0001 ) . Higher levels of physical activity also were associated with lower rates of death from cancer and cardiovascular disease ( P- trend = 0.01 and 0.002 , respectively ) . CONCLUSIONS Engaging in physical activity after cancer diagnosis is associated with better survival among men [24470442] The purpose of these analyses is to test prospect ively whether post-diagnosis running and walking differ significantly in their association with breast cancer mortality . Cox proportional hazard analyses were used to compare breast cancer mortality to baseline exercise energy expenditure ( METs , 1 MET-hour ≅1 km run ) in 272 runners and 714 walkers previously diagnosed with breast cancer from the National Runners ' and Walkers ' Health Studies when adjusted for age , race , menopause , family history , breastfeeding and oral contraceptive use . Diagnosis occurred ( mean ± SD ) 7.9 ± 7.3 years before baseline . Forty-six women ( 13 runners and 33 walkers ) died from breast cancer during 9.1-year mortality surveillance . For the 986 runners and walkers combined , breast cancer mortality decreased an average of 23.9 % MET-hours/day [ 95 % confidence interval ( CI ) : 7.9 - 38.3 % ; p = 0.004 ] . There was a significantly greater decrease in risk for running than walking ( risk per MET-hours/day run vs. walked : p = 0.03 ) . For the 272 runners analyzed separately , breast cancer mortality decreased an average of 40.9 % per MET-hours/day run ( 95 % CI : 19.3 - 60.0 % , p = 0.0004 ) . When analyzed by categories of running energy expenditure , breast cancer mortality was 87.4 % lower for the 1.8 - 3.6 MET-hours/day category ( 95 % CI : 41.3 - 98.2 % lower , p = 0.008 ) and 95.4 % lower for the ≥3.6 MET-hours/day category ( 95 % CI : 71.9 - 100 % lower , p = 0.0004 ) compared to the < 1.07 MET-hours/day category . In contrast , the 714 walkers showed a nonsignificant 4.6 % decrease in breast cancer mortality per MET-hours/day walked ( 95 % CI : 27.3 % decreased risk to 21.3 % increased risk , p = 0.71 ) . These results suggest that post-diagnosis running is associated with significantly lower breast cancer mortality than post-diagnosis walking [21521850] CONTEXT Alterations of the WNT signaling pathway and cadherin-associated protein β 1 ( CTNNB1 or β-catenin ) have been implicated in colorectal carcinogenesis and metabolic diseases . OBJECTIVE To test the hypothesis that CTNNB1 activation in colorectal cancer modifies prognostic associations of body mass index ( BMI ) and level of postdiagnosis physical activity . DESIGN , SETTING , AND PATIENTS Two US prospect i ve cohort studies ( Nurses ' Health Study and the Health Professionals Follow-up Study ) were used to evaluate CTNNB1 localization by immunohistochemistry in 955 patients with stage I , II , III , or IV colon and rectal cancer from 1980 through 2004 . A Cox proportional hazards model was used to compute the hazard ratio ( HR ) for mortality , adjusting for clinical and tumor features , including microsatellite instability , CpG isl and methylator phenotype , level of long interspersed nucleotide element 1 methylation , mutations in KRAS , BRAF , or PIK3CA , and tumor protein p53 . MAIN OUTCOME MEASURES Colorectal cancer-specific mortality and overall mortality through June 30 , 2009 . RESULTS In obese patients ( BMI ≥30 ) , positive status for nuclear CTNNB1 was associated with significantly better colorectal cancer-specific survival ( adjusted HR , 0.24 [ 95 % confidence interval { CI } , 0.12 - 0.49 ] , P < .001 for interaction ; 5-year survival : 0.85 for patients with positive nuclear CTNNB1 status vs 0.78 for those with negative status ) and overall survival ( adjusted HR , 0.56 [ 95 % CI , 0.35 - 0.90 ] , P = .03 for interaction ; 5-year survival : 0.77 for patients with positive nuclear CTNNB1 status vs 0.74 for those with negative status ) , while CTNNB1 status was not associated with prognosis among nonobese patients ( BMI < 30 ) . Among patients with negative status for nuclear CTNNB1 and cancer in stages I , II , or III , postdiagnosis physical activity was associated with better colorectal cancer-specific survival ( adjusted HR , 0.33 [ 95 % CI , 0.13 - 0.81 ] , P = .05 for interaction ; 5-year survival : 0.97 for ≥18 vs 0.89 for < 18 metabolic equivalent task hours/week ) , while postdiagnosis physical activity was not associated with colorectal cancer-specific survival among patients with positive status for nuclear CTNNB1 ( adjusted HR , 1.07 [ 95 % CI , 0.50 - 2.30 ] ) . CONCLUSIONS Among obese patients only , activation of CTNNB1 was associated with better colorectal cancer-specific survival and overall survival . Postdiagnosis physical activity was associated with better colorectal cancer-specific survival only among patients with negative status for nuclear CTNNB1 . These molecular pathological epidemiology findings suggest that the effects of alterations in the WNT-CTNNB1 pathway on outcome are modified by BMI and physical activity [25567329] Aim . The aim of the study was to compare the effects of aerobic exercise training and yoga on the functional capacity , peripheral muscle strength , quality of life ( QOL ) , and fatigue in breast cancer survivors . Material and methods . A total of 52 patients with a diagnosis of breast cancer were included in the study . The patients were r and omly assigned to 2 groups : aerobic exercise ( n = 28 ) and yoga added to aerobic exercise ( n = 24 ) . Both groups participated in submaximal exercise 30 minutes/d , 3 d/wk for 6 weeks . The second group participated in a 1-hour yoga program in addition to aerobic exercise training . Functional capacity was assessed by the 6-Minute Walk Test ( 6MWT ) . Peripheral muscle strength was evaluated with a h and -held dynamometer . The fatigue severity level was assessed with the Fatigue Severity Scale ( FSS ) . The QOL was determined by the European Organisation for Research and Treatment of Cancer Quality of Life Question naire . Results . There were statistically significant increases in peripheral muscle strength , the 6MWT distance , and the perception of QOL in both groups ( P < .05 ) . Additionally , the group with aerobic exercise and yoga showed marked improvement compared with the aerobic exercise group in fatigue perception ( P < .05 ) . Conclusion . According to the data from this study , aerobic exercise training and yoga improved the functional capacity and QOL of breast cancer patients . Aerobic exercise programs can be supported by body mind techniques , such as yoga , in the rehabilitation of cancer patients for improving functional recovery and psychosocial wellness [24633595] UNLABELLED Observational studies suggest that physical activity after a breast cancer diagnosis is associated with improved cancer outcomes ; however , no r and omized data are available . Here , we report an exploratory follow-up of cancer outcomes from the Supervised Trial of Aerobic versus Resistance Training ( START ) . METHODS The START was a Canadian multicenter trial that r and omized 242 breast cancer patients between 2003 and 2005 to usual care ( n = 82 ) , supervised aerobic ( n = 78 ) , or resistance ( n = 82 ) exercise during chemotherapy . The primary end point for this exploratory analysis was disease-free survival ( DFS ) . Secondary end points were overall survival , distant DFS , and recurrence-free interval . The two exercise arms were combined for analysis ( n = 160 ) , and selected subgroups were explored . RESULTS After a median follow-up of 89 months , there were 25/160 ( 15.6 % ) DFS events in the exercise groups and 18/82 ( 22.0 % ) in the control group . Eight-year DFS was 82.7 % for the exercise groups compared with 75.6 % for the control group ( HR , 0.68 ; 95 % confidence interval ( CI ) , 0.37 - 1.24 ; log-rank , P = 0.21 ) . Slightly stronger effects were observed for overall survival ( HR , 0.60 ; 95 % CI , 0.27 - 1.33 ; log-rank , P = 0.21 ) , distant DFS ( HR , 0.62 ; 95 % CI , 0.32 - 1.19 ; log-rank , P = 0.15 ) , and recurrence-free interval ( HR , 0.58 ; 95 % CI , 0.30 - 1.11 ; Gray test , P = 0.095 ) . Subgroup analyses suggested potentially stronger exercise effects on DFS for women who were overweight/obese ( HR , 0.59 ; 95 % CI , 0.27 - 1.27 ) , had stage II/III cancer ( HR , 0.61 ; 95 % CI , 0.31 - 1.20 ) , estrogen receptor-positive tumors ( HR , 0.58 ; 95 % CI , 0.26 - 1.29 ) , human epidermal growth factor receptor 2-positive tumors ( HR , 0.21 ; 95 % CI , 0.04 - 1.02 ) , received taxane-based chemotherapies ( HR , 0.46 ; 95 % CI , 0.19 - 1.15 ) , and ≥85 % of their planned chemotherapy ( HR , 0.50 ; 95 % CI , 0.25 - 1.01 ) . CONCLUSIONS This exploratory follow-up of the START provides the first r and omized data to suggest that adding exercise to st and ard chemotherapy may improve breast cancer outcomes . A definitive phase III trial is warranted

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### Context: [3042101] Objective Research suggests that physical activity is associated with improved breast cancer survival , yet no studies have examined the association between post-diagnosis changes in physical activity and breast cancer outcomes . The aim of this study was to determine whether baseline activity and 1-year change in activity are associated with breast cancer events or mortality . Methods A total of 2,361 post-treatment breast cancer survivors ( Stage I – III ) enrolled in a r and omized controlled trial of dietary change completed physical activity measures at baseline and one year . Physical activity variables ( total , moderate – vigorous , and adherence to guidelines ) were calculated for each time point . Median follow-up was 7.1 years . Outcomes were invasive breast cancer events and all-cause mortality . Results Those who were most active at baseline had a 53 % lower mortality risk compared to the least active women ( HR = 0.47 ; 95 % CI : 0.26 , 0.84 ; p = .01 ) . Adherence to activity guidelines was associated with a 35 % lower mortality risk ( HR = 0.65 , 95 % CI : 0.47 , 0.91 ; p < .01 ) . Neither baseline nor 1-year change in activity was associated with additional breast cancer events . Conclusions Higher baseline ( post-treatment ) physical activity was associated with improved survival . However , change in activity over the following year was not associated with outcomes . These data suggest that long-term physical activity levels are important for breast cancer prognosis [22749425] OBJECTIVE To examine the changes from a combined exercise intervention after radical prostatectomy ( RP ) in elderly patients with prostate cancer , because r and omized controlled trials addressing exercise intervention after RP have been lacking . METHODS From May 2009 to May 2010 , all patients who underwent laparoscopic RP were assessed for eligibility . A total of 66 patients were r and omized to an exercise or a control group . The exercise group received a combined exercise intervention ( resistance , flexibility , and Kegel exercises ) twice a week for 12 weeks , and the control group received only Kegel exercises . The primary outcome was physical function , and the secondary outcomes were continence status and quality of life after the exercise intervention . RESULTS A total of 49 patients completed follow-up to the end of study . After the 12-week exercise intervention , except for grip strength , all physical functions were better in the exercise group than in the control group . The 24-hour pad test results ( 12.2 g in the exercise group , 46.2 g in the control group ) and continence rate ( 73.1 % in exercise group , 43.5 % in the control group ) recovered more promptly in the exercise group . On a question naire study using the International Consultation on Incontinence question naire , Beck Depression Inventory , and Medical Outcomes Study 36-item short-form health survey , only the exercise group showed improvement at the last follow-up visit . CONCLUSION A 12-week combined exercise intervention after RP results in improvement of physical function , continence rate , and quality of life . These results could help with prompt recovery of daily activities [19723652] Purpose : Physical activity in colon cancer survivors has been associated with lower cancer recurrences and improved survival . Whether molecular features of the tumor portend more or less likelihood for benefit from exercise is unknown . Experimental Design : Using two large prospect i ve cohort studies with physical activity assessment s after colon cancer diagnosis , we examined expression of fatty acid synthase , p53 , p21 , and p27 and mutational status of K-ras and phosphatidylinositol 3-kinase(PI3KCA ) . We calculated hazard ratios ( HR ) of colon cancer – specific mortality , adjusted for tumor and patient characteristics , and tested for molecular interactions with exercise . Results : In a cohort of 484 men and women with stage I to III colon cancer , patients who engaged in at least 18 metabolic equivalent task (MET)–hours per week after diagnosis had an adjusted HR for colon cancer – specific mortality of 0.64 [ 95 % confidence interval ( 95 % CI ) , 0.33 - 1.23 ] and for overall mortality of 0.60 ( 95 % CI , 0.41 - 0.86 ) . A statistically significant interaction was detected based on p27 expression ( P = 0.03 ) . For tumors with loss of p27 ( n = 195 ) , physical activity of ≥18 MET-hours/week led to a HR for colon cancer mortality of 1.40 ( 95 % CI , 0.41 - 4.72 ) , compared with those with < 18 MET-hours/week . However , for tumors with expression of p27 ( n = 251 ) , the adjusted HR was 0.33 ( 95 % CI , 0.12 - 0.85 ) . Molecular status of fatty acid synthase , K-ras , p53 , p21 , and PI3KCA did not influence the association between exercise and colon cancer – specific or overall mortality . Conclusion : The benefit of physical activity on outcomes in patients with stage I to III colon cancer may be influenced by p27 status . Further studies are warranted to confirm these findings . ( Clin Cancer Res 2009;15(18):5931–6 [23045575] PURPOSE The purpose of our study was to evaluate the effect of cognitive behavioral therapy ( CBT ) , physical exercise ( PE ) , and of these two interventions combined ( CBT/PE ) on menopausal symptoms ( primary outcome ) , body image , sexual functioning , psychological well-being , and health-related quality of life ( secondary outcomes ) in patients with breast cancer experiencing treatment-induced menopause . PATIENTS AND METHODS Patients with breast cancer reporting treatment-induced menopausal symptoms ( N=422 ) were r and omly assigned to CBT ( n=109 ) , PE ( n=104 ) , CBT/PE ( n=106 ) , or to a waiting list control group ( n=103 ) . Self-report question naires were completed at baseline , 12 weeks , and 6 months . Multilevel procedures were used to compare the intervention groups with the control group over time . RESULTS Compared with the control group , the intervention groups had a significant decrease in levels of endocrine symptoms ( Functional Assessment of Cancer Therapy-Endocrine Symptoms ; P<.001 ; effect size , 0.31 - 0.52 ) and urinary symptoms ( Bristol Female Lower Urinary Tract Symptoms Question naire ; P=.002 ; effect size , 0.29 - 0.33 ) , and they showed an improvement in physical functioning ( 36-Item Short Form Health Survey physical functioning subscale ; P=.002 ; effect size , 0.37 - 0.46 ) . The groups that included CBT also showed a significant decrease in the perceived burden of hot flashes and night sweats ( problem rating scale of the Hot Flush Rating Scale ; P<.001 ; effect size , 0.39 - 0.56 ) and an increase in sexual activity ( Sexual Activity Question naire habit subscale ; P=.027 ; effect size , 0.65 ) . Most of these effects were observed at both the 12-week and 6-month follow-ups . CONCLUSION CBT and PE can have salutary effects on endocrine symptoms and , to a lesser degree , on sexuality and physical functioning of patients with breast cancer experiencing treatment-induced menopause . Future work is needed to improve the design and the planning of these interventions to improve program adherence [21610110] Vigorous activity after diagnosis was recently reported to be inversely associated with prostate cancer-specific mortality . However , men with metastatic disease may decrease their activity due to their disease ; thus , a causal interpretation is uncertain . We therefore prospect ively examined vigorous activity and brisk walking after diagnosis in relation to risk of prostate cancer progression , an outcome less susceptible to reverse causation , among 1,455 men diagnosed with clinical ly localized prostate cancer . Cox proportional hazards regression was used to examine vigorous activity , nonvigorous activity , walking duration , and walking pace after diagnosis and risk of prostate cancer progression . We observed 117 events ( 45 biochemical recurrences , 66 secondary treatments , 3 bone metastases , 3 prostate cancer deaths ) during 2,750 person-years . Walking accounted for nearly half of all activity . Men who walked briskly for 3 h/wk or more had a 57 % lower rate of progression than men who walked at an easy pace for less than 3 h/wk ( HR = 0.43 ; 95 % CI : 0.21 - 0.91 ; P = 0.03 ) . Walking pace was associated with decreased risk of progression independent of duration ( HR brisk vs. easy pace = 0.52 ; 95 % CI : 0.29 - 0.91 ; P(trend ) = 0.01 ) . Few men engaged in vigorous activity , but there was a suggestive inverse association ( HR ≥3 h/wk vs. none = 0.63 ; 95 % CI : 0.32 - 1.23 ; P(trend ) = 0.17 ) . Walking duration and total nonvigorous activity were not associated with risk of progression independent of pace or vigorous activity , respectively . Brisk walking after diagnosis may inhibit or delay prostate cancer progression among men diagnosed with clinical ly localized prostate cancer [22286332] The aim of this study was to determine whether an exercise program , commencing 4–6 weeks post-operatively , reduces upper limb impairments in women treated for early breast cancer . Women ( n = 160 ) were r and omized to either an 8-week exercise program ( n = 81 ) or to a control group ( n = 79 ) following stratification for axillary surgery . The exercise program comprised a weekly session and home program of passive stretching and progressive resistance training for shoulder muscles . The control group attended fortnightly assessment s but no exercises were provided . The primary outcome was self-reported arm symptoms derived from the EORTC breast cancer-specific question naire ( BR23 ) , scored out of 100 with a low score indicative of fewer symptoms . The secondary outcomes included physical measures of shoulder range of motion , strength , and swelling ( i.e. , lymphedema ) . Women were assessed immediately following the intervention and at 6 months post-intervention . The change in symptoms from baseline was not significantly different between groups immediately following the intervention or at 6 m post-intervention . The between group difference immediately following the intervention was 4 ( 95 % CI −1 to 9 ) and 6 months post-intervention was 4 ( −2 to 10 ) . However , the change in range of motion for flexion and abduction was significantly greater in the exercise group immediately following the intervention , as was change in shoulder abductor strength . In conclusion , a supervised exercise program provided some , albeit small , additional benefit at 6 months post-intervention to women who had been provided with written information and reminders to use their arm . Both the groups reported few impairments including swelling immediately following the intervention and 6 months post-intervention . Notably , resistance training in the post-operative period did not precipitate lymphedema [25096607] BACKGROUND Exercise has been reported to decrease cancer-related fatigue and to increase quality of life ( QoL ) in various breast cancer ( BC ) population s. However , studies investigating exercise during radiotherapy or resistance training are scarce . We conducted a r and omized , controlled trial ( BEST study ) to assess the efficacy of 12-week resistance training on fatigue beyond possible psychosocial effects of a group-based intervention . PATIENTS AND METHODS One hundred sixty patients with BC stage 0-III were r and omly assigned to a 12-week progressive resistance training ( 2 times/week ) or a 12-week relaxation control ( RC , 2 times/week ) . Both interventions were group-based . The primary end point fatigue was assessed with a 20-item multidimensional question naire , QoL with EORTC question naires . Statistical analyses were based on analysis of covariance models for the individual changes from baseline to week 13 . RESULTS Adherence to the intervention program as well as the completion rate ( 97 % ) for the primary outcome variable fatigue was high . In intention-to-treat analyses for the N = 155 patients , significant between-group mean differences ( MD ) favoring the exercise group ( EX ) were observed for general fatigue ( P = 0.044 ) , especially for the subscale physical fatigue [ MD = -0.8 ; 95 % confidence interval -1.5 to -0.2 , P = 0.013 ] , but not for affective ( P = 0.91 ) or cognitive fatigue ( P = 0.65 ) . For QoL , significantly larger improvements regarding the role function ( P = 0.035 ) and pain ( P = 0.040 ) were noted among exercisers compared with RCs . Future perspective improved significantly stronger in the RC group compared with the EX group ( P = 0.047 ) . CONCLUSIONS The 12-week resistance training program was a safe , feasible and efficacious strategy to improve cancer-related fatigue and components of QoL in BC patients during adjuvant radiotherapy . As exercise was compared with another group-based intervention , results indicate that resistance training effects on fatigue and QoL go beyond psychosocial benefits , and that the clinical ly relevant overall benefit of resistance exercise compared with usual care can be assumed to be higher . TRIAL REGISTRATION Clinical Trials.gov NCT01468766 [22996743] Summary Our r and omized controlled trial in prematurely menopausal breast cancer survivors showed that impact + resistance training prevented increases in percentage of body fat compared with controls and also improved BMD at the hip and prevented BMD loss at the spine among exercise-trained women who were menopausal for > 1 year . Introduction Cancer treatment-related menopause worsens bone health and body composition in breast cancer survivors ( BCS ) . We investigated whether impact + resistance training could improve bone mineral density ( BMD ) , reduce bone turnover , build muscle , and decrease fat mass in BCS with premature menopause . Methods We conducted a r and omized controlled trial in 71 BCS ( mean age , 46.5 years ) within 5 years of treatment-related menopause . Women were r and omly assigned to one of two groups : ( 1 ) impact + resistance training ( prevent osteoporosis with impact + resistance ( POWIR ) ) or ( 2 ) exercise placebo ( FLEX ) 3 × /week for 1 year . Outcomes were hip and spine BMD ( in grams per square centimeter ) and body composition ( percent body fat ( % BF ) and lean and fat mass ( in kilograms ) ) by DXA and bone turnover markers ( serum osteocalcin ( in nanograms per milliliter ) and urinary deoxypryrodinoline ( in nanomoles per milliliter ) . Results There were no significant group × time interactions for bone outcomes when using an intent-to-treat approach on the full sample . In analyses restricted to BCS who were menopausal for ≥1 year , POWIR increased BMD at the hip and slowed BMD loss at the spine compared with FLEX ( femoral neck — POWIR , 0.004 ± 0.093 g/cm2 vs. FLEX , −0.010 ± 0.089 g/cm2 ; p < 0.01 ; spine — POWIR , −0.003 ± 0.114 g/cm2 vs. FLEX , −0.020 ± 0.110 g/cm2 ; p = 0.03 ) . POWIR prevented increases in % BF ( POWIR , 0.01 % vs. FLEX , 1.3 % ; p < 0.04 ) . Women with attendance to POWIR at ≥64 % had better improvements in % BF than women attending less often ( p < 0.03 ) . Conclusion Impact + resistance training may effectively combat bone loss and worsening body composition from premature menopause in BCS [17638108] Objective With increases in cancer survival , promotion of healthy lifestyle behaviors among survivors is receiving considerable attention . This study compared health behaviors among a large sample of Australian adult cancer survivors with an age- and sex-matched cohort of people with no cancer history . Methods Using the Australian National Health Survey , 968 cancer survivors were identified , and r and omly matched by age and sex to 5,808 respondents without a history of cancer . Six health behaviors were compared ( smoking , physical activity , servings of vegetables , servings of fruit , alcohol use , skin checks ) , along with overweight and obesity , using polytomous logistic regression analyses controlling for selected chronic conditions . Models were applied across both groups and by tumor site . Results Compared to the non-cancer comparison group , cancer survivors were significantly more likely to be current ( OR = 1.35 ) smokers , particularly those under 40 years ( OR = 1.69 ) , and more likely to have regular skin checks ( OR = 1.76 ) . Although not significant , there was consistent evidence that cancer survivors were slightly more likely to be overweight or obese ( p = 0.065 ) and have higher levels of alcohol consumption ( p = 0.088 ) . There was no evidence of differences between survivors and controls for levels of physical inactivity , vegetable consumption or fruit consumption . Women with a history of gynecological cancers were much more likely to be current smokers ( OR = 2.37 ) , while other differences by sex and cancer site were consistent with overall patterns . Cancer survivors were also significantly more likely to report having a range of co-morbid chronic medical conditions . Conclusion Given their increased risk of second cancers and co-morbid chronic conditions , the lack of difference in behavioral risk factors confirms the need for a focus on improving the health behaviors of cancer survivors . Collaborative chronic disease management models may be particularly appropriate in this regard [24460069] Abstract Background . Physical activity during chemotherapy has been shown in several studies to reduce fatigue , improve symptoms and impact positively on health-related quality of life ( HRQoL ) . Challenges associated with intervention studies on physical activity during cancer treatment relate to consistent adherence . The primary objective was to study feasibility and adherence of physical activity intervention among patients with cancer during adjuvant chemotherapy treatment . The secondary objective was to investigate the effects of physical activity on health aspects , including HRQoL , symptoms and surrogate markers for cardiovascular disease . Material and methods . This r and omized controlled trial included patients with breast cancer ( BRCA ) and colorectal cancer ( CRC ) during adjuvant chemotherapy . The intervention continued for 10 weeks and included daily walks of 10 000 steps and a weekly supervised group walk . Adherence was assessed by a pedometer and the number of participants who reported step counts every week and percentage of participants who achieved the target steps every week . Results . Adherence average reached 91 % during the intervention period ; in total 74 % completed the exercise intervention . The majority of the participants achieved an average of 83 % of the target of 10 000 steps per day for 10 weeks . There was a significant increase in daily physical activity ( p = 0.016 ) in the intervention group . Significant differences were also found for some breast cancer-specific symptoms [ swelling , mobility and pain ( p = 0.045 ) ] . The study showed a relatively small weight gain an average of 0.9 kg in the intervention group and 1.3 kg in the control group . Conclusion . Physical activity in the form of walking is feasible during adjuvant chemotherapy treatment despite increasing symptoms . The physical activity increased in the intervention group during the study time and had a positive impact on breast symptoms and the weight gain was lower in comparison to previous studies [25491935] Purpose Few r and omized controlled trials in exercise oncology have examined survival outcomes . Here , we report an exploratory follow-up of progression-free survival ( PFS ) from the Healthy Exercise for Lymphoma Patients ( HELP ) Trial . Methods The HELP Trial r and omized 122 lymphoma patients between 2005 and 2008 to either control ( n = 62 ) or 12 weeks of supervised aerobic exercise ( n = 60 ) . PFS events were abstract ed from medical records in 2013 . In addition to the r and omized comparison , we explored the effects of exercise adherence ( < 80 % vs. ≥80 % ) and control group crossover ( no vs. yes ) . Results After a median follow-up of 61 months ( interquartile range 36–67 ) , the adjusted 5-year PFS was 64.8 % for the exercise group compared with 65.0 % for the control group ( Hazard ratio [ HR ] 1.01 , 95 % CI 0.51–2.01 , p = 0.98 ) . In the secondary analysis , the adjusted 5-year PFS was 59.0 % in the control group without crossover compared with 69.2 % for the control group with crossover ( HR 0.68 , 95 % CI 0.22–2.06 , p = 0.49 ) , 67.7 % for the exercise group with < 80 % adherence ( HR 0.72 , 95 % CI 0.28–1.85 , p = 0.50 ) , and 68.4 % for the exercise group with ≥80 % adherence ( HR 0.70 , 95 % CI 0.32–1.56 , p = 0.39 ) . In a post hoc analysis combining the three groups that received supervised exercise , the adjusted 5-year PFS for the supervised exercise groups was 68.5 % compared with 59.0 % for the group that received no supervised exercise ( HR 0.70 , 95 % CI 0.35–1.39 , p = 0.31 ) . Conclusions This exploratory follow-up of the HELP Trial suggests that supervised aerobic exercise may be associated with improved PFS in lymphoma patients . Larger trials design ed to answer this question are needed [3196245] Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more [25060288] BACKGROUND Participation in physical activity can improve the health outcomes of breast cancer survivors . To impact public health , broad-reaching sustainable interventions that promote physical activity are needed . PURPOSE To evaluate the efficacy of two distance-based interventions for promoting physical activity among breast cancer survivors compared with a st and ard recommendation control . METHODS Breast cancer survivors who had finished ' active ' cancer treatment were eligible to participate . Participants ( n = 330 ) were r and omly assigned to receive one of the following mail-delivered interventions : three computer-tailored newsletters , a previously developed breast cancer-specific physical activity booklet or a pamphlet detailing the public health recommendations for physical activity ( control ) . Primary outcomes were self-reported moderate to vigorous aerobic activity and participant 's self-reported resistance training activity at 4 months post-baseline . Secondary outcomes were pedometer step counts , whether or not participants were meeting the physical activity guidelines , time spent in sedentary behaviour , fatigue and health-related quality of life . RESULTS Participants r and omised into the tailored-print intervention group were three times more likely to commence resistance training and meet the resistance-training guidelines immediately after the intervention than participants allocated to the control group . There were no other significant intervention effects . CONCLUSION Computer-tailored newsletters may be an effective strategy for enhancing resistance-based physical activity among breast cancer survivors . The null findings relating to other outcomes may be due to ceiling effects ( in the case of aerobic activity , fatigue and health-related quality of life ) or the sensitivity of the measure used ( in the case of sitting time ) . These issues require further exploration [15914748] CONTEXT Physical activity has been shown to decrease the incidence of breast cancer , but the effect on recurrence or survival after a breast cancer diagnosis is not known . OBJECTIVE To determine whether physical activity among women with breast cancer decreases their risk of death from breast cancer compared with more sedentary women . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve observational study based on responses from 2987 female registered nurses in the Nurses ' Health Study who were diagnosed with stage I , II , or III breast cancer between 1984 and 1998 and who were followed up until death or June 2002 , whichever came first . MAIN OUTCOME MEASURE Breast cancer mortality risk according to physical activity category ( <3 , 3 - 8.9 , 9 - 14.9 , 15 - 23.9 , or > or = 24 metabolic equivalent task [ MET ] hours per week ) . RESULTS Compared with women who engaged in less than 3 MET-hours per week of physical activity , the adjusted relative risk ( RR ) of death from breast cancer was 0.80 ( 95 % confidence interval [ CI ] , 0.60 - 1.06 ) for 3 to 8.9 MET-hours per week ; 0.50 ( 95 % CI , 0.31 - 0.82 ) for 9 to 14.9 MET-hours per week ; 0.56 ( 95 % CI , 0.38 - 0.84 ) for 15 to 23.9 MET-hours per week ; and 0.60 ( 95 % CI , 0.40 - 0.89 ) for 24 or more MET-hours per week ( P for trend = .004 ) . Three MET-hours is equivalent to walking at average pace of 2 to 2.9 mph for 1 hour . The benefit of physical activity was particularly apparent among women with hormone-responsive tumors . The RR of breast cancer death for women with hormone-responsive tumors who engaged in 9 or more MET-hours per week of activity compared with women with hormone-responsive tumors who engaged in less than 9 MET-hours per week was 0.50 ( 95 % CI , 0.34 - 0.74 ) . Compared with women who engaged in less than 3 MET-hours per week of activity , the absolute unadjusted mortality risk reduction was 6 % at 10 years for women who engaged in 9 or more MET-hours per week . CONCLUSIONS Physical activity after a breast cancer diagnosis may reduce the risk of death from this disease . The greatest benefit occurred in women who performed the equivalent of walking 3 to 5 hours per week at an average pace , with little evidence of a correlation between increased benefit and greater energy expenditure . Women with breast cancer who follow US physical activity recommendations may improve their survival [24532471] OBJECTIVE We conducted this study with the aim of demonstrating the feasibility and efficacy of speed-feedback therapy with a bicycle ergometer on cognitive function in elderly cancer patients . METHODS The subjects were patients with breast or prostate cancer who were 65 years of age or over . Among 146 patients , 78 were r and omly assigned to the intervention group ( n = 38 ) or the control group ( n = 40 ) . The intervention group received speed-feedback therapy with a bicycle ergometer once a week for four successive weeks . The control group was advised to spend the 4-week period engaged in their routine activities . Evaluations were carried out at the baseline and 4 weeks after the baseline ( week 4 ) using the Frontal Assessment Battery , the Barthel Index , the Lawton and Brody Instrumental Activities of Daily Living , and the Functional Assessment of Cancer Therapy-General ver.4 . Data were analyzed by a two-way repeated- measures analysis of variance . RESULTS The mean score of Frontal Assessment Battery for the intervention group was higher than that for the control group at week 4 . In addition to significant main effects of time and group , we also found a significant interaction between the two groups ( p = 0.006 ) . Moreover , all of the subjects in the intervention group could complete all the four sessions of therapy without any pain or distress . CONCLUSION These results suggest that speed-feedback therapy with a bicycle ergometer may be feasible as well as effective for improving the cognitive function in elderly cancer patients [23017985] OBJECTIVE To investigate the effectiveness of an 8-week aquatic program on cancer-related fatigue , as well as physical and psychological outcomes in breast cancer survivors . DESIGN A r and omized controlled trial . SETTING Outpatient clinic , urban , academic medical center , and a sport university swimming pool . PARTICIPANTS Breast cancer survivors ( N=68 ) were r and omly assigned to either an experimental ( aquatic exercise group in deep water pool ) group or a control ( usual care ) group . INTERVENTIONS The intervention group attended aquatic exercise sessions 3 times per week for 8 weeks in a heated deep swimming pool . Sessions lasted 60 minutes in duration : 10 minutes of warm-up , 40 minutes of aerobic and endurance exercises , and 10 minutes of cool-down exercises . Patients allocated to the usual care group followed the oncologist 's recommendations in relation to a healthy lifestyle . MAIN OUTCOME MEASURES Values for fatigue ( Piper Fatigue Scale ) , mood state ( Profile of Mood States ) , and abdominal ( trunk curl static endurance test ) and leg ( multiple sit-to-st and test ) strength were collected at baseline , after the last treatment session , and at a 6-month follow-up . RESULTS Immediately after discharge , the aquatic exercise group showed a large effect size in total fatigue score ( d=.87 ; 95 % confidence interval , .48 - 1.26 ) , trunk curl endurance ( d=.92 ; 95 % confidence interval , 1.97 - 3.83 ) , and leg strength ( d=1.10 ; .55 - 2.76 ) , but negligible effects in vigor , confusion , and disturbance of mood ( d<.25 ) . At the 6-month follow-up period , the aquatic exercise group maintained large to small effect sizes in fatigue scores , multiple sit-to-st and test , and trunk curl static endurance ( .25>d>.90 ) and negligible effects for the fatigue-severity dimension and different scales of the Profile of Mood States ( d<.25 ) . CONCLUSION An aquatic exercise program conducted in deep water was effective for improving cancer-related fatigue and strength in breast cancer survivors [24390808] Purpose This study aim ed to determine whether the Physical Activity and Lymphedema ( PAL ) trial weight training program for breast cancer survivors at risk of or with breast cancer-related lymphedema provided skeletal benefits . Methods Of the 295 participants in the r and omized controlled PAL trial , 258 ( weight training ; N = 128 ; control , N = 130 ) had complete measures of bone mineral density ( BMD ( in grams per square centimeter ) ) of the proximal femur and lumbar spine and were also categorized by T scores . Women in the weight training group performed slowly progressive weight training 2 days/week for 12 months compared to women in the control group who maintained their usual physical activities . Results There were no significant differences in the rate of BMD change at any skeletal site between weight training and control groups , regardless of menopausal status . Distribution of bone health categories was not significantly different between groups at baseline , but became different at 12 months ( p < 0.03 ) among postmenopausal women due to an increase in the percentage of controls who became osteopenic ( 35 to 44 % ) compared to stable bone health in weight lifters . Conclusions The PAL weight training program that increased muscle strength without exacerbating or causing lymphedema among breast cancer survivors was not as efficacious at improving skeletal health . The skeletal loads produced from the PAL program may be insufficient to notably shift BMD , but may have a subtle osteogenic effect . Implication s for cancer survivorsThe safety and efficacy of rigorous weight training programs for improving skeletal health in women at risk for or with breast cancer-related lymphedema remain to be determined [17785708] PURPOSE Breast cancer chemotherapy may cause unfavorable changes in physical functioning , body composition , psychosocial functioning , and quality of life ( QOL ) . We evaluated the relative merits of aerobic and resistance exercise in blunting these effects . PATIENTS AND METHODS We conducted a multicenter r and omized controlled trial in Canada between 2003 and 2005 that r and omly assigned 242 breast cancer patients initiating adjuvant chemotherapy to usual care ( n = 82 ) , supervised resistance exercise ( n = 82 ) , or supervised aerobic exercise ( n = 78 ) for the duration of their chemotherapy ( median , 17 weeks ; 95 % CI , 9 to 24 weeks ) . Our primary end point was cancer-specific QOL assessed by the Functional Assessment of Cancer Therapy-Anemia scale . Secondary end points were fatigue , psychosocial functioning , physical fitness , body composition , chemotherapy completion rate , and lymphedema . RESULTS The follow-up assessment rate for our primary end point was 92.1 % , and adherence to the supervised exercise was 70.2 % . Unadjusted and adjusted mixed-model analyses indicated that aerobic exercise was superior to usual care for improving self-esteem ( P = .015 ) , aerobic fitness ( P = .006 ) , and percent body fat ( adjusted P = .076 ) . Resistance exercise was superior to usual care for improving self-esteem ( P = .018 ) , muscular strength ( P < .001 ) , lean body mass ( P = .015 ) , and chemotherapy completion rate ( P = .033 ) . Changes in cancer-specific QOL , fatigue , depression , and anxiety favored the exercise groups but did not reach statistical significance . Exercise did not cause lymphedema or adverse events . CONCLUSION Neither aerobic nor resistance exercise significantly improved cancer-specific QOL in breast cancer patients receiving chemotherapy , but they did improve self-esteem , physical fitness , body composition , and chemotherapy completion rate without causing lymphedema or significant adverse events [19124485] Introduction : Identifying modifiable factors that reduce the risk of recurrence and improve survival in breast cancer survivors is a pressing concern . The purpose of this study was to examine the association of physical activity following diagnosis and treatment with the risk of breast cancer recurrence and mortality and all-cause mortality in women with early-stage breast cancer . Material s and Methods : The sample consisted of 1,970 women from the Life After Cancer Epidemiology study , a prospect i ve investigation of behavioral risk factors and health outcomes . Self-reported frequency and duration of work-related , household and caregiving , recreational , and transportation-related activities during the six months prior to enrollment were assessed . Outcomes were ascertained from electronic or paper medical charts . Hazard ratios and 95 % confidence intervals were estimated from delayed entry Cox proportional hazards models . Results : Although age-adjusted results suggested that higher levels of physical activity were associated with reduced risk of recurrence and breast cancer mortality ( P for trend = 0.05 and 0.07 , respectively for highest versus lowest level of hours per week of moderate physical activity ) , these associations were attenuated after adjustment for prognostic factors and other confounding variables ( P for trend = 0.36 and 0.26 ) . In contrast , a statistically significant protective association between physical activity and all-cause mortality remained in multivariable analyses ( hazard ratio , 0.66 ; 95 % confidence interval , 0.42 - 1.03 ; P for trend = 0.04 ) . Conclusions : These findings do not support a protective effect of physical activity on breast cancer recurrence or mortality but do suggest that regular physical activity is beneficial for breast cancer survivors in terms of total mortality . ( Cancer Epidemiol Biomarkers Prev 2009;18(1):87–95 [23053793] Background and purpose Previous studies have shown that physical inactivity and obesity are risk factors for the development of colorectal cancer . However , controversy exists regarding the influence of these factors on survival in colorectal cancer patients . We evaluated the impact of recreational physical activity and body mass index ( BMI ) before and after colorectal cancer diagnosis on disease-specific mortality and all-cause mortality . Patients and methods This prospect i ve cohort study included 1,339 women enrolled in the Women ’s Health Initiative study who were diagnosed with colorectal cancer subsequent to study enrollment . BMI and recreational physical activity were measured before cancer diagnosis at study entry ( pre-diagnostic ) and after diagnosis at study follow-up interviews ( post-diagnostic ) . We used Cox regression to estimate the association between pre- and post-diagnostic exposures and survival after colorectal cancer diagnosis . Results Among women diagnosed with colorectal cancer , 265 ( 13 % ) deaths occurred during a median study follow-up of 11.9 years , of which 171 ( 65 % ) were attributed to colorectal cancer . Compared with women reporting no pre-diagnostic recreational physical activity , those reporting activity levels of ≥18 MET-h/week had significantly lower colorectal cancer-specific mortality ( hazard ratio ( HR ) = 0.68 ; 95 % confidence interval ( CI ) : 0.41–1.13 ) and all-cause mortality ( HR = 0.63 ; 95 % CI : 0.42–0.96 ) . Similar inverse associations were seen for post-diagnostic recreational physical activity . Neither pre- nor post-diagnostic BMI were associated with mortality after colorectal cancer diagnosis . Conclusion Recreational physical activity before and after colorectal cancer diagnosis , but not BMI , is associated with more favorable survival [18250341] Previous studies suggest that increased physical activity may lower the risk of breast cancer incidence , but less is known about whether levels of physical activity after breast cancer diagnosis can influence survival . We prospect ively examined the relation between postdiagnosis recreational physical activity and risk of breast cancer death in women who had a previous invasive breast cancer diagnosed between 1988 and 2001 ( at ages 20 - 79 years ) . All women completed a question naire on recent postdiagnosis physical activity and other lifestyle factors . Among 4,482 women without history of recurrence at the time of completing the question naire , 109 died from breast cancer within 6 years of enrollment . Physical activity was expressed as metabolic equivalent task-hours per week ( MET-h/wk ) ; hazard ratios ( HR ) and 95 % confidence intervals ( 95 % CI ) were estimated using Cox proportional hazards regression . After adjusting for age at diagnosis , stage of disease , state of residence , interval between diagnosis and physical activity assessment , body mass index , menopausal status , hormone therapy use , energy intake , education , family history of breast cancer , and treatment modality compared with women expending < 2.8 MET-h/wk in physical activity , women who engaged in greater levels of activity had a significantly lower risk of dying from breast cancer ( HR , 0.65 ; 95 % CI , 0.39 - 1.08 for 2.8 - 7.9 MET-h/wk ; HR , 0.59 ; 95 % CI , 0.35 - 1.01 for 8.0 - 20.9 MET-h/wk ; and HR , 0.51 ; 95 % CI , 0.29 - 0.89 for ≥21.0 MET-h/wk ; P for trend = 0.05 ) . Results were similar for overall survival ( HR , 0.44 ; 95 % CI , 0.32 - 0.60 for ≥21.0 versus < 2.8 MET-h/wk ; P for trend < 0.001 ) and were similar regardless of a woman ’s age , stage of disease , and body mass index . This study provides support for reduced overall mortality and mortality from breast cancer among women who engage in physical activity after breast cancer diagnosis . ( Cancer Epidemiol Biomarkers Prev 2008;17(2):379–86 [26360370] Background : Very little is known about the effect of modifiable lifestyle factors on outcomes of triple-negative breast cancer . We examined this association in a population -based prospect i ve cohort study of patients with triple-negative breast cancer . Methods : A total of 518 women with confirmed triple-negative breast cancer , recruited by the Shanghai Breast Cancer Survival Study , completed 6- , 18- , 36- , and 60-month postdiagnosis surveys . We applied Cox proportional hazard models to evaluate the associations . Results : The mean age at diagnosis was 53.4 ( st and ard deviation = 10.6 ) years old . After a median follow-up of 9.1 years ( range : 0.6–11.8 ) , 128 deaths and 112 recurrences were documented . Exercise during the first 60 months postdiagnosis was inversely associated with total mortality and recurrence/disease-specific mortality with adjusted hazard ratios ( HRs ) of 0.67 ( 95 % confidence interval [ CI ] = 0.46 , 0.96 ) and 0.58 ( 95 % CI = 0.39 , 0.86 ) , respectively . Women with higher exercise-metabolic equivalent scores ( ≥7.6 metabolic equivalent-hours/week ) and longer duration of exercise ( ≥2.5 hours/week ) had lower risk of total and recurrence/disease-specific mortality than did nonexercisers . Compared with nontea drinkers , survival was better among women who were regular tea drinkers during the first 60 months for all cause ( HR = 0.57 , 95 % CI = 0.34 , 0.93 ) and recurrence/disease-specific mortality ( HR = 0.54 , 95 % CI = 0.31 , 0.96 ) . There was no dose – response pattern for tea consumption . No interactions were observed for body mass index , menopausal status , and comorbidity . Conclusions : These findings show that postdiagnosis exercise and tea intake were associated with improved survival among women with triple-negative breast cancer [26606746] Lifestyle factors have been well studied in relation to breast cancer prognosis overall ; however , associations of lifestyle and late outcomes ( > 5 years after diagnosis ) have been much less studied , and no studies have focused on estrogen receptor-positive ( ER+ ) breast cancer survivors , who may have high risk of late recurrence and mortality . We utilized a large prospect i ve pooling study to evaluate the associations of lifestyle factors with late recurrence and all-cause mortality among 6,295 5-year ER+ Stage I-III breast cancer survivors . Pooled and harmonized data were available on clinical factors and lifestyle factors ( pre- to post-diagnosis weight change , body mass index ( BMI ) ( kg/m(2 ) ) , recreational physical activity , alcohol intake and smoking history ) , measured on average 2.1 years after diagnosis . Up date d information for weight only was available . Study heterogeneity was evaluated by the Q-statistic . Multivariable Cox regression models were stratified by study . Adjusting for clinical factors and potential confounders , ≥ 10 % weight gain and obesity ( BMI , 30 - 34.99 and ≥ 35 ) were associated with increased risk of late recurrence ( hazard ratios ( 95 % confidence intervals ) : 1.24 ( 1.00 - 1.53 ) , 1.40 ( 1.05 - 1.86 ) and 1.41 ( 1.02 - 1.93 ) , respectively ) . Daily alcohol intake was associated with late recurrence , 1.28 ( 1.01 - 1.62 ) . Physical activity was inversely associated with late all-cause mortality ( 0.81 ( 0.71 - 0.93 ) and 0.71 ( 0.61 - 0.82 ) for 4.9 to < 17.4 and ≥ 17.4 metabolic equivalent-hr/week ) . A U-shaped association was observed for late all-cause mortality and BMI using up date d weight ( 1.42 ( 1.15 - 1.74 ) and 1.40 ( 1.09 - 1.81 ) , < 21.5 and ≥ 35 , respectively ) . Smoking was associated with increased risk of late outcomes . In this large prospect i ve pooling project , modifiable lifestyle factors were associated with late outcomes among long-term ER+ breast cancer survivors [26774959] BACKGROUND Despite the high global prevalence of prostate cancer ( PCa ) , few epidemiologic studies have assessed physical activity in relation to PCa survival . OBJECTIVE To evaluate different types , intensities , and timing of physical activity relative to PCa survival . DESIGN , SETTING , AND PARTICIPANTS A prospect i ve study was conducted in Alberta , Canada , in a cohort of 830 stage II-IV incident PCa cases diagnosed between 1997 and 2000 with follow-up to 2014 ( up to 17 yr ) . Prediagnosis lifetime activity was self-reported at diagnosis . Postdiagnosis activity was self-reported up to three times during follow-up . OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Cox proportional hazards models related physical activity to all-cause and PCa-specific deaths and to first recurrence/progression of PCa . RESULTS AND LIMITATIONS A total of 458 deaths , 170 PCa-specific deaths , and , after first follow-up , 239 first recurrences/progressions occurred . Postdiagnosis total activity ( > 119 vs ≤42 metabolic equivalent [MET]-hours/week per year ) was associated with a significantly lower all-cause mortality risk ( hazard ratio [ HR ] : 0.58 ; 95 % confidence interval [ CI ] , 0.42 - 0.79 ; p value for trend < 0.01 ) . Postdiagnosis recreational activity ( > 26 vs ≤4 MET-hours/week per year ) was associated with a significantly lower PCa-specific mortality risk ( HR : 0.56 ; 95 % CI , 0.35 - 0.90 ; p value for trend = 0.01 ) . Sustained recreational activity before and after diagnosis ( > 18 - 20 vs < 7 - 8 MET-hours/week per year ) was associated with a lower risk of all-cause mortality ( HR : 0.66 ; 95 % CI , 0.49 - 0.88 ) . Limitations included generalisability to healthier cases and an observational study design . CONCLUSIONS These findings support emerging recommendations to increase physical activity after the diagnosis of PCa and would inform a future exercise intervention trial examining PCa outcomes . PATIENT SUMMARY In a 17-yr prostate cancer ( PCa ) survival study , men who survived at least 2 yr who were more physically active postdiagnosis or performed more recreational physical activity before and after diagnosis survived longer . Recreational physical activity after diagnosis was associated with a lower risk of PCa death [23318529] Background : Previous research has shown exercise to be an effective method to mitigate many adverse treatment-related effects of and rogen suppression therapy ( AST ) but the potential impact of exercise on sexual activity remains unknown . The purpose of this investigation was to report the effect of a 12-week exercise program on sexual activity in prostate cancer patients undergoing AST . Methods : Fifty-seven prostate cancer patients undergoing AST were r and omly assigned to an exercise program ( resistance and aerobic modes ; n=29 ) or usual care control ( n=28 ) . Sexual activity was assessed by the European Organization for Research and Treatment of Cancer prostate cancer-specific quality of life question naire ( QLQ-PR25 ) . Results : QLQ-PR25 data were log transformed and analysis of covariance was used to compare sexual activity between groups following the intervention adjusted for baseline activity . No differences in sexual activity were observed between the exercise and control groups before the intervention . There was a significant ( P=0.045 ) adjusted group difference in sexual activity following the 12-week intervention . Patients undergoing usual care decreased sexual activity while patients in the exercise program maintained their level of sexual activity . At baseline , 20.6 and 22.2 % of participants in the exercise and control groups reported a major interest in sex ( that is , high libido ) . Following the intervention , the exercise group had a significantly higher percentage of participants reporting a major interest in sex ( exercise=17.2 % vs control=0 % ; P=0.024 ) . Conclusions : Participation in a short-term exercise program result ed in the maintenance of sexual activity in prostate cancer patients undergoing AST [21424279] Targeted exercise training could reduce risk factors for fracture and obesity-related diseases that increase from breast cancer treatment , but has not been sufficiently tested . We hypothesized that progressive , moderate-intensity resistance + impact training would increase or maintain hip and spine bone mass , lean mass and fat mass and reduce bone turnover compared to controls who participated in a low-intensity , non-weight bearing stretching program . We conducted a r and omized , controlled trial in 106 women with early stage breast cancer who were > 1 year post-radiation and /or chemotherapy , ≥50 years of age at diagnosis and postmenopausal , free from osteoporosis and medications for bone loss , resistance and impact exercise naïve , and cleared to exercise by a physician . Women were r and omly assigned to participate in 1 year of thrice-weekly progressive , moderate-intensity resistance + impact ( jump ) exercise or in a similar frequency and length control program of progressive , low-intensity stretching . Primary endpoints were bone mineral density ( BMD ; g/cm2 ) of the hip and spine and whole body bone-free lean and fat mass ( kg ) determined by DXA and biomarkers of bone turnover — serum osteocalcin ( ng/ml ) and urinary deoxypyrodiniline cross-links ( nmol/mmolCr ) . Women in the resistance + impact training program preserved BMD at the lumbar spine ( 0.47 vs. −2.13 % ; P = 0.001 ) compared to controls . The resistance + impact group had a smaller increase in osteocalcin ( 7.0 vs. 27 % , P = 0.03 ) and a larger decrease in deoxypyrodinoline ( −49.9 vs. −32.6 % , P = 0.06 ) than controls . Increases in lean mass from resistance + impact training were greatest among women currently taking aromatase inhibitors compared to controls not on this therapy ( P = 0.01 ) . Our combined program of resistance + impact exercise reduced risk factors for fracture among postmenopausal breast cancer survivors ( BCS ) and may be particularly relevant for BCS on aromatase inhibitors ( AIs ) because of the additional benefit of exercise on muscle mass that could reduce falls [16822843] PURPOSE Regular physical activity reduces the risk of developing colon cancer , however , its influence on patients with established disease is unknown . PATIENTS AND METHODS We conducted a prospect i ve observational study of 832 patients with stage III colon cancer enrolled in a r and omized adjuvant chemotherapy trial . Patients reported on various recreational physical activities approximately 6 months after completion of therapy and were observed for recurrence or death . To minimize bias by occult recurrence , we excluded patients who experienced recurrence or died within 90 days of their physical activity assessment . RESULTS Compared with patients engaged in less than three metabolic equivalent task ( MET ) -hours per week of physical activity , the adjusted hazard ratio for disease-free survival was 0.51 ( 95 % CI , 0.26 to 0.97 ) for 18 to 26.9 MET-hours per week and 0.55 ( 95 % CI , 0.33 to 0.91 ) for 27 or more MET-hours per week . The adjusted P for trend was .01 . Postdiagnosis activity was associated with similar improvements in recurrence-free survival ( P for trend = .03 ) and overall survival ( P for trend = .01 ) . The benefit associated with physical activity was not significantly modified by sex , body mass index , number of positive lymph nodes , age , baseline performance status , or chemotherapy received . Moreover , the benefit remained unchanged even after excluding participants who developed cancer recurrence or died within 6 months of activity assessment . CONCLUSION Beyond surgical resection and postoperative adjuvant chemotherapy for stage III colon cancer , for patients who survive and are recurrence free approximately 6 months after adjuvant chemotherapy , physical activity appears to reduce the risk of cancer recurrence and mortality [21892676] Summary The ability of combined step aerobic- and circuit-training to prevent bone loss after breast cancer treatments was related to skeletal site and patients ’ menopausal status . Among premenopausal breast cancer survivors , a 12-month exercise intervention completely prevented bone loss at the femoral neck , whereas no exercise effect was seen at lumbar spine or at neither site in postmenopausal women . Introduction The primary objective of this r and omised clinical trial was to determine the preventive effect of supervised weight-bearing jumping exercises and circuit training on bone loss among breast cancer patients . Methods Of 573 breast cancer survivors aged 35–68 years r and omly allocated into exercise or control group after adjuvant treatments , 498 ( 87 % ) were included in the final analysis . The 12-month exercise intervention comprised weekly supervised step aerobic- and circuit-exercises and similar home training . Bone mineral density ( BMD ) at lumbar spine and femoral neck were measured by dual-energy X-ray absorptiometry . Physical performance was assessed by 2-km walking and figure-8 running tests , and the amount of physical activity was estimated in metabolic equivalent-hours/week . Results In premenopausal women , bone loss at the femoral neck was prevented by exercise , the mean BMD changes being −0.2 % among the trainees vs. −1.4 % among the controls ( p = 0.01 ) . Lumbar bone loss could not be prevented ( −1.9 % vs. −2.2 % ) . In postmenopausal women , no significant exercise-effect on BMD was found either at the lumbar spine ( −1.6 % vs. −2.1 % ) or femoral neck ( −1.1 % vs. −1.1 % ) . Conclusions This 12-month aerobic jumping and circuit training intervention completely prevented femoral neck bone loss in premenopausal breast cancer patients , whereas no effect on BMD was seen in postmenopausal women [21837478] The study was conducted to determine the effect of physical activity on DNA methylation and to predict the consequence of this effect concerning gene expression and breast cancer survival . Blood sample s , collected from 12 breast cancer patients who participated in a r and omized clinical trial of exercise , were examined for exercise-related changes in DNA methylation using a methylation microarray . Tumor sample s of 348 breast cancer patients were analyzed with qRT-PCR and qMSP to determine gene expression and methylation identified in the microarray analysis . Cox regression models were developed to predict survival outcomes in association with gene expression and methylation . After 6 months of moderate-intensity aerobic exercise , changes in DNA methylation ( P < 5 × 10−5 ) in peripheral blood leukocytes were detected in 43 genes from a panel of 14 495 . Based on the list , we analyzed gene expression in association with overall survival in breast tumors and found three genes whose methylation was reduced after exercise were favorably in association with overall survival , i.e. , higher expression associated with better survival . Of the three genes , L3MBTL1 was a putative tumor suppressor gene with known function to repress chromatin for transcription , which is activated mainly in germline stem cells . Further analyses of tumor features among patients indicated that high expression of L3MBTL1 was associated with low grade and hormone receptor – positive tumors , as well as low risk of disease recurrence and breast cancer death . In conclusion , the study suggests that increasing physical activity after a breast cancer diagnosis may affect epigenetic regulation of tumor suppressor genes , which have favorable impacts on survival outcomes of breast cancer patients [23629521] Background : Higher levels of physical activity are associated with lower colorectal carcinoma incidence and mortality , perhaps through influencing energy balance , cellular prosta7 systemic inflammation . Although evidence suggests interactive effects of energetics , sedentary lifestyle , and tumor CTNNB1 ( β-catenin ) or CDKN1B ( p27 ) status on colon cancer prognosis , interactive effects of physical activity and tumor PTGS2 ( the official symbol for COX-2 ) status on clinical outcome remain unknown . Methods : Using molecular pathological epidemiology data base of 605 stage I – III colon and rectal cancers in two prospect i ve cohort studies ( the Nurse 's Health Study and the Health Professionals Follow-up Study ) , we examined patient survival according to postdiagnosis physical activity and tumor PTGS2 status ( with 382 PTGS2-positive and 223 PTGS2-negative tumors by immunohistochemistry ) . Cox proportional hazards models were used to calculate colorectal cancer-specific mortality HR , adjusting for clinical and other tumor variables including microsatellite instability status . Results : Among PTGS2-positive cases , compared with the least active first quartile , the multivariate HRs ( 95 % confidence interval ) were 0.30 ( 0.14–0.62 ) for the second , 0.38 ( 0.20–0.71 ) for the third , and 0.18 ( 0.08–0.41 ) for the fourth quartile of physical activity level ( Ptrend = 0.0002 ) . In contrast , among PTGS2-negative cases , physical activity level was not significantly associated with survival ( Ptrend = 0.84 ; Pinteraction = 0.024 , between physical activity and tumor PTGS2 status ) . Conclusions : Postdiagnosis physical activity is associated with better survival among patients with PTGS2-positive tumors but not among patients with PTGS2-negative tumors . Impact : Immunohistochemical PTGS2 expression in colorectal carcinoma may serve as a predictive biomarker in pathology practice , which may predict stronger benefit from exercise . Cancer Epidemiol Biomarkers Prev ; 22(6 ) ; 1142–52 . © 2013 AACR [24151326] BACKGROUND Exercise improves physical functioning and symptom management during breast cancer chemotherapy , but the effects of different doses and types of exercise are unknown . METHODS A multicenter trial in Canada r and omized 301 breast cancer patients to thrice-weekly supervised exercise during chemotherapy consisting of either a st and ard dose of 25 to 30 minutes of aerobic exercise ( STAN ; n = 96 ) , a higher dose of 50 to 60 minutes of aerobic exercise ( HIGH ; n = 101 ) , or a combined dose of 50 to 60 minutes of aerobic and resistance exercise ( COMB ; n = 104 ) . The primary endpoint was physical functioning assessed by the Medical Outcomes Survey-Short Form (SF)-36 . Secondary endpoints were other physical functioning scales , symptoms , fitness , and chemotherapy completion . All statistical tests were linear mixed model analyses , and the P values were two-sided . RESULTS Follow-up assessment of patient-reported outcomes was 99.0 % . Adjusted linear mixed-model analyses showed that neither HIGH ( + 0.8 ; 95 % confidence interval [ CI ] = -0.8 to 2.4 ; P = .30 ) nor COMB ( + 0.5 ; 95 % CI = -1.1 to 2.1 ; P = .52 ] were superior to STAN for the primary outcome . In secondary analyses not adjusted for multiple comparisons , HIGH was superior to STAN for the SF-36 physical component summary ( P = .04 ) , SF-36 bodily pain ( P = .02 ) , and endocrine symptoms ( P = .02 ) . COMB was superior to STAN for endocrine symptoms ( P = .009 ) and superior to STAN ( P < .001 ) and HIGH ( P < .001 ) for muscular strength . HIGH was superior to COMB for the SF-36 bodily pain ( P = .04 ) and aerobic fitness ( P = .03 ) . No differences emerged for body composition or chemotherapy completion . CONCLUSIONS A higher volume of aerobic or combined exercise is achievable and safe during breast cancer chemotherapy and may manage declines in physical functioning and worsening symptoms better than st and ard volumes [16822844] PURPOSE Physically active individuals have a lower risk of developing colorectal cancer but the influence of exercise on cancer survival is unknown . PATIENTS AND METHODS By a prospect i ve , observational study of 573 women with stage I to III colorectal cancer , we studied colorectal cancer-specific and overall mortality according to predefined physical activity categories before and after diagnosis and by change in activity after diagnosis . To minimize bias by occult recurrences , we excluded women who died within 6 months of their postdiagnosis physical activity assessment . RESULTS Increasing levels of exercise after diagnosis of nonmetastatic colorectal cancer reduced cancer-specific mortality ( P for trend = .008 ) and overall mortality ( P for trend = .003 ) . Compared with women who engaged in less than 3 metabolic equivalent task [ MET ] -hours per week of physical activity , those engaging in at least 18 MET-hours per week had an adjusted hazard ratio for colorectal cancer-specific mortality of 0.39 ( 95 % CI , 0.18 to 0.82 ) and an adjusted hazard ratio for overall mortality of 0.43 ( 95 % CI , 0.25 to 0.74 ) . These results remained unchanged even after excluding women who died within 12 and 24 months of activity assessment . Prediagnosis physical activity was not predictive of mortality . Women who increased their activity ( when comparing prediagnosis to postdiagnosis values ) had a hazard ratio of 0.48 ( 95 % CI , 0.24 to 0.97 ) for colorectal cancer deaths and a hazard ratio of 0.51 ( 95 % CI , 0.30 to 0.85 ) for any-cause death , compared with those with no change in activity . CONCLUSION Recreational physical activity after the diagnosis of stages I to III colorectal cancer may reduce the risk of colorectal cancer-specific and overall mortality [18711185] PURPOSE To investigate the association between pre- and postdiagnosis physical activity ( as well as change in prediagnosis to postdiagnosis physical activity ) and mortality among women with breast cancer . PATIENTS AND METHODS This was a prospect i ve observational study of 933 women enrolled onto the Health , Eating , Activity , and Lifestyle Study who were diagnosed with local or regional breast cancer between 1995 and 1998 and observed until death or September 2004 , whichever came first . The primary outcomes measured were total deaths and breast cancer deaths . The primary exposures were physical activity in the year before and 2 years after diagnosis and the pre- to postdiagnosis change in physical activity . RESULTS Compared with inactive women , the multivariable hazard ratios ( HRs ) for total deaths for women expending at least 9 metabolic equivalent hours per week ( approximately 2 to 3 h/wk of brisk walking ) were 0.69 ( 95 % CI , 0.45 to 1.06 ; P = .045 ) for those active in the year before diagnosis and 0.33 ( 95 % CI , 0.15 to 0.73 ; P = .046 ) for those active 2 years after diagnosis . Compared with women who were inactive both before and after diagnosis , women who increased physical activity after diagnosis had a 45 % lower risk of death ( HR = 0.55 ; 95 % CI , 0.22 to 1.38 ) , and women who decreased physical activity after diagnosis had a four-fold greater risk of death ( HR = 3.95 ; 95 % CI , 1.45 to 10.50 ) . CONCLUSION Moderate-intensity physical activity after a diagnosis of breast cancer may improve prognosis [23225299] Summary We evaluated whether age moderated the effect of impact + resistance exercise on hip BMD in older post-menopausal breast cancer survivors ( BCS ) . Exercise was more beneficial among younger than older women within our sample , suggesting that much older BCS may require different training programs to improve hip health . Purpose Previously , we reported that a program of resistance + impact training stopped bone loss at the spine in older , post-menopausal BCS but had no effect on bone mineral density ( BMD ) at the hip . Aging may blunt the responsiveness of the hip to mechanical loading , so we conducted a secondary data analysis to evaluate whether age moderated the effect of exercise on hip BMD . Methods We analyzed data from our r and omized , controlled trial in older ( ≥ 50 years of age at diagnosis ) , post-menopausal , post-adjuvant treatment BCS ( n = 106 ) comparing women assigned to impact + resistance exercise ( POWIR ) or to a control program of low-intensity stretching ( FLEX ) . We examined effect modification by age on BMD at three hip sites ( greater trochanter , femoral neck , and total hip ) using hierarchical linear modeling adjusting for time since diagnosis and use of adjuvant hormone therapy . Results Age moderated the effect of exercise on total hip BMD such that younger women in POWIR were more likely to see a positive net benefit than FLEX compared to older women where there was little difference between groups ( p = 0.02 ) . Conclusions The skeletal response to loading at the hip within post-menopausal BCS diminishes with age . Whether more vigorous exercise programs and /or longer training periods are required to favorably change hip health in older BCS will require future study and careful thought about the risks and benefits of tougher training programs [26061092] Observational studies have suggested that physical activity may be associated with improved survival after cancer treatment . However , data from controlled clinical trials are required . We analyzed survival data of 103 patients from a previously published r and omized controlled trial in allogeneic stem cell transplant patients who were r and omized to either an exercise intervention ( EX ) or to a social contact control group . EX patients trained prior to hospital admission , during inpatient treatment , and for 6 - 8 weeks after discharge . Survival analyses were used to compare both total mortality ( TM ) and non-relapse mortality ( NRM ) after discharge and transplantation during an observation period of 2 years after transplantation . Analyses were corroborated with Cox and Fine & Gray regression models adjusting for potential confounders . After discharge , EX patients had a significantly lower TM rate than controls ( 12.0 vs. 28.3 % , p = 0.030 ) and a numerically lower NRM rate ( 4.0 vs. 13.5 % , p = 0.086 ) . When the inpatient period was included , absolute risk reductions were similar but not significantly different ( TM : 34.0 vs. 50.9 % , p = 0.112 ; NRM : 26.0 vs. 36.5 % , p = 0.293 ) . The number needed to treat ( NNT ) to prevent one death with EX was about 6 . Furthermore , regression analyses revealed that baseline fitness was protective against mortality . The data suggest that exercise might improve survival in patients undergoing allo-HCT . However , the results should be interpreted with caution as the study was not design ed to detect differences in survival rates , and as no stratification on relevant prognostic factors was carried out [20861399] Background : Aerobic exercise training ( AET ) is known to increase RBC production ; however , this has not been evaluated in breast cancer patients undergoing adjuvant chemotherapy . The purpose of this study was to examine the changes in hemoglobin ( Hb ) levels in the Supervised Trial of Aerobic versus Resistance Training ( START ) and to determine its association with changes in VO2peak . Methods : Two hundred and forty-two breast cancer patients initiating chemotherapy were r and omized to usual care ( n = 82 ) , resistance exercise ( RET , n = 82 ) , or AET ( n = 78 ) groups for the duration of their chemotherapy ( median , 17 weeks ) . Supervised exercise was thrice weekly based on st and ard AET and RET prescriptions . Aerobic fitness ( VO2peak ) and Hb concentration were measured at baseline and end of chemotherapy . Results : Regardless of the exercise group , Hb declined over the course of chemotherapy ( 13.4 ± 10.0 to 11.8 ± 11.5 g/dL , P < 0.01 ) . Both AET and RET groups had significant , moderate correlations between the change in VO2peak and Hb ( AET : r = 0.49 , P < 0.001 ; RET : r = 0.39 , P = 0.001 ) . Conclusion : The results indicate that regular exercise does not protect against the decline in Hb associated with chemotherapy in breast cancer patients , but result ed in a stronger association between Hb and VO2peak . Impact : Even with the chemotherapy-induced decline in Hb , breast cancer patients can maintain their aerobic capacity by participating in regular aerobic exercise . Further studies are required to determine safe intensity levels that may stimulate the maintenance of Hb levels in breast cancer patients . Cancer Epidemiol Biomarkers Prev ; 19(11 ) ; 2826–32 . © 2010 AACR [24500540] INTRODUCTION And rogen deprivation therapy ( ADT ) is associated with significant bone loss and an increase in fracture risk among prostate cancer survivors ( PCS ) . We investigated whether impact + resistance training could stop ADT-related declines in bone mineral density ( BMD ) among PCS on ADT . METHODS We r and omized 51 PCS ( mean age , 70.2 yr ) currently prescribed ADT to participate in 1 yr of impact + resistance training ( Prevent Osteoporosis with Impact + Resistance ( POWIR ) ) or in an exercise placebo program of stretching exercise ( FLEX ) . Outcomes were proximal femur ( total hip , femoral neck , and greater trochanter ) and spine ( L1-L4 ) BMD ( g·cm ) and bone turnover markers ( serum osteocalcin ( ng·mL ) and urinary deoxypyrodinoline cross-links ( nmol·mmol Cr ) ) . RESULTS Retention in the 1-yr study was 84 % and median attendance to supervised classes was 84 % in POWIR and 74 % in FLEX . No study -related injuries were reported . There were no significant differences between groups for average L1-L4 BMD or for BMD at any hip site . When examining individual vertebrae , POWIR has a significant effect on preservation of BMD ( -0.4 % ) at the L4 vertebrae compared with losses ( -3.1 % ) in FLEX ( P = 0.03 ) . CONCLUSION Impact + resistance training was a safe and acceptable form of exercise for older PCS on ADT . Among our limited sample , POWIR did not appear to have a clinical ly meaningful effect on hip or spine BMD , but some evidence of skeletal adaptation to resistance + impact training in an and rogen-deprived state was apparent . Future studies need to be conducted on a larger sample of patients and should consider modifications to POWIR that could further enhance loading across the spine and at the hip to preserve BMD at these clinical ly relevant sites [22993332] AIM The study aim ed at determining whether physical exercise training improves the quality of life ( QoL ) and physical fitness of breast cancer survivors . PATIENTS AND METHODS A total of 573 breast cancer survivors were r and omized into an exercise or a control group , 12-months after adjuvant treatments . EORTC QLQ-C30 and BR-23 question naires were used for evaluation of QoL , FACIT-F for fatigue and the Finnish modified version of Beck 's 13-item depression scale ( RBDI ) for depression . Physical fitness was assessed by a 2-km walking test , and a figure-8 running test and physical activity ( PA ) by metabolic equivalent ( MET ) hours per week ( MET-h/wk ) . RESULTS Figure-8 running time improved significantly among the patients of the intervention group compared with the controls ( p<0.001 ) . No significant between-group differences were observed in 2-km walking time , in PA , EORTC-QLQ-C30 , BR-23 , FACIT-F or BDI . However , there was a linear relationship between increased PA and improved QoL ( p=0.006 ) , irrespective of the intervention . CONCLUSION Increase in physical activity was associated with improved QoL , but no effect of the exercise intervention was observed [25927504] Background . And rogen deprivation therapy ( ADT ) increases survival rates in prostate cancer ( PCa ) patients with locally advanced disease , but is associated with side effects that may impair daily function . Strength training may counteract several side effects of ADT , such as changes in body composition and physical functioning , which in turn may affect health-related quality of life ( HRQOL ) . However , additional r and omised controlled trials are needed to exp and this knowledge . Material and methods . Fifty-eight PCa patients on ADT were r and omised to either 16 weeks of high-load strength training ( n = 28 ) or usual care ( n = 30 ) . The primary outcome was change in total lean body mass ( LBM ) assessed by dual x-ray absorptiometry ( DXA ) . Secondary outcomes were changes in regional LBM , fat mass , and areal bone mineral density ( aBMD ) measured by DXA ; physical functioning assessed by 1-repetition maximum ( 1RM ) tests , sit-to-st and test , stair climbing test and Shuttle walk test ; and HRQOL as measured by the European Organization for the Research and Treatment of Cancer Quality of Life Question naire Core 30 . Results and Conclusion . No statistically significant effect of high-load strength training was demonstrated on total LBM ( p = 0.16 ) , but significant effects were found on LBM in the lower and upper extremities ( 0.49 kg , p < 0.01 and 0.15 kg , p < 0.05 , respectively ) . Compared to usual care , high-load strength training showed no effect on fat mass , aBMD or HRQOL , but beneficial effects were observed in all 1RM tests , sit-to-st and test and stair climbing tests . Adherence to the training program was 88 % for lower body exercises and 84 % for upper body exercises . In summary , high-load strength training improved LBM in extremities and physical functioning , but had no effect on fat mass , aBMD , or HRQOL in PCa patients on ADT [23766391] Background . Chronic fatigue is one of the most restricting symptoms following primary breast cancer treatment , but clinical studies on symptom management are rare . The objective was to evaluate the impact of a multimodal mind – body program ( MMMT ) , including moderate physical activity as compared with a walking intervention alone , on chronic fatigue symptoms of women with stage I to IIIA breast cancer . Patients and Methods . Sixty-four women ( mean age = 56.7 years ) suffering from chronic fatigue after active tumor treatment were r and omly assigned to either an experimental or a control ( n = 32 each ) intervention ( 10 weeks ) . Fatigue , quality of life ( QoL ) , functional well-being , anxiety , and depression were measured with st and ard question naires at baseline , after 10 weeks , and after 3 months . Results . Compared with baseline , both groups had reduced fatigue scores after treatment without any significant difference between groups ( posttreatment , Δ = −0.3 , confidence interval = −1.6 to 1.0 , P = .678 ; follow-up , Δ = −0.4 , confidence interval = −1.8 to 0.9 , P = .510 ) . All patients also improved regarding QoL and general functional well-being . Conclusion . Since both interventions reduced fatigue symptoms and enhanced QoL to a similar extent , we observed no verifiable add-on effect of the MMMT regarding fatigue symptoms . Considering the higher costs with additional expenditure related to MMMT , home-based walking intervention is recommended [23250326] BACKGROUND The number of cancer survivors is increasing rapidly ; however , little is known about whether engaging in physical activity after a cancer diagnosis is associated with lower mortality rates in men . METHODS We conducted a prospect i ve cohort study of 1021 men ( mean age , 71.3 years ) who were diagnosed with cancer ( other than nonmelanoma skin cancer ) . Men reported their physical activities ( walking , stair climbing , and participation in sports and recreational activities ) on question naires in 1988 , a median of 6 years after their cancer diagnosis . Physical activity was up date d in 1993 and men were followed until 2008 , with mortality follow-up > 99 % complete , during which 777 men died ( 337 from cancer , 190 from cardiovascular disease ) . RESULTS In multivariate analyses , the relative risks for all-cause mortality associated with expending < 2100 , 2100 - 4199 , 4200 - 8399 , 8400 - 12,599 , and ≥ 12,600 kJ/week in physical activity were 1.00 ( referent ) , 0.77 , 0.74 , 0.76 , and 0.52 , respectively ( P-trend < 0.0001 ) . Higher levels of physical activity also were associated with lower rates of death from cancer and cardiovascular disease ( P- trend = 0.01 and 0.002 , respectively ) . CONCLUSIONS Engaging in physical activity after cancer diagnosis is associated with better survival among men [24470442] The purpose of these analyses is to test prospect ively whether post-diagnosis running and walking differ significantly in their association with breast cancer mortality . Cox proportional hazard analyses were used to compare breast cancer mortality to baseline exercise energy expenditure ( METs , 1 MET-hour ≅1 km run ) in 272 runners and 714 walkers previously diagnosed with breast cancer from the National Runners ' and Walkers ' Health Studies when adjusted for age , race , menopause , family history , breastfeeding and oral contraceptive use . Diagnosis occurred ( mean ± SD ) 7.9 ± 7.3 years before baseline . Forty-six women ( 13 runners and 33 walkers ) died from breast cancer during 9.1-year mortality surveillance . For the 986 runners and walkers combined , breast cancer mortality decreased an average of 23.9 % MET-hours/day [ 95 % confidence interval ( CI ) : 7.9 - 38.3 % ; p = 0.004 ] . There was a significantly greater decrease in risk for running than walking ( risk per MET-hours/day run vs. walked : p = 0.03 ) . For the 272 runners analyzed separately , breast cancer mortality decreased an average of 40.9 % per MET-hours/day run ( 95 % CI : 19.3 - 60.0 % , p = 0.0004 ) . When analyzed by categories of running energy expenditure , breast cancer mortality was 87.4 % lower for the 1.8 - 3.6 MET-hours/day category ( 95 % CI : 41.3 - 98.2 % lower , p = 0.008 ) and 95.4 % lower for the ≥3.6 MET-hours/day category ( 95 % CI : 71.9 - 100 % lower , p = 0.0004 ) compared to the < 1.07 MET-hours/day category . In contrast , the 714 walkers showed a nonsignificant 4.6 % decrease in breast cancer mortality per MET-hours/day walked ( 95 % CI : 27.3 % decreased risk to 21.3 % increased risk , p = 0.71 ) . These results suggest that post-diagnosis running is associated with significantly lower breast cancer mortality than post-diagnosis walking [21521850] CONTEXT Alterations of the WNT signaling pathway and cadherin-associated protein β 1 ( CTNNB1 or β-catenin ) have been implicated in colorectal carcinogenesis and metabolic diseases . OBJECTIVE To test the hypothesis that CTNNB1 activation in colorectal cancer modifies prognostic associations of body mass index ( BMI ) and level of postdiagnosis physical activity . DESIGN , SETTING , AND PATIENTS Two US prospect i ve cohort studies ( Nurses ' Health Study and the Health Professionals Follow-up Study ) were used to evaluate CTNNB1 localization by immunohistochemistry in 955 patients with stage I , II , III , or IV colon and rectal cancer from 1980 through 2004 . A Cox proportional hazards model was used to compute the hazard ratio ( HR ) for mortality , adjusting for clinical and tumor features , including microsatellite instability , CpG isl and methylator phenotype , level of long interspersed nucleotide element 1 methylation , mutations in KRAS , BRAF , or PIK3CA , and tumor protein p53 . MAIN OUTCOME MEASURES Colorectal cancer-specific mortality and overall mortality through June 30 , 2009 . RESULTS In obese patients ( BMI ≥30 ) , positive status for nuclear CTNNB1 was associated with significantly better colorectal cancer-specific survival ( adjusted HR , 0.24 [ 95 % confidence interval { CI } , 0.12 - 0.49 ] , P < .001 for interaction ; 5-year survival : 0.85 for patients with positive nuclear CTNNB1 status vs 0.78 for those with negative status ) and overall survival ( adjusted HR , 0.56 [ 95 % CI , 0.35 - 0.90 ] , P = .03 for interaction ; 5-year survival : 0.77 for patients with positive nuclear CTNNB1 status vs 0.74 for those with negative status ) , while CTNNB1 status was not associated with prognosis among nonobese patients ( BMI < 30 ) . Among patients with negative status for nuclear CTNNB1 and cancer in stages I , II , or III , postdiagnosis physical activity was associated with better colorectal cancer-specific survival ( adjusted HR , 0.33 [ 95 % CI , 0.13 - 0.81 ] , P = .05 for interaction ; 5-year survival : 0.97 for ≥18 vs 0.89 for < 18 metabolic equivalent task hours/week ) , while postdiagnosis physical activity was not associated with colorectal cancer-specific survival among patients with positive status for nuclear CTNNB1 ( adjusted HR , 1.07 [ 95 % CI , 0.50 - 2.30 ] ) . CONCLUSIONS Among obese patients only , activation of CTNNB1 was associated with better colorectal cancer-specific survival and overall survival . Postdiagnosis physical activity was associated with better colorectal cancer-specific survival only among patients with negative status for nuclear CTNNB1 . These molecular pathological epidemiology findings suggest that the effects of alterations in the WNT-CTNNB1 pathway on outcome are modified by BMI and physical activity [25567329] Aim . The aim of the study was to compare the effects of aerobic exercise training and yoga on the functional capacity , peripheral muscle strength , quality of life ( QOL ) , and fatigue in breast cancer survivors . Material and methods . A total of 52 patients with a diagnosis of breast cancer were included in the study . The patients were r and omly assigned to 2 groups : aerobic exercise ( n = 28 ) and yoga added to aerobic exercise ( n = 24 ) . Both groups participated in submaximal exercise 30 minutes/d , 3 d/wk for 6 weeks . The second group participated in a 1-hour yoga program in addition to aerobic exercise training . Functional capacity was assessed by the 6-Minute Walk Test ( 6MWT ) . Peripheral muscle strength was evaluated with a h and -held dynamometer . The fatigue severity level was assessed with the Fatigue Severity Scale ( FSS ) . The QOL was determined by the European Organisation for Research and Treatment of Cancer Quality of Life Question naire . Results . There were statistically significant increases in peripheral muscle strength , the 6MWT distance , and the perception of QOL in both groups ( P < .05 ) . Additionally , the group with aerobic exercise and yoga showed marked improvement compared with the aerobic exercise group in fatigue perception ( P < .05 ) . Conclusion . According to the data from this study , aerobic exercise training and yoga improved the functional capacity and QOL of breast cancer patients . Aerobic exercise programs can be supported by body mind techniques , such as yoga , in the rehabilitation of cancer patients for improving functional recovery and psychosocial wellness [24633595] UNLABELLED Observational studies suggest that physical activity after a breast cancer diagnosis is associated with improved cancer outcomes ; however , no r and omized data are available . Here , we report an exploratory follow-up of cancer outcomes from the Supervised Trial of Aerobic versus Resistance Training ( START ) . METHODS The START was a Canadian multicenter trial that r and omized 242 breast cancer patients between 2003 and 2005 to usual care ( n = 82 ) , supervised aerobic ( n = 78 ) , or resistance ( n = 82 ) exercise during chemotherapy . The primary end point for this exploratory analysis was disease-free survival ( DFS ) . Secondary end points were overall survival , distant DFS , and recurrence-free interval . The two exercise arms were combined for analysis ( n = 160 ) , and selected subgroups were explored . RESULTS After a median follow-up of 89 months , there were 25/160 ( 15.6 % ) DFS events in the exercise groups and 18/82 ( 22.0 % ) in the control group . Eight-year DFS was 82.7 % for the exercise groups compared with 75.6 % for the control group ( HR , 0.68 ; 95 % confidence interval ( CI ) , 0.37 - 1.24 ; log-rank , P = 0.21 ) . Slightly stronger effects were observed for overall survival ( HR , 0.60 ; 95 % CI , 0.27 - 1.33 ; log-rank , P = 0.21 ) , distant DFS ( HR , 0.62 ; 95 % CI , 0.32 - 1.19 ; log-rank , P = 0.15 ) , and recurrence-free interval ( HR , 0.58 ; 95 % CI , 0.30 - 1.11 ; Gray test , P = 0.095 ) . Subgroup analyses suggested potentially stronger exercise effects on DFS for women who were overweight/obese ( HR , 0.59 ; 95 % CI , 0.27 - 1.27 ) , had stage II/III cancer ( HR , 0.61 ; 95 % CI , 0.31 - 1.20 ) , estrogen receptor-positive tumors ( HR , 0.58 ; 95 % CI , 0.26 - 1.29 ) , human epidermal growth factor receptor 2-positive tumors ( HR , 0.21 ; 95 % CI , 0.04 - 1.02 ) , received taxane-based chemotherapies ( HR , 0.46 ; 95 % CI , 0.19 - 1.15 ) , and ≥85 % of their planned chemotherapy ( HR , 0.50 ; 95 % CI , 0.25 - 1.01 ) . CONCLUSIONS This exploratory follow-up of the START provides the first r and omized data to suggest that adding exercise to st and ard chemotherapy may improve breast cancer outcomes . A definitive phase III trial is warranted Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: Background Recommendations for improved survival after cancer through physical activity ( PA ) exist , although the evidence is still emerging . Our primary objective was to conduct a systematic review and meta- analysis of the association between prediagnosis and postdiagnosis PA and survival ( cancer-specific , all-cause , and cardiovascular disease mortality ) for all cancers and by tumor site . Secondary objectives were to examine the associations within population subgroups , by PA domain , and to determine the optimal dose of PA related to survival . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

29557183

[16920998] PURPOSE We assess the effects of racial or ethnic concordance between caregivers and interventionists on caregiver attrition , change in depression , and change in burden in a multisite r and omized clinical trial . DESIGN AND METHODS Family caregivers of patients with Alzheimer 's disease were r and omized to intervention or control groups at six sites from 1996 to 2000 . Interventionists provided psychosocial interventions aim ed at decreasing caregiver depression and burden . This analysis included 694 caregivers who received face-to-face interventions from 36 interventionists at five sites . We modeled caregiver loss to follow-up at 12 months and changes in depression and burden from baseline by racial or ethnic concordance by using r and om effects logistic and linear regression models , controlling for caregiver age , gender , race or ethnicity , relation to care recipient , interventionist race or ethnicity , and care recipient activities of daily living . The loss to follow-up model also controlled for care recipient institutionalization and death . RESULTS Overall , there was no difference in caregiver loss to follow-up or change in depression or burden by racial or ethnic concordance . African-American caregivers with an interventionist of the same race or ethnicity had greater decreases in depression than did African-American caregivers with interventionists of a different race or ethnicity . However , this finding has to be interpreted cautiously because there were only two African-American interventionists . IMPLICATION S Although these initial findings do not provide conclusive evidence on whether racial or ethnic concordance is associated with intervention outcomes for caregivers of Alzheimer 's disease patients , these results , along with the paucity of research studies evaluating this issue , suggest that the effects of racial or ethnic concordance in research should be systematic ally examined in future studies [2670989] Project ACT is a r and omized controlled trial design ed to test the effectiveness of a non-pharmacological home-based intervention to reduce behavioral and psychological symptoms of dementia ( BPSD ) and caregiver distress . The study targets 272 stressed racially diverse family caregivers providing in-home care to persons with moderate stage dementia with one or more behavioral disturbances . All participants are interviewed at baseline , 4-months ( main trial endpoint ) , and 6-months ( maintenance ) . The four-month intervention involves up to 13 visits from an occupational therapist who works with families to problem-solve potential triggers ( communication style , environmental clutter ) contributing to behaviors , and instruct in strategies to reduce caregiver stress and manage targeted behaviors . To rule out infection or other potential medical contributors to behaviors , a nurse obtains blood and urine sample s from the dementia patient , and conducts a medication review . Participants in the no-treatment control group are offered the nurse arm and one in-home session following trial completion at 6-months . This paper describes the research methods , theoretical and clinical aspects of this multi-component , targeted psycho-social treatment approach , and the measures used to evaluate quality of life improvements for persons with dementia and their families [21357811] BACKGROUND Based on the National Institute on Aging/National Institute of Nursing Research Re sources for Enhancing Alzheimer 's Caregiver Health ( REACH ) r and omized controlled trial ( REACH II ) , REACH VA ( Department of Veterans Affairs ) was the first national clinical translation of a proven behavioral intervention for dementia caregivers , running from September 2007 through August 2009 . This article describes the population and outcomes of the REACH VA translation of REACH II into the VA . METHODS Clinical staff members from 24 VA Medical Center Home-Based Primary Care programs in 15 states delivered the intervention to stressed caregivers of patients with dementia . Like REACH II , the 6-month REACH VA intervention , structured through a protocol and individualized through a risk assessment , targeted education , support , and skills training to address caregiving risk areas of safety , social support , problem behaviors , depression , and health through 12 individual in-home and telephone sessions and 5 telephone support group sessions . Staff members of the Memphis VA Medical Center , Memphis , Tennessee , collected data on burden , depression , health and healthy behaviors , caregiving frustrations , social support , dementia-related behaviors , and time spent providing care and on duty . RESULTS From baseline to 6 months , caregivers reported significantly decreased burden , depression , impact of depression on daily life , caregiving frustrations , and number of troubling dementia-related behaviors . A 2-hour decrease in hours per day on duty approached significance . Caregivers ( 96 % ) believed that the program should be provided by the VA to caregivers . CONCLUSIONS This clinical translation achieved outcomes similar to the REACH II r and omized controlled trial , providing clinical ly significant benefits for caregivers of a veteran with a progressive dementing disease . This model of caregiver support can inform public policy in providing assistance to caregivers [20122038] OBJECTIVES To examine the relationships between changes from baseline to post-Re sources for Enhancing Alzheimer 's Caregiver Health ( REACH ) intervention in caregiver ( CG ) self-reported health , burden , and bother . DESIGN R and omized , multisite clinical trial . SETTING CG and care recipient ( CR ) homes in five U.S. cities . PARTICIPANTS Four hundred ninety-five dementia CG and CR dyads ( 169 Hispanic , 160 white , and 166 African American ) receiving intervention and their controls . INTERVENTION CGs were assigned to the REACH intervention or a no-treatment control group . Intervention subjects received individual risk profiles and the REACH intervention through nine in-home and three telephone sessions over 6 months . Control subjects received two brief " check-in " telephone calls during this 6-month period . MEASUREMENTS The primary outcome was change in CG health status from baseline to after the intervention . Secondary outcomes were CG burden and bother after the intervention . RESULTS After the intervention , CGs reported better self-rated health , sleep quality , physical health , and emotional health , which was related to less burden and bother with their caregiving role than for CGs not receiving the intervention . Changes in depression appeared to mediate these relationships . Several racial and ethnic group differences existed in physical and emotional health , as well as in total frustration with caregiving , emotional burden , and CG-rated bother with CR 's activities of daily living and instrumental activities of daily living at baseline and at follow-up , although differences between baseline and posttest did not vary according to race . CONCLUSION A structured , multicomponent skills training intervention that targeted CG self-care behaviors as one of five target areas , improved self-reported health status , and decreased burden and bother in racially and ethnically diverse CGs of people with dementia [20810376] CONTEXT Optimal treatment to postpone functional decline in patients with dementia is not established . OBJECTIVE To test a nonpharmacologic intervention realigning environmental dem and s with patient capabilities . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve 2-group r and omized trial ( Care of Persons with Dementia in their Environments [ COPE ] ) involving patients with dementia and family caregivers ( community-living dyads ) recruited from March 2006 through June 2008 in Pennsylvania . INTERVENTIONS Up to 12 home or telephone contacts over 4 months by health professionals who assessed patient capabilities and deficits ; obtained blood and urine sample s ; and trained families in home safety , simplifying tasks , and stress reduction . Control group caregivers received 3 telephone calls and educational material s. MAIN OUTCOME MEASURES Functional dependence , quality of life , frequency of agitated behaviors , and engagement for patients and well-being , confidence using activities , and perceived benefits for caregivers at 4 months . RESULTS Of 284 dyads screened , 270 ( 95 % ) were eligible and 237 ( 88 % ) r and omized . Data were collected from 209 dyads ( 88 % ) at 4 months and 173 ( 73 % ) at 9 months . At 4 months , compared with controls , COPE patients had less functional dependence ( adjusted mean difference , 0.24 ; 95 % CI , 0.03 - 0.44 ; P = .02 ; Cohen d = 0.21 ) and less dependence in instrumental activities of daily living ( adjusted mean difference , 0.32 ; 95 % CI , 0.09 - 0.55 ; P = .007 ; Cohen d = 0.43 ) , measured by a 15-item scale modeled after the Functional Independence Measure ; COPE patients also had improved engagement ( adjusted mean difference , 0.12 ; 95 % CI , 0.07 - 0.22 ; P = .03 ; Cohen d = 0.26 ) , measured by a 5-item scale . COPE caregivers improved in their well-being ( adjusted mean difference in Perceived Change Index , 0.22 ; 95 % CI , 0.08 - 0.36 ; P = .002 ; Cohen d = 0.30 ) and confidence using activities ( adjusted mean difference , 0.81 ; 95 % CI , 0.30 - 1.32 ; P = .002 ; Cohen d = 0.54 ) , measured by a 5-item scale . By 4 months , 64 COPE dyads ( 62.7 % ) vs 48 control group dyads ( 44.9 % ) eliminated 1 or more caregiver-identified problems ( chi(2/1 ) = 6.72 , P = . 01 ) . CONCLUSION Among community-living dyads , a nonpharmacologic biobehavioral environmental intervention compared with control result ed in better outcomes for COPE dyads at 4 months . Although no group differences were observed at 9 months for patients , COPE caregivers perceived greater benefits . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00259454 [26954588] ABSTRACT Objectives : Evaluation of long-term effects of an individualized short-term telephone intervention ( seven sessions ) , based on a comprehensive cognitive behavioral therapy ( CBT ) approach . The study goal was to evaluate the maintenance of intervention effects regarding well-being , quality of life , and health at two years post treatment . Method : Participants ( n = 105 ) were ( partly ) r and omized after baseline assessment in a two-arm study ( intervention , control group/usual care ) . Depressive symptoms were assessed with the German version of the Center for Epidemiologic Studies Depression Scale ( CES-D ) . Caregivers ’ physical complaints were measured with the Gießener Beschwerdebogen ( GBB-24 ) , and quality of life with the World Health Organization quality of life -BREF ( WHOQOL-BREF ) . Emotional well-being and perceived health status were assessed using thermometer scaling . Data were analyzed by intention-to-treat analyses , including for those who terminated the intervention prematurely but still delivered data , using ANCOVAs . Results : Long-term intervention effects were found for emotional well-being ( p = 0.019 ) . For the subgroup of caregivers who were still caring at home at follow-up , the intervention led to an increased health status ( p = 0.023 ) , fewer bodily complaints ( global measure p= 0.014 , rheumatic pain p = 0.027 , heart trouble p = 0.042 ) , and a higher quality of life ( overall p = 0.044 and subscale environment p = 0.030 ) . Conclusion : The short-term CBT intervention via telephone showed long-term effects two years after treatment on emotional well-being , health status , bodily complaints , and quality of life [11220813] PURPOSE OF STUDY The authors determined short-term effects of a home environmental intervention on self-efficacy and upset in caregivers and daily function of dementia patients . They also determined if treatment effect varied by caregiver gender , race , and relationship to patient . DESIGN AND METHODS Families ( N = 171 ) of dementia patients were r and omized to intervention or usual care control group . The intervention involved 5 90-min home visits by occupational therapists who provided education and physical and social environmental modifications . RESULTS Compared with controls , intervention caregivers reported fewer declines in patients ' instrumental activities of daily living ( p = .030 ) and less decline in self-care and fewer behavior problems in patients at 3 months post-test . Also , intervention spouses reported reduced upset ( p = .049 ) , women reported enhanced self-efficacy in managing behaviors ( p = .038 ) , and women ( p = .049 ) and minorities ( p = .037 ) reported enhanced self-efficacy in managing functional dependency . IMPLICATION S The environmental program appears to have a modest effect on dementia patients ' IADL dependence . Also , among certain subgroups of caregivers the program improves self-efficacy and reduces upset in specific areas of caregiving [10222636] The goal of this study was to evaluate a community-based psychoeducational-nursing intervention design ed to teach home caregivers to manage behavioral problems of persons with Alzheimer 's disease and related dementias ( ADRD ) using the Progressively Lowered Stress Threshold ( PLST ) model , and to compare this intervention with routine information and referrals for case management , community-based services , and support groups . Previous caregiver studies have overwhelmingly pointed to the adverse effects of caregiving on the caregivers ' physical and mental health , and high prevalence rates of depression among caregivers of persons with ADRD have consistently been reported . Therefore , a primary aim was to evaluate the impact of the intervention on caregivers ' affective responses , especially depression . Data from both the Profile of Moods States and the Geriatric Depression Rating Scale support the effectiveness of this intervention in decreasing depression among caregivers who received the experimental training . Additional analysis of factors associated with caregiver depression are also reported . The pivotal role of psychiatric nurses in the assessment and treatment of depression among caregivers of persons with ADRD is discussed [23290200] OBJECTIVE To evaluate the influence of adherence to the Systematic Care Program for Dementia ( SCPD ) intervention protocol on patient and caregiver outcomes . DESIGN Data were drawn from the SCPD study -a single-blind , multicenter , cluster-r and omized , controlled trial . Multivariate regression analyses were used to assess the influence of adherence on patient and caregiver outcomes . SETTING Six community mental health services ( CMHSs ) across the Netherl and s. PARTICIPANTS Forty-eight mental health professionals treating 125 patient-caregiver dyads who were referred to the CMHS because of suspected patient dementia . INTERVENTION Training of professionals in the SCPD and its subsequent use . The SCPD consists of a systematic assessment of caregiver problems and consequent interventions . MEASUREMENTS The dependent variables were caregiver 's sense of competence , caregiver 's depressive symptoms , caregiver 's distress due to the patient 's behavioral problems , and the severity of patient 's behavioral problems . The main independent variables were adherence to the SCPD intervention protocol and the intensity of the SCPD interventions . The follow-up lasted 12 months . RESULTS Caregivers treated by adhering professionals had a better sense of competence than caregivers treated by nonadhering professionals at follow-up . No differences between intervention groups and controls were found for the other outcomes . CONCLUSION Nonadherence to the intervention protocol might be a reason for the difference found in the sense of competence between the intervention groups . Furthermore , the intensity of the SCPD might have been too low . Moreover , it might be that overburdened caregivers found it difficult to make effective use of the help offered to them . A qualitative process analysis should be executed to explore more in-depth clarifications [3398860] Objective To assess the efficacy at 12 months of an early psychosocial counselling and support programme for out patients with mild Alzheimer ’s disease and their primary care givers . Design Multicentre , r and omised , controlled , rater blinded trial . Setting Primary care and memory clinics in five Danish districts . Participants 330 out patients with mild Alzheimer ’s disease and their 330 primary care givers . Interventions Participating dyads ( patient and primary care giver ) were r and omised to control support during follow-up or to control support plus DAISY intervention ( multifaceted and semi-tailored counselling , education , and support ) . Main outcome measures Primary outcomes at 12 months for patients were change from baseline in mini mental state examination ( MMSE ) score , Cornell depression scale score , and proxy rated European quality of life visual analogue scale ( EQ-VAS ) score . For care givers , outcomes were change from baseline in geriatric depression scale ( GDS 30 items ) score and EQ-VAS score . Results Because of multiple testing , statistical significance was set at an adjusted P limit of < 0.0005 . At 12 months there were no significant differences between the two allocation groups in changes from baseline in the primary and secondary outcomes . However , although non-significant with the adjusted P limit , a small difference was observed for one of the primary patient outcomes ( Cornell depression scale score ) in patients in favour of the DAISY intervention group before and after adjusting for attrition ( P=0.0146 and P=0.0103 respectively ) . Conclusions The multifaceted , semi-tailored intervention with counselling , education , and support for patients with mild Alzheimer ’s disease and their care givers did not have any significant effect beyond that with well structured follow-up support at 12 months after adjustment for multiple comparisons . The small positive effect found in the unadjusted primary outcome addressing depressive symptoms in patients may call for further research focusing on patients with Alzheimer ’s disease and comorbid depression . Trial registration IS RCT N74848736 [11395344] OBJECTIVE To evaluate the efficacy of a brief behaviour management training programme for family carers of patients with dementia and aggressive behaviour . DESIGN A r and omized controlled trial of a four-session , community-based behaviour management programme . The primary outcome measure was the Rating Scale for Aggressive Behaviour in the Elderly . PARTICIPANTS 62 patients with dementia , and their co-resident carers . RESULTS There were no significant differences in aggression scores between behaviour management and control groups at follow-up . After adjusting for baseline differences in Rating Scale for Aggressive Behaviour in the Elderly scores , there was a trend towards a reduction in aggressive behaviour in the patients in the behaviour management group compared with those in the control group ( F = 3.37 , P = 0.071 ) . CONCLUSIONS This study adds to the small evidence base for the effectiveness of behavioural management strategies in dementia [12937336] PURPOSE Few empirical studies have compared the efficacy between psychoeducational ( skill-building ) approaches for reducing caregivers ' psychological distress and interventions modeled after typical community-based support groups . We compare the impact of two distinct interventions on Anglo and Latino caregivers of elderly relatives with dementia . DESIGN AND METHODS The change from pre assessment to post assessment ( baseline to 3 months ) for 213 female caregivers ( 122 Anglo and 91 Latino ) is presented . They were seen weekly for 10 weeks in either the Coping With Caregiving psychoeducational program ( instruction and practice in small groups to learn specific cognitive and behavioral skills ) or in the Enhanced Support Group condition ( guided discussion and empathic listening to develop reciprocal support within the group ) . Both programs were tailored to be sensitive to the cultural concerns of Anglo and Latino caregivers , and they were delivered in either English or Spanish by trained interventionists . RESULTS Overall , participants in the Coping With Caregiving condition reported a significant reduction in depressive symptoms , increased use of adaptive coping strategies , and a trend toward decreased use of negative coping strategies when compared with those in the Enhanced Support Group condition . Results were similar for both ethnic groups : there were no main effects for ethnicity , and no significant ethnicity by treatment interaction effects . IMPLICATION S This study provides empirical support that female caregivers benefit more from a skill-building approach to managing their distress than from support group membership alone . We find it very encouraging that the Latino caregivers responded well on key outcome variables , suggesting that Latinos will participate in clinical research and will benefit from their involvement when services are provided to meet their specific needs [16684985] CONTEXT Most older adults with dementia will be cared for by primary care physicians , but the primary care practice environment presents important challenges to providing quality care . OBJECTIVE To test the effectiveness of a collaborative care model to improve the quality of care for patients with Alzheimer disease . DESIGN , SETTING , AND PATIENTS Controlled clinical trial of 153 older adults with Alzheimer disease and their caregivers who were r and omized by physician to receive collaborative care management ( n = 84 ) or augmented usual care ( n = 69 ) at primary care practice s within 2 US university-affiliated health care systems from January 2002 through August 2004 . Eligible patients ( identified via screening or medical record ) met diagnostic criteria for Alzheimer disease and had a self-identified caregiver . INTERVENTION Intervention patients received 1 year of care management by an interdisciplinary team led by an advanced practice nurse working with the patient 's family caregiver and integrated within primary care . The team used st and ard protocol s to initiate treatment and identify , monitor , and treat behavioral and psychological symptoms of dementia , stressing nonpharmacological management . MAIN OUTCOME MEASURES Neuropsychiatric Inventory ( NPI ) administered at baseline and at 6 , 12 , and 18 months . Secondary outcomes included the Cornell Scale for Depression in Dementia ( CSDD ) , cognition , activities of daily living , re source use , and caregiver 's depression severity . RESULTS Initiated by caregivers ' reports , 89 % of intervention patients triggered at least 1 protocol for behavioral and psychological symptoms of dementia with a mean of 4 per patient from a total of 8 possible protocol s. Intervention patients were more likely to receive cholinesterase inhibitors ( 79.8 % vs 55.1 % ; P = .002 ) and antidepressants ( 45.2 % vs 27.5 % ; P = .03 ) . Intervention patients had significantly fewer behavioral and psychological symptoms of dementia as measured by the total NPI score at 12 months ( mean difference , -5.6 ; P = .01 ) and at 18 months ( mean difference , -5.4 ; P = .01 ) . Intervention caregivers also reported significant improvements in distress as measured by the caregiver NPI at 12 months ; at 18 months , caregivers showed improvement in depression as measured by the Patient Health Question naire-9 . No group differences were found on the CSDD , cognition , activities of daily living , or on rates of hospitalization , nursing home placement , or death . CONCLUSIONS Collaborative care for the treatment of Alzheimer disease result ed in significant improvement in the quality of care and in behavioral and psychological symptoms of dementia among primary care patients and their caregivers . These improvements were achieved without significantly increasing the use of antipsychotics or sedative-hypnotics . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00246896 [22899427] PURPOSE This study examined the efficacy of a newly developed intervention , Acquiring New Skills While Enhancing Remaining Strengths ( ANSWERS ) , for family caregivers of individuals with dementia . ANSWERS was design ed for dyads comprised of an individual with dementia and his/her family caregiver . Using a strength-based approach , ANSWERS combined educational skills ( traditionally used with caregivers ) and cognitive rehabilitation skills training ( traditionally used with individuals with dementia ) into a single protocol for addressing the dyad 's care issues and needs . Key domains addressed by the intervention included : education about dementia and memory loss ; effective communication ; managing memory ; staying active ; and recognizing emotions and behaviors . This analysis focused on outcomes for caregivers . DESIGN & METHODS The Stress Process Model guided the study 's hypotheses and design . Caregiving dyads were r and omly assigned to the control or intervention conditions . Intervention dyads received 6-curriculum guided sessions with an intervention specialist . Data came from in-person baseline interviews with caregivers conducted prior to r and omization and follow-up interviews conducted approximately 14.56 weekspost-baseline . RESULTS Intervention caregivers , compared to controls , had decreased care-related strain as indicated by lower emotional health strain , dyadic relationship strain , role captivity , and higher caregiving mastery . Additionally , intervention caregivers had improved well-being as indicated by fewer symptoms of depression and anxiety . IMPLICATION S ANSWERS was efficacious in improving key strain and psychosocial outcomes for caregivers . Features essential to the success of ANSWERS included a strength-based approach for selecting , developing , and implementing care goals , as well as teaching caregivers educational and cognitive rehabilitation skills for addressing care needs [18310553] OBJECTIVE To test whether the Tailored Activity Program ( TAP ) reduces dementia-related neuropsychiatric behaviors , promotes activity engagement , and enhances caregiver well-being . DESIGN Prospect i ve , two-group ( treatment , wait-list control ) , r and omized , controlled pilot study with 4 months as main trial endpoint . At 4 months , controls received the TAP intervention and were reassessed 4 months later . SETTING Patients ' homes . PARTICIPANTS Sixty dementia patients and family caregivers . INTERVENTION The eight-session occupational therapy intervention involved neuropsychological and functional testing , selection , and customization of activities to match capabilities identified in testing , and instruction to caregivers in use of activities . MEASUREMENTS Behavioral occurrences , activity engagement , and quality of life in dementia patients ; objective and subjective burden and skill enhancement in caregivers . RESULTS At 4 months , compared with controls , intervention caregivers reported reduced frequency of problem behaviors , and specifically for shadowing and repetitive question ing , and greater activity engagement including the ability to keep busy . Fewer intervention caregivers reported agitation or argumentation . Caregiver benefits included fewer hours doing things and being on duty , greater mastery , self-efficacy , and skill enhancement . Wait-list control participants following intervention showed similar benefits for reductions in behavioral frequency and caregiver hours doing things for the patient and mastery . Caregivers with depressed symptoms derived treatment benefits similar to nondepressed caregivers . CONCLUSIONS Tailoring activities to the capabilities of dementia patients and training families in activity use result ed in clinical ly relevant benefits for patients and caregivers . Treatment minimized trigger behaviors for nursing home placement and reduced objective caregiver burden . Noteworthy is that depressed caregivers effectively engaged in and benefited from the intervention [18814197] OBJECTIVES Dementia is a rapidly growing public health problem in low and middle income countries . There is an urgent need , in the absence of formal services , to develop interventions design ed to improve the lives of people with dementia , and their families . This study tests the effectiveness of the 10/66 caregiver intervention among people with dementia , and their carers . DESIGN A single blind parallel group r and omized controlled trial ( IS RCT N41039907 ) . SETTING Moscow . PARTICIPANTS Sixty family caregivers of people aged 65 and over with dementia were r and omized to receive the intervention and medical care as usual ( n = 30 ) or medical care as usual only ( n = 30 ) . Caregiver and person with dementia outcomes were assessed at baseline and after 6 months . INTERVENTION The caregiver education and training intervention was delivered over five , weekly , half-hour sessions and was made up of three modules : ( i ) assessment ( one session ) ; ( ii ) basic education about dementia ( two sessions ) ; and ( iii ) training regarding specific problem behaviors ( two sessions ) . MEASUREMENTS Dementia was diagnosed using DSM-IV criteria . Caregiver : Zarit Carer Burden Interview ; carer psychological distress ( SRQ 20 ) ; and carer Quality of Life ( WHOQOL-BREF ) . Person with dementia : Behavioural and Psychological symptoms ( NPI-Q ) ; quality of life ( DEMQOL ) . RESULTS Caregivers in the intervention group reported large and statistically significant net improvements at 6-month follow-up in burden compared to controls . No group differences were found on caregiver psychological distress and patient and caregiver quality of life . CONCLUSIONS The low-level intervention seems to be as , if not more , effective than similar interventions applied in high income countries [17101889] Objective : To determine the effectiveness of a counseling and support intervention for spouse caregivers in delaying time to nursing home placement of patients with Alzheimer disease ( AD ) , and identify the mechanisms through which the intervention accomplished this goal . Methods : We conducted a r and omized controlled trial of an enhanced counseling and support intervention compared to usual care . Participants were a referred volunteer sample of 406 spouse caregivers of community-dwelling patients who had enrolled in the study over a 9.5-year period . The intervention consisted of six sessions of individual and family counseling , support group participation , and continuous availability of ad hoc telephone counseling . Structured question naires were administered at baseline and at regular follow-up intervals , every 4 months for the first year and every 6 months thereafter . Cox proportional hazard models were used to test the effects of the intervention on the time to nursing home placement for the patients after controlling for multiple time-invariant and time-dependent predictors of placement . Results : Patients whose spouses received the intervention experienced a 28.3 % reduction in the rate of nursing home placement compared with usual care controls ( hazard ratio = 0.717 after covariate adjustment , p = 0.025 ) . The difference in model-predicted median time to placement was 557 days . Improvements in caregivers ’ satisfaction with social support , response to patient behavior problems , and symptoms of depression collectively accounted for 61.2 % of the intervention ’s beneficial impact on placement . Conclusion : Greater access to effective programs of counseling and support could yield considerable benefits for caregivers , patients with Alzheimer disease , and society [12143075] Providing care to a family member with dementia is conceptualized as a chronic stressor with adverse psychological and physical effects . The purpose of this pilot study was to evaluate mood and immune outcomes of caregivers exposed to a community-based psychoeducational nursing intervention based on the progressively lowered stress threshold ( PLST ) model . The PLST intervention is design ed to strengthen the psychological re sources of dementia caregivers by teaching methods of preventing and /or managing behavioral problems exhibited by the person with dementia . Mood and immune outcomes were compared between caregivers r and omly assigned to receive either the PLST or a comparison intervention . Results of this pilot study suggest that caregivers who received the PLST intervention showed significantly stronger T-cell proliferative responses to both PHA and ConA , indicating an improvement in T-cell immune function immediately after the in-home intervention ( T2 ) and again after 6 months of telephone support for application of the PLST model ( T3 ) . Findings do not support the hypothesis that the PLST intervention had a significant effect on total mood disturbance or natural killer cell cytotoxicity over the course of the study [19808841] PURPOSE The current article provides an in-depth description of a dyadic intervention for individuals with dementia and their family caregivers . Using a strength-based approach , caregiving dyads received skills training across 5 key areas : ( a ) education regarding dementia and memory loss , ( b ) effective communication , ( c ) managing memory loss , ( d ) staying active , and ( e ) recognizing emotions and behaviors . Results of the acceptability and feasibility of the intervention protocol s are also presented . DESIGN AND METHODS Caregiving dyads were r and omly assigned to participate in the intervention . Participants in the treatment condition were asked to complete a series of evaluation questions after each intervention session and an overall evaluation of the program . Data were also collected from the intervention specialists who implemented the protocol s. RESULTS Overall , the evaluation data indicated that the content and process of the intervention were viewed as highly acceptable and feasible by both participants and intervention specialists . IMPLICATION S This article highlights the merit of using a strength-based approach for working with caregiving dyads with dementia and how a single intervention protocol can be used to address the goals of both care partners . Furthermore , the intervention program was found to be highly acceptable and feasible , which is an important aspect of developing dyadic protocol [23831174] BACKGROUND / OBJECTIVES Available services and intervention programs for dementia caregivers are often underutilized because of issues such as cost , logistics , lack of knowledge about available services , or insufficient support from others . Information technologies offer the potential of removing these barriers and facilitating the ability of caregivers to access needed support . This project evaluated the feasibility and efficacy of technology-based psychosocial intervention among minority family caregivers of dementia patients . DESIGN A feasibility and efficacy trial . SETTING Participants ' homes in the Greater Miami Community . PARTICIPANTS One hundred ten ( 56 Hispanic American and 54 African American ) caregivers of patients with dementia . INTERVENTION A technology-based multi-component psychosocial intervention was delivered in-home and via videophone technology over 5 months . The intervention was modeled after the REACH II intervention and targeted known areas of caregiver risk . MEASUREMENT St and ardized measures of depression , caregiver burden , social support , and the caregivers ' perception of the caregiver 's experience were administered at baseline and 5 months post-r and omization . RESULTS Overall , caregivers who received the intervention reported a decrease in burden , an increase in perceived social support and positive perceptions of the caregiving experience . No effect was observed for depression . Most participants indicated that the intervention improved their caregiving skills and found the technology to be easy to use . CONCLUSIONS A technology-based format was feasible for delivering a multi-component intervention to minority family dementia caregivers . The intervention improved caregiver outcomes for both Hispanic and African American caregivers . The results suggest that technology may help eliminate disparities in access to caregiver intervention programs [3808080] Objective To assess whether the START ( STrAtegies for RelatTives ) intervention added to treatment as usual is cost effective compared with usual treatment alone . Design Cost effectiveness analysis nested within a pragmatic r and omised controlled trial . Setting Three mental health and one neurological outpatient dementia service in London and Essex , UK . Participants Family carers of people with dementia . Intervention Eight session , manual based , coping intervention delivered by supervised psychology graduates to family carers of people with dementia added to usual treatment , compared with usual treatment alone . Primary outcome measures Costs measured from a health and social care perspective were analysed alongside the Hospital Anxiety and Depression Scale total score ( HADS-T ) of affective symptoms and quality adjusted life years ( QALYs ) in cost effectiveness analyses over eight months from baseline . Results Of the 260 participants recruited to the study , 173 were r and omised to the START intervention , and 87 to usual treatment alone . Mean HADS-T scores were lower in the intervention group than the usual treatment group over the 8 month evaluation period ( mean difference −1.79 ( 95 % CI −3.32 to −0.33 ) ) , indicating better outcomes associated with the START intervention . There was a small improvement in health related quality of life as measured by QALYs ( 0.03 ( −0.01 to 0.08 ) ) . Costs were no different between the intervention and usual treatment groups ( £ 252 ( −28 to 565 ) higher for START group ) . The cost effectiveness calculations suggested that START had a greater than 99 % chance of being cost effective compared with usual treatment alone at a willingness to pay threshold of £ 30 000 per QALY gained , and a high probability of cost effectiveness on the HADS-T measure . Conclusions The manual based coping intervention START , when added to treatment as usual , was cost effective compared with treatment as usual alone by reference to both outcome measures ( affective symptoms for family carers , and carer based QALYs ) . Trial Registration ISCTRN [12083600] To determine if teaching caregivers behavior management techniques ( BMTs ) reduces long-term psychotropic use in Alzheimer 's disease ( AD ) patients , we examined 12-month follow-up data from a 4-month r and omized study com paring placebo , BMTs , trazodone , and haloperidol for the treatment of agitated behaviors in persons with AD . After 4 months , treatment was allowed with any agent . Between 42.8 % and 51 % of AD patients received additional psy chotropics between 4 and 12 months . The relative risk of being prescribed any psychotropic drug after the 4-month trial was at or about 1.0 for subjects in each drug arm or placebo arm versus BMTs . We concluded that teaching caregivers BMTs did not diminish long-term prescription of psychotropic drugs . ( J Geriatr Psychiatry Neurol 2002 ; 15:95 - 98 ) [12919265] BACKGROUND Over recent years multi-sensory stimulation ( MSS ) has become an increasingly popular approach to care and is used in several centres throughout Europe . This popularity could be explained by the limited alternatives available to staff and a widely held belief that MSS is a friendly and highly humane approach . A r and omized controlled trial was therefore essential to evaluate the effectiveness and extent of the benefits of MSS . AIM To assess whether MSS is more effective in changing the behaviour , mood and cognition of older adults with dementia than a control of activity ( playing card games , looking at photographs , doing quizzes , etc . ) . METHODS A total of 136 patients from three countries [ United Kingdom ( UK ) , the Netherl and s and Sweden ] were r and omized to MSS or activity groups . Patients participated in eight 30-minute sessions over 4 weeks . Ratings of behaviour and mood were taken before , during and after sessions to investigate immediate effects . Pre- , mid- , post-trial and follow-up assessment s were taken to investigate any generalization of effects to cognition and behaviour and mood at home/on the ward or at the day hospital . RESULTS There were limited short-term improvements for both the MSS and activity groups immediately after sessions , and limited short-term improvements between the groups during sessions . There were no significant differences between the groups when assessing change in behaviour , mood or cognition at home/on the ward or at the day hospital . In the UK , however , behaviour at the day hospital for both groups remained stable during the trial but deteriorated once the sessions had stopped , and active/disturbed behaviour at home improved but likewise deteriorated once sessions had stopped . CONCLUSIONS Overall , MSS was found to be no more effective than an activity in changing the behaviour , mood or cognition of patients with dementia in the short- or long-term [3092580] We studied changes in apathy among 77 community-dwelling older persons with mild memory loss in a r and omized clinical trial comparing two nonpharmacological interventions over four weeks . The study used a pre-post design with r and omization by site to avoid contamination and diffusion of effect . Interventions were offered twice weekly after baseline evaluations were completed . The treatment group received classroom style mentally stimulating activities ( MSAs ) while the control group received a structured early-stage social support ( SS ) group . The results showed that the MSA group had significantly lower levels of apathy ( P < .001 ) and significantly lower symptoms of depression ( P < .001 ) . While both groups improved on quality of life , the MSA group was significantly better ( P = .02 ) than the SS group . Executive function was not significantly different for the two groups at four weeks , but general cognition improved for the MSA group and declined slightly for the SS group which produced a significant posttest difference ( P < .001 ) . Recruitment and retention of SS group members was difficult in this project , especially in senior center locations , while this was not the case for the MSA group . The examination of the data at this four-week time point shows promising results that the MSA intervention may provide a much needed method of reducing apathy and depressive symptoms , while motivating participation and increasing quality of life [3808082] Objective To assess whether a manual based coping strategy compared with treatment as usual reduces depression and anxiety symptoms in carers of family members with dementia . Design R and omised , parallel group , superiority trial . Setting Three mental health community services and one neurological outpatient dementia service in London and Essex , UK . Participants 260 carers of family members with dementia . Intervention A manual based coping intervention comprising eight sessions and delivered by supervised psychology graduates to carers of family members with dementia . The programme consisted of psychoeducation about dementia , carers ’ stress , and where to get emotional support ; underst and ing behaviours of the family member being cared for , and behavioural management techniques ; changing unhelpful thoughts ; promoting acceptance ; assertive communication ; relaxation ; planning for the future ; increasing pleasant activities ; and maintaining skills learnt . Carers practised these techniques at home , using the manual and relaxation CDs . Main outcome measures Affective symptoms ( hospital anxiety and depression total score ) at four and eight months . Secondary outcomes were depression and anxiety caseness on the hospital anxiety and depression scale ; quality of life of both the carer ( health status question naire , mental health ) and the recipient of care ( quality of life-Alzheimer ’s disease ) ; and potentially abusive behaviour by the carer towards the recipient of care ( modified conflict tactics scale ) . Results 260 carers were recruited ; 173 were r and omised to the intervention and 87 to treatment as usual . Mean total scores on the hospital anxiety and depression scale were lower in the intervention group than in the treatment as usual group over the eight month evaluation period : adjusted difference in means −1.80 points ( 95 % confidence interval −3.29 to −0.31 ; P=0.02 ) and absolute difference in means −2.0 points . Carers in the intervention group were less likely to have case level depression ( odds ratio 0.24 , 95 % confidence interval 0.07 to 0.76 ) and there was a non-significant trend towards reduced case level anxiety ( 0.30 , 0.08 to 1.05 ) . Carers ’ quality of life was higher in the intervention group ( difference in means 4.09 , 95 % confidence interval 0.34 to 7.83 ) but not for the recipient of care ( difference in means 0.59 , −0.72 to 1.89 ) . Carers in the intervention group reported less abusive behaviour towards the recipient of care compared with those in the treatment as usual group ( odds ratio 0.47 , 95 % confidence interval 0.18 to 1.23 ) , although this was not significant . Conclusions A manual based coping strategy was effective in reducing affective symptoms and case level depression in carers of family members with dementia . The carers ’ quality of life also improved . Trial registration Current Controlled Trials ISCTRN70017938 [17116917] Context Providing care for patients with dementia can pose enormous burdens that may be eased with assistance and support . Needs may differ by race or ethnicity . Contributions The investigators r and omly assigned Hispanic , black , and white dementia caregivers to receive written educational material s or an intensive intervention to improve caregiver quality of life . The specific interventions were determined by caregivers , were delivered via trained personnel and telephone support groups , and targeted several dimensions of need . The study found that quality of life improved for Hispanic and white caregivers and for black spousal caregivers in the intervention group but not in the control group . The intervention had no detectable effect on the number of care recipients who were institutionalized . Caution s The study used only a single 6-month follow-up assessment , combined heterogeneous cultures and ethnicities into 3 groups , and excluded some ethnicities . Implication s An intensive intervention targeting several dimensions of caregiver need improved caregiver quality of life without an apparent effect on care recipient institutionalization . The effect did not differ by caregiver race or ethnicity . The Editors Caring for a family member with dementia is extremely stressful , contributes to psychiatric and physical illness , and increases the risk for death ( 1 , 2 ) . The accumulating evidence on the personal , social , and health effects of dementia caregiving has generated a broad range of intervention studies , including r and omized trials aim ed at decreasing the burden and stress of caregiving . Several studies have demonstrated statistically significant effects in reducing caregiver burden , lowering caregiver depression , and delaying institutionalization of care recipients ( 1 , 3 , 4 ) through either targeted interventions that treat a specific caregiver problem , such as depression , or broad-based multicomponent interventions that include counseling , case management , and telephone support . Persistent limitations of caregiver intervention research are the paucity of well-controlled r and omized trials , the limited range of outcomes examined , small sample sizes and insufficient power , geographic limitations , inadequate racial or ethnic variation , and a scarcity of comprehensive multicomponent interventions ( 4 ) . Indeed , none of the 41 r and omized clinical trials published in the last 5 years met Consoli date d St and ards of Reporting Trials ( CONSORT ) recommendations for reporting r and omized trials ( 5 ) , and many have serious method ologic problems that call into question the reported findings ( 4 ) . To address these limitations , the National Institute on Aging and the National Institute of Nursing Research funded a multisite research program design ed to develop and test an effective caregiver intervention : the Re sources for Enhancing Alzheimer 's Caregiver Health ( REACH ) study . We performed the study in 2 phases . In the first phase ( REACH I ) , we tested several different interventions at 6 U.S. sites to identify the most promising approaches to decreasing caregiver burden and depression ( 6 ) . Results from the study showed that active treatments were superior to control conditions in reducing caregiver burden and that active engagement in skills training statistically significantly reduced caregiver depression ( 7 , 8) . The existing literature and findings from REACH I helped guide the design of the REACH II intervention ( 7 , 8) . We based the REACH II study on the premise that caregivers can have problems in several areas at varying levels of intensity , and thus , interventions must be responsive to variations in needs among caregivers . The findings from REACH I also suggest that interventions that use active techniques , such as role-playing and interactive practice , are more effective at improving outcomes , such as depression symptoms , compared with more passive methods , such as providing information ( 7 ) . We based the REACH II intervention on these assumptions and design ed the intervention to maximize outcomes by systematic ally targeting several problem areas , tailored the intervention to respond to the needs of each individual , and actively engaged the caregiver in the intervention process . We hypothesized that participants assigned to the intervention would do better than those in the control group on several indicators of caregiver quality of life , including depression , burden , self-care , and social support and care recipient problem behaviors , and that these differences would be largest among Hispanic or Latino persons because they have lower access to support services ( 8) . In additional analyses , we assessed the effects of treatment on rates of caregiver clinical depression and care recipient institutional placement , as well as the benefits derived from study participation . Methods Caregivers Eligibility criteria for caregivers included the following : Hispanic or Latino , white or Caucasian , or black or African-American race or ethnicity ; age 21 years or older ; living with or sharing cooking facilities with the care recipient ; providing care for a relative with diagnosed Alzheimer disease or related disorders for at least 4 hours per day for at least the past 6 months ; and reported distress associated with caregiving ( reported at least 2 of the following 6 items at baseline assessment : felt overwhelmed , felt like they often needed to cry , were angry or frustrated , felt they were cut off from family or friends , reported moderate to high levels of general stress , or felt their health had declined ) . We excluded caregivers who were involved in another caregiver intervention study , who had participated in REACH I , or who had an illness that would prevent 6 months of study participation . Other requirements were logistic , including having a telephone , planning to remain in the geographic area for at least 6 months , and competency in either English or Spanish ( see Appendix Table 1 for a detailed list of exclusions ) . Appendix Table 1 . Reasons for In eligibility Care Recipients To be eligible for the study , caregivers had to confirm that their relative had diagnosed Alzheimer disease or related disorders . In addition , we screened care recipients for a history of severe mental illness , head injury , Parkinson disease , or stroke , and we administered the MiniMental State Examination ( MMSE ) ( 9 ) . We excluded patients who were bedbound with MMSE scores of 0 because we felt that our intervention had little to offer caregivers who were caring for such patients . Moreover , being bedbound is a risk factor for institutional placement or death , and we sought to exclude caregivers who were likely to transition out of the caregiving role within the 6-month study . For patients who scored more than 23 on the MMSE or had other conditions , such as head injury , we required a physician 's diagnosis of Alzheimer disease or related disorders . Procedures We recruited caregiver and care recipient dyads at 5 sites : Birmingham , Alabama ; Memphis , Tennessee ; Miami , Florida ; Palo Alto , California ; and Philadelphia , Pennsylvania . Enrollment began in June 2002 , and follow-up ended in August 2004 . Recruitment occurred in memory disorder clinics , primary care clinics , social service agencies , physician offices , churches , and community centers and by using professionally design ed brochures , public service announcements on radio stations , newspaper articles , television , targeted newsletters , and community presentations . We translated all intervention material s and assessment instruments into Spanish for the Hispanic or Latino participants by using established techniques for forward- and -back translation and allowing for regional variation in language expression . We used bilingual and bicultural staff at the 3 sites that recruited Hispanic or Latino participants : Palo Alto , Philadelphia , and Miami . At all sites , assessors and interventionists received cultural sensitivity training and were certified before entering the field . Certified assessors were blinded to group assignment of study participants . The institutional review boards of all 5 site institutions and the coordinating center in Pittsburgh , Pennsylvania , approved the study . We obtained written informed consent from all caregivers and from care recipients whenever possible . Caregivers provided consent on behalf of care recipients who could not do so on their own . After telephone screening ( n= 995 ) and baseline assessment ( n= 670 ) , we r and omly assigned participants ( n= 642 ) to the intervention or control group ( Figure ) . We stratified r and omization by using a block size of 2 or 4 within strata defined by the 5 intervention sites , 3 racial or ethnic groups ( Hispanic or Latino , white or Caucasian , and black or African American ) , and 2 caregivercare recipient relationships ( spouse or nonspouse ) . We performed r and omization at the coordinating center by using a computer-generated algorithm and a st and ard protocol for transmitting r and omization information between the coordinating center and the study sites . We administered 1 of 3 follow-up batteries , on the basis of care recipient status at follow-up ( full follow-up , bereavement battery , or placement battery ) , to study participants 6 months after r and omization when the intervention was completed . To maximize the number of individuals who could be included in the outcome analyses , we ensured that the 3 batteries were as similar as possible . We did not ask caregivers about caregiver burden and care recipient functional status if their care recipients had died ; thus , we could not include these caregivers in the primary outcome analysis ( 10 ) . Figure . Study flow diagram . * See Appendix Table 1 for reasons for in eligibility . See Appendix Table 2 ( for reasons for unavailable end points and types of 6-month follow-up . Appendix Table 2 . Reasons for Unavailable End Points and Types of 6-Month Follow-up Trial Groups Intervention The intervention involved a range of strategies : provision of [12496309] OBJECTIVES To test the efficacy of a psychoeducative group program for informal caregivers of persons with dementia . METHODS The study was a multicenter r and omized controlled trial . R and omization was stratified according to sex and kinship . Participants r and omized to the control group were referred to the traditional support groups . Participants in the study group had fifteen 2-hr weekly sessions focusing on stress appraisal and coping . Eligible participants ( primary caregivers of community-dwelling persons with dementia ) were blindly assessed before the r and omization and after 16 weeks on the following measures : frequency and reactions to behavioral problems ( primary outcome ) , burden , psychological distress , anxiety , perceived social support , and personal efficacy . RESULTS A total of 158 participants were r and omized to the study ( n = 79 ) and control ( n = 79 ) groups in 12 successive waves . Results show that study participants presented a 14 % decrease in their reactions to the behavioral problems of the care-receivers as opposed to a 5 % decrease in the control group ( p = .04 ) . The frequency of behavior problems also decreased ( p = .06 ) , as did the cross-product frequency/reaction ( p = .02 ) . There was no significant effect on the secondary outcome variables . DISCUSSION This is one of the first studies showing a significant effect of this type of support group program on the caregivers of participants with dementia [14722336] Behavioral problems are among the most challenging aspects of caring for a person with Alzheimer 's disease . A sample of 406 spouses-caregivers of patients with Alzheimer 's disease was r and omized to an active multicomponent counseling and support intervention condition or to a usual care condition . Caregivers reported on the frequency of troublesome patient behaviors and their reactions to them at baseline and at regular follow-up interviews . R and om-effects regression models over the first 4 years after r and omization revealed that , although the intervention did not affect the frequency of patient behavioral problems , it did significantly reduce caregivers ' reaction ratings . Because caregiver appraisal s have been found to mediate the impact of caregiving stress on depression and to predict nursing home placement rates , they deserve greater attention as an important target of intervention services [2881915] Background Almost all of the 820,000 people in the UK with dementia will experience Behavioural and Psychological Symptoms of Dementia ( BPSD ) . However , research has traditionally focused on treating cognitive symptoms , thus neglecting core clinical symptoms that often have a more profound impact on living with dementia . Recent evidence ( Kales et al , 2007 ; Ballard et al , 2009 ) indicates that the popular approach to managing BPSD - prescription of anti-psychotic medication - can increase mortality and the risk of stroke in people with dementia as well as impair quality of life and accelerate cognitive decline . Consequently , there is a need to evaluate the impact that non-pharmacological interventions have on BPSD ; we believe physical exercise is a particularly promising approach . Methods / Design We will carry out a pragmatic , r and omised , single-blind controlled trial to evaluate the effectiveness of exercise ( planned walking ) on the behavioural and psychological symptoms of individuals with dementia . We aim to recruit 146 people with dementia and their carers to be r and omized into two groups ; one will be trained in a structured , tailored walking programme , while the other will continue with treatment as usual . The primary outcome ( BPSD ) will be assessed with the Neuropsychiatric Inventory ( NPI ) along with relevant secondary outcomes at baseline , 6 and 12 weeks . Discussion Design ing this study has been challenging both ethically and method ologically . In particular to design an intervention that is simple , measurable , safe , non-invasive and enjoyable has been testing and has required a lot of thought . Throughout the design , we have attempted to balance method ological rigour with study feasibility . We will discuss the challenges that were faced and overcome in this paper . Trial Registration IS RCT [12937334] PURPOSE We determine the main outcome effects of a 12-month computer-mediated automated interactive voice response ( IVR ) intervention design ed to assist family caregivers managing persons with disruptive behaviors related to Alzheimer 's disease ( AD ) . DESIGN AND METHODS We conducted a r and omized controlled study of 100 caregivers , 51 in the usual care control group and 49 in the technology intervention group , who received yearlong access to an IVR-mediated system . The system provided caregiver stress monitoring and counseling information , personal voice-mail linkage to AD experts , a voice-mail telephone support group , and a distraction call for care recipients . We conducted analyses by using a repeated measures approach for longitudinal data and an intention-to-treat analytic approach . Outcomes included the caregiver 's appraisal of the bothersome nature of caregiving , anxiety , depression , and mastery at baseline , 6 , 12 , and 18 months . RESULTS There was a significant intervention effect as hypothesized for participants with lower mastery at baseline on all three outcomes : bother ( p = .04 ) , anxiety ( p = .01 ) , and depression ( p = .007 ) . Additionally , wives exhibited a significant intervention effect in the reduction of the bothersome nature of caregiving ( p = .02 ) . IMPLICATION S Wives who exhibited low mastery and high anxiety benefited the most from the automated telecare intervention . Findings suggest that , to optimize outcome effects , similar interventions should be tailored to match the users ' characteristics and preferences [18978250] OBJECTIVE To evaluate the effectiveness of a combination of cholinesterase inhibitor therapy for patients with Alzheimer disease ( AD ) and psychosocial intervention , for their spouse caregivers compared with drug treatment alone in three countries simultaneously . DESIGN R and omized controlled trial . Structured question naires were administered at baseline and at regular follow-up intervals for 24 months by independent raters blind to group assignment . SETTING Outpatient research clinics in New York City , U.S. , Manchester , U.K. and Sydney , Australia . PARTICIPANTS Volunteer sample of 158 spouse caregivers of community dwelling patients with AD . INTERVENTIONS Five sessions of individual and family counseling within 3 months of enrollment and continuous availability of ad hoc telephone counseling were provided for half the caregivers . Donepezil was prescribed for all patients . MAIN OUTCOME MEASURE Depressive symptoms of spouse caregivers measured at intake and follow-up assessment s for 24 months using Beck Depression Inventory ( revised ) . RESULTS Depression scores of caregivers who received counseling decreased over time , whereas the depression scores for caregivers who did not receive counseling increased . The benefit of the psychosocial intervention was significant after controlling for site , gender and country was not accounted for by antidepressant use and increased over 2 years even though the individual and family counseling sessions occurred in the first 3 months . CONCLUSION Effective counseling and support interventions can reduce symptoms of depression in caregivers when patients are taking donepezil . Harmonized multinational psychosocial interventions are feasible . Combined drug and supportive care approaches to the management of people with AD should be a priority [20662955] OBJECTIVES To test the effects of an intervention that helps families manage distressing behaviors in family members with dementia . DESIGN Two-group r and omized trial . SETTING In home . PARTICIPANTS Two hundred seventy-two caregivers and people with dementia . INTERVENTION Up to 11 home and telephone contacts over 16 weeks by health professionals who identified potential triggers of patient behaviors , including communication and environmental factors and patient undiagnosed medical conditions ( by obtaining blood and urine sample s ) and trained caregivers in strategies to modify triggers and reduce their upset . Between 16 and 24 weeks , three telephone contacts reinforced strategy use . MEASUREMENTS Primary outcomes were frequency of targeted problem behavior and caregiver upset with and confidence managing it at 16 weeks . Secondary outcomes were caregiver well-being and management skills at 16 and 24 weeks and caregiver perceived benefits . Prevalence of medical conditions for intervention patients were also examined . RESULTS At 16 weeks , 67.5 % of intervention caregivers reported improvement in targeted problem behavior , compared with 45.8 % of caregivers in a no-treatment control group ( P=.002 ) , and reduced upset with ( P=.03 ) and enhanced confidence managing ( P=.01 ) the behavior . Additionally , intervention caregivers reported less upset with all problem behaviors ( P=.001 ) , less negative communication ( P=.02 ) , less burden ( P=.05 ) , and better well-being ( P=.001 ) than controls . Fewer intervention caregivers had depressive symptoms ( 53.0 % ) than control group caregivers ( 67.8 % , P=.02 ) . Similar caregiver outcomes occurred at 24 weeks . Intervention caregivers perceived more study benefits ( P<.05 ) , including ability to keep family members home , than controls . Blood and urine sample s of intervention patients with dementia showed that 40 ( 34.1 % ) had undiagnosed illnesses requiring physician follow-up . CONCLUSION Targeting behaviors up setting to caregivers and modifying potential triggers improves symptomatology in people with dementia and caregiver well-being and skills [12937335] PURPOSE We developed manual-guided , replicable interventions based on common needs and cultural preferences of White and African American family caregivers ( CGs ) of individuals with dementia , and we evaluated these interventions after a 6-month follow-up . DESIGN AND METHODS We r and omly assigned White ( n = 70 ) and African American ( n = 48 ) CGs of individuals with dementia to either a skills training condition or a minimal support control condition . RESULTS The degree of treatment implementation was method ically assessed , and findings demonstrated that both interventions were delivered according to protocol and were well received by CGs . CGs in both groups reported decreasing levels of problem behaviors and appraisal s of behavioral bother , and increased satisfaction with leisure activities over time . On a measure of appraisal of distress related to behavior problems , White CGs showed more improvement in the minimal support control condition , and African American CGs showed the greatest improvements in the skills training condition . Spouse and nonspouse CGs also showed differential responses to intervention . IMPLICATION S Brief manual-guided interventions can be effective with White and African American CGs , and greater attention should be paid to possible differential responses to interventions by race and relationship to care recipient [15121650] OBJECTIVE The long-term effect of counseling and support on symptoms of depression was examined in spouse-caregivers of patients with Alzheimer 's disease . METHOD The participants were 406 spouse-caregivers of Alzheimer 's disease patients who lived at home at baseline . The caregivers were r and omly assigned to either a group receiving enhanced counseling and support treatment or a group receiving usual care ( control group ) . Caregivers in the enhanced treatment group were provided with six sessions of individual and family counseling , agreed to join support groups 4 months after enrollment , and received ongoing ad hoc counseling . The Geriatric Depression Scale was administered at baseline and at regular follow-up intervals for as long as the caregiver participated in the study . RESULTS After baseline differences were controlled for , caregivers in the enhanced treatment group had significantly fewer depressive symptoms after the intervention than did the control subjects . These effects were sustained for 3.1 years after baseline , similar across gender and patient severity level , and sustained after nursing home placement or death of the patient . CONCLUSIONS Counseling and support lead to sustained benefits in reducing depressive symptoms in spouse-caregivers of Alzheimer 's disease patients and should be widely available to provide effective , evidence -based intervention for family caregivers [23916916] Family caregivers of individuals with dementia are at heightened risk for emotional and mental health problems . Many caregivers do not seek assistance or become isolated in their caregiving role . Multi-component interventions have demonstrated efficacy for reducing emotional distress and burden , although these approaches are potentially costly and are not widely accessible . In response to these issues , we developed the Family Intervention : Telephone Tracking - Caregiver ( FITT-C ) , which is an entirely telephone-based psychosocial intervention . The purpose of this paper is to describe the study design , methodology , and baseline data for the trial . This study uses a r and omized controlled trial design to examine the efficacy of the FITT-C to reduce depressive symptoms and burden in distressed dementia caregivers . All participants ( n=250 ) received a packet of educational material s and were r and omly assigned to receive 6 months of the FITT-C intervention or non-directive telephone support . The FITT-C intervention was design ed to reduce distress in caregivers and is based on the McMaster Model of Family Functioning , transition theory , and Lazarus and Folkman 's Stress and Coping Models . The primary dependent variables were depressive symptoms ( Centers for Epidemiological Studies - Depression ) and burden ( Zarit Burden Interview , Revised Memory and Behavior Problems Checklist - Reaction ) . Secondary outcome measures included family functioning , self-efficacy , and health-related quality of life . Results of the study will provide important data about the efficacy of a telephone-based approach to reduce distress in dementia caregivers [12464756] Background Eighty percent of persons with Alzheimer ’s disease and related disorders are cared for by family members who often lack adequate support and training for this all-consuming job . Objective To evaluate the efficacy of a longitudinal , multisite , community-based intervention design ed to teach home caregivers to manage behavioral problems in persons with Alzheimer ’s disease . Methods Usable data were analyzed from 237 caregiver/care recipient dyads ( n = 132 Experimental;n = 105 Comparison ) . The experimental group received a psychoeducational nursing intervention that was conceptually grounded in the Progressively Lowered Stress Threshold model ( Hall & Buckwalter , 1987 ) . The comparison group received routine information and referrals for case management , community-based services , and support groups . Although a variety of psychosocial outcomes were compared between caregivers in the two groups , this article focuses on frequency and response to behavioral problems and functional decline . Results The Progressively Lowered Stress Threshold intervention had a statistically significant effect on spousal response to memory/behavioral problems ( p < .01 ) for all caregivers and on response to activities of daily living problems ( p < .01 ) for spousal caregivers . In addition , nonspouses in the experimental group reported a reduction in the frequency of memory/behavioral problems ( p < .01 ) . No intervention effect on reports of activities of daily living frequencies was found for either spouses or nonspouses . Conclusions This Progressively Lowered Stress Threshold-based intervention had a positive impact on both the frequency of and response to problem behaviors among spousal caregivers [21797835] OBJECTIVES To test the effects of walking , light exposure , and a combination intervention ( walking , light , and sleep education ) on the sleep of persons with Alzheimer 's disease ( AD ) . DESIGN R and omized , controlled trial with blinded assessors . SETTING Independent community living . PARTICIPANTS One hundred thirty-two people with AD and their in-home caregivers . INTERVENTIONS Participants were r and omly assigned to one of three active treatments ( walking , light , combination treatment ) or contact control and received three or six in-home visits . MEASUREMENTS Primary outcomes were participant total wake time based on wrist actigraphy and caregiver ratings of participant sleep quality on the Sleep Disorders Inventory ( SDI ) . Secondary sleep outcomes included additional actigraphic measurements of sleep percentage , number of awakenings , and total sleep time . RESULTS Participants in walking ( P=.05 ) , light ( P=.04 ) , and combination treatment ( P=.01 ) had significantly greater improvements in total wake time at posttest ( effect size 0.51 - 0.63 ) than controls but no significant improvement on the SDI . Moderate effect size improvements in actigraphic sleep percentage were also observed in active treatment participants . There were no significant differences between the active treatment groups and no group differences for any sleep outcomes at 6 months . Participants with better adherence ( 4 d/wk ) to walking and light exposure recommendations had significantly less total wake time ( P=.006 ) and better sleep efficiency ( P=.005 ) at posttest than those with poorer adherence . CONCLUSION Walking , light exposure , and their combination are potentially effective treatments for improving sleep in community-dwelling persons with AD , but consistent adherence to treatment recommendations is required [16326662] PURPOSE We investigated whether community consultants could be trained to teach family caregivers a systematic behavioral approach for reducing mood and behavior problems in persons with Alzheimer 's disease . DESIGN AND METHODS This study consisted of a r and omized controlled trial ; we r and omly assigned 95 family caregivers and care recipients with Alzheimer 's disease to STAR-caregivers ( STAR-C ) or control groups . Masked interviewers conducted assessment s at baseline , after treatment , and after 6 months . Consultants were master's-level health care professionals who were currently practicing in community setting s serving older adults . We assessed the extent to which consultants were able to learn and adhere to the treatment protocol , and the relationship between adherence and measures of caregiver mood , burden , and care recipient mood and behavior . RESULTS Community consultants were able to learn and adhere to the behavioral treatment protocol . Caregivers receiving STAR-C training showed significant improvements in depression , burden , and reactivity to behavior problems in the care recipient . There were also significant reductions in the frequency and severity of care recipient behavior problems , and improved quality of life . Results were maintained at 6-month follow-up . IMPLICATION S Community-based consultants successfully implemented a behavioral intervention with family caregivers of persons with Alzheimer 's disease . Consequently , STAR-C seems to be a practicable and reasonable evidence d-based approach to caregiver training in actual clinical setting [25698766] BACKGROUND Anxiety is common and problematic in dementia , yet there is a lack of effective treatments . AIMS To develop a cognitive-behavioural therapy ( CBT ) manual for anxiety in dementia and determine its feasibility through a r and omised controlled trial . METHOD A ten-session CBT manual was developed . Participants with dementia and anxiety ( and their carers ) were r and omly allocated to CBT plus treatment as usual ( TAU ) ( n = 25 ) or TAU ( n = 25 ) . Outcome and cost measures were administered at baseline , 15 weeks and 6 months . RESULTS At 15 weeks , there was an adjusted difference in anxiety ( using the Rating Anxiety in Dementia scale ) of ( -3.10 , 95 % CI -6.55 to 0.34 ) for CBT compared with TAU , which just fell short of statistical significance . There were significant improvements in depression at 15 weeks after adjustment ( -5.37 , 95 % CI -9.50 to -1.25 ) . Improvements remained significant at 6 months . CBT was cost neutral . CONCLUSIONS CBT was feasible ( in terms of recruitment , acceptability and attrition ) and effective . A fully powered RCT is now required [24338799] OBJECTIVE The objective of this study is to evaluate the effectiveness of a simple dyadic ( person with dementia and their main carer ) exercise regimen as a therapy for the behavioural and psychological symptoms of dementia . METHOD A two arm , pragmatic , r and omised , controlled , single-blind , parallel-group trial of a dyadic exercise regimen ( individually tailored walking regimen design ed to become progressively intensive and last between 20 - 30 min , at least five times per week).Community-dwelling individuals with ICD-10 confirmed dementia with the following : clinical ly significant behavioural and psychological symptoms , a carer willing and able to co-participate in the exercise regimen , and no physical conditions or symptoms that would preclude exercise participation were invited by mental health or primary care services into the study . RESULTS One hundred and thirty-one dyads were recruited to this study . There was no significant difference in Behavioural and Psychological Symptoms as measured by the Neuropsychiatric Inventory at week 12 between the group receiving the dyadic exercise regimen and those that did not ( adjusted difference in means ( intervention minus control ) = -1.53 , p = 0.6 , 95 % CI [ -7.37 , 4.32 ] ) . There was a significant between-group difference in caregiver 's burden as measured by the Zarit Caregiver Burden Inventory at week 12 ( OR = 0.18 , p = 0.01 , CI [ 0.05 , 0.69 ] ) favouring the exercise group . CONCLUSIONS This study found that regular simple exercise does not appear to improve the behavioural and psychological symptoms of dementia , but did seem to attenuate caregiver burden . Further study to improve exercise uptake are needed [21196773] Background : There is a lack of appropriately design ed trials investigating the efficacy of psychosocial interventions for patients with mild dementia and their family caregivers . This paper reports the rationale and design of the Danish Alzheimer Disease Intervention Study and baseline characteristics of the cohort . Methods : The study was a 1-year multicentre r and omized controlled rater-blinded trial with r and omization to follow-up and a multifaceted semitailored intervention programme or to follow-up only ( with extension of follow-up to 3 years ) . The intervention included a counselling programme , teaching courses , written information and logbooks . The outcomes included clinical efficacy parameters , patient satisfaction and health economic consequences . Results : A total of 330 patients and their 330 caregivers were included during a period of 18 months . The majority ( 65.2 % ) of the caregivers were spouses . At inclusion the mean age of the patients and caregivers was 76.2 and 66.0 years , respectively . Conclusion : The study will explore the added value of a multifaceted intervention programme and contribute to the design of future interventions for patients with mild dementia and their caregivers [20425645] Prior research ( Gallagher-Thompson , D. , Gray , H. , Tang , P. , Pu , C.-Y. , Tse , C. , Hsu , S. , et al. ( 2007 ) . Impact of in-home intervention versus telephone support in reducing depression and stress of Chinese caregivers : Results of a pilot study . American Journal of Geriatric Psychiatry , 15 , 425–434 . ) found that an in-home behavioral management program , derived conceptually from cognitive behavioral theories ( CBT ) , was effective in reducing caregiver related stress and depressive symptoms in Chinese American dementia caregivers ( CGs ) . Results were promising , but a more cost-effective intervention is needed to serve this growing population . Past work also found that a psychoeducational videotaped training program based on CBT was effective in reducing stress due to caregiving in Caucasian and African American dementia family CGs ( Steffen , 2000 , Anger management for dementia caregivers : A preliminary study using video and telephone interventions . Behavior Therapy , 31 , 281–299 . ) . To date no research has been conducted using a technological medium to deliver a similar kind of intervention to Chinese American caregivers . The present study evaluated the effectiveness of a similar but culturally “ tailored ” program in which 70 CGs were r and omly assigned to a 12-week CBT skill training program delivered on a DVD , or to a general educational DVD program on dementia . Both were available in M and arin Chinese or English as preferred . Pre post change analyses indicated that CGs did not differ on change in level of negative depressive symptoms , but positive affect was higher , and patient behaviors were appraised as less stressful and bothersome , for CGs in the CBT skill training program . They were also more satisfied with the program overall and reported that they believed they were able to give care more effectively . Results encourage further development of theoretically based interventions , delivered using modern technology , for this ever increasing group of CGs [19582757] OBJECTIVES We reported the findings of a r and omized controlled trial ( RCT ) to examine the effects of an individualized functional enhancement program ( FEP ) on functional skills and mood symptoms in mild and moderate dementia . SUBJECTS & METHODS 74 Chinese older persons with dementia were recruited into a skills training program by occupational therapists ( OT ) . Thirty seven subjects were trained with an individualized selection of daily activities ( FEP Intervention , I ) ; 37 were trained with general occupational therapy ( Control , C ) . The FEP comprised of twice weekly group sessions of skills training and problem solving using cognitive behavioral approach . RESULTS At 1 month after completion of program , both I and C subjects showed an improvement in process skills of the assessment of motor and process skills (AMPS)(paired t-tests , p < 0.05 ) . At 4 months post-program , the I group showed a further reduction of cornell scale for depression in dementia ( CSDD ) scores ( paired t-test , p = 0.02 ) ; Apathy improved at 1 month post-training ( p = 0.04 ) , but deteriorated at 4 months ( p = 0.01 ) . Group differences in changes of mood and functional scores were not significant ( ANVOCA , p > 0.05 ) . CONCLUSIONS The findings suggested a potential benefit for individualized occupational therapy . It should be tailor made with individual needs and continued for sustained effectiveness [12937331] PURPOSE The majority of persons with Alzheimer 's disease ( AD ) are cared for at home by a family member such as a spouse or daughter . Caregiving places enormous dem and s on these caregivers , and the negative consequences associated with caregiving are well documented . This paper reports results from the Miami site of the REACH ( Re sources for Enhancing Alzheimer 's Caregiver Health ) program that examined the efficacy of a family therapy and technology-based intervention in reducing depressive symptoms ( according to the Center for Epidemiological Studies Depression scale ) among family caregivers of AD patients at 6 months and 18 months follow-up . DESIGN AND METHODS There were 225 White American and Cuban American caregivers that were r and omized into a structural ecosystems therapy , structural ecosystems therapy + computer-telephone integrated system , or minimal support control condition . RESULTS Caregivers in the combined family therapy and technology intervention experienced a significant reduction in depressive symptoms at 6 months . The 18-month follow-up data indicated that the intervention was particularly beneficial for Cuban American husb and and daughter caregivers . IMPLICATION S The results indicate that information technology has a promising role in alleviating distress and depression among groups of AD caregivers . The data also demonstrate that interventions have differential impacts according to ethnic group and the caregiver-patient relationship [17804831] OBJECTIVE The objective of this study was to determine the effects of counseling and support on the physical health of caregivers of spouses of people with Alzheimer disease . METHODS A r and omized controlled trial , conducted between 1987 and 2006 at an outpatient research clinic in the New York City metropolitan area compared outcomes of psychosocial intervention to usual care . Structured question naires were administered at baseline and regular follow-ups . A referred volunteer sample of 406 spouse caregivers of community dwelling patients with Alzheimer disease enrolled over a 9.5-year period . Enhanced counseling and support consisted of six sessions of individual and family counseling , support group participation , and continuous availability of ad-hoc telephone counseling . Indicators of physical health included self-rated health ( SRH ) of caregivers and the number of reported illnesses . RESULTS Controlling for baseline SRH ( mean : 7.24 ) , intervention group caregivers had significantly better SRH than control group caregivers based upon model predicted mean scores four months after baseline ( 6.87 versus 7.21 ) , and this significant difference was maintained for two years ( 6.70 versus 7.01 ) . The effect of the intervention on SRH remained significant after controlling for the effects of patient death , nursing home placement , caregiver depressive symptoms and social support satisfaction . Similar benefits of intervention were found for number of illnesses . CONCLUSION Counseling and support preserved SRH in vulnerable caregivers . Enhancing caregivers ' social support , fostering more benign appraisal s of stressors , and reducing depressive symptoms may yield indirect health benefits . Psychosocial intervention studies with biological measures of physical health outcomes are warranted [15860476] BACKGROUND Few studies evaluate whether short-term intervention effects are maintained over time for families caring for persons with dementia . This article examines whether treatment effects found at 6 months following active treatment were sustained at 12 months for 127 family caregivers who participated in an occupational therapy intervention tested as part of the National Institutes of Health Re sources for Enhancing Alzheimer 's Caregiver Health ( REACH ) initiative . METHODS A r and omized two-group design was implemented with three assessment points : baseline , 6 months , and 12 months . Caregivers were r and omly assigned to a usual care control group or intervention that consisted of six occupational therapy sessions to help families modify the environment to support daily function of the person with dementia and reduce caregiver burden . Following 6-month active treatment , a maintenance phase consisted of one home and three brief telephone sessions to reinforce strategy use and obtain closure . Non-inferiority statistical analysis was used to evaluate whether intervention caregivers maintained treatment benefits from 6 to 12 months in comparison to controls . RESULTS For the sample of 127 at 6 months , caregivers in intervention reported improved skills ( p = .028 ) , less need for help providing assistance ( p = .043 ) , and fewer behavioral occurrences ( p = .019 ) compared to caregivers in control . At 12 months , caregiver affect improved ( p = .033 ) , and there was a trend for maintenance of skills and reduced behavioral occurrences , but not for other outcome measures . CONCLUSION An in-home skills training program helps sustain caregiver affect for those enrolled for more than 1 year . More frequent professional contact and ongoing skills training may be necessary to maintain other clinical ly important outcomes such as reduced upset with behaviors [18378844] OBJECTIVES This study tested the effectiveness of a dementia care management program for Chinese families of relatives with dementia on caregivers ' and patients ' health outcomes over a 12-month follow-up period . METHODS The dementia care management program is an educational and supportive group for caregivers that lasts six months . A controlled trial was conducted with 88 primary caregivers of persons with dementia in two dementia care centers in Hong Kong . Family members were assigned r and omly to either the dementia care program or st and ard care . The two groups were compared for patients ' symptoms and institutionalization rates and caregivers ' quality of life , burden , and social support upon recruitment and six and 12 months after group assignment . RESULTS Over the 12-month follow-up period , patients with family members in the dementia care program showed significantly greater improvements in symptoms and institutionalization rates and their caregivers reported significantly greater improvements in quality of life and burden compared with the control group . CONCLUSIONS The findings provide evidence that the dementia care management program can improve the psychosocial functioning of Chinese persons with dementia and their caregivers [21358385] OBJECTIVE To evaluate the effectiveness of the Systematic Care Program for Dementia ( SCPD ) on patient institutionalization and to determine the predictors of institutionalization . DESIGN Single-blind , multicenter , cluster-r and omized , controlled trial . SETTING Six community mental health services ( CMHSs ) across the Netherl and s. PARTICIPANTS A total of 295 patient-caregiver dyads referred to a CMHS with suspected patient dementia . INTERVENTION Training of health professionals in the SCPD and its subsequent use . The SCPD consists of a systematic assessment of caregiver problems and alerts health professionals in flexible , connecting , proactive interventions to them . The intensity of the SCPD depends on the judgment of the health professional , based on individual caregiver needs . PRIMARY OUTCOME Institutionalization in long-term care facilities at 12 months of follow-up . RESULTS No main intervention effect on institutionalization was found . However , a better sense of competence in the control group reduced the chance of institutionalization but not in the intervention group . The caregiver 's sense of competence and depressive symptoms and the patient 's behavioral problems and severity of dementia were the strongest predictors of institutionalization . The intensity of the program was low , even for dyads exposed to the SCPD . CONCLUSIONS Although no main effect was found , the results suggest that the SCPD might prevent a deterioration of the sense of competence in the intervention group . The intensity of a program is crucial and should be prescribed on the basis of evidence rather than left to the discretion of health professionals . Future controlled trials in daily clinical practice should use a process analysis to control for compliance [24617278] The purpose of this study was to determine if telephone support groups for dementia caregivers have an effect on bother with patient behaviours , burden , depression , and general well-being . The r and omized controlled trial compared telephone support groups ( 15 groups of 5 or 6 caregivers ) with control groups ( print material s ) . Groups met 14 times over 1 year . The 1-hour sessions included content on education , coping skills , and support . Data were collected at baseline and at 6 and 12 months . The sample comprised 154 caregivers , 77 per arm , providing care to veterans with dementia or a veteran caregiver . Bother was found to differ significantly at baseline . There were no significant treatment effect differences between study arms . Participants anecdotally reported improvement . It was concluded that telephone support groups are an efficient way to interact with caregivers . Further research should test different models of care . Interventions that are targeted to specific needs or occur frequently may provide better support for caregivers of individuals with a worsening condition [11317951] OBJECTIVES To investigate short-term effects of Multi-Sensory Stimulation ( MSS ) on behaviour , mood and cognition of older adults with dementia , the generalization of effects to day hospital and home environments and the endurance of any effects over time . DESIGN A r and omized controlled trial comparing MSS with a credible control of one-to-one activities . METHODS Fifty patients with diagnoses of moderate to severe dementia were r and omized to either MSS or Activity groups . Patients participated in eight 30-minute sessions over a 4-week period . Ratings of behaviour and mood were taken before , during and after sessions to investigate immediate effects . Pre , mid , post-trial , and follow-up assessment s were taken to investigate any generalization of effects on cognition , behaviour at the day hospital and behaviour and mood at home and endurance of effects once sessions had ceased . RESULTS Immediately after MSS and Activity sessions patients talked more spontaneously , related better to others , did more from their own initiative , were less bored/inactive , and were more happy , active or alert . Both groups were more attentive to their environment than before , with a significantly greater improvement from the MSS group . At the day hospital , patients in the Activity group improved on their ' speech skills ' ( amount of speech ; initiation of speech ) , whereas the MSS group remained unchanged during the trial . The MSS group showed a significant improvement in mood and behaviour at home compared to the Activity group whose behaviour deteriorated . No longer-term benefits were shown ; indeed , behaviour declined sharply during the month follow-up period . CONCLUSIONS Both MSS and Activity sessions appear to be effective and appropriate therapies for people with dementia [3840334] Objectives To examine the long-term efficacy at the 36-month follow-up of an early psychosocial counselling and support programme lasting 8–12 months for community-dwelling patients with mild Alzheimer 's disease and their caregivers . Design Multicentre , r and omised , controlled , rater-blinded trial . Setting Primary care and memory clinics in five Danish districts . Participants 330 home-dwelling patients with mild Alzheimer 's disease and their primary caregivers ( dyads ) . Interventions Dyads were r and omised to receive intervention during the first year after diagnosis . Both intervention and control groups had follow-up visits at 3 , 6 , 12 and 36 months . Main outcome measures Primary outcomes for the patients assessed at 36-month follow-up were changes from baseline in global cognitive function ( Mini-Mental State Examination ) , depressive symptoms ( Cornell Depression Scale ) and proxy-rated EuroQoL quality of life on visual analogue scale . The primary outcomes for the caregivers were changes from baseline in depressive symptoms ( Geriatric Depression Scale ) and self-rated EuroQoL quality of life on a visual analogue scale . The secondary outcome measures for the patient were proxy-rated Quality of Life Scale for Alzheimer 's disease ( QoL-AD ) , Neuropsychiatric Inventory- Question naire , Alzheimer 's disease Cooperative Study Activities of Daily Living Scale , all-cause mortality and nursing home placement . Results At a 36-month follow-up , 2 years after the completion of the Danish Alzheimer Intervention Study ( DAISY ) , the unadjusted positive effects previously detected at the 12-month follow-up in one patient primary outcome ( Cornell depression score ) and one patient secondary outcome ( proxy-rated QoL-AD ) disappeared ( Cornell depression score , p=0.93 ; proxy-rated QoL-AD , p=0.81 ) . No long-term effect of DAISY intervention on any other primary and secondary outcomes was found at the 36-month follow-up . Conclusions For patients with very mild Alzheimer 's disease and their caregivers , an intensive , multi-component , semitailored psychosocial intervention programme with counselling , education and support during the first year after diagnosis did not show any positive long-term effect on primary and secondary outcomes . Trial registration The study was registered in the Clinical Trial Data base ( http://www.controlled-trials.com/IS RCT N74848736 ) [20228893] The objective of this study was to examine the preliminary efficacy of Family Intervention : Telephone Tracking — Dementia ( FITT-D ) , a multi-component intervention that is delivered in 23 telephone contacts over 12 months . Thirty-three dementia caregivers were r and omly assigned to receive either FITT-D ( n = 16 ) or st and ard care ( n = 17 ) using urn r and omization to balance the groups on dementia severity , caregiver gender and relationship type ( spouse versus other ) . Inclusion criteria included formal dementia diagnosis , caregiving for at least six months , residing with the care recipient , and providing at least four hours of direct supervision per day . Master's-level therapists contacted caregivers by telephone over 12 months . Each contact followed a st and ardized treatment manual , involving assessment and individualized application of interventions to address mood , family functioning , social support and health . Outcomes included Zarit Burden Interview , Revised Memory and Behavior Problem Checklist , and the Geriatric Depression Scale at baseline and 12 months ( end of treatment ) . Caregivers receiving FITT-D exhibited significantly lower burden scores and less severe reactions to memory and behavior problems than caregivers in the st and ard care condition . Findings provide preliminary evidence for the efficacy of FITT-D , a potentially highly accessible , low-cost intervention for dementia caregivers [20602013] OBJECTIVE There is a need , in the absence of formal services , to design interventions aim ed at improving the lives of people with dementia and their families . This study tested the effectiveness of the 10/66 caregiver intervention among people with dementia and their caregivers in Lima , Peru . METHOD DESIGN / PARTICIPANTS a r and omized controlled trial was performed involving 58 caregivers of people with dementia that received the intervention in the beginning of the trial ( n = 29 ) or six months later ( n = 29 ) . The intervention consisted of three modules : 1 ) assessment ( one session ) ; 2 ) basic education about dementia ( two sessions ) ; and 3 ) training regarding specific problem behaviors ( two sessions ) . MAIN OUTCOME MEASURES Caregivers and patients with dementia were assessed at baseline and after six months . For caregivers , the measures included strain ( Zarit Burden Interview ) , psychological distress ( SRQ-20 ) , and quality of life ( WHOQOL-BREF ) . Dementia patients completed scales assessing behavioral and psychological symptoms ( NPI-Q ) and quality of life ( DEMQOL ) . RESULTS Caregivers in the intervention group reported significantly decreased strain measures six months after the intervention compared to controls . No group differences were found in respect to the caregivers ' psychological distress and to quality of life in both caregivers and patients . CONCLUSION The 10/66 intervention seems to be as effective as similar interventions used in more developed countries [14559955] CONTEXT Exercise training for patients with Alzheimer disease combined with teaching caregivers how to manage behavioral problems may help decrease the frailty and behavioral impairment that are often prevalent in patients with Alzheimer disease . OBJECTIVE To determine whether a home-based exercise program combined with caregiver training in behavioral management techniques would reduce functional dependence and delay institutionalization among patients with Alzheimer disease . DESIGN , SETTING , AND PATIENTS R and omized controlled trial of 153 community-dwelling patients meeting National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer Disease and Related Disorders Association criteria for Alzheimer disease , conducted between June 1994 and April 1999 . INTERVENTIONS Patient-caregiver dyads were r and omly assigned to the combined exercise and caregiver training program , Reducing Disability in Alzheimer Disease ( RDAD ) , or to routine medical care ( RMC ) . The RDAD program was conducted in the patients ' home over 3 months . MAIN OUTCOME MEASURES Physical health and function ( 36-item Short-Form Health Survey 's [ SF-36 ] physical functioning and physical role functioning subscales and Sickness Impact Profile 's Mobility subscale ) , and affective status ( Hamilton Depression Rating Scale and Cornell Depression Scale for Depression in Dementia ) . RESULTS At 3 months , in comparison with the routine care patients , more patients in the RDAD group exercised at least 60 min/wk ( odds ratio [ OR ] , 2.82 ; 95 % confidence interval [ CI ] , 1.25 - 6.39 ; P = .01 ) and had fewer days of restricted activity ( OR , 3.10 ; 95 % CI , 1.08 - 8.95 ; P<.001 ) . Patients in the RDAD group also had improved scores for physical role functioning compared with worse scores for patients in the RMC group ( mean difference , 19.29 ; 95 % CI , 8.75 - 29.83 ; P<.001 ) . Patients in the RDAD group had improved Cornell Depression Scale for Depression in Dementia scores while the patients in the RMC group had worse scores ( mean difference , -1.03 ; 95 % CI , -0.17 to -1.91 ; P = .02 ) . At 2 years , the RDAD patients continued to have better physical role functioning scores than the RMC patients ( mean difference , 10.89 ; 95 % CI , 3.62 - 18.16 ; P = .003 ) and showed a trend ( 19 % vs 50 % ) for less institutionalization due to behavioral disturbance . For patients with higher depression scores at baseline , those in the RDAD group improved significantly more at 3 months on the Hamilton Depression Rating Scale ( mean difference , 2.21 ; 95 % CI , 0.22 - 4.20 ; P = .04 ) and maintained that improvement at 24 months ( mean difference , 2.14 ; 95 % CI , 0.14 - 4.17 ; P = .04 ) . CONCLUSION Exercise training combined with teaching caregivers behavioral management techniques improved physical health and depression in patients with Alzheimer disease [19606455] OBJECTIVE To evaluate a case management ( CM ) model for people with mild dementia , whereby re sources within the family and in the community were mobilized and optimally used . METHOD Community dwelling psychiatric and geriatrics out patients with mild dementia were r and omized to receive CM by a trained occupational therapist for 4 months ( CM group , N = 59 ) or usual care only ( control group , N = 43 ) . Primary outcome indicators included the Zarit Burden Scale ( ZBI ) , General Health Question naire ( GHQ ) , and Personal Well-Being Index for Adult ( PWI-A ) of the family caregivers . Secondary outcome indicators included the Mini-Mental State Examination ( MMSE ) , Neuropsychiatric Inventory ( NPI ) , Cornell Scale for Depression in Dementia ( CSDD ) , and Personal Well-Being Index for Intellectually Disabled ( PWI-ID ) of the demented subjects as measured at fourth and twelfth months . RESULT CSDDis reduced in the CM group at fourth month , but not at twelfth month . The changes in outcome variables of persons with dementia did not differ between the groups ( Mann-Whitney U-test , p > 0.05 ) . At follow-up , CM group used more day care and domestic helpers than control group ( chi ( 2 ) , p > 0.05 ) . CONCLUSION Case management for Chinese persons with mild dementia out patients did not show significant effects in reducing caregiver burden , but encouraged family caregivers to seek external support [11347790] OBJECTIVES Family caregiving is an integral part of the care system for persons with dementing disorders , such as Alzheimer 's disease . This study tested role-training intervention as a way to help family caregivers appreciate and assume a more clinical belief set about caregiving and thereby ameliorate the adverse outcomes associated with caregiving . DESIGN Training effectiveness was tested in a trial in which family care receiver dyads were r and omly assigned to training beginning immediately or were placed in a wait-list control group and assigned to receive training in 5 to 6 months , following completion of data collection . SETTING A community-based 14-hour training program provided in seven weekly 2-hour sessions . The training program curriculum was built on a stress and coping theory base . Recruitment and r and omization were ongoing . Programs were begun every 2 months over a two and one half-year period for a total of 16 programs . PARTICIPANTS Community health and social service agencies referred primary caregivers and at least one other family member of community-dwelling persons with dementia to participate . MEASUREMENTS Data reported in this paper were gathered from each participating family at entry to the study and 5 months later . St and ard measures of beliefs about caregiving , burden , depression , and reaction to care receiver behavior were administered to caregivers . A st and ard measure of mental status was administered to the person with dementia and st and ardized instruments were used to gather information from caregivers concerning care receivers ' behavior and abilities to perform activities of daily living ( ADLs ) . RESULTS Data were analyzed from 94 caregiver/care receiver dyads with complete sets of data . Treatment and control caregivers and care receivers were similar at baseline , and care receivers in both groups declined similarly over the 5-month period . Significant within-group improvements occurred with treatment group caregivers on measures of beliefs about caregiving ( P = .044 ) and reaction to behavior ( P = .001 ) . When outcomes were compared , treatment group caregivers were significantly different ( in the expected direction ) from those in the control group on measures of the stress mediator , beliefs ( P = .025 ) , and key outcomes , response to behavior ( P = .019 ) , depression ( P = .040 ) , and burden ( P = .051 ) . There was a significant positive association between the strengthened mediator , the caregivers ' having less-emotionally enmeshed beliefs about caregiving roles and responsibilities , and the outcome , namely improvements in burden ( P = .019 ) and depression ( P = .007 ) . CONCLUSION A caregiver training intervention focused on the work of caregiving and targeted at knowledge , skills , and beliefs benefits caregivers in important outcome dimensions . The results suggest the benefits of providing information , linkage , and role coaching to dementia family caregivers [15877554] OBJECTIVES To evaluate whether a comprehensive sleep education program ( Nighttime Insomnia Treatment and Education for Alzheimer 's Disease ( NITE-AD ) ) could improve sleep in dementia patients living at home with their family caregivers . DESIGN A r and omized , controlled trial . PARTICIPANTS Thirty-six community-dwelling patients with Alzheimer 's disease ( AD ) and their family caregivers . INTERVENTION All participants received written material s describing age- and dementia-related changes in sleep and st and ard principles of good sleep hygiene . Caregivers in active treatment ( n=17 ) received specific recommendations about setting up and implementing a sleep hygiene program for the dementia patient and training in behavior management skills . Patients in active treatment were also instructed to walk daily and increase daytime light exposure with the use of a light box . Control subjects ( n=19 ) received general dementia education and caregiver support . MEASUREMENTS Primary sleep outcomes were derived for patients and caregivers from 1 week of sleep-wake activity measured at baseline , posttest ( 2 months ) , and 6-month follow-up using an Actillume wrist-movement recorder . Secondary patient outcomes included the Epworth Sleepiness Scale , the Cornell Depression Scale , and the Revised Memory and Behavior Problem Checklist . Caregiver self-reports included the Pittsburgh Sleep Quality Index and the Center for Epidemiological Study of Depression Scale . RESULTS Patients participating in NITE-AD showed significantly greater ( P<.05 ) posttest reductions in number of nighttime awakenings , total time awake at night , and depression , and increases in weekly exercise days than control subjects . At 6-month follow-up , treatment gains were maintained , and additional significant improvements in duration of night awakenings emerged . When cognitive level was controlled , NITE-AD patients had lower longitudinal ratings of daytime sleepiness than controls . There was a trend for control subjects to spend more time in bed at 6 months than NITE-AD patients . CONCLUSION This study provides the first evidence that patients with AD who are experiencing sleep problems can benefit from behavioral techniques ( specifically , sleep hygiene education , daily walking , and increased light exposure ) that are known to improve sleep in nondemented , institutionalized older adults [19420314] PURPOSE The Tailored Activity Program ( TAP ) is a home-based occupational therapy intervention shown to reduce behavioral symptoms and caregiver burden in a r and omized trial . This article describes TAP , its assessment s , acceptability , and replication potential . DESIGN AND METHODS TAP involves 8 sessions for a period of 4 months . Interventionists identify preserved capabilities , previous roles , habits , and interests of individuals with dementia ; develop activities customized to individual profiles ; and train families in activity use . Interventionists documented time spent and ease conducting assessment s , and observed receptivity of TAP . For each implemented prescribed activity , caregivers reported the amount of time their relative spent in activity and perceived benefits . RESULTS The TAP assessment , a combination of neuropsychological tests , st and ardized performance-based observations , and clinical interviewing , yielded information on capabilities from which to identify and tailor activities . Assessment s were easy to administer , taking an average of two 1-hr sessions . Of 170 prescribed activities , 81.5 % were used , for an average of 4 times for 23 min by families between treatment sessions for a period of months . Caregivers reported high confidence in using activities , being less upset with behavioral symptoms ( 86 % ) , and enhanced skills ( 93 % ) and personal control ( 95 % ) . Interventionists observed enhanced engagement ( 100 % ) and pleasure ( 98 % ) in individuals with dementia during sessions . IMPLICATION S TAP offers families knowledge of their relative 's capabilities and easy-to-use activities . The program was well received by caregivers . Prescribed activities appeared to be pleasurable and engaging to individuals with dementia . TAP merits further evaluation to establish efficacy with larger more diverse population s and consideration as a nonpharmacological approach to manage behavioral symptoms [18179480] OBJECTIVES To examine the cost-effectiveness of a r and omized , clinical trial of a home-based intervention for caregivers of people with dementia . DESIGN This cost-effectiveness analysis examined Re sources for Enhancing Alzheimer 's Caregivers Health ( REACH II ) , a multisite , r and omized , clinical trial , from June 2002 through December 2004 , funded by the National Institute on Aging and the National Institute of Nursing Research , of a behavioral intervention to decrease caregivers ' stress and improve management of care recipient behavioral problems . SETTING Community-dwelling dementia caregiving dyads from the Memphis REACH II site . PARTICIPANTS Of Memphis ' r and om sample of 55 intervention and 57 control black and white dyads , 46 in each arm completed without death or discontinuation . Family caregivers were aged 21 and older , lived with the care recipient , and had provided 4 or more hours of care per day for 6 months or longer . Care recipients were cognitively and functionally impaired . INTERVENTION(S ) Twelve individual sessions ( 9 home sessions and 3 telephone sessions ) supplemented by five telephone support-group sessions . Control caregivers received two " check in " phone calls . MEASUREMENTS Incremental cost-effectiveness ratio ( ICER ) , the additional cost to bring about one additional unit of benefit ( hours per day of providing care ) . RESULTS At 6 months , there was a significant difference between intervention caregivers and control caregivers in hours providing care ( P=.01 ) . The ICER showed that intervention caregivers had 1 extra hour per day not spent in caregiving , at a cost of $ 5 per day . CONCLUSION The intervention provided that most scarce of caregiver commodities -- time . The emotional and physical costs of dementia caregiving are enormous , and this intervention was able to alleviate some of that cost [11885210] This study evaluated a one year long course education and counseling program with 93 family caregivers of elders afflicted with Alzheimer 's disease . The elders had received treatment for agitation in an inpatient setting and were subsequently discharged to the caregivers ' home . Caregivers were r and omly assigned to an experimental group ( n = 68 ) and a control group ( n = 25 ) . Baseline assessment s ( Time 0 ) were conducted while the elder was an inpatient . Postdischarge interventions and assessment s were conducted at 2 weeks , 6 weeks , 12 weeks , and 6 and 12 months ( Times 1 - 5 respectively ) . There were no significant treatment effects for care recipient agitation , caregiver stress , depression , and physical health , and no significant differences between groups in rates of institutionalization for afflicted elders . Longitudinal data , however , revealed several important trends . Afflicted elders ' agitation rose steadily for control group subjects at Times 3 through 5 but declined for experimental group subjects . Caregiver depression increased for control group subjects at Time 5 , but declined for experimental group subjects . Caregiver physical health declined for control group subjects at Times 4 and 5 but was maintained for experimental group subjects . A significantly higher number of afflicted elders were still at home among experimental group subjects at the end of the one year study . The difficulties in demonstrating efficacy of interventions with family caregivers of Alzheimer 's disease are discussed . Finally , the issue of data collection being perceived as support by control group subjects is evaluated [21518170] AIM Art therapy has been reported to have effects on mental symptoms in patients with dementia , and its usefulness is expected . We performed a controlled trial to evaluate the usefulness of art therapy compared with calculation training in patients with mild Alzheimer 's disease . METHODS Thirty-nine patients with Alzheimer 's disease showing slightly decreased cognitive function allowing treatment on an outpatient basis were r and omly allocated to art therapy and control ( learning therapy using calculation ) groups , and intervention was performed once weekly for 12weeks . RESULTS Comparison of the results of evaluation between before and after therapy in each group showed significant improvement in the Apathy Scale in the art therapy group ( P=0.014 ) and in the Mini-Mental State Examination score ( P=0.015 ) in the calculation drill group , but no significant differences in the other items between the two groups . Patients showing a 10 % or greater improvement were compared between the two groups . Significant improvement in the quality of life ( QOL ) was observed in the art therapy compared with the calculation training group ( P=0.038 , odds ratio , 5.54 ) . anova concerning improvement after each method revealed no significant difference in any item . CONCLUSION These results suggested improvement in at least the vitality and the QOL of patients with mild Alzheimer 's disease after art therapy compared with calculation , but no marked comprehensive differences between the two methods . In non-pharmacological therapy for dementia , studies attaching importance to the motivation and satisfaction of patients and their family members rather than the superiority of methods may be necessary in the future [17596639] Behavioral symptoms of Alzheimer 's disease , particularly agitation , appear to be a major contributing factor to the emotional distress exhibited by family caregivers . Psychosocial interventions have been shown to reduce caregiver emotional distress , but few studies have examined the efficacy of these interventions with caregivers exposed to high levels of dementia-related behavioral symptoms . The purpose of this study is to test the efficacy of a caregiver skill building intervention in reducing emotional distress to agitated behaviors of care recipients . This study analyzed data from a subgroup of caregivers who participated in a larger r and omized clinical trial ( N = 295 ) . Data from 143 caregivers of family members with baseline agitated behaviors indicate that the skill building intervention was more effective than an information and support oriented comparison condition in reducing emotional distress over an 18-month period . These findings indicate that dementia caregivers exposed to agitated behaviors can benefit from psychosocial interventions , particularly those aim ed at building behavioral management skills [11087767] Background : Treatment of agitation is a crucial problem in the care of patients with AD . Although antipsychotic and antidepressant medications and behavior management techniques ( BMT ) have each been used to treat agitation , clinical trials of these treatments have been characterized by small sample sizes and uncontrolled treatment design s. Objective : To compare haloperidol , trazodone , and BMT with placebo in the treatment of agitation in AD out patients . Methods : A total of 149 patients with AD and their caregivers participated in a r and omized , placebo-controlled , multicenter trial . Blind assessment was conducted at baseline and after 16 weeks of treatment . The three active treatments were haloperidol , trazodone , and BMT . The Alzheimer ’s Disease Cooperative Study Clinical Global Impression of Change was the primary outcome measure . Secondary outcomes included patient agitation , cognition , and function , and caregiver burden . Results : Thirty-four percent of subjects improved relative to baseline . No significant differences on outcome were obtained between haloperidol ( mean dose , 1.8 mg/d ) , trazodone ( mean dose , 200 mg/d ) , BMT , or placebo . Significantly fewer adverse events of bradykinesia and parkinsonian gait were evident in the BMT arm . No other significant difference in adverse events was seen . Symptoms did not respond differentially to the different treatments . Conclusions : Comparable modest reductions in agitation occurred in patients receiving haloperidol , trazodone , BMT , and placebo . More effective pharmacologic , nonpharmacologic , and combination treatments are needed [25067886] This study enrolled 184 middle-aged and older women ( 95 Non-Hispanic White and 89 Hispanic/Latino ) who provided in-home h and s-on care to an elderly relative with Alzheimer ’s disease or another form of dementia . Within ethnic group they were r and omly assigned to either a CBT-based small group intervention program called “ Coping with Caregiving ” ( CWC ) that taught a variety of cognitive and behavioral skills to reduce stress and depression , or to a minimal telephone based control condition ( TSC ) . Intervention lasted about 4 months ; one post-treatment assessment was completed 6 months after baseline by interviewers blind to the intervention condition . Interviews and interventions were conducted in English or Spanish by trained staff . Results indicated that those in the CWC ( regardless of ethnicity ) showed greater improvement from pre to post intervention than those in the TSC on measures of depressive symptoms , overall life stress , and caregiving-specific stress . In order to investigate if these changes may have been related to one proposed mechanism of change in CBT ( skill utilization ) , a new measure was constructed . Change in frequency of use and perceived helpfulness of adaptive coping skills were assessed in all caregivers . Results indicated that caregivers in CWC reported greater frequency of use , and greater perceived helpfulness , of these skills at post intervention compared to caregivers in the TSC . Improvement measured by dependent measures was correlated with an increase in these indices for those in the CWC . Tests for mediation suggest that effective skill utilization may mediate the effect of treatment on outcome . Implication s of these findings are discussed and recommendations provided for future research [12937333] PURPOSE This study developed and tested two 24-month primary care interventions to alleviate the psychological distress suffered by the caregivers of those with Alzheimer 's disease . The interventions , using targeted educational material s , were patient behavior management only , and patient behavior management plus caregiver stress-coping management . We hypothesized that the addition of the stress-coping component would improve caregiver outcomes . DESIGN AND METHODS A r and omized clinical trial of 167 caregiver-care recipient dyads was run , of whom 76 completed the study without bereavement or placement . RESULTS During 24 months , caregivers who received the patient behavior management component only , compared with those who also received the stress-coping component , had significantly worse outcomes for general well-being and a trend toward increased risk of depression ( i.e. , a score of > 16 on the Center for Epidemiological Studies Depression scale ) . There was a study wide improvement for bother associated with care recipient behaviors ( according to the Revised Memory and Behavior Problems Checklist ) . IMPLICATION S Our data suggest that brief primary care interventions may be effective in reducing caregiver distress and burden in the long-term management of the dementia patient . They further suggest that interventions that focus only on care recipient behavior , without addressing caregiving issues , may not be as adequate for reducing caregiver distress [19030120] Individuals with cognitive impairment , their family members , and their care providers have all identified " quality of life " as a central goal in the treatment of dementia . In this article , we identify factors that influence quality of life for individuals with cognitive impairment , review evidence -based psychosocial interventions that improve quality of life for community-residing individuals with dementia , and describe innovative ongoing r and omized clinical trials design ed to improve or maintain quality of life for individuals with mild to moderate memory problems [10396888] This 3-year r and omized clinical trial tested the effectiveness of an interdisciplinary psychoeducational family group intervention in decreasing the caregivers ' perceptions of the frequency and severity of behavioral problems in persons with dementia and their reactions to those problems , and in decreasing caregiver burden and depression . The intervention consisted of seven weekly , 2-hour multimedia training sessions that included education , family support , and skills training for 94 primary caregivers and their families . Repeated measures ANOVA was used to test for significant differences between the intervention and waiting list control groups over a 5-month period . The intervention was successful in reducing caregivers ' negative reactions to disruptive behaviors and in reducing caregiver burden over time [17986818] Objective : To test the effect of a short-term psychosocial intervention programme for family carers of patients with dementia and identify characteristics of carers and patients that responded positively . Methods : The study was a multi-centre r and omized controlled trial . Carers of 180 patients suffering from dementia recruited at 7 memory clinics at geriatric or psychiatric departments participated in the study . Carers of the intervention group were educated about dementia and in 6 group meetings taught how to use structured problem-solving . The control group received treatment as usual . The effect on patients was measured with the Neuropsychiatric Inventory and on carers with the Relatives ’ Stress Scale ( RSS ) . Results : The intention-to-treat efficacy analysis included 171 carer/patient dyads . The intervention did not have any effect on the primary outcome variables . The burden measured by the RSS increased in both groups ; however , more carers of the control group converted from a low-burden group to a medium- or high-burden group after 4.5 months . In a subgroup analysis we found a statistically significant difference in the Neuropsychiatric Inventory score in favour of the intervention group among female patients . Conclusion : The predominately negative result of this study emphasizes the need of individually tailored interventions for carers and the use of narrow inclusion criteria when performing group-based interventions , such as the extent of burden as well as gender and kinship [11346473] We investigated the usefulness of a computer-mediated interactive voice response ( IVR ) system integrated with voicemail to help family caregivers manage disruptive behaviours in people with Alzheimer 's disease . The r and omization procedure result ed in 49 caregivers being assigned to the intervention group and 51 to the control group . Using their ordinary telephone , the caregivers were linked to the four components of the IVR system : monitoring and counselling , an in-home support group , ' ask the expert ' , and a respite conversation . During an 18-month study , total system usage amounted to 55 min per user ( SD 78 , range 1 - 318 ) . Half the participants used the system for at least 22 min , and 25 % for at least 70 min . Participants made between one and 45 calls over the study period , averaging 11 calls ( SD 12 ) . Approximately half of the intervention group used the system regularly for two or more months . These ' adopters ' were significantly older , more highly educated and reported a greater sense of management of the situation than ' non-adopters ' . Adopters were much more likely than non-adopters to have been rated as highly proficient by the trainer following the technology training session . The IVR approach appealed to a subset of users . However , the overall preference was for human interaction [18453642] Theories supporting the existence of a use-dependent neuroplasticity in the older brain were used to guide this pilot study . A repeated- measures r and omized design was used to test the effectiveness of a multimodal ( Taiji exercises , cognitive-behavioral therapies , support group ) intervention on cognitive functioning , physical functioning , and behavioral outcomes in persons with dementia . The treatment group ( n = 24 persons with dementia ) participated in a 40-week intervention , with outcomes assessed at 20 and 40 weeks to assess optimal treatment length . Control group subjects ( n = 19 persons with dementia ) received attention-control educational programs . At 20 weeks , differences between groups were found for mental ability and self-esteem , with gains in balance being evident . Also , stability in depression and physical health were evident at 20 and 40 weeks for treatment group subjects . Continued improvement in outcomes was not observed at 40 weeks . However , findings support further testing of the intervention along with potential for achieving positive outcomes in early-stage dementia [2703638] Background Care for people with dementia and their informal caregivers is a challenging aim in healthcare . There is an urgent need for cost-effective support programs that prevent informal caregivers of people with dementia from becoming overburdened , which might result in a delay or decrease of patient institutionalization . For this reason , we have developed the Systematic Care Program for Dementia ( SCPD ) . The SCPD consists of an assessment of caregiver 's sense of competence and suggestions on how to deal with competence deficiencies . The efficiency of the SCPD will be evaluated in our study . Methods and design In our ongoing , cluster , r and omized , single-blind , controlled trial , the participants in six mental health services in four regions of the Netherl and s have been r and omized per service . Professionals of the ambulatory mental health services ( psychologists and social psychiatric nurses ) have been r and omly allocated to either the intervention group or the control group . The study population consists of community-dwelling people with dementia and their informal caregivers ( patient-caregiver dyads ) coming into the health service . The dyads have been clustered to the professionals . The primary outcome measure is the patient 's admission to a nursing home or home for the elderly at 12 months of follow-up . This measure is the most important variable for estimating cost differences between the intervention group and the control group . The secondary outcome measure is the quality of the patient 's and caregiver 's lives . Discussion A novelty in the SCPD is the pro-active and systematic approach . The focus on the caregiver 's sense of competence is relevant to economical healthcare , since this sense of competence is an important determinant of delay of institutionalization of people with dementia . The SCPD might be able to facilitate this with a relatively small cost investment for caregivers ' support , which could result in a major decrease in costs in the management of dementia . Implementation on a national level will be started if the SCPD proves to be efficient . Trial Registration

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### Context: [16920998] PURPOSE We assess the effects of racial or ethnic concordance between caregivers and interventionists on caregiver attrition , change in depression , and change in burden in a multisite r and omized clinical trial . DESIGN AND METHODS Family caregivers of patients with Alzheimer 's disease were r and omized to intervention or control groups at six sites from 1996 to 2000 . Interventionists provided psychosocial interventions aim ed at decreasing caregiver depression and burden . This analysis included 694 caregivers who received face-to-face interventions from 36 interventionists at five sites . We modeled caregiver loss to follow-up at 12 months and changes in depression and burden from baseline by racial or ethnic concordance by using r and om effects logistic and linear regression models , controlling for caregiver age , gender , race or ethnicity , relation to care recipient , interventionist race or ethnicity , and care recipient activities of daily living . The loss to follow-up model also controlled for care recipient institutionalization and death . RESULTS Overall , there was no difference in caregiver loss to follow-up or change in depression or burden by racial or ethnic concordance . African-American caregivers with an interventionist of the same race or ethnicity had greater decreases in depression than did African-American caregivers with interventionists of a different race or ethnicity . However , this finding has to be interpreted cautiously because there were only two African-American interventionists . IMPLICATION S Although these initial findings do not provide conclusive evidence on whether racial or ethnic concordance is associated with intervention outcomes for caregivers of Alzheimer 's disease patients , these results , along with the paucity of research studies evaluating this issue , suggest that the effects of racial or ethnic concordance in research should be systematic ally examined in future studies [2670989] Project ACT is a r and omized controlled trial design ed to test the effectiveness of a non-pharmacological home-based intervention to reduce behavioral and psychological symptoms of dementia ( BPSD ) and caregiver distress . The study targets 272 stressed racially diverse family caregivers providing in-home care to persons with moderate stage dementia with one or more behavioral disturbances . All participants are interviewed at baseline , 4-months ( main trial endpoint ) , and 6-months ( maintenance ) . The four-month intervention involves up to 13 visits from an occupational therapist who works with families to problem-solve potential triggers ( communication style , environmental clutter ) contributing to behaviors , and instruct in strategies to reduce caregiver stress and manage targeted behaviors . To rule out infection or other potential medical contributors to behaviors , a nurse obtains blood and urine sample s from the dementia patient , and conducts a medication review . Participants in the no-treatment control group are offered the nurse arm and one in-home session following trial completion at 6-months . This paper describes the research methods , theoretical and clinical aspects of this multi-component , targeted psycho-social treatment approach , and the measures used to evaluate quality of life improvements for persons with dementia and their families [21357811] BACKGROUND Based on the National Institute on Aging/National Institute of Nursing Research Re sources for Enhancing Alzheimer 's Caregiver Health ( REACH ) r and omized controlled trial ( REACH II ) , REACH VA ( Department of Veterans Affairs ) was the first national clinical translation of a proven behavioral intervention for dementia caregivers , running from September 2007 through August 2009 . This article describes the population and outcomes of the REACH VA translation of REACH II into the VA . METHODS Clinical staff members from 24 VA Medical Center Home-Based Primary Care programs in 15 states delivered the intervention to stressed caregivers of patients with dementia . Like REACH II , the 6-month REACH VA intervention , structured through a protocol and individualized through a risk assessment , targeted education , support , and skills training to address caregiving risk areas of safety , social support , problem behaviors , depression , and health through 12 individual in-home and telephone sessions and 5 telephone support group sessions . Staff members of the Memphis VA Medical Center , Memphis , Tennessee , collected data on burden , depression , health and healthy behaviors , caregiving frustrations , social support , dementia-related behaviors , and time spent providing care and on duty . RESULTS From baseline to 6 months , caregivers reported significantly decreased burden , depression , impact of depression on daily life , caregiving frustrations , and number of troubling dementia-related behaviors . A 2-hour decrease in hours per day on duty approached significance . Caregivers ( 96 % ) believed that the program should be provided by the VA to caregivers . CONCLUSIONS This clinical translation achieved outcomes similar to the REACH II r and omized controlled trial , providing clinical ly significant benefits for caregivers of a veteran with a progressive dementing disease . This model of caregiver support can inform public policy in providing assistance to caregivers [20122038] OBJECTIVES To examine the relationships between changes from baseline to post-Re sources for Enhancing Alzheimer 's Caregiver Health ( REACH ) intervention in caregiver ( CG ) self-reported health , burden , and bother . DESIGN R and omized , multisite clinical trial . SETTING CG and care recipient ( CR ) homes in five U.S. cities . PARTICIPANTS Four hundred ninety-five dementia CG and CR dyads ( 169 Hispanic , 160 white , and 166 African American ) receiving intervention and their controls . INTERVENTION CGs were assigned to the REACH intervention or a no-treatment control group . Intervention subjects received individual risk profiles and the REACH intervention through nine in-home and three telephone sessions over 6 months . Control subjects received two brief " check-in " telephone calls during this 6-month period . MEASUREMENTS The primary outcome was change in CG health status from baseline to after the intervention . Secondary outcomes were CG burden and bother after the intervention . RESULTS After the intervention , CGs reported better self-rated health , sleep quality , physical health , and emotional health , which was related to less burden and bother with their caregiving role than for CGs not receiving the intervention . Changes in depression appeared to mediate these relationships . Several racial and ethnic group differences existed in physical and emotional health , as well as in total frustration with caregiving , emotional burden , and CG-rated bother with CR 's activities of daily living and instrumental activities of daily living at baseline and at follow-up , although differences between baseline and posttest did not vary according to race . CONCLUSION A structured , multicomponent skills training intervention that targeted CG self-care behaviors as one of five target areas , improved self-reported health status , and decreased burden and bother in racially and ethnically diverse CGs of people with dementia [20810376] CONTEXT Optimal treatment to postpone functional decline in patients with dementia is not established . OBJECTIVE To test a nonpharmacologic intervention realigning environmental dem and s with patient capabilities . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve 2-group r and omized trial ( Care of Persons with Dementia in their Environments [ COPE ] ) involving patients with dementia and family caregivers ( community-living dyads ) recruited from March 2006 through June 2008 in Pennsylvania . INTERVENTIONS Up to 12 home or telephone contacts over 4 months by health professionals who assessed patient capabilities and deficits ; obtained blood and urine sample s ; and trained families in home safety , simplifying tasks , and stress reduction . Control group caregivers received 3 telephone calls and educational material s. MAIN OUTCOME MEASURES Functional dependence , quality of life , frequency of agitated behaviors , and engagement for patients and well-being , confidence using activities , and perceived benefits for caregivers at 4 months . RESULTS Of 284 dyads screened , 270 ( 95 % ) were eligible and 237 ( 88 % ) r and omized . Data were collected from 209 dyads ( 88 % ) at 4 months and 173 ( 73 % ) at 9 months . At 4 months , compared with controls , COPE patients had less functional dependence ( adjusted mean difference , 0.24 ; 95 % CI , 0.03 - 0.44 ; P = .02 ; Cohen d = 0.21 ) and less dependence in instrumental activities of daily living ( adjusted mean difference , 0.32 ; 95 % CI , 0.09 - 0.55 ; P = .007 ; Cohen d = 0.43 ) , measured by a 15-item scale modeled after the Functional Independence Measure ; COPE patients also had improved engagement ( adjusted mean difference , 0.12 ; 95 % CI , 0.07 - 0.22 ; P = .03 ; Cohen d = 0.26 ) , measured by a 5-item scale . COPE caregivers improved in their well-being ( adjusted mean difference in Perceived Change Index , 0.22 ; 95 % CI , 0.08 - 0.36 ; P = .002 ; Cohen d = 0.30 ) and confidence using activities ( adjusted mean difference , 0.81 ; 95 % CI , 0.30 - 1.32 ; P = .002 ; Cohen d = 0.54 ) , measured by a 5-item scale . By 4 months , 64 COPE dyads ( 62.7 % ) vs 48 control group dyads ( 44.9 % ) eliminated 1 or more caregiver-identified problems ( chi(2/1 ) = 6.72 , P = . 01 ) . CONCLUSION Among community-living dyads , a nonpharmacologic biobehavioral environmental intervention compared with control result ed in better outcomes for COPE dyads at 4 months . Although no group differences were observed at 9 months for patients , COPE caregivers perceived greater benefits . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00259454 [26954588] ABSTRACT Objectives : Evaluation of long-term effects of an individualized short-term telephone intervention ( seven sessions ) , based on a comprehensive cognitive behavioral therapy ( CBT ) approach . The study goal was to evaluate the maintenance of intervention effects regarding well-being , quality of life , and health at two years post treatment . Method : Participants ( n = 105 ) were ( partly ) r and omized after baseline assessment in a two-arm study ( intervention , control group/usual care ) . Depressive symptoms were assessed with the German version of the Center for Epidemiologic Studies Depression Scale ( CES-D ) . Caregivers ’ physical complaints were measured with the Gießener Beschwerdebogen ( GBB-24 ) , and quality of life with the World Health Organization quality of life -BREF ( WHOQOL-BREF ) . Emotional well-being and perceived health status were assessed using thermometer scaling . Data were analyzed by intention-to-treat analyses , including for those who terminated the intervention prematurely but still delivered data , using ANCOVAs . Results : Long-term intervention effects were found for emotional well-being ( p = 0.019 ) . For the subgroup of caregivers who were still caring at home at follow-up , the intervention led to an increased health status ( p = 0.023 ) , fewer bodily complaints ( global measure p= 0.014 , rheumatic pain p = 0.027 , heart trouble p = 0.042 ) , and a higher quality of life ( overall p = 0.044 and subscale environment p = 0.030 ) . Conclusion : The short-term CBT intervention via telephone showed long-term effects two years after treatment on emotional well-being , health status , bodily complaints , and quality of life [11220813] PURPOSE OF STUDY The authors determined short-term effects of a home environmental intervention on self-efficacy and upset in caregivers and daily function of dementia patients . They also determined if treatment effect varied by caregiver gender , race , and relationship to patient . DESIGN AND METHODS Families ( N = 171 ) of dementia patients were r and omized to intervention or usual care control group . The intervention involved 5 90-min home visits by occupational therapists who provided education and physical and social environmental modifications . RESULTS Compared with controls , intervention caregivers reported fewer declines in patients ' instrumental activities of daily living ( p = .030 ) and less decline in self-care and fewer behavior problems in patients at 3 months post-test . Also , intervention spouses reported reduced upset ( p = .049 ) , women reported enhanced self-efficacy in managing behaviors ( p = .038 ) , and women ( p = .049 ) and minorities ( p = .037 ) reported enhanced self-efficacy in managing functional dependency . IMPLICATION S The environmental program appears to have a modest effect on dementia patients ' IADL dependence . Also , among certain subgroups of caregivers the program improves self-efficacy and reduces upset in specific areas of caregiving [10222636] The goal of this study was to evaluate a community-based psychoeducational-nursing intervention design ed to teach home caregivers to manage behavioral problems of persons with Alzheimer 's disease and related dementias ( ADRD ) using the Progressively Lowered Stress Threshold ( PLST ) model , and to compare this intervention with routine information and referrals for case management , community-based services , and support groups . Previous caregiver studies have overwhelmingly pointed to the adverse effects of caregiving on the caregivers ' physical and mental health , and high prevalence rates of depression among caregivers of persons with ADRD have consistently been reported . Therefore , a primary aim was to evaluate the impact of the intervention on caregivers ' affective responses , especially depression . Data from both the Profile of Moods States and the Geriatric Depression Rating Scale support the effectiveness of this intervention in decreasing depression among caregivers who received the experimental training . Additional analysis of factors associated with caregiver depression are also reported . The pivotal role of psychiatric nurses in the assessment and treatment of depression among caregivers of persons with ADRD is discussed [23290200] OBJECTIVE To evaluate the influence of adherence to the Systematic Care Program for Dementia ( SCPD ) intervention protocol on patient and caregiver outcomes . DESIGN Data were drawn from the SCPD study -a single-blind , multicenter , cluster-r and omized , controlled trial . Multivariate regression analyses were used to assess the influence of adherence on patient and caregiver outcomes . SETTING Six community mental health services ( CMHSs ) across the Netherl and s. PARTICIPANTS Forty-eight mental health professionals treating 125 patient-caregiver dyads who were referred to the CMHS because of suspected patient dementia . INTERVENTION Training of professionals in the SCPD and its subsequent use . The SCPD consists of a systematic assessment of caregiver problems and consequent interventions . MEASUREMENTS The dependent variables were caregiver 's sense of competence , caregiver 's depressive symptoms , caregiver 's distress due to the patient 's behavioral problems , and the severity of patient 's behavioral problems . The main independent variables were adherence to the SCPD intervention protocol and the intensity of the SCPD interventions . The follow-up lasted 12 months . RESULTS Caregivers treated by adhering professionals had a better sense of competence than caregivers treated by nonadhering professionals at follow-up . No differences between intervention groups and controls were found for the other outcomes . CONCLUSION Nonadherence to the intervention protocol might be a reason for the difference found in the sense of competence between the intervention groups . Furthermore , the intensity of the SCPD might have been too low . Moreover , it might be that overburdened caregivers found it difficult to make effective use of the help offered to them . A qualitative process analysis should be executed to explore more in-depth clarifications [3398860] Objective To assess the efficacy at 12 months of an early psychosocial counselling and support programme for out patients with mild Alzheimer ’s disease and their primary care givers . Design Multicentre , r and omised , controlled , rater blinded trial . Setting Primary care and memory clinics in five Danish districts . Participants 330 out patients with mild Alzheimer ’s disease and their 330 primary care givers . Interventions Participating dyads ( patient and primary care giver ) were r and omised to control support during follow-up or to control support plus DAISY intervention ( multifaceted and semi-tailored counselling , education , and support ) . Main outcome measures Primary outcomes at 12 months for patients were change from baseline in mini mental state examination ( MMSE ) score , Cornell depression scale score , and proxy rated European quality of life visual analogue scale ( EQ-VAS ) score . For care givers , outcomes were change from baseline in geriatric depression scale ( GDS 30 items ) score and EQ-VAS score . Results Because of multiple testing , statistical significance was set at an adjusted P limit of < 0.0005 . At 12 months there were no significant differences between the two allocation groups in changes from baseline in the primary and secondary outcomes . However , although non-significant with the adjusted P limit , a small difference was observed for one of the primary patient outcomes ( Cornell depression scale score ) in patients in favour of the DAISY intervention group before and after adjusting for attrition ( P=0.0146 and P=0.0103 respectively ) . Conclusions The multifaceted , semi-tailored intervention with counselling , education , and support for patients with mild Alzheimer ’s disease and their care givers did not have any significant effect beyond that with well structured follow-up support at 12 months after adjustment for multiple comparisons . The small positive effect found in the unadjusted primary outcome addressing depressive symptoms in patients may call for further research focusing on patients with Alzheimer ’s disease and comorbid depression . Trial registration IS RCT N74848736 [11395344] OBJECTIVE To evaluate the efficacy of a brief behaviour management training programme for family carers of patients with dementia and aggressive behaviour . DESIGN A r and omized controlled trial of a four-session , community-based behaviour management programme . The primary outcome measure was the Rating Scale for Aggressive Behaviour in the Elderly . PARTICIPANTS 62 patients with dementia , and their co-resident carers . RESULTS There were no significant differences in aggression scores between behaviour management and control groups at follow-up . After adjusting for baseline differences in Rating Scale for Aggressive Behaviour in the Elderly scores , there was a trend towards a reduction in aggressive behaviour in the patients in the behaviour management group compared with those in the control group ( F = 3.37 , P = 0.071 ) . CONCLUSIONS This study adds to the small evidence base for the effectiveness of behavioural management strategies in dementia [12937336] PURPOSE Few empirical studies have compared the efficacy between psychoeducational ( skill-building ) approaches for reducing caregivers ' psychological distress and interventions modeled after typical community-based support groups . We compare the impact of two distinct interventions on Anglo and Latino caregivers of elderly relatives with dementia . DESIGN AND METHODS The change from pre assessment to post assessment ( baseline to 3 months ) for 213 female caregivers ( 122 Anglo and 91 Latino ) is presented . They were seen weekly for 10 weeks in either the Coping With Caregiving psychoeducational program ( instruction and practice in small groups to learn specific cognitive and behavioral skills ) or in the Enhanced Support Group condition ( guided discussion and empathic listening to develop reciprocal support within the group ) . Both programs were tailored to be sensitive to the cultural concerns of Anglo and Latino caregivers , and they were delivered in either English or Spanish by trained interventionists . RESULTS Overall , participants in the Coping With Caregiving condition reported a significant reduction in depressive symptoms , increased use of adaptive coping strategies , and a trend toward decreased use of negative coping strategies when compared with those in the Enhanced Support Group condition . Results were similar for both ethnic groups : there were no main effects for ethnicity , and no significant ethnicity by treatment interaction effects . IMPLICATION S This study provides empirical support that female caregivers benefit more from a skill-building approach to managing their distress than from support group membership alone . We find it very encouraging that the Latino caregivers responded well on key outcome variables , suggesting that Latinos will participate in clinical research and will benefit from their involvement when services are provided to meet their specific needs [16684985] CONTEXT Most older adults with dementia will be cared for by primary care physicians , but the primary care practice environment presents important challenges to providing quality care . OBJECTIVE To test the effectiveness of a collaborative care model to improve the quality of care for patients with Alzheimer disease . DESIGN , SETTING , AND PATIENTS Controlled clinical trial of 153 older adults with Alzheimer disease and their caregivers who were r and omized by physician to receive collaborative care management ( n = 84 ) or augmented usual care ( n = 69 ) at primary care practice s within 2 US university-affiliated health care systems from January 2002 through August 2004 . Eligible patients ( identified via screening or medical record ) met diagnostic criteria for Alzheimer disease and had a self-identified caregiver . INTERVENTION Intervention patients received 1 year of care management by an interdisciplinary team led by an advanced practice nurse working with the patient 's family caregiver and integrated within primary care . The team used st and ard protocol s to initiate treatment and identify , monitor , and treat behavioral and psychological symptoms of dementia , stressing nonpharmacological management . MAIN OUTCOME MEASURES Neuropsychiatric Inventory ( NPI ) administered at baseline and at 6 , 12 , and 18 months . Secondary outcomes included the Cornell Scale for Depression in Dementia ( CSDD ) , cognition , activities of daily living , re source use , and caregiver 's depression severity . RESULTS Initiated by caregivers ' reports , 89 % of intervention patients triggered at least 1 protocol for behavioral and psychological symptoms of dementia with a mean of 4 per patient from a total of 8 possible protocol s. Intervention patients were more likely to receive cholinesterase inhibitors ( 79.8 % vs 55.1 % ; P = .002 ) and antidepressants ( 45.2 % vs 27.5 % ; P = .03 ) . Intervention patients had significantly fewer behavioral and psychological symptoms of dementia as measured by the total NPI score at 12 months ( mean difference , -5.6 ; P = .01 ) and at 18 months ( mean difference , -5.4 ; P = .01 ) . Intervention caregivers also reported significant improvements in distress as measured by the caregiver NPI at 12 months ; at 18 months , caregivers showed improvement in depression as measured by the Patient Health Question naire-9 . No group differences were found on the CSDD , cognition , activities of daily living , or on rates of hospitalization , nursing home placement , or death . CONCLUSIONS Collaborative care for the treatment of Alzheimer disease result ed in significant improvement in the quality of care and in behavioral and psychological symptoms of dementia among primary care patients and their caregivers . These improvements were achieved without significantly increasing the use of antipsychotics or sedative-hypnotics . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00246896 [22899427] PURPOSE This study examined the efficacy of a newly developed intervention , Acquiring New Skills While Enhancing Remaining Strengths ( ANSWERS ) , for family caregivers of individuals with dementia . ANSWERS was design ed for dyads comprised of an individual with dementia and his/her family caregiver . Using a strength-based approach , ANSWERS combined educational skills ( traditionally used with caregivers ) and cognitive rehabilitation skills training ( traditionally used with individuals with dementia ) into a single protocol for addressing the dyad 's care issues and needs . Key domains addressed by the intervention included : education about dementia and memory loss ; effective communication ; managing memory ; staying active ; and recognizing emotions and behaviors . This analysis focused on outcomes for caregivers . DESIGN & METHODS The Stress Process Model guided the study 's hypotheses and design . Caregiving dyads were r and omly assigned to the control or intervention conditions . Intervention dyads received 6-curriculum guided sessions with an intervention specialist . Data came from in-person baseline interviews with caregivers conducted prior to r and omization and follow-up interviews conducted approximately 14.56 weekspost-baseline . RESULTS Intervention caregivers , compared to controls , had decreased care-related strain as indicated by lower emotional health strain , dyadic relationship strain , role captivity , and higher caregiving mastery . Additionally , intervention caregivers had improved well-being as indicated by fewer symptoms of depression and anxiety . IMPLICATION S ANSWERS was efficacious in improving key strain and psychosocial outcomes for caregivers . Features essential to the success of ANSWERS included a strength-based approach for selecting , developing , and implementing care goals , as well as teaching caregivers educational and cognitive rehabilitation skills for addressing care needs [18310553] OBJECTIVE To test whether the Tailored Activity Program ( TAP ) reduces dementia-related neuropsychiatric behaviors , promotes activity engagement , and enhances caregiver well-being . DESIGN Prospect i ve , two-group ( treatment , wait-list control ) , r and omized , controlled pilot study with 4 months as main trial endpoint . At 4 months , controls received the TAP intervention and were reassessed 4 months later . SETTING Patients ' homes . PARTICIPANTS Sixty dementia patients and family caregivers . INTERVENTION The eight-session occupational therapy intervention involved neuropsychological and functional testing , selection , and customization of activities to match capabilities identified in testing , and instruction to caregivers in use of activities . MEASUREMENTS Behavioral occurrences , activity engagement , and quality of life in dementia patients ; objective and subjective burden and skill enhancement in caregivers . RESULTS At 4 months , compared with controls , intervention caregivers reported reduced frequency of problem behaviors , and specifically for shadowing and repetitive question ing , and greater activity engagement including the ability to keep busy . Fewer intervention caregivers reported agitation or argumentation . Caregiver benefits included fewer hours doing things and being on duty , greater mastery , self-efficacy , and skill enhancement . Wait-list control participants following intervention showed similar benefits for reductions in behavioral frequency and caregiver hours doing things for the patient and mastery . Caregivers with depressed symptoms derived treatment benefits similar to nondepressed caregivers . CONCLUSIONS Tailoring activities to the capabilities of dementia patients and training families in activity use result ed in clinical ly relevant benefits for patients and caregivers . Treatment minimized trigger behaviors for nursing home placement and reduced objective caregiver burden . Noteworthy is that depressed caregivers effectively engaged in and benefited from the intervention [18814197] OBJECTIVES Dementia is a rapidly growing public health problem in low and middle income countries . There is an urgent need , in the absence of formal services , to develop interventions design ed to improve the lives of people with dementia , and their families . This study tests the effectiveness of the 10/66 caregiver intervention among people with dementia , and their carers . DESIGN A single blind parallel group r and omized controlled trial ( IS RCT N41039907 ) . SETTING Moscow . PARTICIPANTS Sixty family caregivers of people aged 65 and over with dementia were r and omized to receive the intervention and medical care as usual ( n = 30 ) or medical care as usual only ( n = 30 ) . Caregiver and person with dementia outcomes were assessed at baseline and after 6 months . INTERVENTION The caregiver education and training intervention was delivered over five , weekly , half-hour sessions and was made up of three modules : ( i ) assessment ( one session ) ; ( ii ) basic education about dementia ( two sessions ) ; and ( iii ) training regarding specific problem behaviors ( two sessions ) . MEASUREMENTS Dementia was diagnosed using DSM-IV criteria . Caregiver : Zarit Carer Burden Interview ; carer psychological distress ( SRQ 20 ) ; and carer Quality of Life ( WHOQOL-BREF ) . Person with dementia : Behavioural and Psychological symptoms ( NPI-Q ) ; quality of life ( DEMQOL ) . RESULTS Caregivers in the intervention group reported large and statistically significant net improvements at 6-month follow-up in burden compared to controls . No group differences were found on caregiver psychological distress and patient and caregiver quality of life . CONCLUSIONS The low-level intervention seems to be as , if not more , effective than similar interventions applied in high income countries [17101889] Objective : To determine the effectiveness of a counseling and support intervention for spouse caregivers in delaying time to nursing home placement of patients with Alzheimer disease ( AD ) , and identify the mechanisms through which the intervention accomplished this goal . Methods : We conducted a r and omized controlled trial of an enhanced counseling and support intervention compared to usual care . Participants were a referred volunteer sample of 406 spouse caregivers of community-dwelling patients who had enrolled in the study over a 9.5-year period . The intervention consisted of six sessions of individual and family counseling , support group participation , and continuous availability of ad hoc telephone counseling . Structured question naires were administered at baseline and at regular follow-up intervals , every 4 months for the first year and every 6 months thereafter . Cox proportional hazard models were used to test the effects of the intervention on the time to nursing home placement for the patients after controlling for multiple time-invariant and time-dependent predictors of placement . Results : Patients whose spouses received the intervention experienced a 28.3 % reduction in the rate of nursing home placement compared with usual care controls ( hazard ratio = 0.717 after covariate adjustment , p = 0.025 ) . The difference in model-predicted median time to placement was 557 days . Improvements in caregivers ’ satisfaction with social support , response to patient behavior problems , and symptoms of depression collectively accounted for 61.2 % of the intervention ’s beneficial impact on placement . Conclusion : Greater access to effective programs of counseling and support could yield considerable benefits for caregivers , patients with Alzheimer disease , and society [12143075] Providing care to a family member with dementia is conceptualized as a chronic stressor with adverse psychological and physical effects . The purpose of this pilot study was to evaluate mood and immune outcomes of caregivers exposed to a community-based psychoeducational nursing intervention based on the progressively lowered stress threshold ( PLST ) model . The PLST intervention is design ed to strengthen the psychological re sources of dementia caregivers by teaching methods of preventing and /or managing behavioral problems exhibited by the person with dementia . Mood and immune outcomes were compared between caregivers r and omly assigned to receive either the PLST or a comparison intervention . Results of this pilot study suggest that caregivers who received the PLST intervention showed significantly stronger T-cell proliferative responses to both PHA and ConA , indicating an improvement in T-cell immune function immediately after the in-home intervention ( T2 ) and again after 6 months of telephone support for application of the PLST model ( T3 ) . Findings do not support the hypothesis that the PLST intervention had a significant effect on total mood disturbance or natural killer cell cytotoxicity over the course of the study [19808841] PURPOSE The current article provides an in-depth description of a dyadic intervention for individuals with dementia and their family caregivers . Using a strength-based approach , caregiving dyads received skills training across 5 key areas : ( a ) education regarding dementia and memory loss , ( b ) effective communication , ( c ) managing memory loss , ( d ) staying active , and ( e ) recognizing emotions and behaviors . Results of the acceptability and feasibility of the intervention protocol s are also presented . DESIGN AND METHODS Caregiving dyads were r and omly assigned to participate in the intervention . Participants in the treatment condition were asked to complete a series of evaluation questions after each intervention session and an overall evaluation of the program . Data were also collected from the intervention specialists who implemented the protocol s. RESULTS Overall , the evaluation data indicated that the content and process of the intervention were viewed as highly acceptable and feasible by both participants and intervention specialists . IMPLICATION S This article highlights the merit of using a strength-based approach for working with caregiving dyads with dementia and how a single intervention protocol can be used to address the goals of both care partners . Furthermore , the intervention program was found to be highly acceptable and feasible , which is an important aspect of developing dyadic protocol [23831174] BACKGROUND / OBJECTIVES Available services and intervention programs for dementia caregivers are often underutilized because of issues such as cost , logistics , lack of knowledge about available services , or insufficient support from others . Information technologies offer the potential of removing these barriers and facilitating the ability of caregivers to access needed support . This project evaluated the feasibility and efficacy of technology-based psychosocial intervention among minority family caregivers of dementia patients . DESIGN A feasibility and efficacy trial . SETTING Participants ' homes in the Greater Miami Community . PARTICIPANTS One hundred ten ( 56 Hispanic American and 54 African American ) caregivers of patients with dementia . INTERVENTION A technology-based multi-component psychosocial intervention was delivered in-home and via videophone technology over 5 months . The intervention was modeled after the REACH II intervention and targeted known areas of caregiver risk . MEASUREMENT St and ardized measures of depression , caregiver burden , social support , and the caregivers ' perception of the caregiver 's experience were administered at baseline and 5 months post-r and omization . RESULTS Overall , caregivers who received the intervention reported a decrease in burden , an increase in perceived social support and positive perceptions of the caregiving experience . No effect was observed for depression . Most participants indicated that the intervention improved their caregiving skills and found the technology to be easy to use . CONCLUSIONS A technology-based format was feasible for delivering a multi-component intervention to minority family dementia caregivers . The intervention improved caregiver outcomes for both Hispanic and African American caregivers . The results suggest that technology may help eliminate disparities in access to caregiver intervention programs [3808080] Objective To assess whether the START ( STrAtegies for RelatTives ) intervention added to treatment as usual is cost effective compared with usual treatment alone . Design Cost effectiveness analysis nested within a pragmatic r and omised controlled trial . Setting Three mental health and one neurological outpatient dementia service in London and Essex , UK . Participants Family carers of people with dementia . Intervention Eight session , manual based , coping intervention delivered by supervised psychology graduates to family carers of people with dementia added to usual treatment , compared with usual treatment alone . Primary outcome measures Costs measured from a health and social care perspective were analysed alongside the Hospital Anxiety and Depression Scale total score ( HADS-T ) of affective symptoms and quality adjusted life years ( QALYs ) in cost effectiveness analyses over eight months from baseline . Results Of the 260 participants recruited to the study , 173 were r and omised to the START intervention , and 87 to usual treatment alone . Mean HADS-T scores were lower in the intervention group than the usual treatment group over the 8 month evaluation period ( mean difference −1.79 ( 95 % CI −3.32 to −0.33 ) ) , indicating better outcomes associated with the START intervention . There was a small improvement in health related quality of life as measured by QALYs ( 0.03 ( −0.01 to 0.08 ) ) . Costs were no different between the intervention and usual treatment groups ( £ 252 ( −28 to 565 ) higher for START group ) . The cost effectiveness calculations suggested that START had a greater than 99 % chance of being cost effective compared with usual treatment alone at a willingness to pay threshold of £ 30 000 per QALY gained , and a high probability of cost effectiveness on the HADS-T measure . Conclusions The manual based coping intervention START , when added to treatment as usual , was cost effective compared with treatment as usual alone by reference to both outcome measures ( affective symptoms for family carers , and carer based QALYs ) . Trial Registration ISCTRN [12083600] To determine if teaching caregivers behavior management techniques ( BMTs ) reduces long-term psychotropic use in Alzheimer 's disease ( AD ) patients , we examined 12-month follow-up data from a 4-month r and omized study com paring placebo , BMTs , trazodone , and haloperidol for the treatment of agitated behaviors in persons with AD . After 4 months , treatment was allowed with any agent . Between 42.8 % and 51 % of AD patients received additional psy chotropics between 4 and 12 months . The relative risk of being prescribed any psychotropic drug after the 4-month trial was at or about 1.0 for subjects in each drug arm or placebo arm versus BMTs . We concluded that teaching caregivers BMTs did not diminish long-term prescription of psychotropic drugs . ( J Geriatr Psychiatry Neurol 2002 ; 15:95 - 98 ) [12919265] BACKGROUND Over recent years multi-sensory stimulation ( MSS ) has become an increasingly popular approach to care and is used in several centres throughout Europe . This popularity could be explained by the limited alternatives available to staff and a widely held belief that MSS is a friendly and highly humane approach . A r and omized controlled trial was therefore essential to evaluate the effectiveness and extent of the benefits of MSS . AIM To assess whether MSS is more effective in changing the behaviour , mood and cognition of older adults with dementia than a control of activity ( playing card games , looking at photographs , doing quizzes , etc . ) . METHODS A total of 136 patients from three countries [ United Kingdom ( UK ) , the Netherl and s and Sweden ] were r and omized to MSS or activity groups . Patients participated in eight 30-minute sessions over 4 weeks . Ratings of behaviour and mood were taken before , during and after sessions to investigate immediate effects . Pre- , mid- , post-trial and follow-up assessment s were taken to investigate any generalization of effects to cognition and behaviour and mood at home/on the ward or at the day hospital . RESULTS There were limited short-term improvements for both the MSS and activity groups immediately after sessions , and limited short-term improvements between the groups during sessions . There were no significant differences between the groups when assessing change in behaviour , mood or cognition at home/on the ward or at the day hospital . In the UK , however , behaviour at the day hospital for both groups remained stable during the trial but deteriorated once the sessions had stopped , and active/disturbed behaviour at home improved but likewise deteriorated once sessions had stopped . CONCLUSIONS Overall , MSS was found to be no more effective than an activity in changing the behaviour , mood or cognition of patients with dementia in the short- or long-term [3092580] We studied changes in apathy among 77 community-dwelling older persons with mild memory loss in a r and omized clinical trial comparing two nonpharmacological interventions over four weeks . The study used a pre-post design with r and omization by site to avoid contamination and diffusion of effect . Interventions were offered twice weekly after baseline evaluations were completed . The treatment group received classroom style mentally stimulating activities ( MSAs ) while the control group received a structured early-stage social support ( SS ) group . The results showed that the MSA group had significantly lower levels of apathy ( P < .001 ) and significantly lower symptoms of depression ( P < .001 ) . While both groups improved on quality of life , the MSA group was significantly better ( P = .02 ) than the SS group . Executive function was not significantly different for the two groups at four weeks , but general cognition improved for the MSA group and declined slightly for the SS group which produced a significant posttest difference ( P < .001 ) . Recruitment and retention of SS group members was difficult in this project , especially in senior center locations , while this was not the case for the MSA group . The examination of the data at this four-week time point shows promising results that the MSA intervention may provide a much needed method of reducing apathy and depressive symptoms , while motivating participation and increasing quality of life [3808082] Objective To assess whether a manual based coping strategy compared with treatment as usual reduces depression and anxiety symptoms in carers of family members with dementia . Design R and omised , parallel group , superiority trial . Setting Three mental health community services and one neurological outpatient dementia service in London and Essex , UK . Participants 260 carers of family members with dementia . Intervention A manual based coping intervention comprising eight sessions and delivered by supervised psychology graduates to carers of family members with dementia . The programme consisted of psychoeducation about dementia , carers ’ stress , and where to get emotional support ; underst and ing behaviours of the family member being cared for , and behavioural management techniques ; changing unhelpful thoughts ; promoting acceptance ; assertive communication ; relaxation ; planning for the future ; increasing pleasant activities ; and maintaining skills learnt . Carers practised these techniques at home , using the manual and relaxation CDs . Main outcome measures Affective symptoms ( hospital anxiety and depression total score ) at four and eight months . Secondary outcomes were depression and anxiety caseness on the hospital anxiety and depression scale ; quality of life of both the carer ( health status question naire , mental health ) and the recipient of care ( quality of life-Alzheimer ’s disease ) ; and potentially abusive behaviour by the carer towards the recipient of care ( modified conflict tactics scale ) . Results 260 carers were recruited ; 173 were r and omised to the intervention and 87 to treatment as usual . Mean total scores on the hospital anxiety and depression scale were lower in the intervention group than in the treatment as usual group over the eight month evaluation period : adjusted difference in means −1.80 points ( 95 % confidence interval −3.29 to −0.31 ; P=0.02 ) and absolute difference in means −2.0 points . Carers in the intervention group were less likely to have case level depression ( odds ratio 0.24 , 95 % confidence interval 0.07 to 0.76 ) and there was a non-significant trend towards reduced case level anxiety ( 0.30 , 0.08 to 1.05 ) . Carers ’ quality of life was higher in the intervention group ( difference in means 4.09 , 95 % confidence interval 0.34 to 7.83 ) but not for the recipient of care ( difference in means 0.59 , −0.72 to 1.89 ) . Carers in the intervention group reported less abusive behaviour towards the recipient of care compared with those in the treatment as usual group ( odds ratio 0.47 , 95 % confidence interval 0.18 to 1.23 ) , although this was not significant . Conclusions A manual based coping strategy was effective in reducing affective symptoms and case level depression in carers of family members with dementia . The carers ’ quality of life also improved . Trial registration Current Controlled Trials ISCTRN70017938 [17116917] Context Providing care for patients with dementia can pose enormous burdens that may be eased with assistance and support . Needs may differ by race or ethnicity . Contributions The investigators r and omly assigned Hispanic , black , and white dementia caregivers to receive written educational material s or an intensive intervention to improve caregiver quality of life . The specific interventions were determined by caregivers , were delivered via trained personnel and telephone support groups , and targeted several dimensions of need . The study found that quality of life improved for Hispanic and white caregivers and for black spousal caregivers in the intervention group but not in the control group . The intervention had no detectable effect on the number of care recipients who were institutionalized . Caution s The study used only a single 6-month follow-up assessment , combined heterogeneous cultures and ethnicities into 3 groups , and excluded some ethnicities . Implication s An intensive intervention targeting several dimensions of caregiver need improved caregiver quality of life without an apparent effect on care recipient institutionalization . The effect did not differ by caregiver race or ethnicity . The Editors Caring for a family member with dementia is extremely stressful , contributes to psychiatric and physical illness , and increases the risk for death ( 1 , 2 ) . The accumulating evidence on the personal , social , and health effects of dementia caregiving has generated a broad range of intervention studies , including r and omized trials aim ed at decreasing the burden and stress of caregiving . Several studies have demonstrated statistically significant effects in reducing caregiver burden , lowering caregiver depression , and delaying institutionalization of care recipients ( 1 , 3 , 4 ) through either targeted interventions that treat a specific caregiver problem , such as depression , or broad-based multicomponent interventions that include counseling , case management , and telephone support . Persistent limitations of caregiver intervention research are the paucity of well-controlled r and omized trials , the limited range of outcomes examined , small sample sizes and insufficient power , geographic limitations , inadequate racial or ethnic variation , and a scarcity of comprehensive multicomponent interventions ( 4 ) . Indeed , none of the 41 r and omized clinical trials published in the last 5 years met Consoli date d St and ards of Reporting Trials ( CONSORT ) recommendations for reporting r and omized trials ( 5 ) , and many have serious method ologic problems that call into question the reported findings ( 4 ) . To address these limitations , the National Institute on Aging and the National Institute of Nursing Research funded a multisite research program design ed to develop and test an effective caregiver intervention : the Re sources for Enhancing Alzheimer 's Caregiver Health ( REACH ) study . We performed the study in 2 phases . In the first phase ( REACH I ) , we tested several different interventions at 6 U.S. sites to identify the most promising approaches to decreasing caregiver burden and depression ( 6 ) . Results from the study showed that active treatments were superior to control conditions in reducing caregiver burden and that active engagement in skills training statistically significantly reduced caregiver depression ( 7 , 8) . The existing literature and findings from REACH I helped guide the design of the REACH II intervention ( 7 , 8) . We based the REACH II study on the premise that caregivers can have problems in several areas at varying levels of intensity , and thus , interventions must be responsive to variations in needs among caregivers . The findings from REACH I also suggest that interventions that use active techniques , such as role-playing and interactive practice , are more effective at improving outcomes , such as depression symptoms , compared with more passive methods , such as providing information ( 7 ) . We based the REACH II intervention on these assumptions and design ed the intervention to maximize outcomes by systematic ally targeting several problem areas , tailored the intervention to respond to the needs of each individual , and actively engaged the caregiver in the intervention process . We hypothesized that participants assigned to the intervention would do better than those in the control group on several indicators of caregiver quality of life , including depression , burden , self-care , and social support and care recipient problem behaviors , and that these differences would be largest among Hispanic or Latino persons because they have lower access to support services ( 8) . In additional analyses , we assessed the effects of treatment on rates of caregiver clinical depression and care recipient institutional placement , as well as the benefits derived from study participation . Methods Caregivers Eligibility criteria for caregivers included the following : Hispanic or Latino , white or Caucasian , or black or African-American race or ethnicity ; age 21 years or older ; living with or sharing cooking facilities with the care recipient ; providing care for a relative with diagnosed Alzheimer disease or related disorders for at least 4 hours per day for at least the past 6 months ; and reported distress associated with caregiving ( reported at least 2 of the following 6 items at baseline assessment : felt overwhelmed , felt like they often needed to cry , were angry or frustrated , felt they were cut off from family or friends , reported moderate to high levels of general stress , or felt their health had declined ) . We excluded caregivers who were involved in another caregiver intervention study , who had participated in REACH I , or who had an illness that would prevent 6 months of study participation . Other requirements were logistic , including having a telephone , planning to remain in the geographic area for at least 6 months , and competency in either English or Spanish ( see Appendix Table 1 for a detailed list of exclusions ) . Appendix Table 1 . Reasons for In eligibility Care Recipients To be eligible for the study , caregivers had to confirm that their relative had diagnosed Alzheimer disease or related disorders . In addition , we screened care recipients for a history of severe mental illness , head injury , Parkinson disease , or stroke , and we administered the MiniMental State Examination ( MMSE ) ( 9 ) . We excluded patients who were bedbound with MMSE scores of 0 because we felt that our intervention had little to offer caregivers who were caring for such patients . Moreover , being bedbound is a risk factor for institutional placement or death , and we sought to exclude caregivers who were likely to transition out of the caregiving role within the 6-month study . For patients who scored more than 23 on the MMSE or had other conditions , such as head injury , we required a physician 's diagnosis of Alzheimer disease or related disorders . Procedures We recruited caregiver and care recipient dyads at 5 sites : Birmingham , Alabama ; Memphis , Tennessee ; Miami , Florida ; Palo Alto , California ; and Philadelphia , Pennsylvania . Enrollment began in June 2002 , and follow-up ended in August 2004 . Recruitment occurred in memory disorder clinics , primary care clinics , social service agencies , physician offices , churches , and community centers and by using professionally design ed brochures , public service announcements on radio stations , newspaper articles , television , targeted newsletters , and community presentations . We translated all intervention material s and assessment instruments into Spanish for the Hispanic or Latino participants by using established techniques for forward- and -back translation and allowing for regional variation in language expression . We used bilingual and bicultural staff at the 3 sites that recruited Hispanic or Latino participants : Palo Alto , Philadelphia , and Miami . At all sites , assessors and interventionists received cultural sensitivity training and were certified before entering the field . Certified assessors were blinded to group assignment of study participants . The institutional review boards of all 5 site institutions and the coordinating center in Pittsburgh , Pennsylvania , approved the study . We obtained written informed consent from all caregivers and from care recipients whenever possible . Caregivers provided consent on behalf of care recipients who could not do so on their own . After telephone screening ( n= 995 ) and baseline assessment ( n= 670 ) , we r and omly assigned participants ( n= 642 ) to the intervention or control group ( Figure ) . We stratified r and omization by using a block size of 2 or 4 within strata defined by the 5 intervention sites , 3 racial or ethnic groups ( Hispanic or Latino , white or Caucasian , and black or African American ) , and 2 caregivercare recipient relationships ( spouse or nonspouse ) . We performed r and omization at the coordinating center by using a computer-generated algorithm and a st and ard protocol for transmitting r and omization information between the coordinating center and the study sites . We administered 1 of 3 follow-up batteries , on the basis of care recipient status at follow-up ( full follow-up , bereavement battery , or placement battery ) , to study participants 6 months after r and omization when the intervention was completed . To maximize the number of individuals who could be included in the outcome analyses , we ensured that the 3 batteries were as similar as possible . We did not ask caregivers about caregiver burden and care recipient functional status if their care recipients had died ; thus , we could not include these caregivers in the primary outcome analysis ( 10 ) . Figure . Study flow diagram . * See Appendix Table 1 for reasons for in eligibility . See Appendix Table 2 ( for reasons for unavailable end points and types of 6-month follow-up . Appendix Table 2 . Reasons for Unavailable End Points and Types of 6-Month Follow-up Trial Groups Intervention The intervention involved a range of strategies : provision of [12496309] OBJECTIVES To test the efficacy of a psychoeducative group program for informal caregivers of persons with dementia . METHODS The study was a multicenter r and omized controlled trial . R and omization was stratified according to sex and kinship . Participants r and omized to the control group were referred to the traditional support groups . Participants in the study group had fifteen 2-hr weekly sessions focusing on stress appraisal and coping . Eligible participants ( primary caregivers of community-dwelling persons with dementia ) were blindly assessed before the r and omization and after 16 weeks on the following measures : frequency and reactions to behavioral problems ( primary outcome ) , burden , psychological distress , anxiety , perceived social support , and personal efficacy . RESULTS A total of 158 participants were r and omized to the study ( n = 79 ) and control ( n = 79 ) groups in 12 successive waves . Results show that study participants presented a 14 % decrease in their reactions to the behavioral problems of the care-receivers as opposed to a 5 % decrease in the control group ( p = .04 ) . The frequency of behavior problems also decreased ( p = .06 ) , as did the cross-product frequency/reaction ( p = .02 ) . There was no significant effect on the secondary outcome variables . DISCUSSION This is one of the first studies showing a significant effect of this type of support group program on the caregivers of participants with dementia [14722336] Behavioral problems are among the most challenging aspects of caring for a person with Alzheimer 's disease . A sample of 406 spouses-caregivers of patients with Alzheimer 's disease was r and omized to an active multicomponent counseling and support intervention condition or to a usual care condition . Caregivers reported on the frequency of troublesome patient behaviors and their reactions to them at baseline and at regular follow-up interviews . R and om-effects regression models over the first 4 years after r and omization revealed that , although the intervention did not affect the frequency of patient behavioral problems , it did significantly reduce caregivers ' reaction ratings . Because caregiver appraisal s have been found to mediate the impact of caregiving stress on depression and to predict nursing home placement rates , they deserve greater attention as an important target of intervention services [2881915] Background Almost all of the 820,000 people in the UK with dementia will experience Behavioural and Psychological Symptoms of Dementia ( BPSD ) . However , research has traditionally focused on treating cognitive symptoms , thus neglecting core clinical symptoms that often have a more profound impact on living with dementia . Recent evidence ( Kales et al , 2007 ; Ballard et al , 2009 ) indicates that the popular approach to managing BPSD - prescription of anti-psychotic medication - can increase mortality and the risk of stroke in people with dementia as well as impair quality of life and accelerate cognitive decline . Consequently , there is a need to evaluate the impact that non-pharmacological interventions have on BPSD ; we believe physical exercise is a particularly promising approach . Methods / Design We will carry out a pragmatic , r and omised , single-blind controlled trial to evaluate the effectiveness of exercise ( planned walking ) on the behavioural and psychological symptoms of individuals with dementia . We aim to recruit 146 people with dementia and their carers to be r and omized into two groups ; one will be trained in a structured , tailored walking programme , while the other will continue with treatment as usual . The primary outcome ( BPSD ) will be assessed with the Neuropsychiatric Inventory ( NPI ) along with relevant secondary outcomes at baseline , 6 and 12 weeks . Discussion Design ing this study has been challenging both ethically and method ologically . In particular to design an intervention that is simple , measurable , safe , non-invasive and enjoyable has been testing and has required a lot of thought . Throughout the design , we have attempted to balance method ological rigour with study feasibility . We will discuss the challenges that were faced and overcome in this paper . Trial Registration IS RCT [12937334] PURPOSE We determine the main outcome effects of a 12-month computer-mediated automated interactive voice response ( IVR ) intervention design ed to assist family caregivers managing persons with disruptive behaviors related to Alzheimer 's disease ( AD ) . DESIGN AND METHODS We conducted a r and omized controlled study of 100 caregivers , 51 in the usual care control group and 49 in the technology intervention group , who received yearlong access to an IVR-mediated system . The system provided caregiver stress monitoring and counseling information , personal voice-mail linkage to AD experts , a voice-mail telephone support group , and a distraction call for care recipients . We conducted analyses by using a repeated measures approach for longitudinal data and an intention-to-treat analytic approach . Outcomes included the caregiver 's appraisal of the bothersome nature of caregiving , anxiety , depression , and mastery at baseline , 6 , 12 , and 18 months . RESULTS There was a significant intervention effect as hypothesized for participants with lower mastery at baseline on all three outcomes : bother ( p = .04 ) , anxiety ( p = .01 ) , and depression ( p = .007 ) . Additionally , wives exhibited a significant intervention effect in the reduction of the bothersome nature of caregiving ( p = .02 ) . IMPLICATION S Wives who exhibited low mastery and high anxiety benefited the most from the automated telecare intervention . Findings suggest that , to optimize outcome effects , similar interventions should be tailored to match the users ' characteristics and preferences [18978250] OBJECTIVE To evaluate the effectiveness of a combination of cholinesterase inhibitor therapy for patients with Alzheimer disease ( AD ) and psychosocial intervention , for their spouse caregivers compared with drug treatment alone in three countries simultaneously . DESIGN R and omized controlled trial . Structured question naires were administered at baseline and at regular follow-up intervals for 24 months by independent raters blind to group assignment . SETTING Outpatient research clinics in New York City , U.S. , Manchester , U.K. and Sydney , Australia . PARTICIPANTS Volunteer sample of 158 spouse caregivers of community dwelling patients with AD . INTERVENTIONS Five sessions of individual and family counseling within 3 months of enrollment and continuous availability of ad hoc telephone counseling were provided for half the caregivers . Donepezil was prescribed for all patients . MAIN OUTCOME MEASURE Depressive symptoms of spouse caregivers measured at intake and follow-up assessment s for 24 months using Beck Depression Inventory ( revised ) . RESULTS Depression scores of caregivers who received counseling decreased over time , whereas the depression scores for caregivers who did not receive counseling increased . The benefit of the psychosocial intervention was significant after controlling for site , gender and country was not accounted for by antidepressant use and increased over 2 years even though the individual and family counseling sessions occurred in the first 3 months . CONCLUSION Effective counseling and support interventions can reduce symptoms of depression in caregivers when patients are taking donepezil . Harmonized multinational psychosocial interventions are feasible . Combined drug and supportive care approaches to the management of people with AD should be a priority [20662955] OBJECTIVES To test the effects of an intervention that helps families manage distressing behaviors in family members with dementia . DESIGN Two-group r and omized trial . SETTING In home . PARTICIPANTS Two hundred seventy-two caregivers and people with dementia . INTERVENTION Up to 11 home and telephone contacts over 16 weeks by health professionals who identified potential triggers of patient behaviors , including communication and environmental factors and patient undiagnosed medical conditions ( by obtaining blood and urine sample s ) and trained caregivers in strategies to modify triggers and reduce their upset . Between 16 and 24 weeks , three telephone contacts reinforced strategy use . MEASUREMENTS Primary outcomes were frequency of targeted problem behavior and caregiver upset with and confidence managing it at 16 weeks . Secondary outcomes were caregiver well-being and management skills at 16 and 24 weeks and caregiver perceived benefits . Prevalence of medical conditions for intervention patients were also examined . RESULTS At 16 weeks , 67.5 % of intervention caregivers reported improvement in targeted problem behavior , compared with 45.8 % of caregivers in a no-treatment control group ( P=.002 ) , and reduced upset with ( P=.03 ) and enhanced confidence managing ( P=.01 ) the behavior . Additionally , intervention caregivers reported less upset with all problem behaviors ( P=.001 ) , less negative communication ( P=.02 ) , less burden ( P=.05 ) , and better well-being ( P=.001 ) than controls . Fewer intervention caregivers had depressive symptoms ( 53.0 % ) than control group caregivers ( 67.8 % , P=.02 ) . Similar caregiver outcomes occurred at 24 weeks . Intervention caregivers perceived more study benefits ( P<.05 ) , including ability to keep family members home , than controls . Blood and urine sample s of intervention patients with dementia showed that 40 ( 34.1 % ) had undiagnosed illnesses requiring physician follow-up . CONCLUSION Targeting behaviors up setting to caregivers and modifying potential triggers improves symptomatology in people with dementia and caregiver well-being and skills [12937335] PURPOSE We developed manual-guided , replicable interventions based on common needs and cultural preferences of White and African American family caregivers ( CGs ) of individuals with dementia , and we evaluated these interventions after a 6-month follow-up . DESIGN AND METHODS We r and omly assigned White ( n = 70 ) and African American ( n = 48 ) CGs of individuals with dementia to either a skills training condition or a minimal support control condition . RESULTS The degree of treatment implementation was method ically assessed , and findings demonstrated that both interventions were delivered according to protocol and were well received by CGs . CGs in both groups reported decreasing levels of problem behaviors and appraisal s of behavioral bother , and increased satisfaction with leisure activities over time . On a measure of appraisal of distress related to behavior problems , White CGs showed more improvement in the minimal support control condition , and African American CGs showed the greatest improvements in the skills training condition . Spouse and nonspouse CGs also showed differential responses to intervention . IMPLICATION S Brief manual-guided interventions can be effective with White and African American CGs , and greater attention should be paid to possible differential responses to interventions by race and relationship to care recipient [15121650] OBJECTIVE The long-term effect of counseling and support on symptoms of depression was examined in spouse-caregivers of patients with Alzheimer 's disease . METHOD The participants were 406 spouse-caregivers of Alzheimer 's disease patients who lived at home at baseline . The caregivers were r and omly assigned to either a group receiving enhanced counseling and support treatment or a group receiving usual care ( control group ) . Caregivers in the enhanced treatment group were provided with six sessions of individual and family counseling , agreed to join support groups 4 months after enrollment , and received ongoing ad hoc counseling . The Geriatric Depression Scale was administered at baseline and at regular follow-up intervals for as long as the caregiver participated in the study . RESULTS After baseline differences were controlled for , caregivers in the enhanced treatment group had significantly fewer depressive symptoms after the intervention than did the control subjects . These effects were sustained for 3.1 years after baseline , similar across gender and patient severity level , and sustained after nursing home placement or death of the patient . CONCLUSIONS Counseling and support lead to sustained benefits in reducing depressive symptoms in spouse-caregivers of Alzheimer 's disease patients and should be widely available to provide effective , evidence -based intervention for family caregivers [23916916] Family caregivers of individuals with dementia are at heightened risk for emotional and mental health problems . Many caregivers do not seek assistance or become isolated in their caregiving role . Multi-component interventions have demonstrated efficacy for reducing emotional distress and burden , although these approaches are potentially costly and are not widely accessible . In response to these issues , we developed the Family Intervention : Telephone Tracking - Caregiver ( FITT-C ) , which is an entirely telephone-based psychosocial intervention . The purpose of this paper is to describe the study design , methodology , and baseline data for the trial . This study uses a r and omized controlled trial design to examine the efficacy of the FITT-C to reduce depressive symptoms and burden in distressed dementia caregivers . All participants ( n=250 ) received a packet of educational material s and were r and omly assigned to receive 6 months of the FITT-C intervention or non-directive telephone support . The FITT-C intervention was design ed to reduce distress in caregivers and is based on the McMaster Model of Family Functioning , transition theory , and Lazarus and Folkman 's Stress and Coping Models . The primary dependent variables were depressive symptoms ( Centers for Epidemiological Studies - Depression ) and burden ( Zarit Burden Interview , Revised Memory and Behavior Problems Checklist - Reaction ) . Secondary outcome measures included family functioning , self-efficacy , and health-related quality of life . Results of the study will provide important data about the efficacy of a telephone-based approach to reduce distress in dementia caregivers [12464756] Background Eighty percent of persons with Alzheimer ’s disease and related disorders are cared for by family members who often lack adequate support and training for this all-consuming job . Objective To evaluate the efficacy of a longitudinal , multisite , community-based intervention design ed to teach home caregivers to manage behavioral problems in persons with Alzheimer ’s disease . Methods Usable data were analyzed from 237 caregiver/care recipient dyads ( n = 132 Experimental;n = 105 Comparison ) . The experimental group received a psychoeducational nursing intervention that was conceptually grounded in the Progressively Lowered Stress Threshold model ( Hall & Buckwalter , 1987 ) . The comparison group received routine information and referrals for case management , community-based services , and support groups . Although a variety of psychosocial outcomes were compared between caregivers in the two groups , this article focuses on frequency and response to behavioral problems and functional decline . Results The Progressively Lowered Stress Threshold intervention had a statistically significant effect on spousal response to memory/behavioral problems ( p < .01 ) for all caregivers and on response to activities of daily living problems ( p < .01 ) for spousal caregivers . In addition , nonspouses in the experimental group reported a reduction in the frequency of memory/behavioral problems ( p < .01 ) . No intervention effect on reports of activities of daily living frequencies was found for either spouses or nonspouses . Conclusions This Progressively Lowered Stress Threshold-based intervention had a positive impact on both the frequency of and response to problem behaviors among spousal caregivers [21797835] OBJECTIVES To test the effects of walking , light exposure , and a combination intervention ( walking , light , and sleep education ) on the sleep of persons with Alzheimer 's disease ( AD ) . DESIGN R and omized , controlled trial with blinded assessors . SETTING Independent community living . PARTICIPANTS One hundred thirty-two people with AD and their in-home caregivers . INTERVENTIONS Participants were r and omly assigned to one of three active treatments ( walking , light , combination treatment ) or contact control and received three or six in-home visits . MEASUREMENTS Primary outcomes were participant total wake time based on wrist actigraphy and caregiver ratings of participant sleep quality on the Sleep Disorders Inventory ( SDI ) . Secondary sleep outcomes included additional actigraphic measurements of sleep percentage , number of awakenings , and total sleep time . RESULTS Participants in walking ( P=.05 ) , light ( P=.04 ) , and combination treatment ( P=.01 ) had significantly greater improvements in total wake time at posttest ( effect size 0.51 - 0.63 ) than controls but no significant improvement on the SDI . Moderate effect size improvements in actigraphic sleep percentage were also observed in active treatment participants . There were no significant differences between the active treatment groups and no group differences for any sleep outcomes at 6 months . Participants with better adherence ( 4 d/wk ) to walking and light exposure recommendations had significantly less total wake time ( P=.006 ) and better sleep efficiency ( P=.005 ) at posttest than those with poorer adherence . CONCLUSION Walking , light exposure , and their combination are potentially effective treatments for improving sleep in community-dwelling persons with AD , but consistent adherence to treatment recommendations is required [16326662] PURPOSE We investigated whether community consultants could be trained to teach family caregivers a systematic behavioral approach for reducing mood and behavior problems in persons with Alzheimer 's disease . DESIGN AND METHODS This study consisted of a r and omized controlled trial ; we r and omly assigned 95 family caregivers and care recipients with Alzheimer 's disease to STAR-caregivers ( STAR-C ) or control groups . Masked interviewers conducted assessment s at baseline , after treatment , and after 6 months . Consultants were master's-level health care professionals who were currently practicing in community setting s serving older adults . We assessed the extent to which consultants were able to learn and adhere to the treatment protocol , and the relationship between adherence and measures of caregiver mood , burden , and care recipient mood and behavior . RESULTS Community consultants were able to learn and adhere to the behavioral treatment protocol . Caregivers receiving STAR-C training showed significant improvements in depression , burden , and reactivity to behavior problems in the care recipient . There were also significant reductions in the frequency and severity of care recipient behavior problems , and improved quality of life . Results were maintained at 6-month follow-up . IMPLICATION S Community-based consultants successfully implemented a behavioral intervention with family caregivers of persons with Alzheimer 's disease . Consequently , STAR-C seems to be a practicable and reasonable evidence d-based approach to caregiver training in actual clinical setting [25698766] BACKGROUND Anxiety is common and problematic in dementia , yet there is a lack of effective treatments . AIMS To develop a cognitive-behavioural therapy ( CBT ) manual for anxiety in dementia and determine its feasibility through a r and omised controlled trial . METHOD A ten-session CBT manual was developed . Participants with dementia and anxiety ( and their carers ) were r and omly allocated to CBT plus treatment as usual ( TAU ) ( n = 25 ) or TAU ( n = 25 ) . Outcome and cost measures were administered at baseline , 15 weeks and 6 months . RESULTS At 15 weeks , there was an adjusted difference in anxiety ( using the Rating Anxiety in Dementia scale ) of ( -3.10 , 95 % CI -6.55 to 0.34 ) for CBT compared with TAU , which just fell short of statistical significance . There were significant improvements in depression at 15 weeks after adjustment ( -5.37 , 95 % CI -9.50 to -1.25 ) . Improvements remained significant at 6 months . CBT was cost neutral . CONCLUSIONS CBT was feasible ( in terms of recruitment , acceptability and attrition ) and effective . A fully powered RCT is now required [24338799] OBJECTIVE The objective of this study is to evaluate the effectiveness of a simple dyadic ( person with dementia and their main carer ) exercise regimen as a therapy for the behavioural and psychological symptoms of dementia . METHOD A two arm , pragmatic , r and omised , controlled , single-blind , parallel-group trial of a dyadic exercise regimen ( individually tailored walking regimen design ed to become progressively intensive and last between 20 - 30 min , at least five times per week).Community-dwelling individuals with ICD-10 confirmed dementia with the following : clinical ly significant behavioural and psychological symptoms , a carer willing and able to co-participate in the exercise regimen , and no physical conditions or symptoms that would preclude exercise participation were invited by mental health or primary care services into the study . RESULTS One hundred and thirty-one dyads were recruited to this study . There was no significant difference in Behavioural and Psychological Symptoms as measured by the Neuropsychiatric Inventory at week 12 between the group receiving the dyadic exercise regimen and those that did not ( adjusted difference in means ( intervention minus control ) = -1.53 , p = 0.6 , 95 % CI [ -7.37 , 4.32 ] ) . There was a significant between-group difference in caregiver 's burden as measured by the Zarit Caregiver Burden Inventory at week 12 ( OR = 0.18 , p = 0.01 , CI [ 0.05 , 0.69 ] ) favouring the exercise group . CONCLUSIONS This study found that regular simple exercise does not appear to improve the behavioural and psychological symptoms of dementia , but did seem to attenuate caregiver burden . Further study to improve exercise uptake are needed [21196773] Background : There is a lack of appropriately design ed trials investigating the efficacy of psychosocial interventions for patients with mild dementia and their family caregivers . This paper reports the rationale and design of the Danish Alzheimer Disease Intervention Study and baseline characteristics of the cohort . Methods : The study was a 1-year multicentre r and omized controlled rater-blinded trial with r and omization to follow-up and a multifaceted semitailored intervention programme or to follow-up only ( with extension of follow-up to 3 years ) . The intervention included a counselling programme , teaching courses , written information and logbooks . The outcomes included clinical efficacy parameters , patient satisfaction and health economic consequences . Results : A total of 330 patients and their 330 caregivers were included during a period of 18 months . The majority ( 65.2 % ) of the caregivers were spouses . At inclusion the mean age of the patients and caregivers was 76.2 and 66.0 years , respectively . Conclusion : The study will explore the added value of a multifaceted intervention programme and contribute to the design of future interventions for patients with mild dementia and their caregivers [20425645] Prior research ( Gallagher-Thompson , D. , Gray , H. , Tang , P. , Pu , C.-Y. , Tse , C. , Hsu , S. , et al. ( 2007 ) . Impact of in-home intervention versus telephone support in reducing depression and stress of Chinese caregivers : Results of a pilot study . American Journal of Geriatric Psychiatry , 15 , 425–434 . ) found that an in-home behavioral management program , derived conceptually from cognitive behavioral theories ( CBT ) , was effective in reducing caregiver related stress and depressive symptoms in Chinese American dementia caregivers ( CGs ) . Results were promising , but a more cost-effective intervention is needed to serve this growing population . Past work also found that a psychoeducational videotaped training program based on CBT was effective in reducing stress due to caregiving in Caucasian and African American dementia family CGs ( Steffen , 2000 , Anger management for dementia caregivers : A preliminary study using video and telephone interventions . Behavior Therapy , 31 , 281–299 . ) . To date no research has been conducted using a technological medium to deliver a similar kind of intervention to Chinese American caregivers . The present study evaluated the effectiveness of a similar but culturally “ tailored ” program in which 70 CGs were r and omly assigned to a 12-week CBT skill training program delivered on a DVD , or to a general educational DVD program on dementia . Both were available in M and arin Chinese or English as preferred . Pre post change analyses indicated that CGs did not differ on change in level of negative depressive symptoms , but positive affect was higher , and patient behaviors were appraised as less stressful and bothersome , for CGs in the CBT skill training program . They were also more satisfied with the program overall and reported that they believed they were able to give care more effectively . Results encourage further development of theoretically based interventions , delivered using modern technology , for this ever increasing group of CGs [19582757] OBJECTIVES We reported the findings of a r and omized controlled trial ( RCT ) to examine the effects of an individualized functional enhancement program ( FEP ) on functional skills and mood symptoms in mild and moderate dementia . SUBJECTS & METHODS 74 Chinese older persons with dementia were recruited into a skills training program by occupational therapists ( OT ) . Thirty seven subjects were trained with an individualized selection of daily activities ( FEP Intervention , I ) ; 37 were trained with general occupational therapy ( Control , C ) . The FEP comprised of twice weekly group sessions of skills training and problem solving using cognitive behavioral approach . RESULTS At 1 month after completion of program , both I and C subjects showed an improvement in process skills of the assessment of motor and process skills (AMPS)(paired t-tests , p < 0.05 ) . At 4 months post-program , the I group showed a further reduction of cornell scale for depression in dementia ( CSDD ) scores ( paired t-test , p = 0.02 ) ; Apathy improved at 1 month post-training ( p = 0.04 ) , but deteriorated at 4 months ( p = 0.01 ) . Group differences in changes of mood and functional scores were not significant ( ANVOCA , p > 0.05 ) . CONCLUSIONS The findings suggested a potential benefit for individualized occupational therapy . It should be tailor made with individual needs and continued for sustained effectiveness [12937331] PURPOSE The majority of persons with Alzheimer 's disease ( AD ) are cared for at home by a family member such as a spouse or daughter . Caregiving places enormous dem and s on these caregivers , and the negative consequences associated with caregiving are well documented . This paper reports results from the Miami site of the REACH ( Re sources for Enhancing Alzheimer 's Caregiver Health ) program that examined the efficacy of a family therapy and technology-based intervention in reducing depressive symptoms ( according to the Center for Epidemiological Studies Depression scale ) among family caregivers of AD patients at 6 months and 18 months follow-up . DESIGN AND METHODS There were 225 White American and Cuban American caregivers that were r and omized into a structural ecosystems therapy , structural ecosystems therapy + computer-telephone integrated system , or minimal support control condition . RESULTS Caregivers in the combined family therapy and technology intervention experienced a significant reduction in depressive symptoms at 6 months . The 18-month follow-up data indicated that the intervention was particularly beneficial for Cuban American husb and and daughter caregivers . IMPLICATION S The results indicate that information technology has a promising role in alleviating distress and depression among groups of AD caregivers . The data also demonstrate that interventions have differential impacts according to ethnic group and the caregiver-patient relationship [17804831] OBJECTIVE The objective of this study was to determine the effects of counseling and support on the physical health of caregivers of spouses of people with Alzheimer disease . METHODS A r and omized controlled trial , conducted between 1987 and 2006 at an outpatient research clinic in the New York City metropolitan area compared outcomes of psychosocial intervention to usual care . Structured question naires were administered at baseline and regular follow-ups . A referred volunteer sample of 406 spouse caregivers of community dwelling patients with Alzheimer disease enrolled over a 9.5-year period . Enhanced counseling and support consisted of six sessions of individual and family counseling , support group participation , and continuous availability of ad-hoc telephone counseling . Indicators of physical health included self-rated health ( SRH ) of caregivers and the number of reported illnesses . RESULTS Controlling for baseline SRH ( mean : 7.24 ) , intervention group caregivers had significantly better SRH than control group caregivers based upon model predicted mean scores four months after baseline ( 6.87 versus 7.21 ) , and this significant difference was maintained for two years ( 6.70 versus 7.01 ) . The effect of the intervention on SRH remained significant after controlling for the effects of patient death , nursing home placement , caregiver depressive symptoms and social support satisfaction . Similar benefits of intervention were found for number of illnesses . CONCLUSION Counseling and support preserved SRH in vulnerable caregivers . Enhancing caregivers ' social support , fostering more benign appraisal s of stressors , and reducing depressive symptoms may yield indirect health benefits . Psychosocial intervention studies with biological measures of physical health outcomes are warranted [15860476] BACKGROUND Few studies evaluate whether short-term intervention effects are maintained over time for families caring for persons with dementia . This article examines whether treatment effects found at 6 months following active treatment were sustained at 12 months for 127 family caregivers who participated in an occupational therapy intervention tested as part of the National Institutes of Health Re sources for Enhancing Alzheimer 's Caregiver Health ( REACH ) initiative . METHODS A r and omized two-group design was implemented with three assessment points : baseline , 6 months , and 12 months . Caregivers were r and omly assigned to a usual care control group or intervention that consisted of six occupational therapy sessions to help families modify the environment to support daily function of the person with dementia and reduce caregiver burden . Following 6-month active treatment , a maintenance phase consisted of one home and three brief telephone sessions to reinforce strategy use and obtain closure . Non-inferiority statistical analysis was used to evaluate whether intervention caregivers maintained treatment benefits from 6 to 12 months in comparison to controls . RESULTS For the sample of 127 at 6 months , caregivers in intervention reported improved skills ( p = .028 ) , less need for help providing assistance ( p = .043 ) , and fewer behavioral occurrences ( p = .019 ) compared to caregivers in control . At 12 months , caregiver affect improved ( p = .033 ) , and there was a trend for maintenance of skills and reduced behavioral occurrences , but not for other outcome measures . CONCLUSION An in-home skills training program helps sustain caregiver affect for those enrolled for more than 1 year . More frequent professional contact and ongoing skills training may be necessary to maintain other clinical ly important outcomes such as reduced upset with behaviors [18378844] OBJECTIVES This study tested the effectiveness of a dementia care management program for Chinese families of relatives with dementia on caregivers ' and patients ' health outcomes over a 12-month follow-up period . METHODS The dementia care management program is an educational and supportive group for caregivers that lasts six months . A controlled trial was conducted with 88 primary caregivers of persons with dementia in two dementia care centers in Hong Kong . Family members were assigned r and omly to either the dementia care program or st and ard care . The two groups were compared for patients ' symptoms and institutionalization rates and caregivers ' quality of life , burden , and social support upon recruitment and six and 12 months after group assignment . RESULTS Over the 12-month follow-up period , patients with family members in the dementia care program showed significantly greater improvements in symptoms and institutionalization rates and their caregivers reported significantly greater improvements in quality of life and burden compared with the control group . CONCLUSIONS The findings provide evidence that the dementia care management program can improve the psychosocial functioning of Chinese persons with dementia and their caregivers [21358385] OBJECTIVE To evaluate the effectiveness of the Systematic Care Program for Dementia ( SCPD ) on patient institutionalization and to determine the predictors of institutionalization . DESIGN Single-blind , multicenter , cluster-r and omized , controlled trial . SETTING Six community mental health services ( CMHSs ) across the Netherl and s. PARTICIPANTS A total of 295 patient-caregiver dyads referred to a CMHS with suspected patient dementia . INTERVENTION Training of health professionals in the SCPD and its subsequent use . The SCPD consists of a systematic assessment of caregiver problems and alerts health professionals in flexible , connecting , proactive interventions to them . The intensity of the SCPD depends on the judgment of the health professional , based on individual caregiver needs . PRIMARY OUTCOME Institutionalization in long-term care facilities at 12 months of follow-up . RESULTS No main intervention effect on institutionalization was found . However , a better sense of competence in the control group reduced the chance of institutionalization but not in the intervention group . The caregiver 's sense of competence and depressive symptoms and the patient 's behavioral problems and severity of dementia were the strongest predictors of institutionalization . The intensity of the program was low , even for dyads exposed to the SCPD . CONCLUSIONS Although no main effect was found , the results suggest that the SCPD might prevent a deterioration of the sense of competence in the intervention group . The intensity of a program is crucial and should be prescribed on the basis of evidence rather than left to the discretion of health professionals . Future controlled trials in daily clinical practice should use a process analysis to control for compliance [24617278] The purpose of this study was to determine if telephone support groups for dementia caregivers have an effect on bother with patient behaviours , burden , depression , and general well-being . The r and omized controlled trial compared telephone support groups ( 15 groups of 5 or 6 caregivers ) with control groups ( print material s ) . Groups met 14 times over 1 year . The 1-hour sessions included content on education , coping skills , and support . Data were collected at baseline and at 6 and 12 months . The sample comprised 154 caregivers , 77 per arm , providing care to veterans with dementia or a veteran caregiver . Bother was found to differ significantly at baseline . There were no significant treatment effect differences between study arms . Participants anecdotally reported improvement . It was concluded that telephone support groups are an efficient way to interact with caregivers . Further research should test different models of care . Interventions that are targeted to specific needs or occur frequently may provide better support for caregivers of individuals with a worsening condition [11317951] OBJECTIVES To investigate short-term effects of Multi-Sensory Stimulation ( MSS ) on behaviour , mood and cognition of older adults with dementia , the generalization of effects to day hospital and home environments and the endurance of any effects over time . DESIGN A r and omized controlled trial comparing MSS with a credible control of one-to-one activities . METHODS Fifty patients with diagnoses of moderate to severe dementia were r and omized to either MSS or Activity groups . Patients participated in eight 30-minute sessions over a 4-week period . Ratings of behaviour and mood were taken before , during and after sessions to investigate immediate effects . Pre , mid , post-trial , and follow-up assessment s were taken to investigate any generalization of effects on cognition , behaviour at the day hospital and behaviour and mood at home and endurance of effects once sessions had ceased . RESULTS Immediately after MSS and Activity sessions patients talked more spontaneously , related better to others , did more from their own initiative , were less bored/inactive , and were more happy , active or alert . Both groups were more attentive to their environment than before , with a significantly greater improvement from the MSS group . At the day hospital , patients in the Activity group improved on their ' speech skills ' ( amount of speech ; initiation of speech ) , whereas the MSS group remained unchanged during the trial . The MSS group showed a significant improvement in mood and behaviour at home compared to the Activity group whose behaviour deteriorated . No longer-term benefits were shown ; indeed , behaviour declined sharply during the month follow-up period . CONCLUSIONS Both MSS and Activity sessions appear to be effective and appropriate therapies for people with dementia [3840334] Objectives To examine the long-term efficacy at the 36-month follow-up of an early psychosocial counselling and support programme lasting 8–12 months for community-dwelling patients with mild Alzheimer 's disease and their caregivers . Design Multicentre , r and omised , controlled , rater-blinded trial . Setting Primary care and memory clinics in five Danish districts . Participants 330 home-dwelling patients with mild Alzheimer 's disease and their primary caregivers ( dyads ) . Interventions Dyads were r and omised to receive intervention during the first year after diagnosis . Both intervention and control groups had follow-up visits at 3 , 6 , 12 and 36 months . Main outcome measures Primary outcomes for the patients assessed at 36-month follow-up were changes from baseline in global cognitive function ( Mini-Mental State Examination ) , depressive symptoms ( Cornell Depression Scale ) and proxy-rated EuroQoL quality of life on visual analogue scale . The primary outcomes for the caregivers were changes from baseline in depressive symptoms ( Geriatric Depression Scale ) and self-rated EuroQoL quality of life on a visual analogue scale . The secondary outcome measures for the patient were proxy-rated Quality of Life Scale for Alzheimer 's disease ( QoL-AD ) , Neuropsychiatric Inventory- Question naire , Alzheimer 's disease Cooperative Study Activities of Daily Living Scale , all-cause mortality and nursing home placement . Results At a 36-month follow-up , 2 years after the completion of the Danish Alzheimer Intervention Study ( DAISY ) , the unadjusted positive effects previously detected at the 12-month follow-up in one patient primary outcome ( Cornell depression score ) and one patient secondary outcome ( proxy-rated QoL-AD ) disappeared ( Cornell depression score , p=0.93 ; proxy-rated QoL-AD , p=0.81 ) . No long-term effect of DAISY intervention on any other primary and secondary outcomes was found at the 36-month follow-up . Conclusions For patients with very mild Alzheimer 's disease and their caregivers , an intensive , multi-component , semitailored psychosocial intervention programme with counselling , education and support during the first year after diagnosis did not show any positive long-term effect on primary and secondary outcomes . Trial registration The study was registered in the Clinical Trial Data base ( http://www.controlled-trials.com/IS RCT N74848736 ) [20228893] The objective of this study was to examine the preliminary efficacy of Family Intervention : Telephone Tracking — Dementia ( FITT-D ) , a multi-component intervention that is delivered in 23 telephone contacts over 12 months . Thirty-three dementia caregivers were r and omly assigned to receive either FITT-D ( n = 16 ) or st and ard care ( n = 17 ) using urn r and omization to balance the groups on dementia severity , caregiver gender and relationship type ( spouse versus other ) . Inclusion criteria included formal dementia diagnosis , caregiving for at least six months , residing with the care recipient , and providing at least four hours of direct supervision per day . Master's-level therapists contacted caregivers by telephone over 12 months . Each contact followed a st and ardized treatment manual , involving assessment and individualized application of interventions to address mood , family functioning , social support and health . Outcomes included Zarit Burden Interview , Revised Memory and Behavior Problem Checklist , and the Geriatric Depression Scale at baseline and 12 months ( end of treatment ) . Caregivers receiving FITT-D exhibited significantly lower burden scores and less severe reactions to memory and behavior problems than caregivers in the st and ard care condition . Findings provide preliminary evidence for the efficacy of FITT-D , a potentially highly accessible , low-cost intervention for dementia caregivers [20602013] OBJECTIVE There is a need , in the absence of formal services , to design interventions aim ed at improving the lives of people with dementia and their families . This study tested the effectiveness of the 10/66 caregiver intervention among people with dementia and their caregivers in Lima , Peru . METHOD DESIGN / PARTICIPANTS a r and omized controlled trial was performed involving 58 caregivers of people with dementia that received the intervention in the beginning of the trial ( n = 29 ) or six months later ( n = 29 ) . The intervention consisted of three modules : 1 ) assessment ( one session ) ; 2 ) basic education about dementia ( two sessions ) ; and 3 ) training regarding specific problem behaviors ( two sessions ) . MAIN OUTCOME MEASURES Caregivers and patients with dementia were assessed at baseline and after six months . For caregivers , the measures included strain ( Zarit Burden Interview ) , psychological distress ( SRQ-20 ) , and quality of life ( WHOQOL-BREF ) . Dementia patients completed scales assessing behavioral and psychological symptoms ( NPI-Q ) and quality of life ( DEMQOL ) . RESULTS Caregivers in the intervention group reported significantly decreased strain measures six months after the intervention compared to controls . No group differences were found in respect to the caregivers ' psychological distress and to quality of life in both caregivers and patients . CONCLUSION The 10/66 intervention seems to be as effective as similar interventions used in more developed countries [14559955] CONTEXT Exercise training for patients with Alzheimer disease combined with teaching caregivers how to manage behavioral problems may help decrease the frailty and behavioral impairment that are often prevalent in patients with Alzheimer disease . OBJECTIVE To determine whether a home-based exercise program combined with caregiver training in behavioral management techniques would reduce functional dependence and delay institutionalization among patients with Alzheimer disease . DESIGN , SETTING , AND PATIENTS R and omized controlled trial of 153 community-dwelling patients meeting National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer Disease and Related Disorders Association criteria for Alzheimer disease , conducted between June 1994 and April 1999 . INTERVENTIONS Patient-caregiver dyads were r and omly assigned to the combined exercise and caregiver training program , Reducing Disability in Alzheimer Disease ( RDAD ) , or to routine medical care ( RMC ) . The RDAD program was conducted in the patients ' home over 3 months . MAIN OUTCOME MEASURES Physical health and function ( 36-item Short-Form Health Survey 's [ SF-36 ] physical functioning and physical role functioning subscales and Sickness Impact Profile 's Mobility subscale ) , and affective status ( Hamilton Depression Rating Scale and Cornell Depression Scale for Depression in Dementia ) . RESULTS At 3 months , in comparison with the routine care patients , more patients in the RDAD group exercised at least 60 min/wk ( odds ratio [ OR ] , 2.82 ; 95 % confidence interval [ CI ] , 1.25 - 6.39 ; P = .01 ) and had fewer days of restricted activity ( OR , 3.10 ; 95 % CI , 1.08 - 8.95 ; P<.001 ) . Patients in the RDAD group also had improved scores for physical role functioning compared with worse scores for patients in the RMC group ( mean difference , 19.29 ; 95 % CI , 8.75 - 29.83 ; P<.001 ) . Patients in the RDAD group had improved Cornell Depression Scale for Depression in Dementia scores while the patients in the RMC group had worse scores ( mean difference , -1.03 ; 95 % CI , -0.17 to -1.91 ; P = .02 ) . At 2 years , the RDAD patients continued to have better physical role functioning scores than the RMC patients ( mean difference , 10.89 ; 95 % CI , 3.62 - 18.16 ; P = .003 ) and showed a trend ( 19 % vs 50 % ) for less institutionalization due to behavioral disturbance . For patients with higher depression scores at baseline , those in the RDAD group improved significantly more at 3 months on the Hamilton Depression Rating Scale ( mean difference , 2.21 ; 95 % CI , 0.22 - 4.20 ; P = .04 ) and maintained that improvement at 24 months ( mean difference , 2.14 ; 95 % CI , 0.14 - 4.17 ; P = .04 ) . CONCLUSION Exercise training combined with teaching caregivers behavioral management techniques improved physical health and depression in patients with Alzheimer disease [19606455] OBJECTIVE To evaluate a case management ( CM ) model for people with mild dementia , whereby re sources within the family and in the community were mobilized and optimally used . METHOD Community dwelling psychiatric and geriatrics out patients with mild dementia were r and omized to receive CM by a trained occupational therapist for 4 months ( CM group , N = 59 ) or usual care only ( control group , N = 43 ) . Primary outcome indicators included the Zarit Burden Scale ( ZBI ) , General Health Question naire ( GHQ ) , and Personal Well-Being Index for Adult ( PWI-A ) of the family caregivers . Secondary outcome indicators included the Mini-Mental State Examination ( MMSE ) , Neuropsychiatric Inventory ( NPI ) , Cornell Scale for Depression in Dementia ( CSDD ) , and Personal Well-Being Index for Intellectually Disabled ( PWI-ID ) of the demented subjects as measured at fourth and twelfth months . RESULT CSDDis reduced in the CM group at fourth month , but not at twelfth month . The changes in outcome variables of persons with dementia did not differ between the groups ( Mann-Whitney U-test , p > 0.05 ) . At follow-up , CM group used more day care and domestic helpers than control group ( chi ( 2 ) , p > 0.05 ) . CONCLUSION Case management for Chinese persons with mild dementia out patients did not show significant effects in reducing caregiver burden , but encouraged family caregivers to seek external support [11347790] OBJECTIVES Family caregiving is an integral part of the care system for persons with dementing disorders , such as Alzheimer 's disease . This study tested role-training intervention as a way to help family caregivers appreciate and assume a more clinical belief set about caregiving and thereby ameliorate the adverse outcomes associated with caregiving . DESIGN Training effectiveness was tested in a trial in which family care receiver dyads were r and omly assigned to training beginning immediately or were placed in a wait-list control group and assigned to receive training in 5 to 6 months , following completion of data collection . SETTING A community-based 14-hour training program provided in seven weekly 2-hour sessions . The training program curriculum was built on a stress and coping theory base . Recruitment and r and omization were ongoing . Programs were begun every 2 months over a two and one half-year period for a total of 16 programs . PARTICIPANTS Community health and social service agencies referred primary caregivers and at least one other family member of community-dwelling persons with dementia to participate . MEASUREMENTS Data reported in this paper were gathered from each participating family at entry to the study and 5 months later . St and ard measures of beliefs about caregiving , burden , depression , and reaction to care receiver behavior were administered to caregivers . A st and ard measure of mental status was administered to the person with dementia and st and ardized instruments were used to gather information from caregivers concerning care receivers ' behavior and abilities to perform activities of daily living ( ADLs ) . RESULTS Data were analyzed from 94 caregiver/care receiver dyads with complete sets of data . Treatment and control caregivers and care receivers were similar at baseline , and care receivers in both groups declined similarly over the 5-month period . Significant within-group improvements occurred with treatment group caregivers on measures of beliefs about caregiving ( P = .044 ) and reaction to behavior ( P = .001 ) . When outcomes were compared , treatment group caregivers were significantly different ( in the expected direction ) from those in the control group on measures of the stress mediator , beliefs ( P = .025 ) , and key outcomes , response to behavior ( P = .019 ) , depression ( P = .040 ) , and burden ( P = .051 ) . There was a significant positive association between the strengthened mediator , the caregivers ' having less-emotionally enmeshed beliefs about caregiving roles and responsibilities , and the outcome , namely improvements in burden ( P = .019 ) and depression ( P = .007 ) . CONCLUSION A caregiver training intervention focused on the work of caregiving and targeted at knowledge , skills , and beliefs benefits caregivers in important outcome dimensions . The results suggest the benefits of providing information , linkage , and role coaching to dementia family caregivers [15877554] OBJECTIVES To evaluate whether a comprehensive sleep education program ( Nighttime Insomnia Treatment and Education for Alzheimer 's Disease ( NITE-AD ) ) could improve sleep in dementia patients living at home with their family caregivers . DESIGN A r and omized , controlled trial . PARTICIPANTS Thirty-six community-dwelling patients with Alzheimer 's disease ( AD ) and their family caregivers . INTERVENTION All participants received written material s describing age- and dementia-related changes in sleep and st and ard principles of good sleep hygiene . Caregivers in active treatment ( n=17 ) received specific recommendations about setting up and implementing a sleep hygiene program for the dementia patient and training in behavior management skills . Patients in active treatment were also instructed to walk daily and increase daytime light exposure with the use of a light box . Control subjects ( n=19 ) received general dementia education and caregiver support . MEASUREMENTS Primary sleep outcomes were derived for patients and caregivers from 1 week of sleep-wake activity measured at baseline , posttest ( 2 months ) , and 6-month follow-up using an Actillume wrist-movement recorder . Secondary patient outcomes included the Epworth Sleepiness Scale , the Cornell Depression Scale , and the Revised Memory and Behavior Problem Checklist . Caregiver self-reports included the Pittsburgh Sleep Quality Index and the Center for Epidemiological Study of Depression Scale . RESULTS Patients participating in NITE-AD showed significantly greater ( P<.05 ) posttest reductions in number of nighttime awakenings , total time awake at night , and depression , and increases in weekly exercise days than control subjects . At 6-month follow-up , treatment gains were maintained , and additional significant improvements in duration of night awakenings emerged . When cognitive level was controlled , NITE-AD patients had lower longitudinal ratings of daytime sleepiness than controls . There was a trend for control subjects to spend more time in bed at 6 months than NITE-AD patients . CONCLUSION This study provides the first evidence that patients with AD who are experiencing sleep problems can benefit from behavioral techniques ( specifically , sleep hygiene education , daily walking , and increased light exposure ) that are known to improve sleep in nondemented , institutionalized older adults [19420314] PURPOSE The Tailored Activity Program ( TAP ) is a home-based occupational therapy intervention shown to reduce behavioral symptoms and caregiver burden in a r and omized trial . This article describes TAP , its assessment s , acceptability , and replication potential . DESIGN AND METHODS TAP involves 8 sessions for a period of 4 months . Interventionists identify preserved capabilities , previous roles , habits , and interests of individuals with dementia ; develop activities customized to individual profiles ; and train families in activity use . Interventionists documented time spent and ease conducting assessment s , and observed receptivity of TAP . For each implemented prescribed activity , caregivers reported the amount of time their relative spent in activity and perceived benefits . RESULTS The TAP assessment , a combination of neuropsychological tests , st and ardized performance-based observations , and clinical interviewing , yielded information on capabilities from which to identify and tailor activities . Assessment s were easy to administer , taking an average of two 1-hr sessions . Of 170 prescribed activities , 81.5 % were used , for an average of 4 times for 23 min by families between treatment sessions for a period of months . Caregivers reported high confidence in using activities , being less upset with behavioral symptoms ( 86 % ) , and enhanced skills ( 93 % ) and personal control ( 95 % ) . Interventionists observed enhanced engagement ( 100 % ) and pleasure ( 98 % ) in individuals with dementia during sessions . IMPLICATION S TAP offers families knowledge of their relative 's capabilities and easy-to-use activities . The program was well received by caregivers . Prescribed activities appeared to be pleasurable and engaging to individuals with dementia . TAP merits further evaluation to establish efficacy with larger more diverse population s and consideration as a nonpharmacological approach to manage behavioral symptoms [18179480] OBJECTIVES To examine the cost-effectiveness of a r and omized , clinical trial of a home-based intervention for caregivers of people with dementia . DESIGN This cost-effectiveness analysis examined Re sources for Enhancing Alzheimer 's Caregivers Health ( REACH II ) , a multisite , r and omized , clinical trial , from June 2002 through December 2004 , funded by the National Institute on Aging and the National Institute of Nursing Research , of a behavioral intervention to decrease caregivers ' stress and improve management of care recipient behavioral problems . SETTING Community-dwelling dementia caregiving dyads from the Memphis REACH II site . PARTICIPANTS Of Memphis ' r and om sample of 55 intervention and 57 control black and white dyads , 46 in each arm completed without death or discontinuation . Family caregivers were aged 21 and older , lived with the care recipient , and had provided 4 or more hours of care per day for 6 months or longer . Care recipients were cognitively and functionally impaired . INTERVENTION(S ) Twelve individual sessions ( 9 home sessions and 3 telephone sessions ) supplemented by five telephone support-group sessions . Control caregivers received two " check in " phone calls . MEASUREMENTS Incremental cost-effectiveness ratio ( ICER ) , the additional cost to bring about one additional unit of benefit ( hours per day of providing care ) . RESULTS At 6 months , there was a significant difference between intervention caregivers and control caregivers in hours providing care ( P=.01 ) . The ICER showed that intervention caregivers had 1 extra hour per day not spent in caregiving , at a cost of $ 5 per day . CONCLUSION The intervention provided that most scarce of caregiver commodities -- time . The emotional and physical costs of dementia caregiving are enormous , and this intervention was able to alleviate some of that cost [11885210] This study evaluated a one year long course education and counseling program with 93 family caregivers of elders afflicted with Alzheimer 's disease . The elders had received treatment for agitation in an inpatient setting and were subsequently discharged to the caregivers ' home . Caregivers were r and omly assigned to an experimental group ( n = 68 ) and a control group ( n = 25 ) . Baseline assessment s ( Time 0 ) were conducted while the elder was an inpatient . Postdischarge interventions and assessment s were conducted at 2 weeks , 6 weeks , 12 weeks , and 6 and 12 months ( Times 1 - 5 respectively ) . There were no significant treatment effects for care recipient agitation , caregiver stress , depression , and physical health , and no significant differences between groups in rates of institutionalization for afflicted elders . Longitudinal data , however , revealed several important trends . Afflicted elders ' agitation rose steadily for control group subjects at Times 3 through 5 but declined for experimental group subjects . Caregiver depression increased for control group subjects at Time 5 , but declined for experimental group subjects . Caregiver physical health declined for control group subjects at Times 4 and 5 but was maintained for experimental group subjects . A significantly higher number of afflicted elders were still at home among experimental group subjects at the end of the one year study . The difficulties in demonstrating efficacy of interventions with family caregivers of Alzheimer 's disease are discussed . Finally , the issue of data collection being perceived as support by control group subjects is evaluated [21518170] AIM Art therapy has been reported to have effects on mental symptoms in patients with dementia , and its usefulness is expected . We performed a controlled trial to evaluate the usefulness of art therapy compared with calculation training in patients with mild Alzheimer 's disease . METHODS Thirty-nine patients with Alzheimer 's disease showing slightly decreased cognitive function allowing treatment on an outpatient basis were r and omly allocated to art therapy and control ( learning therapy using calculation ) groups , and intervention was performed once weekly for 12weeks . RESULTS Comparison of the results of evaluation between before and after therapy in each group showed significant improvement in the Apathy Scale in the art therapy group ( P=0.014 ) and in the Mini-Mental State Examination score ( P=0.015 ) in the calculation drill group , but no significant differences in the other items between the two groups . Patients showing a 10 % or greater improvement were compared between the two groups . Significant improvement in the quality of life ( QOL ) was observed in the art therapy compared with the calculation training group ( P=0.038 , odds ratio , 5.54 ) . anova concerning improvement after each method revealed no significant difference in any item . CONCLUSION These results suggested improvement in at least the vitality and the QOL of patients with mild Alzheimer 's disease after art therapy compared with calculation , but no marked comprehensive differences between the two methods . In non-pharmacological therapy for dementia , studies attaching importance to the motivation and satisfaction of patients and their family members rather than the superiority of methods may be necessary in the future [17596639] Behavioral symptoms of Alzheimer 's disease , particularly agitation , appear to be a major contributing factor to the emotional distress exhibited by family caregivers . Psychosocial interventions have been shown to reduce caregiver emotional distress , but few studies have examined the efficacy of these interventions with caregivers exposed to high levels of dementia-related behavioral symptoms . The purpose of this study is to test the efficacy of a caregiver skill building intervention in reducing emotional distress to agitated behaviors of care recipients . This study analyzed data from a subgroup of caregivers who participated in a larger r and omized clinical trial ( N = 295 ) . Data from 143 caregivers of family members with baseline agitated behaviors indicate that the skill building intervention was more effective than an information and support oriented comparison condition in reducing emotional distress over an 18-month period . These findings indicate that dementia caregivers exposed to agitated behaviors can benefit from psychosocial interventions , particularly those aim ed at building behavioral management skills [11087767] Background : Treatment of agitation is a crucial problem in the care of patients with AD . Although antipsychotic and antidepressant medications and behavior management techniques ( BMT ) have each been used to treat agitation , clinical trials of these treatments have been characterized by small sample sizes and uncontrolled treatment design s. Objective : To compare haloperidol , trazodone , and BMT with placebo in the treatment of agitation in AD out patients . Methods : A total of 149 patients with AD and their caregivers participated in a r and omized , placebo-controlled , multicenter trial . Blind assessment was conducted at baseline and after 16 weeks of treatment . The three active treatments were haloperidol , trazodone , and BMT . The Alzheimer ’s Disease Cooperative Study Clinical Global Impression of Change was the primary outcome measure . Secondary outcomes included patient agitation , cognition , and function , and caregiver burden . Results : Thirty-four percent of subjects improved relative to baseline . No significant differences on outcome were obtained between haloperidol ( mean dose , 1.8 mg/d ) , trazodone ( mean dose , 200 mg/d ) , BMT , or placebo . Significantly fewer adverse events of bradykinesia and parkinsonian gait were evident in the BMT arm . No other significant difference in adverse events was seen . Symptoms did not respond differentially to the different treatments . Conclusions : Comparable modest reductions in agitation occurred in patients receiving haloperidol , trazodone , BMT , and placebo . More effective pharmacologic , nonpharmacologic , and combination treatments are needed [25067886] This study enrolled 184 middle-aged and older women ( 95 Non-Hispanic White and 89 Hispanic/Latino ) who provided in-home h and s-on care to an elderly relative with Alzheimer ’s disease or another form of dementia . Within ethnic group they were r and omly assigned to either a CBT-based small group intervention program called “ Coping with Caregiving ” ( CWC ) that taught a variety of cognitive and behavioral skills to reduce stress and depression , or to a minimal telephone based control condition ( TSC ) . Intervention lasted about 4 months ; one post-treatment assessment was completed 6 months after baseline by interviewers blind to the intervention condition . Interviews and interventions were conducted in English or Spanish by trained staff . Results indicated that those in the CWC ( regardless of ethnicity ) showed greater improvement from pre to post intervention than those in the TSC on measures of depressive symptoms , overall life stress , and caregiving-specific stress . In order to investigate if these changes may have been related to one proposed mechanism of change in CBT ( skill utilization ) , a new measure was constructed . Change in frequency of use and perceived helpfulness of adaptive coping skills were assessed in all caregivers . Results indicated that caregivers in CWC reported greater frequency of use , and greater perceived helpfulness , of these skills at post intervention compared to caregivers in the TSC . Improvement measured by dependent measures was correlated with an increase in these indices for those in the CWC . Tests for mediation suggest that effective skill utilization may mediate the effect of treatment on outcome . Implication s of these findings are discussed and recommendations provided for future research [12937333] PURPOSE This study developed and tested two 24-month primary care interventions to alleviate the psychological distress suffered by the caregivers of those with Alzheimer 's disease . The interventions , using targeted educational material s , were patient behavior management only , and patient behavior management plus caregiver stress-coping management . We hypothesized that the addition of the stress-coping component would improve caregiver outcomes . DESIGN AND METHODS A r and omized clinical trial of 167 caregiver-care recipient dyads was run , of whom 76 completed the study without bereavement or placement . RESULTS During 24 months , caregivers who received the patient behavior management component only , compared with those who also received the stress-coping component , had significantly worse outcomes for general well-being and a trend toward increased risk of depression ( i.e. , a score of > 16 on the Center for Epidemiological Studies Depression scale ) . There was a study wide improvement for bother associated with care recipient behaviors ( according to the Revised Memory and Behavior Problems Checklist ) . IMPLICATION S Our data suggest that brief primary care interventions may be effective in reducing caregiver distress and burden in the long-term management of the dementia patient . They further suggest that interventions that focus only on care recipient behavior , without addressing caregiving issues , may not be as adequate for reducing caregiver distress [19030120] Individuals with cognitive impairment , their family members , and their care providers have all identified " quality of life " as a central goal in the treatment of dementia . In this article , we identify factors that influence quality of life for individuals with cognitive impairment , review evidence -based psychosocial interventions that improve quality of life for community-residing individuals with dementia , and describe innovative ongoing r and omized clinical trials design ed to improve or maintain quality of life for individuals with mild to moderate memory problems [10396888] This 3-year r and omized clinical trial tested the effectiveness of an interdisciplinary psychoeducational family group intervention in decreasing the caregivers ' perceptions of the frequency and severity of behavioral problems in persons with dementia and their reactions to those problems , and in decreasing caregiver burden and depression . The intervention consisted of seven weekly , 2-hour multimedia training sessions that included education , family support , and skills training for 94 primary caregivers and their families . Repeated measures ANOVA was used to test for significant differences between the intervention and waiting list control groups over a 5-month period . The intervention was successful in reducing caregivers ' negative reactions to disruptive behaviors and in reducing caregiver burden over time [17986818] Objective : To test the effect of a short-term psychosocial intervention programme for family carers of patients with dementia and identify characteristics of carers and patients that responded positively . Methods : The study was a multi-centre r and omized controlled trial . Carers of 180 patients suffering from dementia recruited at 7 memory clinics at geriatric or psychiatric departments participated in the study . Carers of the intervention group were educated about dementia and in 6 group meetings taught how to use structured problem-solving . The control group received treatment as usual . The effect on patients was measured with the Neuropsychiatric Inventory and on carers with the Relatives ’ Stress Scale ( RSS ) . Results : The intention-to-treat efficacy analysis included 171 carer/patient dyads . The intervention did not have any effect on the primary outcome variables . The burden measured by the RSS increased in both groups ; however , more carers of the control group converted from a low-burden group to a medium- or high-burden group after 4.5 months . In a subgroup analysis we found a statistically significant difference in the Neuropsychiatric Inventory score in favour of the intervention group among female patients . Conclusion : The predominately negative result of this study emphasizes the need of individually tailored interventions for carers and the use of narrow inclusion criteria when performing group-based interventions , such as the extent of burden as well as gender and kinship [11346473] We investigated the usefulness of a computer-mediated interactive voice response ( IVR ) system integrated with voicemail to help family caregivers manage disruptive behaviours in people with Alzheimer 's disease . The r and omization procedure result ed in 49 caregivers being assigned to the intervention group and 51 to the control group . Using their ordinary telephone , the caregivers were linked to the four components of the IVR system : monitoring and counselling , an in-home support group , ' ask the expert ' , and a respite conversation . During an 18-month study , total system usage amounted to 55 min per user ( SD 78 , range 1 - 318 ) . Half the participants used the system for at least 22 min , and 25 % for at least 70 min . Participants made between one and 45 calls over the study period , averaging 11 calls ( SD 12 ) . Approximately half of the intervention group used the system regularly for two or more months . These ' adopters ' were significantly older , more highly educated and reported a greater sense of management of the situation than ' non-adopters ' . Adopters were much more likely than non-adopters to have been rated as highly proficient by the trainer following the technology training session . The IVR approach appealed to a subset of users . However , the overall preference was for human interaction [18453642] Theories supporting the existence of a use-dependent neuroplasticity in the older brain were used to guide this pilot study . A repeated- measures r and omized design was used to test the effectiveness of a multimodal ( Taiji exercises , cognitive-behavioral therapies , support group ) intervention on cognitive functioning , physical functioning , and behavioral outcomes in persons with dementia . The treatment group ( n = 24 persons with dementia ) participated in a 40-week intervention , with outcomes assessed at 20 and 40 weeks to assess optimal treatment length . Control group subjects ( n = 19 persons with dementia ) received attention-control educational programs . At 20 weeks , differences between groups were found for mental ability and self-esteem , with gains in balance being evident . Also , stability in depression and physical health were evident at 20 and 40 weeks for treatment group subjects . Continued improvement in outcomes was not observed at 40 weeks . However , findings support further testing of the intervention along with potential for achieving positive outcomes in early-stage dementia [2703638] Background Care for people with dementia and their informal caregivers is a challenging aim in healthcare . There is an urgent need for cost-effective support programs that prevent informal caregivers of people with dementia from becoming overburdened , which might result in a delay or decrease of patient institutionalization . For this reason , we have developed the Systematic Care Program for Dementia ( SCPD ) . The SCPD consists of an assessment of caregiver 's sense of competence and suggestions on how to deal with competence deficiencies . The efficiency of the SCPD will be evaluated in our study . Methods and design In our ongoing , cluster , r and omized , single-blind , controlled trial , the participants in six mental health services in four regions of the Netherl and s have been r and omized per service . Professionals of the ambulatory mental health services ( psychologists and social psychiatric nurses ) have been r and omly allocated to either the intervention group or the control group . The study population consists of community-dwelling people with dementia and their informal caregivers ( patient-caregiver dyads ) coming into the health service . The dyads have been clustered to the professionals . The primary outcome measure is the patient 's admission to a nursing home or home for the elderly at 12 months of follow-up . This measure is the most important variable for estimating cost differences between the intervention group and the control group . The secondary outcome measure is the quality of the patient 's and caregiver 's lives . Discussion A novelty in the SCPD is the pro-active and systematic approach . The focus on the caregiver 's sense of competence is relevant to economical healthcare , since this sense of competence is an important determinant of delay of institutionalization of people with dementia . The SCPD might be able to facilitate this with a relatively small cost investment for caregivers ' support , which could result in a major decrease in costs in the management of dementia . Implementation on a national level will be started if the SCPD proves to be efficient . Trial Registration Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: AIM The aim of this study was to explicate the outcomes of home support interventions for older people with dementia and /or their carers to inform clinical practice , policy and research . BACKGROUND Most people with dementia receive support at home . However , components and effectiveness of home support interventions have been little explored . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

26026155

[11796766] Objective : To assess the efficacy and safety of modafinil for the treatment of fatigue in multiple sclerosis ( MS ) . Methods : Patients aged 18–65 years with a diagnosis of MS , a stable disability level ≤6 on the Kurtzke extended disability status scale ( EDSS ) , and a mean score > 4 on the fatigue severity scale ( FSS ) were eligible for the 9 week , single blind , phase 2 , two centre study . Exclusion criteria included a diagnosis of narcolepsy , sleep apnoea , or clinical ly significant major systemic disease and recent use of medications affecting fatigue . All patients , who remained blinded for the treatment regimen , received placebo during weeks 1–2 , 200 mg/day modafinil during weeks 3–4 , 400 mg/day modafinil during weeks 5–6 , and placebo during weeks 7–9 . Safety was evaluated by unblinded investigators . Efficacy was evaluated by self rating scales , using the FSS , the modified fatigue impact scale ( MFIS ) , a visual analogue scale for fatigue ( VAS-F ) , and the Epworth sleepiness scale ( ESS ) . Adverse events were recorded . Results : Seventy two patients ( MS type : 74 % relapsing-remitting ; 7 % primary progressive ; 19 % secondary progressive ) received treatment . After treatment with 200 mg/day modafinil for 2 weeks , a significant improvement in fatigue versus placebo run in was demonstrated . Mean scores after treatment with 200 mg/day modafinil were : FSS , 4.7 versus 5.5 for placebo ( p<0.001 ) ; MFIS , 37.7 versus 44.7 ( p<0.001 ) ; and VAS-F , 5.4 versus 4.5 ( p=0.003 ) . Fatigue scores for 400 mg/day modafinil were not significantly improved versus placebo run in . Mean ESS scores were significantly improved ( p<0.001 ) with 200 mg/day modafinil ( 7.2 ) and 400 mg/day ( 7.0 ) versus the score at baseline ( 9.5 ) . Serious adverse events were not found at either dose . The most common adverse events were headache , nausea , and aesthenia . Sixty five patients ( 90 % ) completed the study . Conclusions : These data suggest that 200 mg/day modafinil significantly improves fatigue and is well tolerated in patients with MS [16549835] PURPOSE A prospect i ve , open-label phase II study was conducted to determine whether donepezil , a US Food and Drug Administration-approved reversible acetylcholinesterase inhibitor used to treat mild to moderate Alzheimer 's type dementia , improved cognitive functioning , mood , and quality of life ( QOL ) in irradiated brain tumor patients . PATIENTS AND METHODS Thirty-four patients received donepezil 5 mg/d for 6 weeks , then 10 mg/d for 18 weeks , followed by a washout period of 6 weeks off drug . Outcomes were assessed at baseline , 12 , 24 ( end of treatment ) , and 30 weeks ( end of wash-out ) . All tests were administered by a trained research nurse . RESULTS Of 35 patients who initiated the study , 24 patients ( mean age , 45 years ) remained on study for 24 weeks and completed all outcome assessment s. All 24 patients had a primary brain tumor , mostly low- grade glioma . Scores significantly improved between baseline ( pretreatment ) and week 24 on measures of attention/concentration , verbal memory , and figural memory and a trend for verbal fluency ( all P < .05 ) . Confused mood also improved from baseline to 24 weeks ( P = .004 ) , with a trend for fatigue and anger ( all P < .05 ) . Health-related QOL improved significantly from baseline to 24 weeks , particularly , for brain specific concerns with a trend for improvement in emotional and social functioning ( all P < .05 ) . CONCLUSION Cognitive functioning , mood , and health-related QOL were significantly improved following a 24-week course of the acetylcholinesterase inhibitor donepezil . Toxicities were minimal . We are planning a double blinded , placebo-controlled , phase III trial of donepezil to confirm these favorable results [2375434] Ifosfamide and cisplatin cause urinary loss of carnitine , which is a fundamental molecule for energy production in mammalian cells . We investigated whether restoration of the carnitine pool might improve chemotherapy-induced fatigue in non-anaemic cancer patients . Consecutive patients with low plasma carnitine levels who experienced fatigue during chemotherapy were considered eligible for study entry . Patients were excluded if they had anaemia or other conditions thought to be causing asthenia . Fatigue was assessed by the Functional Assessment of Cancer Therapy-Fatigue quality of life question naire . Treatment consisted of oral levocarnitine 4 g daily , for 7 days . Fifty patients were enrolled ; chemotherapy was cisplatin-based in 44 patients and ifosfamide-based in six patients . In the whole group , baseline mean Functional Assessment of Cancer Therapy-Fatigue score was 19.7 ( ±6.4 ; st and ard deviation ) and the mean plasma carnitine value was 20.9 μM ( ±6.8 ; st and ard deviation ) . After 1 week , fatigue ameliorated in 45 patients and the mean Functional Assessment of Cancer Therapy-Fatigue score was 34.9 ( ±5.4 ; st and ard deviation ) ( P<.001 ) . All patients achieved normal plasma carnitine levels . Patients maintained the improved Functional Assessment of Cancer Therapy-Fatigue score until the next cycle of chemotherapy . In selected patients , levocarnitine supplementation may be effective in alleviating chemotherapy-induced fatigue . This compound deserves further investigations in a r and omised , placebo-controlled study [14659505] & NA ; A series of health surveys are conducted every sixth to seventh year in Denmark . In the most recent survey of 2000 , a national r and om sample ( > 16 years ) was drawn from the Danish Central Personal Register . Out of the original sample 12,333 ( 74 % ) were interviewed and of these 10,066 returned a completed question naire ( SF‐36 ) . The present study includes only those who both took part in the interview and the postal question naire . Cancer patients were excluded . Persons suffering from chronic pain ( PG ) were identified through the question ‘ Do you have chronic/long lasting pain lasting 6 months or more ’ ? An overall chronic pain prevalence of 19 % was found −16 % for men and 21 % for women . Prevalence of chronic pain increased with increasing age . Persons ≥67 years had 3.9 higher odds of suffering from chronic pain than persons in the age group 16–24 years . Compared with married persons , divorced or separated persons had 1.5 higher odds of chronic pain . Odds for chronic pain were 1.9 higher among those with an education of less than 10 years compared with individuals with an education of 13 years or more . During a 14‐day period reporters of chronic pain had an average of 0.8 days ( range 0–10 ) lost due to illness compared with an average of 0.4 days ( range 0–10 ) for the control group ( CG ) ( Odds Ratio ( OR ) ) 2.0 ) . Persons with a job which required high physical strain were more likely to report chronic pain compared with those with a sedentary job ( OR 2.2 ) . The odds of quitting one 's job because of ill health were seven times higher among people belonging to the PG . A strong association between chronic pain and poor self‐rated health was also demonstrated . The PG had twice as many contacts with various health professionals compared with the CG , and the health care system was , on average , utilised 25 % more ( overall contacts ) by the PG than by the general population . Among the persons in the PG , 33 % were not satisfied with the examinations carried out in connection with their pain condition and 40 % were not satisfied with the treatment offered . Nearly 130,000 adults , corresponding to 3 % of the Danish population , use opioids on a regular basis . Opioids are used by 12 % of the PG [9893656] The aim of this study was to evaluate a low-dose regimen of megestrol acetate ( MA ; 320 mg/day ) on appetite in advanced cancer patients . Out- patients with far-advanced non-hormone responsive tumours and loss of appetite were r and omised in a phase III trial , with two consecutive phases : a 14-day double-blind placebo controlled phase ( phase A ) and a 76-day open phase ( phase B ) . During phase A , patients were treated with MA , two 160 mg tablets/day , or placebo . In phase B , the MA dose was titrated to clinical response in both groups . Appetite , food intake , body weight , performance status , mood and quality of life were evaluated with st and ardised measures ; patients ' global judgement about treatment efficacy was also requested . Of 42 patients entering the study , 33 ( 17 MA and 16 placebo ) were evaluable for efficacy . The appetite score improved significantly with MA after 7 days ( P = 0.0023 ) , and this effect was still significant at 14 days ( P = 0.0064 ) . Patients judged the treatment with MA effective in 88.2 % of cases ( 14th day ) , whilst placebo was considered effective by 25 % ( P = 0.0003 ) . None of the other measures showed significant changes during treatment . The remarkable effect on appetite evident after 7 days , without serious side-effects , shows that MA can produce significant subjective effects at a low-dose even in patients with far-advanced disease [15679006] BACKGROUND Although the underlying pathology is initially confined to the lungs , the associated emotional responses to chronic obstructive pulmonary disease ( COPD ) contribute greatly to the result ing morbidity . The objective of this study was to examine the effect of an antidepressant drug on disease-specific quality of life in patients with end-stage COPD who present significant depressive symptoms . METHODS We conducted a 12-week , r and omized double-blind placebo-controlled trial of Paroxetine in which quality of life measured by the Chronic Respiratory Question naire ( CRQ ) , an evaluative COPD -specific quality -of-life question naire , was the primary outcome . RESULTS 23 patients were r and omized and 15 completed the trial ( 8 on Paroxetine ; 7 on placebo ) . In the per- protocol analysis , we observed statistically and clinical ly significant improvements favoring the active treatment in 2 of the 4 domains of the CRQ : emotional function ( adjusted mean difference : 1.1 ; 95 % confidence interval [ CI ] : 0.0 - 2.2 ) and mastery ( difference : 1.1 ; CI : 0.4 - 1.8 ) . Dyspnea and fatigue improved , but to an extent that did not reach statistical significance . In the intention-to-treat analysis , none of the differences in CRQ scores was significant . Paroxetine was not associated to any worsening of respiratory symptoms . CONCLUSIONS The results of this small r and omized trial indicated that patients with end-stage COPD may benefit from antidepressant drug therapy when significant depressive symptoms are present . This study underlined the difficulties in conducting experimental studies in frail and elderly patients with COPD [2698804] The effectiveness of an 8-week , 125 mg/day intravenous course of methylprednisolone sodium succinate ( MPSS ) for improving quality of life in patients with preterminal cancer was investigated in a double-blind , placebo-controlled , multicenter study . Quality of life was assessed using the Nurses ' Observational Scale for Inpatient Evaluation ( NOSIE ) , the Linear Analog Self- Assessment Scale ( LASA ) , and the Physicians ' Global Evaluation . A total of 403 patients were enrolled : 207 were treated with MPSS and 196 were treated with placebo . MPSS was significantly more effective than placebo in improving quality of life as judged by the changes from baseline in the NOSIE and LASA total scores . ( P less than 0.05 ) and by the Physicians ' Global Evaluation ( P less than 0.001 ) . The mortality rate was similar between MPSS-treated males ( 40.2 % ) , placebo-treated males ( 35.5 % ) , and MPSS-treated females ( 40.0 % ) . However , the mortality rate of 27.7 % for female placebo-treated females was significantly lower than for their MPSS-treated counterparts . The reason for lower mortality among placebo-treated females is unknown and warrants further study [1968469] Patients with breast cancer treated with MPA often report an improvement in appetite . Similar appetite stimulation is seen in patients treated with some corticosteroids , but MPA has a potential advantage over these drugs in that it does not exert a catabolic effect . MPA ( 100 mg tds orally ) has therefore been compared with placebo in 60 patients with advanced malignant disease . Twenty-one patients in the MPA group and 20 in the placebo group were receiving chemotherapy . Patients were treated for 6 weeks and were assessed at weeks 0 , 3 and 6 for appetite , energy , mood and pain using visual analogue scales . Nutritional status was assessed by the measurement of serum proteins and anthropometrics . Karnofsky score was recorded as a measure of performance status . There was a significant improvement in appetite in the MPA group between weeks 0 ( pre- study ) and 3 ( P = 0.0002 ) and 0 and 6 ( P = 0.015 ) . There was no significant improvement in appetite in the placebo group . Supporting this finding was the significant increase in serum thyroid binding pre-albumin and retinol binding protein in the MPA group between weeks 0 and 3 and 0 and 6 ( P = 0.023 and P = 0.039 respectively ) . These two parameters showed no significant change in the placebo group . There was no change in anthropometric measurements , weight , performance status , energy , mood or pain in either group . These data indicate that there was a significant increase in appetite in anorexic patients with advanced cancer treated with MPA which was reflected in increases in rapid turnover proteins reported to reflect nutritional status . However , this apparent increase in appetite did not result in improved weight , performance status , energy levels , mood or relief of pain . Further studies to investigate the effect of higher doses of MPA are indicated [2483687] A total of 173 female terminal cancer patients were r and omized to treatment with daily 125 mg infusions of methylprednisolone sodium succinate or a matching placebo for a period of 8 consecutive weeks . Data were collected relative to quality of life , investigator assessment of efficacy and cause and time of death within the 8-week treatment period . Significant improvement in quality of life was reported across the 8-week follow-up period in the steroid group . Investigator global assessment of efficacy significantly favored the steroid-treatment patients . There were no significant differences between treatment groups with regard to overall mortality rates or time to death . The total number of reported adverse events did not differ significantly between treatment groups . However , significantly more steroid patients reported gastrointestinal and cardiovascular events . The severity and outcome of these events did not differ from the placebo patients . The results of this study confirm previous reports of steroid efficacy in improving quality of life in terminal cancer patients . The absence of any untoward effect on mortality and the favorable safety profile support the use of methylprednisolone as palliative therapy for terminal cancer patients [21777715] OBJECTIVE To evaluate the efficacy and safety of armodafinil in the treatment of fatigue in HIV+ patients , and to assess its effect on depressive symptoms and behavior once fatigue remitted . METHOD HIV+ patients with clinical ly significant fatigue were treated in a placebo-controlled r and omized double-blind trial for 4 weeks . Armodafinil responders and placebo non-responders or relapsers were treated openly for a total of 16 weeks with armodafinil . The primary outcome measure for fatigue and depression was the Clinical Global Impressions-Improvement Scale , supplemented by the Fatigue Severity Scale , the Hamilton Depression Rating Scale , and the Beck Depression Inventory . Safety was assessed with assays of CD4 cell count and HIV RNA viral load and the SAFTEE side effects rating scale . Maximum trial dose of armodafinil was 250 mg/d . RESULTS Seventy patients were enrolled . Attrition was 9 % . In intention-to-treat analyses , fatigue response rate to armodafinil was 75 % and to placebo , 26 % . Armodafinil did not reduce depressive symptoms in the absence of improved energy , but of those patients with an Axis I depressive disorder at study entry whose energy improved , 82 % experienced improved mood as well . Markers of immunologic suppression did not change during treatment . At 6 months , those still taking armodafinil had more energy and fewer depressive symptoms than those who were no longer taking it . CONCLUSIONS As we found in our RCT of modafinil , armodafinil appears effective and well tolerated in treating fatigue in HIV+ patients . Side effects were minimal and most patients reported substantially improved energy and mood [14759641] Treatment with acetyl L-carnitine ( ALCAR ) has been shown to improve fatigue in patients with chronic fatigue syndrome , but there have been no trials on the effect of ALCAR for treating fatigue in multiple sclerosis ( MS ) . To compare the efficacy of ALCAR with that of amantadine , one of the drugs most widely used to treat MS-related fatigue , 36 MS patients presenting fatigue were enrolled in a r and omised , double-blind , crossover study . Patients were treated for 3 months with either amantadine ( 100 mg twice daily ) or ALCAR ( 1 g twice daily ) . After a 3-month washout period , they crossed over to the alternative treatment for 3 months . Patients were rated at baseline and every 3 months according to the Fatigue Severity Scale ( FSS ) , the primary endpoint of the study . Secondary outcome variables were : Fatigue Impact Scale ( FIS ) , Beck Depression Inventory ( BDI ) and Social Experience Checklist ( SEC ) . Six patients withdrew from the study because of adverse reactions ( five on amantadine and one on ALCAR ) . Statistical analysis showed significant effects of ALCAR compared with amantadine for the Fatigue Severity Scale ( p = 0.039 ) . There were no significant effects for any of the secondary outcome variables . The results of this study show that ALCAR is better tolerated and more effective than amantadine for the treatment of MS-related fatigue [10675381] BACKGROUND Extracellular adenosine 5'-triphosphate ( ATP ) is involved in the regulation of a variety of biologic processes , including neurotransmission , muscle contraction , and liver glucose metabolism , via purinergic receptors . In nonr and omized studies involving patients with different tumor types including non-small-cell lung cancer ( NSCLC ) , ATP infusion appeared to inhibit loss of weight and deterioration of quality of life ( QOL ) and performance status . We conducted a r and omized clinical trial to evaluate the effects of ATP in patients with advanced NSCLC ( stage IIIB or IV ) . METHODS Fifty-eight patients were r and omly assigned to receive either 10 intravenous 30-hour ATP infusions , with the infusions given at 2- to 4-week intervals , or no ATP . Outcome parameters were assessed every 4 weeks until 28 weeks . Between-group differences were tested for statistical significance by use of repeated- measures analysis , and reported P values are two-sided . RESULTS Twenty-eight patients were allocated to receive ATP treatment and 30 received no ATP . Mean weight changes per 4-week period were -1.0 kg ( 95 % confidence interval [ CI ] = -1.5 to -0.5 ) in the control group and 0.2 kg ( 95 % CI = -0.2 to + 0.6 ) in the ATP group ( P = .002 ) . Serum albumin concentration declined by -1.2 g/L ( 95 % CI= -2.0 to -0.4 ) per 4 weeks in the control group but remained stable ( 0.0 g/L ; 95 % CI = -0.3 to + 0.3 ) in the ATP group ( P = .006 ) . Elbow flexor muscle strength declined by -5.5 % ( 95 % CI = -9.6 % to -1 . 4 % ) per 4 weeks in the control group but remained stable ( 0.0 % ; 95 % CI= -1.4 % to + 1.4 % ) in the ATP group ( P = .01 ) . A similar pattern was observed for knee extensor muscles ( P = .02 ) . The effects of ATP on body weight , muscle strength , and albumin concentration were especially marked in cachectic patients ( P = .0002 , P = .0001 , and P = . 0001 , respectively , for ATP versus no ATP ) . QOL score changes per 4-week period in the ATP group showed overall less deterioration than in the control group-physical scores ( -0.2 % versus -2.4 % ; P = . 0002 ) ; functional scores ( + 0.4 % versus -5.5 % ; P = .02 ) ; psychologic scores ( -0.7 % versus -2.4 % ; P = .11 ) ; overall QOL score ( + 0.1 % versus -3.5 % ; P = .0001 ) . CONCLUSIONS This r and omized trial demonstrates that ATP has beneficial effects on weight , muscle strength , and QOL in patients with advanced NSCLC [21964738] Limited research is available regarding the efficacy of psychostimulants in treating cognitive function in primary brain tumor patients . An open-label , r and omized , pilot trial examined both the general and differential efficacy of 4 weeks of methylpheni date ( MPH ) and modafinil ( MOD ) in 24 brain tumor patients . Participants completed cognitive tests and self-report measures of fatigue , sleep disturbance , mood and quality of life at baseline and after 4 weeks . Following stimulant treatment , there was evidence of a beneficial effect on test performance in speed of processing and executive function requiring divided attention . Patients with the greatest deficit in executive function at baseline appeared to derive the greatest benefit following stimulant therapy . Inconsistent , differential effects were found on a measure of attention in favor of MPH and on a measure of processing speed in favor of MOD . There was also evidence of a general beneficial effect on patient-reported measures of fatigue , mood , and quality of life , with no statistically significant differences between treatment arms in these measures over time . The results from this small pilot study should be interpreted with caution , but appear to warrant additional research , in larger study sample s , targeting fatigue , processing speed and executive function , and exploring different doses of stimulants . Future studies may also wish to explore the specific patient factors that may be associated with responsiveness to psychostimulant treatment [17406919] Introduction Amisulpride is a substituted benzamide that , at low doses , selectively blocks D2 and D3 presynaptic dopamine receptors , enhancing dopaminergic transmission in frontal cortex and limbic areas . Many clinical studies versus placebo , tricyclic antidepressants and selective serotonin reuptake inhibitors showed amisulpride antidepressant effect , supporting its safety and rapid onset of action . In oncological population , depression is quite frequent and difficult to treat because of the particular sensitivity of cancer patients to the antidepressants ’ side effects . Goals of workThe aims of this study were to evaluate efficacy , safety and tolerability of low doses of amisulpride ( 50 mg ) in oncological , depressed patients during chemotheraphy . Material s and methods One hundred six consecutive cancer out patients with depressive symptoms were treated in a prospect i ve , intention to treat , 4-week study , and were evaluated in single-blind with Montgomery Asberg rating scale for depression ( MADRS ) , clinical global impression ( CGI ) and dosage record treatment emergent symptom scale ( DOTES ) to assess side effects of treatment . Main results After 4 weeks of treatment , scores of MADRS and CGI significantly improved ( p < 0.002 ; p < 0.001 , respectively ) , with a reduction of depressive symptoms concerning both emotional ( such as apparent sadness , reported sadness , inner tension , etc . ) and physical cluster ( such as lack of appetite , reduction in weight , tiredness and insomnia ) with good tolerability ( only two patients dropped out ) . Conclusions This study is the first trial on the use of amisulpride in a cohort of oncological , depressed patients during chemotherapy . Amisulpride demonstrated high efficacy and safety . Controlled studies are needed to confirm these preliminary data [11176767] BACKGROUND Fatigue is a commonly encountered symptom of human immunodeficiency virus ( HIV ) disease , associated with significant psychological and functional morbidity and poor quality of life . Preliminary studies on the treatment of fatigue from the cancer and multiple sclerosis literature suggest that psychostimulants may be effective in reducing fatigue . OBJECTIVE To compare the efficacy of 2 psychostimulant medications , methylpheni date hydrochloride ( Ritalin ) and pemoline ( Cylert ) , with a placebo intervention for the treatment of fatigue in patients with HIV disease . METHODS In this double-blind trial , 144 ambulatory patients with HIV disease and persistent and severe fatigue were r and omized to treatment with methylpheni date , pemoline , or placebo . Medications were titrated up to a maximum dose of 60 mg of methlypheni date hydrochloride , 150 mg of pemoline , or 8 capsules of placebo daily . Fatigue was measured using 2 self-reported rating scales , the Piper Fatigue Scale ( PFS ) and the Visual Analogue Scale for Fatigue ( VAS-F ) . We also used the timed isometric unilateral straight leg-raising task , a measure of muscular endurance . Quality -of-life and psychological well-being measures included the Beck Depression Inventory , the Brief Symptom Inventory , and the 36-Item Short-Form Medical Outcomes Study Health Status Survey . Side effects were monitored using the Systematic Assessment for Treatment Emergent Events and the Extra-pyramidal Symptom Rating Scale . All measures were rated weekly . RESULTS One hundred nine subjects completed the 6-week trial ; 15 patients ( 41 % ) receiving methylpheni date and 12 patients ( 36 % ) receiving pemoline demonstrated clinical ly significant improvement compared with 6 patients ( 15 % ) receiving placebo . Patients receiving methylpheni date or pemoline demonstrated significantly more improvement in fatigue on several self-reported rating scales ( PFS total score , P=.04 ; affective subscale , P=.008 ; sensory subscale , P=.04 ; and VAS-F energy subscale , P=.02 ) . Analysis of the regression slopes by means of hierarchical linear modeling demonstrated a significantly greater rate of improvement in PFS total scores among patients receiving psychostimulants compared with the placebo group ( P=.02 ) . There were no significant differences in the efficacy between methlypheni date and pemoline on any outcome measure studied . Improvement in fatigue was also significantly correlated with improvement in measures of depression , psychological distress , and overall quality of life . Severe side effects were relatively uncommon among this sample , and only hyperactivity or jitteriness occurred significantly more often among subjects receiving active medication . CONCLUSIONS Many patients with HIV- and acquired immunodeficiency syndrome-unrelated fatigue respond favorably to treatment with methylpheni date or pemoline . Both psychostimulants appear to be equally effective and significantly superior to placebo in decreasing fatigue severity with minimal side effects . Moreover , improvement of fatigue was significantly associated with improved quality of life and decreased levels of depression and psychological distress [15824337] Objective : To assess whether modafinil , a wakefulness-promoting agent , is useful for fatigue in patients with multiple sclerosis ( MS ) . Methods : Patients with MS with stable disability , and a baseline score of 45 or more on the Modified Fatigue Impact Scale ( MFIS ) , were eligible for the 5-week r and omized , double-blind , placebo-controlled , parallel group study . The initial daily dose of modafinil was 200 mg for 1 week . Depending on tolerance , the dose was increased by 100 mg every week up to 400 mg/day and remained unchanged between day 21 and day 35 . The primary outcome variable was the change of MFIS score at day 35 . Results : A total of 115 patients with MS were enrolled in the study and in the intention to treat analysis . The mean MFIS score at baseline was 63 ± 9 in the placebo group and 63 ± 10 in the modafinil group . MFIS scores improved between day 0 and day 35 in both placebo-treated and modafinil-treated groups , but no significant difference was detected between the two groups . There was no major safety concern . Conclusions : There was no improvement of fatigue in patients with multiple sclerosis treated with modafinil vs placebo according to the Modified Fatigue Impact Scale [19896571] Cancer and its treatment can induce subjective and objective evidence of diminished functional capacity encompassing physical fatigue and cognitive impairment . Dexmethylpheni date ( D-MPH ; the D-isomer of methylpheni date ) was evaluated for treatment of chemotherapy-related fatigue and cognitive impairment . A r and omized , double-blind , placebo-controlled , parallel-group study evaluated the potential therapeutic effect and safety of D-MPH in the treatment of patients with chemotherapy-related fatigue . Change from baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue Subscale ( FACIT-F ) total score at Week 8 was the primary outcome measure . One hundred fifty-four patients ( predominantly with breast and ovarian cancers ) were r and omized and treated . Compared with placebo , D-MPH-treated subjects demonstrated a significant improvement in fatigue symptoms at Week 8 in the FACIT-F ( P=0.02 ) and the Clinical Global Impression-Severity scores ( P=0.02 ) , without clinical ly relevant changes in hemoglobin levels . Cognitive function was not significantly improved . There was a higher rate of study drug-related adverse events ( AEs ) ( 48 of 76 [ 63 % ] vs. 22 of 78 [ 28 % ] ) and a higher discontinuation rate because of AEs ( 8 of 76 [ 11 % ] vs. 1 of 78 [ 1.3 % ] ) in D-MPH-treated subjects compared with placebo-treated subjects . The most commonly reported AEs independent of study drug relationship in D-MPH-treated subjects were headache , nausea , and dry mouth , and in placebo-treated subjects were headache , diarrhea , and insomnia . D-MPH produced significant improvement in fatigue in subjects previously treated with cytotoxic chemotherapy . Further studies with D-MPH or other agents to explore treatment response in chemotherapy-associated fatigue should be considered [18430965] Testosterone increases fat-free mass ( FFM ) in men infected with human immunodeficiency virus ( HIV ) , but its effects on muscle performance , physical function , mood , and quality of life are poorly understood . Sixty-one HIV-infected men with weight loss were r and omized to receive weekly intramuscular injections of 300 mg of testosterone enanthate or placebo for 16 wk . The primary outcome of interest was physical function ( walking speed , stair-climbing power , and load-carrying ability ) . Secondary outcome measures included body weight and composition , muscle performance , sexual function , mood , and quality of life . Serum nadir free and total testosterone levels increased ( + 188.0 + /- 29.6 and + 720 + /- 86 ng/dl ) in the testosterone , but not placebo , group . Testosterone administration was associated with increased FFM ( 2.8 + /- 0.5 kg ) , which was significantly greater than in the placebo group ( P < 0.0001 ) . Leg press strength increased significantly in testosterone-treated ( P = 0.027 ) , but not placebo-treated , men ; the difference between groups was not significant . Other measures of muscle performance and physical function did not change significantly in either group . Men receiving testosterone demonstrated significantly greater improvements in mental health and quality -of-life scores than those receiving placebo and improvements in fatigue/energy and mood scores that were not significantly different from those receiving placebo . Sexual function scores did not change in either group . In HIV-infected men with weight loss , a supraphysiological dose of testosterone significantly increased FFM but did not improve self-reported or performance-based measures of physical function . Improvements in mood , fatigue , and quality -of-life measures in the testosterone group , although clinical ly important , need further confirmation [23944194] Fatigue and cognitive impairment are common in HIV+ adults and may occur independently or be causally linked . This study examined whether alleviation of fatigue with armodafinil in a placebo-controlled double-blind 4-week trial had an effect on cognitive function among those with and without mild neuropsychological impairment at baseline . Sixty-one patients completed a st and ard battery of neuropsychological tests at study entry and Week 4 : A total of 33 were r and omized to armodafinil and 28 to placebo . While there was a significant effect of active medication on fatigue , cognitive performance measured by a global change score did not differ between treatment groups , or in those on active treatment with or without mild neuropsychological impairment [15754122] Summary Background . Fatigue can significantly interfere with a cancer patient ’s ability to fulfill daily responsibilities and enjoy life . It commonly co-exists with depression in patients undergoing chemotherapy , suggesting that administration of an antidepressant that alleviates symptoms of depression could also reduce fatigue . Methods . We report on a double-blind clinical trial of 94 female breast cancer patients receiving at least four cycles of chemotherapy r and omly assigned to receive either 20 mg of the selective serotonin re-uptake inhibitor ( SSRI ) paroxetine ( Paxil ® , SmithKline Beecham Pharmaceuticals ) or an identical-appearing placebo . Patients began their study medication seven days following their first on- study treatment and continued until seven days following their fourth on- study treatment . Seven days after each treatment , participants completed question naires measuring fatigue ( Multidimensional Assessment of Fatigue , Profile of Mood States-Fatigue/Inertia subscale and Fatigue Symptom Checklist ) and depression ( Profile of Mood States-Depression subscale [ POMS-DD ] and Center for Epidemiologic Studies -Depression [ CES-D ] ) . Results . Repeated- measures ANOVAs , after controlling for baseline measures , showed that paroxetine was more effective than placebo in reducing depression during chemotherapy as measured by the CES-D ( p=0.006 ) and the POMS-DD ( p=0.07 ) but not in reducing fatigue ( all measures , ps > 0.27 ) . Conclusions . Although depression was significantly reduced in the 44 patients receiving paroxetine compared to the 50 patients receiving placebo , indicating that a biologically active dose was used , no significant differences between groups on any of the measures of fatigued were observed . Results suggest that modulation of serotonin may not be a primary mechanism of fatigue related to cancer treatment [12185153] Objective : To determine whether combination therapy with lofepramine , L-phenylalanine , and intramuscular vitamin B-12 ( the “ Cari Loder regime ” ) reduces disability in patients with multiple sclerosis . Methods : A placebo controlled , double blind , r and omised study carried out in five United Kingdom centres on out patients with clinical ly definite multiple sclerosis , measurable disability on Guy 's neurological disability scale ( GNDS ) , no relapse in the preceding six months , and not on antidepressant drugs . Over 24 weeks all patients received vitamin B-12 , 1 mg intramuscularly weekly , and either lofepramine 70 mg and L-phenylalanine 500 mg twice daily , or matching placebo tablets . Outcome was assessed using the GNDS , the Kurtzke exp and ed disability status scale ; the Beck depression inventory , the Chalder fatigue scale , and the Gulick MS specific symptom scale . Results : 138 patients were entered , and two were lost from each group . There was no statistically significant difference between the groups at entry or at follow up . Analysis of covariance suggested that treated patients had better outcomes on four of the five scales used . Both groups showed a reduction of 2 GNDS points within the first two weeks , and when data from all time points were considered , the treated group had a significant improvement of 0.6 GNDS points from two weeks onwards . Conclusions : Patients with multiple sclerosis improved by 2 GNDS points after starting vitamin B-12 injections . The addition of lofepramine and L-phenylalanine added a further 0.6 points benefit . More research is needed to confirm and explore the significance of this clinical ly small difference [2730380] Fatigue is a common symptom of multiple sclerosis ( MS ) that is without an effective treatment . A double-blind , controlled study of fatigue treatment was conducted to evaluate the efficacy of amantadine hydrochloride in treating MS-associated fatigue . Since fatigue can not be characterized by a single symptom or behavior , a variety of neuropsychological , behavioral , and self-report measures were used to monitor changes across different systems . According to patients ' daily diary ratings , amantadine produced small but statistically significant improvements in fatigue across four of seven dimensions ( overall energy level , concentration , problem solving , and sense of well-being ) . In addition , patients with MS who were taking amantadine performed slightly better on the Stroop Interference Test , an attentional measure of freedom from distracting information . Although retrospective reports by patients with MS did not confirm the degree of improvement recorded on a daily basis , the study 's results suggested that amantadine may offer modest benefits in alleviating the day-to-day subjective experience of fatigue [16622259] PURPOSE Maintaining dose-intensity with chemotherapeutic agents is hindered by a number of adverse effects including asthenia/fatigue . Tumor necrosis factor ( TNF ) is one of the cytokines responsible for the fatigue and cachexia associated with malignancies . We used etanercept ( TNF-decoy receptor ) to maintain dose-intensity of weekly docetaxel . PATIENTS AND METHODS Initially , 12 patients with advanced malignancies were r and omly assigned to either docetaxel 43 mg/m2 weekly alone ( cohort A ) or the same docetaxel dose plus etanercept 25 mg subcutaneously twice weekly ( cohort B ) . Subsequently , higher doses of docetaxel in combination with etanercept were evaluated . Pharmacokinetics ( PKs ) , nuclear factor-kappa B ( NF-kappaB ) activation , and intracellular cytokines levels were measured . Patients completed weekly question naires quantifying asthenia/fatigue . RESULTS Twenty-nine of 36 intended docetaxel doses during the first cycle were delivered in cohort A , and 35 of 36 doses were delivered in cohort B ( P = .055 ) . Three cohort B patients received additional cycles in the absence of disease progression or severe toxicity , whereas no patients from cohort A received additional cycles . Escalation to docetaxel 52 mg/m2 weekly with etanercept result ed in neutropenia , not fatigue , as the limiting adverse effect , and the addition of filgrastim permitted the maintenance of dose-intensity in additional patients . Patients r and omly selected to receive etanercept/docetaxel self-reported less fatigue ( P < .001 ) , and docetaxel PKs show no relevant influence of etanercept . NF-kappaB activation and increased expression of TNF-alpha were associated with increments in docetaxel dose . Antitumor activity was noticed exclusively in patients receiving etanercept . CONCLUSION The addition of etanercept is safe and had no impact on docetaxel concentrations . The significant improvement in tolerability and the trend toward preservation of dose-intensity suggests further exploration of TNF blockade as an adjunct to cancer therapies [12844250] The prevention of post-chemotherapy symptoms such as delayed emesis , anorexia , and fatigue induced by irinotecan has not been studied . We compared the effects of dexamethasone ( Dex ) with those of a placebo on these symptoms in a r and omized study . Seventy patients scheduled to receive irinotecan chemotherapy were enrolled in the study and r and omly divided into a treatment or a placebo group . In the treatment group , 8 mg of Dex were administered on days 2–4 after the start of chemotherapy . All patients in both groups received Dex and granisetron for prophylaxis against acute emesis on day 1 . We evaluated 68 patients ( 35 receiving Dex , 33 receiving the placebo ) . Although delayed emesis was completely prevented in most of patients in both groups ( Dex , 82.9 % ; placebo , 78.8 % ) , anorexia and fatigue were more completely prevented in those in the Dex group ( Dex , 62.9 % and 77.1 % , placebo , 39.4 % and 57.6 % , respectively ) . The effect of Dex on improving simultaneous prophylaxis against all three symptoms was almost significant ( Dex , 60.0 % ; placebo , 36.4 % ; P=0.058 ) . The safety profiles of the two groups were not discernibly different . These results suggest that treatment with Dex may be beneficial to reduce post-chemotherapy symptoms induced by irinotecan , specifically anorexia and fatigue , with acceptable toxicities [24778393] PURPOSE Fatigue is a distressing symptom occurring in more than 60 % of patients with cancer . The CNS stimulants modafinil and methylpheni date are recommended for the treatment of cancer-related fatigue , despite a limited evidence base . We aim ed to evaluate the efficacy and tolerability of modafinil in the management of fatigue in patients with non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Adults with advanced NSCLC and performance status of 0 to 2 , who were not treated with chemotherapy or radiotherapy within the last 4 weeks , were r and omly assigned to daily modafinil ( 100 mg on days 1 to 14 ; 200 mg on days 15 to 28 ) or matched placebo . The primary outcome was change in Functional Assessment of Chronic Illness Therapy ( FACIT ) -Fatigue score from baseline to 28 days , adjusted for baseline fatigue and performance status . Secondary outcomes included safety and patient-reported measures of depression , daytime sleepiness , and quality of life . RESULTS A total of 208 patients were r and omly assigned , and 160 patients ( modafinil , n = 75 ; placebo , n = 85 ) completed question naires at both baseline and day 28 and were included in the modified intention-to-treat analysis . FACIT-Fatigue scores improved from baseline to day 28 ( mean score change : modafinil , 5.29 ; 95 % CI , 2.57 to 8.02 ; placebo , 5.09 ; 95 % CI , 2.54 to 7.65 ) , but there was no difference between treatments ( 0.20 ; 95 % CI , -3.56 to 3.97 ) . There was also no difference between treatments for the secondary outcomes ; 47 % of the modafinil group and 23 % of the placebo group stated that the intervention was not helpful . CONCLUSION Modafinil had no effect on cancer-related fatigue and should not be prescribed outside a clinical trial setting . Its use was associated with a clinical ly significant placebo effect [3791269] Thirty-two patients with chronic pain due to advanced cancer were treated with methylpheni date ( 10 mg with breakfast and 5 mg with lunch ) for 3 days , versus placebo , in a r and omized , double-blind , cross-over study design ed to evaluate the capacity of methylpheni date to potentiate the analgesic effect of narcotics and /or to decrease sedation induced by narcotics . In 28 evaluable patients , the intensity of pain ( visual analogue 0 - 100 ) and intake of extra doses of analgesics ( number of doses/day ) were 43 + /- 27 and 2.2 + /- 2.4 during methylpheni date , versus 55 + /- 24 ( P less than 0.02 ) and 2.9 + /- 2.9 ( P less than 0.002 ) during placebo , respectively . Activity and drowsiness ( visual analogue 0 - 100 ) were 57 + /- 25 and 58 + /- 24 after methylpheni date , respectively , versus 41 + /- 26 ( P less than 0.05 ) and 45 + /- 27 ( P less than 0.02 ) after placebo . Upon completion of the study , the investigator and the patient chose methylpheni date blindly as a more useful drug in 23 cases ( 83 % ) and 20 cases ( 70 % ) , respectively ( P less than 0.02 ) . No cases of severe toxicity were observed . We conclude that methylpheni date can increase the analgesic effect and decrease sedation of narcotics in this population [22979982] Abstract Objectives : The purpose of this study was to compare the relative efficacy of acetylsalicylic acid ( ASA ) and amantadine for the treatment of fatigue in multiple sclerosis ( MS ) . Methods : A 10-week , r and omized double-blind crossover clinical trial conducted from October 2009 to September 2010 . Fifty-two patients with MS presenting fatigue at 21 to 53 years of age were r and omly allocated to the two treatment groups . The first group received amantadine ( 100 mg twice daily ) for a total of 4 weeks . The second group received ASA ( 500 mg once daily ) for four weeks . After a 2-week washout period , they crossed over to the alternative treatment for 4 weeks . Patients were rated at baseline and the end of each phase with the Fatigue Severity Scale ( FSS ) . Results : ASA appeared to be equivalent in efficacy and safety to amantadine . A significant decrease in FSS occurred in both groups . Of the 26 patients treated with amantadine , the mean ( SD ) of FSS decreased from 4·8 ( 1·4 ) to 4·0 ( 1·4 ) ( P<0·001 ) . In the 26 patients treated with ASA , the mean ( SD ) of FSS decreased from 4·6 ( 1·4 ) to 3·5 ( 1·5 ) ( P<0·001 ) . Discussion : This study demonstrates that both ASA and amantadine significantly reduce MS-related fatigue . Both ASA and amantadine have previously been shown to reduce fatigue , and we postulate that treatment with ASA and amantadine may have similar benefits [22208450] CONTEXT Fatigue is highly prevalent in population s with advanced illness and is often associated with depressed mood . The role of psychostimulant therapy in the treatment of these conditions remains ill defined . OBJECTIVES To evaluate the response of fatigue and depression in patients with advanced illness to titrated doses of methylpheni date ( MP ) as compared with placebo . METHODS In a r and omized , double-blind , placebo-controlled trial , 30 hospice patients , both in patients and out patients , who had fatigue scores of at least four on a scale of zero to 10 ( 0=no fatigue and 10=worst fatigue ) , were r and omly assigned to receive either 5 mg of MP at 8 am and 1 pm or placebo . Doses of MP were titrated every three days according to response and adverse effects . Home care patients were monitored daily by telephone and visited by a research nurse on Study Days 0 ( baseline ) , 3 , 7 , and 14 . Fatigue was assessed using the Piper Fatigue Scale as the primary outcome measure and vali date d by the Visual Analogue Scale for Fatigue and the Edmonton Symptom Assessment Scale ( ESAS ) fatigue score . Subjects in inpatient facilities were interviewed or assessed by staff on an identical schedule . Depressive symptoms were assessed by the Beck Depression Inventory-II , Center for Epidemiologic Studies Depression Scale , and the ESAS depression score . Primary statistical analysis was conducted using repeated- measures multivariate analysis of the variance . RESULTS Both MP- and placebo-treated groups had similar measures of fatigue at baseline . Patients taking MP were found to have significantly lower fatigue scores ( Piper Fatigue Scale , Visual Analogue Scale for Fatigue , and ESAS ) at Day 14 compared with baseline . The improvement in fatigue with MP treatment was dose-dependent ; the mean average effective dose was 10 mg on Day 3 and 20 mg on Day 14 ( dose range of 10 - 40 mg ) . Placebo-treated individuals showed no significant improvement in fatigue . For patients with clinical ly significant depression on Day 0 , treatment with MP was associated with a significant reduction in all test indices for depressed mood . For the placebo group , the changes in measures of depression were less than observed in the treatment group but were inconsistent between assessment tools . No significant toxicities were observed . CONCLUSION MP reduced symptoms of fatigue and depression when compared with placebo . The effect of MP on fatigue was dose-dependent and sustained over the duration of the study [12883103] Objective : There has long been a belief that depression contributes to fatigue in multiple sclerosis ( MS ) although supporting data are minimal at best . Clinical guidelines for the treatment of fatigue include recommendations for the treatment of depression in the absence of clear empirical support . The goal of this study was to examine the effects of treatment for depression on fatigue in MS . Methods : Sixty patients with a relapsing form of MS and moderate to severe depression were r and omly assigned to one of three vali date d 16‐week treatments for depression : individual cognitive behavioral therapy , group psychotherapy , or sertraline . Assessment s at baseline and treatment cessation included the primary outcome measure , fatigue assessment instrument ( FAI ) , and Beck depression inventory ( BDI ) . Results : The total FAI and the global fatigue severity subscale were significantly reduced over the course of treatment ( p values < .02 ) . Other subscales did not change significantly . Secondary analyses showed change in global fatigue severity was associated with change in BDI ( p = .03 ) but change in total FAI was only marginally related to change in BDI ( p = .05 ) . These relationships were due entirely to change in mood ( p values < .02 ) and not to change in cognitive or vegetative symptoms ( p values > .17 ) . Conclusions : These findings suggest that treatment for depression is associated with reductions in the severity of fatigue symptoms , and that this relationship is due primarily to treatment related changes in mood [3566815] Background : This study was design ed to evaluate the role of epidural methadone-lidocaine in cancer pain combined or not to epidural dexamethasone . Methods : In all , 72 cancer patients , 32- to 67-year-old were r and omized to six groups ( n=12 ) and prospect ively studied to examine analgesia and adverse effects for 3 weeks . Patients received single-dose protocol epidural test drugs : Control group ( CG ) received epidural 40-mg lidocaine diluted to 10-ml volume with saline . Dexamethasone group ( DG ) 40-mg lidocaine plus 10-mg dexamethasone . The 2.5MetG 2.5-mg epidural methadone with 40-mg lidocaine ; the 5MetG , 5-mg epidural methadone plus 40-mg lidocaine , the 7.5MetG , 7.5-mg epidural methadone plus 40-mg lidocaine and finally the 7.5Met-DexG , 7.5-mg methadone with 40-mg lidocaine and 10-mg dexamethasone . Results : Groups CG , DG and 2.5MetG were similar regarding analgesia and side effects . Patients from 5MetG and 7.5MetG took 3±1 and 5±1 days , respectively , to restart oral morphine . Patients from 7.5MetDG took 14±2 to restart oral morphine ( P<0.001 ) . Daily somnolence and appetite improved in the 7.5MetDG during 2-week evaluation ( P<0.005 ) . Fatigue improved for both DG and 7.5MetDG during 2-week evaluation ( P<0.005 ) . By the third week of evaluation , all patients were similar . Conclusions : Epidural methadone plus lidocaine result ed in dose-dependent analgesia , further improved by epidural dexamethasone , which also improved fatigue [9765767] PURPOSE To evaluate the effect of megestrol acetate at a lower dose than previously investigated on the symptoms of cachexia in patients with advanced cancer . METHODS A total of 84 patients with advanced , solid tumours not responsive to hormone therapy were enrolled in this double-blind , crossover study . During phase 1 , patients were r and omly assigned to receive megestrol acetate ( 160 mg 3 times daily ) for 10 days or placebo . During phase 2 , after a 2-day washout period , patients received the alternate treatment for 10 days . Patients underwent daily assessment s of activity , nausea , appetite and well-being by means of a visual analogue scale ( VAS ) . In addition , nutritional status ( weight , tricep skinfold measure , arm muscle circumference ) , energy intake , fatigue ( Piper Fatigue Scale ) and quality of life ( Functional Living Index-Cancer [ FLIC ] ) were assessed . RESULTS Among the 53 evaluable patients megestrol acetate result ed in a significant improvement in appetite ( p = 0.005 ) , activity ( p = 0.007 ) and well-being ( p = 0.03 ) . There was no significant change in the intensity of nausea , nutritional parameters , energy intake or FLIC scores . There was a significant improvement in 2 of the 3 factors measured by the Piper Fatigue Scale and in the overall fatigue score . Upon completion of the study , while still blind to the treatment condition , 30 patients indicated that they felt better overall after megestrol , 15 said they felt better after placebo , and 10 indicated no preference ( p = 0.001 ) . CONCLUSION Treatment with megestrol acetate results in rapid and significant improvement of symptoms in terminally ill patients at lower doses than previously reported . The effects are not secondary to nutritional changes . The FLIC quality -of-life question naire was unable to detect these changes [12727037] The purpose of this study was to vali date the changes in acute pain measurement scales that are most strongly associated with a patient-determined indicator of clinical importance . Measures of pain intensity and pain relief are commonly used outcomes in therapeutic clinical trials . Recent studies of the properties of acute pain measures have provided data defining the cut-off points that are best associated with clinical ly important differences . Validation of these findings in another clinical trial data set is important . Data were obtained from the titration phase of a recently conducted r and omized controlled clinical trial of oral transmucosal fentanyl citrate ( OTFC ) , which compared OTFC to immediate release morphine sulfate ( MSIR ) for the treatment of cancer-related acute breakthrough pain . Changes in pain intensity and pain relief were recorded every 15 minutes for 60 minutes and global medication performance recorded at the end of each study pain episode . At any titration step , if the patient felt that the first dose of the study medication did not provide adequate relief within 30 minutes , an additional rescue medication could be taken . To find the level of each pain scale best associated with this measure of the adequacy of pain relief , the calculated sensitivity , specificity , and accuracy for different cut-off points of the measured pain scales were compared to whether or not the patient needed rescue medication . The overall ability of the pain measures to discriminate episodes for which a rescue was not needed was calculated using area under the receiver operating characteristics ( ROC ) curves . Data were analyzed from 134 OTFC-naive patients who collected data on 1307 episodes of breakthrough pain . Using the criteria of a balanced sensitivity and specificity , the best cut-off points were determined to be : 33 % for the percent pain intensity difference ; > or = 2 for the raw pain intensity difference on a 0 - 10 numeric rating scale ; > or = 2 ( i.e. , moderate or better ) for pain relief ; > or = 33 % for the percent maximum total pain relief ; and > or = 2 ( good or better ) for global medication performance . ROC area under the curve ranged from 0.839 to 0.862 for each of the pain measures listed above , calculated at 60 minutes . These data indicate that the pain scale cut-off points that are best associated with a patient-derived measure of a clinical ly important difference closely approximate those found in an earlier study . ROC analysis provided evidence that the overall pain measures were strongly associated with not requiring an " additional dose of rescue medication . " Thus , the cut-off points determined for these pain scales provide a good surrogate measure of a patient-determined clinical ly important response . This provides support for the usefulness of these values in future clinical trials of pain therapy [10665616] BACKGROUND The goal was to evaluate the efficacy of testosterone in alleviation of hypogonadal symptoms ( diminished libido , depressed mood , low energy , and depleted muscle mass ) in men with symptomatic human immunodeficiency virus illness . METHODS Seventy-four patients were enrolled in a double-blind , placebo-controlled 6-week trial with bi-weekly testosterone injections , followed by 12 weeks of open-label maintenance treatment . Major outcome measures were Clinical Global Impressions Scale ratings for libido , mood , energy , and erectile function ; Hamilton Depression Rating Scale scores , and Chalder Fatigue Scale scores . Body composition changes were assessed with bioelectric impedance analysis . RESULTS Seventy men completed the 6-week trial . Response rates , defined as much or very much improved libido , were 74 % ( 28/38 ) for patients r and omized to testosterone , and 19 % ( 6/32 ) for placebo-treated patients ( P<.001 ) . Of the 62 completers with fatigue at baseline , 59 % ( 20/34 ) receiving testosterone and 25 % ( 7/28 ) receiving placebo reported improved energy ( P<.01 ) . Among the 26 completers with an Axis I depressive disorder at baseline , 58 % of the testosterone-treated patients reported improved mood compared with 14 % of placebo-treated patients ( Fisher exact test = .08 ) . With testosterone treatment , average increase in muscle mass over 12 weeks was 1.6 kg for the whole group , and 2.2 kg for the 14 men with wasting at baseline . Improvement on all parameters was maintained during subsequent open-label treatment for up to 18 weeks . CONCLUSION Testosterone is well tolerated and effective in the short-term treatment of symptoms of clinical hypogonadism in men with symptomatic human immunodeficiency virus illness , restoring libido and energy , alleviating depressed mood , and increasing muscle mass [2972270] In a double-blind placebo-controlled crossover study of ten patients with multiple sclerosis , we found amantadine hydrochloride therapy to be effective in improving fatigability in six . Administration of the drug was associated with significantly higher levels of beta-endorphin-beta-lipotropin and responders had significantly higher levels than nonresponders . Lactate levels were significantly higher and pyruvate levels lower in nonresponders . Amantadine given for fatigue to patients with multiple sclerosis is associated with measurable changes in levels of metabolites and peptides in the circulation [19270033] Cancer-related fatigue is the most prevalent and distressing symptom experienced by patients with advanced cancer . Central nervous system stimulants have been shown to relieve fatigue in nonmalignant disease . Modafinil is a stimulant with a selective site of action in the brain that is better tolerated than traditional stimulants , such as methylpheni date . The aim of this study was to determine the feasibility of conducting a r and omised controlled trial to assess the efficacy and safety of modafinil for the treatment of fatigue in patients with lung cancer . Twenty patients with non-small cell lung cancer were recruited to this open-label study . Modafinil was taken in a fixed dose-titration schedule of 100 mg daily for 7 days followed by 200 mg daily for 7 days . Fifteen patients completed the study . During the study period , there was a rapid and statistically significant reduction in the primary outcome , fatigue ( P = 0.001 ) and the secondary outcomes of daytime sleepiness and depression/anxiety . This improvement in fatigue was also clinical ly significant . Ten patients chose to continue modafinil after the study and the drug was well-tolerated . It would be both feasible and worthwhile to conduct a definitive r and omised controlled trial to determine the role of modafinil in the treatment of cancer-related fatigue [11997203] Abrupt onset of hot flashes poses a significant problem for women treated with chemotherapy for breast cancer . Alternatives to hormone replacement , such as the use of the selective serotonin re-uptake inhibitor ( SSRI ) paroxetine hydrochloride , are being explored as therapies for hot flashes in this patient population . The present study investigated the efficacy of paroxetine for the treatment of hot flashes and associated symptoms in women with breast cancer . This study included 13 patients who were seen in the Psychosocial Clinic at Moffitt Cancer Center . They were referred by their medical oncologist after reporting complaints of significant difficulty with hot flashes . Baseline question naires were completed and a structured diagnostic interview for clinical depression was conducted , all of which were repeated 5 weeks after the paroxetine 20 mg daily was started . Significant improvements were seen in the ratings of hot flash severity ( P = 0.002 ) . In addition , significant improvements were observed in general , emotional , and mental fatigue . Rates of clinical ly significant depressive symptomatology also decreased and sleep quality improved significantly as well . Finally , the incidence of clinical depression improved from 39 % at baseline to 8 % after treatment . These preliminary data suggest that the antidepressant paroxetine can be helpful in the treatment of hot flashes and associated fatigue , sleep disturbance , and depression in women with breast cancer treated with chemotherapy . Further controlled studies are needed to more fully evaluate the efficacy of the SSRIs for hot flashes in women with breast cancer [19367356] Background To investigate the effects of Modafinil on focused attention , motor function and motor excitability in patients with multiple sclerosis ( MS ) and fatigue . Methods 21 MS patients with fatigue were enrolled in this double-blind placebo-controlled study . Modafinil ( MOD ) or placebo ( PL ) was administered for 8 weeks . The d2 alertness test , the Nine Hole Peg Test ( 9HPT ) and several transcranial magnetic stimulation ( TMS ) techniques were applied prior to and after the first drug ingestion and well as after 8 weeks of drug intake . Results Prior to the first drug intake , the two groups were comparable . After the first drug ingestion , fatigue as measured by the Fatigue Severity Scale ( FSS ) , performance of the d2 test and the 9HPT improved significantly in the MOD group and remained better than in the PL group after 8 weeks of treatment . Patients in the MOD group made fewer mistakes in the D2 test without being slower . They completed the 9HPT faster . Motor evoked potential amplitudes produced by paired pulse TMS were larger in the MOD group than the PL group . Motor thresholds and silent period duration s remained unchanged . Conclusions Compared to PL , MOD improved fatigue , focused attention and dexterity and enhanced motor cortex excitability in this group of patients . MOD may be helpful in MS patients with fatigue to improve cognitive and motor abilities [17972110] Background Women who receive adjuvant chemotherapy for breast cancer develop fatigue , and a subset reports cognitive impairment . Methylpheni date is reported to improve fatigue and to decrease cognitive impairment in other population s. Material s and methods Women were r and omised early during their chemotherapy to receive d-methylpheni date ( d-MPH ) , a form of methylpheni date , or an identical appearing placebo . All participants took placebo for one cycle to ensure compliance and then study medication until completion of chemotherapy . Subjects were assessed at baseline , end of chemotherapy and at ∼6 months follow-up with the High Sensitivity Cognitive Screen ( HSCS ) and the Hopkins Verbal Learning Test-Revised ( HVLT-R ) . They also completed the self-report Functional Assessment of Cancer Therapy-General ( FACT-G ) and FACT-F ( F = fatigue ) question naires , evaluating quality of life and fatigue . Results A total of 57 evaluable women were r and omised : 29 to d-MPH and 28 to placebo ; the study did not meet its accrual goal of 170 patients , mainly because women were reluctant to take additional medication in general and methylpheni date in particular . Groups were well matched for age ( median , 50 years ) and education . d-MPH and placebo were well tolerated . There were no significant differences between the r and omised groups in classification of cognitive function by HSCS or in summed FACT-F fatigue scores ( the primary endpoints of the study ) at any of the assessment s. There were also no differences in HLTV-R scores or quality of life . Conclusions This study is underpowered , but there are no trends to suggest that d-MPH , taken concurrently with adjuvant chemotherapy , improves quality of life or fatigue [15736608] An open label trial of modafinil was conducted to determine whether it would be tolerated and effective in treating fatigue for people with amyotrophic lateral sclerosis ( ALS ) . Fifteen patients with ALS were treated for two weeks with either 200 mg or 400 mg of modafinil . Reported side effects of the medication were mild and included diarrhea , headache , nervousness , and insomnia . Side effects did not result in any study dropouts . Following treatment , mean scores on the Fatigue Severity Scale ( FSS ) decreased from 51.3 ( SD 9.2 ) to 42.8 ( SD 10.2 ) . On the Epworth Sleepiness Scale ( ESS ) , mean scores decreased from 8.2 ( SD 2.0 ) to 4.5 ( SD 2.4 ) . Reductions in both the FSS and the ESS were significant at p < 0.001 . Mean scores on the self-report version of the Functional Independence Measure ( FIM-SR ) increased from 115.2 ( SD 5.6 ) to 118.1 ( SD 5.4 ) , with p < 0.01 . This pilot study suggests that modafinil is well-tolerated and may reduce symptoms of fatigue in ALS . Further blinded , controlled studies of modafinil in larger numbers of ALS patients are warranted [16041840] This preliminary study investigated whether bupropion sustained release ( SR ) improved symptomatic fatigue , depression and quality of life in cancer patients and caregiver quality of life . The sample consisted of a prospect i ve open case series of 21 cancer patients , with fatigue and with or without depression at moderate to severe levels , referred for psychiatric assessment from a tertiary care cancer centre . Both patient symptom ratings and caregiver ratings were measured before and after 4 weeks of treatment with the maximally tolerated dose of bupropion in the range of 100 - 300 mg per day . At trial completion , significant improvement was found for symptoms of fatigue and depression . Subjects were divided into two groups : depressed and non-depressed ( based on a cut-off score of 17 on the Hamilton Depression Rating Scale ) . Both groups reported improvement for fatigue and depressive symptoms . Depressed subjects and their caregivers did not experience any change in quality of life , while the non-depressed subjects and their caregivers reported improvements . Results from this small group of patients suggest that bupropion may have potential as an effective pharmaceutical agent for treating cancer-related fatigue . A r and omized , placebo-controlled trial with this medication is indicated [7611638] Because amantadine has been shown to reduce fatigue in patients with multiple sclerosis , we performed a double-blind , placebo-controlled study to assess its efficacy in the disabling symptom of post-polio fatigue . Twenty-three patients completed six weeks of therapy . Fatigue was measured by the patients using visual analogue scales ( twice per day ) and numerical fatigue severity scales ( once per week ) and by overall impression ( at end of therapy ) . Formal neuropsychological testing and serum drug levels were performed to assess compliance . On all measures , no significant difference was found between treatment and placebo groups . Fifty-four percent of patients given amantadine and 43 % given placebo reported a decrease in fatigue ; however , the visual analogue scales and fatigue severity scales failed to reflect any improvement . Several patients in the treatment group elected to continue amantadine therapy after the study was completed . Our findings suggest that amantadine is not significantly better than placebo in reducing the sensation of fatigue in post-polio syndrome , and that the measures we employed were insensitive to capture the subjective response experienced by a few patients [7501140] Objective To determine the relative efficacy of amantadine , pemoline , and placebo in treatment of multiple sclerosis (MS)-related fatigue . Background Fatigue is a complication of MS . Both pemoline and amantadine have been used to treat MS fatigue , but their relative efficacy is not known . Methods Amantadine , pemoline , and placebo were compared in a r and omized , double-blind , placebo-controlled study using a parallel-group design . Ninety-three ambulatory MS patients completed the study . Primary outcome measures were the fatigue seventy scale ( FSS ) ; the MS-specific fatigue scale ( MS-FS ) ; and subjective response determined by verbal self-report . Secondary outcome measures consisted of assessment s of sleep , depression , and vitality . Repeated- measures analysis of variance with planned post-hoc contrasts and Fisher 's exact test were used to compare treatment response . Results Amantadine-treated patients showed a significantly greater reduction in fatigue , as measured by the MS-FS , than did patients treated with placebo ( p = 0.04 ) . By verbal report at the end of the study , 79 % of patients treated with amantadine versus 52 % treated with placebo and 32 % treated with pemoline preferred drug therapy compared with no treatment ( p = 0.03 ) . No significant differences in any primary outcome measures were noted between pemoline and placebo . Neither amantadine nor pemoline affected sleep or depression relative to placebo . Conclusion Amantadine was significantly better than placebo in treating fatigue in MS patients , whereas pemoline was not . The benefit of amantadine was not due to changes in sleep , depression , or neurologic disability [14673053] PURPOSE Fatigue and depression typically occur together in cancer patients , suggesting a common etiology , perhaps based on serotonin . This r and omized clinical trial tested whether paroxetine , a selective serotonin reuptake inhibitor antidepressant known to modulate brain serotonin , would reduce fatigue in cancer patients and whether any reduction was related to depression . PATIENTS AND METHODS Cancer patients undergoing chemotherapy for the first time were assessed for fatigue . Of 704 patients who reported fatigue at their second chemotherapy cycle , 549 patients were r and omly assigned to receive either 20 mg of oral paroxetine hydrochloride daily or placebo for 8 weeks . The assessment s of fatigue and depression were performed at cycles 3 and 4 of chemotherapy . RESULTS A total of 244 patients treated with paroxetine and 235 patients treated with placebo provided assessable data . No difference was detected in fatigue between patient groups . At the end of the study , there was a difference between groups in the mean level of depression ( Center for Epidemiologic Studies Depression scores , 12.0 v 14.8 , respectively ; P < .01 ) . CONCLUSION Paroxetine had no influence on fatigue in patients receiving chemotherapy . A possible explanation is that cancer-related fatigue does not involve a reduction in brain 5-HT levels [16619567] The objective of this r and omised , multicentre , double-blind clinical trial was to investigate the impact of PS76A2 , an aqueous mistletoe extract st and ardised to mistletoe lectins , on quality of life ( QoL ) in breast cancer patients . A total of 352 patients were r and omly allocated to 2 groups receiving PS76A2 ( 15 ng mistletoe lectin/0.5 ml ) or matching placebo twice weekly for 4 to 6 cycles of CMF ( cyclophosphamide , methotrexate , fluorouracil ) chemotherapy followed by 2 months follow-up . The primary efficacy end-point was the change from baseline of 3 FACT-G subscales ( physical , emotional and functional well-being ) during the fourth CMF cycle . Secondary measures included GLQ-8 ( 8 linear analogue self- assessment scales ) , Spitzer 's uniscale and haematological variables . The main variables of safety analysis were adverse events , including injection site reactions and clinical laboratory tests . The results showed that physical , emotional and functional well-being improved upon PS76A2 , but deteriorated following placebo . The treatment differences were statistically significant for the 3 subscales as well as for the summary score FACT-G , which was analysed as O'Brien 's rank sum of its 3 subscales : The total score increased by 4.40 + /- 11.28 , indicating a higher QoL after PS76A2 , but decreased by 5.11 + /- 11.77 with placebo ( p<0.0001 ) . The GLQ-8 sum of 8 LASA scales was analysed as a summary score of GLQ-5 ( sum of item nos. 1 , 5 , 6 , 7 , 8) and GLQ-3 ( sum of item nos. 2 , 3 , 4 ) . GLQ-5 characterises typical aspects of QoL , while GLQ-3 consists of 3 side-effects of CMF ( feeling sick , numbness or pins and needles , loss of hair ) . GLQ-5 decreased by 42.9 + /- 125.0 upon PS76A2 , indicating an improvement in QoL , but increased by 60.3 + /- 94.0 upon placebo ( p<0.0001 ) . GLQ-3 deteriorated in both groups ( PS76A2 : 13.9 + /- 52.4 ; placebo : 34.5 + /- 57.0 ) , but the differences in favour of PS76A2 were , nevertheless , statistically significant ( p=0.0007 ) . The total score GLQ-8 improved by 28.9 + /- 154.6 after PS76A2 and deteriorated by 94.8 + /- 141.1 after placebo ( p<0.0001 ) . Spitzer 's uniscale improved by 12.2 + /- 30.7 upon PS76A2 and deteriorated by 10.8 + /- 26.1 with placebo ( p<0.0001 ) . After follow-up without chemotherapy , a significant treatment difference in favour of PS76A2 was determined by means of FACT-G , GLQ-8 and Spitzer 's uniscale . PS76A2 was well tolerated in this trial , with the exception of slight local reactions in 17.6 % of the PS76A2 group . In conclusion , PS76A2 ( 15 ng mistletoe lectin/0.5 ml twice weekly ) was shown to be safe and effective in improving QoL in breast cancer patients during chemotherapy and follow-up [19620846] Background : Fatigue is a major nonmotor symptom in Parkinson disease ( PD ) . It is associated with reduced activity and lower quality of life . Objective : To determine if modafinil improves subjective fatigue and physical fatigability in PD . Methods : Nineteen PD patients who reported significant fatigue in the Multidimensional Fatigue Inventory ( MFI ) participated in this 8-week study . Subjects took their regular medications and were r and omly assigned to the treatment group ( 9 subjects , modafinil 100-mg capsule BID ) or placebo group ( 10 subjects ) . We used the MFI to measure subjective fatigue and used finger tapping and intermittent force generation to evaluate physical fatigability . Subjects also completed the Epworth Sleepiness Scale ( ESS ) and the Center of Epidemiological Study -Depression Scale . Results : There were no significant differences at baseline and at 1 month in finger tapping and ESS between the modafinil and placebo groups . At 2 months , the modafinil group had a higher tapping frequency ( P < 0.05 ) , shorter dwell time ( P < 0.05 ) , and less fatigability in finger tapping and tended to have lower ESS scores ( P < 0.12 ) than the placebo group . However , there was no difference between groups over time for any dimension of the MFI . Conclusions : This small study demonstrated that although modafinil may be effective in reducing physical fatigability in PD , it did not improve fatigue symptoms [11927189] We have previously shown that the risk of major depression in patients with malignant melanoma undergoing interferon-α ( IFN-α ) therapy can be reduced by pretreatment with the antidepressant , paroxetine . Using dimensional analyses , the present study assessed the expression and treatment responsiveness of specific clusters of neuropsychiatric symptoms over the first three months of IFN-α therapy . Forty patients with malignant melanoma eligible for IFN-α treatment were r and omly assigned to receive either paroxetine or placebo in a double-blind design . Neuropsychiatric assessment s were conducted at regular intervals during the first twelve weeks of IFN-α therapy and included the 21-item Hamilton Depression Rating Scale , the 14-item Hamilton Anxiety Rating Scale and the Neurotoxicity Rating Scale . Neurovegetative and somatic symptoms including anorexia , fatigue and pain appeared within two weeks of IFN-α therapy in a large proportion of patients . In contrast , symptoms of depressed mood , anxiety and cognitive dysfunction appeared later during IFN-α treatment and more specifically in patients who met DSM-IV criteria for major depression . Symptoms of depression , anxiety , cognitive dysfunction and pain were more responsive , whereas symptoms of fatigue and anorexia were less responsive , to paroxetine treatment . These data demonstrate distinct phenomenology and treatment responsiveness of symptom dimensions induced by IFN-α , and suggest that different mechanisms mediate the various behavioral manifestations of cytokine-induced “ sickness behavior . [10721881] We investigated the effect of amantadine on cognitive processing in patients with multiple sclerosis ( MS ) and fatigue with objective electrophysiological measures . Behavioral methods ( Reaction Time , RT ) and two different Event Related Potential ( ERP ) components measuring i ) stimulus selection ( Selection Negativity , SN ) and ii ) response selection ( Lateralized Readiness Potential , LRP ) were employed . Twenty-four patients with clinical definite MS ( 10 relapsing remitting and 14 secondary progressive ) and confirmed fatigue in the past three months ( Fatigue Severity Scale ( FSS ) > 4 ) were included . Patients were r and omized in a double-blind , placebo-controlled cross-over design . We found a difference between the two treatments for ERP measures to stimuli with relevant colour starting at about 200 ms . This negativity had a higher amplitude during amantadine treatment regardless of treatment order . The RT did not differ significantly between the treated and untreated groups . Additional analysis indicated that patients with a disease duration of less than 7 years had a significant test position ( practice effect ) , but no treatment effect , while patients with a longer MS duration showed no practice effect , but rather an improved reaction speed and increased ERP amplitude effects when treated with amantadine . The present findings suggest that amantadine exerts beneficial effects on early cognitive processes in patients with MS , but appears to be limited to subjects with a longer duration of the disease [15327047] Sixty relapsing-remitting multiple sclerosis ( MS ) patients were selected on the basis of their score on the Fatigue Severity Scale ( FSS ) and formed two groups : 40 patients ( fatigued MS ; MSf ) scored above the 75th percentile of a previously assessed representative MS sample ( 100 patients ) , and 20 age- and sex-matched patients ( nonfatigued MS patients ; MSnf ) scored below the 25th percentile . The patients underwent clinical evaluation ( Exp and ed Disability Status Scale ( EDSS ) ) , further assessment of fatigue ( Fatigue Impact Scale ) , scales evaluating depression ( Hamilton Depression Rating Scale ( HDRS ) and Beck ’s Depression Inventory ( BDI ) ) and neuropsychological tests . All patients were evaluated for muscle fatigability and central activation by means of a biomechanical test of sustained contraction ; they also underwent somatosensory evoked potentials ( SSEPs ) and transcranial magnetic stimulation ( TMS ) . The patients of the MSf subgroup were then r and omized to one of the following two treatments : 4-aminopyridine ( 4-AP ) 24 mg/day and fluoxetine ( FLX ) 20 mg/day . After a one-week titration this treatment proceeded for 8 weeks . At the end of the treatment , EDSS , fatigue and depression scores were further evaluated . At baseline , fatigue test scores consistently correlated with depression and cognitive test scores , but not with the fatigability test . Fatigue scores decreased in both treatment groups in a similar way . Due to the design of the study , this can not be disjoined from a placebo effect . The changes of fatigue scores could not be predicted in the FLX group , whereas in the 4-AP group higher basal fatigability test scores were associated with greater reduction in fatigue scores [18304907] The amphetamine , methylpheni date ( Ritaline ) has been proposed as being of interest in the treatment of asthenia in patients with advanced cancer . To evaluate this hypothesis a r and omised controlled double-blind parallel-group national multi-centre trial is proposed versus placebo . Three previous r and omised controlled studies and one open study have suggested that the administration of methylpheni date may be of interest in the palliative care of asthenic cancer patients . However , these studies do not permit a definitive conclusion to be drawn . This article presents the protocol of our new trial . The primary objective is to evaluate the anti-asthenic effect of methylpheni date using a visual analogue scale ( VAS ) after 7 days of treatment of cancer patients in palliative care , i.e. when the cancer is considered to be rapidly evolving or as terminal . One hundred and ten patients are treated for 28 days at a starting dose of 20 mg/day , and adjustment of the dose is possible . It is important to stress that only the concerted efforts of an interdisciplinary team ( somatologues , psychiatrists , psychologists , paramedical carers and social workers ) can tackle the challenges posed by the difficult symptom of asthenia . The medical treatment is only one element of the approach to caring for these patients [8639070] BACKGROUND Amantadine hydrochloride and pemoline , both frequently used to treat the fatigue of multiple sclerosis ( MS ) , may also improve attention and other cognitive functions in MS . To our knowledge , these agents have never been compared in a placebo-controlled trial of patients with MS . OBJECTIVE To evaluate the effects of amantadine and pemoline on cognitive functioning in MS . METHODS A total of 45 ambulatory patients with MS and severe fatigue were treated for 6 weeks with amantadine , pemoline , or placebo using a parallel group design . They underwent comprehensive neuropsychological testing to determine treatment effects on cognitive functioning . Primary outcome measures were tests of attention ( Digit Span , Trail Making Test , and Symbol Digit Modalities Test ) , verbal memory ( Selective Reminding Test ) , nonverbal memory ( Benton Visual Retention Test ) , and motor speed ( Finger Tapping Test ) . RESULTS Fatigue did not significantly correlate with any of the neuropsychological outcome measures at baseline or after treatment . All three treatment groups improved on tests of attention ( P < .003 ) , verbal memory ( P < .001 ) , and motor speed ( P < .002 ) . There were no significant differences between amantadine , pemoline , and placebo . CONCLUSIONS Cognitive functioning in MS is independent of fatigue . Neither amantadine nor pemoline enhances cognitive performance in MS compared with placebo [3902184] We carried out a double blind control study of fatigue in 32 patients with multiple sclerosis , comparing amantadine hydrochloride 100 mg twice a day and placebo . On amantadine 31 % had marked improvement ; 15.6 % moderate improvement ; 15.6 % mild improvement ; and 36.5 % unchanged . On placebo , none noted marked improvement ; one cl aim ed moderate improvement on either amantadine or placebo . 18.7 % reported mild improvement on placebo ; and most of them had similar or more response to amantadine . No patient selected placebo over amantadine at the end of the trial . Overall improvement was seen in 62.5 % of patients on amantadine and 21.8 % on placebo . Additional experience up to two years suggests continued benefit but common and important side-effects [10633535] The goal of this pilot study was to evaluate the effect of dehydroepi and rosterone ( DHEA ) on depressed mood and fatigue in HIV+ men and women , unselected for baseline DHEA level . Secondary questions concerned treatment effects on libido and body cell mass , on serum testosterone levels , and elicitation of short-term side effects . Treatment consisted of an open-label 8-week trial using DHEA doses from 200 to 500 mg/day . Mood responders were maintained for another 4 weeks , then r and omized to a double blind placebo controlled 4-week discontinuation trial . Forty-five patients , including six women , entered the trial . Of 32 week 8 completers , mood was much improved in 72 % , and 81 % were rated responders with respect to fatigue . Response on either parameter was unrelated to baseline serum DHEA level . Twenty-one patients entered the double blind discontinuation phase . No differences in relapse rate between placebo and DHEA groups were observed for either mood or fatigue . Body cell mass increased significantly by week 8 , and this improvement was maintained throughout the double blind phase for patients in both treatment conditions . Libido increased significantly as well . DHEA therapy did not have an effect on CD4 cell count or on serum testosterone levels in men . In conclusion , DHEA may be a promising treatment for HIV+ patients with depressed mood and fatigue , although persistence of response even in placebo-treated patients during the discontinuation phase leaves unresolved questions . A parallel group double blind clinical trial is indicated as the next step to more clearly identify therapeutic efficacy [12195441] Background Modafinil is a unique wake-promoting agent that is chemically distinct from traditional stimulants . Results of a placebo-controlled study showed it to improve fatigue in multiple sclerosis ( MS ) at a dose of 200 mg daily , but not at a dose of 400 mg daily . Objective To establish the efficacy , safety and appropriate dose of modafinil in the treatment of fatigue and sleepiness in patients with multiple sclerosis . Method A total of 50 patients diagnosed with MS ( mean age 40.4 ± 10.3 years , 30 females/20 males ; MS type : 36 relapsing remitting , 1 primary progressive , 13 secondary progressive ; mean disability level 3.8 ± 1.5 on the Kurtzke EDSS ) and complaining of chronic fatigue were enrolled in a prospect i ve 3-month , two-center , open-label study . Efficacy was evaluated with the Fatigue Severity Scale ( FSS , score range 0 - 42 ) , the Epworth Sleepiness Scale ( ESS , score range 0 - 24 ) and by subjective patient appraisal of change of fatigue , quality of life and overall satisfaction with treatment . Adverse effects ( AEs ) were recorded throughout the study . Treatment was started with a single daily dose of 100 mg in all patients . In non-responders the dose was increased by 100 mg increments up to a maximum daily dose of 400 mg . Results Three patients discontinued modafinil because of AEs ( nervousness , dizziness ) . Two patients ( 4 % ) were treated with 50 mg , 25 ( 50 % ) with 100 mg , 21 ( 42 % ) with 200 mg and 2 ( 4 % ) with 300 mg daily . No patient required 400 mg daily . Mean FSS scores were 30.3 ± 8.5 at baseline and 25.4 ± 3.7 at 3 months ( p < 0.0001 ) . Mean ESS scores were 9.7 ± 3.9 at baseline and 4.9 ± 2.9 at 3 months ( p < 0.0001 ) . Self- appraisal of change of fatigue showed clear improvement in 41 patients ( 87.2 % ) , some improvement in 4 ( 8.5 % ) and no change in 2 ( 4.3 % ) . Overall clinical condition was clearly improved in 43 patients ( 91.5 % ) , somewhat improved in 1 patient ( 2.1 % ) , and unchanged in 3 patients ( 6.4 % ) . No patient reported worsening of overall clinical condition . Conclusions Treatment with modafinil significantly improves fatigue and sleepiness and is well tolerated by patients with MS . Unlike the higher dose regimen required in narcolepsy , a low-dose regimen of modafinil is effective in MS [17869448] PURPOSE The quality of life ( QOL ) and neurocognitive function of patients with brain tumors are negatively affected by the symptoms of their disease and brain radiation therapy ( RT ) . We assessed the effect of prophylactic d-threo-methylpheni date HCl ( d-MPH ) , a central nervous system ( CNS ) stimulant on QOL and cognitive function in patients undergoing RT . METHODS AND MATERIAL S Sixty-eight patients with primary or metastatic brain tumors were r and omly assigned to receive d-MPH or placebo . The starting dose of d-MPH was 5 mg twice daily ( b.i.d . ) and was escalated by 5 mg b.i.d . to a maximum of 15 mg b.i.d . The placebo was administered as one pill b.i.d . escalating three pills b.i.d . The primary outcome was fatigue . Patients were assessed at baseline , the end of radiation therapy , and 4 , 8 , and 12 weeks after brain RT using the Functional Assessment of Cancer Therapy with brain and fatigue ( FACIT-F ) subscales , as well as the Center for Epidemiologic Studies Scale and Mini-Mental Status Exam . RESULTS The Mean Fatigue Subscale Score at baseline was 34.7 for the d-MPH arm and 33.3 for the placebo arm ( p = 0.61 ) . At 8 weeks after the completion of brain RT , there was no difference in fatigue between patient groups . The adjusted least squares estimate of the Mean Fatigue Subscale Score was 33.7 for the d-MPH and 35.6 for the placebo arm ( p = 0.64 ) . Secondary outcomes were not different between the two treatment arms . CONCLUSIONS Prophylactic use of d-MPH in brain tumor patients undergoing RT did not result in an improvement in QOL [20054744] BACKGROUND AND PURPOSE Fatigue is a frequent symptom in multiple sclerosis ( MS ) , recognized as the most unpleasant symptom by 50 - 60 % of patients . Amantadine is one of the medications prescribed for fatigue in MS . Some previous studies have demonstrated a positive influences of amantadine on fatigue in MS . The aim of this study was to determine the efficacy of amantadine on Persian MS patients . MATERIAL AND METHODS This prospect i ve study took place in Isfahan , Iran and included 42 MS patients with fatigue who were divided r and omly into two groups . Twenty-one patients received amantadine and all others placebo . The Fatigue Severity Scale ( FSS ) was used to determine the severity of the fatigue . FSS scores at baseline and two months later were compared in the two groups . RESULTS Mean ( SD ) baseline FSS score was 5.27 ( 1.11 ) in the amantadine group and 4.89 ( 1.13 ) in the placebo group ( p > 0.05 ) . Mean FSS at the end of study was 4.00 ( 1.02 ) in the amantadine group and 4.24 ( 1.03 ) in the placebo group ( p > 0.05 ) ; however , the FSS change ( the difference between FSS scores at the end of the study and at the beginning of the study ) in amantadine and placebo groups was -1.27 ( 0.53 ) and -0.66 ( 0.33 ) , respectively , which was significant ( p < 0.05 ) . CONCLUSIONS Our findings demonstrate a significant drop on the fatigue severity scale in MS patients after treatment with amantadine ; nevertheless , more studies on a larger scale with longer duration are needed to confirm this finding [22987089] PURPOSE L-carnitine , a popular complementary and alternative medicine product , is used by patients with cancer for the treatment of fatigue , the most commonly reported symptom in this patient population . The purpose of this study was to determine the efficacy of L-carnitine supplementation as a treatment for fatigue in patients with cancer . PATIENTS AND METHODS In this double-blind , placebo-controlled trial , patients with invasive malignancies and fatigue were r and omly assigned to either 2 g/d of L-carnitine oral supplementation or matching placebo . The primary end point was the change in average daily fatigue from baseline to week 4 using the Brief Fatigue Inventory ( BFI ) . RESULTS Three hundred seventy-six patients were r and omly assigned to treatment with L-carnitine supplementation or placebo . L-carnitine supplementation result ed in significant carnitine plasma level increase by week 4 . The primary outcome , fatigue , measured using the BFI , improved in both arms compared with baseline ( L-carnitine : -0.96 , 95 % CI , -1.32 to -0.60 ; placebo : -1.11 , 95 % CI -1.44 to -0.78 ) . There were no statistically significant differences between arms ( P = .57 ) . Secondary outcomes , including fatigue measured by the Functional Assessment of Chronic Illness Therapy-Fatigue instrument , depression , and pain , did not show significant difference between arms . A separate analysis of patients who were carnitine-deficient at baseline did not show statistically significant improvement in fatigue or other outcomes after L-carnitine supplementation . CONCLUSION Four weeks of 2 g of L-carnitine supplementation did not improve fatigue in patients with invasive malignancies and good performance status [15591014] Nutritional factors are among the postulated causes of fatigue , a highly prevalent symptom in the cancer population , with serious impact on patients ' quality of life . Deficiency of the micronutrient carnitine may play a role by reducing energy production through fatty acid oxidation . We present preliminary data of an open-label , dose-finding study to determine safety and maximally tolerated dose ( MTD ) of 1 week of L-carnitine supplementation in cancer patients with fatigue and carnitine deficiency . Patients who met inclusion /exclusion criteria underwent carnitine level determination . Eighty-three percent of these patients ( 15/18 ) had carnitine deficiency . Preliminary data analysis of 13 patients showed that total carnitine increased from 30.0 + /- 6.9 to 41.0 + /- 12.1 ( mean + /- SD ) after 1 week of supplementation ( P = 0.01 ) , and free carnitine increased from 24.3 + /- 6.1 to 33.8 + /- 9.8 ( P = 0.004 ) . Outcome measures were fatigue ( BFI score ) , depression ( CES-D ) , sleep disruption ( ESS ) , and performance status ( Karnofsky ) . Median ( min , max ) BFI score at baseline was 73 ( 46 , 82 ) versus 50 ( 3 , 82 ) after 1-week supplementation ( P = 0.009 ) . CES-D score at baseline was 29 ( 16 , 42 ) and 22 ( 8 , 32 ) after 1 week ( P = 0.028 ) . ESS at baseline was 46.5 ( 0 , 69 ) and 30.4 ( 0 , 72 ) after 1 week ( P = 0.015 ) . Karnofsky score did not change significantly ( P = 0.38 ) . We are currently conducting a r and omized , double-blind , placebo-controlled study to rigorously assess the role of L-carnitine for the treatment of fatigue and depression in cancer patients [20955776] Increased levels of inflammatory cytokines such as tumor necrosis factor ( TNF ) and interleukin-6 ( IL-6 ) may play a role in depression . Mild depressive-like symptoms can be induced in humans through activation of the innate immune system with endotoxin . Whether preventive treatment with antidepressants can reduce endotoxin-induced symptoms has never been tested . In a double-blind , r and omized , placebo-controlled , cross-over study , we administered intravenous low-dose endotoxin ( 0.8 ng/kg ) or placebo to 11 healthy subjects who had received oral pre-treatment with citalopram ( 10 mg twice a day ) or placebo for 5 days . The Montgomery-Åsberg Depression Rating Scale , the State and Trait Anxiety Inventory , and a visual analog scale were used to measure depressive and anxiety symptoms and social anhedonia . Serum levels of TNF and IL-6 were measured with immunoassays . Compared to placebo , endotoxin administration increased serum levels of TNF and IL-6 , and caused mild depressive-like symptoms , in particular lassitude and social anhedonia . While citalopram pre-treatment had no effect on the innate immune response to endotoxin , it reduced the endotoxin-induced MADRS total score by 50 % , with a moderate effect size ( Cohen 's d=0.5 ) . Most of the MADRS total score was due to the lassitude item , and citalopram pre-treatment specifically reduced endotoxin-induced lassitude with a large effect size ( Cohen 's d=0.9 ) . These results suggest that subchronic pre-treatment with the serotonin-reuptake inhibitor citalopram blunts mood symptoms induced by acute immune system activation with endotoxin without inhibiting the peripheral immune response [12743146] PURPOSE To determine whether fluoxetine improves overall quality of life ( QOL ) in advanced cancer patients with symptoms of depression revealed by a simple survey . PATIENTS AND METHODS One hundred sixty-three patients with an advanced solid tumor and expected survival between 3 and 24 months were r and omly assigned in a double-blinded fashion to receive either fluoxetine ( 20 mg daily ) or placebo for 12 weeks . Patients were screened for at least minimal depressive symptoms and assessed every 3 to 6 weeks for QOL and depression . Patients with recent exposure to antidepressants were excluded . RESULTS The groups were comparable at baseline in terms of age , sex , disease distribution , performance status , and level of depressive symptoms . One hundred twenty-nine patients ( 79 % ) completed at least one follow-up assessment . Analysis using generalized estimating equation modeling revealed that patients treated with fluoxetine exhibited a significant improvement in QOL as shown by the Functional Assessment of Cancer Therapy-General , compared with patients given placebo ( P = .01 ) . Specifically , the level of depressive symptoms expressed was lower in patients treated with fluoxetine ( P = .0005 ) , and the subgroup of patients showing higher levels of depressive symptoms on the two- question screening survey were the most likely to benefit from treatment . CONCLUSION In this mix of patients with advanced cancer who had symptoms of depression as determined by a two- question bedside survey , use of fluoxetine was well tolerated , overall QOL was improved , and depressive symptoms were reduced [11325685] Exercise capacity in patients with end-stage renal disease ( ESRD ) remains impaired despite correction of anemia . Carnitine insufficiency may contribute to impaired exercise and functional capacities in patients with ESRD . Two r and omized placebo-controlled trials were conducted to test whether intravenous L-carnitine improves exercise capacity ( assessed by maximal rate of oxygen consumption [ VO(2max ) ] ) and quality of life ( measured by the Kidney Disease Question naire [ KDQ ] ) in patients with ESRD . In study A , patients were administered L-carnitine , 20 mg/kg ( n = 28 ) , or placebo ( n = 28 ) intravenously at the conclusion of each thrice-weekly dialysis session for 24 weeks . In study B , a dose-ranging study , patients were administered intravenous L-carnitine , 10 mg/kg ( n = 32 ) , 20 mg/kg ( n = 30 ) , or 40 mg/kg ( n = 32 ) , or placebo ( n = 33 ) as in study A. The prospect i ve primary statistical analysis evaluated changes in VO(2max ) in each study and specified that changes in the KDQ were assessed only in the combined population s. L-Carnitine supplementation increased plasma carnitine concentrations , but did not affect VO(2max ) in either study . Because change in VO(2max ) showed significant heterogeneity , a secondary analysis using a mixture of linear models approach on the combined study population s was performed . L-Carnitine therapy ( combined all doses ) was associated with a statistically significant smaller deterioration in VO(2max ) ( -0.88 + /- 0.26 versus -0.05 + /- 0.19 mL/kg/min , placebo versus L-carnitine , respectively ; P = 0.009 ) . L-Carnitine significantly improved the fatigue domain of the KDQ after 12 ( P = 0.01 ) and 24 weeks ( P = 0.03 ) of treatment compared with placebo using the primary analysis but did not significantly affect the total score ( P = 0.10 ) or other domains of the instrument ( P > 0.11 ) . Carnitine was well tolerated , and no drug-related adverse effects were identified . Intravenous L-carnitine treatment increased plasma carnitine concentrations , improved patient-assessed fatigue , and may prevent the decline in peak exercise capacity in hemodialysis patients . VO(2max ) in the primary analysis and other assessed end points were unaffected by carnitine therapy [10789956] Abstract A multivariate analysis of the data was conducted to evaluate the effects of age , gender , and performance status on symptom profile . A comprehensive prospect i ve analysis of symptoms was conducted in 1,000 patients on initial referral to the Palliative Medicine Program of the Clevel and Clinic . The median number of symptoms per patient was 11 ( range 1–27 ) . The ten most prevalent symptoms were pain , easy fatigue , weakness , anorexia , lack of energy , dry mouth , constipation , early satiety , dyspnea , and greater than 10 % weight loss . The prevalence of these 10 symptoms ranged from 50 % to 84 % . Younger age was associated with 11 symptoms : blackout , vomiting , pain , nausea , headache , sedation , bloating , sleep problems , anxiety , depression , and constipation . Gender was associated with 8 symptoms . Males had more dysphagia , hoarseness , > 10 % weight loss and sleep problems ; females , more early satiety , nausea , vomiting , and anxiety . Performance status was associated with 14 symptoms . Advanced cancer patients are polysymptomatic . Ten symptoms are highly prevalent . Symptom prevalence for 24 individual symptoms differs with age , or gender , or performance status [19208404] Our objective was to determine whether modafinil alleviates fatigue in patients with amyotrophic lateral sclerosis ( ALS ) . A placebo controlled trial with a 3:1 modafinil : placebo r and omization in doses up to 300 mg/day for 4 weeks was followed by 8 weeks of open maintenance treatment . The primary endpoint was the Clinical Global Impressions-Improvement Scale . Secondary endpoints were the Fatigue Severity Scale , Epworth Sleepiness Scale , Beck Depression Inventory , Role Function Scale , and visual analog scales . Analysis of covariance was used to assess change at Week 4 . Thirty-two patients were r and omized ; 29 completed the 4-week trial . In intention to treat ( ITT ) analysis , the response was 76 % for modafinil versus 14 % for placebo . In a completer analysis , the modafinil response rate was 86 % , and the placebo response rate remained 14 % . The number needed to treat was 1.6 ( ITT ) . No medically serious adverse events were reported . Modafinil may be a promising intervention for fatigue in ALS patients . Replication in a larger study is needed [14711473] Systemic syndromes characterized by a persistent activity of circulating mediators ( cytokines ) are frequently present with advanced cancer . We grouped under the general heading of " Systemic Immune-Metabolic Syndrome ( SIMS ) " a particular variety of distressing systemic syndrome characterized by dysregulation of the psycho-neuro-immune-endocrine homeostasis , with overlapping clinical manifestations . SIMS may include cachexia , anorexia , nausea , early satiety , fatigue , tumor fever , cognitive changes and superinfection . The aim of this study was to ameliorate some of the SIMS symptoms in a homogeneous group of lung adenocarcinoma patients using a multitargeted therapy . Fifteen patients with evidence of SIMS were studied . SIMS was defined as the presence of weight loss , anorexia , fatigue performance status>/=2 and acute-phase protein response . Patients received medroxyprogesterone ( MPA ) ( 500 mg twice daily ) , celecoxib ( 200 mg twice daily ) , plus oral food supplementation for 6 weeks . After treatment , 13 patients either had stable weight ( + /- 1 % ) or had gained weight . There were significant differences in improvement of body-weight-change rate , nausea , early satiety , fatigue , appetite and performance status . Patients who had any kind of lung infection showed higher levels of IL-10 compared to non-infected patients ( P=0.039 ) . Our results suggest that patients with advanced lung adenocarcinoma , treated with MPA , celecoxib and dietary intervention , might have considerable improvement in certain SIMS outcomes . This multitargeted symptomatic approach deserves further study [20564068] Cancer‐related fatigue is a debilitating symptom affecting psychosocial functioning and quality of life in 70 % to 100 % of cancer patients during and after treatment . The authors examined the effect of 200 mg of modafinil daily on the severity of cancer‐related fatigue [16648508] PURPOSE To evaluate the effectiveness of patient-controlled methylpheni date as compared with placebo in cancer patients with fatigue , as measured by the Functional Assessment for Chronic Illness Therapy-Fatigue ( FACIT-F ) . PATIENTS AND METHODS Patients with a fatigue score of at least 4 on a scale of 0 to 10 ( 0 = no fatigue , 10 = worst possible fatigue ) and hemoglobin level of at least 10 g/dL were included . Patients were r and omly assigned to receive 5 mg methylpheni date or placebo every 2 hours as needed ( maximum of four capsules a day ) , for 7 days . Patients completed a daily diary including study drug record and fatigue intensity . A research nurse telephoned patients daily to assess toxicity and fatigue level . All patients were offered open-label methylpheni date for 4 weeks . FACIT-F and the Edmonton Symptom Assessment System ( ESAS ) were assessed at baseline , and days 8 , 15 , and 36 . The FACIT-F fatigue subscore on day 8 was considered the primary end point . RESULTS Of 112 patients r and omly assigned , 52 patients in the methylpheni date and 53 in the placebo group were assessable for analysis . Fatigue intensity improved significantly on day 8 in both the methylpheni date and placebo groups . However , there was no significant difference in fatigue improvement by FACIT-F ( P = .31 ) or ESAS ( P = .14 ) between groups . In open-label phase , fatigue intensity maintained low as compared with baseline . No significant toxicities were observed . CONCLUSION Both methylpheni date and placebo result ed in significant symptom improvement . Methylpheni date was not significantly superior to placebo after 1 week of treatment . Longer study duration is justified . The role of daily telephone calls from a research nurse should be explored as a palliative care intervention [24445757] Purpose This study assessed the efficacy of methylpheni date versus placebo for cancer-related fatigue reduction . Other objectives were to analyze cytokine levels and to determine the effects of methylpheni date on other symptoms , cognitive function , work yield , and patients ’ perceptions and preferences . Methods Patients were r and omly assigned ( 1:1 ) to receive methylpheni date -placebo or placebo-methylpheni date for 4 weeks . Patients crossed over after 2 weeks . Wilcoxon signed rank tests and McNemar tests were used to assess continuous and categorical variables . The primary efficacy endpoint was change in the level of worst fatigue on the Brief Fatigue Inventory ( BFI ) at the end of each 2-week period . Results The mean baseline BFI score was moderate ( 5.7 ) . Methylpheni date treatment did not affect patients ’ worst level of fatigue or other symptoms . Results from the Wechsler Adult Intelligence Scale Digit Symbol Test and the Hopkins Verbal Learning Test with BFI interference questions and BFI activity questions showed significant improvement in the methylpheni date -treated patients ’ verbal learning , memory , visual perception , analysis , and scanning speed . Patients treated with methylpheni date missed significantly fewer work hours owing to health reasons and worked significantly more hours . After 4 weeks , 64 % of patients reported that methylpheni date improved their cancer-related fatigue , and 58 % wanted to continue treatment . Significant difference in interleukin 6R ( positive ) , interleukin 10 ( negative ) , and tumor necrosis factor & agr ; ( positive ) was noted between the methylpheni date and the placebo group . Conclusions Low-dose methylpheni date did not improve cancer-related fatigue . Patients taking methylpheni date had better cognition and were able to work more hours . Patients tolerated methylpheni date well , and the majority felt better and wanted to continue treatment [15824361] Pharmacotherapeutic options for multiple sclerosis (MS)-related fatigue are limited . Thirty patients were r and omly assigned to aspirin ( ASA ) 1,300 mg/day or placebo in a double-blind crossover study . Results favored ASA for the main clinical outcomes : Modified Fatigue Impact Scale scores ( p = 0.043 ) and treatment preference ( p = 0.012 ) . There were no significant adverse effects . The results warrant further study and support a role for ASA-influenced mechanisms , perhaps immunologic , in the generation of MS-related chronic fatigue [21427431] Fatigue is prevalent among patients with hepatitis C virus ( HCV ) and with HIV/AIDS but there are no established fatigue treatments for either condition or their combination . We analysed data from three trials of modafinil or armodafinil for HIV-positive patients with fatigue , including 36 co-infected with HCV , to compare treatment response and safety parameters related to HCV status . One hundred and twenty patients received active drug and 70 were r and omized to placebo . Fatigue response rate to modafinil/armodafinil was 100 % for patients with HCV ( 18/18 ) and 73 % ( 74/102 ) for patients without HCV . Placebo response rate was 28 % ( 5/18 ) and 29 % ( 15/52 ) , respectively . Depressive symptoms improved only when energy improved . Viral load declined from baseline after 12 and 26 weeks of active medication . CD4 cell count did not change , nor did alanine transaminase and aspartate aminotransferase for patients with HCV . Patients with haematocrit below the reference range responded , as well as patients whose values were within the reference range . Modafinil and armodafinil appear effective and well tolerated for treating fatigue among both HCV-positive and HCV-negative patients with HIV/AIDS , suggesting that they may hold promise for HIV-positive patients considering alpha interferon/ribavirin treatment for HCV . Further investigation in a focused trial is warranted [20625123] PURPOSE Fatigue is one of the most common symptoms experienced by patients with cancer . This trial was developed to evaluate the efficacy of long-acting methylpheni date for improving cancer-related fatigue and to assess its toxicities . PATIENTS AND METHODS Adults with cancer were r and omly assigned in a double-blinded manner to receive methylpheni date ( target dose , 54 mg/d ) or placebo for 4 weeks . The Brief Fatigue Inventory was the primary outcome measure , while secondary outcome measures included a Symptom Experience Diary ( SED ) , the Short Form-36 ( SF-36 ) Vitality Subscale , a linear analog self- assessment , the Pittsburgh Sleep Quality Index , and the Subject Global Impression of Change . RESULTS In total , 148 patients were enrolled . Using an area under the serum concentration-time curve analysis , there was no evidence that methylpheni date , as compared with placebo , improved the primary end point of cancer-related fatigue in this patient population ( P = .35 ) . Comparisons of secondary end points , including clinical ly significant changes in quality -of-life variables and cancer-related fatigue change from baseline , were similarly negative . However , a subset analysis suggested that patients with more severe fatigue and /or with more advanced disease did have some fatigue improvement with methylpheni date ( eg , in patients with stage III or IV disease , the mean improvement in usual fatigue was 19.7 with methylpheni date v 2.1 with placebo ; P = .02 ) . There was a significant difference in self-reported toxicities ( SED ) , with increased levels of nervousness and appetite loss in the methylpheni date arm . CONCLUSION This clinical trial was unable to support the primary pre study hypothesis that the chosen long-acting methylpheni date product would decrease cancer-related fatigue [14585555] Opioid-induced sedation is a major complication in patients with cancer pain . This study assessed the effectiveness of donepezil in opioid-induced sedation and related symptoms in patients with cancer pain . Twenty-seven patients who were receiving strong opioids for pain and reported sedation were enrolled . Donepezil 5 mg was given every morning for 7 days . Changes between baseline and Day 7 in sedation , pain , fatigue and other symptoms were evaluated using the Edmonton Symptom Assessment Scale . Fatigue was also measured using the Functional Assessment of Chronic Illness Therapy-Fatigue ( FACIT-Fatigue ) . Overall usefulness of donepezil was measured by the patient at the end of the study . In 20 evaluable patients , sedation , fatigue , anxiety , well-being , depression , anorexia and problems with sleep were significantly improved . Side effects included nausea , vomiting , diarrhea , muscle and abdominal cramps , and anorexia . Overall , however , the treatment was well tolerated . Donepezil appears to improve sedation and fatigue in patients receiving opioids for cancer pain . R and omized controlled trials of this agent are justified [7539701] Sedation may be a doselimiting side-effect of opioid therapy in some cancer patients . This study was design ed to evaluate further the use of the psychostimulant , methylpheni date , an agent that has been reported to counteract opioid-induced sedation , in patients with cancer-related pain . Patients receiving a stable dose of an opioid for cancer-related pain were recruited for this r and omized , double-blind , crossover clinical trial . In addition to their regular dose of narcotics , they received 5 days of methylpheni date followed by 5 days of placebo , or vice versa . Our data did not definitively demonstrate any statistically significant benefit for methylpheni date , but did suggest that this drug could mildly decrease narcotic-induced drowsiness and could increase night-time sleep . These data , in conjunction with other published data , suggest that methylpheni date can counteract narcotic-induced daytime sedation to a limited degree [17687152] PURPOSE To evaluate the effectiveness of donepezil compared with placebo in cancer patients with fatigue as measured by the Functional Assessment for Chronic Illness Therapy-Fatigue ( FACIT-F ) . PATIENTS AND METHODS Patients with fatigue score > or= 4 on a scale of 0 to 10 ( 0 = no fatigue , 10 = worst possible fatigue ) for more than 1 week were included . Patients were r and omly assigned to receive donepezil 5 mg or placebo orally every morning for 7 days . A research nurse contacted the patients by telephone daily to assess toxicity and fatigue level . All patients were offered open-label donepezil during the second week . FACIT-F and /or the Edmonton Symptom Assessment System ( ESAS ) were assessed at baseline , and days 8 , 11 , and 15 . The FACIT-F fatigue subscale score on day 8 was considered the primary end point . RESULTS Of 142 patients r and omly assigned to treatment , 47 patients in the donepezil group and 56 in the placebo group were assessable for final analysis . Fatigue intensity improved significantly on day 8 in both donepezil and placebo groups . However , there was no significant difference in fatigue improvement by FACIT-F ( P = .57 ) or ESAS ( P = .18 ) between groups . In the open-label phase , fatigue intensity continued to be low as compared with baseline . No significant toxicities were observed . CONCLUSION Donepezil was not significantly superior to placebo in the treatment of cancer-related fatigue [20844926] Summary Background The objectives of this pilot study were to evaluate the safety and efficacy of the central nervous system stimulant methylpheni date in the management of asthenia in breast cancer patients treated with docetaxel . Patients and methods Patients with early breast cancer who presented asthenia > 3 on the Visual Analogue Scale ( VAS ) after the first cycle of docetaxel-based chemotherapy were included . Patients received two additional cycles of chemotherapy , one with methylpheni date ( 10 mg bid ) and the other without methylpheni date . Asthenia was evaluated using VAS and the Functional Assessment of Cancer Therapy-Fatigue ( FACT-F ) scale . Distress was assessed using the Hospital Anxiety and Depression Scale ( HADS ) , and quality of life using FACT-F. Results Ten patients were included and evaluated for efficacy and safety . Overall , cycles with methylpheni date were better tolerated than those without methylpheni date in terms of asthenia ( VAS , p = 0.004 ; FACT-F , p = 0.027 ) and quality of life ( FACT-F , p = 0.047 ) . No significant differences were observed in terms of distress ( HADS , p = 0.297 ) . Six ( 60 % ) patients continued with methylpheni date after study end . Main adverse events during study were palpitations and insomnia ( 30 % of patients each ) . Conclusions This pilot study suggests that methylpheni date may reduce asthenia and improve quality of life in breast cancer patients treated with docetaxel [23897970] PURPOSE Cancer-related fatigue ( CRF ) is the most common symptom in patients with advanced cancer . The primary objective of this prospect i ve , r and omized , double-blind , placebo-controlled study was to compare the effect of dexamethasone and placebo on CRF . PATIENTS AND METHODS Patients with advanced cancer with ≥ three CRF-related symptoms ( ie , fatigue , pain , nausea , loss of appetite , depression , anxiety , or sleep disturbance ) ≥ 4 of 10 on the Edmonton Symptom Assessment Scale ( ESAS ) were eligible . Patients were r and omly assigned to either dexamethasone 4 mg or placebo orally twice per day for 14 days . The primary end point was change in the Functional Assessment of Chronic Illness-Fatigue ( FACIT-F ) subscale from baseline to day 15 . Secondary outcomes included anorexia , anxiety , depression , and symptom distress scores . RESULTS A total of 84 patients were evaluable ( dexamethasone , 43 ; placebo , 41 ) . Mean ( ± st and ard deviation ) improvement in the FACIT-F subscale at day 15 was significantly higher in the dexamethasone than in the placebo group ( 9 [ ± 10.3 ] v 3.1 [ ± 9.59 ] ; P = .008 ) . The improvement in FACIT-F total quality -of-life scores was also significantly better for the dexamethasone group at day 15 ( P = .03 ) . The mean differences in the ESAS physical distress scores at day 15 were significantly better for the dexamethasone group ( P = .013 , respectively ) . No differences were observed for ESAS overall symptom distress ( P = .22 ) or psychological distress score ( P = .76 ) . Frequency of adverse effects was not significantly different between groups ( 41 of 62 v 44 of 58 ; P = .14 ) . CONCLUSION Dexamethasone is more effective than placebo in improving CRF and quality of life in patients with advanced cancer [20492840] OBJECTIVE To evaluate the efficacy and safety of modafinil in the treatment of fatigue in patients with human immunodeficiency virus/acquired immune deficiency syndrome ( HIV/AIDS ) and to assess effect on depressive symptoms . METHOD Patients who were HIV+ and had clinical ly significant fatigue ( according to the Fatigue Severity Scale [ FSS ] ) were included in a 4-week r and omized , placebo-controlled , double-blind trial . This was followed by an additional 8 weeks of open-label treatment for modafinil responders and 12 weeks for placebo nonresponders . The primary outcome measure for fatigue and depression was the Clinical Global Impressions-Improvement scale , supplemented by the FSS , Hamilton Depression Rating Scale , and Beck Depression Inventory . Safety was assessed with assays of CD4 cell count and HIV ribonucleic acid ( RNA ) viral load . Visits were weekly for 4 weeks , then biweekly , with a follow-up visit at 6 months . Maximum trial dose of modafinil was 200 mg/d . Data for this study were collected between December 2004 and December 2008 . RESULTS 115 patients were r and omly assigned . In intention-to-treat analyses , fatigue response rate to modafinil was 73 % and to placebo , 28 % . Attrition was 9 % . Modafinil did not have an effect on mood alone in the absence of improved energy . At week 4 , CD4 cell counts did not change significantly ; HIV RNA viral load showed a trend decline for patients taking modafinil but not for those taking placebo . At 6 months , those still taking modafinil had more energy and fewer depressive symptoms than patients who were not taking modafinil , and only those still taking modafinil showed a significant decline from baseline in their HIV RNA viral load . CONCLUSIONS Modafinil appears to be effective and well tolerated in treating fatigue in HIV+ patients . Consideration of its use is warranted considering the high prevalence of fatigue in the HIV community , its minimal side effects , and overall patient acceptance . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00118378 [24337761] Purpose Modafinil has been reported to benefit a subgroup of patients suffering severe fatigue while undergoing chemotherapy . Docetaxel is associated with fatigue that may lead to premature therapy withdrawal . We investigated whether modafinil could reduce fatigue during docetaxel chemotherapy . Methods This multicenter , r and omized , double-blind , placebo-controlled study evaluated the efficacy of modafinil in patients with metastatic prostate or breast cancer undergoing docetaxel chemotherapy ( every 21 days ; minimum dose 50 mg/m2 ) . At the start of their third or subsequent chemotherapy cycle , patients with significant docetaxel-associated fatigue were r and omized to receive concurrent modafinil 200 mg/day or placebo for 15 days ( “ treatment periods ” ( TP ) ) . Docetaxel was continued for up to four further cycles . Fatigue was evaluated with the fatigue component of the MD And erson Symptom Inventory ( MDASI ) . The primary endpoint was cumulative MDASI area under the curve ( AUC ) during the first 7 days of study medication during TP1 and TP2 . Results Evaluable data were available from 83 patients ( 65 with prostate cancer ) . There was no statistically significant difference between the two treatment arms for the primary endpoint ( MSADI AUC3–10 35.9 vs 39.6 ; 95 % confidence interval −8.9 , 1.4 ; P = 0.15 ) . Overall toxicity was comparable between treatment groups ; however , the incidence of grade ≤2 nausea and vomiting was higher in the modafinil arm ( 45.4 vs 25 % ) . Conclusions Assessing and managing chemotherapy-related fatigue remains a major challenge . There was a lack of difference between the two arms in the planned primary endpoint . However , there was a modest but consistent trend towards improvement of docetaxel-related fatigue in those treated with modafinil . Based on the study findings , modafinil for the treatment of fatigue associated with docetaxel chemotherapy elicits modest improvements . Larger , longer term , r and omized , controlled studies are required to clarify the exact role of modafinil in the treatment of docetaxel-related fatigue [18790598] Fatigue is very common in patients with cancer . Current guidelines suggest that psychostimulants are " reasonable to consider for severe fatigue . " This r and omized , double-blind , placebo-controlled trial investigated the hypothesis that dexamphetamine in fatigued patients with advanced cancer would produce a clinical ly significant improvement with minimal side effects . Fifty patients with advanced cancer , who were receiving palliative care , were r and omized to dexamphetamine 10 mg twice daily or placebo for eight days . Effectiveness was assessed using the Brief Fatigue Inventory and the McGill Quality -of-Life Question naire . The side effects were recorded . The results were analyzed on an intention-to-treat basis . The baseline demographics , fatigue levels , and quality -of-life scores were similar between the two arms . Patients were elderly , had impaired performance status ( Eastern Cooperative Oncology Group score=3 ) , and were taking a range of neurologically active medications . Thirty-nine patients completed the trial . There was a transient improvement in the fatigue levels on day 2 , but no significant difference in fatigue ( P=0.267 ) or quality of life ( P=0.579 ) by the end of the study . Statistical modeling did not reveal any significant predictors of response to dexamphetamine . These results suggest that dexamphetamine 20 mg daily , although well tolerated , does not significantly improve fatigue or quality of life in patients with advanced cancer , as measured by the selected instruments [10492632] A r and omised double-blind placebo-controlled multicentre trial was performed to investigate the effects of megestrol acetate ( MA ) on the quality of life ( QoL ) , appetite , weight and survival of patients with advanced , incurable , hormone-insensitive cancer . QoL was assessed at the start of treatment and at 4 , 8 and 12 weeks , using the EORTC-QLQ-C30 instrument . 255 patients were r and omised to 320 mg of MA daily or placebo for 12 weeks . 244 patients were assessable at baseline , 190 at 4 weeks ( placebo 94 ; MA 96 ) , 150 at 8 weeks ( placebo 69 ; MA 81 ) and 112 at 12 weeks ( placebo 55 ; MA 57 ) . A beneficial effect of MA on appetite loss was observed at week 4 ( P < 0.0001 ) and possibly at week 8 ( P = 0.058 ) . Further weight loss during treatment was significant only in the placebo group . In the first 8 weeks , changes in mean global QoL were small and similar in both groups . By 12 weeks the decrease in mean global QoL was more pronounced in the MA group ( P = 0.028 ) , which was related to a deterioration in physical function , while psychosocial function was not affected . Survival was not affected by MA , and side-effects were mild . The results show that MA has a beneficial effect on appetite and that it may retard weight loss with no adverse impact on survival and with mild toxicity . However , MA does not appear to improve global QoL as measured by the EORTC QLQ-C30 [17157757] Carnitine deficiency is among the many metabolic disturbances that may contribute to fatigue in patients with cancer . Administration of exogenous L-carnitine may hold promise as a treatment for this common symptom . Little is known about L-carnitine safety , tolerability , and dose-response in patients with cancer . We conducted a Phase I/II open-label trial to assess the safety and tolerability of exogenous L-carnitine and clarify the safe dose range associated with symptom effects for future controlled trials . Adult patients with advanced cancer , carnitine deficiency ( free carnitine < 35 for males or < 25 microM/L for females , or acyl/free carnitine ratio > 0.4 ) , moderate to severe fatigue , and a Karnofsky Performance Status ( KPS ) score > or = 50 were entered by groups of at least three into a st and ard maximum tolerated dose design . Each successive group received a higher dose of L-carnitine ( 250 , 750 , 1250 , 1750 , 2250 , 2750 , 3000 mg/day , respectively ) , administered in two daily doses for 7 days . To compare symptom outcomes before and after supplementation , patients completed vali date d measures of fatigue ( Brief Fatigue Inventory [ BFI ] ) , depressed mood ( Center for Epidemiologic Studies Depression Scale [ CES-D ] ) , quality of sleep ( Epworth Sleeplessness Scale [ ESS ] ) , and KPS at baseline and 1 week later . Of the 38 patients screened for carnitine levels , 29 were deficient ( 76 % ) . Twenty-seven patients participated ( " intention to treat , ITT " ) ( 17 males , 10 females ) , and 21 completed the study ( " completers " ) ; 17 of these patients ( " responders , " mean+/-[SD ] age=57.9+/-15 ) had increased carnitine levels at the end of the supplementation period . The highest dose achieved was 3000 mg/day . No patient experienced significant side effects and no toxicities were noted . Analysis of all the patients accrued ( ITT , n=27 ) showed a total carnitine increase from 32.8+/-10 to 54.3+/-23 microM/L ( P<0.001 ) and free carnitine increase from 26.8+/-8 to 44.1+/-17 microM/L ( P<0.001 ) . BFI decreased significantly , from 66+/-12 to 39.7+/-26 ( P<0.001 ) ; ESS decreased from 12.9+/-12 to 9+/-6 ( P=0.001 ) ; and CES-D decreased from 29.2+/-12 to 19+/-12 ( P<0.001 ) . A separate analysis of the 17 " responders " showed a dose-response relationship for total- ( r=0.54 , P=0.03 ) , free-carnitine ( r=0.56 , P=0.02 ) levels , and fatigue ( BFI ) scores ( r=-0.61 , P=0.01 ) . These findings suggest that l-carnitine may be safely administered at doses up to 3000 mg/day and that positive effects may be more likely at relatively higher doses in this range . This study provides the basis for the design of future placebo-controlled studies of l-carnitine supplementation for cancer-related fatigue [17548243] BACKGROUND Depression , anxiety , fatigue , and impaired wellbeing are common , important , and closely related in advanced cancer . We aim ed to identify the effects of an established antidepressant on these symptoms and survival in patients with advanced cancer who did not have major depression as assessed by clinicians . METHODS Between July , 2001 , and February , 2006 , 189 patients with advanced cancer were r and omly assigned sertraline 50 mg ( n=95 ) , or placebo ( n=94 ) , once per day . The primary outcome was depression as assessed by the Centre for Epidemiologic Studies Depression scale ( CES-D ) ; the main secondary outcomes were : anxiety as assessed by Hospital Anxiety and Depression Scales ( HADS-A ) ; overall quality of life and fatigue as assessed by Functional Assessment of Cancer Therapy General and Fatigue scales ( FACT-G and FACT-F , respectively ) ; and clinicians ' ratings of quality of life by use of Spizter 's Quality of Life Index ( SQLI ) . Multiple measures were used for corroboration of the most important outcomes . Primary analyses were done by intention to treat and were based on scale scores at 4 weeks and 8 weeks . The benefits of sertraline compared with placebo are expressed on a range from + 100 ( ie , maximum benefit ) to -100 ( ie , maximum harm ) ; a difference of 10 was deemed clinical ly significant . This clinical trial is registered at Current Controlled Trials website http://www.controlled-trials.com/IS RCT N72466475 . FINDINGS Sertraline had no significant effect ( scale , benefit over placebo [ 95 % CI ] ) on depression ( CES-D 0.4 [ -2.6 to 3.4 ] ) , anxiety ( HADS-A 2.0 [ -1.5 to 5.5 ] ) , fatigue ( FACT-F 0.3 [ -4.3 to 4.9 ] ) , overall quality of life ( FACT-G 1.7 [ -1.3 to 4.7 ] ) , or clinicians ' ratings ( SQLI 2.0 [ -2.5 to 6.5 ] ) , and the 95 % CI ruled out a clinical ly significant benefit for all main outcomes . Sertraline was discontinued more often and earlier than was placebo ( hazard ratio 1.46 [ 1.03 - 2.06 ] , p=0.03 ) . Recruitment was stopped after the first planned interim analysis in February 2006 ( n=150 ) showed that survival was longer in patients assigned placebo than in patients assigned sertraline ( unadjusted hazard ratio 1.60 [ 95 % CI 1.04 - 2.45 ] , log-rank p=0.04 ; adjusted hazard ratio 1.62 [ 1.06 - 2.41 ] , Cox model p=0.02 ) . However , at the final analysis in July 2006 of all patients ( n=189 ) and with longer follow-up , survival did not differ significantly between the treatment groups ( unadjusted hazard ratio 1.35 [ 0.95 - 1.91 ] , log-rank p=0.09 ; adjusted hazard ratio 1.27 [ 0.87 - 1.84 ] , Cox model p=0.20 ) . The trial was closed because it had ruled out a significant benefit of sertraline . INTERPRETATION Sertraline did not improve symptoms , wellbeing , or survival in patients with advanced cancer who do not have major depression , and should be reserved for those with a proven indication [15201369] Objective : To assess the effects of glatiramer acetate and β interferon on fatigue in multiple sclerosis . Methods : Fatigue was measured at baseline and six months using the fatigue impact scale ( FIS ) . Groups ( glatiramer acetate and β interferon ) were evaluated for the proportion improved , using Fisher ’s exact test . Logistic regression analysis assessed the relation between treatment group and improvement and controlled for confounding variables . Results : Six month paired FIS assessment s were available for 218 patients ( 76 % female ) . Ages ranged between 19 and 61 years , with 86 % having relapsing-remitting disease . Glatiramer acetate was used by 61 % and β interferon by 39 % . At baseline , total FIS and subscale scores were comparable in the two groups . More patients improved on glatiramer acetate than on β interferon on total FIS ( 24.8 % v 12.9 % , p = 0.033 ; adjusted odds ratio = 2.36 , 95 % confidence interval 1.03 to 5.42 ) , and on physical ( 28.6 % v 14.1 % , p = 0.013 ) and cognitive subscales ( 21.1 % v 10.6 % , p = 0.045 ) . Logistic regression analysis confirmed the association between glatiramer acetate use and improved fatigue , after accounting for baseline group differences . Conclusions : The odds of reduced multiple sclerosis fatigue were around twice as great with glatiramer acetate treatment as with β interferon . Confirmation of this result is required [4135151] In a controlled double blind study involving 116 patients with far‐advanced gastrointestinal cancer , dexamethasone at dosages of 0.75 and 1.5 mg four times daily produced improved appetite and sense of well‐being in comparison to placebo treatment . This symptomatic palliation , however , was not accompanied by weight gain or improved performance status . Survival of the steroid treated patients was essentially identical to that of the placebo treated patients . Cancer 33:1607–1609 , 1974 [1641137] Fatigue occurs in a majority of patients with MS and is generally independent of measurable neurologic disability . Few options for treatment are available . We conducted a double-blind , placebo-controlled , crossover trial for each of two 4-week treatment periods . Forty-six eligible patients entered and five dropped out due to concurrent exacerbations . Nineteen patients ( 46.3 % ) experienced excellent or good relief of fatigue with pemoline , and eight patients ( 19.5 % ) with placebo ( p = 0.06 , Fisher 's exact test ) . One-fourth of patients did not tolerate the drug well , and 7 % had to discontinue pemoline during the study due to side effects . The most common side effects were anorexia , irritability , and insomnia . Pemoline may be an effective short-term treatment for fatigue associated with MS , but its adverse effects are not well tolerated by many patients [18809275] Carnitine deficiency is prevalent in population s with chronic illness , including cancer . In a recent open-label study , L-carnitine supplementation was well tolerated and appeared to improve fatigue and other outcomes in cancer patients . To further evaluate this finding , adult patients with advanced cancer , carnitine deficiency ( free carnitine more than 35 micromol/L for males or less than 25 micromol/L for females , or acyl/free carnitine ratio of more than 0.4 ) , moderate to severe fatigue , and a Karnofsky Performance Status ( KPS ) score of 50 or more , were r and omly assigned to receive either L-carnitine ( 0.5 g/day for two days , followed by 1g/day for two days , and then 2g/day for 10 days ) or placebo . This double-blind phase was followed by an open-label phase , during which all patients received L-carnitine supplementation for two weeks . Outcomes included the fatigue subscale of the Functional Assessment of Cancer Therapy-Anemia ( FACT-An ) , the Linear Analog Scale Assessment s ( LASA ) , the Mini-Mental State Exam ( MMSE ) , and the KPS . Twenty-nine patients ( 12 placebo , 17 L-carnitine ) were included in the intent-to-treat ( ITT ) analysis . From baseline to the end of the double-blind phase , serum total and free L-carnitine increased from 32.9+/-3.8 to 56.6+/-20.5 ( P=0.004 ) , and from 22.9+/-19.4 to 45.3+/-17.2 ( P=0.004 ) , respectively , in the L-carnitine-treated group , and from 28.2+/-10.2 to 36.2+/-8.7 ( P = ns ) , and from 22.6+/-7.9 to 28.7+/-8.6 ( P = ns ) in the placebo group , respectively . The planned ITT analysis revealed no significant improvement in any of the study 's endpoints , and these negative findings were not different when data from two patients who did not adhere to the protocol were eliminated . However , an exploratory covariate analysis that excluded these two protocol violators and included outcome data from both the double-blind and open-label phases demonstrated significantly improved fatigue on the FACT-An fatigue subscale ( P<0.03 ) , and significantly improved FACT-An functional well-being subscale ( P<0.03 ) , and KPS ( P<0.003 ) , in the group that started with L-carnitine during the double-blind phase . These data do not support the conclusion that L-carnitine in the doses tested reverses cancer-related fatigue in carnitine-deficient patients . However , L-carnitine supplementation does increase L-carnitine serum levels , and the positive findings in an exploratory analysis justify a larger study to determine if this strategy could be of benefit for a sub population of cancer patients [15232328] Background : While testosterone 's ameliorative effects on depressive disorders and fatigue in HIV-positive patients have been suggested in the literature , no placebo-controlled trial selecting for depressive disorders and including a st and ard antidepressant has been conducted . Accordingly , this double-blind trial was design ed to determine whether testosterone , as well as fluoxetine , is superior to placebo for depression , fatigue , or both . Method : One hundred twenty-three men with HIV/AIDS with a Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition depressive disorder entered the 8-week trial and were r and omized to testosterone ( up to 400 mg IM testosterone cypionate biweekly ) , fluoxetine ( up to 60 mg/d ) , or double placebo . Outcome variables were the Clinical Global Impressions Scale for mood and for fatigue , the Hamilton Rating Scale for Depression , and the Chalder Fatigue Scale . Results : Ninety men completed the trial . In intention-to-treat analyses , mood response rates were 54 % , 47 % , and 44 % for fluoxetine , testosterone , and placebo , respectively . Among completers , mood response rates were 70 % , 57 % , and 53 % , respectively ; in neither analysis were differences between treatments statistically significant . In contrast , testosterone was superior to fluoxetine and placebo for completers regarding fatigue . In intention-to-treat analysis , response rates were 39 % , 56 % , and 42 % for fluoxetine , testosterone , and placebo , respectively , and for study completers , 41 % , 63 % , and 52 % , respectively , ( P < 0.05 ) , Conclusion : While over 50 % of patients treated with testosterone reported improved mood , this rate was not statistically superior to placebo . Thus , our findings do not support prescription of testosterone as a first-line treatment for depressive disorders in HIV-positive men . However , if vali date d in additional studies , testosterone may be a useful option for medically ill men experiencing significant fatigue as well as depression [8648360] PURPOSE To investigate the effects of medroxyprogesterone acetate ( MPA ) on appetite , weight , and quality of life ( QL ) in patients with advanced-stage , incurable , non-hormone-sensitive cancer . PATIENTS AND METHODS Two hundred six eligible patients were r and omized between double-blind MPA 500 mg twice daily or placebo . Appetite ( 0 to 10 numerical rating scale ) , weight , and QL ( European Organization for Research and Treatment of Cancer Quality of Life Question naire [ EORTC-QLQ-C30 ] ) were assessed before the start of treatment ( t = 0 ) , and 6 weeks ( t = 6 ) and 12 weeks ( t = 12 ) thereafter . RESULTS One hundred thirty-four patients ( 68 MPA and 66 placebo ) were assessable at t = 6 and 99 patients ( 53 MPA and 46 placebo ) at t = 12 . A beneficial effect of MPA on appetite was observed after both 6 weeks ( P = .008 ) and 12 weeks ( P = .01 ) of treatment . After 12 weeks , a mean weight gain of 0.6 + /- 4.4 kg was seen in the MPA , versus an ongoing mean weight loss of 1.4 + /- 4.6 kg in the placebo group . This difference of 2.0 kg was statistically significant ( P = .04 ) . During the study , several areas of QL deteriorated in the total group of patients . With the exception of an improvement in appetite and possible also a reduction in nausea and vomiting , no measurable beneficial effects of MPA on QL could be demonstrated . The side effects profile of MPA was favorable : only a trend toward an increase in ( usually mild ) peripheral edema was observed . CONCLUSION In weight-losing , advanced-stage non-hormone-sensitive cancer patients , MPA exhibits a mild side effects profile , has a beneficial effect on appetite , and may prevent further weight loss . However , general QL in the present study was not measurably influenced by MPA treatment [10901342] BACKGROUND This report documents findings from a small placebo-controlled trial of dextroamphetamine for depression and fatigue in men with the human immunodeficiency virus ( HIV ) . Dextroamphetamine offers the potential for rapid onset of effect and activation properties , both of which are important to persons with medical illness and an uncertain , but limited , life expectancy . METHOD Primary inclusion criteria included the presence of a DSM-IV depressive disorder , debilitating fatigue , and no history of dependence on stimulants . The study consisted of a 2-week r and omized , placebo-controlled trial , with the blind maintained until week 8 for responders , followed by open treatment through the completion of 6 months . RESULTS Of 23 men who entered the study , 22 completed the 2-week trial . Intent-to-treat analysis indicated that 73 % of patients ( 8/11 ) r and omly assigned to dextroamphetamine reported significant improvement in mood and energy , compared with 25 % ( 3/12 ) among placebo patients ( Fisher exact test , p < .05 ) . Both clinician- and self-administered measures indicated significantly improved mood , energy , and quality of life among patients taking dextroamphetamine . There was no evidence of the development of tolerance of , abuse of , or dependence on the medication . CONCLUSION These results suggest that dextroamphetamine is a potentially effective , fast-acting antidepressant treatment for HIV patients with depression and debilitating fatigue

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### Context: [11796766] Objective : To assess the efficacy and safety of modafinil for the treatment of fatigue in multiple sclerosis ( MS ) . Methods : Patients aged 18–65 years with a diagnosis of MS , a stable disability level ≤6 on the Kurtzke extended disability status scale ( EDSS ) , and a mean score > 4 on the fatigue severity scale ( FSS ) were eligible for the 9 week , single blind , phase 2 , two centre study . Exclusion criteria included a diagnosis of narcolepsy , sleep apnoea , or clinical ly significant major systemic disease and recent use of medications affecting fatigue . All patients , who remained blinded for the treatment regimen , received placebo during weeks 1–2 , 200 mg/day modafinil during weeks 3–4 , 400 mg/day modafinil during weeks 5–6 , and placebo during weeks 7–9 . Safety was evaluated by unblinded investigators . Efficacy was evaluated by self rating scales , using the FSS , the modified fatigue impact scale ( MFIS ) , a visual analogue scale for fatigue ( VAS-F ) , and the Epworth sleepiness scale ( ESS ) . Adverse events were recorded . Results : Seventy two patients ( MS type : 74 % relapsing-remitting ; 7 % primary progressive ; 19 % secondary progressive ) received treatment . After treatment with 200 mg/day modafinil for 2 weeks , a significant improvement in fatigue versus placebo run in was demonstrated . Mean scores after treatment with 200 mg/day modafinil were : FSS , 4.7 versus 5.5 for placebo ( p<0.001 ) ; MFIS , 37.7 versus 44.7 ( p<0.001 ) ; and VAS-F , 5.4 versus 4.5 ( p=0.003 ) . Fatigue scores for 400 mg/day modafinil were not significantly improved versus placebo run in . Mean ESS scores were significantly improved ( p<0.001 ) with 200 mg/day modafinil ( 7.2 ) and 400 mg/day ( 7.0 ) versus the score at baseline ( 9.5 ) . Serious adverse events were not found at either dose . The most common adverse events were headache , nausea , and aesthenia . Sixty five patients ( 90 % ) completed the study . Conclusions : These data suggest that 200 mg/day modafinil significantly improves fatigue and is well tolerated in patients with MS [16549835] PURPOSE A prospect i ve , open-label phase II study was conducted to determine whether donepezil , a US Food and Drug Administration-approved reversible acetylcholinesterase inhibitor used to treat mild to moderate Alzheimer 's type dementia , improved cognitive functioning , mood , and quality of life ( QOL ) in irradiated brain tumor patients . PATIENTS AND METHODS Thirty-four patients received donepezil 5 mg/d for 6 weeks , then 10 mg/d for 18 weeks , followed by a washout period of 6 weeks off drug . Outcomes were assessed at baseline , 12 , 24 ( end of treatment ) , and 30 weeks ( end of wash-out ) . All tests were administered by a trained research nurse . RESULTS Of 35 patients who initiated the study , 24 patients ( mean age , 45 years ) remained on study for 24 weeks and completed all outcome assessment s. All 24 patients had a primary brain tumor , mostly low- grade glioma . Scores significantly improved between baseline ( pretreatment ) and week 24 on measures of attention/concentration , verbal memory , and figural memory and a trend for verbal fluency ( all P < .05 ) . Confused mood also improved from baseline to 24 weeks ( P = .004 ) , with a trend for fatigue and anger ( all P < .05 ) . Health-related QOL improved significantly from baseline to 24 weeks , particularly , for brain specific concerns with a trend for improvement in emotional and social functioning ( all P < .05 ) . CONCLUSION Cognitive functioning , mood , and health-related QOL were significantly improved following a 24-week course of the acetylcholinesterase inhibitor donepezil . Toxicities were minimal . We are planning a double blinded , placebo-controlled , phase III trial of donepezil to confirm these favorable results [2375434] Ifosfamide and cisplatin cause urinary loss of carnitine , which is a fundamental molecule for energy production in mammalian cells . We investigated whether restoration of the carnitine pool might improve chemotherapy-induced fatigue in non-anaemic cancer patients . Consecutive patients with low plasma carnitine levels who experienced fatigue during chemotherapy were considered eligible for study entry . Patients were excluded if they had anaemia or other conditions thought to be causing asthenia . Fatigue was assessed by the Functional Assessment of Cancer Therapy-Fatigue quality of life question naire . Treatment consisted of oral levocarnitine 4 g daily , for 7 days . Fifty patients were enrolled ; chemotherapy was cisplatin-based in 44 patients and ifosfamide-based in six patients . In the whole group , baseline mean Functional Assessment of Cancer Therapy-Fatigue score was 19.7 ( ±6.4 ; st and ard deviation ) and the mean plasma carnitine value was 20.9 μM ( ±6.8 ; st and ard deviation ) . After 1 week , fatigue ameliorated in 45 patients and the mean Functional Assessment of Cancer Therapy-Fatigue score was 34.9 ( ±5.4 ; st and ard deviation ) ( P<.001 ) . All patients achieved normal plasma carnitine levels . Patients maintained the improved Functional Assessment of Cancer Therapy-Fatigue score until the next cycle of chemotherapy . In selected patients , levocarnitine supplementation may be effective in alleviating chemotherapy-induced fatigue . This compound deserves further investigations in a r and omised , placebo-controlled study [14659505] & NA ; A series of health surveys are conducted every sixth to seventh year in Denmark . In the most recent survey of 2000 , a national r and om sample ( > 16 years ) was drawn from the Danish Central Personal Register . Out of the original sample 12,333 ( 74 % ) were interviewed and of these 10,066 returned a completed question naire ( SF‐36 ) . The present study includes only those who both took part in the interview and the postal question naire . Cancer patients were excluded . Persons suffering from chronic pain ( PG ) were identified through the question ‘ Do you have chronic/long lasting pain lasting 6 months or more ’ ? An overall chronic pain prevalence of 19 % was found −16 % for men and 21 % for women . Prevalence of chronic pain increased with increasing age . Persons ≥67 years had 3.9 higher odds of suffering from chronic pain than persons in the age group 16–24 years . Compared with married persons , divorced or separated persons had 1.5 higher odds of chronic pain . Odds for chronic pain were 1.9 higher among those with an education of less than 10 years compared with individuals with an education of 13 years or more . During a 14‐day period reporters of chronic pain had an average of 0.8 days ( range 0–10 ) lost due to illness compared with an average of 0.4 days ( range 0–10 ) for the control group ( CG ) ( Odds Ratio ( OR ) ) 2.0 ) . Persons with a job which required high physical strain were more likely to report chronic pain compared with those with a sedentary job ( OR 2.2 ) . The odds of quitting one 's job because of ill health were seven times higher among people belonging to the PG . A strong association between chronic pain and poor self‐rated health was also demonstrated . The PG had twice as many contacts with various health professionals compared with the CG , and the health care system was , on average , utilised 25 % more ( overall contacts ) by the PG than by the general population . Among the persons in the PG , 33 % were not satisfied with the examinations carried out in connection with their pain condition and 40 % were not satisfied with the treatment offered . Nearly 130,000 adults , corresponding to 3 % of the Danish population , use opioids on a regular basis . Opioids are used by 12 % of the PG [9893656] The aim of this study was to evaluate a low-dose regimen of megestrol acetate ( MA ; 320 mg/day ) on appetite in advanced cancer patients . Out- patients with far-advanced non-hormone responsive tumours and loss of appetite were r and omised in a phase III trial , with two consecutive phases : a 14-day double-blind placebo controlled phase ( phase A ) and a 76-day open phase ( phase B ) . During phase A , patients were treated with MA , two 160 mg tablets/day , or placebo . In phase B , the MA dose was titrated to clinical response in both groups . Appetite , food intake , body weight , performance status , mood and quality of life were evaluated with st and ardised measures ; patients ' global judgement about treatment efficacy was also requested . Of 42 patients entering the study , 33 ( 17 MA and 16 placebo ) were evaluable for efficacy . The appetite score improved significantly with MA after 7 days ( P = 0.0023 ) , and this effect was still significant at 14 days ( P = 0.0064 ) . Patients judged the treatment with MA effective in 88.2 % of cases ( 14th day ) , whilst placebo was considered effective by 25 % ( P = 0.0003 ) . None of the other measures showed significant changes during treatment . The remarkable effect on appetite evident after 7 days , without serious side-effects , shows that MA can produce significant subjective effects at a low-dose even in patients with far-advanced disease [15679006] BACKGROUND Although the underlying pathology is initially confined to the lungs , the associated emotional responses to chronic obstructive pulmonary disease ( COPD ) contribute greatly to the result ing morbidity . The objective of this study was to examine the effect of an antidepressant drug on disease-specific quality of life in patients with end-stage COPD who present significant depressive symptoms . METHODS We conducted a 12-week , r and omized double-blind placebo-controlled trial of Paroxetine in which quality of life measured by the Chronic Respiratory Question naire ( CRQ ) , an evaluative COPD -specific quality -of-life question naire , was the primary outcome . RESULTS 23 patients were r and omized and 15 completed the trial ( 8 on Paroxetine ; 7 on placebo ) . In the per- protocol analysis , we observed statistically and clinical ly significant improvements favoring the active treatment in 2 of the 4 domains of the CRQ : emotional function ( adjusted mean difference : 1.1 ; 95 % confidence interval [ CI ] : 0.0 - 2.2 ) and mastery ( difference : 1.1 ; CI : 0.4 - 1.8 ) . Dyspnea and fatigue improved , but to an extent that did not reach statistical significance . In the intention-to-treat analysis , none of the differences in CRQ scores was significant . Paroxetine was not associated to any worsening of respiratory symptoms . CONCLUSIONS The results of this small r and omized trial indicated that patients with end-stage COPD may benefit from antidepressant drug therapy when significant depressive symptoms are present . This study underlined the difficulties in conducting experimental studies in frail and elderly patients with COPD [2698804] The effectiveness of an 8-week , 125 mg/day intravenous course of methylprednisolone sodium succinate ( MPSS ) for improving quality of life in patients with preterminal cancer was investigated in a double-blind , placebo-controlled , multicenter study . Quality of life was assessed using the Nurses ' Observational Scale for Inpatient Evaluation ( NOSIE ) , the Linear Analog Self- Assessment Scale ( LASA ) , and the Physicians ' Global Evaluation . A total of 403 patients were enrolled : 207 were treated with MPSS and 196 were treated with placebo . MPSS was significantly more effective than placebo in improving quality of life as judged by the changes from baseline in the NOSIE and LASA total scores . ( P less than 0.05 ) and by the Physicians ' Global Evaluation ( P less than 0.001 ) . The mortality rate was similar between MPSS-treated males ( 40.2 % ) , placebo-treated males ( 35.5 % ) , and MPSS-treated females ( 40.0 % ) . However , the mortality rate of 27.7 % for female placebo-treated females was significantly lower than for their MPSS-treated counterparts . The reason for lower mortality among placebo-treated females is unknown and warrants further study [1968469] Patients with breast cancer treated with MPA often report an improvement in appetite . Similar appetite stimulation is seen in patients treated with some corticosteroids , but MPA has a potential advantage over these drugs in that it does not exert a catabolic effect . MPA ( 100 mg tds orally ) has therefore been compared with placebo in 60 patients with advanced malignant disease . Twenty-one patients in the MPA group and 20 in the placebo group were receiving chemotherapy . Patients were treated for 6 weeks and were assessed at weeks 0 , 3 and 6 for appetite , energy , mood and pain using visual analogue scales . Nutritional status was assessed by the measurement of serum proteins and anthropometrics . Karnofsky score was recorded as a measure of performance status . There was a significant improvement in appetite in the MPA group between weeks 0 ( pre- study ) and 3 ( P = 0.0002 ) and 0 and 6 ( P = 0.015 ) . There was no significant improvement in appetite in the placebo group . Supporting this finding was the significant increase in serum thyroid binding pre-albumin and retinol binding protein in the MPA group between weeks 0 and 3 and 0 and 6 ( P = 0.023 and P = 0.039 respectively ) . These two parameters showed no significant change in the placebo group . There was no change in anthropometric measurements , weight , performance status , energy , mood or pain in either group . These data indicate that there was a significant increase in appetite in anorexic patients with advanced cancer treated with MPA which was reflected in increases in rapid turnover proteins reported to reflect nutritional status . However , this apparent increase in appetite did not result in improved weight , performance status , energy levels , mood or relief of pain . Further studies to investigate the effect of higher doses of MPA are indicated [2483687] A total of 173 female terminal cancer patients were r and omized to treatment with daily 125 mg infusions of methylprednisolone sodium succinate or a matching placebo for a period of 8 consecutive weeks . Data were collected relative to quality of life , investigator assessment of efficacy and cause and time of death within the 8-week treatment period . Significant improvement in quality of life was reported across the 8-week follow-up period in the steroid group . Investigator global assessment of efficacy significantly favored the steroid-treatment patients . There were no significant differences between treatment groups with regard to overall mortality rates or time to death . The total number of reported adverse events did not differ significantly between treatment groups . However , significantly more steroid patients reported gastrointestinal and cardiovascular events . The severity and outcome of these events did not differ from the placebo patients . The results of this study confirm previous reports of steroid efficacy in improving quality of life in terminal cancer patients . The absence of any untoward effect on mortality and the favorable safety profile support the use of methylprednisolone as palliative therapy for terminal cancer patients [21777715] OBJECTIVE To evaluate the efficacy and safety of armodafinil in the treatment of fatigue in HIV+ patients , and to assess its effect on depressive symptoms and behavior once fatigue remitted . METHOD HIV+ patients with clinical ly significant fatigue were treated in a placebo-controlled r and omized double-blind trial for 4 weeks . Armodafinil responders and placebo non-responders or relapsers were treated openly for a total of 16 weeks with armodafinil . The primary outcome measure for fatigue and depression was the Clinical Global Impressions-Improvement Scale , supplemented by the Fatigue Severity Scale , the Hamilton Depression Rating Scale , and the Beck Depression Inventory . Safety was assessed with assays of CD4 cell count and HIV RNA viral load and the SAFTEE side effects rating scale . Maximum trial dose of armodafinil was 250 mg/d . RESULTS Seventy patients were enrolled . Attrition was 9 % . In intention-to-treat analyses , fatigue response rate to armodafinil was 75 % and to placebo , 26 % . Armodafinil did not reduce depressive symptoms in the absence of improved energy , but of those patients with an Axis I depressive disorder at study entry whose energy improved , 82 % experienced improved mood as well . Markers of immunologic suppression did not change during treatment . At 6 months , those still taking armodafinil had more energy and fewer depressive symptoms than those who were no longer taking it . CONCLUSIONS As we found in our RCT of modafinil , armodafinil appears effective and well tolerated in treating fatigue in HIV+ patients . Side effects were minimal and most patients reported substantially improved energy and mood [14759641] Treatment with acetyl L-carnitine ( ALCAR ) has been shown to improve fatigue in patients with chronic fatigue syndrome , but there have been no trials on the effect of ALCAR for treating fatigue in multiple sclerosis ( MS ) . To compare the efficacy of ALCAR with that of amantadine , one of the drugs most widely used to treat MS-related fatigue , 36 MS patients presenting fatigue were enrolled in a r and omised , double-blind , crossover study . Patients were treated for 3 months with either amantadine ( 100 mg twice daily ) or ALCAR ( 1 g twice daily ) . After a 3-month washout period , they crossed over to the alternative treatment for 3 months . Patients were rated at baseline and every 3 months according to the Fatigue Severity Scale ( FSS ) , the primary endpoint of the study . Secondary outcome variables were : Fatigue Impact Scale ( FIS ) , Beck Depression Inventory ( BDI ) and Social Experience Checklist ( SEC ) . Six patients withdrew from the study because of adverse reactions ( five on amantadine and one on ALCAR ) . Statistical analysis showed significant effects of ALCAR compared with amantadine for the Fatigue Severity Scale ( p = 0.039 ) . There were no significant effects for any of the secondary outcome variables . The results of this study show that ALCAR is better tolerated and more effective than amantadine for the treatment of MS-related fatigue [10675381] BACKGROUND Extracellular adenosine 5'-triphosphate ( ATP ) is involved in the regulation of a variety of biologic processes , including neurotransmission , muscle contraction , and liver glucose metabolism , via purinergic receptors . In nonr and omized studies involving patients with different tumor types including non-small-cell lung cancer ( NSCLC ) , ATP infusion appeared to inhibit loss of weight and deterioration of quality of life ( QOL ) and performance status . We conducted a r and omized clinical trial to evaluate the effects of ATP in patients with advanced NSCLC ( stage IIIB or IV ) . METHODS Fifty-eight patients were r and omly assigned to receive either 10 intravenous 30-hour ATP infusions , with the infusions given at 2- to 4-week intervals , or no ATP . Outcome parameters were assessed every 4 weeks until 28 weeks . Between-group differences were tested for statistical significance by use of repeated- measures analysis , and reported P values are two-sided . RESULTS Twenty-eight patients were allocated to receive ATP treatment and 30 received no ATP . Mean weight changes per 4-week period were -1.0 kg ( 95 % confidence interval [ CI ] = -1.5 to -0.5 ) in the control group and 0.2 kg ( 95 % CI = -0.2 to + 0.6 ) in the ATP group ( P = .002 ) . Serum albumin concentration declined by -1.2 g/L ( 95 % CI= -2.0 to -0.4 ) per 4 weeks in the control group but remained stable ( 0.0 g/L ; 95 % CI = -0.3 to + 0.3 ) in the ATP group ( P = .006 ) . Elbow flexor muscle strength declined by -5.5 % ( 95 % CI = -9.6 % to -1 . 4 % ) per 4 weeks in the control group but remained stable ( 0.0 % ; 95 % CI= -1.4 % to + 1.4 % ) in the ATP group ( P = .01 ) . A similar pattern was observed for knee extensor muscles ( P = .02 ) . The effects of ATP on body weight , muscle strength , and albumin concentration were especially marked in cachectic patients ( P = .0002 , P = .0001 , and P = . 0001 , respectively , for ATP versus no ATP ) . QOL score changes per 4-week period in the ATP group showed overall less deterioration than in the control group-physical scores ( -0.2 % versus -2.4 % ; P = . 0002 ) ; functional scores ( + 0.4 % versus -5.5 % ; P = .02 ) ; psychologic scores ( -0.7 % versus -2.4 % ; P = .11 ) ; overall QOL score ( + 0.1 % versus -3.5 % ; P = .0001 ) . CONCLUSIONS This r and omized trial demonstrates that ATP has beneficial effects on weight , muscle strength , and QOL in patients with advanced NSCLC [21964738] Limited research is available regarding the efficacy of psychostimulants in treating cognitive function in primary brain tumor patients . An open-label , r and omized , pilot trial examined both the general and differential efficacy of 4 weeks of methylpheni date ( MPH ) and modafinil ( MOD ) in 24 brain tumor patients . Participants completed cognitive tests and self-report measures of fatigue , sleep disturbance , mood and quality of life at baseline and after 4 weeks . Following stimulant treatment , there was evidence of a beneficial effect on test performance in speed of processing and executive function requiring divided attention . Patients with the greatest deficit in executive function at baseline appeared to derive the greatest benefit following stimulant therapy . Inconsistent , differential effects were found on a measure of attention in favor of MPH and on a measure of processing speed in favor of MOD . There was also evidence of a general beneficial effect on patient-reported measures of fatigue , mood , and quality of life , with no statistically significant differences between treatment arms in these measures over time . The results from this small pilot study should be interpreted with caution , but appear to warrant additional research , in larger study sample s , targeting fatigue , processing speed and executive function , and exploring different doses of stimulants . Future studies may also wish to explore the specific patient factors that may be associated with responsiveness to psychostimulant treatment [17406919] Introduction Amisulpride is a substituted benzamide that , at low doses , selectively blocks D2 and D3 presynaptic dopamine receptors , enhancing dopaminergic transmission in frontal cortex and limbic areas . Many clinical studies versus placebo , tricyclic antidepressants and selective serotonin reuptake inhibitors showed amisulpride antidepressant effect , supporting its safety and rapid onset of action . In oncological population , depression is quite frequent and difficult to treat because of the particular sensitivity of cancer patients to the antidepressants ’ side effects . Goals of workThe aims of this study were to evaluate efficacy , safety and tolerability of low doses of amisulpride ( 50 mg ) in oncological , depressed patients during chemotheraphy . Material s and methods One hundred six consecutive cancer out patients with depressive symptoms were treated in a prospect i ve , intention to treat , 4-week study , and were evaluated in single-blind with Montgomery Asberg rating scale for depression ( MADRS ) , clinical global impression ( CGI ) and dosage record treatment emergent symptom scale ( DOTES ) to assess side effects of treatment . Main results After 4 weeks of treatment , scores of MADRS and CGI significantly improved ( p < 0.002 ; p < 0.001 , respectively ) , with a reduction of depressive symptoms concerning both emotional ( such as apparent sadness , reported sadness , inner tension , etc . ) and physical cluster ( such as lack of appetite , reduction in weight , tiredness and insomnia ) with good tolerability ( only two patients dropped out ) . Conclusions This study is the first trial on the use of amisulpride in a cohort of oncological , depressed patients during chemotherapy . Amisulpride demonstrated high efficacy and safety . Controlled studies are needed to confirm these preliminary data [11176767] BACKGROUND Fatigue is a commonly encountered symptom of human immunodeficiency virus ( HIV ) disease , associated with significant psychological and functional morbidity and poor quality of life . Preliminary studies on the treatment of fatigue from the cancer and multiple sclerosis literature suggest that psychostimulants may be effective in reducing fatigue . OBJECTIVE To compare the efficacy of 2 psychostimulant medications , methylpheni date hydrochloride ( Ritalin ) and pemoline ( Cylert ) , with a placebo intervention for the treatment of fatigue in patients with HIV disease . METHODS In this double-blind trial , 144 ambulatory patients with HIV disease and persistent and severe fatigue were r and omized to treatment with methylpheni date , pemoline , or placebo . Medications were titrated up to a maximum dose of 60 mg of methlypheni date hydrochloride , 150 mg of pemoline , or 8 capsules of placebo daily . Fatigue was measured using 2 self-reported rating scales , the Piper Fatigue Scale ( PFS ) and the Visual Analogue Scale for Fatigue ( VAS-F ) . We also used the timed isometric unilateral straight leg-raising task , a measure of muscular endurance . Quality -of-life and psychological well-being measures included the Beck Depression Inventory , the Brief Symptom Inventory , and the 36-Item Short-Form Medical Outcomes Study Health Status Survey . Side effects were monitored using the Systematic Assessment for Treatment Emergent Events and the Extra-pyramidal Symptom Rating Scale . All measures were rated weekly . RESULTS One hundred nine subjects completed the 6-week trial ; 15 patients ( 41 % ) receiving methylpheni date and 12 patients ( 36 % ) receiving pemoline demonstrated clinical ly significant improvement compared with 6 patients ( 15 % ) receiving placebo . Patients receiving methylpheni date or pemoline demonstrated significantly more improvement in fatigue on several self-reported rating scales ( PFS total score , P=.04 ; affective subscale , P=.008 ; sensory subscale , P=.04 ; and VAS-F energy subscale , P=.02 ) . Analysis of the regression slopes by means of hierarchical linear modeling demonstrated a significantly greater rate of improvement in PFS total scores among patients receiving psychostimulants compared with the placebo group ( P=.02 ) . There were no significant differences in the efficacy between methlypheni date and pemoline on any outcome measure studied . Improvement in fatigue was also significantly correlated with improvement in measures of depression , psychological distress , and overall quality of life . Severe side effects were relatively uncommon among this sample , and only hyperactivity or jitteriness occurred significantly more often among subjects receiving active medication . CONCLUSIONS Many patients with HIV- and acquired immunodeficiency syndrome-unrelated fatigue respond favorably to treatment with methylpheni date or pemoline . Both psychostimulants appear to be equally effective and significantly superior to placebo in decreasing fatigue severity with minimal side effects . Moreover , improvement of fatigue was significantly associated with improved quality of life and decreased levels of depression and psychological distress [15824337] Objective : To assess whether modafinil , a wakefulness-promoting agent , is useful for fatigue in patients with multiple sclerosis ( MS ) . Methods : Patients with MS with stable disability , and a baseline score of 45 or more on the Modified Fatigue Impact Scale ( MFIS ) , were eligible for the 5-week r and omized , double-blind , placebo-controlled , parallel group study . The initial daily dose of modafinil was 200 mg for 1 week . Depending on tolerance , the dose was increased by 100 mg every week up to 400 mg/day and remained unchanged between day 21 and day 35 . The primary outcome variable was the change of MFIS score at day 35 . Results : A total of 115 patients with MS were enrolled in the study and in the intention to treat analysis . The mean MFIS score at baseline was 63 ± 9 in the placebo group and 63 ± 10 in the modafinil group . MFIS scores improved between day 0 and day 35 in both placebo-treated and modafinil-treated groups , but no significant difference was detected between the two groups . There was no major safety concern . Conclusions : There was no improvement of fatigue in patients with multiple sclerosis treated with modafinil vs placebo according to the Modified Fatigue Impact Scale [19896571] Cancer and its treatment can induce subjective and objective evidence of diminished functional capacity encompassing physical fatigue and cognitive impairment . Dexmethylpheni date ( D-MPH ; the D-isomer of methylpheni date ) was evaluated for treatment of chemotherapy-related fatigue and cognitive impairment . A r and omized , double-blind , placebo-controlled , parallel-group study evaluated the potential therapeutic effect and safety of D-MPH in the treatment of patients with chemotherapy-related fatigue . Change from baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue Subscale ( FACIT-F ) total score at Week 8 was the primary outcome measure . One hundred fifty-four patients ( predominantly with breast and ovarian cancers ) were r and omized and treated . Compared with placebo , D-MPH-treated subjects demonstrated a significant improvement in fatigue symptoms at Week 8 in the FACIT-F ( P=0.02 ) and the Clinical Global Impression-Severity scores ( P=0.02 ) , without clinical ly relevant changes in hemoglobin levels . Cognitive function was not significantly improved . There was a higher rate of study drug-related adverse events ( AEs ) ( 48 of 76 [ 63 % ] vs. 22 of 78 [ 28 % ] ) and a higher discontinuation rate because of AEs ( 8 of 76 [ 11 % ] vs. 1 of 78 [ 1.3 % ] ) in D-MPH-treated subjects compared with placebo-treated subjects . The most commonly reported AEs independent of study drug relationship in D-MPH-treated subjects were headache , nausea , and dry mouth , and in placebo-treated subjects were headache , diarrhea , and insomnia . D-MPH produced significant improvement in fatigue in subjects previously treated with cytotoxic chemotherapy . Further studies with D-MPH or other agents to explore treatment response in chemotherapy-associated fatigue should be considered [18430965] Testosterone increases fat-free mass ( FFM ) in men infected with human immunodeficiency virus ( HIV ) , but its effects on muscle performance , physical function , mood , and quality of life are poorly understood . Sixty-one HIV-infected men with weight loss were r and omized to receive weekly intramuscular injections of 300 mg of testosterone enanthate or placebo for 16 wk . The primary outcome of interest was physical function ( walking speed , stair-climbing power , and load-carrying ability ) . Secondary outcome measures included body weight and composition , muscle performance , sexual function , mood , and quality of life . Serum nadir free and total testosterone levels increased ( + 188.0 + /- 29.6 and + 720 + /- 86 ng/dl ) in the testosterone , but not placebo , group . Testosterone administration was associated with increased FFM ( 2.8 + /- 0.5 kg ) , which was significantly greater than in the placebo group ( P < 0.0001 ) . Leg press strength increased significantly in testosterone-treated ( P = 0.027 ) , but not placebo-treated , men ; the difference between groups was not significant . Other measures of muscle performance and physical function did not change significantly in either group . Men receiving testosterone demonstrated significantly greater improvements in mental health and quality -of-life scores than those receiving placebo and improvements in fatigue/energy and mood scores that were not significantly different from those receiving placebo . Sexual function scores did not change in either group . In HIV-infected men with weight loss , a supraphysiological dose of testosterone significantly increased FFM but did not improve self-reported or performance-based measures of physical function . Improvements in mood , fatigue , and quality -of-life measures in the testosterone group , although clinical ly important , need further confirmation [23944194] Fatigue and cognitive impairment are common in HIV+ adults and may occur independently or be causally linked . This study examined whether alleviation of fatigue with armodafinil in a placebo-controlled double-blind 4-week trial had an effect on cognitive function among those with and without mild neuropsychological impairment at baseline . Sixty-one patients completed a st and ard battery of neuropsychological tests at study entry and Week 4 : A total of 33 were r and omized to armodafinil and 28 to placebo . While there was a significant effect of active medication on fatigue , cognitive performance measured by a global change score did not differ between treatment groups , or in those on active treatment with or without mild neuropsychological impairment [15754122] Summary Background . Fatigue can significantly interfere with a cancer patient ’s ability to fulfill daily responsibilities and enjoy life . It commonly co-exists with depression in patients undergoing chemotherapy , suggesting that administration of an antidepressant that alleviates symptoms of depression could also reduce fatigue . Methods . We report on a double-blind clinical trial of 94 female breast cancer patients receiving at least four cycles of chemotherapy r and omly assigned to receive either 20 mg of the selective serotonin re-uptake inhibitor ( SSRI ) paroxetine ( Paxil ® , SmithKline Beecham Pharmaceuticals ) or an identical-appearing placebo . Patients began their study medication seven days following their first on- study treatment and continued until seven days following their fourth on- study treatment . Seven days after each treatment , participants completed question naires measuring fatigue ( Multidimensional Assessment of Fatigue , Profile of Mood States-Fatigue/Inertia subscale and Fatigue Symptom Checklist ) and depression ( Profile of Mood States-Depression subscale [ POMS-DD ] and Center for Epidemiologic Studies -Depression [ CES-D ] ) . Results . Repeated- measures ANOVAs , after controlling for baseline measures , showed that paroxetine was more effective than placebo in reducing depression during chemotherapy as measured by the CES-D ( p=0.006 ) and the POMS-DD ( p=0.07 ) but not in reducing fatigue ( all measures , ps > 0.27 ) . Conclusions . Although depression was significantly reduced in the 44 patients receiving paroxetine compared to the 50 patients receiving placebo , indicating that a biologically active dose was used , no significant differences between groups on any of the measures of fatigued were observed . Results suggest that modulation of serotonin may not be a primary mechanism of fatigue related to cancer treatment [12185153] Objective : To determine whether combination therapy with lofepramine , L-phenylalanine , and intramuscular vitamin B-12 ( the “ Cari Loder regime ” ) reduces disability in patients with multiple sclerosis . Methods : A placebo controlled , double blind , r and omised study carried out in five United Kingdom centres on out patients with clinical ly definite multiple sclerosis , measurable disability on Guy 's neurological disability scale ( GNDS ) , no relapse in the preceding six months , and not on antidepressant drugs . Over 24 weeks all patients received vitamin B-12 , 1 mg intramuscularly weekly , and either lofepramine 70 mg and L-phenylalanine 500 mg twice daily , or matching placebo tablets . Outcome was assessed using the GNDS , the Kurtzke exp and ed disability status scale ; the Beck depression inventory , the Chalder fatigue scale , and the Gulick MS specific symptom scale . Results : 138 patients were entered , and two were lost from each group . There was no statistically significant difference between the groups at entry or at follow up . Analysis of covariance suggested that treated patients had better outcomes on four of the five scales used . Both groups showed a reduction of 2 GNDS points within the first two weeks , and when data from all time points were considered , the treated group had a significant improvement of 0.6 GNDS points from two weeks onwards . Conclusions : Patients with multiple sclerosis improved by 2 GNDS points after starting vitamin B-12 injections . The addition of lofepramine and L-phenylalanine added a further 0.6 points benefit . More research is needed to confirm and explore the significance of this clinical ly small difference [2730380] Fatigue is a common symptom of multiple sclerosis ( MS ) that is without an effective treatment . A double-blind , controlled study of fatigue treatment was conducted to evaluate the efficacy of amantadine hydrochloride in treating MS-associated fatigue . Since fatigue can not be characterized by a single symptom or behavior , a variety of neuropsychological , behavioral , and self-report measures were used to monitor changes across different systems . According to patients ' daily diary ratings , amantadine produced small but statistically significant improvements in fatigue across four of seven dimensions ( overall energy level , concentration , problem solving , and sense of well-being ) . In addition , patients with MS who were taking amantadine performed slightly better on the Stroop Interference Test , an attentional measure of freedom from distracting information . Although retrospective reports by patients with MS did not confirm the degree of improvement recorded on a daily basis , the study 's results suggested that amantadine may offer modest benefits in alleviating the day-to-day subjective experience of fatigue [16622259] PURPOSE Maintaining dose-intensity with chemotherapeutic agents is hindered by a number of adverse effects including asthenia/fatigue . Tumor necrosis factor ( TNF ) is one of the cytokines responsible for the fatigue and cachexia associated with malignancies . We used etanercept ( TNF-decoy receptor ) to maintain dose-intensity of weekly docetaxel . PATIENTS AND METHODS Initially , 12 patients with advanced malignancies were r and omly assigned to either docetaxel 43 mg/m2 weekly alone ( cohort A ) or the same docetaxel dose plus etanercept 25 mg subcutaneously twice weekly ( cohort B ) . Subsequently , higher doses of docetaxel in combination with etanercept were evaluated . Pharmacokinetics ( PKs ) , nuclear factor-kappa B ( NF-kappaB ) activation , and intracellular cytokines levels were measured . Patients completed weekly question naires quantifying asthenia/fatigue . RESULTS Twenty-nine of 36 intended docetaxel doses during the first cycle were delivered in cohort A , and 35 of 36 doses were delivered in cohort B ( P = .055 ) . Three cohort B patients received additional cycles in the absence of disease progression or severe toxicity , whereas no patients from cohort A received additional cycles . Escalation to docetaxel 52 mg/m2 weekly with etanercept result ed in neutropenia , not fatigue , as the limiting adverse effect , and the addition of filgrastim permitted the maintenance of dose-intensity in additional patients . Patients r and omly selected to receive etanercept/docetaxel self-reported less fatigue ( P < .001 ) , and docetaxel PKs show no relevant influence of etanercept . NF-kappaB activation and increased expression of TNF-alpha were associated with increments in docetaxel dose . Antitumor activity was noticed exclusively in patients receiving etanercept . CONCLUSION The addition of etanercept is safe and had no impact on docetaxel concentrations . The significant improvement in tolerability and the trend toward preservation of dose-intensity suggests further exploration of TNF blockade as an adjunct to cancer therapies [12844250] The prevention of post-chemotherapy symptoms such as delayed emesis , anorexia , and fatigue induced by irinotecan has not been studied . We compared the effects of dexamethasone ( Dex ) with those of a placebo on these symptoms in a r and omized study . Seventy patients scheduled to receive irinotecan chemotherapy were enrolled in the study and r and omly divided into a treatment or a placebo group . In the treatment group , 8 mg of Dex were administered on days 2–4 after the start of chemotherapy . All patients in both groups received Dex and granisetron for prophylaxis against acute emesis on day 1 . We evaluated 68 patients ( 35 receiving Dex , 33 receiving the placebo ) . Although delayed emesis was completely prevented in most of patients in both groups ( Dex , 82.9 % ; placebo , 78.8 % ) , anorexia and fatigue were more completely prevented in those in the Dex group ( Dex , 62.9 % and 77.1 % , placebo , 39.4 % and 57.6 % , respectively ) . The effect of Dex on improving simultaneous prophylaxis against all three symptoms was almost significant ( Dex , 60.0 % ; placebo , 36.4 % ; P=0.058 ) . The safety profiles of the two groups were not discernibly different . These results suggest that treatment with Dex may be beneficial to reduce post-chemotherapy symptoms induced by irinotecan , specifically anorexia and fatigue , with acceptable toxicities [24778393] PURPOSE Fatigue is a distressing symptom occurring in more than 60 % of patients with cancer . The CNS stimulants modafinil and methylpheni date are recommended for the treatment of cancer-related fatigue , despite a limited evidence base . We aim ed to evaluate the efficacy and tolerability of modafinil in the management of fatigue in patients with non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Adults with advanced NSCLC and performance status of 0 to 2 , who were not treated with chemotherapy or radiotherapy within the last 4 weeks , were r and omly assigned to daily modafinil ( 100 mg on days 1 to 14 ; 200 mg on days 15 to 28 ) or matched placebo . The primary outcome was change in Functional Assessment of Chronic Illness Therapy ( FACIT ) -Fatigue score from baseline to 28 days , adjusted for baseline fatigue and performance status . Secondary outcomes included safety and patient-reported measures of depression , daytime sleepiness , and quality of life . RESULTS A total of 208 patients were r and omly assigned , and 160 patients ( modafinil , n = 75 ; placebo , n = 85 ) completed question naires at both baseline and day 28 and were included in the modified intention-to-treat analysis . FACIT-Fatigue scores improved from baseline to day 28 ( mean score change : modafinil , 5.29 ; 95 % CI , 2.57 to 8.02 ; placebo , 5.09 ; 95 % CI , 2.54 to 7.65 ) , but there was no difference between treatments ( 0.20 ; 95 % CI , -3.56 to 3.97 ) . There was also no difference between treatments for the secondary outcomes ; 47 % of the modafinil group and 23 % of the placebo group stated that the intervention was not helpful . CONCLUSION Modafinil had no effect on cancer-related fatigue and should not be prescribed outside a clinical trial setting . Its use was associated with a clinical ly significant placebo effect [3791269] Thirty-two patients with chronic pain due to advanced cancer were treated with methylpheni date ( 10 mg with breakfast and 5 mg with lunch ) for 3 days , versus placebo , in a r and omized , double-blind , cross-over study design ed to evaluate the capacity of methylpheni date to potentiate the analgesic effect of narcotics and /or to decrease sedation induced by narcotics . In 28 evaluable patients , the intensity of pain ( visual analogue 0 - 100 ) and intake of extra doses of analgesics ( number of doses/day ) were 43 + /- 27 and 2.2 + /- 2.4 during methylpheni date , versus 55 + /- 24 ( P less than 0.02 ) and 2.9 + /- 2.9 ( P less than 0.002 ) during placebo , respectively . Activity and drowsiness ( visual analogue 0 - 100 ) were 57 + /- 25 and 58 + /- 24 after methylpheni date , respectively , versus 41 + /- 26 ( P less than 0.05 ) and 45 + /- 27 ( P less than 0.02 ) after placebo . Upon completion of the study , the investigator and the patient chose methylpheni date blindly as a more useful drug in 23 cases ( 83 % ) and 20 cases ( 70 % ) , respectively ( P less than 0.02 ) . No cases of severe toxicity were observed . We conclude that methylpheni date can increase the analgesic effect and decrease sedation of narcotics in this population [22979982] Abstract Objectives : The purpose of this study was to compare the relative efficacy of acetylsalicylic acid ( ASA ) and amantadine for the treatment of fatigue in multiple sclerosis ( MS ) . Methods : A 10-week , r and omized double-blind crossover clinical trial conducted from October 2009 to September 2010 . Fifty-two patients with MS presenting fatigue at 21 to 53 years of age were r and omly allocated to the two treatment groups . The first group received amantadine ( 100 mg twice daily ) for a total of 4 weeks . The second group received ASA ( 500 mg once daily ) for four weeks . After a 2-week washout period , they crossed over to the alternative treatment for 4 weeks . Patients were rated at baseline and the end of each phase with the Fatigue Severity Scale ( FSS ) . Results : ASA appeared to be equivalent in efficacy and safety to amantadine . A significant decrease in FSS occurred in both groups . Of the 26 patients treated with amantadine , the mean ( SD ) of FSS decreased from 4·8 ( 1·4 ) to 4·0 ( 1·4 ) ( P<0·001 ) . In the 26 patients treated with ASA , the mean ( SD ) of FSS decreased from 4·6 ( 1·4 ) to 3·5 ( 1·5 ) ( P<0·001 ) . Discussion : This study demonstrates that both ASA and amantadine significantly reduce MS-related fatigue . Both ASA and amantadine have previously been shown to reduce fatigue , and we postulate that treatment with ASA and amantadine may have similar benefits [22208450] CONTEXT Fatigue is highly prevalent in population s with advanced illness and is often associated with depressed mood . The role of psychostimulant therapy in the treatment of these conditions remains ill defined . OBJECTIVES To evaluate the response of fatigue and depression in patients with advanced illness to titrated doses of methylpheni date ( MP ) as compared with placebo . METHODS In a r and omized , double-blind , placebo-controlled trial , 30 hospice patients , both in patients and out patients , who had fatigue scores of at least four on a scale of zero to 10 ( 0=no fatigue and 10=worst fatigue ) , were r and omly assigned to receive either 5 mg of MP at 8 am and 1 pm or placebo . Doses of MP were titrated every three days according to response and adverse effects . Home care patients were monitored daily by telephone and visited by a research nurse on Study Days 0 ( baseline ) , 3 , 7 , and 14 . Fatigue was assessed using the Piper Fatigue Scale as the primary outcome measure and vali date d by the Visual Analogue Scale for Fatigue and the Edmonton Symptom Assessment Scale ( ESAS ) fatigue score . Subjects in inpatient facilities were interviewed or assessed by staff on an identical schedule . Depressive symptoms were assessed by the Beck Depression Inventory-II , Center for Epidemiologic Studies Depression Scale , and the ESAS depression score . Primary statistical analysis was conducted using repeated- measures multivariate analysis of the variance . RESULTS Both MP- and placebo-treated groups had similar measures of fatigue at baseline . Patients taking MP were found to have significantly lower fatigue scores ( Piper Fatigue Scale , Visual Analogue Scale for Fatigue , and ESAS ) at Day 14 compared with baseline . The improvement in fatigue with MP treatment was dose-dependent ; the mean average effective dose was 10 mg on Day 3 and 20 mg on Day 14 ( dose range of 10 - 40 mg ) . Placebo-treated individuals showed no significant improvement in fatigue . For patients with clinical ly significant depression on Day 0 , treatment with MP was associated with a significant reduction in all test indices for depressed mood . For the placebo group , the changes in measures of depression were less than observed in the treatment group but were inconsistent between assessment tools . No significant toxicities were observed . CONCLUSION MP reduced symptoms of fatigue and depression when compared with placebo . The effect of MP on fatigue was dose-dependent and sustained over the duration of the study [12883103] Objective : There has long been a belief that depression contributes to fatigue in multiple sclerosis ( MS ) although supporting data are minimal at best . Clinical guidelines for the treatment of fatigue include recommendations for the treatment of depression in the absence of clear empirical support . The goal of this study was to examine the effects of treatment for depression on fatigue in MS . Methods : Sixty patients with a relapsing form of MS and moderate to severe depression were r and omly assigned to one of three vali date d 16‐week treatments for depression : individual cognitive behavioral therapy , group psychotherapy , or sertraline . Assessment s at baseline and treatment cessation included the primary outcome measure , fatigue assessment instrument ( FAI ) , and Beck depression inventory ( BDI ) . Results : The total FAI and the global fatigue severity subscale were significantly reduced over the course of treatment ( p values < .02 ) . Other subscales did not change significantly . Secondary analyses showed change in global fatigue severity was associated with change in BDI ( p = .03 ) but change in total FAI was only marginally related to change in BDI ( p = .05 ) . These relationships were due entirely to change in mood ( p values < .02 ) and not to change in cognitive or vegetative symptoms ( p values > .17 ) . Conclusions : These findings suggest that treatment for depression is associated with reductions in the severity of fatigue symptoms , and that this relationship is due primarily to treatment related changes in mood [3566815] Background : This study was design ed to evaluate the role of epidural methadone-lidocaine in cancer pain combined or not to epidural dexamethasone . Methods : In all , 72 cancer patients , 32- to 67-year-old were r and omized to six groups ( n=12 ) and prospect ively studied to examine analgesia and adverse effects for 3 weeks . Patients received single-dose protocol epidural test drugs : Control group ( CG ) received epidural 40-mg lidocaine diluted to 10-ml volume with saline . Dexamethasone group ( DG ) 40-mg lidocaine plus 10-mg dexamethasone . The 2.5MetG 2.5-mg epidural methadone with 40-mg lidocaine ; the 5MetG , 5-mg epidural methadone plus 40-mg lidocaine , the 7.5MetG , 7.5-mg epidural methadone plus 40-mg lidocaine and finally the 7.5Met-DexG , 7.5-mg methadone with 40-mg lidocaine and 10-mg dexamethasone . Results : Groups CG , DG and 2.5MetG were similar regarding analgesia and side effects . Patients from 5MetG and 7.5MetG took 3±1 and 5±1 days , respectively , to restart oral morphine . Patients from 7.5MetDG took 14±2 to restart oral morphine ( P<0.001 ) . Daily somnolence and appetite improved in the 7.5MetDG during 2-week evaluation ( P<0.005 ) . Fatigue improved for both DG and 7.5MetDG during 2-week evaluation ( P<0.005 ) . By the third week of evaluation , all patients were similar . Conclusions : Epidural methadone plus lidocaine result ed in dose-dependent analgesia , further improved by epidural dexamethasone , which also improved fatigue [9765767] PURPOSE To evaluate the effect of megestrol acetate at a lower dose than previously investigated on the symptoms of cachexia in patients with advanced cancer . METHODS A total of 84 patients with advanced , solid tumours not responsive to hormone therapy were enrolled in this double-blind , crossover study . During phase 1 , patients were r and omly assigned to receive megestrol acetate ( 160 mg 3 times daily ) for 10 days or placebo . During phase 2 , after a 2-day washout period , patients received the alternate treatment for 10 days . Patients underwent daily assessment s of activity , nausea , appetite and well-being by means of a visual analogue scale ( VAS ) . In addition , nutritional status ( weight , tricep skinfold measure , arm muscle circumference ) , energy intake , fatigue ( Piper Fatigue Scale ) and quality of life ( Functional Living Index-Cancer [ FLIC ] ) were assessed . RESULTS Among the 53 evaluable patients megestrol acetate result ed in a significant improvement in appetite ( p = 0.005 ) , activity ( p = 0.007 ) and well-being ( p = 0.03 ) . There was no significant change in the intensity of nausea , nutritional parameters , energy intake or FLIC scores . There was a significant improvement in 2 of the 3 factors measured by the Piper Fatigue Scale and in the overall fatigue score . Upon completion of the study , while still blind to the treatment condition , 30 patients indicated that they felt better overall after megestrol , 15 said they felt better after placebo , and 10 indicated no preference ( p = 0.001 ) . CONCLUSION Treatment with megestrol acetate results in rapid and significant improvement of symptoms in terminally ill patients at lower doses than previously reported . The effects are not secondary to nutritional changes . The FLIC quality -of-life question naire was unable to detect these changes [12727037] The purpose of this study was to vali date the changes in acute pain measurement scales that are most strongly associated with a patient-determined indicator of clinical importance . Measures of pain intensity and pain relief are commonly used outcomes in therapeutic clinical trials . Recent studies of the properties of acute pain measures have provided data defining the cut-off points that are best associated with clinical ly important differences . Validation of these findings in another clinical trial data set is important . Data were obtained from the titration phase of a recently conducted r and omized controlled clinical trial of oral transmucosal fentanyl citrate ( OTFC ) , which compared OTFC to immediate release morphine sulfate ( MSIR ) for the treatment of cancer-related acute breakthrough pain . Changes in pain intensity and pain relief were recorded every 15 minutes for 60 minutes and global medication performance recorded at the end of each study pain episode . At any titration step , if the patient felt that the first dose of the study medication did not provide adequate relief within 30 minutes , an additional rescue medication could be taken . To find the level of each pain scale best associated with this measure of the adequacy of pain relief , the calculated sensitivity , specificity , and accuracy for different cut-off points of the measured pain scales were compared to whether or not the patient needed rescue medication . The overall ability of the pain measures to discriminate episodes for which a rescue was not needed was calculated using area under the receiver operating characteristics ( ROC ) curves . Data were analyzed from 134 OTFC-naive patients who collected data on 1307 episodes of breakthrough pain . Using the criteria of a balanced sensitivity and specificity , the best cut-off points were determined to be : 33 % for the percent pain intensity difference ; > or = 2 for the raw pain intensity difference on a 0 - 10 numeric rating scale ; > or = 2 ( i.e. , moderate or better ) for pain relief ; > or = 33 % for the percent maximum total pain relief ; and > or = 2 ( good or better ) for global medication performance . ROC area under the curve ranged from 0.839 to 0.862 for each of the pain measures listed above , calculated at 60 minutes . These data indicate that the pain scale cut-off points that are best associated with a patient-derived measure of a clinical ly important difference closely approximate those found in an earlier study . ROC analysis provided evidence that the overall pain measures were strongly associated with not requiring an " additional dose of rescue medication . " Thus , the cut-off points determined for these pain scales provide a good surrogate measure of a patient-determined clinical ly important response . This provides support for the usefulness of these values in future clinical trials of pain therapy [10665616] BACKGROUND The goal was to evaluate the efficacy of testosterone in alleviation of hypogonadal symptoms ( diminished libido , depressed mood , low energy , and depleted muscle mass ) in men with symptomatic human immunodeficiency virus illness . METHODS Seventy-four patients were enrolled in a double-blind , placebo-controlled 6-week trial with bi-weekly testosterone injections , followed by 12 weeks of open-label maintenance treatment . Major outcome measures were Clinical Global Impressions Scale ratings for libido , mood , energy , and erectile function ; Hamilton Depression Rating Scale scores , and Chalder Fatigue Scale scores . Body composition changes were assessed with bioelectric impedance analysis . RESULTS Seventy men completed the 6-week trial . Response rates , defined as much or very much improved libido , were 74 % ( 28/38 ) for patients r and omized to testosterone , and 19 % ( 6/32 ) for placebo-treated patients ( P<.001 ) . Of the 62 completers with fatigue at baseline , 59 % ( 20/34 ) receiving testosterone and 25 % ( 7/28 ) receiving placebo reported improved energy ( P<.01 ) . Among the 26 completers with an Axis I depressive disorder at baseline , 58 % of the testosterone-treated patients reported improved mood compared with 14 % of placebo-treated patients ( Fisher exact test = .08 ) . With testosterone treatment , average increase in muscle mass over 12 weeks was 1.6 kg for the whole group , and 2.2 kg for the 14 men with wasting at baseline . Improvement on all parameters was maintained during subsequent open-label treatment for up to 18 weeks . CONCLUSION Testosterone is well tolerated and effective in the short-term treatment of symptoms of clinical hypogonadism in men with symptomatic human immunodeficiency virus illness , restoring libido and energy , alleviating depressed mood , and increasing muscle mass [2972270] In a double-blind placebo-controlled crossover study of ten patients with multiple sclerosis , we found amantadine hydrochloride therapy to be effective in improving fatigability in six . Administration of the drug was associated with significantly higher levels of beta-endorphin-beta-lipotropin and responders had significantly higher levels than nonresponders . Lactate levels were significantly higher and pyruvate levels lower in nonresponders . Amantadine given for fatigue to patients with multiple sclerosis is associated with measurable changes in levels of metabolites and peptides in the circulation [19270033] Cancer-related fatigue is the most prevalent and distressing symptom experienced by patients with advanced cancer . Central nervous system stimulants have been shown to relieve fatigue in nonmalignant disease . Modafinil is a stimulant with a selective site of action in the brain that is better tolerated than traditional stimulants , such as methylpheni date . The aim of this study was to determine the feasibility of conducting a r and omised controlled trial to assess the efficacy and safety of modafinil for the treatment of fatigue in patients with lung cancer . Twenty patients with non-small cell lung cancer were recruited to this open-label study . Modafinil was taken in a fixed dose-titration schedule of 100 mg daily for 7 days followed by 200 mg daily for 7 days . Fifteen patients completed the study . During the study period , there was a rapid and statistically significant reduction in the primary outcome , fatigue ( P = 0.001 ) and the secondary outcomes of daytime sleepiness and depression/anxiety . This improvement in fatigue was also clinical ly significant . Ten patients chose to continue modafinil after the study and the drug was well-tolerated . It would be both feasible and worthwhile to conduct a definitive r and omised controlled trial to determine the role of modafinil in the treatment of cancer-related fatigue [11997203] Abrupt onset of hot flashes poses a significant problem for women treated with chemotherapy for breast cancer . Alternatives to hormone replacement , such as the use of the selective serotonin re-uptake inhibitor ( SSRI ) paroxetine hydrochloride , are being explored as therapies for hot flashes in this patient population . The present study investigated the efficacy of paroxetine for the treatment of hot flashes and associated symptoms in women with breast cancer . This study included 13 patients who were seen in the Psychosocial Clinic at Moffitt Cancer Center . They were referred by their medical oncologist after reporting complaints of significant difficulty with hot flashes . Baseline question naires were completed and a structured diagnostic interview for clinical depression was conducted , all of which were repeated 5 weeks after the paroxetine 20 mg daily was started . Significant improvements were seen in the ratings of hot flash severity ( P = 0.002 ) . In addition , significant improvements were observed in general , emotional , and mental fatigue . Rates of clinical ly significant depressive symptomatology also decreased and sleep quality improved significantly as well . Finally , the incidence of clinical depression improved from 39 % at baseline to 8 % after treatment . These preliminary data suggest that the antidepressant paroxetine can be helpful in the treatment of hot flashes and associated fatigue , sleep disturbance , and depression in women with breast cancer treated with chemotherapy . Further controlled studies are needed to more fully evaluate the efficacy of the SSRIs for hot flashes in women with breast cancer [19367356] Background To investigate the effects of Modafinil on focused attention , motor function and motor excitability in patients with multiple sclerosis ( MS ) and fatigue . Methods 21 MS patients with fatigue were enrolled in this double-blind placebo-controlled study . Modafinil ( MOD ) or placebo ( PL ) was administered for 8 weeks . The d2 alertness test , the Nine Hole Peg Test ( 9HPT ) and several transcranial magnetic stimulation ( TMS ) techniques were applied prior to and after the first drug ingestion and well as after 8 weeks of drug intake . Results Prior to the first drug intake , the two groups were comparable . After the first drug ingestion , fatigue as measured by the Fatigue Severity Scale ( FSS ) , performance of the d2 test and the 9HPT improved significantly in the MOD group and remained better than in the PL group after 8 weeks of treatment . Patients in the MOD group made fewer mistakes in the D2 test without being slower . They completed the 9HPT faster . Motor evoked potential amplitudes produced by paired pulse TMS were larger in the MOD group than the PL group . Motor thresholds and silent period duration s remained unchanged . Conclusions Compared to PL , MOD improved fatigue , focused attention and dexterity and enhanced motor cortex excitability in this group of patients . MOD may be helpful in MS patients with fatigue to improve cognitive and motor abilities [17972110] Background Women who receive adjuvant chemotherapy for breast cancer develop fatigue , and a subset reports cognitive impairment . Methylpheni date is reported to improve fatigue and to decrease cognitive impairment in other population s. Material s and methods Women were r and omised early during their chemotherapy to receive d-methylpheni date ( d-MPH ) , a form of methylpheni date , or an identical appearing placebo . All participants took placebo for one cycle to ensure compliance and then study medication until completion of chemotherapy . Subjects were assessed at baseline , end of chemotherapy and at ∼6 months follow-up with the High Sensitivity Cognitive Screen ( HSCS ) and the Hopkins Verbal Learning Test-Revised ( HVLT-R ) . They also completed the self-report Functional Assessment of Cancer Therapy-General ( FACT-G ) and FACT-F ( F = fatigue ) question naires , evaluating quality of life and fatigue . Results A total of 57 evaluable women were r and omised : 29 to d-MPH and 28 to placebo ; the study did not meet its accrual goal of 170 patients , mainly because women were reluctant to take additional medication in general and methylpheni date in particular . Groups were well matched for age ( median , 50 years ) and education . d-MPH and placebo were well tolerated . There were no significant differences between the r and omised groups in classification of cognitive function by HSCS or in summed FACT-F fatigue scores ( the primary endpoints of the study ) at any of the assessment s. There were also no differences in HLTV-R scores or quality of life . Conclusions This study is underpowered , but there are no trends to suggest that d-MPH , taken concurrently with adjuvant chemotherapy , improves quality of life or fatigue [15736608] An open label trial of modafinil was conducted to determine whether it would be tolerated and effective in treating fatigue for people with amyotrophic lateral sclerosis ( ALS ) . Fifteen patients with ALS were treated for two weeks with either 200 mg or 400 mg of modafinil . Reported side effects of the medication were mild and included diarrhea , headache , nervousness , and insomnia . Side effects did not result in any study dropouts . Following treatment , mean scores on the Fatigue Severity Scale ( FSS ) decreased from 51.3 ( SD 9.2 ) to 42.8 ( SD 10.2 ) . On the Epworth Sleepiness Scale ( ESS ) , mean scores decreased from 8.2 ( SD 2.0 ) to 4.5 ( SD 2.4 ) . Reductions in both the FSS and the ESS were significant at p < 0.001 . Mean scores on the self-report version of the Functional Independence Measure ( FIM-SR ) increased from 115.2 ( SD 5.6 ) to 118.1 ( SD 5.4 ) , with p < 0.01 . This pilot study suggests that modafinil is well-tolerated and may reduce symptoms of fatigue in ALS . Further blinded , controlled studies of modafinil in larger numbers of ALS patients are warranted [16041840] This preliminary study investigated whether bupropion sustained release ( SR ) improved symptomatic fatigue , depression and quality of life in cancer patients and caregiver quality of life . The sample consisted of a prospect i ve open case series of 21 cancer patients , with fatigue and with or without depression at moderate to severe levels , referred for psychiatric assessment from a tertiary care cancer centre . Both patient symptom ratings and caregiver ratings were measured before and after 4 weeks of treatment with the maximally tolerated dose of bupropion in the range of 100 - 300 mg per day . At trial completion , significant improvement was found for symptoms of fatigue and depression . Subjects were divided into two groups : depressed and non-depressed ( based on a cut-off score of 17 on the Hamilton Depression Rating Scale ) . Both groups reported improvement for fatigue and depressive symptoms . Depressed subjects and their caregivers did not experience any change in quality of life , while the non-depressed subjects and their caregivers reported improvements . Results from this small group of patients suggest that bupropion may have potential as an effective pharmaceutical agent for treating cancer-related fatigue . A r and omized , placebo-controlled trial with this medication is indicated [7611638] Because amantadine has been shown to reduce fatigue in patients with multiple sclerosis , we performed a double-blind , placebo-controlled study to assess its efficacy in the disabling symptom of post-polio fatigue . Twenty-three patients completed six weeks of therapy . Fatigue was measured by the patients using visual analogue scales ( twice per day ) and numerical fatigue severity scales ( once per week ) and by overall impression ( at end of therapy ) . Formal neuropsychological testing and serum drug levels were performed to assess compliance . On all measures , no significant difference was found between treatment and placebo groups . Fifty-four percent of patients given amantadine and 43 % given placebo reported a decrease in fatigue ; however , the visual analogue scales and fatigue severity scales failed to reflect any improvement . Several patients in the treatment group elected to continue amantadine therapy after the study was completed . Our findings suggest that amantadine is not significantly better than placebo in reducing the sensation of fatigue in post-polio syndrome , and that the measures we employed were insensitive to capture the subjective response experienced by a few patients [7501140] Objective To determine the relative efficacy of amantadine , pemoline , and placebo in treatment of multiple sclerosis (MS)-related fatigue . Background Fatigue is a complication of MS . Both pemoline and amantadine have been used to treat MS fatigue , but their relative efficacy is not known . Methods Amantadine , pemoline , and placebo were compared in a r and omized , double-blind , placebo-controlled study using a parallel-group design . Ninety-three ambulatory MS patients completed the study . Primary outcome measures were the fatigue seventy scale ( FSS ) ; the MS-specific fatigue scale ( MS-FS ) ; and subjective response determined by verbal self-report . Secondary outcome measures consisted of assessment s of sleep , depression , and vitality . Repeated- measures analysis of variance with planned post-hoc contrasts and Fisher 's exact test were used to compare treatment response . Results Amantadine-treated patients showed a significantly greater reduction in fatigue , as measured by the MS-FS , than did patients treated with placebo ( p = 0.04 ) . By verbal report at the end of the study , 79 % of patients treated with amantadine versus 52 % treated with placebo and 32 % treated with pemoline preferred drug therapy compared with no treatment ( p = 0.03 ) . No significant differences in any primary outcome measures were noted between pemoline and placebo . Neither amantadine nor pemoline affected sleep or depression relative to placebo . Conclusion Amantadine was significantly better than placebo in treating fatigue in MS patients , whereas pemoline was not . The benefit of amantadine was not due to changes in sleep , depression , or neurologic disability [14673053] PURPOSE Fatigue and depression typically occur together in cancer patients , suggesting a common etiology , perhaps based on serotonin . This r and omized clinical trial tested whether paroxetine , a selective serotonin reuptake inhibitor antidepressant known to modulate brain serotonin , would reduce fatigue in cancer patients and whether any reduction was related to depression . PATIENTS AND METHODS Cancer patients undergoing chemotherapy for the first time were assessed for fatigue . Of 704 patients who reported fatigue at their second chemotherapy cycle , 549 patients were r and omly assigned to receive either 20 mg of oral paroxetine hydrochloride daily or placebo for 8 weeks . The assessment s of fatigue and depression were performed at cycles 3 and 4 of chemotherapy . RESULTS A total of 244 patients treated with paroxetine and 235 patients treated with placebo provided assessable data . No difference was detected in fatigue between patient groups . At the end of the study , there was a difference between groups in the mean level of depression ( Center for Epidemiologic Studies Depression scores , 12.0 v 14.8 , respectively ; P < .01 ) . CONCLUSION Paroxetine had no influence on fatigue in patients receiving chemotherapy . A possible explanation is that cancer-related fatigue does not involve a reduction in brain 5-HT levels [16619567] The objective of this r and omised , multicentre , double-blind clinical trial was to investigate the impact of PS76A2 , an aqueous mistletoe extract st and ardised to mistletoe lectins , on quality of life ( QoL ) in breast cancer patients . A total of 352 patients were r and omly allocated to 2 groups receiving PS76A2 ( 15 ng mistletoe lectin/0.5 ml ) or matching placebo twice weekly for 4 to 6 cycles of CMF ( cyclophosphamide , methotrexate , fluorouracil ) chemotherapy followed by 2 months follow-up . The primary efficacy end-point was the change from baseline of 3 FACT-G subscales ( physical , emotional and functional well-being ) during the fourth CMF cycle . Secondary measures included GLQ-8 ( 8 linear analogue self- assessment scales ) , Spitzer 's uniscale and haematological variables . The main variables of safety analysis were adverse events , including injection site reactions and clinical laboratory tests . The results showed that physical , emotional and functional well-being improved upon PS76A2 , but deteriorated following placebo . The treatment differences were statistically significant for the 3 subscales as well as for the summary score FACT-G , which was analysed as O'Brien 's rank sum of its 3 subscales : The total score increased by 4.40 + /- 11.28 , indicating a higher QoL after PS76A2 , but decreased by 5.11 + /- 11.77 with placebo ( p<0.0001 ) . The GLQ-8 sum of 8 LASA scales was analysed as a summary score of GLQ-5 ( sum of item nos. 1 , 5 , 6 , 7 , 8) and GLQ-3 ( sum of item nos. 2 , 3 , 4 ) . GLQ-5 characterises typical aspects of QoL , while GLQ-3 consists of 3 side-effects of CMF ( feeling sick , numbness or pins and needles , loss of hair ) . GLQ-5 decreased by 42.9 + /- 125.0 upon PS76A2 , indicating an improvement in QoL , but increased by 60.3 + /- 94.0 upon placebo ( p<0.0001 ) . GLQ-3 deteriorated in both groups ( PS76A2 : 13.9 + /- 52.4 ; placebo : 34.5 + /- 57.0 ) , but the differences in favour of PS76A2 were , nevertheless , statistically significant ( p=0.0007 ) . The total score GLQ-8 improved by 28.9 + /- 154.6 after PS76A2 and deteriorated by 94.8 + /- 141.1 after placebo ( p<0.0001 ) . Spitzer 's uniscale improved by 12.2 + /- 30.7 upon PS76A2 and deteriorated by 10.8 + /- 26.1 with placebo ( p<0.0001 ) . After follow-up without chemotherapy , a significant treatment difference in favour of PS76A2 was determined by means of FACT-G , GLQ-8 and Spitzer 's uniscale . PS76A2 was well tolerated in this trial , with the exception of slight local reactions in 17.6 % of the PS76A2 group . In conclusion , PS76A2 ( 15 ng mistletoe lectin/0.5 ml twice weekly ) was shown to be safe and effective in improving QoL in breast cancer patients during chemotherapy and follow-up [19620846] Background : Fatigue is a major nonmotor symptom in Parkinson disease ( PD ) . It is associated with reduced activity and lower quality of life . Objective : To determine if modafinil improves subjective fatigue and physical fatigability in PD . Methods : Nineteen PD patients who reported significant fatigue in the Multidimensional Fatigue Inventory ( MFI ) participated in this 8-week study . Subjects took their regular medications and were r and omly assigned to the treatment group ( 9 subjects , modafinil 100-mg capsule BID ) or placebo group ( 10 subjects ) . We used the MFI to measure subjective fatigue and used finger tapping and intermittent force generation to evaluate physical fatigability . Subjects also completed the Epworth Sleepiness Scale ( ESS ) and the Center of Epidemiological Study -Depression Scale . Results : There were no significant differences at baseline and at 1 month in finger tapping and ESS between the modafinil and placebo groups . At 2 months , the modafinil group had a higher tapping frequency ( P < 0.05 ) , shorter dwell time ( P < 0.05 ) , and less fatigability in finger tapping and tended to have lower ESS scores ( P < 0.12 ) than the placebo group . However , there was no difference between groups over time for any dimension of the MFI . Conclusions : This small study demonstrated that although modafinil may be effective in reducing physical fatigability in PD , it did not improve fatigue symptoms [11927189] We have previously shown that the risk of major depression in patients with malignant melanoma undergoing interferon-α ( IFN-α ) therapy can be reduced by pretreatment with the antidepressant , paroxetine . Using dimensional analyses , the present study assessed the expression and treatment responsiveness of specific clusters of neuropsychiatric symptoms over the first three months of IFN-α therapy . Forty patients with malignant melanoma eligible for IFN-α treatment were r and omly assigned to receive either paroxetine or placebo in a double-blind design . Neuropsychiatric assessment s were conducted at regular intervals during the first twelve weeks of IFN-α therapy and included the 21-item Hamilton Depression Rating Scale , the 14-item Hamilton Anxiety Rating Scale and the Neurotoxicity Rating Scale . Neurovegetative and somatic symptoms including anorexia , fatigue and pain appeared within two weeks of IFN-α therapy in a large proportion of patients . In contrast , symptoms of depressed mood , anxiety and cognitive dysfunction appeared later during IFN-α treatment and more specifically in patients who met DSM-IV criteria for major depression . Symptoms of depression , anxiety , cognitive dysfunction and pain were more responsive , whereas symptoms of fatigue and anorexia were less responsive , to paroxetine treatment . These data demonstrate distinct phenomenology and treatment responsiveness of symptom dimensions induced by IFN-α , and suggest that different mechanisms mediate the various behavioral manifestations of cytokine-induced “ sickness behavior . [10721881] We investigated the effect of amantadine on cognitive processing in patients with multiple sclerosis ( MS ) and fatigue with objective electrophysiological measures . Behavioral methods ( Reaction Time , RT ) and two different Event Related Potential ( ERP ) components measuring i ) stimulus selection ( Selection Negativity , SN ) and ii ) response selection ( Lateralized Readiness Potential , LRP ) were employed . Twenty-four patients with clinical definite MS ( 10 relapsing remitting and 14 secondary progressive ) and confirmed fatigue in the past three months ( Fatigue Severity Scale ( FSS ) > 4 ) were included . Patients were r and omized in a double-blind , placebo-controlled cross-over design . We found a difference between the two treatments for ERP measures to stimuli with relevant colour starting at about 200 ms . This negativity had a higher amplitude during amantadine treatment regardless of treatment order . The RT did not differ significantly between the treated and untreated groups . Additional analysis indicated that patients with a disease duration of less than 7 years had a significant test position ( practice effect ) , but no treatment effect , while patients with a longer MS duration showed no practice effect , but rather an improved reaction speed and increased ERP amplitude effects when treated with amantadine . The present findings suggest that amantadine exerts beneficial effects on early cognitive processes in patients with MS , but appears to be limited to subjects with a longer duration of the disease [15327047] Sixty relapsing-remitting multiple sclerosis ( MS ) patients were selected on the basis of their score on the Fatigue Severity Scale ( FSS ) and formed two groups : 40 patients ( fatigued MS ; MSf ) scored above the 75th percentile of a previously assessed representative MS sample ( 100 patients ) , and 20 age- and sex-matched patients ( nonfatigued MS patients ; MSnf ) scored below the 25th percentile . The patients underwent clinical evaluation ( Exp and ed Disability Status Scale ( EDSS ) ) , further assessment of fatigue ( Fatigue Impact Scale ) , scales evaluating depression ( Hamilton Depression Rating Scale ( HDRS ) and Beck ’s Depression Inventory ( BDI ) ) and neuropsychological tests . All patients were evaluated for muscle fatigability and central activation by means of a biomechanical test of sustained contraction ; they also underwent somatosensory evoked potentials ( SSEPs ) and transcranial magnetic stimulation ( TMS ) . The patients of the MSf subgroup were then r and omized to one of the following two treatments : 4-aminopyridine ( 4-AP ) 24 mg/day and fluoxetine ( FLX ) 20 mg/day . After a one-week titration this treatment proceeded for 8 weeks . At the end of the treatment , EDSS , fatigue and depression scores were further evaluated . At baseline , fatigue test scores consistently correlated with depression and cognitive test scores , but not with the fatigability test . Fatigue scores decreased in both treatment groups in a similar way . Due to the design of the study , this can not be disjoined from a placebo effect . The changes of fatigue scores could not be predicted in the FLX group , whereas in the 4-AP group higher basal fatigability test scores were associated with greater reduction in fatigue scores [18304907] The amphetamine , methylpheni date ( Ritaline ) has been proposed as being of interest in the treatment of asthenia in patients with advanced cancer . To evaluate this hypothesis a r and omised controlled double-blind parallel-group national multi-centre trial is proposed versus placebo . Three previous r and omised controlled studies and one open study have suggested that the administration of methylpheni date may be of interest in the palliative care of asthenic cancer patients . However , these studies do not permit a definitive conclusion to be drawn . This article presents the protocol of our new trial . The primary objective is to evaluate the anti-asthenic effect of methylpheni date using a visual analogue scale ( VAS ) after 7 days of treatment of cancer patients in palliative care , i.e. when the cancer is considered to be rapidly evolving or as terminal . One hundred and ten patients are treated for 28 days at a starting dose of 20 mg/day , and adjustment of the dose is possible . It is important to stress that only the concerted efforts of an interdisciplinary team ( somatologues , psychiatrists , psychologists , paramedical carers and social workers ) can tackle the challenges posed by the difficult symptom of asthenia . The medical treatment is only one element of the approach to caring for these patients [8639070] BACKGROUND Amantadine hydrochloride and pemoline , both frequently used to treat the fatigue of multiple sclerosis ( MS ) , may also improve attention and other cognitive functions in MS . To our knowledge , these agents have never been compared in a placebo-controlled trial of patients with MS . OBJECTIVE To evaluate the effects of amantadine and pemoline on cognitive functioning in MS . METHODS A total of 45 ambulatory patients with MS and severe fatigue were treated for 6 weeks with amantadine , pemoline , or placebo using a parallel group design . They underwent comprehensive neuropsychological testing to determine treatment effects on cognitive functioning . Primary outcome measures were tests of attention ( Digit Span , Trail Making Test , and Symbol Digit Modalities Test ) , verbal memory ( Selective Reminding Test ) , nonverbal memory ( Benton Visual Retention Test ) , and motor speed ( Finger Tapping Test ) . RESULTS Fatigue did not significantly correlate with any of the neuropsychological outcome measures at baseline or after treatment . All three treatment groups improved on tests of attention ( P < .003 ) , verbal memory ( P < .001 ) , and motor speed ( P < .002 ) . There were no significant differences between amantadine , pemoline , and placebo . CONCLUSIONS Cognitive functioning in MS is independent of fatigue . Neither amantadine nor pemoline enhances cognitive performance in MS compared with placebo [3902184] We carried out a double blind control study of fatigue in 32 patients with multiple sclerosis , comparing amantadine hydrochloride 100 mg twice a day and placebo . On amantadine 31 % had marked improvement ; 15.6 % moderate improvement ; 15.6 % mild improvement ; and 36.5 % unchanged . On placebo , none noted marked improvement ; one cl aim ed moderate improvement on either amantadine or placebo . 18.7 % reported mild improvement on placebo ; and most of them had similar or more response to amantadine . No patient selected placebo over amantadine at the end of the trial . Overall improvement was seen in 62.5 % of patients on amantadine and 21.8 % on placebo . Additional experience up to two years suggests continued benefit but common and important side-effects [10633535] The goal of this pilot study was to evaluate the effect of dehydroepi and rosterone ( DHEA ) on depressed mood and fatigue in HIV+ men and women , unselected for baseline DHEA level . Secondary questions concerned treatment effects on libido and body cell mass , on serum testosterone levels , and elicitation of short-term side effects . Treatment consisted of an open-label 8-week trial using DHEA doses from 200 to 500 mg/day . Mood responders were maintained for another 4 weeks , then r and omized to a double blind placebo controlled 4-week discontinuation trial . Forty-five patients , including six women , entered the trial . Of 32 week 8 completers , mood was much improved in 72 % , and 81 % were rated responders with respect to fatigue . Response on either parameter was unrelated to baseline serum DHEA level . Twenty-one patients entered the double blind discontinuation phase . No differences in relapse rate between placebo and DHEA groups were observed for either mood or fatigue . Body cell mass increased significantly by week 8 , and this improvement was maintained throughout the double blind phase for patients in both treatment conditions . Libido increased significantly as well . DHEA therapy did not have an effect on CD4 cell count or on serum testosterone levels in men . In conclusion , DHEA may be a promising treatment for HIV+ patients with depressed mood and fatigue , although persistence of response even in placebo-treated patients during the discontinuation phase leaves unresolved questions . A parallel group double blind clinical trial is indicated as the next step to more clearly identify therapeutic efficacy [12195441] Background Modafinil is a unique wake-promoting agent that is chemically distinct from traditional stimulants . Results of a placebo-controlled study showed it to improve fatigue in multiple sclerosis ( MS ) at a dose of 200 mg daily , but not at a dose of 400 mg daily . Objective To establish the efficacy , safety and appropriate dose of modafinil in the treatment of fatigue and sleepiness in patients with multiple sclerosis . Method A total of 50 patients diagnosed with MS ( mean age 40.4 ± 10.3 years , 30 females/20 males ; MS type : 36 relapsing remitting , 1 primary progressive , 13 secondary progressive ; mean disability level 3.8 ± 1.5 on the Kurtzke EDSS ) and complaining of chronic fatigue were enrolled in a prospect i ve 3-month , two-center , open-label study . Efficacy was evaluated with the Fatigue Severity Scale ( FSS , score range 0 - 42 ) , the Epworth Sleepiness Scale ( ESS , score range 0 - 24 ) and by subjective patient appraisal of change of fatigue , quality of life and overall satisfaction with treatment . Adverse effects ( AEs ) were recorded throughout the study . Treatment was started with a single daily dose of 100 mg in all patients . In non-responders the dose was increased by 100 mg increments up to a maximum daily dose of 400 mg . Results Three patients discontinued modafinil because of AEs ( nervousness , dizziness ) . Two patients ( 4 % ) were treated with 50 mg , 25 ( 50 % ) with 100 mg , 21 ( 42 % ) with 200 mg and 2 ( 4 % ) with 300 mg daily . No patient required 400 mg daily . Mean FSS scores were 30.3 ± 8.5 at baseline and 25.4 ± 3.7 at 3 months ( p < 0.0001 ) . Mean ESS scores were 9.7 ± 3.9 at baseline and 4.9 ± 2.9 at 3 months ( p < 0.0001 ) . Self- appraisal of change of fatigue showed clear improvement in 41 patients ( 87.2 % ) , some improvement in 4 ( 8.5 % ) and no change in 2 ( 4.3 % ) . Overall clinical condition was clearly improved in 43 patients ( 91.5 % ) , somewhat improved in 1 patient ( 2.1 % ) , and unchanged in 3 patients ( 6.4 % ) . No patient reported worsening of overall clinical condition . Conclusions Treatment with modafinil significantly improves fatigue and sleepiness and is well tolerated by patients with MS . Unlike the higher dose regimen required in narcolepsy , a low-dose regimen of modafinil is effective in MS [17869448] PURPOSE The quality of life ( QOL ) and neurocognitive function of patients with brain tumors are negatively affected by the symptoms of their disease and brain radiation therapy ( RT ) . We assessed the effect of prophylactic d-threo-methylpheni date HCl ( d-MPH ) , a central nervous system ( CNS ) stimulant on QOL and cognitive function in patients undergoing RT . METHODS AND MATERIAL S Sixty-eight patients with primary or metastatic brain tumors were r and omly assigned to receive d-MPH or placebo . The starting dose of d-MPH was 5 mg twice daily ( b.i.d . ) and was escalated by 5 mg b.i.d . to a maximum of 15 mg b.i.d . The placebo was administered as one pill b.i.d . escalating three pills b.i.d . The primary outcome was fatigue . Patients were assessed at baseline , the end of radiation therapy , and 4 , 8 , and 12 weeks after brain RT using the Functional Assessment of Cancer Therapy with brain and fatigue ( FACIT-F ) subscales , as well as the Center for Epidemiologic Studies Scale and Mini-Mental Status Exam . RESULTS The Mean Fatigue Subscale Score at baseline was 34.7 for the d-MPH arm and 33.3 for the placebo arm ( p = 0.61 ) . At 8 weeks after the completion of brain RT , there was no difference in fatigue between patient groups . The adjusted least squares estimate of the Mean Fatigue Subscale Score was 33.7 for the d-MPH and 35.6 for the placebo arm ( p = 0.64 ) . Secondary outcomes were not different between the two treatment arms . CONCLUSIONS Prophylactic use of d-MPH in brain tumor patients undergoing RT did not result in an improvement in QOL [20054744] BACKGROUND AND PURPOSE Fatigue is a frequent symptom in multiple sclerosis ( MS ) , recognized as the most unpleasant symptom by 50 - 60 % of patients . Amantadine is one of the medications prescribed for fatigue in MS . Some previous studies have demonstrated a positive influences of amantadine on fatigue in MS . The aim of this study was to determine the efficacy of amantadine on Persian MS patients . MATERIAL AND METHODS This prospect i ve study took place in Isfahan , Iran and included 42 MS patients with fatigue who were divided r and omly into two groups . Twenty-one patients received amantadine and all others placebo . The Fatigue Severity Scale ( FSS ) was used to determine the severity of the fatigue . FSS scores at baseline and two months later were compared in the two groups . RESULTS Mean ( SD ) baseline FSS score was 5.27 ( 1.11 ) in the amantadine group and 4.89 ( 1.13 ) in the placebo group ( p > 0.05 ) . Mean FSS at the end of study was 4.00 ( 1.02 ) in the amantadine group and 4.24 ( 1.03 ) in the placebo group ( p > 0.05 ) ; however , the FSS change ( the difference between FSS scores at the end of the study and at the beginning of the study ) in amantadine and placebo groups was -1.27 ( 0.53 ) and -0.66 ( 0.33 ) , respectively , which was significant ( p < 0.05 ) . CONCLUSIONS Our findings demonstrate a significant drop on the fatigue severity scale in MS patients after treatment with amantadine ; nevertheless , more studies on a larger scale with longer duration are needed to confirm this finding [22987089] PURPOSE L-carnitine , a popular complementary and alternative medicine product , is used by patients with cancer for the treatment of fatigue , the most commonly reported symptom in this patient population . The purpose of this study was to determine the efficacy of L-carnitine supplementation as a treatment for fatigue in patients with cancer . PATIENTS AND METHODS In this double-blind , placebo-controlled trial , patients with invasive malignancies and fatigue were r and omly assigned to either 2 g/d of L-carnitine oral supplementation or matching placebo . The primary end point was the change in average daily fatigue from baseline to week 4 using the Brief Fatigue Inventory ( BFI ) . RESULTS Three hundred seventy-six patients were r and omly assigned to treatment with L-carnitine supplementation or placebo . L-carnitine supplementation result ed in significant carnitine plasma level increase by week 4 . The primary outcome , fatigue , measured using the BFI , improved in both arms compared with baseline ( L-carnitine : -0.96 , 95 % CI , -1.32 to -0.60 ; placebo : -1.11 , 95 % CI -1.44 to -0.78 ) . There were no statistically significant differences between arms ( P = .57 ) . Secondary outcomes , including fatigue measured by the Functional Assessment of Chronic Illness Therapy-Fatigue instrument , depression , and pain , did not show significant difference between arms . A separate analysis of patients who were carnitine-deficient at baseline did not show statistically significant improvement in fatigue or other outcomes after L-carnitine supplementation . CONCLUSION Four weeks of 2 g of L-carnitine supplementation did not improve fatigue in patients with invasive malignancies and good performance status [15591014] Nutritional factors are among the postulated causes of fatigue , a highly prevalent symptom in the cancer population , with serious impact on patients ' quality of life . Deficiency of the micronutrient carnitine may play a role by reducing energy production through fatty acid oxidation . We present preliminary data of an open-label , dose-finding study to determine safety and maximally tolerated dose ( MTD ) of 1 week of L-carnitine supplementation in cancer patients with fatigue and carnitine deficiency . Patients who met inclusion /exclusion criteria underwent carnitine level determination . Eighty-three percent of these patients ( 15/18 ) had carnitine deficiency . Preliminary data analysis of 13 patients showed that total carnitine increased from 30.0 + /- 6.9 to 41.0 + /- 12.1 ( mean + /- SD ) after 1 week of supplementation ( P = 0.01 ) , and free carnitine increased from 24.3 + /- 6.1 to 33.8 + /- 9.8 ( P = 0.004 ) . Outcome measures were fatigue ( BFI score ) , depression ( CES-D ) , sleep disruption ( ESS ) , and performance status ( Karnofsky ) . Median ( min , max ) BFI score at baseline was 73 ( 46 , 82 ) versus 50 ( 3 , 82 ) after 1-week supplementation ( P = 0.009 ) . CES-D score at baseline was 29 ( 16 , 42 ) and 22 ( 8 , 32 ) after 1 week ( P = 0.028 ) . ESS at baseline was 46.5 ( 0 , 69 ) and 30.4 ( 0 , 72 ) after 1 week ( P = 0.015 ) . Karnofsky score did not change significantly ( P = 0.38 ) . We are currently conducting a r and omized , double-blind , placebo-controlled study to rigorously assess the role of L-carnitine for the treatment of fatigue and depression in cancer patients [20955776] Increased levels of inflammatory cytokines such as tumor necrosis factor ( TNF ) and interleukin-6 ( IL-6 ) may play a role in depression . Mild depressive-like symptoms can be induced in humans through activation of the innate immune system with endotoxin . Whether preventive treatment with antidepressants can reduce endotoxin-induced symptoms has never been tested . In a double-blind , r and omized , placebo-controlled , cross-over study , we administered intravenous low-dose endotoxin ( 0.8 ng/kg ) or placebo to 11 healthy subjects who had received oral pre-treatment with citalopram ( 10 mg twice a day ) or placebo for 5 days . The Montgomery-Åsberg Depression Rating Scale , the State and Trait Anxiety Inventory , and a visual analog scale were used to measure depressive and anxiety symptoms and social anhedonia . Serum levels of TNF and IL-6 were measured with immunoassays . Compared to placebo , endotoxin administration increased serum levels of TNF and IL-6 , and caused mild depressive-like symptoms , in particular lassitude and social anhedonia . While citalopram pre-treatment had no effect on the innate immune response to endotoxin , it reduced the endotoxin-induced MADRS total score by 50 % , with a moderate effect size ( Cohen 's d=0.5 ) . Most of the MADRS total score was due to the lassitude item , and citalopram pre-treatment specifically reduced endotoxin-induced lassitude with a large effect size ( Cohen 's d=0.9 ) . These results suggest that subchronic pre-treatment with the serotonin-reuptake inhibitor citalopram blunts mood symptoms induced by acute immune system activation with endotoxin without inhibiting the peripheral immune response [12743146] PURPOSE To determine whether fluoxetine improves overall quality of life ( QOL ) in advanced cancer patients with symptoms of depression revealed by a simple survey . PATIENTS AND METHODS One hundred sixty-three patients with an advanced solid tumor and expected survival between 3 and 24 months were r and omly assigned in a double-blinded fashion to receive either fluoxetine ( 20 mg daily ) or placebo for 12 weeks . Patients were screened for at least minimal depressive symptoms and assessed every 3 to 6 weeks for QOL and depression . Patients with recent exposure to antidepressants were excluded . RESULTS The groups were comparable at baseline in terms of age , sex , disease distribution , performance status , and level of depressive symptoms . One hundred twenty-nine patients ( 79 % ) completed at least one follow-up assessment . Analysis using generalized estimating equation modeling revealed that patients treated with fluoxetine exhibited a significant improvement in QOL as shown by the Functional Assessment of Cancer Therapy-General , compared with patients given placebo ( P = .01 ) . Specifically , the level of depressive symptoms expressed was lower in patients treated with fluoxetine ( P = .0005 ) , and the subgroup of patients showing higher levels of depressive symptoms on the two- question screening survey were the most likely to benefit from treatment . CONCLUSION In this mix of patients with advanced cancer who had symptoms of depression as determined by a two- question bedside survey , use of fluoxetine was well tolerated , overall QOL was improved , and depressive symptoms were reduced [11325685] Exercise capacity in patients with end-stage renal disease ( ESRD ) remains impaired despite correction of anemia . Carnitine insufficiency may contribute to impaired exercise and functional capacities in patients with ESRD . Two r and omized placebo-controlled trials were conducted to test whether intravenous L-carnitine improves exercise capacity ( assessed by maximal rate of oxygen consumption [ VO(2max ) ] ) and quality of life ( measured by the Kidney Disease Question naire [ KDQ ] ) in patients with ESRD . In study A , patients were administered L-carnitine , 20 mg/kg ( n = 28 ) , or placebo ( n = 28 ) intravenously at the conclusion of each thrice-weekly dialysis session for 24 weeks . In study B , a dose-ranging study , patients were administered intravenous L-carnitine , 10 mg/kg ( n = 32 ) , 20 mg/kg ( n = 30 ) , or 40 mg/kg ( n = 32 ) , or placebo ( n = 33 ) as in study A. The prospect i ve primary statistical analysis evaluated changes in VO(2max ) in each study and specified that changes in the KDQ were assessed only in the combined population s. L-Carnitine supplementation increased plasma carnitine concentrations , but did not affect VO(2max ) in either study . Because change in VO(2max ) showed significant heterogeneity , a secondary analysis using a mixture of linear models approach on the combined study population s was performed . L-Carnitine therapy ( combined all doses ) was associated with a statistically significant smaller deterioration in VO(2max ) ( -0.88 + /- 0.26 versus -0.05 + /- 0.19 mL/kg/min , placebo versus L-carnitine , respectively ; P = 0.009 ) . L-Carnitine significantly improved the fatigue domain of the KDQ after 12 ( P = 0.01 ) and 24 weeks ( P = 0.03 ) of treatment compared with placebo using the primary analysis but did not significantly affect the total score ( P = 0.10 ) or other domains of the instrument ( P > 0.11 ) . Carnitine was well tolerated , and no drug-related adverse effects were identified . Intravenous L-carnitine treatment increased plasma carnitine concentrations , improved patient-assessed fatigue , and may prevent the decline in peak exercise capacity in hemodialysis patients . VO(2max ) in the primary analysis and other assessed end points were unaffected by carnitine therapy [10789956] Abstract A multivariate analysis of the data was conducted to evaluate the effects of age , gender , and performance status on symptom profile . A comprehensive prospect i ve analysis of symptoms was conducted in 1,000 patients on initial referral to the Palliative Medicine Program of the Clevel and Clinic . The median number of symptoms per patient was 11 ( range 1–27 ) . The ten most prevalent symptoms were pain , easy fatigue , weakness , anorexia , lack of energy , dry mouth , constipation , early satiety , dyspnea , and greater than 10 % weight loss . The prevalence of these 10 symptoms ranged from 50 % to 84 % . Younger age was associated with 11 symptoms : blackout , vomiting , pain , nausea , headache , sedation , bloating , sleep problems , anxiety , depression , and constipation . Gender was associated with 8 symptoms . Males had more dysphagia , hoarseness , > 10 % weight loss and sleep problems ; females , more early satiety , nausea , vomiting , and anxiety . Performance status was associated with 14 symptoms . Advanced cancer patients are polysymptomatic . Ten symptoms are highly prevalent . Symptom prevalence for 24 individual symptoms differs with age , or gender , or performance status [19208404] Our objective was to determine whether modafinil alleviates fatigue in patients with amyotrophic lateral sclerosis ( ALS ) . A placebo controlled trial with a 3:1 modafinil : placebo r and omization in doses up to 300 mg/day for 4 weeks was followed by 8 weeks of open maintenance treatment . The primary endpoint was the Clinical Global Impressions-Improvement Scale . Secondary endpoints were the Fatigue Severity Scale , Epworth Sleepiness Scale , Beck Depression Inventory , Role Function Scale , and visual analog scales . Analysis of covariance was used to assess change at Week 4 . Thirty-two patients were r and omized ; 29 completed the 4-week trial . In intention to treat ( ITT ) analysis , the response was 76 % for modafinil versus 14 % for placebo . In a completer analysis , the modafinil response rate was 86 % , and the placebo response rate remained 14 % . The number needed to treat was 1.6 ( ITT ) . No medically serious adverse events were reported . Modafinil may be a promising intervention for fatigue in ALS patients . Replication in a larger study is needed [14711473] Systemic syndromes characterized by a persistent activity of circulating mediators ( cytokines ) are frequently present with advanced cancer . We grouped under the general heading of " Systemic Immune-Metabolic Syndrome ( SIMS ) " a particular variety of distressing systemic syndrome characterized by dysregulation of the psycho-neuro-immune-endocrine homeostasis , with overlapping clinical manifestations . SIMS may include cachexia , anorexia , nausea , early satiety , fatigue , tumor fever , cognitive changes and superinfection . The aim of this study was to ameliorate some of the SIMS symptoms in a homogeneous group of lung adenocarcinoma patients using a multitargeted therapy . Fifteen patients with evidence of SIMS were studied . SIMS was defined as the presence of weight loss , anorexia , fatigue performance status>/=2 and acute-phase protein response . Patients received medroxyprogesterone ( MPA ) ( 500 mg twice daily ) , celecoxib ( 200 mg twice daily ) , plus oral food supplementation for 6 weeks . After treatment , 13 patients either had stable weight ( + /- 1 % ) or had gained weight . There were significant differences in improvement of body-weight-change rate , nausea , early satiety , fatigue , appetite and performance status . Patients who had any kind of lung infection showed higher levels of IL-10 compared to non-infected patients ( P=0.039 ) . Our results suggest that patients with advanced lung adenocarcinoma , treated with MPA , celecoxib and dietary intervention , might have considerable improvement in certain SIMS outcomes . This multitargeted symptomatic approach deserves further study [20564068] Cancer‐related fatigue is a debilitating symptom affecting psychosocial functioning and quality of life in 70 % to 100 % of cancer patients during and after treatment . The authors examined the effect of 200 mg of modafinil daily on the severity of cancer‐related fatigue [16648508] PURPOSE To evaluate the effectiveness of patient-controlled methylpheni date as compared with placebo in cancer patients with fatigue , as measured by the Functional Assessment for Chronic Illness Therapy-Fatigue ( FACIT-F ) . PATIENTS AND METHODS Patients with a fatigue score of at least 4 on a scale of 0 to 10 ( 0 = no fatigue , 10 = worst possible fatigue ) and hemoglobin level of at least 10 g/dL were included . Patients were r and omly assigned to receive 5 mg methylpheni date or placebo every 2 hours as needed ( maximum of four capsules a day ) , for 7 days . Patients completed a daily diary including study drug record and fatigue intensity . A research nurse telephoned patients daily to assess toxicity and fatigue level . All patients were offered open-label methylpheni date for 4 weeks . FACIT-F and the Edmonton Symptom Assessment System ( ESAS ) were assessed at baseline , and days 8 , 15 , and 36 . The FACIT-F fatigue subscore on day 8 was considered the primary end point . RESULTS Of 112 patients r and omly assigned , 52 patients in the methylpheni date and 53 in the placebo group were assessable for analysis . Fatigue intensity improved significantly on day 8 in both the methylpheni date and placebo groups . However , there was no significant difference in fatigue improvement by FACIT-F ( P = .31 ) or ESAS ( P = .14 ) between groups . In open-label phase , fatigue intensity maintained low as compared with baseline . No significant toxicities were observed . CONCLUSION Both methylpheni date and placebo result ed in significant symptom improvement . Methylpheni date was not significantly superior to placebo after 1 week of treatment . Longer study duration is justified . The role of daily telephone calls from a research nurse should be explored as a palliative care intervention [24445757] Purpose This study assessed the efficacy of methylpheni date versus placebo for cancer-related fatigue reduction . Other objectives were to analyze cytokine levels and to determine the effects of methylpheni date on other symptoms , cognitive function , work yield , and patients ’ perceptions and preferences . Methods Patients were r and omly assigned ( 1:1 ) to receive methylpheni date -placebo or placebo-methylpheni date for 4 weeks . Patients crossed over after 2 weeks . Wilcoxon signed rank tests and McNemar tests were used to assess continuous and categorical variables . The primary efficacy endpoint was change in the level of worst fatigue on the Brief Fatigue Inventory ( BFI ) at the end of each 2-week period . Results The mean baseline BFI score was moderate ( 5.7 ) . Methylpheni date treatment did not affect patients ’ worst level of fatigue or other symptoms . Results from the Wechsler Adult Intelligence Scale Digit Symbol Test and the Hopkins Verbal Learning Test with BFI interference questions and BFI activity questions showed significant improvement in the methylpheni date -treated patients ’ verbal learning , memory , visual perception , analysis , and scanning speed . Patients treated with methylpheni date missed significantly fewer work hours owing to health reasons and worked significantly more hours . After 4 weeks , 64 % of patients reported that methylpheni date improved their cancer-related fatigue , and 58 % wanted to continue treatment . Significant difference in interleukin 6R ( positive ) , interleukin 10 ( negative ) , and tumor necrosis factor & agr ; ( positive ) was noted between the methylpheni date and the placebo group . Conclusions Low-dose methylpheni date did not improve cancer-related fatigue . Patients taking methylpheni date had better cognition and were able to work more hours . Patients tolerated methylpheni date well , and the majority felt better and wanted to continue treatment [15824361] Pharmacotherapeutic options for multiple sclerosis (MS)-related fatigue are limited . Thirty patients were r and omly assigned to aspirin ( ASA ) 1,300 mg/day or placebo in a double-blind crossover study . Results favored ASA for the main clinical outcomes : Modified Fatigue Impact Scale scores ( p = 0.043 ) and treatment preference ( p = 0.012 ) . There were no significant adverse effects . The results warrant further study and support a role for ASA-influenced mechanisms , perhaps immunologic , in the generation of MS-related chronic fatigue [21427431] Fatigue is prevalent among patients with hepatitis C virus ( HCV ) and with HIV/AIDS but there are no established fatigue treatments for either condition or their combination . We analysed data from three trials of modafinil or armodafinil for HIV-positive patients with fatigue , including 36 co-infected with HCV , to compare treatment response and safety parameters related to HCV status . One hundred and twenty patients received active drug and 70 were r and omized to placebo . Fatigue response rate to modafinil/armodafinil was 100 % for patients with HCV ( 18/18 ) and 73 % ( 74/102 ) for patients without HCV . Placebo response rate was 28 % ( 5/18 ) and 29 % ( 15/52 ) , respectively . Depressive symptoms improved only when energy improved . Viral load declined from baseline after 12 and 26 weeks of active medication . CD4 cell count did not change , nor did alanine transaminase and aspartate aminotransferase for patients with HCV . Patients with haematocrit below the reference range responded , as well as patients whose values were within the reference range . Modafinil and armodafinil appear effective and well tolerated for treating fatigue among both HCV-positive and HCV-negative patients with HIV/AIDS , suggesting that they may hold promise for HIV-positive patients considering alpha interferon/ribavirin treatment for HCV . Further investigation in a focused trial is warranted [20625123] PURPOSE Fatigue is one of the most common symptoms experienced by patients with cancer . This trial was developed to evaluate the efficacy of long-acting methylpheni date for improving cancer-related fatigue and to assess its toxicities . PATIENTS AND METHODS Adults with cancer were r and omly assigned in a double-blinded manner to receive methylpheni date ( target dose , 54 mg/d ) or placebo for 4 weeks . The Brief Fatigue Inventory was the primary outcome measure , while secondary outcome measures included a Symptom Experience Diary ( SED ) , the Short Form-36 ( SF-36 ) Vitality Subscale , a linear analog self- assessment , the Pittsburgh Sleep Quality Index , and the Subject Global Impression of Change . RESULTS In total , 148 patients were enrolled . Using an area under the serum concentration-time curve analysis , there was no evidence that methylpheni date , as compared with placebo , improved the primary end point of cancer-related fatigue in this patient population ( P = .35 ) . Comparisons of secondary end points , including clinical ly significant changes in quality -of-life variables and cancer-related fatigue change from baseline , were similarly negative . However , a subset analysis suggested that patients with more severe fatigue and /or with more advanced disease did have some fatigue improvement with methylpheni date ( eg , in patients with stage III or IV disease , the mean improvement in usual fatigue was 19.7 with methylpheni date v 2.1 with placebo ; P = .02 ) . There was a significant difference in self-reported toxicities ( SED ) , with increased levels of nervousness and appetite loss in the methylpheni date arm . CONCLUSION This clinical trial was unable to support the primary pre study hypothesis that the chosen long-acting methylpheni date product would decrease cancer-related fatigue [14585555] Opioid-induced sedation is a major complication in patients with cancer pain . This study assessed the effectiveness of donepezil in opioid-induced sedation and related symptoms in patients with cancer pain . Twenty-seven patients who were receiving strong opioids for pain and reported sedation were enrolled . Donepezil 5 mg was given every morning for 7 days . Changes between baseline and Day 7 in sedation , pain , fatigue and other symptoms were evaluated using the Edmonton Symptom Assessment Scale . Fatigue was also measured using the Functional Assessment of Chronic Illness Therapy-Fatigue ( FACIT-Fatigue ) . Overall usefulness of donepezil was measured by the patient at the end of the study . In 20 evaluable patients , sedation , fatigue , anxiety , well-being , depression , anorexia and problems with sleep were significantly improved . Side effects included nausea , vomiting , diarrhea , muscle and abdominal cramps , and anorexia . Overall , however , the treatment was well tolerated . Donepezil appears to improve sedation and fatigue in patients receiving opioids for cancer pain . R and omized controlled trials of this agent are justified [7539701] Sedation may be a doselimiting side-effect of opioid therapy in some cancer patients . This study was design ed to evaluate further the use of the psychostimulant , methylpheni date , an agent that has been reported to counteract opioid-induced sedation , in patients with cancer-related pain . Patients receiving a stable dose of an opioid for cancer-related pain were recruited for this r and omized , double-blind , crossover clinical trial . In addition to their regular dose of narcotics , they received 5 days of methylpheni date followed by 5 days of placebo , or vice versa . Our data did not definitively demonstrate any statistically significant benefit for methylpheni date , but did suggest that this drug could mildly decrease narcotic-induced drowsiness and could increase night-time sleep . These data , in conjunction with other published data , suggest that methylpheni date can counteract narcotic-induced daytime sedation to a limited degree [17687152] PURPOSE To evaluate the effectiveness of donepezil compared with placebo in cancer patients with fatigue as measured by the Functional Assessment for Chronic Illness Therapy-Fatigue ( FACIT-F ) . PATIENTS AND METHODS Patients with fatigue score > or= 4 on a scale of 0 to 10 ( 0 = no fatigue , 10 = worst possible fatigue ) for more than 1 week were included . Patients were r and omly assigned to receive donepezil 5 mg or placebo orally every morning for 7 days . A research nurse contacted the patients by telephone daily to assess toxicity and fatigue level . All patients were offered open-label donepezil during the second week . FACIT-F and /or the Edmonton Symptom Assessment System ( ESAS ) were assessed at baseline , and days 8 , 11 , and 15 . The FACIT-F fatigue subscale score on day 8 was considered the primary end point . RESULTS Of 142 patients r and omly assigned to treatment , 47 patients in the donepezil group and 56 in the placebo group were assessable for final analysis . Fatigue intensity improved significantly on day 8 in both donepezil and placebo groups . However , there was no significant difference in fatigue improvement by FACIT-F ( P = .57 ) or ESAS ( P = .18 ) between groups . In the open-label phase , fatigue intensity continued to be low as compared with baseline . No significant toxicities were observed . CONCLUSION Donepezil was not significantly superior to placebo in the treatment of cancer-related fatigue [20844926] Summary Background The objectives of this pilot study were to evaluate the safety and efficacy of the central nervous system stimulant methylpheni date in the management of asthenia in breast cancer patients treated with docetaxel . Patients and methods Patients with early breast cancer who presented asthenia > 3 on the Visual Analogue Scale ( VAS ) after the first cycle of docetaxel-based chemotherapy were included . Patients received two additional cycles of chemotherapy , one with methylpheni date ( 10 mg bid ) and the other without methylpheni date . Asthenia was evaluated using VAS and the Functional Assessment of Cancer Therapy-Fatigue ( FACT-F ) scale . Distress was assessed using the Hospital Anxiety and Depression Scale ( HADS ) , and quality of life using FACT-F. Results Ten patients were included and evaluated for efficacy and safety . Overall , cycles with methylpheni date were better tolerated than those without methylpheni date in terms of asthenia ( VAS , p = 0.004 ; FACT-F , p = 0.027 ) and quality of life ( FACT-F , p = 0.047 ) . No significant differences were observed in terms of distress ( HADS , p = 0.297 ) . Six ( 60 % ) patients continued with methylpheni date after study end . Main adverse events during study were palpitations and insomnia ( 30 % of patients each ) . Conclusions This pilot study suggests that methylpheni date may reduce asthenia and improve quality of life in breast cancer patients treated with docetaxel [23897970] PURPOSE Cancer-related fatigue ( CRF ) is the most common symptom in patients with advanced cancer . The primary objective of this prospect i ve , r and omized , double-blind , placebo-controlled study was to compare the effect of dexamethasone and placebo on CRF . PATIENTS AND METHODS Patients with advanced cancer with ≥ three CRF-related symptoms ( ie , fatigue , pain , nausea , loss of appetite , depression , anxiety , or sleep disturbance ) ≥ 4 of 10 on the Edmonton Symptom Assessment Scale ( ESAS ) were eligible . Patients were r and omly assigned to either dexamethasone 4 mg or placebo orally twice per day for 14 days . The primary end point was change in the Functional Assessment of Chronic Illness-Fatigue ( FACIT-F ) subscale from baseline to day 15 . Secondary outcomes included anorexia , anxiety , depression , and symptom distress scores . RESULTS A total of 84 patients were evaluable ( dexamethasone , 43 ; placebo , 41 ) . Mean ( ± st and ard deviation ) improvement in the FACIT-F subscale at day 15 was significantly higher in the dexamethasone than in the placebo group ( 9 [ ± 10.3 ] v 3.1 [ ± 9.59 ] ; P = .008 ) . The improvement in FACIT-F total quality -of-life scores was also significantly better for the dexamethasone group at day 15 ( P = .03 ) . The mean differences in the ESAS physical distress scores at day 15 were significantly better for the dexamethasone group ( P = .013 , respectively ) . No differences were observed for ESAS overall symptom distress ( P = .22 ) or psychological distress score ( P = .76 ) . Frequency of adverse effects was not significantly different between groups ( 41 of 62 v 44 of 58 ; P = .14 ) . CONCLUSION Dexamethasone is more effective than placebo in improving CRF and quality of life in patients with advanced cancer [20492840] OBJECTIVE To evaluate the efficacy and safety of modafinil in the treatment of fatigue in patients with human immunodeficiency virus/acquired immune deficiency syndrome ( HIV/AIDS ) and to assess effect on depressive symptoms . METHOD Patients who were HIV+ and had clinical ly significant fatigue ( according to the Fatigue Severity Scale [ FSS ] ) were included in a 4-week r and omized , placebo-controlled , double-blind trial . This was followed by an additional 8 weeks of open-label treatment for modafinil responders and 12 weeks for placebo nonresponders . The primary outcome measure for fatigue and depression was the Clinical Global Impressions-Improvement scale , supplemented by the FSS , Hamilton Depression Rating Scale , and Beck Depression Inventory . Safety was assessed with assays of CD4 cell count and HIV ribonucleic acid ( RNA ) viral load . Visits were weekly for 4 weeks , then biweekly , with a follow-up visit at 6 months . Maximum trial dose of modafinil was 200 mg/d . Data for this study were collected between December 2004 and December 2008 . RESULTS 115 patients were r and omly assigned . In intention-to-treat analyses , fatigue response rate to modafinil was 73 % and to placebo , 28 % . Attrition was 9 % . Modafinil did not have an effect on mood alone in the absence of improved energy . At week 4 , CD4 cell counts did not change significantly ; HIV RNA viral load showed a trend decline for patients taking modafinil but not for those taking placebo . At 6 months , those still taking modafinil had more energy and fewer depressive symptoms than patients who were not taking modafinil , and only those still taking modafinil showed a significant decline from baseline in their HIV RNA viral load . CONCLUSIONS Modafinil appears to be effective and well tolerated in treating fatigue in HIV+ patients . Consideration of its use is warranted considering the high prevalence of fatigue in the HIV community , its minimal side effects , and overall patient acceptance . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00118378 [24337761] Purpose Modafinil has been reported to benefit a subgroup of patients suffering severe fatigue while undergoing chemotherapy . Docetaxel is associated with fatigue that may lead to premature therapy withdrawal . We investigated whether modafinil could reduce fatigue during docetaxel chemotherapy . Methods This multicenter , r and omized , double-blind , placebo-controlled study evaluated the efficacy of modafinil in patients with metastatic prostate or breast cancer undergoing docetaxel chemotherapy ( every 21 days ; minimum dose 50 mg/m2 ) . At the start of their third or subsequent chemotherapy cycle , patients with significant docetaxel-associated fatigue were r and omized to receive concurrent modafinil 200 mg/day or placebo for 15 days ( “ treatment periods ” ( TP ) ) . Docetaxel was continued for up to four further cycles . Fatigue was evaluated with the fatigue component of the MD And erson Symptom Inventory ( MDASI ) . The primary endpoint was cumulative MDASI area under the curve ( AUC ) during the first 7 days of study medication during TP1 and TP2 . Results Evaluable data were available from 83 patients ( 65 with prostate cancer ) . There was no statistically significant difference between the two treatment arms for the primary endpoint ( MSADI AUC3–10 35.9 vs 39.6 ; 95 % confidence interval −8.9 , 1.4 ; P = 0.15 ) . Overall toxicity was comparable between treatment groups ; however , the incidence of grade ≤2 nausea and vomiting was higher in the modafinil arm ( 45.4 vs 25 % ) . Conclusions Assessing and managing chemotherapy-related fatigue remains a major challenge . There was a lack of difference between the two arms in the planned primary endpoint . However , there was a modest but consistent trend towards improvement of docetaxel-related fatigue in those treated with modafinil . Based on the study findings , modafinil for the treatment of fatigue associated with docetaxel chemotherapy elicits modest improvements . Larger , longer term , r and omized , controlled studies are required to clarify the exact role of modafinil in the treatment of docetaxel-related fatigue [18790598] Fatigue is very common in patients with cancer . Current guidelines suggest that psychostimulants are " reasonable to consider for severe fatigue . " This r and omized , double-blind , placebo-controlled trial investigated the hypothesis that dexamphetamine in fatigued patients with advanced cancer would produce a clinical ly significant improvement with minimal side effects . Fifty patients with advanced cancer , who were receiving palliative care , were r and omized to dexamphetamine 10 mg twice daily or placebo for eight days . Effectiveness was assessed using the Brief Fatigue Inventory and the McGill Quality -of-Life Question naire . The side effects were recorded . The results were analyzed on an intention-to-treat basis . The baseline demographics , fatigue levels , and quality -of-life scores were similar between the two arms . Patients were elderly , had impaired performance status ( Eastern Cooperative Oncology Group score=3 ) , and were taking a range of neurologically active medications . Thirty-nine patients completed the trial . There was a transient improvement in the fatigue levels on day 2 , but no significant difference in fatigue ( P=0.267 ) or quality of life ( P=0.579 ) by the end of the study . Statistical modeling did not reveal any significant predictors of response to dexamphetamine . These results suggest that dexamphetamine 20 mg daily , although well tolerated , does not significantly improve fatigue or quality of life in patients with advanced cancer , as measured by the selected instruments [10492632] A r and omised double-blind placebo-controlled multicentre trial was performed to investigate the effects of megestrol acetate ( MA ) on the quality of life ( QoL ) , appetite , weight and survival of patients with advanced , incurable , hormone-insensitive cancer . QoL was assessed at the start of treatment and at 4 , 8 and 12 weeks , using the EORTC-QLQ-C30 instrument . 255 patients were r and omised to 320 mg of MA daily or placebo for 12 weeks . 244 patients were assessable at baseline , 190 at 4 weeks ( placebo 94 ; MA 96 ) , 150 at 8 weeks ( placebo 69 ; MA 81 ) and 112 at 12 weeks ( placebo 55 ; MA 57 ) . A beneficial effect of MA on appetite loss was observed at week 4 ( P < 0.0001 ) and possibly at week 8 ( P = 0.058 ) . Further weight loss during treatment was significant only in the placebo group . In the first 8 weeks , changes in mean global QoL were small and similar in both groups . By 12 weeks the decrease in mean global QoL was more pronounced in the MA group ( P = 0.028 ) , which was related to a deterioration in physical function , while psychosocial function was not affected . Survival was not affected by MA , and side-effects were mild . The results show that MA has a beneficial effect on appetite and that it may retard weight loss with no adverse impact on survival and with mild toxicity . However , MA does not appear to improve global QoL as measured by the EORTC QLQ-C30 [17157757] Carnitine deficiency is among the many metabolic disturbances that may contribute to fatigue in patients with cancer . Administration of exogenous L-carnitine may hold promise as a treatment for this common symptom . Little is known about L-carnitine safety , tolerability , and dose-response in patients with cancer . We conducted a Phase I/II open-label trial to assess the safety and tolerability of exogenous L-carnitine and clarify the safe dose range associated with symptom effects for future controlled trials . Adult patients with advanced cancer , carnitine deficiency ( free carnitine < 35 for males or < 25 microM/L for females , or acyl/free carnitine ratio > 0.4 ) , moderate to severe fatigue , and a Karnofsky Performance Status ( KPS ) score > or = 50 were entered by groups of at least three into a st and ard maximum tolerated dose design . Each successive group received a higher dose of L-carnitine ( 250 , 750 , 1250 , 1750 , 2250 , 2750 , 3000 mg/day , respectively ) , administered in two daily doses for 7 days . To compare symptom outcomes before and after supplementation , patients completed vali date d measures of fatigue ( Brief Fatigue Inventory [ BFI ] ) , depressed mood ( Center for Epidemiologic Studies Depression Scale [ CES-D ] ) , quality of sleep ( Epworth Sleeplessness Scale [ ESS ] ) , and KPS at baseline and 1 week later . Of the 38 patients screened for carnitine levels , 29 were deficient ( 76 % ) . Twenty-seven patients participated ( " intention to treat , ITT " ) ( 17 males , 10 females ) , and 21 completed the study ( " completers " ) ; 17 of these patients ( " responders , " mean+/-[SD ] age=57.9+/-15 ) had increased carnitine levels at the end of the supplementation period . The highest dose achieved was 3000 mg/day . No patient experienced significant side effects and no toxicities were noted . Analysis of all the patients accrued ( ITT , n=27 ) showed a total carnitine increase from 32.8+/-10 to 54.3+/-23 microM/L ( P<0.001 ) and free carnitine increase from 26.8+/-8 to 44.1+/-17 microM/L ( P<0.001 ) . BFI decreased significantly , from 66+/-12 to 39.7+/-26 ( P<0.001 ) ; ESS decreased from 12.9+/-12 to 9+/-6 ( P=0.001 ) ; and CES-D decreased from 29.2+/-12 to 19+/-12 ( P<0.001 ) . A separate analysis of the 17 " responders " showed a dose-response relationship for total- ( r=0.54 , P=0.03 ) , free-carnitine ( r=0.56 , P=0.02 ) levels , and fatigue ( BFI ) scores ( r=-0.61 , P=0.01 ) . These findings suggest that l-carnitine may be safely administered at doses up to 3000 mg/day and that positive effects may be more likely at relatively higher doses in this range . This study provides the basis for the design of future placebo-controlled studies of l-carnitine supplementation for cancer-related fatigue [17548243] BACKGROUND Depression , anxiety , fatigue , and impaired wellbeing are common , important , and closely related in advanced cancer . We aim ed to identify the effects of an established antidepressant on these symptoms and survival in patients with advanced cancer who did not have major depression as assessed by clinicians . METHODS Between July , 2001 , and February , 2006 , 189 patients with advanced cancer were r and omly assigned sertraline 50 mg ( n=95 ) , or placebo ( n=94 ) , once per day . The primary outcome was depression as assessed by the Centre for Epidemiologic Studies Depression scale ( CES-D ) ; the main secondary outcomes were : anxiety as assessed by Hospital Anxiety and Depression Scales ( HADS-A ) ; overall quality of life and fatigue as assessed by Functional Assessment of Cancer Therapy General and Fatigue scales ( FACT-G and FACT-F , respectively ) ; and clinicians ' ratings of quality of life by use of Spizter 's Quality of Life Index ( SQLI ) . Multiple measures were used for corroboration of the most important outcomes . Primary analyses were done by intention to treat and were based on scale scores at 4 weeks and 8 weeks . The benefits of sertraline compared with placebo are expressed on a range from + 100 ( ie , maximum benefit ) to -100 ( ie , maximum harm ) ; a difference of 10 was deemed clinical ly significant . This clinical trial is registered at Current Controlled Trials website http://www.controlled-trials.com/IS RCT N72466475 . FINDINGS Sertraline had no significant effect ( scale , benefit over placebo [ 95 % CI ] ) on depression ( CES-D 0.4 [ -2.6 to 3.4 ] ) , anxiety ( HADS-A 2.0 [ -1.5 to 5.5 ] ) , fatigue ( FACT-F 0.3 [ -4.3 to 4.9 ] ) , overall quality of life ( FACT-G 1.7 [ -1.3 to 4.7 ] ) , or clinicians ' ratings ( SQLI 2.0 [ -2.5 to 6.5 ] ) , and the 95 % CI ruled out a clinical ly significant benefit for all main outcomes . Sertraline was discontinued more often and earlier than was placebo ( hazard ratio 1.46 [ 1.03 - 2.06 ] , p=0.03 ) . Recruitment was stopped after the first planned interim analysis in February 2006 ( n=150 ) showed that survival was longer in patients assigned placebo than in patients assigned sertraline ( unadjusted hazard ratio 1.60 [ 95 % CI 1.04 - 2.45 ] , log-rank p=0.04 ; adjusted hazard ratio 1.62 [ 1.06 - 2.41 ] , Cox model p=0.02 ) . However , at the final analysis in July 2006 of all patients ( n=189 ) and with longer follow-up , survival did not differ significantly between the treatment groups ( unadjusted hazard ratio 1.35 [ 0.95 - 1.91 ] , log-rank p=0.09 ; adjusted hazard ratio 1.27 [ 0.87 - 1.84 ] , Cox model p=0.20 ) . The trial was closed because it had ruled out a significant benefit of sertraline . INTERPRETATION Sertraline did not improve symptoms , wellbeing , or survival in patients with advanced cancer who do not have major depression , and should be reserved for those with a proven indication [15201369] Objective : To assess the effects of glatiramer acetate and β interferon on fatigue in multiple sclerosis . Methods : Fatigue was measured at baseline and six months using the fatigue impact scale ( FIS ) . Groups ( glatiramer acetate and β interferon ) were evaluated for the proportion improved , using Fisher ’s exact test . Logistic regression analysis assessed the relation between treatment group and improvement and controlled for confounding variables . Results : Six month paired FIS assessment s were available for 218 patients ( 76 % female ) . Ages ranged between 19 and 61 years , with 86 % having relapsing-remitting disease . Glatiramer acetate was used by 61 % and β interferon by 39 % . At baseline , total FIS and subscale scores were comparable in the two groups . More patients improved on glatiramer acetate than on β interferon on total FIS ( 24.8 % v 12.9 % , p = 0.033 ; adjusted odds ratio = 2.36 , 95 % confidence interval 1.03 to 5.42 ) , and on physical ( 28.6 % v 14.1 % , p = 0.013 ) and cognitive subscales ( 21.1 % v 10.6 % , p = 0.045 ) . Logistic regression analysis confirmed the association between glatiramer acetate use and improved fatigue , after accounting for baseline group differences . Conclusions : The odds of reduced multiple sclerosis fatigue were around twice as great with glatiramer acetate treatment as with β interferon . Confirmation of this result is required [4135151] In a controlled double blind study involving 116 patients with far‐advanced gastrointestinal cancer , dexamethasone at dosages of 0.75 and 1.5 mg four times daily produced improved appetite and sense of well‐being in comparison to placebo treatment . This symptomatic palliation , however , was not accompanied by weight gain or improved performance status . Survival of the steroid treated patients was essentially identical to that of the placebo treated patients . Cancer 33:1607–1609 , 1974 [1641137] Fatigue occurs in a majority of patients with MS and is generally independent of measurable neurologic disability . Few options for treatment are available . We conducted a double-blind , placebo-controlled , crossover trial for each of two 4-week treatment periods . Forty-six eligible patients entered and five dropped out due to concurrent exacerbations . Nineteen patients ( 46.3 % ) experienced excellent or good relief of fatigue with pemoline , and eight patients ( 19.5 % ) with placebo ( p = 0.06 , Fisher 's exact test ) . One-fourth of patients did not tolerate the drug well , and 7 % had to discontinue pemoline during the study due to side effects . The most common side effects were anorexia , irritability , and insomnia . Pemoline may be an effective short-term treatment for fatigue associated with MS , but its adverse effects are not well tolerated by many patients [18809275] Carnitine deficiency is prevalent in population s with chronic illness , including cancer . In a recent open-label study , L-carnitine supplementation was well tolerated and appeared to improve fatigue and other outcomes in cancer patients . To further evaluate this finding , adult patients with advanced cancer , carnitine deficiency ( free carnitine more than 35 micromol/L for males or less than 25 micromol/L for females , or acyl/free carnitine ratio of more than 0.4 ) , moderate to severe fatigue , and a Karnofsky Performance Status ( KPS ) score of 50 or more , were r and omly assigned to receive either L-carnitine ( 0.5 g/day for two days , followed by 1g/day for two days , and then 2g/day for 10 days ) or placebo . This double-blind phase was followed by an open-label phase , during which all patients received L-carnitine supplementation for two weeks . Outcomes included the fatigue subscale of the Functional Assessment of Cancer Therapy-Anemia ( FACT-An ) , the Linear Analog Scale Assessment s ( LASA ) , the Mini-Mental State Exam ( MMSE ) , and the KPS . Twenty-nine patients ( 12 placebo , 17 L-carnitine ) were included in the intent-to-treat ( ITT ) analysis . From baseline to the end of the double-blind phase , serum total and free L-carnitine increased from 32.9+/-3.8 to 56.6+/-20.5 ( P=0.004 ) , and from 22.9+/-19.4 to 45.3+/-17.2 ( P=0.004 ) , respectively , in the L-carnitine-treated group , and from 28.2+/-10.2 to 36.2+/-8.7 ( P = ns ) , and from 22.6+/-7.9 to 28.7+/-8.6 ( P = ns ) in the placebo group , respectively . The planned ITT analysis revealed no significant improvement in any of the study 's endpoints , and these negative findings were not different when data from two patients who did not adhere to the protocol were eliminated . However , an exploratory covariate analysis that excluded these two protocol violators and included outcome data from both the double-blind and open-label phases demonstrated significantly improved fatigue on the FACT-An fatigue subscale ( P<0.03 ) , and significantly improved FACT-An functional well-being subscale ( P<0.03 ) , and KPS ( P<0.003 ) , in the group that started with L-carnitine during the double-blind phase . These data do not support the conclusion that L-carnitine in the doses tested reverses cancer-related fatigue in carnitine-deficient patients . However , L-carnitine supplementation does increase L-carnitine serum levels , and the positive findings in an exploratory analysis justify a larger study to determine if this strategy could be of benefit for a sub population of cancer patients [15232328] Background : While testosterone 's ameliorative effects on depressive disorders and fatigue in HIV-positive patients have been suggested in the literature , no placebo-controlled trial selecting for depressive disorders and including a st and ard antidepressant has been conducted . Accordingly , this double-blind trial was design ed to determine whether testosterone , as well as fluoxetine , is superior to placebo for depression , fatigue , or both . Method : One hundred twenty-three men with HIV/AIDS with a Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition depressive disorder entered the 8-week trial and were r and omized to testosterone ( up to 400 mg IM testosterone cypionate biweekly ) , fluoxetine ( up to 60 mg/d ) , or double placebo . Outcome variables were the Clinical Global Impressions Scale for mood and for fatigue , the Hamilton Rating Scale for Depression , and the Chalder Fatigue Scale . Results : Ninety men completed the trial . In intention-to-treat analyses , mood response rates were 54 % , 47 % , and 44 % for fluoxetine , testosterone , and placebo , respectively . Among completers , mood response rates were 70 % , 57 % , and 53 % , respectively ; in neither analysis were differences between treatments statistically significant . In contrast , testosterone was superior to fluoxetine and placebo for completers regarding fatigue . In intention-to-treat analysis , response rates were 39 % , 56 % , and 42 % for fluoxetine , testosterone , and placebo , respectively , and for study completers , 41 % , 63 % , and 52 % , respectively , ( P < 0.05 ) , Conclusion : While over 50 % of patients treated with testosterone reported improved mood , this rate was not statistically superior to placebo . Thus , our findings do not support prescription of testosterone as a first-line treatment for depressive disorders in HIV-positive men . However , if vali date d in additional studies , testosterone may be a useful option for medically ill men experiencing significant fatigue as well as depression [8648360] PURPOSE To investigate the effects of medroxyprogesterone acetate ( MPA ) on appetite , weight , and quality of life ( QL ) in patients with advanced-stage , incurable , non-hormone-sensitive cancer . PATIENTS AND METHODS Two hundred six eligible patients were r and omized between double-blind MPA 500 mg twice daily or placebo . Appetite ( 0 to 10 numerical rating scale ) , weight , and QL ( European Organization for Research and Treatment of Cancer Quality of Life Question naire [ EORTC-QLQ-C30 ] ) were assessed before the start of treatment ( t = 0 ) , and 6 weeks ( t = 6 ) and 12 weeks ( t = 12 ) thereafter . RESULTS One hundred thirty-four patients ( 68 MPA and 66 placebo ) were assessable at t = 6 and 99 patients ( 53 MPA and 46 placebo ) at t = 12 . A beneficial effect of MPA on appetite was observed after both 6 weeks ( P = .008 ) and 12 weeks ( P = .01 ) of treatment . After 12 weeks , a mean weight gain of 0.6 + /- 4.4 kg was seen in the MPA , versus an ongoing mean weight loss of 1.4 + /- 4.6 kg in the placebo group . This difference of 2.0 kg was statistically significant ( P = .04 ) . During the study , several areas of QL deteriorated in the total group of patients . With the exception of an improvement in appetite and possible also a reduction in nausea and vomiting , no measurable beneficial effects of MPA on QL could be demonstrated . The side effects profile of MPA was favorable : only a trend toward an increase in ( usually mild ) peripheral edema was observed . CONCLUSION In weight-losing , advanced-stage non-hormone-sensitive cancer patients , MPA exhibits a mild side effects profile , has a beneficial effect on appetite , and may prevent further weight loss . However , general QL in the present study was not measurably influenced by MPA treatment [10901342] BACKGROUND This report documents findings from a small placebo-controlled trial of dextroamphetamine for depression and fatigue in men with the human immunodeficiency virus ( HIV ) . Dextroamphetamine offers the potential for rapid onset of effect and activation properties , both of which are important to persons with medical illness and an uncertain , but limited , life expectancy . METHOD Primary inclusion criteria included the presence of a DSM-IV depressive disorder , debilitating fatigue , and no history of dependence on stimulants . The study consisted of a 2-week r and omized , placebo-controlled trial , with the blind maintained until week 8 for responders , followed by open treatment through the completion of 6 months . RESULTS Of 23 men who entered the study , 22 completed the 2-week trial . Intent-to-treat analysis indicated that 73 % of patients ( 8/11 ) r and omly assigned to dextroamphetamine reported significant improvement in mood and energy , compared with 25 % ( 3/12 ) among placebo patients ( Fisher exact test , p < .05 ) . Both clinician- and self-administered measures indicated significantly improved mood , energy , and quality of life among patients taking dextroamphetamine . There was no evidence of the development of tolerance of , abuse of , or dependence on the medication . CONCLUSION These results suggest that dextroamphetamine is a potentially effective , fast-acting antidepressant treatment for HIV patients with depression and debilitating fatigue Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND This is an up date d version of the original Cochrane review published in issue 1 2008 ( Minton 2008 ) . Cancer-related fatigue ( CRF ) is common , under-recognised and difficult to treat . There have been studies looking at drug interventions to improve CRF but results have been conflicting depending on the population studied and outcome measures used . No previous review s of this topic have been exhaustive or have synthesis ed all available data . OBJECTIVES To assess the efficacy of drugs for the management of CRF . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

24399660

[24179297] OBJECTIVE To examine whether a social cognitive therapy ( SCT ) intervention increases continuous positive airway pressure ( CPAP ) use compared to equivalent social interaction ( SI ) time . PARTICIPANTS Individuals with obstructive sleep apnea ( OSA ) referred for CPAP therapy . INTERVENTION Participants received a 30-min group education session regarding OSA and CPAP . Groups of three to four participants were then r and omly assigned to an SCT session or social interaction . MEASUREMENTS CPAP usage was assessed at 7 nights , then 1 , 3 , and 6 months . The two primary outcomes were adherence , usage ≥ 4 h per night at 6 months , and uptake of CPAP . Question naires were given pretreatment and posttreatment . RESULTS Two hundred six individuals were r and omized to SI ( n = 97 ) or SCT ( n = 109 ) . CPAP uptake was not different between groups ( 82 % in SI , 88 % in SCT groups , P = 0.35 ) . There were no differences between groups in adherence : 63 - 66 % at 1 week , and at 6 months 55 - 47 % ( P = 0.36 ) . Higher pretreatment apnea-hypopnea index , higher baseline self-efficacy , and use of CPAP ( ≥ 4 h ) at 1 week were independent predictors of CPAP adherence at 6 months . CPAP adherence increased by a factor of 1.8 ( odds ratio = 1.8 , 95 % confidence interval 1.1 - 3.0 ) for every one-unit increase in self-efficacy . There was no difference between groups postintervention in self-efficacy scores , sleepiness , mood , or sleep quality . CONCLUSIONS In this r and omized trial , a single SCT application did not increase adherence when compared with SI time . Although self-efficacy scores prior to CPAP predicted adherence , self-efficacy was not increased by the interventions . Increasing intensity and underst and ing of SCT interventions may be needed to improve CPAP adherence . CLINICAL TRIALS REGISTRATION Australian New Zeal and Clinical Trials Registry , ACTRN12607000424404 [10807830] OBJECTIVES To study the effects of augmentation of continuous positive airway pressure ( CPAP ) education and support on compliance and outcome in patients with obstructive sleep apnea ( OSA ) . DESIGN A r and omized , controlled , parallel study of basic vs augmented CPAP education and support . SETTING A university teaching hospital . PATIENTS A total of 108 OSA patients r and omized into basic-support ( BS ) and augmented-support ( AS ) groups . INTERVENTIONS Patients in the BS group ( n = 54 ) were given educational brochures on OSA and CPAP , CPAP education by nurses , CPAP acclimatization , and were review ed by physicians and nurses at weeks 4 and 12 . Patients in the AS group ( n = 54 ) received more education , including a videotape , telephone support by nurses , and early review at weeks 1 and 2 . MEASUREMENTS Objective CPAP compliance , Calgary sleep apnea quality of life index ( SAQLI ) , and cognitive function after 1 month and 3 months ; and Epworth sleepiness scale ( ESS ) after 3 months of CPAP treatment . RESULTS At 4 weeks , CPAP usage was 5.3 + /- 0.2 h/night ( mean + /- SEM ) vs 5.5 + /- 0.2 h/night in the BS and AS groups , respectively ( p = 0.4 ) . At 12 weeks , CPAP usage was 5.3 + /- 0.3 h/night vs 5.3 + /- 0.2 h/night in the two groups , respectively ( p = 0.98 ) . There was greater improvement of SAQLI at 4 weeks ( p = 0.008 ) and at 12 weeks ( p = 0.047 ) in the AS group . There was no significant difference between BS and AS groups in terms of improvement of ESS and cognitive function . CONCLUSION Augmentation of CPAP education and support does not increase CPAP compliance , but leads to a greater improvement of quality of life during the reinforced period [25766689] Objective To evaluate whether follow-up of patients with obstructive sleep apnoea ( OSA ) undergoing CPAP treatment could be performed in primary care ( PC ) setting s. Design Non-inferiority , r and omised , prospect i ve controlled study . Setting s Sleep unit ( SU ) at the University Hospital and in 8 PC units in Lleida , Spain . Participants Patients with OSA were r and omised to be followed up at the SU or PC units over a 6-month period . Main outcomes measured The primary outcome was CPAP compliance at 6 months . The secondary outcomes were Epworth Sleep Scale ( ESS ) score , EuroQoL , patient satisfaction , body mass index ( BMI ) , blood pressure and cost-effectiveness . Results We included 101 patients in PC ( ( mean±SD ) apnoea – hypopnoea index ( AHI ) 50.8±22.9/h , age 56.2±11 years , 74 % male ) and 109 in the SU ( AHI 51.4±24.4/h , age 55.8±11 years , 77 % male ) ) . The CPAP compliance was ( mean ( 95 % CI ) 4.94 ( 4.47 to 5.5 ) vs 5.23 ( 4.79 to 5.66 ) h , p=0.18 ) in PC and SU groups , respectively . In the SU group , there were greater improvements in ESS scores ( mean change 1.79 , 95 % CI + 0.05 to + 3.53 , p=0.04 ) and patient satisfaction ( −1.49 , 95 % CI −2.22 to −0.76 ) ; there was a significant mean difference in BMI between the groups ( 0.57 , 95 % CI + 0.01 to + 1.13 , p=0.04 ) . In the PC setting , there was a cost saving of 60 % , with similar effectiveness , as well as a decrease in systolic blood pressure ( −5.32 ; 95 % CI −10.91 to + 0.28 , p=0.06 ) . Conclusions For patients with OSA , treatment provided in a PC setting did not result in worse CPAP compliance compared with a specialist model and was shown to be a cost-effective alternative . Trial registration number Clinical Trials NCT01918449 [23332533] OBJECTIVE Weight loss can decrease the severity of obstructive sleep apnea ( OSA ) in many obese individuals ; however , very few studies have investigated the effects of behavioral weight loss interventions for patients with OSA . The aims of this pilot study were to determine the feasibility and initial effects on weight and continuous positive airway pressure ( CPAP ) use of a brief minimal-contact self-monitoring-based weight loss intervention ( SM ) . An additional aim was to investigate the association between weight loss and CPAP adherence . METHODS Forty obese men and women diagnosed with mild or moderate OSA were r and omized to either the SM or an attention-control ( AC ) condition . SM participants completed daily dietary logs for 6 weeks . Participants were weighed at baseline , post-treatment ( 6 weeks ) , and at a 6-week follow up . RESULTS Recruitment and retention were good in this study and attrition rates did not differ significantly by group . Intent to treat repeated measures ANOVA indicated a main effect of time ( but not group ) , such that both groups lost weight over time . Pearson r correlations between weight change and CPAP adherence indicated that among SM participants , 6-week weight loss was correlated with CPAP adherence at post-treatment and follow-up , such that SM participants with greater weight loss at 6 weeks had greater CPAP adherence at 6 and 12 weeks . CONCLUSION This study provides initial support for the beneficial effects of a minimal-contact weight loss intervention for patients with obstructive sleep apnea and highlights a possible association between weight loss and CPAP adherence [4570038] Background Continuous Positive Airway Pressure ( CPAP ) remains the reference treatment for moderate to severe forms of the Sleep Apnea/Hypopnea Syndrome ( SAHS ) . Compliance to the treatment appears to be a key factor to improving health status of these patients . Methods We conducted a multicenter , prospect i ve , r and omized , controlled , parallel group trial of st and ard support completed or not within 3 months of coaching sessions for newly diagnosed SAHS patients starting CPAP therapy . This study has been recorded by AFSSAPS with the RCB number : 2009-A01127 - 50 and received favourably by the Human Studies Committee in France . The coaching session consisted of 5 sessions of telephone-based counselling by competent staff . The primary outcome was the proportion of patients using CPAP more than 3 h per night for 4 months ; the secondary outcome was mean hours of CPAP usage in the 2 groups . Results Three hundred and seventy-nine patients fulfilled the inclusion criteria and were r and omized . The percentage of patients using CPAP more than 3 h per night for 4 months was 65 % for the st and ard support group and 75 % for the coached group . This difference reached a statistical significance ( χ2 = 3.97 ) . The mean CPAP usage was increased in the coached group versus st and ard group . A difference of 26 min was observed ( 4 h34+/−2 h17 and 4 h08+/−2 h25 respectively , p = 0.04 ) . Conclusion This study shows that SAHS patients who benefit from phone coaching are statistically more compliant to CPAP than a st and ard support group is . A simple phone coaching procedure based on knowledge of the disease and reinforcement messages about treatment benefits helps to improve CPAP adherence in SAHS patients .Trial registration [14998250] STUDY OBJECTIVES To identify factors before a trial of nasal continuous positive airway pressure ( CPAP ) treatment that are associated with lower compliance . DESIGN A prospect i ve cohort study . Initial Hospital Anxiety and Depression Scale scores and other demographic data were noted . Machine use was recorded by clock timer after a 1-month trial of treatment . SETTING District General Hospital sleep-disordered breathing clinic . PATIENTS OR PARTICIPANTS Eighty consecutive patients with symptoms of sleep apnea-hypopnea syndrome and a 4 % Sao2 desaturation index greater than 10 events per hour . INTERVENTIONS N/A. MEASUREMENTS AND RESULTS Those reporting ' initial problems ' with CPAP went on to have an average of 2.4 hours of on time per night , while those not reporting initial problems had an on time of 5.0 hours per night ( P < .001 ) . Those living alone had a machine on time of 3.2 hours compared with 4.5 hours for those with partners ( P = .04 ) . Pearson 's correlations between hours on time were -0.08 ( P = .48 ) for initial Anxiety score and 0.10 ( P = .37 ) for initial Depression score . CONCLUSIONS There was no association between baseline anxiety and depression scores , as measured by the Hospital Anxiety and Depression Scale , and subsequent machine use . Other factors observable prior to commencing treatment , in particular , ' initial problems ' ( reported at autotitration ) , ' recent life-events ' and ' living alone ' were associated with lower machine use . Regarding all initial variables , reporting problems after the first night of nCPAP seems the most important predictor of ensuing machine use . A single screening question immediately after autotitration is useful in identifying those at high risk of treatment failure [19920270] Context Approaches that improve adherence to continuous positive airway pressure ( CPAP ) therapy are needed . Contribution In this trial , 160 adults with severe obstructive sleep apnea were r and omly assigned to eszopiclone or placebo for the first 14 nights of CPAP . Adherence to CPAP was then measured weekly for 24 weeks . Patients receiving eszopiclone were less likely to discontinue CPAP and used CPAP more nights and for longer periods per night than did patients receiving placebo . Implication Eszopiclone given during the first 2 weeks of therapy may help improve long-term adherence and use of CPAP in some patients with severe obstructive sleep apnea . The Editors Untreated obstructive sleep apnea ( OSA ) is associated with adverse effects on both health and quality of life ( 1 , 2 ) . Continuous positive airway pressure ( CPAP ) is recommended as first-line therapy for most patients to improve sleep quality , reduce daytime sleepiness , and enhance quality of life . It may also mitigate the increased risk for cardiovascular events ( 36 ) . However , adherence to CPAP is often poor , which limits its efficacy . Of patients who initiate CPAP , approximately 50 % discontinue use within the first year , most within the first month . The initial experience with CPAP influences who accepts and continues treatment ( 7 ) . Patients who experience initial discomfort , intolerance , or lack of perceived benefit are more likely to discontinue therapy ( 8) . Some studies suggest that psychosocial factors may also affect short- and intermediate-term adherence ( 9 , 10 ) . The only consistently reliable predictor of long-term adherence has been the use of CPAP during the initial treatment period ( 11 ) . The average nightly CPAP use during the first 3 months of therapy can predict use at 6 and 12 months ( 12 ) . Furthermore , long-term adherence patterns may be determined within the first few days of therapy ( 13 ) . Therefore , strategies aim ed at improving adherence with therapy should focus on the initial experience with CPAP . In theory , robust patient education , regular follow-up , and improvements in device comfort ( for example , autoadjustable units with heated humidifiers and better- design ed , better-fitted masks ) should increase CPAP tolerance and use . However , intensive support and technological interventions have not consistently or reliably predicted which patients will successfully transition to CPAP ( 1418 ) . Nonbenzodiazepine sedative-hypnotic agents promote sleep onset and continuity without altering sleep architecture . They can safely be used in patients with OSA , especially those already using CPAP ( 19 ) . We hypothesized that a short course of the nonbenzodiazepine sedative-hypnotic eszopiclone during the first 2 weeks of treatment would improve patients ' initial tolerability and use of CPAP and subsequently increase long-term adherence . Methods Study Design Overview We conducted a parallel- design , r and omized , placebo-controlled trial to assess the effects of eszopiclone on CPAP adherence among patients with newly diagnosed OSA who were initiating CPAP . Patients received eszopiclone , 3 mg , or matching placebo every night for the initial 14 nights of CPAP and were followed serially for 24 weeks ( Figures 1 and 2 ) . Patient enrollment began in March 2007 , and final data were collected by December 2008 . Our study is part of the CPAP ASAP ( CPAP Promotion and PrognosisThe Army Sleep Apnea Program ) Trial , which will examine several outcomes related to OSA . Figure 1 . Study flow diagram . CPAP = continuous positive airway pressure . Figure 2 . Study design overview . CPAP = continuous positive airway pressure . Walter Reed Army Medical Center 's Department of Clinical Investigation ( Scientific Review Committee , Human Use Committee , and Institutional Review Board ) , as well as the United States Army Center for Investigational Research Organization , approved our protocol . We obtained informed consent from all study participants . Setting s and Participants We recruited all patients from a single academic sleep medicine center . Our center is part of Walter Reed Army Medical Center , which is a quaternary-care facility providing care to a wide range of patient demographic groups , including active-duty service members , their dependents , and retirees . Consecutive patients between 18 and 64 years of age , with newly diagnosed OSA , and not previously receiving CPAP therapy were approached for enrollment . Obstructive sleep apnea was diagnosed on the basis of an attended , overnight level I polysomnography in all patients . All polysomnograms were interpreted by the study investigators and authors . We established the diagnosis and defined the severity of OSA in accordance with American Academy of Sleep Medicine criteria by using the apneahypopnea index ( 20 ) . We excluded patients with long-term use of hypnotic medications , those who consumed more than 2 alcoholic beverages per night , and those who had hepatic dysfunction or an underlying psychiatric condition that would preclude completion of the study . We also excluded pregnant women . R and omization and Interventions We r and omly assigned patients to receive eszopiclone , 3 mg ( n= 80 ) , or matching placebo ( n= 80 ) . The Walter Reed Army Medical Center 's investigational pharmacy central ly administered and distributed study medications to the patients at the time of enrollment . The referring physician , investigators , and patients were blinded to the r and omization order and treatment group assignment ( eszopiclone or placebo ) . R and omization was implemented by using a computerized program ( R and omization.com , seed 3565 ) and was performed by using 16 fixed blocks ( 10 patients per block ) without stratification by patient criteria or polysomnogram results . The pharmacy maintained r and omization and blinding until after the final data were collected . All persons initiating CPAP at our institution participate in a comprehensive educational program to familiarize them with OSA , its effects , and the available treatment options . Patients undergo formal mask-fitting and receive telephone follow-up after 2 weeks to ensure proper fit . A clinical evaluation is conducted after 1 month of therapy to measure CPAP use and assess clinical response to therapy . Additional follow-up is provided as needed . Nonpharmacologic interventions , including changes in pressures , assessment of leaks , mask changes , or adjustments to and education on proper sleep hygiene and stimulus control , are individualized to promote better CPAP tolerance and adherence . All patients enrolled in this study were also assessed after 3 and 6 months of therapy . Otherwise , study participants were not treated differently from other patients receiving care at our center . After the initial 4 weeks of enrollment , open-label sedatives could be prescribed at the discretion of the physician seeing the patient during follow-up . It is common practice for providers in our clinic to offer a sedative-hypnotic agent to patients who are having difficulties using the CPAP machine despite nonpharmacologic interventions . All enrolled patients received the same model of CPAP ( RemStar Pro M Series with C-Flex and integrated heated humidifiers , Phillips Respironics , Murrysville , Pennsylvania ) . We prescribed CPAP devices for long-term use . We did not use any autoadjustable positive airway pressure devices . Outcomes and Measurements For each participant , we recorded demographic data , information regarding OSA severity , degree of symptoms , and objective measures of CPAP use . The primary outcome measured was CPAP adherence at 24 weeks . Specifically , we computed the percentage of nights used , the mean hours per night for total study nights , and the mean hours per night that CPAP was used during each week of the 24-week study . We also compared the rate of regular use of CPAP between groups , defined as more than 4 hours per night on more than 70 % of nights ( 21 ) . We obtained objective measures of CPAP use from a downloadable smart card adherence-monitoring device ( Encore Pro smart card , Phillips Respironics ) . These cards , which are integrated into the CPAP units , record all use of the devicespecifically , the date , time , and duration that CPAP is used . These cards also record data on mask leaks and residual airflow limitations , data that are useful to troubleshoot barriers to therapeutic adherence . We collected all measured variables at the time of enrollment ( baseline ) and again at 1 , 3 , and 6 months after initiating CPAP . In addition , we collected smart cards at 1 , 3 , and 6 months and recorded and analyzed the downloaded data for each night in 1-week blocks . Secondary outcomes were the rate of CPAP discontinuation and the use of open-label sedative-hypnotic agents between the 2 groups . Because our primary aim was to promote better CPAP adherence , we allowed the open-label use of sedative-hypnotic agents after the first 4 weeks of treatment . These were prescribed at the discretion of the ordering physician and only when nonpharmacologic interventions were unsuccessful . All such prescriptions were monitored and recorded by using a closed electronic medical records system . In addition , we compared the change in Epworth Sleepiness Scale ( ESS ) score , fatigue , and Functional Outcomes of Sleep Question naire score between baseline and the end of the study to determine whether a greater use of CPAP was associated with improvements in symptoms and quality of life . We assessed degree of somnolence by using the ESS and visual analogue fatigue scale ( 22 ) . The ESS score ranges from 0 to 24 . Higher scores indicate greater daytime somnolence , and scores less than 10 are considered normal . We assessed sleep-related quality -of-life scores by using the Functional Outcomes of Sleep Question naire ( 23 ) . The score ranges from 5 to 20 . Higher scores , particularly those greater than 17.9 , suggest improved quality of life . We collected additional data related to mood and depression , libido and erectile dysfunction , and quality of life that will be [15258478] Background : Continuous positive airway pressure ( CPAP ) is an effective therapy for obstructive sleep apnea syndrome ( OSAS ) , although many patients have difficulty adhering to this therapy . The purpose of this study was to investigate the effectiveness of totally automated telephone technology in improving adherence to prescribed CPAP therapy . Research Design : This pilot study was a r and omized clinical trial in 30 patients being started on CPAP therapy for OSAS . Patients were r and omly assigned to use of a computer telephone system design ed to improve CPAP adherence ( telephone-linked communications for CPAP [ TLC-CPAP ] ) in addition to usual care ( n = 15 ) or to usual care alone ( n = 15 ) for a period of 2 months . TLC-CPAP is a computer-based system that monitors patients ’ self-reported behavior and provides education and reinforcement through a structured dialogue . Measures : A sleep symptoms checklist and the Functional Outcomes of Sleep Question naire were administered at study entry and at 2-month follow up . Hours of CPAP use at effective mask pressure were measured by the CPAP device , stored in its memory , and retrieved at the 2-month visit . Results : At 2 months , patients r and omized to TLC-CPAP had fewer reported sleep-related symptoms ( 9.4 vs. 13.4 , P = 0.047 ) than those receiving usual care . The average nightly CPAP use in the TLC-CPAP group was 4.4 hours compared with 2.9 hours ( P = 0.076 ) in the usual-care group . Conclusions : This pilot study suggests that patients with OSAS started on CPAP and a concurrently administered automated education and counseling system had better CPAP adherence and better control of OSAS symptoms [4664526] Background Continuous positive airway pressure ( CPAP ) is widely recommended for the treatment of sleep apnea/hypopnea syndrome ( SAHS ) , but its usage by patients is very low . The aim of this study was to assess intensive educational programs and nursing support for the improvement of CPAP use and outcomes in SAHS patients . Methods Eighty new SAHS patients were r and omized to receive nurse-led intensive interventions or usual support at hospital and home . The main outcome measure was CPAP use ; changes in sleeping , symptoms , mood , and quality of life were also assessed after 12 months of treatment . Results All outcome measures were improved after treatment in both groups . However , patients receiving intensive support with significantly higher CPAP use ( higher daily CPAP usage by 2.2 hours/day ) had greater improvements in SAHS symptoms and mood ( P<0.05 ) . The intervention group further showed an improvement in the Short Form-36 domains of mental and physical health ( P<0.05 ) . Conclusion The CPAP usage and quality of life can be significantly improved by nurse-led intensive program in obstructive sleep apnea patients [15358707] The present study objective was to establish whether pretreatment social cognitive variables may contribute to the explanation of variance in adherence to continuous positive airway pressure ( CPAP ) treatment for patients with obstructive sleep apnoea/hypopnoea syndrome ( OSAHS ) . A total of 119 of 180 consecutive OSAHS patients were recruited to the study prior to initial CPAP titration . Patients completed psychological measures of health value , health locus of control ( incorporating internality , chance , powerful others ) and self-efficacy prior to CPAP titration . Objective adherence data were measured by CPAP unit time clocks and collected at 3-month follow-up . Average nightly use was calculated over this period . Logistic regression of prospect i ve predictors of adherence produced a model comprising psychological ( health value , internality , powerful others ) , as well as clinical variables ( Epworth score , body mass index , apnoea/hypopnoea index , CPAP pressure ) . This model explained 24 % of the variance in CPAP use , and correctly identified 75 % of adherers and 53 % of nonadherers . Although the psychological variables explained only a small amount of the overall variance in adherence behaviour , this result provides further support for the hypothesis that psychological variables contribute , in part , to continuous positive airway pressure adherence . Future research should focus on highlighting discrete variables , which may helpfully inform psychologically based interventions aim ed at improving the use of continuous positive airway pressure by patients with obstructive sleep apnoea/hypopnoea syndrome at risk of discontinuance [11868136] The present study examined the efficacy of a cognitive-behavioral intervention at improving compliance with CPAP and vigilance in older adults with obstructive sleep apnea/hypopnea syndrome ( OSAHS ) . Participants included 12 subjects who were r and omized into one of two groups controlling for age , education , disease severity , and vigilance . The experimental group received two 45-min sessions design ed to educate subjects on the consequences of OSAHS and the efficacy of CPAP . The control group received the same extent of therapist contact but did not receive information on OSAHS or CPAP . All subjects were administered a test of vigilance both before and after the study . Compliance data were collected using CPAP devices with internal microprocessors at were read at 1 , 4 , and 12 weeks after treatment initiation . The results showed that the experimental condition did not enhance compliance after 1 week of treatment but did so by the 12-week follow-up . Subjects in the experimental condition had a run time of 3.2-h per night longer than did those in the control group . Those using CPAP more regularly at 12 weeks also showed greater improvement on vigilance at follow-up . Performance on vigilance testing before the introduction of CPAP was predictive of CPAP use at 12 weeks . In conclusion , a modest cognitive-behavioral intervention may substantially increase CPAP use and vigilance in older adults [24673616] RATIONALE It is unknown whether obstructive sleep apnea ( OSA ) may be a risk factor for incident cardiovascular events in women . OBJECTIVES We sought to investigate whether OSA increases the incidence of a composite of stroke or coronary heart disease ( CHD ) in women , and the role of continuous positive airway pressure ( CPAP ) treatment on this association . METHODS This was a prospect i ve , observational study conducted in two Spanish teaching hospitals between 1998 and 2007 . Consecutive women referred for suspected OSA and free of previous stroke and CHD were analyzed . Women with an apnea-hypopnea index ( AHI ) less than 10 comprised the control group , and those with an AHI greater than or equal to 10 were diagnosed with OSA and classified as CPAP-treated ( adherence ≥ 4 h/d ) or untreated ( adherence < 4 h/d or not prescribed ) . The follow-up ended in December 2010 . MEASUREMENTS AND MAIN RESULTS A total of 967 women were studied ( median follow-up , 6.8 yr ; interquartile range , 5.2 - 8.2 ) . The untreated OSA group showed a greater incidence rate of the composite outcome than the control group ( 2.19 vs. 0.54 per 100 person-years ; P < 0.0005 ) . Compared with the control group , the fully adjusted hazard ratios for the composite outcome incidence were 2.76 ( 95 % confidence interval [ CI ] , 1.35 - 5.62 ) for the untreated OSA group , and 0.91 ( 95 % CI , 0.43 - 1.95 ) for the CPAP-treated group . When the type of cardiovascular event was separately assessed , untreated OSA showed a stronger association with incident stroke ( adjusted hazard ratio , 6.44 ; 95 % CI , 1.46 - 28.3 ) than with CHD ( adjusted hazard ratio , 1.77 ; 95 % CI , 0.76 - 4.09 ) . CONCLUSIONS In women , untreated OSA is associated with increased incidence of serious cardiovascular outcomes , particularly incident stroke . Adequate CPAP treatment seems to reduce this risk [22962427] CONTEXT Few prospect i ve intervention studies have examined the effect of continuous positive airway pressure ( CPAP ) therapy on cardiovascular disease ( CVD ) risk factors in diabetes . OBJECTIVE Our objective was to determine whether CPAP improves CVD risk factors in patients with type 2 diabetes and obstructive sleep apnea ( OSA ) . DESIGN AND SETTING This was a r and omized parallel group intervention trial in an urban Australian community . PATIENTS Fifty-nine participants of the Fremantle Diabetes Study Phase II at high risk for OSA consented to confirmatory polysomnography followed by r and omization to a 3-month CPAP intervention initiated early ( < 1 wk ) or late ( 1 - 2 months ) . MAIN OUTCOME MEASURES Patients were assessed before and 1 and 3 months after CPAP started . Tests for repeated measures were used to compare variables of interest over time . RESULTS Forty-four patients ( 75 % ) completed the study . Their mean ± sd age was 66.1 ± 8.8 yr , and 61.4 % were male . Completers and noncompleters had similar age , sex , diabetes duration , apnea-hypopnea index , and Epworth Sleepiness Scale ( P ≥ 0.29 ) . There were no differences in outcome between early and late r and omization , and the data were pooled . The Epworth Sleepiness Scale decreased between entry and 1 month [ -4.8 ( -6.5 to -3.1 ) , P < 0.001 ] . Blood pressure improved between entry and 3 months ( from 149 ± 23/80 ± 12 to 140 ± 18/73 ± 13 mm Hg ; P ≤ 0.007 ) . Pulse rate declined within the first month [ -6 ( -10 to -2 ) beats/min , P = 0.002 ] . Glycemic control and serum lipids , which were mostly within recommended target ranges at entry , did not change . CONCLUSIONS Three months of CPAP in community-based people with type 2 diabetes significantly decreased blood pressure and pulse rate but did not influence metabolic control [16564210] BACKGROUND AND PURPOSE Interventions to improve treatment outcomes in sleep apnoea-hypopnoea syndrome ( SAHS ) have had mixed success . Most have concentrated on following the use of a continuous positive airway pressure ( CPAP ) machines ; poorer users may not return for machine readings , so any compliance study must take into account rates of attendance rates . We hypothesised that a series of additional , early support measures would improve re-attendance over a sustained period . PATIENTS AND METHODS Prospect i ve , single-blinded interventional study . Seventy-two consecutive patients starting CPAP for SAHS were r and omised to receive st and ard follow-up or extra early support . Attendance rates , CPAP use , Epworth scores , side-effects scores and number of changes to equipment were compared , by intent to treat , in both groups at 1 and 12 months . RESULTS Re-attendance rates were higher in the intervention group at 1 month ( P=0.04 ) , 6 months ( P=0.07 ) and 12 months ( P=0.12 ) . Those who defaulted tended previously to be poor users of the CPAP machine . For those who re-attended there was no difference in machine use or other outcomes . CONCLUSIONS Simple interventions while commencing CPAP improve re-attendance with maximal benefit early on . This could provide more opportunities for solving problems early or considering alternative treatments . By confirming that poorer CPAP users eventually have higher default rates we recommend that future studies on CPAP compliance should first account for re-attendance rates [12505557] INTRODUCTION Apnea is a common disorder in older adults and has been shown to affect cognition . Some studies suggest that treatment for apnea improves certain cognitive deficits , but few studies have examined the relationship between compliance and cognitive improvement . We design ed a study to answer the following questions about sleep apnea , cognition and treatment in older adults : ( 1 ) Which neuropsychological ( NP ) variables are differentially associated with measures of sleep fragmentation and oxygen desaturation ? ( 2 ) Does compliant use of CPAP provide a cognitive advantage over noncompliant use ? ( 3 ) Does NP performance at baseline predict compliance at 3 months ? METHOD Twelve participants were recruited for the study . All had polysomnographically defined sleep apnea with an RDI of 10 or greater . All were also at least 55 years of age , had no other diagnosable sleep disorder and had no previous treatment for sleep apnea syndrome ( SAS ) . Participants were administered a full NP battery before and 3 months after treatment with CPAP . RDI at baseline was associated with delayed verbal recall , while oxygen desaturation was associated with both delayed recall and constructional abilities . Compliant use of CPAP at 3 months was associated with greater improvements in attention , psychomotor speed , executive functioning and nonverbal delayed recall . Finally , attention measures predicted compliance at 3 months suggesting that those who were least vigilant at baseline were more likely to comply with treatment . DISCUSSION Results are discussed in terms of the relevance to targeting special population s for compliance interventions , the ways that treatment may specifically affect older adults and the possible dose-response relationship of CPAP [22618923] CONTEXT Continuous positive airway pressure ( CPAP ) is the first-line treatment for patients with symptomatic obstructive sleep apnea ( OSA ) . However , its indication for all patients with sleep-disordered breathing , regardless of daytime symptoms , is unclear . OBJECTIVE To evaluate the effect of CPAP treatment on the incidence of hypertension or cardiovascular events in a cohort of nonsleepy patients with OSA . DESIGN , SETTING , AND PATIENTS Multicenter , parallel-group , r and omized controlled trial in 14 teaching hospitals in Spain . Between May 2004 and May 2006 , 725 consecutive patients were enrolled who had an apnea-hypopnea index of 20 h(-1 ) or greater and an Epworth Sleepiness Scale score of 10 or less ( scores range from 0 - 24 , with values < 10 suggesting no daytime sleepiness ) . Exclusion criteria were previous cardiovascular event , physical or psychological incapacity , chronic disease , or drug or alcohol addiction . Follow-up ended in May 2009 . INTERVENTION Patients were allocated to receive CPAP treatment or no active intervention . All participants received dietary counseling and sleep hygiene advice . MAIN OUTCOME MEASURES Incidence of either systemic hypertension ( taking antihypertensive medication or blood pressure greater than 140/90 mm Hg ) or cardiovascular event ( nonfatal myocardial infa rct ion , nonfatal stroke , transient ischemic attack , hospitalization for unstable angina or arrhythmia , heart failure , or cardiovascular death ) . RESULTS Seven hundred twenty-three patients underwent follow-up for a median of 4 ( interquartile range , 2.7 - 4.4 ) years ( 1 patient from each group did not receive allocated treatment ) ; 357 in the CPAP group and 366 in the control group were included in the analysis . In the CPAP group there were 68 patients with new hypertension and 28 cardiovascular events ( 17 unstable angina or arrhythmia , 3 nonfatal stroke , 3 heart failure , 2 nonfatal myocardial infa rct ion , 2 transient ischemic attack , 1 cardiovascular death ) . In the control group there were 79 patients with new hypertension and 31 cardiovascular events ( 11 unstable angina or arrhythmia , 8 nonfatal myocardial infa rct ion , 5 transient ischemic attack , 5 heart failure , 2 nonfatal stroke ) . The hypertension or cardiovascular event incidence density rate was 9.20 per 100 person-years ( 95 % CI , 7.36 - 11.04 ) in the CPAP group and 11.02 per 100 person-years ( 95 % CI , 8.96 - 13.08 ) in the control group . The incidence density ratio was 0.83 ( 95 % CI , 0.63 - 1.1 ; P = .20 ) . CONCLUSIONS In patients with OSA without daytime sleepiness , the prescription of CPAP compared with usual care did not result in a statistically significant reduction in the incidence of hypertension or cardiovascular events . However , the study may have had limited power to detect a significant difference . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00127348 [11834653] STUDY OBJECTIVES To determine long-term compliance rates to continuous positive airway pressure ( CPAP ) therapy in patients with obstructive sleep apnea enrolled in a comprehensive CPAP program in the community . DESIGN Prospect i ve cohort longitudinal study . SETTING University sleep disorders center . PATIENTS Two hundred ninety-six patients with an apnea-hypopnea index ( AHI ) > or = 20/h on polysomnography . INTERVENTIONS A CPAP device equipped with a monitoring chip was supplied . Within the first week , daily telephone contacts were made . Patients were seen at 2 weeks , 4 weeks , 3 months , and 6 months . RESULTS Of the 296 subjects enrolled , 81.1 % were males . Mean + /- SD AHI was 64.4 + /- 34.2/h of sleep ; age , 51 + /- 11.7 years ; and body mass index , 35.2 + /- 7.9 kg/m(2 ) . The mean duration of CPAP use was 5.7 h/d at 2 weeks , 5.7 h/d at 4 weeks , 5.9 h/d at 3 months , and 5.8 h/d at 6 months . The percentage of patients using CPAP > or = 3.5 h/d was 89.0 % at 2 weeks , 86.6 % at 4 weeks , 88.6 % at 3 months , and 88.5 % at 6 months . There was a decrease in the Epworth Sleepiness Scale ( ESS ) score of 44 % by 2 weeks of therapy . The patients continue to improve over the follow-up period , with the lowest mean ESS score observed at 6 months . With multiple regression analysis , three variables were found to be significantly correlated with increased CPAP use : female gender , increasing age , and reduction in ESS score . CONCLUSION A population -based CPAP program consisting of consistent follow-up , " troubleshooting , " and regular feedback to both patients and physicians can achieve CPAP compliance rates of > 85 % over 6 months [26253747] Obstructive sleep apnoea syndrome ( OSAS ) is characterised by repetitive collapse of the upper airway during sleep . Continuous positive airway pressure ( CPAP ) applied via a mask is the st and ard treatment for OSAS . CPAP adherence is crucial in therapy to prevent the deleterious consequences of OSAS . We hypothesised that a combination of supervision by telemetry together with targeted telephone support in the first month of CPAP would increase CPAP adherence and treatment success . A total of 113 OSAS patients followed by telemetry-triggered interventions used the device for 5.3 h/night on 28/30 nights , significantly more than the 110 OSAS patients in the control group with 4.6 h/night and 27/30 nights . Telemetry-triggered interventions have a significant impact on adherence rate in early CPAP treatment . These results can be reached with an acceptable additional effort [21965126] Purpose The purpose of this study is to explore the effects of patient education and progressive muscle relaxation ( PMR ) alone or combined on adherence to continuous positive airway pressure ( CPAP ) treatment in obstructive sleep apnea ( OSA ) patients . Methods One hundred and fifty-two Han Chinese OSA patients were r and omly assigned to a control group ( C ) , an education group ( E ) , a PMR group ( P ) , and an education + PMR group ( E + P ) , with 38 patients each group . The adherence to CPAP was defined as 4 or more hours of CPAP usage per night and at least 9 of each 14 nights of ventilator use . The CPAP adherence rates , cumulative patient dropout rates , CPAP usage , and scores of daytime sleepiness , sleep quality , anxiety , and depression were compared among the groups at 4 , 8 , and 12 weeks of intervention . Results All study groups were comparable in baseline characteristics . Group E + P showed significant improvement in CPAP adherence , daytime sleepiness , and sleep quality compared with group C at 4 , 8 , and 12 weeks of intervention . Compared with group C , group E only showed significant improvement in CPAP adherence , daytime sleepiness , and sleep quality at 4 weeks of intervention , while group P showed no significant improvement over time . Scores of anxiety and depression were significantly improved in group E + P compared with group C at 12 weeks of intervention . Conclusions Combined intervention with patient education and PMR can significantly improve CPAP adherence in OSA patients for at least 12 weeks . The intervention paradigm may serve as an important reference for future studies on CPAP adherence [25581921] STUDY OBJECTIVES We tested whether providing adults with obstructive sleep apnea ( OSA ) with daily Web-based access to their positive airway pressure ( PAP ) usage over 3 mo with or without a financial incentive in the first week improves adherence and functional outcomes . SETTING Academic- and community-based sleep centers . PARTICIPANTS One hundred thirty-eight adults with newly diagnosed OSA starting PAP treatment . INTERVENTIONS Participants were r and omized to : usual care , usual care with access to PAP usage , or usual care with access to PAP usage and a financial incentive . PAP data were transmitted daily by wireless modem from the participants ' PAP unit to a website where hours of usage were displayed . Participants in the financial incentive group could earn up to $ 30/day in the first week for objective PAP use ≥ 4 h/day . MEASUREMENTS AND RESULTS Mean hours of daily PAP use in the two groups with access to PAP usage data did not differ from each other but was significantly greater than that in the usual care group in the first week and over 3 mo ( P < 0.0001 ) . Average daily use ( mean ± st and ard deviation ) during the first week of PAP intervention was 4.7 ± 3.3 h in the usual care group , and 5.9 ± 2.5 h and 6.3 ± 2.5 h in the Web access groups with and without financial incentive respectively . Adherence over the 3-mo intervention decreased at a relatively constant rate in all three groups . Functional Outcomes of Sleep Question naire change scores at 3 mo improved within each group ( P < 0.0001 ) but change scores of the two groups with Web access to PAP data were not different than those in the control group ( P > 0.124 ) . CONCLUSIONS Positive airway pressure adherence is significantly improved by giving patients Web access to information about their use of the treatment . Inclusion of a financial incentive in the first week had no additive effect in improving adherence [21471093] RATIONALE Home portable monitor testing is increasingly being used to diagnose patients with obstructive sleep apnea ( OSA ) and to initiate them on continuous positive airway pressure ( CPAP ) treatment . OBJECTIVES To compare functional outcome and treatment adherence in patients who receive ambulatory versus in-laboratory testing for OSA . METHODS Veterans with suspected OSA were r and omized to either home testing or st and ard in-laboratory testing . Home testing consisted of a type 3 portable monitor recording followed by at least three nights using an automatically adjusting positive airway pressure apparatus . Participants diagnosed with OSA were treated with CPAP for 3 months . MEASUREMENTS AND MAIN RESULTS We measured the change in Functional Outcomes of Sleep Question naire score , with an a priori noninferiority delta of -1 , and the mean daily hours of objective ly measured CPAP adherence , with an a priori noninferiority delta of -0.75 hour/day . Of the 296 subjects enrolled , 260 ( 88 % ) were diagnosed with OSA , and 213 ( 75 % ) were initiated on CPAP . Mean ± SD functional outcome score improved 1.74 ± 2.81 in the home group ( P < 0.001 ) and 1.85 ± 2.46 in the in-laboratory group ( P < 0.0001 ) . The lower bound of the one-sided 95 % noninferiority confidence interval was -0.54 . Mean ± SD hours of daily CPAP adherence were 3.5 ± 2.5 hours/day in the home group and 2.9 ± 2.3 hours/day in the in-laboratory group ( P = 0.08 ) . The lower bound of the one-sided 95 % noninferiority confidence interval was 0.03 . CONCLUSIONS Functional outcome and treatment adherence in patients evaluated according to a home testing algorithm is not clinical ly inferior to that in patients receiving st and ard in-laboratory polysomnography [17556641] Objectives : To examine if reported obstructive sleep apnea ( OSA ) symptom improvement , baseline depressive symptoms , or polysomnographically measured sleep parameters are associated with adherence to continuous positive airway pressure ( CPAP ) . CPAP is a highly effective treatment for OSA . Low adherence to CPAP therapy is common and poorly understood . Depression and lack of perceived benefits from CPAP are possible reasons for low adherence . Methods : Seventy-eight patients evaluated for OSA at a sleep medicine center agreed to participate in the study ; 54 patients completed all study assessment s. The Beck Depression Inventory ( BDI ) and the functional outcomes of sleep question naire ( FOSQ ) were administered before polysomnographic evaluation . A card embedded in the CPAP device electronically recorded adherence . The BDI and FOSQ were administered 1 to 2 months after the baseline measurements were obtained . Results : Baseline depressive symptoms were not correlated with mean duration of CPAP use per night . Reported improvements in OSA symptoms were correlated positively with CPAP adherence . There were significant positive correlations between improvement in depressive symptoms and OSA symptoms after initiation of CPAP therapy . The polysomnographic variables measured did not predict improvement in daytime OSA symptoms or CPAP adherence . Post hoc analyses suggested that those individuals with baseline Apnea Hypopnea Index ( AHI ) between 40 and 80 experienced more symptom improvement than those with AHI < 40 or > 80 . Conclusions : Patients with the greatest level of CPAP adherence also reported the greatest improvement in OSA symptoms . Patients who continued to experience OSA symptoms after CPAP treatment also tended to have more depressive symptoms after CPAP treatment . AHI = Apnea Hypopnea Index ; BDI = Beck Depression Inventory ; CPAP = continuous positive airway pressure ; FOSQ = functional outcomes of sleep question naire ; OSA = obstructive sleep apnea [3612462] Incomplete patient adherence with nasal continuous positive airway pressure ( CPAP ) limits the effectiveness of treatment and results in suboptimal obstructive sleep apnea ( OSA ) outcomes . An interactive website specifically design ed for patients with OSA was design ed and utilized in a r and omized clinical trial to test its effect on increasing CPAP adherence . The goal of this paper is to report on CPAP adherence , internet use , privacy concerns and user satisfaction in using the website . The original project was design ed as a r and omized , controlled clinical trial of Usual Care ( UC , control ) versus MyCPAP group ( intervention ) . Question naires were administered to evaluate the patient perspective of using the MyCPAP website . Participation in the MyCPAP intervention result ed in higher CPAP adherence at the two-month time point relative to participation in the UC group ( 3.4 ± 2.4 and 4.1 ± 2.3 hrs/nt ; P = 0.02 ; mean ± SD ) . Participants r and omized to the MyCPAP website increased their use of the internet to obtain OSA related information , but did not increase their use of the internet to get information on general health or medical conditions . Users had very little concern about their CPAP data being viewed daily or being sent over the internet . Future studies should consider the use of newer evaluation criteria for collaborative adaptive interactive technologies [21719490] The aim of this study to evaluate the efficacy of a home-based programme on clinical response , continuous positive airway pressure ( CPAP ) compliance and cost in a population of high pre-test probability of suffering obstructive sleep apnoea syndrome ( OSAS ) . Patients were r and omised into the following three groups . Group A : home respiratory polygraphy ( RP ) and home follow-up ; group B : hospital polysomnography and hospital follow-up ; and group C : home RP and hospital follow-up . Evaluation during 6 months included Epworth Sleepiness Scale ( ESS ) , Functional Outcomes Sleep Question naire ( FOSQ ) , and daily activity and symptom question naires . Compliance was assessed by memory cards ( group A ) and using an hourly counter ( groups B and C ) . 66 patients were included ( 22 per branch ) , 83 % were males , aged mean±sd 52±10 yrs , body mass index 34±7kg·m−2 , apnoea/hypopnoea index 43±20 h−1 , CPAP pressure 8±2 cmH2O , with no between-group differences . Clinical response showed an ESS of mean±sd 15±3 to 6±4 , a FOSQ of 16±3 to 18±2 , symptoms of 43±7 to 25±7 , and activity of 37±11 to 25±8 . At the end of the study , compliance was : group A 73 % , group B 68 % and group C 57 % . The cost per patient was : group A € 590±43 , group B € 894±11 and group C € 644±93 ( p<0.001 ) . In conclusion , patients with a high initial probability of having OSAS can be diagnosed and treated in a home setting , with a high level of CPAP compliance and lower cost than using either a hospital-based approach or home RP/hospital follow-up [22618924] CONTEXT Systemic hypertension is prevalent among patients with obstructive sleep apnea ( OSA ) . Short-term studies indicate that continuous positive airway pressure ( CPAP ) therapy reduces blood pressure in patients with hypertension and OSA . OBJECTIVE To determine whether CPAP therapy is associated with a lower risk of incident hypertension . DESIGN , SETTING , AND PARTICIPANTS A prospect i ve cohort study of 1889 participants without hypertension who were referred to a sleep center in Zaragoza , Spain , for nocturnal polysomnography between January 1 , 1994 , and December 31 , 2000 . Incident hypertension was documented at annual follow-up visits up to January 1 , 2011 . Multivariable models adjusted for confounding factors , including change in body mass index from baseline to censored time , were used to calculate hazard ratios ( HRs ) of incident hypertension in participants without OSA ( controls ) , with untreated OSA , and in those treated with CPAP therapy according to national guidelines . MAIN OUTCOME MEASURE Incidence of new-onset hypertension . RESULTS During 21,003 person-years of follow-up ( median , 12.2 years ) , 705 cases ( 37.3 % ) of incident hypertension were observed . The crude incidence of hypertension per 100 person-years was 2.19 ( 95 % CI , 1.71 - 2.67 ) in controls , 3.34 ( 95 % CI , 2.85 - 3.82 ) in patients with OSA ineligible for CPAP therapy , 5.84 ( 95 % CI , 4.82 - 6.86 ) in patients with OSA who declined CPAP therapy , 5.12 ( 95 % CI , 3.76 - 6.47 ) in patients with OSA nonadherent to CPAP therapy , and 3.06 ( 95 % CI , 2.70 - 3.41 ) in patients with OSA and treated with CPAP therapy . Compared with controls , the adjusted HRs for incident hypertension were greater among patients with OSA ineligible for CPAP therapy ( 1.33 ; 95 % CI , 1.01 - 1.75 ) , among those who declined CPAP therapy ( 1.96 ; 95 % CI , 1.44 - 2.66 ) , and among those nonadherent to CPAP therapy ( 1.78 ; 95 % CI , 1.23 - 2.58 ) , whereas the HR was lower in patients with OSA who were treated with CPAP therapy ( 0.71 ; 95 % CI , 0.53 - 0.94 ) . CONCLUSION Compared with participants without OSA , the presence of OSA was associated with increased adjusted risk of incident hypertension ; however , treatment with CPAP therapy was associated with a lower risk of hypertension [20880872] Background Continuous positive airway pressure ( CPAP ) is the most widely prescribed treatment for obstructive sleep apnoea syndrome ( OSAS ) . Although it has been shown to improve the symptoms of OSAS , many patients have difficulty adhering to this treatment . The purpose of this study was to investigate the effectiveness of an automated telemedicine intervention to improve adherence to CPAP . Methods A r and omised clinical trial was undertaken in 250 patients being started on CPAP therapy for OSAS . Patients were r and omly assigned to use a theory-driven interactive voice response system design ed to improve CPAP adherence ( telephone-linked communications for CPAP ( TLC-CPAP ) , n=124 ) or to an attention placebo control ( n=126 ) for 12 months . TLC-CPAP monitors patients ' self-reported behaviour and CPAP-related symptoms and provides feedback and counselling through a structured dialogue to enhance motivation to use CPAP . A Sleep Symptoms Checklist , the Functional Outcomes of Sleep Question naire , the Center for Epidemiological Studies Depression Scale and the Psychomotor Vigilance Task were administered at study entry and at 6-month and 12-month follow-up . Hours of CPAP usage at effective mask pressure were measured by the CPAP device stored in its memory and retrieved at each visit . Results Median observed CPAP use in patients r and omised to TLC-CPAP was approximately 1 h/night higher than in the control subjects at 6 months and 2 h/night higher at 12 months . Using generalised estimating equation modelling , the intervention had a significant effect on CPAP adherence . For secondary analysis , the effect of CPAP adherence on the secondary outcomes was analysed . CPAP adherence was significantly associated with a greater reduction in sleep apnoea symptoms and depressive symptoms and a greater improvement in functional status . No significant association was observed between CPAP adherence and reaction time . Conclusions The TLC-CPAP intervention result ed in improved CPAP adherence , which was associated with improved functional status and fewer depressive symptoms . Clinical trial.gov NCT00232544 [19129293] Continuous positive airway pressure ( CPAP ) is an effective treatment for obstructive sleep apnoea syndrom ( OSAS ) but therapy adherence is often low . The hypothesis that CPAP-adherence and clinical outcomes can be improved by either using an autoadjusting-CPAP ( APAP ) device or an intensive support was tested . A controlled parallel group study was performed with 100 newly diagnosed OSAS patients , r and omised into 4 groups ( n = 25 each ) : st and ard or intensive support plus either APAP or CPAP . Intensive support included education and monthly home visits for 6 months . Clinical outcome was monitored by polysomnography at CPAP initiation and , after 3 and 9 months , compliance data were downloaded from the CPAP devices . After 9 months , intensively supported patients returned for follow-up in 88 versus 68 % in the st and ard-support-group . Daily usage ( mean±sem 5.7±0.2 for intensive support versus 4.6±0.4 h for st and ard support ) , percentage of days used ( 80.4±2.8 versus 57.0±5.9 % ) and proportion of individual sleep time ( 80.6±3.2 versus 64.9±6.2 % ) were also higher . There was no significant difference between APAP or CPAP , ( daily usage 5.2±0.4 versus 5.1±0.3 h , percentage of days 67.9±5.0 versus 69.2±4.9 % , proportion of sleep time 72.5±5.0 % versus 72.1±5.2 % , for APAP and CPAP ) but retention rate was higher with CPAP . In summary , intensive support after continuous positive airway pressure initiation , rather than the application of autoadjusting-continuous positive airway pressure , increased therapy adherence [24993911] We aim ed to compare the effect of intensive versus st and ard interventions on continuous positive airway pressure ( CPAP ) adherence 2 years after CPAP initiation , as well as on sleepiness , quality of life , depression , hospitalisation and death rate due to cardiovascular disease ( CVD ) . 3100 patients with newly diagnosed sleep apnoea were r and omised into the st and ard group , with usual follow-up care , or the intensive group , with additional visits , telephone calls and education . Subjective daytime sleepiness ( Epworth Sleepiness Scale ; ESS ) , quality of life ( 36-item Short Form Health Survey ; SF-36 ) and the patient ’s level of depression ( Beck Depression Inventory ; BDI ) were recorded before and 2 years after CPAP initiation , together with CVD hospitalisations and death rate . 2 years after CPAP initiation , the intensive group used CPAP significantly more than the st and ard group ( 6.9 versus 5.2 h per night ; p<0.001 ) . ESS , SF-36 and BDI scores were also significantly better in the intensive group . Furthermore , the st and ard group had significantly more deaths and hospitalisations due to CVD . CPAP usage can be improved by both intensive and st and ard patient support . However , the patients who received intensive CPAP support had significantly better ESS , BDI and SF-36 scores , and lower cardiovascular morbidity and mortality , suggesting that an intensive programme could be worthwhile . Intensive CPAP support improves sleepiness , quality of life , depression , hospitalisation and death rate [26310452] Background Compliance with continuous positive airway pressure ( CPAP ) therapy is essential in patients with obstructive sleep apnoea ( OSA ) , but adequate control is not always possible . This is clinical ly important because CPAP can reverse the morbidity and mortality associated with OSA . Telemedicine , with support provided via a web platform and video conferences , could represent a cost-effective alternative to st and ard care management . Aim To assess the telemedicine impact on treatment compliance , cost-effectiveness and improvement in quality of life ( QoL ) when compared with traditional face-to-face follow-up . Methods A r and omised controlled trial was performed to compare a telemedicine-based CPAP follow-up strategy with st and ard face-to-face management . Consecutive OSA patients requiring CPAP treatment , with sufficient internet skills and who agreed to participate , were enrolled . They were followed-up at 1 , 3 and 6 months and answered surveys about sleep , CPAP side effects and lifestyle . We compared CPAP compliance , cost-effectiveness and QoL between the beginning and the end of the study . A Bayesian cost-effectiveness analysis with non-informative priors was performed . Results We r and omised 139 patients . At 6 months , we found similar levels of CPAP compliance , and improved daytime sleepiness , QoL , side effects and degree of satisfaction in both groups . Despite requiring more visits , the telemedicine group was more cost-effective : costs were lower and differences in effectiveness were not relevant . Conclusions A telemedicine-based strategy for the follow-up of CPAP treatment in patients with OSA was as effective as st and ard hospital-based care in terms of CPAP compliance and symptom improvement , with comparable side effects and satisfaction rates . The telemedicine-based strategy had lower total costs due to savings on transport and less lost productivity ( indirect costs ) . Trial register number NCT01716676 [22240218] INTRODUCTION The most commonly used treatment for obstructive sleep apnea syndrome ( OSA ) is the application of continuous positive airway pressure ( CPAP ) during sleep . However compliance with this treatment is frequently below 70 % . METHODS The main aim of this study was to evaluate the feasibility of an educational intervention ( EI ) delivered in phone calls made to OSA patients ( n=66 ) treated with CPAP by a home care provider ( SADIR ) . The educational intervention consisted of five sessions of telephone based counseling intervention by appropriately trained staff delivered on day 3 , 10 , 30 , 60 and 90 after initiation of treatment . Secondary objectives were to compare , using a case-control design , CPAP compliance of OSA patients ( n=133 ) with or without EI . RESULTS Ninety-eight percent of patients accepted the intervention to participate in the study . Fifty-seven patients ( 86 % ) received the full intervention program and 44 patients ( 66 % ) strictly respected the pre-defined timings per protocol . A higher adherence to CPAP at six months was observed in the EI group compared to patient without EI ( 94 % versus 81 % ) ( P<0.05 ) . CPAP compliance at three months was 54minutes higher in the EI group compared to the control group ( 4h39±2h17 and 3h45±2h45 respectively ) but this difference was not statistically significant . CONCLUSION An educational intervention dispensed by phone is applicable and would have an impact on CPAP compliance . Its efficacy on long-term compliance has to be confirmed in a larger group using a r and omized procedure [23483174] IMPORTANCE Due to increasing dem and for sleep services , there has been growing interest in ambulatory models of care for patients with obstructive sleep apnea . With appropriate training and simplified management tools , primary care physicians are ideally positioned to take on a greater role in diagnosis and treatment . OBJECTIVE To compare the clinical efficacy and within-trial costs of a simplified model of diagnosis and care in primary care relative to that in specialist sleep centers . DESIGN , SETTING , AND PATIENTS A r and omized , controlled , noninferiority study involving 155 patients with obstructive sleep apnea that was treated at primary care practice s ( n=81 ) in metropolitan Adelaide , 3 rural regions of South Australia or at a university hospital sleep medicine center in Adelaide , Australia ( n = 74 ) , between September 2008 and June 2010 . INTERVENTIONS Primary care management of obstructive sleep apnea vs usual care in a specialist sleep center ; both plans included continuous positive airway pressure , m and ibular advancement splints , or conservative measures only . MAIN OUTCOME AND MEASURES The primary outcome was 6-month change in Epworth Sleepiness Scale ( ESS ) score , which ranges from 0 ( no daytime sleepiness ) to 24 points ( high level of daytime sleepiness ) . The noninferiority margin was -2.0 . Secondary outcomes included disease-specific and general quality of life measures , obstructive sleep apnea symptoms , adherence to using continuous positive airway pressure , patient satisfaction , and health care costs . RESULTS There were significant improvements in ESS scores from baseline to 6 months in both groups . In the primary care group , the mean baseline score of 12.8 decreased to 7.0 at 6 months ( P < .001 ) , and in the specialist group , the score decreased from a mean of 12.5 to 7.0 ( P < .001 ) . Primary care management was noninferior to specialist management with a mean change in ESS score of 5.8 vs 5.4 ( adjusted difference , -0.13 ; lower bound of 1-sided 95 % CI , -1.5 ; P = .43 ) . There were no differences in secondary outcome measures between groups . Seventeen patients ( 21 % ) withdrew from the study in the primary care group vs 6 patients ( 8 % ) in the specialist group . CONCLUSIONS AND RELEVANCE Among patients with obstructive sleep apnea , treatment under a primary care model compared with a specialist model did not result in worse sleepiness scores , suggesting that the 2 treatment modes may be comparable . TRIAL REGISTRATION anzctr.org.au Identifier : ACTRN12608000514303 [23920211] BACKGROUND : CPAP is currently the treatment of choice for obstructive sleep apnea syndrome , but therapy adherence is poor . Many educational trials have been proposed to increase CPAP adherence . We tested the hypothesis that polysomnograph chart viewing by patients would improve CPAP adherence . METHODS : A controlled parallel group study was performed with 206 newly diagnosed obstructive sleep apnea syndrome patients , r and omized into 2 groups ( n = 103 each ) : st and ard support group , and educational support group . Each educational support group subject viewed 2 consecutive polysomnograms on the computer screen : the first recorded during a st and ard diagnostic overnight polysomnography , and the second during a full-night polysomnography with nasal CPAP . The subject 's attention was drawn only to the flow and oxyhemoglobin saturation curves . Clinical outcomes were assessed via polysomnography at CPAP initiation and after 1 , 3 , and 12 months . RESULTS : After 12 months of CPAP , 76 % of the educational support group and 52 % of the st and ard support group returned for a follow-up visit ( P < .001 ) . Statistical significance had already been reached after 1 and 3 months . Moreover , CPAP use ( measured as hours of use per night ) was higher in the educational support group at each control visit . CONCLUSIONS : Polysomnograph chart viewing by obstructive sleep apnea patients can increase CPAP adherence , as evaluated by rate of return for the follow-up visit and mean nightly CPAP use [14725828] BACKGROUND This pragmatic r and omised , controlled trial investigated annual review of patients with sleep apnea/hypopnea syndrome ( SAHS ) . Clinical outcomes and costs were compared for consultant clinic review versus specialist nurse home visit . METHOD One hundred and seventy-four patients were r and omised to annual review by consultant clinic appointment or by specialist nurse home visit . SAHS symptoms , Epworth score , hospital anxiety and depression scale ( HADS ) , Short Form-36 ( SF-36 ) and hours of use of constant positive airway pressure ( CPAP ) were measured before and 3 months after review . The costs and patient preference for review were determined . RESULTS After review , both groups significantly increased CPAP use ( mean ( SD ) increase : nurse , 0.66 ( 1.71 ) h ; consultant , 0.45 ( 1.69 ) h ) and reduced symptom scores ( nurse , -2 ( 7 ) ; consultant , -3 ( 9 ) ) , compared to baseline . There were no differences between groups in these improvements , or in HADS or SF-36 scores . Average duration of a nurse home visit , excluding travel time , was 26 ( 6 ) min . Total NHS cost per visit was 52.26 UK pounds ( 49.85 ) ( $ 83.62 ( 79.76 ) ) , of which 6.57 UK pounds ( 1.43 ) ( $ 10.51 ( 2.29 ) ) reflected time spent with the patient and the remainder was travel cost . Average duration of consultant review was 10 ( 6 ) min , total NHS cost 6.21 UK pounds ( 3.99 ) ( $ 9.94 ( 6.38 ) ) . However , the cost to the patient of attending the clinic was 23.63 UK pounds ( 23.21 ) ( $ 37.81 ( 37.13 ) ) . Patient preference for review was nurse 16 % , consultant 19 % , and no preference 65 % . CONCLUSION Following annual review , use of CPAP increased and symptoms improved . Outcomes were similar for consultant and nurse led review . Home visits were expensive for the healthcare provider , whereas clinic attendance incurred substantial costs to the patient . The majority of patients would accept nurse review for their sleep apnea management [18829212] OBJECTIVE As many as 50 % of patients diagnosed with obstructive sleep apnea stop adhering to the prescribed medical treatment of continuous positive airway pressure ( CPAP ) within 1 - 3 weeks of onset . Thus , a theory-based intervention using music to support habit formation was design ed to improve CPAP adherence at onset . The intervention material s included directions for CPAP nightly use , a diary for recording nightly use and writing about CPAP benefits or problems . In addition , an audiotape with softly spoken instructions for placing the CPAP mask comfortably , using deep breathing and muscle relaxation along with the slowly decreasing music tempo was provided to listen to at bedtime each night . METHODS Effects of this music intervention were tested in a r and omized , placebo-controlled trial of 97 patients with 53 males ( 55 % ) and 44 females ( 45 % ) . Moderate to severe apnea/hyponea scores ( per sleep laboratory data ) and medical diagnosis of OSA were required for study inclusion . RESULTS Compared to placebo controls , a greater proportion of experimental patients were adhering ( chi(2)=14.67 , p<0.01 ; a large difference , Phi=0.39 ) at the end of the first month of CPAP onset . There were no differences in CPAP adherence at 3 ( X(2)=0.065 , p=0.79 ) and 6 ( X(2)=.118 , p=0.73 ) months . Patients ' diary data and satisfaction survey results indicated the intervention was rated as helpful and guided formation of a relaxing , habitual routine of CPAP nightly use . CONCLUSION The intervention had a strong effect for improving adherence to CPAP at 1 month . PRACTICE IMPLICATION S Adherence at the onset of treatment is critical and the audio music intervention was easily administered . Other interventions that target problems interfering with longer-term CPAP adherence are needed [11812555] BACKGROUND Obstructive sleep apnoea is associated with raised blood pressure . If blood pressure can be reduced by nasal continuous positive airway pressure ( nCPAP ) , such treatment could reduce risk of cardiovascular disease in patients with obstructive sleep apnoea . Our aim was to see whether nCPAP for sleep apnoea reduces blood pressure compared with the most robust control intervention subtherapeutic nCPAP . METHODS We did a r and omised parallel trial to compare change in blood pressure in 118 men with obstructive sleep apnoea ( Epworth score > 9 , and a > 4 % oxygen desaturation index of > 10 per h ) who were assigned to either therapeutic ( n=59 ) or subtherapeutic ( 59 ) nCPAP ( about 1 cm H(2)O pressure ) for 1 month . The primary outcome was the change in 24-h mean blood pressure . Secondary outcomes were changes in systolic , diastolic , sleep , and wake blood pressure , and relations between blood pressure changes , baseline blood pressure , and severity of sleep apnoea . FINDINGS Therapeutic nCPAP reduced mean arterial ambulatory blood pressure by 2.5 mm Hg ( SE 0.8 ) , whereas subtherapeutic nCPAP increased blood pressure by 0.8 mm Hg ( 0.7 ) ( difference -3.3 [ 95 % CI -5.3 to -1.3 ] ; p=0.0013 , unpaired t test ) . This benefit was seen in both systolic and diastolic blood pressure , and during both sleep and wake . The benefit was larger in patients with more severe sleep apnoea than those who had less severe apnoea , but was independent of the baseline blood pressure . The benefit was especially large in patients taking drug treatment for blood pressure . INTERPRETATION In patients with most severe sleep apnoea , nCPAP reduces blood pressure , providing significant vascular risk benefits , and substantially improving excessive daytime sleepiness and quality of life [22945541] Purpose The objective of the study was to evaluate the effectiveness of stage-matched intervention on adherence to continuous positive airway pressure ( CPAP ) in patients with obstructive sleep apnea syndrome . Methods One hundred and ten Chinese patients with newly diagnosed obstructive sleep apnea syndrome were enrolled in this study . They were r and omly assigned into stage-matched care ( SMC ) and st and ard care ( SC ) groups ( 55 patients in each group ) . Patients in the SMC group received stage-matched intervention at different stages of behavior changes , and the SC group received only routine care . The intervention was based on the health action process approach theory and included risk perception , outcome expectancy , and self-efficacy . Question naires included the Self-Efficacy Measure for Sleep Apnea , the Epworth Sleepiness Scale ( ESS ) , and the Pittsburgh Sleep Quality Index ( PSQI ) . Data were collected at baseline and 1 and 3 months after home CPAP treatment , and hours of CPAP usage was also recorded at 1 and 3 months of follow-up . Results At 1 month , CPAP usage was 5.59 ± 0.56 h/night ( mean ± SD ) vs 5.28 ± 0.67 h/night in the SMC and SC groups , respectively ( p = 0.016 ) . At 3 months , CPAP usage was 5.65 ± 0.50 vs 5.26 ± 0.82 h/night in the SMC and SC groups , respectively ( p = 0.006 ) . Repeated ANOVA analysis demonstrated that risk perception , outcome expectancy , and self-efficacy in the SMC group were significantly higher than those of the SC group ( p < 0.05 ) . Moreover , the time × group interaction was significant for outcome expectancy and self-efficacy , indicating that the groups differed significantly in changes in outcome expectancy and self-efficacy over the three time points . There was a significant difference between the SMC and SC groups in terms of improvement in ESS ( p < 0.001 ) and PSQI ( p = 0.013 ) after 3 months of CPAP treatment . Conclusions Stage-matched intervention could not only facilitate intention formation and enhance treatment self-efficacy but significantly improve CPAP adherence in OSA patients for the 3-month treatment [18795985] OBJECTIVES To examine whether treatment of obstructive sleep apnea ( OSA ) with continuous positive airway pressure ( CPAP ) in patients with Alzheimer 's disease ( AD ) results in better cognitive function . DESIGN R and omized double-blind placebo-controlled trial . Participants were r and omized to therapeutic CPAP for 6 weeks or placebo CPAP for 3 weeks followed by therapeutic CPAP for 3 weeks . SETTING General clinical research center . PARTICIPANTS Fifty-two men and women with mild to moderate AD and OSA . INTERVENTION CPAP . MEASUREMENTS A complete neuropsychological test battery was administered before treatment and at 3 and at 6 weeks . RESULTS A comparison of subjects r and omized to 3 weeks of therapeutic versus placebo CPAP suggested no significant improvements in cognition . A comparison of pre- and posttreatment neuropsychological test scores after 3 weeks of therapeutic CPAP in both groups showed a significant improvement in cognition . The study was underpowered to make definitive statements about improvements within specific cognitive constructs , although exploratory post hoc examination of change scores for individual tests suggested improvements in episodic verbal learning and memory and some aspects of executive functioning such as cognitive flexibility and mental processing speed . CONCLUSION OSA may aggravate cognitive dysfunction in dementia and thus may be a reversible cause of cognitive loss in patients with AD . OSA treatment seems to improve some cognitive functioning . Clinicians who care for patients with AD should consider implementing CPAP treatment when OSA is present [16796496] The objective of this study was to test whether a telehealth intervention could improve the compliance with continuous positive airway pressure ( CPAP ) by patients with sleep apnea . These patients had been nonadherent for the initial 3 months of therapy even after receiving the initial st and ard and then supplemental audiotaped/videotaped patient education for adhering to CPAP nightly . The material s and methods included a r and omized testing of experimental and placebo interventions . Interventions were delivered by nurses to two groups in their homes by telehealth over a 12-week period . The placebo intervention was used to control for Hawthorne effect , time and attention influences and the novelty of having telehealth in the home . Results following the telehealth interventions were that significantly more patients in the experimental group 1 ( n = 10 ) than the placebo group 2 ( n = 9 ) were adhering nightly to CPAP ( chi 2 = 4.55 , p = 0.033 ) . Group 1 patients reported greater satisfaction with their intervention . However , both groups rated telehealth delivery positively . The mean cost of each 20-minute telehealth visit was 30 dollars while the total cost of the telehealth intervention for each patient was 420 dollars . These costs included telehealth equipment , initial installation , longdistance telephone charges , nurse salary , and intervention material s. Conclusions are that telehealth interventions are a potentially cost-effective service for increasing adherence to prescribed medical treatments . Replication studies with large sample s and in other clinical groups are recommended [18853940] STUDY OBJECTIVES To compare a clinical pathway using portable monitoring ( PM ) for diagnosis and unattended autotitrating positive airway pressure ( APAP ) for selecting an effective continuous positive airway pressure ( CPAP ) with another pathway using polysomnography ( PSG ) for diagnosis and treatment of obstructive sleep apnea ( OSA ) . DESIGN R and omized parallel group SETTING Veterans Administration Medical Center PATIENTS 106 patients with daytime sleepiness and a high likelihood of having OSA MEASUREMENTS AND RESULTS : The AHI in the PM-APAP group was 29.2 + /- 2.3/h and in the PSG group was 36.8 + /- 4.8/h ( P= NS ) . Patients with an AHI > or = 5 were offered CPAP treatment . Those accepting treatment ( PM-APAP 45 , PSG 43 ) were begun on CPAP using identical devices at similar mean pressures ( 11.2 + /- 0.4 versus 10.9 + /- 0.5 cm H2O ) . At a clinic visit 6 weeks after starting CPAP , 40 patients in the PM-APAP group ( 78.4 % of those with OSA and 88.8 % started on CPAP ) and 39 in the PSG arm ( 81.2 % of those with OSA and 90.6 % of those started on CPAP ) were using CPAP treatment ( P = NS ) . The mean nightly adherence ( PM-APAP : 5.20 + /- 0.28 versus PSG : 5.25 + /- 0.38 h/night ) , decrease in Epworth Sleepiness Scale score ( -6.50 + /- 0.71 versus -6.97 + /- 0.73 ) , improvement in the global Functional Outcome of Sleep Question naire score ( 3.10 + /- 0.05 versus 3.31 + /- 0.52 ) , and CPAP satisfaction did not differ between the groups . CONCLUSIONS A clinical pathway utilizing PM and APAP titration result ed in CPAP adherence and clinical outcomes similar to one using PSG [1470808] In a prospect i ve study aim ed at evaluating objective ly the compliance with nasal continuous positive airway pressure ( CPAP ) treatment , 233 obstructive sleep apnea ( OSA ) ( apnea index , > 10 apneas/hour ) patients and 36 nonapneic snorers were studied . The compliance to treatment was measured by the mean rate of use of the CPAP device , obtained from a built-in time counter . The follow-up period was 874 + /- 48 in OSA patients and 675 + /- 83 in snorers . CPAP was proposed to all OSA patients but only to those snorers who felt improved after an initial laboratory night on CPAP . Nineteen OSA patients refused CPAP . Of the 214 OSA patients who accepted CPAP , 181 are still on treatment , with a mean daily rate of use of 5.6 + /- 0.1 hours ( mean + /- SEM ) ; 22 patients stopped CPAP after a variable period of time ; 10 patients died and one acromegalic patient was considered cured after hypophysectomy for a pituitary adenoma . Depending upon the definition of acceptable compliance , the compliance rate in this group was between 77 % and 89 % . The mean rate of use was correlated with indices of disease severity ( apnea index , apnea+hypopnea index , minimal SaO2 during sleep , daytime PaO2 , pulmonary artery pressure ) . Thirty-six nonapneic snorers accepted CPAP . In this group , 26 are still on CPAP , with a mean daily rate of use of 5.4 + /- 0.5 hours ; one patient died ; one underwent uvolopalatopharyngoplasty without follow-up ; and eight stopped CPAP . The compliance rate in this group was between 58 % and 78 % . This study shows that CPAP is reasonably accepted by OSA patients as well as by nonapneic snorers . ( ABSTRACT TRUNCATED AT 250 WORDS [22103957] OBJECTIVE Adherence to continuous positive airway pressure ( CPAP ) therapy for obstructive sleep apnoea ( OSA ) is poor . We assessed the effectiveness of a motivational interviewing intervention ( motivational interview nurse therapy [ MINT ] ) in addition to best practice st and ard care to improve acceptance and adherence to CPAP therapy in people with a new diagnosis of OSA . METHOD One hundred six Australian adults ( 69 % male ) with a new diagnosis of OSA and a clinical recommendation for CPAP treatment were recruited from a tertiary sleep disorders center . Participants were r and omly assigned to receive either 3 sessions of a motivational interviewing intervention ( MINT ; n = 53 ; mean age = 55.4 years ) or no intervention ( control ; n = 53 ; mean age = 57.74 years ) . The primary outcome was the difference between the groups in objective CPAP adherence at 1-month , 2-month , 3-month , and 12-month follow-ups . RESULTS Fifty ( 94 % ) participants in the MINT group and 50 ( 94 % ) participants in the control group met all inclusion and exclusion criteria and were included in the primary analysis . The number of hours of CPAP use per night in the MINT group at 3 months was 4.63 hr and was 3.16 hr in the control group ( p = .005 ) . This represents almost 50 % better adherence in the MINT group relative to the control group . Patients in the MINT group were substantially more likely to accept CPAP treatment . CONCLUSIONS MINT is a brief , manualized , effective intervention that improves CPAP acceptance and objective adherence rates compared to st and ard care alone [24989482] Background Obstructive sleep apnea syndrome ( OSAS ) is a serious disorder with significant health consequences . Treatment adherence to auto-titrating positive airway pressure ( APAP ) is often below expectations . We investigated the effectiveness of a brief educational intervention using motivational strategies in treatment adherence among patients with OSAS . Methods The study followed a r and omized , controlled design and included 61 patients diagnosed with OSAS , meeting the criteria for APAP therapy . Patients recruited from a Sleep Disorders Unit were r and omly allocated to an intervention group ( IG ) and two control groups ( CG1 and CG2 ) . In the IG motivational strategies were applied according to patient ’s motivation , assessed by the degree of confidence and conviction . In the CG1 , participants received exclusively st and ardized information , and in the CG2 , routine procedures were followed . Assessment included the Apnea Hypopnea Index ( AHI ) , the Epworth Sleepiness Scale ( ESS ) , and sociodemographic and clinical information . Adherence to treatment was measured after 1 ( T1 ) and 2 months ( T2 ) through the APAP software . Results The IG presented higher adherence to APAP — percentage of days of use > 4 h ( 89.8 % p = 0.013 ) , mean effective use per effective day ( 6.2 p = 0.000 ) , and lower AHI ( 2.7 p = 0.019 ) at T2 when compared with the other two groups . Confidence was higher in the IG group at T2 than at T1 ( p = 0.000 ) . The ESS presented a significant reduction ( p = 0.000 ) in the IG and in the CG1 ( p = 0.008 ) , but was higher in the CG2 ( p = 0.015 ) . Conclusions Brief interventions using motivational strategies can improve a patient ’s adherence to APAP [24179298] BACKGROUND Obstructive sleep apnea ( OSA ) is associated with a variety of medical conditions . Positive airway pressure ( PAP ) is an effective treatment for improving sleep , yet adherence rates are low . The aim of the current study is to test two treatments versus st and ard care in improving adherence to PAP . METHOD Two hundred twenty-seven patients with OSA were r and omized to st and ard care ( SC ) , education ( ED ) and motivational enhancement therapy ( MET ) . Adherence was measured objective ly and the first week of adherence ( prior to the intervention ) was used as an a priori moderator of the effect of the various interventions . Mediators of treatment response were also examined using theory-based measures of decisional balance and self-efficacy . RESULTS Adherence declined over time for all three groups . There was a significant interaction between level of adherence during the first week of treatment and treatment group . Those who had moderate levels of adherence during their first week of PAP were more likely to adhere to treatment at follow-up if they had MET ; those who had high levels of adherence during their first week of PAP were more likely to adhere to treatment at follow-up if they had ED . MET treatment increased the perception of the positive aspects of PAP , but ED did not . CONCLUSIONS Initial adherence to positive airway pressure could help guide subsequent treatment plans . The results also support social cognitive theory in that educational approaches might be best suited for those who are ready for change whereas more motivational approaches might be best for those who are ambivalent about change [25056665] Background The treatment of choice for sleep apnoea-hypopnoea syndrome ( SAHS ) is continuous positive airway pressure ( CPAP ) . However , CPAP effectiveness strongly depends on patient adherence to treatment . The aim of this study was to determine the effectiveness of a low-cost , basic intervention on improving CPAP adherence . Methods A controlled parallel-group trial . Participants were SAHS patients for whom CPAP treatment was indicated . Those in the intervention group were shown the results of their sleep test and were told the importance of treatment adherence ; the control group received neither . Outcomes for both groups were compared at 6 months . The primary outcome assessed was CPAP usage . Results One hundred fifty-four patients were included in the intervention group and 167 in the control group . At 6 months , the intervention group had 10 % more participants with CPAP usage ≥4 h , significantly higher adherence as compared to controls ( 5 ± 1.8 h vs 4.3 ± 1.7 , p = 0.031 ) , mean : 0.7 h/day and fewer discontinuations of CPAP . A multiple linear regression model showed that intervention group and daytime sleepiness were variables independently associated with treatment adherence . Conclusions An inexpensive basic intervention involving communication of sleep test results and the importance of CPAP adherence improves adherence to CPAP therapy . In addition , greater daytime sleepiness is associated with higher CPAP adherence [9231954] Effectiveness of continuous positive airway pressure ( CPAP ) as a treatment of obstructive sleep apnea can be limited by poor compliance , but little is known about how to improve compliance . We performed a r and omized , controlled clinical trial among 33 subjects of two interventions to improve compliance . One group of subjects received weekly phone calls to uncover any problems and encourage use , another received written information about sleep apnea and the importance of regular CPAP use , and a third served as control subjects . We found that intervention improved CPAP compliance ( p = 0.059 ) and that the effect was particularly strong when intervention occurred during the first month of CPAP treatment ( p = 0.004 ) . Although the sample size did not allow definitive investigation of other explanatory variables , subjects with lower levels of education or those with relatives who used CPAP may have benefited from intervention more than other subjects . We conclude that simple , inexpensive efforts to improve compliance with CPAP can be effective , especially when applied at the start of CPAP treatment , but optimal intervention may vary with certain patient characteristics [23772186] STUDY OBJECTIVES To evaluate patient ratings of the acceptability of a peer buddy system ( PBS ) . To promote continuous positive airway pressure ( CPAP ) therapy adherence in patients with obstructive sleep apnea ( OSA ) . To obtain preliminary data on the effectiveness of PBS on sleep-specific health-related quality of life and CPAP adherence . DESIGN Prospect i ve , r and omized , and controlled study . SETTING Academic Center . PARTICIPANTS Thirty-nine patients with OSA and 13 patients with OSA who were experienced CPAP users . INTERVENTIONS Recently diagnosed patients with OSA were r and omly assigned to either the PBS to promote CPAP adherence ( intervention group ) or usual care ( control group ) . MEASUREMENTS Patient satisfaction , Functional Outcomes of Sleep Question naire ( FOSQ ) , CPAP adherence , vigilance , self-efficacy , and patient activation were measured . RESULTS Ninety-one percent of the subjects rated the PBS as very satisfactory ( 68 % ) or satisfactory ( 23 % ) . During the 90 days of therapy , weekly CPAP adherence was greater in the intervention than the usual care group ( MANOVA ; F = 2.29 ; p = 0.04 ) . Patient satisfaction was positively correlated with CPAP adherence ( R(2 ) = 0.14 ; p = 0.02 ) . We did not find any group differences for FOSQ , vigilance , self-efficacy , or patient activation in this pilot study . CONCLUSION Our pilot study suggests that the PBS intervention is feasible and received high patient satisfaction ratings . CPAP adherence may be improved by peer-driven intervention , but a larger , adequately powered study is needed . CLINICAL TRIAL INFORMATION Clinical Trials.gov identifier : NCT01164683 . COMMENTARY A commentary on this article appears in this issue on page 551 . CITATION Parthasarathy S ; Wendel C ; Haynes PL ; Atwood C ; Kuna S. A pilot study of CPAP adherence promotion by peer buddies with sleep apnea . J Clin Sleep Med 2013;9(6):543 - 550 [10194151] Continuous positive airway pressure ( CPAP ) therapy is widely prescribed for patients with the sleep apnea/hypopnea syndrome ( SAHS ) , but the use of CPAP for such patients is disappointingly low . We postulated that providing intensive educational programs and nursing support to SAHS patients might improve CPAP use and outcomes . We also examined the hypothesis that CPAP use would be greater among patients who had initiated their own referral than among those asked to seek help by a partner . We r and omized 80 consecutive , new patients with SAHS to receive either usual support or additional nursing input including CPAP education at home and involving their partners , a 3-night trial of CPAP in our institution 's sleep center , and additional home visits once they had begun CPAP . The primary outcome variable was objective CPAP use ; symptoms , mood , and cognitive function were also assessed after 6 mo . CPAP use over 6 mo was greater ( p = 0.003 ) among patients receiving intensive than among those receiving st and ard support ( 5.4 + /- 0.3 versus 3.9 + /- 0 . 4 h/night [ mean + /- SEM ] ) , with greater improvements ( p < 0.05 ) in SAHS symptoms , mood , and reaction time in the intensively supported group . CPAP use was greater ( p = 0.002 ) among patients who initiated their own referrals . CPAP use and outcomes of therapy can be improved by provision of a nurse-led intensive CPAP education and support program . CPAP use is lower among patients whose partners ask them to seek treatment [25142557] STUDY OBJECTIVES Obstructive sleep apnea ( OSA ) is commonly associated with cognitive and functional deficits , some of which are resolved after continuous positive airway pressure ( CPAP ) treatment . The investigation of brain structural changes before and after treatment could provide deep insights into the pathogenesis and the reversibility of this disorder . We hypothesized that severe OSA patients would have altered white matter ( WM ) integrity and cognition and that treatment would improve both the structural damage and the cognitive impairment . DESIGN Prospect i ve clinical study . SETTING The Sleep Disorders Center and the Center of Excellence in High-Field Magnetic Resonance Imaging at Vita-Salute San Raffaele University , Milan , Italy . PARTICIPANTS Seventeen never-treated consecutive OSA patients were evaluated before and after treatment ( after 3 and 12 months ) and compared to 15 matched healthy controls . INTERVENTION CPAP . MEASUREMENTS WM integrity measured by diffusion tensor imaging ( DTI ) and cognitive performance ( measured with neuropsychological testing ) before and after 3 and 12 months of CPAP . RESULTS Results in pre-treatment OSA patients showed impairments in most cognitive areas , mood and sleepiness that were associated with diffuse reduction of WM fiber integrity reflected by diminished fractional anisotropy ( FA ) and mean diffusivity ( MD ) in multiple brain areas . After 3 months of CPAP , only limited changes of WM were found . However , over the course of 12 months CPAP treatment , an almost complete reversal of WM abnormalities in all the affected regions was observed in patients who were compliant with treatment . Significant improvements involving memory , attention , and executive-functioning paralleled WM changes after treatment . CONCLUSIONS Changes of WM DTI " signatures " of brain pathology in OSA patients are appreciable over the course of 12-month treatment with CPAP in most of the regions involved . Recovery of cognitive deficits after treatment is consistent with the presence of a reversible structural neural injury in OSA in patients who were compliant with treatment [21218293] Although of proven health benefit to persons with obstructive sleep apnea ( OSA ) , adherence to continuous positive airway pressure ( CPAP ) therapy is suboptimal , with patterns of use that are established early and that are not easily altered after the initial experience . In a r and omized controlled trial , 70 participants with OSA and cardiovascular disease were assigned to receive either positively or negatively framed education about CPAP . Objective adherence was measured following 30 days of home CPAP therapy . Daytime sleepiness , dispositional optimism , self-efficacy , and depression were also evaluated at baseline and after 30 days . CPAP use was greater in the group receiving negative message framing ( p = .015 ) [16565867] The objective of this study was to compare continuous positive airway pressure ( CPAP ) use , functional status , and client satisfaction in obstructive sleep apnea syndrome ( OSAS ) patients r and omized to either telemedicine support or traditional care . In our university-affiliated sleep disorders center , patients with OSAS who were initiating CPAP therapy were r and omized to receive telemedicine support vs traditional follow-up care for 30 days . The telemedicine group received a “ Health Buddy ” computer that provided daily Internet-based informational support and feedback for problems experienced with CPAP use . At 30 days , there were no significant differences in the hours of CPAP use between groups receiving traditional care ( M=4.22 , SD±2.05 ) and telemedicine support ( M=4.29 , SD±2.15 ) , p=0.87 , or in the proportion of nights with CPAP use between the traditional ( M=50%±33.8 ) and telemedicine groups ( M=47%±34.2 ) , p=0.61 . No significant differences were found between groups in functional status ( M=2.27±4.56 vs M=2.03±3.88 , respectively , p=0.76 ) or client satisfaction ( M=28.0±3.51 vs M=28.5±3.05 , p=0.43 ) . Patients in the telemedicine and traditional groups had similar CPAP use , functional status , and client satisfaction . The data suggest that telemedicine support as provided by our model compares favorably with traditional care . As a provider-extender , telemedicine support for patients initiating use of CPAP may allow for greater practice efficiency while maintaining quality of care [10508797] Effective compliance ( time spent at the effective pressure ) with nasal CPAP in obstructive sleep apnea has been reported to be poor . The aim of our study was to evaluate effective compliance in a large European multicenter study . One hundred twenty-one consecutive newly treated patients ( initial apnea-hypopnea index [ AHI ] = 62.0 + /- 29 . 5/h , AHI under CPAP = 6.4 + /- 8.1/h , CPAP pressure = 8.7 + /- 2.6 cm H(2)O , BMI = 33.1 + /- 6.8 kg/m(2 ) ) were r and omly allocated to a group with ( MC(+ ) ) ( n = 58 ) or without ( MC(- ) ) ( n = 63 ) a control unit measuring effective compliance at 1 , 2 , and 3 mo , which was compared with the built-in time counter data . MC(+ ) data were 94 + /- 10 , 98 + /- 5 , and 96 + /- 9 % of counter data at 1 , 2 , and 3 mo , respectively . Using criteria of regular use already reported in the literature ( at least 4 h of nCPAP per day of use and nCPAP administered more than 70 % of the days ) we found 77 , 82 , and 79 % compliant patients at 1 , 2 , and 3 mo , respectively , 79 % of the patients meeting these criteria each month . Although there were no pulmonary functions or polysomnographic differences between the two subgroups , the compliant patients did report a greater improvement in minor symptoms . We found a close correlation between effective use of CPAP and the machine run time . The main result of our study was a higher effective compliance than previously reported , approximately 80 % of the patients being regular users versus 46 % in a previously published study . This may result from different technical and medical follow-up [19186102] BACKGROUND Obstructive sleep apnea ( OSA ) affects approximately 20 % of US adults , of whom about 90 % are undiagnosed . While OSA may increase risk of perioperative complications , its prevalence among surgical patients is unknown . We tested the feasibility of screening surgical patients for OSA and determined the prevalence of undiagnosed OSA . METHODS In a prospect i ve , observational study adult surgical patients were screened for OSA in an academic hospital . Patients without an OSA diagnosis who screened high-risk were offered a home sleep study to determine if they had OSA . The results were compared with polysomnography ( PSG ) when available . Charts of high-risk patients were examined for postoperative complications . High-risk patients received targeted interventions as part of a hospital safety initiative . RESULTS There were 2877 patients screened ; 661 ( 23.7 % ) screened high-risk for OSA , of whom 534 ( 81 % ) did not have diagnosed OSA . The portable sleep study detected OSA in 170/207 ( 82 % ) high-risk patients without diagnosed OSA . Twenty-six PSGs confirmed OSA in 19 of these patients . Postoperatively there were no respiratory arrests , two unanticipated ICU admissions , and five documented respiratory complications . CONCLUSION Undiagnosed OSA is prevalent in adult surgical patients . Implementing universal screening is feasible and can identify undiagnosed OSA in many surgical patients . Further investigation is needed into perioperative complications and their prevention for patients with undiagnosed OSA [17157557] BACKGROUND AND PURPOSE Compliance with continuous positive airway pressure ( CPAP ) treatment in obstructive sleep apnoea syndrome ( OSAS ) may be difficult . Patient education is important but strategies and their outcomes are not clear . PATIENTS AND METHODS We studied the effects of four education strategies on compliance and quality of life changes with CPAP treatment in seven centres in the French ANTADIR homecare network . Patients received from prescribers either a simple oral explanation ( SP ) or an oral and written explanation ( RP ) of CPAP use . In addition , they received from homecare technicians either a single home visit ( SH ) at CPAP onset or repeated home visits at CPAP onset and at 1 week , 1 month and 3 months after ( RH ) . Compliance and quality of life were evaluated at CPAP onset , and at 3 , 6 and 12 months after initiation of treatment . RESULTS One hundred twelve patients with severe OSAS ( mean age 58+/-11 year , apnoea-hypopnoea index 58+/-25/h ) were allocated r and omly to groups ( SP+SH ; SP+RH ; RP+SH ; RP+RH ) with no initial differences . Quality of life , evaluated by the generic SF-36 question naire , improved in the combined emotional domains . Compliance was over 5h in all four education groups . These effects were sustained over 12 months and were not different between the four groups . We conclude that st and ard education strategies for CPAP induction in France are sufficient for good compliance and improved quality of life with CPAP . Education with reinforced input should be focussed on identified subgroups prone to problems [11311685] Objective : To eluci date the predictive role of age and other pre-treatment , putative confounding factors on compliance with nasal continuous positive airway pressure ( nCPAP ) therapy . Patients and methods : This study was design ed as a prospect i ve cohort study in the setting of a sleep laboratory in a teaching hospital at Saint Antoine , Paris . One hundred and sixty-three patients referred to the sleep laboratory with complaints of snoring and excessive daytime sleepiness for whom nCPAP had been prescribed for obstructive sleep apnea syndrome ( OSAS ; defined as an apnea-hypopnea index ( AHI ) of > 15/h of sleep during a polysomnographic recording ) were followed for a median period of 887 days . The main outcome measure was the risk ratio for elderly patients associated with nCPAP compliance . Results : Four patients , who remained under treatment , died before the end of the study , and 50 patients stopped their nCPAP therapy for reasons other than death ( insomnia , equipment too noisy , etc . ) . When compliance curves were compared by univariate analysis ( log-rank test ) , the oldest group ( 57/163 patients , > 60 years old ) was significantly less compliant with nCPAP than the youngest ( P=0.01 ) . However , in the Cox 's proportional hazards model , age did not exert any independent effect on compliance with nCPAP after controlling for confounding factors ( adjusted relative risk , 1.09 , 0.5 - 2 ; P=0.70 ) . On the other h and , female sex ( adjusted relative risk , 2.8 , 1.4 - 5.4 ; P=0.002 ) , a body mass index ( BMI ) of < /=30 kg/m(2 ) ( adjusted relative risk , 2.2 , 1.2 - 4 ; P=0.006 ) , an Epworth sleepiness scale ( ESS ) score of < /=15 ( adjusted relative risk , 3.2 , 1.1 - 8.9 ; P=0.025 ) , an AHI of < /=30/h ( adjusted relative risk , 2.2 , 1.2 - 4 ; P=0.01 ) and a nCPAP of > /=12 cmH(2)O ( adjusted relative risk , 2.3 , 1.2 - 4.4 ; P=0.011 ) were predictive factors for non-compliance . Conclusion : This study suggests that there is no independent effect of age on compliance with nCPAP therapy [23598607] BACKGROUND OSA is extremely common among patients with resistant hypertension ( HTN ) . However , the impact of the treatment of OSA with CPAP on BP in patients with resistant HTN is not well established . METHODS In the current study , 40 patients with confirmed resistant HTN and moderate to severe OSA confirmed by full polysomnography were r and omized to medical therapy or to medical treatment plus CPAP for 6 months . Patients were evaluated at study baseline and after 6 months by 24-h ambulatory BP monitoring ( ABPM ) . RESULTS Thirty-five patients ( 77 % men ; age , 56 ± 1 years ; BMI , median 32 kg/m² [ 25%-75 % , 28 - 39 kg/m² ] ; apnea-hypopnea index , 29 events/h [ 24 - 48 events/h ] ; Epworth Sleepiness Scale , 10 ± 1 ; systolic/diastolic office BP , 162 ± 4/97 ± 2 mm Hg ; taking four [ four to five ] antihypertensive drugs ) completed the study . CPAP was used for 6:01 ± 0:20 h/night ( 3:42 - 7:44 h/night ) . Compared with the control group , awake systolic/diastolic ABPM decreased significantly in the CPAP group ( Δ : + 3.1 ± 3.3 /+2.1 ± 2.7 mm Hg vs -6.5 ± 3.3/-4.5 ± 1.9 mm Hg , respectively , P < .05 ) . Interestingly , the BP changes were observed only while patients were awake , but not during nocturnal ABPM ( Δ : + 2.8 ± 4.5/+1.8 ± 3.5 mm Hg vs + 1.6 ± 3.5/+0.8 ± 2.9 mm Hg , P = NS ) . CONCLUSIONS The treatment of OSA with CPAP significantly reduces daytime BP in patients with resistant HTN . Therefore , our study reinforces the importance of recognizing and treating OSA in patients with resistant HTN . TRIAL REGISTRY Clinical Trials.gov ; No. : NCT00812695 ; URL : www . clinical trials.gov [1874716] Background Obstructive sleep apnea ( OSA ) is a prevalent and serious medical condition characterized by repeated complete or partial obstructions of the upper airway during sleep and is prevalent in 2 % to 4 % of working middle-aged adults . Nasal continuous positive airway pressure ( CPAP ) is the gold-st and ard treatment for OSA . Because compliance rates with CPAP therapy are disappointingly low , effective interventions are needed to improve CPAP compliance among patients diagnosed with OSA . Objective The aim was to determine whether wireless telemonitoring of CPAP compliance and efficacy data , compared to usual clinical care , results in higher CPAP compliance and improved OSA outcomes . Methods 45 patients newly diagnosed with OSA were r and omized to either telemonitored clinical care or usual clinical care and were followed for their first 2 months of treatment with CPAP therapy . CPAP therapists were not blinded to the participants ’ treatment group . Results 20 participants in each group received the design ated intervention . Patients r and omized to telemonitored clinical care used CPAP an average of 4.1 ± 1.8 hours per night , while the usual clinical care patients averaged 2.8 ± 2.2 hours per night ( P = .07 ) . Telemonitored patients used CPAP on 78 % ± 22 % of the possible nights , while usual care patients used CPAP on 60 % ± 32 % of the nights ( P = .07 ) . No statistically significant differences between the groups were found on measures of CPAP efficacy , including measures of mask leak and the Apnea-Hypopnea Index . Patients in the telemonitored group rated their likelihood to continue using CPAP significantly higher than the patients in the usual care group . Patients in both groups were highly satisfied with the care they received and rated themselves as “ not concerned ” that their CPAP data were being wirelessly monitored . Conclusions Telemonitoring of CPAP compliance and efficacy data and rapid use of those data by the clinical sleep team to guide the collaborative ( ie , patient and provider ) management of CPAP treatment is as effective as usual care in improving compliance rates and outcomes in new CPAP users . This study was design ed as a pilot — larger , well-powered studies are necessary to fully evaluate the clinical and economic efficacy of telemonitoring for this population [10805822] BACKGROUND Sleep-disordered breathing is prevalent in the general population and has been linked to chronically elevated blood pressure in cross-sectional epidemiologic studies . We performed a prospect i ve , population -based study of the association between objective ly measured sleep-disordered breathing and hypertension ( defined as a laboratory-measured blood pressure of at least 140/90 mm Hg or the use of antihypertensive medications ) . METHODS We analyzed data on sleep-disordered breathing , blood pressure , habitus , and health history at base line and after four years of follow-up in 709 participants of the Wisconsin Sleep Cohort Study ( and after eight years of follow-up in the case of 184 of these participants ) . Participants were assessed overnight by 18-channel polysomnography for sleep-disordered breathing , as defined by the apnea-hypopnea index ( the number of episodes of apnea and hypopnea per hour of sleep ) . The odds ratios for the presence of hypertension at the four-year follow-up study according to the apnea-hypopnea index at base line were estimated after adjustment for base-line hypertension status , body-mass index , neck and waist circumference , age , sex , and weekly use of alcohol and cigarettes . RESULTS Relative to the reference category of an apnea-hypopnea index of 0 events per hour at base line , the odds ratios for the presence of hypertension at follow-up were 1.42 ( 95 percent confidence interval , 1.13 to 1.78 ) with an apnea-hypopnea index of 0.1 to 4.9 events per hour at base line as compared with none , 2.03 ( 95 percent confidence interval , 1.29 to 3.17 ) with an apnea-hypopnea index of 5.0 to 14.9 events per hour , and 2.89 ( 95 percent confidence interval , 1.46 to 5.64 ) with an apnea-hypopnea index of 15.0 or more events per hour . CONCLUSIONS We found a dose-response association between sleep-disordered breathing at base line and the presence of hypertension four years later that was independent of known confounding factors . The findings suggest that sleep-disordered breathing is likely to be a risk factor for hypertension and consequent cardiovascular morbidity in the general population [11734445] The evidence linking sleep-disordered breathing to increased mortality and cardiovascular morbidity has been conflicting and inconclusive . We hypothesized that a potential adverse effect of disordered breathing would be more obvious in patients with established vascular disease . In a prospect i ve cohort study 408 patients aged 70 yr or younger with verified coronary disease were followed for a median period of 5.1 yr . An apnea-hypopnea index ( AHI ) of > or = 10 and an oxygen desaturation index ( ODI ) of > or = 5 were used as the diagnostic criteria for sleep-disordered breathing . The primary end point was a composite of death , cerebrovascular events , and myocardial infa rct ion . There was a 70 % relative increase and a 10.7 % absolute increase in the primary composite end point in patients with disordered breathing defined as an ODI of > or = 5 ( risk ratio 1.70 , 95 % confidence interval [ CI ] 1.15 - 2.52 , p = 0.008 ) . Similarly , patients with an AHI of > or = 10 had a 62 % relative increase and a 10.1 % absolute increase in the composite endpoint ( risk ratio 1.62 , 95 % CI 1.09 - 2.41 , p = 0.017 ) . An ODI of > or = 5 and an AHI of > or = 10 were both independently associated with cerebrovascular events ( hazard ratio 2.62 , 95 % CI 1.26 - 5.46 , p = 0.01 , and hazard ratio 2.98 , 95 % CI 1.43 - 6.20 , p = 0.004 , respectively ) . We conclude that sleep-disordered breathing in patients with coronary artery disease is associated with a worse long-term prognosis and has an independent association with cerebrovascular events [19406983] RATIONALE Obstructive sleep apnea ( OSA ) is an independent risk factor for stroke , but little is known about the role of continuous positive airway pressure ( CPAP ) on mortality in patients with stroke . OBJECTIVES To analyze the independent impact of long-term CPAP treatment on mortality in patients with ischemic stroke . METHODS Prospect i ve observational study in 166 patients with ischemic stroke . Sleep study was performed in all of them and CPAP treatment was offered in the case of moderate to severe cases . Patients were followed-up for 5 years to analyze the risk of mortality . MEASUREMENTS AND MAIN RESULTS Of 223 patients consecutively admitted for stroke , a sleep study was performed on 166 of them ( 2 mo after the acute event ) . Thirty-one had an apnea-hypopnea index ( AHI ) of less than 10 ; 39 had an AHI between 10 and 19 , and 96 had an AHI of 20 or greater . CPAP treatment was offered when AHI was 20 or greater . Patients were followed up in our outpatient clinic at 1 , 3 , and 6 months , and for every 6 months thereafter for 5 years ( prospect i ve observational study ) . Mortality data were recorded from our computer data base and official death certificates . The mean age of subjects was 73.3 + /- 11 years ( 59 % males ) , and the mean AHI was 26 ( for all patients with a predominance of obstructive events ) . Patients with an AHI of 20 or greater who did not tolerate CPAP ( n = 68 ) showed an increase adjusted risk of mortality ( hazards ratio [ HR ] , 2.69 ; 95 % confidence interval [ CI ] , 1.32 - 5.61 ) compared with patients with an AHI of less than 20 ( n = 70 ) , and an increased adjusted risk of mortality ( HR , 1.58 ; 95 % CI , 1.01 - 2.49 ; P = 0.04 ) compared with patients with moderate to severe OSA who tolerated CPAP ( n = 28 ) . There were no differences in mortality among patients without OSA , patients with mild disease , and patients who tolerated CPAP . CONCLUSIONS Our results suggest that long-term CPAP treatment in moderate to severe OSA and ischemic stroke is associated with a reduction in excess risk of mortality [15716221] BACKGROUND CPAP remains the treatment of choice for Obstructive Sleep Apnea Hypopnea Syndrome ( OSAHS ) , but compliance with CPAP is poor . Of many interventions tried to improve CPAP compliance , only education and humidification have been shown to be of benefit . Our purpose was to develop and pilot test a video to enhance patient underst and ing of obstructive sleep apnea and of the purpose , logistics , and benefits of CPAP use in patients newly diagnosed with OSAHS . A patient 's CPAP compliance in the first few weeks after starting its use is predictive of long-term compliance with CPAP treatment . It is imperative that patients grasp at the outset both the severity of OSAHS and the effectiveness of CPAP therapy . METHODS An educational video script was written based on recommendations for patient educational video material s and covering identified misconceptions about OSAHS and perceived barriers to CPAP use . The videotape is 15 min in length and features two middle-aged males , one African-American and one Euro-American , discussing OSAHS and CPAP in a factory break room . RESULTS In a r and omized two-group design with a control group , patients with newly diagnosed OSAHS , and who viewed the CPAP educational video on their first clinic , were significantly more likely to use their machine and to return for a 1-month clinic visit than were those in the control group . CONCLUSION Viewing of a patient education video at the initial visit was found to significantly improve the rate of return for the follow-up visit [24810282] BACKGROUND Poor adherence to CPAP treatment in OSA adversely affects the effectiveness of this therapy . This r and omized controlled trial ( RCT ) examined the efficacy of a brief motivational enhancement education program in improving adherence to CPAP treatment in subjects with OSA . METHODS Subjects with newly diagnosed OSA were recruited into this RCT . The control group received usual advice on the importance of CPAP therapy and its care . The intervention group received usual care plus a brief motivational enhancement education program directed at enhancing the subjects ' knowledge , motivation , and self-efficacy to use CPAP through the use of a 25-min video , a 20-min patient-centered interview , and a 10-min telephone follow-up . Self-reported daytime sleepiness adherence-related cognitions and quality of life were assessed at 1 month and 3 months . CPAP usage data were downloaded at the completion of this 3-month study . RESULTS One hundred subjects with OSA ( mean ± SD , age 52 ± 10 years ; Epworth Sleepiness Scales [ ESS ] , 9 ± 5 ; median [ interquartile range ] apnea-hypopnea index , 29 [ 20 , 53 ] events/h ) prescribed CPAP treatment were recruited . The intervention group had better CPAP use ( higher daily CPAP usage by 2 h/d [ Cohen d = 1.33 , P < .001 ] , a fourfold increase in the number using CPAP for ≥ 70 % of days with ≥ 4 h/d [ P < .001 ] ) , and greater improvements in daytime sleepiness ( ESS ) by 2.2 units ( P = .001 ) and treatment self-efficacy by 0.2 units ( P = .012 ) compared with the control group . CONCLUSIONS Subjects with OSA who received motivational enhancement education in addition to usual care were more likely to show better adherence to CPAP treatment , with greater improvements in treatment self-efficacy and daytime sleepiness . TRIAL REGISTRY Clinical Trials.gov ; No. : NCT01173406 ; URL : www . clinical trials.gov [23179140] Purpose Auto-titrating continuous positive airway pressure ( APAP ) is an effective treatment for obstructive sleep apnea/hypopnea syndrome ( OSAHS ) . We investigated whether a single group education session on APAP therapy is effective in promoting adherence among patients with OSAHS . Methods This prospect i ve , r and omized , controlled , parallel group study included patients newly diagnosed with OSAHS who met criteria for APAP therapy . Patients were r and omized into a study group and a control group . All patients in the study group were assigned to a single group education session , 1 month after beginning APAP therapy . Results We evaluated 146 patients . The median percentage of APAP usage days was 88.3 % , with a median duration per day of use of 6.02 h ; 59 % were classified as adherent . Overall , no significant difference in adherence was seen between the study and the control groups . Analyzing patient subgroups , the group session significantly improved APAP adherence among males and patients who were younger ( < 65 years old ) , obese ( BMI ≥35 kg/m2 ) , non-sleepy ( Epworth sleepiness scale ≤11 ) , smokers or past smokers , had hypertension or nocturia and those with non-severe OSAHS . Conclusion To maximize the impact of group education sessions and , by that , saving re sources , it may be important to select patients likely to benefit from these sessions [21886365] BACKGROUND New approaches are needed to treat patients with stroke . Among acute ischemic stroke patients , our primary objectives were to describe the prevalence of sleep apnea and demonstrate the feasibility of providing auto-titrating continuous positive airway pressure ( auto-CPAP ) . A secondary objective was to examine the effect of auto-CPAP on stroke severity . METHODS Stroke patients r and omized to the intervention group received 2 nights of auto-CPAP , but only those with evidence of sleep apnea received auto-CPAP for the remainder of the 30-day period . Intervention patients received polysomnography 30 days post-stroke . Control patients received polysomnography at baseline and after 30 days . Acceptable auto-CPAP adherence was defined as ≥ 4 h/night for ≥ 75 % nights . Change in stroke severity was assessed comparing the NIH Stroke Scale ( NIHSS ) at baseline versus at 30 days . RESULTS The 2 groups ( intervention N = 31 , control N = 24 ) had similar baseline stroke severity ( both median NIHSS , 3.0 ) . Among patients with complete polysomnography data , the majority had sleep apnea : baseline , 13/15 ( 86.7 % ) control patients ; 30 days , 24/35 ( 68.6 % ) control and intervention patients . Intervention patients had greater improvements in NIHSS ( -3.0 ) than control patients ( -1.0 ) ; P = 0.03 . Among patients with sleep apnea , greater improvement was observed with increasing auto-CPAP use : -1.0 for control patients not using auto-CPAP ; -2.5 for intervention patients with some auto-CPAP use ; and -3.0 for intervention patients with acceptable auto-CPAP adherence . CONCLUSIONS The majority of acute stroke patients had sleep apnea . Auto-CPAP was well tolerated , appears to improve neurological recovery from stroke , and may represent a new therapeutic approach for selected patients with acute cerebral infa rct ion [10679542] BACKGROUND Obstructive sleep apnoea ( OSA ) impairs vigilance and may lead to an increased rate of driving accidents . In uncontrolled studies accident rates and simulated steering performance improve following treatment with nasal continuous positive airway pressure ( NCPAP ) . This study seeks to confirm the improvement in steering performance in a r and omised controlled trial using subtherapeutic NCPAP as a control treatment . METHODS Fifty nine men with OSA ( Epworth Sleepiness Score ( ESS ) of > or = 10 , and > or = 10/h dips in SaO(2 ) of > 4 % due to OSA ) received therapeutic or subtherapeutic NCPAP ( approximately 1 cm H(2)O ) for one month . Simulated steering performance over three 30-minute " drives " was quantified as : st and ard deviation ( SD ) of road position , deterioration in SD across the drive , length of drive before " crashing " , and number of off-road events . The reaction times to peripheral target stimuli during the drive were also measured . RESULTS Subtherapeutic NCPAP did not improve overnight > 4 % SaO(2 ) dips/h compared with baseline values , thus acting as a control . The SD of the steering position improved from 0.36 to 0.21 on therapeutic NCPAP , and from 0.35 to 0.30 on subtherapeutic NCPAP ( p = 0.03 ) . Deterioration in SD of the steering position improved from 0.18 to 0.06 SD/h with therapeutic NCPAP and worsened from 0.18 to 0.24 with subtherapeutic NCPAP ( p = 0.04 ) . The reaction time to target stimuli was quicker after therapeutic than after subtherapeutic NCPAP ( 2.3 versus 2.7 seconds , p = 0.04 ) . CONCLUSIONS Therapeutic NCPAP improves steering performance and reaction time to target stimuli in patients with OSA , lending further support to the hypothesis that OSA impairs driving , increases driving accident rates , and that these improve following treatment with NCPAP [14658968] BACKGROUND Results of clinical studies suggest that there may be a relationship between breathing-related sleep disorders and depressive disorders . This study aims to assess the impact of breathing-related sleep disorder on major depressive disorder in the general population . METHOD A cross-sectional telephone survey was carried out between 1994 and 1999 in the general population of the United Kingdom , Germany , Italy , Portugal , and Spain . A total of 18,980 r and omly selected subjects aged 15 to 100 years and representative of the general population of their respective countries participated in the study . The question naire included a series of questions about sleep quality , breathing-related sleep disorder symptoms , mental disorders , and medical conditions . Data are presented using point prevalence . RESULTS 2.1 % of the subjects were found with obstructive sleep apnea syndrome at the time of the interview , and 2.5 % had some other type of DSM-IV breathing-related sleep disorder diagnosis . The association of DSM-IV breathing-related sleep disorder diagnosis and major depressive disorder diagnosis was found in 0.8 % of the sample . As many as 18 % of individuals with a major depressive disorder diagnosis also have a DSM-IV breathing-related sleep disorders diagnosis , and 17.6 % of subjects with a DSM-IV breathing-related sleep disorders diagnosis have a major depressive disorder diagnosis . Multivariate models showed that even after controlling for obesity and hypertension , the odds of having a DSM-IV breathing-related sleep disorders diagnosis was 5.26 for individuals with a major depressive disorder diagnosis . CONCLUSION About 800 of 100,000 individuals have both a breathing-related sleep disorder and a major depressive disorder . The identification of 1 of these 2 disorders should prompt the investigation of the other disorder since nearly a fifth of them have the other disorder [21804670] STUDY OBJECTIVES ( 1 ) To determine the efficacy of automatically adjusted positive airway pressure ( APAP ) with a comfort feature ( A-Flex ) at reducing apneas and hypopneas in participants with moderate to severe OSA . ( 2 ) To determine the relative difference between A-Flex , continuous positive airway pressure ( CPAP ) , and APAP-derived optimal pressure for CPAP ( CPAP(APAP ) ) on adherence to treatment . ( 3 ) To determine the relative difference between APAP with A-Flex , CPAP , and CPAP(APAP ) on long-term change in functional outcomes . DESIGN R and omized , double-blinded , 3-arm , multicenter trial . SETTING University and Veterans Affairs medical centers . PATIENTS OR PARTICIPANTS 168 participants were r and omized , and 140 completed the 180-day study . INTERVENTIONS ( 1 ) A-Flex ; ( 2 ) CPAP ; ( 3 ) APAP for 14 days and then switched to CPAP at a fixed pressure . MEASUREMENTS AND RESULTS Apnea-hypopnea indices , average and minimum oxygen saturation , time spent < 90 % were significantly poorer for A-Flex vs. CPAP at the initiation of study treatment ; with the exception of minimum oxygen saturation , these differences were absent at 180 days . A-Flex had lower average leak values at both 3 and 6 months . There were no significant differences between groups in major efficacy , adherence , and outcome ( subjective sleepiness , objective vigilance , blood pressure , quality of life ) measures . No differences between groups in attitudes toward use were observed at 3 or 6 months ; participant ratings for CPAP were significantly higher than A-Flex on treatment satisfaction and benefit , but not different for sleep quality and mask comfort . CONCLUSIONS We found that A-Flex shows equivalency , but non-superiority ( except for average leak values ) , in efficacy , adherence , and functional outcomes compared to CPAP after either 3 or 6 months . CLINICAL TRIAL REGISTRY Positive Pressure Treatment of Obstructive Sleep Apnea , http://www . clinical trials.gov , NCT00636181 [25364081] STUDY OBJECTIVES Obstructive sleep apnea ( OSA ) has been associated with hypertension , which is one of the intermediary mechanisms leading to increased cardiovascular morbidity . This study aim ed at evaluating the effects of a combination of continuous positive airway pressure ( CPAP ) and telemedicine support on blood pressure ( BP ) reduction in high cardiovascular risk OSA patients . DESIGN A multi-center r and omized controlled trial that compared st and ard CPAP care and CPAP care and a telemedicine intervention . SETTING Sleep clinics in France . PATIENTS OR PARTICIPANTS 107 adult ( 18 - 65 years old ) OSA patients ( AHI > 15 events/h ) with a high cardiovascular risk ( cardiovascular SCORE > 5 % or secondary prevention ) . INTERVENTIONS Patients were r and omized to either st and ard care CPAP ( n = 53 ) or CPAP and telemedicine ( n = 54 ) . Patients assigned to telemedicine were equipped with a smartphone for uploading BP measurements , CPAP adherence , sleepiness , and quality of life data ; in return , they received pictograms containing health-related messages . MEASUREMENTS The main outcome was home self-measured BP and secondary outcomes were cardiovascular risk evolution , objective physical activity , CPAP adherence , sleepiness and quality of life . RESULTS Self-measured BP did not improve in either group ( telemedicine or st and ard care ) . Patients in primary prevention showed greater BP reduction with CPAP treatment than those in secondary prevention . CONCLUSIONS CPAP treatment supported by telemedicine alone did not improve blood pressure and cardiovascular risk in high cardiovascular risk OSA patients . This study emphasizes the need for diet and physical activity training programs in addition to CPAP when aim ing at decreasing cardiometabolic risk factors in these patients . CLINICAL TRIALS REGISTRATION Clinical Trials.gov identifier : NCT01226641 [2024846] Previous reports have described compliance with nasal continuous positive airway pressure ( nCPAP ) for the treatment of obstructive sleep apnea ( OSA ) only in terms of the number of patients able to use it beyond their initial trial night or those continuing after some home use . Because of a possible difference between the level of compliance ( mean number of hours of use per 24 h ) needed for symptomatic relief of OSA versus cardiovascular improvement , the level of hourly compliance in chronic nCPAP users may be important . The first part of this study prospect ively examines compliance in a stable population of OSA patients already using nCPAP for 6 months to 2 yr . The second part is a prospect i ve r and omized , crossover study examining the effect of weekly ( three times ) then monthly ( twice ) positive reinforcement on hourly compliance of new nCPAP users for 3 months versus no reinforcement for 3 months . Positive reinforcement consisted of telephone discussion s with the patients about the severity or complications of OSA , benefits of nCPAP , and suggestions about minimizing side effects . Using self- assessment scales , each patient reported the perceived level of improvement from the untreated to the treated condition and the prevalence and severity of side effects from the nCPAP therapy . The level of compliance in stable , chronic nCPAP users with OSA was 6.1 + /- 2.2 h/24 h ( n = 9 ) . For the new nCPAP users during the nonreinforced period , the mean compliance was 6.0 + /- 2.8 h/24 h ; that during the reinforcement period was 6.0 + /- 2.7 h/24 h ( NS ) . There was no significant correlation between perceived improvement in OSA symptoms or between the perceived side effects of nCPAP versus hourly compliance . ( ABSTRACT TRUNCATED AT 250 WORDS [14592213] BACKGROUND Obstructive sleep apnea is a prevalent condition with potentially serious medical and psychosocial consequences . Nasal continuous positive airway pressure ( CPAP ) is the treatment-of-choice and has been shown to reduce the frequency of nocturnal respiratory events , improve sleep architecture and decrease daytime sleepiness . Patient compliance with CPAP is disappointingly low . Previous studies examining determinants of CPAP compliance have limited the variables studied to patient ( sociodemographic ) , disease status , and treatment variables , with few reliable determinants found . METHODS The purpose of the current study was to investigate the relationship between objective ly measured CPAP compliance and variables from social cognitive theory ( SCT ) and the transtheoretical model ( TM ) . Scales that measure variables from each model were developed and reliability evaluated . The relationship between the SCT and TM variables and compliance at 1-month post-CPAP-fitting was prospect ively evaluated on 51 first-time CPAP users . SCT and TM variables were measured on the day of CPAP-fitting , at 1-week post-CPAP-fitting , and at 1-month post-CPAP-fitting . RESULTS SCT variables measured 1-week post-CPAP-fitting ( R(2)=0.261 , P=0.001 ) and TM variables measured 1-week post-CPAP-fitting ( R(2)=0.17 , P=0.002 ) accounted for a statistically significant amount of variance in objective CPAP compliance measured at 1 month . The decisional balance index ( from TM ) individually accounted for a significant amount of variance in objective CPAP compliance in the above analyses . CONCLUSIONS The ability of these new behavior change scales to predict CPAP compliance provides us with a new direction of research to better underst and factors associated with compliance . The principal advantage of these theory-driven and empirically vali date d scales are that they measure modifiable factors that can provide the basis for sound interventions to improve CPAP compliance [15033131] BACKGROUND AND PURPOSE To evaluate ( a ) whether an active weight reduction strategy based on the cognitive-behavioral approach and an initial very-low-calorie diet might lead to short- and long-term weight loss and alleviation of OSAS ; and ( b ) whether the results of this intervention could be enhanced by combining it with nasal continuous positive airway pressure ( CPAP ) treatment during the first 6 months . PATIENTS AND METHODS Thirty-one obese male symptomatic sleep apnea patients underwent a 2-year weight reduction program with total follow-up of 36 months from baseline . The mean age ( + /-SD ) was 49.1+/-7.9 years , body mass index 43.8+/-5.4 , and oxygen desaturation index ( ODI4 ) 51.3+/-31.1 . The patients were r and omized to CPAP ( 17 patients ) and non-CPAP groups ( 14 patients ) . RESULTS The mean weight loss was 19.1+/-10.2 kg ( 14 % of the original weight ) for the whole group at 6 months , 18.3+/-13.2 ( 13 % ) at 12 months and 12.6+/-14.7 kg ( 9 % ) at 24 months . Excellent or good treatment results , as defined in terms of an ODI4 ( average number of oxygen desaturation events p/h>4 % from baseline ) reduction of at least 50 % from the baseline , were seen in 61 % of patients at 6 months and were still observable in 42 % of patients at 24 months . The correlations between changes in weight and in ODI4 were 0.59 ( P<0.01 ) at 6 months , 0.68 ( P<0.01 ) and 0.75 ( P<0.01 ) at 24 months . Adding CPAP treatment to the weight reduction therapy for the first 6 months did not result in greater weight loss or diminution of desaturation indices ( without CPAP ) at any time point . One year after the termination of the program the mean weight loss was 6.6+/-12.9 kg , and 42 % of patients still showed at least 5 % weight loss as compared with their original weight . CONCLUSION Satisfactory weight loss associated with improvement of OSAS could be achieved by means of a cognitive-behavioral weight loss program . Adding CPAP in the initial phase of the weight reduction program did not result in significantly greater weight loss [22983957] RATIONALE Obstructive sleep apnea ( OSA ) is a risk factor for cardiovascular death in middle-aged subjects , but it is not known whether it is also a risk factor in the elderly . OBJECTIVES To investigate whether OSA is a risk factor for cardiovascular death and to assess whether continuous positive airway pressure ( CPAP ) treatment is associated with a change in risk in the elderly . METHODS Prospect i ve , observational study of a consecutive cohort of elderly patients ( ≥65 yr ) studied for suspicion of OSA between 1998 and 2007 . Patients with an apnea-hypopnea index ( AHI ) less than 15 were the control group . OSA was defined as mild to moderate ( AHI , 15 - 29 ) or severe ( AHI , ≥30 ) . Patients with OSA were classified as CPAP-treated ( adherence ≥ 4 h/d ) or untreated ( adherence < 4 h/d or not prescribed ) . Participants were monitored until December 2009 . The end point was cardiovascular death . A multivariate Cox survival analysis was used to determine the independent impact of OSA and CPAP treatment on cardiovascular mortality . MEASUREMENTS AND MAIN RESULTS A total of 939 elderly were studied ( median follow-up , 69 mo ) . Compared with the control group , the fully adjusted hazard ratios for cardiovascular mortality were 2.25 ( confidence interval [ CI ] , 1.41 to 3.61 ) for the untreated severe OSA group , 0.93 ( CI , 0.46 to 1.89 ) for the CPAP-treated group , and 1.38 ( CI , 0.73 to 2.64 ) for the untreated mild to moderate OSA group . CONCLUSIONS Severe OSA not treated with CPAP is associated with cardiovascular death in the elderly , and adequate CPAP treatment may reduce this risk [17552379] STUDY OBJECTIVE To improve adherence to continuous positive airway pressure ( CPAP ) treatment in participants with obstructive sleep apnea ( OSA ) using a cognitive behavioral therapy ( CBT ) intervention . DESIGN A r and omized controlled trial . SETTING A major teaching hospital in Sydney ( 2005 ) . PARTICIPANTS One hundred individuals ( 96 men ) , ranging in age from 32 to 81 years , diagnosed with OSA . INTERVENTION Two 1-hour CBT interventions ( including a video of real CPAP users ) plus treatment as usual ( mask fitting and information ) or treatment as usual only . MEASUREMENTS AND RESULTS Hours of CPAP usage was assessed at 7 nights and 28 nights . Adherence was defined as usage at least 4 hours per night . Question naires measuring self-efficacy , social support , and expectancy ( mediators of adherence ) were given after intervention or after usual treatment . A higher adherence to CPAP therapy was found in the CBT group ( 2.9 hours difference ) relative to treatment as usual ( P < 0.001 ) at 28 days . Only 4 participants in the CBT group did not initiate treatments after their titration study , compared with 15 in the treatment as usual group ( P < 0.02 ) . The CBT group had significantly higher scores for self-efficacy ( P < 0.001 ) and social support P < 0.008 ) but not for expectancy . CONCLUSIONS The CBT intervention result ed in both increased adherence and " uptake " of CPAP and therefore would be expected to reduce the social , economic , and health-related consequences of untreated OSA [21828324] CONTEXT Sleep-disordered breathing ( characterized by recurrent arousals from sleep and intermittent hypoxemia ) is common among older adults . Cross-sectional studies have linked sleep-disordered breathing to poor cognition ; however , it remains unclear whether sleep-disordered breathing precedes cognitive impairment in older adults . OBJECTIVES To determine the prospect i ve relationship between sleep-disordered breathing and cognitive impairment and to investigate potential mechanisms of this association . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve sleep and cognition study of 298 women without dementia ( mean [ SD ] age : 82.3 [ 3.2 ] years ) who had overnight polysomnography measured between January 2002 and April 2004 in a sub study of the Study of Osteoporotic Fractures . Sleep-disordered breathing was defined as an apnea-hypopnea index of 15 or more events per hour of sleep . Multivariate logistic regression was used to determine the independent association of sleep-disordered breathing with risk of mild cognitive impairment or dementia , adjusting for age , race , body mass index , education level , smoking status , presence of diabetes , presence of hypertension , medication use ( antidepressants , benzodiazepines , or nonbenzodiazepine anxiolytics ) , and baseline cognitive scores . Measures of hypoxia , sleep fragmentation , and sleep duration were investigated as underlying mechanisms for this relationship . MAIN OUTCOME MEASURES Adjudicated cognitive status ( normal , dementia , or mild cognitive impairment ) based on data collected between November 2006 and September 2008 . RESULTS Compared with the 193 women without sleep-disordered breathing , the 105 women ( 35.2 % ) with sleep-disordered breathing were more likely to develop mild cognitive impairment or dementia ( 31.1 % [ n = 60 ] vs 44.8 % [ n = 47 ] ; adjusted odds ratio [ AOR ] , 1.85 ; 95 % confidence interval [ CI ] , 1.11 - 3.08 ) . Elevated oxygen desaturation index ( ≥15 events/hour ) and high percentage of sleep time ( > 7 % ) in apnea or hypopnea ( both measures of disordered breathing ) were associated with risk of developing mild cognitive impairment or dementia ( AOR , 1.71 [ 95 % CI , 1.04 - 2.83 ] and AOR , 2.04 [ 95 % CI , 1.10 - 3.78 ] , respectively ) . Measures of sleep fragmentation ( arousal index and wake after sleep onset ) or sleep duration ( total sleep time ) were not associated with risk of cognitive impairment . CONCLUSION Among older women , those with sleep-disordered breathing compared with those without sleep-disordered breathing had an increased risk of developing cognitive impairment [26065720] BACKGROUND Despite the increasing aging population and the high prevalence of OSA in elderly adults , little is known about cognitive effects of OSA and the effectiveness of CPAP treatment . Therefore , this study investigated whether elderly patients with OSA present cognitive deficits and functional and structural alterations of the brain that could be improved by CPAP treatment . METHODS This r and omized , evaluator-blinded , parallel-group , single-center pilot study involved patients aged ≥ 65 years with newly-diagnosed severe OSA syndrome . Thirty-three patients were assigned to receive either conservative care ( CC ) or CPAP plus CC for 3 months . At baseline and 3 months after treatment , patients underwent a neuropsychologic evaluation and a functional and structural MRI study of connectivity within the default mode network ( DMN ) and of cortical thickness . RESULTS Neuropsychologic evaluation revealed no differences in cognitive performance between OSA groups at baseline . By contrast , after CPAP treatment , patients showed a significant improvement in episodic ( between-group difference in change , 7.60 ; 95 % CI , 1.66 - 13.55 ; P = .014 ) and short-term memory ( between-group difference in change , 1.06 ; 95 % CI , 0.10 - 2.01 ; P = .032 ) and in executive function ( speed of mental processing , 5.74 ; 95 % CI , 1.69 - 9.79 ; P = .007 ; mental flexibility , -47.64 ; 95 % CI , -81.83 to -13.45 ; P = .008 ) , whereas no changes were observed in the CC group . Neuroimaging revealed an increase in the connectivity in the right middle frontal gyrus after 3 months of CPAP treatment and a higher percentage of cortical thinning in the CC group . No association was seen between cognition and brain functional connectivity changes within the DMN . CONCLUSIONS Elderly patients with severe OSA who present with cognitive difficulties could benefit from CPAP treatment . Moreover , CPAP treatment increases the connectivity of the DMN and attenuates cortical thinning . TRIAL REGISTRY Clinical Trials.gov ; No. : NCT01826032 ; URL : www . clinical trials.gov [22467985] STUDY OBJECTIVES First-line therapy for patients with moderate to severe obstructive sleep apnea ( OSA ) is positive airway pressure ( PAP ) . Although PAP is a highly efficacious treatment , adherence to PAP is still a substantial clinical problem . The objective of this study was to determine whether PAP adherence can be improved with a telemedicine monitoring system . DESIGN A nonblinded , single-center , r and omized controlled trial that compared st and ard PAP treatment versus PAP treatment and a telemedicine monitoring system SETTING University sleep disorders program in British Columbia , Canada PATIENTS Adult patients ( ≥ 19 yr of age ) with moderate to severe OSA ( apnea hypopnea index ( AHI ) ≥ 15 events/hr determined by polysomnography ) prescribed PAP INTERVENTIONS : Patients were r and omized to either st and ard care with an autotitrating PAP machine or an autotitrating PAP machine that transmitted physiologic information ( i.e. , adherence , air leak , residual AHI ) daily to a website that could be review ed . If problems were identified from information from the website , the patient was contacted by telephone as necessary . MEASUREMENTS PAP adherence after 3 mo , subjective sleep quality , and side effects RESULTS Seventy-five patients were enrolled ; 39 were r and omized to telemedicine and 36 to st and ard care . The mean age ± st and ard deviation ( SD ) was 53.5 ± 11.2 yr , mean AHI was 41.6 ± 22.1 events/hr , and 80 % of patients were male . After 3 mo , mean PAP adherence was significantly greater in the telemedicine arm ( 191 min per day ) versus the st and ard arm ( 105 min per day ; mean difference = 87 min , 95 % confidence interval ( CI ) : 25 - 148 min , P = 0.006 , unpaired t test ) . On days when PAP was used , mean adherence was 321 min in the telemedicine arm and 207 min in the st and ard arm ( difference = 113 min , 95 % CI : 62 - 164 min , P < 0.0001 ) . Significant independent predictors of adherence included age , baseline Epworth Sleepiness Scale score , and use of telemedicine . On average , an additional 67 min of technician time was spent on patients in the telemedicine arm compared with the st and ard arm ( P = 0.0001 ) . CONCLUSIONS PAP adherence can be improved with the use of a web-based telemedicine system at the initiation of treatment [19136368] RATIONALE Obstructive sleep apnea ( OSA ) is a prevalent disease . Often limited clinical re sources result in long patient waiting lists . Simpler vali date d methods of care are needed . OBJECTIVES To demonstrate that a nurse-led model of care can produce health outcomes in symptomatic moderate-severe OSA not inferior to physician-led care . METHODS A r and omized controlled multicenter noninferiority clinical trial was performed . Of 1,427 potentially eligible patients at 3 centers , 882 consented to the trial . Of these , 263 were excluded on the basis of clinical criteria . Of the remaining 619 , 195 met home oximetry criteria for high-probability moderate-severe OSA and were r and omized to 2 models of care : model A , the simplified model , using home autoadjusting positive airway pressure to set therapeutic continuous positive airway pressure ( CPAP ) , with all care supervised by an experienced nurse ; and model B , involving two laboratory polysomnograms to diagnose and treat OSA , with clinical care supervised by a sleep physician . The primary end point was change in Epworth Sleepiness Scale ( ESS ) score after 3 months of CPAP . Other outcome measures were collected . MEASUREMENTS AND MAIN RESULTS For the primary outcome change in ESS score , nurse-led management was no worse than physician-led management ( 4.02 vs. 4.15 ; difference , -0.13 ; 95 % confidence interval : -1.52 , 1.25 ) given a prespecified noninferiority margin of -2 for the lower 95 % confidence interval . There were also no differences between both groups in CPAP adherence at 3 months or other outcome measures . Within-trial costs were significantly less in model A. CONCLUSIONS A simplified nurse-led model of care has demonstrated noninferior results to physician-directed care in the management of symptomatic moderate-severe OSA , while being less costly . Clinical trial registered with http://www.anzctr.org.au ( ACTRN012605000064606 )

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### Context: [24179297] OBJECTIVE To examine whether a social cognitive therapy ( SCT ) intervention increases continuous positive airway pressure ( CPAP ) use compared to equivalent social interaction ( SI ) time . PARTICIPANTS Individuals with obstructive sleep apnea ( OSA ) referred for CPAP therapy . INTERVENTION Participants received a 30-min group education session regarding OSA and CPAP . Groups of three to four participants were then r and omly assigned to an SCT session or social interaction . MEASUREMENTS CPAP usage was assessed at 7 nights , then 1 , 3 , and 6 months . The two primary outcomes were adherence , usage ≥ 4 h per night at 6 months , and uptake of CPAP . Question naires were given pretreatment and posttreatment . RESULTS Two hundred six individuals were r and omized to SI ( n = 97 ) or SCT ( n = 109 ) . CPAP uptake was not different between groups ( 82 % in SI , 88 % in SCT groups , P = 0.35 ) . There were no differences between groups in adherence : 63 - 66 % at 1 week , and at 6 months 55 - 47 % ( P = 0.36 ) . Higher pretreatment apnea-hypopnea index , higher baseline self-efficacy , and use of CPAP ( ≥ 4 h ) at 1 week were independent predictors of CPAP adherence at 6 months . CPAP adherence increased by a factor of 1.8 ( odds ratio = 1.8 , 95 % confidence interval 1.1 - 3.0 ) for every one-unit increase in self-efficacy . There was no difference between groups postintervention in self-efficacy scores , sleepiness , mood , or sleep quality . CONCLUSIONS In this r and omized trial , a single SCT application did not increase adherence when compared with SI time . Although self-efficacy scores prior to CPAP predicted adherence , self-efficacy was not increased by the interventions . Increasing intensity and underst and ing of SCT interventions may be needed to improve CPAP adherence . CLINICAL TRIALS REGISTRATION Australian New Zeal and Clinical Trials Registry , ACTRN12607000424404 [10807830] OBJECTIVES To study the effects of augmentation of continuous positive airway pressure ( CPAP ) education and support on compliance and outcome in patients with obstructive sleep apnea ( OSA ) . DESIGN A r and omized , controlled , parallel study of basic vs augmented CPAP education and support . SETTING A university teaching hospital . PATIENTS A total of 108 OSA patients r and omized into basic-support ( BS ) and augmented-support ( AS ) groups . INTERVENTIONS Patients in the BS group ( n = 54 ) were given educational brochures on OSA and CPAP , CPAP education by nurses , CPAP acclimatization , and were review ed by physicians and nurses at weeks 4 and 12 . Patients in the AS group ( n = 54 ) received more education , including a videotape , telephone support by nurses , and early review at weeks 1 and 2 . MEASUREMENTS Objective CPAP compliance , Calgary sleep apnea quality of life index ( SAQLI ) , and cognitive function after 1 month and 3 months ; and Epworth sleepiness scale ( ESS ) after 3 months of CPAP treatment . RESULTS At 4 weeks , CPAP usage was 5.3 + /- 0.2 h/night ( mean + /- SEM ) vs 5.5 + /- 0.2 h/night in the BS and AS groups , respectively ( p = 0.4 ) . At 12 weeks , CPAP usage was 5.3 + /- 0.3 h/night vs 5.3 + /- 0.2 h/night in the two groups , respectively ( p = 0.98 ) . There was greater improvement of SAQLI at 4 weeks ( p = 0.008 ) and at 12 weeks ( p = 0.047 ) in the AS group . There was no significant difference between BS and AS groups in terms of improvement of ESS and cognitive function . CONCLUSION Augmentation of CPAP education and support does not increase CPAP compliance , but leads to a greater improvement of quality of life during the reinforced period [25766689] Objective To evaluate whether follow-up of patients with obstructive sleep apnoea ( OSA ) undergoing CPAP treatment could be performed in primary care ( PC ) setting s. Design Non-inferiority , r and omised , prospect i ve controlled study . Setting s Sleep unit ( SU ) at the University Hospital and in 8 PC units in Lleida , Spain . Participants Patients with OSA were r and omised to be followed up at the SU or PC units over a 6-month period . Main outcomes measured The primary outcome was CPAP compliance at 6 months . The secondary outcomes were Epworth Sleep Scale ( ESS ) score , EuroQoL , patient satisfaction , body mass index ( BMI ) , blood pressure and cost-effectiveness . Results We included 101 patients in PC ( ( mean±SD ) apnoea – hypopnoea index ( AHI ) 50.8±22.9/h , age 56.2±11 years , 74 % male ) and 109 in the SU ( AHI 51.4±24.4/h , age 55.8±11 years , 77 % male ) ) . The CPAP compliance was ( mean ( 95 % CI ) 4.94 ( 4.47 to 5.5 ) vs 5.23 ( 4.79 to 5.66 ) h , p=0.18 ) in PC and SU groups , respectively . In the SU group , there were greater improvements in ESS scores ( mean change 1.79 , 95 % CI + 0.05 to + 3.53 , p=0.04 ) and patient satisfaction ( −1.49 , 95 % CI −2.22 to −0.76 ) ; there was a significant mean difference in BMI between the groups ( 0.57 , 95 % CI + 0.01 to + 1.13 , p=0.04 ) . In the PC setting , there was a cost saving of 60 % , with similar effectiveness , as well as a decrease in systolic blood pressure ( −5.32 ; 95 % CI −10.91 to + 0.28 , p=0.06 ) . Conclusions For patients with OSA , treatment provided in a PC setting did not result in worse CPAP compliance compared with a specialist model and was shown to be a cost-effective alternative . Trial registration number Clinical Trials NCT01918449 [23332533] OBJECTIVE Weight loss can decrease the severity of obstructive sleep apnea ( OSA ) in many obese individuals ; however , very few studies have investigated the effects of behavioral weight loss interventions for patients with OSA . The aims of this pilot study were to determine the feasibility and initial effects on weight and continuous positive airway pressure ( CPAP ) use of a brief minimal-contact self-monitoring-based weight loss intervention ( SM ) . An additional aim was to investigate the association between weight loss and CPAP adherence . METHODS Forty obese men and women diagnosed with mild or moderate OSA were r and omized to either the SM or an attention-control ( AC ) condition . SM participants completed daily dietary logs for 6 weeks . Participants were weighed at baseline , post-treatment ( 6 weeks ) , and at a 6-week follow up . RESULTS Recruitment and retention were good in this study and attrition rates did not differ significantly by group . Intent to treat repeated measures ANOVA indicated a main effect of time ( but not group ) , such that both groups lost weight over time . Pearson r correlations between weight change and CPAP adherence indicated that among SM participants , 6-week weight loss was correlated with CPAP adherence at post-treatment and follow-up , such that SM participants with greater weight loss at 6 weeks had greater CPAP adherence at 6 and 12 weeks . CONCLUSION This study provides initial support for the beneficial effects of a minimal-contact weight loss intervention for patients with obstructive sleep apnea and highlights a possible association between weight loss and CPAP adherence [4570038] Background Continuous Positive Airway Pressure ( CPAP ) remains the reference treatment for moderate to severe forms of the Sleep Apnea/Hypopnea Syndrome ( SAHS ) . Compliance to the treatment appears to be a key factor to improving health status of these patients . Methods We conducted a multicenter , prospect i ve , r and omized , controlled , parallel group trial of st and ard support completed or not within 3 months of coaching sessions for newly diagnosed SAHS patients starting CPAP therapy . This study has been recorded by AFSSAPS with the RCB number : 2009-A01127 - 50 and received favourably by the Human Studies Committee in France . The coaching session consisted of 5 sessions of telephone-based counselling by competent staff . The primary outcome was the proportion of patients using CPAP more than 3 h per night for 4 months ; the secondary outcome was mean hours of CPAP usage in the 2 groups . Results Three hundred and seventy-nine patients fulfilled the inclusion criteria and were r and omized . The percentage of patients using CPAP more than 3 h per night for 4 months was 65 % for the st and ard support group and 75 % for the coached group . This difference reached a statistical significance ( χ2 = 3.97 ) . The mean CPAP usage was increased in the coached group versus st and ard group . A difference of 26 min was observed ( 4 h34+/−2 h17 and 4 h08+/−2 h25 respectively , p = 0.04 ) . Conclusion This study shows that SAHS patients who benefit from phone coaching are statistically more compliant to CPAP than a st and ard support group is . A simple phone coaching procedure based on knowledge of the disease and reinforcement messages about treatment benefits helps to improve CPAP adherence in SAHS patients .Trial registration [14998250] STUDY OBJECTIVES To identify factors before a trial of nasal continuous positive airway pressure ( CPAP ) treatment that are associated with lower compliance . DESIGN A prospect i ve cohort study . Initial Hospital Anxiety and Depression Scale scores and other demographic data were noted . Machine use was recorded by clock timer after a 1-month trial of treatment . SETTING District General Hospital sleep-disordered breathing clinic . PATIENTS OR PARTICIPANTS Eighty consecutive patients with symptoms of sleep apnea-hypopnea syndrome and a 4 % Sao2 desaturation index greater than 10 events per hour . INTERVENTIONS N/A. MEASUREMENTS AND RESULTS Those reporting ' initial problems ' with CPAP went on to have an average of 2.4 hours of on time per night , while those not reporting initial problems had an on time of 5.0 hours per night ( P < .001 ) . Those living alone had a machine on time of 3.2 hours compared with 4.5 hours for those with partners ( P = .04 ) . Pearson 's correlations between hours on time were -0.08 ( P = .48 ) for initial Anxiety score and 0.10 ( P = .37 ) for initial Depression score . CONCLUSIONS There was no association between baseline anxiety and depression scores , as measured by the Hospital Anxiety and Depression Scale , and subsequent machine use . Other factors observable prior to commencing treatment , in particular , ' initial problems ' ( reported at autotitration ) , ' recent life-events ' and ' living alone ' were associated with lower machine use . Regarding all initial variables , reporting problems after the first night of nCPAP seems the most important predictor of ensuing machine use . A single screening question immediately after autotitration is useful in identifying those at high risk of treatment failure [19920270] Context Approaches that improve adherence to continuous positive airway pressure ( CPAP ) therapy are needed . Contribution In this trial , 160 adults with severe obstructive sleep apnea were r and omly assigned to eszopiclone or placebo for the first 14 nights of CPAP . Adherence to CPAP was then measured weekly for 24 weeks . Patients receiving eszopiclone were less likely to discontinue CPAP and used CPAP more nights and for longer periods per night than did patients receiving placebo . Implication Eszopiclone given during the first 2 weeks of therapy may help improve long-term adherence and use of CPAP in some patients with severe obstructive sleep apnea . The Editors Untreated obstructive sleep apnea ( OSA ) is associated with adverse effects on both health and quality of life ( 1 , 2 ) . Continuous positive airway pressure ( CPAP ) is recommended as first-line therapy for most patients to improve sleep quality , reduce daytime sleepiness , and enhance quality of life . It may also mitigate the increased risk for cardiovascular events ( 36 ) . However , adherence to CPAP is often poor , which limits its efficacy . Of patients who initiate CPAP , approximately 50 % discontinue use within the first year , most within the first month . The initial experience with CPAP influences who accepts and continues treatment ( 7 ) . Patients who experience initial discomfort , intolerance , or lack of perceived benefit are more likely to discontinue therapy ( 8) . Some studies suggest that psychosocial factors may also affect short- and intermediate-term adherence ( 9 , 10 ) . The only consistently reliable predictor of long-term adherence has been the use of CPAP during the initial treatment period ( 11 ) . The average nightly CPAP use during the first 3 months of therapy can predict use at 6 and 12 months ( 12 ) . Furthermore , long-term adherence patterns may be determined within the first few days of therapy ( 13 ) . Therefore , strategies aim ed at improving adherence with therapy should focus on the initial experience with CPAP . In theory , robust patient education , regular follow-up , and improvements in device comfort ( for example , autoadjustable units with heated humidifiers and better- design ed , better-fitted masks ) should increase CPAP tolerance and use . However , intensive support and technological interventions have not consistently or reliably predicted which patients will successfully transition to CPAP ( 1418 ) . Nonbenzodiazepine sedative-hypnotic agents promote sleep onset and continuity without altering sleep architecture . They can safely be used in patients with OSA , especially those already using CPAP ( 19 ) . We hypothesized that a short course of the nonbenzodiazepine sedative-hypnotic eszopiclone during the first 2 weeks of treatment would improve patients ' initial tolerability and use of CPAP and subsequently increase long-term adherence . Methods Study Design Overview We conducted a parallel- design , r and omized , placebo-controlled trial to assess the effects of eszopiclone on CPAP adherence among patients with newly diagnosed OSA who were initiating CPAP . Patients received eszopiclone , 3 mg , or matching placebo every night for the initial 14 nights of CPAP and were followed serially for 24 weeks ( Figures 1 and 2 ) . Patient enrollment began in March 2007 , and final data were collected by December 2008 . Our study is part of the CPAP ASAP ( CPAP Promotion and PrognosisThe Army Sleep Apnea Program ) Trial , which will examine several outcomes related to OSA . Figure 1 . Study flow diagram . CPAP = continuous positive airway pressure . Figure 2 . Study design overview . CPAP = continuous positive airway pressure . Walter Reed Army Medical Center 's Department of Clinical Investigation ( Scientific Review Committee , Human Use Committee , and Institutional Review Board ) , as well as the United States Army Center for Investigational Research Organization , approved our protocol . We obtained informed consent from all study participants . Setting s and Participants We recruited all patients from a single academic sleep medicine center . Our center is part of Walter Reed Army Medical Center , which is a quaternary-care facility providing care to a wide range of patient demographic groups , including active-duty service members , their dependents , and retirees . Consecutive patients between 18 and 64 years of age , with newly diagnosed OSA , and not previously receiving CPAP therapy were approached for enrollment . Obstructive sleep apnea was diagnosed on the basis of an attended , overnight level I polysomnography in all patients . All polysomnograms were interpreted by the study investigators and authors . We established the diagnosis and defined the severity of OSA in accordance with American Academy of Sleep Medicine criteria by using the apneahypopnea index ( 20 ) . We excluded patients with long-term use of hypnotic medications , those who consumed more than 2 alcoholic beverages per night , and those who had hepatic dysfunction or an underlying psychiatric condition that would preclude completion of the study . We also excluded pregnant women . R and omization and Interventions We r and omly assigned patients to receive eszopiclone , 3 mg ( n= 80 ) , or matching placebo ( n= 80 ) . The Walter Reed Army Medical Center 's investigational pharmacy central ly administered and distributed study medications to the patients at the time of enrollment . The referring physician , investigators , and patients were blinded to the r and omization order and treatment group assignment ( eszopiclone or placebo ) . R and omization was implemented by using a computerized program ( R and omization.com , seed 3565 ) and was performed by using 16 fixed blocks ( 10 patients per block ) without stratification by patient criteria or polysomnogram results . The pharmacy maintained r and omization and blinding until after the final data were collected . All persons initiating CPAP at our institution participate in a comprehensive educational program to familiarize them with OSA , its effects , and the available treatment options . Patients undergo formal mask-fitting and receive telephone follow-up after 2 weeks to ensure proper fit . A clinical evaluation is conducted after 1 month of therapy to measure CPAP use and assess clinical response to therapy . Additional follow-up is provided as needed . Nonpharmacologic interventions , including changes in pressures , assessment of leaks , mask changes , or adjustments to and education on proper sleep hygiene and stimulus control , are individualized to promote better CPAP tolerance and adherence . All patients enrolled in this study were also assessed after 3 and 6 months of therapy . Otherwise , study participants were not treated differently from other patients receiving care at our center . After the initial 4 weeks of enrollment , open-label sedatives could be prescribed at the discretion of the physician seeing the patient during follow-up . It is common practice for providers in our clinic to offer a sedative-hypnotic agent to patients who are having difficulties using the CPAP machine despite nonpharmacologic interventions . All enrolled patients received the same model of CPAP ( RemStar Pro M Series with C-Flex and integrated heated humidifiers , Phillips Respironics , Murrysville , Pennsylvania ) . We prescribed CPAP devices for long-term use . We did not use any autoadjustable positive airway pressure devices . Outcomes and Measurements For each participant , we recorded demographic data , information regarding OSA severity , degree of symptoms , and objective measures of CPAP use . The primary outcome measured was CPAP adherence at 24 weeks . Specifically , we computed the percentage of nights used , the mean hours per night for total study nights , and the mean hours per night that CPAP was used during each week of the 24-week study . We also compared the rate of regular use of CPAP between groups , defined as more than 4 hours per night on more than 70 % of nights ( 21 ) . We obtained objective measures of CPAP use from a downloadable smart card adherence-monitoring device ( Encore Pro smart card , Phillips Respironics ) . These cards , which are integrated into the CPAP units , record all use of the devicespecifically , the date , time , and duration that CPAP is used . These cards also record data on mask leaks and residual airflow limitations , data that are useful to troubleshoot barriers to therapeutic adherence . We collected all measured variables at the time of enrollment ( baseline ) and again at 1 , 3 , and 6 months after initiating CPAP . In addition , we collected smart cards at 1 , 3 , and 6 months and recorded and analyzed the downloaded data for each night in 1-week blocks . Secondary outcomes were the rate of CPAP discontinuation and the use of open-label sedative-hypnotic agents between the 2 groups . Because our primary aim was to promote better CPAP adherence , we allowed the open-label use of sedative-hypnotic agents after the first 4 weeks of treatment . These were prescribed at the discretion of the ordering physician and only when nonpharmacologic interventions were unsuccessful . All such prescriptions were monitored and recorded by using a closed electronic medical records system . In addition , we compared the change in Epworth Sleepiness Scale ( ESS ) score , fatigue , and Functional Outcomes of Sleep Question naire score between baseline and the end of the study to determine whether a greater use of CPAP was associated with improvements in symptoms and quality of life . We assessed degree of somnolence by using the ESS and visual analogue fatigue scale ( 22 ) . The ESS score ranges from 0 to 24 . Higher scores indicate greater daytime somnolence , and scores less than 10 are considered normal . We assessed sleep-related quality -of-life scores by using the Functional Outcomes of Sleep Question naire ( 23 ) . The score ranges from 5 to 20 . Higher scores , particularly those greater than 17.9 , suggest improved quality of life . We collected additional data related to mood and depression , libido and erectile dysfunction , and quality of life that will be [15258478] Background : Continuous positive airway pressure ( CPAP ) is an effective therapy for obstructive sleep apnea syndrome ( OSAS ) , although many patients have difficulty adhering to this therapy . The purpose of this study was to investigate the effectiveness of totally automated telephone technology in improving adherence to prescribed CPAP therapy . Research Design : This pilot study was a r and omized clinical trial in 30 patients being started on CPAP therapy for OSAS . Patients were r and omly assigned to use of a computer telephone system design ed to improve CPAP adherence ( telephone-linked communications for CPAP [ TLC-CPAP ] ) in addition to usual care ( n = 15 ) or to usual care alone ( n = 15 ) for a period of 2 months . TLC-CPAP is a computer-based system that monitors patients ’ self-reported behavior and provides education and reinforcement through a structured dialogue . Measures : A sleep symptoms checklist and the Functional Outcomes of Sleep Question naire were administered at study entry and at 2-month follow up . Hours of CPAP use at effective mask pressure were measured by the CPAP device , stored in its memory , and retrieved at the 2-month visit . Results : At 2 months , patients r and omized to TLC-CPAP had fewer reported sleep-related symptoms ( 9.4 vs. 13.4 , P = 0.047 ) than those receiving usual care . The average nightly CPAP use in the TLC-CPAP group was 4.4 hours compared with 2.9 hours ( P = 0.076 ) in the usual-care group . Conclusions : This pilot study suggests that patients with OSAS started on CPAP and a concurrently administered automated education and counseling system had better CPAP adherence and better control of OSAS symptoms [4664526] Background Continuous positive airway pressure ( CPAP ) is widely recommended for the treatment of sleep apnea/hypopnea syndrome ( SAHS ) , but its usage by patients is very low . The aim of this study was to assess intensive educational programs and nursing support for the improvement of CPAP use and outcomes in SAHS patients . Methods Eighty new SAHS patients were r and omized to receive nurse-led intensive interventions or usual support at hospital and home . The main outcome measure was CPAP use ; changes in sleeping , symptoms , mood , and quality of life were also assessed after 12 months of treatment . Results All outcome measures were improved after treatment in both groups . However , patients receiving intensive support with significantly higher CPAP use ( higher daily CPAP usage by 2.2 hours/day ) had greater improvements in SAHS symptoms and mood ( P<0.05 ) . The intervention group further showed an improvement in the Short Form-36 domains of mental and physical health ( P<0.05 ) . Conclusion The CPAP usage and quality of life can be significantly improved by nurse-led intensive program in obstructive sleep apnea patients [15358707] The present study objective was to establish whether pretreatment social cognitive variables may contribute to the explanation of variance in adherence to continuous positive airway pressure ( CPAP ) treatment for patients with obstructive sleep apnoea/hypopnoea syndrome ( OSAHS ) . A total of 119 of 180 consecutive OSAHS patients were recruited to the study prior to initial CPAP titration . Patients completed psychological measures of health value , health locus of control ( incorporating internality , chance , powerful others ) and self-efficacy prior to CPAP titration . Objective adherence data were measured by CPAP unit time clocks and collected at 3-month follow-up . Average nightly use was calculated over this period . Logistic regression of prospect i ve predictors of adherence produced a model comprising psychological ( health value , internality , powerful others ) , as well as clinical variables ( Epworth score , body mass index , apnoea/hypopnoea index , CPAP pressure ) . This model explained 24 % of the variance in CPAP use , and correctly identified 75 % of adherers and 53 % of nonadherers . Although the psychological variables explained only a small amount of the overall variance in adherence behaviour , this result provides further support for the hypothesis that psychological variables contribute , in part , to continuous positive airway pressure adherence . Future research should focus on highlighting discrete variables , which may helpfully inform psychologically based interventions aim ed at improving the use of continuous positive airway pressure by patients with obstructive sleep apnoea/hypopnoea syndrome at risk of discontinuance [11868136] The present study examined the efficacy of a cognitive-behavioral intervention at improving compliance with CPAP and vigilance in older adults with obstructive sleep apnea/hypopnea syndrome ( OSAHS ) . Participants included 12 subjects who were r and omized into one of two groups controlling for age , education , disease severity , and vigilance . The experimental group received two 45-min sessions design ed to educate subjects on the consequences of OSAHS and the efficacy of CPAP . The control group received the same extent of therapist contact but did not receive information on OSAHS or CPAP . All subjects were administered a test of vigilance both before and after the study . Compliance data were collected using CPAP devices with internal microprocessors at were read at 1 , 4 , and 12 weeks after treatment initiation . The results showed that the experimental condition did not enhance compliance after 1 week of treatment but did so by the 12-week follow-up . Subjects in the experimental condition had a run time of 3.2-h per night longer than did those in the control group . Those using CPAP more regularly at 12 weeks also showed greater improvement on vigilance at follow-up . Performance on vigilance testing before the introduction of CPAP was predictive of CPAP use at 12 weeks . In conclusion , a modest cognitive-behavioral intervention may substantially increase CPAP use and vigilance in older adults [24673616] RATIONALE It is unknown whether obstructive sleep apnea ( OSA ) may be a risk factor for incident cardiovascular events in women . OBJECTIVES We sought to investigate whether OSA increases the incidence of a composite of stroke or coronary heart disease ( CHD ) in women , and the role of continuous positive airway pressure ( CPAP ) treatment on this association . METHODS This was a prospect i ve , observational study conducted in two Spanish teaching hospitals between 1998 and 2007 . Consecutive women referred for suspected OSA and free of previous stroke and CHD were analyzed . Women with an apnea-hypopnea index ( AHI ) less than 10 comprised the control group , and those with an AHI greater than or equal to 10 were diagnosed with OSA and classified as CPAP-treated ( adherence ≥ 4 h/d ) or untreated ( adherence < 4 h/d or not prescribed ) . The follow-up ended in December 2010 . MEASUREMENTS AND MAIN RESULTS A total of 967 women were studied ( median follow-up , 6.8 yr ; interquartile range , 5.2 - 8.2 ) . The untreated OSA group showed a greater incidence rate of the composite outcome than the control group ( 2.19 vs. 0.54 per 100 person-years ; P < 0.0005 ) . Compared with the control group , the fully adjusted hazard ratios for the composite outcome incidence were 2.76 ( 95 % confidence interval [ CI ] , 1.35 - 5.62 ) for the untreated OSA group , and 0.91 ( 95 % CI , 0.43 - 1.95 ) for the CPAP-treated group . When the type of cardiovascular event was separately assessed , untreated OSA showed a stronger association with incident stroke ( adjusted hazard ratio , 6.44 ; 95 % CI , 1.46 - 28.3 ) than with CHD ( adjusted hazard ratio , 1.77 ; 95 % CI , 0.76 - 4.09 ) . CONCLUSIONS In women , untreated OSA is associated with increased incidence of serious cardiovascular outcomes , particularly incident stroke . Adequate CPAP treatment seems to reduce this risk [22962427] CONTEXT Few prospect i ve intervention studies have examined the effect of continuous positive airway pressure ( CPAP ) therapy on cardiovascular disease ( CVD ) risk factors in diabetes . OBJECTIVE Our objective was to determine whether CPAP improves CVD risk factors in patients with type 2 diabetes and obstructive sleep apnea ( OSA ) . DESIGN AND SETTING This was a r and omized parallel group intervention trial in an urban Australian community . PATIENTS Fifty-nine participants of the Fremantle Diabetes Study Phase II at high risk for OSA consented to confirmatory polysomnography followed by r and omization to a 3-month CPAP intervention initiated early ( < 1 wk ) or late ( 1 - 2 months ) . MAIN OUTCOME MEASURES Patients were assessed before and 1 and 3 months after CPAP started . Tests for repeated measures were used to compare variables of interest over time . RESULTS Forty-four patients ( 75 % ) completed the study . Their mean ± sd age was 66.1 ± 8.8 yr , and 61.4 % were male . Completers and noncompleters had similar age , sex , diabetes duration , apnea-hypopnea index , and Epworth Sleepiness Scale ( P ≥ 0.29 ) . There were no differences in outcome between early and late r and omization , and the data were pooled . The Epworth Sleepiness Scale decreased between entry and 1 month [ -4.8 ( -6.5 to -3.1 ) , P < 0.001 ] . Blood pressure improved between entry and 3 months ( from 149 ± 23/80 ± 12 to 140 ± 18/73 ± 13 mm Hg ; P ≤ 0.007 ) . Pulse rate declined within the first month [ -6 ( -10 to -2 ) beats/min , P = 0.002 ] . Glycemic control and serum lipids , which were mostly within recommended target ranges at entry , did not change . CONCLUSIONS Three months of CPAP in community-based people with type 2 diabetes significantly decreased blood pressure and pulse rate but did not influence metabolic control [16564210] BACKGROUND AND PURPOSE Interventions to improve treatment outcomes in sleep apnoea-hypopnoea syndrome ( SAHS ) have had mixed success . Most have concentrated on following the use of a continuous positive airway pressure ( CPAP ) machines ; poorer users may not return for machine readings , so any compliance study must take into account rates of attendance rates . We hypothesised that a series of additional , early support measures would improve re-attendance over a sustained period . PATIENTS AND METHODS Prospect i ve , single-blinded interventional study . Seventy-two consecutive patients starting CPAP for SAHS were r and omised to receive st and ard follow-up or extra early support . Attendance rates , CPAP use , Epworth scores , side-effects scores and number of changes to equipment were compared , by intent to treat , in both groups at 1 and 12 months . RESULTS Re-attendance rates were higher in the intervention group at 1 month ( P=0.04 ) , 6 months ( P=0.07 ) and 12 months ( P=0.12 ) . Those who defaulted tended previously to be poor users of the CPAP machine . For those who re-attended there was no difference in machine use or other outcomes . CONCLUSIONS Simple interventions while commencing CPAP improve re-attendance with maximal benefit early on . This could provide more opportunities for solving problems early or considering alternative treatments . By confirming that poorer CPAP users eventually have higher default rates we recommend that future studies on CPAP compliance should first account for re-attendance rates [12505557] INTRODUCTION Apnea is a common disorder in older adults and has been shown to affect cognition . Some studies suggest that treatment for apnea improves certain cognitive deficits , but few studies have examined the relationship between compliance and cognitive improvement . We design ed a study to answer the following questions about sleep apnea , cognition and treatment in older adults : ( 1 ) Which neuropsychological ( NP ) variables are differentially associated with measures of sleep fragmentation and oxygen desaturation ? ( 2 ) Does compliant use of CPAP provide a cognitive advantage over noncompliant use ? ( 3 ) Does NP performance at baseline predict compliance at 3 months ? METHOD Twelve participants were recruited for the study . All had polysomnographically defined sleep apnea with an RDI of 10 or greater . All were also at least 55 years of age , had no other diagnosable sleep disorder and had no previous treatment for sleep apnea syndrome ( SAS ) . Participants were administered a full NP battery before and 3 months after treatment with CPAP . RDI at baseline was associated with delayed verbal recall , while oxygen desaturation was associated with both delayed recall and constructional abilities . Compliant use of CPAP at 3 months was associated with greater improvements in attention , psychomotor speed , executive functioning and nonverbal delayed recall . Finally , attention measures predicted compliance at 3 months suggesting that those who were least vigilant at baseline were more likely to comply with treatment . DISCUSSION Results are discussed in terms of the relevance to targeting special population s for compliance interventions , the ways that treatment may specifically affect older adults and the possible dose-response relationship of CPAP [22618923] CONTEXT Continuous positive airway pressure ( CPAP ) is the first-line treatment for patients with symptomatic obstructive sleep apnea ( OSA ) . However , its indication for all patients with sleep-disordered breathing , regardless of daytime symptoms , is unclear . OBJECTIVE To evaluate the effect of CPAP treatment on the incidence of hypertension or cardiovascular events in a cohort of nonsleepy patients with OSA . DESIGN , SETTING , AND PATIENTS Multicenter , parallel-group , r and omized controlled trial in 14 teaching hospitals in Spain . Between May 2004 and May 2006 , 725 consecutive patients were enrolled who had an apnea-hypopnea index of 20 h(-1 ) or greater and an Epworth Sleepiness Scale score of 10 or less ( scores range from 0 - 24 , with values < 10 suggesting no daytime sleepiness ) . Exclusion criteria were previous cardiovascular event , physical or psychological incapacity , chronic disease , or drug or alcohol addiction . Follow-up ended in May 2009 . INTERVENTION Patients were allocated to receive CPAP treatment or no active intervention . All participants received dietary counseling and sleep hygiene advice . MAIN OUTCOME MEASURES Incidence of either systemic hypertension ( taking antihypertensive medication or blood pressure greater than 140/90 mm Hg ) or cardiovascular event ( nonfatal myocardial infa rct ion , nonfatal stroke , transient ischemic attack , hospitalization for unstable angina or arrhythmia , heart failure , or cardiovascular death ) . RESULTS Seven hundred twenty-three patients underwent follow-up for a median of 4 ( interquartile range , 2.7 - 4.4 ) years ( 1 patient from each group did not receive allocated treatment ) ; 357 in the CPAP group and 366 in the control group were included in the analysis . In the CPAP group there were 68 patients with new hypertension and 28 cardiovascular events ( 17 unstable angina or arrhythmia , 3 nonfatal stroke , 3 heart failure , 2 nonfatal myocardial infa rct ion , 2 transient ischemic attack , 1 cardiovascular death ) . In the control group there were 79 patients with new hypertension and 31 cardiovascular events ( 11 unstable angina or arrhythmia , 8 nonfatal myocardial infa rct ion , 5 transient ischemic attack , 5 heart failure , 2 nonfatal stroke ) . The hypertension or cardiovascular event incidence density rate was 9.20 per 100 person-years ( 95 % CI , 7.36 - 11.04 ) in the CPAP group and 11.02 per 100 person-years ( 95 % CI , 8.96 - 13.08 ) in the control group . The incidence density ratio was 0.83 ( 95 % CI , 0.63 - 1.1 ; P = .20 ) . CONCLUSIONS In patients with OSA without daytime sleepiness , the prescription of CPAP compared with usual care did not result in a statistically significant reduction in the incidence of hypertension or cardiovascular events . However , the study may have had limited power to detect a significant difference . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00127348 [11834653] STUDY OBJECTIVES To determine long-term compliance rates to continuous positive airway pressure ( CPAP ) therapy in patients with obstructive sleep apnea enrolled in a comprehensive CPAP program in the community . DESIGN Prospect i ve cohort longitudinal study . SETTING University sleep disorders center . PATIENTS Two hundred ninety-six patients with an apnea-hypopnea index ( AHI ) > or = 20/h on polysomnography . INTERVENTIONS A CPAP device equipped with a monitoring chip was supplied . Within the first week , daily telephone contacts were made . Patients were seen at 2 weeks , 4 weeks , 3 months , and 6 months . RESULTS Of the 296 subjects enrolled , 81.1 % were males . Mean + /- SD AHI was 64.4 + /- 34.2/h of sleep ; age , 51 + /- 11.7 years ; and body mass index , 35.2 + /- 7.9 kg/m(2 ) . The mean duration of CPAP use was 5.7 h/d at 2 weeks , 5.7 h/d at 4 weeks , 5.9 h/d at 3 months , and 5.8 h/d at 6 months . The percentage of patients using CPAP > or = 3.5 h/d was 89.0 % at 2 weeks , 86.6 % at 4 weeks , 88.6 % at 3 months , and 88.5 % at 6 months . There was a decrease in the Epworth Sleepiness Scale ( ESS ) score of 44 % by 2 weeks of therapy . The patients continue to improve over the follow-up period , with the lowest mean ESS score observed at 6 months . With multiple regression analysis , three variables were found to be significantly correlated with increased CPAP use : female gender , increasing age , and reduction in ESS score . CONCLUSION A population -based CPAP program consisting of consistent follow-up , " troubleshooting , " and regular feedback to both patients and physicians can achieve CPAP compliance rates of > 85 % over 6 months [26253747] Obstructive sleep apnoea syndrome ( OSAS ) is characterised by repetitive collapse of the upper airway during sleep . Continuous positive airway pressure ( CPAP ) applied via a mask is the st and ard treatment for OSAS . CPAP adherence is crucial in therapy to prevent the deleterious consequences of OSAS . We hypothesised that a combination of supervision by telemetry together with targeted telephone support in the first month of CPAP would increase CPAP adherence and treatment success . A total of 113 OSAS patients followed by telemetry-triggered interventions used the device for 5.3 h/night on 28/30 nights , significantly more than the 110 OSAS patients in the control group with 4.6 h/night and 27/30 nights . Telemetry-triggered interventions have a significant impact on adherence rate in early CPAP treatment . These results can be reached with an acceptable additional effort [21965126] Purpose The purpose of this study is to explore the effects of patient education and progressive muscle relaxation ( PMR ) alone or combined on adherence to continuous positive airway pressure ( CPAP ) treatment in obstructive sleep apnea ( OSA ) patients . Methods One hundred and fifty-two Han Chinese OSA patients were r and omly assigned to a control group ( C ) , an education group ( E ) , a PMR group ( P ) , and an education + PMR group ( E + P ) , with 38 patients each group . The adherence to CPAP was defined as 4 or more hours of CPAP usage per night and at least 9 of each 14 nights of ventilator use . The CPAP adherence rates , cumulative patient dropout rates , CPAP usage , and scores of daytime sleepiness , sleep quality , anxiety , and depression were compared among the groups at 4 , 8 , and 12 weeks of intervention . Results All study groups were comparable in baseline characteristics . Group E + P showed significant improvement in CPAP adherence , daytime sleepiness , and sleep quality compared with group C at 4 , 8 , and 12 weeks of intervention . Compared with group C , group E only showed significant improvement in CPAP adherence , daytime sleepiness , and sleep quality at 4 weeks of intervention , while group P showed no significant improvement over time . Scores of anxiety and depression were significantly improved in group E + P compared with group C at 12 weeks of intervention . Conclusions Combined intervention with patient education and PMR can significantly improve CPAP adherence in OSA patients for at least 12 weeks . The intervention paradigm may serve as an important reference for future studies on CPAP adherence [25581921] STUDY OBJECTIVES We tested whether providing adults with obstructive sleep apnea ( OSA ) with daily Web-based access to their positive airway pressure ( PAP ) usage over 3 mo with or without a financial incentive in the first week improves adherence and functional outcomes . SETTING Academic- and community-based sleep centers . PARTICIPANTS One hundred thirty-eight adults with newly diagnosed OSA starting PAP treatment . INTERVENTIONS Participants were r and omized to : usual care , usual care with access to PAP usage , or usual care with access to PAP usage and a financial incentive . PAP data were transmitted daily by wireless modem from the participants ' PAP unit to a website where hours of usage were displayed . Participants in the financial incentive group could earn up to $ 30/day in the first week for objective PAP use ≥ 4 h/day . MEASUREMENTS AND RESULTS Mean hours of daily PAP use in the two groups with access to PAP usage data did not differ from each other but was significantly greater than that in the usual care group in the first week and over 3 mo ( P < 0.0001 ) . Average daily use ( mean ± st and ard deviation ) during the first week of PAP intervention was 4.7 ± 3.3 h in the usual care group , and 5.9 ± 2.5 h and 6.3 ± 2.5 h in the Web access groups with and without financial incentive respectively . Adherence over the 3-mo intervention decreased at a relatively constant rate in all three groups . Functional Outcomes of Sleep Question naire change scores at 3 mo improved within each group ( P < 0.0001 ) but change scores of the two groups with Web access to PAP data were not different than those in the control group ( P > 0.124 ) . CONCLUSIONS Positive airway pressure adherence is significantly improved by giving patients Web access to information about their use of the treatment . Inclusion of a financial incentive in the first week had no additive effect in improving adherence [21471093] RATIONALE Home portable monitor testing is increasingly being used to diagnose patients with obstructive sleep apnea ( OSA ) and to initiate them on continuous positive airway pressure ( CPAP ) treatment . OBJECTIVES To compare functional outcome and treatment adherence in patients who receive ambulatory versus in-laboratory testing for OSA . METHODS Veterans with suspected OSA were r and omized to either home testing or st and ard in-laboratory testing . Home testing consisted of a type 3 portable monitor recording followed by at least three nights using an automatically adjusting positive airway pressure apparatus . Participants diagnosed with OSA were treated with CPAP for 3 months . MEASUREMENTS AND MAIN RESULTS We measured the change in Functional Outcomes of Sleep Question naire score , with an a priori noninferiority delta of -1 , and the mean daily hours of objective ly measured CPAP adherence , with an a priori noninferiority delta of -0.75 hour/day . Of the 296 subjects enrolled , 260 ( 88 % ) were diagnosed with OSA , and 213 ( 75 % ) were initiated on CPAP . Mean ± SD functional outcome score improved 1.74 ± 2.81 in the home group ( P < 0.001 ) and 1.85 ± 2.46 in the in-laboratory group ( P < 0.0001 ) . The lower bound of the one-sided 95 % noninferiority confidence interval was -0.54 . Mean ± SD hours of daily CPAP adherence were 3.5 ± 2.5 hours/day in the home group and 2.9 ± 2.3 hours/day in the in-laboratory group ( P = 0.08 ) . The lower bound of the one-sided 95 % noninferiority confidence interval was 0.03 . CONCLUSIONS Functional outcome and treatment adherence in patients evaluated according to a home testing algorithm is not clinical ly inferior to that in patients receiving st and ard in-laboratory polysomnography [17556641] Objectives : To examine if reported obstructive sleep apnea ( OSA ) symptom improvement , baseline depressive symptoms , or polysomnographically measured sleep parameters are associated with adherence to continuous positive airway pressure ( CPAP ) . CPAP is a highly effective treatment for OSA . Low adherence to CPAP therapy is common and poorly understood . Depression and lack of perceived benefits from CPAP are possible reasons for low adherence . Methods : Seventy-eight patients evaluated for OSA at a sleep medicine center agreed to participate in the study ; 54 patients completed all study assessment s. The Beck Depression Inventory ( BDI ) and the functional outcomes of sleep question naire ( FOSQ ) were administered before polysomnographic evaluation . A card embedded in the CPAP device electronically recorded adherence . The BDI and FOSQ were administered 1 to 2 months after the baseline measurements were obtained . Results : Baseline depressive symptoms were not correlated with mean duration of CPAP use per night . Reported improvements in OSA symptoms were correlated positively with CPAP adherence . There were significant positive correlations between improvement in depressive symptoms and OSA symptoms after initiation of CPAP therapy . The polysomnographic variables measured did not predict improvement in daytime OSA symptoms or CPAP adherence . Post hoc analyses suggested that those individuals with baseline Apnea Hypopnea Index ( AHI ) between 40 and 80 experienced more symptom improvement than those with AHI < 40 or > 80 . Conclusions : Patients with the greatest level of CPAP adherence also reported the greatest improvement in OSA symptoms . Patients who continued to experience OSA symptoms after CPAP treatment also tended to have more depressive symptoms after CPAP treatment . AHI = Apnea Hypopnea Index ; BDI = Beck Depression Inventory ; CPAP = continuous positive airway pressure ; FOSQ = functional outcomes of sleep question naire ; OSA = obstructive sleep apnea [3612462] Incomplete patient adherence with nasal continuous positive airway pressure ( CPAP ) limits the effectiveness of treatment and results in suboptimal obstructive sleep apnea ( OSA ) outcomes . An interactive website specifically design ed for patients with OSA was design ed and utilized in a r and omized clinical trial to test its effect on increasing CPAP adherence . The goal of this paper is to report on CPAP adherence , internet use , privacy concerns and user satisfaction in using the website . The original project was design ed as a r and omized , controlled clinical trial of Usual Care ( UC , control ) versus MyCPAP group ( intervention ) . Question naires were administered to evaluate the patient perspective of using the MyCPAP website . Participation in the MyCPAP intervention result ed in higher CPAP adherence at the two-month time point relative to participation in the UC group ( 3.4 ± 2.4 and 4.1 ± 2.3 hrs/nt ; P = 0.02 ; mean ± SD ) . Participants r and omized to the MyCPAP website increased their use of the internet to obtain OSA related information , but did not increase their use of the internet to get information on general health or medical conditions . Users had very little concern about their CPAP data being viewed daily or being sent over the internet . Future studies should consider the use of newer evaluation criteria for collaborative adaptive interactive technologies [21719490] The aim of this study to evaluate the efficacy of a home-based programme on clinical response , continuous positive airway pressure ( CPAP ) compliance and cost in a population of high pre-test probability of suffering obstructive sleep apnoea syndrome ( OSAS ) . Patients were r and omised into the following three groups . Group A : home respiratory polygraphy ( RP ) and home follow-up ; group B : hospital polysomnography and hospital follow-up ; and group C : home RP and hospital follow-up . Evaluation during 6 months included Epworth Sleepiness Scale ( ESS ) , Functional Outcomes Sleep Question naire ( FOSQ ) , and daily activity and symptom question naires . Compliance was assessed by memory cards ( group A ) and using an hourly counter ( groups B and C ) . 66 patients were included ( 22 per branch ) , 83 % were males , aged mean±sd 52±10 yrs , body mass index 34±7kg·m−2 , apnoea/hypopnoea index 43±20 h−1 , CPAP pressure 8±2 cmH2O , with no between-group differences . Clinical response showed an ESS of mean±sd 15±3 to 6±4 , a FOSQ of 16±3 to 18±2 , symptoms of 43±7 to 25±7 , and activity of 37±11 to 25±8 . At the end of the study , compliance was : group A 73 % , group B 68 % and group C 57 % . The cost per patient was : group A € 590±43 , group B € 894±11 and group C € 644±93 ( p<0.001 ) . In conclusion , patients with a high initial probability of having OSAS can be diagnosed and treated in a home setting , with a high level of CPAP compliance and lower cost than using either a hospital-based approach or home RP/hospital follow-up [22618924] CONTEXT Systemic hypertension is prevalent among patients with obstructive sleep apnea ( OSA ) . Short-term studies indicate that continuous positive airway pressure ( CPAP ) therapy reduces blood pressure in patients with hypertension and OSA . OBJECTIVE To determine whether CPAP therapy is associated with a lower risk of incident hypertension . DESIGN , SETTING , AND PARTICIPANTS A prospect i ve cohort study of 1889 participants without hypertension who were referred to a sleep center in Zaragoza , Spain , for nocturnal polysomnography between January 1 , 1994 , and December 31 , 2000 . Incident hypertension was documented at annual follow-up visits up to January 1 , 2011 . Multivariable models adjusted for confounding factors , including change in body mass index from baseline to censored time , were used to calculate hazard ratios ( HRs ) of incident hypertension in participants without OSA ( controls ) , with untreated OSA , and in those treated with CPAP therapy according to national guidelines . MAIN OUTCOME MEASURE Incidence of new-onset hypertension . RESULTS During 21,003 person-years of follow-up ( median , 12.2 years ) , 705 cases ( 37.3 % ) of incident hypertension were observed . The crude incidence of hypertension per 100 person-years was 2.19 ( 95 % CI , 1.71 - 2.67 ) in controls , 3.34 ( 95 % CI , 2.85 - 3.82 ) in patients with OSA ineligible for CPAP therapy , 5.84 ( 95 % CI , 4.82 - 6.86 ) in patients with OSA who declined CPAP therapy , 5.12 ( 95 % CI , 3.76 - 6.47 ) in patients with OSA nonadherent to CPAP therapy , and 3.06 ( 95 % CI , 2.70 - 3.41 ) in patients with OSA and treated with CPAP therapy . Compared with controls , the adjusted HRs for incident hypertension were greater among patients with OSA ineligible for CPAP therapy ( 1.33 ; 95 % CI , 1.01 - 1.75 ) , among those who declined CPAP therapy ( 1.96 ; 95 % CI , 1.44 - 2.66 ) , and among those nonadherent to CPAP therapy ( 1.78 ; 95 % CI , 1.23 - 2.58 ) , whereas the HR was lower in patients with OSA who were treated with CPAP therapy ( 0.71 ; 95 % CI , 0.53 - 0.94 ) . CONCLUSION Compared with participants without OSA , the presence of OSA was associated with increased adjusted risk of incident hypertension ; however , treatment with CPAP therapy was associated with a lower risk of hypertension [20880872] Background Continuous positive airway pressure ( CPAP ) is the most widely prescribed treatment for obstructive sleep apnoea syndrome ( OSAS ) . Although it has been shown to improve the symptoms of OSAS , many patients have difficulty adhering to this treatment . The purpose of this study was to investigate the effectiveness of an automated telemedicine intervention to improve adherence to CPAP . Methods A r and omised clinical trial was undertaken in 250 patients being started on CPAP therapy for OSAS . Patients were r and omly assigned to use a theory-driven interactive voice response system design ed to improve CPAP adherence ( telephone-linked communications for CPAP ( TLC-CPAP ) , n=124 ) or to an attention placebo control ( n=126 ) for 12 months . TLC-CPAP monitors patients ' self-reported behaviour and CPAP-related symptoms and provides feedback and counselling through a structured dialogue to enhance motivation to use CPAP . A Sleep Symptoms Checklist , the Functional Outcomes of Sleep Question naire , the Center for Epidemiological Studies Depression Scale and the Psychomotor Vigilance Task were administered at study entry and at 6-month and 12-month follow-up . Hours of CPAP usage at effective mask pressure were measured by the CPAP device stored in its memory and retrieved at each visit . Results Median observed CPAP use in patients r and omised to TLC-CPAP was approximately 1 h/night higher than in the control subjects at 6 months and 2 h/night higher at 12 months . Using generalised estimating equation modelling , the intervention had a significant effect on CPAP adherence . For secondary analysis , the effect of CPAP adherence on the secondary outcomes was analysed . CPAP adherence was significantly associated with a greater reduction in sleep apnoea symptoms and depressive symptoms and a greater improvement in functional status . No significant association was observed between CPAP adherence and reaction time . Conclusions The TLC-CPAP intervention result ed in improved CPAP adherence , which was associated with improved functional status and fewer depressive symptoms . Clinical trial.gov NCT00232544 [19129293] Continuous positive airway pressure ( CPAP ) is an effective treatment for obstructive sleep apnoea syndrom ( OSAS ) but therapy adherence is often low . The hypothesis that CPAP-adherence and clinical outcomes can be improved by either using an autoadjusting-CPAP ( APAP ) device or an intensive support was tested . A controlled parallel group study was performed with 100 newly diagnosed OSAS patients , r and omised into 4 groups ( n = 25 each ) : st and ard or intensive support plus either APAP or CPAP . Intensive support included education and monthly home visits for 6 months . Clinical outcome was monitored by polysomnography at CPAP initiation and , after 3 and 9 months , compliance data were downloaded from the CPAP devices . After 9 months , intensively supported patients returned for follow-up in 88 versus 68 % in the st and ard-support-group . Daily usage ( mean±sem 5.7±0.2 for intensive support versus 4.6±0.4 h for st and ard support ) , percentage of days used ( 80.4±2.8 versus 57.0±5.9 % ) and proportion of individual sleep time ( 80.6±3.2 versus 64.9±6.2 % ) were also higher . There was no significant difference between APAP or CPAP , ( daily usage 5.2±0.4 versus 5.1±0.3 h , percentage of days 67.9±5.0 versus 69.2±4.9 % , proportion of sleep time 72.5±5.0 % versus 72.1±5.2 % , for APAP and CPAP ) but retention rate was higher with CPAP . In summary , intensive support after continuous positive airway pressure initiation , rather than the application of autoadjusting-continuous positive airway pressure , increased therapy adherence [24993911] We aim ed to compare the effect of intensive versus st and ard interventions on continuous positive airway pressure ( CPAP ) adherence 2 years after CPAP initiation , as well as on sleepiness , quality of life , depression , hospitalisation and death rate due to cardiovascular disease ( CVD ) . 3100 patients with newly diagnosed sleep apnoea were r and omised into the st and ard group , with usual follow-up care , or the intensive group , with additional visits , telephone calls and education . Subjective daytime sleepiness ( Epworth Sleepiness Scale ; ESS ) , quality of life ( 36-item Short Form Health Survey ; SF-36 ) and the patient ’s level of depression ( Beck Depression Inventory ; BDI ) were recorded before and 2 years after CPAP initiation , together with CVD hospitalisations and death rate . 2 years after CPAP initiation , the intensive group used CPAP significantly more than the st and ard group ( 6.9 versus 5.2 h per night ; p<0.001 ) . ESS , SF-36 and BDI scores were also significantly better in the intensive group . Furthermore , the st and ard group had significantly more deaths and hospitalisations due to CVD . CPAP usage can be improved by both intensive and st and ard patient support . However , the patients who received intensive CPAP support had significantly better ESS , BDI and SF-36 scores , and lower cardiovascular morbidity and mortality , suggesting that an intensive programme could be worthwhile . Intensive CPAP support improves sleepiness , quality of life , depression , hospitalisation and death rate [26310452] Background Compliance with continuous positive airway pressure ( CPAP ) therapy is essential in patients with obstructive sleep apnoea ( OSA ) , but adequate control is not always possible . This is clinical ly important because CPAP can reverse the morbidity and mortality associated with OSA . Telemedicine , with support provided via a web platform and video conferences , could represent a cost-effective alternative to st and ard care management . Aim To assess the telemedicine impact on treatment compliance , cost-effectiveness and improvement in quality of life ( QoL ) when compared with traditional face-to-face follow-up . Methods A r and omised controlled trial was performed to compare a telemedicine-based CPAP follow-up strategy with st and ard face-to-face management . Consecutive OSA patients requiring CPAP treatment , with sufficient internet skills and who agreed to participate , were enrolled . They were followed-up at 1 , 3 and 6 months and answered surveys about sleep , CPAP side effects and lifestyle . We compared CPAP compliance , cost-effectiveness and QoL between the beginning and the end of the study . A Bayesian cost-effectiveness analysis with non-informative priors was performed . Results We r and omised 139 patients . At 6 months , we found similar levels of CPAP compliance , and improved daytime sleepiness , QoL , side effects and degree of satisfaction in both groups . Despite requiring more visits , the telemedicine group was more cost-effective : costs were lower and differences in effectiveness were not relevant . Conclusions A telemedicine-based strategy for the follow-up of CPAP treatment in patients with OSA was as effective as st and ard hospital-based care in terms of CPAP compliance and symptom improvement , with comparable side effects and satisfaction rates . The telemedicine-based strategy had lower total costs due to savings on transport and less lost productivity ( indirect costs ) . Trial register number NCT01716676 [22240218] INTRODUCTION The most commonly used treatment for obstructive sleep apnea syndrome ( OSA ) is the application of continuous positive airway pressure ( CPAP ) during sleep . However compliance with this treatment is frequently below 70 % . METHODS The main aim of this study was to evaluate the feasibility of an educational intervention ( EI ) delivered in phone calls made to OSA patients ( n=66 ) treated with CPAP by a home care provider ( SADIR ) . The educational intervention consisted of five sessions of telephone based counseling intervention by appropriately trained staff delivered on day 3 , 10 , 30 , 60 and 90 after initiation of treatment . Secondary objectives were to compare , using a case-control design , CPAP compliance of OSA patients ( n=133 ) with or without EI . RESULTS Ninety-eight percent of patients accepted the intervention to participate in the study . Fifty-seven patients ( 86 % ) received the full intervention program and 44 patients ( 66 % ) strictly respected the pre-defined timings per protocol . A higher adherence to CPAP at six months was observed in the EI group compared to patient without EI ( 94 % versus 81 % ) ( P<0.05 ) . CPAP compliance at three months was 54minutes higher in the EI group compared to the control group ( 4h39±2h17 and 3h45±2h45 respectively ) but this difference was not statistically significant . CONCLUSION An educational intervention dispensed by phone is applicable and would have an impact on CPAP compliance . Its efficacy on long-term compliance has to be confirmed in a larger group using a r and omized procedure [23483174] IMPORTANCE Due to increasing dem and for sleep services , there has been growing interest in ambulatory models of care for patients with obstructive sleep apnea . With appropriate training and simplified management tools , primary care physicians are ideally positioned to take on a greater role in diagnosis and treatment . OBJECTIVE To compare the clinical efficacy and within-trial costs of a simplified model of diagnosis and care in primary care relative to that in specialist sleep centers . DESIGN , SETTING , AND PATIENTS A r and omized , controlled , noninferiority study involving 155 patients with obstructive sleep apnea that was treated at primary care practice s ( n=81 ) in metropolitan Adelaide , 3 rural regions of South Australia or at a university hospital sleep medicine center in Adelaide , Australia ( n = 74 ) , between September 2008 and June 2010 . INTERVENTIONS Primary care management of obstructive sleep apnea vs usual care in a specialist sleep center ; both plans included continuous positive airway pressure , m and ibular advancement splints , or conservative measures only . MAIN OUTCOME AND MEASURES The primary outcome was 6-month change in Epworth Sleepiness Scale ( ESS ) score , which ranges from 0 ( no daytime sleepiness ) to 24 points ( high level of daytime sleepiness ) . The noninferiority margin was -2.0 . Secondary outcomes included disease-specific and general quality of life measures , obstructive sleep apnea symptoms , adherence to using continuous positive airway pressure , patient satisfaction , and health care costs . RESULTS There were significant improvements in ESS scores from baseline to 6 months in both groups . In the primary care group , the mean baseline score of 12.8 decreased to 7.0 at 6 months ( P < .001 ) , and in the specialist group , the score decreased from a mean of 12.5 to 7.0 ( P < .001 ) . Primary care management was noninferior to specialist management with a mean change in ESS score of 5.8 vs 5.4 ( adjusted difference , -0.13 ; lower bound of 1-sided 95 % CI , -1.5 ; P = .43 ) . There were no differences in secondary outcome measures between groups . Seventeen patients ( 21 % ) withdrew from the study in the primary care group vs 6 patients ( 8 % ) in the specialist group . CONCLUSIONS AND RELEVANCE Among patients with obstructive sleep apnea , treatment under a primary care model compared with a specialist model did not result in worse sleepiness scores , suggesting that the 2 treatment modes may be comparable . TRIAL REGISTRATION anzctr.org.au Identifier : ACTRN12608000514303 [23920211] BACKGROUND : CPAP is currently the treatment of choice for obstructive sleep apnea syndrome , but therapy adherence is poor . Many educational trials have been proposed to increase CPAP adherence . We tested the hypothesis that polysomnograph chart viewing by patients would improve CPAP adherence . METHODS : A controlled parallel group study was performed with 206 newly diagnosed obstructive sleep apnea syndrome patients , r and omized into 2 groups ( n = 103 each ) : st and ard support group , and educational support group . Each educational support group subject viewed 2 consecutive polysomnograms on the computer screen : the first recorded during a st and ard diagnostic overnight polysomnography , and the second during a full-night polysomnography with nasal CPAP . The subject 's attention was drawn only to the flow and oxyhemoglobin saturation curves . Clinical outcomes were assessed via polysomnography at CPAP initiation and after 1 , 3 , and 12 months . RESULTS : After 12 months of CPAP , 76 % of the educational support group and 52 % of the st and ard support group returned for a follow-up visit ( P < .001 ) . Statistical significance had already been reached after 1 and 3 months . Moreover , CPAP use ( measured as hours of use per night ) was higher in the educational support group at each control visit . CONCLUSIONS : Polysomnograph chart viewing by obstructive sleep apnea patients can increase CPAP adherence , as evaluated by rate of return for the follow-up visit and mean nightly CPAP use [14725828] BACKGROUND This pragmatic r and omised , controlled trial investigated annual review of patients with sleep apnea/hypopnea syndrome ( SAHS ) . Clinical outcomes and costs were compared for consultant clinic review versus specialist nurse home visit . METHOD One hundred and seventy-four patients were r and omised to annual review by consultant clinic appointment or by specialist nurse home visit . SAHS symptoms , Epworth score , hospital anxiety and depression scale ( HADS ) , Short Form-36 ( SF-36 ) and hours of use of constant positive airway pressure ( CPAP ) were measured before and 3 months after review . The costs and patient preference for review were determined . RESULTS After review , both groups significantly increased CPAP use ( mean ( SD ) increase : nurse , 0.66 ( 1.71 ) h ; consultant , 0.45 ( 1.69 ) h ) and reduced symptom scores ( nurse , -2 ( 7 ) ; consultant , -3 ( 9 ) ) , compared to baseline . There were no differences between groups in these improvements , or in HADS or SF-36 scores . Average duration of a nurse home visit , excluding travel time , was 26 ( 6 ) min . Total NHS cost per visit was 52.26 UK pounds ( 49.85 ) ( $ 83.62 ( 79.76 ) ) , of which 6.57 UK pounds ( 1.43 ) ( $ 10.51 ( 2.29 ) ) reflected time spent with the patient and the remainder was travel cost . Average duration of consultant review was 10 ( 6 ) min , total NHS cost 6.21 UK pounds ( 3.99 ) ( $ 9.94 ( 6.38 ) ) . However , the cost to the patient of attending the clinic was 23.63 UK pounds ( 23.21 ) ( $ 37.81 ( 37.13 ) ) . Patient preference for review was nurse 16 % , consultant 19 % , and no preference 65 % . CONCLUSION Following annual review , use of CPAP increased and symptoms improved . Outcomes were similar for consultant and nurse led review . Home visits were expensive for the healthcare provider , whereas clinic attendance incurred substantial costs to the patient . The majority of patients would accept nurse review for their sleep apnea management [18829212] OBJECTIVE As many as 50 % of patients diagnosed with obstructive sleep apnea stop adhering to the prescribed medical treatment of continuous positive airway pressure ( CPAP ) within 1 - 3 weeks of onset . Thus , a theory-based intervention using music to support habit formation was design ed to improve CPAP adherence at onset . The intervention material s included directions for CPAP nightly use , a diary for recording nightly use and writing about CPAP benefits or problems . In addition , an audiotape with softly spoken instructions for placing the CPAP mask comfortably , using deep breathing and muscle relaxation along with the slowly decreasing music tempo was provided to listen to at bedtime each night . METHODS Effects of this music intervention were tested in a r and omized , placebo-controlled trial of 97 patients with 53 males ( 55 % ) and 44 females ( 45 % ) . Moderate to severe apnea/hyponea scores ( per sleep laboratory data ) and medical diagnosis of OSA were required for study inclusion . RESULTS Compared to placebo controls , a greater proportion of experimental patients were adhering ( chi(2)=14.67 , p<0.01 ; a large difference , Phi=0.39 ) at the end of the first month of CPAP onset . There were no differences in CPAP adherence at 3 ( X(2)=0.065 , p=0.79 ) and 6 ( X(2)=.118 , p=0.73 ) months . Patients ' diary data and satisfaction survey results indicated the intervention was rated as helpful and guided formation of a relaxing , habitual routine of CPAP nightly use . CONCLUSION The intervention had a strong effect for improving adherence to CPAP at 1 month . PRACTICE IMPLICATION S Adherence at the onset of treatment is critical and the audio music intervention was easily administered . Other interventions that target problems interfering with longer-term CPAP adherence are needed [11812555] BACKGROUND Obstructive sleep apnoea is associated with raised blood pressure . If blood pressure can be reduced by nasal continuous positive airway pressure ( nCPAP ) , such treatment could reduce risk of cardiovascular disease in patients with obstructive sleep apnoea . Our aim was to see whether nCPAP for sleep apnoea reduces blood pressure compared with the most robust control intervention subtherapeutic nCPAP . METHODS We did a r and omised parallel trial to compare change in blood pressure in 118 men with obstructive sleep apnoea ( Epworth score > 9 , and a > 4 % oxygen desaturation index of > 10 per h ) who were assigned to either therapeutic ( n=59 ) or subtherapeutic ( 59 ) nCPAP ( about 1 cm H(2)O pressure ) for 1 month . The primary outcome was the change in 24-h mean blood pressure . Secondary outcomes were changes in systolic , diastolic , sleep , and wake blood pressure , and relations between blood pressure changes , baseline blood pressure , and severity of sleep apnoea . FINDINGS Therapeutic nCPAP reduced mean arterial ambulatory blood pressure by 2.5 mm Hg ( SE 0.8 ) , whereas subtherapeutic nCPAP increased blood pressure by 0.8 mm Hg ( 0.7 ) ( difference -3.3 [ 95 % CI -5.3 to -1.3 ] ; p=0.0013 , unpaired t test ) . This benefit was seen in both systolic and diastolic blood pressure , and during both sleep and wake . The benefit was larger in patients with more severe sleep apnoea than those who had less severe apnoea , but was independent of the baseline blood pressure . The benefit was especially large in patients taking drug treatment for blood pressure . INTERPRETATION In patients with most severe sleep apnoea , nCPAP reduces blood pressure , providing significant vascular risk benefits , and substantially improving excessive daytime sleepiness and quality of life [22945541] Purpose The objective of the study was to evaluate the effectiveness of stage-matched intervention on adherence to continuous positive airway pressure ( CPAP ) in patients with obstructive sleep apnea syndrome . Methods One hundred and ten Chinese patients with newly diagnosed obstructive sleep apnea syndrome were enrolled in this study . They were r and omly assigned into stage-matched care ( SMC ) and st and ard care ( SC ) groups ( 55 patients in each group ) . Patients in the SMC group received stage-matched intervention at different stages of behavior changes , and the SC group received only routine care . The intervention was based on the health action process approach theory and included risk perception , outcome expectancy , and self-efficacy . Question naires included the Self-Efficacy Measure for Sleep Apnea , the Epworth Sleepiness Scale ( ESS ) , and the Pittsburgh Sleep Quality Index ( PSQI ) . Data were collected at baseline and 1 and 3 months after home CPAP treatment , and hours of CPAP usage was also recorded at 1 and 3 months of follow-up . Results At 1 month , CPAP usage was 5.59 ± 0.56 h/night ( mean ± SD ) vs 5.28 ± 0.67 h/night in the SMC and SC groups , respectively ( p = 0.016 ) . At 3 months , CPAP usage was 5.65 ± 0.50 vs 5.26 ± 0.82 h/night in the SMC and SC groups , respectively ( p = 0.006 ) . Repeated ANOVA analysis demonstrated that risk perception , outcome expectancy , and self-efficacy in the SMC group were significantly higher than those of the SC group ( p < 0.05 ) . Moreover , the time × group interaction was significant for outcome expectancy and self-efficacy , indicating that the groups differed significantly in changes in outcome expectancy and self-efficacy over the three time points . There was a significant difference between the SMC and SC groups in terms of improvement in ESS ( p < 0.001 ) and PSQI ( p = 0.013 ) after 3 months of CPAP treatment . Conclusions Stage-matched intervention could not only facilitate intention formation and enhance treatment self-efficacy but significantly improve CPAP adherence in OSA patients for the 3-month treatment [18795985] OBJECTIVES To examine whether treatment of obstructive sleep apnea ( OSA ) with continuous positive airway pressure ( CPAP ) in patients with Alzheimer 's disease ( AD ) results in better cognitive function . DESIGN R and omized double-blind placebo-controlled trial . Participants were r and omized to therapeutic CPAP for 6 weeks or placebo CPAP for 3 weeks followed by therapeutic CPAP for 3 weeks . SETTING General clinical research center . PARTICIPANTS Fifty-two men and women with mild to moderate AD and OSA . INTERVENTION CPAP . MEASUREMENTS A complete neuropsychological test battery was administered before treatment and at 3 and at 6 weeks . RESULTS A comparison of subjects r and omized to 3 weeks of therapeutic versus placebo CPAP suggested no significant improvements in cognition . A comparison of pre- and posttreatment neuropsychological test scores after 3 weeks of therapeutic CPAP in both groups showed a significant improvement in cognition . The study was underpowered to make definitive statements about improvements within specific cognitive constructs , although exploratory post hoc examination of change scores for individual tests suggested improvements in episodic verbal learning and memory and some aspects of executive functioning such as cognitive flexibility and mental processing speed . CONCLUSION OSA may aggravate cognitive dysfunction in dementia and thus may be a reversible cause of cognitive loss in patients with AD . OSA treatment seems to improve some cognitive functioning . Clinicians who care for patients with AD should consider implementing CPAP treatment when OSA is present [16796496] The objective of this study was to test whether a telehealth intervention could improve the compliance with continuous positive airway pressure ( CPAP ) by patients with sleep apnea . These patients had been nonadherent for the initial 3 months of therapy even after receiving the initial st and ard and then supplemental audiotaped/videotaped patient education for adhering to CPAP nightly . The material s and methods included a r and omized testing of experimental and placebo interventions . Interventions were delivered by nurses to two groups in their homes by telehealth over a 12-week period . The placebo intervention was used to control for Hawthorne effect , time and attention influences and the novelty of having telehealth in the home . Results following the telehealth interventions were that significantly more patients in the experimental group 1 ( n = 10 ) than the placebo group 2 ( n = 9 ) were adhering nightly to CPAP ( chi 2 = 4.55 , p = 0.033 ) . Group 1 patients reported greater satisfaction with their intervention . However , both groups rated telehealth delivery positively . The mean cost of each 20-minute telehealth visit was 30 dollars while the total cost of the telehealth intervention for each patient was 420 dollars . These costs included telehealth equipment , initial installation , longdistance telephone charges , nurse salary , and intervention material s. Conclusions are that telehealth interventions are a potentially cost-effective service for increasing adherence to prescribed medical treatments . Replication studies with large sample s and in other clinical groups are recommended [18853940] STUDY OBJECTIVES To compare a clinical pathway using portable monitoring ( PM ) for diagnosis and unattended autotitrating positive airway pressure ( APAP ) for selecting an effective continuous positive airway pressure ( CPAP ) with another pathway using polysomnography ( PSG ) for diagnosis and treatment of obstructive sleep apnea ( OSA ) . DESIGN R and omized parallel group SETTING Veterans Administration Medical Center PATIENTS 106 patients with daytime sleepiness and a high likelihood of having OSA MEASUREMENTS AND RESULTS : The AHI in the PM-APAP group was 29.2 + /- 2.3/h and in the PSG group was 36.8 + /- 4.8/h ( P= NS ) . Patients with an AHI > or = 5 were offered CPAP treatment . Those accepting treatment ( PM-APAP 45 , PSG 43 ) were begun on CPAP using identical devices at similar mean pressures ( 11.2 + /- 0.4 versus 10.9 + /- 0.5 cm H2O ) . At a clinic visit 6 weeks after starting CPAP , 40 patients in the PM-APAP group ( 78.4 % of those with OSA and 88.8 % started on CPAP ) and 39 in the PSG arm ( 81.2 % of those with OSA and 90.6 % of those started on CPAP ) were using CPAP treatment ( P = NS ) . The mean nightly adherence ( PM-APAP : 5.20 + /- 0.28 versus PSG : 5.25 + /- 0.38 h/night ) , decrease in Epworth Sleepiness Scale score ( -6.50 + /- 0.71 versus -6.97 + /- 0.73 ) , improvement in the global Functional Outcome of Sleep Question naire score ( 3.10 + /- 0.05 versus 3.31 + /- 0.52 ) , and CPAP satisfaction did not differ between the groups . CONCLUSIONS A clinical pathway utilizing PM and APAP titration result ed in CPAP adherence and clinical outcomes similar to one using PSG [1470808] In a prospect i ve study aim ed at evaluating objective ly the compliance with nasal continuous positive airway pressure ( CPAP ) treatment , 233 obstructive sleep apnea ( OSA ) ( apnea index , > 10 apneas/hour ) patients and 36 nonapneic snorers were studied . The compliance to treatment was measured by the mean rate of use of the CPAP device , obtained from a built-in time counter . The follow-up period was 874 + /- 48 in OSA patients and 675 + /- 83 in snorers . CPAP was proposed to all OSA patients but only to those snorers who felt improved after an initial laboratory night on CPAP . Nineteen OSA patients refused CPAP . Of the 214 OSA patients who accepted CPAP , 181 are still on treatment , with a mean daily rate of use of 5.6 + /- 0.1 hours ( mean + /- SEM ) ; 22 patients stopped CPAP after a variable period of time ; 10 patients died and one acromegalic patient was considered cured after hypophysectomy for a pituitary adenoma . Depending upon the definition of acceptable compliance , the compliance rate in this group was between 77 % and 89 % . The mean rate of use was correlated with indices of disease severity ( apnea index , apnea+hypopnea index , minimal SaO2 during sleep , daytime PaO2 , pulmonary artery pressure ) . Thirty-six nonapneic snorers accepted CPAP . In this group , 26 are still on CPAP , with a mean daily rate of use of 5.4 + /- 0.5 hours ; one patient died ; one underwent uvolopalatopharyngoplasty without follow-up ; and eight stopped CPAP . The compliance rate in this group was between 58 % and 78 % . This study shows that CPAP is reasonably accepted by OSA patients as well as by nonapneic snorers . ( ABSTRACT TRUNCATED AT 250 WORDS [22103957] OBJECTIVE Adherence to continuous positive airway pressure ( CPAP ) therapy for obstructive sleep apnoea ( OSA ) is poor . We assessed the effectiveness of a motivational interviewing intervention ( motivational interview nurse therapy [ MINT ] ) in addition to best practice st and ard care to improve acceptance and adherence to CPAP therapy in people with a new diagnosis of OSA . METHOD One hundred six Australian adults ( 69 % male ) with a new diagnosis of OSA and a clinical recommendation for CPAP treatment were recruited from a tertiary sleep disorders center . Participants were r and omly assigned to receive either 3 sessions of a motivational interviewing intervention ( MINT ; n = 53 ; mean age = 55.4 years ) or no intervention ( control ; n = 53 ; mean age = 57.74 years ) . The primary outcome was the difference between the groups in objective CPAP adherence at 1-month , 2-month , 3-month , and 12-month follow-ups . RESULTS Fifty ( 94 % ) participants in the MINT group and 50 ( 94 % ) participants in the control group met all inclusion and exclusion criteria and were included in the primary analysis . The number of hours of CPAP use per night in the MINT group at 3 months was 4.63 hr and was 3.16 hr in the control group ( p = .005 ) . This represents almost 50 % better adherence in the MINT group relative to the control group . Patients in the MINT group were substantially more likely to accept CPAP treatment . CONCLUSIONS MINT is a brief , manualized , effective intervention that improves CPAP acceptance and objective adherence rates compared to st and ard care alone [24989482] Background Obstructive sleep apnea syndrome ( OSAS ) is a serious disorder with significant health consequences . Treatment adherence to auto-titrating positive airway pressure ( APAP ) is often below expectations . We investigated the effectiveness of a brief educational intervention using motivational strategies in treatment adherence among patients with OSAS . Methods The study followed a r and omized , controlled design and included 61 patients diagnosed with OSAS , meeting the criteria for APAP therapy . Patients recruited from a Sleep Disorders Unit were r and omly allocated to an intervention group ( IG ) and two control groups ( CG1 and CG2 ) . In the IG motivational strategies were applied according to patient ’s motivation , assessed by the degree of confidence and conviction . In the CG1 , participants received exclusively st and ardized information , and in the CG2 , routine procedures were followed . Assessment included the Apnea Hypopnea Index ( AHI ) , the Epworth Sleepiness Scale ( ESS ) , and sociodemographic and clinical information . Adherence to treatment was measured after 1 ( T1 ) and 2 months ( T2 ) through the APAP software . Results The IG presented higher adherence to APAP — percentage of days of use > 4 h ( 89.8 % p = 0.013 ) , mean effective use per effective day ( 6.2 p = 0.000 ) , and lower AHI ( 2.7 p = 0.019 ) at T2 when compared with the other two groups . Confidence was higher in the IG group at T2 than at T1 ( p = 0.000 ) . The ESS presented a significant reduction ( p = 0.000 ) in the IG and in the CG1 ( p = 0.008 ) , but was higher in the CG2 ( p = 0.015 ) . Conclusions Brief interventions using motivational strategies can improve a patient ’s adherence to APAP [24179298] BACKGROUND Obstructive sleep apnea ( OSA ) is associated with a variety of medical conditions . Positive airway pressure ( PAP ) is an effective treatment for improving sleep , yet adherence rates are low . The aim of the current study is to test two treatments versus st and ard care in improving adherence to PAP . METHOD Two hundred twenty-seven patients with OSA were r and omized to st and ard care ( SC ) , education ( ED ) and motivational enhancement therapy ( MET ) . Adherence was measured objective ly and the first week of adherence ( prior to the intervention ) was used as an a priori moderator of the effect of the various interventions . Mediators of treatment response were also examined using theory-based measures of decisional balance and self-efficacy . RESULTS Adherence declined over time for all three groups . There was a significant interaction between level of adherence during the first week of treatment and treatment group . Those who had moderate levels of adherence during their first week of PAP were more likely to adhere to treatment at follow-up if they had MET ; those who had high levels of adherence during their first week of PAP were more likely to adhere to treatment at follow-up if they had ED . MET treatment increased the perception of the positive aspects of PAP , but ED did not . CONCLUSIONS Initial adherence to positive airway pressure could help guide subsequent treatment plans . The results also support social cognitive theory in that educational approaches might be best suited for those who are ready for change whereas more motivational approaches might be best for those who are ambivalent about change [25056665] Background The treatment of choice for sleep apnoea-hypopnoea syndrome ( SAHS ) is continuous positive airway pressure ( CPAP ) . However , CPAP effectiveness strongly depends on patient adherence to treatment . The aim of this study was to determine the effectiveness of a low-cost , basic intervention on improving CPAP adherence . Methods A controlled parallel-group trial . Participants were SAHS patients for whom CPAP treatment was indicated . Those in the intervention group were shown the results of their sleep test and were told the importance of treatment adherence ; the control group received neither . Outcomes for both groups were compared at 6 months . The primary outcome assessed was CPAP usage . Results One hundred fifty-four patients were included in the intervention group and 167 in the control group . At 6 months , the intervention group had 10 % more participants with CPAP usage ≥4 h , significantly higher adherence as compared to controls ( 5 ± 1.8 h vs 4.3 ± 1.7 , p = 0.031 ) , mean : 0.7 h/day and fewer discontinuations of CPAP . A multiple linear regression model showed that intervention group and daytime sleepiness were variables independently associated with treatment adherence . Conclusions An inexpensive basic intervention involving communication of sleep test results and the importance of CPAP adherence improves adherence to CPAP therapy . In addition , greater daytime sleepiness is associated with higher CPAP adherence [9231954] Effectiveness of continuous positive airway pressure ( CPAP ) as a treatment of obstructive sleep apnea can be limited by poor compliance , but little is known about how to improve compliance . We performed a r and omized , controlled clinical trial among 33 subjects of two interventions to improve compliance . One group of subjects received weekly phone calls to uncover any problems and encourage use , another received written information about sleep apnea and the importance of regular CPAP use , and a third served as control subjects . We found that intervention improved CPAP compliance ( p = 0.059 ) and that the effect was particularly strong when intervention occurred during the first month of CPAP treatment ( p = 0.004 ) . Although the sample size did not allow definitive investigation of other explanatory variables , subjects with lower levels of education or those with relatives who used CPAP may have benefited from intervention more than other subjects . We conclude that simple , inexpensive efforts to improve compliance with CPAP can be effective , especially when applied at the start of CPAP treatment , but optimal intervention may vary with certain patient characteristics [23772186] STUDY OBJECTIVES To evaluate patient ratings of the acceptability of a peer buddy system ( PBS ) . To promote continuous positive airway pressure ( CPAP ) therapy adherence in patients with obstructive sleep apnea ( OSA ) . To obtain preliminary data on the effectiveness of PBS on sleep-specific health-related quality of life and CPAP adherence . DESIGN Prospect i ve , r and omized , and controlled study . SETTING Academic Center . PARTICIPANTS Thirty-nine patients with OSA and 13 patients with OSA who were experienced CPAP users . INTERVENTIONS Recently diagnosed patients with OSA were r and omly assigned to either the PBS to promote CPAP adherence ( intervention group ) or usual care ( control group ) . MEASUREMENTS Patient satisfaction , Functional Outcomes of Sleep Question naire ( FOSQ ) , CPAP adherence , vigilance , self-efficacy , and patient activation were measured . RESULTS Ninety-one percent of the subjects rated the PBS as very satisfactory ( 68 % ) or satisfactory ( 23 % ) . During the 90 days of therapy , weekly CPAP adherence was greater in the intervention than the usual care group ( MANOVA ; F = 2.29 ; p = 0.04 ) . Patient satisfaction was positively correlated with CPAP adherence ( R(2 ) = 0.14 ; p = 0.02 ) . We did not find any group differences for FOSQ , vigilance , self-efficacy , or patient activation in this pilot study . CONCLUSION Our pilot study suggests that the PBS intervention is feasible and received high patient satisfaction ratings . CPAP adherence may be improved by peer-driven intervention , but a larger , adequately powered study is needed . CLINICAL TRIAL INFORMATION Clinical Trials.gov identifier : NCT01164683 . COMMENTARY A commentary on this article appears in this issue on page 551 . CITATION Parthasarathy S ; Wendel C ; Haynes PL ; Atwood C ; Kuna S. A pilot study of CPAP adherence promotion by peer buddies with sleep apnea . J Clin Sleep Med 2013;9(6):543 - 550 [10194151] Continuous positive airway pressure ( CPAP ) therapy is widely prescribed for patients with the sleep apnea/hypopnea syndrome ( SAHS ) , but the use of CPAP for such patients is disappointingly low . We postulated that providing intensive educational programs and nursing support to SAHS patients might improve CPAP use and outcomes . We also examined the hypothesis that CPAP use would be greater among patients who had initiated their own referral than among those asked to seek help by a partner . We r and omized 80 consecutive , new patients with SAHS to receive either usual support or additional nursing input including CPAP education at home and involving their partners , a 3-night trial of CPAP in our institution 's sleep center , and additional home visits once they had begun CPAP . The primary outcome variable was objective CPAP use ; symptoms , mood , and cognitive function were also assessed after 6 mo . CPAP use over 6 mo was greater ( p = 0.003 ) among patients receiving intensive than among those receiving st and ard support ( 5.4 + /- 0.3 versus 3.9 + /- 0 . 4 h/night [ mean + /- SEM ] ) , with greater improvements ( p < 0.05 ) in SAHS symptoms , mood , and reaction time in the intensively supported group . CPAP use was greater ( p = 0.002 ) among patients who initiated their own referrals . CPAP use and outcomes of therapy can be improved by provision of a nurse-led intensive CPAP education and support program . CPAP use is lower among patients whose partners ask them to seek treatment [25142557] STUDY OBJECTIVES Obstructive sleep apnea ( OSA ) is commonly associated with cognitive and functional deficits , some of which are resolved after continuous positive airway pressure ( CPAP ) treatment . The investigation of brain structural changes before and after treatment could provide deep insights into the pathogenesis and the reversibility of this disorder . We hypothesized that severe OSA patients would have altered white matter ( WM ) integrity and cognition and that treatment would improve both the structural damage and the cognitive impairment . DESIGN Prospect i ve clinical study . SETTING The Sleep Disorders Center and the Center of Excellence in High-Field Magnetic Resonance Imaging at Vita-Salute San Raffaele University , Milan , Italy . PARTICIPANTS Seventeen never-treated consecutive OSA patients were evaluated before and after treatment ( after 3 and 12 months ) and compared to 15 matched healthy controls . INTERVENTION CPAP . MEASUREMENTS WM integrity measured by diffusion tensor imaging ( DTI ) and cognitive performance ( measured with neuropsychological testing ) before and after 3 and 12 months of CPAP . RESULTS Results in pre-treatment OSA patients showed impairments in most cognitive areas , mood and sleepiness that were associated with diffuse reduction of WM fiber integrity reflected by diminished fractional anisotropy ( FA ) and mean diffusivity ( MD ) in multiple brain areas . After 3 months of CPAP , only limited changes of WM were found . However , over the course of 12 months CPAP treatment , an almost complete reversal of WM abnormalities in all the affected regions was observed in patients who were compliant with treatment . Significant improvements involving memory , attention , and executive-functioning paralleled WM changes after treatment . CONCLUSIONS Changes of WM DTI " signatures " of brain pathology in OSA patients are appreciable over the course of 12-month treatment with CPAP in most of the regions involved . Recovery of cognitive deficits after treatment is consistent with the presence of a reversible structural neural injury in OSA in patients who were compliant with treatment [21218293] Although of proven health benefit to persons with obstructive sleep apnea ( OSA ) , adherence to continuous positive airway pressure ( CPAP ) therapy is suboptimal , with patterns of use that are established early and that are not easily altered after the initial experience . In a r and omized controlled trial , 70 participants with OSA and cardiovascular disease were assigned to receive either positively or negatively framed education about CPAP . Objective adherence was measured following 30 days of home CPAP therapy . Daytime sleepiness , dispositional optimism , self-efficacy , and depression were also evaluated at baseline and after 30 days . CPAP use was greater in the group receiving negative message framing ( p = .015 ) [16565867] The objective of this study was to compare continuous positive airway pressure ( CPAP ) use , functional status , and client satisfaction in obstructive sleep apnea syndrome ( OSAS ) patients r and omized to either telemedicine support or traditional care . In our university-affiliated sleep disorders center , patients with OSAS who were initiating CPAP therapy were r and omized to receive telemedicine support vs traditional follow-up care for 30 days . The telemedicine group received a “ Health Buddy ” computer that provided daily Internet-based informational support and feedback for problems experienced with CPAP use . At 30 days , there were no significant differences in the hours of CPAP use between groups receiving traditional care ( M=4.22 , SD±2.05 ) and telemedicine support ( M=4.29 , SD±2.15 ) , p=0.87 , or in the proportion of nights with CPAP use between the traditional ( M=50%±33.8 ) and telemedicine groups ( M=47%±34.2 ) , p=0.61 . No significant differences were found between groups in functional status ( M=2.27±4.56 vs M=2.03±3.88 , respectively , p=0.76 ) or client satisfaction ( M=28.0±3.51 vs M=28.5±3.05 , p=0.43 ) . Patients in the telemedicine and traditional groups had similar CPAP use , functional status , and client satisfaction . The data suggest that telemedicine support as provided by our model compares favorably with traditional care . As a provider-extender , telemedicine support for patients initiating use of CPAP may allow for greater practice efficiency while maintaining quality of care [10508797] Effective compliance ( time spent at the effective pressure ) with nasal CPAP in obstructive sleep apnea has been reported to be poor . The aim of our study was to evaluate effective compliance in a large European multicenter study . One hundred twenty-one consecutive newly treated patients ( initial apnea-hypopnea index [ AHI ] = 62.0 + /- 29 . 5/h , AHI under CPAP = 6.4 + /- 8.1/h , CPAP pressure = 8.7 + /- 2.6 cm H(2)O , BMI = 33.1 + /- 6.8 kg/m(2 ) ) were r and omly allocated to a group with ( MC(+ ) ) ( n = 58 ) or without ( MC(- ) ) ( n = 63 ) a control unit measuring effective compliance at 1 , 2 , and 3 mo , which was compared with the built-in time counter data . MC(+ ) data were 94 + /- 10 , 98 + /- 5 , and 96 + /- 9 % of counter data at 1 , 2 , and 3 mo , respectively . Using criteria of regular use already reported in the literature ( at least 4 h of nCPAP per day of use and nCPAP administered more than 70 % of the days ) we found 77 , 82 , and 79 % compliant patients at 1 , 2 , and 3 mo , respectively , 79 % of the patients meeting these criteria each month . Although there were no pulmonary functions or polysomnographic differences between the two subgroups , the compliant patients did report a greater improvement in minor symptoms . We found a close correlation between effective use of CPAP and the machine run time . The main result of our study was a higher effective compliance than previously reported , approximately 80 % of the patients being regular users versus 46 % in a previously published study . This may result from different technical and medical follow-up [19186102] BACKGROUND Obstructive sleep apnea ( OSA ) affects approximately 20 % of US adults , of whom about 90 % are undiagnosed . While OSA may increase risk of perioperative complications , its prevalence among surgical patients is unknown . We tested the feasibility of screening surgical patients for OSA and determined the prevalence of undiagnosed OSA . METHODS In a prospect i ve , observational study adult surgical patients were screened for OSA in an academic hospital . Patients without an OSA diagnosis who screened high-risk were offered a home sleep study to determine if they had OSA . The results were compared with polysomnography ( PSG ) when available . Charts of high-risk patients were examined for postoperative complications . High-risk patients received targeted interventions as part of a hospital safety initiative . RESULTS There were 2877 patients screened ; 661 ( 23.7 % ) screened high-risk for OSA , of whom 534 ( 81 % ) did not have diagnosed OSA . The portable sleep study detected OSA in 170/207 ( 82 % ) high-risk patients without diagnosed OSA . Twenty-six PSGs confirmed OSA in 19 of these patients . Postoperatively there were no respiratory arrests , two unanticipated ICU admissions , and five documented respiratory complications . CONCLUSION Undiagnosed OSA is prevalent in adult surgical patients . Implementing universal screening is feasible and can identify undiagnosed OSA in many surgical patients . Further investigation is needed into perioperative complications and their prevention for patients with undiagnosed OSA [17157557] BACKGROUND AND PURPOSE Compliance with continuous positive airway pressure ( CPAP ) treatment in obstructive sleep apnoea syndrome ( OSAS ) may be difficult . Patient education is important but strategies and their outcomes are not clear . PATIENTS AND METHODS We studied the effects of four education strategies on compliance and quality of life changes with CPAP treatment in seven centres in the French ANTADIR homecare network . Patients received from prescribers either a simple oral explanation ( SP ) or an oral and written explanation ( RP ) of CPAP use . In addition , they received from homecare technicians either a single home visit ( SH ) at CPAP onset or repeated home visits at CPAP onset and at 1 week , 1 month and 3 months after ( RH ) . Compliance and quality of life were evaluated at CPAP onset , and at 3 , 6 and 12 months after initiation of treatment . RESULTS One hundred twelve patients with severe OSAS ( mean age 58+/-11 year , apnoea-hypopnoea index 58+/-25/h ) were allocated r and omly to groups ( SP+SH ; SP+RH ; RP+SH ; RP+RH ) with no initial differences . Quality of life , evaluated by the generic SF-36 question naire , improved in the combined emotional domains . Compliance was over 5h in all four education groups . These effects were sustained over 12 months and were not different between the four groups . We conclude that st and ard education strategies for CPAP induction in France are sufficient for good compliance and improved quality of life with CPAP . Education with reinforced input should be focussed on identified subgroups prone to problems [11311685] Objective : To eluci date the predictive role of age and other pre-treatment , putative confounding factors on compliance with nasal continuous positive airway pressure ( nCPAP ) therapy . Patients and methods : This study was design ed as a prospect i ve cohort study in the setting of a sleep laboratory in a teaching hospital at Saint Antoine , Paris . One hundred and sixty-three patients referred to the sleep laboratory with complaints of snoring and excessive daytime sleepiness for whom nCPAP had been prescribed for obstructive sleep apnea syndrome ( OSAS ; defined as an apnea-hypopnea index ( AHI ) of > 15/h of sleep during a polysomnographic recording ) were followed for a median period of 887 days . The main outcome measure was the risk ratio for elderly patients associated with nCPAP compliance . Results : Four patients , who remained under treatment , died before the end of the study , and 50 patients stopped their nCPAP therapy for reasons other than death ( insomnia , equipment too noisy , etc . ) . When compliance curves were compared by univariate analysis ( log-rank test ) , the oldest group ( 57/163 patients , > 60 years old ) was significantly less compliant with nCPAP than the youngest ( P=0.01 ) . However , in the Cox 's proportional hazards model , age did not exert any independent effect on compliance with nCPAP after controlling for confounding factors ( adjusted relative risk , 1.09 , 0.5 - 2 ; P=0.70 ) . On the other h and , female sex ( adjusted relative risk , 2.8 , 1.4 - 5.4 ; P=0.002 ) , a body mass index ( BMI ) of < /=30 kg/m(2 ) ( adjusted relative risk , 2.2 , 1.2 - 4 ; P=0.006 ) , an Epworth sleepiness scale ( ESS ) score of < /=15 ( adjusted relative risk , 3.2 , 1.1 - 8.9 ; P=0.025 ) , an AHI of < /=30/h ( adjusted relative risk , 2.2 , 1.2 - 4 ; P=0.01 ) and a nCPAP of > /=12 cmH(2)O ( adjusted relative risk , 2.3 , 1.2 - 4.4 ; P=0.011 ) were predictive factors for non-compliance . Conclusion : This study suggests that there is no independent effect of age on compliance with nCPAP therapy [23598607] BACKGROUND OSA is extremely common among patients with resistant hypertension ( HTN ) . However , the impact of the treatment of OSA with CPAP on BP in patients with resistant HTN is not well established . METHODS In the current study , 40 patients with confirmed resistant HTN and moderate to severe OSA confirmed by full polysomnography were r and omized to medical therapy or to medical treatment plus CPAP for 6 months . Patients were evaluated at study baseline and after 6 months by 24-h ambulatory BP monitoring ( ABPM ) . RESULTS Thirty-five patients ( 77 % men ; age , 56 ± 1 years ; BMI , median 32 kg/m² [ 25%-75 % , 28 - 39 kg/m² ] ; apnea-hypopnea index , 29 events/h [ 24 - 48 events/h ] ; Epworth Sleepiness Scale , 10 ± 1 ; systolic/diastolic office BP , 162 ± 4/97 ± 2 mm Hg ; taking four [ four to five ] antihypertensive drugs ) completed the study . CPAP was used for 6:01 ± 0:20 h/night ( 3:42 - 7:44 h/night ) . Compared with the control group , awake systolic/diastolic ABPM decreased significantly in the CPAP group ( Δ : + 3.1 ± 3.3 /+2.1 ± 2.7 mm Hg vs -6.5 ± 3.3/-4.5 ± 1.9 mm Hg , respectively , P < .05 ) . Interestingly , the BP changes were observed only while patients were awake , but not during nocturnal ABPM ( Δ : + 2.8 ± 4.5/+1.8 ± 3.5 mm Hg vs + 1.6 ± 3.5/+0.8 ± 2.9 mm Hg , P = NS ) . CONCLUSIONS The treatment of OSA with CPAP significantly reduces daytime BP in patients with resistant HTN . Therefore , our study reinforces the importance of recognizing and treating OSA in patients with resistant HTN . TRIAL REGISTRY Clinical Trials.gov ; No. : NCT00812695 ; URL : www . clinical trials.gov [1874716] Background Obstructive sleep apnea ( OSA ) is a prevalent and serious medical condition characterized by repeated complete or partial obstructions of the upper airway during sleep and is prevalent in 2 % to 4 % of working middle-aged adults . Nasal continuous positive airway pressure ( CPAP ) is the gold-st and ard treatment for OSA . Because compliance rates with CPAP therapy are disappointingly low , effective interventions are needed to improve CPAP compliance among patients diagnosed with OSA . Objective The aim was to determine whether wireless telemonitoring of CPAP compliance and efficacy data , compared to usual clinical care , results in higher CPAP compliance and improved OSA outcomes . Methods 45 patients newly diagnosed with OSA were r and omized to either telemonitored clinical care or usual clinical care and were followed for their first 2 months of treatment with CPAP therapy . CPAP therapists were not blinded to the participants ’ treatment group . Results 20 participants in each group received the design ated intervention . Patients r and omized to telemonitored clinical care used CPAP an average of 4.1 ± 1.8 hours per night , while the usual clinical care patients averaged 2.8 ± 2.2 hours per night ( P = .07 ) . Telemonitored patients used CPAP on 78 % ± 22 % of the possible nights , while usual care patients used CPAP on 60 % ± 32 % of the nights ( P = .07 ) . No statistically significant differences between the groups were found on measures of CPAP efficacy , including measures of mask leak and the Apnea-Hypopnea Index . Patients in the telemonitored group rated their likelihood to continue using CPAP significantly higher than the patients in the usual care group . Patients in both groups were highly satisfied with the care they received and rated themselves as “ not concerned ” that their CPAP data were being wirelessly monitored . Conclusions Telemonitoring of CPAP compliance and efficacy data and rapid use of those data by the clinical sleep team to guide the collaborative ( ie , patient and provider ) management of CPAP treatment is as effective as usual care in improving compliance rates and outcomes in new CPAP users . This study was design ed as a pilot — larger , well-powered studies are necessary to fully evaluate the clinical and economic efficacy of telemonitoring for this population [10805822] BACKGROUND Sleep-disordered breathing is prevalent in the general population and has been linked to chronically elevated blood pressure in cross-sectional epidemiologic studies . We performed a prospect i ve , population -based study of the association between objective ly measured sleep-disordered breathing and hypertension ( defined as a laboratory-measured blood pressure of at least 140/90 mm Hg or the use of antihypertensive medications ) . METHODS We analyzed data on sleep-disordered breathing , blood pressure , habitus , and health history at base line and after four years of follow-up in 709 participants of the Wisconsin Sleep Cohort Study ( and after eight years of follow-up in the case of 184 of these participants ) . Participants were assessed overnight by 18-channel polysomnography for sleep-disordered breathing , as defined by the apnea-hypopnea index ( the number of episodes of apnea and hypopnea per hour of sleep ) . The odds ratios for the presence of hypertension at the four-year follow-up study according to the apnea-hypopnea index at base line were estimated after adjustment for base-line hypertension status , body-mass index , neck and waist circumference , age , sex , and weekly use of alcohol and cigarettes . RESULTS Relative to the reference category of an apnea-hypopnea index of 0 events per hour at base line , the odds ratios for the presence of hypertension at follow-up were 1.42 ( 95 percent confidence interval , 1.13 to 1.78 ) with an apnea-hypopnea index of 0.1 to 4.9 events per hour at base line as compared with none , 2.03 ( 95 percent confidence interval , 1.29 to 3.17 ) with an apnea-hypopnea index of 5.0 to 14.9 events per hour , and 2.89 ( 95 percent confidence interval , 1.46 to 5.64 ) with an apnea-hypopnea index of 15.0 or more events per hour . CONCLUSIONS We found a dose-response association between sleep-disordered breathing at base line and the presence of hypertension four years later that was independent of known confounding factors . The findings suggest that sleep-disordered breathing is likely to be a risk factor for hypertension and consequent cardiovascular morbidity in the general population [11734445] The evidence linking sleep-disordered breathing to increased mortality and cardiovascular morbidity has been conflicting and inconclusive . We hypothesized that a potential adverse effect of disordered breathing would be more obvious in patients with established vascular disease . In a prospect i ve cohort study 408 patients aged 70 yr or younger with verified coronary disease were followed for a median period of 5.1 yr . An apnea-hypopnea index ( AHI ) of > or = 10 and an oxygen desaturation index ( ODI ) of > or = 5 were used as the diagnostic criteria for sleep-disordered breathing . The primary end point was a composite of death , cerebrovascular events , and myocardial infa rct ion . There was a 70 % relative increase and a 10.7 % absolute increase in the primary composite end point in patients with disordered breathing defined as an ODI of > or = 5 ( risk ratio 1.70 , 95 % confidence interval [ CI ] 1.15 - 2.52 , p = 0.008 ) . Similarly , patients with an AHI of > or = 10 had a 62 % relative increase and a 10.1 % absolute increase in the composite endpoint ( risk ratio 1.62 , 95 % CI 1.09 - 2.41 , p = 0.017 ) . An ODI of > or = 5 and an AHI of > or = 10 were both independently associated with cerebrovascular events ( hazard ratio 2.62 , 95 % CI 1.26 - 5.46 , p = 0.01 , and hazard ratio 2.98 , 95 % CI 1.43 - 6.20 , p = 0.004 , respectively ) . We conclude that sleep-disordered breathing in patients with coronary artery disease is associated with a worse long-term prognosis and has an independent association with cerebrovascular events [19406983] RATIONALE Obstructive sleep apnea ( OSA ) is an independent risk factor for stroke , but little is known about the role of continuous positive airway pressure ( CPAP ) on mortality in patients with stroke . OBJECTIVES To analyze the independent impact of long-term CPAP treatment on mortality in patients with ischemic stroke . METHODS Prospect i ve observational study in 166 patients with ischemic stroke . Sleep study was performed in all of them and CPAP treatment was offered in the case of moderate to severe cases . Patients were followed-up for 5 years to analyze the risk of mortality . MEASUREMENTS AND MAIN RESULTS Of 223 patients consecutively admitted for stroke , a sleep study was performed on 166 of them ( 2 mo after the acute event ) . Thirty-one had an apnea-hypopnea index ( AHI ) of less than 10 ; 39 had an AHI between 10 and 19 , and 96 had an AHI of 20 or greater . CPAP treatment was offered when AHI was 20 or greater . Patients were followed up in our outpatient clinic at 1 , 3 , and 6 months , and for every 6 months thereafter for 5 years ( prospect i ve observational study ) . Mortality data were recorded from our computer data base and official death certificates . The mean age of subjects was 73.3 + /- 11 years ( 59 % males ) , and the mean AHI was 26 ( for all patients with a predominance of obstructive events ) . Patients with an AHI of 20 or greater who did not tolerate CPAP ( n = 68 ) showed an increase adjusted risk of mortality ( hazards ratio [ HR ] , 2.69 ; 95 % confidence interval [ CI ] , 1.32 - 5.61 ) compared with patients with an AHI of less than 20 ( n = 70 ) , and an increased adjusted risk of mortality ( HR , 1.58 ; 95 % CI , 1.01 - 2.49 ; P = 0.04 ) compared with patients with moderate to severe OSA who tolerated CPAP ( n = 28 ) . There were no differences in mortality among patients without OSA , patients with mild disease , and patients who tolerated CPAP . CONCLUSIONS Our results suggest that long-term CPAP treatment in moderate to severe OSA and ischemic stroke is associated with a reduction in excess risk of mortality [15716221] BACKGROUND CPAP remains the treatment of choice for Obstructive Sleep Apnea Hypopnea Syndrome ( OSAHS ) , but compliance with CPAP is poor . Of many interventions tried to improve CPAP compliance , only education and humidification have been shown to be of benefit . Our purpose was to develop and pilot test a video to enhance patient underst and ing of obstructive sleep apnea and of the purpose , logistics , and benefits of CPAP use in patients newly diagnosed with OSAHS . A patient 's CPAP compliance in the first few weeks after starting its use is predictive of long-term compliance with CPAP treatment . It is imperative that patients grasp at the outset both the severity of OSAHS and the effectiveness of CPAP therapy . METHODS An educational video script was written based on recommendations for patient educational video material s and covering identified misconceptions about OSAHS and perceived barriers to CPAP use . The videotape is 15 min in length and features two middle-aged males , one African-American and one Euro-American , discussing OSAHS and CPAP in a factory break room . RESULTS In a r and omized two-group design with a control group , patients with newly diagnosed OSAHS , and who viewed the CPAP educational video on their first clinic , were significantly more likely to use their machine and to return for a 1-month clinic visit than were those in the control group . CONCLUSION Viewing of a patient education video at the initial visit was found to significantly improve the rate of return for the follow-up visit [24810282] BACKGROUND Poor adherence to CPAP treatment in OSA adversely affects the effectiveness of this therapy . This r and omized controlled trial ( RCT ) examined the efficacy of a brief motivational enhancement education program in improving adherence to CPAP treatment in subjects with OSA . METHODS Subjects with newly diagnosed OSA were recruited into this RCT . The control group received usual advice on the importance of CPAP therapy and its care . The intervention group received usual care plus a brief motivational enhancement education program directed at enhancing the subjects ' knowledge , motivation , and self-efficacy to use CPAP through the use of a 25-min video , a 20-min patient-centered interview , and a 10-min telephone follow-up . Self-reported daytime sleepiness adherence-related cognitions and quality of life were assessed at 1 month and 3 months . CPAP usage data were downloaded at the completion of this 3-month study . RESULTS One hundred subjects with OSA ( mean ± SD , age 52 ± 10 years ; Epworth Sleepiness Scales [ ESS ] , 9 ± 5 ; median [ interquartile range ] apnea-hypopnea index , 29 [ 20 , 53 ] events/h ) prescribed CPAP treatment were recruited . The intervention group had better CPAP use ( higher daily CPAP usage by 2 h/d [ Cohen d = 1.33 , P < .001 ] , a fourfold increase in the number using CPAP for ≥ 70 % of days with ≥ 4 h/d [ P < .001 ] ) , and greater improvements in daytime sleepiness ( ESS ) by 2.2 units ( P = .001 ) and treatment self-efficacy by 0.2 units ( P = .012 ) compared with the control group . CONCLUSIONS Subjects with OSA who received motivational enhancement education in addition to usual care were more likely to show better adherence to CPAP treatment , with greater improvements in treatment self-efficacy and daytime sleepiness . TRIAL REGISTRY Clinical Trials.gov ; No. : NCT01173406 ; URL : www . clinical trials.gov [23179140] Purpose Auto-titrating continuous positive airway pressure ( APAP ) is an effective treatment for obstructive sleep apnea/hypopnea syndrome ( OSAHS ) . We investigated whether a single group education session on APAP therapy is effective in promoting adherence among patients with OSAHS . Methods This prospect i ve , r and omized , controlled , parallel group study included patients newly diagnosed with OSAHS who met criteria for APAP therapy . Patients were r and omized into a study group and a control group . All patients in the study group were assigned to a single group education session , 1 month after beginning APAP therapy . Results We evaluated 146 patients . The median percentage of APAP usage days was 88.3 % , with a median duration per day of use of 6.02 h ; 59 % were classified as adherent . Overall , no significant difference in adherence was seen between the study and the control groups . Analyzing patient subgroups , the group session significantly improved APAP adherence among males and patients who were younger ( < 65 years old ) , obese ( BMI ≥35 kg/m2 ) , non-sleepy ( Epworth sleepiness scale ≤11 ) , smokers or past smokers , had hypertension or nocturia and those with non-severe OSAHS . Conclusion To maximize the impact of group education sessions and , by that , saving re sources , it may be important to select patients likely to benefit from these sessions [21886365] BACKGROUND New approaches are needed to treat patients with stroke . Among acute ischemic stroke patients , our primary objectives were to describe the prevalence of sleep apnea and demonstrate the feasibility of providing auto-titrating continuous positive airway pressure ( auto-CPAP ) . A secondary objective was to examine the effect of auto-CPAP on stroke severity . METHODS Stroke patients r and omized to the intervention group received 2 nights of auto-CPAP , but only those with evidence of sleep apnea received auto-CPAP for the remainder of the 30-day period . Intervention patients received polysomnography 30 days post-stroke . Control patients received polysomnography at baseline and after 30 days . Acceptable auto-CPAP adherence was defined as ≥ 4 h/night for ≥ 75 % nights . Change in stroke severity was assessed comparing the NIH Stroke Scale ( NIHSS ) at baseline versus at 30 days . RESULTS The 2 groups ( intervention N = 31 , control N = 24 ) had similar baseline stroke severity ( both median NIHSS , 3.0 ) . Among patients with complete polysomnography data , the majority had sleep apnea : baseline , 13/15 ( 86.7 % ) control patients ; 30 days , 24/35 ( 68.6 % ) control and intervention patients . Intervention patients had greater improvements in NIHSS ( -3.0 ) than control patients ( -1.0 ) ; P = 0.03 . Among patients with sleep apnea , greater improvement was observed with increasing auto-CPAP use : -1.0 for control patients not using auto-CPAP ; -2.5 for intervention patients with some auto-CPAP use ; and -3.0 for intervention patients with acceptable auto-CPAP adherence . CONCLUSIONS The majority of acute stroke patients had sleep apnea . Auto-CPAP was well tolerated , appears to improve neurological recovery from stroke , and may represent a new therapeutic approach for selected patients with acute cerebral infa rct ion [10679542] BACKGROUND Obstructive sleep apnoea ( OSA ) impairs vigilance and may lead to an increased rate of driving accidents . In uncontrolled studies accident rates and simulated steering performance improve following treatment with nasal continuous positive airway pressure ( NCPAP ) . This study seeks to confirm the improvement in steering performance in a r and omised controlled trial using subtherapeutic NCPAP as a control treatment . METHODS Fifty nine men with OSA ( Epworth Sleepiness Score ( ESS ) of > or = 10 , and > or = 10/h dips in SaO(2 ) of > 4 % due to OSA ) received therapeutic or subtherapeutic NCPAP ( approximately 1 cm H(2)O ) for one month . Simulated steering performance over three 30-minute " drives " was quantified as : st and ard deviation ( SD ) of road position , deterioration in SD across the drive , length of drive before " crashing " , and number of off-road events . The reaction times to peripheral target stimuli during the drive were also measured . RESULTS Subtherapeutic NCPAP did not improve overnight > 4 % SaO(2 ) dips/h compared with baseline values , thus acting as a control . The SD of the steering position improved from 0.36 to 0.21 on therapeutic NCPAP , and from 0.35 to 0.30 on subtherapeutic NCPAP ( p = 0.03 ) . Deterioration in SD of the steering position improved from 0.18 to 0.06 SD/h with therapeutic NCPAP and worsened from 0.18 to 0.24 with subtherapeutic NCPAP ( p = 0.04 ) . The reaction time to target stimuli was quicker after therapeutic than after subtherapeutic NCPAP ( 2.3 versus 2.7 seconds , p = 0.04 ) . CONCLUSIONS Therapeutic NCPAP improves steering performance and reaction time to target stimuli in patients with OSA , lending further support to the hypothesis that OSA impairs driving , increases driving accident rates , and that these improve following treatment with NCPAP [14658968] BACKGROUND Results of clinical studies suggest that there may be a relationship between breathing-related sleep disorders and depressive disorders . This study aims to assess the impact of breathing-related sleep disorder on major depressive disorder in the general population . METHOD A cross-sectional telephone survey was carried out between 1994 and 1999 in the general population of the United Kingdom , Germany , Italy , Portugal , and Spain . A total of 18,980 r and omly selected subjects aged 15 to 100 years and representative of the general population of their respective countries participated in the study . The question naire included a series of questions about sleep quality , breathing-related sleep disorder symptoms , mental disorders , and medical conditions . Data are presented using point prevalence . RESULTS 2.1 % of the subjects were found with obstructive sleep apnea syndrome at the time of the interview , and 2.5 % had some other type of DSM-IV breathing-related sleep disorder diagnosis . The association of DSM-IV breathing-related sleep disorder diagnosis and major depressive disorder diagnosis was found in 0.8 % of the sample . As many as 18 % of individuals with a major depressive disorder diagnosis also have a DSM-IV breathing-related sleep disorders diagnosis , and 17.6 % of subjects with a DSM-IV breathing-related sleep disorders diagnosis have a major depressive disorder diagnosis . Multivariate models showed that even after controlling for obesity and hypertension , the odds of having a DSM-IV breathing-related sleep disorders diagnosis was 5.26 for individuals with a major depressive disorder diagnosis . CONCLUSION About 800 of 100,000 individuals have both a breathing-related sleep disorder and a major depressive disorder . The identification of 1 of these 2 disorders should prompt the investigation of the other disorder since nearly a fifth of them have the other disorder [21804670] STUDY OBJECTIVES ( 1 ) To determine the efficacy of automatically adjusted positive airway pressure ( APAP ) with a comfort feature ( A-Flex ) at reducing apneas and hypopneas in participants with moderate to severe OSA . ( 2 ) To determine the relative difference between A-Flex , continuous positive airway pressure ( CPAP ) , and APAP-derived optimal pressure for CPAP ( CPAP(APAP ) ) on adherence to treatment . ( 3 ) To determine the relative difference between APAP with A-Flex , CPAP , and CPAP(APAP ) on long-term change in functional outcomes . DESIGN R and omized , double-blinded , 3-arm , multicenter trial . SETTING University and Veterans Affairs medical centers . PATIENTS OR PARTICIPANTS 168 participants were r and omized , and 140 completed the 180-day study . INTERVENTIONS ( 1 ) A-Flex ; ( 2 ) CPAP ; ( 3 ) APAP for 14 days and then switched to CPAP at a fixed pressure . MEASUREMENTS AND RESULTS Apnea-hypopnea indices , average and minimum oxygen saturation , time spent < 90 % were significantly poorer for A-Flex vs. CPAP at the initiation of study treatment ; with the exception of minimum oxygen saturation , these differences were absent at 180 days . A-Flex had lower average leak values at both 3 and 6 months . There were no significant differences between groups in major efficacy , adherence , and outcome ( subjective sleepiness , objective vigilance , blood pressure , quality of life ) measures . No differences between groups in attitudes toward use were observed at 3 or 6 months ; participant ratings for CPAP were significantly higher than A-Flex on treatment satisfaction and benefit , but not different for sleep quality and mask comfort . CONCLUSIONS We found that A-Flex shows equivalency , but non-superiority ( except for average leak values ) , in efficacy , adherence , and functional outcomes compared to CPAP after either 3 or 6 months . CLINICAL TRIAL REGISTRY Positive Pressure Treatment of Obstructive Sleep Apnea , http://www . clinical trials.gov , NCT00636181 [25364081] STUDY OBJECTIVES Obstructive sleep apnea ( OSA ) has been associated with hypertension , which is one of the intermediary mechanisms leading to increased cardiovascular morbidity . This study aim ed at evaluating the effects of a combination of continuous positive airway pressure ( CPAP ) and telemedicine support on blood pressure ( BP ) reduction in high cardiovascular risk OSA patients . DESIGN A multi-center r and omized controlled trial that compared st and ard CPAP care and CPAP care and a telemedicine intervention . SETTING Sleep clinics in France . PATIENTS OR PARTICIPANTS 107 adult ( 18 - 65 years old ) OSA patients ( AHI > 15 events/h ) with a high cardiovascular risk ( cardiovascular SCORE > 5 % or secondary prevention ) . INTERVENTIONS Patients were r and omized to either st and ard care CPAP ( n = 53 ) or CPAP and telemedicine ( n = 54 ) . Patients assigned to telemedicine were equipped with a smartphone for uploading BP measurements , CPAP adherence , sleepiness , and quality of life data ; in return , they received pictograms containing health-related messages . MEASUREMENTS The main outcome was home self-measured BP and secondary outcomes were cardiovascular risk evolution , objective physical activity , CPAP adherence , sleepiness and quality of life . RESULTS Self-measured BP did not improve in either group ( telemedicine or st and ard care ) . Patients in primary prevention showed greater BP reduction with CPAP treatment than those in secondary prevention . CONCLUSIONS CPAP treatment supported by telemedicine alone did not improve blood pressure and cardiovascular risk in high cardiovascular risk OSA patients . This study emphasizes the need for diet and physical activity training programs in addition to CPAP when aim ing at decreasing cardiometabolic risk factors in these patients . CLINICAL TRIALS REGISTRATION Clinical Trials.gov identifier : NCT01226641 [2024846] Previous reports have described compliance with nasal continuous positive airway pressure ( nCPAP ) for the treatment of obstructive sleep apnea ( OSA ) only in terms of the number of patients able to use it beyond their initial trial night or those continuing after some home use . Because of a possible difference between the level of compliance ( mean number of hours of use per 24 h ) needed for symptomatic relief of OSA versus cardiovascular improvement , the level of hourly compliance in chronic nCPAP users may be important . The first part of this study prospect ively examines compliance in a stable population of OSA patients already using nCPAP for 6 months to 2 yr . The second part is a prospect i ve r and omized , crossover study examining the effect of weekly ( three times ) then monthly ( twice ) positive reinforcement on hourly compliance of new nCPAP users for 3 months versus no reinforcement for 3 months . Positive reinforcement consisted of telephone discussion s with the patients about the severity or complications of OSA , benefits of nCPAP , and suggestions about minimizing side effects . Using self- assessment scales , each patient reported the perceived level of improvement from the untreated to the treated condition and the prevalence and severity of side effects from the nCPAP therapy . The level of compliance in stable , chronic nCPAP users with OSA was 6.1 + /- 2.2 h/24 h ( n = 9 ) . For the new nCPAP users during the nonreinforced period , the mean compliance was 6.0 + /- 2.8 h/24 h ; that during the reinforcement period was 6.0 + /- 2.7 h/24 h ( NS ) . There was no significant correlation between perceived improvement in OSA symptoms or between the perceived side effects of nCPAP versus hourly compliance . ( ABSTRACT TRUNCATED AT 250 WORDS [14592213] BACKGROUND Obstructive sleep apnea is a prevalent condition with potentially serious medical and psychosocial consequences . Nasal continuous positive airway pressure ( CPAP ) is the treatment-of-choice and has been shown to reduce the frequency of nocturnal respiratory events , improve sleep architecture and decrease daytime sleepiness . Patient compliance with CPAP is disappointingly low . Previous studies examining determinants of CPAP compliance have limited the variables studied to patient ( sociodemographic ) , disease status , and treatment variables , with few reliable determinants found . METHODS The purpose of the current study was to investigate the relationship between objective ly measured CPAP compliance and variables from social cognitive theory ( SCT ) and the transtheoretical model ( TM ) . Scales that measure variables from each model were developed and reliability evaluated . The relationship between the SCT and TM variables and compliance at 1-month post-CPAP-fitting was prospect ively evaluated on 51 first-time CPAP users . SCT and TM variables were measured on the day of CPAP-fitting , at 1-week post-CPAP-fitting , and at 1-month post-CPAP-fitting . RESULTS SCT variables measured 1-week post-CPAP-fitting ( R(2)=0.261 , P=0.001 ) and TM variables measured 1-week post-CPAP-fitting ( R(2)=0.17 , P=0.002 ) accounted for a statistically significant amount of variance in objective CPAP compliance measured at 1 month . The decisional balance index ( from TM ) individually accounted for a significant amount of variance in objective CPAP compliance in the above analyses . CONCLUSIONS The ability of these new behavior change scales to predict CPAP compliance provides us with a new direction of research to better underst and factors associated with compliance . The principal advantage of these theory-driven and empirically vali date d scales are that they measure modifiable factors that can provide the basis for sound interventions to improve CPAP compliance [15033131] BACKGROUND AND PURPOSE To evaluate ( a ) whether an active weight reduction strategy based on the cognitive-behavioral approach and an initial very-low-calorie diet might lead to short- and long-term weight loss and alleviation of OSAS ; and ( b ) whether the results of this intervention could be enhanced by combining it with nasal continuous positive airway pressure ( CPAP ) treatment during the first 6 months . PATIENTS AND METHODS Thirty-one obese male symptomatic sleep apnea patients underwent a 2-year weight reduction program with total follow-up of 36 months from baseline . The mean age ( + /-SD ) was 49.1+/-7.9 years , body mass index 43.8+/-5.4 , and oxygen desaturation index ( ODI4 ) 51.3+/-31.1 . The patients were r and omized to CPAP ( 17 patients ) and non-CPAP groups ( 14 patients ) . RESULTS The mean weight loss was 19.1+/-10.2 kg ( 14 % of the original weight ) for the whole group at 6 months , 18.3+/-13.2 ( 13 % ) at 12 months and 12.6+/-14.7 kg ( 9 % ) at 24 months . Excellent or good treatment results , as defined in terms of an ODI4 ( average number of oxygen desaturation events p/h>4 % from baseline ) reduction of at least 50 % from the baseline , were seen in 61 % of patients at 6 months and were still observable in 42 % of patients at 24 months . The correlations between changes in weight and in ODI4 were 0.59 ( P<0.01 ) at 6 months , 0.68 ( P<0.01 ) and 0.75 ( P<0.01 ) at 24 months . Adding CPAP treatment to the weight reduction therapy for the first 6 months did not result in greater weight loss or diminution of desaturation indices ( without CPAP ) at any time point . One year after the termination of the program the mean weight loss was 6.6+/-12.9 kg , and 42 % of patients still showed at least 5 % weight loss as compared with their original weight . CONCLUSION Satisfactory weight loss associated with improvement of OSAS could be achieved by means of a cognitive-behavioral weight loss program . Adding CPAP in the initial phase of the weight reduction program did not result in significantly greater weight loss [22983957] RATIONALE Obstructive sleep apnea ( OSA ) is a risk factor for cardiovascular death in middle-aged subjects , but it is not known whether it is also a risk factor in the elderly . OBJECTIVES To investigate whether OSA is a risk factor for cardiovascular death and to assess whether continuous positive airway pressure ( CPAP ) treatment is associated with a change in risk in the elderly . METHODS Prospect i ve , observational study of a consecutive cohort of elderly patients ( ≥65 yr ) studied for suspicion of OSA between 1998 and 2007 . Patients with an apnea-hypopnea index ( AHI ) less than 15 were the control group . OSA was defined as mild to moderate ( AHI , 15 - 29 ) or severe ( AHI , ≥30 ) . Patients with OSA were classified as CPAP-treated ( adherence ≥ 4 h/d ) or untreated ( adherence < 4 h/d or not prescribed ) . Participants were monitored until December 2009 . The end point was cardiovascular death . A multivariate Cox survival analysis was used to determine the independent impact of OSA and CPAP treatment on cardiovascular mortality . MEASUREMENTS AND MAIN RESULTS A total of 939 elderly were studied ( median follow-up , 69 mo ) . Compared with the control group , the fully adjusted hazard ratios for cardiovascular mortality were 2.25 ( confidence interval [ CI ] , 1.41 to 3.61 ) for the untreated severe OSA group , 0.93 ( CI , 0.46 to 1.89 ) for the CPAP-treated group , and 1.38 ( CI , 0.73 to 2.64 ) for the untreated mild to moderate OSA group . CONCLUSIONS Severe OSA not treated with CPAP is associated with cardiovascular death in the elderly , and adequate CPAP treatment may reduce this risk [17552379] STUDY OBJECTIVE To improve adherence to continuous positive airway pressure ( CPAP ) treatment in participants with obstructive sleep apnea ( OSA ) using a cognitive behavioral therapy ( CBT ) intervention . DESIGN A r and omized controlled trial . SETTING A major teaching hospital in Sydney ( 2005 ) . PARTICIPANTS One hundred individuals ( 96 men ) , ranging in age from 32 to 81 years , diagnosed with OSA . INTERVENTION Two 1-hour CBT interventions ( including a video of real CPAP users ) plus treatment as usual ( mask fitting and information ) or treatment as usual only . MEASUREMENTS AND RESULTS Hours of CPAP usage was assessed at 7 nights and 28 nights . Adherence was defined as usage at least 4 hours per night . Question naires measuring self-efficacy , social support , and expectancy ( mediators of adherence ) were given after intervention or after usual treatment . A higher adherence to CPAP therapy was found in the CBT group ( 2.9 hours difference ) relative to treatment as usual ( P < 0.001 ) at 28 days . Only 4 participants in the CBT group did not initiate treatments after their titration study , compared with 15 in the treatment as usual group ( P < 0.02 ) . The CBT group had significantly higher scores for self-efficacy ( P < 0.001 ) and social support P < 0.008 ) but not for expectancy . CONCLUSIONS The CBT intervention result ed in both increased adherence and " uptake " of CPAP and therefore would be expected to reduce the social , economic , and health-related consequences of untreated OSA [21828324] CONTEXT Sleep-disordered breathing ( characterized by recurrent arousals from sleep and intermittent hypoxemia ) is common among older adults . Cross-sectional studies have linked sleep-disordered breathing to poor cognition ; however , it remains unclear whether sleep-disordered breathing precedes cognitive impairment in older adults . OBJECTIVES To determine the prospect i ve relationship between sleep-disordered breathing and cognitive impairment and to investigate potential mechanisms of this association . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve sleep and cognition study of 298 women without dementia ( mean [ SD ] age : 82.3 [ 3.2 ] years ) who had overnight polysomnography measured between January 2002 and April 2004 in a sub study of the Study of Osteoporotic Fractures . Sleep-disordered breathing was defined as an apnea-hypopnea index of 15 or more events per hour of sleep . Multivariate logistic regression was used to determine the independent association of sleep-disordered breathing with risk of mild cognitive impairment or dementia , adjusting for age , race , body mass index , education level , smoking status , presence of diabetes , presence of hypertension , medication use ( antidepressants , benzodiazepines , or nonbenzodiazepine anxiolytics ) , and baseline cognitive scores . Measures of hypoxia , sleep fragmentation , and sleep duration were investigated as underlying mechanisms for this relationship . MAIN OUTCOME MEASURES Adjudicated cognitive status ( normal , dementia , or mild cognitive impairment ) based on data collected between November 2006 and September 2008 . RESULTS Compared with the 193 women without sleep-disordered breathing , the 105 women ( 35.2 % ) with sleep-disordered breathing were more likely to develop mild cognitive impairment or dementia ( 31.1 % [ n = 60 ] vs 44.8 % [ n = 47 ] ; adjusted odds ratio [ AOR ] , 1.85 ; 95 % confidence interval [ CI ] , 1.11 - 3.08 ) . Elevated oxygen desaturation index ( ≥15 events/hour ) and high percentage of sleep time ( > 7 % ) in apnea or hypopnea ( both measures of disordered breathing ) were associated with risk of developing mild cognitive impairment or dementia ( AOR , 1.71 [ 95 % CI , 1.04 - 2.83 ] and AOR , 2.04 [ 95 % CI , 1.10 - 3.78 ] , respectively ) . Measures of sleep fragmentation ( arousal index and wake after sleep onset ) or sleep duration ( total sleep time ) were not associated with risk of cognitive impairment . CONCLUSION Among older women , those with sleep-disordered breathing compared with those without sleep-disordered breathing had an increased risk of developing cognitive impairment [26065720] BACKGROUND Despite the increasing aging population and the high prevalence of OSA in elderly adults , little is known about cognitive effects of OSA and the effectiveness of CPAP treatment . Therefore , this study investigated whether elderly patients with OSA present cognitive deficits and functional and structural alterations of the brain that could be improved by CPAP treatment . METHODS This r and omized , evaluator-blinded , parallel-group , single-center pilot study involved patients aged ≥ 65 years with newly-diagnosed severe OSA syndrome . Thirty-three patients were assigned to receive either conservative care ( CC ) or CPAP plus CC for 3 months . At baseline and 3 months after treatment , patients underwent a neuropsychologic evaluation and a functional and structural MRI study of connectivity within the default mode network ( DMN ) and of cortical thickness . RESULTS Neuropsychologic evaluation revealed no differences in cognitive performance between OSA groups at baseline . By contrast , after CPAP treatment , patients showed a significant improvement in episodic ( between-group difference in change , 7.60 ; 95 % CI , 1.66 - 13.55 ; P = .014 ) and short-term memory ( between-group difference in change , 1.06 ; 95 % CI , 0.10 - 2.01 ; P = .032 ) and in executive function ( speed of mental processing , 5.74 ; 95 % CI , 1.69 - 9.79 ; P = .007 ; mental flexibility , -47.64 ; 95 % CI , -81.83 to -13.45 ; P = .008 ) , whereas no changes were observed in the CC group . Neuroimaging revealed an increase in the connectivity in the right middle frontal gyrus after 3 months of CPAP treatment and a higher percentage of cortical thinning in the CC group . No association was seen between cognition and brain functional connectivity changes within the DMN . CONCLUSIONS Elderly patients with severe OSA who present with cognitive difficulties could benefit from CPAP treatment . Moreover , CPAP treatment increases the connectivity of the DMN and attenuates cortical thinning . TRIAL REGISTRY Clinical Trials.gov ; No. : NCT01826032 ; URL : www . clinical trials.gov [22467985] STUDY OBJECTIVES First-line therapy for patients with moderate to severe obstructive sleep apnea ( OSA ) is positive airway pressure ( PAP ) . Although PAP is a highly efficacious treatment , adherence to PAP is still a substantial clinical problem . The objective of this study was to determine whether PAP adherence can be improved with a telemedicine monitoring system . DESIGN A nonblinded , single-center , r and omized controlled trial that compared st and ard PAP treatment versus PAP treatment and a telemedicine monitoring system SETTING University sleep disorders program in British Columbia , Canada PATIENTS Adult patients ( ≥ 19 yr of age ) with moderate to severe OSA ( apnea hypopnea index ( AHI ) ≥ 15 events/hr determined by polysomnography ) prescribed PAP INTERVENTIONS : Patients were r and omized to either st and ard care with an autotitrating PAP machine or an autotitrating PAP machine that transmitted physiologic information ( i.e. , adherence , air leak , residual AHI ) daily to a website that could be review ed . If problems were identified from information from the website , the patient was contacted by telephone as necessary . MEASUREMENTS PAP adherence after 3 mo , subjective sleep quality , and side effects RESULTS Seventy-five patients were enrolled ; 39 were r and omized to telemedicine and 36 to st and ard care . The mean age ± st and ard deviation ( SD ) was 53.5 ± 11.2 yr , mean AHI was 41.6 ± 22.1 events/hr , and 80 % of patients were male . After 3 mo , mean PAP adherence was significantly greater in the telemedicine arm ( 191 min per day ) versus the st and ard arm ( 105 min per day ; mean difference = 87 min , 95 % confidence interval ( CI ) : 25 - 148 min , P = 0.006 , unpaired t test ) . On days when PAP was used , mean adherence was 321 min in the telemedicine arm and 207 min in the st and ard arm ( difference = 113 min , 95 % CI : 62 - 164 min , P < 0.0001 ) . Significant independent predictors of adherence included age , baseline Epworth Sleepiness Scale score , and use of telemedicine . On average , an additional 67 min of technician time was spent on patients in the telemedicine arm compared with the st and ard arm ( P = 0.0001 ) . CONCLUSIONS PAP adherence can be improved with the use of a web-based telemedicine system at the initiation of treatment [19136368] RATIONALE Obstructive sleep apnea ( OSA ) is a prevalent disease . Often limited clinical re sources result in long patient waiting lists . Simpler vali date d methods of care are needed . OBJECTIVES To demonstrate that a nurse-led model of care can produce health outcomes in symptomatic moderate-severe OSA not inferior to physician-led care . METHODS A r and omized controlled multicenter noninferiority clinical trial was performed . Of 1,427 potentially eligible patients at 3 centers , 882 consented to the trial . Of these , 263 were excluded on the basis of clinical criteria . Of the remaining 619 , 195 met home oximetry criteria for high-probability moderate-severe OSA and were r and omized to 2 models of care : model A , the simplified model , using home autoadjusting positive airway pressure to set therapeutic continuous positive airway pressure ( CPAP ) , with all care supervised by an experienced nurse ; and model B , involving two laboratory polysomnograms to diagnose and treat OSA , with clinical care supervised by a sleep physician . The primary end point was change in Epworth Sleepiness Scale ( ESS ) score after 3 months of CPAP . Other outcome measures were collected . MEASUREMENTS AND MAIN RESULTS For the primary outcome change in ESS score , nurse-led management was no worse than physician-led management ( 4.02 vs. 4.15 ; difference , -0.13 ; 95 % confidence interval : -1.52 , 1.25 ) given a prespecified noninferiority margin of -2 for the lower 95 % confidence interval . There were also no differences between both groups in CPAP adherence at 3 months or other outcome measures . Within-trial costs were significantly less in model A. CONCLUSIONS A simplified nurse-led model of care has demonstrated noninferior results to physician-directed care in the management of symptomatic moderate-severe OSA , while being less costly . Clinical trial registered with http://www.anzctr.org.au ( ACTRN012605000064606 ) Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: Background Continuous positive airway pressure ( CPAP ) is typically recommended as first line therapy for obstructive sleep apnea , but the adherence rate of CPAP is problematic . This study ’s objective was to systematic ally review the literature relating to CPAP as first line therapy for OSA and compare it to surgical literature on the same topic . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

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[23348607] OBJECTIVE The purpose of this 24-month phase III study was to examine structural preservation with tofacitinib in patients with rheumatoid arthritis ( RA ) with an inadequate response to methotrexate ( MTX ) . Data from a planned 12-month interim analysis are reported . METHODS In this double-blind , parallel-group , placebo-controlled study , patients receiving background MTX were r and omized 4:4:1:1 to tofacitinib at 5 mg twice daily , tofacitinib at 10 mg twice daily , placebo to tofacitinib at 5 mg twice daily , and placebo to tofacitinib at 10 mg twice daily . At month 3 , nonresponder placebo-treated patients were advanced in a blinded manner to receive tofacitinib as indicated above ; remaining placebo-treated patients were advanced at 6 months . Four primary efficacy end points were all analyzed in a step-down procedure . RESULTS At month 6 , response rates according to the American College of Rheumatology 20 % improvement criteria for tofacitinib at 5 mg and 10 mg twice daily were higher than those for placebo ( 51.5 % and 61.8 % , respectively , versus 25.3 % ; both P < 0.0001 ) . At month 6 , least squares mean ( LSM ) changes in total modified Sharp/van der Heijde score for tofacitinib at 5 mg and 10 mg twice daily were 0.12 and 0.06 , respectively , versus 0.47 for placebo ( P = 0.0792 and P ≤ 0.05 , respectively ) . At month 3 , LSM changes in the Health Assessment Question naire disability index score for tofacitinib at 5 mg and 10 mg twice daily were -0.40 ( significance not declared due to step-down procedure ) and -0.54 ( P < 0.0001 ) , respectively , versus -0.15 for placebo . At month 6 , rates of remission ( defined as a value < 2.6 for the 4-variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate ) for tofacitinib at 5 mg and 10 mg twice daily were 7.2 % ( significance not declared due to step-down procedure ) and 16.0 % ( P < 0.0001 ) , respectively , versus 1.6 % for placebo . The safety profile was consistent with findings in previous studies . CONCLUSION Data from this 12-month interim analysis demonstrate that tofacitinib inhibits progression of structural damage and improves disease activity in patients with RA who are receiving MTX [23070312] The approach to treatment of RA has evolved substantially in recent years with the introduction of highly effective novel therapies that have result ed in new treatment paradigms , such as treat-to-target and the treatment of patients earlier in their disease course [ 1 , 2 ] . Clinicians are very interested in studies that compare the effectiveness of medications that could help them achieve optimal treatment outcomes for their patients . Extrapolation of the results of such studies into clinical practice depends on accurate assessment of data from the clinical trials . This assessment has become increasingly challenging as study design s have become increasingly complex , with multiple arms and changes in treatments over the course of a trial . There are many methods to analyse a given set of data ; with the same data set , depending on the method of analysis , different conclusions can be reached . To help st and ardize this process , a European League Against Rheumatism (EULAR)/ACR committee created guidelines on reporting data from clinical trials [ 3 ] . The complexities of this analysis are illustrated by a recent example . The R and omized Comparative Effectiveness Study of Oral Triple Therapy versus Etanercept plus Methotrexate in the Early , Aggressive Rheumatoid Arthritis ( TEAR ) trial was design ed to address two important clinical questions : ( i ) is it better to intensively treat all early RA patients with multiple DMARDs , or reserve this treatment only for those who do not appropriately respond to MTX monotherapy ? and ( ii ) is the combination therapy of MTX plus etanercept ( ETN ) superior to triple combination therapy of MTX , SSZ and HCQ ( TT ) , either initially or after insufficient efficacy of MTX at 6 months ? [ 4 ] . Patients with early RA were r and omly assigned to receive MTX monotherapy , MTX plus ETN or TT . At 6 months , patients treated with MTX monotherapy who did not achieve DAS28 < 3.2 were stepped up to add either ETN or move to TT and treated for 102 weeks . The primary outcome , by the protocol , was the area under the curve ( AUC ) of DAS28 from weeks 48 to 102 . Although many of the items suggested by a joint EULAR/ACR committee on reporting disease activity in clinical trials of patients [ 3 ] were reported , several facets of the methods of data analysis need to be fully understood in order to establish whether the reader concurs with the authors ’ conclusions that this study showed no difference in clinical outcomes at 2 years between patients initially treated with MTX plus ETN or TT . The data reported were an observed analysis only for patients who continued in the trial from week 48 to 102 patients had to have done well clinical ly and not had a significant adverse event to remain in the study through week 48 . A more traditional statistical analysis , such as a nonresponder imputation or last observation carried forward from day 0 to week 102 might have given different results . The first question posed , whether it is more effective to start either combination or MTX monotherapy , was not answered ; the results are not presented for those patients initially treated with MTX who achieved DAS28 < 3.2 at week 26 and then continued to week 102 . The primary outcome reported in the manuscript was an observed group analysis of change in the mean DAS28-ESR from week 48 to 102 and not the AUC of the DAS28 during this time period . The authors stated that their statistical analysis plan was confirmed by their secondary analyses , which did include non-responder imputation and last observation carried forward . However , these analyses were also performed only on patients in the study from week 48 to 102 . In addition to design and statistical considerations , some of the data can be interpreted differently from the authors , and this might be worth some further examination . For instance , the authors reported that there was no difference in the change in DAS28 , or other clinical measures , between the patient groups studied . However , there was a treatment difference at week 102 between the ETN and TT groups for ACR70 ( 18.2 vs 11.3 % , P = 0.02 ) . This would suggest that ETN plus MTX was more effective in achieving a profound response . This difference in profound response may have led to the significant difference in radiographic progression reported with ETN and MTX treatment vs TT at week 102 . The radiographic difference was noted despite the fact that X-rays were not done in patients who withdrew early ; in other studies , results at the time of exit have been extrapolated to the final endpoint to allow comparison . In this case , radiological data are only in those observed or study completers ; by definition , such patients usually fare quite well and patients who do well have less progression of joint damage . Initial TT and initial MTX monotherapy with step-up had similar ACR20/50/70 response rates at 2 years , [19565475] OBJECTIVE To determine the efficacy , safety , and tolerability of 3 different dosages of CP-690,550 , a potent , orally active JAK inhibitor , in patients with active rheumatoid arthritis ( RA ) in whom methotrexate , etanercept , infliximab , or adalimumab caused an inadequate or toxic response . METHODS Patients ( n = 264 ) were r and omized equally to receive placebo , 5 mg of CP-690,550 , 15 mg of CP-690,550 , or 30 mg of CP-690,550 twice daily for 6 weeks , and were followed up for an additional 6 weeks after treatment . The primary efficacy end point was the American College of Rheumatology 20 % improvement criteria ( ACR20 ) response rate at 6 weeks . RESULTS By week 6 , the ACR20 response rates were 70.5 % , 81.2 % , and 76.8 % in the 5 mg , 15 mg , and 30 mg twice daily groups , respectively , compared with 29.2 % in the placebo group ( P < 0.001 ) . Improvements in disease activity in CP-690,550-treated patients compared with placebo were seen in all treatment groups as early as week 1 . ACR50 and ACR70 response rates significantly improved in all treatment groups by week 4 . The most common adverse events reported were headache and nausea . The infection rate in both the 15 mg twice daily group and the 30 mg twice daily group was 30.4 % ( versus 26.2 % in the placebo group ) . No opportunistic infections or deaths occurred . Increases in mean low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels , and increases in mean serum creatinine level ( 0.04 - 0.06 mg/dl ) were seen in all CP-690,550 treatment arms . CONCLUSION Our findings indicate that CP-690,550 is efficacious in the treatment of RA , result ing in rapid , statistically significant , and clinical ly meaningful reductions in the signs and symptoms of RA . Further studies of CP-690,550 in RA are warranted [16255010] OBJECTIVE To assess the efficacy of low-dose prednisolone on joint damage and disease activity in patients with early rheumatoid arthritis ( RA ) . METHODS At the start of their initial treatment with a disease-modifying antirheumatic drug ( DMARD ) , patients with early ( duration < or = 1 year ) active RA were r and omly assigned to receive either 7.5 mg/day prednisolone or no prednisolone for 2 years . Radiographs of the h and s and feet were obtained at baseline and after 1 and 2 years and scored according to the Sharp score as modified by van der Heijde . Remission was defined as a Disease Activity Score in 28 joints of < 2.6 . Bone mineral density was measured by dual x-ray absorptiometry at baseline and after 2 years . RESULTS Of the 250 patients included , 242 completed the study and 225 had radiographs available both at baseline and at 2 years . At 2 years , the median and interquartile range ( IQR ) change in total Sharp score was lower in the prednisolone group than in the no-prednisolone group ( 1.8 [ IQR 0.5 - 6.0 ] versus 3.5 [ IQR 0.5 - 10 ] ; P = 0.019 ) . In the prednisolone group , there were fewer newly eroded joints per patient after 2 years ( median 0.5 [ IQR 0 - 2 ] versus 1.25 [ IQR 0 - 3.25 ] ; P = 0.007 ) . In the prednisolone group , 25.9 % of patients had radiographic progression beyond the smallest detectable difference compared with 39.3 % of patients in the no-prednisolone group ( P = 0.033 ) . At 2 years , 55.5 % of patients in the prednisolone group had achieved disease remission , compared with 32.8 % of patients in the no-prednisolone group ( P = 0.0005 ) . There were few adverse events that led to withdrawal . Bone loss during the 2-year study was similar in the 2 treatment groups . CONCLUSION Prednisolone at 7.5 mg/day added to the initial DMARD retarded the progression of radiographic damage after 2 years in patients with early RA , provided a high remission rate , and was well tolerated . Therefore , the data support the use of low-dose prednisolone as an adjunct to DMARDs in early active RA [18207016] BACKGROUND Circadian rhythms are changed in patients with rheumatoid arthritis . A new modified-release delivery system has been developed which adapts the release of the administered glucocorticoid to the circadian rhythms of endogenous cortisol and disease symptoms to improve the benefit-risk ratio of glucocorticoid therapy in rheumatoid arthritis . We aim ed to assess the efficacy and safety of a new modified-release prednisone tablet compared with immediate-release prednisone in patients with this disease . METHODS In a 12-week , multicentre , r and omised , double-blind trial , 288 patients with active rheumatoid arthritis were r and omly assigned to either a modified-release prednisone tablet ( n=144 ) or to an immediate-release prednisone tablet ( n=144 ) . The modified-release tablet was taken at bedtime and prednisone was released with a delay of 4 h after ingestion . This treatment was compared with morning administration of immediate-release prednisone as an active comparator . The primary outcome measure was duration of morning stiffness of the joints . Analysis was by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00146640 . FINDINGS The mean relative change in duration of morning stiffness of the joints from baseline to end of treatment was significantly higher with modified-release prednisone than with immediate-release prednisone ( -22.7%vs -0.4 % ; difference=22.4 % [ 95 % CI 0.49 - 44.30 ] ; p=0.045 ) . Patients in the prednisone modified-release group achieved a mean reduction of 44.0 ( SD 136.6 ) min compared with baseline . The absolute difference between the treatment groups was 29.2 min ( 95 % CI -2.59 to 61.9 ) in favour of modified-release prednisone ( p=0.072 ) . The safety profile did not differ between treatments . INTERPRETATION Modified-release prednisone is well tolerated , convenient to administer , and produces a clinical ly relevant reduction of morning stiffness of the joints in addition to all known therapeutic effects of immediate-release prednisone [22393128] BACKGROUND Treatment strategies for tight control of early rheumatoid arthritis ( RA ) are highly effective but can be improved . OBJECTIVE To investigate whether adding prednisone , 10 mg/d , at the start of a methotrexate (MTX)-based treatment strategy for tight control in early RA increases its effectiveness . DESIGN A 2-year , prospect i ve , r and omized , placebo-controlled , double-blind , multicenter trial ( CAMERA-II [ Computer Assisted Management in Early Rheumatoid Arthritis trial-II ] ) . ( International St and ard R and omised Controlled Trial Number : IS RCT N 70365169 ) SETTING 7 hospitals in the Netherl and s. PATIENTS 236 patients with early RA ( duration < 1 year ) . INTERVENTION Patients were r and omly assigned to an MTX-based , tight control strategy starting with either MTX and prednisone or MTX and placebo . Methotrexate treatment was tailored to the individual patient at monthly visits on the basis of predefined response criteria aim ing for remission . MEASUREMENTS The primary outcome was radiographic erosive joint damage after 2 years . Secondary outcomes included response criteria , remission , and the need to add cyclosporine or a biologic agent to the treatment . RESULTS Erosive joint damage after 2 years was limited and less in the group receiving MTX and prednisone ( n = 117 ) than in the group receiving MTX and placebo ( n = 119 ) . The MTX and prednisone strategy was also more effective in reducing disease activity and physical disability , achieving sustained remission , and avoiding the addition of cyclosporine or biologic treatment . Adverse events were similar in both groups , but some occurred less in the MTX and prednisone group . LIMITATION A tight control strategy for RA implies monthly visits to an outpatient clinic , which is not always feasible . CONCLUSION Inclusion of low-dose prednisone in an MTX-based treatment strategy for tight control in early RA improves patient outcomes . PRIMARY FUNDING SOURCE Catharijne Foundation [18662933] Objectives : To compare the occurrence of drug-free remission , functional ability and radiological damage after 4 years of response-driven treatment according to four different treatment strategies for rheumatoid arthritis ( RA ) . Methods : Patients with recent-onset , active RA ( n = 508 ) were r and omly assigned to four different treatment strategies : ( 1 ) sequential monotherapy ; ( 2 ) step-up combination therapy ; ( 3 ) initial combination therapy with prednisone and ( 4 ) initial combination therapy with infliximab . Treatment was adjusted based on 3-monthly disease activity score ( DAS ) assessment s , aim ing at a DAS ⩽2.4 . From the third year , patients with a sustained DAS < 1.6 discontinued treatment . Results : In total , 43 % of patients were in remission ( DAS < 1.6 ) at 4 years and 13 % were in drug-free remission : 14 % , 12 % , 8 % and 18 % of patients in groups 1–4 , respectively . The absence of anti-cyclic citrullinated peptide antibodies , male gender and short symptom duration were independently associated with drug-free remission . Functional ability and remission were maintained in all four groups with the continuation of DAS-driven treatment , without significant differences between the groups . Significant progression of joint damage was observed in 38 % and 31 % of patients in groups 3 and 4 versus 51 % and 54 % of patients in groups 1 and 2 ( p<0.05 , group 4 versus groups 1 and 2 , group 3 versus group 2 ) . Conclusions : In patients with recent-onset active RA , drug-free remission was achieved in up to 18 % of patients . DAS-driven treatment maintained clinical and functional improvement , independent of the treatment strategy . Joint damage progression remained significantly lower after initial combination therapy compared with initial monotherapy [3604583] Summary Addition of 10 mg prednisone daily to a methotrexate-based tight control strategy does not lead to bone loss in early rheumatoid arthritis ( RA ) patients receiving preventive treatment for osteoporosis . A small increase in lumbar bone mineral density ( BMD ) during the first year of treatment was recorded , regardless of use of glucocorticoids . Introduction This study aims to describe effects on BMD of treatment according to EULAR guidelines with a methotrexate-based tight control strategy including 10 mg prednisone daily versus the same strategy without prednisone in early RA patients who received preventive therapy for osteoporosis . Methods Early RA patients were included in the CAMERA-II trial : a r and omized , placebo-controlled , double-blind 2-year trial , in which effects of addition of 10 mg prednisone daily to a methotrexate-based tight control strategy were studied . All patients received calcium , vitamin D and bisphosphonates . Disease activity was assessed every 4 weeks . Radiographs of h and s and feet and dual-energy X-ray absorptiometry of lumbar spine and left hip were performed at baseline and after 1 and 2 years of treatment . Results BMD increased significantly over time in both treatment groups at the lumbar spine with a mean of 2.6 % during the first year ( p < 0.001 ) , but not at the hip ; at none of the time points did BMD differ significantly between the prednisone and placebo group . Higher age and lower weight at baseline and higher disease activity scores during the trial , but not glucocorticoid therapy , were associated with lower BMD at both the lumbar spine and the hip in mixed-model analyses . Conclusion Addition of 10 mg prednisone daily to a methotrexate-based tight control strategy does not lead to bone loss in early RA patients on bisphosphonates . A small increase in lumbar BMD during the first year of treatment was found , regardless of use of glucocorticoids [22516039] BACKGROUND Methotrexate ( MTX ) is a cornerstone in the treatment of rheumatoid arthritis . Despite its widespread use , expert opinions differ about the optimal MTX starting dosage to achieve rapid onset of action while averting increased occurrence of adverse effects . Plasma concentrations have not been assessed in previous studies that monitored clinical efficacy . OBJECTIVE This study was performed to compare the pharmacokinetic parameters and clinical response of a st and ard ( 15 mg ) and an accelerated ( 25 mg ) dosing regimen , each administered orally once a week . METHODS This r and omized , controlled , double-blind , parallel , single-site study included 19 MTX-naïve patients older than 18 years with rheumatoid arthritis . Patients participated for 16 weeks . Disease activity was assessed using the Disease Activity Score in 28 joints ( DAS-28 ) as the primary outcome parameter . Plasma MTX concentrations were measured using HPLC at weeks 1 , 5 , 10 , and 16 . Tolerability was assessed via routine blood analysis ( hematology and clinical chemistry ) and a patient question naire to monitor adverse events . Reported or observed adverse events were recorded along with information about their severity and causal relationship to the study medication . RESULTS Nineteen white patients ( 13 women and 6 men ; mean age , 56 years ; and mean weight , 74 kg ) participated . At study entry , mean ( SD ) DAS-28 - 4v ( erythrocyte sedimentation rate ) was 4.73 ( 1.02 ) . Health Assessment Question naire scores were 1.45 ( 0.85 ) ; for C-reactive protein , 11.45 ( 10.04 ) mg/dL ; for alkaline phosphatase , 73.58 ( 19.91 ) U/L ; for aspartate aminotransferase , 23.32 ( 7.13 ) U/L ; and for creatinine , 0.87 ( 0.22 ) mg/dL. Although pharmacokinetic parameters such as AUC and C(max ) were significantly higher after the accelerated dosing regimen , clinical activity scores ( DAS-28 ) and inflammation parameters ( C-reactive protein ) did not indicate a significant benefit of an accelerated starting regimen . Considering toxicity , no elevation in liver function enzymes and no decrease in renal function were observed using the accelerated dosing ( statistical significance set at P ≤ 0.05 ) . No serious adverse events were noted . All observed adverse events were classified as study related . Overall , adverse events were noted in 58 % of patients . Comparison of the two doses revealed that 60 % of patients receiving the st and ard dosing regimen and 56 % of patients receiving the accelerated dosing regimen reported adverse events , the most frequent being gastrointestinal . These events were generally self-limiting . CONCLUSIONS Differences in clinical response between these two small selected patient groups who received an initial oral dose of either 15 or 25 mg MTX per week did not reach the level of statistical significance . The overall incidence of adverse effects , all classified as study related , was 58 % , with 60 % of patients receiving the st and ard dosage and 56 % of patients receiving the accelerated dosing regimen reporting adverse effects . However , because of the small sample size , this study was not powered to detect differences in the incidence of adverse events between the two dosing groups . Clinical Trials.gov identifier : NCT00695188 [2911916] Introduction Early treatment of rheumatoid arthritis ( RA ) has been shown to retard the development of joint damage for a period of up to 5 years . The aim of this study was to evaluate the radiologic progression beyond that time in patients with early RA initially treated with a combination of three disease-modifying antirheumatic drugs ( DMARDs ) or a single DMARD . Methods A cohort of 199 patients with early active RA were initially r and omized to receive treatment with a combination of methotrexate , sulfasalazine , and hydroxychloroquine with prednisolone ( FIN-RACo ) , or treatment with a single DMARD ( initially , sulfasalazine ) with or without prednisolone ( SINGLE ) . After 2 years , the drug-treatment strategy became unrestricted , but still targeted remission . The radiographs of h and s and feet were analyzed by using the Larsen score at baseline , 2 , 5 , and 11 years , and the radiographs of large joints , at 11 years . Results Sixty-five patients in the FIN-RACo and 65 in the SINGLE group had radiographs of h and s and feet available at baseline and at 11 years . The mean change from baseline to 11 years in Larsen score was 17 ( 95 % CI , 12 to 26 ) in the FIN-RACo group and 27 ( 95 % CI , 22 to 33 ) in the SINGLE group ( P = 0.037 ) . In total , 87 % ( 95 % CI , 74 to 94 ) and 72 % ( 95 % CI , 58 to 84 ) of the patients in the FIN-RACo and the SINGLE treatment arms , respectively , had no erosive changes in large joints at 11 years . Conclusions Targeting to remission with tight clinical controls results in low radiologic progression in most RA patients . Patients treated initially with a combination of DMARDs have less long-term radiologic damage than do those treated initially with DMARD monotherapy . Trial registration Current Controlled Trials IS RCT N18445519 [22679301] Objective To determine the most effective induction disease-modifying antirheumatic drug ( DMARD ) strategy in early rheumatoid arthritis ( RA ) , second to compare one single dose of intramuscular glucocorticoids ( GCs ) with daily oral GCs during the induction phase . Methods The 3-month data of a single-blinded clinical trial in patients with recent-onset arthritis ( tREACH ) were used . Patients were included who had a high probability ( > 70 % ) of progressing to persistent arthritis , based on the prediction model of Visser . Patients were r and omised into three induction therapy strategies : ( A ) combination therapy ( methotrexate ( MTX ) + sulfasalazine + hydroxychloroquine ) with GCs intramuscularly ; ( B ) combination therapy with an oral GC tapering scheme and ( C ) MTX with oral GCs similar to B. A total of 281 patients were r and omly assigned to strategy ( A ) ( n=91 ) , ( B ) ( n=93 ) or ( C ) ( n=97 ) . Results The Disease Activity Score ( DAS ) after 3 months was lower in patients receiving initial combination therapy than in those receiving MTX monotherapy ( 0.39 ( 0.67 to 0.11 , 95 % CI ) ) . DAS did not differ between the different GC bridging treatments . After 3 months 50 % fewer biological agents were prescribed in the combination therapy groups . Although the proportion of patients with medication adjustments differed significantly between the treatment arms , no differences were seen in these adjustments due to adverse events after stratification for drug . Conclusion Triple DMARD induction therapy is better than MTX monotherapy in early RA . Furthermore , no differences were seen in medication adjustments due to adverse events after stratification for drug . Intramuscular and oral GCs are equally effective as bridging treatments and both can be used [22402145] Aim Classifying more patients as rheumatoid arthritis ( RA ) ( 2010 American College of Rheumatology/European League Against Rheumatism criteria for RA ) may improve treatment outcomes but may cause overtreatment in daily practice . The authors determined the efficacy of initial methotrexate ( MTX ) plus prednisone treatment in patients with 1987 or 2010 classified RA and undifferentiated arthritis ( UA ) . Method 610 recent onset RA or UA patients started with MTX 25 mg/week and prednisone 60 mg/day tapered to 7.5 mg/day in 7 weeks . Percentage remissions after 4 months were compared between RA ( 1987 or 2010 criteria ) and UA . Predictors for remission were identified . Results With the 2010 criteria , 19 % more patients were classified as RA than with the 1987 criteria , but similar remission rates were achieved : 291/479 ( 61 % ) 2010 classified RA and 211/264 ( 58 % ) 1987 classified RA patients ( p=0.52 ) , and 79/122 ( 65 % ) UA patients ( p=0.46 ) . Anticitrullinated protein antibodies ( ACPA ) positive RA patients achieved more remission ( 66 % ) than ACPA negative RA patients ( 51 % , p=0.001 ) , but also had a lower mean baseline Disease Activity Score ( DAS ) ( 3.2 vs 3.6 , p<0.001 ) . Independent predictors for remission were male sex , low joint counts , DAS and Health Assessment Question naire , low body mass index and ACPA positivity . Conclusion Initial treatment with MTX and a tapered high dose of prednisone results in similarly high remission percentages after 4 months ( about 60 % ) in RA patients , regardless of fulfilling the 1987 or 2010 criteria , and in UA patients . Independent predictors indicate that initiating treatment while disease activity is relatively low results in more remission [21584942] To compare the efficacy , safety , and tolerability of 4 doses of oral tofacitinib ( CP‐690,550 ) with placebo in Japanese patients with active rheumatoid arthritis ( RA ) receiving stable background methotrexate ( MTX ) who had an inadequate response to MTX alone [21415052] Objective To compare clinical and radiological outcomes of four dynamic treatment strategies in recent-onset rheumatoid arthritis ( RA ) after 5 years follow-up . Methods 508 patients with recent-onset RA were r and omly assigned into four treatment strategies : sequential monotherapy ; step-up combination therapy ; initial combination with prednisone ; initial combination with infliximab . Treatment adjustments were made based on 3-monthly disease activity score ( DAS ) measurements ( if DAS > 2.4 next treatment step ; if DAS ≤2.4 during ≥6 months taper to maintenance dose ; if DAS < 1.6 during ≥6 months stop antirheumatic treatment ) . Primary and secondary outcomes were functional ability , joint damage progression , health-related quality of life and ( drug-free ) remission percentages . Results After 5 years , 48 % of patients were in clinical remission ( DAS < 1.6 ) and 14 % in drug-free remission , irrespective of initial treatment . After an earlier improvement in functional ability and quality of life with initial combination therapy , from 1 year onwards clinical outcomes were comparable across the groups and stable during 5 years . The initial combination groups showed less joint damage in year 1 . In years 2–5 annual progression was comparable across the groups . After 5 years , initial combination therapy result ed in significantly less joint damage progression , reflecting the earlier clinical response . Conclusion Irrespective of initial treatment , an impressive improvement in clinical and radiological outcomes of RA patients can be achieved with dynamic treatment aim ed at reducing disease activity , leading to 48 % remission , 14 % drug-free remission and sustained functional improvement . Starting with combination therapy result ed in earlier clinical improvement and less joint damage without more toxicity [16255011] OBJECTIVE To assess the effect of 5 mg/day prednisolone on disease progression in patients with early rheumatoid arthritis ( RA ) receiving st and ardized disease-modifying antirheumatic drug ( DMARD ) therapy . METHODS Patients with active RA of < 2 years ' duration were r and omly assigned in a double-blinded manner to receive prednisolone or placebo while starting concomitant DMARD therapy ( gold sodium thiomalate or methotrexate ) . H and and foot radiographs were taken at baseline and at 6 , 12 , and 24 months and were evaluated according to the Ratingen score and the total modified Sharp/van der Heijde score ( SHS ) . RESULTS Of 192 included patients , 166 were available for the intent-to-treat analysis ( ITT ) . Seventy-six patients completed the study per protocol ( PP ) . Radiographic progression ( increase in the Ratingen score ) was significantly less with prednisolone than with placebo . The difference in the progression rate between the groups was greatest in the first 6 months . At 24 months in the ITT population , the least squares ( LS ) mean difference was 3.14 ( 95 % confidence interval [ 95 % CI ] 0.94 , 5.34 ) , P = 0.006 . The results were confirmed by the total SHS in the ITT population ( LS mean difference 7.20 [ 95 % CI 0.93 , 13.47 ] , P = 0.022 ) and with the PP population . Clinical and functional outcomes tended to be better and the rate of remissions was higher in the prednisolone group . Side effects were observed more frequently in the prednisolone group than in the control group : weight gain ( 4 versus 0 patients ) , hypertension ( 6 versus 2 patients ) , glaucoma ( 3 versus 0 patients ) , Cushing 's syndrome ( 5 versus 0 patients ) , gastric distress ( 9 versus 4 patients ) , and gastric ulcers ( only with concomitant nonsteroidal antiinflammatory drug therapy ; 3 versus 0 patients ) . No new lumbar fractures were found in either group . CONCLUSION The very low daily dose of 5 mg prednisolone given over 2 years in combination with background DMARD therapy substantially decreased radiographic progression in early RA at low risk [21952978] OBJECTIVE To compare the efficacy , safety , and tolerability of 5 doses of oral tofacitinib ( CP-690,550 ) or adalimumab monotherapy with placebo for the treatment of active rheumatoid arthritis ( RA ) in patients with an inadequate response to disease-modifying antirheumatic drugs . METHODS In this 24-week , double-blind , phase IIb study , patients with RA ( n = 384 ) were r and omized to receive placebo , tofacitinib at 1 , 3 , 5 , 10 , or 15 mg administered orally twice a day , or adalimumab at 40 mg injected subcutaneously every 2 weeks ( total of 6 injections ) followed by oral tofacitinib at 5 mg twice a day for 12 weeks . The primary end point was the responder rate according to the American College of Rheumatology 20 % improvement criteria ( ACR20 ) at week 12 . RESULTS Treatment with tofacitinib at a dose of ≥3 mg twice a day result ed in a rapid response with significant efficacy when compared to placebo , as indicated by the primary end point ( ACR20 response at week 12 ) , achieved in 39.2 % ( 3 mg ; P ≤ 0.05 ) , 59.2 % ( 5 mg ; P < 0.0001 ) , 70.5 % ( 10 mg ; P < 0.0001 ) , and 71.9 % ( 15 mg ; P < 0.0001 ) in the tofacitinib group and 35.9 % of patients in the adalimumab group ( P = 0.105 ) , compared with 22.0 % of patients receiving placebo . Improvements were sustained at week 24 , according to the ACR20 , ACR50 , and ACR70 response rates as well as classifications of remission according to the 3-variable Disease Activity Score in 28 joints ( DAS28 ) using C-reactive protein and the 4-variable DAS28 using the erythrocyte sedimentation rate . The most common treatment-emergent adverse events ( AEs ) in patients across all tofacitinib treatment arms ( n = 272 ) were urinary tract infection ( 7.7 % ) , diarrhea ( 4.8 % ) , headache ( 4.8 % ) , and bronchitis ( 4.8 % ) . CONCLUSION Tofacitinib monotherapy at ≥3 mg twice a day was efficacious in the treatment of patients with active RA over 24 weeks and demonstrated a manageable safety profile [19363607] Bucillamine ( Buc ) , developed in Japan , is a disease-modifying antirheumatic drug ( DMARD ) which has been used to treat numerous patients with rheumatoid arthritis ( RA ) in Japan and Korea with favorable results . However , it has not been used globally . In the present study , we compared the timing of onset of efficacy and the usefulness of this drug with that of the globally accepted agent salazosulfapyridine ( SASP ) . There were 26 patients in the Buc group and 23 in the SASP group . We compared changes in the number of swollen joints , number of painful joints , duration of morning stiffness , grip strength , levels of inflammatory marker [ erythrocyte sedimentation rate ( ESR ) and C-reactive protein ( CRP ) ] , rheumatoid factor ( RF ) , physician ’s rating by visual analogue scale ( VAS ) , patient ’s rating of pain , patient ’s overall rating ( VAS ) , and improvement according to European League against Rheumatism ( EULAR ) criteria ( DAS28-CRP , DAS28-ESR ) in these two groups of patients . Both Buc and SASP were shown to be efficacious within 3 months after the start of treatment . Both drugs were found to be suitable as first-line treatment of early RA . Signs of efficacy tended to occur earlier with Buc than with SASP , and Buc also tended to have higher efficacy than SASP [20223838] Background Glucocorticoids ( GCs ) are often used as early arthritis treatment and it has been suggested that they induce remission or at least delay the development of rheumatoid arthritis ( RA ) and the need to start disease-modifying antirheumatic drugs ( DMARDs ) . Objective To test the effect of GCs on patients with very early arthritis ( symptom duration of < 16 weeks ) in a r and omised controlled trial . Methods Patients received a single intramuscular injection of 120 mg methylprednisolone or placebo ( PL ) and were followed up for 52 weeks . Primary end point was drug-free clinical remission , both at weeks 12 and 52 . Among secondary outcomes were fulfilment of remission criteria at weeks 2 , 12 or 52 , time course of ‘ core set variables ’ and proportion of patients starting DMARDs . Results 17.0 % of all analysed subjects ( 65/383 ) achieved persistent remission : 17.8 % ( 33/185 ) of the PL group , 16.2 % ( 32/198 ) of the patients receiving methylprednisolone ( OR=1.13 , 95 % CI 0.66 to 1.92 , p=0.6847 ) . Analyses of secondary end points showed significant clinical benefits of the GC only at week 2 . These differences subsequently disappeared . DMARDs were started in 162 patients : 50.3 % methylprednisolone and 56.7 % PL patients had to start DMARD treatment ( OR=0.78 , 95 % CI 0.49 to 1.22 , p=0.30 ) . Significantly more patients with polyarthritis than with oligoarthritis received DMARDs ( OR=2.84 , 95 % CI 1.75 to 4.60 , p<0.0001 ) . Conclusions Neither remission nor development of RA is delayed by GC treatment . Remission is rare in the first year of very early arthritis , occurring in < 20 % of the patients . Also , the need to start DMARDs was not influenced by GC treatment [22006202] OBJECTIVE To compare the efficacy , safety , and tolerability of 6 dosages of oral tofacitinib ( CP-690,550 ) with placebo for the treatment of active rheumatoid arthritis ( RA ) in patients receiving a stable background regimen of methotrexate ( MTX ) who have an inadequate response to MTX monotherapy . METHODS In this 24-week , double-blind , phase IIb study , patients with active RA ( n = 507 ) were r and omized to receive placebo or tofacitinib ( 20 mg/day , 1 mg twice daily , 3 mg twice daily , 5 mg twice daily , 10 mg twice daily , or 15 mg twice daily ) . All patients continued to receive a stable dosage of MTX . The primary end point was the American College of Rheumatology 20 % improvement criteria ( ACR20 ) response rate at week 12 . RESULTS At week 12 , ACR20 response rates for patients receiving all tofacitinib dosages ≥3 mg twice daily ( 52.9 % for 3 mg twice daily , 50.7 % for 5 mg twice daily , 58.1 % for 10 mg twice daily , 56.0 % for 15 mg twice daily , and 53.8 % for 20 mg/day ) were significantly ( P ≤ 0.05 ) greater than those for placebo ( 33.3 % ) . Improvements were sustained at week 24 for the ACR20 , ACR50 , and ACR70 responses , scores for the Health Assessment Question naire disability index , the 3-variable Disease Activity Score in 28 joints using the C-reactive protein level ( DAS28-CRP ) , and a 3-variable DAS28-CRP of < 2.6 . The most common treatment-emergent adverse events occurring in > 10 % of patients in any tofacitinib group were diarrhea , upper respiratory tract infection , and headache ; 21 patients ( 4.1 % ) experienced serious adverse events . Sporadic increases in transaminase levels , increases in cholesterol and serum creatinine levels , and decreases in neutrophil and hemoglobin levels were observed . CONCLUSION In patients with active RA in whom the response to MTX has been inadequate , the addition of tofacitinib at a dosage ≥3 mg twice daily showed sustained efficacy and a manageable safety profile over 24 weeks [21229373] In order to compare the efficacy and toxicity of methotrexate and leflunomide for the treatment of rheumatoid arthritis , a double-blind r and omized clinical trial was carried out at the Department of Medicine , Jinnah Medical College Hospital , Korangi , Karachi . The sample size was 240 patients and the duration of the study was 1 year . The patients enrolled were r and omly divided into two groups ( methotrexate and leflunomide ) . RA activity was clinical ly assessed by noting changes in the four primary ( tender joint count , swollen joint count , physician and patient global assessment score ) and three secondary ( morning stiffness , pain intensity , HAQ ) clinical efficacy end-points . Data were expressed as the mean ± SD . A P value of < 0.05 , calculated by paired t test , was considered significant . A total of 368 subjects were enrolled in this study . Of these , 128 subjects were withdrawn during the screening phase . Of the 240 subjects who were r and omized and treated , 129 received leflunomide and 111 received methotrexate . The difference between the baseline and 12 month end-point measurements of all primary clinical efficacy end-points was significantly greater in methotrexate-treated than in leflunomide-treated subjects . Both leflunomide and methotrexate result ed in significant improvements in all secondary clinical efficacy end-points after 1 year of treatment . In both treatment groups , the most common reason for withdrawal during the treatment was adverse events . The results of this study indicate that both leflunomide and methotrexate are effective drugs for the long-term treatment of RA . It was concluded that methotrexate , which is a much cheaper drug than leflunomide , is the drug of choice , especially for patients who belong to low socioeconomic groups [21930734] Objective To investigate the 2-year clinical and radiological outcomes of patients with early rheumatoid arthritis ( RA ; symptom duration < 1 year ) who had initially responded well to methotrexate monotherapy . Methods In the SWEFOT trial , all 487 patients started methotrexate ( target dose 20 mg/week ) . After 3–4 months , 147 had low disease activity , 28-joint based disease activity score ( DAS28 ) ≤3.2 . These patients were not r and omly selected but were followed in regular care for 2 years . Clinical outcomes and radiographic progression according to the van der Heijde modified Sharp ( SvdH ) score were analysed . Results The majority of the 147 patients continued on methotrexate monotherapy . After 1 and 2 years , DAS28 remission was achieved in 59.6 % and 71.8 % and mean observed DAS28 values were 2.53 and 2.25 , respectively . Despite the favourable clinical course , a proportion of the patients progressed radiographically with a mean ( SD ) increase in the SvdH score after 2 years of 3.90 ( 6.84 ) . There was no significant difference in progression between patients in DAS28 remission versus not in remission ( p=0.73 ) . At baseline , approximately half the patients had no radiographic damage , while after 2 years the proportion was approximately 20 % . Conclusion Most early RA patients who achieve low disease activity after 3–4 months of methotrexate monotherapy continue to have low disease activity during 2 years follow-up , and additional treatment is needed infrequently . Some radiological progression occurs in most patients , and may be marked or severe in some , even despite sustained DAS28 remission . Close monitoring for radiological progression is thus warranted [11777359] Drug treatment for rheumatoid arthritis usually consists of a combination of a nonsteroidal anti-inflammatory drug ( NSAID ) and a disease-modifying antirheumatic drug ( for example , sulfasalazine , methotrexate , gold salt , or a combination ) . New biological agents , such as tumor necrosis factor- blocking agents and interleukin-1 receptor antagonists , appear promising ( 1 , 2 ) . Glucocorticoids have had a special place in the treatment of rheumatoid arthritis since the publication of the report by Hench and coworkers showing that cortisone dramatically alleviated the symptoms of rheumatoid arthritis by inhibiting inflammation ( 3 ) . This period of enthusiasm in the 1950s was followed by a long period in which glucocorticoids were applied cautiously for rheumatoid arthritis because of their many side effects and the recognition that inhibition of inflammation is not necessarily associated with retardation of joint damage ( 4 ) . Ongoing research on glucocorticoids in rheumatoid arthritis focused on both inflammation and joint damage . Some recent studies showed that glucocorticoids reduced the progression of joint damage when added to therapy with disease-modifying antirheumatic drugs . These findings suggested that glucocorticoids might also have disease-modifying properties . If this could be confirmed , glucocorticoids might be used more often , especially since potential serious adverse effects of glucocorticoid therapy are more easily managed today ( 5 ) . Secondary osteoporosis is inhibited by potent bisphosphonates , and gastrointestinal complications of glucocorticoid therapy , especially in combination with NSAIDs , can be reduced by misoprostol , proton-pump inhibitors , or cyclooxygenase-2 selective NSAIDs . As yet , disease-modifying properties of low-dose glucocorticoids as monotherapy for patients with early rheumatoid arthritis have not been investigated . The aim of our study was to investigate the clinical efficacy , disease-modifying properties , and side effects of low-dose glucocorticoids as monotherapy for previously untreated patients with early active rheumatoid arthritis . Methods Patients From October 1992 through October 1995 , all consecutive out patients at the rheumatology departments of the Deventer and Zutphen Hospitals , the Netherl and s , who were at least 18 years of age and had early previously untreated rheumatoid arthritis ( disease duration < 1 year ) that satisfied classification criteria were invited to participate in the study [ 6 ] . To be included , patients had to have active disease , which was defined as the presence of at least two of the following three criteria : 1 ) early-morning stiffness lasting 30 minutes or longer , 2 ) 28-joint score for tenderness and 28-joint score for swelling of 3 or more , and 3 ) Westergren erythrocyte sedimentation rate of 28 mm or higher after 1 hour ( 7 , 8) . Exclusion criteria were contraindications to prednisone or NSAIDs , active gastrointestinal problems , serious complicating diseases , severe hypertension , hemorrhagic diathesis , treatment with cytotoxic or immunosuppressive drugs , alcohol or drug abuse , and psychiatric or mental problems . Informed consent was obtained from all patients before participation . Of the 118 eligible patients , 37 declined to participate ( Figure 1 ) . Figure 1 . Trial profile . Intervention Pharmacy personnel at Deventer Hospital used a computer-generated r and omization procedure to r and omly assign the 81 participating patients , in blocks of 10 , to one of two treatment groups . One group received two tablets of prednisone , 5 mg , once daily at breakfast , and one group received placebo . The pharmacology department at Deventer Hospital prepared and labeled the prednisone and placebo tablets , which were identical in shape and color , and distributed them to patients in unlabeled boxes . Only the pharmacist could access the allocation table . Both groups of patients received 500 mg of elementary calcium in the evening . The code of r and omization was broken after 2 years of treatment , and the prednisone dosage was tapered . Surplus tablets of the study medication were counted at every visit , and adherence was satisfactory ( 96 % ) . Use of NSAIDs was not regulated . Local glucocorticoid injections were permitted only when absolutely necessary . Physical therapy and additional use of paracetamol were allowed . After 6 months , sulfasalazine ( 2 g/d ) could be prescribed as rescue medication . The decision to add sulfasalazine was made on clinical grounds ( activity of rheumatoid arthritis ) . Design and Setting The ethics committees of the University Medical Center Utrecht and the Deventer and Zutphen Hospitals approved the trial . The study was considered ethically acceptable when it was design ed ( 19891991 ) ; later , however , it became clear that irreversible joint damage is an early feature of rheumatoid arthritis . With our present knowledge , it would probably be considered unethical to compare the effects of prednisone and placebo in patients who did not receive a disease-modifying antirheumatic drug for at least 6 months . In our study , sulfasalazine could be prescribed as rescue medication only after 6 months to avoid obscuring the effects of prednisone monotherapy . Measurements All clinical outcome measurements , except those for disability and radiologic outcomes , were performed at baseline and every 3 months . Disability , which was assessed with the Health Assessment Question naire , and radiologic outcomes were measured every 6 months . Early-morning stiffness was recorded in minutes ( maximum , 720 minutes ) . Morning pain and general well-being were assessed on a horizontal visual analogue scale ranging from 0 to 100 mm , with 0 representing the best score ( no problems ) and 100 representing the worst score . Swelling and tenderness were assessed with the 28-joint score ( 7 , 8) . Grip strength was measured in kPa with a vigorimeter ( range , 0 to 200 kPa ) ; the mean of three measurements was calculated for each h and . Disability was assessed with a vali date d Dutch version of the Health Assessment Question naire ( Vragenlijst Dagelijks Functioneren ) ( 9 ) , which had a range of 0 to 3 ( 0 represented the best score [ no problems ] , and 3 represented the worst score ) . Serum C-reactive protein level was measured in mg/L. To investigate the possible sparing effect of the trial medication , we recorded the use of NSAIDs and analgesics , the frequency of intra-articular corticosteroid injections , and the use of physiotherapy . The patients recorded the use of NSAIDs , analgesics , and physical therapy in st and ardized patient diaries . To calculate the use of NSAIDs and to compare different NSAIDs , we arbitrarily chose naproxen as a reference . One thous and mg of naproxen was defined as 1 unit and was considered to be approximately equivalent to 600 mg of azapropazone , 100 mg of diclofenac , 200 mg of flurbiprofen , 1600 mg of ibuprofen , 100 mg of indomethacin , 200 mg of ketoprofen , 15 mg of meloxicam , 1000 mg of nabumetone , 20 mg of piroxicam , and 600 mg of tiaprofenic acid . Every 3 months , the first author recorded use of intra-articular corticosteroid injections . Radiologic outcome measures were erosions , joint space narrowing , and the total score for both ( range , 0 to 448 ) . The total score is the sum of the erosions and narrowing scores in 44 joints in the h and s and feet , assessed on plain radiography and scored with the van der Heijde modification of the Sharp method ( 10 , 11 ) . Radiologic outcome measures also included the number of patients with erosive disease in each group and the number of radiologically affected joints per patient . Radiographs were taken at entry and every 6 months . An assistant prepared the radiographs to be read , and all identifying patient data on the radiographs were concealed from the readers . The readers had no knowledge of patient identity when they scored the radiographs . Radiographs were read in r and om patient order and were scored for each patient in temporal order . Scoring in temporal order clearly has advantages , as a comparative study has shown ( 11 ) . However , with this method , scores can either be stable or increase ; a decrease ( indicating improvement ) is not possible . The first author and an independent radiologist viewed all available radiographs at one center . When the readers ' total scores for individual cases differed by 25 % or more , agreement was reached through discussion . Joint damage was defined as a score that exceeded 0 . To correct for possible differences between the two treatment groups in the number of patients who developed little or no joint damage , we also analyzed data only from patients who developed joint damage . Furthermore , radiologic damage was also analyzed with a cutoff point of 4 modified Sharp units . A score of 0 to 3 was interpreted as no damage , and scores of 4 or greater were interpreted as joint damage . This cutoff point seems to reflect clinical ly relevant change ( 12 ) and was also used in our study to define erosive rheumatoid arthritis . At the start of the study and every 3 months for 2 years , st and ardized lists were used to document adverse effects . We noted the occurrence of infections and the use of antibiotics ; the latter was checked at the patient 's pharmacy . For hypertension , the first author used a single device to measure blood pressure in mm Hg . For steroid diabetes , serum glucose level was measured in mmol/L. Hyperglycemia was defined according to the World Health Organization st and ard : postpr and ial , a glucose level of at least 11.0 mmol/L ( 198 mg/dL ) , and fasting , at least 6.6 mmol/L ( 119 mg/dL ) . Urinary glucose level was measured by using a semiquantitative method ( dipstick ) . A value less than 2.7 mmol/L ( 49 mg/dL ) was considered negative , a value of 2.7 to 5.5 mmol/L ( 50 to 99 mg/dL ) was considered a trace , a value of 5.6 to 16.6 mmol/L ( 100 to 299 mg/dL ) was considered 1 + , a value of 16.7 to 54.9 mmol/L ( 300 to 989 mg/dL ) was considered 2 + , and a value of 55 mmol/L or greater ( 990 mg/dL ) was considered 3 + . To assess weight gain , [22873531] BACKGROUND Tofacitinib ( CP-690,550 ) is a novel oral Janus kinase inhibitor that is being investigated for the treatment of rheumatoid arthritis . METHODS In this 12-month , phase 3 trial , 717 patients who were receiving stable doses of methotrexate were r and omly assigned to 5 mg of tofacitinib twice daily , 10 mg of tofacitinib twice daily , 40 mg of adalimumab once every 2 weeks , or placebo . At month 3 , patients in the placebo group who did not have a 20 % reduction from baseline in the number of swollen and tender joints were switched in a blinded fashion to either 5 mg or 10 mg of tofacitinib twice daily ; at month 6 , all patients still receiving placebo were switched to tofacitinib in a blinded fashion . The three primary outcome measures were a 20 % improvement at month 6 in the American College of Rheumatology scale ( ACR 20 ) ; the change from baseline to month 3 in the score on the Health Assessment Question naire-Disability Index ( HAQ-DI ) ( which ranges from 0 to 3 , with higher scores indicating greater disability ) ; and the percentage of patients at month 6 who had a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate ( DAS28 - 4[ESR ] ) of less than 2.6 ( with scores ranging from 0 to 9.4 and higher scores indicating greater disease activity ) . RESULTS At month 6 , ACR 20 response rates were higher among patients receiving 5 mg or 10 mg of tofacitinib ( 51.5 % and 52.6 % , respectively ) and among those receiving adalimumab ( 47.2 % ) than among those receiving placebo ( 28.3 % ) ( P<0.001 for all comparisons ) . There were also greater reductions in the HAQ-DI score at month 3 and higher percentages of patients with a DAS28 - 4(ESR ) below 2.6 at month 6 in the active-treatment groups than in the placebo group . Adverse events occurred more frequently with tofacitinib than with placebo , and pulmonary tuberculosis developed in two patients in the 10-mg tofacitinib group . Tofacitinib was associated with an increase in both low-density and high-density lipoprotein cholesterol levels and with reductions in neutrophil counts . CONCLUSIONS In patients with rheumatoid arthritis receiving background methotrexate , tofacitinib was significantly superior to placebo and was numerically similar to adalimumab in efficacy . ( Funded by Pfizer ; ORAL St and ard Clinical Trials.gov number , NCT00853385 . ) [23294500] BACKGROUND Rheumatoid arthritis is a heterogeneous chronic disease , and no therapeutic agent has been identified which is universally and persistently effective in all patients . We investigated the effectiveness of tofacitinib ( CP-690,550 ) , a novel oral Janus kinase inhibitor , as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis . METHODS We did a 6-month , double-blind , parallel-group phase 3 study at 82 centres in 13 countries , including North America , Europe , and Latin America . 399 patients aged 18 years or older with moderate-to-severe rheumatoid arthritis and inadequate response to tumour necrosis factor inhibitors ( TNFi ) were r and omly assigned in a 2:2:1:1 ratio with an automated internet or telephone system to receive twice a day treatment with : tofacitinib 5 mg ( n=133 ) ; tofacitinib 10 mg ( n=134 ) ; or placebo ( n=132 ) , all with methotrexate . At month 3 , patients given placebo advanced to either tofacitinib 5 mg twice a day ( n=66 ) or 10 mg twice a day ( n=66 ) . Primary endpoints included American College of Rheumatology (ACR)20 response rate , mean change from baseline in Health Assessment Question naire-Disability Index ( HAQ-DI ) , and rates of disease activity score (DAS)28 - 4(ESR ) less than 2·6 ( referred to as DAS28<2·6 ) , all at month 3 . The full analysis set for the primary analysis included all r and omised patients who received at least one dose of study medication and had at least one post-baseline assessment . This trial is registered with www . Clinical Trials.gov , number NCT00960440 . FINDINGS At month 3 , ACR20 response rates were 41·7 % ( 55 of 132 [ 95 % CI vs placebo 6·06 - 28·41 ] ; p=0·0024 ) for tofacitinib 5 mg twice a day and 48·1 % ( 64 of 133 ; [ 12·45 - 34·92 ] ; p<0·0001 ) for tofacitinib 10 mg twice a day versus 24·4 % ( 32 of 131 ) for placebo . Improvements from baseline in HAQ-DI were -0·43 ( [ -0·36 to -0·15 ] ; p<0·0001 ) for 5 mg twice a day and -0·46 ( [ -0·38 to -0·17 ] ; p<0·0001 ) for 10 mg twice a day tofacitinib versus -0·18 for placebo ; DAS28<2·6 rates were 6·7 % ( eight of 119 ; [ 0 - 10·10 ] ; p=0·0496 ) for 5 mg twice a day tofacitinib and 8·8 % ( 11 of 125 [ 1·66 - 12·60 ] ; p=0·0105 ) for 10 mg twice a day tofacitinib versus 1·7 % ( two of 120 ) for placebo . Safety was consistent with phase 2 and 3 studies . The most common adverse events in months 0 - 3 were diarrhoea ( 13 of 267 ; 4·9 % ) , nasopharyngitis ( 11 of 267 ; 4·1 % ) , headache ( 11 of 267 ; 4·1 % ) , and urinary tract infection ( eight of 267 ; 3·0 % ) across tofacitinib groups , and nausea ( nine of 132 ; 6·8 % ) in the placebo group . INTERPRETATION In this treatment-refractory population , tofacitinib with methotrexate had rapid and clinical ly meaningful improvements in signs and symptoms of rheumatoid arthritis and physical function over 6 months with manageable safety . Tofacitinib could provide an effective treatment option in patients with an inadequate response to TNFi . FUNDING Pfizer [12115219] OBJECTIVE To compare the efficacy of combination therapy with methotrexate ( MTX ) and hydroxychloroquine ( HCQ ) , MTX and sulfasalazine ( SSZ ) , and MTX , HCQ , and SSZ in patients with rheumatoid arthritis ( RA ) . METHODS RA patients ( n = 171 ) who had not previously been treated with combinations of the study medications were r and omized to receive 1 of the 3 treatment combinations in this 2-year , double-blind , placebo-controlled protocol . HCQ was given at a dosage of 200 mg twice a day . The dosage of MTX was accelerated from 7.5 mg/week to 17.5 mg/week in all patients who were not in remission . Similarly , the dosage of SSZ was escalated from 500 mg twice a day to 1 gm twice a day in patients who were not in remission . The primary end point of the study was the percentage of patients who had a 20 % response to therapy according to the American College of Rheumatology ( ACR ) criteria at 2 years . RESULTS Intent-to-treat analysis revealed that patients receiving the triple combination responded best , with 78 % achieving an ACR 20 % response at 2 years , compared with 60 % of those treated with MTX and HCQ ( P = 0.05 ) and 49 % of those treated with MTX and SSZ ( P = 0.002 ) . Similar trends were seen for the ACR 50 % response , with 55 % , 40 % , and 29 % of patients in the 3 treatment groups , respectively , achieving these results at 2 years ( P = 0.005 for the triple combination group versus the MTX and SSZ group ) . All combination treatments were well-tolerated . Fourteen patients ( evenly distributed among the 3 groups ) withdrew from the protocol because of symptoms that were potentially related to the study medication . CONCLUSION The triple combination of MTX , SSZ , and HCQ is well-tolerated , and its efficacy is superior to that of the double combination of MTX and SSZ and is marginally superior to that of the double combination of MTX and HCQ [22508468] OBJECTIVE To assess whether it is better to intensively treat all patients with early rheumatoid arthritis ( RA ) using combinations of drugs or to reserve this approach for patients who do not have an appropriate response ( as determined by a Disease Activity Score in 28 joints using the erythrocyte sedimentation rate [ DAS28-ESR ] of ≥ 3.2 at week 24 ) to methotrexate ( MTX ) monotherapy , and to assess whether combination therapy with MTX plus etanercept is superior to the combination of MTX plus sulfasalazine plus hydroxychloroquine . METHODS The Treatment of Early Aggressive Rheumatoid Arthritis ( TEAR ) study is a 2-year , r and omized , double-blind trial . A 2 × 2 factorial design was used to r and omly assign subjects to 1 of 4 treatment arms : immediate treatment with MTX plus etanercept , immediate oral triple therapy ( MTX plus sulfasalazine plus hydroxychloroquine ) , or step-up from MTX monotherapy to one of the combination therapies ( MTX plus etanercept or MTX plus sulfasalazine plus hydroxychloroquine ) at week 24 if the DAS28-ESR was ≥ 3.2 . All treatment arms included matching placebos . The primary outcome was an observed-group analysis of DAS28-ESR values from week 48 to week 102 . RESULTS At week 24 ( beginning of the step-up period ) , subjects in the 2 immediate-treatment groups demonstrated a greater reduction in the DAS28-ESR compared with those in the 2 step-up groups ( 3.6 versus 4.2 ; P < 0.0001 ) ; no differences between the combination-therapy regimens were observed . Between week 48 and week 102 , subjects r and omized to the step-up arms had a DAS28-ESR clinical response that was not different from that of subjects who initially received combination therapy , regardless of the treatment arm . There was no significant difference in the DAS28-ESR between subjects r and omized to oral triple therapy and those r and omized to receive MTX plus etanercept . By week 102 , there was a statistically significant difference in the change in radiographic measurements from baseline between the group receiving MTX plus etanercept and the group receiving oral triple therapy ( 0.64 versus 1.69 ; P = 0.047 ) . CONCLUSION There were no differences in the mean DAS28-ESR during weeks 48 - 102 between subjects r and omized to receive MTX plus etanercept and those r and omized to triple therapy , regardless of whether they received immediate combination treatment or step-up from MTX monotherapy . At 102 weeks , immediate combination treatment with either strategy was more effective than MTX monotherapy prior to the initiation of step-up therapy . Initial use of MTX monotherapy with the addition of sulfasalazine plus hydroxychloroquine ( or etanercept , if necessary , after 6 months ) is a reasonable therapeutic strategy for patients with early RA . Treatment with the combination of MTX plus etanercept result ed in a statistically significant radiographic benefit compared with oral triple therapy [8609945] BACKGROUND Rheumatoid arthritis is a common disease that causes substantial morbidity and mortality . The responses of patients with rheumatoid arthritis to treatment with a single so-called disease-modifying drug , such as methotrexate , are often suboptimal . Despite limited data , many patients are treated with combinations of these drugs . METHODS We enrolled 102 patients with rheumatoid arthritis and poor responses to at least one disease-modifying drug in a two-year , double-blind , r and omized study of treatment with methotrexate alone ( 7.5 to 17.5 mg per week ) , the combination of sulfasalazine ( 500 mg twice daily ) and hydroxychloroquine ( 200 mg twice daily ) , or all three drugs . The dose of methotrexate was adjusted in an attempt to achieve remission in all patients . The primary and point of the study was the successful completion of two years of treatment with 50 percent improvement in composite symptoms of arthritis and no evidence of drug toxicity . RESULTS Fifty of the 102 patients had 50 percent improvement at nine months and maintained at least that degree of improvement for two years without evidence of major drug toxicity . Among them were 24 of 31 patients treated with all three drugs ( 77 percent ) , 12 of 36 patients treated with methotrexate alone ( 33 percent , P < 0.001 for the comparison with the three-drug group ) , and 14 of 35 patients treated with sulfasalazine and hydroxychloroquine ( 40 percent ) , P = 0.003 for the comparison with the three-drug group ) . Seven patients in the methotrexate group and three patients in each of the other two groups discontinued treatment because of drug toxicity . CONCLUSIONS In patients with rheumatoid arthritis , combination therapy with methotrexate , sulfasalazine , and hydroxychloroquine is more effective than either methotrexate alone or a combination of sulfasalazine , and hydroxychloroquine [20398020] In order to identify rate and stability of remission induced by low-dose prednisone comedication in early rheumatoid arthritis ( RA ) , we evaluated patients with early RA ( < 1 year ) who were r and omized to receive ( P ) or not ( non-P ) low-dose prednisone in association with step-up disease-modifying antirheumatic drug therapy over 2 years . Prevalence and duration of clinical remission were evaluated in the first and second year . Each treatment group included 105 patients ; no significant differences were found at baseline . During the first year , P patients achieved higher rates of clinical remission with a time-averaged odds ratio ( OR ) of 1.965 ( CI 95 % 1.214 - 3.182 , P= 0.006 ) . Moreover , they showed a higher probability of sustained remission during the second year ( OR 4.480 , CI 95 % 1.354 - 14.817 , P= 0.014 ) . In conclusion , we found as in early RA low-dose prednisone comedication is associated with higher rate of clinical remission , earlier disease activity control and more stable remission over time [7791815] BACKGROUND Oral glucocorticoids are widely used to treat patients with rheumatoid arthritis , but their effect on joint destruction , as assessed radiologically , is uncertain . METHODS We conducted a r and omized , double-blind trial comparing oral prednisolone ( 7.5 mg daily for two years ) with placebo in 128 adults with active rheumatoid arthritis of less than two years ' duration . Except for systemic corticosteroids , other treatments could be prescribed . The primary outcome variables were the progression of damage as seen on radiographs of the h and after one and two years , as measured by the Larsen index , and the appearance of erosions in h and s that had no erosions at base line . The radiographs were viewed jointly by a radiologist and a rheumatologist who were unaware of the treatment assignment and the time point at which the films were obtained . RESULTS The statistical analysis of radiologically detected changes was based on 106 patients for whom there were films obtained at base line and two years later . After two years , the Larsen scores increased by a mean of 0.72 unit in the prednisolone group , indicating very little change , and by 5.37 units in the placebo group , indicating substantial joint destruction ( P = 0.004 ) . Of the 212 h and s of these patients , 147 ( 69.3 percent ) had no erosions at the start of the study . At two years , 15 of the 68 such h and s in the prednisolone group ( 22.1 percent ) and 36 of the 79 such h and s in the placebo group ( 45.6 percent ) had acquired erosions ( difference , 23.5 percentage points ; 95 percent confidence interval , 5.9 to 40.7 ; P = 0.007 ) . The patients in the prednisolone group had greater reductions than the patients in the placebo group in scores on an articular index and for pain and disability at 3 months ; for pain at 6 months ; and for disability at 6 , 12 , and 15 months ( all P < 0.05 ) . There was no difference between groups in st and ardized scores for the acute-phase response . The adverse events were typical of those encountered with antirheumatoid drugs . CONCLUSIONS In patients with early , active rheumatoid arthritis , prednisolone ( 7.5 mg daily ) given for two years in addition to other treatments substantially reduced the rate of radiologically detected progression of disease [22873530] BACKGROUND Tofacitinib ( CP-690,550 ) is a novel oral Janus kinase inhibitor that is being investigated as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis . METHODS In this phase 3 , double-blind , placebo-controlled , parallel-group , 6-month study , 611 patients were r and omly assigned , in a 4:4:1:1 ratio , to 5 mg of tofacitinib twice daily , 10 mg of tofacitinib twice daily , placebo for 3 months followed by 5 mg of tofacitinib twice daily , or placebo for 3 months followed by 10 mg of tofacitinib twice daily . The primary end points , assessed at month 3 , were the percentage of patients with at least a 20 % improvement in the American College of Rheumatology scale ( ACR 20 ) , the change from baseline in Health Assessment Question naire-Disability Index ( HAQ-DI ) scores ( which range from 0 to 3 , with higher scores indicating greater disability ) , and the percentage of patients with a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate ( DAS28 - 4[ESR ] ) of less than 2.6 ( with scores ranging from 0 to 9.4 and higher scores indicating more disease activity ) . RESULTS At month 3 , a higher percentage of patients in the tofacitinib groups than in the placebo groups met the criteria for an ACR 20 response ( 59.8 % in the 5-mg tofacitinib group and 65.7 % in the 10-mg tofacitinib group vs. 26.7 % in the combined placebo groups , P<0.001 for both comparisons ) . The reductions from baseline in HAQ-DI scores were greater in the 5-mg and 10-mg tofacitinib groups than in the placebo groups ( -0.50 and -0.57 points , respectively , vs. -0.19 points ; P<0.001 ) . The percentage of patients with a DAS28 - 4(ESR ) of less than 2.6 was not significantly higher with tofacitinib than with placebo ( 5.6 % and 8.7 % in the 5-mg and 10-mg tofacitinib groups , respectively , and 4.4 % with placebo ; P=0.62 and P=0.10 for the two comparisons ) . Serious infections developed in six patients who were receiving tofacitinib . Common adverse events were headache and upper respiratory tract infection . Tofacitinib treatment was associated with elevations in low-density lipoprotein cholesterol levels and reductions in neutrophil counts . CONCLUSIONS In patients with active rheumatoid arthritis , tofacitinib monotherapy was associated with reductions in signs and symptoms of rheumatoid arthritis and improvement in physical function . ( Funded by Pfizer ; ORAL Solo Clinical Trials.gov number , NCT00814307 . ) [19638454] OBJECTIVES MTX , either alone or in combination with SSZ , is effective in the treatment of RA . Trials have shown that , after SSZ failure , the addition of MTX to SSZ is more effective than a switch to MTX . Whether this is also the case in daily practice has not been analysed yet . In this study , we compared the efficacy of a switch to MTX monotherapy with that of the addition of MTX to SSZ in the daily clinical practice of RA patients who had failed SSZ monotherapy in the Nijmegen RA Inception Cohort . METHODS For this study , 230 patients who failed to SSZ monotherapy were followed for up to 52 weeks . A total of 124 underwent a switch to MTX alone , whereas 106 patients received the combination of MTX and SSZ . The primary outcome measure was the mean change in the disease activity score ( DAS28 ) after 24 weeks . RESULTS Both treatment groups showed a significant decrease in DAS28 after 24 weeks , which was similar in both groups . Drug survival analysis showed that the chance to stop with a DMARD within 52 weeks was higher in the MTX-SSZ group ( P < 0.01 ) . CONCLUSIONS In RA patients who failed to SSZ the clinical efficacy of a switch to MTX monotherapy was similar to that of the addition of MTX , suggesting that in daily clinical practice a switch to MTX is a good option for patients with an inadequate response to SSZ

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### Context: [23348607] OBJECTIVE The purpose of this 24-month phase III study was to examine structural preservation with tofacitinib in patients with rheumatoid arthritis ( RA ) with an inadequate response to methotrexate ( MTX ) . Data from a planned 12-month interim analysis are reported . METHODS In this double-blind , parallel-group , placebo-controlled study , patients receiving background MTX were r and omized 4:4:1:1 to tofacitinib at 5 mg twice daily , tofacitinib at 10 mg twice daily , placebo to tofacitinib at 5 mg twice daily , and placebo to tofacitinib at 10 mg twice daily . At month 3 , nonresponder placebo-treated patients were advanced in a blinded manner to receive tofacitinib as indicated above ; remaining placebo-treated patients were advanced at 6 months . Four primary efficacy end points were all analyzed in a step-down procedure . RESULTS At month 6 , response rates according to the American College of Rheumatology 20 % improvement criteria for tofacitinib at 5 mg and 10 mg twice daily were higher than those for placebo ( 51.5 % and 61.8 % , respectively , versus 25.3 % ; both P < 0.0001 ) . At month 6 , least squares mean ( LSM ) changes in total modified Sharp/van der Heijde score for tofacitinib at 5 mg and 10 mg twice daily were 0.12 and 0.06 , respectively , versus 0.47 for placebo ( P = 0.0792 and P ≤ 0.05 , respectively ) . At month 3 , LSM changes in the Health Assessment Question naire disability index score for tofacitinib at 5 mg and 10 mg twice daily were -0.40 ( significance not declared due to step-down procedure ) and -0.54 ( P < 0.0001 ) , respectively , versus -0.15 for placebo . At month 6 , rates of remission ( defined as a value < 2.6 for the 4-variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate ) for tofacitinib at 5 mg and 10 mg twice daily were 7.2 % ( significance not declared due to step-down procedure ) and 16.0 % ( P < 0.0001 ) , respectively , versus 1.6 % for placebo . The safety profile was consistent with findings in previous studies . CONCLUSION Data from this 12-month interim analysis demonstrate that tofacitinib inhibits progression of structural damage and improves disease activity in patients with RA who are receiving MTX [23070312] The approach to treatment of RA has evolved substantially in recent years with the introduction of highly effective novel therapies that have result ed in new treatment paradigms , such as treat-to-target and the treatment of patients earlier in their disease course [ 1 , 2 ] . Clinicians are very interested in studies that compare the effectiveness of medications that could help them achieve optimal treatment outcomes for their patients . Extrapolation of the results of such studies into clinical practice depends on accurate assessment of data from the clinical trials . This assessment has become increasingly challenging as study design s have become increasingly complex , with multiple arms and changes in treatments over the course of a trial . There are many methods to analyse a given set of data ; with the same data set , depending on the method of analysis , different conclusions can be reached . To help st and ardize this process , a European League Against Rheumatism (EULAR)/ACR committee created guidelines on reporting data from clinical trials [ 3 ] . The complexities of this analysis are illustrated by a recent example . The R and omized Comparative Effectiveness Study of Oral Triple Therapy versus Etanercept plus Methotrexate in the Early , Aggressive Rheumatoid Arthritis ( TEAR ) trial was design ed to address two important clinical questions : ( i ) is it better to intensively treat all early RA patients with multiple DMARDs , or reserve this treatment only for those who do not appropriately respond to MTX monotherapy ? and ( ii ) is the combination therapy of MTX plus etanercept ( ETN ) superior to triple combination therapy of MTX , SSZ and HCQ ( TT ) , either initially or after insufficient efficacy of MTX at 6 months ? [ 4 ] . Patients with early RA were r and omly assigned to receive MTX monotherapy , MTX plus ETN or TT . At 6 months , patients treated with MTX monotherapy who did not achieve DAS28 < 3.2 were stepped up to add either ETN or move to TT and treated for 102 weeks . The primary outcome , by the protocol , was the area under the curve ( AUC ) of DAS28 from weeks 48 to 102 . Although many of the items suggested by a joint EULAR/ACR committee on reporting disease activity in clinical trials of patients [ 3 ] were reported , several facets of the methods of data analysis need to be fully understood in order to establish whether the reader concurs with the authors ’ conclusions that this study showed no difference in clinical outcomes at 2 years between patients initially treated with MTX plus ETN or TT . The data reported were an observed analysis only for patients who continued in the trial from week 48 to 102 patients had to have done well clinical ly and not had a significant adverse event to remain in the study through week 48 . A more traditional statistical analysis , such as a nonresponder imputation or last observation carried forward from day 0 to week 102 might have given different results . The first question posed , whether it is more effective to start either combination or MTX monotherapy , was not answered ; the results are not presented for those patients initially treated with MTX who achieved DAS28 < 3.2 at week 26 and then continued to week 102 . The primary outcome reported in the manuscript was an observed group analysis of change in the mean DAS28-ESR from week 48 to 102 and not the AUC of the DAS28 during this time period . The authors stated that their statistical analysis plan was confirmed by their secondary analyses , which did include non-responder imputation and last observation carried forward . However , these analyses were also performed only on patients in the study from week 48 to 102 . In addition to design and statistical considerations , some of the data can be interpreted differently from the authors , and this might be worth some further examination . For instance , the authors reported that there was no difference in the change in DAS28 , or other clinical measures , between the patient groups studied . However , there was a treatment difference at week 102 between the ETN and TT groups for ACR70 ( 18.2 vs 11.3 % , P = 0.02 ) . This would suggest that ETN plus MTX was more effective in achieving a profound response . This difference in profound response may have led to the significant difference in radiographic progression reported with ETN and MTX treatment vs TT at week 102 . The radiographic difference was noted despite the fact that X-rays were not done in patients who withdrew early ; in other studies , results at the time of exit have been extrapolated to the final endpoint to allow comparison . In this case , radiological data are only in those observed or study completers ; by definition , such patients usually fare quite well and patients who do well have less progression of joint damage . Initial TT and initial MTX monotherapy with step-up had similar ACR20/50/70 response rates at 2 years , [19565475] OBJECTIVE To determine the efficacy , safety , and tolerability of 3 different dosages of CP-690,550 , a potent , orally active JAK inhibitor , in patients with active rheumatoid arthritis ( RA ) in whom methotrexate , etanercept , infliximab , or adalimumab caused an inadequate or toxic response . METHODS Patients ( n = 264 ) were r and omized equally to receive placebo , 5 mg of CP-690,550 , 15 mg of CP-690,550 , or 30 mg of CP-690,550 twice daily for 6 weeks , and were followed up for an additional 6 weeks after treatment . The primary efficacy end point was the American College of Rheumatology 20 % improvement criteria ( ACR20 ) response rate at 6 weeks . RESULTS By week 6 , the ACR20 response rates were 70.5 % , 81.2 % , and 76.8 % in the 5 mg , 15 mg , and 30 mg twice daily groups , respectively , compared with 29.2 % in the placebo group ( P < 0.001 ) . Improvements in disease activity in CP-690,550-treated patients compared with placebo were seen in all treatment groups as early as week 1 . ACR50 and ACR70 response rates significantly improved in all treatment groups by week 4 . The most common adverse events reported were headache and nausea . The infection rate in both the 15 mg twice daily group and the 30 mg twice daily group was 30.4 % ( versus 26.2 % in the placebo group ) . No opportunistic infections or deaths occurred . Increases in mean low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels , and increases in mean serum creatinine level ( 0.04 - 0.06 mg/dl ) were seen in all CP-690,550 treatment arms . CONCLUSION Our findings indicate that CP-690,550 is efficacious in the treatment of RA , result ing in rapid , statistically significant , and clinical ly meaningful reductions in the signs and symptoms of RA . Further studies of CP-690,550 in RA are warranted [16255010] OBJECTIVE To assess the efficacy of low-dose prednisolone on joint damage and disease activity in patients with early rheumatoid arthritis ( RA ) . METHODS At the start of their initial treatment with a disease-modifying antirheumatic drug ( DMARD ) , patients with early ( duration < or = 1 year ) active RA were r and omly assigned to receive either 7.5 mg/day prednisolone or no prednisolone for 2 years . Radiographs of the h and s and feet were obtained at baseline and after 1 and 2 years and scored according to the Sharp score as modified by van der Heijde . Remission was defined as a Disease Activity Score in 28 joints of < 2.6 . Bone mineral density was measured by dual x-ray absorptiometry at baseline and after 2 years . RESULTS Of the 250 patients included , 242 completed the study and 225 had radiographs available both at baseline and at 2 years . At 2 years , the median and interquartile range ( IQR ) change in total Sharp score was lower in the prednisolone group than in the no-prednisolone group ( 1.8 [ IQR 0.5 - 6.0 ] versus 3.5 [ IQR 0.5 - 10 ] ; P = 0.019 ) . In the prednisolone group , there were fewer newly eroded joints per patient after 2 years ( median 0.5 [ IQR 0 - 2 ] versus 1.25 [ IQR 0 - 3.25 ] ; P = 0.007 ) . In the prednisolone group , 25.9 % of patients had radiographic progression beyond the smallest detectable difference compared with 39.3 % of patients in the no-prednisolone group ( P = 0.033 ) . At 2 years , 55.5 % of patients in the prednisolone group had achieved disease remission , compared with 32.8 % of patients in the no-prednisolone group ( P = 0.0005 ) . There were few adverse events that led to withdrawal . Bone loss during the 2-year study was similar in the 2 treatment groups . CONCLUSION Prednisolone at 7.5 mg/day added to the initial DMARD retarded the progression of radiographic damage after 2 years in patients with early RA , provided a high remission rate , and was well tolerated . Therefore , the data support the use of low-dose prednisolone as an adjunct to DMARDs in early active RA [18207016] BACKGROUND Circadian rhythms are changed in patients with rheumatoid arthritis . A new modified-release delivery system has been developed which adapts the release of the administered glucocorticoid to the circadian rhythms of endogenous cortisol and disease symptoms to improve the benefit-risk ratio of glucocorticoid therapy in rheumatoid arthritis . We aim ed to assess the efficacy and safety of a new modified-release prednisone tablet compared with immediate-release prednisone in patients with this disease . METHODS In a 12-week , multicentre , r and omised , double-blind trial , 288 patients with active rheumatoid arthritis were r and omly assigned to either a modified-release prednisone tablet ( n=144 ) or to an immediate-release prednisone tablet ( n=144 ) . The modified-release tablet was taken at bedtime and prednisone was released with a delay of 4 h after ingestion . This treatment was compared with morning administration of immediate-release prednisone as an active comparator . The primary outcome measure was duration of morning stiffness of the joints . Analysis was by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00146640 . FINDINGS The mean relative change in duration of morning stiffness of the joints from baseline to end of treatment was significantly higher with modified-release prednisone than with immediate-release prednisone ( -22.7%vs -0.4 % ; difference=22.4 % [ 95 % CI 0.49 - 44.30 ] ; p=0.045 ) . Patients in the prednisone modified-release group achieved a mean reduction of 44.0 ( SD 136.6 ) min compared with baseline . The absolute difference between the treatment groups was 29.2 min ( 95 % CI -2.59 to 61.9 ) in favour of modified-release prednisone ( p=0.072 ) . The safety profile did not differ between treatments . INTERPRETATION Modified-release prednisone is well tolerated , convenient to administer , and produces a clinical ly relevant reduction of morning stiffness of the joints in addition to all known therapeutic effects of immediate-release prednisone [22393128] BACKGROUND Treatment strategies for tight control of early rheumatoid arthritis ( RA ) are highly effective but can be improved . OBJECTIVE To investigate whether adding prednisone , 10 mg/d , at the start of a methotrexate (MTX)-based treatment strategy for tight control in early RA increases its effectiveness . DESIGN A 2-year , prospect i ve , r and omized , placebo-controlled , double-blind , multicenter trial ( CAMERA-II [ Computer Assisted Management in Early Rheumatoid Arthritis trial-II ] ) . ( International St and ard R and omised Controlled Trial Number : IS RCT N 70365169 ) SETTING 7 hospitals in the Netherl and s. PATIENTS 236 patients with early RA ( duration < 1 year ) . INTERVENTION Patients were r and omly assigned to an MTX-based , tight control strategy starting with either MTX and prednisone or MTX and placebo . Methotrexate treatment was tailored to the individual patient at monthly visits on the basis of predefined response criteria aim ing for remission . MEASUREMENTS The primary outcome was radiographic erosive joint damage after 2 years . Secondary outcomes included response criteria , remission , and the need to add cyclosporine or a biologic agent to the treatment . RESULTS Erosive joint damage after 2 years was limited and less in the group receiving MTX and prednisone ( n = 117 ) than in the group receiving MTX and placebo ( n = 119 ) . The MTX and prednisone strategy was also more effective in reducing disease activity and physical disability , achieving sustained remission , and avoiding the addition of cyclosporine or biologic treatment . Adverse events were similar in both groups , but some occurred less in the MTX and prednisone group . LIMITATION A tight control strategy for RA implies monthly visits to an outpatient clinic , which is not always feasible . CONCLUSION Inclusion of low-dose prednisone in an MTX-based treatment strategy for tight control in early RA improves patient outcomes . PRIMARY FUNDING SOURCE Catharijne Foundation [18662933] Objectives : To compare the occurrence of drug-free remission , functional ability and radiological damage after 4 years of response-driven treatment according to four different treatment strategies for rheumatoid arthritis ( RA ) . Methods : Patients with recent-onset , active RA ( n = 508 ) were r and omly assigned to four different treatment strategies : ( 1 ) sequential monotherapy ; ( 2 ) step-up combination therapy ; ( 3 ) initial combination therapy with prednisone and ( 4 ) initial combination therapy with infliximab . Treatment was adjusted based on 3-monthly disease activity score ( DAS ) assessment s , aim ing at a DAS ⩽2.4 . From the third year , patients with a sustained DAS < 1.6 discontinued treatment . Results : In total , 43 % of patients were in remission ( DAS < 1.6 ) at 4 years and 13 % were in drug-free remission : 14 % , 12 % , 8 % and 18 % of patients in groups 1–4 , respectively . The absence of anti-cyclic citrullinated peptide antibodies , male gender and short symptom duration were independently associated with drug-free remission . Functional ability and remission were maintained in all four groups with the continuation of DAS-driven treatment , without significant differences between the groups . Significant progression of joint damage was observed in 38 % and 31 % of patients in groups 3 and 4 versus 51 % and 54 % of patients in groups 1 and 2 ( p<0.05 , group 4 versus groups 1 and 2 , group 3 versus group 2 ) . Conclusions : In patients with recent-onset active RA , drug-free remission was achieved in up to 18 % of patients . DAS-driven treatment maintained clinical and functional improvement , independent of the treatment strategy . Joint damage progression remained significantly lower after initial combination therapy compared with initial monotherapy [3604583] Summary Addition of 10 mg prednisone daily to a methotrexate-based tight control strategy does not lead to bone loss in early rheumatoid arthritis ( RA ) patients receiving preventive treatment for osteoporosis . A small increase in lumbar bone mineral density ( BMD ) during the first year of treatment was recorded , regardless of use of glucocorticoids . Introduction This study aims to describe effects on BMD of treatment according to EULAR guidelines with a methotrexate-based tight control strategy including 10 mg prednisone daily versus the same strategy without prednisone in early RA patients who received preventive therapy for osteoporosis . Methods Early RA patients were included in the CAMERA-II trial : a r and omized , placebo-controlled , double-blind 2-year trial , in which effects of addition of 10 mg prednisone daily to a methotrexate-based tight control strategy were studied . All patients received calcium , vitamin D and bisphosphonates . Disease activity was assessed every 4 weeks . Radiographs of h and s and feet and dual-energy X-ray absorptiometry of lumbar spine and left hip were performed at baseline and after 1 and 2 years of treatment . Results BMD increased significantly over time in both treatment groups at the lumbar spine with a mean of 2.6 % during the first year ( p < 0.001 ) , but not at the hip ; at none of the time points did BMD differ significantly between the prednisone and placebo group . Higher age and lower weight at baseline and higher disease activity scores during the trial , but not glucocorticoid therapy , were associated with lower BMD at both the lumbar spine and the hip in mixed-model analyses . Conclusion Addition of 10 mg prednisone daily to a methotrexate-based tight control strategy does not lead to bone loss in early RA patients on bisphosphonates . A small increase in lumbar BMD during the first year of treatment was found , regardless of use of glucocorticoids [22516039] BACKGROUND Methotrexate ( MTX ) is a cornerstone in the treatment of rheumatoid arthritis . Despite its widespread use , expert opinions differ about the optimal MTX starting dosage to achieve rapid onset of action while averting increased occurrence of adverse effects . Plasma concentrations have not been assessed in previous studies that monitored clinical efficacy . OBJECTIVE This study was performed to compare the pharmacokinetic parameters and clinical response of a st and ard ( 15 mg ) and an accelerated ( 25 mg ) dosing regimen , each administered orally once a week . METHODS This r and omized , controlled , double-blind , parallel , single-site study included 19 MTX-naïve patients older than 18 years with rheumatoid arthritis . Patients participated for 16 weeks . Disease activity was assessed using the Disease Activity Score in 28 joints ( DAS-28 ) as the primary outcome parameter . Plasma MTX concentrations were measured using HPLC at weeks 1 , 5 , 10 , and 16 . Tolerability was assessed via routine blood analysis ( hematology and clinical chemistry ) and a patient question naire to monitor adverse events . Reported or observed adverse events were recorded along with information about their severity and causal relationship to the study medication . RESULTS Nineteen white patients ( 13 women and 6 men ; mean age , 56 years ; and mean weight , 74 kg ) participated . At study entry , mean ( SD ) DAS-28 - 4v ( erythrocyte sedimentation rate ) was 4.73 ( 1.02 ) . Health Assessment Question naire scores were 1.45 ( 0.85 ) ; for C-reactive protein , 11.45 ( 10.04 ) mg/dL ; for alkaline phosphatase , 73.58 ( 19.91 ) U/L ; for aspartate aminotransferase , 23.32 ( 7.13 ) U/L ; and for creatinine , 0.87 ( 0.22 ) mg/dL. Although pharmacokinetic parameters such as AUC and C(max ) were significantly higher after the accelerated dosing regimen , clinical activity scores ( DAS-28 ) and inflammation parameters ( C-reactive protein ) did not indicate a significant benefit of an accelerated starting regimen . Considering toxicity , no elevation in liver function enzymes and no decrease in renal function were observed using the accelerated dosing ( statistical significance set at P ≤ 0.05 ) . No serious adverse events were noted . All observed adverse events were classified as study related . Overall , adverse events were noted in 58 % of patients . Comparison of the two doses revealed that 60 % of patients receiving the st and ard dosing regimen and 56 % of patients receiving the accelerated dosing regimen reported adverse events , the most frequent being gastrointestinal . These events were generally self-limiting . CONCLUSIONS Differences in clinical response between these two small selected patient groups who received an initial oral dose of either 15 or 25 mg MTX per week did not reach the level of statistical significance . The overall incidence of adverse effects , all classified as study related , was 58 % , with 60 % of patients receiving the st and ard dosage and 56 % of patients receiving the accelerated dosing regimen reporting adverse effects . However , because of the small sample size , this study was not powered to detect differences in the incidence of adverse events between the two dosing groups . Clinical Trials.gov identifier : NCT00695188 [2911916] Introduction Early treatment of rheumatoid arthritis ( RA ) has been shown to retard the development of joint damage for a period of up to 5 years . The aim of this study was to evaluate the radiologic progression beyond that time in patients with early RA initially treated with a combination of three disease-modifying antirheumatic drugs ( DMARDs ) or a single DMARD . Methods A cohort of 199 patients with early active RA were initially r and omized to receive treatment with a combination of methotrexate , sulfasalazine , and hydroxychloroquine with prednisolone ( FIN-RACo ) , or treatment with a single DMARD ( initially , sulfasalazine ) with or without prednisolone ( SINGLE ) . After 2 years , the drug-treatment strategy became unrestricted , but still targeted remission . The radiographs of h and s and feet were analyzed by using the Larsen score at baseline , 2 , 5 , and 11 years , and the radiographs of large joints , at 11 years . Results Sixty-five patients in the FIN-RACo and 65 in the SINGLE group had radiographs of h and s and feet available at baseline and at 11 years . The mean change from baseline to 11 years in Larsen score was 17 ( 95 % CI , 12 to 26 ) in the FIN-RACo group and 27 ( 95 % CI , 22 to 33 ) in the SINGLE group ( P = 0.037 ) . In total , 87 % ( 95 % CI , 74 to 94 ) and 72 % ( 95 % CI , 58 to 84 ) of the patients in the FIN-RACo and the SINGLE treatment arms , respectively , had no erosive changes in large joints at 11 years . Conclusions Targeting to remission with tight clinical controls results in low radiologic progression in most RA patients . Patients treated initially with a combination of DMARDs have less long-term radiologic damage than do those treated initially with DMARD monotherapy . Trial registration Current Controlled Trials IS RCT N18445519 [22679301] Objective To determine the most effective induction disease-modifying antirheumatic drug ( DMARD ) strategy in early rheumatoid arthritis ( RA ) , second to compare one single dose of intramuscular glucocorticoids ( GCs ) with daily oral GCs during the induction phase . Methods The 3-month data of a single-blinded clinical trial in patients with recent-onset arthritis ( tREACH ) were used . Patients were included who had a high probability ( > 70 % ) of progressing to persistent arthritis , based on the prediction model of Visser . Patients were r and omised into three induction therapy strategies : ( A ) combination therapy ( methotrexate ( MTX ) + sulfasalazine + hydroxychloroquine ) with GCs intramuscularly ; ( B ) combination therapy with an oral GC tapering scheme and ( C ) MTX with oral GCs similar to B. A total of 281 patients were r and omly assigned to strategy ( A ) ( n=91 ) , ( B ) ( n=93 ) or ( C ) ( n=97 ) . Results The Disease Activity Score ( DAS ) after 3 months was lower in patients receiving initial combination therapy than in those receiving MTX monotherapy ( 0.39 ( 0.67 to 0.11 , 95 % CI ) ) . DAS did not differ between the different GC bridging treatments . After 3 months 50 % fewer biological agents were prescribed in the combination therapy groups . Although the proportion of patients with medication adjustments differed significantly between the treatment arms , no differences were seen in these adjustments due to adverse events after stratification for drug . Conclusion Triple DMARD induction therapy is better than MTX monotherapy in early RA . Furthermore , no differences were seen in medication adjustments due to adverse events after stratification for drug . Intramuscular and oral GCs are equally effective as bridging treatments and both can be used [22402145] Aim Classifying more patients as rheumatoid arthritis ( RA ) ( 2010 American College of Rheumatology/European League Against Rheumatism criteria for RA ) may improve treatment outcomes but may cause overtreatment in daily practice . The authors determined the efficacy of initial methotrexate ( MTX ) plus prednisone treatment in patients with 1987 or 2010 classified RA and undifferentiated arthritis ( UA ) . Method 610 recent onset RA or UA patients started with MTX 25 mg/week and prednisone 60 mg/day tapered to 7.5 mg/day in 7 weeks . Percentage remissions after 4 months were compared between RA ( 1987 or 2010 criteria ) and UA . Predictors for remission were identified . Results With the 2010 criteria , 19 % more patients were classified as RA than with the 1987 criteria , but similar remission rates were achieved : 291/479 ( 61 % ) 2010 classified RA and 211/264 ( 58 % ) 1987 classified RA patients ( p=0.52 ) , and 79/122 ( 65 % ) UA patients ( p=0.46 ) . Anticitrullinated protein antibodies ( ACPA ) positive RA patients achieved more remission ( 66 % ) than ACPA negative RA patients ( 51 % , p=0.001 ) , but also had a lower mean baseline Disease Activity Score ( DAS ) ( 3.2 vs 3.6 , p<0.001 ) . Independent predictors for remission were male sex , low joint counts , DAS and Health Assessment Question naire , low body mass index and ACPA positivity . Conclusion Initial treatment with MTX and a tapered high dose of prednisone results in similarly high remission percentages after 4 months ( about 60 % ) in RA patients , regardless of fulfilling the 1987 or 2010 criteria , and in UA patients . Independent predictors indicate that initiating treatment while disease activity is relatively low results in more remission [21584942] To compare the efficacy , safety , and tolerability of 4 doses of oral tofacitinib ( CP‐690,550 ) with placebo in Japanese patients with active rheumatoid arthritis ( RA ) receiving stable background methotrexate ( MTX ) who had an inadequate response to MTX alone [21415052] Objective To compare clinical and radiological outcomes of four dynamic treatment strategies in recent-onset rheumatoid arthritis ( RA ) after 5 years follow-up . Methods 508 patients with recent-onset RA were r and omly assigned into four treatment strategies : sequential monotherapy ; step-up combination therapy ; initial combination with prednisone ; initial combination with infliximab . Treatment adjustments were made based on 3-monthly disease activity score ( DAS ) measurements ( if DAS > 2.4 next treatment step ; if DAS ≤2.4 during ≥6 months taper to maintenance dose ; if DAS < 1.6 during ≥6 months stop antirheumatic treatment ) . Primary and secondary outcomes were functional ability , joint damage progression , health-related quality of life and ( drug-free ) remission percentages . Results After 5 years , 48 % of patients were in clinical remission ( DAS < 1.6 ) and 14 % in drug-free remission , irrespective of initial treatment . After an earlier improvement in functional ability and quality of life with initial combination therapy , from 1 year onwards clinical outcomes were comparable across the groups and stable during 5 years . The initial combination groups showed less joint damage in year 1 . In years 2–5 annual progression was comparable across the groups . After 5 years , initial combination therapy result ed in significantly less joint damage progression , reflecting the earlier clinical response . Conclusion Irrespective of initial treatment , an impressive improvement in clinical and radiological outcomes of RA patients can be achieved with dynamic treatment aim ed at reducing disease activity , leading to 48 % remission , 14 % drug-free remission and sustained functional improvement . Starting with combination therapy result ed in earlier clinical improvement and less joint damage without more toxicity [16255011] OBJECTIVE To assess the effect of 5 mg/day prednisolone on disease progression in patients with early rheumatoid arthritis ( RA ) receiving st and ardized disease-modifying antirheumatic drug ( DMARD ) therapy . METHODS Patients with active RA of < 2 years ' duration were r and omly assigned in a double-blinded manner to receive prednisolone or placebo while starting concomitant DMARD therapy ( gold sodium thiomalate or methotrexate ) . H and and foot radiographs were taken at baseline and at 6 , 12 , and 24 months and were evaluated according to the Ratingen score and the total modified Sharp/van der Heijde score ( SHS ) . RESULTS Of 192 included patients , 166 were available for the intent-to-treat analysis ( ITT ) . Seventy-six patients completed the study per protocol ( PP ) . Radiographic progression ( increase in the Ratingen score ) was significantly less with prednisolone than with placebo . The difference in the progression rate between the groups was greatest in the first 6 months . At 24 months in the ITT population , the least squares ( LS ) mean difference was 3.14 ( 95 % confidence interval [ 95 % CI ] 0.94 , 5.34 ) , P = 0.006 . The results were confirmed by the total SHS in the ITT population ( LS mean difference 7.20 [ 95 % CI 0.93 , 13.47 ] , P = 0.022 ) and with the PP population . Clinical and functional outcomes tended to be better and the rate of remissions was higher in the prednisolone group . Side effects were observed more frequently in the prednisolone group than in the control group : weight gain ( 4 versus 0 patients ) , hypertension ( 6 versus 2 patients ) , glaucoma ( 3 versus 0 patients ) , Cushing 's syndrome ( 5 versus 0 patients ) , gastric distress ( 9 versus 4 patients ) , and gastric ulcers ( only with concomitant nonsteroidal antiinflammatory drug therapy ; 3 versus 0 patients ) . No new lumbar fractures were found in either group . CONCLUSION The very low daily dose of 5 mg prednisolone given over 2 years in combination with background DMARD therapy substantially decreased radiographic progression in early RA at low risk [21952978] OBJECTIVE To compare the efficacy , safety , and tolerability of 5 doses of oral tofacitinib ( CP-690,550 ) or adalimumab monotherapy with placebo for the treatment of active rheumatoid arthritis ( RA ) in patients with an inadequate response to disease-modifying antirheumatic drugs . METHODS In this 24-week , double-blind , phase IIb study , patients with RA ( n = 384 ) were r and omized to receive placebo , tofacitinib at 1 , 3 , 5 , 10 , or 15 mg administered orally twice a day , or adalimumab at 40 mg injected subcutaneously every 2 weeks ( total of 6 injections ) followed by oral tofacitinib at 5 mg twice a day for 12 weeks . The primary end point was the responder rate according to the American College of Rheumatology 20 % improvement criteria ( ACR20 ) at week 12 . RESULTS Treatment with tofacitinib at a dose of ≥3 mg twice a day result ed in a rapid response with significant efficacy when compared to placebo , as indicated by the primary end point ( ACR20 response at week 12 ) , achieved in 39.2 % ( 3 mg ; P ≤ 0.05 ) , 59.2 % ( 5 mg ; P < 0.0001 ) , 70.5 % ( 10 mg ; P < 0.0001 ) , and 71.9 % ( 15 mg ; P < 0.0001 ) in the tofacitinib group and 35.9 % of patients in the adalimumab group ( P = 0.105 ) , compared with 22.0 % of patients receiving placebo . Improvements were sustained at week 24 , according to the ACR20 , ACR50 , and ACR70 response rates as well as classifications of remission according to the 3-variable Disease Activity Score in 28 joints ( DAS28 ) using C-reactive protein and the 4-variable DAS28 using the erythrocyte sedimentation rate . The most common treatment-emergent adverse events ( AEs ) in patients across all tofacitinib treatment arms ( n = 272 ) were urinary tract infection ( 7.7 % ) , diarrhea ( 4.8 % ) , headache ( 4.8 % ) , and bronchitis ( 4.8 % ) . CONCLUSION Tofacitinib monotherapy at ≥3 mg twice a day was efficacious in the treatment of patients with active RA over 24 weeks and demonstrated a manageable safety profile [19363607] Bucillamine ( Buc ) , developed in Japan , is a disease-modifying antirheumatic drug ( DMARD ) which has been used to treat numerous patients with rheumatoid arthritis ( RA ) in Japan and Korea with favorable results . However , it has not been used globally . In the present study , we compared the timing of onset of efficacy and the usefulness of this drug with that of the globally accepted agent salazosulfapyridine ( SASP ) . There were 26 patients in the Buc group and 23 in the SASP group . We compared changes in the number of swollen joints , number of painful joints , duration of morning stiffness , grip strength , levels of inflammatory marker [ erythrocyte sedimentation rate ( ESR ) and C-reactive protein ( CRP ) ] , rheumatoid factor ( RF ) , physician ’s rating by visual analogue scale ( VAS ) , patient ’s rating of pain , patient ’s overall rating ( VAS ) , and improvement according to European League against Rheumatism ( EULAR ) criteria ( DAS28-CRP , DAS28-ESR ) in these two groups of patients . Both Buc and SASP were shown to be efficacious within 3 months after the start of treatment . Both drugs were found to be suitable as first-line treatment of early RA . Signs of efficacy tended to occur earlier with Buc than with SASP , and Buc also tended to have higher efficacy than SASP [20223838] Background Glucocorticoids ( GCs ) are often used as early arthritis treatment and it has been suggested that they induce remission or at least delay the development of rheumatoid arthritis ( RA ) and the need to start disease-modifying antirheumatic drugs ( DMARDs ) . Objective To test the effect of GCs on patients with very early arthritis ( symptom duration of < 16 weeks ) in a r and omised controlled trial . Methods Patients received a single intramuscular injection of 120 mg methylprednisolone or placebo ( PL ) and were followed up for 52 weeks . Primary end point was drug-free clinical remission , both at weeks 12 and 52 . Among secondary outcomes were fulfilment of remission criteria at weeks 2 , 12 or 52 , time course of ‘ core set variables ’ and proportion of patients starting DMARDs . Results 17.0 % of all analysed subjects ( 65/383 ) achieved persistent remission : 17.8 % ( 33/185 ) of the PL group , 16.2 % ( 32/198 ) of the patients receiving methylprednisolone ( OR=1.13 , 95 % CI 0.66 to 1.92 , p=0.6847 ) . Analyses of secondary end points showed significant clinical benefits of the GC only at week 2 . These differences subsequently disappeared . DMARDs were started in 162 patients : 50.3 % methylprednisolone and 56.7 % PL patients had to start DMARD treatment ( OR=0.78 , 95 % CI 0.49 to 1.22 , p=0.30 ) . Significantly more patients with polyarthritis than with oligoarthritis received DMARDs ( OR=2.84 , 95 % CI 1.75 to 4.60 , p<0.0001 ) . Conclusions Neither remission nor development of RA is delayed by GC treatment . Remission is rare in the first year of very early arthritis , occurring in < 20 % of the patients . Also , the need to start DMARDs was not influenced by GC treatment [22006202] OBJECTIVE To compare the efficacy , safety , and tolerability of 6 dosages of oral tofacitinib ( CP-690,550 ) with placebo for the treatment of active rheumatoid arthritis ( RA ) in patients receiving a stable background regimen of methotrexate ( MTX ) who have an inadequate response to MTX monotherapy . METHODS In this 24-week , double-blind , phase IIb study , patients with active RA ( n = 507 ) were r and omized to receive placebo or tofacitinib ( 20 mg/day , 1 mg twice daily , 3 mg twice daily , 5 mg twice daily , 10 mg twice daily , or 15 mg twice daily ) . All patients continued to receive a stable dosage of MTX . The primary end point was the American College of Rheumatology 20 % improvement criteria ( ACR20 ) response rate at week 12 . RESULTS At week 12 , ACR20 response rates for patients receiving all tofacitinib dosages ≥3 mg twice daily ( 52.9 % for 3 mg twice daily , 50.7 % for 5 mg twice daily , 58.1 % for 10 mg twice daily , 56.0 % for 15 mg twice daily , and 53.8 % for 20 mg/day ) were significantly ( P ≤ 0.05 ) greater than those for placebo ( 33.3 % ) . Improvements were sustained at week 24 for the ACR20 , ACR50 , and ACR70 responses , scores for the Health Assessment Question naire disability index , the 3-variable Disease Activity Score in 28 joints using the C-reactive protein level ( DAS28-CRP ) , and a 3-variable DAS28-CRP of < 2.6 . The most common treatment-emergent adverse events occurring in > 10 % of patients in any tofacitinib group were diarrhea , upper respiratory tract infection , and headache ; 21 patients ( 4.1 % ) experienced serious adverse events . Sporadic increases in transaminase levels , increases in cholesterol and serum creatinine levels , and decreases in neutrophil and hemoglobin levels were observed . CONCLUSION In patients with active RA in whom the response to MTX has been inadequate , the addition of tofacitinib at a dosage ≥3 mg twice daily showed sustained efficacy and a manageable safety profile over 24 weeks [21229373] In order to compare the efficacy and toxicity of methotrexate and leflunomide for the treatment of rheumatoid arthritis , a double-blind r and omized clinical trial was carried out at the Department of Medicine , Jinnah Medical College Hospital , Korangi , Karachi . The sample size was 240 patients and the duration of the study was 1 year . The patients enrolled were r and omly divided into two groups ( methotrexate and leflunomide ) . RA activity was clinical ly assessed by noting changes in the four primary ( tender joint count , swollen joint count , physician and patient global assessment score ) and three secondary ( morning stiffness , pain intensity , HAQ ) clinical efficacy end-points . Data were expressed as the mean ± SD . A P value of < 0.05 , calculated by paired t test , was considered significant . A total of 368 subjects were enrolled in this study . Of these , 128 subjects were withdrawn during the screening phase . Of the 240 subjects who were r and omized and treated , 129 received leflunomide and 111 received methotrexate . The difference between the baseline and 12 month end-point measurements of all primary clinical efficacy end-points was significantly greater in methotrexate-treated than in leflunomide-treated subjects . Both leflunomide and methotrexate result ed in significant improvements in all secondary clinical efficacy end-points after 1 year of treatment . In both treatment groups , the most common reason for withdrawal during the treatment was adverse events . The results of this study indicate that both leflunomide and methotrexate are effective drugs for the long-term treatment of RA . It was concluded that methotrexate , which is a much cheaper drug than leflunomide , is the drug of choice , especially for patients who belong to low socioeconomic groups [21930734] Objective To investigate the 2-year clinical and radiological outcomes of patients with early rheumatoid arthritis ( RA ; symptom duration < 1 year ) who had initially responded well to methotrexate monotherapy . Methods In the SWEFOT trial , all 487 patients started methotrexate ( target dose 20 mg/week ) . After 3–4 months , 147 had low disease activity , 28-joint based disease activity score ( DAS28 ) ≤3.2 . These patients were not r and omly selected but were followed in regular care for 2 years . Clinical outcomes and radiographic progression according to the van der Heijde modified Sharp ( SvdH ) score were analysed . Results The majority of the 147 patients continued on methotrexate monotherapy . After 1 and 2 years , DAS28 remission was achieved in 59.6 % and 71.8 % and mean observed DAS28 values were 2.53 and 2.25 , respectively . Despite the favourable clinical course , a proportion of the patients progressed radiographically with a mean ( SD ) increase in the SvdH score after 2 years of 3.90 ( 6.84 ) . There was no significant difference in progression between patients in DAS28 remission versus not in remission ( p=0.73 ) . At baseline , approximately half the patients had no radiographic damage , while after 2 years the proportion was approximately 20 % . Conclusion Most early RA patients who achieve low disease activity after 3–4 months of methotrexate monotherapy continue to have low disease activity during 2 years follow-up , and additional treatment is needed infrequently . Some radiological progression occurs in most patients , and may be marked or severe in some , even despite sustained DAS28 remission . Close monitoring for radiological progression is thus warranted [11777359] Drug treatment for rheumatoid arthritis usually consists of a combination of a nonsteroidal anti-inflammatory drug ( NSAID ) and a disease-modifying antirheumatic drug ( for example , sulfasalazine , methotrexate , gold salt , or a combination ) . New biological agents , such as tumor necrosis factor- blocking agents and interleukin-1 receptor antagonists , appear promising ( 1 , 2 ) . Glucocorticoids have had a special place in the treatment of rheumatoid arthritis since the publication of the report by Hench and coworkers showing that cortisone dramatically alleviated the symptoms of rheumatoid arthritis by inhibiting inflammation ( 3 ) . This period of enthusiasm in the 1950s was followed by a long period in which glucocorticoids were applied cautiously for rheumatoid arthritis because of their many side effects and the recognition that inhibition of inflammation is not necessarily associated with retardation of joint damage ( 4 ) . Ongoing research on glucocorticoids in rheumatoid arthritis focused on both inflammation and joint damage . Some recent studies showed that glucocorticoids reduced the progression of joint damage when added to therapy with disease-modifying antirheumatic drugs . These findings suggested that glucocorticoids might also have disease-modifying properties . If this could be confirmed , glucocorticoids might be used more often , especially since potential serious adverse effects of glucocorticoid therapy are more easily managed today ( 5 ) . Secondary osteoporosis is inhibited by potent bisphosphonates , and gastrointestinal complications of glucocorticoid therapy , especially in combination with NSAIDs , can be reduced by misoprostol , proton-pump inhibitors , or cyclooxygenase-2 selective NSAIDs . As yet , disease-modifying properties of low-dose glucocorticoids as monotherapy for patients with early rheumatoid arthritis have not been investigated . The aim of our study was to investigate the clinical efficacy , disease-modifying properties , and side effects of low-dose glucocorticoids as monotherapy for previously untreated patients with early active rheumatoid arthritis . Methods Patients From October 1992 through October 1995 , all consecutive out patients at the rheumatology departments of the Deventer and Zutphen Hospitals , the Netherl and s , who were at least 18 years of age and had early previously untreated rheumatoid arthritis ( disease duration < 1 year ) that satisfied classification criteria were invited to participate in the study [ 6 ] . To be included , patients had to have active disease , which was defined as the presence of at least two of the following three criteria : 1 ) early-morning stiffness lasting 30 minutes or longer , 2 ) 28-joint score for tenderness and 28-joint score for swelling of 3 or more , and 3 ) Westergren erythrocyte sedimentation rate of 28 mm or higher after 1 hour ( 7 , 8) . Exclusion criteria were contraindications to prednisone or NSAIDs , active gastrointestinal problems , serious complicating diseases , severe hypertension , hemorrhagic diathesis , treatment with cytotoxic or immunosuppressive drugs , alcohol or drug abuse , and psychiatric or mental problems . Informed consent was obtained from all patients before participation . Of the 118 eligible patients , 37 declined to participate ( Figure 1 ) . Figure 1 . Trial profile . Intervention Pharmacy personnel at Deventer Hospital used a computer-generated r and omization procedure to r and omly assign the 81 participating patients , in blocks of 10 , to one of two treatment groups . One group received two tablets of prednisone , 5 mg , once daily at breakfast , and one group received placebo . The pharmacology department at Deventer Hospital prepared and labeled the prednisone and placebo tablets , which were identical in shape and color , and distributed them to patients in unlabeled boxes . Only the pharmacist could access the allocation table . Both groups of patients received 500 mg of elementary calcium in the evening . The code of r and omization was broken after 2 years of treatment , and the prednisone dosage was tapered . Surplus tablets of the study medication were counted at every visit , and adherence was satisfactory ( 96 % ) . Use of NSAIDs was not regulated . Local glucocorticoid injections were permitted only when absolutely necessary . Physical therapy and additional use of paracetamol were allowed . After 6 months , sulfasalazine ( 2 g/d ) could be prescribed as rescue medication . The decision to add sulfasalazine was made on clinical grounds ( activity of rheumatoid arthritis ) . Design and Setting The ethics committees of the University Medical Center Utrecht and the Deventer and Zutphen Hospitals approved the trial . The study was considered ethically acceptable when it was design ed ( 19891991 ) ; later , however , it became clear that irreversible joint damage is an early feature of rheumatoid arthritis . With our present knowledge , it would probably be considered unethical to compare the effects of prednisone and placebo in patients who did not receive a disease-modifying antirheumatic drug for at least 6 months . In our study , sulfasalazine could be prescribed as rescue medication only after 6 months to avoid obscuring the effects of prednisone monotherapy . Measurements All clinical outcome measurements , except those for disability and radiologic outcomes , were performed at baseline and every 3 months . Disability , which was assessed with the Health Assessment Question naire , and radiologic outcomes were measured every 6 months . Early-morning stiffness was recorded in minutes ( maximum , 720 minutes ) . Morning pain and general well-being were assessed on a horizontal visual analogue scale ranging from 0 to 100 mm , with 0 representing the best score ( no problems ) and 100 representing the worst score . Swelling and tenderness were assessed with the 28-joint score ( 7 , 8) . Grip strength was measured in kPa with a vigorimeter ( range , 0 to 200 kPa ) ; the mean of three measurements was calculated for each h and . Disability was assessed with a vali date d Dutch version of the Health Assessment Question naire ( Vragenlijst Dagelijks Functioneren ) ( 9 ) , which had a range of 0 to 3 ( 0 represented the best score [ no problems ] , and 3 represented the worst score ) . Serum C-reactive protein level was measured in mg/L. To investigate the possible sparing effect of the trial medication , we recorded the use of NSAIDs and analgesics , the frequency of intra-articular corticosteroid injections , and the use of physiotherapy . The patients recorded the use of NSAIDs , analgesics , and physical therapy in st and ardized patient diaries . To calculate the use of NSAIDs and to compare different NSAIDs , we arbitrarily chose naproxen as a reference . One thous and mg of naproxen was defined as 1 unit and was considered to be approximately equivalent to 600 mg of azapropazone , 100 mg of diclofenac , 200 mg of flurbiprofen , 1600 mg of ibuprofen , 100 mg of indomethacin , 200 mg of ketoprofen , 15 mg of meloxicam , 1000 mg of nabumetone , 20 mg of piroxicam , and 600 mg of tiaprofenic acid . Every 3 months , the first author recorded use of intra-articular corticosteroid injections . Radiologic outcome measures were erosions , joint space narrowing , and the total score for both ( range , 0 to 448 ) . The total score is the sum of the erosions and narrowing scores in 44 joints in the h and s and feet , assessed on plain radiography and scored with the van der Heijde modification of the Sharp method ( 10 , 11 ) . Radiologic outcome measures also included the number of patients with erosive disease in each group and the number of radiologically affected joints per patient . Radiographs were taken at entry and every 6 months . An assistant prepared the radiographs to be read , and all identifying patient data on the radiographs were concealed from the readers . The readers had no knowledge of patient identity when they scored the radiographs . Radiographs were read in r and om patient order and were scored for each patient in temporal order . Scoring in temporal order clearly has advantages , as a comparative study has shown ( 11 ) . However , with this method , scores can either be stable or increase ; a decrease ( indicating improvement ) is not possible . The first author and an independent radiologist viewed all available radiographs at one center . When the readers ' total scores for individual cases differed by 25 % or more , agreement was reached through discussion . Joint damage was defined as a score that exceeded 0 . To correct for possible differences between the two treatment groups in the number of patients who developed little or no joint damage , we also analyzed data only from patients who developed joint damage . Furthermore , radiologic damage was also analyzed with a cutoff point of 4 modified Sharp units . A score of 0 to 3 was interpreted as no damage , and scores of 4 or greater were interpreted as joint damage . This cutoff point seems to reflect clinical ly relevant change ( 12 ) and was also used in our study to define erosive rheumatoid arthritis . At the start of the study and every 3 months for 2 years , st and ardized lists were used to document adverse effects . We noted the occurrence of infections and the use of antibiotics ; the latter was checked at the patient 's pharmacy . For hypertension , the first author used a single device to measure blood pressure in mm Hg . For steroid diabetes , serum glucose level was measured in mmol/L. Hyperglycemia was defined according to the World Health Organization st and ard : postpr and ial , a glucose level of at least 11.0 mmol/L ( 198 mg/dL ) , and fasting , at least 6.6 mmol/L ( 119 mg/dL ) . Urinary glucose level was measured by using a semiquantitative method ( dipstick ) . A value less than 2.7 mmol/L ( 49 mg/dL ) was considered negative , a value of 2.7 to 5.5 mmol/L ( 50 to 99 mg/dL ) was considered a trace , a value of 5.6 to 16.6 mmol/L ( 100 to 299 mg/dL ) was considered 1 + , a value of 16.7 to 54.9 mmol/L ( 300 to 989 mg/dL ) was considered 2 + , and a value of 55 mmol/L or greater ( 990 mg/dL ) was considered 3 + . To assess weight gain , [22873531] BACKGROUND Tofacitinib ( CP-690,550 ) is a novel oral Janus kinase inhibitor that is being investigated for the treatment of rheumatoid arthritis . METHODS In this 12-month , phase 3 trial , 717 patients who were receiving stable doses of methotrexate were r and omly assigned to 5 mg of tofacitinib twice daily , 10 mg of tofacitinib twice daily , 40 mg of adalimumab once every 2 weeks , or placebo . At month 3 , patients in the placebo group who did not have a 20 % reduction from baseline in the number of swollen and tender joints were switched in a blinded fashion to either 5 mg or 10 mg of tofacitinib twice daily ; at month 6 , all patients still receiving placebo were switched to tofacitinib in a blinded fashion . The three primary outcome measures were a 20 % improvement at month 6 in the American College of Rheumatology scale ( ACR 20 ) ; the change from baseline to month 3 in the score on the Health Assessment Question naire-Disability Index ( HAQ-DI ) ( which ranges from 0 to 3 , with higher scores indicating greater disability ) ; and the percentage of patients at month 6 who had a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate ( DAS28 - 4[ESR ] ) of less than 2.6 ( with scores ranging from 0 to 9.4 and higher scores indicating greater disease activity ) . RESULTS At month 6 , ACR 20 response rates were higher among patients receiving 5 mg or 10 mg of tofacitinib ( 51.5 % and 52.6 % , respectively ) and among those receiving adalimumab ( 47.2 % ) than among those receiving placebo ( 28.3 % ) ( P<0.001 for all comparisons ) . There were also greater reductions in the HAQ-DI score at month 3 and higher percentages of patients with a DAS28 - 4(ESR ) below 2.6 at month 6 in the active-treatment groups than in the placebo group . Adverse events occurred more frequently with tofacitinib than with placebo , and pulmonary tuberculosis developed in two patients in the 10-mg tofacitinib group . Tofacitinib was associated with an increase in both low-density and high-density lipoprotein cholesterol levels and with reductions in neutrophil counts . CONCLUSIONS In patients with rheumatoid arthritis receiving background methotrexate , tofacitinib was significantly superior to placebo and was numerically similar to adalimumab in efficacy . ( Funded by Pfizer ; ORAL St and ard Clinical Trials.gov number , NCT00853385 . ) [23294500] BACKGROUND Rheumatoid arthritis is a heterogeneous chronic disease , and no therapeutic agent has been identified which is universally and persistently effective in all patients . We investigated the effectiveness of tofacitinib ( CP-690,550 ) , a novel oral Janus kinase inhibitor , as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis . METHODS We did a 6-month , double-blind , parallel-group phase 3 study at 82 centres in 13 countries , including North America , Europe , and Latin America . 399 patients aged 18 years or older with moderate-to-severe rheumatoid arthritis and inadequate response to tumour necrosis factor inhibitors ( TNFi ) were r and omly assigned in a 2:2:1:1 ratio with an automated internet or telephone system to receive twice a day treatment with : tofacitinib 5 mg ( n=133 ) ; tofacitinib 10 mg ( n=134 ) ; or placebo ( n=132 ) , all with methotrexate . At month 3 , patients given placebo advanced to either tofacitinib 5 mg twice a day ( n=66 ) or 10 mg twice a day ( n=66 ) . Primary endpoints included American College of Rheumatology (ACR)20 response rate , mean change from baseline in Health Assessment Question naire-Disability Index ( HAQ-DI ) , and rates of disease activity score (DAS)28 - 4(ESR ) less than 2·6 ( referred to as DAS28<2·6 ) , all at month 3 . The full analysis set for the primary analysis included all r and omised patients who received at least one dose of study medication and had at least one post-baseline assessment . This trial is registered with www . Clinical Trials.gov , number NCT00960440 . FINDINGS At month 3 , ACR20 response rates were 41·7 % ( 55 of 132 [ 95 % CI vs placebo 6·06 - 28·41 ] ; p=0·0024 ) for tofacitinib 5 mg twice a day and 48·1 % ( 64 of 133 ; [ 12·45 - 34·92 ] ; p<0·0001 ) for tofacitinib 10 mg twice a day versus 24·4 % ( 32 of 131 ) for placebo . Improvements from baseline in HAQ-DI were -0·43 ( [ -0·36 to -0·15 ] ; p<0·0001 ) for 5 mg twice a day and -0·46 ( [ -0·38 to -0·17 ] ; p<0·0001 ) for 10 mg twice a day tofacitinib versus -0·18 for placebo ; DAS28<2·6 rates were 6·7 % ( eight of 119 ; [ 0 - 10·10 ] ; p=0·0496 ) for 5 mg twice a day tofacitinib and 8·8 % ( 11 of 125 [ 1·66 - 12·60 ] ; p=0·0105 ) for 10 mg twice a day tofacitinib versus 1·7 % ( two of 120 ) for placebo . Safety was consistent with phase 2 and 3 studies . The most common adverse events in months 0 - 3 were diarrhoea ( 13 of 267 ; 4·9 % ) , nasopharyngitis ( 11 of 267 ; 4·1 % ) , headache ( 11 of 267 ; 4·1 % ) , and urinary tract infection ( eight of 267 ; 3·0 % ) across tofacitinib groups , and nausea ( nine of 132 ; 6·8 % ) in the placebo group . INTERPRETATION In this treatment-refractory population , tofacitinib with methotrexate had rapid and clinical ly meaningful improvements in signs and symptoms of rheumatoid arthritis and physical function over 6 months with manageable safety . Tofacitinib could provide an effective treatment option in patients with an inadequate response to TNFi . FUNDING Pfizer [12115219] OBJECTIVE To compare the efficacy of combination therapy with methotrexate ( MTX ) and hydroxychloroquine ( HCQ ) , MTX and sulfasalazine ( SSZ ) , and MTX , HCQ , and SSZ in patients with rheumatoid arthritis ( RA ) . METHODS RA patients ( n = 171 ) who had not previously been treated with combinations of the study medications were r and omized to receive 1 of the 3 treatment combinations in this 2-year , double-blind , placebo-controlled protocol . HCQ was given at a dosage of 200 mg twice a day . The dosage of MTX was accelerated from 7.5 mg/week to 17.5 mg/week in all patients who were not in remission . Similarly , the dosage of SSZ was escalated from 500 mg twice a day to 1 gm twice a day in patients who were not in remission . The primary end point of the study was the percentage of patients who had a 20 % response to therapy according to the American College of Rheumatology ( ACR ) criteria at 2 years . RESULTS Intent-to-treat analysis revealed that patients receiving the triple combination responded best , with 78 % achieving an ACR 20 % response at 2 years , compared with 60 % of those treated with MTX and HCQ ( P = 0.05 ) and 49 % of those treated with MTX and SSZ ( P = 0.002 ) . Similar trends were seen for the ACR 50 % response , with 55 % , 40 % , and 29 % of patients in the 3 treatment groups , respectively , achieving these results at 2 years ( P = 0.005 for the triple combination group versus the MTX and SSZ group ) . All combination treatments were well-tolerated . Fourteen patients ( evenly distributed among the 3 groups ) withdrew from the protocol because of symptoms that were potentially related to the study medication . CONCLUSION The triple combination of MTX , SSZ , and HCQ is well-tolerated , and its efficacy is superior to that of the double combination of MTX and SSZ and is marginally superior to that of the double combination of MTX and HCQ [22508468] OBJECTIVE To assess whether it is better to intensively treat all patients with early rheumatoid arthritis ( RA ) using combinations of drugs or to reserve this approach for patients who do not have an appropriate response ( as determined by a Disease Activity Score in 28 joints using the erythrocyte sedimentation rate [ DAS28-ESR ] of ≥ 3.2 at week 24 ) to methotrexate ( MTX ) monotherapy , and to assess whether combination therapy with MTX plus etanercept is superior to the combination of MTX plus sulfasalazine plus hydroxychloroquine . METHODS The Treatment of Early Aggressive Rheumatoid Arthritis ( TEAR ) study is a 2-year , r and omized , double-blind trial . A 2 × 2 factorial design was used to r and omly assign subjects to 1 of 4 treatment arms : immediate treatment with MTX plus etanercept , immediate oral triple therapy ( MTX plus sulfasalazine plus hydroxychloroquine ) , or step-up from MTX monotherapy to one of the combination therapies ( MTX plus etanercept or MTX plus sulfasalazine plus hydroxychloroquine ) at week 24 if the DAS28-ESR was ≥ 3.2 . All treatment arms included matching placebos . The primary outcome was an observed-group analysis of DAS28-ESR values from week 48 to week 102 . RESULTS At week 24 ( beginning of the step-up period ) , subjects in the 2 immediate-treatment groups demonstrated a greater reduction in the DAS28-ESR compared with those in the 2 step-up groups ( 3.6 versus 4.2 ; P < 0.0001 ) ; no differences between the combination-therapy regimens were observed . Between week 48 and week 102 , subjects r and omized to the step-up arms had a DAS28-ESR clinical response that was not different from that of subjects who initially received combination therapy , regardless of the treatment arm . There was no significant difference in the DAS28-ESR between subjects r and omized to oral triple therapy and those r and omized to receive MTX plus etanercept . By week 102 , there was a statistically significant difference in the change in radiographic measurements from baseline between the group receiving MTX plus etanercept and the group receiving oral triple therapy ( 0.64 versus 1.69 ; P = 0.047 ) . CONCLUSION There were no differences in the mean DAS28-ESR during weeks 48 - 102 between subjects r and omized to receive MTX plus etanercept and those r and omized to triple therapy , regardless of whether they received immediate combination treatment or step-up from MTX monotherapy . At 102 weeks , immediate combination treatment with either strategy was more effective than MTX monotherapy prior to the initiation of step-up therapy . Initial use of MTX monotherapy with the addition of sulfasalazine plus hydroxychloroquine ( or etanercept , if necessary , after 6 months ) is a reasonable therapeutic strategy for patients with early RA . Treatment with the combination of MTX plus etanercept result ed in a statistically significant radiographic benefit compared with oral triple therapy [8609945] BACKGROUND Rheumatoid arthritis is a common disease that causes substantial morbidity and mortality . The responses of patients with rheumatoid arthritis to treatment with a single so-called disease-modifying drug , such as methotrexate , are often suboptimal . Despite limited data , many patients are treated with combinations of these drugs . METHODS We enrolled 102 patients with rheumatoid arthritis and poor responses to at least one disease-modifying drug in a two-year , double-blind , r and omized study of treatment with methotrexate alone ( 7.5 to 17.5 mg per week ) , the combination of sulfasalazine ( 500 mg twice daily ) and hydroxychloroquine ( 200 mg twice daily ) , or all three drugs . The dose of methotrexate was adjusted in an attempt to achieve remission in all patients . The primary and point of the study was the successful completion of two years of treatment with 50 percent improvement in composite symptoms of arthritis and no evidence of drug toxicity . RESULTS Fifty of the 102 patients had 50 percent improvement at nine months and maintained at least that degree of improvement for two years without evidence of major drug toxicity . Among them were 24 of 31 patients treated with all three drugs ( 77 percent ) , 12 of 36 patients treated with methotrexate alone ( 33 percent , P < 0.001 for the comparison with the three-drug group ) , and 14 of 35 patients treated with sulfasalazine and hydroxychloroquine ( 40 percent ) , P = 0.003 for the comparison with the three-drug group ) . Seven patients in the methotrexate group and three patients in each of the other two groups discontinued treatment because of drug toxicity . CONCLUSIONS In patients with rheumatoid arthritis , combination therapy with methotrexate , sulfasalazine , and hydroxychloroquine is more effective than either methotrexate alone or a combination of sulfasalazine , and hydroxychloroquine [20398020] In order to identify rate and stability of remission induced by low-dose prednisone comedication in early rheumatoid arthritis ( RA ) , we evaluated patients with early RA ( < 1 year ) who were r and omized to receive ( P ) or not ( non-P ) low-dose prednisone in association with step-up disease-modifying antirheumatic drug therapy over 2 years . Prevalence and duration of clinical remission were evaluated in the first and second year . Each treatment group included 105 patients ; no significant differences were found at baseline . During the first year , P patients achieved higher rates of clinical remission with a time-averaged odds ratio ( OR ) of 1.965 ( CI 95 % 1.214 - 3.182 , P= 0.006 ) . Moreover , they showed a higher probability of sustained remission during the second year ( OR 4.480 , CI 95 % 1.354 - 14.817 , P= 0.014 ) . In conclusion , we found as in early RA low-dose prednisone comedication is associated with higher rate of clinical remission , earlier disease activity control and more stable remission over time [7791815] BACKGROUND Oral glucocorticoids are widely used to treat patients with rheumatoid arthritis , but their effect on joint destruction , as assessed radiologically , is uncertain . METHODS We conducted a r and omized , double-blind trial comparing oral prednisolone ( 7.5 mg daily for two years ) with placebo in 128 adults with active rheumatoid arthritis of less than two years ' duration . Except for systemic corticosteroids , other treatments could be prescribed . The primary outcome variables were the progression of damage as seen on radiographs of the h and after one and two years , as measured by the Larsen index , and the appearance of erosions in h and s that had no erosions at base line . The radiographs were viewed jointly by a radiologist and a rheumatologist who were unaware of the treatment assignment and the time point at which the films were obtained . RESULTS The statistical analysis of radiologically detected changes was based on 106 patients for whom there were films obtained at base line and two years later . After two years , the Larsen scores increased by a mean of 0.72 unit in the prednisolone group , indicating very little change , and by 5.37 units in the placebo group , indicating substantial joint destruction ( P = 0.004 ) . Of the 212 h and s of these patients , 147 ( 69.3 percent ) had no erosions at the start of the study . At two years , 15 of the 68 such h and s in the prednisolone group ( 22.1 percent ) and 36 of the 79 such h and s in the placebo group ( 45.6 percent ) had acquired erosions ( difference , 23.5 percentage points ; 95 percent confidence interval , 5.9 to 40.7 ; P = 0.007 ) . The patients in the prednisolone group had greater reductions than the patients in the placebo group in scores on an articular index and for pain and disability at 3 months ; for pain at 6 months ; and for disability at 6 , 12 , and 15 months ( all P < 0.05 ) . There was no difference between groups in st and ardized scores for the acute-phase response . The adverse events were typical of those encountered with antirheumatoid drugs . CONCLUSIONS In patients with early , active rheumatoid arthritis , prednisolone ( 7.5 mg daily ) given for two years in addition to other treatments substantially reduced the rate of radiologically detected progression of disease [22873530] BACKGROUND Tofacitinib ( CP-690,550 ) is a novel oral Janus kinase inhibitor that is being investigated as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis . METHODS In this phase 3 , double-blind , placebo-controlled , parallel-group , 6-month study , 611 patients were r and omly assigned , in a 4:4:1:1 ratio , to 5 mg of tofacitinib twice daily , 10 mg of tofacitinib twice daily , placebo for 3 months followed by 5 mg of tofacitinib twice daily , or placebo for 3 months followed by 10 mg of tofacitinib twice daily . The primary end points , assessed at month 3 , were the percentage of patients with at least a 20 % improvement in the American College of Rheumatology scale ( ACR 20 ) , the change from baseline in Health Assessment Question naire-Disability Index ( HAQ-DI ) scores ( which range from 0 to 3 , with higher scores indicating greater disability ) , and the percentage of patients with a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate ( DAS28 - 4[ESR ] ) of less than 2.6 ( with scores ranging from 0 to 9.4 and higher scores indicating more disease activity ) . RESULTS At month 3 , a higher percentage of patients in the tofacitinib groups than in the placebo groups met the criteria for an ACR 20 response ( 59.8 % in the 5-mg tofacitinib group and 65.7 % in the 10-mg tofacitinib group vs. 26.7 % in the combined placebo groups , P<0.001 for both comparisons ) . The reductions from baseline in HAQ-DI scores were greater in the 5-mg and 10-mg tofacitinib groups than in the placebo groups ( -0.50 and -0.57 points , respectively , vs. -0.19 points ; P<0.001 ) . The percentage of patients with a DAS28 - 4(ESR ) of less than 2.6 was not significantly higher with tofacitinib than with placebo ( 5.6 % and 8.7 % in the 5-mg and 10-mg tofacitinib groups , respectively , and 4.4 % with placebo ; P=0.62 and P=0.10 for the two comparisons ) . Serious infections developed in six patients who were receiving tofacitinib . Common adverse events were headache and upper respiratory tract infection . Tofacitinib treatment was associated with elevations in low-density lipoprotein cholesterol levels and reductions in neutrophil counts . CONCLUSIONS In patients with active rheumatoid arthritis , tofacitinib monotherapy was associated with reductions in signs and symptoms of rheumatoid arthritis and improvement in physical function . ( Funded by Pfizer ; ORAL Solo Clinical Trials.gov number , NCT00814307 . ) [19638454] OBJECTIVES MTX , either alone or in combination with SSZ , is effective in the treatment of RA . Trials have shown that , after SSZ failure , the addition of MTX to SSZ is more effective than a switch to MTX . Whether this is also the case in daily practice has not been analysed yet . In this study , we compared the efficacy of a switch to MTX monotherapy with that of the addition of MTX to SSZ in the daily clinical practice of RA patients who had failed SSZ monotherapy in the Nijmegen RA Inception Cohort . METHODS For this study , 230 patients who failed to SSZ monotherapy were followed for up to 52 weeks . A total of 124 underwent a switch to MTX alone , whereas 106 patients received the combination of MTX and SSZ . The primary outcome measure was the mean change in the disease activity score ( DAS28 ) after 24 weeks . RESULTS Both treatment groups showed a significant decrease in DAS28 after 24 weeks , which was similar in both groups . Drug survival analysis showed that the chance to stop with a DMARD within 52 weeks was higher in the MTX-SSZ group ( P < 0.01 ) . CONCLUSIONS In RA patients who failed to SSZ the clinical efficacy of a switch to MTX monotherapy was similar to that of the addition of MTX , suggesting that in daily clinical practice a switch to MTX is a good option for patients with an inadequate response to SSZ Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Rheumatoid arthritis ( RA ) is initially treated with methotrexate and other disease-modifying antirheumatic drugs ( DMARDs ) . Active RA patients who fail such treatments can receive tumour necrosis factor inhibitors ( TNFis ) , which are effective but expensive . OBJECTIVE We assessed whether or not combination DMARDs ( cDMARDs ) give equivalent clinical benefits at lower costs in RA patients eligible for TNFis . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

28566267

[17466110] BACKGROUND Subthreshold depression is a highly prevalent condition and a risk factor for developing a major depressive episode . Internet-based cognitive behaviour therapy may be a promising approach for the treatment of subthreshold depression . The current study had two aims : ( 1 ) to determine whether an internet-based cognitive behaviour therapy intervention and a group cognitive behaviour therapy intervention are more effective than a waiting-list control group ; and ( 2 ) to determine whether the effect of the internet-based cognitive behaviour therapy differs from the group cognitive behaviour therapy intervention . METHOD A total of 191 women and 110 men with subthreshold depression were r and omized into internet-based treatment , group cognitive behaviour therapy ( Lewinsohn 's Coping With Depression course ) , or a waiting-list control condition . The main outcome measure was treatment response after 10 weeks , defined as the difference in pre- and post-treatment scores on the Beck Depression Inventory ( BDI ) . Missing data , a major limitation of this study , were imputed using the Multiple Imputation ( MI ) procedure Data Augmentation . RESULTS In the waiting-list control group , we found a pre- to post-improvement effect size of 0.45 , which was 0.65 in the group cognitive behaviour therapy condition and 1.00 within the internet-based treatment condition . Helmert contrasts showed a significant difference between the waiting-list condition and the two treatment conditions ( p=0.04 ) and no significant difference between both treatment conditions ( p=0.62 ) . CONCLUSIONS An internet-based intervention may be at least as effective as a commonly used group cognitive behaviour therapy intervention for subthreshold depression in people over 50 years of age [1874722] Background The Internet has potential as a medium for health behavior change programs , but no controlled studies have yet evaluated the impact of a fully automated physical activity intervention over several months with real-time objective feedback from a monitor . Objective The aim was to evaluate the impact of a physical activity program based on the Internet and mobile phone technology provided to individuals for 9 weeks . Methods A single-center , r and omized , stratified controlled trial was conducted from September to December 2005 in Bedfordshire , United Kingdom , with 77 healthy adults whose mean age was 40.4 years ( SD = 7.6 ) and mean body mass index was 26.3 ( SD = 3.4 ) . Participants were r and omized to a test group that had access to an Internet and mobile phone – based physical activity program ( n = 47 ) or to a control group ( n = 30 ) that received no support . The test group received tailored solutions for perceived barriers , a schedule to plan weekly exercise sessions with mobile phone and email reminders , a message board to share their experiences with others , and feedback on their level of physical activity . Both groups were issued a wrist-worn accelerometer to monitor their level of physical activity ; only the test group received real-time feedback via the Internet . The main outcome measures were accelerometer data and self-report of physical activity . Results At the end of the study period , the test group reported a significantly greater increase over baseline than did the control group for perceived control ( P < .001 ) and intention/expectation to exercise ( P < .001 ) . Intent-to-treat analyses of both the accelerometer data ( P = .02 ) and leisure time self-report data ( P = .03 ) found a higher level of moderate physical activity in the test group . The average increase ( over the control group ) in accelerometer-measured moderate physical activity was 2 h 18 min per week . The test group also lost more percent body fat than the control group ( test group : −2.18 , SD = 0.59 ; control group : −0.17 , SD = 0.81 ; P = .04 ) . Conclusions A fully automated Internet and mobile phone – based motivation and action support system can significantly increase and maintain the level of physical activity in healthy adults [3362510] Background and aims Psychodynamic psychotherapy ( PDT ) is an effective treatment for major depressive disorder ( MDD ) , but not all clients with MDD can receive psychotherapy . Using the Internet to provide psychodynamic treatments is one way of improving access to psychological treatments for MDD . The aim of this r and omised controlled trial was to investigate the efficacy of an Internet-based psychodynamic guided self-help treatment for MDD . Methods Ninety-two participants who were diagnosed with MDD according to the Mini-International Neuropsychiatric Interview were r and omised to treatment or an active control . The treatment consisted of nine treatment modules based on psychodynamic principles with online therapist contact . The active control condition was a structured support intervention and contained psychoeducation and scheduled weekly contacts online . Both interventions lasted for 10 weeks . The primary outcome measure was the Beck Depression Inventory-II ( BDI-II ) . Results Mixed-effects model analyses of all r and omised participants showed that participants receiving Internet-based PDT made large and superior improvements compared with the active control group on the BDI-II ( between-group Cohen 's d = 1.11 ) . Treatment effects were maintained at a 10-month follow-up . Conclusions Internet-based psychodynamic guided self-help is an efficacious treatment for MDD that has the potential to increase accessibility and availability of PDT for MDD . Trial Registration Clinical trials.gov : [16260822] BACKGROUND Major depression can be treated by means of cognitive-behavioural therapy , but as skilled therapists are in short supply there is a need for self-help approaches . Many individuals with depression use the internet for discussion of symptoms and to share their experience . AIMS To investigate the effects of an internet-administered self-help programme including participation in a monitored , web-based discussion group , compared with participation in web-based discussion group only . METHOD A r and omised controlled trial was conducted to compare the effects of internet-based cognitive-behavioural therapy with minimal therapist contact ( plus participation in a discussion group ) with the effects of participation in a discussion group only . RESULTS Internet-based therapy with minimal therapist contact , combined with activity in a discussion group , result ed in greater reductions of depressive symptoms compared with activity in a discussion group only ( waiting-list control group ) . At 6 months ' follow-up , improvement was maintained to a large extent . CONCLUSIONS Internet-delivered cognitive cognitive-behavioural therapy should be pursued further as a complement or treatment alternative for mild-to-moderate depression [22060248] Internet-delivered self-help for depression with therapist guidance has shown efficacy in several trials . Results from meta-analyses suggest that guidance is important and that self-help programs without support are less effective . However , there are no direct experimental comparisons between guided and unguided internet-based treatments for depression . The present study compared the benefits of a 10-week web-based unguided self-help treatment with the same intervention complemented with weekly therapist support via e-mail . A waiting-list control group was also included . Seventy-six individuals meeting the diagnostic criteria of major depression or dysthymia were r and omly assigned to one of the three conditions . The Beck Depression Inventory ( BDI-II ) was used as the primary outcome measure . Secondary outcomes included general psychopathology , interpersonal problems , and quality of life . Sixty-nine participants ( 91 % ) completed the assessment at posttreatment and 59 ( 78 % ) at 6-month follow-up . Results showed significant symptom reductions in both treatment groups compared to the waiting-list control group . At posttreatment , between-group effect sizes on the BDI-II were d = .66 for unguided self-help versus waiting-list and d = 1.14 for guided self-help versus waiting-list controls . In the comparison of the two active treatments , small-to-moderate , but not statistically significant effects in favor of the guided condition were found on all measured dimensions . In both groups , treatment gains were maintained at 6-month follow-up . The findings provide evidence that internet-delivered treatments for depression can be effective whether support is added or not . However , all participants were interviewed in a structured diagnostic telephone interview before inclusion , which prohibits conclusions regarding unguided treatments that are without any human contact [5052463] Background Depression is a burdensome , recurring mental health disorder with high prevalence . Even in developed countries , patients have to wait for several months to receive treatment . In many parts of the world there is only one mental health professional for over 200 people . Smartphones are ubiquitous and have a large complement of sensors that can potentially be useful in monitoring behavioral patterns that might be indicative of depressive symptoms and providing context -sensitive intervention support . Objective The objective of this study is 2-fold , first to explore the detection of daily-life behavior based on sensor information to identify subjects with a clinical ly meaningful depression level , second to explore the potential of context sensitive intervention delivery to provide in-situ support for people with depressive symptoms . Methods A total of 126 adults ( age 20 - 57 ) were recruited to use the smartphone app Mobile Sensing and Support ( MOSS ) , collecting context -sensitive sensor information and providing just-in-time interventions derived from cognitive behavior therapy . Real-time learning-systems were deployed to adapt to each subject ’s preferences to optimize recommendations with respect to time , location , and personal preference . Biweekly , participants were asked to complete a self-reported depression survey ( PHQ-9 ) to track symptom progression . Wilcoxon tests were conducted to compare scores before and after intervention . Correlation analysis was used to test the relationship between adherence and change in PHQ-9 . One hundred twenty features were constructed based on smartphone usage and sensors including accelerometer , Wifi , and global positioning systems ( GPS ) . Machine-learning models used these features to infer behavior and context for PHQ-9 level prediction and tailored intervention delivery . Results A total of 36 subjects used MOSS for ≥2 weeks . For subjects with clinical depression ( PHQ-9≥11 ) at baseline and adherence ≥8 weeks ( n=12 ) , a significant drop in PHQ-9 was observed ( P=.01 ) . This group showed a negative trend between adherence and change in PHQ-9 scores ( rho=−.498 , P=.099 ) . Binary classification performance for biweekly PHQ-9 sample s ( n=143 ) , with a cutoff of PHQ-9≥11 , based on R and om Forest and Support Vector Machine leave-one-out cross validation result ed in 60.1 % and 59.1 % accuracy , respectively . Conclusions Proxies for social and physical behavior derived from smartphone sensor data was successfully deployed to deliver context -sensitive and personalized interventions to people with depressive symptoms . Subjects who used the app for an extended period of time showed significant reduction in self-reported symptom severity . Nonlinear classification models trained on features extracted from smartphone sensor data including Wifi , accelerometer , GPS , and phone use , demonstrated a proof of concept for the detection of depression superior to r and om classification . While findings of effectiveness must be reproduced in a RCT to proof causation , they pave the way for a new generation of digital health interventions leveraging smartphone sensors to provide context sensitive information for in-situ support and unobtrusive monitoring of critical mental health states [22677231] Depression is among the most prevalent disorders worldwide . In view of numerous treatment barriers , internet-based interventions are increasingly adopted to " treat the untreated " . The present trial ( registered as NCT01401296 ) was conducted over the internet and aim ed to assess the efficacy of an online self-help program for depression ( Deprexis ) . In r and om order , participants with elevated depression symptoms received program access or were allocated to a wait-list control condition . After eight weeks , participants were invited to take part in an online re- assessment . To compensate for common problems of online studies , such as low completion rates and unclear diagnostic status , reminders and incentives were used , and clinical diagnoses were externally confirmed in a subgroup of 29 % of participants . Relative to the wait-list group , program users experienced significant symptom decline on the Beck Depression Inventory ( BDI ; primary outcome ) , the Dysfunctional Attitudes Scale ( DAS ) , the Quality of Life scale ( WHOQOL-BREF ) and the Rosenberg Self-Esteem Scale ( RSE ) . Compared to wait-list participants , symptom decline was especially pronounced among those with moderate symptoms at baseline as well as those not currently consulting a therapist . Completion ( 82 % ) and re-test reliability of the instruments ( r = .72-.87 ) were good . The results of this trial suggest that online treatment can be beneficial for people with depression , particularly for those with moderate symptoms [3709106] Background . Psychodynamic psychotherapy is a psychological treatment approach that has a growing empirical base . Research has indicated an association between therapist-facilitated affective experience and outcome in psychodynamic therapy . Affect-phobia therapy ( APT ) , as outlined by McCullough et al. , is a psychodynamic treatment that emphasizes a strong focus on expression and experience of affect . This model has neither been evaluated for depression nor anxiety disorders in a r and omized controlled trial . While Internet-delivered psychodynamic treatments for depression and generalized anxiety disorder exist , they have not been based on APT . The aim of this r and omized controlled trial was to investigate the efficacy of an Internet-based , psychodynamic , guided self-help treatment based on APT for depression and anxiety disorders . Methods . One hundred participants with diagnoses of mood and anxiety disorders participated in a r and omized ( 1:1 ratio ) controlled trial of an active group versus a control condition . The treatment group received a 10-week , psychodynamic , guided self-help treatment based on APT that was delivered through the Internet . The treatment consisted of eight text-based treatment modules and included therapist contact ( 9.5 min per client and week , on average ) in a secure online environment . Participants in the control group also received online therapist support and clinical monitoring of symptoms , but received no treatment modules . Outcome measures were the 9-item Patient Health Question naire Depression Scale ( PHQ-9 ) and the 7-item Generalized Anxiety Disorder Scale ( GAD-7 ) . Process measures were also included . All measures were administered weekly during the treatment period and at a 7-month follow-up . Results . Mixed models analyses using the full intention-to-treat sample revealed significant interaction effects of group and time on all outcome measures , when comparing treatment to the control group . A large between-group effect size of Cohen ’s d = 0.77 ( 95 % CI : 0.37–1.18 ) was found on the PHQ-9 and a moderately large between-group effect size d = 0.48 ( 95 % CI : 0.08–0.87 ) was found on the GAD-7 . The number of patients who recovered ( had no diagnoses of depression and anxiety , and had less than 10 on both the PHQ-9 and the GAD-7 ) were at post-treatment 52 % in the treatment group and 24 % in the control group . This difference was significant , χ2(N = 100 , d f = 1 ) = 8.3 , p < .01 . From post-treatment to follow-up , treatment gains were maintained on the PHQ-9 , and significant improvements were seen on the GAD-7 . Conclusion . This study provides initial support for the efficacy of Internet-delivered psychodynamic therapy based on the affect-phobia model in the treatment of depression and anxiety disorders . The results support the conclusion that psychodynamic treatment approaches may be transferred to the guided self-help format and delivered via the Internet [4346073] Background : Access to mental health care is limited . Internet-based interventions ( IBIs ) may help bridge that gap by improving access especially for those who are unable to receive expert care . Aim : This review explores current research on the effectiveness of IBIs for depression and anxiety . Results : For depression , therapist-guided cognitive behavioral therapy ( CBT ) had larger effect sizes consistently across studies , ranging from 0.6 to 1.9 ; while st and -alone CBT ( without therapist guidance ) had a more modest effect size of 0.3–0.7 . Even other interventions for depression ( non-CBT/non-r and omized controlled trial ( RCT ) ) showed modestly high effect sizes ( 0.2–1.7 ) . For anxiety disorders , studies showed robust effect sizes for therapist-assisted interventions with effect sizes of 0.7–1.7 ( efficacy similar to face-to-face CBT ) and st and -alone CBT studies also showed large effect sizes ( 0.6–1.7 ) . Non-CBT/Non- RCT studies ( only 3 ) also showed significant reduction in anxiety scores at the end of the interventions . Conclusion : IBIs for anxiety and depression appear to be effective in reducing symptomatology for both depression and anxiety , which were enhanced by the guidance of a therapist . Further research is needed to identify various predictive factors and the extent to which st and -alone Internet therapies may be effective in the future as well as effects for different patient population [19567900] BACKGROUND Computerised cognitive-behavioural therapy ( CCBT ) might offer a solution to the current undertreatment of depression . AIMS To determine the clinical effectiveness of online , unsupported CCBT for depression in primary care . METHOD Three hundred and three people with depression were r and omly allocated to one of three groups : Colour Your Life ; treatment as usual ( TAU ) by a general practitioner ; or Colour Your Life and TAU combined . Colour Your Life is an online , multimedia , interactive CCBT programme . No assistance was offered . We had a 6-month follow-up period . RESULTS No significant differences in outcome between the three interventions were found in the intention-to-treat and per protocol analyses . CONCLUSIONS Online , unsupported CCBT did not outperform usual care , and the combination of both did not have additional effects . Decrease in depressive symptoms in people with moderate to severe depression was moderate in all three interventions . Online CCBT without support is not beneficial for all individuals with depression [3898729] Background Depression and anxiety are major causes of absence from work and underperformance in the workplace . Cognitive behavioural therapy ( CBT ) can be effective in treating such problems and online versions offer many practical advantages . The aim of the study was to investigate the effectiveness of a computerized CBT intervention ( MoodGYM ) in a workplace context . Method The study was a phase III two-arm , parallel r and omized controlled trial whose main outcome was total score on the Work and Social Adjustment Scale ( WSAS ) . Depression , anxiety , psychological functioning , costs and acceptability of the online process were also measured . Most data were collected online for 637 participants at baseline , 359 at 6 weeks marking the end of the intervention and 251 participants at 12 weeks post-baseline . Results In both experimental and control groups depression scores improved over 6 weeks but attrition was high . There was no evidence for a difference in the average treatment effect of MoodGYM on the WSAS , nor for a difference in any of the secondary outcomes . Conclusions This study found no evidence that MoodGYM was superior to informational websites in terms of psychological outcomes or service use , although improvement to subthreshold levels of depression was seen in nearly half the patients in both groups [3792189] Objective . The main hypothesis , and the objective of the study , was to test if the participants allocated to the treatment group would show a larger reduction in depressive symptoms than those in the control group . Methods . This study was a r and omized nine week trial of an Internet-administered treatment based on guided physical exercise for Major Depressive Disorder ( MDD ) . A total of 48 participants with mild to moderate depression , diagnosed using the Structured Clinical Interview for DSM-IV Axis I Disorders , were r and omized either to a treatment intervention or to a waiting-list control group . The main outcome measure for depression was the Beck Depression Inventory-II ( BDI-II ) , and physical activity level was measured using the International Physical Activity Question naire ( IPAQ ) . The treatment program consisted of nine text modules , and included therapist guidance on a weekly basis . Results . The results showed significant reductions of depressive symptoms in the treatment group compared to the control group , with a moderate between-group effect size ( Cohen ’s d = 0.67 ; 95 % confidence interval : 0.09–1.25 ) . No difference was found between the groups with regards to increase of physical activity level . For the treatment group , the reduction in depressive symptoms persisted at six months follow-up . Conclusions . Physical activity as a treatment for depression can be delivered in the form of guided Internet-based self-help . Trial Registration . The trial was registered at Clinical Trials.gov ( NCT01573130 ) [1550641] Background Guided self-help programs for depression ( with associated therapist contact ) have been successfully delivered over the Internet . However , previous trials of pure self-help Internet programs for depression ( without therapist contact ) , including an earlier trial conducted by us , have failed to yield positive results . We hypothesized that methods to increase participant usage of the intervention , such as postcard or telephone reminders , might result in significant effects on depression . Objectives This paper presents a second r and omized trial of a pure self-help Internet site , ODIN ( Overcoming Depression on the InterNet ) , for adults with self-reported depression . We hypothesized that frequently reminded participants receiving the Internet program would report greater reduction in depression symptoms and greater improvements in mental and physical health functioning than a comparison group with usual treatment and no access to ODIN . Methods This was a three-arm r and omized control trial with a usual treatment control group and two ODIN intervention groups receiving reminders through postcards or brief telephone calls . The setting was a nonprofit health maintenance organization ( HMO ) . We mailed recruitment brochures by US post to two groups : adults ( n = 6030 ) who received depression medication or psychotherapy in the previous 30 days , and an age- and gender-matched group of adults ( n = 6021 ) who did not receive such services . At enrollment and at 5- , 10- and 16-weeks follow-up , participants were reminded by email ( and telephone , if nonresponsive ) to complete online versions of the Center for Epidemiological Studies Depression Scale ( CES-D ) and the Short Form 12 ( SF-12 ) . We also recorded participant HMO health care services utilization in the 12 months following study enrollment . Results Out of a recruitment pool of 12051 approached subjects , 255 persons accessed the Internet enrollment site , completed the online consent form , and were r and omized to one of the three groups : ( 1 ) treatment as usual control group without access to the ODIN website ( n = 100 ) , ( 2 ) ODIN program group with postcard reminders ( n = 75 ) , and ( 3 ) ODIN program group with telephone reminders ( n = 80 ) . Across all groups , follow-up completion rates were 64 % ( n = 164 ) at 5 weeks , 68 % ( n = 173 ) at 10 weeks , and 66 % ( n = 169 ) at 16 weeks . In an intention-to-treat analysis , intervention participants reported greater reductions in depression compared to the control group ( P = .03 ; effect size = 0.277 st and ard deviation units ) . A more pronounced effect was detected among participants who were more severely depressed at baseline ( P = .02 ; effect size = 0.537 st and ard deviation units ) . By the end of the study , 20 % more intervention participants moved from the disordered to normal range on the CES-D. We found no difference between the two intervention groups with different reminders in outcomes measures or in frequency of log-ons . We also found no significant intervention effects on the SF-12 or health care services . Conclusions In contrast to our earlier trial , in which participants were not reminded to use ODIN , in this trial we found a positive effect of the ODIN intervention compared to the control group . Future studies should address limitations of this trial , including relatively low enrollment and follow-up completion rates , and a restricted number of outcome measures . However , the low incremental costs of delivering this Internet program makes it feasible to offer this type of program to large population s with widespread Internet access [22663903] OBJECTIVE Develop and pilot an Internet-facilitated cognitive-behavioral treatment intervention for depression , tailored to economically disadvantaged mothers of young children . METHOD Mothers ( N = 70 ) of children enrolled in Head Start , who reported elevated levels of depressive symptoms , were r and omized to either the 8-session , Internet-facilitated intervention ( Mom-Net ) or delayed intervention/facilitated treatment-as-usual ( DI/TAU ) . Outcomes were measured using the Beck Depression Inventory ( BDI-II ; Beck , Steer , & Brown , 1996 ) ; the Patient Health Question naire 9 ( PHQ-9 ; Spitzer et al. , 1999 ) , Behavioral Observations of Parent-Child Interactions using the Living in Family Environments coding system ( LIFE ; Hops , Davis , & Longoria , 1995 ) ; the Dyadic Parent-Child Interaction Coding Systems ( DPICS ; Eyberg , Nelson , Duke , & Boggs , 2005 ) ; the Parent Behavior Inventory ( PBI ; Lovejoy , Weis , O'Hare , & Rubin , 1999 ) ; and the Parenting Sense of Competence scale ( PSOC ; Gibaud-Wallston & W and ersman , 1978 ) . RESULTS Mom-Net demonstrated high levels of feasibility as indicated by low attrition and high program usage and satisfaction ratings . Participants in the Mom-Net condition demonstrated significantly greater reduction in depression , the primary outcome , at the level of both symptoms and estimates of criteria -based diagnoses over the course of the intervention . They also demonstrated significantly greater improvement on a question naire measure of parent satisfaction and efficacy as well as on both question naire and observational indices of harsh parenting behavior . CONCLUSIONS Initial results suggest that the Mom-Net intervention is feasible and efficacious as a remotely delivered intervention for economically disadvantaged mothers [2762808] BACKGROUND Depression is associated with immense suffering and costs , and many patients receive inadequate care , often because of the limited availability of treatment . Web-based treatments may play an increasingly important role in closing this gap between dem and and supply . We developed the integrative , Web-based program Deprexis , which covers therapeutic approaches such as behavioral activation , cognitive restructuring , mindfulness/acceptance exercises , and social skills training . OBJECTIVE To evaluate the effectiveness of the Web-based intervention in a r and omized controlled trial . METHODS There were 396 adults recruited via Internet depression forums in Germany , and they were r and omly assigned in an 80:20 weighted r and omization sequence to either 9 weeks of immediate-program-access as an add-on to treatment-as-usual ( N = 320 ) , or to a 9-week delayed-access plus treatment-as-usual condition ( N = 76 ) . At pre- and post-treatment and 6-month follow-up , we measured depression ( Beck Depression Inventory ) as the primary outcome measure and social functioning ( Work and Social Adjustment Scale ) as the secondary outcome measure . Complete analyses and intention-to-treat analyses were performed . RESULTS Of 396 participants , 216 ( 55 % ) completed the post-measurement 9 weeks later . Available case analyses revealed a significant reduction in depression severity ( BDI ) , Cohen 's d = .64 ( CI 95 % = 0.33 - 0.94 ) , and significant improvement in social functioning ( WSA ) , Cohen 's d = .64 , 95 % ( CI 95 % = 0.33 - 0.95 ) . These improvements were maintained at 6-month follow-up . Intention-to-treat analyses confirmed significant effects on depression and social functioning improvements ( BDI : Cohen 's d = .30 , CI 95 % = 0.05 - 0.55 ; WSA : Cohen 's d = .36 , CI 95 % = 0.10 - 0.61 ) . Moreover , a much higher percentage of patients in the intervention group experienced a significant reduction of depression symptoms ( BDI : odds ratio [ OR ] = 6.8 , CI 95 % = 2.90 - 18.19 ) and recovered more often ( OR = 17.3 , 95 % CI 2.3 - 130 ) . More than 80 % of the users felt subjectively that the program had been helpful . CONCLUSIONS This integrative , Web-based intervention was effective in reducing symptoms of depression and in improving social functioning . Findings suggest that the program could serve as an adjunctive or st and -alone treatment tool for patients suffering from symptoms of depression [22177742] INTRODUCTION Although depression can be treated effectively with Cognitive Behaviour Therapy ( CBT ) , only a small percentage of Chinese Australians access evidence -based treatment due to practical and cultural barriers . The present study examined the efficacy and acceptability of an Internet delivered CBT ( iCBT ) program to treat Chinese Australians with depression . METHODS The Chinese depression iCBT program ( the Brighten Your Mood Program ) is a culturally adapted version of the clinical ly efficacious Sadness iCBT Program . Fifty-five Chinese Australians with depression were r and omly allocated to either an immediate treatment group or to a waitlist control group . Treatment consisted of an 8 week program with 6 CBT online educational lessons , homework assignments , additional re sources presented in Chinese and English , and weekly telephone support with M and arin/Cantonese-speaking support personnel . An intention-to-treat model was used for data analyses . RESULTS Seventeen of twenty-five ( 68 % ) treatment group participants completed all lessons within the timeframe . Compared to controls , treatment group participants reported significantly reduced symptoms of depression on the Chinese versions of the Beck Depression Inventory ( CBDI ) and Patient Health Question naire-9 item ( CB-PHQ-9 ) . The within- and between-group effect sizes ( Cohen 's d ) were 1.41 and 0.93 on the CBDI , and 0.90 and 0.50 on the CB-PHQ-9 , respectively . Participants rated the procedure as acceptable , and gains were sustained at three-month follow-up . LIMITATIONS The study included several sub clinical participants and some measures that have not been previously vali date d with Chinese Australians . CONCLUSIONS Results provide preliminary support for the efficacy and acceptability of an iCBT program at reducing symptoms of depression in Chinese Australians [9294380] BACKGROUND Previous studies in non clinical sample s have shown psychosocial treatments to be efficacious in the treatment of adolescent depression , but few psychotherapy treatment studies have been conducted in clinical ly referred , depressed adolescents . METHODS One hundred seven adolescent patients with DSM-III-R major depressive disorder ( MDD ) were r and omly assigned to 1 of 3 treatments : individual cognitive behavior therapy , systemic behavior family therapy ( SBFT ) , or individual nondirective supportive therapy ( NST ) . Treatments were 12 to 16 sessions provided in as many weeks . Intent-to-treat analyses were conducted using all follow-up data . RESULTS Of the 107 patients enrolled in the study , 78 ( 72.9 % ) completed the study , 4 ( 3.7 % ) never initiated treatment , 10 ( 9.3 % ) had exclusionary criteria that were undetected at entry , 8 ( 7.5 % ) dropped out , and 7 ( 6.5 % ) were removed for clinical reasons . Cognitive behavior therapy showed a lower rate of MDD at the end of treatment compared with NST ( 17.1 % vs 42.4 % ; P = .02 ) , and result ed in a higher rate of remission ( 64.7 % , defined as absence of MDD and at least 3 consecutive Beck Depression Inventory scores < 9 ) than SBFT ( 37.9 % ; P = .03 ) or NST ( 39.4 % ; p = .04 ) . Cognitive behavior therapy result ed in more rapid relief in interviewer-rated ( vs both treatments , P = .03 ) and self-reported depression ( vs SBFT , P = .02 ) . All 3 treatments showed significant and similar reductions in suicidality and functional impairment . Parents ' views of the credibility of cognitive behavior therapy improved compared with parents ' views of both SBFT ( P = .01 ) and NST ( P = .05 ) . CONCLUSIONS Cognitive behavior therapy is more efficacious than SBFT or NST for adolescent MDD in clinical setting s , result ing in more rapid and complete treatment response [20152960] Internet-delivered psychological treatment of major depression has been investigated in several trials , but the role of personalized treatment is less investigated . Studies suggest that guidance is important and that automated computerized programmes without therapist support are less effective . Individualized e-mail therapy for depression has not been studied in a controlled trial . Eighty-eight individuals with major depression were r and omized to two different forms of Internet-delivered cognitive behaviour therapy ( CBT ) , or to a waiting-list control group . One form of Internet treatment consisted of guided self-help , with weekly modules and homework assignments . St and ard CBT components were presented and brief support was provided during the treatment . The other group received e-mail therapy , which was tailored and did not use the self-help texts i.e. , all e-mails were written for the unique patient . Both treatments lasted for 8 weeks . In the guided self-help 93 % completed ( 27/29 ) and in the e-mail therapy 96 % ( 29/30 ) completed the posttreatment assessment . Results showed significant symptom reductions in both treatment groups with moderate to large effect sizes . At posttreatment 34.5 % of the guided self-help group and 30 % of the e-mail therapy group reached the criteria of high-end-state functioning ( Beck Depression Inventory score below 9 ) . At six-month follow-up the corresponding figures were 47.4 % and 43.3 % . Overall , the difference between guided self-help and e-mail therapy was small , but in favour of the latter . These findings indicate that both guided self-help and individualized e-mail therapy can be effective [3376511] Background Internet-delivered interventions can effectively change health risk behaviors and their determinants , but adherence to these interventions once they are accessed is very low . Therefore , it is relevant and necessary to systematic ally manipulate website characteristics to test their effect on website use . This study focuses on user control as a website characteristic . Objective To test whether and how user control ( the freedom of choice to skip pages ) can increase website use and knowledge gained from the website . Methods Participants older than 18 years were drawn from the Dutch Internet population ( in June 2011 ) and completed a hepatitis knowledge question naire . Subsequently , they were r and omly assigned to three groups : ( 1 ) a tunneled version of the website with less user control ; ( 2 ) a high user control version of the website where visitors had the freedom of choice to skip pages ; and ( 3 ) a control group that was not exposed to the website . Participants completed ( 1 ) a question naire of vali date d measures regarding user perceptions immediately after exposure to the website ( except for the control group ) , and ( 2 ) a hepatitis knowledge question naire after one week to test whether participants in the experimental groups only clicked through the website or actually processed and learned its content . Server registration s were used to assess website use . Analyses of covariance ( ANCOVA ) using all available data were conducted to determine whether user control increases website use . Structural equation models ( SEM ) using all available data were constructed to test how user control increases website use — a latent variable derived from number of pages visited and time on website . Results Of the 1044 persons invited to participate , 668 took part ( 668/1044 , 64.0 % ) . One half of participants ( 332/668 49.7 % ) were female and the mean age was 49 years ( SD 16 ) . A total of 571 participants completed the one-week follow-up measure regarding hepatitis knowledge ( 571/668 , 85.5 % ) . The findings demonstrate that having less user control ( ie , a tunneled version of the website ) had a negative effect on users ’ perception of efficiency ( F1,452 = 97.69 , P < .001 ) , but a positive effect on number of pages visited ( F1,452 = 171.49 , P < .001 ) , time on the website ( F1,452 = 6.32 , P = .01 ) , and knowledge gained from the website ( F1,452 = 134.32 , P < .001 ) . The direct effect of having less user control appeared to surpass the effect mediated by efficiency , because website use was higher among participants exposed to the tunneled version of the website in comparison with those having the freedom of choice to skip pages . Conclusions The key finding that visitors demonstrated increased website use in the tunneled version of the website indicates that visitors should be carefully guided through the intervention for future intervention websites [26523885] BACKGROUND Internet-delivered treatments for depression have proved successful , with supported programs offering the potential for improved adherence and outcomes . Internet interventions are particularly interesting in the context of increasing access to interventions , and delivering interventions population -wide . METHODS The study was a r and omized controlled trial of an 7-module internet-delivered cognitive behavioral therapy ( iCBT ) program for adults with depressive symptoms ( n = 96 ) compared to a waiting-list control group ( n = 92 ) . Participants received weekly support from a trained supporter . The primary outcome was depressive symptoms as measured by the Beck Depression Inventory ( BDI-II ) . The program was made available nationwide from an established and recognized charity for depression . RESULTS For the treatment group , post-treatment effect sizes reported were large for the primary outcome measure ( d = 0.91 ) . The between-group effects were moderate to large and statistically significant for the primary outcomes ( d = 0.50 ) favoring the treatment group . Gains were maintained at 6-month follow-up . CONCLUSION The study has demonstrated the efficacy of the internet-delivered Space from Depression treatment . Participants demonstrated reliable and statistically significant changes in symptoms from pre-to post-intervention . The study supports a model for delivering online depression interventions population -wide using trained supporters . TRIAL REGISTRATION NUMBER Current Controlled Trials IS RCT N03704676 . http://dx.doi.org/10.1186/IS RCT N03704676 [17950163] PURPOSE The Internet offers a potential medium for delivering smoking cessation treatment to adolescents . However , few Internet-based cessation programs for adolescents have been evaluated . We describe adolescent use of a home-based Internet intervention to stop smoking ( Stomp Out Smokes [ SOS ] ) and explore baseline characteristics associated with SOS use . METHODS Participants were 70 adolescent smokers aged 12 - 18 years ( 50 % female , 90 % Caucasian ) r and omized to receive the SOS intervention for 24 weeks as part of a larger clinical trial . SOS comprised 40 components , of which eight were primarily interactive ( e.g. , discussion support group , ask an expert , quit plan ) and 32 were primarily informational ( e.g. , managing withdrawal , medications to stop smoking ) . SOS use data were captured electronically , including total logins to the site , and type of SOS components used defined by page hits on the interactive and information components . RESULTS A total of 7,708 SOS website pages ( 6825 interactive and 883 informational ) were accessed over the 24 weeks . The highest proportion of page hits was for the discussion support group ( 35 % ) and quit plan ( 30 % ) . Interactive pages were significantly more likely to be used than informational pages ( median 65 vs. 6 , p < .001 ) . Males accessed fewer interactive pages compared with females ( p = .04 ) . No other baseline characteristics were univariately associated with total logins or use of informational or interactive pages . CONCLUSIONS Adolescent smokers most often used a discussion support group and other interactive Internet-based cessation components . Future studies design ed to increase adolescent use , and efficacy of , Internet-based cessation programs are warranted [3742404] Background Most patients with mild to moderate depression receive treatment in primary care , but despite guideline recommendations , structured psychological interventions are infrequently delivered . Research supports the effectiveness of Internet-based treatment for depression ; however , few trials have studied the effect of the MoodGYM program plus therapist support . The use of such interventions could improve the delivery of treatment in primary care . Objective To evaluate the effectiveness and acceptability of a guided Web-based intervention for mild to moderate depression , which could be suitable for implementation in general practice . Methods Participants ( N=106 ) aged between 18 and 65 years were recruited from primary care and r and omly allocated to a treatment condition comprising 6 weeks of therapist-assisted Web-based cognitive behavioral therapy ( CBT ) , or to a 6-week delayed treatment condition . The intervention included the Norwegian version of the MoodGYM program , brief face-to-face support from a psychologist , and reminder emails . The primary outcome measure , depression symptoms , was measured by the Beck Depression Inventory-II ( BDI-II ) . Secondary outcome measures included the Beck Anxiety Inventory ( BAI ) , the Hospital Anxiety and Depression Scale ( HADS ) , the Satisfaction with Life Scale ( SWLS ) , and the EuroQol Group 5-Dimension Self-Report Question naire ( EQ-5D ) . All outcomes were based on self-report and were assessed at baseline , postintervention , and at 6-month follow-up . Results Postintervention measures were completed by 37 ( 71 % ) and 47 ( 87 % ) of the 52 participants in the intervention and 54 participants in the delayed treatment group , respectively . Linear mixed-models analyses revealed a significant difference in time trends between the groups for the BDI-II , ( P=.002 ) , for HADS depression and anxiety subscales ( P<.001 and P=.001 , respectively ) , and for the SWLS ( P<.001 ) . No differential group effects were found for the BAI and the EQ-5D . In comparison to the control group , significantly more participants in the intervention group experienced recovery from depression as measured by the BDI-II . Of the 52 participants in the treatment program , 31 ( 60 % ) adhered to the program , and overall treatment satisfaction was high . The reduction of depression and anxiety symptoms was largely maintained at 6-month follow-up , and positive gains in life satisfaction were partly maintained . Conclusions The intervention combining MoodGYM and brief therapist support can be an effective treatment of depression in a sample of primary care patients . The intervention alleviates depressive symptoms and has a significant positive effect on anxiety symptoms and satisfaction with life . Moderate rates of nonadherence and predominately positive evaluations of the treatment also indicate the acceptability of the intervention . The intervention could potentially be used in a stepped-care approach , but remains to be tested in regular primary health care . Trial Registration Australian New Zeal and Clinical Trials Registry : ACTRN12610000257066 ; http://apps.who.int/trial search /trial.aspx?trialid = ACTRN12610000257066 ( Archived by WebCite at http://www.webcitation.org/6Ie3YhIZa ) [16971674] The aim of this study was to evaluate the effectiveness of a computer-tailored physical activity intervention delivered through the Internet in a real-life setting . Healthy adults ( n=526 ) , recruited in six worksites , between 25 and 55 years of age were r and omized to one of three conditions receiving , respectively , ( i ) online-tailored physical activity advice + stage-based reinforcement e-mails , ( ii ) online-tailored physical activity advice only , ( iii ) online non-tailored st and ard physical activity advice . At 6-month follow-up , no differences in physical activity between study conditions were found ; total physical activity , physical activity at moderate intensity and physical activity in leisure time significantly increased in all study conditions between baseline and follow-up . Further evaluation of the intervention material s showed that the tailored advice was more read , printed and discussed with others than the st and ard advice . Most of the respondents in the e-mail group indicated to be satisfied about the number , frequency and usefulness of the stage-based e-mails . In conclusion , although tailored advice was appreciated more than st and ard advice , no evidence was found that an online-tailored physical activity intervention program outperformed online st and ard information [4393573] Background Depression is a common comorbidity in individuals with cognitive impairment . Those with cognitive impairments face unique challenges in receiving the benefits of many conventional therapies for depression , and may have poorer outcomes in areas such as recovery and quality of life . However , the stigmatization of mental health disorders , cost barriers and physical disabilities may prevent these individuals from seeking mental health care . An online , self-help intervention specifically developed for adults with cognitive deficits and depression may be particularly beneficial to this population . We aim to inform the design of such an intervention through a systematic review by answering the following research question : among adults with cognitive impairment ( including those with acquired brain injuries or neurodegenerative diseases ) , which technology-amenable interventions have been shown to effectively decrease symptoms of depression ? Specifically , psychotherapeutic and /or behavioural interventions that could be delivered in a self-guided , online system will be included . Methods Comprehensive electronic search es will be conducted in MEDLINE , EMBASE , PsycINFO and CINAHL . Additional studies will be obtained through manually search ing the references of relevant systematic review s , contacting primary authors of select articles and tracking conference proceedings and trial registries . Article titles and abstract s will be screened using predefined eligibility criteria , and then judged for their amenability to the proposed self-help , technology-based intervention . The full text of those articles with selected interventions will then be screened to determine final eligibility for inclusion . Included articles will be categorized by intervention type and assessed for risk of bias using the Cochrane Effective Practice and Organization of Care Risk of Bias tool for non-r and omized trials , controlled before-after studies and interrupted time series . The primary outcome will be a change in score on a vali date d depression scale , and adverse events will be documented as a secondary outcome . After data extraction from selected articles , pooling of data and meta- analysis will be conducted if a sufficient pool of studies with comparable methodology and quality are identified . Alternatively , plain language summaries will be developed . The quality of evidence will be assessed using the Grading of Recommendations Assessment , Development and Evaluation ( GRADE ) system . Systematic review registration PROSPERO [18236303] The sizeable percentage of adults who use smokeless tobacco ( ST ) represents an important public health target since the majority of ST users have a strong desire to quit , but many lack re sources . We tested the impact of an interactive , tailored Web-based intervention ( Enhanced Condition ) versus a more linear , text-based website ( Basic Condition ) in a r and omized trial with 2523 adult ST users . As is common in Internet-based research , there was considerable attrition : follow-up rates at 3 months , 6 months , and for both 3 and 6 months were 48 % , 45 % and 34 % , respectively . Results using repeated point prevalence of all tobacco use at 3 and 6 months showed that participants in the Enhanced Condition quit at significantly higher rates than those in the Basic Condition . Using a Complete Case analysis , abstinence was 40.6 % in the Enhanced Condition vs. 21.2 % in the Basic Condition ( p < .001 ) . Using intent-to-treat analysis , quit rates were 12.6 % vs. 7.9 % , respectively ( p < .001 ) . Similar results were obtained for only ST use . Unobtrusive measures of program exposure indicated that program use was significantly related to outcome as well as to attrition . We conclude that a tailored , interactive Web-assisted cessation program can be an efficacious method for assisting adult ST users to quit [1550629] Background In r and omized controlled trials Internet sites have been shown to be effective in the treatment of depression and anxiety . However , it is unclear if the positive effects demonstrated in these trials transfer to community users of such sites . Objective To compare anxiety and depression outcomes for spontaneous visitors to a publicly accessible cognitive behavior therapy website ( MoodGYM ) ( http://moodgym.anu.edu.au ) with outcomes achieved through a r and omized controlled efficacy trial of the same site . Methods All community visitors to the MoodGYM site between April 2001 and September 2003 were sample d : 182 participants in the BlueMood Trial who had been r and omly assigned to the MoodGYM site as part of a large trial and 19607 visitors ( public registrants ) to the site . Symptom assessment s ( quizzes ) were repeated within the website intervention to allow the examination of change in symptoms across modules . Outcome variables were ( 1 ) age , gender , initial depression severity scores , and number of assessment s attempted , and ( 2 ) symptom change measures based on Goldberg anxiety and depression scores recorded on a least two occasions . Results Public registrants did not differ from trial participants in gender , age , or initial level of depression , which was high for both groups relative to previously published epidemiological data sets . Trial participants completed more assessment s. No significant differences in anxiety or depression change scores were observed , with both public registrants and trial participants improving through the training program . Conclusions Public registrants to a cognitive behavior therapy website show significant change in anxiety and depression symptoms . The extent of change does not differ from that exhibited by participants enrolled on the website for a r and omized controlled trial [21731830] OBJECTIVE The aim of this study was to examine the sensitivity and specificity of the suicide item on the 9-item Patient Health Question naire ( PHQ-9 ) when compared to a structured interview ( the Structured Clinical Interview for DSM-IV ; SCID-I mood module ) in primary care patients with elevated depression symptoms . METHOD In this cross-sectional study , we analyzed data from 166 patients from 2 primary care clinics , 1 in Rhode Isl and and 1 in Massachusetts , who were enrolled in studies that focused on depression in primary care . Of the total participants , 101 were enrolled in the survey study , and 65 were screened for or enrolled in either an open trial or a pilot r and omized controlled trial . Data were collected between May 2004 and May 2009 . RESULTS We found that the specificity of the PHQ-9 suicide screening item was 0.84 and sensitivity was 0.69 for the sample as a whole . CONCLUSIONS This study suggests that the routine use of the PHQ-9 may be useful in primary care practice in that it may identify individuals at risk for suicide who would not otherwise have been identified . However , denial of suicidality on the PHQ-9 should be probed further if there are other risk factors for suicide present . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00541957 [26453910] Introduction Help4Mood is an interactive system with an embodied virtual agent ( avatar ) to assist in self-monitoring of patients receiving treatment for depression . Help4Mood supports self-report and biometric monitoring and includes elements of cognitive behavioural therapy . We aim ed to evaluate system use and acceptability , to explore likely recruitment and retention rates in a clinical trial and to obtain an estimate of potential treatment response with a view to conducting a future r and omised controlled trial ( RCT ) . Methods We conducted a pilot RCT of Help4Mood in three centres , in Romania , Spain and Scotl and , UK . Patients with diagnosed depression ( major depressive disorder ) and current mild/moderate depressive symptoms were r and omised to use the system for four weeks in addition to treatment as usual ( TAU ) or to TAU alone . Results Twenty-seven individuals were r and omised and follow-up data were obtained from 21 participants ( 12/13 Help4Mood , 9/14 TAU ) . Half of participants r and omised to Help4Mood used it regularly ( more than 10 times ) ; none used it every day . Acceptability varied between users . Some valued the emotional responsiveness of the system , while others found it too repetitive . Intention to treat analysis showed a small difference in change of Beck Depression Inventory II ( BDI-2 ) scores ( Help4Mood –5.7 points , TAU –4.2 ) . Post-hoc on-treatment analysis suggested that participants who used Help4Mood regularly experienced a median change in BDI-2 of –8 points . Conclusion Help4Mood is acceptable to some patients receiving treatment for depression although none used it as regularly as intended . Changes in depression symptoms in individuals who used the system regularly reached potentially meaningful levels [26253644] Low-intensity interventions for people suffering from depressive symptoms are highly desirable . The aim of the present study was to investigate the outcomes of a web-based acceptance and commitment therapy (ACT)–based intervention without face-to-face contact for people suffering from depressive symptoms . Participants ( N = 39 ) with depressive symptoms were r and omly assigned to an Internet-delivered acceptance and commitment therapy ( iACT ) intervention or a waiting list control condition ( WLC ) . Participants were evaluated with st and ardized self-reporting measures ( Beck Depression Inventory [ BDI-II ] , Symptom Checklist–90 [ SCL-90 ] , Acceptance and Action Question naire [ AAQ-2 ] , Five Facet Mindfulness Question naire [ FFMQ ] , Automatic Thoughts Question naire [ ATQ ] , and White Bear Suppression Inventory [ WBSI ] ) at pre- and post-measurement . Long-term effects in the iACT group were examined using a 12-month follow-up . The iACT program comprised home assignments , online feedback given by master’s-level students of psychology over a 7-week intervention period , and automated email-based reminders . Significant effects were observed in favor of the iACT group on depression symptomatology ( between effect sizes [ ESs ] at post-treatment , iACT/WLC , g = .83 ) , psychological and physiological symptoms ( g = .60 ) , psychological flexibility ( g = .67 ) , mindfulness skills ( g = .53 ) , and frequency of automatic thoughts ( g = .57 ) as well as thought suppression ( g = .53 ) . The treatment effects in the iACT group were maintained over the 12-month follow-up period ( within-iACT ES : BDI-II , g = 1.33 ; SCL-90 , g = 1.04 ; ATQF/B [ Frequency/Believability ] , FFMQ , WBSI , AAQ-II , g = .74 - 1.08 ) . The iACT participants stated that they would be happy to recommend the same intervention to others with depressive symptoms . We conclude that an ACT-based guided Internet-delivered treatment with minimal contact can be effective for people with depressive symptoms [19207345] AIMS To evaluate computer- versus therapist-delivered psychological treatment for people with comorbid depression and alcohol/cannabis use problems . DESIGN R and omized controlled trial . SETTING Community-based participants in the Hunter Region of New South Wales , Australia . PARTICIPANTS Ninety-seven people with comorbid major depression and alcohol/cannabis misuse . INTERVENTION All participants received a brief intervention ( BI ) for depressive symptoms and substance misuse , followed by r and om assignment to : no further treatment ( BI alone ) ; or nine sessions of motivational interviewing and cognitive behaviour therapy ( intensive MI/CBT ) . Participants allocated to the intensive MI/CBT condition were selected at r and om to receive their treatment ' live ' ( i.e. delivered by a psychologist ) or via a computer-based program ( with brief weekly input from a psychologist ) . MEASUREMENTS Depression , alcohol/cannabis use and hazardous substance use index scores measured at baseline , and 3 , 6 and 12 months post-baseline assessment . FINDINGS ( i ) Depression responded better to intensive MI/CBT compared to BI alone , with ' live ' treatment demonstrating a strong short-term beneficial effect which was matched by computer-based treatment at 12-month follow-up ; ( ii ) problematic alcohol use responded well to BI alone and even better to the intensive MI/CBT intervention ; ( iii ) intensive MI/CBT was significantly better than BI alone in reducing cannabis use and hazardous substance use , with computer-based therapy showing the largest treatment effect . CONCLUSIONS Computer-based treatment , targeting both depression and substance use simultaneously , results in at least equivalent 12-month outcomes relative to a ' live ' intervention . For clinicians treating people with comorbid depression and alcohol problems , BIs addressing both issues appear to be an appropriate and efficacious treatment option . Primary care of those with comorbid depression and cannabis use problems could involve computer-based integrated interventions for depression and cannabis use , with brief regular contact with the clinician to check on progress [4260664] Depression presents a serious condition for the individual and a major challenge to health care and society . Internet-based cognitive behavior therapy ( ICBT ) is a treatment option supported in several trials , but there is as yet a lack of effective studies of ICBT in “ real world ” primary care setting s. We examined whether ICBT differed from treatment-as-usual ( TAU ) in reducing depressive symptoms after 3 months . TAU comprised of visits to general practitioner , registered nurse , antidepressant drugs , waiting list for , or psychotherapy , or combinations of these alternatives . Patients , aged ≥ 18 years , who tentatively met criteria for mild to moderate depression at 16 primary care centers in the south-western region of Sweden were recruited and then assessed in a diagnostic interview . A total of 90 patients were r and omized to either TAU or ICBT . The ICBT treatment included interactive elements online , a workbook , a CD with mindfulness and acceptance exercises , and minimal therapist contact . The treatment period lasted for 12 weeks after which both groups were assessed . The main outcome measure was Beck Depression Inventory-II ( BDI-II ) . Additional measures were Montgomery Åsberg Depression Rating Scale – self rating version ( MADRS-S ) and Beck Anxiety Inventory ( BAI ) . The analyses revealed no significant difference between the two groups at post treatment , neither on BDI-II , MADRS-S , nor BAI . Twenty patients ( 56 % ) in the ICBT treatment completed all seven modules . Our findings suggest that ICBT may be successfully delivered in primary care and that the effectiveness , after 3 months , is at par with TAU [4607393] Background Internet-delivered mental health ( eMental Health ) interventions produce treatment effects similar to those observed in face-to-face treatment . However , there is a large degree of variation in treatment effects observed from program to program , and eMental Health interventions remain somewhat of a black box in terms of the mechanisms by which they exert their therapeutic benefit . Trials of eMental Health interventions typically use large sample sizes and therefore provide an ideal context within which to systematic ally investigate the therapeutic benefit of specific program features . Furthermore , the growth and impact of mobile phone technology within eMental Health interventions provides an opportunity to examine associations between symptom improvement and the use of program features delivered across computer and mobile phone platforms . Objective The objective of this study was to identify the patterns of program usage associated with treatment outcome in a r and omized controlled trial ( RCT ) of a fully automated , mobile phone- and Web-based self-help program , “ myCompass ” , for individuals with mild-to-moderate symptoms of depression , anxiety , and /or stress . The core features of the program include interactive psychotherapy modules , a symptom tracking feature , short motivational messages , symptom tracking reminders , and a diary , with many of these features accessible via both computer and mobile phone . Methods Patterns of program usage were recorded for 231 participants with mild-to-moderate depression , anxiety , and /or stress , and who were r and omly allocated to receive access to myCompass for seven weeks during the RCT . Depression , anxiety , stress , and functional impairment were examined at baseline and at eight weeks . Results Log data indicated that the most commonly used components were the short motivational messages ( used by 68.4 % , 158/231 of participants ) and the symptom tracking feature ( used by 61.5 % , 142/231 of participants ) . Further , after controlling for baseline symptom severity , increased use of these alert features was associated with significant improvements in anxiety and functional impairment . Associations between use of symptom tracking reminders and improved treatment outcome remained significant after controlling for frequency of symptom tracking . Although correlations were not statistically significant , reminders received via SMS ( ie , text message ) were more strongly associated with symptom reduction than were reminders received via email . Conclusions These findings indicate that alerts may be an especially potent component of eMental Health interventions , both via their association with enhanced program usage , as well as independently . Although there was evidence of a stronger association between symptom improvement and use of alerts via the mobile phone platform , the degree of overlap between use of email and SMS alerts may have precluded identification of alert delivery modalities that were most strongly associated with symptom reduction . Future research using r and om assignment to computer and mobile delivery is needed to fully determine the most ideal platform for delivery of this and other features of online interventions . Trial Registration Australian New Zeal and Clinical Trials Registry ( ACTRN ) : 12610000625077 ; http://www.anzctr.org.au/Trial Search .aspx ? ( Archived by WebCite http://www.webcitation.org/6WPqHK0mQ ) [22390738] OBJECTIVES Underst and ing the gap between people 's intentions and actual health behavior is an important issue in health psychology . Our aim in this study was to investigate whether self-regulatory processes ( monitoring goal progress and responding to discrepancies ) mediate the intention-behavior relation in relation to HIV medication adherence ( Study 1 ) and intensive exercise behavior ( Study 2 ) . METHOD In Study 1 , question naire and electronically monitored adherence data were collected at baseline and 3 months later from patients in the control arm of an HIV-adherence intervention study . In Study 2 , question naire data was collected at 3 time points 6-weeks apart in a cohort study of physical activity . RESULTS Complete data at all time points were obtained from 51 HIV-infected patients and 499 intensive exercise participants . Intentions were good predictors of behavior and explained 25 to 30 % of the variance . Self-regulatory processes explained an additional 11 % ( Study 1 ) and 6 % ( Study 2 ) of variance in behavior on top of intentions . Regression and bootstrap analyses revealed at least partial , and possibly full , mediation of the intention-behavior relation by self-regulatory processes . CONCLUSIONS The present studies indicate that self-regulatory processes may explain how intentions drive behavior . Future tests , using different health behaviors and experimental design s , could firmly establish whether self-regulatory processes complement current health behavior theories and should become routine targets for intervention . ( PsycINFO Data base Record ( c ) 2012 APA , all rights reserved ) [3352859] Background and Aims Major depression can be treated by means of cognitive behavior therapy , delivered via the Internet as guided self-help . Individually tailored guided self-help treatments have shown promising results in the treatment of anxiety disorders . This r and omized controlled trial tested the efficacy of an Internet-based individually tailored guided self-help treatment which specifically targeted depression with comorbid symptoms . The treatment was compared both to st and ardized ( non-tailored ) Internet-based treatment and to an active control group in the form of a monitored online discussion group . Both guided self-help treatments were based on cognitive behavior therapy and lasted for 10 weeks . The discussion group consisted of weekly discussion themes related to depression and the treatment of depression . Methods A total of 121 participants with diagnosed major depressive disorder and with a range of comorbid symptoms were r and omized to three groups . The tailored treatment consisted of a prescribed set of modules targeting depression as well as comorbid problems . The st and ardized treatment was a previously tested guided self-help program for depression . Results From pre-treatment to post-treatment , both treatment groups improved on measures of depression , anxiety and quality of life . The results were maintained at a 6-month follow-up . Subgroup analyses showed that the tailored treatment was more effective than the st and ardized treatment among participants with higher levels of depression at baseline and more comorbidity , both in terms of reduction of depressive symptoms and on recovery rates . In the subgroup with lower baseline scores of depression , few differences were seen between treatments and the discussion group . Conclusions This study shows that tailored Internet-based treatment for depression is effective and that addressing comorbidity by tailoring may be one way of making guided self-help treatments more effective than st and ardized approaches in the treatment of more severe depression . Trial Registration Clinical trials.gov [3689826] Background Self-help or self-management strategies are commonly used to deal with depression , but not all are thought to be helpful . A previous study found that sub-threshold depression symptoms were improved by an e-mail intervention that encouraged the use of evidence -based self-help strategies . Aim To investigate whether these e-mails were effective for adults with a range of depression symptomatology including major depression . Method The study was a parallel-group r and omised controlled trial . Adult participants with any level of depressive symptoms were recruited over the internet from the United Kingdom , Australia , Canada , Irel and , New Zeal and and the United States . Participants were r and omised to receive a series of e-mails either promoting the use of evidence -based self-help strategies or containing depression information as a control . E-mails were sent automatically twice a week for six weeks . Depression symptoms were assessed with the self-rated Patient Health Question naire depression scale ( PHQ-9 ) . Results 1736 participants with a wide range of symptom severity were recruited and assigned to active ( n = 862 ) and control ( n = 874 ) groups . However , there was a significant attrition rate , with 66.9 % lost to follow-up at post-intervention . Both groups showed large improvements in depression symptoms overall , with no significant difference in improvement at the end of the study ( mean difference in improvement 0.35 points , 95 % CI : −0.57 to 1.28 , d = 0.11 , 95 % CI : −0.06 to 0.27 ) , although there was a small effect at the study mid-point . Results were similar for the sub-group of participants with major depression . The active group showed small to moderate improvements in self-help behaviour ( d = 0.40 , 95 % CI : 0.23 to 0.56 ) . Conclusions These results suggest that the e-mails were able to increase participants ’ use of evidence -based self-help , but that this did not improve depression more than an attention control . Clinical Trials.gov [3571935] Background This paper reports the results of a pilot r and omized controlled trial comparing the delivery modality ( mobile phone/tablet or fixed computer ) of a cognitive behavioural therapy intervention for the treatment of depression . The aim was to establish whether a previously vali date d computerized program ( The Sadness Program ) remained efficacious when delivered via a mobile application . Method 35 participants were recruited with Major Depression ( 80 % female ) and r and omly allocated to access the program using a mobile app ( on either a mobile phone or iPad ) or a computer . Participants completed 6 lessons , weekly homework assignments , and received weekly email contact from a clinical psychologist or psychiatrist until completion of lesson 2 . After lesson 2 email contact was only provided in response to participant request , or in response to a deterioration in psychological distress scores . The primary outcome measure was the Patient Health Question naire 9 ( PHQ-9 ) . Of the 35 participants recruited , 68.6 % completed 6 lessons and 65.7 % completed the 3-months follow up . Attrition was h and led using mixed-model repeated- measures ANOVA . Results Both the Mobile and Computer Groups were associated with statistically significantly benefits in the PHQ-9 at post-test . At 3 months follow up , the reduction seen for both groups remained significant . Conclusions These results provide evidence to indicate that delivering a CBT program using a mobile application , can result in clinical ly significant improvements in outcomes for patients with depression . Trial registration Australian New Zeal and Clinical Trials Registry ACTRN [4444307] Background There is need for more cost and time effective treatments for depression . This is the first r and omised controlled trial in which a blended treatment - including four face-to-face sessions and a smartphone application - was compared against a full behavioural treatment . Hence , the aim of the current paper was to examine whether a blended smartphone treatment was non-inferior to a full behavioural activation treatment for depression . Methods This was a r and omised controlled non-inferiority trial ( NCT01819025 ) comparing a blended treatment ( n=46 ) against a full ten-session treatment ( n=47 ) for people suffering from major depression . Primary outcome measure was the BDI-II , that was administered at pre- and post-treatment , as well as six months after the treatment . Results Results showed significant improvements in both groups across time on the primary outcome measure ( within-group Cohen ’s d=1.35 ; CI [ −0.82 , 3.52 ] to d=1.47 ; CI [ −0.41 , 3.35 ] ; between group d=−0.13 CI [ −2.37 , 2.09 ] and d=−0.10 CI [ −2.53 , 2.33 ] ) . At the same time , the blended treatment reduced the therapist time with an average of 47 % . Conclusions We could not establish whether the blended treatment was non-inferior to a full BA treatment . Nevertheless , this study points to that the blended treatment approach could possibly treat nearly twice as many patients suffering from depression by using a smartphone applica¬tion as add-on . More studies are needed before we can suggest that the blended treatment method is a promising cost-effective alternative to regular face-to-face treatment for depression . Trial Registration Cognitive Behavioral Therapy Treatment of Depression With Smartphone Support [22464008] BACKGROUND Mobile phone text message technology has the potential to improve outcomes for patients with depression and co-morbid Alcohol Use Disorder ( AUD ) . AIMS To perform a r and omised rater-blinded trial to explore the effects of supportive text messages on mood and abstinence outcomes for patients with depression and co-morbid AUD . METHODS Participants ( n=54 ) with a DSM IV diagnosis of unipolar depression and AUD who completed an in-patient dual diagnosis treatment programme were r and omised to receive twice daily supportive text messages ( n=26 ) or a fortnightly thank you text message ( n=28 ) for three months . Primary outcome measures were Beck 's Depression Inventory ( BDI-II ) scores and Cumulative Abstinence Duration ( CAD ) in days at three months . TRIAL REGISTRATION NCT0137868 . RESULTS There was a statistically significant difference in three month BDI-II scores between the intervention and control groups ; 8.5 ( SD=8.0 ) vs. 16.7 ( SD=10.3 ) respectively after adjusting for the baseline scores , F ( 1 , 49)=9.54 , p=0.003 , η(p)(2)=0.17 . The mean difference in change BDI-II scores was -7.9 ( 95 % CI -13.06 to -2.76 , Cohen'sd=0.85 ) . There was a trend for a greater CAD in the text message group than the control group : 88.3 ( SD=6.2 ) vs. 79.3 ( SD=24.1 ) , t=1.78 , df=48 , p=0.08 . LIMITATIONS Limitations of the study include the small sample size , the potential for loss of rater blinding and the lack of long term follow-up to determine the longer term effects of the intervention . CONCLUSION Supportive text messages have the potential to improve outcomes for patients with comorbid depression and alcohol dependency syndrome [19700005] BACKGROUND Despite strong evidence for its effectiveness , cognitive-behavioural therapy ( CBT ) remains difficult to access . Computerised programs have been developed to improve accessibility , but whether these interventions are responsive to individual needs is unknown . We investigated the effectiveness of CBT delivered online in real time by a therapist for patients with depression in primary care . METHODS In this multicentre , r and omised controlled trial , 297 individuals with a score of 14 or more on the Beck depression inventory ( BDI ) and a confirmed diagnosis of depression were recruited from 55 general practice s in Bristol , London , and Warwickshire , UK . Participants were r and omly assigned , by a computer-generated code , to online CBT in addition to usual care ( intervention ; n=149 ) or to usual care from their general practitioner while on an 8-month waiting list for online CBT ( control ; n=148 ) . Participants , research ers involved in recruitment , and therapists were masked in advance to allocation . The primary outcome was recovery from depression ( BDI score < 10 ) at 4 months . Analysis was by intention to treat . This trial is registered , number IS RCT N 45444578 . FINDINGS 113 participants in the intervention group and 97 in the control group completed 4-month follow-up . 43 ( 38 % ) patients recovered from depression ( BDI score < 10 ) in the intervention group versus 23 ( 24 % ) in the control group at 4 months ( odds ratio 2.39 , 95 % CI 1.23 - 4.67 ; p=0.011 ) , and 46 ( 42 % ) versus 26 ( 26 % ) at 8 months ( 2.07 , 1.11 - 3.87 ; p=0.023 ) . INTERPRETATION CBT seems to be effective when delivered online in real time by a therapist , with benefits maintained over 8 months . This method of delivery could broaden access to CBT . FUNDING BUPA Foundation [19508931] OBJECTIVE To investigate use and views of a Web site design ed for weight control . DESIGN Question naire-based evaluation with data collected at baseline , 6 months , and 12 months . SETTING Data were collected as part of a community-based , r and omized controlled trial . PARTICIPANTS Subjects ( n = 111 ) were participants of the intervention arm of a r and omized controlled trial evaluating effectiveness of a Web site design ed for weight control in an obese sample . INTERVENTION Participants were asked to use the intervention Web site for weight control over a 12-month period . MAIN OUTCOME MEASURE(S ) Participants were asked to report their use and views of the Web site . In addition , use of the Web site was automatically recorded on logging onto the Web site . ANALYSIS Descriptive statistics , factor analysis . RESULTS Fifty-nine participants ( 53 % ) reported using the Web site at 6 months , with 32 participants ( 29 % ) still using it at 12 months . The average time spent on the Web site per visit was 21.1 minutes ( SD = 16.6 ) at 6 months and 13.6 minutes ( SD = 9.3 ) at 12 months , with an average number of logons of 15.8 ( SD = 15.2 ) over the trial period . In general , satisfaction scores for the Web site were positive . Scores for ability of the re source to encourage positive behavior change for weight control were marginally negative . Social support sections of the Web site were used least and received the lowest satisfaction ratings . CONCLUSIONS AND IMPLICATION S Despite positive satisfaction scores , use of the re source was limited . It is expected that participants ' limited ability to use the Internet may have limited the use of the re source and consequently reduced the social support available to participants . Future investigation of the views and use patterns of current users of Internet-based weight loss re sources would help inform future development of such tools [23886401] BACKGROUND AND AIMS In the past decade , a large body of research has demonstrated that internet-based interventions can have beneficial effects on depression . However , only a few clinical trials have compared internet-based depression therapy with an equivalent face-to-face treatment . The primary aim of this study was to compare treatment outcomes of an internet-based intervention with a face-to-face intervention for depression in a r and omized non-inferiority trial . METHOD A total of 62 participants suffering from depression were r and omly assigned to the therapist-supported internet-based intervention group ( n=32 ) and to the face-to-face intervention ( n=30 ) . The 8 week interventions were based on cognitive-behavioral therapy principles . Patients in both groups received the same treatment modules in the same chronological order and time-frame . Primary outcome measure was the Beck Depression Inventory-II ( BDI-II ) ; secondary outcome variables were suicidal ideation , anxiety , hopelessness and automatic thoughts . RESULTS The intention-to-treat analysis yielded no significant between-group difference ( online vs. face-to-face group ) for any of the pre- to post-treatment measurements . At post-treatment both treatment conditions revealed significant symptom changes compared to before the intervention . Within group effect sizes for depression in the online group ( d=1.27 ) and the face-to-face group ( d=1.37 ) can be considered large . At 3-month follow-up , results in the online group remained stable . In contrast to this , participants in the face-to-face group showed significantly worsened depressive symptoms three months after termination of treatment ( t=-2.05 , df=19 , p<.05 ) . LIMITATIONS Due to the small sample size , it will be important to evaluate these outcomes in adequately-powered trials . CONCLUSIONS This study shows that an internet-based intervention for depression is equally beneficial to regular face-to-face therapy . However , more long term efficacy , indicated by continued symptom reduction three months after treatment , could be only be found for the online group [2483918] Background People with chronic obstructive pulmonary disease ( COPD ) continue to experience dyspnea with activities of daily living ( ADL ) despite optimal medical management . Information and communication technologies may facilitate collaborative symptom management and could potentially increase the reach of such interventions to those who are unable to attend face-to-face pulmonary rehabilitation or self-management programs . Objective The purpose of this r and omized study was to test the efficacy of two 6-month dyspnea self-management programs , Internet-based ( eDSMP ) and face-to-face ( fDSMP ) , on dyspnea with ADL in people living with COPD . Methods We r and omly assigned 50 participants with moderate to severe COPD who were current Internet users to either the eDSMP ( n = 26 ) or fDSMP ( n = 24 ) group . The content of the two programs was similar , focusing on education , skills training , and ongoing support for dyspnea self-management , including independent exercise . The only difference was the mode ( Internet/personal digital assistant [ PDA ] or face-to-face ) in which the education sessions , reinforcement contacts , and peer interactions took place . Participants returned to one of two academic clinical sites for evaluation at 3 and 6 months . The primary outcome of dyspnea with ADL was measured with the Chronic Respiratory Question naire . Secondary outcomes of exercise behavior , exercise performance , COPD exacerbations , and mediators , such as self-efficacy and social support , were also measured . A satisfaction survey was administered and a semistructured exit interview was conducted at the final visit . Results The study was stopped early due to multiple technical challenges with the eDSMP , but follow-up was completed on all enrolled participants . Data were available for 39 participants who completed the study ( female : 44 % ; age : 69.5 ± 8.5 years ; percent predicted forced expiratory volume in 1 s : 49.6 ± 17.0 % ) . The fDSMP and eDSMP showed similar clinical ly meaningful changes in dyspnea with ADL from baseline to 3 months ( fDSMP : + 3.3 points ; eDSMP : + 3.5 points ) and sustained these improvements at 6 months ( fDSMP : + 4.0 points ; eDSMP : + 2.5 points ; time effects P < .001 ; group by time P = .51 ) . Self-reported endurance exercise time ( P = .001 ) , physical functioning ( P = .04 ) , and self-efficacy for managing dyspnea ( P = .02 ) also showed positive improvements over time in both groups with no significant differences with respect to program modality . Participants who completed the study reported favorable satisfaction with the programs . Conclusions Although there were numerous technical challenges with the eDSMP , both dyspnea self-management programs were effective in reducing dyspnea with ADL in the short term . Our findings will need to be confirmed in a larger r and omized trial with more mature Web and personal digital assistant tools , use of a control group , and longer follow-up . Trial registration clinical trials.gov NCT00102401 , [2882336] Background Internet-based cognitive behavioural therapy ( iCBT ) for depression is effective when guided by a clinician , less so if unguided . Question : Would guidance from a technician be as effective as guidance from a clinician ? Method R and omized controlled non-inferiority trial comparing three groups : Clinician-assisted vs. technician-assisted vs. delayed treatment . Community-based volunteers applied to the VirtualClinic ( www.virtualclinic.org.au ) research program , and 141 participants with major depressive disorder were r and omized . Participants in the clinician- and technician-assisted groups received access to an iCBT program for depression comprising 6 online lessons , weekly homework assignments , and weekly supportive contact over a treatment period of 8 weeks . Participants in the clinician-assisted group also received access to a moderated online discussion forum . The main outcome measures were the Beck Depression Inventory ( BDI-II ) and the Patient Health Question naire-9 Item ( PHQ-9 ) . Completion rates were high , and at post-treatment , both treatment groups reduced scores on the BDI-II ( p<0.001 ) and PHQ-9 ( p<0.001 ) compared to the delayed treatment group but did not differ from each other . Within group effect sizes on the BDI-II were 1.27 and 1.20 for the clinician- and technician-assisted groups respectively , and on the PHQ-9 , were 1.54 and 1.60 respectively . At 4-month follow-up participants in the technician group had made further improvements and had significantly lower scores on the PHQ-9 than those in the clinician group . A total of approximately 60 minutes of clinician or technician time was required per participant during the 8-week treatment program . Conclusions Both clinician- and technician-assisted treatment result ed in large effect sizes and clinical ly significant improvements comparable to those associated with face-to-face treatment , while a delayed treatment control group did not improve . These results provide support for large scale trials to determine the clinical effectiveness and acceptability of technician-assisted iCBT programs for depression . This form of treatment has potential to increase the capacity of existing mental health services . Trial Registration Australian New Zeal and Clinical Trials Registry [25645168] UNLABELLED Depression is a common and significant health problem among older adults . Unfortunately , while effective psychological treatments exist , few older adults access treatment . The aim of the present r and omized controlled trial ( RCT ) was to examine the efficacy , long-term outcomes , and cost-effectiveness of a therapist-guided internet-delivered cognitive behavior therapy ( iCBT ) intervention for Australian adults over 60 years of age with symptoms of depression . Participants were r and omly allocated to either a treatment group ( n=29 ) or a delayed-treatment waitlist control group ( n=25 ) . Twenty-seven treatment group participants started the iCBT treatment and 70 % completed the treatment within the 8-week course , with 85 % of participants providing data at posttreatment . Treatment comprised an online 5-lesson iCBT course with brief weekly contact with a clinical psychologist , delivered over 8 weeks . The primary outcome measure was the Patient Health Question naire-9 Item ( PHQ-9 ) , a measure of symptoms and severity of depression . Significantly lower scores on the PHQ-9 ( Cohen 's d=2.08 ; 95 % CI : 1.38 - 2.72 ) and on a measure of anxiety ( Generalized Anxiety Disorder-7 Item ) ( Cohen 's d=1.22 ; 95 % CI : 0.61 - 1.79 ) were observed in the treatment group compared to the control group at posttreatment . The treatment group maintained these lower scores at the 3-month and 12-month follow-up time points and the iCBT treatment was rated as acceptable by participants . The treatment group had slightly higher Quality -Adjusted Life-Years ( QALYs ) than the control group at posttreatment ( estimate : 0.012 ; 95 % CI : 0.004 to 0.020 ) and , while being a higher cost ( estimate $ 52.9l 95 % CI : -23.8 to 128.2 ) , the intervention was cost-effective according to commonly used willingness-to-pay thresholds in Australia . The results support the potential efficacy and cost-effectiveness of therapist-guided iCBT as a treatment for older adults with symptoms of depression . TRIAL REGISTRATION Australian and New Zeal and Clinical Trials Registry : ACTRN12611000927921 ; https://www.anzctr.org.au/Trial/ Registration /Trial Review .aspx?id=343384 [25127179] The aim of the present study was to investigate two interventions based on Acceptance and Commitment Therapy ( ACT ) for depressive symptoms : A face-to-face treatment ( ACT group ) was compared to a guided self-help treatment delivered via the Internet consisting of two assessment sessions ( pre and post ) and an ACT-based Internet program ( iACT ) . Out patients experiencing at least mild depressive symptoms were r and omized to either approach . The iACT treatment group received access to an ACT-based Internet program and supportive web-based contact over a period of 6 weeks . The face-to-face group received ACT-based treatment once a week over the same period of time . In both groups , the results showed a significant effect on depression symptomatology , and general wellbeing after treatment and at the 18-month follow-up . However , the data indicated that the iACT group changed differently regarding depressive symptoms and wellbeing as compared to the face-to face ACT group . Results showed large pre-treatment to 18-month follow-up within-group effect sizes for all symptom measures in the iACT treatment group ( 1.59 - 2.08 ) , and for most outcome measures in the face-to-face ACT group ( 1.12 - 1.37 ) . This non-inferiority study provides evidence that guided Internet-delivered ACT intervention can be as effective as ACT-based face-to-face treatment for out patients reporting depressive symptoms , and it may offer some advantages over a face-to-face intervention [18576310] OBJECTIVE To determine the efficacy of an Internet-based Arthritis Self-Management Program ( ASMP ) as a re source for arthritis patients unable or unwilling to attend small-group ASMPs , which have proven effective in changing health-related behaviors and improving health status measures . METHODS R and omized intervention participants were compared with usual care controls at 6 months and 1 year using repeated- measures analyses of variance . Patients with rheumatoid arthritis , osteoarthritis , or fibromyalgia and Internet and e-mail access ( n = 855 ) were r and omized to an intervention ( n = 433 ) or usual care control ( n = 422 ) group . Measures included 6 health status variables ( pain , fatigue , activity limitation , health distress , disability , and self-reported global health ) , 4 health behaviors ( aerobic exercise , stretching and strengthening exercise , practice of stress management , and communication with physicians ) , 5 utilization variables ( physician visits , emergency room visits , chiropractic visits , physical therapist visits , and nights in hospital ) , and self-efficacy . RESULTS At 1 year , the intervention group significantly improved in 4 of 6 health status measures and self-efficacy . No significant differences in health behaviors or health care utilization were found . CONCLUSION The Internet-based ASMP proved effective in improving health status measures at 1 year and is a viable alternative to the small-group ASMP [24035673] BACKGROUND Guided internet-delivered cognitive behaviour therapy ( ICBT ) has been found to be effective in the treatment of mild to moderate depression , but there have been no direct comparisons with the more established group-based CBT with a long-term follow-up . METHOD Participants with mild to moderate depression were recruited from the general population and r and omized to either guided ICBT ( n=33 ) or to live group treatment ( n=36 ) . Measures were completed before and after the intervention to assess depression , anxiety , and quality of life . Follow-ups were conducted at one-year and three-year after the treatment had ended . RESULTS Data were analysed on an intention-to-treat basis using linear mixed-effects regression analysis . Results on the self-rated version of the Montgomery-Åsberg Depression Scale showed significant improvements in both groups across time indicating non-inferiority of guided ICBT , and there was even a tendency for the guided ICBT group to be superior to group-based CBT at three year follow-up . Within-group effect sizes for the ICBT condition at post-treatment showed a Cohen 's d=1.46 , with a similar large effect at 3-year follow-up , d=1.78 . For the group CBT the corresponding within-group effects were d=0.99 and d=1.34 , respectively . LIMITATIONS The study was small with two active treatments and there was no placebo or credible control condition . CONCLUSIONS Guided ICBT is at least as effective as group-based CBT and long-term effects can be sustained up to 3 years after treatment [19028519] OBJECTIVE To evaluate the use of a local neighborhood environment-focused physical activity website and its effects on walking and overall physical activity in middle-aged adults . METHOD One-hundred and six ( 72 % women ) inactive adults aged 52+/-4.6 years were r and omly allocated to receive access to a neighborhood environment-focused website , ( Neighborhood group , n=52 ) or a motivational-information website ( Comparison group n=54 ) . Participants also received eleven emails over the 26 weeks . Study outcomes were objective ly-monitored website use , and self-reported total walking ( min/wk ) , total physical activity ( min/wk ) and neighborhood walking ( min/wk ) collected at baseline , 12 and 26 weeks . The study was conducted between August 2005 and February 2006 in Brisbane , Australia . RESULTS Website use was significantly greater among Neighborhood participants ( p=0.01 ) . Statistically significant increases in walking and total physical activity were observed in both groups . There was also a statistically significant interaction effect for total physical activity , with Neighborhood group participants maintaining more of their initial increase in physical activity at week-26 ( p<0.05 ) . Further , those in the Neighborhood group who used the website more often reported significantly more walking along the community trail at week-26 ( p=0.05 ) compared with those who did not . CONCLUSIONS A local neighborhood-environment focused physical activity website was more effective at engaging participants than a motivational-information website . Moreover , its use result ed in meaningful increases in physical activity relative to the comparison website [20560847] Objective : To determine the efficacy of an Internet-based clinician-assisted cognitive behavioural treatment program ( the Panic program ) for panic disorder ( with or without agoraphobia ) . Method : Fifty-nine individuals meeting diagnostic criteria for panic disorder with agoraphobia were r and omly assigned to a treatment group or to a waitlist control group . Treatment group participants completed the Panic program , comprising six on-line lessons , weekly homework assignments , received weekly email contact from a psychiatry registrar , and contributed to a moderated online discussion forum with other participants . An intention-to-treat model was used for data analyses . Results : Twenty-three ( 79 % ) of treatment group participants completed all lessons within the 8-week program , and post-treatment data were collected from 22/29 treatment group and 22/25 waitlist group participants . Compared to the control group , treatment group participants reported significantly reduced symptoms of panic as measured by the Panic Disorder Severity Scale , Body Sensation Question naire , and Agoraphobic Cognitions Question naires . Significant reductions were also reported on measures of disability and depression . The mean within- and between-group effect size ( Cohen 's d ) on the Panic Disorder Severity Scale was 0.93 and 0.59 , respectively , and effects were sustained at 1-month follow-up . Mean therapist time per participant was 75 minutes for the program . Conclusions : These results replicate those from the open trial of the Panic Program indicating the efficacy of the Internet-based clinician-assisted cognitive behavioural treatment program for panic disorder with agoraphobia [21401534] Holländare F , Johnsson S , R and estad M , Tillfors M , Carlbring P , And ersson G , Engström I. R and omized trial of Internet‐based relapse prevention for partially remitted depression [22788983] Life- review therapy has been recognized as an effective therapeutic approach for depression in older adults . Additionally , the use of new media is becoming increasingly common in psychological interventions . The aim of this study was to investigate a life- review therapy in a face-to-face setting with additional computer use . This study explored whether a six-week life- review therapy with computer supplements from the e-mental health Butler system constitutes an effective approach to treat depression in older adults aged 65 and over . A total of 36 participants with elevated levels of depressive symptoms were r and omized to a treatment group or a waiting-list control group and completed the post- assessment . Fourteen individuals in the intervention group completed the follow-up assessment . Analyses revealed significant changes from pre- to post-treatment or follow-up for depression , well-being , self-esteem , and obsessive reminiscence , but not for integrative reminiscence and life satisfaction . Depressive symptoms decreased significantly over time until the three-month follow-up in the intervention group compared to the control group ( pre to post : d = 1.13 ; pre to follow-up : d = 1.27 ; and group × time effect pre to post : d = 0.72 ) . Furthermore , the therapy led to an increase in well-being and a decrease in obsessive reminiscence among the participants in the intervention group from pre-treatment to follow-up ( well-being : d = 0.70 ; obsessive reminiscence : d = 0.93 ) . Analyses further revealed a significant but small group × time effect regarding self-esteem ( d = 0.19 ) . By and large , the results indicate that the life- review therapy in this combined setting could be recommended for depressive older adults [10710839] The bidirectional causal relationships between psychotherapy homework ( HW ) compliance and changes in depression were assessed in 2 groups of depressed out patients treated with cognitive-behavioral therapy using nonrecursive structural equation modeling techniques . The data were consistent with the hypothesis that HW compliance had a causal effect on changes in depression , and the magnitude of this effect was large . Patients who did the most HW improved much more than patients who did little or no HW . In contrast , depression severity did not appear to influence HW compliance . HW compliance did not appear to be a proxy for any other , unobserved ( 3rd ) variable , such as motivation . Although the causal effect of HW on depression was large , the correlation between HW and depression was small . Some possible explanations , along with suggestions for future studies , are proposed [21679925] Disorder-specific cognitive behavioural therapy programs delivered over the internet ( iCBT ) with clinician guidance are effective at treating specific anxiety disorders and depression . The present study examined the efficacy of a transdiagnostic iCBT protocol to treat three anxiety disorders and /or depression within the same program ( the Wellbeing Program ) . Seventy-seven individuals with a principal diagnosis of major depression , generalised anxiety disorder , panic disorder , and /or social phobia were r and omly assigned to a Treatment or Waitlist Control group . Treatment consisted of CBT-based online educational lessons and homework assignments , weekly email or telephone contact from a clinical psychologist , access to a moderated online discussion forum , and automated emails . Eighty one percent of Treatment group participants completed all 8 lessons within the 10 week program . Post-treatment data were collected from 34/37 Treatment group and 35/37 Control group participants , and 3-month follow-up data were collected from 32/37 Treatment group participants . Relative to Controls , Treatment group participants reported significantly reduced symptoms of anxiety and depression as measured by the Depression Anxiety and Stress Scales-21 item , Patient Health Question naire-9 item , and Generalised Anxiety Disorder-7 item scales , with corresponding between-groups effect sizes ( Cohen 's d ) at post treatment of.56,.58 , and .52 , respectively . The clinician spent a mean time of 84.76 min ( SD=50.37 ) per person over the program . Participants rated the procedure as highly acceptable , and gains were sustained at follow-up . These results provide preliminary support for the efficacy of transdiagnostic iCBT in the treatment of anxiety and depressive disorders [26422822] Disorder-specific cognitive behavior therapy ( DS-CBT ) is effective at treating major depressive disorder ( MDD ) while transdiagnostic CBT ( TD-CBT ) addresses both principal and comorbid disorders by targeting underlying and common symptoms . The relative benefits of these two models of therapy have not been determined . Participants with MDD ( n=290 ) were r and omly allocated to receive an internet delivered TD-CBT or DS-CBT intervention delivered in either clinician-guided ( CG-CBT ) or self-guided ( SG-CBT ) formats . Large reductions in symptoms of MDD ( Cohen 's d≥1.44 ; avg . reduction≥45 % ) and moderate-to-large reductions in symptoms of comorbid generalised anxiety disorder ( Cohen 's d≥1.08 ; avg . reduction≥43 % ) , social anxiety disorder ( Cohen 's d≥0.65 ; avg . reduction≥29 % ) and panic disorder ( Cohen 's d≥0.45 ; avg . reduction≥31 % ) were found . No marked or consistent differences were observed across the four conditions , highlighting the efficacy of different forms of CBT at treating MDD and comorbid disorders [3701078] Background Depression and anxiety are common , disabling and chronic . Self-guided internet-delivered treatments are popular , but few people complete them . New strategies are required to realise their potential . Aims To evaluate the effect of automated emails on the effectiveness , safety , and acceptability of a new automated transdiagnostic self-guided internet-delivered treatment , the Wellbeing Course , for people with depression and anxiety . Method A r and omised controlled trial was conducted through the website : www.ecentreclinic.org . Two hundred and fifty seven people with elevated symptoms were r and omly allocated to the 8 week course either with or without automated emails , or to a waitlist control group . Primary outcome measures were the Patient Health Question naire 9-Item ( PHQ-9 ) and the Generalized Anxiety Disorder 7-Item ( GAD-7 ) . Results Participants in the treatment groups had lower PHQ-9 and GAD-7 scores at post-treatment than controls . Automated emails increased rates of course completion ( 58 % vs. 35 % ) , and improved outcomes in a sub sample with elevated symptoms . Conclusions The new self-guided course was beneficial , and automated emails facilitated outcomes . Further attention to strategies that facilitate adherence , learning , and safety will help realise the potential of self-guided interventions . Trial Registration Australian and New Zeal and Clinical Trials Registry [23357657] BACKGROUND Internet-based cognitive behavior therapy for depression has been tested in several trials but there are no internet studies on behavioral activation ( BA ) , and no studies on BA over the internet including components of acceptance and commitment therapy ( ACT ) . The aim of this study was to develop and test the effects of internet-delivered BA combined with ACT against a waiting list control condition as a first test of the effects of treatment . METHODS Selection took place with a computerized screening interview and a subsequent semi-structured telephone interview . A total of 80 individuals from the general public were r and omized to one of two conditions . The treatment lasted for 8 weeks after which both groups were assessed . We also included a 3 month follow-up . The treatment included interactive elements online and a CD-ROM for mindfulness and acceptance exercises . In addition , written support and feedback was given by a therapist every week . RESULTS Results at posttreatment showed a large between group effect size on the Beck Depression inventory II d=0.98 ( 95%CI=0.51 - 1.44 ) . In the treated group 25 % ( 10/40 ) reached remission defined as a BDI score ≤ 10 vs. 5 % ( 2/40 ) in the control group . Results on secondary measures were smaller . While few dropped out from the study ( N=2 ) at posttreatment , the average number of completed modules was M=5.1 out of the seven modules . LIMITATIONS The study only included a waiting-list comparison and it is not possible to determine which treatment components were the most effective . CONCLUSIONS We conclude that there is initial evidence that BA with components of ACT can be effective in reducing symptoms of depression [19221919] Depression is common but undertreated . Web-based self-help provides a widely accessible treatment alternative for mild to moderate depression . However , the lack of therapist guidance may limit its efficacy . The authors assess the efficacy of therapist-guided web-based cognitive behavioural treatment ( web-CBT ) of mild to moderate depression . Fifty-four individuals with chronic , moderate depression participated in a r and omized wait-list controlled trial , with an 18-month follow-up ( immediate treatment : n = 36 , wait-list control : n = 18 ) . Primary outcome measures were the Beck Depression Inventory ( BDI-IA ) and the Depression scale of the Symptom Checklist-90-Revised ( SCL-90-R. DEP ) . Secondary outcome measures were the Depression Anxiety Stress Scales and the Well-Being Question naire . Five participants ( 9 % ) dropped out . Intention-to-treat analyses of covariance revealed that participants in the treatment condition improved significantly more than those in the wait-list control condition ( .011 < p < .015 ) . With regard to the primary measures , between-group effects ( d ) were 0.7 for the BDI-IA and 1.1 for the SCL-90-R DEP . Posttest SCL-90- R DEP scores indicated recovery of 49 % of the participants in the treatment group compared with 6 % in the control group ( odds ratio = 14.5 ; p < .004 ) . On average , the effects were stable up to 18 months ( n = 39 ) , although medication was a strong predictor of relapse . The results demonstrate the efficacy of web-CBT for mild to moderate depression and the importance of therapist guidance in psychological interventions [23419552] BACKGROUND Major depressive disorder ( MDD ) and generalized anxiety disorder ( GAD ) have the highest co-morbidity rates within the internalizing disorders cluster , yet no Internet-based cognitive behavioural therapy ( iCBT ) programme exists for their combined treatment . METHOD We design ed a six-lesson therapist-assisted iCBT programme for mixed anxiety and depression . Study 1 was a r and omized controlled trial ( RCT ) comparing the iCBT programme ( n = 46 ) versus wait-list control ( WLC ; n = 53 ) for patients diagnosed by structured clinical interview with MDD , GAD or co-morbid GAD/MDD . Primary outcome measures were the Patient Health Question naire nine-item scale ( depression ) , Generalized Anxiety Disorder seven-item scale ( generalized anxiety ) , Kessler 10-item Psychological Distress scale ( distress ) and 12-item World Health Organization Disability Assessment Schedule II ( disability ) . The iCBT group was followed up at 3 months post-treatment . In study 2 , we investigated the adherence to , and efficacy of the same programme in a primary care setting , where patients ( n = 136 ) completed the programme under the supervision of primary care clinicians . RESULTS The RCT showed that the iCBT programme was more effective than WLC , with large within- and between-groups effect sizes found ( > 0.8 ) . Adherence was also high ( 89 % ) , and gains were maintained at 3-month follow-up . In study 2 in primary care , adherence to the iCBT programme was low ( 41 % ) , yet effect sizes were large ( > 0.8 ) . Of the non-completers , 30 % experienced benefit . CONCLUSIONS Together , the results show that iCBT is effective and adherence is high in research setting s , but there is a problem of adherence when translated into the ' real world ' . Future efforts need to be placed on developing improved adherence to iCBT in primary care setting

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### Context: [17466110] BACKGROUND Subthreshold depression is a highly prevalent condition and a risk factor for developing a major depressive episode . Internet-based cognitive behaviour therapy may be a promising approach for the treatment of subthreshold depression . The current study had two aims : ( 1 ) to determine whether an internet-based cognitive behaviour therapy intervention and a group cognitive behaviour therapy intervention are more effective than a waiting-list control group ; and ( 2 ) to determine whether the effect of the internet-based cognitive behaviour therapy differs from the group cognitive behaviour therapy intervention . METHOD A total of 191 women and 110 men with subthreshold depression were r and omized into internet-based treatment , group cognitive behaviour therapy ( Lewinsohn 's Coping With Depression course ) , or a waiting-list control condition . The main outcome measure was treatment response after 10 weeks , defined as the difference in pre- and post-treatment scores on the Beck Depression Inventory ( BDI ) . Missing data , a major limitation of this study , were imputed using the Multiple Imputation ( MI ) procedure Data Augmentation . RESULTS In the waiting-list control group , we found a pre- to post-improvement effect size of 0.45 , which was 0.65 in the group cognitive behaviour therapy condition and 1.00 within the internet-based treatment condition . Helmert contrasts showed a significant difference between the waiting-list condition and the two treatment conditions ( p=0.04 ) and no significant difference between both treatment conditions ( p=0.62 ) . CONCLUSIONS An internet-based intervention may be at least as effective as a commonly used group cognitive behaviour therapy intervention for subthreshold depression in people over 50 years of age [1874722] Background The Internet has potential as a medium for health behavior change programs , but no controlled studies have yet evaluated the impact of a fully automated physical activity intervention over several months with real-time objective feedback from a monitor . Objective The aim was to evaluate the impact of a physical activity program based on the Internet and mobile phone technology provided to individuals for 9 weeks . Methods A single-center , r and omized , stratified controlled trial was conducted from September to December 2005 in Bedfordshire , United Kingdom , with 77 healthy adults whose mean age was 40.4 years ( SD = 7.6 ) and mean body mass index was 26.3 ( SD = 3.4 ) . Participants were r and omized to a test group that had access to an Internet and mobile phone – based physical activity program ( n = 47 ) or to a control group ( n = 30 ) that received no support . The test group received tailored solutions for perceived barriers , a schedule to plan weekly exercise sessions with mobile phone and email reminders , a message board to share their experiences with others , and feedback on their level of physical activity . Both groups were issued a wrist-worn accelerometer to monitor their level of physical activity ; only the test group received real-time feedback via the Internet . The main outcome measures were accelerometer data and self-report of physical activity . Results At the end of the study period , the test group reported a significantly greater increase over baseline than did the control group for perceived control ( P < .001 ) and intention/expectation to exercise ( P < .001 ) . Intent-to-treat analyses of both the accelerometer data ( P = .02 ) and leisure time self-report data ( P = .03 ) found a higher level of moderate physical activity in the test group . The average increase ( over the control group ) in accelerometer-measured moderate physical activity was 2 h 18 min per week . The test group also lost more percent body fat than the control group ( test group : −2.18 , SD = 0.59 ; control group : −0.17 , SD = 0.81 ; P = .04 ) . Conclusions A fully automated Internet and mobile phone – based motivation and action support system can significantly increase and maintain the level of physical activity in healthy adults [3362510] Background and aims Psychodynamic psychotherapy ( PDT ) is an effective treatment for major depressive disorder ( MDD ) , but not all clients with MDD can receive psychotherapy . Using the Internet to provide psychodynamic treatments is one way of improving access to psychological treatments for MDD . The aim of this r and omised controlled trial was to investigate the efficacy of an Internet-based psychodynamic guided self-help treatment for MDD . Methods Ninety-two participants who were diagnosed with MDD according to the Mini-International Neuropsychiatric Interview were r and omised to treatment or an active control . The treatment consisted of nine treatment modules based on psychodynamic principles with online therapist contact . The active control condition was a structured support intervention and contained psychoeducation and scheduled weekly contacts online . Both interventions lasted for 10 weeks . The primary outcome measure was the Beck Depression Inventory-II ( BDI-II ) . Results Mixed-effects model analyses of all r and omised participants showed that participants receiving Internet-based PDT made large and superior improvements compared with the active control group on the BDI-II ( between-group Cohen 's d = 1.11 ) . Treatment effects were maintained at a 10-month follow-up . Conclusions Internet-based psychodynamic guided self-help is an efficacious treatment for MDD that has the potential to increase accessibility and availability of PDT for MDD . Trial Registration Clinical trials.gov : [16260822] BACKGROUND Major depression can be treated by means of cognitive-behavioural therapy , but as skilled therapists are in short supply there is a need for self-help approaches . Many individuals with depression use the internet for discussion of symptoms and to share their experience . AIMS To investigate the effects of an internet-administered self-help programme including participation in a monitored , web-based discussion group , compared with participation in web-based discussion group only . METHOD A r and omised controlled trial was conducted to compare the effects of internet-based cognitive-behavioural therapy with minimal therapist contact ( plus participation in a discussion group ) with the effects of participation in a discussion group only . RESULTS Internet-based therapy with minimal therapist contact , combined with activity in a discussion group , result ed in greater reductions of depressive symptoms compared with activity in a discussion group only ( waiting-list control group ) . At 6 months ' follow-up , improvement was maintained to a large extent . CONCLUSIONS Internet-delivered cognitive cognitive-behavioural therapy should be pursued further as a complement or treatment alternative for mild-to-moderate depression [22060248] Internet-delivered self-help for depression with therapist guidance has shown efficacy in several trials . Results from meta-analyses suggest that guidance is important and that self-help programs without support are less effective . However , there are no direct experimental comparisons between guided and unguided internet-based treatments for depression . The present study compared the benefits of a 10-week web-based unguided self-help treatment with the same intervention complemented with weekly therapist support via e-mail . A waiting-list control group was also included . Seventy-six individuals meeting the diagnostic criteria of major depression or dysthymia were r and omly assigned to one of the three conditions . The Beck Depression Inventory ( BDI-II ) was used as the primary outcome measure . Secondary outcomes included general psychopathology , interpersonal problems , and quality of life . Sixty-nine participants ( 91 % ) completed the assessment at posttreatment and 59 ( 78 % ) at 6-month follow-up . Results showed significant symptom reductions in both treatment groups compared to the waiting-list control group . At posttreatment , between-group effect sizes on the BDI-II were d = .66 for unguided self-help versus waiting-list and d = 1.14 for guided self-help versus waiting-list controls . In the comparison of the two active treatments , small-to-moderate , but not statistically significant effects in favor of the guided condition were found on all measured dimensions . In both groups , treatment gains were maintained at 6-month follow-up . The findings provide evidence that internet-delivered treatments for depression can be effective whether support is added or not . However , all participants were interviewed in a structured diagnostic telephone interview before inclusion , which prohibits conclusions regarding unguided treatments that are without any human contact [5052463] Background Depression is a burdensome , recurring mental health disorder with high prevalence . Even in developed countries , patients have to wait for several months to receive treatment . In many parts of the world there is only one mental health professional for over 200 people . Smartphones are ubiquitous and have a large complement of sensors that can potentially be useful in monitoring behavioral patterns that might be indicative of depressive symptoms and providing context -sensitive intervention support . Objective The objective of this study is 2-fold , first to explore the detection of daily-life behavior based on sensor information to identify subjects with a clinical ly meaningful depression level , second to explore the potential of context sensitive intervention delivery to provide in-situ support for people with depressive symptoms . Methods A total of 126 adults ( age 20 - 57 ) were recruited to use the smartphone app Mobile Sensing and Support ( MOSS ) , collecting context -sensitive sensor information and providing just-in-time interventions derived from cognitive behavior therapy . Real-time learning-systems were deployed to adapt to each subject ’s preferences to optimize recommendations with respect to time , location , and personal preference . Biweekly , participants were asked to complete a self-reported depression survey ( PHQ-9 ) to track symptom progression . Wilcoxon tests were conducted to compare scores before and after intervention . Correlation analysis was used to test the relationship between adherence and change in PHQ-9 . One hundred twenty features were constructed based on smartphone usage and sensors including accelerometer , Wifi , and global positioning systems ( GPS ) . Machine-learning models used these features to infer behavior and context for PHQ-9 level prediction and tailored intervention delivery . Results A total of 36 subjects used MOSS for ≥2 weeks . For subjects with clinical depression ( PHQ-9≥11 ) at baseline and adherence ≥8 weeks ( n=12 ) , a significant drop in PHQ-9 was observed ( P=.01 ) . This group showed a negative trend between adherence and change in PHQ-9 scores ( rho=−.498 , P=.099 ) . Binary classification performance for biweekly PHQ-9 sample s ( n=143 ) , with a cutoff of PHQ-9≥11 , based on R and om Forest and Support Vector Machine leave-one-out cross validation result ed in 60.1 % and 59.1 % accuracy , respectively . Conclusions Proxies for social and physical behavior derived from smartphone sensor data was successfully deployed to deliver context -sensitive and personalized interventions to people with depressive symptoms . Subjects who used the app for an extended period of time showed significant reduction in self-reported symptom severity . Nonlinear classification models trained on features extracted from smartphone sensor data including Wifi , accelerometer , GPS , and phone use , demonstrated a proof of concept for the detection of depression superior to r and om classification . While findings of effectiveness must be reproduced in a RCT to proof causation , they pave the way for a new generation of digital health interventions leveraging smartphone sensors to provide context sensitive information for in-situ support and unobtrusive monitoring of critical mental health states [22677231] Depression is among the most prevalent disorders worldwide . In view of numerous treatment barriers , internet-based interventions are increasingly adopted to " treat the untreated " . The present trial ( registered as NCT01401296 ) was conducted over the internet and aim ed to assess the efficacy of an online self-help program for depression ( Deprexis ) . In r and om order , participants with elevated depression symptoms received program access or were allocated to a wait-list control condition . After eight weeks , participants were invited to take part in an online re- assessment . To compensate for common problems of online studies , such as low completion rates and unclear diagnostic status , reminders and incentives were used , and clinical diagnoses were externally confirmed in a subgroup of 29 % of participants . Relative to the wait-list group , program users experienced significant symptom decline on the Beck Depression Inventory ( BDI ; primary outcome ) , the Dysfunctional Attitudes Scale ( DAS ) , the Quality of Life scale ( WHOQOL-BREF ) and the Rosenberg Self-Esteem Scale ( RSE ) . Compared to wait-list participants , symptom decline was especially pronounced among those with moderate symptoms at baseline as well as those not currently consulting a therapist . Completion ( 82 % ) and re-test reliability of the instruments ( r = .72-.87 ) were good . The results of this trial suggest that online treatment can be beneficial for people with depression , particularly for those with moderate symptoms [3709106] Background . Psychodynamic psychotherapy is a psychological treatment approach that has a growing empirical base . Research has indicated an association between therapist-facilitated affective experience and outcome in psychodynamic therapy . Affect-phobia therapy ( APT ) , as outlined by McCullough et al. , is a psychodynamic treatment that emphasizes a strong focus on expression and experience of affect . This model has neither been evaluated for depression nor anxiety disorders in a r and omized controlled trial . While Internet-delivered psychodynamic treatments for depression and generalized anxiety disorder exist , they have not been based on APT . The aim of this r and omized controlled trial was to investigate the efficacy of an Internet-based , psychodynamic , guided self-help treatment based on APT for depression and anxiety disorders . Methods . One hundred participants with diagnoses of mood and anxiety disorders participated in a r and omized ( 1:1 ratio ) controlled trial of an active group versus a control condition . The treatment group received a 10-week , psychodynamic , guided self-help treatment based on APT that was delivered through the Internet . The treatment consisted of eight text-based treatment modules and included therapist contact ( 9.5 min per client and week , on average ) in a secure online environment . Participants in the control group also received online therapist support and clinical monitoring of symptoms , but received no treatment modules . Outcome measures were the 9-item Patient Health Question naire Depression Scale ( PHQ-9 ) and the 7-item Generalized Anxiety Disorder Scale ( GAD-7 ) . Process measures were also included . All measures were administered weekly during the treatment period and at a 7-month follow-up . Results . Mixed models analyses using the full intention-to-treat sample revealed significant interaction effects of group and time on all outcome measures , when comparing treatment to the control group . A large between-group effect size of Cohen ’s d = 0.77 ( 95 % CI : 0.37–1.18 ) was found on the PHQ-9 and a moderately large between-group effect size d = 0.48 ( 95 % CI : 0.08–0.87 ) was found on the GAD-7 . The number of patients who recovered ( had no diagnoses of depression and anxiety , and had less than 10 on both the PHQ-9 and the GAD-7 ) were at post-treatment 52 % in the treatment group and 24 % in the control group . This difference was significant , χ2(N = 100 , d f = 1 ) = 8.3 , p < .01 . From post-treatment to follow-up , treatment gains were maintained on the PHQ-9 , and significant improvements were seen on the GAD-7 . Conclusion . This study provides initial support for the efficacy of Internet-delivered psychodynamic therapy based on the affect-phobia model in the treatment of depression and anxiety disorders . The results support the conclusion that psychodynamic treatment approaches may be transferred to the guided self-help format and delivered via the Internet [4346073] Background : Access to mental health care is limited . Internet-based interventions ( IBIs ) may help bridge that gap by improving access especially for those who are unable to receive expert care . Aim : This review explores current research on the effectiveness of IBIs for depression and anxiety . Results : For depression , therapist-guided cognitive behavioral therapy ( CBT ) had larger effect sizes consistently across studies , ranging from 0.6 to 1.9 ; while st and -alone CBT ( without therapist guidance ) had a more modest effect size of 0.3–0.7 . Even other interventions for depression ( non-CBT/non-r and omized controlled trial ( RCT ) ) showed modestly high effect sizes ( 0.2–1.7 ) . For anxiety disorders , studies showed robust effect sizes for therapist-assisted interventions with effect sizes of 0.7–1.7 ( efficacy similar to face-to-face CBT ) and st and -alone CBT studies also showed large effect sizes ( 0.6–1.7 ) . Non-CBT/Non- RCT studies ( only 3 ) also showed significant reduction in anxiety scores at the end of the interventions . Conclusion : IBIs for anxiety and depression appear to be effective in reducing symptomatology for both depression and anxiety , which were enhanced by the guidance of a therapist . Further research is needed to identify various predictive factors and the extent to which st and -alone Internet therapies may be effective in the future as well as effects for different patient population [19567900] BACKGROUND Computerised cognitive-behavioural therapy ( CCBT ) might offer a solution to the current undertreatment of depression . AIMS To determine the clinical effectiveness of online , unsupported CCBT for depression in primary care . METHOD Three hundred and three people with depression were r and omly allocated to one of three groups : Colour Your Life ; treatment as usual ( TAU ) by a general practitioner ; or Colour Your Life and TAU combined . Colour Your Life is an online , multimedia , interactive CCBT programme . No assistance was offered . We had a 6-month follow-up period . RESULTS No significant differences in outcome between the three interventions were found in the intention-to-treat and per protocol analyses . CONCLUSIONS Online , unsupported CCBT did not outperform usual care , and the combination of both did not have additional effects . Decrease in depressive symptoms in people with moderate to severe depression was moderate in all three interventions . Online CCBT without support is not beneficial for all individuals with depression [3898729] Background Depression and anxiety are major causes of absence from work and underperformance in the workplace . Cognitive behavioural therapy ( CBT ) can be effective in treating such problems and online versions offer many practical advantages . The aim of the study was to investigate the effectiveness of a computerized CBT intervention ( MoodGYM ) in a workplace context . Method The study was a phase III two-arm , parallel r and omized controlled trial whose main outcome was total score on the Work and Social Adjustment Scale ( WSAS ) . Depression , anxiety , psychological functioning , costs and acceptability of the online process were also measured . Most data were collected online for 637 participants at baseline , 359 at 6 weeks marking the end of the intervention and 251 participants at 12 weeks post-baseline . Results In both experimental and control groups depression scores improved over 6 weeks but attrition was high . There was no evidence for a difference in the average treatment effect of MoodGYM on the WSAS , nor for a difference in any of the secondary outcomes . Conclusions This study found no evidence that MoodGYM was superior to informational websites in terms of psychological outcomes or service use , although improvement to subthreshold levels of depression was seen in nearly half the patients in both groups [3792189] Objective . The main hypothesis , and the objective of the study , was to test if the participants allocated to the treatment group would show a larger reduction in depressive symptoms than those in the control group . Methods . This study was a r and omized nine week trial of an Internet-administered treatment based on guided physical exercise for Major Depressive Disorder ( MDD ) . A total of 48 participants with mild to moderate depression , diagnosed using the Structured Clinical Interview for DSM-IV Axis I Disorders , were r and omized either to a treatment intervention or to a waiting-list control group . The main outcome measure for depression was the Beck Depression Inventory-II ( BDI-II ) , and physical activity level was measured using the International Physical Activity Question naire ( IPAQ ) . The treatment program consisted of nine text modules , and included therapist guidance on a weekly basis . Results . The results showed significant reductions of depressive symptoms in the treatment group compared to the control group , with a moderate between-group effect size ( Cohen ’s d = 0.67 ; 95 % confidence interval : 0.09–1.25 ) . No difference was found between the groups with regards to increase of physical activity level . For the treatment group , the reduction in depressive symptoms persisted at six months follow-up . Conclusions . Physical activity as a treatment for depression can be delivered in the form of guided Internet-based self-help . Trial Registration . The trial was registered at Clinical Trials.gov ( NCT01573130 ) [1550641] Background Guided self-help programs for depression ( with associated therapist contact ) have been successfully delivered over the Internet . However , previous trials of pure self-help Internet programs for depression ( without therapist contact ) , including an earlier trial conducted by us , have failed to yield positive results . We hypothesized that methods to increase participant usage of the intervention , such as postcard or telephone reminders , might result in significant effects on depression . Objectives This paper presents a second r and omized trial of a pure self-help Internet site , ODIN ( Overcoming Depression on the InterNet ) , for adults with self-reported depression . We hypothesized that frequently reminded participants receiving the Internet program would report greater reduction in depression symptoms and greater improvements in mental and physical health functioning than a comparison group with usual treatment and no access to ODIN . Methods This was a three-arm r and omized control trial with a usual treatment control group and two ODIN intervention groups receiving reminders through postcards or brief telephone calls . The setting was a nonprofit health maintenance organization ( HMO ) . We mailed recruitment brochures by US post to two groups : adults ( n = 6030 ) who received depression medication or psychotherapy in the previous 30 days , and an age- and gender-matched group of adults ( n = 6021 ) who did not receive such services . At enrollment and at 5- , 10- and 16-weeks follow-up , participants were reminded by email ( and telephone , if nonresponsive ) to complete online versions of the Center for Epidemiological Studies Depression Scale ( CES-D ) and the Short Form 12 ( SF-12 ) . We also recorded participant HMO health care services utilization in the 12 months following study enrollment . Results Out of a recruitment pool of 12051 approached subjects , 255 persons accessed the Internet enrollment site , completed the online consent form , and were r and omized to one of the three groups : ( 1 ) treatment as usual control group without access to the ODIN website ( n = 100 ) , ( 2 ) ODIN program group with postcard reminders ( n = 75 ) , and ( 3 ) ODIN program group with telephone reminders ( n = 80 ) . Across all groups , follow-up completion rates were 64 % ( n = 164 ) at 5 weeks , 68 % ( n = 173 ) at 10 weeks , and 66 % ( n = 169 ) at 16 weeks . In an intention-to-treat analysis , intervention participants reported greater reductions in depression compared to the control group ( P = .03 ; effect size = 0.277 st and ard deviation units ) . A more pronounced effect was detected among participants who were more severely depressed at baseline ( P = .02 ; effect size = 0.537 st and ard deviation units ) . By the end of the study , 20 % more intervention participants moved from the disordered to normal range on the CES-D. We found no difference between the two intervention groups with different reminders in outcomes measures or in frequency of log-ons . We also found no significant intervention effects on the SF-12 or health care services . Conclusions In contrast to our earlier trial , in which participants were not reminded to use ODIN , in this trial we found a positive effect of the ODIN intervention compared to the control group . Future studies should address limitations of this trial , including relatively low enrollment and follow-up completion rates , and a restricted number of outcome measures . However , the low incremental costs of delivering this Internet program makes it feasible to offer this type of program to large population s with widespread Internet access [22663903] OBJECTIVE Develop and pilot an Internet-facilitated cognitive-behavioral treatment intervention for depression , tailored to economically disadvantaged mothers of young children . METHOD Mothers ( N = 70 ) of children enrolled in Head Start , who reported elevated levels of depressive symptoms , were r and omized to either the 8-session , Internet-facilitated intervention ( Mom-Net ) or delayed intervention/facilitated treatment-as-usual ( DI/TAU ) . Outcomes were measured using the Beck Depression Inventory ( BDI-II ; Beck , Steer , & Brown , 1996 ) ; the Patient Health Question naire 9 ( PHQ-9 ; Spitzer et al. , 1999 ) , Behavioral Observations of Parent-Child Interactions using the Living in Family Environments coding system ( LIFE ; Hops , Davis , & Longoria , 1995 ) ; the Dyadic Parent-Child Interaction Coding Systems ( DPICS ; Eyberg , Nelson , Duke , & Boggs , 2005 ) ; the Parent Behavior Inventory ( PBI ; Lovejoy , Weis , O'Hare , & Rubin , 1999 ) ; and the Parenting Sense of Competence scale ( PSOC ; Gibaud-Wallston & W and ersman , 1978 ) . RESULTS Mom-Net demonstrated high levels of feasibility as indicated by low attrition and high program usage and satisfaction ratings . Participants in the Mom-Net condition demonstrated significantly greater reduction in depression , the primary outcome , at the level of both symptoms and estimates of criteria -based diagnoses over the course of the intervention . They also demonstrated significantly greater improvement on a question naire measure of parent satisfaction and efficacy as well as on both question naire and observational indices of harsh parenting behavior . CONCLUSIONS Initial results suggest that the Mom-Net intervention is feasible and efficacious as a remotely delivered intervention for economically disadvantaged mothers [2762808] BACKGROUND Depression is associated with immense suffering and costs , and many patients receive inadequate care , often because of the limited availability of treatment . Web-based treatments may play an increasingly important role in closing this gap between dem and and supply . We developed the integrative , Web-based program Deprexis , which covers therapeutic approaches such as behavioral activation , cognitive restructuring , mindfulness/acceptance exercises , and social skills training . OBJECTIVE To evaluate the effectiveness of the Web-based intervention in a r and omized controlled trial . METHODS There were 396 adults recruited via Internet depression forums in Germany , and they were r and omly assigned in an 80:20 weighted r and omization sequence to either 9 weeks of immediate-program-access as an add-on to treatment-as-usual ( N = 320 ) , or to a 9-week delayed-access plus treatment-as-usual condition ( N = 76 ) . At pre- and post-treatment and 6-month follow-up , we measured depression ( Beck Depression Inventory ) as the primary outcome measure and social functioning ( Work and Social Adjustment Scale ) as the secondary outcome measure . Complete analyses and intention-to-treat analyses were performed . RESULTS Of 396 participants , 216 ( 55 % ) completed the post-measurement 9 weeks later . Available case analyses revealed a significant reduction in depression severity ( BDI ) , Cohen 's d = .64 ( CI 95 % = 0.33 - 0.94 ) , and significant improvement in social functioning ( WSA ) , Cohen 's d = .64 , 95 % ( CI 95 % = 0.33 - 0.95 ) . These improvements were maintained at 6-month follow-up . Intention-to-treat analyses confirmed significant effects on depression and social functioning improvements ( BDI : Cohen 's d = .30 , CI 95 % = 0.05 - 0.55 ; WSA : Cohen 's d = .36 , CI 95 % = 0.10 - 0.61 ) . Moreover , a much higher percentage of patients in the intervention group experienced a significant reduction of depression symptoms ( BDI : odds ratio [ OR ] = 6.8 , CI 95 % = 2.90 - 18.19 ) and recovered more often ( OR = 17.3 , 95 % CI 2.3 - 130 ) . More than 80 % of the users felt subjectively that the program had been helpful . CONCLUSIONS This integrative , Web-based intervention was effective in reducing symptoms of depression and in improving social functioning . Findings suggest that the program could serve as an adjunctive or st and -alone treatment tool for patients suffering from symptoms of depression [22177742] INTRODUCTION Although depression can be treated effectively with Cognitive Behaviour Therapy ( CBT ) , only a small percentage of Chinese Australians access evidence -based treatment due to practical and cultural barriers . The present study examined the efficacy and acceptability of an Internet delivered CBT ( iCBT ) program to treat Chinese Australians with depression . METHODS The Chinese depression iCBT program ( the Brighten Your Mood Program ) is a culturally adapted version of the clinical ly efficacious Sadness iCBT Program . Fifty-five Chinese Australians with depression were r and omly allocated to either an immediate treatment group or to a waitlist control group . Treatment consisted of an 8 week program with 6 CBT online educational lessons , homework assignments , additional re sources presented in Chinese and English , and weekly telephone support with M and arin/Cantonese-speaking support personnel . An intention-to-treat model was used for data analyses . RESULTS Seventeen of twenty-five ( 68 % ) treatment group participants completed all lessons within the timeframe . Compared to controls , treatment group participants reported significantly reduced symptoms of depression on the Chinese versions of the Beck Depression Inventory ( CBDI ) and Patient Health Question naire-9 item ( CB-PHQ-9 ) . The within- and between-group effect sizes ( Cohen 's d ) were 1.41 and 0.93 on the CBDI , and 0.90 and 0.50 on the CB-PHQ-9 , respectively . Participants rated the procedure as acceptable , and gains were sustained at three-month follow-up . LIMITATIONS The study included several sub clinical participants and some measures that have not been previously vali date d with Chinese Australians . CONCLUSIONS Results provide preliminary support for the efficacy and acceptability of an iCBT program at reducing symptoms of depression in Chinese Australians [9294380] BACKGROUND Previous studies in non clinical sample s have shown psychosocial treatments to be efficacious in the treatment of adolescent depression , but few psychotherapy treatment studies have been conducted in clinical ly referred , depressed adolescents . METHODS One hundred seven adolescent patients with DSM-III-R major depressive disorder ( MDD ) were r and omly assigned to 1 of 3 treatments : individual cognitive behavior therapy , systemic behavior family therapy ( SBFT ) , or individual nondirective supportive therapy ( NST ) . Treatments were 12 to 16 sessions provided in as many weeks . Intent-to-treat analyses were conducted using all follow-up data . RESULTS Of the 107 patients enrolled in the study , 78 ( 72.9 % ) completed the study , 4 ( 3.7 % ) never initiated treatment , 10 ( 9.3 % ) had exclusionary criteria that were undetected at entry , 8 ( 7.5 % ) dropped out , and 7 ( 6.5 % ) were removed for clinical reasons . Cognitive behavior therapy showed a lower rate of MDD at the end of treatment compared with NST ( 17.1 % vs 42.4 % ; P = .02 ) , and result ed in a higher rate of remission ( 64.7 % , defined as absence of MDD and at least 3 consecutive Beck Depression Inventory scores < 9 ) than SBFT ( 37.9 % ; P = .03 ) or NST ( 39.4 % ; p = .04 ) . Cognitive behavior therapy result ed in more rapid relief in interviewer-rated ( vs both treatments , P = .03 ) and self-reported depression ( vs SBFT , P = .02 ) . All 3 treatments showed significant and similar reductions in suicidality and functional impairment . Parents ' views of the credibility of cognitive behavior therapy improved compared with parents ' views of both SBFT ( P = .01 ) and NST ( P = .05 ) . CONCLUSIONS Cognitive behavior therapy is more efficacious than SBFT or NST for adolescent MDD in clinical setting s , result ing in more rapid and complete treatment response [20152960] Internet-delivered psychological treatment of major depression has been investigated in several trials , but the role of personalized treatment is less investigated . Studies suggest that guidance is important and that automated computerized programmes without therapist support are less effective . Individualized e-mail therapy for depression has not been studied in a controlled trial . Eighty-eight individuals with major depression were r and omized to two different forms of Internet-delivered cognitive behaviour therapy ( CBT ) , or to a waiting-list control group . One form of Internet treatment consisted of guided self-help , with weekly modules and homework assignments . St and ard CBT components were presented and brief support was provided during the treatment . The other group received e-mail therapy , which was tailored and did not use the self-help texts i.e. , all e-mails were written for the unique patient . Both treatments lasted for 8 weeks . In the guided self-help 93 % completed ( 27/29 ) and in the e-mail therapy 96 % ( 29/30 ) completed the posttreatment assessment . Results showed significant symptom reductions in both treatment groups with moderate to large effect sizes . At posttreatment 34.5 % of the guided self-help group and 30 % of the e-mail therapy group reached the criteria of high-end-state functioning ( Beck Depression Inventory score below 9 ) . At six-month follow-up the corresponding figures were 47.4 % and 43.3 % . Overall , the difference between guided self-help and e-mail therapy was small , but in favour of the latter . These findings indicate that both guided self-help and individualized e-mail therapy can be effective [3376511] Background Internet-delivered interventions can effectively change health risk behaviors and their determinants , but adherence to these interventions once they are accessed is very low . Therefore , it is relevant and necessary to systematic ally manipulate website characteristics to test their effect on website use . This study focuses on user control as a website characteristic . Objective To test whether and how user control ( the freedom of choice to skip pages ) can increase website use and knowledge gained from the website . Methods Participants older than 18 years were drawn from the Dutch Internet population ( in June 2011 ) and completed a hepatitis knowledge question naire . Subsequently , they were r and omly assigned to three groups : ( 1 ) a tunneled version of the website with less user control ; ( 2 ) a high user control version of the website where visitors had the freedom of choice to skip pages ; and ( 3 ) a control group that was not exposed to the website . Participants completed ( 1 ) a question naire of vali date d measures regarding user perceptions immediately after exposure to the website ( except for the control group ) , and ( 2 ) a hepatitis knowledge question naire after one week to test whether participants in the experimental groups only clicked through the website or actually processed and learned its content . Server registration s were used to assess website use . Analyses of covariance ( ANCOVA ) using all available data were conducted to determine whether user control increases website use . Structural equation models ( SEM ) using all available data were constructed to test how user control increases website use — a latent variable derived from number of pages visited and time on website . Results Of the 1044 persons invited to participate , 668 took part ( 668/1044 , 64.0 % ) . One half of participants ( 332/668 49.7 % ) were female and the mean age was 49 years ( SD 16 ) . A total of 571 participants completed the one-week follow-up measure regarding hepatitis knowledge ( 571/668 , 85.5 % ) . The findings demonstrate that having less user control ( ie , a tunneled version of the website ) had a negative effect on users ’ perception of efficiency ( F1,452 = 97.69 , P < .001 ) , but a positive effect on number of pages visited ( F1,452 = 171.49 , P < .001 ) , time on the website ( F1,452 = 6.32 , P = .01 ) , and knowledge gained from the website ( F1,452 = 134.32 , P < .001 ) . The direct effect of having less user control appeared to surpass the effect mediated by efficiency , because website use was higher among participants exposed to the tunneled version of the website in comparison with those having the freedom of choice to skip pages . Conclusions The key finding that visitors demonstrated increased website use in the tunneled version of the website indicates that visitors should be carefully guided through the intervention for future intervention websites [26523885] BACKGROUND Internet-delivered treatments for depression have proved successful , with supported programs offering the potential for improved adherence and outcomes . Internet interventions are particularly interesting in the context of increasing access to interventions , and delivering interventions population -wide . METHODS The study was a r and omized controlled trial of an 7-module internet-delivered cognitive behavioral therapy ( iCBT ) program for adults with depressive symptoms ( n = 96 ) compared to a waiting-list control group ( n = 92 ) . Participants received weekly support from a trained supporter . The primary outcome was depressive symptoms as measured by the Beck Depression Inventory ( BDI-II ) . The program was made available nationwide from an established and recognized charity for depression . RESULTS For the treatment group , post-treatment effect sizes reported were large for the primary outcome measure ( d = 0.91 ) . The between-group effects were moderate to large and statistically significant for the primary outcomes ( d = 0.50 ) favoring the treatment group . Gains were maintained at 6-month follow-up . CONCLUSION The study has demonstrated the efficacy of the internet-delivered Space from Depression treatment . Participants demonstrated reliable and statistically significant changes in symptoms from pre-to post-intervention . The study supports a model for delivering online depression interventions population -wide using trained supporters . TRIAL REGISTRATION NUMBER Current Controlled Trials IS RCT N03704676 . http://dx.doi.org/10.1186/IS RCT N03704676 [17950163] PURPOSE The Internet offers a potential medium for delivering smoking cessation treatment to adolescents . However , few Internet-based cessation programs for adolescents have been evaluated . We describe adolescent use of a home-based Internet intervention to stop smoking ( Stomp Out Smokes [ SOS ] ) and explore baseline characteristics associated with SOS use . METHODS Participants were 70 adolescent smokers aged 12 - 18 years ( 50 % female , 90 % Caucasian ) r and omized to receive the SOS intervention for 24 weeks as part of a larger clinical trial . SOS comprised 40 components , of which eight were primarily interactive ( e.g. , discussion support group , ask an expert , quit plan ) and 32 were primarily informational ( e.g. , managing withdrawal , medications to stop smoking ) . SOS use data were captured electronically , including total logins to the site , and type of SOS components used defined by page hits on the interactive and information components . RESULTS A total of 7,708 SOS website pages ( 6825 interactive and 883 informational ) were accessed over the 24 weeks . The highest proportion of page hits was for the discussion support group ( 35 % ) and quit plan ( 30 % ) . Interactive pages were significantly more likely to be used than informational pages ( median 65 vs. 6 , p < .001 ) . Males accessed fewer interactive pages compared with females ( p = .04 ) . No other baseline characteristics were univariately associated with total logins or use of informational or interactive pages . CONCLUSIONS Adolescent smokers most often used a discussion support group and other interactive Internet-based cessation components . Future studies design ed to increase adolescent use , and efficacy of , Internet-based cessation programs are warranted [3742404] Background Most patients with mild to moderate depression receive treatment in primary care , but despite guideline recommendations , structured psychological interventions are infrequently delivered . Research supports the effectiveness of Internet-based treatment for depression ; however , few trials have studied the effect of the MoodGYM program plus therapist support . The use of such interventions could improve the delivery of treatment in primary care . Objective To evaluate the effectiveness and acceptability of a guided Web-based intervention for mild to moderate depression , which could be suitable for implementation in general practice . Methods Participants ( N=106 ) aged between 18 and 65 years were recruited from primary care and r and omly allocated to a treatment condition comprising 6 weeks of therapist-assisted Web-based cognitive behavioral therapy ( CBT ) , or to a 6-week delayed treatment condition . The intervention included the Norwegian version of the MoodGYM program , brief face-to-face support from a psychologist , and reminder emails . The primary outcome measure , depression symptoms , was measured by the Beck Depression Inventory-II ( BDI-II ) . Secondary outcome measures included the Beck Anxiety Inventory ( BAI ) , the Hospital Anxiety and Depression Scale ( HADS ) , the Satisfaction with Life Scale ( SWLS ) , and the EuroQol Group 5-Dimension Self-Report Question naire ( EQ-5D ) . All outcomes were based on self-report and were assessed at baseline , postintervention , and at 6-month follow-up . Results Postintervention measures were completed by 37 ( 71 % ) and 47 ( 87 % ) of the 52 participants in the intervention and 54 participants in the delayed treatment group , respectively . Linear mixed-models analyses revealed a significant difference in time trends between the groups for the BDI-II , ( P=.002 ) , for HADS depression and anxiety subscales ( P<.001 and P=.001 , respectively ) , and for the SWLS ( P<.001 ) . No differential group effects were found for the BAI and the EQ-5D . In comparison to the control group , significantly more participants in the intervention group experienced recovery from depression as measured by the BDI-II . Of the 52 participants in the treatment program , 31 ( 60 % ) adhered to the program , and overall treatment satisfaction was high . The reduction of depression and anxiety symptoms was largely maintained at 6-month follow-up , and positive gains in life satisfaction were partly maintained . Conclusions The intervention combining MoodGYM and brief therapist support can be an effective treatment of depression in a sample of primary care patients . The intervention alleviates depressive symptoms and has a significant positive effect on anxiety symptoms and satisfaction with life . Moderate rates of nonadherence and predominately positive evaluations of the treatment also indicate the acceptability of the intervention . The intervention could potentially be used in a stepped-care approach , but remains to be tested in regular primary health care . Trial Registration Australian New Zeal and Clinical Trials Registry : ACTRN12610000257066 ; http://apps.who.int/trial search /trial.aspx?trialid = ACTRN12610000257066 ( Archived by WebCite at http://www.webcitation.org/6Ie3YhIZa ) [16971674] The aim of this study was to evaluate the effectiveness of a computer-tailored physical activity intervention delivered through the Internet in a real-life setting . Healthy adults ( n=526 ) , recruited in six worksites , between 25 and 55 years of age were r and omized to one of three conditions receiving , respectively , ( i ) online-tailored physical activity advice + stage-based reinforcement e-mails , ( ii ) online-tailored physical activity advice only , ( iii ) online non-tailored st and ard physical activity advice . At 6-month follow-up , no differences in physical activity between study conditions were found ; total physical activity , physical activity at moderate intensity and physical activity in leisure time significantly increased in all study conditions between baseline and follow-up . Further evaluation of the intervention material s showed that the tailored advice was more read , printed and discussed with others than the st and ard advice . Most of the respondents in the e-mail group indicated to be satisfied about the number , frequency and usefulness of the stage-based e-mails . In conclusion , although tailored advice was appreciated more than st and ard advice , no evidence was found that an online-tailored physical activity intervention program outperformed online st and ard information [4393573] Background Depression is a common comorbidity in individuals with cognitive impairment . Those with cognitive impairments face unique challenges in receiving the benefits of many conventional therapies for depression , and may have poorer outcomes in areas such as recovery and quality of life . However , the stigmatization of mental health disorders , cost barriers and physical disabilities may prevent these individuals from seeking mental health care . An online , self-help intervention specifically developed for adults with cognitive deficits and depression may be particularly beneficial to this population . We aim to inform the design of such an intervention through a systematic review by answering the following research question : among adults with cognitive impairment ( including those with acquired brain injuries or neurodegenerative diseases ) , which technology-amenable interventions have been shown to effectively decrease symptoms of depression ? Specifically , psychotherapeutic and /or behavioural interventions that could be delivered in a self-guided , online system will be included . Methods Comprehensive electronic search es will be conducted in MEDLINE , EMBASE , PsycINFO and CINAHL . Additional studies will be obtained through manually search ing the references of relevant systematic review s , contacting primary authors of select articles and tracking conference proceedings and trial registries . Article titles and abstract s will be screened using predefined eligibility criteria , and then judged for their amenability to the proposed self-help , technology-based intervention . The full text of those articles with selected interventions will then be screened to determine final eligibility for inclusion . Included articles will be categorized by intervention type and assessed for risk of bias using the Cochrane Effective Practice and Organization of Care Risk of Bias tool for non-r and omized trials , controlled before-after studies and interrupted time series . The primary outcome will be a change in score on a vali date d depression scale , and adverse events will be documented as a secondary outcome . After data extraction from selected articles , pooling of data and meta- analysis will be conducted if a sufficient pool of studies with comparable methodology and quality are identified . Alternatively , plain language summaries will be developed . The quality of evidence will be assessed using the Grading of Recommendations Assessment , Development and Evaluation ( GRADE ) system . Systematic review registration PROSPERO [18236303] The sizeable percentage of adults who use smokeless tobacco ( ST ) represents an important public health target since the majority of ST users have a strong desire to quit , but many lack re sources . We tested the impact of an interactive , tailored Web-based intervention ( Enhanced Condition ) versus a more linear , text-based website ( Basic Condition ) in a r and omized trial with 2523 adult ST users . As is common in Internet-based research , there was considerable attrition : follow-up rates at 3 months , 6 months , and for both 3 and 6 months were 48 % , 45 % and 34 % , respectively . Results using repeated point prevalence of all tobacco use at 3 and 6 months showed that participants in the Enhanced Condition quit at significantly higher rates than those in the Basic Condition . Using a Complete Case analysis , abstinence was 40.6 % in the Enhanced Condition vs. 21.2 % in the Basic Condition ( p < .001 ) . Using intent-to-treat analysis , quit rates were 12.6 % vs. 7.9 % , respectively ( p < .001 ) . Similar results were obtained for only ST use . Unobtrusive measures of program exposure indicated that program use was significantly related to outcome as well as to attrition . We conclude that a tailored , interactive Web-assisted cessation program can be an efficacious method for assisting adult ST users to quit [1550629] Background In r and omized controlled trials Internet sites have been shown to be effective in the treatment of depression and anxiety . However , it is unclear if the positive effects demonstrated in these trials transfer to community users of such sites . Objective To compare anxiety and depression outcomes for spontaneous visitors to a publicly accessible cognitive behavior therapy website ( MoodGYM ) ( http://moodgym.anu.edu.au ) with outcomes achieved through a r and omized controlled efficacy trial of the same site . Methods All community visitors to the MoodGYM site between April 2001 and September 2003 were sample d : 182 participants in the BlueMood Trial who had been r and omly assigned to the MoodGYM site as part of a large trial and 19607 visitors ( public registrants ) to the site . Symptom assessment s ( quizzes ) were repeated within the website intervention to allow the examination of change in symptoms across modules . Outcome variables were ( 1 ) age , gender , initial depression severity scores , and number of assessment s attempted , and ( 2 ) symptom change measures based on Goldberg anxiety and depression scores recorded on a least two occasions . Results Public registrants did not differ from trial participants in gender , age , or initial level of depression , which was high for both groups relative to previously published epidemiological data sets . Trial participants completed more assessment s. No significant differences in anxiety or depression change scores were observed , with both public registrants and trial participants improving through the training program . Conclusions Public registrants to a cognitive behavior therapy website show significant change in anxiety and depression symptoms . The extent of change does not differ from that exhibited by participants enrolled on the website for a r and omized controlled trial [21731830] OBJECTIVE The aim of this study was to examine the sensitivity and specificity of the suicide item on the 9-item Patient Health Question naire ( PHQ-9 ) when compared to a structured interview ( the Structured Clinical Interview for DSM-IV ; SCID-I mood module ) in primary care patients with elevated depression symptoms . METHOD In this cross-sectional study , we analyzed data from 166 patients from 2 primary care clinics , 1 in Rhode Isl and and 1 in Massachusetts , who were enrolled in studies that focused on depression in primary care . Of the total participants , 101 were enrolled in the survey study , and 65 were screened for or enrolled in either an open trial or a pilot r and omized controlled trial . Data were collected between May 2004 and May 2009 . RESULTS We found that the specificity of the PHQ-9 suicide screening item was 0.84 and sensitivity was 0.69 for the sample as a whole . CONCLUSIONS This study suggests that the routine use of the PHQ-9 may be useful in primary care practice in that it may identify individuals at risk for suicide who would not otherwise have been identified . However , denial of suicidality on the PHQ-9 should be probed further if there are other risk factors for suicide present . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00541957 [26453910] Introduction Help4Mood is an interactive system with an embodied virtual agent ( avatar ) to assist in self-monitoring of patients receiving treatment for depression . Help4Mood supports self-report and biometric monitoring and includes elements of cognitive behavioural therapy . We aim ed to evaluate system use and acceptability , to explore likely recruitment and retention rates in a clinical trial and to obtain an estimate of potential treatment response with a view to conducting a future r and omised controlled trial ( RCT ) . Methods We conducted a pilot RCT of Help4Mood in three centres , in Romania , Spain and Scotl and , UK . Patients with diagnosed depression ( major depressive disorder ) and current mild/moderate depressive symptoms were r and omised to use the system for four weeks in addition to treatment as usual ( TAU ) or to TAU alone . Results Twenty-seven individuals were r and omised and follow-up data were obtained from 21 participants ( 12/13 Help4Mood , 9/14 TAU ) . Half of participants r and omised to Help4Mood used it regularly ( more than 10 times ) ; none used it every day . Acceptability varied between users . Some valued the emotional responsiveness of the system , while others found it too repetitive . Intention to treat analysis showed a small difference in change of Beck Depression Inventory II ( BDI-2 ) scores ( Help4Mood –5.7 points , TAU –4.2 ) . Post-hoc on-treatment analysis suggested that participants who used Help4Mood regularly experienced a median change in BDI-2 of –8 points . Conclusion Help4Mood is acceptable to some patients receiving treatment for depression although none used it as regularly as intended . Changes in depression symptoms in individuals who used the system regularly reached potentially meaningful levels [26253644] Low-intensity interventions for people suffering from depressive symptoms are highly desirable . The aim of the present study was to investigate the outcomes of a web-based acceptance and commitment therapy (ACT)–based intervention without face-to-face contact for people suffering from depressive symptoms . Participants ( N = 39 ) with depressive symptoms were r and omly assigned to an Internet-delivered acceptance and commitment therapy ( iACT ) intervention or a waiting list control condition ( WLC ) . Participants were evaluated with st and ardized self-reporting measures ( Beck Depression Inventory [ BDI-II ] , Symptom Checklist–90 [ SCL-90 ] , Acceptance and Action Question naire [ AAQ-2 ] , Five Facet Mindfulness Question naire [ FFMQ ] , Automatic Thoughts Question naire [ ATQ ] , and White Bear Suppression Inventory [ WBSI ] ) at pre- and post-measurement . Long-term effects in the iACT group were examined using a 12-month follow-up . The iACT program comprised home assignments , online feedback given by master’s-level students of psychology over a 7-week intervention period , and automated email-based reminders . Significant effects were observed in favor of the iACT group on depression symptomatology ( between effect sizes [ ESs ] at post-treatment , iACT/WLC , g = .83 ) , psychological and physiological symptoms ( g = .60 ) , psychological flexibility ( g = .67 ) , mindfulness skills ( g = .53 ) , and frequency of automatic thoughts ( g = .57 ) as well as thought suppression ( g = .53 ) . The treatment effects in the iACT group were maintained over the 12-month follow-up period ( within-iACT ES : BDI-II , g = 1.33 ; SCL-90 , g = 1.04 ; ATQF/B [ Frequency/Believability ] , FFMQ , WBSI , AAQ-II , g = .74 - 1.08 ) . The iACT participants stated that they would be happy to recommend the same intervention to others with depressive symptoms . We conclude that an ACT-based guided Internet-delivered treatment with minimal contact can be effective for people with depressive symptoms [19207345] AIMS To evaluate computer- versus therapist-delivered psychological treatment for people with comorbid depression and alcohol/cannabis use problems . DESIGN R and omized controlled trial . SETTING Community-based participants in the Hunter Region of New South Wales , Australia . PARTICIPANTS Ninety-seven people with comorbid major depression and alcohol/cannabis misuse . INTERVENTION All participants received a brief intervention ( BI ) for depressive symptoms and substance misuse , followed by r and om assignment to : no further treatment ( BI alone ) ; or nine sessions of motivational interviewing and cognitive behaviour therapy ( intensive MI/CBT ) . Participants allocated to the intensive MI/CBT condition were selected at r and om to receive their treatment ' live ' ( i.e. delivered by a psychologist ) or via a computer-based program ( with brief weekly input from a psychologist ) . MEASUREMENTS Depression , alcohol/cannabis use and hazardous substance use index scores measured at baseline , and 3 , 6 and 12 months post-baseline assessment . FINDINGS ( i ) Depression responded better to intensive MI/CBT compared to BI alone , with ' live ' treatment demonstrating a strong short-term beneficial effect which was matched by computer-based treatment at 12-month follow-up ; ( ii ) problematic alcohol use responded well to BI alone and even better to the intensive MI/CBT intervention ; ( iii ) intensive MI/CBT was significantly better than BI alone in reducing cannabis use and hazardous substance use , with computer-based therapy showing the largest treatment effect . CONCLUSIONS Computer-based treatment , targeting both depression and substance use simultaneously , results in at least equivalent 12-month outcomes relative to a ' live ' intervention . For clinicians treating people with comorbid depression and alcohol problems , BIs addressing both issues appear to be an appropriate and efficacious treatment option . Primary care of those with comorbid depression and cannabis use problems could involve computer-based integrated interventions for depression and cannabis use , with brief regular contact with the clinician to check on progress [4260664] Depression presents a serious condition for the individual and a major challenge to health care and society . Internet-based cognitive behavior therapy ( ICBT ) is a treatment option supported in several trials , but there is as yet a lack of effective studies of ICBT in “ real world ” primary care setting s. We examined whether ICBT differed from treatment-as-usual ( TAU ) in reducing depressive symptoms after 3 months . TAU comprised of visits to general practitioner , registered nurse , antidepressant drugs , waiting list for , or psychotherapy , or combinations of these alternatives . Patients , aged ≥ 18 years , who tentatively met criteria for mild to moderate depression at 16 primary care centers in the south-western region of Sweden were recruited and then assessed in a diagnostic interview . A total of 90 patients were r and omized to either TAU or ICBT . The ICBT treatment included interactive elements online , a workbook , a CD with mindfulness and acceptance exercises , and minimal therapist contact . The treatment period lasted for 12 weeks after which both groups were assessed . The main outcome measure was Beck Depression Inventory-II ( BDI-II ) . Additional measures were Montgomery Åsberg Depression Rating Scale – self rating version ( MADRS-S ) and Beck Anxiety Inventory ( BAI ) . The analyses revealed no significant difference between the two groups at post treatment , neither on BDI-II , MADRS-S , nor BAI . Twenty patients ( 56 % ) in the ICBT treatment completed all seven modules . Our findings suggest that ICBT may be successfully delivered in primary care and that the effectiveness , after 3 months , is at par with TAU [4607393] Background Internet-delivered mental health ( eMental Health ) interventions produce treatment effects similar to those observed in face-to-face treatment . However , there is a large degree of variation in treatment effects observed from program to program , and eMental Health interventions remain somewhat of a black box in terms of the mechanisms by which they exert their therapeutic benefit . Trials of eMental Health interventions typically use large sample sizes and therefore provide an ideal context within which to systematic ally investigate the therapeutic benefit of specific program features . Furthermore , the growth and impact of mobile phone technology within eMental Health interventions provides an opportunity to examine associations between symptom improvement and the use of program features delivered across computer and mobile phone platforms . Objective The objective of this study was to identify the patterns of program usage associated with treatment outcome in a r and omized controlled trial ( RCT ) of a fully automated , mobile phone- and Web-based self-help program , “ myCompass ” , for individuals with mild-to-moderate symptoms of depression , anxiety , and /or stress . The core features of the program include interactive psychotherapy modules , a symptom tracking feature , short motivational messages , symptom tracking reminders , and a diary , with many of these features accessible via both computer and mobile phone . Methods Patterns of program usage were recorded for 231 participants with mild-to-moderate depression , anxiety , and /or stress , and who were r and omly allocated to receive access to myCompass for seven weeks during the RCT . Depression , anxiety , stress , and functional impairment were examined at baseline and at eight weeks . Results Log data indicated that the most commonly used components were the short motivational messages ( used by 68.4 % , 158/231 of participants ) and the symptom tracking feature ( used by 61.5 % , 142/231 of participants ) . Further , after controlling for baseline symptom severity , increased use of these alert features was associated with significant improvements in anxiety and functional impairment . Associations between use of symptom tracking reminders and improved treatment outcome remained significant after controlling for frequency of symptom tracking . Although correlations were not statistically significant , reminders received via SMS ( ie , text message ) were more strongly associated with symptom reduction than were reminders received via email . Conclusions These findings indicate that alerts may be an especially potent component of eMental Health interventions , both via their association with enhanced program usage , as well as independently . Although there was evidence of a stronger association between symptom improvement and use of alerts via the mobile phone platform , the degree of overlap between use of email and SMS alerts may have precluded identification of alert delivery modalities that were most strongly associated with symptom reduction . Future research using r and om assignment to computer and mobile delivery is needed to fully determine the most ideal platform for delivery of this and other features of online interventions . Trial Registration Australian New Zeal and Clinical Trials Registry ( ACTRN ) : 12610000625077 ; http://www.anzctr.org.au/Trial Search .aspx ? ( Archived by WebCite http://www.webcitation.org/6WPqHK0mQ ) [22390738] OBJECTIVES Underst and ing the gap between people 's intentions and actual health behavior is an important issue in health psychology . Our aim in this study was to investigate whether self-regulatory processes ( monitoring goal progress and responding to discrepancies ) mediate the intention-behavior relation in relation to HIV medication adherence ( Study 1 ) and intensive exercise behavior ( Study 2 ) . METHOD In Study 1 , question naire and electronically monitored adherence data were collected at baseline and 3 months later from patients in the control arm of an HIV-adherence intervention study . In Study 2 , question naire data was collected at 3 time points 6-weeks apart in a cohort study of physical activity . RESULTS Complete data at all time points were obtained from 51 HIV-infected patients and 499 intensive exercise participants . Intentions were good predictors of behavior and explained 25 to 30 % of the variance . Self-regulatory processes explained an additional 11 % ( Study 1 ) and 6 % ( Study 2 ) of variance in behavior on top of intentions . Regression and bootstrap analyses revealed at least partial , and possibly full , mediation of the intention-behavior relation by self-regulatory processes . CONCLUSIONS The present studies indicate that self-regulatory processes may explain how intentions drive behavior . Future tests , using different health behaviors and experimental design s , could firmly establish whether self-regulatory processes complement current health behavior theories and should become routine targets for intervention . ( PsycINFO Data base Record ( c ) 2012 APA , all rights reserved ) [3352859] Background and Aims Major depression can be treated by means of cognitive behavior therapy , delivered via the Internet as guided self-help . Individually tailored guided self-help treatments have shown promising results in the treatment of anxiety disorders . This r and omized controlled trial tested the efficacy of an Internet-based individually tailored guided self-help treatment which specifically targeted depression with comorbid symptoms . The treatment was compared both to st and ardized ( non-tailored ) Internet-based treatment and to an active control group in the form of a monitored online discussion group . Both guided self-help treatments were based on cognitive behavior therapy and lasted for 10 weeks . The discussion group consisted of weekly discussion themes related to depression and the treatment of depression . Methods A total of 121 participants with diagnosed major depressive disorder and with a range of comorbid symptoms were r and omized to three groups . The tailored treatment consisted of a prescribed set of modules targeting depression as well as comorbid problems . The st and ardized treatment was a previously tested guided self-help program for depression . Results From pre-treatment to post-treatment , both treatment groups improved on measures of depression , anxiety and quality of life . The results were maintained at a 6-month follow-up . Subgroup analyses showed that the tailored treatment was more effective than the st and ardized treatment among participants with higher levels of depression at baseline and more comorbidity , both in terms of reduction of depressive symptoms and on recovery rates . In the subgroup with lower baseline scores of depression , few differences were seen between treatments and the discussion group . Conclusions This study shows that tailored Internet-based treatment for depression is effective and that addressing comorbidity by tailoring may be one way of making guided self-help treatments more effective than st and ardized approaches in the treatment of more severe depression . Trial Registration Clinical trials.gov [3689826] Background Self-help or self-management strategies are commonly used to deal with depression , but not all are thought to be helpful . A previous study found that sub-threshold depression symptoms were improved by an e-mail intervention that encouraged the use of evidence -based self-help strategies . Aim To investigate whether these e-mails were effective for adults with a range of depression symptomatology including major depression . Method The study was a parallel-group r and omised controlled trial . Adult participants with any level of depressive symptoms were recruited over the internet from the United Kingdom , Australia , Canada , Irel and , New Zeal and and the United States . Participants were r and omised to receive a series of e-mails either promoting the use of evidence -based self-help strategies or containing depression information as a control . E-mails were sent automatically twice a week for six weeks . Depression symptoms were assessed with the self-rated Patient Health Question naire depression scale ( PHQ-9 ) . Results 1736 participants with a wide range of symptom severity were recruited and assigned to active ( n = 862 ) and control ( n = 874 ) groups . However , there was a significant attrition rate , with 66.9 % lost to follow-up at post-intervention . Both groups showed large improvements in depression symptoms overall , with no significant difference in improvement at the end of the study ( mean difference in improvement 0.35 points , 95 % CI : −0.57 to 1.28 , d = 0.11 , 95 % CI : −0.06 to 0.27 ) , although there was a small effect at the study mid-point . Results were similar for the sub-group of participants with major depression . The active group showed small to moderate improvements in self-help behaviour ( d = 0.40 , 95 % CI : 0.23 to 0.56 ) . Conclusions These results suggest that the e-mails were able to increase participants ’ use of evidence -based self-help , but that this did not improve depression more than an attention control . Clinical Trials.gov [3571935] Background This paper reports the results of a pilot r and omized controlled trial comparing the delivery modality ( mobile phone/tablet or fixed computer ) of a cognitive behavioural therapy intervention for the treatment of depression . The aim was to establish whether a previously vali date d computerized program ( The Sadness Program ) remained efficacious when delivered via a mobile application . Method 35 participants were recruited with Major Depression ( 80 % female ) and r and omly allocated to access the program using a mobile app ( on either a mobile phone or iPad ) or a computer . Participants completed 6 lessons , weekly homework assignments , and received weekly email contact from a clinical psychologist or psychiatrist until completion of lesson 2 . After lesson 2 email contact was only provided in response to participant request , or in response to a deterioration in psychological distress scores . The primary outcome measure was the Patient Health Question naire 9 ( PHQ-9 ) . Of the 35 participants recruited , 68.6 % completed 6 lessons and 65.7 % completed the 3-months follow up . Attrition was h and led using mixed-model repeated- measures ANOVA . Results Both the Mobile and Computer Groups were associated with statistically significantly benefits in the PHQ-9 at post-test . At 3 months follow up , the reduction seen for both groups remained significant . Conclusions These results provide evidence to indicate that delivering a CBT program using a mobile application , can result in clinical ly significant improvements in outcomes for patients with depression . Trial registration Australian New Zeal and Clinical Trials Registry ACTRN [4444307] Background There is need for more cost and time effective treatments for depression . This is the first r and omised controlled trial in which a blended treatment - including four face-to-face sessions and a smartphone application - was compared against a full behavioural treatment . Hence , the aim of the current paper was to examine whether a blended smartphone treatment was non-inferior to a full behavioural activation treatment for depression . Methods This was a r and omised controlled non-inferiority trial ( NCT01819025 ) comparing a blended treatment ( n=46 ) against a full ten-session treatment ( n=47 ) for people suffering from major depression . Primary outcome measure was the BDI-II , that was administered at pre- and post-treatment , as well as six months after the treatment . Results Results showed significant improvements in both groups across time on the primary outcome measure ( within-group Cohen ’s d=1.35 ; CI [ −0.82 , 3.52 ] to d=1.47 ; CI [ −0.41 , 3.35 ] ; between group d=−0.13 CI [ −2.37 , 2.09 ] and d=−0.10 CI [ −2.53 , 2.33 ] ) . At the same time , the blended treatment reduced the therapist time with an average of 47 % . Conclusions We could not establish whether the blended treatment was non-inferior to a full BA treatment . Nevertheless , this study points to that the blended treatment approach could possibly treat nearly twice as many patients suffering from depression by using a smartphone applica¬tion as add-on . More studies are needed before we can suggest that the blended treatment method is a promising cost-effective alternative to regular face-to-face treatment for depression . Trial Registration Cognitive Behavioral Therapy Treatment of Depression With Smartphone Support [22464008] BACKGROUND Mobile phone text message technology has the potential to improve outcomes for patients with depression and co-morbid Alcohol Use Disorder ( AUD ) . AIMS To perform a r and omised rater-blinded trial to explore the effects of supportive text messages on mood and abstinence outcomes for patients with depression and co-morbid AUD . METHODS Participants ( n=54 ) with a DSM IV diagnosis of unipolar depression and AUD who completed an in-patient dual diagnosis treatment programme were r and omised to receive twice daily supportive text messages ( n=26 ) or a fortnightly thank you text message ( n=28 ) for three months . Primary outcome measures were Beck 's Depression Inventory ( BDI-II ) scores and Cumulative Abstinence Duration ( CAD ) in days at three months . TRIAL REGISTRATION NCT0137868 . RESULTS There was a statistically significant difference in three month BDI-II scores between the intervention and control groups ; 8.5 ( SD=8.0 ) vs. 16.7 ( SD=10.3 ) respectively after adjusting for the baseline scores , F ( 1 , 49)=9.54 , p=0.003 , η(p)(2)=0.17 . The mean difference in change BDI-II scores was -7.9 ( 95 % CI -13.06 to -2.76 , Cohen'sd=0.85 ) . There was a trend for a greater CAD in the text message group than the control group : 88.3 ( SD=6.2 ) vs. 79.3 ( SD=24.1 ) , t=1.78 , df=48 , p=0.08 . LIMITATIONS Limitations of the study include the small sample size , the potential for loss of rater blinding and the lack of long term follow-up to determine the longer term effects of the intervention . CONCLUSION Supportive text messages have the potential to improve outcomes for patients with comorbid depression and alcohol dependency syndrome [19700005] BACKGROUND Despite strong evidence for its effectiveness , cognitive-behavioural therapy ( CBT ) remains difficult to access . Computerised programs have been developed to improve accessibility , but whether these interventions are responsive to individual needs is unknown . We investigated the effectiveness of CBT delivered online in real time by a therapist for patients with depression in primary care . METHODS In this multicentre , r and omised controlled trial , 297 individuals with a score of 14 or more on the Beck depression inventory ( BDI ) and a confirmed diagnosis of depression were recruited from 55 general practice s in Bristol , London , and Warwickshire , UK . Participants were r and omly assigned , by a computer-generated code , to online CBT in addition to usual care ( intervention ; n=149 ) or to usual care from their general practitioner while on an 8-month waiting list for online CBT ( control ; n=148 ) . Participants , research ers involved in recruitment , and therapists were masked in advance to allocation . The primary outcome was recovery from depression ( BDI score < 10 ) at 4 months . Analysis was by intention to treat . This trial is registered , number IS RCT N 45444578 . FINDINGS 113 participants in the intervention group and 97 in the control group completed 4-month follow-up . 43 ( 38 % ) patients recovered from depression ( BDI score < 10 ) in the intervention group versus 23 ( 24 % ) in the control group at 4 months ( odds ratio 2.39 , 95 % CI 1.23 - 4.67 ; p=0.011 ) , and 46 ( 42 % ) versus 26 ( 26 % ) at 8 months ( 2.07 , 1.11 - 3.87 ; p=0.023 ) . INTERPRETATION CBT seems to be effective when delivered online in real time by a therapist , with benefits maintained over 8 months . This method of delivery could broaden access to CBT . FUNDING BUPA Foundation [19508931] OBJECTIVE To investigate use and views of a Web site design ed for weight control . DESIGN Question naire-based evaluation with data collected at baseline , 6 months , and 12 months . SETTING Data were collected as part of a community-based , r and omized controlled trial . PARTICIPANTS Subjects ( n = 111 ) were participants of the intervention arm of a r and omized controlled trial evaluating effectiveness of a Web site design ed for weight control in an obese sample . INTERVENTION Participants were asked to use the intervention Web site for weight control over a 12-month period . MAIN OUTCOME MEASURE(S ) Participants were asked to report their use and views of the Web site . In addition , use of the Web site was automatically recorded on logging onto the Web site . ANALYSIS Descriptive statistics , factor analysis . RESULTS Fifty-nine participants ( 53 % ) reported using the Web site at 6 months , with 32 participants ( 29 % ) still using it at 12 months . The average time spent on the Web site per visit was 21.1 minutes ( SD = 16.6 ) at 6 months and 13.6 minutes ( SD = 9.3 ) at 12 months , with an average number of logons of 15.8 ( SD = 15.2 ) over the trial period . In general , satisfaction scores for the Web site were positive . Scores for ability of the re source to encourage positive behavior change for weight control were marginally negative . Social support sections of the Web site were used least and received the lowest satisfaction ratings . CONCLUSIONS AND IMPLICATION S Despite positive satisfaction scores , use of the re source was limited . It is expected that participants ' limited ability to use the Internet may have limited the use of the re source and consequently reduced the social support available to participants . Future investigation of the views and use patterns of current users of Internet-based weight loss re sources would help inform future development of such tools [23886401] BACKGROUND AND AIMS In the past decade , a large body of research has demonstrated that internet-based interventions can have beneficial effects on depression . However , only a few clinical trials have compared internet-based depression therapy with an equivalent face-to-face treatment . The primary aim of this study was to compare treatment outcomes of an internet-based intervention with a face-to-face intervention for depression in a r and omized non-inferiority trial . METHOD A total of 62 participants suffering from depression were r and omly assigned to the therapist-supported internet-based intervention group ( n=32 ) and to the face-to-face intervention ( n=30 ) . The 8 week interventions were based on cognitive-behavioral therapy principles . Patients in both groups received the same treatment modules in the same chronological order and time-frame . Primary outcome measure was the Beck Depression Inventory-II ( BDI-II ) ; secondary outcome variables were suicidal ideation , anxiety , hopelessness and automatic thoughts . RESULTS The intention-to-treat analysis yielded no significant between-group difference ( online vs. face-to-face group ) for any of the pre- to post-treatment measurements . At post-treatment both treatment conditions revealed significant symptom changes compared to before the intervention . Within group effect sizes for depression in the online group ( d=1.27 ) and the face-to-face group ( d=1.37 ) can be considered large . At 3-month follow-up , results in the online group remained stable . In contrast to this , participants in the face-to-face group showed significantly worsened depressive symptoms three months after termination of treatment ( t=-2.05 , df=19 , p<.05 ) . LIMITATIONS Due to the small sample size , it will be important to evaluate these outcomes in adequately-powered trials . CONCLUSIONS This study shows that an internet-based intervention for depression is equally beneficial to regular face-to-face therapy . However , more long term efficacy , indicated by continued symptom reduction three months after treatment , could be only be found for the online group [2483918] Background People with chronic obstructive pulmonary disease ( COPD ) continue to experience dyspnea with activities of daily living ( ADL ) despite optimal medical management . Information and communication technologies may facilitate collaborative symptom management and could potentially increase the reach of such interventions to those who are unable to attend face-to-face pulmonary rehabilitation or self-management programs . Objective The purpose of this r and omized study was to test the efficacy of two 6-month dyspnea self-management programs , Internet-based ( eDSMP ) and face-to-face ( fDSMP ) , on dyspnea with ADL in people living with COPD . Methods We r and omly assigned 50 participants with moderate to severe COPD who were current Internet users to either the eDSMP ( n = 26 ) or fDSMP ( n = 24 ) group . The content of the two programs was similar , focusing on education , skills training , and ongoing support for dyspnea self-management , including independent exercise . The only difference was the mode ( Internet/personal digital assistant [ PDA ] or face-to-face ) in which the education sessions , reinforcement contacts , and peer interactions took place . Participants returned to one of two academic clinical sites for evaluation at 3 and 6 months . The primary outcome of dyspnea with ADL was measured with the Chronic Respiratory Question naire . Secondary outcomes of exercise behavior , exercise performance , COPD exacerbations , and mediators , such as self-efficacy and social support , were also measured . A satisfaction survey was administered and a semistructured exit interview was conducted at the final visit . Results The study was stopped early due to multiple technical challenges with the eDSMP , but follow-up was completed on all enrolled participants . Data were available for 39 participants who completed the study ( female : 44 % ; age : 69.5 ± 8.5 years ; percent predicted forced expiratory volume in 1 s : 49.6 ± 17.0 % ) . The fDSMP and eDSMP showed similar clinical ly meaningful changes in dyspnea with ADL from baseline to 3 months ( fDSMP : + 3.3 points ; eDSMP : + 3.5 points ) and sustained these improvements at 6 months ( fDSMP : + 4.0 points ; eDSMP : + 2.5 points ; time effects P < .001 ; group by time P = .51 ) . Self-reported endurance exercise time ( P = .001 ) , physical functioning ( P = .04 ) , and self-efficacy for managing dyspnea ( P = .02 ) also showed positive improvements over time in both groups with no significant differences with respect to program modality . Participants who completed the study reported favorable satisfaction with the programs . Conclusions Although there were numerous technical challenges with the eDSMP , both dyspnea self-management programs were effective in reducing dyspnea with ADL in the short term . Our findings will need to be confirmed in a larger r and omized trial with more mature Web and personal digital assistant tools , use of a control group , and longer follow-up . Trial registration clinical trials.gov NCT00102401 , [2882336] Background Internet-based cognitive behavioural therapy ( iCBT ) for depression is effective when guided by a clinician , less so if unguided . Question : Would guidance from a technician be as effective as guidance from a clinician ? Method R and omized controlled non-inferiority trial comparing three groups : Clinician-assisted vs. technician-assisted vs. delayed treatment . Community-based volunteers applied to the VirtualClinic ( www.virtualclinic.org.au ) research program , and 141 participants with major depressive disorder were r and omized . Participants in the clinician- and technician-assisted groups received access to an iCBT program for depression comprising 6 online lessons , weekly homework assignments , and weekly supportive contact over a treatment period of 8 weeks . Participants in the clinician-assisted group also received access to a moderated online discussion forum . The main outcome measures were the Beck Depression Inventory ( BDI-II ) and the Patient Health Question naire-9 Item ( PHQ-9 ) . Completion rates were high , and at post-treatment , both treatment groups reduced scores on the BDI-II ( p<0.001 ) and PHQ-9 ( p<0.001 ) compared to the delayed treatment group but did not differ from each other . Within group effect sizes on the BDI-II were 1.27 and 1.20 for the clinician- and technician-assisted groups respectively , and on the PHQ-9 , were 1.54 and 1.60 respectively . At 4-month follow-up participants in the technician group had made further improvements and had significantly lower scores on the PHQ-9 than those in the clinician group . A total of approximately 60 minutes of clinician or technician time was required per participant during the 8-week treatment program . Conclusions Both clinician- and technician-assisted treatment result ed in large effect sizes and clinical ly significant improvements comparable to those associated with face-to-face treatment , while a delayed treatment control group did not improve . These results provide support for large scale trials to determine the clinical effectiveness and acceptability of technician-assisted iCBT programs for depression . This form of treatment has potential to increase the capacity of existing mental health services . Trial Registration Australian New Zeal and Clinical Trials Registry [25645168] UNLABELLED Depression is a common and significant health problem among older adults . Unfortunately , while effective psychological treatments exist , few older adults access treatment . The aim of the present r and omized controlled trial ( RCT ) was to examine the efficacy , long-term outcomes , and cost-effectiveness of a therapist-guided internet-delivered cognitive behavior therapy ( iCBT ) intervention for Australian adults over 60 years of age with symptoms of depression . Participants were r and omly allocated to either a treatment group ( n=29 ) or a delayed-treatment waitlist control group ( n=25 ) . Twenty-seven treatment group participants started the iCBT treatment and 70 % completed the treatment within the 8-week course , with 85 % of participants providing data at posttreatment . Treatment comprised an online 5-lesson iCBT course with brief weekly contact with a clinical psychologist , delivered over 8 weeks . The primary outcome measure was the Patient Health Question naire-9 Item ( PHQ-9 ) , a measure of symptoms and severity of depression . Significantly lower scores on the PHQ-9 ( Cohen 's d=2.08 ; 95 % CI : 1.38 - 2.72 ) and on a measure of anxiety ( Generalized Anxiety Disorder-7 Item ) ( Cohen 's d=1.22 ; 95 % CI : 0.61 - 1.79 ) were observed in the treatment group compared to the control group at posttreatment . The treatment group maintained these lower scores at the 3-month and 12-month follow-up time points and the iCBT treatment was rated as acceptable by participants . The treatment group had slightly higher Quality -Adjusted Life-Years ( QALYs ) than the control group at posttreatment ( estimate : 0.012 ; 95 % CI : 0.004 to 0.020 ) and , while being a higher cost ( estimate $ 52.9l 95 % CI : -23.8 to 128.2 ) , the intervention was cost-effective according to commonly used willingness-to-pay thresholds in Australia . The results support the potential efficacy and cost-effectiveness of therapist-guided iCBT as a treatment for older adults with symptoms of depression . TRIAL REGISTRATION Australian and New Zeal and Clinical Trials Registry : ACTRN12611000927921 ; https://www.anzctr.org.au/Trial/ Registration /Trial Review .aspx?id=343384 [25127179] The aim of the present study was to investigate two interventions based on Acceptance and Commitment Therapy ( ACT ) for depressive symptoms : A face-to-face treatment ( ACT group ) was compared to a guided self-help treatment delivered via the Internet consisting of two assessment sessions ( pre and post ) and an ACT-based Internet program ( iACT ) . Out patients experiencing at least mild depressive symptoms were r and omized to either approach . The iACT treatment group received access to an ACT-based Internet program and supportive web-based contact over a period of 6 weeks . The face-to-face group received ACT-based treatment once a week over the same period of time . In both groups , the results showed a significant effect on depression symptomatology , and general wellbeing after treatment and at the 18-month follow-up . However , the data indicated that the iACT group changed differently regarding depressive symptoms and wellbeing as compared to the face-to face ACT group . Results showed large pre-treatment to 18-month follow-up within-group effect sizes for all symptom measures in the iACT treatment group ( 1.59 - 2.08 ) , and for most outcome measures in the face-to-face ACT group ( 1.12 - 1.37 ) . This non-inferiority study provides evidence that guided Internet-delivered ACT intervention can be as effective as ACT-based face-to-face treatment for out patients reporting depressive symptoms , and it may offer some advantages over a face-to-face intervention [18576310] OBJECTIVE To determine the efficacy of an Internet-based Arthritis Self-Management Program ( ASMP ) as a re source for arthritis patients unable or unwilling to attend small-group ASMPs , which have proven effective in changing health-related behaviors and improving health status measures . METHODS R and omized intervention participants were compared with usual care controls at 6 months and 1 year using repeated- measures analyses of variance . Patients with rheumatoid arthritis , osteoarthritis , or fibromyalgia and Internet and e-mail access ( n = 855 ) were r and omized to an intervention ( n = 433 ) or usual care control ( n = 422 ) group . Measures included 6 health status variables ( pain , fatigue , activity limitation , health distress , disability , and self-reported global health ) , 4 health behaviors ( aerobic exercise , stretching and strengthening exercise , practice of stress management , and communication with physicians ) , 5 utilization variables ( physician visits , emergency room visits , chiropractic visits , physical therapist visits , and nights in hospital ) , and self-efficacy . RESULTS At 1 year , the intervention group significantly improved in 4 of 6 health status measures and self-efficacy . No significant differences in health behaviors or health care utilization were found . CONCLUSION The Internet-based ASMP proved effective in improving health status measures at 1 year and is a viable alternative to the small-group ASMP [24035673] BACKGROUND Guided internet-delivered cognitive behaviour therapy ( ICBT ) has been found to be effective in the treatment of mild to moderate depression , but there have been no direct comparisons with the more established group-based CBT with a long-term follow-up . METHOD Participants with mild to moderate depression were recruited from the general population and r and omized to either guided ICBT ( n=33 ) or to live group treatment ( n=36 ) . Measures were completed before and after the intervention to assess depression , anxiety , and quality of life . Follow-ups were conducted at one-year and three-year after the treatment had ended . RESULTS Data were analysed on an intention-to-treat basis using linear mixed-effects regression analysis . Results on the self-rated version of the Montgomery-Åsberg Depression Scale showed significant improvements in both groups across time indicating non-inferiority of guided ICBT , and there was even a tendency for the guided ICBT group to be superior to group-based CBT at three year follow-up . Within-group effect sizes for the ICBT condition at post-treatment showed a Cohen 's d=1.46 , with a similar large effect at 3-year follow-up , d=1.78 . For the group CBT the corresponding within-group effects were d=0.99 and d=1.34 , respectively . LIMITATIONS The study was small with two active treatments and there was no placebo or credible control condition . CONCLUSIONS Guided ICBT is at least as effective as group-based CBT and long-term effects can be sustained up to 3 years after treatment [19028519] OBJECTIVE To evaluate the use of a local neighborhood environment-focused physical activity website and its effects on walking and overall physical activity in middle-aged adults . METHOD One-hundred and six ( 72 % women ) inactive adults aged 52+/-4.6 years were r and omly allocated to receive access to a neighborhood environment-focused website , ( Neighborhood group , n=52 ) or a motivational-information website ( Comparison group n=54 ) . Participants also received eleven emails over the 26 weeks . Study outcomes were objective ly-monitored website use , and self-reported total walking ( min/wk ) , total physical activity ( min/wk ) and neighborhood walking ( min/wk ) collected at baseline , 12 and 26 weeks . The study was conducted between August 2005 and February 2006 in Brisbane , Australia . RESULTS Website use was significantly greater among Neighborhood participants ( p=0.01 ) . Statistically significant increases in walking and total physical activity were observed in both groups . There was also a statistically significant interaction effect for total physical activity , with Neighborhood group participants maintaining more of their initial increase in physical activity at week-26 ( p<0.05 ) . Further , those in the Neighborhood group who used the website more often reported significantly more walking along the community trail at week-26 ( p=0.05 ) compared with those who did not . CONCLUSIONS A local neighborhood-environment focused physical activity website was more effective at engaging participants than a motivational-information website . Moreover , its use result ed in meaningful increases in physical activity relative to the comparison website [20560847] Objective : To determine the efficacy of an Internet-based clinician-assisted cognitive behavioural treatment program ( the Panic program ) for panic disorder ( with or without agoraphobia ) . Method : Fifty-nine individuals meeting diagnostic criteria for panic disorder with agoraphobia were r and omly assigned to a treatment group or to a waitlist control group . Treatment group participants completed the Panic program , comprising six on-line lessons , weekly homework assignments , received weekly email contact from a psychiatry registrar , and contributed to a moderated online discussion forum with other participants . An intention-to-treat model was used for data analyses . Results : Twenty-three ( 79 % ) of treatment group participants completed all lessons within the 8-week program , and post-treatment data were collected from 22/29 treatment group and 22/25 waitlist group participants . Compared to the control group , treatment group participants reported significantly reduced symptoms of panic as measured by the Panic Disorder Severity Scale , Body Sensation Question naire , and Agoraphobic Cognitions Question naires . Significant reductions were also reported on measures of disability and depression . The mean within- and between-group effect size ( Cohen 's d ) on the Panic Disorder Severity Scale was 0.93 and 0.59 , respectively , and effects were sustained at 1-month follow-up . Mean therapist time per participant was 75 minutes for the program . Conclusions : These results replicate those from the open trial of the Panic Program indicating the efficacy of the Internet-based clinician-assisted cognitive behavioural treatment program for panic disorder with agoraphobia [21401534] Holländare F , Johnsson S , R and estad M , Tillfors M , Carlbring P , And ersson G , Engström I. R and omized trial of Internet‐based relapse prevention for partially remitted depression [22788983] Life- review therapy has been recognized as an effective therapeutic approach for depression in older adults . Additionally , the use of new media is becoming increasingly common in psychological interventions . The aim of this study was to investigate a life- review therapy in a face-to-face setting with additional computer use . This study explored whether a six-week life- review therapy with computer supplements from the e-mental health Butler system constitutes an effective approach to treat depression in older adults aged 65 and over . A total of 36 participants with elevated levels of depressive symptoms were r and omized to a treatment group or a waiting-list control group and completed the post- assessment . Fourteen individuals in the intervention group completed the follow-up assessment . Analyses revealed significant changes from pre- to post-treatment or follow-up for depression , well-being , self-esteem , and obsessive reminiscence , but not for integrative reminiscence and life satisfaction . Depressive symptoms decreased significantly over time until the three-month follow-up in the intervention group compared to the control group ( pre to post : d = 1.13 ; pre to follow-up : d = 1.27 ; and group × time effect pre to post : d = 0.72 ) . Furthermore , the therapy led to an increase in well-being and a decrease in obsessive reminiscence among the participants in the intervention group from pre-treatment to follow-up ( well-being : d = 0.70 ; obsessive reminiscence : d = 0.93 ) . Analyses further revealed a significant but small group × time effect regarding self-esteem ( d = 0.19 ) . By and large , the results indicate that the life- review therapy in this combined setting could be recommended for depressive older adults [10710839] The bidirectional causal relationships between psychotherapy homework ( HW ) compliance and changes in depression were assessed in 2 groups of depressed out patients treated with cognitive-behavioral therapy using nonrecursive structural equation modeling techniques . The data were consistent with the hypothesis that HW compliance had a causal effect on changes in depression , and the magnitude of this effect was large . Patients who did the most HW improved much more than patients who did little or no HW . In contrast , depression severity did not appear to influence HW compliance . HW compliance did not appear to be a proxy for any other , unobserved ( 3rd ) variable , such as motivation . Although the causal effect of HW on depression was large , the correlation between HW and depression was small . Some possible explanations , along with suggestions for future studies , are proposed [21679925] Disorder-specific cognitive behavioural therapy programs delivered over the internet ( iCBT ) with clinician guidance are effective at treating specific anxiety disorders and depression . The present study examined the efficacy of a transdiagnostic iCBT protocol to treat three anxiety disorders and /or depression within the same program ( the Wellbeing Program ) . Seventy-seven individuals with a principal diagnosis of major depression , generalised anxiety disorder , panic disorder , and /or social phobia were r and omly assigned to a Treatment or Waitlist Control group . Treatment consisted of CBT-based online educational lessons and homework assignments , weekly email or telephone contact from a clinical psychologist , access to a moderated online discussion forum , and automated emails . Eighty one percent of Treatment group participants completed all 8 lessons within the 10 week program . Post-treatment data were collected from 34/37 Treatment group and 35/37 Control group participants , and 3-month follow-up data were collected from 32/37 Treatment group participants . Relative to Controls , Treatment group participants reported significantly reduced symptoms of anxiety and depression as measured by the Depression Anxiety and Stress Scales-21 item , Patient Health Question naire-9 item , and Generalised Anxiety Disorder-7 item scales , with corresponding between-groups effect sizes ( Cohen 's d ) at post treatment of.56,.58 , and .52 , respectively . The clinician spent a mean time of 84.76 min ( SD=50.37 ) per person over the program . Participants rated the procedure as highly acceptable , and gains were sustained at follow-up . These results provide preliminary support for the efficacy of transdiagnostic iCBT in the treatment of anxiety and depressive disorders [26422822] Disorder-specific cognitive behavior therapy ( DS-CBT ) is effective at treating major depressive disorder ( MDD ) while transdiagnostic CBT ( TD-CBT ) addresses both principal and comorbid disorders by targeting underlying and common symptoms . The relative benefits of these two models of therapy have not been determined . Participants with MDD ( n=290 ) were r and omly allocated to receive an internet delivered TD-CBT or DS-CBT intervention delivered in either clinician-guided ( CG-CBT ) or self-guided ( SG-CBT ) formats . Large reductions in symptoms of MDD ( Cohen 's d≥1.44 ; avg . reduction≥45 % ) and moderate-to-large reductions in symptoms of comorbid generalised anxiety disorder ( Cohen 's d≥1.08 ; avg . reduction≥43 % ) , social anxiety disorder ( Cohen 's d≥0.65 ; avg . reduction≥29 % ) and panic disorder ( Cohen 's d≥0.45 ; avg . reduction≥31 % ) were found . No marked or consistent differences were observed across the four conditions , highlighting the efficacy of different forms of CBT at treating MDD and comorbid disorders [3701078] Background Depression and anxiety are common , disabling and chronic . Self-guided internet-delivered treatments are popular , but few people complete them . New strategies are required to realise their potential . Aims To evaluate the effect of automated emails on the effectiveness , safety , and acceptability of a new automated transdiagnostic self-guided internet-delivered treatment , the Wellbeing Course , for people with depression and anxiety . Method A r and omised controlled trial was conducted through the website : www.ecentreclinic.org . Two hundred and fifty seven people with elevated symptoms were r and omly allocated to the 8 week course either with or without automated emails , or to a waitlist control group . Primary outcome measures were the Patient Health Question naire 9-Item ( PHQ-9 ) and the Generalized Anxiety Disorder 7-Item ( GAD-7 ) . Results Participants in the treatment groups had lower PHQ-9 and GAD-7 scores at post-treatment than controls . Automated emails increased rates of course completion ( 58 % vs. 35 % ) , and improved outcomes in a sub sample with elevated symptoms . Conclusions The new self-guided course was beneficial , and automated emails facilitated outcomes . Further attention to strategies that facilitate adherence , learning , and safety will help realise the potential of self-guided interventions . Trial Registration Australian and New Zeal and Clinical Trials Registry [23357657] BACKGROUND Internet-based cognitive behavior therapy for depression has been tested in several trials but there are no internet studies on behavioral activation ( BA ) , and no studies on BA over the internet including components of acceptance and commitment therapy ( ACT ) . The aim of this study was to develop and test the effects of internet-delivered BA combined with ACT against a waiting list control condition as a first test of the effects of treatment . METHODS Selection took place with a computerized screening interview and a subsequent semi-structured telephone interview . A total of 80 individuals from the general public were r and omized to one of two conditions . The treatment lasted for 8 weeks after which both groups were assessed . We also included a 3 month follow-up . The treatment included interactive elements online and a CD-ROM for mindfulness and acceptance exercises . In addition , written support and feedback was given by a therapist every week . RESULTS Results at posttreatment showed a large between group effect size on the Beck Depression inventory II d=0.98 ( 95%CI=0.51 - 1.44 ) . In the treated group 25 % ( 10/40 ) reached remission defined as a BDI score ≤ 10 vs. 5 % ( 2/40 ) in the control group . Results on secondary measures were smaller . While few dropped out from the study ( N=2 ) at posttreatment , the average number of completed modules was M=5.1 out of the seven modules . LIMITATIONS The study only included a waiting-list comparison and it is not possible to determine which treatment components were the most effective . CONCLUSIONS We conclude that there is initial evidence that BA with components of ACT can be effective in reducing symptoms of depression [19221919] Depression is common but undertreated . Web-based self-help provides a widely accessible treatment alternative for mild to moderate depression . However , the lack of therapist guidance may limit its efficacy . The authors assess the efficacy of therapist-guided web-based cognitive behavioural treatment ( web-CBT ) of mild to moderate depression . Fifty-four individuals with chronic , moderate depression participated in a r and omized wait-list controlled trial , with an 18-month follow-up ( immediate treatment : n = 36 , wait-list control : n = 18 ) . Primary outcome measures were the Beck Depression Inventory ( BDI-IA ) and the Depression scale of the Symptom Checklist-90-Revised ( SCL-90-R. DEP ) . Secondary outcome measures were the Depression Anxiety Stress Scales and the Well-Being Question naire . Five participants ( 9 % ) dropped out . Intention-to-treat analyses of covariance revealed that participants in the treatment condition improved significantly more than those in the wait-list control condition ( .011 < p < .015 ) . With regard to the primary measures , between-group effects ( d ) were 0.7 for the BDI-IA and 1.1 for the SCL-90-R DEP . Posttest SCL-90- R DEP scores indicated recovery of 49 % of the participants in the treatment group compared with 6 % in the control group ( odds ratio = 14.5 ; p < .004 ) . On average , the effects were stable up to 18 months ( n = 39 ) , although medication was a strong predictor of relapse . The results demonstrate the efficacy of web-CBT for mild to moderate depression and the importance of therapist guidance in psychological interventions [23419552] BACKGROUND Major depressive disorder ( MDD ) and generalized anxiety disorder ( GAD ) have the highest co-morbidity rates within the internalizing disorders cluster , yet no Internet-based cognitive behavioural therapy ( iCBT ) programme exists for their combined treatment . METHOD We design ed a six-lesson therapist-assisted iCBT programme for mixed anxiety and depression . Study 1 was a r and omized controlled trial ( RCT ) comparing the iCBT programme ( n = 46 ) versus wait-list control ( WLC ; n = 53 ) for patients diagnosed by structured clinical interview with MDD , GAD or co-morbid GAD/MDD . Primary outcome measures were the Patient Health Question naire nine-item scale ( depression ) , Generalized Anxiety Disorder seven-item scale ( generalized anxiety ) , Kessler 10-item Psychological Distress scale ( distress ) and 12-item World Health Organization Disability Assessment Schedule II ( disability ) . The iCBT group was followed up at 3 months post-treatment . In study 2 , we investigated the adherence to , and efficacy of the same programme in a primary care setting , where patients ( n = 136 ) completed the programme under the supervision of primary care clinicians . RESULTS The RCT showed that the iCBT programme was more effective than WLC , with large within- and between-groups effect sizes found ( > 0.8 ) . Adherence was also high ( 89 % ) , and gains were maintained at 3-month follow-up . In study 2 in primary care , adherence to the iCBT programme was low ( 41 % ) , yet effect sizes were large ( > 0.8 ) . Of the non-completers , 30 % experienced benefit . CONCLUSIONS Together , the results show that iCBT is effective and adherence is high in research setting s , but there is a problem of adherence when translated into the ' real world ' . Future efforts need to be placed on developing improved adherence to iCBT in primary care setting Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Self-management education programmes are complex interventions specifically targeted at patient education and behaviour modification . They are design ed to encourage people with chronic disease to take an active self-management role to supplement medical care and improve outcomes . OBJECTIVES To assess the effectiveness of self-management education programmes for people with osteoarthritis . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

21531533

[12538202] Minute sphere acupressure has been used for more than 2000 yr and remains popular in Japan . The points most relevant to abdominal surgery are those associated with meridian flows crossing or originating in the abdomen . We tested the hypothesis that minute sphere therapy reduces pain and analgesic requirements after open abdominal surgery . Participating patients were given st and ardized desflurane and fentanyl anesthetic . On completion of surgery , they were r and omly assigned to untreated control or minute sphere acupressure at the Neiguan , Zusanli , Sanyinjiao , and Gongsun points . Each site was covered with bulky gauze dressings so that patients could not determine their assignments . Postoperative pain was treated with IV morphine via a patient-controlled analgesia pump . Our primary a priori end-points were pain and opioid consumption on the first postoperative morning . Data are reported as median ( 25th percentile , 75th percentile ) . Fifty-three patients ( 30 controls and 23 minute spheres ) completed the study . Morphine requirements ( 47 mg [ 27 , 58 ] vs 41 mg [ 25 , 69 ] ) and pain scores ( 29.5 mm [ 16 , 59 ] vs 40 mm [ 22 , 58 ] ) were similar in the control and acupressure groups . These data provide an 80 % power for detecting a 50 % difference in morphine consumption at an alpha of 0.05 . Minute sphere treatment at the Neiguan , Zusanli , Sanyinjiao , and Gongsun points thus failed to provide analgesia after abdominal surgery . Minute sphere therapy is a form of acupuncture . We tested whether minute spheres placed on three acupressure points relevant to abdominal surgery reduced pain and morphine requirements after abdominal surgery . Treatment and control patients received a similar covering . Neither pain nor morphine requirements were different between the groups [17318558] Objective To compare the effectiveness of acupressure and vitamin B6 in the outpatient treatment of nausea and vomiting in early pregnancy . Study design Pregnant volunteers with symptoms of mild to moderate nausea and vomiting between 6 and 12 weeks ’ gestation participated in a 7-day clinical trial . Participants were r and omly assigned to receive a device for acupressure therapy and placebo drug or an otherwise identical but non-stimulating placebo device and vitamin B6 . The primary outcome measure was self-recorded symptoms according to Rhodes index . Secondary outcome measures were weight gain and medication use . Results The mean change in Rhodes index was not significantly different between the two groups . There were no statistically significant differences in weight gain and medication use between the two groups . Conclusion Acupressure therapy is not more effective than vitamin B6 in reducing nausea and vomiting in symptomatic women in the first trimester of pregnancy [17388769] OBJECTIVES The onset of depression is often triggered by breathlessness in persons with chronic obstructive pulmonary disease ( COPD ) . It is hypothesized that these are the psychologic consequences of chronic dyspnea . Lessening dyspnea might alleviate depressive symptoms . Acupressure has been shown in other studies to produce relaxation . The aim of this study was to determine if it would lessen dyspnea and reduce depression in patients with COPD . SUBJECTS AND DESIGN Subjects diagnosed with COPD were chosen from one medical center and three regional hospitals in Taipei , Taiwan . A r and omized , block experimental design was used , with subjects and the data collector blinded . Using age , gender , pulmonary function , smoking , and steroid use as matching factors , 44 subjects were r and omly assigned to either the true acupressure or the sham acupressure groups . The true acupressure group received a program of acupressure using appropriate acupoints that promote relaxation and relieve dyspnea . The sham acupressure group received acupressure using sham acupoints different from the meridians and ganglionic sections of the true acupressure group . Both acupressure programs lasted 4 weeks , with five sessions per week that lasted 16 minutes per session . OUTCOME MEASURES The Geriatric Depression Scale ( GDS ) and Dyspnea Visual Analogue Scale ( DVAS ) were administered prior to the program as a baseline , and again following the completion of the 4-week program . Oxygen saturation and other physiological indicators were measured before and after each session . RESULTS The results of this study showed that the GDS scores , DVAS scores , oxygen saturation , and physiological indicators of the true acupressure group were significantly improved , compared to those of the sham acupressure group . CONCLUSIONS These findings provide health professionals with an evidence -based intervention to use with persons with COPD . Applying this acupressure program in clinical practice , communities , and long-term care units may lessen chronic dyspnea and depression in persons with COPD [12400430] The present study aims at comparing the effects of acupressure using new combination of acupoints , and Ibuprofen on the severity of primary dysmenorrhea ( PD ) . 216 female high school students , aged between 14 to 18 years , were r and omly selected and divided into three groups . Each group underwent different treatment techniques : acupressure , Ibuprofen and sham acupressure as a placebo . The results indicated that the three therapeutic techniques were significantly effective in reducing the pain . However the therapeutic efficacies of acupressure and Ibuprofen were similar with no significant difference , and were significantly better than the placebo . Thus acupressure , with no complications , is recommended as an alternative and also a better choice in the decrease of the severity of PD [17388768] OBJECTIVES The aim of this study was to determine if aromatherapy acupressure , compared to acupressure alone , was effective in reducing hemiplegic shoulder pain and improving motor power in stroke patients . DESIGN This work was a r and omized , controlled trial . SUBJECTS Thirty ( 30 ) stroke patients with hemiplegic shoulder pain participated in this study . INTERVENTION Subjects were r and omly assigned to either an aromatherapy acupressure group ( N = 15 ) or an acupressure group ( N = 15 ) , with aromatherapy acupressure using lavender , rosemary , and peppermint given only to the former group . Each acupressure session lasted 20 minutes and was performed twice-daily for 2 weeks . OUTCOMES MEASURES Shoulder pain and motor power were the outcome measures used in this study . RESULTS The pain scores were markedly reduced in both groups at post-treatment , compared to pretreatment ( both aroma acupressure and acupressure group , p < 0.001 ) . A nonparametric statistical analysis revealed that the pain score differed significantly between the 2 groups at post-treatment ( p < 0.01 ) . The motor power significantly improved at post-treatment , compared to pretreatment , in both groups ( p < 0.005 ) . However , there was no intergroup difference between two groups . CONCLUSIONS These results suggest that aromatherapy acupressure exerts positive effects on hemiplegic shoulder pain , compared to acupressure alone , in stroke patients [12705488] OBJECTIVE To evaluate the effectiveness of acupressure applied at meridian P6 point for prevention of nausea and vomiting in patients undergoing laparoscopic cholecystectomy . METHODOLOGY A r and omized double blind study was performed in 50 ASA I and II patients scheduled for laparoscopic cholecystectomy . Patients were divided into two groups ; control and placebo . In the control group acupressure was applied at P6 point half an hour before surgery while in the placebo group the acupressure b and was tied on meridian P6 point but the plastic bead was placed on the dosum of right forearm away from meridian P6 point . Patients were assessed for nausea and vomiting for six hours after surgery . Anaesthetic technique and postoperative analgesia were st and ardized for all patients . RESULTS Results showed that the incidence of postoperative nausea and vomiting was 36 % in the treatment group and 40 % in placebo group , which is statistically insignificant . CONCLUSION Application of acupressure at P6 point half an hour before induction of anaesthesia does not significantly alter the incidence of postoperative nausea and /or vomiting within 6 hours after surgery [12067865] Purpose To compare the efficacy of acupressure wrist b and s and ondansetron for the prevention of postoperative nausea and vomiting ( PONV ) . Methods One hundred and fifty ASA I – II , patients undergoing elective laparoscopic cholecystectomy were included in a r and omized , prospect i ve , double-blind and placebo-controlled study . Patients were divided into three groups of SO . Group I was the control ; Group II received ondansetron 4 mgiv just prior to induction of anesthesia ; in Group III acupressure wristb and s were applied at the P6 points . Acupressure wrist b and s were placed inappropriately in Groups I and II . The acupressure wrist b and s were applied 30 min prior to induction of anesthesia and removed six hours following surgery . Anesthesia was st and ardized . PONV were evaluated separately as none , mild , moderate or severe within six hours of patients ’ arrival in the postanesthesia care unit and then at 24 hr after surgery by a blinded observer . If patients vomited more than once , they were given 4 mg ondansetroniv as the rescue antiemetic . Results were analyzed by Ztest . AP value of < 0.05 was taken as significant . Results The incidence of PONV and the requirement of rescue medication were significantly lower in both the acupressure and ondansetron groups during the first six hours . Conclusion Acupressure at P6 causes a significant reduction in the incidence of PONV and the requirement for rescue medication in the first six hours following laparoscopic cholecystectomy , similar to that of ondansetron 4 mgiv . RésuméObjectifComparer l’efficacité des b and es d’acupression et de l’ondansétron comme prévention des nausées et vomissements postopératoires (NVPO).MéthodeCent cinquante patients d’état physique ASA I– II devant subir une cholécystectomie laparoscopique ont été recrutés pour une étude prospect i ve , r and omisée et à double insu contre placebo . Ils ont été répartis en trois groupes de 50 . Le groupe I a été le groupe témoin ; les patients du groupe II ont reçu 4 mg iv d’ondansétron juste avant l’induction de l’anesthésie ; chez les patients du groupe III , on a appliqué des b and es d’acupression aux point P6 . Des b and es d’acupression ont été placées de façon inappropriée chez les patients des groupes I et II . Les b and es ont été appliquées 30 min avant l’induction et enlevées six heures après l’opération . Lanesthésie a été normalisée . Les NVPO ont été évalués séparément comme inexistants , légers , modérés ou sévères pendant les six premières heures en salle de réveil , puis 24 h après l’opération par un observateur impartial . Si les patients vomissaient plus d’une fois , ils recevaient 4 mg d’ondansétron iv comme antiémétique de secours . Les résultats ont été analysés avec le test Z. Une valeur de P < 0,05 était considérée significative . RésultatsL’incidence de NVPO et les besoins de médication de secours ont été significativement plus faibles autant avec l’acupression qu’avec l’ondansétron pendant les six premières heures . Conclusion Lacupression en Pô réduit de façon significative l’incidence de NVPO et la nécessité d’antiémétique de secours pendant les six premières heures suivant la cholécystectomie laparoscopique . Son effet est donc similaire à celui de 4 mg iv d’ondansétron [16522418] OBJECTIVE The purpose of this study was to evaluate the efficacy of acupressure at the P6 point for the in-patient treatment of severe nausea and vomiting in early pregnancy . STUDY DESIGN This was a prospect i ve single-blind r and omized control trial that involved 80 patients with nausea and vomiting plus ketonuria before 14 weeks of gestation . RESULTS There was no difference between length of stay , amount of medication , or fluid required between the acupressure and placebo groups , although acupressure reduced the number of patients who stayed > or = 4 nights in the hospital . Acupressure was well tolerated and not associated with an increase in perinatal morbidity or death . CONCLUSION The use of acupressure at the P6 point does not reduce the amount of antiemetic medication that is required , the requirement for intravenous fluid , and median duration of in-patient stay more than the use of placebo . A small reduction was seen in the number of women who required > or = 4 days in the hospital [16164475] AIMS This paper reports an investigation of the effects of acupressure therapy on dyspnoea , anxiety and physiological indicators of heart rate and respiratory rate in patients with chronic obstructive pulmonary disease having mechanical ventilation support . BACKGROUND Patients with chronic obstructive pulmonary disease who are using mechanical ventilation often experience dyspnoea and anxiety , which affects successful ventilator use . METHODS The study had an experimental blocking design , using sex , age and length of ventilator use as a blocking factor . Qualified patients in two intermediate respiratory intensive care units were r and omly assigned to an acupressure group and a comparison group . A total of 52 patients with chronic obstructive pulmonary disease in northern Taiwan participated . Those in the experimental group received daily acupressure therapy and massage treatment for 10 days . Patients in the comparison group received massage treatment and h and holding . The primary outcome measures were the visual analogue scales for dyspnoea and anxiety , and physiological indicators of heart rate and respiratory rate . Data were collected every day from baseline ( day 1 ) , during the treatment ( days 2 - 10 ) and follow-up ( days 11 - 17 ) . Data were analysed using generalized estimation equations . The study was carried out in 2003 . RESULTS Patients with chronic obstructive pulmonary disease who were using prolonged mechanical ventilatory support experienced high levels of dyspnoea and anxiety . Dyspnoea ( P = 0.009 ) , anxiety ( P = 0.011 ) and physiological indicators ( P < 0.0001 ) in the acupressure group improved statistically significantly over time when compared with those of the comparison group . CONCLUSIONS This results support the suggestion that acupressure therapy could decrease sympathetic stimulation and improve perceived symptoms of dyspnoea and anxiety in patients with chronic obstructive pulmonary disease who are using prolonged mechanical ventilation [17352966] BACKGROUND Nausea , and to a lesser extend vomiting , remain significant clinical problems after the administration of chemotherapy , with up to 60 % of patients reporting nausea despite use of antiemetics . Combining antiemetics with other non-pharmacological treatments may prove more effective in decreasing nausea than antiemetics alone . Hence , the aim of the current study was to evaluate the effectiveness of using acupressure in Pericardium 6 ( Neiguan ) acu-point in managing chemotherapy-induced nausea and vomiting . METHODS This was a r and omised controlled trial . Acupressure was applied using wristb and s ( Sea-B and ) which patients in the experimental group had to wear for the 5 days following the chemotherapy administration . Assessment s of nausea , retching and vomiting were obtained from all patients daily for 5 days . Thirty-six patients completed the study from two centres in the UK , with 19 patients allocated to the control arm and 17 to the experimental arm . RESULTS It was found that nausea and retching experience , and nausea , vomiting and retching occurrence and distress were all significantly lower in the experimental group compared to the control group ( P<0.05 ) . The only exception was with the vomiting experience , which was close to significance ( P=0.06 ) . DISCUSSION Results highlight the important role of safe and convenient non-pharmacological complementary therapies , such as acupressure , in the management of the complex symptoms of chemotherapy-related nausea and vomiting [16492848] Nausea and vomiting are major adverse effects during spinal anesthesia for cesarean delivery . Stimulation of the P6 ( Neiguan ) acupoint is a traditional Chinese acupuncture technique used for effective antiemetic purpose s. In this study , we evaluated the antiemetic effect of P6 acupressure in parturients during spinal anesthesia for cesarean delivery . In a r and omized , double-blind , controlled trial , 110 parturients scheduled for elective cesarean delivery were enrolled in the study . Thirty minutes before initiation of spinal anesthesia , parturients were r and omized to acupressure b and s or placebo b and s bilaterally on the P6 acupoint and nausea and vomiting were observed over the study period . There were no statistically significant differences in maternal characteristics . Incidence rates for intraoperative nausea were 64 % ( acupressure group ) and 71 % ( control group ) ( P = 0.416 ) , with an incidence of intraoperative vomiting of 22 % ( acupressure group ) and 27 % ( control group ) ( P = 0.506 ) . The results suggest that prophylactic use of acupressure b and s bilaterally on the P6 acupoint failed to prevent nausea and vomiting during spinal anesthesia for cesarean delivery [10823097] The efficacy of acupressure at the P6 point in the prevention of nausea and vomiting during and after Caesarean section was studied . A double-blind , r and omized controlled study of acupressure vs placebo was design ed . Ninety-four patients scheduled for Caesarean section were included . The anaesthetic technique and postoperative analgesia were st and ardized . The use of acupressure reduced the incidence of nausea or vomiting from 53 % to 23 % compared with placebo ( 95 % confidence interval ( CI ) 0.34 - 0.25 ; P = 0.002 ) during the operation and from 66 % to 36 % compared with placebo ( 95 % CI 0.34 - 0.19 ; P = 0.003 ) after the operation . Other variables were similar between the groups [15500532] AIM This paper presents the findings of a study that assessed the effects of acupressure at the Sanyinjiao point on symptoms of primary dysmenorrhoea among adolescent girls . BACKGROUND Dysmenorrhoea is the most common gynaecological disorder among adolescents . Traditional Chinese acupressure derived from acupuncture is a non-invasive technique . Despite renewed interest in the use of acupressure , relatively few studies have been undertaken to examine its effects on primary dysmenorrhoea . METHODS An experimental study was conducted between December 2000 and August 2001 . Participants were female students attending a technical college in Taiwan . None of the 69 participants had a prior history of gynaecological disease or secondary dysmenorrhoea , and all were rated higher than five for pain on a visual analogue scale from 0 to 10 . The experimental group ( n = 35 ) received acupressure at Sanyinjiao ( above the ankle ) while the control group ( n = 34 ) rested for 20 min , while the control group underwent rest in the school health centre for 20 min without receiving acupressure . Fifty participants ( 30 experimental , 20 control ) completed the 4 - 6-week follow-up session . Five instruments were used to collect pretest and post-test data at each session : ( 1 ) Visual Analogue Scale for pain ; ( 2 ) the Short-Form McGill Pain Question naire ; ( 3 ) the Menstrual Distress Question naire ; ( 4 ) the Visual Analogue Scale for anxiety ; and , for the experimental group only , ( 5 ) the Acupressure Self- Assessment Form . Data were analysed using the chi-square test , two- sample t-test and repeated measures two-way anova . RESULTS Acupressure at Sanyinjiao during the initial session reduced the pain and anxiety typical of dysmenorrhoea . In the self-treatment follow-up session , acupressure at Sanyinjiao significantly reduced menstrual pain but not anxiety . Thirty-one ( 87 % ) of the 35 experimental participants reported that acupressure was helpful , and 33 ( 94 % ) were satisfied with acupressure in terms of its providing pain relief and psychological support during dysmenorrhoea . CONCLUSION The findings suggest that acupressure at Sanyinjiao can be an effective , cost-free intervention for reducing pain and anxiety during dysmenorrhoea , and we recommend its use for self-care of primary dysmenorrhoea [16488895] Abstract Objective To evaluate the effectiveness of acupressure in terms of disability , pain scores , and functional status . Design R and omised controlled trial . Setting Orthopaedic clinic in Kaohsiung , Taiwan . Participants 129 patients with chronic low back pain . Intervention Acupressure or physical therapy for one month . Main outcome measures Self administered Chinese versions of st and ard outcome measures for low back pain ( primary outcome : Rol and and Morris disability question naire ) at baseline , after treatment , and at six month follow-up . Results The mean total Rol and and Morris disability question naire score after treatment was significantly lower in the acupressure group than in the physical therapy group regardless of the difference in absolute score ( - 3.8 , 95 % confidence interval - 5.7 to - 1.9 ) or mean change from the baseline ( - 4.64 , - 6.39 to - 2.89 ) . Acupressure conferred an 89 % ( 95 % confidence interval 61 % to 97 % ) reduction in significant disability compared with physical therapy . The improvement in disability score in the acupressure group compared with the physical group remained at six month follow-up . Statistically significant differences also occurred between the two groups for all six domains of the core outcome , pain visual scale , and modified Oswestry disability question naire after treatment and at six month follow-up . Conclusions Acupressure was effective in reducing low back pain in terms of disability , pain scores , and functional status . The benefit was sustained for six months [15207999] BACKGROUND Although acupressure has been reported to be effective in managing various types of pain , its efficacy in relieving pain associated with low back pain ( LBP ) remains unclear . The aim of this study is to compare the efficacy of acupressure with that of physical therapy in reducing low back pain . METHODS A r and omized controlled clinical trial in an orthopedic referral hospital in Taiwan was conducted between December 20 , 2000 , and March 2 , 2001 . A total of 146 participants with chronic low back pain were r and omly assigned to the acupressure group ( 69 ) or the physical therapy group ( 77 ) , each with a different treatment technique . Self-appraised pain scores were obtained before treatment as baseline and after treatment as outcomes using the Chinese version of Short-Form Pain Question naire ( SF-PQ ) . RESULTS There were no significant differences in baseline characteristics among patients r and omized into the two groups . The mean of posttreatment pain score after a 4-week treatment ( 2.28 , SD = 2.62 ) in the acupressure group was significantly lower than that in the physical therapy group ( 5.05 , SD = 5.11 ) ( P = 0.0002 ) . At the 6-month follow-up assessment , the mean of pain score in the acupressure group ( 1.08 , SD = 1.43 ) was still significantly lower than that in the physical therapy group ( 3.15 , SD = 3.62 ) ( P = 0.0004 ) . CONCLUSIONS Our results suggest that acupressure is another effective alternative medicine in reducing low back pain , although the st and ard operating procedures involved with acupressure treatment should be carefully assessed in the future [14608559] The purpose of this study was to evaluate the effectiveness of acupressure b and s , droperidol , and the combined modalities , administered preoperatively , in reducing PONV in inpatient gynecologic patients . One hundred and forty-three patients were r and omized to one of four groups : droperidol and acupressure b and s , droperidol and placebo b and s , placebo drug and acupressure b and s , or placebo drug and placebo b and s. Overall , during their hospital stay , 69 % of the women experienced PONV and 45 % experienced vomiting at some time . Although droperidol was most effective the day of surgery , neither acupressure b and s or droperidol were effective in reducing PONV [15136963] Fatigue and depressive mood are the most significant symptoms experienced by patients with end-stage renal disease . The purpose of this study was to examine the effectiveness of acupressure with massage in fatigue and depression in patients with end-stage renal disease ( ESRD ) receiving hemodialysis treatment . The study applied an experimental pretest and posttest design . Sixty-two hemodialysis patients participated in the study . Data were collected from two hemodialysis clinics in major hospitals in southern Taiwan . Following consent to the study , subjects were r and omly assigned to an acupressure group or a control group . Patients in the acupressure group received acupoint massage for 12 minutes per day , three days per week , for four weeks . Subjects in the control group only received routine unit care . The measures included the Revised Piper Fatigue Scale , and Beck ' s Depression Inventory . Descriptive statistics , chi 2 tests , t-test and analyses of covariance were used for data analysis . The results indicate that subjects experienced a moderate level of fatigue . Nearly 65 % of hemodialysis patients had a depressed mood . ANCOVA results indicated that fatigue ( F((1.54 ) ) = 9.05 , p = .004 ) and depression ( F((1.54 ) ) = 4.20 , p = .045 ) among patients in the acupressure group showed significantly greater improvement than patients in the control group . The findings of this study provide an interventional model for nurses taking care of ESRD patients [11303547] OBJECTIVE To find out whether acupressure wristb and can alleviate nausea and vomiting in early pregnancy . DESIGN Double-blind , placebo-controlled study . SUBJECTS 97 women with mean gestational length completed 8 - 12 weeks . MAIN OUTCOME MEASURES Symptoms were recorded according to intensity , duration and nature of complaints . RESULTS 71 % of women in the intervention group reported both less intensive morning sickness and reduced duration of symptoms . The same tendency was seen in the placebo group , with 59 % reporting less intensity and 63 % shorter duration of symptoms . However , a significance level of 5 % was reached only in the case of duration of symptoms , which was reduced by 2.74 hours in the intervention group compared to 0.85 hours in the placebo group ( p = 0.018 ) . CONCLUSIONS Acupressure wristb and might be an alternative therapy for morning sickness in early pregnancy , especially before pharmaceutical treatment is considered [16895618] Background and objectives : To evaluate the effectiveness of acupressure in preventing nausea and vomiting in patients undergoing gynaecological operations and receiving a patient‐controlled analgesia device . Methods : Patients aged between 40 and 65 yr were included . Exclusion criteria were obesity , diabetes mellitus , and history of motion sickness , postoperative nausea and vomiting , or smoking . Patients were r and omized into one of two groups , acupressure and control . In the acupressure group , acupressure b and s were placed on both wrists with the plastic bead positioned at the P6 point . In controls , beads were placed at a non‐acupoint site . All patients received a st and ard general anaesthetic . Postoperatively , patients were connected to a patient‐controlled analgesia device with morphine ( loading dose 5 mg , background infusion 1 mg h−1 , bolus dose 1 mg and lock‐out time 10 min ) . Pain and sedation scores , respiratory rate , heart rate , arterial pressure and oxygen saturation were recorded for 24 h. Metoclopramide 10 mg was administered intravenously as a rescue antiemetic . Results : Fifty patients received acupressure and 50 were controls . In the acupressure group , 33 % of patients had nausea compared with 63 % controls . The cumulative incidence of vomiting at 24 h was 25 % with acupressure and 61 % in controls . The incidence of nausea , vomiting and antiemetic use was significantly lower with acupressure . Conclusions : Acupressure at the P6 meridian point is an effective alternative for the prevention of nausea and vomiting in patients receiving patient‐controlled analgesia with morphine after gynaecological surgery [15004444] Objective : The aim of this study was to evaluate the antiemetic effect of acupuncture ( AP ) and acupressure ( APr ) of the Pc 6 acupoint in pregnant women with hyperemesis gravidarum ( HG ) . Methods : A prospect i ve , placebo-controlled trial included 36 pregnant women with HG . Two methods of acupuncture were used : bilateral manual AP of the Pc 6 ( Neiguan ) acupoint ( group 1 , n = 10 ) and bilateral APr of the Pc 6 acupoint ( group 2 , n = 11 ) ; furthermore , superficial intracutaneous placebo AP ( group 3 , n = 8) and placebo APr ( group 4 , n = 7 ) was carried out . Results : Anxiodepressive symptoms occurred in 9 pregnant women with HG from group 1 , 8 women from group 2 , 7 women from group 3 , and 5 women from group 4 ( p < 0.001 ) . The average gestation age at the occurrence of HG symptoms and the beginning of treatment was 7 weeks in group 1 and 8 weeks in groups 2 , 3 , and 4 . Four women from group 1 and 7 women from groups 2 , 3 , an 4 needed intravenous compensation of liquid and electrolytes . The antiemetic metoclopramide was given intravenously to 1 woman from group 1 , 2 women from group 2 , 6 women from group 3 , and 4 women from group 4 . Promethazine was given to 1 woman from group 2 , 1 woman from group 3 , and to 3 women from group 4 . The efficiency of the HG treatment with AP of the point Pc 6 was 90 % , with APr of the Pc 6 63.6 % , with placebo AP 12.5 % , and with placebo APr 0 % . Conclusion : Acupuncture ( p < 0.0001 ) and acupressure ( p < 0.1 ) are effective , nonpharmacologic methods for the treatment of HG [14720242] BACKGROUND Patients with chronic obstructive pulmonary disease ( COPD ) suffer from dyspnoea in their daily life and this may be increased by anxiety . Acupressure may promote relaxation and relieve dyspnoea . Thus , it is appropriate to explore the effectiveness of acupressure on dyspnoea in patients with COPD . AIMS To compare outcomes of acupressure using sham acupoints on different meridians and ganglionic sections with that using true acupoints , in patients with COPD who are living at home . METHODS Patients diagnosed with COPD were selected from a medical centre and three regional hospitals in Taipei . A r and omized block experimental design was used . Using age , sex , pulmonary function , smoking , and steroid use as matching factors , 44 patients were r and omly assigned either to a true acupoint acupressure or a sham group . The true acupoint acupressure group received a programme to decrease dyspnoea . Those in the sham group received acupressure using sham pressure points . Both acupressure programmes consisted of five sessions per week lasting 16 minutes per session , extending over 4 weeks for a total of 20 sessions . Before acupressure was initiated and at the conclusion of the 20th session , the Pulmonary Functional Status and Dyspnoea Question naire-modified scale and the Spielberger State Anxiety scale were administered , and a 6-minute walking distance test was performed . Physiological indicators of oxygen saturation and respiratory rate were measured before and after every session . RESULTS The results of this study showed that the pulmonary function and dyspnoea scores , 6-minute walking distance measurements , state anxiety scale scores , and physiological indicators of the true acupoint acupressure group improved significantly compared with those of the sham group . CONCLUSIONS The findings suggest that acupressure can be used as a nursing intervention to improve dyspnoea in patients with COPD [12165194] OBJECTIVES To develop and test the safety and effectiveness of an acupressure garment ( the Relief Brief ) in decreasing the pain and symptom distress associated with dysmenorrhea . DESIGN A r and omized clinical trial applied a 2 ( Relief Brief use or control group ) x 3 ( baseline and two treatment measurement occasions ) mixed factorial design . PARTICIPANTS Sixty-one ( 61 ) women with moderately severe primary dysmenorrhea were r and omly assigned to the st and ard treatment control group or the Relief Brief acupressure device group after one pretreatment menses , with 58 women reporting the effect on their pain during two post-treatment menstrual cycles . The acupressure garment : The Relief Brief is a cotton Lycra panty brief with a fixed number of lower abdominal and lower back latex foam acupads that provide pressure to dysmenorrhea-relieving Chinese acupressure points . OUTCOME MEASURES Menstrual pain severity ( worst pain and symptom intensity ) , pain medication use , and adverse effects were analyzed using between-groups and repeated measures analyses of treatment effects . Statistical and clinical significance criteria were applied a priori . RESULTS For pain measures and pain medication use , the group main effect , time main effect and group x time interaction were statistically significant . Median pain medication use , the same for both groups at baseline ( 6 pills per day ) , dropped to 2 pills per day for the Relief Brief group but remained at 6 pills for the control group at the second treatment cycle . Predicted clinical significance criteria were surpassed : almost all ( 90 % ) women wearing the Relief Brief obtained at least a 25 % reduction in menstrual pain severity ( a 2 - 3 point drop ) compared to only 8 % of the control group ( z = 6.07 ; p < 0.05 ) . Relief Brief use was associated with at least a 50 % decline in menstrual pain symptom intensity in more than two thirds of the women . CONCLUSIONS An acupressure device is an effective and safe nonpharmacologic strategy for the treatment of primary dysmenorrhea . With design modifications , it could serve as a main treatment modality for women who suffer from primary dysmenorrhea and do not wish to or can not use the conventional pharmacologic agents . In addition , this acupressure device may serve as an adjuvant therapy to medication in more severe cases of dysmenorrhea [12801491] OBJECTIVES To assess the effectiveness of continuous PC6 acupressure as an adjunct to antiemetic drug therapy in the prevention and control of nausea and vomiting in the first 24h after myocardial infa rct ion ( MI ) . DESIGN Partially r and omised , partially blinded placebo-controlled , exploratory clinical study . SETTING Coronary Care Unit , Torbay Hospital , Torquay , Devon . PARTICIPANTS A total of 301 consecutive patients ( 205 males , 96 females ) admitted following acute MI . INTERVENTION The first 125 patients recruited received no additional intervention . Subsequent patients were r and omised to receive either continuous PC6 acupressure or placebo acupressure . OUTCOME MEASURES ( 1 ) Incidence of post-MI nausea and /or vomiting , ( 2 ) severity of symptoms , ( 3 ) use of antiemetic drugs , over 24h . RESULTS There were no significant differences between the groups for the whole 24-h treatment period . However , the PC6 acupressure group experienced significantly lower incidence of nausea and /or vomiting during the last 20h ( 18 % ) , compared with the placebo ( 32 % ) or control ( 43 % ) groups ( P<0.05 ) . The severity of symptoms and the need for antiemetic drugs were also reduced in the acupressure group , but these differences were not statistically significant . CONCLUSIONS Continuous 24-h PC6 acupressure therapy as an adjunct to st and ard antiemetic medication for post-MI nausea and vomiting is feasible and is well accepted and tolerated by patients . In view of its benefits , further studies are worthwhile using earlier onset of treatment [17920972] BACKGROUND Pain during transportation is a common phenomenon in emergency medicine . As acupressure has been deemed effective for pain management by the National Institutes of Health , we conducted a study to evaluate its effectiveness in prehospital patients with isolated distal radial fracture . METHODS This was a prospect i ve , r and omized , double-blind study . Thirty-two patients were enrolled . Acupressure was performed either at " true " points or at " sham " points . Vital signs and pain and anxiety scores were recorded before and after the acupressure treatment . Normally distributed values were compared using the Student t test . RESULTS Pretreatment scores for pain and anxiety were similar in the 2 groups ( 47.6 + /- 8.9 vs 51.2 + /- 8.7 visual analog scale [ VAS ] score for pain , 52.4 + /- 6.0 vs 47.5 + /- 9.3 VAS score for anxiety ) . At the hospital , patients in the true-points group had significantly lower pain ( 36.6 + /- 11.0 vs 56.0 + /- 13.3 VAS score , P < .001 ) and anxiety scores ( 34.9 + /- 22.2 vs 53.4 + /- 19.7 VAS score , P = .022 ) . CONCLUSION Acupressure in the prehospital setting effectively reduces pain and anxiety in patients with distal radial trauma [12198060] Untreated pain during the transportation of patients after minor trauma is a common problem in emergency medicine . Because paramedics usually are not allowed to perform invasive procedures or to give drugs for pain treatment , a noninvasive , nondrug-based method would be helpful . Acupressure is a traditional Chinese treatment for pain that is based on pain relief followed by a short mechanical stimulation of specific points . Consequently , we tested the hypothesis that effective pain therapy is possible by paramedics who are trained in acupressure . In a double-blinded trial we included 60 trauma patients . We r and omly assigned them into three groups ( “ true points , ” “ sham-points , ” and “ no acupressure ” ) . An independent observer , blinded to the treatment assignment , recorded vital variables and visual analog scales for pain and anxiety before and after treatment . At the end of transport , we asked for ratings of overall satisfaction . For statistical evaluation , one-way analysis of variance and the Scheffé F test were used . P < 0.05 was considered statistically significant . Morphometric and demographic data and potential confounding factors such as age , sex , pain , anxiety , blood pressure , and heart rate before treatment did not differ among the groups . At the end of transport we found significantly less pain , anxiety , and heart rate and a greater satisfaction in the “ true points ” groups ( P < 0.01 ) . Our results show that acupressure is an effective and simple-to-learn treatment of pain in emergency trauma care and leads to an improvement of the quality of care in emergency transport . We suggest that this technique is easy to learn and risk free and may improve paramedic-based rescue systems [16131291] BACKGROUND Previous reports have suggested that acupressure is effective in reducing pain and improving sleep quality ; however , its effects on alertness have not been characterized . OBJECTIVES The aim of this study was to determine whether two different acupressure treatments have opposing effects on alertness in a full-day classroom setting . DESIGN This was a cross-over ( two-treatments ; three periods ) , single-blinded , r and omized trial . SETTING The University of Michigan School of Public Health was the setting . SUBJECTS Students attending a course in clinical research design and statistical analysis at the University of Michigan participated in the study . INTERVENTIONS AND OUTCOME MEASURES Blinded subjects were r and omized to two acupressure treatment sequences : stimulation-relaxation-relaxation or relaxation-stimulation-stimulation . Acupressure treatments were self administered over 3 consecutive days . Pre- and post-treatment alertness scores were assessed each day using the Stanford Sleepiness Scale ( SSS ) . Changes in the SSS score ( afternoon-morning ) were analyzed using a mixed regression model of fixed and r and om effects . Important factors that were expected to affect alertness , such as caffeine and previous night 's sleep , were also assessed . RESULTS Baseline characteristics and protocol compliance were similar between the two sequences . Stimulation acupressure treatment yielded a 0.56-point greater difference in score on the SSS , corresponding to less fatigue , compared to the relaxation acupressure treatment ( p = 0.019 ) . Day of study ( p = 0.004 ) and hours of overnight sleep ( p = 0.042 ) also significantly affected the change in SSS scores . Incorporating participants ' beliefs as to which treatment they received did not significantly alter the observed treatment effect . CONCLUSIONS Acupressure at stimulation and relaxation points has differential effects on alertness in a classroom setting . Further research is necessary to confirm these findings and to determine whether stimulation and relaxation acupressure are equally effective in influencing alertness [19134445] The objective of this study was to determine the feasibility and effectiveness of acupressure therapy in preventing chemotherapy-associated nausea in children . A prospect i ve , r and omized , crossover trial was conducted among pediatric oncology patients at Brenner Children 's Hospital ( Winston-Salem , NC ) . Patients were r and omized to one of two treatment sequences involving acupressure wrist b and s and placebo b and s , separated by a st and ard care treatment with no b and s. All patients received st and ard antiemetic therapy for each treatment . Expectations and outcomes of nausea and vomiting were assessed by question naires . Of 21 patients approached , 21 were enrolled and 18 completed all three study treatments . Patients ' ages ranged from 5 to 19 years , 14 of 18 were Caucasian , and 9 were male . In general , patients expressed moderate expectations that acupressure would prevent nausea and vomiting . Following the session with an acupressure b and , a third of all patients reported better than expected nausea prevention . There was no significant difference in nausea or vomiting between the three groups ; there were no significant side effects from acupressure or placebo b and s. Pediatric oncology patients have moderate expectations about the effectiveness of acupressure in preventing nausea and vomiting . Acupressure is feasible and well tolerated but was not more effective than placebo in this sample of patients who were also treated with st and ard antiemetic therapies [12477673] Purpose To investigate the effect of sensory stimulation of the P6 point on postoperative nausea and vomiting ( PONV ) after gynecological surgery in the everyday clinical setting ( effectiveness study ) . Methods Four hundred and ten women undergoing general anesthesia for elective gynecological surgery were included in a prospect i ve , consecutive , r and omized , multicentre , placebo-controlled , double-blind clinical trial with a reference group . One group was given bilateral P6 acupressure ( n = 135 ) , a second group similar pressure on bilateral non-acupressure points ( n = 139 ) , and a third group ( n = 136 ) served as reference group . Nausea ( scale 0–6 ) , vomiting , pain , and satisfaction with the treatment were recorded . Primary outcome was complete response , i.e. , no nausea , vomiting or rescue medication for 24 hr . Results were analyzed by applying logistic regression with indicators of treatments , type of operation and risk score for PONV as explanatory variables . Results Complete response was more frequent in the P6 acupressure group than in the reference group ( P = 0.0194 ) Conversely , the incidence of PONV was 46 % in the reference group , 38 % after pressure on a non-acupoint and 33 % after P6 acupressure . The decrease from 46 % to 33 % was statistically significant . When considering vaginal cases separately , the decrease in PONV was from 36 % to 20 % ( P = 0.0168 ) . The corresponding decrease from 59 % to 55 % in the laparoscopic surgery group was not statistically significant . Conclusion P6 acupressure is a non-invasive method that may have a place as prophylactic antiemetic therapy during gynecological surgery . RésuméObjectifRechercher l’effet d’une stimulation sensorielle acupressive en P6 sur les nausées et vomissements postopératoires ( NVPO ) à la suite d’une intervention chirurgicale gynécologique dans un cadre clinique normal ( étude d’efficacité).MéthodeUn essai clinique prospect if , r and omisé , multicentrique , en double aveugle contre placebo et comportant un groupe de référence a été réalisé auprès de 410 femmes qui se sont présentées successivement pour une intervention gynécologique non urgente sous anesthésie générale . Les patientes d’un premier groupe ont reçu de l’acupression en P6 ( n = 135 ) , celles d’un second groupe ont reçu une pression semblable sur des points bilatéraux , non d’acupression , ( n = 139 ) et un troisième groupe ( n = 136 ) a servi de référence . Les nausées ( échelle de 0–6 ) , les vomissements , la douleur et la satisfaction face au traitement ont été notés . Le premier résultat était une réponse complète , donc absence de nausées , de vomissements ou de médication de secours pendant 24 h. Les résultats ont été analysés par régression logistique avec des indicateurs de traitements , le type d’intervention et le taux de risque de NVPO comme variables explicatives . RésultatsLa réponse complète a été plus fréquente avec l’acupression en P6 que chez les patientes témoins ( P = 0,0194 ) . Inversement , l’incidence de NVPO a été de 46 % dans le groupe de référence , 38 % après une pression de points non acupresseurs et 33 % après l’acupression en P6 . La diminution de 46 % à 33 % était significative . L’examen séparé des cas d’intervention vaginale indique une baisse des NVPO de 36 % à 20 % ( P = 0,0168 ) . La baisse correspondante de 59 % à 55 % dans les cas d’intervention laparoscopique n’était pas significative . Conclusion L’acupression en P6 représente une méthode non effractive de traitement antiémétique prophylactique qui peut avoir sa place pendant une intervention gynécologique [15344424] The purpose of this study was to test the effectiveness of acupressure and Transcutaneous Electrical Acupoint Stimulation ( TEAS ) on fatigue , sleep quality and depression in patients who were receiving routine hemodialysis treatment . The study was a r and omized controlled trial ; qualified patients were r and omly assigned to acupressure , TEAS or control groups . Patients in the acupressure and TEAS groups received 15 minutes of treatment 3 times a week for 1 month , whereas patients in the control group only received routine unit care . A total of 106 patients participated in the study . Methods of measurement included the revised Piper Fatigue Scale ( PFS ) , the Pittsburgh Sleep Quality Index and the Beck Depression Inventory . Data were collected at baseline , during the intervention and post-treatment . The results indicated that patients in the acupressure and TEAS groups had significantly lower levels of fatigue , a better sleep quality and less depressed moods compared with patients in the control group based upon the adjusted baseline differences . However , there were no differences between acupressure and TEAS groups in outcome measures . This study provides an alternative method for health care providers in managing dialysis patients with symptoms of fatigue , poor sleep or depression [11584487] OBJECTIVE To compare the antiemetic effect of acupressure at the Neiguan point ( P6 ) in a group of healthy women with normal pregnancy and nausea and vomiting during pregnancy ( NVP ) with a similar group receiving acupressure at a placebo point and another , similar group not receiving any treatment . STUDY DESIGN A r and omized , placebo-controlled , pilot study involving 60 women . RESULTS It is possible to reduce NVP significantly with acupressure at P6 as compared to acupressure at a placebo point or no treatment at all in healthy women with normal pregnancies . Relief from nausea appeared one day after starting treatment in both the P6 and placebo groups but lasted for only six days in the placebo group . The P6 group , however , experienced significantly less nausea after 14 days as compared to the other two groups . CONCLUSION This study involved 60 healthy women with normal pregnancy and suffering from NVP . According to the results , in healthy women with normal pregnancy it is possible to reduce NVP significantly at P6 as compared to acupressure at a placebo point and to no treatment [12139646] BACKGROUND Post-operative nausea and vomiting is a common complication following general anaesthesia . Traditional Chinese medicine indicates that acupressure therapy may reduce nausea and vomiting in certain ailments . AIM ( S ) OF THE STUDY The aim of this study was to examine the effect of stimulating two acupressure points on prevention of post-operative nausea and vomiting . DESIGN AND METHODS A r and omized block experimental design was used . The Rhodes Index of Nausea , Vomiting and Retching ( INVR ) question naire was used as a tool to measure incidence . To control the motion sickness variable , the subjects who underwent functional endoscopic sinus surgery ( FESS ) under general anaesthesia were r and omly assigned to a finger-pressing group , a wrist-b and group , and a control group . There were 150 subjects in total with each group consisting of 50 subjects . The acupoints and treatment times were similar in the finger-pressing group and wrist-b and pressing group , whereas only conversation was employed in the control group . RESULTS Significant differences in the incidence of the post-operative nausea and vomiting were found between the acupressure , wrist-b and , and control groups , with a reduction in the incidence rate of nausea from 73.0 % to 43.2 % and vomiting incidence rate from 90.5 % to 42.9 % in the former . The amount of vomitus and the degree of discomfort were , respectively , less and lower in the former group . CONCLUSION In view of the total absence of side-effects in acupressure , its application is worthy of use . This study confirmed the effectiveness of acupressure in preventing post-operative nausea and vomiting [12670382] BACKGROUND Traditional Chinese acupressure is a noninvasive technique that employs pressure and massage to acupoints in order to stimulate the balance of life energy that promotes health and comfort . Sleep disturbance is common in patients with end-stage renal disease but no intervention studies have addressed this problem . Aim . The purpose of the present study was to test the effectiveness of acupoints massage for patients with end-stage renal disease and experiencing sleep disturbances and diminished quality of life . METHODS The study was a r and omized control trial . A total of 98 end-stage renal disease patients with sleep disturbances were r and omly assigned into an acupressure group , a sham acupressure group , and a control group . Acupressure and sham acupressure group patients received acupoints or no acupoints massage three times a week during haemodialysis treatment for a total of 4 weeks . The measures included the Pittsburgh Sleep Quality Index , Sleep Log , and the Medical Outcome Study - Short Form 36 . FINDINGS The results indicated significant differences between the acupressure group and the control group in Pittsburgh Sleep Quality Index subscale scores of subjective sleep quality , sleep duration , habitual sleep efficiency , sleep sufficiency , and global Pittsburgh Sleep Quality Index scores . Sleep log data revealed that the acupressure group significantly decreased wake time and experienced an improved quality of sleep at night over the control group . Medical Outcome Study - Short Form 36 data also documented that acupressure group patients experienced significantly improved quality of life . CONCLUSION This study supports the effectiveness of acupoints massage in improving the quality of sleep and life quality of end-stage renal disease patients , and offers a noninvasive therapy for sleep-disturbed patients [10660922] PURPOSE / OBJECTIVES To compare differences in nausea experience and intensity in women undergoing chemotherapy for breast cancer between those receiving usual care plus acupressure training and treatment and those receiving only usual care . DESIGN Single-cycle , r and omized clinical trial . SETTING Outpatient oncology clinic in a major teaching medical center and a private outpatient oncology practice . SAMPLE Seventeen women participated in the study . The typical participant was 49.5 years old ( SD = 6.0 ) , Caucasian ( 59 % ) , not married/partnered ( 76 % ) , on disability ( 53 % ) , born a U.S. citizen ( 76 % ) , and heterosexual ( 88 % ) ; lived alone ( 59 % ) ; had at least graduated from high school ( 100 % ) ; and had an annual personal income of $ 50,000 or greater ( 65 % ) . METHODS The intervention included finger acupressure bilaterally at P6 and ST36 , acupressure points located on the forearm and by the knee . Baseline and post study question naires plus a daily log were used to collect data . MAIN RESEARCH VARIABLES Nausea experience measured by the Rhodes inventory of Nausea , Vomiting , and Retching and nausea intensity . FINDINGS Significant differences existed between the two groups in regard to nausea experience ( p < 0.01 ) and nausea intensity ( p < 0.04 ) during the first 10 days of the chemotherapy cycle , with the acupressure group reporting less intensity and experience of nausea . CONCLUSIONS Finger acupressure may decrease nausea among women undergoing chemotherapy for breast cancer . IMPLICATION S FOR NURSING PRACTICE This study must be replicated prior to advising patients about the efficacy of acupressure for the treatment of nausea [14670399] The purpose of the study is to investigate the effectiveness of acupressure on fatigue in patients with end-stage renal-disease ( ESRD ) . The study was a r and omized control trial ; qualified patients were r and omly assigned into acupressure group , sham group or control group . A total of 106 participants were included in the study . The measures included the revised Piper Fatigue Scale ( PFS ) , VAS of Fatigue , the Pittsburgh Sleep Quality Index and the Beck Depression Inventory . Data of fatigue measures were collected at pretreatment and a week following treatment . Sleep quality and depression were collected during post-test only . The statistical methods included the descriptive statistics , one-way ANOVA , ANCOVA , and repeated- measures ANOVA . ANCOVA that adjusted for differences in baseline fatigue scores ( PFS ) , post-test of depression and sleep quality , result was significant , F(2,100)=3.99 , p=0.02 . Post-hoc tests revealed that patients in the acupressure group were significantly having lower scores of fatigue than patients in the control group . ANCOVA results also significant for VAS of Fatigue among groups , F(2,100)=5.63 , p=0.003 . Comparisons indicated that there were significant differences between the acupressure group and the control group ( p=0.01 ) and between the sham group and control group ( p=0.003 ) . Predialysis fatigue was assessed routinely by using a rating of 0 - 10 . Repeated- measures ANOVA results demonstrate the group main effect was significant in the perceived fatigue ( F(2,88)=19.46 , p<0.001 ) . Follow-up tests indicated there were significant differences between the acupressure group and the control group ( p<0.001 ) and between the sham group and control group ( p<0.001 ) . The study provided an alternative method for health care providers to managing ESRD patients with fatigue [17402962] AIMS AND OBJECTIVES To examine and compare the effects of acupressure on the perceived health-related quality of life of the participants with bronchiectasis . BACKGROUND In an attempt to offer comfort , pain control and symptom management , nursing is becoming increasingly involved in offering complementary-alternative medicine as part of its caring-healing focus in comprehensive patient care . Acupressure is one such modality that is being increasingly used by both medical and nursing professionals . While acupressure has been reported to have beneficial effects in patients with respiratory disease , the benefits to bronchiectasis patients have remained uncertain . DESIGN A r and omized , partially blinded study consisting of three groups . METHODS Thirty-five out- patients of both genders , aged 59.46 SD 11.52 years , who were suffering from bronchiectasis , were r and omly split into one of three groups : st and ard care with supplemental acupressure for eight weeks ( 11 participants ) ; st and ard care with supplemental sham acupressure for eight weeks ( 11 participants ) ; and st and ard care alone ( 13 participants ) . Outcomes were determined by changes in daily sputum amounts , sputum self- assessment , six-minute walking distance , breathing difficulty ( measured on the dyspnea visual analogue scale ) and health-related quality of life ( measured by the Saint George Respiratory Question naire ) . RESULTS The sputum self- assessment score improved over time for the sham acupressure participants ( P = 0.03 ) , when compared with the controls . For acupressure participants , the Saint George respiratory question naire activity component scores also improved over time , compared with controls ( P = 0.01 ) after adjustment for covariates ( treatment , time , age , sex and baseline values ) . Other variables did not differ between the st and ard care alone group and the other two groups . CONCLUSIONS Eight weeks of self-administered acupressure could be useful in reducing the effects of bronchiectasis on a patient 's daily activities . RELEVANCE TO CLINICAL PRACTICE Acupressure may be regarded as a viable nursing intervention [15673989] OBJECTIVE The purpose of this study was to evaluate the effects of SP6 acupressure on labor pain and delivery time in women in labor . DESIGN R and omized clinical trial . SETTING /LOCATION Delivery room in a university hospital . PARTICIPANTS Seventy-five ( 75 ) women in labor were r and omly assigned to either the SP6 acupressure ( n = 36 ) or SP6 touch control ( n = 39 ) group . The participants were matched according to parity , cervical dilation , labor stage , rupture of amniotic membrane , and husb and 's presence during labor . There were no additional oxytocin augmentation or administration of analgesics during the study period . INTERVENTION The 30-minute acupressure or touch on SP6 acupoint was performed . OUTCOME MEASURES Labor pain was measured four times using a structured question naire , a subjective labor pain scale ( visual-analogue scale [ VAS ] ) : before intervention , immediately after the intervention , and 30 and 60 minutes after the intervention . Length of delivery time was calculated in two stages : from 3 cm cervical dilation to full cervical dilatation , and full cervical dilatation to the delivery . RESULTS There were significant differences between the groups in subjective labor pain scores at all time points following the intervention : immediately after the intervention ( p = 0.012 ) ; 30 minutes after the intervention ( p = 0.021 ) ; and 60 minutes after the intervention ( p = 0.012 ) . The total labor time ( 3 cm dilatation to delivery ) was significantly shorter in the SP6 acupressure intervention group than in the control group ( p = 0.006 ) . CONCLUSIONS These findings showed that SP6 acupressure was effective for decreasing labor pain and shortening the length of delivery time . SP6 acupressure can be an effective nursing management for women in labor [12906958] As an adjunct to st and ard antiemetics for the relief of chemotherapy-induced nausea and vomiting ( NV ) , 739 patients were r and omly assigned to either : 1 ) acupressure b and s , 2 ) an acustimulation b and , or 3 ) a no b and control condition . Patients in the acupressure condition experienced less nausea on the day of treatment compared to controls ( P<0.05 ) . There were no significant differences in delayed nausea or vomiting among the three treatment conditions . Additional analyses revealed pronounced gender differences . Men in the acustimulation condition , but not the acupressure condition , had less NV compared to controls ( P<0.05 ) . No significant differences among the three treatment conditions were observed in women , although the reduction in nausea on the day of treatment in the acupressure , compared to the no b and condition , closely approached statistical significance ( P=0.052 ) . Expected efficacy of the b and s was related to outcomes for the acupressure but not the acustimulation conditions [6074339] Ann Saudi Med 28(4 ) July-August 2008 www.saudiannals.net 287 Nausea and vomiting almost always occur aft ter general and regional anesthesia . Despite minimally invasive surgical methods like lapt aroscopy and rapidt and shorttacting anesthesia , naut sea and vomiting after surgery remain a common probt lem.1t5 Nausea and vomiting can result in dehydration , electrolyte imbalance and delay in discharge from the hospital . Serious complications , such as pressure on the suture lines and venous hypertension , may also occur . The incidence of posttoperative nausea and vomiting ( PONV ) has been estimated as 60 % to 70 % following laparoscopic cholecystecomy.6t11 Various factors can int fluence PONV , such as the type of surgery , anesthesia technique , certain drugs , pain and vertigo upon walkt ing . In Chinese and acupuncture medicine , the P6 ( neit guam ) meridian point is recognized as a target point for reducing nausea and vomiting.12t17 Several studies have shown that stimulus of P6 results in a reduction in the incidence of nausea and vomiting after surgery.8,11t13 A Cochrane systemic review concluded that P6 acuprest sure point stimulation seems to reduce the risk of naut sea despite conflicting results in r and omized trials.18 Our study investigated the effect of placement of acut pressure wristb and s at the P6 point in decreasing naut sea and vomiting after laparoscopic cholecystectomy in comparison with metoclopramide [12550145] The purpose of the study is to test the effectiveness of acupressure on sleep quality of end-stage renal disease patients . The study was a r and omized controlled trial ; qualified patients in the dialysis centers of four major hospitals were r and omly assigned into an acupressure group , a sham acupressure group , and a control group . A total of 98 participants were included in the study . The main outcomes measured were the Pittsburgh sleep quality index ( PSQI ) and the sleep log . Data were collected at pretreatment and following treatment . Primary statistical analysis was by means of Analysis of Covariance , the Kruskal-Wallis Test and repeated measure ANOVA . The results indicated that PSQI scores of the acupressure group have a significantly greater improvement ( p < 0.01 ) than the control group . However , there were no differences between the acupressure group and the sham group or the sham group and the control group ( p > 0.05 ) . Subscales of PSQI were further analyzed . Results demonstrated significant differences between the acupressure group and the control group in subjective sleep quality ( p = 0.009 ) , sleep duration ( p = 0.004 ) , habitual sleep efficiency ( p = 0.001 ) , and sleep sufficiency ( p = 0.004 ) . Significant differences in the subscale of subjective sleep quality ( p = 0.003 ) between the sham acupressure group and the control group were also observed . Sleep log data showed that the acupressure group significantly decreased awake time and improved quality of sleep over time more than the control group ( p < 0.01 ) . The improvement could be seen as soon as the acupoints massage was implemented , and it was maintained through the post intervention [14973803] OBJECTIVE To determine whether the application of acupressure b and s would lead to a reduction in postoperative nausea and vomiting after cardiac surgery . DESIGN Prospect i ve , r and omized , double-blind clinical trial . SETTING University-affiliated tertiary care teaching hospital . PARTICIPANTS Adult patients undergoing cardiac surgery . INTERVENTIONS One hundred fifty-two patients were enrolled to receive either acupressure treatment ( n = 75 ) or placebo ( n = 77 ) . All patients had acupressure b and s placed on both wrists before induction of anesthesia ; those in the treatment group had a bead placed in contact with the P6 point on the forearm . MEASUREMENTS AND MAIN RESULTS Patients were assessed for nausea , vomiting , and pain scores during the first 24 hours of the postoperative period . The incidences of nausea , vomiting , pain scores , and analgesic and antiemetic requirements were similar between the 2 groups . A subgroup analysis by gender implied that acupressure treatment may be effective only in female patients . CONCLUSION Acupressure treatment did not lead to a reduction in nausea , vomiting , or antiemetic requirements in patients after cardiac surgery [14685931] Acupressure is said to promote the circulation of blood and qi , the harmony of yin and yang , and the secretion of neurotransmitters , thus maintaining the normal functions of the human body and providing comfort . However , there has been little research -based evidence to support the positive effects of acupressure in the area of obstetric nursing . The purpose of this study is to determine the effect of LI4 and BL67 acupressure on labor pain and uterine contractions during the first stage of labor . An experimental study with a pretest and posttest control group design was utilized . A total of 127 parturient women were r and omly assigned to three groups . Each group received only one of the following treatments , LI4 and BL67 acupressure , light skin stroking , or no treatment/conversation only . Data collected from the VAS and external fetal monitoring strips were used for analysis . Findings indicated that there was a significant difference in decreased labor pain during the active phase of the first stage of labor among the three groups . There was no significant difference in effectiveness of uterine contractions during the first stage of labor among the three groups . Results of the study confirmed the effect of LI4 and BL67 acupressure in lessening labor pain during the active phase of the first stage of labor . There were no verified effects on uterine contractions [17645494] AIM This paper is a report of a study to examine the effect of Nei-Guan point acupressure on nausea , vomiting and ketonuria levels in women diagnosed with hyperemesis gravidarum . BACKGROUND Previous studies have shown that acupressure application on the Nei-Guan point is effective in relieving nausea and vomiting associated with pregnancy and surgery . However , no findings have been supported by physiological data . METHOD A r and omized control group pretest-post-test design was implemented from 1 April 2003 to 30 April 2004 using three groups : a Nei-Guan point acupressure group , a placebo group and a control group which received only conventional intravenous treatment . The participants were 66 women admitted to two general hospitals in Korea with hyperemesis gravidarum . RESULTS The degree of nausea and vomiting was statistically significantly lower in the Nei-Guan point acupressure group in comparison with the placebo and control groups . Ketonuria levels were reduced over time and , on days three and four of hospitalization , levels in the treatment group were statistically significantly lower than in the placebo or control groups ( P < 0.05 ) . CONCLUSION Nei-Guan point acupressure is a useful treatment for relieving symptoms experienced by women with hyperemesis gravidarum [18054724] BACKGROUND Cancer-related fatigue after chemotherapy is a difficult symptom to manage in practice and the most disruptive symptom in patients ' lives . Acupuncture is a popular complementary therapy among cancer patients and some evidence exists that it could potentially alleviate fatigue by stimulating ' energy ' points in the body . Hence , this study was carried out to assess the effects of acupuncture and acupressure in managing cancer-related fatigue and the feasibility of running a r and omised trial with these two complementary therapies in preparation for a large trial . METHODS This study was a r and omised controlled trial . Forty-seven patients with cancer who experienced moderate to severe fatigue were r and omised either to an acupuncture group ( n=15 ) , an acupressure group ( n=16 ) or a sham acupressure group ( n=16 ) . The acupuncture group received six 20-min sessions over 2 weeks , while the patients in the two acupressure groups were taught to massage/press the points and did so daily thereafter for 2 weeks on their own . Patients completed the Multidimensional Fatigue Inventory before r and omisation , at the end of the 2-week intervention and again about 2 weeks after the end of the intervention . RESULTS Significant improvements were found with regards to General fatigue ( P<0.001 ) , Physical fatigue ( P=0.016 ) , Activity ( p=0.004 ) and Motivation ( P=0.024 ) . At the end of the intervention , there was a 36 % improvement in fatigue levels in the acupuncture group , while the acupressure group improved by 19 % and the sham acupressure by 0.6 % . Improvements were observed even 2 weeks after treatments , although they were lower ( 22 % , 15 % , 7 % , respectively ) . Acupuncture was a more effective method than acupressure or sham acupressure . Subjects needed a longer treatment period to have more sustained results . The trial was method ologically feasible . CONCLUSION Acupuncture shows great potential in the management of cancer-related fatigue . As a r and omised trial with acupuncture is feasible and preliminary data shows significant improvements , it should be tested further using a large sample and a multicentre design [19034253] AIM Insomnia is a major problem which decreases life quality . Many causes are involved with it and anxiety is often associated . The underlying mechanism is not completely understood , even though different factors seem to be associated . Among them melatonin and its circadian rhythm is thought to have an important role . In addition , acupressure and acupuncture are known to ameliorate insomnia and anxiety , when a specific wrist point is stimulated ( HT 7 Shenmen ) . With these bases , the aim of the present study has been to evaluate the efficacy of an acupressure device , ' ' H7-insomnia control ' ' , positioned on HT 7 points , during the night , in terms of general health and anxiety levels , together with the evaluation of sleep quality and the urinary melatonin metabolite 6-hydroxymelatonin sulphate determination , in a number of insomniacs . METHODS Forty patients with insomnia were divided into two groups and r and omly received either the H7 or placebo treatments , in a double-blind protocol , for 20 nights . Before and after treatments every subject answered a series of question naires ( General Health Question naire 28 items ; State-Trait Anxiety Inventory ; Pittsburgh Sleep Quality Index ) and collected 24 h urines , divided into two sample s of 12 h each . Urinary melatonin metabolite was then determined using a RIA method . RESULTS Data obtained indicate that the device H7-insomnia control is efficacious to ameliorate quality of sleep and reduce anxiety levels in insomniacs , at a higher extent than in the placebo group . In addition , the 24 hours urinary melatonin metabolite rhythm , obtained at the end of treatment , was considered as being normal in a higher percentage of H7-treated patients , with respect to the placebo group . CONCLUSION It is plausible to hypothesize that the wrist acupressure device might be considered a valid tool , without adverse effects since it does not contain pharmaceutical products , that is able to naturally ameliorate sleep quality in insomniacs , acting through a not jet completely clarified mechanism , that may involve melatonin [14629844] OBJECTIVES Acupuncture and acupressure are known to relieve symptoms associated with asthma , but the benefits to patients with chronic obstructive asthma have not been fully evaluated . In this pilot clinical study , acupuncture or acupressure was incorporated into the st and ard care for adult patients with chronic obstructive asthma to determine their contribution to the improvement of their quality of life and relief of symptoms . DESIGN A prospect i ve , r and omized study that involved 8 weeks of treatment at Chang Gung Memorial Hospital ( Tao-Yuan , Taiwan ) was conducted between March 1997 and September 1998 . Forty-one ( n = 41 ) patients with chronic obstructive asthma were enrolled . Patients were r and omly assigned to receive acupuncture in addition to st and ard care ( n = 11 ) , acupressure and st and ard care ( n = 17 ) , or st and ard care alone ( n = 13 ) . Twenty ( 20 ) acupuncture treatments were administered , and self-administered acupressure was performed daily for 8 weeks . Six-minute walking , the Dyspnea Visual Analogue Scale , the modified Borg scale , St. George 's Respiratory Question naire ( SGRQ ) , and the Bronchitis Emphysema Symptom Checklist ( BESC ) were used at the beginning and end of the 8 weeks of treatment . RESULTS The total SGRQ score of acupuncture subjects showed an average 18.5-fold improvement ( 95 % confidence interval [ CI ] 1.54 - 211.48 , p = 0.02 ) ; the improvement for the acupressure subjects was 6.57-fold ( 95 % C.I. 0.98 - 44.00 , p = 0.05 ) . Additionally , for patients who received acupressure , the irritability domain score determined by the BESC exhibited an 11.8-fold improvement ( 95 % C.I. 0.88 - 158.64 , p = 0.06 ) after adjustment for covariables . The other variables did not differ from those of the controls . CONCLUSIONS Patients with clinical ly stable , chronic obstructive asthma experienced clinical ly significant improvements in quality of life when their st and ard care was supplemented with acupuncture or acupressure [19328650] Previous studies have shown that acupressure b and s can reduce chemotherapy-related nausea . Patients ' expectations of efficacy account for part of this outcome . We conducted a three-arm r and omized clinical trial to investigate the effectiveness of acupressure b and s in controlling radiation therapy-induced nausea and to test whether an informational manipulation design ed to increase expectation of efficacy would enhance the effectiveness of the acupressure b and s. Patients who experienced nausea at prior treatments were r and omized to either st and ard care ( Arm 1 , n=29 ) or st and ard care plus acupressure b and s with either neutral ( Arm 2 , n=30 ) or positive ( Arm 3 , n=29 ) information regarding the efficacy of the b and s. Patients reported nausea for two days prior to r and omization ( baseline ) and for five days following using a seven-point semantic rating scale ( 1=not nauseated to 7=extremely nauseated ) . Patients in Arms 2 and 3 combined reported greater reduction in average nausea than patients in Arm 1 ( P=0.01 ; mean(b and s)=0.70 , mean(no b and s)=0.10 ) . This equates to a 23.8 % decrease in nausea in the b and groups compared to a 4.8 % decrease in the control group , a 19 % difference . The informational manipulation failed to alter efficacy expectations and there was no statistically significant difference in nausea between patients in Arms 2 and 3 . Acupressure b and s are an effective , low-cost , nonintrusive , well-accepted , and safe adjunct to st and ard antiemetic medication . An attempt to boost the efficacy of the acupressure b and s by providing positive information was not successful [10764175] Purpose : To evaluate the efficacy of acupressure wristb and s in the prevention of postoperative nausea and vomiting ( PONV ) . Methods : Two hundred ASAI - II patients undergoing elective endoscopic urological procedures were included in a r and omized , prospect i ve , double blind , placebo-controlled study . Spherical beads of acupressure wristb and s were placed at the P6 points in the anterior surface of both forearms in Group 1 patients ( acupressure group , n=100 ) whereas , in Group 2(control group , n=100 ) they were placed inappropriately on the posterior surface . The acupressure wristb and s were applied 30 min before induction of anesthesia and were removed six hours postoperatively . Anesthesia was induced with thiopental and maintained with nitrous oxide and oxygen , fentanly , isoflurane and vecuronium . The tracheas were extubated on the operation table after patients received neostigmine and atropine . Post operative nausea and vomiting were evaluated separately as none , mild , moderate or severe at the time of patient ’s arrival in PACU , then at six hours and twenty-four hours after surgery by a blinded observer . Results : In the acupressure group , 25 patients had PONV compared with 29 patients in the control group ( P = NS ) . Conclusion : Application of acupressure wristb and s at the P6 of both forearms 30 min before induction of anesthesia did not decrease the incidence of PONV in patients undergoing endoscopic urological procedures .RésuméObjectif : Évaluer l’efficacité de bracelets d’acupression utilisés pour la prévention des nausées et des vomissements postopératoires (NVPO).Méthode : Deux cents patients , ASA I – II , devant subir une intervention urologique endoscopique planifiée ont participé à l’étude r and omisée , prospect i ve et à double insu contre placebo . Des bracelets de billes d’acupression ont été placés aux points P6 de la face antérieure des deux avant-bras des patients du Groupe 1 ( groupe d’acupression , n=100 ) t and is que dans le Groupe 2 , ( groupe témoin , n=100 ) , ils l’ont été , de façon inappropriée , sur la face postérieure . On les a appliqués 30 min avant l’induction de l’anesthésie et retirés six heures après l’opération . L’anesthésie comportait du thiopental , à l’induction , et du protoxyde d’azote , de l’oxygène , du fentanyl , de l’isoflurane et du vécuronium . L’extubation trachéale a eu lieu à la salle d’opération après l’administration de néostigmine et d’atropine . Un observateur objectif a évalué les nausées et les vomissements postopératoires comme absents , légers , modérés ou sévères au moment où le patient est arrivé à la salle de réveil , puis six et vingt-quatre heures après l’opération . Résultats : Dans le groupe d’acupression , 25 patients ont eu des NVPO , comparativement à 29 patients du groupe témoin ( P = NS ) . Conclusion : L’application de bracelets d’acupression en P6 aux deux avant-bras , 30 min avant l’induction de l’anesthésie , n’a pas diminué l’incidence de NVPO chez des patients qui subissent une intervention urologique endoscopique

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### Context: [12538202] Minute sphere acupressure has been used for more than 2000 yr and remains popular in Japan . The points most relevant to abdominal surgery are those associated with meridian flows crossing or originating in the abdomen . We tested the hypothesis that minute sphere therapy reduces pain and analgesic requirements after open abdominal surgery . Participating patients were given st and ardized desflurane and fentanyl anesthetic . On completion of surgery , they were r and omly assigned to untreated control or minute sphere acupressure at the Neiguan , Zusanli , Sanyinjiao , and Gongsun points . Each site was covered with bulky gauze dressings so that patients could not determine their assignments . Postoperative pain was treated with IV morphine via a patient-controlled analgesia pump . Our primary a priori end-points were pain and opioid consumption on the first postoperative morning . Data are reported as median ( 25th percentile , 75th percentile ) . Fifty-three patients ( 30 controls and 23 minute spheres ) completed the study . Morphine requirements ( 47 mg [ 27 , 58 ] vs 41 mg [ 25 , 69 ] ) and pain scores ( 29.5 mm [ 16 , 59 ] vs 40 mm [ 22 , 58 ] ) were similar in the control and acupressure groups . These data provide an 80 % power for detecting a 50 % difference in morphine consumption at an alpha of 0.05 . Minute sphere treatment at the Neiguan , Zusanli , Sanyinjiao , and Gongsun points thus failed to provide analgesia after abdominal surgery . Minute sphere therapy is a form of acupuncture . We tested whether minute spheres placed on three acupressure points relevant to abdominal surgery reduced pain and morphine requirements after abdominal surgery . Treatment and control patients received a similar covering . Neither pain nor morphine requirements were different between the groups [17318558] Objective To compare the effectiveness of acupressure and vitamin B6 in the outpatient treatment of nausea and vomiting in early pregnancy . Study design Pregnant volunteers with symptoms of mild to moderate nausea and vomiting between 6 and 12 weeks ’ gestation participated in a 7-day clinical trial . Participants were r and omly assigned to receive a device for acupressure therapy and placebo drug or an otherwise identical but non-stimulating placebo device and vitamin B6 . The primary outcome measure was self-recorded symptoms according to Rhodes index . Secondary outcome measures were weight gain and medication use . Results The mean change in Rhodes index was not significantly different between the two groups . There were no statistically significant differences in weight gain and medication use between the two groups . Conclusion Acupressure therapy is not more effective than vitamin B6 in reducing nausea and vomiting in symptomatic women in the first trimester of pregnancy [17388769] OBJECTIVES The onset of depression is often triggered by breathlessness in persons with chronic obstructive pulmonary disease ( COPD ) . It is hypothesized that these are the psychologic consequences of chronic dyspnea . Lessening dyspnea might alleviate depressive symptoms . Acupressure has been shown in other studies to produce relaxation . The aim of this study was to determine if it would lessen dyspnea and reduce depression in patients with COPD . SUBJECTS AND DESIGN Subjects diagnosed with COPD were chosen from one medical center and three regional hospitals in Taipei , Taiwan . A r and omized , block experimental design was used , with subjects and the data collector blinded . Using age , gender , pulmonary function , smoking , and steroid use as matching factors , 44 subjects were r and omly assigned to either the true acupressure or the sham acupressure groups . The true acupressure group received a program of acupressure using appropriate acupoints that promote relaxation and relieve dyspnea . The sham acupressure group received acupressure using sham acupoints different from the meridians and ganglionic sections of the true acupressure group . Both acupressure programs lasted 4 weeks , with five sessions per week that lasted 16 minutes per session . OUTCOME MEASURES The Geriatric Depression Scale ( GDS ) and Dyspnea Visual Analogue Scale ( DVAS ) were administered prior to the program as a baseline , and again following the completion of the 4-week program . Oxygen saturation and other physiological indicators were measured before and after each session . RESULTS The results of this study showed that the GDS scores , DVAS scores , oxygen saturation , and physiological indicators of the true acupressure group were significantly improved , compared to those of the sham acupressure group . CONCLUSIONS These findings provide health professionals with an evidence -based intervention to use with persons with COPD . Applying this acupressure program in clinical practice , communities , and long-term care units may lessen chronic dyspnea and depression in persons with COPD [12400430] The present study aims at comparing the effects of acupressure using new combination of acupoints , and Ibuprofen on the severity of primary dysmenorrhea ( PD ) . 216 female high school students , aged between 14 to 18 years , were r and omly selected and divided into three groups . Each group underwent different treatment techniques : acupressure , Ibuprofen and sham acupressure as a placebo . The results indicated that the three therapeutic techniques were significantly effective in reducing the pain . However the therapeutic efficacies of acupressure and Ibuprofen were similar with no significant difference , and were significantly better than the placebo . Thus acupressure , with no complications , is recommended as an alternative and also a better choice in the decrease of the severity of PD [17388768] OBJECTIVES The aim of this study was to determine if aromatherapy acupressure , compared to acupressure alone , was effective in reducing hemiplegic shoulder pain and improving motor power in stroke patients . DESIGN This work was a r and omized , controlled trial . SUBJECTS Thirty ( 30 ) stroke patients with hemiplegic shoulder pain participated in this study . INTERVENTION Subjects were r and omly assigned to either an aromatherapy acupressure group ( N = 15 ) or an acupressure group ( N = 15 ) , with aromatherapy acupressure using lavender , rosemary , and peppermint given only to the former group . Each acupressure session lasted 20 minutes and was performed twice-daily for 2 weeks . OUTCOMES MEASURES Shoulder pain and motor power were the outcome measures used in this study . RESULTS The pain scores were markedly reduced in both groups at post-treatment , compared to pretreatment ( both aroma acupressure and acupressure group , p < 0.001 ) . A nonparametric statistical analysis revealed that the pain score differed significantly between the 2 groups at post-treatment ( p < 0.01 ) . The motor power significantly improved at post-treatment , compared to pretreatment , in both groups ( p < 0.005 ) . However , there was no intergroup difference between two groups . CONCLUSIONS These results suggest that aromatherapy acupressure exerts positive effects on hemiplegic shoulder pain , compared to acupressure alone , in stroke patients [12705488] OBJECTIVE To evaluate the effectiveness of acupressure applied at meridian P6 point for prevention of nausea and vomiting in patients undergoing laparoscopic cholecystectomy . METHODOLOGY A r and omized double blind study was performed in 50 ASA I and II patients scheduled for laparoscopic cholecystectomy . Patients were divided into two groups ; control and placebo . In the control group acupressure was applied at P6 point half an hour before surgery while in the placebo group the acupressure b and was tied on meridian P6 point but the plastic bead was placed on the dosum of right forearm away from meridian P6 point . Patients were assessed for nausea and vomiting for six hours after surgery . Anaesthetic technique and postoperative analgesia were st and ardized for all patients . RESULTS Results showed that the incidence of postoperative nausea and vomiting was 36 % in the treatment group and 40 % in placebo group , which is statistically insignificant . CONCLUSION Application of acupressure at P6 point half an hour before induction of anaesthesia does not significantly alter the incidence of postoperative nausea and /or vomiting within 6 hours after surgery [12067865] Purpose To compare the efficacy of acupressure wrist b and s and ondansetron for the prevention of postoperative nausea and vomiting ( PONV ) . Methods One hundred and fifty ASA I – II , patients undergoing elective laparoscopic cholecystectomy were included in a r and omized , prospect i ve , double-blind and placebo-controlled study . Patients were divided into three groups of SO . Group I was the control ; Group II received ondansetron 4 mgiv just prior to induction of anesthesia ; in Group III acupressure wristb and s were applied at the P6 points . Acupressure wrist b and s were placed inappropriately in Groups I and II . The acupressure wrist b and s were applied 30 min prior to induction of anesthesia and removed six hours following surgery . Anesthesia was st and ardized . PONV were evaluated separately as none , mild , moderate or severe within six hours of patients ’ arrival in the postanesthesia care unit and then at 24 hr after surgery by a blinded observer . If patients vomited more than once , they were given 4 mg ondansetroniv as the rescue antiemetic . Results were analyzed by Ztest . AP value of < 0.05 was taken as significant . Results The incidence of PONV and the requirement of rescue medication were significantly lower in both the acupressure and ondansetron groups during the first six hours . Conclusion Acupressure at P6 causes a significant reduction in the incidence of PONV and the requirement for rescue medication in the first six hours following laparoscopic cholecystectomy , similar to that of ondansetron 4 mgiv . RésuméObjectifComparer l’efficacité des b and es d’acupression et de l’ondansétron comme prévention des nausées et vomissements postopératoires (NVPO).MéthodeCent cinquante patients d’état physique ASA I– II devant subir une cholécystectomie laparoscopique ont été recrutés pour une étude prospect i ve , r and omisée et à double insu contre placebo . Ils ont été répartis en trois groupes de 50 . Le groupe I a été le groupe témoin ; les patients du groupe II ont reçu 4 mg iv d’ondansétron juste avant l’induction de l’anesthésie ; chez les patients du groupe III , on a appliqué des b and es d’acupression aux point P6 . Des b and es d’acupression ont été placées de façon inappropriée chez les patients des groupes I et II . Les b and es ont été appliquées 30 min avant l’induction et enlevées six heures après l’opération . Lanesthésie a été normalisée . Les NVPO ont été évalués séparément comme inexistants , légers , modérés ou sévères pendant les six premières heures en salle de réveil , puis 24 h après l’opération par un observateur impartial . Si les patients vomissaient plus d’une fois , ils recevaient 4 mg d’ondansétron iv comme antiémétique de secours . Les résultats ont été analysés avec le test Z. Une valeur de P < 0,05 était considérée significative . RésultatsL’incidence de NVPO et les besoins de médication de secours ont été significativement plus faibles autant avec l’acupression qu’avec l’ondansétron pendant les six premières heures . Conclusion Lacupression en Pô réduit de façon significative l’incidence de NVPO et la nécessité d’antiémétique de secours pendant les six premières heures suivant la cholécystectomie laparoscopique . Son effet est donc similaire à celui de 4 mg iv d’ondansétron [16522418] OBJECTIVE The purpose of this study was to evaluate the efficacy of acupressure at the P6 point for the in-patient treatment of severe nausea and vomiting in early pregnancy . STUDY DESIGN This was a prospect i ve single-blind r and omized control trial that involved 80 patients with nausea and vomiting plus ketonuria before 14 weeks of gestation . RESULTS There was no difference between length of stay , amount of medication , or fluid required between the acupressure and placebo groups , although acupressure reduced the number of patients who stayed > or = 4 nights in the hospital . Acupressure was well tolerated and not associated with an increase in perinatal morbidity or death . CONCLUSION The use of acupressure at the P6 point does not reduce the amount of antiemetic medication that is required , the requirement for intravenous fluid , and median duration of in-patient stay more than the use of placebo . A small reduction was seen in the number of women who required > or = 4 days in the hospital [16164475] AIMS This paper reports an investigation of the effects of acupressure therapy on dyspnoea , anxiety and physiological indicators of heart rate and respiratory rate in patients with chronic obstructive pulmonary disease having mechanical ventilation support . BACKGROUND Patients with chronic obstructive pulmonary disease who are using mechanical ventilation often experience dyspnoea and anxiety , which affects successful ventilator use . METHODS The study had an experimental blocking design , using sex , age and length of ventilator use as a blocking factor . Qualified patients in two intermediate respiratory intensive care units were r and omly assigned to an acupressure group and a comparison group . A total of 52 patients with chronic obstructive pulmonary disease in northern Taiwan participated . Those in the experimental group received daily acupressure therapy and massage treatment for 10 days . Patients in the comparison group received massage treatment and h and holding . The primary outcome measures were the visual analogue scales for dyspnoea and anxiety , and physiological indicators of heart rate and respiratory rate . Data were collected every day from baseline ( day 1 ) , during the treatment ( days 2 - 10 ) and follow-up ( days 11 - 17 ) . Data were analysed using generalized estimation equations . The study was carried out in 2003 . RESULTS Patients with chronic obstructive pulmonary disease who were using prolonged mechanical ventilatory support experienced high levels of dyspnoea and anxiety . Dyspnoea ( P = 0.009 ) , anxiety ( P = 0.011 ) and physiological indicators ( P < 0.0001 ) in the acupressure group improved statistically significantly over time when compared with those of the comparison group . CONCLUSIONS This results support the suggestion that acupressure therapy could decrease sympathetic stimulation and improve perceived symptoms of dyspnoea and anxiety in patients with chronic obstructive pulmonary disease who are using prolonged mechanical ventilation [17352966] BACKGROUND Nausea , and to a lesser extend vomiting , remain significant clinical problems after the administration of chemotherapy , with up to 60 % of patients reporting nausea despite use of antiemetics . Combining antiemetics with other non-pharmacological treatments may prove more effective in decreasing nausea than antiemetics alone . Hence , the aim of the current study was to evaluate the effectiveness of using acupressure in Pericardium 6 ( Neiguan ) acu-point in managing chemotherapy-induced nausea and vomiting . METHODS This was a r and omised controlled trial . Acupressure was applied using wristb and s ( Sea-B and ) which patients in the experimental group had to wear for the 5 days following the chemotherapy administration . Assessment s of nausea , retching and vomiting were obtained from all patients daily for 5 days . Thirty-six patients completed the study from two centres in the UK , with 19 patients allocated to the control arm and 17 to the experimental arm . RESULTS It was found that nausea and retching experience , and nausea , vomiting and retching occurrence and distress were all significantly lower in the experimental group compared to the control group ( P<0.05 ) . The only exception was with the vomiting experience , which was close to significance ( P=0.06 ) . DISCUSSION Results highlight the important role of safe and convenient non-pharmacological complementary therapies , such as acupressure , in the management of the complex symptoms of chemotherapy-related nausea and vomiting [16492848] Nausea and vomiting are major adverse effects during spinal anesthesia for cesarean delivery . Stimulation of the P6 ( Neiguan ) acupoint is a traditional Chinese acupuncture technique used for effective antiemetic purpose s. In this study , we evaluated the antiemetic effect of P6 acupressure in parturients during spinal anesthesia for cesarean delivery . In a r and omized , double-blind , controlled trial , 110 parturients scheduled for elective cesarean delivery were enrolled in the study . Thirty minutes before initiation of spinal anesthesia , parturients were r and omized to acupressure b and s or placebo b and s bilaterally on the P6 acupoint and nausea and vomiting were observed over the study period . There were no statistically significant differences in maternal characteristics . Incidence rates for intraoperative nausea were 64 % ( acupressure group ) and 71 % ( control group ) ( P = 0.416 ) , with an incidence of intraoperative vomiting of 22 % ( acupressure group ) and 27 % ( control group ) ( P = 0.506 ) . The results suggest that prophylactic use of acupressure b and s bilaterally on the P6 acupoint failed to prevent nausea and vomiting during spinal anesthesia for cesarean delivery [10823097] The efficacy of acupressure at the P6 point in the prevention of nausea and vomiting during and after Caesarean section was studied . A double-blind , r and omized controlled study of acupressure vs placebo was design ed . Ninety-four patients scheduled for Caesarean section were included . The anaesthetic technique and postoperative analgesia were st and ardized . The use of acupressure reduced the incidence of nausea or vomiting from 53 % to 23 % compared with placebo ( 95 % confidence interval ( CI ) 0.34 - 0.25 ; P = 0.002 ) during the operation and from 66 % to 36 % compared with placebo ( 95 % CI 0.34 - 0.19 ; P = 0.003 ) after the operation . Other variables were similar between the groups [15500532] AIM This paper presents the findings of a study that assessed the effects of acupressure at the Sanyinjiao point on symptoms of primary dysmenorrhoea among adolescent girls . BACKGROUND Dysmenorrhoea is the most common gynaecological disorder among adolescents . Traditional Chinese acupressure derived from acupuncture is a non-invasive technique . Despite renewed interest in the use of acupressure , relatively few studies have been undertaken to examine its effects on primary dysmenorrhoea . METHODS An experimental study was conducted between December 2000 and August 2001 . Participants were female students attending a technical college in Taiwan . None of the 69 participants had a prior history of gynaecological disease or secondary dysmenorrhoea , and all were rated higher than five for pain on a visual analogue scale from 0 to 10 . The experimental group ( n = 35 ) received acupressure at Sanyinjiao ( above the ankle ) while the control group ( n = 34 ) rested for 20 min , while the control group underwent rest in the school health centre for 20 min without receiving acupressure . Fifty participants ( 30 experimental , 20 control ) completed the 4 - 6-week follow-up session . Five instruments were used to collect pretest and post-test data at each session : ( 1 ) Visual Analogue Scale for pain ; ( 2 ) the Short-Form McGill Pain Question naire ; ( 3 ) the Menstrual Distress Question naire ; ( 4 ) the Visual Analogue Scale for anxiety ; and , for the experimental group only , ( 5 ) the Acupressure Self- Assessment Form . Data were analysed using the chi-square test , two- sample t-test and repeated measures two-way anova . RESULTS Acupressure at Sanyinjiao during the initial session reduced the pain and anxiety typical of dysmenorrhoea . In the self-treatment follow-up session , acupressure at Sanyinjiao significantly reduced menstrual pain but not anxiety . Thirty-one ( 87 % ) of the 35 experimental participants reported that acupressure was helpful , and 33 ( 94 % ) were satisfied with acupressure in terms of its providing pain relief and psychological support during dysmenorrhoea . CONCLUSION The findings suggest that acupressure at Sanyinjiao can be an effective , cost-free intervention for reducing pain and anxiety during dysmenorrhoea , and we recommend its use for self-care of primary dysmenorrhoea [16488895] Abstract Objective To evaluate the effectiveness of acupressure in terms of disability , pain scores , and functional status . Design R and omised controlled trial . Setting Orthopaedic clinic in Kaohsiung , Taiwan . Participants 129 patients with chronic low back pain . Intervention Acupressure or physical therapy for one month . Main outcome measures Self administered Chinese versions of st and ard outcome measures for low back pain ( primary outcome : Rol and and Morris disability question naire ) at baseline , after treatment , and at six month follow-up . Results The mean total Rol and and Morris disability question naire score after treatment was significantly lower in the acupressure group than in the physical therapy group regardless of the difference in absolute score ( - 3.8 , 95 % confidence interval - 5.7 to - 1.9 ) or mean change from the baseline ( - 4.64 , - 6.39 to - 2.89 ) . Acupressure conferred an 89 % ( 95 % confidence interval 61 % to 97 % ) reduction in significant disability compared with physical therapy . The improvement in disability score in the acupressure group compared with the physical group remained at six month follow-up . Statistically significant differences also occurred between the two groups for all six domains of the core outcome , pain visual scale , and modified Oswestry disability question naire after treatment and at six month follow-up . Conclusions Acupressure was effective in reducing low back pain in terms of disability , pain scores , and functional status . The benefit was sustained for six months [15207999] BACKGROUND Although acupressure has been reported to be effective in managing various types of pain , its efficacy in relieving pain associated with low back pain ( LBP ) remains unclear . The aim of this study is to compare the efficacy of acupressure with that of physical therapy in reducing low back pain . METHODS A r and omized controlled clinical trial in an orthopedic referral hospital in Taiwan was conducted between December 20 , 2000 , and March 2 , 2001 . A total of 146 participants with chronic low back pain were r and omly assigned to the acupressure group ( 69 ) or the physical therapy group ( 77 ) , each with a different treatment technique . Self-appraised pain scores were obtained before treatment as baseline and after treatment as outcomes using the Chinese version of Short-Form Pain Question naire ( SF-PQ ) . RESULTS There were no significant differences in baseline characteristics among patients r and omized into the two groups . The mean of posttreatment pain score after a 4-week treatment ( 2.28 , SD = 2.62 ) in the acupressure group was significantly lower than that in the physical therapy group ( 5.05 , SD = 5.11 ) ( P = 0.0002 ) . At the 6-month follow-up assessment , the mean of pain score in the acupressure group ( 1.08 , SD = 1.43 ) was still significantly lower than that in the physical therapy group ( 3.15 , SD = 3.62 ) ( P = 0.0004 ) . CONCLUSIONS Our results suggest that acupressure is another effective alternative medicine in reducing low back pain , although the st and ard operating procedures involved with acupressure treatment should be carefully assessed in the future [14608559] The purpose of this study was to evaluate the effectiveness of acupressure b and s , droperidol , and the combined modalities , administered preoperatively , in reducing PONV in inpatient gynecologic patients . One hundred and forty-three patients were r and omized to one of four groups : droperidol and acupressure b and s , droperidol and placebo b and s , placebo drug and acupressure b and s , or placebo drug and placebo b and s. Overall , during their hospital stay , 69 % of the women experienced PONV and 45 % experienced vomiting at some time . Although droperidol was most effective the day of surgery , neither acupressure b and s or droperidol were effective in reducing PONV [15136963] Fatigue and depressive mood are the most significant symptoms experienced by patients with end-stage renal disease . The purpose of this study was to examine the effectiveness of acupressure with massage in fatigue and depression in patients with end-stage renal disease ( ESRD ) receiving hemodialysis treatment . The study applied an experimental pretest and posttest design . Sixty-two hemodialysis patients participated in the study . Data were collected from two hemodialysis clinics in major hospitals in southern Taiwan . Following consent to the study , subjects were r and omly assigned to an acupressure group or a control group . Patients in the acupressure group received acupoint massage for 12 minutes per day , three days per week , for four weeks . Subjects in the control group only received routine unit care . The measures included the Revised Piper Fatigue Scale , and Beck ' s Depression Inventory . Descriptive statistics , chi 2 tests , t-test and analyses of covariance were used for data analysis . The results indicate that subjects experienced a moderate level of fatigue . Nearly 65 % of hemodialysis patients had a depressed mood . ANCOVA results indicated that fatigue ( F((1.54 ) ) = 9.05 , p = .004 ) and depression ( F((1.54 ) ) = 4.20 , p = .045 ) among patients in the acupressure group showed significantly greater improvement than patients in the control group . The findings of this study provide an interventional model for nurses taking care of ESRD patients [11303547] OBJECTIVE To find out whether acupressure wristb and can alleviate nausea and vomiting in early pregnancy . DESIGN Double-blind , placebo-controlled study . SUBJECTS 97 women with mean gestational length completed 8 - 12 weeks . MAIN OUTCOME MEASURES Symptoms were recorded according to intensity , duration and nature of complaints . RESULTS 71 % of women in the intervention group reported both less intensive morning sickness and reduced duration of symptoms . The same tendency was seen in the placebo group , with 59 % reporting less intensity and 63 % shorter duration of symptoms . However , a significance level of 5 % was reached only in the case of duration of symptoms , which was reduced by 2.74 hours in the intervention group compared to 0.85 hours in the placebo group ( p = 0.018 ) . CONCLUSIONS Acupressure wristb and might be an alternative therapy for morning sickness in early pregnancy , especially before pharmaceutical treatment is considered [16895618] Background and objectives : To evaluate the effectiveness of acupressure in preventing nausea and vomiting in patients undergoing gynaecological operations and receiving a patient‐controlled analgesia device . Methods : Patients aged between 40 and 65 yr were included . Exclusion criteria were obesity , diabetes mellitus , and history of motion sickness , postoperative nausea and vomiting , or smoking . Patients were r and omized into one of two groups , acupressure and control . In the acupressure group , acupressure b and s were placed on both wrists with the plastic bead positioned at the P6 point . In controls , beads were placed at a non‐acupoint site . All patients received a st and ard general anaesthetic . Postoperatively , patients were connected to a patient‐controlled analgesia device with morphine ( loading dose 5 mg , background infusion 1 mg h−1 , bolus dose 1 mg and lock‐out time 10 min ) . Pain and sedation scores , respiratory rate , heart rate , arterial pressure and oxygen saturation were recorded for 24 h. Metoclopramide 10 mg was administered intravenously as a rescue antiemetic . Results : Fifty patients received acupressure and 50 were controls . In the acupressure group , 33 % of patients had nausea compared with 63 % controls . The cumulative incidence of vomiting at 24 h was 25 % with acupressure and 61 % in controls . The incidence of nausea , vomiting and antiemetic use was significantly lower with acupressure . Conclusions : Acupressure at the P6 meridian point is an effective alternative for the prevention of nausea and vomiting in patients receiving patient‐controlled analgesia with morphine after gynaecological surgery [15004444] Objective : The aim of this study was to evaluate the antiemetic effect of acupuncture ( AP ) and acupressure ( APr ) of the Pc 6 acupoint in pregnant women with hyperemesis gravidarum ( HG ) . Methods : A prospect i ve , placebo-controlled trial included 36 pregnant women with HG . Two methods of acupuncture were used : bilateral manual AP of the Pc 6 ( Neiguan ) acupoint ( group 1 , n = 10 ) and bilateral APr of the Pc 6 acupoint ( group 2 , n = 11 ) ; furthermore , superficial intracutaneous placebo AP ( group 3 , n = 8) and placebo APr ( group 4 , n = 7 ) was carried out . Results : Anxiodepressive symptoms occurred in 9 pregnant women with HG from group 1 , 8 women from group 2 , 7 women from group 3 , and 5 women from group 4 ( p < 0.001 ) . The average gestation age at the occurrence of HG symptoms and the beginning of treatment was 7 weeks in group 1 and 8 weeks in groups 2 , 3 , and 4 . Four women from group 1 and 7 women from groups 2 , 3 , an 4 needed intravenous compensation of liquid and electrolytes . The antiemetic metoclopramide was given intravenously to 1 woman from group 1 , 2 women from group 2 , 6 women from group 3 , and 4 women from group 4 . Promethazine was given to 1 woman from group 2 , 1 woman from group 3 , and to 3 women from group 4 . The efficiency of the HG treatment with AP of the point Pc 6 was 90 % , with APr of the Pc 6 63.6 % , with placebo AP 12.5 % , and with placebo APr 0 % . Conclusion : Acupuncture ( p < 0.0001 ) and acupressure ( p < 0.1 ) are effective , nonpharmacologic methods for the treatment of HG [14720242] BACKGROUND Patients with chronic obstructive pulmonary disease ( COPD ) suffer from dyspnoea in their daily life and this may be increased by anxiety . Acupressure may promote relaxation and relieve dyspnoea . Thus , it is appropriate to explore the effectiveness of acupressure on dyspnoea in patients with COPD . AIMS To compare outcomes of acupressure using sham acupoints on different meridians and ganglionic sections with that using true acupoints , in patients with COPD who are living at home . METHODS Patients diagnosed with COPD were selected from a medical centre and three regional hospitals in Taipei . A r and omized block experimental design was used . Using age , sex , pulmonary function , smoking , and steroid use as matching factors , 44 patients were r and omly assigned either to a true acupoint acupressure or a sham group . The true acupoint acupressure group received a programme to decrease dyspnoea . Those in the sham group received acupressure using sham pressure points . Both acupressure programmes consisted of five sessions per week lasting 16 minutes per session , extending over 4 weeks for a total of 20 sessions . Before acupressure was initiated and at the conclusion of the 20th session , the Pulmonary Functional Status and Dyspnoea Question naire-modified scale and the Spielberger State Anxiety scale were administered , and a 6-minute walking distance test was performed . Physiological indicators of oxygen saturation and respiratory rate were measured before and after every session . RESULTS The results of this study showed that the pulmonary function and dyspnoea scores , 6-minute walking distance measurements , state anxiety scale scores , and physiological indicators of the true acupoint acupressure group improved significantly compared with those of the sham group . CONCLUSIONS The findings suggest that acupressure can be used as a nursing intervention to improve dyspnoea in patients with COPD [12165194] OBJECTIVES To develop and test the safety and effectiveness of an acupressure garment ( the Relief Brief ) in decreasing the pain and symptom distress associated with dysmenorrhea . DESIGN A r and omized clinical trial applied a 2 ( Relief Brief use or control group ) x 3 ( baseline and two treatment measurement occasions ) mixed factorial design . PARTICIPANTS Sixty-one ( 61 ) women with moderately severe primary dysmenorrhea were r and omly assigned to the st and ard treatment control group or the Relief Brief acupressure device group after one pretreatment menses , with 58 women reporting the effect on their pain during two post-treatment menstrual cycles . The acupressure garment : The Relief Brief is a cotton Lycra panty brief with a fixed number of lower abdominal and lower back latex foam acupads that provide pressure to dysmenorrhea-relieving Chinese acupressure points . OUTCOME MEASURES Menstrual pain severity ( worst pain and symptom intensity ) , pain medication use , and adverse effects were analyzed using between-groups and repeated measures analyses of treatment effects . Statistical and clinical significance criteria were applied a priori . RESULTS For pain measures and pain medication use , the group main effect , time main effect and group x time interaction were statistically significant . Median pain medication use , the same for both groups at baseline ( 6 pills per day ) , dropped to 2 pills per day for the Relief Brief group but remained at 6 pills for the control group at the second treatment cycle . Predicted clinical significance criteria were surpassed : almost all ( 90 % ) women wearing the Relief Brief obtained at least a 25 % reduction in menstrual pain severity ( a 2 - 3 point drop ) compared to only 8 % of the control group ( z = 6.07 ; p < 0.05 ) . Relief Brief use was associated with at least a 50 % decline in menstrual pain symptom intensity in more than two thirds of the women . CONCLUSIONS An acupressure device is an effective and safe nonpharmacologic strategy for the treatment of primary dysmenorrhea . With design modifications , it could serve as a main treatment modality for women who suffer from primary dysmenorrhea and do not wish to or can not use the conventional pharmacologic agents . In addition , this acupressure device may serve as an adjuvant therapy to medication in more severe cases of dysmenorrhea [12801491] OBJECTIVES To assess the effectiveness of continuous PC6 acupressure as an adjunct to antiemetic drug therapy in the prevention and control of nausea and vomiting in the first 24h after myocardial infa rct ion ( MI ) . DESIGN Partially r and omised , partially blinded placebo-controlled , exploratory clinical study . SETTING Coronary Care Unit , Torbay Hospital , Torquay , Devon . PARTICIPANTS A total of 301 consecutive patients ( 205 males , 96 females ) admitted following acute MI . INTERVENTION The first 125 patients recruited received no additional intervention . Subsequent patients were r and omised to receive either continuous PC6 acupressure or placebo acupressure . OUTCOME MEASURES ( 1 ) Incidence of post-MI nausea and /or vomiting , ( 2 ) severity of symptoms , ( 3 ) use of antiemetic drugs , over 24h . RESULTS There were no significant differences between the groups for the whole 24-h treatment period . However , the PC6 acupressure group experienced significantly lower incidence of nausea and /or vomiting during the last 20h ( 18 % ) , compared with the placebo ( 32 % ) or control ( 43 % ) groups ( P<0.05 ) . The severity of symptoms and the need for antiemetic drugs were also reduced in the acupressure group , but these differences were not statistically significant . CONCLUSIONS Continuous 24-h PC6 acupressure therapy as an adjunct to st and ard antiemetic medication for post-MI nausea and vomiting is feasible and is well accepted and tolerated by patients . In view of its benefits , further studies are worthwhile using earlier onset of treatment [17920972] BACKGROUND Pain during transportation is a common phenomenon in emergency medicine . As acupressure has been deemed effective for pain management by the National Institutes of Health , we conducted a study to evaluate its effectiveness in prehospital patients with isolated distal radial fracture . METHODS This was a prospect i ve , r and omized , double-blind study . Thirty-two patients were enrolled . Acupressure was performed either at " true " points or at " sham " points . Vital signs and pain and anxiety scores were recorded before and after the acupressure treatment . Normally distributed values were compared using the Student t test . RESULTS Pretreatment scores for pain and anxiety were similar in the 2 groups ( 47.6 + /- 8.9 vs 51.2 + /- 8.7 visual analog scale [ VAS ] score for pain , 52.4 + /- 6.0 vs 47.5 + /- 9.3 VAS score for anxiety ) . At the hospital , patients in the true-points group had significantly lower pain ( 36.6 + /- 11.0 vs 56.0 + /- 13.3 VAS score , P < .001 ) and anxiety scores ( 34.9 + /- 22.2 vs 53.4 + /- 19.7 VAS score , P = .022 ) . CONCLUSION Acupressure in the prehospital setting effectively reduces pain and anxiety in patients with distal radial trauma [12198060] Untreated pain during the transportation of patients after minor trauma is a common problem in emergency medicine . Because paramedics usually are not allowed to perform invasive procedures or to give drugs for pain treatment , a noninvasive , nondrug-based method would be helpful . Acupressure is a traditional Chinese treatment for pain that is based on pain relief followed by a short mechanical stimulation of specific points . Consequently , we tested the hypothesis that effective pain therapy is possible by paramedics who are trained in acupressure . In a double-blinded trial we included 60 trauma patients . We r and omly assigned them into three groups ( “ true points , ” “ sham-points , ” and “ no acupressure ” ) . An independent observer , blinded to the treatment assignment , recorded vital variables and visual analog scales for pain and anxiety before and after treatment . At the end of transport , we asked for ratings of overall satisfaction . For statistical evaluation , one-way analysis of variance and the Scheffé F test were used . P < 0.05 was considered statistically significant . Morphometric and demographic data and potential confounding factors such as age , sex , pain , anxiety , blood pressure , and heart rate before treatment did not differ among the groups . At the end of transport we found significantly less pain , anxiety , and heart rate and a greater satisfaction in the “ true points ” groups ( P < 0.01 ) . Our results show that acupressure is an effective and simple-to-learn treatment of pain in emergency trauma care and leads to an improvement of the quality of care in emergency transport . We suggest that this technique is easy to learn and risk free and may improve paramedic-based rescue systems [16131291] BACKGROUND Previous reports have suggested that acupressure is effective in reducing pain and improving sleep quality ; however , its effects on alertness have not been characterized . OBJECTIVES The aim of this study was to determine whether two different acupressure treatments have opposing effects on alertness in a full-day classroom setting . DESIGN This was a cross-over ( two-treatments ; three periods ) , single-blinded , r and omized trial . SETTING The University of Michigan School of Public Health was the setting . SUBJECTS Students attending a course in clinical research design and statistical analysis at the University of Michigan participated in the study . INTERVENTIONS AND OUTCOME MEASURES Blinded subjects were r and omized to two acupressure treatment sequences : stimulation-relaxation-relaxation or relaxation-stimulation-stimulation . Acupressure treatments were self administered over 3 consecutive days . Pre- and post-treatment alertness scores were assessed each day using the Stanford Sleepiness Scale ( SSS ) . Changes in the SSS score ( afternoon-morning ) were analyzed using a mixed regression model of fixed and r and om effects . Important factors that were expected to affect alertness , such as caffeine and previous night 's sleep , were also assessed . RESULTS Baseline characteristics and protocol compliance were similar between the two sequences . Stimulation acupressure treatment yielded a 0.56-point greater difference in score on the SSS , corresponding to less fatigue , compared to the relaxation acupressure treatment ( p = 0.019 ) . Day of study ( p = 0.004 ) and hours of overnight sleep ( p = 0.042 ) also significantly affected the change in SSS scores . Incorporating participants ' beliefs as to which treatment they received did not significantly alter the observed treatment effect . CONCLUSIONS Acupressure at stimulation and relaxation points has differential effects on alertness in a classroom setting . Further research is necessary to confirm these findings and to determine whether stimulation and relaxation acupressure are equally effective in influencing alertness [19134445] The objective of this study was to determine the feasibility and effectiveness of acupressure therapy in preventing chemotherapy-associated nausea in children . A prospect i ve , r and omized , crossover trial was conducted among pediatric oncology patients at Brenner Children 's Hospital ( Winston-Salem , NC ) . Patients were r and omized to one of two treatment sequences involving acupressure wrist b and s and placebo b and s , separated by a st and ard care treatment with no b and s. All patients received st and ard antiemetic therapy for each treatment . Expectations and outcomes of nausea and vomiting were assessed by question naires . Of 21 patients approached , 21 were enrolled and 18 completed all three study treatments . Patients ' ages ranged from 5 to 19 years , 14 of 18 were Caucasian , and 9 were male . In general , patients expressed moderate expectations that acupressure would prevent nausea and vomiting . Following the session with an acupressure b and , a third of all patients reported better than expected nausea prevention . There was no significant difference in nausea or vomiting between the three groups ; there were no significant side effects from acupressure or placebo b and s. Pediatric oncology patients have moderate expectations about the effectiveness of acupressure in preventing nausea and vomiting . Acupressure is feasible and well tolerated but was not more effective than placebo in this sample of patients who were also treated with st and ard antiemetic therapies [12477673] Purpose To investigate the effect of sensory stimulation of the P6 point on postoperative nausea and vomiting ( PONV ) after gynecological surgery in the everyday clinical setting ( effectiveness study ) . Methods Four hundred and ten women undergoing general anesthesia for elective gynecological surgery were included in a prospect i ve , consecutive , r and omized , multicentre , placebo-controlled , double-blind clinical trial with a reference group . One group was given bilateral P6 acupressure ( n = 135 ) , a second group similar pressure on bilateral non-acupressure points ( n = 139 ) , and a third group ( n = 136 ) served as reference group . Nausea ( scale 0–6 ) , vomiting , pain , and satisfaction with the treatment were recorded . Primary outcome was complete response , i.e. , no nausea , vomiting or rescue medication for 24 hr . Results were analyzed by applying logistic regression with indicators of treatments , type of operation and risk score for PONV as explanatory variables . Results Complete response was more frequent in the P6 acupressure group than in the reference group ( P = 0.0194 ) Conversely , the incidence of PONV was 46 % in the reference group , 38 % after pressure on a non-acupoint and 33 % after P6 acupressure . The decrease from 46 % to 33 % was statistically significant . When considering vaginal cases separately , the decrease in PONV was from 36 % to 20 % ( P = 0.0168 ) . The corresponding decrease from 59 % to 55 % in the laparoscopic surgery group was not statistically significant . Conclusion P6 acupressure is a non-invasive method that may have a place as prophylactic antiemetic therapy during gynecological surgery . RésuméObjectifRechercher l’effet d’une stimulation sensorielle acupressive en P6 sur les nausées et vomissements postopératoires ( NVPO ) à la suite d’une intervention chirurgicale gynécologique dans un cadre clinique normal ( étude d’efficacité).MéthodeUn essai clinique prospect if , r and omisé , multicentrique , en double aveugle contre placebo et comportant un groupe de référence a été réalisé auprès de 410 femmes qui se sont présentées successivement pour une intervention gynécologique non urgente sous anesthésie générale . Les patientes d’un premier groupe ont reçu de l’acupression en P6 ( n = 135 ) , celles d’un second groupe ont reçu une pression semblable sur des points bilatéraux , non d’acupression , ( n = 139 ) et un troisième groupe ( n = 136 ) a servi de référence . Les nausées ( échelle de 0–6 ) , les vomissements , la douleur et la satisfaction face au traitement ont été notés . Le premier résultat était une réponse complète , donc absence de nausées , de vomissements ou de médication de secours pendant 24 h. Les résultats ont été analysés par régression logistique avec des indicateurs de traitements , le type d’intervention et le taux de risque de NVPO comme variables explicatives . RésultatsLa réponse complète a été plus fréquente avec l’acupression en P6 que chez les patientes témoins ( P = 0,0194 ) . Inversement , l’incidence de NVPO a été de 46 % dans le groupe de référence , 38 % après une pression de points non acupresseurs et 33 % après l’acupression en P6 . La diminution de 46 % à 33 % était significative . L’examen séparé des cas d’intervention vaginale indique une baisse des NVPO de 36 % à 20 % ( P = 0,0168 ) . La baisse correspondante de 59 % à 55 % dans les cas d’intervention laparoscopique n’était pas significative . Conclusion L’acupression en P6 représente une méthode non effractive de traitement antiémétique prophylactique qui peut avoir sa place pendant une intervention gynécologique [15344424] The purpose of this study was to test the effectiveness of acupressure and Transcutaneous Electrical Acupoint Stimulation ( TEAS ) on fatigue , sleep quality and depression in patients who were receiving routine hemodialysis treatment . The study was a r and omized controlled trial ; qualified patients were r and omly assigned to acupressure , TEAS or control groups . Patients in the acupressure and TEAS groups received 15 minutes of treatment 3 times a week for 1 month , whereas patients in the control group only received routine unit care . A total of 106 patients participated in the study . Methods of measurement included the revised Piper Fatigue Scale ( PFS ) , the Pittsburgh Sleep Quality Index and the Beck Depression Inventory . Data were collected at baseline , during the intervention and post-treatment . The results indicated that patients in the acupressure and TEAS groups had significantly lower levels of fatigue , a better sleep quality and less depressed moods compared with patients in the control group based upon the adjusted baseline differences . However , there were no differences between acupressure and TEAS groups in outcome measures . This study provides an alternative method for health care providers in managing dialysis patients with symptoms of fatigue , poor sleep or depression [11584487] OBJECTIVE To compare the antiemetic effect of acupressure at the Neiguan point ( P6 ) in a group of healthy women with normal pregnancy and nausea and vomiting during pregnancy ( NVP ) with a similar group receiving acupressure at a placebo point and another , similar group not receiving any treatment . STUDY DESIGN A r and omized , placebo-controlled , pilot study involving 60 women . RESULTS It is possible to reduce NVP significantly with acupressure at P6 as compared to acupressure at a placebo point or no treatment at all in healthy women with normal pregnancies . Relief from nausea appeared one day after starting treatment in both the P6 and placebo groups but lasted for only six days in the placebo group . The P6 group , however , experienced significantly less nausea after 14 days as compared to the other two groups . CONCLUSION This study involved 60 healthy women with normal pregnancy and suffering from NVP . According to the results , in healthy women with normal pregnancy it is possible to reduce NVP significantly at P6 as compared to acupressure at a placebo point and to no treatment [12139646] BACKGROUND Post-operative nausea and vomiting is a common complication following general anaesthesia . Traditional Chinese medicine indicates that acupressure therapy may reduce nausea and vomiting in certain ailments . AIM ( S ) OF THE STUDY The aim of this study was to examine the effect of stimulating two acupressure points on prevention of post-operative nausea and vomiting . DESIGN AND METHODS A r and omized block experimental design was used . The Rhodes Index of Nausea , Vomiting and Retching ( INVR ) question naire was used as a tool to measure incidence . To control the motion sickness variable , the subjects who underwent functional endoscopic sinus surgery ( FESS ) under general anaesthesia were r and omly assigned to a finger-pressing group , a wrist-b and group , and a control group . There were 150 subjects in total with each group consisting of 50 subjects . The acupoints and treatment times were similar in the finger-pressing group and wrist-b and pressing group , whereas only conversation was employed in the control group . RESULTS Significant differences in the incidence of the post-operative nausea and vomiting were found between the acupressure , wrist-b and , and control groups , with a reduction in the incidence rate of nausea from 73.0 % to 43.2 % and vomiting incidence rate from 90.5 % to 42.9 % in the former . The amount of vomitus and the degree of discomfort were , respectively , less and lower in the former group . CONCLUSION In view of the total absence of side-effects in acupressure , its application is worthy of use . This study confirmed the effectiveness of acupressure in preventing post-operative nausea and vomiting [12670382] BACKGROUND Traditional Chinese acupressure is a noninvasive technique that employs pressure and massage to acupoints in order to stimulate the balance of life energy that promotes health and comfort . Sleep disturbance is common in patients with end-stage renal disease but no intervention studies have addressed this problem . Aim . The purpose of the present study was to test the effectiveness of acupoints massage for patients with end-stage renal disease and experiencing sleep disturbances and diminished quality of life . METHODS The study was a r and omized control trial . A total of 98 end-stage renal disease patients with sleep disturbances were r and omly assigned into an acupressure group , a sham acupressure group , and a control group . Acupressure and sham acupressure group patients received acupoints or no acupoints massage three times a week during haemodialysis treatment for a total of 4 weeks . The measures included the Pittsburgh Sleep Quality Index , Sleep Log , and the Medical Outcome Study - Short Form 36 . FINDINGS The results indicated significant differences between the acupressure group and the control group in Pittsburgh Sleep Quality Index subscale scores of subjective sleep quality , sleep duration , habitual sleep efficiency , sleep sufficiency , and global Pittsburgh Sleep Quality Index scores . Sleep log data revealed that the acupressure group significantly decreased wake time and experienced an improved quality of sleep at night over the control group . Medical Outcome Study - Short Form 36 data also documented that acupressure group patients experienced significantly improved quality of life . CONCLUSION This study supports the effectiveness of acupoints massage in improving the quality of sleep and life quality of end-stage renal disease patients , and offers a noninvasive therapy for sleep-disturbed patients [10660922] PURPOSE / OBJECTIVES To compare differences in nausea experience and intensity in women undergoing chemotherapy for breast cancer between those receiving usual care plus acupressure training and treatment and those receiving only usual care . DESIGN Single-cycle , r and omized clinical trial . SETTING Outpatient oncology clinic in a major teaching medical center and a private outpatient oncology practice . SAMPLE Seventeen women participated in the study . The typical participant was 49.5 years old ( SD = 6.0 ) , Caucasian ( 59 % ) , not married/partnered ( 76 % ) , on disability ( 53 % ) , born a U.S. citizen ( 76 % ) , and heterosexual ( 88 % ) ; lived alone ( 59 % ) ; had at least graduated from high school ( 100 % ) ; and had an annual personal income of $ 50,000 or greater ( 65 % ) . METHODS The intervention included finger acupressure bilaterally at P6 and ST36 , acupressure points located on the forearm and by the knee . Baseline and post study question naires plus a daily log were used to collect data . MAIN RESEARCH VARIABLES Nausea experience measured by the Rhodes inventory of Nausea , Vomiting , and Retching and nausea intensity . FINDINGS Significant differences existed between the two groups in regard to nausea experience ( p < 0.01 ) and nausea intensity ( p < 0.04 ) during the first 10 days of the chemotherapy cycle , with the acupressure group reporting less intensity and experience of nausea . CONCLUSIONS Finger acupressure may decrease nausea among women undergoing chemotherapy for breast cancer . IMPLICATION S FOR NURSING PRACTICE This study must be replicated prior to advising patients about the efficacy of acupressure for the treatment of nausea [14670399] The purpose of the study is to investigate the effectiveness of acupressure on fatigue in patients with end-stage renal-disease ( ESRD ) . The study was a r and omized control trial ; qualified patients were r and omly assigned into acupressure group , sham group or control group . A total of 106 participants were included in the study . The measures included the revised Piper Fatigue Scale ( PFS ) , VAS of Fatigue , the Pittsburgh Sleep Quality Index and the Beck Depression Inventory . Data of fatigue measures were collected at pretreatment and a week following treatment . Sleep quality and depression were collected during post-test only . The statistical methods included the descriptive statistics , one-way ANOVA , ANCOVA , and repeated- measures ANOVA . ANCOVA that adjusted for differences in baseline fatigue scores ( PFS ) , post-test of depression and sleep quality , result was significant , F(2,100)=3.99 , p=0.02 . Post-hoc tests revealed that patients in the acupressure group were significantly having lower scores of fatigue than patients in the control group . ANCOVA results also significant for VAS of Fatigue among groups , F(2,100)=5.63 , p=0.003 . Comparisons indicated that there were significant differences between the acupressure group and the control group ( p=0.01 ) and between the sham group and control group ( p=0.003 ) . Predialysis fatigue was assessed routinely by using a rating of 0 - 10 . Repeated- measures ANOVA results demonstrate the group main effect was significant in the perceived fatigue ( F(2,88)=19.46 , p<0.001 ) . Follow-up tests indicated there were significant differences between the acupressure group and the control group ( p<0.001 ) and between the sham group and control group ( p<0.001 ) . The study provided an alternative method for health care providers to managing ESRD patients with fatigue [17402962] AIMS AND OBJECTIVES To examine and compare the effects of acupressure on the perceived health-related quality of life of the participants with bronchiectasis . BACKGROUND In an attempt to offer comfort , pain control and symptom management , nursing is becoming increasingly involved in offering complementary-alternative medicine as part of its caring-healing focus in comprehensive patient care . Acupressure is one such modality that is being increasingly used by both medical and nursing professionals . While acupressure has been reported to have beneficial effects in patients with respiratory disease , the benefits to bronchiectasis patients have remained uncertain . DESIGN A r and omized , partially blinded study consisting of three groups . METHODS Thirty-five out- patients of both genders , aged 59.46 SD 11.52 years , who were suffering from bronchiectasis , were r and omly split into one of three groups : st and ard care with supplemental acupressure for eight weeks ( 11 participants ) ; st and ard care with supplemental sham acupressure for eight weeks ( 11 participants ) ; and st and ard care alone ( 13 participants ) . Outcomes were determined by changes in daily sputum amounts , sputum self- assessment , six-minute walking distance , breathing difficulty ( measured on the dyspnea visual analogue scale ) and health-related quality of life ( measured by the Saint George Respiratory Question naire ) . RESULTS The sputum self- assessment score improved over time for the sham acupressure participants ( P = 0.03 ) , when compared with the controls . For acupressure participants , the Saint George respiratory question naire activity component scores also improved over time , compared with controls ( P = 0.01 ) after adjustment for covariates ( treatment , time , age , sex and baseline values ) . Other variables did not differ between the st and ard care alone group and the other two groups . CONCLUSIONS Eight weeks of self-administered acupressure could be useful in reducing the effects of bronchiectasis on a patient 's daily activities . RELEVANCE TO CLINICAL PRACTICE Acupressure may be regarded as a viable nursing intervention [15673989] OBJECTIVE The purpose of this study was to evaluate the effects of SP6 acupressure on labor pain and delivery time in women in labor . DESIGN R and omized clinical trial . SETTING /LOCATION Delivery room in a university hospital . PARTICIPANTS Seventy-five ( 75 ) women in labor were r and omly assigned to either the SP6 acupressure ( n = 36 ) or SP6 touch control ( n = 39 ) group . The participants were matched according to parity , cervical dilation , labor stage , rupture of amniotic membrane , and husb and 's presence during labor . There were no additional oxytocin augmentation or administration of analgesics during the study period . INTERVENTION The 30-minute acupressure or touch on SP6 acupoint was performed . OUTCOME MEASURES Labor pain was measured four times using a structured question naire , a subjective labor pain scale ( visual-analogue scale [ VAS ] ) : before intervention , immediately after the intervention , and 30 and 60 minutes after the intervention . Length of delivery time was calculated in two stages : from 3 cm cervical dilation to full cervical dilatation , and full cervical dilatation to the delivery . RESULTS There were significant differences between the groups in subjective labor pain scores at all time points following the intervention : immediately after the intervention ( p = 0.012 ) ; 30 minutes after the intervention ( p = 0.021 ) ; and 60 minutes after the intervention ( p = 0.012 ) . The total labor time ( 3 cm dilatation to delivery ) was significantly shorter in the SP6 acupressure intervention group than in the control group ( p = 0.006 ) . CONCLUSIONS These findings showed that SP6 acupressure was effective for decreasing labor pain and shortening the length of delivery time . SP6 acupressure can be an effective nursing management for women in labor [12906958] As an adjunct to st and ard antiemetics for the relief of chemotherapy-induced nausea and vomiting ( NV ) , 739 patients were r and omly assigned to either : 1 ) acupressure b and s , 2 ) an acustimulation b and , or 3 ) a no b and control condition . Patients in the acupressure condition experienced less nausea on the day of treatment compared to controls ( P<0.05 ) . There were no significant differences in delayed nausea or vomiting among the three treatment conditions . Additional analyses revealed pronounced gender differences . Men in the acustimulation condition , but not the acupressure condition , had less NV compared to controls ( P<0.05 ) . No significant differences among the three treatment conditions were observed in women , although the reduction in nausea on the day of treatment in the acupressure , compared to the no b and condition , closely approached statistical significance ( P=0.052 ) . Expected efficacy of the b and s was related to outcomes for the acupressure but not the acustimulation conditions [6074339] Ann Saudi Med 28(4 ) July-August 2008 www.saudiannals.net 287 Nausea and vomiting almost always occur aft ter general and regional anesthesia . Despite minimally invasive surgical methods like lapt aroscopy and rapidt and shorttacting anesthesia , naut sea and vomiting after surgery remain a common probt lem.1t5 Nausea and vomiting can result in dehydration , electrolyte imbalance and delay in discharge from the hospital . Serious complications , such as pressure on the suture lines and venous hypertension , may also occur . The incidence of posttoperative nausea and vomiting ( PONV ) has been estimated as 60 % to 70 % following laparoscopic cholecystecomy.6t11 Various factors can int fluence PONV , such as the type of surgery , anesthesia technique , certain drugs , pain and vertigo upon walkt ing . In Chinese and acupuncture medicine , the P6 ( neit guam ) meridian point is recognized as a target point for reducing nausea and vomiting.12t17 Several studies have shown that stimulus of P6 results in a reduction in the incidence of nausea and vomiting after surgery.8,11t13 A Cochrane systemic review concluded that P6 acuprest sure point stimulation seems to reduce the risk of naut sea despite conflicting results in r and omized trials.18 Our study investigated the effect of placement of acut pressure wristb and s at the P6 point in decreasing naut sea and vomiting after laparoscopic cholecystectomy in comparison with metoclopramide [12550145] The purpose of the study is to test the effectiveness of acupressure on sleep quality of end-stage renal disease patients . The study was a r and omized controlled trial ; qualified patients in the dialysis centers of four major hospitals were r and omly assigned into an acupressure group , a sham acupressure group , and a control group . A total of 98 participants were included in the study . The main outcomes measured were the Pittsburgh sleep quality index ( PSQI ) and the sleep log . Data were collected at pretreatment and following treatment . Primary statistical analysis was by means of Analysis of Covariance , the Kruskal-Wallis Test and repeated measure ANOVA . The results indicated that PSQI scores of the acupressure group have a significantly greater improvement ( p < 0.01 ) than the control group . However , there were no differences between the acupressure group and the sham group or the sham group and the control group ( p > 0.05 ) . Subscales of PSQI were further analyzed . Results demonstrated significant differences between the acupressure group and the control group in subjective sleep quality ( p = 0.009 ) , sleep duration ( p = 0.004 ) , habitual sleep efficiency ( p = 0.001 ) , and sleep sufficiency ( p = 0.004 ) . Significant differences in the subscale of subjective sleep quality ( p = 0.003 ) between the sham acupressure group and the control group were also observed . Sleep log data showed that the acupressure group significantly decreased awake time and improved quality of sleep over time more than the control group ( p < 0.01 ) . The improvement could be seen as soon as the acupoints massage was implemented , and it was maintained through the post intervention [14973803] OBJECTIVE To determine whether the application of acupressure b and s would lead to a reduction in postoperative nausea and vomiting after cardiac surgery . DESIGN Prospect i ve , r and omized , double-blind clinical trial . SETTING University-affiliated tertiary care teaching hospital . PARTICIPANTS Adult patients undergoing cardiac surgery . INTERVENTIONS One hundred fifty-two patients were enrolled to receive either acupressure treatment ( n = 75 ) or placebo ( n = 77 ) . All patients had acupressure b and s placed on both wrists before induction of anesthesia ; those in the treatment group had a bead placed in contact with the P6 point on the forearm . MEASUREMENTS AND MAIN RESULTS Patients were assessed for nausea , vomiting , and pain scores during the first 24 hours of the postoperative period . The incidences of nausea , vomiting , pain scores , and analgesic and antiemetic requirements were similar between the 2 groups . A subgroup analysis by gender implied that acupressure treatment may be effective only in female patients . CONCLUSION Acupressure treatment did not lead to a reduction in nausea , vomiting , or antiemetic requirements in patients after cardiac surgery [14685931] Acupressure is said to promote the circulation of blood and qi , the harmony of yin and yang , and the secretion of neurotransmitters , thus maintaining the normal functions of the human body and providing comfort . However , there has been little research -based evidence to support the positive effects of acupressure in the area of obstetric nursing . The purpose of this study is to determine the effect of LI4 and BL67 acupressure on labor pain and uterine contractions during the first stage of labor . An experimental study with a pretest and posttest control group design was utilized . A total of 127 parturient women were r and omly assigned to three groups . Each group received only one of the following treatments , LI4 and BL67 acupressure , light skin stroking , or no treatment/conversation only . Data collected from the VAS and external fetal monitoring strips were used for analysis . Findings indicated that there was a significant difference in decreased labor pain during the active phase of the first stage of labor among the three groups . There was no significant difference in effectiveness of uterine contractions during the first stage of labor among the three groups . Results of the study confirmed the effect of LI4 and BL67 acupressure in lessening labor pain during the active phase of the first stage of labor . There were no verified effects on uterine contractions [17645494] AIM This paper is a report of a study to examine the effect of Nei-Guan point acupressure on nausea , vomiting and ketonuria levels in women diagnosed with hyperemesis gravidarum . BACKGROUND Previous studies have shown that acupressure application on the Nei-Guan point is effective in relieving nausea and vomiting associated with pregnancy and surgery . However , no findings have been supported by physiological data . METHOD A r and omized control group pretest-post-test design was implemented from 1 April 2003 to 30 April 2004 using three groups : a Nei-Guan point acupressure group , a placebo group and a control group which received only conventional intravenous treatment . The participants were 66 women admitted to two general hospitals in Korea with hyperemesis gravidarum . RESULTS The degree of nausea and vomiting was statistically significantly lower in the Nei-Guan point acupressure group in comparison with the placebo and control groups . Ketonuria levels were reduced over time and , on days three and four of hospitalization , levels in the treatment group were statistically significantly lower than in the placebo or control groups ( P < 0.05 ) . CONCLUSION Nei-Guan point acupressure is a useful treatment for relieving symptoms experienced by women with hyperemesis gravidarum [18054724] BACKGROUND Cancer-related fatigue after chemotherapy is a difficult symptom to manage in practice and the most disruptive symptom in patients ' lives . Acupuncture is a popular complementary therapy among cancer patients and some evidence exists that it could potentially alleviate fatigue by stimulating ' energy ' points in the body . Hence , this study was carried out to assess the effects of acupuncture and acupressure in managing cancer-related fatigue and the feasibility of running a r and omised trial with these two complementary therapies in preparation for a large trial . METHODS This study was a r and omised controlled trial . Forty-seven patients with cancer who experienced moderate to severe fatigue were r and omised either to an acupuncture group ( n=15 ) , an acupressure group ( n=16 ) or a sham acupressure group ( n=16 ) . The acupuncture group received six 20-min sessions over 2 weeks , while the patients in the two acupressure groups were taught to massage/press the points and did so daily thereafter for 2 weeks on their own . Patients completed the Multidimensional Fatigue Inventory before r and omisation , at the end of the 2-week intervention and again about 2 weeks after the end of the intervention . RESULTS Significant improvements were found with regards to General fatigue ( P<0.001 ) , Physical fatigue ( P=0.016 ) , Activity ( p=0.004 ) and Motivation ( P=0.024 ) . At the end of the intervention , there was a 36 % improvement in fatigue levels in the acupuncture group , while the acupressure group improved by 19 % and the sham acupressure by 0.6 % . Improvements were observed even 2 weeks after treatments , although they were lower ( 22 % , 15 % , 7 % , respectively ) . Acupuncture was a more effective method than acupressure or sham acupressure . Subjects needed a longer treatment period to have more sustained results . The trial was method ologically feasible . CONCLUSION Acupuncture shows great potential in the management of cancer-related fatigue . As a r and omised trial with acupuncture is feasible and preliminary data shows significant improvements , it should be tested further using a large sample and a multicentre design [19034253] AIM Insomnia is a major problem which decreases life quality . Many causes are involved with it and anxiety is often associated . The underlying mechanism is not completely understood , even though different factors seem to be associated . Among them melatonin and its circadian rhythm is thought to have an important role . In addition , acupressure and acupuncture are known to ameliorate insomnia and anxiety , when a specific wrist point is stimulated ( HT 7 Shenmen ) . With these bases , the aim of the present study has been to evaluate the efficacy of an acupressure device , ' ' H7-insomnia control ' ' , positioned on HT 7 points , during the night , in terms of general health and anxiety levels , together with the evaluation of sleep quality and the urinary melatonin metabolite 6-hydroxymelatonin sulphate determination , in a number of insomniacs . METHODS Forty patients with insomnia were divided into two groups and r and omly received either the H7 or placebo treatments , in a double-blind protocol , for 20 nights . Before and after treatments every subject answered a series of question naires ( General Health Question naire 28 items ; State-Trait Anxiety Inventory ; Pittsburgh Sleep Quality Index ) and collected 24 h urines , divided into two sample s of 12 h each . Urinary melatonin metabolite was then determined using a RIA method . RESULTS Data obtained indicate that the device H7-insomnia control is efficacious to ameliorate quality of sleep and reduce anxiety levels in insomniacs , at a higher extent than in the placebo group . In addition , the 24 hours urinary melatonin metabolite rhythm , obtained at the end of treatment , was considered as being normal in a higher percentage of H7-treated patients , with respect to the placebo group . CONCLUSION It is plausible to hypothesize that the wrist acupressure device might be considered a valid tool , without adverse effects since it does not contain pharmaceutical products , that is able to naturally ameliorate sleep quality in insomniacs , acting through a not jet completely clarified mechanism , that may involve melatonin [14629844] OBJECTIVES Acupuncture and acupressure are known to relieve symptoms associated with asthma , but the benefits to patients with chronic obstructive asthma have not been fully evaluated . In this pilot clinical study , acupuncture or acupressure was incorporated into the st and ard care for adult patients with chronic obstructive asthma to determine their contribution to the improvement of their quality of life and relief of symptoms . DESIGN A prospect i ve , r and omized study that involved 8 weeks of treatment at Chang Gung Memorial Hospital ( Tao-Yuan , Taiwan ) was conducted between March 1997 and September 1998 . Forty-one ( n = 41 ) patients with chronic obstructive asthma were enrolled . Patients were r and omly assigned to receive acupuncture in addition to st and ard care ( n = 11 ) , acupressure and st and ard care ( n = 17 ) , or st and ard care alone ( n = 13 ) . Twenty ( 20 ) acupuncture treatments were administered , and self-administered acupressure was performed daily for 8 weeks . Six-minute walking , the Dyspnea Visual Analogue Scale , the modified Borg scale , St. George 's Respiratory Question naire ( SGRQ ) , and the Bronchitis Emphysema Symptom Checklist ( BESC ) were used at the beginning and end of the 8 weeks of treatment . RESULTS The total SGRQ score of acupuncture subjects showed an average 18.5-fold improvement ( 95 % confidence interval [ CI ] 1.54 - 211.48 , p = 0.02 ) ; the improvement for the acupressure subjects was 6.57-fold ( 95 % C.I. 0.98 - 44.00 , p = 0.05 ) . Additionally , for patients who received acupressure , the irritability domain score determined by the BESC exhibited an 11.8-fold improvement ( 95 % C.I. 0.88 - 158.64 , p = 0.06 ) after adjustment for covariables . The other variables did not differ from those of the controls . CONCLUSIONS Patients with clinical ly stable , chronic obstructive asthma experienced clinical ly significant improvements in quality of life when their st and ard care was supplemented with acupuncture or acupressure [19328650] Previous studies have shown that acupressure b and s can reduce chemotherapy-related nausea . Patients ' expectations of efficacy account for part of this outcome . We conducted a three-arm r and omized clinical trial to investigate the effectiveness of acupressure b and s in controlling radiation therapy-induced nausea and to test whether an informational manipulation design ed to increase expectation of efficacy would enhance the effectiveness of the acupressure b and s. Patients who experienced nausea at prior treatments were r and omized to either st and ard care ( Arm 1 , n=29 ) or st and ard care plus acupressure b and s with either neutral ( Arm 2 , n=30 ) or positive ( Arm 3 , n=29 ) information regarding the efficacy of the b and s. Patients reported nausea for two days prior to r and omization ( baseline ) and for five days following using a seven-point semantic rating scale ( 1=not nauseated to 7=extremely nauseated ) . Patients in Arms 2 and 3 combined reported greater reduction in average nausea than patients in Arm 1 ( P=0.01 ; mean(b and s)=0.70 , mean(no b and s)=0.10 ) . This equates to a 23.8 % decrease in nausea in the b and groups compared to a 4.8 % decrease in the control group , a 19 % difference . The informational manipulation failed to alter efficacy expectations and there was no statistically significant difference in nausea between patients in Arms 2 and 3 . Acupressure b and s are an effective , low-cost , nonintrusive , well-accepted , and safe adjunct to st and ard antiemetic medication . An attempt to boost the efficacy of the acupressure b and s by providing positive information was not successful [10764175] Purpose : To evaluate the efficacy of acupressure wristb and s in the prevention of postoperative nausea and vomiting ( PONV ) . Methods : Two hundred ASAI - II patients undergoing elective endoscopic urological procedures were included in a r and omized , prospect i ve , double blind , placebo-controlled study . Spherical beads of acupressure wristb and s were placed at the P6 points in the anterior surface of both forearms in Group 1 patients ( acupressure group , n=100 ) whereas , in Group 2(control group , n=100 ) they were placed inappropriately on the posterior surface . The acupressure wristb and s were applied 30 min before induction of anesthesia and were removed six hours postoperatively . Anesthesia was induced with thiopental and maintained with nitrous oxide and oxygen , fentanly , isoflurane and vecuronium . The tracheas were extubated on the operation table after patients received neostigmine and atropine . Post operative nausea and vomiting were evaluated separately as none , mild , moderate or severe at the time of patient ’s arrival in PACU , then at six hours and twenty-four hours after surgery by a blinded observer . Results : In the acupressure group , 25 patients had PONV compared with 29 patients in the control group ( P = NS ) . Conclusion : Application of acupressure wristb and s at the P6 of both forearms 30 min before induction of anesthesia did not decrease the incidence of PONV in patients undergoing endoscopic urological procedures .RésuméObjectif : Évaluer l’efficacité de bracelets d’acupression utilisés pour la prévention des nausées et des vomissements postopératoires (NVPO).Méthode : Deux cents patients , ASA I – II , devant subir une intervention urologique endoscopique planifiée ont participé à l’étude r and omisée , prospect i ve et à double insu contre placebo . Des bracelets de billes d’acupression ont été placés aux points P6 de la face antérieure des deux avant-bras des patients du Groupe 1 ( groupe d’acupression , n=100 ) t and is que dans le Groupe 2 , ( groupe témoin , n=100 ) , ils l’ont été , de façon inappropriée , sur la face postérieure . On les a appliqués 30 min avant l’induction de l’anesthésie et retirés six heures après l’opération . L’anesthésie comportait du thiopental , à l’induction , et du protoxyde d’azote , de l’oxygène , du fentanyl , de l’isoflurane et du vécuronium . L’extubation trachéale a eu lieu à la salle d’opération après l’administration de néostigmine et d’atropine . Un observateur objectif a évalué les nausées et les vomissements postopératoires comme absents , légers , modérés ou sévères au moment où le patient est arrivé à la salle de réveil , puis six et vingt-quatre heures après l’opération . Résultats : Dans le groupe d’acupression , 25 patients ont eu des NVPO , comparativement à 29 patients du groupe témoin ( P = NS ) . Conclusion : L’application de bracelets d’acupression en P6 aux deux avant-bras , 30 min avant l’induction de l’anesthésie , n’a pas diminué l’incidence de NVPO chez des patients qui subissent une intervention urologique endoscopique Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: OBJECTIVES To explore the commonly utilized sham acupressure procedures in existing acupressure trials , and to assess whether different types of sham interventions yield different therapeutic outcomes , and , as far as possible , to identify directions for the future development of an adequate sham acupressure method . CONCLUSIONS A great diversity of sham acupressure controls have been used in clinical practice and research . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

15495109

[14569523] The objective of this study was to compare the effect of two different degrees of m and ibular advancement ( MA ) , 75 % versus 50 % , on somnographic variables after 6 months of dental appliance treatment in patients with severe obstructive sleep apnea ( OSA ) . A further purpose was to compare the number of adverse events on the stomatognathic system and the effects of dental appliance treatment on the presence of daytime sleepiness . Eighty-six males with severe OSA ( apnea index ≥ 20 ) were r and omly allocated to either 75 % or 50 % MA . Forty patients in the 75 % MA group and 37 patients in the 50 % MA group completed the 6-month follow-up . The effectiveness of treatment in terms of normalization ( apnea index < 5 and apnea/hypopnea index < 10 ) with 75 % MA was 52 % , which was significantly higher ( p = 0.04 ) than the 31 % achieved with 50 % MA . The dental appliance had few adverse events on the stomatognathic system regardless of group , and the number of adverse events did not differ between the two groups . Finally , the mean value of Epworth Sleepiness Scale scores decreased significantly from 11.6 at baseline to 8.0 at follow-up ( p < 0.001 ) . No significant difference was observed between the two groups . The results indicate that a dental appliance could be an alternative treatment for some patients with severe OSA [12204875] The aim of this study was to evaluate the effect of a m and ibular advancement splint ( MAS ) on daytime sleepiness and a range of other symptoms in obstructive sleep apnea ( OSA ) . Using a r and omized crossover design , patients received 4 weeks of treatment with MAS and a control device ( inactive oral appliance ) , with an intervening 1-week washout . At the end of each treatment period , patients were reassessed by question naire , polysomnography , and multiple sleep latency test . Fifty-nine men and 14 women with a mean ( + /- SD ) age of 48 + /- 11 years and proven OSA experienced a significantly improved mean ( + /- SEM ) sleep latency on the multiple sleep latency test ( 10.3 + /- 0.5 versus 9.1 + /- 0.5 minutes , p = 0.01 ) and Epworth sleepiness scale score ( 7 + /- 1 versus 9 + /- 1 , p < 0.0001 ) with the MAS compared with the control device after 4 weeks . The proportion of patients with normal subjective sleepiness was significantly higher with the MAS than with the control device ( 82 versus 62 % , p < 0.01 ) , but this was not so for objective sleepiness ( 48 versus 34 % , p = 0.08 ) . Other OSA symptoms were controlled in significantly more patients with the MAS than with the control device . MAS therapy improves a range of symptoms associated with OSA [15358707] The present study objective was to establish whether pretreatment social cognitive variables may contribute to the explanation of variance in adherence to continuous positive airway pressure ( CPAP ) treatment for patients with obstructive sleep apnoea/hypopnoea syndrome ( OSAHS ) . A total of 119 of 180 consecutive OSAHS patients were recruited to the study prior to initial CPAP titration . Patients completed psychological measures of health value , health locus of control ( incorporating internality , chance , powerful others ) and self-efficacy prior to CPAP titration . Objective adherence data were measured by CPAP unit time clocks and collected at 3-month follow-up . Average nightly use was calculated over this period . Logistic regression of prospect i ve predictors of adherence produced a model comprising psychological ( health value , internality , powerful others ) , as well as clinical variables ( Epworth score , body mass index , apnoea/hypopnoea index , CPAP pressure ) . This model explained 24 % of the variance in CPAP use , and correctly identified 75 % of adherers and 53 % of nonadherers . Although the psychological variables explained only a small amount of the overall variance in adherence behaviour , this result provides further support for the hypothesis that psychological variables contribute , in part , to continuous positive airway pressure adherence . Future research should focus on highlighting discrete variables , which may helpfully inform psychologically based interventions aim ed at improving the use of continuous positive airway pressure by patients with obstructive sleep apnoea/hypopnoea syndrome at risk of discontinuance [12231497] M and ibular repositioning splints ( MRSs ) and continuous positive airway pressure ( CPAP ) are used to treat the sleep apnea/hypopnea syndrome ( SAHS ) . There are some data suggesting that patients with milder symptoms prefer MRS , but there are few comparative data on outcomes . Therefore , we performed a r and omized crossover trial of 8 weeks of CPAP and 8 weeks of MRS treatment in consecutive new out patients diagnosed with SAHS ( apnea/hypopnea index [ AHI ] > or= 5/hour , and > or= 2 symptoms including sleepiness ) . Assessment s at the end of both limbs comprised home sleep study , subjective ratings of treatment value , sleepiness , symptoms , and well-being , and objective tests of sleepiness and cognition . Forty-eight of 51 recruited patients completed the trial ( 12 women ; age [ mean + /- SD ] , 46 + /- 9 years ; Epworth 14 + /- 4 ; median AHI , 22/hour ; interquartile ratio [ IQR ] , 11 - 43/hour ) . Significant ( p < or= 0.01 ) differences between MRS and CPAP were observed for 7 of 21 variables ( effect sizes , 0.3 - 0.6 SDs ) , all favoring CPAP , including AHI ( 15 + /- 16 and 8 + /- 6/hour , respectively ) , effectiveness rating , symptoms , Epworth ( 12 + /- 5 and 8 + /- 5 , respectively ) , functional outcomes of sleepiness question naire , short-form 36 health survey mental component , and health transition scores . Objective sleepiness , cognitive performance , and preference for treatments were not different . In patients experiencing a mild form of the syndrome ( AHI < 15 , n = 18 ) , symptoms , treatment efficacy and satisfaction , and subjective sleepiness were also better with CPAP than with MRS ( effect sizes , 0.7 - 1.1 SDs ) . These results do not support these MRS devices as first-line treatment for sleepy patients with SAHS [17121868] Background : Patients with mild to moderate obstructive sleep apnoea ( OSA ) may be managed with different treatment options . This study compared the effectiveness of three commonly used non-surgical treatment modalities . Methods : Subjects with mild to moderate OSA were r and omised to one of three treatment groups for 10 weeks : conservative measures ( sleep hygiene ) only , continuous positive airways pressure ( CPAP ) in addition to conservative measures or an oral appliance in addition to conservative measures . All overweight subjects were referred to a weight-reduction class . OSA was assessed by polysomnography . Blood pressure was recorded in the morning and evening in the sleep laboratory . Daytime sleepiness was assessed with the Epworth Sleepiness Scale . Health-related quality of life ( HRQOL ) was assessed with the 36-Item Short-Form Health Survey ( SF-36 ) and Sleep Apnoea Quality of Life Index ( SAQLI ) . Results : 101 subjects with a mean ( SEM ) apnoea – hypopnoea index ( AHI ) of 21.4 ( 1.1 ) were r and omised to one of the three groups . The severity of sleep-disordered breathing was decreased in the CPAP and oral appliance groups compared with the conservative measures group , and the CPAP group was significantly better than the oral appliance group . Relief from sleepiness was significantly better in the CPAP group . CPAP was also better than the oral appliance or conservative measures in improving the “ bodily pain ” domain , and better than conservative measures in improving the “ physical function ” domain of SF-36 . Both CPAP and the oral appliance were more effective than conservative measures in improving the SAQLI , although no difference was detected between the CPAP and oral appliance groups . CPAP and the oral appliance significantly lowered the morning diastolic blood pressure compared with baseline values , but there was no difference in the changes in blood pressure between the groups . There was also a linear relationship between the changes in AHI and body weight . Conclusion : CPAP produced the best improvement in terms of physiological , symptomatic and HRQOL measures , while the oral appliance was slightly less effective . Weight loss , if achieved , result ed in an improvement in sleep parameters , but weight control alone was not uniformly effective [12199005] AIM To assess the efficacy of a m and ibular advancement splint ( MAS ) in the treatment of obstructive sleep apnoea syndrome ( OSAS ) . METHODS Nineteen patients using a MAS for symptomatic OSAS underwent polysomnography , with MAS use r and omised to one half of the night . Indices of snoring and OSAS were compared . Side effects , compliance and treatment response were evaluated by question naire . RESULTS Use of the MAS improved total respiratory disturbance index ( RDI ) from 22.2 + /- 19.8 ( SD ) events per hour to 16.5 + /- 21.4/hr ( p = 0.03 ) , supine RDI ( 30.8 + /- 23.8/hr to 18.8 + /- 22.1/hr , p = 0.01 ) , arousal index ( 25.2 + /- 18.9/hr to 19.3 + /- 14.2/hr , p = 0.01 ) and snoring intensity ( 52.7 + /- 4.1 to 50.7 + /- 2.7 dB , p = 0.02 ) but not total snore frequency ( p > 0.05 ) . Using polysomnographic criteria , MAS treatment was completely successful in four ( 21 % ) patients , partially successful in ten ( 52.6 % ) and a failure in five ( 26.3 % ) . Treatment over a median of 6.5 weeks ( range 2 - 48 ) was perceived as beneficial by ten of eleven partners . Fifteen patients ( 79 % ) reported side effects , 9 ( 46 % ) did not use the device every night and four ( 21 % ) used the device less than three nights per week . CONCLUSION The use of the MAS result ed in significant reductions in indices of OSAS and snoring . However , a significant number of patients had difficulty tolerating and regularly using the device [10445069] The enthusiasm for uvulopalatopharyngoplasty ( UPPP ) in the treatment of obstructive sleep apnoea ( OSA ) has declined in recent years , partly because of a lower success rate over time and partly because of adverse effects . Reports on the beneficial effects of dental appliances exist , but only one prospect i ve r and omized study has been published comparing dental appliances with nasal continuous positive airway pressure ( CPAP ) treatment . No study has been published comparing dental appliance treatment with UPPP . Ninety-five male patients with confirmed OSA , subjective daytime sleepiness and an apnoea index ( AI ) > 5 were r and omized for subsequent treatment with either a dental appliance or UPPP . There were 49 patients in the dental appliance group and 46 in the UPPP group . Thirty-seven patients in the dental appliance group and 43 in the UPPP group completed the 12-month follow-up . The success rate ( rate of patients with at least a 50 % reduction in AI ) for the dental appliance group was 95 % , which was significantly higher ( p < 0.01 ) than the 70 % success rate for the UPPP group . According to the criteria for OSA ( apnoea index > or = 5 or apnoea/hypopnoea index > or = 10 ) , 78 % of the dental appliance group and 51 % of the UPPP group were normalized after 12 months . The difference between the groups was significant ( p < 0.05 ) . These findings suggest that the dental appliance technique is useful in the treatment of mild to moderate OSA [8464434] BACKGROUND Limited data have suggested that sleep-disordered breathing , a condition of repeated episodes of apnea and hypopnea during sleep , is prevalent among adults . Data from the Wisconsin Sleep Cohort Study , a longitudinal study of the natural history of cardiopulmonary disorders of sleep , were used to estimate the prevalence of undiagnosed sleep-disordered breathing among adults and address its importance to the public health . METHODS A r and om sample of 602 employed men and women 30 to 60 years old were studied by overnight polysomnography to determine the frequency of episodes of apnea and hypopnea per hour of sleep ( the apnea-hypopnea score ) . We measured the age- and sex-specific prevalence of sleep-disordered breathing in this group using three cutoff points for the apnea-hypopnea score ( > or = 5 , > or = 10 , and > or = 15 ) ; we used logistic regression to investigate risk factors . RESULTS The estimated prevalence of sleep-disordered breathing , defined as an apnea-hypopnea score of 5 or higher , was 9 percent for women and 24 percent for men . We estimated that 2 percent of women and 4 percent of men in the middle-aged work force meet the minimal diagnostic criteria for the sleep apnea syndrome ( an apnea-hypopnea score of 5 or higher and daytime hypersomnolence ) . Male sex and obesity were strongly associated with the presence of sleep-disordered breathing . Habitual snorers , both men and women , tended to have a higher prevalence of apnea-hypopnea scores of 15 or higher . CONCLUSIONS The prevalence of undiagnosed sleep-disordered breathing is high among men and is much higher than previously suspected among women . Undiagnosed sleep-disordered breathing is associated with daytime hypersomnolence [15785917] The purpose of this study was to investigate the effects of an oral appliance ( OA ) , with and without m and ible advance , in the treatment of obstructive sleep apnea syndrome ( OSA ) . Twenty-four patients diagnosed with OSA agreed to participate in this study . The patients were treated for 3 months ( with a removable soft elastic silicone positioner customized with thermoplastic silicone and with a 5-mm opening ) . Patients were selected , using a r and omized design , to receive an OA model either with ( 12 patients ) or without advance ( 12 patients ) . Before treatment , a snoring question naire , the Medical Outcomes Study 36-Item Short-Form Health Survey ( SF-36 ) , the Functional Outcomes of Sleep Question naire ( FOSQ ) , the Epworth Sleepiness Scale ( ESS ) , and polysomnography were completed . Fifteen subjects completed the protocol ( 13 men , two women ) . With respect to basal values , the m and ible-advanced OA group presented a decrease in the mean apnea – hypopnea index ( AHI ) ( 33.8±4.7 versus 9.6±2.1 ; p<0.01 ) , number of arousals per hour ( 33.8±13.9 versus 16.0±1.5 ; p<0.05 ) , ESS score ( 14.7±5.1 versus 5.1±1.9 ; p<0.05 ) , snoring score ( 15.4±1.9 versus 10.1±3.2 ; p<0.05 ) , and total FOSQ score ( 78.1±22.6 versus 99.3±14.4 ; p<0.05 ) . After treatment , the non-advanced group presented a decrease in the mean AHI ( 24.0±12.2 versus . 11.7±7.9 ; p<0.05 ) . However , no significant differences were found in the number of arousals per hour , ESS score , snoring , and total FOSQ score in the non-advanced group . Neither study group showed significant difference in mean SF36 scores . Oral appliances , especially those that advance the m and ible , offer an effective treatment for OSA [15453552] STUDY OBJECTIVE To investigate the short-term effect ( 4 weeks ) of oral appliance therapy for obstructive sleep apnea on blood pressure . DESIGN R and omized , controlled , crossover trial . SETTING Multidisciplinary sleep disorders clinic in a university teaching hospital . PATIENTS Sixty-one patients diagnosed with obstructive sleep apnea on polysomnography ( apnea hypopnea index > or = 10 per hour and at least 2 of the following symptoms -- daytime sleepiness , snoring , witnessed apneas , fragmented sleep ; age > 20 years ; and minimum m and ibular protrusion of 3 mm ) . INTERVENTION A m and ibular advancement splint ( MAS ) and control oral appliance for 4 weeks each . MEASUREMENTS AND RESULTS Polysomnography and 24-hour ambulatory blood pressure monitoring were carried out at baseline and following each 4-week intervention period . Patients showed a 50 % reduction in mean apnea hypopnea index with MAS compared with the control and a significant improvement in both minimum oxygen saturation and arousal index . There was a significant reduction with the MAS in mean ( + /- SEM ) 24-hour diastolic blood pressure ( 1.8 + /- 0.5 mmHg ) compared with the control ( P = .001 ) but not in 24-hour systolic blood pressure . Awake blood-pressure variables were reduced with the MAS by an estimated mean ( + /- SEM ) of 3.3 + /- 1.1 mmHg for systolic blood pressure ( P = .003 ) and 3.4 + /- 0.9 mmHg for diastolic blood pressure ( P < .0001 ) . There was no significant difference in blood pressure measured asleep . CONCLUSION Oral appliance therapy for obstructive sleep apnea over 4 weeks results in a reduction in blood pressure , similar to that reported with continuous positive airway pressure therapy [10591454] In a prospect i ve study , 95 patients with mild to moderate obstructive sleep apnoea ( OSA ) were r and omised to receive either surgical treatment , uvulopalatopharyngoplasty , ( 4 - 6 patients ) or treatment with a nocturnal dental appliance for m and ibular advancement ( 49 patients ) . Of the 49 dental appliance patients , 37 completed the 12-month follow-up . The aim of this study was to evaluate the effects and adverse events of dental appliance treatment from a one-year perspective . Somnography was employed to measure treatment effects before and 12 months post-treatment . At the 12-month control , somnography was performed twice : the first time with the dental appliance and the second time without it . Adverse events were recorded 2 weeks and 3 , 6 , and 12 months after treatment was initiated . The patients used the dental appliance on average 6 nights/week . After 12 months of treatment , the apnoea , apnoea/hypopnoea , oxygen desaturation , and snoring indices decreased significantly . Ninety-five per cent of the patients reduced their apnoea index by > or = 50 % and 78 % of the patients were normalised following treatment . At the somnographic registration without the dental appliance , the values were found comparable to what they were before treatment . M and ibular mobility and occlusion were constant throughout the study . The adverse events result ing from using the dental appliance were relatively minor and infrequent , and no serious complications were observed except for two patients who reported pain from the temporom and ibular joint . In conclusion , the dental appliance has been shown to be a valuable treatment method for mild to moderate OSA with few adverse events in the stomatognathic system or other complications [17564405] STUDY OBJECTIVES This study aim ed to assess the efficacy of a custom-made m and ibular advancement splint for the treatment of obstructive sleep apnea with respect to neuropsychological functioning and mood state . METHODS A r and omized controlled crossover design was used in which 73 participants ( mean age = 48.4 , SD = 11.0 , % men = 80.8 ) with at least 2 symptoms of obstructive sleep apnea and an apnea hypopnea index > or = 10 per hour underwent treatment with both m and ibular advancement splint and an inactive oral device . Polysomnographic , neuropsychological and self-report measures were conducted at baseline and repeated after each of the two 4-week treatment phases . RESULTS MAS treatment was associated with improvements on the somatic component of the Beck Depression Inventory and the Vigor-Activity and Fatigue-Inertia scales of the Profile of Mood States . While there were no improvements within the neuropsychological domains of attention/working memory , verbal memory , visuospatial or executive functioning , treatment with the m and ibular advancement splint was associated with faster performance on a test of vigilance/psychomotor speed . These changes , however , did not correspond to the improved subjective sleepiness or apnea-hypopnea index during treatment . CONCLUSIONS Treatment with the m and ibular advancement splint results in improvements in self-reported sleepiness , fatigue/energy levels and vigilance/psychomotor speed in patients with obstructive sleep apnea [11371418] Although there is increasing interest in the use of oral appliances to treat obstructive sleep apnea ( OSA ) , the evidence base for this is weak . Furthermore , the precise mechanisms of action are uncertain . We aim ed to systematic ally investigate the efficacy of a novel m and ibular advancement splint ( MAS ) in patients with OSA . The sample consisted of 28 patients with proven OSA . A r and omized , controlled three-period ( ABB/BAA ) crossover study design was used . After an acclimatization period , patients underwent three polysomnographs with either a control oral plate , which did not advance the m and ible ( A ) , or MAS ( B ) , 1 wk apart , in either the ABB or BAA sequence . Complete response ( CR ) was defined as a resolution of symptoms and a reduction in Apnea/Hypopnea Index ( AHI ) to < 5/h , and partial response ( PR ) as a > or = 50 % reduction in AHI , but remaining > or = 5/h . Twenty-four patients ( 19 men , 5 women ) completed the protocol . Subjective improvements with the MAS were reported by the majority of patients ( 96 % ) . There were significant improvements in AHI ( 30 + /- 2/h versus 14 + /- 2/h , p < 0.0001 ) , MinSa(O(2 ) ) ( 87 + /- 1 % versus 91 + /- 1 % , p < 0.0001 ) , and arousal index ( 41 + /- 2/h versus 27 + /- 2/h , p < 0.0001 ) with MAS , compared with the control . The control plate had no significant effect on AHI and MinSa(O(2 ) ) . CR ( n = 9 ) or PR ( n = 6 ) was achieved in 62.5 % of patients . The MAS is an effective treatment in some patients with OSA , including those patients with moderate or severe OSA [10382693] BACKGROUND Nasal continuous positive airway pressure ( NCPAP ) is widely used as a treatment for obstructive sleep apnoea . However , to date there are no r and omised controlled trials of this therapy against a well-matched control . We undertook a r and omised prospect i ve parallel trial of therapeutic NCPAP for obstructive sleep apnoea compared with a control group on subtherapeutic NCPAP . METHODS Men with obstructive sleep apnoea , defined as an Epworth sleepiness score of 10 or more and ten or more dips per h of more than 4 % SaO2 caused by obstructive sleep apnoea on overnight sleep study , were r and omly assigned therapeutic NCPAP or subtherapeutic NCPAP ( about 1 cm H2O ) for 1 month . Primary outcomes were subjective sleepiness ( Epworth sleepiness score ) , objective sleepiness ( maintenance of wakefulness test ) , and SF-36 question naire measurements of self-reported functioning and well-being . FINDINGS 107 men entered the study : 53 received subtherapeutic NCPAP and 54 therapeutic NCPAP . Use of NCPAP by the two treatment groups was similar : 5.4 h ( therapeutic ) and 4.6 h ( subtherapeutic ) per night . Subtherapeutic NCPAP did not alter the overnight number of SaO2 dips per h compared with baseline , and thus acted as a control . Therapeutic NCPAP was superior to subtherapeutic NCPAP in all primary outcome measures . The Epworth score was decreased from a median of 15.5 to 7.0 on therapeutic NCPAP , and from 15.0 to 13.0 on subtherapeutic NCPAP ( between treatments , p<0.0001 ) . Mean maintenance-of-wakefulness time increased from 22.5 to 32.9 min on therapeutic NCPAP and , not significantly , from 20.0 to 23.5 min on subtherapeutic NCPAP ( between treatments p<0.005 ) . Effect sizes for SF-36 measures of energy and vitality were 1.68 ( therapeutic ) and 0.97 ( subtherapeutic ) NCPAP ( between treatments p<0.0001 ) . For mental summary score , the corresponding values were 1.02 and 0.4 ( between treatments p=0.002 ) . INTERPRETATION Therapeutic NCPAP reduces excessive daytime sleepiness and improves self-reported health status compared with a subtherapeutic control . Compared with controls , the effects of therapeutic NCPAP are large and confirm previous uncontrolled clinical observations and the results of controlled trials that used an oral placebo [9515847] OBJECTIVE To evaluate the effects of a m and ibular advancement device on apneas and sleep in mild , moderate , and severe obstructive sleep apnea . DESIGN Prospect i ve study . SUBJECTS Forty-four of 47 patients included . INTERVENTION Individually adjusted m and ibular advancement devices . MEASUREMENTS Polysomnographic sleep recordings for 1 night without the device and 1 night with it , with a median of 1 day and no changes in weight , medication , or sleep position between the recordings . RESULTS The device reduced the median obstructive apnea-hypopnea index from 11 ( range , 7 to 19 ) to 5 ( range , 0 to 17 ) ( p<0.001 ) in 21 patients with mild sleep apnea , from 27 ( range , 20 to 38 ) to 7 ( range , 1 to 19 ) ( p<0.001 ) in 15 patients with moderate sleep apnea , and from 53 ( range , 44 to 66 ) to 14 ( range , 2 to 32 ) ( p<0.05 ) in 8 patients with severe sleep apnea . The arousal index decreased and the sleep stage patterns improved in all severity groups . Twenty-eight of 44 patients were successfully treated with an obstructive apnea-hypopnea index of below 10 and a subjective reduction in snoring . Nine of 16 patients with treatment failure still reported a reduction in snoring . The success rate correlated inversely to the disease severity ( r=-0.41 ; p<0.01 ) . CONCLUSIONS A m and ibular advancement device reduces apneas and improves sleep quality in patients with obstructive sleep apnea , especially in those with mild and moderate disease . A follow-up sleep recording during treatment is necessary because of the risk of silent obstructive apneas without subjective snoring with the device [17245607] Impaired simulated driving performance has been demonstrated in obstructive sleep apnoea – hypopnoea syndrome ( OSAHS ) patients . Although continuous positive airway pressure ( CPAP ) generally improves simulated driving performance , the effects of oral-appliance ( OA ) therapy are unknown . The aims of this study were to determine to what extent OSAHS patients have more difficulty with a monotonous simulated driving test when compared with control subjects and to compare the effects of OA with CPAP therapy . Simulated driving performance was evaluated in 20 OSAHS patients and 16 control subjects during a 25-min driving test . After r and omization , ten patients started OA and CPAP therapy , respectively . After 2 to 3 months of treatment , patients repeated the driving test . At baseline , the total number of lapses of attention during driving was significantly higher in OSAHS patients as compared with control subjects . As a result of treatment , the total number of lapses of attention was significantly decreased in both the OA and CPAP group . When comparing driving performance between the OA and CPAP group , no significant differences were noted . OSAHS patients perform worse on a simulated driving test when compared with control subjects . When evaluating the effects of treatment , adequate OSAHS management with either OA or CPAP therapy usually result ed in substantial improvements of simulated driving . Conclusions beyond both treatments improving simulated driving performance are , however , not justified by the data in the present study [9196520] BACKGROUND Although oral appliances are effective in some patients with obstructive sleep apnoea ( OSA ) , they are not universally effective . A novel anterior m and ibular positioner ( AMP ) has been developed with an adjustable hinge that allows progressive advancement of the m and ible . The objective of this prospect i ve crossover study was to compare efficacy , side effects , patient compliance , and preference between AMP and nasal continuous positive airway pressure ( nCPAP ) in patients with symptomatic mild to moderate OSA . METHODS Twenty four patients of mean ( SD ) age 44.0 ( 10.6 ) years were recruited with a mean ( SD ) body mass index of 32.0 ( 8.2 ) kg/m2 , Epworth sleepiness score 10.7 ( 3.4 ) , and apnoea/hypopnoea index 26.8 (11.9)/hour . There was a two week wash-in and a two week wash-out period and two treatment periods ( AMP and nCPAP ) each of four months . Efficacy , side effects , compliance , and preference were evaluated by a question naire and home sleep monitoring . RESULTS One patient dropped out early in the study and three refused to cross over so treatment results are presented on the remaining 20 patients . The apnoea/hypopnoea index ( AHI ) was lower with nasal CPAP 4.2 (2.2)/hour than with the AMP 13.6 (14.5)/hour ( p < 0.01 ) . Eleven of the 20 patients ( 55 % ) who used the AMP were treatment successes ( reduction of AHI to < 10/hour and relief of symptoms ) , one ( 5 % ) was a compliance failure ( unable or unwilling to use the treatment ) , and eight ( 40 % ) were treatment failures ( failure to reduce AHI to < 10/hour and /or failure to relieve symptoms ) . Fourteen of the 20 patients ( 70 % ) who used nCPAP were treatment successes , six ( 30 % ) were compliance failures , and there were no treatment failures . There was greater patient satisfaction with the AMP ( p < 0.01 ) than with nCPAP but no difference in reported side effects or compliance . CONCLUSIONS AMP is an effective treatment in some patients with mild to moderate OSA and is associated with greater patient satisfaction than nCPAP [12143089] This r and omized placebo-controlled cross-over trial assessed the effectiveness of a m and ibular advancement appliance ( MAA ) in managing obstructive sleep apnoea ( OSA ) . Twenty-one adults , with confirmed OSA , were provided with a maxillary placebo appliance and a MAA for 4 - 6 weeks each , in a r and omized order . Question naires at baseline and after each appliance assessed bed-partners ' reports of snoring severity ( loudness and number of nights per week ) , and patients ' daytime sleepiness ( Epworth Sleepiness Score , ESS ) . The Apnoea Hypopnoea Index ( AHI ) and Oxygen Desaturation Index ( ODI ) were measured at baseline and with each appliance during single night sleep studies . Seventy-nine per cent of subjects wore their MAA for at least 4 hours at night . Sixty-eight per cent of subjects wore their MAA for 6 - 7 nights per week . Excessive salivation was the most commonly reported complication . One subject was unable to tolerate the MAA and withdrew from the study . Among the remaining 20 subjects , the MAA produced significantly lower AHI and ODI values than the placebo . However , although the reported frequency and loudness of snoring and the ESS values were lower with the MAA than the placebo , these differences were not statistically significant . When wearing the MAA , 35 per cent of the OSA subjects had a reduction in the pre-treatment ODI to 10 or less , while 33 per cent had an AHI of 10 or less . The MAA was less effective in the subjects with the most severe OSA ( pre-treatment ODI > 50 and /or pre-treatment AHI > 50 ) [14960007] The objective of this study was to evaluate the effect of 2 different degrees of m and ibular advancement , 50 % vs. 75 % of maximum protrusive capacity , on somnographic variables after 1 year of dental appliance treatment in patients with mild to moderate obstructive sleep apnea ( OSA ) . A further purpose was to compare the number of adverse events on the stomatognathic system . In a prospect i ve study , 74 male patients were r and omly allocated to receive a dental appliance with either 50 % ( 38 patients ) or 75 % m and ibular advancement ( 36 patients ) . After 1 year of treatment , 55 patients completed the follow‐up . Somnography was performed to measure treatment effects before and 12 months post‐treatment . The apnea , apnea/hypopnea , and oxygen desaturation indices decreased significantly in both groups after 1 year ( P<0.001 ) ; however , there were no differences between the groups . Normalization ( apnea index < 5 and apnea/hypopnea index < 10 ) was observed in 79 % in group 50 and in 73 % in group 75 . Few patients ( < 5 % ) reported symptoms from the stomatognathic system except for headache ( > once a week ) , which was reported in one‐third of the patients . Headache was significantly more infrequent after 1 year of treatment in both groups ( P<0.001 ) . No serious complications were observed except for 2 patients who reported a painful condition from the temporom and ibular joint in either group . In conclusion , m and ibular advancement with a dental appliance effectively reduces the sleep‐breathing disorder measured as frequency of apneas , and a pronounced m and ibular advancement did not show a greater improvement of the medical problem compared to less advancement for patients with mild to moderate OSA . On the basis of few adverse events in the stomatognathic system or other complications we can recommend dental appliance treatment and , for patients with mild to moderate obstructive sleep apnea , not starting treatment by more than 50 % m and ibular advancement [10903249] Our purpose was to compare the effectiveness and side effects of a novel , single-piece m and ibular advancement device ( OSA-Monobloc ) for sleep apnea therapy with those of a two-piece appliance with lateral Herbst attachments ( OSA-Herbst ) as used in previous studies . An OSA-Monobloc and an OSA-Herbst with equal protrusion were fitted in 24 obstructive sleep apnea patients unable to use continuous positive airway pressure ( CPAP ) therapy . After an adaptation period of 156 + /- 14 d ( mean + /- SE ) , patients used the OSA-Monobloc , the OSA-Herbst , and no appliance in r and om order , using each appliance for 1 wk . Symptom scores were recorded and sleep studies were done at the end of each week . Several symptom scores were significantly improved with both appliances , but to a greater degree with the OSA-Monobloc . Epworth Sleepiness Scale scores were 8.8 + /- 0.7 with the OSA-Herbst , and 8.6 + /- 0.8 with the OSA-Monobloc devices , and 13.1 + /- 0.9 without therapy ( p < 0.05 versus both appliances ) . The apnea/hypopnea index was 8.7 + /- 1.5/h with the OSA-Herbst and 7.9 + /- 1.6/h with the OSA-Monobloc device , and 22.6 + /- 3.1/h without therapy ( p < 0.05 versus both appliances ) . Side effects were mild and of equal prevalence with both appliances . Fifteen patients preferred the OSA-Monobloc , eight patients had no preference , and one patient preferred the OSA-Herbst device ( p < 0.008 versus OSA-Monobloc ) . We conclude that both the OSA-Herbst and the OSA-Monobloc are effective therapeutic devices for sleep apnea . The OSA-Monobloc relieved symptoms to a greater extent than the OSA-Herbst , and was preferred by the majority of patients on the basis of its simple application [8769497] OBJECTIVE This study compared the efficacy of a removable anterior m and ibular positioning ( AMP ) device to continuous positive airway pressure ( CPAP ) in patients with obstructive sleep apnea ( OSA ) using a fully balanced crossover design . DESIGN Twenty-three male subjects with confirmed OSA were recruited from the Technion Sleep Laboratory in Haifa , Israel , from February 18 , 1991 to December 17 , 1992 . Twenty-one of the 23 subjects enrolled completed all aspects of the study . RESULTS The mean apnea-hypopnea index ( AHI ) before treatment was 33.86 + /- 14.30 . The mean AHI decreased with CPAP to 59.50 % , but decreased only 38.91 % with the AMP device . The lowest mean recorded oxygen saturation level for the 21 subjects was 84.30 before treatment , 91.10 after CPAP treatment , and 90.20 after AMP treatment . Sleep data revealed a significant decrease in stage 1 and 2 ( p=0.0088 ) and an increase in rapid eye movement percent ( p=0.0066 ) for both treatments when compared with baseline . Three- to 10-month posttreatment phone interviews showed that 1 subject was not using either device , 1 subject was using CPAP , and 2 subjects were using the AMP device intermittently due to occasional temporom and ibular joint pain symptoms . The remaining 17 subjects were all using the AMP device nightly . The symptoms of excessive daytime sleepiness also decreased significantly by both AMP and CPAP . CONCLUSIONS The AMP device achieved substantial success in most cases , but was less effective than CPAP , especially for the more severe cases . In general , the AMP device was strongly preferred over the CPAP by the subjects of this study [12143088] This prospect i ve , r and omized , cross-over trial was design ed to compare the efficacy of a m and ibular advancement splint ( MAS ) with that of nasal continuous positive airway pressure ( nCPAP ) in patients with obstructive sleep apnoea ( OSA ) . Twenty-four patients ( 20 males and four females ) with mild to moderate OSA ( AHI between 10 and 49 events per hour ) were enrolled in the study . Each patient used both MAS and nCPAP , with the initial therapy being allocated at r and om . Treatment periods lasted for two months with a two-week wash-out interval between . Polysomnography was performed prior to the study and after each clinical intervention . Patient and partner question naires were used to assess changes in general health and daytime somnolence . The AHI decreased from 22.2 to 3.1 using nCPAP , and to 8.0 using the MAS ( P < 0.001 for both devices ) and there was no statistically significant difference between the two treatments . The Epworth Sleepiness Score ( ESS ) fell from 13.4 to 8.1 with nCPAP , and to 9.2 with MAS ( P < 0.001 ) , again with no differences between the use of MAS or nCPAP . The question naire data showed an improvement in general health scores ( P < 0.001 ) after both treatments , but daytime sleepiness only improved significantly using nCPAP ( P < 0.001 ) . Despite this , 17 out of the 21 subjects who completed both arms of the study preferred the MAS . The splints were well tolerated and their efficacy suggests that the MAS may be a suitable alternative to nCPAP in the management of patients with mild or moderate OSA [8686675] Knowledge of how dental appliances alter upper airway muscle activity when they are used for the treatment of snoring and /or obstructive sleep apnea ( OSA ) is very limited . The purpose of this study was to define the effect of a tongue retaining device ( TRD ) on awake genioglossus ( GG ) muscle activity in 10 adult subjects with OSA and in 6 age and body mass index ( BMI ) matched symptom-free control subjects . The TRD is a custom-made appliance design ed to allow the tongue to remain in a forward position between the anterior teeth by holding the tongue in an anterior bulb with negative pressure , during sleep . This pulls the tongue forward to enlarge the volume of the upper airway and to reduce upper airway resistance . In this study , two customized TRDs were used for each subject . The TRD-A did not have an anterior bulb but incorporated lingual surface electrodes to record the GG electromyographic ( EMG ) activity . The TRD-B contained an anterior bulb and two similar electrodes . The GG EMG activity was also recorded while patients used the TRD-B but were instructed to keep their tongue at rest outside the anterior bulb ; this condition is hereafter referred to as TRD-X. The GG EMG activity and nasal airflow were simultaneously recorded while subjects used these customized TRDs during spontaneous awake breathing in both the upright and supine position . The following results were obtained and were consistent whether subjects were in the upright or the supine position . The GG EMG activity was greater with the TRD-B than with the TRD-A in control subjects ( p < 0.05 ) , whereas the GG EMG activity was less with the TRD-B than with the TRD-A in subjects with OSA ( p < 0.01 ) . Furthermore , there was no significant difference between the GG EMG activity of the TRD-A and the TRD-X in control subjects , whereas there was less activity with the TRD-X than with the TRD-A in subjects with OSA ( p < 0.05 ) . On the basis of these findings , it was concluded that the TRD has different effects on the awake GG muscle activity in control subjects and patients with OSA . The result ant change in the anatomic configuration of the upper airway caused by the TRD may be important in the treatment of OSA because such a change may alleviate the impaired upper airway function [11812555] BACKGROUND Obstructive sleep apnoea is associated with raised blood pressure . If blood pressure can be reduced by nasal continuous positive airway pressure ( nCPAP ) , such treatment could reduce risk of cardiovascular disease in patients with obstructive sleep apnoea . Our aim was to see whether nCPAP for sleep apnoea reduces blood pressure compared with the most robust control intervention subtherapeutic nCPAP . METHODS We did a r and omised parallel trial to compare change in blood pressure in 118 men with obstructive sleep apnoea ( Epworth score > 9 , and a > 4 % oxygen desaturation index of > 10 per h ) who were assigned to either therapeutic ( n=59 ) or subtherapeutic ( 59 ) nCPAP ( about 1 cm H(2)O pressure ) for 1 month . The primary outcome was the change in 24-h mean blood pressure . Secondary outcomes were changes in systolic , diastolic , sleep , and wake blood pressure , and relations between blood pressure changes , baseline blood pressure , and severity of sleep apnoea . FINDINGS Therapeutic nCPAP reduced mean arterial ambulatory blood pressure by 2.5 mm Hg ( SE 0.8 ) , whereas subtherapeutic nCPAP increased blood pressure by 0.8 mm Hg ( 0.7 ) ( difference -3.3 [ 95 % CI -5.3 to -1.3 ] ; p=0.0013 , unpaired t test ) . This benefit was seen in both systolic and diastolic blood pressure , and during both sleep and wake . The benefit was larger in patients with more severe sleep apnoea than those who had less severe apnoea , but was independent of the baseline blood pressure . The benefit was especially large in patients taking drug treatment for blood pressure . INTERPRETATION In patients with most severe sleep apnoea , nCPAP reduces blood pressure , providing significant vascular risk benefits , and substantially improving excessive daytime sleepiness and quality of life [12001556] M and ibular advancement appliances ( MAAs ) are accepted as a treatment option for snoring and mild obstructive sleep disorders . In the present clinical study two differently design ed devices were examined for their effectiveness in treating obstructive sleep apnoea ( OSA ) . The study was based on an assessment of 26 patients with a polysomnographic diagnosis of mild OSA [ 22 men , four women ; mean body mass index 27.3 kg/m2 ( SD 3.1 ) ; mean age 56.8 years ( SD 5.2 ) ; mean respiratory disturbance index ( RDI ) : 16.0 events/hour ( SD 4.4 ) ] . After insertion of the first MAA and a 6 - 8-week habituation period , a cardio-respiratory home-sleep study was carried out . Following a 2 - 3-week period with no treatment , the second appliance was inserted . The sequence of the devices was r and omized . Once the patients had become accustomed to the second appliance , another somnographic registration was carried out . Daytime sleepiness , snoring , and sleep quality were assessed subjectively on a visual analogue scale . The results showed that a statistically significant improvement in the respiratory parameters was achieved with both appliances ( P < 0.01 ) . However , the activator [ RDI : 5.5 events/hour , SD 3.3 ; apnoea index ( AI ) : 3.4 events/hour , SD 2.1 ] was significantly more effective ( P < 0.01 ) than the Silencor ( RDI , 7.3 events/hour , SD 5.3 ; AI : 5.8 events/hour , SD 3.2 ) . No difference was recorded in the subjective assessment of the therapeutic effects . Both appliances reduced daytime sleepiness and snoring and improved sleep quality , and both influenced the treatment outcome [11779741] To evaluate the clinical usefulness and tolerability of an oral jaw-positioning appliance in the treatment of obstructive sleep apnea syndrome in children , we studied 32 patients ( mean age , 7.1 + /- 2.6 yr ; 20 males ) with symptoms of obstructive sleep apnea , malocclusion , and a baseline apnea index > 1 event/h . A group of 19 subjects was r and omly assigned to a 6-mo trial of an oral appliance ; the remainder acted as control subjects . At baseline and after the trial all patients underwent physical examination , a st and ard polysomnography , and orthodontic assessment . A modified version of the Brouillette question naire related to obstructive sleep apnea symptoms was administered to parents before and after the trial and a clinical score was calculated . Of the 32 subjects enrolled , 4 treated subjects and 5 control subjects were lost to follow-up . Polysomnography after the trial showed that treated subjects all had significantly lower apnea index ( p < 0.001 ) and hypopnea index values ( p < 0.001 ) than before the trial , whereas in untreated control subjects these values remained almost unchanged . Clinical assessment before and after treatment showed that in 7 of the 14 subjects ( 50 % ) the oral appliance had reduced ( a fall of at least 2 points in the respiratory score ) and in 7 had resolved the main respiratory symptoms , whereas untreated patients continued to have symptoms . In conclusion , treatment of obstructive sleep apnea syndrome with an oral appliance in children with malocclusion is effective and well tolerated [7812552] Snoring and obstructive sleep apnea ( OSA ) are related to narrowing of the upper airway . A m and ibular advancement splint ( MAS ) could improve both conditions by increasing oropharyngeal and hypopharyngeal dimensions . The effects of a MAS on snoring and OSA was evaluated 3.5 + /- 2.1 ( mean + /- SD ) mo after issue in 57 subjects with habitual loud snoring , 39 of whom had an apnea-hypopnea index ( AHI ) > or = 10 . Assessment was by question naire ( all subjects ) and polysomnography ( 51 subjects , 47 male ) including measurement of sound intensity . Use of the MAS was r and omized to first or second half of study . Snores were scored where inspiratory noise was greater than 5 dB above background . Total sleep time , sleep efficiency , % REM sleep , and % sleep spent supine were similar ( p > 0.05 ) with and without the MAS . Snores per sleep minute , corrected for time in apnea , and sound intensity of snores ( % snores > or = 50 dB ) decreased with the MAS from 11.0 + /- 5.8 and 42.0 + /- 25.0 % to 9.0 + /- 6.0 ( p < 0.01 ) and 26.2 + /- 25.2 % ( p < 0.01 ) , respectively . Using the MAS significantly improved OSA : AHI decreased from 32.2 + /- 28.5 to 17.5 + /- 22.7 ( p < 0.01 ) and arousal index decreased from 31.4 + /- 20.6 to 19.0 + /- 14.6 ( p < 0.01 ) . AHI decreased to < 20 with the MAS in 12 of 17 subjects where untreated AHI was between 20 and 60 , and in 2 of 9 subjects where untreated AHI was > 60 . Forty-five patients continued to use the MAS regularly . ( ABSTRACT TRUNCATED AT 250 WORDS [15743867] This prospect i ve , r and omized , crossover study of 16 patients with obstructive sleep apnoea ( OSA ) [ 12 males , four females ; median body mass index ( BMI ) 29.2 kg/m(2 ) ( range 23.8 - 51.1 ) ; median age 44.8 years ( range 24.0 - 68.4 ) ] analysed the efficacy of the Twin Block ( TB ) in relation to the Herbst appliance as a m and ibular advancement splint ( MAS ) . Each subject was fitted with a TB and Herbst MAS in a r and om order with a washout period of 2 weeks between appliances . Once each patient was subjectively happy with the performance of each appliance , question naires and a visual analogue scale ( VAS ) were used to determine differences in snoring , daytime sleepiness , quality of life , side-effects of the appliances and patient preference . All patients underwent overnight domiciliary sleep recordings prior to and after fitting each appliance in order to objective ly assess sleep quality in terms of the apnoea-hypopnoea index ( AHI ) , snoring frequency and arterial oxygen saturation . The results suggested that there was no difference in the treatment performance of the TB and Herbst MAS for AHI ( P = 0.71 ) , snoring frequency ( P = 0.49 ) , arterial blood oxygen saturation ( P = 0.97 ) , quality of life and side-effects . The Herbst MAS proved to be the more effective appliance for reducing daytime sleepiness ( P = 0.04 ) and was the more popular appliance among the patients . Side-effects with both appliances were minor and improved in the longer term . The TB MAS represents a viable alternative to the Herbst MAS in the treatment of patients with OSA [12231498] The aim of this study was to assess the effect of bite opening induced by a m and ibular advancement splint ( MAS ) on efficacy and side effects in the treatment of obstructive sleep apnea . In a r and omized crossover fashion , 23 adult patients received either MAS-1 ( 4 mm of interincisal opening ) or MAS-2 ( 14 mm of interincisal opening ) for 2 weeks , followed by the alternate treatment for 2 weeks , with an intervening 1-week washout . Complete response was defined as a resolution of symptoms and a reduction in apnea/hypopnea index ( AHI ) to less than 5 per hour . Partial response was defined as improved symptoms and a reduction in AHI of 50 % or more , with the AHI remaining at a value of 5 or more per hour . Both MAS-1 and MAS-2 produced similar reductions in mean ( + /- SEM ) AHI from baseline : 21 + /- 2 versus 8 + /- 1/hour and 21 + /- 2 versus 10 + /- 2/hour , respectively ( p < 0.001 ) . Either complete response or partial response occurred in 74 and 61 % of patients with MAS-1 and MAS-2 , respectively . Subjective improvements were reported with both appliances by the majority of patients . Patients preferred MAS-1 ( 78 versus 22 % , p = 0.007 ) . This study suggests that the amount of bite opening induced by MAS does not have a significant impact on treatment efficacy but does have an impact on patient acceptance [14718430] STUDY OBJECTIVES The effect of therapy using a cervicom and ibular support collar ( CMSC ) to manage obstructive sleep apnea ( OSA ) was compared with st and ard therapy , nasal continuous positive airway pressure ( nCPAP ) . DESIGN Subjects received treatment with CMSC or nCPAP each for 1 month in r and om order . The study was analyzed on an intention-to-treat basis . SETTING Tom McKendrick Sleep Laboratory , Dunedin Hospital . PARTICIPANTS Ten adult subjects with mild-to-moderate OSA ( apnea-hypopnea index [ AHI ] , 24 + /- 13/h slept [ mean + /- SD ] ) completed the study . INTERVENTIONS The CMSC was design ed to prevent m and ibular movement and hold the head in slight extension , thus preventing the postural changes that might contribute to OSA . Positioning of the CMSC was confirmed by an externally applied cervical range of motion ( CROM ) instrument and by cephalometry . Subjects were carefully instructed in the use of each device and completed a symptom diary . After 1 month , subjects underwent polysomnography with each of the allocated devices in situ , and symptom question naires were administered . MEASUREMENTS AND RESULTS Treatment success ( AHI < /= 10/h slept ) with CMSC was achieved in only 2 of 10 subjects , partial success ( AHI > 10/h to < /= 15/h slept ) was achieved in 2 subjects , and in 6 of 10 subjects there was no benefit . In contrast , treatment success was achieved in 7 of 10 subjects receiving nCPAP . Mean AHI was 29.4 + /- 13.4/h at baseline , 26.9 + /- 17.2/h slept with CMSC , and 9.9 + /- 8.0/h slept with nCPAP ( p = 0.001 ) . No significant differences in sleep architecture or sleep efficiency were achieved using nCPAP compared to CMSC . The efficacy of the CMSC in maintaining the desired head position was confirmed by cephalometry and the CROM instrument . CONCLUSIONS Our results , although negative , provide important evidence that control of head and neck posture , perhaps adopted as a second-line treatment , is not helpful in the management of OSA . It appears that other anatomic and physiologic factors have a dynamic overriding influence on upper airway closure compared to simple skeletal relationships [9871945] The precise role of maxillary constriction in the pathophysiology of obstructive sleep apnea ( OSA ) is unclear . However , it is known that subjects with maxillary constriction have increased nasal resistance and result ant mouth-breathing , features typically seen in OSA patients . Maxillary constriction is also associated with alterations in tongue posture which could result in retroglossal airway narrowing , another feature of OSA . Rapid maxillary expansion ( RME ) is an orthodontic treatment for maxillary constriction which increases the width of the maxilla and reduces nasal resistance . The aim of this pilot study was to investigate the effect of rapid maxillary expansion in OSA . We studied 10 young adults ( 8 male , 2 female , mean age 27 + /- 2 [ sem ] years ) with mild to moderate OSA ( apnea/hypopnea index-AHI 19 + /- 4 and minimum SaO2 89 + /- 1 % ) , and evidence of maxillary constriction on orthodontic evaluation . All patients underwent treatment with RME , six cases requiring elective surgical assistance . Polysomnography was repeated at the completion of treatment . Nine of the 10 patients reported improvements in snoring and hypersomnolence . There was a significant reduction in AHI ( 19 + /- 4 vs 7 + /- 4 , p < 0.05 ) in the entire group . In seven patients , the AHI returned to normal ( i.e. , = < 5 ) ; only one patient showed no improvement . These preliminary data suggest that RME may be a useful treatment alternative for selected patients with OSA [7996343] The purpose of this study was to compare the effects of a modified Herbst appliance ( mHA ) and a muscle relaxation appliance ( MR ) on nocturnal breathing and body movement activity in patients with obstructive sleep apnoea syndrome ( OSAS ) . To increase the airway space posterior to the tongue base without severely affecting the craniom and ibular joint , the mHA was adjusted to anchor the m and ible at 50 % of maximum protrusion . MR producing an occlusal coverage but no protrusion served as a control appliance . All-night static charge-sensitive bed ( SCSB ) and finger oximeter recordings were done to six male patients in three conditions : first without dental device and then with mHA and with MR , in a r and om order , after a 2 month period of habituation . The oxyhaemoglobin desaturation events were 44.7 h-1 of recording observed during the control night , 29.6 h-1 with mHA ( P = 0.087 ) . The frequency of body movements decreased from 34.9 to 20.4 h-1 ( P = 0.0079 ) , respectively . MR had no significant effects either on the frequency of the desaturation events or the frequency of body movements , but the increased respiratory resistance breathing , indicating presence of partial upper airway obstruction , was reduced from 14.3 to 6.9 % of the time in bed ( P = 0.022 ) . We conclude that 50 % protrusion chosen for these experiments , produced with a mHA , brought about some alleviation of upper airway obstruction in our preselected patients , but did not lead to sufficient control of apnoea . The reduction of partial upper airway obstruction induced with a MR warrants further studies in a larger patient population [10767241] STUDY OBJECTIVES To examine dose-dependent effects of m and ibular advancement on collapsibility of the passive pharynx and sleep-disordered breathing ( SDB ) . DESIGN Prospect i ve , r and omized study . SETTING University hospital . PATIENTS Thirty-seven adult patients with SDB . INTERVENTIONS Oral appliances with 2- , 4- , and 6-mm advancement of the m and ible . MEASUREMENTS AND RESULTS Overnight oximetry was performed with and without oral appliances . Each 2-mm m and ibular advancement coincided with approximately 20 % improvement in number and severity of nocturnal desaturations . Percentages of patients producing a > 50 % improvement rate of the number of desaturations were 25 % , 48 % , and 65 % with use of oral appliances with 2- , 4- , and 6-mm m and ibular advancement , respectively . Static pharyngeal mechanics were evaluated in six completely paralyzed patients with SDB under general anesthesia with and without the oral appliances . Advancement of m and ibular position was found to produce dose-dependent closing pressure reduction of all pharyngeal segments . Normalization of nocturnal oxygenation was associated with negative closing pressure , especially at the velopharynx . CONCLUSIONS We conclude that improvement of both nocturnal oxygenation and pharyngeal collapsibility significantly depends on the m and ibular position [8625679] STUDY OBJECTIVE To compare efficacy , side effects , patient compliance , and preference between oral appliance ( OA ) therapy and nasal-continuous positive airway pressure ( N-CPAP ) therapy . DESIGN R and omized , prospect i ve , crossover study . SETTING University hospital and tertiary sleep referral center . PATIENTS Twenty-seven unselected patients with mild-moderate obstructive sleep apnea ( OSA ) . INTERVENTIONS There was a 2-week wash-in and a 2-week wash-out period , and 2 x 4-month treatment periods ( OA and N-CPAP ) . Efficacy , side effects , compliance , and preference were evaluated by a question naire and home sleep monitoring . MEASUREMENTS AND RESULTS Two patients dropped out early in the study and treatment results are presented on the remaining 25 patients . The apnea/hypopnea index was lower with N-CPAP ( 3.5 + /- 1.6 ) ( mean + /- SD ) than with the OA ( 9.7 + /- 7.3 ) ( p < 0.05 ) . Twelve of the 25 patients who used the OA ( 48 % ) were treatment successes ( reduction of apnea/hypopnea to < 10/h and relief of symptoms ) , 6 ( 24 % ) were compliance failures ( unable or unwilling to use the treatment ) , and 7 ( 28 % ) were treatment failures ( failure to reduce apnea/hypopnea index to < 10/h and /or failure to relieve symptoms ) . Four people refused to use N-CPAP after using the OA . Thirteen of the 21 patients who used N-CPAP were overall treatment successes ( 62 % ) , 8 were compliance failures ( 38 % ) , and there were no treatment failures . Side effects were more common and the patients were less satisfied with N-CPAP ( p < 0.005 ) . Seven patients were treatment successes with both treatments , six of these patients preferred OA , and one preferred N-CPAP as a long-term treatment . CONCLUSIONS We conclude that OA is an effective treatment in some patients with mild-moderate OSA and is associated with fewer side effects and greater patient satisfaction than N-CPAP [11734445] The evidence linking sleep-disordered breathing to increased mortality and cardiovascular morbidity has been conflicting and inconclusive . We hypothesized that a potential adverse effect of disordered breathing would be more obvious in patients with established vascular disease . In a prospect i ve cohort study 408 patients aged 70 yr or younger with verified coronary disease were followed for a median period of 5.1 yr . An apnea-hypopnea index ( AHI ) of > or = 10 and an oxygen desaturation index ( ODI ) of > or = 5 were used as the diagnostic criteria for sleep-disordered breathing . The primary end point was a composite of death , cerebrovascular events , and myocardial infa rct ion . There was a 70 % relative increase and a 10.7 % absolute increase in the primary composite end point in patients with disordered breathing defined as an ODI of > or = 5 ( risk ratio 1.70 , 95 % confidence interval [ CI ] 1.15 - 2.52 , p = 0.008 ) . Similarly , patients with an AHI of > or = 10 had a 62 % relative increase and a 10.1 % absolute increase in the composite endpoint ( risk ratio 1.62 , 95 % CI 1.09 - 2.41 , p = 0.017 ) . An ODI of > or = 5 and an AHI of > or = 10 were both independently associated with cerebrovascular events ( hazard ratio 2.62 , 95 % CI 1.26 - 5.46 , p = 0.01 , and hazard ratio 2.98 , 95 % CI 1.43 - 6.20 , p = 0.004 , respectively ) . We conclude that sleep-disordered breathing in patients with coronary artery disease is associated with a worse long-term prognosis and has an independent association with cerebrovascular events [10893096] STUDY OBJECTIVES To measure the effects of a titratable anterior m and ibular repositioner on airway size and Obstructive Sleep Apnea ( OSA ) and to evaluate its compliance . DESIGN Before and after insertion sleep studies were obtained in a total of 38 OSA patients of varying severity from three different sites . Covert compliance was measured by means of a newly-developed , miniaturized , temperature-sensitive , imbedded monitor . Validity testing was completed in six adult volunteers who wore monitors imbedded into small acrylic appliances . MEASUREMENTS AND RESULTS The mean RDI before treatment was 32.6 ( SEM 2.1 ) and after the insertion of the appliance , the RDI was reduced to 12.1 ( SEM 1.7 , p<0.001 ) . RDI was reduced to less than 15/hour in 80 % of a group of moderate OSA patients ( RDI 15 to 30 ) and in 61 % of a group of severe OSA patients ( RDI > 30 ) with respect to baseline RDI . Fiber optic video endoscopy was performed on 9 OSA patients with and without the appliance . No significant differences in hypopharynx or oropharynx cross sectional areas were found , but at the level of the velopharynx , the airway size was significantly increased ( p<0.05 ) . The index of agreement was 0.99 between the monitor clock time and the subject 's log sheets . Compliance data from eight OSA subjects instructed to wear the appliance during sleep indicated that it was worn for a mean of 6.8 hours with a range of 5.6 to 7.5 hours per night . CONCLUSION The titratable adjustable m and ibular advancement appliance , made from thermoelastic acrylic , significantly reduces RDI in moderate to severe OSA patients , has a direct effect on airway size and is well worn throughout the night [8583709] We studied the short-term effects and complications of the use of a dental device ( prosthetic m and ibular advancement : PMA ) in 72 patients with obstructive sleep apnea syndrome ( OSAS ) , and the compliance of these patients with this treatment . In 61 ( 84.5 % ) of the 72 patients , the apnea index decreased by more than 50 % . The lowest SaO2 and symptom scores also improved significantly . The severity of OSAS was not related to the percent reduction in apnea index . Complications of PMA use were observed in 22 patients ( 30.6 % ) , but no severe adverse effects were observed . Sixty-two of the 72 patients continued using the PMA throughout the entire study period ( overall compliance rate , 86.1 % ) . In addition , the long-term compliance rate ( more than 5 years ) was 61.5 % . We conclude that the effects of PMA in patients with OSAS are clinical ly significant , that there are no severe complications , and that compliance with treatment is good [9155816] Previous case reports have indicated dental devices can be an effective nonsurgical treatment for snoring and obstructive sleep apnea . This pilot study evaluated the effectiveness of two intraoral devices in reducing the Respiratory Disturbance Index ( RDI ) and Epworth Sleepiness Scale ( ESS ) scores in a group of 24 adult volunteers with a history of loud snoring . Subjects were r and omly assigned to two groups . Twelve subjects were fitted with a dental device design ed to increase vertical dimension and protrude the m and ible ( device A ) . The other 12 subjects received a different device design ed to minimally increase vertical opening without protruding the m and ible ( device B ) . Unattended home sleep monitoring ( Edentrace II Digital Recorder , Edentech Corp. ) was used to compute RDI at two time periods : ( T0 ) before using any dental device and ( T1 ) while using a dental device 2 weeks after the initial delivery date . The mean RDI and ESS scores at T0 for subjects in the device A group were 35.6 + /- 28.4 and 12.0 + /- 3.9 , respectively . Means for the same measures at T1 were 21.1 + /- 21.4 and 8.2 + /- 4.0 . For subjects in the device B group , means for RDI and ESS scores at T0 were 36.5 + /- 43.7 and 13.0 + /- 4.5 , the means at T1 were 46.8 + /- 47.0 and 12.5 + /- 5.7 . The effectiveness of the two devices was estimated by comparing the difference in RDI scores from T0 to T1 for the 10 subjects who were using device A and completed the study and the 8 subjects who were using device B and completed the study . Six subjects withdrew for various reasons . From T0 to T1 , device A reduced RDI scores in 9 of 10 subjects , with a mean reduction in RDI of 14.5 ( p < or = 0.05 ) and in ESS score of 3.8 ( p < or = 0.005 ) . Device B showed no change or an increased RDI score in 8 of 8 subjects . Seven of the eight subjects who showed no improvement in RDI with device B were then fitted with device A. Four of these seven subjects showed a reduction in RDI and five showed a reduction in ESS after using device A for 2 weeks . The mean reduction in RDI and ESS was 2.4 + /- 19.8 and 2.4 + /- 3.0 , respectively . Hence , we conclude that a dental device that advances the m and ible and increases the vertical dimension to open the upper airway is more effective in reducing the number of apneic and snoring events during sleep than one which does not [12867898] The aim of this prospect i ve , r and omized study was to analyze dental and skeletal side effects after 4 years of treating obstructive sleep apnea ( OSA ) patients with a m and ibular advancement device ( MAD ) compared with uvulopalatopharyngoplasty ( UPPP ) . With the appliance in position , the m and ible was advanced 50 % of maximum protrusion capacity ( ie , 4 - 6 mm ) ; the vertical opening between the incisal edges was , on average , 3 mm . Thirty patients in the MAD group and 37 in the UPPP group completed the 4-year follow-up . There were no differences between the MAD and the UPPP groups in any of the dental or skeletal variables measured after the 4-year treatment period . In the MAD group , small but statistically significant changes were found : there was a posterior rotation of the m and ible ( m and ibular line [ML]/nasion-sella line [ NSL ] ) ( mean 0.5 degrees [ 95 % confidence interval ( CI ) 0.1 - 0.8 degrees ] ) . Correlated to the posterior rotation of the m and ible , the distances incision superius ML , incision superius-NSL , and incision inferius-NSL increased by means ( 95 % CI ) of 0.7 ( 0.5 - 1.2 ) , 0.8 ( 0.4 - 1.1 ) , and 1.3 ( 0.8 - 1.8 ) mm , respectively . Overjet and overbite did not change significantly , nor was there a significant change in the m and ibular length . The observed changes were considered clinical ly insignificant because overbite and overjet stayed within normal limits . Only the vertical position of the maxillary incisors in relation to ML changed to the extent that the 95 % CI of the mean for the change was outside that of the mean of the change in the UPPP group and measurement error . Treatment of OSA with a dental appliance is probably a lifelong process , and long-term follow-up studies should therefore be undertaken to control both the treatment effect on OSA and the side effects on the masticatory system [11888954] STUDY OBJECTIVES To evaluate the effects of treatment with a dental appliance or uvulopalatopharyngoplasty ( UPPP ) on somnographic variables in patients with mild-to-moderate obstructive sleep apnea ( OSA ) followed up for 4 years , and compliance and complementary treatment . DESIGN R and omized study . SETTING Central Hospital , Västerås , Uppsala University , Sweden . PATIENTS Ninety-five male patients with confirmed mild-to-moderate OSA ( apnea index [ AI ] > 5 and < 25 ) were r and omized to treatment with a dental appliance or UPPP . Sleep studies were performed before and 1 year and 4 years after intervention . Thirty-two patients in the dental-appliance group and 40 patients in the UPPP group completed the 4-year follow-up . RESULTS The success rate ( percentage of patients with at least 50 % reduction in AI ) in the dental-appliance group was 81 % , which was significantly higher than in the UPPP group , 53 % ( p < 0.05 ) . Normalization ( AI < 5 or apnea/hypopnea index < 10 ) was observed in 63 % of the dental-appliance group and 33 % of the UPPP group after 4 years . The difference between the groups was significant ( p < 0.05 ) . The compliance to use of the dental appliance was 62 % at the 4-year follow-up . Thirty patients ( 75 % ) in the UPPP group continued without complementary treatment . The dental appliances had few adverse effects on the stomatognathic system , and the number of adjustments and repairs of the appliances over time was moderate . Pronounced complaints of nasopharyngeal regurgitation of fluid and difficulty with swallowing after UPPP were reported by 8 % and 10 % , respectively . CONCLUSIONS The dental-appliance group showed significantly higher success and normalization rates regarding the somnographic variables compared to the UPPP group , but the effectiveness of the dental appliance was partly invali date d by the compliance of 62 % at the 4-year follow-up . However , the appliances had few adverse effects on the stomatognathic system and required only moderate adjustments . Use of a dental appliance with regular follow-up can be recommended for long-term treatment of OSA [1857312] OBJECTIVE To test the effects on snoring and sleep disordered breathing of a dental prosthesis ( Snore-No-More ) which is design ed to decrease snoring by preventing mouth breathing during sleep . DESIGN A crossover controlled trial . Each subject was studied on two nights a week apart . There was a control ( no treatment ) night and an experimental ( treatment ) night . The order of control and experimental nights was r and omised . SETTING The Royal Adelaide Hospital Sleep Laboratory . PARTICIPANTS Fourteen male volunteers ( age range , 36 - 59 years ) were studied . All had a history of chronic snoring but denied other symptoms of obstructive sleep apnoea syndrome . INTERVENTIONS On experimental nights subjects wore the dental prosthesis for the whole study period . On control nights no device was worn . MAIN OUTCOME MEASURES Studies were conducted overnight during the subject 's normal sleep period . The following measurements were made : ( i ) frequency and loudness of snores ; ( ii ) frequency of disordered breathing events ( apnoeas and hypopnoeas ) ; ( iii ) mean and minimum arterial oxygen saturation while asleep ; and ( iv ) sleep stages . RESULTS The dental prosthesis did not change the mean frequency or mean intensity of snores . The number of sleep disordered breathing events per hour of sleep decreased by approximately one-third on experimental nights ( mean + /- SEM events/h : control , 24.7 + /- 5.3 ; experimental , 16.1 + /- 3.3 , P less than 0.05 ) . Neither sleep architecture nor arterial oxygen saturation differed between control and experimental nights . CONCLUSION Snores using the dental prosthesis Snore-No-More to produce obligatory nasal breathing are unlikely to experience clinical benefit [11012871] The objectives of this study were : to evaluate the change in the three quality of life ( QOL ) dimensions of vitality , contentment and sleep before intervention and 1 year after treatment with a dental appliance or uvulopalatopharyngoplasty ( UPPP ) ; to compare the effect of treatment between these two treatment groups on these three dimensions ; and to determine the relation between the QOL scores and somnographic values . Ninety-five patients with mild to moderate obstructive sleep apnoea ( OSA ) ( AI > 5 ) were r and omly allocated to either a dental appliance or UPPP treatment group . Seven patients withdrew after r and omization but before treatment , leaving 88 patients eligible for treatment . The patients were examined using somnography and administered the Minor Symptoms Evaluation-Profile ( MSE-P ) , a QOL question naire , before and 1 year after intervention . Thirty-seven patients in the dental appliance group and 43 in the UPPP group completed the 1-year follow-up . The mean values for the three dimensions vitality , contentment and sleep improved significantly 1 year after intervention in the dental appliance and UPPP groups . No difference in the QOL scores at baseline was noted between the groups . One year after intervention the UPPP group showed significantly more contentment than the dental appliance group . In contrast , vitality and sleep dimensions did not differ between the two treatment groups . No significant correlations were observed between the QOL scores and somnographic values . In conclusion , quality of life improved significantly in the dental appliance and UPPP groups 1 year after intervention . However , the dental appliance group showed a lower level of contentment than the UPPP group , even though the somnographic values were superior in the former group [9085488] The role of oral appliances in the routine treatment of obstructive sleep apnea ( OSA ) is not well defined . This prospect i ve study attempts to clarify the clinical role of a specific oral appliance , the m and ibular repositioning device ( MRD ) . This study evaluated the demographic , polysomnographic , and cephalometric radiographic findings predictive of treatment success or failure with the MRD . Twenty-nine patients were diagnosed with mild to severe OSA by nocturnal polysomnography . The majority of these patients were intolerant to nasal continuous positive airway pressure ( CPAP ) and all were fitted with a MRD . Twenty-three of these patients were compliant initially with MRD use and received post-treatment nocturnal polysomnogrpahy at a mean of 104 days after receiving the device . The respiratory disturbance index ( RDI ) decreased with MRD use ( 37 + /- 23 versus 18 + /- 20 events/hour , p < 0.001 ) , and 16 of the 23 patients ( 69 % ) were considered responders ( decrease in RDI > or = 50 % and posttreatment RDI < or = 20 ) . Measurements of subjective and objective daytime sleepiness , nocturnal oxygen desaturation , and snoring were all improved with MRD use . A pre-treatment RDI > 40 was present in four of the seven ( 67 % ) non-responders . Age , body mass index , and cephalometric radiographic measurements were not predictive of treatment outcome . Sixteen of 23 patients ( 70 % ) continue to use the MRD after 3.4 + /- 0.7 years . This study suggests that the MRD is useful in the long-term treatment of patients with OSA of mild to moderate severity [12171833] BACKGROUND For the treatment of nonsevere obstructive sleep apnea syndrome ( OSAS ) , m and ibular advancement devices ( MADs ) are employed as an alternative to nasal continuous positive airway pressure ( CPAP ) therapy . However , very few specific data on the effectiveness of MADs in this group of patients are available . We therefore compared an individually adjustable intraoral sleep apnea device ( ISAD ) that permits movements of the lower jaw in three dimensions , with CPAP in the treatment of patients with an apnea/hypopnea index ( AHI ) < or = 30/h . METHODS In a r and omized crossover study , 16 men and 4 women ( mean + /- SD age , 56.5 + /- 10.2 years ; body mass index , 31.2 + /- 6.4 ; AHI , 17.5 + /- 7.7/h ) were treated for 6 weeks with each modality . RESULTS In the initial phase , a significant improvement in AHI ( baseline , 17.5 + /- 7.7/h ; ISAD , 10.5 + /- 7.5/h [ p < 0.05 ] ; CPAP , 3.5 + /- 2.9/h [ p < 0.01 ] ) and in breathing-related arousals ( baseline , 8.9 + /- 6.1/h ; ISAD , 3.7 + /- 3.3/h [ p < 0.01 ] ; CPAP , 1.4 + /- 1.6/h [ p < 0.01 ] ) was achieved with both modalities . Considering all 20 subjects , after 6 weeks of treatment , normalization of the respiratory parameters was seen only with CPAP . However , 30 % of the patients had a lasting reduction in AHI to < 10/h with the ISAD also . The patients considered the ISAD to be easier to use ( scale of 1 to 6 : ISAD , 1.8 + /- 1.1 ; CPAP , 3.1 + /- 1.5 [ p < 0.05 ] ) , and indicated greater utilization of the device in comparison with CPAP . CONCLUSION Even in patients with mild-to-moderate OSAS , CPAP is the more effective long-term treatment modality . In the individual case , the better compliance seen with the ISAD may be advantageous [15201136] The efficacy of currently recommended treatments is uncertain in patients with mild to moderate obstructive sleep apnea ( apnea-hypopnea index [ AHI ] , 5 - 30 ) . A group of 114 sleep clinic patients with an AHI of 5 - 30 have participated in a r and omized controlled crossover trial of 3 months of treatment with each of nasal continuous positive airway pressure ( CPAP ) , a m and ibular advancement splint , and a placebo tablet . Outcomes were sleep fragmentation and hypoxemia , daytime sleepiness , quality of life , neurobehavioral function , and blood pressure . Both active treatments improved sleep outcomes , but positive airway pressure had a greater effect . The quality of life , symptoms , and subjective but not objective sleepiness improved to a similar degree with both treatments ; however , many of the improvements seen in neuropsychologic function and mood were not better than the placebo effect . Some aspects of nocturnal blood pressure were improved with the splint but not with CPAP . This study has shown that although both CPAP and m and ibular advancement splint effectively treated sleep-disordered breathing and sleepiness , the expected response in neurobehavioral function was incomplete . This may be due to the splint having a lesser therapeutic effect and CPAP being poorly tolerated and therefore used less in this patient group

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### Context: [14569523] The objective of this study was to compare the effect of two different degrees of m and ibular advancement ( MA ) , 75 % versus 50 % , on somnographic variables after 6 months of dental appliance treatment in patients with severe obstructive sleep apnea ( OSA ) . A further purpose was to compare the number of adverse events on the stomatognathic system and the effects of dental appliance treatment on the presence of daytime sleepiness . Eighty-six males with severe OSA ( apnea index ≥ 20 ) were r and omly allocated to either 75 % or 50 % MA . Forty patients in the 75 % MA group and 37 patients in the 50 % MA group completed the 6-month follow-up . The effectiveness of treatment in terms of normalization ( apnea index < 5 and apnea/hypopnea index < 10 ) with 75 % MA was 52 % , which was significantly higher ( p = 0.04 ) than the 31 % achieved with 50 % MA . The dental appliance had few adverse events on the stomatognathic system regardless of group , and the number of adverse events did not differ between the two groups . Finally , the mean value of Epworth Sleepiness Scale scores decreased significantly from 11.6 at baseline to 8.0 at follow-up ( p < 0.001 ) . No significant difference was observed between the two groups . The results indicate that a dental appliance could be an alternative treatment for some patients with severe OSA [12204875] The aim of this study was to evaluate the effect of a m and ibular advancement splint ( MAS ) on daytime sleepiness and a range of other symptoms in obstructive sleep apnea ( OSA ) . Using a r and omized crossover design , patients received 4 weeks of treatment with MAS and a control device ( inactive oral appliance ) , with an intervening 1-week washout . At the end of each treatment period , patients were reassessed by question naire , polysomnography , and multiple sleep latency test . Fifty-nine men and 14 women with a mean ( + /- SD ) age of 48 + /- 11 years and proven OSA experienced a significantly improved mean ( + /- SEM ) sleep latency on the multiple sleep latency test ( 10.3 + /- 0.5 versus 9.1 + /- 0.5 minutes , p = 0.01 ) and Epworth sleepiness scale score ( 7 + /- 1 versus 9 + /- 1 , p < 0.0001 ) with the MAS compared with the control device after 4 weeks . The proportion of patients with normal subjective sleepiness was significantly higher with the MAS than with the control device ( 82 versus 62 % , p < 0.01 ) , but this was not so for objective sleepiness ( 48 versus 34 % , p = 0.08 ) . Other OSA symptoms were controlled in significantly more patients with the MAS than with the control device . MAS therapy improves a range of symptoms associated with OSA [15358707] The present study objective was to establish whether pretreatment social cognitive variables may contribute to the explanation of variance in adherence to continuous positive airway pressure ( CPAP ) treatment for patients with obstructive sleep apnoea/hypopnoea syndrome ( OSAHS ) . A total of 119 of 180 consecutive OSAHS patients were recruited to the study prior to initial CPAP titration . Patients completed psychological measures of health value , health locus of control ( incorporating internality , chance , powerful others ) and self-efficacy prior to CPAP titration . Objective adherence data were measured by CPAP unit time clocks and collected at 3-month follow-up . Average nightly use was calculated over this period . Logistic regression of prospect i ve predictors of adherence produced a model comprising psychological ( health value , internality , powerful others ) , as well as clinical variables ( Epworth score , body mass index , apnoea/hypopnoea index , CPAP pressure ) . This model explained 24 % of the variance in CPAP use , and correctly identified 75 % of adherers and 53 % of nonadherers . Although the psychological variables explained only a small amount of the overall variance in adherence behaviour , this result provides further support for the hypothesis that psychological variables contribute , in part , to continuous positive airway pressure adherence . Future research should focus on highlighting discrete variables , which may helpfully inform psychologically based interventions aim ed at improving the use of continuous positive airway pressure by patients with obstructive sleep apnoea/hypopnoea syndrome at risk of discontinuance [12231497] M and ibular repositioning splints ( MRSs ) and continuous positive airway pressure ( CPAP ) are used to treat the sleep apnea/hypopnea syndrome ( SAHS ) . There are some data suggesting that patients with milder symptoms prefer MRS , but there are few comparative data on outcomes . Therefore , we performed a r and omized crossover trial of 8 weeks of CPAP and 8 weeks of MRS treatment in consecutive new out patients diagnosed with SAHS ( apnea/hypopnea index [ AHI ] > or= 5/hour , and > or= 2 symptoms including sleepiness ) . Assessment s at the end of both limbs comprised home sleep study , subjective ratings of treatment value , sleepiness , symptoms , and well-being , and objective tests of sleepiness and cognition . Forty-eight of 51 recruited patients completed the trial ( 12 women ; age [ mean + /- SD ] , 46 + /- 9 years ; Epworth 14 + /- 4 ; median AHI , 22/hour ; interquartile ratio [ IQR ] , 11 - 43/hour ) . Significant ( p < or= 0.01 ) differences between MRS and CPAP were observed for 7 of 21 variables ( effect sizes , 0.3 - 0.6 SDs ) , all favoring CPAP , including AHI ( 15 + /- 16 and 8 + /- 6/hour , respectively ) , effectiveness rating , symptoms , Epworth ( 12 + /- 5 and 8 + /- 5 , respectively ) , functional outcomes of sleepiness question naire , short-form 36 health survey mental component , and health transition scores . Objective sleepiness , cognitive performance , and preference for treatments were not different . In patients experiencing a mild form of the syndrome ( AHI < 15 , n = 18 ) , symptoms , treatment efficacy and satisfaction , and subjective sleepiness were also better with CPAP than with MRS ( effect sizes , 0.7 - 1.1 SDs ) . These results do not support these MRS devices as first-line treatment for sleepy patients with SAHS [17121868] Background : Patients with mild to moderate obstructive sleep apnoea ( OSA ) may be managed with different treatment options . This study compared the effectiveness of three commonly used non-surgical treatment modalities . Methods : Subjects with mild to moderate OSA were r and omised to one of three treatment groups for 10 weeks : conservative measures ( sleep hygiene ) only , continuous positive airways pressure ( CPAP ) in addition to conservative measures or an oral appliance in addition to conservative measures . All overweight subjects were referred to a weight-reduction class . OSA was assessed by polysomnography . Blood pressure was recorded in the morning and evening in the sleep laboratory . Daytime sleepiness was assessed with the Epworth Sleepiness Scale . Health-related quality of life ( HRQOL ) was assessed with the 36-Item Short-Form Health Survey ( SF-36 ) and Sleep Apnoea Quality of Life Index ( SAQLI ) . Results : 101 subjects with a mean ( SEM ) apnoea – hypopnoea index ( AHI ) of 21.4 ( 1.1 ) were r and omised to one of the three groups . The severity of sleep-disordered breathing was decreased in the CPAP and oral appliance groups compared with the conservative measures group , and the CPAP group was significantly better than the oral appliance group . Relief from sleepiness was significantly better in the CPAP group . CPAP was also better than the oral appliance or conservative measures in improving the “ bodily pain ” domain , and better than conservative measures in improving the “ physical function ” domain of SF-36 . Both CPAP and the oral appliance were more effective than conservative measures in improving the SAQLI , although no difference was detected between the CPAP and oral appliance groups . CPAP and the oral appliance significantly lowered the morning diastolic blood pressure compared with baseline values , but there was no difference in the changes in blood pressure between the groups . There was also a linear relationship between the changes in AHI and body weight . Conclusion : CPAP produced the best improvement in terms of physiological , symptomatic and HRQOL measures , while the oral appliance was slightly less effective . Weight loss , if achieved , result ed in an improvement in sleep parameters , but weight control alone was not uniformly effective [12199005] AIM To assess the efficacy of a m and ibular advancement splint ( MAS ) in the treatment of obstructive sleep apnoea syndrome ( OSAS ) . METHODS Nineteen patients using a MAS for symptomatic OSAS underwent polysomnography , with MAS use r and omised to one half of the night . Indices of snoring and OSAS were compared . Side effects , compliance and treatment response were evaluated by question naire . RESULTS Use of the MAS improved total respiratory disturbance index ( RDI ) from 22.2 + /- 19.8 ( SD ) events per hour to 16.5 + /- 21.4/hr ( p = 0.03 ) , supine RDI ( 30.8 + /- 23.8/hr to 18.8 + /- 22.1/hr , p = 0.01 ) , arousal index ( 25.2 + /- 18.9/hr to 19.3 + /- 14.2/hr , p = 0.01 ) and snoring intensity ( 52.7 + /- 4.1 to 50.7 + /- 2.7 dB , p = 0.02 ) but not total snore frequency ( p > 0.05 ) . Using polysomnographic criteria , MAS treatment was completely successful in four ( 21 % ) patients , partially successful in ten ( 52.6 % ) and a failure in five ( 26.3 % ) . Treatment over a median of 6.5 weeks ( range 2 - 48 ) was perceived as beneficial by ten of eleven partners . Fifteen patients ( 79 % ) reported side effects , 9 ( 46 % ) did not use the device every night and four ( 21 % ) used the device less than three nights per week . CONCLUSION The use of the MAS result ed in significant reductions in indices of OSAS and snoring . However , a significant number of patients had difficulty tolerating and regularly using the device [10445069] The enthusiasm for uvulopalatopharyngoplasty ( UPPP ) in the treatment of obstructive sleep apnoea ( OSA ) has declined in recent years , partly because of a lower success rate over time and partly because of adverse effects . Reports on the beneficial effects of dental appliances exist , but only one prospect i ve r and omized study has been published comparing dental appliances with nasal continuous positive airway pressure ( CPAP ) treatment . No study has been published comparing dental appliance treatment with UPPP . Ninety-five male patients with confirmed OSA , subjective daytime sleepiness and an apnoea index ( AI ) > 5 were r and omized for subsequent treatment with either a dental appliance or UPPP . There were 49 patients in the dental appliance group and 46 in the UPPP group . Thirty-seven patients in the dental appliance group and 43 in the UPPP group completed the 12-month follow-up . The success rate ( rate of patients with at least a 50 % reduction in AI ) for the dental appliance group was 95 % , which was significantly higher ( p < 0.01 ) than the 70 % success rate for the UPPP group . According to the criteria for OSA ( apnoea index > or = 5 or apnoea/hypopnoea index > or = 10 ) , 78 % of the dental appliance group and 51 % of the UPPP group were normalized after 12 months . The difference between the groups was significant ( p < 0.05 ) . These findings suggest that the dental appliance technique is useful in the treatment of mild to moderate OSA [8464434] BACKGROUND Limited data have suggested that sleep-disordered breathing , a condition of repeated episodes of apnea and hypopnea during sleep , is prevalent among adults . Data from the Wisconsin Sleep Cohort Study , a longitudinal study of the natural history of cardiopulmonary disorders of sleep , were used to estimate the prevalence of undiagnosed sleep-disordered breathing among adults and address its importance to the public health . METHODS A r and om sample of 602 employed men and women 30 to 60 years old were studied by overnight polysomnography to determine the frequency of episodes of apnea and hypopnea per hour of sleep ( the apnea-hypopnea score ) . We measured the age- and sex-specific prevalence of sleep-disordered breathing in this group using three cutoff points for the apnea-hypopnea score ( > or = 5 , > or = 10 , and > or = 15 ) ; we used logistic regression to investigate risk factors . RESULTS The estimated prevalence of sleep-disordered breathing , defined as an apnea-hypopnea score of 5 or higher , was 9 percent for women and 24 percent for men . We estimated that 2 percent of women and 4 percent of men in the middle-aged work force meet the minimal diagnostic criteria for the sleep apnea syndrome ( an apnea-hypopnea score of 5 or higher and daytime hypersomnolence ) . Male sex and obesity were strongly associated with the presence of sleep-disordered breathing . Habitual snorers , both men and women , tended to have a higher prevalence of apnea-hypopnea scores of 15 or higher . CONCLUSIONS The prevalence of undiagnosed sleep-disordered breathing is high among men and is much higher than previously suspected among women . Undiagnosed sleep-disordered breathing is associated with daytime hypersomnolence [15785917] The purpose of this study was to investigate the effects of an oral appliance ( OA ) , with and without m and ible advance , in the treatment of obstructive sleep apnea syndrome ( OSA ) . Twenty-four patients diagnosed with OSA agreed to participate in this study . The patients were treated for 3 months ( with a removable soft elastic silicone positioner customized with thermoplastic silicone and with a 5-mm opening ) . Patients were selected , using a r and omized design , to receive an OA model either with ( 12 patients ) or without advance ( 12 patients ) . Before treatment , a snoring question naire , the Medical Outcomes Study 36-Item Short-Form Health Survey ( SF-36 ) , the Functional Outcomes of Sleep Question naire ( FOSQ ) , the Epworth Sleepiness Scale ( ESS ) , and polysomnography were completed . Fifteen subjects completed the protocol ( 13 men , two women ) . With respect to basal values , the m and ible-advanced OA group presented a decrease in the mean apnea – hypopnea index ( AHI ) ( 33.8±4.7 versus 9.6±2.1 ; p<0.01 ) , number of arousals per hour ( 33.8±13.9 versus 16.0±1.5 ; p<0.05 ) , ESS score ( 14.7±5.1 versus 5.1±1.9 ; p<0.05 ) , snoring score ( 15.4±1.9 versus 10.1±3.2 ; p<0.05 ) , and total FOSQ score ( 78.1±22.6 versus 99.3±14.4 ; p<0.05 ) . After treatment , the non-advanced group presented a decrease in the mean AHI ( 24.0±12.2 versus . 11.7±7.9 ; p<0.05 ) . However , no significant differences were found in the number of arousals per hour , ESS score , snoring , and total FOSQ score in the non-advanced group . Neither study group showed significant difference in mean SF36 scores . Oral appliances , especially those that advance the m and ible , offer an effective treatment for OSA [15453552] STUDY OBJECTIVE To investigate the short-term effect ( 4 weeks ) of oral appliance therapy for obstructive sleep apnea on blood pressure . DESIGN R and omized , controlled , crossover trial . SETTING Multidisciplinary sleep disorders clinic in a university teaching hospital . PATIENTS Sixty-one patients diagnosed with obstructive sleep apnea on polysomnography ( apnea hypopnea index > or = 10 per hour and at least 2 of the following symptoms -- daytime sleepiness , snoring , witnessed apneas , fragmented sleep ; age > 20 years ; and minimum m and ibular protrusion of 3 mm ) . INTERVENTION A m and ibular advancement splint ( MAS ) and control oral appliance for 4 weeks each . MEASUREMENTS AND RESULTS Polysomnography and 24-hour ambulatory blood pressure monitoring were carried out at baseline and following each 4-week intervention period . Patients showed a 50 % reduction in mean apnea hypopnea index with MAS compared with the control and a significant improvement in both minimum oxygen saturation and arousal index . There was a significant reduction with the MAS in mean ( + /- SEM ) 24-hour diastolic blood pressure ( 1.8 + /- 0.5 mmHg ) compared with the control ( P = .001 ) but not in 24-hour systolic blood pressure . Awake blood-pressure variables were reduced with the MAS by an estimated mean ( + /- SEM ) of 3.3 + /- 1.1 mmHg for systolic blood pressure ( P = .003 ) and 3.4 + /- 0.9 mmHg for diastolic blood pressure ( P < .0001 ) . There was no significant difference in blood pressure measured asleep . CONCLUSION Oral appliance therapy for obstructive sleep apnea over 4 weeks results in a reduction in blood pressure , similar to that reported with continuous positive airway pressure therapy [10591454] In a prospect i ve study , 95 patients with mild to moderate obstructive sleep apnoea ( OSA ) were r and omised to receive either surgical treatment , uvulopalatopharyngoplasty , ( 4 - 6 patients ) or treatment with a nocturnal dental appliance for m and ibular advancement ( 49 patients ) . Of the 49 dental appliance patients , 37 completed the 12-month follow-up . The aim of this study was to evaluate the effects and adverse events of dental appliance treatment from a one-year perspective . Somnography was employed to measure treatment effects before and 12 months post-treatment . At the 12-month control , somnography was performed twice : the first time with the dental appliance and the second time without it . Adverse events were recorded 2 weeks and 3 , 6 , and 12 months after treatment was initiated . The patients used the dental appliance on average 6 nights/week . After 12 months of treatment , the apnoea , apnoea/hypopnoea , oxygen desaturation , and snoring indices decreased significantly . Ninety-five per cent of the patients reduced their apnoea index by > or = 50 % and 78 % of the patients were normalised following treatment . At the somnographic registration without the dental appliance , the values were found comparable to what they were before treatment . M and ibular mobility and occlusion were constant throughout the study . The adverse events result ing from using the dental appliance were relatively minor and infrequent , and no serious complications were observed except for two patients who reported pain from the temporom and ibular joint . In conclusion , the dental appliance has been shown to be a valuable treatment method for mild to moderate OSA with few adverse events in the stomatognathic system or other complications [17564405] STUDY OBJECTIVES This study aim ed to assess the efficacy of a custom-made m and ibular advancement splint for the treatment of obstructive sleep apnea with respect to neuropsychological functioning and mood state . METHODS A r and omized controlled crossover design was used in which 73 participants ( mean age = 48.4 , SD = 11.0 , % men = 80.8 ) with at least 2 symptoms of obstructive sleep apnea and an apnea hypopnea index > or = 10 per hour underwent treatment with both m and ibular advancement splint and an inactive oral device . Polysomnographic , neuropsychological and self-report measures were conducted at baseline and repeated after each of the two 4-week treatment phases . RESULTS MAS treatment was associated with improvements on the somatic component of the Beck Depression Inventory and the Vigor-Activity and Fatigue-Inertia scales of the Profile of Mood States . While there were no improvements within the neuropsychological domains of attention/working memory , verbal memory , visuospatial or executive functioning , treatment with the m and ibular advancement splint was associated with faster performance on a test of vigilance/psychomotor speed . These changes , however , did not correspond to the improved subjective sleepiness or apnea-hypopnea index during treatment . CONCLUSIONS Treatment with the m and ibular advancement splint results in improvements in self-reported sleepiness , fatigue/energy levels and vigilance/psychomotor speed in patients with obstructive sleep apnea [11371418] Although there is increasing interest in the use of oral appliances to treat obstructive sleep apnea ( OSA ) , the evidence base for this is weak . Furthermore , the precise mechanisms of action are uncertain . We aim ed to systematic ally investigate the efficacy of a novel m and ibular advancement splint ( MAS ) in patients with OSA . The sample consisted of 28 patients with proven OSA . A r and omized , controlled three-period ( ABB/BAA ) crossover study design was used . After an acclimatization period , patients underwent three polysomnographs with either a control oral plate , which did not advance the m and ible ( A ) , or MAS ( B ) , 1 wk apart , in either the ABB or BAA sequence . Complete response ( CR ) was defined as a resolution of symptoms and a reduction in Apnea/Hypopnea Index ( AHI ) to < 5/h , and partial response ( PR ) as a > or = 50 % reduction in AHI , but remaining > or = 5/h . Twenty-four patients ( 19 men , 5 women ) completed the protocol . Subjective improvements with the MAS were reported by the majority of patients ( 96 % ) . There were significant improvements in AHI ( 30 + /- 2/h versus 14 + /- 2/h , p < 0.0001 ) , MinSa(O(2 ) ) ( 87 + /- 1 % versus 91 + /- 1 % , p < 0.0001 ) , and arousal index ( 41 + /- 2/h versus 27 + /- 2/h , p < 0.0001 ) with MAS , compared with the control . The control plate had no significant effect on AHI and MinSa(O(2 ) ) . CR ( n = 9 ) or PR ( n = 6 ) was achieved in 62.5 % of patients . The MAS is an effective treatment in some patients with OSA , including those patients with moderate or severe OSA [10382693] BACKGROUND Nasal continuous positive airway pressure ( NCPAP ) is widely used as a treatment for obstructive sleep apnoea . However , to date there are no r and omised controlled trials of this therapy against a well-matched control . We undertook a r and omised prospect i ve parallel trial of therapeutic NCPAP for obstructive sleep apnoea compared with a control group on subtherapeutic NCPAP . METHODS Men with obstructive sleep apnoea , defined as an Epworth sleepiness score of 10 or more and ten or more dips per h of more than 4 % SaO2 caused by obstructive sleep apnoea on overnight sleep study , were r and omly assigned therapeutic NCPAP or subtherapeutic NCPAP ( about 1 cm H2O ) for 1 month . Primary outcomes were subjective sleepiness ( Epworth sleepiness score ) , objective sleepiness ( maintenance of wakefulness test ) , and SF-36 question naire measurements of self-reported functioning and well-being . FINDINGS 107 men entered the study : 53 received subtherapeutic NCPAP and 54 therapeutic NCPAP . Use of NCPAP by the two treatment groups was similar : 5.4 h ( therapeutic ) and 4.6 h ( subtherapeutic ) per night . Subtherapeutic NCPAP did not alter the overnight number of SaO2 dips per h compared with baseline , and thus acted as a control . Therapeutic NCPAP was superior to subtherapeutic NCPAP in all primary outcome measures . The Epworth score was decreased from a median of 15.5 to 7.0 on therapeutic NCPAP , and from 15.0 to 13.0 on subtherapeutic NCPAP ( between treatments , p<0.0001 ) . Mean maintenance-of-wakefulness time increased from 22.5 to 32.9 min on therapeutic NCPAP and , not significantly , from 20.0 to 23.5 min on subtherapeutic NCPAP ( between treatments p<0.005 ) . Effect sizes for SF-36 measures of energy and vitality were 1.68 ( therapeutic ) and 0.97 ( subtherapeutic ) NCPAP ( between treatments p<0.0001 ) . For mental summary score , the corresponding values were 1.02 and 0.4 ( between treatments p=0.002 ) . INTERPRETATION Therapeutic NCPAP reduces excessive daytime sleepiness and improves self-reported health status compared with a subtherapeutic control . Compared with controls , the effects of therapeutic NCPAP are large and confirm previous uncontrolled clinical observations and the results of controlled trials that used an oral placebo [9515847] OBJECTIVE To evaluate the effects of a m and ibular advancement device on apneas and sleep in mild , moderate , and severe obstructive sleep apnea . DESIGN Prospect i ve study . SUBJECTS Forty-four of 47 patients included . INTERVENTION Individually adjusted m and ibular advancement devices . MEASUREMENTS Polysomnographic sleep recordings for 1 night without the device and 1 night with it , with a median of 1 day and no changes in weight , medication , or sleep position between the recordings . RESULTS The device reduced the median obstructive apnea-hypopnea index from 11 ( range , 7 to 19 ) to 5 ( range , 0 to 17 ) ( p<0.001 ) in 21 patients with mild sleep apnea , from 27 ( range , 20 to 38 ) to 7 ( range , 1 to 19 ) ( p<0.001 ) in 15 patients with moderate sleep apnea , and from 53 ( range , 44 to 66 ) to 14 ( range , 2 to 32 ) ( p<0.05 ) in 8 patients with severe sleep apnea . The arousal index decreased and the sleep stage patterns improved in all severity groups . Twenty-eight of 44 patients were successfully treated with an obstructive apnea-hypopnea index of below 10 and a subjective reduction in snoring . Nine of 16 patients with treatment failure still reported a reduction in snoring . The success rate correlated inversely to the disease severity ( r=-0.41 ; p<0.01 ) . CONCLUSIONS A m and ibular advancement device reduces apneas and improves sleep quality in patients with obstructive sleep apnea , especially in those with mild and moderate disease . A follow-up sleep recording during treatment is necessary because of the risk of silent obstructive apneas without subjective snoring with the device [17245607] Impaired simulated driving performance has been demonstrated in obstructive sleep apnoea – hypopnoea syndrome ( OSAHS ) patients . Although continuous positive airway pressure ( CPAP ) generally improves simulated driving performance , the effects of oral-appliance ( OA ) therapy are unknown . The aims of this study were to determine to what extent OSAHS patients have more difficulty with a monotonous simulated driving test when compared with control subjects and to compare the effects of OA with CPAP therapy . Simulated driving performance was evaluated in 20 OSAHS patients and 16 control subjects during a 25-min driving test . After r and omization , ten patients started OA and CPAP therapy , respectively . After 2 to 3 months of treatment , patients repeated the driving test . At baseline , the total number of lapses of attention during driving was significantly higher in OSAHS patients as compared with control subjects . As a result of treatment , the total number of lapses of attention was significantly decreased in both the OA and CPAP group . When comparing driving performance between the OA and CPAP group , no significant differences were noted . OSAHS patients perform worse on a simulated driving test when compared with control subjects . When evaluating the effects of treatment , adequate OSAHS management with either OA or CPAP therapy usually result ed in substantial improvements of simulated driving . Conclusions beyond both treatments improving simulated driving performance are , however , not justified by the data in the present study [9196520] BACKGROUND Although oral appliances are effective in some patients with obstructive sleep apnoea ( OSA ) , they are not universally effective . A novel anterior m and ibular positioner ( AMP ) has been developed with an adjustable hinge that allows progressive advancement of the m and ible . The objective of this prospect i ve crossover study was to compare efficacy , side effects , patient compliance , and preference between AMP and nasal continuous positive airway pressure ( nCPAP ) in patients with symptomatic mild to moderate OSA . METHODS Twenty four patients of mean ( SD ) age 44.0 ( 10.6 ) years were recruited with a mean ( SD ) body mass index of 32.0 ( 8.2 ) kg/m2 , Epworth sleepiness score 10.7 ( 3.4 ) , and apnoea/hypopnoea index 26.8 (11.9)/hour . There was a two week wash-in and a two week wash-out period and two treatment periods ( AMP and nCPAP ) each of four months . Efficacy , side effects , compliance , and preference were evaluated by a question naire and home sleep monitoring . RESULTS One patient dropped out early in the study and three refused to cross over so treatment results are presented on the remaining 20 patients . The apnoea/hypopnoea index ( AHI ) was lower with nasal CPAP 4.2 (2.2)/hour than with the AMP 13.6 (14.5)/hour ( p < 0.01 ) . Eleven of the 20 patients ( 55 % ) who used the AMP were treatment successes ( reduction of AHI to < 10/hour and relief of symptoms ) , one ( 5 % ) was a compliance failure ( unable or unwilling to use the treatment ) , and eight ( 40 % ) were treatment failures ( failure to reduce AHI to < 10/hour and /or failure to relieve symptoms ) . Fourteen of the 20 patients ( 70 % ) who used nCPAP were treatment successes , six ( 30 % ) were compliance failures , and there were no treatment failures . There was greater patient satisfaction with the AMP ( p < 0.01 ) than with nCPAP but no difference in reported side effects or compliance . CONCLUSIONS AMP is an effective treatment in some patients with mild to moderate OSA and is associated with greater patient satisfaction than nCPAP [12143089] This r and omized placebo-controlled cross-over trial assessed the effectiveness of a m and ibular advancement appliance ( MAA ) in managing obstructive sleep apnoea ( OSA ) . Twenty-one adults , with confirmed OSA , were provided with a maxillary placebo appliance and a MAA for 4 - 6 weeks each , in a r and omized order . Question naires at baseline and after each appliance assessed bed-partners ' reports of snoring severity ( loudness and number of nights per week ) , and patients ' daytime sleepiness ( Epworth Sleepiness Score , ESS ) . The Apnoea Hypopnoea Index ( AHI ) and Oxygen Desaturation Index ( ODI ) were measured at baseline and with each appliance during single night sleep studies . Seventy-nine per cent of subjects wore their MAA for at least 4 hours at night . Sixty-eight per cent of subjects wore their MAA for 6 - 7 nights per week . Excessive salivation was the most commonly reported complication . One subject was unable to tolerate the MAA and withdrew from the study . Among the remaining 20 subjects , the MAA produced significantly lower AHI and ODI values than the placebo . However , although the reported frequency and loudness of snoring and the ESS values were lower with the MAA than the placebo , these differences were not statistically significant . When wearing the MAA , 35 per cent of the OSA subjects had a reduction in the pre-treatment ODI to 10 or less , while 33 per cent had an AHI of 10 or less . The MAA was less effective in the subjects with the most severe OSA ( pre-treatment ODI > 50 and /or pre-treatment AHI > 50 ) [14960007] The objective of this study was to evaluate the effect of 2 different degrees of m and ibular advancement , 50 % vs. 75 % of maximum protrusive capacity , on somnographic variables after 1 year of dental appliance treatment in patients with mild to moderate obstructive sleep apnea ( OSA ) . A further purpose was to compare the number of adverse events on the stomatognathic system . In a prospect i ve study , 74 male patients were r and omly allocated to receive a dental appliance with either 50 % ( 38 patients ) or 75 % m and ibular advancement ( 36 patients ) . After 1 year of treatment , 55 patients completed the follow‐up . Somnography was performed to measure treatment effects before and 12 months post‐treatment . The apnea , apnea/hypopnea , and oxygen desaturation indices decreased significantly in both groups after 1 year ( P<0.001 ) ; however , there were no differences between the groups . Normalization ( apnea index < 5 and apnea/hypopnea index < 10 ) was observed in 79 % in group 50 and in 73 % in group 75 . Few patients ( < 5 % ) reported symptoms from the stomatognathic system except for headache ( > once a week ) , which was reported in one‐third of the patients . Headache was significantly more infrequent after 1 year of treatment in both groups ( P<0.001 ) . No serious complications were observed except for 2 patients who reported a painful condition from the temporom and ibular joint in either group . In conclusion , m and ibular advancement with a dental appliance effectively reduces the sleep‐breathing disorder measured as frequency of apneas , and a pronounced m and ibular advancement did not show a greater improvement of the medical problem compared to less advancement for patients with mild to moderate OSA . On the basis of few adverse events in the stomatognathic system or other complications we can recommend dental appliance treatment and , for patients with mild to moderate obstructive sleep apnea , not starting treatment by more than 50 % m and ibular advancement [10903249] Our purpose was to compare the effectiveness and side effects of a novel , single-piece m and ibular advancement device ( OSA-Monobloc ) for sleep apnea therapy with those of a two-piece appliance with lateral Herbst attachments ( OSA-Herbst ) as used in previous studies . An OSA-Monobloc and an OSA-Herbst with equal protrusion were fitted in 24 obstructive sleep apnea patients unable to use continuous positive airway pressure ( CPAP ) therapy . After an adaptation period of 156 + /- 14 d ( mean + /- SE ) , patients used the OSA-Monobloc , the OSA-Herbst , and no appliance in r and om order , using each appliance for 1 wk . Symptom scores were recorded and sleep studies were done at the end of each week . Several symptom scores were significantly improved with both appliances , but to a greater degree with the OSA-Monobloc . Epworth Sleepiness Scale scores were 8.8 + /- 0.7 with the OSA-Herbst , and 8.6 + /- 0.8 with the OSA-Monobloc devices , and 13.1 + /- 0.9 without therapy ( p < 0.05 versus both appliances ) . The apnea/hypopnea index was 8.7 + /- 1.5/h with the OSA-Herbst and 7.9 + /- 1.6/h with the OSA-Monobloc device , and 22.6 + /- 3.1/h without therapy ( p < 0.05 versus both appliances ) . Side effects were mild and of equal prevalence with both appliances . Fifteen patients preferred the OSA-Monobloc , eight patients had no preference , and one patient preferred the OSA-Herbst device ( p < 0.008 versus OSA-Monobloc ) . We conclude that both the OSA-Herbst and the OSA-Monobloc are effective therapeutic devices for sleep apnea . The OSA-Monobloc relieved symptoms to a greater extent than the OSA-Herbst , and was preferred by the majority of patients on the basis of its simple application [8769497] OBJECTIVE This study compared the efficacy of a removable anterior m and ibular positioning ( AMP ) device to continuous positive airway pressure ( CPAP ) in patients with obstructive sleep apnea ( OSA ) using a fully balanced crossover design . DESIGN Twenty-three male subjects with confirmed OSA were recruited from the Technion Sleep Laboratory in Haifa , Israel , from February 18 , 1991 to December 17 , 1992 . Twenty-one of the 23 subjects enrolled completed all aspects of the study . RESULTS The mean apnea-hypopnea index ( AHI ) before treatment was 33.86 + /- 14.30 . The mean AHI decreased with CPAP to 59.50 % , but decreased only 38.91 % with the AMP device . The lowest mean recorded oxygen saturation level for the 21 subjects was 84.30 before treatment , 91.10 after CPAP treatment , and 90.20 after AMP treatment . Sleep data revealed a significant decrease in stage 1 and 2 ( p=0.0088 ) and an increase in rapid eye movement percent ( p=0.0066 ) for both treatments when compared with baseline . Three- to 10-month posttreatment phone interviews showed that 1 subject was not using either device , 1 subject was using CPAP , and 2 subjects were using the AMP device intermittently due to occasional temporom and ibular joint pain symptoms . The remaining 17 subjects were all using the AMP device nightly . The symptoms of excessive daytime sleepiness also decreased significantly by both AMP and CPAP . CONCLUSIONS The AMP device achieved substantial success in most cases , but was less effective than CPAP , especially for the more severe cases . In general , the AMP device was strongly preferred over the CPAP by the subjects of this study [12143088] This prospect i ve , r and omized , cross-over trial was design ed to compare the efficacy of a m and ibular advancement splint ( MAS ) with that of nasal continuous positive airway pressure ( nCPAP ) in patients with obstructive sleep apnoea ( OSA ) . Twenty-four patients ( 20 males and four females ) with mild to moderate OSA ( AHI between 10 and 49 events per hour ) were enrolled in the study . Each patient used both MAS and nCPAP , with the initial therapy being allocated at r and om . Treatment periods lasted for two months with a two-week wash-out interval between . Polysomnography was performed prior to the study and after each clinical intervention . Patient and partner question naires were used to assess changes in general health and daytime somnolence . The AHI decreased from 22.2 to 3.1 using nCPAP , and to 8.0 using the MAS ( P < 0.001 for both devices ) and there was no statistically significant difference between the two treatments . The Epworth Sleepiness Score ( ESS ) fell from 13.4 to 8.1 with nCPAP , and to 9.2 with MAS ( P < 0.001 ) , again with no differences between the use of MAS or nCPAP . The question naire data showed an improvement in general health scores ( P < 0.001 ) after both treatments , but daytime sleepiness only improved significantly using nCPAP ( P < 0.001 ) . Despite this , 17 out of the 21 subjects who completed both arms of the study preferred the MAS . The splints were well tolerated and their efficacy suggests that the MAS may be a suitable alternative to nCPAP in the management of patients with mild or moderate OSA [8686675] Knowledge of how dental appliances alter upper airway muscle activity when they are used for the treatment of snoring and /or obstructive sleep apnea ( OSA ) is very limited . The purpose of this study was to define the effect of a tongue retaining device ( TRD ) on awake genioglossus ( GG ) muscle activity in 10 adult subjects with OSA and in 6 age and body mass index ( BMI ) matched symptom-free control subjects . The TRD is a custom-made appliance design ed to allow the tongue to remain in a forward position between the anterior teeth by holding the tongue in an anterior bulb with negative pressure , during sleep . This pulls the tongue forward to enlarge the volume of the upper airway and to reduce upper airway resistance . In this study , two customized TRDs were used for each subject . The TRD-A did not have an anterior bulb but incorporated lingual surface electrodes to record the GG electromyographic ( EMG ) activity . The TRD-B contained an anterior bulb and two similar electrodes . The GG EMG activity was also recorded while patients used the TRD-B but were instructed to keep their tongue at rest outside the anterior bulb ; this condition is hereafter referred to as TRD-X. The GG EMG activity and nasal airflow were simultaneously recorded while subjects used these customized TRDs during spontaneous awake breathing in both the upright and supine position . The following results were obtained and were consistent whether subjects were in the upright or the supine position . The GG EMG activity was greater with the TRD-B than with the TRD-A in control subjects ( p < 0.05 ) , whereas the GG EMG activity was less with the TRD-B than with the TRD-A in subjects with OSA ( p < 0.01 ) . Furthermore , there was no significant difference between the GG EMG activity of the TRD-A and the TRD-X in control subjects , whereas there was less activity with the TRD-X than with the TRD-A in subjects with OSA ( p < 0.05 ) . On the basis of these findings , it was concluded that the TRD has different effects on the awake GG muscle activity in control subjects and patients with OSA . The result ant change in the anatomic configuration of the upper airway caused by the TRD may be important in the treatment of OSA because such a change may alleviate the impaired upper airway function [11812555] BACKGROUND Obstructive sleep apnoea is associated with raised blood pressure . If blood pressure can be reduced by nasal continuous positive airway pressure ( nCPAP ) , such treatment could reduce risk of cardiovascular disease in patients with obstructive sleep apnoea . Our aim was to see whether nCPAP for sleep apnoea reduces blood pressure compared with the most robust control intervention subtherapeutic nCPAP . METHODS We did a r and omised parallel trial to compare change in blood pressure in 118 men with obstructive sleep apnoea ( Epworth score > 9 , and a > 4 % oxygen desaturation index of > 10 per h ) who were assigned to either therapeutic ( n=59 ) or subtherapeutic ( 59 ) nCPAP ( about 1 cm H(2)O pressure ) for 1 month . The primary outcome was the change in 24-h mean blood pressure . Secondary outcomes were changes in systolic , diastolic , sleep , and wake blood pressure , and relations between blood pressure changes , baseline blood pressure , and severity of sleep apnoea . FINDINGS Therapeutic nCPAP reduced mean arterial ambulatory blood pressure by 2.5 mm Hg ( SE 0.8 ) , whereas subtherapeutic nCPAP increased blood pressure by 0.8 mm Hg ( 0.7 ) ( difference -3.3 [ 95 % CI -5.3 to -1.3 ] ; p=0.0013 , unpaired t test ) . This benefit was seen in both systolic and diastolic blood pressure , and during both sleep and wake . The benefit was larger in patients with more severe sleep apnoea than those who had less severe apnoea , but was independent of the baseline blood pressure . The benefit was especially large in patients taking drug treatment for blood pressure . INTERPRETATION In patients with most severe sleep apnoea , nCPAP reduces blood pressure , providing significant vascular risk benefits , and substantially improving excessive daytime sleepiness and quality of life [12001556] M and ibular advancement appliances ( MAAs ) are accepted as a treatment option for snoring and mild obstructive sleep disorders . In the present clinical study two differently design ed devices were examined for their effectiveness in treating obstructive sleep apnoea ( OSA ) . The study was based on an assessment of 26 patients with a polysomnographic diagnosis of mild OSA [ 22 men , four women ; mean body mass index 27.3 kg/m2 ( SD 3.1 ) ; mean age 56.8 years ( SD 5.2 ) ; mean respiratory disturbance index ( RDI ) : 16.0 events/hour ( SD 4.4 ) ] . After insertion of the first MAA and a 6 - 8-week habituation period , a cardio-respiratory home-sleep study was carried out . Following a 2 - 3-week period with no treatment , the second appliance was inserted . The sequence of the devices was r and omized . Once the patients had become accustomed to the second appliance , another somnographic registration was carried out . Daytime sleepiness , snoring , and sleep quality were assessed subjectively on a visual analogue scale . The results showed that a statistically significant improvement in the respiratory parameters was achieved with both appliances ( P < 0.01 ) . However , the activator [ RDI : 5.5 events/hour , SD 3.3 ; apnoea index ( AI ) : 3.4 events/hour , SD 2.1 ] was significantly more effective ( P < 0.01 ) than the Silencor ( RDI , 7.3 events/hour , SD 5.3 ; AI : 5.8 events/hour , SD 3.2 ) . No difference was recorded in the subjective assessment of the therapeutic effects . Both appliances reduced daytime sleepiness and snoring and improved sleep quality , and both influenced the treatment outcome [11779741] To evaluate the clinical usefulness and tolerability of an oral jaw-positioning appliance in the treatment of obstructive sleep apnea syndrome in children , we studied 32 patients ( mean age , 7.1 + /- 2.6 yr ; 20 males ) with symptoms of obstructive sleep apnea , malocclusion , and a baseline apnea index > 1 event/h . A group of 19 subjects was r and omly assigned to a 6-mo trial of an oral appliance ; the remainder acted as control subjects . At baseline and after the trial all patients underwent physical examination , a st and ard polysomnography , and orthodontic assessment . A modified version of the Brouillette question naire related to obstructive sleep apnea symptoms was administered to parents before and after the trial and a clinical score was calculated . Of the 32 subjects enrolled , 4 treated subjects and 5 control subjects were lost to follow-up . Polysomnography after the trial showed that treated subjects all had significantly lower apnea index ( p < 0.001 ) and hypopnea index values ( p < 0.001 ) than before the trial , whereas in untreated control subjects these values remained almost unchanged . Clinical assessment before and after treatment showed that in 7 of the 14 subjects ( 50 % ) the oral appliance had reduced ( a fall of at least 2 points in the respiratory score ) and in 7 had resolved the main respiratory symptoms , whereas untreated patients continued to have symptoms . In conclusion , treatment of obstructive sleep apnea syndrome with an oral appliance in children with malocclusion is effective and well tolerated [7812552] Snoring and obstructive sleep apnea ( OSA ) are related to narrowing of the upper airway . A m and ibular advancement splint ( MAS ) could improve both conditions by increasing oropharyngeal and hypopharyngeal dimensions . The effects of a MAS on snoring and OSA was evaluated 3.5 + /- 2.1 ( mean + /- SD ) mo after issue in 57 subjects with habitual loud snoring , 39 of whom had an apnea-hypopnea index ( AHI ) > or = 10 . Assessment was by question naire ( all subjects ) and polysomnography ( 51 subjects , 47 male ) including measurement of sound intensity . Use of the MAS was r and omized to first or second half of study . Snores were scored where inspiratory noise was greater than 5 dB above background . Total sleep time , sleep efficiency , % REM sleep , and % sleep spent supine were similar ( p > 0.05 ) with and without the MAS . Snores per sleep minute , corrected for time in apnea , and sound intensity of snores ( % snores > or = 50 dB ) decreased with the MAS from 11.0 + /- 5.8 and 42.0 + /- 25.0 % to 9.0 + /- 6.0 ( p < 0.01 ) and 26.2 + /- 25.2 % ( p < 0.01 ) , respectively . Using the MAS significantly improved OSA : AHI decreased from 32.2 + /- 28.5 to 17.5 + /- 22.7 ( p < 0.01 ) and arousal index decreased from 31.4 + /- 20.6 to 19.0 + /- 14.6 ( p < 0.01 ) . AHI decreased to < 20 with the MAS in 12 of 17 subjects where untreated AHI was between 20 and 60 , and in 2 of 9 subjects where untreated AHI was > 60 . Forty-five patients continued to use the MAS regularly . ( ABSTRACT TRUNCATED AT 250 WORDS [15743867] This prospect i ve , r and omized , crossover study of 16 patients with obstructive sleep apnoea ( OSA ) [ 12 males , four females ; median body mass index ( BMI ) 29.2 kg/m(2 ) ( range 23.8 - 51.1 ) ; median age 44.8 years ( range 24.0 - 68.4 ) ] analysed the efficacy of the Twin Block ( TB ) in relation to the Herbst appliance as a m and ibular advancement splint ( MAS ) . Each subject was fitted with a TB and Herbst MAS in a r and om order with a washout period of 2 weeks between appliances . Once each patient was subjectively happy with the performance of each appliance , question naires and a visual analogue scale ( VAS ) were used to determine differences in snoring , daytime sleepiness , quality of life , side-effects of the appliances and patient preference . All patients underwent overnight domiciliary sleep recordings prior to and after fitting each appliance in order to objective ly assess sleep quality in terms of the apnoea-hypopnoea index ( AHI ) , snoring frequency and arterial oxygen saturation . The results suggested that there was no difference in the treatment performance of the TB and Herbst MAS for AHI ( P = 0.71 ) , snoring frequency ( P = 0.49 ) , arterial blood oxygen saturation ( P = 0.97 ) , quality of life and side-effects . The Herbst MAS proved to be the more effective appliance for reducing daytime sleepiness ( P = 0.04 ) and was the more popular appliance among the patients . Side-effects with both appliances were minor and improved in the longer term . The TB MAS represents a viable alternative to the Herbst MAS in the treatment of patients with OSA [12231498] The aim of this study was to assess the effect of bite opening induced by a m and ibular advancement splint ( MAS ) on efficacy and side effects in the treatment of obstructive sleep apnea . In a r and omized crossover fashion , 23 adult patients received either MAS-1 ( 4 mm of interincisal opening ) or MAS-2 ( 14 mm of interincisal opening ) for 2 weeks , followed by the alternate treatment for 2 weeks , with an intervening 1-week washout . Complete response was defined as a resolution of symptoms and a reduction in apnea/hypopnea index ( AHI ) to less than 5 per hour . Partial response was defined as improved symptoms and a reduction in AHI of 50 % or more , with the AHI remaining at a value of 5 or more per hour . Both MAS-1 and MAS-2 produced similar reductions in mean ( + /- SEM ) AHI from baseline : 21 + /- 2 versus 8 + /- 1/hour and 21 + /- 2 versus 10 + /- 2/hour , respectively ( p < 0.001 ) . Either complete response or partial response occurred in 74 and 61 % of patients with MAS-1 and MAS-2 , respectively . Subjective improvements were reported with both appliances by the majority of patients . Patients preferred MAS-1 ( 78 versus 22 % , p = 0.007 ) . This study suggests that the amount of bite opening induced by MAS does not have a significant impact on treatment efficacy but does have an impact on patient acceptance [14718430] STUDY OBJECTIVES The effect of therapy using a cervicom and ibular support collar ( CMSC ) to manage obstructive sleep apnea ( OSA ) was compared with st and ard therapy , nasal continuous positive airway pressure ( nCPAP ) . DESIGN Subjects received treatment with CMSC or nCPAP each for 1 month in r and om order . The study was analyzed on an intention-to-treat basis . SETTING Tom McKendrick Sleep Laboratory , Dunedin Hospital . PARTICIPANTS Ten adult subjects with mild-to-moderate OSA ( apnea-hypopnea index [ AHI ] , 24 + /- 13/h slept [ mean + /- SD ] ) completed the study . INTERVENTIONS The CMSC was design ed to prevent m and ibular movement and hold the head in slight extension , thus preventing the postural changes that might contribute to OSA . Positioning of the CMSC was confirmed by an externally applied cervical range of motion ( CROM ) instrument and by cephalometry . Subjects were carefully instructed in the use of each device and completed a symptom diary . After 1 month , subjects underwent polysomnography with each of the allocated devices in situ , and symptom question naires were administered . MEASUREMENTS AND RESULTS Treatment success ( AHI < /= 10/h slept ) with CMSC was achieved in only 2 of 10 subjects , partial success ( AHI > 10/h to < /= 15/h slept ) was achieved in 2 subjects , and in 6 of 10 subjects there was no benefit . In contrast , treatment success was achieved in 7 of 10 subjects receiving nCPAP . Mean AHI was 29.4 + /- 13.4/h at baseline , 26.9 + /- 17.2/h slept with CMSC , and 9.9 + /- 8.0/h slept with nCPAP ( p = 0.001 ) . No significant differences in sleep architecture or sleep efficiency were achieved using nCPAP compared to CMSC . The efficacy of the CMSC in maintaining the desired head position was confirmed by cephalometry and the CROM instrument . CONCLUSIONS Our results , although negative , provide important evidence that control of head and neck posture , perhaps adopted as a second-line treatment , is not helpful in the management of OSA . It appears that other anatomic and physiologic factors have a dynamic overriding influence on upper airway closure compared to simple skeletal relationships [9871945] The precise role of maxillary constriction in the pathophysiology of obstructive sleep apnea ( OSA ) is unclear . However , it is known that subjects with maxillary constriction have increased nasal resistance and result ant mouth-breathing , features typically seen in OSA patients . Maxillary constriction is also associated with alterations in tongue posture which could result in retroglossal airway narrowing , another feature of OSA . Rapid maxillary expansion ( RME ) is an orthodontic treatment for maxillary constriction which increases the width of the maxilla and reduces nasal resistance . The aim of this pilot study was to investigate the effect of rapid maxillary expansion in OSA . We studied 10 young adults ( 8 male , 2 female , mean age 27 + /- 2 [ sem ] years ) with mild to moderate OSA ( apnea/hypopnea index-AHI 19 + /- 4 and minimum SaO2 89 + /- 1 % ) , and evidence of maxillary constriction on orthodontic evaluation . All patients underwent treatment with RME , six cases requiring elective surgical assistance . Polysomnography was repeated at the completion of treatment . Nine of the 10 patients reported improvements in snoring and hypersomnolence . There was a significant reduction in AHI ( 19 + /- 4 vs 7 + /- 4 , p < 0.05 ) in the entire group . In seven patients , the AHI returned to normal ( i.e. , = < 5 ) ; only one patient showed no improvement . These preliminary data suggest that RME may be a useful treatment alternative for selected patients with OSA [7996343] The purpose of this study was to compare the effects of a modified Herbst appliance ( mHA ) and a muscle relaxation appliance ( MR ) on nocturnal breathing and body movement activity in patients with obstructive sleep apnoea syndrome ( OSAS ) . To increase the airway space posterior to the tongue base without severely affecting the craniom and ibular joint , the mHA was adjusted to anchor the m and ible at 50 % of maximum protrusion . MR producing an occlusal coverage but no protrusion served as a control appliance . All-night static charge-sensitive bed ( SCSB ) and finger oximeter recordings were done to six male patients in three conditions : first without dental device and then with mHA and with MR , in a r and om order , after a 2 month period of habituation . The oxyhaemoglobin desaturation events were 44.7 h-1 of recording observed during the control night , 29.6 h-1 with mHA ( P = 0.087 ) . The frequency of body movements decreased from 34.9 to 20.4 h-1 ( P = 0.0079 ) , respectively . MR had no significant effects either on the frequency of the desaturation events or the frequency of body movements , but the increased respiratory resistance breathing , indicating presence of partial upper airway obstruction , was reduced from 14.3 to 6.9 % of the time in bed ( P = 0.022 ) . We conclude that 50 % protrusion chosen for these experiments , produced with a mHA , brought about some alleviation of upper airway obstruction in our preselected patients , but did not lead to sufficient control of apnoea . The reduction of partial upper airway obstruction induced with a MR warrants further studies in a larger patient population [10767241] STUDY OBJECTIVES To examine dose-dependent effects of m and ibular advancement on collapsibility of the passive pharynx and sleep-disordered breathing ( SDB ) . DESIGN Prospect i ve , r and omized study . SETTING University hospital . PATIENTS Thirty-seven adult patients with SDB . INTERVENTIONS Oral appliances with 2- , 4- , and 6-mm advancement of the m and ible . MEASUREMENTS AND RESULTS Overnight oximetry was performed with and without oral appliances . Each 2-mm m and ibular advancement coincided with approximately 20 % improvement in number and severity of nocturnal desaturations . Percentages of patients producing a > 50 % improvement rate of the number of desaturations were 25 % , 48 % , and 65 % with use of oral appliances with 2- , 4- , and 6-mm m and ibular advancement , respectively . Static pharyngeal mechanics were evaluated in six completely paralyzed patients with SDB under general anesthesia with and without the oral appliances . Advancement of m and ibular position was found to produce dose-dependent closing pressure reduction of all pharyngeal segments . Normalization of nocturnal oxygenation was associated with negative closing pressure , especially at the velopharynx . CONCLUSIONS We conclude that improvement of both nocturnal oxygenation and pharyngeal collapsibility significantly depends on the m and ibular position [8625679] STUDY OBJECTIVE To compare efficacy , side effects , patient compliance , and preference between oral appliance ( OA ) therapy and nasal-continuous positive airway pressure ( N-CPAP ) therapy . DESIGN R and omized , prospect i ve , crossover study . SETTING University hospital and tertiary sleep referral center . PATIENTS Twenty-seven unselected patients with mild-moderate obstructive sleep apnea ( OSA ) . INTERVENTIONS There was a 2-week wash-in and a 2-week wash-out period , and 2 x 4-month treatment periods ( OA and N-CPAP ) . Efficacy , side effects , compliance , and preference were evaluated by a question naire and home sleep monitoring . MEASUREMENTS AND RESULTS Two patients dropped out early in the study and treatment results are presented on the remaining 25 patients . The apnea/hypopnea index was lower with N-CPAP ( 3.5 + /- 1.6 ) ( mean + /- SD ) than with the OA ( 9.7 + /- 7.3 ) ( p < 0.05 ) . Twelve of the 25 patients who used the OA ( 48 % ) were treatment successes ( reduction of apnea/hypopnea to < 10/h and relief of symptoms ) , 6 ( 24 % ) were compliance failures ( unable or unwilling to use the treatment ) , and 7 ( 28 % ) were treatment failures ( failure to reduce apnea/hypopnea index to < 10/h and /or failure to relieve symptoms ) . Four people refused to use N-CPAP after using the OA . Thirteen of the 21 patients who used N-CPAP were overall treatment successes ( 62 % ) , 8 were compliance failures ( 38 % ) , and there were no treatment failures . Side effects were more common and the patients were less satisfied with N-CPAP ( p < 0.005 ) . Seven patients were treatment successes with both treatments , six of these patients preferred OA , and one preferred N-CPAP as a long-term treatment . CONCLUSIONS We conclude that OA is an effective treatment in some patients with mild-moderate OSA and is associated with fewer side effects and greater patient satisfaction than N-CPAP [11734445] The evidence linking sleep-disordered breathing to increased mortality and cardiovascular morbidity has been conflicting and inconclusive . We hypothesized that a potential adverse effect of disordered breathing would be more obvious in patients with established vascular disease . In a prospect i ve cohort study 408 patients aged 70 yr or younger with verified coronary disease were followed for a median period of 5.1 yr . An apnea-hypopnea index ( AHI ) of > or = 10 and an oxygen desaturation index ( ODI ) of > or = 5 were used as the diagnostic criteria for sleep-disordered breathing . The primary end point was a composite of death , cerebrovascular events , and myocardial infa rct ion . There was a 70 % relative increase and a 10.7 % absolute increase in the primary composite end point in patients with disordered breathing defined as an ODI of > or = 5 ( risk ratio 1.70 , 95 % confidence interval [ CI ] 1.15 - 2.52 , p = 0.008 ) . Similarly , patients with an AHI of > or = 10 had a 62 % relative increase and a 10.1 % absolute increase in the composite endpoint ( risk ratio 1.62 , 95 % CI 1.09 - 2.41 , p = 0.017 ) . An ODI of > or = 5 and an AHI of > or = 10 were both independently associated with cerebrovascular events ( hazard ratio 2.62 , 95 % CI 1.26 - 5.46 , p = 0.01 , and hazard ratio 2.98 , 95 % CI 1.43 - 6.20 , p = 0.004 , respectively ) . We conclude that sleep-disordered breathing in patients with coronary artery disease is associated with a worse long-term prognosis and has an independent association with cerebrovascular events [10893096] STUDY OBJECTIVES To measure the effects of a titratable anterior m and ibular repositioner on airway size and Obstructive Sleep Apnea ( OSA ) and to evaluate its compliance . DESIGN Before and after insertion sleep studies were obtained in a total of 38 OSA patients of varying severity from three different sites . Covert compliance was measured by means of a newly-developed , miniaturized , temperature-sensitive , imbedded monitor . Validity testing was completed in six adult volunteers who wore monitors imbedded into small acrylic appliances . MEASUREMENTS AND RESULTS The mean RDI before treatment was 32.6 ( SEM 2.1 ) and after the insertion of the appliance , the RDI was reduced to 12.1 ( SEM 1.7 , p<0.001 ) . RDI was reduced to less than 15/hour in 80 % of a group of moderate OSA patients ( RDI 15 to 30 ) and in 61 % of a group of severe OSA patients ( RDI > 30 ) with respect to baseline RDI . Fiber optic video endoscopy was performed on 9 OSA patients with and without the appliance . No significant differences in hypopharynx or oropharynx cross sectional areas were found , but at the level of the velopharynx , the airway size was significantly increased ( p<0.05 ) . The index of agreement was 0.99 between the monitor clock time and the subject 's log sheets . Compliance data from eight OSA subjects instructed to wear the appliance during sleep indicated that it was worn for a mean of 6.8 hours with a range of 5.6 to 7.5 hours per night . CONCLUSION The titratable adjustable m and ibular advancement appliance , made from thermoelastic acrylic , significantly reduces RDI in moderate to severe OSA patients , has a direct effect on airway size and is well worn throughout the night [8583709] We studied the short-term effects and complications of the use of a dental device ( prosthetic m and ibular advancement : PMA ) in 72 patients with obstructive sleep apnea syndrome ( OSAS ) , and the compliance of these patients with this treatment . In 61 ( 84.5 % ) of the 72 patients , the apnea index decreased by more than 50 % . The lowest SaO2 and symptom scores also improved significantly . The severity of OSAS was not related to the percent reduction in apnea index . Complications of PMA use were observed in 22 patients ( 30.6 % ) , but no severe adverse effects were observed . Sixty-two of the 72 patients continued using the PMA throughout the entire study period ( overall compliance rate , 86.1 % ) . In addition , the long-term compliance rate ( more than 5 years ) was 61.5 % . We conclude that the effects of PMA in patients with OSAS are clinical ly significant , that there are no severe complications , and that compliance with treatment is good [9155816] Previous case reports have indicated dental devices can be an effective nonsurgical treatment for snoring and obstructive sleep apnea . This pilot study evaluated the effectiveness of two intraoral devices in reducing the Respiratory Disturbance Index ( RDI ) and Epworth Sleepiness Scale ( ESS ) scores in a group of 24 adult volunteers with a history of loud snoring . Subjects were r and omly assigned to two groups . Twelve subjects were fitted with a dental device design ed to increase vertical dimension and protrude the m and ible ( device A ) . The other 12 subjects received a different device design ed to minimally increase vertical opening without protruding the m and ible ( device B ) . Unattended home sleep monitoring ( Edentrace II Digital Recorder , Edentech Corp. ) was used to compute RDI at two time periods : ( T0 ) before using any dental device and ( T1 ) while using a dental device 2 weeks after the initial delivery date . The mean RDI and ESS scores at T0 for subjects in the device A group were 35.6 + /- 28.4 and 12.0 + /- 3.9 , respectively . Means for the same measures at T1 were 21.1 + /- 21.4 and 8.2 + /- 4.0 . For subjects in the device B group , means for RDI and ESS scores at T0 were 36.5 + /- 43.7 and 13.0 + /- 4.5 , the means at T1 were 46.8 + /- 47.0 and 12.5 + /- 5.7 . The effectiveness of the two devices was estimated by comparing the difference in RDI scores from T0 to T1 for the 10 subjects who were using device A and completed the study and the 8 subjects who were using device B and completed the study . Six subjects withdrew for various reasons . From T0 to T1 , device A reduced RDI scores in 9 of 10 subjects , with a mean reduction in RDI of 14.5 ( p < or = 0.05 ) and in ESS score of 3.8 ( p < or = 0.005 ) . Device B showed no change or an increased RDI score in 8 of 8 subjects . Seven of the eight subjects who showed no improvement in RDI with device B were then fitted with device A. Four of these seven subjects showed a reduction in RDI and five showed a reduction in ESS after using device A for 2 weeks . The mean reduction in RDI and ESS was 2.4 + /- 19.8 and 2.4 + /- 3.0 , respectively . Hence , we conclude that a dental device that advances the m and ible and increases the vertical dimension to open the upper airway is more effective in reducing the number of apneic and snoring events during sleep than one which does not [12867898] The aim of this prospect i ve , r and omized study was to analyze dental and skeletal side effects after 4 years of treating obstructive sleep apnea ( OSA ) patients with a m and ibular advancement device ( MAD ) compared with uvulopalatopharyngoplasty ( UPPP ) . With the appliance in position , the m and ible was advanced 50 % of maximum protrusion capacity ( ie , 4 - 6 mm ) ; the vertical opening between the incisal edges was , on average , 3 mm . Thirty patients in the MAD group and 37 in the UPPP group completed the 4-year follow-up . There were no differences between the MAD and the UPPP groups in any of the dental or skeletal variables measured after the 4-year treatment period . In the MAD group , small but statistically significant changes were found : there was a posterior rotation of the m and ible ( m and ibular line [ML]/nasion-sella line [ NSL ] ) ( mean 0.5 degrees [ 95 % confidence interval ( CI ) 0.1 - 0.8 degrees ] ) . Correlated to the posterior rotation of the m and ible , the distances incision superius ML , incision superius-NSL , and incision inferius-NSL increased by means ( 95 % CI ) of 0.7 ( 0.5 - 1.2 ) , 0.8 ( 0.4 - 1.1 ) , and 1.3 ( 0.8 - 1.8 ) mm , respectively . Overjet and overbite did not change significantly , nor was there a significant change in the m and ibular length . The observed changes were considered clinical ly insignificant because overbite and overjet stayed within normal limits . Only the vertical position of the maxillary incisors in relation to ML changed to the extent that the 95 % CI of the mean for the change was outside that of the mean of the change in the UPPP group and measurement error . Treatment of OSA with a dental appliance is probably a lifelong process , and long-term follow-up studies should therefore be undertaken to control both the treatment effect on OSA and the side effects on the masticatory system [11888954] STUDY OBJECTIVES To evaluate the effects of treatment with a dental appliance or uvulopalatopharyngoplasty ( UPPP ) on somnographic variables in patients with mild-to-moderate obstructive sleep apnea ( OSA ) followed up for 4 years , and compliance and complementary treatment . DESIGN R and omized study . SETTING Central Hospital , Västerås , Uppsala University , Sweden . PATIENTS Ninety-five male patients with confirmed mild-to-moderate OSA ( apnea index [ AI ] > 5 and < 25 ) were r and omized to treatment with a dental appliance or UPPP . Sleep studies were performed before and 1 year and 4 years after intervention . Thirty-two patients in the dental-appliance group and 40 patients in the UPPP group completed the 4-year follow-up . RESULTS The success rate ( percentage of patients with at least 50 % reduction in AI ) in the dental-appliance group was 81 % , which was significantly higher than in the UPPP group , 53 % ( p < 0.05 ) . Normalization ( AI < 5 or apnea/hypopnea index < 10 ) was observed in 63 % of the dental-appliance group and 33 % of the UPPP group after 4 years . The difference between the groups was significant ( p < 0.05 ) . The compliance to use of the dental appliance was 62 % at the 4-year follow-up . Thirty patients ( 75 % ) in the UPPP group continued without complementary treatment . The dental appliances had few adverse effects on the stomatognathic system , and the number of adjustments and repairs of the appliances over time was moderate . Pronounced complaints of nasopharyngeal regurgitation of fluid and difficulty with swallowing after UPPP were reported by 8 % and 10 % , respectively . CONCLUSIONS The dental-appliance group showed significantly higher success and normalization rates regarding the somnographic variables compared to the UPPP group , but the effectiveness of the dental appliance was partly invali date d by the compliance of 62 % at the 4-year follow-up . However , the appliances had few adverse effects on the stomatognathic system and required only moderate adjustments . Use of a dental appliance with regular follow-up can be recommended for long-term treatment of OSA [1857312] OBJECTIVE To test the effects on snoring and sleep disordered breathing of a dental prosthesis ( Snore-No-More ) which is design ed to decrease snoring by preventing mouth breathing during sleep . DESIGN A crossover controlled trial . Each subject was studied on two nights a week apart . There was a control ( no treatment ) night and an experimental ( treatment ) night . The order of control and experimental nights was r and omised . SETTING The Royal Adelaide Hospital Sleep Laboratory . PARTICIPANTS Fourteen male volunteers ( age range , 36 - 59 years ) were studied . All had a history of chronic snoring but denied other symptoms of obstructive sleep apnoea syndrome . INTERVENTIONS On experimental nights subjects wore the dental prosthesis for the whole study period . On control nights no device was worn . MAIN OUTCOME MEASURES Studies were conducted overnight during the subject 's normal sleep period . The following measurements were made : ( i ) frequency and loudness of snores ; ( ii ) frequency of disordered breathing events ( apnoeas and hypopnoeas ) ; ( iii ) mean and minimum arterial oxygen saturation while asleep ; and ( iv ) sleep stages . RESULTS The dental prosthesis did not change the mean frequency or mean intensity of snores . The number of sleep disordered breathing events per hour of sleep decreased by approximately one-third on experimental nights ( mean + /- SEM events/h : control , 24.7 + /- 5.3 ; experimental , 16.1 + /- 3.3 , P less than 0.05 ) . Neither sleep architecture nor arterial oxygen saturation differed between control and experimental nights . CONCLUSION Snores using the dental prosthesis Snore-No-More to produce obligatory nasal breathing are unlikely to experience clinical benefit [11012871] The objectives of this study were : to evaluate the change in the three quality of life ( QOL ) dimensions of vitality , contentment and sleep before intervention and 1 year after treatment with a dental appliance or uvulopalatopharyngoplasty ( UPPP ) ; to compare the effect of treatment between these two treatment groups on these three dimensions ; and to determine the relation between the QOL scores and somnographic values . Ninety-five patients with mild to moderate obstructive sleep apnoea ( OSA ) ( AI > 5 ) were r and omly allocated to either a dental appliance or UPPP treatment group . Seven patients withdrew after r and omization but before treatment , leaving 88 patients eligible for treatment . The patients were examined using somnography and administered the Minor Symptoms Evaluation-Profile ( MSE-P ) , a QOL question naire , before and 1 year after intervention . Thirty-seven patients in the dental appliance group and 43 in the UPPP group completed the 1-year follow-up . The mean values for the three dimensions vitality , contentment and sleep improved significantly 1 year after intervention in the dental appliance and UPPP groups . No difference in the QOL scores at baseline was noted between the groups . One year after intervention the UPPP group showed significantly more contentment than the dental appliance group . In contrast , vitality and sleep dimensions did not differ between the two treatment groups . No significant correlations were observed between the QOL scores and somnographic values . In conclusion , quality of life improved significantly in the dental appliance and UPPP groups 1 year after intervention . However , the dental appliance group showed a lower level of contentment than the UPPP group , even though the somnographic values were superior in the former group [9085488] The role of oral appliances in the routine treatment of obstructive sleep apnea ( OSA ) is not well defined . This prospect i ve study attempts to clarify the clinical role of a specific oral appliance , the m and ibular repositioning device ( MRD ) . This study evaluated the demographic , polysomnographic , and cephalometric radiographic findings predictive of treatment success or failure with the MRD . Twenty-nine patients were diagnosed with mild to severe OSA by nocturnal polysomnography . The majority of these patients were intolerant to nasal continuous positive airway pressure ( CPAP ) and all were fitted with a MRD . Twenty-three of these patients were compliant initially with MRD use and received post-treatment nocturnal polysomnogrpahy at a mean of 104 days after receiving the device . The respiratory disturbance index ( RDI ) decreased with MRD use ( 37 + /- 23 versus 18 + /- 20 events/hour , p < 0.001 ) , and 16 of the 23 patients ( 69 % ) were considered responders ( decrease in RDI > or = 50 % and posttreatment RDI < or = 20 ) . Measurements of subjective and objective daytime sleepiness , nocturnal oxygen desaturation , and snoring were all improved with MRD use . A pre-treatment RDI > 40 was present in four of the seven ( 67 % ) non-responders . Age , body mass index , and cephalometric radiographic measurements were not predictive of treatment outcome . Sixteen of 23 patients ( 70 % ) continue to use the MRD after 3.4 + /- 0.7 years . This study suggests that the MRD is useful in the long-term treatment of patients with OSA of mild to moderate severity [12171833] BACKGROUND For the treatment of nonsevere obstructive sleep apnea syndrome ( OSAS ) , m and ibular advancement devices ( MADs ) are employed as an alternative to nasal continuous positive airway pressure ( CPAP ) therapy . However , very few specific data on the effectiveness of MADs in this group of patients are available . We therefore compared an individually adjustable intraoral sleep apnea device ( ISAD ) that permits movements of the lower jaw in three dimensions , with CPAP in the treatment of patients with an apnea/hypopnea index ( AHI ) < or = 30/h . METHODS In a r and omized crossover study , 16 men and 4 women ( mean + /- SD age , 56.5 + /- 10.2 years ; body mass index , 31.2 + /- 6.4 ; AHI , 17.5 + /- 7.7/h ) were treated for 6 weeks with each modality . RESULTS In the initial phase , a significant improvement in AHI ( baseline , 17.5 + /- 7.7/h ; ISAD , 10.5 + /- 7.5/h [ p < 0.05 ] ; CPAP , 3.5 + /- 2.9/h [ p < 0.01 ] ) and in breathing-related arousals ( baseline , 8.9 + /- 6.1/h ; ISAD , 3.7 + /- 3.3/h [ p < 0.01 ] ; CPAP , 1.4 + /- 1.6/h [ p < 0.01 ] ) was achieved with both modalities . Considering all 20 subjects , after 6 weeks of treatment , normalization of the respiratory parameters was seen only with CPAP . However , 30 % of the patients had a lasting reduction in AHI to < 10/h with the ISAD also . The patients considered the ISAD to be easier to use ( scale of 1 to 6 : ISAD , 1.8 + /- 1.1 ; CPAP , 3.1 + /- 1.5 [ p < 0.05 ] ) , and indicated greater utilization of the device in comparison with CPAP . CONCLUSION Even in patients with mild-to-moderate OSAS , CPAP is the more effective long-term treatment modality . In the individual case , the better compliance seen with the ISAD may be advantageous [15201136] The efficacy of currently recommended treatments is uncertain in patients with mild to moderate obstructive sleep apnea ( apnea-hypopnea index [ AHI ] , 5 - 30 ) . A group of 114 sleep clinic patients with an AHI of 5 - 30 have participated in a r and omized controlled crossover trial of 3 months of treatment with each of nasal continuous positive airway pressure ( CPAP ) , a m and ibular advancement splint , and a placebo tablet . Outcomes were sleep fragmentation and hypoxemia , daytime sleepiness , quality of life , neurobehavioral function , and blood pressure . Both active treatments improved sleep outcomes , but positive airway pressure had a greater effect . The quality of life , symptoms , and subjective but not objective sleepiness improved to a similar degree with both treatments ; however , many of the improvements seen in neuropsychologic function and mood were not better than the placebo effect . Some aspects of nocturnal blood pressure were improved with the splint but not with CPAP . This study has shown that although both CPAP and m and ibular advancement splint effectively treated sleep-disordered breathing and sleepiness , the expected response in neurobehavioral function was incomplete . This may be due to the splint having a lesser therapeutic effect and CPAP being poorly tolerated and therefore used less in this patient group Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: Summary Obstructive sleep apnoea-hypopnoea ( OSAH ) causes excessive daytime sleepiness , impairs quality -of-life , and increases cardiovascular disease and road traffic accident risks . Continuous positive airway pressure ( CPAP ) treatment and m and ibular advancement devices ( MAD ) have been shown to be effective in individual trials but their effectiveness particularly relative to disease severity is unclear . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

30069801

[27607876] OBJECTIVE : To investigate the effect of a supervised home-based exercise program on the recurrence and severity of gestational diabetes mellitus ( GDM ) together with other aspects of maternal health and obstetric and neonatal outcomes . METHODS : This r and omized controlled trial allocated women with a history of GDM to an exercise intervention ( 14-week supervised home-based stationary cycling program ) or to a control group ( st and ard care ) at 13±1 weeks of gestation . The primary outcome was a diagnosis of GDM . Secondary outcomes included maternal fitness , psychological well-being , and obstetric and neonatal outcomes . A sample size of 180 ( 90 in each group ) was required to attain 80 % power to detect a 40 % reduction in the incidence of GDM . RESULTS : Between June 2011 and July 2014 , 205 women provided written consent and completed baseline assessment s. Of these , 33 ( 16 % ) were subsequently excluded as a result of an elevated baseline oral glucose tolerance test ( OGTT ) , leaving 172 r and omized to exercise ( n=85 ) or control ( n=87 ) . Three women miscarried before the assessment of outcome measures ( control=2 ; exercise=1 ) . All remaining women completed the postintervention OGTT . The recurrence rate of GDM was similar between groups ( control 40 % [ n=34 ] ; exercise 40.5 % [ n=34 ] ; P=.95 ) and the severity of GDM at diagnosis was unaffected by the exercise program with similar glucose and insulin responses to the OGTT ( glucose 2 hours post-OGTT 7.7±1.5 compared with 7.6±1.6 mmol/L ; P>.05 ) . Maternal fitness was improved by the exercise program ( P<.01 ) and psychological distress was reduced ( P=.02 ) . There were no differences in obstetric and neonatal outcomes between groups ( P>.05 ) . CONCLUSION : Supervised home-based exercise started at 14 weeks of gestation did not prevent the recurrence of GDM ; however , it was associated with important benefits for maternal fitness and psychological well-being . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , https:// clinical trials.gov , NCT01283854 [2628875] Background To evaluate the effectiveness and safety of water aerobics during pregnancy . Methods A r and omized controlled trial carried out in 71 low-risk sedentary pregnant women , r and omly allocated to water aerobics or no physical exercise . Maternal body composition and perinatal outcomes were evaluated . For statistical analysis Chi-square , Fisher 's or Student 's t-tests were applied . Risk ratios and their 95 % CI were estimated for main outcomes . Body composition was evaluated across time using MANOVA or Friedman multiple analysis . Results There were no significant differences between the groups regarding maternal weight gain , BMI or percentage of body fat during pregnancy . Incidence of preterm births ( RR = 0.84 ; 95%CI:0.28–2.53 ) , vaginal births ( RR = 1.24 ; 95%CI:0.73–2.09 ) , low birthweight ( RR = 1.30 ; 95%CI:0.61–2.79 ) and adequate weight for gestational age ( RR = 1.50 ; 95%CI:0.65–3.48 ) were also not significantly different between groups . There were no significant differences in systolic and diastolic blood pressure and heart rate between before and immediately after the water aerobics session . Conclusion Water aerobics for sedentary pregnant women proved to be safe and was not associated with any alteration in maternal body composition , type of delivery , preterm birth rate , neonatal well-being or weight [24002348] INTRODUCTION Walking may be a strategy for increasing moderate-intensity physical activity ( MPA ) during pregnancy . PURPOSE This study aim ed to promote MPA among overweight and obese pregnant women , via walking , and to evaluate the effect of the intervention on maternal and birth outcomes . METHODS Thirty-seven overweight or obese pregnant women were r and omly assigned to a walking intervention or control group . Anthropometric and objective PA ( StepWatch ™ Activity Monitor ) data were collected for four 1-wk periods : weeks 10 - 14 ( V1 ) , weeks 17 - 19 ( V2 ) , weeks 27 - 29 ( V3 ) , and weeks 34 - 36 ( V4 ) of gestation . Participants provided information about maternal and birth outcomes . A cadence of ≥ 80 steps per minute was defined as MPA , and " meaningful walking " was defined as moderate walking in ≥ 8-min bouts . ANOVA was used to determine the differences in walking amount and meaningful walks , the Kolmogorov-Smirnov test was used for walking intensity distribution analysis , and Fisher 's exact test was used for maternal and infant outcomes analyses . Pearson correlation was used to examine the association between prepregnancy body mass index and gestational weight gain ( GWG ) . RESULTS There was significantly more MPA among women in the intervention group compared with those in the control group at V2 ( overweight , P < 0.0001 ; obese , P < 0.025 ) , V3 ( overweight , P < 0.0001 ) , and V4 ( overweight , P < 0.0001 ; obese , P < 0.025 ) . Women in the intervention group significantly increased their meaningful walks at V2 ( P = 0.054 ) , V3 ( P = 0.01 ) , and V4 ( P = 0.014 ) . There were trends for intervention group women to have more favorable maternal and birth outcomes compared with the control group . Rates of GWG at measurement points during pregnancy were significantly associated with preceding rates of GWG . CONCLUSION The pilot , unsupervised walking intervention increased the MPA of overweight and obese women during pregnancy [24901666] Few studies have investigated the impact of lifestyle interventions during pregnancy on post-partum weight retention and infant growth . Thirty seven previously non-exercising , overweight or obese pregnant women were r and omly assigned to a walking intervention or non-intervention control . For the follow-up study , weight of the mother and weight , length and body composition of the infant were collected at 1 month post-partum ( n=37 ) and 6 months post-partum ( n=33 ) . Analysis of variance and linear regression were conducted to determine the differences and association in maternal post-partum weight retention and child outcomes . At 6 months post-partum , weight retention of obese women in the intervention group ( Int-OB ) was -0.10±8.11 kg ; while , obese women in the control group ( Con-OB ) was 6.35±7.47 kg . A significantly higher percentage of Con-OB women retained more than 5 kg at 6 months post-partum ( P=0.046 ) . Even though statistically non-significant between the groups , the growth trend observed among offspring of obese women in the control group was consistently higher than the offspring of obese women in the intervention group from birth to 6-months . Third trimester gestational weight gain rate significantly predicted 6-m weight-for-length z-score after controlling for birth weight , treatment group and pre-pregnancy body mass index ( r 2=0.31 , β=1.75 , P=0.03 ) . The reduced post-partum weight retention observed among the obese women in the intervention group may be explained in part by the lifestyle modification during pregnancy [27622854] ABSTRACT Accumulating research indicates that the regular practice of physical exercise is beneficial to the human brain . From the improvement of academic achievement in children to the prevention of Alzheimer ’s disease in the elderly , exercise appears beneficial across the developmental spectrum . Recent work from animal studies also indicates that a pregnant mother can transfer the benefits of exercise during gestation to her offspring ’s brain . Exercising pregnant rats give birth to pups that have better memory and spatial learning as well as increased synaptic density . To investigate whether this transfer from the pregnant mother to her child also occurs in humans , we conducted a r and omized controlled trial ( n = 18 ) and measured the impact of exercise during pregnancy on the neuroelectric response of the neonatal brain with electroencephalography ( EEG ) . Here we show that , compared to the newborns of mothers who were inactive during their pregnancy , the children of exercising pregnant women are born with more mature brains . This was measured with the infant slow positive mismatch response ( SPMMR ) , an electroencephalographic potential known to decrease in amplitude with age . The SPMMR reflects processes associated with brain maturation via its response to sound discrimination and auditory memory . In this study , the children of the mothers who exercised throughout their pregnancy have a smaller SPMMR than the children of mothers who remained sedentary ( p = .019 ) . Our results demonstrate the impact regular exercise during pregnancy can have on the development of the human fetal brain [11864675] OBJECTIVE To evaluate the influence of exercise on maternal and perinatal outcome in a low‐risk healthy obstetric population . METHODS We conducted a prospect i ve observational study of low‐risk healthy women exercising during their pregnancy . An extensive question naire collected antepartum , intrapartum , and postpartum patient information on 750 women . The women were divided into four groups based on exercise level during pregnancy . RESULTS There were no differences among groups for maternal demographic characteristics , antenatal illnesses , stress , social support , or smoking . Heavily exercising women were older ( P = .042 ) , had higher incomes ( P = .001 ) , and were exercising more at conception ( P = .001 ) . Women who did more exercise were more likely to need an induction of labor ( P = .033 , relative risk 1.84 , 95 % confidence interval 1.05 , 3.20 ) , induction or augmentation with oxytocin ( P = .015 , relative risk 1.53 , 95 % confidence interval 1.19 , 1.97 ) , and had longer first‐stage labors ( P = .032 ) result ing in longer total labors ( P = .011 ) . The difference in the length of first‐stage labor was even greater if the no‐exercise group was compared with the strongly exercising group ( P = .009 , relative risk 1.38 , 95 % confidence interval 0.16 , 2.60 ) . Fewer umbilical cord abnormalities ( P = .034 ) were observed with exercise , but exercising women had more colds and flu ( P = .008 ) . Heavily exercising women had smaller infants ( mean difference 86.5 g ) compared with sedentary women . CONCLUSION Exercise in working women is associated with smaller babies , increased number of inductions and augmentations of labor , and longer labors . Colds and flu are more frequent in exercising women [25350037] AIM The effect of exercise training during the course of pregnancy on the newborn 's birth weight is unclear . This study examines the effect of aerobic and strength conditioning exercise performed during the second and the third trimester of pregnancy in nulliparous , previously inactive women on the newborn 's outcome . METHODS Sixty-three nulliparous , previously sedentary , were r and omly assigned to either an exercise ( N.=30 ) or a control ( N.=33 ) group . The subjects participated in the exercise group ( EG ) focused on aerobic and strength-conditioning exercise in three sessions for about 20 weeks . We registered the birth weight , birth length , gestational age at time of delivery , Apgar score and head circumference of the newborn . RESULTS There were no statistically significant differences between the two groups in mean birth weight , length , head circumference , and length of gestation . There was a significant difference between two groups in Apgar scores at 1 min ( P=0.036 ) and 5 min ( P=0.015 ) with newborns of the EG scoring higher than the CG . CONCLUSION Supervised , aerobic and strength conditioning exercise performed over the second and third trimester of pregnancy does not have a negative impact on the newborn 's body size and health [10647530] PURPOSE The present study examined the effects of exercise on physical and psychological variables in sedentary primigravidae ( PRA ) . METHODS A total of nine women r and omly assigned to an exercise ( E ) ( mean age = 31.3 + /- 3.1 yr ) and six subjects r and omly assigned to a control ( C ) group ( mean age = 27.8 + /- 3.1 yr ) fulfilled all requirements for the study . Exercise included a variety of exercise activities performed to a target heart rate of 150 - 156 beats x min(-1 ) , three times per week for 15 wk . RESULTS Results showed no significant differences between E and C groups in physical characteristics initially . A repeated measures ANOVA showed a significant group effect ( P < 0.05 ) and a significant group by time interaction ( P = 0.001 ) with the E group showing a significantly longer amount of time on the PWC150 test than the C group . There was no significant group , time , or group by time interaction for lactate accumulation . This occurred , despite the fact that the E group spent 56 % longer on the PWC150 test and the C group spent 30 % less time on the same test at the conclusion of the study . Finally , the E group in comparison to the C group showed more favorable improvements in several items related to health and well-being on the Body Cathexis Scale . There were no significant differences between E and C groups in any pregnancy outcome measures . All babies were delivered healthy at term . CONCLUSIONS These data suggest that a vigorous exercise program can lead to significant improvements in aerobic fitness at similar lactate concentrations compared to a control group and can be well tolerated by low risk sedentary PRA without any deleterious effects occurring to herself or unborn child [8990428] Objective To examine the effectiveness of a partially homebased , moderate-intensity aerobic exercise program for women with gestational diabetes . Methods This was a r and omized experimental design . Thirty-three women with gestational diabetes were r and omly assigned to the exercise or the no-exercise group . Subjects underwent hemoglobin A1C assay and submaximal cycle ergometer fitness tests at baseline and at study conclusion . Subjects kept diaries of home fasting and 2-hour postpr and ial blood glucose determinations . Exercise subjects were asked to exercise for 30 minutes three to four times weekly at 70 % of estimated maximal heart rate for the weeks of study participation . Two exercise sessions weekly were supervised by the investigator , and two were unsupervised at home . Control-group subjects were asked to maintain their current activity level . Results Daily fasting and postpr and ial blood glucose levels , hemoglobin A1C , incidence of exogenous insulin therapy , and incidence of newborn hypoglycemia were not different between the groups . There was a training effect in the exercise group ( P = .005 ) but not in the control group ( P = .25 ) . A significant decline in daily grams of carbohydrate consumed was observed in the control group ( P = .03 ) , but not in the exercise group ( P = .97 ) . No complications were found in the subjects who exercised . Conclusions A partially home-based exercise program did not reduce blood glucose levels , but did result in a modest increase in cardiorespiratory fitness . The intervention appeared safe [7771999] EDITORIAL COMMENT : When this paper was review ed the question was raised that the period of gestation is an obvious factor which can determine birth‐weight and the authors were asked how this may have affected their results The authors response was as follows [25823187] OBJECTIVE To assess the effect of aerobic exercise training on maternal and neonatal outcome METHODS The case-control study was conducted between January and July , 2011 . It was approved by the Research Ethics Committee of Toyserkan Azad University , and data was collected at prenatal clinics and delivery centres located in Hamedan , Iran . It comprised 80 pregnant women between 20 - 26 weeks of gestation r and omly assigned to two equal and matching groups of cases and controls . The intervention group did exercise continuously on a bicycle ergometre for 15 minutes , three times a week ; the intensity being 50 - 60 % of maximal heart rate . The control group did not do any exercise training . All information was obtained from the clinics , delivery centres , and from the reports of delivery room midwives . RESULTS No statistically significant difference was found between the two groups in gestational weight gain , pregnancy length , mode of delivery , first and second stage of labour , perineal tear , and 1st and 5th min Apgar score . Mean neonatal weight was significantly less in the intervention group than the control group ( p < 0.001 ) . CONCLUSION Exercising on a bicycle ergometer during pregnancy seems to be safe for the mother and the neonate [19747869] AIM The significant deterioration of insulin sensitivity and glucose tolerance during pregnancy can have serious health implication s for both the pregnant woman and her baby . Although it is well established that regular exercise benefits insulin sensitivity in the nonpregnant population , the effect on glucose tolerance in obese pregnant women is not known . The purpose of this study was to investigate the effect of a supervised 10-week , home-based , exercise programme , beginning at week 18 of gestation , on glucose tolerance and aerobic fitness in previously sedentary obese women . METHODS Twelve sedentary obese women were r and omized into an exercise ( EX ; n=6 ) or control ( CON ; n=6 ) group at 18 weeks of gestation . Those r and omized to EX engaged in 10 weeks of supervised home-based exercise ( three sessions a week of stationary cycling ) , while those in the CON group maintained their usual daily activity . Their glucose and insulin responses to an oral glucose tolerance test ( OGTT ) , as well as their aerobic fitness , were assessed both pre- and postintervention . RESULTS Reduced glucose tolerance in the CON , but not EX , group was indicated by a tendency postintervention towards higher blood glucose levels at 1h of the OGTT ( P=0.072 ) . Furthermore , at 2h of the postintervention OGTT , blood glucose tended to remain elevated from baseline in the CON ( P=0.077 ) . There was also a trend towards increased fitness in the EX ( P=0.064 ) , but not the CON group . CONCLUSION Regular aerobic exercise begun during pregnancy may have favourable effects on glucose tolerance and fitness in obese women , and warrants further investigation in a larger sample population [2613131] Background To evaluate the association between water aerobics , maternal cardiovascular capacity during pregnancy , labor and neonatal outcomes . Methods A r and omized , controlled clinical trial was carried out in which 34 pregnant women were allocated to a water aerobics group and 37 to a control group . All women were su bmi tted to submaximal ergometric tests on a treadmill at 19 , 25 and 35 weeks of pregnancy and were followed up until delivery . Oxygen consumption ( VO2 max ) , cardiac output ( CO ) , physical fitness , skin temperature , data on labor and delivery , and neonate outcomes were evaluated . Frequency distributions of the baseline variables of both groups were initially performed and then analysis of the outcomes was carried out . Categorical data were compared using the chi-square test , and numerical using Student 's t or Mann-Whitney tests . Wilk 's Lambda or Friedman 's analysis of repeat measurements were applied for comparison of physical capacity , cardiovascular outcomes and maternal temperature . Results VO2 max and physical fitness were higher in both groups in the second trimester , returning to basal levels in the third trimester . In both groups , CO increased as pregnancy progressed and peak exercise temperature was higher than resting temperature , increasing further after five minutes of recovery and remaining at this level until 15 minutes after exercise completion . There was no difference between the two groups regarding duration ( 457.9 ± SD 249.6 vs 428.9 ± SD 203.2 minutes ) or type of delivery . Labor analgesia was requested by significantly fewer women in the water aerobics group ( 27 % vs 65 % ; RR = 0.42 95%CI 0.23–0.77 ) . Neonatal results were similar in both groups . Conclusion The regular practice of moderate water aerobics by sedentary and low risk pregnant women was not detrimental to the health of the mother or the child . There was no influence on maternal cardiovascular capacity , duration of labor or type of delivery ; however , there were fewer requests for analgesia during labor in the water aerobics group [10870784] Does strenuous antenatal exercise reduce birth‐weight ? Does reducing maternal exercise increase birthweight ? What to advise about exercise during pregnancy [22364387] Objective . To study lumbopelvic pain in women r and omized to a regular exercise program during pregnancy in comparison to women receiving st and ard antenatal care . Design . A two‐armed , two‐center , r and omized controlled trial . Setting . St Olavs Hospital , Trondheim University Hospital and Stavanger University Hospital . Population . A total of 855 pregnant women were r and omized to intervention or control groups . Methods . The intervention was a 12 week exercise program , including aerobic and strengthening exercises , conducted between 20 and 36 weeks of pregnancy . One weekly group session was led by physiotherapists , and home exercises were encouraged twice a week . The control group received st and ard antenatal care . Main outcome measures . Self‐reports of lumbopelvic pain and sick leave due to lumbopelvic pain . The data were analysed according to the “ intention‐to‐treat ” principle . Results . There were no significant differences between groups of women reporting lumbopelvic pain at 36 weeks ( 74 vs. 75 % , p=0.76 ) . The proportion of women on sick leave due to lumbopelvic pain was lower in the intervention group ( 22 % vs 31 % , p=0.01 ) . Conclusions . Exercise during pregnancy does not influence the prevalence of lumbopelvic pain , but women offered a regular exercise course seem to h and le the disorder better [21948120] Objective The influence of an exercise programme performed by healthy pregnant women on maternal glucose tolerance was studied . Study design A physical activity ( PA , l and /aquatic activities ) programme during the entire pregnancy ( three sessions per week ) was conducted by a qualified instructor . 83 healthy pregnant women were r and omly assigned to either an exercise group ( EG , n=40 ) or a control ( CG , n=43 ) group . 50 g maternal glucose screen ( MGS ) , maternal weight gain and several pregnancy outcomes were recorded . Results Significant differences were found between study groups on the 50 g MGS . Values corresponding to the EG ( 103.8±20.4 mg/dl ) were better than those of the CG ( 126.9±29.5 mg/dl ) , p=0.000 . In addition , no differences in maternal weight gain and no cases of gestational diabetes in EG versus 3 in CG ( 7 % ) ( p>0.05 ) were found . Conclusion A moderate PA programme performed during pregnancy improves levels of maternal glucose tolerance [28161306] BACKGROUND : Obesity and being overweight are becoming epidemic , and indeed , the proportion of such women of reproductive age has increased in recent times . Being overweight or obese prior to pregnancy is a risk factor for gestational diabetes mellitus , and increases the risk of adverse pregnancy outcome for both mothers and their offspring . Furthermore , the combination of gestational diabetes mellitus with obesity/overweight status may increase the risk of adverse pregnancy outcome attributable to either factor alone . Regular exercise has the potential to reduce the risk of developing gestational diabetes mellitus and can be used during pregnancy ; however , its efficacy remain controversial . At present , most exercise training interventions are implemented on Caucasian women and in the second trimester , and there is a paucity of studies focusing on overweight/obese pregnant women . OBJECTIVE : We sought to test the efficacy of regular exercise in early pregnancy to prevent gestational diabetes mellitus in Chinese overweight/obese pregnant women . STUDY DESIGN : This was a prospect i ve r and omized clinical trial in which nonsmoking women age > 18 years with a singleton pregnancy who met the criteria for overweight/obese status ( body mass index 24≤28 kg/m2 ) and had an uncomplicated pregnancy at < 12 + 6 weeks of gestation were r and omly allocated to either exercise or a control group . Patients did not have contraindications to physical activity . Patients allocated to the exercise group were assigned to exercise 3 times per week ( at least 30 min/session with a rating of perceived exertion between 12‐14 ) via a cycling program begun within 3 days of r and omization until 37 weeks of gestation . Those in the control group continued their usual daily activities . Both groups received st and ard prenatal care , albeit without special dietary recommendations . The primary outcome was incidence of gestational diabetes mellitus . RESULTS : From December 2014 through July 2016 , 300 singleton women at 10 weeks ’ gestational age and with a mean prepregnancy body mass index of 26.78 ± 2.75 kg/m2 were recruited . They were r and omized into an exercise group ( n = 150 ) or a control group ( n = 150 ) . In all , 39 ( 26.0 % ) and 38 ( 25.3 % ) participants were obese in each group , respectively . Women r and omized to the exercise group had a significantly lower incidence of gestational diabetes mellitus ( 22.0 % vs 40.6 % ; P < .001 ) . These women also had significantly less gestational weight gain by 25 gestational weeks ( 4.08 ± 3.02 vs 5.92 ± 2.58 kg ; P < .001 ) and at the end of pregnancy ( 8.38 ± 3.65 vs 10.47 ± 3.33 kg ; P < .001 ) , and reduced insulin resistance levels ( 2.92 ± 1.27 vs 3.38 ± 2.00 ; P = .033 ) at 25 gestational weeks . Other secondary outcomes , including gestational weight gain between 25‐36 gestational weeks ( 4.55 ± 2.06 vs 4.59 ± 2.31 kg ; P = .9 ) , insulin resistance levels at 36 gestational weeks ( 3.56 ± 1.89 vs 4.07 ± 2.33 ; P = .1 ) , hypertensive disorders of pregnancy ( 17.0 % vs 19.3 % ; odds ratio , 0.854 ; 95 % confidence interval , 0.434–2.683 ; P = .6 ) , cesarean delivery ( except for scar uterus ) ( 29.5 % vs 32.5 % ; odds ratio , 0.869 ; 95 % confidence interval , 0.494–1.529 ; P = .6 ) , mean gestational age at birth ( 39.02 ± 1.29 vs 38.89 ± 1.37 weeks ’ gestation ; P = .5 ) ; preterm birth ( 2.7 % vs 4.4 % , odds ratio , 0.600 ; 95 % confidence interval , 0.140–2.573 ; P = .5 ) , macrosomia ( defined as birthweight > 4000 g ) ( 6.3 % vs 9.6 % ; odds ratio , 0.624 ; 95 % confidence interval , 0.233–1.673 ; P = .3 ) , and large‐for‐gestational‐age infants ( 14.3 % vs 22.8 % ; odds ratio , 0.564 ; 95 % confidence interval , 0.284–1.121 ; P = .1 ) were also lower in the exercise group compared to the control group , but without significant difference . However , infants born to women following the exercise intervention had a significantly lower birthweight compared with those born to women allocated to the control group ( 3345.27 ± 397.07 vs 3457.46 ± 446.00 g ; P = .049 ) . CONCLUSION : Cycling exercise initiated early in pregnancy and performed at least 30 minutes , 3 times per week , is associated with a significant reduction in the frequency of gestational diabetes mellitus in overweight/obese pregnant women . And this effect is very relevant to that exercise at the beginning of pregnancy decreases the gestational weight gain before the mid‐second trimester . Furthermore , there was no evidence that the exercise prescribed in this study increased the risk of preterm birth or reduced the mean gestational age at birth [8317440] The value of exercise during pregnancy is controversial ; both benefits and risks have been hypothesized . As empiric evidence is scant , the issue was investigated in a prospect i ve study that assessed the impact on fetal growth of maternal exercise in each trimester of pregnancy . A cohort of over 800 prenatal patients was recruited from obstetric practice s in Pennsylvania and New York between January 1987 and June 1989 . Subjects were interviewed at entry into care and recontacted at 28 and 36 weeks of gestation . In women with prior adverse outcomes or a lack of conditioning , the associations between maternal exercise and fetal growth were equivocal . In fit , low-risk , prenatal patients , exercise was positively associated with fetal growth . With low-moderate exercise levels , the adjusted mean birth weights were about 100 g higher than in nonexercisers ( 117 g ; 95 % confidence interval 17 to 217 g ) . With heavier exercise , larger birth weight increments were seen , close to 300 g in those who exercised throughout pregnancy at levels of about 2,000 kcal/week in energy expenditure ( 276 g ; 95 % confidence interval 54 to 497 g ) . These results suggest that the guidelines issued by the American College of Obstetricians and Gynecologists may be too stringent for well-conditioned , low-risk , prenatal patients . Additional research to define safe limits more precisely seems warranted [10078577] OBJECTIVE To investigate if water-gymnastics during pregnancy may reduce the intensity of back/low back pain and the number of days on sick-leave . METHODS A prospect i ve , r and omized study . One hundred and twenty-nine women were r and omized to participate in water-gymnastics once a week during the second half of pregnancy and 129 were r and omized to a control group . The women in both groups filled in question naires in gestational weeks 18 , 34 and within the first postpartum week . Every day from week 18 to labor they assessed the intensity of back/low back pain . RESULTS Back pain intensity increased during pregnancy . No excess risk for the pregnancy associated with water-gymnastics was observed . The women participating in water-gymnastics recorded a lower intensity of back/low back pain . The total number of days on sick-leave because of back/low back pain was 982 in the water-gymnastics group ( 124 women ) compared with 1484 in the control group ( 120 women ) . After weeks 32 33 , seven women in the water-gymnastics group compared with 17 in the control group were on sickleave because of back/ low back pain ( p=0.031 ) . CONCLUSIONS Intensity of back/low back pain increased with advancing pregnancy . There was no excess risk for urinary or vaginal infections associated with water-gymnastics . Water-gymnastics during the second half of pregnancy significantly reduced the intensity of back/ low back pain . Water-gymnastics decreased the number of women on sick-leave because of back/low back pain . Water-gymnastics during pregnancy can be recommended as a method to relieve back pain and may reduce the need for sick-leave [19636320] Objective : We examined the effect of light intensity resistance exercise training performed during the second and third trimester of pregnancy on the newborn 's birth size . We also studied the association between maternal body weight prior to pregnancy and newborn 's birth size . Design : R and omised controlled trial . Subjects : We r and omly assigned 160 sedentary gravidae to either a training ( n=80 ) or a control ( n=80 ) group . The training programme focused on light resistance and toning exercises ( three times per week , 35–40 min per session ) . We recorded the Apgar score , birth weight , birth length , and head circumference of the newborn , as well as gestational age at time of delivery from hospital perinatal records . We also measured maternal weight and height before parity and gestational weight gain . Results : Maternal characteristics neither differed between groups ( all P>0.1 ) nor newborn characteristics ( all P>0.1 ) . Maternal body weight was positively and significantly associated with newborn 's birth weight and length only in the control group ( β=19.20 and 0.065 , respectively , P<0.01 ) . Conclusion : Light intensity resistance training performed over the second and third trimester of pregnancy does not have a negative impact on the newborn 's body size or overall health . Exercise interventions might attenuate the adverse consequences of maternal body weight before pregnancy on the newborn 's birth size [3198740] Background Birth weight plays an important role in infant mortality and morbidity , childhood development , and adult health . To date there are contradictory results regarding the role of physical activity on birth weight . In addition , it is question ed whether exercise during second and third trimesters of pregnancy might affect gestational age and increase the risk of preterm delivery . Hence , the purpose of this study was to examine the effect of a supervised exercise-program on birth weight , gestational age at delivery and Apgar-score . Methods Sedentary , nulliparous pregnant women ( N = 105 ) , mean age 30.7 ± 4.0 years , pre-pregnancy BMI 23.8 ± 4.3 were r and omized to either an exercise group ( EG , n = 52 ) or a control group ( CG , n = 53 ) . The exercise program consisted of supervised aerobic dance and strength training for 60 minutes , twice per week for a minimum of 12 weeks , with an additional 30 minutes of self-imposed physical activity on the non-supervised week-days . Results There was no statistically significant difference between groups in mean birth weight , low birth weight ( < 2500 g ) or macrosomia ( ≥ 4000 g ) . Per protocol analyses showed higher Apgar score ( 1 min ) in the EG compared with the CG ( p = 0.02 ) . No difference was seen in length of gestation . Conclusion Aerobic-dance exercise was not associated with reduction in birth weight , preterm birth rate or neonatal well-being . Trial Registration Clinical Trials.gov : [5062054] Non-r and omised studies of the effects of interventions are critical to many areas of healthcare evaluation , but their results may be biased . It is therefore important to underst and and appraise their strengths and weaknesses . We developed ROBINS-I ( “ Risk Of Bias In Non-r and omised Studies - of Interventions ” ) , a new tool for evaluating risk of bias in estimates of the comparative effectiveness ( harm or benefit ) of interventions from studies that did not use r and omisation to allocate units ( individuals or clusters of individuals ) to comparison groups . The tool will be particularly useful to those undertaking systematic review s that include non-r and omised studies [4431606] Objective To determine the effectiveness of a physical activity intervention for smoking cessation during pregnancy . Design Parallel group , r and omised controlled , multicentre trial . Setting 13 hospitals in Engl and , April 2009 to January 2014 . Participants 789 pregnant smokers , aged 16 - 50 years and at 10 - 24 weeks ’ gestation , who smoked at least one cigarette daily and were prepared to quit smoking one week after enrollment were r and omised ( 1:1 ) ; 785 were included in the intention to treat analyses , with 392 assigned to the physical activity group . Interventions Interventions began one week before a target quit date . Participants were r and omised to six weekly sessions of behavioural support for smoking cessation ( control ) or to this support plus 14 sessions combining supervised treadmill exercise and physical activity consultations . Main outcome measures The primary outcome was continuous smoking abstinence from the target quit date until end of pregnancy , vali date d by exhaled carbon monoxide or salivary cotinine levels . To assess adherence , levels of moderate-vigorous intensity physical activity were self reported and in a 11.5 % ( n=90 ) r and om sub sample of participants , physical activity was objective ly measured by an accelerometer . Results No significant difference was found in rates of smoking abstinence at end of pregnancy between the physical activity and control groups ( 8 % v 6 % ; odds ratio 1.21 , 95 % confidence interval 0.70 to 2.10 ) . For the physical activity group compared with the control group , there was a 40 % ( 95 % confidence interval 13 % to 73 % ) , 34 % ( 6 % to 69 % ) , and 46 % ( 12 % to 91 % ) greater increase in self reported minutes carrying out physical activity per week from baseline to one week , four weeks , and six weeks post-quit day , respectively . According to the accelerometer data there was no significant difference in physical activity levels between the groups . Participants attended a median of four treatment sessions in the intervention group and three in the control group . Adverse events and birth outcomes were similar between the two groups , except for significantly more caesarean births in the control group than in the physical activity group ( 29 % v 21 % , P=0.023 ) . Conclusion Adding a physical activity intervention to behavioural smoking cessation support for pregnant women did not increase cessation rates at end of pregnancy . During pregnancy , physical activity is not recommended for smoking cessation but remains indicated for general health benefits . Trial registration Current Controlled Trials IS RCT N48600346 [5360254] Background Maternal obesity associates with complications during pregnancy and childbirth . Our aim was to investigate if exercise during pregnancy in overweight/obese women could influence birth weight or other neonatal and maternal outcomes at delivery . Material and methods This is a secondary analysis of a r and omised controlled trial of exercise training in pregnancy for women with body mass index ( BMI ) ≥ 28 kg/m2 . Ninety-one women ( 31.3 ± 4.3 years , BMI 34.5 ± 4.2 kg/m2 ) were allocated 1:1 to supervised exercise during pregnancy or to st and ard care . The exercise group was offered three weekly training sessions consisting of 35 minutes of moderate intensity walking/running followed by 25 minutes of strength training . Data from 74 women ( exercise 38 , control 36 ) were analysed at delivery . Results Birth weight was 3719 ± 695 g in the exercise group and 3912 ± 413 g in the control group ( CI -460.96 , 74.89 , p = 0.16 ) . Birth weight > 4000 g was 35 % in the exercise group and 52 % in the control group ( p = 0.16 ) . Mean gestational age at delivery was 39.1 weeks in the exercise group and 39.5 weeks in the control group ( CI -1.33 , 0.43 , p = 0.31 ) . No significant between-group differences were found in neonatal body size , skinfold thickness , placental weight ratio , or Apgar score . The prevalence of caesarean section was 24 % in the exercise group and 17 % in the control group ( CI 0.20 , 2.05 , p = 0.57 ) . Mean length of hospital stay was 4.8 days in the exercise group and 4.5 days in the control group ( CI -0.45 , 1.00 , p = 0.45 ) . Conclusions Offering supervised exercise during pregnancy for overweight and obese women did not influence birth weight or other neonatal and maternal outcomes at delivery . However our trial was limited by low sample size and poor adherence to the exercise protocol , and further research is needed . Trial registration Clinical Trials.gov [3753734] Objectives . To evaluate the association between physical exercise supervised in pregnant women with chronic hypertension and /or previous preeclampsia and maternal and neonatal outcomes . Method . R and omized controlled trial , which included 116 pregnant women with chronic hypertension and /or previous preeclampsia , considered risk of preeclampsia development . They were divided into two groups : study group that performed physical exercise with a stationary bicycle once a week , for 30 minutes ; the intensity was controlled ( heart rate 20 % above resting values ) , under professional supervision and a control group that was not engaged in any physical exercise . The data was retrieved from medical charts . Significance level assumed was 5 % . Results . Women from study group performed 9.24 ± 7.03 of physical exercise sessions . There were no differences between groups comparing type of delivery and maternal outcomes , including maternal morbidity and hospitalization in intensive unit care , and neonatal outcomes , including birth weight , adequacy of weight to gestational age , prematurity , Apgar scale at first and fifth minutes , hospitalization in intensive unit care , and neonatal morbidity . Conclusions . Physical exercise using a stationary bicycle in pregnant women with chronic hypertension and /or previous preeclampsia , once a week , under professional supervision , did not interfere in the delivery method and did not produce maternal and neonatal risks of the occurrence of morbidity . This trial is registered with Clinical Trials.gov NCT01395342 [3787488] Objectives The long-term consequences of maternal physical activity during pregnancy for offspring cardiovascular health are unknown . We examined the association of maternal self-reported physical activity in pregnancy ( 18 weeks gestation ) with offspring cardiovascular risk factors at age 15 . Design Prospect i ve cohort study . Setting The Avon Longitudinal Study of Parents and Children ( ALSPAC ) . Participants 4665 maternal-offspring pairs ( based on a sample with multiple imputation to deal with missing data ) from the ALSPAC , a prospect i ve cohort based in the South West of Engl and with mothers recruited in pregnancy in 1991–1992 . Primary and secondary outcome measures Offspring cardiovascular risk factors at age 15 ; body mass index ( BMI ) , waist circumference , systolic blood pressure , diastolic blood pressure , glucose , insulin , low-density lipoprotein cholesterol , high-density lipoprotein cholesterol and triglycerides . Results Greater maternal physical activity was associated with lower BMI , waist circumference , glucose and insulin in unadjusted analyses . The magnitude of associations was generally small with wide CIs , and most associations attenuated towards the null after adjusting for confounders . The strongest evidence of association after adjustment for confounders was for glucose , although the 95 % CI for this association includes the null ; a one SD greater physical activity during pregnancy was associated with a −0.013 mmol/L difference in offspring glucose levels ( equivalent to approximately one-third of a SD ; 95 % CI −0.027 to 0.001 mmol/L ) . Conclusions Our results suggest that maternal physical activity in pregnancy , measured at 18 weeks gestation , is unlikely to be an important determinant of later offspring cardiovascular health . There was some suggestion of association with offspring glucose , but given that all other associations ( including insulin ) were null after adjustment for confounders , this result should be interpreted with caution [19608151] OBJECTIVE We examined the effect of light-intensity resistance exercise training that is performed during the second and third trimester of pregnancy by previously sedentary and healthy women on the type of delivery and on the dilation , expulsion , and childbirth time . STUDY DESIGN We r and omly assigned 160 sedentary women to either a training ( n=80 ) or a control ( n=80 ) group . We recorded several maternal and newborn characteristics , the type of delivery ( normal , instrumental , or cesarean ) , and dilation , expulsion , and childbirth time . RESULTS The percentage of women who had normal , instrumental , or cesarean delivery was similar in the training ( 70.8 % , 13.9 % , and 15.3 % , respectively ) and control ( 71.4 % , 12.9 % , and 15.7 % , respectively ) groups . The mean dilation , expulsion , and childbirth time did not differ between groups . CONCLUSION Light-intensity resistance training that is performed over the second and third trimester of pregnancy does not affect the type of delivery [16055571] Objective : To evaluate the effects of aerobic training on submaximal cardiorespiratory capacity in overweight pregnant women . Methods : We conducted a r and omized clinical trial in a referral center prenatal clinic during the period 2000–2002 . Of 132 overweight ( body mass index 26–31 kg/m2 ) but otherwise healthy volunteers , at 20 years of age or older , with gestational age of 20 weeks or less , and without diabetes or hypertension , 92 consented to participate and were r and omized . Intervention consisted of 3 one-hour aerobic exercise sessions per week ; the control group received weekly relaxation and focus group discussion s. The main outcome measure was submaximal exercise capacity evaluated by oxygen uptake at the anaerobic ( first ventilatory ) threshold during cardiopulmonary treadmill testing 12 weeks after r and omization . Results : Oxygen uptake at the anaerobic threshold increased 18 % ( 15.9 ± 2.6 to 18.1 ± 3.1 mL · min−1 · kg−1 ) in the exercise group but decreased 16 % ( 16.9 ± 3.0 to 15.8 ± 2.6 mL · min−1 · kg−1 ) among the control group . Oxygen consumption at the anaerobic threshold , adjusted through analysis of covariance for baseline oxygen uptake , was 2.68 ( 95 % confidence interval 1.23 to 4.12 ) mL · min−1 · kg−1 greater in the exercise group . Women in the exercise group were approximately 5 times more likely than those in the control group to have regular or good cardiorespiratory capacity ( 12/38 versus 2/38 ; relative risk 5.2 , 95 % confidence interval 1.2 to 22.0 , number needed to treat 5 ) . Conclusion : Aerobic training in overweight pregnant women substantially increases submaximal exercise capacity , overcoming the otherwise negative effects of pregnancy in this regard . Additional studies are required to evaluate its effect on major clinical outcomes . LEVEL OF EVIDENCE : [5530125] Aim To evaluate the association between maternal physical activity and infant ’s birth weight or risk of inappropriate weight for gestational age ( GA ) , and whether this association differs by infant ’s sex , maternal body mass index ( BMI ) or pregnancy complications in a prospect i ve cohort study . Methods 1913 pregnant women from the 3D Birth Cohort ( Québec , Canada ) completed the Pregnancy Physical Activity Question naire at each trimester . Energy expenditure ( metabolic equivalent of task (MET)*hours/week ) for total activity , sports and exercise and vigorous intensity activities was calculated . The associations with birth weight and risk of inappropriate weight for GA were evaluated by regression modelling . Interactions were tested with infant ’s sex , maternal prepregnancy BMI , gestational diabetes , hypertensive disorders and prematurity . Results Each 1 MET/hours/week increase in sports and exercise in the first trimester was associated with a 2.5 g reduction in infant ’s birth weight ( 95 % CI −4.8 to −0.3 ) but was not associated with the risk of small weight for GA . In contrast , although not significant , a 17 % reduction in the risk of large weight for GA was observed with increasing sports and exercise . Furthermore , in women with subsequent pre-eclampsia ( but not normotensive or hypertensive women ) , each 1 MET/hours/week increment spent in any vigorous exercise in the first trimester reduced the infant ’s birth weight by 19.8 g ( 95 % CI −35.2 to −4.3 ) . Conclusions Pregnant women with higher sports and exercise levels in the first trimester delivered infants with a lower birth weight . The risk of reducing infant ’s birth weight with vigorous exercise in women who develop pre-eclampsia later in pregnancy requires evaluation [24290112] OBJECTIVE To study the effect on maternal weight gain of a supervised light- to moderate-intensity exercise-based intervention performed from the ninth week of pregnancy . PARTICIPANTS AND METHODS A total of 962 healthy pregnant women were r and omly assigned to a st and ard care or exercise intervention group conducted between September 1 , 2007 , and January 31 , 2011 . The intervention included light- to moderate-intensity aerobic and resistance exercises performed 3 days a week ( 50 - 55 minutes per session ) . Excessive gestational weight gain was calculated on the basis of the 2009 Institute of Medicine ( IOM ) recommendations . Gestational body weight gain was calculated on the basis of the weight measured at the first prenatal visit ( fifth to sixth weeks of gestation ) and weight measured at the last visit to the clinic before delivery . Women were categorized into normal weight or overweight or obese . RESULTS Women in the intervention group gained less weight ( adjusted mean difference , 1.039 kg ; 95 % CI , 0.534 - 1.545 kg ; P<.001 ) and were less likely to gain weight above the IOM recommendations ( odds ratio , 0.625 ; 95 % CI , 0.461 - 0.847 ) compared with those in the st and ard care group . The main treatment effects according to body mass index category were that normal weight women in the intervention group gained less weight ( adjusted mean difference , 1.393 kg ; 95 % CI , 0.813 - 1.972 kg ; P<.001 ) and were less likely to gain weight above the IOM recommendations ( odds ratio , 0.508 ; 95 % CI , 0.334 - 0.774 ) than normal weight women who received st and ard care . No significant treatment effect was observed in overweight or obese women . CONCLUSION Supervised exercise of light to moderate intensity can be used to prevent excessive gestational weight gain , especially in normal weight women . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01790347 [26575838] Background : Both large and small birth sizes are associated with an increased risk of developing cardiovascular and metabolic problems later in life . We studied whether such associations can be observed at prepubertal age . Methods : A cohort of 49 large ( LGA ) , 56 appropriate ( AGA ) , and 23 small for gestational age (SGA)-born children ( age range 5 - 8 years ) were studied . Being born SGA , AGA , or LGA was the exposure , and being overweight at prepubertal age was the main outcome . Blood pressure measurements , laboratory parameters , and whole-body dual-energy X-ray absorptiometry were secondary outcomes . Results : The LGA-born children were significantly taller than the AGA controls ( p = 0.03 ) , and the SGA children were lighter and shorter compared to the AGA ( p = 0.002 and 0.001 ) and LGA children ( p < 0.001 ) . The mean plasma glucose was higher in the LGA than in the SGA group ( p = 0.006 ) . Being born LGA ( OR 3.82 ) and the ponderal index Z-score at birth ( OR 4.24 ) were strong predictors for being overweight or obese in childhood . Conclusion : The children born LGA remained taller and heavier than those born AGA or SGA in mid-childhood , and they had a higher body mass index and body fat percentage than the SGA-born children . The differences in other cardiometabolic risk factors were minimal between the birth size groups [24787489] BACKGROUND Several recent " developmental origins " studies have reported increased long-term risks of adiposity , especially truncal adiposity , among children born small for gestational age ( SGA ) . OBJECTIVE We assessed the effects of SGA birth and weight gain in early infancy on adiposity at age 11.5 y. DESIGN From a cluster-r and omized breastfeeding promotion trial in 17,046 Belarusian children , we measured height , weight , waist and hip circumferences , triceps and subscapular skinfold thicknesses , and bioimpedance measures of percentage body fat at age 11.5 y. Children born SGA ( birth weight < 10th percentile ) and those born large for gestational age ( LGA ; > 90th percentile for gestational age ) were compared with those born appropriate for gestational age ( AGA ) . Weight gain from birth to 6 mo was categorized as high ( > 0.67-SD increase in weight-for-age ) , low ( > 0.67-SD decrease in weight-for-age ) , or normal . Multilevel statistical models accounted for clustered measurement and controlled for maternal and paternal height and body mass index ( BMI ) , maternal education , geographic region , urban compared with rural residence , and the child 's exact age at follow-up . RESULTS Children born SGA had a significantly lower BMI , percentage body fat , and fat mass index than did those born AGA , with a dose-response effect across 2 subcategories of SGA ( P < 0.001 for all comparisons ) . No difference was observed in waist-to-hip ratio , although the subscapular-to-triceps skinfold ratio was slightly but significantly ( P < 0.001 ) higher in children born SGA . Differences among the study groups continued to increase since the previous follow-up at 6.5 y. SGA infants with catch-up growth in the first 3 - 6 mo had growth and adiposity measures intermediate between those born SGA without catch-up and those born AGA . Opposite effects of similar magnitude were observed in children born LGA . CONCLUSION The 11.5-y-old Belarusian children born SGA were shorter , were thinner , and had less body fat than their non-SGA peers , irrespective of postnatal weight gain . The Promotion of Breastfeeding Intervention Trial was registered at www.is rct n.org as IS RCT N-37687716 [11120515] OBJECTIVE Our purpose was to test the null hypothesis that beginning regular , moderate-intensity exercise in early pregnancy has no effect on fetoplacental growth . STUDY DESIGN Forty-six women who did not exercise regularly were r and omly assigned at 8 weeks either to no exercise ( n = 24 ) or to weight-bearing exercise ( n = 22 ) 3 to 5 times a week for the remainder of pregnancy . Outcome variables included antenatal placental growth rate and neonatal and placental morphometric measurements . RESULTS The offspring of the exercising women were significantly heavier ( corrected birth weight : 3.75 + /- 0.08 kg vs 3.49 + /- 0.07 kg ) and longer ( 51.8 + /- 0.3 cm vs 50.6 + /- 0.3 cm ) than those born to control women . The difference in birth weight was the result of an increase in both lean body mass and fat mass . In addition , midtrimester placental growth rate was faster ( 26 + /- 2 cm(3)/wk vs 21 + /- 1 cm(3)/wk ) and morphometric indexes of placental function were greater in the exercise group . There were no significant differences in neonatal percentage body fat , head circumference , ponderal index , or maternal weight gain . CONCLUSIONS These data indicate that beginning a moderate regimen of weight-bearing exercise in early pregnancy enhances fetoplacental growth [22825089] OBJECTIVE : To estimate the effect of supervised physical exercise on maternal physical fitness , fetoplacental blood flow , and fetal growth . METHODS : This was a r and omized controlled trial comparing three groups of pregnant women . Groups were as follows : exercise initiated at 13 weeks ( group A ) ; exercise initiated at 20 weeks ( group B ) ; and a control group ( no supervised exercise ; group C ) . The women in groups A and B walked at moderate intensity three times weekly . Physical fitness level was evaluated at weeks 13 , 20 , and 28 . Fetal growth and uteroplacental blood flow were evaluated monthly . Birth weight was registered . Analysis of variance for repeat measures was used for outcomes evaluated throughout pregnancy . Risk ratio was used as a measure of the relative risk of preeclampsia , fetal growth restriction , macrosomia , small-for-gestational-age newborns , and large-for-gestational-age newborns . RESULTS : All the women analyzed completed more than 85 % of the program . According to the evaluation conducted at week 28 , physical fitness improved , with mean maximal oxygen consumptions ( VO2max ) of 27.3±4.3 ( group A ) , 28±3.3 ( group B ) , and 25.5±3.8 ( group C ; P=.03 ) . Mean birth weights were 3,279±453 g ( group A ) , 3,285±477 g ( group B ) , and 3,378±593 g ( group C ; P=.53 ) , with no difference in the frequency of large for gestational age or small for gestational age . No association was found between the practice of physical activity and the variables investigated ( preeclampsia , fetal weight , blood pressure , and pulsatility index of the uterine , umbilical , and middle cerebral arteries ) . CONCLUSION : Moderate-intensity walking improved the physical fitness level of healthy , pregnant , previously sedentary women without affecting fetoplacental blood flow or fetal growth . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00641550 . LEVEL OF EVIDENCE : [20864072] OBJECTIVE The objective of the study was to evaluate the effect of a resistance exercise program with an elastic b and on insulin requirement and glycemic control in patients with gestational diabetes mellitus ( GDM ) . STUDY DESIGN Sixty-four patients with gestational diabetes mellitus were r and omly assigned into 2 groups : an exercise group ( EG ; n = 32 ) and a control group not su bmi tted to the exercise program ( CG ; n = 32 ) . RESULTS A significant reduction in the number of patients who required insulin was observed in the EG ( 7/32 ) compared with the CG group ( 18/32 ) ( P = .005 ) . The percentage of time spent within the proposed target glucose range ( of at least 80 % of weekly measurements below the limits preestablished for the disease ) was significantly higher in EG compared with the CG group ( EG = 0.63 ± 0.30 ; CG = 0.41 ± 0.31 ; P = .006 ) . CONCLUSION The resistance exercise program was effective in reducing the number of patients with GDM who required insulin and in improving capillary glycemic control in this population [15733880] OBJECTIVE To investigate the effect of exercise during pregnancy on the intensity of low back pain and kinematics of spine . METHOD A prospect i ve r and omized study was design ed . 107 women participated in an exercise program three times a week during second half of pregnancy for 12 weeks and 105 as control group . All filled a question naire between 17 - 22 weeks of gestation and 12 weeks later for assessment of their back pain intensity . Lordosis and flexibility of spine were measured by Flexible ruler and Side bending test , respectively , at the same times . Weight gain during pregnancy , Pregnancy length and neonatal weight were recorded . RESULT Low back pain intensity was increased in the control group . The exercise group showed significant reduction in the intensity of low back pain after exercise ( p<0.0001 ) . Flexibility of spine decreased more in the exercise group ( p<0.0001 ) . Weight gain during pregnancy , pregnancy length and neonatal weight were not different between the two groups . CONCLUSION Exercise during second half of the pregnancy significantly reduced the intensity of low back pain , had no detectable effect on lordosis and had significant effect on flexibility of spine [22715981] Objective : In this study , the authors assessed the effects of a structured , moderate-intensity exercise program during the entire length of pregnancy on a woman ’s method of delivery . Methods : A r and omized controlled trial was conducted with 290 healthy pregnant Caucasian ( Spanish ) women with a singleton gestation who were r and omly assigned to either an exercise ( n = 138 ) or a control ( n = 152 ) group . Pregnancy outcomes , including the type of delivery , were measured at the end of the pregnancy . Results : The percentage of cesarean and instrumental deliveries in the exercise group were lower than in the control group ( 15.9 % , n = 22 ; 11.6 % , n = 16 vs. 23 % , n = 35 ; 19.1 % , n = 29 , respectively ; p = 0.03 ) . The overall health status of the newborn as well as other pregnancy outcomes was unaffected . Conclusions : Based on these results , a supervised program of moderate-intensity exercise performed throughout pregnancy was associated with a reduction in the rate of cesarean , instrumental deliveries and can be recommended for healthy women in pregnancy [29055674] PROBLEM Gestational diabetes mellitus , defined as any carbohydrate intolerance first diagnosed during pregnancy , is associated with a variety of adverse outcomes , both for the mother and her child . AIM To investigate the impact of a structured exercise programme which consisted of aerobic and resistance exercises on the parameters of glycaemic control and other health-related outcomes in pregnant women diagnosed with gestational diabetes mellitus . METHODS Thirty-eight pregnant women diagnosed with gestational diabetes mellitus were r and omised to two groups . Experimental group was treated with st and ard antenatal care for gestational diabetes mellitus , and regular supervised exercise programme plus daily brisk walks of at least 30min . Control group received only st and ard antenatal care for gestational diabetes mellitus . The exercise programme was started from the time of diagnosis of diabetes until birth . It was performed two times per week and sessions lasted 50 - 55min . FINDINGS The experimental group had lower postpr and ial glucose levels at the end of pregnancy ( P<0.001 ) . There was no significant difference between groups in the level of fasting glucose at the end of pregnancy . Also , there were no significant differences in the rate of complications during pregnancy and birth , need for pharmacological therapy , maternal body mass and body fat percentage gains during pregnancy , and neonatal Apgar scores , body mass and ponderal index . Neonatal body mass index was higher in the experimental group ( P=0.035 ) . CONCLUSION The structured exercise programme had a beneficial effect on postpr and ial glucose levels at the end of pregnancy [21895947] Please cite this paper as : Nascimento S , Surita F , Parpinelli M , Siani S , Pinto e Silva J. The effect of an antenatal physical exercise programme on maternal/perinatal outcomes and quality of life in overweight and obese pregnant women : a r and omised clinical trial . BJOG 2011;118:1455–1463 [7674866] To investigate the effects of participation in aerobic exercise on pregnancy outcome , 388 women ( mean age = 31.7 , range = 18 - 42 ) were followed from a mean 16.5-wk gestation through delivery . Frequency , duration , and mode of aerobic exercise prior to conception and during the first trimester were determined by in-person interviews . Activity patterns during the second and third trimesters were assessed by telephone interviews . For each time period , women were categorized into one of the following exercise groups : Level I = aerobic exercise , excluding vigorous walking , at least three times a week for at least 20 min a time ; Level II = aerobic exercise at least three times a week and 20 min at a time , if and only if vigorous walking is included ; Level III = aerobic exercise less than three times a week , 20 min a time ; and Level IV = aerobic exercise less than once a week . Mean birthweight was statistically unrelated to level of exercise preconceptionally or in any trimester . Gestational age , weight gain , and other pregnancy outcomes were also unassociated with exercise level . However , pregnancy symptoms were inversely associated with level of exercise ; women who exercised more earlier in pregnancy reported fewer discomforts later in pregnancy ( P = 0.01 ) . These data suggest that participation in aerobic exercise during pregnancy at a level great enough to produce or maintain a training effect does not adversely affect birthweight or other maternal and infant outcomes but may be associated temporally with fewer perceived pregnancy-associated discomforts [24652353] OBJECTIVE There is controversy concerning whether exercise during pregnancy may increase preterm delivery risk and type of delivery . The effect of pregnant Latin-American women engaging in vigorous exercise during the second and third trimester was examined regarding type of delivery and gestational age . MATERIAL S AND METHODS This was a secondary analysis of data from a controlled r and omized trial for determining the influence of physical exercise on pregnant women 's endothelial function . The study included 35 nulliparous women , gestational week 16 - 20 attending prenatal care at three tertiary hospitals in Colombia , who were r and omly assigned to one of two groups . The experimental group engaged in aerobic exercise involving 55 % - 75 % maximum heart rate for 60 min , three times a week for 12 weeks . The control group engaged in their usual physical activity . Maternal weight , height , weight gain , blood pressure and type of delivery were recorded ; gender , abdominal and head circumference ( cm ) , weight ( g ) , height ( cm ) , vitality ( Apgar score at 1 and 5 min ) and gestational age at the time of delivery ( in weeks , days ) were recorded for the newborn . RESULTS There was no difference in type of delivery by the end of the 12-week program ( p > 0.05 ) , nor regarding newborn anthropometric variables , Apgar score , or maternal variables concerning weight , height , relative weight gain , blood pressure or weeks of gestation ( p>0.05 ) . CONCLUSION The potential public health benefits of vigorous exercise were enormous . This study supported existing guidelines indicating that Latin-American women may begin or maintain an on-going exercise program during pregnancy . TRIAL REGISTRATION NCT00741312 [5629829] Background : In this study , we aim ed to determine comprehensive maternal characteristics associated with birth weight using Bayesian modeling . Material s and Methods : A total of 526 participants were included in this prospect i ve study . Nutritional status , supplement consumption during the pregnancy , demographic and socioeconomic characteristics , anthropometric measures , physical activity , and pregnancy outcomes were considered as effective variables on the birth weight . Bayesian approach of complex statistical models using Markov chain Monte Carlo approach was used for modeling the data considering the real distribution of the response variable . Results : There was strong positive correlation between infant birth weight and the maternal intake of Vitamin C , folic acid , Vitamin B3 , Vitamin A , selenium , calcium , iron , phosphorus , potassium , magnesium as micronutrients , and fiber and protein as macronutrients based on the 95 % high posterior density regions for parameters in the Bayesian model . None of the maternal characteristics had statistical association with birth weight . Conclusion : Higher maternal macro- and micro-nutrient intake during pregnancy was associated with a lower risk of delivering low birth weight infants . These findings support recommendations to exp and intake of nutrients during pregnancy to high level [2890340] OBJECTIVE To examine the feasibility of an individualized exercise program to prevent gestational diabetes mellitus ( GDM ) in obese pregnant women . RESEARCH DESIGN AND METHODS The study was a pilot r and omized controlled trial with obese pregnant women ( intervention group , individualized exercise program [ n = 25 ] ; control group , usual care [ n = 25 ] ) . Average weekly energy expenditure ( MET hours per week and kilocalories per week ) of exercise-specific activity was assessed during pregnancy using the Pregnancy Physical Activity Question naire . Fasting glucose and insulin and homeostasis model assessment of insulin resistance ( HOMA-IR ) were assessed at baseline and 20 , 28 , and 36 weeks ' gestation . RESULTS Of the women in the intervention group , 16 of 22 ( 73 % ) achieved more than 900 kcal/week of exercise-based activity at 28 weeks compared with 8 of 19 women in the control group ( 42 % ) , P = 0.047 . However , insulin resistance ( HOMA-IR ) did not differ between the groups . CONCLUSION This intervention was feasible and prompted a modest increase in physical activity . However , we are not confident that this intervention would be sufficient to prevent GDM [937989] One hundred and three primigravidae were studied to establish the correlation between physical fitness and heart volume . Twenty-three of the mothers were allocated at r and om to the exercise group and 21 to control group 1 , between the 10th and 14th weeks of pregnancy . In addition , 59 mothers were allocated to control group 2 , which was formed two weeks before term . The exercise group underwent a rather strenuous training programme during pregnancy . Physical fitness was measured by work tests on a bicycle ergometer two weeks before term . The heart volume was determined radiologically on the 6th day post partum . There was a positive correlation between physical fitness and the relative heart volume , which was greatest when physical fitness was measured by a method which takes the level of training into consideration . The relative heart volume of the exercise group was almost significantly greater than that of control group 1 . The physical performance of the exercise group was very significantly greater than in the control groups . There was no significant correlation between either physical fitness or relative heart volume and the duration of pregnancy or the weight of newborn [4428637] Methods We are conducting a parallel arm r and omized controlled clinical trial in Auckl and , New Zeal and ( NZ ) . Eligible participants were enrolled to the study from March 2013 to April 2014 . The intervention group participated in a 16-week home-based moderate-intensity exercise programme utilising stationary cycles and heart rate monitors . Maternal measures including weight , aerobic fitness , physical activity and diet were assessed at baseline and end of intervention . Neonatal and maternal body composition were assessed 14 days after delivery [25333246] PURPOSE The objective of this study is to assess the effectiveness of a maternal exercise program ( l and /aquatic activities , both aerobic and muscular conditioning ) in preventing gestational diabetes mellitus ( GDM ) . METHODS Three hundred and forty-two pregnant women from Spain ( age , 33.24 ± 4.3 yr ) without obstetric contraindications were recruited for a clinical r and omized controlled trial . The intervention group ( IG , n = 101 ) exercised for 60 and 50 min on l and and in water , respectively , three times per week . The control group ( n = 156 ) received usual st and ard care . RESULTS The prevalence of GDM was reduced in the IG group ( IG , 1 % , n = 1 , vs control group , 8.8 % , n = 13 ( χ1 = 6.84 , P = 0.009 ) ) with a significant risk estimate ( odds ratio = 0.103 ; 95 % confidence interval , 0.013 - 0.803 ) . CONCLUSION The exercise program performed during pregnancy reduced the prevalence of GDM by preserving glucose tolerance [24200335] Purpose . The aim of the present study was to examine the influence of a program of moderate physical exercise throughout pregnancy on maternal and fetal parameters . Design . The study design was a r and omized controlled trial . Setting . The study took place at the Hospital of Fuenlabrada in Madrid , Spain . Sample . Analyzed were 200 pregnant women ( 31.54 ± 3.86 years ) , all of whom had uncomplicated and singleton gestation . Of these subjects , 107 were allocated to the exercise group ( EG ) and 93 to the control group ( CG ) . Intervention . Women from EG participated in a physical conditioning program throughout pregnancy , which included a total of 55- to 60-minute weekly sessions , 3 days per week . Measures . Pregnancy outcomes . Maternal : gestational age , weight gain , type of delivery , blood pressure during pregnancy , gestational diabetes ( n/% ) . Fetal : birth weight , birth size , head circumference , Apgar score , pH of umbilical cord . Analysis . Student 's unpaired t-test and χ2 test were used ; p values of ≤ .05 indicated statistical significance . Cohen 's d was used to determine the effect size . Results . There were significantly more pregnant women in the CG who gained excessive weight during their pregnancies than in the EG group ( CG : N = 31 , 35.6 % versus N = 22 , 21.2 % ; χ2 = 4.95 ; p = .02 ) . The effect size was small ( Phi value = .16 ) . Other pregnancy outcome showed no differences between groups . Conclusion . A regular and moderate physical exercise program throughout pregnancy is not a risk to maternal and fetal well-being , and it helps to control excessive weight gain [22616913] Please cite this paper as : Oostdam N , van Poppel M , Wouters M , Eekhoff E , Bekedam D , Kuchenbecker W , Quartero H , Heres M , van Mechelen W. No effect of the FitFor2 exercise programme on blood glucose , insulin sensitivity , and birthweight in pregnant women who were overweight and at risk for gestational diabetes : results of a r and omised controlled trial . BJOG 2012;119:1098–1107 [9704242] We sought to test the hypothesis that long-term postnatal development may be modified by metabolic experiences in utero . We enrolled offspring of women with pregestational diabetes ( this included type 1 and type 2 diabetes ) and gestational diabetes in a prospect i ve study from 1977 to 1983 . Fetal beta-cell function was assessed by measurement of amniotic fluid insulin ( AFI ) concentration at 32 - 38 weeks ' gestation . Postnatally , offspring were seen yearly for neuropsychological testing , measurement of anthropometrics , and modified glucose tolerance testing . Neuropsychological control subjects were followed longitudinally . Additional control subjects had anthropometrics measured once , and a r and om subset of these had a single oral glucose challenge at 10 - 16 years . The rates of major neuropsychological disturbances in our cohort did not differ significantly from national estimates . However , aberrant maternal metabolism was associated with poorer intellectual performance and psychomotor development . The macrosomia observed at birth in offspring of diabetic mothers ( ODM ) resolves by 1 year of age . Obesity recurs in childhood ; and by 14 - 17 years , the mean BMI is 24.6 + /- 5.8 kg/m2 in ODM versus 20.9 + /- 3.4 kg/m2 in control subjects . Obesity in adolescence is associated with sex , mother 's weight , and AFI concentration . Impaired glucose tolerance ( IGT ) is found in 36 % of ODM and is also associated with elevated amniotic fluid insulin in utero . In confirmation of our original hypothesis , aberrant maternal metabolism is associated with poorer intellectual and psychomotor development , obesity , and IGT in offspring . Excessive insulin secretion in utero , as assessed by AFI concentration , is a predictor of both obesity and IGT in adolescence . This study is a long-term prospect i ve evaluation of the effects of maternal diabetes on pregnant women and their offspring . In this article , we report the results of the correlations between indexes of maternal and fetal metabolism during pregnancy and the offspring 's subsequent physical , metabolic , and psychological development from birth through adolescence [16008324] To study the efficacy of yoga on the outcome of complicated pregnancy , 121 women attending antenatal clinic at Gunasheela Surgical and Maternity Hospital ( GSMH ) in Bangalore , India , were enrolled between 18 - 20 weeks of pregnancy in a prospect i ve , matched , observational study . Sixty-eight women were in the yoga group and 53 women in the control group . Women were matched for age , gravida and Doppler velocimetry scores of umbilical and uterine arteries . Yoga practice s including physical postures , breathing and meditation were practised by the yoga group , one hour daily , from the date of entry into the study until delivery . The control group walked half an hour twice a day during the study period . Compliance in both the groups was ensured . In babies the birth-weight is significantly higher ( P < 0.018 ) in the Yoga group ( 2.78 + /- 0.52 kg ) , compared to the control group ( 2.55 + /- 0.52 kg ) . Occurrence of complications of pregnancy ( pregnancy-induced hypertension , intrauterine growth retardation , pre-term delivery ) shows lower trends in yoga group [22843114] OBJECTIVE A prospect i ve r and omized controlled trial was design ed to assess the benefits and possible risks of aerobic exercise during pregnancy , using a fitness regimen based on the 2002 American College of Obstetricians and Gynecologists guidelines for exercise during pregnancy . METHODS Inactive women were r and omized at 12 - 14 wk gestation to a group that remained sedentary or to a group that performed moderate aerobic exercise 45 - 60 min , 4 d·wk , through 36 wk gestation . Thirty-one subjects in each group completed the study . RESULTS Compared with women who remained sedentary , active women improved aerobic fitness ( P < 0.05 ) and muscular strength ( P < 0.01 ) , delivered comparable size infants with significantly fewer cesarean deliveries ( P < 0.01 ) , and recovered faster postpartum ( P < 0.05 ) , at least related to the lower incidence of cesarean section . Active women developed no gestational hypertension ( P = 0.16 compared with controls ) and reported no injuries related to the exercise regimen . In the active group , there was one premature birth at 33 wk by a woman with a history of premature delivery of twins at 34 wk . There were no differences between groups in the incidence of gestational diabetes , musculoskeletal pains during pregnancy , flexibility on sit- and -reach test , mean length of pregnancy , neonatal Apgar scores , placenta weights , overall length of labor , weight gain during pregnancy , or weight retention postpartum . CONCLUSION Previously sedentary women who began exercising at 12 - 14 wk improved fitness and delivery outcomes [20335449] CONTEXT Epidemiological studies have identified the importance of the in utero environment in providing a healthy start to life . Previous studies have suggested that the maternal environment , in particular a reduction in maternal insulin sensitivity , contributes significantly to fetal growth . Regular aerobic exercise , through an effect on maternal insulin sensitivity , may influence offspring size by regulating nutrient supply to the fetus . OBJECTIVE The aim of the study was to determine the effects of aerobic exercise training in the second half of pregnancy on maternal insulin sensitivity and neonatal outcomes . DESIGN AND SETTING We conducted a community-based , r and omized , controlled trial of exercise in pregnancy . PARTICIPANTS Eighty-four healthy nulliparous women ( mean + /- sd , age , 30 + /- 4 yr ; body mass index , 25.5 + /- 4 kg/m(2 ) ) participated in the study . INTERVENTION Subjects participated in a home-based stationary cycling program from 20 wk gestation to delivery . MAIN OUTCOME MEASURES Maternal insulin sensitivity , neonatal auxology , body composition , and growth-related peptides in cord blood were measured . RESULTS Offspring of exercisers had lower birth weight ( sd score , control , 0.23 + /- 0.8 ; exercise , -0.19 + /- 0.9 ; P = 0.03 ) and body mass index at birth ( sd score , control , 0.40 + /- 0.9 ; exercise , -0.01 + /- 0.09 ; P = 0.04 ) . The reduction in maternal insulin sensitivity in late gestation was not affected by exercise ( P = 0.45 ) and was unrelated to offspring size . Exercise offspring had lower cord serum IGF-I ( P = 0.03 ) and IGF-II ( P = 0.04 ) . CONCLUSIONS Regular exercise was associated with lower birth weights and reduced cord concentrations of growth-related peptides , suggesting an influence of exercise on endocrine regulation of fetal growth . These effects on offspring growth were not associated with an exercise training effect on maternal insulin sensitivity [23676311] BACKGROUND In spite of an extensive knowledge of the physiologic features of exercise during pregnancy , we still lack a comprehensive underst and ing of the effects of different types , intensities and duration of exercise throughout pregnancy on maternal and fetal well being . The aim of the current study was to examine the influence of an aerobic exercise program throughout pregnancy on gestational age at the moment of delivery . METHODS This study was a r and omized controlled trial . Three hundred and twenty Caucasian ( Spanish ) healthy pregnant women with singleton gestation were r and omly assigned to either an exercise ( n = 160 ) or a control ( n = 160 ) group . Gestational age ( weeks ) and other outcomes were measured . The exercise program included 85 sessions ( general fitness class , 3 times/week , 55 - 60 min/session from weeks 8 - 10 to weeks 38 - 39 of pregnancy ) . RESULTS Two hundred and ninety women were analyzed ( exercise group EG , n = 138 , control group CG , n = 152 ) . The mean gestational age did not differ between groups ( EG= 39.7 ± 1.3 vs CG= 39.6 ± 1.1 weeks , P = .81 ) . Relative to preterm deliveries in EG we found 6 ( 4.3 % ) and 11 ( 7.2 % ) in CG , ( P = .73 ) . CONCLUSIONS A supervised program of moderate exercise performed throughout pregnancy is not a risk of preterm delivery for healthy pregnant women [26105368] INTRODUCTION Physical activity ( PA ) has been proposed as an important part of hypertension 's treatment and has been studied as a possibility for the prevention of preeclampsia ( PE ) and its complications . PA is recommended during pregnancy because it may be beneficial to maternal health . However , some studies relate the difficulty in adherence to exercise during pregnancy . OBJECTIVES The objective of this study was to evaluate the adherence to exercise with bicycle in pregnant women with risk of preeclampsia development and characterize these pregnants . METHODS This is a secondary analysis of a r and omized clinical trial at the Women 's Hospital Dr. José Aristodemo Pinotti - CAISM/Unicamp , Brazil . We enrolled 116 pregnant women presenting with chronic hypertension ( CH ) , previous PE or both factors associated ( risk of PE development ) . Women from 12 to 20 gestational weeks were selected from the prenatal outpatient clinic and r and omly allocated to the study ( SG ) or non-interventional group ( NIG ) . Women at the SG performed exercise using stationary bicycle ( horizontal bench model ) during 30min , once a week , under a physical therapist supervision . The HR was maintained at 20 % above resting heart rate and up to 140 beats per minute , and the BP was evaluated before and after exercise . The NIG followed regular prenatal routine with weekly returns for HR and BP measurements . We analyzed the adherence of the SG to exercise with bicycle and their sociodemographic and clinical characteristics . RESULTS We invited 152 pregnants to participate and 33 ( 21.7 % ) refused . 116 pregnants were r and omized and 58 were allocated to the SG . The mean age was 31.7±6.2 and mean of Body Mass Index ( BMI ) was 34.9±7.9kg/m(2 ) . Previous PE were prevalent in 16 ( 27.6 % ) pregnant , CH in 51 ( 87.9 % ) pregnant and 9 ( 15.5(10.5 % ) pregnants relate to exercise before pregnancy . The average sessions performed by the SG using stationary bicycle were 9.24±7.03 . That those who realized less than the mean session of the SG 14 had discontinued , 3 changed the prenatal city , 4 had TPP , 3 had difficulty in controlling blood pressure , 1 had autoimmune hepatitis diagnosis and 1 had fetal malformation . Considering the sociodemographic and clinical characteristics of these 27 the majority were obese and had had CH , they were not used to practice any type of exercise before pregnancy . Most of them were not primiparous , also had more children at home and found difficul to find time for exercise . The majority did not live next to our center . CONCLUSION The majority of our population were obese , sedentary before pregnancy and with CH . In this study exercise , performed once a week , using stationary bicycle in pregnant women of high risk PE , seems to be difficult [20110815] Background : Exercise in pregnancy is recommended in many countries , and swimming is considered by many to be an ideal activity for pregnant women . Disinfection by-products in swimming pool water may , however , be associated with adverse effects on various reproductive outcomes . We examined the association between swimming in pregnancy and preterm and postterm birth , fetal growth measures , small-for-gestational-age , and congenital malformations . Methods : We used self-reported exercise data ( swimming , bicycling , or no exercise ) that were prospect ively collected twice during pregnancy for 74,486 singleton pregnancies . Recruitment to The Danish National Birth Cohort took place 1996–2002 . Using Cox , linear and logistic regression analyses , depending on the outcome , we compared swimmers with physically inactive pregnant women ; to separate a possible swimming effect from an effect of exercise , bicyclists were included as an additional comparison group . Results : Risk estimates were similar for swimmers and bicyclists , including those who swam throughout pregnancy and those who swam more than 1.5 hours per week . Compared with nonexercisers , women who swam in early/mid-pregnancy had a slightly reduced risk of giving birth preterm ( hazard ratio = 0.80 [ 95 % confidence interval = 0.72–0.88 ] ) or giving birth to a child with congenital malformations ( odds ratio = 0.89 [ 0.80–0.98 ] ) . Conclusions : These data do not indicate that swimming in pool water is associated with adverse reproductive outcomes [25615706] Purpose . The aim of the present study was to examine the influence of moderate physical exercise throughout pregnancy on the duration of labor stages . Design . Study was a r and omized controlled trial . Setting . The study took place at Hospital Puerta de Hierro and Hospital Severo Ochoa in Madrid , Spain . Subjects . We examined 166 pregnant women ( 31.6 ± 3.8 years ) , and all had uncomplicated and singleton gestation . Of these 83 were allocated to the exercise group ( EG ) and 83 to the control group ( CG ) . Intervention . Women from the EG participated in a physical conditioning program throughout pregnancy , which included 55- to 60-minute sessions , 3 days per week . Measures . Pregnancy outcomes were measured : duration of labor stages , gestational age , weight gain , type of delivery , birth weight , birth size , head circumference , Apgar score , pH of umbilical cord . Analysis . Student 's unpaired t-tests and χ2 tests were used ; p values of < .05 indicated statistical significance . Cohen 's d was used to determine the effect size . Results . Significant differences were found in the duration of the first stage of labor ( EG = 389.6 ± 347.64 minutes vs. CG = 515.72 ± 353.36 minutes ; p = .02 , effect size Cohen 's d = .36 ) . The second and third stages did not differ between the study groups . Conclusion . A physical exercise program during pregnancy is associated with a shorter first stage of labor . These results may have important relevance to public health

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### Context: [27607876] OBJECTIVE : To investigate the effect of a supervised home-based exercise program on the recurrence and severity of gestational diabetes mellitus ( GDM ) together with other aspects of maternal health and obstetric and neonatal outcomes . METHODS : This r and omized controlled trial allocated women with a history of GDM to an exercise intervention ( 14-week supervised home-based stationary cycling program ) or to a control group ( st and ard care ) at 13±1 weeks of gestation . The primary outcome was a diagnosis of GDM . Secondary outcomes included maternal fitness , psychological well-being , and obstetric and neonatal outcomes . A sample size of 180 ( 90 in each group ) was required to attain 80 % power to detect a 40 % reduction in the incidence of GDM . RESULTS : Between June 2011 and July 2014 , 205 women provided written consent and completed baseline assessment s. Of these , 33 ( 16 % ) were subsequently excluded as a result of an elevated baseline oral glucose tolerance test ( OGTT ) , leaving 172 r and omized to exercise ( n=85 ) or control ( n=87 ) . Three women miscarried before the assessment of outcome measures ( control=2 ; exercise=1 ) . All remaining women completed the postintervention OGTT . The recurrence rate of GDM was similar between groups ( control 40 % [ n=34 ] ; exercise 40.5 % [ n=34 ] ; P=.95 ) and the severity of GDM at diagnosis was unaffected by the exercise program with similar glucose and insulin responses to the OGTT ( glucose 2 hours post-OGTT 7.7±1.5 compared with 7.6±1.6 mmol/L ; P>.05 ) . Maternal fitness was improved by the exercise program ( P<.01 ) and psychological distress was reduced ( P=.02 ) . There were no differences in obstetric and neonatal outcomes between groups ( P>.05 ) . CONCLUSION : Supervised home-based exercise started at 14 weeks of gestation did not prevent the recurrence of GDM ; however , it was associated with important benefits for maternal fitness and psychological well-being . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , https:// clinical trials.gov , NCT01283854 [2628875] Background To evaluate the effectiveness and safety of water aerobics during pregnancy . Methods A r and omized controlled trial carried out in 71 low-risk sedentary pregnant women , r and omly allocated to water aerobics or no physical exercise . Maternal body composition and perinatal outcomes were evaluated . For statistical analysis Chi-square , Fisher 's or Student 's t-tests were applied . Risk ratios and their 95 % CI were estimated for main outcomes . Body composition was evaluated across time using MANOVA or Friedman multiple analysis . Results There were no significant differences between the groups regarding maternal weight gain , BMI or percentage of body fat during pregnancy . Incidence of preterm births ( RR = 0.84 ; 95%CI:0.28–2.53 ) , vaginal births ( RR = 1.24 ; 95%CI:0.73–2.09 ) , low birthweight ( RR = 1.30 ; 95%CI:0.61–2.79 ) and adequate weight for gestational age ( RR = 1.50 ; 95%CI:0.65–3.48 ) were also not significantly different between groups . There were no significant differences in systolic and diastolic blood pressure and heart rate between before and immediately after the water aerobics session . Conclusion Water aerobics for sedentary pregnant women proved to be safe and was not associated with any alteration in maternal body composition , type of delivery , preterm birth rate , neonatal well-being or weight [24002348] INTRODUCTION Walking may be a strategy for increasing moderate-intensity physical activity ( MPA ) during pregnancy . PURPOSE This study aim ed to promote MPA among overweight and obese pregnant women , via walking , and to evaluate the effect of the intervention on maternal and birth outcomes . METHODS Thirty-seven overweight or obese pregnant women were r and omly assigned to a walking intervention or control group . Anthropometric and objective PA ( StepWatch ™ Activity Monitor ) data were collected for four 1-wk periods : weeks 10 - 14 ( V1 ) , weeks 17 - 19 ( V2 ) , weeks 27 - 29 ( V3 ) , and weeks 34 - 36 ( V4 ) of gestation . Participants provided information about maternal and birth outcomes . A cadence of ≥ 80 steps per minute was defined as MPA , and " meaningful walking " was defined as moderate walking in ≥ 8-min bouts . ANOVA was used to determine the differences in walking amount and meaningful walks , the Kolmogorov-Smirnov test was used for walking intensity distribution analysis , and Fisher 's exact test was used for maternal and infant outcomes analyses . Pearson correlation was used to examine the association between prepregnancy body mass index and gestational weight gain ( GWG ) . RESULTS There was significantly more MPA among women in the intervention group compared with those in the control group at V2 ( overweight , P < 0.0001 ; obese , P < 0.025 ) , V3 ( overweight , P < 0.0001 ) , and V4 ( overweight , P < 0.0001 ; obese , P < 0.025 ) . Women in the intervention group significantly increased their meaningful walks at V2 ( P = 0.054 ) , V3 ( P = 0.01 ) , and V4 ( P = 0.014 ) . There were trends for intervention group women to have more favorable maternal and birth outcomes compared with the control group . Rates of GWG at measurement points during pregnancy were significantly associated with preceding rates of GWG . CONCLUSION The pilot , unsupervised walking intervention increased the MPA of overweight and obese women during pregnancy [24901666] Few studies have investigated the impact of lifestyle interventions during pregnancy on post-partum weight retention and infant growth . Thirty seven previously non-exercising , overweight or obese pregnant women were r and omly assigned to a walking intervention or non-intervention control . For the follow-up study , weight of the mother and weight , length and body composition of the infant were collected at 1 month post-partum ( n=37 ) and 6 months post-partum ( n=33 ) . Analysis of variance and linear regression were conducted to determine the differences and association in maternal post-partum weight retention and child outcomes . At 6 months post-partum , weight retention of obese women in the intervention group ( Int-OB ) was -0.10±8.11 kg ; while , obese women in the control group ( Con-OB ) was 6.35±7.47 kg . A significantly higher percentage of Con-OB women retained more than 5 kg at 6 months post-partum ( P=0.046 ) . Even though statistically non-significant between the groups , the growth trend observed among offspring of obese women in the control group was consistently higher than the offspring of obese women in the intervention group from birth to 6-months . Third trimester gestational weight gain rate significantly predicted 6-m weight-for-length z-score after controlling for birth weight , treatment group and pre-pregnancy body mass index ( r 2=0.31 , β=1.75 , P=0.03 ) . The reduced post-partum weight retention observed among the obese women in the intervention group may be explained in part by the lifestyle modification during pregnancy [27622854] ABSTRACT Accumulating research indicates that the regular practice of physical exercise is beneficial to the human brain . From the improvement of academic achievement in children to the prevention of Alzheimer ’s disease in the elderly , exercise appears beneficial across the developmental spectrum . Recent work from animal studies also indicates that a pregnant mother can transfer the benefits of exercise during gestation to her offspring ’s brain . Exercising pregnant rats give birth to pups that have better memory and spatial learning as well as increased synaptic density . To investigate whether this transfer from the pregnant mother to her child also occurs in humans , we conducted a r and omized controlled trial ( n = 18 ) and measured the impact of exercise during pregnancy on the neuroelectric response of the neonatal brain with electroencephalography ( EEG ) . Here we show that , compared to the newborns of mothers who were inactive during their pregnancy , the children of exercising pregnant women are born with more mature brains . This was measured with the infant slow positive mismatch response ( SPMMR ) , an electroencephalographic potential known to decrease in amplitude with age . The SPMMR reflects processes associated with brain maturation via its response to sound discrimination and auditory memory . In this study , the children of the mothers who exercised throughout their pregnancy have a smaller SPMMR than the children of mothers who remained sedentary ( p = .019 ) . Our results demonstrate the impact regular exercise during pregnancy can have on the development of the human fetal brain [11864675] OBJECTIVE To evaluate the influence of exercise on maternal and perinatal outcome in a low‐risk healthy obstetric population . METHODS We conducted a prospect i ve observational study of low‐risk healthy women exercising during their pregnancy . An extensive question naire collected antepartum , intrapartum , and postpartum patient information on 750 women . The women were divided into four groups based on exercise level during pregnancy . RESULTS There were no differences among groups for maternal demographic characteristics , antenatal illnesses , stress , social support , or smoking . Heavily exercising women were older ( P = .042 ) , had higher incomes ( P = .001 ) , and were exercising more at conception ( P = .001 ) . Women who did more exercise were more likely to need an induction of labor ( P = .033 , relative risk 1.84 , 95 % confidence interval 1.05 , 3.20 ) , induction or augmentation with oxytocin ( P = .015 , relative risk 1.53 , 95 % confidence interval 1.19 , 1.97 ) , and had longer first‐stage labors ( P = .032 ) result ing in longer total labors ( P = .011 ) . The difference in the length of first‐stage labor was even greater if the no‐exercise group was compared with the strongly exercising group ( P = .009 , relative risk 1.38 , 95 % confidence interval 0.16 , 2.60 ) . Fewer umbilical cord abnormalities ( P = .034 ) were observed with exercise , but exercising women had more colds and flu ( P = .008 ) . Heavily exercising women had smaller infants ( mean difference 86.5 g ) compared with sedentary women . CONCLUSION Exercise in working women is associated with smaller babies , increased number of inductions and augmentations of labor , and longer labors . Colds and flu are more frequent in exercising women [25350037] AIM The effect of exercise training during the course of pregnancy on the newborn 's birth weight is unclear . This study examines the effect of aerobic and strength conditioning exercise performed during the second and the third trimester of pregnancy in nulliparous , previously inactive women on the newborn 's outcome . METHODS Sixty-three nulliparous , previously sedentary , were r and omly assigned to either an exercise ( N.=30 ) or a control ( N.=33 ) group . The subjects participated in the exercise group ( EG ) focused on aerobic and strength-conditioning exercise in three sessions for about 20 weeks . We registered the birth weight , birth length , gestational age at time of delivery , Apgar score and head circumference of the newborn . RESULTS There were no statistically significant differences between the two groups in mean birth weight , length , head circumference , and length of gestation . There was a significant difference between two groups in Apgar scores at 1 min ( P=0.036 ) and 5 min ( P=0.015 ) with newborns of the EG scoring higher than the CG . CONCLUSION Supervised , aerobic and strength conditioning exercise performed over the second and third trimester of pregnancy does not have a negative impact on the newborn 's body size and health [10647530] PURPOSE The present study examined the effects of exercise on physical and psychological variables in sedentary primigravidae ( PRA ) . METHODS A total of nine women r and omly assigned to an exercise ( E ) ( mean age = 31.3 + /- 3.1 yr ) and six subjects r and omly assigned to a control ( C ) group ( mean age = 27.8 + /- 3.1 yr ) fulfilled all requirements for the study . Exercise included a variety of exercise activities performed to a target heart rate of 150 - 156 beats x min(-1 ) , three times per week for 15 wk . RESULTS Results showed no significant differences between E and C groups in physical characteristics initially . A repeated measures ANOVA showed a significant group effect ( P < 0.05 ) and a significant group by time interaction ( P = 0.001 ) with the E group showing a significantly longer amount of time on the PWC150 test than the C group . There was no significant group , time , or group by time interaction for lactate accumulation . This occurred , despite the fact that the E group spent 56 % longer on the PWC150 test and the C group spent 30 % less time on the same test at the conclusion of the study . Finally , the E group in comparison to the C group showed more favorable improvements in several items related to health and well-being on the Body Cathexis Scale . There were no significant differences between E and C groups in any pregnancy outcome measures . All babies were delivered healthy at term . CONCLUSIONS These data suggest that a vigorous exercise program can lead to significant improvements in aerobic fitness at similar lactate concentrations compared to a control group and can be well tolerated by low risk sedentary PRA without any deleterious effects occurring to herself or unborn child [8990428] Objective To examine the effectiveness of a partially homebased , moderate-intensity aerobic exercise program for women with gestational diabetes . Methods This was a r and omized experimental design . Thirty-three women with gestational diabetes were r and omly assigned to the exercise or the no-exercise group . Subjects underwent hemoglobin A1C assay and submaximal cycle ergometer fitness tests at baseline and at study conclusion . Subjects kept diaries of home fasting and 2-hour postpr and ial blood glucose determinations . Exercise subjects were asked to exercise for 30 minutes three to four times weekly at 70 % of estimated maximal heart rate for the weeks of study participation . Two exercise sessions weekly were supervised by the investigator , and two were unsupervised at home . Control-group subjects were asked to maintain their current activity level . Results Daily fasting and postpr and ial blood glucose levels , hemoglobin A1C , incidence of exogenous insulin therapy , and incidence of newborn hypoglycemia were not different between the groups . There was a training effect in the exercise group ( P = .005 ) but not in the control group ( P = .25 ) . A significant decline in daily grams of carbohydrate consumed was observed in the control group ( P = .03 ) , but not in the exercise group ( P = .97 ) . No complications were found in the subjects who exercised . Conclusions A partially home-based exercise program did not reduce blood glucose levels , but did result in a modest increase in cardiorespiratory fitness . The intervention appeared safe [7771999] EDITORIAL COMMENT : When this paper was review ed the question was raised that the period of gestation is an obvious factor which can determine birth‐weight and the authors were asked how this may have affected their results The authors response was as follows [25823187] OBJECTIVE To assess the effect of aerobic exercise training on maternal and neonatal outcome METHODS The case-control study was conducted between January and July , 2011 . It was approved by the Research Ethics Committee of Toyserkan Azad University , and data was collected at prenatal clinics and delivery centres located in Hamedan , Iran . It comprised 80 pregnant women between 20 - 26 weeks of gestation r and omly assigned to two equal and matching groups of cases and controls . The intervention group did exercise continuously on a bicycle ergometre for 15 minutes , three times a week ; the intensity being 50 - 60 % of maximal heart rate . The control group did not do any exercise training . All information was obtained from the clinics , delivery centres , and from the reports of delivery room midwives . RESULTS No statistically significant difference was found between the two groups in gestational weight gain , pregnancy length , mode of delivery , first and second stage of labour , perineal tear , and 1st and 5th min Apgar score . Mean neonatal weight was significantly less in the intervention group than the control group ( p < 0.001 ) . CONCLUSION Exercising on a bicycle ergometer during pregnancy seems to be safe for the mother and the neonate [19747869] AIM The significant deterioration of insulin sensitivity and glucose tolerance during pregnancy can have serious health implication s for both the pregnant woman and her baby . Although it is well established that regular exercise benefits insulin sensitivity in the nonpregnant population , the effect on glucose tolerance in obese pregnant women is not known . The purpose of this study was to investigate the effect of a supervised 10-week , home-based , exercise programme , beginning at week 18 of gestation , on glucose tolerance and aerobic fitness in previously sedentary obese women . METHODS Twelve sedentary obese women were r and omized into an exercise ( EX ; n=6 ) or control ( CON ; n=6 ) group at 18 weeks of gestation . Those r and omized to EX engaged in 10 weeks of supervised home-based exercise ( three sessions a week of stationary cycling ) , while those in the CON group maintained their usual daily activity . Their glucose and insulin responses to an oral glucose tolerance test ( OGTT ) , as well as their aerobic fitness , were assessed both pre- and postintervention . RESULTS Reduced glucose tolerance in the CON , but not EX , group was indicated by a tendency postintervention towards higher blood glucose levels at 1h of the OGTT ( P=0.072 ) . Furthermore , at 2h of the postintervention OGTT , blood glucose tended to remain elevated from baseline in the CON ( P=0.077 ) . There was also a trend towards increased fitness in the EX ( P=0.064 ) , but not the CON group . CONCLUSION Regular aerobic exercise begun during pregnancy may have favourable effects on glucose tolerance and fitness in obese women , and warrants further investigation in a larger sample population [2613131] Background To evaluate the association between water aerobics , maternal cardiovascular capacity during pregnancy , labor and neonatal outcomes . Methods A r and omized , controlled clinical trial was carried out in which 34 pregnant women were allocated to a water aerobics group and 37 to a control group . All women were su bmi tted to submaximal ergometric tests on a treadmill at 19 , 25 and 35 weeks of pregnancy and were followed up until delivery . Oxygen consumption ( VO2 max ) , cardiac output ( CO ) , physical fitness , skin temperature , data on labor and delivery , and neonate outcomes were evaluated . Frequency distributions of the baseline variables of both groups were initially performed and then analysis of the outcomes was carried out . Categorical data were compared using the chi-square test , and numerical using Student 's t or Mann-Whitney tests . Wilk 's Lambda or Friedman 's analysis of repeat measurements were applied for comparison of physical capacity , cardiovascular outcomes and maternal temperature . Results VO2 max and physical fitness were higher in both groups in the second trimester , returning to basal levels in the third trimester . In both groups , CO increased as pregnancy progressed and peak exercise temperature was higher than resting temperature , increasing further after five minutes of recovery and remaining at this level until 15 minutes after exercise completion . There was no difference between the two groups regarding duration ( 457.9 ± SD 249.6 vs 428.9 ± SD 203.2 minutes ) or type of delivery . Labor analgesia was requested by significantly fewer women in the water aerobics group ( 27 % vs 65 % ; RR = 0.42 95%CI 0.23–0.77 ) . Neonatal results were similar in both groups . Conclusion The regular practice of moderate water aerobics by sedentary and low risk pregnant women was not detrimental to the health of the mother or the child . There was no influence on maternal cardiovascular capacity , duration of labor or type of delivery ; however , there were fewer requests for analgesia during labor in the water aerobics group [10870784] Does strenuous antenatal exercise reduce birth‐weight ? Does reducing maternal exercise increase birthweight ? What to advise about exercise during pregnancy [22364387] Objective . To study lumbopelvic pain in women r and omized to a regular exercise program during pregnancy in comparison to women receiving st and ard antenatal care . Design . A two‐armed , two‐center , r and omized controlled trial . Setting . St Olavs Hospital , Trondheim University Hospital and Stavanger University Hospital . Population . A total of 855 pregnant women were r and omized to intervention or control groups . Methods . The intervention was a 12 week exercise program , including aerobic and strengthening exercises , conducted between 20 and 36 weeks of pregnancy . One weekly group session was led by physiotherapists , and home exercises were encouraged twice a week . The control group received st and ard antenatal care . Main outcome measures . Self‐reports of lumbopelvic pain and sick leave due to lumbopelvic pain . The data were analysed according to the “ intention‐to‐treat ” principle . Results . There were no significant differences between groups of women reporting lumbopelvic pain at 36 weeks ( 74 vs. 75 % , p=0.76 ) . The proportion of women on sick leave due to lumbopelvic pain was lower in the intervention group ( 22 % vs 31 % , p=0.01 ) . Conclusions . Exercise during pregnancy does not influence the prevalence of lumbopelvic pain , but women offered a regular exercise course seem to h and le the disorder better [21948120] Objective The influence of an exercise programme performed by healthy pregnant women on maternal glucose tolerance was studied . Study design A physical activity ( PA , l and /aquatic activities ) programme during the entire pregnancy ( three sessions per week ) was conducted by a qualified instructor . 83 healthy pregnant women were r and omly assigned to either an exercise group ( EG , n=40 ) or a control ( CG , n=43 ) group . 50 g maternal glucose screen ( MGS ) , maternal weight gain and several pregnancy outcomes were recorded . Results Significant differences were found between study groups on the 50 g MGS . Values corresponding to the EG ( 103.8±20.4 mg/dl ) were better than those of the CG ( 126.9±29.5 mg/dl ) , p=0.000 . In addition , no differences in maternal weight gain and no cases of gestational diabetes in EG versus 3 in CG ( 7 % ) ( p>0.05 ) were found . Conclusion A moderate PA programme performed during pregnancy improves levels of maternal glucose tolerance [28161306] BACKGROUND : Obesity and being overweight are becoming epidemic , and indeed , the proportion of such women of reproductive age has increased in recent times . Being overweight or obese prior to pregnancy is a risk factor for gestational diabetes mellitus , and increases the risk of adverse pregnancy outcome for both mothers and their offspring . Furthermore , the combination of gestational diabetes mellitus with obesity/overweight status may increase the risk of adverse pregnancy outcome attributable to either factor alone . Regular exercise has the potential to reduce the risk of developing gestational diabetes mellitus and can be used during pregnancy ; however , its efficacy remain controversial . At present , most exercise training interventions are implemented on Caucasian women and in the second trimester , and there is a paucity of studies focusing on overweight/obese pregnant women . OBJECTIVE : We sought to test the efficacy of regular exercise in early pregnancy to prevent gestational diabetes mellitus in Chinese overweight/obese pregnant women . STUDY DESIGN : This was a prospect i ve r and omized clinical trial in which nonsmoking women age > 18 years with a singleton pregnancy who met the criteria for overweight/obese status ( body mass index 24≤28 kg/m2 ) and had an uncomplicated pregnancy at < 12 + 6 weeks of gestation were r and omly allocated to either exercise or a control group . Patients did not have contraindications to physical activity . Patients allocated to the exercise group were assigned to exercise 3 times per week ( at least 30 min/session with a rating of perceived exertion between 12‐14 ) via a cycling program begun within 3 days of r and omization until 37 weeks of gestation . Those in the control group continued their usual daily activities . Both groups received st and ard prenatal care , albeit without special dietary recommendations . The primary outcome was incidence of gestational diabetes mellitus . RESULTS : From December 2014 through July 2016 , 300 singleton women at 10 weeks ’ gestational age and with a mean prepregnancy body mass index of 26.78 ± 2.75 kg/m2 were recruited . They were r and omized into an exercise group ( n = 150 ) or a control group ( n = 150 ) . In all , 39 ( 26.0 % ) and 38 ( 25.3 % ) participants were obese in each group , respectively . Women r and omized to the exercise group had a significantly lower incidence of gestational diabetes mellitus ( 22.0 % vs 40.6 % ; P < .001 ) . These women also had significantly less gestational weight gain by 25 gestational weeks ( 4.08 ± 3.02 vs 5.92 ± 2.58 kg ; P < .001 ) and at the end of pregnancy ( 8.38 ± 3.65 vs 10.47 ± 3.33 kg ; P < .001 ) , and reduced insulin resistance levels ( 2.92 ± 1.27 vs 3.38 ± 2.00 ; P = .033 ) at 25 gestational weeks . Other secondary outcomes , including gestational weight gain between 25‐36 gestational weeks ( 4.55 ± 2.06 vs 4.59 ± 2.31 kg ; P = .9 ) , insulin resistance levels at 36 gestational weeks ( 3.56 ± 1.89 vs 4.07 ± 2.33 ; P = .1 ) , hypertensive disorders of pregnancy ( 17.0 % vs 19.3 % ; odds ratio , 0.854 ; 95 % confidence interval , 0.434–2.683 ; P = .6 ) , cesarean delivery ( except for scar uterus ) ( 29.5 % vs 32.5 % ; odds ratio , 0.869 ; 95 % confidence interval , 0.494–1.529 ; P = .6 ) , mean gestational age at birth ( 39.02 ± 1.29 vs 38.89 ± 1.37 weeks ’ gestation ; P = .5 ) ; preterm birth ( 2.7 % vs 4.4 % , odds ratio , 0.600 ; 95 % confidence interval , 0.140–2.573 ; P = .5 ) , macrosomia ( defined as birthweight > 4000 g ) ( 6.3 % vs 9.6 % ; odds ratio , 0.624 ; 95 % confidence interval , 0.233–1.673 ; P = .3 ) , and large‐for‐gestational‐age infants ( 14.3 % vs 22.8 % ; odds ratio , 0.564 ; 95 % confidence interval , 0.284–1.121 ; P = .1 ) were also lower in the exercise group compared to the control group , but without significant difference . However , infants born to women following the exercise intervention had a significantly lower birthweight compared with those born to women allocated to the control group ( 3345.27 ± 397.07 vs 3457.46 ± 446.00 g ; P = .049 ) . CONCLUSION : Cycling exercise initiated early in pregnancy and performed at least 30 minutes , 3 times per week , is associated with a significant reduction in the frequency of gestational diabetes mellitus in overweight/obese pregnant women . And this effect is very relevant to that exercise at the beginning of pregnancy decreases the gestational weight gain before the mid‐second trimester . Furthermore , there was no evidence that the exercise prescribed in this study increased the risk of preterm birth or reduced the mean gestational age at birth [8317440] The value of exercise during pregnancy is controversial ; both benefits and risks have been hypothesized . As empiric evidence is scant , the issue was investigated in a prospect i ve study that assessed the impact on fetal growth of maternal exercise in each trimester of pregnancy . A cohort of over 800 prenatal patients was recruited from obstetric practice s in Pennsylvania and New York between January 1987 and June 1989 . Subjects were interviewed at entry into care and recontacted at 28 and 36 weeks of gestation . In women with prior adverse outcomes or a lack of conditioning , the associations between maternal exercise and fetal growth were equivocal . In fit , low-risk , prenatal patients , exercise was positively associated with fetal growth . With low-moderate exercise levels , the adjusted mean birth weights were about 100 g higher than in nonexercisers ( 117 g ; 95 % confidence interval 17 to 217 g ) . With heavier exercise , larger birth weight increments were seen , close to 300 g in those who exercised throughout pregnancy at levels of about 2,000 kcal/week in energy expenditure ( 276 g ; 95 % confidence interval 54 to 497 g ) . These results suggest that the guidelines issued by the American College of Obstetricians and Gynecologists may be too stringent for well-conditioned , low-risk , prenatal patients . Additional research to define safe limits more precisely seems warranted [10078577] OBJECTIVE To investigate if water-gymnastics during pregnancy may reduce the intensity of back/low back pain and the number of days on sick-leave . METHODS A prospect i ve , r and omized study . One hundred and twenty-nine women were r and omized to participate in water-gymnastics once a week during the second half of pregnancy and 129 were r and omized to a control group . The women in both groups filled in question naires in gestational weeks 18 , 34 and within the first postpartum week . Every day from week 18 to labor they assessed the intensity of back/low back pain . RESULTS Back pain intensity increased during pregnancy . No excess risk for the pregnancy associated with water-gymnastics was observed . The women participating in water-gymnastics recorded a lower intensity of back/low back pain . The total number of days on sick-leave because of back/low back pain was 982 in the water-gymnastics group ( 124 women ) compared with 1484 in the control group ( 120 women ) . After weeks 32 33 , seven women in the water-gymnastics group compared with 17 in the control group were on sickleave because of back/ low back pain ( p=0.031 ) . CONCLUSIONS Intensity of back/low back pain increased with advancing pregnancy . There was no excess risk for urinary or vaginal infections associated with water-gymnastics . Water-gymnastics during the second half of pregnancy significantly reduced the intensity of back/ low back pain . Water-gymnastics decreased the number of women on sick-leave because of back/low back pain . Water-gymnastics during pregnancy can be recommended as a method to relieve back pain and may reduce the need for sick-leave [19636320] Objective : We examined the effect of light intensity resistance exercise training performed during the second and third trimester of pregnancy on the newborn 's birth size . We also studied the association between maternal body weight prior to pregnancy and newborn 's birth size . Design : R and omised controlled trial . Subjects : We r and omly assigned 160 sedentary gravidae to either a training ( n=80 ) or a control ( n=80 ) group . The training programme focused on light resistance and toning exercises ( three times per week , 35–40 min per session ) . We recorded the Apgar score , birth weight , birth length , and head circumference of the newborn , as well as gestational age at time of delivery from hospital perinatal records . We also measured maternal weight and height before parity and gestational weight gain . Results : Maternal characteristics neither differed between groups ( all P>0.1 ) nor newborn characteristics ( all P>0.1 ) . Maternal body weight was positively and significantly associated with newborn 's birth weight and length only in the control group ( β=19.20 and 0.065 , respectively , P<0.01 ) . Conclusion : Light intensity resistance training performed over the second and third trimester of pregnancy does not have a negative impact on the newborn 's body size or overall health . Exercise interventions might attenuate the adverse consequences of maternal body weight before pregnancy on the newborn 's birth size [3198740] Background Birth weight plays an important role in infant mortality and morbidity , childhood development , and adult health . To date there are contradictory results regarding the role of physical activity on birth weight . In addition , it is question ed whether exercise during second and third trimesters of pregnancy might affect gestational age and increase the risk of preterm delivery . Hence , the purpose of this study was to examine the effect of a supervised exercise-program on birth weight , gestational age at delivery and Apgar-score . Methods Sedentary , nulliparous pregnant women ( N = 105 ) , mean age 30.7 ± 4.0 years , pre-pregnancy BMI 23.8 ± 4.3 were r and omized to either an exercise group ( EG , n = 52 ) or a control group ( CG , n = 53 ) . The exercise program consisted of supervised aerobic dance and strength training for 60 minutes , twice per week for a minimum of 12 weeks , with an additional 30 minutes of self-imposed physical activity on the non-supervised week-days . Results There was no statistically significant difference between groups in mean birth weight , low birth weight ( < 2500 g ) or macrosomia ( ≥ 4000 g ) . Per protocol analyses showed higher Apgar score ( 1 min ) in the EG compared with the CG ( p = 0.02 ) . No difference was seen in length of gestation . Conclusion Aerobic-dance exercise was not associated with reduction in birth weight , preterm birth rate or neonatal well-being . Trial Registration Clinical Trials.gov : [5062054] Non-r and omised studies of the effects of interventions are critical to many areas of healthcare evaluation , but their results may be biased . It is therefore important to underst and and appraise their strengths and weaknesses . We developed ROBINS-I ( “ Risk Of Bias In Non-r and omised Studies - of Interventions ” ) , a new tool for evaluating risk of bias in estimates of the comparative effectiveness ( harm or benefit ) of interventions from studies that did not use r and omisation to allocate units ( individuals or clusters of individuals ) to comparison groups . The tool will be particularly useful to those undertaking systematic review s that include non-r and omised studies [4431606] Objective To determine the effectiveness of a physical activity intervention for smoking cessation during pregnancy . Design Parallel group , r and omised controlled , multicentre trial . Setting 13 hospitals in Engl and , April 2009 to January 2014 . Participants 789 pregnant smokers , aged 16 - 50 years and at 10 - 24 weeks ’ gestation , who smoked at least one cigarette daily and were prepared to quit smoking one week after enrollment were r and omised ( 1:1 ) ; 785 were included in the intention to treat analyses , with 392 assigned to the physical activity group . Interventions Interventions began one week before a target quit date . Participants were r and omised to six weekly sessions of behavioural support for smoking cessation ( control ) or to this support plus 14 sessions combining supervised treadmill exercise and physical activity consultations . Main outcome measures The primary outcome was continuous smoking abstinence from the target quit date until end of pregnancy , vali date d by exhaled carbon monoxide or salivary cotinine levels . To assess adherence , levels of moderate-vigorous intensity physical activity were self reported and in a 11.5 % ( n=90 ) r and om sub sample of participants , physical activity was objective ly measured by an accelerometer . Results No significant difference was found in rates of smoking abstinence at end of pregnancy between the physical activity and control groups ( 8 % v 6 % ; odds ratio 1.21 , 95 % confidence interval 0.70 to 2.10 ) . For the physical activity group compared with the control group , there was a 40 % ( 95 % confidence interval 13 % to 73 % ) , 34 % ( 6 % to 69 % ) , and 46 % ( 12 % to 91 % ) greater increase in self reported minutes carrying out physical activity per week from baseline to one week , four weeks , and six weeks post-quit day , respectively . According to the accelerometer data there was no significant difference in physical activity levels between the groups . Participants attended a median of four treatment sessions in the intervention group and three in the control group . Adverse events and birth outcomes were similar between the two groups , except for significantly more caesarean births in the control group than in the physical activity group ( 29 % v 21 % , P=0.023 ) . Conclusion Adding a physical activity intervention to behavioural smoking cessation support for pregnant women did not increase cessation rates at end of pregnancy . During pregnancy , physical activity is not recommended for smoking cessation but remains indicated for general health benefits . Trial registration Current Controlled Trials IS RCT N48600346 [5360254] Background Maternal obesity associates with complications during pregnancy and childbirth . Our aim was to investigate if exercise during pregnancy in overweight/obese women could influence birth weight or other neonatal and maternal outcomes at delivery . Material and methods This is a secondary analysis of a r and omised controlled trial of exercise training in pregnancy for women with body mass index ( BMI ) ≥ 28 kg/m2 . Ninety-one women ( 31.3 ± 4.3 years , BMI 34.5 ± 4.2 kg/m2 ) were allocated 1:1 to supervised exercise during pregnancy or to st and ard care . The exercise group was offered three weekly training sessions consisting of 35 minutes of moderate intensity walking/running followed by 25 minutes of strength training . Data from 74 women ( exercise 38 , control 36 ) were analysed at delivery . Results Birth weight was 3719 ± 695 g in the exercise group and 3912 ± 413 g in the control group ( CI -460.96 , 74.89 , p = 0.16 ) . Birth weight > 4000 g was 35 % in the exercise group and 52 % in the control group ( p = 0.16 ) . Mean gestational age at delivery was 39.1 weeks in the exercise group and 39.5 weeks in the control group ( CI -1.33 , 0.43 , p = 0.31 ) . No significant between-group differences were found in neonatal body size , skinfold thickness , placental weight ratio , or Apgar score . The prevalence of caesarean section was 24 % in the exercise group and 17 % in the control group ( CI 0.20 , 2.05 , p = 0.57 ) . Mean length of hospital stay was 4.8 days in the exercise group and 4.5 days in the control group ( CI -0.45 , 1.00 , p = 0.45 ) . Conclusions Offering supervised exercise during pregnancy for overweight and obese women did not influence birth weight or other neonatal and maternal outcomes at delivery . However our trial was limited by low sample size and poor adherence to the exercise protocol , and further research is needed . Trial registration Clinical Trials.gov [3753734] Objectives . To evaluate the association between physical exercise supervised in pregnant women with chronic hypertension and /or previous preeclampsia and maternal and neonatal outcomes . Method . R and omized controlled trial , which included 116 pregnant women with chronic hypertension and /or previous preeclampsia , considered risk of preeclampsia development . They were divided into two groups : study group that performed physical exercise with a stationary bicycle once a week , for 30 minutes ; the intensity was controlled ( heart rate 20 % above resting values ) , under professional supervision and a control group that was not engaged in any physical exercise . The data was retrieved from medical charts . Significance level assumed was 5 % . Results . Women from study group performed 9.24 ± 7.03 of physical exercise sessions . There were no differences between groups comparing type of delivery and maternal outcomes , including maternal morbidity and hospitalization in intensive unit care , and neonatal outcomes , including birth weight , adequacy of weight to gestational age , prematurity , Apgar scale at first and fifth minutes , hospitalization in intensive unit care , and neonatal morbidity . Conclusions . Physical exercise using a stationary bicycle in pregnant women with chronic hypertension and /or previous preeclampsia , once a week , under professional supervision , did not interfere in the delivery method and did not produce maternal and neonatal risks of the occurrence of morbidity . This trial is registered with Clinical Trials.gov NCT01395342 [3787488] Objectives The long-term consequences of maternal physical activity during pregnancy for offspring cardiovascular health are unknown . We examined the association of maternal self-reported physical activity in pregnancy ( 18 weeks gestation ) with offspring cardiovascular risk factors at age 15 . Design Prospect i ve cohort study . Setting The Avon Longitudinal Study of Parents and Children ( ALSPAC ) . Participants 4665 maternal-offspring pairs ( based on a sample with multiple imputation to deal with missing data ) from the ALSPAC , a prospect i ve cohort based in the South West of Engl and with mothers recruited in pregnancy in 1991–1992 . Primary and secondary outcome measures Offspring cardiovascular risk factors at age 15 ; body mass index ( BMI ) , waist circumference , systolic blood pressure , diastolic blood pressure , glucose , insulin , low-density lipoprotein cholesterol , high-density lipoprotein cholesterol and triglycerides . Results Greater maternal physical activity was associated with lower BMI , waist circumference , glucose and insulin in unadjusted analyses . The magnitude of associations was generally small with wide CIs , and most associations attenuated towards the null after adjusting for confounders . The strongest evidence of association after adjustment for confounders was for glucose , although the 95 % CI for this association includes the null ; a one SD greater physical activity during pregnancy was associated with a −0.013 mmol/L difference in offspring glucose levels ( equivalent to approximately one-third of a SD ; 95 % CI −0.027 to 0.001 mmol/L ) . Conclusions Our results suggest that maternal physical activity in pregnancy , measured at 18 weeks gestation , is unlikely to be an important determinant of later offspring cardiovascular health . There was some suggestion of association with offspring glucose , but given that all other associations ( including insulin ) were null after adjustment for confounders , this result should be interpreted with caution [19608151] OBJECTIVE We examined the effect of light-intensity resistance exercise training that is performed during the second and third trimester of pregnancy by previously sedentary and healthy women on the type of delivery and on the dilation , expulsion , and childbirth time . STUDY DESIGN We r and omly assigned 160 sedentary women to either a training ( n=80 ) or a control ( n=80 ) group . We recorded several maternal and newborn characteristics , the type of delivery ( normal , instrumental , or cesarean ) , and dilation , expulsion , and childbirth time . RESULTS The percentage of women who had normal , instrumental , or cesarean delivery was similar in the training ( 70.8 % , 13.9 % , and 15.3 % , respectively ) and control ( 71.4 % , 12.9 % , and 15.7 % , respectively ) groups . The mean dilation , expulsion , and childbirth time did not differ between groups . CONCLUSION Light-intensity resistance training that is performed over the second and third trimester of pregnancy does not affect the type of delivery [16055571] Objective : To evaluate the effects of aerobic training on submaximal cardiorespiratory capacity in overweight pregnant women . Methods : We conducted a r and omized clinical trial in a referral center prenatal clinic during the period 2000–2002 . Of 132 overweight ( body mass index 26–31 kg/m2 ) but otherwise healthy volunteers , at 20 years of age or older , with gestational age of 20 weeks or less , and without diabetes or hypertension , 92 consented to participate and were r and omized . Intervention consisted of 3 one-hour aerobic exercise sessions per week ; the control group received weekly relaxation and focus group discussion s. The main outcome measure was submaximal exercise capacity evaluated by oxygen uptake at the anaerobic ( first ventilatory ) threshold during cardiopulmonary treadmill testing 12 weeks after r and omization . Results : Oxygen uptake at the anaerobic threshold increased 18 % ( 15.9 ± 2.6 to 18.1 ± 3.1 mL · min−1 · kg−1 ) in the exercise group but decreased 16 % ( 16.9 ± 3.0 to 15.8 ± 2.6 mL · min−1 · kg−1 ) among the control group . Oxygen consumption at the anaerobic threshold , adjusted through analysis of covariance for baseline oxygen uptake , was 2.68 ( 95 % confidence interval 1.23 to 4.12 ) mL · min−1 · kg−1 greater in the exercise group . Women in the exercise group were approximately 5 times more likely than those in the control group to have regular or good cardiorespiratory capacity ( 12/38 versus 2/38 ; relative risk 5.2 , 95 % confidence interval 1.2 to 22.0 , number needed to treat 5 ) . Conclusion : Aerobic training in overweight pregnant women substantially increases submaximal exercise capacity , overcoming the otherwise negative effects of pregnancy in this regard . Additional studies are required to evaluate its effect on major clinical outcomes . LEVEL OF EVIDENCE : [5530125] Aim To evaluate the association between maternal physical activity and infant ’s birth weight or risk of inappropriate weight for gestational age ( GA ) , and whether this association differs by infant ’s sex , maternal body mass index ( BMI ) or pregnancy complications in a prospect i ve cohort study . Methods 1913 pregnant women from the 3D Birth Cohort ( Québec , Canada ) completed the Pregnancy Physical Activity Question naire at each trimester . Energy expenditure ( metabolic equivalent of task (MET)*hours/week ) for total activity , sports and exercise and vigorous intensity activities was calculated . The associations with birth weight and risk of inappropriate weight for GA were evaluated by regression modelling . Interactions were tested with infant ’s sex , maternal prepregnancy BMI , gestational diabetes , hypertensive disorders and prematurity . Results Each 1 MET/hours/week increase in sports and exercise in the first trimester was associated with a 2.5 g reduction in infant ’s birth weight ( 95 % CI −4.8 to −0.3 ) but was not associated with the risk of small weight for GA . In contrast , although not significant , a 17 % reduction in the risk of large weight for GA was observed with increasing sports and exercise . Furthermore , in women with subsequent pre-eclampsia ( but not normotensive or hypertensive women ) , each 1 MET/hours/week increment spent in any vigorous exercise in the first trimester reduced the infant ’s birth weight by 19.8 g ( 95 % CI −35.2 to −4.3 ) . Conclusions Pregnant women with higher sports and exercise levels in the first trimester delivered infants with a lower birth weight . The risk of reducing infant ’s birth weight with vigorous exercise in women who develop pre-eclampsia later in pregnancy requires evaluation [24290112] OBJECTIVE To study the effect on maternal weight gain of a supervised light- to moderate-intensity exercise-based intervention performed from the ninth week of pregnancy . PARTICIPANTS AND METHODS A total of 962 healthy pregnant women were r and omly assigned to a st and ard care or exercise intervention group conducted between September 1 , 2007 , and January 31 , 2011 . The intervention included light- to moderate-intensity aerobic and resistance exercises performed 3 days a week ( 50 - 55 minutes per session ) . Excessive gestational weight gain was calculated on the basis of the 2009 Institute of Medicine ( IOM ) recommendations . Gestational body weight gain was calculated on the basis of the weight measured at the first prenatal visit ( fifth to sixth weeks of gestation ) and weight measured at the last visit to the clinic before delivery . Women were categorized into normal weight or overweight or obese . RESULTS Women in the intervention group gained less weight ( adjusted mean difference , 1.039 kg ; 95 % CI , 0.534 - 1.545 kg ; P<.001 ) and were less likely to gain weight above the IOM recommendations ( odds ratio , 0.625 ; 95 % CI , 0.461 - 0.847 ) compared with those in the st and ard care group . The main treatment effects according to body mass index category were that normal weight women in the intervention group gained less weight ( adjusted mean difference , 1.393 kg ; 95 % CI , 0.813 - 1.972 kg ; P<.001 ) and were less likely to gain weight above the IOM recommendations ( odds ratio , 0.508 ; 95 % CI , 0.334 - 0.774 ) than normal weight women who received st and ard care . No significant treatment effect was observed in overweight or obese women . CONCLUSION Supervised exercise of light to moderate intensity can be used to prevent excessive gestational weight gain , especially in normal weight women . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01790347 [26575838] Background : Both large and small birth sizes are associated with an increased risk of developing cardiovascular and metabolic problems later in life . We studied whether such associations can be observed at prepubertal age . Methods : A cohort of 49 large ( LGA ) , 56 appropriate ( AGA ) , and 23 small for gestational age (SGA)-born children ( age range 5 - 8 years ) were studied . Being born SGA , AGA , or LGA was the exposure , and being overweight at prepubertal age was the main outcome . Blood pressure measurements , laboratory parameters , and whole-body dual-energy X-ray absorptiometry were secondary outcomes . Results : The LGA-born children were significantly taller than the AGA controls ( p = 0.03 ) , and the SGA children were lighter and shorter compared to the AGA ( p = 0.002 and 0.001 ) and LGA children ( p < 0.001 ) . The mean plasma glucose was higher in the LGA than in the SGA group ( p = 0.006 ) . Being born LGA ( OR 3.82 ) and the ponderal index Z-score at birth ( OR 4.24 ) were strong predictors for being overweight or obese in childhood . Conclusion : The children born LGA remained taller and heavier than those born AGA or SGA in mid-childhood , and they had a higher body mass index and body fat percentage than the SGA-born children . The differences in other cardiometabolic risk factors were minimal between the birth size groups [24787489] BACKGROUND Several recent " developmental origins " studies have reported increased long-term risks of adiposity , especially truncal adiposity , among children born small for gestational age ( SGA ) . OBJECTIVE We assessed the effects of SGA birth and weight gain in early infancy on adiposity at age 11.5 y. DESIGN From a cluster-r and omized breastfeeding promotion trial in 17,046 Belarusian children , we measured height , weight , waist and hip circumferences , triceps and subscapular skinfold thicknesses , and bioimpedance measures of percentage body fat at age 11.5 y. Children born SGA ( birth weight < 10th percentile ) and those born large for gestational age ( LGA ; > 90th percentile for gestational age ) were compared with those born appropriate for gestational age ( AGA ) . Weight gain from birth to 6 mo was categorized as high ( > 0.67-SD increase in weight-for-age ) , low ( > 0.67-SD decrease in weight-for-age ) , or normal . Multilevel statistical models accounted for clustered measurement and controlled for maternal and paternal height and body mass index ( BMI ) , maternal education , geographic region , urban compared with rural residence , and the child 's exact age at follow-up . RESULTS Children born SGA had a significantly lower BMI , percentage body fat , and fat mass index than did those born AGA , with a dose-response effect across 2 subcategories of SGA ( P < 0.001 for all comparisons ) . No difference was observed in waist-to-hip ratio , although the subscapular-to-triceps skinfold ratio was slightly but significantly ( P < 0.001 ) higher in children born SGA . Differences among the study groups continued to increase since the previous follow-up at 6.5 y. SGA infants with catch-up growth in the first 3 - 6 mo had growth and adiposity measures intermediate between those born SGA without catch-up and those born AGA . Opposite effects of similar magnitude were observed in children born LGA . CONCLUSION The 11.5-y-old Belarusian children born SGA were shorter , were thinner , and had less body fat than their non-SGA peers , irrespective of postnatal weight gain . The Promotion of Breastfeeding Intervention Trial was registered at www.is rct n.org as IS RCT N-37687716 [11120515] OBJECTIVE Our purpose was to test the null hypothesis that beginning regular , moderate-intensity exercise in early pregnancy has no effect on fetoplacental growth . STUDY DESIGN Forty-six women who did not exercise regularly were r and omly assigned at 8 weeks either to no exercise ( n = 24 ) or to weight-bearing exercise ( n = 22 ) 3 to 5 times a week for the remainder of pregnancy . Outcome variables included antenatal placental growth rate and neonatal and placental morphometric measurements . RESULTS The offspring of the exercising women were significantly heavier ( corrected birth weight : 3.75 + /- 0.08 kg vs 3.49 + /- 0.07 kg ) and longer ( 51.8 + /- 0.3 cm vs 50.6 + /- 0.3 cm ) than those born to control women . The difference in birth weight was the result of an increase in both lean body mass and fat mass . In addition , midtrimester placental growth rate was faster ( 26 + /- 2 cm(3)/wk vs 21 + /- 1 cm(3)/wk ) and morphometric indexes of placental function were greater in the exercise group . There were no significant differences in neonatal percentage body fat , head circumference , ponderal index , or maternal weight gain . CONCLUSIONS These data indicate that beginning a moderate regimen of weight-bearing exercise in early pregnancy enhances fetoplacental growth [22825089] OBJECTIVE : To estimate the effect of supervised physical exercise on maternal physical fitness , fetoplacental blood flow , and fetal growth . METHODS : This was a r and omized controlled trial comparing three groups of pregnant women . Groups were as follows : exercise initiated at 13 weeks ( group A ) ; exercise initiated at 20 weeks ( group B ) ; and a control group ( no supervised exercise ; group C ) . The women in groups A and B walked at moderate intensity three times weekly . Physical fitness level was evaluated at weeks 13 , 20 , and 28 . Fetal growth and uteroplacental blood flow were evaluated monthly . Birth weight was registered . Analysis of variance for repeat measures was used for outcomes evaluated throughout pregnancy . Risk ratio was used as a measure of the relative risk of preeclampsia , fetal growth restriction , macrosomia , small-for-gestational-age newborns , and large-for-gestational-age newborns . RESULTS : All the women analyzed completed more than 85 % of the program . According to the evaluation conducted at week 28 , physical fitness improved , with mean maximal oxygen consumptions ( VO2max ) of 27.3±4.3 ( group A ) , 28±3.3 ( group B ) , and 25.5±3.8 ( group C ; P=.03 ) . Mean birth weights were 3,279±453 g ( group A ) , 3,285±477 g ( group B ) , and 3,378±593 g ( group C ; P=.53 ) , with no difference in the frequency of large for gestational age or small for gestational age . No association was found between the practice of physical activity and the variables investigated ( preeclampsia , fetal weight , blood pressure , and pulsatility index of the uterine , umbilical , and middle cerebral arteries ) . CONCLUSION : Moderate-intensity walking improved the physical fitness level of healthy , pregnant , previously sedentary women without affecting fetoplacental blood flow or fetal growth . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00641550 . LEVEL OF EVIDENCE : [20864072] OBJECTIVE The objective of the study was to evaluate the effect of a resistance exercise program with an elastic b and on insulin requirement and glycemic control in patients with gestational diabetes mellitus ( GDM ) . STUDY DESIGN Sixty-four patients with gestational diabetes mellitus were r and omly assigned into 2 groups : an exercise group ( EG ; n = 32 ) and a control group not su bmi tted to the exercise program ( CG ; n = 32 ) . RESULTS A significant reduction in the number of patients who required insulin was observed in the EG ( 7/32 ) compared with the CG group ( 18/32 ) ( P = .005 ) . The percentage of time spent within the proposed target glucose range ( of at least 80 % of weekly measurements below the limits preestablished for the disease ) was significantly higher in EG compared with the CG group ( EG = 0.63 ± 0.30 ; CG = 0.41 ± 0.31 ; P = .006 ) . CONCLUSION The resistance exercise program was effective in reducing the number of patients with GDM who required insulin and in improving capillary glycemic control in this population [15733880] OBJECTIVE To investigate the effect of exercise during pregnancy on the intensity of low back pain and kinematics of spine . METHOD A prospect i ve r and omized study was design ed . 107 women participated in an exercise program three times a week during second half of pregnancy for 12 weeks and 105 as control group . All filled a question naire between 17 - 22 weeks of gestation and 12 weeks later for assessment of their back pain intensity . Lordosis and flexibility of spine were measured by Flexible ruler and Side bending test , respectively , at the same times . Weight gain during pregnancy , Pregnancy length and neonatal weight were recorded . RESULT Low back pain intensity was increased in the control group . The exercise group showed significant reduction in the intensity of low back pain after exercise ( p<0.0001 ) . Flexibility of spine decreased more in the exercise group ( p<0.0001 ) . Weight gain during pregnancy , pregnancy length and neonatal weight were not different between the two groups . CONCLUSION Exercise during second half of the pregnancy significantly reduced the intensity of low back pain , had no detectable effect on lordosis and had significant effect on flexibility of spine [22715981] Objective : In this study , the authors assessed the effects of a structured , moderate-intensity exercise program during the entire length of pregnancy on a woman ’s method of delivery . Methods : A r and omized controlled trial was conducted with 290 healthy pregnant Caucasian ( Spanish ) women with a singleton gestation who were r and omly assigned to either an exercise ( n = 138 ) or a control ( n = 152 ) group . Pregnancy outcomes , including the type of delivery , were measured at the end of the pregnancy . Results : The percentage of cesarean and instrumental deliveries in the exercise group were lower than in the control group ( 15.9 % , n = 22 ; 11.6 % , n = 16 vs. 23 % , n = 35 ; 19.1 % , n = 29 , respectively ; p = 0.03 ) . The overall health status of the newborn as well as other pregnancy outcomes was unaffected . Conclusions : Based on these results , a supervised program of moderate-intensity exercise performed throughout pregnancy was associated with a reduction in the rate of cesarean , instrumental deliveries and can be recommended for healthy women in pregnancy [29055674] PROBLEM Gestational diabetes mellitus , defined as any carbohydrate intolerance first diagnosed during pregnancy , is associated with a variety of adverse outcomes , both for the mother and her child . AIM To investigate the impact of a structured exercise programme which consisted of aerobic and resistance exercises on the parameters of glycaemic control and other health-related outcomes in pregnant women diagnosed with gestational diabetes mellitus . METHODS Thirty-eight pregnant women diagnosed with gestational diabetes mellitus were r and omised to two groups . Experimental group was treated with st and ard antenatal care for gestational diabetes mellitus , and regular supervised exercise programme plus daily brisk walks of at least 30min . Control group received only st and ard antenatal care for gestational diabetes mellitus . The exercise programme was started from the time of diagnosis of diabetes until birth . It was performed two times per week and sessions lasted 50 - 55min . FINDINGS The experimental group had lower postpr and ial glucose levels at the end of pregnancy ( P<0.001 ) . There was no significant difference between groups in the level of fasting glucose at the end of pregnancy . Also , there were no significant differences in the rate of complications during pregnancy and birth , need for pharmacological therapy , maternal body mass and body fat percentage gains during pregnancy , and neonatal Apgar scores , body mass and ponderal index . Neonatal body mass index was higher in the experimental group ( P=0.035 ) . CONCLUSION The structured exercise programme had a beneficial effect on postpr and ial glucose levels at the end of pregnancy [21895947] Please cite this paper as : Nascimento S , Surita F , Parpinelli M , Siani S , Pinto e Silva J. The effect of an antenatal physical exercise programme on maternal/perinatal outcomes and quality of life in overweight and obese pregnant women : a r and omised clinical trial . BJOG 2011;118:1455–1463 [7674866] To investigate the effects of participation in aerobic exercise on pregnancy outcome , 388 women ( mean age = 31.7 , range = 18 - 42 ) were followed from a mean 16.5-wk gestation through delivery . Frequency , duration , and mode of aerobic exercise prior to conception and during the first trimester were determined by in-person interviews . Activity patterns during the second and third trimesters were assessed by telephone interviews . For each time period , women were categorized into one of the following exercise groups : Level I = aerobic exercise , excluding vigorous walking , at least three times a week for at least 20 min a time ; Level II = aerobic exercise at least three times a week and 20 min at a time , if and only if vigorous walking is included ; Level III = aerobic exercise less than three times a week , 20 min a time ; and Level IV = aerobic exercise less than once a week . Mean birthweight was statistically unrelated to level of exercise preconceptionally or in any trimester . Gestational age , weight gain , and other pregnancy outcomes were also unassociated with exercise level . However , pregnancy symptoms were inversely associated with level of exercise ; women who exercised more earlier in pregnancy reported fewer discomforts later in pregnancy ( P = 0.01 ) . These data suggest that participation in aerobic exercise during pregnancy at a level great enough to produce or maintain a training effect does not adversely affect birthweight or other maternal and infant outcomes but may be associated temporally with fewer perceived pregnancy-associated discomforts [24652353] OBJECTIVE There is controversy concerning whether exercise during pregnancy may increase preterm delivery risk and type of delivery . The effect of pregnant Latin-American women engaging in vigorous exercise during the second and third trimester was examined regarding type of delivery and gestational age . MATERIAL S AND METHODS This was a secondary analysis of data from a controlled r and omized trial for determining the influence of physical exercise on pregnant women 's endothelial function . The study included 35 nulliparous women , gestational week 16 - 20 attending prenatal care at three tertiary hospitals in Colombia , who were r and omly assigned to one of two groups . The experimental group engaged in aerobic exercise involving 55 % - 75 % maximum heart rate for 60 min , three times a week for 12 weeks . The control group engaged in their usual physical activity . Maternal weight , height , weight gain , blood pressure and type of delivery were recorded ; gender , abdominal and head circumference ( cm ) , weight ( g ) , height ( cm ) , vitality ( Apgar score at 1 and 5 min ) and gestational age at the time of delivery ( in weeks , days ) were recorded for the newborn . RESULTS There was no difference in type of delivery by the end of the 12-week program ( p > 0.05 ) , nor regarding newborn anthropometric variables , Apgar score , or maternal variables concerning weight , height , relative weight gain , blood pressure or weeks of gestation ( p>0.05 ) . CONCLUSION The potential public health benefits of vigorous exercise were enormous . This study supported existing guidelines indicating that Latin-American women may begin or maintain an on-going exercise program during pregnancy . TRIAL REGISTRATION NCT00741312 [5629829] Background : In this study , we aim ed to determine comprehensive maternal characteristics associated with birth weight using Bayesian modeling . Material s and Methods : A total of 526 participants were included in this prospect i ve study . Nutritional status , supplement consumption during the pregnancy , demographic and socioeconomic characteristics , anthropometric measures , physical activity , and pregnancy outcomes were considered as effective variables on the birth weight . Bayesian approach of complex statistical models using Markov chain Monte Carlo approach was used for modeling the data considering the real distribution of the response variable . Results : There was strong positive correlation between infant birth weight and the maternal intake of Vitamin C , folic acid , Vitamin B3 , Vitamin A , selenium , calcium , iron , phosphorus , potassium , magnesium as micronutrients , and fiber and protein as macronutrients based on the 95 % high posterior density regions for parameters in the Bayesian model . None of the maternal characteristics had statistical association with birth weight . Conclusion : Higher maternal macro- and micro-nutrient intake during pregnancy was associated with a lower risk of delivering low birth weight infants . These findings support recommendations to exp and intake of nutrients during pregnancy to high level [2890340] OBJECTIVE To examine the feasibility of an individualized exercise program to prevent gestational diabetes mellitus ( GDM ) in obese pregnant women . RESEARCH DESIGN AND METHODS The study was a pilot r and omized controlled trial with obese pregnant women ( intervention group , individualized exercise program [ n = 25 ] ; control group , usual care [ n = 25 ] ) . Average weekly energy expenditure ( MET hours per week and kilocalories per week ) of exercise-specific activity was assessed during pregnancy using the Pregnancy Physical Activity Question naire . Fasting glucose and insulin and homeostasis model assessment of insulin resistance ( HOMA-IR ) were assessed at baseline and 20 , 28 , and 36 weeks ' gestation . RESULTS Of the women in the intervention group , 16 of 22 ( 73 % ) achieved more than 900 kcal/week of exercise-based activity at 28 weeks compared with 8 of 19 women in the control group ( 42 % ) , P = 0.047 . However , insulin resistance ( HOMA-IR ) did not differ between the groups . CONCLUSION This intervention was feasible and prompted a modest increase in physical activity . However , we are not confident that this intervention would be sufficient to prevent GDM [937989] One hundred and three primigravidae were studied to establish the correlation between physical fitness and heart volume . Twenty-three of the mothers were allocated at r and om to the exercise group and 21 to control group 1 , between the 10th and 14th weeks of pregnancy . In addition , 59 mothers were allocated to control group 2 , which was formed two weeks before term . The exercise group underwent a rather strenuous training programme during pregnancy . Physical fitness was measured by work tests on a bicycle ergometer two weeks before term . The heart volume was determined radiologically on the 6th day post partum . There was a positive correlation between physical fitness and the relative heart volume , which was greatest when physical fitness was measured by a method which takes the level of training into consideration . The relative heart volume of the exercise group was almost significantly greater than that of control group 1 . The physical performance of the exercise group was very significantly greater than in the control groups . There was no significant correlation between either physical fitness or relative heart volume and the duration of pregnancy or the weight of newborn [4428637] Methods We are conducting a parallel arm r and omized controlled clinical trial in Auckl and , New Zeal and ( NZ ) . Eligible participants were enrolled to the study from March 2013 to April 2014 . The intervention group participated in a 16-week home-based moderate-intensity exercise programme utilising stationary cycles and heart rate monitors . Maternal measures including weight , aerobic fitness , physical activity and diet were assessed at baseline and end of intervention . Neonatal and maternal body composition were assessed 14 days after delivery [25333246] PURPOSE The objective of this study is to assess the effectiveness of a maternal exercise program ( l and /aquatic activities , both aerobic and muscular conditioning ) in preventing gestational diabetes mellitus ( GDM ) . METHODS Three hundred and forty-two pregnant women from Spain ( age , 33.24 ± 4.3 yr ) without obstetric contraindications were recruited for a clinical r and omized controlled trial . The intervention group ( IG , n = 101 ) exercised for 60 and 50 min on l and and in water , respectively , three times per week . The control group ( n = 156 ) received usual st and ard care . RESULTS The prevalence of GDM was reduced in the IG group ( IG , 1 % , n = 1 , vs control group , 8.8 % , n = 13 ( χ1 = 6.84 , P = 0.009 ) ) with a significant risk estimate ( odds ratio = 0.103 ; 95 % confidence interval , 0.013 - 0.803 ) . CONCLUSION The exercise program performed during pregnancy reduced the prevalence of GDM by preserving glucose tolerance [24200335] Purpose . The aim of the present study was to examine the influence of a program of moderate physical exercise throughout pregnancy on maternal and fetal parameters . Design . The study design was a r and omized controlled trial . Setting . The study took place at the Hospital of Fuenlabrada in Madrid , Spain . Sample . Analyzed were 200 pregnant women ( 31.54 ± 3.86 years ) , all of whom had uncomplicated and singleton gestation . Of these subjects , 107 were allocated to the exercise group ( EG ) and 93 to the control group ( CG ) . Intervention . Women from EG participated in a physical conditioning program throughout pregnancy , which included a total of 55- to 60-minute weekly sessions , 3 days per week . Measures . Pregnancy outcomes . Maternal : gestational age , weight gain , type of delivery , blood pressure during pregnancy , gestational diabetes ( n/% ) . Fetal : birth weight , birth size , head circumference , Apgar score , pH of umbilical cord . Analysis . Student 's unpaired t-test and χ2 test were used ; p values of ≤ .05 indicated statistical significance . Cohen 's d was used to determine the effect size . Results . There were significantly more pregnant women in the CG who gained excessive weight during their pregnancies than in the EG group ( CG : N = 31 , 35.6 % versus N = 22 , 21.2 % ; χ2 = 4.95 ; p = .02 ) . The effect size was small ( Phi value = .16 ) . Other pregnancy outcome showed no differences between groups . Conclusion . A regular and moderate physical exercise program throughout pregnancy is not a risk to maternal and fetal well-being , and it helps to control excessive weight gain [22616913] Please cite this paper as : Oostdam N , van Poppel M , Wouters M , Eekhoff E , Bekedam D , Kuchenbecker W , Quartero H , Heres M , van Mechelen W. No effect of the FitFor2 exercise programme on blood glucose , insulin sensitivity , and birthweight in pregnant women who were overweight and at risk for gestational diabetes : results of a r and omised controlled trial . BJOG 2012;119:1098–1107 [9704242] We sought to test the hypothesis that long-term postnatal development may be modified by metabolic experiences in utero . We enrolled offspring of women with pregestational diabetes ( this included type 1 and type 2 diabetes ) and gestational diabetes in a prospect i ve study from 1977 to 1983 . Fetal beta-cell function was assessed by measurement of amniotic fluid insulin ( AFI ) concentration at 32 - 38 weeks ' gestation . Postnatally , offspring were seen yearly for neuropsychological testing , measurement of anthropometrics , and modified glucose tolerance testing . Neuropsychological control subjects were followed longitudinally . Additional control subjects had anthropometrics measured once , and a r and om subset of these had a single oral glucose challenge at 10 - 16 years . The rates of major neuropsychological disturbances in our cohort did not differ significantly from national estimates . However , aberrant maternal metabolism was associated with poorer intellectual performance and psychomotor development . The macrosomia observed at birth in offspring of diabetic mothers ( ODM ) resolves by 1 year of age . Obesity recurs in childhood ; and by 14 - 17 years , the mean BMI is 24.6 + /- 5.8 kg/m2 in ODM versus 20.9 + /- 3.4 kg/m2 in control subjects . Obesity in adolescence is associated with sex , mother 's weight , and AFI concentration . Impaired glucose tolerance ( IGT ) is found in 36 % of ODM and is also associated with elevated amniotic fluid insulin in utero . In confirmation of our original hypothesis , aberrant maternal metabolism is associated with poorer intellectual and psychomotor development , obesity , and IGT in offspring . Excessive insulin secretion in utero , as assessed by AFI concentration , is a predictor of both obesity and IGT in adolescence . This study is a long-term prospect i ve evaluation of the effects of maternal diabetes on pregnant women and their offspring . In this article , we report the results of the correlations between indexes of maternal and fetal metabolism during pregnancy and the offspring 's subsequent physical , metabolic , and psychological development from birth through adolescence [16008324] To study the efficacy of yoga on the outcome of complicated pregnancy , 121 women attending antenatal clinic at Gunasheela Surgical and Maternity Hospital ( GSMH ) in Bangalore , India , were enrolled between 18 - 20 weeks of pregnancy in a prospect i ve , matched , observational study . Sixty-eight women were in the yoga group and 53 women in the control group . Women were matched for age , gravida and Doppler velocimetry scores of umbilical and uterine arteries . Yoga practice s including physical postures , breathing and meditation were practised by the yoga group , one hour daily , from the date of entry into the study until delivery . The control group walked half an hour twice a day during the study period . Compliance in both the groups was ensured . In babies the birth-weight is significantly higher ( P < 0.018 ) in the Yoga group ( 2.78 + /- 0.52 kg ) , compared to the control group ( 2.55 + /- 0.52 kg ) . Occurrence of complications of pregnancy ( pregnancy-induced hypertension , intrauterine growth retardation , pre-term delivery ) shows lower trends in yoga group [22843114] OBJECTIVE A prospect i ve r and omized controlled trial was design ed to assess the benefits and possible risks of aerobic exercise during pregnancy , using a fitness regimen based on the 2002 American College of Obstetricians and Gynecologists guidelines for exercise during pregnancy . METHODS Inactive women were r and omized at 12 - 14 wk gestation to a group that remained sedentary or to a group that performed moderate aerobic exercise 45 - 60 min , 4 d·wk , through 36 wk gestation . Thirty-one subjects in each group completed the study . RESULTS Compared with women who remained sedentary , active women improved aerobic fitness ( P < 0.05 ) and muscular strength ( P < 0.01 ) , delivered comparable size infants with significantly fewer cesarean deliveries ( P < 0.01 ) , and recovered faster postpartum ( P < 0.05 ) , at least related to the lower incidence of cesarean section . Active women developed no gestational hypertension ( P = 0.16 compared with controls ) and reported no injuries related to the exercise regimen . In the active group , there was one premature birth at 33 wk by a woman with a history of premature delivery of twins at 34 wk . There were no differences between groups in the incidence of gestational diabetes , musculoskeletal pains during pregnancy , flexibility on sit- and -reach test , mean length of pregnancy , neonatal Apgar scores , placenta weights , overall length of labor , weight gain during pregnancy , or weight retention postpartum . CONCLUSION Previously sedentary women who began exercising at 12 - 14 wk improved fitness and delivery outcomes [20335449] CONTEXT Epidemiological studies have identified the importance of the in utero environment in providing a healthy start to life . Previous studies have suggested that the maternal environment , in particular a reduction in maternal insulin sensitivity , contributes significantly to fetal growth . Regular aerobic exercise , through an effect on maternal insulin sensitivity , may influence offspring size by regulating nutrient supply to the fetus . OBJECTIVE The aim of the study was to determine the effects of aerobic exercise training in the second half of pregnancy on maternal insulin sensitivity and neonatal outcomes . DESIGN AND SETTING We conducted a community-based , r and omized , controlled trial of exercise in pregnancy . PARTICIPANTS Eighty-four healthy nulliparous women ( mean + /- sd , age , 30 + /- 4 yr ; body mass index , 25.5 + /- 4 kg/m(2 ) ) participated in the study . INTERVENTION Subjects participated in a home-based stationary cycling program from 20 wk gestation to delivery . MAIN OUTCOME MEASURES Maternal insulin sensitivity , neonatal auxology , body composition , and growth-related peptides in cord blood were measured . RESULTS Offspring of exercisers had lower birth weight ( sd score , control , 0.23 + /- 0.8 ; exercise , -0.19 + /- 0.9 ; P = 0.03 ) and body mass index at birth ( sd score , control , 0.40 + /- 0.9 ; exercise , -0.01 + /- 0.09 ; P = 0.04 ) . The reduction in maternal insulin sensitivity in late gestation was not affected by exercise ( P = 0.45 ) and was unrelated to offspring size . Exercise offspring had lower cord serum IGF-I ( P = 0.03 ) and IGF-II ( P = 0.04 ) . CONCLUSIONS Regular exercise was associated with lower birth weights and reduced cord concentrations of growth-related peptides , suggesting an influence of exercise on endocrine regulation of fetal growth . These effects on offspring growth were not associated with an exercise training effect on maternal insulin sensitivity [23676311] BACKGROUND In spite of an extensive knowledge of the physiologic features of exercise during pregnancy , we still lack a comprehensive underst and ing of the effects of different types , intensities and duration of exercise throughout pregnancy on maternal and fetal well being . The aim of the current study was to examine the influence of an aerobic exercise program throughout pregnancy on gestational age at the moment of delivery . METHODS This study was a r and omized controlled trial . Three hundred and twenty Caucasian ( Spanish ) healthy pregnant women with singleton gestation were r and omly assigned to either an exercise ( n = 160 ) or a control ( n = 160 ) group . Gestational age ( weeks ) and other outcomes were measured . The exercise program included 85 sessions ( general fitness class , 3 times/week , 55 - 60 min/session from weeks 8 - 10 to weeks 38 - 39 of pregnancy ) . RESULTS Two hundred and ninety women were analyzed ( exercise group EG , n = 138 , control group CG , n = 152 ) . The mean gestational age did not differ between groups ( EG= 39.7 ± 1.3 vs CG= 39.6 ± 1.1 weeks , P = .81 ) . Relative to preterm deliveries in EG we found 6 ( 4.3 % ) and 11 ( 7.2 % ) in CG , ( P = .73 ) . CONCLUSIONS A supervised program of moderate exercise performed throughout pregnancy is not a risk of preterm delivery for healthy pregnant women [26105368] INTRODUCTION Physical activity ( PA ) has been proposed as an important part of hypertension 's treatment and has been studied as a possibility for the prevention of preeclampsia ( PE ) and its complications . PA is recommended during pregnancy because it may be beneficial to maternal health . However , some studies relate the difficulty in adherence to exercise during pregnancy . OBJECTIVES The objective of this study was to evaluate the adherence to exercise with bicycle in pregnant women with risk of preeclampsia development and characterize these pregnants . METHODS This is a secondary analysis of a r and omized clinical trial at the Women 's Hospital Dr. José Aristodemo Pinotti - CAISM/Unicamp , Brazil . We enrolled 116 pregnant women presenting with chronic hypertension ( CH ) , previous PE or both factors associated ( risk of PE development ) . Women from 12 to 20 gestational weeks were selected from the prenatal outpatient clinic and r and omly allocated to the study ( SG ) or non-interventional group ( NIG ) . Women at the SG performed exercise using stationary bicycle ( horizontal bench model ) during 30min , once a week , under a physical therapist supervision . The HR was maintained at 20 % above resting heart rate and up to 140 beats per minute , and the BP was evaluated before and after exercise . The NIG followed regular prenatal routine with weekly returns for HR and BP measurements . We analyzed the adherence of the SG to exercise with bicycle and their sociodemographic and clinical characteristics . RESULTS We invited 152 pregnants to participate and 33 ( 21.7 % ) refused . 116 pregnants were r and omized and 58 were allocated to the SG . The mean age was 31.7±6.2 and mean of Body Mass Index ( BMI ) was 34.9±7.9kg/m(2 ) . Previous PE were prevalent in 16 ( 27.6 % ) pregnant , CH in 51 ( 87.9 % ) pregnant and 9 ( 15.5(10.5 % ) pregnants relate to exercise before pregnancy . The average sessions performed by the SG using stationary bicycle were 9.24±7.03 . That those who realized less than the mean session of the SG 14 had discontinued , 3 changed the prenatal city , 4 had TPP , 3 had difficulty in controlling blood pressure , 1 had autoimmune hepatitis diagnosis and 1 had fetal malformation . Considering the sociodemographic and clinical characteristics of these 27 the majority were obese and had had CH , they were not used to practice any type of exercise before pregnancy . Most of them were not primiparous , also had more children at home and found difficul to find time for exercise . The majority did not live next to our center . CONCLUSION The majority of our population were obese , sedentary before pregnancy and with CH . In this study exercise , performed once a week , using stationary bicycle in pregnant women of high risk PE , seems to be difficult [20110815] Background : Exercise in pregnancy is recommended in many countries , and swimming is considered by many to be an ideal activity for pregnant women . Disinfection by-products in swimming pool water may , however , be associated with adverse effects on various reproductive outcomes . We examined the association between swimming in pregnancy and preterm and postterm birth , fetal growth measures , small-for-gestational-age , and congenital malformations . Methods : We used self-reported exercise data ( swimming , bicycling , or no exercise ) that were prospect ively collected twice during pregnancy for 74,486 singleton pregnancies . Recruitment to The Danish National Birth Cohort took place 1996–2002 . Using Cox , linear and logistic regression analyses , depending on the outcome , we compared swimmers with physically inactive pregnant women ; to separate a possible swimming effect from an effect of exercise , bicyclists were included as an additional comparison group . Results : Risk estimates were similar for swimmers and bicyclists , including those who swam throughout pregnancy and those who swam more than 1.5 hours per week . Compared with nonexercisers , women who swam in early/mid-pregnancy had a slightly reduced risk of giving birth preterm ( hazard ratio = 0.80 [ 95 % confidence interval = 0.72–0.88 ] ) or giving birth to a child with congenital malformations ( odds ratio = 0.89 [ 0.80–0.98 ] ) . Conclusions : These data do not indicate that swimming in pool water is associated with adverse reproductive outcomes [25615706] Purpose . The aim of the present study was to examine the influence of moderate physical exercise throughout pregnancy on the duration of labor stages . Design . Study was a r and omized controlled trial . Setting . The study took place at Hospital Puerta de Hierro and Hospital Severo Ochoa in Madrid , Spain . Subjects . We examined 166 pregnant women ( 31.6 ± 3.8 years ) , and all had uncomplicated and singleton gestation . Of these 83 were allocated to the exercise group ( EG ) and 83 to the control group ( CG ) . Intervention . Women from the EG participated in a physical conditioning program throughout pregnancy , which included 55- to 60-minute sessions , 3 days per week . Measures . Pregnancy outcomes were measured : duration of labor stages , gestational age , weight gain , type of delivery , birth weight , birth size , head circumference , Apgar score , pH of umbilical cord . Analysis . Student 's unpaired t-tests and χ2 tests were used ; p values of < .05 indicated statistical significance . Cohen 's d was used to determine the effect size . Results . Significant differences were found in the duration of the first stage of labor ( EG = 389.6 ± 347.64 minutes vs. CG = 515.72 ± 353.36 minutes ; p = .02 , effect size Cohen 's d = .36 ) . The second and third stages did not differ between the study groups . Conclusion . A physical exercise program during pregnancy is associated with a shorter first stage of labor . These results may have important relevance to public health Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: Objective We aim ed to identify the relationship between maternal prenatal exercise and birth complications , and neonatal and childhood morphometric , metabolic and developmental outcomes . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

25864059

[4194375] Background Overweight and obesity is a significant health concern during pregnancy . Our aim was to investigate the effect of providing antenatal dietary and lifestyle advice to women who are overweight or obese on components of maternal diet and physical activity . Methods We conducted a r and omised controlled trial , in which pregnant women with a body mass index ≥25 kg/m2 , and singleton gestation between 10 + 0 to 20 + 0 weeks were recruited and r and omised to Lifestyle Advice ( involving a comprehensive dietary and lifestyle intervention over their pregnancy ) or St and ard Care . Within the intervention group , we conducted a nested r and omised trial in which a subgroup of women were further r and omised to receive access to supervised group walking sessions in addition to the st and ard information presented during the intervention contacts ( the Walking group ) or st and ard information only . The outcome measures were maternal dietary intake , ( including food groups , macronutrient and micronutrient intake , diet quality ( using the Healthy Eating Index ; HEI ) , dietary glycaemic load , and glycaemic index ) and maternal physical activity . Women completed the Harvard Semi-Structured Food Frequency Question naire , and the Short Question naire to Assess Health-enhancing Physical Activity ( SQUASH ) , at trial entry , 28 and 36 weeks ’ gestational age , and 4 months postpartum . Analyses were performed on an intention-to-treat basis , using linear mixed effects models with adjustment for the stratification variables . Results Women r and omised to Lifestyle Advice demonstrated a statistically significant increase in the number of servings of fruit and vegetables consumed per day , as well as increased consumption of fibre , and reduced percentage energy intake from saturated fats ( P < 0.05 for all ) . Maternal HEI was significantly improved at both 28 ( 73.35 ± 6.62 versus 71.86 ± 7.01 ; adjusted difference in means 1.58 ; 95 % CI 0.89 to 2.27 ; P < 0.0001 ) and 36 ( 72.95 ± 6.82 versus 71.17 ± 7.69 ; adjusted difference in means 1.77 ; 95 % CI 1.01 to 2.53 ; P < 0.0001 ) weeks . There were no differences in dietary glycaemic index or glycaemic load . Women r and omised to Lifestyle Advice also demonstrated greater total physical activity ( adjusted difference in means 359.76 metabolic equivalent task units ( MET ) minutes/week ; 95 % CI 74.87 to 644.65 ; P = 0.01 ) compared with women receiving St and ard Care . The supervised walking group was poorly utilised . Conclusions For women who are overweight or obese , antenatal lifestyle advice improves maternal diet and physical activity during pregnancy . Please see related articles : http://www.biomed central .com/1741 - 7015/12/163 and http://www.biomed central .com/1741 - 7015/12/201.Trial registration Australian and New Zeal and Clinical Trials Registry ( http://ACTRN12607000161426 [3219553] Background Obesity is a significant global health problem , with the proportion of women entering pregnancy with a body mass index greater than or equal to 25 kg/m2 approaching 50 % . Obesity during pregnancy is associated with a well-recognised increased risk of adverse health outcomes both for the woman and her infant , however there is more limited information available regarding effective interventions to improve health outcomes .The aims of this r and omised controlled trial are to assess whether the implementation of a package of dietary and lifestyle advice to overweight and obese women during pregnancy to limit gestational weight gain is effective in improving maternal , fetal and infant health outcomes . Methods / Design Design : Multicentred r and omised , controlled trial . Inclusion Criteria : Women with a singleton , live gestation between 10 + 0 - 20 + 0 weeks who are obese or overweight ( defined as body mass index greater than or equal to 25 kg/m2 ) , at the first antenatal visit . Trial Entry & R and omisation : Eligible , consenting women will be r and omised between 10 + 0 and 20 + 0 weeks gestation using a central telephone r and omisation service , and r and omisation schedule prepared by non- clinical research staff with balanced variable blocks . Stratification will be according to maternal BMI at trial entry , parity , and centre where planned to give birth . Treatment Schedules : Women r and omised to the Dietary and Lifestyle Advice Group will receive a series of inputs from research assistants and research dietician to limit gestational weight gain , and will include a combination of dietary , exercise and behavioural strategies . Women r and omised to the St and ard Care Group will continue to receive their pregnancy care according to local hospital guidelines , which does not currently include routine provision of dietary , lifestyle and behavioural advice . Outcome assessors will be blinded to the allocated treatment group . Primary Study Outcome : infant large for gestational age ( defined as infant birth weight ≥ 90th centile for gestational age ) . Sample Size : 2,180 women to detect a 30 % reduction in large for gestational age infants from 14.40 % ( p = 0.05 , 80 % power , two-tailed ) . Discussion This is a protocol for a r and omised trial . The findings will contribute to the development of evidence based clinical practice guidelines .Trial Registration Australian and New Zeal and Clinical Trials Registry [3669050] Background Gestational Diabetes Mellitus ( GDM ) has well recognised adverse health implication s for the mother and her newborn that are both short and long term . Obesity is a significant risk factor for developing GDM and the prevalence of obesity is increasing globally . It is a matter of public health importance that clinicians have evidence based strategies to inform practice and currently there is insufficient evidence regarding the impact of dietary and lifestyle interventions on improving maternal and newborn outcomes . The primary aim of this study is to measure the impact of a telephone based intervention that promotes positive lifestyle modifications on the incidence of GDM . Secondary aims include : the impact on gestational weight gain ; large for gestational age babies ; differences in blood glucose levels taken at the Oral Glucose Tolerance Test ( OGTT ) and selected factors relating to self-efficacy and psychological wellbeing . Method / design A r and omised controlled trial ( RCT ) will be conducted involving pregnant women who are overweight ( BMI > 25 to 29.9 k/gm2 ) or obese ( BMI > 30 kgm/2 ) , less than 14 weeks gestation and recruited from the Barwon South West region of Victoria , Australia . From recruitment until birth , women in the intervention group will receive a program informed by the Theory of Self-efficacy and employing Motivational Interviewing . Brief ( less than 5 minute ) phone contact will alternate with a text message/email and will involve goal setting , behaviour change reinforcement with weekly weighing and charting , and the provision of health information . Those in the control group will receive usual care . Data for primary and secondary outcomes will be collected from medical record review and a question naire at 36 weeks gestation . Discussion Evidence based strategies that reduce the incidence of GDM are a priority for contemporary maternity care . Changing health behaviours is a complex undertaking and trialling a composite intervention that can be adopted in various primary health setting s is required so women can be accessed as early in pregnancy as possible . Using a sound theoretical base to inform such an intervention will add depth to our underst and ing of this approach and to the interpretation of results , contributing to the evidence base for practice and policy . Trial registration This trial is registered with the Australian New Zeal and Clinical Trials Registry ( ANZCTR ) : [3565864] Background The costs of gestational diabetes mellitus ( GDM ) screening have been frequently reported , but total GDM-related health care costs compared to the health care costs of women without GDM have not been reported . The aim of this study was to analyse GDM-related health care costs among women with an elevated risk of GDM . Methods The study was based on a cluster-r and omised GDM prevention trial ( N = 848 ) carried out at maternity clinics , combined with data from the Finnish Medical Birth Register and Care Registers for Social Welfare and Health Care . Costs of outpatient visits to primary and secondary care , cost of inpatient hospital care before and after delivery , the use of insulin , delivery costs and babies ’ stay in the neonatal intensive care unit were analysed . Women who developed GDM were compared to those who were not diagnosed with GDM . Results Total mean health care costs adjusted for age , body mass index and education were 25.1 % higher among women diagnosed with GDM ( € 6,432 vs. € 5,143 , p < 0.001 ) than among women without GDM . The cost of inpatient visits was 44 % higher and neonatal intensive care unit use was 49 % higher in the GDM group than among women without GDM . The delivery costs were the largest single component in both groups . Conclusions A confirmed GDM diagnosis was associated with a significant increase in total health care costs . Effective lifestyle counselling by primary health care providers may offer a means of reducing the high costs of secondary care [3403888] Background Fetal conditions are known to be partly responsible for the child ’s risk for obesity . Our pilot study aim ed to determine the effect of gestational lifestyle counseling on the offspring weight gain until 4 years of age and to estimate power for future studies . Design and methods First-time pregnant mothers participated in a controlled trial conducted in maternity health clinics during 2004 – 2006 . The intervention included individual counseling on physical activity and diet , and an option to attend supervised group exercise sessions . The participant mothers ( N = 109 ) received a follow-up question naire concerning 13 repeated growth measurements of their offspring . Response rate to the follow-up question naire was 66.1 % ( N = 72/109 ) . Results The increase of BMI z-score between 24–48 months was not significantly slower among the intervention group offspring ( 95 % CI −0.025 to 0.009 , p = 0.34 ) compared to control group . Z-scores for weight-for-length/height did not differ between groups when the period 0–48 months was analyzed ( 95 % CI −0.010 to 0.014 , p = 0.75 ) . Conclusions In this pilot study gestational lifestyle counseling did not significantly slow the weight gain of the offspring . Gestational intervention studies with at least 300 mothers per group are needed to confirm the possible effect on offspring ’s risk for obesity . Trial registration Current Controlled Trials IS RCT N21512277 [3078095] Background In conjunction with the growing prevalence of obesity and the older age of pregnant women gestational diabetes ( GDM ) is a major health problem . The aim of the study was to evaluate if a lifestyle intervention since early pregnancy is feasible in improving the glucose tolerance of women at a high-risk for GDM in Finl and . Methods A 75-g oral glucose tolerance test ( OGTT ) was performed in early pregnancy ( n = 102 ) . Women at high risk for GDM ( n = 54 ) were r and omized at weeks 8 - 12 from Apr 2005 to May 2006 to a lifestyle intervention group ( n = 27 ) or to a close follow-up group ( n = 27 ) . An OGTT was performed again at weeks 26 - 28 for the lifestyle intervention and close follow-up groups . Results The values of the OGTT during the second trimester did not differ between the lifestyle intervention and close follow-up groups . In the lifestyle intervention group three women had GDM in the second trimester and respectively one woman in the close follow up group . Insulin therapy was not required in both groups . The intervention result ed in somewhat lower weight gain 11.4 ± 6.0 kg vs. 13.9 ± 5.1 kg , p = 0.062 , adjusted by the prepregnancy weight . Conclusions Early intervention with an OGTT and simple lifestyle advice is feasible . A more intensive lifestyle intervention did not offer additional benefits with respect to glucose tolerance , although it tended to ameliorate the weight gain . Trial Registration Clinical Trials.gov : [3295699] Background Pregnancy is a time of significant physiological and physical change for women . In particular , it is a time at which many women are at risk of gaining excessive weight . We describe the rationale and methods of the Health in Pregnancy and Post-birth ( HIPP ) Study , a study which aims primarily to determine the effectiveness of a specialized health coaching ( HC ) intervention during pregnancy , compared to education alone , in preventing excessive gestational weight gain and postpartum weight retention 12 months post birth . A secondary aim of this study is to evaluate the mechanisms by which our HC intervention impacts on weight management both during pregnancy and post birth . Methods / Design The r and omized controlled trial will be conducted with 220 women who have a BMI > 18.5 ( American IOM cut-off for normal weight ) , are 18 years of age or older , English speaking , no history of disordered eating or diabetes and are less than 18 weeks gestation at recruitment . Women will be r and omly allocated to either a specialized HC intervention group or an Education Alone group . Our specialized HC intervention has two components : ( 1 ) one-on-one sessions with a Health Coach , and ( 2 ) two by two hour educational group sessions led by a Health Coach . Women in the Education Alone group will receive two by two hour educational group sessions with no HC components . Body Mass Index , waist circumference , and psychological factors including motivation , readiness to change , symptoms of depression and anxiety , and body dissatisfaction will be assessed at baseline ( 14 - 16 weeks gestation ) , and again at follow-up : 32 weeks gestation , 6 weeks , 6 months and 12 months postpartum . Discussion Our study responds to the urgent need to design effective interventions in pregnancy to prevent excessive gestational weight gain and postpartum weight retention . Our pregnancy HC intervention is novel and innovative and has been design ed to be easily adopted by health professionals who work with pregnant women , such as obstetricians , midwives , allied health professionals and health psychologists . Trial registration Australian New Zeal and Clinical Trials Registry [3938821] Background Despite the widespread recognition that obesity in pregnant women is associated with adverse outcomes for mother and child , there is no intervention proven to reduce the risk of these complications . The primary aim of this r and omised controlled trial is to assess in obese pregnant women , whether a complex behavioural intervention , based on changing diet ( to foods with a lower glycemic index ) and physical activity , will reduce the risk of gestational diabetes ( GDM ) and delivery of a large for gestational age ( LGA ) infant . A secondary aim is to determine whether the intervention lowers the long term risk of obesity in the offspring . Methods / Design Multicentre r and omised controlled trial comparing a behavioural intervention design ed to improve glycemic control with st and ard antenatal care in obese pregnant women . Inclusion criteria ; women with a BMI ≥30 kg/m2 and a singleton pregnancy between 15 + 0 weeks and 18 + 6 weeks ’ gestation . Exclusion criteria ; pre-defined , pre-existing diseases and multiple pregnancy . R and omisation is on-line by a computer generated programme and is minimised by BMI category , maternal age , ethnicity , parity and centre . Intervention ; this is delivered by a health trainer over 8 sessions . Based on control theory , with elements of social cognitive theory , the intervention is design ed to improve maternal glycemic control . Women r and omised to the control arm receive st and ard antenatal care until delivery according to local guidelines . All women have a 75 g oral glucose tolerance test at 27 + 0- 28 + 6 weeks ’ gestation . Primary outcome ; Maternal : diagnosis of GDM , according to the International Association of Diabetes in Pregnancy Study Group ( IADPSG ) criteria . Neonatal ; infant LGA defined as > 90th customised birth weight centile . Sample size ; 1546 women to provide 80 % power to detect a 25 % reduction in the incidence of GDM and a 30 % reduction in infants large for gestational age . Discussion All aspects of this protocol have been evaluated in a pilot r and omised controlled trial , with subsequent optimisation of the intervention . The findings of this trial will inform whether lifestyle mediated improvement of glycemic control in obese pregnant women can minimise the risk of pregnancy complications . Trial registration Current controlled trials ; IS RCT N89971375 [4194368] Background Overweight and obesity during pregnancy represents a considerable health burden . While research has focused on interventions to limit gestational weight gain , there is little information describing their impact on neonatal health . Our aim was to investigate the effect on a range of pre-specified secondary neonatal outcomes of providing antenatal dietary and lifestyle advice to women who are overweight or obese . Methods We report a range of pre-specified secondary neonatal outcomes from a large r and omised trial in which antenatal dietary and lifestyle advice was provided to women who were overweight or obese . Pregnant women were eligible for participation with a body mass index of 25 kg/m2 or over , and singleton gestation between 10 + 0 and 20 + 0 weeks . Outcome measures included gestational age at birth ; Apgar score below 7 at 5 minutes of age ; need for resuscitation at birth ; birth weight above 4.5 kg or below 2.5 kg ; birth weight , length and head circumference ( and Z-scores ) ; admission to the nursery ; respiratory distress syndrome ; and postnatal length of stay . Data relating to the primary outcome ( large for gestational age infants defined as birth weight above the 90th centile ) and birth weight above 4 kg have been reported previously . Analyses used intention-to-treat principles . Results In total , 2,142 infants were included in the analyses . Infants born to women following lifestyle advice were significantly less likely to have birth weight above 4.5 kg ( 2.15 % versus 3.69 % ; adjusted risk ratio ( aRR ) = 0.59 ; 95 % confidence interval ( CI ) 0.36 to 0.98 ; P = 0.04 ) , or respiratory distress syndrome ( 1.22 % versus 2.57 % ; aRR = 0.47 ; 95 % CI 0.24 to 0.90 ; P = 0.02 ) , particularly moderate or severe disease , and had a shorter length of postnatal hospital stay ( 3.94 ± 7.26 days versus 4.41 ± 9.87 days ; adjusted ratio of means 0.89 ; 95 % CI 0.82 to 0.97 ; P = 0.006 ) compared with infants born to women who received St and ard Care . Conclusions For women who are overweight or obese , antenatal dietary and lifestyle advice has health benefits for infants , without an increase in the risk of harm . Continued follow-up into childhood will be important to assess the longer-term effects of a reduction in high infant birth weight on risk of child obesity . Please see related articles : http://www.biomed central .com/1741 - 7015/12/161 and http://www.biomed central .com/1741 - 7015/12/201 . Clinical trial registration Australian and New Zeal and Clinical Trials Registry ( http://ACTRN12607000161426 [24122103] Oxidized LDL lipids ( ox-LDL ) are associated with lifestyle diseases such as cardiovascular diseases , metabolic syndrome and type 2 diabetes . The present study investigated how postpartum weight retention effects on ox-LDL and serum lipids . The study is a nested comparative research of a cluster-r and omized controlled trial , NELLI ( lifestyle and counselling during pregnancy ) . During early pregnancy ( 8–12 weeks ) and 1 year postpartum , 141 women participated in measurements for determining of plasma lipids : total cholesterol ( T-C ) , LDL-cholesterol ( LDL-C ) , HDL-cholesterol ( HDL-C ) , triacylglycerols ( TAG ) and ox-LDL . Subjects were stratified into tertiles ( weight loss , unaltered weight and weight gain groups ) based on their weight change from baseline to follow-up . Ox-LDL was determined by baseline level of conjugated dienes in LDL lipids . Among the group of weight gainers , concentration of TAG reduced less ( −0.14 vs. −0.33 , p = 0.002 ) , HDL-C reduced more ( −0.31 vs. −0.16 , p = 0.003 ) and ox-LDL/HDL-C ratio increased ( 3.0 vs. −0.2 , p = 0.003 ) when compared to group of weight loss . Both T-C and LDL-C elevated more ( 0.14 vs. −0.21 , p = 0.008 ; 0.31 vs. 0.07 , p = 0.015 ) and TAG and ox-LDL reduced less ( −0.33 vs. 0.20 , p = 0.033 ; −3.33 vs. −0.68 , p = 0.026 ) in unaltered weight group compared to weight loss group . The women who gained weight developed higher TAG and ox-LDL/HDL-C ratio as compared to those who lost weight . Postpartum weight retention of 3.4 kg or more is associated with atherogenic lipid profile [12081815] Reliable tables of glycemic index ( GI ) compiled from the scientific literature are instrumental in improving the quality of research examining the relation between GI , glycemic load , and health . The GI has proven to be a more useful nutritional concept than is the chemical classification of carbohydrate ( as simple or complex , as sugars or starches , or as available or unavailable ) , permitting new insights into the relation between the physiologic effects of carbohydrate-rich foods and health . Several prospect i ve observational studies have shown that the chronic consumption of a diet with a high glycemic load ( GI x dietary carbohydrate content ) is independently associated with an increased risk of developing type 2 diabetes , cardiovascular disease , and certain cancers . This revised table contains almost 3 times the number of foods listed in the original table ( first published in this Journal in 1995 ) and contains nearly 1300 data entries derived from published and unpublished verified sources , representing > 750 different types of foods tested with the use of st and ard methods . The revised table also lists the glycemic load associated with the consumption of specified serving sizes of different foods [6259925] The determine the effect of different foods on the blood glucose , 62 commonly eaten foods and sugars were fed individually to groups of 5 to 10 healthy fasting volunteers . Blood glucose levels were measured over 2 h , and expressed as a percentage of the area under the glucose response curve when the same amount of carbohydrate was taken as glucose . The largest rises were seen with vegetables ( 70 + /- 5 % ) , followed by breakfast cereals ( 65 + /- 5 % ) , cereals and biscuits ( 60 + /- 3 % ) , fruit ( 50 + /- 5 % ) , dairy products ( 35 + /- 1 % ) , and dried legumes ( 31 + /- 3 % ) . A significant negative relationship was seen between fat ( p less than 0.01 ) and protein ( p less than 0.001 ) and postpr and ial glucose rise but not with fiber or sugar content [18582171] OBJECTIVE Studies in predominantly non-Hispanic white population s have suggested that physical activity during pregnancy is associated with a reduced risk of gestational diabetes mellitus ( GDM ) . There are few such studies in Hispanic women , a group at increased risk for GDM . METHODS We conducted a prospect i ve cohort study of household/caregiving , occupational , sports/exercise , and active living habits and the risk of GDM among 1006 Hispanic ( predominantly Puerto Rican ) prenatal care patients in western Massachusetts from 2000 to 2004 . Prepregnancy , early pregnancy , and midpregnancy physical activity was assessed using the Kaiser Physical Activity Survey . RESULTS A total of 33 women ( 3.3 % ) were diagnosed with GDM , and 119 women ( 11.8 % ) were diagnosed with abnormal glucose tolerance . There were no significant associations between GDM risk and occupational and active living activities in prepregnancy , early pregnancy , and midpregnancy or with a change in levels of household/caregiving , occupational , and active living activities from prepregnancy to during pregnancy . However , after controlling for age and prepregnancy body mass index ( BMI ) , women in the highest quartile of prepregnancy ( OR = 0.2 , 95 % CI 0.1 - 0.8 , p(trend ) = 0.03 ) and midpregnancy ( OR = 0.2 , 95 % CI 0.1 - 0.8 , p(trend ) = 0.004 ) household/caregiving activities as well as midpregnancy sports/exercise ( 0.1 , 95 % CI 0.0 - 0.7 , p(trend ) = 0.12 ) had a reduced risk of GDM compared with women in the lowest quartile . CONCLUSIONS Findings in this Hispanic population , although based on small numbers of cases , are consistent with prior research among predominantly non-Hispanic white population [3718707] Background Excessive gestational weight gain ( GWG ) is associated with short- and long-term health problems among mothers and their offspring . There is a strong need for effective intervention strategies targeting excessive GWG to prevent adverse outcomes . Methods We performed a cluster-r and omized controlled intervention trial in eight gynecological practice s evaluating the feasibility and effectiveness of a lifestyle intervention presented to all pregnant women ; 250 healthy , pregnant women were recruited for the study . The intervention program consisted of two individually delivered counseling sessions focusing on diet , physical activity , and weight monitoring . The primary outcome was the proportion of pregnant women exceeding weight gain recommendations of the Institute of Medicine ( IOM ) . Secondary outcome variables were maternal weight retention and short-term obstetric and neonatal outcomes . Results The intervention result ed in a lower proportion of women exceeding IOM guidelines among women in the intervention group ( 38 % ) compared with the control group ( 60 % ) ( odds ratio ( OR ) : 0.5 ; 95 % confidence interval ( CI ) : 0.3 to 0.9 ) without prompting an increase in the proportion of pregnancies with suboptimal weight gain ( 19 % vs. 21 % ) . Participants in the intervention group gained significantly less weight than those in the control group . Only 17 % of the women in the intervention group showed substantial weight retention of more than 5 kg compared with 31 % of those in the control group at month four postpartum ( pp ) ( OR : 0.5 ; 95 % CI : 0.2 to 0.9 ) . There were no significant differences in obstetric and neonatal outcomes . Conclusions Lifestyle counseling given to pregnant women reduced the proportion of pregnancies with excessive GWG without increasing suboptimal weight gain , and may exert favorable effects on pp weight retention . Trial registration German Clinical Trials Register DRKS00003801 [21494772] Aims /hypothesisNew diagnostic criteria for gestational diabetes mellitus ( GDM ) have recently been published . We wished to evaluate what impact these new criteria would have on GDM prevalence and outcomes in a predominantly European population . Methods The Atlantic Diabetes In Pregnancy ( DIP ) programme performed screening for GDM in 5,500 women with an oral glucose tolerance test at 24–28 weeks . GDM was defined according to the new International Association of Diabetes and Pregnancy Study Groups ( IADPSG ) criteria and compared with previous WHO criteria ; maternal and neonatal adverse outcomes were prospect ively recorded . Results Of the participants , 12.4 % and 9.4 % were diagnosed with GDM using IADPSG and WHO criteria , respectively . IADPSG GDM pregnancies were associated with a statistically significant increased incidence of adverse maternal outcomes ( gestational hypertension , polyhydramnios and Caesarean section ) and neonatal outcomes ( prematurity , large for gestational age , neonatal unit admission , neonatal hypoglycaemia and respiratory distress ) . The odds ratio for the development of these adverse outcomes remained significant after adjustment for maternal age , body mass index and non-European ethnicity . Those women who were classified as having normal glucose tolerance by WHO criteria but as having GDM by IADPSG criteria also had significant adverse pregnancy outcomes . Conclusions /interpretationGDM prevalence is higher when using newer IADPSG , compared with WHO , criteria , and these women and their offspring experience significant adverse pregnancy outcomes . Higher rates of GDM pose a challenge to healthcare systems , but improved screening provides an opportunity to attempt to reduce the associated morbidity for mother and child [3718630] Background Complex interventions in obese pregnant women should be theoretically based , feasible and shown to demonstrate anticipated behavioural change prior to inception of large r and omised controlled trials ( RCTs ) . The aim was to determine if a ) a complex intervention in obese pregnant women leads to anticipated changes in diet and physical activity behaviours , and b ) to refine the intervention protocol through process evaluation of intervention fidelity . Methods We undertook a pilot RCT of a complex intervention in obese pregnant women , comparing routine antenatal care with an intervention to reduce dietary glycaemic load and saturated fat intake , and increase physical activity . Subjects included 183 obese pregnant women ( mean BMI 36.3 kg/m2).Diet was assessed by repeated triple pass 24-hour dietary recall and physical activity by accelerometry and question naire , at 16 + 0 to 18 + 6 and at 27 + 0 to 28 + 6 weeks ’ gestation in women in control and intervention arms . Attitudes to behaviour change and quality of life were assessed and a process evaluation undertaken . The full RCT protocol was undertaken to assess feasibility . Results Compared to women in the control arm , women in the intervention arm had a significant reduction in dietary glycaemic load ( 33 points , 95 % CI −47 to −20 ) , ( p < 0.001 ) and saturated fat intake ( −1.6 % energy , 95 % CI −2.8 to −0 . 3 ) at 28 weeks ’ gestation . Objective ly measured physical activity did not change . Physical discomfort and sustained barriers to physical activity were common at 28 weeks ’ gestation . Process evaluation identified barriers to recruitment , group attendance and compliance , leading to modification of intervention delivery . Conclusions This pilot trial of a complex intervention in obese pregnant women suggests greater potential for change in dietary intake than for change in physical activity , and through process evaluation illustrates the considerable advantage of performing an exploratory trial of a complex intervention in obese pregnant women before undertaking a large RCT .Trial registration Trial Registration Number : IS RCT [3919179] Objective To determine the effect of antenatal dietary and lifestyle interventions on health outcomes in overweight and obese pregnant women . Design Multicentre r and omised trial . We utilised a central telephone r and omisation server , with computer generated schedule , balanced variable blocks , and stratification for parity , body mass index ( BMI ) category , and hospital . Setting Three public maternity hospitals across South Australia . Participants 2212 women with a singleton pregnancy , between 10 + 0 and 20 + 0 weeks ’ gestation , and BMI ≥25 . Interventions 1108 women were r and omised to a comprehensive dietary and lifestyle intervention delivered by research staff ; 1104 were r and omised to st and ard care and received pregnancy care according to local guidelines , which did not include such information . Main outcome measures Incidence of infants born large for gestational age ( birth weight ≥90th centile for gestation and sex ) . Prespecified secondary outcomes included birth weight > 4000 g , hypertension , pre-eclampsia , and gestational diabetes . Analyses used intention to treat principles . Results 2152 women and 2142 liveborn infants were included in the analyses . The risk of the infant being large for gestational age was not significantly different in the two groups ( lifestyle advice 203/1075 ( 19 % ) v st and ard care 224/1067 ( 21 % ) ; adjusted relative risk 0.90 , 95 % confidence interval 0.77 to 1.07 ; P=0.24 ) . Infants born to women after lifestyle advice were significantly less likely to have birth weight above 4000 g ( lifestyle advice 164/1075 ( 15 % ) v st and ard care 201/1067 ( 19 % ) ; 0.82 , 0.68 to 0.99 ; number needed to treat ( NNT ) 28 , 15 to 263 ; P=0.04 ) . There were no differences in maternal pregnancy and birth outcomes between the two treatment groups . Conclusions For women who were overweight or obese , the antenatal lifestyle advice used in this study did not reduce the risk delivering a baby weighing above the 90th centile for gestational age and sex or improve maternal pregnancy and birth outcomes . Trial registration Australian and New Zeal and Clinical Trials Registry ( ACTRN12607000161426 ) [3928878] Background Maternal overweight , obesity and consequently the incidence of gestational diabetes are increasing rapidly worldwide . The objective of the study was to assess the efficacy and cost-effectiveness of a combined diet and physical activity intervention implemented before , during and after pregnancy in a primary health care setting for preventing gestational diabetes , later type 2 diabetes and other metabolic consequences . Methods RADIEL is a r and omized controlled multi-center intervention trial in women at high risk for diabetes ( a previous history of gestational diabetes or prepregnancy BMI ≥30 kg/m2 ) . Participants planning pregnancy or in the first half of pregnancy were parallel-group r and omized into an intervention arm which received lifestyle counseling and a control arm which received usual care given at their local antenatal clinics . All participants visited a study nurse every three months before and during pregnancy , and at 6 weeks , 6 and 12 months postpartum . Measurements and laboratory tests were performed on all participants with special focus on dietary and exercise habits and metabolic markers . Of the 728 women [ mean age 32.5 years ( SD 4.7 ) ; median parity 1 ( range 0 - 9 ) ] considered to be eligible for the study 235 were non-pregnant and 493 pregnant [ mean gestational age 13 ( range 6 to 18 ) weeks ] at the time of enrollment . The proportion of nulliparous women was 29.8 % ( n = 217 ) . Out of all participants , 79.6 % of the non-pregnant and 40.4 % of the pregnant women had previous gestational diabetes and 20.4 % of the non-pregnant and 59.6 % of the pregnant women were recruited because of a prepregnancy BMI ≥30 kg/m2 . Mean BMI at first visit was 30.1 kg/m2 ( SD 6.2 ) in the non-pregnant and 32.7 kg/m2 ( SD 5.6 ) in the pregnant group . Discussion To our knowledge , this is the first r and omized lifestyle intervention trial , which includes , besides the pregnancy period , both the prepregnancy and the postpartum period . This study design also provides an opportunity to focus upon the health of the next generation . The study is expected to produce novel information on the optimal timing and setting of interventions and for allocating re sources to prevent obesity and diabetes in women of reproductive age . Trial registration Clinical trials.gov Identifier : [18826999] CONTEXT A past history of gestational diabetes mellitus ( GDM ) confers a very high risk of postpartum development of diabetes , particularly type 2 diabetes . OBJECTIVE The Diabetes Prevention Program ( DPP ) sought to identify individuals with impaired glucose tolerance ( IGT ) and intervene in an effort to prevent or delay their progression to diabetes . This analysis examined the differences between women enrolled in DPP with and without a reported history of GDM . DESIGN The DPP was a r and omized , controlled clinical trial . SETTING The study was a multicenter , National Institutes of Health-sponsored trial carried out at 27 centers including academic and Indian Health Services sites . PATIENTS A total of 2190 women were r and omized into the DPP and provided information for past history of GDM . This analysis addressed the differences between those 350 women providing a past history of GDM and those 1416 women with a previous live birth but no history of GDM . INTERVENTIONS Subjects were r and omized to either st and ard lifestyle and placebo or metformin therapy or to an intensive lifestyle intervention . MAIN OUTCOMES The primary outcome was the time to development of diabetes ascertained by semiannual fasting plasma glucose and annual oral glucose tolerance testing . Assessment s of insulin secretion and insulin sensitivity were also performed . RESULTS Whereas entering the study with similar glucose levels , women with a history of GDM r and omized to placebo had a crude incidence rate of diabetes 71 % higher than that of women without such a history . Among women reporting a history of GDM , both intensive lifestyle and metformin therapy reduced the incidence of diabetes by approximately 50 % compared with the placebo group , whereas this reduction was 49 and 14 % , respectively in parous women without GDM . These data suggest that metformin may be more effective in women with a GDM history as compared with those without . CONCLUSIONS Progression to diabetes is more common in women with a history of GDM compared with those without GDM history despite equivalent degrees of IGT at baseline . Both intensive lifestyle and metformin are highly effective in delaying or preventing diabetes in women with IGT and a history of GDM [23784892] OBJECTIVE Optimizing gestational weight gain ( GWG ) in early pregnancy is of clinical and public health importance , especially in higher risk pregnancies . DESIGN AND METHODS In a robustly design ed , r and omized controlled trial , 228 pregnant women at risk of developing gestational diabetes mellitus ( GDM ) were allocated to either control ( written health information only ) or intervention ( four-session lifestyle program ) . All women received st and ard maternal care . Measures were completed at 12 - 15 and 26 - 28 weeks gestation . Measures included anthropometrics ( weight and height ) , physical activity ( pedometer and International Physical Activity Question naire ) , question naires ( risk perception ) , and GDM screening . RESULTS The mean ( SD ) age [ 31.7 ( 4.5 ) and 32.4 ( 4.7 ) years ] and body mass index [ BMI ; 30.3 ( 5.9 ) and 30.4 ( 5.6 ) kg/m(2 ) ] were similar between control and intervention groups , respectively . By 28 weeks , GWG was significantly different between control and intervention groups [ 6.9 ( 3.3 ) vs. 6.0 ( 2.8 ) kg , P < 0.05 ] . When stratified according to baseline BMI , overweight women in the control group gained significantly more weight compared to overweight women in the intervention group [ 7.8 ( 3.4 ) vs. 6.0 ( 2.2 ) kg , P < 0.05 ] , yet in obese women , GWG was similar in both groups . Physical activity levels declined by 28 weeks gestation overall ( P < 0.01 ) ; however , the intervention group retained a 20 % higher step count compared to controls [ 5,203 ( 3,368 ) vs. 4,140 ( 2,420 ) steps/day , P < 0.05 ] . Overall , GDM prevalence was 22.8 % [ Corrected ] , with a trend toward less cases in the intervention group ( P = 0.1 ) . CONCLUSIONS Results indicate that a low-intensity lifestyle intervention , integrated with antenatal care , optimizes healthy GWG and attenuates physical activity decline in early pregnancy . Efficacy in limiting weight gain was greatest in overweight women and in high-risk ethnically diverse women [3511276] Abstract Background Women who are physically active during early pregnancy have notably lower odds of developing gestational diabetes than do inactive women . The purpose of the intervention was to examine whether intensified physical activity ( PA ) counseling in Finnish maternity care is feasible and effective in promoting leisure-time PA ( LTPA ) among pregnant women at risk of gestational diabetes . Methods Fourteen municipalities were r and omized to intervention ( INT ) and usual care group ( UC ) . Nurses in INT integrated five PA counseling sessions into routine maternity visits and offered monthly group meetings on PA instructed by physiotherapists . In UC conventional practice s were continued . Feasibility evaluation included safety ( incidence of PA-related adverse events ; question naire ) , realization ( timing and duration of sessions , number of sessions missed , attendance at group meetings ; systematic record-keeping of the nurses and physiotherapists ) and applicability ( nurses ’ views ; telephone interview ) . Effectiveness outcomes were weekly frequency and duration of total and intensity-specific LTPA and meeting PA recommendation for health self-reported at 8 - 12 ( baseline ) , 26 - 28 and 36 - 37 weeks ’ gestation . Multilevel analysis with adjustments was used in testing for between-group differences in PA changes . Results The decrease in the weekly days of total and moderate-to-vigorous-intensity LTPA was smaller in INT ( N = 219 ) than in UC ( N = 180 ) from baseline to the first follow-up ( 0.1 vs. -1.2 , p = 0.040 and −0.2 vs. -1.3 , p = 0.016 ) . A similar trend was seen in meeting the PA recommendation ( −11%-points vs. -28%-points , p = 0.06 ) . INT did not experience more adverse events classified as warning signs to terminate exercise than UC , counseling was implemented as planned and viewed positively by the nurses . Conclusions Intensified counseling had no effects on the duration of total or intensity-specific weekly LTPA . However , it was able to reduce the decrease in the weekly frequency of total and moderate-to-vigorous-intensity LTPA from baseline to the end of second trimester and was feasibly embedded into routine practice s . Trial registration IS RCT N 33885819 ( http://www.is rct n.org [22017967] Please cite this paper as : Hui A , Back L , Ludwig S , Gardiner P , Sevenhuysen G , Dean H , Sellers E , McGavock J , Morris M , Bruce S , Murray R , Shen G. Lifestyle intervention on diet and exercise reduced excessive gestational weight gain in pregnant women under a r and omised controlled trial . BJOG 2012;119:70–77 [22453250] PURPOSE This study aim ed to evaluate the effect of an exercise program of two different intensities , with nutritional control , on gestational weight gain ( GWG ) , infant birth weight , and maternal weight retention at 2 months postpartum ( 2 mopp ) . METHODS Pregnant women ( prepregnancy body mass index = 18.5 - 24.9 kg·m ) were r and omized at study entry ( 16 - 20 wk of gestation ) to a low-intensity ( LI , 30 % HR reserve ( HRR ) , n = 23 ) or moderate-intensity ( MI , 70 % HRR , n = 26 ) exercise program , with nutritional control . The exercise program consisted of walking sessions three to four times per week , gradually increasing exercise time from 25 to 40 min per session . Forty-five normal-weight women who did not participate in any structured exercise program during pregnancy and had singleton births were used as a historical control group . RESULTS Total GWG was higher in the control group ( 18.3 ± 5.3 kg ) compared with the LI ( 15.3 ± 2.9 kg , P = 0.01 ) and MI ( 14.9 ± 3.8 kg , P = 0.003 ) groups . During the intervention , GWG was similar in both intervention groups , with weekly rates of weight gain of 0.49 ± 0.1 and 0.47 ± 0.1 kg·wk in the LI and MI groups , respectively . Excessive GWG during the intervention was prevented in 70 % of the women in the LI group and 77 % of those in the MI group . Excessive GWG occurred before the intervention began . At 2 mopp , 18 % and 28 % of the women in the LI and MI groups , respectively , retained ≤2.0 kg compared with only 7 % of those in the control group . Infant birth weight was not different between the groups . CONCLUSIONS Results suggest that a prenatal nutrition and exercise program regardless of exercise intensity , reduced excessive GWG and decreased weight retention at 2 mopp in women of normal weight before pregnancy [4221718] Background Pregnancy is a recognised high risk period for excessive weight gain , contributing to postpartum weight retention and obesity development long-term . We aim ed to reduce postpartum weight retention following a low-intensity , self-management intervention integrated with routine antenatal care during pregnancy . Methods 228 women at increased risk of gestational diabetes , < 15 weeks gestation were r and omised to intervention ( 4 self-management sessions ) or control ( generic health information ) . Outcomes , collected at baseline and 6 weeks postpartum , included anthropometrics ( weight and height ) , physical activity ( pedometer ) and question naires ( health behaviours ) . Results Mean age ( 32.3 ± 4.7 and 31.7 ± 4.4 years ) and body mass index ( 30.4 ± 5.6 and 30.3 ± 5.9 kg/m2 ) were similar between intervention and control groups , respectively at baseline . By 6 weeks postpartum , weight change in the control group was significantly higher than the intervention group with a between group difference of 1.45 ± 5.1 kg ( 95 % CI : -2.86,-0.02 ; p < h0.05 ) overall , with a greater difference in weight found in overweight , but not obese women . Intervention group allocation , higher baseline BMI , GDM diagnosis , country of birth and higher age were all independent predictors of lower weight retention at 6 weeks postpartum on multivariable linear regression . Other factors related to weight including physical activity , did not differ between groups . Conclusions A low intensity intervention , integrated with st and ard antenatal care is effective in limiting postpartum weight retention . Implementation research is now required for scale-up to optimise antenatal health care . Trial registration Australian New Zeal and Clinical Trial Registry Number : ACTRN12608000233325 . Registered 7/5/2008 [19155899] OBJECTIVE : To estimate whether an organized , consistent program of dietary and lifestyle counseling prevents excessive weight gain in pregnancy . METHODS : This r and omized controlled trial assigned women to receive either an organized , consistent program of intensive dietary and lifestyle counseling or routine prenatal care . The primary study outcome was the proportion of patients whose gestational weight gain was within the Institute of Medicine ( IOM ) guidelines . Secondary outcomes included mode of delivery , rate of operative vaginal delivery , neonatal weight , and the incidence of preeclampsia , gestational diabetes mellitus ( GDM ) , vaginal/perineal lacerations , and shoulder dystocia . RESULTS : A total of 100 women were r and omized to the study ( lifestyle counseling 57 , routine prenatal care 43 ) . Baseline demographic characteristics were similar between the study groups . The lifestyle counseling group gained significantly less weight than did the routine prenatal care group ( 28.7±12.5 lb compared with 35.6±15.5 lb , P=.01 ) . The routine prenatal care group had significantly more cesarean deliveries due to “ failure to progress ” ( routine prenatal care 58.3 % compared with lifestyle counseling 25.0 % , P=.02 ) . Across groups , patients who were not adherent to the IOM guidelines had significantly heavier neonates ( adherent 3,203.2±427.2 g compared with not adherent 3,517.4±572.4 g , P<.01 ) . Nulliparous women gained significantly more weight than did parous women ( 36.5±14.5 lb compared with 27.7±12.7 lb , P<.01 ) . The most predictive factor of IOM adherence was having a normal prepregnancy body mass index . No statistically significant differences were noted between the groups in adherence to IOM guidelines , rate of cesarean delivery , preeclampsia , GDM , operative vaginal delivery , or vaginal lacerations . CONCLUSION : An organized , consistent program of dietary and lifestyle counseling did reduce weight gain in pregnancy . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00792480 LEVEL OF EVIDENCE : [15951574] BACKGROUND We conducted a r and omized clinical trial to determine whether treatment of women with gestational diabetes mellitus reduced the risk of perinatal complications . METHODS We r and omly assigned women between 24 and 34 weeks ' gestation who had gestational diabetes to receive dietary advice , blood glucose monitoring , and insulin therapy as needed ( the intervention group ) or routine care . Primary outcomes included serious perinatal complications ( defined as death , shoulder dystocia , bone fracture , and nerve palsy ) , admission to the neonatal nursery , jaundice requiring phototherapy , induction of labor , cesarean birth , and maternal anxiety , depression , and health status . RESULTS The rate of serious perinatal complications was significantly lower among the infants of the 490 women in the intervention group than among the infants of the 510 women in the routine-care group ( 1 percent vs. 4 percent ; relative risk adjusted for maternal age , race or ethnic group , and parity , 0.33 ; 95 percent confidence interval , 0.14 to 0.75 ; P=0.01 ) . However , more infants of women in the intervention group were admitted to the neonatal nursery ( 71 percent vs. 61 percent ; adjusted relative risk , 1.13 ; 95 percent confidence interval , 1.03 to 1.23 ; P=0.01 ) . Women in the intervention group had a higher rate of induction of labor than the women in the routine-care group ( 39 percent vs. 29 percent ; adjusted relative risk , 1.36 ; 95 percent confidence interval , 1.15 to 1.62 ; P<0.001 ) , although the rates of cesarean delivery were similar ( 31 percent and 32 percent , respectively ; adjusted relative risk , 0.97 ; 95 percent confidence interval , 0.81 to 1.16 ; P=0.73 ) . At three months post partum , data on the women 's mood and quality of life , available for 573 women , revealed lower rates of depression and higher scores , consistent with improved health status , in the intervention group . CONCLUSIONS Treatment of gestational diabetes reduces serious perinatal morbidity and may also improve the woman 's health-related quality of life [1523339] Background Preventing excessive weight gain during pregnancy is potentially important in the prevention of overweight and obesity among women of childbearing age . However , few intervention studies aim ing at weight management during pregnancy have been performed and most of these interventions were not as successful as expected . In this paper the design of the New Life(style ) study is described as well as the content of the individually tailored intervention program , which focuses on controlling weight development during pregnancy . Methods The effectiveness of the New Life(style ) intervention program versus usual care by midwives is evaluated in a r and omised controlled trial . Women who expect their first child and visit one of the participating midwifery practice s are included . The intervention is st and ardised in a protocol and executed by trained counsellors with the women who are r and omised in the intervention group . During 5 sessions – at 18 , 22 , 30 and 36 weeks of pregnancy and at 8 weeks postpartum – individual weight gain is discussed in relation to weight gain guidelines for pregnant women of the American Institute of Medicine . Counsellors coach the women to maintain or optimise a healthy lifestyle , in a period of drastic physical and mental changes . Data is collected at 15 , 25 , 35 weeks of pregnancy and at 6 , 26 , and 52 weeks after delivery . Primary outcome measures are body weight , BMI , and skinfold thickness . Secondary outcome measures include physical activity , nutrition and blood levels of factors that are associated with energy homeostasis . Discussion Results of the current RCT will improve the knowledge of determinants of weight gain during pregnancy , weight retention after childbirth and of the effectiveness of the intervention program that is described . Caregivers and research ers in the field of health promotion are offered more insight in specific elements of the New Life(style ) intervention program [25300260] Overweight and obesity during pregnancy are common and are associated with an increased risk of adverse health outcomes for both the mother and the infant . However , robust evidence about the effect of antenatal dietary and lifestyle interventions on health outcomes is lacking . We conducted a multicenter , r and omized trial , recruiting 2,212 women ( from 3 public maternity hospitals across South Australia ) with a singleton pregnancy between 10 + 0 and 20 + 0 weeks ' gestation and a BMI ≥25 . The women were r and omized to lifestyle advice ( n = 1,108 ) or st and ard care ( n = 1,104 ) . Women r and omized to lifestyle advice participated in a comprehensive dietary and lifestyle intervention over the course of their pregnancy ( delivered by research staff ) , while women r and omized to st and ard care received pregnancy care according to local guidelines , which did not include such information . Provision of the lifestyle intervention was associated with a significant 18 % relative risk reduction in the chance of infants being born with a birth weight above 4 kg . No other significant differences were identified in maternal pregnancy and birth outcomes between the two treatment groups . Observational studies highlight the association between a high infant birth weight and the subsequent risk of childhood and adulthood obesity . Antenatal interventions that are effective in reducing high infant birth weights therefore represent a significant strategy to tackle obesity from a population health perspective , while ongoing interrogation of the biospecimens and measurements , including ongoing childhood follow-up , will provide a unique opportunity to evaluate the mechanistic pathways of maternal-to-infant/childhood obesity [22638902] Depression during the prenatal and postpartum periods is associated with poor maternal , perinatal and child outcomes . This study examines the effectiveness of a culturally and linguistically tailored , social support-based , healthy lifestyle intervention led by trained community health workers in reducing depressive symptoms among pregnant and early postpartum Latinas . A sample of 275 pregnant Latinas was r and omized to the Healthy MOMs Healthy Lifestyle Intervention ( MOMs ) or the Healthy Pregnancy Education ( control ) group . More than one-third of participants were at risk for depression at baseline . MOMs participants were less likely than control group participants to be at risk for depression at follow-up . Between baseline and 6 weeks postpartum , MOMs participants experienced a significant decline in depressive symptoms ; control participants experienced a marginally significant decline . For MOMs participants , most of this decline occurred during the pregnancy intervention period , a time when no change occurred for control participants . The change in depressive symptoms during this period was greater among MOMs than control participants ( “ intervention effect ” ) . From baseline to postpartum , there was a significant intervention effect among non-English-speaking women only . These findings provide evidence that a community-planned , culturally tailored healthy lifestyle intervention led by community health workers can reduce depressive symptoms among pregnant , Spanish-speaking Latinas [21470082] OBJECTIVE The International Association of Diabetes and Pregnancy Study Groups ( IADPSG ) has proposed new criteria for the diagnosis of gestational diabetes mellitus ( GDM ) . The aim of this study was to compare the prevalence of GDM when IADPSG criteria were used with the prevalence when the current Australasian Diabetes in Pregnancy Society ( ADIPS ) criteria were used . DESIGN , SETTING AND PARTICIPANTS This was a prospect i ve study over a 6-month period , examining the results of all glucose tolerance tests ( GTTs ) conducted for the diagnosis of GDM in Wollongong , a city using the public and private sectors . MAIN OUTCOME MEASURES The prevalence of GDM using the existing ( ADIPS ) and the proposed ( IADPSG ) criteria . RESULTS There were 1275 evaluable GTTs ( 571 public and 704 private ) . Using the current ADIPS diagnostic criteria , the prevalence of GDM was 8.6 % ( public ) , 10.5 % ( private ) and 9.6 % ( overall ) . Using the proposed IADPSG criteria , the prevalence of GDM was 9.1 % ( public ) , 16.2 % ( private ) and 13.0 % ( overall ) . CONCLUSIONS The proposed IADPSG criteria would increase the prevalence of GDM from 9.6 % to 13.0 % ( P < 0.001 ) . In our study in the Wollongong area , which has a population with a predominantly white background , this increase came mainly from older women attending a private pathology provider . Data from both the public and private sectors need to be included in any discussion on the change in prevalence of GDM [3710199] Background Gestational diabetes mellitus ( GDM ) is an increasing problem world-wide . Lifestyle interventions and /or vitamin D supplementation might help prevent GDM in some women . Methods / design Pregnant women at risk of GDM ( BMI ≥29 ( kg/m2 ) ) from 9 European countries will be invited to participate and consent obtained before 19 + 6 weeks of gestation . After giving informed consent , women without GDM will be included ( based on IADPSG criteria : fasting glucose<5.1mmol ; 1 hour glucose < 10.0 mmol ; 2 hour glucose < 8.5 mmol ) and r and omized to one of the 8 intervention arms using a 2 × (2 × 2 ) factorial design : ( 1 ) healthy eating ( HE ) , 2 ) physical activity ( PA ) , 3 ) HE+PA , 4 ) control , 5 ) HE+PA+vitamin D , 6 ) HE+PA+placebo , 7 ) vitamin D alone , 8) placebo alone ) , pre-stratified for each site . In total , 880 women will be included with 110 women allocated to each arm . Between entry and 35 weeks of gestation , women allocated to a lifestyle intervention will receive 5 face-to-face , and 4 telephone coaching sessions , based on the principles of motivational interviewing . The lifestyle intervention includes a discussion about the risks of GDM , a weight gain target < 5 kg and either 7 healthy eating ‘ messages ’ and /or 5 physical activity ‘ messages ’ depending on r and omization . Fidelity is monitored by the use of a personal digital assistance ( PDA ) system . Participants r and omized to the vitamin D intervention receive either 1600 IU vitamin D or placebo for daily intake until delivery . Data is collected at baseline measurement , at 24–28 weeks , 35–37 weeks of gestation and after delivery . Primary outcome measures are gestational weight gain , fasting glucose and insulin sensitivity , with a range of obstetric secondary outcome measures including birth weight . Discussion DALI is a unique Europe-wide r and omised controlled trial , which will gain insight into preventive measures against the development of GDM in overweight and obese women . Trial registration IS RCT [3506505] Abstract Background The Australian Carbohydrate Intolerance Study in Pregnant Women ( ACHOIS ) showed that treatment of pregnant women with mild gestational diabetes mellitus is beneficial for both women and their infants . It is still uncertain whether there are benefits of similar treatment for women with borderline gestational diabetes . This trial aims to assess whether dietary and lifestyle advice and treatment given to pregnant women who screen for borderline gestational diabetes reduces neonatal complications and maternal morbidities . Methods / design Design : Multicentre , r and omised controlled trial . Inclusion criteria : Women between 240 and 346 weeks gestation with a singleton pregnancy , a positive oral glucose challenge test ( venous plasma glucose ≥7.8 mmol/L ) and a normal oral 75 gram glucose tolerance test ( fasting venous plasma glucose < 5.5 mmol/L and a 2 hour glucose < 7.8 mmol/L ) with written , informed consent . Trial entry and r and omisation : Women with an abnormal oral glucose tolerance test ( fasting venous plasma glucose ≥5.5 mmol/L or 2 hour glucose ≥7.8 mmol/L ) will not be eligible and will be offered treatment for gestational diabetes , consistent with recommendations based on results of the ACHOIS trial . Eligible women will be r and omised into either the ‘ Routine Care Group ’ or the ‘ Intervention Group ’ . Study groups : Women in the ‘ Routine Care Group ’ will receive routine obstetric care reflecting current clinical practice in Australian hospitals . Women in the ‘ Intervention Group ’ will receive obstetric care , which will include dietary and lifestyle advice , monitoring of blood glucose and further medical treatment for hyperglycaemia as appropriate . Primary study outcome : Incidence of large for gestational age infants . Sample size : A sample size of 682 women will be sufficient to show a 50 % reduction in the risk of large for gestational age infants ( alpha 0.05 two-tailed , 80 % power , 4 % loss to follow up ) from 14 % to 7 % with dietary and lifestyle advice and treatment . Discussion A conclusive trial outcome will provide reliable evidence of relevance for the care of women with borderline glucose intolerance in pregnancy and their infants . Trial registration Australian New Zeal and Clinical Trials Registry - [4280000] Background We conducted a nested r and omised trial to evaluate the effect of an educational DVD , providing information about healthy food choices and exercise during pregnancy , on diet and physical activity , among pregnant women who were overweight or obese . Methods We conducted a nested r and omised trial within the context of the LIMIT r and omised trial . Women were eligible with a singleton pregnancy between 10 and 20 weeks gestation , and body mass index at the time of their first antenatal appointment of ≥25 kg/m2 . All women who were r and omised to the Lifestyle Advice Group of the LIMIT trial received a series of consultations with both research dieticians and research assistants , in addition to st and ard written dietary and exercise material s ( St and ard Material s Group ) . Women r and omised to the DVD Group received the same consultations and written material s , and additionally received an educational DVD ( DVD Group ) . The primary study outcome was the Healthy Eating Index . Other study outcomes included physical activity , and gestational weight gain . Women completed a qualitative evaluation of all the material s provided . Results 1,108 women in the LIMIT Lifestyle Advice Group participated in the nested trial , with 543 women r and omised to the DVD Group , and 565 women to the St and ard Material s Group . Women who received the DVD compared with those who did not , had a higher mean Healthy Eating Index at 36 weeks gestation ( 73.6 vs 72.3 ; adjusted mean difference 1.2 ; 95 % CI 0.2 to 2.3 ; p = 0.02 ) , but not at 28 weeks gestation ( 73.2 vs 73.5 ; adjusted mean difference −0.1 ; 95 % CI −1.1 to 0.9 ; p = 0.82 ) . There were no statistically significant differences in physical activity or total gestational weight gain . While most women evaluated the material s positively , frequency of utilisation was poor . Conclusions Ongoing attention to the delivery of information is required , particularly with the increased use and availability of digital and multi-media interactive technologies . Trial registration Australian and New Zeal and Clinical Trials Registry [3973835] Background Recent studies suggest that excessive gestational weight gain ( GWG ) leads to adverse maternal and fetal outcomes including weight retention in the mother and an increased risk of childhood obesity in the offspring . The aim of the GeliS study is to examine the effect of a lifestyle intervention programme during pregnancy to avoid excessive GWG and , hence , to reduce pregnancy and obstetric complications as well as the risk of maternal and offspring obesity . Methods and design The GeliS study is a multicentre cluster-r and omized controlled trial . A total number of 2500 pregnant women ( singleton pregnancy ) with a pre-pregnancy BMI ≥ 18.5 kg/m2 and ≤ 40 kg/m2 will be recruited in practice s of gynaecologists and midwives in ten Bavarian regions . The intervention comprises three structured and individualised counselling sessions on a healthy diet , regular physical activity as well as weight monitoring during pregnancy and one session after delivery , respectively . The counselling sessions are attached to routine pre- and postnatal visits using st and ardised material s and procedures . In the control regions , general recommendations for a healthy lifestyle are given . An oral glucose tolerance test is offered to all participants .The primary outcome is the proportion of participants with excessive GWG . Secondary outcomes include pregnancy and obstetric complications such as frequency of gestational diabetes , preeclampsia and caesarean sections as well as weight retention in the mothers and BMI and other health variables in the offspring . A 5-year follow-up of both mothers and their infants is planned . Discussion The GeliS lifestyle intervention programme has been adapted to the existing routine health care system for pregnant women . If shown to be effective , it could be immediately implemented in routine care . Trial registration The study protocol is registered at the Clinical Trials.gov Protocol Registration System ( NCT01958307 ) [4176103] Background Maternal diet is known to impact pregnancy outcome . Following a low glycemic index ( GI ) diet during pregnancy has been shown to improve maternal glycemia and reduce infant birthweight and may be associated with a higher fibre intake . We assessed the impact of a low GI dietary intervention on maternal GI , nutritional intake and gestational weight gain ( GWG ) during pregnancy . Compliance and acceptability of the low GI diet was also examined . Method Eight hundred women were r and omised in early pregnancy to receive low GI and healthy eating dietary advice or to receive st and ard maternity care . The intervention group received dietary advice at a group education session before 22 weeks gestation . All women completed a 3 day food diary during each trimester of pregnancy . Two hundred and thirty five women from the intervention arm and 285 women from the control arm returned complete 3x3d FDs and were included in the present analysis . Results Maternal GI was significantly reduced in the intervention group at trimester 2 and 3 . The numbers of women within the lowest quartile of GI increased from 37 % in trimester 1 to 52 % in trimester 3 ( P < 0.001 ) among the intervention group . The intervention group had significantly lower energy intake ( P < 0.05 ) , higher protein ( % TE ) ( P < 0.01 ) and higher dietary fibre intake ( P < 0.01 ) post intervention . Consumption of food groups with known high GI values were significantly reduced among the intervention group . Women in the intervention low GI group were less likely to exceed the Institute of Medicine ’s GWG goals . Conclusion A dietary intervention in early pregnancy had a positive influence on maternal GI , food and nutrient intakes and GWG . Following a low GI diet may be particularly beneficial for women at risk of exceeding the GWG goals for pregnancy . Trial registration Current Controlled Trials Registration Number : IS RCT N54392969 [4287470] Background The objectives of this study were to assess the efficacy of lifestyle intervention on gestational weight gain in pregnant women with normal and above normal body mass index ( BMI ) in a r and omized controlled trial . Methods A total of 116 pregnant women ( < 20 weeks of pregnancy ) without diabetes were enrolled and 113 pregnant women completed the program . Participants were r and omized into intervention and control groups . Women in the intervention group received weekly trainer-led group exercise sessions , instructed home exercise for 3 - 5-times/week during 20 - 36 weeks of gestation , and dietary counseling twice during pregnancy . Participants in the control group did not receive the intervention . All participants completed a physical activity question naire and a 3-day food record at enrolment and 2 months after enrolment . Results The participants in the intervention group with normal pre-pregnancy BMI ( ≤24.9 kg/M2 , n = 30 ) had lower gestational weight gain ( GWG ) , offspring birth weight and excessive gestational weight gain ( EGWG ) on pregnancy weight gain compared to the control group ( n = 27 , p < 0.05 ) . Those weight related-changes were not detected between the intervention ( n = 27 ) and control group ( n = 29 ) in the above normal pre-pregnancy BMI participants . Intervention reduced total calorie , total fat , saturated fat and cholesterol intake were detected in women with normal or above normal pre-pregnancy BMI compared to the control group ( p < 0.05 or 0.01 ) . Increased physical activity and reduced carbohydrate intake were detected in women with normal ( p < 0.05 ) , but not above normal , pre-pregnancy BMI at 2 months after the onset of the intervention compared to the control group . Conclusion The results of the present study demonstrated that the lifestyle intervention program decreased EGWG , GWG , offspring birth weight in pregnant women with normal , but not above normal , pre-pregnancy BMI , which was associated with increased physical activity and decreased carbohydrate intake . Trial registration [2527301] Background The purpose of the study is to examine the effects and feasibility of individual physical activity ( PA ) counseling in maternity and child health clinics in Finl and . Methods Three clinics including both maternity and child health care signed up for the experimental ( EXP ) and three for the control group ( CON ) . The participants were 132 pregnant and 92 postpartum primiparas . The nurses in EXP integrated a primary and four booster PA counseling sessions into routine visits . An option for supervised group exercise was offered . In CON former practice s , usually including brief PA advice , were continued . Leisure-time PA ( LTPA ) prior to pregnancy was elicited by question naire and followed 16–18 and 36–37 weeks ' gestation in maternity clinics and 5 and 10 months postpartum in child health clinics . Feasibility included safety , participant responsiveness , realization of counseling and applicability . Results According to analysis of covariance adjusted for baseline LTPA and possible confounders , no relative between-group differences in LTPA were found at the first follow-up in either maternity or child health clinics . At the last follow-up in maternity clinics the weekly number of at least moderate-intensity LTPA days was 43 % ( 95 % CI : 9 , 87 ) higher and the weekly duration of at least moderate-intensity LTPA 154 % ( 95 % CI : 16 , 455 ) higher in EXP compared with CON . Counseling proved feasible in both maternity and child health clinics . Conclusion Counseling encouraged pregnant women to sustain their moderate-intensity LTPA and was feasible in routine practice s. No effects were observed if counseling was initiated postpartum . Trial registration Current Controlled Trials IS RCT [25306925] AIMS To pilot the feasibility of a prenatal lifestyle intervention to modify physical activity and diet among pregnant overweight and obese Hispanic women , with the aim of reducing risk factors for gestational diabetes mellitus . METHODS Women were r and omized either to a lifestyle intervention ( n = 33 , 48.5 % ) , consisting of a culturally and linguistically modified , motivationally targeted , individually tailored 6-month prenatal programme , or to st and ard care ( n = 35 , 51.5 % ) . Bilingual and bicultural health educators encouraged women to achieve guidelines for physical activity , decrease saturated fat and increase dietary fibre . Outcomes included gestational weight gain , infant birth weight and biomarkers associated with insulin resistance . RESULTS Patient retention up to delivery was 97 % in both study groups . The lifestyle intervention attenuated the pregnancy-associated decline in moderate-intensity physical activity , but differences between groups were not significant ( mean ± se -23.4 ± 16.6 vs -27.0 ± 16.2 metabolic equivalent of task h/week ; P = 0.88 ) . Vigorous-intensity activity increased during the course of pregnancy in the lifestyle intervention group ( mean ± se 1.6 ± 0.8 metabolic equivalent of task h/week ) and declined in the st and ard care group ( -0.8 ± 0.8 metabolic equivalent of task h/week ; P = 0.04 ) . The lifestyle intervention group also had slightly lower gestational weight gain and infant birth weights compared with the st and ard care group ; however , these differences were not statistically significant . There were no statistically significant differences in biomarkers of insulin resistance between groups . CONCLUSIONS Findings suggest that a motivationally matched lifestyle intervention is feasible and may help attenuate pregnancy-related decreases in vigorous physical activity in a population of overweight and obese Hispanic women . The intervention protocol can readily be translated into clinical practice in underserved and minority population [11333990] BACKGROUND Type 2 diabetes mellitus is increasingly common , primarily because of increases in the prevalence of a sedentary lifestyle and obesity . Whether type 2 diabetes can be prevented by interventions that affect the lifestyles of subjects at high risk for the disease is not known . METHODS We r and omly assigned 522 middle-aged , overweight subjects ( 172 men and 350 women ; mean age , 55 years ; mean body-mass index [ weight in kilograms divided by the square of the height in meters ] , 31 ) with impaired glucose tolerance to either the intervention group or the control group . Each subject in the intervention group received individualized counseling aim ed at reducing weight , total intake of fat , and intake of saturated fat and increasing intake of fiber and physical activity . An oral glucose-tolerance test was performed annually ; the diagnosis of diabetes was confirmed by a second test . The mean duration of follow-up was 3.2 years . RESULTS The mean ( + /-SD ) amount of weight lost between base line and the end of year 1 was 4.2+/-5.1 kg in the intervention group and 0.8+/-3.7 kg in the control group ; the net loss by the end of year 2 was 3.5+/-5.5 kg in the intervention group and 0.8+/-4.4 kg in the control group ( P<0.001 for both comparisons between the groups ) . The cumulative incidence of diabetes after four years was 11 percent ( 95 percent confidence interval , 6 to 15 percent ) in the intervention group and 23 percent ( 95 percent confidence interval , 17 to 29 percent ) in the control group . During the trial , the risk of diabetes was reduced by 58 percent ( P<0.001 ) in the intervention group . The reduction in the incidence of diabetes was directly associated with changes in lifestyle . CONCLUSIONS Type 2 diabetes can be prevented by changes in the lifestyles of high-risk subjects [24284438] BACKGROUND Excessive weight gain during pregnancy is a risk factor for postpartum weight retention and future weight gain and obesity . Whether a behavioral intervention in pregnancy can reduce long-term weight retention is unknown . OBJECTIVE This r and omized trial tested whether a low-intensity behavioral intervention to prevent excessive gestational weight gain could increase the proportion of women who returned to prepregnancy weight by 12 mo postpartum . DESIGN Women ( n = 401 , 13.5 wk of gestation , 50 % normal weight , 50 % overweight/obese ) were r and omly assigned into an intervention or control group ; 79 % completed the 12-mo assessment . The telephone-based intervention targeted gestational weight gain , healthy eating , and exercise and was discontinued at delivery . RESULTS In modified intent-to-treat analyses that excluded women with miscarriages ( n = 6 ) , gestational diabetes ( n = 32 ) , or subsequent pregnancies ( n = 32 ) , the intervention had no significant effect on the odds of achieving prepregnancy weight at 12 mo postpartum ( n = 331 ; 35.4 % compared with 28.1 % ; P = 0.18 ) . Completer analyses suggested that the intervention tended to increase the percentages of women who reached prepregnancy weight ( n = 261 ; 45.3 % compared with 35.3 % ; P = 0.09 ) and significantly reduced the magnitude of mean ± SD postpartum weight retained ( 1.4 ± 6.3 compared with 3.0 ± 5.7 kg ; P = 0.046 ) at 12 mo . Women in the intervention group reported higher dietary restraint through 6 mo postpartum ( P = 0.023 ) and more frequent self-monitoring of body weight ( P < 0.02 for all ) throughout the study . CONCLUSIONS A low-intensity behavioral intervention in pregnancy can reduce 12-mo postpartum weight retention and improve dietary restraint and self-weighing in study completers . Future research is needed to test the long-term effects of more intensive behavioral interventions in pregnancy . This trial was registered at clinical trials.gov as NCT01117961 [12439652] BACKGROUND : The Institute of Medicine ( IOM ) recommends that normal‐weight women ( BMI ( body mass index ) of 19.8–26.0 ) gain 25–35 lb ( 11.4–15.9 kg ) during pregnancy , and that overweight women ( BMI of 26.1–29.0 ) gain 15–25 lbs ( 6.8–11.4 kg ) . A significant number of normal‐weight women and an even greater proportion of overweight women exceed these guidelines , which increases postpartum weight retention and may contribute to the development of obesity . OBJECTIVE : To determine whether a stepped care , behavioral intervention will decrease the percentage of women who gain more than the IOM recommendation . DESIGN : R and omized controlled trial comparing a stepped-care behavioral intervention with usual care . Women ( n=120 ) who had a BMI > 19.8 , age>18 and < 20 weeks gestation were recruited from a hospital-based clinic serving low-income women and r and omized by race and BMI category to the intervention or control group . The intervention group received education about weight gain , healthy eating , and exercise and individual graphs of their weight gain . Those exceeding weight gain goals were given more intensive intervention . Women were followed through pregnancy to their first postpartum clinic visit . The main outcome measure was weight gain during pregnancy categorized as above the IOM recommendations vs below or within the IOM recommendations . RESULTS : The intervention significantly decreased the percentage of normal-weight women who exceeded the IOM recommendations ( 33 vs 58 % , P<0.05 ) . There was a non-significant ( P=0.09 ) effect in the opposite direction among overweight women ( 59 % of intervention and 32 % of control gained more than recommended ) . Postpartum weight retention was strongly related to weight gain during pregnancy ( r=0.89 ) . CONCLUSIONS : The intervention reduced excessive weight gain during pregnancy among normal weight women [22465256] BACKGROUND Obesity and excessive weight gain during pregnancy are associated with adverse pregnancy outcomes . Observational studies suggest that minimal or no gestational weight gain ( GWG ) may minimize the risk of adverse pregnancy outcomes for obese women . OBJECTIVE This report describes the design of Healthy Moms , a r and omized trial testing a weekly , group-based , weight management intervention design ed to help limit GWG to 3 % of weight ( measured at the time of r and omization ) among obese pregnant women ( BMI ≥30 kg/m(2 ) ) . Participants are r and omized at 10 - 20 weeks gestation to either the intervention or a single dietary advice control condition . PRIMARY OUTCOMES The study is powered for the primary outcome of total GWG , yielding a target sample size of 160 women . Additional secondary outcomes include weight change between r and omization and one-year postpartum and proportion of infants with birth weight>90th percentile for gestational age . Statistical analyses will be based on intention-to-treat . METHODS Following r and omization , all participants receive a 45-minute dietary consultation . They are encouraged to follow the Dietary Approaches to Stop Hypertension diet without sodium restriction . Intervention group participants receive an individualized calorie intake goal , a second individual counseling session and attend weekly group meetings until they give birth . Research staff assesses all participants at 34-weeks gestation and at 2-weeks and one-year postpartum with their infants . SUMMARY The Healthy Moms study is testing weight management techniques that have been used with non-pregnant adults . We aim to help obese women limit GWG to improve their long-term health and the health of their offspring [3872607] Background : Abnormal weight gain during pregnancy increases the adverse health outcomes during the pregnancy , delivery , and the postpartum period . Most of the pregnant women develop weight gain more than the recommended limits ; therefore , interventions to manage such disproportionate weight gain are needed . In this paper , the design of the maternal centered life-style intervention study is described , which focuses on controlling weight gaining during pregnancy for all body mass index ( BMI ) groups . Material s and Methods : In our r and omized field trial , 160 pregnant women with 6 - 10 weeks of gestational age who visit one of the participating Isfahan four urban public-health centers and 4 private obstetric offices are included . The maternal centered life-style intervention carried out by trained midwives is st and ardized in a protocol . All the participants are visited at 6 - 10 , 11 - 15 , 16 - 20 , 21 - 25 , 26 - 30 , 31 - 34 , 35 - 37 , 38 , 39 , and 40 weeks of pregnancy . The women who are r and omized in the intervention group receive maternal centered educational package of prenatal care for the pregnant woman and a log book in the first visit . Counselors accompany the pregnant women to maintain or develop a healthy life-style . Data collection will perform monthly measuring body weight , BMI . Conclusion : Because , we do n’t have structured protocol for weight management during pregnancy especially , in private sectors if the maternal centered life-style intervention proves to be effective , it will be suggested to merge this package to routine care . Therewith by empowering women to manage their weight the public-health burden can be reduced . Beside that private obstetricians also have structured protocol for their client management [25300266] Background : Obesity in pregnancy is associated with fetal macrosomia , a raised neonatal fat mass and an increased risk of obesity and poor metabolic health in childhood which persists into adulthood . The offspring of obese women are more likely to be obese than the offspring of lean women when they become pregnant themselves , perpetuating a cycle of obesity and its associated negative metabolic consequences . Increasing physical activity during pregnancy could improve insulin sensitivity and reduce the risk of maternal and offspring adverse outcomes . The UK Pregnancy Better Eating and Activity Trial ( UPBEAT ) is a trial of a complex intervention design ed to improve pregnancy outcomes through dietary changes and physical activity . Data from the pilot trial of 183 women were available for analysis . The relationship between the time spent at different physical activity levels and maternal and infant pregnancy outcomes was examined . Key Messages : Strong evidence exists that physical activity improves insulin sensitivity in non-pregnant population s , and lifestyle interventions of proven effectiveness in non-pregnant population s have been developed . Women who are active in pregnancy demonstrate better glucose control and favourable pregnancy outcomes . There is a lack of effective interventions to support obese pregnant women to be physically active . Conclusions : No difference was detected in objective ly measured physical activity between women r and omised to the intervention and control arms of the UPBEAT pilot trial . Light-intensity physical activity was lower in early pregnancy in women who delivered macrosomic infants . Maternal sedentary time at 35 - 36 weeks ' gestation was positively associated and moderate-intensity physical activity was inversely associated with neonatal abdominal circumference . Maternal physical activity is associated with infant birth weight and abdominal circumference and is an appropriate target for intervention to improve infant outcomes . The challenge remains to develop an effective intervention to support obese pregnant women to be physically active [9704236] The objective of this study was to test the hypothesis that a woman 's dietary carbohydrate mix modifies the glucose and insulin response to both mixed caloric intake and exercise . Either a prospect i ve r and omized or a prospect i ve r and omized crossover design was used to examine the effects of two isocaloric , high-carbohydrate diets on the whole-blood glucose and insulin responses to mixed caloric intake and exercise in healthy nonpregnant ( n = 14 ) and pregnant ( n = 12 ) women . The diets differed only in the type of carbohydrate ingested . Those in one had low glycemic indexes and those in the other had high glycemic indexes . In nonpregnant women , the blood glucose response to a meal containing low-glycemic carbohydrate was half that seen with high-glycemic carbohydrate , and the effect of exercise on blood glucose was more pronounced while eating the high-glycemic carbohydrate diet . During pregnancy , women on the low-glycemic carbohydrate diet experienced no significant change in their glycemic response to mixed caloric intake , whereas those who switched to the high-glycemic carbohydrate diet experienced a 190 % increase in their response . In conclusion , the type of dietary carbohydrate in a healthy , physically active woman 's diet influences both her postpr and ial blood glucose profile and her blood sugar response to exercise [22773616] Background . Intervention fidelity is an increasingly important method ological concept in process evaluations . In this article , the authors investigated the intervention fidelity in a r and omized controlled trial on excessive weight gain prevention in pregnancy . Method . A sample of 109 audiotaped counseling sessions , linked to 65 women in the intervention group of the New Life(style ) trial , was drawn . The following criteria were quantitatively evaluated using a fidelity checklist : ( a ) reach , ( b ) dose , ( c ) adherence to study objectives , ( d ) adherence to underlying problem-solving treatment ( PST ) theory , and ( e ) counselor competence . Results . A total of 60.4 % received all counseling sessions . The dose of intervention components was generally moderate ( 50.9 % to 60.4 % ) , and the dose of PST components was low ( 17.3 % ) . Adherence to study objectives was moderate ( 64.2 % ) and adherence to PST theory was low ( 43.2 % ) . The counselors sufficiently stimulated the participant to optimize lifestyle ( 54.2 % of the sessions ) , provided positive feedback ( 50.5 % ) , and left the initiative regarding problem solving to the participant ( 71 % ) . One of the two counselors performed significantly better on all measured criteria ( p < .001 ) . Conclusions . Intervention fidelity in the New Life(style ) trial was generally low to moderate . In future interventions , it is recommended to put more emphasis on counselor recruitment , training , and intervention protocol contents . Fellow research ers are encouraged to embed a process evaluation into all study stages , taking into account all essential process elements , and to link process outcomes to more distal , health outcomes [15177856] OBJECTIVE To examine the potential effect of low-risk pregnancy on women 's recreational activity patterns and to explore pregnant women 's beliefs and information sources regarding physical exercise participation . DESIGN Preliminary , prospect i ve survey SETTING Participants ' homes in the East Midl and s , UK . PARTICIPANTS Fifty-seven nulliparous , pregnant women . MEASUREMENTS Levels of maternal physical activity participation were assessed by semi-structured interview at 16 , 25 , 34 and 38 weeks gestation . The modified Baecke question naire provided a measure of women 's habitual sport and leisure activities in the 12 months prior to pregnancy . A 10-item scale assessed maternal beliefs regarding the importance of physical activity in pregnancy . The fetal health locus of control scale measured the extent to which women believed their own behaviour , the behaviour of others and /or chance would influence fetal health . Open-ended questions assessed women 's information sources . FINDINGS Fourteen of the 36 ( 39 % ) women who reported participating in some form of weekly exercise before pregnancy did not report pursuing any similar activities during pregnancy . Rest and relaxation were perceived as being significantly more important during pregnancy than was regular exercise or the maintenance of an active lifestyle . Fifty-five respondents ( 96 % ) indicated that they had received advice about physical activity at least once during pregnancy . At 16 weeks gestation , women obtained most of their information from books and magazines . Between 25 and 38 weeks gestation , most advice came from family and friends . Participants who reported receiving this advice were significantly older , more educated and of a higher activity level pre-pregnancy . KEY CONCLUSIONS Levels of maternal exercise may decline during pregnancy both as a result of the physical changes of pregnancy and from a combination of social and psychological factors . Present health education may be failing to correct inaccurate perceptions of the risks associated with physical exercise in pregnancy . IMPLICATION S FOR PRACTICE Improving the quantity and quality of information related to physical exercise has the potential to correct inaccurate perceptions and confer several benefits on maternal and fetal health . Effective intervention strategies should focus not only on the pregnant woman but also extend to her family , friends and exercise provider [18502303] BACKGROUND Intensive lifestyle interventions can reduce the incidence of type 2 diabetes in people with impaired glucose tolerance , but how long these benefits extend beyond the period of active intervention , and whether such interventions reduce the risk of cardiovascular disease ( CVD ) and mortality , is unclear . We aim ed to assess whether intensive lifestyle interventions have a long-term effect on the risk of diabetes , diabetes-related macrovascular and microvascular complications , and mortality . METHODS In 1986 , 577 adults with impaired glucose tolerance from 33 clinics in China were r and omly assigned to either the control group or to one of three lifestyle intervention groups ( diet , exercise , or diet plus exercise ) . Active intervention took place over 6 years until 1992 . In 2006 , study participants were followed-up to assess the long-term effect of the interventions . The primary outcomes were diabetes incidence , CVD incidence and mortality , and all-cause mortality . FINDINGS Compared with control participants , those in the combined lifestyle intervention groups had a 51 % lower incidence of diabetes ( hazard rate ratio [ HRR ] 0.49 ; 95 % CI 0.33 - 0.73 ) during the active intervention period and a 43 % lower incidence ( 0.57 ; 0.41 - 0.81 ) over the 20 year period , controlled for age and clustering by clinic . The average annual incidence of diabetes was 7 % for intervention participants versus 11 % in control participants , with 20-year cumulative incidence of 80 % in the intervention groups and 93 % in the control group . Participants in the intervention group spent an average of 3.6 fewer years with diabetes than those in the control group . There was no significant difference between the intervention and control groups in the rate of first CVD events ( HRR 0.98 ; 95 % CI 0.71 - 1.37 ) , CVD mortality ( 0.83 ; 0.48 - 1.40 ) , and all-cause mortality ( 0.96 ; 0.65 - 1.41 ) , but our study had limited statistical power to detect differences for these outcomes . INTERPRETATION Group-based lifestyle interventions over 6 years can prevent or delay diabetes for up to 14 years after the active intervention . However , whether lifestyle intervention also leads to reduced CVD and mortality remains unclear [24738837] Self‐weighing is important for weight management in general population s ; however its role in optimising gestational weight gain is less clear . Our r and omised trial in early pregnancy found regular self‐weighing when combined with a self‐management intervention , optimised weight gain at 28 weeks gestation ( 5.66 ± 2.6 kg vs 7.03 ± 3.56 kg , P = 0.02 ) and reduced postpartum weight retention ( −0.57 ± 3.94 kg vs 1.48 ± 5.49 kg , P < 0.05 ) compared with control participants . Results highlight the importance of self‐monitoring strategies during pregnancy [11832527] BACKGROUND Type 2 diabetes affects approximately 8 percent of adults in the United States . Some risk factors -- elevated plasma glucose concentrations in the fasting state and after an oral glucose load , overweight , and a sedentary lifestyle -- are potentially reversible . We hypothesized that modifying these factors with a lifestyle-intervention program or the administration of metformin would prevent or delay the development of diabetes . METHODS We r and omly assigned 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concentrations to placebo , metformin ( 850 mg twice daily ) , or a lifestyle-modification program with the goals of at least a 7 percent weight loss and at least 150 minutes of physical activity per week . The mean age of the participants was 51 years , and the mean body-mass index ( the weight in kilograms divided by the square of the height in meters ) was 34.0 ; 68 percent were women , and 45 percent were members of minority groups . RESULTS The average follow-up was 2.8 years . The incidence of diabetes was 11.0 , 7.8 , and 4.8 cases per 100 person-years in the placebo , metformin , and lifestyle groups , respectively . The lifestyle intervention reduced the incidence by 58 percent ( 95 percent confidence interval , 48 to 66 percent ) and metformin by 31 percent ( 95 percent confidence interval , 17 to 43 percent ) , as compared with placebo ; the lifestyle intervention was significantly more effective than metformin . To prevent one case of diabetes during a period of three years , 6.9 persons would have to participate in the lifestyle-intervention program , and 13.9 would have to receive metformin . CONCLUSIONS Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk . The lifestyle intervention was more effective than metformin [24629718] AIM This r and omized controlled trial was carried out to investigate the effect of mindfulness eating and yoga exercise on blood sugar levels among pregnant Thai women with GDM . BACKGROUND Interventions promoting achievement of good glycemic control result in desired pregnancy outcomes . Little is known about the health benefits of mindfulness eating and yoga exercise on blood sugar levels among pregnant with GDM . METHODS A r and omized controlled trial was carried out . Main outcome measures were capillary fasting plasma glucose , 2-h postpr and ial blood glucose , and hemoglobin A1c . RESULTS The intervention group showed significantly reduced fasting plasma glucose , 2-h postpr and ial blood glucose , and glycosylated hemoglobin ( HbA1c ) in the intervention group ( p<0.05 ) . CONCLUSIONS Mindfulness eating and yoga exercise had health benefits on glycemic control in pregnant women with GDM . It should be recommended in clinical and community health services [6315514] Summary Non-obese women in the second half of pregnancy were r and omised into a control group receiving st and ard dietary advice and a group advised to make high fibre whole-food substitutions in their diets at every opportunity . Glucose and insulin profiles were performed over 24-h periods at 29 and 35 weeks gestation when the diets were equivalent in available carbohydrate , protein and fat , but the control group ingested 12.4 g dietary fibre/24 h and the high fibre group 51.4g/24h . Glucose homeostasis was similar in both groups but there was a significant attenuation of post-pr and ial insulin secretion in the high fibre group . It is suggested that the characteristic post-pr and ial peaks of plasma insulin observed in Western pregnant women are an unphysiological response to dietary fibre depletion [22843114] OBJECTIVE A prospect i ve r and omized controlled trial was design ed to assess the benefits and possible risks of aerobic exercise during pregnancy , using a fitness regimen based on the 2002 American College of Obstetricians and Gynecologists guidelines for exercise during pregnancy . METHODS Inactive women were r and omized at 12 - 14 wk gestation to a group that remained sedentary or to a group that performed moderate aerobic exercise 45 - 60 min , 4 d·wk , through 36 wk gestation . Thirty-one subjects in each group completed the study . RESULTS Compared with women who remained sedentary , active women improved aerobic fitness ( P < 0.05 ) and muscular strength ( P < 0.01 ) , delivered comparable size infants with significantly fewer cesarean deliveries ( P < 0.01 ) , and recovered faster postpartum ( P < 0.05 ) , at least related to the lower incidence of cesarean section . Active women developed no gestational hypertension ( P = 0.16 compared with controls ) and reported no injuries related to the exercise regimen . In the active group , there was one premature birth at 33 wk by a woman with a history of premature delivery of twins at 34 wk . There were no differences between groups in the incidence of gestational diabetes , musculoskeletal pains during pregnancy , flexibility on sit- and -reach test , mean length of pregnancy , neonatal Apgar scores , placenta weights , overall length of labor , weight gain during pregnancy , or weight retention postpartum . CONCLUSION Previously sedentary women who began exercising at 12 - 14 wk improved fitness and delivery outcomes [11810100] OBJECTIVE The purpose of this study was to test the null hypothesis that the volume of exercise at different times during pregnancy has no effect on fetoplacental growth . STUDY DESIGN Seventy-five women who exercised regularly were evaluated before pregnancy and r and omly assigned at 8 weeks ' gestation to one of 3 exercise regimens for the remainder of pregnancy . Primary outcome variables included placental growth rate , birth weight , and placental volume at term . RESULTS The offspring of the women who were r and omly assigned to a high volume of exercise in mid and late pregnancy were significantly lighter ( 3.39 kg vs 3.81 kg ) and thinner ( 8.3 % fat vs 12.1 % fat ) than those offspring born of women who were r and omly assigned to reduce their exercise volume after the 20th week . Maternal weight gain , fresh placental volumes , and histomorphometric indices of placental function were greater in the high-low group . CONCLUSION These data indicate that a high volume of moderate-intensity , weight-bearing exercise in mid and late pregnancy symmetrically reduces fetoplacental growth , whereas a reduction in exercise volume enhances fetoplacental growth with a proportionally greater increase in fat mass than in lean body mass [2923097] Background Annual prevalence of gestational diabetes mellitus ( GDM ) is 12.5 % among Finnish pregnant women . The prevalence is expected to rise with the increasing overweight among women before pregnancy . Physical activity and diet are both known to have favourable effects on insulin resistance and possibly on the risk of GDM . We aim ed to investigate , whether GDM can be prevented by counseling on diet , physical activity and gestational weight gain during pregnancy . Methods / Design A cluster-r and omized controlled trial was conducted in 14 municipalities in the southern part of Finl and . Pairwise r and omization was performed in order to take into account socioeconomic differences . Recruited women were at 8 - 12 weeks ' gestation and fulfilled at least one of the following criteria : body mass index ≥ 25 kg/m2 , history of earlier gestational glucose intolerance or macrosomic newborn ( > 4500 g ) , age ≥ 40 years , first or second degree relative with history of type 1 or 2 diabetes . Main exclusion criterion was pathological oral glucose tolerance test ( OGTT ) at 8 - 12 weeks ' gestation . The trial included one counseling session on physical activity at 8 - 12 weeks ' gestation and one for diet at 16 - 18 weeks ' gestation , and three to four booster sessions during other routine visits . In the control clinics women received usual care . Information on height , weight gain and other gestational factors was obtained from maternity cards . Physical activity , dietary intake and quality of life were followed by question naires during pregnancy and at 1-year postpartum . Blood sample s for lipid status , hormones , insulin and OGTT were taken at 8 - 12 and 26 - 28 weeks ' gestation and 1 year postpartum . Workability and return to work were elicited by a question naire at 1- year postpartum . Linkage to the national birth register of years 2007 - 2009 will provide information on perinatal complications and GDM incidence among the non- participants of the study . Cost-effectiveness evaluation will be based on quality -adjusted life years . This study has received ethical approval from the Ethical board of Pirkanmaa Hospital District . Discussion The study will provide information on the effectiveness and cost-effectiveness of gestational physical activity and dietary counseling on prevention of GDM in a risk group of women . Also information on the prevalence of GDM and postpartum metabolic syndrome will be gained . Results on maintaining the possible health behaviour changes are important in order to prevent chronic diseases such as cardiovascular disease and diabetes . Trial registration The trial is registered IS RCT N [24646172] The benefits of exercise and behavioural recommendations in gestational diabetes mellitus ( GDM ) are controversial . In a r and omized trial with a 2 × 2 factorial design , we examined the effect of exercise and behavioural recommendations on metabolic variables , and maternal/neonatal outcomes in 200 GDM patients . All women were given the same diet : group D received dietary recommendations only ; group E was advised to briskly walk 20‐min/day ; group B received behavioural dietary recommendations ; group BE was prescribed the same as B + E. Dietary habits improved in all groups . In a multivariable regression model , fasting glucose did not change . Exercise , but not behavioural recommendations , was associated with the reduction of postpr and ial glucose ( p < 0001 ) , glycated haemoglobin ( HbA1c ; p < 0.001 ) , triglycerides ( p = 0.02 ) and C‐reactive protein ( CRP ; p < 0.001 ) and reduced any maternal/neonatal complications ( OR = 0.50 ; 95%CI=0.28–0.89;p = 0.02 ) . In GDM patients a simple exercise programme reduced maternal postpr and ial glucose , HbA1c , CRP , triglycerides and any maternal/neonatal complications , but not fasting glucose values [19797280] BACKGROUND It is uncertain whether treatment of mild gestational diabetes mellitus improves pregnancy outcomes . METHODS Women who were in the 24th to 31st week of gestation and who met the criteria for mild gestational diabetes mellitus ( i.e. , an abnormal result on an oral glucose-tolerance test but a fasting glucose level below 95 mg per deciliter [ 5.3 mmol per liter ] ) were r and omly assigned to usual prenatal care ( control group ) or dietary intervention , self-monitoring of blood glucose , and insulin therapy , if necessary ( treatment group ) . The primary outcome was a composite of stillbirth or perinatal death and neonatal complications , including hyperbilirubinemia , hypoglycemia , hyperinsulinemia , and birth trauma . RESULTS A total of 958 women were r and omly assigned to a study group--485 to the treatment group and 473 to the control group . We observed no significant difference between groups in the frequency of the composite outcome ( 32.4 % and 37.0 % in the treatment and control groups , respectively ; P=0.14 ) . There were no perinatal deaths . However , there were significant reductions with treatment as compared with usual care in several prespecified secondary outcomes , including mean birth weight ( 3302 vs. 3408 g ) , neonatal fat mass ( 427 vs. 464 g ) , the frequency of large-for-gestational-age infants ( 7.1 % vs. 14.5 % ) , birth weight greater than 4000 g ( 5.9 % vs. 14.3 % ) , shoulder dystocia ( 1.5 % vs. 4.0 % ) , and cesarean delivery ( 26.9 % vs. 33.8 % ) . Treatment of gestational diabetes mellitus , as compared with usual care , was also associated with reduced rates of preeclampsia and gestational hypertension ( combined rates for the two conditions , 8.6 % vs. 13.6 % ; P=0.01 ) . CONCLUSIONS Although treatment of mild gestational diabetes mellitus did not significantly reduce the frequency of a composite outcome that included stillbirth or perinatal death and several neonatal complications , it did reduce the risks of fetal overgrowth , shoulder dystocia , cesarean delivery , and hypertensive disorders . ( Clinical Trials.gov number , NCT00069576 . [3096610] In a cluster-r and omized trial , Riitta Luoto and colleagues find that counseling on diet and activity can reduce the birthweight of babies born to women at risk of developing gestational diabetes mellitus ( GDM ) , but fail to find an effect on GDM [24175912] Abstract Objectives : To determine whether changes in lifestyle in women with BMI > 25 could decrease gestational weight gain and unfavorable pregnancy outcomes . Methods : Women with BMI > 25 were r and omized at 1st trimester to no intervention or a Therapeutic Lifestyle Changes ( TLC ) Program including diet ( overweight : 1700 kcal/day , obese : 1800 kcal/day ) and mild physical activity ( 30 min/day , 3 times/week ) . At baseline and at the 36th week women filled-in a Food Frequency Question naire . Outcomes : gestational weight gain , gestational diabetes mellitus , gestational hypertension , preterm delivery . Data stratified by BMI categories . Results : Socio-demographic features were similar between groups ( TLC : 33 cases , Controls : 28 cases ) . At term , gestational weight gain in obese women r and omized to TLC group was lower ( 6.7 ± 4.3 kg ) versus controls ( 10.1 ± 5.6 kg , p = 0.047 ) . Gestational diabetes mellitus , gestational hypertension and preterm delivery were also significantly lower . TLC was an independent factor in preventing gestational weight gain , gestational diabetes mellitus , gestational hypertension . Significant changes in eating habits occurred in the TLC group , which increased the number of snacks , the intake of fruits – vegetables and decreased the consumption of sugar . Conclusions : A caloric restriction associated to changes in eating behavior and constant physical activity , is able to reduce gestational weight gain and related pregnancy complications in obese women [21310836] BACKGROUND Excessive weight gain during pregnancy is a major risk factor for postpartum weight retention and future weight gain and obesity in women , but few adequately powered r and omized controlled trials have examined the efficacy of a behavioral weight-control intervention during pregnancy . OBJECTIVE This study examined whether a behavioral intervention during pregnancy could decrease the proportion of women who exceeded the 1990 Institute of Medicine ( IOM ) recommendations for gestational weight gains and increase the proportion of women who returned to pregravid weights by 6 mo postpartum . DESIGN This study was a r and omized , assessor-blind , controlled trial . Participants were pregnant ( 13.5 wk gestation ) , normal-weight ( NW ; n = 201 ) and overweight or obese ( OW/OB ; n = 200 ) women whose average age was 28.8 y. Participants were r and omly assigned within the 1990 IOM weight category ( NW compared with OW/OB ) to st and ard care ( n = 200 ) or to a behavioral intervention to prevent excessive gestational weight gain ( n = 201 ) . The intervention included one face-to-face visit ; weekly mailed material s that promoted an appropriate weight gain , healthy eating , and exercise ; individual graphs of weight gain ; and telephone-based feedback . The retention at the 6-mo postpartum assessment was 82 % . RESULTS Intent-to-treat analyses showed that the intervention , compared with st and ard care , decreased the percentage of NW women who exceeded IOM recommendations ( 40.2 % compared with 52.1 % ; P = 0.003 ) and increased the percentages of NW and OW/OB women who returned to their pregravid weights or below by 6 mo postpartum ( 30.7 % compared with 18.7 % ; P = 0.005 ) . CONCLUSION A low-intensity behavioral intervention during pregnancy reduced excessive gestational weight gains in NW women and prevented postpartum weight retention in NW and OW/OB women . This trial was registered at clinical trials.gov as NCT01117961

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### Context: [4194375] Background Overweight and obesity is a significant health concern during pregnancy . Our aim was to investigate the effect of providing antenatal dietary and lifestyle advice to women who are overweight or obese on components of maternal diet and physical activity . Methods We conducted a r and omised controlled trial , in which pregnant women with a body mass index ≥25 kg/m2 , and singleton gestation between 10 + 0 to 20 + 0 weeks were recruited and r and omised to Lifestyle Advice ( involving a comprehensive dietary and lifestyle intervention over their pregnancy ) or St and ard Care . Within the intervention group , we conducted a nested r and omised trial in which a subgroup of women were further r and omised to receive access to supervised group walking sessions in addition to the st and ard information presented during the intervention contacts ( the Walking group ) or st and ard information only . The outcome measures were maternal dietary intake , ( including food groups , macronutrient and micronutrient intake , diet quality ( using the Healthy Eating Index ; HEI ) , dietary glycaemic load , and glycaemic index ) and maternal physical activity . Women completed the Harvard Semi-Structured Food Frequency Question naire , and the Short Question naire to Assess Health-enhancing Physical Activity ( SQUASH ) , at trial entry , 28 and 36 weeks ’ gestational age , and 4 months postpartum . Analyses were performed on an intention-to-treat basis , using linear mixed effects models with adjustment for the stratification variables . Results Women r and omised to Lifestyle Advice demonstrated a statistically significant increase in the number of servings of fruit and vegetables consumed per day , as well as increased consumption of fibre , and reduced percentage energy intake from saturated fats ( P < 0.05 for all ) . Maternal HEI was significantly improved at both 28 ( 73.35 ± 6.62 versus 71.86 ± 7.01 ; adjusted difference in means 1.58 ; 95 % CI 0.89 to 2.27 ; P < 0.0001 ) and 36 ( 72.95 ± 6.82 versus 71.17 ± 7.69 ; adjusted difference in means 1.77 ; 95 % CI 1.01 to 2.53 ; P < 0.0001 ) weeks . There were no differences in dietary glycaemic index or glycaemic load . Women r and omised to Lifestyle Advice also demonstrated greater total physical activity ( adjusted difference in means 359.76 metabolic equivalent task units ( MET ) minutes/week ; 95 % CI 74.87 to 644.65 ; P = 0.01 ) compared with women receiving St and ard Care . The supervised walking group was poorly utilised . Conclusions For women who are overweight or obese , antenatal lifestyle advice improves maternal diet and physical activity during pregnancy . Please see related articles : http://www.biomed central .com/1741 - 7015/12/163 and http://www.biomed central .com/1741 - 7015/12/201.Trial registration Australian and New Zeal and Clinical Trials Registry ( http://ACTRN12607000161426 [3219553] Background Obesity is a significant global health problem , with the proportion of women entering pregnancy with a body mass index greater than or equal to 25 kg/m2 approaching 50 % . Obesity during pregnancy is associated with a well-recognised increased risk of adverse health outcomes both for the woman and her infant , however there is more limited information available regarding effective interventions to improve health outcomes .The aims of this r and omised controlled trial are to assess whether the implementation of a package of dietary and lifestyle advice to overweight and obese women during pregnancy to limit gestational weight gain is effective in improving maternal , fetal and infant health outcomes . Methods / Design Design : Multicentred r and omised , controlled trial . Inclusion Criteria : Women with a singleton , live gestation between 10 + 0 - 20 + 0 weeks who are obese or overweight ( defined as body mass index greater than or equal to 25 kg/m2 ) , at the first antenatal visit . Trial Entry & R and omisation : Eligible , consenting women will be r and omised between 10 + 0 and 20 + 0 weeks gestation using a central telephone r and omisation service , and r and omisation schedule prepared by non- clinical research staff with balanced variable blocks . Stratification will be according to maternal BMI at trial entry , parity , and centre where planned to give birth . Treatment Schedules : Women r and omised to the Dietary and Lifestyle Advice Group will receive a series of inputs from research assistants and research dietician to limit gestational weight gain , and will include a combination of dietary , exercise and behavioural strategies . Women r and omised to the St and ard Care Group will continue to receive their pregnancy care according to local hospital guidelines , which does not currently include routine provision of dietary , lifestyle and behavioural advice . Outcome assessors will be blinded to the allocated treatment group . Primary Study Outcome : infant large for gestational age ( defined as infant birth weight ≥ 90th centile for gestational age ) . Sample Size : 2,180 women to detect a 30 % reduction in large for gestational age infants from 14.40 % ( p = 0.05 , 80 % power , two-tailed ) . Discussion This is a protocol for a r and omised trial . The findings will contribute to the development of evidence based clinical practice guidelines .Trial Registration Australian and New Zeal and Clinical Trials Registry [3669050] Background Gestational Diabetes Mellitus ( GDM ) has well recognised adverse health implication s for the mother and her newborn that are both short and long term . Obesity is a significant risk factor for developing GDM and the prevalence of obesity is increasing globally . It is a matter of public health importance that clinicians have evidence based strategies to inform practice and currently there is insufficient evidence regarding the impact of dietary and lifestyle interventions on improving maternal and newborn outcomes . The primary aim of this study is to measure the impact of a telephone based intervention that promotes positive lifestyle modifications on the incidence of GDM . Secondary aims include : the impact on gestational weight gain ; large for gestational age babies ; differences in blood glucose levels taken at the Oral Glucose Tolerance Test ( OGTT ) and selected factors relating to self-efficacy and psychological wellbeing . Method / design A r and omised controlled trial ( RCT ) will be conducted involving pregnant women who are overweight ( BMI > 25 to 29.9 k/gm2 ) or obese ( BMI > 30 kgm/2 ) , less than 14 weeks gestation and recruited from the Barwon South West region of Victoria , Australia . From recruitment until birth , women in the intervention group will receive a program informed by the Theory of Self-efficacy and employing Motivational Interviewing . Brief ( less than 5 minute ) phone contact will alternate with a text message/email and will involve goal setting , behaviour change reinforcement with weekly weighing and charting , and the provision of health information . Those in the control group will receive usual care . Data for primary and secondary outcomes will be collected from medical record review and a question naire at 36 weeks gestation . Discussion Evidence based strategies that reduce the incidence of GDM are a priority for contemporary maternity care . Changing health behaviours is a complex undertaking and trialling a composite intervention that can be adopted in various primary health setting s is required so women can be accessed as early in pregnancy as possible . Using a sound theoretical base to inform such an intervention will add depth to our underst and ing of this approach and to the interpretation of results , contributing to the evidence base for practice and policy . Trial registration This trial is registered with the Australian New Zeal and Clinical Trials Registry ( ANZCTR ) : [3565864] Background The costs of gestational diabetes mellitus ( GDM ) screening have been frequently reported , but total GDM-related health care costs compared to the health care costs of women without GDM have not been reported . The aim of this study was to analyse GDM-related health care costs among women with an elevated risk of GDM . Methods The study was based on a cluster-r and omised GDM prevention trial ( N = 848 ) carried out at maternity clinics , combined with data from the Finnish Medical Birth Register and Care Registers for Social Welfare and Health Care . Costs of outpatient visits to primary and secondary care , cost of inpatient hospital care before and after delivery , the use of insulin , delivery costs and babies ’ stay in the neonatal intensive care unit were analysed . Women who developed GDM were compared to those who were not diagnosed with GDM . Results Total mean health care costs adjusted for age , body mass index and education were 25.1 % higher among women diagnosed with GDM ( € 6,432 vs. € 5,143 , p < 0.001 ) than among women without GDM . The cost of inpatient visits was 44 % higher and neonatal intensive care unit use was 49 % higher in the GDM group than among women without GDM . The delivery costs were the largest single component in both groups . Conclusions A confirmed GDM diagnosis was associated with a significant increase in total health care costs . Effective lifestyle counselling by primary health care providers may offer a means of reducing the high costs of secondary care [3403888] Background Fetal conditions are known to be partly responsible for the child ’s risk for obesity . Our pilot study aim ed to determine the effect of gestational lifestyle counseling on the offspring weight gain until 4 years of age and to estimate power for future studies . Design and methods First-time pregnant mothers participated in a controlled trial conducted in maternity health clinics during 2004 – 2006 . The intervention included individual counseling on physical activity and diet , and an option to attend supervised group exercise sessions . The participant mothers ( N = 109 ) received a follow-up question naire concerning 13 repeated growth measurements of their offspring . Response rate to the follow-up question naire was 66.1 % ( N = 72/109 ) . Results The increase of BMI z-score between 24–48 months was not significantly slower among the intervention group offspring ( 95 % CI −0.025 to 0.009 , p = 0.34 ) compared to control group . Z-scores for weight-for-length/height did not differ between groups when the period 0–48 months was analyzed ( 95 % CI −0.010 to 0.014 , p = 0.75 ) . Conclusions In this pilot study gestational lifestyle counseling did not significantly slow the weight gain of the offspring . Gestational intervention studies with at least 300 mothers per group are needed to confirm the possible effect on offspring ’s risk for obesity . Trial registration Current Controlled Trials IS RCT N21512277 [3078095] Background In conjunction with the growing prevalence of obesity and the older age of pregnant women gestational diabetes ( GDM ) is a major health problem . The aim of the study was to evaluate if a lifestyle intervention since early pregnancy is feasible in improving the glucose tolerance of women at a high-risk for GDM in Finl and . Methods A 75-g oral glucose tolerance test ( OGTT ) was performed in early pregnancy ( n = 102 ) . Women at high risk for GDM ( n = 54 ) were r and omized at weeks 8 - 12 from Apr 2005 to May 2006 to a lifestyle intervention group ( n = 27 ) or to a close follow-up group ( n = 27 ) . An OGTT was performed again at weeks 26 - 28 for the lifestyle intervention and close follow-up groups . Results The values of the OGTT during the second trimester did not differ between the lifestyle intervention and close follow-up groups . In the lifestyle intervention group three women had GDM in the second trimester and respectively one woman in the close follow up group . Insulin therapy was not required in both groups . The intervention result ed in somewhat lower weight gain 11.4 ± 6.0 kg vs. 13.9 ± 5.1 kg , p = 0.062 , adjusted by the prepregnancy weight . Conclusions Early intervention with an OGTT and simple lifestyle advice is feasible . A more intensive lifestyle intervention did not offer additional benefits with respect to glucose tolerance , although it tended to ameliorate the weight gain . Trial Registration Clinical Trials.gov : [3295699] Background Pregnancy is a time of significant physiological and physical change for women . In particular , it is a time at which many women are at risk of gaining excessive weight . We describe the rationale and methods of the Health in Pregnancy and Post-birth ( HIPP ) Study , a study which aims primarily to determine the effectiveness of a specialized health coaching ( HC ) intervention during pregnancy , compared to education alone , in preventing excessive gestational weight gain and postpartum weight retention 12 months post birth . A secondary aim of this study is to evaluate the mechanisms by which our HC intervention impacts on weight management both during pregnancy and post birth . Methods / Design The r and omized controlled trial will be conducted with 220 women who have a BMI > 18.5 ( American IOM cut-off for normal weight ) , are 18 years of age or older , English speaking , no history of disordered eating or diabetes and are less than 18 weeks gestation at recruitment . Women will be r and omly allocated to either a specialized HC intervention group or an Education Alone group . Our specialized HC intervention has two components : ( 1 ) one-on-one sessions with a Health Coach , and ( 2 ) two by two hour educational group sessions led by a Health Coach . Women in the Education Alone group will receive two by two hour educational group sessions with no HC components . Body Mass Index , waist circumference , and psychological factors including motivation , readiness to change , symptoms of depression and anxiety , and body dissatisfaction will be assessed at baseline ( 14 - 16 weeks gestation ) , and again at follow-up : 32 weeks gestation , 6 weeks , 6 months and 12 months postpartum . Discussion Our study responds to the urgent need to design effective interventions in pregnancy to prevent excessive gestational weight gain and postpartum weight retention . Our pregnancy HC intervention is novel and innovative and has been design ed to be easily adopted by health professionals who work with pregnant women , such as obstetricians , midwives , allied health professionals and health psychologists . Trial registration Australian New Zeal and Clinical Trials Registry [3938821] Background Despite the widespread recognition that obesity in pregnant women is associated with adverse outcomes for mother and child , there is no intervention proven to reduce the risk of these complications . The primary aim of this r and omised controlled trial is to assess in obese pregnant women , whether a complex behavioural intervention , based on changing diet ( to foods with a lower glycemic index ) and physical activity , will reduce the risk of gestational diabetes ( GDM ) and delivery of a large for gestational age ( LGA ) infant . A secondary aim is to determine whether the intervention lowers the long term risk of obesity in the offspring . Methods / Design Multicentre r and omised controlled trial comparing a behavioural intervention design ed to improve glycemic control with st and ard antenatal care in obese pregnant women . Inclusion criteria ; women with a BMI ≥30 kg/m2 and a singleton pregnancy between 15 + 0 weeks and 18 + 6 weeks ’ gestation . Exclusion criteria ; pre-defined , pre-existing diseases and multiple pregnancy . R and omisation is on-line by a computer generated programme and is minimised by BMI category , maternal age , ethnicity , parity and centre . Intervention ; this is delivered by a health trainer over 8 sessions . Based on control theory , with elements of social cognitive theory , the intervention is design ed to improve maternal glycemic control . Women r and omised to the control arm receive st and ard antenatal care until delivery according to local guidelines . All women have a 75 g oral glucose tolerance test at 27 + 0- 28 + 6 weeks ’ gestation . Primary outcome ; Maternal : diagnosis of GDM , according to the International Association of Diabetes in Pregnancy Study Group ( IADPSG ) criteria . Neonatal ; infant LGA defined as > 90th customised birth weight centile . Sample size ; 1546 women to provide 80 % power to detect a 25 % reduction in the incidence of GDM and a 30 % reduction in infants large for gestational age . Discussion All aspects of this protocol have been evaluated in a pilot r and omised controlled trial , with subsequent optimisation of the intervention . The findings of this trial will inform whether lifestyle mediated improvement of glycemic control in obese pregnant women can minimise the risk of pregnancy complications . Trial registration Current controlled trials ; IS RCT N89971375 [4194368] Background Overweight and obesity during pregnancy represents a considerable health burden . While research has focused on interventions to limit gestational weight gain , there is little information describing their impact on neonatal health . Our aim was to investigate the effect on a range of pre-specified secondary neonatal outcomes of providing antenatal dietary and lifestyle advice to women who are overweight or obese . Methods We report a range of pre-specified secondary neonatal outcomes from a large r and omised trial in which antenatal dietary and lifestyle advice was provided to women who were overweight or obese . Pregnant women were eligible for participation with a body mass index of 25 kg/m2 or over , and singleton gestation between 10 + 0 and 20 + 0 weeks . Outcome measures included gestational age at birth ; Apgar score below 7 at 5 minutes of age ; need for resuscitation at birth ; birth weight above 4.5 kg or below 2.5 kg ; birth weight , length and head circumference ( and Z-scores ) ; admission to the nursery ; respiratory distress syndrome ; and postnatal length of stay . Data relating to the primary outcome ( large for gestational age infants defined as birth weight above the 90th centile ) and birth weight above 4 kg have been reported previously . Analyses used intention-to-treat principles . Results In total , 2,142 infants were included in the analyses . Infants born to women following lifestyle advice were significantly less likely to have birth weight above 4.5 kg ( 2.15 % versus 3.69 % ; adjusted risk ratio ( aRR ) = 0.59 ; 95 % confidence interval ( CI ) 0.36 to 0.98 ; P = 0.04 ) , or respiratory distress syndrome ( 1.22 % versus 2.57 % ; aRR = 0.47 ; 95 % CI 0.24 to 0.90 ; P = 0.02 ) , particularly moderate or severe disease , and had a shorter length of postnatal hospital stay ( 3.94 ± 7.26 days versus 4.41 ± 9.87 days ; adjusted ratio of means 0.89 ; 95 % CI 0.82 to 0.97 ; P = 0.006 ) compared with infants born to women who received St and ard Care . Conclusions For women who are overweight or obese , antenatal dietary and lifestyle advice has health benefits for infants , without an increase in the risk of harm . Continued follow-up into childhood will be important to assess the longer-term effects of a reduction in high infant birth weight on risk of child obesity . Please see related articles : http://www.biomed central .com/1741 - 7015/12/161 and http://www.biomed central .com/1741 - 7015/12/201 . Clinical trial registration Australian and New Zeal and Clinical Trials Registry ( http://ACTRN12607000161426 [24122103] Oxidized LDL lipids ( ox-LDL ) are associated with lifestyle diseases such as cardiovascular diseases , metabolic syndrome and type 2 diabetes . The present study investigated how postpartum weight retention effects on ox-LDL and serum lipids . The study is a nested comparative research of a cluster-r and omized controlled trial , NELLI ( lifestyle and counselling during pregnancy ) . During early pregnancy ( 8–12 weeks ) and 1 year postpartum , 141 women participated in measurements for determining of plasma lipids : total cholesterol ( T-C ) , LDL-cholesterol ( LDL-C ) , HDL-cholesterol ( HDL-C ) , triacylglycerols ( TAG ) and ox-LDL . Subjects were stratified into tertiles ( weight loss , unaltered weight and weight gain groups ) based on their weight change from baseline to follow-up . Ox-LDL was determined by baseline level of conjugated dienes in LDL lipids . Among the group of weight gainers , concentration of TAG reduced less ( −0.14 vs. −0.33 , p = 0.002 ) , HDL-C reduced more ( −0.31 vs. −0.16 , p = 0.003 ) and ox-LDL/HDL-C ratio increased ( 3.0 vs. −0.2 , p = 0.003 ) when compared to group of weight loss . Both T-C and LDL-C elevated more ( 0.14 vs. −0.21 , p = 0.008 ; 0.31 vs. 0.07 , p = 0.015 ) and TAG and ox-LDL reduced less ( −0.33 vs. 0.20 , p = 0.033 ; −3.33 vs. −0.68 , p = 0.026 ) in unaltered weight group compared to weight loss group . The women who gained weight developed higher TAG and ox-LDL/HDL-C ratio as compared to those who lost weight . Postpartum weight retention of 3.4 kg or more is associated with atherogenic lipid profile [12081815] Reliable tables of glycemic index ( GI ) compiled from the scientific literature are instrumental in improving the quality of research examining the relation between GI , glycemic load , and health . The GI has proven to be a more useful nutritional concept than is the chemical classification of carbohydrate ( as simple or complex , as sugars or starches , or as available or unavailable ) , permitting new insights into the relation between the physiologic effects of carbohydrate-rich foods and health . Several prospect i ve observational studies have shown that the chronic consumption of a diet with a high glycemic load ( GI x dietary carbohydrate content ) is independently associated with an increased risk of developing type 2 diabetes , cardiovascular disease , and certain cancers . This revised table contains almost 3 times the number of foods listed in the original table ( first published in this Journal in 1995 ) and contains nearly 1300 data entries derived from published and unpublished verified sources , representing > 750 different types of foods tested with the use of st and ard methods . The revised table also lists the glycemic load associated with the consumption of specified serving sizes of different foods [6259925] The determine the effect of different foods on the blood glucose , 62 commonly eaten foods and sugars were fed individually to groups of 5 to 10 healthy fasting volunteers . Blood glucose levels were measured over 2 h , and expressed as a percentage of the area under the glucose response curve when the same amount of carbohydrate was taken as glucose . The largest rises were seen with vegetables ( 70 + /- 5 % ) , followed by breakfast cereals ( 65 + /- 5 % ) , cereals and biscuits ( 60 + /- 3 % ) , fruit ( 50 + /- 5 % ) , dairy products ( 35 + /- 1 % ) , and dried legumes ( 31 + /- 3 % ) . A significant negative relationship was seen between fat ( p less than 0.01 ) and protein ( p less than 0.001 ) and postpr and ial glucose rise but not with fiber or sugar content [18582171] OBJECTIVE Studies in predominantly non-Hispanic white population s have suggested that physical activity during pregnancy is associated with a reduced risk of gestational diabetes mellitus ( GDM ) . There are few such studies in Hispanic women , a group at increased risk for GDM . METHODS We conducted a prospect i ve cohort study of household/caregiving , occupational , sports/exercise , and active living habits and the risk of GDM among 1006 Hispanic ( predominantly Puerto Rican ) prenatal care patients in western Massachusetts from 2000 to 2004 . Prepregnancy , early pregnancy , and midpregnancy physical activity was assessed using the Kaiser Physical Activity Survey . RESULTS A total of 33 women ( 3.3 % ) were diagnosed with GDM , and 119 women ( 11.8 % ) were diagnosed with abnormal glucose tolerance . There were no significant associations between GDM risk and occupational and active living activities in prepregnancy , early pregnancy , and midpregnancy or with a change in levels of household/caregiving , occupational , and active living activities from prepregnancy to during pregnancy . However , after controlling for age and prepregnancy body mass index ( BMI ) , women in the highest quartile of prepregnancy ( OR = 0.2 , 95 % CI 0.1 - 0.8 , p(trend ) = 0.03 ) and midpregnancy ( OR = 0.2 , 95 % CI 0.1 - 0.8 , p(trend ) = 0.004 ) household/caregiving activities as well as midpregnancy sports/exercise ( 0.1 , 95 % CI 0.0 - 0.7 , p(trend ) = 0.12 ) had a reduced risk of GDM compared with women in the lowest quartile . CONCLUSIONS Findings in this Hispanic population , although based on small numbers of cases , are consistent with prior research among predominantly non-Hispanic white population [3718707] Background Excessive gestational weight gain ( GWG ) is associated with short- and long-term health problems among mothers and their offspring . There is a strong need for effective intervention strategies targeting excessive GWG to prevent adverse outcomes . Methods We performed a cluster-r and omized controlled intervention trial in eight gynecological practice s evaluating the feasibility and effectiveness of a lifestyle intervention presented to all pregnant women ; 250 healthy , pregnant women were recruited for the study . The intervention program consisted of two individually delivered counseling sessions focusing on diet , physical activity , and weight monitoring . The primary outcome was the proportion of pregnant women exceeding weight gain recommendations of the Institute of Medicine ( IOM ) . Secondary outcome variables were maternal weight retention and short-term obstetric and neonatal outcomes . Results The intervention result ed in a lower proportion of women exceeding IOM guidelines among women in the intervention group ( 38 % ) compared with the control group ( 60 % ) ( odds ratio ( OR ) : 0.5 ; 95 % confidence interval ( CI ) : 0.3 to 0.9 ) without prompting an increase in the proportion of pregnancies with suboptimal weight gain ( 19 % vs. 21 % ) . Participants in the intervention group gained significantly less weight than those in the control group . Only 17 % of the women in the intervention group showed substantial weight retention of more than 5 kg compared with 31 % of those in the control group at month four postpartum ( pp ) ( OR : 0.5 ; 95 % CI : 0.2 to 0.9 ) . There were no significant differences in obstetric and neonatal outcomes . Conclusions Lifestyle counseling given to pregnant women reduced the proportion of pregnancies with excessive GWG without increasing suboptimal weight gain , and may exert favorable effects on pp weight retention . Trial registration German Clinical Trials Register DRKS00003801 [21494772] Aims /hypothesisNew diagnostic criteria for gestational diabetes mellitus ( GDM ) have recently been published . We wished to evaluate what impact these new criteria would have on GDM prevalence and outcomes in a predominantly European population . Methods The Atlantic Diabetes In Pregnancy ( DIP ) programme performed screening for GDM in 5,500 women with an oral glucose tolerance test at 24–28 weeks . GDM was defined according to the new International Association of Diabetes and Pregnancy Study Groups ( IADPSG ) criteria and compared with previous WHO criteria ; maternal and neonatal adverse outcomes were prospect ively recorded . Results Of the participants , 12.4 % and 9.4 % were diagnosed with GDM using IADPSG and WHO criteria , respectively . IADPSG GDM pregnancies were associated with a statistically significant increased incidence of adverse maternal outcomes ( gestational hypertension , polyhydramnios and Caesarean section ) and neonatal outcomes ( prematurity , large for gestational age , neonatal unit admission , neonatal hypoglycaemia and respiratory distress ) . The odds ratio for the development of these adverse outcomes remained significant after adjustment for maternal age , body mass index and non-European ethnicity . Those women who were classified as having normal glucose tolerance by WHO criteria but as having GDM by IADPSG criteria also had significant adverse pregnancy outcomes . Conclusions /interpretationGDM prevalence is higher when using newer IADPSG , compared with WHO , criteria , and these women and their offspring experience significant adverse pregnancy outcomes . Higher rates of GDM pose a challenge to healthcare systems , but improved screening provides an opportunity to attempt to reduce the associated morbidity for mother and child [3718630] Background Complex interventions in obese pregnant women should be theoretically based , feasible and shown to demonstrate anticipated behavioural change prior to inception of large r and omised controlled trials ( RCTs ) . The aim was to determine if a ) a complex intervention in obese pregnant women leads to anticipated changes in diet and physical activity behaviours , and b ) to refine the intervention protocol through process evaluation of intervention fidelity . Methods We undertook a pilot RCT of a complex intervention in obese pregnant women , comparing routine antenatal care with an intervention to reduce dietary glycaemic load and saturated fat intake , and increase physical activity . Subjects included 183 obese pregnant women ( mean BMI 36.3 kg/m2).Diet was assessed by repeated triple pass 24-hour dietary recall and physical activity by accelerometry and question naire , at 16 + 0 to 18 + 6 and at 27 + 0 to 28 + 6 weeks ’ gestation in women in control and intervention arms . Attitudes to behaviour change and quality of life were assessed and a process evaluation undertaken . The full RCT protocol was undertaken to assess feasibility . Results Compared to women in the control arm , women in the intervention arm had a significant reduction in dietary glycaemic load ( 33 points , 95 % CI −47 to −20 ) , ( p < 0.001 ) and saturated fat intake ( −1.6 % energy , 95 % CI −2.8 to −0 . 3 ) at 28 weeks ’ gestation . Objective ly measured physical activity did not change . Physical discomfort and sustained barriers to physical activity were common at 28 weeks ’ gestation . Process evaluation identified barriers to recruitment , group attendance and compliance , leading to modification of intervention delivery . Conclusions This pilot trial of a complex intervention in obese pregnant women suggests greater potential for change in dietary intake than for change in physical activity , and through process evaluation illustrates the considerable advantage of performing an exploratory trial of a complex intervention in obese pregnant women before undertaking a large RCT .Trial registration Trial Registration Number : IS RCT [3919179] Objective To determine the effect of antenatal dietary and lifestyle interventions on health outcomes in overweight and obese pregnant women . Design Multicentre r and omised trial . We utilised a central telephone r and omisation server , with computer generated schedule , balanced variable blocks , and stratification for parity , body mass index ( BMI ) category , and hospital . Setting Three public maternity hospitals across South Australia . Participants 2212 women with a singleton pregnancy , between 10 + 0 and 20 + 0 weeks ’ gestation , and BMI ≥25 . Interventions 1108 women were r and omised to a comprehensive dietary and lifestyle intervention delivered by research staff ; 1104 were r and omised to st and ard care and received pregnancy care according to local guidelines , which did not include such information . Main outcome measures Incidence of infants born large for gestational age ( birth weight ≥90th centile for gestation and sex ) . Prespecified secondary outcomes included birth weight > 4000 g , hypertension , pre-eclampsia , and gestational diabetes . Analyses used intention to treat principles . Results 2152 women and 2142 liveborn infants were included in the analyses . The risk of the infant being large for gestational age was not significantly different in the two groups ( lifestyle advice 203/1075 ( 19 % ) v st and ard care 224/1067 ( 21 % ) ; adjusted relative risk 0.90 , 95 % confidence interval 0.77 to 1.07 ; P=0.24 ) . Infants born to women after lifestyle advice were significantly less likely to have birth weight above 4000 g ( lifestyle advice 164/1075 ( 15 % ) v st and ard care 201/1067 ( 19 % ) ; 0.82 , 0.68 to 0.99 ; number needed to treat ( NNT ) 28 , 15 to 263 ; P=0.04 ) . There were no differences in maternal pregnancy and birth outcomes between the two treatment groups . Conclusions For women who were overweight or obese , the antenatal lifestyle advice used in this study did not reduce the risk delivering a baby weighing above the 90th centile for gestational age and sex or improve maternal pregnancy and birth outcomes . Trial registration Australian and New Zeal and Clinical Trials Registry ( ACTRN12607000161426 ) [3928878] Background Maternal overweight , obesity and consequently the incidence of gestational diabetes are increasing rapidly worldwide . The objective of the study was to assess the efficacy and cost-effectiveness of a combined diet and physical activity intervention implemented before , during and after pregnancy in a primary health care setting for preventing gestational diabetes , later type 2 diabetes and other metabolic consequences . Methods RADIEL is a r and omized controlled multi-center intervention trial in women at high risk for diabetes ( a previous history of gestational diabetes or prepregnancy BMI ≥30 kg/m2 ) . Participants planning pregnancy or in the first half of pregnancy were parallel-group r and omized into an intervention arm which received lifestyle counseling and a control arm which received usual care given at their local antenatal clinics . All participants visited a study nurse every three months before and during pregnancy , and at 6 weeks , 6 and 12 months postpartum . Measurements and laboratory tests were performed on all participants with special focus on dietary and exercise habits and metabolic markers . Of the 728 women [ mean age 32.5 years ( SD 4.7 ) ; median parity 1 ( range 0 - 9 ) ] considered to be eligible for the study 235 were non-pregnant and 493 pregnant [ mean gestational age 13 ( range 6 to 18 ) weeks ] at the time of enrollment . The proportion of nulliparous women was 29.8 % ( n = 217 ) . Out of all participants , 79.6 % of the non-pregnant and 40.4 % of the pregnant women had previous gestational diabetes and 20.4 % of the non-pregnant and 59.6 % of the pregnant women were recruited because of a prepregnancy BMI ≥30 kg/m2 . Mean BMI at first visit was 30.1 kg/m2 ( SD 6.2 ) in the non-pregnant and 32.7 kg/m2 ( SD 5.6 ) in the pregnant group . Discussion To our knowledge , this is the first r and omized lifestyle intervention trial , which includes , besides the pregnancy period , both the prepregnancy and the postpartum period . This study design also provides an opportunity to focus upon the health of the next generation . The study is expected to produce novel information on the optimal timing and setting of interventions and for allocating re sources to prevent obesity and diabetes in women of reproductive age . Trial registration Clinical trials.gov Identifier : [18826999] CONTEXT A past history of gestational diabetes mellitus ( GDM ) confers a very high risk of postpartum development of diabetes , particularly type 2 diabetes . OBJECTIVE The Diabetes Prevention Program ( DPP ) sought to identify individuals with impaired glucose tolerance ( IGT ) and intervene in an effort to prevent or delay their progression to diabetes . This analysis examined the differences between women enrolled in DPP with and without a reported history of GDM . DESIGN The DPP was a r and omized , controlled clinical trial . SETTING The study was a multicenter , National Institutes of Health-sponsored trial carried out at 27 centers including academic and Indian Health Services sites . PATIENTS A total of 2190 women were r and omized into the DPP and provided information for past history of GDM . This analysis addressed the differences between those 350 women providing a past history of GDM and those 1416 women with a previous live birth but no history of GDM . INTERVENTIONS Subjects were r and omized to either st and ard lifestyle and placebo or metformin therapy or to an intensive lifestyle intervention . MAIN OUTCOMES The primary outcome was the time to development of diabetes ascertained by semiannual fasting plasma glucose and annual oral glucose tolerance testing . Assessment s of insulin secretion and insulin sensitivity were also performed . RESULTS Whereas entering the study with similar glucose levels , women with a history of GDM r and omized to placebo had a crude incidence rate of diabetes 71 % higher than that of women without such a history . Among women reporting a history of GDM , both intensive lifestyle and metformin therapy reduced the incidence of diabetes by approximately 50 % compared with the placebo group , whereas this reduction was 49 and 14 % , respectively in parous women without GDM . These data suggest that metformin may be more effective in women with a GDM history as compared with those without . CONCLUSIONS Progression to diabetes is more common in women with a history of GDM compared with those without GDM history despite equivalent degrees of IGT at baseline . Both intensive lifestyle and metformin are highly effective in delaying or preventing diabetes in women with IGT and a history of GDM [23784892] OBJECTIVE Optimizing gestational weight gain ( GWG ) in early pregnancy is of clinical and public health importance , especially in higher risk pregnancies . DESIGN AND METHODS In a robustly design ed , r and omized controlled trial , 228 pregnant women at risk of developing gestational diabetes mellitus ( GDM ) were allocated to either control ( written health information only ) or intervention ( four-session lifestyle program ) . All women received st and ard maternal care . Measures were completed at 12 - 15 and 26 - 28 weeks gestation . Measures included anthropometrics ( weight and height ) , physical activity ( pedometer and International Physical Activity Question naire ) , question naires ( risk perception ) , and GDM screening . RESULTS The mean ( SD ) age [ 31.7 ( 4.5 ) and 32.4 ( 4.7 ) years ] and body mass index [ BMI ; 30.3 ( 5.9 ) and 30.4 ( 5.6 ) kg/m(2 ) ] were similar between control and intervention groups , respectively . By 28 weeks , GWG was significantly different between control and intervention groups [ 6.9 ( 3.3 ) vs. 6.0 ( 2.8 ) kg , P < 0.05 ] . When stratified according to baseline BMI , overweight women in the control group gained significantly more weight compared to overweight women in the intervention group [ 7.8 ( 3.4 ) vs. 6.0 ( 2.2 ) kg , P < 0.05 ] , yet in obese women , GWG was similar in both groups . Physical activity levels declined by 28 weeks gestation overall ( P < 0.01 ) ; however , the intervention group retained a 20 % higher step count compared to controls [ 5,203 ( 3,368 ) vs. 4,140 ( 2,420 ) steps/day , P < 0.05 ] . Overall , GDM prevalence was 22.8 % [ Corrected ] , with a trend toward less cases in the intervention group ( P = 0.1 ) . CONCLUSIONS Results indicate that a low-intensity lifestyle intervention , integrated with antenatal care , optimizes healthy GWG and attenuates physical activity decline in early pregnancy . Efficacy in limiting weight gain was greatest in overweight women and in high-risk ethnically diverse women [3511276] Abstract Background Women who are physically active during early pregnancy have notably lower odds of developing gestational diabetes than do inactive women . The purpose of the intervention was to examine whether intensified physical activity ( PA ) counseling in Finnish maternity care is feasible and effective in promoting leisure-time PA ( LTPA ) among pregnant women at risk of gestational diabetes . Methods Fourteen municipalities were r and omized to intervention ( INT ) and usual care group ( UC ) . Nurses in INT integrated five PA counseling sessions into routine maternity visits and offered monthly group meetings on PA instructed by physiotherapists . In UC conventional practice s were continued . Feasibility evaluation included safety ( incidence of PA-related adverse events ; question naire ) , realization ( timing and duration of sessions , number of sessions missed , attendance at group meetings ; systematic record-keeping of the nurses and physiotherapists ) and applicability ( nurses ’ views ; telephone interview ) . Effectiveness outcomes were weekly frequency and duration of total and intensity-specific LTPA and meeting PA recommendation for health self-reported at 8 - 12 ( baseline ) , 26 - 28 and 36 - 37 weeks ’ gestation . Multilevel analysis with adjustments was used in testing for between-group differences in PA changes . Results The decrease in the weekly days of total and moderate-to-vigorous-intensity LTPA was smaller in INT ( N = 219 ) than in UC ( N = 180 ) from baseline to the first follow-up ( 0.1 vs. -1.2 , p = 0.040 and −0.2 vs. -1.3 , p = 0.016 ) . A similar trend was seen in meeting the PA recommendation ( −11%-points vs. -28%-points , p = 0.06 ) . INT did not experience more adverse events classified as warning signs to terminate exercise than UC , counseling was implemented as planned and viewed positively by the nurses . Conclusions Intensified counseling had no effects on the duration of total or intensity-specific weekly LTPA . However , it was able to reduce the decrease in the weekly frequency of total and moderate-to-vigorous-intensity LTPA from baseline to the end of second trimester and was feasibly embedded into routine practice s . Trial registration IS RCT N 33885819 ( http://www.is rct n.org [22017967] Please cite this paper as : Hui A , Back L , Ludwig S , Gardiner P , Sevenhuysen G , Dean H , Sellers E , McGavock J , Morris M , Bruce S , Murray R , Shen G. Lifestyle intervention on diet and exercise reduced excessive gestational weight gain in pregnant women under a r and omised controlled trial . BJOG 2012;119:70–77 [22453250] PURPOSE This study aim ed to evaluate the effect of an exercise program of two different intensities , with nutritional control , on gestational weight gain ( GWG ) , infant birth weight , and maternal weight retention at 2 months postpartum ( 2 mopp ) . METHODS Pregnant women ( prepregnancy body mass index = 18.5 - 24.9 kg·m ) were r and omized at study entry ( 16 - 20 wk of gestation ) to a low-intensity ( LI , 30 % HR reserve ( HRR ) , n = 23 ) or moderate-intensity ( MI , 70 % HRR , n = 26 ) exercise program , with nutritional control . The exercise program consisted of walking sessions three to four times per week , gradually increasing exercise time from 25 to 40 min per session . Forty-five normal-weight women who did not participate in any structured exercise program during pregnancy and had singleton births were used as a historical control group . RESULTS Total GWG was higher in the control group ( 18.3 ± 5.3 kg ) compared with the LI ( 15.3 ± 2.9 kg , P = 0.01 ) and MI ( 14.9 ± 3.8 kg , P = 0.003 ) groups . During the intervention , GWG was similar in both intervention groups , with weekly rates of weight gain of 0.49 ± 0.1 and 0.47 ± 0.1 kg·wk in the LI and MI groups , respectively . Excessive GWG during the intervention was prevented in 70 % of the women in the LI group and 77 % of those in the MI group . Excessive GWG occurred before the intervention began . At 2 mopp , 18 % and 28 % of the women in the LI and MI groups , respectively , retained ≤2.0 kg compared with only 7 % of those in the control group . Infant birth weight was not different between the groups . CONCLUSIONS Results suggest that a prenatal nutrition and exercise program regardless of exercise intensity , reduced excessive GWG and decreased weight retention at 2 mopp in women of normal weight before pregnancy [4221718] Background Pregnancy is a recognised high risk period for excessive weight gain , contributing to postpartum weight retention and obesity development long-term . We aim ed to reduce postpartum weight retention following a low-intensity , self-management intervention integrated with routine antenatal care during pregnancy . Methods 228 women at increased risk of gestational diabetes , < 15 weeks gestation were r and omised to intervention ( 4 self-management sessions ) or control ( generic health information ) . Outcomes , collected at baseline and 6 weeks postpartum , included anthropometrics ( weight and height ) , physical activity ( pedometer ) and question naires ( health behaviours ) . Results Mean age ( 32.3 ± 4.7 and 31.7 ± 4.4 years ) and body mass index ( 30.4 ± 5.6 and 30.3 ± 5.9 kg/m2 ) were similar between intervention and control groups , respectively at baseline . By 6 weeks postpartum , weight change in the control group was significantly higher than the intervention group with a between group difference of 1.45 ± 5.1 kg ( 95 % CI : -2.86,-0.02 ; p < h0.05 ) overall , with a greater difference in weight found in overweight , but not obese women . Intervention group allocation , higher baseline BMI , GDM diagnosis , country of birth and higher age were all independent predictors of lower weight retention at 6 weeks postpartum on multivariable linear regression . Other factors related to weight including physical activity , did not differ between groups . Conclusions A low intensity intervention , integrated with st and ard antenatal care is effective in limiting postpartum weight retention . Implementation research is now required for scale-up to optimise antenatal health care . Trial registration Australian New Zeal and Clinical Trial Registry Number : ACTRN12608000233325 . Registered 7/5/2008 [19155899] OBJECTIVE : To estimate whether an organized , consistent program of dietary and lifestyle counseling prevents excessive weight gain in pregnancy . METHODS : This r and omized controlled trial assigned women to receive either an organized , consistent program of intensive dietary and lifestyle counseling or routine prenatal care . The primary study outcome was the proportion of patients whose gestational weight gain was within the Institute of Medicine ( IOM ) guidelines . Secondary outcomes included mode of delivery , rate of operative vaginal delivery , neonatal weight , and the incidence of preeclampsia , gestational diabetes mellitus ( GDM ) , vaginal/perineal lacerations , and shoulder dystocia . RESULTS : A total of 100 women were r and omized to the study ( lifestyle counseling 57 , routine prenatal care 43 ) . Baseline demographic characteristics were similar between the study groups . The lifestyle counseling group gained significantly less weight than did the routine prenatal care group ( 28.7±12.5 lb compared with 35.6±15.5 lb , P=.01 ) . The routine prenatal care group had significantly more cesarean deliveries due to “ failure to progress ” ( routine prenatal care 58.3 % compared with lifestyle counseling 25.0 % , P=.02 ) . Across groups , patients who were not adherent to the IOM guidelines had significantly heavier neonates ( adherent 3,203.2±427.2 g compared with not adherent 3,517.4±572.4 g , P<.01 ) . Nulliparous women gained significantly more weight than did parous women ( 36.5±14.5 lb compared with 27.7±12.7 lb , P<.01 ) . The most predictive factor of IOM adherence was having a normal prepregnancy body mass index . No statistically significant differences were noted between the groups in adherence to IOM guidelines , rate of cesarean delivery , preeclampsia , GDM , operative vaginal delivery , or vaginal lacerations . CONCLUSION : An organized , consistent program of dietary and lifestyle counseling did reduce weight gain in pregnancy . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00792480 LEVEL OF EVIDENCE : [15951574] BACKGROUND We conducted a r and omized clinical trial to determine whether treatment of women with gestational diabetes mellitus reduced the risk of perinatal complications . METHODS We r and omly assigned women between 24 and 34 weeks ' gestation who had gestational diabetes to receive dietary advice , blood glucose monitoring , and insulin therapy as needed ( the intervention group ) or routine care . Primary outcomes included serious perinatal complications ( defined as death , shoulder dystocia , bone fracture , and nerve palsy ) , admission to the neonatal nursery , jaundice requiring phototherapy , induction of labor , cesarean birth , and maternal anxiety , depression , and health status . RESULTS The rate of serious perinatal complications was significantly lower among the infants of the 490 women in the intervention group than among the infants of the 510 women in the routine-care group ( 1 percent vs. 4 percent ; relative risk adjusted for maternal age , race or ethnic group , and parity , 0.33 ; 95 percent confidence interval , 0.14 to 0.75 ; P=0.01 ) . However , more infants of women in the intervention group were admitted to the neonatal nursery ( 71 percent vs. 61 percent ; adjusted relative risk , 1.13 ; 95 percent confidence interval , 1.03 to 1.23 ; P=0.01 ) . Women in the intervention group had a higher rate of induction of labor than the women in the routine-care group ( 39 percent vs. 29 percent ; adjusted relative risk , 1.36 ; 95 percent confidence interval , 1.15 to 1.62 ; P<0.001 ) , although the rates of cesarean delivery were similar ( 31 percent and 32 percent , respectively ; adjusted relative risk , 0.97 ; 95 percent confidence interval , 0.81 to 1.16 ; P=0.73 ) . At three months post partum , data on the women 's mood and quality of life , available for 573 women , revealed lower rates of depression and higher scores , consistent with improved health status , in the intervention group . CONCLUSIONS Treatment of gestational diabetes reduces serious perinatal morbidity and may also improve the woman 's health-related quality of life [1523339] Background Preventing excessive weight gain during pregnancy is potentially important in the prevention of overweight and obesity among women of childbearing age . However , few intervention studies aim ing at weight management during pregnancy have been performed and most of these interventions were not as successful as expected . In this paper the design of the New Life(style ) study is described as well as the content of the individually tailored intervention program , which focuses on controlling weight development during pregnancy . Methods The effectiveness of the New Life(style ) intervention program versus usual care by midwives is evaluated in a r and omised controlled trial . Women who expect their first child and visit one of the participating midwifery practice s are included . The intervention is st and ardised in a protocol and executed by trained counsellors with the women who are r and omised in the intervention group . During 5 sessions – at 18 , 22 , 30 and 36 weeks of pregnancy and at 8 weeks postpartum – individual weight gain is discussed in relation to weight gain guidelines for pregnant women of the American Institute of Medicine . Counsellors coach the women to maintain or optimise a healthy lifestyle , in a period of drastic physical and mental changes . Data is collected at 15 , 25 , 35 weeks of pregnancy and at 6 , 26 , and 52 weeks after delivery . Primary outcome measures are body weight , BMI , and skinfold thickness . Secondary outcome measures include physical activity , nutrition and blood levels of factors that are associated with energy homeostasis . Discussion Results of the current RCT will improve the knowledge of determinants of weight gain during pregnancy , weight retention after childbirth and of the effectiveness of the intervention program that is described . Caregivers and research ers in the field of health promotion are offered more insight in specific elements of the New Life(style ) intervention program [25300260] Overweight and obesity during pregnancy are common and are associated with an increased risk of adverse health outcomes for both the mother and the infant . However , robust evidence about the effect of antenatal dietary and lifestyle interventions on health outcomes is lacking . We conducted a multicenter , r and omized trial , recruiting 2,212 women ( from 3 public maternity hospitals across South Australia ) with a singleton pregnancy between 10 + 0 and 20 + 0 weeks ' gestation and a BMI ≥25 . The women were r and omized to lifestyle advice ( n = 1,108 ) or st and ard care ( n = 1,104 ) . Women r and omized to lifestyle advice participated in a comprehensive dietary and lifestyle intervention over the course of their pregnancy ( delivered by research staff ) , while women r and omized to st and ard care received pregnancy care according to local guidelines , which did not include such information . Provision of the lifestyle intervention was associated with a significant 18 % relative risk reduction in the chance of infants being born with a birth weight above 4 kg . No other significant differences were identified in maternal pregnancy and birth outcomes between the two treatment groups . Observational studies highlight the association between a high infant birth weight and the subsequent risk of childhood and adulthood obesity . Antenatal interventions that are effective in reducing high infant birth weights therefore represent a significant strategy to tackle obesity from a population health perspective , while ongoing interrogation of the biospecimens and measurements , including ongoing childhood follow-up , will provide a unique opportunity to evaluate the mechanistic pathways of maternal-to-infant/childhood obesity [22638902] Depression during the prenatal and postpartum periods is associated with poor maternal , perinatal and child outcomes . This study examines the effectiveness of a culturally and linguistically tailored , social support-based , healthy lifestyle intervention led by trained community health workers in reducing depressive symptoms among pregnant and early postpartum Latinas . A sample of 275 pregnant Latinas was r and omized to the Healthy MOMs Healthy Lifestyle Intervention ( MOMs ) or the Healthy Pregnancy Education ( control ) group . More than one-third of participants were at risk for depression at baseline . MOMs participants were less likely than control group participants to be at risk for depression at follow-up . Between baseline and 6 weeks postpartum , MOMs participants experienced a significant decline in depressive symptoms ; control participants experienced a marginally significant decline . For MOMs participants , most of this decline occurred during the pregnancy intervention period , a time when no change occurred for control participants . The change in depressive symptoms during this period was greater among MOMs than control participants ( “ intervention effect ” ) . From baseline to postpartum , there was a significant intervention effect among non-English-speaking women only . These findings provide evidence that a community-planned , culturally tailored healthy lifestyle intervention led by community health workers can reduce depressive symptoms among pregnant , Spanish-speaking Latinas [21470082] OBJECTIVE The International Association of Diabetes and Pregnancy Study Groups ( IADPSG ) has proposed new criteria for the diagnosis of gestational diabetes mellitus ( GDM ) . The aim of this study was to compare the prevalence of GDM when IADPSG criteria were used with the prevalence when the current Australasian Diabetes in Pregnancy Society ( ADIPS ) criteria were used . DESIGN , SETTING AND PARTICIPANTS This was a prospect i ve study over a 6-month period , examining the results of all glucose tolerance tests ( GTTs ) conducted for the diagnosis of GDM in Wollongong , a city using the public and private sectors . MAIN OUTCOME MEASURES The prevalence of GDM using the existing ( ADIPS ) and the proposed ( IADPSG ) criteria . RESULTS There were 1275 evaluable GTTs ( 571 public and 704 private ) . Using the current ADIPS diagnostic criteria , the prevalence of GDM was 8.6 % ( public ) , 10.5 % ( private ) and 9.6 % ( overall ) . Using the proposed IADPSG criteria , the prevalence of GDM was 9.1 % ( public ) , 16.2 % ( private ) and 13.0 % ( overall ) . CONCLUSIONS The proposed IADPSG criteria would increase the prevalence of GDM from 9.6 % to 13.0 % ( P < 0.001 ) . In our study in the Wollongong area , which has a population with a predominantly white background , this increase came mainly from older women attending a private pathology provider . Data from both the public and private sectors need to be included in any discussion on the change in prevalence of GDM [3710199] Background Gestational diabetes mellitus ( GDM ) is an increasing problem world-wide . Lifestyle interventions and /or vitamin D supplementation might help prevent GDM in some women . Methods / design Pregnant women at risk of GDM ( BMI ≥29 ( kg/m2 ) ) from 9 European countries will be invited to participate and consent obtained before 19 + 6 weeks of gestation . After giving informed consent , women without GDM will be included ( based on IADPSG criteria : fasting glucose<5.1mmol ; 1 hour glucose < 10.0 mmol ; 2 hour glucose < 8.5 mmol ) and r and omized to one of the 8 intervention arms using a 2 × (2 × 2 ) factorial design : ( 1 ) healthy eating ( HE ) , 2 ) physical activity ( PA ) , 3 ) HE+PA , 4 ) control , 5 ) HE+PA+vitamin D , 6 ) HE+PA+placebo , 7 ) vitamin D alone , 8) placebo alone ) , pre-stratified for each site . In total , 880 women will be included with 110 women allocated to each arm . Between entry and 35 weeks of gestation , women allocated to a lifestyle intervention will receive 5 face-to-face , and 4 telephone coaching sessions , based on the principles of motivational interviewing . The lifestyle intervention includes a discussion about the risks of GDM , a weight gain target < 5 kg and either 7 healthy eating ‘ messages ’ and /or 5 physical activity ‘ messages ’ depending on r and omization . Fidelity is monitored by the use of a personal digital assistance ( PDA ) system . Participants r and omized to the vitamin D intervention receive either 1600 IU vitamin D or placebo for daily intake until delivery . Data is collected at baseline measurement , at 24–28 weeks , 35–37 weeks of gestation and after delivery . Primary outcome measures are gestational weight gain , fasting glucose and insulin sensitivity , with a range of obstetric secondary outcome measures including birth weight . Discussion DALI is a unique Europe-wide r and omised controlled trial , which will gain insight into preventive measures against the development of GDM in overweight and obese women . Trial registration IS RCT [3506505] Abstract Background The Australian Carbohydrate Intolerance Study in Pregnant Women ( ACHOIS ) showed that treatment of pregnant women with mild gestational diabetes mellitus is beneficial for both women and their infants . It is still uncertain whether there are benefits of similar treatment for women with borderline gestational diabetes . This trial aims to assess whether dietary and lifestyle advice and treatment given to pregnant women who screen for borderline gestational diabetes reduces neonatal complications and maternal morbidities . Methods / design Design : Multicentre , r and omised controlled trial . Inclusion criteria : Women between 240 and 346 weeks gestation with a singleton pregnancy , a positive oral glucose challenge test ( venous plasma glucose ≥7.8 mmol/L ) and a normal oral 75 gram glucose tolerance test ( fasting venous plasma glucose < 5.5 mmol/L and a 2 hour glucose < 7.8 mmol/L ) with written , informed consent . Trial entry and r and omisation : Women with an abnormal oral glucose tolerance test ( fasting venous plasma glucose ≥5.5 mmol/L or 2 hour glucose ≥7.8 mmol/L ) will not be eligible and will be offered treatment for gestational diabetes , consistent with recommendations based on results of the ACHOIS trial . Eligible women will be r and omised into either the ‘ Routine Care Group ’ or the ‘ Intervention Group ’ . Study groups : Women in the ‘ Routine Care Group ’ will receive routine obstetric care reflecting current clinical practice in Australian hospitals . Women in the ‘ Intervention Group ’ will receive obstetric care , which will include dietary and lifestyle advice , monitoring of blood glucose and further medical treatment for hyperglycaemia as appropriate . Primary study outcome : Incidence of large for gestational age infants . Sample size : A sample size of 682 women will be sufficient to show a 50 % reduction in the risk of large for gestational age infants ( alpha 0.05 two-tailed , 80 % power , 4 % loss to follow up ) from 14 % to 7 % with dietary and lifestyle advice and treatment . Discussion A conclusive trial outcome will provide reliable evidence of relevance for the care of women with borderline glucose intolerance in pregnancy and their infants . Trial registration Australian New Zeal and Clinical Trials Registry - [4280000] Background We conducted a nested r and omised trial to evaluate the effect of an educational DVD , providing information about healthy food choices and exercise during pregnancy , on diet and physical activity , among pregnant women who were overweight or obese . Methods We conducted a nested r and omised trial within the context of the LIMIT r and omised trial . Women were eligible with a singleton pregnancy between 10 and 20 weeks gestation , and body mass index at the time of their first antenatal appointment of ≥25 kg/m2 . All women who were r and omised to the Lifestyle Advice Group of the LIMIT trial received a series of consultations with both research dieticians and research assistants , in addition to st and ard written dietary and exercise material s ( St and ard Material s Group ) . Women r and omised to the DVD Group received the same consultations and written material s , and additionally received an educational DVD ( DVD Group ) . The primary study outcome was the Healthy Eating Index . Other study outcomes included physical activity , and gestational weight gain . Women completed a qualitative evaluation of all the material s provided . Results 1,108 women in the LIMIT Lifestyle Advice Group participated in the nested trial , with 543 women r and omised to the DVD Group , and 565 women to the St and ard Material s Group . Women who received the DVD compared with those who did not , had a higher mean Healthy Eating Index at 36 weeks gestation ( 73.6 vs 72.3 ; adjusted mean difference 1.2 ; 95 % CI 0.2 to 2.3 ; p = 0.02 ) , but not at 28 weeks gestation ( 73.2 vs 73.5 ; adjusted mean difference −0.1 ; 95 % CI −1.1 to 0.9 ; p = 0.82 ) . There were no statistically significant differences in physical activity or total gestational weight gain . While most women evaluated the material s positively , frequency of utilisation was poor . Conclusions Ongoing attention to the delivery of information is required , particularly with the increased use and availability of digital and multi-media interactive technologies . Trial registration Australian and New Zeal and Clinical Trials Registry [3973835] Background Recent studies suggest that excessive gestational weight gain ( GWG ) leads to adverse maternal and fetal outcomes including weight retention in the mother and an increased risk of childhood obesity in the offspring . The aim of the GeliS study is to examine the effect of a lifestyle intervention programme during pregnancy to avoid excessive GWG and , hence , to reduce pregnancy and obstetric complications as well as the risk of maternal and offspring obesity . Methods and design The GeliS study is a multicentre cluster-r and omized controlled trial . A total number of 2500 pregnant women ( singleton pregnancy ) with a pre-pregnancy BMI ≥ 18.5 kg/m2 and ≤ 40 kg/m2 will be recruited in practice s of gynaecologists and midwives in ten Bavarian regions . The intervention comprises three structured and individualised counselling sessions on a healthy diet , regular physical activity as well as weight monitoring during pregnancy and one session after delivery , respectively . The counselling sessions are attached to routine pre- and postnatal visits using st and ardised material s and procedures . In the control regions , general recommendations for a healthy lifestyle are given . An oral glucose tolerance test is offered to all participants .The primary outcome is the proportion of participants with excessive GWG . Secondary outcomes include pregnancy and obstetric complications such as frequency of gestational diabetes , preeclampsia and caesarean sections as well as weight retention in the mothers and BMI and other health variables in the offspring . A 5-year follow-up of both mothers and their infants is planned . Discussion The GeliS lifestyle intervention programme has been adapted to the existing routine health care system for pregnant women . If shown to be effective , it could be immediately implemented in routine care . Trial registration The study protocol is registered at the Clinical Trials.gov Protocol Registration System ( NCT01958307 ) [4176103] Background Maternal diet is known to impact pregnancy outcome . Following a low glycemic index ( GI ) diet during pregnancy has been shown to improve maternal glycemia and reduce infant birthweight and may be associated with a higher fibre intake . We assessed the impact of a low GI dietary intervention on maternal GI , nutritional intake and gestational weight gain ( GWG ) during pregnancy . Compliance and acceptability of the low GI diet was also examined . Method Eight hundred women were r and omised in early pregnancy to receive low GI and healthy eating dietary advice or to receive st and ard maternity care . The intervention group received dietary advice at a group education session before 22 weeks gestation . All women completed a 3 day food diary during each trimester of pregnancy . Two hundred and thirty five women from the intervention arm and 285 women from the control arm returned complete 3x3d FDs and were included in the present analysis . Results Maternal GI was significantly reduced in the intervention group at trimester 2 and 3 . The numbers of women within the lowest quartile of GI increased from 37 % in trimester 1 to 52 % in trimester 3 ( P < 0.001 ) among the intervention group . The intervention group had significantly lower energy intake ( P < 0.05 ) , higher protein ( % TE ) ( P < 0.01 ) and higher dietary fibre intake ( P < 0.01 ) post intervention . Consumption of food groups with known high GI values were significantly reduced among the intervention group . Women in the intervention low GI group were less likely to exceed the Institute of Medicine ’s GWG goals . Conclusion A dietary intervention in early pregnancy had a positive influence on maternal GI , food and nutrient intakes and GWG . Following a low GI diet may be particularly beneficial for women at risk of exceeding the GWG goals for pregnancy . Trial registration Current Controlled Trials Registration Number : IS RCT N54392969 [4287470] Background The objectives of this study were to assess the efficacy of lifestyle intervention on gestational weight gain in pregnant women with normal and above normal body mass index ( BMI ) in a r and omized controlled trial . Methods A total of 116 pregnant women ( < 20 weeks of pregnancy ) without diabetes were enrolled and 113 pregnant women completed the program . Participants were r and omized into intervention and control groups . Women in the intervention group received weekly trainer-led group exercise sessions , instructed home exercise for 3 - 5-times/week during 20 - 36 weeks of gestation , and dietary counseling twice during pregnancy . Participants in the control group did not receive the intervention . All participants completed a physical activity question naire and a 3-day food record at enrolment and 2 months after enrolment . Results The participants in the intervention group with normal pre-pregnancy BMI ( ≤24.9 kg/M2 , n = 30 ) had lower gestational weight gain ( GWG ) , offspring birth weight and excessive gestational weight gain ( EGWG ) on pregnancy weight gain compared to the control group ( n = 27 , p < 0.05 ) . Those weight related-changes were not detected between the intervention ( n = 27 ) and control group ( n = 29 ) in the above normal pre-pregnancy BMI participants . Intervention reduced total calorie , total fat , saturated fat and cholesterol intake were detected in women with normal or above normal pre-pregnancy BMI compared to the control group ( p < 0.05 or 0.01 ) . Increased physical activity and reduced carbohydrate intake were detected in women with normal ( p < 0.05 ) , but not above normal , pre-pregnancy BMI at 2 months after the onset of the intervention compared to the control group . Conclusion The results of the present study demonstrated that the lifestyle intervention program decreased EGWG , GWG , offspring birth weight in pregnant women with normal , but not above normal , pre-pregnancy BMI , which was associated with increased physical activity and decreased carbohydrate intake . Trial registration [2527301] Background The purpose of the study is to examine the effects and feasibility of individual physical activity ( PA ) counseling in maternity and child health clinics in Finl and . Methods Three clinics including both maternity and child health care signed up for the experimental ( EXP ) and three for the control group ( CON ) . The participants were 132 pregnant and 92 postpartum primiparas . The nurses in EXP integrated a primary and four booster PA counseling sessions into routine visits . An option for supervised group exercise was offered . In CON former practice s , usually including brief PA advice , were continued . Leisure-time PA ( LTPA ) prior to pregnancy was elicited by question naire and followed 16–18 and 36–37 weeks ' gestation in maternity clinics and 5 and 10 months postpartum in child health clinics . Feasibility included safety , participant responsiveness , realization of counseling and applicability . Results According to analysis of covariance adjusted for baseline LTPA and possible confounders , no relative between-group differences in LTPA were found at the first follow-up in either maternity or child health clinics . At the last follow-up in maternity clinics the weekly number of at least moderate-intensity LTPA days was 43 % ( 95 % CI : 9 , 87 ) higher and the weekly duration of at least moderate-intensity LTPA 154 % ( 95 % CI : 16 , 455 ) higher in EXP compared with CON . Counseling proved feasible in both maternity and child health clinics . Conclusion Counseling encouraged pregnant women to sustain their moderate-intensity LTPA and was feasible in routine practice s. No effects were observed if counseling was initiated postpartum . Trial registration Current Controlled Trials IS RCT [25306925] AIMS To pilot the feasibility of a prenatal lifestyle intervention to modify physical activity and diet among pregnant overweight and obese Hispanic women , with the aim of reducing risk factors for gestational diabetes mellitus . METHODS Women were r and omized either to a lifestyle intervention ( n = 33 , 48.5 % ) , consisting of a culturally and linguistically modified , motivationally targeted , individually tailored 6-month prenatal programme , or to st and ard care ( n = 35 , 51.5 % ) . Bilingual and bicultural health educators encouraged women to achieve guidelines for physical activity , decrease saturated fat and increase dietary fibre . Outcomes included gestational weight gain , infant birth weight and biomarkers associated with insulin resistance . RESULTS Patient retention up to delivery was 97 % in both study groups . The lifestyle intervention attenuated the pregnancy-associated decline in moderate-intensity physical activity , but differences between groups were not significant ( mean ± se -23.4 ± 16.6 vs -27.0 ± 16.2 metabolic equivalent of task h/week ; P = 0.88 ) . Vigorous-intensity activity increased during the course of pregnancy in the lifestyle intervention group ( mean ± se 1.6 ± 0.8 metabolic equivalent of task h/week ) and declined in the st and ard care group ( -0.8 ± 0.8 metabolic equivalent of task h/week ; P = 0.04 ) . The lifestyle intervention group also had slightly lower gestational weight gain and infant birth weights compared with the st and ard care group ; however , these differences were not statistically significant . There were no statistically significant differences in biomarkers of insulin resistance between groups . CONCLUSIONS Findings suggest that a motivationally matched lifestyle intervention is feasible and may help attenuate pregnancy-related decreases in vigorous physical activity in a population of overweight and obese Hispanic women . The intervention protocol can readily be translated into clinical practice in underserved and minority population [11333990] BACKGROUND Type 2 diabetes mellitus is increasingly common , primarily because of increases in the prevalence of a sedentary lifestyle and obesity . Whether type 2 diabetes can be prevented by interventions that affect the lifestyles of subjects at high risk for the disease is not known . METHODS We r and omly assigned 522 middle-aged , overweight subjects ( 172 men and 350 women ; mean age , 55 years ; mean body-mass index [ weight in kilograms divided by the square of the height in meters ] , 31 ) with impaired glucose tolerance to either the intervention group or the control group . Each subject in the intervention group received individualized counseling aim ed at reducing weight , total intake of fat , and intake of saturated fat and increasing intake of fiber and physical activity . An oral glucose-tolerance test was performed annually ; the diagnosis of diabetes was confirmed by a second test . The mean duration of follow-up was 3.2 years . RESULTS The mean ( + /-SD ) amount of weight lost between base line and the end of year 1 was 4.2+/-5.1 kg in the intervention group and 0.8+/-3.7 kg in the control group ; the net loss by the end of year 2 was 3.5+/-5.5 kg in the intervention group and 0.8+/-4.4 kg in the control group ( P<0.001 for both comparisons between the groups ) . The cumulative incidence of diabetes after four years was 11 percent ( 95 percent confidence interval , 6 to 15 percent ) in the intervention group and 23 percent ( 95 percent confidence interval , 17 to 29 percent ) in the control group . During the trial , the risk of diabetes was reduced by 58 percent ( P<0.001 ) in the intervention group . The reduction in the incidence of diabetes was directly associated with changes in lifestyle . CONCLUSIONS Type 2 diabetes can be prevented by changes in the lifestyles of high-risk subjects [24284438] BACKGROUND Excessive weight gain during pregnancy is a risk factor for postpartum weight retention and future weight gain and obesity . Whether a behavioral intervention in pregnancy can reduce long-term weight retention is unknown . OBJECTIVE This r and omized trial tested whether a low-intensity behavioral intervention to prevent excessive gestational weight gain could increase the proportion of women who returned to prepregnancy weight by 12 mo postpartum . DESIGN Women ( n = 401 , 13.5 wk of gestation , 50 % normal weight , 50 % overweight/obese ) were r and omly assigned into an intervention or control group ; 79 % completed the 12-mo assessment . The telephone-based intervention targeted gestational weight gain , healthy eating , and exercise and was discontinued at delivery . RESULTS In modified intent-to-treat analyses that excluded women with miscarriages ( n = 6 ) , gestational diabetes ( n = 32 ) , or subsequent pregnancies ( n = 32 ) , the intervention had no significant effect on the odds of achieving prepregnancy weight at 12 mo postpartum ( n = 331 ; 35.4 % compared with 28.1 % ; P = 0.18 ) . Completer analyses suggested that the intervention tended to increase the percentages of women who reached prepregnancy weight ( n = 261 ; 45.3 % compared with 35.3 % ; P = 0.09 ) and significantly reduced the magnitude of mean ± SD postpartum weight retained ( 1.4 ± 6.3 compared with 3.0 ± 5.7 kg ; P = 0.046 ) at 12 mo . Women in the intervention group reported higher dietary restraint through 6 mo postpartum ( P = 0.023 ) and more frequent self-monitoring of body weight ( P < 0.02 for all ) throughout the study . CONCLUSIONS A low-intensity behavioral intervention in pregnancy can reduce 12-mo postpartum weight retention and improve dietary restraint and self-weighing in study completers . Future research is needed to test the long-term effects of more intensive behavioral interventions in pregnancy . This trial was registered at clinical trials.gov as NCT01117961 [12439652] BACKGROUND : The Institute of Medicine ( IOM ) recommends that normal‐weight women ( BMI ( body mass index ) of 19.8–26.0 ) gain 25–35 lb ( 11.4–15.9 kg ) during pregnancy , and that overweight women ( BMI of 26.1–29.0 ) gain 15–25 lbs ( 6.8–11.4 kg ) . A significant number of normal‐weight women and an even greater proportion of overweight women exceed these guidelines , which increases postpartum weight retention and may contribute to the development of obesity . OBJECTIVE : To determine whether a stepped care , behavioral intervention will decrease the percentage of women who gain more than the IOM recommendation . DESIGN : R and omized controlled trial comparing a stepped-care behavioral intervention with usual care . Women ( n=120 ) who had a BMI > 19.8 , age>18 and < 20 weeks gestation were recruited from a hospital-based clinic serving low-income women and r and omized by race and BMI category to the intervention or control group . The intervention group received education about weight gain , healthy eating , and exercise and individual graphs of their weight gain . Those exceeding weight gain goals were given more intensive intervention . Women were followed through pregnancy to their first postpartum clinic visit . The main outcome measure was weight gain during pregnancy categorized as above the IOM recommendations vs below or within the IOM recommendations . RESULTS : The intervention significantly decreased the percentage of normal-weight women who exceeded the IOM recommendations ( 33 vs 58 % , P<0.05 ) . There was a non-significant ( P=0.09 ) effect in the opposite direction among overweight women ( 59 % of intervention and 32 % of control gained more than recommended ) . Postpartum weight retention was strongly related to weight gain during pregnancy ( r=0.89 ) . CONCLUSIONS : The intervention reduced excessive weight gain during pregnancy among normal weight women [22465256] BACKGROUND Obesity and excessive weight gain during pregnancy are associated with adverse pregnancy outcomes . Observational studies suggest that minimal or no gestational weight gain ( GWG ) may minimize the risk of adverse pregnancy outcomes for obese women . OBJECTIVE This report describes the design of Healthy Moms , a r and omized trial testing a weekly , group-based , weight management intervention design ed to help limit GWG to 3 % of weight ( measured at the time of r and omization ) among obese pregnant women ( BMI ≥30 kg/m(2 ) ) . Participants are r and omized at 10 - 20 weeks gestation to either the intervention or a single dietary advice control condition . PRIMARY OUTCOMES The study is powered for the primary outcome of total GWG , yielding a target sample size of 160 women . Additional secondary outcomes include weight change between r and omization and one-year postpartum and proportion of infants with birth weight>90th percentile for gestational age . Statistical analyses will be based on intention-to-treat . METHODS Following r and omization , all participants receive a 45-minute dietary consultation . They are encouraged to follow the Dietary Approaches to Stop Hypertension diet without sodium restriction . Intervention group participants receive an individualized calorie intake goal , a second individual counseling session and attend weekly group meetings until they give birth . Research staff assesses all participants at 34-weeks gestation and at 2-weeks and one-year postpartum with their infants . SUMMARY The Healthy Moms study is testing weight management techniques that have been used with non-pregnant adults . We aim to help obese women limit GWG to improve their long-term health and the health of their offspring [3872607] Background : Abnormal weight gain during pregnancy increases the adverse health outcomes during the pregnancy , delivery , and the postpartum period . Most of the pregnant women develop weight gain more than the recommended limits ; therefore , interventions to manage such disproportionate weight gain are needed . In this paper , the design of the maternal centered life-style intervention study is described , which focuses on controlling weight gaining during pregnancy for all body mass index ( BMI ) groups . Material s and Methods : In our r and omized field trial , 160 pregnant women with 6 - 10 weeks of gestational age who visit one of the participating Isfahan four urban public-health centers and 4 private obstetric offices are included . The maternal centered life-style intervention carried out by trained midwives is st and ardized in a protocol . All the participants are visited at 6 - 10 , 11 - 15 , 16 - 20 , 21 - 25 , 26 - 30 , 31 - 34 , 35 - 37 , 38 , 39 , and 40 weeks of pregnancy . The women who are r and omized in the intervention group receive maternal centered educational package of prenatal care for the pregnant woman and a log book in the first visit . Counselors accompany the pregnant women to maintain or develop a healthy life-style . Data collection will perform monthly measuring body weight , BMI . Conclusion : Because , we do n’t have structured protocol for weight management during pregnancy especially , in private sectors if the maternal centered life-style intervention proves to be effective , it will be suggested to merge this package to routine care . Therewith by empowering women to manage their weight the public-health burden can be reduced . Beside that private obstetricians also have structured protocol for their client management [25300266] Background : Obesity in pregnancy is associated with fetal macrosomia , a raised neonatal fat mass and an increased risk of obesity and poor metabolic health in childhood which persists into adulthood . The offspring of obese women are more likely to be obese than the offspring of lean women when they become pregnant themselves , perpetuating a cycle of obesity and its associated negative metabolic consequences . Increasing physical activity during pregnancy could improve insulin sensitivity and reduce the risk of maternal and offspring adverse outcomes . The UK Pregnancy Better Eating and Activity Trial ( UPBEAT ) is a trial of a complex intervention design ed to improve pregnancy outcomes through dietary changes and physical activity . Data from the pilot trial of 183 women were available for analysis . The relationship between the time spent at different physical activity levels and maternal and infant pregnancy outcomes was examined . Key Messages : Strong evidence exists that physical activity improves insulin sensitivity in non-pregnant population s , and lifestyle interventions of proven effectiveness in non-pregnant population s have been developed . Women who are active in pregnancy demonstrate better glucose control and favourable pregnancy outcomes . There is a lack of effective interventions to support obese pregnant women to be physically active . Conclusions : No difference was detected in objective ly measured physical activity between women r and omised to the intervention and control arms of the UPBEAT pilot trial . Light-intensity physical activity was lower in early pregnancy in women who delivered macrosomic infants . Maternal sedentary time at 35 - 36 weeks ' gestation was positively associated and moderate-intensity physical activity was inversely associated with neonatal abdominal circumference . Maternal physical activity is associated with infant birth weight and abdominal circumference and is an appropriate target for intervention to improve infant outcomes . The challenge remains to develop an effective intervention to support obese pregnant women to be physically active [9704236] The objective of this study was to test the hypothesis that a woman 's dietary carbohydrate mix modifies the glucose and insulin response to both mixed caloric intake and exercise . Either a prospect i ve r and omized or a prospect i ve r and omized crossover design was used to examine the effects of two isocaloric , high-carbohydrate diets on the whole-blood glucose and insulin responses to mixed caloric intake and exercise in healthy nonpregnant ( n = 14 ) and pregnant ( n = 12 ) women . The diets differed only in the type of carbohydrate ingested . Those in one had low glycemic indexes and those in the other had high glycemic indexes . In nonpregnant women , the blood glucose response to a meal containing low-glycemic carbohydrate was half that seen with high-glycemic carbohydrate , and the effect of exercise on blood glucose was more pronounced while eating the high-glycemic carbohydrate diet . During pregnancy , women on the low-glycemic carbohydrate diet experienced no significant change in their glycemic response to mixed caloric intake , whereas those who switched to the high-glycemic carbohydrate diet experienced a 190 % increase in their response . In conclusion , the type of dietary carbohydrate in a healthy , physically active woman 's diet influences both her postpr and ial blood glucose profile and her blood sugar response to exercise [22773616] Background . Intervention fidelity is an increasingly important method ological concept in process evaluations . In this article , the authors investigated the intervention fidelity in a r and omized controlled trial on excessive weight gain prevention in pregnancy . Method . A sample of 109 audiotaped counseling sessions , linked to 65 women in the intervention group of the New Life(style ) trial , was drawn . The following criteria were quantitatively evaluated using a fidelity checklist : ( a ) reach , ( b ) dose , ( c ) adherence to study objectives , ( d ) adherence to underlying problem-solving treatment ( PST ) theory , and ( e ) counselor competence . Results . A total of 60.4 % received all counseling sessions . The dose of intervention components was generally moderate ( 50.9 % to 60.4 % ) , and the dose of PST components was low ( 17.3 % ) . Adherence to study objectives was moderate ( 64.2 % ) and adherence to PST theory was low ( 43.2 % ) . The counselors sufficiently stimulated the participant to optimize lifestyle ( 54.2 % of the sessions ) , provided positive feedback ( 50.5 % ) , and left the initiative regarding problem solving to the participant ( 71 % ) . One of the two counselors performed significantly better on all measured criteria ( p < .001 ) . Conclusions . Intervention fidelity in the New Life(style ) trial was generally low to moderate . In future interventions , it is recommended to put more emphasis on counselor recruitment , training , and intervention protocol contents . Fellow research ers are encouraged to embed a process evaluation into all study stages , taking into account all essential process elements , and to link process outcomes to more distal , health outcomes [15177856] OBJECTIVE To examine the potential effect of low-risk pregnancy on women 's recreational activity patterns and to explore pregnant women 's beliefs and information sources regarding physical exercise participation . DESIGN Preliminary , prospect i ve survey SETTING Participants ' homes in the East Midl and s , UK . PARTICIPANTS Fifty-seven nulliparous , pregnant women . MEASUREMENTS Levels of maternal physical activity participation were assessed by semi-structured interview at 16 , 25 , 34 and 38 weeks gestation . The modified Baecke question naire provided a measure of women 's habitual sport and leisure activities in the 12 months prior to pregnancy . A 10-item scale assessed maternal beliefs regarding the importance of physical activity in pregnancy . The fetal health locus of control scale measured the extent to which women believed their own behaviour , the behaviour of others and /or chance would influence fetal health . Open-ended questions assessed women 's information sources . FINDINGS Fourteen of the 36 ( 39 % ) women who reported participating in some form of weekly exercise before pregnancy did not report pursuing any similar activities during pregnancy . Rest and relaxation were perceived as being significantly more important during pregnancy than was regular exercise or the maintenance of an active lifestyle . Fifty-five respondents ( 96 % ) indicated that they had received advice about physical activity at least once during pregnancy . At 16 weeks gestation , women obtained most of their information from books and magazines . Between 25 and 38 weeks gestation , most advice came from family and friends . Participants who reported receiving this advice were significantly older , more educated and of a higher activity level pre-pregnancy . KEY CONCLUSIONS Levels of maternal exercise may decline during pregnancy both as a result of the physical changes of pregnancy and from a combination of social and psychological factors . Present health education may be failing to correct inaccurate perceptions of the risks associated with physical exercise in pregnancy . IMPLICATION S FOR PRACTICE Improving the quantity and quality of information related to physical exercise has the potential to correct inaccurate perceptions and confer several benefits on maternal and fetal health . Effective intervention strategies should focus not only on the pregnant woman but also extend to her family , friends and exercise provider [18502303] BACKGROUND Intensive lifestyle interventions can reduce the incidence of type 2 diabetes in people with impaired glucose tolerance , but how long these benefits extend beyond the period of active intervention , and whether such interventions reduce the risk of cardiovascular disease ( CVD ) and mortality , is unclear . We aim ed to assess whether intensive lifestyle interventions have a long-term effect on the risk of diabetes , diabetes-related macrovascular and microvascular complications , and mortality . METHODS In 1986 , 577 adults with impaired glucose tolerance from 33 clinics in China were r and omly assigned to either the control group or to one of three lifestyle intervention groups ( diet , exercise , or diet plus exercise ) . Active intervention took place over 6 years until 1992 . In 2006 , study participants were followed-up to assess the long-term effect of the interventions . The primary outcomes were diabetes incidence , CVD incidence and mortality , and all-cause mortality . FINDINGS Compared with control participants , those in the combined lifestyle intervention groups had a 51 % lower incidence of diabetes ( hazard rate ratio [ HRR ] 0.49 ; 95 % CI 0.33 - 0.73 ) during the active intervention period and a 43 % lower incidence ( 0.57 ; 0.41 - 0.81 ) over the 20 year period , controlled for age and clustering by clinic . The average annual incidence of diabetes was 7 % for intervention participants versus 11 % in control participants , with 20-year cumulative incidence of 80 % in the intervention groups and 93 % in the control group . Participants in the intervention group spent an average of 3.6 fewer years with diabetes than those in the control group . There was no significant difference between the intervention and control groups in the rate of first CVD events ( HRR 0.98 ; 95 % CI 0.71 - 1.37 ) , CVD mortality ( 0.83 ; 0.48 - 1.40 ) , and all-cause mortality ( 0.96 ; 0.65 - 1.41 ) , but our study had limited statistical power to detect differences for these outcomes . INTERPRETATION Group-based lifestyle interventions over 6 years can prevent or delay diabetes for up to 14 years after the active intervention . However , whether lifestyle intervention also leads to reduced CVD and mortality remains unclear [24738837] Self‐weighing is important for weight management in general population s ; however its role in optimising gestational weight gain is less clear . Our r and omised trial in early pregnancy found regular self‐weighing when combined with a self‐management intervention , optimised weight gain at 28 weeks gestation ( 5.66 ± 2.6 kg vs 7.03 ± 3.56 kg , P = 0.02 ) and reduced postpartum weight retention ( −0.57 ± 3.94 kg vs 1.48 ± 5.49 kg , P < 0.05 ) compared with control participants . Results highlight the importance of self‐monitoring strategies during pregnancy [11832527] BACKGROUND Type 2 diabetes affects approximately 8 percent of adults in the United States . Some risk factors -- elevated plasma glucose concentrations in the fasting state and after an oral glucose load , overweight , and a sedentary lifestyle -- are potentially reversible . We hypothesized that modifying these factors with a lifestyle-intervention program or the administration of metformin would prevent or delay the development of diabetes . METHODS We r and omly assigned 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concentrations to placebo , metformin ( 850 mg twice daily ) , or a lifestyle-modification program with the goals of at least a 7 percent weight loss and at least 150 minutes of physical activity per week . The mean age of the participants was 51 years , and the mean body-mass index ( the weight in kilograms divided by the square of the height in meters ) was 34.0 ; 68 percent were women , and 45 percent were members of minority groups . RESULTS The average follow-up was 2.8 years . The incidence of diabetes was 11.0 , 7.8 , and 4.8 cases per 100 person-years in the placebo , metformin , and lifestyle groups , respectively . The lifestyle intervention reduced the incidence by 58 percent ( 95 percent confidence interval , 48 to 66 percent ) and metformin by 31 percent ( 95 percent confidence interval , 17 to 43 percent ) , as compared with placebo ; the lifestyle intervention was significantly more effective than metformin . To prevent one case of diabetes during a period of three years , 6.9 persons would have to participate in the lifestyle-intervention program , and 13.9 would have to receive metformin . CONCLUSIONS Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk . The lifestyle intervention was more effective than metformin [24629718] AIM This r and omized controlled trial was carried out to investigate the effect of mindfulness eating and yoga exercise on blood sugar levels among pregnant Thai women with GDM . BACKGROUND Interventions promoting achievement of good glycemic control result in desired pregnancy outcomes . Little is known about the health benefits of mindfulness eating and yoga exercise on blood sugar levels among pregnant with GDM . METHODS A r and omized controlled trial was carried out . Main outcome measures were capillary fasting plasma glucose , 2-h postpr and ial blood glucose , and hemoglobin A1c . RESULTS The intervention group showed significantly reduced fasting plasma glucose , 2-h postpr and ial blood glucose , and glycosylated hemoglobin ( HbA1c ) in the intervention group ( p<0.05 ) . CONCLUSIONS Mindfulness eating and yoga exercise had health benefits on glycemic control in pregnant women with GDM . It should be recommended in clinical and community health services [6315514] Summary Non-obese women in the second half of pregnancy were r and omised into a control group receiving st and ard dietary advice and a group advised to make high fibre whole-food substitutions in their diets at every opportunity . Glucose and insulin profiles were performed over 24-h periods at 29 and 35 weeks gestation when the diets were equivalent in available carbohydrate , protein and fat , but the control group ingested 12.4 g dietary fibre/24 h and the high fibre group 51.4g/24h . Glucose homeostasis was similar in both groups but there was a significant attenuation of post-pr and ial insulin secretion in the high fibre group . It is suggested that the characteristic post-pr and ial peaks of plasma insulin observed in Western pregnant women are an unphysiological response to dietary fibre depletion [22843114] OBJECTIVE A prospect i ve r and omized controlled trial was design ed to assess the benefits and possible risks of aerobic exercise during pregnancy , using a fitness regimen based on the 2002 American College of Obstetricians and Gynecologists guidelines for exercise during pregnancy . METHODS Inactive women were r and omized at 12 - 14 wk gestation to a group that remained sedentary or to a group that performed moderate aerobic exercise 45 - 60 min , 4 d·wk , through 36 wk gestation . Thirty-one subjects in each group completed the study . RESULTS Compared with women who remained sedentary , active women improved aerobic fitness ( P < 0.05 ) and muscular strength ( P < 0.01 ) , delivered comparable size infants with significantly fewer cesarean deliveries ( P < 0.01 ) , and recovered faster postpartum ( P < 0.05 ) , at least related to the lower incidence of cesarean section . Active women developed no gestational hypertension ( P = 0.16 compared with controls ) and reported no injuries related to the exercise regimen . In the active group , there was one premature birth at 33 wk by a woman with a history of premature delivery of twins at 34 wk . There were no differences between groups in the incidence of gestational diabetes , musculoskeletal pains during pregnancy , flexibility on sit- and -reach test , mean length of pregnancy , neonatal Apgar scores , placenta weights , overall length of labor , weight gain during pregnancy , or weight retention postpartum . CONCLUSION Previously sedentary women who began exercising at 12 - 14 wk improved fitness and delivery outcomes [11810100] OBJECTIVE The purpose of this study was to test the null hypothesis that the volume of exercise at different times during pregnancy has no effect on fetoplacental growth . STUDY DESIGN Seventy-five women who exercised regularly were evaluated before pregnancy and r and omly assigned at 8 weeks ' gestation to one of 3 exercise regimens for the remainder of pregnancy . Primary outcome variables included placental growth rate , birth weight , and placental volume at term . RESULTS The offspring of the women who were r and omly assigned to a high volume of exercise in mid and late pregnancy were significantly lighter ( 3.39 kg vs 3.81 kg ) and thinner ( 8.3 % fat vs 12.1 % fat ) than those offspring born of women who were r and omly assigned to reduce their exercise volume after the 20th week . Maternal weight gain , fresh placental volumes , and histomorphometric indices of placental function were greater in the high-low group . CONCLUSION These data indicate that a high volume of moderate-intensity , weight-bearing exercise in mid and late pregnancy symmetrically reduces fetoplacental growth , whereas a reduction in exercise volume enhances fetoplacental growth with a proportionally greater increase in fat mass than in lean body mass [2923097] Background Annual prevalence of gestational diabetes mellitus ( GDM ) is 12.5 % among Finnish pregnant women . The prevalence is expected to rise with the increasing overweight among women before pregnancy . Physical activity and diet are both known to have favourable effects on insulin resistance and possibly on the risk of GDM . We aim ed to investigate , whether GDM can be prevented by counseling on diet , physical activity and gestational weight gain during pregnancy . Methods / Design A cluster-r and omized controlled trial was conducted in 14 municipalities in the southern part of Finl and . Pairwise r and omization was performed in order to take into account socioeconomic differences . Recruited women were at 8 - 12 weeks ' gestation and fulfilled at least one of the following criteria : body mass index ≥ 25 kg/m2 , history of earlier gestational glucose intolerance or macrosomic newborn ( > 4500 g ) , age ≥ 40 years , first or second degree relative with history of type 1 or 2 diabetes . Main exclusion criterion was pathological oral glucose tolerance test ( OGTT ) at 8 - 12 weeks ' gestation . The trial included one counseling session on physical activity at 8 - 12 weeks ' gestation and one for diet at 16 - 18 weeks ' gestation , and three to four booster sessions during other routine visits . In the control clinics women received usual care . Information on height , weight gain and other gestational factors was obtained from maternity cards . Physical activity , dietary intake and quality of life were followed by question naires during pregnancy and at 1-year postpartum . Blood sample s for lipid status , hormones , insulin and OGTT were taken at 8 - 12 and 26 - 28 weeks ' gestation and 1 year postpartum . Workability and return to work were elicited by a question naire at 1- year postpartum . Linkage to the national birth register of years 2007 - 2009 will provide information on perinatal complications and GDM incidence among the non- participants of the study . Cost-effectiveness evaluation will be based on quality -adjusted life years . This study has received ethical approval from the Ethical board of Pirkanmaa Hospital District . Discussion The study will provide information on the effectiveness and cost-effectiveness of gestational physical activity and dietary counseling on prevention of GDM in a risk group of women . Also information on the prevalence of GDM and postpartum metabolic syndrome will be gained . Results on maintaining the possible health behaviour changes are important in order to prevent chronic diseases such as cardiovascular disease and diabetes . Trial registration The trial is registered IS RCT N [24646172] The benefits of exercise and behavioural recommendations in gestational diabetes mellitus ( GDM ) are controversial . In a r and omized trial with a 2 × 2 factorial design , we examined the effect of exercise and behavioural recommendations on metabolic variables , and maternal/neonatal outcomes in 200 GDM patients . All women were given the same diet : group D received dietary recommendations only ; group E was advised to briskly walk 20‐min/day ; group B received behavioural dietary recommendations ; group BE was prescribed the same as B + E. Dietary habits improved in all groups . In a multivariable regression model , fasting glucose did not change . Exercise , but not behavioural recommendations , was associated with the reduction of postpr and ial glucose ( p < 0001 ) , glycated haemoglobin ( HbA1c ; p < 0.001 ) , triglycerides ( p = 0.02 ) and C‐reactive protein ( CRP ; p < 0.001 ) and reduced any maternal/neonatal complications ( OR = 0.50 ; 95%CI=0.28–0.89;p = 0.02 ) . In GDM patients a simple exercise programme reduced maternal postpr and ial glucose , HbA1c , CRP , triglycerides and any maternal/neonatal complications , but not fasting glucose values [19797280] BACKGROUND It is uncertain whether treatment of mild gestational diabetes mellitus improves pregnancy outcomes . METHODS Women who were in the 24th to 31st week of gestation and who met the criteria for mild gestational diabetes mellitus ( i.e. , an abnormal result on an oral glucose-tolerance test but a fasting glucose level below 95 mg per deciliter [ 5.3 mmol per liter ] ) were r and omly assigned to usual prenatal care ( control group ) or dietary intervention , self-monitoring of blood glucose , and insulin therapy , if necessary ( treatment group ) . The primary outcome was a composite of stillbirth or perinatal death and neonatal complications , including hyperbilirubinemia , hypoglycemia , hyperinsulinemia , and birth trauma . RESULTS A total of 958 women were r and omly assigned to a study group--485 to the treatment group and 473 to the control group . We observed no significant difference between groups in the frequency of the composite outcome ( 32.4 % and 37.0 % in the treatment and control groups , respectively ; P=0.14 ) . There were no perinatal deaths . However , there were significant reductions with treatment as compared with usual care in several prespecified secondary outcomes , including mean birth weight ( 3302 vs. 3408 g ) , neonatal fat mass ( 427 vs. 464 g ) , the frequency of large-for-gestational-age infants ( 7.1 % vs. 14.5 % ) , birth weight greater than 4000 g ( 5.9 % vs. 14.3 % ) , shoulder dystocia ( 1.5 % vs. 4.0 % ) , and cesarean delivery ( 26.9 % vs. 33.8 % ) . Treatment of gestational diabetes mellitus , as compared with usual care , was also associated with reduced rates of preeclampsia and gestational hypertension ( combined rates for the two conditions , 8.6 % vs. 13.6 % ; P=0.01 ) . CONCLUSIONS Although treatment of mild gestational diabetes mellitus did not significantly reduce the frequency of a composite outcome that included stillbirth or perinatal death and several neonatal complications , it did reduce the risks of fetal overgrowth , shoulder dystocia , cesarean delivery , and hypertensive disorders . ( Clinical Trials.gov number , NCT00069576 . [3096610] In a cluster-r and omized trial , Riitta Luoto and colleagues find that counseling on diet and activity can reduce the birthweight of babies born to women at risk of developing gestational diabetes mellitus ( GDM ) , but fail to find an effect on GDM [24175912] Abstract Objectives : To determine whether changes in lifestyle in women with BMI > 25 could decrease gestational weight gain and unfavorable pregnancy outcomes . Methods : Women with BMI > 25 were r and omized at 1st trimester to no intervention or a Therapeutic Lifestyle Changes ( TLC ) Program including diet ( overweight : 1700 kcal/day , obese : 1800 kcal/day ) and mild physical activity ( 30 min/day , 3 times/week ) . At baseline and at the 36th week women filled-in a Food Frequency Question naire . Outcomes : gestational weight gain , gestational diabetes mellitus , gestational hypertension , preterm delivery . Data stratified by BMI categories . Results : Socio-demographic features were similar between groups ( TLC : 33 cases , Controls : 28 cases ) . At term , gestational weight gain in obese women r and omized to TLC group was lower ( 6.7 ± 4.3 kg ) versus controls ( 10.1 ± 5.6 kg , p = 0.047 ) . Gestational diabetes mellitus , gestational hypertension and preterm delivery were also significantly lower . TLC was an independent factor in preventing gestational weight gain , gestational diabetes mellitus , gestational hypertension . Significant changes in eating habits occurred in the TLC group , which increased the number of snacks , the intake of fruits – vegetables and decreased the consumption of sugar . Conclusions : A caloric restriction associated to changes in eating behavior and constant physical activity , is able to reduce gestational weight gain and related pregnancy complications in obese women [21310836] BACKGROUND Excessive weight gain during pregnancy is a major risk factor for postpartum weight retention and future weight gain and obesity in women , but few adequately powered r and omized controlled trials have examined the efficacy of a behavioral weight-control intervention during pregnancy . OBJECTIVE This study examined whether a behavioral intervention during pregnancy could decrease the proportion of women who exceeded the 1990 Institute of Medicine ( IOM ) recommendations for gestational weight gains and increase the proportion of women who returned to pregravid weights by 6 mo postpartum . DESIGN This study was a r and omized , assessor-blind , controlled trial . Participants were pregnant ( 13.5 wk gestation ) , normal-weight ( NW ; n = 201 ) and overweight or obese ( OW/OB ; n = 200 ) women whose average age was 28.8 y. Participants were r and omly assigned within the 1990 IOM weight category ( NW compared with OW/OB ) to st and ard care ( n = 200 ) or to a behavioral intervention to prevent excessive gestational weight gain ( n = 201 ) . The intervention included one face-to-face visit ; weekly mailed material s that promoted an appropriate weight gain , healthy eating , and exercise ; individual graphs of weight gain ; and telephone-based feedback . The retention at the 6-mo postpartum assessment was 82 % . RESULTS Intent-to-treat analyses showed that the intervention , compared with st and ard care , decreased the percentage of NW women who exceeded IOM recommendations ( 40.2 % compared with 52.1 % ; P = 0.003 ) and increased the percentages of NW and OW/OB women who returned to their pregravid weights or below by 6 mo postpartum ( 30.7 % compared with 18.7 % ; P = 0.005 ) . CONCLUSION A low-intensity behavioral intervention during pregnancy reduced excessive gestational weight gains in NW women and prevented postpartum weight retention in NW and OW/OB women . This trial was registered at clinical trials.gov as NCT01117961 Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Gestational diabetes mellitus ( GDM ) is associated with a wide range of adverse health consequences for women and their infants in the short and long term . With an increasing prevalence of GDM worldwide , there is an urgent need to assess strategies for GDM prevention , such as combined diet and exercise interventions . This is an up date of a Cochrane review that was first published in 2015 . OBJECTIVES To assess the effects of diet interventions in combination with exercise interventions for pregnant women for preventing GDM , and associated adverse health consequences for the mother and her infant/child . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

11687182

[9596304] OBJECTIVE To determine the ability of budesonide via an inhaler ( Pulmicort Turbuhaler ; Astra Draco AB ) to replace oral glucocorticosteroids ( GCSs ) in adult subjects with moderate-to-severe asthma . DESIGN Double-blind , r and omized , and placebo-controlled study , with parallel groups . SETTING Multicenter study in outpatient setting . PARTICIPANTS Eighty men and 79 women , aged 20 to 69 years , with moderate-to-severe asthma and a mean FEV1 of 58.3 % predicted normal . All subjects were receiving oral GCS treatment and 79 % of subjects were also receiving inhaled beclomethasone dipropionate ( BDP ) . The mean daily doses of prednisone at baseline , including converted dose of BDP , for the placebo , budesonide 400 microg , and budesonide 800 microg , respectively , were 19.7 mg , 19.5 mg , and 18.7 mg . MEASUREMENTS AND INTERVENTIONS After a 2-week baseline period , subjects entered a 20-week treatment period , during which the oral dose of prednisone was reduced by forced down-titration at 2-weekly intervals . RESULTS Subjects receiving 400 microg or 800 microg bid of budesonide achieved a significantly greater reduction ( 82.9 % and 79.0 % respectively ) in oral GCS dose compared with placebo-treated subjects ( 27 % ; p<0.001 ) . Two thirds of the subjects receiving budesonide were able to achieve sustained oral corticosteroid cessation , compared with 8 % in the placebo group . Additionally , both doses of budesonide result ed in significant improvement in results of pulmonary function tests and asthma symptoms scores , and a significant decrease in the use of bronchodilator therapy . The mean plasma cortisol levels before and after adrenocorticotropic hormone stimulation increased most toward the normal range in the budesonide-treated groups compared with placebo-treated subjects . CONCLUSION Budesonide administered via Turbuhaler has a significant oral GCS-sparing capacity with maintained or improved asthma control in adult subjects with moderate-to-severe asthma [8066909] Two hundred and forty-one children with perennial asthma had their normal dose of budesonide ( administered via Nebuhaler ) reduced by 50 % . Asthma control deteriorated in 126 patients to such an extent that budesonide had to be increased to the normal dose . During a subsequent two week run-in these 126 patients were treated with their normal dose of budesonide via Nebuhaler . Thereafter 64 were r and omized to treatment with their normal budesonide therapy and 62 to treatment with half their normal budesonide dose via Turbuhaler for nine weeks . Asthma symptoms , peak-flow measurements , and beta 2-agonist use were recorded . Pulmonary function tests , exercise tests and 24 hour urine sample collection s were performed . There were no differences between the groups in any of the parameters studied during run-in or during the study period , except for use of beta 2-agonist , which was significantly lower in the Turbuhaler-treated group . We conclude that Turbuhaler is more effective than Nebuhaler in the treatment of asthma . Therefore the dose of budesonide should be reduced when patients are switched from Nebuhaler to Turbuhaler treatment [10400838] BACKGROUND Optimal management of chronic , mild-to-moderate asthma with inhaled steroids may include use of the lowest possible doses , as recommended in guidelines , and a reduction in the frequency of daily administration for greater convenience . Lower doses and once daily treatment with inhaled steroids must be rigorously evaluated in controlled clinical trials . OBJECTIVES The objective of this study was to assess the efficacy and safety of once daily treatment with budesonide in subjects with stable asthma . METHODS Once daily budesonide was assessed in 309 adult subjects , including those who were and were not using an inhaled steroid at baseline . The subjects were stratified by inhaled steroid use and r and omly assigned to one of 3 treatments : 200 microgram budesonide , 400 microgram budesonide , or placebo administered by means of Turbuhaler once daily in the morning for 6 weeks . Beyond this point , treatment was continued unchanged for another 12 weeks ( maintenance ) in those receiving 200 microgram budesonide once daily and placebo . In those who received 400 microgram budesonide once daily , the dose was reduced to 200 microgram once daily at week 6 and held constant for the remaining 12 weeks ( 400/200 microgram group ) . Primary efficacy endpoints were mean change from baseline in FEV1 and morning peak expiratory flow . RESULTS Once daily budesonide was well tolerated and result ed in significant improvements in all efficacy endpoints , even though baselines were well stabilized . Baseline lung function was elevated with little room for improvement ; however , mean increases in FEV1 during the maintenance period were 0.10 L and 0.11 L in the 200 microgram and 400/200 microgram groups , respectively , versus a decrease of -0.09 L in the placebo arm ( P < .001 ) . Results for peak expiratory flow were similar . Significant improvements in secondary endpoints , including symptoms , beta-agonist use , and quality of life , also developed with budesonide 200 and 400 microgram once daily . CONCLUSION Inhaled budesonide , in doses as low as 200 microgram , may be an appropriate introductory or maintenance dose in subjects with stable , mild-to-moderate asthma [8024295] Two hundred and forty one children with chronic perennial asthma , who had been treated with budesonide via a metered dose inhaler with a spacer device ( Nebuhaler ) , had their normal dose of budesonide reduced by 50 % to determine if they had been overtreated . Within three weeks , asthma control deteriorated in 126 patients to such an extent that budesonide had to be increased to the normal dose . After stabilising their asthma , these children were enrolled in a r and omised , double blind , double dummy , parallel study , performed to compare the effect of budesonide via Nebuhaler with that of half the dose of budesonide via Turbuhaler . The study started with a two week run-in during which patients were treated with their normal dose of budesonide via Nebuhaler . After run-in , 64 children were r and omised to treatment with their normal budesonide treatment and the remaining 62 children to treatment with half their normal dose via Turbuhaler for nine weeks . Throughout the study , patients recorded asthma symptoms , peak flow measurements , and beta 2 agonist use in a diary . Pulmonary function tests , exercise tests , and 24 hour urine sample collection s were performed at hospital visits during run-in and the study period . Apart from beta 2 agonist use , which was significantly lower for patients on Turbuhaler treatment than on Nebuhaler treatment , there were no differences between the groups in any of the parameters studied during run-in or during the study period . Furthermore , there was no trend of deterioration in asthma control when the dose of budesonide was reduced by 50 % when Turbuhaler was the inhalation device . It is concluded that budesonide via Turbuhaler is more effective than via Nebuhaler in the treatment of asthma . Based on this finding , attempts should be made to reduce the dose of budesonide when patients are switched from Nebuhaler to Turbuhaler treatment [7979494] The budesonide dose delivered to the patient from three different spacer devices ( Nebuhaler = 750 ml , Aerochamber = 140 ml , and Babyspacer = 260 ml ) was assessed by measuring the budesonide dose deposited on a filter inserted between the spacer outlet and the mouth of the patient . Twenty children aged 10 - 25 months were given a single dose of 200 micrograms budesonide from each spacer device in a r and omised crossover study . All spacers had a facemask attached and a one way valve system . The children breathed through the inhalation system for 30 seconds . Furthermore , the minute ventilation of the children through a tightly fitting facemask was measured . The filter dose of budesonide was significantly lower after Aerochamber treatment ( 39.4 micrograms , range 19 - 67 micrograms ) than after Nebuhaler ( 53.5 micrograms , range 34 - 88 micrograms ) and Babyspacer ( 55.5 micrograms , range 39 - 76 micrograms ) treatment . The minute ventilation of the children varied from 1.4 l/min to 7.0 l/min ( mean 5.0 l/min ) . This was sufficient to empty all spacers within the 30 seconds of inhalation . It is concluded that spacer volume does not seem to be so important for children aged 10 - 25 months as long as spacers with a volume lower than 750 ml are used [10325913] BACKGROUND It is desirable to prescribe the minimal effective dose of inhaled steroids to control asthma . To ensure that inflammation is suppressed whilst using the lowest possible dose , a sensitive and specific method for assessing airway inflammation is needed . METHODS The usefulness of exhaled nitric oxide ( NO ) , sputum eosinophils , and methacholine airway responsiveness ( PC20 ) for monitoring airway inflammatory changes following four weeks of treatment with an inhaled corticosteroid ( budesonide via Turbohaler ) were compared . Mild stable steroid naive asthmatic subjects were r and omised into two double blind , placebo controlled studies . The first was a parallel group study involving three groups receiving either 100 μg/day budesonide ( n = 8) , 400 μg/day budesonide ( n = 7 ) , or a matched placebo ( n = 6 ) . The second was a crossover study involving 10 subjects r and omised to receive 1600 μg budesonide or placebo . The groups were matched with respect to age , PC20 , baseline FEV1 ( % predicted ) , exhaled NO , and sputum eosinophilia . RESULTS There were significant improvements in FEV1 following 400 μg and 1600 μg budesonide ( 11.3 % and 6.5 % , respectively , p<0.05 ) . This was accompanied by significant reductions in eosinophil numbers in induced sputum ( 0.7 and 0.9 fold , p<0.05 ) . However , levels of exhaled NO were reduced following each budesonide dose while PC20was improved only with 1600 μg budesonide . These results suggest that exhaled NO and PC20 may not reflect the control of airway inflammation as accurately as the number of eosinophils in sputum . There were dose dependent changes in exhaled NO , sputum eosinophils , and PC20 to inhaled budesonide but a plateau response of exhaled NO was found at a dose of 400 μg daily . CONCLUSION Monitoring the number of eosinophils in induced sputum may be the most accurate guide to establish the minimum dose of inhaled steroids needed to control inflammation . This , however , requires further studies involving a larger number of patients [9864004] The aim of the present study was to examine the efficacy of low-dose inhaled budesonide ( BUD ) administered via Turbuhaler once or twice daily on symptoms , lung function and bronchial hyperreactivity in children with mild asthma . One hundred and sixty-three children ( mean age 9.9 yrs , 56 females/107 males ) with mild asthma ( forced expiratory volume in one second ( FEV1 ) 103 % of predicted , morning peak expiratory flow ( PEF ) 87 % pred , reversibility in FEV1 3 % , fall in FEV1 after exercise 10.4 % from pre-exercise value ) and not previously treated with inhaled steroids , were included in a double-blind , r and omized , parallel-group study . After a two-week run-in period , the children received inhaled BUD 100 microg or 200 microg once daily in the morning , 100 microg twice daily or placebo for 12 weeks . Exercise and methacholine challenges were performed before and at the end of treatment . After 12 weeks of therapy , the fall in FEV1 after an exercise test was significantly less in all three BUD groups ( 43 - 5.1 % ) than in the placebo group ( 8.6 % ) . Bronchial hyperreactivity to methacholine with the provocative dose causing a 20 % fall in FEV1 decreased significantly in the BUD 100 microg twice-daily group compared with placebo ( ratio at the end of treatment 156 % ) . Changes in baseline lung function ( FEV1 and PEF ) were less marked than changes in bronchial responsiveness . In conclusion , low doses of inhaled budesonide , given once or twice daily , provided protection against exercise-induced bronchoconstriction in children with mild asthma and near normal lung function [9655717] New British guidelines on the treatment of asthma ( 9 ) advocate starting with a higher dose of inhaled corticosteroids in newly detected asthma patients . We investigated whether initiating inhaled steroid treatment with a higher dose is clinical ly more effective than a lower dose in steroid naive patients with asthma . The study had a 13-wk r and omized , double-blind , parallel design : 1-mo treatment with 400 microg budesonide twice a day , or 100 microg budesonide twice a day by dry powder inhaler , and follow-up treatment period of 2 mo with 200 microg budesonide once daily for all patients . Forty patients started with 400 microg budesonide twice daily , 44 with 100 microg budesonide twice daily . Mean age was 32 yr , baseline FEV1 value 84 % predicted , reversibility 9 % from baseline , and mean bronchodilator use 1.6 inhalations/d in the run-in period . After 4 wk of treatment with 400 microg and 100 microg budesonide twice daily mean morning peak expiratory flow ( PEF ) increased 27 L/min ( SD 50 ) , and 38 L/ min ( SD 53 ) , respectively ( p = 0.30 ) ; mean symptom score improved from 1.1 to 0.6 and from 1.1 to 0.5 . These effects were maintained in the 2 mo follow-up . This study suggests that starting inhaled corticosteroids at a higher dose is not superior to a lower dose in the treatment of newly detected asthma [9519224] The study objective was to compare the effect of budesonide administered as a nebulized suspension as compared to a spray with a spacer in adult asthmatics . In a double-blind , double-dummy crossover study , 26 adult patients with moderately severe unstable asthma were r and omized to three 4-week treatment periods with budesonide 0.8 mg b.i.d . administered by a pressurized metered-dose inhaler ( pMDI ) with spacer ( Nebuhaler ) and budesonide 1 mg and 4 mg b.i.d . administered by a Pari Inhalier Boy jet nebulizer . The nebulizer was activated only during inspiration . The total mass output was similar from the two devices but their fraction of small particles differed by a factor of 2 in favour of pMDI . Effect was evaluated from daily home measurements of peak expiratory flow ( PEF ) , need of beta 2-agonist and symptom scores . Plasma cortisol and budesonide levels were measured in a subgroup of 10 patients . A consistent trend showed the nebulizer treatment to be at least as efficient as the pMDI plus spacer treatment . In actual fact , the apparent order of effect was : 4 mg nebulized suspension treatment > or = 1 mg nebulized suspension treatment > or = 0.8 mg pMDI with spacer treatment . Plasma budesonide and plasma cortisol also exhibited dose-related levels independent of device . The adverse effects reported appeared to be related to the dose rather than delivery device . Accordingly , the effect was related to total mass output , rather than to the small particle fraction of the budesonide aerosol . These results attest to the efficiency of jet-nebulized budesonide suspension , and indicate nebulized budesonide to be equipotent to st and ard budesonide therapy delivered by pMDI with Nebuhaler , provided nebulization is synchronized with inspiration and no loss of aerosol occurs during expiration [3287996] Budesonide by inhalation and placebo were tested in 18 patients with moderate chronic bronchial asthma . Three dose levels of budesonide were used ( 25 , 100 and 400 μg q.i.d . ) and the patients were to take two puffs q.i.d . in all periods . The active treatment was investigated using double‐blind cross‐over technique , and placebo at the end of the trial . The duration of each treatment period was 2 weeks . The study showed a high drop‐out frequency while on placebo and that the PEF values were influenced in a dose‐dependent way by budesonide . In spite of the double‐blindness the patients had a tendency towards overuse of the trial aerosol on the lowest dose , but they used significantly less than prescribed during the period with the highest dose . No side effects were reported [2090474] Budesonide 400 micrograms daily , in nonsteroid-dependent asthma , can produce improvements in airway responsiveness and clinical asthma severity , with some patients returning to normal responsiveness and becoming asymptomatic . This study examined whether similar improvements occur when asthmatics , who are dependent upon inhaled steroids , take either a regular maintenance dose of inhaled steroid or twice that amount for a year . Thirty two asthmatics were each stabilized on the minimum amount of inhaled steroid that would keep symptoms non-troublesome . In a double-blind , r and omized manner , half were assigned to remain on a maintenance dose ( MD ) and the rest received twice that dose ( MDx2 ) for one year . Before and monthly throughout the study , airway responsiveness to methacholine was measured and clinical asthma severity assessed by question naire , inhaled bronchodilator use and number of asthma exacerbations . There was a significant improvement in airway responsiveness and clinical asthma severity in both treatment groups . Those on MDx2 showed the greatest improvement but the difference between the two groups did not reach significance . This study provides strong evidence that prolonged use of inhaled steroids is associated with improvement in airway responsiveness and clinical asthma severity in inhaled steroid-dependent asthma with a suggestion that the improvements are dose related [11035676] OBJECTIVES We wished to evaluate the effects of once-daily combination therapy on surrogate inflammatory markers . METHODS Fifteen patients with atopic persistent asthma were evaluated ( mean age , 32.4 years ; FEV(1 ) , 75.2 % predicted ) in a r and omized , double-blind , double-dummy , placebo-controlled crossover study with a 1-week placebo washout period , comparing the following once-daily nighttime treatments : ( 1 ) formoterol ( FM ) , 12 microg , for 2 weeks and FM , 24 microg , for 2 weeks ; or ( 2 ) budesonide ( BUD ) , 400 microg , for 2 weeks and BUD , 800 microg , for 2 weeks ; or ( 3 ) FM , 12 microg , plus BUD , 400 microg , for 2 weeks and FM , 24 microg , plus BUD , 800 microg , for 2 weeks . Adenosine monophosphate ( AMP ) bronchial challenge , exhaled nitric oxide ( NO ) , and serum eosinophilic cationic protein ( ECP ) were evaluated at 12 h postdosing after administration of each placebo and after 2 and 4 weeks of each treatment . RESULTS The results of AMP challenge ( provocative concentration causing a 20 % fall in FEV(1 ) ) at 4 weeks showed significant ( p<0.05 ) improvements after patients had received all active treatments compared to placebo ( 20 mg/mL ) , with FM plus BUD , 261 mg/mL , being superior ( p<0.05 ) to FM alone , 82 mg/mL , but not to BUD , 201 mg/mL. NO and ECP showed significant ( p<0.05 ) reductions compared to placebo with FM plus BUD or BUD alone but not with FM alone . Combination therapy was associated with optimal patient preference ( rank order , FM plus BUD > FM > BUD ; p<0.0005 ) , highest domiciliary peak expiratory flow , and lowest rescue inhaler usage . All three treatments produced equivalent improvements in spirometry . CONCLUSIONS Patients preferred once-daily combination therapy , but this had no greater effect on inflammatory markers than therapy with BUD alone . FM alone had no anti-inflammatory activity but exhibited bronchoprotection . This emphasizes the importance of first optimizing anti-inflammatory control with inhaled corticosteroids before considering adding a regular long-acting beta(2)-agonist [1579391] Linear growth was investigated with weekly knemometry in a population of 43 schoolchildren with mild asthma treated with inhaled budesonide . The design was a r and omized , double-blind , parallel group study with three dose groups of 200 , 400 , and 800 micrograms of budesonide per day . Each dose group received budesonide for 8 consecutive weeks . Placebo was given for either 4 weeks before or after budesonide treatment . Twelve children in the 200-micrograms group , 14 in the 400-micrograms group , and 12 in the 800-micrograms group completed the 12-week study period . There was no significant difference in mean growth velocity among the three dose groups during placebo treatment . Compared with placebo ( growth velocity : 0.39 mm/wk ) , mean lower leg growth velocity was reduced with 0.26 mm/wk ( P less than .001 , t = 5.0 , df = 11 ; 95 % confidence interval 0.14 to 0.37 mm/wk ) in children treated with 800 micrograms of budesonide . There was no statistically significant difference in growth velocity between 200- or 400-micrograms budesonide treatments and placebo . These data indicate that inhaled budesonide can be safely used in doses up to 400 micrograms/d in schoolchildren with asthma [9821415] BACKGROUND Twice-daily administration of inhaled budesonide ( 400 micrograms ) suppresses short-term growth in children with asthma . OBJECTIVE To compare short-term growth and markers of collagen turnover during treatment with 800 micrograms of inhaled budesonide administered once daily in the morning and 400 micrograms administered twice daily . PATIENTS Twenty-four children with asthma aged 5.6 to 12.5 years . SETTING An outpatient secondary referral center . METHODS A r and omized , double-blind , crossover trial with 2 treatment periods of 4 weeks was conducted , and growth was assessed with a knemometer . The carboxy terminal propeptide of type I procollagen , the amino terminal propeptide of type I procollagen ( PINP ) , the carboxy terminal pyridinoline cross-linked telopeptide of type I collagen , the amino terminal propeptide of type III procollagen ( PIIINP ) , and urinary pyridinoline and deoxypyridinoline were evaluated . RESULTS Mean lower leg growth rate ( P = .04 ) , PINP ( P = .03 ) , and PIIINP ( P < .01 ) were suppressed during twice-daily administration of budesonide , 400 micrograms . Otherwise , no statistically significant differences were detected . CONCLUSIONS As compared with 400 micrograms of inhaled budesonide administered twice daily , 800 micrograms administered once daily in the morning has a sparing effect on short-term growth and collagen turnover [11014718] PURPOSE Inhaled corticosteroids have beneficial effects on pulmonary function and inflammation in patients with asthma , but they also cause systemic adverse effects , such as adrenal suppression . We evaluated the therapeutic index of inhaled corticosteroids in asthmatic patients by comparing their dose-response effects on lung function , surrogate markers of airway inflammation , and tests of adrenal function . SUBJECTS AND METHODS After a 10-day placebo run-in , we evaluated the effects of 200 microg , 400 microg , and 800 microg of inhaled budesonide , each dose given twice daily sequentially for 3 weeks in 26 patients , aged 35 + /- 12 years ( mean + /- SD ) , with mild-to-moderate asthma . Measurements were made of bronchial reactivity , exhaled nitric oxide ( a marker of airway inflammation ) , spirometry , serum eosinophilic cationic protein concentration , and 10-hour overnight urinary cortisol excretion . Plasma cortisol levels were measured at 8 AM and after stimulation with human corticotropin releasing factor . RESULTS For measurements of pulmonary function and exhaled nitric oxide , there was a plateau in the mean response to budesonide between 400 microg ( low dose ) and 800 microg ( medium dose ) per day , whereas for eosinophilic cationic protein and bronchial challenge , maximal benefits occurred between 800 and 1,600 microg ( high dose ) per day . Effects on plasma cortisol levels showed maximal suppression at 1,600 microg of budesonide per day . The proportion of patients with an optimal therapeutic index , in terms of a good airway response ( fourfold decrease in bronchial hyperreactivity ) and minimal systemic response ( overnight urinary cortisol greater than 20 nmol ) , was similar at low-dose ( 46 % ) and at high-dose ( 52 % ) budesonide . The proportion of patients with a suboptimal therapeutic index , a good airway response with a marked systemic response ( overnight urinary cortisol greater than 20 nmol ) , increased from 4 % at low dose to 38 % at high dose . CONCLUSIONS In patients with mild-to-moderate atopic asthma , there were dose-related effects of budesonide on surrogate markers of inflammation ( bronchial hyperreactivity and serum eosinophilic cationic protein ) , although higher doses were associated with adrenal suppression and a decrease in the therapeutic index [9596110] Electrostatic charge in plastic spacer devices has been shown in vitro to reduce delivery of asthma medications intended for inhalation , but the effect of static charge on in vivo drug deposition is unknown . A six-way r and omized crossover study was conducted in 10 mild asthmatic patients . Two plastic spacers ( Nebuhaler and Volumatic ) and one metal spacer ( Nebuchamber ) were tested . The spacers were used either " primed " or " unprimed " . Priming was performed by firing 20 doses of placebo aerosol into a new spacer , hence coating the inner surface with surfactant and minimizing static charge . Unprimed spacers were new and were not treated . Pressurized aerosol canisters delivering budesonide ( 200 microg Pulmicort ) were radiolabelled with the radionuclide 99mTc and lung deposition was measured by gamma scintigraphy . The radiolabel was shown to be a valid marker for the drug substance prior to the clinical phase of the study . Priming significantly increased mean whole lung deposition following inhalation from plastic spacers ( Nebuhaler primed 37.7 % and unprimed 26.7 % , p=0.01 ; Volumatic primed 32.0 % and unprimed 22.1 % , p=0.02 ) . Priming had no effect on the mean whole lung deposition following inhalation from the Nebuchamber ( primed 33.5 % and unprimed 32.9 % ) . Lung deposition in vivo from plastic spacer devices will vary according to the electrostatic charge on the spacer walls . Priming reduces retention of drug on plastic spacer devices and increases lung deposition . Metal spacers are not susceptible to static charge , which should result in more predictable lung deposition [9230238] Few thorough comparisons of the systemic effects of inhaled corticosteroids in children are available . The aim of this study was to compare the effect of budesonide and fluticasone propionate on short-term lower leg growth . Fluticasone propionate , budesonide and placebo were administered for 2 weeks in a r and omized , double-blind , double-dummy , cross-over design . Twenty four children aged 6 - 12 yrs received 200 microg x day(-1 ) of each drug , or placebo . Another 24 children aged 6 - 12 years received 400 microg x day(-1 ) of each drug , or placebo . Dry powder inhalers were used . Lower leg length was measured by knemometry twice a week during all three treatment periods , and 24 h cortisol excretion in the urine was measured at the end of each period . In the low-dose group , lower leg growth rate was the same during treatment with placebo ( 0.35 mm x week(-1 ) ) , fluticasone propionate ( 0.38 mm x week(-1 ) ) or budesonide ( 0.26 mm x week(-1 ) ) . No significant difference ( p=0.39 ) in lower leg growth rate was found between treatment with 400 microg x day(-1 ) budesonide ( 0.30 mm x week(-1 ) ) and 400 microg fluticasone propionate treatment ( 0.37 mm x week(-1 ) ) . Growth rate during treatment with budesonide , 400 microg x day(-1 ) , was significantly lower than during placebo treatment ( 0.52 mm x week(-1 ) ) . Cortisol excretion in the urine during treatment with 200 microg x day(-1 ) fluticasone propionate was significantly reduced as compared with placebo ( p=0.006 ) , but not when compared with 200 microg x day(-1 ) budesonide ( p=0.07 ) . Budesonide 200 microg x day(-1 ) was not significantly different from placebo . Fluticasone propionate and budesonide , both at 400 microg x day(-1 ) , result ed in a significant reduction in cortisol excretion in the urine as compared with placebo ( p=0.001 ) . It is concluded that , dose-for-dose , budesonide Turbuhaler and fluticasone propionate Diskhaler have similar systemic effects [10968496] The aim of this study was to determine whether outcomes in poorly controlled asthma can be further improved with a starting dose of inhaled budesonide higher than that recommended in international guidelines . The study had a parallel-group design and included 61 subjects with poorly controlled asthma , r and omized to receive 3,200 microg or 1,600 microg budesonide daily by Turbuhaler for 8 weeks ( double-blind ) , then 1,600 microg x day(-1 ) for 8 weeks ( single-blind ) , followed by 14 months of open-label budesonide dose down-titration using a novel algorithm , with a written asthma crisis plan based on electronic peak expiratory flow monitoring . The primary outcome variable for weeks 1 - 16 was change in airway hyperresponsiveness ( AHR ) , and , for the open-label phase , mean daily budesonide dose . By week 16 , there were large changes from baseline in all outcomes , with no significant differences between the 3,200- and 1,600-microg x day(-1 ) starting dose groups ( AHR increased by 3.2 versus 3.0 doubling doses , p=0.7 ; morning peak flow increased by 134 versus 127 L x min(-1 ) , p=0.8 ) . Subjects starting with 3,200 microg x day(-1 ) were 3.8 times more likely to achieve AHR within the normal range , as defined by a provocative dose of histamine causing a 20 % fall in forced expiratory volume in one second ( PD20 ) of > or = 3.92 micromol by week 16 ( p=0.03 ) [ corrected ] . During dose titration , there was no significant difference in mean budesonide dose ( 1,327 versus 1,325 microg x day(-1 ) , p>0.3 ) . Optimal asthma control was achieved in the majority of subjects ( at completion/withdrawal : median symptoms 0.0 days x week(-1 ) , beta2-agonist use 0.2 occasions x day(-1 ) , and PD20 2.4 micromol ) . In subjects with poorly controlled asthma , a starting dose of 1,600 microg x day(-1 ) budesonide was sufficient to lead to optimal control in most subjects . The high degree of control achieved , compared with previous studies , warrants further investigation [10893016] The aim of this study was to compare the clinical efficacy of low-dose inhaled budesonide ( once or twice daily ) and placebo , administered via Turbuhaler , on exercise-induced bronchoconstriction ( EIB ) in children with mild asthma . Fifty-seven steroid-naive children ( 7 - 16 years old ; 41 boys , 16 girls ) with EIB participated in this sub- population study according to the following inclusion criterion : a maximum fall in forced expiratory volume in 1 s ( FEV1 ) > or = 10 % after a st and ardized treadmill test . Mean baseline FEV1 was 100.3 % of predicted , and mean maximum fall in FEV1 after the st and ardized exercise test was 22 % . The study was a double-blind , r and omized , parallel-group design . After 2 weeks of run-in , the children received inhaled budesonide 100 microg or 200 microg once daily in the morning , 100 microg twice daily , or placebo , for 12 weeks . After 12 weeks of treatment , the fall in FEV1 after the exercise test was significantly less in all three budesonide groups ( 7.2 - 7.8 % ) vs. placebo ( 16.7 % ) . Daytime symptom scores were significantly lower in all three budesonide groups compared with placebo ( p < 0.02 ) . The three budesonide groups did not differ significantly , and no significant change in lung function was found in any group . Therefore children with mild asthma , but with significant EIB , improved their exercise tolerance and symptom control after 3 months of treatment with a low dose of inhaled budesonide given once or twice daily [8681664] An open , r and omized , parallel-group study was conducted to investigate whether asthmatic patients , considered adequately treated with a corticosteroid and /or short-acting beta 2-agonist via pressurized metered-dose inhaler ( pMDI ) , could be transferred to a corresponding nominal dose of budesonide and /or terbutaline via Turbuhaler , an inspiratory flow-driven multidose dry powder inhaler ( Astra Draco ; Lund , Sweden ) , without a decrease in the effect of treatment . One thous and four patients ( 555 women ; mean age , 44 years ; mean peak expiratory flow [ PEF ] , 102 % predicted normal value ) were r and omized and treated with either pMDI ( current therapy ) or Turbuhaler for 52 weeks . The variables studied were asthma-related events , morning PEF , and inhaler-induced clinical symptoms . Asthma-related events were defined in two ways : ( 1 ) sum of health-care contacts plus doublings or additions of steroids , and ( 2 ) number of 2 consecutive days with PEF less than 80 % of baseline . Baseline was obtained from a 2-week run-in period while receiving previous therapy . No statistically significant difference was found in asthma-related events according to definition 1 . According to definition 2 , there was a statistically significant difference between the groups in favor of Turbuhaler ( p = 0.008 ) . The mean number of events was 1.7 with Turbuhaler and 2.2 with pMDI . The mean number of weeks per patient with a PEF less than 90 % of baseline was 4.5 with Turbuhaler compared with 6.0 with pMDI ( p = 0.002 ) . The sum of inhaler-induced symptoms after 1 year of use was statistically significantly lower with Turbuhaler ( 0.40 ) than with pMDI ( 0.75 ) ( p = 0.0001 ) . In conclusion , budesonide and terbutaline in Turbuhaler offered a superior alternative to corticosteroids and bronchodilators delivered by pMDIs in the maintenance treatment of asthma [11428735] BACKGROUND The incidence of pediatric asthma has increased dramatically over the past few decades , with approximately 5 % of American children affected by the disease . OBJECTIVES To compare the efficacy and safety of once-daily budesonide Turbuhaler with placebo in asthmatic children previously treated with orally inhaled corticosteroids . METHODS This r and omized , double-blind , placebo-controlled , multicenter ( 17 centers ) study included 274 male and female children ( aged 6 to 17 years ) with a history of asthma for at least the previous 6 months . Patients received placebo or budesonide Turbuhaler ( 200 microg or 400 microg ) once daily for 12 weeks . Efficacy variables included mean changes from baseline in forced expiratory volume in 1 second ( FEV1 ) , AM and PM peak expiratory flow rates ( PEFRs ) , nighttime and daytime asthma symptom severity scores , patient discontinuations , use of beta2-agonists as breakthrough medication , forced vital capacity ( FVC ) , and midexpiratory flow rate between 25 % and 75 % of FVC ( FEF25%-75 % ) . Safety was evaluated by adverse events , physical examinations , vital signs , and laboratory tests . RESULTS Baseline characteristics were comparable among treatment groups . Percentage of predicted FEV1 at baseline was 76.6 + /- 6.9 for placebo , 77.5 + /- 7.1 , and 77.0 + /- 7.8 for the budesonide Turbuhaler 200 microg and 400 microg groups , respectively . Significantly ( P < or = 0.024 ) more placebo patients ( 24 % ) discontinued treatment because of disease deterioration or no improvement than budesonide Turbuhaler 200 microg ( 11 % ) or 400 microg patients ( 10 % ) . Patients receiving budesonide Turbuhaler experienced significant improvements in FEV1 compared with patients receiving placebo ( P < or = 0.015 ) . Significant ( P < or = 0.041 ) improvements over placebo also were observed in AM and PM PEFRs , FVC , FEF25%-75 % , nighttime and daytime asthma symptoms , and amount of beta2-agonist used in both budesonide Turbuhaler groups . Adverse events were generally mild or moderate in intensity and similar among treatment groups . CONCLUSIONS Once-daily budesonide Turbuhaler is effective and safe in children with persistent asthma previously maintained on at least twice-daily dosing regimens of inhaled corticosteroids [9141112] We compared the clinical effect of the glucocorticoid budesonide delivered from two nebulizers Aiolos and Pari LL in 38 children less than 4 years of age ( mean age , 20.2 months ) with chronic wheeze . The design was a controlled , single-blind , r and omized , cross-over , dose titration study . After a 1-week run-in , patients were r and omized to treatment with 1 mg budesonide b.i.d . for 2 weeks from either an Aiolos or a Pari LL nebulizer . This was followed by a gradual dose reduction period during which the budesonide dose was reduced at 2-week intervals until unacceptable asthma symptoms appeared or the placebo level was reached . The patient was then switched to budesonide 1 mg b.i.d . from the other nebulizer for 2 weeks , after which the dose was reduced at 2-week intervals as described for the first period . Patients who completed the study on placebo for 2 weeks without deterioration of their asthma were not included in the statistical analysis . During Period # 1 the minimum effective dose of budesonide was 2 mg/day in 9 patients , 1 mg/day in 10 patients , and 0.5 mg/day in 13 patients . In Period # 2 the corresponding figures were 14 , 5 , and 13 patients . Six patients were excluded after the first period because their asthma control did not deteriorate during dose reduction and when finishing on placebo for 2 weeks . For both nebulizers the reduction in budesonide dose was associated with a small increase in symptoms and use of rescue terbutaline . The mean dose of budesonide delivered to the patient by the Aiolos was twice as large as that delivered by the Pari LL : 26 % vs. 13 % of the nominal dose assessed by the filter method . Nevertheless , no statistically significant difference in clinical effect or mean minimal effective dose ( 1.1 mg for Aiolos and 1.2 mg for Pari LL ) could be detected between the two nebulizers . No serious adverse events were observed . We conclude that the minimal effective dose of nebulized budesonide varies from 0.5 to 2.0 mg/day in young children with asthma . A higher drug delivery , as assessed by the filter method , does not necessarily result in better clinical control or lower minimal effective dose . Further studies are needed to assess whether this is due to insufficient sensitivity of the study design in detecting a difference in clinical effect , or whether measurements of drug delivery by the filter method do not reflect lung deposition or clinical effect in young children with wheezing [9894371] This double-blind study aim ed to determine whether superior asthma control is achieved with budesonide ( Pulmicort Turbohaler ) at a loading dose ( LD ) ( 400 micrograms b.d . ) for 6 weeks , followed by step down to 400 micrograms nocte for 12 weeks , compared with a static dose ( SD ) ( 400 micrograms nocte ) for 18 weeks . A total of 682 patients ( mean peak expiratory flow rate ( PEFR ) 413 l/min ) , who demonstrated > or = 15 % reversibility in PEFR , were r and omised into the study . After 18 weeks , patients experienced improvements in morning PEFR ( + 45 l/min , both groups ) , symptom score ( LD -0.57 , SD -0.49 , on a scale of 0 - 3 ) , sleep disturbance ( LD -1.21 nights/week , SD -1.06 nights/week ) and beta 2-agonist use ( LD -1.36 puffs/day , SD -1.06 puffs/day ) , within both groups ( each p = 0.0001 ) . At 18 weeks , 82 % ( LD ) and 84 % ( SD ) of patients benefited from no nocturnal wakening in the previous 7 days . Overall , at 18 weeks , asthma control was not significantly different between the groups . After 6 weeks , improvements in morning PEFR ( LD + 36 l/min , SD + 26 l/min ) and beta 2-agonist use ( LD -1.10 puffs/day , SD -0.94 puffs/day ) were greater in the loading dose than in the static dose group ( each p < 0.05 ) . The greater improvement in morning PEFR in the loading dose group was significant by day 7 ( p < 0.05 ) . While both regimens are equally effective in achieving asthma control at 18 weeks , early clinical advantage is gained with initial loading dose budesonide ( 400 micrograms b.d . ) [2653086] The aim of this open , r and omized cross‐over study was to compare the efficacy and safety of inhaled budesonide administered either via a pressurised metered dose inhaler with a 750 ml spacer attached , or via a new dry powder inhaler , Turbuhaler ® , in 28 patients with stable bronchial asthma . During the 2‐week run‐in period , the patients received their ordinary inhaled steroid treatment . This was followed by two 4–week periods of active treatment with inhaled budesonide given via Turbuhaler or pressurized MDI . The patients were divided into two groups according to their previous , inhaled steroid doses . Group A received 400 μg of budesonide b.i.d , and Group B 800 μg of budesonide b.i.d . Diary cards were used by the patients at home to report asthma symptoms , ( 32‐agonist consumption , and PEF twice daily , as well as the number of coughs experienced in a 5‐min period after steroid inhalation . Budesonide Turbuhaler produced a significantly better effect on morning peak flow than budesonide MDI . The number of coughs in the 5 min after steroid inhalation was significantly lower with the Turbuhaler than with the MDI . In all other parameters recorded ( e.g. FEV1 , evening PEF , histamine PC20 and other diary measurements ) there were no statistically significant differences between the two devices . Turbuhaler was significantly more appreciated than MDI in all questions of preference . The study showed that budesonide via Turbuhaler was at least as effective and safe as budesonide via a pressurized MDI at daily doses of 800 and 1,600 μg . The absence of additives , the lower incidence of cough after dose intake , the easiness of use , and higher preference , make Turbuhaler a valuable contribution in the treatment of asthmatics [9819291] BACKGROUND Budesonide ( BUD ) has recently been licensed for treatment of asthma in the United States , whereas triamcinolone acetonide ( TAA ) has been used for many years . OBJECTIVE We sought to evaluate the dose-response effect of inhaled BUD and TAA in terms of adrenal , bone , and blood markers . METHODS Twelve asthmatic subjects ( mean age , 32 years ; mean FEV1 , 91 % of predicted value ) were studied in a r and omized design comparing 3 days of treatment with placebo and low ( 200 micrograms twice daily ) , medium ( 400 micrograms twice daily ) , and high ( 800 micrograms twice daily ) doses of BUD ( Pulmicort Turbuhaler , 100 micrograms ) and TAA ( Azmacort integrated actuator/spacer , 100 micrograms ) with a 7-day period at crossover , when patients received their usual inhaled corticosteroid therapy . Measurements were made at 8 am for serum cortisol , osteocalcin , and blood eosinophils . Measurements were also made for overnight urinary cortisol/creatinine excretion . RESULTS For all measurements there were no significant differences between the 2 treatments at any dose level . Ratios between BUD and TAA ( 95 % CI ) at the highest dose levels were as follows : 8 am serum cortisol , 1.08-fold ( 0.63 to 1 . 85 ) ; urinary cortisol , 1.09-fold ( 0.63 to 1.86 ) ; eosinophils , 0 . 98-fold ( 0.69 to 1.38 ) ; and osteocalcin 1.05-fold ( 0.78 to 1.41 ) . There was no evidence of a significant overall dose-response effect for any parameter of hypothalamo-pituitary-adrenocortical axis activity , with neither drug being significantly different from placebo at any dose . For the 3 dose levels of both drugs , total abnormal low values for 8 am serum cortisol ( ie , < 5.4 micrograms/dL [ < 150 nmol/L ] ) showed 2 of 36 for BUD and 2 of 36 for TAA . There was also no significant overall dose-response effect for eosinophils or osteocalcin , although both drugs were significantly ( P < .05 ) different from placebo at the highest dose : eosinophils ( x10(9)/L ) , placebo : 0.36 , TAA : 0.24 , and BUD : 0.23 ; and osteocalcin ( nmol/L ) , placebo : 1.04 , TAA : 0.73 , and BUD : 0.77 . CONCLUSION There were no significant differences in the systemic bioactivity profiles , in terms of adrenal , blood , and bone markers , between BUD administered by means of Turbuhaler and TAA administered by means of an integrated actuator/spacer in a dose range of 400 micrograms to 1600 micrograms/day . Both drugs exhibited a significant degree of detectable systemic bioactivity but only at the highest dose of 1600 micrograms/day for effects on eosinophil count and osteocalcin [3556202] Twenty-four patients with severe steroid-dependent asthma participated in a double-blind cross-over study performed in two centers . After a run-in period of 2 weeks when beclomethasone dipropionate ( BDP ) ( 400 micrograms/day ) was used , the patients were treated for 4 weeks with either a high-dose ( 1600 micrograms/day ) or a low-dose ( 400 micrograms/day ) of budesonide ( Pulmicort ) . Thereafter the doses of budesonide were switched and the treatment continued for a further 4-week period . Patients treated with high-dose budesonide displayed significant improvements in airway functions . In addition , subjective scores for cough , sputum production and dyspnoea were more improved in the high-dose group than in the low-dose group . The need for concomitant beta 2-agonist therapy was also significantly reduced during the high-dose treatment . No significant changes in plasma cortisol levels were detected and no adverse effects of importance were registered . The results indicate that high-dose budesonide treatment improves the clinical status of patients with severe steroid-dependent asthma more than a low-dose therapy but without causing systemic side-effects [9814730] In recent years , measurement of serum osteocalcin has been introduced for assessment of bone turnover in patients treated with exogenous glucocorticoids . Studies in children with asthma on inhaled glucocorticoids , however , have shown inconsistent results . The aim of the present study is to assess bone turnover in prepubertal children and in adolescents with asthma treated with inhaled budesonide using three different osteocalcin assays : the Pharmacia Osteocalcin CAP FEIA , the CIS OSTK-PR and CIS IRMA ELSA-OSTEO assays . Two studies were conducted : 1 ) a r and omised double blind two-period crossover study of 22 prepubertal children aged 5 - 12 years . In one period 800 microg budesonide was given once in the morning , in the other 400 microg was given twice daily ; 2 ) a r and omised double blind placebo controlled two period crossover study of inhaled budesonide 400 microg twice daily in fourteen 13 - 16 year old adolescents with pubertal stages II-V. In both studies , treatment periods were of four weeks duration , and blood sample s were collected at the last day of each period . In the prepubertal children none of the osteocalcin assays detected any statistically significant differences between any of the periods . In the adolescent group reduced levels of osteocalcin were seen during budesonide treatment . The suppression reached statistical significance with the CAP FEIA ( P = 0.03 ) and the OSTK-PR ( P = 0.01 ) assays , but not with the ELSA-OSTEO assay ( P = 0.06 ) . Correlation analyses showed statistically significant correlation coefficients varying between 0.58 and 0.91 ( P = 0.03 and P < 0.0001 , respectively ) . The effect of inhaled glucocorticoids on serum osteocalcin may depend on the assay applied , and inhaled glucocorticoids have differential effects in children and adolescents [1878641] OBJECTIVE --To determine whether the inhaled glucocorticosteroid budesonide has any adverse effect on short term linear growth in children with mild asthma . SETTING --Outpatient clinic in secondary referral centre . PATIENTS --15 children aged 6 - 13 years with normal statural growth velocity during the previous year , no signs of puberty , and no use of systemic or topical steroids in the two months before the study . DESIGN OF INTERVENTIONS --Double blind , r and omised crossover trial with two active periods in which budesonide was given in divided daily doses of 200 micrograms and 800 micrograms . During run in and two washout periods placebo was given . After the second washout period the children received open treatment with 400 micrograms budesonide daily . All periods were of 18 days ' duration . MAIN OUTCOME MEASURE -- Growth of the lower leg as measured twice a week by knemometry . RESULTS --Mean growth velocity of the lower leg was 0.63 mm/week during run in and during washout 0.64 mm/week . Budesonide treatment was associated with a significant dose related reduction of growth velocity : the mean reduction in growth velocity during treatment was 0.11 ( 95 % confidence interval -0.15 0.36 ( 0.13 to 0.59 ) mm/week with 800 micrograms budesonide ( p less than 0.05 ; Page 's test ) . During treatment with 400 micrograms budesonide a reduction of 0.17 ( -0.10 to 0.45 ) mm/week was found . CONCLUSIONS --Treatment with inhaled budesonide is associated with a dose related suppression of short term linear growth in children with mild asthma [11112113] Inhaled corticosteroids have become the mainstay treatment of bronchial asthma . However , simultaneous evaluations of efficacy and side effects are few . This study aim ed to compare the relative effect of fluticasone propionate ( FP ) and budesonide ( BUD ) on bronchial responsiveness and endogenous cortisol secretion in adults with asthma . The study was double-blind and included 66 adults with asthma , who were r and omized to FP ( n = 33 ) or BUD ( n = 33 ) . Pre study , all participants were clinical ly stable , using inhaled corticosteroids and hyperresponsive to methacholine . Eligible patients were r and omized to three consecutive 2-wk periods with either FP 250 microg twice daily , FP 500 microg twice daily , and FP 1,000 microg twice daily , or BUD 400 microg twice daily , BUD 800 microg twice daily , and BUD 1,600 microg twice daily , delivered by Diskhaler and Turbuhaler , respectively . Before r and omization and at the end of each treatment , bronchial methacholine PD(20 ) , 24-h urinary cortisol excretion ( 24-h UC ) , plasma cortisol , serum osteocalcin , and blood eosinophils were determined . The relative PD(20 ) potency between FP and BUD was 2.51 ( 95 % CI , 1.05 - 5.99 ; p < 0 . 05 ) , while the relative 24-h UC potency was 0.60 ( 95 % CI , 0.44 - 0.83 ; p < 0.01 ) . The differential therapeutic ratio ( FP/BUD ) based on PD(20 ) potency and 24-h UC was 4.18 ( 95 % CI , 1.16 - 15.03 ; p < 0.05 ) . The difference in systemic potency was also seen for plasma cortisol , serum osteocalcin , and blood eosinophils . Therapeutic ratio over a wide dose range , determined by impact on bronchial responsiveness and endogenous corticosteroid production , seems to favor FP [7119301] The influence of various dosing regimens on the response of asthmatic patients to aerosol steroid was investigated . Budesonide , a topically active corticosteroid like beclomethasone dipropionate , was given q.i.d . or b.i.d . , in the morning or A.M./P.M. , at doses of 400 , 800 , and 1600 micrograms/day . Each patient ( n = 34 ) took every treatment combination for 2 wk . The antiasthmatic and systemic effects , measured by changes in peak expiratory flow rate ( PEFR ) , blood eosinophils , and serum cortisol levels increased approximately linearly on log dose budesonide ( p less than 0.0005 ) . Systemic effects of the drug were nonsignificant at low dosage . At high dosage , morning dosing conserved hypothalamic-pituitary-adrenal function , but at the cost of a marginal reduction in efficacy ( delta PEFR , p = 0.12 ) . Having the dose frequency reduced the antiasthmatic potency of the drug , i.e. , PEFR fell by an amount equivalent to approximately eightfold reduction in daily dosage ( p = 0.002 ) . This effect was not evident when asthma was in remission but became so with asthma in relapse . Overall , the q.i.d . A.M./P.M. regimen showed the best risk-benefit relationships . The data indicate ( 1 ) that reductions in dose frequency made with the hope of improving patient compliance and thus conserving the drug 's long-term efficacy are likely to lead to the reverse effect , ( 2 ) that the clinician can conserve a better balance of risk vs benefit by titrating dosage in terms of puffs per dose rather than doses per day , and ( 3 ) that patients can increase the antiasthmatic efficacy of this aerosol steroid without any increase in drug costs ( or apparent risk ) by simply increasing dosing frequency . These therapeutic considerations probably apply to some or all of the other topically active steroids currently used to treat asthma [7822661] OBJECTIVE The purpose of the study was to evaluate the dose-response relationships of the inhaled corticosteroid budesonide in a double blind crossover study in 19 children with moderate and severe asthma . METHODS A 2-week placebo treatment period ( run-in ) was followed by three 4-week treatment periods during which 100 , 200 , and 400 micrograms of budesonide were given per day in r and omized order . Urinary cortisol excretion , lung functions , and protection against exercise-induced asthma were assessed at the end of run-in and each treatment period . Furthermore , morning and evening peak expiratory flow rates , day and night symptoms , and use of rescue beta 2-agonists were recorded throughout the study . RESULTS One hundred micrograms of budesonide per day markedly improved symptoms , morning and evening peak expiratory flow rates , and use of rescue beta 2-agonists ( p < 0.01 ) . No further improvement was seen in these parameters with increasing doses of budesonide . In contrast , a significant dose-response effect was found on lung functions measured at the hospital and fall in lung functions after exercise ( p < 0.001 ) ; 200 micrograms was significantly better than 100 micrograms , and 400 micrograms was significantly better than 200 micrograms . About 53 % of the maximum effect against exercise-induced asthma was achieved by the lowest budesonide dose ( p < 0.001 ) , and about 83 % by the highest dose . No significant differences were seen in urinary cortisol excretion between run-in and the various budesonide doses . CONCLUSIONS Low doses of budesonide , which are not associated with any systemic side effects , have a marked antiasthma effect in children . Protection against exercise-induced asthma requires higher doses than achievement of symptom control [10353578] BACKGROUND Budesonide ( Pulmicort ) is an inhaled corticosteroid with high topical potency but low systemic activity . Turbuhaler is a novel breath-actuated , multi-dose , dry-powder inhaler . OBJECTIVES This study was conducted to determine the efficacy and safety of two different dose regimens of budesonide Turbuhaler , compared with placebo , in adult patients with mild-to-moderate asthma not well-controlled with bronchodilator therapy . METHODS This double-blind , r and omized , placebo-controlled , parallel-group , multicenter study compared the efficacy and safety of 200 microg and 400 microg of budesonide , administered twice daily via Turbuhaler , with placebo , in 273 adult patients ( aged 19 to 70 years ) with mild-to-moderate asthma ( FEV1 67 % of predicted normal ) , not well-controlled with bronchodilator therapy . Efficacy was assessed by pulmonary function tests and patient assessment s of asthma symptom control . Safety was assessed in terms of adverse events , laboratory evaluations , and physical examinations . RESULTS Two hundred and 400 microg of budesonide bid were significantly more effective than placebo at improving morning PEF ( mean differences from placebo of 43.63 L/min and 40.10 L/min , respectively ; P < .001 ) and FEV1 ( mean differences from placebo of 0.44 L , and 0.50 L , respectively ; P < .001 ) over the 12-week treatment period . Onset of action as assessed by morning PEF was within two days . Basal and stimulated plasma cortisol concentrations were not significantly affected by budesonide treatment compared with placebo . CONCLUSIONS Treatment of adults suffering from mild-to-moderate asthma with budesonide Turbuhaler is well tolerated and results in a rapid onset of asthma control which is maintained over time [10669688] OBJECTIVES This study was design ed to compare the effects of a 6-month treatment with budesonide 100 microg bid ( low dose ) and 400 microg bid ( st and ard reference dose ) in controlling symptoms and lung function in a group of asthmatics with moderate asthma ( baseline FEV(1 ) > or = 50 % and < or = 90 % of predicted values ) previously treated with inhaled beclomethasone dipropionate ( 500 to 1,000 microg/d ) . Moreover , we investigated whether or not asthma exacerbations could be treated by a short-term increase in the daily dose of budesonide . METHODS After a 2-week run-in period and 1-month treatment with a high dose of budesonide ( 800 microg bid ) , 213 patients with moderate asthma were assigned to r and omized treatments . Daily treatment included budesonide ( bid ) plus an additional treatment in case of exacerbation ( qid for 7 days ) . Treatments were as follows : budesonide 400 microg plus placebo ( group 1 ) ; budesonide 100 microg plus budesonide 200 microg ( group 2 ) ; and budesonide 100 microg plus placebo ( group 3 ) . Symptoms and a peak expiratory flow ( PEF ) diary were recorded and lung function was measured each month . An exacerbation was defined as a decrease in PEF > 30 % below baseline values on 2 consecutive days . RESULTS We found that that 1-month treatment with a high budesonide dose remarkably reduced all asthma symptoms . Moreover , symptoms were under control in all treatment groups throughout the study period . Similarly , lung function improved and remained stable , and no relevant differences between groups were observed . In each treatment group , the majority of patients had no exacerbations . In patients treated with the st and ard budesonide dose ( group 1 ) , the number of exacerbations and days with exacerbations were significantly lower than in group 3 ( intention-to-treat analysis ) . Additionally , patients treated with low budesonide dose plus budesonide ( group 2 ) experienced a significantly lower number of exacerbations and days with exacerbations compared to group 3 ( per- protocol analysis ) . CONCLUSIONS This study demonstrates that when patients with moderate asthma had reached a stable clinical condition with a high dose of budesonide , a low dose of budesonide ( 200 microg/d ) is as effective as the st and ard dose ( 800 microg/d ) in the control of symptoms and lung function over a period of several months . Furthermore , results showed that the addition of inhaled budesonide ( 800 microg/d ) at onset of an asthmatic exacerbation has a beneficial clinical effect [9564798] BACKGROUND There are no data currently available on the correct schedule for the initiation of treatment with nebulized suspension of budesonide in children with recurrent wheezing episodes . We compared the efficacy and safety of starting with a high dose followed by a stepwise decrease to a continuous low dose . METHODS In a double-blind design , 42 children aged 6 months to 3 years were r and omly allocated to receive either a high starting dose of 1 mg budesonide twice daily followed by a stepwise decrease of 25 % every second day for 1 week ( group A ) or a low dose of 0.25 mg twice daily for 1 week ( group B ) . Efficacy was assessed with daily symptom scores and the systemic effect of the corticosteroids with the adrenocorticotropic hormone test . RESULTS The two groups were comparable for all parameters evaluated . During the first week of treatment , there was a significant decrease in asthmatic symptomatology only in group A : a 59 % decrease for wheezing ( p = 0.0001 ) , 39 % for diurnal cough ( p = 0.036 ) , and 39 % for nocturnal cough ( p = 0.04 ) . Mean time to clinical response was 3.0 days in group A and 5.7 days in group B ( p = 0.02 ) . This early improvement was sustained for the rest of the follow-up period . The high dose starting schedule was not associated with any change in serum cortisol level . CONCLUSIONS The administration of nebulized suspension of budesonide at a high starting dose schedule followed by a rapid ( 1 week ) stepwise decrease yields a significant early improvement in asthma symptoms and causes no change in serum cortisol levels [3532011] An open , cross-over trial was conducted on 25 asthmatic children , aged 6 - 13 years , who required inhaled steroids . They inhaled Budesonide 200 micrograms twice daily , either directly from the metered dose inhaler or via the pear spacer ( PS ) , for 2 months on each , in r and omized order . The effects of the treatment were monitored with diary cards recording peak expiratory flow rates twice daily , symptoms and treatment taken , and with monthly clinical assessment s including more sensitive lung function studies ( flow-volume loops and single breath nitrogen wash-out tests ) . There was no specifically PS-related improvement in symptoms or in the majority of tests , but the results showed improvement with time when using either method . The improvement was more distinct in some tests reflecting proximal airway calibre ( i.e. , PEFR ) than in tests thought to reflect predominantly peripheral airway calibre ( i.e. , F50 , RV ) . The bronchodilator responsiveness , as shown by the increase in lung function tests after a beta-agonist was given , was significantly greater for FVC during the periods when the PS was used , although there was no significant improvement in FEV2 or PEFR . The improvement in tests reflecting proximal airways may have been due to optimization of the inhalation technique , greater underst and ing of asthma , or better compliance with medication associated with regular attendance for the study . The greater bronchodilator response whilst children were inhaling budesonide by the PS may have been due to increased deposition or better distribution of the steroid but was probably related to a difference between the two groups in initial baseline function tests [9692099] Inhaled steroid therapy is the most important treatment in the management of chronic asthma and currently twice-daily administration is recommended in mild to moderate asthma . Compliance is often a problem in asymptomatic patients and may lead to reduced disease control . Our aim was to investigate whether budesonide 0.2 mg once daily administered via the Turbuhaler is as effective as 0.1 mg twice daily . A r and omized , double-blind , parallel group study was carried out in which 76 adult patients with mild to moderate asthma ( FEV1 86 % of predicted ) were allocated to budesonide once or twice daily . After a run-in period of 2 weeks on present inhaled steroid treatment ( 0.2 - 0.5 mg day-1 ) there was an 8 week treatment period , followed by a washout period in which patients received no steroid for 4 weeks unless a drop in morning peak flow of at least 20 % occurred or the use of beta 2-agonists increased by 50 % . Both treatment groups improved minimally in peak flow ( 1.7 and 4.31 min-1 in the once-daily and twice-daily groups respectively ) but the differences between the two groups were not significant . Testing the reverse hypothesis revealed clinical equivalence . The 90 % confidence interval of the difference in the change of peak flow from run-in was between + 30 and -30 l min-1 , the limits deemed to be clinical ly relevant . There were no differences in symptom scores , beta 2-agonist use or spirometry measurements between the two groups . In the washout period there was a significant deterioration in peak flow and symptoms . This study shows that 0.2 mg budesonide given once a day is as affective as 0.1 mg given twice daily in patients with mild to moderate asthma [2669554] The dose‐response effects of inhaled beclomethasone dipropionate ( BDP ) and budesonide ( BUD ) administered b.i.d . with the aid of metered dose aerosols were studied in 128 patients ( 67 men and 61 women , mean age 53 years ) suffering from asthma bronchiale . The study was design ed as a multi‐centre , double‐blind , four‐period cross‐over study , followed by a single‐blind double placebo period . BDP was administered in doses of 400 and 1000 μg , and BUD in doses of 400 and 800 μg . The results in terms of peak expiratory flow ( PEF ) in the morning and evening , daily symptoms score and use of inhaled β2‐agonists did not reveal any clinical ly significant differences between the drugs or between high ( 800 μg BUD , 1000 μg BDP ) and low ( 400 mg BUD/BDP ) doses . However , statistically significant differences were recorded for the corresponding parameters when comparing the placebo with preceding steroid periods . Adverse effects consisting mainly of oropharyngeal c and idiasis , hoarseness and cough occurred in 54 of 468 treatment months ( 12 % ) . The carry‐over effects of inhaled steroids are longer lasting than was previously assumed [10971469] Repeated low‐dose allergen challenge increases airway hyperresponsiveness and sputum eosinophils in atopic asthmatics . Inhaled corticosteroids attenuate the airway responses to high‐dose allergen challenge , but have not been evaluated against repeated low dose challenge [9744142] One hundred and sixty seven children on 0 - 200 microgram/day of inhaled steroid with asthma symptoms and sub-optimal peak flow values ( less than 90 % of that predicted for their height ) were r and omly allocated either 400 microgram once daily ( nocte with placebo o.m . ) or 200 mircrogram twice daily of budesonide Turbohaler for 8 weeks . Bronchdilator usage and symptoms were reduced in both groups at 4 and 8 weeks compared with baseline . There was a significant increase within both groups in morning and evening PEF after 4 and 8 weeks . The increase in evening PEF after 8 weeks was greater in the once-daily group than in the twice-daily group but there were no other significant differences between the groups ( morning : + 24.6 l/min vs 15.2 l/min , p = 0.059 ; evening : + 19.7 l/min vs + 8.31 l/min ; p = 0.013 ) . Budesonide Turbohaler 400 microgram once daily is therefore as effective as 200 microgram twice daily in achieving asthma control in children [8640047] Maintenance treatment with nebulized budesonide was studied in young children with asthma not controlled without steroids . In a blind parallel‐group study for 18 weeks , 102 children , mean age 22 ( 5–47 ) months , were r and omized for treatment starting with 0.25 or 1 mg b.i.d . The patients were review ed every 3 weeks , and if symptom control had been achieved the dose was reduced , otherwise it was kept . The clinical effect was very good with both dose regimens . The median time to 7 consecutive days without any asthma symptoms was about 1 month with both , highlighting the importance of the duration of therapy rather than the benefits of a high starting dose . In 18 of 24 children who attained the placebo stage , symptoms had reappeared at the last visit . Although an overall minimal effective maintenance dose could not be demonstrated , 47 % achieved symptom control on 0.25 mg b.i.d . , i.e. fulfilled criteria for further dose reduction . No significant side effects were seen . On average , 25 % of the nominal dose reached the patients [9358137] BACKGROUND The role of long-acting , inhaled beta2-agonists in treating asthma is uncertain . In a double-blind study , we evaluated the effects of adding inhaled formoterol to both lower and higher doses of the inhaled glucocorticoid budesonide . METHODS After a four-week run-in period of treatment with budesonide ( 800 microg twice daily ) , 852 patients being treated with glucocorticoids were r and omly assigned to one of four treatments given twice daily by means of a dry-powder inhaler ( Turbuhaler ) : 100 microg of budesonide plus placebo , 100 microg of budesonide plus 12 microg of formoterol , 400 microg of budesonide plus placebo , or 400 microg of budesonide plus 12 microg of formoterol . Terbutaline was permitted as needed . Treatment continued for one year ; we compared the frequency of exacerbations of asthma , symptoms , and lung function in the four groups . A severe exacerbation was defined by the need for oral glucocorticoids or a decrease in the peak flow to more than 30 percent below the base-line value on two consecutive days . RESULTS The rates of severe and mild exacerbations were reduced by 26 percent and 40 percent , respectively , when formoterol was added to the lower dose of budesonide . The higher dose of budesonide alone reduced the rates of severe and mild exacerbations by 49 percent and 37 percent , respectively . Patients treated with formoterol and the higher dose of budesonide had the greatest reductions -- 63 percent and 62 percent , respectively . Symptoms of asthma and lung function improved with both formoterol and the higher dose of budesonide , but the improvements with formoterol were greater . CONCLUSIONS In patients who have persistent symptoms of asthma despite treatment with inhaled glucocorticoids , the addition of formoterol to budesonide therapy or the use of a higher dose of budesonide may be beneficial . The addition of formoterol to budesonide therapy improves symptoms and lung function without lessening the control of asthma [7638369] Measurement of short term lower leg growth with the knemometer has recently been shown to be a sensitive method for assessment of systemic activity of exogeneous glucocorticosteroids in children with asthma ( 1 ) . It is not known , however , whether short term knemometry is more sensitive than established measures of adrenal function , such as 24 h urine free cortisol excretion . We recently found that knemometric growth rates were suppressed in a dose-related manner in asthmatic children treated with 200 , 400 and 800,~g of inhaled budesonide ( 2 ) . In the present paper , we report the 24 h urine free cortisol excretion in the same children for comparison with the knemometry data , to evaluate if there is any correlation between the two measures of systemic activity , and to assess which method is the more sensitive [3512282] Forty-five steroid-dependent asthmatic out patients were treated twice daily for 51 weeks with a new inhalation steroid , budesonide ( BUD ) , using a 750 ml spacer . During the initial 15 weeks the prednisone-sparing effects of a high daily dose ( 1600 micrograms ) and a conventional dose ( 400 micrograms per day ) were compared in a double-blind r and omized trial including 50 patients . During the remaining 36 weeks 45 patients were treated openly with 1600 micrograms daily . All patients used other antiasthmatic drugs which were maintained throughout the study , except for inhalations of beta-2 agonists that could be used whenever needed . All patients but 2 were able to reduce the daily dose of oral prednisone . The mean daily dose decreased from 13.9 mg to 5.3 mg . Eighteen patients ( 40 % ) were able to discontinue oral prednisone . Adrenal gl and function improved considerably as prednisone intake decreased . Oropharyngeal thrush frequency showed no change . No severe side effects were observed [3276257] In a double-blind study of 2 parallel groups of 15 allergic asthmatic patients each , we investigated whether treatment with inhaled budesonide has a dose- and time-dependent effect on the degree of bronchial hyperreactivity . The patients were r and omly allocated to treatment with either 200 or 800 micrograms budesonide per day for a period of 8 wk . The active treatment period was preceded by a selection period of 3 wk , and a single-blind placebo period of 2 wk . During these initial 5 wk the maintenance treatment of the patients , including cromolyn sodium and inhaled corticosteroids , was withheld . Spirometry and inhalation provocation tests with methacholine were carried out , and the symptom score was recorded every 2 wk . The methacholine provocation concentrations ( geometric mean ) causing a decrease in FEV1 of 20 % ( PC20 ) in the 200 and 800 micrograms/day treatment groups just before the active treatment period were 0.90 and 0.91 mg/ml , respectively . These values increased significantly to 1.21 and 1.84 mg/ml after 2 wk of treatment ( p less than 0.05 and p less than 0.001 , respectively ) and to 1.55 and 2.74 mg/ml after 8 wk of treatment ( p less than 0.01 and p less than 0.001 ) . During the whole study period budesonide in a dosage of 800 micrograms/day induced a significantly larger change in PC20 than in a dosage of 200 micrograms/day . The FEV1 before treatment was 91 + /- 3 % ( SEM ) and 84 + /- 2 % of the predicted value in the 200 and 800 micrograms/day treatment groups , respectively . ( ABSTRACT TRUNCATED AT 250 WORDS [10926339] The importance of early initiation of inhaled steroids even in mild asthma has been documented in several studies . It is not , however , clear whether the treatment should be started with a high or a low dose of the inhaled steroid . We have compared the effects of high and low dose inhaled steroid , budesonide , in patients with newly detected asthma . We studied 101 adult patients with newly detected bronchial asthma who were without inhaled steroid or any regular pharmacological treatment for their asthma . The patients were r and omly allocated to two treatment groups : one to receive 800 microg inhaled budesonide per day and the other to receive 200 microg inhaled budesonide per day . The drugs were given with a Turbuhaler dry powder inhaler . During the 3-month treatment period , no significant differences between the treatment groups were noted in morning or evening PEF values , in spirometric parameters , in asthmatic symptoms or in the use of rescue beta2-agonists . The decrease in bronchial hyperresponsiveness was , however , more marked in the high dose budesonide group , reaching a borderline significance ( P=0.10 high vs. low dose budesonide ) . In addition , in serum markers of asthmatic inflammation significant differences were shown between the treatment groups . The decrease in the number of blood eosinophils during the treatment was more marked in the high dose budesonide group ( P=0.02 ; high vs. low dose budesonide ) . In serum ECP no change was observed in the low dose budesonide group , but a marked decrease in the high-dose budesonide group ( P=0.008 ; high vs. low dose budesonide ) . The change was even more marked with regard to serum EPX ( P=0.005 ; high vs. low dose budesonide ) . Our results support the view that the treatment of newly detected asthma should be started with a high dose of inhaled steroid . The low dose may not be enough to suppress asthmatic inflammation despite good clinical primary response [7540898] Serum concentrations of growth hormone – dependent insulin – like growth factor I ( IGF – I ) and insulinlike growth factor binding protein–3 ( IGFBP–3 ) , the carboxy terminal propeptide of type I procollagen ( PICP ) , the carboxy terminal pyridinoline cross – linked telopeptide of type I collagen ( ICTP ) and the amino terminal propeptide of type III procollagen ( PIIINP ) were studied in 14 prepubertal children with asthma ( mean age 9.7 years ) during treatment with inhaled budesonide . The study design was a r and omized , crossover trial with two double – blind treatment periods ( 200 and 800 μg ) and one open , non – r and omized treatment period ( 400 μg ) . All periods were 18 days ’ duration . Budesonide treatment was associated with a dose – related suppressive trend in serum concentrations of PIIINP when the 400 μg period was included ( p < 0.01 ; z = –2.7 ) and when it was excluded from the calculations ( p < 0.01 ; z = –2.6 ) , indicating reduced synthesis of type III collagen . A similar trend was observed in ICTP levels when the 400 μg period was excluded from the calculations ( p= 0.05 ; z = –1.9 ) . No other statistically significant variations were seen [9525445] BACKGROUND As a general phenomenon , corticosteroids may suppress the activity in the hypothalamic-pituitary-adrenal ( HPA ) axis . The adrenal stimulation test is a commonly used method to assess the relative risk of exogenous corticosteroids to induce systemic side effects . OBJECTIVES This clinical trial was performed to assess the effects of budesonide on the HPA axis ( at 800 , 1600 , or 3200 microg/day , given as a twice daily regimen , administered by means of the Turbuhaler ) in adult patients with mild , non-steroid-dependent asthma . METHODS Sixty-four asthmatic patients received budesonide or placebo by inhalation or 10 mg/day oral prednisone once daily as a positive control in a double-blind , double-dummy , r and omized , placebo-controlled , parallel-group , multicenter study . Plasma cortisol concentration was measured to assess the effect on the HPA axis before and during a 6-hour infusion of synthetic adrenocorticotropic hormone ( ACTH ) , cosyntropin . RESULTS After 6 weeks of treatment , plasma cortisol concentrations after adrenal stimulation by cosyntropin infusion had fallen by 4 % in the placebo group ; by 13 % , 11 % , and 27 % in the budesonide groups ( 800 , 1600 , and 3200 microg/day , respectively ) ; and by 35 % in the prednisone group . The decrease was significant only in the 3200 microg/day budesonide ( p = 0.03 ) and prednisone ( p = 0.005 ) groups . Over the same time period , decreases in basal plasma cortisol concentrations were 1 % in the placebo group ; 19 % , 19 % , and 34 % in the three budesonide groups ; and 37 % in the prednisone group . Only in the prednisone group was the decrease significant ( p = 0.03 vs placebo ) . CONCLUSIONS In this study budesonide inhaled by means of the Turbuhaler , at doses recommended for clinical use ( 800 or 1600 microg/day ) , did not produce any statistically significant suppression of the HPA axis compared with placebo [10390394] We assessed the systemic effects of budesonide ( BUD ) and fluticasone propionate ( FP ) in 23 patients with asthma , using a double-blind , placebo-controlled , double-dummy , and cross-over design . The following five treatments were given in a r and omized order for 1 wk with a washout period in between of 2 wk : ( 1 ) placebo ; ( 2 ) FP , 200 micrograms twice a day , inhaled from a Diskhaler ; ( 3 ) FP , 1,000 micrograms twice a day , inhaled from a Diskhaler ; ( 4 ) BUD , 200 micrograms twice a day , inhaled from a Turbuhaler ; and ( 5 ) BUD , 800 micrograms twice a day , inhaled from a Turbuhaler . The primary variable was the area under the curve of serum cortisol versus time ( AUC0 - 20 ) , derived from serum sample s taken every 2 h over a 20-h period following the last evening dose at 10:00 P.M. The lower doses of BUD and FLU did not cause any adrenal suppression . Compared with placebo , however , FP ( 1 , 000 micrograms , twice daily and BUD ( 800 micrograms , twice daily ) decreased the AUC0 - 20 by 34 and 16 % , respectively . Fluticasone ( 1,000 micrograms , twice daily ) was more suppressive than BUD ( 800 micrograms , twice daily ) ( p = 0.0006 ) . The FEV1 , measured the morning after the last inhalation , was significantly higher after the active treatments , compared with placebo ( p < 0.02 ) , but did not differ between all active treatments . We conclude that high doses of BUD and FP ( in particular the latter ) , inhaled via their respective dry powder inhalers for 1 wk , result in a measurable systemic activity in patients with asthma [9819296] BACKGROUND Inhaled glucocorticosteroids are indicated for the treatment of persistent asthma ; however , many young children are unable to effectively use currently available inhalers . OBJECTIVE We sought to evaluate the efficacy and safety of 3 different twice daily doses of budesonide inhalation suspension ( Pulmicort Respules ) in inhaled steroid-dependent asthmatic children . METHODS This was a 12-week , r and omized , double-blind , placebo-controlled , parallel-group study involving 178 children ( age range , 4 to 8 years ) at 17 centers in the United States . Budesonide inhalation suspension doses of 0.25 mg , 0.50 mg , or 1.0 mg twice daily were administered by means of a jet nebulizer and air compressor system . Efficacy was assessed by recording at home nighttime and daytime asthma symptom scores , use of rescue medication , pulmonary function tests , and treatment discontinuation because of worsening symptoms . Safety was assessed by reported adverse events and changes in baseline and adrenocorticotrophic hormone-stimulated plasma cortisol levels in a subset of patients . RESULTS Baseline demographics , symptom scores , and pulmonary function data were similar across treatment groups . All doses of budesonide inhalation suspension were superior to placebo in improving nighttime and daytime asthma symptom scores ( P < /=.026 ) , reducing use of breakthrough medication ( P < /=.032 ) , and improving morning peak expiratory flow ( P < /=.030 ) . The number of dropouts because of worsening asthma was also significantly fewer in the budesonide groups ( P < /=.015 ) . There were no differences between doses of budesonide . Adverse events and basal and adrenocorticotrophic hormone-stimulated cortisol responses were not different between budesonide and placebo groups . CONCLUSION Budesonide inhalation suspension , 0.25 mg , 0.50 mg , and 1.0 mg twice daily , is an effective and safe treatment for young children with inhaled steroid-dependent , persistent asthma [10510140] AIMS The present pharmacokinetic study was undertaken to determine the dose proportionality of three different doses of budesonide-400 microg , 800 microg or 1600 microg administered twice daily by a dry-powder inhaler ( Turbuhaler ) in adult patients with mild asthma . METHODS A total of 38 patients received budesonide by inhalation , 13 received 400 microg twice daily , 12 received 800 microg twice daily and 13 received 1600 microg twice daily . Mean FEV1 at inclusion was 3.4 , 4.0 and 3.9 l min-1 in the three groups , respectively . Blood sample s were taken after a single dose , and after 3 weeks of daily treatment , for pharmacokinetic evaluation . Plasma concentrations of budesonide were determined by liquid chromatography plus mass spectrometry . RESULTS Eleven evaluable patients remained in each dose group . Mean time to peak budesonide plasma concentration ( tmax ) was short ( 0.28 - 0.40 h ) and did not differ between treatment groups . Budesonide concentrations declined rapidly thereafter , indicating efficient pulmonary absorption and rapid elimination with a half-life of approximately 3 h. Cmax was 1 . 4(2.0 ) nmol l-1 ( single ( repeated ) doses ) , 2.6(3.6 ) nmol l-1 and 5 . 4(6.4 ) nmol l-1 after 400 , 800 and 1600 microg twice daily , respectively . The corresponding results for the area under the plasma concentration vs time curve ( AUC ) were 271(325 ) , 490(628 ) and 915(1096 ) nmol l-1 min . Ninety percent confidence intervals for pairwise dose-normalized Cmax and AUC comparisons between groups were large but contained unity in all cases , thus indicating dose-proportional pharmacokinetics . Regression on analysis supported these findings . Mean AUC after repeated doses ( AUC(0,12 h , RD ) ) was on average 23 % higher than the mean AUC after single doses ( AUC(0 , infinity , SD)(P=0.04 ) with no significant differences between doses , indicating slight accumulation following bid dosing . CONCLUSIONS In this relatively small study , budesonide inhaled via Turbuhaler appeared to have dose-proportional pharmacokinetics , both within and above the clinical ly recommended dose range for asthmatic patients [9627589] OBJECTIVE To determine the efficacy and safety of budesonide delivered by an inhalation-driven dry powder inhaler ( Turbuhaler ) in children with moderate to severe persistent asthma . STUDY DESIGN In our r and omized , double-blind , placebo-controlled , parallel-group , multicenter study , a total of 404 children with asthma , who were aged 6 to 18 years and who had been receiving inhaled glucocorticosteroid therapy , were r and omly assigned to receive either 100 , 200 , or 400 micrograms of budesonide or placebo twice daily for 12 weeks . At baseline , mean forced expiratory volume in 1 second ( FEV1 ) was 74.6 % ( range , 30.7 % to 123.3 % ) of the predicted normal value . RESULTS Patients in each of the three budesonide treatment groups showed significant dose-related improvements in lung function ( morning peak expiratory flow and FEV1 ) , in asthma symptoms , and with a significant decrease in inhaled beta 2-agonist use in comparison with placebo . Improvements were evident within 2 weeks and were maintained throughout the 12 weeks . Budesonide treatment had no significant effect on hypothalamic-pituitary-adrenal axis function , and the incidence of reported adverse events was similar in all treatment groups . CONCLUSION Budesonide administered via a dry powder inhaler provided dose-related improvements in lung function and clinical status and was well tolerated by children ( 6 to 18 years of age ) with moderate to severe persistent asthma [2035313] Bisgaard , H. , Pedersen S. , Damkjær Nielsen M and Østerballe O. ( Department of Paediatrics , University Hospital of Copenhagen , County of Gentofte , Copenhagen ; Department of Paediatrics , County Hospital of Kolding ; Department of Clinical Physiology , University Hospital of Copenhagen , County of Glostrup , Copenhagen ; Department of Paediatrics , County Hospital of Viborg , Denmark ) . Adrenal function in asthmatic children treated with inhaled budesonide . Acta Paediatr Sc and 80 : 213 , [9114906] 1 . The aim of this pharmacokinetic study was to evaluate to what extent oropharyngeal deposition of drug contributes to the systemic availability of budesonide inhaled from a dry powder inhaler ( Turbuhaler ) . 2 . The design was a r and omized cross-over study in eight children aged 7 - 13 years . The plasma concentrations of the two epimers of budesonide ( 22R and 22S ) after inhalation of 1 mg budesonide from a Turbuhaler were compared with the plasma concentrations obtained when the absorption of the drug deposited in the oropharynx was blocked by drinking and rinsing the mouth with charcoal before and after the inhalation . 3 . The plasma concentrations of budesonide were significantly reduced by the charcoal treatment ( P < 0.01 ) and the area under the time vs plasma concentration curve 0 - 4 h was significantly reduced from 9.5 to 8.0 mmol l-1 h for 22S ( P < 0.01 ) and from 7.6 to 5.7 mmol l-1 h for 22R ( P < 0.01 ) . 4 . The plasma concentrations and the AUCs after both Turbuhaler administrations were markedly higher than those obtained in earlier studies using other inhalers suggesting a higher intrapulmonary deposition of drug after Turbuhaler treatment . 5 . It is concluded that oropharyngeal deposition of drug accounts for about 20 % of the total systemic availability of budesonide inhaled from Turbuhaler . Thus , the main contribution to the system comes from budesonide absorbed in the airways [9768574] BACKGROUND A simple laboratory method to evaluate relative potency of inhaled corticosteroids in asthma would be valuable . Single-dose studies with the allergen-induced late asthmatic response have failed to show a useful dose-response relationship . Treatment for several days with inhaled corticosteroids will also inhibit the allergen-induced early asthmatic response . METHODS Twelve atopic asthmatic subjects were studied during a season when no medications were required except ipratropium bromide as needed . These subjects had positive allergen and methacholine inhalation tests and FEV1 greater than 70 % of predicted value . A double-blind , r and omized , cross-over study compared placebo and budesonide 100 , 200 , and 400 microg administered by means of Turbuhaler twice daily for 7 days with 6-day washout periods . Methacholine PC20 was measured before and after 6 days of treatment , and allergen PC15 was measured after 7 days of treatment . RESULTS The allergen PC15 ( n = 11 ) was significantly larger ( P = .0001 ) for all doses of budesonide compared with placebo , but there was no significant difference between the 3 doses of budesonide , and no dose response was demonstrated . The methacholine PC20 was significantly larger after all budesonide treatments compared with placebo ( P = .024 ) , but there was no difference between the 3 doses . There was a progressive increase in the allergen PC15 chronologically ( sequence effect ) that was not explained by improvement in FEV1 or airway responsiveness ; sequence effects were not seen for FEV1 or for pretreatment or posttreatment methacholine PC20 . Statistical adjustment for sequence effect did not alter allergen PC15 statistics . CONCLUSION A 7-day course of budesonide administered by means of Turbuhaler at 200 , 400 , or 800 microg per day provided marked and significant inhibition of the allergen-induced early asthmatic response compared with placebo . There was , however , no difference between the 3 doses . Therefore this method with these doses is not useful for providing assessment of relative potency [10507269] BACKGROUND Inhaled glucocorticosteroids ( GCS ) are the most effective long-term controller medications for the treatment of persistent asthma . Currently , however , available delivery devices limit their use in young children . A nebulized formulation of budesonide has been developed to address the needs of infants and young children . OBJECTIVE To evaluate the efficacy and safety of once-daily budesonide inhalation suspension in children 6 months to 8 years old with mild persistent asthma not on inhaled GCS . METHODS Three hundred fifty-nine children were r and omized to receive once-daily budesonide inhalation suspension ( 0.25 mg , 0.50 mg , or 1.0 mg ) or placebo via a Pari LC-Jet Plus nebulizer for 12 weeks . Efficacy assessment s included nighttime/daytime asthma symptoms , pulmonary function ( subset of patients ) , rescue medication use , and treatment discontinuations . Safety was based on adverse events and assessment of HPA-axis function . RESULTS Demographics , baseline characteristics , asthma symptoms , and pulmonary function were similar across treatment groups . Mean nighttime/daytime asthma symptom scores were 1.19 + /- 0.63 and 1.34 + /- 0.53 , respectively . Mean duration of asthma was 36.3 months and mean FEV1 was 81.3 % of predicted with 27.7 % reversibility . Following 12 weeks of treatment , all budesonide inhalation suspension doses produced significant improvements in nighttime/daytime symptoms ( P < or = .049 ) and significant decreases in rescue medication use ( P < or = .038 ) compared with placebo . Significant improvements ( P < or = .044 ) in FEV1 were observed in the 0.5- and 1.0-mg budesonide inhalation suspension groups . There were no differences between doses of budesonide inhalation suspension . Adverse events and basal and ACTH-stimulated cortisol levels were similar among all groups . CONCLUSION Once-daily administration of budesonide inhalation suspension was well tolerated and effective for the treatment of mild persistent asthma in infants and young children not adequately controlled with bronchodilators or non-GCS antiinflammatory treatments [9042043] To determine therapeutically and systemically equivalent dosages of budesonide inhaled through the Turbuhaler dry powder inhalation device ( Astra Pharma Production AB , Södertälje , Sweden ) or pressurized metered-dose inhaler ( pMDI ) plus Nebuhaler spacer ( Astra Pharma Production AB ) , we compared these devices in a r and omized , open , parallel-group trial . Adults with moderate to severe asthma inhaled budesonide ( 0.4 , 0.8 , 1.6 , and 2.4 mg/day ) , for 2 weeks at each dose level , through the Turbuhaler ( n = 30 ) or pMDI + Nebuhaler ( n = 28 ) . Dose-dependent effects were demonstrated on asthma symptoms ( p = 0.0001 ) , daily peak expiratory flow ( p = 0.02 ) , blood eosinophils ( p = 0.0001 ) , urinary cortisol output per day ( p = 0.0001 ) , serum cortisol ( p = 0.006 ) , serum osteocalcin ( p = 0.0001 ) , and the oropharyngeal C and ida colony count ( p = 0.0007 . analysis of covariance ) . The ratio of the responses to the two inhalation devices approximated 1.0 for each index measured ; that is , no significant between-device difference was found ( p > or = 0.29 ) . However , the 95 % confidence limits for the ratio of their respective systemic effects on osteocalcin production were 0.83 to 1.48 . Thus in adults who use inhalation devices efficiently and have optimally controlled asthma , conversions from the pMDI + Nebuhaler to the Turbuhaler may reasonably be made at milligram equivalent doses of budesonide , then down-titrated to minimize possible systemic effects . Because earlier studies have shown that the Turbuhaler can double intrapulmonary drug delivery in comparison with a pMDI without a spacer , a 50 % dose reduction may be indicated when converting from a pMDI to the Turbuhaler [8630596] The object of this investigation was to study the long-term effects of antiasthma treatment on blood markers of inflammation and lung function in adult asthmatic subjects . For this purpose 85 allergic and nonallergic asthmatic subjects were r and omized into three groups , which were given high-dose ( 1,600 micrograms/d ) inhaled budesonide , low-dose ( 400 micrograms/d ) inhaled budesonide , and oral theophylline ( 600 mg/d ) , respectively , and were followed for 11 mo with testing of lung function and blood sampling for the assay in serum of eosinophil cationic protein ( ECP ) , eosinophil protein x/eosinophil derived neurotoxin ( EPX/EDN ) as eosinophil markers , and myeloperoxidase ( MPO ) and lactoferrin ( LF ) as neutrophil markers . Lung functions ( FEV1 % predicted , and histamine PC20 ) and the eosinophil markers ECP and EPX/EDN were improved and reduced , respectively , by budesonide in a dose-dependent and temporally parallel fashion . Theophylline did not alter lung functions but reduced ECP and EPX/EDN after prolonged treatment . The treatment efficacy of budesonide was attributed solely to an effect on nonsmoking asthmatic subjects , since neither lung functions nor eosinophil markers changed in smokers even with high-dose budesonide . MPO but not LF was reduced after several months of treatment in all three groups , but only in nonsmokers . We conclude that ECP and EPX/EDN may be used to monitor antiinflammatory treatment in asthmatic patients , and that smoking asthmatic subjects are resistant to inhaled corticosteroids [9564797] BACKGROUND Airway inflammation is a hallmark of asthma , therefore current treatment recommendations include the use of inhaled glucocorticosteroids ( GCS ) . However , there is little evidence that the effects of inhaled GCS are dose dependent . OBJECTIVES The objective of this study was to assess the efficacy and safety of a second-generation GCS , budesonide , delivered by Turbuhaler , in adults with chronic asthma . METHODS In a 12-week , r and omized , double-blind , multicenter , parallel-group study , 473 subjects 18 to 70 years of age received either placebo or budesonide ( 200 , 400 , 800 , or 1600 microg total daily dose ) administered twice daily . Primary efficacy end points were mean change from baseline for FEV1 and morning peak expiratory flow . Safety was assessed by reported adverse events and by a cosyntropin-stimulation test . RESULTS The mean baseline FEV1 was 63 % to 66 % of predicted normal value between groups . All doses of budesonide were more effective than placebo ( p < 0.001 ) . The mean changes in morning peak expiratory flow were 12 , 22 , 27 , and 30 L/min in the 200 , 400 , 800 , and 1600 microg budesonide total daily dose groups , respectively , and -27 L/min for the placebo group . A statistically significant dose-response effect for the mean change from baseline over the 12-week study was seen for both morning peak expiratory flow and FEV1 . Budesonide-treated subjects also demonstrated significant reduction in asthma symptoms and bronchodilator use compared with placebo . There were no clinical ly significant differences in treatment-related adverse experiences among groups . CONCLUSIONS Budesonide administered by Turbuhaler exhibited a dose response and was effective at low doses . It was well tolerated and significantly more effective than placebo

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### Context: [9596304] OBJECTIVE To determine the ability of budesonide via an inhaler ( Pulmicort Turbuhaler ; Astra Draco AB ) to replace oral glucocorticosteroids ( GCSs ) in adult subjects with moderate-to-severe asthma . DESIGN Double-blind , r and omized , and placebo-controlled study , with parallel groups . SETTING Multicenter study in outpatient setting . PARTICIPANTS Eighty men and 79 women , aged 20 to 69 years , with moderate-to-severe asthma and a mean FEV1 of 58.3 % predicted normal . All subjects were receiving oral GCS treatment and 79 % of subjects were also receiving inhaled beclomethasone dipropionate ( BDP ) . The mean daily doses of prednisone at baseline , including converted dose of BDP , for the placebo , budesonide 400 microg , and budesonide 800 microg , respectively , were 19.7 mg , 19.5 mg , and 18.7 mg . MEASUREMENTS AND INTERVENTIONS After a 2-week baseline period , subjects entered a 20-week treatment period , during which the oral dose of prednisone was reduced by forced down-titration at 2-weekly intervals . RESULTS Subjects receiving 400 microg or 800 microg bid of budesonide achieved a significantly greater reduction ( 82.9 % and 79.0 % respectively ) in oral GCS dose compared with placebo-treated subjects ( 27 % ; p<0.001 ) . Two thirds of the subjects receiving budesonide were able to achieve sustained oral corticosteroid cessation , compared with 8 % in the placebo group . Additionally , both doses of budesonide result ed in significant improvement in results of pulmonary function tests and asthma symptoms scores , and a significant decrease in the use of bronchodilator therapy . The mean plasma cortisol levels before and after adrenocorticotropic hormone stimulation increased most toward the normal range in the budesonide-treated groups compared with placebo-treated subjects . CONCLUSION Budesonide administered via Turbuhaler has a significant oral GCS-sparing capacity with maintained or improved asthma control in adult subjects with moderate-to-severe asthma [8066909] Two hundred and forty-one children with perennial asthma had their normal dose of budesonide ( administered via Nebuhaler ) reduced by 50 % . Asthma control deteriorated in 126 patients to such an extent that budesonide had to be increased to the normal dose . During a subsequent two week run-in these 126 patients were treated with their normal dose of budesonide via Nebuhaler . Thereafter 64 were r and omized to treatment with their normal budesonide therapy and 62 to treatment with half their normal budesonide dose via Turbuhaler for nine weeks . Asthma symptoms , peak-flow measurements , and beta 2-agonist use were recorded . Pulmonary function tests , exercise tests and 24 hour urine sample collection s were performed . There were no differences between the groups in any of the parameters studied during run-in or during the study period , except for use of beta 2-agonist , which was significantly lower in the Turbuhaler-treated group . We conclude that Turbuhaler is more effective than Nebuhaler in the treatment of asthma . Therefore the dose of budesonide should be reduced when patients are switched from Nebuhaler to Turbuhaler treatment [10400838] BACKGROUND Optimal management of chronic , mild-to-moderate asthma with inhaled steroids may include use of the lowest possible doses , as recommended in guidelines , and a reduction in the frequency of daily administration for greater convenience . Lower doses and once daily treatment with inhaled steroids must be rigorously evaluated in controlled clinical trials . OBJECTIVES The objective of this study was to assess the efficacy and safety of once daily treatment with budesonide in subjects with stable asthma . METHODS Once daily budesonide was assessed in 309 adult subjects , including those who were and were not using an inhaled steroid at baseline . The subjects were stratified by inhaled steroid use and r and omly assigned to one of 3 treatments : 200 microgram budesonide , 400 microgram budesonide , or placebo administered by means of Turbuhaler once daily in the morning for 6 weeks . Beyond this point , treatment was continued unchanged for another 12 weeks ( maintenance ) in those receiving 200 microgram budesonide once daily and placebo . In those who received 400 microgram budesonide once daily , the dose was reduced to 200 microgram once daily at week 6 and held constant for the remaining 12 weeks ( 400/200 microgram group ) . Primary efficacy endpoints were mean change from baseline in FEV1 and morning peak expiratory flow . RESULTS Once daily budesonide was well tolerated and result ed in significant improvements in all efficacy endpoints , even though baselines were well stabilized . Baseline lung function was elevated with little room for improvement ; however , mean increases in FEV1 during the maintenance period were 0.10 L and 0.11 L in the 200 microgram and 400/200 microgram groups , respectively , versus a decrease of -0.09 L in the placebo arm ( P < .001 ) . Results for peak expiratory flow were similar . Significant improvements in secondary endpoints , including symptoms , beta-agonist use , and quality of life , also developed with budesonide 200 and 400 microgram once daily . CONCLUSION Inhaled budesonide , in doses as low as 200 microgram , may be an appropriate introductory or maintenance dose in subjects with stable , mild-to-moderate asthma [8024295] Two hundred and forty one children with chronic perennial asthma , who had been treated with budesonide via a metered dose inhaler with a spacer device ( Nebuhaler ) , had their normal dose of budesonide reduced by 50 % to determine if they had been overtreated . Within three weeks , asthma control deteriorated in 126 patients to such an extent that budesonide had to be increased to the normal dose . After stabilising their asthma , these children were enrolled in a r and omised , double blind , double dummy , parallel study , performed to compare the effect of budesonide via Nebuhaler with that of half the dose of budesonide via Turbuhaler . The study started with a two week run-in during which patients were treated with their normal dose of budesonide via Nebuhaler . After run-in , 64 children were r and omised to treatment with their normal budesonide treatment and the remaining 62 children to treatment with half their normal dose via Turbuhaler for nine weeks . Throughout the study , patients recorded asthma symptoms , peak flow measurements , and beta 2 agonist use in a diary . Pulmonary function tests , exercise tests , and 24 hour urine sample collection s were performed at hospital visits during run-in and the study period . Apart from beta 2 agonist use , which was significantly lower for patients on Turbuhaler treatment than on Nebuhaler treatment , there were no differences between the groups in any of the parameters studied during run-in or during the study period . Furthermore , there was no trend of deterioration in asthma control when the dose of budesonide was reduced by 50 % when Turbuhaler was the inhalation device . It is concluded that budesonide via Turbuhaler is more effective than via Nebuhaler in the treatment of asthma . Based on this finding , attempts should be made to reduce the dose of budesonide when patients are switched from Nebuhaler to Turbuhaler treatment [7979494] The budesonide dose delivered to the patient from three different spacer devices ( Nebuhaler = 750 ml , Aerochamber = 140 ml , and Babyspacer = 260 ml ) was assessed by measuring the budesonide dose deposited on a filter inserted between the spacer outlet and the mouth of the patient . Twenty children aged 10 - 25 months were given a single dose of 200 micrograms budesonide from each spacer device in a r and omised crossover study . All spacers had a facemask attached and a one way valve system . The children breathed through the inhalation system for 30 seconds . Furthermore , the minute ventilation of the children through a tightly fitting facemask was measured . The filter dose of budesonide was significantly lower after Aerochamber treatment ( 39.4 micrograms , range 19 - 67 micrograms ) than after Nebuhaler ( 53.5 micrograms , range 34 - 88 micrograms ) and Babyspacer ( 55.5 micrograms , range 39 - 76 micrograms ) treatment . The minute ventilation of the children varied from 1.4 l/min to 7.0 l/min ( mean 5.0 l/min ) . This was sufficient to empty all spacers within the 30 seconds of inhalation . It is concluded that spacer volume does not seem to be so important for children aged 10 - 25 months as long as spacers with a volume lower than 750 ml are used [10325913] BACKGROUND It is desirable to prescribe the minimal effective dose of inhaled steroids to control asthma . To ensure that inflammation is suppressed whilst using the lowest possible dose , a sensitive and specific method for assessing airway inflammation is needed . METHODS The usefulness of exhaled nitric oxide ( NO ) , sputum eosinophils , and methacholine airway responsiveness ( PC20 ) for monitoring airway inflammatory changes following four weeks of treatment with an inhaled corticosteroid ( budesonide via Turbohaler ) were compared . Mild stable steroid naive asthmatic subjects were r and omised into two double blind , placebo controlled studies . The first was a parallel group study involving three groups receiving either 100 μg/day budesonide ( n = 8) , 400 μg/day budesonide ( n = 7 ) , or a matched placebo ( n = 6 ) . The second was a crossover study involving 10 subjects r and omised to receive 1600 μg budesonide or placebo . The groups were matched with respect to age , PC20 , baseline FEV1 ( % predicted ) , exhaled NO , and sputum eosinophilia . RESULTS There were significant improvements in FEV1 following 400 μg and 1600 μg budesonide ( 11.3 % and 6.5 % , respectively , p<0.05 ) . This was accompanied by significant reductions in eosinophil numbers in induced sputum ( 0.7 and 0.9 fold , p<0.05 ) . However , levels of exhaled NO were reduced following each budesonide dose while PC20was improved only with 1600 μg budesonide . These results suggest that exhaled NO and PC20 may not reflect the control of airway inflammation as accurately as the number of eosinophils in sputum . There were dose dependent changes in exhaled NO , sputum eosinophils , and PC20 to inhaled budesonide but a plateau response of exhaled NO was found at a dose of 400 μg daily . CONCLUSION Monitoring the number of eosinophils in induced sputum may be the most accurate guide to establish the minimum dose of inhaled steroids needed to control inflammation . This , however , requires further studies involving a larger number of patients [9864004] The aim of the present study was to examine the efficacy of low-dose inhaled budesonide ( BUD ) administered via Turbuhaler once or twice daily on symptoms , lung function and bronchial hyperreactivity in children with mild asthma . One hundred and sixty-three children ( mean age 9.9 yrs , 56 females/107 males ) with mild asthma ( forced expiratory volume in one second ( FEV1 ) 103 % of predicted , morning peak expiratory flow ( PEF ) 87 % pred , reversibility in FEV1 3 % , fall in FEV1 after exercise 10.4 % from pre-exercise value ) and not previously treated with inhaled steroids , were included in a double-blind , r and omized , parallel-group study . After a two-week run-in period , the children received inhaled BUD 100 microg or 200 microg once daily in the morning , 100 microg twice daily or placebo for 12 weeks . Exercise and methacholine challenges were performed before and at the end of treatment . After 12 weeks of therapy , the fall in FEV1 after an exercise test was significantly less in all three BUD groups ( 43 - 5.1 % ) than in the placebo group ( 8.6 % ) . Bronchial hyperreactivity to methacholine with the provocative dose causing a 20 % fall in FEV1 decreased significantly in the BUD 100 microg twice-daily group compared with placebo ( ratio at the end of treatment 156 % ) . Changes in baseline lung function ( FEV1 and PEF ) were less marked than changes in bronchial responsiveness . In conclusion , low doses of inhaled budesonide , given once or twice daily , provided protection against exercise-induced bronchoconstriction in children with mild asthma and near normal lung function [9655717] New British guidelines on the treatment of asthma ( 9 ) advocate starting with a higher dose of inhaled corticosteroids in newly detected asthma patients . We investigated whether initiating inhaled steroid treatment with a higher dose is clinical ly more effective than a lower dose in steroid naive patients with asthma . The study had a 13-wk r and omized , double-blind , parallel design : 1-mo treatment with 400 microg budesonide twice a day , or 100 microg budesonide twice a day by dry powder inhaler , and follow-up treatment period of 2 mo with 200 microg budesonide once daily for all patients . Forty patients started with 400 microg budesonide twice daily , 44 with 100 microg budesonide twice daily . Mean age was 32 yr , baseline FEV1 value 84 % predicted , reversibility 9 % from baseline , and mean bronchodilator use 1.6 inhalations/d in the run-in period . After 4 wk of treatment with 400 microg and 100 microg budesonide twice daily mean morning peak expiratory flow ( PEF ) increased 27 L/min ( SD 50 ) , and 38 L/ min ( SD 53 ) , respectively ( p = 0.30 ) ; mean symptom score improved from 1.1 to 0.6 and from 1.1 to 0.5 . These effects were maintained in the 2 mo follow-up . This study suggests that starting inhaled corticosteroids at a higher dose is not superior to a lower dose in the treatment of newly detected asthma [9519224] The study objective was to compare the effect of budesonide administered as a nebulized suspension as compared to a spray with a spacer in adult asthmatics . In a double-blind , double-dummy crossover study , 26 adult patients with moderately severe unstable asthma were r and omized to three 4-week treatment periods with budesonide 0.8 mg b.i.d . administered by a pressurized metered-dose inhaler ( pMDI ) with spacer ( Nebuhaler ) and budesonide 1 mg and 4 mg b.i.d . administered by a Pari Inhalier Boy jet nebulizer . The nebulizer was activated only during inspiration . The total mass output was similar from the two devices but their fraction of small particles differed by a factor of 2 in favour of pMDI . Effect was evaluated from daily home measurements of peak expiratory flow ( PEF ) , need of beta 2-agonist and symptom scores . Plasma cortisol and budesonide levels were measured in a subgroup of 10 patients . A consistent trend showed the nebulizer treatment to be at least as efficient as the pMDI plus spacer treatment . In actual fact , the apparent order of effect was : 4 mg nebulized suspension treatment > or = 1 mg nebulized suspension treatment > or = 0.8 mg pMDI with spacer treatment . Plasma budesonide and plasma cortisol also exhibited dose-related levels independent of device . The adverse effects reported appeared to be related to the dose rather than delivery device . Accordingly , the effect was related to total mass output , rather than to the small particle fraction of the budesonide aerosol . These results attest to the efficiency of jet-nebulized budesonide suspension , and indicate nebulized budesonide to be equipotent to st and ard budesonide therapy delivered by pMDI with Nebuhaler , provided nebulization is synchronized with inspiration and no loss of aerosol occurs during expiration [3287996] Budesonide by inhalation and placebo were tested in 18 patients with moderate chronic bronchial asthma . Three dose levels of budesonide were used ( 25 , 100 and 400 μg q.i.d . ) and the patients were to take two puffs q.i.d . in all periods . The active treatment was investigated using double‐blind cross‐over technique , and placebo at the end of the trial . The duration of each treatment period was 2 weeks . The study showed a high drop‐out frequency while on placebo and that the PEF values were influenced in a dose‐dependent way by budesonide . In spite of the double‐blindness the patients had a tendency towards overuse of the trial aerosol on the lowest dose , but they used significantly less than prescribed during the period with the highest dose . No side effects were reported [2090474] Budesonide 400 micrograms daily , in nonsteroid-dependent asthma , can produce improvements in airway responsiveness and clinical asthma severity , with some patients returning to normal responsiveness and becoming asymptomatic . This study examined whether similar improvements occur when asthmatics , who are dependent upon inhaled steroids , take either a regular maintenance dose of inhaled steroid or twice that amount for a year . Thirty two asthmatics were each stabilized on the minimum amount of inhaled steroid that would keep symptoms non-troublesome . In a double-blind , r and omized manner , half were assigned to remain on a maintenance dose ( MD ) and the rest received twice that dose ( MDx2 ) for one year . Before and monthly throughout the study , airway responsiveness to methacholine was measured and clinical asthma severity assessed by question naire , inhaled bronchodilator use and number of asthma exacerbations . There was a significant improvement in airway responsiveness and clinical asthma severity in both treatment groups . Those on MDx2 showed the greatest improvement but the difference between the two groups did not reach significance . This study provides strong evidence that prolonged use of inhaled steroids is associated with improvement in airway responsiveness and clinical asthma severity in inhaled steroid-dependent asthma with a suggestion that the improvements are dose related [11035676] OBJECTIVES We wished to evaluate the effects of once-daily combination therapy on surrogate inflammatory markers . METHODS Fifteen patients with atopic persistent asthma were evaluated ( mean age , 32.4 years ; FEV(1 ) , 75.2 % predicted ) in a r and omized , double-blind , double-dummy , placebo-controlled crossover study with a 1-week placebo washout period , comparing the following once-daily nighttime treatments : ( 1 ) formoterol ( FM ) , 12 microg , for 2 weeks and FM , 24 microg , for 2 weeks ; or ( 2 ) budesonide ( BUD ) , 400 microg , for 2 weeks and BUD , 800 microg , for 2 weeks ; or ( 3 ) FM , 12 microg , plus BUD , 400 microg , for 2 weeks and FM , 24 microg , plus BUD , 800 microg , for 2 weeks . Adenosine monophosphate ( AMP ) bronchial challenge , exhaled nitric oxide ( NO ) , and serum eosinophilic cationic protein ( ECP ) were evaluated at 12 h postdosing after administration of each placebo and after 2 and 4 weeks of each treatment . RESULTS The results of AMP challenge ( provocative concentration causing a 20 % fall in FEV(1 ) ) at 4 weeks showed significant ( p<0.05 ) improvements after patients had received all active treatments compared to placebo ( 20 mg/mL ) , with FM plus BUD , 261 mg/mL , being superior ( p<0.05 ) to FM alone , 82 mg/mL , but not to BUD , 201 mg/mL. NO and ECP showed significant ( p<0.05 ) reductions compared to placebo with FM plus BUD or BUD alone but not with FM alone . Combination therapy was associated with optimal patient preference ( rank order , FM plus BUD > FM > BUD ; p<0.0005 ) , highest domiciliary peak expiratory flow , and lowest rescue inhaler usage . All three treatments produced equivalent improvements in spirometry . CONCLUSIONS Patients preferred once-daily combination therapy , but this had no greater effect on inflammatory markers than therapy with BUD alone . FM alone had no anti-inflammatory activity but exhibited bronchoprotection . This emphasizes the importance of first optimizing anti-inflammatory control with inhaled corticosteroids before considering adding a regular long-acting beta(2)-agonist [1579391] Linear growth was investigated with weekly knemometry in a population of 43 schoolchildren with mild asthma treated with inhaled budesonide . The design was a r and omized , double-blind , parallel group study with three dose groups of 200 , 400 , and 800 micrograms of budesonide per day . Each dose group received budesonide for 8 consecutive weeks . Placebo was given for either 4 weeks before or after budesonide treatment . Twelve children in the 200-micrograms group , 14 in the 400-micrograms group , and 12 in the 800-micrograms group completed the 12-week study period . There was no significant difference in mean growth velocity among the three dose groups during placebo treatment . Compared with placebo ( growth velocity : 0.39 mm/wk ) , mean lower leg growth velocity was reduced with 0.26 mm/wk ( P less than .001 , t = 5.0 , df = 11 ; 95 % confidence interval 0.14 to 0.37 mm/wk ) in children treated with 800 micrograms of budesonide . There was no statistically significant difference in growth velocity between 200- or 400-micrograms budesonide treatments and placebo . These data indicate that inhaled budesonide can be safely used in doses up to 400 micrograms/d in schoolchildren with asthma [9821415] BACKGROUND Twice-daily administration of inhaled budesonide ( 400 micrograms ) suppresses short-term growth in children with asthma . OBJECTIVE To compare short-term growth and markers of collagen turnover during treatment with 800 micrograms of inhaled budesonide administered once daily in the morning and 400 micrograms administered twice daily . PATIENTS Twenty-four children with asthma aged 5.6 to 12.5 years . SETTING An outpatient secondary referral center . METHODS A r and omized , double-blind , crossover trial with 2 treatment periods of 4 weeks was conducted , and growth was assessed with a knemometer . The carboxy terminal propeptide of type I procollagen , the amino terminal propeptide of type I procollagen ( PINP ) , the carboxy terminal pyridinoline cross-linked telopeptide of type I collagen , the amino terminal propeptide of type III procollagen ( PIIINP ) , and urinary pyridinoline and deoxypyridinoline were evaluated . RESULTS Mean lower leg growth rate ( P = .04 ) , PINP ( P = .03 ) , and PIIINP ( P < .01 ) were suppressed during twice-daily administration of budesonide , 400 micrograms . Otherwise , no statistically significant differences were detected . CONCLUSIONS As compared with 400 micrograms of inhaled budesonide administered twice daily , 800 micrograms administered once daily in the morning has a sparing effect on short-term growth and collagen turnover [11014718] PURPOSE Inhaled corticosteroids have beneficial effects on pulmonary function and inflammation in patients with asthma , but they also cause systemic adverse effects , such as adrenal suppression . We evaluated the therapeutic index of inhaled corticosteroids in asthmatic patients by comparing their dose-response effects on lung function , surrogate markers of airway inflammation , and tests of adrenal function . SUBJECTS AND METHODS After a 10-day placebo run-in , we evaluated the effects of 200 microg , 400 microg , and 800 microg of inhaled budesonide , each dose given twice daily sequentially for 3 weeks in 26 patients , aged 35 + /- 12 years ( mean + /- SD ) , with mild-to-moderate asthma . Measurements were made of bronchial reactivity , exhaled nitric oxide ( a marker of airway inflammation ) , spirometry , serum eosinophilic cationic protein concentration , and 10-hour overnight urinary cortisol excretion . Plasma cortisol levels were measured at 8 AM and after stimulation with human corticotropin releasing factor . RESULTS For measurements of pulmonary function and exhaled nitric oxide , there was a plateau in the mean response to budesonide between 400 microg ( low dose ) and 800 microg ( medium dose ) per day , whereas for eosinophilic cationic protein and bronchial challenge , maximal benefits occurred between 800 and 1,600 microg ( high dose ) per day . Effects on plasma cortisol levels showed maximal suppression at 1,600 microg of budesonide per day . The proportion of patients with an optimal therapeutic index , in terms of a good airway response ( fourfold decrease in bronchial hyperreactivity ) and minimal systemic response ( overnight urinary cortisol greater than 20 nmol ) , was similar at low-dose ( 46 % ) and at high-dose ( 52 % ) budesonide . The proportion of patients with a suboptimal therapeutic index , a good airway response with a marked systemic response ( overnight urinary cortisol greater than 20 nmol ) , increased from 4 % at low dose to 38 % at high dose . CONCLUSIONS In patients with mild-to-moderate atopic asthma , there were dose-related effects of budesonide on surrogate markers of inflammation ( bronchial hyperreactivity and serum eosinophilic cationic protein ) , although higher doses were associated with adrenal suppression and a decrease in the therapeutic index [9596110] Electrostatic charge in plastic spacer devices has been shown in vitro to reduce delivery of asthma medications intended for inhalation , but the effect of static charge on in vivo drug deposition is unknown . A six-way r and omized crossover study was conducted in 10 mild asthmatic patients . Two plastic spacers ( Nebuhaler and Volumatic ) and one metal spacer ( Nebuchamber ) were tested . The spacers were used either " primed " or " unprimed " . Priming was performed by firing 20 doses of placebo aerosol into a new spacer , hence coating the inner surface with surfactant and minimizing static charge . Unprimed spacers were new and were not treated . Pressurized aerosol canisters delivering budesonide ( 200 microg Pulmicort ) were radiolabelled with the radionuclide 99mTc and lung deposition was measured by gamma scintigraphy . The radiolabel was shown to be a valid marker for the drug substance prior to the clinical phase of the study . Priming significantly increased mean whole lung deposition following inhalation from plastic spacers ( Nebuhaler primed 37.7 % and unprimed 26.7 % , p=0.01 ; Volumatic primed 32.0 % and unprimed 22.1 % , p=0.02 ) . Priming had no effect on the mean whole lung deposition following inhalation from the Nebuchamber ( primed 33.5 % and unprimed 32.9 % ) . Lung deposition in vivo from plastic spacer devices will vary according to the electrostatic charge on the spacer walls . Priming reduces retention of drug on plastic spacer devices and increases lung deposition . Metal spacers are not susceptible to static charge , which should result in more predictable lung deposition [9230238] Few thorough comparisons of the systemic effects of inhaled corticosteroids in children are available . The aim of this study was to compare the effect of budesonide and fluticasone propionate on short-term lower leg growth . Fluticasone propionate , budesonide and placebo were administered for 2 weeks in a r and omized , double-blind , double-dummy , cross-over design . Twenty four children aged 6 - 12 yrs received 200 microg x day(-1 ) of each drug , or placebo . Another 24 children aged 6 - 12 years received 400 microg x day(-1 ) of each drug , or placebo . Dry powder inhalers were used . Lower leg length was measured by knemometry twice a week during all three treatment periods , and 24 h cortisol excretion in the urine was measured at the end of each period . In the low-dose group , lower leg growth rate was the same during treatment with placebo ( 0.35 mm x week(-1 ) ) , fluticasone propionate ( 0.38 mm x week(-1 ) ) or budesonide ( 0.26 mm x week(-1 ) ) . No significant difference ( p=0.39 ) in lower leg growth rate was found between treatment with 400 microg x day(-1 ) budesonide ( 0.30 mm x week(-1 ) ) and 400 microg fluticasone propionate treatment ( 0.37 mm x week(-1 ) ) . Growth rate during treatment with budesonide , 400 microg x day(-1 ) , was significantly lower than during placebo treatment ( 0.52 mm x week(-1 ) ) . Cortisol excretion in the urine during treatment with 200 microg x day(-1 ) fluticasone propionate was significantly reduced as compared with placebo ( p=0.006 ) , but not when compared with 200 microg x day(-1 ) budesonide ( p=0.07 ) . Budesonide 200 microg x day(-1 ) was not significantly different from placebo . Fluticasone propionate and budesonide , both at 400 microg x day(-1 ) , result ed in a significant reduction in cortisol excretion in the urine as compared with placebo ( p=0.001 ) . It is concluded that , dose-for-dose , budesonide Turbuhaler and fluticasone propionate Diskhaler have similar systemic effects [10968496] The aim of this study was to determine whether outcomes in poorly controlled asthma can be further improved with a starting dose of inhaled budesonide higher than that recommended in international guidelines . The study had a parallel-group design and included 61 subjects with poorly controlled asthma , r and omized to receive 3,200 microg or 1,600 microg budesonide daily by Turbuhaler for 8 weeks ( double-blind ) , then 1,600 microg x day(-1 ) for 8 weeks ( single-blind ) , followed by 14 months of open-label budesonide dose down-titration using a novel algorithm , with a written asthma crisis plan based on electronic peak expiratory flow monitoring . The primary outcome variable for weeks 1 - 16 was change in airway hyperresponsiveness ( AHR ) , and , for the open-label phase , mean daily budesonide dose . By week 16 , there were large changes from baseline in all outcomes , with no significant differences between the 3,200- and 1,600-microg x day(-1 ) starting dose groups ( AHR increased by 3.2 versus 3.0 doubling doses , p=0.7 ; morning peak flow increased by 134 versus 127 L x min(-1 ) , p=0.8 ) . Subjects starting with 3,200 microg x day(-1 ) were 3.8 times more likely to achieve AHR within the normal range , as defined by a provocative dose of histamine causing a 20 % fall in forced expiratory volume in one second ( PD20 ) of > or = 3.92 micromol by week 16 ( p=0.03 ) [ corrected ] . During dose titration , there was no significant difference in mean budesonide dose ( 1,327 versus 1,325 microg x day(-1 ) , p>0.3 ) . Optimal asthma control was achieved in the majority of subjects ( at completion/withdrawal : median symptoms 0.0 days x week(-1 ) , beta2-agonist use 0.2 occasions x day(-1 ) , and PD20 2.4 micromol ) . In subjects with poorly controlled asthma , a starting dose of 1,600 microg x day(-1 ) budesonide was sufficient to lead to optimal control in most subjects . The high degree of control achieved , compared with previous studies , warrants further investigation [10893016] The aim of this study was to compare the clinical efficacy of low-dose inhaled budesonide ( once or twice daily ) and placebo , administered via Turbuhaler , on exercise-induced bronchoconstriction ( EIB ) in children with mild asthma . Fifty-seven steroid-naive children ( 7 - 16 years old ; 41 boys , 16 girls ) with EIB participated in this sub- population study according to the following inclusion criterion : a maximum fall in forced expiratory volume in 1 s ( FEV1 ) > or = 10 % after a st and ardized treadmill test . Mean baseline FEV1 was 100.3 % of predicted , and mean maximum fall in FEV1 after the st and ardized exercise test was 22 % . The study was a double-blind , r and omized , parallel-group design . After 2 weeks of run-in , the children received inhaled budesonide 100 microg or 200 microg once daily in the morning , 100 microg twice daily , or placebo , for 12 weeks . After 12 weeks of treatment , the fall in FEV1 after the exercise test was significantly less in all three budesonide groups ( 7.2 - 7.8 % ) vs. placebo ( 16.7 % ) . Daytime symptom scores were significantly lower in all three budesonide groups compared with placebo ( p < 0.02 ) . The three budesonide groups did not differ significantly , and no significant change in lung function was found in any group . Therefore children with mild asthma , but with significant EIB , improved their exercise tolerance and symptom control after 3 months of treatment with a low dose of inhaled budesonide given once or twice daily [8681664] An open , r and omized , parallel-group study was conducted to investigate whether asthmatic patients , considered adequately treated with a corticosteroid and /or short-acting beta 2-agonist via pressurized metered-dose inhaler ( pMDI ) , could be transferred to a corresponding nominal dose of budesonide and /or terbutaline via Turbuhaler , an inspiratory flow-driven multidose dry powder inhaler ( Astra Draco ; Lund , Sweden ) , without a decrease in the effect of treatment . One thous and four patients ( 555 women ; mean age , 44 years ; mean peak expiratory flow [ PEF ] , 102 % predicted normal value ) were r and omized and treated with either pMDI ( current therapy ) or Turbuhaler for 52 weeks . The variables studied were asthma-related events , morning PEF , and inhaler-induced clinical symptoms . Asthma-related events were defined in two ways : ( 1 ) sum of health-care contacts plus doublings or additions of steroids , and ( 2 ) number of 2 consecutive days with PEF less than 80 % of baseline . Baseline was obtained from a 2-week run-in period while receiving previous therapy . No statistically significant difference was found in asthma-related events according to definition 1 . According to definition 2 , there was a statistically significant difference between the groups in favor of Turbuhaler ( p = 0.008 ) . The mean number of events was 1.7 with Turbuhaler and 2.2 with pMDI . The mean number of weeks per patient with a PEF less than 90 % of baseline was 4.5 with Turbuhaler compared with 6.0 with pMDI ( p = 0.002 ) . The sum of inhaler-induced symptoms after 1 year of use was statistically significantly lower with Turbuhaler ( 0.40 ) than with pMDI ( 0.75 ) ( p = 0.0001 ) . In conclusion , budesonide and terbutaline in Turbuhaler offered a superior alternative to corticosteroids and bronchodilators delivered by pMDIs in the maintenance treatment of asthma [11428735] BACKGROUND The incidence of pediatric asthma has increased dramatically over the past few decades , with approximately 5 % of American children affected by the disease . OBJECTIVES To compare the efficacy and safety of once-daily budesonide Turbuhaler with placebo in asthmatic children previously treated with orally inhaled corticosteroids . METHODS This r and omized , double-blind , placebo-controlled , multicenter ( 17 centers ) study included 274 male and female children ( aged 6 to 17 years ) with a history of asthma for at least the previous 6 months . Patients received placebo or budesonide Turbuhaler ( 200 microg or 400 microg ) once daily for 12 weeks . Efficacy variables included mean changes from baseline in forced expiratory volume in 1 second ( FEV1 ) , AM and PM peak expiratory flow rates ( PEFRs ) , nighttime and daytime asthma symptom severity scores , patient discontinuations , use of beta2-agonists as breakthrough medication , forced vital capacity ( FVC ) , and midexpiratory flow rate between 25 % and 75 % of FVC ( FEF25%-75 % ) . Safety was evaluated by adverse events , physical examinations , vital signs , and laboratory tests . RESULTS Baseline characteristics were comparable among treatment groups . Percentage of predicted FEV1 at baseline was 76.6 + /- 6.9 for placebo , 77.5 + /- 7.1 , and 77.0 + /- 7.8 for the budesonide Turbuhaler 200 microg and 400 microg groups , respectively . Significantly ( P < or = 0.024 ) more placebo patients ( 24 % ) discontinued treatment because of disease deterioration or no improvement than budesonide Turbuhaler 200 microg ( 11 % ) or 400 microg patients ( 10 % ) . Patients receiving budesonide Turbuhaler experienced significant improvements in FEV1 compared with patients receiving placebo ( P < or = 0.015 ) . Significant ( P < or = 0.041 ) improvements over placebo also were observed in AM and PM PEFRs , FVC , FEF25%-75 % , nighttime and daytime asthma symptoms , and amount of beta2-agonist used in both budesonide Turbuhaler groups . Adverse events were generally mild or moderate in intensity and similar among treatment groups . CONCLUSIONS Once-daily budesonide Turbuhaler is effective and safe in children with persistent asthma previously maintained on at least twice-daily dosing regimens of inhaled corticosteroids [9141112] We compared the clinical effect of the glucocorticoid budesonide delivered from two nebulizers Aiolos and Pari LL in 38 children less than 4 years of age ( mean age , 20.2 months ) with chronic wheeze . The design was a controlled , single-blind , r and omized , cross-over , dose titration study . After a 1-week run-in , patients were r and omized to treatment with 1 mg budesonide b.i.d . for 2 weeks from either an Aiolos or a Pari LL nebulizer . This was followed by a gradual dose reduction period during which the budesonide dose was reduced at 2-week intervals until unacceptable asthma symptoms appeared or the placebo level was reached . The patient was then switched to budesonide 1 mg b.i.d . from the other nebulizer for 2 weeks , after which the dose was reduced at 2-week intervals as described for the first period . Patients who completed the study on placebo for 2 weeks without deterioration of their asthma were not included in the statistical analysis . During Period # 1 the minimum effective dose of budesonide was 2 mg/day in 9 patients , 1 mg/day in 10 patients , and 0.5 mg/day in 13 patients . In Period # 2 the corresponding figures were 14 , 5 , and 13 patients . Six patients were excluded after the first period because their asthma control did not deteriorate during dose reduction and when finishing on placebo for 2 weeks . For both nebulizers the reduction in budesonide dose was associated with a small increase in symptoms and use of rescue terbutaline . The mean dose of budesonide delivered to the patient by the Aiolos was twice as large as that delivered by the Pari LL : 26 % vs. 13 % of the nominal dose assessed by the filter method . Nevertheless , no statistically significant difference in clinical effect or mean minimal effective dose ( 1.1 mg for Aiolos and 1.2 mg for Pari LL ) could be detected between the two nebulizers . No serious adverse events were observed . We conclude that the minimal effective dose of nebulized budesonide varies from 0.5 to 2.0 mg/day in young children with asthma . A higher drug delivery , as assessed by the filter method , does not necessarily result in better clinical control or lower minimal effective dose . Further studies are needed to assess whether this is due to insufficient sensitivity of the study design in detecting a difference in clinical effect , or whether measurements of drug delivery by the filter method do not reflect lung deposition or clinical effect in young children with wheezing [9894371] This double-blind study aim ed to determine whether superior asthma control is achieved with budesonide ( Pulmicort Turbohaler ) at a loading dose ( LD ) ( 400 micrograms b.d . ) for 6 weeks , followed by step down to 400 micrograms nocte for 12 weeks , compared with a static dose ( SD ) ( 400 micrograms nocte ) for 18 weeks . A total of 682 patients ( mean peak expiratory flow rate ( PEFR ) 413 l/min ) , who demonstrated > or = 15 % reversibility in PEFR , were r and omised into the study . After 18 weeks , patients experienced improvements in morning PEFR ( + 45 l/min , both groups ) , symptom score ( LD -0.57 , SD -0.49 , on a scale of 0 - 3 ) , sleep disturbance ( LD -1.21 nights/week , SD -1.06 nights/week ) and beta 2-agonist use ( LD -1.36 puffs/day , SD -1.06 puffs/day ) , within both groups ( each p = 0.0001 ) . At 18 weeks , 82 % ( LD ) and 84 % ( SD ) of patients benefited from no nocturnal wakening in the previous 7 days . Overall , at 18 weeks , asthma control was not significantly different between the groups . After 6 weeks , improvements in morning PEFR ( LD + 36 l/min , SD + 26 l/min ) and beta 2-agonist use ( LD -1.10 puffs/day , SD -0.94 puffs/day ) were greater in the loading dose than in the static dose group ( each p < 0.05 ) . The greater improvement in morning PEFR in the loading dose group was significant by day 7 ( p < 0.05 ) . While both regimens are equally effective in achieving asthma control at 18 weeks , early clinical advantage is gained with initial loading dose budesonide ( 400 micrograms b.d . ) [2653086] The aim of this open , r and omized cross‐over study was to compare the efficacy and safety of inhaled budesonide administered either via a pressurised metered dose inhaler with a 750 ml spacer attached , or via a new dry powder inhaler , Turbuhaler ® , in 28 patients with stable bronchial asthma . During the 2‐week run‐in period , the patients received their ordinary inhaled steroid treatment . This was followed by two 4–week periods of active treatment with inhaled budesonide given via Turbuhaler or pressurized MDI . The patients were divided into two groups according to their previous , inhaled steroid doses . Group A received 400 μg of budesonide b.i.d , and Group B 800 μg of budesonide b.i.d . Diary cards were used by the patients at home to report asthma symptoms , ( 32‐agonist consumption , and PEF twice daily , as well as the number of coughs experienced in a 5‐min period after steroid inhalation . Budesonide Turbuhaler produced a significantly better effect on morning peak flow than budesonide MDI . The number of coughs in the 5 min after steroid inhalation was significantly lower with the Turbuhaler than with the MDI . In all other parameters recorded ( e.g. FEV1 , evening PEF , histamine PC20 and other diary measurements ) there were no statistically significant differences between the two devices . Turbuhaler was significantly more appreciated than MDI in all questions of preference . The study showed that budesonide via Turbuhaler was at least as effective and safe as budesonide via a pressurized MDI at daily doses of 800 and 1,600 μg . The absence of additives , the lower incidence of cough after dose intake , the easiness of use , and higher preference , make Turbuhaler a valuable contribution in the treatment of asthmatics [9819291] BACKGROUND Budesonide ( BUD ) has recently been licensed for treatment of asthma in the United States , whereas triamcinolone acetonide ( TAA ) has been used for many years . OBJECTIVE We sought to evaluate the dose-response effect of inhaled BUD and TAA in terms of adrenal , bone , and blood markers . METHODS Twelve asthmatic subjects ( mean age , 32 years ; mean FEV1 , 91 % of predicted value ) were studied in a r and omized design comparing 3 days of treatment with placebo and low ( 200 micrograms twice daily ) , medium ( 400 micrograms twice daily ) , and high ( 800 micrograms twice daily ) doses of BUD ( Pulmicort Turbuhaler , 100 micrograms ) and TAA ( Azmacort integrated actuator/spacer , 100 micrograms ) with a 7-day period at crossover , when patients received their usual inhaled corticosteroid therapy . Measurements were made at 8 am for serum cortisol , osteocalcin , and blood eosinophils . Measurements were also made for overnight urinary cortisol/creatinine excretion . RESULTS For all measurements there were no significant differences between the 2 treatments at any dose level . Ratios between BUD and TAA ( 95 % CI ) at the highest dose levels were as follows : 8 am serum cortisol , 1.08-fold ( 0.63 to 1 . 85 ) ; urinary cortisol , 1.09-fold ( 0.63 to 1.86 ) ; eosinophils , 0 . 98-fold ( 0.69 to 1.38 ) ; and osteocalcin 1.05-fold ( 0.78 to 1.41 ) . There was no evidence of a significant overall dose-response effect for any parameter of hypothalamo-pituitary-adrenocortical axis activity , with neither drug being significantly different from placebo at any dose . For the 3 dose levels of both drugs , total abnormal low values for 8 am serum cortisol ( ie , < 5.4 micrograms/dL [ < 150 nmol/L ] ) showed 2 of 36 for BUD and 2 of 36 for TAA . There was also no significant overall dose-response effect for eosinophils or osteocalcin , although both drugs were significantly ( P < .05 ) different from placebo at the highest dose : eosinophils ( x10(9)/L ) , placebo : 0.36 , TAA : 0.24 , and BUD : 0.23 ; and osteocalcin ( nmol/L ) , placebo : 1.04 , TAA : 0.73 , and BUD : 0.77 . CONCLUSION There were no significant differences in the systemic bioactivity profiles , in terms of adrenal , blood , and bone markers , between BUD administered by means of Turbuhaler and TAA administered by means of an integrated actuator/spacer in a dose range of 400 micrograms to 1600 micrograms/day . Both drugs exhibited a significant degree of detectable systemic bioactivity but only at the highest dose of 1600 micrograms/day for effects on eosinophil count and osteocalcin [3556202] Twenty-four patients with severe steroid-dependent asthma participated in a double-blind cross-over study performed in two centers . After a run-in period of 2 weeks when beclomethasone dipropionate ( BDP ) ( 400 micrograms/day ) was used , the patients were treated for 4 weeks with either a high-dose ( 1600 micrograms/day ) or a low-dose ( 400 micrograms/day ) of budesonide ( Pulmicort ) . Thereafter the doses of budesonide were switched and the treatment continued for a further 4-week period . Patients treated with high-dose budesonide displayed significant improvements in airway functions . In addition , subjective scores for cough , sputum production and dyspnoea were more improved in the high-dose group than in the low-dose group . The need for concomitant beta 2-agonist therapy was also significantly reduced during the high-dose treatment . No significant changes in plasma cortisol levels were detected and no adverse effects of importance were registered . The results indicate that high-dose budesonide treatment improves the clinical status of patients with severe steroid-dependent asthma more than a low-dose therapy but without causing systemic side-effects [9814730] In recent years , measurement of serum osteocalcin has been introduced for assessment of bone turnover in patients treated with exogenous glucocorticoids . Studies in children with asthma on inhaled glucocorticoids , however , have shown inconsistent results . The aim of the present study is to assess bone turnover in prepubertal children and in adolescents with asthma treated with inhaled budesonide using three different osteocalcin assays : the Pharmacia Osteocalcin CAP FEIA , the CIS OSTK-PR and CIS IRMA ELSA-OSTEO assays . Two studies were conducted : 1 ) a r and omised double blind two-period crossover study of 22 prepubertal children aged 5 - 12 years . In one period 800 microg budesonide was given once in the morning , in the other 400 microg was given twice daily ; 2 ) a r and omised double blind placebo controlled two period crossover study of inhaled budesonide 400 microg twice daily in fourteen 13 - 16 year old adolescents with pubertal stages II-V. In both studies , treatment periods were of four weeks duration , and blood sample s were collected at the last day of each period . In the prepubertal children none of the osteocalcin assays detected any statistically significant differences between any of the periods . In the adolescent group reduced levels of osteocalcin were seen during budesonide treatment . The suppression reached statistical significance with the CAP FEIA ( P = 0.03 ) and the OSTK-PR ( P = 0.01 ) assays , but not with the ELSA-OSTEO assay ( P = 0.06 ) . Correlation analyses showed statistically significant correlation coefficients varying between 0.58 and 0.91 ( P = 0.03 and P < 0.0001 , respectively ) . The effect of inhaled glucocorticoids on serum osteocalcin may depend on the assay applied , and inhaled glucocorticoids have differential effects in children and adolescents [1878641] OBJECTIVE --To determine whether the inhaled glucocorticosteroid budesonide has any adverse effect on short term linear growth in children with mild asthma . SETTING --Outpatient clinic in secondary referral centre . PATIENTS --15 children aged 6 - 13 years with normal statural growth velocity during the previous year , no signs of puberty , and no use of systemic or topical steroids in the two months before the study . DESIGN OF INTERVENTIONS --Double blind , r and omised crossover trial with two active periods in which budesonide was given in divided daily doses of 200 micrograms and 800 micrograms . During run in and two washout periods placebo was given . After the second washout period the children received open treatment with 400 micrograms budesonide daily . All periods were of 18 days ' duration . MAIN OUTCOME MEASURE -- Growth of the lower leg as measured twice a week by knemometry . RESULTS --Mean growth velocity of the lower leg was 0.63 mm/week during run in and during washout 0.64 mm/week . Budesonide treatment was associated with a significant dose related reduction of growth velocity : the mean reduction in growth velocity during treatment was 0.11 ( 95 % confidence interval -0.15 0.36 ( 0.13 to 0.59 ) mm/week with 800 micrograms budesonide ( p less than 0.05 ; Page 's test ) . During treatment with 400 micrograms budesonide a reduction of 0.17 ( -0.10 to 0.45 ) mm/week was found . CONCLUSIONS --Treatment with inhaled budesonide is associated with a dose related suppression of short term linear growth in children with mild asthma [11112113] Inhaled corticosteroids have become the mainstay treatment of bronchial asthma . However , simultaneous evaluations of efficacy and side effects are few . This study aim ed to compare the relative effect of fluticasone propionate ( FP ) and budesonide ( BUD ) on bronchial responsiveness and endogenous cortisol secretion in adults with asthma . The study was double-blind and included 66 adults with asthma , who were r and omized to FP ( n = 33 ) or BUD ( n = 33 ) . Pre study , all participants were clinical ly stable , using inhaled corticosteroids and hyperresponsive to methacholine . Eligible patients were r and omized to three consecutive 2-wk periods with either FP 250 microg twice daily , FP 500 microg twice daily , and FP 1,000 microg twice daily , or BUD 400 microg twice daily , BUD 800 microg twice daily , and BUD 1,600 microg twice daily , delivered by Diskhaler and Turbuhaler , respectively . Before r and omization and at the end of each treatment , bronchial methacholine PD(20 ) , 24-h urinary cortisol excretion ( 24-h UC ) , plasma cortisol , serum osteocalcin , and blood eosinophils were determined . The relative PD(20 ) potency between FP and BUD was 2.51 ( 95 % CI , 1.05 - 5.99 ; p < 0 . 05 ) , while the relative 24-h UC potency was 0.60 ( 95 % CI , 0.44 - 0.83 ; p < 0.01 ) . The differential therapeutic ratio ( FP/BUD ) based on PD(20 ) potency and 24-h UC was 4.18 ( 95 % CI , 1.16 - 15.03 ; p < 0.05 ) . The difference in systemic potency was also seen for plasma cortisol , serum osteocalcin , and blood eosinophils . Therapeutic ratio over a wide dose range , determined by impact on bronchial responsiveness and endogenous corticosteroid production , seems to favor FP [7119301] The influence of various dosing regimens on the response of asthmatic patients to aerosol steroid was investigated . Budesonide , a topically active corticosteroid like beclomethasone dipropionate , was given q.i.d . or b.i.d . , in the morning or A.M./P.M. , at doses of 400 , 800 , and 1600 micrograms/day . Each patient ( n = 34 ) took every treatment combination for 2 wk . The antiasthmatic and systemic effects , measured by changes in peak expiratory flow rate ( PEFR ) , blood eosinophils , and serum cortisol levels increased approximately linearly on log dose budesonide ( p less than 0.0005 ) . Systemic effects of the drug were nonsignificant at low dosage . At high dosage , morning dosing conserved hypothalamic-pituitary-adrenal function , but at the cost of a marginal reduction in efficacy ( delta PEFR , p = 0.12 ) . Having the dose frequency reduced the antiasthmatic potency of the drug , i.e. , PEFR fell by an amount equivalent to approximately eightfold reduction in daily dosage ( p = 0.002 ) . This effect was not evident when asthma was in remission but became so with asthma in relapse . Overall , the q.i.d . A.M./P.M. regimen showed the best risk-benefit relationships . The data indicate ( 1 ) that reductions in dose frequency made with the hope of improving patient compliance and thus conserving the drug 's long-term efficacy are likely to lead to the reverse effect , ( 2 ) that the clinician can conserve a better balance of risk vs benefit by titrating dosage in terms of puffs per dose rather than doses per day , and ( 3 ) that patients can increase the antiasthmatic efficacy of this aerosol steroid without any increase in drug costs ( or apparent risk ) by simply increasing dosing frequency . These therapeutic considerations probably apply to some or all of the other topically active steroids currently used to treat asthma [7822661] OBJECTIVE The purpose of the study was to evaluate the dose-response relationships of the inhaled corticosteroid budesonide in a double blind crossover study in 19 children with moderate and severe asthma . METHODS A 2-week placebo treatment period ( run-in ) was followed by three 4-week treatment periods during which 100 , 200 , and 400 micrograms of budesonide were given per day in r and omized order . Urinary cortisol excretion , lung functions , and protection against exercise-induced asthma were assessed at the end of run-in and each treatment period . Furthermore , morning and evening peak expiratory flow rates , day and night symptoms , and use of rescue beta 2-agonists were recorded throughout the study . RESULTS One hundred micrograms of budesonide per day markedly improved symptoms , morning and evening peak expiratory flow rates , and use of rescue beta 2-agonists ( p < 0.01 ) . No further improvement was seen in these parameters with increasing doses of budesonide . In contrast , a significant dose-response effect was found on lung functions measured at the hospital and fall in lung functions after exercise ( p < 0.001 ) ; 200 micrograms was significantly better than 100 micrograms , and 400 micrograms was significantly better than 200 micrograms . About 53 % of the maximum effect against exercise-induced asthma was achieved by the lowest budesonide dose ( p < 0.001 ) , and about 83 % by the highest dose . No significant differences were seen in urinary cortisol excretion between run-in and the various budesonide doses . CONCLUSIONS Low doses of budesonide , which are not associated with any systemic side effects , have a marked antiasthma effect in children . Protection against exercise-induced asthma requires higher doses than achievement of symptom control [10353578] BACKGROUND Budesonide ( Pulmicort ) is an inhaled corticosteroid with high topical potency but low systemic activity . Turbuhaler is a novel breath-actuated , multi-dose , dry-powder inhaler . OBJECTIVES This study was conducted to determine the efficacy and safety of two different dose regimens of budesonide Turbuhaler , compared with placebo , in adult patients with mild-to-moderate asthma not well-controlled with bronchodilator therapy . METHODS This double-blind , r and omized , placebo-controlled , parallel-group , multicenter study compared the efficacy and safety of 200 microg and 400 microg of budesonide , administered twice daily via Turbuhaler , with placebo , in 273 adult patients ( aged 19 to 70 years ) with mild-to-moderate asthma ( FEV1 67 % of predicted normal ) , not well-controlled with bronchodilator therapy . Efficacy was assessed by pulmonary function tests and patient assessment s of asthma symptom control . Safety was assessed in terms of adverse events , laboratory evaluations , and physical examinations . RESULTS Two hundred and 400 microg of budesonide bid were significantly more effective than placebo at improving morning PEF ( mean differences from placebo of 43.63 L/min and 40.10 L/min , respectively ; P < .001 ) and FEV1 ( mean differences from placebo of 0.44 L , and 0.50 L , respectively ; P < .001 ) over the 12-week treatment period . Onset of action as assessed by morning PEF was within two days . Basal and stimulated plasma cortisol concentrations were not significantly affected by budesonide treatment compared with placebo . CONCLUSIONS Treatment of adults suffering from mild-to-moderate asthma with budesonide Turbuhaler is well tolerated and results in a rapid onset of asthma control which is maintained over time [10669688] OBJECTIVES This study was design ed to compare the effects of a 6-month treatment with budesonide 100 microg bid ( low dose ) and 400 microg bid ( st and ard reference dose ) in controlling symptoms and lung function in a group of asthmatics with moderate asthma ( baseline FEV(1 ) > or = 50 % and < or = 90 % of predicted values ) previously treated with inhaled beclomethasone dipropionate ( 500 to 1,000 microg/d ) . Moreover , we investigated whether or not asthma exacerbations could be treated by a short-term increase in the daily dose of budesonide . METHODS After a 2-week run-in period and 1-month treatment with a high dose of budesonide ( 800 microg bid ) , 213 patients with moderate asthma were assigned to r and omized treatments . Daily treatment included budesonide ( bid ) plus an additional treatment in case of exacerbation ( qid for 7 days ) . Treatments were as follows : budesonide 400 microg plus placebo ( group 1 ) ; budesonide 100 microg plus budesonide 200 microg ( group 2 ) ; and budesonide 100 microg plus placebo ( group 3 ) . Symptoms and a peak expiratory flow ( PEF ) diary were recorded and lung function was measured each month . An exacerbation was defined as a decrease in PEF > 30 % below baseline values on 2 consecutive days . RESULTS We found that that 1-month treatment with a high budesonide dose remarkably reduced all asthma symptoms . Moreover , symptoms were under control in all treatment groups throughout the study period . Similarly , lung function improved and remained stable , and no relevant differences between groups were observed . In each treatment group , the majority of patients had no exacerbations . In patients treated with the st and ard budesonide dose ( group 1 ) , the number of exacerbations and days with exacerbations were significantly lower than in group 3 ( intention-to-treat analysis ) . Additionally , patients treated with low budesonide dose plus budesonide ( group 2 ) experienced a significantly lower number of exacerbations and days with exacerbations compared to group 3 ( per- protocol analysis ) . CONCLUSIONS This study demonstrates that when patients with moderate asthma had reached a stable clinical condition with a high dose of budesonide , a low dose of budesonide ( 200 microg/d ) is as effective as the st and ard dose ( 800 microg/d ) in the control of symptoms and lung function over a period of several months . Furthermore , results showed that the addition of inhaled budesonide ( 800 microg/d ) at onset of an asthmatic exacerbation has a beneficial clinical effect [9564798] BACKGROUND There are no data currently available on the correct schedule for the initiation of treatment with nebulized suspension of budesonide in children with recurrent wheezing episodes . We compared the efficacy and safety of starting with a high dose followed by a stepwise decrease to a continuous low dose . METHODS In a double-blind design , 42 children aged 6 months to 3 years were r and omly allocated to receive either a high starting dose of 1 mg budesonide twice daily followed by a stepwise decrease of 25 % every second day for 1 week ( group A ) or a low dose of 0.25 mg twice daily for 1 week ( group B ) . Efficacy was assessed with daily symptom scores and the systemic effect of the corticosteroids with the adrenocorticotropic hormone test . RESULTS The two groups were comparable for all parameters evaluated . During the first week of treatment , there was a significant decrease in asthmatic symptomatology only in group A : a 59 % decrease for wheezing ( p = 0.0001 ) , 39 % for diurnal cough ( p = 0.036 ) , and 39 % for nocturnal cough ( p = 0.04 ) . Mean time to clinical response was 3.0 days in group A and 5.7 days in group B ( p = 0.02 ) . This early improvement was sustained for the rest of the follow-up period . The high dose starting schedule was not associated with any change in serum cortisol level . CONCLUSIONS The administration of nebulized suspension of budesonide at a high starting dose schedule followed by a rapid ( 1 week ) stepwise decrease yields a significant early improvement in asthma symptoms and causes no change in serum cortisol levels [3532011] An open , cross-over trial was conducted on 25 asthmatic children , aged 6 - 13 years , who required inhaled steroids . They inhaled Budesonide 200 micrograms twice daily , either directly from the metered dose inhaler or via the pear spacer ( PS ) , for 2 months on each , in r and omized order . The effects of the treatment were monitored with diary cards recording peak expiratory flow rates twice daily , symptoms and treatment taken , and with monthly clinical assessment s including more sensitive lung function studies ( flow-volume loops and single breath nitrogen wash-out tests ) . There was no specifically PS-related improvement in symptoms or in the majority of tests , but the results showed improvement with time when using either method . The improvement was more distinct in some tests reflecting proximal airway calibre ( i.e. , PEFR ) than in tests thought to reflect predominantly peripheral airway calibre ( i.e. , F50 , RV ) . The bronchodilator responsiveness , as shown by the increase in lung function tests after a beta-agonist was given , was significantly greater for FVC during the periods when the PS was used , although there was no significant improvement in FEV2 or PEFR . The improvement in tests reflecting proximal airways may have been due to optimization of the inhalation technique , greater underst and ing of asthma , or better compliance with medication associated with regular attendance for the study . The greater bronchodilator response whilst children were inhaling budesonide by the PS may have been due to increased deposition or better distribution of the steroid but was probably related to a difference between the two groups in initial baseline function tests [9692099] Inhaled steroid therapy is the most important treatment in the management of chronic asthma and currently twice-daily administration is recommended in mild to moderate asthma . Compliance is often a problem in asymptomatic patients and may lead to reduced disease control . Our aim was to investigate whether budesonide 0.2 mg once daily administered via the Turbuhaler is as effective as 0.1 mg twice daily . A r and omized , double-blind , parallel group study was carried out in which 76 adult patients with mild to moderate asthma ( FEV1 86 % of predicted ) were allocated to budesonide once or twice daily . After a run-in period of 2 weeks on present inhaled steroid treatment ( 0.2 - 0.5 mg day-1 ) there was an 8 week treatment period , followed by a washout period in which patients received no steroid for 4 weeks unless a drop in morning peak flow of at least 20 % occurred or the use of beta 2-agonists increased by 50 % . Both treatment groups improved minimally in peak flow ( 1.7 and 4.31 min-1 in the once-daily and twice-daily groups respectively ) but the differences between the two groups were not significant . Testing the reverse hypothesis revealed clinical equivalence . The 90 % confidence interval of the difference in the change of peak flow from run-in was between + 30 and -30 l min-1 , the limits deemed to be clinical ly relevant . There were no differences in symptom scores , beta 2-agonist use or spirometry measurements between the two groups . In the washout period there was a significant deterioration in peak flow and symptoms . This study shows that 0.2 mg budesonide given once a day is as affective as 0.1 mg given twice daily in patients with mild to moderate asthma [2669554] The dose‐response effects of inhaled beclomethasone dipropionate ( BDP ) and budesonide ( BUD ) administered b.i.d . with the aid of metered dose aerosols were studied in 128 patients ( 67 men and 61 women , mean age 53 years ) suffering from asthma bronchiale . The study was design ed as a multi‐centre , double‐blind , four‐period cross‐over study , followed by a single‐blind double placebo period . BDP was administered in doses of 400 and 1000 μg , and BUD in doses of 400 and 800 μg . The results in terms of peak expiratory flow ( PEF ) in the morning and evening , daily symptoms score and use of inhaled β2‐agonists did not reveal any clinical ly significant differences between the drugs or between high ( 800 μg BUD , 1000 μg BDP ) and low ( 400 mg BUD/BDP ) doses . However , statistically significant differences were recorded for the corresponding parameters when comparing the placebo with preceding steroid periods . Adverse effects consisting mainly of oropharyngeal c and idiasis , hoarseness and cough occurred in 54 of 468 treatment months ( 12 % ) . The carry‐over effects of inhaled steroids are longer lasting than was previously assumed [10971469] Repeated low‐dose allergen challenge increases airway hyperresponsiveness and sputum eosinophils in atopic asthmatics . Inhaled corticosteroids attenuate the airway responses to high‐dose allergen challenge , but have not been evaluated against repeated low dose challenge [9744142] One hundred and sixty seven children on 0 - 200 microgram/day of inhaled steroid with asthma symptoms and sub-optimal peak flow values ( less than 90 % of that predicted for their height ) were r and omly allocated either 400 microgram once daily ( nocte with placebo o.m . ) or 200 mircrogram twice daily of budesonide Turbohaler for 8 weeks . Bronchdilator usage and symptoms were reduced in both groups at 4 and 8 weeks compared with baseline . There was a significant increase within both groups in morning and evening PEF after 4 and 8 weeks . The increase in evening PEF after 8 weeks was greater in the once-daily group than in the twice-daily group but there were no other significant differences between the groups ( morning : + 24.6 l/min vs 15.2 l/min , p = 0.059 ; evening : + 19.7 l/min vs + 8.31 l/min ; p = 0.013 ) . Budesonide Turbohaler 400 microgram once daily is therefore as effective as 200 microgram twice daily in achieving asthma control in children [8640047] Maintenance treatment with nebulized budesonide was studied in young children with asthma not controlled without steroids . In a blind parallel‐group study for 18 weeks , 102 children , mean age 22 ( 5–47 ) months , were r and omized for treatment starting with 0.25 or 1 mg b.i.d . The patients were review ed every 3 weeks , and if symptom control had been achieved the dose was reduced , otherwise it was kept . The clinical effect was very good with both dose regimens . The median time to 7 consecutive days without any asthma symptoms was about 1 month with both , highlighting the importance of the duration of therapy rather than the benefits of a high starting dose . In 18 of 24 children who attained the placebo stage , symptoms had reappeared at the last visit . Although an overall minimal effective maintenance dose could not be demonstrated , 47 % achieved symptom control on 0.25 mg b.i.d . , i.e. fulfilled criteria for further dose reduction . No significant side effects were seen . On average , 25 % of the nominal dose reached the patients [9358137] BACKGROUND The role of long-acting , inhaled beta2-agonists in treating asthma is uncertain . In a double-blind study , we evaluated the effects of adding inhaled formoterol to both lower and higher doses of the inhaled glucocorticoid budesonide . METHODS After a four-week run-in period of treatment with budesonide ( 800 microg twice daily ) , 852 patients being treated with glucocorticoids were r and omly assigned to one of four treatments given twice daily by means of a dry-powder inhaler ( Turbuhaler ) : 100 microg of budesonide plus placebo , 100 microg of budesonide plus 12 microg of formoterol , 400 microg of budesonide plus placebo , or 400 microg of budesonide plus 12 microg of formoterol . Terbutaline was permitted as needed . Treatment continued for one year ; we compared the frequency of exacerbations of asthma , symptoms , and lung function in the four groups . A severe exacerbation was defined by the need for oral glucocorticoids or a decrease in the peak flow to more than 30 percent below the base-line value on two consecutive days . RESULTS The rates of severe and mild exacerbations were reduced by 26 percent and 40 percent , respectively , when formoterol was added to the lower dose of budesonide . The higher dose of budesonide alone reduced the rates of severe and mild exacerbations by 49 percent and 37 percent , respectively . Patients treated with formoterol and the higher dose of budesonide had the greatest reductions -- 63 percent and 62 percent , respectively . Symptoms of asthma and lung function improved with both formoterol and the higher dose of budesonide , but the improvements with formoterol were greater . CONCLUSIONS In patients who have persistent symptoms of asthma despite treatment with inhaled glucocorticoids , the addition of formoterol to budesonide therapy or the use of a higher dose of budesonide may be beneficial . The addition of formoterol to budesonide therapy improves symptoms and lung function without lessening the control of asthma [7638369] Measurement of short term lower leg growth with the knemometer has recently been shown to be a sensitive method for assessment of systemic activity of exogeneous glucocorticosteroids in children with asthma ( 1 ) . It is not known , however , whether short term knemometry is more sensitive than established measures of adrenal function , such as 24 h urine free cortisol excretion . We recently found that knemometric growth rates were suppressed in a dose-related manner in asthmatic children treated with 200 , 400 and 800,~g of inhaled budesonide ( 2 ) . In the present paper , we report the 24 h urine free cortisol excretion in the same children for comparison with the knemometry data , to evaluate if there is any correlation between the two measures of systemic activity , and to assess which method is the more sensitive [3512282] Forty-five steroid-dependent asthmatic out patients were treated twice daily for 51 weeks with a new inhalation steroid , budesonide ( BUD ) , using a 750 ml spacer . During the initial 15 weeks the prednisone-sparing effects of a high daily dose ( 1600 micrograms ) and a conventional dose ( 400 micrograms per day ) were compared in a double-blind r and omized trial including 50 patients . During the remaining 36 weeks 45 patients were treated openly with 1600 micrograms daily . All patients used other antiasthmatic drugs which were maintained throughout the study , except for inhalations of beta-2 agonists that could be used whenever needed . All patients but 2 were able to reduce the daily dose of oral prednisone . The mean daily dose decreased from 13.9 mg to 5.3 mg . Eighteen patients ( 40 % ) were able to discontinue oral prednisone . Adrenal gl and function improved considerably as prednisone intake decreased . Oropharyngeal thrush frequency showed no change . No severe side effects were observed [3276257] In a double-blind study of 2 parallel groups of 15 allergic asthmatic patients each , we investigated whether treatment with inhaled budesonide has a dose- and time-dependent effect on the degree of bronchial hyperreactivity . The patients were r and omly allocated to treatment with either 200 or 800 micrograms budesonide per day for a period of 8 wk . The active treatment period was preceded by a selection period of 3 wk , and a single-blind placebo period of 2 wk . During these initial 5 wk the maintenance treatment of the patients , including cromolyn sodium and inhaled corticosteroids , was withheld . Spirometry and inhalation provocation tests with methacholine were carried out , and the symptom score was recorded every 2 wk . The methacholine provocation concentrations ( geometric mean ) causing a decrease in FEV1 of 20 % ( PC20 ) in the 200 and 800 micrograms/day treatment groups just before the active treatment period were 0.90 and 0.91 mg/ml , respectively . These values increased significantly to 1.21 and 1.84 mg/ml after 2 wk of treatment ( p less than 0.05 and p less than 0.001 , respectively ) and to 1.55 and 2.74 mg/ml after 8 wk of treatment ( p less than 0.01 and p less than 0.001 ) . During the whole study period budesonide in a dosage of 800 micrograms/day induced a significantly larger change in PC20 than in a dosage of 200 micrograms/day . The FEV1 before treatment was 91 + /- 3 % ( SEM ) and 84 + /- 2 % of the predicted value in the 200 and 800 micrograms/day treatment groups , respectively . ( ABSTRACT TRUNCATED AT 250 WORDS [10926339] The importance of early initiation of inhaled steroids even in mild asthma has been documented in several studies . It is not , however , clear whether the treatment should be started with a high or a low dose of the inhaled steroid . We have compared the effects of high and low dose inhaled steroid , budesonide , in patients with newly detected asthma . We studied 101 adult patients with newly detected bronchial asthma who were without inhaled steroid or any regular pharmacological treatment for their asthma . The patients were r and omly allocated to two treatment groups : one to receive 800 microg inhaled budesonide per day and the other to receive 200 microg inhaled budesonide per day . The drugs were given with a Turbuhaler dry powder inhaler . During the 3-month treatment period , no significant differences between the treatment groups were noted in morning or evening PEF values , in spirometric parameters , in asthmatic symptoms or in the use of rescue beta2-agonists . The decrease in bronchial hyperresponsiveness was , however , more marked in the high dose budesonide group , reaching a borderline significance ( P=0.10 high vs. low dose budesonide ) . In addition , in serum markers of asthmatic inflammation significant differences were shown between the treatment groups . The decrease in the number of blood eosinophils during the treatment was more marked in the high dose budesonide group ( P=0.02 ; high vs. low dose budesonide ) . In serum ECP no change was observed in the low dose budesonide group , but a marked decrease in the high-dose budesonide group ( P=0.008 ; high vs. low dose budesonide ) . The change was even more marked with regard to serum EPX ( P=0.005 ; high vs. low dose budesonide ) . Our results support the view that the treatment of newly detected asthma should be started with a high dose of inhaled steroid . The low dose may not be enough to suppress asthmatic inflammation despite good clinical primary response [7540898] Serum concentrations of growth hormone – dependent insulin – like growth factor I ( IGF – I ) and insulinlike growth factor binding protein–3 ( IGFBP–3 ) , the carboxy terminal propeptide of type I procollagen ( PICP ) , the carboxy terminal pyridinoline cross – linked telopeptide of type I collagen ( ICTP ) and the amino terminal propeptide of type III procollagen ( PIIINP ) were studied in 14 prepubertal children with asthma ( mean age 9.7 years ) during treatment with inhaled budesonide . The study design was a r and omized , crossover trial with two double – blind treatment periods ( 200 and 800 μg ) and one open , non – r and omized treatment period ( 400 μg ) . All periods were 18 days ’ duration . Budesonide treatment was associated with a dose – related suppressive trend in serum concentrations of PIIINP when the 400 μg period was included ( p < 0.01 ; z = –2.7 ) and when it was excluded from the calculations ( p < 0.01 ; z = –2.6 ) , indicating reduced synthesis of type III collagen . A similar trend was observed in ICTP levels when the 400 μg period was excluded from the calculations ( p= 0.05 ; z = –1.9 ) . No other statistically significant variations were seen [9525445] BACKGROUND As a general phenomenon , corticosteroids may suppress the activity in the hypothalamic-pituitary-adrenal ( HPA ) axis . The adrenal stimulation test is a commonly used method to assess the relative risk of exogenous corticosteroids to induce systemic side effects . OBJECTIVES This clinical trial was performed to assess the effects of budesonide on the HPA axis ( at 800 , 1600 , or 3200 microg/day , given as a twice daily regimen , administered by means of the Turbuhaler ) in adult patients with mild , non-steroid-dependent asthma . METHODS Sixty-four asthmatic patients received budesonide or placebo by inhalation or 10 mg/day oral prednisone once daily as a positive control in a double-blind , double-dummy , r and omized , placebo-controlled , parallel-group , multicenter study . Plasma cortisol concentration was measured to assess the effect on the HPA axis before and during a 6-hour infusion of synthetic adrenocorticotropic hormone ( ACTH ) , cosyntropin . RESULTS After 6 weeks of treatment , plasma cortisol concentrations after adrenal stimulation by cosyntropin infusion had fallen by 4 % in the placebo group ; by 13 % , 11 % , and 27 % in the budesonide groups ( 800 , 1600 , and 3200 microg/day , respectively ) ; and by 35 % in the prednisone group . The decrease was significant only in the 3200 microg/day budesonide ( p = 0.03 ) and prednisone ( p = 0.005 ) groups . Over the same time period , decreases in basal plasma cortisol concentrations were 1 % in the placebo group ; 19 % , 19 % , and 34 % in the three budesonide groups ; and 37 % in the prednisone group . Only in the prednisone group was the decrease significant ( p = 0.03 vs placebo ) . CONCLUSIONS In this study budesonide inhaled by means of the Turbuhaler , at doses recommended for clinical use ( 800 or 1600 microg/day ) , did not produce any statistically significant suppression of the HPA axis compared with placebo [10390394] We assessed the systemic effects of budesonide ( BUD ) and fluticasone propionate ( FP ) in 23 patients with asthma , using a double-blind , placebo-controlled , double-dummy , and cross-over design . The following five treatments were given in a r and omized order for 1 wk with a washout period in between of 2 wk : ( 1 ) placebo ; ( 2 ) FP , 200 micrograms twice a day , inhaled from a Diskhaler ; ( 3 ) FP , 1,000 micrograms twice a day , inhaled from a Diskhaler ; ( 4 ) BUD , 200 micrograms twice a day , inhaled from a Turbuhaler ; and ( 5 ) BUD , 800 micrograms twice a day , inhaled from a Turbuhaler . The primary variable was the area under the curve of serum cortisol versus time ( AUC0 - 20 ) , derived from serum sample s taken every 2 h over a 20-h period following the last evening dose at 10:00 P.M. The lower doses of BUD and FLU did not cause any adrenal suppression . Compared with placebo , however , FP ( 1 , 000 micrograms , twice daily and BUD ( 800 micrograms , twice daily ) decreased the AUC0 - 20 by 34 and 16 % , respectively . Fluticasone ( 1,000 micrograms , twice daily ) was more suppressive than BUD ( 800 micrograms , twice daily ) ( p = 0.0006 ) . The FEV1 , measured the morning after the last inhalation , was significantly higher after the active treatments , compared with placebo ( p < 0.02 ) , but did not differ between all active treatments . We conclude that high doses of BUD and FP ( in particular the latter ) , inhaled via their respective dry powder inhalers for 1 wk , result in a measurable systemic activity in patients with asthma [9819296] BACKGROUND Inhaled glucocorticosteroids are indicated for the treatment of persistent asthma ; however , many young children are unable to effectively use currently available inhalers . OBJECTIVE We sought to evaluate the efficacy and safety of 3 different twice daily doses of budesonide inhalation suspension ( Pulmicort Respules ) in inhaled steroid-dependent asthmatic children . METHODS This was a 12-week , r and omized , double-blind , placebo-controlled , parallel-group study involving 178 children ( age range , 4 to 8 years ) at 17 centers in the United States . Budesonide inhalation suspension doses of 0.25 mg , 0.50 mg , or 1.0 mg twice daily were administered by means of a jet nebulizer and air compressor system . Efficacy was assessed by recording at home nighttime and daytime asthma symptom scores , use of rescue medication , pulmonary function tests , and treatment discontinuation because of worsening symptoms . Safety was assessed by reported adverse events and changes in baseline and adrenocorticotrophic hormone-stimulated plasma cortisol levels in a subset of patients . RESULTS Baseline demographics , symptom scores , and pulmonary function data were similar across treatment groups . All doses of budesonide inhalation suspension were superior to placebo in improving nighttime and daytime asthma symptom scores ( P < /=.026 ) , reducing use of breakthrough medication ( P < /=.032 ) , and improving morning peak expiratory flow ( P < /=.030 ) . The number of dropouts because of worsening asthma was also significantly fewer in the budesonide groups ( P < /=.015 ) . There were no differences between doses of budesonide . Adverse events and basal and adrenocorticotrophic hormone-stimulated cortisol responses were not different between budesonide and placebo groups . CONCLUSION Budesonide inhalation suspension , 0.25 mg , 0.50 mg , and 1.0 mg twice daily , is an effective and safe treatment for young children with inhaled steroid-dependent , persistent asthma [10510140] AIMS The present pharmacokinetic study was undertaken to determine the dose proportionality of three different doses of budesonide-400 microg , 800 microg or 1600 microg administered twice daily by a dry-powder inhaler ( Turbuhaler ) in adult patients with mild asthma . METHODS A total of 38 patients received budesonide by inhalation , 13 received 400 microg twice daily , 12 received 800 microg twice daily and 13 received 1600 microg twice daily . Mean FEV1 at inclusion was 3.4 , 4.0 and 3.9 l min-1 in the three groups , respectively . Blood sample s were taken after a single dose , and after 3 weeks of daily treatment , for pharmacokinetic evaluation . Plasma concentrations of budesonide were determined by liquid chromatography plus mass spectrometry . RESULTS Eleven evaluable patients remained in each dose group . Mean time to peak budesonide plasma concentration ( tmax ) was short ( 0.28 - 0.40 h ) and did not differ between treatment groups . Budesonide concentrations declined rapidly thereafter , indicating efficient pulmonary absorption and rapid elimination with a half-life of approximately 3 h. Cmax was 1 . 4(2.0 ) nmol l-1 ( single ( repeated ) doses ) , 2.6(3.6 ) nmol l-1 and 5 . 4(6.4 ) nmol l-1 after 400 , 800 and 1600 microg twice daily , respectively . The corresponding results for the area under the plasma concentration vs time curve ( AUC ) were 271(325 ) , 490(628 ) and 915(1096 ) nmol l-1 min . Ninety percent confidence intervals for pairwise dose-normalized Cmax and AUC comparisons between groups were large but contained unity in all cases , thus indicating dose-proportional pharmacokinetics . Regression on analysis supported these findings . Mean AUC after repeated doses ( AUC(0,12 h , RD ) ) was on average 23 % higher than the mean AUC after single doses ( AUC(0 , infinity , SD)(P=0.04 ) with no significant differences between doses , indicating slight accumulation following bid dosing . CONCLUSIONS In this relatively small study , budesonide inhaled via Turbuhaler appeared to have dose-proportional pharmacokinetics , both within and above the clinical ly recommended dose range for asthmatic patients [9627589] OBJECTIVE To determine the efficacy and safety of budesonide delivered by an inhalation-driven dry powder inhaler ( Turbuhaler ) in children with moderate to severe persistent asthma . STUDY DESIGN In our r and omized , double-blind , placebo-controlled , parallel-group , multicenter study , a total of 404 children with asthma , who were aged 6 to 18 years and who had been receiving inhaled glucocorticosteroid therapy , were r and omly assigned to receive either 100 , 200 , or 400 micrograms of budesonide or placebo twice daily for 12 weeks . At baseline , mean forced expiratory volume in 1 second ( FEV1 ) was 74.6 % ( range , 30.7 % to 123.3 % ) of the predicted normal value . RESULTS Patients in each of the three budesonide treatment groups showed significant dose-related improvements in lung function ( morning peak expiratory flow and FEV1 ) , in asthma symptoms , and with a significant decrease in inhaled beta 2-agonist use in comparison with placebo . Improvements were evident within 2 weeks and were maintained throughout the 12 weeks . Budesonide treatment had no significant effect on hypothalamic-pituitary-adrenal axis function , and the incidence of reported adverse events was similar in all treatment groups . CONCLUSION Budesonide administered via a dry powder inhaler provided dose-related improvements in lung function and clinical status and was well tolerated by children ( 6 to 18 years of age ) with moderate to severe persistent asthma [2035313] Bisgaard , H. , Pedersen S. , Damkjær Nielsen M and Østerballe O. ( Department of Paediatrics , University Hospital of Copenhagen , County of Gentofte , Copenhagen ; Department of Paediatrics , County Hospital of Kolding ; Department of Clinical Physiology , University Hospital of Copenhagen , County of Glostrup , Copenhagen ; Department of Paediatrics , County Hospital of Viborg , Denmark ) . Adrenal function in asthmatic children treated with inhaled budesonide . Acta Paediatr Sc and 80 : 213 , [9114906] 1 . The aim of this pharmacokinetic study was to evaluate to what extent oropharyngeal deposition of drug contributes to the systemic availability of budesonide inhaled from a dry powder inhaler ( Turbuhaler ) . 2 . The design was a r and omized cross-over study in eight children aged 7 - 13 years . The plasma concentrations of the two epimers of budesonide ( 22R and 22S ) after inhalation of 1 mg budesonide from a Turbuhaler were compared with the plasma concentrations obtained when the absorption of the drug deposited in the oropharynx was blocked by drinking and rinsing the mouth with charcoal before and after the inhalation . 3 . The plasma concentrations of budesonide were significantly reduced by the charcoal treatment ( P < 0.01 ) and the area under the time vs plasma concentration curve 0 - 4 h was significantly reduced from 9.5 to 8.0 mmol l-1 h for 22S ( P < 0.01 ) and from 7.6 to 5.7 mmol l-1 h for 22R ( P < 0.01 ) . 4 . The plasma concentrations and the AUCs after both Turbuhaler administrations were markedly higher than those obtained in earlier studies using other inhalers suggesting a higher intrapulmonary deposition of drug after Turbuhaler treatment . 5 . It is concluded that oropharyngeal deposition of drug accounts for about 20 % of the total systemic availability of budesonide inhaled from Turbuhaler . Thus , the main contribution to the system comes from budesonide absorbed in the airways [9768574] BACKGROUND A simple laboratory method to evaluate relative potency of inhaled corticosteroids in asthma would be valuable . Single-dose studies with the allergen-induced late asthmatic response have failed to show a useful dose-response relationship . Treatment for several days with inhaled corticosteroids will also inhibit the allergen-induced early asthmatic response . METHODS Twelve atopic asthmatic subjects were studied during a season when no medications were required except ipratropium bromide as needed . These subjects had positive allergen and methacholine inhalation tests and FEV1 greater than 70 % of predicted value . A double-blind , r and omized , cross-over study compared placebo and budesonide 100 , 200 , and 400 microg administered by means of Turbuhaler twice daily for 7 days with 6-day washout periods . Methacholine PC20 was measured before and after 6 days of treatment , and allergen PC15 was measured after 7 days of treatment . RESULTS The allergen PC15 ( n = 11 ) was significantly larger ( P = .0001 ) for all doses of budesonide compared with placebo , but there was no significant difference between the 3 doses of budesonide , and no dose response was demonstrated . The methacholine PC20 was significantly larger after all budesonide treatments compared with placebo ( P = .024 ) , but there was no difference between the 3 doses . There was a progressive increase in the allergen PC15 chronologically ( sequence effect ) that was not explained by improvement in FEV1 or airway responsiveness ; sequence effects were not seen for FEV1 or for pretreatment or posttreatment methacholine PC20 . Statistical adjustment for sequence effect did not alter allergen PC15 statistics . CONCLUSION A 7-day course of budesonide administered by means of Turbuhaler at 200 , 400 , or 800 microg per day provided marked and significant inhibition of the allergen-induced early asthmatic response compared with placebo . There was , however , no difference between the 3 doses . Therefore this method with these doses is not useful for providing assessment of relative potency [10507269] BACKGROUND Inhaled glucocorticosteroids ( GCS ) are the most effective long-term controller medications for the treatment of persistent asthma . Currently , however , available delivery devices limit their use in young children . A nebulized formulation of budesonide has been developed to address the needs of infants and young children . OBJECTIVE To evaluate the efficacy and safety of once-daily budesonide inhalation suspension in children 6 months to 8 years old with mild persistent asthma not on inhaled GCS . METHODS Three hundred fifty-nine children were r and omized to receive once-daily budesonide inhalation suspension ( 0.25 mg , 0.50 mg , or 1.0 mg ) or placebo via a Pari LC-Jet Plus nebulizer for 12 weeks . Efficacy assessment s included nighttime/daytime asthma symptoms , pulmonary function ( subset of patients ) , rescue medication use , and treatment discontinuations . Safety was based on adverse events and assessment of HPA-axis function . RESULTS Demographics , baseline characteristics , asthma symptoms , and pulmonary function were similar across treatment groups . Mean nighttime/daytime asthma symptom scores were 1.19 + /- 0.63 and 1.34 + /- 0.53 , respectively . Mean duration of asthma was 36.3 months and mean FEV1 was 81.3 % of predicted with 27.7 % reversibility . Following 12 weeks of treatment , all budesonide inhalation suspension doses produced significant improvements in nighttime/daytime symptoms ( P < or = .049 ) and significant decreases in rescue medication use ( P < or = .038 ) compared with placebo . Significant improvements ( P < or = .044 ) in FEV1 were observed in the 0.5- and 1.0-mg budesonide inhalation suspension groups . There were no differences between doses of budesonide inhalation suspension . Adverse events and basal and ACTH-stimulated cortisol levels were similar among all groups . CONCLUSION Once-daily administration of budesonide inhalation suspension was well tolerated and effective for the treatment of mild persistent asthma in infants and young children not adequately controlled with bronchodilators or non-GCS antiinflammatory treatments [9042043] To determine therapeutically and systemically equivalent dosages of budesonide inhaled through the Turbuhaler dry powder inhalation device ( Astra Pharma Production AB , Södertälje , Sweden ) or pressurized metered-dose inhaler ( pMDI ) plus Nebuhaler spacer ( Astra Pharma Production AB ) , we compared these devices in a r and omized , open , parallel-group trial . Adults with moderate to severe asthma inhaled budesonide ( 0.4 , 0.8 , 1.6 , and 2.4 mg/day ) , for 2 weeks at each dose level , through the Turbuhaler ( n = 30 ) or pMDI + Nebuhaler ( n = 28 ) . Dose-dependent effects were demonstrated on asthma symptoms ( p = 0.0001 ) , daily peak expiratory flow ( p = 0.02 ) , blood eosinophils ( p = 0.0001 ) , urinary cortisol output per day ( p = 0.0001 ) , serum cortisol ( p = 0.006 ) , serum osteocalcin ( p = 0.0001 ) , and the oropharyngeal C and ida colony count ( p = 0.0007 . analysis of covariance ) . The ratio of the responses to the two inhalation devices approximated 1.0 for each index measured ; that is , no significant between-device difference was found ( p > or = 0.29 ) . However , the 95 % confidence limits for the ratio of their respective systemic effects on osteocalcin production were 0.83 to 1.48 . Thus in adults who use inhalation devices efficiently and have optimally controlled asthma , conversions from the pMDI + Nebuhaler to the Turbuhaler may reasonably be made at milligram equivalent doses of budesonide , then down-titrated to minimize possible systemic effects . Because earlier studies have shown that the Turbuhaler can double intrapulmonary drug delivery in comparison with a pMDI without a spacer , a 50 % dose reduction may be indicated when converting from a pMDI to the Turbuhaler [8630596] The object of this investigation was to study the long-term effects of antiasthma treatment on blood markers of inflammation and lung function in adult asthmatic subjects . For this purpose 85 allergic and nonallergic asthmatic subjects were r and omized into three groups , which were given high-dose ( 1,600 micrograms/d ) inhaled budesonide , low-dose ( 400 micrograms/d ) inhaled budesonide , and oral theophylline ( 600 mg/d ) , respectively , and were followed for 11 mo with testing of lung function and blood sampling for the assay in serum of eosinophil cationic protein ( ECP ) , eosinophil protein x/eosinophil derived neurotoxin ( EPX/EDN ) as eosinophil markers , and myeloperoxidase ( MPO ) and lactoferrin ( LF ) as neutrophil markers . Lung functions ( FEV1 % predicted , and histamine PC20 ) and the eosinophil markers ECP and EPX/EDN were improved and reduced , respectively , by budesonide in a dose-dependent and temporally parallel fashion . Theophylline did not alter lung functions but reduced ECP and EPX/EDN after prolonged treatment . The treatment efficacy of budesonide was attributed solely to an effect on nonsmoking asthmatic subjects , since neither lung functions nor eosinophil markers changed in smokers even with high-dose budesonide . MPO but not LF was reduced after several months of treatment in all three groups , but only in nonsmokers . We conclude that ECP and EPX/EDN may be used to monitor antiinflammatory treatment in asthmatic patients , and that smoking asthmatic subjects are resistant to inhaled corticosteroids [9564797] BACKGROUND Airway inflammation is a hallmark of asthma , therefore current treatment recommendations include the use of inhaled glucocorticosteroids ( GCS ) . However , there is little evidence that the effects of inhaled GCS are dose dependent . OBJECTIVES The objective of this study was to assess the efficacy and safety of a second-generation GCS , budesonide , delivered by Turbuhaler , in adults with chronic asthma . METHODS In a 12-week , r and omized , double-blind , multicenter , parallel-group study , 473 subjects 18 to 70 years of age received either placebo or budesonide ( 200 , 400 , 800 , or 1600 microg total daily dose ) administered twice daily . Primary efficacy end points were mean change from baseline for FEV1 and morning peak expiratory flow . Safety was assessed by reported adverse events and by a cosyntropin-stimulation test . RESULTS The mean baseline FEV1 was 63 % to 66 % of predicted normal value between groups . All doses of budesonide were more effective than placebo ( p < 0.001 ) . The mean changes in morning peak expiratory flow were 12 , 22 , 27 , and 30 L/min in the 200 , 400 , 800 , and 1600 microg budesonide total daily dose groups , respectively , and -27 L/min for the placebo group . A statistically significant dose-response effect for the mean change from baseline over the 12-week study was seen for both morning peak expiratory flow and FEV1 . Budesonide-treated subjects also demonstrated significant reduction in asthma symptoms and bronchodilator use compared with placebo . There were no clinical ly significant differences in treatment-related adverse experiences among groups . CONCLUSIONS Budesonide administered by Turbuhaler exhibited a dose response and was effective at low doses . It was well tolerated and significantly more effective than placebo Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Inhaled corticosteroids ( ICS ) are the first-line treatment for children with persistent asthma . Their potential for growth suppression remains a matter of concern for parents and physicians . OBJECTIVES To assess whether increasing the dose of ICS is associated with slower linear growth , weight gain and skeletal maturation in children with asthma . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

28244303

[3848560] Background In the majority of patients with osteoarthritis of the knee the disease originates in the medial compartment . There are two fundamentally different approaches to knee replacement for patients with unicompartmental disease : some surgeons feel that it is always best to replace both the knee compartments with a total knee replacement ( TKR ) ; whereas others feel it is best to replace just the damaged component of the knee using a partial or unicompartment replacement ( UKR ) . Both interventions are established and well-documented procedures . Little evidence exists to prove the clinical and cost-effectiveness of either management option . This provides an explanation for the high variation in treatment of choice by individual surgeons for the same knee pathology . The aim of the TOPKAT study will be to assess the clinical and cost effectiveness of TKRs compared to UKRs in patients with medial compartment osteoarthritis . Methods / Design The design of the study is a single layer multicentre superiority type r and omised controlled trial of unilateral knee replacement patients . Blinding will not be possible as the surgical scars for each procedure differ . We aim to recruit 500 patients from approximately 28 secondary care orthopaedic units from across the UK including district general and teaching hospitals . Participants will be r and omised to either UKR or TKR . R and omisation will occur using a web-based r and omisation system . The study is pragmatic in terms of implant selection for the knee replacement operation . Participants will be followed up for 5 years . The primary outcome is the Oxford Knee Score , which will be collected via question naires at 2 months , 1 year and then annually to 5 years . Secondary outcomes will include cost-effectiveness , patient satisfaction and complications data .Trial registration Current Controlled Trials IS RCT N03013488 ; Clinical Trials.gov Identifier : [25002462] Background : Autologous chondrocyte implantation ( ACI ) has been shown to be effective in the midterm for the treatment of symptomatic articular cartilage lesions of the knee , but few long-term series have been published . The multioperated chronic articular cartilage defect remains a difficult condition to treat . Purpose : To examine the long-term clinical results of ACI for large chronic articular cartilage defects , many treated as salvage . Study Design : Case series ; Level of evidence , 4 . Methods : This is a prospect i ve case series of 104 patients with a mean age of 30.2 years and a symptomatic lesion of the articular cartilage in the knee , who underwent ACI between 1998 and 2001 . The mean duration of symptoms before surgery was 7.8 years . The mean number of previous surgical procedures on the cartilage defect , excluding arthroscopic debridement , was 1.3 . The defects were large , with a mean size of 477.1 mm2 ( range , 120 - 2500 mm2 ) . The modified Cincinnati , Stanmore/Bentley , and visual analog scale for pain scoring systems were used to assess pain and functional outcomes at a minimum 10 years ( mean , 10.4 years ; range , 10 - 12 years ) . Results : Twenty-seven patients ( 26 % ) experienced graft failure at a mean of 5.7 years after ACI . Of the 73 patients who did not fail , 46 patients ( 63 % of patients with a surviving graft ) had an excellent result , 18 ( 25 % ) were good , 6 ( 8 % ) were fair , and 3 ( 4 % ) had a poor result . Of a total of 100 patients successfully followed up , 98 were satisfied with the ACI technique for their chronic knee pain and would undergo the procedure again . Conclusion : Autologous chondrocyte implantation can provide a long-term solution in more than 70 % of young patients of a difficult-to-treat group with large chronic articular cartilage lesions , even in the salvage situation [21460066] Background : There are currently several approaches being pursued to treat focal defects of articular cartilage , each having specific advantages or challenges . A single-stage procedure that uses autologous cartilage fragments , Cartilage Autograft Implantation System ( CAIS ) , is being evaluated in patients and may offer a clinical ly effective option . Purpose : To establish the safety of CAIS and to test whether CAIS improves quality of life by using st and ardized outcomes assessment tools . Study Design : R and omized controlled trial ; Level of evidence , 2 . Methods : Patients ( n = 29 ) were r and omized ( 1:2 ) with the intent to treat with either a control ( microfracture [ MFX ] ) or an experimental ( CAIS ) procedure . Patients were followed at predetermined time points for 2 years using several st and ardized outcomes assessment tools ( SF-36 , International Knee Documentation Committee [ IKDC ] , Knee injury and Osteoarthritis Outcome Score [ KOOS ] ) . Magnetic resonance imaging was performed at baseline , 3 weeks , and 6 , 12 , and 24 months . Results : Lesion size and International Cartilage Repair Society ( ICRS ) grade were similar in both groups . General outcome measures ( eg , physical component score of the SF-36 ) indicated an overall improvement in both groups , and no differences in the number of adverse effects were noted in comparisons between the CAIS and MFX groups . The IKDC score of the CAIS group was significantly higher ( 73.9 ± 14.72 at 12 months and 82.95 ± 14.88 at 24 months ) compared with the MFX group ( 57.78 ± 18.31 at 12 months and 59.5 ± 13.44 at 24 months ) . Select subdomains ( 4/5 ) in the KOOS instrument were significantly different at 12 and 18 months , and all subdomains ( Symptoms and Stiffness , Pain , Activities of Daily Living , Sports and Recreation , Knee-related Quality of Life ) were significantly increased at 24 months in CAIS with scores of 88.47 ± 11.68 , 90.64 ± 7.87 , 97.29 ± 3.8 , 78.16 ± 22.06 , and 69 ± 23.15 compared with 75 ± 9.31 , 78.94 ± 13.73 , 89.46 ± 8.13 , 51.67 ± 26.01 , and 37.15 ± 21.67 in the MFX group . These significant improvements were maintained at 24 months in both IKDC and KOOS . Qualitative analysis of the imaging data did not note differences between the 2 groups in fill of the graft bed , tissue integration , or presence of subchondral cysts . Patients treated with MFX had a significantly higher incidence of intralesional osteophyte formation ( 54 % and 70 % of total number of lesions treated ) at 6 and 12 months when compared with CAIS ( 8 % and 25 % of total number of lesions treated ) . Conclusion : The first clinical experience in using CAIS for treating patients with focal chondral defects indicates that it is a safe , feasible , and effective method that may improve long-term clinical outcomes [19261905] Background Marrow stimulation techniques such as drilling or microfracture are first-line treatment options for symptomatic cartilage defects . Common knowledge holds that these treatments do not compromise subsequent cartilage repair procedures with autologous chondrocyte implantation . Hypothesis Cartilage defects pretreated with marrow stimulation techniques will have an increased failure rate . Study Design Cohort study ; Level of evidence , 2 . Methods The first 321 consecutive patients treated at one institution with autologous chondrocyte implantation for full-thickness cartilage defects that reached more than 2 years of follow-up were evaluated by prospect ively collected data . Patients were grouped based on whether they had undergone prior treatment with a marrow stimulation technique . Outcomes were classified as complete failure if more than 25 % of a grafted defect area had to be removed in later procedures because of persistent symptoms . Results There were 522 defects in 321 patients ( 325 joints ) treated with autologous chondrocyte implantation . On average , there were 1.7 lesions per patient . Of these joints , 111 had previously undergone surgery that penetrated the subchondral bone ; 214 joints had no prior treatment that affected the subchondral bone and served as controls . Within the marrow stimulation group , there were 29 ( 26 % ) failures , compared with 17 ( 8 % ) failures in the control group . Conclusion Defects that had prior treatment affecting the subchondral bone failed at a rate 3 times that of nontreated defects . The failure rates for drilling ( 28 % ) , abrasion arthroplasty ( 27 % ) , and microfracture ( 20 % ) were not significantly different , possibly because of the lower number of microfracture patients in this cohort ( 25 of 110 marrow-stimulation procedures ) . The data demonstrate that marrow stimulation techniques have a strong negative effect on subsequent cartilage repair with autologous chondrocyte implantation and therefore should be used judiciously in larger cartilage defects that could require future treatment with autologous chondrocyte implantation [21080737] Abstract Background : Knee cartilage lesions increase the risk of developing osteoarthritis ( OA ) , and may eventually result in a total knee replacement ( TKR ) . There is currently no consensus on the optimal treatment of cartilage lesions . ChondroCelect ® ( CC ) is a cell-based therapy approved for use in autologous chondrocytes implantation ( ACI ) to treat symptomatic cartilage defects of the femoral condyle . Its capacity to safely restore good- quality cartilage was demonstrated in a r and omized controlled trial ( RCT ) versus the surgical procedure microfracture ( MFX ) . Objective : This study investigated the cost utility of CC used in ACI compared with MFX to treat symptomatic knee cartilage lesions in Belgium . Methods : A decision tree model comparing CC with MFX over a 40-year horizon was developed in TreeAge Pro ™ . The key timepoints of the model were ( i ) clinical assessment 5 years after initial intervention ( success or no success , with or without re-operation ) ; ( ii ) development of OA at 15 years ( yes/no ) ; ( iii ) need for TKR at 20 years ( yes/no ) ; and ( iv ) need for prosthesis revision at 35 years ( yes/no ) . Clinical data provided by the RCT of CC versus MFX were the clinical success ( response ) rate based on the Knee injury and Osteoarthritis Outcome Score ( KOOS ) at 36 months ( 82.9 % vs 62.0 % ; p = 0.048 ) and the proportion of good structural repair/presence of hyaline cartilage based on International Cartilage Repair Society ( ICRS II ) visual item at 12 months ( 44.9 % vs 23.2 % ; p= 0.023 ) . Utility scores by surgery outcome were derived from the SF-36 question naire responses collected in the RCT . Conservative assumptions related to the incidences of OA , TKR and prosthesis revision relied on a literature search . A patient chart review ( n = 82 ) provided follow-up costs by surgery outcome . National tariffs were applied to direct medical re sources used ( healthcare payer perspective , year 2008 costs ) . Annual discounting was applied to costs ( 3 % ) and effects ( 1.5 % ) as recommended by the Belgian pharmacoeconomic guidelines . Results : The incremental cost per QALY gained for CC compared with MFX was € 16 229 , with a difference in costs of € 20 802 and 1.282 QALYs gained . Sensitivity analyses indicated that the key model drivers were the proportion of patients with hyaline cartilage and the correlation between hyaline cartilage formation and later avoidance of OA . Probabilistic sensitivity analyses showed robustness of the results , with 80 % of the simulations below the usual UK National Institute for Health and Clinical Excellence ( NICE ) threshold of € 22 000 per QALY . Conclusions : Assuming a good correlation between high- quality cartilage repair and avoidance of OA at a later stage , the benefits of the cell therapy CC over MFX in terms of QALYs gained and OA-related costs avoided appear real . Further research is required to explore long-term effects of cartilage repair and reduce uncertainty on quality of life of patients with OA before and after joint replacement [22637204] BACKGROUND Despite introduction of autologous chondrocyte therapy for repair of hyaline articular cartilage injury in 1994 , microfracture remains a primary st and ard of care . NeoCart , an autologous cartilage tissue implant , was compared with microfracture in a multisite prospect i ve , r and omized trial of a tissue-engineered bioimplant for treating articular cartilage injuries in the knee . METHODS Thirty patients were r and omized at a ratio of two to one ( two were treated with an autologous cartilage tissue implant [ NeoCart ] for each patient treated with microfracture ) at the time of arthroscopic confirmation of an International Cartilage Repair Society ( ICRS ) grade -III lesion(s ) . Microfracture or cartilage biopsy was performed . NeoCart , produced by seeding a type-I collagen matrix scaffold with autogenous chondrocytes and bioreactor treatment , was implanted six weeks following arthroscopic cartilage biopsy . St and ard evaluations were performed with vali date d clinical outcomes measures . RESULTS Three , six , twelve , and twenty-four-month data are reported . The mean duration of follow-up ( and st and ard deviation ) was 26 ± 2 months . There were twenty-one patients in the NeoCart group and nine in the microfracture group . The mean age ( 40 ± 9 years ) , body mass index ( BMI ) ( 28 ± 4 kg/m2 ) , duration between the first symptoms and treatment ( 3 ± 5 years ) , and lesion size ( 287 ± 138 mm2 in the NeoCart group and 252 ± 135 mm2 in the microfracture group ) were similar between the groups . Adverse event rates per procedure did not differ between the treatment arms . The scores on the Short Form-36 ( SF-36 ) , Knee Injury and Osteoarthritis Outcome Score ( KOOS ) activities of daily living ( ADL ) scale , and International Knee Documentation Committee ( IKDC ) form improved from baseline ( p < 0.05 ) to two years postoperatively in both treatment groups . In the NeoCart group , improvement , compared with baseline , was significant ( p < 0.05 ) for all measures at six , twelve , and twenty-four months . Improvement in the NeoCart group was significantly greater ( p < 0.05 ) than that in the microfracture group for the KOOS pain score at six , twelve , and twenty-four months ; the KOOS symptom score at six months ; the IKDC , KOOS sports , and visual analog scale ( VAS ) pain scores at twelve and twenty-four months ; and the KOOS quality of life ( QOL ) score at twenty-four months . Analysis of covariance ( ANCOVA ) at one year indicated that the change in the KOOS pain ( p = 0.016 ) and IKDC ( p = 0.028 ) scores from pretreatment levels favored the NeoCart group . Significantly more NeoCart-treated patients ( p = 0.0125 ) had responded to therapy ( were therapeutic responders ) at six months ( 43 % versus 25 % in the microfracture group ) and twelve months ( 76 % versus 22 % in the microfracture group ) . This trend continued , as the proportion of NeoCart-treated patients ( fifteen of nineteen ) who were therapeutic responders at twenty-four months was greater than the proportion of microfracture-treated participants ( four of nine ) who were therapeutic responders at that time . CONCLUSIONS This r and omized study suggests that the safety of autologous cartilage tissue implantation , with use of the NeoCart technique , is similar to that of microfracture surgery and is associated with greater clinical efficacy at two years after treatment [25031368] BACKGROUND Osteoarthritis of the knee is commonly diagnosed and monitored with radiography . However , the reliability of radiographic classification systems for osteoarthritis and the correlation of these classifications with the actual degree of confirmed degeneration of the articular cartilage of the tibiofemoral joint have not been adequately studied . METHODS As the Multicenter ACL ( anterior cruciate ligament ) Revision Study ( MARS ) Group , we conducted a multicenter , prospect i ve longitudinal cohort study of patients undergoing revision surgery after anterior cruciate ligament reconstruction . We followed 632 patients who underwent radiographic evaluation of the knee ( an anteroposterior weight-bearing radiograph , a posteroanterior weight-bearing radiograph made with the knee in 45 ° of flexion [ Rosenberg radiograph ] , or both ) and arthroscopic evaluation of the articular surfaces . Three blinded examiners independently grade d radiographic findings according to six commonly used systems-the Kellgren-Lawrence , International Knee Documentation Committee , Fairbank , Br and t et al. , Ahlbäck , and Jäger-Wirth classifications . Interobserver reliability was assessed with use of the intraclass correlation coefficient . The association between radiographic classification and arthroscopic findings of tibiofemoral chondral disease was assessed with use of the Spearman correlation coefficient . RESULTS Overall , 45 ° posteroanterior flexion weight-bearing radiographs had higher interobserver reliability ( intraclass correlation coefficient = 0.63 ; 95 % confidence interval , 0.61 to 0.65 ) compared with anteroposterior radiographs ( intraclass correlation coefficient = 0.55 ; 95 % confidence interval , 0.53 to 0.56 ) . Similarly , the 45 ° posteroanterior flexion weight-bearing radiographs had higher correlation with arthroscopic findings of chondral disease ( Spearman rho = 0.36 ; 95 % confidence interval , 0.32 to 0.39 ) compared with anteroposterior radiographs ( Spearman rho = 0.29 ; 95 % confidence interval , 0.26 to 0.32 ) . With respect to st and ards for the magnitude of the reliability coefficient and correlation coefficient ( Spearman rho ) , the International Knee Documentation Committee classification demonstrated the best combination of good interobserver reliability and medium correlation with arthroscopic findings . CONCLUSIONS The overall estimates with the six radiographic classification systems demonstrated moderate ( anteroposterior radiographs ) to good ( 45 ° posteroanterior flexion weight-bearing radiographs ) interobserver reliability and medium correlation with arthroscopic findings . The International Knee Documentation Committee classification assessed with use of 45 ° posteroanterior flexion weight-bearing radiographs had the most favorable combination of reliability and correlation . LEVEL OF EVIDENCE Diagnostic Level I. See Instructions for Authors for a complete description of levels of evidence [20692745] BACKGROUND Matrix-induced autologous chondrocyte implantation is a technique for repairing articular cartilage defects in the knee . Despite reported improvements in pain , little is known about the recovery of knee biomechanics during walking gait . METHODS A r and omized controlled study design was used to investigate knee biomechanics during gait in 61 patients following matrix-induced autologous chondrocyte implantation , in conjunction with either ' accelerated ' or ' traditional ' approaches to post-operative weight-bearing rehabilitation . Gait analysis was performed at 3 , 6 and 12 months post-surgery in both patient groups , and two matched , unaffected control groups for comparison . FINDINGS The spatiotemporal and ground reaction force parameters were similar between patient groups and their respective control groups at all time points . When compared with controls , both patient groups demonstrated significantly reduced knee extension moments up until , and including , 12 months . The traditional group demonstrated a significantly reduced knee adduction moment at 3 , 6 and 12 months , and a significantly reduced knee flexion moment at 3 months . There were no differences in these knee moments between the accelerated patient group and controls . INTERPRETATION Overall , a higher level of gait dysfunction was observed in patients who underwent traditional rehabilitation . Future research is needed to investigate the recovery of normal gait following matrix-induced autologous chondrocyte implantation , and its effect on repair tissue development [23880403] Background : Matrix-induced autologous chondrocyte implantation ( MACI ) has become an established technique for the repair of full-thickness chondral defects in the knee , although best patient outcomes appear limited by a lack of evidence -based knowledge on how to progressively increase postoperative weightbearing ( WB ) and rehabilitation exercises . Hypothesis : To determine the safety and efficacy of an accelerated WB regimen after MACI in the tibiofemoral joint . Study Design : R and omized controlled trial ; Level of evidence , 1 . Methods : Clinical and radiological assessment s were performed in 28 knees at 12 months after MACI to the medial or lateral femoral condyle . Both rehabilitation interventions sought to protect the implant for an initial period and then incrementally increase load bearing . Under the “ accelerated ” ( AR ) protocol , patients reached full WB at 6 weeks after surgery compared with 8 weeks for what was considered to be the current “ best practice ” ( CR ) WB regimen based on previous research . Assessment s included the Knee Injury and Osteoarthritis Outcome Score ( KOOS ) , 36-Item Short Form Health Survey ( SF-36 ) , visual analog scale , 6-minute walk test , and active knee range of motion ( ROM ) . High-resolution magnetic resonance imaging ( MRI ) was used to describe the quality and quantity of repair tissue via the assessment of pertinent parameters of graft repair as well as an MRI composite score . Results : Patients in both groups demonstrated significant improvement ( P < .05 ) in all clinical measures over the preoperative and postoperative timeline from before surgery to 12 months after surgery . The AR group reported significantly better ( P < .05 ) SF-36 physical component scores at 8 weeks and significantly greater ( P < .05 ) KOOS quality of life scores at 6 and 12 months postoperatively . Although no differences ( P > .05 ) were observed between the 2 groups for active knee ROM , the AR group did achieve full active knee extension as early as 4 weeks compared with the CR group at 12 weeks . There was no difference ( P > .05 ) in graft quality as assessed by MRI ( MOCART composite score : AR , 3.34 ; CR , 3.04 ) , with no patients suffering any adverse effects from the implant up to 12 months , regardless of the rehabilitation protocol employed . Conclusion : The AR approach that reduced the length of time spent ambulating on crutches result ed in improved general physical function and quality of life and an earlier attainment of full active knee extension when compared with the CR approach . There were no graft complications ascertained through MRI . This regimen appears safe and may potentially speed up the recovery of normal gait function . A larger patient cohort and follow-up are required to observe long-term graft outcomes [19653049] Young patients with early osteoarthritis wishing to remain functionally active have limited treatment options . Existing studies examining the use of autologous chondrocyte implantation ( ACI ) have included patients with early degenerative changes ; however , none specifically investigated the outcome of ACI with this challenging problem . We prospect ively followed 153 patients ( 155 knees ) for up to 11 years after treatment with ACI for early-stage osteoarthritis . Patient pain and function was assessed using WOMAC , modified Cincinnati , SF-36 , Knee Society score , and a satisfaction question naire . Mean patient age was 38.3 years . On average , 2.1 defects were treated per knee ; the mean defect size was 4.9 cm2 and total area per knee was 10.4 cm2 . Eight percent of joints were considered treatment failures that went on to arthroplasty and the remaining patients experienced 50 % to 75 % improvement in WOMAC subscales . Our data suggest that ACI in patients with early osteoarthritis results in clinical ly relevant reductions in pain and improvement in function . At 5 years postoperatively , 92 % of patients were functioning well and were able to delay the need for joint replacement . Given the limited number of treatment options for this subset of patients , autologous chondrocyte implantation may offer improved quality of life for young osteoarthritic patients .Level of Evidence : Level IV , case series . See Guidelines for Authors for a complete description of levels of evidence [12571292] Background : Current methods used to restore the joint surface in patients with localized articular cartilage defects include transplantation of an autologous osteochondral cylinder and implantation of autologous chondrocytes . The purpose of this study was to evaluate the clinical and histological outcomes of these two techniques . Methods : We performed a prospect i ve clinical study to investigate the two-year outcomes in forty patients with an articular cartilage lesion of the femoral condyle who had been r and omly treated with either transplantation of an autologous osteochondral cylinder or implantation of autologous chondrocytes . Biopsy specimens from representative patients of both groups were evaluated with histological staining , immunohistochemistry , and scanning electron microscopy . Results : According to the postoperative Lysholm score , the recovery after autologous chondrocyte implantation was slower than that after osteochondral transplantation at six months ( p ⩽ 0.015 ) , twelve months ( p ⩽ 0.001 ) , and twenty-four months ( p ⩽ 0.012 ) . On the basis of the Meyers score and the Tegner activity score , the results were equally good with the two methods two years after treatment . Histomorphological evaluation of biopsy specimens within two years after autologous chondrocyte implantation demonstrated a complete , mechanically stable resurfacing of the defect in all patients . The tissue consisted mainly of fibrocartilage , while localized areas of hyaline-like regenerative cartilage could be detected close to the subchondral bone . Although a gap remained at the site of the transplantation in all five biopsy specimens examined as long as two years after osteochondral cylinder transplantation , histomorphological analysis and scanning electron microscopy revealed no differences between the osteochondral transplants and the surrounding original cartilage . Conclusions : Both treatments result ed in a decrease in symptoms . However , the improvement provided by the autologous chondrocyte implantation lagged behind that provided by the osteochondral cylinder transplantation . Histologically , the defects treated with autologous chondrocyte implantation were primarily filled with fibrocartilage , whereas the osteochondral cylinder transplants retained their hyaline character , although there was a persistent interface between the transplant and the surrounding original cartilage . Limitations of our study included the small number of patients , the relatively short ( two-year ) follow-up , and the absence of a control group . Level of Evidence : Therapeutic study , Level II-2 ( poor- quality r and omized controlled trial [ e.g. , < 80 % follow-up ] ) . See Instructions to Authors for a complete description of levels of evidence [23857885] Background : Sexual dimorphism in humans has already been documented at different levels , and preliminary findings also suggest the importance of patient sex on clinical outcome in the treatment of cartilage lesions . Purpose : To document and analyze the influence of sex on clinical outcome in a large cohort of patients treated with a cartilage regenerative procedure for knee chondral lesions and prospect ively followed at midterm follow-up . Study Design : Cohort study ; Level of evidence , 3 . Methods : A total of 250 knees were treated with matrix-assisted autologous chondrocyte transplantation ( MACT ) and prospect ively evaluated with International Knee Documentation Committee ( IKDC ) , EuroQol visual analog scale ( EQ-VAS ) , and Tegner scores at 1- , 2- , and minimum 5-year follow-ups to compare results obtained in men and women . The lesions were focal International Cartilage Repair Society grade III-IV chondral knee defects involving femoral condyles , trochleae , and patellae . Two homogeneous groups of 56 male patients and 56 female patients were then selected by a blinded statistician for a matched-pair analysis . Results : A statistically significant improvement in all the scores in both men and women was observed in the general population . The IKDC subjective score showed better results for men at all follow-up times : at 5 years , the mean IKDC subjective score was 79.5 ± 18.6 versus 64.3 ± 20.2 for men and women , respectively ( P < .0005 ) , and the same trend was confirmed with the EQ-VAS and Tegner scores . The matched-pair analysis confirmed the difference of final results achieved ( 74.1 ± 19.8 vs 63.7 ± 20.2 , respectively ; P = .006 ) . However , men and women started with different preoperative levels , and the analysis of the improvement obtained was not significantly different . Finally , when scores were st and ardized for each patient , according to the mean score typical for the corresponding age and sex category in a healthy population , a sex-related difference was not confirmed at any of the follow-ups . Etiological factors , lesion site , and preinjury activity level differed in women and men of the general population and were the confounding factors responsible for the different outcome not confirmed by the analysis of homogeneous cohorts of patients . Conclusion : Women have a different knee chondral lesion pattern and more often have unfavorable conditions related to the cause of injury , site , and activity level , and they also have lower raw , not st and ardized , scores . However , a matched-pair analysis with data st and ardized for the specific patient categories showed that , on equal terms , women have the same possibilities for successful outcome as men after surgical treatment for knee cartilage regeneration [17372718] A biodegradable , hyaluronian-based biocompatible scaffold was used for autologous chondrocyte transplantation . This prospect i ve study analyzes a clinical outcome of 70 consecutive patients treated by arthroscopic autologous chondrocyte transplantation at minimum 24 months follow up ( 47 of these patients achieved minimum 36 months follow-up and 21 patients minimum 48 months follow-up ) in order to establish clear indication criteria for this type of treatment . 31 of these patients presented isolated chondral lesions , while 39 patients with associated lesions ( 23 ACL lesions , 28 meniscal lesions , 1 varus knee ) were treated during the same surgical procedure with cartilage harvesting . A statistically significant clinical improvement was shown just at 24 months and the second-look arthroscopy demonstrated a complete coverage of the grafted area with a hyaline cartilage-like tissue in 12 of 15 analyzed patients . A better clinical outcome was observed in young , well-trained patients and in traumatic lesions . Other factors , such as defect size , localization , previous and associated surgery did not influence significantly the results . This matrix autologous chondrocyte transplantation procedure simplifies the surgical procedure and can be performed arthroscopically , thus reducing surgical morbidity and recovery time [19669763] This prospect i ve six-year longitudinal study review s the clinical outcome of patients undergoing autologous chondrocyte implantation ( ACI ) and a porcine type I/III collagen membrane cover for deep chondral defects of the knee . We present 57 patients ( 31 male , 26 female ) with a mean age of 31.6 years ( range 15–51 years ) that have undergone ACI since July 1998 . The mean size of the defect was 3.14 cm2 ( range 1.0–7.0 cm2 ) . All patients were assessed annually using seven independent vali date d clinical rating scores with the data analysed using ANOVA . ACI using a porcine type I/III collagen membrane cover produced statistically significant improvements ( p < 0.001 ) , maintained for up to six years , in knee symptoms compared to pre-operative levels . This study provides evidence of the medium-term benefit achieved by transplanting autologous chondrocytes to osteochondral defects [16644224] INTRODUCTION The results for autologous chondrocyte implantation ( ACI ) in the treatment of full thickness chondral defects in the knee are encouraging . At present two techniques have been described to retain the chondrocyte suspension within the defect . The first involves using a periosteal cover ( ACI-P ) and the second involves using a type I/III collagen membrane ( ACI-C ) . To the authors knowledge there are no comparative studies of these two techniques in the current literature . We have therefore undertaken such a study to establish if there is a difference between the 2 techniques based on a clinical and arthroscopic assessment . METHODS A total of 68 patients with a mean age of 30.52 years with symptomatic articular cartilage defects were r and omised to have either ACI-P ( 33 patients ) or ACI-C ( 35 patients ) . The mean defect size was 4.54 cm2 . All patients were followed up at 24 months . RESULTS A clinical and functional assessment showed that 74 % of patients had a good or excellent result following the ACI-C compared with 67 % after the ACI-P at 2 years . Arthroscopy at 1 year also demonstrated similar results for both techniques . However , 36.4 % of the ACI-P grafts required shaving for hypertrophy compared with none for the ACI-C grafts at 1 year . DISCUSSION This study has shown no statistical difference between the clinical outcome of ACI-C versus ACI-P at 2 years . A significant number of patients who had the ACI-P required shaving of a hypertrophied graft . We conclude that there is no advantage in using periosteum as a cover for retaining chondrocytes within an osteochondral defect ; as a result we advocate the use of an alternative cover such as a manufactured type I/III collagen membrane [15995447] Peterson ’s pioneering experience with the first clinical application of autologous chondrocyte implantation showed improvement in clinical outcomes , durable as much as 11 years , for a difficult patient population . An assessment of the general applicability of this technology in the United States requires long-term , multicenter followup . The purpose of this multicenter cohort study was to assess the clinical outcomes of patients treated with autologous chondrocyte implantation for lesions of the distal femur . Modified 10-point scales of the Cincinnati knee rating system were used to measure outcomes assessment s at baseline and at 5 years . Eighty-seven percent ( 87 of 100 ) of patients completed 5-year followup assessment s. Patients were an average 37 years of age , had a mean total defect size of 4.9 cm2 , and had low baseline overall condition scores . At least one prior cartilage repair procedure had failed in 70 % of the patients . At followup , 87 patients reported a mean improvement of 2.6 points in the overall condition score , including 62 with improved conditions , six with no change in condition , and 19 with worsened conditions . Of the 62 patients who improved , the mean overall condition score improved 4.1 points at followup . Patients treated with autologous chondrocyte implantation for large cartilage defects in the distal femur reported improvement in outcome scores at 5 years followup . Level of Evidence : Therapeutic study , Level II-1 ( prospect i ve cohort study ) . See the Guidelines for Authors for a complete description of levels of evidence [3313891] Background The results of R and omized Controlled Trials ( RCTs ) on time-to-event outcomes that are usually reported are median time to events and Cox Hazard Ratio . These do not constitute the sufficient statistics required for meta- analysis or cost-effectiveness analysis , and their use in secondary analyses requires strong assumptions that may not have been adequately tested . In order to enhance the quality of secondary data analyses , we propose a method which derives from the published Kaplan Meier survival curves a close approximation to the original individual patient time-to-event data from which they were generated . Methods We develop an algorithm that maps from digitised curves back to KM data by finding numerical solutions to the inverted KM equations , using where available information on number of events and numbers at risk . The reproducibility and accuracy of survival probabilities , median survival times and hazard ratios based on reconstructed KM data was assessed by comparing published statistics ( survival probabilities , medians and hazard ratios ) with statistics based on repeated reconstructions by multiple observers . Results The validation exercise established there was no material systematic error and that there was a high degree of reproducibility for all statistics . Accuracy was excellent for survival probabilities and medians , for hazard ratios reasonable accuracy can only be obtained if at least numbers at risk or total number of events are reported . Conclusion The algorithm is a reliable tool for meta- analysis and cost-effectiveness analyses of RCTs reporting time-to-event data . It is recommended that all RCTs should report information on numbers at risk and total number of events alongside KM curves [4297066] Early osteoarthritis ( OA ) is increasingly being recognized in patients who wish to remain active while not accepting the limitations of conservative treatment or joint replacement . The aim of this systematic review was to evaluate the existing evidence for treatment of patients with early OA using articular cartilage repair techniques . A systematic search was performed in EMBASE , MEDLINE , and the Cochrane collaboration . Articles were screened for relevance and appraised for quality . Nine articles of generally low method ological quality ( mean Coleman score 58 ) including a total of 502 patients ( mean age range = 36 - 57 years ) could be included . In the reports , both radiological and clinical criteria for early OA were applied . Of all patients included in this review , 75 % were treated with autologous chondrocyte implantation . Good short-term clinical outcome up to 9 years was shown . Failure rates varied from 8 % to 27.3 % . The conversion to total knee arthroplasty rate was 2.5 % to 6.5 % . Although a ( r and omized controlled ) trial in this patient category with long-term follow-up is needed , the literature suggests autologous chondrocyte implantation could provide good short- to mid-term clinical outcome and delay the need for total knee arthroplasty . The use of st and ardized criteria for early OA and implementation of ( r and omized ) trials with long-term follow-up may allow for further expansion of the research field in articular cartilage repair to the challenging population with ( early ) OA [3626217] Objectives Matrix-assisted autologous chondrocyte transplantation ( MACT ) has been developed and applied in the clinical practice in the last decade to overcome most of the disadvantages of the first generation procedures . The purpose of this systematic review is to document and analyse the available literature on the results of MACT in the treatment of chondral and osteochondral lesions of the knee . Methods All studies published in English addressing MACT procedures were identified , including those that fulfilled the following criteria : 1 ) level I-IV evidence , 2 ) measures of functional or clinical outcome , 3 ) outcome related to cartilage lesions of the knee cartilage . Results The literature analysis showed a progressively increasing number of articles per year . A total of 51 articles were selected : three r and omised studies , ten comparative studies , 33 case series and five case reports . Several scaffolds have been developed and studied , with good results reported at short to medium follow-up . Conclusions MACT procedures are a therapeutic option for the treatment of chondral lesions that can offer a positive outcome over time for specific patient categories , but high-level studies are lacking . Systematic long-term evaluation of these techniques and r and omised controlled trials are necessary to confirm the potential of this treatment approach , especially when comparing against less ambitious traditional treatments [15855365] Autologous chondrocyte implantation ( ACI ) is used widely as a treatment for symptomatic chondral and osteochondral defects of the knee . Variations of the original periosteum-cover technique include the use of porcine-derived type I/type III collagen as a cover ( ACI-C ) and matrix-induced autologous chondrocyte implantation ( MACI ) using a collagen bilayer seeded with chondrocytes . We have performed a prospect i ve , r and omised comparison of ACI-C and MACI for the treatment of symptomatic chondral defects of the knee in 91 patients , of whom 44 received ACI-C and 47 MACI grafts . Both treatments result ed in improvement of the clinical score after one year . The mean modified Cincinnati knee score increased by 17.6 in the ACI-C group and 19.6 in the MACI group ( p = 0.32 ) . Arthroscopic assessment s performed after one year showed a good to excellent International Cartilage Repair Society score in 79.2 % of ACI-C and 66.6 % of MACI grafts . Hyaline-like cartilage or hyaline-like cartilage with fibrocartilage was found in the biopsies of 43.9 % of the ACI-C and 36.4 % of the MACI grafts after one year . The rate of hypertrophy of the graft was 9 % ( 4 of 44 ) in the ACI-C group and 6 % ( 3 of 47 ) in the MACI group . The frequency of re-operation was 9 % in each group . We conclude that the clinical , arthroscopic and histological outcomes are comparable for both ACI-C and MACI . While MACI is technically attractive , further long-term studies are required before the technique is widely adopted [12678357] Autologous chondrocyte implantation ( ACI ) and mosaicplasty are both cl aim ed to be successful for the repair of defects of the articular cartilage of the knee but there has been no comparative study of the two methods . A total of 100 patients with a mean age of 31.3 years ( 16 to 49 ) and with a symptomatic lesion of the articular cartilage in the knee which was suitable for cartilage repair was r and omised to undergo either ACI or mosaicplasty ; 58 patients had ACI and 42 mosaicplasty . Most lesions were post-traumatic and the mean size of the defect was 4.66 cm2 . The mean duration of symptoms was 7.2 years and the mean number of previous operations , excluding arthroscopy , was 1.5 . The mean follow-up was 19 months ( 12 to 26 ) . Functional assessment using the modified Cincinatti and Stanmore scores and objective clinical assessment showed that 88 % had excellent or good results after ACI compared with 69 % after mosaicplasty . Arthroscopy at one year demonstrated excellent or good repairs in 82 % after ACI and in 34 % after mosaicplasty . All five patellar mosaicplasties failed . Our prospect i ve , r and omised , clinical trial has shown significant superiority of ACI over mosaicplasty for the repair of articular defects in the knee . The results for ACI are comparable with those in other studies , but those for mosaicplasty suggest that its continued use is of dubious value [4462252] Objective The efficacy and safety of BST-CarGel ® , a chitosan scaffold for cartilage repair was compared with microfracture alone at 1 year during a multicenter r and omized controlled trial in the knee . This report was undertaken to investigate 5-year structural and clinical outcomes . Design The international r and omized controlled trial enrolled 80 patients , aged 18 to 55 years , with grade III or IV focal lesions on the femoral condyles . Patients were r and omized to receive BST-CarGel ® treatment or microfracture alone , and followed st and ardized 12-week rehabilitation . Co- primary endpoints of repair tissue quantity and quality were evaluated by 3-dimensional MRI quantification of the degree of lesion filling ( % ) and T2 relaxation times . Secondary endpoints were clinical benefit measured with WOMAC ( Western Ontario and McMaster Universities Osteoarthritis Index ) question naires and safety . General estimating equations were used for longitudinal statistical analysis of repeated measures . Results Blinded MRI analysis demonstrated that BST-CarGel ® -treated patients showed a significantly greater treatment effect for lesion filling ( P = 0.017 ) over 5 years compared with microfracture alone . A significantly greater treatment effect for BST-CarGel ® was also found for repair tissue T2 relaxation times ( P = 0.026 ) , which were closer to native cartilage compared to the microfracture group . BST-CarGel ® and microfracture groups showed highly significant improvement at 5 years from pretreatment baseline for each WOMAC subscale ( P < 0.0001 ) , and there were no differences between the treatment groups . Safety was comparable for both groups . Conclusions BST-CarGel ® was shown to be an effective mid-term cartilage repair treatment . At 5 years , BST-CarGel ® treatment result ed in sustained and significantly superior repair tissue quantity and quality over microfracture alone . Clinical benefit following BST-CarGel ® and microfracture treatment were highly significant over baseline levels [4297098] Objective : To compare the responsiveness of six common patient-reported outcomes ( PROs ) following autologous chondrocyte implantation ( ACI ) . Design : A systematic search was conducted to identify reports of PROs following ACI . Study quality was evaluated using the modified Coleman Methodology Score ( mCMS ) . For each outcome score , pre- to postoperative paired Hedge ’s g effect sizes were calculated with 95 % confidence intervals ( CIs ) . R and om effects meta-analyses were performed to provide a summary response for each PRO at time points ( TP ) I ( < 1 year ) , II ( 1 year to < 2 years ) , III ( 2 years to < 4 years ) , IV ( ≥4 years ) , and overall . Results : The mean mCMS for the 42 articles included was 50.9 ± 9.2 . For all evaluated instruments , none of the mean effect size CIs encompassed zero . The International Knee Documentation Committee Subjective Knee Form ( IKDC ) had increasing responsiveness over time with TP-IV , demonstrating greater mean effect size [ confidence interval ] ( 1.78 [ 1.33 , 2.24 ] ) than TP-I ( 0.88 [ 0.69 , 1.07 ] ) . The Knee Injury and Osteoarthritis Outcome Score – Sports and recreation subscale ( KOOS-Sports ) was more responsive at TP-III ( 1.76 [ 0.87 , 2.64 ] ) and TP-IV ( 0.98 [ 0.81 , 1.15 ] ) than TP-I ( 0.61 [ 0.44 , 0.78 ] ) . Overall , the Medical Outcomes Study 36-Item Short Form Health Survey Physical Component Scale ( 0.60 [ 0.46 , 0.74 ] ) was least responsive . Both the Lysholm Scale ( 1.42 [ 1.14 , 1.72 ] ) and the IKDC ( 1.37 [ 1.13 , 1.62 ] ) appear more responsive than the KOOS-Sports ( 0.90 [ 0.73 , 1.07 ] ) . All other KOOS subscales had overall effect sizes ranging from 0.90 ( 0.74 , 1.22 ) ( Symptoms ) to 1.15 ( 0.76 , 1.54 ) ( Quality of Life ) . Conclusions : All instruments were responsive to improvements in function following ACI . The Lysholm and IKDC were the most responsive instruments across time . IKDC and KOOS-Sports may be more responsive to long-term outcomes , especially among active individuals [25416965] Abstract Purpose To evaluate the long-term clinical outcome after microfracture treatment of focal chondral defects of the knee and to investigate possible early determinants of the outcome . Methods A prospect i ve cohort of 110 patients , treated with microfracture , was evaluated at a median of 12 years ( range 10–14 ) by Lysholm score , VAS of knee function and VAS of knee pain . Pre- and perioperative information was collected , and additional surgery to the same knee during the follow-up period was recorded . Analysis of variance and paired t test were used for comparison of the long-term data to results from the baseline examination and a former 5-year ( midterm ) follow-up evaluation . Results Forty-three patients needed additional surgery to the knee including seven knee replacements . Fifty had a poor long-term outcome —defined as a knee replacement surgery or Lysholm score below 64 . A poor result was more common in subgroups with mild degenerative changes in the cartilage surrounding the treated defect , concurrent partial meniscectomy , poor baseline Lysholm score or long-st and ing knee symptoms . The Lysholm score , function VAS and pain VAS all significantly improved from the baseline values to the mean scores of 65 ( SD 24 ) , 65 ( SD 24 ) and 31 ( SD 24 ) , respectively , at the long-term evaluation . The long-term scores did not differ significantly from the midterm scores . Conclusions The outcome scores improved significantly from baseline to the long-term evaluation and were not different from the midterm outcome . Still , a normal knee function was generally not achieved , and many patients had further surgery . The results call for more research and , at present , caution in recommending microfracture in articular cartilage defects , especially in subgroups with worse prognosis . Level of evidence Case series , Level IV [19059899] Background Various approaches have been proposed to treat articular cartilage lesions , which are plagued by inherent limited healing potential . Purpose To compare the clinical outcome of patients treated with second-generation autologous chondrocyte implantation implants with those treated with the microfracture repair technique at 5-year follow-up . Study Design Cohort study ; Level of evidence , 2 . Methods Eighty active patients ( mean age , 29.8 years ) and grade III to IV cartilage lesions of the femoral condyles or trochlea were treated with arthroscopic second-generation autologous chondrocyte implantation Hyalograft C or microfracture ( 40 patients per group ) . Patients achieved a minimum 5-year follow-up and were prospect ively evaluated . Results Both groups showed statistically significant improvement of all clinical scores from preoperative interval to 5-year follow-up . There was a significant improvement for the International Knee Documentation Committee subjective score from preoperative to 5-year follow-up ( Wilcoxon test , P < .001 ) . In the microfracture group , the International Knee Documentation Committee objective score increased from 2.5 % normal and nearly normal knees before the operation to 75 % normal and nearly normal knees at 5-year follow-up , and the subjective score increased from 41.1 ± 12.3 preoperatively to 70.2 ± 14.7 at 5-year follow-up . In the group treated with Hyalograft C , the International Knee Documentation Committee objective score increased from 15 % normal and nearly normal knees before the operation to 90 % normal and nearly normal knees at 5-year follow-up , and its subjective score increased from 40.5 ± 15.2 preoperatively to 80.2 ± 19.1 at 5-year follow-up ( Wilcoxon test , P < .001 ) . When comparing the groups , better improvement of the International Knee Documentation Committee objective ( P < .001 ) and subjective ( P = .003 ) scores was observed in the Hyalograft C group at 5-year follow-up . The return to sports at 2 years was similar in both groups and remained stable after 5 years in the Hyalograft C group ; it worsened in the microfracture group . Conclusion Both methods have shown satisfactory clinical outcome at medium-term follow-up . Better clinical results and sport activity resumption were noted in the group treated with second-generation autologous chondrocyte transplantation [20062969] Cartilage defects occur in approximately 12 % of the population and can result in significant function impairment and reduction in quality of life . Evidence for the variety of surgical treatments available is inconclusive . This study aim ed to compare the clinical outcomes of patients with symptomatic cartilage defects treated with matrix-induced autologous chondrocyte implantation ( MACI ™ or microfracture ( MF ) . Included patients were ≥18 and ≤50 years of age with symptomatic , post-traumatic , single , isolated chondral defects ( 4–10 cm2 ) and were r and omised to receive MACI ™ or MF . Patients were followed up 8–12 , 22–26 and 50–54 weeks post-operatively for efficacy and safety evaluation . Outcome measures were the Tegner , Lysholm and ICRS scores . Sixty patients were included in a r and omised study ( 40 MACI ™ , 20 MF ) . The difference between baseline and 24 months post-operatively for both treatment groups was significant for the Lysholm , Tegner , patient ICRS and surgeon ICRS scores ( all P < 0.0001 ) . However , MACI ™ was significantly more effective over time ( 24 months versus baseline ) than MF according to the Lysholm ( P = 0.005 ) , Tegner ( P = 0.04 ) , ICRS patient ( P = 0.03 ) and ICRS surgeon ( P = 0.02 ) scores . There were no safety issues related to MACI ™ or MF during the study . MACI ™ is superior to MF in the treatment of articular defects over 2 years . MACI ™ and MF are complementary procedures , depending on the size of the defect and symptom recurrence . The MACI ™ technique represents a significant advance over both first and second generation chondrocyte-based cartilage repair techniques for surgeons , patients , health care institutions and payers in terms of reproducibility , safety , intraoperative time , surgical simplicity and reduced invasiveness [24051505] Abstract Purpose Microfracture is a well-established treatment procedure for chondral defects in high-dem and population with good short-term results . The purpose of our study was to evaluate long-term clinical outcome of microfracture treatment in athletes with full-thickness chondral defects . Methods Between 1991 and 2001 , 170 patients were treated with microfracture for full-thickness knee chondral lesions at our institute and 67 of them were included in this study and prospect ively followed up . Sixty-one athletes ( 91 % ) were available at final follow-up ( average 15.1 years ) . Average lesion size was 401 ± 27 mm2 . Lysholm , Tegner and International Knee Documentation Committee ( IKDC ) ( subjective– objective ) scores were utilized pre-operatively and at 2-year , 5-year and final follow-up ; Knee injury and Osteoarthritis Outcome Score ( KOOS ) , visual analog scale ( VAS ) and Marx scores were also collected at final follow-up . Results IKDC , Lysholm and Tegner scores increased significantly at 2 years , but gradually deteriorated at long term ; however , average scores were significantly above baseline at final follow-up . Seven patients ( 11 % ) were considered as failures as they underwent another operation because of reinjury or persistent pain during the first 5 years . Pain and swelling during strenuous activities was reported only in nine patients by the end of 2 years and in 35 patients at final follow-up . Patients with smaller lesions ( ≤400 mm² ) and younger patients ( ≤30 years ) showed significantly better results in KOOS , VAS and Marx scores . Radiographs performed at final follow-up showed evidence of progression of osteoarthritis changes in 40 % of the knees , with higher rate in older patients with large or multiple lesions ( p < 0.05 ) . Conclusions Microfracture when applied in young patients with smaller lesions can offer good clinical results at short- and long-term follow-up ; lesion size is more important prognostic factor of outcome than age . Deterioration of the clinical outcome should be expected after 2 and 5 years post-treatment , and degenerative changes are present at long-term follow-up , with higher rate in older athletes with large , multiple lesions . Level of evidence IV [16110716] OBJECTIVES Chondral defects of the knee cartilage are prevalent . Autologous chondrocyte implantation ( ACI ) and mosaicplasty are increasingly used to treat symptomatic knee defects . This study assessed the costs and health status outcomes after ACI and mosaicplasty . METHODS Patients were eligible to participate in this cross-sectional study if they received ACI or mosaicplasty at the Royal National Orthopaedic Hospital between 1997 and 2001 or were on a waiting list for ACI . Secondary -care re source use was collected to 2 years postoperatively using a re source collection proforma . Participants responded to postal questions about sociodemographic characteristics and knee-related ( Modified Cincinnati Knee Rating System ) and general health status ( EQ-5D ) . RESULTS Fifty-three ACI , twenty mosaicplasty , and twenty-two patients waiting for ACI participated . The average cost per patient was higher for ACI ( 10,600 pounds sterling : 95 percent confidence interval [ CI ] , 10,036 pounds sterling-11,214 pounds sterling ) than mosaicplasty ( 7,948 pounds sterling : 95 percent CI , 6,957 pounds sterling-9,243 pounds sterling ) . Postoperatively , ACI and mosaicplasty patients ( combined ) experienced better health status than those waiting for ACI . ACI patients tended to have better health status outcomes than mosaicplasty patients ( not statistically significant ) . Estimated average EQ-5D social tariff improvements for quality -adjusted life year ( QALY ) calculations were 0.23 ( ACI ) and 0.06 ( mosaicplasty ) . Average costs per QALY were 23,043 pounds sterling ( ACI ) and 66,233 pounds sterling ( mosaicplasty ) . The incremental cost effectiveness ratio ( ICER ) for providing ACI over mosaicplasty was 16,349 pounds sterling . CONCLUSIONS Average costs were higher for ACI than mosaicplasty . However , both the estimated cost per QALY and ICER for providing ACI over mosaicplasty fell beneath an implicit English funding threshold of 30,000 pounds sterling per QALY . Prospect i ve studies should include measures of utility to confirm the estimated cost utility ratios of ACI and mosaicplasty [23024150] Background : Various techniques have proven to be effective for treating articular cartilage defect ( ACD ) and osteochondral defect ( OCD ) of the knee joint , but knowledge regarding which method is best still remains uncertain . Purpose : To evaluate and compare the outcomes of mosaic-type osteochondral autologous transplantation ( OAT ) and microfracture ( MF ) procedures for the treatment of articular cartilage defects of the knee joint in young active athletes . This article represents an up date of the clinical results at 10 years . Study Design : R and omized controlled trial ; Level of evidence , 1 . Methods : Between 1998 and 2002 , a total of 60 athletes with a mean age of 24.3 years ( range , 15 - 40 years ) and with a symptomatic ACD or OCD in the knee were r and omized to undergo either OAT or MF . Patients were then evaluated postoperatively using the International Cartilage Repair Society ( ICRS ) score , Tegner activity score , radiographs , and magnetic resonance imaging . The mean follow-up time was 10.4 years ( range , 9 - 11 years ) . Results : Three to 10 years after the OAT and MF procedures , patients had lower ICRS and Tegner scores ( P < .05 ) , but both groups still had significant clinical improvement over presurgery scores according to ICRS scores at 10-year follow-up . Statistically significantly better results were detected in patients in the OAT group compared with those in the MF group at 10 years ( P < .005 ) . At 10-year follow-up , there were 15 failures ( 26 % ) , including 4 failures ( 14 % ) of the OAT and 11 failures ( 38 % ) of MF treatment ( P < .05 ) . Seven patients ( 25 % ) from the OAT group and 14 patients ( 48 % ) from the MF group had radiographic evidence of Kellgren-Lawrence grade I osteoarthritis at 10 years , but these differences were not significant ( P = .083 ) or related to the clinical results . The ICRS and Tegner scores of younger athletes ( < 25 years at the time of primary surgery ) remained significantly higher after 10 years compared with older patients ( P < .05 ) ; 15 of 20 patients ( 75 % ) in the OAT group and 8 of 22 patients ( 37 % ) in the MF group maintained the same physical activity level . Conclusion : The OAT technique for ACD or OCD repair in the athletic population allows for a higher rate of return to and maintenance of sports at the preinjury level compared with MF [22637203] BACKGROUND There is limited information regarding direct comparisons of the outcome of osteochondral autograft transfer ( OAT ) mosaicplasty and microfracture for the treatment of isolated articular cartilage defects of the knee . The purpose of this retrospective comparative study was to compare the general health outcomes , knee function , and Marx Activity Rating Scale scores for patients treated with OAT or microfracture for symptomatic chondral defects of the femoral condyles or trochlea . We hypothesized that the patients in the two treatment groups would have similar clinical outcomes at intermediate-term follow-up . METHODS Ninety-six patients with full-thickness cartilage defects of the femoral condyles or trochlea were treated with either OAT mosaicplasty ( n = 48 ) or microfracture ( n = 48 ) . The average age of the patients ( thirty-two male and sixteen female in each group ) at the time of surgery was 29.7 years in the OAT group and 32.5 years in the microfracture group . Patients were prospect ively evaluated at baseline and at one , two , three , and five years postoperatively with use of vali date d clinical outcome measures including the Short Form-36 ( SF-36 ) physical component , International Knee Documentation Committee ( IKDC ) , Knee Outcome Survey activities of daily living , and Marx Activity Rating Scale instruments . Comparisons between outcomes before and after treatment or between outcomes after microfracture and mosaicplasty were made with use of two-tailed tests . RESULTS At the time of the latest follow-up , both groups demonstrated significant increases in SF-36 physical component , Knee Outcome Survey activities of daily living , and IKDC scores compared with baseline . These scores did not differ significantly between the two groups at any of the follow-up time points . However , the OAT group demonstrated a significantly greater improvement in the Marx Activity Rating Scale scores from baseline to the two-year ( p = 0.001 ) , three-year ( p = 0.03 ) , and five-year ( p = 0.02 ) time points compared with the microfracture group . CONCLUSIONS In the present retrospective comparative study , the hypothesis that patients treated with microfracture or OAT mosaicplasty for symptomatic articular cartilage defects of the femoral condyles or trochlea would have similar clinical outcomes at intermediate-term follow-up was affirmed for general health outcome and for knee function . However , patients treated with OAT mosaicplasty maintained a superior level of athletic activity compared with those treated with microfracture [10513484] OBJECTIVE To investigate the relationship between anxiety and depression and reporting of knee pain in the community . METHODS Subjects ( n = 374 ) were community volunteers aged 40 years and above who are participants in the Baltimore Longitudinal Study of Aging , a prospect i ve multidisciplinary research study of normative aging . Knee pain was defined by the First National Health and Nutrition Examination Survey question " have you ever had pain in or around your knee on most days for at least one month ? " ; anxiety and depression were measured by the relevant subscales of the Arthritis Impact Measurement Scales question naire . All subjects had st and ing anteroposterior radiographs , read for Kellgren and Lawrence ( K + L ) grade . RESULTS After adjustment for age , women reporting " ever " knee pain had significantly higher anxiety scores than those reporting " never " pain ( 3.06 + /- 0.26 versus 2.35 + /- 0.17 ; P = 0.025 ) . Pain reporting was related neither to anxiety scores in men , nor to depression in either sex . Analysis stratified by radiographic severity , adjusted for age and gender , showed that differences in anxiety were confined to those reporting knee pain in the absence of radiographic change ( i.e. , K + L grade 0 ) . CONCLUSIONS In the community , women reporting knee pain in the absence of radiographic osteoarthritis have higher anxiety scores than those without pain . Depression was not significantly related to knee pain in this population . Psychosocial factors may explain some of the discrepancy between reported knee pain and structural change as seen on x-ray [15663280] Abstract Aim of the study : To compare outcomes of surgical treatment of deep cartilage defects of the knee in a group of patients treated by autologous chondrograft transplantation versus patients treated by abrasive techniques . Material s and methods : An original method of chondrograft preparation based on cultivated autologous chondrocytes in a three-dimensional carrier-fibrin glue ( Tissucol , Baxter , Austria ) has been described . Pre clinical tests in human cadavres and porcine models have established the possibility of chondrograft use in humans . Of the 50 patients included in the study , 25 patients ( 50 % ) underwent autologous chondrograft transplantation ( group I ) and 25 patients ( 50 % ) were treated using abrasive techniques according to Johnson ( group II ) . These two groups were similar with respect to age , size of defect , depth and localization , and presence of concomitant knee injuries . The Lysholm knee and IKDC ( International Knee Documentation Committee ) subjective scores were used to evaluate the results . Results : The preoperative value of the Lysholm knee score for patients in group I was 47.60 points ; 5 months after surgery 77.20 points ; and 12 months after surgery 86.48 points . The values for the Lysholm knee score for patients in group II preoperatively , 5 months postop , and 12 months postop were 52.60 , 69.20 , and 74.48 respectively . Results 12 months after surgery were significantly better in group I as compared to group II ( p < 0.001 ) . The preoperative value of the IKDC subjective score in group I was 41.28 points ; 5 months after surgery 67.00 points ; and 12 months after surgery 76.48 points . The values for the IKDC subjective score in group II preoperatively , 5 months postop , and 12 months postop were 45.00 , 62.28 , and 68.08 respectively . Results 12 months after surgery were significantly better in group I when compared to group II ( p < 0.05 ) . Conclusions : The results obtained in this study have confirmed the better outcome in patients treated with autologous chondrograft transplantation . This original method was found to be just as effective as abrasive techniques . We recommend its use in clinical practice [21908720] Background : Characterized chondrocyte implantation ( CCI ) results in significantly better early structural tissue regeneration than microfracture ( MF ) , and CCI has a midterm clinical benefit over microfracture . Purpose : This study was undertaken to evaluate the 5-year clinical outcome of CCI in a r and omized comparison with MF for the treatment of symptomatic cartilage defects of the femoral condyles of the knee . Study Design : R and omized controlled trial ; Level of evidence , 1 . Methods : Participants aged 18 to 50 years with a symptomatic isolated International Cartilage Repair Society ( ICRS ) grade III or IV cartilage lesion of the femoral condyles between 1 and 5 cm2 were r and omized to either CCI or MF . Clinical outcomes were measured up to 60 months after surgery using the Knee Injury and Osteoarthritis Outcome Score ( KOOS ) . The main outcome parameter was change from baseline in overall KOOS ( oKOOS ) . Adverse events were monitored . Results : Fifty-one participants were treated with CCI and 61 with MF . On average , clinical benefit was maintained through the 60-month follow-up period . The average change from baseline in oKOOS was not different between both groups ( least squares [ LS ] mean ± st and ard error [ SE ] 18.84 ± 3.58 for CCI vs 13.21 ± 5.63 for MF ; P = .116 ) . Treatment failures were comparable ( n = 7 in CCI vs n = 10 in MF ) , although MF failures tended to occur earlier . Subgroup analysis revealed that CCI result ed in better outcome in participants with time since symptom onset of less than 3 years , which was statistically significant and clinical ly relevant ( change in oKOOS <3 years mean ± SE 25.96 ± 3.45 for CCI vs 15.28 ± 3.17 for MF ; P = .026 vs oKOOS > 3 years mean ± SE 13.09 ± 4.78 for CCI vs 17.02 ± 4.50 for MF , P = .554 ) . Other subgroup analyses such as age ( cutoff 35 years ) did not show a difference . Female patients showed more failures irrespective of treatment . Conclusion : At 5 years after treatment , clinical outcomes for CCI and MF were comparable . In the early treatment group , CCI obtained statistically significant and clinical ly relevant better results than MF . Delayed treatment result ed in less predictable outcomes for CCI . These results provide strong evidence that time since onset of symptoms is an essential variable that should be taken into account in future treatment algorithms for cartilage repair of the knee [24714783] Background : R and omized controlled trials study ing the efficacy and safety of matrix-applied characterized autologous cultured chondrocytes ( MACI ) versus microfracture ( MFX ) for treating cartilage defects are limited . Purpose : To compare the clinical efficacy and safety of MACI versus MFX in the treatment of patients with symptomatic cartilage defects of the knee . Study Design : R and omized controlled clinical trial ; Level of evidence , 1 . Methods : Patients enrolled in the SUMMIT ( Demonstrate the Superiority of MACI implant to Microfracture Treatment ) trial had ≥1 symptomatic focal cartilage defect ( Outerbridge grade III or IV ; ≥3 cm2 ) of the femoral condyles or trochlea , with a baseline Knee Injury and Osteoarthritis Outcome Score ( KOOS ) pain value < 55 . The co– primary efficacy endpoint was the change in the KOOS pain and function subscores from baseline to 2 years . Histological evaluation and magnetic resonance imaging ( MRI ) assessment s of structural repair tissue , treatment failure , the remaining 3 KOOS subscales , and safety were also assessed . Results : Of the 144 patients treated , 137 ( 95 % ) completed the 2-year assessment . Patients had a mean age of 33.8 years and a mean lesion size of 4.8 cm2 . The mean KOOS pain and function subscores from baseline to 2 years were significantly more improved with MACI than with MFX ( pain : MACI , 37.0 to 82.5 vs MFX , 35.5 to 70.9 ; function : MACI , 14.9 to 60.9 vs MFX , 12.6 to 48.7 ; P = .001 ) . A significant improvement in scores was also observed on the KOOS subscales of activities of daily living ( MACI , 43.5 to 87.2 vs MFX , 42.6 to 75.8 ; P < .001 ) , knee-related quality of life ( MACI , 18.8 to 56.2 vs MFX , 17.2 to 47.3 ; P = .029 ) , and other symptoms ( MACI , 48.3 to 83.7 vs MFX , 44.4 to 72.2 ; P < .001 ) for patients treated with MACI compared with MFX . Repair tissue quality was good as assessed by histology/MRI , but no difference was shown between treatments . A low number of treatment failures ( nonresponders : MACI , 12.5 % vs MFX , 31.9 % ; P = .016 ) and no unexpected safety findings were reported . Conclusion : The treatment of symptomatic cartilage knee defects ≥3 cm2 in size using MACI was clinical ly and statistically significantly better than with MFX , with similar structural repair tissue and safety , in this heterogeneous patient population . Moreover , MACI offers a more efficacious alternative than MFX with a similar safety profile for the treatment of symptomatic articular cartilage defects of the knee [19846694] Background Damaged articular cartilage has limited capacity for self-repair . Autologous chondrocyte implantation using a characterized cell therapy product results in significantly better early structural repair as compared with microfracture in patients with symptomatic joint surface defects of the femoral condyles of the knee . Purpose To evaluate clinical outcome at 36 months after characterized chondrocyte implantation ( CCI ) versus microfracture ( MF ) . Study Design R and omized controlled trial ; Level of evidence , 1 . Methods Patients aged 18 to 50 years with single International Cartilage Repair Society ( ICRS ) grade III/IV symptomatic cartilage defects of the femoral condyles were r and omized to CCI ( n = 57 ) or MF ( n = 61 ) . Clinical outcome was measured over 36 months by the Knee injury and Osteoarthritis Outcome Score ( KOOS ) . Serial magnetic resonance imaging ( MRI ) scans were scored using the Magnetic resonance Observation of Cartilage Repair Tissue ( MOCART ) system and 9 additional items . Gene expression profile scores associated with ectopic cartilage formation were determined by RT-PCR . Results Baseline mean overall KOOS ( ±SE ) was comparable between the CCI and MF groups ( 56.30 ± 1.91 vs 59.46 ± 1.98 , respectively ) . Mean improvement ( ±SE ) from baseline to 36 months in overall KOOS was greater in the CCI group than the MF group ( 21.25 ± 3.60 vs 15.83 ± 3.48 , respectively ) , while in a mixed linear model analysis with time as a categorical variable , significant differences favoring CCI were shown in overall KOOS ( P = .048 ) and the subdomains of Pain ( P = .044 ) and QoL ( P = .036 ) . More CCI- than MF-treated patients were treatment responders ( 83 % vs 62 % , respectively ) . In patients with symptom onset of < 2 years , the mean improvement ( ±SE ) from baseline to 36 months in overall KOOS was greater with CCI than MF ( 24.98 ± 4.34 vs 16.50 ± 3.99 , respectively ) and even greater in patients with symptom onset of <3 years ( 26.08 ± 4.10 vs 17.09 ± 3.77 , respectively ) . Characterized chondrocyte implantation patients with high ( > 2 ) versus low ( < 2 ) gene profile scores showed greater improvement from baseline in mean overall KOOS ( ±SE ) at 36 months ( 28.91 ± 5.69 vs 18.18 ± 5.08 , respectively ) . Subchondral bone reaction significantly worsened over time with MF compared with CCI ( P < .05 ) . Conclusion Characterized chondrocyte implantation for the treatment of articular cartilage defects of the femoral condyles of the knee results in significantly better clinical outcome at 36 months in a r and omized trial compared with MF . Time to treatment and chondrocyte quality were shown to affect outcome [22539536] Background : While structured postoperative rehabilitation after matrix-induced autologous chondrocyte implantation ( MACI ) is considered critical , very little has been made available on how best to progressively increase weightbearing and exercise after surgery . Hypothesis : A significant improvement will exist in clinical and magnetic resonance imaging (MRI)–based scoring measures to 5 years after surgery . Furthermore , there will be no significant differences in outcomes in MACI patients at 5 years when comparing a traditional and an accelerated postoperative weightbearing regimen . Finally , patient demographics , cartilage defect parameters , and injury/surgery history will be associated with graft outcome . Study Design : R and omized controlled trial ; Level of evidence , 1 . Methods : Clinical and radiological outcomes were studied in 70 patients who underwent MACI to the medial or lateral femoral condyle , in conjunction with either an “ accelerated ” or a “ traditional ” approach to postoperative weightbearing rehabilitation . Under the accelerated protocol , patients reached full weightbearing at 8 weeks after surgery , compared with 11 weeks for the traditional group . Clinical measures ( Knee Injury and Osteoarthritis Outcome Score [ KOOS ] , Short-Form Health Survey [ SF-36 ] , visual analog scale [ VAS ] , 6-minute walk test , and knee range of motion ) were assessed before surgery and at 3 , 6 , 12 , and 24 months and 5 years after surgery . High-resolution MRI was undertaken at 3 , 12 , and 24 months and 5 years after surgery and assessed 8 previously defined pertinent parameters of graft repair as well as a combined MRI composite score . The association between clinical and MRI-based outcomes , patient demographics , chondral defect parameters , and injury/surgery history was investigated . Results : Of the 70 patients recruited , 63 ( 31 accelerated , 32 traditional ) underwent clinical follow-up at 5 years ; 58 ( 29 accelerated , 29 traditional ) also underwent radiological assessment . A significant time effect ( P < .05 ) was demonstrated for all clinical and MRI-based scores over the 5-year period . While the VAS demonstrated significantly less frequent pain at 5 years in the accelerated group , there were no other significant differences between the 2 groups . Between 24 months and 5 years , a significant improvement ( P < .05 ) in both groups was observed for the sport and recreation subscale of the KOOS as well as a significant decrease ( P < .05 ) in active knee extension for the traditional group . There were no significant differences ( P > .05 ) in the MRI-based scores between 24 months and 5 years after surgery . Patient age and defect size exhibited significant negative correlations ( P < .05 ) with several MRI-based outcomes at 5 years , while there were no significant correlations ( P > .05 ) between clinical and MRI-based outcomes . At 5 years after surgery , 94 % and 95 % were satisfied with the ability of MACI to relieve their knee pain and improve their ability to undertake daily activities , respectively . Conclusion : The outcomes of this r and omized trial demonstrate a safe and effective accelerated rehabilitation protocol as well as a regimen that provides comparable , if not superior , clinical outcomes to patients throughout the postoperative timeline [23142295] PURPOSE To compare the concomitant treatment of articular cartilage damage in the medial femoral condyle with osteochondral autologous transplantation ( OAT ) , microfracture , or debridement procedures at the time of anterior cruciate ligament ( ACL ) reconstruction . METHODS Between 2006 and 2009 , 102 patients with a mean age of 34.1 years and with an ACL rupture and articular cartilage damage in the medial femoral condyle of the knee were r and omized to undergo OAT , microfractures , or debridement at the time of ACL reconstruction . A matched control group was included , comprising 34 patients with intact articular cartilage at the time of ACL reconstruction . There were 34 patients in the OAT-ACL group , 34 in the microfracture (MF)-ACL group , 34 in the debridement (D)-ACL group , and 34 in the control group with intact articular cartilage ( IAC-ACL group ) . The mean time from ACL injury to operation was 19.32 ± 3.43 months , and the mean follow-up was 36.1 months ( range , 34 to 37 months ) . Patients were evaluated with the International Knee Documentation Committee ( IKDC ) score , Tegner activity score , and clinical assessment . RESULTS Of 102 patients , 97 ( 95 % ) were available for the final follow-up . According to the subjective IKDC score , all 4 groups fared significantly better at the 3-year follow-up than preoperatively ( P < .005 ) . The OAT-ACL group 's IKDC subjective knee evaluation was significantly better than that of the MF-ACL group ( P = .024 ) and D-ACL group ( P = .018 ) . However , the IKDC subjective score of the IAC-ACL group was significantly better than the OAT-ACL group 's IKDC evaluation ( P = .043 ) . There was no significant difference between the MF-ACL and D-ACL groups ' IKDC subjective scores ( P = .058 ) . Evaluation of manual pivot-shift knee laxity according to the IKDC knee examination form showed similar findings for the 4 groups immediately postoperatively and at 3-year follow-up , and the findings were rated as normal or nearly normal ( IKDC grade A or B ) in 29 of 33 patients ( 88 % ) in the OAT-ACL group , 28 of 32 patients ( 88 % ) in the MF-ACL group , 27 of 32 patients ( 84 % ) in the D-ACL group , and 31 of 34 patients ( 91 % ) in the IAC-ACL group . CONCLUSIONS Our study shows that intact articular cartilage during ACL reconstruction yields more favorable IKDC subjective scores compared with any other articular cartilage surgery type . However , if an articular defect is present , the subjective IKDC scores are significantly better for OAT versus microfracture or debridement after a mean period of 3 years . Anterior knee stability results were not significantly affected by the different articular cartilage treatment methods . LEVEL OF EVIDENCE Level II , prospect i ve comparative study [17908884] BACKGROUND The optimal treatment for cartilage lesions has not yet been established . The objective of this r and omized trial was to compare autologous chondrocyte implantation with microfracture . This paper represents an up date , with presentation of the clinical results at five years . METHODS Eighty patients who had a single chronic symptomatic cartilage defect on the femoral condyle in a stable knee without general osteoarthritis were included in the study . Forty patients were treated with autologous chondrocyte implantation , and forty were treated with microfracture . We used the International Cartilage Repair Society , Lysholm , Short Form-36 , and Tegner forms to collect clinical data , and radiographs were evaluated with use of the Kellgren and Lawrence grading system . RESULTS At two and five years , both groups had significant clinical improvement compared with the preoperative status . At the five-year follow-up interval , there were nine failures ( 23 % ) in both groups compared with two failures of the autologous chondrocyte implantation and one failure of the microfracture treatment at two years . Younger patients did better in both groups . We did not find a correlation between histological quality and clinical outcome . However , none of the patients with the best- quality cartilage ( predominantly hyaline ) at the two-year mark had a later failure . One-third of the patients in both groups had radiographic evidence of early osteoarthritis at five years . CONCLUSIONS Both methods provided satisfactory results in 77 % of the patients at five years . There was no significant difference in the clinical and radiographic results between the two treatment groups and no correlation between the histological findings and the clinical outcome . One-third of the patients had early radiographic signs of osteoarthritis five years after the surgery . Further long-term follow-up is needed to determine if one method is better than the other and to study the progression of osteoarthritis [16003035] Objective : To compare the respective performance and effectiveness of autologous chondrocyte implantation ( ACI ) and mosaicplasty at resurfacing local full-thickness chondral defects of the knee . Design : R and omized clinical trial . Setting : Multicenter trial at orthopedic clinics and university hospitals conducted from 1997 to 2000 . Patients : A population of patients selected according to eligibility criteria of age , traumatic origin of the defect , its localization , size , and gravity , and above all , no previous surgical treatment of the lesion . Forty-seven patients were r and omly assigned to ACI or mosaicplasty and subjected to arthroscopic debridement of the lesion at the time of enrollment . They were called for surgery 6 months after the initial debridement . Main Outcome : Improved knee functionality as assessed by repeated clinical evaluation based on the International Knee Documentation Committee Scale and the Lysholm Knee Scoring Scale . Results : Fourteen patients ( 31.8 % ) experienced substantial improvement following the initial debridement and , being clinical ly cured , received no further treatment . Seven patients ( 15.9 % ) were lost to follow-up . Among the 23 patients ( 52.3 % ) who could effectively be evaluated , a complete recovery ( ie , Lysholm Knee Scoring Scale score , 90 - 100 ) was observed upon clinical examination in 88 % of the mosaicplasty-treated patients and in 68 % of the ACI-treated ones ( P = 0.093 ) . Conclusions : Although the low power of our study prevents definitive conclusions , ACI and mosaicplasty are cartilage repair techniques that are clinical ly equivalent and similar in performance . The high percentage of spontaneous improvement ( ⅓ of the patients ) observed after simple debridement calls into question the need for prompt surgical treatment of patients with lesions similar to those included in this clinical trial . Moreover , this finding warrants further investigation , ideally through r and omized clinical trials in which patients subjected to debridement alone are compared with patients undergoing reconstructive surgery [15194101] Arthroscopy and washout of the knee is commonly performed for early osteoarthritis . Very little information exists regarding long-term prognosis , especially in terms of avoidance of further surgery . Using a prospect ively gathered data base , 100 consecutive patients having knee arthroscopy with a finding of OA between 1991 and 1993 were identified and their outcome at 5 years ascertained . Ninety-nine patients with 100 arthroscoped knees were identified . Fifty-eight had isolated medial compartment disease and six had isolated lateral compartment disease . In 36 , both compartments were affected . Eighteen knees had further major surgery during follow up ; 11 had total knee replacement , four had high tibial osteotomy and three had unicondylar knee arthroplasty . Those requiring surgery were significantly older ( 62 cf . 53 years , P=0.008 ) . Meniscectomy was not an important risk factor ( chi2 , P=0.67 ) . The rate of knee survival without operation at 5 years was much lower in those aged over 60 years than in those younger ( 68 % cf . 89 % ) . ( chi2 , P=0.02 ) . Only 18 % of patients progress to major knee surgery within 5 years of arthroscopic washout for osteoarthritis . Age greater than 60 years worsens the prognosis considerably [11043126] INTRODUCTION The treatment of full-thickness cartilage defects still represents a problem that has not yet been solved satisfactorily . Current methods used to cover defects in the knee joint are osteochondral cylinder transplantation ( OCT ) and autologous chondrocyte transplantation ( ACT ) . METHODS With a prospect i ve clinical investigation , at the time being with 2-year results , we have examined ACT in comparison to OCT in 20 patients with regard to clinical and histomorphological ( histology , immunohistochemistry , RES ) outcome . RESULTS We found equally good results with both methods in Lysholm , Meyers and Tegner Activity Scores . Histomorphologic evaluation of biopsies obtained by arthroscopy after ACT showed a defect filling in all cases , mainly with fibrous cartilage , while localized areas of hyalinelike regenerative cartilage were documented near the base . We did not see any histomorphologically visible change in the transplants after OCT . CONCLUSION At the time we prefer OCT instead of ACT given the correct indication [19865812] We compared the results of microfracture in single versus multiple symptomatic articular cartilage defects in the knee in 110 patients with a median age of 38 years ( range 15–60 ) . Cases of reoperation of the cartilage defect were classified as failures . Clinical outcome in non-failures was evaluated by the Lysholm score and grading of knee pain and function of the knee by the use of patient-administered visual analog scales ( VAS ; 0–100 ) . Data were prospect ively collected before the operation and at the 2- to 9-year follow-up . The single lesion or the largest of multiple lesions were located on the medial femoral condyle ( n = 62 ) , trochlea ( n = 18 ) , lateral tibia ( n = 11 ) , patella ( n = 10 ) or lateral femoral condyle ( n = 9 ) . We treated one ( n = 76 ) , two ( n = 27 ) or three ( n = 7 ) lesions with a median total area of 4 cm2 ( range 1–15 ) . A total of 24 failures ( 22 % ) were registered—18 % in the single-defect subgroup and 29 % in the multiple-defects subgroup . In the remaining group of patients ( n = 86 ) , the mean Lysholm score , mean pain-score ( 0 = no pain ; 100 = worst possible pain ) and mean function-score ( 0 = useless ; 100 = full function ) improved from 51 , 52 and 41 , respectively , to 71 ( P < 0.001 ) , 30 ( P < 0.001 ) and 69 ( P < 0.001 ) at the follow-up . The pain-score was significant lower ( P = 0.042 ) , and the function-score significantly higher ( P = 0.001 ) in the group of patients with a single lesion compared to the group with 2 or 3 lesions . The Lysholm score did not differ significantly between the two subgroups ( P = 0.06 ) [12110735] BACKGROUND Many patients report symptomatic relief after undergoing arthroscopy of the knee for osteoarthritis , but it is unclear how the procedure achieves this result . We conducted a r and omized , placebo-controlled trial to evaluate the efficacy of arthroscopy for osteoarthritis of the knee . METHODS A total of 180 patients with osteoarthritis of the knee were r and omly assigned to receive arthroscopic débridement , arthroscopic lavage , or placebo surgery . Patients in the placebo group received skin incisions and underwent a simulated débridement without insertion of the arthroscope . Patients and assessors of outcome were blinded to the treatment-group assignment . Outcomes were assessed at multiple points over a 24-month period with the use of five self-reported scores -- three on scales for pain and two on scales for function-- and one objective test of walking and stair climbing . A total of 165 patients completed the trial . RESULTS At no point did either of the intervention groups report less pain or better function than the placebo group . For example , mean ( + /-SD ) scores on the Knee-Specific Pain Scale ( range , 0 to 100 , with higher scores indicating more severe pain ) were similar in the placebo , lavage , and débridement groups : 48.9+/-21.9 , 54.8+/-19.8 , and 51.7+/-22.4 , respectively , at one year ( P=0.14 for the comparison between placebo and lavage ; P=0.51 for the comparison between placebo and débridement ) and 51.6+/-23.7 , 53.7+/-23.7 , and 51.4+/-23.2 , respectively , at two years ( P=0.64 and P=0.96 , respectively ) . Furthermore , the 95 percent confidence intervals for the differences between the placebo group and the intervention groups exclude any clinical ly meaningful difference . CONCLUSIONS In this controlled trial involving patients with osteoarthritis of the knee , the outcomes after arthroscopic lavage or arthroscopic débridement were no better than those after a placebo procedure [16928947] OBJECTIVE The purpose of this study was to use the Kellgren-Lawrence , Ahlback , and Br and t grading scales to correlate radiographic grade of osteoarthritis with the actual degree of articular cartilage degeneration within the tibiofemoral joint in patients with chronic knee pain . SUBJECTS AND METHODS The study group consisted of 125 patients with symptomatic osteoarthritis of the tibiofemoral joint . For all patients , st and ing anteroposterior radiographs of the knee were obtained before arthroscopic knee surgery . Each articular surface of the tibiofemoral joint was grade d at arthroscopy . Two radiologists retrospectively review ed the knee radiographs without knowledge of the arthroscopic findings to determine the presence and severity of osteoarthritis of the tibiofemoral joint using the Kellgren-Lawrence , Ahlback , and Br and t grading scales . Correlation coefficients describing the relation between grade of osteoarthritis and severity of articular cartilage degeneration were calculated for each grading scale . RESULTS The correlation coefficients for the Kellgren-Lawrence , Ahlback , and Br and t grading scales were 0.49 , 0.41 , and 0.56 , respectively . The differences between the correlation coefficients for the Kellgren-Lawrence and Ahlback grading scales and the correlation coefficients for the Br and t and Ahlback grading scales were statistically significant ( p < 0.05 ) . Many patients with no radiographic findings of osteoarthritis had significant articular cartilage degeneration within the tibiofemoral joint . CONCLUSION The Kellgren-Lawrence and Br and t grading scales were equally effective in defining the presence of and estimating the severity of osteoarthritis of the tibiofemoral joint but had only a moderately strong correlation with the actual degree of articular cartilage degeneration [8666628] In a prospect i ve r and omised trial 76 knees with isolated degenerative changes in the medial femoral condyle of grade s 3 or 4 were treated by either arthroscopic debridement ( 40 ) or washout ( 36 ) . All knees were followed up for at least one year and 58 for five years . The mean follow-up time was 4.5 years in the debridement group and 4.3 years in the washout group . At one year 32 of the debridement group and five of the washout group were painfree and at five years 19 of a total of 32 survivors in the debridement group and three of the 26 in the washout group were also free from pain . The mean improvement in a modified Lysholm score was 28 for the debridement group at one year and 21 at five years . In the washout group it was only 5 at one year and 4 at five years . For knees with lesions of the medial femoral condyle of grade s 3 or 4 , arthroscopic debridement appears to be the treatment of choice with over half the patients free from pain after five years [22434467] Autologous chondrocyte implantation ( ACI ) and mosaicplasty are methods of treating symptomatic articular cartilage defects in the knee . This study represents the first long-term r and omised comparison of the two techniques in 100 patients at a minimum follow-up of ten years . The mean age of the patients at the time of surgery was 31.3 years ( 16 to 49 ) ; the mean duration of symptoms pre-operatively was 7.2 years ( 9 months to 20 years ) . The lesions were large with the mean size for the ACI group being 440.9 mm(2 ) ( 100 to 1050 ) and the mosaicplasty group being 399.6 mm(2 ) ( 100 to 2000 ) . Patients had a mean of 1.5 previous operations ( 0 to 4 ) to the articular cartilage defect . Patients were assessed using the modified Cincinnati knee score and the Stanmore-Bentley Functional Rating system . The number of patients whose repair had failed at ten years was ten of 58 ( 17 % ) in the ACI group and 23 of 42 ( 55 % ) in the mosaicplasty group ( p < 0.001 ) . The functional outcome of those patients with a surviving graft was significantly better in patients who underwent ACI compared with mosaicplasty ( p = 0.02 ) [22422593] Background Many surgical techniques , including microfracture , periosteal and perichondral grafts , chondrocyte transplantation , and osteochondral grafts , have been studied in an attempt to restore damaged articular cartilage . However , there is no consensus regarding the best method to repair isolated articular cartilage defects of the knee . Questions / purpose sWe compared postoperative functional outcomes , followup MRI appearance , and arthroscopic examination after microfracture ( MF ) , osteochondral autograft transplantation ( OAT ) , or autologous chondrocyte implantation ( ACI ) . Methods We prospect ively investigated 30 knees with MF , 22 with OAT , and 18 with ACI . Minimum followup was 3 years ( mean , 5 years ; range , 3–10 years ) . We included only patients with isolated cartilage defects and without other knee injuries . The three procedures were compared in terms of function using the Lysholm knee evaluation scale , Tegner activity scale , and Hospital for Special Surgery ( HSS ) score ; modified Outerbridge cartilage grade s using MRI ; and International Cartilage Repair Society ( ICRS ) repair grade using arthroscopy . Results All three procedures showed improvement in functional scores . There were no differences in functional scores and postoperative MRI grade s among the groups . Arthroscopy at 1 year showed excellent or good results in 80 % after MF , 82 % after OAT , and 80 % after ACI . Our study did not show a clear benefit of either ACI or OAT over MF . Conclusions Owing to a lack of superiority of any one treatment , we believe MF is a reasonable option as a first-line therapy given its ease and affordability relative to ACI or OAT.Level of Evidence Level II , therapeutic study . See Guidelines for Authors for a complete description of levels of evidence [15278206] AIM Matrix-guided autologous chondrocyte implantation ( MACI ) was compared with microfracture ( MFX ) to demonstrate the reconstitution of cartilage over a two-year period using the morphological capabilities of MRI . PATIENTS AND METHODS 27 patients ( 9 females and 18 males , mean age 33 years ) underwent MACI on the knee joint . The defects originated from trauma ( 15 cases ) , osteochondritis dissecans ( 8 cases ) and chronic repetitive trauma ( 4 cases ) and were localized at the condyles ( 24 cases ) or patella ( 3 cases ) . All patients were examined postoperatively after 1 , 3 , 6 , 12 and 24 months with a 1,5 T unit ( Gyroscan , Philips ) using proton- and T2w spinecho and T1w fatsuppressed 3D gradientecho sequences . We measured the signal intensities of the implant and neighbouring cartilage to calculate the contrast-to-noise ratio ( CNR ) , and the thickness of cartilage and implant layers to define the defect filling rate . Finally , partial and complete remission was defined on MRI and compared with clinical data and morphology on MRI . Additionally , 7 patients were treated with MFX and , subsequently examined on MRI with the same protocol . RESULTS After MACI , MRI showed a partial but no complete equilibration of signal intensities of implant and adjacent cartilage over the 1 and 2 year follow-up periods which was shown by reduction of CNR from 21 to 10 on 3D-GE and from 26 to 9 on T2w SE sequences . Continuous growth of the implants result ed in an increased filling of the defects starting at 40 % after 0.5 year to 85 % after 1 or 2 years . Complete remission was found on MRI in 17/27 cases , and remission rate was influenced by etiology of cartilage defect but not by age and gender of patients or size and location of defects . The Lysholm-Gillquist score improved from 49.7 to 97.3 . After MFX equilibration of signal intensities and growth of the regenerating fibrous cartilage was less pronounced and complete remission was found in only 2/7 cases . In addition , the clinical score improved from 45.5 to 74.2 . CONCLUSION Direct imaging of cartilage with MRI and assessment of clinical scores allowed improved documentation of the outcome after MACI and MFX . MRI showed that MACI is superior to MFX concerning rate of complete remissions and filling of the defect with regenerating tissue . Clinical examinations showed better scores for MACI than for MFX [23979923] Background Autologous chondrocyte implantation ( ACI ) has demonstrated good and excellent results in over 75 % of patients up to 10 years after surgery . Reports of longer-term outcomes , however , remain limited . Questions / purpose sThe purpose s of this study were to describe the ( 1 ) survivorship of ACI grafts ; ( 2 ) the long-term functional outcomes using vali date d scoring tools after ACI ; and ( 3 ) to provide an analysis of potential predictors for failure . Methods Two hundred ten patients treated with ACI were followed for more than 10 years . Indications for the procedure included symptomatic cartilage defects in all compartments of the knee unresponsive to nonoperative measures . Mean age at surgery was 36 ± 9 years ; mean defect size measured 8.4 ± 5.5 cm2 . Outcome scores were prospect ively collected pre- and postoperatively at the last followup . Results At a mean of 12 ± 2 years followup , 53 of 210 patients ( 25 % ) had at least one failed ACI graft . Nineteen of these patients went on to arthroplasty , 27 patients were salvaged with revision cartilage repair , and seven patients declined further treatment ; three patients were lost to followup . The modified Cincinnati increased from 3.9 ± 1.5 to 6.4 ± 1.5 , WOMAC improved from 39 ± 21 to 23 ± 16 , Knee Society Score ( KSS ) knee score rose from 54 ± 18 to 79 ± 19 , and KSS function from 65 ± 23 to 78 ± 17 ( all p < 0.0001 ) . The Physical Component of the SF-36 score increased from 33 ± 14 to 49 ± 18 , whereas the Mental Component improved from 46 ± 14 to 52 ± 15 ( both p < 0.001 ) . Survivorship was higher in patients with complex versus salvage-type lesions ( p = 0.03 ) with primary ACI versus ACI after prior marrow stimulation ( p = 0.004 ) and with concomitant high tibial osteotomy ( HTO ) versus no HTO ( p = 0.01 ) . Conclusions ACI provided durable outcomes with a survivorship of 71 % at 10 years and improved function in 75 % of patients with symptomatic cartilage defects of the knee at a minimum of 10 years after surgery . A history of prior marrow stimulation as well as the treatment of very large defects was associated with an increased risk of failure . Level of Evidence Level IV , therapeutic study . See Guidelines for Authors for a complete description of levels of evidence [14996869] BACKGROUND New methods have been used , with promising results , to treat full-thickness cartilage defects . The objective of the present study was to compare autologous chondrocyte implantation with microfracture in a r and omized trial . We are not aware of any previous r and omized studies comparing these methods . METHODS Eighty patients without general osteoarthritis who had a single symptomatic cartilage defect on the femoral condyle in a stable knee were treated with autologous chondrocyte implantation or microfracture ( forty in each group ) . We used the International Cartilage Repair Society , Lysholm , Short Form-36 ( SF-36 ) , and Tegner forms to collect data . An independent observer performed a follow-up examination at twelve and twenty-four months . Two years postoperatively , arthroscopy with biopsy for histological evaluation was carried out . The histological evaluation was done by a pathologist and a clinical scientist , both of whom were blinded to each patient 's treatment . RESULTS In general , there were small differences between the two treatment groups . At two years , both groups had significant clinical improvement . According to the SF-36 physical component score at two years postoperatively , the improvement in the microfracture group was significantly better than that in the autologous chondrocyte implantation group ( p = 0.004 ) . Younger and more active patients did better in both groups . There were two failures in the autologous chondrocyte implantation group and one in the microfracture group . No serious complications were reported . Biopsy specimens were obtained from 84 % of the patients , and histological evaluation of repair tissues showed no significant differences between the two groups . We did not find any association between the histological quality of the tissue and the clinical outcome according to the scores on the Lysholm or SF-36 form or the visual analog scale . CONCLUSIONS Both methods had acceptable short-term clinical results . There was no significant difference in macroscopic or histological results between the two treatment groups and no association between the histological findings and the clinical outcome at the two-year time-point . LEVEL OF EVIDENCE Therapeutic study , Level I-1a ( r and omized controlled trial [ significant difference ] ) . See Instructions to Authors for a complete description of levels of evidence [21257846] Background : The availability remains limited of midterm clinical and radiologic results into matrix-induced autologous chondrocyte implantation ( MACI ) . Outcomes are required to vali date the efficacy of MACI as a suitable surgical treatment option for articular cartilage defects in the knee . Hypothesis : A significant improvement in clinical and magnetic resonance imaging – based ( MRI-based ) outcomes after MACI will exist throughout the postoperative timeline to 5 years after surgery . Furthermore , patient demographics , cartilage defect parameters , and injury/surgery history will be associated with patient and graft outcome , whereas a significant correlation will exist between clinical and MRI-based outcomes at 5 years after surgery . Study Design : Case series ; Level of evidence , 4 . Methods : A prospect i ve evaluation was undertaken to assess clinical and MRI-based outcomes to 5 years in 41 patients ( 53 grafts ) after MACI to the knee . After MACI surgery and a 12-week structured rehabilitation program , patients underwent clinical assessment s ( Knee injury and Osteoarthritis Outcome Score , SF-36 , 6-minute walk test , knee range of motion ) and MRI assessment s at 3 , 12 , and 24 months , as well as 5 years after surgery . The MRI evaluation assessed 8 previously defined pertinent parameters of graft repair , as well as a combined MRI composite score . Results : A significant improvement ( P < .05 ) was demonstrated for all Knee injury and Osteoarthritis Outcome Score and SF-36 subscales over the postoperative timeline , as well as the 6-minute walk test and active knee extension . A significant improvement ( P < .0001 ) was observed for the MRI composite score , as well as several individual graft scoring parameters . At 5 years after surgery , 67 % of MACI grafts demonstrated complete infill , whereas 89 % demonstrated good to excellent filling of the chondral defect . Patient demographics , cartilage defect parameters , and injury/surgery history demonstrated no significant pertinent correlations with clinical or MRI-based outcomes at 5 years , and no significant correlations existed between clinical and MRI-based outcome measures . At 5 years after surgery , 98 % of patients were satisfied with the ability of MACI surgery to relieve knee pain ; 86 % , with improvement in their ability to perform normal daily tasks ; and 73 % , with their ability to participate in sport 5 years after MACI . Conclusion : These results suggest that MACI provides a suitable midterm treatment option for articular cartilage defects in the knee . Long-term follow-up is essential to confirm whether the repair tissue has the durability required to maintain long-term patient quality of life [18202295] Background As the natural healing capacity of damaged articular cartilage is poor , joint surface injuries are a prime target for regenerative medicine . Characterized chondrocyte implantation uses an autologous cartilage cell therapy product that has been optimized for its biological potency to form stable cartilage tissue in vivo . Purpose To determine whether , in symptomatic cartilage defects of the femoral condyle , structural regeneration with characterized chondrocyte implantation is superior to repair with microfracture . Study Design R and omized controlled trial ; Level of evidence , 1 . Methods Characterized chondrocyte implantation was compared with microfracture in patients with single grade III to IV symptomatic cartilage defects of the femoral condyles in a multicenter trial . Patients aged 18 to 50 years were r and omized to characterized chondrocyte implantation ( n = 57 ) or microfracture ( n = 61 ) . Structural repair was blindly assessed in biopsy specimens taken at 1 year using ( 1 ) computerized histomorphometry and ( 2 ) evaluation of overall histological components of structural repair . Clinical outcome was measured using the self administered Knee injury and Osteoarthritis Outcome Score . Adverse events were recorded throughout the study . Results Characterized chondrocyte implantation result ed in better structural repair , as assessed by histomorphometry ( P = .003 ) and overall histologic evaluation ( P = .012 ) . Aspects of structural repair relating to chondrocyte phenotype and tissue structure were superior with characterized chondrocyte implantation . Clinical outcome as measured by the Knee injury and Osteoarthritis Outcome Score at 12 to 18 months after characterized chondrocyte implantation was comparable with microfracture at this stage . Both treatment groups had a similar mean baseline overall Knee injury and Osteoarthritis Outcome Score ( 56.30 ± 13.61 and 59.53 ± 14.95 for microfracture and characterized chondrocyte implantation , respectively ) , which increased in both groups to 70.56 ± 12.39 and 72.63 ± 15.55 at 6 months , 73.26 ± 14.66 and 73.10 ± 16.01 at 12 months , and 74.73 ± 17.01 and 75.04 ± 14.50 at 18 months , respectively . Both techniques were generally well tolerated ; the incidence of adverse events after characterized chondrocyte implantation was not markedly increased compared with that for microfracture . Conclusion One year after treatment , characterized chondrocyte implantation was associated with a tissue regenerate that was superior to that after microfracture . Short-term clinical outcome was similar for both treatments . The superior structural outcome may result in improved long-term clinical benefit with characterized chondrocyte implantation . Long-term follow-up is needed to confirm these findings [24595400] Background : Cartilage defects in the patella are common , and a subset of patients does not respond to nonoperative measures . While most cartilage repair techniques have demonstrated good outcomes in the femoral condyles , the patellofemoral compartment poses special challenges . Hypothesis : Repair of patellar cartilage defects with autologous chondrocyte implantation ( ACI ) will provide lasting improvements in pain and function . Study Design : Case series ; Level of evidence , 4 . Methods : Patients were treated at 1 of 4 participating cartilage repair centers with ACI for cartilage defects in the patella ; bipolar ( patella + trochlea ) defects were included as well . All patients were followed prospect ively for at least 4 years with multiple patient-reported outcome instruments , including the International Knee Documentation Committee , Short Form–12 , modified Cincinnati Rating Scale , Western Ontario and McMaster Universities Osteoarthritis Index , and Knee Society scores . Treatment failure was defined as structural failure of the graft combined with pain requiring revision surgery . Results : A total of 110 patients were available for analysis . As a group , they experienced both statistically significant and clinical ly important improvements in pain and function in all physical outcome scales . The International Knee Documentation Committee improved from 40 ± 14 preoperatively to 69 ± 20 at the last follow-up ; the Cincinnati Rating Scale , from 3.2 ± 1.2 to 6.2 ± 1.8 ; and the Western Ontario and McMaster Universities Osteoarthritis Index , from 50 ± 22 to 29 ± 22 ( all P < .0001 ) . Ninety-two percent of patients stated that they would choose to undergo ACI again , and 86 % rated their knees as good or excellent at the time of final follow-up . Nine patients ( 8 % ) were considered treatment failures , and 16 % reported that their knees were not improved . Conclusion : Cartilage repair in the patellofemoral joint is arguably not without its challenges . Autologous chondrocyte implantation remains off-label in the patella , a fact that needs to be discussed with prospect i ve patients during the informed consent process . However , when performed with attention to patellofemoral biomechanics , self-rated subjective good and excellent outcomes can be achieved in more than 80 % of patients treated with ACI , even in a patient population with large and frequently bipolar defects such as the one presented in this study . However , final functional scores , although significantly improved , still reflected residual disability in this challenging group of patients

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### Context: [3848560] Background In the majority of patients with osteoarthritis of the knee the disease originates in the medial compartment . There are two fundamentally different approaches to knee replacement for patients with unicompartmental disease : some surgeons feel that it is always best to replace both the knee compartments with a total knee replacement ( TKR ) ; whereas others feel it is best to replace just the damaged component of the knee using a partial or unicompartment replacement ( UKR ) . Both interventions are established and well-documented procedures . Little evidence exists to prove the clinical and cost-effectiveness of either management option . This provides an explanation for the high variation in treatment of choice by individual surgeons for the same knee pathology . The aim of the TOPKAT study will be to assess the clinical and cost effectiveness of TKRs compared to UKRs in patients with medial compartment osteoarthritis . Methods / Design The design of the study is a single layer multicentre superiority type r and omised controlled trial of unilateral knee replacement patients . Blinding will not be possible as the surgical scars for each procedure differ . We aim to recruit 500 patients from approximately 28 secondary care orthopaedic units from across the UK including district general and teaching hospitals . Participants will be r and omised to either UKR or TKR . R and omisation will occur using a web-based r and omisation system . The study is pragmatic in terms of implant selection for the knee replacement operation . Participants will be followed up for 5 years . The primary outcome is the Oxford Knee Score , which will be collected via question naires at 2 months , 1 year and then annually to 5 years . Secondary outcomes will include cost-effectiveness , patient satisfaction and complications data .Trial registration Current Controlled Trials IS RCT N03013488 ; Clinical Trials.gov Identifier : [25002462] Background : Autologous chondrocyte implantation ( ACI ) has been shown to be effective in the midterm for the treatment of symptomatic articular cartilage lesions of the knee , but few long-term series have been published . The multioperated chronic articular cartilage defect remains a difficult condition to treat . Purpose : To examine the long-term clinical results of ACI for large chronic articular cartilage defects , many treated as salvage . Study Design : Case series ; Level of evidence , 4 . Methods : This is a prospect i ve case series of 104 patients with a mean age of 30.2 years and a symptomatic lesion of the articular cartilage in the knee , who underwent ACI between 1998 and 2001 . The mean duration of symptoms before surgery was 7.8 years . The mean number of previous surgical procedures on the cartilage defect , excluding arthroscopic debridement , was 1.3 . The defects were large , with a mean size of 477.1 mm2 ( range , 120 - 2500 mm2 ) . The modified Cincinnati , Stanmore/Bentley , and visual analog scale for pain scoring systems were used to assess pain and functional outcomes at a minimum 10 years ( mean , 10.4 years ; range , 10 - 12 years ) . Results : Twenty-seven patients ( 26 % ) experienced graft failure at a mean of 5.7 years after ACI . Of the 73 patients who did not fail , 46 patients ( 63 % of patients with a surviving graft ) had an excellent result , 18 ( 25 % ) were good , 6 ( 8 % ) were fair , and 3 ( 4 % ) had a poor result . Of a total of 100 patients successfully followed up , 98 were satisfied with the ACI technique for their chronic knee pain and would undergo the procedure again . Conclusion : Autologous chondrocyte implantation can provide a long-term solution in more than 70 % of young patients of a difficult-to-treat group with large chronic articular cartilage lesions , even in the salvage situation [21460066] Background : There are currently several approaches being pursued to treat focal defects of articular cartilage , each having specific advantages or challenges . A single-stage procedure that uses autologous cartilage fragments , Cartilage Autograft Implantation System ( CAIS ) , is being evaluated in patients and may offer a clinical ly effective option . Purpose : To establish the safety of CAIS and to test whether CAIS improves quality of life by using st and ardized outcomes assessment tools . Study Design : R and omized controlled trial ; Level of evidence , 2 . Methods : Patients ( n = 29 ) were r and omized ( 1:2 ) with the intent to treat with either a control ( microfracture [ MFX ] ) or an experimental ( CAIS ) procedure . Patients were followed at predetermined time points for 2 years using several st and ardized outcomes assessment tools ( SF-36 , International Knee Documentation Committee [ IKDC ] , Knee injury and Osteoarthritis Outcome Score [ KOOS ] ) . Magnetic resonance imaging was performed at baseline , 3 weeks , and 6 , 12 , and 24 months . Results : Lesion size and International Cartilage Repair Society ( ICRS ) grade were similar in both groups . General outcome measures ( eg , physical component score of the SF-36 ) indicated an overall improvement in both groups , and no differences in the number of adverse effects were noted in comparisons between the CAIS and MFX groups . The IKDC score of the CAIS group was significantly higher ( 73.9 ± 14.72 at 12 months and 82.95 ± 14.88 at 24 months ) compared with the MFX group ( 57.78 ± 18.31 at 12 months and 59.5 ± 13.44 at 24 months ) . Select subdomains ( 4/5 ) in the KOOS instrument were significantly different at 12 and 18 months , and all subdomains ( Symptoms and Stiffness , Pain , Activities of Daily Living , Sports and Recreation , Knee-related Quality of Life ) were significantly increased at 24 months in CAIS with scores of 88.47 ± 11.68 , 90.64 ± 7.87 , 97.29 ± 3.8 , 78.16 ± 22.06 , and 69 ± 23.15 compared with 75 ± 9.31 , 78.94 ± 13.73 , 89.46 ± 8.13 , 51.67 ± 26.01 , and 37.15 ± 21.67 in the MFX group . These significant improvements were maintained at 24 months in both IKDC and KOOS . Qualitative analysis of the imaging data did not note differences between the 2 groups in fill of the graft bed , tissue integration , or presence of subchondral cysts . Patients treated with MFX had a significantly higher incidence of intralesional osteophyte formation ( 54 % and 70 % of total number of lesions treated ) at 6 and 12 months when compared with CAIS ( 8 % and 25 % of total number of lesions treated ) . Conclusion : The first clinical experience in using CAIS for treating patients with focal chondral defects indicates that it is a safe , feasible , and effective method that may improve long-term clinical outcomes [19261905] Background Marrow stimulation techniques such as drilling or microfracture are first-line treatment options for symptomatic cartilage defects . Common knowledge holds that these treatments do not compromise subsequent cartilage repair procedures with autologous chondrocyte implantation . Hypothesis Cartilage defects pretreated with marrow stimulation techniques will have an increased failure rate . Study Design Cohort study ; Level of evidence , 2 . Methods The first 321 consecutive patients treated at one institution with autologous chondrocyte implantation for full-thickness cartilage defects that reached more than 2 years of follow-up were evaluated by prospect ively collected data . Patients were grouped based on whether they had undergone prior treatment with a marrow stimulation technique . Outcomes were classified as complete failure if more than 25 % of a grafted defect area had to be removed in later procedures because of persistent symptoms . Results There were 522 defects in 321 patients ( 325 joints ) treated with autologous chondrocyte implantation . On average , there were 1.7 lesions per patient . Of these joints , 111 had previously undergone surgery that penetrated the subchondral bone ; 214 joints had no prior treatment that affected the subchondral bone and served as controls . Within the marrow stimulation group , there were 29 ( 26 % ) failures , compared with 17 ( 8 % ) failures in the control group . Conclusion Defects that had prior treatment affecting the subchondral bone failed at a rate 3 times that of nontreated defects . The failure rates for drilling ( 28 % ) , abrasion arthroplasty ( 27 % ) , and microfracture ( 20 % ) were not significantly different , possibly because of the lower number of microfracture patients in this cohort ( 25 of 110 marrow-stimulation procedures ) . The data demonstrate that marrow stimulation techniques have a strong negative effect on subsequent cartilage repair with autologous chondrocyte implantation and therefore should be used judiciously in larger cartilage defects that could require future treatment with autologous chondrocyte implantation [21080737] Abstract Background : Knee cartilage lesions increase the risk of developing osteoarthritis ( OA ) , and may eventually result in a total knee replacement ( TKR ) . There is currently no consensus on the optimal treatment of cartilage lesions . ChondroCelect ® ( CC ) is a cell-based therapy approved for use in autologous chondrocytes implantation ( ACI ) to treat symptomatic cartilage defects of the femoral condyle . Its capacity to safely restore good- quality cartilage was demonstrated in a r and omized controlled trial ( RCT ) versus the surgical procedure microfracture ( MFX ) . Objective : This study investigated the cost utility of CC used in ACI compared with MFX to treat symptomatic knee cartilage lesions in Belgium . Methods : A decision tree model comparing CC with MFX over a 40-year horizon was developed in TreeAge Pro ™ . The key timepoints of the model were ( i ) clinical assessment 5 years after initial intervention ( success or no success , with or without re-operation ) ; ( ii ) development of OA at 15 years ( yes/no ) ; ( iii ) need for TKR at 20 years ( yes/no ) ; and ( iv ) need for prosthesis revision at 35 years ( yes/no ) . Clinical data provided by the RCT of CC versus MFX were the clinical success ( response ) rate based on the Knee injury and Osteoarthritis Outcome Score ( KOOS ) at 36 months ( 82.9 % vs 62.0 % ; p = 0.048 ) and the proportion of good structural repair/presence of hyaline cartilage based on International Cartilage Repair Society ( ICRS II ) visual item at 12 months ( 44.9 % vs 23.2 % ; p= 0.023 ) . Utility scores by surgery outcome were derived from the SF-36 question naire responses collected in the RCT . Conservative assumptions related to the incidences of OA , TKR and prosthesis revision relied on a literature search . A patient chart review ( n = 82 ) provided follow-up costs by surgery outcome . National tariffs were applied to direct medical re sources used ( healthcare payer perspective , year 2008 costs ) . Annual discounting was applied to costs ( 3 % ) and effects ( 1.5 % ) as recommended by the Belgian pharmacoeconomic guidelines . Results : The incremental cost per QALY gained for CC compared with MFX was € 16 229 , with a difference in costs of € 20 802 and 1.282 QALYs gained . Sensitivity analyses indicated that the key model drivers were the proportion of patients with hyaline cartilage and the correlation between hyaline cartilage formation and later avoidance of OA . Probabilistic sensitivity analyses showed robustness of the results , with 80 % of the simulations below the usual UK National Institute for Health and Clinical Excellence ( NICE ) threshold of € 22 000 per QALY . Conclusions : Assuming a good correlation between high- quality cartilage repair and avoidance of OA at a later stage , the benefits of the cell therapy CC over MFX in terms of QALYs gained and OA-related costs avoided appear real . Further research is required to explore long-term effects of cartilage repair and reduce uncertainty on quality of life of patients with OA before and after joint replacement [22637204] BACKGROUND Despite introduction of autologous chondrocyte therapy for repair of hyaline articular cartilage injury in 1994 , microfracture remains a primary st and ard of care . NeoCart , an autologous cartilage tissue implant , was compared with microfracture in a multisite prospect i ve , r and omized trial of a tissue-engineered bioimplant for treating articular cartilage injuries in the knee . METHODS Thirty patients were r and omized at a ratio of two to one ( two were treated with an autologous cartilage tissue implant [ NeoCart ] for each patient treated with microfracture ) at the time of arthroscopic confirmation of an International Cartilage Repair Society ( ICRS ) grade -III lesion(s ) . Microfracture or cartilage biopsy was performed . NeoCart , produced by seeding a type-I collagen matrix scaffold with autogenous chondrocytes and bioreactor treatment , was implanted six weeks following arthroscopic cartilage biopsy . St and ard evaluations were performed with vali date d clinical outcomes measures . RESULTS Three , six , twelve , and twenty-four-month data are reported . The mean duration of follow-up ( and st and ard deviation ) was 26 ± 2 months . There were twenty-one patients in the NeoCart group and nine in the microfracture group . The mean age ( 40 ± 9 years ) , body mass index ( BMI ) ( 28 ± 4 kg/m2 ) , duration between the first symptoms and treatment ( 3 ± 5 years ) , and lesion size ( 287 ± 138 mm2 in the NeoCart group and 252 ± 135 mm2 in the microfracture group ) were similar between the groups . Adverse event rates per procedure did not differ between the treatment arms . The scores on the Short Form-36 ( SF-36 ) , Knee Injury and Osteoarthritis Outcome Score ( KOOS ) activities of daily living ( ADL ) scale , and International Knee Documentation Committee ( IKDC ) form improved from baseline ( p < 0.05 ) to two years postoperatively in both treatment groups . In the NeoCart group , improvement , compared with baseline , was significant ( p < 0.05 ) for all measures at six , twelve , and twenty-four months . Improvement in the NeoCart group was significantly greater ( p < 0.05 ) than that in the microfracture group for the KOOS pain score at six , twelve , and twenty-four months ; the KOOS symptom score at six months ; the IKDC , KOOS sports , and visual analog scale ( VAS ) pain scores at twelve and twenty-four months ; and the KOOS quality of life ( QOL ) score at twenty-four months . Analysis of covariance ( ANCOVA ) at one year indicated that the change in the KOOS pain ( p = 0.016 ) and IKDC ( p = 0.028 ) scores from pretreatment levels favored the NeoCart group . Significantly more NeoCart-treated patients ( p = 0.0125 ) had responded to therapy ( were therapeutic responders ) at six months ( 43 % versus 25 % in the microfracture group ) and twelve months ( 76 % versus 22 % in the microfracture group ) . This trend continued , as the proportion of NeoCart-treated patients ( fifteen of nineteen ) who were therapeutic responders at twenty-four months was greater than the proportion of microfracture-treated participants ( four of nine ) who were therapeutic responders at that time . CONCLUSIONS This r and omized study suggests that the safety of autologous cartilage tissue implantation , with use of the NeoCart technique , is similar to that of microfracture surgery and is associated with greater clinical efficacy at two years after treatment [25031368] BACKGROUND Osteoarthritis of the knee is commonly diagnosed and monitored with radiography . However , the reliability of radiographic classification systems for osteoarthritis and the correlation of these classifications with the actual degree of confirmed degeneration of the articular cartilage of the tibiofemoral joint have not been adequately studied . METHODS As the Multicenter ACL ( anterior cruciate ligament ) Revision Study ( MARS ) Group , we conducted a multicenter , prospect i ve longitudinal cohort study of patients undergoing revision surgery after anterior cruciate ligament reconstruction . We followed 632 patients who underwent radiographic evaluation of the knee ( an anteroposterior weight-bearing radiograph , a posteroanterior weight-bearing radiograph made with the knee in 45 ° of flexion [ Rosenberg radiograph ] , or both ) and arthroscopic evaluation of the articular surfaces . Three blinded examiners independently grade d radiographic findings according to six commonly used systems-the Kellgren-Lawrence , International Knee Documentation Committee , Fairbank , Br and t et al. , Ahlbäck , and Jäger-Wirth classifications . Interobserver reliability was assessed with use of the intraclass correlation coefficient . The association between radiographic classification and arthroscopic findings of tibiofemoral chondral disease was assessed with use of the Spearman correlation coefficient . RESULTS Overall , 45 ° posteroanterior flexion weight-bearing radiographs had higher interobserver reliability ( intraclass correlation coefficient = 0.63 ; 95 % confidence interval , 0.61 to 0.65 ) compared with anteroposterior radiographs ( intraclass correlation coefficient = 0.55 ; 95 % confidence interval , 0.53 to 0.56 ) . Similarly , the 45 ° posteroanterior flexion weight-bearing radiographs had higher correlation with arthroscopic findings of chondral disease ( Spearman rho = 0.36 ; 95 % confidence interval , 0.32 to 0.39 ) compared with anteroposterior radiographs ( Spearman rho = 0.29 ; 95 % confidence interval , 0.26 to 0.32 ) . With respect to st and ards for the magnitude of the reliability coefficient and correlation coefficient ( Spearman rho ) , the International Knee Documentation Committee classification demonstrated the best combination of good interobserver reliability and medium correlation with arthroscopic findings . CONCLUSIONS The overall estimates with the six radiographic classification systems demonstrated moderate ( anteroposterior radiographs ) to good ( 45 ° posteroanterior flexion weight-bearing radiographs ) interobserver reliability and medium correlation with arthroscopic findings . The International Knee Documentation Committee classification assessed with use of 45 ° posteroanterior flexion weight-bearing radiographs had the most favorable combination of reliability and correlation . LEVEL OF EVIDENCE Diagnostic Level I. See Instructions for Authors for a complete description of levels of evidence [20692745] BACKGROUND Matrix-induced autologous chondrocyte implantation is a technique for repairing articular cartilage defects in the knee . Despite reported improvements in pain , little is known about the recovery of knee biomechanics during walking gait . METHODS A r and omized controlled study design was used to investigate knee biomechanics during gait in 61 patients following matrix-induced autologous chondrocyte implantation , in conjunction with either ' accelerated ' or ' traditional ' approaches to post-operative weight-bearing rehabilitation . Gait analysis was performed at 3 , 6 and 12 months post-surgery in both patient groups , and two matched , unaffected control groups for comparison . FINDINGS The spatiotemporal and ground reaction force parameters were similar between patient groups and their respective control groups at all time points . When compared with controls , both patient groups demonstrated significantly reduced knee extension moments up until , and including , 12 months . The traditional group demonstrated a significantly reduced knee adduction moment at 3 , 6 and 12 months , and a significantly reduced knee flexion moment at 3 months . There were no differences in these knee moments between the accelerated patient group and controls . INTERPRETATION Overall , a higher level of gait dysfunction was observed in patients who underwent traditional rehabilitation . Future research is needed to investigate the recovery of normal gait following matrix-induced autologous chondrocyte implantation , and its effect on repair tissue development [23880403] Background : Matrix-induced autologous chondrocyte implantation ( MACI ) has become an established technique for the repair of full-thickness chondral defects in the knee , although best patient outcomes appear limited by a lack of evidence -based knowledge on how to progressively increase postoperative weightbearing ( WB ) and rehabilitation exercises . Hypothesis : To determine the safety and efficacy of an accelerated WB regimen after MACI in the tibiofemoral joint . Study Design : R and omized controlled trial ; Level of evidence , 1 . Methods : Clinical and radiological assessment s were performed in 28 knees at 12 months after MACI to the medial or lateral femoral condyle . Both rehabilitation interventions sought to protect the implant for an initial period and then incrementally increase load bearing . Under the “ accelerated ” ( AR ) protocol , patients reached full WB at 6 weeks after surgery compared with 8 weeks for what was considered to be the current “ best practice ” ( CR ) WB regimen based on previous research . Assessment s included the Knee Injury and Osteoarthritis Outcome Score ( KOOS ) , 36-Item Short Form Health Survey ( SF-36 ) , visual analog scale , 6-minute walk test , and active knee range of motion ( ROM ) . High-resolution magnetic resonance imaging ( MRI ) was used to describe the quality and quantity of repair tissue via the assessment of pertinent parameters of graft repair as well as an MRI composite score . Results : Patients in both groups demonstrated significant improvement ( P < .05 ) in all clinical measures over the preoperative and postoperative timeline from before surgery to 12 months after surgery . The AR group reported significantly better ( P < .05 ) SF-36 physical component scores at 8 weeks and significantly greater ( P < .05 ) KOOS quality of life scores at 6 and 12 months postoperatively . Although no differences ( P > .05 ) were observed between the 2 groups for active knee ROM , the AR group did achieve full active knee extension as early as 4 weeks compared with the CR group at 12 weeks . There was no difference ( P > .05 ) in graft quality as assessed by MRI ( MOCART composite score : AR , 3.34 ; CR , 3.04 ) , with no patients suffering any adverse effects from the implant up to 12 months , regardless of the rehabilitation protocol employed . Conclusion : The AR approach that reduced the length of time spent ambulating on crutches result ed in improved general physical function and quality of life and an earlier attainment of full active knee extension when compared with the CR approach . There were no graft complications ascertained through MRI . This regimen appears safe and may potentially speed up the recovery of normal gait function . A larger patient cohort and follow-up are required to observe long-term graft outcomes [19653049] Young patients with early osteoarthritis wishing to remain functionally active have limited treatment options . Existing studies examining the use of autologous chondrocyte implantation ( ACI ) have included patients with early degenerative changes ; however , none specifically investigated the outcome of ACI with this challenging problem . We prospect ively followed 153 patients ( 155 knees ) for up to 11 years after treatment with ACI for early-stage osteoarthritis . Patient pain and function was assessed using WOMAC , modified Cincinnati , SF-36 , Knee Society score , and a satisfaction question naire . Mean patient age was 38.3 years . On average , 2.1 defects were treated per knee ; the mean defect size was 4.9 cm2 and total area per knee was 10.4 cm2 . Eight percent of joints were considered treatment failures that went on to arthroplasty and the remaining patients experienced 50 % to 75 % improvement in WOMAC subscales . Our data suggest that ACI in patients with early osteoarthritis results in clinical ly relevant reductions in pain and improvement in function . At 5 years postoperatively , 92 % of patients were functioning well and were able to delay the need for joint replacement . Given the limited number of treatment options for this subset of patients , autologous chondrocyte implantation may offer improved quality of life for young osteoarthritic patients .Level of Evidence : Level IV , case series . See Guidelines for Authors for a complete description of levels of evidence [12571292] Background : Current methods used to restore the joint surface in patients with localized articular cartilage defects include transplantation of an autologous osteochondral cylinder and implantation of autologous chondrocytes . The purpose of this study was to evaluate the clinical and histological outcomes of these two techniques . Methods : We performed a prospect i ve clinical study to investigate the two-year outcomes in forty patients with an articular cartilage lesion of the femoral condyle who had been r and omly treated with either transplantation of an autologous osteochondral cylinder or implantation of autologous chondrocytes . Biopsy specimens from representative patients of both groups were evaluated with histological staining , immunohistochemistry , and scanning electron microscopy . Results : According to the postoperative Lysholm score , the recovery after autologous chondrocyte implantation was slower than that after osteochondral transplantation at six months ( p ⩽ 0.015 ) , twelve months ( p ⩽ 0.001 ) , and twenty-four months ( p ⩽ 0.012 ) . On the basis of the Meyers score and the Tegner activity score , the results were equally good with the two methods two years after treatment . Histomorphological evaluation of biopsy specimens within two years after autologous chondrocyte implantation demonstrated a complete , mechanically stable resurfacing of the defect in all patients . The tissue consisted mainly of fibrocartilage , while localized areas of hyaline-like regenerative cartilage could be detected close to the subchondral bone . Although a gap remained at the site of the transplantation in all five biopsy specimens examined as long as two years after osteochondral cylinder transplantation , histomorphological analysis and scanning electron microscopy revealed no differences between the osteochondral transplants and the surrounding original cartilage . Conclusions : Both treatments result ed in a decrease in symptoms . However , the improvement provided by the autologous chondrocyte implantation lagged behind that provided by the osteochondral cylinder transplantation . Histologically , the defects treated with autologous chondrocyte implantation were primarily filled with fibrocartilage , whereas the osteochondral cylinder transplants retained their hyaline character , although there was a persistent interface between the transplant and the surrounding original cartilage . Limitations of our study included the small number of patients , the relatively short ( two-year ) follow-up , and the absence of a control group . Level of Evidence : Therapeutic study , Level II-2 ( poor- quality r and omized controlled trial [ e.g. , < 80 % follow-up ] ) . See Instructions to Authors for a complete description of levels of evidence [23857885] Background : Sexual dimorphism in humans has already been documented at different levels , and preliminary findings also suggest the importance of patient sex on clinical outcome in the treatment of cartilage lesions . Purpose : To document and analyze the influence of sex on clinical outcome in a large cohort of patients treated with a cartilage regenerative procedure for knee chondral lesions and prospect ively followed at midterm follow-up . Study Design : Cohort study ; Level of evidence , 3 . Methods : A total of 250 knees were treated with matrix-assisted autologous chondrocyte transplantation ( MACT ) and prospect ively evaluated with International Knee Documentation Committee ( IKDC ) , EuroQol visual analog scale ( EQ-VAS ) , and Tegner scores at 1- , 2- , and minimum 5-year follow-ups to compare results obtained in men and women . The lesions were focal International Cartilage Repair Society grade III-IV chondral knee defects involving femoral condyles , trochleae , and patellae . Two homogeneous groups of 56 male patients and 56 female patients were then selected by a blinded statistician for a matched-pair analysis . Results : A statistically significant improvement in all the scores in both men and women was observed in the general population . The IKDC subjective score showed better results for men at all follow-up times : at 5 years , the mean IKDC subjective score was 79.5 ± 18.6 versus 64.3 ± 20.2 for men and women , respectively ( P < .0005 ) , and the same trend was confirmed with the EQ-VAS and Tegner scores . The matched-pair analysis confirmed the difference of final results achieved ( 74.1 ± 19.8 vs 63.7 ± 20.2 , respectively ; P = .006 ) . However , men and women started with different preoperative levels , and the analysis of the improvement obtained was not significantly different . Finally , when scores were st and ardized for each patient , according to the mean score typical for the corresponding age and sex category in a healthy population , a sex-related difference was not confirmed at any of the follow-ups . Etiological factors , lesion site , and preinjury activity level differed in women and men of the general population and were the confounding factors responsible for the different outcome not confirmed by the analysis of homogeneous cohorts of patients . Conclusion : Women have a different knee chondral lesion pattern and more often have unfavorable conditions related to the cause of injury , site , and activity level , and they also have lower raw , not st and ardized , scores . However , a matched-pair analysis with data st and ardized for the specific patient categories showed that , on equal terms , women have the same possibilities for successful outcome as men after surgical treatment for knee cartilage regeneration [17372718] A biodegradable , hyaluronian-based biocompatible scaffold was used for autologous chondrocyte transplantation . This prospect i ve study analyzes a clinical outcome of 70 consecutive patients treated by arthroscopic autologous chondrocyte transplantation at minimum 24 months follow up ( 47 of these patients achieved minimum 36 months follow-up and 21 patients minimum 48 months follow-up ) in order to establish clear indication criteria for this type of treatment . 31 of these patients presented isolated chondral lesions , while 39 patients with associated lesions ( 23 ACL lesions , 28 meniscal lesions , 1 varus knee ) were treated during the same surgical procedure with cartilage harvesting . A statistically significant clinical improvement was shown just at 24 months and the second-look arthroscopy demonstrated a complete coverage of the grafted area with a hyaline cartilage-like tissue in 12 of 15 analyzed patients . A better clinical outcome was observed in young , well-trained patients and in traumatic lesions . Other factors , such as defect size , localization , previous and associated surgery did not influence significantly the results . This matrix autologous chondrocyte transplantation procedure simplifies the surgical procedure and can be performed arthroscopically , thus reducing surgical morbidity and recovery time [19669763] This prospect i ve six-year longitudinal study review s the clinical outcome of patients undergoing autologous chondrocyte implantation ( ACI ) and a porcine type I/III collagen membrane cover for deep chondral defects of the knee . We present 57 patients ( 31 male , 26 female ) with a mean age of 31.6 years ( range 15–51 years ) that have undergone ACI since July 1998 . The mean size of the defect was 3.14 cm2 ( range 1.0–7.0 cm2 ) . All patients were assessed annually using seven independent vali date d clinical rating scores with the data analysed using ANOVA . ACI using a porcine type I/III collagen membrane cover produced statistically significant improvements ( p < 0.001 ) , maintained for up to six years , in knee symptoms compared to pre-operative levels . This study provides evidence of the medium-term benefit achieved by transplanting autologous chondrocytes to osteochondral defects [16644224] INTRODUCTION The results for autologous chondrocyte implantation ( ACI ) in the treatment of full thickness chondral defects in the knee are encouraging . At present two techniques have been described to retain the chondrocyte suspension within the defect . The first involves using a periosteal cover ( ACI-P ) and the second involves using a type I/III collagen membrane ( ACI-C ) . To the authors knowledge there are no comparative studies of these two techniques in the current literature . We have therefore undertaken such a study to establish if there is a difference between the 2 techniques based on a clinical and arthroscopic assessment . METHODS A total of 68 patients with a mean age of 30.52 years with symptomatic articular cartilage defects were r and omised to have either ACI-P ( 33 patients ) or ACI-C ( 35 patients ) . The mean defect size was 4.54 cm2 . All patients were followed up at 24 months . RESULTS A clinical and functional assessment showed that 74 % of patients had a good or excellent result following the ACI-C compared with 67 % after the ACI-P at 2 years . Arthroscopy at 1 year also demonstrated similar results for both techniques . However , 36.4 % of the ACI-P grafts required shaving for hypertrophy compared with none for the ACI-C grafts at 1 year . DISCUSSION This study has shown no statistical difference between the clinical outcome of ACI-C versus ACI-P at 2 years . A significant number of patients who had the ACI-P required shaving of a hypertrophied graft . We conclude that there is no advantage in using periosteum as a cover for retaining chondrocytes within an osteochondral defect ; as a result we advocate the use of an alternative cover such as a manufactured type I/III collagen membrane [15995447] Peterson ’s pioneering experience with the first clinical application of autologous chondrocyte implantation showed improvement in clinical outcomes , durable as much as 11 years , for a difficult patient population . An assessment of the general applicability of this technology in the United States requires long-term , multicenter followup . The purpose of this multicenter cohort study was to assess the clinical outcomes of patients treated with autologous chondrocyte implantation for lesions of the distal femur . Modified 10-point scales of the Cincinnati knee rating system were used to measure outcomes assessment s at baseline and at 5 years . Eighty-seven percent ( 87 of 100 ) of patients completed 5-year followup assessment s. Patients were an average 37 years of age , had a mean total defect size of 4.9 cm2 , and had low baseline overall condition scores . At least one prior cartilage repair procedure had failed in 70 % of the patients . At followup , 87 patients reported a mean improvement of 2.6 points in the overall condition score , including 62 with improved conditions , six with no change in condition , and 19 with worsened conditions . Of the 62 patients who improved , the mean overall condition score improved 4.1 points at followup . Patients treated with autologous chondrocyte implantation for large cartilage defects in the distal femur reported improvement in outcome scores at 5 years followup . Level of Evidence : Therapeutic study , Level II-1 ( prospect i ve cohort study ) . See the Guidelines for Authors for a complete description of levels of evidence [3313891] Background The results of R and omized Controlled Trials ( RCTs ) on time-to-event outcomes that are usually reported are median time to events and Cox Hazard Ratio . These do not constitute the sufficient statistics required for meta- analysis or cost-effectiveness analysis , and their use in secondary analyses requires strong assumptions that may not have been adequately tested . In order to enhance the quality of secondary data analyses , we propose a method which derives from the published Kaplan Meier survival curves a close approximation to the original individual patient time-to-event data from which they were generated . Methods We develop an algorithm that maps from digitised curves back to KM data by finding numerical solutions to the inverted KM equations , using where available information on number of events and numbers at risk . The reproducibility and accuracy of survival probabilities , median survival times and hazard ratios based on reconstructed KM data was assessed by comparing published statistics ( survival probabilities , medians and hazard ratios ) with statistics based on repeated reconstructions by multiple observers . Results The validation exercise established there was no material systematic error and that there was a high degree of reproducibility for all statistics . Accuracy was excellent for survival probabilities and medians , for hazard ratios reasonable accuracy can only be obtained if at least numbers at risk or total number of events are reported . Conclusion The algorithm is a reliable tool for meta- analysis and cost-effectiveness analyses of RCTs reporting time-to-event data . It is recommended that all RCTs should report information on numbers at risk and total number of events alongside KM curves [4297066] Early osteoarthritis ( OA ) is increasingly being recognized in patients who wish to remain active while not accepting the limitations of conservative treatment or joint replacement . The aim of this systematic review was to evaluate the existing evidence for treatment of patients with early OA using articular cartilage repair techniques . A systematic search was performed in EMBASE , MEDLINE , and the Cochrane collaboration . Articles were screened for relevance and appraised for quality . Nine articles of generally low method ological quality ( mean Coleman score 58 ) including a total of 502 patients ( mean age range = 36 - 57 years ) could be included . In the reports , both radiological and clinical criteria for early OA were applied . Of all patients included in this review , 75 % were treated with autologous chondrocyte implantation . Good short-term clinical outcome up to 9 years was shown . Failure rates varied from 8 % to 27.3 % . The conversion to total knee arthroplasty rate was 2.5 % to 6.5 % . Although a ( r and omized controlled ) trial in this patient category with long-term follow-up is needed , the literature suggests autologous chondrocyte implantation could provide good short- to mid-term clinical outcome and delay the need for total knee arthroplasty . The use of st and ardized criteria for early OA and implementation of ( r and omized ) trials with long-term follow-up may allow for further expansion of the research field in articular cartilage repair to the challenging population with ( early ) OA [3626217] Objectives Matrix-assisted autologous chondrocyte transplantation ( MACT ) has been developed and applied in the clinical practice in the last decade to overcome most of the disadvantages of the first generation procedures . The purpose of this systematic review is to document and analyse the available literature on the results of MACT in the treatment of chondral and osteochondral lesions of the knee . Methods All studies published in English addressing MACT procedures were identified , including those that fulfilled the following criteria : 1 ) level I-IV evidence , 2 ) measures of functional or clinical outcome , 3 ) outcome related to cartilage lesions of the knee cartilage . Results The literature analysis showed a progressively increasing number of articles per year . A total of 51 articles were selected : three r and omised studies , ten comparative studies , 33 case series and five case reports . Several scaffolds have been developed and studied , with good results reported at short to medium follow-up . Conclusions MACT procedures are a therapeutic option for the treatment of chondral lesions that can offer a positive outcome over time for specific patient categories , but high-level studies are lacking . Systematic long-term evaluation of these techniques and r and omised controlled trials are necessary to confirm the potential of this treatment approach , especially when comparing against less ambitious traditional treatments [15855365] Autologous chondrocyte implantation ( ACI ) is used widely as a treatment for symptomatic chondral and osteochondral defects of the knee . Variations of the original periosteum-cover technique include the use of porcine-derived type I/type III collagen as a cover ( ACI-C ) and matrix-induced autologous chondrocyte implantation ( MACI ) using a collagen bilayer seeded with chondrocytes . We have performed a prospect i ve , r and omised comparison of ACI-C and MACI for the treatment of symptomatic chondral defects of the knee in 91 patients , of whom 44 received ACI-C and 47 MACI grafts . Both treatments result ed in improvement of the clinical score after one year . The mean modified Cincinnati knee score increased by 17.6 in the ACI-C group and 19.6 in the MACI group ( p = 0.32 ) . Arthroscopic assessment s performed after one year showed a good to excellent International Cartilage Repair Society score in 79.2 % of ACI-C and 66.6 % of MACI grafts . Hyaline-like cartilage or hyaline-like cartilage with fibrocartilage was found in the biopsies of 43.9 % of the ACI-C and 36.4 % of the MACI grafts after one year . The rate of hypertrophy of the graft was 9 % ( 4 of 44 ) in the ACI-C group and 6 % ( 3 of 47 ) in the MACI group . The frequency of re-operation was 9 % in each group . We conclude that the clinical , arthroscopic and histological outcomes are comparable for both ACI-C and MACI . While MACI is technically attractive , further long-term studies are required before the technique is widely adopted [12678357] Autologous chondrocyte implantation ( ACI ) and mosaicplasty are both cl aim ed to be successful for the repair of defects of the articular cartilage of the knee but there has been no comparative study of the two methods . A total of 100 patients with a mean age of 31.3 years ( 16 to 49 ) and with a symptomatic lesion of the articular cartilage in the knee which was suitable for cartilage repair was r and omised to undergo either ACI or mosaicplasty ; 58 patients had ACI and 42 mosaicplasty . Most lesions were post-traumatic and the mean size of the defect was 4.66 cm2 . The mean duration of symptoms was 7.2 years and the mean number of previous operations , excluding arthroscopy , was 1.5 . The mean follow-up was 19 months ( 12 to 26 ) . Functional assessment using the modified Cincinatti and Stanmore scores and objective clinical assessment showed that 88 % had excellent or good results after ACI compared with 69 % after mosaicplasty . Arthroscopy at one year demonstrated excellent or good repairs in 82 % after ACI and in 34 % after mosaicplasty . All five patellar mosaicplasties failed . Our prospect i ve , r and omised , clinical trial has shown significant superiority of ACI over mosaicplasty for the repair of articular defects in the knee . The results for ACI are comparable with those in other studies , but those for mosaicplasty suggest that its continued use is of dubious value [4462252] Objective The efficacy and safety of BST-CarGel ® , a chitosan scaffold for cartilage repair was compared with microfracture alone at 1 year during a multicenter r and omized controlled trial in the knee . This report was undertaken to investigate 5-year structural and clinical outcomes . Design The international r and omized controlled trial enrolled 80 patients , aged 18 to 55 years , with grade III or IV focal lesions on the femoral condyles . Patients were r and omized to receive BST-CarGel ® treatment or microfracture alone , and followed st and ardized 12-week rehabilitation . Co- primary endpoints of repair tissue quantity and quality were evaluated by 3-dimensional MRI quantification of the degree of lesion filling ( % ) and T2 relaxation times . Secondary endpoints were clinical benefit measured with WOMAC ( Western Ontario and McMaster Universities Osteoarthritis Index ) question naires and safety . General estimating equations were used for longitudinal statistical analysis of repeated measures . Results Blinded MRI analysis demonstrated that BST-CarGel ® -treated patients showed a significantly greater treatment effect for lesion filling ( P = 0.017 ) over 5 years compared with microfracture alone . A significantly greater treatment effect for BST-CarGel ® was also found for repair tissue T2 relaxation times ( P = 0.026 ) , which were closer to native cartilage compared to the microfracture group . BST-CarGel ® and microfracture groups showed highly significant improvement at 5 years from pretreatment baseline for each WOMAC subscale ( P < 0.0001 ) , and there were no differences between the treatment groups . Safety was comparable for both groups . Conclusions BST-CarGel ® was shown to be an effective mid-term cartilage repair treatment . At 5 years , BST-CarGel ® treatment result ed in sustained and significantly superior repair tissue quantity and quality over microfracture alone . Clinical benefit following BST-CarGel ® and microfracture treatment were highly significant over baseline levels [4297098] Objective : To compare the responsiveness of six common patient-reported outcomes ( PROs ) following autologous chondrocyte implantation ( ACI ) . Design : A systematic search was conducted to identify reports of PROs following ACI . Study quality was evaluated using the modified Coleman Methodology Score ( mCMS ) . For each outcome score , pre- to postoperative paired Hedge ’s g effect sizes were calculated with 95 % confidence intervals ( CIs ) . R and om effects meta-analyses were performed to provide a summary response for each PRO at time points ( TP ) I ( < 1 year ) , II ( 1 year to < 2 years ) , III ( 2 years to < 4 years ) , IV ( ≥4 years ) , and overall . Results : The mean mCMS for the 42 articles included was 50.9 ± 9.2 . For all evaluated instruments , none of the mean effect size CIs encompassed zero . The International Knee Documentation Committee Subjective Knee Form ( IKDC ) had increasing responsiveness over time with TP-IV , demonstrating greater mean effect size [ confidence interval ] ( 1.78 [ 1.33 , 2.24 ] ) than TP-I ( 0.88 [ 0.69 , 1.07 ] ) . The Knee Injury and Osteoarthritis Outcome Score – Sports and recreation subscale ( KOOS-Sports ) was more responsive at TP-III ( 1.76 [ 0.87 , 2.64 ] ) and TP-IV ( 0.98 [ 0.81 , 1.15 ] ) than TP-I ( 0.61 [ 0.44 , 0.78 ] ) . Overall , the Medical Outcomes Study 36-Item Short Form Health Survey Physical Component Scale ( 0.60 [ 0.46 , 0.74 ] ) was least responsive . Both the Lysholm Scale ( 1.42 [ 1.14 , 1.72 ] ) and the IKDC ( 1.37 [ 1.13 , 1.62 ] ) appear more responsive than the KOOS-Sports ( 0.90 [ 0.73 , 1.07 ] ) . All other KOOS subscales had overall effect sizes ranging from 0.90 ( 0.74 , 1.22 ) ( Symptoms ) to 1.15 ( 0.76 , 1.54 ) ( Quality of Life ) . Conclusions : All instruments were responsive to improvements in function following ACI . The Lysholm and IKDC were the most responsive instruments across time . IKDC and KOOS-Sports may be more responsive to long-term outcomes , especially among active individuals [25416965] Abstract Purpose To evaluate the long-term clinical outcome after microfracture treatment of focal chondral defects of the knee and to investigate possible early determinants of the outcome . Methods A prospect i ve cohort of 110 patients , treated with microfracture , was evaluated at a median of 12 years ( range 10–14 ) by Lysholm score , VAS of knee function and VAS of knee pain . Pre- and perioperative information was collected , and additional surgery to the same knee during the follow-up period was recorded . Analysis of variance and paired t test were used for comparison of the long-term data to results from the baseline examination and a former 5-year ( midterm ) follow-up evaluation . Results Forty-three patients needed additional surgery to the knee including seven knee replacements . Fifty had a poor long-term outcome —defined as a knee replacement surgery or Lysholm score below 64 . A poor result was more common in subgroups with mild degenerative changes in the cartilage surrounding the treated defect , concurrent partial meniscectomy , poor baseline Lysholm score or long-st and ing knee symptoms . The Lysholm score , function VAS and pain VAS all significantly improved from the baseline values to the mean scores of 65 ( SD 24 ) , 65 ( SD 24 ) and 31 ( SD 24 ) , respectively , at the long-term evaluation . The long-term scores did not differ significantly from the midterm scores . Conclusions The outcome scores improved significantly from baseline to the long-term evaluation and were not different from the midterm outcome . Still , a normal knee function was generally not achieved , and many patients had further surgery . The results call for more research and , at present , caution in recommending microfracture in articular cartilage defects , especially in subgroups with worse prognosis . Level of evidence Case series , Level IV [19059899] Background Various approaches have been proposed to treat articular cartilage lesions , which are plagued by inherent limited healing potential . Purpose To compare the clinical outcome of patients treated with second-generation autologous chondrocyte implantation implants with those treated with the microfracture repair technique at 5-year follow-up . Study Design Cohort study ; Level of evidence , 2 . Methods Eighty active patients ( mean age , 29.8 years ) and grade III to IV cartilage lesions of the femoral condyles or trochlea were treated with arthroscopic second-generation autologous chondrocyte implantation Hyalograft C or microfracture ( 40 patients per group ) . Patients achieved a minimum 5-year follow-up and were prospect ively evaluated . Results Both groups showed statistically significant improvement of all clinical scores from preoperative interval to 5-year follow-up . There was a significant improvement for the International Knee Documentation Committee subjective score from preoperative to 5-year follow-up ( Wilcoxon test , P < .001 ) . In the microfracture group , the International Knee Documentation Committee objective score increased from 2.5 % normal and nearly normal knees before the operation to 75 % normal and nearly normal knees at 5-year follow-up , and the subjective score increased from 41.1 ± 12.3 preoperatively to 70.2 ± 14.7 at 5-year follow-up . In the group treated with Hyalograft C , the International Knee Documentation Committee objective score increased from 15 % normal and nearly normal knees before the operation to 90 % normal and nearly normal knees at 5-year follow-up , and its subjective score increased from 40.5 ± 15.2 preoperatively to 80.2 ± 19.1 at 5-year follow-up ( Wilcoxon test , P < .001 ) . When comparing the groups , better improvement of the International Knee Documentation Committee objective ( P < .001 ) and subjective ( P = .003 ) scores was observed in the Hyalograft C group at 5-year follow-up . The return to sports at 2 years was similar in both groups and remained stable after 5 years in the Hyalograft C group ; it worsened in the microfracture group . Conclusion Both methods have shown satisfactory clinical outcome at medium-term follow-up . Better clinical results and sport activity resumption were noted in the group treated with second-generation autologous chondrocyte transplantation [20062969] Cartilage defects occur in approximately 12 % of the population and can result in significant function impairment and reduction in quality of life . Evidence for the variety of surgical treatments available is inconclusive . This study aim ed to compare the clinical outcomes of patients with symptomatic cartilage defects treated with matrix-induced autologous chondrocyte implantation ( MACI ™ or microfracture ( MF ) . Included patients were ≥18 and ≤50 years of age with symptomatic , post-traumatic , single , isolated chondral defects ( 4–10 cm2 ) and were r and omised to receive MACI ™ or MF . Patients were followed up 8–12 , 22–26 and 50–54 weeks post-operatively for efficacy and safety evaluation . Outcome measures were the Tegner , Lysholm and ICRS scores . Sixty patients were included in a r and omised study ( 40 MACI ™ , 20 MF ) . The difference between baseline and 24 months post-operatively for both treatment groups was significant for the Lysholm , Tegner , patient ICRS and surgeon ICRS scores ( all P < 0.0001 ) . However , MACI ™ was significantly more effective over time ( 24 months versus baseline ) than MF according to the Lysholm ( P = 0.005 ) , Tegner ( P = 0.04 ) , ICRS patient ( P = 0.03 ) and ICRS surgeon ( P = 0.02 ) scores . There were no safety issues related to MACI ™ or MF during the study . MACI ™ is superior to MF in the treatment of articular defects over 2 years . MACI ™ and MF are complementary procedures , depending on the size of the defect and symptom recurrence . The MACI ™ technique represents a significant advance over both first and second generation chondrocyte-based cartilage repair techniques for surgeons , patients , health care institutions and payers in terms of reproducibility , safety , intraoperative time , surgical simplicity and reduced invasiveness [24051505] Abstract Purpose Microfracture is a well-established treatment procedure for chondral defects in high-dem and population with good short-term results . The purpose of our study was to evaluate long-term clinical outcome of microfracture treatment in athletes with full-thickness chondral defects . Methods Between 1991 and 2001 , 170 patients were treated with microfracture for full-thickness knee chondral lesions at our institute and 67 of them were included in this study and prospect ively followed up . Sixty-one athletes ( 91 % ) were available at final follow-up ( average 15.1 years ) . Average lesion size was 401 ± 27 mm2 . Lysholm , Tegner and International Knee Documentation Committee ( IKDC ) ( subjective– objective ) scores were utilized pre-operatively and at 2-year , 5-year and final follow-up ; Knee injury and Osteoarthritis Outcome Score ( KOOS ) , visual analog scale ( VAS ) and Marx scores were also collected at final follow-up . Results IKDC , Lysholm and Tegner scores increased significantly at 2 years , but gradually deteriorated at long term ; however , average scores were significantly above baseline at final follow-up . Seven patients ( 11 % ) were considered as failures as they underwent another operation because of reinjury or persistent pain during the first 5 years . Pain and swelling during strenuous activities was reported only in nine patients by the end of 2 years and in 35 patients at final follow-up . Patients with smaller lesions ( ≤400 mm² ) and younger patients ( ≤30 years ) showed significantly better results in KOOS , VAS and Marx scores . Radiographs performed at final follow-up showed evidence of progression of osteoarthritis changes in 40 % of the knees , with higher rate in older patients with large or multiple lesions ( p < 0.05 ) . Conclusions Microfracture when applied in young patients with smaller lesions can offer good clinical results at short- and long-term follow-up ; lesion size is more important prognostic factor of outcome than age . Deterioration of the clinical outcome should be expected after 2 and 5 years post-treatment , and degenerative changes are present at long-term follow-up , with higher rate in older athletes with large , multiple lesions . Level of evidence IV [16110716] OBJECTIVES Chondral defects of the knee cartilage are prevalent . Autologous chondrocyte implantation ( ACI ) and mosaicplasty are increasingly used to treat symptomatic knee defects . This study assessed the costs and health status outcomes after ACI and mosaicplasty . METHODS Patients were eligible to participate in this cross-sectional study if they received ACI or mosaicplasty at the Royal National Orthopaedic Hospital between 1997 and 2001 or were on a waiting list for ACI . Secondary -care re source use was collected to 2 years postoperatively using a re source collection proforma . Participants responded to postal questions about sociodemographic characteristics and knee-related ( Modified Cincinnati Knee Rating System ) and general health status ( EQ-5D ) . RESULTS Fifty-three ACI , twenty mosaicplasty , and twenty-two patients waiting for ACI participated . The average cost per patient was higher for ACI ( 10,600 pounds sterling : 95 percent confidence interval [ CI ] , 10,036 pounds sterling-11,214 pounds sterling ) than mosaicplasty ( 7,948 pounds sterling : 95 percent CI , 6,957 pounds sterling-9,243 pounds sterling ) . Postoperatively , ACI and mosaicplasty patients ( combined ) experienced better health status than those waiting for ACI . ACI patients tended to have better health status outcomes than mosaicplasty patients ( not statistically significant ) . Estimated average EQ-5D social tariff improvements for quality -adjusted life year ( QALY ) calculations were 0.23 ( ACI ) and 0.06 ( mosaicplasty ) . Average costs per QALY were 23,043 pounds sterling ( ACI ) and 66,233 pounds sterling ( mosaicplasty ) . The incremental cost effectiveness ratio ( ICER ) for providing ACI over mosaicplasty was 16,349 pounds sterling . CONCLUSIONS Average costs were higher for ACI than mosaicplasty . However , both the estimated cost per QALY and ICER for providing ACI over mosaicplasty fell beneath an implicit English funding threshold of 30,000 pounds sterling per QALY . Prospect i ve studies should include measures of utility to confirm the estimated cost utility ratios of ACI and mosaicplasty [23024150] Background : Various techniques have proven to be effective for treating articular cartilage defect ( ACD ) and osteochondral defect ( OCD ) of the knee joint , but knowledge regarding which method is best still remains uncertain . Purpose : To evaluate and compare the outcomes of mosaic-type osteochondral autologous transplantation ( OAT ) and microfracture ( MF ) procedures for the treatment of articular cartilage defects of the knee joint in young active athletes . This article represents an up date of the clinical results at 10 years . Study Design : R and omized controlled trial ; Level of evidence , 1 . Methods : Between 1998 and 2002 , a total of 60 athletes with a mean age of 24.3 years ( range , 15 - 40 years ) and with a symptomatic ACD or OCD in the knee were r and omized to undergo either OAT or MF . Patients were then evaluated postoperatively using the International Cartilage Repair Society ( ICRS ) score , Tegner activity score , radiographs , and magnetic resonance imaging . The mean follow-up time was 10.4 years ( range , 9 - 11 years ) . Results : Three to 10 years after the OAT and MF procedures , patients had lower ICRS and Tegner scores ( P < .05 ) , but both groups still had significant clinical improvement over presurgery scores according to ICRS scores at 10-year follow-up . Statistically significantly better results were detected in patients in the OAT group compared with those in the MF group at 10 years ( P < .005 ) . At 10-year follow-up , there were 15 failures ( 26 % ) , including 4 failures ( 14 % ) of the OAT and 11 failures ( 38 % ) of MF treatment ( P < .05 ) . Seven patients ( 25 % ) from the OAT group and 14 patients ( 48 % ) from the MF group had radiographic evidence of Kellgren-Lawrence grade I osteoarthritis at 10 years , but these differences were not significant ( P = .083 ) or related to the clinical results . The ICRS and Tegner scores of younger athletes ( < 25 years at the time of primary surgery ) remained significantly higher after 10 years compared with older patients ( P < .05 ) ; 15 of 20 patients ( 75 % ) in the OAT group and 8 of 22 patients ( 37 % ) in the MF group maintained the same physical activity level . Conclusion : The OAT technique for ACD or OCD repair in the athletic population allows for a higher rate of return to and maintenance of sports at the preinjury level compared with MF [22637203] BACKGROUND There is limited information regarding direct comparisons of the outcome of osteochondral autograft transfer ( OAT ) mosaicplasty and microfracture for the treatment of isolated articular cartilage defects of the knee . The purpose of this retrospective comparative study was to compare the general health outcomes , knee function , and Marx Activity Rating Scale scores for patients treated with OAT or microfracture for symptomatic chondral defects of the femoral condyles or trochlea . We hypothesized that the patients in the two treatment groups would have similar clinical outcomes at intermediate-term follow-up . METHODS Ninety-six patients with full-thickness cartilage defects of the femoral condyles or trochlea were treated with either OAT mosaicplasty ( n = 48 ) or microfracture ( n = 48 ) . The average age of the patients ( thirty-two male and sixteen female in each group ) at the time of surgery was 29.7 years in the OAT group and 32.5 years in the microfracture group . Patients were prospect ively evaluated at baseline and at one , two , three , and five years postoperatively with use of vali date d clinical outcome measures including the Short Form-36 ( SF-36 ) physical component , International Knee Documentation Committee ( IKDC ) , Knee Outcome Survey activities of daily living , and Marx Activity Rating Scale instruments . Comparisons between outcomes before and after treatment or between outcomes after microfracture and mosaicplasty were made with use of two-tailed tests . RESULTS At the time of the latest follow-up , both groups demonstrated significant increases in SF-36 physical component , Knee Outcome Survey activities of daily living , and IKDC scores compared with baseline . These scores did not differ significantly between the two groups at any of the follow-up time points . However , the OAT group demonstrated a significantly greater improvement in the Marx Activity Rating Scale scores from baseline to the two-year ( p = 0.001 ) , three-year ( p = 0.03 ) , and five-year ( p = 0.02 ) time points compared with the microfracture group . CONCLUSIONS In the present retrospective comparative study , the hypothesis that patients treated with microfracture or OAT mosaicplasty for symptomatic articular cartilage defects of the femoral condyles or trochlea would have similar clinical outcomes at intermediate-term follow-up was affirmed for general health outcome and for knee function . However , patients treated with OAT mosaicplasty maintained a superior level of athletic activity compared with those treated with microfracture [10513484] OBJECTIVE To investigate the relationship between anxiety and depression and reporting of knee pain in the community . METHODS Subjects ( n = 374 ) were community volunteers aged 40 years and above who are participants in the Baltimore Longitudinal Study of Aging , a prospect i ve multidisciplinary research study of normative aging . Knee pain was defined by the First National Health and Nutrition Examination Survey question " have you ever had pain in or around your knee on most days for at least one month ? " ; anxiety and depression were measured by the relevant subscales of the Arthritis Impact Measurement Scales question naire . All subjects had st and ing anteroposterior radiographs , read for Kellgren and Lawrence ( K + L ) grade . RESULTS After adjustment for age , women reporting " ever " knee pain had significantly higher anxiety scores than those reporting " never " pain ( 3.06 + /- 0.26 versus 2.35 + /- 0.17 ; P = 0.025 ) . Pain reporting was related neither to anxiety scores in men , nor to depression in either sex . Analysis stratified by radiographic severity , adjusted for age and gender , showed that differences in anxiety were confined to those reporting knee pain in the absence of radiographic change ( i.e. , K + L grade 0 ) . CONCLUSIONS In the community , women reporting knee pain in the absence of radiographic osteoarthritis have higher anxiety scores than those without pain . Depression was not significantly related to knee pain in this population . Psychosocial factors may explain some of the discrepancy between reported knee pain and structural change as seen on x-ray [15663280] Abstract Aim of the study : To compare outcomes of surgical treatment of deep cartilage defects of the knee in a group of patients treated by autologous chondrograft transplantation versus patients treated by abrasive techniques . Material s and methods : An original method of chondrograft preparation based on cultivated autologous chondrocytes in a three-dimensional carrier-fibrin glue ( Tissucol , Baxter , Austria ) has been described . Pre clinical tests in human cadavres and porcine models have established the possibility of chondrograft use in humans . Of the 50 patients included in the study , 25 patients ( 50 % ) underwent autologous chondrograft transplantation ( group I ) and 25 patients ( 50 % ) were treated using abrasive techniques according to Johnson ( group II ) . These two groups were similar with respect to age , size of defect , depth and localization , and presence of concomitant knee injuries . The Lysholm knee and IKDC ( International Knee Documentation Committee ) subjective scores were used to evaluate the results . Results : The preoperative value of the Lysholm knee score for patients in group I was 47.60 points ; 5 months after surgery 77.20 points ; and 12 months after surgery 86.48 points . The values for the Lysholm knee score for patients in group II preoperatively , 5 months postop , and 12 months postop were 52.60 , 69.20 , and 74.48 respectively . Results 12 months after surgery were significantly better in group I as compared to group II ( p < 0.001 ) . The preoperative value of the IKDC subjective score in group I was 41.28 points ; 5 months after surgery 67.00 points ; and 12 months after surgery 76.48 points . The values for the IKDC subjective score in group II preoperatively , 5 months postop , and 12 months postop were 45.00 , 62.28 , and 68.08 respectively . Results 12 months after surgery were significantly better in group I when compared to group II ( p < 0.05 ) . Conclusions : The results obtained in this study have confirmed the better outcome in patients treated with autologous chondrograft transplantation . This original method was found to be just as effective as abrasive techniques . We recommend its use in clinical practice [21908720] Background : Characterized chondrocyte implantation ( CCI ) results in significantly better early structural tissue regeneration than microfracture ( MF ) , and CCI has a midterm clinical benefit over microfracture . Purpose : This study was undertaken to evaluate the 5-year clinical outcome of CCI in a r and omized comparison with MF for the treatment of symptomatic cartilage defects of the femoral condyles of the knee . Study Design : R and omized controlled trial ; Level of evidence , 1 . Methods : Participants aged 18 to 50 years with a symptomatic isolated International Cartilage Repair Society ( ICRS ) grade III or IV cartilage lesion of the femoral condyles between 1 and 5 cm2 were r and omized to either CCI or MF . Clinical outcomes were measured up to 60 months after surgery using the Knee Injury and Osteoarthritis Outcome Score ( KOOS ) . The main outcome parameter was change from baseline in overall KOOS ( oKOOS ) . Adverse events were monitored . Results : Fifty-one participants were treated with CCI and 61 with MF . On average , clinical benefit was maintained through the 60-month follow-up period . The average change from baseline in oKOOS was not different between both groups ( least squares [ LS ] mean ± st and ard error [ SE ] 18.84 ± 3.58 for CCI vs 13.21 ± 5.63 for MF ; P = .116 ) . Treatment failures were comparable ( n = 7 in CCI vs n = 10 in MF ) , although MF failures tended to occur earlier . Subgroup analysis revealed that CCI result ed in better outcome in participants with time since symptom onset of less than 3 years , which was statistically significant and clinical ly relevant ( change in oKOOS <3 years mean ± SE 25.96 ± 3.45 for CCI vs 15.28 ± 3.17 for MF ; P = .026 vs oKOOS > 3 years mean ± SE 13.09 ± 4.78 for CCI vs 17.02 ± 4.50 for MF , P = .554 ) . Other subgroup analyses such as age ( cutoff 35 years ) did not show a difference . Female patients showed more failures irrespective of treatment . Conclusion : At 5 years after treatment , clinical outcomes for CCI and MF were comparable . In the early treatment group , CCI obtained statistically significant and clinical ly relevant better results than MF . Delayed treatment result ed in less predictable outcomes for CCI . These results provide strong evidence that time since onset of symptoms is an essential variable that should be taken into account in future treatment algorithms for cartilage repair of the knee [24714783] Background : R and omized controlled trials study ing the efficacy and safety of matrix-applied characterized autologous cultured chondrocytes ( MACI ) versus microfracture ( MFX ) for treating cartilage defects are limited . Purpose : To compare the clinical efficacy and safety of MACI versus MFX in the treatment of patients with symptomatic cartilage defects of the knee . Study Design : R and omized controlled clinical trial ; Level of evidence , 1 . Methods : Patients enrolled in the SUMMIT ( Demonstrate the Superiority of MACI implant to Microfracture Treatment ) trial had ≥1 symptomatic focal cartilage defect ( Outerbridge grade III or IV ; ≥3 cm2 ) of the femoral condyles or trochlea , with a baseline Knee Injury and Osteoarthritis Outcome Score ( KOOS ) pain value < 55 . The co– primary efficacy endpoint was the change in the KOOS pain and function subscores from baseline to 2 years . Histological evaluation and magnetic resonance imaging ( MRI ) assessment s of structural repair tissue , treatment failure , the remaining 3 KOOS subscales , and safety were also assessed . Results : Of the 144 patients treated , 137 ( 95 % ) completed the 2-year assessment . Patients had a mean age of 33.8 years and a mean lesion size of 4.8 cm2 . The mean KOOS pain and function subscores from baseline to 2 years were significantly more improved with MACI than with MFX ( pain : MACI , 37.0 to 82.5 vs MFX , 35.5 to 70.9 ; function : MACI , 14.9 to 60.9 vs MFX , 12.6 to 48.7 ; P = .001 ) . A significant improvement in scores was also observed on the KOOS subscales of activities of daily living ( MACI , 43.5 to 87.2 vs MFX , 42.6 to 75.8 ; P < .001 ) , knee-related quality of life ( MACI , 18.8 to 56.2 vs MFX , 17.2 to 47.3 ; P = .029 ) , and other symptoms ( MACI , 48.3 to 83.7 vs MFX , 44.4 to 72.2 ; P < .001 ) for patients treated with MACI compared with MFX . Repair tissue quality was good as assessed by histology/MRI , but no difference was shown between treatments . A low number of treatment failures ( nonresponders : MACI , 12.5 % vs MFX , 31.9 % ; P = .016 ) and no unexpected safety findings were reported . Conclusion : The treatment of symptomatic cartilage knee defects ≥3 cm2 in size using MACI was clinical ly and statistically significantly better than with MFX , with similar structural repair tissue and safety , in this heterogeneous patient population . Moreover , MACI offers a more efficacious alternative than MFX with a similar safety profile for the treatment of symptomatic articular cartilage defects of the knee [19846694] Background Damaged articular cartilage has limited capacity for self-repair . Autologous chondrocyte implantation using a characterized cell therapy product results in significantly better early structural repair as compared with microfracture in patients with symptomatic joint surface defects of the femoral condyles of the knee . Purpose To evaluate clinical outcome at 36 months after characterized chondrocyte implantation ( CCI ) versus microfracture ( MF ) . Study Design R and omized controlled trial ; Level of evidence , 1 . Methods Patients aged 18 to 50 years with single International Cartilage Repair Society ( ICRS ) grade III/IV symptomatic cartilage defects of the femoral condyles were r and omized to CCI ( n = 57 ) or MF ( n = 61 ) . Clinical outcome was measured over 36 months by the Knee injury and Osteoarthritis Outcome Score ( KOOS ) . Serial magnetic resonance imaging ( MRI ) scans were scored using the Magnetic resonance Observation of Cartilage Repair Tissue ( MOCART ) system and 9 additional items . Gene expression profile scores associated with ectopic cartilage formation were determined by RT-PCR . Results Baseline mean overall KOOS ( ±SE ) was comparable between the CCI and MF groups ( 56.30 ± 1.91 vs 59.46 ± 1.98 , respectively ) . Mean improvement ( ±SE ) from baseline to 36 months in overall KOOS was greater in the CCI group than the MF group ( 21.25 ± 3.60 vs 15.83 ± 3.48 , respectively ) , while in a mixed linear model analysis with time as a categorical variable , significant differences favoring CCI were shown in overall KOOS ( P = .048 ) and the subdomains of Pain ( P = .044 ) and QoL ( P = .036 ) . More CCI- than MF-treated patients were treatment responders ( 83 % vs 62 % , respectively ) . In patients with symptom onset of < 2 years , the mean improvement ( ±SE ) from baseline to 36 months in overall KOOS was greater with CCI than MF ( 24.98 ± 4.34 vs 16.50 ± 3.99 , respectively ) and even greater in patients with symptom onset of <3 years ( 26.08 ± 4.10 vs 17.09 ± 3.77 , respectively ) . Characterized chondrocyte implantation patients with high ( > 2 ) versus low ( < 2 ) gene profile scores showed greater improvement from baseline in mean overall KOOS ( ±SE ) at 36 months ( 28.91 ± 5.69 vs 18.18 ± 5.08 , respectively ) . Subchondral bone reaction significantly worsened over time with MF compared with CCI ( P < .05 ) . Conclusion Characterized chondrocyte implantation for the treatment of articular cartilage defects of the femoral condyles of the knee results in significantly better clinical outcome at 36 months in a r and omized trial compared with MF . Time to treatment and chondrocyte quality were shown to affect outcome [22539536] Background : While structured postoperative rehabilitation after matrix-induced autologous chondrocyte implantation ( MACI ) is considered critical , very little has been made available on how best to progressively increase weightbearing and exercise after surgery . Hypothesis : A significant improvement will exist in clinical and magnetic resonance imaging (MRI)–based scoring measures to 5 years after surgery . Furthermore , there will be no significant differences in outcomes in MACI patients at 5 years when comparing a traditional and an accelerated postoperative weightbearing regimen . Finally , patient demographics , cartilage defect parameters , and injury/surgery history will be associated with graft outcome . Study Design : R and omized controlled trial ; Level of evidence , 1 . Methods : Clinical and radiological outcomes were studied in 70 patients who underwent MACI to the medial or lateral femoral condyle , in conjunction with either an “ accelerated ” or a “ traditional ” approach to postoperative weightbearing rehabilitation . Under the accelerated protocol , patients reached full weightbearing at 8 weeks after surgery , compared with 11 weeks for the traditional group . Clinical measures ( Knee Injury and Osteoarthritis Outcome Score [ KOOS ] , Short-Form Health Survey [ SF-36 ] , visual analog scale [ VAS ] , 6-minute walk test , and knee range of motion ) were assessed before surgery and at 3 , 6 , 12 , and 24 months and 5 years after surgery . High-resolution MRI was undertaken at 3 , 12 , and 24 months and 5 years after surgery and assessed 8 previously defined pertinent parameters of graft repair as well as a combined MRI composite score . The association between clinical and MRI-based outcomes , patient demographics , chondral defect parameters , and injury/surgery history was investigated . Results : Of the 70 patients recruited , 63 ( 31 accelerated , 32 traditional ) underwent clinical follow-up at 5 years ; 58 ( 29 accelerated , 29 traditional ) also underwent radiological assessment . A significant time effect ( P < .05 ) was demonstrated for all clinical and MRI-based scores over the 5-year period . While the VAS demonstrated significantly less frequent pain at 5 years in the accelerated group , there were no other significant differences between the 2 groups . Between 24 months and 5 years , a significant improvement ( P < .05 ) in both groups was observed for the sport and recreation subscale of the KOOS as well as a significant decrease ( P < .05 ) in active knee extension for the traditional group . There were no significant differences ( P > .05 ) in the MRI-based scores between 24 months and 5 years after surgery . Patient age and defect size exhibited significant negative correlations ( P < .05 ) with several MRI-based outcomes at 5 years , while there were no significant correlations ( P > .05 ) between clinical and MRI-based outcomes . At 5 years after surgery , 94 % and 95 % were satisfied with the ability of MACI to relieve their knee pain and improve their ability to undertake daily activities , respectively . Conclusion : The outcomes of this r and omized trial demonstrate a safe and effective accelerated rehabilitation protocol as well as a regimen that provides comparable , if not superior , clinical outcomes to patients throughout the postoperative timeline [23142295] PURPOSE To compare the concomitant treatment of articular cartilage damage in the medial femoral condyle with osteochondral autologous transplantation ( OAT ) , microfracture , or debridement procedures at the time of anterior cruciate ligament ( ACL ) reconstruction . METHODS Between 2006 and 2009 , 102 patients with a mean age of 34.1 years and with an ACL rupture and articular cartilage damage in the medial femoral condyle of the knee were r and omized to undergo OAT , microfractures , or debridement at the time of ACL reconstruction . A matched control group was included , comprising 34 patients with intact articular cartilage at the time of ACL reconstruction . There were 34 patients in the OAT-ACL group , 34 in the microfracture (MF)-ACL group , 34 in the debridement (D)-ACL group , and 34 in the control group with intact articular cartilage ( IAC-ACL group ) . The mean time from ACL injury to operation was 19.32 ± 3.43 months , and the mean follow-up was 36.1 months ( range , 34 to 37 months ) . Patients were evaluated with the International Knee Documentation Committee ( IKDC ) score , Tegner activity score , and clinical assessment . RESULTS Of 102 patients , 97 ( 95 % ) were available for the final follow-up . According to the subjective IKDC score , all 4 groups fared significantly better at the 3-year follow-up than preoperatively ( P < .005 ) . The OAT-ACL group 's IKDC subjective knee evaluation was significantly better than that of the MF-ACL group ( P = .024 ) and D-ACL group ( P = .018 ) . However , the IKDC subjective score of the IAC-ACL group was significantly better than the OAT-ACL group 's IKDC evaluation ( P = .043 ) . There was no significant difference between the MF-ACL and D-ACL groups ' IKDC subjective scores ( P = .058 ) . Evaluation of manual pivot-shift knee laxity according to the IKDC knee examination form showed similar findings for the 4 groups immediately postoperatively and at 3-year follow-up , and the findings were rated as normal or nearly normal ( IKDC grade A or B ) in 29 of 33 patients ( 88 % ) in the OAT-ACL group , 28 of 32 patients ( 88 % ) in the MF-ACL group , 27 of 32 patients ( 84 % ) in the D-ACL group , and 31 of 34 patients ( 91 % ) in the IAC-ACL group . CONCLUSIONS Our study shows that intact articular cartilage during ACL reconstruction yields more favorable IKDC subjective scores compared with any other articular cartilage surgery type . However , if an articular defect is present , the subjective IKDC scores are significantly better for OAT versus microfracture or debridement after a mean period of 3 years . Anterior knee stability results were not significantly affected by the different articular cartilage treatment methods . LEVEL OF EVIDENCE Level II , prospect i ve comparative study [17908884] BACKGROUND The optimal treatment for cartilage lesions has not yet been established . The objective of this r and omized trial was to compare autologous chondrocyte implantation with microfracture . This paper represents an up date , with presentation of the clinical results at five years . METHODS Eighty patients who had a single chronic symptomatic cartilage defect on the femoral condyle in a stable knee without general osteoarthritis were included in the study . Forty patients were treated with autologous chondrocyte implantation , and forty were treated with microfracture . We used the International Cartilage Repair Society , Lysholm , Short Form-36 , and Tegner forms to collect clinical data , and radiographs were evaluated with use of the Kellgren and Lawrence grading system . RESULTS At two and five years , both groups had significant clinical improvement compared with the preoperative status . At the five-year follow-up interval , there were nine failures ( 23 % ) in both groups compared with two failures of the autologous chondrocyte implantation and one failure of the microfracture treatment at two years . Younger patients did better in both groups . We did not find a correlation between histological quality and clinical outcome . However , none of the patients with the best- quality cartilage ( predominantly hyaline ) at the two-year mark had a later failure . One-third of the patients in both groups had radiographic evidence of early osteoarthritis at five years . CONCLUSIONS Both methods provided satisfactory results in 77 % of the patients at five years . There was no significant difference in the clinical and radiographic results between the two treatment groups and no correlation between the histological findings and the clinical outcome . One-third of the patients had early radiographic signs of osteoarthritis five years after the surgery . Further long-term follow-up is needed to determine if one method is better than the other and to study the progression of osteoarthritis [16003035] Objective : To compare the respective performance and effectiveness of autologous chondrocyte implantation ( ACI ) and mosaicplasty at resurfacing local full-thickness chondral defects of the knee . Design : R and omized clinical trial . Setting : Multicenter trial at orthopedic clinics and university hospitals conducted from 1997 to 2000 . Patients : A population of patients selected according to eligibility criteria of age , traumatic origin of the defect , its localization , size , and gravity , and above all , no previous surgical treatment of the lesion . Forty-seven patients were r and omly assigned to ACI or mosaicplasty and subjected to arthroscopic debridement of the lesion at the time of enrollment . They were called for surgery 6 months after the initial debridement . Main Outcome : Improved knee functionality as assessed by repeated clinical evaluation based on the International Knee Documentation Committee Scale and the Lysholm Knee Scoring Scale . Results : Fourteen patients ( 31.8 % ) experienced substantial improvement following the initial debridement and , being clinical ly cured , received no further treatment . Seven patients ( 15.9 % ) were lost to follow-up . Among the 23 patients ( 52.3 % ) who could effectively be evaluated , a complete recovery ( ie , Lysholm Knee Scoring Scale score , 90 - 100 ) was observed upon clinical examination in 88 % of the mosaicplasty-treated patients and in 68 % of the ACI-treated ones ( P = 0.093 ) . Conclusions : Although the low power of our study prevents definitive conclusions , ACI and mosaicplasty are cartilage repair techniques that are clinical ly equivalent and similar in performance . The high percentage of spontaneous improvement ( ⅓ of the patients ) observed after simple debridement calls into question the need for prompt surgical treatment of patients with lesions similar to those included in this clinical trial . Moreover , this finding warrants further investigation , ideally through r and omized clinical trials in which patients subjected to debridement alone are compared with patients undergoing reconstructive surgery [15194101] Arthroscopy and washout of the knee is commonly performed for early osteoarthritis . Very little information exists regarding long-term prognosis , especially in terms of avoidance of further surgery . Using a prospect ively gathered data base , 100 consecutive patients having knee arthroscopy with a finding of OA between 1991 and 1993 were identified and their outcome at 5 years ascertained . Ninety-nine patients with 100 arthroscoped knees were identified . Fifty-eight had isolated medial compartment disease and six had isolated lateral compartment disease . In 36 , both compartments were affected . Eighteen knees had further major surgery during follow up ; 11 had total knee replacement , four had high tibial osteotomy and three had unicondylar knee arthroplasty . Those requiring surgery were significantly older ( 62 cf . 53 years , P=0.008 ) . Meniscectomy was not an important risk factor ( chi2 , P=0.67 ) . The rate of knee survival without operation at 5 years was much lower in those aged over 60 years than in those younger ( 68 % cf . 89 % ) . ( chi2 , P=0.02 ) . Only 18 % of patients progress to major knee surgery within 5 years of arthroscopic washout for osteoarthritis . Age greater than 60 years worsens the prognosis considerably [11043126] INTRODUCTION The treatment of full-thickness cartilage defects still represents a problem that has not yet been solved satisfactorily . Current methods used to cover defects in the knee joint are osteochondral cylinder transplantation ( OCT ) and autologous chondrocyte transplantation ( ACT ) . METHODS With a prospect i ve clinical investigation , at the time being with 2-year results , we have examined ACT in comparison to OCT in 20 patients with regard to clinical and histomorphological ( histology , immunohistochemistry , RES ) outcome . RESULTS We found equally good results with both methods in Lysholm , Meyers and Tegner Activity Scores . Histomorphologic evaluation of biopsies obtained by arthroscopy after ACT showed a defect filling in all cases , mainly with fibrous cartilage , while localized areas of hyalinelike regenerative cartilage were documented near the base . We did not see any histomorphologically visible change in the transplants after OCT . CONCLUSION At the time we prefer OCT instead of ACT given the correct indication [19865812] We compared the results of microfracture in single versus multiple symptomatic articular cartilage defects in the knee in 110 patients with a median age of 38 years ( range 15–60 ) . Cases of reoperation of the cartilage defect were classified as failures . Clinical outcome in non-failures was evaluated by the Lysholm score and grading of knee pain and function of the knee by the use of patient-administered visual analog scales ( VAS ; 0–100 ) . Data were prospect ively collected before the operation and at the 2- to 9-year follow-up . The single lesion or the largest of multiple lesions were located on the medial femoral condyle ( n = 62 ) , trochlea ( n = 18 ) , lateral tibia ( n = 11 ) , patella ( n = 10 ) or lateral femoral condyle ( n = 9 ) . We treated one ( n = 76 ) , two ( n = 27 ) or three ( n = 7 ) lesions with a median total area of 4 cm2 ( range 1–15 ) . A total of 24 failures ( 22 % ) were registered—18 % in the single-defect subgroup and 29 % in the multiple-defects subgroup . In the remaining group of patients ( n = 86 ) , the mean Lysholm score , mean pain-score ( 0 = no pain ; 100 = worst possible pain ) and mean function-score ( 0 = useless ; 100 = full function ) improved from 51 , 52 and 41 , respectively , to 71 ( P < 0.001 ) , 30 ( P < 0.001 ) and 69 ( P < 0.001 ) at the follow-up . The pain-score was significant lower ( P = 0.042 ) , and the function-score significantly higher ( P = 0.001 ) in the group of patients with a single lesion compared to the group with 2 or 3 lesions . The Lysholm score did not differ significantly between the two subgroups ( P = 0.06 ) [12110735] BACKGROUND Many patients report symptomatic relief after undergoing arthroscopy of the knee for osteoarthritis , but it is unclear how the procedure achieves this result . We conducted a r and omized , placebo-controlled trial to evaluate the efficacy of arthroscopy for osteoarthritis of the knee . METHODS A total of 180 patients with osteoarthritis of the knee were r and omly assigned to receive arthroscopic débridement , arthroscopic lavage , or placebo surgery . Patients in the placebo group received skin incisions and underwent a simulated débridement without insertion of the arthroscope . Patients and assessors of outcome were blinded to the treatment-group assignment . Outcomes were assessed at multiple points over a 24-month period with the use of five self-reported scores -- three on scales for pain and two on scales for function-- and one objective test of walking and stair climbing . A total of 165 patients completed the trial . RESULTS At no point did either of the intervention groups report less pain or better function than the placebo group . For example , mean ( + /-SD ) scores on the Knee-Specific Pain Scale ( range , 0 to 100 , with higher scores indicating more severe pain ) were similar in the placebo , lavage , and débridement groups : 48.9+/-21.9 , 54.8+/-19.8 , and 51.7+/-22.4 , respectively , at one year ( P=0.14 for the comparison between placebo and lavage ; P=0.51 for the comparison between placebo and débridement ) and 51.6+/-23.7 , 53.7+/-23.7 , and 51.4+/-23.2 , respectively , at two years ( P=0.64 and P=0.96 , respectively ) . Furthermore , the 95 percent confidence intervals for the differences between the placebo group and the intervention groups exclude any clinical ly meaningful difference . CONCLUSIONS In this controlled trial involving patients with osteoarthritis of the knee , the outcomes after arthroscopic lavage or arthroscopic débridement were no better than those after a placebo procedure [16928947] OBJECTIVE The purpose of this study was to use the Kellgren-Lawrence , Ahlback , and Br and t grading scales to correlate radiographic grade of osteoarthritis with the actual degree of articular cartilage degeneration within the tibiofemoral joint in patients with chronic knee pain . SUBJECTS AND METHODS The study group consisted of 125 patients with symptomatic osteoarthritis of the tibiofemoral joint . For all patients , st and ing anteroposterior radiographs of the knee were obtained before arthroscopic knee surgery . Each articular surface of the tibiofemoral joint was grade d at arthroscopy . Two radiologists retrospectively review ed the knee radiographs without knowledge of the arthroscopic findings to determine the presence and severity of osteoarthritis of the tibiofemoral joint using the Kellgren-Lawrence , Ahlback , and Br and t grading scales . Correlation coefficients describing the relation between grade of osteoarthritis and severity of articular cartilage degeneration were calculated for each grading scale . RESULTS The correlation coefficients for the Kellgren-Lawrence , Ahlback , and Br and t grading scales were 0.49 , 0.41 , and 0.56 , respectively . The differences between the correlation coefficients for the Kellgren-Lawrence and Ahlback grading scales and the correlation coefficients for the Br and t and Ahlback grading scales were statistically significant ( p < 0.05 ) . Many patients with no radiographic findings of osteoarthritis had significant articular cartilage degeneration within the tibiofemoral joint . CONCLUSION The Kellgren-Lawrence and Br and t grading scales were equally effective in defining the presence of and estimating the severity of osteoarthritis of the tibiofemoral joint but had only a moderately strong correlation with the actual degree of articular cartilage degeneration [8666628] In a prospect i ve r and omised trial 76 knees with isolated degenerative changes in the medial femoral condyle of grade s 3 or 4 were treated by either arthroscopic debridement ( 40 ) or washout ( 36 ) . All knees were followed up for at least one year and 58 for five years . The mean follow-up time was 4.5 years in the debridement group and 4.3 years in the washout group . At one year 32 of the debridement group and five of the washout group were painfree and at five years 19 of a total of 32 survivors in the debridement group and three of the 26 in the washout group were also free from pain . The mean improvement in a modified Lysholm score was 28 for the debridement group at one year and 21 at five years . In the washout group it was only 5 at one year and 4 at five years . For knees with lesions of the medial femoral condyle of grade s 3 or 4 , arthroscopic debridement appears to be the treatment of choice with over half the patients free from pain after five years [22434467] Autologous chondrocyte implantation ( ACI ) and mosaicplasty are methods of treating symptomatic articular cartilage defects in the knee . This study represents the first long-term r and omised comparison of the two techniques in 100 patients at a minimum follow-up of ten years . The mean age of the patients at the time of surgery was 31.3 years ( 16 to 49 ) ; the mean duration of symptoms pre-operatively was 7.2 years ( 9 months to 20 years ) . The lesions were large with the mean size for the ACI group being 440.9 mm(2 ) ( 100 to 1050 ) and the mosaicplasty group being 399.6 mm(2 ) ( 100 to 2000 ) . Patients had a mean of 1.5 previous operations ( 0 to 4 ) to the articular cartilage defect . Patients were assessed using the modified Cincinnati knee score and the Stanmore-Bentley Functional Rating system . The number of patients whose repair had failed at ten years was ten of 58 ( 17 % ) in the ACI group and 23 of 42 ( 55 % ) in the mosaicplasty group ( p < 0.001 ) . The functional outcome of those patients with a surviving graft was significantly better in patients who underwent ACI compared with mosaicplasty ( p = 0.02 ) [22422593] Background Many surgical techniques , including microfracture , periosteal and perichondral grafts , chondrocyte transplantation , and osteochondral grafts , have been studied in an attempt to restore damaged articular cartilage . However , there is no consensus regarding the best method to repair isolated articular cartilage defects of the knee . Questions / purpose sWe compared postoperative functional outcomes , followup MRI appearance , and arthroscopic examination after microfracture ( MF ) , osteochondral autograft transplantation ( OAT ) , or autologous chondrocyte implantation ( ACI ) . Methods We prospect ively investigated 30 knees with MF , 22 with OAT , and 18 with ACI . Minimum followup was 3 years ( mean , 5 years ; range , 3–10 years ) . We included only patients with isolated cartilage defects and without other knee injuries . The three procedures were compared in terms of function using the Lysholm knee evaluation scale , Tegner activity scale , and Hospital for Special Surgery ( HSS ) score ; modified Outerbridge cartilage grade s using MRI ; and International Cartilage Repair Society ( ICRS ) repair grade using arthroscopy . Results All three procedures showed improvement in functional scores . There were no differences in functional scores and postoperative MRI grade s among the groups . Arthroscopy at 1 year showed excellent or good results in 80 % after MF , 82 % after OAT , and 80 % after ACI . Our study did not show a clear benefit of either ACI or OAT over MF . Conclusions Owing to a lack of superiority of any one treatment , we believe MF is a reasonable option as a first-line therapy given its ease and affordability relative to ACI or OAT.Level of Evidence Level II , therapeutic study . See Guidelines for Authors for a complete description of levels of evidence [15278206] AIM Matrix-guided autologous chondrocyte implantation ( MACI ) was compared with microfracture ( MFX ) to demonstrate the reconstitution of cartilage over a two-year period using the morphological capabilities of MRI . PATIENTS AND METHODS 27 patients ( 9 females and 18 males , mean age 33 years ) underwent MACI on the knee joint . The defects originated from trauma ( 15 cases ) , osteochondritis dissecans ( 8 cases ) and chronic repetitive trauma ( 4 cases ) and were localized at the condyles ( 24 cases ) or patella ( 3 cases ) . All patients were examined postoperatively after 1 , 3 , 6 , 12 and 24 months with a 1,5 T unit ( Gyroscan , Philips ) using proton- and T2w spinecho and T1w fatsuppressed 3D gradientecho sequences . We measured the signal intensities of the implant and neighbouring cartilage to calculate the contrast-to-noise ratio ( CNR ) , and the thickness of cartilage and implant layers to define the defect filling rate . Finally , partial and complete remission was defined on MRI and compared with clinical data and morphology on MRI . Additionally , 7 patients were treated with MFX and , subsequently examined on MRI with the same protocol . RESULTS After MACI , MRI showed a partial but no complete equilibration of signal intensities of implant and adjacent cartilage over the 1 and 2 year follow-up periods which was shown by reduction of CNR from 21 to 10 on 3D-GE and from 26 to 9 on T2w SE sequences . Continuous growth of the implants result ed in an increased filling of the defects starting at 40 % after 0.5 year to 85 % after 1 or 2 years . Complete remission was found on MRI in 17/27 cases , and remission rate was influenced by etiology of cartilage defect but not by age and gender of patients or size and location of defects . The Lysholm-Gillquist score improved from 49.7 to 97.3 . After MFX equilibration of signal intensities and growth of the regenerating fibrous cartilage was less pronounced and complete remission was found in only 2/7 cases . In addition , the clinical score improved from 45.5 to 74.2 . CONCLUSION Direct imaging of cartilage with MRI and assessment of clinical scores allowed improved documentation of the outcome after MACI and MFX . MRI showed that MACI is superior to MFX concerning rate of complete remissions and filling of the defect with regenerating tissue . Clinical examinations showed better scores for MACI than for MFX [23979923] Background Autologous chondrocyte implantation ( ACI ) has demonstrated good and excellent results in over 75 % of patients up to 10 years after surgery . Reports of longer-term outcomes , however , remain limited . Questions / purpose sThe purpose s of this study were to describe the ( 1 ) survivorship of ACI grafts ; ( 2 ) the long-term functional outcomes using vali date d scoring tools after ACI ; and ( 3 ) to provide an analysis of potential predictors for failure . Methods Two hundred ten patients treated with ACI were followed for more than 10 years . Indications for the procedure included symptomatic cartilage defects in all compartments of the knee unresponsive to nonoperative measures . Mean age at surgery was 36 ± 9 years ; mean defect size measured 8.4 ± 5.5 cm2 . Outcome scores were prospect ively collected pre- and postoperatively at the last followup . Results At a mean of 12 ± 2 years followup , 53 of 210 patients ( 25 % ) had at least one failed ACI graft . Nineteen of these patients went on to arthroplasty , 27 patients were salvaged with revision cartilage repair , and seven patients declined further treatment ; three patients were lost to followup . The modified Cincinnati increased from 3.9 ± 1.5 to 6.4 ± 1.5 , WOMAC improved from 39 ± 21 to 23 ± 16 , Knee Society Score ( KSS ) knee score rose from 54 ± 18 to 79 ± 19 , and KSS function from 65 ± 23 to 78 ± 17 ( all p < 0.0001 ) . The Physical Component of the SF-36 score increased from 33 ± 14 to 49 ± 18 , whereas the Mental Component improved from 46 ± 14 to 52 ± 15 ( both p < 0.001 ) . Survivorship was higher in patients with complex versus salvage-type lesions ( p = 0.03 ) with primary ACI versus ACI after prior marrow stimulation ( p = 0.004 ) and with concomitant high tibial osteotomy ( HTO ) versus no HTO ( p = 0.01 ) . Conclusions ACI provided durable outcomes with a survivorship of 71 % at 10 years and improved function in 75 % of patients with symptomatic cartilage defects of the knee at a minimum of 10 years after surgery . A history of prior marrow stimulation as well as the treatment of very large defects was associated with an increased risk of failure . Level of Evidence Level IV , therapeutic study . See Guidelines for Authors for a complete description of levels of evidence [14996869] BACKGROUND New methods have been used , with promising results , to treat full-thickness cartilage defects . The objective of the present study was to compare autologous chondrocyte implantation with microfracture in a r and omized trial . We are not aware of any previous r and omized studies comparing these methods . METHODS Eighty patients without general osteoarthritis who had a single symptomatic cartilage defect on the femoral condyle in a stable knee were treated with autologous chondrocyte implantation or microfracture ( forty in each group ) . We used the International Cartilage Repair Society , Lysholm , Short Form-36 ( SF-36 ) , and Tegner forms to collect data . An independent observer performed a follow-up examination at twelve and twenty-four months . Two years postoperatively , arthroscopy with biopsy for histological evaluation was carried out . The histological evaluation was done by a pathologist and a clinical scientist , both of whom were blinded to each patient 's treatment . RESULTS In general , there were small differences between the two treatment groups . At two years , both groups had significant clinical improvement . According to the SF-36 physical component score at two years postoperatively , the improvement in the microfracture group was significantly better than that in the autologous chondrocyte implantation group ( p = 0.004 ) . Younger and more active patients did better in both groups . There were two failures in the autologous chondrocyte implantation group and one in the microfracture group . No serious complications were reported . Biopsy specimens were obtained from 84 % of the patients , and histological evaluation of repair tissues showed no significant differences between the two groups . We did not find any association between the histological quality of the tissue and the clinical outcome according to the scores on the Lysholm or SF-36 form or the visual analog scale . CONCLUSIONS Both methods had acceptable short-term clinical results . There was no significant difference in macroscopic or histological results between the two treatment groups and no association between the histological findings and the clinical outcome at the two-year time-point . LEVEL OF EVIDENCE Therapeutic study , Level I-1a ( r and omized controlled trial [ significant difference ] ) . See Instructions to Authors for a complete description of levels of evidence [21257846] Background : The availability remains limited of midterm clinical and radiologic results into matrix-induced autologous chondrocyte implantation ( MACI ) . Outcomes are required to vali date the efficacy of MACI as a suitable surgical treatment option for articular cartilage defects in the knee . Hypothesis : A significant improvement in clinical and magnetic resonance imaging – based ( MRI-based ) outcomes after MACI will exist throughout the postoperative timeline to 5 years after surgery . Furthermore , patient demographics , cartilage defect parameters , and injury/surgery history will be associated with patient and graft outcome , whereas a significant correlation will exist between clinical and MRI-based outcomes at 5 years after surgery . Study Design : Case series ; Level of evidence , 4 . Methods : A prospect i ve evaluation was undertaken to assess clinical and MRI-based outcomes to 5 years in 41 patients ( 53 grafts ) after MACI to the knee . After MACI surgery and a 12-week structured rehabilitation program , patients underwent clinical assessment s ( Knee injury and Osteoarthritis Outcome Score , SF-36 , 6-minute walk test , knee range of motion ) and MRI assessment s at 3 , 12 , and 24 months , as well as 5 years after surgery . The MRI evaluation assessed 8 previously defined pertinent parameters of graft repair , as well as a combined MRI composite score . Results : A significant improvement ( P < .05 ) was demonstrated for all Knee injury and Osteoarthritis Outcome Score and SF-36 subscales over the postoperative timeline , as well as the 6-minute walk test and active knee extension . A significant improvement ( P < .0001 ) was observed for the MRI composite score , as well as several individual graft scoring parameters . At 5 years after surgery , 67 % of MACI grafts demonstrated complete infill , whereas 89 % demonstrated good to excellent filling of the chondral defect . Patient demographics , cartilage defect parameters , and injury/surgery history demonstrated no significant pertinent correlations with clinical or MRI-based outcomes at 5 years , and no significant correlations existed between clinical and MRI-based outcome measures . At 5 years after surgery , 98 % of patients were satisfied with the ability of MACI surgery to relieve knee pain ; 86 % , with improvement in their ability to perform normal daily tasks ; and 73 % , with their ability to participate in sport 5 years after MACI . Conclusion : These results suggest that MACI provides a suitable midterm treatment option for articular cartilage defects in the knee . Long-term follow-up is essential to confirm whether the repair tissue has the durability required to maintain long-term patient quality of life [18202295] Background As the natural healing capacity of damaged articular cartilage is poor , joint surface injuries are a prime target for regenerative medicine . Characterized chondrocyte implantation uses an autologous cartilage cell therapy product that has been optimized for its biological potency to form stable cartilage tissue in vivo . Purpose To determine whether , in symptomatic cartilage defects of the femoral condyle , structural regeneration with characterized chondrocyte implantation is superior to repair with microfracture . Study Design R and omized controlled trial ; Level of evidence , 1 . Methods Characterized chondrocyte implantation was compared with microfracture in patients with single grade III to IV symptomatic cartilage defects of the femoral condyles in a multicenter trial . Patients aged 18 to 50 years were r and omized to characterized chondrocyte implantation ( n = 57 ) or microfracture ( n = 61 ) . Structural repair was blindly assessed in biopsy specimens taken at 1 year using ( 1 ) computerized histomorphometry and ( 2 ) evaluation of overall histological components of structural repair . Clinical outcome was measured using the self administered Knee injury and Osteoarthritis Outcome Score . Adverse events were recorded throughout the study . Results Characterized chondrocyte implantation result ed in better structural repair , as assessed by histomorphometry ( P = .003 ) and overall histologic evaluation ( P = .012 ) . Aspects of structural repair relating to chondrocyte phenotype and tissue structure were superior with characterized chondrocyte implantation . Clinical outcome as measured by the Knee injury and Osteoarthritis Outcome Score at 12 to 18 months after characterized chondrocyte implantation was comparable with microfracture at this stage . Both treatment groups had a similar mean baseline overall Knee injury and Osteoarthritis Outcome Score ( 56.30 ± 13.61 and 59.53 ± 14.95 for microfracture and characterized chondrocyte implantation , respectively ) , which increased in both groups to 70.56 ± 12.39 and 72.63 ± 15.55 at 6 months , 73.26 ± 14.66 and 73.10 ± 16.01 at 12 months , and 74.73 ± 17.01 and 75.04 ± 14.50 at 18 months , respectively . Both techniques were generally well tolerated ; the incidence of adverse events after characterized chondrocyte implantation was not markedly increased compared with that for microfracture . Conclusion One year after treatment , characterized chondrocyte implantation was associated with a tissue regenerate that was superior to that after microfracture . Short-term clinical outcome was similar for both treatments . The superior structural outcome may result in improved long-term clinical benefit with characterized chondrocyte implantation . Long-term follow-up is needed to confirm these findings [24595400] Background : Cartilage defects in the patella are common , and a subset of patients does not respond to nonoperative measures . While most cartilage repair techniques have demonstrated good outcomes in the femoral condyles , the patellofemoral compartment poses special challenges . Hypothesis : Repair of patellar cartilage defects with autologous chondrocyte implantation ( ACI ) will provide lasting improvements in pain and function . Study Design : Case series ; Level of evidence , 4 . Methods : Patients were treated at 1 of 4 participating cartilage repair centers with ACI for cartilage defects in the patella ; bipolar ( patella + trochlea ) defects were included as well . All patients were followed prospect ively for at least 4 years with multiple patient-reported outcome instruments , including the International Knee Documentation Committee , Short Form–12 , modified Cincinnati Rating Scale , Western Ontario and McMaster Universities Osteoarthritis Index , and Knee Society scores . Treatment failure was defined as structural failure of the graft combined with pain requiring revision surgery . Results : A total of 110 patients were available for analysis . As a group , they experienced both statistically significant and clinical ly important improvements in pain and function in all physical outcome scales . The International Knee Documentation Committee improved from 40 ± 14 preoperatively to 69 ± 20 at the last follow-up ; the Cincinnati Rating Scale , from 3.2 ± 1.2 to 6.2 ± 1.8 ; and the Western Ontario and McMaster Universities Osteoarthritis Index , from 50 ± 22 to 29 ± 22 ( all P < .0001 ) . Ninety-two percent of patients stated that they would choose to undergo ACI again , and 86 % rated their knees as good or excellent at the time of final follow-up . Nine patients ( 8 % ) were considered treatment failures , and 16 % reported that their knees were not improved . Conclusion : Cartilage repair in the patellofemoral joint is arguably not without its challenges . Autologous chondrocyte implantation remains off-label in the patella , a fact that needs to be discussed with prospect i ve patients during the informed consent process . However , when performed with attention to patellofemoral biomechanics , self-rated subjective good and excellent outcomes can be achieved in more than 80 % of patients treated with ACI , even in a patient population with large and frequently bipolar defects such as the one presented in this study . However , final functional scores , although significantly improved , still reflected residual disability in this challenging group of patients Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: Background : Recent studies demonstrated a 5 % increase in cartilage repair procedures annually in the United States . There is currently no consensus regarding a superior technique , nor has there been a comprehensive evaluation of postoperative clinical outcomes with respect to a minimal clinical ly important difference ( MCID ) . Purpose : To determine the proportion of available cartilage repair studies that meet or exceed MCID values for clinical outcomes improvement over short- , mid- , and long-term follow-up . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

25739460

[18356337] The goal of this study was to evaluate the impact of Mexico 's conditional cash transfer program , Oportunidades , on the growth of children < 24 mo of age living in urban areas . Beneficiary families received cash transfers , a fortified food ( targeted to pregnant and lactating women , children 6 - 23 mo , and children with low weight 2 - 4 y ) , and curative health services , among other benefits . Program benefits were conditional on preventative health care utilization and attendance of health and nutrition education sessions . We estimated the impact of the program after 2 y of operation in a panel of 432 children < 24 mo of age at baseline ( 2002 ) . We used difference-in-difference propensity score matching , which takes into account nonr and om program participation and the effects of unobserved fixed characteristics on outcomes . All models controlled for child age , sex , baseline anthropometry , and maternal height . Anthropometric Z-scores were calculated using the new WHO growth reference st and ards . There was no overall association between program participation and growth in children 6 to 24 mo of age . Children in intervention families younger than 6 mo of age at baseline grew 1.5 cm ( P < 0.05 ) more than children in comparison families , corresponding to 0.41 height-for-age Z-scores ( HAZ ) ( P < 0.05 ) . They also gained an additional 0.76 kg ( P < 0.01 ) or 0.47 weight-for-height Z-scores ( P < 0.05 ) . Children living in the poorest intervention households tended ( 0.05 < P < 0.10 ) to be taller than comparison children ( 0.9 cm , 0.27 HAZ ) . Oportunidades , with its strong nutrition component , is an effective tool to improve the growth of infants in poor urban households [24225356] BACKGROUND Haiti has experienced rapid urbanization that has exacerbated poverty and undernutrition in large slum areas . Stunting affects 1 in 5 young children . OBJECTIVE We aim ed to test the efficacy of a daily lipid-based nutrient supplement ( LNS ) for increased linear growth in young children . DESIGN Healthy , singleton infants aged 6 - 11 mo ( n = 589 ) were recruited from an urban slum of Cap Haitien and r and omly assigned to receive : 1 ) a control ; 2 ) a 3-mo LNS ; or 3 ) a 6-mo LNS . The LNS provided 108 kcal and other nutrients including vitamin A , vitamin B-12 , iron , and zinc at ≥80 % of the recommended amounts . Infants were followed monthly on growth , morbidity , and developmental outcomes over a 6-mo intervention period and at one additional time point 6 mo postintervention to assess sustained effects . The Bonferroni multiple comparisons test was applied , and generalized least-squares ( GLS ) regressions with mixed effects was used to examine impacts longitudinally . RESULTS Baseline characteristics did not differ by trial arm except for a higher mean age in the 6-mo LNS group . GLS modeling showed LNS supplementation for 6 mo significantly increased the length-for-age z score ( ±SE ) by 0.13 ± 0.05 and the weight-for-age z score by 0.12 ± 0.02 compared with in the control group after adjustment for child age ( P < 0.001 ) . The effects were sustained 6 mo postintervention . Morbidity and developmental outcomes did not differ by trial arm . CONCLUSION A low-energy , fortified product improved the linear growth of young children in this urban setting . The trial was registered at clinical trials.gov as NCT01552512 [10986782] OBJECTIVE To determine whether utilization of iron from infant cereal and pureed meat was sufficient to prevent iron depletion and /or anaemia in infants 6 to 12 months old fed whole cow milk ( WCM ) as their primary milk source . DESIGN Six-month-old infants were r and omized into a treatment group ( n = 43 ) receiving iron-fortified infant cereal ( 10.2 mg iron ) , pureed meat ( 0.75 - 1.7 mg iron ) and WCM for six months or a control group ( n = 54 ) receiving no dietary intervention . Haemoglobin < 110 g/L or ferritin < 10 micrograms/L ( measured bi-monthly ) , confirmed in a second blood sample , defined end-points . RESULTS Proportion reaching end-point was similar between the treatment ( 3/43 ) and control infants ( 5/54 ) ( p = 0.66 ) . Infants not complying with the protocol were at greater risk of reaching end-point ( p = 0.0002 ) . Change in haemoglobin and ferritin across age was similar in both groups . CONCLUSIONS Iron deficiency is not a concern in WCM-fed infants after six months of age if iron-containing complementary foods are concurrently ingested [19591885] The aim of this study was to test the ability of two new products , an instant infant flour and a food supplement containing amylases , to increase energy and micronutrient intakes of infants older than 6 months . Three groups of 48 infants were r and omly constituted . Infants in groups 1 and 2 consumed at least twice a day gruel made either from the instant flour or from the food supplement . Infants from the control group received complementary foods prepared in the usual way . Each infant was surveyed during a whole day in order to measure feeding frequencies and characteristics as well as amounts of the different types of complementary foods consumed . Foods consumed by infants in the two experimental groups differed considerably in energy , micronutrient density and in consistency from the home-made complementary foods . Due to the incorporation of amylases , gruels made from the food supplement had a higher energy density , a more appropriate consistency and result ed in higher intakes per meal than gruels made from instant flour . In comparison with home-made complementary foods , both experimental products result ed in significantly higher energy and nutrient intakes . The two experimental products appeared to increase sufficiently both energy and nutrient intakes of infants to complement their breastmilk intake [11435512] It is unclear whether a substantial decline in malnutrition among infants in developing countries can be achieved by increasing food availability and nutrition counseling without concurrent morbidity-reducing interventions . The study was design ed to determine whether provision of generous amounts of a micronutrient-fortified food supplement supported by counseling or nutritional counseling alone would significantly improve physical growth between 4 and 12 mo of age . In a controlled trial , 418 infants 4 mo of age were individually r and omized to one of the four groups and followed until 12 mo of age . The first group received a milk-based cereal and nutritional counseling ; the second group monthly nutritional counseling alone . To control for the effect of twice-weekly home visits for morbidity ascertainment , similar visits were made in one of the control groups ( visitation group ) ; the fourth group received no intervention . The median energy intake from nonbreast milk sources was higher in the food supplementation group than in the visitation group by 1212 kJ at 26 wk ( P < 0.001 ) , 1739 kJ at 38 wk ( P < 0.001 ) and 2257 kJ at 52 wk ( P < 0.001 ) . The food supplementation infants gained 250 g ( 95 % confidence interval : 20 - -480 g ) more weight than did the visitation group . The difference in the mean increment in length during the study was 0.4 cm ( 95 % confidence interval : -0.1 - -0.9 cm ) . The nutritional counseling group had higher energy intakes ranging from 280 to 752 kJ at different ages ( P < 0.05 at all ages ) but no significant benefit on weight and length increments . Methods to enhance the impact of these interventions need to be identified [20691525] The importance of reducing childhood undernutrition has been enshrined in the United Nations ' Millennium Development Goals . This study explores the relationship between alternative indicators of poverty and childhood undernutrition in developing countries within the context of a multi-national cohort study ( Young Lives ) . Approximately 2000 children in each of four countries - Ethiopia , India ( And hra Pradesh ) , Peru and Vietnam - had their heights measured and were weighed when they were aged between 6 and 17 months ( survey one ) and again between 4.5 and 5.5 years ( survey two ) . The anthropometric outcomes of stunted , underweight and wasted were calculated using World Health Organization 2006 reference st and ards . Maximum-likelihood probit estimation was employed to model the relationship within each country and survey between alternative measures of living st and ards ( principally a wealth index developed using principal components analysis ) and each anthropometric outcome . An extensive set of covariates was incorporated into the models to remove as much individual heterogeneity as possible . The fully adjusted models revealed a negative and statistically significant coefficient on wealth for all outcomes in all countries , with the exception of the outcome of wasted in India ( And hra Pradesh ) and Vietnam ( survey one ) and the outcome of underweight in Vietnam ( surveys one and two ) . In survey one , the partial effects of wealth on the probabilities of stunting , being underweight and wasting was to reduce them by between 1.4 and 5.1 percentage points , 1.0 and 6.4 percentage points , and 0.3 and 4.5 percentage points , respectively , with each unit ( 10 % ) increase in wealth . The partial effects of wealth on the probabilities of anthropometric outcomes were larger in the survey two models . In both surveys , children residing in the lowest wealth quintile households had significantly increased probabilities of being stunted in all four study countries and of being underweight in Ethiopia , India ( And hra Pradesh ) and Peru in comparison to children residing in the highest wealth quintile households . R and om effects probit models confirmed the statistical significance of increased wealth in reducing the probability of being stunted and underweight across all four study countries . We conclude that , although multi-faceted , childhood undernutrition in developing countries is strongly rooted in poverty [9394687] Does short-term supplementary feeding during infancy and childhood have long-lasting effects ? In 1986 , 334 children aged 6 - 60 mo living on rural tea plantations in West Java , Indonesia , participated in a 3-mo r and omized trial to test the effects of a dietary supplement providing approximately 1672 kJ ( 400 kcal ) energy/d , with about the same nutrient density as local foods . We returned to the same communities in 1994 and enrolled 231 ( 125 supplemented , 106 control ) of the original subjects in a follow-up study of the long-term effects of supplementation . We assessed these subjects by using several measures : anthropometry , iron status , information processing , Peabody Picture Vocabulary Test , word fluency , and an arithmetic test . The supplemented group showed no differences from those in the control group . However , when the analysis was limited to subjects who had received the supplement before the age of 18 mo ( n = 73 ) , the supplemented children performed better than control children on the Sternberg test of working memory ( decision time intercept : probe absent , P = 0.002 ; probe present , P = 0.053 ) . After considering possible confounders , we concluded that the supplementation during infancy was responsible for the difference . This finding shows that supplementation can have long-lasting effects on a specific domain if the child receives it at the appropriate stage of development [3189208] A study of the effects of providing high-calorie and vitamin-mineral supplements to preschool village children retarded in growth and development in Chiang Mai , Thail and was done . The preschool children of 24 villages with a population of approximately 11,000 were divided into five control and intervention groups . The interventions consisted of a village health program , high-calorie snacks , and vitamin-mineral supplements . The supplements when used were provided in day care centers for preschool children . The health and nutrition interventions used did not significantly affect growth during the study period reported from December 1981 to October 1983 . Monthly changes in length and weight observed in this and a previous study indicate that growth patterns in Thai children are different from those seen in industrialized societies . Factors other than lack of nutrients and infection may be responsible for the inadequate growth often reported in developing countries [1897471] The benefits of nutritional supplementation , with or without psychosocial stimulation , on the growth of stunted children were evaluated . Children aged 9 - 24 mo with lengths less than -2 SD of the National Center for Health Statistics references ( n = 129 ) were r and omly assigned to four groups : control , nutritional supplementation , stimulation , and both interventions . A fifth group with lengths greater than -1 SD was also enrolled . Length , weight , head and arm circumferences , and triceps and subscapular skinfold thicknesses were measured on enrollment and 6 and 12 mo later . Multiple-regression analysis was used to determine the effects of the interventions in which age , sex , initial status , initial dietary intake , and several socioeconomic variables were controlled for . Stimulation had no effect on growth and there was no interaction between the interventions . After 12 mo supplemented children had significantly increased length , weight , and head circumference ( all P less than 0.01 ) . The effects of supplementation were not cumulative but occurred in the first 6 mo [7282613] The effect of food supplementation on physical growth during the last trimester of pregnancy and the first 3 yr of life was studied in a sample of families at risk of malnutrition living in the urban slums of Bogota , Colombia . Families in which the mother was pregnant and at least one-half of the children under 5 yr of age were below 85 % of weight for age were selected for the study . All were provided with free obstetrical and pediatric care . The families were then r and omly assigned to control and supplemented groups . The supplemented families received a daily allotment of 600 cal or 30 g of protein per capita for home consumption from the onset of the 3rd trimester of pregnancy until the subject children reached the age of 3 yr . Calorie consumption from the supplement by the study children ( offspring of the target pregnancy ) was 458 ± 249 calories at age 18 months and 363 ± 283 cal at age 36 months . Protein consumption at those ages was 34 . 1 ± 20.6 and 23.6 ± 19.7 g,'day . However , substitution of the supplement for foods from the regular diet result ed in net supplementation of approximately 200 cal and 22 g of protein per day . There were significant differences in weight between supplemented and control groups beginning at age 3 months and in length beginning at age 6 months . Supplementation reduced the total prevalence of malnutrition ( Gomez classification ) only slightly ; at 36 months of age , 72 % of the supplemented group and 77.8 % of the control group were malnourished . On the other h and , the prevalence of moderate and severe malnutrition ( Gomez II and III ) , was significantly reduced by supplementation . At 36 months , 20.6 % of the control group and 8.8 % of the supplemented group fell into those categories . Despite improved physical growth in the supplemented group , their height and weight remained substantially below those of the high socioeconomic Colombian st and ards . The failure of supplementation to close the gap between low and high socioeconomic groups was attributed , in part , to the high incidence of diarrheal disease among subjects of the study . It is postulated that simple provision of food supplements , without effective prevention of diarrheal disease , is likely to have limited effects on physical growth among disadvantaged children . Am . J. Clin . Nutr . 34 : 1885 - 1892 , 1981 [1951149] This study assessed the developmental effects of supplementary feeding over 90 consecutive days on infants aged 6 - 20 mo at six tea plantations in West Java , Indonesia . Every day except Sunday , the infants attended day-care centers distributed throughout the plantations . Twenty centers and 113 infants were selected ; the infants in 9 centers received a dietary supplement , while the infants in 11 centers served as control subjects . Supplements were given twice a day providing , on average , 10.66 kJ ( 400 kcal ) and 5 g protein/d . Measurements of body growth , dietary intake , and mental and motor development were made on all infants . Supplementary feeding had significant effects on weight gain and on motor development . Changes in caloric intake were independently associated with changes in weight and in motor test scores . The data suggest that the effects of the supplement may not have followed a simple mechanistic relationship from intake to weight change to motor development , but , rather , intake may have affected both growth and development domains simultaneously [18203907] Linear growth retardation and anemia are the most prevalent nutritional problems in the world ; effective interventions are urgently needed . We evaluated Ecuador 's National Food Nutrition Program ( PANN 2000 ) that included a micronutrient-fortified complementary food ( FCF ) , Mi Papilla , in poor periurban and rural communities of Ecuador . The program is preventive and targeted to all infants and young children living in poor communities and receiving government health services . We compared dietary intake , micronutrient status , and growth over 11 mo in a cohort of children from the catchment areas of the PANN 2000 with same-age control children in nearby communities eligible to enter the program 1 y later . PANN 2000 children enrolled in the program when they were age 9 - 14 mo and were age 20 - 25 mo at the final survey . They consumed significantly more energy , protein , fat , iron , zinc , vitamin A , and calcium than control children because of their FCF consumption . Anemia , 76 % in both groups at baseline , fell to 27 % in PANN 2000 children but only to 44 % in control children ( P < 0.001 ) . The odds of being anemic were 58 % lower for PANN 2000 children ( P = 0.003 ) . The effects on linear growth and weight were limited to children who were older when the program began ( 12 - 14 mo ) and were significant for weight ( interaction with age , 0.38 kg ; P = 0.029 ) and positive but not significant for length ( 0.66 cm ; P = 0.08 ) . An FCF , including ferrous sulfate , delivered through public health services , is highly effective in improving weight and hemoglobin and reducing anemia [2058589] Three-month recovery rates from moderate wasting ( less than 90 % weight-for-length ) were compared in 6 - 24-mo-old children in four Guatemalan villages that had been r and omly assigned to receive a moderate ( Atole ) or low ( Fresco ) energy supplement . The recovery rate ( Rr ) in the Atole villages was 12 % higher than in the Fresco villages ( P less than 0.05 ) . This effect was above all due to the children in the Atole villages who consumed greater than or equal to 10 % of the daily recommended dietary intake of energy ( RDI ) from the supplement ( high-Atole group ) and whose total energy intake ( including home diet ) was 10.5 % of the RDI higher than a comparable high-Fresco group with low supplemental energy intake . All those in the high-Atole group whose wasting was due to malnutrition recovered . Much of this recovery ( range 29 - 52 % ) was due to the increased supplementation . This proportion rose after potential confounding variables were controlled for [8839497] The effect of supplementation on growth was tested by means of four similar controlled r and omized trials in the Congo ( n = 120 ) , Senegal ( n = 110 ) , Bolivia ( n = 127 ) , and New Caledonia ( n = 90 ) . Four-month-old infants were r and omly allocated to supplement or control groups . A cereal-based precooked porridge was offered twice daily for 3 mo and consumption was monitored . Both groups were free to eat local food . At 7 mo of age , all infants were still breast-fed in the Congo , Senegal , and Bolivia compared with 47 % in New Caledonia . Mean daily consumption of the supplement varied among countries ( 558 - 790 kJ/d ) . Mean length at 4 mo was lowest in Bolivia , higher in Senegal and the Congo , and near the National Center for Health Statistics reference in New Caledonia . The mean 4 - 7 mo length increment was 0.48 cm higher for supplemented than for control infants in Senegal ( P < 0.05 ) , whereas weight increments did not differ . No significant effect was found in the other countries [9250101] It is not known whether nutritional supplementation in early childhood has long-term benefits on stunted children 's mental development . We followed up 127 7 - 8-y old children who had been stunted in early childhood and received supplementation , stimulation , or both . At 9 - 24 mo of age , the children had been r and omly assigned to four treatment groups : nutritional supplementation , stimulation , both treatments , and control . After 2 y , supplementation and stimulation had independent benefits on the children 's development and the effects were additive . The group receiving both treatments caught up to a matched group of 32 nonstunted children . Four years after the end of the 2-y intervention 97 % of the children were given a battery of cognitive function , school achievement , and fine motor tests . An additional 52 nonstunted children were included . Factor analyses of the test scores produced three factors : general cognitive , perceptual-motor , and memory . One , the perceptual-motor factor , showed a significant benefit from stimulation , and supplementation benefited only those children whose mothers had higher verbal intelligence quotients . However , each intervention group had higher scores than the control subjects on more tests than would be expected by chance ( supplemented and both groups on 14 of 15 tests , P = 0.002 ; stimulated group in 13 of 15 tests , P = 0.01 ) , suggesting a very small global benefit . There was no longer an additive effect of combined treatments at the end of the intervention . The stunted control group had significantly lower scores than the nonstunted children on most tests . Stunted children 's heights and head circumferences on enrollment significantly predicted intelligence quotient at follow-up [7722691] The Cali Study involved the r and om assignment of 301 malnourished children to be exposed to one ( CT1 , n = 113 ) , two ( CT2 , n = 64 ) , three ( CT3 , n = 62 ) or four ( CT4 , n = 62 ) 9-mo periods of a multifocal day care-based intervention ( i.e. , education , health and nutrition ) . The ages at which the intervention was initiated for Groups CT4 , CT3 , CT2 and CT1 were 3.5 , 4.2 , 5.2 and 6.1 y , respectively . After the experimental phase , children were followed up in elementary school until they were 10.4 y old . Our secondary data analyses show that children who were exposed at an earlier age and for a longer period of time showed the highest degree ( P < or = 0.05 ) of improvement in weight and linear growth during the pre-school period . These improvements in physical growth could no longer be detected 3 y after the termination of the intervention [15213048] BACKGROUND Previous analyses derived the relative risk ( RR ) of dying as a result of low weight-for-age and calculated the proportion of child deaths worldwide attributable to underweight . OBJECTIVES The objectives were to examine whether the risk of dying because of underweight varies by cause of death and to estimate the fraction of deaths by cause attributable to underweight . DESIGN Data were obtained from investigators of 10 cohort studies with both weight-for-age category ( < -3 SDs , -3 to < -2 SDs , -2 to < -1 SD , and > -1 SD ) and cause of death information . All 10 studies contributed information on weight-for-age and risk of diarrhea , pneumonia , and all-cause mortality ; however , only 6 studies contributed information on deaths because of measles , and only 3 studies contributed information on deaths because of malaria or fever . With use of weighted r and om effects models , we related the log mortality rate by cause and anthropometric status in each study to derive cause-specific RRs of dying because of undernutrition . Prevalences of each weight-for-age category were obtained from analyses of 310 national nutrition surveys . With use of the RR and prevalence information , we then calculated the fraction of deaths by cause attributable to undernutrition . RESULTS The RR of mortality because of low weight-for-age was elevated for each cause of death and for all-cause mortality . Overall , 52.5 % of all deaths in young children were attributable to undernutrition , varying from 44.8 % for deaths because of measles to 60.7 % for deaths because of diarrhea . CONCLUSION A significant proportion of deaths in young children worldwide is attributable to low weight-for-age , and efforts to reduce malnutrition should be a policy priority [17273956] R and omization in r and omized controlled trials involves more than generation of a r and om sequence by which to assign subjects . For r and omization to be successfully implemented , the r and omization sequence must be adequately protected ( concealed ) so that investigators , involved health care providers , and subjects are not aware of the upcoming assignment . The absence of adequate allocation concealment can lead to selection bias , one of the very problems that r and omization was supposed to eliminate . Authors of reports of r and omized trials should provide enough details on how allocation concealment was achieved so the reader can determine the likelihood of success . Fortunately , a plan of allocation concealment can always be incorporated into the design of a r and omized trial . Certain methods minimize the risk of concealment failing more than others . Keeping knowledge of subjects ' assignment after allocation from subjects , investigators/health care providers , or those assessing outcomes is referred to as masking ( also known as blinding ) . The goal of masking is to prevent ascertainment bias . In contrast to allocation concealment , masking can not always be incorporated into a r and omized controlled trial . Both allocation concealment and masking add to the elimination of bias in r and omized controlled trials [10902992] Objectives : This paper reports the effects of an energy and micronutrient supplementation on quantitative and qualitative aspects of play among poorly nourished children . At issue is whether the supplement led to a progression in complexity of play . Design : two cohorts of children were r and omly assigned to three treatments : E=1171 kJ+12 mg iron ; M=12 mg iron+209 kJ ; S=104 kJ. Supplementation was given for 6 months . Evaluations of play behavior were repeated four times . Setting : The sites were six tea plantations in Pangalengan , West Java . Subjects : The present study utilized a sub sample of 55 children recruited for the larger Pangalengan project 6 months into the study . Thirty-eight children were recruited late enough to allow for longitudinal observations . The remaining cases were used for cross sectional observations only . Inclusion criteria were : no chronic disease ; length-for-age ≤−1 st and ard deviation ( s.d . ) and weight-for-length between −1 and −2 s.d . of the median of the reference of the World Health Organization . Methods : The children were videotaped during play . These tapes were coded for eight mutually exclusive categories of activities . Four activities coded represented manipulative , relational , functional and symbolic play . Results : Treatment did not affect qualitative play . Girls that received E increased functional play but boys showed the opposite effect . Children in the S group were breastfed more during play as compared to the E group . Children in the E group waited less to begin play . Sponsorship : Nestlé Foundation . European Journal of Clinical Nutrition ( 2000 ) 54 , Suppl 2 , [16166365] Study objective : There is little guidance on how to select the best available evidence of health effects of social interventions . The aim of this paper was to assess the implication s of setting particular inclusion criteria for evidence synthesis . Design : Analysis of all relevant studies for one systematic review , followed by sensitivity analysis of the effects of selecting studies based on a two dimensional hierarchy of study design and study population . Setting : Case study of a systematic review of the effectiveness of interventions in promoting a population shift from using cars towards walking and cycling . Main results : The distribution of available evidence was skewed . Population level interventions were less likely than individual level interventions to have been studied using the most rigorous study design s ; nearly all of the population level evidence would have been missed if only r and omised controlled trials had been included . Examining the studies that were excluded did not change the overall conclusions about effectiveness , but did identify additional categories of intervention such as health walks and parking charges that merit further research , and provided evidence to challenge assumptions about the actual effects of progressive urban transport policies . Conclusions : Unthinking adherence to a hierarchy of study design as a means of selecting studies may reduce the value of evidence synthesis and reinforce an “ inverse evidence law ” whereby the least is known about the effects of interventions most likely to influence whole population s. Producing generalisable estimates of effect sizes is only one possible objective of evidence synthesis . Mapping the available evidence and uncertainty about effects may also be important [12907410] The study was conducted to look at the effectiveness of a multimicronutrient-fortified complementary food on the micronutrient status , linear growth and psychomotor development of 6- to 12-month-old infants from a black urban disadvantaged community in the Western Cape , South Africa . The study was design ed as an intervention study . In both the experimental and control groups , serum retinol concentration showed a decline over the intervention period of 6 months . The decline was less pronounced in the experimental group . This result ed in a significantly ( P<005 ) higher serum retinol concentration at 12 months in the experimental group ( 26.8±5.8 μg/dl ) compared with the control group ( 21.4±5 μg/dl ) . Serum iron concentration also declined over the intervention period . The decline was less pronounced in the experimental group . No difference was observed in haemoglobin levels between the groups at 12 months . Serum zinc concentration did not differ significantly between the two groups at follow up . Weight gain over the 6 months period did not differ significantly between the experimental ( 2.1±0.9 kg ) and control groups ( 2.1±1.2 kg ) . There was no difference in linear growth between the experimental ( 10.0±1.5 cm ) and control group ( 10.1±2.1 cm ) at the end of the follow-up period . Weight and length at 6 months significantly predicted weight and length at 12 months . No difference was observed in psychomotor developmental scores between the two groups after 6 months of intervention . Introducing a multimicronutrient-fortified complementary food into the diet of 6- to 12-month-old infants seemed to have an arresting effect on declining serum retinol and iron concentration in the experimental group . No benefit was observed in serum zinc concentration , linear growth and psychomotor development [3274449] Background There is a lack of information on the optimal timing of food supplementation to malnourished pregnant women and possible combined effects of food and multiple micronutrient supplementations ( MMS ) on their offspring 's growth . We evaluated the effects of prenatal food and micronutrient interventions on postnatal child growth . The hypothesis was that prenatal MMS and early invitation to food supplementation would increase physical growth in the offspring during 0 - 54 months and a combination of these interventions would further improve these outcomes . Methods In the large , r and omized MINIMat trial ( Maternal and Infant Nutrition Interventions in Matlab ) , Bangladesh , 4436 pregnant women were enrolled between November 2001 and October 2003 and their children were followed until March 2009 . Participants were r and omized into six groups comprising 30 mg Fe and 400 μg folic acid ( Fe30F ) , 60 mg Fe and 400 μg folic acid ( Fe60F ) or MMS combined with either an early ( immediately after identification of pregnancy ) or a later usual ( at the time of their choosing , i.e. , usual care in this community ) program invitation to food supplementation . The anthropometry of 3267 children was followed from birth to 54 months , and 2735 children were available for analysis at 54 months . Results There were no differences in characteristics of mothers and households among the different intervention groups . The average birth weight was 2694 g and birth length was 47.7 cm , with no difference among intervention groups . Early invitation to food supplementation ( in comparison with usual invitation ) reduced the proportion of stunting from early infancy up to 54 months for boys ( p = 0.01 ) , but not for girls ( p = 0.31 ) . MMS result ed in more stunting than st and ard Fe60F ( p = 0.02 ) . There was no interaction between the food and micronutrient supplementation on the growth outcome . Conclusions Early food supplementation in pregnancy reduced the occurrence of stunting during 0 - 54 months in boys , but not in girls , and prenatal MMS increased the proportion of stunting in boys . These effects on postnatal growth suggest programming effects in early fetal life . Trial registration numberIS RCT N : IS RCT [8886347] The study assessed the effects of supplementary feeding over 180 consecutive days on iron status of infants and toddlers at six tea plantation in West Java , Indonesia . The design used was a clinical trial : two eohorts ( i.e. , 12 and 18 months old children ) and three treatment groups ( i.e. , energy + micronutrient , micronutrient alone , and placebo ) per cohort . Every day except Sunday , the infants attended day-care centers . Twenty four centers and 136 infants were selected . The infants were screened for weight and length and those meeting the criteria ( i.e. , < -1 SD of length-for-age , and between -1 and -2 SD of weight-for-length of the NCHS reference ) were included . The experimental unit was the day-care centers ( DCC ) , where each DCC was r and omly assigned to one of the three treatment . As expected , groups of energy + micronutrient and micronutrient alone of the 12 months cohort experienced a significant upward shift in hemoglobin , ferritin and TS and a downward change in FEP , while the values for the group of placebo remain about the same as at base line . In the first 6 month of treatments , the ANOVA for each iron indicator yielded significant main effects of treatment ( P < 0.01 ) and for Hb with ( P = 0.059 ) on 12 months cohort . On the other h and , the main effects of treatment on hemoglobin , TS , ferritin and FEP were not significant for the 18 months cohort . In the second 6 months of treatments , the only significant of the treatment effect ( P < 0.01 ) was in serum ferritin on 18-month cohort . Under these circumstances , energy has a positive role in improving iron stores . It is likely that the equilibrium of hemoglobin and each iron indicators were reached in 6 months of treatment except ferritin still continued to increase up to 12 month . The effects of treatment on the improvement of iron status was stronger in 12 months than in 18 months [15868035] To assess the effectiveness on child growth and body composition of a supplementary feeding program ( Milk Supplement Program ) , a prospect i ve , controlled study was conducted in Northeast Brazil . When entering the Program , children from 10 municipalities with the highest coverage rates in the Program ( intervention group ) were compared to non-beneficiary children from 10 municipalities with the lowest coverage rates ( control group ) . A total of 219 children aged 6 - 18 months were enrolled . At entry , both groups were comparable in terms of age , sex , and nutritional status . There were frequent gaps in delivery of the supplement , no extra milk was provided to siblings less than 5 years of age , intra-household redistribution of milk was high , and maternal compliance with recommendations was low . Adjusted analyses by multilevel modelling showed average changes in weight , length , weight-age and length-age Z-scores , and % body water ( deuterium method ) , at 6 months , of 1.53 kg , 6.34 cm , 0.33 , 0.05 , and 1.11 % respectively among supplemented children as compared to 1.54 kg , 6.5 cm , 0.26 , 0.07 , and 4.10 % among controls , with no statistically significant difference between groups . Thus , the Program failed to compensate for nutritional deficiencies in undernourished children in Northeast Brazil [7722707] Supplementary feeding programs are common in developing countries . These programs often can not demonstrate an impact on child growth , however , possibly because they tend to reach older children . This study examines the impact of nutritional supplementation on annual growth rates in length and weight from birth to 7 y of age in 1208 rural Guatemalan children . A series of multiple linear regression models is used to control for initial body size , diarrheal disease , home diet , socioeconomic status and gender . During the first year of life , each 100 kcal/d ( 418 kJ ) of supplement was associated with approximately 9 mm in additional length gain and 350 g in additional weight gain ; the benefit decreased to approximately 5 mm in length gain and 250 g in weight gain during the 2nd y of life . Between 24 and 36 mo of age , supplement only had a significant impact on length . There was no impact of nutritional supplementation on growth between 3 and 7 y of age . Patterns were the same if supplement intakes were expressed as a percent of recommended allowances or growth was expressed as a percent of the expected rate . These impacts of nutritional supplementation on growth coincide with the ages when growth velocities , as well as growth deficits , are greatest in this population [10902989] Objectives : This paper investigates simultaneously the growth and activity of children that received an early energy and micronutrient supplement , adjusting for all non-supplemental energy intakes . Any additional change in growth and activity after this adjustment was then compared across supplements at three points felt to be representative of the study . Design : Two cohorts of children were r and omly assigned to three treatments : E=1171 kJ+12 mg iron ; M=209 kJ+12 mg iron ; S=104 kJ. Supplementation was given for 12 months . Setting : The sites were six tea plantations in Pangalengan , West Java . Subjects : A 12-month-old ( n=53 ) and an 18-month-old ( n=83 ) cohort were recruited from day-care-centers . Twenty children that received S belonged to the 12- and 18-month-old cohorts . Inclusion criteria were : no chronic disease ; length-for-age ≤−1 st and ard deviation ( s.d . ) and weight-for-length between −1 and −2 s.d . of the median of the reference of the World Health Organization . Methods : Length was measured with a portable measuring board ; a Detecto scale with an accuracy of 0.1 kg was used for the measurement of body weight . Arm and head circumferences were measured using similar fiberglass tapes . Motor activity was assessed through continuous 4 h observations at home and at day care centers . Anthropometry and activity were measured every two months over 12 months . Results : After correcting for non-supplemental sources of energy intake , the effects of the supplement on weight and activity were observed at 2 months ; effects on length and activity were observed at 6 months ; and effects on weight alone were observed at 12 months . Sponsorship : Nestlé Foundation . European Journal of Clinical Nutrition ( 2000 ) 54 , Suppl 2 , [12503232] Integrated nutrition programs are widely used to prevent and /or reverse childhood malnutrition , but rarely rigorously evaluated . The impact of such a program on the physical growth of young rural Vietnamese children was measured . We r and omized six communes to receive an integrated nutrition program implemented by Save the Children . We matched six communes to serve as controls . Our sample consisted of 238 children ( n = 119 per group ) who were 5 to 30 months old on entry . Between December 1999 and December 2000 , we measured weight and height monthly for six months and again at month 12 . Principle outcomes were weight-for-age Z score ( WAZ ) , height-for-age Z score ( HAZ ) , and weight-for-height Z score ( WHZ ) , and the changes among these measures . As expected , anthropometric indicators relative to international references worsened as the children aged . Overall , children in the intervention communes who were exposed to the integrated nutrition program did not show statistically significant better growth than comparison children . Intervention children who were younger ( 15 months or less ) and more malnourished ( less than −2 Z ) at baseline , however , deteriorated significantly less than their comparable counterparts . Between baseline and month four , for example , intervention children who were malnourished and less than 15 months old at entry lost on average 0.05 WAZ while similar comparison children lost 0.25 WAZ ( p = .02 ) . Lack of overall impact on growth may be due to a lower than expected prevalence of malnutrition at baseline and /or deworming of comparison children . Targeting nutrition interventions at very young children will have the maximum impact on growth [19073791] BACKGROUND In breastfed infants , iron deficiency at < 6 mo of life , although uncommon , is observed in industrialized countries . Iron supplementation starting at an early age may prevent iron deficiency . OBJECTIVE The study assessed the effect of early iron supplementation of breastfed infants and tested the hypothesis that iron supplementation enhances iron status . Potential adverse effects ( tolerance and growth ) were monitored . DESIGN The prospect i ve , placebo-controlled study involved exclusively breastfed infants who were r and omly assigned at 1 mo of age to iron ( n = 37 ) or placebo ( n = 38 ) . Iron ( 7 mg/d as multivitamin preparation with ferrous sulfate ) or placebo ( multivitamin preparation without iron ) was given from 1 to 5.5 mo of age . Complementary foods were allowed at > 4 mo . Infants were followed to 18 mo . Blood concentrations of ferritin , transferrin receptor , hemoglobin , and red cell indexes were determined at bimonthly intervals . Stool consistency and color and feeding behavior were recorded . RESULTS Iron supplementation caused modest augmentation of iron status during the intervention at 4 and 5.5 mo but not thereafter . Iron supplements were well tolerated and had no measurable effect on growth . One infant developed iron deficiency anemia by 5.5 mo of age . Plasma ferritin and hemoglobin tracked over time . CONCLUSION Early iron supplementation of breastfed infants is feasible and transiently increases iron status but not hematologic status . Iron is tolerated by most infants . The prevalence of iron deficiency anemia is low ( 3 % ) among unsupplemented breastfed infants in the first 6 mo of life [20861218] Although widely used , there is little information concerning the efficacy of corn-soy blend ( CSB ) supplementation in the treatment of moderate underweight in African children . Lipid-based nutrient supplements ( LNS ) , which have proven to be beneficial treatment for severely wasted children , could offer benefits to less severely affected individuals . We conducted a clinical r and omized trial to determine whether LNS or CSB supplementation improves weight gain of moderately underweight children . A total of 182 underweight [ weight-for-age Z-score ( WAZ ) < -2 ] 6- to 15-mo-old children were r and omized to receive for 12 wk a ration of 43 g/d LNS or 71 g/d CSB , providing 1189 and 921 kJ , respectively , or no supplementation ( control ) . The primary outcome was weight change ; secondary outcomes included changes in anthropometric indices , hemoglobin levels , and morbidity . The body weight increases ( mean ± SD ) did not differ and were 620 ± 470 , 510 ± 350 , and 470 ± 350 g in the LNS , CSB , and control groups , respectively ( P = 0.11 ) . Compared with controls , infants and children in the LNS group gained more weight [ mean ( 95 % CI ) = 150 g ( 0 - 300 g ) ; P = 0.05 ] and had a greater increase in WAZ [ 0.33 ( -0.02 - 0.65 ) ; P = 0.04 ] . Weight and WAZ changes did not differ between the control and CSB groups . In exploratory stratified analysis , the weight increase was higher in the LNS group compared with the control group among those with lower initial WAZ [ 250 g ( 60 - 430 g ; P = 0.01 ] . Supplementation with LNS but not CSB modestly increases weight gain among moderately underweight children and the effect appears most pronounced among those with a lower initial WAZ [10902988] Objectives : This paper reports the effects of an energy and micronutrient supplement on the motor development , motor milestones and motor activity of nutritionally at risk infants and toddlers in Pangalengan , Indonesia . Design : Two cohorts of children were r and omly assigned to three treatments E=1171 kJ+12 mg iron ; M=209 kJ+12 mg iron ; S=104 kJ. Supplementation was given for 12 months . Setting : The sites were six tea plantations in Pangalengan , West Java . Subjects : A 12-month-old ( n=53 ) and an 18-month-old ( n=83 ) cohort were recruited from day-care-centers . Twenty children that received S belonged to the 12- and 18-month-old cohorts . Inclusion criteria were : no chronic disease ; length-for-age≤−1 st and ard deviation ( s.d . ) and weight-for-length between −1 and −2 s.d . of the median of the reference of the World Health Organization . Methods : Evaluations of intake were made at baseline and every 2 months thereafter . Motor development was assessed with the Bayley Scale and with a custom-made scale to assess gross motor development leading to bipedal locomotion . Motor activity was assessed through 4 h continuous observations of the child ’s interaction with the social and physical environment . Results : In the 12-month-old cohort , as compared to the M and S groups the children that received the E supplement walked at an earlier age , had higher scores in the Bayley Scale and were motorically more active . Similar intergroup differences were observed in the 18-month-old cohort in the total motor activity score . Sponsorship : Nestlé Foundation . European Journal of Clinical Nutrition ( 2000 ) 54 , Suppl 2 , [10902987] Objectives : This paper reports the effects of early supplementary feeding on body weight , length , head circumference and arm circumference among the children in the Pangalengan study . Design : Two cohorts of children were r and omly assigned to three treatments : E=1171 kJ+12 mg iron ; M=209 kJ+12 mg iron ; S=104 kJ. Supplementation was given for 12 months . Setting : The sites were six tea plantations in Pangalengan , West Java . Subjects : A 12-month-old ( n=53 ) and an 18-month-old ( n=83 ) cohort were recruited from day-care centers . Twenty children that received S belonged to the 12- and 18-month cohorts . Inclusion criteria were : no chronic disease ; length-for-age≤−1 st and ard deviation ( s.d . ) and weight-for-length between −1 and −2 s.d . of the median of the reference of the World Health Organization . Methods : Length was measured with a portable measuring board ; a Detecto scale with an accuracy of 0.1 kg was used for the measurement of body weight . Arm and head circumferences were measured using similar fiberglass tapes . Results : Body weight showed effects on both cohorts at 2 , 8 and 12 months ; head circumference showed effects at 4 months in the 12-month-old cohort and at 10 months among the females of the 18-month-old cohort ; and arm circumference showed effects across cohorts at 2 , 8 and 12 months . In general the benefits are clearer for females and for the 12-month-old cohort . Sponsorship : Nestlé Foundation . European Journal of Clinical Nutrition ( 2000 ) 54 , Suppl 2 , [10902983] Objectives : To describe the method ologies of a clinical trial on the effects of an energy and micronutrient supplement on the growth and development of undernourished children . Design : This trial included two cohorts of children classified as nutritionally-at-risk who were r and omly assigned to three treatments ( condensed milk+micronutrients ( E ) ; skimmed milk+micronutrients ( M ) ; skimmed milk ( S ) ) . Supplements were given for a period up to 12 months . Setting : Six tea plantations in Pangalengan , West Java were the site for this study .Subjects : A 12-month-old ( N=53 ) and an 18-month-old ( N=83 ) cohort were recruited from 24 day-care-centers ( DCC ) . Twenty children that received the S supplement were part of the 12- and 18 month-old cohort . Criteria for case inclusion were absence of chronic disease ; length-for-age≤−1 st and ard deviation ( s.d . ) and weight-for-length between −1 and −2 s.d . of the median of the reference of the World Health Organization . Variables : Social variables included assessment of health facilities , childcare , housing , income and parental education . Nutrition and growth variables included dietary intake measured over a 24 hr period every 2 months ; hemoglobin and three iron indicators measured at baseline , 6 and 12 months ; anthropometry measured every 2 months and skeletal maturation measured every 6 months . Cognition and behavior included the assessment of mental and motor development and the behavior of the child under natural conditions . Data analysis : An ANOVA was the statistic most frequently used to test inter-group differences and structural equation modeling was used to test the internal validity of the conceptual model of the study .Sponsorship : Nestlé Foundation . European Journal of Clinical Nutrition ( 2000 ) 54 , Suppl 2 , [15173147] CONTEXT Malnutrition causes death and impaired health in millions of children . Existing interventions are effective under controlled conditions ; however , little information is available on their effectiveness in large-scale programs . OBJECTIVE To document the short-term nutritional impact of a large-scale , incentive-based development program in Mexico ( Progresa ) , which included a nutritional component . DESIGN , SETTING , AND PARTICIPANTS A r and omized effectiveness study of 347 communities r and omly assigned to immediate incorporation to the program in 1998 ( intervention group ; n = 205 ) or to incorporation in 1999 ( crossover intervention group ; n = 142 ) . A r and om sample of children in those communities was surveyed at baseline and at 1 and 2 years afterward . Participants were from low-income households in poor rural communities in 6 central Mexican states . Children ( N = 650 ) 12 months of age or younger ( n = 373 intervention group ; n = 277 crossover intervention group ) were included in the analyses . INTERVENTION Children and pregnant and lactating women in participating households received fortified nutrition supplements , and the families received nutrition education , health care , and cash transfers . MAIN OUTCOME MEASURES Two-year height increments and anemia rates as measured by blood hemoglobin levels in participating children . RESULTS Progresa was associated with better growth in height among the poorest and younger infants . Age- and length-adjusted height was greater by 1.1 cm ( 26.4 cm in the intervention group vs 25.3 cm in the crossover intervention group ) among infants younger than 6 months at baseline and who lived in the poorest households . After 1 year , mean hemoglobin values were higher in the intervention group ( 11.12 g/dL ; 95 % confidence interval [ CI ] , 10.9 - 11.3 g/dL ) than in the crossover intervention group ( 10.75 g/dL ; 95 % CI , 10.5 - 11.0 g/dL ) who had not yet received the benefits of the intervention ( P = .01 ) . There were no differences in hemoglobin levels between the 2 groups at year 2 after both groups were receiving the intervention . The age-adjusted rate of anemia ( hemoglobin level < 11 g/dL ) in 1999 was higher in the crossover intervention group than in the intervention group ( 54.9 % vs 44.3 % ; P = .03 ) , whereas in 2000 the difference was not significant ( 23.0 % vs 25.8 % , respectively ; P = .40 ) . CONCLUSION Progresa , a large-scale , incentive-based development program with a nutritional intervention , is associated with better growth and lower rates of anemia in low-income , rural infants and children in Mexico [19225128] Moderate childhood wasting is defined as having a weight-for-height Z-score ( WHZ ) < -2 , but > or = -3 . These children are typically given fortified corn/soy blended flour ( CSB ) , but this intervention has shown limited effectiveness . Fortified spreads ( FS ) can be used as supplementary foods instead ; they are energy-dense , lipid-based pastes with added powdered micronutrients . In this r and omized clinical effectiveness trial , the recovery rates were compared among children with moderate wasting who received either milk/peanut FS , soy/peanut FS , or CSB . Children received isoenergetic quantities of food , 314 kJ x kg(-1 ) x d(-1 ) , for up to 8 wk with biweekly follow-up . The primary outcome was recovery , defined as having a WHZ > -2 . Time-event analysis was used to compare the recovery rate . A total of 1362 children were enrolled in the study . Children receiving soy/peanut FS had a similar recovery rate to those receiving milk/peanut FS and children in either FS group were more likely to recover than those receiving CSB ( 80 % in both FS groups vs. 72 % in the CSB group ; P < 0.01 ) . The rate of weight gain in the first 2 wk was greater among children receiving milk/peanut FS ( 2.6 g x kg(-1 ) x d(-1 ) , n = 465 ) or children receiving soy/peanut FS ( 2.4 g x kg(-1 ) x d(-1 ) , n = 450 ) than among children receiving CSB ( 2.0 g x kg(-1 ) x d(-1 ) , n = 447 ; P < 0.05 ) . Rates of length gain did not differ among the 3 groups . A total of 8 % of children in each feeding group developed edema , indicative of severe malnutrition , while receiving supplemental feeding . We conclude that FS are superior supplementary foods to CSB for moderately wasted Malawian children [1676083] There is little unequivocal evidence that nutritional supplementation of undernourished children has a beneficial effect on their mental development . The effects of nutritional supplementation , with or without psychosocial stimulation , of growth-retarded ( stunted ) children aged 9 - 24 months were assessed in a study in Kingston , Jamaica . 129 children from poor neighbourhoods were r and omly assigned to four groups -- control , supplemented only , stimulated only , and supplemented plus stimulated . A group of matched non-stunted children ( n = 32 ) was also included . The supplement comprised 1 kg milk-based formula per week for 2 years , and the stimulation weekly play sessions at home with a community health aide . The children 's development ( DQ ) was assessed on the Griffiths mental development scales . Initially the stunted groups ' DQs were lower than those of the non-stunted group , and those of the control group declined during the study , increasing their deficit . Stimulation and supplementation had significant independent beneficial effects on the children 's development . Estimates of the supplementation effect ranged from 2.2 ( 95 % confidence limits-1.4 , 5.7 ) for the h and and eye subscale to 12.4 ( 5.4 , 19.5 ) for the locomotor subscale and those for the stimulation effect from 6.4 ( 2.8 , 10.0 ) for h and and eye to 10.3 ( 3.3 , 17.3 ) for locomotor . The treatment effects were additive , and combined interventions were significantly more effective than either alone . These findings suggest that poor mental development in stunted children is at least partly attributable to undernutrition [1376586] An energy-dense supplementary food , together with nutrition education , was given to a group of moderately malnourished children aged 6 - 12 months in a poor slum community of urban Bangladesh . An age- and sex-matched control group received only nutrition education . Both groups were followed monthly with respect to weight gain and morbidity . The purpose of the study was to assess the differential impact of a targeted supplementary feeding programme with nutrition education and a nutrition education programme alone on monthly weight gain during 6 months . During the 1st 3 months of the intervention , the monthly weight gain of the supplemented children was 205 g vs 159 g in the control children ( p less than 0.05 ) . In the following 3 months , differences in weight gain were no more significant . Several possible explanations for this transient impact are discussed . It is suggested that nutrition education in the control group may have been responsible for the limited difference between the two groups , but seasonal and epidemiological factors may also have played a part [16599106] The study was a controlled , comparative clinical effectiveness trial of two supplementary feeding regimens in children at risk of malnutrition from seven centres in rural Malawi . Being at risk of malnutrition was defined as weight-for-height < 85 % , but > 80 % of the international st and ard . A stepped-wedge design with systematic allocation was used for assigning children to receive either ready-to-use therapeutic food ( RUTF ) ( n=331 ) or micronutrient-fortified corn/soy-blend ( n=41 ) for up to eight weeks . The primary outcomes were recovery , defined as weight-for-height > 90 % , and the rate of weight gain . Children receiving RUTF were more likely to recover ( 58 % vs 22 % ; difference 36 % ; 95 % confidence interval [ CI ] 20 - 52 ) and had greater rates of weight gain ( 3.1 g/kg.d vs 1.4 g/kg x d ; difference 1.7 ; 95 % CI 0.8 - 2.6 ) than children receiving corn/soy-blend . The results of this preliminary work suggest that supplementary feeding with RUTF promotes better growth in children at risk of malnutrition than the st and ard fortified cereal/legume-blended food [21205399] OBJECTIVE To determine the effectiveness of the nutritional supplement developed for the Oportunidades programme on growth , prevalence of anaemia , morbidity and cognitive function of pre-school children . DESIGN In a r and omised , placebo-controlled longitudinal trial , children were assigned to one of three experimental treatment groups : Oportunidades food supplement ( OFS ) , powdered milk ( PM ) and placebo ( PL ) . Treatments were administered daily for 6 months . Weight , height and Hb were measured in all participants before and after supplementation . Morbidity was assessed two times per week for 6 months using vali date d question naires . The Bayley Scale of Infant Development Test was administered at baseline and after 6 months . SETTING Three marginal rural communities of the state of Queretaro , Mexico . SUBJECTS A total of 224 children , mean age 22·4 ( SD 5·9 ) months , were recruited . After the 6-month intervention , 186 completed the study . RESULTS No differences were found in the adjusted changes of weight , height or anaemia between treatment groups and PL . No differences were found in the number of episodes of gastrointestinal or respiratory disease , nor were there any differences in cognitive performance between treatment and PL groups after 6 months of supplementation . CONCLUSIONS Daily supplementation of 12 - 24-month-old children with OFS has no additional benefits in growth , anaemia , morbidity or cognitive performance [10902993] Objectives : This paper presents the results of a structural equation model testing whether the longitudinal data of the Pangalengan subjects fit the theoretical model regarding the intellectual delay of undernourished children . Design : Two cohorts of children were r and omly assigned to three treatments : E=1171 kJ+12 mg iron ; M=12 mg iron+209 kJ ; S=104 kJ. Supplementation was given for 6 months . Setting : The sites were six tea plantations in Indonesia . Subjects : A 12-month-old ( n=53 ) and an 18-month-old ( n=83 ) cohort were recruited from day-care-centers . Inclusion criteria were : no chronic disease ; length-for-age=<1 st and ard deviation ( s.d . ) and weight-for-length between −1 and −2 s.d . of the median of the reference of the World Health Organization . Methods : Twenty-four-hour dietary intakes were assessed using the weighted individual inventory technique . Body weight and length were obtained using st and ard procedures ; motor development was assessed with the Bayley Scale and with a custom made scale for motor development leading to bipedal locomotion . Four-hour observations were made of the child ’s interactions with the environment . Carrying a child in the arms and exploratory behavior were used as indicators of caregiving and exploration . All measurements were obtained every 2 months . Results : The original model did not fit the data . The model was then modified with the inclusion of two new pathways : from activity and from motor development to mental development . Following these adjustments the model fit the data for each cohort and for both cohorts combined . Sponsorship : Nestlé Foundation . European Journal of Clinical Nutrition ( 2000 ) 54 , Suppl 2 , [16131023] OBJECTIVE To investigate the effect of yogurt supplementation on the growth of preschool children in Beijing suburbs . METHODS Four hundred and two preschool children ( 217 males , 185 females ) , aged 3 - 5 years , whose height for age and /or weight for age were less than the reference level , were selected as subjects from 7 kindergartens in Beijing Fangshan District . The subjects were divided r and omly into control group ( CG , 201 ) and yogurt supplemented group ( YG , 201 ) . Each subject in YG was given one serving of yogurt ( 125 g ) for 5 days a week from March to December in 2001 , while nothing additional was provided to CG . All subjects kept their usual diet during the study . Anthropometry ( body height and weight and upper-arm circumference ) and the bone mineral density ( BMD ) of forearm were measured every 3 months . Disease status and dietary intake were also recorded and assessed . RESULTS The intake of calcium , zinc , and vitamin B2 in YG was significantly higher than that in CG . The incidence and duration of upper-respiratory infection and diarrhea of children in YG were significantly less than those in CG . The height gain of children in YG was significantly higher than that in CG after yogurt was supplemented for 3 , 6 , and 9 months ( P<0.05 ) ( 1.90+/-0.49 cm vs 1.77+/-0.54 cm , 3.83+/-0.57 cm vs 3.64+/-0.66 cm and 5.43+/-0.69 cm vs 5.24+/-0.76 cm , respectively ) . The weight gain of children in YG was significantly higher than that in CG after yogurt was supplemented for 3 , 6 , and 9 months ( P<0.05 ) ( 0.70+/-0.43 kg vs 0.49+/-0.35 kg , 0.98+/-0.62 kg vs 0.80+/-0.60 kg and 1.42+/-0.76 kg vs 1.20+/-0.67 kg , respectively ) . The BMD of children in YG was significantly higher than that in CG after yogurt was supplemented for 9 months ( P<0.05 ) ( 0.415+/-0.058 g/cm2 vs 0.400+/-0.065 g/cm2 ) . CONCLUSION Yogurt is beneficial to the improvement of calcium , zinc , and vitamin B2 intake , the decreasing of the incidence and duration of upper-respiratory infection and diarrhea , and the promotion of the health and the growth and development of preschool children [12591556] OBJECTIVE Breast milk alone is insufficient to support normal growth during the second half of infancy , so I investigated supplementary feeding for infants ' successful transition to solid food . METHODS The nutrition status of 30 infants from a low socioeconomic background weaned onto an extruded formulated complementary diet from maize and cowpea ( L(1)A(1 ) ) were compared with 30 infants with a similar socioeconomic background ( L(2)N , control group ) and 30 infants from an above-average socioeconomic background ( HN , reference group ) without the supplementary diet . Infants within the control and reference groups were weaned onto different foods of the mothers ' choice . The formulated diet was analyzed for nutrient composition . RESULTS The results showed similarity in the estimated annual family income of the L(1)A(1 ) and L(2)N groups , which ranged from N 25 000 to 74 000 ( US $ 208.30 to 616.70 ) , whereas the estimated family income for the HN group was above N 225 000 ( US $ 1875.00 ) annually . The formulated blend contained 17.3 % protein , 5.0 % fat , and 2106 kJ of energy . Mean weight at birth and 4 mo before the feeding intervention in HN infants was statistically ( P < 0.05 ) higher than in L(1)A(1 ) and L(2)N infants . At the end of the study , L(1)A(1 ) and HN infants had a mean length within -1 st and ard deviation of the st and ard length for age . The mean length of L(2)N infants was within -3 st and ard deviations of the st and ard length for age . The effectiveness of the formulated diet was expressed in terms of similarity in anthropometric measurements of L(1)A(1 ) ) and HN infants . CONCLUSIONS Based on similarities in socioeconomic background and weight at birth and 4 mo in the L(1)A(1 ) and L(2)N infants , the better nutrition status of the L(1)A(1 ) is attributed to the formulated complementary diet . The contribution of this mixture to total nutrient intake seemed substantial enough to meet the infants ' nutritional requirements . The use of a cheaply available plant protein will go a long way in reducing protein-energy malnutrition among children in developing countries . However , because of the low purchasing power of the low-income family , the costs of this product should be studied [7223696] Infants born to families at risk of malnutrition were studied prospect ively from the beginning of the 3rd trimester of the mother 's pregnancy until the child reached 3 yr of age to ascertain the effects of nutritional supplementation and /or a maternal education program on their cognitive development . Four hundred thirty-three families were assigned r and omly to six groups : group A served as a control ; group B received the supplement from the age of 6 months to 3 yr ; group C received the supplement during the 3rd trimester of pregnancy and the first 6 months of the child 's life ; and group D received the supplement throughout the entire study period . In addition , group A1 was enrolled in a maternal education program but received no nutritional supplement and group B1 received both treatments . The Griffiths test of infant development was administered at 4 , 6 , 12 , 18 , 24 , and 36 months of age , and the Corman-Escalona Einstein scale was administered at each age up to 18 months . Children who received food supplementation performed better than those who did not , especially on subtests that were primarily motoric . The effect of food supplementation on behavior appeared to be contemporaneous . In addition , the treatment effects were more pronounced for girls than for boys in this sample . Although these interventions reduced the gap in cognitive performance between lower and upper socioeconomic classes , a disparity nevertheless remained by the end of the study [19155454] CONTEXT Ready-to-use therapeutic foods ( RUTFs ) are an important component of effective outpatient treatment of severe wasting . However , their effectiveness in the population -based prevention of moderate and severe wasting has not been evaluated . OBJECTIVE To evaluate the effect of a 3-month distribution of RUTF on the nutritional status , mortality , and morbidity of children aged 6 to 60 months in Niger . DESIGN , SETTING , AND PARTICIPANTS A cluster r and omized trial of 12 villages in Maradi , Niger . Six villages were r and omized to intervention and 6 to no intervention . All children in the study villages aged 6 to 60 months were eligible for recruitment . INTERVENTION Children with weight-for-height 80 % or more of the National Center for Health Statistics reference median in the 6 intervention villages received a monthly distribution of 1 packet per day of RUTF ( 92 g [ 500 kcal/d ] ) from August to October 2006 . Children in the 6 nonintervention villages received no preventive supplementation . Active surveillance for conditions requiring medical or nutritional treatment was conducted monthly in all 12 study villages from August 2006 to March 2007 . MAIN OUTCOME MEASURES Changes in weight-for-height z score ( WHZ ) according to the World Health Organization Child Growth St and ards and incidence of wasting ( WHZ < -2 ) over 8 months of follow-up . RESULTS The number of children with height and weight measurements in August , October , December , and February was 3166 , 3110 , 2936 , and 3026 , respectively . The WHZ difference between the intervention and nonintervention groups was -0.10 z ( 95 % confidence interval [ CI ] , -0.23 to 0.03 ) at baseline and 0.12 z ( 95 % CI , 0.02 to 0.21 ) after 8 months of follow-up . The adjusted effect of the intervention on WHZ from baseline to the end of follow-up was thus 0.22 z ( 95 % CI , 0.13 to 0.30 ) . The absolute rate of wasting and severe wasting , respectively , was 0.17 events per child-year ( 140 events/841 child-years ) and 0.03 events per child-year ( 29 events/943 child-years ) in the intervention villages , compared with 0.26 events per child-year ( 233 events/895 child-years ) and 0.07 events per child-year ( 71 events/1029 child-years ) in the nonintervention villages . The intervention thus result ed in a 36 % ( 95 % CI , 17 % to 50 % ; P < .001 ) reduction in the incidence of wasting and a 58 % ( 95 % CI , 43 % to 68 % ; P < .001 ) reduction in the incidence of severe wasting . There was no reduction in mortality , with a mortality rate of 0.007 deaths per child-year ( 7 deaths/986 child-years ) in the intervention villages and 0.016 deaths per child-year ( 18 deaths/1099 child-years ) in the nonintervention villages ( adjusted hazard ratio , 0.51 ; 95 % CI , 0.25 to 1.05 ) . CONCLUSION Short-term supplementation of nonmalnourished children with RUTF reduced the decline in WHZ and the incidence of wasting and severe wasting over 8 months . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00682708 [16599102] This prospect i ve r and omized trial was carried out to test the efficacy of a specific intervention for reducing the extent of their malnutrition and to change behaviour of mothers relating to child-feeding practice s , care-giving , and health-seeking practice s under the Bangladesh Integrated Nutrition Project ( BINP ) . The study was conducted in rural Bangladesh among 282 moderately-malnourished ( weight-for-age between 61 % and 75 % of median of the National Center for Health Statistics st and ard ) children aged 6 - 24 months . Mothers of the first intervention group received intensive nutrition education ( INE group ) twice a week for three months . The second intervention group received the same nutrition education , and their children received additional supplementary feeding ( INE+SF group ) . The comparison group received nutrition education from the community nutrition promoters twice a month according to the st and ard routine service of BINP . The children were observed for a further six months . After three months of interventions , a significantly higher proportion of children in the INE and INE+SF groups improved ( 37 % and 47 % respectively ) from moderate to mild or normal nutrition compared to the comparison group ( 18 % ) ( p < 0.001 ) . At the end of six months of observation , the nutritional status of children in the intervention groups improved further from moderate to mild or normal nutrition compared to the comparison group ( 59 % and 86 % vs 30 % , p < 0.0001 ) . As the intensive nutrition education and supplementation given were highly effective , more children improved from moderate malnutrition to mild or normal nutritional status despite a higher incidence of morbidity . The frequency of child feeding and home-based complementary feeding improved significantly ( p < 0.001 ) in both the intervention groups after three months of interventions and six months of observation . Body-weight gain was positively associated with age , length-for-age , weight-for-length , frequency of feeding of khichuri , egg , and potato ( p < 0.05 ) . Ability of mothers to identify malnutrition improved from 15 % to 99 % in the INE group and from 15 % to 100 % in the INE+SF group , but reduced from 24 % to 21 % in the comparison group . Use of separate feed pots , frequency of feeding , and cooking of additional complementary feeds improved significantly in the INE and INE+SF groups compared to the comparison group after three months of interventions and six months of observation . It can be concluded from the findings of the study that intensive nutrition education significantly improves the status of moderately-malnourished children with or without supplementary feeding [17033530] Objective : Fortified spreads ( FSs ) have proven effective in the rehabilitation of severely malnourished children . We examined acceptability , growth and change in blood haemoglobin ( Hb ) concentration among moderately underweight ambulatory infants given FS . Methods : This was a r and omised , controlled , parallel-group , investigator-blind clinical trial in rural Malawi . Six- to 17-month-old underweight infants ( weight for age < −2 ) , whose weight was greater than 5.5 kg and weight-for-height z score greater than −3 received for 12 weeks at home 1 of 8 food supplementation schemes : nothing , 5 , 25 , 50 , or 75 g/day milk-based FS or 25 , 50 , or 75 g/day soy-based FS . Outcome measures included change in weight , length and blood Hb concentration . Results : A total of 126 infants started and 125 completed the intervention . All infants accepted the spread well , and no intolerance was recorded . Average weight and length gains were higher among infants receiving daily 25 to 75 g FS than among those receiving only 0 to 5 g FS . Mean Hb concentration remained unchanged among unsupplemented controls but increased by 10 to 17 g/L among infants receiving any FS . All average gains were largest among infants receiving 50 g of FS daily : mean difference ( 95 % confidence interval ) in the 12-week gain between infants in 50 g milk-based FS group and the unsupplemented group was 290 g ( range , −130 to 700 g ) , 0.9 cm ( range , −0.3 to 2.2 cm ) , and 17 g/L ( range , 0 to 34 g/L ) for weight , length and blood Hb concentration , respectively . In soy- vs milk-based FS groups , average outcomes were comparable . Conclusions : Supplementation with 25 to 75 g/day of highly fortified spread is feasible and may promote growth and alleviate anaemia among moderately malnourished infants . Further trials should test this hypothesis [10902991] Objectives : This paper reports the effects of an energy and micronutrient supplement on mental development and on the social – cognitive and emotionally regulatory behaviors of nutritionally at risk infants and toddlers in Pangalengan , Indonesia . Design : Two cohorts of children were r and omly assigned to three treatments : E=1171 kJ+12 mg iron ; M=12 mg iron+209 kJ ; S=104 kJoule . Supplementation was given for 12 months . Setting : The sites were six tea plantations in Pangalengan , West Java . Subjects : A 12-month-old ( N=53 ) and an 18-month-old ( N=83 ) cohort were recruited from day-care-centers . Twenty children who received S belonged to the 12- and 18-month-old cohort . Inclusion criteria were : no chronic disease ; length-for-age ≤−1 st and ard deviation ( s.d . ) and weight-for-length between −1 and −2 s.d . of the median of the reference of the World Health Organization . Methods : Evaluations of intake were made at baseline and every 2 months thereafter . Motor development was assessed with the Bayley Scale and with a custom-made scale to assess gross motor development leading to bipedal locomotion . Four hours of continuous observations were made of the child ’s interaction with the social and physical environment . Results : In the 12-month-old cohort , as compared with the M and S groups , the children who received the E supplement walked at an earlier age , had higher scores in the Bayley Scale and showed more mature social – cognitive and emotional regulatory behaviors . Similar intergroup differences were observed in the 18-month-old cohort in social cognition and regulation of emotions . Sponsorship : Nestlé Foundation . European Journal of Clinical Nutrition ( 2000 ) 54 , Suppl 2 , [10902986] Objectives : This paper reports the dietary intake ( home , day care centers , supplement and breast milk ) of the children in the clinical trial in Pangalengan . Design : Two cohorts of children were r and omly assigned to three treatments : E=1171 kJ+12 mg iron ; M=209 kJ+12 mg iron ; S=104 kJ. Supplementation was given for 12 months . Setting : The sites were six tea plantations in Pangalengan , West Java . Subjects : A 12-month-old ( n=53 ) and an 18-month-old ( n=83 ) cohort were recruited from day-care-centers . Twenty children who received S belong to the 12- and 18-month-old cohorts . Inclusion criteria were : no chronic disease ; length-for-age ≤−1 st and ard deviation ( s.d . ) and weight-for-length between −1 and −2 s.d . of the median of the reference of the World Health Organization . Methods : E=1171 kJ+12 mg iron ; M=209 kJ+12 mg iron ; S = 104 kJ. Supplementation was given for 12 months . Evaluations of intake were made at baseline and every 2 months thereafter . Results : For the 12-month-old cohort the mean increase in daily energy intake∼2931 kJ for E , ∼1675 kJ for M , and ∼837 kJ increase over the 6 months for the S group . For the 18-month-old cohort the changes were ∼2512 kJ for E∼1675 for the M group and ∼1047 for the S group . Sponsorship : Nestlé Foundation . European Journal of Clinical Nutrition ( 2000 ) 54 , Suppl 2 , [8556899] It is frequently assumed that undernutrition in young children leads to poor development through reduced activity . 3 groups of 26 1-year-old stunted children were studied : nutritional supplementation , supplementation with psychosocial stimulation , and controls . 26 nonstunted comparison children were also studied . Activity levels were measured by extensive observation in the homes , and development using 4 subscales of the Griffith 's Mental Development Scales . Initially , stunted children were less active than nonstunted ones ( p < .01 ) , but after 6 months they caught up regardless of treatment . The mental ages of the stunted children were lower than those of the nonstunted children initially , and improved with either treatment . Initially , activity levels made a significant contribution to the variance in the locomotor subscale only , but not 6 months later . Activity did not predict change in development over 6 or 12 months , nor did change in activity over 6 months predict change in development over 12 months [23795976] Low nutritional value of complementary foods is associated with high incidence of childhood growth stunting in low-income countries . This study was done to test a hypothesis that dietary complementation with lipid-based nutrient supplements ( LNS ) promotes linear growth and reduces the incidence of severe stunting among at-risk infants . A total of 840 6-month-old healthy infants in rural Malawi were enrolled to a r and omised assessor-blinded trial . The participants received 12-month supplementation with nothing , milk-LNS , soy-LNS , or corn-soy blend ( CSB ) . Supplements provided micronutrients and approximately 280 kcal energy per day . Outcomes were incidence of severe and very severe stunting [ length-for-age z-score , ( LAZ ) < -3.00 and < -3.50 , respectively ] , and change in LAZ . The incidence of severe stunting was 11.8 % , 8.2 % , 9.1 % and 15.5 % ( P = 0.098 ) and that of very severe stunting 7.4 % , 2.9 % , 8.0 % and 6.4 % ( P = 0.138 ) in control , milk-LNS , soy-LNS and CSB groups , respectively . Between 9 and 12 months of age , the mean change in LAZ was -0.15 , -0.02 , -0.12 and -0.18 ( P = 0.045 ) for control , milk-LNS , soy-LNS and CSB groups , respectively . There was no significant between-group difference in linear growth during other age-intervals . Although participants who received milk-LNS had the lowest incidence of severe and very severe stunting , the differences between the groups were smaller than expected . Thus , the results do not provide conclusive evidence on a causal association between the LNS supplementation and the lower incidence of stunting . Exploratory analyses suggest that provision of milk-LNS , but not soy-LNS promotes linear growth among at-risk infants mainly between 9 and 12 months of age [7536830] This is an overview of the design and methods of the INCAP longitudinal study ( 1969 - 77 ) and its follow-up study ( 1988 - 89 ) . The first study had the objective of assessing the effects of intrauterine and preschool malnutrition on growth and mental development . To achieve this , food supplements were provided to pregnant women and young children residing in four Gautemalan villages . Two villages were given a high-protein , high-energy drink and two were provided a no-protein , low-energy drink . Both supplements contained vitamins and minerals . Longitudinal information was collected during the first seven years of life on physical growth , mental development , attendance and consumption of supplement , home diet , morbidity and on characteristics of the family . Health and nutrition data on mothers also were collected . The INCAP follow-up study was a cross-sectional evaluation of former participants of the first study and was carried out when the subjects were 11 - 27 y old . The hypothesis of the INCAP follow-up study was that improved nutrition in early childhood leads to enhanced human capital formation in adolescents and adults . Data were collected on physical growth and body composition , maturation , work capacity , intellectual performance and school achievement

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### Context: [18356337] The goal of this study was to evaluate the impact of Mexico 's conditional cash transfer program , Oportunidades , on the growth of children < 24 mo of age living in urban areas . Beneficiary families received cash transfers , a fortified food ( targeted to pregnant and lactating women , children 6 - 23 mo , and children with low weight 2 - 4 y ) , and curative health services , among other benefits . Program benefits were conditional on preventative health care utilization and attendance of health and nutrition education sessions . We estimated the impact of the program after 2 y of operation in a panel of 432 children < 24 mo of age at baseline ( 2002 ) . We used difference-in-difference propensity score matching , which takes into account nonr and om program participation and the effects of unobserved fixed characteristics on outcomes . All models controlled for child age , sex , baseline anthropometry , and maternal height . Anthropometric Z-scores were calculated using the new WHO growth reference st and ards . There was no overall association between program participation and growth in children 6 to 24 mo of age . Children in intervention families younger than 6 mo of age at baseline grew 1.5 cm ( P < 0.05 ) more than children in comparison families , corresponding to 0.41 height-for-age Z-scores ( HAZ ) ( P < 0.05 ) . They also gained an additional 0.76 kg ( P < 0.01 ) or 0.47 weight-for-height Z-scores ( P < 0.05 ) . Children living in the poorest intervention households tended ( 0.05 < P < 0.10 ) to be taller than comparison children ( 0.9 cm , 0.27 HAZ ) . Oportunidades , with its strong nutrition component , is an effective tool to improve the growth of infants in poor urban households [24225356] BACKGROUND Haiti has experienced rapid urbanization that has exacerbated poverty and undernutrition in large slum areas . Stunting affects 1 in 5 young children . OBJECTIVE We aim ed to test the efficacy of a daily lipid-based nutrient supplement ( LNS ) for increased linear growth in young children . DESIGN Healthy , singleton infants aged 6 - 11 mo ( n = 589 ) were recruited from an urban slum of Cap Haitien and r and omly assigned to receive : 1 ) a control ; 2 ) a 3-mo LNS ; or 3 ) a 6-mo LNS . The LNS provided 108 kcal and other nutrients including vitamin A , vitamin B-12 , iron , and zinc at ≥80 % of the recommended amounts . Infants were followed monthly on growth , morbidity , and developmental outcomes over a 6-mo intervention period and at one additional time point 6 mo postintervention to assess sustained effects . The Bonferroni multiple comparisons test was applied , and generalized least-squares ( GLS ) regressions with mixed effects was used to examine impacts longitudinally . RESULTS Baseline characteristics did not differ by trial arm except for a higher mean age in the 6-mo LNS group . GLS modeling showed LNS supplementation for 6 mo significantly increased the length-for-age z score ( ±SE ) by 0.13 ± 0.05 and the weight-for-age z score by 0.12 ± 0.02 compared with in the control group after adjustment for child age ( P < 0.001 ) . The effects were sustained 6 mo postintervention . Morbidity and developmental outcomes did not differ by trial arm . CONCLUSION A low-energy , fortified product improved the linear growth of young children in this urban setting . The trial was registered at clinical trials.gov as NCT01552512 [10986782] OBJECTIVE To determine whether utilization of iron from infant cereal and pureed meat was sufficient to prevent iron depletion and /or anaemia in infants 6 to 12 months old fed whole cow milk ( WCM ) as their primary milk source . DESIGN Six-month-old infants were r and omized into a treatment group ( n = 43 ) receiving iron-fortified infant cereal ( 10.2 mg iron ) , pureed meat ( 0.75 - 1.7 mg iron ) and WCM for six months or a control group ( n = 54 ) receiving no dietary intervention . Haemoglobin < 110 g/L or ferritin < 10 micrograms/L ( measured bi-monthly ) , confirmed in a second blood sample , defined end-points . RESULTS Proportion reaching end-point was similar between the treatment ( 3/43 ) and control infants ( 5/54 ) ( p = 0.66 ) . Infants not complying with the protocol were at greater risk of reaching end-point ( p = 0.0002 ) . Change in haemoglobin and ferritin across age was similar in both groups . CONCLUSIONS Iron deficiency is not a concern in WCM-fed infants after six months of age if iron-containing complementary foods are concurrently ingested [19591885] The aim of this study was to test the ability of two new products , an instant infant flour and a food supplement containing amylases , to increase energy and micronutrient intakes of infants older than 6 months . Three groups of 48 infants were r and omly constituted . Infants in groups 1 and 2 consumed at least twice a day gruel made either from the instant flour or from the food supplement . Infants from the control group received complementary foods prepared in the usual way . Each infant was surveyed during a whole day in order to measure feeding frequencies and characteristics as well as amounts of the different types of complementary foods consumed . Foods consumed by infants in the two experimental groups differed considerably in energy , micronutrient density and in consistency from the home-made complementary foods . Due to the incorporation of amylases , gruels made from the food supplement had a higher energy density , a more appropriate consistency and result ed in higher intakes per meal than gruels made from instant flour . In comparison with home-made complementary foods , both experimental products result ed in significantly higher energy and nutrient intakes . The two experimental products appeared to increase sufficiently both energy and nutrient intakes of infants to complement their breastmilk intake [11435512] It is unclear whether a substantial decline in malnutrition among infants in developing countries can be achieved by increasing food availability and nutrition counseling without concurrent morbidity-reducing interventions . The study was design ed to determine whether provision of generous amounts of a micronutrient-fortified food supplement supported by counseling or nutritional counseling alone would significantly improve physical growth between 4 and 12 mo of age . In a controlled trial , 418 infants 4 mo of age were individually r and omized to one of the four groups and followed until 12 mo of age . The first group received a milk-based cereal and nutritional counseling ; the second group monthly nutritional counseling alone . To control for the effect of twice-weekly home visits for morbidity ascertainment , similar visits were made in one of the control groups ( visitation group ) ; the fourth group received no intervention . The median energy intake from nonbreast milk sources was higher in the food supplementation group than in the visitation group by 1212 kJ at 26 wk ( P < 0.001 ) , 1739 kJ at 38 wk ( P < 0.001 ) and 2257 kJ at 52 wk ( P < 0.001 ) . The food supplementation infants gained 250 g ( 95 % confidence interval : 20 - -480 g ) more weight than did the visitation group . The difference in the mean increment in length during the study was 0.4 cm ( 95 % confidence interval : -0.1 - -0.9 cm ) . The nutritional counseling group had higher energy intakes ranging from 280 to 752 kJ at different ages ( P < 0.05 at all ages ) but no significant benefit on weight and length increments . Methods to enhance the impact of these interventions need to be identified [20691525] The importance of reducing childhood undernutrition has been enshrined in the United Nations ' Millennium Development Goals . This study explores the relationship between alternative indicators of poverty and childhood undernutrition in developing countries within the context of a multi-national cohort study ( Young Lives ) . Approximately 2000 children in each of four countries - Ethiopia , India ( And hra Pradesh ) , Peru and Vietnam - had their heights measured and were weighed when they were aged between 6 and 17 months ( survey one ) and again between 4.5 and 5.5 years ( survey two ) . The anthropometric outcomes of stunted , underweight and wasted were calculated using World Health Organization 2006 reference st and ards . Maximum-likelihood probit estimation was employed to model the relationship within each country and survey between alternative measures of living st and ards ( principally a wealth index developed using principal components analysis ) and each anthropometric outcome . An extensive set of covariates was incorporated into the models to remove as much individual heterogeneity as possible . The fully adjusted models revealed a negative and statistically significant coefficient on wealth for all outcomes in all countries , with the exception of the outcome of wasted in India ( And hra Pradesh ) and Vietnam ( survey one ) and the outcome of underweight in Vietnam ( surveys one and two ) . In survey one , the partial effects of wealth on the probabilities of stunting , being underweight and wasting was to reduce them by between 1.4 and 5.1 percentage points , 1.0 and 6.4 percentage points , and 0.3 and 4.5 percentage points , respectively , with each unit ( 10 % ) increase in wealth . The partial effects of wealth on the probabilities of anthropometric outcomes were larger in the survey two models . In both surveys , children residing in the lowest wealth quintile households had significantly increased probabilities of being stunted in all four study countries and of being underweight in Ethiopia , India ( And hra Pradesh ) and Peru in comparison to children residing in the highest wealth quintile households . R and om effects probit models confirmed the statistical significance of increased wealth in reducing the probability of being stunted and underweight across all four study countries . We conclude that , although multi-faceted , childhood undernutrition in developing countries is strongly rooted in poverty [9394687] Does short-term supplementary feeding during infancy and childhood have long-lasting effects ? In 1986 , 334 children aged 6 - 60 mo living on rural tea plantations in West Java , Indonesia , participated in a 3-mo r and omized trial to test the effects of a dietary supplement providing approximately 1672 kJ ( 400 kcal ) energy/d , with about the same nutrient density as local foods . We returned to the same communities in 1994 and enrolled 231 ( 125 supplemented , 106 control ) of the original subjects in a follow-up study of the long-term effects of supplementation . We assessed these subjects by using several measures : anthropometry , iron status , information processing , Peabody Picture Vocabulary Test , word fluency , and an arithmetic test . The supplemented group showed no differences from those in the control group . However , when the analysis was limited to subjects who had received the supplement before the age of 18 mo ( n = 73 ) , the supplemented children performed better than control children on the Sternberg test of working memory ( decision time intercept : probe absent , P = 0.002 ; probe present , P = 0.053 ) . After considering possible confounders , we concluded that the supplementation during infancy was responsible for the difference . This finding shows that supplementation can have long-lasting effects on a specific domain if the child receives it at the appropriate stage of development [3189208] A study of the effects of providing high-calorie and vitamin-mineral supplements to preschool village children retarded in growth and development in Chiang Mai , Thail and was done . The preschool children of 24 villages with a population of approximately 11,000 were divided into five control and intervention groups . The interventions consisted of a village health program , high-calorie snacks , and vitamin-mineral supplements . The supplements when used were provided in day care centers for preschool children . The health and nutrition interventions used did not significantly affect growth during the study period reported from December 1981 to October 1983 . Monthly changes in length and weight observed in this and a previous study indicate that growth patterns in Thai children are different from those seen in industrialized societies . Factors other than lack of nutrients and infection may be responsible for the inadequate growth often reported in developing countries [1897471] The benefits of nutritional supplementation , with or without psychosocial stimulation , on the growth of stunted children were evaluated . Children aged 9 - 24 mo with lengths less than -2 SD of the National Center for Health Statistics references ( n = 129 ) were r and omly assigned to four groups : control , nutritional supplementation , stimulation , and both interventions . A fifth group with lengths greater than -1 SD was also enrolled . Length , weight , head and arm circumferences , and triceps and subscapular skinfold thicknesses were measured on enrollment and 6 and 12 mo later . Multiple-regression analysis was used to determine the effects of the interventions in which age , sex , initial status , initial dietary intake , and several socioeconomic variables were controlled for . Stimulation had no effect on growth and there was no interaction between the interventions . After 12 mo supplemented children had significantly increased length , weight , and head circumference ( all P less than 0.01 ) . The effects of supplementation were not cumulative but occurred in the first 6 mo [7282613] The effect of food supplementation on physical growth during the last trimester of pregnancy and the first 3 yr of life was studied in a sample of families at risk of malnutrition living in the urban slums of Bogota , Colombia . Families in which the mother was pregnant and at least one-half of the children under 5 yr of age were below 85 % of weight for age were selected for the study . All were provided with free obstetrical and pediatric care . The families were then r and omly assigned to control and supplemented groups . The supplemented families received a daily allotment of 600 cal or 30 g of protein per capita for home consumption from the onset of the 3rd trimester of pregnancy until the subject children reached the age of 3 yr . Calorie consumption from the supplement by the study children ( offspring of the target pregnancy ) was 458 ± 249 calories at age 18 months and 363 ± 283 cal at age 36 months . Protein consumption at those ages was 34 . 1 ± 20.6 and 23.6 ± 19.7 g,'day . However , substitution of the supplement for foods from the regular diet result ed in net supplementation of approximately 200 cal and 22 g of protein per day . There were significant differences in weight between supplemented and control groups beginning at age 3 months and in length beginning at age 6 months . Supplementation reduced the total prevalence of malnutrition ( Gomez classification ) only slightly ; at 36 months of age , 72 % of the supplemented group and 77.8 % of the control group were malnourished . On the other h and , the prevalence of moderate and severe malnutrition ( Gomez II and III ) , was significantly reduced by supplementation . At 36 months , 20.6 % of the control group and 8.8 % of the supplemented group fell into those categories . Despite improved physical growth in the supplemented group , their height and weight remained substantially below those of the high socioeconomic Colombian st and ards . The failure of supplementation to close the gap between low and high socioeconomic groups was attributed , in part , to the high incidence of diarrheal disease among subjects of the study . It is postulated that simple provision of food supplements , without effective prevention of diarrheal disease , is likely to have limited effects on physical growth among disadvantaged children . Am . J. Clin . Nutr . 34 : 1885 - 1892 , 1981 [1951149] This study assessed the developmental effects of supplementary feeding over 90 consecutive days on infants aged 6 - 20 mo at six tea plantations in West Java , Indonesia . Every day except Sunday , the infants attended day-care centers distributed throughout the plantations . Twenty centers and 113 infants were selected ; the infants in 9 centers received a dietary supplement , while the infants in 11 centers served as control subjects . Supplements were given twice a day providing , on average , 10.66 kJ ( 400 kcal ) and 5 g protein/d . Measurements of body growth , dietary intake , and mental and motor development were made on all infants . Supplementary feeding had significant effects on weight gain and on motor development . Changes in caloric intake were independently associated with changes in weight and in motor test scores . The data suggest that the effects of the supplement may not have followed a simple mechanistic relationship from intake to weight change to motor development , but , rather , intake may have affected both growth and development domains simultaneously [18203907] Linear growth retardation and anemia are the most prevalent nutritional problems in the world ; effective interventions are urgently needed . We evaluated Ecuador 's National Food Nutrition Program ( PANN 2000 ) that included a micronutrient-fortified complementary food ( FCF ) , Mi Papilla , in poor periurban and rural communities of Ecuador . The program is preventive and targeted to all infants and young children living in poor communities and receiving government health services . We compared dietary intake , micronutrient status , and growth over 11 mo in a cohort of children from the catchment areas of the PANN 2000 with same-age control children in nearby communities eligible to enter the program 1 y later . PANN 2000 children enrolled in the program when they were age 9 - 14 mo and were age 20 - 25 mo at the final survey . They consumed significantly more energy , protein , fat , iron , zinc , vitamin A , and calcium than control children because of their FCF consumption . Anemia , 76 % in both groups at baseline , fell to 27 % in PANN 2000 children but only to 44 % in control children ( P < 0.001 ) . The odds of being anemic were 58 % lower for PANN 2000 children ( P = 0.003 ) . The effects on linear growth and weight were limited to children who were older when the program began ( 12 - 14 mo ) and were significant for weight ( interaction with age , 0.38 kg ; P = 0.029 ) and positive but not significant for length ( 0.66 cm ; P = 0.08 ) . An FCF , including ferrous sulfate , delivered through public health services , is highly effective in improving weight and hemoglobin and reducing anemia [2058589] Three-month recovery rates from moderate wasting ( less than 90 % weight-for-length ) were compared in 6 - 24-mo-old children in four Guatemalan villages that had been r and omly assigned to receive a moderate ( Atole ) or low ( Fresco ) energy supplement . The recovery rate ( Rr ) in the Atole villages was 12 % higher than in the Fresco villages ( P less than 0.05 ) . This effect was above all due to the children in the Atole villages who consumed greater than or equal to 10 % of the daily recommended dietary intake of energy ( RDI ) from the supplement ( high-Atole group ) and whose total energy intake ( including home diet ) was 10.5 % of the RDI higher than a comparable high-Fresco group with low supplemental energy intake . All those in the high-Atole group whose wasting was due to malnutrition recovered . Much of this recovery ( range 29 - 52 % ) was due to the increased supplementation . This proportion rose after potential confounding variables were controlled for [8839497] The effect of supplementation on growth was tested by means of four similar controlled r and omized trials in the Congo ( n = 120 ) , Senegal ( n = 110 ) , Bolivia ( n = 127 ) , and New Caledonia ( n = 90 ) . Four-month-old infants were r and omly allocated to supplement or control groups . A cereal-based precooked porridge was offered twice daily for 3 mo and consumption was monitored . Both groups were free to eat local food . At 7 mo of age , all infants were still breast-fed in the Congo , Senegal , and Bolivia compared with 47 % in New Caledonia . Mean daily consumption of the supplement varied among countries ( 558 - 790 kJ/d ) . Mean length at 4 mo was lowest in Bolivia , higher in Senegal and the Congo , and near the National Center for Health Statistics reference in New Caledonia . The mean 4 - 7 mo length increment was 0.48 cm higher for supplemented than for control infants in Senegal ( P < 0.05 ) , whereas weight increments did not differ . No significant effect was found in the other countries [9250101] It is not known whether nutritional supplementation in early childhood has long-term benefits on stunted children 's mental development . We followed up 127 7 - 8-y old children who had been stunted in early childhood and received supplementation , stimulation , or both . At 9 - 24 mo of age , the children had been r and omly assigned to four treatment groups : nutritional supplementation , stimulation , both treatments , and control . After 2 y , supplementation and stimulation had independent benefits on the children 's development and the effects were additive . The group receiving both treatments caught up to a matched group of 32 nonstunted children . Four years after the end of the 2-y intervention 97 % of the children were given a battery of cognitive function , school achievement , and fine motor tests . An additional 52 nonstunted children were included . Factor analyses of the test scores produced three factors : general cognitive , perceptual-motor , and memory . One , the perceptual-motor factor , showed a significant benefit from stimulation , and supplementation benefited only those children whose mothers had higher verbal intelligence quotients . However , each intervention group had higher scores than the control subjects on more tests than would be expected by chance ( supplemented and both groups on 14 of 15 tests , P = 0.002 ; stimulated group in 13 of 15 tests , P = 0.01 ) , suggesting a very small global benefit . There was no longer an additive effect of combined treatments at the end of the intervention . The stunted control group had significantly lower scores than the nonstunted children on most tests . Stunted children 's heights and head circumferences on enrollment significantly predicted intelligence quotient at follow-up [7722691] The Cali Study involved the r and om assignment of 301 malnourished children to be exposed to one ( CT1 , n = 113 ) , two ( CT2 , n = 64 ) , three ( CT3 , n = 62 ) or four ( CT4 , n = 62 ) 9-mo periods of a multifocal day care-based intervention ( i.e. , education , health and nutrition ) . The ages at which the intervention was initiated for Groups CT4 , CT3 , CT2 and CT1 were 3.5 , 4.2 , 5.2 and 6.1 y , respectively . After the experimental phase , children were followed up in elementary school until they were 10.4 y old . Our secondary data analyses show that children who were exposed at an earlier age and for a longer period of time showed the highest degree ( P < or = 0.05 ) of improvement in weight and linear growth during the pre-school period . These improvements in physical growth could no longer be detected 3 y after the termination of the intervention [15213048] BACKGROUND Previous analyses derived the relative risk ( RR ) of dying as a result of low weight-for-age and calculated the proportion of child deaths worldwide attributable to underweight . OBJECTIVES The objectives were to examine whether the risk of dying because of underweight varies by cause of death and to estimate the fraction of deaths by cause attributable to underweight . DESIGN Data were obtained from investigators of 10 cohort studies with both weight-for-age category ( < -3 SDs , -3 to < -2 SDs , -2 to < -1 SD , and > -1 SD ) and cause of death information . All 10 studies contributed information on weight-for-age and risk of diarrhea , pneumonia , and all-cause mortality ; however , only 6 studies contributed information on deaths because of measles , and only 3 studies contributed information on deaths because of malaria or fever . With use of weighted r and om effects models , we related the log mortality rate by cause and anthropometric status in each study to derive cause-specific RRs of dying because of undernutrition . Prevalences of each weight-for-age category were obtained from analyses of 310 national nutrition surveys . With use of the RR and prevalence information , we then calculated the fraction of deaths by cause attributable to undernutrition . RESULTS The RR of mortality because of low weight-for-age was elevated for each cause of death and for all-cause mortality . Overall , 52.5 % of all deaths in young children were attributable to undernutrition , varying from 44.8 % for deaths because of measles to 60.7 % for deaths because of diarrhea . CONCLUSION A significant proportion of deaths in young children worldwide is attributable to low weight-for-age , and efforts to reduce malnutrition should be a policy priority [17273956] R and omization in r and omized controlled trials involves more than generation of a r and om sequence by which to assign subjects . For r and omization to be successfully implemented , the r and omization sequence must be adequately protected ( concealed ) so that investigators , involved health care providers , and subjects are not aware of the upcoming assignment . The absence of adequate allocation concealment can lead to selection bias , one of the very problems that r and omization was supposed to eliminate . Authors of reports of r and omized trials should provide enough details on how allocation concealment was achieved so the reader can determine the likelihood of success . Fortunately , a plan of allocation concealment can always be incorporated into the design of a r and omized trial . Certain methods minimize the risk of concealment failing more than others . Keeping knowledge of subjects ' assignment after allocation from subjects , investigators/health care providers , or those assessing outcomes is referred to as masking ( also known as blinding ) . The goal of masking is to prevent ascertainment bias . In contrast to allocation concealment , masking can not always be incorporated into a r and omized controlled trial . Both allocation concealment and masking add to the elimination of bias in r and omized controlled trials [10902992] Objectives : This paper reports the effects of an energy and micronutrient supplementation on quantitative and qualitative aspects of play among poorly nourished children . At issue is whether the supplement led to a progression in complexity of play . Design : two cohorts of children were r and omly assigned to three treatments : E=1171 kJ+12 mg iron ; M=12 mg iron+209 kJ ; S=104 kJ. Supplementation was given for 6 months . Evaluations of play behavior were repeated four times . Setting : The sites were six tea plantations in Pangalengan , West Java . Subjects : The present study utilized a sub sample of 55 children recruited for the larger Pangalengan project 6 months into the study . Thirty-eight children were recruited late enough to allow for longitudinal observations . The remaining cases were used for cross sectional observations only . Inclusion criteria were : no chronic disease ; length-for-age ≤−1 st and ard deviation ( s.d . ) and weight-for-length between −1 and −2 s.d . of the median of the reference of the World Health Organization . Methods : The children were videotaped during play . These tapes were coded for eight mutually exclusive categories of activities . Four activities coded represented manipulative , relational , functional and symbolic play . Results : Treatment did not affect qualitative play . Girls that received E increased functional play but boys showed the opposite effect . Children in the S group were breastfed more during play as compared to the E group . Children in the E group waited less to begin play . Sponsorship : Nestlé Foundation . European Journal of Clinical Nutrition ( 2000 ) 54 , Suppl 2 , [16166365] Study objective : There is little guidance on how to select the best available evidence of health effects of social interventions . The aim of this paper was to assess the implication s of setting particular inclusion criteria for evidence synthesis . Design : Analysis of all relevant studies for one systematic review , followed by sensitivity analysis of the effects of selecting studies based on a two dimensional hierarchy of study design and study population . Setting : Case study of a systematic review of the effectiveness of interventions in promoting a population shift from using cars towards walking and cycling . Main results : The distribution of available evidence was skewed . Population level interventions were less likely than individual level interventions to have been studied using the most rigorous study design s ; nearly all of the population level evidence would have been missed if only r and omised controlled trials had been included . Examining the studies that were excluded did not change the overall conclusions about effectiveness , but did identify additional categories of intervention such as health walks and parking charges that merit further research , and provided evidence to challenge assumptions about the actual effects of progressive urban transport policies . Conclusions : Unthinking adherence to a hierarchy of study design as a means of selecting studies may reduce the value of evidence synthesis and reinforce an “ inverse evidence law ” whereby the least is known about the effects of interventions most likely to influence whole population s. Producing generalisable estimates of effect sizes is only one possible objective of evidence synthesis . Mapping the available evidence and uncertainty about effects may also be important [12907410] The study was conducted to look at the effectiveness of a multimicronutrient-fortified complementary food on the micronutrient status , linear growth and psychomotor development of 6- to 12-month-old infants from a black urban disadvantaged community in the Western Cape , South Africa . The study was design ed as an intervention study . In both the experimental and control groups , serum retinol concentration showed a decline over the intervention period of 6 months . The decline was less pronounced in the experimental group . This result ed in a significantly ( P<005 ) higher serum retinol concentration at 12 months in the experimental group ( 26.8±5.8 μg/dl ) compared with the control group ( 21.4±5 μg/dl ) . Serum iron concentration also declined over the intervention period . The decline was less pronounced in the experimental group . No difference was observed in haemoglobin levels between the groups at 12 months . Serum zinc concentration did not differ significantly between the two groups at follow up . Weight gain over the 6 months period did not differ significantly between the experimental ( 2.1±0.9 kg ) and control groups ( 2.1±1.2 kg ) . There was no difference in linear growth between the experimental ( 10.0±1.5 cm ) and control group ( 10.1±2.1 cm ) at the end of the follow-up period . Weight and length at 6 months significantly predicted weight and length at 12 months . No difference was observed in psychomotor developmental scores between the two groups after 6 months of intervention . Introducing a multimicronutrient-fortified complementary food into the diet of 6- to 12-month-old infants seemed to have an arresting effect on declining serum retinol and iron concentration in the experimental group . No benefit was observed in serum zinc concentration , linear growth and psychomotor development [3274449] Background There is a lack of information on the optimal timing of food supplementation to malnourished pregnant women and possible combined effects of food and multiple micronutrient supplementations ( MMS ) on their offspring 's growth . We evaluated the effects of prenatal food and micronutrient interventions on postnatal child growth . The hypothesis was that prenatal MMS and early invitation to food supplementation would increase physical growth in the offspring during 0 - 54 months and a combination of these interventions would further improve these outcomes . Methods In the large , r and omized MINIMat trial ( Maternal and Infant Nutrition Interventions in Matlab ) , Bangladesh , 4436 pregnant women were enrolled between November 2001 and October 2003 and their children were followed until March 2009 . Participants were r and omized into six groups comprising 30 mg Fe and 400 μg folic acid ( Fe30F ) , 60 mg Fe and 400 μg folic acid ( Fe60F ) or MMS combined with either an early ( immediately after identification of pregnancy ) or a later usual ( at the time of their choosing , i.e. , usual care in this community ) program invitation to food supplementation . The anthropometry of 3267 children was followed from birth to 54 months , and 2735 children were available for analysis at 54 months . Results There were no differences in characteristics of mothers and households among the different intervention groups . The average birth weight was 2694 g and birth length was 47.7 cm , with no difference among intervention groups . Early invitation to food supplementation ( in comparison with usual invitation ) reduced the proportion of stunting from early infancy up to 54 months for boys ( p = 0.01 ) , but not for girls ( p = 0.31 ) . MMS result ed in more stunting than st and ard Fe60F ( p = 0.02 ) . There was no interaction between the food and micronutrient supplementation on the growth outcome . Conclusions Early food supplementation in pregnancy reduced the occurrence of stunting during 0 - 54 months in boys , but not in girls , and prenatal MMS increased the proportion of stunting in boys . These effects on postnatal growth suggest programming effects in early fetal life . Trial registration numberIS RCT N : IS RCT [8886347] The study assessed the effects of supplementary feeding over 180 consecutive days on iron status of infants and toddlers at six tea plantation in West Java , Indonesia . The design used was a clinical trial : two eohorts ( i.e. , 12 and 18 months old children ) and three treatment groups ( i.e. , energy + micronutrient , micronutrient alone , and placebo ) per cohort . Every day except Sunday , the infants attended day-care centers . Twenty four centers and 136 infants were selected . The infants were screened for weight and length and those meeting the criteria ( i.e. , < -1 SD of length-for-age , and between -1 and -2 SD of weight-for-length of the NCHS reference ) were included . The experimental unit was the day-care centers ( DCC ) , where each DCC was r and omly assigned to one of the three treatment . As expected , groups of energy + micronutrient and micronutrient alone of the 12 months cohort experienced a significant upward shift in hemoglobin , ferritin and TS and a downward change in FEP , while the values for the group of placebo remain about the same as at base line . In the first 6 month of treatments , the ANOVA for each iron indicator yielded significant main effects of treatment ( P < 0.01 ) and for Hb with ( P = 0.059 ) on 12 months cohort . On the other h and , the main effects of treatment on hemoglobin , TS , ferritin and FEP were not significant for the 18 months cohort . In the second 6 months of treatments , the only significant of the treatment effect ( P < 0.01 ) was in serum ferritin on 18-month cohort . Under these circumstances , energy has a positive role in improving iron stores . It is likely that the equilibrium of hemoglobin and each iron indicators were reached in 6 months of treatment except ferritin still continued to increase up to 12 month . The effects of treatment on the improvement of iron status was stronger in 12 months than in 18 months [15868035] To assess the effectiveness on child growth and body composition of a supplementary feeding program ( Milk Supplement Program ) , a prospect i ve , controlled study was conducted in Northeast Brazil . When entering the Program , children from 10 municipalities with the highest coverage rates in the Program ( intervention group ) were compared to non-beneficiary children from 10 municipalities with the lowest coverage rates ( control group ) . A total of 219 children aged 6 - 18 months were enrolled . At entry , both groups were comparable in terms of age , sex , and nutritional status . There were frequent gaps in delivery of the supplement , no extra milk was provided to siblings less than 5 years of age , intra-household redistribution of milk was high , and maternal compliance with recommendations was low . Adjusted analyses by multilevel modelling showed average changes in weight , length , weight-age and length-age Z-scores , and % body water ( deuterium method ) , at 6 months , of 1.53 kg , 6.34 cm , 0.33 , 0.05 , and 1.11 % respectively among supplemented children as compared to 1.54 kg , 6.5 cm , 0.26 , 0.07 , and 4.10 % among controls , with no statistically significant difference between groups . Thus , the Program failed to compensate for nutritional deficiencies in undernourished children in Northeast Brazil [7722707] Supplementary feeding programs are common in developing countries . These programs often can not demonstrate an impact on child growth , however , possibly because they tend to reach older children . This study examines the impact of nutritional supplementation on annual growth rates in length and weight from birth to 7 y of age in 1208 rural Guatemalan children . A series of multiple linear regression models is used to control for initial body size , diarrheal disease , home diet , socioeconomic status and gender . During the first year of life , each 100 kcal/d ( 418 kJ ) of supplement was associated with approximately 9 mm in additional length gain and 350 g in additional weight gain ; the benefit decreased to approximately 5 mm in length gain and 250 g in weight gain during the 2nd y of life . Between 24 and 36 mo of age , supplement only had a significant impact on length . There was no impact of nutritional supplementation on growth between 3 and 7 y of age . Patterns were the same if supplement intakes were expressed as a percent of recommended allowances or growth was expressed as a percent of the expected rate . These impacts of nutritional supplementation on growth coincide with the ages when growth velocities , as well as growth deficits , are greatest in this population [10902989] Objectives : This paper investigates simultaneously the growth and activity of children that received an early energy and micronutrient supplement , adjusting for all non-supplemental energy intakes . Any additional change in growth and activity after this adjustment was then compared across supplements at three points felt to be representative of the study . Design : Two cohorts of children were r and omly assigned to three treatments : E=1171 kJ+12 mg iron ; M=209 kJ+12 mg iron ; S=104 kJ. Supplementation was given for 12 months . Setting : The sites were six tea plantations in Pangalengan , West Java . Subjects : A 12-month-old ( n=53 ) and an 18-month-old ( n=83 ) cohort were recruited from day-care-centers . Twenty children that received S belonged to the 12- and 18-month-old cohorts . Inclusion criteria were : no chronic disease ; length-for-age ≤−1 st and ard deviation ( s.d . ) and weight-for-length between −1 and −2 s.d . of the median of the reference of the World Health Organization . Methods : Length was measured with a portable measuring board ; a Detecto scale with an accuracy of 0.1 kg was used for the measurement of body weight . Arm and head circumferences were measured using similar fiberglass tapes . Motor activity was assessed through continuous 4 h observations at home and at day care centers . Anthropometry and activity were measured every two months over 12 months . Results : After correcting for non-supplemental sources of energy intake , the effects of the supplement on weight and activity were observed at 2 months ; effects on length and activity were observed at 6 months ; and effects on weight alone were observed at 12 months . Sponsorship : Nestlé Foundation . European Journal of Clinical Nutrition ( 2000 ) 54 , Suppl 2 , [12503232] Integrated nutrition programs are widely used to prevent and /or reverse childhood malnutrition , but rarely rigorously evaluated . The impact of such a program on the physical growth of young rural Vietnamese children was measured . We r and omized six communes to receive an integrated nutrition program implemented by Save the Children . We matched six communes to serve as controls . Our sample consisted of 238 children ( n = 119 per group ) who were 5 to 30 months old on entry . Between December 1999 and December 2000 , we measured weight and height monthly for six months and again at month 12 . Principle outcomes were weight-for-age Z score ( WAZ ) , height-for-age Z score ( HAZ ) , and weight-for-height Z score ( WHZ ) , and the changes among these measures . As expected , anthropometric indicators relative to international references worsened as the children aged . Overall , children in the intervention communes who were exposed to the integrated nutrition program did not show statistically significant better growth than comparison children . Intervention children who were younger ( 15 months or less ) and more malnourished ( less than −2 Z ) at baseline , however , deteriorated significantly less than their comparable counterparts . Between baseline and month four , for example , intervention children who were malnourished and less than 15 months old at entry lost on average 0.05 WAZ while similar comparison children lost 0.25 WAZ ( p = .02 ) . Lack of overall impact on growth may be due to a lower than expected prevalence of malnutrition at baseline and /or deworming of comparison children . Targeting nutrition interventions at very young children will have the maximum impact on growth [19073791] BACKGROUND In breastfed infants , iron deficiency at < 6 mo of life , although uncommon , is observed in industrialized countries . Iron supplementation starting at an early age may prevent iron deficiency . OBJECTIVE The study assessed the effect of early iron supplementation of breastfed infants and tested the hypothesis that iron supplementation enhances iron status . Potential adverse effects ( tolerance and growth ) were monitored . DESIGN The prospect i ve , placebo-controlled study involved exclusively breastfed infants who were r and omly assigned at 1 mo of age to iron ( n = 37 ) or placebo ( n = 38 ) . Iron ( 7 mg/d as multivitamin preparation with ferrous sulfate ) or placebo ( multivitamin preparation without iron ) was given from 1 to 5.5 mo of age . Complementary foods were allowed at > 4 mo . Infants were followed to 18 mo . Blood concentrations of ferritin , transferrin receptor , hemoglobin , and red cell indexes were determined at bimonthly intervals . Stool consistency and color and feeding behavior were recorded . RESULTS Iron supplementation caused modest augmentation of iron status during the intervention at 4 and 5.5 mo but not thereafter . Iron supplements were well tolerated and had no measurable effect on growth . One infant developed iron deficiency anemia by 5.5 mo of age . Plasma ferritin and hemoglobin tracked over time . CONCLUSION Early iron supplementation of breastfed infants is feasible and transiently increases iron status but not hematologic status . Iron is tolerated by most infants . The prevalence of iron deficiency anemia is low ( 3 % ) among unsupplemented breastfed infants in the first 6 mo of life [20861218] Although widely used , there is little information concerning the efficacy of corn-soy blend ( CSB ) supplementation in the treatment of moderate underweight in African children . Lipid-based nutrient supplements ( LNS ) , which have proven to be beneficial treatment for severely wasted children , could offer benefits to less severely affected individuals . We conducted a clinical r and omized trial to determine whether LNS or CSB supplementation improves weight gain of moderately underweight children . A total of 182 underweight [ weight-for-age Z-score ( WAZ ) < -2 ] 6- to 15-mo-old children were r and omized to receive for 12 wk a ration of 43 g/d LNS or 71 g/d CSB , providing 1189 and 921 kJ , respectively , or no supplementation ( control ) . The primary outcome was weight change ; secondary outcomes included changes in anthropometric indices , hemoglobin levels , and morbidity . The body weight increases ( mean ± SD ) did not differ and were 620 ± 470 , 510 ± 350 , and 470 ± 350 g in the LNS , CSB , and control groups , respectively ( P = 0.11 ) . Compared with controls , infants and children in the LNS group gained more weight [ mean ( 95 % CI ) = 150 g ( 0 - 300 g ) ; P = 0.05 ] and had a greater increase in WAZ [ 0.33 ( -0.02 - 0.65 ) ; P = 0.04 ] . Weight and WAZ changes did not differ between the control and CSB groups . In exploratory stratified analysis , the weight increase was higher in the LNS group compared with the control group among those with lower initial WAZ [ 250 g ( 60 - 430 g ; P = 0.01 ] . Supplementation with LNS but not CSB modestly increases weight gain among moderately underweight children and the effect appears most pronounced among those with a lower initial WAZ [10902988] Objectives : This paper reports the effects of an energy and micronutrient supplement on the motor development , motor milestones and motor activity of nutritionally at risk infants and toddlers in Pangalengan , Indonesia . Design : Two cohorts of children were r and omly assigned to three treatments E=1171 kJ+12 mg iron ; M=209 kJ+12 mg iron ; S=104 kJ. Supplementation was given for 12 months . Setting : The sites were six tea plantations in Pangalengan , West Java . Subjects : A 12-month-old ( n=53 ) and an 18-month-old ( n=83 ) cohort were recruited from day-care-centers . Twenty children that received S belonged to the 12- and 18-month-old cohorts . Inclusion criteria were : no chronic disease ; length-for-age≤−1 st and ard deviation ( s.d . ) and weight-for-length between −1 and −2 s.d . of the median of the reference of the World Health Organization . Methods : Evaluations of intake were made at baseline and every 2 months thereafter . Motor development was assessed with the Bayley Scale and with a custom-made scale to assess gross motor development leading to bipedal locomotion . Motor activity was assessed through 4 h continuous observations of the child ’s interaction with the social and physical environment . Results : In the 12-month-old cohort , as compared to the M and S groups the children that received the E supplement walked at an earlier age , had higher scores in the Bayley Scale and were motorically more active . Similar intergroup differences were observed in the 18-month-old cohort in the total motor activity score . Sponsorship : Nestlé Foundation . European Journal of Clinical Nutrition ( 2000 ) 54 , Suppl 2 , [10902987] Objectives : This paper reports the effects of early supplementary feeding on body weight , length , head circumference and arm circumference among the children in the Pangalengan study . Design : Two cohorts of children were r and omly assigned to three treatments : E=1171 kJ+12 mg iron ; M=209 kJ+12 mg iron ; S=104 kJ. Supplementation was given for 12 months . Setting : The sites were six tea plantations in Pangalengan , West Java . Subjects : A 12-month-old ( n=53 ) and an 18-month-old ( n=83 ) cohort were recruited from day-care centers . Twenty children that received S belonged to the 12- and 18-month cohorts . Inclusion criteria were : no chronic disease ; length-for-age≤−1 st and ard deviation ( s.d . ) and weight-for-length between −1 and −2 s.d . of the median of the reference of the World Health Organization . Methods : Length was measured with a portable measuring board ; a Detecto scale with an accuracy of 0.1 kg was used for the measurement of body weight . Arm and head circumferences were measured using similar fiberglass tapes . Results : Body weight showed effects on both cohorts at 2 , 8 and 12 months ; head circumference showed effects at 4 months in the 12-month-old cohort and at 10 months among the females of the 18-month-old cohort ; and arm circumference showed effects across cohorts at 2 , 8 and 12 months . In general the benefits are clearer for females and for the 12-month-old cohort . Sponsorship : Nestlé Foundation . European Journal of Clinical Nutrition ( 2000 ) 54 , Suppl 2 , [10902983] Objectives : To describe the method ologies of a clinical trial on the effects of an energy and micronutrient supplement on the growth and development of undernourished children . Design : This trial included two cohorts of children classified as nutritionally-at-risk who were r and omly assigned to three treatments ( condensed milk+micronutrients ( E ) ; skimmed milk+micronutrients ( M ) ; skimmed milk ( S ) ) . Supplements were given for a period up to 12 months . Setting : Six tea plantations in Pangalengan , West Java were the site for this study .Subjects : A 12-month-old ( N=53 ) and an 18-month-old ( N=83 ) cohort were recruited from 24 day-care-centers ( DCC ) . Twenty children that received the S supplement were part of the 12- and 18 month-old cohort . Criteria for case inclusion were absence of chronic disease ; length-for-age≤−1 st and ard deviation ( s.d . ) and weight-for-length between −1 and −2 s.d . of the median of the reference of the World Health Organization . Variables : Social variables included assessment of health facilities , childcare , housing , income and parental education . Nutrition and growth variables included dietary intake measured over a 24 hr period every 2 months ; hemoglobin and three iron indicators measured at baseline , 6 and 12 months ; anthropometry measured every 2 months and skeletal maturation measured every 6 months . Cognition and behavior included the assessment of mental and motor development and the behavior of the child under natural conditions . Data analysis : An ANOVA was the statistic most frequently used to test inter-group differences and structural equation modeling was used to test the internal validity of the conceptual model of the study .Sponsorship : Nestlé Foundation . European Journal of Clinical Nutrition ( 2000 ) 54 , Suppl 2 , [15173147] CONTEXT Malnutrition causes death and impaired health in millions of children . Existing interventions are effective under controlled conditions ; however , little information is available on their effectiveness in large-scale programs . OBJECTIVE To document the short-term nutritional impact of a large-scale , incentive-based development program in Mexico ( Progresa ) , which included a nutritional component . DESIGN , SETTING , AND PARTICIPANTS A r and omized effectiveness study of 347 communities r and omly assigned to immediate incorporation to the program in 1998 ( intervention group ; n = 205 ) or to incorporation in 1999 ( crossover intervention group ; n = 142 ) . A r and om sample of children in those communities was surveyed at baseline and at 1 and 2 years afterward . Participants were from low-income households in poor rural communities in 6 central Mexican states . Children ( N = 650 ) 12 months of age or younger ( n = 373 intervention group ; n = 277 crossover intervention group ) were included in the analyses . INTERVENTION Children and pregnant and lactating women in participating households received fortified nutrition supplements , and the families received nutrition education , health care , and cash transfers . MAIN OUTCOME MEASURES Two-year height increments and anemia rates as measured by blood hemoglobin levels in participating children . RESULTS Progresa was associated with better growth in height among the poorest and younger infants . Age- and length-adjusted height was greater by 1.1 cm ( 26.4 cm in the intervention group vs 25.3 cm in the crossover intervention group ) among infants younger than 6 months at baseline and who lived in the poorest households . After 1 year , mean hemoglobin values were higher in the intervention group ( 11.12 g/dL ; 95 % confidence interval [ CI ] , 10.9 - 11.3 g/dL ) than in the crossover intervention group ( 10.75 g/dL ; 95 % CI , 10.5 - 11.0 g/dL ) who had not yet received the benefits of the intervention ( P = .01 ) . There were no differences in hemoglobin levels between the 2 groups at year 2 after both groups were receiving the intervention . The age-adjusted rate of anemia ( hemoglobin level < 11 g/dL ) in 1999 was higher in the crossover intervention group than in the intervention group ( 54.9 % vs 44.3 % ; P = .03 ) , whereas in 2000 the difference was not significant ( 23.0 % vs 25.8 % , respectively ; P = .40 ) . CONCLUSION Progresa , a large-scale , incentive-based development program with a nutritional intervention , is associated with better growth and lower rates of anemia in low-income , rural infants and children in Mexico [19225128] Moderate childhood wasting is defined as having a weight-for-height Z-score ( WHZ ) < -2 , but > or = -3 . These children are typically given fortified corn/soy blended flour ( CSB ) , but this intervention has shown limited effectiveness . Fortified spreads ( FS ) can be used as supplementary foods instead ; they are energy-dense , lipid-based pastes with added powdered micronutrients . In this r and omized clinical effectiveness trial , the recovery rates were compared among children with moderate wasting who received either milk/peanut FS , soy/peanut FS , or CSB . Children received isoenergetic quantities of food , 314 kJ x kg(-1 ) x d(-1 ) , for up to 8 wk with biweekly follow-up . The primary outcome was recovery , defined as having a WHZ > -2 . Time-event analysis was used to compare the recovery rate . A total of 1362 children were enrolled in the study . Children receiving soy/peanut FS had a similar recovery rate to those receiving milk/peanut FS and children in either FS group were more likely to recover than those receiving CSB ( 80 % in both FS groups vs. 72 % in the CSB group ; P < 0.01 ) . The rate of weight gain in the first 2 wk was greater among children receiving milk/peanut FS ( 2.6 g x kg(-1 ) x d(-1 ) , n = 465 ) or children receiving soy/peanut FS ( 2.4 g x kg(-1 ) x d(-1 ) , n = 450 ) than among children receiving CSB ( 2.0 g x kg(-1 ) x d(-1 ) , n = 447 ; P < 0.05 ) . Rates of length gain did not differ among the 3 groups . A total of 8 % of children in each feeding group developed edema , indicative of severe malnutrition , while receiving supplemental feeding . We conclude that FS are superior supplementary foods to CSB for moderately wasted Malawian children [1676083] There is little unequivocal evidence that nutritional supplementation of undernourished children has a beneficial effect on their mental development . The effects of nutritional supplementation , with or without psychosocial stimulation , of growth-retarded ( stunted ) children aged 9 - 24 months were assessed in a study in Kingston , Jamaica . 129 children from poor neighbourhoods were r and omly assigned to four groups -- control , supplemented only , stimulated only , and supplemented plus stimulated . A group of matched non-stunted children ( n = 32 ) was also included . The supplement comprised 1 kg milk-based formula per week for 2 years , and the stimulation weekly play sessions at home with a community health aide . The children 's development ( DQ ) was assessed on the Griffiths mental development scales . Initially the stunted groups ' DQs were lower than those of the non-stunted group , and those of the control group declined during the study , increasing their deficit . Stimulation and supplementation had significant independent beneficial effects on the children 's development . Estimates of the supplementation effect ranged from 2.2 ( 95 % confidence limits-1.4 , 5.7 ) for the h and and eye subscale to 12.4 ( 5.4 , 19.5 ) for the locomotor subscale and those for the stimulation effect from 6.4 ( 2.8 , 10.0 ) for h and and eye to 10.3 ( 3.3 , 17.3 ) for locomotor . The treatment effects were additive , and combined interventions were significantly more effective than either alone . These findings suggest that poor mental development in stunted children is at least partly attributable to undernutrition [1376586] An energy-dense supplementary food , together with nutrition education , was given to a group of moderately malnourished children aged 6 - 12 months in a poor slum community of urban Bangladesh . An age- and sex-matched control group received only nutrition education . Both groups were followed monthly with respect to weight gain and morbidity . The purpose of the study was to assess the differential impact of a targeted supplementary feeding programme with nutrition education and a nutrition education programme alone on monthly weight gain during 6 months . During the 1st 3 months of the intervention , the monthly weight gain of the supplemented children was 205 g vs 159 g in the control children ( p less than 0.05 ) . In the following 3 months , differences in weight gain were no more significant . Several possible explanations for this transient impact are discussed . It is suggested that nutrition education in the control group may have been responsible for the limited difference between the two groups , but seasonal and epidemiological factors may also have played a part [16599106] The study was a controlled , comparative clinical effectiveness trial of two supplementary feeding regimens in children at risk of malnutrition from seven centres in rural Malawi . Being at risk of malnutrition was defined as weight-for-height < 85 % , but > 80 % of the international st and ard . A stepped-wedge design with systematic allocation was used for assigning children to receive either ready-to-use therapeutic food ( RUTF ) ( n=331 ) or micronutrient-fortified corn/soy-blend ( n=41 ) for up to eight weeks . The primary outcomes were recovery , defined as weight-for-height > 90 % , and the rate of weight gain . Children receiving RUTF were more likely to recover ( 58 % vs 22 % ; difference 36 % ; 95 % confidence interval [ CI ] 20 - 52 ) and had greater rates of weight gain ( 3.1 g/kg.d vs 1.4 g/kg x d ; difference 1.7 ; 95 % CI 0.8 - 2.6 ) than children receiving corn/soy-blend . The results of this preliminary work suggest that supplementary feeding with RUTF promotes better growth in children at risk of malnutrition than the st and ard fortified cereal/legume-blended food [21205399] OBJECTIVE To determine the effectiveness of the nutritional supplement developed for the Oportunidades programme on growth , prevalence of anaemia , morbidity and cognitive function of pre-school children . DESIGN In a r and omised , placebo-controlled longitudinal trial , children were assigned to one of three experimental treatment groups : Oportunidades food supplement ( OFS ) , powdered milk ( PM ) and placebo ( PL ) . Treatments were administered daily for 6 months . Weight , height and Hb were measured in all participants before and after supplementation . Morbidity was assessed two times per week for 6 months using vali date d question naires . The Bayley Scale of Infant Development Test was administered at baseline and after 6 months . SETTING Three marginal rural communities of the state of Queretaro , Mexico . SUBJECTS A total of 224 children , mean age 22·4 ( SD 5·9 ) months , were recruited . After the 6-month intervention , 186 completed the study . RESULTS No differences were found in the adjusted changes of weight , height or anaemia between treatment groups and PL . No differences were found in the number of episodes of gastrointestinal or respiratory disease , nor were there any differences in cognitive performance between treatment and PL groups after 6 months of supplementation . CONCLUSIONS Daily supplementation of 12 - 24-month-old children with OFS has no additional benefits in growth , anaemia , morbidity or cognitive performance [10902993] Objectives : This paper presents the results of a structural equation model testing whether the longitudinal data of the Pangalengan subjects fit the theoretical model regarding the intellectual delay of undernourished children . Design : Two cohorts of children were r and omly assigned to three treatments : E=1171 kJ+12 mg iron ; M=12 mg iron+209 kJ ; S=104 kJ. Supplementation was given for 6 months . Setting : The sites were six tea plantations in Indonesia . Subjects : A 12-month-old ( n=53 ) and an 18-month-old ( n=83 ) cohort were recruited from day-care-centers . Inclusion criteria were : no chronic disease ; length-for-age=<1 st and ard deviation ( s.d . ) and weight-for-length between −1 and −2 s.d . of the median of the reference of the World Health Organization . Methods : Twenty-four-hour dietary intakes were assessed using the weighted individual inventory technique . Body weight and length were obtained using st and ard procedures ; motor development was assessed with the Bayley Scale and with a custom made scale for motor development leading to bipedal locomotion . Four-hour observations were made of the child ’s interactions with the environment . Carrying a child in the arms and exploratory behavior were used as indicators of caregiving and exploration . All measurements were obtained every 2 months . Results : The original model did not fit the data . The model was then modified with the inclusion of two new pathways : from activity and from motor development to mental development . Following these adjustments the model fit the data for each cohort and for both cohorts combined . Sponsorship : Nestlé Foundation . European Journal of Clinical Nutrition ( 2000 ) 54 , Suppl 2 , [16131023] OBJECTIVE To investigate the effect of yogurt supplementation on the growth of preschool children in Beijing suburbs . METHODS Four hundred and two preschool children ( 217 males , 185 females ) , aged 3 - 5 years , whose height for age and /or weight for age were less than the reference level , were selected as subjects from 7 kindergartens in Beijing Fangshan District . The subjects were divided r and omly into control group ( CG , 201 ) and yogurt supplemented group ( YG , 201 ) . Each subject in YG was given one serving of yogurt ( 125 g ) for 5 days a week from March to December in 2001 , while nothing additional was provided to CG . All subjects kept their usual diet during the study . Anthropometry ( body height and weight and upper-arm circumference ) and the bone mineral density ( BMD ) of forearm were measured every 3 months . Disease status and dietary intake were also recorded and assessed . RESULTS The intake of calcium , zinc , and vitamin B2 in YG was significantly higher than that in CG . The incidence and duration of upper-respiratory infection and diarrhea of children in YG were significantly less than those in CG . The height gain of children in YG was significantly higher than that in CG after yogurt was supplemented for 3 , 6 , and 9 months ( P<0.05 ) ( 1.90+/-0.49 cm vs 1.77+/-0.54 cm , 3.83+/-0.57 cm vs 3.64+/-0.66 cm and 5.43+/-0.69 cm vs 5.24+/-0.76 cm , respectively ) . The weight gain of children in YG was significantly higher than that in CG after yogurt was supplemented for 3 , 6 , and 9 months ( P<0.05 ) ( 0.70+/-0.43 kg vs 0.49+/-0.35 kg , 0.98+/-0.62 kg vs 0.80+/-0.60 kg and 1.42+/-0.76 kg vs 1.20+/-0.67 kg , respectively ) . The BMD of children in YG was significantly higher than that in CG after yogurt was supplemented for 9 months ( P<0.05 ) ( 0.415+/-0.058 g/cm2 vs 0.400+/-0.065 g/cm2 ) . CONCLUSION Yogurt is beneficial to the improvement of calcium , zinc , and vitamin B2 intake , the decreasing of the incidence and duration of upper-respiratory infection and diarrhea , and the promotion of the health and the growth and development of preschool children [12591556] OBJECTIVE Breast milk alone is insufficient to support normal growth during the second half of infancy , so I investigated supplementary feeding for infants ' successful transition to solid food . METHODS The nutrition status of 30 infants from a low socioeconomic background weaned onto an extruded formulated complementary diet from maize and cowpea ( L(1)A(1 ) ) were compared with 30 infants with a similar socioeconomic background ( L(2)N , control group ) and 30 infants from an above-average socioeconomic background ( HN , reference group ) without the supplementary diet . Infants within the control and reference groups were weaned onto different foods of the mothers ' choice . The formulated diet was analyzed for nutrient composition . RESULTS The results showed similarity in the estimated annual family income of the L(1)A(1 ) and L(2)N groups , which ranged from N 25 000 to 74 000 ( US $ 208.30 to 616.70 ) , whereas the estimated family income for the HN group was above N 225 000 ( US $ 1875.00 ) annually . The formulated blend contained 17.3 % protein , 5.0 % fat , and 2106 kJ of energy . Mean weight at birth and 4 mo before the feeding intervention in HN infants was statistically ( P < 0.05 ) higher than in L(1)A(1 ) and L(2)N infants . At the end of the study , L(1)A(1 ) and HN infants had a mean length within -1 st and ard deviation of the st and ard length for age . The mean length of L(2)N infants was within -3 st and ard deviations of the st and ard length for age . The effectiveness of the formulated diet was expressed in terms of similarity in anthropometric measurements of L(1)A(1 ) ) and HN infants . CONCLUSIONS Based on similarities in socioeconomic background and weight at birth and 4 mo in the L(1)A(1 ) and L(2)N infants , the better nutrition status of the L(1)A(1 ) is attributed to the formulated complementary diet . The contribution of this mixture to total nutrient intake seemed substantial enough to meet the infants ' nutritional requirements . The use of a cheaply available plant protein will go a long way in reducing protein-energy malnutrition among children in developing countries . However , because of the low purchasing power of the low-income family , the costs of this product should be studied [7223696] Infants born to families at risk of malnutrition were studied prospect ively from the beginning of the 3rd trimester of the mother 's pregnancy until the child reached 3 yr of age to ascertain the effects of nutritional supplementation and /or a maternal education program on their cognitive development . Four hundred thirty-three families were assigned r and omly to six groups : group A served as a control ; group B received the supplement from the age of 6 months to 3 yr ; group C received the supplement during the 3rd trimester of pregnancy and the first 6 months of the child 's life ; and group D received the supplement throughout the entire study period . In addition , group A1 was enrolled in a maternal education program but received no nutritional supplement and group B1 received both treatments . The Griffiths test of infant development was administered at 4 , 6 , 12 , 18 , 24 , and 36 months of age , and the Corman-Escalona Einstein scale was administered at each age up to 18 months . Children who received food supplementation performed better than those who did not , especially on subtests that were primarily motoric . The effect of food supplementation on behavior appeared to be contemporaneous . In addition , the treatment effects were more pronounced for girls than for boys in this sample . Although these interventions reduced the gap in cognitive performance between lower and upper socioeconomic classes , a disparity nevertheless remained by the end of the study [19155454] CONTEXT Ready-to-use therapeutic foods ( RUTFs ) are an important component of effective outpatient treatment of severe wasting . However , their effectiveness in the population -based prevention of moderate and severe wasting has not been evaluated . OBJECTIVE To evaluate the effect of a 3-month distribution of RUTF on the nutritional status , mortality , and morbidity of children aged 6 to 60 months in Niger . DESIGN , SETTING , AND PARTICIPANTS A cluster r and omized trial of 12 villages in Maradi , Niger . Six villages were r and omized to intervention and 6 to no intervention . All children in the study villages aged 6 to 60 months were eligible for recruitment . INTERVENTION Children with weight-for-height 80 % or more of the National Center for Health Statistics reference median in the 6 intervention villages received a monthly distribution of 1 packet per day of RUTF ( 92 g [ 500 kcal/d ] ) from August to October 2006 . Children in the 6 nonintervention villages received no preventive supplementation . Active surveillance for conditions requiring medical or nutritional treatment was conducted monthly in all 12 study villages from August 2006 to March 2007 . MAIN OUTCOME MEASURES Changes in weight-for-height z score ( WHZ ) according to the World Health Organization Child Growth St and ards and incidence of wasting ( WHZ < -2 ) over 8 months of follow-up . RESULTS The number of children with height and weight measurements in August , October , December , and February was 3166 , 3110 , 2936 , and 3026 , respectively . The WHZ difference between the intervention and nonintervention groups was -0.10 z ( 95 % confidence interval [ CI ] , -0.23 to 0.03 ) at baseline and 0.12 z ( 95 % CI , 0.02 to 0.21 ) after 8 months of follow-up . The adjusted effect of the intervention on WHZ from baseline to the end of follow-up was thus 0.22 z ( 95 % CI , 0.13 to 0.30 ) . The absolute rate of wasting and severe wasting , respectively , was 0.17 events per child-year ( 140 events/841 child-years ) and 0.03 events per child-year ( 29 events/943 child-years ) in the intervention villages , compared with 0.26 events per child-year ( 233 events/895 child-years ) and 0.07 events per child-year ( 71 events/1029 child-years ) in the nonintervention villages . The intervention thus result ed in a 36 % ( 95 % CI , 17 % to 50 % ; P < .001 ) reduction in the incidence of wasting and a 58 % ( 95 % CI , 43 % to 68 % ; P < .001 ) reduction in the incidence of severe wasting . There was no reduction in mortality , with a mortality rate of 0.007 deaths per child-year ( 7 deaths/986 child-years ) in the intervention villages and 0.016 deaths per child-year ( 18 deaths/1099 child-years ) in the nonintervention villages ( adjusted hazard ratio , 0.51 ; 95 % CI , 0.25 to 1.05 ) . CONCLUSION Short-term supplementation of nonmalnourished children with RUTF reduced the decline in WHZ and the incidence of wasting and severe wasting over 8 months . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00682708 [16599102] This prospect i ve r and omized trial was carried out to test the efficacy of a specific intervention for reducing the extent of their malnutrition and to change behaviour of mothers relating to child-feeding practice s , care-giving , and health-seeking practice s under the Bangladesh Integrated Nutrition Project ( BINP ) . The study was conducted in rural Bangladesh among 282 moderately-malnourished ( weight-for-age between 61 % and 75 % of median of the National Center for Health Statistics st and ard ) children aged 6 - 24 months . Mothers of the first intervention group received intensive nutrition education ( INE group ) twice a week for three months . The second intervention group received the same nutrition education , and their children received additional supplementary feeding ( INE+SF group ) . The comparison group received nutrition education from the community nutrition promoters twice a month according to the st and ard routine service of BINP . The children were observed for a further six months . After three months of interventions , a significantly higher proportion of children in the INE and INE+SF groups improved ( 37 % and 47 % respectively ) from moderate to mild or normal nutrition compared to the comparison group ( 18 % ) ( p < 0.001 ) . At the end of six months of observation , the nutritional status of children in the intervention groups improved further from moderate to mild or normal nutrition compared to the comparison group ( 59 % and 86 % vs 30 % , p < 0.0001 ) . As the intensive nutrition education and supplementation given were highly effective , more children improved from moderate malnutrition to mild or normal nutritional status despite a higher incidence of morbidity . The frequency of child feeding and home-based complementary feeding improved significantly ( p < 0.001 ) in both the intervention groups after three months of interventions and six months of observation . Body-weight gain was positively associated with age , length-for-age , weight-for-length , frequency of feeding of khichuri , egg , and potato ( p < 0.05 ) . Ability of mothers to identify malnutrition improved from 15 % to 99 % in the INE group and from 15 % to 100 % in the INE+SF group , but reduced from 24 % to 21 % in the comparison group . Use of separate feed pots , frequency of feeding , and cooking of additional complementary feeds improved significantly in the INE and INE+SF groups compared to the comparison group after three months of interventions and six months of observation . It can be concluded from the findings of the study that intensive nutrition education significantly improves the status of moderately-malnourished children with or without supplementary feeding [17033530] Objective : Fortified spreads ( FSs ) have proven effective in the rehabilitation of severely malnourished children . We examined acceptability , growth and change in blood haemoglobin ( Hb ) concentration among moderately underweight ambulatory infants given FS . Methods : This was a r and omised , controlled , parallel-group , investigator-blind clinical trial in rural Malawi . Six- to 17-month-old underweight infants ( weight for age < −2 ) , whose weight was greater than 5.5 kg and weight-for-height z score greater than −3 received for 12 weeks at home 1 of 8 food supplementation schemes : nothing , 5 , 25 , 50 , or 75 g/day milk-based FS or 25 , 50 , or 75 g/day soy-based FS . Outcome measures included change in weight , length and blood Hb concentration . Results : A total of 126 infants started and 125 completed the intervention . All infants accepted the spread well , and no intolerance was recorded . Average weight and length gains were higher among infants receiving daily 25 to 75 g FS than among those receiving only 0 to 5 g FS . Mean Hb concentration remained unchanged among unsupplemented controls but increased by 10 to 17 g/L among infants receiving any FS . All average gains were largest among infants receiving 50 g of FS daily : mean difference ( 95 % confidence interval ) in the 12-week gain between infants in 50 g milk-based FS group and the unsupplemented group was 290 g ( range , −130 to 700 g ) , 0.9 cm ( range , −0.3 to 2.2 cm ) , and 17 g/L ( range , 0 to 34 g/L ) for weight , length and blood Hb concentration , respectively . In soy- vs milk-based FS groups , average outcomes were comparable . Conclusions : Supplementation with 25 to 75 g/day of highly fortified spread is feasible and may promote growth and alleviate anaemia among moderately malnourished infants . Further trials should test this hypothesis [10902991] Objectives : This paper reports the effects of an energy and micronutrient supplement on mental development and on the social – cognitive and emotionally regulatory behaviors of nutritionally at risk infants and toddlers in Pangalengan , Indonesia . Design : Two cohorts of children were r and omly assigned to three treatments : E=1171 kJ+12 mg iron ; M=12 mg iron+209 kJ ; S=104 kJoule . Supplementation was given for 12 months . Setting : The sites were six tea plantations in Pangalengan , West Java . Subjects : A 12-month-old ( N=53 ) and an 18-month-old ( N=83 ) cohort were recruited from day-care-centers . Twenty children who received S belonged to the 12- and 18-month-old cohort . Inclusion criteria were : no chronic disease ; length-for-age ≤−1 st and ard deviation ( s.d . ) and weight-for-length between −1 and −2 s.d . of the median of the reference of the World Health Organization . Methods : Evaluations of intake were made at baseline and every 2 months thereafter . Motor development was assessed with the Bayley Scale and with a custom-made scale to assess gross motor development leading to bipedal locomotion . Four hours of continuous observations were made of the child ’s interaction with the social and physical environment . Results : In the 12-month-old cohort , as compared with the M and S groups , the children who received the E supplement walked at an earlier age , had higher scores in the Bayley Scale and showed more mature social – cognitive and emotional regulatory behaviors . Similar intergroup differences were observed in the 18-month-old cohort in social cognition and regulation of emotions . Sponsorship : Nestlé Foundation . European Journal of Clinical Nutrition ( 2000 ) 54 , Suppl 2 , [10902986] Objectives : This paper reports the dietary intake ( home , day care centers , supplement and breast milk ) of the children in the clinical trial in Pangalengan . Design : Two cohorts of children were r and omly assigned to three treatments : E=1171 kJ+12 mg iron ; M=209 kJ+12 mg iron ; S=104 kJ. Supplementation was given for 12 months . Setting : The sites were six tea plantations in Pangalengan , West Java . Subjects : A 12-month-old ( n=53 ) and an 18-month-old ( n=83 ) cohort were recruited from day-care-centers . Twenty children who received S belong to the 12- and 18-month-old cohorts . Inclusion criteria were : no chronic disease ; length-for-age ≤−1 st and ard deviation ( s.d . ) and weight-for-length between −1 and −2 s.d . of the median of the reference of the World Health Organization . Methods : E=1171 kJ+12 mg iron ; M=209 kJ+12 mg iron ; S = 104 kJ. Supplementation was given for 12 months . Evaluations of intake were made at baseline and every 2 months thereafter . Results : For the 12-month-old cohort the mean increase in daily energy intake∼2931 kJ for E , ∼1675 kJ for M , and ∼837 kJ increase over the 6 months for the S group . For the 18-month-old cohort the changes were ∼2512 kJ for E∼1675 for the M group and ∼1047 for the S group . Sponsorship : Nestlé Foundation . European Journal of Clinical Nutrition ( 2000 ) 54 , Suppl 2 , [8556899] It is frequently assumed that undernutrition in young children leads to poor development through reduced activity . 3 groups of 26 1-year-old stunted children were studied : nutritional supplementation , supplementation with psychosocial stimulation , and controls . 26 nonstunted comparison children were also studied . Activity levels were measured by extensive observation in the homes , and development using 4 subscales of the Griffith 's Mental Development Scales . Initially , stunted children were less active than nonstunted ones ( p < .01 ) , but after 6 months they caught up regardless of treatment . The mental ages of the stunted children were lower than those of the nonstunted children initially , and improved with either treatment . Initially , activity levels made a significant contribution to the variance in the locomotor subscale only , but not 6 months later . Activity did not predict change in development over 6 or 12 months , nor did change in activity over 6 months predict change in development over 12 months [23795976] Low nutritional value of complementary foods is associated with high incidence of childhood growth stunting in low-income countries . This study was done to test a hypothesis that dietary complementation with lipid-based nutrient supplements ( LNS ) promotes linear growth and reduces the incidence of severe stunting among at-risk infants . A total of 840 6-month-old healthy infants in rural Malawi were enrolled to a r and omised assessor-blinded trial . The participants received 12-month supplementation with nothing , milk-LNS , soy-LNS , or corn-soy blend ( CSB ) . Supplements provided micronutrients and approximately 280 kcal energy per day . Outcomes were incidence of severe and very severe stunting [ length-for-age z-score , ( LAZ ) < -3.00 and < -3.50 , respectively ] , and change in LAZ . The incidence of severe stunting was 11.8 % , 8.2 % , 9.1 % and 15.5 % ( P = 0.098 ) and that of very severe stunting 7.4 % , 2.9 % , 8.0 % and 6.4 % ( P = 0.138 ) in control , milk-LNS , soy-LNS and CSB groups , respectively . Between 9 and 12 months of age , the mean change in LAZ was -0.15 , -0.02 , -0.12 and -0.18 ( P = 0.045 ) for control , milk-LNS , soy-LNS and CSB groups , respectively . There was no significant between-group difference in linear growth during other age-intervals . Although participants who received milk-LNS had the lowest incidence of severe and very severe stunting , the differences between the groups were smaller than expected . Thus , the results do not provide conclusive evidence on a causal association between the LNS supplementation and the lower incidence of stunting . Exploratory analyses suggest that provision of milk-LNS , but not soy-LNS promotes linear growth among at-risk infants mainly between 9 and 12 months of age [7536830] This is an overview of the design and methods of the INCAP longitudinal study ( 1969 - 77 ) and its follow-up study ( 1988 - 89 ) . The first study had the objective of assessing the effects of intrauterine and preschool malnutrition on growth and mental development . To achieve this , food supplements were provided to pregnant women and young children residing in four Gautemalan villages . Two villages were given a high-protein , high-energy drink and two were provided a no-protein , low-energy drink . Both supplements contained vitamins and minerals . Longitudinal information was collected during the first seven years of life on physical growth , mental development , attendance and consumption of supplement , home diet , morbidity and on characteristics of the family . Health and nutrition data on mothers also were collected . The INCAP follow-up study was a cross-sectional evaluation of former participants of the first study and was carried out when the subjects were 11 - 27 y old . The hypothesis of the INCAP follow-up study was that improved nutrition in early childhood leads to enhanced human capital formation in adolescents and adults . Data were collected on physical growth and body composition , maturation , work capacity , intellectual performance and school achievement Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Moderate acute malnutrition , also called moderate wasting , affects around 10 % of children under five years of age in low- and middle-income countries . There are different approaches to addressing malnutrition with prepared foods in these setting s ; for example , providing lipid-based nutrient supplements or blended foods , either a full daily dose or in a low dose as a complement to the usual diet . There is no definitive consensus on the most effective way to treat children with moderate acute malnutrition . OBJECTIVES To evaluate the safety and effectiveness of different types of specially formulated foods for children with moderate acute malnutrition in low- and middle-income countries , and to assess whether foods complying or not complying with specific nutritional compositions , such as the WHO technical specifications , are safe and effective . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

20824847

[2470310] Two hundred and forty-one patients , with advanced squamous cell carcinoma of head and neck , were r and omized to receive three courses of induction chemotherapy . The chemotherapy regimens were delivered every 3 weeks , and consisted in 1 ) cisplatin , 80 mg/m2 given alone ( CDDP regimen ) , or 2 ) in combination with vincristine , 1 mg , d 1 , methotrexate 10 mg/m2 d 1 , 2 , 3 , and bleomycin 10 mg/m2 , d 1 , 2 , and 3 ( MOB-P ) . Tolerance was significantly better with the CDDP regimen ( p less than 0.05 ) ; severe side effects , affecting mainly digestive tract , and bone marrow , were encountered in 7 % of the patients in the CDDP group , vs 15 % in the MOB-P group , without death related to pancytopenia . Short-term results were better for patients treated by the MOB-P regimen , with a 42 % response rate ( including 9 complete responses ) vs 22 % with the CDDP regimen ( p = 0.01 ) . A superiority of combination chemotherapy was more significant for primary sites than regional lymph nodes . The relapse-free survival was not statistically different in the 2 groups , as well as the 2 years overall survival . Among responders , the survival was found highly correlated with a good initial general status ( p less than 0.01 ) , and with the highest total doses of cisplatin ( p less than 0.02 ) . ( ABSTRACT TRUNCATED AT 250 WORDS [8233298] In a prospect i ve , r and omized , multicenter study , neoadjuvant chemotherapy ( CT ) with carboplatin and 5-fluorouracil ( 5-FU ) followed by locoregional treatment ( LRT ) was compared with locoregional treatment alone in the treatment of patients with head and neck cancer . This study , which includes 324 patients , was conducted from January 1988 to July 1991 . The aim of this study was to evaluate the impact of the carboplatin/5-FU regimen both on the incidence of mutilating surgery and on the survival rate . Chemotherapy consisted of three cycles of carboplatin 400 mg/m2 day 1 and 5-FU 1 g/m2 days 1 - 5 , repeated every 3 weeks . Patients with a complete tumor response then received radiotherapy alone , instead of the treatment planned initially . Three hundred patients were analyzed : 79 had tumors of the oral cavity , 106 oropharyngeal tumors , and 115 pharyngolaryngeal tumors . One hundred fifty patients underwent CT+LRT ; 150 patients had LRT alone . Grade 3 and 4 toxicity rates were minimal in the CT+LRT group ; toxicity was mainly hematologic ( 24 % neutropenia , 19 % thrombocytopenia ) . There were 3 toxic deaths ( 2 % ) , 2 due to septicemia and 1 due to cardiac toxicity . One hundred forty-three patients were evaluable for efficacy . The tumor objective response rate was 63 % and complete response rate was 31 % ( 35 % for oropharyngeal , 34 % for pharyngolaryngeal tumors , 22.5 % for oral cavity tumors ) , which led to a 29 % decrease in the rate of mutilating surgery . Conservative treatment was performed in 57 % of patients in the CT+LRT group vs. 24 % in the LRT group ( p = 0.001 ) . There was no significant difference between survival curves in the CT+LRT and LRT groups . At 4 years , overall survival rates were 56 and 46 % ; disease-free survival rates were 33 and 30 % in the CT+LRT and the LRT groups , respectively . The survival rates were not significantly different in the two groups . The locoregional recurrence rates were 35 % in the CT+LRT arm and 25 % in the LRT arm ( p = 0.04 ) , with median follow-up of 25 months . The rates of secondary localization and distant metastasis were not significantly different in the two groups [15718308] PURPOSE To report the results and corresponding acute and late reactions of a prospect i ve , r and omized , clinical study in locally advanced head and neck cancer comparing concurrent fluorouracil ( FU ) and mitomycin ( MMC ) chemotherapy and hyperfractionated accelerated radiation therapy ( C-HART ; 70.6 Gy ) to hyperfractionated accelerated radiation therapy alone ( HART ; 77.6 Gy ) . PATIENTS AND METHODS Three hundred eighty-four stage III ( 6 % ) and IV ( 94 % ) oropharyngeal ( 59.4 % ) , hypopharyngeal ( 32.3 % ) , and oral cavity ( 8.3 % ) cancer patients were r and omly assigned to receive either 30 Gy ( 2 Gy every day ) followed by 1.4 Gy bid to a total of 70.6 Gy concurrently with FU ( 600 mg/m(2 ) , 120 hours continuous infusion ) days 1 through 5 and MMC ( 10 mg/m(2 ) ) on days 5 and 36 ( C-HART ) or 14 Gy ( 2 Gy every day ) followed by 1.4 Gy bid to a total dose of 77.6 Gy ( HART ) . The data were analyzed on an intent-to-treat basis . RESULTS At 5 years , the locoregional control and overall survival rates were 49.9 % and 28.6 % for C-HART versus 37.4 % and 23.7 % for HART , respectively ( P = .001 and P = .023 , respectively ) . Progression-free and freedom from metastases rates were 29.3 % and 51.9 % for C-HART versus 26.6 % and 54.7 % for HART , respectively ( P = .009 and P = .575 , respectively ) . For C-HART , maximum acute reactions of mucositis , moist desquamation , and erythema were lower than with HART , whereas no differences in late reactions and overall rates of secondary neoplasms were observed . CONCLUSION C-HART ( 70.6 Gy ) is superior to dose-escalated HART ( 77.6 Gy ) with comparable or less acute reactions and equivalent late reactions , indicating an improvement of the therapeutic ratio [14657228] PURPOSE We report the 5-year survival and late toxicity results of a r and omized clinical trial , which showed a 3-year improvement in overall survival and locoregional control of stage III or IV oropharynx carcinoma , using concomitant radiochemotherapy ( arm B ) , compared with st and ard radiotherapy ( arm A ) . PATIENTS AND METHODS A total of 226 patients were entered onto a phase III multicenter r and omized trial comparing radiotherapy alone ( 70 Gy in 35 fractions ; arm A ) with concomitant radiochemotherapy ( 70 Gy in 35 fractions with three cycles of a 4-day regimen comprising carboplatin and fluorouracil ; arm B ) . Prognostic factors were evaluated by univariate and multivariate analysis . Five-year late toxicity was evaluated using National Cancer Institute Common Toxicity Criteria for neurological toxicity , hearing , taste , m and ibula , and teeth damage , and Radiation Therapy Oncology Group toxicity criteria for skin , salivary gl and , and mucosa . RESULTS Five-year overall survival , specific disease-free survival , and locoregional control rates were 22 % and 16 % ( log-rank P = .05 ) , 27 % and 15 % ( P = .01 ) , and 48 % and 25 % ( P = .002 ) , in arm B and arm A , respectively . Stage IV , hemoglobin level lower than 125 g/L , and st and ard treatment were independent prognostic factors of short survival and locoregional failure by univariate and multivariate analysis . One or more grade 3 to 4 complications occurred in 56 % of the patients in arm B , compared with 30 % in arm A ( P was not significant ) . CONCLUSION Concomitant radiochemotherapy improved overall survival and locoregional control rates and does not statistically increase severe late morbidity . Anemia was the most important prognostic factor for survival in both arms [2317751] Forty‐eight patients with locally confined ( MO ) squamous cell head and neck cancer were prospect ively r and omized to receive either simultaneous ( SIM ) or sequential ( SEQ ) combined technique therapy with a 5‐fluorouracil infusion , a cisplatin bolus injection , and radiation therapy . Patients with residual resectable disease underwent surgery after induction therapy , whereas those achieving a complete response to induction did not require surgery . Patients on the two treatment arms were equivalent in all measured variables , including disease extent . Toxicities of the SIM and SEQ arms also were equivalent except for mucositis and the result ant weight loss , which were more severe on the SIM arm ( P = 0.002 ) . With a follow‐up time ranging from 9 to 41 months , seven of the 24 SIM patients and 14 of the 24 SEQ patients are considered treatment failures . The relapse‐free survival is significantly better on the SIM arm ( P = 0.03 ) , although an overall survival advantage has not yet been demonstrated ( P = 0.13 ) . The achievement of a complete response after induction therapy correlates with both the relapse‐free ( P = 0.0005 ) and overall ( P = 0.05 ) survival , and the likelihood of an induction complete response also is significantly better for those treated with the SIM schedule ( P = 0.02 ) . Eighteen patients did not require surgery after achieving an induction complete response . Relapse‐free survival does not appear to be compromised in this patient subset [9739379] Purpose To assess the survival rate , the probability of local control , the patterns of relapse and late sequelae including self-reported quality of life in patients treated with hyperfractionated radiotherapy ( RT ) and simultaneous CDDP chemotherapy for stage-III to stage-IV carcinomas of the head and neck . Methods From 1988 to 1994 , 64 patients ( median age 55.5 years ) with carcinomas of different subsites , excluding the nasopharynx , were treated in a pilot study with 1.2 Gy bid ( 6 h interval ; total dose 74.4 Gy ) and simultaneous CDDP ( 20 mg/m2 daily , 5 days in week 1 and 5 ) and followed at regular intervals . Overall survival and local control , as well as the rates of late toxicity , were estimated using the actuarial method . Median follow-up was 3.3 years for all and 5.2 years for surviving patients . To assess the quality of life , the EORTC QLQ-C 30 question naire and the H&N35 module question naire were sent to the patients surviving with no evidence of disease or second primary tumors ; they were answered by 15/23 ( 67 % ) . Results Overall survival was 37 % at 5 years , whereas disease-specific survival was 59 % . Twenty-three patients died from uncontrolled head and neck cancer . Second primary tumors were observed in 13 patients , most frequently in the lung . Local control without salvage surgery was 74 % at 5 years for all subsites and stages , and loco-regional disease-free survival was 72 % . Eleven patients developed distant metastases , which was the only site of failure in 6 cases . Salvage surgery was successful in 2 cases . The actuarial estimates of ≥ grade -3 late toxicity was 4 % for the m and ibular bone and 23 % for dysphagia , and 50 % of the patients experienced a permanent xerostomy . Self-reported global quality of life in surviving patients was good ( mean 68 points on a scale 0 to 100 ) ; consequences of impaired salivary function had most impact on nutritional and social aspects . Conclusions Hyperfractionated RT with concomitant CDDP is well tolerated and highly efficient in controlling moderately advanced to advanced cancers of the head and neck . Second primary tumors are the main cause of death after 3 years and were observed outside of the irradiated area , most frequently in the lung . Even after RT of large volumes to a high dose , salvage surgery can be successfully performed in individual cases . Self-reported quality of life of surviving patients is good , despite xerostomy-associated nutritional difficulties . ZusammenfassungZielAnalyse der Überlebensrate , des krankheitsspezifischen Überlebens , des Rezidivmusters , der Spättoxizität sowie der subjektiven Lebensqualität nach hyperfraktionierter Radiotherapie ( RT ) und gleichzeitiger Cisplatin-Chemotherapie ( CDDP ) bei Patienten mit mindestens zwei Jahren Beobachtungszeit i m Rahmen einer prospektiven Phase-II-Studie . Patienten und Method eIm Rahmen einer Pilotstudie ( 1988 bis 1994 ) wurden 64 Patienten ( medianes Alter 55,5 Jahre ) mit Stadium III oder IV kombiniert beh and elt : RT 1,2 Gy zweimal täglich bis 74,4 Gy , CDDP 20 mg/m2 täglich an den Tagen 1 bis 5 der ersten und fünften Woche . Die Überlebenskurven sowie die Toxizität wurden aktuariell berechnet . Die mediane Beobachtungszeit war 3,3 Jahre für alle respektive 5,2 Jahre für die überlebenden Patienten . Zur Einschätzung der Lebensqualität wurden 23 tumorfrei überlebende Patienten angefragt , den EORTC-QLQ-C30-Fragebogen sowie das ergänzende Modul für Kopf-Hals-Tumoren H&N35 auszufüllen . ErgebnisseDas Gesamtüberleben betrug nach fünf Jahren 37 % , während das krankheitsspezifische Überleben mit 59 % deutlich höher lag . 23 Patienten sind am Tumor verstorben . Zweittumoren , hauptsächlich Lungenkarzinome ( n=8 ) , wurden bei 13 Patienten registriert und waren die hauptsächliche Todesursache nach über drei Jahren . Die lokale Tumorkontrolle ohne zusätzliche Chirurgie betrug 74 % nach fünf Jahren und war für alle Lokalisationen und Stadien gleich ; die lokoregionäre Tumorkontrollrate lag bei 64 % . Fernmetastasen ohne ein lokoregionäres Therapieversagen wurden bei sechs Patienten gesehen . Eine „ Rettungschirurgie ” wurde in zwei Fällen erfolgreich durchgeführt . Die aktuarielle Spätkomplikationsrate ≥ Grad 3 betrug 4 % für den Kieferknochen und 23 % für Dysphagie ; 50 % der Patienten hatten eine bleibende komplette Xerostomie . Die globale Lebensqualität war gut ( i m Mittel 68 Punkte auf einer Skala von 0 bis 100 ) . Folgen der gestörten Speichelsekretion hatten die größte Auswirkung auf die funktionelle Behinderung der Ernährung sowie der sozialen Kontakte . SchlußfolgerungenDie hyperfraktionierte RT mit gleichzeitiger CDDP-Gabe wird hinsichtlich Spättoxizität gut toleriert und ist effizient zur Beh and lung fortgeschrittener Kopf-Hals-Tumoren . I m Gegensatz zu chirurgischen Serien treten Zweitkarzinome praktisch nur außerhalb des ursprünglichen Tumorbereichs auf . Eine „ Rettungschirurgie ” nach initialem Therapieversagen ist auch nach RT mit 74,4 Gy in Einzelfällen erfolgreich . Die selbstrapportierte Lebensqualität bei den Langzeitüberlebenden ist generell gut trotz gewisser , vorwiegend xerostomiebedingter Einschränkungen [11054514] BACKGROUND AND PURPOSE Radiation therapy is often the primary treatment for advanced cases of head and neck cancers not considered suitable for radical surgery . In these cases locoregional tumour control rates are low and has warranted innovative treatment modifications , such as altered fractionation schedules and combination with chemotherapy . PATIENTS AND METHODS From October 1990 to December 1997 , 239 patients with squamous cell cancers originating in the head and neck region were r and omized to one of three treatment options . St and ard therapy consisting of conventional fractionation with 70 Gy in 7 weeks in 35 fractions ( CF ) . The second treatment option consisted of a continuous hyperfractionated accelerated radiotherapy delivering a total dose of 55.3 Gy in 33 fractions over 17 consecutive days ( V-CHART ) . The third study arm had identical fractionation and dose as the above accelerated treatment , with the additional administration of 20 mg/m(2 ) mitomycin C ( MMC ) on day 5 of treatment ( V-CHART+MMC ) . RESULTS Main toxicity result ed from accelerated fractionation in confluent mucositis ( Grade 3 - 4 in 95 % ) requiring nasogastral tube feeding , analgetics and antiphlogistics in the majority of cases . Haematological toxicity Grade 3 - 4 was seen after MMC administration in 18 % . MMC administration did not influence mucosal reaction . Overall duration of mucositis was not different in the three treatment groups . Loco-regional tumour control was 31 % after CF , 32 % after V-CHART and 48 % after V-CHART+MMC , respectively ( P<0.05 ) . Overall crude survival was 24 % after CF , 31 % following V-CHART and 41 % after V-CHART+MMC , respectively ( P<0.05 ) . Median follow up was 48 months ( assessment performed in February 1999 ) . CONCLUSION Following shortening overall treatment time from 7 weeks to 17 consecutive days and dose of radiotherapy from 70 to 55.3 Gy the results in the radiotherapy only treated patients are identical . A significant improvement regarding local tumour control and survival was seen following administration of MMC to the accelerated fractionated treatment [2650723] From March 1983 to June 1986 , 100 patients with locally advanced squamous cell carcinoma of the head and neck were r and omized to receive either two courses of chemotherapy prior to local therapy ( group A ) , or local therapy alone ( group B ) . Local treatment consisted of primary radiotherapy in all patients . When a poor response was observed after 55 Gy , surgery was performed . The chemotherapy regimen was a combination of cisplatinum , bleomycin , vindesine , and mitomycin C. The response rate to induction chemotherapy ( group A ) was 50 % for the primary tumor ( CR : 10 % and PR : 40 % ) . At the end of radiotherapy , the overall tumor response rates in the two groups A and B , were 77 % and 79 % respectively . Complete disappearance of the primary tumor occurred more often than that of the lymph node metastases . The response rate to induction chemotherapy for lymph node metastases was 27.1 % ( CR : 9 % and PR : 18.1 % ) . An initial major response to chemotherapy predicted subsequent efficacy of irradiation on 90 % of the cases , while a failure of chemotherapy had no predictive value in this respect . The survival rates in groups A and B were 66.5 % vs. 65.1 % at 1 year and 35 % vs. 46.2 % at 2 years . Local disease-free and disease-free intervals were similar in both groups . A Cox 's multi-step regression analysis revealed two significant independant prognostic factors : size of primary tumor and nodal status . After adjustment for these factors , the chemotherapy did not seem to improve the effectiveness of the local treatment in terms of loco-regional control and survival [1378641] From January 1981 through December 1983 , 49 untreated patients with locally advanced head and neck cancers were r and omized in two groups to receive different radiochemotherapy regimens . Group A , including 29 cases , received 4 cycles of induction chemotherapy with Bleomycin , Methotrexate and Hydroxyurea before definitive external radiotherapy ( 60 Gy ) ; group B , including 20 patients , received the same total dose of radiotherapy but the 4 cycles of chemotherapy , as described above , were administered between the 20- and the 40-Gy doses . Both groups were compared with a control group treated in the same period with radiotherapy ( 60 Gy ) alone . The response to treatment was evaluated at the end of chemotherapy or radiotherapy alone and at the end of combined regimens . Long-term survival rates were analyzed for all groups relative to complete tumor response , disease-free interval and time to disease progression . In our experience the radio-chemotherapy combination , according to the described schedules , failed to improve both local control and overall survival ; the comparison with the control group does not suggest that induction or intercalated chemotherapy can increase long-term survival even if initial complete and partial response rates are high [1376306] Between December 1982 and October 1986 , 131 patients with stage II‐III‐IV squamous cell carcinoma of the oropharynx or oral cavity were r and omized to induction chemotherapy , consisting of bleomycin ( 10 mg/m2/day in continuous infusion from day 1 to day 5 ) , methotrexate ( 120 mg/m2 on day 2 ) followed by folinic acid , 5‐fluorouracil ( 5 FU ) ( 600 mg/m2 on day 2 ) , and cisplatin ( 120 mg/m2 on day 4 ) every 4 weeks for a total of three cycles followed by definitive locoregional treatment versus locoregional treatment alone . The modalities of definitive treatment ( radiotherapy ± surgery ) were chosen prior to r and omization . A total of 116 patients were evaluable . Of 55 patients in the chemotherapy arm , four ( 7 % ) had a complete response ( CR ) and 23 ( 42 % ) a partial response ( PR ) following the induction regimen . At the completion of locoregional treatment , 76 % ( 42 of 55 ) of patients in the experimental group were in CR compared to 89 % ( 54 of 61 ) in the control group . There was no difference in survival , cause‐specific survival , and pattern of relapse between both groups . The median survival was 22 months in the chemotherapy group and 29 months in the control group . Responders to chemotherapy did not fare better than nonresponders . Chemotherapy‐related toxicities were few and most of them related to cisplatin which was reduced to 100 mg/m2 for 35 patients . There were no treatment‐related deaths and , in the experimental arm of the trial , no increased morbidity from locoregional treatment . This induction regimen does not offer any advantages over st and ard treatment [15128894] BACKGROUND We compared concomitant cisplatin and irradiation with radiotherapy alone as adjuvant treatment for stage III or IV head and neck cancer . METHODS After undergoing surgery with curative intent , 167 patients were r and omly assigned to receive radiotherapy alone ( 66 Gy over a period of 6 1/2 weeks ) and 167 to receive the same radiotherapy regimen combined with 100 mg of cisplatin per square meter of body-surface area on days 1 , 22 , and 43 of the radiotherapy regimen . RESULTS After a median follow-up of 60 months , the rate of progression-free survival was significantly higher in the combined-therapy group than in the group given radiotherapy alone ( P=0.04 by the log-rank test ; hazard ratio for disease progression , 0.75 ; 95 percent confidence interval , 0.56 to 0.99 ) , with 5-year Kaplan-Meier estimates of progression-free survival of 47 percent and 36 percent , respectively . The overall survival rate was also significantly higher in the combined-therapy group than in the radiotherapy group ( P=0.02 by the log-rank test ; hazard ratio for death , 0.70 ; 95 percent confidence interval , 0.52 to 0.95 ) , with five-year Kaplan-Meier estimates of overall survival of 53 percent and 40 percent , respectively . The cumulative incidence of local or regional relapses was significantly lower in the combined-therapy group ( P=0.007 ) . The estimated five-year cumulative incidence of local or regional relapses ( considering death from other causes as a competing risk ) was 31 percent after radiotherapy and 18 percent after combined therapy . Severe ( grade 3 or higher ) adverse effects were more frequent after combined therapy ( 41 percent ) than after radiotherapy ( 21 percent , P=0.001 ) ; the types of severe mucosal adverse effects were similar in the two groups , as was the incidence of late adverse effects . CONCLUSIONS Postoperative concurrent administration of high-dose cisplatin with radiotherapy is more efficacious than radiotherapy alone in patients with locally advanced head and neck cancer and does not cause an undue number of late complications [19357741] BACKGROUND Management of advanced head and neck carcinoma is a challenging proposition . Presently concomitant chemo-irradiation has become the st and ard of care in such patients . Many chemotherapeutic drugs have shown radio-sensitising effects when used concomitantly along with radiation . The present study was carried out with the objective of assessing the feasibility and efficacy of low dose gemcitabine as radiosensitizer when used during radical radiotherapeutic management of patients with locally advanced head and neck carcinomas . PATIENTS AND METHODS From November 2000 to March 2003 , eighty histopathologically proven cases of squamous cell head and neck carcinoma were included in this trial , 40 patients were r and omly assigned to receive radiotherapy alone and 40 patients to receive gemcitabine along with radiotherapy . RESULTS All patients were assessable for toxicity and response . Severe mucositis ( WHO level 5 reactions were observed in 67 % patients in the CT/RT group vs 16 % patients in the RT only group . No severe hematological toxicity was seen . The rates of complete and partial responses were 42.5 % & 57.5 % respectively for RT only and 62.5 % & 37.5 % , respectively for CT/RT group . There was no significant difference in the response rates at the end of treatment but disease free survival at three years was better in the CT/RT group ( 63.3 % vs 20 % ) . Nine of the 17 patients with complete response in the radiation only group developed relapse while no relapses were seen in CT/RT group . CONCLUSION In the present study the combination of gemcitabine and radiotherapy has not shown any statistical difference in locoregional control but survival advantage was seen as compared to radiotherapy alone . At the same time more mucosal and skin toxicity was encountered when Gemcitabine is given concurrently with radiation [10601378] BACKGROUND We design ed a r and omized clinical trial to test whether the addition of three cycles of chemotherapy during st and ard radiation therapy would improve disease-free survival in patients with stages III and IV ( i.e. , advanced oropharynx carcinoma ) . METHODS A total of 226 patients have been entered in a phase III multicenter , r and omized trial comparing radiotherapy alone ( arm A ) with radiotherapy with concomitant chemotherapy ( arm B ) . Radiotherapy was identical in the two arms , delivering , with conventional fractionation , 70 Gy in 35 fractions . In arm B , patients received during the period of radiotherapy three cycles of a 4-day regimen containing carboplatin ( 70 mg/m(2 ) per day ) and 5-fluorouracil ( 600 mg/m(2 ) per day ) by continuous infusion . The two arms were equally balanced with regard to age , sex , stage , performance status , histology , and primary tumor site . RESULTS Radiotherapy compliance was similar in the two arms with respect to total dose , treatment duration , and treatment interruption . The rate of grade s 3 and 4 mucositis was statistically significantly higher in arm B ( 71 % ; 95 % confidence interval [ CI ] = 54%-85 % ) than in arm A ( 39 % ; 95 % CI = 29%-56 % ) . Skin toxicity was not different between the two arms . Hematologic toxicity was higher in arm B as measured by neutrophil count and hemoglobin level . Three-year overall actuarial survival and disease-free survival rates were , respectively , 51 % ( 95 % CI = 39%-68 % ) versus 31 % ( 95 % CI = 18%-49 % ) and 42 % ( 95 % CI = 30%-57 % ) versus 20 % ( 95 % CI = 10%-33 % ) for patients treated with combined modality versus radiation therapy alone ( P = .02 and .04 , respectively ) . The locoregional control rate was improved in arm B ( 66 % ; 95 % CI = 51%-78 % ) versus arm A ( 42 % ; 95 % CI = 31%-56 % ) . CONCLUSION The statistically significant improvement in overall survival that was obtained supports the use of concomitant chemotherapy as an adjunct to radiotherapy in the management of carcinoma of the oropharynx [9632446] BACKGROUND Radiotherapy is often the primary treatment for advanced head and neck cancer , but the rates of locoregional recurrence are high and survival is poor . We investigated whether hyperfractionated irradiation plus concurrent chemotherapy ( combined treatment ) is superior to hyperfractionated irradiation alone . METHODS Patients with advanced head and neck cancer who were treated only with hyperfractionated irradiation received 125 cGy twice daily , for a total of 7500 cGy . Patients in the combined-treatment group received 125 cGy twice daily , for a total of 7000 cGy , and five days of treatment with 12 mg of cisplatin per square meter of body-surface area per day and 600 mg of fluorouracil per square meter per day during weeks 1 and 6 of irradiation . Two cycles of cisplatin and fluorouracil were given to most patients after the completion of radiotherapy . RESULTS Of 122 patients who underwent r and omization , 116 were included in the analysis . Most patients in both treatment groups had unresectable disease . The median follow-up was 41 months ( range , 19 to 86 ) . At three years the rate of overall survival was 55 percent in the combined-therapy group and 34 percent in the hyperfractionation group ( P=0.07 ) . The relapse-free survival rate was higher in the combined-treatment group ( 61 percent vs. 41 percent , P=0.08 ) . The rate of locoregional control of disease at three years was 70 percent in the combined-treatment group and 44 percent in the hyperfractionation group ( P=0.01 ) . Confluent mucositis developed in 77 percent and 75 percent of the two groups , respectively . Severe complications occurred in three patients in the hyperfractionation group and five patients in the combined-treatment group . CONCLUSIONS Combined treatment for advanced head and neck cancer is more efficacious and not more toxic than hyperfractionated irradiation alone [1612948] From March 1983 to December 1989 , 208 patients with locally advanced squamous cell carcinoma of the head and neck were successively included into two r and omized induction chemotherapy trials . The chemotherapy regimen of the first trial , which included 100 patients , consisted of two cycles of a combination of cisplatin , bleomycin , vindesine and mitomycin C ; while that of the second trial , which included 108 patients , consisted of three cycles of a combination cisplatin , 5-fluorouracil by continuous infusion and vindesine . Local treatment was the same in the two trials : primary radiotherapy in all patients . The response was then evaluated ; in the case of a poor response at 55 Grays surgery was performed ; otherwise , radiotherapy was continued to full doses ( possibly followed by salvage surgery ) . The tumor and lymph node responses to chemotherapy ( complete and partial response ) were higher in the second trial than in the first : 70 % versus 50 % for primary lesions , 47 % versus 25 % for lymph nodes . The toxicity of the two chemotherapy regimens was minimal . In the two trials , an initial major response to chemotherapy predicted subsequent efficacy of irradiation in 80 % of the patients . The significance of the complete response at the end of the irradiation varies with the previous response to the chemotherapy . With a median follow-up of 60 months with the first chemotherapy regimen and 30 months with the second , overall survival and disease-free interval were very similar in the two groups . The incidence of distant metastasis was significantly reduced ( p less than 0.03 ) with chemotherapy . This trial suggests the need to test new chemotherapy protocol s according to new schemes of treatment , with chemotherapy given concurrently with or following the completion of st and ard treatment by means of multicenter r and omized trials [2451954] Two hundred and nine patients , with locoregional or metastatic recurrences of head and neck epidermoid carcinoma , were r and omized to receive a palliative chemotherapy . The chemotherapy regimens were delivered every 3 weeks , and consisted in ( 1 ) cisplatin , 80 mg/m2 given alone ( CDDP regimen ) , or ( 2 ) in combination with vincristine , 1 mg , methotrexate 10 mg/m2 d 1 , 2 , 3 , and bleomycin 10 mg/m2 , d 1 , 2 and 3 ( 1040 regimen ) . Short-term results were better for patients treated by the 1040 regimen , with a 30 % response rate ( including 4 complete responses ) vs 15 % with the CDDP regimen ( P = 0.01 ) . A superiority of combination chemotherapy was found for all tumoral sites , but was particularly significant for pulmonary and cutaneous metastases , in previously un irradiated areas ( P = 0.001 ) . Tolerance was significantly better with the CDDP regimen ( P = 0.001 ) ; severe side effects , affecting mainly general status , digestive tract and bone marrow were encountered in 5 % of the patients in the CDDP group , vs 21 % in the 1040 group , with one death related to pancytopenia . The median duration of remissions was not statistically different in the 2 groups , as well as the 2 years overall survival . Among responders , the survival was slightly better in those treated with CDDP alone ; moreover , the quality of long term results was found highly correlated with a good initial general status , and with low levels of side effects . Those results confirm recent data of the literature , and lead to the following conclusions : ( 1 ) combination chemotherapy with CDDP give a better response rate than CDDP alone , ( 2 ) response rate does n't influence overall duration of survival , ( 3 ) tolerance to treatment is crucial to preserve quality of life , and thus , ( 4 ) palliative chemotherapy in head and neck cancer should be efficient but also as short of intensity as possible [9845100] PURPOSE To evaluate the effect of mitomycin C to an accelerated hyperfractionated radiation therapy . The aim was to test a very short schedule with/without mitomycin C ( MMC ) with conventional fractionation in histologically verified squamous cell carcinoma of the head and neck region . METHODS AND MATERIAL S From October 1990 to December 1996 , 188 patients entered the trial . Tumors originated in the oral cavity in 54 , oropharynx in 82 , larynx in 20 , and hypopharynx in 32 cases , respectively . Patients ' stages were predominantly T3 and T4 ( 158/188 , 84 % ) and most patients had lymph node metastases ( 144/188 , 77 % ) at diagnosis . Only 22 patients were female , 166 were male , the median age of patients was 57 years ( range 34 to 76 years ) . Patients were r and omized to one of the following three treatment options : conventional fractionation ( CF ) consisting of 70 Gy in 35 fractions over 7 weeks ( 65 patients ) or continuous hyperfractionated accelerated radiation therapy ( V-CHART ; 62 patients ) or continuous hyperfractionated accelerated radiation therapy with 20 mg/sqm MMC on day 5 ( V-CHART + MMC ; 61 patients ) . By the accelerated regimens , the total dose of 55.3 Gy was delivered within 17 consecutive days , by 33 fractions . On day 1 , a single dose of 2.5 Gy was given , from day 2 to 17 a dose of 1.65 Gy was delivered twice : the interfraction interval was 6 hours or more . RESULTS Mucositis was very intense after accelerated therapy , most patients experiencing a grade III/IV reaction . The mucosal reaction did not differ whether MMC was administered or not . Patients treated by accelerated fractionation experienced a confluent mucosal reaction 12 - 14 days following start of therapy and recovered ( no reaction ) within 6 weeks . The skin reaction was not considered different in the three treatment groups . Those patients treated with additional chemotherapy experienced a grade III/IV hematologic toxicity in 12/61 patients . Initial complete response ( CR ) was recorded in 43 % following CF , 58 % after V-CHART , and 67 % after V-CHART + MMC , respectively ( p < 0.05 ) . Actuarial survival ( Kaplan-Meier ) was significantly improved in the combined treated patients . Local tumor control was 28 % , 32 % , and 56 % following CF , V-CHART , and V-CHART + MMC , respectively ( p < 0.05 ) . CONCLUSION We conclude that our continuous hyperfractionated accelerated radiation therapy regimen is equal to conventional fractionation , suggesting that by shortening the overall treatment time from 7 weeks to 17 days a reduction in dose from 70 Gy to 55.3 Gy is possible , with maintenance of local tumor control rates . The administration of MMC to the accelerated regimen is tolerable and improves the outcome for patients significantly [17724671] Men are approximately 3 times more likely to develop squamous cancers of the head and neck ( oral cavity , pharynx , and larynx ) than women . Very few prospect i ve studies have examined the association between cigarette smoking and cancers of the head and neck in women , even though the rates of smoking in women are increasing rapidly worldwide [12758236] BACKGROUND AND PURPOSE Single agent mitomycin c ( MMC ) has been shown to improve the outcome of radiotherapy in single institution trials . In order to confirm these findings in a broader worldwide setting , the International Atomic Energy Agency ( IAEA ) initiated a multicentre trial r and omising between radiotherapy alone versus radiotherapy plus MMC . MATERIAL AND METHODS Patients with advanced head and neck cancer were treated with primary curative radiotherapy ( 66 Gy in 33 fractions with five fractions per week ) + /-a single injection ( 15 mg/m(2 ) ) of MMC at the end of the first week of radiotherapy . Stratification parameters were tumour localization , T-stage , N-stage , and institution . A total of 558 patients were recruited in the trial from February 1996 to December 1999 . Insufficient accrual and reporting led to the exclusion of three centres . The final study population consisted of 478 patients from seven centres . Patients had stage III ( n=223 ) or stage IV ( n=255 ) squamous cell carcinoma of the oral cavity ( n=230 ) , oropharynx ( n=140 ) , hypopharynx ( n=65 ) or larynx ( n=43 ) . Prognostic factors like age , gender , site , size , differentiation and stage were well balanced between the two arms . RESULTS The haematological side effects of MMC were very modest ( < 5 % grade 3 - 4 ) and did not require any specific interventions . Furthermore , MMC did not enhance the incidence or severity of acute and late radiation side effects . Confluent mucositis and dry skin desquamation was common , occurring in 56 % and 62 % of patients , respectively . The overall 3-year primary locoregional tumour control , disease-specific and overall survival rates were 19 , 36 and 30 % , respectively . Gender , haemoglobin drop , tumour site , tumour and nodal stage were significant parameters for loco-regional tumour control . There was no significant effect of MMC on locoregional control or survival , except for the 161 N0 patients , where MMC result ed in a better loco-regional control ( 3-year estimate 16 % vs. 29 % , P=0.01 ) . CONCLUSIONS The study did not show any major influence of MMC on loco-regional tumour control , survival or morbidity after primary radiotherapy in stage III-IV head and neck cancer except in N0 patients where loco-regional control was significantly improved [2363468] The objective of the study was to evaluate the effect of neoadjuvant chemotherapy on the survival of patients with oropharyngeal cancer . Patients with a squamous cell carcinoma of the oropharynx for whom curative radiotherapy or surgery was considered feasible were entered in a multicentric r and omized trial comparing neoadjuvant chemotherapy followed by loco-regional treatment to the same loco-regional treatment without chemotherapy . The loco-regional treatment consisted either of surgery plus radiotherapy or of radiotherapy alone . Three cycles of chemotherapy consisting of Cisplatin ( 100 mg/m2 ) on day 1 followed by a 24-hour i.v . infusion of fluorouracil ( 1000 mg/m2/day ) for 5 days were delivered every 21 days . 2–3 weeks after the end of chemotherapy , local treatment was performed . The trial was conducted by the Groupe d'Etude des Tumeurs de la Tête Et du Cou ( GETTEC ) . A total of 318 patients were enrolled in the study between 1986 and 1992 . Overall survival was significantly better ( P = 0.03 ) in the neoadjuvant chemotherapy group than in the control group , with a median survival of 5.1 years versus 3.3 years in the no chemotherapy group . The effect of neoadjuvant chemotherapy on event-free survival was smaller and of borderline significance ( P = 0.11 ) . Stratification of the results on the type of local treatment , surgery plus radiotherapy or radiotherapy alone , did not reveal any heterogeneity in the effect of chemotherapy . © 2000 Cancer Research Campaign [7751897] PURPOSE A r and omized trial was design ed to compare cisplatin ( CDDP ) and fluorouracil ( FU ) versus carboplatin ( CBDCA ) and FU as neoadjuvant treatment in stage IV-M0 head and neck cancer to assess whether CBDCA-FU is better than CDDP-FU with regard to response and toxicity . PATIENTS AND METHODS Patients were r and omized to receive CDDP 100 mg/m2 intravenously on day 1 and FU 5,000 mg/m2 over a 120-hour continuous infusion , or CBDCA 400 mg/m2 over a 24-hour continuous infusion on day 1 and FU with the same schedule . Both regimens were repeated every 21 days . The patients received three courses of chemotherapy , excluding those who failed to achieve a partial response ( PR ) after the second course . Complete responders were treated with radiotherapy . The remaining patients underwent surgery if the tumor was resectable . RESULTS Interim analysis was performed when 95 patients were included . The trial was stopped due to significantly better results in the control arm . Differences in response ( P = .04 ) were favorable to CDDP-FU . Hematologic toxicity predominated in the CBDCA-FU arm ( P < .001 ) . Mucositis and vomiting predominated in the CDDP-FU arm ( P = .03 , P < .001 , respectively ) . Favorable outcomes ( complete response [ CR ] plus any grade of toxicity and PR plus grade 0 to 3 toxicity ) predominated in the CDDP-FU arm ( P = .02 ) . Only the treatment assigned was associated with response ( P = .02 ) and favorable outcomes ( P = .009 ) in the logistic regression analysis . In the CDDP-FU arm , disease-free and overall survival were significantly better . Cox regression analysis showed that only treatment association with disease-free survival remains significant . CONCLUSION Our results indicate that CDDP-FU is more effective than CBDCA-FU as neoadjuvant treatment in stage IV-M0 head and neck cancer [3307601] 136 patients with previously untreated stage III or IV squamous cell carcinoma of the head and neck entered a prospect i ve r and omized trial to compare the efficacy and toxicity of DDP vs DDP-VP 16 213 ( Etoposide ) . 69 patients ( group A ) were given three courses of DDP 100 mg/m2 administered on day 1 , while 67 patients ( group B ) were given three courses of a combination of Etoposide 100 mg/m2 per os administered on days 1 to 5 and DDP 100 mg/m2 on day 4 . Objective response rate appeared to be low in both groups : in group A ( 60 evaluated patients ) CR = 1 , PR = 9 ; CR + PR = 14.5 % , and in group B ( 57 evaluated patients ) CR = 3 , PR = 8 ; CR + PR = 16.4 % ( p greater than 0.4 ) . One drug-related death occurred in each group . There was no difference in toxicity between the two treatments with regard to leukopenia , thrombopenia , vomiting and nephrotoxicity . Thus this schedule of oral Etoposide does not seem to increase either the efficacy or the toxicity of DDP [8487051] PURPOSE The purpose of this study was to develop and vali date an instrument for clinical trials to measure radiation-related acute morbidity and quality of life from the perspective of patients with head and neck cancer ( HNC ) treated with radiotherapy . METHODS The Head and Neck Radiotherapy Question naire ( HNRQ ) was developed by a panel of health care workers and patients , was pretested in a pilot study of HNC patients , and was vali date d in a r and omized double-blind trial of concomitant fluorouracil ( FUra ) infusional therapy ( 1.2 g/m2 per 24 hours ) or saline placebo administered for 72 hours in the first and third weeks of a 6 1/2-week course of radiation therapy . The HNRQ was vali date d against existing toxicity and performance status indices , all of which were measured weekly for the 6 1/2 weeks of treatment and for 4 weeks posttreatment . RESULTS There were three a priori constructs : ( 1 ) that the HNRQ scores would conform to a shallow U-shaped pattern to reflect declining quality of life ( increasing morbidity ) during radiation and recovery posttreatment ; ( 2 ) that the HNRQ would correlate with existing toxicity indices ( World Health Organization [ WHO ] stomatitis , Byfield stomatitis , WHO skin toxicity , Eastern Cooperative Oncology Group [ ECOG ] and Karnofsky performance status ) ; and ( 3 ) that the HNRQ would discriminate between FUra and placebo groups . The HNRQ and its domain scores all showed a change from baseline reflecting increased morbidity during radiation ( analysis of variance [ ANOVA ] , P < .00001 ) . The HNRQ correlated well with all other indices ( r > or = .60 ) , and domain scores correlated best with other indices that assess the same symptom complex ( eg , HNRQ skin domain and WHO skin toxicity index , r = .77 ) . There was a significant difference in HNRQ scores between the FUra and placebo groups during radiation ( ANOVA , P = .0007 ) , and all HNRQ domains also discriminated between the treatment groups . CONCLUSION The HNRQ is a valid measure of acute morbidity due to radiation therapy in patients with locally advanced HNC , and may be useful as an outcome measure for future clinical trials of radiation treatment strategies [2451135] This trial of treatment for head and neck carcinoma was initiated in 1973 by the European Organization for Research and Treatment of Cancer . Its purpose was to investigate the value of single-agent chemotherapy with bleomycin ( BLM ) given during the course of a conventional treatment by external radiotherapy ( RT ) compared to treatment by external RT alone . In this r and omized study , we compared treatment results in 2 groups of patients with squamous cell carcinoma of the oropharynx ( T2 , T3 , and T4 ; International Union Against Cancer classification ) . One group of 92 patients was treated by RT at the prescribed dose of 70 Gy . The other group of 107 patients received radiation according to the same protocol and simultaneously received i m injection of BLM at a dose of 15 mg twice a week , 2 hours prior to the session of RT , for a total dose of 150 mg in 5 weeks . The occurrence of local toxic effects ( i.e. , mucositis and epidermatitis ) was significantly greater in the RT-BLM group ( RT-BLM , 72 % , vs. RT , 21 % ) . Primary tumor response 6 weeks after completion of RT was the same in both arms of the study ( RT , 68 % , vs. RT-BLM , 67 % ) . The 6-year survival rate was 24 % ( RT-BLM ) versus 22 % ( RT ) . Long-term analysis ( 10 yr ) is given [11735172] AIMS A prospect i ve r and omized study was conducted to evaluate the benefit of adjuvant levamisole/UFT ( futraful and uracil ) chemotherapy in head and neck squamous cell carcinoma . METHODS Sixty-five patients with stage III and IV squamous cell carcinomas of oral cavity , oropharynx , hypopharynx and larynx with no distant metastasis were r and omized for the chemotherapy study . Thirty-one patients were r and omized for chemotherapy and two of them were subsequently excluded . In this study , a total of 29 patients on levamisole/UFT therapy and 34 patients on the control group were analysed . The main outcome was measured by the 5-year disease-free actuarial survival rate . RESULTS The rates of distant metastasis were 10 % for chemotherapy group and 32 % for control group ( P=0.06 ) . The 5-year disease-free actuarial survival rates for patients with and without adjuvant chemotherapy were 57 % and 39 % respectively ( P=0.207 ) . CONCLUSIONS A trend of better distant control in head and neck cancer patients with post-operative adjuvant oral chemotherapy was observed . The side effects were minimal . However , there was no statistically significant improvement in the overall long-term survival . It may be of value to conduct a large-scale multi-centre prospect i ve r and omized study to verify the efficacy of levamisole and UFT as post-operative adjuvant chemotherapy for the control of distant metastasis in high-risk population [11082723] The aim of the study was to test whether the addition of three cycles of chemotherapy during st and ard radiation therapy would improve disease-free survival in patients with stages III and IV oropharynx carcinoma . A total of 226 patients have been entered in a phase III multicentric r and omized trial comparing radiotherapy alone ( arm A ) to radiotherapy with concomitant chemotherapy ( arm B ) . Radiotherapy was identical in the two arms , delivering , with conventional fractionation , 70 Gy in 35 fractions . In arm B patients received simultaneously 3 cycles of a four-day regimen containing carboplatin ( 70 mg/m2/d ) and 5 fluorouracil ( 600 mg/m2/d ) continuous infusion . The two arms were equally balanced regarding to age , gender , stage , performance status , histology , and primary tumor site . Radiotherapy compliance was similar in the two arms regarding to total dose , treatment duration and treatment interruption . Grade 3 and 4 mucositis rate was significantly higher in arm B ( 67 % versus 36 % ) . Skin toxicity was not different . Haematologic toxicity was higher in arm B on neutrophil count and hemoglobin level . Three-year overall actuarial survival and disease-free survival rates were respectively 51 % versus 31 % and 42 % versus 20 % for patients treated with combined modality versus radiation alone ( p = 0.022 and 0.043 ) . Local and regional control rate has been improved in arm B ( 66 % versus 42 % ) . The statistically significant improvement in overall survival obtained support the use of concomitant chemotherapy as an adjunct to radiotherapy in the management of carcinoma of the oropharynx [12506176] PURPOSE The Head and Neck Intergroup conducted a phase III r and omized trial to test the benefit of adding chemotherapy to radiation in patients with unresectable squamous cell head and neck cancer . PATIENTS AND METHODS Eligible patients were r and omly assigned between arm A ( the control ) , single daily fractionated radiation ( 70 Gy at 2 Gy/d ) ; arm B , identical radiation therapy with concurrent bolus cisplatin , given on days 1 , 22 , and 43 ; and arm C , a split course of single daily fractionated radiation and three cycles of concurrent infusional fluorouracil and bolus cisplatin chemotherapy , 30 Gy given with the first cycle and 30 to 40 Gy given with the third cycle . Surgical resection was encouraged if possible after the second chemotherapy cycle on arm C and , if necessary , as salvage therapy on all three treatment arms . Survival data were compared between each experimental arm and the control arm using a one-sided log-rank test . RESULTS Between 1992 and 1999 , 295 patients were entered on this trial . This did not meet the accrual goal of 362 patients and result ed in premature study closure . Grade 3 or worse toxicity occurred in 52 % of patients enrolled in arm A , compared with 89 % enrolled in arm B ( P < .0001 ) and 77 % enrolled in arm C ( P < .001 ) . With a median follow-up of 41 months , the 3-year projected overall survival for patients enrolled in arm A is 23 % , compared with 37 % for arm B ( P = .014 ) and 27 % for arm C ( P = not significant ) . CONCLUSION The addition of concurrent high-dose , single-agent cisplatin to conventional single daily fractionated radiation significantly improves survival , although it also increases toxicity . The loss of efficacy result ing from split-course radiation was not offset by either multiagent chemotherapy or the possibility of midcourse surgery [2451713] A cooperative r and omized study was begun in August 1983 to compare a sequential program of induction chemotherapy followed by definitive treatment , arm A , with an alternation of chemotherapy and radiotherapy ( three courses of 20 Gy in ten daily fractions ) , arm B. The same chemotherapy was used in both arms : 6 mg/m2 , vinblastine , hour 0 ; 30 mg , bleomycin , hour 6 ; 200 mg , methotrexate , hours 24 to 26 ; 45 mg , leucovorin , hour 48 . One hundred sixteen patients entered the study , 55 in arm A and 61 in arm B. The patients all had previously untreated squamous cell carcinoma of the head and neck ( SCCHN ) . Forty-five patients had stage III and 71 had stage IV disease . The two arms were fully comparable . As of April 1986 , 116 patients were evaluable for survival , while 112 were evaluable for toxicity and 105 for response . Response analysis shows that there were 14 complete responses ( CR ) and 11 partial responses ( PR ) , for an overall response rate ( ORR ) of 52 % in arm A , and 30 CRs and seven PRs , for an ORR of 64.9 % in arm B. The difference in terms of CR between the two arms was statistically significant ( P less than .03 ) . Progression-free survival ( PFS ) was also statistically different , with an advantage for arm B ( P less than .05 ) , but without differences in overall survival . Arm B correlates with a significant increase in mucositis compared with arm A ( P less than .001 ) [10802364] PURPOSE To determine whether any difference in toxicity or efficacy occurs when head and neck cancer patients are treated postoperatively with (60)C0 , 4 MV , or 6 MV photon beam . METHODS AND MATERIAL S This is a secondary analysis of the Intergroup Study 0034 . Three hundred ninety-two patients were evaluable for comparison between treatment with (60)C0 , 4 MV , or 6 MV photon beam . All patients had advanced but operable squamous cell carcinoma of the oral cavity , oropharynx , hypopharynx , or larynx . Patients were r and omized following surgical resection to receive treatment with either postoperative irradiation alone , or postoperative irradiation plus three cycles of cisplatin and 5-fluorouracil . Patients were categorized as having either " low risk " or " high risk " treatment volumes based on whether the surgical margin was 5 mm or less , presence of extra capsular nodal extension , and /or carcinoma in situ at the surgical margins . Low-risk volumes received 50 - 54 Gy , and high-risk volumes were given 60 Gy . Patients were compared in regards to acute and late radiotherapy toxicities as well as overall survival and loco-regional control according to the beam energy used . RESULTS One-hundred fifty-seven , 140 , and 95 patients were treated by (60)C0 , 4 MV , and 6 MV , respectively . No differences were seen in acute or late toxicity among treatment groups . Locoregional control was achieved in 75 % , 79 % , and 80 % of patients treated with (60)C0 , 4 MV , or 6 MV ( p = 0.61 ) . Patients treated with 6 MV had a higher incidence of ipsilateral neck failure as first event ( 13 % ) than patients treated by (60)C0 and 4 MV ( 9 % ) . This difference was not statistically significant . CONCLUSION No differences in outcome , acute , or late toxicity were discernible in patients with advanced head and neck cancer treated with (60)C0 , 4 MV , or 6 MV . This result should be interpreted with caution as increased incidence , albeit nonsignificant , of ipsilateral neck recurrence was observed in patients treated with 6 MV and the power of the study to detect a statistically significant difference is small [21573534] Several phase II studies have shown that concurrent chemotherapy and radiotherapy ( RT ) improves the response rates and locoregional control in patients with advanced , unresectable squamous-cell carcinoma of the head and neck ( H&N ) . However , it is still unclear which is the drug of choice to be given with RT . We therefore conducted a r and omized comparison of cisplatin (CDDP)-RT versus carboplatin (CRP)-RT in such patients . The two platinum compounds were given at equitoxic doses . The primary objective of the study was to compare the side effects and the response rates of the two regimens . Radiotherapy was given at conventional dosages , 2 Gy for 5 days every week for a total dose of 64 Gy with CDDP 80 mg/m2 or CRP 375 mg/m2 for three cycles on days 1 , 21 and 42 . At present 53 patients are entered in the study : 27 in the CDDP arm and 26 in the CRP . The two arms were balanced for all the pre-treatment characteristics . Both the schedules were well tolerated . However , incidence of nausea and vomiting ( p=0.0045 ) ; anemia ( p=0.032 ) and peripheral neuropathy ( p=0.032 ) was significantly greater with CDDP-RT as compared to CRP-RT . On the other h and , CRP-RT gives a significantly higher incidence of stomatitis ( p=0.0067 ) and a marginally worse thrombocytopenia ( p=0.09 ) . The complete response ( CR ) rates were similar in the two arms ( 55.5 % in the CDDP-RT versus 61.5 % in that CRP-RT , respectively ) as well as the overall response rates ( 92.5 % versus 84.5 % , respectively ; p=0.36 ) . The estimated 1 - and 2 year overall and disease-free survival rates were not significantly different in the two arms . In both the groups logistic-regression models showed that those patients with a CR ( p=0.017 ) ; stage III ( p=0.011 ) ; smaller primary ( p=0.025 ) and limited node-involvement ( p<0.001 ) had a significant better survival . We conclude that concurrent chemo-radiotherapy is an effective and safe treatment for patients with locally advanced H&N cancer . The combination CRP-RT possess a similar activity but a different , and perhaps a more favorable , spectrum of toxicity when compared to the CDDP-RT therapy . Survival results need to be assessed in a larger series and followed for a more prolonged time [1618662] To test the efficacy of sequential chemotherapy as an adjuvant to surgery and postoperative radiotherapy for patients with locally-advanced but operable squamous cell cancers of the head and neck region , a r and omized clinical trial was conducted under the auspices of the Head and Neck Intergroup ( Radiation Therapy Oncology Group , Southwest Oncology Group , Eastern Oncology Group , Cancer and Leukemia Group B , Northern California Oncology Group , and Southeast Group ) . Eligible patients had completely resected tumors of the oral cavity , oropharynx , hypopharynx , or larynx . They were then r and omized to receive either three cycles of cis-platinum and 5-FU chemotherapy followed by postoperative radiotherapy ( CT/RT ) or postoperative radiotherapy alone ( RT ) . Patients were categorized as having either " low-risk " or " high-risk " treatment volumes depending on whether the surgical margin was greater than or equal to 5 mm , there was extracapsular nodal extension , and /or there was carcinoma-in-situ at the surgical margins . Radiation doses of 50 - 54 Gy were given to " low-risk " volumes and 60 Gy were given to " high-risk " volumes . A total of 442 analyzable patients were entered into this study with the mean-time-at-risk being 45.7 months at the time of the present analysis . The 4-year actuarial survival rate was 44 % on the RT arm and 48 % on the CT/RT arm ( p = n.s . ) . Disease-free survival at 4 years was 38 % on the RT arm compared to 46 % on the CT/RT arm ( p = n.s . ) . At 4 years the local/regional failure rate was 29 % vs. 26 % for the RT and CT/RT arms , respectively ( p = n.s . ) . The incidence of first failure in the neck nodes was 10 % on the RT arm compared to 5 % on the CT/RT arm ( p = 0.03 without adjusting for multiple testing ) and the overall incidence of distant metastases was 23 % on the RT arm compared to 15 % on the CT/RT arm ( p = 0.03 ) . Treatment related toxicity is discussed in detail , but , in general , the chemotherapy was satisfactorily tolerated and did not affect the ability to deliver the subsequent radiotherapy . Implication s for future clinical trials are discussed [9348577] This study compared the activity and toxicity of fluorouracil (5-FU)/ cisplatin with the combination tegafur and uracil (UFT)/cisplatin in the neoadjuvant treatment of locally advanced-stage III or IV (MO)-head and neck cancer . A total of 67 patients were r and omly assigned to treatment with cisplatin 100 mg/m2 on day 1 followed by either a continuous infusion of 5-FU 1,000 mg/m2/day on days 2 through 6 ( group 1 ) or oral administration of UFT 300 mg/m2/day on days 2 through 20 ( group 2 ) . Both treatments were repeated every 21 days for four cycles . Responding patients received locoregional st and ard radiotherapy ( 50 to 70 Gy ) after chemotherapy . Group 1 was comprised of 34 patients , 30 of whom were men , with a median age of 57.5 years ; 79 % of this group had a Karnofsky performance status of 90 % to 100 % ; 70 % had a squamous and 29 % an undifferentiated histology . The majority ( 85 % ) had stage IV disease . Of the 33 patients in group 2 , 29 were men . The median age was 56 years . Most ( 88 % ) had a performance status of 90 % to 100 % . More patients had a squamous than an undifferentiated histology ( 82 % vs 18 % ) and most ( 88 % ) had stage IV disease . Overall response in group 1 was 73 % ( 21 % complete ) compared with 79 % ( 18 % complete ) in group 2 . At a median follow-up of 84 months , no significant differences have emerged in overall survival , 15 vs 37 months , or time to progression , 8.5 vs 14.5 months , for groups 1 and 2 , respectively . Toxicity was also similar , except for phlebitis , which occurred significantly more often in group 1 ( 71 % vs 9 % ) . Cisplatin/UFT was as effective as the classic cisplatin/5-FU regimen and has the advantages of outpatient oral administration and a lower incidence of phlebitis [15534360] PURPOSE To determine whether the application of two courses of cisplatin simultaneously with hyperfractionated radiotherapy improves the outcome in locally advanced and /or node-positive nonmetastatic carcinomas of the head and neck , compared with hyperfractionated radiotherapy alone . PATIENTS AND METHODS From July 1994 to July 2000 , 224 patients with squamous cell carcinomas of the head and neck ( excluding nasopharynx and paranasal sinus ) were r and omly assigned to hyperfractionated radiotherapy ( median dose , 74.4 Gy ; 1.2 Gy twice daily ) or the same radiotherapy combined with two cycles of concomitant cisplatin ( 20 mg/m2 on 5 days of weeks 1 and 5 ) . The primary end point was time to any treatment failure ; secondary end points were locoregional failure , metastatic relapse , overall survival , and late toxicity . RESULTS There was no difference in radiotherapy between both treatment arms ( 74.4 Gy in 44 days ) . The full cisplatin dose was applied in 93 % and 71 % of patients during the first and second treatment cycles , respectively . Acute toxicity was similar in both arms . Median time to any treatment failure was not significantly different between treatment arms ( 19 months for combined treatment and 16 months for radiotherapy only , respectively ) and the failure-free rate at 2.5 years was 45 % and 33 % , respectively . Locoregional control and distant disease-free survival were significantly improved with cisplatin ( log-rank test , P = .039 and .011 , respectively ) . The difference in overall survival did not reach significance ( log-rank test , P = .147 ) . Late toxicity was comparable in both treatment groups . CONCLUSION The therapeutic index of hyperfractionated radiotherapy is improved by concomitant cisplatin [1691811] Between August 1983 and December 1986 , 116 previously untreated patients with squamous cell carcinoma of the head and neck were r and omized to receive induction chemotherapy followed by radiotherapy given in conventional fractions ( 55 patients , arm A ) or an alternating chemotherapy and radiotherapy ( 3 courses of 20 Gy , 10 daily fractions each ; 61 patients , arm B ) . The same chemotherapy was used in both arms : 6 mg/m2 vinblastine sulfate , hour 0 ; 30 mg bleomycin , hour 6 ; 200 mg methotrexate , hours 24 to 26 ; 45 mg leucovorin , hour 48 . Forty-five patients had stage III disease and 71 had stage IV disease . All patients were evaluated for survival , 112 for toxicity , and 105 for analyses of response and time from the start of treatment until progression of disease . At the end of the combined treatment , we observed an overall response rate of 52 % in arm A and an overall response rate of 64.9 % in arm B. The incidence of mucositis was more relevant in arm B compared to arm A ( P less than .00004 ) . The difference in complete response , progression-free survival , and survival was statistically significant , with an advantage for arm B ( P less than .03 , P less than .02 , and P less than .03 , respectively ) . The analysis at a median follow-up of 36 months ( range = 19 to 59 ) demonstrates a higher effectiveness for the alternating program [7539873] Fifty-four previously untreated patients with locally advanced resectable squamous cell carcinoma of the head and neck ( SCCHN ) were enrolled into a prospect i ve r and omized controlled trial to evaluate whether induction chemotherapy improves the disease-free survival compared to the st and ard treatment ( surgery + radiation ) . Thirty patients received chemotherapy , which consisted of cisplatin 20 mg/m2 day 1 - 5 , bleomycin 10 mg/m2 , continuous infusion from day 3 - 7 , and methotrexate 40 mg/m2 given on day 15 and day 22 . The cycle was repeated on day 29 for two cycles . Twenty patients completed chemotherapy courses . Overall response rate was 77 % ( 23 of 30 ) . No survival improvement was observed . Kaplan-Meier analysis indicated survival ( and 95 % confidence interval ) at 3 years was 57 % ( 29%-84 % ) for the control group and 60 % ( 34%-87 % ) for the chemotherapy group , and 57 % ( 29%-84 % ) and 45 % ( 12%-78 % ) at 4 years ( P = 0.736 ) . However , patients who had a complete response were significantly better in terms of long-term survivors ( 5 of 7 patients were still alive ) , in contrast to patients who had partial responses among whom only 4 of 16 were alive . Toxicities of this induction protocol are tolerable ; one chemotherapy-related death occurred from profound thrombocytopenia . If efforts in determining a chemotherapy-sensitive patient were successfully established , along with a better sequence and the discovery of new and safer drugs , survival of SCCHN should be much improved [2885080] To determine the efficacy of adjuvant chemotherapy in patients with advanced head and neck squamous carcinoma , the National Cancer Institute initiated a multi-institutional , prospect i ve r and omized trial termed the Head and Neck Contracts Program . Between 1978 and 1982 , 462 patients with resectable Stage III or IV cancers of the oral cavity , larynx , or hypopharynx were r and omly assigned to receive one of three treatment options : induction chemotherapy consisting of a single course of cisplatin and bleomycin followed by st and ard therapy ( surgery and postoperative radiotherapy ) ; induction chemotherapy and st and ard therapy followed by maintenance chemotherapy which consisted of six cycles of monthly cisplatin ; or st and ard therapy alone . Toxicity from the chemotherapy regimens was minimal . Induction therapy result ed in an overall complete response of 3 % and a partial response in 34 % of patients . With a median follow-up of 61 months , overall survival and disease-free survival were not markedly different among the three groups ( P = 0.86 and P = 0.16 , respectively ) . The incidence of distant relapse was reduced in the maintenance group compared to st and ard or induction groups ( P = 0.025 and P = 0.021 , respectively ) and time to first distant relapse was prolonged ( P = 0.032 and P = 0.022 , respectively ) . The results confirm the feasibility of administering chemotherapy prior to surgery or radiation in patients with head and neck cancer but fail to demonstrate a significant impact of one cycle of induction chemotherapy on clinical outcome . The suggestion that distant relapse rates may be reduced with the addition of maintenance chemotherapy supports the need to test traditional adjuvant approaches in patients with advanced head and neck cancer [16376489] BACKGROUND Unresectable carcinomas of the oropharynx and hypopharynx still have a poor long-term prognosis . Following a previous phase II study , this phase III multicenter trial was conducted between November 1997 and March 2002 . METHODS Nontreated , strictly unresectable cases were eligible . Twice-daily radiation : two fractions of 1.2 Gy/day , 5 days per week , with no split ( D1 - ->D46 ) . Total tumor doses : 80.4 Gy/46 day ( oropharynx ) , 75.6 Gy/44 day ( hypopharynx ) . Chemotherapy ( arm B ) : Cisplatin 100 mg/m2 ( D1 , D22 , D43 ) ; 5FU , continuous infusion ( D1 - ->D5 ) , 750 mg/m2/day cycle 1 ; 430 mg/m2/day cycles 2 and 3 . RESULTS A total of 163 evaluable patients . Grade 3 - 4 acute mucositis 82.6 % arm B/69.5 % arm A ( NS ) ; Grade 3 - 4 neutropenia 33.3 % arm B/2.4 % arm A ( p < 0.05 ) . Enteral nutrition through gastrostomy tube was more frequent in arm B before treatment and at 6 months ( p < 0.01 ) . At 24 months , overall survival ( OS ) , disease-free survival ( DFS ) , and specific survival ( SS ) were significantly better in arm B. OS : 37.8 % arm B vs. 20.1 % arm A ( p = 0.038 ) ; DFS : 48.2 % vs. 25.2 % ( p = 0.002 ) ; SS : 44.5 % vs. 30.2 % ( p = 0.021 ) . No significant difference between the two arms in the amount of side effects at 1 and 2 years . CONCLUSION For these unresectable cases , chemoradiation provides better outcome than radiation alone , even with an " aggressive " dose-intensity radiotherapy schedule [11716226] Long-term follow-up for patients who receive chemoradiation for head and neck cancer is lacking from most studies reported in the literature . This report gives a 15-year review of the use of concomitant methotrexate and radiation in advanced head and neck cancer . Although there has not been any significant benefit in overall survival , the primary control rate is higher in patients who received methotrexate in addition to radiotherapy . However , in those with oropharyngeal cancer , both primary control and survival were significantly improved when chemotherapy was used . The other most significant benefit from chemoradiation is the much lower rate of salvage operations for primary recurrence . The addition of methotrexate failed to show any effect on the development of metastatic neck nodes . The rate of block dissection of the neck was similar in both arms of the study and is comparable with the historical data collected at this institute . There has not been any significant increase in serious late morbidity . The timing of the methotrexate with radiotherapy has a significant influence on primary control and survival in head and neck cancer [9165134] Between January 1988 and December 1991 , 159 patients with Stage III/IV ( M0 ) squamous cell carcinoma of the head and neck were r and omized to receive st and ard fraction RT ( 70 Gy ) ( group I ) or the same RT plus either 6 mg/m2 of cisplatin ( CDPP ) ( group II ) or 25 mg/ m2 of carboplatin ( CBDCA ) both given daily during RT ( group III ) . Patients in groups II and III had significantly higher overall response rates then those in group I ( P = 0.011 and P = 0.0025 , respectively ) with no difference between groups II and III ( P = 0.60 ) . They also had significantly longer median survival time ( MST ) and higher 5-year survival rates than those in group I ( MST , 32 months ( 32 % ) and 30 months ( 29 % ) versus 16 months ( 15 % ) , respectively ; P = 0.011 and P = 0.019 , respectively ) , with no difference between the two RT/CHT groups . Median time to local recurrence ( MTLR ) and 5-year local recurrence-free survival ( LRFS ) were significantly higher for both RT/CHT when compared to RT alone ( MTLR , not attained yet and 30 months versus 10 months , respectively ; 5-year LRFS , 51 % and 48 % versus 27 % , respectively ; P = 0.018 and P = 0.040 , respectively ) with no difference between the two RT/CHT groups . There was no difference between the three treatment groups regarding regional lymph node and distant metastasis control . Apart from acute high grade ( > or =3 ) hematological toxicity that was significantly more frequent in the two RT/CHT groups and no different between the two RT/CHT groups , other acute high grade toxicity was similar between the three treatment groups . Late high grade toxicity was infrequent and similar between the three treatment groups [15128893] BACKGROUND Despite the use of resection and postoperative radiotherapy , high-risk squamous-cell carcinoma of the head and neck frequently recurs in the original tumor bed . We tested the hypothesis that concurrent postoperative administration of cisplatin and radiotherapy would improve the rate of local and regional control . METHODS Between September 9 , 1995 , and April 28 , 2000 , 459 patients were enrolled . After undergoing total resection of all visible and palpable disease , 231 patients were r and omly assigned to receive radiotherapy alone ( 60 to 66 Gy in 30 to 33 fractions over a period of 6 to 6.6 weeks ) and 228 patients to receive the identical treatment plus concurrent cisplatin ( 100 mg per square meter of body-surface area intravenously on days 1 , 22 , and 43 ) . RESULTS After a median follow-up of 45.9 months , the rate of local and regional control was significantly higher in the combined-therapy group than in the group given radiotherapy alone ( hazard ratio for local or regional recurrence , 0.61 ; 95 percent confidence interval , 0.41 to 0.91 ; P=0.01 ) . The estimated two-year rate of local and regional control was 82 percent in the combined-therapy group , as compared with 72 percent in the radiotherapy group . Disease-free survival was significantly longer in the combined-therapy group than in the radiotherapy group ( hazard ratio for disease or death , 0.78 ; 95 percent confidence interval , 0.61 to 0.99 ; P=0.04 ) , but overall survival was not ( hazard ratio for death , 0.84 ; 95 percent confidence interval , 0.65 to 1.09 ; P=0.19 ) . The incidence of acute adverse effects of grade 3 or greater was 34 percent in the radiotherapy group and 77 percent in the combined-therapy group ( P<0.001 ) . Four patients who received combined therapy died as a direct result of the treatment . CONCLUSIONS Among high-risk patients with resected head and neck cancer , concurrent postoperative chemotherapy and radiotherapy significantly improve the rates of local and regional control and disease-free survival . However , the combined treatment is associated with a substantial increase in adverse effects [807952] Ninety-six patients with advanced squamous cell carcinoma of the head and neck were r and omized to treatment with intravenous methotrexate followed by radical irradiation or radiotherapy alone . No significant differences were demonstrated in local disease control or actuarial survival rates at three and five years . Some patients with local treatment failure were surgically salvaged [7989940] PURPOSE To determine whether the addition of infusional fluorouracil ( I-FU ) to st and ard radiotherapy improves survival at acceptable toxicity in patients with locally advanced squamous cell head and neck cancer ( SCHNC ) . PATIENTS AND METHODS Consenting patients with an Eastern Cooperative Oncology Group ( ECOG ) performance status < or = 2 ; with stage III or IV SCHNC of the oral cavity , oropharynx , hypopharynx , or larynx ; and who were recommended for radiotherapy with curative intent received 66 Gy of radiation therapy delivered in 2-Gy fractions once daily 5 days per week for 6 1/2 weeks . Those in the experimental arm received I-FU 1.2 g/m2/d , as a 72-hour infusion in the first and third weeks of radiation . Saline infusions were used in the placebo arm . RESULTS One hundred seventy-five patients were r and omized ( 88 to I-FU and 87 to placebo ) , and the treatment arms were well balanced . The complete response rate was 68 % for I-FU and 56 % for placebo ( P = .04 ) . The overall median survival duration was 33 months for I-FU and 25 months for placebo ( P = .08 ) . Progression-free survival also favored I-FU ( P = .06 ) . Toxicity was greater in I-FU patients , but did not interfere with the scheduled delivery or completion of radiation . CONCLUSION The addition of I-FU to st and ard radiation in SCHNC improved the complete response rate and was associated with beneficial trends in progression-free and overall survival compared with radiation alone . I-FU patients also experienced greater morbidity , but this did not compromise delivery of radiotherapy [3550340] It is often suggested that tumors will respond to induction chemotherapy and result in improved survival for patients with squamous cell carcinoma of the head and neck . Two regimens of induction chemotherapy were studied in separate r and omized , prospect i ve trials over the last 6 years . Eighty-three patients with advanced disease were entered into the first study ( 43/chemotherapy ; 40/control ) , and 60 into the second ( 27/chemotherapy ; 33/control ) . Patient r and omization was stratified by stage ( III/IV ) and site ( oral cavity , oropharynx , nasopharynx , hypopharynx , larynx , paranasal sinuses ) . The first study utilized bleomycin , Cytoxan , methotrexate and 5-fluorouracil in two cycles ( one cycle if no tumor response ) , followed by st and ard treatment which consisted of combined irradiation and surgery or , in some instances , primary irradiation alone . The second study utilized cisplatin and 5-fluorouracil in three cycles prior to st and ard treatment . An objective tumor response to chemotherapy was observed in 68 % in the first study and 85 % in the second . The patient survival in both studies ( at 24 months in the first ; at 19 in the second ) was better in the control than that in the experimental groups ( 43 % to 31 % ; 69 % to 46 % ) . In the second study , the average length of delay of st and ard treatment was longer than in the first study ( 95 days vs. 66 days ; P less than .02 ) . Results combining the P-values of both studies indicate that the relative risk of having persistent disease was 2.9 times greater for patients who received chemotherapy . While toxicity to chemotherapy was not a factor in survival , the number of patients who withdrew from the studies and those who did not comply with treatment were greater in the chemotherapy groups . Except for new drug regimens of exceptional promise , it is recommended that future studies be design ed so that chemotherapy is given concurrent with , or following the completion of st and ard treatment [7410127] Abstract This report culminates a 4-year study on the benefits attained by intravenous Methotrexate adjuvant and prior to definitive irradiation of advanced head and neck cancers . Three hundred twenty-six patients were r and omized to receive definitive radiotherapy alone while 312 similar patients first received intravenous Methotrexate , 25 mgm every third day for 5 doses , followed immediately by full-course irradiation . Population characteristics by specific disease site , stage ( T and N ) , age , and sex were similar between the two patient population s ; no significant bias was demonstrated . Eligibility included advanced primary ( T3 4 ) and /or nodal stage disease . The number of annual deaths among the two r and omized categories was essentially equal during the first 5 years of follow-up . Nearly one-half occurred in the first year ( 146 for radiation alone and 143 in the chemotherapy plus irradiation groups ) . Median metastasis-free survival was between 12–13 months in both categories . The unadjusted 5 year survivals were in the 11–22 % range for oral cavity , oropharynx , and supraglottic larynx and 3–9 % for hypopharynx primaries . Although several variables did exert an impact upon survival , primary ( T ) and lymph node ( N ) stage seem to be of paramount importance and Methotrexate of minor consideration . Median and 5-year survivals within the various anatomic regions ( oral cavity , supraglottic larynx , and hypopharynx ) were consistently better when Methotrexate was given . However , these improvements were minimal ( 1–4 mos . median or 2–6 % at 5 yrs ) and depended upon whether comparisons were performed on adjusted or unadjusted survival figures . Any “ real ” gain achieved directly by Methotrexate is conjecture , since several uncontrolled biases were identified among these various categories . In view of the modest benefits attained by using this Methotrexate regimen the authors suggest that other adjuvant programs be investigated and that this schedule not be adopted for routine clinical usage [9332685] PURPOSE The goal of the present analyses is to assess the association between different therapeutic approaches and both the probability of achieving a complete response and the risk of death in patients with stage III-IV , inoperable , squamous cell carcinoma of the head and neck ( SCC-HN ) . PATIENTS AND METHODS Between August 1983 and December 1990 , 273 patients with stage III-IV , previously untreated , unresectable SCC of the oral cavity , pharynx and larynx , were included into two consecutive r and omized multi-institutional trials ( HN-7 and HN-8 protocol s ) coordinated by the National Institute for Cancer Research ( NICR ) of Genoa . The HN-7 protocol compared neo-adjuvant chemotherapy ( four cycles of vinblastine , 6 mg/m2 i.v . followed by bleomycin , 30 IU i.m . six hours later , day 1 ; methotrexate , 200 mg i.v . , day 2 ; leucovorin , 45 mg orally , day 3 ) ( VBM ) followed by st and ard radiotherapy ( 70 - 75 Gy in 7 - 8 weeks ) ( 55 patients ) to alternating chemoradiotherapy based on four cycles of the same chemotherapy alternated with three splits of radiation , 20 Gy each ( 61 patients ) . In the HN-8 protocol st and ard radiotherapy ( 77 patients ) was compared to the same alternating program as the one used in the previous protocol but employing cisplatin , 20 mg/m2/day and fluorouracil , 200 mg/m2/day , bolus , both given for five consecutive days ( CF ) instead of VBM ( 80 patients ) . A single data base was created with the patients on the two protocol s. Age at diagnosis , gender , site of the primary tumor , size of the primary , nodal involvement , performance status and treatment approach were analyzed by the multiple logistic regression model and the Cox regression method . The analyses were repeated including the treating institutions as a covariate ( coordinating center versus others ) . RESULTS The multiple logistic regression analysis indicates that treatment ( alternating more so than others , regardless of the chemotherapy regimen used ) ( P = 0.0001 ) is more likely to be associated with complete response . In addition , size of the primary tumor ( P = 0.004 ) , nodal involvement ( P = 0.02 ) and performance status ( P = 0.009 ) are prognostic variables affecting the probability of achieving a complete response . The Cox regression analysis indicates that treatment , performance status , size of the primary tumor , nodal involvement and , marginally , site of the primary tumor , are independent prognostic variables affecting the risk of death . When the radiation-alone therapy is adopted as the reference treatment , the relative risk of death is 0.58 ( 95 % confidence interval ( CI ) 0.40 - 0.84 ) for alternating CF and radiation , 0.79 ( 95 % CI 0.53 - 1.16 ) for alternating VBM and radiation and 1.30 ( 95 % CI 0.89 - 1.92 ) for sequential VBM and radiation . When the treating institution is included in the model , a 34 % increased risk of death ( P = 0.04 ) is observed for patients treated outside the coordinating center . CONCLUSION In our series of patients with advanced , unresectable SCC-HN , treatment with cisplatin and fluorouracil alternating with radiation was associated with a more favourable prognosis . The role of the treating institution in the modulation of the treatment outcomes was also relevant [1703916] Between 1983 and 1986 , the National Institute for Cancer Research in Genoa and affiliated institutions conducted a r and omized study to compare two different ways of combining chemotherapy ( CT ) and radiation therapy ( RT ) . One hundred sixteen patients were r and omized to receive neoadjuvant CT followed by definitive RT ( treatment arm A ) or alternating CT and RT . In treatment arm A , RT consisted of 70 Gy to the involved areas and 50 Gy to the uninvolved neck at 2 Gy/fraction , five fractions per week . In treatment arm B , RT consisted of 60 Gy to involved areas and 50 Gy to the uninvolved neck in three courses of 20 Gy each , 2 Gy/fraction , ten fractions/2 weeks alternated with four courses of CT . CT consisted of vinblastine 6 mg/m2 intravenously followed 6 hours later by bleomycin 30 IU intramuscularly , day 1 ; methotrexate 200 mg intravenously , day 2 ; leucovorin rescue , day 3 . CT was repeated every 2 weeks up to four courses . The same CT was used in both treatment arms of the study . Fifty‐five patients were entered in treatment arm A and 61 in treatment arm B. Complete responses were 7/48 and 19/57 in treatment arms A and B , respectively ( P < 0.03 ) . Four‐year progression‐free survival was 4 % in treatment arm A and 12 % in treatment arm B ( P < 0.02 ) , and four‐year survival was 10 % in A and 22 % in B ( P < 0.02 ) . Mucosal tolerance was significantly worse in treatment arm B ( P < 0.00004 ) . The subgroup analysis shows the major improvement of alternating CT and RT in patients with the worst prognostic characteristics [2419292] A prospect i ve , r and omized trial of induction chemotherapy in advanced squamous cell carcinomas of the upper aerodigestive tract ( UAD ) was conducted between July 1979 and September 1982 . Eighty-three patients with locally advanced Stage III-IV tumors received st and ard treatment ( STD RX ; defined as preoperative irradiation and radical excision or irradiation alone ) , or induction chemotherapy ( CTX ) followed by STD RX . Chemotherapy consisted of two cycles of bleomycin ( 30 units/day by continuous infusions Days 1 - 4 ) , cyclophosphamide ( 200 mg/m2 IV Days 1 - 5 ) , methotrexate ( 30 mg/m2 Days 1 + 5 ) , and 5-fluorouracil ( 400 mg/m2 IV Days 1 - 5 ) . Response to CTX was complete in 2 and partial ( greater than 50 % reduction ) in 27 ; the overall response rate was 68 % . Tumor clearance was documented in 30/40 STD RX patients at completion of irradiation and /or surgery and in 24/43 CTX patients ( 17/29 responders , 7/14 non-responders ) . Freedom from local-regional disease was noted at 2 years in 53 % STD RX and 35 % CTX patients ( p less than .06 ) . CTX patients had a higher proportion of local-regional persistence and recurrence . The difference was apparent only in the subset of patients treated with primary irradiation ; local-regional control following irradiation and surgery was equal in STD RX and CTX groups . Survival at 2 years was 43 % STD RX and 31 % CTX . Disease-free survival in those with clearance was 64 % STD RX and 59 % CTX . Induction chemotherapy did not improve tumor clearance or survival in this series . Caution regarding local-regional control with CTX and primary irradiation is noted [6345489] The r and omized Radiation Therapy Oncology Group ( RTOG ) Methotrexate trial in advanced squamous cancers of the head and neck has reported no control or survival benefits when the chemotherapy adjuvant was administered to patients just prior to definitive irradiation . The required data collection and outcome reporting among 146 patients bearing oral cavity primaries and 354 patients with oropharyngeal cancers has allowed a multi-variate approach seeking answers to many unresolved questions . As anticipated , the ability to control these squamous cancers is largely a function of size ( T & N stage ) with a superior clearance among T3 - 4 primaries of the oropharynx ( 66 % ) contrasted to identically staged oral cavity tumors ( 48 % ) . Adjusted median survival is more than doubled to 26.6 months or 19.8 months among oral cavity and oropharynx patients respectively , when compared to the 8 month median survival when neither primary nor cervical nodes are controlled . Lymph node deposits also impact upon survival , especially among oropharynx patients where the 17.6 month adjusted median survival among N0 patients declines to 11.0 months when the primaries are associated with N3 nodes . Surprisingly , the ability to control nodel deposits of all sizes ( N1 , N2 , or N3 ) is superior among oropharynx patients when compared with identical oral cavity metastases ( e.g. 71.4 % adjusted clearance in N3 oropharyngeal deposits versus 46.1 % in N3 nodes secondary to oral cavity primaries ) . Adjustments for maldistribution of advanced N-stages in association with T-4 primary stage eliminated an apparent T-stage effect upon nodal clearance within both anatomic regions . Finally , the association of T and N-stage upon distant metastases was investigated , with the surprising conclusion that neither initial T nor N-stage exerts any apparent influence on the observed 10 - 12 % occurrence . The interrelationship of these various prognostic variables is explored using the Cox and logistic models [3121233] Three hundred and thirteen patients with squamous cell cancer of the head and neck were entered in a r and omised clinical trial to determine whether the addition of methotrexate during the course of irradiation improved the rate of primary control and subsequent survival . The overall primary control ( P = 0.016 ) and survival ( P = 0.075 ) for the patients receiving methotrexate was better than the patients treated by radiotherapy alone . The improvement in primary control ( P = 0.0019 ) and survival ( P = 0.0089 ) in patients with oropharyngeal cancers who had methotrexate in addition to radiotherapy is statistically significant . The treatment was well tolerated and there has been no increase of late morbidity [8609658] BACKGROUND In 1992 , we reported the first analysis of a r and omized trial comparing alternating radiotherapy and chemotherapy with radiotherapy alone in the treatment of squamous cell carcinoma of the head and neck . The results of that 3-year analysis indicated that the combined treatment had superior efficacy . PURPOSE After an additional 2 years of follow-up , we again compared the efficacy of the two treatment regimens , with attention paid to differences in overall survival , progression-free survival , and locoregional relapse-free survival . METHODS One hundred fifty-seven patients with untreated , unresectable squamous cell carcinoma of the head and neck were r and omly assigned to receive either chemotherapy ( four courses of cisplatin [ 20 mg/m2 ] and fluorouracil [ 200 mg/m2 ] , given daily for 5 consecutive days during weeks 1 , 4 , 7 , and 10 ) plus radiotherapy ( three courses of 20 Gy each , given in fractions of 2 Gy per day during weeks 2 - 3 , 5 - 6 , and 8 - 9 ) or radiotherapy alone ( 70 Gy total dose , given in fractions of 2 Gy per day , 5 days per week ) . Eighty patients received the combined therapy , and 77 were treated with radiotherapy alone . Responses , failures , and toxic effects associated with the two treatment regimens were compared . Overall survival , progression-free survival , and locoregional relapse-free survival were calculated according to the Kaplan-Meier method ; the logrank test was used to compare survival parameters between the two patient groups . Reported P values are two-sided . RESULTS As reported previously , toxic effects associated with the combined therapy included both chemotherapy- and radiotherapy-related effects ; however , the incidence and severity of mucositis were nearly identical among patients in the two treatment arms . The combined treatment was associated with a statistically significant increase in the frequency of complete response ( i.e. , the disappearance of clinical ly detectable disease for at least 4 weeks ) ( 43 % for the combined-treatment group compared with 22 % for the radiotherapy-only group ; P = .037 , chi-squared test ) . Five-year estimates of overall survival in the combined-treatment group compared with the radiotherapy-only group were 24 % ( 95 % confidence interval [ CI ] = 14%-40 % ) and 10 % ( 95 % CI = 4%-24 % ) , respectively ( P = .01 , logrank test ) . The estimates of progression-free survival at 5 years in the combined-treatment group compared with the radiotherapy-only group were 21 % ( 95 % CI = 11%-37 % ) and 9 % ( 95 % CI = 3%-22 % ) , respectively ( P = .008 , logrank test ) . Finally , the 5-year estimates of locoregional relapse-free survival were 64 % ( 95 % CI = 36%-84 % ) in the combined-treatment group and 32 % ( 95 % CI = 10%-65 % ) in the radiotherapy-only group ( P = .038 , logrank test ) . CONCLUSIONS AND IMPLICATION S The superiority of alternating chemotherapy and radiotherapy over radiotherapy alone in treating unresectable squamous cell carcinoma of the head and neck seen at 3 years was confirmed at 5 years . However , additional trials must be conducted before considering the combined approach as st and ard therapy [18154124] Three regimes of combined treatment for intraoral and oropharyngeal cancer were compared . In group A , cisplatin 6 mg/m2 was given intravenously , daily ; group B--40 mg/m2 , weekly ; group C--100 mg/m2 , once in 3 weeks . All patients simultaneously received distant radiation therapy in a st and ard fractionated dose of 2 Gy per fraction , 5 times a week , up to TTD of 68 - 70 Gy . Among relatively frequent side-effects were granulocytopenia , asthenia and stomatitis . Overall immediate effectiveness was : group A--100 % , group B--96 % and group C--100 % . The rates of complete tumor resorption were : group A--27.3 % , group B--19.2 % and group C--16.7 % [3528055] There were 79 patients with squamous cell head and neck cancer r and omized to receive simultaneous or 1 hour sequential methotrexate-5 fluorouracil ( MTX--5-FU ) chemotherapy : 47 patients were previously untreated and 32 patients had recurrent disease . The treatment groups were comparable for important prognostic features . The median survival for the 47 newly presenting patients was 22 months and for recurrent disease patients was 14 months . No difference could be detected in the survival of patients who received simultaneous versus sequential chemotherapy . When only chemotherapy responders were compared , no difference in survival was detected for those who received sequential versus simultaneous therapy . Subsequently , 19 chemotherapy responders received radical radiation therapy , and 15 were rendered disease-free whereas only 4 of 17 chemotherapy nonresponders were rendered disease-free by subsequent radiation ( P = .002 ) . The survival of the 19 chemotherapy responders was 34 months compared with 16 months for the 17 chemotherapy nonresponders treated with radiation . We conclude that there is no therapeutic advantage for 1 hour sequential MTX-5 FU chemotherapy compared with simultaneous use of these drugs in squamous cell head and neck cancer . Chemotherapy responders are more likely to respond to radiation therapy [74335] The purpose of this r and omized trial was to verify some experimental and clinical data suggesting a possible potentiating effect of bleomycin when used concomitantly with radiotherapy . Out of 220 patients with a biopsy proven epidermoid carcinoma of the oropharynx , 186 evaluable cases are reported here . One group of 87 patients was treated with radiotherapy alone ( Cobalt 60 ∼ 6400 rad ∼ 7–8.5 weeks ) , the other group of 99 patients received radiotherapy combined with bleomycin , the latter administered at the dose of 15 mg i.m . twice a week for 5 weeks ( total dose : 150 mg ) . Analysis of the treatment groups showed their comparability with regard to the most important prognostic factors ( TNM , sites of primary , sex , age … ) . Complication rates of mucositis and epidermitis were significantly increased ( 71 % ) in the radiotherapy + bleomycin group and were considered responsible of frequent denutrition and weight loss in this group . Such side effects necessitated a delay of radiotherapy in 22 % of patients and definitive interruption in 5 % in the combined treatment group whereas in the radiotherapy alone group no interruption of treatment was recorded and only 5 treatments ( 6 % ) were postponed . Considering tumor regressions measured 6 weeks after completion of radiation therapy , total regression rates were not significantly different in both groups as far as primary tumor ( 67.9–67 % ) or neck nodes ( 49–62 % ) are concerned . Survival curves obtained by the actuarial method showed the same 50 % survival in both groups at 15 months of follow-up [11753959] The authors previously have found that in patients with locally advanced squamous cell carcinoma of the head and neck ( SCC‐HN ) , alternating chemoradiotherapy ( ALT ) was superior to low‐total‐dose conventional radiotherapy alone . The purpose of this r and omized trial was to compare the same chemoradiotherapy approach with high‐total‐dose partly accelerated radiotherapy [12504040] PURPOSE To prospect ively assess 5-year late toxicity in patients treated by concomitant radiochemotherapy for locally advanced oropharynx carcinoma using three different toxicity scales . METHODS AND MATERIAL S A total of 226 patients were entered in a Phase III multicenter , r and omized trial comparing radiotherapy alone ( 70 Gy in 35 fractions : Arm A ) with concomitant radiochemotherapy ( 70 Gy in 35 fractions with three cycles of a 4-day regimen containing carboplatin and 5-fluorouracil : Arm B ) . Five living patients , free of local or distant recurrences , could not be evaluated for late toxicity . Forty-four patients were eligible for late toxicity with a median follow-up of 5 years . Late toxicity was evaluated by the radiation oncologist using a large question naire containing 120 mixed items of three scales ( NCI-CTC , LENT/SOMA , and RTOG ) . The data were then transposed on separate scales using corresponding grade s. RESULTS The 5-year overall survival rate was 22 % in Arm B and 16 % in Arm A ( p = 0.05 ) . The 5-year locoregional control rate was 48 % in Arm B and 25 % in Arm A ( p = 0.002 ) . The spinal cord was not affected by the concomitant adjunct of chemotherapy , and no deaths were caused by late toxicity . Using the three late toxicity scales , 100 % of the patients treated with the combined modality ( Arm B ) developed one or more late complications vs. 94 % in the radiotherapy-alone arm ( Arm A ) . The difference was not statistically significant . The most commonly damaged organs ( all Grade 1 - 4 ) were the salivary gl and s ( 100 % in Arm B vs. 82 % in Arm A , p < 0.05 ) , skin ( 78 % vs. 47 % , p < 0.05 ) , teeth ( 67 % vs. 18 % , p < 0.05 ) , mucosa ( 59 % vs. 63 % p = not significant ) , and m and ible ( 44 % vs. 12 % , p < 0.05 ) . One or more Grade 3 - 4 complications occurred in 82 % of the patients in Arm B vs. 47 % in Arm A ( p = 0.02 ) but concerned only the teeth . The correlation between the RTOG and LENT/SOMA scale and between the NCI-CTC and LENT/SOMA scale were low for Grade 1 - 4 toxicity ( near 30 % ) . The transposability of a patient 's symptoms was significantly greater using the LENT/SOMA or RTOG/EORTC scaling systems than using the NCI-CTC system . CONCLUSION Concomitant radiochemotherapy increased overall survival and locoregional control rates . The difference between the two treatment groups for Grade 3 - 4 complications was only significant for the teeth . The late toxicity assessment of a treatment may depend on the toxicity scale used . The LENT/SOMA scale seems to be the most accurate scale , but most of the score results were not concordant with those obtained with other scales . The results of this study confirm the necessity of using a common late toxicity scale in clinical trials [12525526] PURPOSE Prognosis of patients with advanced oral cavity cancer is worth improving . Chemotherapy has been reported to be especially active in oral cavity tumors . Here we repeat the results of a r and omized , multicenter trial enrolling patients with a resectable , stage T2-T4 ( > 3 cm ) , N0-N2 , M0 untreated , squamous cell carcinoma of the oral cavity . PATIENTS AND METHODS Patients were r and omly assigned to three cycles of cisplatin and fluorouracil followed by surgery ( chemotherapy arm ) or surgery alone ( control arm ) . In both arms , postoperative radiotherapy was reserved to high-risk patients , and surgery was modulated depending on the tumor 's closeness to the m and ible . Patients ' accrual was opened in 1989 and closed in 1999 . It included 195 patients . RESULTS In the chemotherapy arm , three toxic deaths were recorded . No significant difference in overall survival was found . Five-year overall survival was , for both arms , 55 % . Postoperative radiotherapy was administered in 33 % of patients in the chemotherapy arm , versus 46 % in the control arm . A m and ible resection was performed in 52 % of patients in the control arm , versus 31 % in the chemotherapy arm . CONCLUSION The addition of primary chemotherapy to st and ard surgery was unable to improve survival . However , in this study , primary chemotherapy seemed to play a role in reducing the number of patients who needed to undergo m and ibulectomy and /or radiation therapy . Variations in the criteria used to select patients for these treatment options may make it difficult to generalize these results , but there appears to be room for using preoperative chemotherapy to spare destructive surgery or radiation therapy in patients with advanced , resectable oral cavity cancer [1283088] From March 1983 to December 1989 , 208 patients with locally advanced squamous cell carcinoma of the head and neck were successively included into two trials r and omizing induction chemotherapy versus no pre-irradiation treatment . The chemotherapy regimen of the first trial , which included 100 patients , consisted of two cycles of a combination of cisplatin , bleomycin , vindesine , mitomycin C ; while that of the second trial , which included 108 patients , consisted of three cycles of a combination cisplatin , 5-fluorouracil ( continuous infusion ) and vindesine . Local treatment was the same in two trials : ' primary ' radiotherapy in all patients . The response was then evaluated at 55 Gy ; in the case of poor response , surgery was performed , otherwise radiotherapy was continued to full doses ( possibly followed by salvage surgery ) . The tumor and lymph node responses to chemotherapy ( complete and partial response ) were higher in the second trial and in the first one : 70 % versus 50 % for primary lesions , 47 % versus 25 % for lymph nodes . The toxicity of the two chemotherapy regimens was minimal . In the two trials , an initial major response to chemotherapy predicted subsequent efficacy of irradiation in 80 % of the patients . Complete response rate at the end of irradiation correlates with the previous response to the chemotherapy . With a median follow-up of 60 months with the first chemotherapy regimen and 30 months with the second , overall survival and disease-free interval did not significantly differ in the two groups of patients , with or without chemotherapy . The incidence of distant metastasis was significantly reduced ( P < 0.03 ) in the chemotherapy arms . This negative trial encourages the design of new chemotherapy protocol s according to new schemes of treatment . For advanced stages of head and neck cancers ( T3 , T4 , N2 , N3 ) , we recently launched a pilot study combining platinum and irradiation , but according to a concomitant schedule [8176922] Patient compliance with the increasingly complex adjuvant therapy protocol s has always been of concern , particularly in the head and neck cancer population . The Head and Neck Intergroup recently concluded a phase III prospect i ve r and omized trial testing the addition of three courses of cisplatinum containing combination chemotherapy to st and ard treatment defined as surgery and postoperative radiotherapy for advanced stage III and IV squamous cell carcinoma . The chemotherapy was administered following the surgery prior to the postoperative radiotherapy . Variation from protocol is ranked retrospectively as minor acceptable , major acceptable , and major unacceptable . The incidence of major unacceptable variation from the protocol for radiotherapy immediately following the surgery was 15 % vs. 19 % in the population that completed all three courses of the chemotherapy ( P < 0.10 ) . However , for those patients that completed less than the three courses of chemotherapy , the incidence of major unacceptable variation in radiotherapy was 33 % ( P < 0.001 ) . This observation was controlled for site , stage , performance status , age , sex , surgical margins and experience of participating institution . We conclude that compliance with a multicourse adjuvant chemotherapy regimen is predictive of subsequent compliance to radiotherapy in the head and neck cancer population

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### Context: [2470310] Two hundred and forty-one patients , with advanced squamous cell carcinoma of head and neck , were r and omized to receive three courses of induction chemotherapy . The chemotherapy regimens were delivered every 3 weeks , and consisted in 1 ) cisplatin , 80 mg/m2 given alone ( CDDP regimen ) , or 2 ) in combination with vincristine , 1 mg , d 1 , methotrexate 10 mg/m2 d 1 , 2 , 3 , and bleomycin 10 mg/m2 , d 1 , 2 , and 3 ( MOB-P ) . Tolerance was significantly better with the CDDP regimen ( p less than 0.05 ) ; severe side effects , affecting mainly digestive tract , and bone marrow , were encountered in 7 % of the patients in the CDDP group , vs 15 % in the MOB-P group , without death related to pancytopenia . Short-term results were better for patients treated by the MOB-P regimen , with a 42 % response rate ( including 9 complete responses ) vs 22 % with the CDDP regimen ( p = 0.01 ) . A superiority of combination chemotherapy was more significant for primary sites than regional lymph nodes . The relapse-free survival was not statistically different in the 2 groups , as well as the 2 years overall survival . Among responders , the survival was found highly correlated with a good initial general status ( p less than 0.01 ) , and with the highest total doses of cisplatin ( p less than 0.02 ) . ( ABSTRACT TRUNCATED AT 250 WORDS [8233298] In a prospect i ve , r and omized , multicenter study , neoadjuvant chemotherapy ( CT ) with carboplatin and 5-fluorouracil ( 5-FU ) followed by locoregional treatment ( LRT ) was compared with locoregional treatment alone in the treatment of patients with head and neck cancer . This study , which includes 324 patients , was conducted from January 1988 to July 1991 . The aim of this study was to evaluate the impact of the carboplatin/5-FU regimen both on the incidence of mutilating surgery and on the survival rate . Chemotherapy consisted of three cycles of carboplatin 400 mg/m2 day 1 and 5-FU 1 g/m2 days 1 - 5 , repeated every 3 weeks . Patients with a complete tumor response then received radiotherapy alone , instead of the treatment planned initially . Three hundred patients were analyzed : 79 had tumors of the oral cavity , 106 oropharyngeal tumors , and 115 pharyngolaryngeal tumors . One hundred fifty patients underwent CT+LRT ; 150 patients had LRT alone . Grade 3 and 4 toxicity rates were minimal in the CT+LRT group ; toxicity was mainly hematologic ( 24 % neutropenia , 19 % thrombocytopenia ) . There were 3 toxic deaths ( 2 % ) , 2 due to septicemia and 1 due to cardiac toxicity . One hundred forty-three patients were evaluable for efficacy . The tumor objective response rate was 63 % and complete response rate was 31 % ( 35 % for oropharyngeal , 34 % for pharyngolaryngeal tumors , 22.5 % for oral cavity tumors ) , which led to a 29 % decrease in the rate of mutilating surgery . Conservative treatment was performed in 57 % of patients in the CT+LRT group vs. 24 % in the LRT group ( p = 0.001 ) . There was no significant difference between survival curves in the CT+LRT and LRT groups . At 4 years , overall survival rates were 56 and 46 % ; disease-free survival rates were 33 and 30 % in the CT+LRT and the LRT groups , respectively . The survival rates were not significantly different in the two groups . The locoregional recurrence rates were 35 % in the CT+LRT arm and 25 % in the LRT arm ( p = 0.04 ) , with median follow-up of 25 months . The rates of secondary localization and distant metastasis were not significantly different in the two groups [15718308] PURPOSE To report the results and corresponding acute and late reactions of a prospect i ve , r and omized , clinical study in locally advanced head and neck cancer comparing concurrent fluorouracil ( FU ) and mitomycin ( MMC ) chemotherapy and hyperfractionated accelerated radiation therapy ( C-HART ; 70.6 Gy ) to hyperfractionated accelerated radiation therapy alone ( HART ; 77.6 Gy ) . PATIENTS AND METHODS Three hundred eighty-four stage III ( 6 % ) and IV ( 94 % ) oropharyngeal ( 59.4 % ) , hypopharyngeal ( 32.3 % ) , and oral cavity ( 8.3 % ) cancer patients were r and omly assigned to receive either 30 Gy ( 2 Gy every day ) followed by 1.4 Gy bid to a total of 70.6 Gy concurrently with FU ( 600 mg/m(2 ) , 120 hours continuous infusion ) days 1 through 5 and MMC ( 10 mg/m(2 ) ) on days 5 and 36 ( C-HART ) or 14 Gy ( 2 Gy every day ) followed by 1.4 Gy bid to a total dose of 77.6 Gy ( HART ) . The data were analyzed on an intent-to-treat basis . RESULTS At 5 years , the locoregional control and overall survival rates were 49.9 % and 28.6 % for C-HART versus 37.4 % and 23.7 % for HART , respectively ( P = .001 and P = .023 , respectively ) . Progression-free and freedom from metastases rates were 29.3 % and 51.9 % for C-HART versus 26.6 % and 54.7 % for HART , respectively ( P = .009 and P = .575 , respectively ) . For C-HART , maximum acute reactions of mucositis , moist desquamation , and erythema were lower than with HART , whereas no differences in late reactions and overall rates of secondary neoplasms were observed . CONCLUSION C-HART ( 70.6 Gy ) is superior to dose-escalated HART ( 77.6 Gy ) with comparable or less acute reactions and equivalent late reactions , indicating an improvement of the therapeutic ratio [14657228] PURPOSE We report the 5-year survival and late toxicity results of a r and omized clinical trial , which showed a 3-year improvement in overall survival and locoregional control of stage III or IV oropharynx carcinoma , using concomitant radiochemotherapy ( arm B ) , compared with st and ard radiotherapy ( arm A ) . PATIENTS AND METHODS A total of 226 patients were entered onto a phase III multicenter r and omized trial comparing radiotherapy alone ( 70 Gy in 35 fractions ; arm A ) with concomitant radiochemotherapy ( 70 Gy in 35 fractions with three cycles of a 4-day regimen comprising carboplatin and fluorouracil ; arm B ) . Prognostic factors were evaluated by univariate and multivariate analysis . Five-year late toxicity was evaluated using National Cancer Institute Common Toxicity Criteria for neurological toxicity , hearing , taste , m and ibula , and teeth damage , and Radiation Therapy Oncology Group toxicity criteria for skin , salivary gl and , and mucosa . RESULTS Five-year overall survival , specific disease-free survival , and locoregional control rates were 22 % and 16 % ( log-rank P = .05 ) , 27 % and 15 % ( P = .01 ) , and 48 % and 25 % ( P = .002 ) , in arm B and arm A , respectively . Stage IV , hemoglobin level lower than 125 g/L , and st and ard treatment were independent prognostic factors of short survival and locoregional failure by univariate and multivariate analysis . One or more grade 3 to 4 complications occurred in 56 % of the patients in arm B , compared with 30 % in arm A ( P was not significant ) . CONCLUSION Concomitant radiochemotherapy improved overall survival and locoregional control rates and does not statistically increase severe late morbidity . Anemia was the most important prognostic factor for survival in both arms [2317751] Forty‐eight patients with locally confined ( MO ) squamous cell head and neck cancer were prospect ively r and omized to receive either simultaneous ( SIM ) or sequential ( SEQ ) combined technique therapy with a 5‐fluorouracil infusion , a cisplatin bolus injection , and radiation therapy . Patients with residual resectable disease underwent surgery after induction therapy , whereas those achieving a complete response to induction did not require surgery . Patients on the two treatment arms were equivalent in all measured variables , including disease extent . Toxicities of the SIM and SEQ arms also were equivalent except for mucositis and the result ant weight loss , which were more severe on the SIM arm ( P = 0.002 ) . With a follow‐up time ranging from 9 to 41 months , seven of the 24 SIM patients and 14 of the 24 SEQ patients are considered treatment failures . The relapse‐free survival is significantly better on the SIM arm ( P = 0.03 ) , although an overall survival advantage has not yet been demonstrated ( P = 0.13 ) . The achievement of a complete response after induction therapy correlates with both the relapse‐free ( P = 0.0005 ) and overall ( P = 0.05 ) survival , and the likelihood of an induction complete response also is significantly better for those treated with the SIM schedule ( P = 0.02 ) . Eighteen patients did not require surgery after achieving an induction complete response . Relapse‐free survival does not appear to be compromised in this patient subset [9739379] Purpose To assess the survival rate , the probability of local control , the patterns of relapse and late sequelae including self-reported quality of life in patients treated with hyperfractionated radiotherapy ( RT ) and simultaneous CDDP chemotherapy for stage-III to stage-IV carcinomas of the head and neck . Methods From 1988 to 1994 , 64 patients ( median age 55.5 years ) with carcinomas of different subsites , excluding the nasopharynx , were treated in a pilot study with 1.2 Gy bid ( 6 h interval ; total dose 74.4 Gy ) and simultaneous CDDP ( 20 mg/m2 daily , 5 days in week 1 and 5 ) and followed at regular intervals . Overall survival and local control , as well as the rates of late toxicity , were estimated using the actuarial method . Median follow-up was 3.3 years for all and 5.2 years for surviving patients . To assess the quality of life , the EORTC QLQ-C 30 question naire and the H&N35 module question naire were sent to the patients surviving with no evidence of disease or second primary tumors ; they were answered by 15/23 ( 67 % ) . Results Overall survival was 37 % at 5 years , whereas disease-specific survival was 59 % . Twenty-three patients died from uncontrolled head and neck cancer . Second primary tumors were observed in 13 patients , most frequently in the lung . Local control without salvage surgery was 74 % at 5 years for all subsites and stages , and loco-regional disease-free survival was 72 % . Eleven patients developed distant metastases , which was the only site of failure in 6 cases . Salvage surgery was successful in 2 cases . The actuarial estimates of ≥ grade -3 late toxicity was 4 % for the m and ibular bone and 23 % for dysphagia , and 50 % of the patients experienced a permanent xerostomy . Self-reported global quality of life in surviving patients was good ( mean 68 points on a scale 0 to 100 ) ; consequences of impaired salivary function had most impact on nutritional and social aspects . Conclusions Hyperfractionated RT with concomitant CDDP is well tolerated and highly efficient in controlling moderately advanced to advanced cancers of the head and neck . Second primary tumors are the main cause of death after 3 years and were observed outside of the irradiated area , most frequently in the lung . Even after RT of large volumes to a high dose , salvage surgery can be successfully performed in individual cases . Self-reported quality of life of surviving patients is good , despite xerostomy-associated nutritional difficulties . ZusammenfassungZielAnalyse der Überlebensrate , des krankheitsspezifischen Überlebens , des Rezidivmusters , der Spättoxizität sowie der subjektiven Lebensqualität nach hyperfraktionierter Radiotherapie ( RT ) und gleichzeitiger Cisplatin-Chemotherapie ( CDDP ) bei Patienten mit mindestens zwei Jahren Beobachtungszeit i m Rahmen einer prospektiven Phase-II-Studie . Patienten und Method eIm Rahmen einer Pilotstudie ( 1988 bis 1994 ) wurden 64 Patienten ( medianes Alter 55,5 Jahre ) mit Stadium III oder IV kombiniert beh and elt : RT 1,2 Gy zweimal täglich bis 74,4 Gy , CDDP 20 mg/m2 täglich an den Tagen 1 bis 5 der ersten und fünften Woche . Die Überlebenskurven sowie die Toxizität wurden aktuariell berechnet . Die mediane Beobachtungszeit war 3,3 Jahre für alle respektive 5,2 Jahre für die überlebenden Patienten . Zur Einschätzung der Lebensqualität wurden 23 tumorfrei überlebende Patienten angefragt , den EORTC-QLQ-C30-Fragebogen sowie das ergänzende Modul für Kopf-Hals-Tumoren H&N35 auszufüllen . ErgebnisseDas Gesamtüberleben betrug nach fünf Jahren 37 % , während das krankheitsspezifische Überleben mit 59 % deutlich höher lag . 23 Patienten sind am Tumor verstorben . Zweittumoren , hauptsächlich Lungenkarzinome ( n=8 ) , wurden bei 13 Patienten registriert und waren die hauptsächliche Todesursache nach über drei Jahren . Die lokale Tumorkontrolle ohne zusätzliche Chirurgie betrug 74 % nach fünf Jahren und war für alle Lokalisationen und Stadien gleich ; die lokoregionäre Tumorkontrollrate lag bei 64 % . Fernmetastasen ohne ein lokoregionäres Therapieversagen wurden bei sechs Patienten gesehen . Eine „ Rettungschirurgie ” wurde in zwei Fällen erfolgreich durchgeführt . Die aktuarielle Spätkomplikationsrate ≥ Grad 3 betrug 4 % für den Kieferknochen und 23 % für Dysphagie ; 50 % der Patienten hatten eine bleibende komplette Xerostomie . Die globale Lebensqualität war gut ( i m Mittel 68 Punkte auf einer Skala von 0 bis 100 ) . Folgen der gestörten Speichelsekretion hatten die größte Auswirkung auf die funktionelle Behinderung der Ernährung sowie der sozialen Kontakte . SchlußfolgerungenDie hyperfraktionierte RT mit gleichzeitiger CDDP-Gabe wird hinsichtlich Spättoxizität gut toleriert und ist effizient zur Beh and lung fortgeschrittener Kopf-Hals-Tumoren . I m Gegensatz zu chirurgischen Serien treten Zweitkarzinome praktisch nur außerhalb des ursprünglichen Tumorbereichs auf . Eine „ Rettungschirurgie ” nach initialem Therapieversagen ist auch nach RT mit 74,4 Gy in Einzelfällen erfolgreich . Die selbstrapportierte Lebensqualität bei den Langzeitüberlebenden ist generell gut trotz gewisser , vorwiegend xerostomiebedingter Einschränkungen [11054514] BACKGROUND AND PURPOSE Radiation therapy is often the primary treatment for advanced cases of head and neck cancers not considered suitable for radical surgery . In these cases locoregional tumour control rates are low and has warranted innovative treatment modifications , such as altered fractionation schedules and combination with chemotherapy . PATIENTS AND METHODS From October 1990 to December 1997 , 239 patients with squamous cell cancers originating in the head and neck region were r and omized to one of three treatment options . St and ard therapy consisting of conventional fractionation with 70 Gy in 7 weeks in 35 fractions ( CF ) . The second treatment option consisted of a continuous hyperfractionated accelerated radiotherapy delivering a total dose of 55.3 Gy in 33 fractions over 17 consecutive days ( V-CHART ) . The third study arm had identical fractionation and dose as the above accelerated treatment , with the additional administration of 20 mg/m(2 ) mitomycin C ( MMC ) on day 5 of treatment ( V-CHART+MMC ) . RESULTS Main toxicity result ed from accelerated fractionation in confluent mucositis ( Grade 3 - 4 in 95 % ) requiring nasogastral tube feeding , analgetics and antiphlogistics in the majority of cases . Haematological toxicity Grade 3 - 4 was seen after MMC administration in 18 % . MMC administration did not influence mucosal reaction . Overall duration of mucositis was not different in the three treatment groups . Loco-regional tumour control was 31 % after CF , 32 % after V-CHART and 48 % after V-CHART+MMC , respectively ( P<0.05 ) . Overall crude survival was 24 % after CF , 31 % following V-CHART and 41 % after V-CHART+MMC , respectively ( P<0.05 ) . Median follow up was 48 months ( assessment performed in February 1999 ) . CONCLUSION Following shortening overall treatment time from 7 weeks to 17 consecutive days and dose of radiotherapy from 70 to 55.3 Gy the results in the radiotherapy only treated patients are identical . A significant improvement regarding local tumour control and survival was seen following administration of MMC to the accelerated fractionated treatment [2650723] From March 1983 to June 1986 , 100 patients with locally advanced squamous cell carcinoma of the head and neck were r and omized to receive either two courses of chemotherapy prior to local therapy ( group A ) , or local therapy alone ( group B ) . Local treatment consisted of primary radiotherapy in all patients . When a poor response was observed after 55 Gy , surgery was performed . The chemotherapy regimen was a combination of cisplatinum , bleomycin , vindesine , and mitomycin C. The response rate to induction chemotherapy ( group A ) was 50 % for the primary tumor ( CR : 10 % and PR : 40 % ) . At the end of radiotherapy , the overall tumor response rates in the two groups A and B , were 77 % and 79 % respectively . Complete disappearance of the primary tumor occurred more often than that of the lymph node metastases . The response rate to induction chemotherapy for lymph node metastases was 27.1 % ( CR : 9 % and PR : 18.1 % ) . An initial major response to chemotherapy predicted subsequent efficacy of irradiation on 90 % of the cases , while a failure of chemotherapy had no predictive value in this respect . The survival rates in groups A and B were 66.5 % vs. 65.1 % at 1 year and 35 % vs. 46.2 % at 2 years . Local disease-free and disease-free intervals were similar in both groups . A Cox 's multi-step regression analysis revealed two significant independant prognostic factors : size of primary tumor and nodal status . After adjustment for these factors , the chemotherapy did not seem to improve the effectiveness of the local treatment in terms of loco-regional control and survival [1378641] From January 1981 through December 1983 , 49 untreated patients with locally advanced head and neck cancers were r and omized in two groups to receive different radiochemotherapy regimens . Group A , including 29 cases , received 4 cycles of induction chemotherapy with Bleomycin , Methotrexate and Hydroxyurea before definitive external radiotherapy ( 60 Gy ) ; group B , including 20 patients , received the same total dose of radiotherapy but the 4 cycles of chemotherapy , as described above , were administered between the 20- and the 40-Gy doses . Both groups were compared with a control group treated in the same period with radiotherapy ( 60 Gy ) alone . The response to treatment was evaluated at the end of chemotherapy or radiotherapy alone and at the end of combined regimens . Long-term survival rates were analyzed for all groups relative to complete tumor response , disease-free interval and time to disease progression . In our experience the radio-chemotherapy combination , according to the described schedules , failed to improve both local control and overall survival ; the comparison with the control group does not suggest that induction or intercalated chemotherapy can increase long-term survival even if initial complete and partial response rates are high [1376306] Between December 1982 and October 1986 , 131 patients with stage II‐III‐IV squamous cell carcinoma of the oropharynx or oral cavity were r and omized to induction chemotherapy , consisting of bleomycin ( 10 mg/m2/day in continuous infusion from day 1 to day 5 ) , methotrexate ( 120 mg/m2 on day 2 ) followed by folinic acid , 5‐fluorouracil ( 5 FU ) ( 600 mg/m2 on day 2 ) , and cisplatin ( 120 mg/m2 on day 4 ) every 4 weeks for a total of three cycles followed by definitive locoregional treatment versus locoregional treatment alone . The modalities of definitive treatment ( radiotherapy ± surgery ) were chosen prior to r and omization . A total of 116 patients were evaluable . Of 55 patients in the chemotherapy arm , four ( 7 % ) had a complete response ( CR ) and 23 ( 42 % ) a partial response ( PR ) following the induction regimen . At the completion of locoregional treatment , 76 % ( 42 of 55 ) of patients in the experimental group were in CR compared to 89 % ( 54 of 61 ) in the control group . There was no difference in survival , cause‐specific survival , and pattern of relapse between both groups . The median survival was 22 months in the chemotherapy group and 29 months in the control group . Responders to chemotherapy did not fare better than nonresponders . Chemotherapy‐related toxicities were few and most of them related to cisplatin which was reduced to 100 mg/m2 for 35 patients . There were no treatment‐related deaths and , in the experimental arm of the trial , no increased morbidity from locoregional treatment . This induction regimen does not offer any advantages over st and ard treatment [15128894] BACKGROUND We compared concomitant cisplatin and irradiation with radiotherapy alone as adjuvant treatment for stage III or IV head and neck cancer . METHODS After undergoing surgery with curative intent , 167 patients were r and omly assigned to receive radiotherapy alone ( 66 Gy over a period of 6 1/2 weeks ) and 167 to receive the same radiotherapy regimen combined with 100 mg of cisplatin per square meter of body-surface area on days 1 , 22 , and 43 of the radiotherapy regimen . RESULTS After a median follow-up of 60 months , the rate of progression-free survival was significantly higher in the combined-therapy group than in the group given radiotherapy alone ( P=0.04 by the log-rank test ; hazard ratio for disease progression , 0.75 ; 95 percent confidence interval , 0.56 to 0.99 ) , with 5-year Kaplan-Meier estimates of progression-free survival of 47 percent and 36 percent , respectively . The overall survival rate was also significantly higher in the combined-therapy group than in the radiotherapy group ( P=0.02 by the log-rank test ; hazard ratio for death , 0.70 ; 95 percent confidence interval , 0.52 to 0.95 ) , with five-year Kaplan-Meier estimates of overall survival of 53 percent and 40 percent , respectively . The cumulative incidence of local or regional relapses was significantly lower in the combined-therapy group ( P=0.007 ) . The estimated five-year cumulative incidence of local or regional relapses ( considering death from other causes as a competing risk ) was 31 percent after radiotherapy and 18 percent after combined therapy . Severe ( grade 3 or higher ) adverse effects were more frequent after combined therapy ( 41 percent ) than after radiotherapy ( 21 percent , P=0.001 ) ; the types of severe mucosal adverse effects were similar in the two groups , as was the incidence of late adverse effects . CONCLUSIONS Postoperative concurrent administration of high-dose cisplatin with radiotherapy is more efficacious than radiotherapy alone in patients with locally advanced head and neck cancer and does not cause an undue number of late complications [19357741] BACKGROUND Management of advanced head and neck carcinoma is a challenging proposition . Presently concomitant chemo-irradiation has become the st and ard of care in such patients . Many chemotherapeutic drugs have shown radio-sensitising effects when used concomitantly along with radiation . The present study was carried out with the objective of assessing the feasibility and efficacy of low dose gemcitabine as radiosensitizer when used during radical radiotherapeutic management of patients with locally advanced head and neck carcinomas . PATIENTS AND METHODS From November 2000 to March 2003 , eighty histopathologically proven cases of squamous cell head and neck carcinoma were included in this trial , 40 patients were r and omly assigned to receive radiotherapy alone and 40 patients to receive gemcitabine along with radiotherapy . RESULTS All patients were assessable for toxicity and response . Severe mucositis ( WHO level 5 reactions were observed in 67 % patients in the CT/RT group vs 16 % patients in the RT only group . No severe hematological toxicity was seen . The rates of complete and partial responses were 42.5 % & 57.5 % respectively for RT only and 62.5 % & 37.5 % , respectively for CT/RT group . There was no significant difference in the response rates at the end of treatment but disease free survival at three years was better in the CT/RT group ( 63.3 % vs 20 % ) . Nine of the 17 patients with complete response in the radiation only group developed relapse while no relapses were seen in CT/RT group . CONCLUSION In the present study the combination of gemcitabine and radiotherapy has not shown any statistical difference in locoregional control but survival advantage was seen as compared to radiotherapy alone . At the same time more mucosal and skin toxicity was encountered when Gemcitabine is given concurrently with radiation [10601378] BACKGROUND We design ed a r and omized clinical trial to test whether the addition of three cycles of chemotherapy during st and ard radiation therapy would improve disease-free survival in patients with stages III and IV ( i.e. , advanced oropharynx carcinoma ) . METHODS A total of 226 patients have been entered in a phase III multicenter , r and omized trial comparing radiotherapy alone ( arm A ) with radiotherapy with concomitant chemotherapy ( arm B ) . Radiotherapy was identical in the two arms , delivering , with conventional fractionation , 70 Gy in 35 fractions . In arm B , patients received during the period of radiotherapy three cycles of a 4-day regimen containing carboplatin ( 70 mg/m(2 ) per day ) and 5-fluorouracil ( 600 mg/m(2 ) per day ) by continuous infusion . The two arms were equally balanced with regard to age , sex , stage , performance status , histology , and primary tumor site . RESULTS Radiotherapy compliance was similar in the two arms with respect to total dose , treatment duration , and treatment interruption . The rate of grade s 3 and 4 mucositis was statistically significantly higher in arm B ( 71 % ; 95 % confidence interval [ CI ] = 54%-85 % ) than in arm A ( 39 % ; 95 % CI = 29%-56 % ) . Skin toxicity was not different between the two arms . Hematologic toxicity was higher in arm B as measured by neutrophil count and hemoglobin level . Three-year overall actuarial survival and disease-free survival rates were , respectively , 51 % ( 95 % CI = 39%-68 % ) versus 31 % ( 95 % CI = 18%-49 % ) and 42 % ( 95 % CI = 30%-57 % ) versus 20 % ( 95 % CI = 10%-33 % ) for patients treated with combined modality versus radiation therapy alone ( P = .02 and .04 , respectively ) . The locoregional control rate was improved in arm B ( 66 % ; 95 % CI = 51%-78 % ) versus arm A ( 42 % ; 95 % CI = 31%-56 % ) . CONCLUSION The statistically significant improvement in overall survival that was obtained supports the use of concomitant chemotherapy as an adjunct to radiotherapy in the management of carcinoma of the oropharynx [9632446] BACKGROUND Radiotherapy is often the primary treatment for advanced head and neck cancer , but the rates of locoregional recurrence are high and survival is poor . We investigated whether hyperfractionated irradiation plus concurrent chemotherapy ( combined treatment ) is superior to hyperfractionated irradiation alone . METHODS Patients with advanced head and neck cancer who were treated only with hyperfractionated irradiation received 125 cGy twice daily , for a total of 7500 cGy . Patients in the combined-treatment group received 125 cGy twice daily , for a total of 7000 cGy , and five days of treatment with 12 mg of cisplatin per square meter of body-surface area per day and 600 mg of fluorouracil per square meter per day during weeks 1 and 6 of irradiation . Two cycles of cisplatin and fluorouracil were given to most patients after the completion of radiotherapy . RESULTS Of 122 patients who underwent r and omization , 116 were included in the analysis . Most patients in both treatment groups had unresectable disease . The median follow-up was 41 months ( range , 19 to 86 ) . At three years the rate of overall survival was 55 percent in the combined-therapy group and 34 percent in the hyperfractionation group ( P=0.07 ) . The relapse-free survival rate was higher in the combined-treatment group ( 61 percent vs. 41 percent , P=0.08 ) . The rate of locoregional control of disease at three years was 70 percent in the combined-treatment group and 44 percent in the hyperfractionation group ( P=0.01 ) . Confluent mucositis developed in 77 percent and 75 percent of the two groups , respectively . Severe complications occurred in three patients in the hyperfractionation group and five patients in the combined-treatment group . CONCLUSIONS Combined treatment for advanced head and neck cancer is more efficacious and not more toxic than hyperfractionated irradiation alone [1612948] From March 1983 to December 1989 , 208 patients with locally advanced squamous cell carcinoma of the head and neck were successively included into two r and omized induction chemotherapy trials . The chemotherapy regimen of the first trial , which included 100 patients , consisted of two cycles of a combination of cisplatin , bleomycin , vindesine and mitomycin C ; while that of the second trial , which included 108 patients , consisted of three cycles of a combination cisplatin , 5-fluorouracil by continuous infusion and vindesine . Local treatment was the same in the two trials : primary radiotherapy in all patients . The response was then evaluated ; in the case of a poor response at 55 Grays surgery was performed ; otherwise , radiotherapy was continued to full doses ( possibly followed by salvage surgery ) . The tumor and lymph node responses to chemotherapy ( complete and partial response ) were higher in the second trial than in the first : 70 % versus 50 % for primary lesions , 47 % versus 25 % for lymph nodes . The toxicity of the two chemotherapy regimens was minimal . In the two trials , an initial major response to chemotherapy predicted subsequent efficacy of irradiation in 80 % of the patients . The significance of the complete response at the end of the irradiation varies with the previous response to the chemotherapy . With a median follow-up of 60 months with the first chemotherapy regimen and 30 months with the second , overall survival and disease-free interval were very similar in the two groups . The incidence of distant metastasis was significantly reduced ( p less than 0.03 ) with chemotherapy . This trial suggests the need to test new chemotherapy protocol s according to new schemes of treatment , with chemotherapy given concurrently with or following the completion of st and ard treatment by means of multicenter r and omized trials [2451954] Two hundred and nine patients , with locoregional or metastatic recurrences of head and neck epidermoid carcinoma , were r and omized to receive a palliative chemotherapy . The chemotherapy regimens were delivered every 3 weeks , and consisted in ( 1 ) cisplatin , 80 mg/m2 given alone ( CDDP regimen ) , or ( 2 ) in combination with vincristine , 1 mg , methotrexate 10 mg/m2 d 1 , 2 , 3 , and bleomycin 10 mg/m2 , d 1 , 2 and 3 ( 1040 regimen ) . Short-term results were better for patients treated by the 1040 regimen , with a 30 % response rate ( including 4 complete responses ) vs 15 % with the CDDP regimen ( P = 0.01 ) . A superiority of combination chemotherapy was found for all tumoral sites , but was particularly significant for pulmonary and cutaneous metastases , in previously un irradiated areas ( P = 0.001 ) . Tolerance was significantly better with the CDDP regimen ( P = 0.001 ) ; severe side effects , affecting mainly general status , digestive tract and bone marrow were encountered in 5 % of the patients in the CDDP group , vs 21 % in the 1040 group , with one death related to pancytopenia . The median duration of remissions was not statistically different in the 2 groups , as well as the 2 years overall survival . Among responders , the survival was slightly better in those treated with CDDP alone ; moreover , the quality of long term results was found highly correlated with a good initial general status , and with low levels of side effects . Those results confirm recent data of the literature , and lead to the following conclusions : ( 1 ) combination chemotherapy with CDDP give a better response rate than CDDP alone , ( 2 ) response rate does n't influence overall duration of survival , ( 3 ) tolerance to treatment is crucial to preserve quality of life , and thus , ( 4 ) palliative chemotherapy in head and neck cancer should be efficient but also as short of intensity as possible [9845100] PURPOSE To evaluate the effect of mitomycin C to an accelerated hyperfractionated radiation therapy . The aim was to test a very short schedule with/without mitomycin C ( MMC ) with conventional fractionation in histologically verified squamous cell carcinoma of the head and neck region . METHODS AND MATERIAL S From October 1990 to December 1996 , 188 patients entered the trial . Tumors originated in the oral cavity in 54 , oropharynx in 82 , larynx in 20 , and hypopharynx in 32 cases , respectively . Patients ' stages were predominantly T3 and T4 ( 158/188 , 84 % ) and most patients had lymph node metastases ( 144/188 , 77 % ) at diagnosis . Only 22 patients were female , 166 were male , the median age of patients was 57 years ( range 34 to 76 years ) . Patients were r and omized to one of the following three treatment options : conventional fractionation ( CF ) consisting of 70 Gy in 35 fractions over 7 weeks ( 65 patients ) or continuous hyperfractionated accelerated radiation therapy ( V-CHART ; 62 patients ) or continuous hyperfractionated accelerated radiation therapy with 20 mg/sqm MMC on day 5 ( V-CHART + MMC ; 61 patients ) . By the accelerated regimens , the total dose of 55.3 Gy was delivered within 17 consecutive days , by 33 fractions . On day 1 , a single dose of 2.5 Gy was given , from day 2 to 17 a dose of 1.65 Gy was delivered twice : the interfraction interval was 6 hours or more . RESULTS Mucositis was very intense after accelerated therapy , most patients experiencing a grade III/IV reaction . The mucosal reaction did not differ whether MMC was administered or not . Patients treated by accelerated fractionation experienced a confluent mucosal reaction 12 - 14 days following start of therapy and recovered ( no reaction ) within 6 weeks . The skin reaction was not considered different in the three treatment groups . Those patients treated with additional chemotherapy experienced a grade III/IV hematologic toxicity in 12/61 patients . Initial complete response ( CR ) was recorded in 43 % following CF , 58 % after V-CHART , and 67 % after V-CHART + MMC , respectively ( p < 0.05 ) . Actuarial survival ( Kaplan-Meier ) was significantly improved in the combined treated patients . Local tumor control was 28 % , 32 % , and 56 % following CF , V-CHART , and V-CHART + MMC , respectively ( p < 0.05 ) . CONCLUSION We conclude that our continuous hyperfractionated accelerated radiation therapy regimen is equal to conventional fractionation , suggesting that by shortening the overall treatment time from 7 weeks to 17 days a reduction in dose from 70 Gy to 55.3 Gy is possible , with maintenance of local tumor control rates . The administration of MMC to the accelerated regimen is tolerable and improves the outcome for patients significantly [17724671] Men are approximately 3 times more likely to develop squamous cancers of the head and neck ( oral cavity , pharynx , and larynx ) than women . Very few prospect i ve studies have examined the association between cigarette smoking and cancers of the head and neck in women , even though the rates of smoking in women are increasing rapidly worldwide [12758236] BACKGROUND AND PURPOSE Single agent mitomycin c ( MMC ) has been shown to improve the outcome of radiotherapy in single institution trials . In order to confirm these findings in a broader worldwide setting , the International Atomic Energy Agency ( IAEA ) initiated a multicentre trial r and omising between radiotherapy alone versus radiotherapy plus MMC . MATERIAL AND METHODS Patients with advanced head and neck cancer were treated with primary curative radiotherapy ( 66 Gy in 33 fractions with five fractions per week ) + /-a single injection ( 15 mg/m(2 ) ) of MMC at the end of the first week of radiotherapy . Stratification parameters were tumour localization , T-stage , N-stage , and institution . A total of 558 patients were recruited in the trial from February 1996 to December 1999 . Insufficient accrual and reporting led to the exclusion of three centres . The final study population consisted of 478 patients from seven centres . Patients had stage III ( n=223 ) or stage IV ( n=255 ) squamous cell carcinoma of the oral cavity ( n=230 ) , oropharynx ( n=140 ) , hypopharynx ( n=65 ) or larynx ( n=43 ) . Prognostic factors like age , gender , site , size , differentiation and stage were well balanced between the two arms . RESULTS The haematological side effects of MMC were very modest ( < 5 % grade 3 - 4 ) and did not require any specific interventions . Furthermore , MMC did not enhance the incidence or severity of acute and late radiation side effects . Confluent mucositis and dry skin desquamation was common , occurring in 56 % and 62 % of patients , respectively . The overall 3-year primary locoregional tumour control , disease-specific and overall survival rates were 19 , 36 and 30 % , respectively . Gender , haemoglobin drop , tumour site , tumour and nodal stage were significant parameters for loco-regional tumour control . There was no significant effect of MMC on locoregional control or survival , except for the 161 N0 patients , where MMC result ed in a better loco-regional control ( 3-year estimate 16 % vs. 29 % , P=0.01 ) . CONCLUSIONS The study did not show any major influence of MMC on loco-regional tumour control , survival or morbidity after primary radiotherapy in stage III-IV head and neck cancer except in N0 patients where loco-regional control was significantly improved [2363468] The objective of the study was to evaluate the effect of neoadjuvant chemotherapy on the survival of patients with oropharyngeal cancer . Patients with a squamous cell carcinoma of the oropharynx for whom curative radiotherapy or surgery was considered feasible were entered in a multicentric r and omized trial comparing neoadjuvant chemotherapy followed by loco-regional treatment to the same loco-regional treatment without chemotherapy . The loco-regional treatment consisted either of surgery plus radiotherapy or of radiotherapy alone . Three cycles of chemotherapy consisting of Cisplatin ( 100 mg/m2 ) on day 1 followed by a 24-hour i.v . infusion of fluorouracil ( 1000 mg/m2/day ) for 5 days were delivered every 21 days . 2–3 weeks after the end of chemotherapy , local treatment was performed . The trial was conducted by the Groupe d'Etude des Tumeurs de la Tête Et du Cou ( GETTEC ) . A total of 318 patients were enrolled in the study between 1986 and 1992 . Overall survival was significantly better ( P = 0.03 ) in the neoadjuvant chemotherapy group than in the control group , with a median survival of 5.1 years versus 3.3 years in the no chemotherapy group . The effect of neoadjuvant chemotherapy on event-free survival was smaller and of borderline significance ( P = 0.11 ) . Stratification of the results on the type of local treatment , surgery plus radiotherapy or radiotherapy alone , did not reveal any heterogeneity in the effect of chemotherapy . © 2000 Cancer Research Campaign [7751897] PURPOSE A r and omized trial was design ed to compare cisplatin ( CDDP ) and fluorouracil ( FU ) versus carboplatin ( CBDCA ) and FU as neoadjuvant treatment in stage IV-M0 head and neck cancer to assess whether CBDCA-FU is better than CDDP-FU with regard to response and toxicity . PATIENTS AND METHODS Patients were r and omized to receive CDDP 100 mg/m2 intravenously on day 1 and FU 5,000 mg/m2 over a 120-hour continuous infusion , or CBDCA 400 mg/m2 over a 24-hour continuous infusion on day 1 and FU with the same schedule . Both regimens were repeated every 21 days . The patients received three courses of chemotherapy , excluding those who failed to achieve a partial response ( PR ) after the second course . Complete responders were treated with radiotherapy . The remaining patients underwent surgery if the tumor was resectable . RESULTS Interim analysis was performed when 95 patients were included . The trial was stopped due to significantly better results in the control arm . Differences in response ( P = .04 ) were favorable to CDDP-FU . Hematologic toxicity predominated in the CBDCA-FU arm ( P < .001 ) . Mucositis and vomiting predominated in the CDDP-FU arm ( P = .03 , P < .001 , respectively ) . Favorable outcomes ( complete response [ CR ] plus any grade of toxicity and PR plus grade 0 to 3 toxicity ) predominated in the CDDP-FU arm ( P = .02 ) . Only the treatment assigned was associated with response ( P = .02 ) and favorable outcomes ( P = .009 ) in the logistic regression analysis . In the CDDP-FU arm , disease-free and overall survival were significantly better . Cox regression analysis showed that only treatment association with disease-free survival remains significant . CONCLUSION Our results indicate that CDDP-FU is more effective than CBDCA-FU as neoadjuvant treatment in stage IV-M0 head and neck cancer [3307601] 136 patients with previously untreated stage III or IV squamous cell carcinoma of the head and neck entered a prospect i ve r and omized trial to compare the efficacy and toxicity of DDP vs DDP-VP 16 213 ( Etoposide ) . 69 patients ( group A ) were given three courses of DDP 100 mg/m2 administered on day 1 , while 67 patients ( group B ) were given three courses of a combination of Etoposide 100 mg/m2 per os administered on days 1 to 5 and DDP 100 mg/m2 on day 4 . Objective response rate appeared to be low in both groups : in group A ( 60 evaluated patients ) CR = 1 , PR = 9 ; CR + PR = 14.5 % , and in group B ( 57 evaluated patients ) CR = 3 , PR = 8 ; CR + PR = 16.4 % ( p greater than 0.4 ) . One drug-related death occurred in each group . There was no difference in toxicity between the two treatments with regard to leukopenia , thrombopenia , vomiting and nephrotoxicity . Thus this schedule of oral Etoposide does not seem to increase either the efficacy or the toxicity of DDP [8487051] PURPOSE The purpose of this study was to develop and vali date an instrument for clinical trials to measure radiation-related acute morbidity and quality of life from the perspective of patients with head and neck cancer ( HNC ) treated with radiotherapy . METHODS The Head and Neck Radiotherapy Question naire ( HNRQ ) was developed by a panel of health care workers and patients , was pretested in a pilot study of HNC patients , and was vali date d in a r and omized double-blind trial of concomitant fluorouracil ( FUra ) infusional therapy ( 1.2 g/m2 per 24 hours ) or saline placebo administered for 72 hours in the first and third weeks of a 6 1/2-week course of radiation therapy . The HNRQ was vali date d against existing toxicity and performance status indices , all of which were measured weekly for the 6 1/2 weeks of treatment and for 4 weeks posttreatment . RESULTS There were three a priori constructs : ( 1 ) that the HNRQ scores would conform to a shallow U-shaped pattern to reflect declining quality of life ( increasing morbidity ) during radiation and recovery posttreatment ; ( 2 ) that the HNRQ would correlate with existing toxicity indices ( World Health Organization [ WHO ] stomatitis , Byfield stomatitis , WHO skin toxicity , Eastern Cooperative Oncology Group [ ECOG ] and Karnofsky performance status ) ; and ( 3 ) that the HNRQ would discriminate between FUra and placebo groups . The HNRQ and its domain scores all showed a change from baseline reflecting increased morbidity during radiation ( analysis of variance [ ANOVA ] , P < .00001 ) . The HNRQ correlated well with all other indices ( r > or = .60 ) , and domain scores correlated best with other indices that assess the same symptom complex ( eg , HNRQ skin domain and WHO skin toxicity index , r = .77 ) . There was a significant difference in HNRQ scores between the FUra and placebo groups during radiation ( ANOVA , P = .0007 ) , and all HNRQ domains also discriminated between the treatment groups . CONCLUSION The HNRQ is a valid measure of acute morbidity due to radiation therapy in patients with locally advanced HNC , and may be useful as an outcome measure for future clinical trials of radiation treatment strategies [2451135] This trial of treatment for head and neck carcinoma was initiated in 1973 by the European Organization for Research and Treatment of Cancer . Its purpose was to investigate the value of single-agent chemotherapy with bleomycin ( BLM ) given during the course of a conventional treatment by external radiotherapy ( RT ) compared to treatment by external RT alone . In this r and omized study , we compared treatment results in 2 groups of patients with squamous cell carcinoma of the oropharynx ( T2 , T3 , and T4 ; International Union Against Cancer classification ) . One group of 92 patients was treated by RT at the prescribed dose of 70 Gy . The other group of 107 patients received radiation according to the same protocol and simultaneously received i m injection of BLM at a dose of 15 mg twice a week , 2 hours prior to the session of RT , for a total dose of 150 mg in 5 weeks . The occurrence of local toxic effects ( i.e. , mucositis and epidermatitis ) was significantly greater in the RT-BLM group ( RT-BLM , 72 % , vs. RT , 21 % ) . Primary tumor response 6 weeks after completion of RT was the same in both arms of the study ( RT , 68 % , vs. RT-BLM , 67 % ) . The 6-year survival rate was 24 % ( RT-BLM ) versus 22 % ( RT ) . Long-term analysis ( 10 yr ) is given [11735172] AIMS A prospect i ve r and omized study was conducted to evaluate the benefit of adjuvant levamisole/UFT ( futraful and uracil ) chemotherapy in head and neck squamous cell carcinoma . METHODS Sixty-five patients with stage III and IV squamous cell carcinomas of oral cavity , oropharynx , hypopharynx and larynx with no distant metastasis were r and omized for the chemotherapy study . Thirty-one patients were r and omized for chemotherapy and two of them were subsequently excluded . In this study , a total of 29 patients on levamisole/UFT therapy and 34 patients on the control group were analysed . The main outcome was measured by the 5-year disease-free actuarial survival rate . RESULTS The rates of distant metastasis were 10 % for chemotherapy group and 32 % for control group ( P=0.06 ) . The 5-year disease-free actuarial survival rates for patients with and without adjuvant chemotherapy were 57 % and 39 % respectively ( P=0.207 ) . CONCLUSIONS A trend of better distant control in head and neck cancer patients with post-operative adjuvant oral chemotherapy was observed . The side effects were minimal . However , there was no statistically significant improvement in the overall long-term survival . It may be of value to conduct a large-scale multi-centre prospect i ve r and omized study to verify the efficacy of levamisole and UFT as post-operative adjuvant chemotherapy for the control of distant metastasis in high-risk population [11082723] The aim of the study was to test whether the addition of three cycles of chemotherapy during st and ard radiation therapy would improve disease-free survival in patients with stages III and IV oropharynx carcinoma . A total of 226 patients have been entered in a phase III multicentric r and omized trial comparing radiotherapy alone ( arm A ) to radiotherapy with concomitant chemotherapy ( arm B ) . Radiotherapy was identical in the two arms , delivering , with conventional fractionation , 70 Gy in 35 fractions . In arm B patients received simultaneously 3 cycles of a four-day regimen containing carboplatin ( 70 mg/m2/d ) and 5 fluorouracil ( 600 mg/m2/d ) continuous infusion . The two arms were equally balanced regarding to age , gender , stage , performance status , histology , and primary tumor site . Radiotherapy compliance was similar in the two arms regarding to total dose , treatment duration and treatment interruption . Grade 3 and 4 mucositis rate was significantly higher in arm B ( 67 % versus 36 % ) . Skin toxicity was not different . Haematologic toxicity was higher in arm B on neutrophil count and hemoglobin level . Three-year overall actuarial survival and disease-free survival rates were respectively 51 % versus 31 % and 42 % versus 20 % for patients treated with combined modality versus radiation alone ( p = 0.022 and 0.043 ) . Local and regional control rate has been improved in arm B ( 66 % versus 42 % ) . The statistically significant improvement in overall survival obtained support the use of concomitant chemotherapy as an adjunct to radiotherapy in the management of carcinoma of the oropharynx [12506176] PURPOSE The Head and Neck Intergroup conducted a phase III r and omized trial to test the benefit of adding chemotherapy to radiation in patients with unresectable squamous cell head and neck cancer . PATIENTS AND METHODS Eligible patients were r and omly assigned between arm A ( the control ) , single daily fractionated radiation ( 70 Gy at 2 Gy/d ) ; arm B , identical radiation therapy with concurrent bolus cisplatin , given on days 1 , 22 , and 43 ; and arm C , a split course of single daily fractionated radiation and three cycles of concurrent infusional fluorouracil and bolus cisplatin chemotherapy , 30 Gy given with the first cycle and 30 to 40 Gy given with the third cycle . Surgical resection was encouraged if possible after the second chemotherapy cycle on arm C and , if necessary , as salvage therapy on all three treatment arms . Survival data were compared between each experimental arm and the control arm using a one-sided log-rank test . RESULTS Between 1992 and 1999 , 295 patients were entered on this trial . This did not meet the accrual goal of 362 patients and result ed in premature study closure . Grade 3 or worse toxicity occurred in 52 % of patients enrolled in arm A , compared with 89 % enrolled in arm B ( P < .0001 ) and 77 % enrolled in arm C ( P < .001 ) . With a median follow-up of 41 months , the 3-year projected overall survival for patients enrolled in arm A is 23 % , compared with 37 % for arm B ( P = .014 ) and 27 % for arm C ( P = not significant ) . CONCLUSION The addition of concurrent high-dose , single-agent cisplatin to conventional single daily fractionated radiation significantly improves survival , although it also increases toxicity . The loss of efficacy result ing from split-course radiation was not offset by either multiagent chemotherapy or the possibility of midcourse surgery [2451713] A cooperative r and omized study was begun in August 1983 to compare a sequential program of induction chemotherapy followed by definitive treatment , arm A , with an alternation of chemotherapy and radiotherapy ( three courses of 20 Gy in ten daily fractions ) , arm B. The same chemotherapy was used in both arms : 6 mg/m2 , vinblastine , hour 0 ; 30 mg , bleomycin , hour 6 ; 200 mg , methotrexate , hours 24 to 26 ; 45 mg , leucovorin , hour 48 . One hundred sixteen patients entered the study , 55 in arm A and 61 in arm B. The patients all had previously untreated squamous cell carcinoma of the head and neck ( SCCHN ) . Forty-five patients had stage III and 71 had stage IV disease . The two arms were fully comparable . As of April 1986 , 116 patients were evaluable for survival , while 112 were evaluable for toxicity and 105 for response . Response analysis shows that there were 14 complete responses ( CR ) and 11 partial responses ( PR ) , for an overall response rate ( ORR ) of 52 % in arm A , and 30 CRs and seven PRs , for an ORR of 64.9 % in arm B. The difference in terms of CR between the two arms was statistically significant ( P less than .03 ) . Progression-free survival ( PFS ) was also statistically different , with an advantage for arm B ( P less than .05 ) , but without differences in overall survival . Arm B correlates with a significant increase in mucositis compared with arm A ( P less than .001 ) [10802364] PURPOSE To determine whether any difference in toxicity or efficacy occurs when head and neck cancer patients are treated postoperatively with (60)C0 , 4 MV , or 6 MV photon beam . METHODS AND MATERIAL S This is a secondary analysis of the Intergroup Study 0034 . Three hundred ninety-two patients were evaluable for comparison between treatment with (60)C0 , 4 MV , or 6 MV photon beam . All patients had advanced but operable squamous cell carcinoma of the oral cavity , oropharynx , hypopharynx , or larynx . Patients were r and omized following surgical resection to receive treatment with either postoperative irradiation alone , or postoperative irradiation plus three cycles of cisplatin and 5-fluorouracil . Patients were categorized as having either " low risk " or " high risk " treatment volumes based on whether the surgical margin was 5 mm or less , presence of extra capsular nodal extension , and /or carcinoma in situ at the surgical margins . Low-risk volumes received 50 - 54 Gy , and high-risk volumes were given 60 Gy . Patients were compared in regards to acute and late radiotherapy toxicities as well as overall survival and loco-regional control according to the beam energy used . RESULTS One-hundred fifty-seven , 140 , and 95 patients were treated by (60)C0 , 4 MV , and 6 MV , respectively . No differences were seen in acute or late toxicity among treatment groups . Locoregional control was achieved in 75 % , 79 % , and 80 % of patients treated with (60)C0 , 4 MV , or 6 MV ( p = 0.61 ) . Patients treated with 6 MV had a higher incidence of ipsilateral neck failure as first event ( 13 % ) than patients treated by (60)C0 and 4 MV ( 9 % ) . This difference was not statistically significant . CONCLUSION No differences in outcome , acute , or late toxicity were discernible in patients with advanced head and neck cancer treated with (60)C0 , 4 MV , or 6 MV . This result should be interpreted with caution as increased incidence , albeit nonsignificant , of ipsilateral neck recurrence was observed in patients treated with 6 MV and the power of the study to detect a statistically significant difference is small [21573534] Several phase II studies have shown that concurrent chemotherapy and radiotherapy ( RT ) improves the response rates and locoregional control in patients with advanced , unresectable squamous-cell carcinoma of the head and neck ( H&N ) . However , it is still unclear which is the drug of choice to be given with RT . We therefore conducted a r and omized comparison of cisplatin (CDDP)-RT versus carboplatin (CRP)-RT in such patients . The two platinum compounds were given at equitoxic doses . The primary objective of the study was to compare the side effects and the response rates of the two regimens . Radiotherapy was given at conventional dosages , 2 Gy for 5 days every week for a total dose of 64 Gy with CDDP 80 mg/m2 or CRP 375 mg/m2 for three cycles on days 1 , 21 and 42 . At present 53 patients are entered in the study : 27 in the CDDP arm and 26 in the CRP . The two arms were balanced for all the pre-treatment characteristics . Both the schedules were well tolerated . However , incidence of nausea and vomiting ( p=0.0045 ) ; anemia ( p=0.032 ) and peripheral neuropathy ( p=0.032 ) was significantly greater with CDDP-RT as compared to CRP-RT . On the other h and , CRP-RT gives a significantly higher incidence of stomatitis ( p=0.0067 ) and a marginally worse thrombocytopenia ( p=0.09 ) . The complete response ( CR ) rates were similar in the two arms ( 55.5 % in the CDDP-RT versus 61.5 % in that CRP-RT , respectively ) as well as the overall response rates ( 92.5 % versus 84.5 % , respectively ; p=0.36 ) . The estimated 1 - and 2 year overall and disease-free survival rates were not significantly different in the two arms . In both the groups logistic-regression models showed that those patients with a CR ( p=0.017 ) ; stage III ( p=0.011 ) ; smaller primary ( p=0.025 ) and limited node-involvement ( p<0.001 ) had a significant better survival . We conclude that concurrent chemo-radiotherapy is an effective and safe treatment for patients with locally advanced H&N cancer . The combination CRP-RT possess a similar activity but a different , and perhaps a more favorable , spectrum of toxicity when compared to the CDDP-RT therapy . Survival results need to be assessed in a larger series and followed for a more prolonged time [1618662] To test the efficacy of sequential chemotherapy as an adjuvant to surgery and postoperative radiotherapy for patients with locally-advanced but operable squamous cell cancers of the head and neck region , a r and omized clinical trial was conducted under the auspices of the Head and Neck Intergroup ( Radiation Therapy Oncology Group , Southwest Oncology Group , Eastern Oncology Group , Cancer and Leukemia Group B , Northern California Oncology Group , and Southeast Group ) . Eligible patients had completely resected tumors of the oral cavity , oropharynx , hypopharynx , or larynx . They were then r and omized to receive either three cycles of cis-platinum and 5-FU chemotherapy followed by postoperative radiotherapy ( CT/RT ) or postoperative radiotherapy alone ( RT ) . Patients were categorized as having either " low-risk " or " high-risk " treatment volumes depending on whether the surgical margin was greater than or equal to 5 mm , there was extracapsular nodal extension , and /or there was carcinoma-in-situ at the surgical margins . Radiation doses of 50 - 54 Gy were given to " low-risk " volumes and 60 Gy were given to " high-risk " volumes . A total of 442 analyzable patients were entered into this study with the mean-time-at-risk being 45.7 months at the time of the present analysis . The 4-year actuarial survival rate was 44 % on the RT arm and 48 % on the CT/RT arm ( p = n.s . ) . Disease-free survival at 4 years was 38 % on the RT arm compared to 46 % on the CT/RT arm ( p = n.s . ) . At 4 years the local/regional failure rate was 29 % vs. 26 % for the RT and CT/RT arms , respectively ( p = n.s . ) . The incidence of first failure in the neck nodes was 10 % on the RT arm compared to 5 % on the CT/RT arm ( p = 0.03 without adjusting for multiple testing ) and the overall incidence of distant metastases was 23 % on the RT arm compared to 15 % on the CT/RT arm ( p = 0.03 ) . Treatment related toxicity is discussed in detail , but , in general , the chemotherapy was satisfactorily tolerated and did not affect the ability to deliver the subsequent radiotherapy . Implication s for future clinical trials are discussed [9348577] This study compared the activity and toxicity of fluorouracil (5-FU)/ cisplatin with the combination tegafur and uracil (UFT)/cisplatin in the neoadjuvant treatment of locally advanced-stage III or IV (MO)-head and neck cancer . A total of 67 patients were r and omly assigned to treatment with cisplatin 100 mg/m2 on day 1 followed by either a continuous infusion of 5-FU 1,000 mg/m2/day on days 2 through 6 ( group 1 ) or oral administration of UFT 300 mg/m2/day on days 2 through 20 ( group 2 ) . Both treatments were repeated every 21 days for four cycles . Responding patients received locoregional st and ard radiotherapy ( 50 to 70 Gy ) after chemotherapy . Group 1 was comprised of 34 patients , 30 of whom were men , with a median age of 57.5 years ; 79 % of this group had a Karnofsky performance status of 90 % to 100 % ; 70 % had a squamous and 29 % an undifferentiated histology . The majority ( 85 % ) had stage IV disease . Of the 33 patients in group 2 , 29 were men . The median age was 56 years . Most ( 88 % ) had a performance status of 90 % to 100 % . More patients had a squamous than an undifferentiated histology ( 82 % vs 18 % ) and most ( 88 % ) had stage IV disease . Overall response in group 1 was 73 % ( 21 % complete ) compared with 79 % ( 18 % complete ) in group 2 . At a median follow-up of 84 months , no significant differences have emerged in overall survival , 15 vs 37 months , or time to progression , 8.5 vs 14.5 months , for groups 1 and 2 , respectively . Toxicity was also similar , except for phlebitis , which occurred significantly more often in group 1 ( 71 % vs 9 % ) . Cisplatin/UFT was as effective as the classic cisplatin/5-FU regimen and has the advantages of outpatient oral administration and a lower incidence of phlebitis [15534360] PURPOSE To determine whether the application of two courses of cisplatin simultaneously with hyperfractionated radiotherapy improves the outcome in locally advanced and /or node-positive nonmetastatic carcinomas of the head and neck , compared with hyperfractionated radiotherapy alone . PATIENTS AND METHODS From July 1994 to July 2000 , 224 patients with squamous cell carcinomas of the head and neck ( excluding nasopharynx and paranasal sinus ) were r and omly assigned to hyperfractionated radiotherapy ( median dose , 74.4 Gy ; 1.2 Gy twice daily ) or the same radiotherapy combined with two cycles of concomitant cisplatin ( 20 mg/m2 on 5 days of weeks 1 and 5 ) . The primary end point was time to any treatment failure ; secondary end points were locoregional failure , metastatic relapse , overall survival , and late toxicity . RESULTS There was no difference in radiotherapy between both treatment arms ( 74.4 Gy in 44 days ) . The full cisplatin dose was applied in 93 % and 71 % of patients during the first and second treatment cycles , respectively . Acute toxicity was similar in both arms . Median time to any treatment failure was not significantly different between treatment arms ( 19 months for combined treatment and 16 months for radiotherapy only , respectively ) and the failure-free rate at 2.5 years was 45 % and 33 % , respectively . Locoregional control and distant disease-free survival were significantly improved with cisplatin ( log-rank test , P = .039 and .011 , respectively ) . The difference in overall survival did not reach significance ( log-rank test , P = .147 ) . Late toxicity was comparable in both treatment groups . CONCLUSION The therapeutic index of hyperfractionated radiotherapy is improved by concomitant cisplatin [1691811] Between August 1983 and December 1986 , 116 previously untreated patients with squamous cell carcinoma of the head and neck were r and omized to receive induction chemotherapy followed by radiotherapy given in conventional fractions ( 55 patients , arm A ) or an alternating chemotherapy and radiotherapy ( 3 courses of 20 Gy , 10 daily fractions each ; 61 patients , arm B ) . The same chemotherapy was used in both arms : 6 mg/m2 vinblastine sulfate , hour 0 ; 30 mg bleomycin , hour 6 ; 200 mg methotrexate , hours 24 to 26 ; 45 mg leucovorin , hour 48 . Forty-five patients had stage III disease and 71 had stage IV disease . All patients were evaluated for survival , 112 for toxicity , and 105 for analyses of response and time from the start of treatment until progression of disease . At the end of the combined treatment , we observed an overall response rate of 52 % in arm A and an overall response rate of 64.9 % in arm B. The incidence of mucositis was more relevant in arm B compared to arm A ( P less than .00004 ) . The difference in complete response , progression-free survival , and survival was statistically significant , with an advantage for arm B ( P less than .03 , P less than .02 , and P less than .03 , respectively ) . The analysis at a median follow-up of 36 months ( range = 19 to 59 ) demonstrates a higher effectiveness for the alternating program [7539873] Fifty-four previously untreated patients with locally advanced resectable squamous cell carcinoma of the head and neck ( SCCHN ) were enrolled into a prospect i ve r and omized controlled trial to evaluate whether induction chemotherapy improves the disease-free survival compared to the st and ard treatment ( surgery + radiation ) . Thirty patients received chemotherapy , which consisted of cisplatin 20 mg/m2 day 1 - 5 , bleomycin 10 mg/m2 , continuous infusion from day 3 - 7 , and methotrexate 40 mg/m2 given on day 15 and day 22 . The cycle was repeated on day 29 for two cycles . Twenty patients completed chemotherapy courses . Overall response rate was 77 % ( 23 of 30 ) . No survival improvement was observed . Kaplan-Meier analysis indicated survival ( and 95 % confidence interval ) at 3 years was 57 % ( 29%-84 % ) for the control group and 60 % ( 34%-87 % ) for the chemotherapy group , and 57 % ( 29%-84 % ) and 45 % ( 12%-78 % ) at 4 years ( P = 0.736 ) . However , patients who had a complete response were significantly better in terms of long-term survivors ( 5 of 7 patients were still alive ) , in contrast to patients who had partial responses among whom only 4 of 16 were alive . Toxicities of this induction protocol are tolerable ; one chemotherapy-related death occurred from profound thrombocytopenia . If efforts in determining a chemotherapy-sensitive patient were successfully established , along with a better sequence and the discovery of new and safer drugs , survival of SCCHN should be much improved [2885080] To determine the efficacy of adjuvant chemotherapy in patients with advanced head and neck squamous carcinoma , the National Cancer Institute initiated a multi-institutional , prospect i ve r and omized trial termed the Head and Neck Contracts Program . Between 1978 and 1982 , 462 patients with resectable Stage III or IV cancers of the oral cavity , larynx , or hypopharynx were r and omly assigned to receive one of three treatment options : induction chemotherapy consisting of a single course of cisplatin and bleomycin followed by st and ard therapy ( surgery and postoperative radiotherapy ) ; induction chemotherapy and st and ard therapy followed by maintenance chemotherapy which consisted of six cycles of monthly cisplatin ; or st and ard therapy alone . Toxicity from the chemotherapy regimens was minimal . Induction therapy result ed in an overall complete response of 3 % and a partial response in 34 % of patients . With a median follow-up of 61 months , overall survival and disease-free survival were not markedly different among the three groups ( P = 0.86 and P = 0.16 , respectively ) . The incidence of distant relapse was reduced in the maintenance group compared to st and ard or induction groups ( P = 0.025 and P = 0.021 , respectively ) and time to first distant relapse was prolonged ( P = 0.032 and P = 0.022 , respectively ) . The results confirm the feasibility of administering chemotherapy prior to surgery or radiation in patients with head and neck cancer but fail to demonstrate a significant impact of one cycle of induction chemotherapy on clinical outcome . The suggestion that distant relapse rates may be reduced with the addition of maintenance chemotherapy supports the need to test traditional adjuvant approaches in patients with advanced head and neck cancer [16376489] BACKGROUND Unresectable carcinomas of the oropharynx and hypopharynx still have a poor long-term prognosis . Following a previous phase II study , this phase III multicenter trial was conducted between November 1997 and March 2002 . METHODS Nontreated , strictly unresectable cases were eligible . Twice-daily radiation : two fractions of 1.2 Gy/day , 5 days per week , with no split ( D1 - ->D46 ) . Total tumor doses : 80.4 Gy/46 day ( oropharynx ) , 75.6 Gy/44 day ( hypopharynx ) . Chemotherapy ( arm B ) : Cisplatin 100 mg/m2 ( D1 , D22 , D43 ) ; 5FU , continuous infusion ( D1 - ->D5 ) , 750 mg/m2/day cycle 1 ; 430 mg/m2/day cycles 2 and 3 . RESULTS A total of 163 evaluable patients . Grade 3 - 4 acute mucositis 82.6 % arm B/69.5 % arm A ( NS ) ; Grade 3 - 4 neutropenia 33.3 % arm B/2.4 % arm A ( p < 0.05 ) . Enteral nutrition through gastrostomy tube was more frequent in arm B before treatment and at 6 months ( p < 0.01 ) . At 24 months , overall survival ( OS ) , disease-free survival ( DFS ) , and specific survival ( SS ) were significantly better in arm B. OS : 37.8 % arm B vs. 20.1 % arm A ( p = 0.038 ) ; DFS : 48.2 % vs. 25.2 % ( p = 0.002 ) ; SS : 44.5 % vs. 30.2 % ( p = 0.021 ) . No significant difference between the two arms in the amount of side effects at 1 and 2 years . CONCLUSION For these unresectable cases , chemoradiation provides better outcome than radiation alone , even with an " aggressive " dose-intensity radiotherapy schedule [11716226] Long-term follow-up for patients who receive chemoradiation for head and neck cancer is lacking from most studies reported in the literature . This report gives a 15-year review of the use of concomitant methotrexate and radiation in advanced head and neck cancer . Although there has not been any significant benefit in overall survival , the primary control rate is higher in patients who received methotrexate in addition to radiotherapy . However , in those with oropharyngeal cancer , both primary control and survival were significantly improved when chemotherapy was used . The other most significant benefit from chemoradiation is the much lower rate of salvage operations for primary recurrence . The addition of methotrexate failed to show any effect on the development of metastatic neck nodes . The rate of block dissection of the neck was similar in both arms of the study and is comparable with the historical data collected at this institute . There has not been any significant increase in serious late morbidity . The timing of the methotrexate with radiotherapy has a significant influence on primary control and survival in head and neck cancer [9165134] Between January 1988 and December 1991 , 159 patients with Stage III/IV ( M0 ) squamous cell carcinoma of the head and neck were r and omized to receive st and ard fraction RT ( 70 Gy ) ( group I ) or the same RT plus either 6 mg/m2 of cisplatin ( CDPP ) ( group II ) or 25 mg/ m2 of carboplatin ( CBDCA ) both given daily during RT ( group III ) . Patients in groups II and III had significantly higher overall response rates then those in group I ( P = 0.011 and P = 0.0025 , respectively ) with no difference between groups II and III ( P = 0.60 ) . They also had significantly longer median survival time ( MST ) and higher 5-year survival rates than those in group I ( MST , 32 months ( 32 % ) and 30 months ( 29 % ) versus 16 months ( 15 % ) , respectively ; P = 0.011 and P = 0.019 , respectively ) , with no difference between the two RT/CHT groups . Median time to local recurrence ( MTLR ) and 5-year local recurrence-free survival ( LRFS ) were significantly higher for both RT/CHT when compared to RT alone ( MTLR , not attained yet and 30 months versus 10 months , respectively ; 5-year LRFS , 51 % and 48 % versus 27 % , respectively ; P = 0.018 and P = 0.040 , respectively ) with no difference between the two RT/CHT groups . There was no difference between the three treatment groups regarding regional lymph node and distant metastasis control . Apart from acute high grade ( > or =3 ) hematological toxicity that was significantly more frequent in the two RT/CHT groups and no different between the two RT/CHT groups , other acute high grade toxicity was similar between the three treatment groups . Late high grade toxicity was infrequent and similar between the three treatment groups [15128893] BACKGROUND Despite the use of resection and postoperative radiotherapy , high-risk squamous-cell carcinoma of the head and neck frequently recurs in the original tumor bed . We tested the hypothesis that concurrent postoperative administration of cisplatin and radiotherapy would improve the rate of local and regional control . METHODS Between September 9 , 1995 , and April 28 , 2000 , 459 patients were enrolled . After undergoing total resection of all visible and palpable disease , 231 patients were r and omly assigned to receive radiotherapy alone ( 60 to 66 Gy in 30 to 33 fractions over a period of 6 to 6.6 weeks ) and 228 patients to receive the identical treatment plus concurrent cisplatin ( 100 mg per square meter of body-surface area intravenously on days 1 , 22 , and 43 ) . RESULTS After a median follow-up of 45.9 months , the rate of local and regional control was significantly higher in the combined-therapy group than in the group given radiotherapy alone ( hazard ratio for local or regional recurrence , 0.61 ; 95 percent confidence interval , 0.41 to 0.91 ; P=0.01 ) . The estimated two-year rate of local and regional control was 82 percent in the combined-therapy group , as compared with 72 percent in the radiotherapy group . Disease-free survival was significantly longer in the combined-therapy group than in the radiotherapy group ( hazard ratio for disease or death , 0.78 ; 95 percent confidence interval , 0.61 to 0.99 ; P=0.04 ) , but overall survival was not ( hazard ratio for death , 0.84 ; 95 percent confidence interval , 0.65 to 1.09 ; P=0.19 ) . The incidence of acute adverse effects of grade 3 or greater was 34 percent in the radiotherapy group and 77 percent in the combined-therapy group ( P<0.001 ) . Four patients who received combined therapy died as a direct result of the treatment . CONCLUSIONS Among high-risk patients with resected head and neck cancer , concurrent postoperative chemotherapy and radiotherapy significantly improve the rates of local and regional control and disease-free survival . However , the combined treatment is associated with a substantial increase in adverse effects [807952] Ninety-six patients with advanced squamous cell carcinoma of the head and neck were r and omized to treatment with intravenous methotrexate followed by radical irradiation or radiotherapy alone . No significant differences were demonstrated in local disease control or actuarial survival rates at three and five years . Some patients with local treatment failure were surgically salvaged [7989940] PURPOSE To determine whether the addition of infusional fluorouracil ( I-FU ) to st and ard radiotherapy improves survival at acceptable toxicity in patients with locally advanced squamous cell head and neck cancer ( SCHNC ) . PATIENTS AND METHODS Consenting patients with an Eastern Cooperative Oncology Group ( ECOG ) performance status < or = 2 ; with stage III or IV SCHNC of the oral cavity , oropharynx , hypopharynx , or larynx ; and who were recommended for radiotherapy with curative intent received 66 Gy of radiation therapy delivered in 2-Gy fractions once daily 5 days per week for 6 1/2 weeks . Those in the experimental arm received I-FU 1.2 g/m2/d , as a 72-hour infusion in the first and third weeks of radiation . Saline infusions were used in the placebo arm . RESULTS One hundred seventy-five patients were r and omized ( 88 to I-FU and 87 to placebo ) , and the treatment arms were well balanced . The complete response rate was 68 % for I-FU and 56 % for placebo ( P = .04 ) . The overall median survival duration was 33 months for I-FU and 25 months for placebo ( P = .08 ) . Progression-free survival also favored I-FU ( P = .06 ) . Toxicity was greater in I-FU patients , but did not interfere with the scheduled delivery or completion of radiation . CONCLUSION The addition of I-FU to st and ard radiation in SCHNC improved the complete response rate and was associated with beneficial trends in progression-free and overall survival compared with radiation alone . I-FU patients also experienced greater morbidity , but this did not compromise delivery of radiotherapy [3550340] It is often suggested that tumors will respond to induction chemotherapy and result in improved survival for patients with squamous cell carcinoma of the head and neck . Two regimens of induction chemotherapy were studied in separate r and omized , prospect i ve trials over the last 6 years . Eighty-three patients with advanced disease were entered into the first study ( 43/chemotherapy ; 40/control ) , and 60 into the second ( 27/chemotherapy ; 33/control ) . Patient r and omization was stratified by stage ( III/IV ) and site ( oral cavity , oropharynx , nasopharynx , hypopharynx , larynx , paranasal sinuses ) . The first study utilized bleomycin , Cytoxan , methotrexate and 5-fluorouracil in two cycles ( one cycle if no tumor response ) , followed by st and ard treatment which consisted of combined irradiation and surgery or , in some instances , primary irradiation alone . The second study utilized cisplatin and 5-fluorouracil in three cycles prior to st and ard treatment . An objective tumor response to chemotherapy was observed in 68 % in the first study and 85 % in the second . The patient survival in both studies ( at 24 months in the first ; at 19 in the second ) was better in the control than that in the experimental groups ( 43 % to 31 % ; 69 % to 46 % ) . In the second study , the average length of delay of st and ard treatment was longer than in the first study ( 95 days vs. 66 days ; P less than .02 ) . Results combining the P-values of both studies indicate that the relative risk of having persistent disease was 2.9 times greater for patients who received chemotherapy . While toxicity to chemotherapy was not a factor in survival , the number of patients who withdrew from the studies and those who did not comply with treatment were greater in the chemotherapy groups . Except for new drug regimens of exceptional promise , it is recommended that future studies be design ed so that chemotherapy is given concurrent with , or following the completion of st and ard treatment [7410127] Abstract This report culminates a 4-year study on the benefits attained by intravenous Methotrexate adjuvant and prior to definitive irradiation of advanced head and neck cancers . Three hundred twenty-six patients were r and omized to receive definitive radiotherapy alone while 312 similar patients first received intravenous Methotrexate , 25 mgm every third day for 5 doses , followed immediately by full-course irradiation . Population characteristics by specific disease site , stage ( T and N ) , age , and sex were similar between the two patient population s ; no significant bias was demonstrated . Eligibility included advanced primary ( T3 4 ) and /or nodal stage disease . The number of annual deaths among the two r and omized categories was essentially equal during the first 5 years of follow-up . Nearly one-half occurred in the first year ( 146 for radiation alone and 143 in the chemotherapy plus irradiation groups ) . Median metastasis-free survival was between 12–13 months in both categories . The unadjusted 5 year survivals were in the 11–22 % range for oral cavity , oropharynx , and supraglottic larynx and 3–9 % for hypopharynx primaries . Although several variables did exert an impact upon survival , primary ( T ) and lymph node ( N ) stage seem to be of paramount importance and Methotrexate of minor consideration . Median and 5-year survivals within the various anatomic regions ( oral cavity , supraglottic larynx , and hypopharynx ) were consistently better when Methotrexate was given . However , these improvements were minimal ( 1–4 mos . median or 2–6 % at 5 yrs ) and depended upon whether comparisons were performed on adjusted or unadjusted survival figures . Any “ real ” gain achieved directly by Methotrexate is conjecture , since several uncontrolled biases were identified among these various categories . In view of the modest benefits attained by using this Methotrexate regimen the authors suggest that other adjuvant programs be investigated and that this schedule not be adopted for routine clinical usage [9332685] PURPOSE The goal of the present analyses is to assess the association between different therapeutic approaches and both the probability of achieving a complete response and the risk of death in patients with stage III-IV , inoperable , squamous cell carcinoma of the head and neck ( SCC-HN ) . PATIENTS AND METHODS Between August 1983 and December 1990 , 273 patients with stage III-IV , previously untreated , unresectable SCC of the oral cavity , pharynx and larynx , were included into two consecutive r and omized multi-institutional trials ( HN-7 and HN-8 protocol s ) coordinated by the National Institute for Cancer Research ( NICR ) of Genoa . The HN-7 protocol compared neo-adjuvant chemotherapy ( four cycles of vinblastine , 6 mg/m2 i.v . followed by bleomycin , 30 IU i.m . six hours later , day 1 ; methotrexate , 200 mg i.v . , day 2 ; leucovorin , 45 mg orally , day 3 ) ( VBM ) followed by st and ard radiotherapy ( 70 - 75 Gy in 7 - 8 weeks ) ( 55 patients ) to alternating chemoradiotherapy based on four cycles of the same chemotherapy alternated with three splits of radiation , 20 Gy each ( 61 patients ) . In the HN-8 protocol st and ard radiotherapy ( 77 patients ) was compared to the same alternating program as the one used in the previous protocol but employing cisplatin , 20 mg/m2/day and fluorouracil , 200 mg/m2/day , bolus , both given for five consecutive days ( CF ) instead of VBM ( 80 patients ) . A single data base was created with the patients on the two protocol s. Age at diagnosis , gender , site of the primary tumor , size of the primary , nodal involvement , performance status and treatment approach were analyzed by the multiple logistic regression model and the Cox regression method . The analyses were repeated including the treating institutions as a covariate ( coordinating center versus others ) . RESULTS The multiple logistic regression analysis indicates that treatment ( alternating more so than others , regardless of the chemotherapy regimen used ) ( P = 0.0001 ) is more likely to be associated with complete response . In addition , size of the primary tumor ( P = 0.004 ) , nodal involvement ( P = 0.02 ) and performance status ( P = 0.009 ) are prognostic variables affecting the probability of achieving a complete response . The Cox regression analysis indicates that treatment , performance status , size of the primary tumor , nodal involvement and , marginally , site of the primary tumor , are independent prognostic variables affecting the risk of death . When the radiation-alone therapy is adopted as the reference treatment , the relative risk of death is 0.58 ( 95 % confidence interval ( CI ) 0.40 - 0.84 ) for alternating CF and radiation , 0.79 ( 95 % CI 0.53 - 1.16 ) for alternating VBM and radiation and 1.30 ( 95 % CI 0.89 - 1.92 ) for sequential VBM and radiation . When the treating institution is included in the model , a 34 % increased risk of death ( P = 0.04 ) is observed for patients treated outside the coordinating center . CONCLUSION In our series of patients with advanced , unresectable SCC-HN , treatment with cisplatin and fluorouracil alternating with radiation was associated with a more favourable prognosis . The role of the treating institution in the modulation of the treatment outcomes was also relevant [1703916] Between 1983 and 1986 , the National Institute for Cancer Research in Genoa and affiliated institutions conducted a r and omized study to compare two different ways of combining chemotherapy ( CT ) and radiation therapy ( RT ) . One hundred sixteen patients were r and omized to receive neoadjuvant CT followed by definitive RT ( treatment arm A ) or alternating CT and RT . In treatment arm A , RT consisted of 70 Gy to the involved areas and 50 Gy to the uninvolved neck at 2 Gy/fraction , five fractions per week . In treatment arm B , RT consisted of 60 Gy to involved areas and 50 Gy to the uninvolved neck in three courses of 20 Gy each , 2 Gy/fraction , ten fractions/2 weeks alternated with four courses of CT . CT consisted of vinblastine 6 mg/m2 intravenously followed 6 hours later by bleomycin 30 IU intramuscularly , day 1 ; methotrexate 200 mg intravenously , day 2 ; leucovorin rescue , day 3 . CT was repeated every 2 weeks up to four courses . The same CT was used in both treatment arms of the study . Fifty‐five patients were entered in treatment arm A and 61 in treatment arm B. Complete responses were 7/48 and 19/57 in treatment arms A and B , respectively ( P < 0.03 ) . Four‐year progression‐free survival was 4 % in treatment arm A and 12 % in treatment arm B ( P < 0.02 ) , and four‐year survival was 10 % in A and 22 % in B ( P < 0.02 ) . Mucosal tolerance was significantly worse in treatment arm B ( P < 0.00004 ) . The subgroup analysis shows the major improvement of alternating CT and RT in patients with the worst prognostic characteristics [2419292] A prospect i ve , r and omized trial of induction chemotherapy in advanced squamous cell carcinomas of the upper aerodigestive tract ( UAD ) was conducted between July 1979 and September 1982 . Eighty-three patients with locally advanced Stage III-IV tumors received st and ard treatment ( STD RX ; defined as preoperative irradiation and radical excision or irradiation alone ) , or induction chemotherapy ( CTX ) followed by STD RX . Chemotherapy consisted of two cycles of bleomycin ( 30 units/day by continuous infusions Days 1 - 4 ) , cyclophosphamide ( 200 mg/m2 IV Days 1 - 5 ) , methotrexate ( 30 mg/m2 Days 1 + 5 ) , and 5-fluorouracil ( 400 mg/m2 IV Days 1 - 5 ) . Response to CTX was complete in 2 and partial ( greater than 50 % reduction ) in 27 ; the overall response rate was 68 % . Tumor clearance was documented in 30/40 STD RX patients at completion of irradiation and /or surgery and in 24/43 CTX patients ( 17/29 responders , 7/14 non-responders ) . Freedom from local-regional disease was noted at 2 years in 53 % STD RX and 35 % CTX patients ( p less than .06 ) . CTX patients had a higher proportion of local-regional persistence and recurrence . The difference was apparent only in the subset of patients treated with primary irradiation ; local-regional control following irradiation and surgery was equal in STD RX and CTX groups . Survival at 2 years was 43 % STD RX and 31 % CTX . Disease-free survival in those with clearance was 64 % STD RX and 59 % CTX . Induction chemotherapy did not improve tumor clearance or survival in this series . Caution regarding local-regional control with CTX and primary irradiation is noted [6345489] The r and omized Radiation Therapy Oncology Group ( RTOG ) Methotrexate trial in advanced squamous cancers of the head and neck has reported no control or survival benefits when the chemotherapy adjuvant was administered to patients just prior to definitive irradiation . The required data collection and outcome reporting among 146 patients bearing oral cavity primaries and 354 patients with oropharyngeal cancers has allowed a multi-variate approach seeking answers to many unresolved questions . As anticipated , the ability to control these squamous cancers is largely a function of size ( T & N stage ) with a superior clearance among T3 - 4 primaries of the oropharynx ( 66 % ) contrasted to identically staged oral cavity tumors ( 48 % ) . Adjusted median survival is more than doubled to 26.6 months or 19.8 months among oral cavity and oropharynx patients respectively , when compared to the 8 month median survival when neither primary nor cervical nodes are controlled . Lymph node deposits also impact upon survival , especially among oropharynx patients where the 17.6 month adjusted median survival among N0 patients declines to 11.0 months when the primaries are associated with N3 nodes . Surprisingly , the ability to control nodel deposits of all sizes ( N1 , N2 , or N3 ) is superior among oropharynx patients when compared with identical oral cavity metastases ( e.g. 71.4 % adjusted clearance in N3 oropharyngeal deposits versus 46.1 % in N3 nodes secondary to oral cavity primaries ) . Adjustments for maldistribution of advanced N-stages in association with T-4 primary stage eliminated an apparent T-stage effect upon nodal clearance within both anatomic regions . Finally , the association of T and N-stage upon distant metastases was investigated , with the surprising conclusion that neither initial T nor N-stage exerts any apparent influence on the observed 10 - 12 % occurrence . The interrelationship of these various prognostic variables is explored using the Cox and logistic models [3121233] Three hundred and thirteen patients with squamous cell cancer of the head and neck were entered in a r and omised clinical trial to determine whether the addition of methotrexate during the course of irradiation improved the rate of primary control and subsequent survival . The overall primary control ( P = 0.016 ) and survival ( P = 0.075 ) for the patients receiving methotrexate was better than the patients treated by radiotherapy alone . The improvement in primary control ( P = 0.0019 ) and survival ( P = 0.0089 ) in patients with oropharyngeal cancers who had methotrexate in addition to radiotherapy is statistically significant . The treatment was well tolerated and there has been no increase of late morbidity [8609658] BACKGROUND In 1992 , we reported the first analysis of a r and omized trial comparing alternating radiotherapy and chemotherapy with radiotherapy alone in the treatment of squamous cell carcinoma of the head and neck . The results of that 3-year analysis indicated that the combined treatment had superior efficacy . PURPOSE After an additional 2 years of follow-up , we again compared the efficacy of the two treatment regimens , with attention paid to differences in overall survival , progression-free survival , and locoregional relapse-free survival . METHODS One hundred fifty-seven patients with untreated , unresectable squamous cell carcinoma of the head and neck were r and omly assigned to receive either chemotherapy ( four courses of cisplatin [ 20 mg/m2 ] and fluorouracil [ 200 mg/m2 ] , given daily for 5 consecutive days during weeks 1 , 4 , 7 , and 10 ) plus radiotherapy ( three courses of 20 Gy each , given in fractions of 2 Gy per day during weeks 2 - 3 , 5 - 6 , and 8 - 9 ) or radiotherapy alone ( 70 Gy total dose , given in fractions of 2 Gy per day , 5 days per week ) . Eighty patients received the combined therapy , and 77 were treated with radiotherapy alone . Responses , failures , and toxic effects associated with the two treatment regimens were compared . Overall survival , progression-free survival , and locoregional relapse-free survival were calculated according to the Kaplan-Meier method ; the logrank test was used to compare survival parameters between the two patient groups . Reported P values are two-sided . RESULTS As reported previously , toxic effects associated with the combined therapy included both chemotherapy- and radiotherapy-related effects ; however , the incidence and severity of mucositis were nearly identical among patients in the two treatment arms . The combined treatment was associated with a statistically significant increase in the frequency of complete response ( i.e. , the disappearance of clinical ly detectable disease for at least 4 weeks ) ( 43 % for the combined-treatment group compared with 22 % for the radiotherapy-only group ; P = .037 , chi-squared test ) . Five-year estimates of overall survival in the combined-treatment group compared with the radiotherapy-only group were 24 % ( 95 % confidence interval [ CI ] = 14%-40 % ) and 10 % ( 95 % CI = 4%-24 % ) , respectively ( P = .01 , logrank test ) . The estimates of progression-free survival at 5 years in the combined-treatment group compared with the radiotherapy-only group were 21 % ( 95 % CI = 11%-37 % ) and 9 % ( 95 % CI = 3%-22 % ) , respectively ( P = .008 , logrank test ) . Finally , the 5-year estimates of locoregional relapse-free survival were 64 % ( 95 % CI = 36%-84 % ) in the combined-treatment group and 32 % ( 95 % CI = 10%-65 % ) in the radiotherapy-only group ( P = .038 , logrank test ) . CONCLUSIONS AND IMPLICATION S The superiority of alternating chemotherapy and radiotherapy over radiotherapy alone in treating unresectable squamous cell carcinoma of the head and neck seen at 3 years was confirmed at 5 years . However , additional trials must be conducted before considering the combined approach as st and ard therapy [18154124] Three regimes of combined treatment for intraoral and oropharyngeal cancer were compared . In group A , cisplatin 6 mg/m2 was given intravenously , daily ; group B--40 mg/m2 , weekly ; group C--100 mg/m2 , once in 3 weeks . All patients simultaneously received distant radiation therapy in a st and ard fractionated dose of 2 Gy per fraction , 5 times a week , up to TTD of 68 - 70 Gy . Among relatively frequent side-effects were granulocytopenia , asthenia and stomatitis . Overall immediate effectiveness was : group A--100 % , group B--96 % and group C--100 % . The rates of complete tumor resorption were : group A--27.3 % , group B--19.2 % and group C--16.7 % [3528055] There were 79 patients with squamous cell head and neck cancer r and omized to receive simultaneous or 1 hour sequential methotrexate-5 fluorouracil ( MTX--5-FU ) chemotherapy : 47 patients were previously untreated and 32 patients had recurrent disease . The treatment groups were comparable for important prognostic features . The median survival for the 47 newly presenting patients was 22 months and for recurrent disease patients was 14 months . No difference could be detected in the survival of patients who received simultaneous versus sequential chemotherapy . When only chemotherapy responders were compared , no difference in survival was detected for those who received sequential versus simultaneous therapy . Subsequently , 19 chemotherapy responders received radical radiation therapy , and 15 were rendered disease-free whereas only 4 of 17 chemotherapy nonresponders were rendered disease-free by subsequent radiation ( P = .002 ) . The survival of the 19 chemotherapy responders was 34 months compared with 16 months for the 17 chemotherapy nonresponders treated with radiation . We conclude that there is no therapeutic advantage for 1 hour sequential MTX-5 FU chemotherapy compared with simultaneous use of these drugs in squamous cell head and neck cancer . Chemotherapy responders are more likely to respond to radiation therapy [74335] The purpose of this r and omized trial was to verify some experimental and clinical data suggesting a possible potentiating effect of bleomycin when used concomitantly with radiotherapy . Out of 220 patients with a biopsy proven epidermoid carcinoma of the oropharynx , 186 evaluable cases are reported here . One group of 87 patients was treated with radiotherapy alone ( Cobalt 60 ∼ 6400 rad ∼ 7–8.5 weeks ) , the other group of 99 patients received radiotherapy combined with bleomycin , the latter administered at the dose of 15 mg i.m . twice a week for 5 weeks ( total dose : 150 mg ) . Analysis of the treatment groups showed their comparability with regard to the most important prognostic factors ( TNM , sites of primary , sex , age … ) . Complication rates of mucositis and epidermitis were significantly increased ( 71 % ) in the radiotherapy + bleomycin group and were considered responsible of frequent denutrition and weight loss in this group . Such side effects necessitated a delay of radiotherapy in 22 % of patients and definitive interruption in 5 % in the combined treatment group whereas in the radiotherapy alone group no interruption of treatment was recorded and only 5 treatments ( 6 % ) were postponed . Considering tumor regressions measured 6 weeks after completion of radiation therapy , total regression rates were not significantly different in both groups as far as primary tumor ( 67.9–67 % ) or neck nodes ( 49–62 % ) are concerned . Survival curves obtained by the actuarial method showed the same 50 % survival in both groups at 15 months of follow-up [11753959] The authors previously have found that in patients with locally advanced squamous cell carcinoma of the head and neck ( SCC‐HN ) , alternating chemoradiotherapy ( ALT ) was superior to low‐total‐dose conventional radiotherapy alone . The purpose of this r and omized trial was to compare the same chemoradiotherapy approach with high‐total‐dose partly accelerated radiotherapy [12504040] PURPOSE To prospect ively assess 5-year late toxicity in patients treated by concomitant radiochemotherapy for locally advanced oropharynx carcinoma using three different toxicity scales . METHODS AND MATERIAL S A total of 226 patients were entered in a Phase III multicenter , r and omized trial comparing radiotherapy alone ( 70 Gy in 35 fractions : Arm A ) with concomitant radiochemotherapy ( 70 Gy in 35 fractions with three cycles of a 4-day regimen containing carboplatin and 5-fluorouracil : Arm B ) . Five living patients , free of local or distant recurrences , could not be evaluated for late toxicity . Forty-four patients were eligible for late toxicity with a median follow-up of 5 years . Late toxicity was evaluated by the radiation oncologist using a large question naire containing 120 mixed items of three scales ( NCI-CTC , LENT/SOMA , and RTOG ) . The data were then transposed on separate scales using corresponding grade s. RESULTS The 5-year overall survival rate was 22 % in Arm B and 16 % in Arm A ( p = 0.05 ) . The 5-year locoregional control rate was 48 % in Arm B and 25 % in Arm A ( p = 0.002 ) . The spinal cord was not affected by the concomitant adjunct of chemotherapy , and no deaths were caused by late toxicity . Using the three late toxicity scales , 100 % of the patients treated with the combined modality ( Arm B ) developed one or more late complications vs. 94 % in the radiotherapy-alone arm ( Arm A ) . The difference was not statistically significant . The most commonly damaged organs ( all Grade 1 - 4 ) were the salivary gl and s ( 100 % in Arm B vs. 82 % in Arm A , p < 0.05 ) , skin ( 78 % vs. 47 % , p < 0.05 ) , teeth ( 67 % vs. 18 % , p < 0.05 ) , mucosa ( 59 % vs. 63 % p = not significant ) , and m and ible ( 44 % vs. 12 % , p < 0.05 ) . One or more Grade 3 - 4 complications occurred in 82 % of the patients in Arm B vs. 47 % in Arm A ( p = 0.02 ) but concerned only the teeth . The correlation between the RTOG and LENT/SOMA scale and between the NCI-CTC and LENT/SOMA scale were low for Grade 1 - 4 toxicity ( near 30 % ) . The transposability of a patient 's symptoms was significantly greater using the LENT/SOMA or RTOG/EORTC scaling systems than using the NCI-CTC system . CONCLUSION Concomitant radiochemotherapy increased overall survival and locoregional control rates . The difference between the two treatment groups for Grade 3 - 4 complications was only significant for the teeth . The late toxicity assessment of a treatment may depend on the toxicity scale used . The LENT/SOMA scale seems to be the most accurate scale , but most of the score results were not concordant with those obtained with other scales . The results of this study confirm the necessity of using a common late toxicity scale in clinical trials [12525526] PURPOSE Prognosis of patients with advanced oral cavity cancer is worth improving . Chemotherapy has been reported to be especially active in oral cavity tumors . Here we repeat the results of a r and omized , multicenter trial enrolling patients with a resectable , stage T2-T4 ( > 3 cm ) , N0-N2 , M0 untreated , squamous cell carcinoma of the oral cavity . PATIENTS AND METHODS Patients were r and omly assigned to three cycles of cisplatin and fluorouracil followed by surgery ( chemotherapy arm ) or surgery alone ( control arm ) . In both arms , postoperative radiotherapy was reserved to high-risk patients , and surgery was modulated depending on the tumor 's closeness to the m and ible . Patients ' accrual was opened in 1989 and closed in 1999 . It included 195 patients . RESULTS In the chemotherapy arm , three toxic deaths were recorded . No significant difference in overall survival was found . Five-year overall survival was , for both arms , 55 % . Postoperative radiotherapy was administered in 33 % of patients in the chemotherapy arm , versus 46 % in the control arm . A m and ible resection was performed in 52 % of patients in the control arm , versus 31 % in the chemotherapy arm . CONCLUSION The addition of primary chemotherapy to st and ard surgery was unable to improve survival . However , in this study , primary chemotherapy seemed to play a role in reducing the number of patients who needed to undergo m and ibulectomy and /or radiation therapy . Variations in the criteria used to select patients for these treatment options may make it difficult to generalize these results , but there appears to be room for using preoperative chemotherapy to spare destructive surgery or radiation therapy in patients with advanced , resectable oral cavity cancer [1283088] From March 1983 to December 1989 , 208 patients with locally advanced squamous cell carcinoma of the head and neck were successively included into two trials r and omizing induction chemotherapy versus no pre-irradiation treatment . The chemotherapy regimen of the first trial , which included 100 patients , consisted of two cycles of a combination of cisplatin , bleomycin , vindesine , mitomycin C ; while that of the second trial , which included 108 patients , consisted of three cycles of a combination cisplatin , 5-fluorouracil ( continuous infusion ) and vindesine . Local treatment was the same in two trials : ' primary ' radiotherapy in all patients . The response was then evaluated at 55 Gy ; in the case of poor response , surgery was performed , otherwise radiotherapy was continued to full doses ( possibly followed by salvage surgery ) . The tumor and lymph node responses to chemotherapy ( complete and partial response ) were higher in the second trial and in the first one : 70 % versus 50 % for primary lesions , 47 % versus 25 % for lymph nodes . The toxicity of the two chemotherapy regimens was minimal . In the two trials , an initial major response to chemotherapy predicted subsequent efficacy of irradiation in 80 % of the patients . Complete response rate at the end of irradiation correlates with the previous response to the chemotherapy . With a median follow-up of 60 months with the first chemotherapy regimen and 30 months with the second , overall survival and disease-free interval did not significantly differ in the two groups of patients , with or without chemotherapy . The incidence of distant metastasis was significantly reduced ( P < 0.03 ) in the chemotherapy arms . This negative trial encourages the design of new chemotherapy protocol s according to new schemes of treatment . For advanced stages of head and neck cancers ( T3 , T4 , N2 , N3 ) , we recently launched a pilot study combining platinum and irradiation , but according to a concomitant schedule [8176922] Patient compliance with the increasingly complex adjuvant therapy protocol s has always been of concern , particularly in the head and neck cancer population . The Head and Neck Intergroup recently concluded a phase III prospect i ve r and omized trial testing the addition of three courses of cisplatinum containing combination chemotherapy to st and ard treatment defined as surgery and postoperative radiotherapy for advanced stage III and IV squamous cell carcinoma . The chemotherapy was administered following the surgery prior to the postoperative radiotherapy . Variation from protocol is ranked retrospectively as minor acceptable , major acceptable , and major unacceptable . The incidence of major unacceptable variation from the protocol for radiotherapy immediately following the surgery was 15 % vs. 19 % in the population that completed all three courses of the chemotherapy ( P < 0.10 ) . However , for those patients that completed less than the three courses of chemotherapy , the incidence of major unacceptable variation in radiotherapy was 33 % ( P < 0.001 ) . This observation was controlled for site , stage , performance status , age , sex , surgical margins and experience of participating institution . We conclude that compliance with a multicourse adjuvant chemotherapy regimen is predictive of subsequent compliance to radiotherapy in the head and neck cancer population Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Oral cavity and oropharyngeal cancers are frequently described as part of a group of oral cancers or head and neck cancer . Treatment of oral cavity cancer is generally surgery followed by radiotherapy , whereas oropharyngeal cancers , which are more likely to be advanced at the time of diagnosis , are managed with radiotherapy or chemoradiation . Surgery for oral cancers can be disfiguring and both surgery and radiotherapy have significant functional side effects , notably impaired ability to eat , drink and talk . The development of new chemotherapy agents , new combinations of agents and changes in the relative timing of surgery , radiotherapy , and chemotherapy treatments may potentially bring about increases in both survival and quality of life for this group of patients . OBJECTIVES To determine whether chemotherapy , in addition to radiotherapy and /or surgery for oral cavity and oropharyngeal cancer results in improved survival , disease free survival , progression free survival , locoregional control and reduced recurrence of disease . To determine which regimen and time of administration ( induction , concomitant or adjuvant ) is associated with better outcomes . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

20091527

[16495392] BACKGROUND Glucosamine and chondroitin sulfate are used to treat osteoarthritis . The multicenter , double-blind , placebo- and celecoxib-controlled Glucosamine/chondroitin Arthritis Intervention Trial ( GAIT ) evaluated their efficacy and safety as a treatment for knee pain from osteoarthritis . METHODS We r and omly assigned 1583 patients with symptomatic knee osteoarthritis to receive 1500 mg of glucosamine daily , 1200 mg of chondroitin sulfate daily , both glucosamine and chondroitin sulfate , 200 mg of celecoxib daily , or placebo for 24 weeks . Up to 4000 mg of acetaminophen daily was allowed as rescue analgesia . Assignment was stratified according to the severity of knee pain ( mild [ N=1229 ] vs. moderate to severe [ N=354 ] ) . The primary outcome measure was a 20 percent decrease in knee pain from baseline to week 24 . RESULTS The mean age of the patients was 59 years , and 64 percent were women . Overall , glucosamine and chondroitin sulfate were not significantly better than placebo in reducing knee pain by 20 percent . As compared with the rate of response to placebo ( 60.1 percent ) , the rate of response to glucosamine was 3.9 percentage points higher ( P=0.30 ) , the rate of response to chondroitin sulfate was 5.3 percentage points higher ( P=0.17 ) , and the rate of response to combined treatment was 6.5 percentage points higher ( P=0.09 ) . The rate of response in the celecoxib control group was 10.0 percentage points higher than that in the placebo control group ( P=0.008 ) . For patients with moderate-to-severe pain at baseline , the rate of response was significantly higher with combined therapy than with placebo ( 79.2 percent vs. 54.3 percent , P=0.002 ) . Adverse events were mild , infrequent , and evenly distributed among the groups . CONCLUSIONS Glucosamine and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with osteoarthritis of the knee . Exploratory analyses suggest that the combination of glucosamine and chondroitin sulfate may be effective in the subgroup of patients with moderate-to-severe knee pain . ( Clinical Trials.gov number , NCT00032890 . ) [15478160] OBJECTIVE To assess the efficacy of glucosamine sulfate in knee osteoarthritis ( OA ) . METHODS A 4-center , 6-month , r and omized , double-blind , placebo-controlled glucosamine discontinuation trial was conducted in 137 current users of glucosamine with knee OA who had experienced at least moderate improvement in knee pain after starting glucosamine . Study medication dosage was equivalent to the dosage of glucosamine taken prior to the study ( maximum 1,500 mg/day ) . Followup continued for 6 months or until disease flare , whichever occurred first . The primary outcome was the proportion of disease flares in the glucosamine and placebo groups using an intent-to-treat analysis . Secondary outcomes included time to disease flare ; analgesic medication use ; severity of disease flare ; and change in pain , stiffness , function and quality of life in the glucosamine and placebo groups . RESULTS Disease flare was seen in 28 ( 42 % ) of 66 placebo patients and 32 ( 45 % ) of 71 glucosamine patients ( difference -3 % ; 95 % confidence interval [ 95 % CI ] -19 , 14 ; P = 0.76 ) . In the Cox regression analysis , after adjustment for sex , study site , and OA radiographic severity , time to disease flare was not significantly different in the glucosamine compared with placebo group ( hazard ratio of flare = 0.8 ; 95 % CI 0.5 , 1.4 ; P = 0.45 ) . At final study visit , acetaminophen was used in 27 % and 21 % of placebo and glucosamine patients , respectively ( P = 0.40 ) , nonsteroidal antiinflammatory drugs were used in 29 % and 30 % ( P = 0.92 ) , and both were used in 20 % and 21 % ( P = 0.84 ) . No differences were found in severity of disease flare or other secondary outcomes between placebo and glucosamine patients . CONCLUSION In patients with knee OA with at least moderate subjective improvement with prior glucosamine use , this study provides no evidence of symptomatic benefit from continued use of glucosamine sulfate [15996072] OBJECTIVE To determine whether it is possible to specify different score patterns for hip and knee osteoarthritis ( OA ) , and to identify the degree of responsiveness and the validity of the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) factors , which are alternative health dimensions obtained by factor analysis of the WOMAC items . METHODS WOMAC scales and WOMAC factors were compared in a prospect i ve setting examining patients with hip and knee OA before and after rehabilitative inpatient intervention ( n = 317 ) . In a partial sample ( n = 103 ) , the validity of the WOMAC factors was determined by a global rating of their activities . RESULTS The WOMAC factor " ascending/descending " was significantly different for hip and knee OA in the health state before therapy ( score in hip 5.09 , in knee 6.59 ; p < 0.001 ) ; this was also true of the effect size after therapy ( hip 0.39 , knee 0.65 ; p = 0.012 ) . The WOMAC scales did not differ for the 2 conditions . The WOMAC factor " ascending/descending " was the most responsive dimension in knee OA ( effect size 0.65 ) , but in hip OA the WOMAC pain scale was most responsive ( effect size 0.55 ) . Most of the WOMAC factors correlated moderately ( r = 0.52 - 0.69 ) with the patient 's self-rating on the validation question naire . CONCLUSION The WOMAC factors are valid measures . Analyzing the WOMAC by the WOMAC factors facilitates and improves the differential relevance and accuracy of the WOMAC for specific conditions such as hip and knee OA [18591906] Objectives To compare the effect of acupuncture ( manual and electroacupuncture ) with that of a non-penetrating sham ( ‘ placebo ’ needle ) in patients with osteoarthritic knee pain and disability who are blind to the treatment allocation . Methods Acupuncture naive patients with symptomatic and radiological evidence of osteoarthritis of the knee were r and omly allocated to a course of either acupuncture or non-penetrating sham acupuncture using a sheathed ‘ placebo ’ needle system . Acupuncture points for pain and stiffness were selected according to acupuncture theory for treating Bi syndrome . Both manual and electrical stimulation were used . Response was assessed using the WOMAC index for osteoarthritis of the knee , self reported pain scale , the EuroQol score and plasma β-endorphin . The effectiveness of blinding was assessed . Results There were 34 patients in each group . The primary end point was the change in WOMAC pain score after the course of treatment . Comparison between the two treatment groups found a significantly greater improvement with acupuncture ( mean difference 60 , 95 % CI 5 to 116 , P=0.035 ) than with sham . Within the acupuncture group there was a significant improvement in pain ( baseline 294 , mean change 95 , 95 % CI 60 to 130 , P<0.001 ) which was not seen by those who had sham acupuncture ( baseline 261 , mean change 35 , 95 % CI-10 to 80 , P=0.12 ) . Similar effects within group , but not between groups , were seen with the secondary end points of WOMAC stiffness , WOMAC function , and self reported pain . One month after treatment the between group pain difference had been lost ( mean difference 46 ; 95 % CI −9 to 100 , P=0.10 ) although the acupuncture group was still benefiting compared to baseline ( mean difference 59 ; 95 % CI 16 to 102 , P=0.009 ) . The EuroQol score , a generic measure of health related quality of life , was not altered by the treatments . A minority of patients correctly guessed their treatment group ( 41 % in the acupuncture group and 44 % in the control group ) . Plasma β-endorphin levels were not affected by either treatment . Conclusions Acupuncture gives symptomatic improvement for patients with osteoarthritis of the knee , and is significantly superior to non-penetrating sham acupuncture . The study did not confirm earlier reports of release of plasma β-endorphin during acupuncture [15077933] Background Using an open r and omised controlled study , we examined the effectiveness of manual and electroacupuncture on symptom relief for patients with osteoarthritis of the knee . Methods Patients with symptomatic osteoarthritis of the knee were r and omised to one of three treatment groups . Group A had acupuncture alone , group B had acupuncture but continued on their symptomatic medication , and group C used their symptomatic medication for the first five weeks and then had a course of acupuncture added . Patients receiving acupuncture were treated twice weekly over five weeks . Needles were inserted ( with manual and electrical stimulation ) in acupuncture points for pain and stiffness , selected according to traditional acupuncture theory for treating Bi syndrome . Patients were assessed by a blinded observer before treatment , after five weeks ’ treatment and at one month follow up , using a visual analogue pain scale ( VAS ) and the Western Ontario McMaster ( WOMAC ) question naire for osteoarthritis of the knee . Results The 30 patients in our study were well matched for age , body mass index , disease duration , baseline VAS pain score and baseline WOMAC scores . Repeated measure analyses gave a highly significant improvement in pain ( VAS ) after the courses of acupuncture in groups A ( P=0.012 ) and B ( P=0.001 ) ; there was no change in group C until after the course of acupuncture , when the improvement was significant ( P=0.001 ) . Similarly significant changes were seen with the WOMAC pain and stiffness scores . These benefits were maintained during the one month after the course of acupuncture . Patients ’ rating of global assessment was higher than that of the acupuncturist . Conclusion We conclude that manual and electroacupuncture causes a significant improvement in the symptoms of osteoarthritis of the knee , either on its own or as an adjunct therapy , with no loss of benefit after one month [16046146] Clinical and experimental data indicate that most acupuncture clinical results are mediated by the central nervous system , but the specific effects of acupuncture on the human brain remain unclear . Even less is known about its effects on the cerebellum . This fMRI study demonstrated that manual acupuncture at ST 36 ( Stomach 36 , Zusanli ) , a main acupoint on the leg , modulated neural activity at multiple levels of the cerebro-cerebellar and limbic systems . The pattern of hemodynamic response depended on the psychophysical response to needle manipulation . Acupuncture stimulation typically elicited a composite of sensations termed deqi that is related to clinical efficacy according to traditional Chinese medicine . The limbic and paralimbic structures of cortical and subcortical regions in the telencephalon , diencephalon , brainstem and cerebellum demonstrated a concerted attenuation of signal intensity when the subjects experienced deqi . When deqi was mixed with sharp pain , the hemodynamic response was mixed , showing a predominance of signal increases instead . Tactile stimulation as control also elicited a predominance of signal increase in a subset of these regions . The study provides preliminary evidence for an integrated response of the human cerebro-cerebellar and limbic systems to acupuncture stimulation at ST 36 that correlates with the psychophysical response [6346029] A prospect i ve , controlled clinical trial was undertaken to assess the relative efficacies of physiotherapy and electroacupuncture in the treatment of cervical spondylosis . The results suggested that , while both methods were effective , electroacupuncture produced an earlier symptomatic improvement with increased neck movement , especially in patients with mild degenerative changes of the cervical spine [10378713] OBJECTIVE The purpose of this study was to investigate the efficacy of acupuncture as an adjunctive therapy to st and ard care for the relief of pain and dysfunction in elderly patients with osteoarthritis ( OA ) of the knee . METHODS Seventy-three patients with symptomatic OA of the knee were r and omly assigned to treatment ( acupuncture ) or st and ard care ( control ) . Analysis was performed on last score carried forward to account for patients who dropped out before completion . Patients self-scored Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) and Lequesne indices at baseline and at 4 , 8 and 12 weeks . Patients in the control group were offered acupuncture treatment after 12 weeks . The data for these patients are pooled with those from the original acupuncture group for within-group analysis . RESULTS Patients r and omized to acupuncture improved on both WOMAC and Lequesne indices compared to those who received st and ard treatment alone . Significant differences on total WOMAC Scale were seen at 4 and 8 weeks . There appears to be a slight decline in effect at 4 weeks after cessation of treatment ( 12 weeks after first treatment ) . No adverse effects of acupuncture were reported . CONCLUSION These data suggest that acupuncture is an effective and safe adjunctive therapy to conventional care for patients with OA of the knee [16005336] BACKGROUND Acupuncture is widely used by patients with chronic pain although there is little evidence of its effectiveness . We investigated the efficacy of acupuncture compared with minimal acupuncture and with no acupuncture in patients with osteoarthritis of the knee . METHODS Patients with chronic osteoarthritis of the knee ( Kellgren grade < or = 2 ) were r and omly assigned to acupuncture ( n=150 ) , minimal acupuncture ( superficial needling at non-acupuncture points ; n=76 ) , or a waiting list control ( n=74 ) . Specialised physicians , in 28 outpatient centres , administered acupuncture and minimal acupuncture in 12 sessions over 8 weeks . Patients completed st and ard question naires at baseline and after 8 weeks , 26 weeks , and 52 weeks . The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis ( WOMAC ) index at the end of week 8 ( adjusted for baseline score ) . All main analyses were by intention to treat . RESULTS 294 patients were enrolled from March 6 , 2002 , to January 17 , 2003 ; eight patients were lost to follow-up after r and omisation , but were included in the final analysis . The mean baseline-adjusted WOMAC index at week 8 was 26.9 ( SE 1.4 ) in the acupuncture group , 35.8 ( 1.9 ) in the minimal acupuncture group , and 49.6 ( 2.0 ) in the waiting list group ( treatment difference acupuncture vs minimal acupuncture -8.8 , [ 95 % CI -13.5 to -4.2 ] , p=0.0002 ; acupuncture vs waiting list -22.7 [ -27.5 to -17.9 ] , p<0.0001 ) . After 52 weeks the difference between the acupuncture and minimal acupuncture groups was no longer significant ( p=0.08 ) . INTERPRETATION After 8 weeks of treatment , pain and joint function are improved more with acupuncture than with minimal acupuncture or no acupuncture in patients with osteoarthritis of the knee . However , this benefit decreases over time [17604311] OBJECTIVE To evaluate the effects of st and ardized western acupuncture and physiotherapy on pain and functional ability in patients with severe osteoarthritic knee pain awaiting knee arthroplasty . METHODS Three-arm , assessor-blind , r and omized controlled trial . PARTICIPANTS 181 patients awaiting knee arthroplasty . INTERVENTIONS acupuncture for 6 weeks ; physiotherapy for 6 weeks ; st and ardized advice . MAIN OUTCOME MEASURES Oxford Knee Score question naire ( OKS ) ( primary ) ; 50 m timed walk , and duration of hospital stay following knee arthroplasty . RESULTS There was no baseline difference between groups . At 7 weeks , there was a 10 % reduction in OKS in the acupuncture group which was a significant difference between the acupuncture and the control group : Mean ( s.d . ) acupuncture 36.8 ( 7.20 ) ; physiotherapy 39.2 ( 8.22 ) ; control 40.3 ( 8.48 ) ( P = 0.0497 ) . These effects were no longer present at 12 weeks . There was a trend ( P = 0.0984 ) towards a shorter in-patient stay of 1 day for the physiotherapy group [ mean 6.50 days ( s.d . 2.0 ) ] compared with the acupuncture group [ mean 7.77 days ( s.d . 3.96 ) ] . CONCLUSIONS We have demonstrated that patients with severe knee osteoarthritis can achieve a short-term reduction in OKS when treated with acupuncture . However , we failed to demonstrate any other clinical ly or statically significant effects between the groups . Both interventions can be delivered effectively in an out-patient group setting at a district general hospital . Further study is needed to evaluate the combined effects of these treatments [10729968] The purpose of this study was to compare the effectiveness of transcutaneous nerve stimulation ( TENS ) , electroacupuncture ( EA ) , and ice massage with placebo treatment for the treatment of pain . Subjects ( n = 100 ) diagnosed with osteoarthritis ( OA ) of the knee were treated with these modalities . The parameters for evaluating the effectiveness of treatment include pain at rest , stiffness , 50 foot walking time , quadriceps muscle strength , and knee flexion degree . The results showed ( a ) that all three methods could be effective in decreasing not only pain but also the objective parameters in a short period of time ; and ( b ) that the treatment results in TENS , EA and ice massage were superior to placebo [2268695] Background The present study tests whether a combined treatment of acupuncture and transcutaneous electrical nerve stimulation ( TENS ) is more effective than acupuncture or TENS alone for treating knee osteoarthritis ( OA ) . Methods Thirty-two patients with knee OA were r and omly allocated to four groups . The acupuncture group ( ACP ) received only acupuncture treatment at selected acupoints for knee pain ; the TENS group ( TENS ) received only TENS treatment at pain areas ; the acupuncture and TENS group ( A&T ) received both acupuncture and TENS treatments ; the control group ( CT ) received topical poultice ( only when necessary ) . Each group received specific weekly treatment five times during the study . Outcome measures were pain intensity in a visual analogue scale ( VAS ) and knee function in terms of the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) . Results The ACP , TENS and A&T groups reported lower VAS and WOMAC scores than the control group . Significant reduction in pain intensity ( P = 0.039 ) and significant improvement in knee function ( P = 0.008 ) were shown in the A&T group . Conclusion Combined acupuncture and TENS treatment was effective in pain relief and knee function improvement for the sample d patients suffering from knee OA [15611487] Context Previous studies of acupuncture for osteoarthritis have had conflicting results . This may have occurred because most studies have included small sample s , a limited number of treatment sessions , or other limitations . Contribution This r and omized , controlled trial compared 24 acupuncture sessions over 26 weeks with sham acupuncture or arthritis education in 570 patients with osteoarthritis of the knee . Acupuncture led to greater improvements in function but not pain after 8 weeks and in both pain and function after 26 weeks . No adverse effects were associated with acupuncture . Caution s Many participants dropped out of the study , so readers should interpret the findings at 26 weeks with caution . The Editors Osteoarthritis is the most common form of arthritis and is a major cause of morbidity , limitation of activity , and health care utilization , especially in elderly patients ( 1 , 2 ) . Pain and functional limitation are the primary clinical manifestations of osteoarthritis of the knee . Current recommendations for managing osteoarthritis , including guidelines published by the American College of Rheumatology ( 3 ) and European League of Associations of Rheumatology ( 4 ) , focus on relieving pain and stiffness and maintaining or improving physical function as important goals of therapy . No curative therapies exist for osteoarthritis ; thus , both pharmacologic and nonpharmacologic management focus on controlling pain and reducing functional limitation ( 5 ) . Nonpharmacologic therapy , which includes patient education , social support , physical and occupational therapy , aerobic and resistive exercises , and weight loss , is the cornerstone of a multidisciplinary approach to osteoarthritis patient management ( 3 ) . Pharmacologic therapies include nonopioid analgesics ( such as acetaminophen ) , nonsteroidal anti-inflammatory drugs ( NSAIDs ) ( including cyclooxygenase-2 [ COX-2 ] enzyme selective inhibitors ) , topical analgesics ( capsaicin cream ) , opioid analgesics , and intra-articular steroid and hyaluronate injections . Often , these agents are used in combination for additive analgesic efficacy ( 6 ) . Pharmacologic management of osteoarthritis is often ineffective , and agents such as NSAIDs may cause unwanted and dangerous side effects ( 7 , 8) . Complementary and alternative medicine is another approach to treating osteoarthritis ( 9 - 12 ) , particularly in Asian societies ( 13 ) . Many U.S. patients with osteoarthritis also use complementary and alternative medical therapies ( 14 ) . A systematic review of acupuncture and knee osteoarthritis ( 15 ) identified 7 small r and omized , controlled trials published in English . Within the method ologic limitations of the studies , the evidence suggested that acupuncture seemed to alleviate knee pain and function compared with sham acupuncture controls , although 2 trials comparing acupuncture with an active , nonpharmacologic treatment ( physical therapy ) did not indicate such an effect ( 16 , 17 ) . Before conducting our large-scale trial , we completed both a pilot study ( 18 ) and a r and omized , single-blind trial ( 19 ) of the effect of acupuncture on osteoarthritis of the knee . Participants in the uncontrolled pilot study ( n= 12 ) showed statistically significant improvement in both self-reported pain and physical function , as well as performance measures of physical function after 8 weeks of acupuncture treatment and at 12-week follow-up as compared with their baseline ( 18 ) . In our larger r and omized , single-blind trial ( n= 73 ) , which examined the benefit of acupuncture added to st and ard management with NSAIDs , the acupuncture treatment group experienced statistically significant improvements in self-reported pain and disability scores compared with a st and ard-care control group as late as 4 weeks after the end of treatment ( 19 ) . However , this effect diminished within 18 weeks ( 26 weeks after the beginning of the trial ) after the final acupuncture treatment . Together , however , the previously conducted trials ( both our preliminary studies [ 18 , 19 ] and those referenced in the systematic review [ 15 ] ) have 3 method ologic limitations : lack of credible controls for the placebo effect , inadequate assessment of long-term treatment benefits , and insufficient sample sizes . We tested the hypothesis that an 8-week intensive acupuncture treatment regimen , followed by an 18-week tapering regimen , reduces pain and improves function among patients with knee osteoarthritis as compared with both sham acupuncture and education control groups . Methods Patient Recruitment We recruited patients for this multisite , placebo-controlled trial from March 2000 through December 2003 , primarily through print and radio advertisements . The 3 sites were the Integrative Medicine Clinic of the University of Maryl and School of Medicine , Baltimore , Maryl and ; the Innovative Medical Research Center ( a private research firm ) , Towson , Maryl and ; and the Hospital for Special Surgery , New York City , New York . The institutional review boards of the 3 sites approved the study . We determined the sample size ( n= 570 ) by a power analysis based on our r and omized pilot study ( 19 ) , adjusted by the estimated decrease in effect size result ing from the inclusion of a sham acupuncture group design ed to control for placebo effects . Patients met the following inclusion criteria : age 50 years or older , a diagnosis of osteoarthritis of the knee , radiographic evidence of at least 1 osteophyte at the tibiofemoral joint ( KellgrenLawrence grade 2 ) , moderate or greater clinical ly significant knee pain on most days during the past month , and willingness to be r and omly assigned . Exclusion criteria were the presence of serious medical conditions that precluded participation in study , bleeding disorders that might contraindicate acupuncture , intra-articular corticosteroid or hyaluronate injections ( as well as any knee surgeries or concomitant use of topical capsaicin cream ) during the past 6 months , previous experience with acupuncture , or any planned events ( including total knee replacement ) that would interfere with participation in the study during the following 26 weeks . After a brief telephone screening , patients were scheduled to visit 1 of the 3 participating sites to sign an informed consent statement and undergo a brief rheumatologic examination ( including radiographic examination of affected knees ) by a physician or a nurse practitioner . Because the education course was a group activity , patients were recruited until a cohort of 12 to 21 patients was formed , at which point each cohort at each site was r and omly assigned to 1 of 3 groups by a computer-generated process using r and omly selected blocks of 3 , 6 , and 9 . We assured allocation concealment by using disguised letter codes that were generated and sent to the site coordinators by a central statistical core . We used this procedure to ensure that approximately equal numbers of participants were in each treatment group across the course of the study , to ensure that each cohort would have participants assigned to all 3 treatment groups , and to make the breaking of the group assignment process more difficult . The research assistants who collected assessment s from participants , the participants themselves ( in the true acupuncture and sham acupuncture groups ) , and the statistician were blinded to group assignment . Assessment s were conducted at baseline and 4 , 8 , 14 , and 26 weeks after r and omization . Study Interventions We developed and modified the acupuncture treatment and sham control protocol s from previously reported and vali date d procedures ( 18 - 21 ) . During the trial , 7 acupuncturists were used : 3 at the Integrative Medicine Clinic , 3 at the Innovative Medical Research Center , and 1 at the Hospital for Special Surgery . In general , acupuncturists were assigned to the same participants throughout the 26-week treatment schedule , except for vacation conflicts and staff turnover , and provided approximately the same proportions of true versus sham procedures . All acupuncturists were state-licensed and had at least 2 years of clinical experience . The study 's principal acupuncturist trained and supervised the acupuncturists in performing true or sham procedures and avoiding interactions that could inadvertently communicate group assignment . True Acupuncture The true acupuncture ( experimental ) group underwent 26 weeks of gradually tapering treatment according to the following schedule : 8 weeks of 2 treatments per week followed by 2 weeks of 1 treatment per week , 4 weeks of 1 treatment every other week , and 12 weeks of 1 treatment per month . We based the acupuncture point selection s on Traditional Chinese Medicine meridian theory to treat knee joint pain , known as the Bi syndrome . These points consisted of 5 local points ( Yanglinquan [ gall bladder meridian point 34 ] , Yinlinquan [ spleen meridian point 9 ] , Zhusanli [ stomach meridian point 36 ] , Dubi [ stomach meridian point 35 ] , and extra point Xiyan ) and 4 distal points ( Kunlun [ urinarybladder , meridian point 60 ] , Xuanzhong [ gall bladder meridian point 39 ] , Sanyinjiao [ spleen meridian point 6 ] , and Taixi [ kidney meridian point 3 ] ) on meridians that traverse the area of pain ( 22 , 23 ) . The same points were treated for each affected leg . If both knees were affected , 9 needles were inserted in each leg . ( The outcome measures were not specifically targeted to whether the patient had osteoarthritis in 1 or both knees , and we observed no differential effects on the basis of the number of knees treated . ) The acupuncturists inserted 1.5-inch ( for local points ) and 1-inch ( for distal points ) 32-gauge ( 0.25-mm diameter ) acupuncture needles to a conventional depth of approximately 0.3 to 1.0 inch , depending on point location . All participants in the treatment group achieved the De-Qi sensation , a local sensation of heaviness , numbness , soreness , or paresthesia that accompanies the insertion and manipulation of needles during acupuncture , at these 9 points . Acupuncturists applied electrical [16505266] BACKGROUND Acupuncture is widely used by patients with low back pain , although its effectiveness is unclear . We investigated the efficacy of acupuncture compared with minimal acupuncture and with no acupuncture in patients with chronic low back pain . METHODS Patients were r and omized to treatment with acupuncture , minimal acupuncture ( superficial needling at nonacupuncture points ) , or a waiting list control . Acupuncture and minimal acupuncture were administered by specialized acupuncture physicians in 30 outpatient centers , and consisted of 12 sessions per patient over 8 weeks . Patients completed st and ardized question naires at baseline and at 8 , 26 , and 52 weeks after r and omization . The primary outcome variable was the change in low back pain intensity from baseline to the end of week 8 , as determined on a visual analog scale ( range , 0 - 100 mm ) . RESULTS A total of 298 patients ( 67.8 % female ; mean + /- SD age , 59 + /- 9 years ) were included . Between baseline and week 8 , pain intensity decreased by a mean + /- SD of 28.7 + /- 30.3 mm in the acupuncture group , 23.6 + /- 31.0 mm in the minimal acupuncture group , and 6.9 + /- 22.0 mm in the waiting list group . The difference for the acupuncture vs minimal acupuncture group was 5.1 mm ( 95 % confidence interval , -3.7 to 13.9 mm ; P = .26 ) , and the difference for the acupuncture vs waiting list group was 21.7 mm ( 95 % confidence interval , 13.9 - 30.0 mm ; P<.001 ) . Also , at 26 ( P=.96 ) and 52 ( P=.61 ) weeks , pain did not differ significantly between the acupuncture and the minimal acupuncture groups . CONCLUSION Acupuncture was more effective in improving pain than no acupuncture treatment in patients with chronic low back pain , whereas there were no significant differences between acupuncture and minimal acupuncture [14629842] OBJECTIVES To examine the relative effectiveness of electro-acupuncture ( EA ) and transcutaneous electrical nerve stimulation ( TENS ) in alleviating osteoarthritic (OA)-induced knee pain . DESIGN Single-blinded , r and omized controlled study . SUBJECTS Twenty-four ( 24 ) subjects ( 23 women and 1 man ) , mean age 85 , were recruited from eight subsidized Care & Attention Homes for the elderly . INTERVENTIONS Subjects were r and omly assigned to the EA , TENS , or control groups . Subjects in the EA group ( n = 8) received low-frequency EA ( 2 Hz ) on two acupuncture points ( ST-35 , Dubi and EX-LE-4 , Neixiyan ) of the painful knee for 20 minutes . Subjects in the TENS group ( n = 8) received low-frequency TENS of 2 Hz and pulse width of 200 micros on the same acupuncture points for 20 minutes . In both treatment groups , electrical treatment was carried out for a total of eight sessions in 2 weeks . Eight subjects received osteoarthritic knee care and education only in a control group . All subjects were evaluated before the first treatment , after the last treatment , and at 2-week follow-up periods . RESULTS After eight sessions of treatment , there was significant reduction of knee pain in both EA group and TENS group , as measured by the Numeric Rating Scale ( NRS ) of pain ( p < 0.01 ) . Prolonged analgesic effect was maintained in the EA and the TENS groups at a 2-week follow-up evaluation . The Timed Up- and -Go Test ( TUGT ) score of the EA group was significantly lower than that of the control group ( p < 0.05 ) , but such change was not observed in the TENS group . CONCLUSIONS Both EA and TENS treatments were effective in reducing OA-induced knee pain . EA had the additional advantage of enhancing the TUGT results as opposed to TENS treatment or no treatment , which did not produce such corollary effect [15611488] Context Chronic neck pain is a common , disabling condition and is difficult to treat . Because traditional therapies , such as physical therapy and nonsteroidal anti-inflammatory drugs , have limited effectiveness and can have adverse effects , many patients seek alternative therapies , such as acupuncture . Contribution This r and omized , controlled trial of acupuncture versus sham transcutaneous electrical stimulation for patients with chronic mechanical neck pain identified no clinical ly significant benefit of acupuncture over placebo with respect to pain , function , or analgesic use . Implication s Acupuncture did not lead to clinical ly significant improvement in chronic mechanical neck pain when compared with placebo . The Editors Chronic mechanical neck pain can be caused by dysfunction of a variety of structures within the neck ( 1 - 3 ) but specifically excludes systemic problems such as rheumatoid arthritis . It is usually associated with unspecified degenerative changes ( cervical spondylosis ) that include osteoarthritis . Neck pain presents a substantial problem and may be responsible for as many days of work absenteeism as low back pain ( 4 ) . Osteoarthritis is the most common of the chronic diseases and affects most people older than 65 years of age ( 5 ) . It is degenerative and progressive in nature ( 1 - 3 , 6 ) . Because there is no cure for cervical spondylosis , treatment tends to center on symptom relief ( 7 , 8) . If the condition is symptomatic and symptoms are left untreated , this manifests as increasing episodic pain , stiffness , or both , and patients may then experience a spiral of increasing dysfunction ( 9 ) . Two systematic review s of conventional conservative physical therapy suggest that little evidence supports the efficacy of such intervention ( 8 , 10 ) . Nonsteroidal anti-inflammatory drugs , the mainstay of pharmacologic treatment , are associated with a wide spectrum of serious and well-documented adverse reactions ( 5 ) . There has been a huge increase in the use of complementary and alternative medicine in both the United States and the United Kingdom ( 11 , 12 ) . Acupuncture is the most frequently used type of complementary and alternative medicine therapy for the treatment of osteoarthritis ( 13 ) . Despite little sound evidence of efficacy ( 14 ) , approximately 1 million people seek complementary and alternative medicine treatment annually in the United States ( 15 ) . Two systematic review s of acupuncture in neck pain ( 4 , 16 ) suggest that there has been insufficient research in this area and that the published studies are of poor quality . Therefore , we conducted a rigorous evaluation to test whether western-style acupuncture performs better than placebo for treatment of chronic mechanical neck pain . We defined western acupuncture as a conventional diagnosis followed by individualized acupuncture treatment using a combination of prescriptive tender , local , and distal points . This is in contrast to a traditional Chinese approach , which would formulate an individualized diagnosis based on traditional Chinese theories of meridians and energy ( or qi ) . Methods Study Design and Patient Selection We design ed a r and omized , single-blind , placebo-controlled trial using a pragmatic treatment regimen . The study was conducted in the outpatient departments of Southampton General Hospital and Salisbury District Hospital in the United Kingdom . Between 1999 and 2001 , patients were referred by rheumatologists or family physicians or from physiotherapy waiting lists . Appropriate ethical approval was obtained from the Southampton and South West Hampshire Joint Research Ethics Committee . Patients were 18 to 80 years of age , had chronic ( > 2 months ) mechanical neck pain , and had a pain score of more than 30 mm on a visual analogue scale ( VAS ) for 5 of 7 pretreatment days ( possible score on this VAS ranges from 0 to 100 mm ) . We excluded pregnant patients ; those with a history of fracture or surgery to the neck , cervical congenital abnormality , uncontrolled low back pain , contraindication to acetaminophen , systemic illness ( for example , rheumatoid arthritis ) , or ongoing neck-related litigation or disability cl aims ; and those with current or recent manual neck treatment or steroid use ( oral or local injection ) . Sample Size Previous studies suggested a 50 % to 75 % improvement using acupuncture for patients with chronic pain , compared with 30 % for placebo treatment ( 17 ) . We used these findings as the basis for our power calculation . At 5 % significance and 90 % power , 53 patients were required in each group to detect a 30 % difference in response between active and placebo treatments . Interventions Informed consent was obtained along with a full medical history , neurologic examination , cervical radiography , and laboratory investigations ( full blood count , erythrocyte sedimentation rate , and liver function tests ) . We told patients that we were comparing 2 types of intervention : 1 ) acupuncture with needles and 2 ) treatment with a machine design ed to stimulate acupuncture points through skin electrodes . The patients were informed that the treatment might or might not prove to be effective and that there was a 50 % chance that they would be assigned to a placebo but were not told what the placebo was . Blinding was not broken until 1 year after treatment . One practitioner performed all interventions . Acupuncture We used single-use , sterile , silver-h and le , prepacked needles without guide tubes . Sizes used were 13 mm 0.25 mm , 25 mm 0.25 mm , and 40 mm 0.25 mm . We based point selection on individualized western acupuncture techniques by using a list of points previously reported as being effective in neck pain ( 18 , 19 ) and by reaching a consensus according to our own clinical and teaching practice ( Appendix Table ) . The specific points for each individual were defined at each treatment session , depending on the patient 's pain distribution and palpation of the neck and thorax to determine ah-shi points , or local tender points , for acupuncture . At least 1 distal point was used . Point location and depth of insertion were as described in traditional texts ( 19 ) . Six points on average , per side if pain was bilateral , were used on each patient , and deqi ( a term used to describe acupuncture needle sensation ) was obtained on each needle . Twenty-minute treatment sessions were given . The patient was checked every 6 or 7 minutes to ascertain whether deqi was still present , and needles were manipulated again if required . Placebo There is considerable debate about the ideal placebo for acupuncture studies ( 20 ) . To enhance the rigor of our study , we chose to use a previously well-vali date d placebo ( 17 , 21 - 23 ) that could not have a specific physiologic effect . The Noma FM-4 electroacupuncture stimulator ( Noma Ltd. , Southampton , United Kingdom ) was used . It has 4 channels , allowing pseudostimulation of up to 8 acupuncture points simultaneously , and emits visual and audio signals . Reusable electrodes ( Body Clock Health Care Ltd. , London , United Kingdom ) were fixed to the surface of the patient 's skin and were connected to the stimulator through decommissioned cables . The cables were severed inside the output plug , so that no current could reach the patient . Examination and point selection were the same as with real acupuncture for each treatment . Point location and treatment variables were changed during subsequent treatment sessions if patients felt they were not progressing . Patients were told that the machine could stimulate acupuncture points through high-frequency , low-intensity stimulation and therefore would not produce any sensation . If patients reported sensation , the therapist adjusted the unit for comfort ( although since this was a sham procedure , such adjustment made no real difference ) . Patients in both groups were instructed to use acetaminophen alone for pain relief and were not given or permitted any other form of treatment , including exercises or stretches , during the study and for 2 months after treatment ended . Patients were treated twice per week for 4 weeks . The therapist had taken an Acupuncture Association of Chartered Physiotherapists accredited course on western acupuncture techniques and had 7 years of experience practicing acupuncture . R and omization R and omization lists for Southampton General Hospital and Salisbury District Hospital were generated by using a computer program , R and omlogue , produced by Southampton University Department of Medical Statistics , Southampton , United Kingdom . Sealed envelopes containing the individual r and omization codes , numbered consecutively with sex and age strata , were then prepared ( sex strata were male and female , and age strata were 18 to 49 years and 50 to 80 years ) Patients were strictly allocated across 4 strata for either of the study hospitals according to the next available envelope number . Data Collection Before r and omization , patients were instructed to use a daily pain diary ( on a VAS ) to record pain and acetaminophen use for 7 consecutive days . After a week , the pain diaries were examined , and if the inclusion criteria ( which were unknown to the patients ) were satisfied , r and omization occurred . Patients completed the various question naires before treatment and at 1 and 8 weeks after treatment . Pain continued to be recorded either weekly or daily throughout treatment and up to 8 weeks after treatment . Additional question naires and pain evaluation were also completed at 6 and 12 months after treatment . Figure 1 shows a flow chart of the trial . Figure 1 . Study flow with outcome assessment s. Outcomes The VAS score for pain 1 week after treatment , recorded daily for 7 consecutive days , was the primary outcome . Pain was recorded on a scale of 0 mm ( indicating no pain ) to 100 mm ( indicating worst pain imaginable ) . A significant outcome for acupuncture was considered to be a 30 % difference in VAS score between groups 5 weeks after r and omization ( 1 week after treatment ) , taking into account baseline pain . Secondary [11879884] Blinding embodies a rich history spanning over two centuries . Most research ers worldwide underst and blinding terminology , but confusion lurks beyond a general comprehension . Terms such as single blind , double blind , and triple blind mean different things to different people . Moreover , many medical research ers confuse blinding with allocation concealment . Such confusion indicates misunderst and ings of both . The term blinding refers to keeping trial participants , investigators ( usually health-care providers ) , or assessors ( those collecting outcome data ) unaware of the assigned intervention , so that they will not be influenced by that knowledge . Blinding usually reduces differential assessment of outcomes ( information bias ) , but can also improve compliance and retention of trial participants while reducing biased supplemental care or treatment ( sometimes called co-intervention ) . Many investigators and readers naïvely consider a r and omised trial as high quality simply because it is double blind , as if double-blinding is the sine qua non of a r and omised controlled trial . Although double blinding ( blinding investigators , participants , and outcome assessors ) indicates a strong design , trials that are not double blinded should not automatically be deemed inferior . Rather than solely relying on terminology like double blinding , research ers should explicitly state who was blinded , and how . We recommend placing greater credence in results when investigators at least blind outcome assessment s , except with objective outcomes , such as death , which leave little room for bias . If investigators properly report their blinding efforts , readers can judge them . Unfortunately , many articles do not contain proper reporting . If an article cl aims blinding without any accompanying clarification , readers should remain sceptical about its effect on bias reduction [16452103] Abstract Objective To investigate whether a sham device ( a vali date d sham acupuncture needle ) has a greater placebo effect than an inert pill in patients with persistent arm pain . Design A single blind r and omised controlled trial created from the two week placebo run-in periods for two nested trials that compared acupuncture and amitriptyline with their respective placebo controls . Comparison of participants who remained on placebo continued beyond the run-in period to the end of the study . Setting Academic medical centre . Participants 270 adults with arm pain due to repetitive use that had lasted at least three months despite treatment and who scored ≥3 on a 10 point pain scale . Interventions Acupuncture with sham device twice a week for six weeks or placebo pill once a day for eight weeks . Main outcome measures Arm pain measured on a 10 point pain scale . Secondary outcomes were symptoms measured by the Levine symptom severity scale , function measured by Pransky 's upper extremity function scale , and grip strength . Results Pain decreased during the two week placebo run-in period in both the sham device and placebo pill groups , but changes were not different between the groups ( −0.14 , 95 % confidence interval −0.52 to 0.25 , P = 0.49 ) . Changes in severity scores for arm symptoms and grip strength were similar between groups , but arm function improved more in the placebo pill group ( 2.0 , 0.06 to 3.92 , P = 0.04 ) . Longitudinal regression analyses that followed participants throughout the treatment period showed significantly greater downward slopes per week on the 10 point arm pain scale in the sham device group than in the placebo pill group ( −0.33 ( −0.40 to −0.26 ) v −0.15 ( −0.21 to −0.09 ) , P = 0.0001 ) and on the symptom severity scale ( −0.07 ( −0.09 to −0.05 ) v −0.05 ( −0.06 to −0.03 ) , P = 0.02 ) . Differences were not significant , however , on the function scale or for grip strength . Reported adverse effects were different in the two groups . Conclusions The sham device had greater effects than the placebo pill on self reported pain and severity of symptoms over the entire course of treatment but not during the two week placebo run in . Placebo effects seem to be malleable and depend on the behaviours embedded in medical rituals [1277952] Introduction Use of complementary and alternative medicine ( CAM ) for chronic conditions has increased in recent years . There is little information , however , on CAM use among adults with clinic-confirmed diagnoses , including arthritis , who are treated by primary care physicians . Methods To assess the frequency and types of CAM therapy used by Hispanic and non-Hispanic white women and men with osteoarthritis , rheumatoid arthritis , or fibromyalgia , we used stratified r and om selection to identify 612 participants aged 18–84 years and seen in university-based primary care clinics . Respondents completed an interviewer-administered survey in English or Spanish . Results Nearly half ( 44.6 % ) of the study population was of Hispanic ethnicity , 71.4 % were women , and 65.0 % had annual incomes of less than $ 25,000 . Most ( 90.2 % ) had ever used CAM for arthritis , and 69.2 % were using CAM at the time of the interview . Current use was highest for oral supplements ( mainly glucosamine and chondroitin ) ( 34.1 % ) , mind-body therapies ( 29.0 % ) , and herbal topical ointments ( 25.1 % ) . Fewer participants made current use of vitamins and minerals ( 16.6 % ) , herbs taken orally ( 13.6 % ) , a CAM therapist ( 12.7 % ) , CAM movement therapies ( 10.6 % ) , special diets ( 10.1 % ) , or copper jewelry or magnets ( 9.2 % ) . Those with fibromyalgia currently used an average of 3.9 CAM therapies versus 2.4 for those with rheumatoid arthritis and 2.1 for those with osteoarthritis . Current CAM use was significantly associated with being female , being under 55 years of age , and having some college education . Conclusion Hispanic and non-Hispanic white arthritis patients used CAM to supplement conventional treatments . Health care providers should be aware of the high use of CAM and incorporate questions about its use into routine assessment s and treatment planning [15527186] An estimated 40,000 physicians offer acupuncture treatment to patients in Germany . Due to a decision of the German Federal Committee of SHI-accredited Physicians and Health Insurance Funds , acupuncture treatment for chronic low back pain , headache and osteoarthritic pain may be reimbursed from 2000 onwards if patients and physicians participate in specific scientifically evaluated model projects of the Statutory Health Insurance Funds . Currently , three separate acupuncture programmes are offered by different Statutory Health Insurance Funds . The scientific evaluation of all these programmes includes both r and omised trials ( comparing acupuncture to no treatment , sham acupuncture or st and ard treatment in 300 to several thous and s of patients ) and large cohort studies . Details of the three programmes will be presented in the following chapters [395837] Background Controlled clinical trials produced contradictory results with respect to a specific analgesic effect of acupuncture . There is a lack of large multi-centre acupuncture trials . The German Acupuncture Trial represents the largest multi-centre study of acupuncture in the treatment of chronic pain caused by gonarthrosis up to now . Methods 900 patients will be r and omised to three treatment arms . One group receives verum acupuncture , the second sham acupuncture , and the third conservative st and ard therapy . The trial protocol is described with eligibility criteria , detailed information on the treatment definition , blinding , endpoints , safety evaluation , statistical methods , sample size determination , monitoring , legal aspects , and the current status of the trial . Discussion A critical discussion is given regarding the considerations about st and ardisation of the acupuncture treatment , the choice of the control group , and the blinding of patients and observers [11900500] [ The cure for the headache ] was a kind of leaf , which required to be accompanied by a charm , and if a person would repeat the charm at the same time that he used the cure , he would be made whole ; but that without the charm the leaf would be of no avail . Socrates , according to Plato ( 1 ) There is a renewed interest in placebos and the placebo effecton their reality , their ethics , their place in medicine , or not , both in and out of the clinic and academy . The U.S. National Institutes of Health recently sponsored a large conference called Science of the Placebo ( 2 ) . At least five serious books on the subject ( 3 - 7 ) plus a book of poetry ( 8) and a novel (9)each titled Placebo Effecthave been published since 1997 . In the past 10 years , the National Library of Medicine has annually listed an average of 3972 scholarly papers with the keywords placebo , placebos , or placebo effect , with a low of 3362 papers in 1992 and a high of 4814 in 2000 . During the fall of 2000 , a discussion of the effect of new drag free suits , which might give an edge to Olympic swimmers , appeared in US News and World Report : [S]wimming officials are n't convinced this is anything more than the placebo effect . Swimmers excel because they think they 've got an edge ( 10 ) . One widely reported study , which concluded that placebos were powerless ( 11 ) , or represented the Wizard of Oz ( 12 ) , occasioned a blizzard of criticism ( 13 - 26 ) and some support ( 27 ) . It 's in the papers ( 28 , 29 ) . It 's in the air . Yet the most recent serious attempt to try logically to define the placebo effect failed utterly ( 30 ) . Given the ways people have gone about it , this seems unsurprising . Arthur K. Shapiro , MD , who spent much of his career as a psychiatrist study ing the placebo effect , recently wrote : A placebo is a substance or procedure that is objective ly without specific activity for the condition being treated The placebo effect is the therapeutic effect produced by a placebo . ( 31 ) If we replace the word placebo in the second sentence with its definition from the first , we get : The placebo effect is the therapeutic effect produced by [ things ] objective ly without specific activity for the condition being treated . This makes no sense whatsoever . Indeed , it flies in the face of the obvious . The one thing of which we can be absolutely certain is that placebos do not cause placebo effects . Placebos are inert and do n't cause anything . Moreover , people frequently exp and the concept of the placebo effect very broadly to include just about every conceivable sort of beneficial biological , social , or human interaction that does n't involve some drug well-known to the pharmacopoeia . A narrower form of this expansion includes identifying natural history or regression to the mean ( as we might observe them in a r and omized , controlled trial ) as part of the placebo effect . But natural history and regression occur not only in the control group . Nothing in the theory of regression to the mean ( 31 ) hints that when people are selected for being extreme on some measure ( blood pressure or cholesterol , for example ) , they are immune to regression if they receive active treatment . Such recipients are as likely ( or unlikely ) to move toward homeostasis as are control group patients . So , regression to the mean is in no meaningful way a placebo effect . Ernst and Resch ( 32 ) took an important step in trying to clarify this situation by differentiating the true from the perceived placebo effect . But true placebo effect has n't really caught on as a viable concept . The concept of the placebo effect has been exp and ed much more broadly than this . Some attribute the effects of various alternative medical systems , such as homeopathy ( 33 ) or chiropractic ( 34 ) , to the placebo effect . Others have described studies that show the positive effects of enhanced communication , such as Egbert 's ( 35 ) , as the placebo response without the placebo ( 7 ) . No wonder things are confusing . Meaning and Medicine We suggest thinking about this issue in a new way . A group of medical students was asked to participate in a study of two new drugs , one a tranquilizer and the other a stimulant [ 36 ] . Each student was given a packet containing either one or two blue or red tablets ; the tablets were inert . The students ' responses to a question naire indicated that 1 ) the red tablets acted as stimulants while the blue ones acted as depressants and 2 ) two tablets had more effect than one . The students were not responding to the inertness of the tablets . Moreover , these responses can not be easily accounted for by natural history , regression to the mean , or physician enthusiasm [ presumably the experimenters were as enthusiastic about the reds as the blues ] . Instead , they can be explained by the meanings in the experiment : 1 ) Red means up , hot , danger , while blue means down , cool , quiet and 2 ) two means more than one . These effects of color ( 37 - 40 ) and number ( 41 , 42 ) have been widely replicated . In a British study , 835 women who regularly used analgesics for headache were r and omly assigned to one of four groups ( 43 ) . One group received aspirin labeled with a widely advertised br and name ( one of the most popular analgesics in the United Kingdom that had been widely available for many years and supported by extensive advertising ) . The other groups received the same aspirin in a plain package , placebo marked with the same widely advertised br and name , or unmarked placebo . In this study , br and ed aspirin worked better than unbr and ed aspirin , which worked better than br and ed placebo , which worked better than unbr and ed placebo . Among 435 headaches reported by br and ed placebo users , 64 % were reported as improved 1 hour after pill administration compared with only 45 % of the 410 headaches reported as improved among the unbr and ed placebo users . Aspirin relieves headaches , but so does the knowledge that the pills you are taking are good ones . In a study of the benefits of aerobic exercise , two groups participated in a 10-week exercise program . One group was told that the exercise would enhance their aerobic capacity , while the other group was told that the exercise would enhance aerobic capacity and psychological well-being . Both groups improved their aerobic capacity , but only the second group improved in psychological well-being ( actually self-esteem ) . The research ers called this strong evidence that exercise may enhance psychological well-being via a strong placebo effect ( 44 ) . In the red versus blue pill study , we can correctly ( if not very helpfully ) classify the responses of the students as placebo effects because they did indeed receive inert tablets ; it seems clear , however , that they responded not to the pills but to their colors . In the second study , the presence of the br and name enhanced the effect of both the inert and the active drug . It does n't seem reasonable to classify the br and name effect as a placebo effect because no placebos are necessarily involved . Meanwhile , calling the consequences of authoritative instruction to the exercisers a placebo effect could come only from someone who believes that words do not affect the world , someone who has never been told I love you or who has never read the review s of a rejected grant proposal . It seems reasonable to label all these effects ( except , of course , of the aspirin and the exercise ) as meaning responses , a term that seeks , among other things , to recall Dr. Herbert Benson 's relaxation response ( 45 ) . Ironically , although placebos clearly can not do anything themselves , their meaning can . We define the meaning response as the physiologic or psychological effects of meaning in the origins or treatment of illness ; meaning responses elicited after the use of inert or sham treatment can be called the placebo effect when they are desirable and the nocebo effect ( 46 ) when they are undesirable . This is obviously a complex notion with several terms that would be challenging to unpack ( desirable , effect , meaning , treatment , illness)an exercise that can not be carried out here . Note that this definition excludes several elements that are usually included in our underst and ing of the placebo effect , such as natural history , regression , experimenter or subject bias , and error in measurement or reporting . Note as well that the definition is not phrased in terms of nonspecific effects ; although many elements of the meaning response or placebo effect may seem nonspecific , they are often quite specific in principle after they are understood . Meaning Permeates Medical Treatment Insofar as medicine is meaningful , it can affect patients , and it can affect the outcome of treatment ( 47 - 49 ) . Most elements of medicine are meaningful , even if practitioners do not intend them to be so . The physician 's costume ( the white coat with stethoscope hanging out of the pocket ) ( 50 ) , manner ( enthusiastic or not ) , style ( therapeutic or experimental ) , and language ( 51 ) are all meaningful and can be shown to affect the outcome ; indeed , we argue that both diagnosis ( 52 ) and prognosis ( 53 ) can be important forms of treatment . Many studies can be cited to document aspects of the therapeutic quality of the practitioner 's manner ( 54 ) . In one , a strong message of the effect of a drug ( an inert capsule ) substantially reduced the patients ' report of the pain of m and ibular block injection compared with the pain after a weak message . Patients who received the weak message reported less pain than a group that received no placebos and no message at all ( 55 ) . In another study , 200 patients with symptoms but no abnormal physical signs were r and omly assigned to a positive or a negative consultation . In a survey of patients 2 weeks later , 64 % of patients in the positive consultation group said they were all better , while only 39 % of those who had negative consultations thought they were better ( 56 ) . Although there is strong evidence for such physician effects , little evidence shows that patient effects are very important . A mass of research in the [11471578] Acupuncture is becoming a common technique within the physiotherapy profession as a treatment modality for pain relief ; however , few r and omised controlled trials have been undertaken to assess the effectiveness of acupuncture , particularly in the treatment of osteoarthritis ( OA ) of the hip . Therefore , a r and omised trial to compare the effectiveness of acupuncture with advice and exercises on the symptomatic treatment of OA of the hip was carried out . Thirty-two patients awaiting a total hip arthroplasty were r and omly allocated to either the experimental group , ( A ) , to have six sessions of acupuncture each lasting up to 25 minutes , or the control group , ( B ) , to be given advice and exercises for their hip over a six week period . Group A consisted of three men and 13 women , and group B consisted of four men and eight women . The average age in group A was 66 years and in group B it was 68 years . Patients were assessed for pain and functional ability , using a modified version of the WOMAC question naire , pre-treatment , immediately post-treatment and at eight weeks post-treatment . The pre-treatment WOMAC scores in the two groups were similar ( p=0.85 ) . There was a significant improvement in group A ( decrease in WOMAC score ) immediately post-treatment ( p=0.002 ) and this was maintained at the eight-week follow-up ( p=0.03 ) . There were no significant changes in group B. When the changes in WOMAC scores were compared between groups , a significantly greater improvement was found between pre-treatment and immediately post-treatment in group A , compared with group B ( p=0.02 ) . The changes between pre-treatment and the eight-week follow-up also showed a significant improvement in group A compared with group B ( p=0.03 ) . In conclusion , this trial supports the hypothesis that acupuncture is more effective than advice and exercises in the symptomatic treatment of OA of the hip [102323] Background The purpose of this study was to compare the efficacy of electroacupuncture ( EA ) , diclofenac and their combination in symptomatic treatment of osteoarthritis ( OA ) of the knee . Methods This study was a r and omized , single-blind , placebo controlled trial . The 193 out- patients with OA of the knee were r and omized into four groups : placebo , diclofenac , EA and combined ( diclofenac plus EA ) . Paracetamol tablets were prescribed as a rescue analgesic during the study . The patients were evaluated after a run-in period of one week ( week 0 ) and again at the end of the study ( week 4 ) . The clinical assessment s included the amount of paracetamol taken/week , visual analog scale ( VAS ) , Western Ontario and McMaster Universities ( WOMAC ) OA Index , Lequesne 's functional index , 50 feet-walk time , and the orthopedist 's and patient 's opinion of change . Results One hundred and eighty six patients completed the study . The improvement of symptoms ( reduction in mean changes ) in most outcome parameters was greatest in the EA group . The proportions of responders and patients with an overall opinion of " much better " were also greatest in the EA group . The improvement in VAS was significantly different between the EA and placebo group as well as the EA and diclofenac group . The improvement in Lequesne 's functional index also differed significantly between the EA and placebo group . In addition , there was a significant improvement in WOMAC pain index between the combined and placebo group . Conclusion EA is significantly more effective than placebo and diclofenac in the symptomatic treatment of OA of the knee in some circumstances . However , the combination of EA and diclofenac treatment was no more effective than EA treatment alone [1816730] Forty-four patients with chronic cervical osteoarthritis took part in this study . Patients were treated with acupuncture , sham-acupuncture , diazepam or placebo-diazepam in r and omized order . Pain was rated on visual analogue scales before , during , and after treatment . Two scales were separately used to rate the intensity ( sensory component ) and the unpleasantness ( affective component ) of pain . The results analyzed from these trials show that diazepam , placebo-diazepam , acupuncture and sham-acupuncture have a more pronounced effect on the affective than on the sensory component of pain . Acupuncture was significantly more effective than placebo-diazepam ( p less than 0.05 ) , but not significantly more effective than diazepam or sham-acupuncture [7727550] OBJECTIVE The purpose of this study was to determine whether acupuncture was more effective than sham acupuncture in the reduction of pain in persons with osteoarthritis ( OA ) of the knee . METHODS Forty subjects ( 20 men , 20 women ) with radiographic evidence of OA of the knee were stratified by gender and r and omly assigned to either the experimental ( real acupuncture ) or control ( sham acupuncture ) groups . Subjects were treated three times per week for 3 weeks and evaluated at three test sessions . Outcome measures were : 1 ) the Pain Rating Index of the McGill Pain Question naire , 2 ) the Western Ontario and McMaster Universities ( WOMAC ) Osteoarthritis Index , and 3 ) pain threshold at four sites at the knee . RESULTS The analyses of variance showed that both real and sham acupuncture significantly reduced pain , stiffness , and physical disability in the OA knee , but that there were no significant differences between groups . CONCLUSIONS Acupuncture is not more effective than sham acupuncture in the treatment of OA pain [15850733] Both specific and non-specific factors may play a role in acupuncture therapy for pain . We explored the cerebral consequences of needling and expectation with real acupuncture , placebo acupuncture and skin-prick , using a single-blind , r and omized crossover design with 14 patients suffering from painful osteoarthritis , who were scanned with positron emission tomography ( PET ) . The three interventions , all of which were sub-optimal acupuncture treatment , did not modify the patient 's pain . The insula ipsilateral to the site of needling was activated to a greater extent during real acupuncture than during the placebo intervention . Real acupuncture and placebo ( with the same expectation of effect as real acupuncture ) caused greater activation than skin prick ( no expectation of a therapeutic effect ) in the right dorsolateral prefrontal cortex , anterior cingulate cortex , and midbrain . These results suggest that real acupuncture has a specific physiological effect and that patients ' expectation and belief regarding a potentially beneficial treatment modulate activity in component areas of the reward system [12972723] Background : We report on the study design and protocol s of two r and omized controlled trials ( Acupuncture R and omized Trials = ART ) that investigate the efficacy of acupuncture in the treatment of chronic low back pain and osteoarthritis of the knee , respectively . Objective : To investigate whether acupuncture is more efficacious than ( a ) no treatment or ( b ) minimal acupuncture in the treatment of low back pain and osteoarthritis . Design : Two r and omized , controlled , multicenter trials with three treatment arms and a total follow-up time of 52 weeks . Setting : 30 practitioners and outpatient units in Germany specialized in acupuncture treatment . Patients : 300 patients will be included in each study . In the low back pain trial , patients will be included according to clinical diagnosis . In the osteoarthritis pain trial , patients will be included according to the American College of Rheumatology criteria . Interventions : Patients are r and omly assigned to receive either ( 1 ) semi-st and ardized acupuncture ( 150 patients ) , ( 2 ) minimal acupuncture at non-acupuncture points ( 75 patients ) , or ( 3 ) no treatment for two months followed by semi-st and ardized acupuncture ( 75 patients , waiting list control ) . Acupuncture treatment consists of 12 sessions per patient over a period of 8 weeks . Main Outcome Measure : The main outcome measure is the difference between baseline and the end of the 8-week treatment period in the following parameters : pain intensity as measured by a visual analogue scale ( VAS ; 0–100 mm ) in the low back pain trial and by the Western Ontario and McMaster Universities Osteoarthritis Score ( WOMAC ) in the osteoarthritis trial . Outlook : The results of these two studies ( available in 2004 ) will provide health care providers and policy makers with the information needed to make scientifically sound assessment s of acupuncture therapy [6218776] A single-blind , r and omised , placebo-controlled trial of superficial acupuncture in the treatment of low back pain was carried out by comparing 8 patients treated by acupuncture with 9 patients treated by placebo . In all five measures of efficacy chosen for study the acupuncture group achieved better responses than the placebo group ; four of the five inter-group differences were statistically significant . In addition , an overall mean for all five measures combined showed significant superiority of acupuncture over placebo [1514335] Purpose : Acupuncture treatment of patients waiting for arthroplasty surgery . Methods : 29 patients with a total of 42 osteoarthritic knees were r and omized to two groups . Group A was treated while Group B served as a no‐treatment control group . After 9 weeks Group B was treated too . Analgesic consumption , pain and objective measurements were registered . All objective measures were done by investigators who were “ blinded ” as to Group A & B. In the second part of the study 17 patients ( 26 knees ) continued with treatments once a month . Registration of analgesic consumption , pain and objective measurements continued . Total study period 49 weeks . Results : Comparing Group A to B there was a significant reduction in pain , analgesic consumption and in most objective measures . In Group A + B combined there was an 80 % subjective improvement , and a significantly increased knee range movement – an increase mainly in the worst knees . Results were significantly better in those who had not been ill for a long time . In the second part of the study , it was shown that it was possible to maintain the improvements . Conclusions : Acupuncture can ease the discomfort while waiting for an operation and perhaps even serve as an alternative to surgery . Seven patients have responded so well that at present they do not want an operation . ( USD 9000 saved per operation ) [3068365] Within the context of a double blind r and omized controlled parallel trial of 2 nonsteroidal antiinflammatory drugs , we vali date d WOMAC , a new multidimensional , self-administered health status instrument for patients with osteoarthritis of the hip or knee . The pain , stiffness and physical function subscales fulfil conventional criteria for face , content and construct validity , reliability , responsiveness and relative efficiency . WOMAC is a disease-specific purpose built high performance instrument for evaluative research in osteoarthritis clinical trials [16317692] Severe acetaminophen hepatotoxicity frequently leads to acute liver failure ( ALF ) . We determined the incidence , risk factors , and outcomes of acetaminophen-induced ALF at 22 tertiary care centers in the United States . Detailed prospect i ve data were gathered on 662 consecutive patients over a 6-year period fulfilling st and ard criteria for ALF ( coagulopathy and encephalopathy ) , from which 275 ( 42 % ) were determined to result from acetaminophen liver injury . The annual percentage of acetaminophen-related ALF rose during the study from 28 % in 1998 to 51 % in 2003 . Median dose ingested was 24 g ( equivalent to 48 extra-strength tablets ) . Unintentional overdoses accounted for 131 ( 48 % ) cases , intentional ( suicide attempts ) 122 ( 44 % ) , and 22 ( 8 % ) were of unknown intent . In the unintentional group , 38 % took two or more acetaminophen preparations simultaneously , and 63 % used narcotic-containing compounds . Eighty-one percent of unintentional patients reported taking acetaminophen and /or other analgesics for acute or chronic pain syndromes . Overall , 178 subjects ( 65 % ) survived , 74 ( 27 % ) died without transplantation , and 23 subjects ( 8 % ) underwent liver transplantation ; 71 % were alive at 3 weeks . Transplant-free survival rate and rate of liver transplantation were similar between intentional and unintentional groups . In conclusion , acetaminophen hepatotoxicity far exceeds other causes of acute liver failure in the United States . Susceptible patients have concomitant depression , chronic pain , alcohol or narcotic use , and /or take several preparations simultaneously . Education of patients , physicians , and pharmacies to limit high-risk use setting s is recommended [18283204] Context Although many patients use glucosamine to treat osteoarthritis , available studies have reported inconsistent effects of glucosamine on symptoms and joint changes . In addition , previous studies have more often included patients with knee than with hip osteoarthritis . Contribution The investigators r and omly assigned 222 patients with hip osteoarthritis to glucosamine , 1500 mg/d , or placebo . After 2 years of treatment , no clinical ly significant effect on pain , function , or joint space narrowing was found . Caution Twenty of the patients in the trial had joint replacement during the study . The Editors The effectiveness of glucosamine sulfate for treating osteoarthritis is controversial . A 2005 systematic review of 20 trials found evidence to be inconclusive ( 1 ) . In the 15 trials comparing glucosamine with placebo , the overall effect on pain favored glucosamine , but 8 of the trials found no effect on pain . More recent trials ( 24 ) have also yielded inconclusive results . In the Netherl and s and other countries , glucosamine is sold as an over-the-counter dietary supplement and is used by many patients , often on the advice of their physicians . Given the prevalent use of glucosamine , definitive evidence about its effectiveness is needed . Some studies suggest that glucosamine may provide greater benefit to patients with less severe radiographic osteoarthritis than to patients with more severe disease ( 5 , 6 ) . Most previous trials have studied only patients with knee osteoarthritis , with the exception of 3 early trials that included patients with other affected joints ( 79 ) . Trials specifically testing glucosamine in patients with hip osteoarthritis have not been available . Although osteoarthritis of the knee is more common than hip osteoarthritis , hip osteoarthritis is common enough to warrant assessment of glucosamine for this condition . To date , only 2 trials have published data on the effects of glucosamine sulfate on joint structure ( 10 , 11 ) . Some expressed concern about the radiography protocol used in these trials ( 1214 ) , and further study is needed to clarify these findings . To explore some of the uncertainties regarding the effectiveness of glucosamine sulfate , we conducted a 2-year , blinded , r and omized , placebo-controlled trial to evaluate the effect of glucosamine sulfate on the symptomatic and radiographic progression of hip osteoarthritis in patients recruited from primary care setting s. Methods Study Design In this trial , all outcome assessors , patients , data analysts , and research ers were blinded to group assignment . The Medical Ethics Committee of the Erasmus Medical Center , Rotterdam , the Netherl and s , approved the study design , and patients provided written informed consent . We reported the detailed study protocol in 2005 ( 15 ) and summarize it here . Setting and Participants General practitioners in the Rotterdam area recruited study patients . Patients were eligible for inclusion if they met the American College of Rheumatology clinical criteria for hip osteoarthritis ( 16 ) during a screening examination at the research center . Patients who had undergone or were awaiting hip replacement surgery were not eligible . We excluded patients who had a Kellgren and Lawrence score of 4 ( 17 ) , renal disease , liver disease , diabetes mellitus , or a disabling comorbid condition that would make visits to the research center impossible , as well as patients already receiving glucosamine and those unable to fill out Dutch question naires . We encouraged patients who violated study protocol and those who had total hip arthroplasty during the study to complete data collection to limit the loss to follow-up . R and omization and Intervention Eligible patients were r and omly assigned to receive either 1500 mg of oral glucosamine sulfate ( administered once daily as two 750-mg tablets ) or placebo for 2 years . The glucosamine used in this study was provided by Numico Research BV ( Wageningen , the Netherl and s ) but was manufactured by Nutricia Manufacturing USA ( Greenville , South Carolina ) . It contained 2000 mg of D-glucosamine sulfate 2-potassium chloride , which results in a net content of 1500 mg of glucosamine sulfate per 2 pills . The placebo pills were identical in appearance , smell , and taste . We used a computer-generated , blinded r and omization list provided by an independent research er to r and omly assign patients to glucosamine sulfate or placebo . This list , which was r and omized per block of 6 numbers , stratified patients by radiologic findings ( Kellgren and Lawrence score < 2 vs. 2 ) and by local versus generalized osteoarthritis ; patients received a number in chronological order ( 15 ) . Assignment of patients to the right stratum of the r and om assignment list was done by the main research er , who was blinded to therapy . To evaluate blinding , patients had to indicate in the last question naire to which treatment they thought they were r and omly assigned . Outcomes and Follow-up Primary outcome measures were WOMAC 3.1 ( 5-point Likert format ) pain and function over 24 months and joint space narrowing after 24 months ( 18 , 19 ) . Secondary outcome measures were WOMAC pain , function , and stiffness after 3 , 12 , and 24 months ; overall WOMAC stiffness ; a visual analogue scale ( VAS ) to measure pain in the past week ; and pain medication use . The WOMAC subscales are presented as normalized scores ( 0 to 100 , where 0 equals no symptoms ) . We recorded the use of pain medication ; classified patients as never , occasional , or daily users ; and then determined whether people increased , decreased , or did not change their use of pain medication from baseline . In the case of patients with bilateral hip symptoms , we asked patients to indicate their most affected hip for our analyses of joint space narrowing . For patients who were undecided , we used the hip with the highest Kellgren and Lawrence score or the smallest internal rotation during a physical examination . We used QBone Planner 5.4 ( Medis , Leiden , the Netherl and s ) to measure joint space width on calibrated digital radiographs of the hip joints . We read radiographs from both time points ( baseline and 24 months ) side by side . One research er measured joint space width manually on predefined lateral , superior , axial , and medial sites ( 20 ) . In addition to these 4 points , we visually identified and measured the minimal joint space width on both the baseline and 24-month radiograph . We used the smallest of these 6 measurements as the actual minimum joint space width for analyses . A second observer also measured the joint space width in a r and om subset of 28 study patients , and we found high interobserver agreement ( intraclass correlation coefficient of minimal joint space width , 0.98 ) . We collected data for the primary and secondary outcome measures at different time points throughout the study . At baseline and after 24 months , patients came to the Erasmus Medical Center for radiography and to complete study question naires . Weight-bearing , anteroposterior digital radiography of the pelvis was performed according to a highly st and ardized protocol to allow reliable measurement of joint space narrowing ( 15 ) . At baseline and then every 3 months through month 24 , we asked patients to complete the WOMAC instrument , a VAS for pain in the past week ( score range , 0 to 100 ; 0 equals no pain ) , and a checklist for specific adverse events and to answer questions regarding pain medication and adherence . We mailed the intermediate question naires to the patients for completion at home . A research er visited patients every 6 months to deliver a new supply of study medication and evaluate adherence by using the Brief Medication Question naire ( BMQ ) ( 21 ) and a pill count . The BMQ monitors the amount of days per week that patients have taken their study medication . For overall effect , we considered patients to be adherent if they ingested more than 80 % of the total study medication . Statistical Analysis We used the data from all nine 3-month question naires ( at baseline and 3 , 6 , 9 , 12 , 15 , 18 , 21 , and 24 months ) . We also report outcomes for measurements at 3 , 12 , and 24 months and a mean effect of the therapy over 24 months incorporating all scores . We performed the analyses by using SPSS 11.0.1 ( SPSS , Chicago , Illinois ) and SAS 8.2 ( SAS Institute , Cary , North Carolina ) . We used linear mixed models to analyze the data , assuming that data were missing at r and om . We chose an unstructured covariance structure to model the covariance of repeated measures by patients , because this yielded the lowest Akaike information criterion . Fixed effects were time , time by therapy , and the covariates we adjusted for . For patients who had total hip arthroplasty during the trial , we included observed data before surgery in the analysis and assumed data after surgery to be missing . For patients who were lost to follow-up , we included all observed data in the analysis . We adjusted the WOMAC and VAS pain analyses for body mass index , sex , and agefactors that may have influenced symptoms ( 22 , 23 ) . We also adjusted analyses for pain medication use and Kellgren and Lawrence score . The analyses for joint space narrowing were adjusted for Kellgren and Lawrence score ( 24 ) , age , and sex ( 25 ) . We used ordinal regression analysis to assess the effect of glucosamine sulfate on pain medication use by using data from all patients who completed the study and did not have total hip arthroplasty . We performed additional analyses to assess the effect of adherence on the outcome . To explore the validity of the missing-at-r and om data assumption for patients who underwent total hip arthroplasty during the study , we did sensitivity analyses on the WOMAC pain data . In 5 scenarios , the missing data for patients who underwent total hip arthroplasty were imputed with extreme scores : mean of the 5 best scores for the glucosamine sulfate recipients and that of the 5 worst scores for the placebo recipients ( traditional best case ) ; mean of the best scores for placebo recipients [17257756] Abstract In a pooled analysis of four r and omized controlled trials of acupuncture in patients with migraine , tension‐type headache , chronic low back pain , and osteoarthritis of the knee we investigated the influence of expectations on clinical outcome . The 864 patients included in the analysis received either 12 sessions of acupuncture or minimal ( i.e. sham ) acupuncture ( superficial needling of non‐acupuncture points ) over an 8 week period . Patients were asked at baseline whether they considered acupuncture to be an effective therapy in general and what they personally expected from the treatment . After three acupuncture sessions patients were asked how confident they were that they would benefit from the treatment strategy they were receiving . Patients were classified as responders if the respective main outcome measure improved by at least fifty percent . Both univariate and multivariate analyses adjusted for potential confounders ( such as condition , intervention group , age , sex , duration of complaints , etc . ) consistently showed a significant influence of attitudes and expectations on outcome . After completion of treatment , the odds ratio for response between patients considering acupuncture an effective or highly effective therapy and patients who were more sceptical was 1.67 ( 95 % confidence interval 1.20–2.32 ) . For personal expectations and confidence after the third session , odds ratios were 2.03 ( 1.26–3.26 ) and 2.35 ( 1.68–3.30 ) , respectively . Results from the 6‐month follow‐up were similar . In conclusion , in our trials a significant association was shown between better improvement and higher outcome expectations [3524727] Twenty-five out- patients with chronic neck pain participated in a prospect i ve , r and omized trial of acupuncture versus placebo transcutaneous nerve stimulation . A single-blind , non-cross-over design incorporated several outcome measures in an attempt to determine any particular facet of pain that responded to acupuncture . No significant difference between the two treatments was found either post-treatment or at follow-up . Whilst the small population studied limits the conclusions that may be drawn , these findings suggest that acupuncture may have no greater effect than that of a powerful placebo [11532841] Recent reports have highlighted the importance of having good evidence on the safety of acupuncture . 1 2 Sound evidence on the risks associated with acupuncture is , however , scarce.3 Our primary aim , therefore , was to describe the type and frequency of adverse events after acupuncture . A secondary aim was to examine mild transient reactions associated with acupuncture , some of which may indicate a positive response to treatment . The study involved a prospect i ve postal audit of treatments undertaken during a four week period in 2000 . All 1848 professional acupuncturists who were members of the British Acupuncture Council and were practising in the United Kingdom were invited to record details of adverse events and mild transient reactions after treatment . St and ardised self report forms were used . Participating practitioners also provided information on themselves , including age , sex , length of training , and years of practice . To have a [16636704] OBJECTIVE The research ers sought to assess whether the widely used 1994 Cochrane Highly Sensitive Search Strategy ( HSSS ) for r and omized controlled trials ( RCTs ) in MEDLINE could be improved in terms of sensitivity , precision , or parsimony . METHODS A gold st and ard of 1,347 RCT records and a comparison group of 2,400 non-trials were r and omly selected from MEDLINE . Terms occurring in at least 1 % of RCT records were identified . Fifty percent of the RCT and comparison group records were r and omly selected , and the ability of the terms to discriminate RCTs from non-trial records was determined using logistic regression . The best performing combinations of terms were tested on the remaining records and in MEDLINE . RESULTS The best discriminating term was " Clinical Trial " ( Publication Type ) . In years where the Cochrane assessment of MEDLINE records had taken place , the strategies identified few additional unindexed records of trials . In years where Cochrane assessment has yet to take place , " R and omized Controlled Trial " ( Publication Type ) proved highly sensitive and precise . Adding six more search terms identified further , unindexed trials at reasonable levels of precision and with sensitivity almost equal to the Cochrane HSSS . CONCLUSIONS Most reports of RCTs in MEDLINE can now be identified easily using " R and omized Controlled Trial " ( Publication Type ) . More sensitive search es can be achieved by a brief strategy , the Centre for Review s and Dissemination/Cochrane Highly Sensitive Search Strategy ( 2005 revision ) [11532840] Acupuncture is increasingly popular , but it is not free from risk for the patient.1 Safety is best established with prospect i ve surveys . Our aim was to ascertain the incidence of adverse events related to acupuncture treatment , as currently practised in Britain by doctors and physiotherapists . Volunteer acupuncture practitioners were recruited through journals circulated to members of the British Medical Acupuncture Society and the Acupuncture Association of Chartered Physiotherapists ( approximately 2750 members).2 A prospect i ve survey was undertaken using forms for intensive event monitoring that had been piloted previously.3 Minor adverse events were defined as “ any ill-effect , no matter how small , that is unintended and non-therapeutic , even if not unexpected . ” These events were reported every month , along with the total number of consultations . Minor or serious events that were considered to be “ significant”—“unusual , novel , dangerous , significantly inconvenient , or requiring further information”—were reported on separate forms when they occurred . Anonymous reporting was accepted . A sample size of [18356795] Background There is evidence for the efficacy of acupuncture treatment in knee osteoarthritis , but it remains unclear which acupuncture modes are most effective . We evaluated the effects of trigger point acupuncture on pain and quality of life in knee osteoarthritis patients , compared with acupuncture at st and ard points , and sham acupuncture . Methods Thirty patients ( 27 women , 3 men ; aged 61–82 years ) with non-radiating knee osteoarthritis pain for at least six months and normal neurological examination were r and omised to one of three groups for the study period of 21 weeks . Each group received five acupuncture treatment sessions . The st and ard acupuncture point group ( n=10 ) received treatment at traditional acupuncture points for knee pain ; the trigger point acupuncture group ( n=10 ) received treatment at trigger points ; and the third group ( n=10 ) received sham acupuncture treatment at the trigger points . Outcome measures were pain intensity ( visual analogue scale , VAS ) and WOMAC index ( Western Ontario and McMaster Universities Arthritis Index ) . The groups were compared by the area under the curve method . Results Five patients dropped out of the study because of lack of improvement , and one patient ( in the trigger point acupuncture group ) dropped out because of deterioration of symptoms ; the remaining 24 patients were included in the analysis . After treatment , the trigger point acupuncture group reported less pain intensity on VAS than the st and ard acupuncture or sham treatment group , but both the trigger point acupuncture and st and ard acupuncture groups reported improvement of function of knee . There was a significant reduction in pain intensity between pre-treatment and five weeks after treatment for the trigger point acupuncture ( P<0.01 ) and st and ard acupuncture groups ( P<0.01 ) included in the analysis , but not for the sham treatment group . Group comparison using the area under the curves demonstrated a significant difference only between trigger point acupuncture and sham treatment groups analysed ( P<0.025 for VAS , and P<0.031 for WOMAC ) . Conclusion These results suggest that trigger point acupuncture therapy may be more effective for osteoarthritis of the knee in some elderly patients than st and ard acupuncture therapy [11926599] We report a prospect i ve controlled trial , comparing acupuncture with no treatment , in patients with advanced osteoarthritis of the knee awaiting total knee replacement . Knee function was assessed at the beginning of study and at the end of two months , using four parameters : HSS score , time to walk 50 metres , time to climb 20 steps , and degree of pain . Acupuncture was given at four local points around the knee and at one distal point . The acupuncture group improved in all parameters , whereas the control group deteriorated , a finding that was highly statistically significant ( p<0.0002 ) . Further r and omised-controlled trials with longer follow-up are required to confirm these findings [17075849] OBJECTIVE To investigate the effectiveness of acupuncture in addition to routine care , compared with routine care alone , in the treatment of patients with chronic pain due to osteoarthritis ( OA ) of the knee or hip . METHODS In a r and omized , controlled trial , patients with chronic pain due to OA of the knee or hip were r and omly allocated to undergo up to 15 sessions of acupuncture in a 3-month period or to a control group receiving no acupuncture . Another group of patients who did not consent to r and omization underwent acupuncture treatment . All patients were allowed to receive usual medical care in addition to the study treatment . Clinical OA severity ( Western Ontario and McMaster Universities Osteoarthritis Index [ WOMAC ] ) and health-related quality of life ( Short Form 36 ) were assessed at baseline and after 3 months and 6 months . RESULTS Of 3,633 patients ( mean + /- SD age 61.8 + /- 10.8 years ; 61 % female ) , 357 were r and omized to the acupuncture group and 355 to the control group , and 2,921 were included in the nonr and omized acupuncture group . At 3 months , the WOMAC had improved by a mean + /- SEM of 17.6 + /- 1.0 in the acupuncture group and 0.9 + /- 1.0 in the control group ( 3-month scores 30.5 + /- 1.0 and 47.3 + /- 1.0 , respectively [ difference in improvement 16.7 + /- 1.4 ; P < 0.001 ] ) . Similarly , quality of life improvements were more pronounced in the acupuncture group versus the control group ( P < 0.001 ) . Treatment success was maintained through 6 months . The changes in outcome in nonr and omized patients were comparable with those in r and omized patients who received acupuncture . CONCLUSION These results indicate that acupuncture plus routine care is associated with marked clinical improvement in patients with chronic OA-associated pain of the knee or hip [9717924] BACKGROUND A problem acupuncture research has to face is the concept of a control group . If , in control groups , non-acupoint needling is done , physiological acupuncture effects are implied . Therefore the effects shown in this group are often close to those shown in the acupuncture group . In other trials , control groups have received obviously different treatments , such as transcutaneous electrical nervous stimulation or TENS-laser treatment ; it is not clear if the effects of acupuncture are due only to the psychological effects of the treatment . METHODS We developed a placebo acupuncture needle , with which it should be possible to simulate an acupuncture procedure without penetrating the skin . In a cross-over experiment with 60 volunteers we tested whether needling with the placebo needle feels any different from real acupuncture . FINDINGS Of 60 volunteers , 54 felt a penetration with acupuncture ( mean visual analogue scale [ VAS ] 13.4 ; SD 10.58 ) and 47 felt it with placebo ( VAS 8.86 ; SD 10.55 ) , 34 felt a dull pain sensation ( DEQI ) with acupuncture and 13 with placebo . None of the volunteers suspected that the needle may not have penetrated the skin . INTERPRETATION The placebo needle is sufficiently credible to be used in investigations of the effects of acupuncture [11527062] The aim of this investigation was to determine whether bee venom ( BV ) administered directly into an acupoint was a clinical ly effective and safe method for relieving the pain of patients with knee osteoarthritis ( OA ) as compared to traditional needle acupuncture . We evaluated the efficacy of BV acupuncture using both pain relief scores and computerized infrared thermography ( IRT ) following 4 weeks of BV acupuncture treatment . We observed that a significantly higher proportion of subjects receiving BV acupuncture reported substantial pain relief as compared with those receiving traditional needle acupuncture therapy . Furthermore , the IRT score was significantly improved and paralleled the level of pain relief [11452568] OBJECTIVE To determine whether demographic , medical history , or arthritis assessment data may influence outcome and rate of decay for patients with osteoarthritis treated with acupuncture . DESIGN Seventy-three persons with symptomatic osteoarthritis of the knee were recruited for this r and omized controlled trial . Both treatment and crossover control groups received acupuncture treatments twice weekly for 8 weeks . Patients self-scored on the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) and the Lequesne Algofunctional Index at baseline and 4 , 8 , and 12 weeks . Sample size for this outcome analysis was 60 patients at 4 weeks , 58 at 8 weeks , and 52 at 12 weeks . RESULTS Patients ' scores on both indexes improved at 4 , 8 , and 12 weeks . Scores were stable regardless of the baseline severity of the osteoarthritis . Despite some decay in outcomes at week 12 , measures were significantly improved over baseline . With WOMAC scores partitioned into equal quartiles , a strong effect on outcome was apparent at 12 weeks ( 4 weeks after treatment ) related to initial WOMAC scores . The group with the least disability and pain rebounded to original levels to a greater degree than did those who initially were more disabled . The more disabled groups retained the benefits of acupuncture treatment through the 12-week period . CONCLUSION Acupuncture for patients with osteoarthritis of the knee may best be used early in the treatment plan , with a method ical decrease in frequency in treatment once the acute treatment period is completed to avoid a rebound effect . Demographic and medical history data were not mediating variables [17209110] Participants are often not informed by investigators who conduct r and omised , placebo-controlled acupuncture trials that they may receive a sham acupuncture intervention . Instead , they are told that one or more forms of acupuncture are being compared in the study . This deceptive disclosure practice lacks a compelling method ological rationale and violates the ethical requirement to obtain informed consent . Participants in placebo-controlled acupuncture trials should be provided an accurate disclosure regarding the use of sham acupuncture , consistent with the practice of placebo-controlled drug trials [15501201] PURPOSE To present the safety and effectiveness results of a prototypical 12-week , double-blind , r and omized placebo-controlled trial of glucosamine among subjects with knee osteoarthritis who were recruited and followed entirely over the Internet . METHODS The study comprised 205 subjects aged 45 years or older with symptomatic knee osteoarthritis who were recruited over the Internet ; eligibility was authenticated through medical record review . Participants were assigned r and omly to 1.5 g/d of glucosamine ( n = 101 ) or placebo ( n = 104 ) , of whom 108 completed the intervention ( 93 in each arm ) . The primary outcome measure was the pain subscale of the Western Ontario and McMaster Universities Osteoarthritis Index ( Likert version ) . Additional outcome measures included the physical function and stiffness subscales and overall score of the question naire , and analgesic use . RESULTS There was no difference between treatment and control groups in terms of change in pain score ( 2.0 + /- 3.4 vs. 2.5 + /- 3.8 , P = 0.41 ) , stiffness ( 0.7 + /- 1.6 vs. 0.8 + /- 1.5 , P = 0.52 ) , physical function ( 5.2 + /- 9.5 vs. 4.6 + /- 9.6 , P = 0.49 ) , overall score ( 7.8 + /- 13.1 vs. 7.8 + /- 13.5 , P = 0.81 ) , and analgesic use ( 133 + /- 553 vs. -88 + /- 755 , P = 0.12 ) . Stratification by osteoarthritis severity , glucosamine product , and use of a nonsteroidal anti-inflammatory drug , as well as exclusion of opiate users , did not alter the results . The number and type of adverse events reported was similar between the groups . CONCLUSION Our results suggest that although glucosamine appears to be safe , it is no more effective than placebo in treating the symptoms of knee osteoarthritis [17908057] OBJECTIVES To examine the efficacy of periosteal stimulation therapy ( PST , osteopuncture ) for the treatment of chronic pain associated with advanced knee osteoarthritis . DESIGN R and omized , controlled clinical trial . SETTING Outpatient pain clinic . PARTICIPANTS Eighty-eight community-dwelling older adults with moderate knee pain or greater for 3 months or longer and Kellgren-Lawrence ( K-L ) grade 2 through 4 radiographic severity ( 80 % had K-L 4 ) . INTERVENTION Participants were r and omized to receive PST or control PST once a week for 6 weeks . MEASUREMENTS Pain severity and self-reported function ( Western Ontario and McMasters University Osteoarthritis Index ( WOMAC ) ) and physical performance ( Short Physical Performance Battery ( SPPB ) ) were assessed at baseline , after the last PST session ( post ) , and 3 months later ( follow-up ) . Pain severity was also assessed monthly using the multidimensional pain inventory short form . RESULTS Pain was reduced significantly more in the PST group than in the control PST group at post ( P=.003 ; mean WOMAC pain subscale baseline 9.4 vs 6.4 ) and 1 month later ( P<.001 ) , but by 2 months , pain levels had regressed to pre-intervention levels . The group-by-time interaction for the WOMAC function scale was significant at post ( P=.04 ) but not at follow-up ( P=.63 ) . No significant group differences were found for the SPPB . Neither analgesic use nor global improvement differed between groups . There were four treatment dropouts . CONCLUSION PST affords short-term modest pain reduction for older adults with advanced knee OA . Future research should test the effectiveness of booster treatments in sustaining analgesic benefits and of combining PST with therapeutic exercise in ameliorating disability risk [15791763] OBJECTIVES This report presents health statistics from the 2002 National Health Interview Survey ( NHIS ) for the civilian noninstitutionalized adult population , classified by sex , age , race and Hispanic origin , education , income , poverty status , health insurance coverage , marital status , place of residence , and region of residence for chronic condition prevalence , health status , functional limitations , health care access and utilization , health behaviors , and human immunodeficiency virus testing . The presentation of percentages and percent distributions in both age-adjusted and unadjusted versions is new this year . SOURCE OF DATA The NHIS is a household , multistage probability sample survey conducted annually by interviewers of the U.S. Census Bureau for the Centers for Disease Control and Prevention 's National Center for Health Statistics . In 2002 , data were collected for 31,044 adults for the Sample Adult question naire . The conditional response rate was 84.4 % , and the final response rate was 74.4 % . The health information for adults in this report was obtained from one r and omly selected adult per family . HIGHLIGHTS In 2002 , 62 % of adults 18 years of age or over reported excellent or very good health . Fifty-nine percent of adults never participated in any type of vigorous leisure-time physical activity , and 14 % of adults did not have a usual place of health care . Eleven percent of adults had been told by a doctor or health professional that they had heart disease , and 21 % had been told on two or more visits that they had hypertension . Twenty-two percent of all adults were current smokers , and 23 % were former smokers . Based on their body mass index , 35 % of adults were overweight , and 23 % were obese [11824949] OBJECTIVE To estimate minimal clinical ly important differences ( MCID ) of effects measured by the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) in patients with osteoarthritis ( OA ) of the lower extremities undergoing a comprehensive inpatient rehabilitation intervention . METHODS A prospect i ve cohort study assessed patients ' health by the WOMAC at baseline ( entry into the clinic ) and at the 3 month followup , and by a transition question naire asking about the change of " health in general related to the OA joint " during that time period . The WOMAC section score differences between the " equal " group and the " slightly better " and " slightly worse " groups result ed in the MCID for improvement and for worsening . RESULTS In total 192 patients were followed up . The MCID for improvement ranged from 0.80 to 1.01 points on the continuous WOMAC numerical rating scale from 0 to 10 , reflecting changes of 17 to 22 % of baseline scores . The MCID for worsening conditions ranged from 0.29 ( 6 % ) to 1.03 points ( 22 % ) . In the transition reply subjectively unchanged patients reported a " pessimistic bias " of 0.35 to 0.51 points , except for the stiffness section . Both MCID and pessimistic bias showed regression to the mean and baseline dependency . CONCLUSION The assessment of MCID using the transition method is a heuristic and valid strategy to detect particular rehabilitation effects in patients with OA of the lower extremities with the use of the WOMAC , and it is worth implementing . The size of the MCID and of the systematic bias is comparable to that assessed by other methods and in other therapeutic setting [17699546] Objective To investigate the benefit of adding acupuncture to a course of advice and exercise delivered by physiotherapists for pain reduction in patients with osteoarthritis of the knee . Design Multicentre , r and omised controlled trial . Setting 37 physiotherapy centres accepting primary care patients referred from general practitioners in the Midl and s , United Kingdom . Participants 352 adults aged 50 or more with a clinical diagnosis of knee osteoarthritis . Interventions Advice and exercise ( n=116 ) , advice and exercise plus true acupuncture ( n=117 ) , and advice and exercise plus non-penetrating acupuncture ( n=119 ) . Main outcome measures The primary outcome was change in scores on the Western Ontario and McMaster Universities osteoarthritis index pain subscale at six months . Secondary outcomes included function , pain intensity , and unpleasantness of pain at two weeks , six weeks , six months , and 12 months . Results Follow-up rate at six months was 94 % . The mean ( SD ) baseline pain score was 9.2 ( 3.8 ) . At six months mean reductions in pain were 2.28 ( 3.8 ) for advice and exercise , 2.32 ( 3.6 ) for advice and exercise plus true acupuncture , and 2.53 ( 4.2 ) for advice and exercise plus non-penetrating acupuncture . Mean differences in change scores between advice and exercise alone and each acupuncture group were 0.08 ( 95 % confidence interval −1.0 to 0.9 ) for advice and exercise plus true acupuncture and 0.25 ( −0.8 to 1.3 ) for advice and exercise plus non-penetrating acupuncture . Similar non-significant differences were seen at other follow-up points . Compared with advice and exercise alone there were small , statistically significant improvements in pain intensity and unpleasantness at two and six weeks for true acupuncture and at all follow-up points for non-penetrating acupuncture . Conclusion The addition of acupuncture to a course of advice and exercise for osteoarthritis of the knee delivered by physiotherapists provided no additional improvement in pain scores . Small benefits in pain intensity and unpleasantness were observed in both acupuncture groups , making it unlikely that this was due to acupuncture needling effects . Trial registration Current Controlled Trials IS RCT N88597683 [3213064] A comparative study between acupuncture and physical therapy in patients with gonarthrosis is reported . Patients treated with physical therapy showed 4 parameters significantly reduced after a treatment duration of 2 weeks , and 7 out of 10 parameters after 4 weeks of therapy . Acupuncture could better 2 parameters but only after 4 weeks of treatment . Although physical therapy was superior in most of the objective measurements , the subjective judgement by the patients of the efficacy of both treatments found no significant difference . In summary acupuncture is thought to be only an additional form of treatment in gonarthrosis [11444887] OBJECTIVES The effectiveness of acupuncture treatment in patients with osteoarthritis of the hip was tested . DESIGN This is a prospect i ve , r and omized , controlled , patient- and investigator-blinded clinical trial . PATIENTS AND SETTING The study was performed at a university department for physical medicine and rehabilitation . Sixty-seven patients were separated into two treatment groups . INTERVENTIONS Group 1 ( treatment ) had traditional needle placement and manipulation , whereas in group 2 ( control ) needles were placed away from classic positions and not manipulated . In both groups needles were placed within the L2 to L5 dermatomes . Outcome parameters were : pain ( VAS ) , functional impairment ( hip score ) , activity in daily life ( ADL ) and overall satisfaction before treatment , and 2 weeks and 2 months after treatment . RESULTS For all parameters there was a significant improvement versus baseline in both groups 2 weeks and 2 months following treatment , but no significant difference between the two treatment groups . CONCLUSIONS We conclude from these results that needle placement in the area of the affected hip is associated with improvement in the symptoms of osteoarthritis . It appears to be less important to follow the rules of traditional acupuncture techniques [7053030] Thirty patients with cervical spine pain syndromes persisting a mean of 8 years were assigned r and omly into equal treatment and control groups . After 12 weeks , 12 of 15 ( 80 % ) of the treated group felt improved , some dramatically , with a mean 40 % reduction of pain score , 54 % reduction of pain pills , 68 % reduction of pain hours per day and 32 % less limitation of activity . Two of 15 ( 13 % ) of the control group reported slight improvement after 12.8 weeks . The control group had a mean 2 % worsening of the pain score , 10 % reduction in pain pills , no lessening of pain hours and 12 % less limitation of activity [11471577] We report a prospect i ve r and omised trial of acupuncture given to 44 patients with advanced osteoarthritis ( OA ) of the knee awaiting total knee joint replacement . Patients were r and omly allocated into two groups , group A receiving acupuncture to the most affected knee only and group B receiving acupuncture to both knees . Acupuncture was given to four local points around the knee and one distal point . The local points were Spleen 9 ( Yinlinquan , SP9 ) , Spleen 10 ( Xuehai , SP10 ) , Stomach 34 ( Liangqui , ST34 ) , and Stomach 36 ( Zusanli , ST36 ) . The distal point was Large Intestine 4 ( Hegu , LI4 ) on the first web space of the ipsilateral h and . A blinded observer assessed knee function before starting treatment , and at the end of two and six months . Analysis of the results showed a significant reduction in symptoms in both groups , and this improvement was sustained for six months . There was no statistically significant difference between the groups . In conclusion , unilateral acupuncture is as effective as bilateral acupuncture in increasing function and reducing the pain associated with OA of the knee . This trial is not able to distinguish the specific from the non-specific effects of the treatment [15100594] Objectives : The aim of the study was to evaluate the therapeutic effect of electro-acupuncture ( EA ) and hydrotherapy , both in combination with patient education or with patient education alone , in the treatment of osteoarthritis in the hip . Methods : Forty-five patients , aged 42–86 years , with radiographic changes consistent with osteoarthritis in the hip , pain related to motion , pain on load , and ache were chosen . They were r and omly allocated to EA , hydrotherapy , both in combination with patient education , or patient education alone . Outcome measures were the disability rating index ( DRI ) , global self-rating index ( GSI ) , and visual analogue scale ( VAS ) . Assessment s were done before the intervention and immediately after the last treatment and 1 , 3 , and 6 months after the last treatment . Results : Pain related to motion and pain on load was reduced up to 3 months after last the treatment in the hydrotherapy group and up to 6 months in the EA group . Ache during the day was significantly improved in both the EA and hydrotherapy group up to 3 months after the last treatment . Ache during the night was reduced in the hydrotherapy group up to 3 months after the last treatment and in the EA group up to 6 months after . Disability in functional activities was improved in EA and hydrotherapy groups up to 6 months after the last treatment . Quality of life was also improved in EA and hydrotherapy groups up to 3 months after the last treatment . There were no changes in the education group alone . Discussion : In conclusion , EA and hydrotherapy , both in combination with patient education , induce long-lasting effects , shown by reduced pain and ache and by increased functional activity and quality of life , as demonstrated by differences in the pre- and post-treatment assessment

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### Context: [16495392] BACKGROUND Glucosamine and chondroitin sulfate are used to treat osteoarthritis . The multicenter , double-blind , placebo- and celecoxib-controlled Glucosamine/chondroitin Arthritis Intervention Trial ( GAIT ) evaluated their efficacy and safety as a treatment for knee pain from osteoarthritis . METHODS We r and omly assigned 1583 patients with symptomatic knee osteoarthritis to receive 1500 mg of glucosamine daily , 1200 mg of chondroitin sulfate daily , both glucosamine and chondroitin sulfate , 200 mg of celecoxib daily , or placebo for 24 weeks . Up to 4000 mg of acetaminophen daily was allowed as rescue analgesia . Assignment was stratified according to the severity of knee pain ( mild [ N=1229 ] vs. moderate to severe [ N=354 ] ) . The primary outcome measure was a 20 percent decrease in knee pain from baseline to week 24 . RESULTS The mean age of the patients was 59 years , and 64 percent were women . Overall , glucosamine and chondroitin sulfate were not significantly better than placebo in reducing knee pain by 20 percent . As compared with the rate of response to placebo ( 60.1 percent ) , the rate of response to glucosamine was 3.9 percentage points higher ( P=0.30 ) , the rate of response to chondroitin sulfate was 5.3 percentage points higher ( P=0.17 ) , and the rate of response to combined treatment was 6.5 percentage points higher ( P=0.09 ) . The rate of response in the celecoxib control group was 10.0 percentage points higher than that in the placebo control group ( P=0.008 ) . For patients with moderate-to-severe pain at baseline , the rate of response was significantly higher with combined therapy than with placebo ( 79.2 percent vs. 54.3 percent , P=0.002 ) . Adverse events were mild , infrequent , and evenly distributed among the groups . CONCLUSIONS Glucosamine and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with osteoarthritis of the knee . Exploratory analyses suggest that the combination of glucosamine and chondroitin sulfate may be effective in the subgroup of patients with moderate-to-severe knee pain . ( Clinical Trials.gov number , NCT00032890 . ) [15478160] OBJECTIVE To assess the efficacy of glucosamine sulfate in knee osteoarthritis ( OA ) . METHODS A 4-center , 6-month , r and omized , double-blind , placebo-controlled glucosamine discontinuation trial was conducted in 137 current users of glucosamine with knee OA who had experienced at least moderate improvement in knee pain after starting glucosamine . Study medication dosage was equivalent to the dosage of glucosamine taken prior to the study ( maximum 1,500 mg/day ) . Followup continued for 6 months or until disease flare , whichever occurred first . The primary outcome was the proportion of disease flares in the glucosamine and placebo groups using an intent-to-treat analysis . Secondary outcomes included time to disease flare ; analgesic medication use ; severity of disease flare ; and change in pain , stiffness , function and quality of life in the glucosamine and placebo groups . RESULTS Disease flare was seen in 28 ( 42 % ) of 66 placebo patients and 32 ( 45 % ) of 71 glucosamine patients ( difference -3 % ; 95 % confidence interval [ 95 % CI ] -19 , 14 ; P = 0.76 ) . In the Cox regression analysis , after adjustment for sex , study site , and OA radiographic severity , time to disease flare was not significantly different in the glucosamine compared with placebo group ( hazard ratio of flare = 0.8 ; 95 % CI 0.5 , 1.4 ; P = 0.45 ) . At final study visit , acetaminophen was used in 27 % and 21 % of placebo and glucosamine patients , respectively ( P = 0.40 ) , nonsteroidal antiinflammatory drugs were used in 29 % and 30 % ( P = 0.92 ) , and both were used in 20 % and 21 % ( P = 0.84 ) . No differences were found in severity of disease flare or other secondary outcomes between placebo and glucosamine patients . CONCLUSION In patients with knee OA with at least moderate subjective improvement with prior glucosamine use , this study provides no evidence of symptomatic benefit from continued use of glucosamine sulfate [15996072] OBJECTIVE To determine whether it is possible to specify different score patterns for hip and knee osteoarthritis ( OA ) , and to identify the degree of responsiveness and the validity of the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) factors , which are alternative health dimensions obtained by factor analysis of the WOMAC items . METHODS WOMAC scales and WOMAC factors were compared in a prospect i ve setting examining patients with hip and knee OA before and after rehabilitative inpatient intervention ( n = 317 ) . In a partial sample ( n = 103 ) , the validity of the WOMAC factors was determined by a global rating of their activities . RESULTS The WOMAC factor " ascending/descending " was significantly different for hip and knee OA in the health state before therapy ( score in hip 5.09 , in knee 6.59 ; p < 0.001 ) ; this was also true of the effect size after therapy ( hip 0.39 , knee 0.65 ; p = 0.012 ) . The WOMAC scales did not differ for the 2 conditions . The WOMAC factor " ascending/descending " was the most responsive dimension in knee OA ( effect size 0.65 ) , but in hip OA the WOMAC pain scale was most responsive ( effect size 0.55 ) . Most of the WOMAC factors correlated moderately ( r = 0.52 - 0.69 ) with the patient 's self-rating on the validation question naire . CONCLUSION The WOMAC factors are valid measures . Analyzing the WOMAC by the WOMAC factors facilitates and improves the differential relevance and accuracy of the WOMAC for specific conditions such as hip and knee OA [18591906] Objectives To compare the effect of acupuncture ( manual and electroacupuncture ) with that of a non-penetrating sham ( ‘ placebo ’ needle ) in patients with osteoarthritic knee pain and disability who are blind to the treatment allocation . Methods Acupuncture naive patients with symptomatic and radiological evidence of osteoarthritis of the knee were r and omly allocated to a course of either acupuncture or non-penetrating sham acupuncture using a sheathed ‘ placebo ’ needle system . Acupuncture points for pain and stiffness were selected according to acupuncture theory for treating Bi syndrome . Both manual and electrical stimulation were used . Response was assessed using the WOMAC index for osteoarthritis of the knee , self reported pain scale , the EuroQol score and plasma β-endorphin . The effectiveness of blinding was assessed . Results There were 34 patients in each group . The primary end point was the change in WOMAC pain score after the course of treatment . Comparison between the two treatment groups found a significantly greater improvement with acupuncture ( mean difference 60 , 95 % CI 5 to 116 , P=0.035 ) than with sham . Within the acupuncture group there was a significant improvement in pain ( baseline 294 , mean change 95 , 95 % CI 60 to 130 , P<0.001 ) which was not seen by those who had sham acupuncture ( baseline 261 , mean change 35 , 95 % CI-10 to 80 , P=0.12 ) . Similar effects within group , but not between groups , were seen with the secondary end points of WOMAC stiffness , WOMAC function , and self reported pain . One month after treatment the between group pain difference had been lost ( mean difference 46 ; 95 % CI −9 to 100 , P=0.10 ) although the acupuncture group was still benefiting compared to baseline ( mean difference 59 ; 95 % CI 16 to 102 , P=0.009 ) . The EuroQol score , a generic measure of health related quality of life , was not altered by the treatments . A minority of patients correctly guessed their treatment group ( 41 % in the acupuncture group and 44 % in the control group ) . Plasma β-endorphin levels were not affected by either treatment . Conclusions Acupuncture gives symptomatic improvement for patients with osteoarthritis of the knee , and is significantly superior to non-penetrating sham acupuncture . The study did not confirm earlier reports of release of plasma β-endorphin during acupuncture [15077933] Background Using an open r and omised controlled study , we examined the effectiveness of manual and electroacupuncture on symptom relief for patients with osteoarthritis of the knee . Methods Patients with symptomatic osteoarthritis of the knee were r and omised to one of three treatment groups . Group A had acupuncture alone , group B had acupuncture but continued on their symptomatic medication , and group C used their symptomatic medication for the first five weeks and then had a course of acupuncture added . Patients receiving acupuncture were treated twice weekly over five weeks . Needles were inserted ( with manual and electrical stimulation ) in acupuncture points for pain and stiffness , selected according to traditional acupuncture theory for treating Bi syndrome . Patients were assessed by a blinded observer before treatment , after five weeks ’ treatment and at one month follow up , using a visual analogue pain scale ( VAS ) and the Western Ontario McMaster ( WOMAC ) question naire for osteoarthritis of the knee . Results The 30 patients in our study were well matched for age , body mass index , disease duration , baseline VAS pain score and baseline WOMAC scores . Repeated measure analyses gave a highly significant improvement in pain ( VAS ) after the courses of acupuncture in groups A ( P=0.012 ) and B ( P=0.001 ) ; there was no change in group C until after the course of acupuncture , when the improvement was significant ( P=0.001 ) . Similarly significant changes were seen with the WOMAC pain and stiffness scores . These benefits were maintained during the one month after the course of acupuncture . Patients ’ rating of global assessment was higher than that of the acupuncturist . Conclusion We conclude that manual and electroacupuncture causes a significant improvement in the symptoms of osteoarthritis of the knee , either on its own or as an adjunct therapy , with no loss of benefit after one month [16046146] Clinical and experimental data indicate that most acupuncture clinical results are mediated by the central nervous system , but the specific effects of acupuncture on the human brain remain unclear . Even less is known about its effects on the cerebellum . This fMRI study demonstrated that manual acupuncture at ST 36 ( Stomach 36 , Zusanli ) , a main acupoint on the leg , modulated neural activity at multiple levels of the cerebro-cerebellar and limbic systems . The pattern of hemodynamic response depended on the psychophysical response to needle manipulation . Acupuncture stimulation typically elicited a composite of sensations termed deqi that is related to clinical efficacy according to traditional Chinese medicine . The limbic and paralimbic structures of cortical and subcortical regions in the telencephalon , diencephalon , brainstem and cerebellum demonstrated a concerted attenuation of signal intensity when the subjects experienced deqi . When deqi was mixed with sharp pain , the hemodynamic response was mixed , showing a predominance of signal increases instead . Tactile stimulation as control also elicited a predominance of signal increase in a subset of these regions . The study provides preliminary evidence for an integrated response of the human cerebro-cerebellar and limbic systems to acupuncture stimulation at ST 36 that correlates with the psychophysical response [6346029] A prospect i ve , controlled clinical trial was undertaken to assess the relative efficacies of physiotherapy and electroacupuncture in the treatment of cervical spondylosis . The results suggested that , while both methods were effective , electroacupuncture produced an earlier symptomatic improvement with increased neck movement , especially in patients with mild degenerative changes of the cervical spine [10378713] OBJECTIVE The purpose of this study was to investigate the efficacy of acupuncture as an adjunctive therapy to st and ard care for the relief of pain and dysfunction in elderly patients with osteoarthritis ( OA ) of the knee . METHODS Seventy-three patients with symptomatic OA of the knee were r and omly assigned to treatment ( acupuncture ) or st and ard care ( control ) . Analysis was performed on last score carried forward to account for patients who dropped out before completion . Patients self-scored Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) and Lequesne indices at baseline and at 4 , 8 and 12 weeks . Patients in the control group were offered acupuncture treatment after 12 weeks . The data for these patients are pooled with those from the original acupuncture group for within-group analysis . RESULTS Patients r and omized to acupuncture improved on both WOMAC and Lequesne indices compared to those who received st and ard treatment alone . Significant differences on total WOMAC Scale were seen at 4 and 8 weeks . There appears to be a slight decline in effect at 4 weeks after cessation of treatment ( 12 weeks after first treatment ) . No adverse effects of acupuncture were reported . CONCLUSION These data suggest that acupuncture is an effective and safe adjunctive therapy to conventional care for patients with OA of the knee [16005336] BACKGROUND Acupuncture is widely used by patients with chronic pain although there is little evidence of its effectiveness . We investigated the efficacy of acupuncture compared with minimal acupuncture and with no acupuncture in patients with osteoarthritis of the knee . METHODS Patients with chronic osteoarthritis of the knee ( Kellgren grade < or = 2 ) were r and omly assigned to acupuncture ( n=150 ) , minimal acupuncture ( superficial needling at non-acupuncture points ; n=76 ) , or a waiting list control ( n=74 ) . Specialised physicians , in 28 outpatient centres , administered acupuncture and minimal acupuncture in 12 sessions over 8 weeks . Patients completed st and ard question naires at baseline and after 8 weeks , 26 weeks , and 52 weeks . The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis ( WOMAC ) index at the end of week 8 ( adjusted for baseline score ) . All main analyses were by intention to treat . RESULTS 294 patients were enrolled from March 6 , 2002 , to January 17 , 2003 ; eight patients were lost to follow-up after r and omisation , but were included in the final analysis . The mean baseline-adjusted WOMAC index at week 8 was 26.9 ( SE 1.4 ) in the acupuncture group , 35.8 ( 1.9 ) in the minimal acupuncture group , and 49.6 ( 2.0 ) in the waiting list group ( treatment difference acupuncture vs minimal acupuncture -8.8 , [ 95 % CI -13.5 to -4.2 ] , p=0.0002 ; acupuncture vs waiting list -22.7 [ -27.5 to -17.9 ] , p<0.0001 ) . After 52 weeks the difference between the acupuncture and minimal acupuncture groups was no longer significant ( p=0.08 ) . INTERPRETATION After 8 weeks of treatment , pain and joint function are improved more with acupuncture than with minimal acupuncture or no acupuncture in patients with osteoarthritis of the knee . However , this benefit decreases over time [17604311] OBJECTIVE To evaluate the effects of st and ardized western acupuncture and physiotherapy on pain and functional ability in patients with severe osteoarthritic knee pain awaiting knee arthroplasty . METHODS Three-arm , assessor-blind , r and omized controlled trial . PARTICIPANTS 181 patients awaiting knee arthroplasty . INTERVENTIONS acupuncture for 6 weeks ; physiotherapy for 6 weeks ; st and ardized advice . MAIN OUTCOME MEASURES Oxford Knee Score question naire ( OKS ) ( primary ) ; 50 m timed walk , and duration of hospital stay following knee arthroplasty . RESULTS There was no baseline difference between groups . At 7 weeks , there was a 10 % reduction in OKS in the acupuncture group which was a significant difference between the acupuncture and the control group : Mean ( s.d . ) acupuncture 36.8 ( 7.20 ) ; physiotherapy 39.2 ( 8.22 ) ; control 40.3 ( 8.48 ) ( P = 0.0497 ) . These effects were no longer present at 12 weeks . There was a trend ( P = 0.0984 ) towards a shorter in-patient stay of 1 day for the physiotherapy group [ mean 6.50 days ( s.d . 2.0 ) ] compared with the acupuncture group [ mean 7.77 days ( s.d . 3.96 ) ] . CONCLUSIONS We have demonstrated that patients with severe knee osteoarthritis can achieve a short-term reduction in OKS when treated with acupuncture . However , we failed to demonstrate any other clinical ly or statically significant effects between the groups . Both interventions can be delivered effectively in an out-patient group setting at a district general hospital . Further study is needed to evaluate the combined effects of these treatments [10729968] The purpose of this study was to compare the effectiveness of transcutaneous nerve stimulation ( TENS ) , electroacupuncture ( EA ) , and ice massage with placebo treatment for the treatment of pain . Subjects ( n = 100 ) diagnosed with osteoarthritis ( OA ) of the knee were treated with these modalities . The parameters for evaluating the effectiveness of treatment include pain at rest , stiffness , 50 foot walking time , quadriceps muscle strength , and knee flexion degree . The results showed ( a ) that all three methods could be effective in decreasing not only pain but also the objective parameters in a short period of time ; and ( b ) that the treatment results in TENS , EA and ice massage were superior to placebo [2268695] Background The present study tests whether a combined treatment of acupuncture and transcutaneous electrical nerve stimulation ( TENS ) is more effective than acupuncture or TENS alone for treating knee osteoarthritis ( OA ) . Methods Thirty-two patients with knee OA were r and omly allocated to four groups . The acupuncture group ( ACP ) received only acupuncture treatment at selected acupoints for knee pain ; the TENS group ( TENS ) received only TENS treatment at pain areas ; the acupuncture and TENS group ( A&T ) received both acupuncture and TENS treatments ; the control group ( CT ) received topical poultice ( only when necessary ) . Each group received specific weekly treatment five times during the study . Outcome measures were pain intensity in a visual analogue scale ( VAS ) and knee function in terms of the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) . Results The ACP , TENS and A&T groups reported lower VAS and WOMAC scores than the control group . Significant reduction in pain intensity ( P = 0.039 ) and significant improvement in knee function ( P = 0.008 ) were shown in the A&T group . Conclusion Combined acupuncture and TENS treatment was effective in pain relief and knee function improvement for the sample d patients suffering from knee OA [15611487] Context Previous studies of acupuncture for osteoarthritis have had conflicting results . This may have occurred because most studies have included small sample s , a limited number of treatment sessions , or other limitations . Contribution This r and omized , controlled trial compared 24 acupuncture sessions over 26 weeks with sham acupuncture or arthritis education in 570 patients with osteoarthritis of the knee . Acupuncture led to greater improvements in function but not pain after 8 weeks and in both pain and function after 26 weeks . No adverse effects were associated with acupuncture . Caution s Many participants dropped out of the study , so readers should interpret the findings at 26 weeks with caution . The Editors Osteoarthritis is the most common form of arthritis and is a major cause of morbidity , limitation of activity , and health care utilization , especially in elderly patients ( 1 , 2 ) . Pain and functional limitation are the primary clinical manifestations of osteoarthritis of the knee . Current recommendations for managing osteoarthritis , including guidelines published by the American College of Rheumatology ( 3 ) and European League of Associations of Rheumatology ( 4 ) , focus on relieving pain and stiffness and maintaining or improving physical function as important goals of therapy . No curative therapies exist for osteoarthritis ; thus , both pharmacologic and nonpharmacologic management focus on controlling pain and reducing functional limitation ( 5 ) . Nonpharmacologic therapy , which includes patient education , social support , physical and occupational therapy , aerobic and resistive exercises , and weight loss , is the cornerstone of a multidisciplinary approach to osteoarthritis patient management ( 3 ) . Pharmacologic therapies include nonopioid analgesics ( such as acetaminophen ) , nonsteroidal anti-inflammatory drugs ( NSAIDs ) ( including cyclooxygenase-2 [ COX-2 ] enzyme selective inhibitors ) , topical analgesics ( capsaicin cream ) , opioid analgesics , and intra-articular steroid and hyaluronate injections . Often , these agents are used in combination for additive analgesic efficacy ( 6 ) . Pharmacologic management of osteoarthritis is often ineffective , and agents such as NSAIDs may cause unwanted and dangerous side effects ( 7 , 8) . Complementary and alternative medicine is another approach to treating osteoarthritis ( 9 - 12 ) , particularly in Asian societies ( 13 ) . Many U.S. patients with osteoarthritis also use complementary and alternative medical therapies ( 14 ) . A systematic review of acupuncture and knee osteoarthritis ( 15 ) identified 7 small r and omized , controlled trials published in English . Within the method ologic limitations of the studies , the evidence suggested that acupuncture seemed to alleviate knee pain and function compared with sham acupuncture controls , although 2 trials comparing acupuncture with an active , nonpharmacologic treatment ( physical therapy ) did not indicate such an effect ( 16 , 17 ) . Before conducting our large-scale trial , we completed both a pilot study ( 18 ) and a r and omized , single-blind trial ( 19 ) of the effect of acupuncture on osteoarthritis of the knee . Participants in the uncontrolled pilot study ( n= 12 ) showed statistically significant improvement in both self-reported pain and physical function , as well as performance measures of physical function after 8 weeks of acupuncture treatment and at 12-week follow-up as compared with their baseline ( 18 ) . In our larger r and omized , single-blind trial ( n= 73 ) , which examined the benefit of acupuncture added to st and ard management with NSAIDs , the acupuncture treatment group experienced statistically significant improvements in self-reported pain and disability scores compared with a st and ard-care control group as late as 4 weeks after the end of treatment ( 19 ) . However , this effect diminished within 18 weeks ( 26 weeks after the beginning of the trial ) after the final acupuncture treatment . Together , however , the previously conducted trials ( both our preliminary studies [ 18 , 19 ] and those referenced in the systematic review [ 15 ] ) have 3 method ologic limitations : lack of credible controls for the placebo effect , inadequate assessment of long-term treatment benefits , and insufficient sample sizes . We tested the hypothesis that an 8-week intensive acupuncture treatment regimen , followed by an 18-week tapering regimen , reduces pain and improves function among patients with knee osteoarthritis as compared with both sham acupuncture and education control groups . Methods Patient Recruitment We recruited patients for this multisite , placebo-controlled trial from March 2000 through December 2003 , primarily through print and radio advertisements . The 3 sites were the Integrative Medicine Clinic of the University of Maryl and School of Medicine , Baltimore , Maryl and ; the Innovative Medical Research Center ( a private research firm ) , Towson , Maryl and ; and the Hospital for Special Surgery , New York City , New York . The institutional review boards of the 3 sites approved the study . We determined the sample size ( n= 570 ) by a power analysis based on our r and omized pilot study ( 19 ) , adjusted by the estimated decrease in effect size result ing from the inclusion of a sham acupuncture group design ed to control for placebo effects . Patients met the following inclusion criteria : age 50 years or older , a diagnosis of osteoarthritis of the knee , radiographic evidence of at least 1 osteophyte at the tibiofemoral joint ( KellgrenLawrence grade 2 ) , moderate or greater clinical ly significant knee pain on most days during the past month , and willingness to be r and omly assigned . Exclusion criteria were the presence of serious medical conditions that precluded participation in study , bleeding disorders that might contraindicate acupuncture , intra-articular corticosteroid or hyaluronate injections ( as well as any knee surgeries or concomitant use of topical capsaicin cream ) during the past 6 months , previous experience with acupuncture , or any planned events ( including total knee replacement ) that would interfere with participation in the study during the following 26 weeks . After a brief telephone screening , patients were scheduled to visit 1 of the 3 participating sites to sign an informed consent statement and undergo a brief rheumatologic examination ( including radiographic examination of affected knees ) by a physician or a nurse practitioner . Because the education course was a group activity , patients were recruited until a cohort of 12 to 21 patients was formed , at which point each cohort at each site was r and omly assigned to 1 of 3 groups by a computer-generated process using r and omly selected blocks of 3 , 6 , and 9 . We assured allocation concealment by using disguised letter codes that were generated and sent to the site coordinators by a central statistical core . We used this procedure to ensure that approximately equal numbers of participants were in each treatment group across the course of the study , to ensure that each cohort would have participants assigned to all 3 treatment groups , and to make the breaking of the group assignment process more difficult . The research assistants who collected assessment s from participants , the participants themselves ( in the true acupuncture and sham acupuncture groups ) , and the statistician were blinded to group assignment . Assessment s were conducted at baseline and 4 , 8 , 14 , and 26 weeks after r and omization . Study Interventions We developed and modified the acupuncture treatment and sham control protocol s from previously reported and vali date d procedures ( 18 - 21 ) . During the trial , 7 acupuncturists were used : 3 at the Integrative Medicine Clinic , 3 at the Innovative Medical Research Center , and 1 at the Hospital for Special Surgery . In general , acupuncturists were assigned to the same participants throughout the 26-week treatment schedule , except for vacation conflicts and staff turnover , and provided approximately the same proportions of true versus sham procedures . All acupuncturists were state-licensed and had at least 2 years of clinical experience . The study 's principal acupuncturist trained and supervised the acupuncturists in performing true or sham procedures and avoiding interactions that could inadvertently communicate group assignment . True Acupuncture The true acupuncture ( experimental ) group underwent 26 weeks of gradually tapering treatment according to the following schedule : 8 weeks of 2 treatments per week followed by 2 weeks of 1 treatment per week , 4 weeks of 1 treatment every other week , and 12 weeks of 1 treatment per month . We based the acupuncture point selection s on Traditional Chinese Medicine meridian theory to treat knee joint pain , known as the Bi syndrome . These points consisted of 5 local points ( Yanglinquan [ gall bladder meridian point 34 ] , Yinlinquan [ spleen meridian point 9 ] , Zhusanli [ stomach meridian point 36 ] , Dubi [ stomach meridian point 35 ] , and extra point Xiyan ) and 4 distal points ( Kunlun [ urinarybladder , meridian point 60 ] , Xuanzhong [ gall bladder meridian point 39 ] , Sanyinjiao [ spleen meridian point 6 ] , and Taixi [ kidney meridian point 3 ] ) on meridians that traverse the area of pain ( 22 , 23 ) . The same points were treated for each affected leg . If both knees were affected , 9 needles were inserted in each leg . ( The outcome measures were not specifically targeted to whether the patient had osteoarthritis in 1 or both knees , and we observed no differential effects on the basis of the number of knees treated . ) The acupuncturists inserted 1.5-inch ( for local points ) and 1-inch ( for distal points ) 32-gauge ( 0.25-mm diameter ) acupuncture needles to a conventional depth of approximately 0.3 to 1.0 inch , depending on point location . All participants in the treatment group achieved the De-Qi sensation , a local sensation of heaviness , numbness , soreness , or paresthesia that accompanies the insertion and manipulation of needles during acupuncture , at these 9 points . Acupuncturists applied electrical [16505266] BACKGROUND Acupuncture is widely used by patients with low back pain , although its effectiveness is unclear . We investigated the efficacy of acupuncture compared with minimal acupuncture and with no acupuncture in patients with chronic low back pain . METHODS Patients were r and omized to treatment with acupuncture , minimal acupuncture ( superficial needling at nonacupuncture points ) , or a waiting list control . Acupuncture and minimal acupuncture were administered by specialized acupuncture physicians in 30 outpatient centers , and consisted of 12 sessions per patient over 8 weeks . Patients completed st and ardized question naires at baseline and at 8 , 26 , and 52 weeks after r and omization . The primary outcome variable was the change in low back pain intensity from baseline to the end of week 8 , as determined on a visual analog scale ( range , 0 - 100 mm ) . RESULTS A total of 298 patients ( 67.8 % female ; mean + /- SD age , 59 + /- 9 years ) were included . Between baseline and week 8 , pain intensity decreased by a mean + /- SD of 28.7 + /- 30.3 mm in the acupuncture group , 23.6 + /- 31.0 mm in the minimal acupuncture group , and 6.9 + /- 22.0 mm in the waiting list group . The difference for the acupuncture vs minimal acupuncture group was 5.1 mm ( 95 % confidence interval , -3.7 to 13.9 mm ; P = .26 ) , and the difference for the acupuncture vs waiting list group was 21.7 mm ( 95 % confidence interval , 13.9 - 30.0 mm ; P<.001 ) . Also , at 26 ( P=.96 ) and 52 ( P=.61 ) weeks , pain did not differ significantly between the acupuncture and the minimal acupuncture groups . CONCLUSION Acupuncture was more effective in improving pain than no acupuncture treatment in patients with chronic low back pain , whereas there were no significant differences between acupuncture and minimal acupuncture [14629842] OBJECTIVES To examine the relative effectiveness of electro-acupuncture ( EA ) and transcutaneous electrical nerve stimulation ( TENS ) in alleviating osteoarthritic (OA)-induced knee pain . DESIGN Single-blinded , r and omized controlled study . SUBJECTS Twenty-four ( 24 ) subjects ( 23 women and 1 man ) , mean age 85 , were recruited from eight subsidized Care & Attention Homes for the elderly . INTERVENTIONS Subjects were r and omly assigned to the EA , TENS , or control groups . Subjects in the EA group ( n = 8) received low-frequency EA ( 2 Hz ) on two acupuncture points ( ST-35 , Dubi and EX-LE-4 , Neixiyan ) of the painful knee for 20 minutes . Subjects in the TENS group ( n = 8) received low-frequency TENS of 2 Hz and pulse width of 200 micros on the same acupuncture points for 20 minutes . In both treatment groups , electrical treatment was carried out for a total of eight sessions in 2 weeks . Eight subjects received osteoarthritic knee care and education only in a control group . All subjects were evaluated before the first treatment , after the last treatment , and at 2-week follow-up periods . RESULTS After eight sessions of treatment , there was significant reduction of knee pain in both EA group and TENS group , as measured by the Numeric Rating Scale ( NRS ) of pain ( p < 0.01 ) . Prolonged analgesic effect was maintained in the EA and the TENS groups at a 2-week follow-up evaluation . The Timed Up- and -Go Test ( TUGT ) score of the EA group was significantly lower than that of the control group ( p < 0.05 ) , but such change was not observed in the TENS group . CONCLUSIONS Both EA and TENS treatments were effective in reducing OA-induced knee pain . EA had the additional advantage of enhancing the TUGT results as opposed to TENS treatment or no treatment , which did not produce such corollary effect [15611488] Context Chronic neck pain is a common , disabling condition and is difficult to treat . Because traditional therapies , such as physical therapy and nonsteroidal anti-inflammatory drugs , have limited effectiveness and can have adverse effects , many patients seek alternative therapies , such as acupuncture . Contribution This r and omized , controlled trial of acupuncture versus sham transcutaneous electrical stimulation for patients with chronic mechanical neck pain identified no clinical ly significant benefit of acupuncture over placebo with respect to pain , function , or analgesic use . Implication s Acupuncture did not lead to clinical ly significant improvement in chronic mechanical neck pain when compared with placebo . The Editors Chronic mechanical neck pain can be caused by dysfunction of a variety of structures within the neck ( 1 - 3 ) but specifically excludes systemic problems such as rheumatoid arthritis . It is usually associated with unspecified degenerative changes ( cervical spondylosis ) that include osteoarthritis . Neck pain presents a substantial problem and may be responsible for as many days of work absenteeism as low back pain ( 4 ) . Osteoarthritis is the most common of the chronic diseases and affects most people older than 65 years of age ( 5 ) . It is degenerative and progressive in nature ( 1 - 3 , 6 ) . Because there is no cure for cervical spondylosis , treatment tends to center on symptom relief ( 7 , 8) . If the condition is symptomatic and symptoms are left untreated , this manifests as increasing episodic pain , stiffness , or both , and patients may then experience a spiral of increasing dysfunction ( 9 ) . Two systematic review s of conventional conservative physical therapy suggest that little evidence supports the efficacy of such intervention ( 8 , 10 ) . Nonsteroidal anti-inflammatory drugs , the mainstay of pharmacologic treatment , are associated with a wide spectrum of serious and well-documented adverse reactions ( 5 ) . There has been a huge increase in the use of complementary and alternative medicine in both the United States and the United Kingdom ( 11 , 12 ) . Acupuncture is the most frequently used type of complementary and alternative medicine therapy for the treatment of osteoarthritis ( 13 ) . Despite little sound evidence of efficacy ( 14 ) , approximately 1 million people seek complementary and alternative medicine treatment annually in the United States ( 15 ) . Two systematic review s of acupuncture in neck pain ( 4 , 16 ) suggest that there has been insufficient research in this area and that the published studies are of poor quality . Therefore , we conducted a rigorous evaluation to test whether western-style acupuncture performs better than placebo for treatment of chronic mechanical neck pain . We defined western acupuncture as a conventional diagnosis followed by individualized acupuncture treatment using a combination of prescriptive tender , local , and distal points . This is in contrast to a traditional Chinese approach , which would formulate an individualized diagnosis based on traditional Chinese theories of meridians and energy ( or qi ) . Methods Study Design and Patient Selection We design ed a r and omized , single-blind , placebo-controlled trial using a pragmatic treatment regimen . The study was conducted in the outpatient departments of Southampton General Hospital and Salisbury District Hospital in the United Kingdom . Between 1999 and 2001 , patients were referred by rheumatologists or family physicians or from physiotherapy waiting lists . Appropriate ethical approval was obtained from the Southampton and South West Hampshire Joint Research Ethics Committee . Patients were 18 to 80 years of age , had chronic ( > 2 months ) mechanical neck pain , and had a pain score of more than 30 mm on a visual analogue scale ( VAS ) for 5 of 7 pretreatment days ( possible score on this VAS ranges from 0 to 100 mm ) . We excluded pregnant patients ; those with a history of fracture or surgery to the neck , cervical congenital abnormality , uncontrolled low back pain , contraindication to acetaminophen , systemic illness ( for example , rheumatoid arthritis ) , or ongoing neck-related litigation or disability cl aims ; and those with current or recent manual neck treatment or steroid use ( oral or local injection ) . Sample Size Previous studies suggested a 50 % to 75 % improvement using acupuncture for patients with chronic pain , compared with 30 % for placebo treatment ( 17 ) . We used these findings as the basis for our power calculation . At 5 % significance and 90 % power , 53 patients were required in each group to detect a 30 % difference in response between active and placebo treatments . Interventions Informed consent was obtained along with a full medical history , neurologic examination , cervical radiography , and laboratory investigations ( full blood count , erythrocyte sedimentation rate , and liver function tests ) . We told patients that we were comparing 2 types of intervention : 1 ) acupuncture with needles and 2 ) treatment with a machine design ed to stimulate acupuncture points through skin electrodes . The patients were informed that the treatment might or might not prove to be effective and that there was a 50 % chance that they would be assigned to a placebo but were not told what the placebo was . Blinding was not broken until 1 year after treatment . One practitioner performed all interventions . Acupuncture We used single-use , sterile , silver-h and le , prepacked needles without guide tubes . Sizes used were 13 mm 0.25 mm , 25 mm 0.25 mm , and 40 mm 0.25 mm . We based point selection on individualized western acupuncture techniques by using a list of points previously reported as being effective in neck pain ( 18 , 19 ) and by reaching a consensus according to our own clinical and teaching practice ( Appendix Table ) . The specific points for each individual were defined at each treatment session , depending on the patient 's pain distribution and palpation of the neck and thorax to determine ah-shi points , or local tender points , for acupuncture . At least 1 distal point was used . Point location and depth of insertion were as described in traditional texts ( 19 ) . Six points on average , per side if pain was bilateral , were used on each patient , and deqi ( a term used to describe acupuncture needle sensation ) was obtained on each needle . Twenty-minute treatment sessions were given . The patient was checked every 6 or 7 minutes to ascertain whether deqi was still present , and needles were manipulated again if required . Placebo There is considerable debate about the ideal placebo for acupuncture studies ( 20 ) . To enhance the rigor of our study , we chose to use a previously well-vali date d placebo ( 17 , 21 - 23 ) that could not have a specific physiologic effect . The Noma FM-4 electroacupuncture stimulator ( Noma Ltd. , Southampton , United Kingdom ) was used . It has 4 channels , allowing pseudostimulation of up to 8 acupuncture points simultaneously , and emits visual and audio signals . Reusable electrodes ( Body Clock Health Care Ltd. , London , United Kingdom ) were fixed to the surface of the patient 's skin and were connected to the stimulator through decommissioned cables . The cables were severed inside the output plug , so that no current could reach the patient . Examination and point selection were the same as with real acupuncture for each treatment . Point location and treatment variables were changed during subsequent treatment sessions if patients felt they were not progressing . Patients were told that the machine could stimulate acupuncture points through high-frequency , low-intensity stimulation and therefore would not produce any sensation . If patients reported sensation , the therapist adjusted the unit for comfort ( although since this was a sham procedure , such adjustment made no real difference ) . Patients in both groups were instructed to use acetaminophen alone for pain relief and were not given or permitted any other form of treatment , including exercises or stretches , during the study and for 2 months after treatment ended . Patients were treated twice per week for 4 weeks . The therapist had taken an Acupuncture Association of Chartered Physiotherapists accredited course on western acupuncture techniques and had 7 years of experience practicing acupuncture . R and omization R and omization lists for Southampton General Hospital and Salisbury District Hospital were generated by using a computer program , R and omlogue , produced by Southampton University Department of Medical Statistics , Southampton , United Kingdom . Sealed envelopes containing the individual r and omization codes , numbered consecutively with sex and age strata , were then prepared ( sex strata were male and female , and age strata were 18 to 49 years and 50 to 80 years ) Patients were strictly allocated across 4 strata for either of the study hospitals according to the next available envelope number . Data Collection Before r and omization , patients were instructed to use a daily pain diary ( on a VAS ) to record pain and acetaminophen use for 7 consecutive days . After a week , the pain diaries were examined , and if the inclusion criteria ( which were unknown to the patients ) were satisfied , r and omization occurred . Patients completed the various question naires before treatment and at 1 and 8 weeks after treatment . Pain continued to be recorded either weekly or daily throughout treatment and up to 8 weeks after treatment . Additional question naires and pain evaluation were also completed at 6 and 12 months after treatment . Figure 1 shows a flow chart of the trial . Figure 1 . Study flow with outcome assessment s. Outcomes The VAS score for pain 1 week after treatment , recorded daily for 7 consecutive days , was the primary outcome . Pain was recorded on a scale of 0 mm ( indicating no pain ) to 100 mm ( indicating worst pain imaginable ) . A significant outcome for acupuncture was considered to be a 30 % difference in VAS score between groups 5 weeks after r and omization ( 1 week after treatment ) , taking into account baseline pain . Secondary [11879884] Blinding embodies a rich history spanning over two centuries . Most research ers worldwide underst and blinding terminology , but confusion lurks beyond a general comprehension . Terms such as single blind , double blind , and triple blind mean different things to different people . Moreover , many medical research ers confuse blinding with allocation concealment . Such confusion indicates misunderst and ings of both . The term blinding refers to keeping trial participants , investigators ( usually health-care providers ) , or assessors ( those collecting outcome data ) unaware of the assigned intervention , so that they will not be influenced by that knowledge . Blinding usually reduces differential assessment of outcomes ( information bias ) , but can also improve compliance and retention of trial participants while reducing biased supplemental care or treatment ( sometimes called co-intervention ) . Many investigators and readers naïvely consider a r and omised trial as high quality simply because it is double blind , as if double-blinding is the sine qua non of a r and omised controlled trial . Although double blinding ( blinding investigators , participants , and outcome assessors ) indicates a strong design , trials that are not double blinded should not automatically be deemed inferior . Rather than solely relying on terminology like double blinding , research ers should explicitly state who was blinded , and how . We recommend placing greater credence in results when investigators at least blind outcome assessment s , except with objective outcomes , such as death , which leave little room for bias . If investigators properly report their blinding efforts , readers can judge them . Unfortunately , many articles do not contain proper reporting . If an article cl aims blinding without any accompanying clarification , readers should remain sceptical about its effect on bias reduction [16452103] Abstract Objective To investigate whether a sham device ( a vali date d sham acupuncture needle ) has a greater placebo effect than an inert pill in patients with persistent arm pain . Design A single blind r and omised controlled trial created from the two week placebo run-in periods for two nested trials that compared acupuncture and amitriptyline with their respective placebo controls . Comparison of participants who remained on placebo continued beyond the run-in period to the end of the study . Setting Academic medical centre . Participants 270 adults with arm pain due to repetitive use that had lasted at least three months despite treatment and who scored ≥3 on a 10 point pain scale . Interventions Acupuncture with sham device twice a week for six weeks or placebo pill once a day for eight weeks . Main outcome measures Arm pain measured on a 10 point pain scale . Secondary outcomes were symptoms measured by the Levine symptom severity scale , function measured by Pransky 's upper extremity function scale , and grip strength . Results Pain decreased during the two week placebo run-in period in both the sham device and placebo pill groups , but changes were not different between the groups ( −0.14 , 95 % confidence interval −0.52 to 0.25 , P = 0.49 ) . Changes in severity scores for arm symptoms and grip strength were similar between groups , but arm function improved more in the placebo pill group ( 2.0 , 0.06 to 3.92 , P = 0.04 ) . Longitudinal regression analyses that followed participants throughout the treatment period showed significantly greater downward slopes per week on the 10 point arm pain scale in the sham device group than in the placebo pill group ( −0.33 ( −0.40 to −0.26 ) v −0.15 ( −0.21 to −0.09 ) , P = 0.0001 ) and on the symptom severity scale ( −0.07 ( −0.09 to −0.05 ) v −0.05 ( −0.06 to −0.03 ) , P = 0.02 ) . Differences were not significant , however , on the function scale or for grip strength . Reported adverse effects were different in the two groups . Conclusions The sham device had greater effects than the placebo pill on self reported pain and severity of symptoms over the entire course of treatment but not during the two week placebo run in . Placebo effects seem to be malleable and depend on the behaviours embedded in medical rituals [1277952] Introduction Use of complementary and alternative medicine ( CAM ) for chronic conditions has increased in recent years . There is little information , however , on CAM use among adults with clinic-confirmed diagnoses , including arthritis , who are treated by primary care physicians . Methods To assess the frequency and types of CAM therapy used by Hispanic and non-Hispanic white women and men with osteoarthritis , rheumatoid arthritis , or fibromyalgia , we used stratified r and om selection to identify 612 participants aged 18–84 years and seen in university-based primary care clinics . Respondents completed an interviewer-administered survey in English or Spanish . Results Nearly half ( 44.6 % ) of the study population was of Hispanic ethnicity , 71.4 % were women , and 65.0 % had annual incomes of less than $ 25,000 . Most ( 90.2 % ) had ever used CAM for arthritis , and 69.2 % were using CAM at the time of the interview . Current use was highest for oral supplements ( mainly glucosamine and chondroitin ) ( 34.1 % ) , mind-body therapies ( 29.0 % ) , and herbal topical ointments ( 25.1 % ) . Fewer participants made current use of vitamins and minerals ( 16.6 % ) , herbs taken orally ( 13.6 % ) , a CAM therapist ( 12.7 % ) , CAM movement therapies ( 10.6 % ) , special diets ( 10.1 % ) , or copper jewelry or magnets ( 9.2 % ) . Those with fibromyalgia currently used an average of 3.9 CAM therapies versus 2.4 for those with rheumatoid arthritis and 2.1 for those with osteoarthritis . Current CAM use was significantly associated with being female , being under 55 years of age , and having some college education . Conclusion Hispanic and non-Hispanic white arthritis patients used CAM to supplement conventional treatments . Health care providers should be aware of the high use of CAM and incorporate questions about its use into routine assessment s and treatment planning [15527186] An estimated 40,000 physicians offer acupuncture treatment to patients in Germany . Due to a decision of the German Federal Committee of SHI-accredited Physicians and Health Insurance Funds , acupuncture treatment for chronic low back pain , headache and osteoarthritic pain may be reimbursed from 2000 onwards if patients and physicians participate in specific scientifically evaluated model projects of the Statutory Health Insurance Funds . Currently , three separate acupuncture programmes are offered by different Statutory Health Insurance Funds . The scientific evaluation of all these programmes includes both r and omised trials ( comparing acupuncture to no treatment , sham acupuncture or st and ard treatment in 300 to several thous and s of patients ) and large cohort studies . Details of the three programmes will be presented in the following chapters [395837] Background Controlled clinical trials produced contradictory results with respect to a specific analgesic effect of acupuncture . There is a lack of large multi-centre acupuncture trials . The German Acupuncture Trial represents the largest multi-centre study of acupuncture in the treatment of chronic pain caused by gonarthrosis up to now . Methods 900 patients will be r and omised to three treatment arms . One group receives verum acupuncture , the second sham acupuncture , and the third conservative st and ard therapy . The trial protocol is described with eligibility criteria , detailed information on the treatment definition , blinding , endpoints , safety evaluation , statistical methods , sample size determination , monitoring , legal aspects , and the current status of the trial . Discussion A critical discussion is given regarding the considerations about st and ardisation of the acupuncture treatment , the choice of the control group , and the blinding of patients and observers [11900500] [ The cure for the headache ] was a kind of leaf , which required to be accompanied by a charm , and if a person would repeat the charm at the same time that he used the cure , he would be made whole ; but that without the charm the leaf would be of no avail . Socrates , according to Plato ( 1 ) There is a renewed interest in placebos and the placebo effecton their reality , their ethics , their place in medicine , or not , both in and out of the clinic and academy . The U.S. National Institutes of Health recently sponsored a large conference called Science of the Placebo ( 2 ) . At least five serious books on the subject ( 3 - 7 ) plus a book of poetry ( 8) and a novel (9)each titled Placebo Effecthave been published since 1997 . In the past 10 years , the National Library of Medicine has annually listed an average of 3972 scholarly papers with the keywords placebo , placebos , or placebo effect , with a low of 3362 papers in 1992 and a high of 4814 in 2000 . During the fall of 2000 , a discussion of the effect of new drag free suits , which might give an edge to Olympic swimmers , appeared in US News and World Report : [S]wimming officials are n't convinced this is anything more than the placebo effect . Swimmers excel because they think they 've got an edge ( 10 ) . One widely reported study , which concluded that placebos were powerless ( 11 ) , or represented the Wizard of Oz ( 12 ) , occasioned a blizzard of criticism ( 13 - 26 ) and some support ( 27 ) . It 's in the papers ( 28 , 29 ) . It 's in the air . Yet the most recent serious attempt to try logically to define the placebo effect failed utterly ( 30 ) . Given the ways people have gone about it , this seems unsurprising . Arthur K. Shapiro , MD , who spent much of his career as a psychiatrist study ing the placebo effect , recently wrote : A placebo is a substance or procedure that is objective ly without specific activity for the condition being treated The placebo effect is the therapeutic effect produced by a placebo . ( 31 ) If we replace the word placebo in the second sentence with its definition from the first , we get : The placebo effect is the therapeutic effect produced by [ things ] objective ly without specific activity for the condition being treated . This makes no sense whatsoever . Indeed , it flies in the face of the obvious . The one thing of which we can be absolutely certain is that placebos do not cause placebo effects . Placebos are inert and do n't cause anything . Moreover , people frequently exp and the concept of the placebo effect very broadly to include just about every conceivable sort of beneficial biological , social , or human interaction that does n't involve some drug well-known to the pharmacopoeia . A narrower form of this expansion includes identifying natural history or regression to the mean ( as we might observe them in a r and omized , controlled trial ) as part of the placebo effect . But natural history and regression occur not only in the control group . Nothing in the theory of regression to the mean ( 31 ) hints that when people are selected for being extreme on some measure ( blood pressure or cholesterol , for example ) , they are immune to regression if they receive active treatment . Such recipients are as likely ( or unlikely ) to move toward homeostasis as are control group patients . So , regression to the mean is in no meaningful way a placebo effect . Ernst and Resch ( 32 ) took an important step in trying to clarify this situation by differentiating the true from the perceived placebo effect . But true placebo effect has n't really caught on as a viable concept . The concept of the placebo effect has been exp and ed much more broadly than this . Some attribute the effects of various alternative medical systems , such as homeopathy ( 33 ) or chiropractic ( 34 ) , to the placebo effect . Others have described studies that show the positive effects of enhanced communication , such as Egbert 's ( 35 ) , as the placebo response without the placebo ( 7 ) . No wonder things are confusing . Meaning and Medicine We suggest thinking about this issue in a new way . A group of medical students was asked to participate in a study of two new drugs , one a tranquilizer and the other a stimulant [ 36 ] . Each student was given a packet containing either one or two blue or red tablets ; the tablets were inert . The students ' responses to a question naire indicated that 1 ) the red tablets acted as stimulants while the blue ones acted as depressants and 2 ) two tablets had more effect than one . The students were not responding to the inertness of the tablets . Moreover , these responses can not be easily accounted for by natural history , regression to the mean , or physician enthusiasm [ presumably the experimenters were as enthusiastic about the reds as the blues ] . Instead , they can be explained by the meanings in the experiment : 1 ) Red means up , hot , danger , while blue means down , cool , quiet and 2 ) two means more than one . These effects of color ( 37 - 40 ) and number ( 41 , 42 ) have been widely replicated . In a British study , 835 women who regularly used analgesics for headache were r and omly assigned to one of four groups ( 43 ) . One group received aspirin labeled with a widely advertised br and name ( one of the most popular analgesics in the United Kingdom that had been widely available for many years and supported by extensive advertising ) . The other groups received the same aspirin in a plain package , placebo marked with the same widely advertised br and name , or unmarked placebo . In this study , br and ed aspirin worked better than unbr and ed aspirin , which worked better than br and ed placebo , which worked better than unbr and ed placebo . Among 435 headaches reported by br and ed placebo users , 64 % were reported as improved 1 hour after pill administration compared with only 45 % of the 410 headaches reported as improved among the unbr and ed placebo users . Aspirin relieves headaches , but so does the knowledge that the pills you are taking are good ones . In a study of the benefits of aerobic exercise , two groups participated in a 10-week exercise program . One group was told that the exercise would enhance their aerobic capacity , while the other group was told that the exercise would enhance aerobic capacity and psychological well-being . Both groups improved their aerobic capacity , but only the second group improved in psychological well-being ( actually self-esteem ) . The research ers called this strong evidence that exercise may enhance psychological well-being via a strong placebo effect ( 44 ) . In the red versus blue pill study , we can correctly ( if not very helpfully ) classify the responses of the students as placebo effects because they did indeed receive inert tablets ; it seems clear , however , that they responded not to the pills but to their colors . In the second study , the presence of the br and name enhanced the effect of both the inert and the active drug . It does n't seem reasonable to classify the br and name effect as a placebo effect because no placebos are necessarily involved . Meanwhile , calling the consequences of authoritative instruction to the exercisers a placebo effect could come only from someone who believes that words do not affect the world , someone who has never been told I love you or who has never read the review s of a rejected grant proposal . It seems reasonable to label all these effects ( except , of course , of the aspirin and the exercise ) as meaning responses , a term that seeks , among other things , to recall Dr. Herbert Benson 's relaxation response ( 45 ) . Ironically , although placebos clearly can not do anything themselves , their meaning can . We define the meaning response as the physiologic or psychological effects of meaning in the origins or treatment of illness ; meaning responses elicited after the use of inert or sham treatment can be called the placebo effect when they are desirable and the nocebo effect ( 46 ) when they are undesirable . This is obviously a complex notion with several terms that would be challenging to unpack ( desirable , effect , meaning , treatment , illness)an exercise that can not be carried out here . Note that this definition excludes several elements that are usually included in our underst and ing of the placebo effect , such as natural history , regression , experimenter or subject bias , and error in measurement or reporting . Note as well that the definition is not phrased in terms of nonspecific effects ; although many elements of the meaning response or placebo effect may seem nonspecific , they are often quite specific in principle after they are understood . Meaning Permeates Medical Treatment Insofar as medicine is meaningful , it can affect patients , and it can affect the outcome of treatment ( 47 - 49 ) . Most elements of medicine are meaningful , even if practitioners do not intend them to be so . The physician 's costume ( the white coat with stethoscope hanging out of the pocket ) ( 50 ) , manner ( enthusiastic or not ) , style ( therapeutic or experimental ) , and language ( 51 ) are all meaningful and can be shown to affect the outcome ; indeed , we argue that both diagnosis ( 52 ) and prognosis ( 53 ) can be important forms of treatment . Many studies can be cited to document aspects of the therapeutic quality of the practitioner 's manner ( 54 ) . In one , a strong message of the effect of a drug ( an inert capsule ) substantially reduced the patients ' report of the pain of m and ibular block injection compared with the pain after a weak message . Patients who received the weak message reported less pain than a group that received no placebos and no message at all ( 55 ) . In another study , 200 patients with symptoms but no abnormal physical signs were r and omly assigned to a positive or a negative consultation . In a survey of patients 2 weeks later , 64 % of patients in the positive consultation group said they were all better , while only 39 % of those who had negative consultations thought they were better ( 56 ) . Although there is strong evidence for such physician effects , little evidence shows that patient effects are very important . A mass of research in the [11471578] Acupuncture is becoming a common technique within the physiotherapy profession as a treatment modality for pain relief ; however , few r and omised controlled trials have been undertaken to assess the effectiveness of acupuncture , particularly in the treatment of osteoarthritis ( OA ) of the hip . Therefore , a r and omised trial to compare the effectiveness of acupuncture with advice and exercises on the symptomatic treatment of OA of the hip was carried out . Thirty-two patients awaiting a total hip arthroplasty were r and omly allocated to either the experimental group , ( A ) , to have six sessions of acupuncture each lasting up to 25 minutes , or the control group , ( B ) , to be given advice and exercises for their hip over a six week period . Group A consisted of three men and 13 women , and group B consisted of four men and eight women . The average age in group A was 66 years and in group B it was 68 years . Patients were assessed for pain and functional ability , using a modified version of the WOMAC question naire , pre-treatment , immediately post-treatment and at eight weeks post-treatment . The pre-treatment WOMAC scores in the two groups were similar ( p=0.85 ) . There was a significant improvement in group A ( decrease in WOMAC score ) immediately post-treatment ( p=0.002 ) and this was maintained at the eight-week follow-up ( p=0.03 ) . There were no significant changes in group B. When the changes in WOMAC scores were compared between groups , a significantly greater improvement was found between pre-treatment and immediately post-treatment in group A , compared with group B ( p=0.02 ) . The changes between pre-treatment and the eight-week follow-up also showed a significant improvement in group A compared with group B ( p=0.03 ) . In conclusion , this trial supports the hypothesis that acupuncture is more effective than advice and exercises in the symptomatic treatment of OA of the hip [102323] Background The purpose of this study was to compare the efficacy of electroacupuncture ( EA ) , diclofenac and their combination in symptomatic treatment of osteoarthritis ( OA ) of the knee . Methods This study was a r and omized , single-blind , placebo controlled trial . The 193 out- patients with OA of the knee were r and omized into four groups : placebo , diclofenac , EA and combined ( diclofenac plus EA ) . Paracetamol tablets were prescribed as a rescue analgesic during the study . The patients were evaluated after a run-in period of one week ( week 0 ) and again at the end of the study ( week 4 ) . The clinical assessment s included the amount of paracetamol taken/week , visual analog scale ( VAS ) , Western Ontario and McMaster Universities ( WOMAC ) OA Index , Lequesne 's functional index , 50 feet-walk time , and the orthopedist 's and patient 's opinion of change . Results One hundred and eighty six patients completed the study . The improvement of symptoms ( reduction in mean changes ) in most outcome parameters was greatest in the EA group . The proportions of responders and patients with an overall opinion of " much better " were also greatest in the EA group . The improvement in VAS was significantly different between the EA and placebo group as well as the EA and diclofenac group . The improvement in Lequesne 's functional index also differed significantly between the EA and placebo group . In addition , there was a significant improvement in WOMAC pain index between the combined and placebo group . Conclusion EA is significantly more effective than placebo and diclofenac in the symptomatic treatment of OA of the knee in some circumstances . However , the combination of EA and diclofenac treatment was no more effective than EA treatment alone [1816730] Forty-four patients with chronic cervical osteoarthritis took part in this study . Patients were treated with acupuncture , sham-acupuncture , diazepam or placebo-diazepam in r and omized order . Pain was rated on visual analogue scales before , during , and after treatment . Two scales were separately used to rate the intensity ( sensory component ) and the unpleasantness ( affective component ) of pain . The results analyzed from these trials show that diazepam , placebo-diazepam , acupuncture and sham-acupuncture have a more pronounced effect on the affective than on the sensory component of pain . Acupuncture was significantly more effective than placebo-diazepam ( p less than 0.05 ) , but not significantly more effective than diazepam or sham-acupuncture [7727550] OBJECTIVE The purpose of this study was to determine whether acupuncture was more effective than sham acupuncture in the reduction of pain in persons with osteoarthritis ( OA ) of the knee . METHODS Forty subjects ( 20 men , 20 women ) with radiographic evidence of OA of the knee were stratified by gender and r and omly assigned to either the experimental ( real acupuncture ) or control ( sham acupuncture ) groups . Subjects were treated three times per week for 3 weeks and evaluated at three test sessions . Outcome measures were : 1 ) the Pain Rating Index of the McGill Pain Question naire , 2 ) the Western Ontario and McMaster Universities ( WOMAC ) Osteoarthritis Index , and 3 ) pain threshold at four sites at the knee . RESULTS The analyses of variance showed that both real and sham acupuncture significantly reduced pain , stiffness , and physical disability in the OA knee , but that there were no significant differences between groups . CONCLUSIONS Acupuncture is not more effective than sham acupuncture in the treatment of OA pain [15850733] Both specific and non-specific factors may play a role in acupuncture therapy for pain . We explored the cerebral consequences of needling and expectation with real acupuncture , placebo acupuncture and skin-prick , using a single-blind , r and omized crossover design with 14 patients suffering from painful osteoarthritis , who were scanned with positron emission tomography ( PET ) . The three interventions , all of which were sub-optimal acupuncture treatment , did not modify the patient 's pain . The insula ipsilateral to the site of needling was activated to a greater extent during real acupuncture than during the placebo intervention . Real acupuncture and placebo ( with the same expectation of effect as real acupuncture ) caused greater activation than skin prick ( no expectation of a therapeutic effect ) in the right dorsolateral prefrontal cortex , anterior cingulate cortex , and midbrain . These results suggest that real acupuncture has a specific physiological effect and that patients ' expectation and belief regarding a potentially beneficial treatment modulate activity in component areas of the reward system [12972723] Background : We report on the study design and protocol s of two r and omized controlled trials ( Acupuncture R and omized Trials = ART ) that investigate the efficacy of acupuncture in the treatment of chronic low back pain and osteoarthritis of the knee , respectively . Objective : To investigate whether acupuncture is more efficacious than ( a ) no treatment or ( b ) minimal acupuncture in the treatment of low back pain and osteoarthritis . Design : Two r and omized , controlled , multicenter trials with three treatment arms and a total follow-up time of 52 weeks . Setting : 30 practitioners and outpatient units in Germany specialized in acupuncture treatment . Patients : 300 patients will be included in each study . In the low back pain trial , patients will be included according to clinical diagnosis . In the osteoarthritis pain trial , patients will be included according to the American College of Rheumatology criteria . Interventions : Patients are r and omly assigned to receive either ( 1 ) semi-st and ardized acupuncture ( 150 patients ) , ( 2 ) minimal acupuncture at non-acupuncture points ( 75 patients ) , or ( 3 ) no treatment for two months followed by semi-st and ardized acupuncture ( 75 patients , waiting list control ) . Acupuncture treatment consists of 12 sessions per patient over a period of 8 weeks . Main Outcome Measure : The main outcome measure is the difference between baseline and the end of the 8-week treatment period in the following parameters : pain intensity as measured by a visual analogue scale ( VAS ; 0–100 mm ) in the low back pain trial and by the Western Ontario and McMaster Universities Osteoarthritis Score ( WOMAC ) in the osteoarthritis trial . Outlook : The results of these two studies ( available in 2004 ) will provide health care providers and policy makers with the information needed to make scientifically sound assessment s of acupuncture therapy [6218776] A single-blind , r and omised , placebo-controlled trial of superficial acupuncture in the treatment of low back pain was carried out by comparing 8 patients treated by acupuncture with 9 patients treated by placebo . In all five measures of efficacy chosen for study the acupuncture group achieved better responses than the placebo group ; four of the five inter-group differences were statistically significant . In addition , an overall mean for all five measures combined showed significant superiority of acupuncture over placebo [1514335] Purpose : Acupuncture treatment of patients waiting for arthroplasty surgery . Methods : 29 patients with a total of 42 osteoarthritic knees were r and omized to two groups . Group A was treated while Group B served as a no‐treatment control group . After 9 weeks Group B was treated too . Analgesic consumption , pain and objective measurements were registered . All objective measures were done by investigators who were “ blinded ” as to Group A & B. In the second part of the study 17 patients ( 26 knees ) continued with treatments once a month . Registration of analgesic consumption , pain and objective measurements continued . Total study period 49 weeks . Results : Comparing Group A to B there was a significant reduction in pain , analgesic consumption and in most objective measures . In Group A + B combined there was an 80 % subjective improvement , and a significantly increased knee range movement – an increase mainly in the worst knees . Results were significantly better in those who had not been ill for a long time . In the second part of the study , it was shown that it was possible to maintain the improvements . Conclusions : Acupuncture can ease the discomfort while waiting for an operation and perhaps even serve as an alternative to surgery . Seven patients have responded so well that at present they do not want an operation . ( USD 9000 saved per operation ) [3068365] Within the context of a double blind r and omized controlled parallel trial of 2 nonsteroidal antiinflammatory drugs , we vali date d WOMAC , a new multidimensional , self-administered health status instrument for patients with osteoarthritis of the hip or knee . The pain , stiffness and physical function subscales fulfil conventional criteria for face , content and construct validity , reliability , responsiveness and relative efficiency . WOMAC is a disease-specific purpose built high performance instrument for evaluative research in osteoarthritis clinical trials [16317692] Severe acetaminophen hepatotoxicity frequently leads to acute liver failure ( ALF ) . We determined the incidence , risk factors , and outcomes of acetaminophen-induced ALF at 22 tertiary care centers in the United States . Detailed prospect i ve data were gathered on 662 consecutive patients over a 6-year period fulfilling st and ard criteria for ALF ( coagulopathy and encephalopathy ) , from which 275 ( 42 % ) were determined to result from acetaminophen liver injury . The annual percentage of acetaminophen-related ALF rose during the study from 28 % in 1998 to 51 % in 2003 . Median dose ingested was 24 g ( equivalent to 48 extra-strength tablets ) . Unintentional overdoses accounted for 131 ( 48 % ) cases , intentional ( suicide attempts ) 122 ( 44 % ) , and 22 ( 8 % ) were of unknown intent . In the unintentional group , 38 % took two or more acetaminophen preparations simultaneously , and 63 % used narcotic-containing compounds . Eighty-one percent of unintentional patients reported taking acetaminophen and /or other analgesics for acute or chronic pain syndromes . Overall , 178 subjects ( 65 % ) survived , 74 ( 27 % ) died without transplantation , and 23 subjects ( 8 % ) underwent liver transplantation ; 71 % were alive at 3 weeks . Transplant-free survival rate and rate of liver transplantation were similar between intentional and unintentional groups . In conclusion , acetaminophen hepatotoxicity far exceeds other causes of acute liver failure in the United States . Susceptible patients have concomitant depression , chronic pain , alcohol or narcotic use , and /or take several preparations simultaneously . Education of patients , physicians , and pharmacies to limit high-risk use setting s is recommended [18283204] Context Although many patients use glucosamine to treat osteoarthritis , available studies have reported inconsistent effects of glucosamine on symptoms and joint changes . In addition , previous studies have more often included patients with knee than with hip osteoarthritis . Contribution The investigators r and omly assigned 222 patients with hip osteoarthritis to glucosamine , 1500 mg/d , or placebo . After 2 years of treatment , no clinical ly significant effect on pain , function , or joint space narrowing was found . Caution Twenty of the patients in the trial had joint replacement during the study . The Editors The effectiveness of glucosamine sulfate for treating osteoarthritis is controversial . A 2005 systematic review of 20 trials found evidence to be inconclusive ( 1 ) . In the 15 trials comparing glucosamine with placebo , the overall effect on pain favored glucosamine , but 8 of the trials found no effect on pain . More recent trials ( 24 ) have also yielded inconclusive results . In the Netherl and s and other countries , glucosamine is sold as an over-the-counter dietary supplement and is used by many patients , often on the advice of their physicians . Given the prevalent use of glucosamine , definitive evidence about its effectiveness is needed . Some studies suggest that glucosamine may provide greater benefit to patients with less severe radiographic osteoarthritis than to patients with more severe disease ( 5 , 6 ) . Most previous trials have studied only patients with knee osteoarthritis , with the exception of 3 early trials that included patients with other affected joints ( 79 ) . Trials specifically testing glucosamine in patients with hip osteoarthritis have not been available . Although osteoarthritis of the knee is more common than hip osteoarthritis , hip osteoarthritis is common enough to warrant assessment of glucosamine for this condition . To date , only 2 trials have published data on the effects of glucosamine sulfate on joint structure ( 10 , 11 ) . Some expressed concern about the radiography protocol used in these trials ( 1214 ) , and further study is needed to clarify these findings . To explore some of the uncertainties regarding the effectiveness of glucosamine sulfate , we conducted a 2-year , blinded , r and omized , placebo-controlled trial to evaluate the effect of glucosamine sulfate on the symptomatic and radiographic progression of hip osteoarthritis in patients recruited from primary care setting s. Methods Study Design In this trial , all outcome assessors , patients , data analysts , and research ers were blinded to group assignment . The Medical Ethics Committee of the Erasmus Medical Center , Rotterdam , the Netherl and s , approved the study design , and patients provided written informed consent . We reported the detailed study protocol in 2005 ( 15 ) and summarize it here . Setting and Participants General practitioners in the Rotterdam area recruited study patients . Patients were eligible for inclusion if they met the American College of Rheumatology clinical criteria for hip osteoarthritis ( 16 ) during a screening examination at the research center . Patients who had undergone or were awaiting hip replacement surgery were not eligible . We excluded patients who had a Kellgren and Lawrence score of 4 ( 17 ) , renal disease , liver disease , diabetes mellitus , or a disabling comorbid condition that would make visits to the research center impossible , as well as patients already receiving glucosamine and those unable to fill out Dutch question naires . We encouraged patients who violated study protocol and those who had total hip arthroplasty during the study to complete data collection to limit the loss to follow-up . R and omization and Intervention Eligible patients were r and omly assigned to receive either 1500 mg of oral glucosamine sulfate ( administered once daily as two 750-mg tablets ) or placebo for 2 years . The glucosamine used in this study was provided by Numico Research BV ( Wageningen , the Netherl and s ) but was manufactured by Nutricia Manufacturing USA ( Greenville , South Carolina ) . It contained 2000 mg of D-glucosamine sulfate 2-potassium chloride , which results in a net content of 1500 mg of glucosamine sulfate per 2 pills . The placebo pills were identical in appearance , smell , and taste . We used a computer-generated , blinded r and omization list provided by an independent research er to r and omly assign patients to glucosamine sulfate or placebo . This list , which was r and omized per block of 6 numbers , stratified patients by radiologic findings ( Kellgren and Lawrence score < 2 vs. 2 ) and by local versus generalized osteoarthritis ; patients received a number in chronological order ( 15 ) . Assignment of patients to the right stratum of the r and om assignment list was done by the main research er , who was blinded to therapy . To evaluate blinding , patients had to indicate in the last question naire to which treatment they thought they were r and omly assigned . Outcomes and Follow-up Primary outcome measures were WOMAC 3.1 ( 5-point Likert format ) pain and function over 24 months and joint space narrowing after 24 months ( 18 , 19 ) . Secondary outcome measures were WOMAC pain , function , and stiffness after 3 , 12 , and 24 months ; overall WOMAC stiffness ; a visual analogue scale ( VAS ) to measure pain in the past week ; and pain medication use . The WOMAC subscales are presented as normalized scores ( 0 to 100 , where 0 equals no symptoms ) . We recorded the use of pain medication ; classified patients as never , occasional , or daily users ; and then determined whether people increased , decreased , or did not change their use of pain medication from baseline . In the case of patients with bilateral hip symptoms , we asked patients to indicate their most affected hip for our analyses of joint space narrowing . For patients who were undecided , we used the hip with the highest Kellgren and Lawrence score or the smallest internal rotation during a physical examination . We used QBone Planner 5.4 ( Medis , Leiden , the Netherl and s ) to measure joint space width on calibrated digital radiographs of the hip joints . We read radiographs from both time points ( baseline and 24 months ) side by side . One research er measured joint space width manually on predefined lateral , superior , axial , and medial sites ( 20 ) . In addition to these 4 points , we visually identified and measured the minimal joint space width on both the baseline and 24-month radiograph . We used the smallest of these 6 measurements as the actual minimum joint space width for analyses . A second observer also measured the joint space width in a r and om subset of 28 study patients , and we found high interobserver agreement ( intraclass correlation coefficient of minimal joint space width , 0.98 ) . We collected data for the primary and secondary outcome measures at different time points throughout the study . At baseline and after 24 months , patients came to the Erasmus Medical Center for radiography and to complete study question naires . Weight-bearing , anteroposterior digital radiography of the pelvis was performed according to a highly st and ardized protocol to allow reliable measurement of joint space narrowing ( 15 ) . At baseline and then every 3 months through month 24 , we asked patients to complete the WOMAC instrument , a VAS for pain in the past week ( score range , 0 to 100 ; 0 equals no pain ) , and a checklist for specific adverse events and to answer questions regarding pain medication and adherence . We mailed the intermediate question naires to the patients for completion at home . A research er visited patients every 6 months to deliver a new supply of study medication and evaluate adherence by using the Brief Medication Question naire ( BMQ ) ( 21 ) and a pill count . The BMQ monitors the amount of days per week that patients have taken their study medication . For overall effect , we considered patients to be adherent if they ingested more than 80 % of the total study medication . Statistical Analysis We used the data from all nine 3-month question naires ( at baseline and 3 , 6 , 9 , 12 , 15 , 18 , 21 , and 24 months ) . We also report outcomes for measurements at 3 , 12 , and 24 months and a mean effect of the therapy over 24 months incorporating all scores . We performed the analyses by using SPSS 11.0.1 ( SPSS , Chicago , Illinois ) and SAS 8.2 ( SAS Institute , Cary , North Carolina ) . We used linear mixed models to analyze the data , assuming that data were missing at r and om . We chose an unstructured covariance structure to model the covariance of repeated measures by patients , because this yielded the lowest Akaike information criterion . Fixed effects were time , time by therapy , and the covariates we adjusted for . For patients who had total hip arthroplasty during the trial , we included observed data before surgery in the analysis and assumed data after surgery to be missing . For patients who were lost to follow-up , we included all observed data in the analysis . We adjusted the WOMAC and VAS pain analyses for body mass index , sex , and agefactors that may have influenced symptoms ( 22 , 23 ) . We also adjusted analyses for pain medication use and Kellgren and Lawrence score . The analyses for joint space narrowing were adjusted for Kellgren and Lawrence score ( 24 ) , age , and sex ( 25 ) . We used ordinal regression analysis to assess the effect of glucosamine sulfate on pain medication use by using data from all patients who completed the study and did not have total hip arthroplasty . We performed additional analyses to assess the effect of adherence on the outcome . To explore the validity of the missing-at-r and om data assumption for patients who underwent total hip arthroplasty during the study , we did sensitivity analyses on the WOMAC pain data . In 5 scenarios , the missing data for patients who underwent total hip arthroplasty were imputed with extreme scores : mean of the 5 best scores for the glucosamine sulfate recipients and that of the 5 worst scores for the placebo recipients ( traditional best case ) ; mean of the best scores for placebo recipients [17257756] Abstract In a pooled analysis of four r and omized controlled trials of acupuncture in patients with migraine , tension‐type headache , chronic low back pain , and osteoarthritis of the knee we investigated the influence of expectations on clinical outcome . The 864 patients included in the analysis received either 12 sessions of acupuncture or minimal ( i.e. sham ) acupuncture ( superficial needling of non‐acupuncture points ) over an 8 week period . Patients were asked at baseline whether they considered acupuncture to be an effective therapy in general and what they personally expected from the treatment . After three acupuncture sessions patients were asked how confident they were that they would benefit from the treatment strategy they were receiving . Patients were classified as responders if the respective main outcome measure improved by at least fifty percent . Both univariate and multivariate analyses adjusted for potential confounders ( such as condition , intervention group , age , sex , duration of complaints , etc . ) consistently showed a significant influence of attitudes and expectations on outcome . After completion of treatment , the odds ratio for response between patients considering acupuncture an effective or highly effective therapy and patients who were more sceptical was 1.67 ( 95 % confidence interval 1.20–2.32 ) . For personal expectations and confidence after the third session , odds ratios were 2.03 ( 1.26–3.26 ) and 2.35 ( 1.68–3.30 ) , respectively . Results from the 6‐month follow‐up were similar . In conclusion , in our trials a significant association was shown between better improvement and higher outcome expectations [3524727] Twenty-five out- patients with chronic neck pain participated in a prospect i ve , r and omized trial of acupuncture versus placebo transcutaneous nerve stimulation . A single-blind , non-cross-over design incorporated several outcome measures in an attempt to determine any particular facet of pain that responded to acupuncture . No significant difference between the two treatments was found either post-treatment or at follow-up . Whilst the small population studied limits the conclusions that may be drawn , these findings suggest that acupuncture may have no greater effect than that of a powerful placebo [11532841] Recent reports have highlighted the importance of having good evidence on the safety of acupuncture . 1 2 Sound evidence on the risks associated with acupuncture is , however , scarce.3 Our primary aim , therefore , was to describe the type and frequency of adverse events after acupuncture . A secondary aim was to examine mild transient reactions associated with acupuncture , some of which may indicate a positive response to treatment . The study involved a prospect i ve postal audit of treatments undertaken during a four week period in 2000 . All 1848 professional acupuncturists who were members of the British Acupuncture Council and were practising in the United Kingdom were invited to record details of adverse events and mild transient reactions after treatment . St and ardised self report forms were used . Participating practitioners also provided information on themselves , including age , sex , length of training , and years of practice . To have a [16636704] OBJECTIVE The research ers sought to assess whether the widely used 1994 Cochrane Highly Sensitive Search Strategy ( HSSS ) for r and omized controlled trials ( RCTs ) in MEDLINE could be improved in terms of sensitivity , precision , or parsimony . METHODS A gold st and ard of 1,347 RCT records and a comparison group of 2,400 non-trials were r and omly selected from MEDLINE . Terms occurring in at least 1 % of RCT records were identified . Fifty percent of the RCT and comparison group records were r and omly selected , and the ability of the terms to discriminate RCTs from non-trial records was determined using logistic regression . The best performing combinations of terms were tested on the remaining records and in MEDLINE . RESULTS The best discriminating term was " Clinical Trial " ( Publication Type ) . In years where the Cochrane assessment of MEDLINE records had taken place , the strategies identified few additional unindexed records of trials . In years where Cochrane assessment has yet to take place , " R and omized Controlled Trial " ( Publication Type ) proved highly sensitive and precise . Adding six more search terms identified further , unindexed trials at reasonable levels of precision and with sensitivity almost equal to the Cochrane HSSS . CONCLUSIONS Most reports of RCTs in MEDLINE can now be identified easily using " R and omized Controlled Trial " ( Publication Type ) . More sensitive search es can be achieved by a brief strategy , the Centre for Review s and Dissemination/Cochrane Highly Sensitive Search Strategy ( 2005 revision ) [11532840] Acupuncture is increasingly popular , but it is not free from risk for the patient.1 Safety is best established with prospect i ve surveys . Our aim was to ascertain the incidence of adverse events related to acupuncture treatment , as currently practised in Britain by doctors and physiotherapists . Volunteer acupuncture practitioners were recruited through journals circulated to members of the British Medical Acupuncture Society and the Acupuncture Association of Chartered Physiotherapists ( approximately 2750 members).2 A prospect i ve survey was undertaken using forms for intensive event monitoring that had been piloted previously.3 Minor adverse events were defined as “ any ill-effect , no matter how small , that is unintended and non-therapeutic , even if not unexpected . ” These events were reported every month , along with the total number of consultations . Minor or serious events that were considered to be “ significant”—“unusual , novel , dangerous , significantly inconvenient , or requiring further information”—were reported on separate forms when they occurred . Anonymous reporting was accepted . A sample size of [18356795] Background There is evidence for the efficacy of acupuncture treatment in knee osteoarthritis , but it remains unclear which acupuncture modes are most effective . We evaluated the effects of trigger point acupuncture on pain and quality of life in knee osteoarthritis patients , compared with acupuncture at st and ard points , and sham acupuncture . Methods Thirty patients ( 27 women , 3 men ; aged 61–82 years ) with non-radiating knee osteoarthritis pain for at least six months and normal neurological examination were r and omised to one of three groups for the study period of 21 weeks . Each group received five acupuncture treatment sessions . The st and ard acupuncture point group ( n=10 ) received treatment at traditional acupuncture points for knee pain ; the trigger point acupuncture group ( n=10 ) received treatment at trigger points ; and the third group ( n=10 ) received sham acupuncture treatment at the trigger points . Outcome measures were pain intensity ( visual analogue scale , VAS ) and WOMAC index ( Western Ontario and McMaster Universities Arthritis Index ) . The groups were compared by the area under the curve method . Results Five patients dropped out of the study because of lack of improvement , and one patient ( in the trigger point acupuncture group ) dropped out because of deterioration of symptoms ; the remaining 24 patients were included in the analysis . After treatment , the trigger point acupuncture group reported less pain intensity on VAS than the st and ard acupuncture or sham treatment group , but both the trigger point acupuncture and st and ard acupuncture groups reported improvement of function of knee . There was a significant reduction in pain intensity between pre-treatment and five weeks after treatment for the trigger point acupuncture ( P<0.01 ) and st and ard acupuncture groups ( P<0.01 ) included in the analysis , but not for the sham treatment group . Group comparison using the area under the curves demonstrated a significant difference only between trigger point acupuncture and sham treatment groups analysed ( P<0.025 for VAS , and P<0.031 for WOMAC ) . Conclusion These results suggest that trigger point acupuncture therapy may be more effective for osteoarthritis of the knee in some elderly patients than st and ard acupuncture therapy [11926599] We report a prospect i ve controlled trial , comparing acupuncture with no treatment , in patients with advanced osteoarthritis of the knee awaiting total knee replacement . Knee function was assessed at the beginning of study and at the end of two months , using four parameters : HSS score , time to walk 50 metres , time to climb 20 steps , and degree of pain . Acupuncture was given at four local points around the knee and at one distal point . The acupuncture group improved in all parameters , whereas the control group deteriorated , a finding that was highly statistically significant ( p<0.0002 ) . Further r and omised-controlled trials with longer follow-up are required to confirm these findings [17075849] OBJECTIVE To investigate the effectiveness of acupuncture in addition to routine care , compared with routine care alone , in the treatment of patients with chronic pain due to osteoarthritis ( OA ) of the knee or hip . METHODS In a r and omized , controlled trial , patients with chronic pain due to OA of the knee or hip were r and omly allocated to undergo up to 15 sessions of acupuncture in a 3-month period or to a control group receiving no acupuncture . Another group of patients who did not consent to r and omization underwent acupuncture treatment . All patients were allowed to receive usual medical care in addition to the study treatment . Clinical OA severity ( Western Ontario and McMaster Universities Osteoarthritis Index [ WOMAC ] ) and health-related quality of life ( Short Form 36 ) were assessed at baseline and after 3 months and 6 months . RESULTS Of 3,633 patients ( mean + /- SD age 61.8 + /- 10.8 years ; 61 % female ) , 357 were r and omized to the acupuncture group and 355 to the control group , and 2,921 were included in the nonr and omized acupuncture group . At 3 months , the WOMAC had improved by a mean + /- SEM of 17.6 + /- 1.0 in the acupuncture group and 0.9 + /- 1.0 in the control group ( 3-month scores 30.5 + /- 1.0 and 47.3 + /- 1.0 , respectively [ difference in improvement 16.7 + /- 1.4 ; P < 0.001 ] ) . Similarly , quality of life improvements were more pronounced in the acupuncture group versus the control group ( P < 0.001 ) . Treatment success was maintained through 6 months . The changes in outcome in nonr and omized patients were comparable with those in r and omized patients who received acupuncture . CONCLUSION These results indicate that acupuncture plus routine care is associated with marked clinical improvement in patients with chronic OA-associated pain of the knee or hip [9717924] BACKGROUND A problem acupuncture research has to face is the concept of a control group . If , in control groups , non-acupoint needling is done , physiological acupuncture effects are implied . Therefore the effects shown in this group are often close to those shown in the acupuncture group . In other trials , control groups have received obviously different treatments , such as transcutaneous electrical nervous stimulation or TENS-laser treatment ; it is not clear if the effects of acupuncture are due only to the psychological effects of the treatment . METHODS We developed a placebo acupuncture needle , with which it should be possible to simulate an acupuncture procedure without penetrating the skin . In a cross-over experiment with 60 volunteers we tested whether needling with the placebo needle feels any different from real acupuncture . FINDINGS Of 60 volunteers , 54 felt a penetration with acupuncture ( mean visual analogue scale [ VAS ] 13.4 ; SD 10.58 ) and 47 felt it with placebo ( VAS 8.86 ; SD 10.55 ) , 34 felt a dull pain sensation ( DEQI ) with acupuncture and 13 with placebo . None of the volunteers suspected that the needle may not have penetrated the skin . INTERPRETATION The placebo needle is sufficiently credible to be used in investigations of the effects of acupuncture [11527062] The aim of this investigation was to determine whether bee venom ( BV ) administered directly into an acupoint was a clinical ly effective and safe method for relieving the pain of patients with knee osteoarthritis ( OA ) as compared to traditional needle acupuncture . We evaluated the efficacy of BV acupuncture using both pain relief scores and computerized infrared thermography ( IRT ) following 4 weeks of BV acupuncture treatment . We observed that a significantly higher proportion of subjects receiving BV acupuncture reported substantial pain relief as compared with those receiving traditional needle acupuncture therapy . Furthermore , the IRT score was significantly improved and paralleled the level of pain relief [11452568] OBJECTIVE To determine whether demographic , medical history , or arthritis assessment data may influence outcome and rate of decay for patients with osteoarthritis treated with acupuncture . DESIGN Seventy-three persons with symptomatic osteoarthritis of the knee were recruited for this r and omized controlled trial . Both treatment and crossover control groups received acupuncture treatments twice weekly for 8 weeks . Patients self-scored on the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) and the Lequesne Algofunctional Index at baseline and 4 , 8 , and 12 weeks . Sample size for this outcome analysis was 60 patients at 4 weeks , 58 at 8 weeks , and 52 at 12 weeks . RESULTS Patients ' scores on both indexes improved at 4 , 8 , and 12 weeks . Scores were stable regardless of the baseline severity of the osteoarthritis . Despite some decay in outcomes at week 12 , measures were significantly improved over baseline . With WOMAC scores partitioned into equal quartiles , a strong effect on outcome was apparent at 12 weeks ( 4 weeks after treatment ) related to initial WOMAC scores . The group with the least disability and pain rebounded to original levels to a greater degree than did those who initially were more disabled . The more disabled groups retained the benefits of acupuncture treatment through the 12-week period . CONCLUSION Acupuncture for patients with osteoarthritis of the knee may best be used early in the treatment plan , with a method ical decrease in frequency in treatment once the acute treatment period is completed to avoid a rebound effect . Demographic and medical history data were not mediating variables [17209110] Participants are often not informed by investigators who conduct r and omised , placebo-controlled acupuncture trials that they may receive a sham acupuncture intervention . Instead , they are told that one or more forms of acupuncture are being compared in the study . This deceptive disclosure practice lacks a compelling method ological rationale and violates the ethical requirement to obtain informed consent . Participants in placebo-controlled acupuncture trials should be provided an accurate disclosure regarding the use of sham acupuncture , consistent with the practice of placebo-controlled drug trials [15501201] PURPOSE To present the safety and effectiveness results of a prototypical 12-week , double-blind , r and omized placebo-controlled trial of glucosamine among subjects with knee osteoarthritis who were recruited and followed entirely over the Internet . METHODS The study comprised 205 subjects aged 45 years or older with symptomatic knee osteoarthritis who were recruited over the Internet ; eligibility was authenticated through medical record review . Participants were assigned r and omly to 1.5 g/d of glucosamine ( n = 101 ) or placebo ( n = 104 ) , of whom 108 completed the intervention ( 93 in each arm ) . The primary outcome measure was the pain subscale of the Western Ontario and McMaster Universities Osteoarthritis Index ( Likert version ) . Additional outcome measures included the physical function and stiffness subscales and overall score of the question naire , and analgesic use . RESULTS There was no difference between treatment and control groups in terms of change in pain score ( 2.0 + /- 3.4 vs. 2.5 + /- 3.8 , P = 0.41 ) , stiffness ( 0.7 + /- 1.6 vs. 0.8 + /- 1.5 , P = 0.52 ) , physical function ( 5.2 + /- 9.5 vs. 4.6 + /- 9.6 , P = 0.49 ) , overall score ( 7.8 + /- 13.1 vs. 7.8 + /- 13.5 , P = 0.81 ) , and analgesic use ( 133 + /- 553 vs. -88 + /- 755 , P = 0.12 ) . Stratification by osteoarthritis severity , glucosamine product , and use of a nonsteroidal anti-inflammatory drug , as well as exclusion of opiate users , did not alter the results . The number and type of adverse events reported was similar between the groups . CONCLUSION Our results suggest that although glucosamine appears to be safe , it is no more effective than placebo in treating the symptoms of knee osteoarthritis [17908057] OBJECTIVES To examine the efficacy of periosteal stimulation therapy ( PST , osteopuncture ) for the treatment of chronic pain associated with advanced knee osteoarthritis . DESIGN R and omized , controlled clinical trial . SETTING Outpatient pain clinic . PARTICIPANTS Eighty-eight community-dwelling older adults with moderate knee pain or greater for 3 months or longer and Kellgren-Lawrence ( K-L ) grade 2 through 4 radiographic severity ( 80 % had K-L 4 ) . INTERVENTION Participants were r and omized to receive PST or control PST once a week for 6 weeks . MEASUREMENTS Pain severity and self-reported function ( Western Ontario and McMasters University Osteoarthritis Index ( WOMAC ) ) and physical performance ( Short Physical Performance Battery ( SPPB ) ) were assessed at baseline , after the last PST session ( post ) , and 3 months later ( follow-up ) . Pain severity was also assessed monthly using the multidimensional pain inventory short form . RESULTS Pain was reduced significantly more in the PST group than in the control PST group at post ( P=.003 ; mean WOMAC pain subscale baseline 9.4 vs 6.4 ) and 1 month later ( P<.001 ) , but by 2 months , pain levels had regressed to pre-intervention levels . The group-by-time interaction for the WOMAC function scale was significant at post ( P=.04 ) but not at follow-up ( P=.63 ) . No significant group differences were found for the SPPB . Neither analgesic use nor global improvement differed between groups . There were four treatment dropouts . CONCLUSION PST affords short-term modest pain reduction for older adults with advanced knee OA . Future research should test the effectiveness of booster treatments in sustaining analgesic benefits and of combining PST with therapeutic exercise in ameliorating disability risk [15791763] OBJECTIVES This report presents health statistics from the 2002 National Health Interview Survey ( NHIS ) for the civilian noninstitutionalized adult population , classified by sex , age , race and Hispanic origin , education , income , poverty status , health insurance coverage , marital status , place of residence , and region of residence for chronic condition prevalence , health status , functional limitations , health care access and utilization , health behaviors , and human immunodeficiency virus testing . The presentation of percentages and percent distributions in both age-adjusted and unadjusted versions is new this year . SOURCE OF DATA The NHIS is a household , multistage probability sample survey conducted annually by interviewers of the U.S. Census Bureau for the Centers for Disease Control and Prevention 's National Center for Health Statistics . In 2002 , data were collected for 31,044 adults for the Sample Adult question naire . The conditional response rate was 84.4 % , and the final response rate was 74.4 % . The health information for adults in this report was obtained from one r and omly selected adult per family . HIGHLIGHTS In 2002 , 62 % of adults 18 years of age or over reported excellent or very good health . Fifty-nine percent of adults never participated in any type of vigorous leisure-time physical activity , and 14 % of adults did not have a usual place of health care . Eleven percent of adults had been told by a doctor or health professional that they had heart disease , and 21 % had been told on two or more visits that they had hypertension . Twenty-two percent of all adults were current smokers , and 23 % were former smokers . Based on their body mass index , 35 % of adults were overweight , and 23 % were obese [11824949] OBJECTIVE To estimate minimal clinical ly important differences ( MCID ) of effects measured by the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) in patients with osteoarthritis ( OA ) of the lower extremities undergoing a comprehensive inpatient rehabilitation intervention . METHODS A prospect i ve cohort study assessed patients ' health by the WOMAC at baseline ( entry into the clinic ) and at the 3 month followup , and by a transition question naire asking about the change of " health in general related to the OA joint " during that time period . The WOMAC section score differences between the " equal " group and the " slightly better " and " slightly worse " groups result ed in the MCID for improvement and for worsening . RESULTS In total 192 patients were followed up . The MCID for improvement ranged from 0.80 to 1.01 points on the continuous WOMAC numerical rating scale from 0 to 10 , reflecting changes of 17 to 22 % of baseline scores . The MCID for worsening conditions ranged from 0.29 ( 6 % ) to 1.03 points ( 22 % ) . In the transition reply subjectively unchanged patients reported a " pessimistic bias " of 0.35 to 0.51 points , except for the stiffness section . Both MCID and pessimistic bias showed regression to the mean and baseline dependency . CONCLUSION The assessment of MCID using the transition method is a heuristic and valid strategy to detect particular rehabilitation effects in patients with OA of the lower extremities with the use of the WOMAC , and it is worth implementing . The size of the MCID and of the systematic bias is comparable to that assessed by other methods and in other therapeutic setting [17699546] Objective To investigate the benefit of adding acupuncture to a course of advice and exercise delivered by physiotherapists for pain reduction in patients with osteoarthritis of the knee . Design Multicentre , r and omised controlled trial . Setting 37 physiotherapy centres accepting primary care patients referred from general practitioners in the Midl and s , United Kingdom . Participants 352 adults aged 50 or more with a clinical diagnosis of knee osteoarthritis . Interventions Advice and exercise ( n=116 ) , advice and exercise plus true acupuncture ( n=117 ) , and advice and exercise plus non-penetrating acupuncture ( n=119 ) . Main outcome measures The primary outcome was change in scores on the Western Ontario and McMaster Universities osteoarthritis index pain subscale at six months . Secondary outcomes included function , pain intensity , and unpleasantness of pain at two weeks , six weeks , six months , and 12 months . Results Follow-up rate at six months was 94 % . The mean ( SD ) baseline pain score was 9.2 ( 3.8 ) . At six months mean reductions in pain were 2.28 ( 3.8 ) for advice and exercise , 2.32 ( 3.6 ) for advice and exercise plus true acupuncture , and 2.53 ( 4.2 ) for advice and exercise plus non-penetrating acupuncture . Mean differences in change scores between advice and exercise alone and each acupuncture group were 0.08 ( 95 % confidence interval −1.0 to 0.9 ) for advice and exercise plus true acupuncture and 0.25 ( −0.8 to 1.3 ) for advice and exercise plus non-penetrating acupuncture . Similar non-significant differences were seen at other follow-up points . Compared with advice and exercise alone there were small , statistically significant improvements in pain intensity and unpleasantness at two and six weeks for true acupuncture and at all follow-up points for non-penetrating acupuncture . Conclusion The addition of acupuncture to a course of advice and exercise for osteoarthritis of the knee delivered by physiotherapists provided no additional improvement in pain scores . Small benefits in pain intensity and unpleasantness were observed in both acupuncture groups , making it unlikely that this was due to acupuncture needling effects . Trial registration Current Controlled Trials IS RCT N88597683 [3213064] A comparative study between acupuncture and physical therapy in patients with gonarthrosis is reported . Patients treated with physical therapy showed 4 parameters significantly reduced after a treatment duration of 2 weeks , and 7 out of 10 parameters after 4 weeks of therapy . Acupuncture could better 2 parameters but only after 4 weeks of treatment . Although physical therapy was superior in most of the objective measurements , the subjective judgement by the patients of the efficacy of both treatments found no significant difference . In summary acupuncture is thought to be only an additional form of treatment in gonarthrosis [11444887] OBJECTIVES The effectiveness of acupuncture treatment in patients with osteoarthritis of the hip was tested . DESIGN This is a prospect i ve , r and omized , controlled , patient- and investigator-blinded clinical trial . PATIENTS AND SETTING The study was performed at a university department for physical medicine and rehabilitation . Sixty-seven patients were separated into two treatment groups . INTERVENTIONS Group 1 ( treatment ) had traditional needle placement and manipulation , whereas in group 2 ( control ) needles were placed away from classic positions and not manipulated . In both groups needles were placed within the L2 to L5 dermatomes . Outcome parameters were : pain ( VAS ) , functional impairment ( hip score ) , activity in daily life ( ADL ) and overall satisfaction before treatment , and 2 weeks and 2 months after treatment . RESULTS For all parameters there was a significant improvement versus baseline in both groups 2 weeks and 2 months following treatment , but no significant difference between the two treatment groups . CONCLUSIONS We conclude from these results that needle placement in the area of the affected hip is associated with improvement in the symptoms of osteoarthritis . It appears to be less important to follow the rules of traditional acupuncture techniques [7053030] Thirty patients with cervical spine pain syndromes persisting a mean of 8 years were assigned r and omly into equal treatment and control groups . After 12 weeks , 12 of 15 ( 80 % ) of the treated group felt improved , some dramatically , with a mean 40 % reduction of pain score , 54 % reduction of pain pills , 68 % reduction of pain hours per day and 32 % less limitation of activity . Two of 15 ( 13 % ) of the control group reported slight improvement after 12.8 weeks . The control group had a mean 2 % worsening of the pain score , 10 % reduction in pain pills , no lessening of pain hours and 12 % less limitation of activity [11471577] We report a prospect i ve r and omised trial of acupuncture given to 44 patients with advanced osteoarthritis ( OA ) of the knee awaiting total knee joint replacement . Patients were r and omly allocated into two groups , group A receiving acupuncture to the most affected knee only and group B receiving acupuncture to both knees . Acupuncture was given to four local points around the knee and one distal point . The local points were Spleen 9 ( Yinlinquan , SP9 ) , Spleen 10 ( Xuehai , SP10 ) , Stomach 34 ( Liangqui , ST34 ) , and Stomach 36 ( Zusanli , ST36 ) . The distal point was Large Intestine 4 ( Hegu , LI4 ) on the first web space of the ipsilateral h and . A blinded observer assessed knee function before starting treatment , and at the end of two and six months . Analysis of the results showed a significant reduction in symptoms in both groups , and this improvement was sustained for six months . There was no statistically significant difference between the groups . In conclusion , unilateral acupuncture is as effective as bilateral acupuncture in increasing function and reducing the pain associated with OA of the knee . This trial is not able to distinguish the specific from the non-specific effects of the treatment [15100594] Objectives : The aim of the study was to evaluate the therapeutic effect of electro-acupuncture ( EA ) and hydrotherapy , both in combination with patient education or with patient education alone , in the treatment of osteoarthritis in the hip . Methods : Forty-five patients , aged 42–86 years , with radiographic changes consistent with osteoarthritis in the hip , pain related to motion , pain on load , and ache were chosen . They were r and omly allocated to EA , hydrotherapy , both in combination with patient education , or patient education alone . Outcome measures were the disability rating index ( DRI ) , global self-rating index ( GSI ) , and visual analogue scale ( VAS ) . Assessment s were done before the intervention and immediately after the last treatment and 1 , 3 , and 6 months after the last treatment . Results : Pain related to motion and pain on load was reduced up to 3 months after last the treatment in the hydrotherapy group and up to 6 months in the EA group . Ache during the day was significantly improved in both the EA and hydrotherapy group up to 3 months after the last treatment . Ache during the night was reduced in the hydrotherapy group up to 3 months after the last treatment and in the EA group up to 6 months after . Disability in functional activities was improved in EA and hydrotherapy groups up to 6 months after the last treatment . Quality of life was also improved in EA and hydrotherapy groups up to 3 months after the last treatment . There were no changes in the education group alone . Discussion : In conclusion , EA and hydrotherapy , both in combination with patient education , induce long-lasting effects , shown by reduced pain and ache and by increased functional activity and quality of life , as demonstrated by differences in the pre- and post-treatment assessment Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Hip osteoarthritis ( OA ) is a major cause of pain and functional limitation . Few hip OA treatments have been evaluated for safety and effectiveness . Acupuncture is a traditional Chinese medical therapy which aims to treat disease by inserting very thin needles at specific points on the body . OBJECTIVES To assess the benefits and harms of acupuncture in patients with hip OA . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

24154977

[11117277] Background : Lycopene has previously been shown to have high antioxidative activity . In view of the controversy regarding the beneficial effect of antioxidants on asthma , the acute effects of lycopene ( LYC‐O‐MATOTM ) on airway hyperreactivity were assessed in patients with exercise‐induced asthma ( EIA ) [3782678] Sixteen adult subjects with asthma in a clinical steady state were studied . On day 1 , after baseline spirometry , they underwent four histamine inhalation tests with functional recovery between each test . The provocative concentration causing a 20 % fall in FEV1 ( PC20 ) was obtained after each test . On days 2 , 3 , and 4 , after baseline spirometry , active and placebo ascorbic acid ( 2 gm ) was administered orally , double-blind , according to a 4.3.1 two-treatment crossover study design . One hour later , spirometry was performed , and PC20 was reassessed . We found no significant changes in FEV1 and FVC after ascorbic acid as compared with placebo administration . There was no difference between PC20 on days 2 , 3 , and 4 and by st and ardizing for the four PC20 results obtained on day 1 . We conclude that ascorbic acid has no acute bronchodilator effect and does not alter bronchial responsiveness to histamine in subjects with asthma [15498043] The inflammatory response to ozone in atopic asthma suggests that soluble mediators of inflammation are released in response to oxidant stress . Antioxidants may alleviate additional oxidative stress associated with photochemical oxidant pollution . This study investigates the impact of antioxidant supplementation on the nasal inflammatory response to ozone exposure in atopic asthmatic children . We conducted a r and omized trial using a double‐blinded design . Children with asthma ( n = 117 ) , residents of Mexico City , were given r and omly a daily supplement of vitamins ( 50 mg/day of vitamin E and 250 mg/day of vitamin C ) or placebo . Nasal lavages were performed three times during the 4‐month follow‐up and analysed for content of interleukin‐6 ( IL‐6 ) , IL‐8 , uric acid and glutathione ( GSx ) . IL‐6 levels in the nasal lavage were increased significantly in the placebo group after ozone exposure while no increase was observed in the supplement group . The difference in response to ozone exposure between the two groups was significant ( P = 0·02 ) . Results were similar for IL‐8 , but with no significant difference between the groups ( P = 0·12 ) . GSx decreased significantly in both groups . Uric acid decreased slightly in the placebo group . Our data suggest that vitamin C and E supplementation above the minimum dietary requirement in asthmatic children with a low intake of vitamin E might provide some protection against the nasal acute inflammatory response to ozone [18516713] Abstract . Objective : Our aim was to investigate the effects of 12-week oral magnesium ( Mg ) supplementation on the RBC redox system in stable , persistent , moderately asthmatic children ( N = 40 , 24 boys , 16 girls ) aged 4–16 years in a r and omized , double-blind , placebo-controlled study . Design : Oxidized ( GSSG ) and reduced ( GSH ) glutathione , oxyhaemoglobin , methaemoglobin ( metHb ) , hemichrome and bilirubin levels before and after treatment were determined , and GSH stability tests were performed . Result : The GSH concentration was significantly higher in the Mg-treated than in the placebo-treated patients after the treatment period . There was a positive correlation between the decreased plasma metHb and hemichrome levels and the decreased plasma haemoglobin concentrations in the Mg-treated patients at the end of the study . Conclusion : Mg in the given doses exerts antioxidant activity and influences the glutathione redox system [22854412] BACKGROUND Antioxidant-rich diets are associated with reduced asthma prevalence in epidemiologic studies . We previously showed that short-term manipulation of antioxidant defenses leads to changes in asthma outcomes . OBJECTIVE The objective was to investigate the effects of a high-antioxidant diet compared with those of a low-antioxidant diet , with or without lycopene supplementation , in asthma . DESIGN Asthmatic adults ( n = 137 ) were r and omly assigned to a high-antioxidant diet ( 5 servings of vegetables and 2 servings of fruit daily ; n = 46 ) or a low-antioxidant diet ( ≤2 servings of vegetables and 1 serving of fruit daily ; n = 91 ) for 14 d and then commenced a parallel , r and omized , controlled supplementation trial . Subjects who consumed the high-antioxidant diet received placebo . Subjects who consumed the low-antioxidant diet received placebo or tomato extract ( 45 mg lycopene/d ) . The intervention continued until week 14 or until an exacerbation occurred . RESULTS After 14 d , subjects consuming the low-antioxidant diet had a lower percentage predicted forced expiratory volume in 1 s and percentage predicted forced vital capacity than did those consuming the high-antioxidant diet . Subjects in the low-antioxidant diet group had increased plasma C-reactive protein at week 14 . At the end of the trial , time to exacerbation was greater in the high-antioxidant than in the low-antioxidant diet group , and the low-antioxidant diet group was 2.26 ( 95 % CI : 1.04 , 4.91 ; P = 0.039 ) times as likely to exacerbate . Of the subjects in the low-antioxidant diet group , no difference in airway or systemic inflammation or clinical outcomes was observed between the groups that consumed the tomato extract and those who consumed placebo . CONCLUSIONS Modifying the dietary intake of carotenoids alters clinical asthma outcomes . Improvements were evident only after increased fruit and vegetable intake , which suggests that whole-food interventions are most effective . This trial was registered at http://www.actr.org.au as ACTRN012606000286549 [3672916] Background : Adverse health effects associated with diesel exhaust ( DE ) are thought to be mediated in part by oxidative stress , but the detailed mechanisms are largely unknown . MicroRNAs ( miRNAs ) regulate gene expression post-transcriptionally and may respond to exposures such as DE . Objectives : We profiled peripheral blood cellular miRNAs in participants with mild asthma who were exposed to controlled DE with and without antioxidant supplementation . Methods : Thirteen participants with asthma underwent controlled inhalation of filtered air and DE in a double-blinded , r and omized crossover study of three conditions : a ) DE plus placebo ( DEP ) , b ) filtered air plus placebo ( FAP ) , or c ) DE with N-acetylcysteine supplementation ( DEN ) . Total cellular RNA was extracted from blood drawn before exposure and 6 hr after exposure for miRNA profiling by the NanoString nCounter assay . MiRNAs significantly associated with DEP exposure and a predicted target [ nuclear factor ( erythroid-derived 2)-like 2 ( NRF2 ) ] as well as antioxidant enzyme genes were assessed by reverse transcription – quantitative polymerase chain reaction ( RT-qPCR ) for validation , and we also assessed the ability of N-acetylcysteine supplementation to block the effect of DE on these specific miRNAs . 8-hydroxy-2´-deoxyguanosine ( 8-OHdG ) was measured in plasma as a systemic oxidative stress marker . Results : Expression of miR-21 , miR-30e , miR-215 , and miR-144 was significantly associated with DEP . The change in miR-144 was vali date d by RT-qPCR . NRF2 and its downstream antioxidant genes [ glutamate cysteine ligase catalytic subunit ( GCLC ) and NAD(P)H : quinone oxidoreductase 1 ( NQO1 ) ] were negatively associated with miR-144 levels . Increases in miR-144 and miR-21 were associated with plasma 8-hydroxydeoxyguanosine 8-OHdG level and were blunted by antioxidant ( i.e , DEN ) . Conclusions : Systemic miRNAs with plausible biological function are altered by acute moderate-dose DE exposure . Oxidative stress appears to mediate DE-associated changes in miR-144 [20889523] Background Prenatal antioxidant supplementation might influence fetal lung growth and development and reduce infant respiratory morbidity . The aim of this study was to test the hypothesis that infants of mothers at risk of pre-eclampsia who were r and omised to receive high-dose vitamins C and E ( 1000 mg vitamin C and 400 IU RRR α-tocopherol daily ) during pregnancy would have better respiratory outcomes than infants whose mothers were r and omised to receive placebo . Methods Respiratory outcomes to 2 years of age were documented using question naires and , in a subset , by recording their healthcare utilisation and calculating the cost of care data . Results 330 women who had taken vitamin supplementation and 313 who had taken placebo completed the respiratory question naire ( 386 and 366 infants , respectively ) . There were no significant differences between the two groups in the proportions diagnosed with asthma . 54 women who had taken vitamin supplementation and 45 who had taken placebo took part in the healthcare utilisation study ( 65 and 53 infants , respectively ) . On average , infants of mothers receiving vitamin supplementation had 2.6 ( 99 % CI 0.8 to 5.1 ) times more A&E/outpatient visits and 3.2 ( 99 % CI 0.2 to 6.9 ) times more GP visits than infants of mothers receiving placebo , and their costs of care were £ 226 ( 99 % CI £ 27 to £ 488 ) more for outpatient admissions , £ 57 ( 99 % CI £ 3 to £ 123 ) more for GP visits and £ 22 ( 99 % CI £ 3 to £ 50 ) more for medications . Conclusions High-dose antenatal vitamin C and E supplementation does not improve infant respiratory outcome and is associated with increased healthcare utilisation and cost of care [10445599] In asthmatic patients , antioxidant defence is decreased . Although inhaled corticosteroids decrease asthmatic inflammation and modulate reactive oxygen species ( ROS ) generation , little is known of their effect on cellular antioxidant levels . The aim of this study was to evaluate the effect of inhaled beclomethasone dipropionate ( BDP ; 1,000 microg x day(-1 ) ) on erythrocyte antioxidant levels in stable asthmatic patients . Forty patients with stable , mild asthma were treated in a double-blind , placebo-controlled , parallel-group study with BDP 250 microg , two puffs b.i.d . for 6 weeks . At entry and every 2 weeks during treatment , erythrocyte antioxidant levels , haematological parameters , pulmonary function tests and asthma symptoms were determined . The results show that during treatment with BDP , erythrocyte catalase levels increased ( at entry ( mean + /-SEM ) 41+/-4 , after 6 weeks 54+/-4 micromol H2O2 x min(-1 ) x g haemoglobin (Hb)(-1 ) , p = 0.05 in comparison with placebo ) . Erythrocyte total glutathione levels significantly decreased after 6 weeks treatment with BDP ( from 7.0+/-0.4 to 6.6+/-0.3 micromol x g Hb(-1 ) ( p = 0.04 ) ) . In the BDP-treated patients , blood eosinophil counts were higher in patients who responded with an increase in erythrocyte catalase levels during BDP treatment , as compared to those not responding ( ( mean + /-SEM ) 340+/-39 and 153+/-52x10(6 ) cells x L(-1 ) , respectively , p = 0.05 ) . The present study shows that treatment with inhaled bedomethasone dipropionate results in changes in antioxidant levels in erythrocytes of patients with stable , mild asthma [17234657] Background : Epidemiological evidence from observational studies has suggested that blood levels and dietary intake of selenium of adults with asthma are lower than those of controls . The only previous trial of selenium supplementation in adults with asthma found no objective evidence of benefit but involved only 24 participants . Methods : A r and omised , double blind , placebo-controlled trial of selenium supplementation was performed in adults with asthma in London , UK , the majority of whom ( 75 % ) reported inhaled steroid use at baseline . 197 participants were r and omised to receive either a high-selenium yeast preparation ( 100 µg daily , n = 99 ) or placebo ( yeast only , n = 98 ) for 24 weeks . The primary outcome was asthma-related quality of life ( QoL ) score . Secondary outcomes included lung function , asthma symptom scores , peak flow and bronchodilator usage . Linear regression was used to analyse the change in outcome between the two treatment arms by “ intention to treat ” . Results : There was a 48 % increase in plasma selenium between baseline and end of trial in the active treatment group but no change in the placebo group . While the QoL score improved more in the active treatment group than in the placebo group , the difference in change in score between the two groups was not significant ( −0.05 ( 95 % CI −0.19 to 0.09 ) ; p = 0.47 ) . Selenium supplementation was not associated with any significant improvement in secondary outcomes compared with placebo . Conclusions : Selenium supplementation had no clinical benefit in adults with asthma , the majority of whom were taking inhaled steroids [12639402] Asthma is characterized as a chronic inflammatory process . Pycnogenol((R ) ) , a bioflavonoid mixture extracted from Pinus maritima , is known to scavenge free radicals while possessing antioxidant and antiinflammatory properties . The objective of this study was to evaluate the efficiency of this agent in a r and omized , double-blinded , placebo-controlled , crossover study in patients with varying asthma severity . Twenty-six patients who fulfilled the American Thoracic Society criteria for asthma were enrolled in the study . Medical history , physical examination , blood sample analyses , and spirometric values were obtained at baseline , 4 weeks , and 8 weeks . The patients were r and omly assigned to receive either 1 mg/lb/day ( maximum 200 mg/day ) Pycnogenol or placebo for the first period of 4 weeks and then crossed over to the alternate regimen for the next 4 weeks . No adverse effects were observed related to the study drug . Within the contingent of 22 patients who completed the study , almost all responded favorably to Pycnogenol in contrast to placebo . Pycnogenol treatment also significantly reduced serum leukotrienes compared with placebo . The results of this pilot study indicate that Pycnogenol may be a valuable nutraceutical in the management of chronic asthma . We recommend that further clinical trials be conducted in larger groups of asthmatics to establish its efficacy [14573726] Aims : To explore the effects in normal and asthmatic adults of exposure to 200 ppb sulphur dioxide ( SO2 ) and 200 μg/m3 and 2000 μg/m3 aerosols of ammonium bisulphate ( AB ) and sulphuric acid ( SA ) ( MMD 0.3 μm ) . Methods : Exposures were placebo controlled , for one hour at rest , double blind in r and om order . ΔFEV1 was the primary outcome ; secondary outcomes included symptoms , ventilation , exhaled nitric oxide ( NO ) concentrations , and nasal lavage fluid ascorbic ( AA ) and uric acid ( UA ) concentrations . Results : There were no significant changes in spirometry or symptoms with any exposure in either group . SO2 exposure was associated with an increased respiratory rate relative to air exposure in the asthmatic group ( SO2 : 958.9 breaths/hour ; air : 906.8 breaths/hour ) but the mean volume breathed did not differ significantly ( SO2 : 318.8 litres ; air : 311.4 litres ) . AB exposures were associated with a significant rise in [ NO ] in the asthmatic ( + 1.51 ppb , and + 1.39 ppb ) , but not in the normal group . Mean pre- and post-exposure [ AA ] tended to be higher in the normal than in the asthmatic group . Within each group , [ AA ] did not change significantly with any exposure . Post-exposure [ UA ] were greater than pre-exposure concentrations for all exposures , significantly so in the normal group for all exposures except SO2 . There were no significant differences in the mean change in [ UA ] for any exposure relative to air . Conclusions : The pollutant exposure concentrations employed in this study were generally much greater than ambient . It is unlikely that short lived exposures at lower concentrations would show significant effects , but effects of longer term lower concentration exposures can not be ruled out [18339679] Background : R and omised data in men show a small but significant reduction in the risk of adult-onset asthma among those given aspirin . The results from an observational study in women suggest that frequent use of aspirin decreases the risk of adult-onset asthma , but r and omised data in women are lacking . A study was undertaken to test the effect of 100 mg aspirin or placebo on alternate days on the risk of adult-onset asthma in the Women ’s Health Study . Methods : A r and omised , double-blind , placebo-controlled clinical trial of aspirin and vitamin E was performed in apparently healthy women with no indication or contraindication to aspirin therapy and no history of asthma at study entry . Female health professionals self-reported an asthma diagnosis on yearly question naires . Results : Among 37 270 women with no reported history of asthma prior to r and omisation and during 10 years of follow-up , there were 872 new cases diagnosed with asthma in the aspirin group and 963 in the placebo group ( hazard ratio 0.90 ; 95 % CI 0.82 to 0.99 ; p = 0.027 ) . This apparent 10 % lower relative risk of incident adult-onset asthma among those assigned to aspirin was significantly modified by body mass index , with no effect in women with a body mass index of ⩾30 kg/m2 . The effect of aspirin on adult-onset asthma was not significantly modified by age , smoking status , exercise levels , postmenopausal hormone use or r and omised vitamin E assignment . Conclusions : In this large r and omised clinical trial of apparently healthy adult women , administration of 100 mg aspirin on alternate days reduced the relative risk of a newly reported diagnosis of asthma . Trial registration number : [23648395] This pilot study aims to provide effect size confidence intervals , clinical trial and intervention feasibility data , and procedural material s for a full-scale r and omized controlled trial that will determine the efficacy of Dietary Approaches to Stop Hypertension ( DASH ) as adjunct therapy to st and ard care for adults with uncontrolled asthma . The DASH diet encompasses foods ( e.g. , fresh fruit , vegetables , and nuts ) and antioxidant nutrients ( e.g. , vitamins A , C , E , and zinc ) with potential benefits for persons with asthma , but it is unknown whether the whole diet is beneficial . Participants ( n = 90 ) will be r and omized to receive usual care alone or combined with a DASH intervention consisting of 8 group and 3 individual sessions during the first 3 months , followed by at least monthly phone consultations for another 3 months . Follow-up assessment s will occur at 3 and 6 months . The primary outcome measure is the 7-item Juniper Asthma Control Question naire , a vali date d composite measure of daytime and nocturnal symptoms , activity limitations , rescue medication use , and percentage predicted forced expiratory volume in 1 second . We will explore changes in inflammatory markers important to asthma pathophysiology ( e.g. , fractional exhaled nitric oxide ) and their potential to mediate the intervention effect on disease control . We will also conduct pre-specified subgroup analyses by genotype ( e.g. , polymorphisms on the glutathione S transferase gene ) and phenotype ( e.g. , atopy , obesity ) . By evaluating a dietary pattern approach to improving asthma control , this study could advance the evidence base for refining clinical guidelines and public health recommendations regarding the role of dietary modifications in asthma management [9111435] OBJECTIVE To determine if vitamin C ( ascorbic acid ) has a protective effect on the hyperreactive airways of patients with exercise-induced asthma ( EIA ) . DESIGN All the patients underwent pulmonary function tests at rest , before and 1 hour after receiving 2 g of oral ascorbic acid . They were then r and omly assigned in a double-blind manner to receive 2 g of ascorbic acid or a placebo 1 hour before a 7-minute exercise session on a treadmill . Pulmonary function tests were performed after an 8-minute rest . This procedure was repeated 1 week later , with each patient receiving the alternative medication . SETTING A university hospital . PARTICIPANTS Twenty patients with asthma ( 13 males and 7 females ) , with ages ranging from 7 to 28 years ( mean , 13.8 years ) . All patients who had a decline of at least 15 % in their forced expiratory volume in 1 second after a st and ard exercise test on a motorized treadmill received a diagnosis of EIA . MAIN- OUTCOME MEASURES : All patients were advised to stop using their regular asthma medication or bronchodilator 12 hours before the test . Pulmonary function tests were performed in the same ambient conditions on all patients . RESULTS All patients received a diagnosis of EIA . Ascorbic acid administration did not change the results of pulmonary functions at rest after 1 hour . In 9 patients , a protective effect on exercise-induced hyperreactive airways was documented . Four of 5 patients who received ascorbic acid and documented a protective effect on EIA continued to receive ascorbic acid , 0.5 g/d , for 2 more weeks with the same protective effect . CONCLUSIONS The efficacy of vitamin C in preventing EIA can not be predicted . However , vitamin C may have a protective effect on airway hyperreactivity in some patients with EIA [16140229] Exhaled carbon monoxide ( eCO ) is a potential non-invasive marker of airway inflammation . We have investigated the cross-sectional and longitudinal relationship between eCO and lung function and bronchial reactivity in 69 adults with atopic asthma , in the course of participation in a 6-week r and omised placebo-controlled trial of vitamin E supplementation . At baseline , there was no cross-sectional association between absolute eCO levels and either forced expiratory volume ( FEV(1 ) ) , forced vital capacity ( FVC ) or bronchial reactivity . However , in the longitudinal analysis within the placebo group , a rise in mean eCO was significantly associated with improvement in bronchial reactivity ( change in eCO ( parts per million ) per natural log unit change in bronchial hyperreactivity 0.498 , 95 % confidence interval 0.071 to 0.924 , P=0.024 ) . These findings suggest that , contrary to previous data , there is no cross-sectional relationship between eCO and lung function or bronchial reactivity , but that there may be a longitudinal trend with bronchial reactivity that is worth further investigation [29070392] OVER THE PAST THREE DECADES , many studies have been published of the associations between a variety of different measures of antioxidants and both asthma and lung function . While there is always a risk of publication bias , the general trend of these studies has been to suggest an association between higher dietary antioxidant intake with less asthma and better lung function . The study by Yoon et al. in this issue of the Journal adds to this body of literature by identifying 100 patients with relatively stable asthma , and demonstrating that those with a serum total antioxidant capacity ( TAC ) over the mean value have a higher baseline lung function than those with a serum TAC less than the mean value , although there was no signifi ca nt difference in bronchial reactivity.1 However , TAC levels were not signifi cantly correlated with longitudinal changes in pulmonary function , although the higher baseline lung function result ed in greater forced expiratory volume both one and two years after enrolment — as would probably be expected . As serum TAC refl ects a composite of endogenous and exogenous factors , only the latter category can be considered amenable to intervention . These include environmental tobacco exposure ( which was not adjusted for in the article by Yoon et al. ) , ambient pollution and dietary antioxidants.2 Recognition is growing of the importance of societal level interventions to reduce tobacco consumption and hence exposure to this and other forms of ambient pollution . The challenge for epidemiological research ers is to distinguish causality from association ; this is particularly true for nutritional research , where the problems of confounding by lifestyle , pre-natal exposures and possibly even pre-conception exposures ( via epigenetics ) are manifold . The only study design that can deliver these answers is the r and omised controlled trial , and these are better able to consider the secondary treatment of diseases such as asthma , rather than the primary prevention of asthma due to logistical considerations such as cost and recruitment . However , selection of the intervention is diffi cult , as relatively small studies ( compared to pharmaceutical studies ) of individual antioxidants have not been encouraging.3,4 One particular problem observed in these studies is that the individuals who volunteer to participate in these studies are often already eating a healthy diet , have an interest in healthy eating and hence may have little room for nutritional improvement . The most promising nutritional interventions in asthma have tended to involve combinations of antioxidants5 and , more recently , increased fruit and vegetable intake.6 The latter study suggested that those who received fi ve servings of vegetables and two servings of fruit daily were less than half as likely to have an exacerbation during the following 14 weeks . Further r and omised controlled studies of this nature are required to permit an enhanced underst and ing of the role of oxidation with regard to asthma aetiology and severity , and hopefully to permit translation of epidemiological observations into tangible effects from which the individual patient can benefi [10489824] In this study , the perceptions of asthmatics to change in their disease was associated with observed changes in clinical asthma measures , in order to identify the threshold where changes in clinical asthma measures are perceivable by patients . The study included 281 asthmatic patients , aged 18 - 63 yrs , in a r and omized , placebo-controlled clinical trial of a leukotriene antagonist . Changes were related in : 1 ) asthma symptom scores ; 2 ) inhaled beta-agonist use ; 3 ) forced expiratory volume in one second ( FEV1 ) ; and 4 ) peak expiratory flow ( PEF ) to a global question that queried overall change in asthma since starting the study drug . Additional analyses examined differences in the group reporting minimal improvement by treatment ( active treatment versus placebo ) , sex and age groups . The average minimal patient perceivable improvement for each measure was : 1 ) -0.31 points for the symptom score on a scale of 0 - 6 ; 2 ) -0.81 puffs x day(-1 ) for inhaled beta-agonist use ; 3 ) 0.23 L for FEV1 ; and 4 ) 18.79 L x min(-1 ) for PEF . In general placebo-treated patients and older patients , who reported minimal improvement , experienced less mean improvement from baseline than active-treated patients and younger patients , who reported minimal improvement . Determining the minimal patient perceivable improvement value for a measure may be helpful to interpret changes . However , interpretation should be carried out cautiously when reporting a single value as a clinical ly important change [3447618] This present trial investigated the efficacy of supplementation with Chlorella vulgaris , a bioactive microalga rich in macro- and micronutrients , in the improvement of biochemical and clinical symptoms in patients with obstructive pulmonary disorders . Ninety-seven patients with chronic obstructive pulmonary disease ( COPD ) or asthma who were under conventional treatment regimens were r and omly assigned to C. vulgaris extract ( CVE ) ( n=48 ; 2700 mg/day ) or no adjunctive therapy ( n=49 ) for eight weeks . Serum levels of antioxidants along with spirometric parameters and clinical symptoms were evaluated pre- and post-trial . The magnitude of increases in the concentrations of glutathione , vitamin E , and vitamin C , and activities of glutathione peroxidase , catalase , and superoxide dismutase enzymes were all significantly greater in the CVE vs. control group ( p<0.05 ) . In spite of increases , none of the assessed spirometric parameters ( FVC , FEV1 , FEV1/FVC , and FEF25–75 % ) did significantly differ by the end of the trial in the study groups , apart from a significant elevation of FEV1 in the control group ( p=0.03 ) . The frequency of coughing , shortness of breath , wheezing , and sputum brought up were all significantly reduced in both CVE and control groups ( p<0.05 ) . The rate of improvement for sputum brought up and wheezing were significantly greater in the CVE group compared to the control group ( p<0.05 ) . Although CVE was found to ameliorate serum antioxidant status , its supplementation was not associated with any bronchodilatory activity . The results of the present trial do not support any clinical efficacy for CVE in patients with obstructive pulmonary disorders [21614939] PURPOSE The purpose of this study was to test the effectiveness of an integrative medicine approach to the management of asthma compared to st and ard clinical care on quality of life ( QOL ) and clinical outcomes . METHODS This was a prospect i ve parallel group repeated measurement r and omized design . Participants were adults aged 18 to 80 years with asthma . The intervention consisted of six group sessions on the use of nutritional manipulation , yoga techniques , and journaling . Participants also received nutritional supplements : fish oil , vitamin C , and a st and ardized hops extract . The control group received usual care . Primary outcome measures were the Asthma Quality of Life Question naire ( AQLQ ) , The Medical Outcomes Study Short Form-12 ( SF-12 ) , and st and ard pulmonary function tests ( PFTs ) . RESULTS In total , 154 patients were r and omized and included in the intention-to-treat analysis ( 77 control , 77 treatment ) . Treatment participants showed greater improvement than controls at 6 months for the AQLQ total score ( P<.001 ) and for three subscales , Activity ( P < 0.001 ) , Symptoms ( P= .02 ) , and Emotion ( P<.001 ) . Treatment participants also showed greater improvement than controls on three of the SF-12 subscales , Physical functioning ( P=.003 ) ; Role limitations , Physical ( P < .001 ) ; and Social functioning ( P= 0.03 ) , as well as in the aggregate scores for Physical and Mental health ( P= .003 and .02 , respectively ) . There was no change in PFTs in either group . CONCLUSION A low-cost group-oriented integrative medicine intervention can lead to significant improvement in QOL in adults with asthma [2248797] Introduction Our study was undertaken to determine the association between use of a health plan-sponsored health club benefit by older adults and total health care costs over 2 years . Methods This retrospective cohort study used administrative and cl aims data from a Medicare Advantage plan . Participants ( n = 4766 ) were enrolled in the plan for at least 1 year before participating in the plan-sponsored health club benefit ( Silver Sneakers ) . Controls ( n = 9035 ) were matched to participants by age and sex according to the index date of Silver Sneakers enrollment . Multivariate regression models were used to estimate health care use and costs and to make subgroup comparisons according to frequency of health club visits . Results Compared with controls , Silver Sneakers participants were older and more likely to be male , used more preventive services , and had higher total health care costs at baseline . Adjusted total health care costs for Silver Sneakers participants and controls did not differ significantly in year 1 . By year 2 , compared with controls , Silver Sneakers participants had significantly fewer inpatient admissions ( −2.3 % , 95 % confidence interval , −3.3 % to −1.2 % ; P < .001 ) and lower total health care costs ( −$500 ; 95 % confidence interval , −$892 to −$106 ; P = .01 ] . Silver Sneakers participants who averaged at least two health club visits per week over 2 years incurred at least $ 1252 ( 95 % confidence interval , −$1937 to −$567 ; P < .001 ) less in health care costs in year 2 than did those who visited on average less than once per week . Conclusion Regular use of a health club benefit was associated with slower growth in total health care costs in the long term but not in the short term . These findings warrant additional prospect i ve investigations to determine whether policies to offer health club benefits and promote physical activity among older adults can reduce increases in health care costs [20683104] Airway mucus hypersecretion and increased oxidative stress are clinical and pathophysiological features of asthma exacerbation . We studied effects of N-acetylcysteine ( NAC ) as a mucolytic and antioxidant agent in asthma exacerbation . In this r and omized , single-blinded , placebo-controlled study 50 patients ( 17 male , 33 female , mean age 48.94+/-13.68 ) with asthma exacerbation were r and omized to receive either oral 600 mg b.d . N-acetylcysteine or placebo in addition to st and ard treatment during 5 days hospitalization . Daily measurements of wheezing , dyspnea , cough , sputum , expectoration , night sleep scores and morning PEFR were performed . There was no significant difference in wheezing score between patients assigned NAC and those assigned placebo in day 5(0.84[SD 0.94 ] VS 0.87[SD 0.79 ] ) and also in cough score ( 0.72[SD 0.84 ] VS 0.79[SD 0.97 ] ) , dyspnea score ( 0.84[SD 1.06 ] VS 0.91[SD 1.01 ] ) , sputum score(0.79[SD 0.83 ] VS 0.62[SD 0.71 ] ) , expectoration score(0.79[SD 0.97 ] VS 0.83[SD 1.09 ] ) , night sleep score(1[SD 1.17 ] VS 0.67[SD 0.98 ] and morning PEFR ( 256[SD 96.36 ] VS 282[SD 98.86 ] ) . We concluded that addition of N-acetylcysteine to usual asthma medication has no significant effect in treatment of asthma exacerbation [17412579] BACKGROUND Previous research has shown that diet can modify the bronchoconstrictor response to exercise in asthmatic subjects . OBJECTIVE Determine the effect of ascorbic acid supplementation on pulmonary function and several urinary markers of airway inflammation in asthmatic subjects with exercise-induced bronchoconstriction ( EIB ) . METHODS Eight asthmatic subjects with documented EIB participated in a r and omized , placebo controlled double-blind crossover trial . Subjects entered the study on their usual diet and were placed on either 2 weeks of ascorbic acid supplementation ( 1500 mg/day ) or placebo , followed by a 1-week washout period , before crossing over to the alternative diet . Pre- and post-exercise pulmonary function , asthma symptom scores , fraction of exhaled nitric oxide ( FENO ) , and urinary leukotriene ( LT ) C4-E4 and 9alpha , 11beta-prostagladin ( PG ) F2 ] were assessed at the beginning of the trial ( usual diet ) and at the end of each treatment period . RESULTS The ascorbic acid diet significantly reduced ( p < 0.05 ) the maximum fall in post-exercise FEV1 ( -6.4 + /- 2.4 % ) compared to usual ( -14.3 + /- 1.6 % ) and placebo diet ( -12.9 + /- 2.4 % ) . Asthma symptoms scores significantly improved ( p<0.05 ) on the ascorbic acid diet compared to the placebo and usual diet . Post-exercise FENO , LTC4-E4 and 9alpha , 11beta-PGF2 concentration was significantly lower ( p<0.05 ) on the ascorbic acid diet compared to the placebo and usual diet . CONCLUSION Ascorbic acid supplementation provides a protective effect against exercise-induced airway narrowing in asthmatic subjects [18324527] Antioxidant-rich diets are associated with reduced asthma prevalence . However , direct evidence that altering intake of antioxidant-rich foods affects asthma is lacking . The objective was to investigate changes in asthma and airway inflammation result ing from a low antioxidant diet and subsequent use of lycopene-rich treatments . Asthmatic adults ( n=32 ) consumed a low antioxidant diet for 10 days , then commenced a r and omized , cross-over trial involving 3 × 7 day treatment arms ( placebo , tomato extract ( 45 mg lycopene/day ) and tomato juice ( 45 mg lycopene/day ) ) . With consumption of a low antioxidant diet , plasma carotenoid concentrations decreased , Asthma Control Score worsened , % FEV1 and % FVC decreased and % sputum neutrophils increased . Treatment with both tomato juice and extract reduced airway neutrophil influx . Treatment with tomato extract also reduced sputum neutrophil elastase activity . In conclusion , dietary antioxidant consumption modifies clinical asthma outcomes . Changing dietary antioxidant intake may be contributing to rising asthma prevalence . Lycopene-rich supplements should be further investigated as a therapeutic intervention [14694237] BACKGROUND We recently reported that antioxidant supplementation with vitamins C and E mitigated ozone related decline in forced expiratory flow ( FEF(25 - 75 ) ) in 158 asthmatic children in an area with high ozone exposure in Mexico City . METHODS A study was undertaken to determine whether deletion of glutathione S-transferase M1 ( GSTM1 null genotype ) , a gene involved in response to oxidative stress , influences ozone related decline in FEF(25 - 75 ) and the benefit of antioxidant supplementation . RESULTS GSTM1 null children receiving placebo had significant ozone related decrements in FEF(25 - 75 ) ( percentage change per 50 ppb of ozone 2.9 ( 95 % CI -5.2 to -0.6 ) , p=0.01 ) ; GSTM1 positive children did not . Conversely , the effect of antioxidants was stronger in children with the GSTM1 null genotype . CONCLUSIONS Asthmatic children with a genetic deficiency of GSTM1 may be more susceptible to the deleterious effects of ozone on the small airways and might derive greater benefit from antioxidant supplementation [22741171] Associations have been reported between suboptimal maternal vitamin E intake during pregnancy and childhood asthma . This pilot study conducted in 2008/2009 investigated the feasibility and acceptability of a food-based r and omized controlled trial in pregnant women to optimize dietary vitamin E intake to 15 mg/day . A food-based intervention using " food exchanges " to individually optimize dietary vitamin E intake to 15 mg/day was developed and included in an advice booklet . Forty-three pregnant women with a personal/partner history of asthma were recruited at 12 weeks gestation and r and omized to food-based intervention or a control group until 20 weeks gestation . A registered dietitian assessed the vitamin E intake of 22 women and provided tailored advice on food-based exchanges to optimize their intake to 15 mg/day . The 21 control women were not given dietary advice . The food-based intervention was completed by 19 women and increased mean vitamin E intake : food diary data , 7.13 mg/day ( 95 % confidence interval : 5.63 to 18.6 ) to 17.4 mg/day ( 95 % confidence interval : 14.4 to 20.5 ) ( P<0.001 ) . This pilot study demonstrates the feasibility and acceptability of a food-exchange-based intervention to optimize dietary vitamin E intake during pregnancy . Additional work is required to determine whether this intervention , if sustained for the rest of pregnancy , reduces the likelihood of childhood asthma . The methodology used in the design of this novel food-based intervention could be transferred to other nutrients [15823446] To further establish the role of oxidative stress in the pathogenesis of acute bronchial asthma , we investigated the effects of platelet-activating factor ( PAF ) challenge on systemic oxidant-antioxidant balance in 12 asthmatic patients ( age , 25+/-3[SEM ] yr ; FEV1 , 95+/-10 % predicted ) , using a double blinded , controlled with Lyso-PAF ( L-PAF ) , cross-over design . Respiratory system resistance ( Rrs ) , arterial blood gases , peripheral blood neutrophils and oxidant-antioxidant balance , including thiobarbituric acid (TBA)-malondialdehyde ( MDA ) adducts , protein sulphydryls and Trolox equivalent antioxidant capacity ( TEAC ) , were assessed at baseline and 5 , 15 and 45 min after PAF and L-PAF ( 18 microg each ) bronchoprovocation . Urinary leukotriene E4 ( uLTE4 ) elimination was measured 120 min after challenge . Compared with baseline , as expected , PAF increased significantly Rrs and AaPO2 and decreased PaO2 and peripheral blood neutrophils along with a rebound neutrophilia and increased uLTE4 . By contrast , markers of systemic oxidative stress remained unaltered throughout the study . Unlike PAF , L-PAF-induced changes were negligible . We conclude that there is no systemic oxidant-antioxidant imbalance during acute bronchoconstriction induced by PAF in these patients with mild asthma [20926152] BACKGROUND Chronic airway inflammation in asthma or chronic obstructive pulmonary disease ( COPD ) may be involved in the pathogenesis of type 2 diabetes ; however , prospect i ve data have been limited . METHODS A prospect i ve cohort of 38,570 women who were aged ≥ 45 years , free of cardiovascular disease and cancer at baseline , and free of diabetes at baseline and in the first 12 months were analyzed . We classified all women into three groups according to the presence and absence of self-reported asthma or COPD ( including emphysema , chronic bronchitis , and bronchiectasis ) . RESULTS During a median follow-up of 12.2 years , 2472 incident type 2 diabetes events were documented . Women who had ever reported asthma or COPD were associated with an increased diabetes risk ; the multivariate RRs were 1.37 ( 95 % CI , 1.20 - 1.57 ) for women who had asthma alone and 1.38 ( 95 % CI , 1.14 - 1.67 ) for COPD without asthmatic symptoms . Furthermore , these associations were not significantly modified by age , smoking status , physical activity , BMI , alcohol intake , hormone replacement therapy , menopausal status or r and omized treatment . CONCLUSIONS Asthma and COPD were individually and independently associated with an increased risk of type 2 diabetes in women , indicating that chronic airway inflammation may contribute to diabetes pathogenesis [14519140] Background Epidemiological studies suggest that higher intakes of dietary vitamin C and magnesium may be associated with a reduced risk of asthma [12204869] To evaluate whether acute effects of ozone , nitrogen dioxide , and particulates with mass median diameter less than 10 micro m could be attenuated by antioxidant vitamin supplementation , we conducted a r and omized trial using a double-blinded design . Children with asthma ( n = 158 ) who were residents of Mexico City were r and omly given a daily supplement of vitamins ( 50 mg/day of vitamin E and 250 mg/day of vitamin C ) or a placebo and were followed from October 1998 to April 2000 . Pulmonary function tests were carried out twice a week in the morning . During the follow-up observation period , the mean 1-hour maximum ozone level was 102 ppb ( SD = 47 ) , and the mean 24-hour average PM(10 ) level was 56.7 micro g/m(3 ) ( SD = 27.4 ) . In children with moderate and severe asthma , ozone levels 1 day before spirometry were inversely associated significantly with forced expiratory flow ( FEF(25 - 75 ) ) ( -13.32 ml/second/10 ppb ; p = 0.000 ) , FEV(1 ) ( -4.59 ml/10 ppb ; p = 0.036 ) , and peak expiratory flow ( PEF ) ( -15.01 ml/second/10 ppb ; p = 0.04 ) in the placebo group after adjusting for potential confounding factors . No association between ozone and lung functions was observed in the supplement group . We observed significant differences in lung function decrements between groups for FEF(25 - 75 ) and PEF . Our results suggest that supplementation with antioxidants might modulate the impact of ozone exposure on the small airways of children with moderate to severe asthma [15641633] To determine if micronutrient intake is associated with asthma severity , we administered the Block food frequency question naire to participants in a r and omized clinical trial of the safety of influenza vaccine for asthmatics . The nutrition sub study included 1033 participants , aged 12–75 . Intake of antioxidant vitamins , soy isoflavones , total fruits and vegetables , fats , and fiber was compared with asthma severity at baseline [ forced expiratory volume in 1 second ( FEV1 ) , peak expiratory flow rate ( PEF ) , asthma symptoms ] and the rate of asthma exacerbations during the 2 weeks following influenza vaccination . The only nutrient that had a consistent association with asthma severity was genistein , a soy isoflavone . None of the nutrients evaluated were related to asthma exacerbation rate when adjusted for known confounders . The FEV1 in genistein consumers of at least 250 µg/1000 Kcal/day was 82.1 % predicted , 79.9 % predicted for those who consumed between 1 and 249 µg/1000 kcal , and 76.2 % predicted in genistein nonconsumers ( p = 0.006 ) ; the PEF was 82.7 % predicted , 80.8 % predicted , and 78.3 % predicted , respectively ( p = 0.009 ) . There were no differences in the Asthma Symptom Utility Index ( ASUI ) . We could not account for these results based on differences in demographics , body mass index , or consumption of other nutrients . Thus , increasing consumption of genistein is associated with better lung function in patients with asthma . Further studies are needed to determine whether dietary supplementation with genistein can reduce asthma severity [12424331] The human lung , due to the oxidative and ozone stress to which it is exposed , is particularly vulnerable to oxidative damage . Concentrations of dietary antioxidants in the lung epithelial lining and lining fluids may provide protection against oxidative damage . A r and omized clinical trial was conducted to study the effects of supplemental , carotenoid-rich vegetable Juice ( V-8 ) on lung function macrophage levels of carotenoids and in moderating ozone-induced lung damage . Healthy young adults ( n = 23 ) were exposed to 0.4 ppm ozone in a chamber for 2 hr after either 2 weeks of antioxidant supplementation ( including one can of V-8 juice daily ) or placebo . Mean lung concentrations of lycopene increased by 12 % , and lung epithelial cell DNA damage as measured by the Comet Assay decreased 20 % In supplemented subjects . No change in peripheral blood lymphocyte DNA damage was observed as evidence d by no change in mean comet area or length in supplemented or placebo subjects . We were not able to separate the effects of lycopene from other carotenoids or antioxidants administered in this study ; however , lycopene is the predominant carotenold in V-8 ( it represents 88 % of total carotenoids ) . A review of the epidemiologic literature providing evidence for the effect of lycopene ( diet or serum ) or tomatoes on the risk of lung cancer reveals 27 observational epidemiologic studies ( 18 case-control and nine cohort studies ) reporting relative risk ( RR ) estimates . RR estimates for cohort studies ranged from 0.63 to 1.24 ( mean RR = 0.93 , SD = 0.16 ) . Odds ratios ( OR ) for case-control studies ranged from 0.27 to 0.93 ( mean OR = 0.61 , SD = 0.16 ) . Both plasma levels ( RR = 1.01 , OR = 0.37 ) and estimated intakes of lycopene from dietary sources ( mean RR = 0.93 , RR range = 0.80–1.05 ; mean OR = 0.67 , OR range = 0.27–0.93 ) were examined . Seventeen studies , three of which were cohorts , reported their results at the level of tomato consumption rather than , or in addition to , lycopene consumption ( mean RR = 0.89 , RR range = 0.63–1.24 ; mean OR = 0.61 , OR range = 0.37–0.80 ) . The published epidemiologic literature shows an Interaction between study design and the relationship between lycopene and /or tomatoes and risk of lung cancer . Overall , cohort studies did not show an association , whereas case-control studies showed a decreased risk with greater consumption of lycopene and tomatoes . Altough lycopene can be found in the human lung , and there is evidence , albeit weak , for a protective association with lung cancer , its biologic role remains to be eluci date [363773] The effect of vitamin C pretreatment in preventing ragweed-induced bronchospasm was evaluated in 6 ragweed-sensitive asthmatics studied in a double-blind r and omized fashion . The patients received either lactose capsules or 500 mg of ascorbic acid and were studied out of season . Antigen dose-response curves were determined prior to the administration of lactose or ascorbic acid in each individual subject and subsequently after administration of ascorbic acid or lactose . Bothe PD20FEV1 ( provocation dose necessary for a 20 % reduction in forced expiratory volume in 1 second ) and PD35SGaw ( provocation dose necessary for a 35 % reduction in specific airways conductance ) were determined . In none of the six patients was there a change in baseline FEV 1 ( p greater than 0.70 ) nor the overall average baseline specific airways conductance ( rho greater than 0.90 ) . Additionally , no statistically significant difference ( p greater than 0.60 ) was noted between log PD35SGaw vitamin C day and lactose day . Likewise , no statistically significant difference ( p greater than 0.60 ) was evident when comparing log PD20FEV1 lactose and ascorbic acid days . Vitamin C ( 500 MG ) HAS NO PROTECTIVE EFFECT AGAINST RAGWEED ANTIGEN-INDUCED BRONCHOSPASM [12061080] Selenium ( Se ) deficiency attenuates the host immune response , thereby increasing the risk of bacterial and viral infections . We have examined the effects of selenium supplementation ( SeS ) in corticoid-dependent asthmatics ( CDAs ) with lowered circulatory Se status . Twenty CDAs ( 10 males and 10 females , average age 54.5 yrs ) were enrolled into the study . The average duration of the disease was 10 yrs . The asthmatics were receiving 200 micrograms of Se per day for a period of 6 months , in addition to regular treatment with inhaled corticosteroids and beta-agonists . The expression of adhesion molecules ( CD11a , CD11b , CD18 , CD49d , CD54 , CD62L ) on peripheral blood mononuclear cells ( P BMC s ) of asthmatics and the expression of E- and P-selectins , ICAM-1 , VCAM-1 on cultured human umbilical vein endothelial cells ( HUVEC ) after stimulation with P BMC s from CDAs before and after 3 and 6 months of SeS were assessed by st and ard monoclonal antibodies and analyzed by flow cytometry . The concentrations of soluble adhesion molecules P-selectin , E-selectin , ICAM-1 and VCAM-1 were determined by ELISA method . The expression of adhesion molecules on P BMC s : After 3- and 6-months of SeS , a decreased expression of molecules CD11a , CD11b and CD62L was observed ( p < 0.02 , p < 0.005 , p < 0.003 ) . No changes were seen in the expression of CD18 , CD49d except for the increased expression of CD54 ( p < 0.005 ) . Modulation of adhesion molecules expression on HUVEC : We observed a significant increase in VCAM-1 , P- and E-selectins expressions in the group of asthmatics without SeS in comparison with the control group ( p < 0.05 , p < 0.01 , p < 0.05 ) . During SeS a significant decrease in molecules VCAM-1 , E-selectin ( after 3 months ) ( p < 0.05 , p < 0.05 ) and P-selectins and ICAM-1 ( after 6 months ) ( p < 0.05 , p < 0.01 ) were observed . Soluble adhesion molecules : After 3 months of SeS we noticed a significant decrease in VCAM-1 and P-selectin expressions ( p < 0.05 , p < 0.05 ) and after 6 months the level of VCAM-1 decreased ( p < 0.01 ) . The effect of Se on the adhesion molecules expression in endothelial cells in vitro experiments : Se blocks the expression of adhesion molecules stimulated by IFN-gamma in a dose-dependent way after addition of Se into a culture of endothelial cells . Concentration of 10 micrograms/ml inhibits the increase in expression of ICAM-1 ( p < 0.05 ) but not that of VCAM-1 , E- or P-selectins . The inhibition of expression in Se concentration of 10 micrograms/ml is over 80 % ( p < 0.01 ) . Our data demonstrate that Se is able to affect the adhesion molecules expressions that are crucial in the inflammatory process . ( Fig. 5 , Ref . 22 . [12741429] STUDY OBJECTIVES To characterize asthma symptoms and pulmonary function throughout two menstrual cycles , with and without exogenous estradiol administration , in women with premenstrual asthma , and to determine the effect of estradiol administration on asthma symptoms , pulmonary function , quality of life , and biomarkers of airway inflammation . DESIGN Double-blind , r and omized , placebo-controlled , crossover study . SETTING Respiratory clinic and clinical research center . SUBJECTS Twelve women with documented premenstrual asthma ( > or = 20 % premenstrual worsening of asthma symptoms and /or of peak expiratory flow [ PEF ] during a 1-month screening phase ) . INTERVENTION Each woman received either estradiol 2 mg or placebo orally between cycle days 23 and 28 ( i.e. , premenstrually , or before the onset of menses ) in the first cycle and then crossed over to the other arm in the second cycle . Throughout both cycles , the women recorded daily morning and evening PEF readings and asthma symptoms . MEASUREMENTS AND MAIN RESULTS Spirometry testing and measurement of serum estradiol and biomarkers of airway inflammation were performed on days 8 ( follicular phase ) , 22 ( luteal phase ) , and 28 ( premenstrually ) of both the estradiol and placebo cycles . During the two premenstrual visits , the Asthma Quality of Life Question naire was administered . No notable differences were observed between the estradiol and placebo cycles in daily PEF recordings or composite asthma symptoms scores . The area under the curve ( AUC ) for the composite asthma symptoms versus time profile was numerically , but not statistically , lower ( denoting less severe symptoms ) during the estradiol cycle than during the placebo cycle . Likewise , no significant difference in AUC values for morning PEF or evening PEF was found between the estradiol cycle and the placebo cycle . Despite differences ( p<0.05 ) in day-28 estradiol concentrations for estradiol and placebo cycles , no significant differences were found in forced expiratory volume in 1 second , serum endothelin-1 , serum and urine eosinophil protein X , urine leukotriene E4 , or quality -of-life scores . CONCLUSION Exogenously administered estradiol did not have a significant effect in women with premenstrual asthma whose asthma was classified predominantly as mild and under excellent control . As in the case of premenstrual syndrome , the placebo effect may be prominent in premenstrual asthma . Further trials , involving women with more severe asthma under poorer control , are warranted to discern underlying mechanisms for the worsening of asthma in relation to menstruation [15641632] A r and omized , placebo‐controlled , double‐blind study involving 60 subjects , aged 6–18 years old , was conducted over a period of 3 months to determine the effect of Pycnogenol ® ( a proprietary mixture of water‐soluble bioflavonoids extracted from French maritime pine ) on mild‐to‐moderate asthma . After baseline evaluation , subjects were r and omized into two groups to receive either Pycnogenol ® or placebo . Subjects were instructed to record their peak expiratory flow with an Assess ® Peak Flow Meter each evening . At the same time , symptoms , daily use of rescue inhalers ( albuterol ) , and any changes in oral medications were also recorded . Urine sample s were obtained from the subjects at the end of the run‐in period , and at 1‐ , 2‐ , and 3‐month visits . Urinary leukotriene C4/D4/E4 was measured by an enzyme immunoassay . Compared with subjects taking placebo , the group who took Pycnogenol ® had significantly more improvement in pulmonary functions and asthma symptoms . The Pycnogenol ® group was able to reduce or discontinue their use of rescue inhalers more often than the placebo group . There was also a significant reduction of urinary leukotrienes in the Pycnogenol ® group . The results of this study demonstrate the efficacy of Pycnogenol ® as an adjunct in the management of mild‐to‐moderate childhood asthma [11480500] Abstract Ozone exposure aggravates asthma , as has been demonstrated in both controlled exposures and epidemiologic studies . In the current double-blind crossover study , the authors evaluated the effects of dietary antioxidants ( i.e. , 400 IU vitamin E/500 mg vitamin C ) on ozone-induced bronchial hyperresponsiveness in adult subjects with asthma . Seventeen subjects were exposed to 0.12 ppm of ozone or to air for 45 min during intermittent moderate exercise . Bronchial hyperresponsiveness was assessed with 10-min sulfur dioxide ( i.e. , 0.10 ppm and 0.25 ppm ) inhalation challenges . Subjects who were given dietary antioxidants responded less severely to sulfur dioxide challenge than subjects given a placebo ( i.e. , forced expiratory volume in the 1st sec : -1.2 % vs. 4.4 % , respectively ; peak flow : + 2.2 % vs. -3.0 % , respectively ; and mid-forced expiratory flow : + 2.0 % vs. -4.3 % , respectively ) . Effects were more pronounced when subjects were grouped by response to sulfur dioxide at the screening visit . The results suggest that dietary supplementation with vitamins E and C benefits asthmatic adults who are exposed to air pollutants [8815279] To eluci date the effect of antioxidants aevit and glutaminic acid on the course of bronchial asthma ( BA ) and free radical processes in this disease , 54 BA patients were divided into 2 groups : glucocorticoid-untreated and glucocorticoid-treated . Each of two subgroups made of these groups either received antioxidants ( AO ) or not . The response was assessed by clinical BA symptoms and free radical processes reflecting production of active oxygen forms by leukocytes ( PAOFL ) and free radical peroxidation ( FRPO ) . PAOFL was studied using luminol-dependent chemiluminescence ( CL ) . CL basal and stimulated values were calculated . FRPO was measured by plasma levels of malonic dialdehyde . Aevit and glutaminic acid treated BA patients improved clinical ly and exhibited reduced CL of PAOFL and malonic dialdehyde in plasma compared to BA patients on conventional therapy or conventional therapy plus glucocorticoids . Aevit and glutaminic acid are recommended for BA patients [3353464] Methods Mild asthmatics and normal controls were recruited as study subjects . This crossover study was double-blinded , r and omized and counter-balanced to the order of three conditions : diesel exhaust with anti-oxidant , diesel exhaust with placebo , or filtered air with placebo . The subjects were exposed to either filtered air or diesel exhaust ( 300 ug PM2.5/m ) in a state-of-the-art diesel exhaust exposure facility . An anti-oxidant , N-acetylcysteine ( 600 mg ) , or a placebo was taken orally for five days preceding , and on the day of the exposure . Each subject was exposed to each of the three conditions . Peripheral blood sample s were taken pre-exposure , and also at 2 , 6 , and 30 hours after the beginning of exposure . Sputum induction was performed by inhalation of hypertonic saline according to ATS guidelines pre-exposure , and also at 6 , and 30 hours after the beginning of exposure . FACSCanto II ( BD Biosciences ) was used for flow cytometry . A 5-colour , 12-marker ( CD3/CD9/ CD14/CD16/CD19/CD20/CD45/CD56/CD83/CD206/ CD326/HLA-DR ) combination was used to identify dendritic cells , macrophages , monocytes , neutrophils , eosinophils , and bronchial epithelial cells . Direct immunolabelling was performed on whole peripheral blood . After incubation , red blood cells were lysed . Remaining cells were washed and resuspended in PBS with 0.5 % paraformaldehyde . Sputum plugs were homogenized with 0.1 % DTT , filtered , and then centrifuged to remove supernatant . Sputum cells were resuspended in PBS at 1 million per mL. Direct immunolabelling was performed . After incubation , cells were washed and resuspended in PBS with 0.5 % paraformaldehyde . Spectral compensation for flow cytometry was performed using an automatic calibration technique ( BD CompBeads ) . Cellular debris was eliminated on the SSC/FSC scattergram . A gating strategy was design ed to identify the leukocyte sub- population s and bronchial epithelial cells . Surface markers were chosen based on differential cell-specific expression according to existing literature [15282383] Background : Increased dietary vitamin E intake is associated with a reduced incidence of asthma , and combinations of antioxidant supplements including vitamin E are effective in reducing ozone induced bronchoconstriction . A study was undertaken to investigate the effect of supplementation with vitamin E for 6 weeks on bronchial hyperresponsiveness in atopic adults with asthma . Methods : 72 participants from a clinical trial register of adults with asthma were r and omised to receive 500 mg natural vitamin E or matched placebo for 6 weeks in a placebo controlled , double blind parallel group clinical trial . Inclusion criteria included age 18–60 years , maintenance treatment of at least one dose of inhaled corticosteroid per day , a positive skin prick test to one of three common allergens , and bronchial hyperresponsiveness to methacholine ( defined as a dose provoking a 20 % fall in forced expiratory volume in 1 second ( FEV1 ) ( PD20 ) of 12.25 μmol ) . Secondary outcomes were FEV1 , forced vital capacity , mean morning and evening peak flow , symptom scores , bronchodilator use , and serum immunoglobulin E levels . Results : In the primary intention to treat analysis the change in PD20 was similar in the vitamin E and placebo groups with a mean difference of + 0.25 doubling doses of methacholine ( 95 % confidence interval −0.67 to + 1.16 greater with vitamin E ) . There was no effect of vitamin E supplementation on any other measure of asthma control , either in the intention to treat or per protocol analysis . There was also no effect of vitamin E supplementation on serum immunoglobulin levels . Conclusion : Dietary supplementation with vitamin E adds no benefit to current st and ard treatment in adults with mild to moderate asthma [7423602] Forty-one asthmatic patients in remission were r and omly allocated to two treatment groups in a double-blind trial . One group took 1 g , of ascorbic acid as one effervescent tablet once daily and the second group took a matching placebo . The asthmatics were selected from those attending the Asthma Clinic . One criterion for selection was the increase in exacerbation during the rainy season . These exacerbations were precipitated by respiratory infection . After 14 weeks , an assessment of the severity and rate of attacks showed that those on ascorbic acid suffered less severe and less frequent attacks of asthma during the study period . Plasma ascorbic acid astimations showed a significant rise in the level in those taking ascorbic acid over those on placebo . ( P < 0.01 ) . Cessation of ascorbic acid in the group taking it increased attack rates . It is concluded that high dose ascorbic acid is probably a good prophylaxis in some bronchial asthmatics [6342165] Sixteen White children with bronchial asthma were divided into two groups ; one received st and ard anti-asthma chemoprophylaxis ( SAC ) and the other SAC supplemented with 1 g ascorbic acid ( Redoxon ) given as a single daily dose for a 6-month period . In 10 patients the effects of ascorbic acid on exercise-induced bronchoconstriction ( EIB ) were assessed by comparing the pre-ascorbic acid results with those obtained 2 1/2 hours after the intravenous injection of 1 g ascorbic acid . Immunological investigations performed on the two groups were assessment of polymorphonuclear leucocyte ( PMNL ) motility , phagocytosis and nitroblue tetrazolium reduction and measurement of secretory IgA , serum immunoglobulin and total haemolytic complement levels and levels of the components C3 and C4 , alpha 1-antitrypsin , antistreptolysin O ( ASO ) , C-reactive protein and antibodies to certain respiratory viruses . These investigations were performed before and 1 , 3 and 6 months after the commencement of therapy . Radio-allergosorbent testing for sensitivity to four common allergens was carried out at the outset and after 6 months of therapy . Injection of ascorbic acid had no detectable effects on the degree of EIB . Slight but not significant immunological changes were observed in the SAC group over the 6-month study period . However , in the SAC plus ascorbic acid group significantly improved PMNL motility and decreased ASO levels and reduced ( although not to a significant extent ) IgE levels and titres of antibodies to the respiratory viruses were observed [16177596] PURPOSE Reactive oxygen/nitrogen species ( ROS/RNS ) in resident airway cells may be important in bronchoconstriction following exercise . Glutathione ( GSH ) is a major lung antioxidant and could influence pathological outcomes in individuals with exercise-induced bronchoconstriction ( EIB ) . This study examined the effects of supplementation with undenatured whey protein ( UWP ) in subjects exhibiting airway narrowing following eucapnic voluntary hyperventilation ( EVH ) , a surrogate challenge for diagnosis of EIB . UWP is a cysteine donor that augments GSH production . METHODS In a r and omized , double-blind , placebo-controlled study , 18 EIB-positive subjects ( age : 25.2 + /- 9.01 yr ; weight : 77.3 + /- 18.92 kg ; height : 1.7 + /- 0.09 m ) with post-EVH falls of > or = 10 % in FEV1 received 30 g UWP ( TX ) or casein placebo (PL)/d . Subjects performed 6-min EVH challenges before and after 4 and 8 wk of supplementation . Exhaled nitric oxide ( eNO ) was measured serially before spirometry and at 1-wk intervals . Spirometry was performed pre- and 5 , 10 , and 15 min postchallenge . RESULTS Subjects exhibited significant mean improvement in postchallenge falls in FEV(1 ) from 0 wk ( -22.6 + /- 12.22 % ) with TX at 4 ( -18.9 + /- 12.89 % , P < 0.05 ) and 8 wk ( -16.98 + /- 11.61 % , P < 0.05 ) and significant mean reduction in post-EVH peak falls in FEF(25 - 75 ) from 0 wk ( -40.6 + /- 15.28 % ) with TX at 4 ( -33.1 + /- 17.11 % , P < 0.01 ) and 8 ( -29.7 + /- 17.42 % , P < 0.05 ) wk . No changes in FEV(1 ) or FEF(25 - 75 ) were observed in the PL group at any time point . Mean eNO for PL and TX groups at 0 , 4 , and 8 wk ( 46.8 + /- 31.33 , 46.5 + /- 35.73 , 49.3 + /- 37.12 vs 35.2 + /- 26.87 , 29.1 + /- 17.26 , 34.7 + /- 21.11 ppb , respectively ) was not significantly different . CONCLUSIONS UWP may augment pulmonary antioxidant capacity and be therapeutically beneficial in individuals exhibiting EIB , as postchallenge pulmonary function improved with supplementation . The lack of significant change in eNO suggests that the pulmonary function improvements from UWP supplementation are independent of eNO [1852141] Two groups of six asthmatic patients with biphasic bronchospastic response to inhaled Dermatophagoides pteronyssinus allergen extract were studied in a double-blind fashion . Early and late asthmatic reactions to allergen inhalation challenge were determined before and at the end of a 2-week treatment period with nimesulide ( 100 mg bid orally ) , a sulfonanilide with antioxidant properties , or placebo . Bronchial responsiveness to methacholine was evaluated 24 hours before and after allergen inhalation challenges . The dose of allergen causing EAR ( 15 % decrease in FEV1 ) and the severity of LAR ( maximum FEV1 fall ) were similar before and at the end of the treatment period in both groups . In patients treated with nimesulide , bronchial responsiveness to methacholine was significantly increased after allergen inhalation challenge both before and at the end of the treatment period . These results do not support the hypothesis that the production of oxygen-free radicals plays a significant role in the development of bronchial hyperresponsiveness and late phase reaction to allergen in asthma [11306340] PURPOSE To evaluate the association between active and passive smoking and frequency of colds in women . METHODS Data on cigarette smoking and frequency and duration of colds were analyzed in the Women 's Health Study ( WHS ) , a r and omized , double-blind , placebo-controlled trial of low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease and cancer among 39,876 female health professionals . RESULTS After adjustment for age , body-mass index , prevalence of asthma and chronic lung diseases , alcohol intake , physical activity , and multivitamin use , current heavy smokers had no appreciable increase in the frequency of colds ( relative risk ( RR ) for > or= 3 versus no colds in the past year , 1.05 ; 95 % confidence interval ( CI ) , 0.80 - 1.39 ) , but a significantly increased risk of prolonged colds ( RR for colds of > 7 vs. 1 - 3 days , 2.53 ; 95 % CI , 1.95 - 3.29 ) . There was no difference in the number of days confined to home . Nonsmoking women passively exposed to cigarette smoke had a slightly increased risk of both more frequent colds ( RR , 1.33 ; 95 % CI , 1.18 - 1.51 ) and more prolonged colds during the previous year ( RR , 1.12 ; 95 % CI , 0.99 - 1.27 ) . CONCLUSIONS Women who are currently heavy smokers are at increased risk of having colds with longer duration compared with nonsmokers . Nonsmoking women passively exposed to cigarette smoking are at slightly increased risk of having more frequent and longer colds than nonsmoking women not exposed to passive smoke [11980114] AIM To compare clinical , device and biochemical aspects of monotherapy with flixotide vs combination of flixotide with serevent in patients with moderate bronchial asthma ( MBA ) . MATERIAL AND METHODS 18 patients with MBA received flixotide and 18 MBA patients flixotide plus serevent for two weeks of lead-in and eight weeks of basic treatment . A special study was made of neutrophils which were examined for activity of LPO-antioxidants and phospholipid spectrum of membranes . RESULTS There were similar changes in function of the system LPO-antioxidants and lipid structure in neutrophilic membranes of moderate BA patients of both the groups . CONCLUSION Clinicobiochemical efficacy of mean doses of a new topic inhalation glucocorticoid flixotide alone or in combination with prolonged beta 2-adrenostimulator serevent is demonstrated . There were positive trends in metabolic processes in neurophilic membrane . Use of flixotide in combination with serevent is clinical ly preferable [22502622] OBJECTIVE To examine the effects of nutritional supplement therapy on oxidant-antioxidant status , inflammation and immune system responses , pulmonary function , and health-related quality of life in patients with mild to moderate allergic asthma . METHODS Adult asthma patients ( n=30 ) received daily multiple nutrient supplements for two months . Age- and gender-matched healthy controls ( n=30 ) did not receive any supplements . Enzymatic and non-enzymatic antioxidant status , malondialdehyde ( MDA ) , high-sensitivity C-reactive protein ( hs-CRP ) , immunoglobulin E ( IgE ) and T-lymphocyte subsets , pulmonary function indices , as well as scores for asthma control and quality of life , were assessed at baseline , at one month of treatment , and at two months of treatment , which was also the end of the study . RESULTS At baseline , asthma patients had significantly higher IgE , MDA , copper ( Cu ) , hs-CRP , and CD19 and CD4/CD8 lymphocyte ratios , and decreased selenium ( Se ) , zinc ( Zn ) , β-carotene , vitamins C and E , and catalase , glutathione peroxidase ( GPx ) and glutathione reductase ( GR ) activities compared to healthy controls ( p < 0.05 ) . During the study period , asthmatics showed non-significantly increased pulmonary function and a trend toward lower IgE levels , markedly reduced MDA , Cu , hs-CRP , and CD19 and CD4/CD8 ratios , and increases in levels of Se , Zn , β-carotene , vitamins C and E , and enzymatic antioxidant activities . Also , their asthma control and health-related quality -of-life scores increased significantly by the end of the study . CONCLUSION Our results indicate that nutritional supplement therapy may improve dysregulated oxidant and antioxidant status , inflammation and immune responses , pulmonary function , and health-related quality of life in patients with mild to moderate allergic asthma [7114587] In order to study the potential benefit of ascorbic acid in asthma we investigated its role in exercise-induced bronchospasm ( EIB ) . Twelve asthmatic subjects were recruited on the basis of findings compatible with EIB . On two subsequent days the subjects ingested 500 mg . of ascorbic acid or a placebo . The study was performed in a double-blind r and omized fashion . Partial and maximal expiratory flow volume ( PEFV and MEFV ) curves were used to determine pulmonary function changes . Pretreatment with ascorbic acid led to a significant attenuation of the bronchospasm seen five minutes after exercise compared to placebo , as measured by FVC ( 0.23 + /- 0.08 L decrease after ascorbic acid , 0.48 + /- 0.14 L decrease after placebo ) and by FEV1 ( 0.24 + /- 0.06 decrease after ascorbic acid , 0.44 + /- 0.14 decrease after placebo ) Mean + /- SE ) . These results suggest a mild antibronchospastic action of ascorbic acid in subjects with EIB [15572850] Mild persistent asthma is most effectively controlled with inhaled corticosteroids . Leukotriene receptor antagonists have complementary effects to corticosteroids on inflammation control . The additional effect of a leukotriene receptor antagonist , zafirlukast , was investigated in stable asthma patients under control with inhaled budesonide . We conducted a r and omised , double-blind , placebo-controlled , single center trial to investigate the effects of add-on zafirlukast treatment to budesonide , on symptom score , pulmonary function , bronchial responsiveness , and serum levels of eosinophilic cationic protein ( ECP ) and antioxidant capacity in stable asthmatic patients under control with inhaled budesonide . The present study included 21 mild or moderate asthmatic patients ( 8 males and 13 females ) , who were stable at least for 6 weeks with inhaled budesonide ( 400 microg/day ) . Serum total antioxidant capacity ( TAC ) and ECP levels were measured , and symptom scoring , spirometry , and bronchial provocation with methacholine were performed . Then , the patients were r and omised to use either placebo or oral zafirlukast ( 40 mg/day ) in addition to budesonide for 6 weeks . At the 6th week , symptom scoring , spirometry , and bronchial provocation tests were repeated and serum TAC and ECP levels were measured again . After add-on zafirlukast treatment to budesonide , forced expiratory volume in 1 second ( FEV(1 ) ) , TAC and ECP values did not change significantly ( p > 0.05 ) but bronchial hyperresponsiveness and symptom score decreased significantly ( p = 0.022 ) compared to baseline . Thus , in stable asthmatic patients , add-on zafirlukast treatment to budesonide improves symptoms and decreases bronchial hyperresponsiveness [22885561] BACKGROUND Broad dietary patterns have been linked to asthma but the relative contribution of specific nutrients is unclear . Soy genistein has important anti-inflammatory and other biological effects that might be beneficial in asthma . A positive association was previously reported between soy genistein intake and lung function but not with asthma exacerbations . AIMS To conduct a post-hoc analysis of patients with inadequately controlled asthma enrolled in a prospect i ve multicentre clinical trial to replicate this association . METHODS A total of 300 study participants were included in the analysis . Dietary soy genistein intake was measured using the Block Soy Foods Screener . The level of soy genistein intake ( little or no intake , moderate intake , or high intake ) was compared with baseline lung function ( pre-bronchodilator forced expiratory volume in 1 second ( FEV(1 ) ) ) and asthma control ( proportion of participants with an episode of poor asthma control ( EPAC ) and annualised rates of EPACs over a 6-month follow-up period . RESULTS Participants with little or no genistein intake had a lower baseline FEV(1 ) than those with a moderate or high intake ( 2.26 L vs. 2.53 L and 2.47 L , respectively ; p=0.01 ) . EPACs were more common among those with no genistein intake than in those with a moderate or high intake ( 54 % vs. 35 % vs. 40 % , respectively ; p<0.001 ) . These findings remained significant after adjustment for patient demographics and body mass index . CONCLUSIONS In patients with asthma , consumption of a diet with moderate to high amounts of soy genistein is associated with better lung function and better asthma control [17339866] In this study , prospect ively , we aim ed to determine the effects of the different treatment alternatives on the oxidant system and inflammatory and clinic determinants during the stable period of 1 month following an asthmatic attack . Thirty‐one patients ( 22 female , nine male ) were r and omly divided into three groups following the stabilization of an acute asthma attack . The control group that is an additional group to the three patient groups consisted of 10 healthy volunteers ( five female , five male ) . The following protocol s were used for 4 weeks : Group I : short‐acting inhaler β2 mimetic as required ( treatment A)+800 μg inhaler budesonide ( treatment B)+leukotriene receptor antagonist ; Group II : treatment A and B ; Group III : treatment A and B+vitamin E. The serum levels before and after treatment of eosinophilic cationic protein ( ECP ) , leukotriene E4 ( LTE4 ) , and malondialdehyde ( MDA ) were determined . The values before and after treatment were statistically compared both with each other and control values . Pretreatment ECP , LTE4 , and MDA levels for the three groups were significantly higher compared with post‐treatment levels ( P<0.05 to P<0.001 ) and the control levels ( P<0.01 to P<0.001 ) . However , when post‐treatment levels were compared with those of the control group , no significant differences were found ( P>0.05 ) . Lack of significant variation was observed when the pre‐ and post‐treatment differences in the three groups were compared for each one of ECP , LTE4 , and MDA levels ( P>0.05 ) . Leukotriene receptor antagonist or antioxidant agents added to st and ard asthma treatment did not make a significant contribution on ECP , LTE4 , and MDA levels and respiratory parameters such as spirometric function tests . Etiologic factors and /or the possible changes in different pathogenetic ways of the inflammation process may have been responsible for nonsignificant intertreatment difference in the biomarker levels . The result confirms that suppressing the inflammation in asthma enables the entire inflammatory pathologic process to be controlled [15875530] BACKGROUND It has been suggested that exercise-induced bronchoconstriction may involve oxidative stress . Strenuous exercise promotes free radical production , which can lead to many of the pathophysiologic changes associated with asthma , including bronchoconstriction , mucus secretion , and microvascular leakage . Lycopene has been shown to have high antioxidative activity . OBJECTIVE To evaluate the effect of lycopene supplementation on airway hyperreactivity and inflammation in young athletes who complain of difficulty in breathing related to physical exertion . METHODS Nineteen young athletes with exercise-related difficulty in breathing visited the exercise laboratory 3 times . During the first visit , participants underwent a baseline evaluation of exercise-induced bronchoconstriction . Daily for 1 week before each of the 2 subsequent visits , participants ingested 30 mg of lycopene ( a natural antioxidant ) or placebo ( in r and omized order , double-blind ) . A 2-week washout period was given between each visit . During each visit , lung functions were evaluated before and after an 8-minute run on the treadmill ( 85 % of the predicted maximal heart rate ) . RESULTS There was no difference in the mean+/-SD decrease in forced expiratory volume in 1 second after exercise during lycopene treatment compared with placebo treatment ( 11.8%+/-12.5 % and 11.0%+/-11.6 % ) . In addition , there was no apparent division into responders and nonresponders . CONCLUSION A daily dose of lycopene for 1 week does not affect lung function after exercise and may not provide any protective effect against clinical difficulty in breathing in young athletes [10575337] Objective : We report on the effect of glutathione , an antioxidant compound on the airway response to the ultrasonically nebulised distilled water ( UNDW , ‘ fog ’ ) challenge . Methods : 12 subjects with mild-to-moderate bronchial asthma underwent double-blind , cross-over pretreatment , administered 30 min earlier , in a r and omised order with inhaled glutathione ( G ) ( 600 mg ) , sodium cromoglycate ( SCG ) ( 20 mg ) and placebo ( P ) , followed by the challenge . Results : After P pretreatment UNDW challenge caused a mean 20.41 % decrease in FEV-1 ( p < 0.05 ) , after G , a mean 6.04 % fall in FEV-1 ( p = n.s . ) , and after SCG a mean 5.99 % fall in FEV-1 ( p = n.s . ) . Conclusions : G significantly attenuated ‘ fog’-induced falls in FEV-1 ( p < 0.001 compared with P ) and showed a protective effect on UNDW-induced bronchoconstriction [16338599] AIM The study aims to assess the a priori hypothesis that regular supplementation with vitamin C or magnesium will permit a reduction in the corticosteroid dose required to maintain asthma control in adults . METHODS We invited all participants recruited from primary care centres who completed a parallel-group , r and omised , placebo-controlled , 16-week supplementation trial of 1g/day vitamin C or 450 mg/day magnesium to continue and participate in a structured corticosteroid reduction protocol over 10 weeks . RESULTS A total of 92 participants ( 29 vitamin C , 31 magnesium and 32 placebo ) entered the study . Assuming no reduction in corticosteroid dose in the 10 who subsequently withdrew , the geometric mean reductions in inhaled corticosteroid dose achieved with vitamin C , magnesium and placebo were 49 , 13 and 11 microg , respectively . Relative to placebo , the unadjusted effect of vitamin C was significant , and remained at borderline significance after adjustment for baseline corticosteroid dose ( relative reduction ratio=4.03 , 95 % CI 0.95 to 17.1 , P=0.06 ) . CONCLUSIONS We conclude that while vitamin C supplements may have modest corticosteroid sparing effects and hence the potential to reduce exposure to their side effects , magnesium supplements have no effect on the inhaled corticosteroid dose required to maintain asthma control [11120898] BACKGROUND Glutathione is central to the antioxidant defences of the lung . The aim of this study was to determine whether sputum induction can be used for the measurement of glutathione in the respiratory tract . METHODS Saliva and induced sputum ( 3 % NaCl , 20 minutes ) sample s were collected from 10 healthy individuals and 10 patients with stable asthma receiving treatment with inhaled corticosteroids . Sample s were chilled on ice and dispersed by dilution with ice cold phosphate buffered saline and pipetting . Cell-free supernatants were obtained by centrifugation of sample s and filtration of supernatants and analysed for total glutathione , glutathione disulfide , and albumin content . The cells were treated with dithiothreitol and cell numbers , cell viability , and differential cell patterns were determined . RESULTS As judged by cell viability and percentage of non-squamous cells , adequate sputum sample s were obtained from nine healthy and nine asthmatic subjects . The salivary total glutathione content was low ( median concentration 1.2 μM ( range 0.8–1.5 ) in healthy subjects and 0.9 μM ( 0.7–1.2 ) in asthmatic subjects ) . The sputum total glutathione content of both healthy and asthmatic subjects was within the same range ( 3.9 ( 1.0–12.3 ) μM and 6.4 ( 1.3–19.2 ) μM , respectively ; p=0.35 ) . Surprisingly , and in marked contrast to results obtained with bronchoalveolar lavage , sputum levels of glutathione disulfide represented more than 50 % of the total glutathione in both groups ( 50.9 % ( range 24.6–83.1 ) and 72.3 % ( range 36.5–97.4 ) , respectively ; p=0.2 ) . CONCLUSIONS The results of this study indicate that sputum induction can be used to measure the glutathione content of bronchial secretions . Sputum glutathione levels of stable asthmatic patients did not differ significantly from healthy controls [11728816] Apocynin is an inhibitor of NADPH oxidase present in inflammatory cells such as eosinophils and neutrophils . We investigated the effect of inhaled apocynin on ozone-induced bronchial hyperresponsiveness in vivo . Seven mild atopic asthmatics participated in a placebo-controlled , cross-over study with two exposures to O(3 ) at 2-week intervals . Apocynin ( 3 ml of 0.5 mg/ml ) was inhaled 2 times before and 6 times after O(3 ) exposure at hourly intervals . At 36 h before and 16 h after O(3 ) exposure , methacholine inhalation challenge tests ( Mch ) were performed , and PC(20 ) and maximal % fall from baseline ( MFEV(1 ) ) were calculated from dose-response curves . O(3)-induced change in PC(20 ) ( Delta PC(20 ) ) after placebo treatment was -1.94 + /- 0.39 DD ( mean + /- SEM doubling dose Mch ) ( p = .001 ) and apocynin was -0.6 + /- 0.33 DD ( p = .17 ) . The difference between apocynin and placebo treatment was 1.3 DD + /- 0.42 ( p = .02 ) . O(3)-induced Delta MFEV(1 ) was 11.9 + /- 1.5 % ( p = .008 ) during placebo inhalation and 3.85 + /- 1.8 % during apocynin ( p = .47 ) . Apocynin reduced the Delta MFEV(1 ) by 8.05 % compared to placebo ( p = .025 ) . We conclude that apocynin markedly reduced O(3)-induced hyperreactivity for Mch as well as maximal airway narrowing . The results suggest that apocynin may have a role in preventing ozone-induced exacerbations of asthma [16756149] UNLABELLED The aim of study was to analyze the effect of treatment with inhaled corticosteroids and long acting beta2-agonists on antioxidative-prooxidative balance in children with asthma . MATERIAL S AND METHODS Twenty children with newly diagnosed asthma before treatment ( group 1 ) , fourteen children with diagnosed asthma treated with inhaled corticosteroids and long acting beta2-agonists and 57 healthy children were ioncluded in the study . In all cases plasma protein carbonyls and activity of erythrocyte SOD was assayed . RESULTS Plasma protein carbonyls in both group I ( 1,01 nmol/g of protein , SD=0,30 ) and group II ( 0,94 ; SD=0,15 ) was significantly higher than in group III ( 0,85 ; SD=0,24 ) ( I vs III p<0,033 ; II vs III p<0,031 ) . The highest SOD activity was found in group II ( 3156,4 U/gHb ; SD=976,1 ) ( II vs I p<0,02 ; II vs III p<0,0001 ) . SOD activity n group I ( 2435,8 , SD=730,2 ) was higher than in group III ( 1533,1 , SD=703,8 ) ( p<0,0001 ) . CONCLUSIONS The increase in SOD activity in children with asthma seems to be a response to intensification of oxidative stress . Treatment of asthma with inhaled corticosteroids and long acting beta2-agonists augments antioxidative defense by increase in superoxide dismutase activity [9032803] We investigated the effect of theophylline administration on circulating vitamin levels in children with asthma . Twenty-three asthmatic children , ranging in age from 7 to 15 with a mean of 10.8 years and including 16 patients who were treated with slow-release theophylline and 7 patients not receiving any type of theophylline preparation , were enrolled in this study . They all were in patients who had been hospitalized for the control of asthma . Steady-state serum theophylline and vitamin A , B1 , B2 , B6 , B12 and C levels were evaluated in these patients . Circulating vitamin B1 and B6 levels were depressed in asthmatic children treated with theophylline compared to those not receiving the agent ( 38.4 + /- 1.6 ( mean + /- SEM ) vs. 46.4 + /- 3.5 ng/ml and 7.1 + /- 0.5 vs. 11.8 + /- 2.1 ng/ml , respectively , p < 0.05 ) . A significant negative correlation between theophylline and circulating levels of vitamin B6 was demonstrated in the subjects of this study ( rs = -0.657 , p < 0.001 ) . In contrast , no relationship was noted between theophylline and circulating vitamin B1 levels . Theophylline did not affect circulating vitamin A , B2 , B12 or C levels . We conclude that theophylline induces depression of circulating vitamin B1 and B6 levels in asthmatic children , although a dose-dependent interaction between theophylline and vitamin B1 would be unlikely

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### Context: [11117277] Background : Lycopene has previously been shown to have high antioxidative activity . In view of the controversy regarding the beneficial effect of antioxidants on asthma , the acute effects of lycopene ( LYC‐O‐MATOTM ) on airway hyperreactivity were assessed in patients with exercise‐induced asthma ( EIA ) [3782678] Sixteen adult subjects with asthma in a clinical steady state were studied . On day 1 , after baseline spirometry , they underwent four histamine inhalation tests with functional recovery between each test . The provocative concentration causing a 20 % fall in FEV1 ( PC20 ) was obtained after each test . On days 2 , 3 , and 4 , after baseline spirometry , active and placebo ascorbic acid ( 2 gm ) was administered orally , double-blind , according to a 4.3.1 two-treatment crossover study design . One hour later , spirometry was performed , and PC20 was reassessed . We found no significant changes in FEV1 and FVC after ascorbic acid as compared with placebo administration . There was no difference between PC20 on days 2 , 3 , and 4 and by st and ardizing for the four PC20 results obtained on day 1 . We conclude that ascorbic acid has no acute bronchodilator effect and does not alter bronchial responsiveness to histamine in subjects with asthma [15498043] The inflammatory response to ozone in atopic asthma suggests that soluble mediators of inflammation are released in response to oxidant stress . Antioxidants may alleviate additional oxidative stress associated with photochemical oxidant pollution . This study investigates the impact of antioxidant supplementation on the nasal inflammatory response to ozone exposure in atopic asthmatic children . We conducted a r and omized trial using a double‐blinded design . Children with asthma ( n = 117 ) , residents of Mexico City , were given r and omly a daily supplement of vitamins ( 50 mg/day of vitamin E and 250 mg/day of vitamin C ) or placebo . Nasal lavages were performed three times during the 4‐month follow‐up and analysed for content of interleukin‐6 ( IL‐6 ) , IL‐8 , uric acid and glutathione ( GSx ) . IL‐6 levels in the nasal lavage were increased significantly in the placebo group after ozone exposure while no increase was observed in the supplement group . The difference in response to ozone exposure between the two groups was significant ( P = 0·02 ) . Results were similar for IL‐8 , but with no significant difference between the groups ( P = 0·12 ) . GSx decreased significantly in both groups . Uric acid decreased slightly in the placebo group . Our data suggest that vitamin C and E supplementation above the minimum dietary requirement in asthmatic children with a low intake of vitamin E might provide some protection against the nasal acute inflammatory response to ozone [18516713] Abstract . Objective : Our aim was to investigate the effects of 12-week oral magnesium ( Mg ) supplementation on the RBC redox system in stable , persistent , moderately asthmatic children ( N = 40 , 24 boys , 16 girls ) aged 4–16 years in a r and omized , double-blind , placebo-controlled study . Design : Oxidized ( GSSG ) and reduced ( GSH ) glutathione , oxyhaemoglobin , methaemoglobin ( metHb ) , hemichrome and bilirubin levels before and after treatment were determined , and GSH stability tests were performed . Result : The GSH concentration was significantly higher in the Mg-treated than in the placebo-treated patients after the treatment period . There was a positive correlation between the decreased plasma metHb and hemichrome levels and the decreased plasma haemoglobin concentrations in the Mg-treated patients at the end of the study . Conclusion : Mg in the given doses exerts antioxidant activity and influences the glutathione redox system [22854412] BACKGROUND Antioxidant-rich diets are associated with reduced asthma prevalence in epidemiologic studies . We previously showed that short-term manipulation of antioxidant defenses leads to changes in asthma outcomes . OBJECTIVE The objective was to investigate the effects of a high-antioxidant diet compared with those of a low-antioxidant diet , with or without lycopene supplementation , in asthma . DESIGN Asthmatic adults ( n = 137 ) were r and omly assigned to a high-antioxidant diet ( 5 servings of vegetables and 2 servings of fruit daily ; n = 46 ) or a low-antioxidant diet ( ≤2 servings of vegetables and 1 serving of fruit daily ; n = 91 ) for 14 d and then commenced a parallel , r and omized , controlled supplementation trial . Subjects who consumed the high-antioxidant diet received placebo . Subjects who consumed the low-antioxidant diet received placebo or tomato extract ( 45 mg lycopene/d ) . The intervention continued until week 14 or until an exacerbation occurred . RESULTS After 14 d , subjects consuming the low-antioxidant diet had a lower percentage predicted forced expiratory volume in 1 s and percentage predicted forced vital capacity than did those consuming the high-antioxidant diet . Subjects in the low-antioxidant diet group had increased plasma C-reactive protein at week 14 . At the end of the trial , time to exacerbation was greater in the high-antioxidant than in the low-antioxidant diet group , and the low-antioxidant diet group was 2.26 ( 95 % CI : 1.04 , 4.91 ; P = 0.039 ) times as likely to exacerbate . Of the subjects in the low-antioxidant diet group , no difference in airway or systemic inflammation or clinical outcomes was observed between the groups that consumed the tomato extract and those who consumed placebo . CONCLUSIONS Modifying the dietary intake of carotenoids alters clinical asthma outcomes . Improvements were evident only after increased fruit and vegetable intake , which suggests that whole-food interventions are most effective . This trial was registered at http://www.actr.org.au as ACTRN012606000286549 [3672916] Background : Adverse health effects associated with diesel exhaust ( DE ) are thought to be mediated in part by oxidative stress , but the detailed mechanisms are largely unknown . MicroRNAs ( miRNAs ) regulate gene expression post-transcriptionally and may respond to exposures such as DE . Objectives : We profiled peripheral blood cellular miRNAs in participants with mild asthma who were exposed to controlled DE with and without antioxidant supplementation . Methods : Thirteen participants with asthma underwent controlled inhalation of filtered air and DE in a double-blinded , r and omized crossover study of three conditions : a ) DE plus placebo ( DEP ) , b ) filtered air plus placebo ( FAP ) , or c ) DE with N-acetylcysteine supplementation ( DEN ) . Total cellular RNA was extracted from blood drawn before exposure and 6 hr after exposure for miRNA profiling by the NanoString nCounter assay . MiRNAs significantly associated with DEP exposure and a predicted target [ nuclear factor ( erythroid-derived 2)-like 2 ( NRF2 ) ] as well as antioxidant enzyme genes were assessed by reverse transcription – quantitative polymerase chain reaction ( RT-qPCR ) for validation , and we also assessed the ability of N-acetylcysteine supplementation to block the effect of DE on these specific miRNAs . 8-hydroxy-2´-deoxyguanosine ( 8-OHdG ) was measured in plasma as a systemic oxidative stress marker . Results : Expression of miR-21 , miR-30e , miR-215 , and miR-144 was significantly associated with DEP . The change in miR-144 was vali date d by RT-qPCR . NRF2 and its downstream antioxidant genes [ glutamate cysteine ligase catalytic subunit ( GCLC ) and NAD(P)H : quinone oxidoreductase 1 ( NQO1 ) ] were negatively associated with miR-144 levels . Increases in miR-144 and miR-21 were associated with plasma 8-hydroxydeoxyguanosine 8-OHdG level and were blunted by antioxidant ( i.e , DEN ) . Conclusions : Systemic miRNAs with plausible biological function are altered by acute moderate-dose DE exposure . Oxidative stress appears to mediate DE-associated changes in miR-144 [20889523] Background Prenatal antioxidant supplementation might influence fetal lung growth and development and reduce infant respiratory morbidity . The aim of this study was to test the hypothesis that infants of mothers at risk of pre-eclampsia who were r and omised to receive high-dose vitamins C and E ( 1000 mg vitamin C and 400 IU RRR α-tocopherol daily ) during pregnancy would have better respiratory outcomes than infants whose mothers were r and omised to receive placebo . Methods Respiratory outcomes to 2 years of age were documented using question naires and , in a subset , by recording their healthcare utilisation and calculating the cost of care data . Results 330 women who had taken vitamin supplementation and 313 who had taken placebo completed the respiratory question naire ( 386 and 366 infants , respectively ) . There were no significant differences between the two groups in the proportions diagnosed with asthma . 54 women who had taken vitamin supplementation and 45 who had taken placebo took part in the healthcare utilisation study ( 65 and 53 infants , respectively ) . On average , infants of mothers receiving vitamin supplementation had 2.6 ( 99 % CI 0.8 to 5.1 ) times more A&E/outpatient visits and 3.2 ( 99 % CI 0.2 to 6.9 ) times more GP visits than infants of mothers receiving placebo , and their costs of care were £ 226 ( 99 % CI £ 27 to £ 488 ) more for outpatient admissions , £ 57 ( 99 % CI £ 3 to £ 123 ) more for GP visits and £ 22 ( 99 % CI £ 3 to £ 50 ) more for medications . Conclusions High-dose antenatal vitamin C and E supplementation does not improve infant respiratory outcome and is associated with increased healthcare utilisation and cost of care [10445599] In asthmatic patients , antioxidant defence is decreased . Although inhaled corticosteroids decrease asthmatic inflammation and modulate reactive oxygen species ( ROS ) generation , little is known of their effect on cellular antioxidant levels . The aim of this study was to evaluate the effect of inhaled beclomethasone dipropionate ( BDP ; 1,000 microg x day(-1 ) ) on erythrocyte antioxidant levels in stable asthmatic patients . Forty patients with stable , mild asthma were treated in a double-blind , placebo-controlled , parallel-group study with BDP 250 microg , two puffs b.i.d . for 6 weeks . At entry and every 2 weeks during treatment , erythrocyte antioxidant levels , haematological parameters , pulmonary function tests and asthma symptoms were determined . The results show that during treatment with BDP , erythrocyte catalase levels increased ( at entry ( mean + /-SEM ) 41+/-4 , after 6 weeks 54+/-4 micromol H2O2 x min(-1 ) x g haemoglobin (Hb)(-1 ) , p = 0.05 in comparison with placebo ) . Erythrocyte total glutathione levels significantly decreased after 6 weeks treatment with BDP ( from 7.0+/-0.4 to 6.6+/-0.3 micromol x g Hb(-1 ) ( p = 0.04 ) ) . In the BDP-treated patients , blood eosinophil counts were higher in patients who responded with an increase in erythrocyte catalase levels during BDP treatment , as compared to those not responding ( ( mean + /-SEM ) 340+/-39 and 153+/-52x10(6 ) cells x L(-1 ) , respectively , p = 0.05 ) . The present study shows that treatment with inhaled bedomethasone dipropionate results in changes in antioxidant levels in erythrocytes of patients with stable , mild asthma [17234657] Background : Epidemiological evidence from observational studies has suggested that blood levels and dietary intake of selenium of adults with asthma are lower than those of controls . The only previous trial of selenium supplementation in adults with asthma found no objective evidence of benefit but involved only 24 participants . Methods : A r and omised , double blind , placebo-controlled trial of selenium supplementation was performed in adults with asthma in London , UK , the majority of whom ( 75 % ) reported inhaled steroid use at baseline . 197 participants were r and omised to receive either a high-selenium yeast preparation ( 100 µg daily , n = 99 ) or placebo ( yeast only , n = 98 ) for 24 weeks . The primary outcome was asthma-related quality of life ( QoL ) score . Secondary outcomes included lung function , asthma symptom scores , peak flow and bronchodilator usage . Linear regression was used to analyse the change in outcome between the two treatment arms by “ intention to treat ” . Results : There was a 48 % increase in plasma selenium between baseline and end of trial in the active treatment group but no change in the placebo group . While the QoL score improved more in the active treatment group than in the placebo group , the difference in change in score between the two groups was not significant ( −0.05 ( 95 % CI −0.19 to 0.09 ) ; p = 0.47 ) . Selenium supplementation was not associated with any significant improvement in secondary outcomes compared with placebo . Conclusions : Selenium supplementation had no clinical benefit in adults with asthma , the majority of whom were taking inhaled steroids [12639402] Asthma is characterized as a chronic inflammatory process . Pycnogenol((R ) ) , a bioflavonoid mixture extracted from Pinus maritima , is known to scavenge free radicals while possessing antioxidant and antiinflammatory properties . The objective of this study was to evaluate the efficiency of this agent in a r and omized , double-blinded , placebo-controlled , crossover study in patients with varying asthma severity . Twenty-six patients who fulfilled the American Thoracic Society criteria for asthma were enrolled in the study . Medical history , physical examination , blood sample analyses , and spirometric values were obtained at baseline , 4 weeks , and 8 weeks . The patients were r and omly assigned to receive either 1 mg/lb/day ( maximum 200 mg/day ) Pycnogenol or placebo for the first period of 4 weeks and then crossed over to the alternate regimen for the next 4 weeks . No adverse effects were observed related to the study drug . Within the contingent of 22 patients who completed the study , almost all responded favorably to Pycnogenol in contrast to placebo . Pycnogenol treatment also significantly reduced serum leukotrienes compared with placebo . The results of this pilot study indicate that Pycnogenol may be a valuable nutraceutical in the management of chronic asthma . We recommend that further clinical trials be conducted in larger groups of asthmatics to establish its efficacy [14573726] Aims : To explore the effects in normal and asthmatic adults of exposure to 200 ppb sulphur dioxide ( SO2 ) and 200 μg/m3 and 2000 μg/m3 aerosols of ammonium bisulphate ( AB ) and sulphuric acid ( SA ) ( MMD 0.3 μm ) . Methods : Exposures were placebo controlled , for one hour at rest , double blind in r and om order . ΔFEV1 was the primary outcome ; secondary outcomes included symptoms , ventilation , exhaled nitric oxide ( NO ) concentrations , and nasal lavage fluid ascorbic ( AA ) and uric acid ( UA ) concentrations . Results : There were no significant changes in spirometry or symptoms with any exposure in either group . SO2 exposure was associated with an increased respiratory rate relative to air exposure in the asthmatic group ( SO2 : 958.9 breaths/hour ; air : 906.8 breaths/hour ) but the mean volume breathed did not differ significantly ( SO2 : 318.8 litres ; air : 311.4 litres ) . AB exposures were associated with a significant rise in [ NO ] in the asthmatic ( + 1.51 ppb , and + 1.39 ppb ) , but not in the normal group . Mean pre- and post-exposure [ AA ] tended to be higher in the normal than in the asthmatic group . Within each group , [ AA ] did not change significantly with any exposure . Post-exposure [ UA ] were greater than pre-exposure concentrations for all exposures , significantly so in the normal group for all exposures except SO2 . There were no significant differences in the mean change in [ UA ] for any exposure relative to air . Conclusions : The pollutant exposure concentrations employed in this study were generally much greater than ambient . It is unlikely that short lived exposures at lower concentrations would show significant effects , but effects of longer term lower concentration exposures can not be ruled out [18339679] Background : R and omised data in men show a small but significant reduction in the risk of adult-onset asthma among those given aspirin . The results from an observational study in women suggest that frequent use of aspirin decreases the risk of adult-onset asthma , but r and omised data in women are lacking . A study was undertaken to test the effect of 100 mg aspirin or placebo on alternate days on the risk of adult-onset asthma in the Women ’s Health Study . Methods : A r and omised , double-blind , placebo-controlled clinical trial of aspirin and vitamin E was performed in apparently healthy women with no indication or contraindication to aspirin therapy and no history of asthma at study entry . Female health professionals self-reported an asthma diagnosis on yearly question naires . Results : Among 37 270 women with no reported history of asthma prior to r and omisation and during 10 years of follow-up , there were 872 new cases diagnosed with asthma in the aspirin group and 963 in the placebo group ( hazard ratio 0.90 ; 95 % CI 0.82 to 0.99 ; p = 0.027 ) . This apparent 10 % lower relative risk of incident adult-onset asthma among those assigned to aspirin was significantly modified by body mass index , with no effect in women with a body mass index of ⩾30 kg/m2 . The effect of aspirin on adult-onset asthma was not significantly modified by age , smoking status , exercise levels , postmenopausal hormone use or r and omised vitamin E assignment . Conclusions : In this large r and omised clinical trial of apparently healthy adult women , administration of 100 mg aspirin on alternate days reduced the relative risk of a newly reported diagnosis of asthma . Trial registration number : [23648395] This pilot study aims to provide effect size confidence intervals , clinical trial and intervention feasibility data , and procedural material s for a full-scale r and omized controlled trial that will determine the efficacy of Dietary Approaches to Stop Hypertension ( DASH ) as adjunct therapy to st and ard care for adults with uncontrolled asthma . The DASH diet encompasses foods ( e.g. , fresh fruit , vegetables , and nuts ) and antioxidant nutrients ( e.g. , vitamins A , C , E , and zinc ) with potential benefits for persons with asthma , but it is unknown whether the whole diet is beneficial . Participants ( n = 90 ) will be r and omized to receive usual care alone or combined with a DASH intervention consisting of 8 group and 3 individual sessions during the first 3 months , followed by at least monthly phone consultations for another 3 months . Follow-up assessment s will occur at 3 and 6 months . The primary outcome measure is the 7-item Juniper Asthma Control Question naire , a vali date d composite measure of daytime and nocturnal symptoms , activity limitations , rescue medication use , and percentage predicted forced expiratory volume in 1 second . We will explore changes in inflammatory markers important to asthma pathophysiology ( e.g. , fractional exhaled nitric oxide ) and their potential to mediate the intervention effect on disease control . We will also conduct pre-specified subgroup analyses by genotype ( e.g. , polymorphisms on the glutathione S transferase gene ) and phenotype ( e.g. , atopy , obesity ) . By evaluating a dietary pattern approach to improving asthma control , this study could advance the evidence base for refining clinical guidelines and public health recommendations regarding the role of dietary modifications in asthma management [9111435] OBJECTIVE To determine if vitamin C ( ascorbic acid ) has a protective effect on the hyperreactive airways of patients with exercise-induced asthma ( EIA ) . DESIGN All the patients underwent pulmonary function tests at rest , before and 1 hour after receiving 2 g of oral ascorbic acid . They were then r and omly assigned in a double-blind manner to receive 2 g of ascorbic acid or a placebo 1 hour before a 7-minute exercise session on a treadmill . Pulmonary function tests were performed after an 8-minute rest . This procedure was repeated 1 week later , with each patient receiving the alternative medication . SETTING A university hospital . PARTICIPANTS Twenty patients with asthma ( 13 males and 7 females ) , with ages ranging from 7 to 28 years ( mean , 13.8 years ) . All patients who had a decline of at least 15 % in their forced expiratory volume in 1 second after a st and ard exercise test on a motorized treadmill received a diagnosis of EIA . MAIN- OUTCOME MEASURES : All patients were advised to stop using their regular asthma medication or bronchodilator 12 hours before the test . Pulmonary function tests were performed in the same ambient conditions on all patients . RESULTS All patients received a diagnosis of EIA . Ascorbic acid administration did not change the results of pulmonary functions at rest after 1 hour . In 9 patients , a protective effect on exercise-induced hyperreactive airways was documented . Four of 5 patients who received ascorbic acid and documented a protective effect on EIA continued to receive ascorbic acid , 0.5 g/d , for 2 more weeks with the same protective effect . CONCLUSIONS The efficacy of vitamin C in preventing EIA can not be predicted . However , vitamin C may have a protective effect on airway hyperreactivity in some patients with EIA [16140229] Exhaled carbon monoxide ( eCO ) is a potential non-invasive marker of airway inflammation . We have investigated the cross-sectional and longitudinal relationship between eCO and lung function and bronchial reactivity in 69 adults with atopic asthma , in the course of participation in a 6-week r and omised placebo-controlled trial of vitamin E supplementation . At baseline , there was no cross-sectional association between absolute eCO levels and either forced expiratory volume ( FEV(1 ) ) , forced vital capacity ( FVC ) or bronchial reactivity . However , in the longitudinal analysis within the placebo group , a rise in mean eCO was significantly associated with improvement in bronchial reactivity ( change in eCO ( parts per million ) per natural log unit change in bronchial hyperreactivity 0.498 , 95 % confidence interval 0.071 to 0.924 , P=0.024 ) . These findings suggest that , contrary to previous data , there is no cross-sectional relationship between eCO and lung function or bronchial reactivity , but that there may be a longitudinal trend with bronchial reactivity that is worth further investigation [29070392] OVER THE PAST THREE DECADES , many studies have been published of the associations between a variety of different measures of antioxidants and both asthma and lung function . While there is always a risk of publication bias , the general trend of these studies has been to suggest an association between higher dietary antioxidant intake with less asthma and better lung function . The study by Yoon et al. in this issue of the Journal adds to this body of literature by identifying 100 patients with relatively stable asthma , and demonstrating that those with a serum total antioxidant capacity ( TAC ) over the mean value have a higher baseline lung function than those with a serum TAC less than the mean value , although there was no signifi ca nt difference in bronchial reactivity.1 However , TAC levels were not signifi cantly correlated with longitudinal changes in pulmonary function , although the higher baseline lung function result ed in greater forced expiratory volume both one and two years after enrolment — as would probably be expected . As serum TAC refl ects a composite of endogenous and exogenous factors , only the latter category can be considered amenable to intervention . These include environmental tobacco exposure ( which was not adjusted for in the article by Yoon et al. ) , ambient pollution and dietary antioxidants.2 Recognition is growing of the importance of societal level interventions to reduce tobacco consumption and hence exposure to this and other forms of ambient pollution . The challenge for epidemiological research ers is to distinguish causality from association ; this is particularly true for nutritional research , where the problems of confounding by lifestyle , pre-natal exposures and possibly even pre-conception exposures ( via epigenetics ) are manifold . The only study design that can deliver these answers is the r and omised controlled trial , and these are better able to consider the secondary treatment of diseases such as asthma , rather than the primary prevention of asthma due to logistical considerations such as cost and recruitment . However , selection of the intervention is diffi cult , as relatively small studies ( compared to pharmaceutical studies ) of individual antioxidants have not been encouraging.3,4 One particular problem observed in these studies is that the individuals who volunteer to participate in these studies are often already eating a healthy diet , have an interest in healthy eating and hence may have little room for nutritional improvement . The most promising nutritional interventions in asthma have tended to involve combinations of antioxidants5 and , more recently , increased fruit and vegetable intake.6 The latter study suggested that those who received fi ve servings of vegetables and two servings of fruit daily were less than half as likely to have an exacerbation during the following 14 weeks . Further r and omised controlled studies of this nature are required to permit an enhanced underst and ing of the role of oxidation with regard to asthma aetiology and severity , and hopefully to permit translation of epidemiological observations into tangible effects from which the individual patient can benefi [10489824] In this study , the perceptions of asthmatics to change in their disease was associated with observed changes in clinical asthma measures , in order to identify the threshold where changes in clinical asthma measures are perceivable by patients . The study included 281 asthmatic patients , aged 18 - 63 yrs , in a r and omized , placebo-controlled clinical trial of a leukotriene antagonist . Changes were related in : 1 ) asthma symptom scores ; 2 ) inhaled beta-agonist use ; 3 ) forced expiratory volume in one second ( FEV1 ) ; and 4 ) peak expiratory flow ( PEF ) to a global question that queried overall change in asthma since starting the study drug . Additional analyses examined differences in the group reporting minimal improvement by treatment ( active treatment versus placebo ) , sex and age groups . The average minimal patient perceivable improvement for each measure was : 1 ) -0.31 points for the symptom score on a scale of 0 - 6 ; 2 ) -0.81 puffs x day(-1 ) for inhaled beta-agonist use ; 3 ) 0.23 L for FEV1 ; and 4 ) 18.79 L x min(-1 ) for PEF . In general placebo-treated patients and older patients , who reported minimal improvement , experienced less mean improvement from baseline than active-treated patients and younger patients , who reported minimal improvement . Determining the minimal patient perceivable improvement value for a measure may be helpful to interpret changes . However , interpretation should be carried out cautiously when reporting a single value as a clinical ly important change [3447618] This present trial investigated the efficacy of supplementation with Chlorella vulgaris , a bioactive microalga rich in macro- and micronutrients , in the improvement of biochemical and clinical symptoms in patients with obstructive pulmonary disorders . Ninety-seven patients with chronic obstructive pulmonary disease ( COPD ) or asthma who were under conventional treatment regimens were r and omly assigned to C. vulgaris extract ( CVE ) ( n=48 ; 2700 mg/day ) or no adjunctive therapy ( n=49 ) for eight weeks . Serum levels of antioxidants along with spirometric parameters and clinical symptoms were evaluated pre- and post-trial . The magnitude of increases in the concentrations of glutathione , vitamin E , and vitamin C , and activities of glutathione peroxidase , catalase , and superoxide dismutase enzymes were all significantly greater in the CVE vs. control group ( p<0.05 ) . In spite of increases , none of the assessed spirometric parameters ( FVC , FEV1 , FEV1/FVC , and FEF25–75 % ) did significantly differ by the end of the trial in the study groups , apart from a significant elevation of FEV1 in the control group ( p=0.03 ) . The frequency of coughing , shortness of breath , wheezing , and sputum brought up were all significantly reduced in both CVE and control groups ( p<0.05 ) . The rate of improvement for sputum brought up and wheezing were significantly greater in the CVE group compared to the control group ( p<0.05 ) . Although CVE was found to ameliorate serum antioxidant status , its supplementation was not associated with any bronchodilatory activity . The results of the present trial do not support any clinical efficacy for CVE in patients with obstructive pulmonary disorders [21614939] PURPOSE The purpose of this study was to test the effectiveness of an integrative medicine approach to the management of asthma compared to st and ard clinical care on quality of life ( QOL ) and clinical outcomes . METHODS This was a prospect i ve parallel group repeated measurement r and omized design . Participants were adults aged 18 to 80 years with asthma . The intervention consisted of six group sessions on the use of nutritional manipulation , yoga techniques , and journaling . Participants also received nutritional supplements : fish oil , vitamin C , and a st and ardized hops extract . The control group received usual care . Primary outcome measures were the Asthma Quality of Life Question naire ( AQLQ ) , The Medical Outcomes Study Short Form-12 ( SF-12 ) , and st and ard pulmonary function tests ( PFTs ) . RESULTS In total , 154 patients were r and omized and included in the intention-to-treat analysis ( 77 control , 77 treatment ) . Treatment participants showed greater improvement than controls at 6 months for the AQLQ total score ( P<.001 ) and for three subscales , Activity ( P < 0.001 ) , Symptoms ( P= .02 ) , and Emotion ( P<.001 ) . Treatment participants also showed greater improvement than controls on three of the SF-12 subscales , Physical functioning ( P=.003 ) ; Role limitations , Physical ( P < .001 ) ; and Social functioning ( P= 0.03 ) , as well as in the aggregate scores for Physical and Mental health ( P= .003 and .02 , respectively ) . There was no change in PFTs in either group . CONCLUSION A low-cost group-oriented integrative medicine intervention can lead to significant improvement in QOL in adults with asthma [2248797] Introduction Our study was undertaken to determine the association between use of a health plan-sponsored health club benefit by older adults and total health care costs over 2 years . Methods This retrospective cohort study used administrative and cl aims data from a Medicare Advantage plan . Participants ( n = 4766 ) were enrolled in the plan for at least 1 year before participating in the plan-sponsored health club benefit ( Silver Sneakers ) . Controls ( n = 9035 ) were matched to participants by age and sex according to the index date of Silver Sneakers enrollment . Multivariate regression models were used to estimate health care use and costs and to make subgroup comparisons according to frequency of health club visits . Results Compared with controls , Silver Sneakers participants were older and more likely to be male , used more preventive services , and had higher total health care costs at baseline . Adjusted total health care costs for Silver Sneakers participants and controls did not differ significantly in year 1 . By year 2 , compared with controls , Silver Sneakers participants had significantly fewer inpatient admissions ( −2.3 % , 95 % confidence interval , −3.3 % to −1.2 % ; P < .001 ) and lower total health care costs ( −$500 ; 95 % confidence interval , −$892 to −$106 ; P = .01 ] . Silver Sneakers participants who averaged at least two health club visits per week over 2 years incurred at least $ 1252 ( 95 % confidence interval , −$1937 to −$567 ; P < .001 ) less in health care costs in year 2 than did those who visited on average less than once per week . Conclusion Regular use of a health club benefit was associated with slower growth in total health care costs in the long term but not in the short term . These findings warrant additional prospect i ve investigations to determine whether policies to offer health club benefits and promote physical activity among older adults can reduce increases in health care costs [20683104] Airway mucus hypersecretion and increased oxidative stress are clinical and pathophysiological features of asthma exacerbation . We studied effects of N-acetylcysteine ( NAC ) as a mucolytic and antioxidant agent in asthma exacerbation . In this r and omized , single-blinded , placebo-controlled study 50 patients ( 17 male , 33 female , mean age 48.94+/-13.68 ) with asthma exacerbation were r and omized to receive either oral 600 mg b.d . N-acetylcysteine or placebo in addition to st and ard treatment during 5 days hospitalization . Daily measurements of wheezing , dyspnea , cough , sputum , expectoration , night sleep scores and morning PEFR were performed . There was no significant difference in wheezing score between patients assigned NAC and those assigned placebo in day 5(0.84[SD 0.94 ] VS 0.87[SD 0.79 ] ) and also in cough score ( 0.72[SD 0.84 ] VS 0.79[SD 0.97 ] ) , dyspnea score ( 0.84[SD 1.06 ] VS 0.91[SD 1.01 ] ) , sputum score(0.79[SD 0.83 ] VS 0.62[SD 0.71 ] ) , expectoration score(0.79[SD 0.97 ] VS 0.83[SD 1.09 ] ) , night sleep score(1[SD 1.17 ] VS 0.67[SD 0.98 ] and morning PEFR ( 256[SD 96.36 ] VS 282[SD 98.86 ] ) . We concluded that addition of N-acetylcysteine to usual asthma medication has no significant effect in treatment of asthma exacerbation [17412579] BACKGROUND Previous research has shown that diet can modify the bronchoconstrictor response to exercise in asthmatic subjects . OBJECTIVE Determine the effect of ascorbic acid supplementation on pulmonary function and several urinary markers of airway inflammation in asthmatic subjects with exercise-induced bronchoconstriction ( EIB ) . METHODS Eight asthmatic subjects with documented EIB participated in a r and omized , placebo controlled double-blind crossover trial . Subjects entered the study on their usual diet and were placed on either 2 weeks of ascorbic acid supplementation ( 1500 mg/day ) or placebo , followed by a 1-week washout period , before crossing over to the alternative diet . Pre- and post-exercise pulmonary function , asthma symptom scores , fraction of exhaled nitric oxide ( FENO ) , and urinary leukotriene ( LT ) C4-E4 and 9alpha , 11beta-prostagladin ( PG ) F2 ] were assessed at the beginning of the trial ( usual diet ) and at the end of each treatment period . RESULTS The ascorbic acid diet significantly reduced ( p < 0.05 ) the maximum fall in post-exercise FEV1 ( -6.4 + /- 2.4 % ) compared to usual ( -14.3 + /- 1.6 % ) and placebo diet ( -12.9 + /- 2.4 % ) . Asthma symptoms scores significantly improved ( p<0.05 ) on the ascorbic acid diet compared to the placebo and usual diet . Post-exercise FENO , LTC4-E4 and 9alpha , 11beta-PGF2 concentration was significantly lower ( p<0.05 ) on the ascorbic acid diet compared to the placebo and usual diet . CONCLUSION Ascorbic acid supplementation provides a protective effect against exercise-induced airway narrowing in asthmatic subjects [18324527] Antioxidant-rich diets are associated with reduced asthma prevalence . However , direct evidence that altering intake of antioxidant-rich foods affects asthma is lacking . The objective was to investigate changes in asthma and airway inflammation result ing from a low antioxidant diet and subsequent use of lycopene-rich treatments . Asthmatic adults ( n=32 ) consumed a low antioxidant diet for 10 days , then commenced a r and omized , cross-over trial involving 3 × 7 day treatment arms ( placebo , tomato extract ( 45 mg lycopene/day ) and tomato juice ( 45 mg lycopene/day ) ) . With consumption of a low antioxidant diet , plasma carotenoid concentrations decreased , Asthma Control Score worsened , % FEV1 and % FVC decreased and % sputum neutrophils increased . Treatment with both tomato juice and extract reduced airway neutrophil influx . Treatment with tomato extract also reduced sputum neutrophil elastase activity . In conclusion , dietary antioxidant consumption modifies clinical asthma outcomes . Changing dietary antioxidant intake may be contributing to rising asthma prevalence . Lycopene-rich supplements should be further investigated as a therapeutic intervention [14694237] BACKGROUND We recently reported that antioxidant supplementation with vitamins C and E mitigated ozone related decline in forced expiratory flow ( FEF(25 - 75 ) ) in 158 asthmatic children in an area with high ozone exposure in Mexico City . METHODS A study was undertaken to determine whether deletion of glutathione S-transferase M1 ( GSTM1 null genotype ) , a gene involved in response to oxidative stress , influences ozone related decline in FEF(25 - 75 ) and the benefit of antioxidant supplementation . RESULTS GSTM1 null children receiving placebo had significant ozone related decrements in FEF(25 - 75 ) ( percentage change per 50 ppb of ozone 2.9 ( 95 % CI -5.2 to -0.6 ) , p=0.01 ) ; GSTM1 positive children did not . Conversely , the effect of antioxidants was stronger in children with the GSTM1 null genotype . CONCLUSIONS Asthmatic children with a genetic deficiency of GSTM1 may be more susceptible to the deleterious effects of ozone on the small airways and might derive greater benefit from antioxidant supplementation [22741171] Associations have been reported between suboptimal maternal vitamin E intake during pregnancy and childhood asthma . This pilot study conducted in 2008/2009 investigated the feasibility and acceptability of a food-based r and omized controlled trial in pregnant women to optimize dietary vitamin E intake to 15 mg/day . A food-based intervention using " food exchanges " to individually optimize dietary vitamin E intake to 15 mg/day was developed and included in an advice booklet . Forty-three pregnant women with a personal/partner history of asthma were recruited at 12 weeks gestation and r and omized to food-based intervention or a control group until 20 weeks gestation . A registered dietitian assessed the vitamin E intake of 22 women and provided tailored advice on food-based exchanges to optimize their intake to 15 mg/day . The 21 control women were not given dietary advice . The food-based intervention was completed by 19 women and increased mean vitamin E intake : food diary data , 7.13 mg/day ( 95 % confidence interval : 5.63 to 18.6 ) to 17.4 mg/day ( 95 % confidence interval : 14.4 to 20.5 ) ( P<0.001 ) . This pilot study demonstrates the feasibility and acceptability of a food-exchange-based intervention to optimize dietary vitamin E intake during pregnancy . Additional work is required to determine whether this intervention , if sustained for the rest of pregnancy , reduces the likelihood of childhood asthma . The methodology used in the design of this novel food-based intervention could be transferred to other nutrients [15823446] To further establish the role of oxidative stress in the pathogenesis of acute bronchial asthma , we investigated the effects of platelet-activating factor ( PAF ) challenge on systemic oxidant-antioxidant balance in 12 asthmatic patients ( age , 25+/-3[SEM ] yr ; FEV1 , 95+/-10 % predicted ) , using a double blinded , controlled with Lyso-PAF ( L-PAF ) , cross-over design . Respiratory system resistance ( Rrs ) , arterial blood gases , peripheral blood neutrophils and oxidant-antioxidant balance , including thiobarbituric acid (TBA)-malondialdehyde ( MDA ) adducts , protein sulphydryls and Trolox equivalent antioxidant capacity ( TEAC ) , were assessed at baseline and 5 , 15 and 45 min after PAF and L-PAF ( 18 microg each ) bronchoprovocation . Urinary leukotriene E4 ( uLTE4 ) elimination was measured 120 min after challenge . Compared with baseline , as expected , PAF increased significantly Rrs and AaPO2 and decreased PaO2 and peripheral blood neutrophils along with a rebound neutrophilia and increased uLTE4 . By contrast , markers of systemic oxidative stress remained unaltered throughout the study . Unlike PAF , L-PAF-induced changes were negligible . We conclude that there is no systemic oxidant-antioxidant imbalance during acute bronchoconstriction induced by PAF in these patients with mild asthma [20926152] BACKGROUND Chronic airway inflammation in asthma or chronic obstructive pulmonary disease ( COPD ) may be involved in the pathogenesis of type 2 diabetes ; however , prospect i ve data have been limited . METHODS A prospect i ve cohort of 38,570 women who were aged ≥ 45 years , free of cardiovascular disease and cancer at baseline , and free of diabetes at baseline and in the first 12 months were analyzed . We classified all women into three groups according to the presence and absence of self-reported asthma or COPD ( including emphysema , chronic bronchitis , and bronchiectasis ) . RESULTS During a median follow-up of 12.2 years , 2472 incident type 2 diabetes events were documented . Women who had ever reported asthma or COPD were associated with an increased diabetes risk ; the multivariate RRs were 1.37 ( 95 % CI , 1.20 - 1.57 ) for women who had asthma alone and 1.38 ( 95 % CI , 1.14 - 1.67 ) for COPD without asthmatic symptoms . Furthermore , these associations were not significantly modified by age , smoking status , physical activity , BMI , alcohol intake , hormone replacement therapy , menopausal status or r and omized treatment . CONCLUSIONS Asthma and COPD were individually and independently associated with an increased risk of type 2 diabetes in women , indicating that chronic airway inflammation may contribute to diabetes pathogenesis [14519140] Background Epidemiological studies suggest that higher intakes of dietary vitamin C and magnesium may be associated with a reduced risk of asthma [12204869] To evaluate whether acute effects of ozone , nitrogen dioxide , and particulates with mass median diameter less than 10 micro m could be attenuated by antioxidant vitamin supplementation , we conducted a r and omized trial using a double-blinded design . Children with asthma ( n = 158 ) who were residents of Mexico City were r and omly given a daily supplement of vitamins ( 50 mg/day of vitamin E and 250 mg/day of vitamin C ) or a placebo and were followed from October 1998 to April 2000 . Pulmonary function tests were carried out twice a week in the morning . During the follow-up observation period , the mean 1-hour maximum ozone level was 102 ppb ( SD = 47 ) , and the mean 24-hour average PM(10 ) level was 56.7 micro g/m(3 ) ( SD = 27.4 ) . In children with moderate and severe asthma , ozone levels 1 day before spirometry were inversely associated significantly with forced expiratory flow ( FEF(25 - 75 ) ) ( -13.32 ml/second/10 ppb ; p = 0.000 ) , FEV(1 ) ( -4.59 ml/10 ppb ; p = 0.036 ) , and peak expiratory flow ( PEF ) ( -15.01 ml/second/10 ppb ; p = 0.04 ) in the placebo group after adjusting for potential confounding factors . No association between ozone and lung functions was observed in the supplement group . We observed significant differences in lung function decrements between groups for FEF(25 - 75 ) and PEF . Our results suggest that supplementation with antioxidants might modulate the impact of ozone exposure on the small airways of children with moderate to severe asthma [15641633] To determine if micronutrient intake is associated with asthma severity , we administered the Block food frequency question naire to participants in a r and omized clinical trial of the safety of influenza vaccine for asthmatics . The nutrition sub study included 1033 participants , aged 12–75 . Intake of antioxidant vitamins , soy isoflavones , total fruits and vegetables , fats , and fiber was compared with asthma severity at baseline [ forced expiratory volume in 1 second ( FEV1 ) , peak expiratory flow rate ( PEF ) , asthma symptoms ] and the rate of asthma exacerbations during the 2 weeks following influenza vaccination . The only nutrient that had a consistent association with asthma severity was genistein , a soy isoflavone . None of the nutrients evaluated were related to asthma exacerbation rate when adjusted for known confounders . The FEV1 in genistein consumers of at least 250 µg/1000 Kcal/day was 82.1 % predicted , 79.9 % predicted for those who consumed between 1 and 249 µg/1000 kcal , and 76.2 % predicted in genistein nonconsumers ( p = 0.006 ) ; the PEF was 82.7 % predicted , 80.8 % predicted , and 78.3 % predicted , respectively ( p = 0.009 ) . There were no differences in the Asthma Symptom Utility Index ( ASUI ) . We could not account for these results based on differences in demographics , body mass index , or consumption of other nutrients . Thus , increasing consumption of genistein is associated with better lung function in patients with asthma . Further studies are needed to determine whether dietary supplementation with genistein can reduce asthma severity [12424331] The human lung , due to the oxidative and ozone stress to which it is exposed , is particularly vulnerable to oxidative damage . Concentrations of dietary antioxidants in the lung epithelial lining and lining fluids may provide protection against oxidative damage . A r and omized clinical trial was conducted to study the effects of supplemental , carotenoid-rich vegetable Juice ( V-8 ) on lung function macrophage levels of carotenoids and in moderating ozone-induced lung damage . Healthy young adults ( n = 23 ) were exposed to 0.4 ppm ozone in a chamber for 2 hr after either 2 weeks of antioxidant supplementation ( including one can of V-8 juice daily ) or placebo . Mean lung concentrations of lycopene increased by 12 % , and lung epithelial cell DNA damage as measured by the Comet Assay decreased 20 % In supplemented subjects . No change in peripheral blood lymphocyte DNA damage was observed as evidence d by no change in mean comet area or length in supplemented or placebo subjects . We were not able to separate the effects of lycopene from other carotenoids or antioxidants administered in this study ; however , lycopene is the predominant carotenold in V-8 ( it represents 88 % of total carotenoids ) . A review of the epidemiologic literature providing evidence for the effect of lycopene ( diet or serum ) or tomatoes on the risk of lung cancer reveals 27 observational epidemiologic studies ( 18 case-control and nine cohort studies ) reporting relative risk ( RR ) estimates . RR estimates for cohort studies ranged from 0.63 to 1.24 ( mean RR = 0.93 , SD = 0.16 ) . Odds ratios ( OR ) for case-control studies ranged from 0.27 to 0.93 ( mean OR = 0.61 , SD = 0.16 ) . Both plasma levels ( RR = 1.01 , OR = 0.37 ) and estimated intakes of lycopene from dietary sources ( mean RR = 0.93 , RR range = 0.80–1.05 ; mean OR = 0.67 , OR range = 0.27–0.93 ) were examined . Seventeen studies , three of which were cohorts , reported their results at the level of tomato consumption rather than , or in addition to , lycopene consumption ( mean RR = 0.89 , RR range = 0.63–1.24 ; mean OR = 0.61 , OR range = 0.37–0.80 ) . The published epidemiologic literature shows an Interaction between study design and the relationship between lycopene and /or tomatoes and risk of lung cancer . Overall , cohort studies did not show an association , whereas case-control studies showed a decreased risk with greater consumption of lycopene and tomatoes . Altough lycopene can be found in the human lung , and there is evidence , albeit weak , for a protective association with lung cancer , its biologic role remains to be eluci date [363773] The effect of vitamin C pretreatment in preventing ragweed-induced bronchospasm was evaluated in 6 ragweed-sensitive asthmatics studied in a double-blind r and omized fashion . The patients received either lactose capsules or 500 mg of ascorbic acid and were studied out of season . Antigen dose-response curves were determined prior to the administration of lactose or ascorbic acid in each individual subject and subsequently after administration of ascorbic acid or lactose . Bothe PD20FEV1 ( provocation dose necessary for a 20 % reduction in forced expiratory volume in 1 second ) and PD35SGaw ( provocation dose necessary for a 35 % reduction in specific airways conductance ) were determined . In none of the six patients was there a change in baseline FEV 1 ( p greater than 0.70 ) nor the overall average baseline specific airways conductance ( rho greater than 0.90 ) . Additionally , no statistically significant difference ( p greater than 0.60 ) was noted between log PD35SGaw vitamin C day and lactose day . Likewise , no statistically significant difference ( p greater than 0.60 ) was evident when comparing log PD20FEV1 lactose and ascorbic acid days . Vitamin C ( 500 MG ) HAS NO PROTECTIVE EFFECT AGAINST RAGWEED ANTIGEN-INDUCED BRONCHOSPASM [12061080] Selenium ( Se ) deficiency attenuates the host immune response , thereby increasing the risk of bacterial and viral infections . We have examined the effects of selenium supplementation ( SeS ) in corticoid-dependent asthmatics ( CDAs ) with lowered circulatory Se status . Twenty CDAs ( 10 males and 10 females , average age 54.5 yrs ) were enrolled into the study . The average duration of the disease was 10 yrs . The asthmatics were receiving 200 micrograms of Se per day for a period of 6 months , in addition to regular treatment with inhaled corticosteroids and beta-agonists . The expression of adhesion molecules ( CD11a , CD11b , CD18 , CD49d , CD54 , CD62L ) on peripheral blood mononuclear cells ( P BMC s ) of asthmatics and the expression of E- and P-selectins , ICAM-1 , VCAM-1 on cultured human umbilical vein endothelial cells ( HUVEC ) after stimulation with P BMC s from CDAs before and after 3 and 6 months of SeS were assessed by st and ard monoclonal antibodies and analyzed by flow cytometry . The concentrations of soluble adhesion molecules P-selectin , E-selectin , ICAM-1 and VCAM-1 were determined by ELISA method . The expression of adhesion molecules on P BMC s : After 3- and 6-months of SeS , a decreased expression of molecules CD11a , CD11b and CD62L was observed ( p < 0.02 , p < 0.005 , p < 0.003 ) . No changes were seen in the expression of CD18 , CD49d except for the increased expression of CD54 ( p < 0.005 ) . Modulation of adhesion molecules expression on HUVEC : We observed a significant increase in VCAM-1 , P- and E-selectins expressions in the group of asthmatics without SeS in comparison with the control group ( p < 0.05 , p < 0.01 , p < 0.05 ) . During SeS a significant decrease in molecules VCAM-1 , E-selectin ( after 3 months ) ( p < 0.05 , p < 0.05 ) and P-selectins and ICAM-1 ( after 6 months ) ( p < 0.05 , p < 0.01 ) were observed . Soluble adhesion molecules : After 3 months of SeS we noticed a significant decrease in VCAM-1 and P-selectin expressions ( p < 0.05 , p < 0.05 ) and after 6 months the level of VCAM-1 decreased ( p < 0.01 ) . The effect of Se on the adhesion molecules expression in endothelial cells in vitro experiments : Se blocks the expression of adhesion molecules stimulated by IFN-gamma in a dose-dependent way after addition of Se into a culture of endothelial cells . Concentration of 10 micrograms/ml inhibits the increase in expression of ICAM-1 ( p < 0.05 ) but not that of VCAM-1 , E- or P-selectins . The inhibition of expression in Se concentration of 10 micrograms/ml is over 80 % ( p < 0.01 ) . Our data demonstrate that Se is able to affect the adhesion molecules expressions that are crucial in the inflammatory process . ( Fig. 5 , Ref . 22 . [12741429] STUDY OBJECTIVES To characterize asthma symptoms and pulmonary function throughout two menstrual cycles , with and without exogenous estradiol administration , in women with premenstrual asthma , and to determine the effect of estradiol administration on asthma symptoms , pulmonary function , quality of life , and biomarkers of airway inflammation . DESIGN Double-blind , r and omized , placebo-controlled , crossover study . SETTING Respiratory clinic and clinical research center . SUBJECTS Twelve women with documented premenstrual asthma ( > or = 20 % premenstrual worsening of asthma symptoms and /or of peak expiratory flow [ PEF ] during a 1-month screening phase ) . INTERVENTION Each woman received either estradiol 2 mg or placebo orally between cycle days 23 and 28 ( i.e. , premenstrually , or before the onset of menses ) in the first cycle and then crossed over to the other arm in the second cycle . Throughout both cycles , the women recorded daily morning and evening PEF readings and asthma symptoms . MEASUREMENTS AND MAIN RESULTS Spirometry testing and measurement of serum estradiol and biomarkers of airway inflammation were performed on days 8 ( follicular phase ) , 22 ( luteal phase ) , and 28 ( premenstrually ) of both the estradiol and placebo cycles . During the two premenstrual visits , the Asthma Quality of Life Question naire was administered . No notable differences were observed between the estradiol and placebo cycles in daily PEF recordings or composite asthma symptoms scores . The area under the curve ( AUC ) for the composite asthma symptoms versus time profile was numerically , but not statistically , lower ( denoting less severe symptoms ) during the estradiol cycle than during the placebo cycle . Likewise , no significant difference in AUC values for morning PEF or evening PEF was found between the estradiol cycle and the placebo cycle . Despite differences ( p<0.05 ) in day-28 estradiol concentrations for estradiol and placebo cycles , no significant differences were found in forced expiratory volume in 1 second , serum endothelin-1 , serum and urine eosinophil protein X , urine leukotriene E4 , or quality -of-life scores . CONCLUSION Exogenously administered estradiol did not have a significant effect in women with premenstrual asthma whose asthma was classified predominantly as mild and under excellent control . As in the case of premenstrual syndrome , the placebo effect may be prominent in premenstrual asthma . Further trials , involving women with more severe asthma under poorer control , are warranted to discern underlying mechanisms for the worsening of asthma in relation to menstruation [15641632] A r and omized , placebo‐controlled , double‐blind study involving 60 subjects , aged 6–18 years old , was conducted over a period of 3 months to determine the effect of Pycnogenol ® ( a proprietary mixture of water‐soluble bioflavonoids extracted from French maritime pine ) on mild‐to‐moderate asthma . After baseline evaluation , subjects were r and omized into two groups to receive either Pycnogenol ® or placebo . Subjects were instructed to record their peak expiratory flow with an Assess ® Peak Flow Meter each evening . At the same time , symptoms , daily use of rescue inhalers ( albuterol ) , and any changes in oral medications were also recorded . Urine sample s were obtained from the subjects at the end of the run‐in period , and at 1‐ , 2‐ , and 3‐month visits . Urinary leukotriene C4/D4/E4 was measured by an enzyme immunoassay . Compared with subjects taking placebo , the group who took Pycnogenol ® had significantly more improvement in pulmonary functions and asthma symptoms . The Pycnogenol ® group was able to reduce or discontinue their use of rescue inhalers more often than the placebo group . There was also a significant reduction of urinary leukotrienes in the Pycnogenol ® group . The results of this study demonstrate the efficacy of Pycnogenol ® as an adjunct in the management of mild‐to‐moderate childhood asthma [11480500] Abstract Ozone exposure aggravates asthma , as has been demonstrated in both controlled exposures and epidemiologic studies . In the current double-blind crossover study , the authors evaluated the effects of dietary antioxidants ( i.e. , 400 IU vitamin E/500 mg vitamin C ) on ozone-induced bronchial hyperresponsiveness in adult subjects with asthma . Seventeen subjects were exposed to 0.12 ppm of ozone or to air for 45 min during intermittent moderate exercise . Bronchial hyperresponsiveness was assessed with 10-min sulfur dioxide ( i.e. , 0.10 ppm and 0.25 ppm ) inhalation challenges . Subjects who were given dietary antioxidants responded less severely to sulfur dioxide challenge than subjects given a placebo ( i.e. , forced expiratory volume in the 1st sec : -1.2 % vs. 4.4 % , respectively ; peak flow : + 2.2 % vs. -3.0 % , respectively ; and mid-forced expiratory flow : + 2.0 % vs. -4.3 % , respectively ) . Effects were more pronounced when subjects were grouped by response to sulfur dioxide at the screening visit . The results suggest that dietary supplementation with vitamins E and C benefits asthmatic adults who are exposed to air pollutants [8815279] To eluci date the effect of antioxidants aevit and glutaminic acid on the course of bronchial asthma ( BA ) and free radical processes in this disease , 54 BA patients were divided into 2 groups : glucocorticoid-untreated and glucocorticoid-treated . Each of two subgroups made of these groups either received antioxidants ( AO ) or not . The response was assessed by clinical BA symptoms and free radical processes reflecting production of active oxygen forms by leukocytes ( PAOFL ) and free radical peroxidation ( FRPO ) . PAOFL was studied using luminol-dependent chemiluminescence ( CL ) . CL basal and stimulated values were calculated . FRPO was measured by plasma levels of malonic dialdehyde . Aevit and glutaminic acid treated BA patients improved clinical ly and exhibited reduced CL of PAOFL and malonic dialdehyde in plasma compared to BA patients on conventional therapy or conventional therapy plus glucocorticoids . Aevit and glutaminic acid are recommended for BA patients [3353464] Methods Mild asthmatics and normal controls were recruited as study subjects . This crossover study was double-blinded , r and omized and counter-balanced to the order of three conditions : diesel exhaust with anti-oxidant , diesel exhaust with placebo , or filtered air with placebo . The subjects were exposed to either filtered air or diesel exhaust ( 300 ug PM2.5/m ) in a state-of-the-art diesel exhaust exposure facility . An anti-oxidant , N-acetylcysteine ( 600 mg ) , or a placebo was taken orally for five days preceding , and on the day of the exposure . Each subject was exposed to each of the three conditions . Peripheral blood sample s were taken pre-exposure , and also at 2 , 6 , and 30 hours after the beginning of exposure . Sputum induction was performed by inhalation of hypertonic saline according to ATS guidelines pre-exposure , and also at 6 , and 30 hours after the beginning of exposure . FACSCanto II ( BD Biosciences ) was used for flow cytometry . A 5-colour , 12-marker ( CD3/CD9/ CD14/CD16/CD19/CD20/CD45/CD56/CD83/CD206/ CD326/HLA-DR ) combination was used to identify dendritic cells , macrophages , monocytes , neutrophils , eosinophils , and bronchial epithelial cells . Direct immunolabelling was performed on whole peripheral blood . After incubation , red blood cells were lysed . Remaining cells were washed and resuspended in PBS with 0.5 % paraformaldehyde . Sputum plugs were homogenized with 0.1 % DTT , filtered , and then centrifuged to remove supernatant . Sputum cells were resuspended in PBS at 1 million per mL. Direct immunolabelling was performed . After incubation , cells were washed and resuspended in PBS with 0.5 % paraformaldehyde . Spectral compensation for flow cytometry was performed using an automatic calibration technique ( BD CompBeads ) . Cellular debris was eliminated on the SSC/FSC scattergram . A gating strategy was design ed to identify the leukocyte sub- population s and bronchial epithelial cells . Surface markers were chosen based on differential cell-specific expression according to existing literature [15282383] Background : Increased dietary vitamin E intake is associated with a reduced incidence of asthma , and combinations of antioxidant supplements including vitamin E are effective in reducing ozone induced bronchoconstriction . A study was undertaken to investigate the effect of supplementation with vitamin E for 6 weeks on bronchial hyperresponsiveness in atopic adults with asthma . Methods : 72 participants from a clinical trial register of adults with asthma were r and omised to receive 500 mg natural vitamin E or matched placebo for 6 weeks in a placebo controlled , double blind parallel group clinical trial . Inclusion criteria included age 18–60 years , maintenance treatment of at least one dose of inhaled corticosteroid per day , a positive skin prick test to one of three common allergens , and bronchial hyperresponsiveness to methacholine ( defined as a dose provoking a 20 % fall in forced expiratory volume in 1 second ( FEV1 ) ( PD20 ) of 12.25 μmol ) . Secondary outcomes were FEV1 , forced vital capacity , mean morning and evening peak flow , symptom scores , bronchodilator use , and serum immunoglobulin E levels . Results : In the primary intention to treat analysis the change in PD20 was similar in the vitamin E and placebo groups with a mean difference of + 0.25 doubling doses of methacholine ( 95 % confidence interval −0.67 to + 1.16 greater with vitamin E ) . There was no effect of vitamin E supplementation on any other measure of asthma control , either in the intention to treat or per protocol analysis . There was also no effect of vitamin E supplementation on serum immunoglobulin levels . Conclusion : Dietary supplementation with vitamin E adds no benefit to current st and ard treatment in adults with mild to moderate asthma [7423602] Forty-one asthmatic patients in remission were r and omly allocated to two treatment groups in a double-blind trial . One group took 1 g , of ascorbic acid as one effervescent tablet once daily and the second group took a matching placebo . The asthmatics were selected from those attending the Asthma Clinic . One criterion for selection was the increase in exacerbation during the rainy season . These exacerbations were precipitated by respiratory infection . After 14 weeks , an assessment of the severity and rate of attacks showed that those on ascorbic acid suffered less severe and less frequent attacks of asthma during the study period . Plasma ascorbic acid astimations showed a significant rise in the level in those taking ascorbic acid over those on placebo . ( P < 0.01 ) . Cessation of ascorbic acid in the group taking it increased attack rates . It is concluded that high dose ascorbic acid is probably a good prophylaxis in some bronchial asthmatics [6342165] Sixteen White children with bronchial asthma were divided into two groups ; one received st and ard anti-asthma chemoprophylaxis ( SAC ) and the other SAC supplemented with 1 g ascorbic acid ( Redoxon ) given as a single daily dose for a 6-month period . In 10 patients the effects of ascorbic acid on exercise-induced bronchoconstriction ( EIB ) were assessed by comparing the pre-ascorbic acid results with those obtained 2 1/2 hours after the intravenous injection of 1 g ascorbic acid . Immunological investigations performed on the two groups were assessment of polymorphonuclear leucocyte ( PMNL ) motility , phagocytosis and nitroblue tetrazolium reduction and measurement of secretory IgA , serum immunoglobulin and total haemolytic complement levels and levels of the components C3 and C4 , alpha 1-antitrypsin , antistreptolysin O ( ASO ) , C-reactive protein and antibodies to certain respiratory viruses . These investigations were performed before and 1 , 3 and 6 months after the commencement of therapy . Radio-allergosorbent testing for sensitivity to four common allergens was carried out at the outset and after 6 months of therapy . Injection of ascorbic acid had no detectable effects on the degree of EIB . Slight but not significant immunological changes were observed in the SAC group over the 6-month study period . However , in the SAC plus ascorbic acid group significantly improved PMNL motility and decreased ASO levels and reduced ( although not to a significant extent ) IgE levels and titres of antibodies to the respiratory viruses were observed [16177596] PURPOSE Reactive oxygen/nitrogen species ( ROS/RNS ) in resident airway cells may be important in bronchoconstriction following exercise . Glutathione ( GSH ) is a major lung antioxidant and could influence pathological outcomes in individuals with exercise-induced bronchoconstriction ( EIB ) . This study examined the effects of supplementation with undenatured whey protein ( UWP ) in subjects exhibiting airway narrowing following eucapnic voluntary hyperventilation ( EVH ) , a surrogate challenge for diagnosis of EIB . UWP is a cysteine donor that augments GSH production . METHODS In a r and omized , double-blind , placebo-controlled study , 18 EIB-positive subjects ( age : 25.2 + /- 9.01 yr ; weight : 77.3 + /- 18.92 kg ; height : 1.7 + /- 0.09 m ) with post-EVH falls of > or = 10 % in FEV1 received 30 g UWP ( TX ) or casein placebo (PL)/d . Subjects performed 6-min EVH challenges before and after 4 and 8 wk of supplementation . Exhaled nitric oxide ( eNO ) was measured serially before spirometry and at 1-wk intervals . Spirometry was performed pre- and 5 , 10 , and 15 min postchallenge . RESULTS Subjects exhibited significant mean improvement in postchallenge falls in FEV(1 ) from 0 wk ( -22.6 + /- 12.22 % ) with TX at 4 ( -18.9 + /- 12.89 % , P < 0.05 ) and 8 wk ( -16.98 + /- 11.61 % , P < 0.05 ) and significant mean reduction in post-EVH peak falls in FEF(25 - 75 ) from 0 wk ( -40.6 + /- 15.28 % ) with TX at 4 ( -33.1 + /- 17.11 % , P < 0.01 ) and 8 ( -29.7 + /- 17.42 % , P < 0.05 ) wk . No changes in FEV(1 ) or FEF(25 - 75 ) were observed in the PL group at any time point . Mean eNO for PL and TX groups at 0 , 4 , and 8 wk ( 46.8 + /- 31.33 , 46.5 + /- 35.73 , 49.3 + /- 37.12 vs 35.2 + /- 26.87 , 29.1 + /- 17.26 , 34.7 + /- 21.11 ppb , respectively ) was not significantly different . CONCLUSIONS UWP may augment pulmonary antioxidant capacity and be therapeutically beneficial in individuals exhibiting EIB , as postchallenge pulmonary function improved with supplementation . The lack of significant change in eNO suggests that the pulmonary function improvements from UWP supplementation are independent of eNO [1852141] Two groups of six asthmatic patients with biphasic bronchospastic response to inhaled Dermatophagoides pteronyssinus allergen extract were studied in a double-blind fashion . Early and late asthmatic reactions to allergen inhalation challenge were determined before and at the end of a 2-week treatment period with nimesulide ( 100 mg bid orally ) , a sulfonanilide with antioxidant properties , or placebo . Bronchial responsiveness to methacholine was evaluated 24 hours before and after allergen inhalation challenges . The dose of allergen causing EAR ( 15 % decrease in FEV1 ) and the severity of LAR ( maximum FEV1 fall ) were similar before and at the end of the treatment period in both groups . In patients treated with nimesulide , bronchial responsiveness to methacholine was significantly increased after allergen inhalation challenge both before and at the end of the treatment period . These results do not support the hypothesis that the production of oxygen-free radicals plays a significant role in the development of bronchial hyperresponsiveness and late phase reaction to allergen in asthma [11306340] PURPOSE To evaluate the association between active and passive smoking and frequency of colds in women . METHODS Data on cigarette smoking and frequency and duration of colds were analyzed in the Women 's Health Study ( WHS ) , a r and omized , double-blind , placebo-controlled trial of low-dose aspirin and vitamin E in the primary prevention of cardiovascular disease and cancer among 39,876 female health professionals . RESULTS After adjustment for age , body-mass index , prevalence of asthma and chronic lung diseases , alcohol intake , physical activity , and multivitamin use , current heavy smokers had no appreciable increase in the frequency of colds ( relative risk ( RR ) for > or= 3 versus no colds in the past year , 1.05 ; 95 % confidence interval ( CI ) , 0.80 - 1.39 ) , but a significantly increased risk of prolonged colds ( RR for colds of > 7 vs. 1 - 3 days , 2.53 ; 95 % CI , 1.95 - 3.29 ) . There was no difference in the number of days confined to home . Nonsmoking women passively exposed to cigarette smoke had a slightly increased risk of both more frequent colds ( RR , 1.33 ; 95 % CI , 1.18 - 1.51 ) and more prolonged colds during the previous year ( RR , 1.12 ; 95 % CI , 0.99 - 1.27 ) . CONCLUSIONS Women who are currently heavy smokers are at increased risk of having colds with longer duration compared with nonsmokers . Nonsmoking women passively exposed to cigarette smoking are at slightly increased risk of having more frequent and longer colds than nonsmoking women not exposed to passive smoke [11980114] AIM To compare clinical , device and biochemical aspects of monotherapy with flixotide vs combination of flixotide with serevent in patients with moderate bronchial asthma ( MBA ) . MATERIAL AND METHODS 18 patients with MBA received flixotide and 18 MBA patients flixotide plus serevent for two weeks of lead-in and eight weeks of basic treatment . A special study was made of neutrophils which were examined for activity of LPO-antioxidants and phospholipid spectrum of membranes . RESULTS There were similar changes in function of the system LPO-antioxidants and lipid structure in neutrophilic membranes of moderate BA patients of both the groups . CONCLUSION Clinicobiochemical efficacy of mean doses of a new topic inhalation glucocorticoid flixotide alone or in combination with prolonged beta 2-adrenostimulator serevent is demonstrated . There were positive trends in metabolic processes in neurophilic membrane . Use of flixotide in combination with serevent is clinical ly preferable [22502622] OBJECTIVE To examine the effects of nutritional supplement therapy on oxidant-antioxidant status , inflammation and immune system responses , pulmonary function , and health-related quality of life in patients with mild to moderate allergic asthma . METHODS Adult asthma patients ( n=30 ) received daily multiple nutrient supplements for two months . Age- and gender-matched healthy controls ( n=30 ) did not receive any supplements . Enzymatic and non-enzymatic antioxidant status , malondialdehyde ( MDA ) , high-sensitivity C-reactive protein ( hs-CRP ) , immunoglobulin E ( IgE ) and T-lymphocyte subsets , pulmonary function indices , as well as scores for asthma control and quality of life , were assessed at baseline , at one month of treatment , and at two months of treatment , which was also the end of the study . RESULTS At baseline , asthma patients had significantly higher IgE , MDA , copper ( Cu ) , hs-CRP , and CD19 and CD4/CD8 lymphocyte ratios , and decreased selenium ( Se ) , zinc ( Zn ) , β-carotene , vitamins C and E , and catalase , glutathione peroxidase ( GPx ) and glutathione reductase ( GR ) activities compared to healthy controls ( p < 0.05 ) . During the study period , asthmatics showed non-significantly increased pulmonary function and a trend toward lower IgE levels , markedly reduced MDA , Cu , hs-CRP , and CD19 and CD4/CD8 ratios , and increases in levels of Se , Zn , β-carotene , vitamins C and E , and enzymatic antioxidant activities . Also , their asthma control and health-related quality -of-life scores increased significantly by the end of the study . CONCLUSION Our results indicate that nutritional supplement therapy may improve dysregulated oxidant and antioxidant status , inflammation and immune responses , pulmonary function , and health-related quality of life in patients with mild to moderate allergic asthma [7114587] In order to study the potential benefit of ascorbic acid in asthma we investigated its role in exercise-induced bronchospasm ( EIB ) . Twelve asthmatic subjects were recruited on the basis of findings compatible with EIB . On two subsequent days the subjects ingested 500 mg . of ascorbic acid or a placebo . The study was performed in a double-blind r and omized fashion . Partial and maximal expiratory flow volume ( PEFV and MEFV ) curves were used to determine pulmonary function changes . Pretreatment with ascorbic acid led to a significant attenuation of the bronchospasm seen five minutes after exercise compared to placebo , as measured by FVC ( 0.23 + /- 0.08 L decrease after ascorbic acid , 0.48 + /- 0.14 L decrease after placebo ) and by FEV1 ( 0.24 + /- 0.06 decrease after ascorbic acid , 0.44 + /- 0.14 decrease after placebo ) Mean + /- SE ) . These results suggest a mild antibronchospastic action of ascorbic acid in subjects with EIB [15572850] Mild persistent asthma is most effectively controlled with inhaled corticosteroids . Leukotriene receptor antagonists have complementary effects to corticosteroids on inflammation control . The additional effect of a leukotriene receptor antagonist , zafirlukast , was investigated in stable asthma patients under control with inhaled budesonide . We conducted a r and omised , double-blind , placebo-controlled , single center trial to investigate the effects of add-on zafirlukast treatment to budesonide , on symptom score , pulmonary function , bronchial responsiveness , and serum levels of eosinophilic cationic protein ( ECP ) and antioxidant capacity in stable asthmatic patients under control with inhaled budesonide . The present study included 21 mild or moderate asthmatic patients ( 8 males and 13 females ) , who were stable at least for 6 weeks with inhaled budesonide ( 400 microg/day ) . Serum total antioxidant capacity ( TAC ) and ECP levels were measured , and symptom scoring , spirometry , and bronchial provocation with methacholine were performed . Then , the patients were r and omised to use either placebo or oral zafirlukast ( 40 mg/day ) in addition to budesonide for 6 weeks . At the 6th week , symptom scoring , spirometry , and bronchial provocation tests were repeated and serum TAC and ECP levels were measured again . After add-on zafirlukast treatment to budesonide , forced expiratory volume in 1 second ( FEV(1 ) ) , TAC and ECP values did not change significantly ( p > 0.05 ) but bronchial hyperresponsiveness and symptom score decreased significantly ( p = 0.022 ) compared to baseline . Thus , in stable asthmatic patients , add-on zafirlukast treatment to budesonide improves symptoms and decreases bronchial hyperresponsiveness [22885561] BACKGROUND Broad dietary patterns have been linked to asthma but the relative contribution of specific nutrients is unclear . Soy genistein has important anti-inflammatory and other biological effects that might be beneficial in asthma . A positive association was previously reported between soy genistein intake and lung function but not with asthma exacerbations . AIMS To conduct a post-hoc analysis of patients with inadequately controlled asthma enrolled in a prospect i ve multicentre clinical trial to replicate this association . METHODS A total of 300 study participants were included in the analysis . Dietary soy genistein intake was measured using the Block Soy Foods Screener . The level of soy genistein intake ( little or no intake , moderate intake , or high intake ) was compared with baseline lung function ( pre-bronchodilator forced expiratory volume in 1 second ( FEV(1 ) ) ) and asthma control ( proportion of participants with an episode of poor asthma control ( EPAC ) and annualised rates of EPACs over a 6-month follow-up period . RESULTS Participants with little or no genistein intake had a lower baseline FEV(1 ) than those with a moderate or high intake ( 2.26 L vs. 2.53 L and 2.47 L , respectively ; p=0.01 ) . EPACs were more common among those with no genistein intake than in those with a moderate or high intake ( 54 % vs. 35 % vs. 40 % , respectively ; p<0.001 ) . These findings remained significant after adjustment for patient demographics and body mass index . CONCLUSIONS In patients with asthma , consumption of a diet with moderate to high amounts of soy genistein is associated with better lung function and better asthma control [17339866] In this study , prospect ively , we aim ed to determine the effects of the different treatment alternatives on the oxidant system and inflammatory and clinic determinants during the stable period of 1 month following an asthmatic attack . Thirty‐one patients ( 22 female , nine male ) were r and omly divided into three groups following the stabilization of an acute asthma attack . The control group that is an additional group to the three patient groups consisted of 10 healthy volunteers ( five female , five male ) . The following protocol s were used for 4 weeks : Group I : short‐acting inhaler β2 mimetic as required ( treatment A)+800 μg inhaler budesonide ( treatment B)+leukotriene receptor antagonist ; Group II : treatment A and B ; Group III : treatment A and B+vitamin E. The serum levels before and after treatment of eosinophilic cationic protein ( ECP ) , leukotriene E4 ( LTE4 ) , and malondialdehyde ( MDA ) were determined . The values before and after treatment were statistically compared both with each other and control values . Pretreatment ECP , LTE4 , and MDA levels for the three groups were significantly higher compared with post‐treatment levels ( P<0.05 to P<0.001 ) and the control levels ( P<0.01 to P<0.001 ) . However , when post‐treatment levels were compared with those of the control group , no significant differences were found ( P>0.05 ) . Lack of significant variation was observed when the pre‐ and post‐treatment differences in the three groups were compared for each one of ECP , LTE4 , and MDA levels ( P>0.05 ) . Leukotriene receptor antagonist or antioxidant agents added to st and ard asthma treatment did not make a significant contribution on ECP , LTE4 , and MDA levels and respiratory parameters such as spirometric function tests . Etiologic factors and /or the possible changes in different pathogenetic ways of the inflammation process may have been responsible for nonsignificant intertreatment difference in the biomarker levels . The result confirms that suppressing the inflammation in asthma enables the entire inflammatory pathologic process to be controlled [15875530] BACKGROUND It has been suggested that exercise-induced bronchoconstriction may involve oxidative stress . Strenuous exercise promotes free radical production , which can lead to many of the pathophysiologic changes associated with asthma , including bronchoconstriction , mucus secretion , and microvascular leakage . Lycopene has been shown to have high antioxidative activity . OBJECTIVE To evaluate the effect of lycopene supplementation on airway hyperreactivity and inflammation in young athletes who complain of difficulty in breathing related to physical exertion . METHODS Nineteen young athletes with exercise-related difficulty in breathing visited the exercise laboratory 3 times . During the first visit , participants underwent a baseline evaluation of exercise-induced bronchoconstriction . Daily for 1 week before each of the 2 subsequent visits , participants ingested 30 mg of lycopene ( a natural antioxidant ) or placebo ( in r and omized order , double-blind ) . A 2-week washout period was given between each visit . During each visit , lung functions were evaluated before and after an 8-minute run on the treadmill ( 85 % of the predicted maximal heart rate ) . RESULTS There was no difference in the mean+/-SD decrease in forced expiratory volume in 1 second after exercise during lycopene treatment compared with placebo treatment ( 11.8%+/-12.5 % and 11.0%+/-11.6 % ) . In addition , there was no apparent division into responders and nonresponders . CONCLUSION A daily dose of lycopene for 1 week does not affect lung function after exercise and may not provide any protective effect against clinical difficulty in breathing in young athletes [10575337] Objective : We report on the effect of glutathione , an antioxidant compound on the airway response to the ultrasonically nebulised distilled water ( UNDW , ‘ fog ’ ) challenge . Methods : 12 subjects with mild-to-moderate bronchial asthma underwent double-blind , cross-over pretreatment , administered 30 min earlier , in a r and omised order with inhaled glutathione ( G ) ( 600 mg ) , sodium cromoglycate ( SCG ) ( 20 mg ) and placebo ( P ) , followed by the challenge . Results : After P pretreatment UNDW challenge caused a mean 20.41 % decrease in FEV-1 ( p < 0.05 ) , after G , a mean 6.04 % fall in FEV-1 ( p = n.s . ) , and after SCG a mean 5.99 % fall in FEV-1 ( p = n.s . ) . Conclusions : G significantly attenuated ‘ fog’-induced falls in FEV-1 ( p < 0.001 compared with P ) and showed a protective effect on UNDW-induced bronchoconstriction [16338599] AIM The study aims to assess the a priori hypothesis that regular supplementation with vitamin C or magnesium will permit a reduction in the corticosteroid dose required to maintain asthma control in adults . METHODS We invited all participants recruited from primary care centres who completed a parallel-group , r and omised , placebo-controlled , 16-week supplementation trial of 1g/day vitamin C or 450 mg/day magnesium to continue and participate in a structured corticosteroid reduction protocol over 10 weeks . RESULTS A total of 92 participants ( 29 vitamin C , 31 magnesium and 32 placebo ) entered the study . Assuming no reduction in corticosteroid dose in the 10 who subsequently withdrew , the geometric mean reductions in inhaled corticosteroid dose achieved with vitamin C , magnesium and placebo were 49 , 13 and 11 microg , respectively . Relative to placebo , the unadjusted effect of vitamin C was significant , and remained at borderline significance after adjustment for baseline corticosteroid dose ( relative reduction ratio=4.03 , 95 % CI 0.95 to 17.1 , P=0.06 ) . CONCLUSIONS We conclude that while vitamin C supplements may have modest corticosteroid sparing effects and hence the potential to reduce exposure to their side effects , magnesium supplements have no effect on the inhaled corticosteroid dose required to maintain asthma control [11120898] BACKGROUND Glutathione is central to the antioxidant defences of the lung . The aim of this study was to determine whether sputum induction can be used for the measurement of glutathione in the respiratory tract . METHODS Saliva and induced sputum ( 3 % NaCl , 20 minutes ) sample s were collected from 10 healthy individuals and 10 patients with stable asthma receiving treatment with inhaled corticosteroids . Sample s were chilled on ice and dispersed by dilution with ice cold phosphate buffered saline and pipetting . Cell-free supernatants were obtained by centrifugation of sample s and filtration of supernatants and analysed for total glutathione , glutathione disulfide , and albumin content . The cells were treated with dithiothreitol and cell numbers , cell viability , and differential cell patterns were determined . RESULTS As judged by cell viability and percentage of non-squamous cells , adequate sputum sample s were obtained from nine healthy and nine asthmatic subjects . The salivary total glutathione content was low ( median concentration 1.2 μM ( range 0.8–1.5 ) in healthy subjects and 0.9 μM ( 0.7–1.2 ) in asthmatic subjects ) . The sputum total glutathione content of both healthy and asthmatic subjects was within the same range ( 3.9 ( 1.0–12.3 ) μM and 6.4 ( 1.3–19.2 ) μM , respectively ; p=0.35 ) . Surprisingly , and in marked contrast to results obtained with bronchoalveolar lavage , sputum levels of glutathione disulfide represented more than 50 % of the total glutathione in both groups ( 50.9 % ( range 24.6–83.1 ) and 72.3 % ( range 36.5–97.4 ) , respectively ; p=0.2 ) . CONCLUSIONS The results of this study indicate that sputum induction can be used to measure the glutathione content of bronchial secretions . Sputum glutathione levels of stable asthmatic patients did not differ significantly from healthy controls [11728816] Apocynin is an inhibitor of NADPH oxidase present in inflammatory cells such as eosinophils and neutrophils . We investigated the effect of inhaled apocynin on ozone-induced bronchial hyperresponsiveness in vivo . Seven mild atopic asthmatics participated in a placebo-controlled , cross-over study with two exposures to O(3 ) at 2-week intervals . Apocynin ( 3 ml of 0.5 mg/ml ) was inhaled 2 times before and 6 times after O(3 ) exposure at hourly intervals . At 36 h before and 16 h after O(3 ) exposure , methacholine inhalation challenge tests ( Mch ) were performed , and PC(20 ) and maximal % fall from baseline ( MFEV(1 ) ) were calculated from dose-response curves . O(3)-induced change in PC(20 ) ( Delta PC(20 ) ) after placebo treatment was -1.94 + /- 0.39 DD ( mean + /- SEM doubling dose Mch ) ( p = .001 ) and apocynin was -0.6 + /- 0.33 DD ( p = .17 ) . The difference between apocynin and placebo treatment was 1.3 DD + /- 0.42 ( p = .02 ) . O(3)-induced Delta MFEV(1 ) was 11.9 + /- 1.5 % ( p = .008 ) during placebo inhalation and 3.85 + /- 1.8 % during apocynin ( p = .47 ) . Apocynin reduced the Delta MFEV(1 ) by 8.05 % compared to placebo ( p = .025 ) . We conclude that apocynin markedly reduced O(3)-induced hyperreactivity for Mch as well as maximal airway narrowing . The results suggest that apocynin may have a role in preventing ozone-induced exacerbations of asthma [16756149] UNLABELLED The aim of study was to analyze the effect of treatment with inhaled corticosteroids and long acting beta2-agonists on antioxidative-prooxidative balance in children with asthma . MATERIAL S AND METHODS Twenty children with newly diagnosed asthma before treatment ( group 1 ) , fourteen children with diagnosed asthma treated with inhaled corticosteroids and long acting beta2-agonists and 57 healthy children were ioncluded in the study . In all cases plasma protein carbonyls and activity of erythrocyte SOD was assayed . RESULTS Plasma protein carbonyls in both group I ( 1,01 nmol/g of protein , SD=0,30 ) and group II ( 0,94 ; SD=0,15 ) was significantly higher than in group III ( 0,85 ; SD=0,24 ) ( I vs III p<0,033 ; II vs III p<0,031 ) . The highest SOD activity was found in group II ( 3156,4 U/gHb ; SD=976,1 ) ( II vs I p<0,02 ; II vs III p<0,0001 ) . SOD activity n group I ( 2435,8 , SD=730,2 ) was higher than in group III ( 1533,1 , SD=703,8 ) ( p<0,0001 ) . CONCLUSIONS The increase in SOD activity in children with asthma seems to be a response to intensification of oxidative stress . Treatment of asthma with inhaled corticosteroids and long acting beta2-agonists augments antioxidative defense by increase in superoxide dismutase activity [9032803] We investigated the effect of theophylline administration on circulating vitamin levels in children with asthma . Twenty-three asthmatic children , ranging in age from 7 to 15 with a mean of 10.8 years and including 16 patients who were treated with slow-release theophylline and 7 patients not receiving any type of theophylline preparation , were enrolled in this study . They all were in patients who had been hospitalized for the control of asthma . Steady-state serum theophylline and vitamin A , B1 , B2 , B6 , B12 and C levels were evaluated in these patients . Circulating vitamin B1 and B6 levels were depressed in asthmatic children treated with theophylline compared to those not receiving the agent ( 38.4 + /- 1.6 ( mean + /- SEM ) vs. 46.4 + /- 3.5 ng/ml and 7.1 + /- 0.5 vs. 11.8 + /- 2.1 ng/ml , respectively , p < 0.05 ) . A significant negative correlation between theophylline and circulating levels of vitamin B6 was demonstrated in the subjects of this study ( rs = -0.657 , p < 0.001 ) . In contrast , no relationship was noted between theophylline and circulating vitamin B1 levels . Theophylline did not affect circulating vitamin A , B2 , B12 or C levels . We conclude that theophylline induces depression of circulating vitamin B1 and B6 levels in asthmatic children , although a dose-dependent interaction between theophylline and vitamin B1 would be unlikely Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Leukotriene-receptor antagonists ( LTRAs ) are recommended as an alternative treatment in patients with mild asthma , but their effect compared with placebo is unclear . PURPOSE To determine the benefits and harms of LTRAs as monotherapy or in combination with inhaled corticosteroids compared with placebo in adults and adolescents with asthma . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

22513932

[17987229] INTRODUCTION Children in Singapore receive vaccination against hepatitis B virus ( HBV ) at 0 , 1 and 5 or 6 months of age , and vaccination against pertussis , diphtheria , tetanus , and polio at 3 , 4 and 5 months of age . Parents often choose to vaccinate with the combined acellular-pertussis-inactivated polio-Hib vaccine ( DTPa-IPV/Hib ) . We investigated whether a combined hexavalent vaccine , DTPa-HBV-IPV/Hib , could replace the separate administration of DTPa-IPV/Hib and HBV for the final vaccination at 5 months of age ( Trial DTPa-HBV-IPV-075 ) . MATERIAL S AND METHODS In an open study , 150 children were r and omised to complete their vaccination schedule with DTPa-IPV/Hib + HBV or DTPa-HBV-IPV/Hib . RESULTS One month after the final vaccination , there was no difference between groups in seroprotection rates or antibody concentrations against HBV . Seroprotection rates against diphtheria , tetanus , Hib and polio , as well as vaccine response rates to pertussis antigens were also similar between groups . Local and general symptoms occurred at a similar rate after the third dose of either vaccine . CONCLUSION The immunogenicity and reactogenicity of the hexavalent vaccine DTPa-HBV-IPV/Hib ( Infanrix hexa , GSK ) group is comparable to that of separately administered DTPa-IPV/Hib and HBV vaccines . Combined hexavalent vaccine , DTPa-HBV-IPV/Hib , could replace the separate administration of DTPa-IPV/Hib and HBV for vaccination at 5 months of age , thereby reducing the number of injections required [21372751] Background and Aims : Assessment of a new , fully liquid , investigational hexavalent DTaP-IPV-Hep B-PRP-T vaccine ( Hexaxim , Sanofi Pasteur ) , containing the same active ingredients as Pentaxim ( DTaP-IPV//PRT-T ) and 10 & mgr;g Hansenula polymorpha-derived recombinant hepatitis B ( Hep B ) surface antigen , Sanofi Pasteur , in Argentinean infants . Methods : Infants born to Hep B surface antigen seronegative mothers were r and omized to receive the DTaP-IPV-Hep B-PRP-T vaccine or Pentaxim and Engerix B Pediatrico ( Hep B monovalent ) vaccines at 2 , 4 , 6 months of age . Antibody titers were measured before and 1 month after 3-month primary vaccination . Noninferiority analyses were performed on seroprotection/seroconversion rates . Safety was evaluated descriptively up to 1 month after primary vaccination . Results : A total of 624 participants were enrolled , 312 participants were r and omized to each group , and 604 participants completed the trial . The DTaP-IPV-Hep B-PRP-T vaccine was demonstrated as noninferior to the Pentaxim and Hep B monovalent vaccines with seroprotection/seroconversion rates 1 month postdose 3 for each valence . The anti-Hep B geometric mean titer 1-month postdose 3 for the investigational DTaP-IPV-Hep B-PRP-T primary series was similar to the monovalent Hep B control . The overall incidence of adverse events was similar among the 2 groups . Conclusions : The new , fully liquid , investigational DTaP-IPV-Hep B-PRP-T vaccine ( Hexaxim ) is highly immunogenic and safe when compared with licensed comparators , warranting further development [10479180] Antibody avidity to Haemophilus influenzae type b ( Hib ) polysaccharide ( PS ) was assessed in infants vaccinated with diphtheria-tetanus-acellular pertussis ( DTaP ) combined with Hib-PS conjugated to tetanus toxoid ( PRP-T ) and hepatitis B ( HB ) ( DTaP-PRP-T-HB ) and after a PRP-conjugate ( CRM197-OS ) booster 3 - 7 months later . Avidity differed between infants with anti-Hib-PS IgG antibody < 1 or > 1 microg/mL post primary series ( avidity index [ AI ] , 42 % , 95 % confidence interval [ CI ] , 35%-49 % , and 68 % and 63%-72 % , respectively ; P<.0001 ) . For infants with < 1 microgram/mL anti-Hib-PS IgG antibody , mean AI rose by the time of preboost immunization to 61 % ( 95 % CI , 57%-65 % ) , even though total IgG antibody levels fell . Spontaneous Hib-PS antibody rises after primary series DTaP-PRP-T-HB vaccination were followed by high postboost anti-Hib-PS IgG antibody levels and avidity . The DTaP-PRP-T-HB combination vaccine studied elicits high avidity antibody , and affinity maturation appears to occur in the absence of further antigen exposure even in those with very low anti-Hib-PS antibody [17532669] Abstract Objectives : The aim of this open , r and omised , multicentre trial was to evaluate the immunogenicity and reactogenicity of the tetravalent diphtheria-tetanus-acellular pertussis-hepatitis B ( DTaP-HBV ) vaccine when given either as a mixed or as a separate concomitant injection with the Haemophilus influenzae type b ( Hib ) vaccine at 3 , 5 and 11 months of age . Methods : Antibody against diphtheria , tetanus , pertussis ( ELISA ) , hepatitis B ( radioimmunoassay ) and Hib polyribosylribitol phosphate ( PRP ) [ radiolabeled antigen binding assay ] was determined . Solicited local and systemic adverse events were evaluated on the day of each vaccination and for three subsequent days . Follow-up of unsolicited and serious adverse events was conducted for 30 days following each vaccination . Results : A total of 360 subjects were enrolled in the study . After completion of the three-dose vaccination course , seroprotective antibody concentrations against diphtheria , tetanus and hepatitis B , together with a pertussis vaccine response , were seen in almost all subjects with immunogenicity results ( n = 336 ) . All subjects had post-vaccination Hib anti-PRP antibody concentrations of at least 0.15 μg/mL , and 97.0 % and 99.4 % , respectively , of the subjects receiving a single or separate injections had Hib anti-PRP antibody concentrations ≥1.0 μg/mL. Addition of the Hib vaccine to the tetravalent DTaP-HBV vaccine did not increase the incidence of local or systemic reactions . Conclusions : Combination of DTaP-HBV and Hib vaccines in a single injection is safe , immunogenic and well tolerated , and thus has the potential to simplify the childhood immunisation schedule in Italy [11732460] OBJECTIVES To evaluate the immunogenicity and reactogenicity of a pentavalent vaccine prepared by extemporaneously mixing diphtheria-tetanus pertussis-hepatitis B vaccine ( DTP-HBV ) and lyophilised Haemophilus influenzae type B (Hib)-tetanus conjugate vaccines in the same syringe , compared with the same vaccines given as separate , concomitant administrations . DESIGN Open , r and omised comparative study . SETTING Durban , South Africa . SUBJECTS A total of 120 healthy male and female infants were enrolled in the trial and r and omised into two groups ; group 1 received the combined administration ( DTP-HBV-Hib ) , and group 2 received separate administrations of DTP-HBV and Hib vaccines . Vaccines were given as a three-dose primary vaccination course at 2 , 4 and 6 months [ corrected ] of age . OUTCOME MEASURES Antibody levels were measured using st and ard techniques and local and general solicited symptoms were recorded using diary cards . RESULTS All subjects had seroprotective titres against diphtheria and tetanus ; and antipolyribose-ribitol phosphate ( PRP ) titres > or = 0.15 microgram/ml 1 month after the final dose . A vaccine response ( defined as post-vaccination titres > or = 15 ELISA (EL).U/ml in initially seronegative subjects ; and as post-vaccination titres > or = pre-vaccination titres in initially seropositive subjects ) against the pertussis component was seen in 83 % and 85 % of subjects in the groups receiving combined and separate administration . No differences were seen in any of the geometric mean titres ( GMTs ) between the two administrations either 2 months after the second dose or 1 month after the final dose . There was no observed increase in reactogenicity in the group receiving the mixed administration . CONCLUSIONS The results demonstrate that combined DTP-HBV-Hib vaccine is well tolerated and immunogenic [21093342] OBJECTIVES In this open-label , non-r and omized phase II study , the safety and immunogenicity of a fully liquid diphtheria-tetanus-whole cell pertussis-hepatitis B-Haemophilus influenzae type b ( DTPw-HepB-Hib ) combination vaccine ( Quinvaxem ( ® ) ) were assessed in infants who had or had not received a birth dose of hepatitis B ( HepB ) vaccine . STUDY DESIGN Two groups of infants , ' HepB at birth ' ( n=110 ) and ' no HepB at birth ' ( n=108 ) , were enrolled and received a primary vaccination course using a 2 - 4 - 6 months schedule . RESULTS Seroprotection/seroconversion rates of > 95 % were achieved against all antigens included in the combination vaccine for both study groups . Although significantly higher anti-hepatitis B virus ( p<0.001 ) and anti-tetanus ( p=0.031 ) antibody titers were achieved in group ' HepB at birth ' when compared with group ' no HepB at birth ' , the proportion of ' no HepB at birth ' subjects achieving protective titers was non-inferior to the proportion of subjects in group ' HepB at birth ' . The birth dose of HepB vaccine did not seem to influence the safety pattern of the DTPw-HepB-Hib combination vaccine . CONCLUSIONS The present study demonstrated that the fully liquid DTPw-HepB-Hib vaccine was safe and immunogenic when administered using a 2 - 4 - 6 months immunization schedule , regardless of whether or not infants had received a dose of HepB vaccine at birth [9007484] Abstract The lack of an adequate immune response to the major polysaccharide of the Haemophilus influenzae type b ( Hib ) capsule ( polyribosyl ribitol phosphate ) ( PRP ) in very young infants ( < 18 months ) can be overcome by conjugating PRP to a T-cell dependent carrier protein . We studied whether administration of a tetanus-PRP conjugate vaccine reconstituted with a diphtheria-tetanus-acellular pertussis-hepatitis B ( DTPa-HBV ) vaccine as a three dose primary course at 3 , 4 and 5 months of age induced PRP-specific immunological memory , by examining the anti-PRP response to a dose of unconjugated PRP given with the DTPa-HBV booster approximately 1 year later . The unconjugated PRP elicited protective anti-PRP antibody levels ( ≥ 0.15 μg/ml ) in all but 3 of the 369 vaccinees , including 13 infants who failed to demonstrate a measurable immune response after the primary course . In a sub-cohort of 54 subjects all had anti-PRP levels ≥ 0.5 μg/ml within 7–14 days of the booster showing a rapid anamnestic type response . Both primary and booster responses were predominantly IgG1 indicating a T-cell dependent response . The DTPa-HBV components elicited protective anti-diphtheria , anti-tetanus and anti-HBs antibody levels in ≥ 98.5 % of vaccinees , and immune responses to each of the acellular pertussis vaccine components in 92.3%–97.3 % of subjects . Conclusion The tetanus-PRP conjugate vaccine not only elicited a good primary humoral response , but also induced immunological memory so that the infants were able to mount a large and rapid immune response to subsequent exposure to plain PRP , indicating that protection against circulating wild-type Hib had been generated . Successful induction of immunological memory occurred even when there was no measurable humoral anti-PRP response to the primary course . Tetanus-PRP conjugate vaccine can be used in combination with DTPa-HBV vaccine , when administered separately or as a single injection in the same syringe , in primary immunisation schedules at 3 , 4 and 5 months of age [16640847] OBJECTIVES In 1998 the World Health Organization ( WHO ) recommended the inclusion of Haemophilus influenza type B ( Hib ) conjugate vaccines in infant immunization programs , whenever in accordance with national priorities . GlaxoSmithKline Biologicals has developed a new pentavalent combined diphtheria-tetanus-whole cell pertussis-hepatitis B/Hib ( DTPw-HB/Hib ) vaccine containing 5 microg of polyribosylribitol phosphate ( PRP ) , and we assessed the immunogenicity and reactogenicity of primary and booster vaccination of healthy children with this new vaccine compared with a reference regimen consisting of the licensed DTPw-HB ( Tritanrix ) and Hib ( Hiberix ) vaccines given as simultaneous concomitant injections . METHODS We performed a r and omized , double-blind study from September 1998 to August 1999 to establish the immunogenicity and reactogenicity of primary and booster vaccination of healthy children with the new pentavalent combined DTPw-HB/Hib vaccine given as a single injection , compared with the reference regimen . RESULTS Both vaccination regimens elicited excellent immune responses , with all subjects in both groups achieving seroprotective anti-PRP antibody concentrations of > or = 0.15 microg/mL one month after primary vaccination . The combined DTPw-HB/Hib vaccine was non-inferior to the licensed vaccines in terms of seroprotection/seropositivity/vaccine response rates for all antigen components . Persistence of antibodies against all study vaccine antigens up to the time of booster vaccination was comparable between groups , and a marked increase of all antibody concentrations was observed after the booster dose . Both vaccine regimens were similar in terms of their overall reactogenicity profiles . CONCLUSIONS Our results indicate that the new DTPw-HB/Hib pentavalent combination vaccine provides an efficient and reliable way of implementing WHO recommendations for controlling hepatitis B and Hib infections on a worldwide basis [17012882] A DTaP-IPV//PRP-T combination vaccine ( Pentacel ™ ) has been universally used in Canada to provide immunization against diphtheria , tetanus , pertussis , polio , and Haemophilus influenzae type b with single injections at 2 , 4 , 6 , and 18 months of age . This r and omized , multicenter study was conducted to evaluate administration of a fourth dose of DTaP-IPV//PRP-T at 15 to 18 months of age , similar to the US immunization schedule . Participants who had received three doses of DTaP-IPV//PRP-T by 8 months of age were enrolled at 12 months and r and omized to receive a fourth dose at 15 , 16 , 17 , or 18 months . Antibody levels for each vaccine antigen were measured prior to and 4 weeks following booster vaccination . Overall , 1782 subjects were immunized and monitored for adverse events , and 735 were evaluated for immune responses . Pre-immunization antibody levels differed minimally by age , for all antigens . The immune responses elicited by DTaP-IPV//PRP-T were comparable between participants vaccinated at 15 or 16 months and those vaccinated at 17 or 18 months , as demonstrated by specific antibody geometric mean titers , seroprotection/seroresponse rates , and reverse cumulative distribution curves . The fourth dose was well tolerated in all age groups . Toddlers at 15 , 16 , 17 , or 18 months of age are equally suitable recipients for booster immunization with the DTaP-IPV//PRP-T vaccine [15602195] Background : Recently an increase in the number of invasive Haemophilus influenzae type b ( Hib ) cases was observed in the United Kingdom , which coincided with a temporary change from diphtheria-tetanus toxoids-wild-type pertussis to diphtheria-tetanus toxoids-acellular pertussis ( DTaP ) Hib vaccines . A study in Germany based on approximately 2 years of follow-up , estimated vaccine effectiveness ( VE ) of DTaP/Hib and DTaP-inactivated poliovirus/Hib combination vaccines against invasive Hib disease to be high . Objectives : To assess VE of DTaP-containing Hib vaccines against Hib in Germany with the use of extended follow-up of case surveillance and vaccine uptake . Subjects and Methods : Cases with confirmed systemic Hib infections in children born between June 1 , 1996 and December 31 , 1998 were ascertained by a nationwide active surveillance system from January 1998 through June 2002 . A representative subcohort of 667 children born in the same time frame was r and omly sample d in a nationwide vaccine coverage survey . VE was determined with a case-cohort approach of Cox regression with time-dependent covariates . Results : Thirty-six cases of Hib disease were reported . Of these , 10 were vaccinated with DTaP-containing Hib vaccines only and 20 were not vaccinated . Of the 10 vaccinated cases , 4 had received an incomplete primary series ( 1–2 doses ) , and 6 had received the full primary series ( 3 doses ) , 3 of whom also received the booster dose . VE of combination vaccines against invasive Hib infection was 89.6 % [ 95 % confidence interval ( CI ) , 67.0–96.7 ] for an incomplete primary series , 96.7 % ( 95 % CI 87.7–99.1 ) for a full primary series and 98.5 % ( 95 % CI 94.5–99.6 ) for a booster dose ( irrespective of priming ) . Conclusion : Hib combination vaccines containing acellular pertussis antigens continue to be highly effective in Germany [15665713] Background : The 7-valent pneumococcal ( 7vPn ) conjugate vaccine is licensed for primary and booster vaccination according to the same immunization schedules as routinely recommended diphtheria-tetanus-pertussis-based childhood vaccines and can be coadministered during the same vaccination visit . Methods : An open , r and omized study evaluated the immunogenicity and safety of a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio virus-Haemophilus influenzae type b ( DTPa-HBV-IPV/Hib ) vaccine and a 7vPn conjugate vaccine when coadministered at 2 , 3 and 4 months and 12–23 months of age , compared with the administration of the hexavalent DTPa-HBV-IPV/Hib vaccine given alone . Serum antibody titers were measured before and 1 month after the primary course and before and 1 month after the booster dose . Solicited local and general adverse events were recorded for 4 days and unsolicited adverse events were recorded for 30 days after each vaccine dose . Results : A total of 345 subjects were enrolled for primary vaccination with the hexavalent vaccine ( 170 without and 175 with the 7vPn vaccine coadministered ) and 266 returned for booster vaccination ( 122 without and 144 with coadministration of the 7vPn vaccine ) . After primary vaccination , antibody responses against the common antigens were similar in both groups , with seroprotection rates of 93.6–100 % and with similar antibody decay before booster vaccination . The fourth dose induced a vigorous booster response , with seroprotection/vaccine response rates of 96.8–100 % . Response to the 7vPn primary and booster vaccination was within previously reported ranges . Differences in reactogenicity result ed from higher incidences of symptoms after concomitant vaccination . Rectal temperature > 39.5 ° C was observed after 1.2 % of the coadministered vaccine doses during primary vaccination and after 2.8 % of the booster vaccine doses . Conclusion : Coadministration of the DTPa-HBV-IPV/Hib and 7vPn vaccines at separate injection sites during the same vaccination visit was effective and safe [11257348] Combination vaccines are essential to enable administration of all the required antigens in routine infant immunisation schedules at any single visit . Some combinations of diphtheria-tetanus-acellular pertussis ( DTPa ) with Haemophilus influenzae type b ( Hib ) conjugate vaccines have been shown to result in lower Hib titres than when Hib is administered separately . While confirming that a primary series with a DTPa-HBV-IPV/Hib combination gives lower antibody levels than separate Hib conjugates , we show that the nature ( isotype and IgG subclasses ) and function ( avidity and opsonic activity ) of the antibodies are the same , and immunologic memory is induced . It is likely therefore that the DTPa-HBV-IPV/Hib combination will be efficacious against Hib disease [12424582] Abstract . In an open r and omised trial , 312 eligible infants were enrolled to receive either a single injection of the hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B virus-inactivated polio/Haemophilus influenzae b ( DTPa-HBV-IPV/Hib ) vaccine , or concomitant injections of commercial DTPa-IPV/Hib and HBV vaccines ( comparator ) . Vaccines were administered at 3 , 5 and 11 months of age . The statistical approach for non-inferiority showed that the DTPa-HBV-IPV/Hib vaccine was at least as immunogenic as the comparator vaccines in terms of immunogenicity of all antigens 1 month after the 2nd dose . Non-inferiority criteria were also met immediately before and 1 month after the 3rd dose for all antigens except poliovirus type 3 prior to the 3rd dose . The majority of subjects were seroprotected against diphtheria , tetanus , polyribosyl-ribitol-phosphate , hepatitis B and poliovirus after the 2nd dose and maintained seroprotective antibody levels until the 3rd dose . A marked difference was observed in anti-HBs antibody geometric mean antibody concentrations ( GMCs ) at 1 month after the 2nd dose ( higher GMCs in DTPa-HBV-IPV/Hib group ) . Reactogenicity ( incidence of solicited local and general symptoms ) was similar between the two study groups and no vaccine-related serious adverse events occurred . Conclusion : the new diphtheria-tetanus-acellular pertussis-hepatitis B virus-inactivated polio/Haemophilus influenzae b vaccine administered at 3 , 5 and 11 months of age was safe and at least as immunogenic as the comparator vaccines thus providing an effective and more comfortable option for this infant vaccination schedule [11228385] We evaluated the immunogenicity and reactogenicity of a new liquid pentavalent combination vaccine , which incorporates a diphtheria , tetanus and whole-cell pertussis vaccine ( DTP ) with Hib ( PRP-OMPC ) and hepatitis B vaccine ( HB ) , in a series of three studies involving 2156 infants . The vaccination schedule was 2 , 4 , 6 and 18 months for all studies . In addition , subjects in the third study also received a dose of monovalent hepatitis B vaccine at birth . The principal study was a r and omised double blind trial of two separate , but concurrently administered vaccines in each of three groups : pentavalent vaccine [ DTP-Hib-HB ] plus placebo ( Group A , n=619 ) ; quadrivalent vaccine [ DTP-HB ] plus Hib vaccine ( Group B , n=620 ) ; and bivalent vaccine [ Hib-HB ] plus DTP ( Group C , n=226 ) . The second study ( Group D , n=231 ) was an open trial of three separate , but concurrently administered licensed control vaccines ( DTP , Hib and HB ) . The third study ( Group E , n=460 ) administered a dose of monovalent hepatitis B vaccine at birth followed by pentavalent vaccine as for Group A. Subjects were bled prior to the 2- and 18-month vaccinations , and a month after the 6- and 18-month vaccinations . A diary card was used to record subject temperatures and other systemic and local clinical signs for 7 days after each vaccination . The pentavalent vaccine , whether or not preceded by a birth dose of hepatitis B vaccine , was generally well tolerated at all administration times , and had a reactogenicity profile similar to that observed for licensed vaccine controls . Diphtheria and tetanus antibody levels were substantially above protective levels in all study groups . The anti-HBs responses ( % > or = 10 mIU/ml ) following the 6-month dose of vaccines were , respectively , for Groups A-E : 83.2 , 91.7 , 96.5 , 98.8 and 93.9 % , and following the 18-month doses : 87.9 , 97.5 , 98.8 , 98.8 and 92.8 % . Anti-PRP responses ( % > or = 1.0 microg/ml ) following the 6-month dose for Groups A-D were 86.0 , 90.5 , 91.2 , and 74.4 % , and after the 18-month dose for Groups A-E were 97.3 , 98.3 , 98.1 , 97.0 , and 99.5 % . Consistently higher geometric mean titres ( GMTs ) for pertussis antibodies to agglutinogens ( Agg2 , Agg3 ) and pertactin were recorded for the pentavalent vaccine compared to the licensed control vaccine , though they were somewhat lower for pertussigen ( PT ) . Except for the hepatitis B response , antibody responses induced by the pentavalent vaccine to all antigens with a schedule commencing at 2 months of age and completed at 18 months were equivalent to responses to the same antigens induced by the separate , but concurrently administered licensed control vaccines . A regimen of a birth dose of hepatitis B vaccine followed by pentavalent vaccine at 2 , 4 , 6 and 18 months was not countered by any clinical ly significant decrease in seroresponses [17961876] This paper presents the results of four separate phase III trials , which assessed the immunogenicity and reactogenicity of DTPw-HBV/Hib 2.5 in comparison with licensed Tritanrix-Hep B ( GlaxoSmithKline Biologicals ) and Hiberix ( 10 microg PRP ) , given as separate or mixed injections ( 3 trials ) or with or without hepatitis B vaccine at birth ( 1 trial ) . The immunogenicity of DTPw-HBV/Hib 2.5 was non-inferior to the reference vaccine regimen in terms of seropositivity rates . The overall reactogenicity profile of DTPw-HBV/Hib 2.5 was also similar to that of the reference vaccine regimen . These results confirm the previously established immunogenicity and safety of reduced dose PRP conjugated vaccine regimens [18690013] The use of combination vaccines in the routine childhood program reduces distress to the recipients and is likely to improve uptake rates and timeliness of vaccination but requires careful evaluation and surveillance . The aim of this study was to evaluate the immunogenicity and reactogenicity of two commercial diphtheria-tetanus- acellular pertussis-hepatitis b-inactivated polio virus-Haemophilus influenzae type b ( DTaP-HBV-IPV/Hib ) combination vaccines when administered to infants at 3 , 5 and 11 - 12 months of age A total of 494 infants were r and omized to receive three doses of either Infanrix hexa ™ ( GlaxoSmithKline Biologicals ; N=246 ) or Hexavac ™ ( Sanofi Pasteur MSD ; N=248 ) in 10 centers in Italy , Finl and and Sweden . After the third dose , antibodies to diphtheria , tetanus , polio and Hib were at the protective level in nearly all infants in both groups whereas the proportion of subjects who had achieved the protective concentration of ≥10 mIU/ml to hepatitis B surface antigen was 99.1 % ( 95 % CI 96.7 - 99.9 ) in the Infanrix hexa ™ group as compared to 94.4 % ( 95 % CI 90.4 - 97.1 ) in the Hexavac ™ group . Antibody titers to all three polio antigens were highest in Italy and lowest in Finl and . Clinical ly relevant general reactions ( such as fever of > 39.5 ° C ) were mostly reported in less than 5 % of the vaccinees . Three doses of DTaP-HBV-IPV/Hib combination vaccines produced sufficient immune responses in nearly all vaccinees [10333123] Abstract The immunogenic responses and local reactions to four Haemophilus influenzae type b ( Hib ) conjugate vaccines licensed for primary immunisation ( Hiberix , ActHib , Pedvax , HibTITER ) when administered concomitantly but in the opposite thigh with a c and i date diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus vaccine were studied in 549 healthy infants at 3 , 4.5 and 6 months of age . Local reactions were mild , but different between the four groups , a tetanus conjugate Hib vaccine showing the fewest reactions . All local reactions resolved without sequelae . There was no apparent general reaction . The immunogenic response was similar with all four vaccines , geometric mean concentrations ranging from 4.95 to 7.2 μg/ml . All but one subject had anti-polyribosylribitol phosphate polysaccharide antibody titres ≥0.15 μg/ml , and 88.0 % to 96 % achieved high titres ( > 1.0 μg/ml ) generally associated with long-term protection against Hib disease . Conclusion There does not appear to be any interference with the immune response when current commercial Haemophilus influenzae type b conjugate vaccines are concomitantly administered with a c and i date diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio virus vaccine as separate injections [15665717] The effect of pertussis toxoid on the immunogenicity of diphtheria and tetanus toxoids ( DT ) was studied during a double blind efficacy trial of an acellular pertussis vaccine . Infants received DT with or without pertussis toxoid at 3 , 5 and 12 months of age . Geometric mean concentrations were higher in the DT than in the DT-pertussis toxoid group 1 month ( diphtheria toxoid 4.76 versus 3.58 IU/mL , P = 0.009 ; tetanus toxoid 4.42 versus 2.66 IU/mL , P < 0.0001 ) and 2 years after the third injection ( diphtheria toxoid 0.15 versus 0.10 IU/mL , P < 0.0001 ; tetanus toxoid 0.38 versus 0.18 IU/mL , P < 0.0001 ) . Pertussis toxoid causes a small but significant reduction of the immunogenicity of diphtheria toxoid and tetanus toxoid [10969252] OBJECTIVE The aim of this open , multicenter , r and omized trial was to evaluate the immunogenicity and reactogenicity of a c and i date combined diphtheria-tetanus-acellular pertussis-hepatitis B virus-inactivated polio virus ( DTaP-HBV-IPV ) vaccine when given as either a mixed or as separate concomitant injections with Haemophilus influenzae type b ( Hib ) vaccine . STUDY DESIGN A total of 359 subjects were r and omized to receive either DTaP-HBV-IPV/Hib ( mixed administration - 180 subjects ) or DTaP-HBV-IPV + Hib ( separate administration in opposite limbs - 179 subjects ) at 2 , 3 , and 4 months of age . RESULTS After vaccination , seroprotective antibody concentrations against diphtheria , tetanus , hepatitis B , and polio viruses and a high ( > or = 97 % ) pertussis vaccine response were seen in almost all study participants . All subjects except one in the mixed administration group had postvaccination Hib anti-PRP antibody concentrations > or = 0.15 microg/mL. Of subjects in the mixed and separate group , 77.2 % ( geometric mean antibody concentration , 2 . 62 microg/mL ) and 88.6 % ( geometric mean antibody concentration , 4.45 microg/mL ) had Hib anti-PRP concentrations > or = 1 microg/mL , respectively . The addition of the Hib component to the 5-component vaccine did not increase the incidence of local or general reactions . CONCLUSION Both administrations of the c and i date vaccine were found to be safe , immunogenic , and well tolerated . Although anti-PRP geometric mean antibody concentrations and the percent of subjects achieving the 1 microg/mL seroprotective level were lower after the mixed administration , they were in the range seen with monovalent Hib vaccines or with other DTaP-based/Hib combinations licensed in some European countries . Therefore both administrations have the potential to simplify childhood immunization [9431382] We compared antibody levels following separate but simultaneous administration of diphtheria and tetanus toxoids with acellular pertussis vaccine ( DTaP ) containing pertussis toxoid , filamentous hemagglutinin , and pertactin ( PRN ) ; hepatitis B vaccine ; and Haemophilus influenzae type b polysaccharide ( polyribosylribitol phosphate ; PRP ) vaccine conjugated to tetanus toxoid ( PRP-T ) with those following administration of a combination of a DTaP-hepatitis B vaccine-PRP-T to infants at 2 , 4 , and 6 months of age . The antibody response to a booster dose of PRP conjugate vaccine ( CRM197-OS ) in infants with low ( < 1 microgram/mL ) or undetectable ( < 0.10 microgram/mL ) postpriming levels of antibody to PRP was also studied . Antibody levels were quantitated before and after dose 3 by enzyme-linked immunosorbent assay , radioimmunoassay , or neutralization assay . Seroresponse rates were not different between the two vaccine groups except for rates of response to PRP . There was a trend that levels of antibody to all the antigens included in the combination vaccine were lower than those of antibody to antigens in separate vaccines ; for levels of antibody to diphtheria toxoid ( P = .001 ) , PRN ( P < .0001 ) , and PRP ( P < .0001 ) , the differences were significant . Despite low or undetectable postpriming levels of antibody to PRP , high-titered ( geometric mean concentration , 9.02 micrograms/mL ; range , 1.0 - 81.5 micrograms/mL ) , immunoglobulin G-predominant antibody to PRP was produced following a booster dose of CRM197-OS , a finding consistent with a memory response [12431356] OBJECTIVE The DTPw-HB/Hib pentavalent combination vaccine has been developed following recommendations of the World Health Organization for the introduction of hepatitis B ( HB ) and Haemophilus influenzae type b ( Hib ) vaccines into routine childhood vaccination programs . The objectives of this study were to : 1 ) analyze the immunogenicity and the reactogenicity of the DTPw-HB/Hib pentavalent combination vaccine in comparison to separate injections of DTPw-HB and Hib vaccines as primary vaccination in a group of children who had received a dose of HB vaccine at birth and 2 ) in the second year of life to assess the antibody persistence as well as the response to a DTPw-HB/Hib or DTPw/Hib booster . METHODS In the first part of the study ( primary -vaccination stage ) , conducted in 1998 - 1999 , we analyzed the immunogenicity and reactogenicity of the DTPw-HB/Hib combination vaccine in comparison to separate injections of DTPw-HB and Hib vaccines as primary vaccination at 2 , 4 , and 6 months of age in 207 Costa Rican children who had received a dose of HB vaccine at birth . Later , in the booster-vaccination stage of the study , in 1999 - 2000 , in a subset of the children ( 69 toddlers , now 15 - 18 months old ) , antibody persistence was measured , and response to a DTPw-HB/Hib or DTPw/Hib booster was also assessed . RESULTS In both primary -vaccination groups , at least 97.5 % of the infants reached protective levels of antibodies ( seropositivity ) against the antigens employed in the vaccines . The DTPw-HB/Hib pentavalent combination vaccine did not result in more local reactions than did the DTPw-HB vaccine alone , and , in terms of general reactions , there was no clinical ly significant difference between the combination or separate injections , and with the pentavalent vaccine having the benefit of needing one less injection . Nine months after the third dose of the primary -vaccination course , antibody persistence was similar in both groups , with over 93 % of children still having protective/seropositive titers for Hib , HB , and tetanus and about 50 % for diphtheria and Bordetella pertussis . At 15 months of age , virtually all the toddlers responded with a strong boost response to all the vaccine antigens , whether they received the DTPw-HB/Hib pentavalent vaccine or the DTPw/Hib vaccine as a booster . Both booster regimens were equally well tolerated , indicating that up to five doses of the HB vaccine can be given without impact on safety . CONCLUSIONS Our study confirms that the DTPw-HB/Hib pentavalent vaccine is highly immunogenic as a primary vaccination in children who received an HB vaccine at birth , with the pentavalent combination inducing both persisting immunity and boostable memory . The pentavalent vaccine was safe both for primary and booster vaccinations . Thus , this study in Costa Rican infants supports the routine use of the pentavalent DTPw-HB/Hib vaccine as part of childhood vaccination programs in Latin America and the Caribbean [11144370] Objective . The immunogenicity and safety of a new liquid hexavalent vaccine ( diphtheria-tetanus-acellular pertussis-inactivated polio vaccine-hepatitis B-polyribosyl ribitol phosphate conjugated to tetanus protein ; Hexavac ; Aventis Pasteur MSD , Lyon , France ) are compared with those of reference vaccines [ diphtheria-tetanus-acellular pertussis-inactivated polio vaccine reconstituting lyophilized purified Haemophilus influenzae polysaccharide conjugated to tetanus protein vaccine ( Pentavac ; Aventis Pasteur MSD ) and hepatitis B vaccine ( H-B-Vax II ; Aventis Pasteur MSD ) ] injected separately at the same visit in a prospect i ve multicenter , comparative , open label trial . Methods . Infants were r and omized to receive Hexavac ( n = 423 ) or Pentavac and H-B-Vax II ( n = 425 ) as a primary immunization series at 2 , 4 and 6 months of age . Seroprotection and seroconversion rates against all antigens at 1 month after the primary series were compared between the two vaccine groups with 95 % confidence intervals ( CI0.95 ) and were considered clinical ly equivalent ( not inferior ) when the upper limit of the 95 % confidence interval on the difference ( reference , hexavalent ) was below predefined differences . Results . Hexavac met and surpassed the predefined criteria for clinical equivalence to Pentavac and H-B-Vax II given concomitantly . It elicited similar seroprotection and seroconversion rates against all antigens . Seroprotection and seroconversion rates obtained 1 month after the third dose of Hexavac were > 90 % for all antigens . The postimmunization antibody geometric mean titers ( GMT ) for hepatitis B and purified Haemophilus influenzae polysaccharide were about 2-fold higher in infants who received the reference vaccines than in infants who had received Hexavac . GMTs for poliovirus antibodies tended to be enhanced in infants vaccinated with Hexavac . GMTs for all other antigens were very similar among both groups . Hexavac was generally well-tolerated . At least one local reaction was reported in 20.3 % of Hexavac injections compared with 15.8 % at the Pentavac injections site and 3.8 % at the H-B-Vax II injections site . These reactions were generally mild and transient . At least one systemic adverse event was reported in 45.7 % of Hexavac injections compared with 42.2 % of Pentavac and H-B-Vax II injections ( mild fever , irritability and drowsiness were most frequently reported ) . The frequency of adverse events was not significantly different between groups . No vaccine-related serious adverse event occurred during the study . Conclusion . This liquid hexavalent vaccine was generally well-tolerated and provided immune responses adequate to be protective against six infectious diseases with a single injection , given at 2 , 4 and 6 months of age [12718838] OBJECTIVES To determine the immunogenicity and reactogenicity of a combined DTPw-HBV/Hib vaccine , in comparison with DTPw-HBV and Hib vaccines given as separate concomitant injections . METHODS In an open , r and omized study , healthy infants were injected with either DTPw-HBV/Hib vaccine or separate DTPw-HBV and Hib vaccines at 2 , 4 and 6 months of age , with a booster at 18 months . RESULTS Both vaccination regimens were immunogenic , with seropositivity rates of 100 % after the booster vaccination for all vaccine components . Even as early as 2 months after the second dose of the primary vaccination , most patients had seroprotective antibody titers , the proportion of seropositive subjects approaching 100 % for tetanus , hepatitis B , and Hib . Post- primary and post-booster geometric mean titers ( GMTs ) were well above seroprotective thresholds for each vaccine antigen in both groups , with no clinical ly relevant differences in the groups . The separate and combined administrations showed comparable reactogenicity profiles , and neither showed a significant increase in reactogenicity with successive doses . CONCLUSIONS The results of this study support the combination of Hib and DTPw-HBV vaccination in routine infant immunization at 2 , 4 and 6 months of age with a booster at 18 months . Maximum benefit is obtained from compliance with the full course , but substantial benefit is likely to be achieved even in partially compliant patients , provided they receive at least two doses . Furthermore , these results demonstrate the tolerability of a fourth ( booster ) administration , where the addition of the Hib vaccine to DTPw-HBV did not lead to an increase in the overall reactogenicity [11457553] An open , r and omised , multicentre trial was performed to assess the reactogenicity and safety profile of the administration of a c and i date Haemophilus influenzae type b ( Hib ) conjugate vaccine with a quadrivalent diphtheria-tetanus-acellular pertussis-hepatitis B ( DTPa-HBV ) vaccine as a single injection ( Group 1 ) versus the simultaneous administration of the latter vaccine ( DTPa-HBV ) and an available Hib conjugate vaccine ( Group 2 ) in opposite thighs , as a primary vaccination course to healthy infants at 2 , 4 and 6 months of age . Eight hundred and eighty five infants ( 9.3+/-1.4 weeks old ) were r and omly allocated to Group 1 ( n=665 ) and Group 2 ( n=221 ) . Oral polio vaccine was given concomitantly to all subjects . Blood sample s ( pre-vaccination and 1 month after the third dose ) were obtained from a subset of infants ( Group 1 , 73 ; Group 2 , 22 ) for serological determinations . Local and general symptoms were recorded by parents on diary cards . 2614 diary cards ( Group 1 , 1966 ; Group 2 , 648 ) were collected . There were no statistically significant differences in the incidence of local and general symptoms between groups . Pain such that the infant cried when limb was moved was reported in 0.6 and 0.2 % in groups 1 and 2 , respectively . Redness and swelling ( > 20 mm in diameter ) were recorded between 2.1 and 3 % in both groups . Fussiness preventing normal activities was the most frequently reported general symptom in both groups ( 1.6 and 1.9 % in groups 1 and 2 , respectively ) . Fever ( rectal temperature > 39.5 degrees C ) was reported in 0.4 % ( Group 1 ) and 0.3 % ( Group 2 ) . All subjects included in the immunogenicity analysis had seroprotective or seropositive titres to the diphtheria , tetanus , hepatitis B and pertussis components of the vaccines . About 99 and 100 % of infants had anti-PRP titres > or = 0.15 mcg/ml in groups 1 and 2 , respectively . This study indicates that DTPa-HBV vaccine given in a single injection with a c and i date Hib conjugate vaccine has a similar reactogenicity profile to that of two commercially available vaccines ( DTPa-HBV , Hib ) given in two simultaneous injections to infants 2 , 4 and 6 months of age [9569468] Safety , immunogenicity and lot consistency of five-component pertussis combination vaccine ( CPDT-IPV//PRP-T ) in infants were compared to that of whole cell pertussis combination vaccine ( DPT-IPV//PRP-T ) , as were separate and combined injections of CPDT-IPV and PRP-T. No significant differences in adverse event rates were observed between lots of CPDT-IPV//PRP-T or between separate or combined injections of CPDT-IPV and PRP-T. Minor differences in antibody responses were observed between lots of component pertussis vaccine . Higher concentrations of diphtheria and tetanus antitoxins were induced by separate than by combined injection of CPDT-IPV and PRP-T , but no other differences in immunogenicity were observed . Adverse reactions were more than twice as frequent after whole cell than after component pertussis vaccines . Antibody responses to pertussis toxoid , filamentous hemagglutin and pertactin were significantly greater after component vaccines , while the response to type 3 poliovirus was higher after whole cell vaccine . No significant differences were observed for other vaccine components . CPDT-IPV//PRP-T was safe and immunogenic in infants . Antibody results were similar to those observed in a Swedish field trial that demonstrated CPDT to be 85 % effective in preventing clinical pertussis [11803003] BACKGROUND The diphtheria-tetanus-whole-cell pertussis ( DTPw ) vaccine is being replaced in Western countries , and in several Spanish Autonomous Communities , by the diphtheria-tetanus-acellular pertussis ( DTPa ) vaccine . Although the administration of booster doses of DTPw or DTPa and Haemophilus influenzae type b conjugate ( Hib ) vaccines to toddlers is a current practice ina number of countries , there are few data comparing the reactogenicity profiles of their administration as a single injection . SUBJECTS AND METHOD An open , prospect i ve , r and omised , multicentre trial was conducted to compare the reactogenicity profile of a single injection of DTPa and Hib vaccines ( DTPa/Hib ) with that of a single injection of DTPw and Hib vaccines ( DTPw/Hib ) as booster doses to toddlers -- previously primed with DTPw and Hib vaccines . 200 children ( 15.1 + /-1.0 months-old ) were r and omised to receive DTPa/Hib ( group 1;n = 101 ) or DTPw/Hib ( group 2 ; n = 99 ) and followed up to 30 days post-vaccination . All subjects received the oral polio vaccine concomitantly . Local and general symptoms were recorded by parents on diary cards . RESULTS Incidences of any local reaction and any general symptom < < probably related>>/<<suspected>>to vaccination were reported more frequently in group 2 than in group 1 ( p < 0.0001 ) . Pain at the injection site was reported by 29 % and 66 % of subjects in groups 1 and 2 , respectively ( p < 0.0001 ) . Pain such that the child cried when limb was moved was also more frequently recorded in group 2 ( 15 % ) than in group 1 ( 1 % ) ( p < 0.0001 ) . Differences in prevalence of any swelling(16 % in group 1 , 30 % in group 2 ) and swelling > 20 mm reached statistical significance ( p ( 3/4 ) 0.012 ) . Fever ( rectal temperature>= 38 degrees C ) was reported by 17 % and 41 % in groups 1 and 2 subjects , respectively ( p < 0.0001 ) . Fussiness , loss of appetite and restlessness were also more frequently reported in DTPw/Hib subjects and reached statistical significance ( at least p = 0.015).Analgesics/antipyretics were prescribed as a prophylactic treatment in only 14 % of cases ( 9 and 19 subjects in groups 1 and 2 , respectively;p = 0.0424 ) . Antipyretic treatment after vaccination was significantly more prescribed in group 2 ( 27 cases ) than in group 1 ( 8) ( p < 0.015 ) . CONCLUSION The administration of DTPa/Hib as a single injection leads to a better reactogenicity profile than the administration of DTPw/Hib , also as a single injection , as booster doses to toddlers primed with DTPw and Hib vaccines [9796053] This double-blind , r and omised study was performed to assess the immunogenicity and reactogenicity of three lots of a quadrivalent diphtheria-tetanus-acellular pertussis-hepatitis B vaccine ( DTPa-HBV ) co-administered with three lots of Haemophilus influenzae type b conjugate ( Hib ) vaccine in one injection , as a primary vaccination course in healthy infants at 2 , 4 and 6 months of age . 269 infants ( 8 - 11 weeks of age ) were r and omly allocated to three groups to receive DTPa-HBV/Hib vaccines , concomitantly with oral polio vaccine . Blood sample s for antibody determinations were taken before vaccination and 1 month after the third dose in 262 subjects . Local and general symptoms were recorded by parents on diary cards . All vaccinees had post-vaccination protective anti-D and anti-T ( > or = 0.1 IU ml-1 ) antibodies , and 98 % had protective anti-HBs antibody titres ( > or = 10 mIU ml-1 ) . There were no statistically significant differences between groups in post-vaccination anti-D , anti-T , anti-HBs antibody geometric mean titres ( GMT ) , these being 3.49 IU ml-1 , 5.92 IU ml-1 and 1109 mIU ml-1 , respectively . All subjects responded to three pertussis components , i.e. pertussis toxin ( PT ) , filamentous haemagglutinin ( FHA ) and pertactin ( PRN ) . Although statistically significant differences in GMTs of anti-PT , anti-FHA and anti-PRN were found between groups , these were not believed to be of any clinical relevance as the minimum GMTs were 60 , 193 and 230 EL.U ml-1 for anti-PT , anti-FHA and anti-PRN , respectively . There were no statistically significant differences in anti-PRP antibody GMT ( 4.05 micrograms ml-1 ) between groups , 100 % and 85 % of subjects having titres > or = 0.15 and 1.0 microgram ml-1 , respectively . No symptoms were reported for one third of the subjects . Fever ( > 38 degrees C ) was reported after 16 % of doses , with < 1 % having > 39.5 degrees C. Almost all local and general symptoms were mild or moderate , and lasted less than 48 h. No subject dropped out due to a severe adverse reaction . The administration of an experimental mix of DTPa-HBV and Hib vaccines in a single injection is safe , well-tolerated and immunogenic for all vaccine components [17012890] We assessed the safety and immunogenicity of a fully liquid , DTPw-HepB-Hib combination vaccine ( Quinvaxem ™ ) in comparison with separately administered DTPw-Hib and hepatitis B vaccines . Infants participating in this open-label , r and omized , phase II study received a primary vaccination course using a 2 - 3 - 4 month schedule . Blood sample s were taken immediately prior to the first and one month after the third vaccination . Adverse events were assessed over a 7-day post-vaccination period using subject diaries . After completion of the primary vaccination course , 94.7 % [ 95%CI : 89.8 – 97.7 % ] of infants receiving the combination vaccine achieved protective anti-HBs antibody titers ( ? 10 mIU/mL ) with a mean 39-fold increase in GMTs in comparison with 99.3 % [ 95%CI : 96.3 – 100 % ] seroprotection and a mean 29-fold GMT increase in the comparator group . Diphtheria , tetanus , and Haemophilus influenzae type B ( Hib ) seroprotection rates and pertussis seroconversion rates were also similar between the two groups . There was no statistically significant difference in GMTs for diphtheria between the two groups , but significant differences were shown for tetanus , Hib , and pertussis with higher GMTs for each antigen observed in the comparator group . The combination vaccine was well tolerated , with fever ( body temperature 38 ° C ) being the most frequently reported adverse event in both the DTPw-HepB-Hib ( 12.5 % [ 95%CI : 7.7 – 18.8 % ] ) and comparator ( 12.6 % [ 95%CI : 7.7 – 19.0 % ] ) groups . This study demonstrated that the fully liquid DTPw-HepB-Hib combination vaccine has safety and immunogenicity profiles similar to the DTPw-Hib and hepatitis B vaccines when administered separately [21289531] Background : Assessment of primary vaccination of a new fully liquid , hexavalent investigational DTaP-IPV-Hep B-PRP-T vaccine ( Hexaxim ) in South African infants . Methods : Infants were r and omized to the following at 6 , 10 , and 14 weeks of age ( Exp and ed Program on Immunization schedule ) : DTaP-IPV-Hep B-PRP-T ( Group 1 ; N = 286 ) ; DTwP-Hib , hepatitis B , and OPV vaccines ( Group 2 ; N = 286 ) ; or DTaP-IPV-Hep B-PRP-T vaccine with hepatitis B vaccine at birth ( Group 3 ; N = 143 ) . Antibody titers were measured before vaccination ( pertussis toxoid , filamentous hemagglutinin ) and post primary vaccination ( all valences ) . Noninferiority analyses were performed for Group 1 versus Group 2 for seroprotection rates . Safety was evaluated from parental reports . Results : Noninferiority ( Group 1 minus Group 2 ) was demonstrated for anti-HBs , -PRP , -diphtheria , -tetanus , and -polio 1 , 2 , 3 ( lower 95 % confidence interval for the difference was −8.20 to 3.46 ) . Anti-HBs antibody titers ≥10 mIU/mL and anti-PRP ≥0.15 & mgr;g/mL were ≥95.4 % in each group . Seroprotection rates were also high for the other antigens . Seroconversion rates ( 4-fold increase from pre- to postvaccination ) were 93.6 % , 83.2 % , and 95.1 % in Groups 1 , 2 , and 3 , respectively , for anti-pertussis toxoid and 93.1 % , 57.7 % , and 90.0 % for anti-filamentous hemagglutinin . Anti-HBs GMTs were 330 , 148 , and 1913 mIU/mL for Groups 1 , 2 , and 3 , respectively . Reactogenicity was similar in each group . Fever ≥39.0 ° C occurred in 1.7 % , 0.4 % , and 0.0 % of infants in Groups 1 , 2 , and 3 , respectively ; no extensive limb swelling , hypotonic-hyporesponsive episodes , or vaccine-related serious adverse events were reported . Conclusions : The new , fully liquid , investigational hexavalent vaccine in the Exp and ed Program on Immunization schedule , with/without hepatitis B at birth , is highly immunogenic and safe compared with control vaccines , warranting further development [11906779] This multicentre study was design ed to establish the reactogenicity and immunogenicity profiles of primary and booster vaccination with diphtheria , tetanus , and pertussis whole-cell-hepatitis B/Haemophilus influenzae type-b ( DTPw-HB/Hib ) administered as either a syringe mix or as separate injections in 400 Latin American children . Both vaccine regimens were equally well tolerated and elicited post- primary excellent seropositivity rates at or close to 100 % for all five component antigens . With regard to HB , 100 % of subjects in the combined vaccination group , and 98.8 % subjects in the separate injection vaccination group reached seroprotective antibody concentrations ( > or=10 mIU/ml ) 1 month after the primary vaccination course . Equally high anti-PRP antibody concentrations were reached 1 month after vaccination , with 100 % of seroprotected subjects in the combined vaccination group ( antibody concentrations > or=0.15 microg/ml ) , against 99.4 % in the separate injection vaccination group . Seroprotective anti-HBs and anti-PRP antibody concentration levels persisted approximately 1 year after the primary vaccination course , just prior to booster vaccination . Finally , a significant increase of all antibody concentrations could be observed after the booster vaccination , since all but one subject in the separate injection vaccination group had protective levels of anti-HBs and anti-PRP antibodies 1 month after the booster dose . These results suggest that the combination of DTPw-HB and Hib vaccines provides an effective means for increasing vaccine coverage in childhood vaccination programmes [19124057] Combination vaccines improve parental and provider satisfaction and schedule compliance by decreasing the number of injections . In a Phase 2 , r and omized , double-blind , multicenter study , we compared four formulations of a liquid , hexavalent diphtheria-tetanus-acellular pertussis-inactivated poliovirus-Haemophilus influenzae b conjugate-hepatitis B virus ( DTaP-IPV-Hib-HBV ) vaccine in 708 infants immunized at 2 , 3 , 4 , and 12 - 14 months of age . The formulations contained identical DTaP and IPV components , differing in the contents of Hib polyribosylribitol phosphate ( PRP ) conjugate component ( tetanus-toxoid [ PRP-T , 12microg ] or Neisseria meningitidis outer-membrane-protein-complex [ PRP-OMPC , 3microg or 6microg ] ) , and in hepatitis B surface antigen ( HBsAg , 10microg or 15microg ) . A minimum acceptable postdose 3 antibody response rate was defined by the lower limit of the 95 % confidence interval exceeding a prespecified target . Rates of adverse events ( AEs ) were similar among groups , with a trend for increased solicited injection-site reactions ( pain , redness , swelling ) with increasing PRP-OMPC and HBsAg concentration . Serious AEs reported by eight subjects were not considered to be vaccine related . All PRP-OMPC formulations met prespecified acceptability criteria for postdose 3 immunogenicity for all antigens : PRP , HBsAg , pertussis , diphtheria , tetanus and polio . Apart from the Hib response , the postdose 3 responses obtained with the PRP-T formulation met the acceptability criterion for each antigen . Postdose 4 responses were acceptable for all antigens in all formulations . All vaccine formulations were well tolerated . The three PRP-OMPC formulations met prespecified immunogenicity criteria , and the one with the lowest PRP-OMPC concentration was selected for further optimization of immunogenicity [21134456] The current recommended infant vaccination schedules require many injections at multiple sites , which increase stress for infants and parents and may create challenges to vaccination compliance . Therefore , combination vaccines , which reduce the number of injections at each medical visit , can be an essential method to improve compliance . The objective of this study was to assess the safety and immunogenicity of an investigational , liquid , hexavalent , pediatric vaccine at 2 , 4 , 6 , and 12 - 14 months of age . In this multicenter , open-label controlled study , 756 infants were r and omized in approximately equal numbers to receive 0.5mL intramuscular dose of diptheria-tetanus-pertussis-polio-Haemophilus influenzae type b+hepatitis B vaccine , or 1 of 3 double-blind investigational formulations . All formulations included a hepatitis B surface antigen ( HBsAg ) concentration of 10μg/0.5mL. The three hexavalent vaccine formulations used in this study contained either Hib polyribosylribitol phosphate ( PRP ) conjugate component ( tetanus toxoid [ PRP-T , 12μg ] or Neisseria meningitidis outer membrane protein complex [ PRP-OPMC , 3μg or 6μg ] ) : a minimum acceptable postdose 3 antibody response rate for each antigen was defined by the lower limit of a 95 % confidence interval exceeding a prespecified target . Rates of adverse events ( AEs ) were similar among groups , with a trend for increased solicited vaccine-related injection-site reactions ( pain , erythema , swelling ) with increasing PRP-OMPC dose . No serious vaccine-related AEs were reported in the investigational groups . Both PRP-OMPC formulations met prespecified acceptability criteria for all antigens : PRP , HBsAg , pertussis , diphtheria , tetanus and poliovirus . The PRP-T formulation met the acceptability criterion for antibody responses to all antigens other than PRP at postdose 3 . Postdose 4 responses were adequate for all antigens in all formulations . All vaccine formulations were well-tolerated . Both PRP-OMPC formulations met prespecified immunogenicity criteria of PRP-OMPC evaluation [15629356] The safety and reactogenicity of a booster dose of GSK Biologicals ' hexavalent DTPa-HBV-IPV/Hib vaccine ( N=4725 ) was compared with the separate administration of GSK Biologicals ' DTPa-IPV/Hib and HBV vaccines ( N=4474 ) in two open , r and omized multicenter studies ( A and B ) . Solicited symptoms occurring within 4 days of vaccination were recorded on diary cards and serious adverse events ( SAEs ) were collected throughout the study period . In Study A ( N=1149 ) , incidences of solicited symptoms were similar in both groups ; there were no SAEs either reported within 4 days of vaccination or considered to be causally related to vaccination . In study B ( N=8050 ) , where fever was the only solicited symptom , rectal temperature > or = 39.5 degrees C was observed in 2.5 % and 2.8 % of the subjects , respectively . Fever > or = 40.0 degrees C was rare ( 0.6 % ) , and only two cases of febrile convulsions were recorded during the 4 days following vaccination both in the control group . Large swelling reactions ( defined as local injection site swelling with diameter > 50 mm , noticeable diffuse injection site swelling or noticeable increased circumference of the injected limb ) were reported following 2.3 % of the booster vaccine doses , regardless of the vaccine used . Extensive swelling reactions involving an adjacent joint were reported in 0.1 % of the subjects . Two SAEs , both reported after booster doses of DTPa-IPV/Hib and HBV vaccines administered separately , were considered by the investigators to be related to vaccination . Both resolved completely without sequelae . The hexavalent DTPa-HBV-IPV/Hib vaccine and the DTPa-IPV/Hib and HBV vaccines administered separately have similar good reactogenicity and safety profiles when given as booster doses in the second year of life [10496155] A study was undertaken to evaluate the safety and immunogenicity of a combination vaccine ( TETRAMUNE ) of conjugate Haemophilus influenzae type b ( Hib ) vaccine ( HibTITER ) and DTP ( Diphtheria , Tetanus and Pertussis ) vaccine . A total of 93 healthy children were r and omized to receive either TETRAMUNE ( combined group ) , or DTP and HibTITER administered concurrently ( separate group ) in separate syringes at approximately 2 , 4 and 6 months of age in Taiwan . Serologic responses were largely comparable between the two vaccine groups ; almost all subjects were seropositive to Hib PRP ( polyribosylribitol phosphate ) and were protected against diphtheria and tetanus after 2 doses of vaccine and mounted prominent responses to the components of Bordetella pertussis . Subjects in the combined group did not experience more adverse reactions compared with those in the separate group . We concluded that HibTITER was highly immunogenic and safe when administered concurrently with DTP vaccine to Taiwanese children . TETRAMUNE was also safe and immunogenic and might reduce the number of injections to achieve the same protection [17012870] Objectives : To assess the safety , immunogenicity and lot consistency of a liquid hexavalent combined vaccine ( DTaP-IPV-PRP ~ T-HBs , HEXAVAC ® ) ( Sanofi-Pasteur MSD , France ) administered to infants at 2 , 4 , and 6 months of age . Methods : A total of 1028 infants were vaccinated with one of 3 vaccine lots , in a r and omized , double-blind fashion . Equivalence testing was used to compare post-vaccination seroprotection/seroconversion rates and geometric mean titers ( GMTs ) for each antigen between the three lots . Blood sample s were drawn before vaccination and one month after the third dose . Local and systemic adverse events were monitored for 3 days following each injection . Results : Equivalence between lots was demonstrated for all antigens , on post-dose 3 seroprotection/seroconversion rates and GMTs . Reported rates of local and systemic adverse events tended to increase with subsequent doses . Altogether , 11.8 % of the infants reported at least one adverse local event ( mainly redness and in duration /swelling ) after the first dose and 36.1 % after the third dose . Systemic adverse events ( mainly irritability and fever ) were reported by 39.2 % of the infants after the first dose and by 57.5 % after the third one . Conclusion : Three separate lots of the liquid hexavalent combined vaccine induced consistently protective antibody responses against all antigens . These results and the well established clinical tolerability of this combined vaccine make it suitable for primary immunization of infants at 2 , 4 , and 6 months of age [15370670] A combined DTPa-HBV-IPV/Hib vaccine containing diphtheria ( D ) , tetanus ( T ) , acellular pertussis ( Pa ) , hepatitis B ( HBV ) and types 1 , 2 and 3 inactivated polioviruses ( IPV ) extemporaneously mixed with a conjugated Haemophilus influenzae type b ( Hib ) vaccine ( Group 1 ) was compared to the DTPa-HBV-IPV and Hib vaccines ( Group 2 ) administered separately at 3 , 5 and 11 months of age ( n=440 ) . A microneutralization assay was used to detect antibodies against the 3 polio virus types ( cut-off 1:8 dil ) , RIA for anti-HBs antibodies ( cut-off 10 mIU/ml ) and ELISA for antibodies against all other vaccine antigens ( cut-off : 0.1 IU/ml for anti-tetanus and anti-diphtheria antibodies ; 5 El . U/ml for antibodies against each of the 3 acellular pertussis antigens and 0.15 μg/ml for anti-PRP antibodies ) . Similar immune responses were observed in both groups 1 month after dose 2 as well as after dose 3 . Six months after dose 2 however , the proportion of subjects maintaining an anti-tetanus antibody concentration ≥0.1 IU/ml was lower in Group 2 and a slight group difference in favour of Group 1 was also observed for anti-PRP , anti-diphtheria and anti-polio type 1 antibody persistence prior to the third dose . The overall incidence of local and general solicited symptoms was similar in both groups . One subject discontinued study vaccination following an SAE considered to be related to vaccination . The DTPa-HBV-IPV/Hib combined vaccine is immunogenic and well tolerated when administered according to a 3 , 5 and 11 month vaccination schedule and can therefore be considered as a feasible alternative to the separate administration of the pentavalent DTPa-HBV-IPV and the monovalent Hib vaccines [15149781] Safety , reactogenicity and immunogenicity of GSK Biologicals ' hexavalent DTPa-HBV-IPV/Hib vaccine (Infanrix)hexa ) was assessed when used for primary vaccination at 3 , 4 and 5 months of age ( N = 2163 ) , compared to the separate administration of DTPa-IPV/Hib and HBV vaccines ( N = 720 ) . A similar safety and reactogenicity profile was demonstrated for both vaccine regimens , as well as a good immune response for all antigen components . By offering protection against six diseases in a series of single injections , the hexavalent DTPa-HBV-IPV/Hib vaccine was shown to be a safe , well tolerated and immunogenic alternative to primary immunization with licensed separately administered vaccines [16404468] OBJECTIVE The ability to accurately identify articles about therapy in large bibliographic data bases such as EMBASE is important for research ers and clinicians . Our study aim ed to develop optimal search strategies for detecting sound treatment studies in EMBASE in the year 2000 . METHODS H and search es of journals were compared with retrievals from EMBASE for c and i date search strategies . Six trained research assistants review ed fifty-five journals indexed in EMBASE and rated articles using purpose and quality indicators . C and i date search strategies were developed for identifying treatment articles and then tested , and the retrievals were compared with the h and - search data . The operating characteristics of the strategies were calculated . RESULTS Three thous and eight hundred fifty articles were original studies on treatment , of which 1,256 ( 32.6 % ) were method ologically sound . Combining search terms revealed a top performing strategy ( r and om:.tw . OR clinical trial:.mp . OR exp health care quality ) with sensitivity of 98.9 % and specificity of 72.0 % . Maximizing specificity , a top performing strategy ( double-blind:.mp . OR placebo:.tw . OR blind : .tw . ) achieved a value over 96.0 % , but with compromised sensitivity at 51.7 % . A 3-term strategy achieved the best optimization of sensitivity and specificity ( r and om:.tw . OR placebo:.mp . OR double-blind:.tw . ) , with both these values over 92.0 % . CONCLUSION Search strategies can achieve high performance for retrieving sound treatment studies in EMBASE [11144372] BACKGROUND Combination vaccines are urgently needed to reduce the number of injections given to young children . The aim of the study was to evaluate the safety and immunogenicity of a combination vaccine that contains diphtheria and tetanus toxoids and acellular pertussis antigens ( DTaP ) , recombinant hepatitis B surface antigen ( HepB ) and Haemophilus influenzae type b ( Hib ) polysaccharide conjugated to tetanus toxoid ( PRP-T ) . METHODS Four hundred five infants were r and omized equally to three groups and immunized at 2 , 4 and 6 months of age with : ( 1 ) DTaP/HepB vaccine used to reconstitute lyophilized PRP-T vaccine and administered as a single injection ; ( 2 ) DTaP/HepB vaccine and PRP-T vaccine administered as two separate injections ; or ( 3 ) DTaP , HepB and PRP-T vaccines administered as three separate injections . Safety was closely monitored , and blood specimens were obtained to assess antibody responses to each vaccine antigen . RESULTS All study vaccines were well-tolerated , and the rates of systemic and injection site reactions were similar between groups . After the third dose the geometric mean antibody concentrations to Hib were significantly lower in subjects in Group 1 ( 1.63 microg/ml ) compared with subjects in Groups 2 and 3 ( 6.26 and 6.15 microg/ml , respectively ; P < 0.0001 ) . Subjects with antibody concentrations < 1.0 microg/ml after the third dose responded well to a booster dose of Hib conjugate vaccine given at 11 to 15 months of age ( 41 of 44 with anti-PRP > or = 1.0 microg/ml ) . Differences between groups for antibody responses to the other vaccine components were not clinical ly significant . CONCLUSIONS Infants given a combined DTaP/ HepB/PRP-T vaccine experienced a significantly lower antibody response to the PRP-T component than infants given PRP-T vaccine as a separate injection . However , the immune response to a booster dose of Hib conjugate vaccine indicated the presence of immunologic memory [12901568] Objective : To evaluate , in an open study , the immunogenicity , safety and reactogenicity of a birth dose of hepatitis B vaccine followed by a three-dose course of diphtheria – tetanus whole-cell pertussis – hepatitis B vaccine , extemporaneously mixed with Haemophilus influenzae b ( Hib ) vaccine . Methods : At 2 , 4 and 6 months of age , a single group of 120 Colombian infants were enrolled in this study to receive a regimen consisting of three doses of the combination vaccine following a dose of hepatitis B vaccine at birth . Results : Seroprotection/vaccine response rates to all vaccine antigens was 98–100 % 1 month after completion of the full vaccination course . The vaccine had an acceptable reactogenicity profile and the incidence of reported local and general symptoms decreased with the administration of subsequent vaccine doses . Conclusion : The mixed DTPw – HB/Hib vaccine was safe and well-tolerated , with high immunogenicity against all component antigens . Compared with previous studies , reactogenicity did not increase with the additional dose of hepatitis B vaccine given at birth . The DTPw – HB/Hib combination can be used to provide primary vaccination of infants who have already received a first dose of hepatitis B vaccine at birth [19333002] The study was planned to assess and compare the immune response and safety of an indigenous DTPwHB-Hib pentavalent liquid combination vaccine ( Shan 5 ) with Easyfive and Tritanrix HB + Hiberix , the two available pentavalent combination vaccines . Four hundred infants were r and omized to receive three doses of either Shan 5 or one of the two comparators . Antibody analysis was performed prior to and four to six weeks post third vaccine dose . Solicited local and systemic events upto three days and unsolicited adverse events in the 30 days follow up period after each dose were recorded . A total of 365 subjects completed the study . Four to six weeks after third dose , 98.32 % of the subjects in Shan 5 group had seroprotective Anti PRP-T IgG antibody concentrations ( ≥0.15 µg/mL ) as compared to 100 % and 98.94 % subjects in Tritanrix HB + Hiberix and Easyfive groups respectively . Seroprotective levels for Anti-HBs ( ≥10 mIU/mL ) were observed in 97.77 % , 97.83 % and 98.94 % subjects in Shan 5 , Tritanrix HB + Hiberix and Easyfive groups respectively . Comparable immune responses were observed for the three other components ( D , T and P ) in all the groups . Four Serious Adverse Events ( SAEs ) were reported ( three with Shan 5 and one with Easyfive ) , all unrelated to the respective vaccines . Most commonly reported adverse events in all the groups were pain at injection site , mild fever ( < 103 ° F ) and minor swelling at injection site . The study proved that Shan 5 was safe and immunogenic compared to the two other licensed vaccines [15837232] Infants ( N = 459 ) were r and omly assigned to receive either Infanrix hexa or Hexavac vaccines at 2 , 4 and 6 months of age as a primary vaccination schedule . The immunogenicity of the hepatitis B component was statistically significantly higher for Infanrix hexa compared to Hexavac in terms of both seroprotection ( 98.6 % versus 94.7 % , p = 0.0302 ) and GMCs ( 905.6 versus 226.4 , p < 0.0001 ) . Significantly ( p < or = 0.0001 ) higher antibody levels against diphtheria and the 3 polio components were also induced by Infanrix hexa . The responses to tetanus , Hib and pertussis components were similar . The incidences of clinical ly relevant solicited symptoms , unsolicited symptoms or serious adverse events were low in both groups [16356598] This study assessed compatibility of concurrently administered 7-valent pneumococcal conjugate ( PCV7 ) , hepatitis B ( HB ) and DTaP.IPV/Hib vaccines . Infants were given DTaP.IPV/Hib and HB at 2 , 4 , 6 months and r and omly assigned ( 2:1 ) to receive PCV7 concurrently or sequentially ( at 3 , 5 , 7 months ) . Antibody levels were compared in 246 concurrent and 122 sequential vaccinees . Responses to PCV7 , DTaP.IPV/Hib and HB were generally unaltered with concurrent administration except that Hib responses were increased ( p=0.008 ) and HB responses were reduced ( p=0.006 ) with concurrent dosing , the latter possibly from same thigh injection with DTaP.IPV/Hib . We conclude that PCV7 , DTaP.IPV/Hib and HB are compatible with concurrent , separate injections [11115705] Three hundred and twenty eligible infants were enrolled in an open r and omized clinical trial and allocated to one of two groups to receive either separate concomitant injections of a c and i date combined DTPa-HBV-IPV and commercial Hib vaccine ( c and i date administration : DTPa-HBV-IPV+Hib ) or separate concomitant injections of licensed DTPw-IPV mixed in the same syringe with Hib and HBV vaccines ( comparator administration : DTPw-IPV/Hib+HBV ) . Vaccines were administered at 6 , 10 and 14 weeks of age preceded by a monovalent dose of HBV at birth . The c and i date vaccine administration was shown to be at least as immunogenic ( primary objective ) as the c and i date administration with respect to the diphtheria , tetanus , polio , HBs and PRP seroprotection rates ( primary endpoints ) . Post vaccination , both vaccine administrations showed an equivalent level of seroprotection with nearly all subjects ( > 96 % ) acquiring seroprotective titers against diphtheria , tetanus , polioviruses , HBsAg and PRP antigens . A markedly higher anti-HBs response post dose 2 at week 14 in the group receiving the c and i date vaccine , 98.6 % of subjects had seroprotective titers ( GMT of 505.7 mIU/ml ) compared with only 88.7 % ( GMT of 107.5 mIU/ml ) in the comparator group . There was a lower incidence of adverse events following the DTPa-based c and i date administration compared with the DTPw-based comparator . Despite the early age and short interval between doses , both administrations were immunogenic , with the concomitant administration of DTPa-HBV-IPV and Hib vaccines showing an improved tolerability over the commercial vaccines DTPw-IPV/Hib and HBV [15519702] A new single-injection combination vaccine against six diseases has been developed to accommo date the growing number of recommended paediatric vaccines . A pentavalent liquid diphtheria , tetanus , acellular pertussis ( 3-component ) , hepatitis B , and inactivated polio ( types 1 - 3 ) combined vaccine ( DTPa-HBV-IPV ) is extemporaneously mixed with a lyophilized Haemophilus influenza type B ( Hib ) conjugate vaccine ( polyribosyl-ribitol phosphate (PRP)-T ) and given as a single-injection . A cohort of 368 healthy infants was initially studied to evaluate the immunogenicity and reactogenicity of this hexavalent combination given as a primary course at 2 , 4 , and 6 months of age . At 15 months of age , from this cohort , 219 children received a booster dose of a licensed DTPa/Hib ( PRP-T ) vaccine to assess the booster response , while 70 received a challenge dose of unconjugated PRP ( PRP ) vaccine ( to evaluate Hib-specific memory ) plus a separate DTPa vaccine . Seven to 10 days following plain PRP challenge , anti-PRP geometric mean antibody concentrations ( GMCs ) had increased 13-fold to 5.67 microg/ml , and thirty days after conjugated PRP booster vaccination , anti-PRP antibody GMCs increased 102-fold . Both responses are indicative of immune memory . Vaccination was well tolerated following all primary and booster doses , although 10.5 % of booster recipients experienced > 50-mm local swelling at the site of DTPa vaccination . We conclude that DTPa-HBV-IPV/Hib is safe and immunogenic for primary vaccination , and that Hib-specific memory is induced by primary vaccination [12922087] An open , r and omised , multicentre trial was performed to compare the reactogenicity and safety profile of the administration of a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio ( DTPa-HBV-IPV ) vaccine administered in one injection mixed with Haemophilus influenzae type b ( Hib ) conjugate vaccine ( Group 1 ) with that of a pentavalent DTPa-IPV vaccine mixed with a Hib vaccine ( DTPa-IPV/Hib ) , simultaneously administered with HBV ( Group 2 ) in two injections in opposite thighs , as a primary vaccination course , to healthy infants at 2 , 4 and 6 months of age . A total of 235 completed the study , 120 from Group 1 and 115 from Group 2 . Blood sample s ( pre-vaccination and 1 month after the third dose ) were obtained from a subset of infants ( Group 1 : 40 ; Group 2 : 31 ) to assess the immune response to vaccination . Local and general solicited symptoms were recorded by parents on diary cards . Seven hundred and five diary cards ( Group 1 : 360 ; Group 2 : 345 ) were collected . The clinical ly relevant and most commonly reported local reaction was pain ( infant cried when the limb was moved ) in 2.5 % ( Group 1 ) and 1.2 % ( Group 2 ) of diary cards . Fever was more frequently reported in Group 1 ( 21 % of diary cards ) than in Group 2 ( 12 % of diary cards ) . However only 3 and 2 % of doses in Groups 1 and 2 , respectively , were responsible for a rectal temperature between 38.6 and 39.5 degrees C and only one case ( Group 2 ) had > or = 39.5 degrees C. Other clinical ly relevant general symptoms were rarely recorded : irritability ( 2 - 2.8 % ) , loss of appetite ( 0.3 - 0.6 % ) and drowsiness ( 0.3 - 0.3 % ) . All subjects included in the immunogenicity analysis had seroprotective titres to diphtheria , tetanus , polio virus types 1 and 3 , Hib . Almost all subjects were seroprotected for anti-polio type 2 and hepatitis B ( with the exception of 1 subject in Group 1 for each antigen ) . The vaccines response rates to pertussis antigens were over 97 and 90 % in Groups 1 and 2 , respectively . This study shows that , from a clinical perspective , the DTPa-HBV-IPV/Hib vaccine given in a single injection has a similar reactogenicity and safety profile to that of two licensed vaccines ( DTPa-IPV/Hib , HBV ) given in two simultaneous injections to infants at 2 , 4 and 6 months of age . This is a valuable advantage , since in some countries , such as Spain and the UK , an additional injection ( for the administration of meningococcal C conjugate vaccine ) has been recently included in the infants ' vaccination calendars [10772563] An open , r and omized , clinical trial was conducted in order to assess the reactogenicity and immunogenicity of DTPw-HBV and Haemophilus influenzae type b ( Hib ) vaccines when given either as a mixed administration or as separate concomitant injections using the WHO schedule at 6 , 10 and 14 weeks of age , following a dose of HBV at birth . There were no clinical ly relevant differences in the immune response to any component between the mixed and separate administrations . In fact the anti-tetanus GMTs were significantly higher ( p=0.002 ) in mixed administration ( 3.9 IU/ml ) compared with the separate administration ( 1.9 IU/ml ) . However although all subjects achieved anti-PRP titers > or = 0.15 microg/ml , higher anti-PRP GMTs were seen in the group receiving the separate administration . Importantly , the addition of Hib did not adversely alter the reactogenicity profile of DTPw-HBV . This report which demonstrates that this novel combination can be used in WHO recommended schedule [12908031] Vaccination of infants with conjugated Haemophilus influenzae type b ( Hib ) vaccines has been proven to reduce Hib meningitis by 95 % and pneumoniae by 20 % . The routine use of Hib vaccine is facilitated by the introduction of combination vaccines into the EPI ( Exp and ed Plan of Immunization ) . The objective of this study was to compare the immunogenicity and reactogenicity of an extemporaneously mixed DTPw/Hib ( diphtheria-tetanus-whole cell pertussis ) combination , using the technology of two Brazilian manufacturers , against a licensed DTPw/Hib European combination in 108 infants vaccinated at 2 , 4 and 6 months according to the local national schedule . The Brazilian combination was highly immunogenic with Hib seroprotection rates ( anti-PRP > 0.15 mg /ml of 98 % after 2 doses and 100 % after 3 ) . Also for tetanus and pertussis the new Brazilian combination was as immunogenic as the European counterpart , except the diphtheria seroprotection rates and titers were lower . There was also no clinical ly relevant difference in reactogenicity . If these feasibility results are confirmed , the Brazilian DTPw/Hib combination should help to boost the uptake of Hib vaccination in Brazil [12839281] Aim : Combining paediatric vaccines is a rational solution to reduce the number of injections during a single clinical visit , to maintain parents ' compliance and to extend vaccine coverage . Different diphtheria , tetanus and whole cell pertussis (DTwP)‐containing combination vaccines are licensed and used world‐wide . This study assessed the immunogenicity and safety in infants of a combined diphtheria‐tetanus‐whole cell pertussis‐Haemophilus influenzae type b‐CRM197 conjugate full liquid vaccine . Methods : The safety and efficacy of a combined ready‐to‐use liquid vaccine containing diphtheria and tetanus toxoids , cell suspension of Bordetella pertussis and H. influenzae type b‐CRM197 conjugate vaccine ( DTwPHib ) were assessed in infants eligible for the local Exp and ed Programme on Immunization ( EPI ) in Valencia , Spain . The comparative group received separate injections of reference vaccines DTwP + Hib . Results : Local and systemic reactions and adverse events were generally mild and similar in the two groups . DTwPHib elicited anti‐PRP antibody titres ±0.15 μg ml−1 in 97 % and DTwP + Hib in 94 % of infants . Furthermore , 89 % of DTwPHib and 78 % of DTwP + Hib recipients attained anti‐PRP antibody titres ±1.0 μg ml−1 , signifying long‐term protection . The anti‐PRP geometric mean titre was significantly higher in the combined DTwPHib vaccine group ( 6.65 vs 3.57 μg ml−1 ) . In both groups , 99 % of infants achieved protective ( ±0.01 IU ml−1 ) anti‐diphtheria antibody levels and all children achieved protective ( ±0.1 IU ml−1 ) anti‐tetanus antibody levels . DTwPHib caused a ±2‐fold increase in anti‐pertactin antibody titres in 91 % and a ±4‐fold increase in 82 % of recipients . The corresponding proportions in the DTwP + Hib group were 95 % and 90 % . DTwPHib induced a ±2‐fold increase in anti‐Agg 12 and 3 antibody levels in 79 % and a ±4‐fold increase in 73 % of recipients . The corresponding proportions among DTwP + Hib infants were 85 and 82 % . Conclusion : Overall , the combined liquid vaccine DTwPHib is a safe and effective immunogenic vaccine for EPI use in infants [16874170] Background : Combined vaccines containing diphtheria-tetanus-pertussis whole-cell ( DTPw ) , Haemophilus influenzae type b ( Hib ) , and hepatitis-B vaccines are essential for the continuing success of vaccination programs in developing nations . This r and omized , dose-ranging study assessed the immunogenicity and reactogenicity of primary and booster vaccination with pentavalent DTPw-HBV/Hib vaccines containing 10 , 5 or 2.5μg of polyribosylribitol phosphate ( PRP ) conjugated to tetanus toxoid ( trials Hib-052/064 ) . Methods : Six hundred eighty infants were r and omized to receive one of 5 vaccine combinations at 6 , 10 , and 14 weeks of age . Of these , 351 received the same vaccine at 15–24 months of age . The immune response was evaluated on blood sample s collected 1 month after the 3-dose primary course and before and 6 weeks after the booster dose . Reactogenicity was assessed during a 4-day period after each vaccine dose using diary cards . Results : After primary vaccination , all subjects had seroprotective anti-PRP antibody concentrations ( ≥0.15 μg/mL ) and > 95 % had concentrations ≥1.0 μg/mL , irrespective of the PRP dose administered . Anti-PRP antibody avidity after primary vaccination and antibody persistence until the second year of life were similar among groups . The booster dose induced marked increases in anti-PRP antibody GMCs and antibody avidity , indicative of effective priming and the presence of immune memory . All vaccination regimens elicited good immune responses and comparable antibody persistence to the other vaccine antigens , with significant increases in all antibody concentrations observed after boosting . All vaccination regimens were safe , with similar overall reactogenicity profiles . Conclusion : Hib conjugate vaccines containing reduced amounts of PRP can be effectively combined with the licensed DTPw-HBV vaccine to provide protection against 5 major childhood pathogens in a single injection

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### Context: [17987229] INTRODUCTION Children in Singapore receive vaccination against hepatitis B virus ( HBV ) at 0 , 1 and 5 or 6 months of age , and vaccination against pertussis , diphtheria , tetanus , and polio at 3 , 4 and 5 months of age . Parents often choose to vaccinate with the combined acellular-pertussis-inactivated polio-Hib vaccine ( DTPa-IPV/Hib ) . We investigated whether a combined hexavalent vaccine , DTPa-HBV-IPV/Hib , could replace the separate administration of DTPa-IPV/Hib and HBV for the final vaccination at 5 months of age ( Trial DTPa-HBV-IPV-075 ) . MATERIAL S AND METHODS In an open study , 150 children were r and omised to complete their vaccination schedule with DTPa-IPV/Hib + HBV or DTPa-HBV-IPV/Hib . RESULTS One month after the final vaccination , there was no difference between groups in seroprotection rates or antibody concentrations against HBV . Seroprotection rates against diphtheria , tetanus , Hib and polio , as well as vaccine response rates to pertussis antigens were also similar between groups . Local and general symptoms occurred at a similar rate after the third dose of either vaccine . CONCLUSION The immunogenicity and reactogenicity of the hexavalent vaccine DTPa-HBV-IPV/Hib ( Infanrix hexa , GSK ) group is comparable to that of separately administered DTPa-IPV/Hib and HBV vaccines . Combined hexavalent vaccine , DTPa-HBV-IPV/Hib , could replace the separate administration of DTPa-IPV/Hib and HBV for vaccination at 5 months of age , thereby reducing the number of injections required [21372751] Background and Aims : Assessment of a new , fully liquid , investigational hexavalent DTaP-IPV-Hep B-PRP-T vaccine ( Hexaxim , Sanofi Pasteur ) , containing the same active ingredients as Pentaxim ( DTaP-IPV//PRT-T ) and 10 & mgr;g Hansenula polymorpha-derived recombinant hepatitis B ( Hep B ) surface antigen , Sanofi Pasteur , in Argentinean infants . Methods : Infants born to Hep B surface antigen seronegative mothers were r and omized to receive the DTaP-IPV-Hep B-PRP-T vaccine or Pentaxim and Engerix B Pediatrico ( Hep B monovalent ) vaccines at 2 , 4 , 6 months of age . Antibody titers were measured before and 1 month after 3-month primary vaccination . Noninferiority analyses were performed on seroprotection/seroconversion rates . Safety was evaluated descriptively up to 1 month after primary vaccination . Results : A total of 624 participants were enrolled , 312 participants were r and omized to each group , and 604 participants completed the trial . The DTaP-IPV-Hep B-PRP-T vaccine was demonstrated as noninferior to the Pentaxim and Hep B monovalent vaccines with seroprotection/seroconversion rates 1 month postdose 3 for each valence . The anti-Hep B geometric mean titer 1-month postdose 3 for the investigational DTaP-IPV-Hep B-PRP-T primary series was similar to the monovalent Hep B control . The overall incidence of adverse events was similar among the 2 groups . Conclusions : The new , fully liquid , investigational DTaP-IPV-Hep B-PRP-T vaccine ( Hexaxim ) is highly immunogenic and safe when compared with licensed comparators , warranting further development [10479180] Antibody avidity to Haemophilus influenzae type b ( Hib ) polysaccharide ( PS ) was assessed in infants vaccinated with diphtheria-tetanus-acellular pertussis ( DTaP ) combined with Hib-PS conjugated to tetanus toxoid ( PRP-T ) and hepatitis B ( HB ) ( DTaP-PRP-T-HB ) and after a PRP-conjugate ( CRM197-OS ) booster 3 - 7 months later . Avidity differed between infants with anti-Hib-PS IgG antibody < 1 or > 1 microg/mL post primary series ( avidity index [ AI ] , 42 % , 95 % confidence interval [ CI ] , 35%-49 % , and 68 % and 63%-72 % , respectively ; P<.0001 ) . For infants with < 1 microgram/mL anti-Hib-PS IgG antibody , mean AI rose by the time of preboost immunization to 61 % ( 95 % CI , 57%-65 % ) , even though total IgG antibody levels fell . Spontaneous Hib-PS antibody rises after primary series DTaP-PRP-T-HB vaccination were followed by high postboost anti-Hib-PS IgG antibody levels and avidity . The DTaP-PRP-T-HB combination vaccine studied elicits high avidity antibody , and affinity maturation appears to occur in the absence of further antigen exposure even in those with very low anti-Hib-PS antibody [17532669] Abstract Objectives : The aim of this open , r and omised , multicentre trial was to evaluate the immunogenicity and reactogenicity of the tetravalent diphtheria-tetanus-acellular pertussis-hepatitis B ( DTaP-HBV ) vaccine when given either as a mixed or as a separate concomitant injection with the Haemophilus influenzae type b ( Hib ) vaccine at 3 , 5 and 11 months of age . Methods : Antibody against diphtheria , tetanus , pertussis ( ELISA ) , hepatitis B ( radioimmunoassay ) and Hib polyribosylribitol phosphate ( PRP ) [ radiolabeled antigen binding assay ] was determined . Solicited local and systemic adverse events were evaluated on the day of each vaccination and for three subsequent days . Follow-up of unsolicited and serious adverse events was conducted for 30 days following each vaccination . Results : A total of 360 subjects were enrolled in the study . After completion of the three-dose vaccination course , seroprotective antibody concentrations against diphtheria , tetanus and hepatitis B , together with a pertussis vaccine response , were seen in almost all subjects with immunogenicity results ( n = 336 ) . All subjects had post-vaccination Hib anti-PRP antibody concentrations of at least 0.15 μg/mL , and 97.0 % and 99.4 % , respectively , of the subjects receiving a single or separate injections had Hib anti-PRP antibody concentrations ≥1.0 μg/mL. Addition of the Hib vaccine to the tetravalent DTaP-HBV vaccine did not increase the incidence of local or systemic reactions . Conclusions : Combination of DTaP-HBV and Hib vaccines in a single injection is safe , immunogenic and well tolerated , and thus has the potential to simplify the childhood immunisation schedule in Italy [11732460] OBJECTIVES To evaluate the immunogenicity and reactogenicity of a pentavalent vaccine prepared by extemporaneously mixing diphtheria-tetanus pertussis-hepatitis B vaccine ( DTP-HBV ) and lyophilised Haemophilus influenzae type B (Hib)-tetanus conjugate vaccines in the same syringe , compared with the same vaccines given as separate , concomitant administrations . DESIGN Open , r and omised comparative study . SETTING Durban , South Africa . SUBJECTS A total of 120 healthy male and female infants were enrolled in the trial and r and omised into two groups ; group 1 received the combined administration ( DTP-HBV-Hib ) , and group 2 received separate administrations of DTP-HBV and Hib vaccines . Vaccines were given as a three-dose primary vaccination course at 2 , 4 and 6 months [ corrected ] of age . OUTCOME MEASURES Antibody levels were measured using st and ard techniques and local and general solicited symptoms were recorded using diary cards . RESULTS All subjects had seroprotective titres against diphtheria and tetanus ; and antipolyribose-ribitol phosphate ( PRP ) titres > or = 0.15 microgram/ml 1 month after the final dose . A vaccine response ( defined as post-vaccination titres > or = 15 ELISA (EL).U/ml in initially seronegative subjects ; and as post-vaccination titres > or = pre-vaccination titres in initially seropositive subjects ) against the pertussis component was seen in 83 % and 85 % of subjects in the groups receiving combined and separate administration . No differences were seen in any of the geometric mean titres ( GMTs ) between the two administrations either 2 months after the second dose or 1 month after the final dose . There was no observed increase in reactogenicity in the group receiving the mixed administration . CONCLUSIONS The results demonstrate that combined DTP-HBV-Hib vaccine is well tolerated and immunogenic [21093342] OBJECTIVES In this open-label , non-r and omized phase II study , the safety and immunogenicity of a fully liquid diphtheria-tetanus-whole cell pertussis-hepatitis B-Haemophilus influenzae type b ( DTPw-HepB-Hib ) combination vaccine ( Quinvaxem ( ® ) ) were assessed in infants who had or had not received a birth dose of hepatitis B ( HepB ) vaccine . STUDY DESIGN Two groups of infants , ' HepB at birth ' ( n=110 ) and ' no HepB at birth ' ( n=108 ) , were enrolled and received a primary vaccination course using a 2 - 4 - 6 months schedule . RESULTS Seroprotection/seroconversion rates of > 95 % were achieved against all antigens included in the combination vaccine for both study groups . Although significantly higher anti-hepatitis B virus ( p<0.001 ) and anti-tetanus ( p=0.031 ) antibody titers were achieved in group ' HepB at birth ' when compared with group ' no HepB at birth ' , the proportion of ' no HepB at birth ' subjects achieving protective titers was non-inferior to the proportion of subjects in group ' HepB at birth ' . The birth dose of HepB vaccine did not seem to influence the safety pattern of the DTPw-HepB-Hib combination vaccine . CONCLUSIONS The present study demonstrated that the fully liquid DTPw-HepB-Hib vaccine was safe and immunogenic when administered using a 2 - 4 - 6 months immunization schedule , regardless of whether or not infants had received a dose of HepB vaccine at birth [9007484] Abstract The lack of an adequate immune response to the major polysaccharide of the Haemophilus influenzae type b ( Hib ) capsule ( polyribosyl ribitol phosphate ) ( PRP ) in very young infants ( < 18 months ) can be overcome by conjugating PRP to a T-cell dependent carrier protein . We studied whether administration of a tetanus-PRP conjugate vaccine reconstituted with a diphtheria-tetanus-acellular pertussis-hepatitis B ( DTPa-HBV ) vaccine as a three dose primary course at 3 , 4 and 5 months of age induced PRP-specific immunological memory , by examining the anti-PRP response to a dose of unconjugated PRP given with the DTPa-HBV booster approximately 1 year later . The unconjugated PRP elicited protective anti-PRP antibody levels ( ≥ 0.15 μg/ml ) in all but 3 of the 369 vaccinees , including 13 infants who failed to demonstrate a measurable immune response after the primary course . In a sub-cohort of 54 subjects all had anti-PRP levels ≥ 0.5 μg/ml within 7–14 days of the booster showing a rapid anamnestic type response . Both primary and booster responses were predominantly IgG1 indicating a T-cell dependent response . The DTPa-HBV components elicited protective anti-diphtheria , anti-tetanus and anti-HBs antibody levels in ≥ 98.5 % of vaccinees , and immune responses to each of the acellular pertussis vaccine components in 92.3%–97.3 % of subjects . Conclusion The tetanus-PRP conjugate vaccine not only elicited a good primary humoral response , but also induced immunological memory so that the infants were able to mount a large and rapid immune response to subsequent exposure to plain PRP , indicating that protection against circulating wild-type Hib had been generated . Successful induction of immunological memory occurred even when there was no measurable humoral anti-PRP response to the primary course . Tetanus-PRP conjugate vaccine can be used in combination with DTPa-HBV vaccine , when administered separately or as a single injection in the same syringe , in primary immunisation schedules at 3 , 4 and 5 months of age [16640847] OBJECTIVES In 1998 the World Health Organization ( WHO ) recommended the inclusion of Haemophilus influenza type B ( Hib ) conjugate vaccines in infant immunization programs , whenever in accordance with national priorities . GlaxoSmithKline Biologicals has developed a new pentavalent combined diphtheria-tetanus-whole cell pertussis-hepatitis B/Hib ( DTPw-HB/Hib ) vaccine containing 5 microg of polyribosylribitol phosphate ( PRP ) , and we assessed the immunogenicity and reactogenicity of primary and booster vaccination of healthy children with this new vaccine compared with a reference regimen consisting of the licensed DTPw-HB ( Tritanrix ) and Hib ( Hiberix ) vaccines given as simultaneous concomitant injections . METHODS We performed a r and omized , double-blind study from September 1998 to August 1999 to establish the immunogenicity and reactogenicity of primary and booster vaccination of healthy children with the new pentavalent combined DTPw-HB/Hib vaccine given as a single injection , compared with the reference regimen . RESULTS Both vaccination regimens elicited excellent immune responses , with all subjects in both groups achieving seroprotective anti-PRP antibody concentrations of > or = 0.15 microg/mL one month after primary vaccination . The combined DTPw-HB/Hib vaccine was non-inferior to the licensed vaccines in terms of seroprotection/seropositivity/vaccine response rates for all antigen components . Persistence of antibodies against all study vaccine antigens up to the time of booster vaccination was comparable between groups , and a marked increase of all antibody concentrations was observed after the booster dose . Both vaccine regimens were similar in terms of their overall reactogenicity profiles . CONCLUSIONS Our results indicate that the new DTPw-HB/Hib pentavalent combination vaccine provides an efficient and reliable way of implementing WHO recommendations for controlling hepatitis B and Hib infections on a worldwide basis [17012882] A DTaP-IPV//PRP-T combination vaccine ( Pentacel ™ ) has been universally used in Canada to provide immunization against diphtheria , tetanus , pertussis , polio , and Haemophilus influenzae type b with single injections at 2 , 4 , 6 , and 18 months of age . This r and omized , multicenter study was conducted to evaluate administration of a fourth dose of DTaP-IPV//PRP-T at 15 to 18 months of age , similar to the US immunization schedule . Participants who had received three doses of DTaP-IPV//PRP-T by 8 months of age were enrolled at 12 months and r and omized to receive a fourth dose at 15 , 16 , 17 , or 18 months . Antibody levels for each vaccine antigen were measured prior to and 4 weeks following booster vaccination . Overall , 1782 subjects were immunized and monitored for adverse events , and 735 were evaluated for immune responses . Pre-immunization antibody levels differed minimally by age , for all antigens . The immune responses elicited by DTaP-IPV//PRP-T were comparable between participants vaccinated at 15 or 16 months and those vaccinated at 17 or 18 months , as demonstrated by specific antibody geometric mean titers , seroprotection/seroresponse rates , and reverse cumulative distribution curves . The fourth dose was well tolerated in all age groups . Toddlers at 15 , 16 , 17 , or 18 months of age are equally suitable recipients for booster immunization with the DTaP-IPV//PRP-T vaccine [15602195] Background : Recently an increase in the number of invasive Haemophilus influenzae type b ( Hib ) cases was observed in the United Kingdom , which coincided with a temporary change from diphtheria-tetanus toxoids-wild-type pertussis to diphtheria-tetanus toxoids-acellular pertussis ( DTaP ) Hib vaccines . A study in Germany based on approximately 2 years of follow-up , estimated vaccine effectiveness ( VE ) of DTaP/Hib and DTaP-inactivated poliovirus/Hib combination vaccines against invasive Hib disease to be high . Objectives : To assess VE of DTaP-containing Hib vaccines against Hib in Germany with the use of extended follow-up of case surveillance and vaccine uptake . Subjects and Methods : Cases with confirmed systemic Hib infections in children born between June 1 , 1996 and December 31 , 1998 were ascertained by a nationwide active surveillance system from January 1998 through June 2002 . A representative subcohort of 667 children born in the same time frame was r and omly sample d in a nationwide vaccine coverage survey . VE was determined with a case-cohort approach of Cox regression with time-dependent covariates . Results : Thirty-six cases of Hib disease were reported . Of these , 10 were vaccinated with DTaP-containing Hib vaccines only and 20 were not vaccinated . Of the 10 vaccinated cases , 4 had received an incomplete primary series ( 1–2 doses ) , and 6 had received the full primary series ( 3 doses ) , 3 of whom also received the booster dose . VE of combination vaccines against invasive Hib infection was 89.6 % [ 95 % confidence interval ( CI ) , 67.0–96.7 ] for an incomplete primary series , 96.7 % ( 95 % CI 87.7–99.1 ) for a full primary series and 98.5 % ( 95 % CI 94.5–99.6 ) for a booster dose ( irrespective of priming ) . Conclusion : Hib combination vaccines containing acellular pertussis antigens continue to be highly effective in Germany [15665713] Background : The 7-valent pneumococcal ( 7vPn ) conjugate vaccine is licensed for primary and booster vaccination according to the same immunization schedules as routinely recommended diphtheria-tetanus-pertussis-based childhood vaccines and can be coadministered during the same vaccination visit . Methods : An open , r and omized study evaluated the immunogenicity and safety of a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio virus-Haemophilus influenzae type b ( DTPa-HBV-IPV/Hib ) vaccine and a 7vPn conjugate vaccine when coadministered at 2 , 3 and 4 months and 12–23 months of age , compared with the administration of the hexavalent DTPa-HBV-IPV/Hib vaccine given alone . Serum antibody titers were measured before and 1 month after the primary course and before and 1 month after the booster dose . Solicited local and general adverse events were recorded for 4 days and unsolicited adverse events were recorded for 30 days after each vaccine dose . Results : A total of 345 subjects were enrolled for primary vaccination with the hexavalent vaccine ( 170 without and 175 with the 7vPn vaccine coadministered ) and 266 returned for booster vaccination ( 122 without and 144 with coadministration of the 7vPn vaccine ) . After primary vaccination , antibody responses against the common antigens were similar in both groups , with seroprotection rates of 93.6–100 % and with similar antibody decay before booster vaccination . The fourth dose induced a vigorous booster response , with seroprotection/vaccine response rates of 96.8–100 % . Response to the 7vPn primary and booster vaccination was within previously reported ranges . Differences in reactogenicity result ed from higher incidences of symptoms after concomitant vaccination . Rectal temperature > 39.5 ° C was observed after 1.2 % of the coadministered vaccine doses during primary vaccination and after 2.8 % of the booster vaccine doses . Conclusion : Coadministration of the DTPa-HBV-IPV/Hib and 7vPn vaccines at separate injection sites during the same vaccination visit was effective and safe [11257348] Combination vaccines are essential to enable administration of all the required antigens in routine infant immunisation schedules at any single visit . Some combinations of diphtheria-tetanus-acellular pertussis ( DTPa ) with Haemophilus influenzae type b ( Hib ) conjugate vaccines have been shown to result in lower Hib titres than when Hib is administered separately . While confirming that a primary series with a DTPa-HBV-IPV/Hib combination gives lower antibody levels than separate Hib conjugates , we show that the nature ( isotype and IgG subclasses ) and function ( avidity and opsonic activity ) of the antibodies are the same , and immunologic memory is induced . It is likely therefore that the DTPa-HBV-IPV/Hib combination will be efficacious against Hib disease [12424582] Abstract . In an open r and omised trial , 312 eligible infants were enrolled to receive either a single injection of the hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B virus-inactivated polio/Haemophilus influenzae b ( DTPa-HBV-IPV/Hib ) vaccine , or concomitant injections of commercial DTPa-IPV/Hib and HBV vaccines ( comparator ) . Vaccines were administered at 3 , 5 and 11 months of age . The statistical approach for non-inferiority showed that the DTPa-HBV-IPV/Hib vaccine was at least as immunogenic as the comparator vaccines in terms of immunogenicity of all antigens 1 month after the 2nd dose . Non-inferiority criteria were also met immediately before and 1 month after the 3rd dose for all antigens except poliovirus type 3 prior to the 3rd dose . The majority of subjects were seroprotected against diphtheria , tetanus , polyribosyl-ribitol-phosphate , hepatitis B and poliovirus after the 2nd dose and maintained seroprotective antibody levels until the 3rd dose . A marked difference was observed in anti-HBs antibody geometric mean antibody concentrations ( GMCs ) at 1 month after the 2nd dose ( higher GMCs in DTPa-HBV-IPV/Hib group ) . Reactogenicity ( incidence of solicited local and general symptoms ) was similar between the two study groups and no vaccine-related serious adverse events occurred . Conclusion : the new diphtheria-tetanus-acellular pertussis-hepatitis B virus-inactivated polio/Haemophilus influenzae b vaccine administered at 3 , 5 and 11 months of age was safe and at least as immunogenic as the comparator vaccines thus providing an effective and more comfortable option for this infant vaccination schedule [11228385] We evaluated the immunogenicity and reactogenicity of a new liquid pentavalent combination vaccine , which incorporates a diphtheria , tetanus and whole-cell pertussis vaccine ( DTP ) with Hib ( PRP-OMPC ) and hepatitis B vaccine ( HB ) , in a series of three studies involving 2156 infants . The vaccination schedule was 2 , 4 , 6 and 18 months for all studies . In addition , subjects in the third study also received a dose of monovalent hepatitis B vaccine at birth . The principal study was a r and omised double blind trial of two separate , but concurrently administered vaccines in each of three groups : pentavalent vaccine [ DTP-Hib-HB ] plus placebo ( Group A , n=619 ) ; quadrivalent vaccine [ DTP-HB ] plus Hib vaccine ( Group B , n=620 ) ; and bivalent vaccine [ Hib-HB ] plus DTP ( Group C , n=226 ) . The second study ( Group D , n=231 ) was an open trial of three separate , but concurrently administered licensed control vaccines ( DTP , Hib and HB ) . The third study ( Group E , n=460 ) administered a dose of monovalent hepatitis B vaccine at birth followed by pentavalent vaccine as for Group A. Subjects were bled prior to the 2- and 18-month vaccinations , and a month after the 6- and 18-month vaccinations . A diary card was used to record subject temperatures and other systemic and local clinical signs for 7 days after each vaccination . The pentavalent vaccine , whether or not preceded by a birth dose of hepatitis B vaccine , was generally well tolerated at all administration times , and had a reactogenicity profile similar to that observed for licensed vaccine controls . Diphtheria and tetanus antibody levels were substantially above protective levels in all study groups . The anti-HBs responses ( % > or = 10 mIU/ml ) following the 6-month dose of vaccines were , respectively , for Groups A-E : 83.2 , 91.7 , 96.5 , 98.8 and 93.9 % , and following the 18-month doses : 87.9 , 97.5 , 98.8 , 98.8 and 92.8 % . Anti-PRP responses ( % > or = 1.0 microg/ml ) following the 6-month dose for Groups A-D were 86.0 , 90.5 , 91.2 , and 74.4 % , and after the 18-month dose for Groups A-E were 97.3 , 98.3 , 98.1 , 97.0 , and 99.5 % . Consistently higher geometric mean titres ( GMTs ) for pertussis antibodies to agglutinogens ( Agg2 , Agg3 ) and pertactin were recorded for the pentavalent vaccine compared to the licensed control vaccine , though they were somewhat lower for pertussigen ( PT ) . Except for the hepatitis B response , antibody responses induced by the pentavalent vaccine to all antigens with a schedule commencing at 2 months of age and completed at 18 months were equivalent to responses to the same antigens induced by the separate , but concurrently administered licensed control vaccines . A regimen of a birth dose of hepatitis B vaccine followed by pentavalent vaccine at 2 , 4 , 6 and 18 months was not countered by any clinical ly significant decrease in seroresponses [17961876] This paper presents the results of four separate phase III trials , which assessed the immunogenicity and reactogenicity of DTPw-HBV/Hib 2.5 in comparison with licensed Tritanrix-Hep B ( GlaxoSmithKline Biologicals ) and Hiberix ( 10 microg PRP ) , given as separate or mixed injections ( 3 trials ) or with or without hepatitis B vaccine at birth ( 1 trial ) . The immunogenicity of DTPw-HBV/Hib 2.5 was non-inferior to the reference vaccine regimen in terms of seropositivity rates . The overall reactogenicity profile of DTPw-HBV/Hib 2.5 was also similar to that of the reference vaccine regimen . These results confirm the previously established immunogenicity and safety of reduced dose PRP conjugated vaccine regimens [18690013] The use of combination vaccines in the routine childhood program reduces distress to the recipients and is likely to improve uptake rates and timeliness of vaccination but requires careful evaluation and surveillance . The aim of this study was to evaluate the immunogenicity and reactogenicity of two commercial diphtheria-tetanus- acellular pertussis-hepatitis b-inactivated polio virus-Haemophilus influenzae type b ( DTaP-HBV-IPV/Hib ) combination vaccines when administered to infants at 3 , 5 and 11 - 12 months of age A total of 494 infants were r and omized to receive three doses of either Infanrix hexa ™ ( GlaxoSmithKline Biologicals ; N=246 ) or Hexavac ™ ( Sanofi Pasteur MSD ; N=248 ) in 10 centers in Italy , Finl and and Sweden . After the third dose , antibodies to diphtheria , tetanus , polio and Hib were at the protective level in nearly all infants in both groups whereas the proportion of subjects who had achieved the protective concentration of ≥10 mIU/ml to hepatitis B surface antigen was 99.1 % ( 95 % CI 96.7 - 99.9 ) in the Infanrix hexa ™ group as compared to 94.4 % ( 95 % CI 90.4 - 97.1 ) in the Hexavac ™ group . Antibody titers to all three polio antigens were highest in Italy and lowest in Finl and . Clinical ly relevant general reactions ( such as fever of > 39.5 ° C ) were mostly reported in less than 5 % of the vaccinees . Three doses of DTaP-HBV-IPV/Hib combination vaccines produced sufficient immune responses in nearly all vaccinees [10333123] Abstract The immunogenic responses and local reactions to four Haemophilus influenzae type b ( Hib ) conjugate vaccines licensed for primary immunisation ( Hiberix , ActHib , Pedvax , HibTITER ) when administered concomitantly but in the opposite thigh with a c and i date diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus vaccine were studied in 549 healthy infants at 3 , 4.5 and 6 months of age . Local reactions were mild , but different between the four groups , a tetanus conjugate Hib vaccine showing the fewest reactions . All local reactions resolved without sequelae . There was no apparent general reaction . The immunogenic response was similar with all four vaccines , geometric mean concentrations ranging from 4.95 to 7.2 μg/ml . All but one subject had anti-polyribosylribitol phosphate polysaccharide antibody titres ≥0.15 μg/ml , and 88.0 % to 96 % achieved high titres ( > 1.0 μg/ml ) generally associated with long-term protection against Hib disease . Conclusion There does not appear to be any interference with the immune response when current commercial Haemophilus influenzae type b conjugate vaccines are concomitantly administered with a c and i date diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio virus vaccine as separate injections [15665717] The effect of pertussis toxoid on the immunogenicity of diphtheria and tetanus toxoids ( DT ) was studied during a double blind efficacy trial of an acellular pertussis vaccine . Infants received DT with or without pertussis toxoid at 3 , 5 and 12 months of age . Geometric mean concentrations were higher in the DT than in the DT-pertussis toxoid group 1 month ( diphtheria toxoid 4.76 versus 3.58 IU/mL , P = 0.009 ; tetanus toxoid 4.42 versus 2.66 IU/mL , P < 0.0001 ) and 2 years after the third injection ( diphtheria toxoid 0.15 versus 0.10 IU/mL , P < 0.0001 ; tetanus toxoid 0.38 versus 0.18 IU/mL , P < 0.0001 ) . Pertussis toxoid causes a small but significant reduction of the immunogenicity of diphtheria toxoid and tetanus toxoid [10969252] OBJECTIVE The aim of this open , multicenter , r and omized trial was to evaluate the immunogenicity and reactogenicity of a c and i date combined diphtheria-tetanus-acellular pertussis-hepatitis B virus-inactivated polio virus ( DTaP-HBV-IPV ) vaccine when given as either a mixed or as separate concomitant injections with Haemophilus influenzae type b ( Hib ) vaccine . STUDY DESIGN A total of 359 subjects were r and omized to receive either DTaP-HBV-IPV/Hib ( mixed administration - 180 subjects ) or DTaP-HBV-IPV + Hib ( separate administration in opposite limbs - 179 subjects ) at 2 , 3 , and 4 months of age . RESULTS After vaccination , seroprotective antibody concentrations against diphtheria , tetanus , hepatitis B , and polio viruses and a high ( > or = 97 % ) pertussis vaccine response were seen in almost all study participants . All subjects except one in the mixed administration group had postvaccination Hib anti-PRP antibody concentrations > or = 0.15 microg/mL. Of subjects in the mixed and separate group , 77.2 % ( geometric mean antibody concentration , 2 . 62 microg/mL ) and 88.6 % ( geometric mean antibody concentration , 4.45 microg/mL ) had Hib anti-PRP concentrations > or = 1 microg/mL , respectively . The addition of the Hib component to the 5-component vaccine did not increase the incidence of local or general reactions . CONCLUSION Both administrations of the c and i date vaccine were found to be safe , immunogenic , and well tolerated . Although anti-PRP geometric mean antibody concentrations and the percent of subjects achieving the 1 microg/mL seroprotective level were lower after the mixed administration , they were in the range seen with monovalent Hib vaccines or with other DTaP-based/Hib combinations licensed in some European countries . Therefore both administrations have the potential to simplify childhood immunization [9431382] We compared antibody levels following separate but simultaneous administration of diphtheria and tetanus toxoids with acellular pertussis vaccine ( DTaP ) containing pertussis toxoid , filamentous hemagglutinin , and pertactin ( PRN ) ; hepatitis B vaccine ; and Haemophilus influenzae type b polysaccharide ( polyribosylribitol phosphate ; PRP ) vaccine conjugated to tetanus toxoid ( PRP-T ) with those following administration of a combination of a DTaP-hepatitis B vaccine-PRP-T to infants at 2 , 4 , and 6 months of age . The antibody response to a booster dose of PRP conjugate vaccine ( CRM197-OS ) in infants with low ( < 1 microgram/mL ) or undetectable ( < 0.10 microgram/mL ) postpriming levels of antibody to PRP was also studied . Antibody levels were quantitated before and after dose 3 by enzyme-linked immunosorbent assay , radioimmunoassay , or neutralization assay . Seroresponse rates were not different between the two vaccine groups except for rates of response to PRP . There was a trend that levels of antibody to all the antigens included in the combination vaccine were lower than those of antibody to antigens in separate vaccines ; for levels of antibody to diphtheria toxoid ( P = .001 ) , PRN ( P < .0001 ) , and PRP ( P < .0001 ) , the differences were significant . Despite low or undetectable postpriming levels of antibody to PRP , high-titered ( geometric mean concentration , 9.02 micrograms/mL ; range , 1.0 - 81.5 micrograms/mL ) , immunoglobulin G-predominant antibody to PRP was produced following a booster dose of CRM197-OS , a finding consistent with a memory response [12431356] OBJECTIVE The DTPw-HB/Hib pentavalent combination vaccine has been developed following recommendations of the World Health Organization for the introduction of hepatitis B ( HB ) and Haemophilus influenzae type b ( Hib ) vaccines into routine childhood vaccination programs . The objectives of this study were to : 1 ) analyze the immunogenicity and the reactogenicity of the DTPw-HB/Hib pentavalent combination vaccine in comparison to separate injections of DTPw-HB and Hib vaccines as primary vaccination in a group of children who had received a dose of HB vaccine at birth and 2 ) in the second year of life to assess the antibody persistence as well as the response to a DTPw-HB/Hib or DTPw/Hib booster . METHODS In the first part of the study ( primary -vaccination stage ) , conducted in 1998 - 1999 , we analyzed the immunogenicity and reactogenicity of the DTPw-HB/Hib combination vaccine in comparison to separate injections of DTPw-HB and Hib vaccines as primary vaccination at 2 , 4 , and 6 months of age in 207 Costa Rican children who had received a dose of HB vaccine at birth . Later , in the booster-vaccination stage of the study , in 1999 - 2000 , in a subset of the children ( 69 toddlers , now 15 - 18 months old ) , antibody persistence was measured , and response to a DTPw-HB/Hib or DTPw/Hib booster was also assessed . RESULTS In both primary -vaccination groups , at least 97.5 % of the infants reached protective levels of antibodies ( seropositivity ) against the antigens employed in the vaccines . The DTPw-HB/Hib pentavalent combination vaccine did not result in more local reactions than did the DTPw-HB vaccine alone , and , in terms of general reactions , there was no clinical ly significant difference between the combination or separate injections , and with the pentavalent vaccine having the benefit of needing one less injection . Nine months after the third dose of the primary -vaccination course , antibody persistence was similar in both groups , with over 93 % of children still having protective/seropositive titers for Hib , HB , and tetanus and about 50 % for diphtheria and Bordetella pertussis . At 15 months of age , virtually all the toddlers responded with a strong boost response to all the vaccine antigens , whether they received the DTPw-HB/Hib pentavalent vaccine or the DTPw/Hib vaccine as a booster . Both booster regimens were equally well tolerated , indicating that up to five doses of the HB vaccine can be given without impact on safety . CONCLUSIONS Our study confirms that the DTPw-HB/Hib pentavalent vaccine is highly immunogenic as a primary vaccination in children who received an HB vaccine at birth , with the pentavalent combination inducing both persisting immunity and boostable memory . The pentavalent vaccine was safe both for primary and booster vaccinations . Thus , this study in Costa Rican infants supports the routine use of the pentavalent DTPw-HB/Hib vaccine as part of childhood vaccination programs in Latin America and the Caribbean [11144370] Objective . The immunogenicity and safety of a new liquid hexavalent vaccine ( diphtheria-tetanus-acellular pertussis-inactivated polio vaccine-hepatitis B-polyribosyl ribitol phosphate conjugated to tetanus protein ; Hexavac ; Aventis Pasteur MSD , Lyon , France ) are compared with those of reference vaccines [ diphtheria-tetanus-acellular pertussis-inactivated polio vaccine reconstituting lyophilized purified Haemophilus influenzae polysaccharide conjugated to tetanus protein vaccine ( Pentavac ; Aventis Pasteur MSD ) and hepatitis B vaccine ( H-B-Vax II ; Aventis Pasteur MSD ) ] injected separately at the same visit in a prospect i ve multicenter , comparative , open label trial . Methods . Infants were r and omized to receive Hexavac ( n = 423 ) or Pentavac and H-B-Vax II ( n = 425 ) as a primary immunization series at 2 , 4 and 6 months of age . Seroprotection and seroconversion rates against all antigens at 1 month after the primary series were compared between the two vaccine groups with 95 % confidence intervals ( CI0.95 ) and were considered clinical ly equivalent ( not inferior ) when the upper limit of the 95 % confidence interval on the difference ( reference , hexavalent ) was below predefined differences . Results . Hexavac met and surpassed the predefined criteria for clinical equivalence to Pentavac and H-B-Vax II given concomitantly . It elicited similar seroprotection and seroconversion rates against all antigens . Seroprotection and seroconversion rates obtained 1 month after the third dose of Hexavac were > 90 % for all antigens . The postimmunization antibody geometric mean titers ( GMT ) for hepatitis B and purified Haemophilus influenzae polysaccharide were about 2-fold higher in infants who received the reference vaccines than in infants who had received Hexavac . GMTs for poliovirus antibodies tended to be enhanced in infants vaccinated with Hexavac . GMTs for all other antigens were very similar among both groups . Hexavac was generally well-tolerated . At least one local reaction was reported in 20.3 % of Hexavac injections compared with 15.8 % at the Pentavac injections site and 3.8 % at the H-B-Vax II injections site . These reactions were generally mild and transient . At least one systemic adverse event was reported in 45.7 % of Hexavac injections compared with 42.2 % of Pentavac and H-B-Vax II injections ( mild fever , irritability and drowsiness were most frequently reported ) . The frequency of adverse events was not significantly different between groups . No vaccine-related serious adverse event occurred during the study . Conclusion . This liquid hexavalent vaccine was generally well-tolerated and provided immune responses adequate to be protective against six infectious diseases with a single injection , given at 2 , 4 and 6 months of age [12718838] OBJECTIVES To determine the immunogenicity and reactogenicity of a combined DTPw-HBV/Hib vaccine , in comparison with DTPw-HBV and Hib vaccines given as separate concomitant injections . METHODS In an open , r and omized study , healthy infants were injected with either DTPw-HBV/Hib vaccine or separate DTPw-HBV and Hib vaccines at 2 , 4 and 6 months of age , with a booster at 18 months . RESULTS Both vaccination regimens were immunogenic , with seropositivity rates of 100 % after the booster vaccination for all vaccine components . Even as early as 2 months after the second dose of the primary vaccination , most patients had seroprotective antibody titers , the proportion of seropositive subjects approaching 100 % for tetanus , hepatitis B , and Hib . Post- primary and post-booster geometric mean titers ( GMTs ) were well above seroprotective thresholds for each vaccine antigen in both groups , with no clinical ly relevant differences in the groups . The separate and combined administrations showed comparable reactogenicity profiles , and neither showed a significant increase in reactogenicity with successive doses . CONCLUSIONS The results of this study support the combination of Hib and DTPw-HBV vaccination in routine infant immunization at 2 , 4 and 6 months of age with a booster at 18 months . Maximum benefit is obtained from compliance with the full course , but substantial benefit is likely to be achieved even in partially compliant patients , provided they receive at least two doses . Furthermore , these results demonstrate the tolerability of a fourth ( booster ) administration , where the addition of the Hib vaccine to DTPw-HBV did not lead to an increase in the overall reactogenicity [11457553] An open , r and omised , multicentre trial was performed to assess the reactogenicity and safety profile of the administration of a c and i date Haemophilus influenzae type b ( Hib ) conjugate vaccine with a quadrivalent diphtheria-tetanus-acellular pertussis-hepatitis B ( DTPa-HBV ) vaccine as a single injection ( Group 1 ) versus the simultaneous administration of the latter vaccine ( DTPa-HBV ) and an available Hib conjugate vaccine ( Group 2 ) in opposite thighs , as a primary vaccination course to healthy infants at 2 , 4 and 6 months of age . Eight hundred and eighty five infants ( 9.3+/-1.4 weeks old ) were r and omly allocated to Group 1 ( n=665 ) and Group 2 ( n=221 ) . Oral polio vaccine was given concomitantly to all subjects . Blood sample s ( pre-vaccination and 1 month after the third dose ) were obtained from a subset of infants ( Group 1 , 73 ; Group 2 , 22 ) for serological determinations . Local and general symptoms were recorded by parents on diary cards . 2614 diary cards ( Group 1 , 1966 ; Group 2 , 648 ) were collected . There were no statistically significant differences in the incidence of local and general symptoms between groups . Pain such that the infant cried when limb was moved was reported in 0.6 and 0.2 % in groups 1 and 2 , respectively . Redness and swelling ( > 20 mm in diameter ) were recorded between 2.1 and 3 % in both groups . Fussiness preventing normal activities was the most frequently reported general symptom in both groups ( 1.6 and 1.9 % in groups 1 and 2 , respectively ) . Fever ( rectal temperature > 39.5 degrees C ) was reported in 0.4 % ( Group 1 ) and 0.3 % ( Group 2 ) . All subjects included in the immunogenicity analysis had seroprotective or seropositive titres to the diphtheria , tetanus , hepatitis B and pertussis components of the vaccines . About 99 and 100 % of infants had anti-PRP titres > or = 0.15 mcg/ml in groups 1 and 2 , respectively . This study indicates that DTPa-HBV vaccine given in a single injection with a c and i date Hib conjugate vaccine has a similar reactogenicity profile to that of two commercially available vaccines ( DTPa-HBV , Hib ) given in two simultaneous injections to infants 2 , 4 and 6 months of age [9569468] Safety , immunogenicity and lot consistency of five-component pertussis combination vaccine ( CPDT-IPV//PRP-T ) in infants were compared to that of whole cell pertussis combination vaccine ( DPT-IPV//PRP-T ) , as were separate and combined injections of CPDT-IPV and PRP-T. No significant differences in adverse event rates were observed between lots of CPDT-IPV//PRP-T or between separate or combined injections of CPDT-IPV and PRP-T. Minor differences in antibody responses were observed between lots of component pertussis vaccine . Higher concentrations of diphtheria and tetanus antitoxins were induced by separate than by combined injection of CPDT-IPV and PRP-T , but no other differences in immunogenicity were observed . Adverse reactions were more than twice as frequent after whole cell than after component pertussis vaccines . Antibody responses to pertussis toxoid , filamentous hemagglutin and pertactin were significantly greater after component vaccines , while the response to type 3 poliovirus was higher after whole cell vaccine . No significant differences were observed for other vaccine components . CPDT-IPV//PRP-T was safe and immunogenic in infants . Antibody results were similar to those observed in a Swedish field trial that demonstrated CPDT to be 85 % effective in preventing clinical pertussis [11803003] BACKGROUND The diphtheria-tetanus-whole-cell pertussis ( DTPw ) vaccine is being replaced in Western countries , and in several Spanish Autonomous Communities , by the diphtheria-tetanus-acellular pertussis ( DTPa ) vaccine . Although the administration of booster doses of DTPw or DTPa and Haemophilus influenzae type b conjugate ( Hib ) vaccines to toddlers is a current practice ina number of countries , there are few data comparing the reactogenicity profiles of their administration as a single injection . SUBJECTS AND METHOD An open , prospect i ve , r and omised , multicentre trial was conducted to compare the reactogenicity profile of a single injection of DTPa and Hib vaccines ( DTPa/Hib ) with that of a single injection of DTPw and Hib vaccines ( DTPw/Hib ) as booster doses to toddlers -- previously primed with DTPw and Hib vaccines . 200 children ( 15.1 + /-1.0 months-old ) were r and omised to receive DTPa/Hib ( group 1;n = 101 ) or DTPw/Hib ( group 2 ; n = 99 ) and followed up to 30 days post-vaccination . All subjects received the oral polio vaccine concomitantly . Local and general symptoms were recorded by parents on diary cards . RESULTS Incidences of any local reaction and any general symptom < < probably related>>/<<suspected>>to vaccination were reported more frequently in group 2 than in group 1 ( p < 0.0001 ) . Pain at the injection site was reported by 29 % and 66 % of subjects in groups 1 and 2 , respectively ( p < 0.0001 ) . Pain such that the child cried when limb was moved was also more frequently recorded in group 2 ( 15 % ) than in group 1 ( 1 % ) ( p < 0.0001 ) . Differences in prevalence of any swelling(16 % in group 1 , 30 % in group 2 ) and swelling > 20 mm reached statistical significance ( p ( 3/4 ) 0.012 ) . Fever ( rectal temperature>= 38 degrees C ) was reported by 17 % and 41 % in groups 1 and 2 subjects , respectively ( p < 0.0001 ) . Fussiness , loss of appetite and restlessness were also more frequently reported in DTPw/Hib subjects and reached statistical significance ( at least p = 0.015).Analgesics/antipyretics were prescribed as a prophylactic treatment in only 14 % of cases ( 9 and 19 subjects in groups 1 and 2 , respectively;p = 0.0424 ) . Antipyretic treatment after vaccination was significantly more prescribed in group 2 ( 27 cases ) than in group 1 ( 8) ( p < 0.015 ) . CONCLUSION The administration of DTPa/Hib as a single injection leads to a better reactogenicity profile than the administration of DTPw/Hib , also as a single injection , as booster doses to toddlers primed with DTPw and Hib vaccines [9796053] This double-blind , r and omised study was performed to assess the immunogenicity and reactogenicity of three lots of a quadrivalent diphtheria-tetanus-acellular pertussis-hepatitis B vaccine ( DTPa-HBV ) co-administered with three lots of Haemophilus influenzae type b conjugate ( Hib ) vaccine in one injection , as a primary vaccination course in healthy infants at 2 , 4 and 6 months of age . 269 infants ( 8 - 11 weeks of age ) were r and omly allocated to three groups to receive DTPa-HBV/Hib vaccines , concomitantly with oral polio vaccine . Blood sample s for antibody determinations were taken before vaccination and 1 month after the third dose in 262 subjects . Local and general symptoms were recorded by parents on diary cards . All vaccinees had post-vaccination protective anti-D and anti-T ( > or = 0.1 IU ml-1 ) antibodies , and 98 % had protective anti-HBs antibody titres ( > or = 10 mIU ml-1 ) . There were no statistically significant differences between groups in post-vaccination anti-D , anti-T , anti-HBs antibody geometric mean titres ( GMT ) , these being 3.49 IU ml-1 , 5.92 IU ml-1 and 1109 mIU ml-1 , respectively . All subjects responded to three pertussis components , i.e. pertussis toxin ( PT ) , filamentous haemagglutinin ( FHA ) and pertactin ( PRN ) . Although statistically significant differences in GMTs of anti-PT , anti-FHA and anti-PRN were found between groups , these were not believed to be of any clinical relevance as the minimum GMTs were 60 , 193 and 230 EL.U ml-1 for anti-PT , anti-FHA and anti-PRN , respectively . There were no statistically significant differences in anti-PRP antibody GMT ( 4.05 micrograms ml-1 ) between groups , 100 % and 85 % of subjects having titres > or = 0.15 and 1.0 microgram ml-1 , respectively . No symptoms were reported for one third of the subjects . Fever ( > 38 degrees C ) was reported after 16 % of doses , with < 1 % having > 39.5 degrees C. Almost all local and general symptoms were mild or moderate , and lasted less than 48 h. No subject dropped out due to a severe adverse reaction . The administration of an experimental mix of DTPa-HBV and Hib vaccines in a single injection is safe , well-tolerated and immunogenic for all vaccine components [17012890] We assessed the safety and immunogenicity of a fully liquid , DTPw-HepB-Hib combination vaccine ( Quinvaxem ™ ) in comparison with separately administered DTPw-Hib and hepatitis B vaccines . Infants participating in this open-label , r and omized , phase II study received a primary vaccination course using a 2 - 3 - 4 month schedule . Blood sample s were taken immediately prior to the first and one month after the third vaccination . Adverse events were assessed over a 7-day post-vaccination period using subject diaries . After completion of the primary vaccination course , 94.7 % [ 95%CI : 89.8 – 97.7 % ] of infants receiving the combination vaccine achieved protective anti-HBs antibody titers ( ? 10 mIU/mL ) with a mean 39-fold increase in GMTs in comparison with 99.3 % [ 95%CI : 96.3 – 100 % ] seroprotection and a mean 29-fold GMT increase in the comparator group . Diphtheria , tetanus , and Haemophilus influenzae type B ( Hib ) seroprotection rates and pertussis seroconversion rates were also similar between the two groups . There was no statistically significant difference in GMTs for diphtheria between the two groups , but significant differences were shown for tetanus , Hib , and pertussis with higher GMTs for each antigen observed in the comparator group . The combination vaccine was well tolerated , with fever ( body temperature 38 ° C ) being the most frequently reported adverse event in both the DTPw-HepB-Hib ( 12.5 % [ 95%CI : 7.7 – 18.8 % ] ) and comparator ( 12.6 % [ 95%CI : 7.7 – 19.0 % ] ) groups . This study demonstrated that the fully liquid DTPw-HepB-Hib combination vaccine has safety and immunogenicity profiles similar to the DTPw-Hib and hepatitis B vaccines when administered separately [21289531] Background : Assessment of primary vaccination of a new fully liquid , hexavalent investigational DTaP-IPV-Hep B-PRP-T vaccine ( Hexaxim ) in South African infants . Methods : Infants were r and omized to the following at 6 , 10 , and 14 weeks of age ( Exp and ed Program on Immunization schedule ) : DTaP-IPV-Hep B-PRP-T ( Group 1 ; N = 286 ) ; DTwP-Hib , hepatitis B , and OPV vaccines ( Group 2 ; N = 286 ) ; or DTaP-IPV-Hep B-PRP-T vaccine with hepatitis B vaccine at birth ( Group 3 ; N = 143 ) . Antibody titers were measured before vaccination ( pertussis toxoid , filamentous hemagglutinin ) and post primary vaccination ( all valences ) . Noninferiority analyses were performed for Group 1 versus Group 2 for seroprotection rates . Safety was evaluated from parental reports . Results : Noninferiority ( Group 1 minus Group 2 ) was demonstrated for anti-HBs , -PRP , -diphtheria , -tetanus , and -polio 1 , 2 , 3 ( lower 95 % confidence interval for the difference was −8.20 to 3.46 ) . Anti-HBs antibody titers ≥10 mIU/mL and anti-PRP ≥0.15 & mgr;g/mL were ≥95.4 % in each group . Seroprotection rates were also high for the other antigens . Seroconversion rates ( 4-fold increase from pre- to postvaccination ) were 93.6 % , 83.2 % , and 95.1 % in Groups 1 , 2 , and 3 , respectively , for anti-pertussis toxoid and 93.1 % , 57.7 % , and 90.0 % for anti-filamentous hemagglutinin . Anti-HBs GMTs were 330 , 148 , and 1913 mIU/mL for Groups 1 , 2 , and 3 , respectively . Reactogenicity was similar in each group . Fever ≥39.0 ° C occurred in 1.7 % , 0.4 % , and 0.0 % of infants in Groups 1 , 2 , and 3 , respectively ; no extensive limb swelling , hypotonic-hyporesponsive episodes , or vaccine-related serious adverse events were reported . Conclusions : The new , fully liquid , investigational hexavalent vaccine in the Exp and ed Program on Immunization schedule , with/without hepatitis B at birth , is highly immunogenic and safe compared with control vaccines , warranting further development [11906779] This multicentre study was design ed to establish the reactogenicity and immunogenicity profiles of primary and booster vaccination with diphtheria , tetanus , and pertussis whole-cell-hepatitis B/Haemophilus influenzae type-b ( DTPw-HB/Hib ) administered as either a syringe mix or as separate injections in 400 Latin American children . Both vaccine regimens were equally well tolerated and elicited post- primary excellent seropositivity rates at or close to 100 % for all five component antigens . With regard to HB , 100 % of subjects in the combined vaccination group , and 98.8 % subjects in the separate injection vaccination group reached seroprotective antibody concentrations ( > or=10 mIU/ml ) 1 month after the primary vaccination course . Equally high anti-PRP antibody concentrations were reached 1 month after vaccination , with 100 % of seroprotected subjects in the combined vaccination group ( antibody concentrations > or=0.15 microg/ml ) , against 99.4 % in the separate injection vaccination group . Seroprotective anti-HBs and anti-PRP antibody concentration levels persisted approximately 1 year after the primary vaccination course , just prior to booster vaccination . Finally , a significant increase of all antibody concentrations could be observed after the booster vaccination , since all but one subject in the separate injection vaccination group had protective levels of anti-HBs and anti-PRP antibodies 1 month after the booster dose . These results suggest that the combination of DTPw-HB and Hib vaccines provides an effective means for increasing vaccine coverage in childhood vaccination programmes [19124057] Combination vaccines improve parental and provider satisfaction and schedule compliance by decreasing the number of injections . In a Phase 2 , r and omized , double-blind , multicenter study , we compared four formulations of a liquid , hexavalent diphtheria-tetanus-acellular pertussis-inactivated poliovirus-Haemophilus influenzae b conjugate-hepatitis B virus ( DTaP-IPV-Hib-HBV ) vaccine in 708 infants immunized at 2 , 3 , 4 , and 12 - 14 months of age . The formulations contained identical DTaP and IPV components , differing in the contents of Hib polyribosylribitol phosphate ( PRP ) conjugate component ( tetanus-toxoid [ PRP-T , 12microg ] or Neisseria meningitidis outer-membrane-protein-complex [ PRP-OMPC , 3microg or 6microg ] ) , and in hepatitis B surface antigen ( HBsAg , 10microg or 15microg ) . A minimum acceptable postdose 3 antibody response rate was defined by the lower limit of the 95 % confidence interval exceeding a prespecified target . Rates of adverse events ( AEs ) were similar among groups , with a trend for increased solicited injection-site reactions ( pain , redness , swelling ) with increasing PRP-OMPC and HBsAg concentration . Serious AEs reported by eight subjects were not considered to be vaccine related . All PRP-OMPC formulations met prespecified acceptability criteria for postdose 3 immunogenicity for all antigens : PRP , HBsAg , pertussis , diphtheria , tetanus and polio . Apart from the Hib response , the postdose 3 responses obtained with the PRP-T formulation met the acceptability criterion for each antigen . Postdose 4 responses were acceptable for all antigens in all formulations . All vaccine formulations were well tolerated . The three PRP-OMPC formulations met prespecified immunogenicity criteria , and the one with the lowest PRP-OMPC concentration was selected for further optimization of immunogenicity [21134456] The current recommended infant vaccination schedules require many injections at multiple sites , which increase stress for infants and parents and may create challenges to vaccination compliance . Therefore , combination vaccines , which reduce the number of injections at each medical visit , can be an essential method to improve compliance . The objective of this study was to assess the safety and immunogenicity of an investigational , liquid , hexavalent , pediatric vaccine at 2 , 4 , 6 , and 12 - 14 months of age . In this multicenter , open-label controlled study , 756 infants were r and omized in approximately equal numbers to receive 0.5mL intramuscular dose of diptheria-tetanus-pertussis-polio-Haemophilus influenzae type b+hepatitis B vaccine , or 1 of 3 double-blind investigational formulations . All formulations included a hepatitis B surface antigen ( HBsAg ) concentration of 10μg/0.5mL. The three hexavalent vaccine formulations used in this study contained either Hib polyribosylribitol phosphate ( PRP ) conjugate component ( tetanus toxoid [ PRP-T , 12μg ] or Neisseria meningitidis outer membrane protein complex [ PRP-OPMC , 3μg or 6μg ] ) : a minimum acceptable postdose 3 antibody response rate for each antigen was defined by the lower limit of a 95 % confidence interval exceeding a prespecified target . Rates of adverse events ( AEs ) were similar among groups , with a trend for increased solicited vaccine-related injection-site reactions ( pain , erythema , swelling ) with increasing PRP-OMPC dose . No serious vaccine-related AEs were reported in the investigational groups . Both PRP-OMPC formulations met prespecified acceptability criteria for all antigens : PRP , HBsAg , pertussis , diphtheria , tetanus and poliovirus . The PRP-T formulation met the acceptability criterion for antibody responses to all antigens other than PRP at postdose 3 . Postdose 4 responses were adequate for all antigens in all formulations . All vaccine formulations were well-tolerated . Both PRP-OMPC formulations met prespecified immunogenicity criteria of PRP-OMPC evaluation [15629356] The safety and reactogenicity of a booster dose of GSK Biologicals ' hexavalent DTPa-HBV-IPV/Hib vaccine ( N=4725 ) was compared with the separate administration of GSK Biologicals ' DTPa-IPV/Hib and HBV vaccines ( N=4474 ) in two open , r and omized multicenter studies ( A and B ) . Solicited symptoms occurring within 4 days of vaccination were recorded on diary cards and serious adverse events ( SAEs ) were collected throughout the study period . In Study A ( N=1149 ) , incidences of solicited symptoms were similar in both groups ; there were no SAEs either reported within 4 days of vaccination or considered to be causally related to vaccination . In study B ( N=8050 ) , where fever was the only solicited symptom , rectal temperature > or = 39.5 degrees C was observed in 2.5 % and 2.8 % of the subjects , respectively . Fever > or = 40.0 degrees C was rare ( 0.6 % ) , and only two cases of febrile convulsions were recorded during the 4 days following vaccination both in the control group . Large swelling reactions ( defined as local injection site swelling with diameter > 50 mm , noticeable diffuse injection site swelling or noticeable increased circumference of the injected limb ) were reported following 2.3 % of the booster vaccine doses , regardless of the vaccine used . Extensive swelling reactions involving an adjacent joint were reported in 0.1 % of the subjects . Two SAEs , both reported after booster doses of DTPa-IPV/Hib and HBV vaccines administered separately , were considered by the investigators to be related to vaccination . Both resolved completely without sequelae . The hexavalent DTPa-HBV-IPV/Hib vaccine and the DTPa-IPV/Hib and HBV vaccines administered separately have similar good reactogenicity and safety profiles when given as booster doses in the second year of life [10496155] A study was undertaken to evaluate the safety and immunogenicity of a combination vaccine ( TETRAMUNE ) of conjugate Haemophilus influenzae type b ( Hib ) vaccine ( HibTITER ) and DTP ( Diphtheria , Tetanus and Pertussis ) vaccine . A total of 93 healthy children were r and omized to receive either TETRAMUNE ( combined group ) , or DTP and HibTITER administered concurrently ( separate group ) in separate syringes at approximately 2 , 4 and 6 months of age in Taiwan . Serologic responses were largely comparable between the two vaccine groups ; almost all subjects were seropositive to Hib PRP ( polyribosylribitol phosphate ) and were protected against diphtheria and tetanus after 2 doses of vaccine and mounted prominent responses to the components of Bordetella pertussis . Subjects in the combined group did not experience more adverse reactions compared with those in the separate group . We concluded that HibTITER was highly immunogenic and safe when administered concurrently with DTP vaccine to Taiwanese children . TETRAMUNE was also safe and immunogenic and might reduce the number of injections to achieve the same protection [17012870] Objectives : To assess the safety , immunogenicity and lot consistency of a liquid hexavalent combined vaccine ( DTaP-IPV-PRP ~ T-HBs , HEXAVAC ® ) ( Sanofi-Pasteur MSD , France ) administered to infants at 2 , 4 , and 6 months of age . Methods : A total of 1028 infants were vaccinated with one of 3 vaccine lots , in a r and omized , double-blind fashion . Equivalence testing was used to compare post-vaccination seroprotection/seroconversion rates and geometric mean titers ( GMTs ) for each antigen between the three lots . Blood sample s were drawn before vaccination and one month after the third dose . Local and systemic adverse events were monitored for 3 days following each injection . Results : Equivalence between lots was demonstrated for all antigens , on post-dose 3 seroprotection/seroconversion rates and GMTs . Reported rates of local and systemic adverse events tended to increase with subsequent doses . Altogether , 11.8 % of the infants reported at least one adverse local event ( mainly redness and in duration /swelling ) after the first dose and 36.1 % after the third dose . Systemic adverse events ( mainly irritability and fever ) were reported by 39.2 % of the infants after the first dose and by 57.5 % after the third one . Conclusion : Three separate lots of the liquid hexavalent combined vaccine induced consistently protective antibody responses against all antigens . These results and the well established clinical tolerability of this combined vaccine make it suitable for primary immunization of infants at 2 , 4 , and 6 months of age [15370670] A combined DTPa-HBV-IPV/Hib vaccine containing diphtheria ( D ) , tetanus ( T ) , acellular pertussis ( Pa ) , hepatitis B ( HBV ) and types 1 , 2 and 3 inactivated polioviruses ( IPV ) extemporaneously mixed with a conjugated Haemophilus influenzae type b ( Hib ) vaccine ( Group 1 ) was compared to the DTPa-HBV-IPV and Hib vaccines ( Group 2 ) administered separately at 3 , 5 and 11 months of age ( n=440 ) . A microneutralization assay was used to detect antibodies against the 3 polio virus types ( cut-off 1:8 dil ) , RIA for anti-HBs antibodies ( cut-off 10 mIU/ml ) and ELISA for antibodies against all other vaccine antigens ( cut-off : 0.1 IU/ml for anti-tetanus and anti-diphtheria antibodies ; 5 El . U/ml for antibodies against each of the 3 acellular pertussis antigens and 0.15 μg/ml for anti-PRP antibodies ) . Similar immune responses were observed in both groups 1 month after dose 2 as well as after dose 3 . Six months after dose 2 however , the proportion of subjects maintaining an anti-tetanus antibody concentration ≥0.1 IU/ml was lower in Group 2 and a slight group difference in favour of Group 1 was also observed for anti-PRP , anti-diphtheria and anti-polio type 1 antibody persistence prior to the third dose . The overall incidence of local and general solicited symptoms was similar in both groups . One subject discontinued study vaccination following an SAE considered to be related to vaccination . The DTPa-HBV-IPV/Hib combined vaccine is immunogenic and well tolerated when administered according to a 3 , 5 and 11 month vaccination schedule and can therefore be considered as a feasible alternative to the separate administration of the pentavalent DTPa-HBV-IPV and the monovalent Hib vaccines [15149781] Safety , reactogenicity and immunogenicity of GSK Biologicals ' hexavalent DTPa-HBV-IPV/Hib vaccine (Infanrix)hexa ) was assessed when used for primary vaccination at 3 , 4 and 5 months of age ( N = 2163 ) , compared to the separate administration of DTPa-IPV/Hib and HBV vaccines ( N = 720 ) . A similar safety and reactogenicity profile was demonstrated for both vaccine regimens , as well as a good immune response for all antigen components . By offering protection against six diseases in a series of single injections , the hexavalent DTPa-HBV-IPV/Hib vaccine was shown to be a safe , well tolerated and immunogenic alternative to primary immunization with licensed separately administered vaccines [16404468] OBJECTIVE The ability to accurately identify articles about therapy in large bibliographic data bases such as EMBASE is important for research ers and clinicians . Our study aim ed to develop optimal search strategies for detecting sound treatment studies in EMBASE in the year 2000 . METHODS H and search es of journals were compared with retrievals from EMBASE for c and i date search strategies . Six trained research assistants review ed fifty-five journals indexed in EMBASE and rated articles using purpose and quality indicators . C and i date search strategies were developed for identifying treatment articles and then tested , and the retrievals were compared with the h and - search data . The operating characteristics of the strategies were calculated . RESULTS Three thous and eight hundred fifty articles were original studies on treatment , of which 1,256 ( 32.6 % ) were method ologically sound . Combining search terms revealed a top performing strategy ( r and om:.tw . OR clinical trial:.mp . OR exp health care quality ) with sensitivity of 98.9 % and specificity of 72.0 % . Maximizing specificity , a top performing strategy ( double-blind:.mp . OR placebo:.tw . OR blind : .tw . ) achieved a value over 96.0 % , but with compromised sensitivity at 51.7 % . A 3-term strategy achieved the best optimization of sensitivity and specificity ( r and om:.tw . OR placebo:.mp . OR double-blind:.tw . ) , with both these values over 92.0 % . CONCLUSION Search strategies can achieve high performance for retrieving sound treatment studies in EMBASE [11144372] BACKGROUND Combination vaccines are urgently needed to reduce the number of injections given to young children . The aim of the study was to evaluate the safety and immunogenicity of a combination vaccine that contains diphtheria and tetanus toxoids and acellular pertussis antigens ( DTaP ) , recombinant hepatitis B surface antigen ( HepB ) and Haemophilus influenzae type b ( Hib ) polysaccharide conjugated to tetanus toxoid ( PRP-T ) . METHODS Four hundred five infants were r and omized equally to three groups and immunized at 2 , 4 and 6 months of age with : ( 1 ) DTaP/HepB vaccine used to reconstitute lyophilized PRP-T vaccine and administered as a single injection ; ( 2 ) DTaP/HepB vaccine and PRP-T vaccine administered as two separate injections ; or ( 3 ) DTaP , HepB and PRP-T vaccines administered as three separate injections . Safety was closely monitored , and blood specimens were obtained to assess antibody responses to each vaccine antigen . RESULTS All study vaccines were well-tolerated , and the rates of systemic and injection site reactions were similar between groups . After the third dose the geometric mean antibody concentrations to Hib were significantly lower in subjects in Group 1 ( 1.63 microg/ml ) compared with subjects in Groups 2 and 3 ( 6.26 and 6.15 microg/ml , respectively ; P < 0.0001 ) . Subjects with antibody concentrations < 1.0 microg/ml after the third dose responded well to a booster dose of Hib conjugate vaccine given at 11 to 15 months of age ( 41 of 44 with anti-PRP > or = 1.0 microg/ml ) . Differences between groups for antibody responses to the other vaccine components were not clinical ly significant . CONCLUSIONS Infants given a combined DTaP/ HepB/PRP-T vaccine experienced a significantly lower antibody response to the PRP-T component than infants given PRP-T vaccine as a separate injection . However , the immune response to a booster dose of Hib conjugate vaccine indicated the presence of immunologic memory [12901568] Objective : To evaluate , in an open study , the immunogenicity , safety and reactogenicity of a birth dose of hepatitis B vaccine followed by a three-dose course of diphtheria – tetanus whole-cell pertussis – hepatitis B vaccine , extemporaneously mixed with Haemophilus influenzae b ( Hib ) vaccine . Methods : At 2 , 4 and 6 months of age , a single group of 120 Colombian infants were enrolled in this study to receive a regimen consisting of three doses of the combination vaccine following a dose of hepatitis B vaccine at birth . Results : Seroprotection/vaccine response rates to all vaccine antigens was 98–100 % 1 month after completion of the full vaccination course . The vaccine had an acceptable reactogenicity profile and the incidence of reported local and general symptoms decreased with the administration of subsequent vaccine doses . Conclusion : The mixed DTPw – HB/Hib vaccine was safe and well-tolerated , with high immunogenicity against all component antigens . Compared with previous studies , reactogenicity did not increase with the additional dose of hepatitis B vaccine given at birth . The DTPw – HB/Hib combination can be used to provide primary vaccination of infants who have already received a first dose of hepatitis B vaccine at birth [19333002] The study was planned to assess and compare the immune response and safety of an indigenous DTPwHB-Hib pentavalent liquid combination vaccine ( Shan 5 ) with Easyfive and Tritanrix HB + Hiberix , the two available pentavalent combination vaccines . Four hundred infants were r and omized to receive three doses of either Shan 5 or one of the two comparators . Antibody analysis was performed prior to and four to six weeks post third vaccine dose . Solicited local and systemic events upto three days and unsolicited adverse events in the 30 days follow up period after each dose were recorded . A total of 365 subjects completed the study . Four to six weeks after third dose , 98.32 % of the subjects in Shan 5 group had seroprotective Anti PRP-T IgG antibody concentrations ( ≥0.15 µg/mL ) as compared to 100 % and 98.94 % subjects in Tritanrix HB + Hiberix and Easyfive groups respectively . Seroprotective levels for Anti-HBs ( ≥10 mIU/mL ) were observed in 97.77 % , 97.83 % and 98.94 % subjects in Shan 5 , Tritanrix HB + Hiberix and Easyfive groups respectively . Comparable immune responses were observed for the three other components ( D , T and P ) in all the groups . Four Serious Adverse Events ( SAEs ) were reported ( three with Shan 5 and one with Easyfive ) , all unrelated to the respective vaccines . Most commonly reported adverse events in all the groups were pain at injection site , mild fever ( < 103 ° F ) and minor swelling at injection site . The study proved that Shan 5 was safe and immunogenic compared to the two other licensed vaccines [15837232] Infants ( N = 459 ) were r and omly assigned to receive either Infanrix hexa or Hexavac vaccines at 2 , 4 and 6 months of age as a primary vaccination schedule . The immunogenicity of the hepatitis B component was statistically significantly higher for Infanrix hexa compared to Hexavac in terms of both seroprotection ( 98.6 % versus 94.7 % , p = 0.0302 ) and GMCs ( 905.6 versus 226.4 , p < 0.0001 ) . Significantly ( p < or = 0.0001 ) higher antibody levels against diphtheria and the 3 polio components were also induced by Infanrix hexa . The responses to tetanus , Hib and pertussis components were similar . The incidences of clinical ly relevant solicited symptoms , unsolicited symptoms or serious adverse events were low in both groups [16356598] This study assessed compatibility of concurrently administered 7-valent pneumococcal conjugate ( PCV7 ) , hepatitis B ( HB ) and DTaP.IPV/Hib vaccines . Infants were given DTaP.IPV/Hib and HB at 2 , 4 , 6 months and r and omly assigned ( 2:1 ) to receive PCV7 concurrently or sequentially ( at 3 , 5 , 7 months ) . Antibody levels were compared in 246 concurrent and 122 sequential vaccinees . Responses to PCV7 , DTaP.IPV/Hib and HB were generally unaltered with concurrent administration except that Hib responses were increased ( p=0.008 ) and HB responses were reduced ( p=0.006 ) with concurrent dosing , the latter possibly from same thigh injection with DTaP.IPV/Hib . We conclude that PCV7 , DTaP.IPV/Hib and HB are compatible with concurrent , separate injections [11115705] Three hundred and twenty eligible infants were enrolled in an open r and omized clinical trial and allocated to one of two groups to receive either separate concomitant injections of a c and i date combined DTPa-HBV-IPV and commercial Hib vaccine ( c and i date administration : DTPa-HBV-IPV+Hib ) or separate concomitant injections of licensed DTPw-IPV mixed in the same syringe with Hib and HBV vaccines ( comparator administration : DTPw-IPV/Hib+HBV ) . Vaccines were administered at 6 , 10 and 14 weeks of age preceded by a monovalent dose of HBV at birth . The c and i date vaccine administration was shown to be at least as immunogenic ( primary objective ) as the c and i date administration with respect to the diphtheria , tetanus , polio , HBs and PRP seroprotection rates ( primary endpoints ) . Post vaccination , both vaccine administrations showed an equivalent level of seroprotection with nearly all subjects ( > 96 % ) acquiring seroprotective titers against diphtheria , tetanus , polioviruses , HBsAg and PRP antigens . A markedly higher anti-HBs response post dose 2 at week 14 in the group receiving the c and i date vaccine , 98.6 % of subjects had seroprotective titers ( GMT of 505.7 mIU/ml ) compared with only 88.7 % ( GMT of 107.5 mIU/ml ) in the comparator group . There was a lower incidence of adverse events following the DTPa-based c and i date administration compared with the DTPw-based comparator . Despite the early age and short interval between doses , both administrations were immunogenic , with the concomitant administration of DTPa-HBV-IPV and Hib vaccines showing an improved tolerability over the commercial vaccines DTPw-IPV/Hib and HBV [15519702] A new single-injection combination vaccine against six diseases has been developed to accommo date the growing number of recommended paediatric vaccines . A pentavalent liquid diphtheria , tetanus , acellular pertussis ( 3-component ) , hepatitis B , and inactivated polio ( types 1 - 3 ) combined vaccine ( DTPa-HBV-IPV ) is extemporaneously mixed with a lyophilized Haemophilus influenza type B ( Hib ) conjugate vaccine ( polyribosyl-ribitol phosphate (PRP)-T ) and given as a single-injection . A cohort of 368 healthy infants was initially studied to evaluate the immunogenicity and reactogenicity of this hexavalent combination given as a primary course at 2 , 4 , and 6 months of age . At 15 months of age , from this cohort , 219 children received a booster dose of a licensed DTPa/Hib ( PRP-T ) vaccine to assess the booster response , while 70 received a challenge dose of unconjugated PRP ( PRP ) vaccine ( to evaluate Hib-specific memory ) plus a separate DTPa vaccine . Seven to 10 days following plain PRP challenge , anti-PRP geometric mean antibody concentrations ( GMCs ) had increased 13-fold to 5.67 microg/ml , and thirty days after conjugated PRP booster vaccination , anti-PRP antibody GMCs increased 102-fold . Both responses are indicative of immune memory . Vaccination was well tolerated following all primary and booster doses , although 10.5 % of booster recipients experienced > 50-mm local swelling at the site of DTPa vaccination . We conclude that DTPa-HBV-IPV/Hib is safe and immunogenic for primary vaccination , and that Hib-specific memory is induced by primary vaccination [12922087] An open , r and omised , multicentre trial was performed to compare the reactogenicity and safety profile of the administration of a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio ( DTPa-HBV-IPV ) vaccine administered in one injection mixed with Haemophilus influenzae type b ( Hib ) conjugate vaccine ( Group 1 ) with that of a pentavalent DTPa-IPV vaccine mixed with a Hib vaccine ( DTPa-IPV/Hib ) , simultaneously administered with HBV ( Group 2 ) in two injections in opposite thighs , as a primary vaccination course , to healthy infants at 2 , 4 and 6 months of age . A total of 235 completed the study , 120 from Group 1 and 115 from Group 2 . Blood sample s ( pre-vaccination and 1 month after the third dose ) were obtained from a subset of infants ( Group 1 : 40 ; Group 2 : 31 ) to assess the immune response to vaccination . Local and general solicited symptoms were recorded by parents on diary cards . Seven hundred and five diary cards ( Group 1 : 360 ; Group 2 : 345 ) were collected . The clinical ly relevant and most commonly reported local reaction was pain ( infant cried when the limb was moved ) in 2.5 % ( Group 1 ) and 1.2 % ( Group 2 ) of diary cards . Fever was more frequently reported in Group 1 ( 21 % of diary cards ) than in Group 2 ( 12 % of diary cards ) . However only 3 and 2 % of doses in Groups 1 and 2 , respectively , were responsible for a rectal temperature between 38.6 and 39.5 degrees C and only one case ( Group 2 ) had > or = 39.5 degrees C. Other clinical ly relevant general symptoms were rarely recorded : irritability ( 2 - 2.8 % ) , loss of appetite ( 0.3 - 0.6 % ) and drowsiness ( 0.3 - 0.3 % ) . All subjects included in the immunogenicity analysis had seroprotective titres to diphtheria , tetanus , polio virus types 1 and 3 , Hib . Almost all subjects were seroprotected for anti-polio type 2 and hepatitis B ( with the exception of 1 subject in Group 1 for each antigen ) . The vaccines response rates to pertussis antigens were over 97 and 90 % in Groups 1 and 2 , respectively . This study shows that , from a clinical perspective , the DTPa-HBV-IPV/Hib vaccine given in a single injection has a similar reactogenicity and safety profile to that of two licensed vaccines ( DTPa-IPV/Hib , HBV ) given in two simultaneous injections to infants at 2 , 4 and 6 months of age . This is a valuable advantage , since in some countries , such as Spain and the UK , an additional injection ( for the administration of meningococcal C conjugate vaccine ) has been recently included in the infants ' vaccination calendars [10772563] An open , r and omized , clinical trial was conducted in order to assess the reactogenicity and immunogenicity of DTPw-HBV and Haemophilus influenzae type b ( Hib ) vaccines when given either as a mixed administration or as separate concomitant injections using the WHO schedule at 6 , 10 and 14 weeks of age , following a dose of HBV at birth . There were no clinical ly relevant differences in the immune response to any component between the mixed and separate administrations . In fact the anti-tetanus GMTs were significantly higher ( p=0.002 ) in mixed administration ( 3.9 IU/ml ) compared with the separate administration ( 1.9 IU/ml ) . However although all subjects achieved anti-PRP titers > or = 0.15 microg/ml , higher anti-PRP GMTs were seen in the group receiving the separate administration . Importantly , the addition of Hib did not adversely alter the reactogenicity profile of DTPw-HBV . This report which demonstrates that this novel combination can be used in WHO recommended schedule [12908031] Vaccination of infants with conjugated Haemophilus influenzae type b ( Hib ) vaccines has been proven to reduce Hib meningitis by 95 % and pneumoniae by 20 % . The routine use of Hib vaccine is facilitated by the introduction of combination vaccines into the EPI ( Exp and ed Plan of Immunization ) . The objective of this study was to compare the immunogenicity and reactogenicity of an extemporaneously mixed DTPw/Hib ( diphtheria-tetanus-whole cell pertussis ) combination , using the technology of two Brazilian manufacturers , against a licensed DTPw/Hib European combination in 108 infants vaccinated at 2 , 4 and 6 months according to the local national schedule . The Brazilian combination was highly immunogenic with Hib seroprotection rates ( anti-PRP > 0.15 mg /ml of 98 % after 2 doses and 100 % after 3 ) . Also for tetanus and pertussis the new Brazilian combination was as immunogenic as the European counterpart , except the diphtheria seroprotection rates and titers were lower . There was also no clinical ly relevant difference in reactogenicity . If these feasibility results are confirmed , the Brazilian DTPw/Hib combination should help to boost the uptake of Hib vaccination in Brazil [12839281] Aim : Combining paediatric vaccines is a rational solution to reduce the number of injections during a single clinical visit , to maintain parents ' compliance and to extend vaccine coverage . Different diphtheria , tetanus and whole cell pertussis (DTwP)‐containing combination vaccines are licensed and used world‐wide . This study assessed the immunogenicity and safety in infants of a combined diphtheria‐tetanus‐whole cell pertussis‐Haemophilus influenzae type b‐CRM197 conjugate full liquid vaccine . Methods : The safety and efficacy of a combined ready‐to‐use liquid vaccine containing diphtheria and tetanus toxoids , cell suspension of Bordetella pertussis and H. influenzae type b‐CRM197 conjugate vaccine ( DTwPHib ) were assessed in infants eligible for the local Exp and ed Programme on Immunization ( EPI ) in Valencia , Spain . The comparative group received separate injections of reference vaccines DTwP + Hib . Results : Local and systemic reactions and adverse events were generally mild and similar in the two groups . DTwPHib elicited anti‐PRP antibody titres ±0.15 μg ml−1 in 97 % and DTwP + Hib in 94 % of infants . Furthermore , 89 % of DTwPHib and 78 % of DTwP + Hib recipients attained anti‐PRP antibody titres ±1.0 μg ml−1 , signifying long‐term protection . The anti‐PRP geometric mean titre was significantly higher in the combined DTwPHib vaccine group ( 6.65 vs 3.57 μg ml−1 ) . In both groups , 99 % of infants achieved protective ( ±0.01 IU ml−1 ) anti‐diphtheria antibody levels and all children achieved protective ( ±0.1 IU ml−1 ) anti‐tetanus antibody levels . DTwPHib caused a ±2‐fold increase in anti‐pertactin antibody titres in 91 % and a ±4‐fold increase in 82 % of recipients . The corresponding proportions in the DTwP + Hib group were 95 % and 90 % . DTwPHib induced a ±2‐fold increase in anti‐Agg 12 and 3 antibody levels in 79 % and a ±4‐fold increase in 73 % of recipients . The corresponding proportions among DTwP + Hib infants were 85 and 82 % . Conclusion : Overall , the combined liquid vaccine DTwPHib is a safe and effective immunogenic vaccine for EPI use in infants [16874170] Background : Combined vaccines containing diphtheria-tetanus-pertussis whole-cell ( DTPw ) , Haemophilus influenzae type b ( Hib ) , and hepatitis-B vaccines are essential for the continuing success of vaccination programs in developing nations . This r and omized , dose-ranging study assessed the immunogenicity and reactogenicity of primary and booster vaccination with pentavalent DTPw-HBV/Hib vaccines containing 10 , 5 or 2.5μg of polyribosylribitol phosphate ( PRP ) conjugated to tetanus toxoid ( trials Hib-052/064 ) . Methods : Six hundred eighty infants were r and omized to receive one of 5 vaccine combinations at 6 , 10 , and 14 weeks of age . Of these , 351 received the same vaccine at 15–24 months of age . The immune response was evaluated on blood sample s collected 1 month after the 3-dose primary course and before and 6 weeks after the booster dose . Reactogenicity was assessed during a 4-day period after each vaccine dose using diary cards . Results : After primary vaccination , all subjects had seroprotective anti-PRP antibody concentrations ( ≥0.15 μg/mL ) and > 95 % had concentrations ≥1.0 μg/mL , irrespective of the PRP dose administered . Anti-PRP antibody avidity after primary vaccination and antibody persistence until the second year of life were similar among groups . The booster dose induced marked increases in anti-PRP antibody GMCs and antibody avidity , indicative of effective priming and the presence of immune memory . All vaccination regimens elicited good immune responses and comparable antibody persistence to the other vaccine antigens , with significant increases in all antibody concentrations observed after boosting . All vaccination regimens were safe , with similar overall reactogenicity profiles . Conclusion : Hib conjugate vaccines containing reduced amounts of PRP can be effectively combined with the licensed DTPw-HBV vaccine to provide protection against 5 major childhood pathogens in a single injection Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Pneumonia , caused by Streptococcus pneumoniae , is a major cause of morbidity and mortality among children in low-income countries . The effectiveness of pneumococcal conjugate vaccines ( PCVs ) against invasive pneumococcal disease ( IPD ) , pneumonia , and mortality needs to be evaluated . OBJECTIVES To up date the 2004 review on the efficacy of PCVs in preventing vaccine-serotypes IPD ( VT-IPD ) , X-ray defined pneumonia among HIV-1 negative children , and other new outcomes . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

31581312

[3691177] Background Observational studies suggest high prenatal vitamin D intake may be associated with reduced childhood wheezing . We examined the effect of prenatal vitamin D on childhood wheezing in an interventional study . Methods We r and omised 180 pregnant women at 27 weeks gestation to either no vitamin D , 800 IU ergocalciferol daily until delivery or single oral bolus of 200,000 IU cholecalciferol , in an ethnically stratified , r and omised controlled trial . Supplementation improved but did not optimise vitamin D status . Research ers blind to allocation assessed offspring at 3 years . Primary outcome was any history of wheeze assessed by vali date d question naire . Secondary outcomes included atopy , respiratory infection , impulse oscillometry and exhaled nitric oxide . Primary analyses used logistic and linear regression . Results We evaluated 158 of 180 ( 88 % ) offspring at age 3 years for the primary outcome . Atopy was assessed by skin test for 95 children ( 53 % ) , serum IgE for 86 ( 48 % ) , exhaled nitric oxide for 62 ( 34 % ) and impulse oscillometry of acceptable quality for 51 ( 28 % ) . We found no difference between supplemented and control groups in risk of wheeze [ no vitamin D : 14/50 ( 28 % ) ; any vitamin D : 26/108 ( 24 % ) ( risk ratio 0.86 ; 95 % confidence interval 0.49 , 1.50 ; P = 0.69 ) ] . There was no significant difference in atopy , eczema risk , lung function or exhaled nitric oxide between supplemented groups and controls . Conclusion Prenatal vitamin D supplementation in late pregnancy that had a modest effect on cord blood vitamin D level , was not associated with decreased wheezing in offspring at age three years . Trial Registration Controlled-Trials.com IS RCT [24344104] OBJECTIVE : To determine the vitamin D dose necessary to achieve serum 25-hydroxyvitamin D ( 25(OH)D ) concentration ≥20 ng/mL during infancy . METHODS : A r and omized , double-blind , placebo-controlled trial in New Zeal and . Pregnant mothers , from 27 weeks ’ gestation to birth , and then their infants , from birth to age 6 months , were r and omly assigned to 1 of 3 mother/infant groups : placebo/placebo , vitamin D3 1000/400 IU , or vitamin D3 2000/800 IU . Serum 25(OH)D and calcium concentrations were measured at enrollment , 36 weeks ’ gestation , in cord blood , and in infants at 2 , 4 , and 6 months of age . RESULTS : Two-hundred- and -sixty pregnant women were r and omized . At enrollment , the proportions with serum 25(OH)D ≥20 ng/mL for placebo , lower-dose , and higher-dose groups were 54 % , 64 % , and 55 % , respectively . The proportion with 25(OH)D ≥20 ng/mL was larger in both intervention groups at 36 weeks ’ gestation ( 50 % , 91 % , 89 % , P < .001 ) . In comparison with placebo , the proportion of infants with 25(OH)D ≥20 ng/mL was larger in both intervention groups to age 4 months : cord blood ( 22 % , 72 % , 71 % , P < .001 ) , 2 months ( 50 % , 82 % , 92 % , P < .001 ) , and 4 months ( 66 % , 87 % , 87 % , P = .004 ) , but only in the higher-dose group at age 6 months ( 74 % , 82 % , 89 % , P = .07 ; higher dose versus placebo P = .03 , lower dose versus placebo P = .21 ) . CONCLUSIONS : Daily vitamin D supplementation during pregnancy and then infancy with 1000/400 IU or 2000/800 IU increases the proportion of infants with 25(OH)D ≥20 ng/mL , with the higher dose sustaining this increase for longer [24614387] There is intense interest in the role of vitamin D in the development of asthma and allergies . However , studies differ on whether a higher vitamin D intake or status in pregnancy or at birth is protective against asthma and allergies . To address this uncertainty , the Vitamin D Antenatal Asthma Reduction Trial ( VDAART ) was developed . VDAART is a r and omized , double-blind , placebo-controlled trial of vitamin D supplementation in pregnant women to determine whether prenatal supplementation can prevent the development of asthma and allergies in women 's offspring . A secondary aim is to determine whether vitamin D supplementation can prevent the development of pregnancy complications , such as preeclampsia , preterm birth , and gestational diabetes . Women were r and omized to the treatment arm of 4000IU/day of vitamin D3 plus a daily multivitamin that contained 400IU of vitamin D3 or the placebo arm of placebo plus a multivitamin that contained 400IU daily of vitamin D3 . Women who were between the gestational ages of 10 and 18 weeks were r and omized from three clinical centers across the United States - Boston Medical Center , Washington University in St. Louis , and Kaiser Permanente Southern California Region ( San Diego , CA ) . Supplementation took place throughout pregnancy . Monthly monitoring of urinary calcium to creatinine ratio was performed in addition to medical record review for adverse events . Offspring are being evaluated quarterly through question naires and yearly during in-person visits until the 3rd birthday of the child . Ancillary studies will investigate neonatal T-regulatory cell function , maternal vaginal flora , and maternal and child intestinal flora [24714660] Aim / Background : Vitamin D supplementation during pregnancy is a well-accepted recommendation worldwide ; however , the debate about the correct dose is ongoing . We aim ed to compare daily doses of 600 , 1,200 , and 2,000 IU in this r and omized , controlled study . Methods : The study group consisted of 91 pregnant women aged 16 - 42 years admitted to Kocaeli Maternity and Children Hospital between April 2011 and April 2012 . The participants were r and omly divided into 3 groups . 600 , 1,200 , and 2,000 IU/day of vitamin D was supplemented to group 1 ( control group , n = 31 ) , group 2 ( n = 31 ) , and group 3 ( n = 32 ) , respectively . Serum calcium , 25-hydroxyvitamin D ( 25OHD ) , and the calcium/creatinine ratio in spot urine sample s were measured in the follow-up period . The serum calcium and 25OHD levels of the mothers ' infants were measured as well . Results : The frequency of vitamin D sufficiency after supplementation was 80 % in group 3 and it was significantly higher than in groups 1 ( 42 % ) and 2 ( 39 % ) ( p = 0.03 ) . The frequency of vitamin D sufficiency in the infants of the participants was 91 % in group 3 and it was significantly higher than in groups 1 ( 36 % ) and 2 ( 52 % ) ( p = 0.006 ) . Conclusions : At least 2,000 IU/day of vitamin D is needed to ensure adequate vitamin D status in pregnancy and early infancy [28878035] Background : To prevent preeclampsia , the WHO recommends antenatal calcium supplementation in population s with inadequate habitual intake . The WHO recommends 1500 - 2000 mg Ca/d with iron-folic acid ( IFA ) taken separately , a complex pill-taking regimen . Objective : The objective of this study was to test the hypothesis that simpler regimens with lower daily dosages would lead to higher adherence and similar supplement intake . Methods : In the Micronutrient Initiative Calcium Supplementation study , we compared the mean daily supplement intake associated with 2 dosing regimens with the use of a parallel , cluster-r and omized noninferiority trial implemented in 16 primary health care facilities in rural Kenya . The st and ard regimen was 3 × 500 mg Ca/d in 3 pill-taking events , and the low-dose regimen was 2 × 500 mg Ca/d in 2 pill-taking events ; both regimens included a 200 IU cholecalciferol and calcium pill and a separate IFA pill . We enrolled 990 pregnant women between 16 and 30 wk of gestation . The primary outcome was supplemental calcium intake measured by pill counts 4 and 8 wk after recruitment . We carried out intention-to-treat analyses with the use of mixed-effect models , with regimen as the fixed effect and health care facilities as a r and om effect , by using a noninferiority margin of 125 mg Ca/d . Results : Women in facilities assigned to the st and ard regimen consumed a mean of 1198 mg Ca/d , whereas those assigned to the low-dose regimen consumed 810 mg Ca/d . The difference in intake was 388 mg Ca/d ( 95 % CI = 341 , 434 mg Ca/d ) , exceeding the prespecified margin of 125 mg Ca/d . The overall adherence rate was 80 % and did not differ between study arms . Conclusions : Contrary to our expectation , a simpler , lower-dose regimen led to significantly lower supplement intake than the regimen recommended by the WHO . Further studies are needed to precisely characterize the dose-response relation of calcium supplementation and preeclampsia risk and to examine cost effectiveness of lower and simpler regimens in program setting s. This trial was registered at clinical trials.gov as NCT02238704 [27840206] Objective To identify the combined effect of prenatal and postnatal vitamin D3 supplementation on the vitamin D status of pregnant and lactating women and their exclusively breastfed infants . Design Double‐blind , r and omized controlled trial . Setting Upper Midwestern U.S. , hospital‐based obstetric practice . Participants Pregnant women ( N = 13 ) planning to exclusively breastfeed were r and omized at 24 to 28 weeks gestation to receive vitamin D3 at a dosage of 400 IU ( control group , n = 6 ) or 3,800 IU ( intervention group , n = 7 ) daily through 4 to 6 weeks postpartum . Vitamin D status was determined at enrollment and in mother – infant dyads at 24 to 72 hours after birth and 4 to 6 weeks postpartum . Methods Serum 25‐hydroxyvitamin D levels were measured to determine the effect of vitamin D3 supplementation on the vitamin D status of mothers and infants . Analysis of covariance was used to compare differences in 25‐hydroxyvitamin D levels between the control and intervention groups . Results The mothers ’ vitamin D levels were significantly higher in the intervention group than in the control group at birth ( p = .044 ) and at 4 to 6 weeks postpartum ( p = .002 ) . Infants in the intervention group had significantly higher vitamin D levels at birth ( p = .021 ) and nonsignificant , clinical ly relevant increases at 4 to 6 weeks of age ( p = .256 ) . No differences were found between maternal groups in serum calcium or parathyroid hormone levels . Conclusion Prenatal to postpartum vitamin D3 supplementation is an effective intervention to increase a mother ’s vitamin D status and to promote optimal vitamin D status in newborns and exclusively breastfed infants [27841759] BACKGROUND Low vitamin D status in pregnancy was proposed as a risk factor of preeclampsia . METHODS We assessed the effect of vitamin D supplementation ( 4,400 vs. 400 IU/day ) , initiated early in pregnancy ( 10 - 18 weeks ) , on the development of preeclampsia . The effects of serum vitamin D ( 25-hydroxyvitamin D [ 25OHD ] ) levels on preeclampsia incidence at trial entry and in the third trimester ( 32 - 38 weeks ) were studied . We also conducted a nested case-control study of 157 women to investigate peripheral blood vitamin D-associated gene expression profiles at 10 to 18 weeks in 47 participants who developed preeclampsia . RESULTS Of 881 women r and omized , outcome data were available for 816 , with 67 ( 8.2 % ) developing preeclampsia . There was no significant difference between treatment ( N = 408 ) or control ( N = 408 ) groups in the incidence of preeclampsia ( 8.08 % vs. 8.33 % , respectively ; relative risk : 0.97 ; 95 % CI , 0.61 - 1.53 ) . However , in a cohort analysis and after adjustment for confounders , a significant effect of sufficient vitamin D status ( 25OHD ≥30 ng/ml ) was observed in both early and late pregnancy compared with insufficient levels ( 25OHD < 30 ng/ml ) ( adjusted odds ratio , 0.28 ; 95 % CI , 0.10 - 0.96 ) . Differential expression of 348 vitamin D-associated genes ( 158 upregulated ) was found in peripheral blood of women who developed preeclampsia ( FDR < 0.05 in the Vitamin D Antenatal Asthma Reduction Trial [ VDAART ] ; P < 0.05 in a replication cohort ) . Functional enrichment and network analyses of this vitamin D-associated gene set suggests several highly functional modules related to systematic inflammatory and immune responses , including some nodes with a high degree of connectivity . CONCLUSIONS Vitamin D supplementation initiated in weeks 10 - 18 of pregnancy did not reduce preeclampsia incidence in the intention-to-treat paradigm . However , vitamin D levels of 30 ng/ml or higher at trial entry and in late pregnancy were associated with a lower risk of preeclampsia . Differentially expressed vitamin D-associated transcriptomes implicated the emergence of an early pregnancy , distinctive immune response in women who went on to develop preeclampsia . TRIAL REGISTRATION Clinical Trials.gov NCT00920621 . FUNDING Quebec Breast Cancer Foundation and Genome Canada Innovation Network . This trial was funded by the National Heart , Lung , and Blood Institute . For details see Acknowledgments [5400884] Background Although there have been marked improvements in our underst and ing of vitamin D functions in different diseases , gaps on its role during pregnancy remain . Due to the lack of consensus on the most accurate marker of vitamin D deficiency during pregnancy and the optimal level of 25-hydroxyvitamin D , 25(OH)D , for its definition , vitamin D deficiency assessment during pregnancy is a complicated process . Besides , the optimal protocol for treatment of hypovitaminosis D and its effect on maternal and neonatal outcomes are still unclear . Objective The aim of our study was to estimate the prevalence of vitamin D deficiency in the first trimester of pregnancy and to compare vitamin D screening strategy with no screening . Also , we intended to compare the effectiveness of various treatment regimens on maternal and neonatal outcomes in Masjed-Soleyman and Shushtar cities of Khuzestan province , Iran . Methods This was a two-phase study . First , a population -based cross-sectional study was conducted ; recruiting 1600 and 900 first trimester pregnant women from health centers of Masjed-Soleyman and Shushtar , respectively , using stratified multistage cluster sampling with probability proportional to size ( PPS ) method . Second , to assess the effect of screening strategy on maternal and neonatal outcomes , Masjed-Soleyman participants were assigned to a screening program versus Shushtar participants who became the nonscreening arm . Within the framework of the screening regimen , an 8-arm blind r and omized clinical trial was undertaken to compare the effects of various treatment protocol s. A total of 800 pregnant women with vitamin D deficiency were selected using simple r and om sampling from the 1600 individuals of Masjed-Soleyman as interventional groups . Serum concentrations of 25(OH)D were classified as : ( 1 ) severe deficient ( < 10ng/ml ) , ( 2 ) moderate deficient ( 10 - 20ng/ml ) , and ( 3 ) normal status ( > 20ng/ml ) . Those with severe and moderate deficiency were r and omly divided into 4 subgroups and received vitamin D3 based on protocol and were followed until delivery . Data was analyzed according to the intention-to-treat principle . Results Recruitment commenced in July , 2014 , and as estimated , nearly 3.5 years is needed to complete the study . Results of this study will ( 1 ) provide reliable information regarding the prevalence of vitamin D deficiency during pregnancy using universal vitamin D screening approach and ( 2 ) determine the beneficial effects of universal screening and compare the various treatment protocol s in terms of pregnancy outcomes . Conclusions Since vitamin D deficiency is a prevalent disorder in pregnancy among Iranian population , this study will ensure creation of reliable evidence -based findings and will enable clinicians to better evaluate and treat vitamin D deficient pregnant women . Trial Registration International St and ard R and omized Controlled Trial Number ( IS RCT N ) : 2014102519660N1 ; http://www.i rct .ir/ search result .php?keyword=&id=19660&number=1&prt=7805&total=10&m=1 ( Archived by WebCite at http://www.webcitation.org/6p3lkqFdV [29550150] BACKGROUND Vitamin D plays pivotal role in decidualization and implantation of the placenta . Recent research es have shown that low level of vitamin D3 " 25-hydroxyvitamin D ( 25[OH]D ) " in serum is a risk factor for pre-eclampsia . Latest evidence supports role of vitamin D3 deficiency treatment in reducing the risk of pre-eclampsia . The aim of this study is to determine the effect of antenatal supplementation of vitamin D3 on the risk of pre-eclampsia and to explore the dose effect in attaining the vitamin D3 normal level . METHOD An open labelled r and omized controlled study was conducted on 179 pregnant women presenting in King Fahad Medical City antenatal clinic from Oct 2012-Oct 2015 . Patients with age less than 20 years or more than 40 years , pregnancy with fetal anomalies , history of hypertension , pre-eclampsia , recurrent miscarriage , chronic renal or hepatic disease and malignancy were excluded from the study . Serum 25[OH]D was analysed during the first trimester ( between 6 and 12 weeks of pregnancy ) . Patients with vitamin D3 deficiency ( serum levels < 25 nmol/L ) were included in the study and r and omized for vitamin D3 supplementation 400 IU ( Group 1 ) versus 4000 IU ( Group 2 ) . Both groups were compared for the prevalence of pre-eclampsia and dose effect on vitamin D level . RESULTS Of 179 gravidae enrolled , 164 completed the trial . Mean maternal 25[OH]D was significantly increased in group 2 from 16.3 ± 5 nmol/mL to 72.3 ± 30.9 nmol/mL compared with group 1 from 17.5 ± 6.7 nmol/mL to 35.3 ± 20.7 nmol/mL ( p > 0.0001 ) . The relative risk reduction ( RRR ) for attaining ≥75 nmol/L before delivery was significantly higher ( RRR 93.2 [ CI 79 - 98 ] when treated with 4000 IU . The total incidence of pre-eclampsia in the study population was 4.3 % . In comparison to group 1 , the group 2 reported fewer pre-eclampsia events during the study period ( 8.6 % versus 1.2 % ; p < 0.05 ) . The total number of IUGRs was lesser in the group 2 ( 9.6 % ) versus group 1 ( 22.2 % ) ; p = 0.027 . However , other obstetric outcomes were comparable between both groups . CONCLUSION Vitamin D supplementation in the deficient group reduces the risk of pre-eclampsia and IUGR in a dose dependant manner . However larger clinical trials are essential to investigate optimum dosage of vitamin D3 in this group [28216083] INTRODUCTION Maternal circulating 25-hydroxyvitamin D [ 25(OH)D ] has been shown to optimize production of 1,25-dihydroxyvitamin D [ 1,25(OH)2D ] during pregnancy at approximately 100nmoles/L , which has pronounced effects on fetal health outcomes . Additionally , associations are noted between low maternal 25(OH)D concentrations and vascular pregnancy complications , such as preeclampsia . To further eluci date the effects of vitamin D activity in pregnancy , we investigated the role of maternal 25(OH)D , the nutritional indicator of vitamin D status , in relation to placental maintenance and , specifically , expression of placental gene targets related to angiogenesis and vitamin D metabolism . METHODS A focused analysis of placental mRNA expression related to angiogenesis , pregnancy maintenance , and vitamin D metabolism was conducted in placentas from 43 subjects enrolled in a r and omized controlled trial supplementing 400IU or 4400IU of vitamin D3 per day during pregnancy . Placental mRNA was isolated from biopsies within one hour of delivery , followed by quantitative PCR . We classified pregnant women with circulating concentrations of < 100nmoles/L as deficient and those with ≥100nmoles/L as sufficient . The value of each gene 's change in the PCR cycle threshold ( ΔCT ) , which is a relative measure of target concentration , was compared with maternal 25(OH)D concentrations < 100nmoles/L and ≥100nmoles/L based on a two- sample Wilcoxon test . RESULTS Soluble FMS-like tyrosine kinase 1 ( sFlt-1 ) and vascular endothelial growth factor ( VEGF ) gene expression was significantly downregulated in the maternal subgroup with circulating 25(OH)D ≥100ng/mL compared to the subgroup < 100ng/mL. DISCUSSION Here , we report a significant association between maternal vitamin D status and the expression of sFlt-1 and VEGF at the mRNA level . Achieving maternal circulating 25(OH)D ≥100nmoles/L suggests the impact of maternal vitamin D3 supplementation on gene transcription in the placenta , thereby potentially decreasing antiangiogenic factors that may contribute to vascular pregnancy complications [5064894] Background Early infancy is a high-risk period for severe acute respiratory infection ( ARI ) , particularly in low-income countries with re source -limited health systems . Lower respiratory tract infection ( LRTI ) is commonly preceded by upper respiratory infection ( URTI ) , and often caused by respiratory syncytial virus ( RSV ) , influenza and other common community-acquired viral pathogens . Vitamin D status is a c and i date modifiable early-life determinant of the host antiviral immune response and thus may influence the risk of ARI-associated morbidity in high-risk population s. Methods / Design In the Maternal Vitamin D for Infant Growth ( MDIG ) study in Dhaka , Bangladesh ( NCT01924013 ) , 1300 pregnant women are r and omized to one of five groups : placebo , 4200 IU/week , 16,800 IU/week , or 28,000 IU/week from 2nd trimester to delivery plus placebo from 0–6 months postpartum ; or , 28,000 IU/week prenatal and until 6-months postpartum . In the Maternal Vitamin D for ARI in Infancy ( MDARI ) sub- study nested within the MDIG trial , trained personnel conduct weekly postnatal home visits to inquire about ARI symptoms and conduct a st and ardized clinical assessment . Supplementary home visits between surveillance visits are conducted when caregivers make phone notifications of new infant symptoms . Mid-turbinate nasal swab sample s are obtained from infants who meet st and ardized clinical ARI criteria . Specimens are tested by polymerase chain reaction ( PCR ) for 8 viruses ( influenza A/B , parainfluenza 1/2/3 , RSV , adenovirus , and human metapneumovirus ) , and nasal carriage density of Streptococcus pneumoniae . The primary outcome is the incidence rate of microbiologically-positive viral ARI , using incidence rate ratios to estimate between-group differences . We hypothesize that among infants 0–6 months of age , the incidence of microbiologically-confirmed viral ARI will be significantly lower in infants whose mothers received high-dose prenatal/postpartum vitamin D supplements versus placebo . Secondary outcomes include incidence of ARI associated with specific pathogens ( influenza A or B , RSV ) , clinical ARI , and density of pneumococcal carriage . Discussion If shown to reduce the risk of viral ARI in infancy , integration of maternal prenatal/postpartum vitamin D supplementation into antenatal care programs in South Asia may be a feasible primary preventive strategy to reduce the burden of ARI-associated morbidity and mortality in young infants . Trial registration NCT02388516 , registered March 9 , 2015 [27628045] We studied bone mineral content ( BMC ) , bone mineral density ( BMD ) , and body composition in offspring of women supplemented with vitamin D during pregnancy . Pregnant women were r and omized to receive oral cholecalciferol 60,000 units 4 weekly ( group 1 ) , 8 weekly ( group 2 ) , or placebo ( group 3 ) . All received 1 g calcium daily ( groups 1 and 2 without , and group 3 with 400 units vitamin D ) . Offspring at 12–16 months underwent dual-energy X-ray absorptiometry . Maternal hypovitaminosis D at recruitment was common ( serum 25OHD < 50 nmol/L in 88 % ) and severe ( 25OHD < 25 nmol/L in 46 % ) . Groups 1 and 2 ( n = 23 and 13 , median age 14 months ) had higher cord blood 25OHD ( 47.8 ± 13.8 and 31.0 ± 14.0 nmol/L ) versus group 3 ( n = 16 , median age 16 months , 17.8 ± 13.5 nmol/L , p < 0.001 ) . Babies in group 3 had higher whole-body BMC ( 250.8 ± 42.5 gm ) and BMD ( 0.335 ± 0.033 gm/cm2 ) compared to group 1 ( 213.1 ± 46.2 gm and 0.295 ± 0.041 gm/cm2 ) and group 2 ( 202.9 ± 29.9 gm and 0.287 ± 0.023 gm/cm2 ) ( p = 0.006 and 0.001 , respectively ) . In multivariate analysis , age , weight z score , and lean body mass remained significant contributors to BMC . Parameters of body composition were comparable among the groups . Vitamin D supplementation to pregnant women with severe deficiency in doses that improved cord blood 25OHD did not result in improved bone health or body composition in offspring at 12–16 months , compared to a dose too small to improve 25OHD levels [21706518] The need , safety , and effectiveness of vitamin D supplementation during pregnancy remain controversial . In this r and omized , controlled trial , women with a singleton pregnancy at 12 to 16 weeks ' gestation received 400 , 2000 , or 4000 IU of vitamin D(3 ) per day until delivery . The primary outcome was maternal/neonatal circulating 25-hydroxyvitamin D [ 25(OH)D ] concentration at delivery , with secondary outcomes of a 25(OH)D concentration of 80 nmol/L or greater achieved and the 25(OH)D concentration required to achieve maximal 1,25-dihydroxyvitamin D(3 ) [ 1,25(OH)(2)D(3 ) ] production . Of the 494 women enrolled , 350 women continued until delivery : Mean 25(OH)D concentrations by group at delivery and 1 month before delivery were significantly different ( p < 0.0001 ) , and the percent who achieved sufficiency was significantly different by group , greatest in 4000-IU group ( p < 0.0001 ) . The relative risk ( RR ) for achieving a concentration of 80 nmol/L or greater within 1 month of delivery was significantly different between the 2000- and the 400-IU groups ( RR = 1.52 , 95 % CI 1.24 - 1.86 ) , the 4000- and the 400-IU groups ( RR = 1.60 , 95 % CI 1.32 - 1.95 ) but not between the 4000- and . 2000-IU groups ( RR = 1.06 , 95 % CI 0.93 - 1.19 ) . Circulating 25(OH)D had a direct influence on circulating 1,25(OH)(2)D(3 ) concentrations throughout pregnancy ( p < 0.0001 ) , with maximal production of 1,25(OH)(2)D(3 ) in all strata in the 4000-IU group . There were no differences between groups on any safety measure . Not a single adverse event was attributed to vitamin D supplementation or circulating 25(OH)D levels . It is concluded that vitamin D supplementation of 4000 IU/d for pregnant women is safe and most effective in achieving sufficiency in all women and their neonates regardless of race , whereas the current estimated average requirement is comparatively ineffective at achieving adequate circulating 25(OH)D concentrations , especially in African Americans [4855961] Introduction : Pregnant women represent a typical group susceptible to dietary and mineral deficiencies . This study was sought to assess the efficacy and safety of various doses of 25-hydroxyvitamin D ( 25[OH]D ) supplementation during pregnancy and ratify the inadequacy of the recommended daily allowance for Vitamin D in vulnerable groups . Material s and Methods : A total of 100 pregnant women were included in this open-label , parallel group , prospect i ve , r and omized , and controlled trial . Study subjects were assigned to four treatment groups : Group 1 ( n = 26 ) , 1000 IU of Vitamin D daily ; Group 2 ( n = 21 ) , 30,000 IU of Vitamin D monthly ; Group 3 ( n = 27 ) , 2000 IU of Vitamin D daily ; and Group 4 ( n = 26 ) , 60,000 IU Vitamin D monthly . Group 1 and 2 were further analyzed together as Group 1 K ( 1000 IU daily and 30,000 IU monthly ) , and Group 3 and 4 as Group 2 K ( 2000 IU daily and 60,000 IU monthly ) . The analysis was done on an intention to treat basis . Results : A total of 87 patients completed the study ; 21 in Group 1 , 25 in Group 2 , 18 in Group 3 , and 23 in Group 4 . The levels of 25(OH)D at baseline ranged from 1.3 to 58.0 with a mean of 24.2 ± 15.1 ng/ml . Postsupplementation , 25(OH)D levels ranged from 11.5 to 70.3 with a mean of 40.2 ± 12.2 ng/ml . The postsupplementation levels of 25(OH)D were higher in Group 2 K ( 42.86 ± 12.83 ) than in Group 1 K ( 36.96 ± 10.56 ) with P value of 0.023 . Conclusion : We concluded that Vitamin D supplementation with 2000 IU/day or 60,000 IU/month is very effective and safe in achieving Vitamin D sufficiency in pregnant women [4695683] Background : Vitamin D supplementation during pregnancy has been supposed to defend against adverse gestational outcomes . Objective : This r and omized clinical trial study was conducted to assess the effects of 50,000 IU of vitamin D every two weeks supplementation on the incidence of gestational diabetes ( GDM ) , gestational hypertension , preeclampsia and preterm labor , vitamin D status at term and neonatal outcomes contrasted with pregnant women that received 400 IU vitamin D daily . Material s and Methods : 500 women with gestational age 12 - 16 weeks and serum 25 hydroxy vitamin D ( 25 ( OH ) D ) less than 30 ng/ml r and omly categorized in two groups . Group A received 400 IU vitamin D daily and group B 50,000 IU vitamin D every 2 weeks orally until delivery . Maternal and Neonatal outcomes were assessed in two groups . Results : The incidence of GDM in group B was significantly lower than group A ( 6.7 % versus 13.4 % ) and odds ratio ( 95 % Confidence interval ) was 0.46 ( 0.24 - 0.87 ) ( P=0.01 ) . The mean ± SD level of 25 ( OH ) D at the time of delivery in mothers in group B was significantly higher than A ( 37.9 ± 19.8 versus 27.2 ± 18.8 ng/ml , respectively ) ( P=0.001 ) . There were no differences in the incidence of preeclampsia , gestational hypertension , preterm labor , and low birth weight between two groups . The mean level of 25 ( OH ) D in cord blood of group B was significantly higher than group A ( 37.9 ± 18 versus 29.7 ± 19ng/ml , respectively ) . Anthropometric measures between neonates were not significantly different . Conclusion : Our study showed 50,000 IU vitamin D every 2 weeks decreased the incidence of GDM [2821652] Objective . To determine if adherence as measured by pill count would show a significant association with serum-based measures of adherence . Methods . Data were obtained from a prenatal vitamin D supplementation trial where subjects were stratified by race and r and omized into three dosing groups : 400 ( control ) , 2000 , or 4000 IU vitamin D3/day . One measurement of adherence was obtained via pill counts remaining compared to a novel definition for adherence using serum 25-hydroxy-vitamin D ( 25-OH-D ) levels ( absolute change in 25(OH)D over the study period and the subject 's steady-state variation in their 25(OH)D levels ) . A multivariate logistic regression model examined whether mean percent adherence by pill count was significantly associated with the adherence measure by serum metabolite levels . Results . Subjects ' mean percentage of adherence by pill count was not a significant predictor of adherence by serum metabolite levels . This finding was robust across a series of sensitivity analyses . Conclusions . Based on our novel definition of adherence , pill count was not a reliable predictor of adherence to protocol , and calls into question how adherence is measured in clinical research . Our findings have implication s regarding the determination of efficacy of medications under study and offer an alternative approach to measuring adherence of long half-life supplements/medications [5053446] Background Patterns of gene expression of human pregnancy are poorly understood . In a trial of vitamin D supplementation in pregnant women , peripheral blood transcriptomes were measured longitudinally on 30 women and used to characterize gene co-expression networks . Objective Studies suggest that increased maternal Vitamin D levels may reduce the risk of asthma in early life , yet the underlying mechanisms have not been examined . In this study , we used a network-based approach to examine changes in gene expression profiles during the course of normal pregnancy and evaluated their association with maternal Vitamin D levels . Design The VDAART study is a r and omized clinical trial of vitamin D supplementation in pregnancy for reduction of pediatric asthma risk . The trial enrolled 881 women at 10–18 weeks of gestation . Longitudinal gene expression measures were obtained on thirty pregnant women , using RNA isolated from peripheral blood sample s obtained in the first and third trimesters . Differentially expressed genes were identified using significance of analysis of microarrays ( SAM ) , and clustered using a weighted gene co-expression network analysis ( WGCNA ) . Gene-set enrichment was performed to identify major biological pathways . Results Comparison of transcriptional profiles between first and third trimesters of pregnancy identified 5839 significantly differentially expressed genes ( FDR<0.05 ) . Weighted gene co-expression network analysis clustered these transcripts into 14 co-expression modules of which two showed significant correlation with maternal vitamin D levels . Pathway analysis of these two modules revealed genes enriched in immune defense pathways and extracellular matrix reorganization as well as genes enriched in notch signaling and transcription factor networks . Conclusion Our data show that gene expression profiles of healthy pregnant women change during the course of pregnancy and suggest that maternal Vitamin D levels influence transcriptional profiles . These alterations of the maternal transcriptome may contribute to fetal immune imprinting and reduce allergic sensitization in early life . Trial Registration clinical trials.gov [4499946] Background Vitamin D regulates bone mineral metabolism and skeletal development . Some observational studies have suggested that prenatal vitamin D deficiency increases the risk of adverse pregnancy and /or birth outcomes ; however , there is scant evidence from controlled trials , leading the World Health Organization to advise against routine vitamin D supplementation in pregnancy . Importantly , little is known about the effect of maternal vitamin D status on infant linear growth in communities in South Asia where stunting is highly prevalent and maternal-infant vitamin D status is commonly suboptimal . Methods / Design The Maternal Vitamin D for Infant Growth study is a r and omized , placebo-controlled , dose-ranging trial of maternal vitamin D supplementation during pregnancy and lactation in Dhaka , Bangladesh . The primary aims are to estimate ( 1 ) the effect of maternal prenatal oral vitamin D3 supplementation ( 4200 IU/wk , 16,800 IU/wk , or 28,000 IU/wk , administered as weekly doses ) versus placebo on infant length at 1 year of age and ( 2 ) the effect of maternal postpartum oral vitamin D3 supplementation ( 28,000 IU/wk ) versus placebo on length at 1 year of age among infants born to women who received vitamin D 28,000 IU/wk during pregnancy . Generally healthy pregnant women ( n = 1300 ) in the second trimester ( 17–24 weeks of gestation ) are r and omized to one of five parallel arms : placebo 4200 IU/wk , 16,800 IU/wk , or 28,000 IU/wk in the prenatal period and placebo in the postpartum period or 28,000 IU/wk in the prenatal period and 28,000 IU/wk in the postpartum period . Household- and clinic-based follow-up of mother-infant pairs is conducted weekly by trained personnel until 26 weeks postpartum and every 3 months thereafter . The primary trial outcome measure is length for age z-score at 1 year of age . Anthropometric measurements , clinical information , and biological specimens collected at scheduled intervals will enable the assessment of a range of maternal , perinatal , and infant outcomes . Discussion The role of vitamin D in maternal and infant health remains unresolved . This trial is expected to contribute unique insights into the effects of improving maternal-infant vitamin D status in a low-income setting where stunting and adverse perinatal outcomes represent significant public health burdens . Trial registration Clinical Trials.gov identifier : NCT01924013 . Registered on 13 August [27588106] It has previously been reported that the influence of vitamin D on the metabolism of calcium and phosphorus is associated with diabetes , cardiovascular disease , Alzheimer 's disease , cancer and other systemic diseases , and is considered an important indicator of general health . The present study was conducted to determine the effect of various doses of vitamin D supplementation on glucose metabolism , lipid concentrations , inflammation and the levels of oxidative stress of pregnant women with gestational diabetes mellitus ( GDM ) . The present r and omized , double-blind placebo-controlled clinical trial was conducted on 133 pregnant women with GDM during weeks 24 - 28 of pregnancy . The patients were r and omly divided into four groups . The control group ( n=20 ) received a placebo ( sucrose ; one granule/day ) , the low dosage group ( n=38 ) received the daily recommended intake of 200 IU vitamin D ( calciferol ) daily , the medium dosage group ( n=38 ) received 50,000 IU monthly ( 2,000 IU daily for 25 days ) and the high dosage group ( n=37 ) received 50,000 IU every 2 weeks ( 4,000 IU daily for 12.5 days ) . The general characteristics and dietary intakes of the patients with GDM were similar between each group . Using ELISA kits , it was determined that insulin , homeostatic model assessment -insulin resistance and total cholesterol were significantly reduced by high dosage vitamin D supplementation ( P<0.05 ) . Total antioxidant capacity and total glutathione levels were significantly elevated as a result of high dosage vitamin D supplementation ( P<0.01 ) . In conclusion , high-dose vitamin D supplementation ( 50,000 IU every 2 weeks ) significantly improved insulin resistance in pregnant women with GDM [28552588] & NA ; Figure . No caption available . Background : Programming of the immune system during fetal development can influence asthma‐related risk factors and outcomes in later life . Vitamin D is a well‐recognized immune modulator , and deficiency of this nutrient during pregnancy is hypothesized to influence disease development in offspring . Objective : We sought to investigate the effect on neonatal immunity of maternal supplementation with 4400 IU/d vitamin D3 during the second and third trimesters of pregnancy by using a subset of cord blood sample s from a r and omized , double‐blind , placebo‐controlled clinical trial ( the Vitamin D Antenatal Asthma Reduction Trial ) . Methods : Cord blood sample s from neonates born to mothers supplemented with 4400 IU/d ( n = 26 ) or 400 IU/d ( n = 25 ) of vitamin D3 were analyzed for immune cell composition by flow cytometry , Toll‐like receptor ( TLR ) expression by quantitative PCR , and cytokine secretion after stimulation with mitogenic , TLR , and T‐cell stimuli by cytometric bead array . Responsiveness to the glucocorticoid dexamethasone was determined . Results : Supplementation of mothers with 4400 IU of vitamin D3 result ed in an enhanced broad‐spectrum proinflammatory cytokine response of cord blood mononuclear cells to innate and mitogenic stimuli ( P = .0009 ) , with an average 1.7‐ to 2.1‐fold increase in levels of several proinflammatory cytokines ( GM‐CSF , IFN‐&ggr ; , IL‐1&bgr ; , IL‐6 , and IL‐8 ) across stimuli , a higher gene expression level of TLR2 ( P = .02 ) and TLR9 ( P = .02 ) , a greater than 4‐fold increase in IL‐17A ( P = .03 ) production after polyclonal T‐cell stimulation , and an enhanced IL‐10 response of cord blood mononuclear cells to dexamethasone treatment in culture ( P = .018 ) . Conclusion : Vitamin D exposure during fetal development influences the immune system of the neonate , which can contribute to protection from asthma‐related , including infectious , outcomes in early life [4785305] Introduction The vitamin D recommended doses during pregnancy differ between societies . The WHO guidelines do not recommend routine prenatal supplementation , but they underscore the fact that women with the lowest levels may benefit most . The effects of routine supplementation during pregnancy on maternal and neonatal clinical outcomes have not been investigated in the Middle East , where hypovitaminosis D is prevalent . Our hypothesis is that in Middle Eastern pregnant women , a vitamin D dose of 3000 IU/day is required to reach a desirable maternal 25-hydroxyvitamin D [ 25(OH)D ] level , and to positively impact infant bone mineral content ( BMC ) . Methods and analysis This is a multicentre blinded r and omised controlled trial . Pregnant women presenting to the Obstetrics and Gynaecology clinics will be approached . Eligible women will be r and omised to daily equivalent doses of cholecalciferol , 600 IU or 3000 IU , from 15 to 18 weeks gestation until delivery . Maternal 25(OH)D and chemistries will be assessed at study entry , during the third trimester and at delivery . Neonatal anthropometric variables and 25(OH)D level will be measured at birth , and bone and fat mass assessment by dual-energy X-ray absorptiometry scan at 1 month . A sample size of 280 pregnant women is needed to demonstrate a statistically significant difference in the proportion of women reaching a 25(OH)D level ≥50 nmol/L at delivery , and a difference in infant BMC of 6 (10)g , for a 90 % power and a 2.5 % level of significance . The proportions of women achieving a target 25(OH)D level will be compared between the two arms , using χ2 . An independent t test will be used to compare mean infant BMC between the two arms . The primary analysis is an intention-to-treat analysis of unadjusted results . Ethics and dissemination The protocol has been approved by the Institutional Review Board at the American University of Beirut-Lebanon ( IM.GEHF.22 ) . The trial results will be published in peer- review ed medical journals and presented at scientific conferences . Trial registration number NCT02434380 [3705320] A pharmacokinetic study was conducted to assess the biochemical dose-response and tolerability of high-dose prenatal vitamin D3 supplementation in Dhaka , Bangladesh ( 23 ° N ) . Pregnant women at 27–30 weeks gestation ( n = 28 ) were r and omized to 70,000 IU once + 35,000 IU/week vitamin D3 ( group PH : pregnant , higher dose ) or 14,000 IU/week vitamin D3 ( PL : pregnant , lower dose ) until delivery . A group of non-pregnant women ( n = 16 ) was similarly administered 70,000 IU once + 35,000 IU/week for 10 weeks ( NH : non-pregnant , higher-dose ) . Rise ( ∆ ) in serum 25-hydroxyvitamin D concentration ( [ 25(OH)D ] ) above baseline was the primary pharmacokinetic outcome . Baseline mean [ 25(OH)D ] were similar in PH and PL ( 35 nmol/L vs. 31 nmol/L , p = 0.34 ) . A dose-response effect was observed : ∆[25(OH)D ] at modeled steady-state was 19 nmol/L ( 95 % CI , 1 to 37 ) higher in PH vs. PL ( p = 0.044 ) . ∆[25(OH)D ] at modeled steady-state was lower in PH versus NH but the difference was not significant ( −15 nmol/L , 95 % CI −34 to 5 ; p = 0.13 ) . In PH , 100 % attained [ 25(OH)D ] ≥ 50 nmol/L and 90 % attained [ 25(OH)D ] ≥ 80 nmol/L ; in PL , 89 % attained [ 25(OH)D ] ≥ 50 nmol/L but 56 % attained [ 25(OH)D ] ≥ 80 nmol/L. Cord [ 25(OH)D ] ( n = 23 ) was slightly higher in PH versus PL ( 117 nmol/L vs. 98 nmol/L ; p = 0.07 ) . Vitamin D3 was well tolerated ; there were no supplement-related serious adverse clinical events or hypercalcemia . In summary , a regimen of an initial dose of 70,000 IU and 35,000 IU/week vitamin D3 in the third trimester of pregnancy was non-hypercalcemic and attained [ 25(OH)D ] ≥ 80 nmol/L in virtually all mothers and newborns . Further research is required to establish the safety of high-dose vitamin D3 in pregnancy and to determine if supplement-induced [ 25(OH)D ] elevations lead to maternal-infant health benefits [28285844] Background Nutrient trials differ from drug trials because participants have varying circulating levels at entry into the trial . Objective We sought to study the effect of a vitamin D intervention in pregnancy between subjects of different races and the association between 25‐hydroxyvitamin D3 ( 25[OH]D ) levels in pregnancy and the risk of asthma/recurrent wheeze in offspring . Methods The Vitamin D Antenatal Asthma Reduction Trial is a r and omized trial of pregnant women at risk of having children with asthma r and omized to 4400 international units/d vitamin D or placebo plus 400 international units/d vitamin D. Asthma and recurrent wheezing until age 3 years were recorded . Results African American ( AA ) women ( n = 312 ) had lower initial levels of 25(OH)D ( mean [ SD ] , 17.6 ng/mL [ 8.3 ng/mL ] ) compared with non‐AA women ( n = 400 ; 27.1 ng/mL [ 9.7 ng/mL ] , P < .001 ) . No racial difference was found from vitamin D supplementation in pregnancy on asthma/recurrent wheezing in offspring ( P for interaction = .77 ) . Having an initial level of greater than 30 ng/mL and being r and omized to the intervention group was associated with the lowest risk for asthma/recurrent wheeze by age 3 years compared with having an initial level of less than 20 ng/mL and receiving placebo ( adjusted odds ratio , 0.42 ; 95 % CI , 0.19‐0.91 ) . Conclusions We did not find differences between AA and non‐AA mothers in the effect of maternal vitamin D supplementation and asthma/recurrent wheeze in offspring at 3 years . Maternal supplementation of vitamin D , particularly in mothers with initial 25(OH)D levels of greater than 30 ng/mL , reduced asthma/recurrent wheeze in the offspring through age 3 years , suggesting that higher vitamin D status beginning in early pregnancy is necessary for asthma/recurrent wheeze prevention in early life . Graphical abstract Figure . No Caption available [27558577] BACKGROUND Many countries recommend daily infant vitamin D supplementation during breastfeeding , but compliance is often poor . A monthly , high-dose maternal regimen may offer an alternative strategy , but its efficacy is unknown . OBJECTIVE The objective of the study was to determine the effect of 2 different monthly maternal doses of cholecalciferol on maternal and infant 25-hydroxyvitamin D [ 25(OH)D ] status during the first 5 mo of breastfeeding . METHODS With the use of a r and omized , double-blind , placebo-controlled design , women who were planning to exclusively breastfeed for 6 mo ( n = 90 ; mean age : 32.1 y ; 71 % exclusively breastfeeding at week 20 ) were r and omly assigned to receive either cholecalciferol ( 50,000 or 100,000 IU ) or a placebo monthly from week 4 to week 20 postpartum . The treatment effects relative to placebo were estimated as changes in maternal and infant serum 25(OH)D from baseline to week 20 postpartum by using a linear fixed-effects regression model . Additional secondary analyses , adjusted for potential confounders such as season of birth , vitamin D-fortified formula intake , and infant or maternal skin color , were also conducted . RESULTS After 16 wk of supplementation , changes in maternal serum 25(OH)D were significantly higher in the 50,000-IU/mo ( 12.8 nmol/L ; 95 % CI : 0.4 , 25.2 nmol/L ) and 100,000-IU/mo ( 21.5 nmol/L ; 95 % CI : 9.2 , 33.8 nmol/L ) groups than in the placebo group ( P = 0.43 and P < 0.001 , respectively ) . For infants , the unadjusted mean changes in serum 25(OH)D were 4.5 nmol/L ( 95 % CI : -16.2 , 25.0 nmol/L ) for the 50,000-IU/mo group and 15.8 nmol/L ( 95 % CI : -4.7 , 36.4 nmol/L ) for the 100,000-IU/mo group , but the changes did not differ from the placebo reference group . However , after adjustment for season of birth , vitamin D-fortified formula intake , and infant skin color , the mean change effect size for the 100,000-IU/mo group was 19.1 nmol/L ( 95 % CI : 2.5 , 35.6 nmol/L ; P = 0.025 ) higher than that in the placebo group . CONCLUSIONS Maternal cholecalciferol supplementation at a dose of 100,000 IU/mo during the first 5 mo of breastfeeding potentially benefits infant vitamin D status . Further studies are required to determine optimum dose and dosing frequency . This trial was registered at www.anzctr.org.au as ACTRN12611000108910 [22212646] Hypovitaminosis D is common in India . In the present prospect i ve partially r and omised study of vitamin D ( D₃ ) supplementation during pregnancy , subjects were r and omised in the second trimester to receive either one oral dose of 1500 μg vitamin D₃ ( group 1 , n 48 ) or two doses of 3000 μg vitamin D₃ each in the second and third trimesters ( group 2 , n 49 ) . Maternal 25-hydroxyvitamin D ( 25(OH)D ) at term , cord blood ( CB ) alkaline phosphatase ( ALP ) , neonatal serum Ca and anthropometry were measured in these subjects and in forty-three non-supplemented mother-infant pairs ( usual care ) . Median maternal 25(OH)D at term was higher in group 2 ( 58·7 , interquartile range ( IQR ) 38·4 - 89·4 nmol/l ) v. group 1 ( 26·2 , IQR 17·7 - 57·7 nmol/l ) and usual-care group ( 39·2 , IQR 21·2 - 73·4 nmol/l ) ( P = 0·000 ) . CB ALP was increased ( > 8.02 μkat/l or > 480 IU/l ) in 66·7 % of the usual-care group v. 41·9 % of group 1 and 38·9 % of group 2 ( P = 0·03 ) . Neonatal Ca and CB 25(OH)D did not differ significantly in the three groups . Birth weight , length and head circumference were greater and the anterior fontanelle was smaller in groups 1 and 2 ( 3·08 and 3·03 kg , 50·3 and 50·1 cm , 34·5 and 34·4 cm , 2·6 and 2·5 cm , respectively ) v. usual care ( 2·77 kg , 49·4 , 33·6 , 3·3 cm ; P = 0·000 for length , head circumference and fontanelle and P = 0·003 for weight ) . These differences were still evident at 9 months . We conclude that both 1500 μg and two doses of 3000 μg vitamin D₃ had a beneficial effect on infant anthropometry , the larger dose also improving CB ALP and maternal [26702121] BACKGROUND Human milk is typically low in vitamin D activity ( VDA ) . Whether the vitamin D content of breast milk at birth can be increased by supplementing the mother during pregnancy has not been reported to the best of our knowledge . OBJECTIVE We examined the effect of vitamin D supplementation during pregnancy on breast-milk VDA in the first 2 mo of lactation . DESIGN Breast-milk sample s were obtained from women who were enrolled in a r and omized , double-blinded , placebo-controlled trial of vitamin D supplementation during pregnancy . Pregnant women were enrolled at 27 wk of gestation and r and omly assigned to the following 3 groups : a placebo group , a group who received one dosage of daily oral vitamin D3 ( 1000 IU ) , or a group who received 2 dosages of daily oral vitamin D3 ( 2000 IU ) . Serum 25-hydroxyvitamin D [ 25(OH)D ] was measured at enrollment , at 36 wk of gestation , and in cord blood at birth . Study participants who were breastfeeding were invited to provide breast-milk sample s for VDA measurement [ concentration of vitamin D2 , vitamin D3 , 25(OH)D2 , and 25(OH)D3 ] at 2 wk and 2 mo postpartum . A linear mixed model was used to compare breast-milk VDA between the 3 study groups . RESULTS A total of 75 women provided breast-milk sample s ( 44 women provided breast-milk sample s at both 2 wk and 2 mo postpartum ) . The mean ( 95 % CI ) VDA at age 2 wk was 52 IU/L ( 12 , 217 IU/L ) in the placebo group , 51 IU/L ( 17 , 151 IU/L ) in the 1000-IU group , and 74 IU/L ( 25 , 221 IU/L ) in the 2000-IU group ; and at age 2 mo , the mean ( 95 % CI ) VDA was 45 IU/L ( 16 , 124 IU/L ) , 43 IU/L ( 18 , 103 IU/L ) , and 58 IU/L ( 15 , 224 IU/L ) , respectively . There was no significant interaction in VDA between the sample - collection time and treatment ( P = 0.61 ) , but there was a difference between lower- and higher-dosage treatment groups ( P = 0.04 ) . CONCLUSION Maternal vitamin D supplementation during pregnancy of 2000 IU/d ( compared with 1000 IU/d and with a placebo ) results in a higher VDA of breast milk ≥2 mo postpartum . This trial was registered at the Australian New Zeal and Clinical Trials Registry as ACTRN12610000483055 [26813208] IMPORTANCE Observational studies have suggested that increased dietary vitamin D intake during pregnancy may protect against wheezing in the offspring , but the preventive effect of vitamin D supplementation to pregnant women is unknown . OBJECTIVE To determine whether supplementation of vitamin D3 during the third trimester of pregnancy reduces the risk of persistent wheeze in the offspring . DESIGN , SETTING , AND PARTICIPANTS A double-blind , single-center , r and omized clinical trial conducted within the Copenhagen Prospect i ve Studies on Asthma in Childhood 2010 cohort . Enrollment began March 2009 with a goal of 708 participants , but due to delayed ethical approval , only 623 women were recruited at 24 weeks of pregnancy . Follow-up of the children ( N = 581 ) was completed when the youngest child reached age 3 years in March 2014 . INTERVENTIONS Vitamin D3 ( 2400 IU/d ; n = 315 ) or matching placebo tablets ( n = 308 ) from pregnancy week 24 to 1 week postpartum . All women received 400 IU/d of vitamin D3 as part of usual pregnancy care . MAIN OUTCOMES AND MEASURES Age at onset of persistent wheeze in the first 3 years of life . Secondary outcomes included number of episodes of troublesome lung symptoms , asthma , respiratory tract infections , and neonatal airway immunology . Adverse events were assessed . RESULTS Of the 581 children , persistent wheeze was diagnosed during the first 3 years of life in 47 children ( 16 % ) in the vitamin D3 group and 57 children ( 20 % ) in the control group . Vitamin D3 supplementation was not associated with the risk of persistent wheeze , but the number of episodes of troublesome lung symptoms was reduced , and the airway immune profile was up-regulated ( principal component analysis , P = .04 ) . There was no effect on additional end points . Intrauterine death was observed in 1 fetus ( < 1 % ) in the vitamin D3 group vs 3 fetuses ( 1 % ) in the control group and congenital malformations in 17 neonates ( 5 % ) in the vitamin D3 group vs 23 neonates ( 8 % ) in the control group . [ table : see text ] . CONCLUSIONS AND RELEVANCE The use of 2800 IU/d of vitamin D3 during the third trimester of pregnancy compared with 400 IU/d did not result in a statistically significant reduced risk of persistent wheeze in the offspring through age 3 years . However , interpretation of the study is limited by a wide CI that includes a clinical ly important protective effect . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00856947 [23350644] Abstract Low serum vitamin D levels are correlated with insulin resistance during pregnancy . We have assessed the effects of different doses of vitamin D on insulin resistance during pregnancy . A r and omized clinical trial was done on 120 women with a gestational age of less than 12 weeks . The women were divided into three groups r and omly . Group A received 200 IU vitamin D daily , group B 50 000 IU vitamin D monthly and group C 50 000 IU vitamin D every 2 weeks from 12 weeks of pregnancy until delivery . The serum levels of fasting blood sugar ( FBS ) , insulin , calcium and 25-hydroxyvitamin D were measured before and after intervention . We used the homeostatic model assessment of insulin resistance ( HOMA-IR ) as a surrogate measure of insulin resistance . The mean ± st and ard deviation of serum 25-hydroxyvitamin D increased in group C from 7.3 ± 5.9 to 34.1 ± 11.5 ng/ml and in group B it increased from 7.3 ± 5.3 to 27.23 ± 10.7 ng/ml , but the level of vitamin D in group A increased from 8.3 ± 7.8 to 17.7 ± 9.3 ng/ml ( p < 0.001 ) . The mean differences of insulin and HOMA-IR before and after intervention in groups A and C were significant ( p = 0.01 , p = 0.02 ) . This study has shown that supplementation of pregnant women with 50 000 IU vitamin D every 2 weeks improved insulin resistance significantly [27655755] BACKGROUND Vitamin D deficiency is widespread in pregnancy and has been associated with adverse health conditions in mothers and infants . Vitamin D supplementation in pregnancy may support the maintenance of pregnancy by its effects on innate and adaptive immunity . OBJECTIVE We assessed the effects of vitamin D supplementation during pregnancy on vitamin D status and markers of immune function associated with adverse pregnancy outcomes . METHODS We conducted a r and omized , controlled , double-blind intervention of 2 doses of cholecalciferol ( 400 and 2000 IU/d ) from < 20 wk to delivery in 57 pregnant women . Vitamin D status , regulatory and inflammatory T cells , markers of innate immunity and systemic inflammation , and clinical outcomes including maternal blood pressure and birth weight were assessed at 26 and 36 wk of pregnancy . RESULTS Supplementation with 2000 IU/d vitamin D had a greater effect on the change in vitamin D status over pregnancy ( P < 0.0001 ) and the final value at 36 wk ( P < 0.0001 ) than 400 IU/d , increasing serum 25-hydroxyvitamin D from 81.1 nmol/L at baseline to 116 nmol/L at 36 wk and from 69.6 nmol/L at baseline to 85.6 nmol/L at 36 wk , respectively . The 2000-IU/d group had 36 % more interleukin-10 + regulatory CD4 + T cells at 36 wk than did the 400-IU/d group ( P < 0.007 ) . The daily intake of 2000 compared with 400 IU/d tended to dampen the pregnancy-related increase in diastolic blood pressure by 1.3-fold ( P = 0.06 ) and increase birth weight by 8.6 % ( P = 0.06 ) , but these differences were not statistically significant . CONCLUSIONS Supplementation with 2000 IU/d is more effective at increasing vitamin D status in pregnant women than 400 IU/d and is associated with increased regulatory T cell immunity that may prevent adverse outcomes caused by excess inflammation . This trial was registered at clinical trials.gov as NCT01417351 [23716156] INTRODUCTION The exact amount of vitamin D required for pregnant women to adequately supply the foetus during pregnancy is still unclear . This r and omised trial attempted to determine the optimal dose of vitamin D necessary during pregnancy in order to attain a vitamin D level > 20 ng/mL in neonates . METHODS A total of 51 healthy , pregnant women in Yazd , Iran , were recruited in 2009 . Of these , 34 were r and omised to receive either 50,000 IU ( Group A ) or 100,000 IU ( Group B ) of vitamin D3 per month from the second trimester of pregnancy . The remaining 17 pregnant women , who formed the third group ( Group C ) and were found to have vitamin D deficiency , were initially treated with 200,000 IU of vitamin D3 , following which the dose was adjusted to 50,000 IU per month . 25-hydroxyvitamin D ( 25[OH]D ) in cord blood was measured by chemiluminescence immunoassay , and a serum 25(OH)D level < 20 ng/mL was defined as deficiency . RESULTS All the pregnant women had a vitamin D level < 30 ng/mL at the beginning of the second trimester . The neonates of 76 % of women from Group A had sufficient levels of 25(OH)D. All the neonates born to women in Groups B and C had 25(OH)D > 20 ng/mL. No side effects were observed in our participants during the period of vitamin D supplementation . CONCLUSION A vitamin D3dose > 50,000 IU/month is required during the second and third trimesters of pregnancy for vitamin D-deficient pregnant women in order for their neonates to achieve serum 25(OH)D levels > 20 ng/mL. Supplementation with < 50,000 IU/month is insufficient to ensure a vitamin D level > 20 ng/mL in all neonates born to vitamin D-deficient pregnant women [27060679] Vitamin D has immune‐modulating effects . We determined whether vitamin D supplementation during pregnancy and infancy prevents aeroallergen sensitization and primary care respiratory illness presentations [29141476] Abstract Introduction : Maternal vitamin D deficiency is widespread health problem that is more important in pregnant women , which affects fetus growth and bone development . The aim of this study was to evaluate the effect of sun exposure versus vitamin D supplementation for pregnant women with vitamin D deficiency . Material s and methods : This prospect i ve clinical trial was performed on 87 pregnant women with vitamin D deficiency . Group A was treated with vitamin D 4000 IU per day for 10 weeks , while group B was recommended for sun exposure for 30 minutes daily ( 30 % body surface area ) for 10 weeks in summer and between 10 am–4 pm in direct sunlight . After the delivery , 25-hydroxyvitamin D3 levels were measured in the same previous center . Moreover , weight , height , and head circumference of fetus were measured at delivery in both groups and compared with each other . Results : After 10-week intervention , 25-hydroxyvitamin D3 levels was significantly higher in group treated with vitamin D as compared to sun expose group ( 31.27 versus 19.79 ng/ml ) . ( p < .001 ) . However , height ( p = .118 ) , weight ( p = .245 ) , and head circumference ( p = .681 ) of infants in both groups did not show significant differences . Conclusions : Vitamin D supplementation is more effective than sun exposure in increasing 25-hydroxyvitamin D3 in pregnant women with vitamin D deficiency [29782187] INTRODUCTION Mothers and infants are at high risk for inadequate vitamin D status . Mechanisms by which vitamin D may affect maternal and infant DNA methylation are poorly understood . OBJECTIVE This study quantified the effects of vitamin D3 supplementation on DNA methylation in pregnant and lactating women and their breastfed infants . MATERIAL S AND METHODS In this r and omized controlled pilot study , pregnant women received vitamin D3 400 international units ( IU ) ( n = 6 ; control ) or 3,800 IU ( n = 7 ; intervention ) daily from late second trimester through 4 - 6 weeks postpartum . Epigenome-wide DNA methylation was quantified in leukocytes collected from mothers at birth and mother-infant dyads at 4 - 6 weeks postpartum . RESULTS At birth , intervention group mothers showed DNA methylation gain and loss at 76 and 89 cytosine-guanine ( CpG ) dinucleotides , respectively , compared to controls . Postpartum , methylation gain was noted at 200 and loss at 102 CpGs . Associated gene clusters showed strongest biologic relevance for cell migration/motility and cellular membrane function at birth and cadherin signaling and immune function at postpartum . Breastfed 4 - 6-week-old infants of intervention mothers showed DNA methylation gain and loss in 217 and 213 CpGs , respectively , compared to controls . Genes showing differential methylation mapped most strongly to collagen metabolic processes and regulation of apoptosis . CONCLUSIONS Maternal vitamin D supplementation during pregnancy and lactation alters DNA methylation in mothers and breastfed infants . Additional work is needed to fully eluci date the short- and long-term biologic effects of vitamin D supplementation at varying doses , which could hold important implication s for establishing clinical recommendations for prenatal and offspring health promotion [3755517] & NA ; A r and omized study was conducted to evaluate the effects of single‐dose and daily vitamin D supplementation in pregnant women during the last trimester of a winter pregnancy in the Northwest of France . The women were divided into three r and omized groups : one ( N = 21 ) was given a vitamin D2 supplement of 1000 IU/day during the last three months of pregnancy , one ( N = 27 ) was given a single oral dose of 5 mg at the seventh month of pregnancy , and one ( N = 29 ) acted as a control . Venous plasma sample s were obtained at delivery from the women and from cord blood , and levels of calcium , 25‐OHD , and 1,25(OH)2D were determined . No significant difference in plasma calcium concentration was found among the three groups , but within each group plasma calcium concentrations were higher in the cord sample s than in the respective maternal sample s. The levels of the two metabolites measured were consistently lower in the cord sample s than in the respective maternal sample s. Cord 25‐OHD concentrations correlated with those of maternal plasma . No significant modification of maternal calciuria or of the birth weight of term infants was observed . 25‐OHD concentrations were greater in maternal and cord plasma from treated mothers , but only a slight difference was observed between the supplemented groups . 1,25(OH)2D concentrations were not significantly different in the three groups . A single 5‐mg dose of vitamin D given orally at the seventh month of pregnancy provides effective prophylaxis in the authors ’ region . ( Obstet Gynecol 68:300 , 1986 [28502503] OBJECTIVE This study was performed to evaluate the effects of vitamin D and omega-3 fatty acids co-supplementation on glucose metabolism and lipid concentrations in gestational diabetes ( GDM ) patients . METHODS This r and omized double-blind placebo-controlled clinical trial was done among 140 GDM patients . Participants were r and omly divided into 4 groups to receive : ( 1 ) 1000 mg omega-3 fatty acids containing 360 mg eicosapentaenoic acid and 240 mg docosahexaenoic acid ( DHA ) twice a day + vitamin D placebo ( n = 35 ) ; ( 2 ) 50,000 IU vitamin D every 2 weeks + omega-3 fatty acids placebo ( n = 35 ) ; ( 3 ) 50,000 IU vitamin D every 2 weeks + 1000 mg omega-3 fatty acids twice a day ( n = 35 ) , and ( 4 ) vitamin D placebo + omega-3 fatty acids placebo ( n = 35 ) for 6 weeks . RESULTS After 6 weeks of intervention , patients who received combined vitamin D and omega-3 fatty acids supplements compared with vitamin D , omega-3 fatty acids , and placebo had significantly decreased fasting plasma glucose ( -7.3 ± 7.8 , -6.9 ± 6.6 , -4.0 ± 2.5 , and + 1.0 ± 11.4 mg/dL , respectively , P < .001 ) , serum insulin levels ( -1.9 ± 1.9 , -1.3 ± 6.3 , -0.4 ± 6.3 , and + 2.6 ± 6.5 μIU/mL , respectively , P = .005 ) , homeostatic model of assessment for insulin resistance ( -0.7 ± 0.6 , -0.5 ± 1.4 , -0.2 ± 1.5 , and + 0.6 ± 1.5 , respectively , P < .001 ) and increased quantitative insulin sensitivity check index ( + 0.01 ± 0.01 , + 0.008 ± 0.02 , + 0.002 ± 0.02 , and -0.005 ± 0.02 , respectively , P = .001 ) . In addition , changes in serum triglycerides ( -8.2 ± 41.0 , + 7.6 ± 31.5 , + 3.6 ± 29.9 , and + 20.1 ± 29.6 mg/dL , respectively , P = .006 ) and very low-density lipoprotein cholesterol ( -1.6 ± 8.2 , + 1.5 ± 6.3 , + 0.8 ± 6.0 , and + 4.0 ± 5.9 mg/dL , respectively , P = .006 ) in the vitamin D plus omega-3 fatty acids group were significantly different from the changes in these indicators in the vitamin D , omega-3 fatty acids , and placebo groups . CONCLUSION Overall , vitamin D and omega-3 fatty acids co-supplementation for 6 weeks among GDM patients had beneficial effects on fasting plasma glucose , serum insulin levels , homeostatic model of assessment for insulin resistance , quantitative insulin sensitivity check index , serum triglycerides , and very low-density lipoprotein cholesterol levels [23559082] BACKGROUND Vitamin D ( vD ) deficiency in pregnancy is a global health problem and the amount of vD supplementation to prevent vD deficiency is controversial . OBJECTIVE The objective of the study was to determine effectiveness and safety of prenatal 2000 IU and 4000 IU/d compared with 400 IU/d vD3 supplementation in a r and omized controlled trial in population in which vD deficiency is endemic . DESIGN / METHODS Arab women were r and omized at 12 - 16 weeks of gestation to 400 , 2000 , and 4000 IU/d vD3 , which were continued to delivery . Serum 25-hydroxyvitamin D [ 25(OH)D ] concentrations were measured during pregnancy and at delivery . The primary outcome was the maternal and cord blood 25(OH)D , and the secondary outcomes were the achievement of sufficient serum 25(OH)D of 32 ng/mL or greater ( ≥80 nmol/L ) at delivery . SETTING The locations were primary care and tertiary perinatal care centers . RESULTS Of 192 enrolled , 162 ( 84 % ) continued to delivery . Mean serum 25(OH)D of 8.2 ng/mL ( 20.5 nmol/L ) at enrollment was low . Mean serum 25(OH)D concentrations at delivery and in cord blood were significantly higher in the 2000 and 4000 IU than the 400 IU/d group ( P < .001 ) and was highest in the 4000 IU/d group . The percent who achieved 25(OH)D greater than 32 ng/mL and greater than 20 ng/mL concentrations in mothers and infants was highest in 4000 IU/d group . Safety measurements were similar by group and no adverse event related to vD supplementation . CONCLUSIONS Vitamin D supplementation of 2000 and 4000 IU/d appeared safe in pregnancy , and 4000 IU/d was most effective in optimizing serum 25(OH)D concentrations in mothers and their infants . These findings could apply to other population s in which vD deficiency is endemic [29796622] Background Interpretation of serum vitamin D biomarkers across pregnancy is complex due to limited underst and ing of pregnancy adaptations in vitamin D metabolism . During pregnancy , both gestational age and serum 25-hydroxyvitamin D [ 25(OH)D ] concentrations may influence the concentrations of 1,25-dihydroxyvitamin D [ 1,25(OH)2D ] , 24,25-dihydroxyvitamin D [ 24,25(OH)2D ] , and parathyroid hormone ( PTH ) . Objective We aim ed to identify predictors of change in serum 25(OH)D across gestation in pregnant adolescents and to assess the contribution made by cholecalciferol ( vitamin D3 ) supplementation . We sought to determine whether gestational age and 25(OH)D concentration interacted to affect serum 1,25(OH)2D , 24,25(OH)2D , or PTH . Methods Pregnant adolescents ( n = 78 , 59 % African American , mean ± SD age : 17 ± 1 y ) living in Rochester , NY ( latitude 43 ° N ) were supplemented with 200 IU or 2000 IU vitamin D3/d and allowed to continue their daily prenatal supplement that contained 400 IU vitamin D3 . Serum was collected at study entry ( 18 ± 5 wk of gestation ) , halfway through study participation , and at delivery ( 40 ± 2 wk ) . Serum concentrations of the biochemical markers were modeled with linear mixed-effects regression models . Results Vitamin D3 supplement intake and season of delivery determined change in 25(OH)D across pregnancy . Fall-winter delivery was associated with a decline in 25(OH)D unless vitamin D3 supplement intake was > 872 IU/d . The interaction of gestational age and 25(OH)D affected 24,25(OH)2D concentrations . For a given 25(OH)D concentration , model-predicted serum 24,25(OH)2D increased across gestation except when 25(OH)D was < 13 ng/mL. Below this threshold , 24,25(OH)2D was predicted to decline over time . Mean serum 1,25(OH)2D was elevated ( > 100 pg/mL ) throughout the study . Conclusion Our results suggest that when maternal serum 25(OH)D was low , its catabolism into 24,25(OH)2D decreased or remained stable as pregnancy progressed in order to maintain persistently elevated serum 1,25(OH)2D . Furthermore , in adolescents living at latitude 43 ° N , st and ard prenatal supplementation did not prevent a seasonal decline in 25(OH)D during pregnancy . This study was registered at clinical trials.gov as NCT01815047 [23131462] OBJECTIVE We sought to determine whether 4000 IU/d ( vs 2000 IU/d ) of vitamin D during pregnancy is safe and improves maternal/neonatal 25-hydroxyvitamin D [ 25(OH)D ] in a dose-dependent manner . STUDY DESIGN A total of 257 pregnant women 12 - 16 weeks ' gestation were enrolled . R and omization to 2000 vs 4000 IU/d followed 1-month run-in at 2000 IU/d . Participants were monitored for hypercalciuria , hypercalcemia , and 25(OH)D status . RESULTS Maternal 25(OH)D ( n = 161 ) increased from 22.7 ng/mL ( SD 9.7 ) at baseline to 36.2 ng/mL ( SD 15 ) and 37.9 ng/mL ( SD 13.5 ) in the 2000 and 4000 IU groups , respectively . While maternal 25(OH)D change from baseline did not differ between groups , 25(OH)D monthly increase differed between groups ( P < .01 ) . No supplementation-related adverse events occurred . Mean cord blood 25(OH)D was 22.1 ± 10.3 ng/mL in 2000 IU and 27.0 ± 13.3 ng/mL in 4000 IU groups ( P = .024 ) . After controlling for race and study site , preterm birth and labor were inversely associated with predelivery and mean 25(OH)D , but not baseline 25(OH)D. CONCLUSION Maternal supplementation with vitamin D 2000 and 4000 IU/d during pregnancy improved maternal/neonatal vitamin D status . Evidence of risk reduction in infection , preterm labor , and preterm birth was suggestive , requiring additional studies powered for these endpoints [29788364] Context Despite evidence on the association between hypovitaminosis D and adverse pregnancy outcomes and the positive impact of vitamin D supplementation , no evidence exists supporting a universal screening program in pregnancy as part of routine prenatal care . Objective We sought to determine the effectiveness of a prenatal screening program on optimizing 25-hydroxyvitamin D [ 25(OH)D ] levels and preventing pregnancy complications . Also , to identify a safe regimen , we compared several regimens in a subgroup of vitamin D-deficient pregnant women . Design Two cities of Masjed-Soleyman and Shushtar from Khuzestan province , Iran , were selected as the screening and nonscreening arms , respectively . Within the screening arm , a r and omized controlled trial was conducted on 800 pregnant women . Setting Health centers of Masjed-Soleyman and Shushtar cities . Patients or Participants Pregnant women aged 18 to 40 years . Intervention Women with moderate [ 25(OH)D , 10 to 20 ng/mL ] and severe [ 25(OH)D , < 10 ng/mL ] deficiency were r and omly divided into four subgroups and received vitamin D3 ( D3 ) until delivery . Main Outcome Measure Maternal concentration of 25(OH)D at delivery and rate of pregnancy complications . Results After supplementation , only 2 % of the women in the nonscreening site met the sufficiency level ( > 20 ng/mL ) vs 53 % of the women in the screening site . Adverse pregnancy outcomes , including preeclampsia , gestational diabetes mellitus , and preterm delivery , were decreased by 60 % , 50 % , and 40 % , respectively , in the screening site . A D3 injection in addition to monthly 50,000 IU maintenance therapy contributed the most to achievement of sufficient levels at delivery . Conclusions A prenatal vitamin D screening and treatment program is an effective approach in detecting deficient women , improving 25(OH)D levels , and decreasing pregnancy adverse outcomes [6600055] ABSTRACT Background In the absence of dose-response data , Dietary Reference Values for vitamin D in nonpregnant adults are extended to pregnancy . Objective The aim was to estimate vitamin D intake needed to maintain maternal 25-hydroxyvitamin D [ 25(OH)D ] in late gestation at a concentration sufficient to prevent newborn 25(OH)D < 25–30 nmol/L , a threshold indicative of increased risk of nutritional rickets . Design We conducted a 3-arm , dose-response , double-blind , r and omized placebo-controlled trial in Cork , Irel and ( 51.9oN ) . A total of 144 white-skinned pregnant women were assigned to receive 0 , 10 ( 400 IU ) , or 20 ( 800 IU ) µg vitamin D3/d from ≤18 wk of gestation . Vitamin D metabolites at 14 , 24 , and 36 wk of gestation and in cord sera , including 25(OH)D3 , 3-epi-25(OH)D3 , 24,25(OH)2D3 , and 25(OH)D2 were quantified by liquid chromatography – t and em mass spectrometry . A curvilinear regression model predicted the total vitamin D intake ( from diet and antenatal supplements plus treatment dose ) that maintained maternal 25(OH)D in late gestation at a concentration sufficient to maintain cord 25(OH)D at ≥25–30 nmol/L. Results Mean ± SD baseline 25(OH)D was 54.9 ± 10.7 nmol/L. Total vitamin D intakes at the study endpoint ( 36 wk of gestation ) were 12.1 ± 8.0 , 21.9 ± 5.3 , and 33.7 ± 5.1 µg/d in the placebo and 10-µg and 20-µg vitamin D3 groups , respectively ; and 25(OH)D was 24.3 ± 5.8 and 29.2 ± 5.6 nmol/L higher in the 10- and 20-µg groups , respectively , compared with placebo ( P < 0.001 ) . For maternal 25(OH)D concentrations ≥50 nmol/L , 95 % of cord sera were ≥30 nmol/L and 99 % were > 25 nmol/L. The estimated vitamin D intake required to maintain serum 25(OH)D at ≥50 nmol/L in 97.5 % of women was 28.9 µg/d . Conclusions Thirty micrograms of vitamin D per day safely maintained serum 25(OH)D concentrations at ≥50 nmol/L in almost all white-skinned women during pregnancy at a northern latitude , which kept 25(OH)D at > 25 nmol/L in 99 % and ≥30 nmol/L in 95 % of umbilical cord sera . This trial was registered at www . clinical trials.gov as NCT02506439 [6004541] Background It is unclear whether maternal vitamin D supplementation during pregnancy and lactation improves fetal and infant growth in regions where vitamin D deficiency is common . Methods We conducted a r and omized , double‐blind , placebo‐controlled trial in Bangladesh to assess the effects of weekly prenatal vitamin D supplementation ( from 17 to 24 weeks of gestation until birth ) and postpartum vitamin D supplementation on the primary outcome of infants ' length‐for‐age z scores at 1 year according to World Health Organization ( WHO ) child growth st and ards . One group received neither prenatal nor postpartum vitamin D ( placebo group ) . Three groups received prenatal supplementation only , in doses of 4200 IU ( prenatal 4200 group ) , 16,800 IU ( prenatal 16,800 group ) , and 28,000 IU ( prenatal 28,000 group ) . The fifth group received prenatal supplementation as well as 26 weeks of postpartum supplementation in the amount of 28,000 IU ( prenatal and postpartum 28,000 group ) . Results Among 1164 infants assessed at 1 year of age ( 89.5 % of 1300 pregnancies ) , there were no significant differences across groups in the mean ( ±SD ) length‐for‐age z scores . Scores were as follows : placebo , ‐0.93±1.05 ; prenatal 4200 , ‐1.11±1.12 ; prenatal 16,800 , ‐0.97±0.97 ; prenatal 28,000 , ‐1.06±1.07 ; and prenatal and postpartum 28,000 , ‐0.94±1.00 ( P=0.23 for a global test of differences across groups ) . Other anthropometric measures , birth outcomes , and morbidity did not differ significantly across groups . Vitamin D supplementation had expected effects on maternal and infant serum 25‐hydroxyvitamin D and calcium concentrations , maternal urinary calcium excretion , and maternal parathyroid hormone concentrations . There were no significant differences in the frequencies of adverse events across groups , with the exception of a higher rate of possible hypercalciuria among the women receiving the highest dose . Conclusions In a population with widespread prenatal vitamin D deficiency and fetal and infant growth restriction , maternal vitamin D supplementation from midpregnancy until birth or until 6 months post partum did not improve fetal or infant growth . ( Funded by the Bill and Melinda Gates Foundation ; Clinical Trials.gov number , NCT01924013 . [26813209] IMPORTANCE Asthma and wheezing begin early in life , and prenatal vitamin D deficiency has been variably associated with these disorders in offspring . OBJECTIVE To determine whether prenatal vitamin D ( cholecalciferol ) supplementation can prevent asthma or recurrent wheeze in early childhood . DESIGN , SETTING , AND PARTICIPANTS The Vitamin D Antenatal Asthma Reduction Trial was a r and omized , double-blind , placebo-controlled trial conducted in 3 centers across the United States . Enrollment began in October 2009 and completed follow-up in January 2015 . Eight hundred eighty-one pregnant women between the ages of 18 and 39 years at high risk of having children with asthma were r and omized at 10 to 18 weeks ' gestation . Five participants were deemed ineligible shortly after r and omization and were discontinued . INTERVENTIONS Four hundred forty women were r and omized to receive daily 4000 IU vitamin D plus a prenatal vitamin containing 400 IU vitamin D , and 436 women were r and omized to receive a placebo plus a prenatal vitamin containing 400 IU vitamin D. MAIN OUTCOMES AND MEASURES Co primary outcomes of ( 1 ) parental report of physician-diagnosed asthma or recurrent wheezing through 3 years of age and ( 2 ) third trimester maternal 25-hydroxyvitamin D levels . RESULTS Eight hundred ten infants were born in the study , and 806 were included in the analyses for the 3-year outcomes . Two hundred eighteen children developed asthma or recurrent wheeze : 98 of 405 ( 24.3 % ; 95 % CI , 18.7%-28.5 % ) in the 4400-IU group vs 120 of 401 ( 30.4 % , 95 % CI , 25.7%-73.1 % ) in the 400-IU group ( hazard ratio , 0.8 ; 95 % CI , 0.6 - 1.0 ; P = .051 ) . Of the women in the 4400-IU group whose blood levels were checked , 289 ( 74.9 % ) had 25-hydroxyvitamin D levels of 30 ng/mL or higher by the third trimester of pregnancy compared with 133 of 391 ( 34.0 % ) in the 400-IU group ( difference , 40.9 % ; 95 % CI , 34.2%-47.5 % , P < .001 ) . CONCLUSIONS AND RELEVANCE In pregnant women at risk of having a child with asthma , supplementation with 4400 IU/d of vitamin D compared with 400 IU/d significantly increased vitamin D levels in the women . The incidence of asthma and recurrent wheezing in their children at age 3 years was lower by 6.1 % , but this did not meet statistical significance ; however , the study may have been underpowered . Longer follow-up of the children is ongoing to determine whether the difference is clinical ly important . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00920621 [27746239] Background : The gut microbiome in infancy influences immune system maturation , and may have an important impact on allergic disease risk . Objective : We sought to determine how prenatal and early life factors impact the gut microbiome in a relatively large , ethnically diverse study population of infants at age 3 to 6 months , who were enrolled in Vitamin D Antenatal Asthma Reduction Trial , a clinical trial of vitamin D supplementation in pregnancy to prevent asthma and allergies in offspring . Methods : We performed 16S rRNA gene sequencing on 333 infants ' stool sample s. Microbial diversity was computed using the Shannon index . Factor analysis applied to the top 25 most abundant taxa revealed 4 underlying bacterial coabundance groups ; the first dominated by Firmicutes ( Lachnospiraceae/Clostridiales ) , the second by Proteobacteria ( Klebsiella/Enterobacter ) , the third by Bacteriodetes , and the fourth by Veillonella . Scores for coabundance groups were used as outcomes in regression models , with prenatal/birth and demographic characteristics as independent predictors . Multivariate analysis , using all microbial community members , was also conducted . Results : White race/ethnicity was associated with lower diversity but higher Bacteroidetes coabundance scores . C‐section birth was associated with higher diversity , but decreased Bacteroidetes coabundance scores . Firmicutes scores were higher for infants born by C‐section . Breast‐fed infants had lower proportions of Clostridiales . Cord blood vitamin D was linked to increased Lachnobacterium , but decreased Lactococcus . Conclusions : The findings presented here suggest that race , mode of delivery , breast‐feeding , and cord blood vitamin D levels are associated with infant gut microbiome composition , with possible long‐term implication s for immune system modulation and asthma/allergic disease incidence [26399867] BACKGROUND The role of maternal 25-hydroxyvitamin D [ 25(OH)D ] in fetal development is uncertain , and findings of observational studies have been inconsistent . Most studies have assessed 25(OH)D only one time during pregnancy , but to our knowledge , the tracking of an individual 's 25(OH)D during pregnancy has not been assessed previously . OBJECTIVE We determined the tracking of serum 25(OH)D from early to late pregnancy and factors that influence this . DESIGN The Southampton Women 's Survey is a prospect i ve mother-offspring birth-cohort study . Lifestyle , diet , and 25(OH)D status were assessed at 11 and 34 wk of gestation . A Fourier transformation was used to model the seasonal variation in 25(OH)D for early and late pregnancy separately , and the difference between the measured and seasonally modeled 25(OH)D was calculated to generate a season-corrected 25(OH)D. Tracking was assessed with the use of the Pearson correlation coefficient , and multivariate linear regression was used to determine factors associated with the change in season-corrected 25(OH)D. RESULTS A total of 1753 women had 25(OH)D measured in both early and late pregnancy . There was a moderate correlation between season-corrected 25(OH)D measurements at 11 and 34 wk of gestation ( r = 0.53 , P < 0.0001 ; n = 1753 ) . Vitamin D supplementation was the strongest predictor of tracking ; in comparison with women who never used supplements , the discontinuation of supplementation after 11 wk was associated with a reduction in season-corrected 25(OH)D ( β = -7.3 nmol/L ; P < 0.001 ) , whereas the commencement ( β = 12.6 nmol/L ; P < 0.001 ) or continuation ( β = 6.6 nmol/L ; P < 0.001 ) of supplementation was associated with increases in season-corrected 25(OH)D. Higher pregnancy weight gain was associated with a reduction in season-corrected 25(OH)D ( β = -0.4 nmol · L(-1 ) · kg(-1 ) ; P = 0.015 ) , whereas greater physical activity ( β = 0.4 nmol/L per h/wk ; P = 0.011 ) was associated with increases . CONCLUSIONS There is a moderate tracking of 25(OH)D status through pregnancy ; factors such as vitamin D supplementation , weight gain , and physical activity are associated with changes in season-corrected 25(OH)D from early to late gestation . These findings have implication s for study design s and analyses and approaches to intervention studies and clinical care [29046301] Background : Little is known about bone mineral density ( BMD ) during pregnancy . Advances in technology with lower radiation emissions by dual-energy X-ray absorptiometry instruments now permit the safe measurement of BMD during pregnancy . Objective : We evaluated maternal BMD during pregnancy as a function of vitamin D status in women of diverse racial/ethnic background s. Design : A total of 301 women who underwent BMD measurements at 12 - 20 wk of gestation and again at 0 - 14 wk postpartum were included in this analysis . Women were a subset of subjects who were recruited for a r and omized , controlled , double-blind trial of vitamin D supplementation in pregnancy ( 400 , 2000 , or 4000 IU/d ) . Results : Treatment had no significant effect on changes in BMD that occurred between 12 - 20 wk of gestation and 0 - 14 wk postpartum . Similarly , changes in spine and femoral neck bone mineral contents ( BMC s ) were not significantly different in the treatment groups . In addition , vitamin D inadequacy ( serum 25-hydroxyvitamin D concentration , averaged across pregnancy , < 50 nmol/L ) was not associated with changes in BMD or BMC . There were significant racial/ethnic differences in spine BMD . African Americans lost more spine BMD than did Caucasians ( -0.04 ± 0.04 compared with -0.02 ± 0.04 g/cm2 ; P = 0.033 ) . In addition , baseline obesity was associated with a greater loss of femoral neck BMD . The means ± SDs of femoral neck BMD loss were -0.02 ± 0.05 and 0.0 ± 0.03 g/cm2 for groups with baseline body mass index ( BMI ; in kg/m2 ) ≥30 and < 30 , respectively . Conclusion : These findings do not support a dose effect of vitamin D supplementation on bone health and suggest that race/ethnicity and BMI play an important role in pregnancy bone health . This trial was registered at clinical trials.gov as NCT00292591 [24210789] OBJECTIVE To determine whether treatment of low serum vitamin D in pregnant women improves fetal growth indices . STUDY DESIGN In this open-label r and omized clinical trial , 130 Iranian pregnant women ( 24 - 26 weeks of gestation ) with vitamin D deficiency or insufficiency [ 25(OH)D < 30ng/ml ] were divided at r and om into an intervention group and a control group . The control group received 200 mg calcium plus a multivitamin ( containing vitamin D3 400U ) each day , and the intervention group received 200 mg calcium plus a multivitamin ( containing vitamin D3 400U ) each day , plus vitamin D3 ( 50,000U ) each week for 8 weeks . At delivery , maternal and cord blood 25(OH)D levels , maternal weight gain , neonatal length , neonatal weight and neonatal head circumference were compared between two groups . Serum vitamin D was measured using enzyme-linked immunosorbent assay . A multivariate regression analysis was performed to examine the independent effect of maternal vitamin D level on fetal growth indices . RESULTS Mean ( ±st and ard deviation ) length ( intervention group : 49±1.6 cm ; control group : 48.2±1.7 cm ; p=0.001 ) , head circumference ( intervention group : 35.9±0.7 cm ; control group : 35.3±1.0 cm ; p=0.001 ) and weight ( intervention group : 3429±351.9 g ; control group : 3258.8±328.2 g ; p=0.01 ) were higher in the intervention group compared with the control group . Mean maternal weight gain was higher in the intervention group compared with the control group ( 13.3±2.4 kg vs 11.7±2.7 kg ; p=0.006 ) . Multivariate regression analysis for maternal weight gain , neonatal length , neonatal weight and neonatal head circumference showed an independent correlation with maternal vitamin D level . CONCLUSION Treatment of low serum vitamin D during pregnancy improves fetal growth indices and maternal weight gain [26156737] BACKGROUND Vitamin D supplementation is recommended for breastfed infants . Maternal supplementation beginning in gestation is a potential alternative , but its efficacy in maintaining infant 25-hydroxyvitamin D [ 25(OH)D ] concentration after birth is unknown . OBJECTIVES We determined the effect of 3 doses of maternal vitamin D supplementation beginning in gestation and continued in lactation on infant serum 25(OH)D and compared the prevalence of infant serum 25(OH)D cutoffs ( > 30 , > 40 , > 50 , and > 75 nmol/L ) by dose at 8 wk of age . DESIGN Pregnant women ( n = 226 ) were r and omly allocated to receive 10 , 25 , or 50 μg vitamin D₃/d from 13 to 24 wk of gestation until 8 wk postpartum , with no infant supplementation . Mother and infant blood was collected at 8 wk postpartum . RESULTS At 8 wk postpartum , mean [ nmol/L ( 95 % CI ) ] infant 25(OH)D at 8 wk was higher in the 50-μg/d [ 75 ( 67 , 83 ) ] than in the 25-μg/d [ 52 ( 45 , 58 ) ] or 10-μg/d [ 45 ( 38 , 52 ) ] vitamin D groups ( P < 0.05 ) . Fewer infants born to mothers in the 50-μg/d group had a 25(OH)D concentration < 30 nmol/L ( indicative of deficiency ) than infants in the 25- and 10-μg/d groups , respectively ( 2 % compared with 16 % and 43 % ; P < 0.05 ) . Fewer than 15 % of infants in the 10- or 25-μg/d groups achieved a 25(OH)D concentration > 75 nmol/L compared with 44 % in the 50-μg/d group ( P < 0.05 ) . Almost all infants ( ∼98 % , n = 44 ) born to mothers in the 50-μg/d group achieved a 25(OH)D concentration > 30 nmol/L. At 8 wk postpartum , mean maternal 25(OH)D concentration was higher in the 50-μg/d [ 88 ( 84 , 91 ) ] than in the 25-μg/d [ 78 ( 74 , 81 ) ] or 10-μg/d [ 69 ( 66 , 73 ) ] groups ( P < 0.05 ) . CONCLUSIONS Maternal supplementation beginning in gestation with 50 μg vitamin D₃/d protects 98 % of unsupplemented breastfed infants against 25(OH)D deficiency ( < 30 nmol/L ) to at least 8 wk , whereas 10 or 25 μg vitamin D/d protects only 57 % and 84 % of infants , respectively

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### Context: [3691177] Background Observational studies suggest high prenatal vitamin D intake may be associated with reduced childhood wheezing . We examined the effect of prenatal vitamin D on childhood wheezing in an interventional study . Methods We r and omised 180 pregnant women at 27 weeks gestation to either no vitamin D , 800 IU ergocalciferol daily until delivery or single oral bolus of 200,000 IU cholecalciferol , in an ethnically stratified , r and omised controlled trial . Supplementation improved but did not optimise vitamin D status . Research ers blind to allocation assessed offspring at 3 years . Primary outcome was any history of wheeze assessed by vali date d question naire . Secondary outcomes included atopy , respiratory infection , impulse oscillometry and exhaled nitric oxide . Primary analyses used logistic and linear regression . Results We evaluated 158 of 180 ( 88 % ) offspring at age 3 years for the primary outcome . Atopy was assessed by skin test for 95 children ( 53 % ) , serum IgE for 86 ( 48 % ) , exhaled nitric oxide for 62 ( 34 % ) and impulse oscillometry of acceptable quality for 51 ( 28 % ) . We found no difference between supplemented and control groups in risk of wheeze [ no vitamin D : 14/50 ( 28 % ) ; any vitamin D : 26/108 ( 24 % ) ( risk ratio 0.86 ; 95 % confidence interval 0.49 , 1.50 ; P = 0.69 ) ] . There was no significant difference in atopy , eczema risk , lung function or exhaled nitric oxide between supplemented groups and controls . Conclusion Prenatal vitamin D supplementation in late pregnancy that had a modest effect on cord blood vitamin D level , was not associated with decreased wheezing in offspring at age three years . Trial Registration Controlled-Trials.com IS RCT [24344104] OBJECTIVE : To determine the vitamin D dose necessary to achieve serum 25-hydroxyvitamin D ( 25(OH)D ) concentration ≥20 ng/mL during infancy . METHODS : A r and omized , double-blind , placebo-controlled trial in New Zeal and . Pregnant mothers , from 27 weeks ’ gestation to birth , and then their infants , from birth to age 6 months , were r and omly assigned to 1 of 3 mother/infant groups : placebo/placebo , vitamin D3 1000/400 IU , or vitamin D3 2000/800 IU . Serum 25(OH)D and calcium concentrations were measured at enrollment , 36 weeks ’ gestation , in cord blood , and in infants at 2 , 4 , and 6 months of age . RESULTS : Two-hundred- and -sixty pregnant women were r and omized . At enrollment , the proportions with serum 25(OH)D ≥20 ng/mL for placebo , lower-dose , and higher-dose groups were 54 % , 64 % , and 55 % , respectively . The proportion with 25(OH)D ≥20 ng/mL was larger in both intervention groups at 36 weeks ’ gestation ( 50 % , 91 % , 89 % , P < .001 ) . In comparison with placebo , the proportion of infants with 25(OH)D ≥20 ng/mL was larger in both intervention groups to age 4 months : cord blood ( 22 % , 72 % , 71 % , P < .001 ) , 2 months ( 50 % , 82 % , 92 % , P < .001 ) , and 4 months ( 66 % , 87 % , 87 % , P = .004 ) , but only in the higher-dose group at age 6 months ( 74 % , 82 % , 89 % , P = .07 ; higher dose versus placebo P = .03 , lower dose versus placebo P = .21 ) . CONCLUSIONS : Daily vitamin D supplementation during pregnancy and then infancy with 1000/400 IU or 2000/800 IU increases the proportion of infants with 25(OH)D ≥20 ng/mL , with the higher dose sustaining this increase for longer [24614387] There is intense interest in the role of vitamin D in the development of asthma and allergies . However , studies differ on whether a higher vitamin D intake or status in pregnancy or at birth is protective against asthma and allergies . To address this uncertainty , the Vitamin D Antenatal Asthma Reduction Trial ( VDAART ) was developed . VDAART is a r and omized , double-blind , placebo-controlled trial of vitamin D supplementation in pregnant women to determine whether prenatal supplementation can prevent the development of asthma and allergies in women 's offspring . A secondary aim is to determine whether vitamin D supplementation can prevent the development of pregnancy complications , such as preeclampsia , preterm birth , and gestational diabetes . Women were r and omized to the treatment arm of 4000IU/day of vitamin D3 plus a daily multivitamin that contained 400IU of vitamin D3 or the placebo arm of placebo plus a multivitamin that contained 400IU daily of vitamin D3 . Women who were between the gestational ages of 10 and 18 weeks were r and omized from three clinical centers across the United States - Boston Medical Center , Washington University in St. Louis , and Kaiser Permanente Southern California Region ( San Diego , CA ) . Supplementation took place throughout pregnancy . Monthly monitoring of urinary calcium to creatinine ratio was performed in addition to medical record review for adverse events . Offspring are being evaluated quarterly through question naires and yearly during in-person visits until the 3rd birthday of the child . Ancillary studies will investigate neonatal T-regulatory cell function , maternal vaginal flora , and maternal and child intestinal flora [24714660] Aim / Background : Vitamin D supplementation during pregnancy is a well-accepted recommendation worldwide ; however , the debate about the correct dose is ongoing . We aim ed to compare daily doses of 600 , 1,200 , and 2,000 IU in this r and omized , controlled study . Methods : The study group consisted of 91 pregnant women aged 16 - 42 years admitted to Kocaeli Maternity and Children Hospital between April 2011 and April 2012 . The participants were r and omly divided into 3 groups . 600 , 1,200 , and 2,000 IU/day of vitamin D was supplemented to group 1 ( control group , n = 31 ) , group 2 ( n = 31 ) , and group 3 ( n = 32 ) , respectively . Serum calcium , 25-hydroxyvitamin D ( 25OHD ) , and the calcium/creatinine ratio in spot urine sample s were measured in the follow-up period . The serum calcium and 25OHD levels of the mothers ' infants were measured as well . Results : The frequency of vitamin D sufficiency after supplementation was 80 % in group 3 and it was significantly higher than in groups 1 ( 42 % ) and 2 ( 39 % ) ( p = 0.03 ) . The frequency of vitamin D sufficiency in the infants of the participants was 91 % in group 3 and it was significantly higher than in groups 1 ( 36 % ) and 2 ( 52 % ) ( p = 0.006 ) . Conclusions : At least 2,000 IU/day of vitamin D is needed to ensure adequate vitamin D status in pregnancy and early infancy [28878035] Background : To prevent preeclampsia , the WHO recommends antenatal calcium supplementation in population s with inadequate habitual intake . The WHO recommends 1500 - 2000 mg Ca/d with iron-folic acid ( IFA ) taken separately , a complex pill-taking regimen . Objective : The objective of this study was to test the hypothesis that simpler regimens with lower daily dosages would lead to higher adherence and similar supplement intake . Methods : In the Micronutrient Initiative Calcium Supplementation study , we compared the mean daily supplement intake associated with 2 dosing regimens with the use of a parallel , cluster-r and omized noninferiority trial implemented in 16 primary health care facilities in rural Kenya . The st and ard regimen was 3 × 500 mg Ca/d in 3 pill-taking events , and the low-dose regimen was 2 × 500 mg Ca/d in 2 pill-taking events ; both regimens included a 200 IU cholecalciferol and calcium pill and a separate IFA pill . We enrolled 990 pregnant women between 16 and 30 wk of gestation . The primary outcome was supplemental calcium intake measured by pill counts 4 and 8 wk after recruitment . We carried out intention-to-treat analyses with the use of mixed-effect models , with regimen as the fixed effect and health care facilities as a r and om effect , by using a noninferiority margin of 125 mg Ca/d . Results : Women in facilities assigned to the st and ard regimen consumed a mean of 1198 mg Ca/d , whereas those assigned to the low-dose regimen consumed 810 mg Ca/d . The difference in intake was 388 mg Ca/d ( 95 % CI = 341 , 434 mg Ca/d ) , exceeding the prespecified margin of 125 mg Ca/d . The overall adherence rate was 80 % and did not differ between study arms . Conclusions : Contrary to our expectation , a simpler , lower-dose regimen led to significantly lower supplement intake than the regimen recommended by the WHO . Further studies are needed to precisely characterize the dose-response relation of calcium supplementation and preeclampsia risk and to examine cost effectiveness of lower and simpler regimens in program setting s. This trial was registered at clinical trials.gov as NCT02238704 [27840206] Objective To identify the combined effect of prenatal and postnatal vitamin D3 supplementation on the vitamin D status of pregnant and lactating women and their exclusively breastfed infants . Design Double‐blind , r and omized controlled trial . Setting Upper Midwestern U.S. , hospital‐based obstetric practice . Participants Pregnant women ( N = 13 ) planning to exclusively breastfeed were r and omized at 24 to 28 weeks gestation to receive vitamin D3 at a dosage of 400 IU ( control group , n = 6 ) or 3,800 IU ( intervention group , n = 7 ) daily through 4 to 6 weeks postpartum . Vitamin D status was determined at enrollment and in mother – infant dyads at 24 to 72 hours after birth and 4 to 6 weeks postpartum . Methods Serum 25‐hydroxyvitamin D levels were measured to determine the effect of vitamin D3 supplementation on the vitamin D status of mothers and infants . Analysis of covariance was used to compare differences in 25‐hydroxyvitamin D levels between the control and intervention groups . Results The mothers ’ vitamin D levels were significantly higher in the intervention group than in the control group at birth ( p = .044 ) and at 4 to 6 weeks postpartum ( p = .002 ) . Infants in the intervention group had significantly higher vitamin D levels at birth ( p = .021 ) and nonsignificant , clinical ly relevant increases at 4 to 6 weeks of age ( p = .256 ) . No differences were found between maternal groups in serum calcium or parathyroid hormone levels . Conclusion Prenatal to postpartum vitamin D3 supplementation is an effective intervention to increase a mother ’s vitamin D status and to promote optimal vitamin D status in newborns and exclusively breastfed infants [27841759] BACKGROUND Low vitamin D status in pregnancy was proposed as a risk factor of preeclampsia . METHODS We assessed the effect of vitamin D supplementation ( 4,400 vs. 400 IU/day ) , initiated early in pregnancy ( 10 - 18 weeks ) , on the development of preeclampsia . The effects of serum vitamin D ( 25-hydroxyvitamin D [ 25OHD ] ) levels on preeclampsia incidence at trial entry and in the third trimester ( 32 - 38 weeks ) were studied . We also conducted a nested case-control study of 157 women to investigate peripheral blood vitamin D-associated gene expression profiles at 10 to 18 weeks in 47 participants who developed preeclampsia . RESULTS Of 881 women r and omized , outcome data were available for 816 , with 67 ( 8.2 % ) developing preeclampsia . There was no significant difference between treatment ( N = 408 ) or control ( N = 408 ) groups in the incidence of preeclampsia ( 8.08 % vs. 8.33 % , respectively ; relative risk : 0.97 ; 95 % CI , 0.61 - 1.53 ) . However , in a cohort analysis and after adjustment for confounders , a significant effect of sufficient vitamin D status ( 25OHD ≥30 ng/ml ) was observed in both early and late pregnancy compared with insufficient levels ( 25OHD < 30 ng/ml ) ( adjusted odds ratio , 0.28 ; 95 % CI , 0.10 - 0.96 ) . Differential expression of 348 vitamin D-associated genes ( 158 upregulated ) was found in peripheral blood of women who developed preeclampsia ( FDR < 0.05 in the Vitamin D Antenatal Asthma Reduction Trial [ VDAART ] ; P < 0.05 in a replication cohort ) . Functional enrichment and network analyses of this vitamin D-associated gene set suggests several highly functional modules related to systematic inflammatory and immune responses , including some nodes with a high degree of connectivity . CONCLUSIONS Vitamin D supplementation initiated in weeks 10 - 18 of pregnancy did not reduce preeclampsia incidence in the intention-to-treat paradigm . However , vitamin D levels of 30 ng/ml or higher at trial entry and in late pregnancy were associated with a lower risk of preeclampsia . Differentially expressed vitamin D-associated transcriptomes implicated the emergence of an early pregnancy , distinctive immune response in women who went on to develop preeclampsia . TRIAL REGISTRATION Clinical Trials.gov NCT00920621 . FUNDING Quebec Breast Cancer Foundation and Genome Canada Innovation Network . This trial was funded by the National Heart , Lung , and Blood Institute . For details see Acknowledgments [5400884] Background Although there have been marked improvements in our underst and ing of vitamin D functions in different diseases , gaps on its role during pregnancy remain . Due to the lack of consensus on the most accurate marker of vitamin D deficiency during pregnancy and the optimal level of 25-hydroxyvitamin D , 25(OH)D , for its definition , vitamin D deficiency assessment during pregnancy is a complicated process . Besides , the optimal protocol for treatment of hypovitaminosis D and its effect on maternal and neonatal outcomes are still unclear . Objective The aim of our study was to estimate the prevalence of vitamin D deficiency in the first trimester of pregnancy and to compare vitamin D screening strategy with no screening . Also , we intended to compare the effectiveness of various treatment regimens on maternal and neonatal outcomes in Masjed-Soleyman and Shushtar cities of Khuzestan province , Iran . Methods This was a two-phase study . First , a population -based cross-sectional study was conducted ; recruiting 1600 and 900 first trimester pregnant women from health centers of Masjed-Soleyman and Shushtar , respectively , using stratified multistage cluster sampling with probability proportional to size ( PPS ) method . Second , to assess the effect of screening strategy on maternal and neonatal outcomes , Masjed-Soleyman participants were assigned to a screening program versus Shushtar participants who became the nonscreening arm . Within the framework of the screening regimen , an 8-arm blind r and omized clinical trial was undertaken to compare the effects of various treatment protocol s. A total of 800 pregnant women with vitamin D deficiency were selected using simple r and om sampling from the 1600 individuals of Masjed-Soleyman as interventional groups . Serum concentrations of 25(OH)D were classified as : ( 1 ) severe deficient ( < 10ng/ml ) , ( 2 ) moderate deficient ( 10 - 20ng/ml ) , and ( 3 ) normal status ( > 20ng/ml ) . Those with severe and moderate deficiency were r and omly divided into 4 subgroups and received vitamin D3 based on protocol and were followed until delivery . Data was analyzed according to the intention-to-treat principle . Results Recruitment commenced in July , 2014 , and as estimated , nearly 3.5 years is needed to complete the study . Results of this study will ( 1 ) provide reliable information regarding the prevalence of vitamin D deficiency during pregnancy using universal vitamin D screening approach and ( 2 ) determine the beneficial effects of universal screening and compare the various treatment protocol s in terms of pregnancy outcomes . Conclusions Since vitamin D deficiency is a prevalent disorder in pregnancy among Iranian population , this study will ensure creation of reliable evidence -based findings and will enable clinicians to better evaluate and treat vitamin D deficient pregnant women . Trial Registration International St and ard R and omized Controlled Trial Number ( IS RCT N ) : 2014102519660N1 ; http://www.i rct .ir/ search result .php?keyword=&id=19660&number=1&prt=7805&total=10&m=1 ( Archived by WebCite at http://www.webcitation.org/6p3lkqFdV [29550150] BACKGROUND Vitamin D plays pivotal role in decidualization and implantation of the placenta . Recent research es have shown that low level of vitamin D3 " 25-hydroxyvitamin D ( 25[OH]D ) " in serum is a risk factor for pre-eclampsia . Latest evidence supports role of vitamin D3 deficiency treatment in reducing the risk of pre-eclampsia . The aim of this study is to determine the effect of antenatal supplementation of vitamin D3 on the risk of pre-eclampsia and to explore the dose effect in attaining the vitamin D3 normal level . METHOD An open labelled r and omized controlled study was conducted on 179 pregnant women presenting in King Fahad Medical City antenatal clinic from Oct 2012-Oct 2015 . Patients with age less than 20 years or more than 40 years , pregnancy with fetal anomalies , history of hypertension , pre-eclampsia , recurrent miscarriage , chronic renal or hepatic disease and malignancy were excluded from the study . Serum 25[OH]D was analysed during the first trimester ( between 6 and 12 weeks of pregnancy ) . Patients with vitamin D3 deficiency ( serum levels < 25 nmol/L ) were included in the study and r and omized for vitamin D3 supplementation 400 IU ( Group 1 ) versus 4000 IU ( Group 2 ) . Both groups were compared for the prevalence of pre-eclampsia and dose effect on vitamin D level . RESULTS Of 179 gravidae enrolled , 164 completed the trial . Mean maternal 25[OH]D was significantly increased in group 2 from 16.3 ± 5 nmol/mL to 72.3 ± 30.9 nmol/mL compared with group 1 from 17.5 ± 6.7 nmol/mL to 35.3 ± 20.7 nmol/mL ( p > 0.0001 ) . The relative risk reduction ( RRR ) for attaining ≥75 nmol/L before delivery was significantly higher ( RRR 93.2 [ CI 79 - 98 ] when treated with 4000 IU . The total incidence of pre-eclampsia in the study population was 4.3 % . In comparison to group 1 , the group 2 reported fewer pre-eclampsia events during the study period ( 8.6 % versus 1.2 % ; p < 0.05 ) . The total number of IUGRs was lesser in the group 2 ( 9.6 % ) versus group 1 ( 22.2 % ) ; p = 0.027 . However , other obstetric outcomes were comparable between both groups . CONCLUSION Vitamin D supplementation in the deficient group reduces the risk of pre-eclampsia and IUGR in a dose dependant manner . However larger clinical trials are essential to investigate optimum dosage of vitamin D3 in this group [28216083] INTRODUCTION Maternal circulating 25-hydroxyvitamin D [ 25(OH)D ] has been shown to optimize production of 1,25-dihydroxyvitamin D [ 1,25(OH)2D ] during pregnancy at approximately 100nmoles/L , which has pronounced effects on fetal health outcomes . Additionally , associations are noted between low maternal 25(OH)D concentrations and vascular pregnancy complications , such as preeclampsia . To further eluci date the effects of vitamin D activity in pregnancy , we investigated the role of maternal 25(OH)D , the nutritional indicator of vitamin D status , in relation to placental maintenance and , specifically , expression of placental gene targets related to angiogenesis and vitamin D metabolism . METHODS A focused analysis of placental mRNA expression related to angiogenesis , pregnancy maintenance , and vitamin D metabolism was conducted in placentas from 43 subjects enrolled in a r and omized controlled trial supplementing 400IU or 4400IU of vitamin D3 per day during pregnancy . Placental mRNA was isolated from biopsies within one hour of delivery , followed by quantitative PCR . We classified pregnant women with circulating concentrations of < 100nmoles/L as deficient and those with ≥100nmoles/L as sufficient . The value of each gene 's change in the PCR cycle threshold ( ΔCT ) , which is a relative measure of target concentration , was compared with maternal 25(OH)D concentrations < 100nmoles/L and ≥100nmoles/L based on a two- sample Wilcoxon test . RESULTS Soluble FMS-like tyrosine kinase 1 ( sFlt-1 ) and vascular endothelial growth factor ( VEGF ) gene expression was significantly downregulated in the maternal subgroup with circulating 25(OH)D ≥100ng/mL compared to the subgroup < 100ng/mL. DISCUSSION Here , we report a significant association between maternal vitamin D status and the expression of sFlt-1 and VEGF at the mRNA level . Achieving maternal circulating 25(OH)D ≥100nmoles/L suggests the impact of maternal vitamin D3 supplementation on gene transcription in the placenta , thereby potentially decreasing antiangiogenic factors that may contribute to vascular pregnancy complications [5064894] Background Early infancy is a high-risk period for severe acute respiratory infection ( ARI ) , particularly in low-income countries with re source -limited health systems . Lower respiratory tract infection ( LRTI ) is commonly preceded by upper respiratory infection ( URTI ) , and often caused by respiratory syncytial virus ( RSV ) , influenza and other common community-acquired viral pathogens . Vitamin D status is a c and i date modifiable early-life determinant of the host antiviral immune response and thus may influence the risk of ARI-associated morbidity in high-risk population s. Methods / Design In the Maternal Vitamin D for Infant Growth ( MDIG ) study in Dhaka , Bangladesh ( NCT01924013 ) , 1300 pregnant women are r and omized to one of five groups : placebo , 4200 IU/week , 16,800 IU/week , or 28,000 IU/week from 2nd trimester to delivery plus placebo from 0–6 months postpartum ; or , 28,000 IU/week prenatal and until 6-months postpartum . In the Maternal Vitamin D for ARI in Infancy ( MDARI ) sub- study nested within the MDIG trial , trained personnel conduct weekly postnatal home visits to inquire about ARI symptoms and conduct a st and ardized clinical assessment . Supplementary home visits between surveillance visits are conducted when caregivers make phone notifications of new infant symptoms . Mid-turbinate nasal swab sample s are obtained from infants who meet st and ardized clinical ARI criteria . Specimens are tested by polymerase chain reaction ( PCR ) for 8 viruses ( influenza A/B , parainfluenza 1/2/3 , RSV , adenovirus , and human metapneumovirus ) , and nasal carriage density of Streptococcus pneumoniae . The primary outcome is the incidence rate of microbiologically-positive viral ARI , using incidence rate ratios to estimate between-group differences . We hypothesize that among infants 0–6 months of age , the incidence of microbiologically-confirmed viral ARI will be significantly lower in infants whose mothers received high-dose prenatal/postpartum vitamin D supplements versus placebo . Secondary outcomes include incidence of ARI associated with specific pathogens ( influenza A or B , RSV ) , clinical ARI , and density of pneumococcal carriage . Discussion If shown to reduce the risk of viral ARI in infancy , integration of maternal prenatal/postpartum vitamin D supplementation into antenatal care programs in South Asia may be a feasible primary preventive strategy to reduce the burden of ARI-associated morbidity and mortality in young infants . Trial registration NCT02388516 , registered March 9 , 2015 [27628045] We studied bone mineral content ( BMC ) , bone mineral density ( BMD ) , and body composition in offspring of women supplemented with vitamin D during pregnancy . Pregnant women were r and omized to receive oral cholecalciferol 60,000 units 4 weekly ( group 1 ) , 8 weekly ( group 2 ) , or placebo ( group 3 ) . All received 1 g calcium daily ( groups 1 and 2 without , and group 3 with 400 units vitamin D ) . Offspring at 12–16 months underwent dual-energy X-ray absorptiometry . Maternal hypovitaminosis D at recruitment was common ( serum 25OHD < 50 nmol/L in 88 % ) and severe ( 25OHD < 25 nmol/L in 46 % ) . Groups 1 and 2 ( n = 23 and 13 , median age 14 months ) had higher cord blood 25OHD ( 47.8 ± 13.8 and 31.0 ± 14.0 nmol/L ) versus group 3 ( n = 16 , median age 16 months , 17.8 ± 13.5 nmol/L , p < 0.001 ) . Babies in group 3 had higher whole-body BMC ( 250.8 ± 42.5 gm ) and BMD ( 0.335 ± 0.033 gm/cm2 ) compared to group 1 ( 213.1 ± 46.2 gm and 0.295 ± 0.041 gm/cm2 ) and group 2 ( 202.9 ± 29.9 gm and 0.287 ± 0.023 gm/cm2 ) ( p = 0.006 and 0.001 , respectively ) . In multivariate analysis , age , weight z score , and lean body mass remained significant contributors to BMC . Parameters of body composition were comparable among the groups . Vitamin D supplementation to pregnant women with severe deficiency in doses that improved cord blood 25OHD did not result in improved bone health or body composition in offspring at 12–16 months , compared to a dose too small to improve 25OHD levels [21706518] The need , safety , and effectiveness of vitamin D supplementation during pregnancy remain controversial . In this r and omized , controlled trial , women with a singleton pregnancy at 12 to 16 weeks ' gestation received 400 , 2000 , or 4000 IU of vitamin D(3 ) per day until delivery . The primary outcome was maternal/neonatal circulating 25-hydroxyvitamin D [ 25(OH)D ] concentration at delivery , with secondary outcomes of a 25(OH)D concentration of 80 nmol/L or greater achieved and the 25(OH)D concentration required to achieve maximal 1,25-dihydroxyvitamin D(3 ) [ 1,25(OH)(2)D(3 ) ] production . Of the 494 women enrolled , 350 women continued until delivery : Mean 25(OH)D concentrations by group at delivery and 1 month before delivery were significantly different ( p < 0.0001 ) , and the percent who achieved sufficiency was significantly different by group , greatest in 4000-IU group ( p < 0.0001 ) . The relative risk ( RR ) for achieving a concentration of 80 nmol/L or greater within 1 month of delivery was significantly different between the 2000- and the 400-IU groups ( RR = 1.52 , 95 % CI 1.24 - 1.86 ) , the 4000- and the 400-IU groups ( RR = 1.60 , 95 % CI 1.32 - 1.95 ) but not between the 4000- and . 2000-IU groups ( RR = 1.06 , 95 % CI 0.93 - 1.19 ) . Circulating 25(OH)D had a direct influence on circulating 1,25(OH)(2)D(3 ) concentrations throughout pregnancy ( p < 0.0001 ) , with maximal production of 1,25(OH)(2)D(3 ) in all strata in the 4000-IU group . There were no differences between groups on any safety measure . Not a single adverse event was attributed to vitamin D supplementation or circulating 25(OH)D levels . It is concluded that vitamin D supplementation of 4000 IU/d for pregnant women is safe and most effective in achieving sufficiency in all women and their neonates regardless of race , whereas the current estimated average requirement is comparatively ineffective at achieving adequate circulating 25(OH)D concentrations , especially in African Americans [4855961] Introduction : Pregnant women represent a typical group susceptible to dietary and mineral deficiencies . This study was sought to assess the efficacy and safety of various doses of 25-hydroxyvitamin D ( 25[OH]D ) supplementation during pregnancy and ratify the inadequacy of the recommended daily allowance for Vitamin D in vulnerable groups . Material s and Methods : A total of 100 pregnant women were included in this open-label , parallel group , prospect i ve , r and omized , and controlled trial . Study subjects were assigned to four treatment groups : Group 1 ( n = 26 ) , 1000 IU of Vitamin D daily ; Group 2 ( n = 21 ) , 30,000 IU of Vitamin D monthly ; Group 3 ( n = 27 ) , 2000 IU of Vitamin D daily ; and Group 4 ( n = 26 ) , 60,000 IU Vitamin D monthly . Group 1 and 2 were further analyzed together as Group 1 K ( 1000 IU daily and 30,000 IU monthly ) , and Group 3 and 4 as Group 2 K ( 2000 IU daily and 60,000 IU monthly ) . The analysis was done on an intention to treat basis . Results : A total of 87 patients completed the study ; 21 in Group 1 , 25 in Group 2 , 18 in Group 3 , and 23 in Group 4 . The levels of 25(OH)D at baseline ranged from 1.3 to 58.0 with a mean of 24.2 ± 15.1 ng/ml . Postsupplementation , 25(OH)D levels ranged from 11.5 to 70.3 with a mean of 40.2 ± 12.2 ng/ml . The postsupplementation levels of 25(OH)D were higher in Group 2 K ( 42.86 ± 12.83 ) than in Group 1 K ( 36.96 ± 10.56 ) with P value of 0.023 . Conclusion : We concluded that Vitamin D supplementation with 2000 IU/day or 60,000 IU/month is very effective and safe in achieving Vitamin D sufficiency in pregnant women [4695683] Background : Vitamin D supplementation during pregnancy has been supposed to defend against adverse gestational outcomes . Objective : This r and omized clinical trial study was conducted to assess the effects of 50,000 IU of vitamin D every two weeks supplementation on the incidence of gestational diabetes ( GDM ) , gestational hypertension , preeclampsia and preterm labor , vitamin D status at term and neonatal outcomes contrasted with pregnant women that received 400 IU vitamin D daily . Material s and Methods : 500 women with gestational age 12 - 16 weeks and serum 25 hydroxy vitamin D ( 25 ( OH ) D ) less than 30 ng/ml r and omly categorized in two groups . Group A received 400 IU vitamin D daily and group B 50,000 IU vitamin D every 2 weeks orally until delivery . Maternal and Neonatal outcomes were assessed in two groups . Results : The incidence of GDM in group B was significantly lower than group A ( 6.7 % versus 13.4 % ) and odds ratio ( 95 % Confidence interval ) was 0.46 ( 0.24 - 0.87 ) ( P=0.01 ) . The mean ± SD level of 25 ( OH ) D at the time of delivery in mothers in group B was significantly higher than A ( 37.9 ± 19.8 versus 27.2 ± 18.8 ng/ml , respectively ) ( P=0.001 ) . There were no differences in the incidence of preeclampsia , gestational hypertension , preterm labor , and low birth weight between two groups . The mean level of 25 ( OH ) D in cord blood of group B was significantly higher than group A ( 37.9 ± 18 versus 29.7 ± 19ng/ml , respectively ) . Anthropometric measures between neonates were not significantly different . Conclusion : Our study showed 50,000 IU vitamin D every 2 weeks decreased the incidence of GDM [2821652] Objective . To determine if adherence as measured by pill count would show a significant association with serum-based measures of adherence . Methods . Data were obtained from a prenatal vitamin D supplementation trial where subjects were stratified by race and r and omized into three dosing groups : 400 ( control ) , 2000 , or 4000 IU vitamin D3/day . One measurement of adherence was obtained via pill counts remaining compared to a novel definition for adherence using serum 25-hydroxy-vitamin D ( 25-OH-D ) levels ( absolute change in 25(OH)D over the study period and the subject 's steady-state variation in their 25(OH)D levels ) . A multivariate logistic regression model examined whether mean percent adherence by pill count was significantly associated with the adherence measure by serum metabolite levels . Results . Subjects ' mean percentage of adherence by pill count was not a significant predictor of adherence by serum metabolite levels . This finding was robust across a series of sensitivity analyses . Conclusions . Based on our novel definition of adherence , pill count was not a reliable predictor of adherence to protocol , and calls into question how adherence is measured in clinical research . Our findings have implication s regarding the determination of efficacy of medications under study and offer an alternative approach to measuring adherence of long half-life supplements/medications [5053446] Background Patterns of gene expression of human pregnancy are poorly understood . In a trial of vitamin D supplementation in pregnant women , peripheral blood transcriptomes were measured longitudinally on 30 women and used to characterize gene co-expression networks . Objective Studies suggest that increased maternal Vitamin D levels may reduce the risk of asthma in early life , yet the underlying mechanisms have not been examined . In this study , we used a network-based approach to examine changes in gene expression profiles during the course of normal pregnancy and evaluated their association with maternal Vitamin D levels . Design The VDAART study is a r and omized clinical trial of vitamin D supplementation in pregnancy for reduction of pediatric asthma risk . The trial enrolled 881 women at 10–18 weeks of gestation . Longitudinal gene expression measures were obtained on thirty pregnant women , using RNA isolated from peripheral blood sample s obtained in the first and third trimesters . Differentially expressed genes were identified using significance of analysis of microarrays ( SAM ) , and clustered using a weighted gene co-expression network analysis ( WGCNA ) . Gene-set enrichment was performed to identify major biological pathways . Results Comparison of transcriptional profiles between first and third trimesters of pregnancy identified 5839 significantly differentially expressed genes ( FDR<0.05 ) . Weighted gene co-expression network analysis clustered these transcripts into 14 co-expression modules of which two showed significant correlation with maternal vitamin D levels . Pathway analysis of these two modules revealed genes enriched in immune defense pathways and extracellular matrix reorganization as well as genes enriched in notch signaling and transcription factor networks . Conclusion Our data show that gene expression profiles of healthy pregnant women change during the course of pregnancy and suggest that maternal Vitamin D levels influence transcriptional profiles . These alterations of the maternal transcriptome may contribute to fetal immune imprinting and reduce allergic sensitization in early life . Trial Registration clinical trials.gov [4499946] Background Vitamin D regulates bone mineral metabolism and skeletal development . Some observational studies have suggested that prenatal vitamin D deficiency increases the risk of adverse pregnancy and /or birth outcomes ; however , there is scant evidence from controlled trials , leading the World Health Organization to advise against routine vitamin D supplementation in pregnancy . Importantly , little is known about the effect of maternal vitamin D status on infant linear growth in communities in South Asia where stunting is highly prevalent and maternal-infant vitamin D status is commonly suboptimal . Methods / Design The Maternal Vitamin D for Infant Growth study is a r and omized , placebo-controlled , dose-ranging trial of maternal vitamin D supplementation during pregnancy and lactation in Dhaka , Bangladesh . The primary aims are to estimate ( 1 ) the effect of maternal prenatal oral vitamin D3 supplementation ( 4200 IU/wk , 16,800 IU/wk , or 28,000 IU/wk , administered as weekly doses ) versus placebo on infant length at 1 year of age and ( 2 ) the effect of maternal postpartum oral vitamin D3 supplementation ( 28,000 IU/wk ) versus placebo on length at 1 year of age among infants born to women who received vitamin D 28,000 IU/wk during pregnancy . Generally healthy pregnant women ( n = 1300 ) in the second trimester ( 17–24 weeks of gestation ) are r and omized to one of five parallel arms : placebo 4200 IU/wk , 16,800 IU/wk , or 28,000 IU/wk in the prenatal period and placebo in the postpartum period or 28,000 IU/wk in the prenatal period and 28,000 IU/wk in the postpartum period . Household- and clinic-based follow-up of mother-infant pairs is conducted weekly by trained personnel until 26 weeks postpartum and every 3 months thereafter . The primary trial outcome measure is length for age z-score at 1 year of age . Anthropometric measurements , clinical information , and biological specimens collected at scheduled intervals will enable the assessment of a range of maternal , perinatal , and infant outcomes . Discussion The role of vitamin D in maternal and infant health remains unresolved . This trial is expected to contribute unique insights into the effects of improving maternal-infant vitamin D status in a low-income setting where stunting and adverse perinatal outcomes represent significant public health burdens . Trial registration Clinical Trials.gov identifier : NCT01924013 . Registered on 13 August [27588106] It has previously been reported that the influence of vitamin D on the metabolism of calcium and phosphorus is associated with diabetes , cardiovascular disease , Alzheimer 's disease , cancer and other systemic diseases , and is considered an important indicator of general health . The present study was conducted to determine the effect of various doses of vitamin D supplementation on glucose metabolism , lipid concentrations , inflammation and the levels of oxidative stress of pregnant women with gestational diabetes mellitus ( GDM ) . The present r and omized , double-blind placebo-controlled clinical trial was conducted on 133 pregnant women with GDM during weeks 24 - 28 of pregnancy . The patients were r and omly divided into four groups . The control group ( n=20 ) received a placebo ( sucrose ; one granule/day ) , the low dosage group ( n=38 ) received the daily recommended intake of 200 IU vitamin D ( calciferol ) daily , the medium dosage group ( n=38 ) received 50,000 IU monthly ( 2,000 IU daily for 25 days ) and the high dosage group ( n=37 ) received 50,000 IU every 2 weeks ( 4,000 IU daily for 12.5 days ) . The general characteristics and dietary intakes of the patients with GDM were similar between each group . Using ELISA kits , it was determined that insulin , homeostatic model assessment -insulin resistance and total cholesterol were significantly reduced by high dosage vitamin D supplementation ( P<0.05 ) . Total antioxidant capacity and total glutathione levels were significantly elevated as a result of high dosage vitamin D supplementation ( P<0.01 ) . In conclusion , high-dose vitamin D supplementation ( 50,000 IU every 2 weeks ) significantly improved insulin resistance in pregnant women with GDM [28552588] & NA ; Figure . No caption available . Background : Programming of the immune system during fetal development can influence asthma‐related risk factors and outcomes in later life . Vitamin D is a well‐recognized immune modulator , and deficiency of this nutrient during pregnancy is hypothesized to influence disease development in offspring . Objective : We sought to investigate the effect on neonatal immunity of maternal supplementation with 4400 IU/d vitamin D3 during the second and third trimesters of pregnancy by using a subset of cord blood sample s from a r and omized , double‐blind , placebo‐controlled clinical trial ( the Vitamin D Antenatal Asthma Reduction Trial ) . Methods : Cord blood sample s from neonates born to mothers supplemented with 4400 IU/d ( n = 26 ) or 400 IU/d ( n = 25 ) of vitamin D3 were analyzed for immune cell composition by flow cytometry , Toll‐like receptor ( TLR ) expression by quantitative PCR , and cytokine secretion after stimulation with mitogenic , TLR , and T‐cell stimuli by cytometric bead array . Responsiveness to the glucocorticoid dexamethasone was determined . Results : Supplementation of mothers with 4400 IU of vitamin D3 result ed in an enhanced broad‐spectrum proinflammatory cytokine response of cord blood mononuclear cells to innate and mitogenic stimuli ( P = .0009 ) , with an average 1.7‐ to 2.1‐fold increase in levels of several proinflammatory cytokines ( GM‐CSF , IFN‐&ggr ; , IL‐1&bgr ; , IL‐6 , and IL‐8 ) across stimuli , a higher gene expression level of TLR2 ( P = .02 ) and TLR9 ( P = .02 ) , a greater than 4‐fold increase in IL‐17A ( P = .03 ) production after polyclonal T‐cell stimulation , and an enhanced IL‐10 response of cord blood mononuclear cells to dexamethasone treatment in culture ( P = .018 ) . Conclusion : Vitamin D exposure during fetal development influences the immune system of the neonate , which can contribute to protection from asthma‐related , including infectious , outcomes in early life [4785305] Introduction The vitamin D recommended doses during pregnancy differ between societies . The WHO guidelines do not recommend routine prenatal supplementation , but they underscore the fact that women with the lowest levels may benefit most . The effects of routine supplementation during pregnancy on maternal and neonatal clinical outcomes have not been investigated in the Middle East , where hypovitaminosis D is prevalent . Our hypothesis is that in Middle Eastern pregnant women , a vitamin D dose of 3000 IU/day is required to reach a desirable maternal 25-hydroxyvitamin D [ 25(OH)D ] level , and to positively impact infant bone mineral content ( BMC ) . Methods and analysis This is a multicentre blinded r and omised controlled trial . Pregnant women presenting to the Obstetrics and Gynaecology clinics will be approached . Eligible women will be r and omised to daily equivalent doses of cholecalciferol , 600 IU or 3000 IU , from 15 to 18 weeks gestation until delivery . Maternal 25(OH)D and chemistries will be assessed at study entry , during the third trimester and at delivery . Neonatal anthropometric variables and 25(OH)D level will be measured at birth , and bone and fat mass assessment by dual-energy X-ray absorptiometry scan at 1 month . A sample size of 280 pregnant women is needed to demonstrate a statistically significant difference in the proportion of women reaching a 25(OH)D level ≥50 nmol/L at delivery , and a difference in infant BMC of 6 (10)g , for a 90 % power and a 2.5 % level of significance . The proportions of women achieving a target 25(OH)D level will be compared between the two arms , using χ2 . An independent t test will be used to compare mean infant BMC between the two arms . The primary analysis is an intention-to-treat analysis of unadjusted results . Ethics and dissemination The protocol has been approved by the Institutional Review Board at the American University of Beirut-Lebanon ( IM.GEHF.22 ) . The trial results will be published in peer- review ed medical journals and presented at scientific conferences . Trial registration number NCT02434380 [3705320] A pharmacokinetic study was conducted to assess the biochemical dose-response and tolerability of high-dose prenatal vitamin D3 supplementation in Dhaka , Bangladesh ( 23 ° N ) . Pregnant women at 27–30 weeks gestation ( n = 28 ) were r and omized to 70,000 IU once + 35,000 IU/week vitamin D3 ( group PH : pregnant , higher dose ) or 14,000 IU/week vitamin D3 ( PL : pregnant , lower dose ) until delivery . A group of non-pregnant women ( n = 16 ) was similarly administered 70,000 IU once + 35,000 IU/week for 10 weeks ( NH : non-pregnant , higher-dose ) . Rise ( ∆ ) in serum 25-hydroxyvitamin D concentration ( [ 25(OH)D ] ) above baseline was the primary pharmacokinetic outcome . Baseline mean [ 25(OH)D ] were similar in PH and PL ( 35 nmol/L vs. 31 nmol/L , p = 0.34 ) . A dose-response effect was observed : ∆[25(OH)D ] at modeled steady-state was 19 nmol/L ( 95 % CI , 1 to 37 ) higher in PH vs. PL ( p = 0.044 ) . ∆[25(OH)D ] at modeled steady-state was lower in PH versus NH but the difference was not significant ( −15 nmol/L , 95 % CI −34 to 5 ; p = 0.13 ) . In PH , 100 % attained [ 25(OH)D ] ≥ 50 nmol/L and 90 % attained [ 25(OH)D ] ≥ 80 nmol/L ; in PL , 89 % attained [ 25(OH)D ] ≥ 50 nmol/L but 56 % attained [ 25(OH)D ] ≥ 80 nmol/L. Cord [ 25(OH)D ] ( n = 23 ) was slightly higher in PH versus PL ( 117 nmol/L vs. 98 nmol/L ; p = 0.07 ) . Vitamin D3 was well tolerated ; there were no supplement-related serious adverse clinical events or hypercalcemia . In summary , a regimen of an initial dose of 70,000 IU and 35,000 IU/week vitamin D3 in the third trimester of pregnancy was non-hypercalcemic and attained [ 25(OH)D ] ≥ 80 nmol/L in virtually all mothers and newborns . Further research is required to establish the safety of high-dose vitamin D3 in pregnancy and to determine if supplement-induced [ 25(OH)D ] elevations lead to maternal-infant health benefits [28285844] Background Nutrient trials differ from drug trials because participants have varying circulating levels at entry into the trial . Objective We sought to study the effect of a vitamin D intervention in pregnancy between subjects of different races and the association between 25‐hydroxyvitamin D3 ( 25[OH]D ) levels in pregnancy and the risk of asthma/recurrent wheeze in offspring . Methods The Vitamin D Antenatal Asthma Reduction Trial is a r and omized trial of pregnant women at risk of having children with asthma r and omized to 4400 international units/d vitamin D or placebo plus 400 international units/d vitamin D. Asthma and recurrent wheezing until age 3 years were recorded . Results African American ( AA ) women ( n = 312 ) had lower initial levels of 25(OH)D ( mean [ SD ] , 17.6 ng/mL [ 8.3 ng/mL ] ) compared with non‐AA women ( n = 400 ; 27.1 ng/mL [ 9.7 ng/mL ] , P < .001 ) . No racial difference was found from vitamin D supplementation in pregnancy on asthma/recurrent wheezing in offspring ( P for interaction = .77 ) . Having an initial level of greater than 30 ng/mL and being r and omized to the intervention group was associated with the lowest risk for asthma/recurrent wheeze by age 3 years compared with having an initial level of less than 20 ng/mL and receiving placebo ( adjusted odds ratio , 0.42 ; 95 % CI , 0.19‐0.91 ) . Conclusions We did not find differences between AA and non‐AA mothers in the effect of maternal vitamin D supplementation and asthma/recurrent wheeze in offspring at 3 years . Maternal supplementation of vitamin D , particularly in mothers with initial 25(OH)D levels of greater than 30 ng/mL , reduced asthma/recurrent wheeze in the offspring through age 3 years , suggesting that higher vitamin D status beginning in early pregnancy is necessary for asthma/recurrent wheeze prevention in early life . Graphical abstract Figure . No Caption available [27558577] BACKGROUND Many countries recommend daily infant vitamin D supplementation during breastfeeding , but compliance is often poor . A monthly , high-dose maternal regimen may offer an alternative strategy , but its efficacy is unknown . OBJECTIVE The objective of the study was to determine the effect of 2 different monthly maternal doses of cholecalciferol on maternal and infant 25-hydroxyvitamin D [ 25(OH)D ] status during the first 5 mo of breastfeeding . METHODS With the use of a r and omized , double-blind , placebo-controlled design , women who were planning to exclusively breastfeed for 6 mo ( n = 90 ; mean age : 32.1 y ; 71 % exclusively breastfeeding at week 20 ) were r and omly assigned to receive either cholecalciferol ( 50,000 or 100,000 IU ) or a placebo monthly from week 4 to week 20 postpartum . The treatment effects relative to placebo were estimated as changes in maternal and infant serum 25(OH)D from baseline to week 20 postpartum by using a linear fixed-effects regression model . Additional secondary analyses , adjusted for potential confounders such as season of birth , vitamin D-fortified formula intake , and infant or maternal skin color , were also conducted . RESULTS After 16 wk of supplementation , changes in maternal serum 25(OH)D were significantly higher in the 50,000-IU/mo ( 12.8 nmol/L ; 95 % CI : 0.4 , 25.2 nmol/L ) and 100,000-IU/mo ( 21.5 nmol/L ; 95 % CI : 9.2 , 33.8 nmol/L ) groups than in the placebo group ( P = 0.43 and P < 0.001 , respectively ) . For infants , the unadjusted mean changes in serum 25(OH)D were 4.5 nmol/L ( 95 % CI : -16.2 , 25.0 nmol/L ) for the 50,000-IU/mo group and 15.8 nmol/L ( 95 % CI : -4.7 , 36.4 nmol/L ) for the 100,000-IU/mo group , but the changes did not differ from the placebo reference group . However , after adjustment for season of birth , vitamin D-fortified formula intake , and infant skin color , the mean change effect size for the 100,000-IU/mo group was 19.1 nmol/L ( 95 % CI : 2.5 , 35.6 nmol/L ; P = 0.025 ) higher than that in the placebo group . CONCLUSIONS Maternal cholecalciferol supplementation at a dose of 100,000 IU/mo during the first 5 mo of breastfeeding potentially benefits infant vitamin D status . Further studies are required to determine optimum dose and dosing frequency . This trial was registered at www.anzctr.org.au as ACTRN12611000108910 [22212646] Hypovitaminosis D is common in India . In the present prospect i ve partially r and omised study of vitamin D ( D₃ ) supplementation during pregnancy , subjects were r and omised in the second trimester to receive either one oral dose of 1500 μg vitamin D₃ ( group 1 , n 48 ) or two doses of 3000 μg vitamin D₃ each in the second and third trimesters ( group 2 , n 49 ) . Maternal 25-hydroxyvitamin D ( 25(OH)D ) at term , cord blood ( CB ) alkaline phosphatase ( ALP ) , neonatal serum Ca and anthropometry were measured in these subjects and in forty-three non-supplemented mother-infant pairs ( usual care ) . Median maternal 25(OH)D at term was higher in group 2 ( 58·7 , interquartile range ( IQR ) 38·4 - 89·4 nmol/l ) v. group 1 ( 26·2 , IQR 17·7 - 57·7 nmol/l ) and usual-care group ( 39·2 , IQR 21·2 - 73·4 nmol/l ) ( P = 0·000 ) . CB ALP was increased ( > 8.02 μkat/l or > 480 IU/l ) in 66·7 % of the usual-care group v. 41·9 % of group 1 and 38·9 % of group 2 ( P = 0·03 ) . Neonatal Ca and CB 25(OH)D did not differ significantly in the three groups . Birth weight , length and head circumference were greater and the anterior fontanelle was smaller in groups 1 and 2 ( 3·08 and 3·03 kg , 50·3 and 50·1 cm , 34·5 and 34·4 cm , 2·6 and 2·5 cm , respectively ) v. usual care ( 2·77 kg , 49·4 , 33·6 , 3·3 cm ; P = 0·000 for length , head circumference and fontanelle and P = 0·003 for weight ) . These differences were still evident at 9 months . We conclude that both 1500 μg and two doses of 3000 μg vitamin D₃ had a beneficial effect on infant anthropometry , the larger dose also improving CB ALP and maternal [26702121] BACKGROUND Human milk is typically low in vitamin D activity ( VDA ) . Whether the vitamin D content of breast milk at birth can be increased by supplementing the mother during pregnancy has not been reported to the best of our knowledge . OBJECTIVE We examined the effect of vitamin D supplementation during pregnancy on breast-milk VDA in the first 2 mo of lactation . DESIGN Breast-milk sample s were obtained from women who were enrolled in a r and omized , double-blinded , placebo-controlled trial of vitamin D supplementation during pregnancy . Pregnant women were enrolled at 27 wk of gestation and r and omly assigned to the following 3 groups : a placebo group , a group who received one dosage of daily oral vitamin D3 ( 1000 IU ) , or a group who received 2 dosages of daily oral vitamin D3 ( 2000 IU ) . Serum 25-hydroxyvitamin D [ 25(OH)D ] was measured at enrollment , at 36 wk of gestation , and in cord blood at birth . Study participants who were breastfeeding were invited to provide breast-milk sample s for VDA measurement [ concentration of vitamin D2 , vitamin D3 , 25(OH)D2 , and 25(OH)D3 ] at 2 wk and 2 mo postpartum . A linear mixed model was used to compare breast-milk VDA between the 3 study groups . RESULTS A total of 75 women provided breast-milk sample s ( 44 women provided breast-milk sample s at both 2 wk and 2 mo postpartum ) . The mean ( 95 % CI ) VDA at age 2 wk was 52 IU/L ( 12 , 217 IU/L ) in the placebo group , 51 IU/L ( 17 , 151 IU/L ) in the 1000-IU group , and 74 IU/L ( 25 , 221 IU/L ) in the 2000-IU group ; and at age 2 mo , the mean ( 95 % CI ) VDA was 45 IU/L ( 16 , 124 IU/L ) , 43 IU/L ( 18 , 103 IU/L ) , and 58 IU/L ( 15 , 224 IU/L ) , respectively . There was no significant interaction in VDA between the sample - collection time and treatment ( P = 0.61 ) , but there was a difference between lower- and higher-dosage treatment groups ( P = 0.04 ) . CONCLUSION Maternal vitamin D supplementation during pregnancy of 2000 IU/d ( compared with 1000 IU/d and with a placebo ) results in a higher VDA of breast milk ≥2 mo postpartum . This trial was registered at the Australian New Zeal and Clinical Trials Registry as ACTRN12610000483055 [26813208] IMPORTANCE Observational studies have suggested that increased dietary vitamin D intake during pregnancy may protect against wheezing in the offspring , but the preventive effect of vitamin D supplementation to pregnant women is unknown . OBJECTIVE To determine whether supplementation of vitamin D3 during the third trimester of pregnancy reduces the risk of persistent wheeze in the offspring . DESIGN , SETTING , AND PARTICIPANTS A double-blind , single-center , r and omized clinical trial conducted within the Copenhagen Prospect i ve Studies on Asthma in Childhood 2010 cohort . Enrollment began March 2009 with a goal of 708 participants , but due to delayed ethical approval , only 623 women were recruited at 24 weeks of pregnancy . Follow-up of the children ( N = 581 ) was completed when the youngest child reached age 3 years in March 2014 . INTERVENTIONS Vitamin D3 ( 2400 IU/d ; n = 315 ) or matching placebo tablets ( n = 308 ) from pregnancy week 24 to 1 week postpartum . All women received 400 IU/d of vitamin D3 as part of usual pregnancy care . MAIN OUTCOMES AND MEASURES Age at onset of persistent wheeze in the first 3 years of life . Secondary outcomes included number of episodes of troublesome lung symptoms , asthma , respiratory tract infections , and neonatal airway immunology . Adverse events were assessed . RESULTS Of the 581 children , persistent wheeze was diagnosed during the first 3 years of life in 47 children ( 16 % ) in the vitamin D3 group and 57 children ( 20 % ) in the control group . Vitamin D3 supplementation was not associated with the risk of persistent wheeze , but the number of episodes of troublesome lung symptoms was reduced , and the airway immune profile was up-regulated ( principal component analysis , P = .04 ) . There was no effect on additional end points . Intrauterine death was observed in 1 fetus ( < 1 % ) in the vitamin D3 group vs 3 fetuses ( 1 % ) in the control group and congenital malformations in 17 neonates ( 5 % ) in the vitamin D3 group vs 23 neonates ( 8 % ) in the control group . [ table : see text ] . CONCLUSIONS AND RELEVANCE The use of 2800 IU/d of vitamin D3 during the third trimester of pregnancy compared with 400 IU/d did not result in a statistically significant reduced risk of persistent wheeze in the offspring through age 3 years . However , interpretation of the study is limited by a wide CI that includes a clinical ly important protective effect . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00856947 [23350644] Abstract Low serum vitamin D levels are correlated with insulin resistance during pregnancy . We have assessed the effects of different doses of vitamin D on insulin resistance during pregnancy . A r and omized clinical trial was done on 120 women with a gestational age of less than 12 weeks . The women were divided into three groups r and omly . Group A received 200 IU vitamin D daily , group B 50 000 IU vitamin D monthly and group C 50 000 IU vitamin D every 2 weeks from 12 weeks of pregnancy until delivery . The serum levels of fasting blood sugar ( FBS ) , insulin , calcium and 25-hydroxyvitamin D were measured before and after intervention . We used the homeostatic model assessment of insulin resistance ( HOMA-IR ) as a surrogate measure of insulin resistance . The mean ± st and ard deviation of serum 25-hydroxyvitamin D increased in group C from 7.3 ± 5.9 to 34.1 ± 11.5 ng/ml and in group B it increased from 7.3 ± 5.3 to 27.23 ± 10.7 ng/ml , but the level of vitamin D in group A increased from 8.3 ± 7.8 to 17.7 ± 9.3 ng/ml ( p < 0.001 ) . The mean differences of insulin and HOMA-IR before and after intervention in groups A and C were significant ( p = 0.01 , p = 0.02 ) . This study has shown that supplementation of pregnant women with 50 000 IU vitamin D every 2 weeks improved insulin resistance significantly [27655755] BACKGROUND Vitamin D deficiency is widespread in pregnancy and has been associated with adverse health conditions in mothers and infants . Vitamin D supplementation in pregnancy may support the maintenance of pregnancy by its effects on innate and adaptive immunity . OBJECTIVE We assessed the effects of vitamin D supplementation during pregnancy on vitamin D status and markers of immune function associated with adverse pregnancy outcomes . METHODS We conducted a r and omized , controlled , double-blind intervention of 2 doses of cholecalciferol ( 400 and 2000 IU/d ) from < 20 wk to delivery in 57 pregnant women . Vitamin D status , regulatory and inflammatory T cells , markers of innate immunity and systemic inflammation , and clinical outcomes including maternal blood pressure and birth weight were assessed at 26 and 36 wk of pregnancy . RESULTS Supplementation with 2000 IU/d vitamin D had a greater effect on the change in vitamin D status over pregnancy ( P < 0.0001 ) and the final value at 36 wk ( P < 0.0001 ) than 400 IU/d , increasing serum 25-hydroxyvitamin D from 81.1 nmol/L at baseline to 116 nmol/L at 36 wk and from 69.6 nmol/L at baseline to 85.6 nmol/L at 36 wk , respectively . The 2000-IU/d group had 36 % more interleukin-10 + regulatory CD4 + T cells at 36 wk than did the 400-IU/d group ( P < 0.007 ) . The daily intake of 2000 compared with 400 IU/d tended to dampen the pregnancy-related increase in diastolic blood pressure by 1.3-fold ( P = 0.06 ) and increase birth weight by 8.6 % ( P = 0.06 ) , but these differences were not statistically significant . CONCLUSIONS Supplementation with 2000 IU/d is more effective at increasing vitamin D status in pregnant women than 400 IU/d and is associated with increased regulatory T cell immunity that may prevent adverse outcomes caused by excess inflammation . This trial was registered at clinical trials.gov as NCT01417351 [23716156] INTRODUCTION The exact amount of vitamin D required for pregnant women to adequately supply the foetus during pregnancy is still unclear . This r and omised trial attempted to determine the optimal dose of vitamin D necessary during pregnancy in order to attain a vitamin D level > 20 ng/mL in neonates . METHODS A total of 51 healthy , pregnant women in Yazd , Iran , were recruited in 2009 . Of these , 34 were r and omised to receive either 50,000 IU ( Group A ) or 100,000 IU ( Group B ) of vitamin D3 per month from the second trimester of pregnancy . The remaining 17 pregnant women , who formed the third group ( Group C ) and were found to have vitamin D deficiency , were initially treated with 200,000 IU of vitamin D3 , following which the dose was adjusted to 50,000 IU per month . 25-hydroxyvitamin D ( 25[OH]D ) in cord blood was measured by chemiluminescence immunoassay , and a serum 25(OH)D level < 20 ng/mL was defined as deficiency . RESULTS All the pregnant women had a vitamin D level < 30 ng/mL at the beginning of the second trimester . The neonates of 76 % of women from Group A had sufficient levels of 25(OH)D. All the neonates born to women in Groups B and C had 25(OH)D > 20 ng/mL. No side effects were observed in our participants during the period of vitamin D supplementation . CONCLUSION A vitamin D3dose > 50,000 IU/month is required during the second and third trimesters of pregnancy for vitamin D-deficient pregnant women in order for their neonates to achieve serum 25(OH)D levels > 20 ng/mL. Supplementation with < 50,000 IU/month is insufficient to ensure a vitamin D level > 20 ng/mL in all neonates born to vitamin D-deficient pregnant women [27060679] Vitamin D has immune‐modulating effects . We determined whether vitamin D supplementation during pregnancy and infancy prevents aeroallergen sensitization and primary care respiratory illness presentations [29141476] Abstract Introduction : Maternal vitamin D deficiency is widespread health problem that is more important in pregnant women , which affects fetus growth and bone development . The aim of this study was to evaluate the effect of sun exposure versus vitamin D supplementation for pregnant women with vitamin D deficiency . Material s and methods : This prospect i ve clinical trial was performed on 87 pregnant women with vitamin D deficiency . Group A was treated with vitamin D 4000 IU per day for 10 weeks , while group B was recommended for sun exposure for 30 minutes daily ( 30 % body surface area ) for 10 weeks in summer and between 10 am–4 pm in direct sunlight . After the delivery , 25-hydroxyvitamin D3 levels were measured in the same previous center . Moreover , weight , height , and head circumference of fetus were measured at delivery in both groups and compared with each other . Results : After 10-week intervention , 25-hydroxyvitamin D3 levels was significantly higher in group treated with vitamin D as compared to sun expose group ( 31.27 versus 19.79 ng/ml ) . ( p < .001 ) . However , height ( p = .118 ) , weight ( p = .245 ) , and head circumference ( p = .681 ) of infants in both groups did not show significant differences . Conclusions : Vitamin D supplementation is more effective than sun exposure in increasing 25-hydroxyvitamin D3 in pregnant women with vitamin D deficiency [29782187] INTRODUCTION Mothers and infants are at high risk for inadequate vitamin D status . Mechanisms by which vitamin D may affect maternal and infant DNA methylation are poorly understood . OBJECTIVE This study quantified the effects of vitamin D3 supplementation on DNA methylation in pregnant and lactating women and their breastfed infants . MATERIAL S AND METHODS In this r and omized controlled pilot study , pregnant women received vitamin D3 400 international units ( IU ) ( n = 6 ; control ) or 3,800 IU ( n = 7 ; intervention ) daily from late second trimester through 4 - 6 weeks postpartum . Epigenome-wide DNA methylation was quantified in leukocytes collected from mothers at birth and mother-infant dyads at 4 - 6 weeks postpartum . RESULTS At birth , intervention group mothers showed DNA methylation gain and loss at 76 and 89 cytosine-guanine ( CpG ) dinucleotides , respectively , compared to controls . Postpartum , methylation gain was noted at 200 and loss at 102 CpGs . Associated gene clusters showed strongest biologic relevance for cell migration/motility and cellular membrane function at birth and cadherin signaling and immune function at postpartum . Breastfed 4 - 6-week-old infants of intervention mothers showed DNA methylation gain and loss in 217 and 213 CpGs , respectively , compared to controls . Genes showing differential methylation mapped most strongly to collagen metabolic processes and regulation of apoptosis . CONCLUSIONS Maternal vitamin D supplementation during pregnancy and lactation alters DNA methylation in mothers and breastfed infants . Additional work is needed to fully eluci date the short- and long-term biologic effects of vitamin D supplementation at varying doses , which could hold important implication s for establishing clinical recommendations for prenatal and offspring health promotion [3755517] & NA ; A r and omized study was conducted to evaluate the effects of single‐dose and daily vitamin D supplementation in pregnant women during the last trimester of a winter pregnancy in the Northwest of France . The women were divided into three r and omized groups : one ( N = 21 ) was given a vitamin D2 supplement of 1000 IU/day during the last three months of pregnancy , one ( N = 27 ) was given a single oral dose of 5 mg at the seventh month of pregnancy , and one ( N = 29 ) acted as a control . Venous plasma sample s were obtained at delivery from the women and from cord blood , and levels of calcium , 25‐OHD , and 1,25(OH)2D were determined . No significant difference in plasma calcium concentration was found among the three groups , but within each group plasma calcium concentrations were higher in the cord sample s than in the respective maternal sample s. The levels of the two metabolites measured were consistently lower in the cord sample s than in the respective maternal sample s. Cord 25‐OHD concentrations correlated with those of maternal plasma . No significant modification of maternal calciuria or of the birth weight of term infants was observed . 25‐OHD concentrations were greater in maternal and cord plasma from treated mothers , but only a slight difference was observed between the supplemented groups . 1,25(OH)2D concentrations were not significantly different in the three groups . A single 5‐mg dose of vitamin D given orally at the seventh month of pregnancy provides effective prophylaxis in the authors ’ region . ( Obstet Gynecol 68:300 , 1986 [28502503] OBJECTIVE This study was performed to evaluate the effects of vitamin D and omega-3 fatty acids co-supplementation on glucose metabolism and lipid concentrations in gestational diabetes ( GDM ) patients . METHODS This r and omized double-blind placebo-controlled clinical trial was done among 140 GDM patients . Participants were r and omly divided into 4 groups to receive : ( 1 ) 1000 mg omega-3 fatty acids containing 360 mg eicosapentaenoic acid and 240 mg docosahexaenoic acid ( DHA ) twice a day + vitamin D placebo ( n = 35 ) ; ( 2 ) 50,000 IU vitamin D every 2 weeks + omega-3 fatty acids placebo ( n = 35 ) ; ( 3 ) 50,000 IU vitamin D every 2 weeks + 1000 mg omega-3 fatty acids twice a day ( n = 35 ) , and ( 4 ) vitamin D placebo + omega-3 fatty acids placebo ( n = 35 ) for 6 weeks . RESULTS After 6 weeks of intervention , patients who received combined vitamin D and omega-3 fatty acids supplements compared with vitamin D , omega-3 fatty acids , and placebo had significantly decreased fasting plasma glucose ( -7.3 ± 7.8 , -6.9 ± 6.6 , -4.0 ± 2.5 , and + 1.0 ± 11.4 mg/dL , respectively , P < .001 ) , serum insulin levels ( -1.9 ± 1.9 , -1.3 ± 6.3 , -0.4 ± 6.3 , and + 2.6 ± 6.5 μIU/mL , respectively , P = .005 ) , homeostatic model of assessment for insulin resistance ( -0.7 ± 0.6 , -0.5 ± 1.4 , -0.2 ± 1.5 , and + 0.6 ± 1.5 , respectively , P < .001 ) and increased quantitative insulin sensitivity check index ( + 0.01 ± 0.01 , + 0.008 ± 0.02 , + 0.002 ± 0.02 , and -0.005 ± 0.02 , respectively , P = .001 ) . In addition , changes in serum triglycerides ( -8.2 ± 41.0 , + 7.6 ± 31.5 , + 3.6 ± 29.9 , and + 20.1 ± 29.6 mg/dL , respectively , P = .006 ) and very low-density lipoprotein cholesterol ( -1.6 ± 8.2 , + 1.5 ± 6.3 , + 0.8 ± 6.0 , and + 4.0 ± 5.9 mg/dL , respectively , P = .006 ) in the vitamin D plus omega-3 fatty acids group were significantly different from the changes in these indicators in the vitamin D , omega-3 fatty acids , and placebo groups . CONCLUSION Overall , vitamin D and omega-3 fatty acids co-supplementation for 6 weeks among GDM patients had beneficial effects on fasting plasma glucose , serum insulin levels , homeostatic model of assessment for insulin resistance , quantitative insulin sensitivity check index , serum triglycerides , and very low-density lipoprotein cholesterol levels [23559082] BACKGROUND Vitamin D ( vD ) deficiency in pregnancy is a global health problem and the amount of vD supplementation to prevent vD deficiency is controversial . OBJECTIVE The objective of the study was to determine effectiveness and safety of prenatal 2000 IU and 4000 IU/d compared with 400 IU/d vD3 supplementation in a r and omized controlled trial in population in which vD deficiency is endemic . DESIGN / METHODS Arab women were r and omized at 12 - 16 weeks of gestation to 400 , 2000 , and 4000 IU/d vD3 , which were continued to delivery . Serum 25-hydroxyvitamin D [ 25(OH)D ] concentrations were measured during pregnancy and at delivery . The primary outcome was the maternal and cord blood 25(OH)D , and the secondary outcomes were the achievement of sufficient serum 25(OH)D of 32 ng/mL or greater ( ≥80 nmol/L ) at delivery . SETTING The locations were primary care and tertiary perinatal care centers . RESULTS Of 192 enrolled , 162 ( 84 % ) continued to delivery . Mean serum 25(OH)D of 8.2 ng/mL ( 20.5 nmol/L ) at enrollment was low . Mean serum 25(OH)D concentrations at delivery and in cord blood were significantly higher in the 2000 and 4000 IU than the 400 IU/d group ( P < .001 ) and was highest in the 4000 IU/d group . The percent who achieved 25(OH)D greater than 32 ng/mL and greater than 20 ng/mL concentrations in mothers and infants was highest in 4000 IU/d group . Safety measurements were similar by group and no adverse event related to vD supplementation . CONCLUSIONS Vitamin D supplementation of 2000 and 4000 IU/d appeared safe in pregnancy , and 4000 IU/d was most effective in optimizing serum 25(OH)D concentrations in mothers and their infants . These findings could apply to other population s in which vD deficiency is endemic [29796622] Background Interpretation of serum vitamin D biomarkers across pregnancy is complex due to limited underst and ing of pregnancy adaptations in vitamin D metabolism . During pregnancy , both gestational age and serum 25-hydroxyvitamin D [ 25(OH)D ] concentrations may influence the concentrations of 1,25-dihydroxyvitamin D [ 1,25(OH)2D ] , 24,25-dihydroxyvitamin D [ 24,25(OH)2D ] , and parathyroid hormone ( PTH ) . Objective We aim ed to identify predictors of change in serum 25(OH)D across gestation in pregnant adolescents and to assess the contribution made by cholecalciferol ( vitamin D3 ) supplementation . We sought to determine whether gestational age and 25(OH)D concentration interacted to affect serum 1,25(OH)2D , 24,25(OH)2D , or PTH . Methods Pregnant adolescents ( n = 78 , 59 % African American , mean ± SD age : 17 ± 1 y ) living in Rochester , NY ( latitude 43 ° N ) were supplemented with 200 IU or 2000 IU vitamin D3/d and allowed to continue their daily prenatal supplement that contained 400 IU vitamin D3 . Serum was collected at study entry ( 18 ± 5 wk of gestation ) , halfway through study participation , and at delivery ( 40 ± 2 wk ) . Serum concentrations of the biochemical markers were modeled with linear mixed-effects regression models . Results Vitamin D3 supplement intake and season of delivery determined change in 25(OH)D across pregnancy . Fall-winter delivery was associated with a decline in 25(OH)D unless vitamin D3 supplement intake was > 872 IU/d . The interaction of gestational age and 25(OH)D affected 24,25(OH)2D concentrations . For a given 25(OH)D concentration , model-predicted serum 24,25(OH)2D increased across gestation except when 25(OH)D was < 13 ng/mL. Below this threshold , 24,25(OH)2D was predicted to decline over time . Mean serum 1,25(OH)2D was elevated ( > 100 pg/mL ) throughout the study . Conclusion Our results suggest that when maternal serum 25(OH)D was low , its catabolism into 24,25(OH)2D decreased or remained stable as pregnancy progressed in order to maintain persistently elevated serum 1,25(OH)2D . Furthermore , in adolescents living at latitude 43 ° N , st and ard prenatal supplementation did not prevent a seasonal decline in 25(OH)D during pregnancy . This study was registered at clinical trials.gov as NCT01815047 [23131462] OBJECTIVE We sought to determine whether 4000 IU/d ( vs 2000 IU/d ) of vitamin D during pregnancy is safe and improves maternal/neonatal 25-hydroxyvitamin D [ 25(OH)D ] in a dose-dependent manner . STUDY DESIGN A total of 257 pregnant women 12 - 16 weeks ' gestation were enrolled . R and omization to 2000 vs 4000 IU/d followed 1-month run-in at 2000 IU/d . Participants were monitored for hypercalciuria , hypercalcemia , and 25(OH)D status . RESULTS Maternal 25(OH)D ( n = 161 ) increased from 22.7 ng/mL ( SD 9.7 ) at baseline to 36.2 ng/mL ( SD 15 ) and 37.9 ng/mL ( SD 13.5 ) in the 2000 and 4000 IU groups , respectively . While maternal 25(OH)D change from baseline did not differ between groups , 25(OH)D monthly increase differed between groups ( P < .01 ) . No supplementation-related adverse events occurred . Mean cord blood 25(OH)D was 22.1 ± 10.3 ng/mL in 2000 IU and 27.0 ± 13.3 ng/mL in 4000 IU groups ( P = .024 ) . After controlling for race and study site , preterm birth and labor were inversely associated with predelivery and mean 25(OH)D , but not baseline 25(OH)D. CONCLUSION Maternal supplementation with vitamin D 2000 and 4000 IU/d during pregnancy improved maternal/neonatal vitamin D status . Evidence of risk reduction in infection , preterm labor , and preterm birth was suggestive , requiring additional studies powered for these endpoints [29788364] Context Despite evidence on the association between hypovitaminosis D and adverse pregnancy outcomes and the positive impact of vitamin D supplementation , no evidence exists supporting a universal screening program in pregnancy as part of routine prenatal care . Objective We sought to determine the effectiveness of a prenatal screening program on optimizing 25-hydroxyvitamin D [ 25(OH)D ] levels and preventing pregnancy complications . Also , to identify a safe regimen , we compared several regimens in a subgroup of vitamin D-deficient pregnant women . Design Two cities of Masjed-Soleyman and Shushtar from Khuzestan province , Iran , were selected as the screening and nonscreening arms , respectively . Within the screening arm , a r and omized controlled trial was conducted on 800 pregnant women . Setting Health centers of Masjed-Soleyman and Shushtar cities . Patients or Participants Pregnant women aged 18 to 40 years . Intervention Women with moderate [ 25(OH)D , 10 to 20 ng/mL ] and severe [ 25(OH)D , < 10 ng/mL ] deficiency were r and omly divided into four subgroups and received vitamin D3 ( D3 ) until delivery . Main Outcome Measure Maternal concentration of 25(OH)D at delivery and rate of pregnancy complications . Results After supplementation , only 2 % of the women in the nonscreening site met the sufficiency level ( > 20 ng/mL ) vs 53 % of the women in the screening site . Adverse pregnancy outcomes , including preeclampsia , gestational diabetes mellitus , and preterm delivery , were decreased by 60 % , 50 % , and 40 % , respectively , in the screening site . A D3 injection in addition to monthly 50,000 IU maintenance therapy contributed the most to achievement of sufficient levels at delivery . Conclusions A prenatal vitamin D screening and treatment program is an effective approach in detecting deficient women , improving 25(OH)D levels , and decreasing pregnancy adverse outcomes [6600055] ABSTRACT Background In the absence of dose-response data , Dietary Reference Values for vitamin D in nonpregnant adults are extended to pregnancy . Objective The aim was to estimate vitamin D intake needed to maintain maternal 25-hydroxyvitamin D [ 25(OH)D ] in late gestation at a concentration sufficient to prevent newborn 25(OH)D < 25–30 nmol/L , a threshold indicative of increased risk of nutritional rickets . Design We conducted a 3-arm , dose-response , double-blind , r and omized placebo-controlled trial in Cork , Irel and ( 51.9oN ) . A total of 144 white-skinned pregnant women were assigned to receive 0 , 10 ( 400 IU ) , or 20 ( 800 IU ) µg vitamin D3/d from ≤18 wk of gestation . Vitamin D metabolites at 14 , 24 , and 36 wk of gestation and in cord sera , including 25(OH)D3 , 3-epi-25(OH)D3 , 24,25(OH)2D3 , and 25(OH)D2 were quantified by liquid chromatography – t and em mass spectrometry . A curvilinear regression model predicted the total vitamin D intake ( from diet and antenatal supplements plus treatment dose ) that maintained maternal 25(OH)D in late gestation at a concentration sufficient to maintain cord 25(OH)D at ≥25–30 nmol/L. Results Mean ± SD baseline 25(OH)D was 54.9 ± 10.7 nmol/L. Total vitamin D intakes at the study endpoint ( 36 wk of gestation ) were 12.1 ± 8.0 , 21.9 ± 5.3 , and 33.7 ± 5.1 µg/d in the placebo and 10-µg and 20-µg vitamin D3 groups , respectively ; and 25(OH)D was 24.3 ± 5.8 and 29.2 ± 5.6 nmol/L higher in the 10- and 20-µg groups , respectively , compared with placebo ( P < 0.001 ) . For maternal 25(OH)D concentrations ≥50 nmol/L , 95 % of cord sera were ≥30 nmol/L and 99 % were > 25 nmol/L. The estimated vitamin D intake required to maintain serum 25(OH)D at ≥50 nmol/L in 97.5 % of women was 28.9 µg/d . Conclusions Thirty micrograms of vitamin D per day safely maintained serum 25(OH)D concentrations at ≥50 nmol/L in almost all white-skinned women during pregnancy at a northern latitude , which kept 25(OH)D at > 25 nmol/L in 99 % and ≥30 nmol/L in 95 % of umbilical cord sera . This trial was registered at www . clinical trials.gov as NCT02506439 [6004541] Background It is unclear whether maternal vitamin D supplementation during pregnancy and lactation improves fetal and infant growth in regions where vitamin D deficiency is common . Methods We conducted a r and omized , double‐blind , placebo‐controlled trial in Bangladesh to assess the effects of weekly prenatal vitamin D supplementation ( from 17 to 24 weeks of gestation until birth ) and postpartum vitamin D supplementation on the primary outcome of infants ' length‐for‐age z scores at 1 year according to World Health Organization ( WHO ) child growth st and ards . One group received neither prenatal nor postpartum vitamin D ( placebo group ) . Three groups received prenatal supplementation only , in doses of 4200 IU ( prenatal 4200 group ) , 16,800 IU ( prenatal 16,800 group ) , and 28,000 IU ( prenatal 28,000 group ) . The fifth group received prenatal supplementation as well as 26 weeks of postpartum supplementation in the amount of 28,000 IU ( prenatal and postpartum 28,000 group ) . Results Among 1164 infants assessed at 1 year of age ( 89.5 % of 1300 pregnancies ) , there were no significant differences across groups in the mean ( ±SD ) length‐for‐age z scores . Scores were as follows : placebo , ‐0.93±1.05 ; prenatal 4200 , ‐1.11±1.12 ; prenatal 16,800 , ‐0.97±0.97 ; prenatal 28,000 , ‐1.06±1.07 ; and prenatal and postpartum 28,000 , ‐0.94±1.00 ( P=0.23 for a global test of differences across groups ) . Other anthropometric measures , birth outcomes , and morbidity did not differ significantly across groups . Vitamin D supplementation had expected effects on maternal and infant serum 25‐hydroxyvitamin D and calcium concentrations , maternal urinary calcium excretion , and maternal parathyroid hormone concentrations . There were no significant differences in the frequencies of adverse events across groups , with the exception of a higher rate of possible hypercalciuria among the women receiving the highest dose . Conclusions In a population with widespread prenatal vitamin D deficiency and fetal and infant growth restriction , maternal vitamin D supplementation from midpregnancy until birth or until 6 months post partum did not improve fetal or infant growth . ( Funded by the Bill and Melinda Gates Foundation ; Clinical Trials.gov number , NCT01924013 . [26813209] IMPORTANCE Asthma and wheezing begin early in life , and prenatal vitamin D deficiency has been variably associated with these disorders in offspring . OBJECTIVE To determine whether prenatal vitamin D ( cholecalciferol ) supplementation can prevent asthma or recurrent wheeze in early childhood . DESIGN , SETTING , AND PARTICIPANTS The Vitamin D Antenatal Asthma Reduction Trial was a r and omized , double-blind , placebo-controlled trial conducted in 3 centers across the United States . Enrollment began in October 2009 and completed follow-up in January 2015 . Eight hundred eighty-one pregnant women between the ages of 18 and 39 years at high risk of having children with asthma were r and omized at 10 to 18 weeks ' gestation . Five participants were deemed ineligible shortly after r and omization and were discontinued . INTERVENTIONS Four hundred forty women were r and omized to receive daily 4000 IU vitamin D plus a prenatal vitamin containing 400 IU vitamin D , and 436 women were r and omized to receive a placebo plus a prenatal vitamin containing 400 IU vitamin D. MAIN OUTCOMES AND MEASURES Co primary outcomes of ( 1 ) parental report of physician-diagnosed asthma or recurrent wheezing through 3 years of age and ( 2 ) third trimester maternal 25-hydroxyvitamin D levels . RESULTS Eight hundred ten infants were born in the study , and 806 were included in the analyses for the 3-year outcomes . Two hundred eighteen children developed asthma or recurrent wheeze : 98 of 405 ( 24.3 % ; 95 % CI , 18.7%-28.5 % ) in the 4400-IU group vs 120 of 401 ( 30.4 % , 95 % CI , 25.7%-73.1 % ) in the 400-IU group ( hazard ratio , 0.8 ; 95 % CI , 0.6 - 1.0 ; P = .051 ) . Of the women in the 4400-IU group whose blood levels were checked , 289 ( 74.9 % ) had 25-hydroxyvitamin D levels of 30 ng/mL or higher by the third trimester of pregnancy compared with 133 of 391 ( 34.0 % ) in the 400-IU group ( difference , 40.9 % ; 95 % CI , 34.2%-47.5 % , P < .001 ) . CONCLUSIONS AND RELEVANCE In pregnant women at risk of having a child with asthma , supplementation with 4400 IU/d of vitamin D compared with 400 IU/d significantly increased vitamin D levels in the women . The incidence of asthma and recurrent wheezing in their children at age 3 years was lower by 6.1 % , but this did not meet statistical significance ; however , the study may have been underpowered . Longer follow-up of the children is ongoing to determine whether the difference is clinical ly important . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00920621 [27746239] Background : The gut microbiome in infancy influences immune system maturation , and may have an important impact on allergic disease risk . Objective : We sought to determine how prenatal and early life factors impact the gut microbiome in a relatively large , ethnically diverse study population of infants at age 3 to 6 months , who were enrolled in Vitamin D Antenatal Asthma Reduction Trial , a clinical trial of vitamin D supplementation in pregnancy to prevent asthma and allergies in offspring . Methods : We performed 16S rRNA gene sequencing on 333 infants ' stool sample s. Microbial diversity was computed using the Shannon index . Factor analysis applied to the top 25 most abundant taxa revealed 4 underlying bacterial coabundance groups ; the first dominated by Firmicutes ( Lachnospiraceae/Clostridiales ) , the second by Proteobacteria ( Klebsiella/Enterobacter ) , the third by Bacteriodetes , and the fourth by Veillonella . Scores for coabundance groups were used as outcomes in regression models , with prenatal/birth and demographic characteristics as independent predictors . Multivariate analysis , using all microbial community members , was also conducted . Results : White race/ethnicity was associated with lower diversity but higher Bacteroidetes coabundance scores . C‐section birth was associated with higher diversity , but decreased Bacteroidetes coabundance scores . Firmicutes scores were higher for infants born by C‐section . Breast‐fed infants had lower proportions of Clostridiales . Cord blood vitamin D was linked to increased Lachnobacterium , but decreased Lactococcus . Conclusions : The findings presented here suggest that race , mode of delivery , breast‐feeding , and cord blood vitamin D levels are associated with infant gut microbiome composition , with possible long‐term implication s for immune system modulation and asthma/allergic disease incidence [26399867] BACKGROUND The role of maternal 25-hydroxyvitamin D [ 25(OH)D ] in fetal development is uncertain , and findings of observational studies have been inconsistent . Most studies have assessed 25(OH)D only one time during pregnancy , but to our knowledge , the tracking of an individual 's 25(OH)D during pregnancy has not been assessed previously . OBJECTIVE We determined the tracking of serum 25(OH)D from early to late pregnancy and factors that influence this . DESIGN The Southampton Women 's Survey is a prospect i ve mother-offspring birth-cohort study . Lifestyle , diet , and 25(OH)D status were assessed at 11 and 34 wk of gestation . A Fourier transformation was used to model the seasonal variation in 25(OH)D for early and late pregnancy separately , and the difference between the measured and seasonally modeled 25(OH)D was calculated to generate a season-corrected 25(OH)D. Tracking was assessed with the use of the Pearson correlation coefficient , and multivariate linear regression was used to determine factors associated with the change in season-corrected 25(OH)D. RESULTS A total of 1753 women had 25(OH)D measured in both early and late pregnancy . There was a moderate correlation between season-corrected 25(OH)D measurements at 11 and 34 wk of gestation ( r = 0.53 , P < 0.0001 ; n = 1753 ) . Vitamin D supplementation was the strongest predictor of tracking ; in comparison with women who never used supplements , the discontinuation of supplementation after 11 wk was associated with a reduction in season-corrected 25(OH)D ( β = -7.3 nmol/L ; P < 0.001 ) , whereas the commencement ( β = 12.6 nmol/L ; P < 0.001 ) or continuation ( β = 6.6 nmol/L ; P < 0.001 ) of supplementation was associated with increases in season-corrected 25(OH)D. Higher pregnancy weight gain was associated with a reduction in season-corrected 25(OH)D ( β = -0.4 nmol · L(-1 ) · kg(-1 ) ; P = 0.015 ) , whereas greater physical activity ( β = 0.4 nmol/L per h/wk ; P = 0.011 ) was associated with increases . CONCLUSIONS There is a moderate tracking of 25(OH)D status through pregnancy ; factors such as vitamin D supplementation , weight gain , and physical activity are associated with changes in season-corrected 25(OH)D from early to late gestation . These findings have implication s for study design s and analyses and approaches to intervention studies and clinical care [29046301] Background : Little is known about bone mineral density ( BMD ) during pregnancy . Advances in technology with lower radiation emissions by dual-energy X-ray absorptiometry instruments now permit the safe measurement of BMD during pregnancy . Objective : We evaluated maternal BMD during pregnancy as a function of vitamin D status in women of diverse racial/ethnic background s. Design : A total of 301 women who underwent BMD measurements at 12 - 20 wk of gestation and again at 0 - 14 wk postpartum were included in this analysis . Women were a subset of subjects who were recruited for a r and omized , controlled , double-blind trial of vitamin D supplementation in pregnancy ( 400 , 2000 , or 4000 IU/d ) . Results : Treatment had no significant effect on changes in BMD that occurred between 12 - 20 wk of gestation and 0 - 14 wk postpartum . Similarly , changes in spine and femoral neck bone mineral contents ( BMC s ) were not significantly different in the treatment groups . In addition , vitamin D inadequacy ( serum 25-hydroxyvitamin D concentration , averaged across pregnancy , < 50 nmol/L ) was not associated with changes in BMD or BMC . There were significant racial/ethnic differences in spine BMD . African Americans lost more spine BMD than did Caucasians ( -0.04 ± 0.04 compared with -0.02 ± 0.04 g/cm2 ; P = 0.033 ) . In addition , baseline obesity was associated with a greater loss of femoral neck BMD . The means ± SDs of femoral neck BMD loss were -0.02 ± 0.05 and 0.0 ± 0.03 g/cm2 for groups with baseline body mass index ( BMI ; in kg/m2 ) ≥30 and < 30 , respectively . Conclusion : These findings do not support a dose effect of vitamin D supplementation on bone health and suggest that race/ethnicity and BMI play an important role in pregnancy bone health . This trial was registered at clinical trials.gov as NCT00292591 [24210789] OBJECTIVE To determine whether treatment of low serum vitamin D in pregnant women improves fetal growth indices . STUDY DESIGN In this open-label r and omized clinical trial , 130 Iranian pregnant women ( 24 - 26 weeks of gestation ) with vitamin D deficiency or insufficiency [ 25(OH)D < 30ng/ml ] were divided at r and om into an intervention group and a control group . The control group received 200 mg calcium plus a multivitamin ( containing vitamin D3 400U ) each day , and the intervention group received 200 mg calcium plus a multivitamin ( containing vitamin D3 400U ) each day , plus vitamin D3 ( 50,000U ) each week for 8 weeks . At delivery , maternal and cord blood 25(OH)D levels , maternal weight gain , neonatal length , neonatal weight and neonatal head circumference were compared between two groups . Serum vitamin D was measured using enzyme-linked immunosorbent assay . A multivariate regression analysis was performed to examine the independent effect of maternal vitamin D level on fetal growth indices . RESULTS Mean ( ±st and ard deviation ) length ( intervention group : 49±1.6 cm ; control group : 48.2±1.7 cm ; p=0.001 ) , head circumference ( intervention group : 35.9±0.7 cm ; control group : 35.3±1.0 cm ; p=0.001 ) and weight ( intervention group : 3429±351.9 g ; control group : 3258.8±328.2 g ; p=0.01 ) were higher in the intervention group compared with the control group . Mean maternal weight gain was higher in the intervention group compared with the control group ( 13.3±2.4 kg vs 11.7±2.7 kg ; p=0.006 ) . Multivariate regression analysis for maternal weight gain , neonatal length , neonatal weight and neonatal head circumference showed an independent correlation with maternal vitamin D level . CONCLUSION Treatment of low serum vitamin D during pregnancy improves fetal growth indices and maternal weight gain [26156737] BACKGROUND Vitamin D supplementation is recommended for breastfed infants . Maternal supplementation beginning in gestation is a potential alternative , but its efficacy in maintaining infant 25-hydroxyvitamin D [ 25(OH)D ] concentration after birth is unknown . OBJECTIVES We determined the effect of 3 doses of maternal vitamin D supplementation beginning in gestation and continued in lactation on infant serum 25(OH)D and compared the prevalence of infant serum 25(OH)D cutoffs ( > 30 , > 40 , > 50 , and > 75 nmol/L ) by dose at 8 wk of age . DESIGN Pregnant women ( n = 226 ) were r and omly allocated to receive 10 , 25 , or 50 μg vitamin D₃/d from 13 to 24 wk of gestation until 8 wk postpartum , with no infant supplementation . Mother and infant blood was collected at 8 wk postpartum . RESULTS At 8 wk postpartum , mean [ nmol/L ( 95 % CI ) ] infant 25(OH)D at 8 wk was higher in the 50-μg/d [ 75 ( 67 , 83 ) ] than in the 25-μg/d [ 52 ( 45 , 58 ) ] or 10-μg/d [ 45 ( 38 , 52 ) ] vitamin D groups ( P < 0.05 ) . Fewer infants born to mothers in the 50-μg/d group had a 25(OH)D concentration < 30 nmol/L ( indicative of deficiency ) than infants in the 25- and 10-μg/d groups , respectively ( 2 % compared with 16 % and 43 % ; P < 0.05 ) . Fewer than 15 % of infants in the 10- or 25-μg/d groups achieved a 25(OH)D concentration > 75 nmol/L compared with 44 % in the 50-μg/d group ( P < 0.05 ) . Almost all infants ( ∼98 % , n = 44 ) born to mothers in the 50-μg/d group achieved a 25(OH)D concentration > 30 nmol/L. At 8 wk postpartum , mean maternal 25(OH)D concentration was higher in the 50-μg/d [ 88 ( 84 , 91 ) ] than in the 25-μg/d [ 78 ( 74 , 81 ) ] or 10-μg/d [ 69 ( 66 , 73 ) ] groups ( P < 0.05 ) . CONCLUSIONS Maternal supplementation beginning in gestation with 50 μg vitamin D₃/d protects 98 % of unsupplemented breastfed infants against 25(OH)D deficiency ( < 30 nmol/L ) to at least 8 wk , whereas 10 or 25 μg vitamin D/d protects only 57 % and 84 % of infants , respectively Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Hip osteoarthritis ( OA ) is a major cause of pain and functional limitation . Few hip OA treatments have been evaluated for safety and effectiveness . Acupuncture is a traditional Chinese medical therapy which aims to treat disease by inserting very thin needles at specific points on the body . OBJECTIVES To assess the benefits and harms of acupuncture in patients with hip OA . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

26017383

[3305975] Background : Despite thous and s of papers , the value of quality of life ( QoL ) in curing disease remains uncertain . Until now , we lacked tools for the diagnosis and specific treatment of diseased QoL. We approached this problem stepwise by theory building , modelling , an exploratory trial and now a definitive r and omised controlled trial ( RCT ) in breast cancer , whose results we report here . Methods : In all , 200 representative Bavarian primary breast cancer patients were recruited by five hospitals and treated by 146 care professionals . Patients were r and omised to either ( 1 ) a novel care pathway including diagnosis of ‘ diseased ’ QoL ( any QoL measure below 50 points ) using a QoL profile and expert report sent to the patient 's coordinating practitioner , who arranged QoL therapy consisting of up to five st and ardised treatments for specific QoL defects or ( 2 ) st and ard postoperative care adhering to the German national guideline for breast cancer . The primary end point was the proportion of patients in each group with diseased QoL 6 months after surgery . Patients were blinded to their allocated group . Results : At 0 and 3 months after surgery , diseased QoL was diagnosed in 70 % of patients . The QoL pathway reduced rates of diseased QoL to 56 % at 6 months , especially in emotion and coping , compared with 71 % in controls ( P=0.048 ) . Relative risk reduction was 21 % ( 95 % confidence interval ( CI ) : 0–37 ) , absolute risk reduction 15 % ( 95 % CI : 0.3–29 ) , number needed to treat (NNT)=7 ( 95 % CI : 3–37 ) . When QoL therapy finished after successful treatment , diseased QoL often returned again , indicating good responsiveness of the QoL pathway . Conclusion : A three-component outcome system including clinician-derived objective , patient-reported subjective end points and qualitative analysis of clinical relevance was developed in the last 10 years for cancer as a complex intervention . A separate QoL pathway was implemented for the diagnosis and treatment of diseased QoL and its effectiveness tested in a community-based , pragmatic , definitive RCT . While the pathway was active , it was effective with an NNT of 7 [15712339] In a r and omized controlled design , this study tested the efficacy of a theoretically based uncertainty management intervention delivered to older long-term breast cancer survivors . The sample included 509 recurrence-free women ( 360 Caucasian , 149 African-American women ) with a mean age of 64 years ( S.D.=8.9 years ) who were 5 - 9 years post-treated for breast cancer . Women were r and omly assigned to either the intervention or usual care control condition . The intervention was delivered during four weekly telephone sessions , in which study nurses guided cancer survivors in the use of audiotaped cognitive-behavioral strategies to manage uncertainty about recurrence , and a self-help manual design ed to help women underst and and manage long-term treatment side effects and other symptoms . Treatment outcome data on uncertainty management were gathered at pre-intervention and 10-months afterward . Repeated measures MANOVA evaluating treatment group , ethnic group , and treatment by ethnic interaction effects indicated that training in uncertainty management result ed in improvements in cognitive reframing , cancer knowledge , patient-health care provider communication , and a variety of coping skills . Results are discussed in terms of the importance of theory-based interventions for cancer survivors that target triggers of uncertainty about recurrence and in terms of ethnic differences in response to the intervention [3172715] Objectives : The internet offers new possibilities in psychosocial patient care . However , empirical data are lacking for oncological patients . A field-experimental study was conducted to obtain initial data to enable evaluation of the effectiveness of online counseling via e-mail for breast cancer patients . A secondary objective was to explore how patients reached by the service can be characterized on psychosocial status and illness . Methods : On a dedicated German- language website , 235 breast cancer patients registered for psychosocial counseling via e-mail . 133 registrants were r and omly assigned to a treatment group to receive immediate counseling or to a waiting list control group . The two-month counseling session took the form of a psychoeducation , individually tailored to each patient . Psychosocial outcome measures including psychological distress ( BSI ) and quality of life ( EORTC QLQ-C30 ) were assessed at registration and at a two-month follow-up . Descriptive data were recorded at registration . At the conclusion of the program , participants were asked to complete a patient satisfaction question naire ( ZUF-8 ) . Results : BSI responses showed that 85 % of all patients were initially diagnosable with comorbid psychopathology . Despite high severity of distress and attendant large reductions in quality of life , 72 % of all patients were not obtaining conventional assistance . Among counseling participants ( n=31 ) , no significant improvements in distress or quality of life were found in comparison to the control group ( n=34 ) , but patient satisfaction was nonetheless high . Conclusion : The study demonstrates that online counseling via e-mail reaches patients with unmet therapeutic needs , but also indicated its limitations , suggesting that the online setting may be most useful for prompting and supporting a transition to conventional counseling services [16135471] PURPOSE To evaluate the efficacy of a psychoeducational intervention in improving cancer-related fatigue . PATIENTS AND METHODS This r and omized controlled trial involved 109 women commencing adjuvant chemotherapy for stage I or II breast cancer in five chemotherapy treatment centers . Intervention group patients received an individualized fatigue education and support program delivered in the clinic and by phone over three 10- to 20-minute sessions 1 week apart . Instruments included a numeric rating scale assessing confidence with managing fatigue ; 11-point numeric rating scales measuring fatigue at worst , average , and best ; the Functional Assessment of Cancer Therapy-Fatigue and Piper Fatigue Scales ; the Cancer Self-Efficacy Scale ; the European Organisation for Research and Treatment of Cancer Quality of Life Question naire C30 ; and the Hospital Anxiety and Depression Scale . For each outcome , separate analyses of covariance of change scores between baseline ( T1 ) and the three follow-up time points ( T2 , T3 , and T4 ) were conducted , controlling for the variable 's corresponding baseline value . RESULTS Compared with the intervention group , mean difference scores between the baseline ( T1 ) and immediate after the test ( T2 ) assessment s increased significantly more for the control group for worst and average fatigue , Functional Assessment of Cancer Therapy-Fatigue , and Piper fatigue severity and interference measures . These differences were not observed between baseline and T3 and T4 assessment s. No significant differences were identified for any pre- or post-test change scores for confidence with managing fatigue , cancer self-efficacy , anxiety , depression , or quality of life . CONCLUSION Preparatory education and support has the potential to assist women to cope with cancer-related fatigue in the short term . However , further research is needed to identify ways to improve the potency and sustainability of psychoeducational interventions for managing cancer-related fatigue [17935144] OBJECTIVE The aim is to evaluate the effectiveness of a manualized 12-week supportive-expressive group therapy program among primary breast cancer patients treated in community setting s , to determine whether highly distressed patients were most likely to benefit and whether therapist 's training or experience was related to outcome . METHOD Three hundred and fifty-three women within one year of diagnosis with primary breast cancer were r and omly assigned to receive supportive-expressive group therapy or to an education control condition . Participants were recruited from two academic centers and nine oncology practice s , which were members of NCI 's Community Clinical Oncology Program ( CCOP ) and were followed over 2 years . RESULTS A 2x2x19 analysis of variance was conducted with main effects of treatment condition , cohort , and baseline distress and their interactions . There was no main effect for treatment condition after removing one subject with an extreme score . Highly distressed women did not derive a greater benefit from treatment . Therapist training and psychotherapy experience were not associated with a treatment effect . CONCLUSIONS This study provides no evidence of reduction in distress as the result of a brief supportive-expressive intervention for women with primary breast cancer . Future studies might productively focus on women with higher initial levels of distress [19016270] The question of whether stress poses a risk for cancer progression has been difficult to answer . A r and omized clinical trial tested the hypothesis that cancer patients coping with their recent diagnosis but receiving a psychologic intervention would have improved survival compared with patients who were only assessed [19235193] OBJECTIVES Considerable morbidity persists among survivors of breast cancer ( BC ) including high levels of psychological stress , anxiety , depression , fear of recurrence , and physical symptoms including pain , fatigue , and sleep disturbances , and impaired quality of life . Effective interventions are needed during this difficult transitional period . METHODS We conducted a r and omized controlled trial of 84 female BC survivors ( Stages 0-III ) recruited from the H. Lee Moffitt Cancer and Research Institute . All subjects were within 18 months of treatment completion with surgery and adjuvant radiation and /or chemotherapy . Subjects were r and omly assigned to a 6-week Mindfulness-Based Stress Reduction ( MBSR ) program design ed to self-regulate arousal to stressful circumstances or symptoms ( n=41 ) or to usual care ( n=43 ) . Outcome measures compared at 6 weeks by r and om assignment included vali date d measures of psychological status ( depression , anxiety , perceived stress , fear of recurrence , optimism , social support ) and psychological and physical subscales of quality of life ( SF-36 ) . RESULTS Compared with usual care , subjects assigned to MBSR(BC ) had significantly lower ( two-sided p<0.05 ) adjusted mean levels of depression ( 6.3 vs 9.6 ) , anxiety ( 28.3 vs 33.0 ) , and fear of recurrence ( 9.3 vs 11.6 ) at 6 weeks , along with higher energy ( 53.5 vs 49.2 ) , physical functioning ( 50.1 vs 47.0 ) , and physical role functioning ( 49.1 vs 42.8 ) . In stratified analyses , subjects more compliant with MBSR tended to experience greater improvements in measures of energy and physical functioning . CONCLUSIONS Among BC survivors within 18 months of treatment completion , a 6-week MBSR(BC ) program result ed in significant improvements in psychological status and quality of life compared with usual care [9024474] The effects of 8-week cancer support groups ( CSGs ) with and without coaching on adaptation were tested in a sample of 181 women with newly diagnosed early stage breast cancer . CSG participation with coaching result ed in higher quality of relationship with significant other at CSG conclusion ; this effect was not sustained 8 weeks later . CSG participation had no effect on symptom distress , emotional distress , or functional status . On average , symptom distress was low , emotional distress was moderate , and functional status was relatively high . Independent of CSGs , symptom distress decreased and functional status increased over time from entry into the study to 16 weeks later . Further research is needed to determine the optimal starting time and length for CSGs [23081984] OBJECTIVE The current report provides the result of a Phase II clinical trial regarding the effectiveness and feasibility of problem-solving therapy for psychological distress experienced by Japanese early-stage breast cancer patients . METHODS Participants were 36 post-surgery Japanese breast cancer patients in a university hospital located in Osaka Prefecture , Japan . After screening for psychological distress using the Distress and Impact Thermometer and the Hospital Anxiety and Depression Scale , highly distressed patients were exposed to 5 weekly sessions of the problem-solving therapy program . RESULTS Nineteen patients completed the intervention and follow-up . There was a significant difference between the pre-intervention and the 3-month follow-up in the total Hospital Anxiety and Depression Scale score ( P = 0.02 ) , and the mean change score from the pre-intervention to the follow-up was 6.05 ( SD = 1.94 ) . The intervention had a large effect size ( d = 0.82 ) . There were also significant changes in worry , self-efficacy and quality of life measures . CONCLUSIONS The findings of our study suggest that the problem-solving therapy program has potential to be effective for alleviating psychological distress experienced by Japanese early-stage breast cancer patients . The true effectiveness of the program should be confirmed by a future r and omized control trial [21458989] PURPOSE To test the effectiveness of a psycho-educational group intervention to improve psychological distress measured by POMS TMD , Quality of Life measured by European Organisation for Research and Treatment of Cancer ( EORTC ) , the core and breast cancer module , Mental Adjustment measured by MAC and marital relationship measured by BLRI in women with primary breast cancer conducted 10 weeks after surgery . A secondary outcome was 4-year survival . PATIENTS AND METHODS We r and omly assigned 210 patients with primary breast cancer to a control or an intervention group . Patients in the intervention group were offered two weekly 6-h sessions of psycho-education and eight weekly 2-h sessions of group psychotherapy . All participants were followed up for Quality of Life , coping ability and social relations 1 , 6 and 12 months after the intervention and on survival 4 years after surgical treatment . RESULTS No statistically significant effects of the intervention were found on any of the psychosocial question naire outcomes . There were not enough cases of death to analyse overall survival . The only statistically significant result was for patients who used anti depressive medication , for whom almost all measures improved over time , in both the control and intervention groups . CONCLUSION Psycho-education and group psychotherapy did not decrease psychological distress or increase Quality of Life , Mental Adjustment or improve marital relationship among patients with primary breast cancer [12424783] A Roy adaptation model-based support and education intervention for women with early-stage breast cancer was tested in a three-group , three-phase r and omized clinical trial of a sample of 125 women . The experimental group received 13 months of combined individual telephone and in-person group support and education , Control Group 1 received 13 months of telephone-only individual support and education , and Control Group 2 received one-time mailed educational information . The experimental group and Control Group 1 reported less mood disturbance at the end of all three phases , less loneliness at the end of Phases II and III , and a higher- quality relationship with a significant other at the end of Phase II than did Control Group 2 . No group differences were found for cancer-related worry or well-being . The findings suggest that individual telephone support may provide an effective alternative to in-person support groups . Further study of telephone interventions is recommended using ethnically and economically heterogeneous sample [19622708] Objectives : To test experimentally whether a psychological intervention reduces depression-related symptoms and markers of inflammation among cancer patients and to test one mechanism for the intervention effects . Depression and inflammation are common among cancer patients . Data suggest that inflammation can contribute to depressive symptoms , although the converse remains untested . Methods : As part of a r and omized clinical trial , newly diagnosed breast cancer patients ( n = 45 ) with clinical ly significant depressive symptoms were evaluated and r and omized to psychological intervention with assessment or assessment only study arms . The intervention spanned 12 months , with assessment s at baseline , 4 , 8 , and 12 months . Mixed-effects modeling tested the hypothesis that the intervention reduced self-reported depressive symptoms ( Center for Epidemiological Studies Depression scale , Profile of Mood States Depression and Fatigue subscales , and Medical Outcomes Study -Short Form 36 Bodily Pain subscale ) and immune cell numbers that are elevated in the presence of inflammation ( white blood cell count , neutrophil count , and helper/suppressor ratio ) . Mediation analyses tested whether change in depressive symptoms , pain , or fatigue predicted change in white blood cell count , neutrophil count , or the helper/suppressor ratio . Results : The intervention reduced significantly depressive symptoms , pain , fatigue , and inflammation markers . Moreover , the intervention effect on inflammation was mediated by its effect on depressive symptoms . Conclusions : This is the first experiment to test whether psychological treatment effective in reducing depressive symptoms would also reduce indicators of inflammation . Data show that the intervention reduced directly depressive symptoms and reduced indirectly inflammation . Psychological treatment may treat effectively depressive symptoms , pain , and fatigue among cancer patients . CES-D = Center for Epidemiological Studies -Depression scale , Iowa short form ; SF-36 = Medical Outcomes Study -Short Form 36 ; KPS = Karnofsky Performance Status [16442463] OBJECTIVE The importance of psychosocial counselling after a diagnosis of cancer has been acknowledged and many intervention studies have been carried out , with the aim to find out which types of intervention are most effective in enhancing quality of life in cancer patients . A factor which could be part of effective counselling could be the time of offering psychosocial counselling . The aim of this study was to research the effect of time of enrolment in a psychosocial group intervention on psychosocial adjustment . METHODS In the present study , 67 women with early stage breast cancer were r and omised in a psychosocial group intervention program starting within 4 months after surgery or in the same intervention program starting at least 3 months later . RESULTS The main conclusion of this study is that women who started with their intervention early were less distressed at 6 months follow-up than women who were in the delayed condition . Medical and demographic variables were predictive for some psychosocial adjustment indicators , but were not associated with time of enrolment . Regardless of time of enrolment , women improved in distress , body image and recreational activities , but showed a decrease in social interaction . CONCLUSION Though results are limited , based on these results we suggest that psychosocial counselling should be offered as soon after diagnosis or surgery for breast cancer . PRACTICE IMPLICATION S Women diagnosed with primary breast cancer should be able to start with psychological counselling soon after being diagnosed , to prevent them from becoming distressed at long term [14987957] OBJECTIVE This study examined the effect of a cognitive-behavioral stress management ( CBSM ) intervention on emotional well-being and immune function among women in the months following surgery for early-stage breast cancer . METHOD Twenty-nine women were r and omly assigned to receive either a 10-week CBSM intervention ( n=18 ) or a comparison experience ( n=11 ) . The primary psychological outcome measure was benefit finding . The primary immune function outcome measure was in vitro lymphocyte proliferative response to anti CD3 . RESULTS Women in the CBSM intervention reported greater perceptions of benefit from having breast cancer compared to the women in the comparison group . At 3-month follow-up , women in the CBSM group also had improved lymphocyte proliferation . Finally , increases in benefit finding after the 10-week intervention predicted increases in lymphocyte proliferation at the 3-month follow-up . CONCLUSION A CBSM intervention for women with early-stage breast cancer facilitated positive emotional responses to their breast cancer experience in parallel with later improvement in cellular immune function [18544286] In a phase I National Cancer Institute (NCI)-funded clinical trial , 34 breast cancer survivors , six weeks to one year post-treatment , were recruited to participate in a 6-class , 8-week long imagery stress reduction program entitled " Envision the Rhythms of Life . " Patients practice d imagery during and between sessions . Outcomes for quality of life and cortisol rhythm were assessed pre- to post-intervention , in two subsets of survivors ( intravenous [ IV ] chemotherapy , or no IV chemotherapy ) . Thirty survivors completed the 8-week program . Quality of life outcomes demonstrated statistically and clinical ly significant outcomes for the functional assessment of cancer therapy-general ( FACT-G ) global index ( p<.001 ) , representing improvements in survivor quality of life related to physical , social/family , emotional , and function well-being . Survivors also improved significantly on the breast cancer ( p<.001 ) and spiritual subscales ( p = .008 . ) Brief symptom inventory ( BSI ) assessment reported significant improvement for the global index ( p<.001 ) which included the categories of depression , somatization and anxiety . At eight weeks , cortisol rhythm , a biochemical indicator of stress and likelihood of cancer recurrence , produced a trend toward improvement for the fifth time point of the day ( p = .18 ) . Likert-based stress scales showed highly significant reductions in stress ( p<.0001 ) with subjects practicing imagery the most producing the best scores . Outcomes suggest the imagery program may significantly improve survivor quality of life and reduce stress [21831722] UNLABELLED This r and omized controlled trial assessed the effect of a SMART ( Stress Management and Resiliency Training ) program among 25 women diagnosed with breast cancer . Resilience , perceived stress , anxiety , and quality of life improved at 12 weeks in the active but not the control arm . A brief training in the SMART program can enhance resilience and quality of life and decrease stress and anxiety . INTRODUCTION Patients with breast cancer experience stress and anxiety related to their diagnosis , with result ing lower quality of life . The purpose of this study was to assess the effect of a SMART ( Stress Management and Resiliency Training ) program for increasing resiliency and for decreasing stress and anxiety among mentors who themselves were previously diagnosed with breast cancer . MATERIAL S AND METHODS The program consisted of two 90-minute group training sessions , a brief individual session , and 3 follow-up telephone calls . Twenty-four mentors at Mayo Clinic in Rochester , Minnesota , were r and omized in a single-blind , wait-list controlled clinical trial to either the SMART intervention or a control group for 12 weeks . Primary outcome measures assessed at baseline and at week 12 included the Connor Davidson Resilience Scale , Perceived Stress Scale , Smith Anxiety Scale , and Linear Analog Self Assessment Scale . RESULTS Twenty patients completed the study . A statistically significant improvement in resilience , perceived stress , anxiety , and overall quality of life at 12 weeks , compared with baseline was observed in the study arm . No significant difference in any of these measures was noted in the control group . CONCLUSION This study demonstrates that a brief , predominantly group-based resilience training intervention is feasible in patients with previous breast cancer ; also , it may be efficacious [18061756] OBJECTIVE Treatment of breast cancer is usually associated with significant psychological stress . In this study , we examined the effects of relaxation and visualization therapy ( RVT ) on psychological distress , cortisol levels , and immunological parameters of breast cancer patients undergoing radiotherapy . METHODS Participants were r and omly assigned to either the experimental ( n=20 ) who underwent group RVT for 24 consecutive days or control group ( n=14 ) who were on radiotherapy only . Psychological scores ( stress , anxiety , and depression ) were measured by structured clinical interviews . Salivary cortisol was assessed along the day . Lymphocytes were isolated and cultured to measure T-cell proliferation and sensitivity to glucocorticoids ( GCs ) . RESULTS RVT was effective to reduce stress , anxiety , and depression scores ( all P<.05 ) . However , cortisol levels as well as proliferation remained unchanged following RVT . Although T cells of experimental group were more sensitive to GCs than cells of controls at baseline , no changes were noted following RVT . Cortisol levels were positively correlated to anxiety and depression scores and inversely correlated to T-cell proliferation and sensitivity to GCs . CONCLUSION We conclude that the psychological intervention was capable to attenuate the emotional distress presented during radiotherapy treatment . A longer RVT or worse psychological morbidity at baseline may be necessary to translate psychological into biological changes [11570653] The authors report a 3-year follow-up of the effects of 8-week support group interventions on the quality of life of women with early stage breast cancer . Shortly after diagnosis , women were r and omly assigned to 1 of 4 conditions : control , education , peer discussion , and education plus peer discussion . The education group intervention focused on providing information to enhance control over the illness experience , whereas the peer discussion group intervention focused on providing emotional support through the expression of feelings . Consistent with the results that emerged 6 months after the interventions ( V. S. Helgeson , S. Cohen , R. Schulz , & J. Yasko , 1999 ) , the authors found that the benefits of the education intervention were maintained over a 3-year period ( N=252 ) , although effects dissipated with time . The authors continued to find no benefits of the peer discussion intervention , either alone or in combination with education [15337807] PURPOSE This r and omized clinical trial tests the hypothesis that a psychological intervention can reduce emotional distress , improve health behaviors and dose-intensity , and enhance immune responses . PATIENTS AND METHODS We studied 227 women who were surgically treated for regional breast cancer . Before adjuvant therapy , women completed interviews and question naires assessing emotional distress , social adjustment , and health behaviors . A 60-mL blood sample was drawn for immune assays . Patients were r and omly assigned to either the intervention group or assessment only group . The intervention was conducted in small patient groups , with one session per week for 4 months . The sessions included strategies to reduce stress , improve mood , alter health behaviors , and maintain adherence to cancer treatment and care . Re assessment occurred after completion of the intervention . RESULTS As predicted , patients receiving the intervention showed significant lowering of anxiety , improvements in perceived social support , improved dietary habits , and reduction in smoking ( all P < .05 ) . Analyses of adjuvant chemotherapy dose-intensity revealed significantly more variability ( ie , more dispersion in the dose-intensity values ) for the assessment arm ( P < .05 ) . Immune responses for the intervention patients paralleled their psychological and behavioral improvements . T-cell proliferation in response to phytohemagglutinin and concanavalin A remained stable or increased for the Intervention patients , whereas both responses declined for Assessment patients ; this effect was replicated across three concentrations for each assay ( all P < .01 ) . CONCLUSION These data show a convergence of significant psychological , health behavior , and biologic effects after a psychological intervention for cancer patients [16492649] Abstract The survivor uncertainty management intervention study is a r and omized controlled study design ed to test the efficacy of an intervention that combines training in audiotaped cognitive behavioral strategies to manage uncertainty about cancer recurrence with a self-help manual design ed to help women underst and and manage long-term treatment side effects and other symptoms . Specifically , women were taught to recognize their own personal triggers of uncertainty ( places , events or surroundings , that bring back memories , feelings , or concerns about breast cancer ) , and then use coping skills such as relaxation , distraction , and calming self-talk to deal with uncertainty . Also , women were taught to use the manual as a re source for dealing with fatigue , lymphedema , pain and other symptoms . Treatment outcome data ( Mishel et al. , in press ) indicated that the uncertainty management intervention result ed in improvements in cognitive reframing , cancer knowledge , social support , knowledge of symptoms and side effects , and coping skills when compared to a control condition . The purpose of the present paper was to report on the use and helpfulness of the intervention components by the 244 women who were in the intervention . Findings indicated that women regularly used the intervention components to deal with triggers of breast cancer recurrence and long-term treatment side effects and most women found the strategies very helpful [12923794] BACKGROUND We conducted a r and omised , controlled trial of cognitive-existential group therapy ( CEGT ) for women with early stage breast cancer receiving adjuvant chemotherapy with the aim of improving mood and mental attitude to cancer . METHODS Women were r and omised to 20 sessions of weekly group therapy plus 3 relaxation classes or to a control arm receiving 3 relaxation classes . Assessment s , independently done at baseline , 6 and 12 months , included a structured psychiatric interview and vali date d question naires covering mood , attitudes to cancer , family relationships , and satisfaction with therapy . RESULTS Three hundred and three of 491 ( 62 % ) eligible patients participated over 3 years . Distress was high pre-intervention : 10 % were diagnosed as suffering from major depression , 27 % from minor depression and 9 % from anxiety disorders . On an intention-to-treat analysis , there was a trend for those receiving group therapy ( n=154 ) to have reduced anxiety ( p=0.05 , 2-sided ) compared to controls ( n=149 ) . Women in group therapy also showed a trend towards improved family functioning compared to controls ( p=0.07 , 2-sided ) . The women in the groups reported greater satisfaction with their therapy ( p<0.001 , 2-sided ) , appreciating the support and citing better coping , self-growth and increased knowledge about cancer and its treatment . They valued the CEGT therapy . Overall effect size for the group intervention was small ( d=0.25 ) , with cancer recurrence having a deleterious effect in three of the 19 therapy groups . Psychologists as a discipline achieved a moderate mean effect size ( d=0.52 ) . CONCLUSION CEGT is a useful adjuvant psychological therapy for women with early stage breast cancer . Interaction effects between group members and therapists are relevant to outcome . Group-as-a-whole effects are powerful , but the training and experience of the therapist is especially critical to an efficacious outcome [17311247] PURPOSE The r and omized study aim ed to determine the efficacy of psychological intervention consisting of relaxation and guided imagery to reduce anxiety and depression in gynecologic and breast cancer patients undergoing brachytherapy during hospitalization . METHODS AND MATERIAL S Sixty-six patients programmed to receive brachytherapy in two hospitals in Barcelona ( Spain ) were included in this study . The patients were r and omly allocated to either the study group ( n=32 ) or the control group ( n=34 ) . Patients in both groups received training regarding brachytherapy , but only study group patients received training in relaxation and guided imagery . After collection of sociodemographic data , all patients were given a set of question naires on anxiety and depression : the Hospital Anxiety and Depression Scale ( HADS ) , and on quality of life : Cuestionario de Calidad de Vida QL-CA-AFex ( CCV ) , prior to , during and after brachytherapy . RESULTS The study group demonstrated a statistically significant reduction in anxiety ( p=0.008 ) , depression ( p=0.03 ) and body discomfort ( p=0.04 ) compared with the control group . CONCLUSIONS The use of relaxation techniques and guided imagery is effective in reducing the levels of anxiety , depression and body discomfort in patients who must remain isolated while undergoing brachytherapy . This simple and inexpensive intervention enhances the psychological wellness in patients undergoing brachytherapy . State : This study has passed Ethical Committee review [21988544] OBJECTIVE Major depression is the most common psychiatric disorder among breast cancer patients and is associated with substantial impairment . Although some research has explored the utility of psychotherapy with breast cancer patients , only 2 small trials have investigated the potential benefits of behavior therapy among patients with well-diagnosed depression . METHOD In a primarily Caucasian , well-educated sample of women ( age = 55.4 years , SD = 11.9 ) diagnosed with breast cancer and major depression ( n = 80 ) , this study was a r and omized clinical trial testing the efficacy of 8 sessions of behavioral activation treatment for depression ( BATD ) compared to problem-solving therapy . Primary outcome measures assessed depression , environmental reward , anxiety , quality of life , social support , and medical outcomes . RESULTS Across both treatments , results revealed strong treatment integrity , excellent patient satisfaction with treatment protocol s , and low patient attrition ( 19 % ) . Intent-to-treat analyses suggested both treatments were efficacious , with both evidencing significant pre-post treatment gains across all outcome measures . Across both treatments , gains were associated with strong effect sizes , and based on response and remission criteria , a reliable change index , and numbers-needed-to-treat analyses , approximately ¾ of patients exhibited clinical ly significant improvement . No significant group differences were found at posttreatment . Treatment gains were maintained at 12-month follow-up , with some support for stronger maintenance of gains in the BATD group . CONCLUSIONS BATD and problem-solving interventions represent practical interventions that may improve psychological outcomes and quality of life among depressed breast cancer patients . Study limitations and future research directions are discussed [22383279] OBJECTIVE This study evaluated the psychological effects of a pre-surgical stress management training ( SMT ) in cancer patients . METHODS Stress management training comprised four sessions in total : on 5 days and 1 day pre-surgery and on 2 days and 1 month post-surgery . Patients also received audio CDs with relaxation and coping skills exercises . Patients were r and omly assigned to the SMT ( N = 34 ) or a regular care condition ( N = 36 ) . Depression , anxiety , quality of life , perception of control , fatigue , pain , sleep problems , and surgery-related somatic symptoms were measured at Day 6 and Day 1 pre-surgery , and Day 2 , 5 , 30 and 90 post-surgery . RESULTS Depression and fatigue decreased in the intervention group and increased in the control group , leading to significant group differences at Day 2 ( fatigue ) and Day 5 post-surgery ( fatigue and depression ) . It also appeared that surgery-related symptoms had increased more in the control group 3 months post-surgery than in the SMT group . No intervention effects were observed for anxiety , pain , and sleep problems . CONCLUSION The use of a short psychological intervention is effective in reducing depression and fatigue in the post-surgical period , although the effects are of short duration [3236414] Background . Previous integrative literature review s and meta-analyses have yielded conflicting results regarding the effectiveness of psychosocial interventions for cancer patients . Methods . An integrative review of the literature focused on 19 r and omized , controlled trials ( 2006–2011 ) was completed to examine the effectiveness of psychosocial interventions for cancer patients . Eligibility criteria : Inclusion criteria were the study was an English language r and omized controlled clinical trial . Results . Seven studies involved nurses . Eleven studies result ed in positive outcomes . Overall , study quality was limited . In eight studies the intervention was not adequately described , 7 studies did not contain a hypothesis , 4 did not include clear eligibility criteria , 10 studies did not r and omize appropriately , 9 did not list recruitment date s , 11 did not include a power analysis , 14 did not include blinded patients or data collectors , 11 did not use an intent-to-treat analysis , 10 did not clarify reasons for drop outs , and 11 did not discuss treatment fidelity . Conclusions . Future studies should build on previous findings , use comparable outcome measures , and adhere to st and ards of quality research . Qualitative studies are needed to determine what cancer patients of varied ages , cancer stages , and racial/ethnic background s believe would be an effective intervention to manage their psychosocial needs [2242455] OBJECTIVES --To assess outside a clinical trial the psychological outcome of different treatment policies in women with early breast cancer who underwent either mastectomy or breast conservation surgery depending on the surgeon 's opinion or the patient 's choice . To determine whether the extent of psychiatric morbidity reported in women who underwent breast conservation surgery was associated with their participation in a r and omised clinical trial . DESIGN -- Prospect i ve , multicentre study capitalising on individual and motivational differences among patients and the different management policies among surgeons for treating patients with early breast cancer . SETTING --12 District general hospitals , three London teaching hospitals , and four private hospitals . PATIENTS --269 Women under 75 with a probable diagnosis of stage I or II breast cancer who were referred to 22 different surgeons . INTERVENTIONS --Surgery and radiotherapy or adjuvant chemotherapy , or both , depending on the individual surgeon 's stated preferences for managing early breast cancer . MAIN OUTCOME MEASURES --Anxiety and depression as assessed by st and ard methods two weeks , three months , and 12 months after surgery . RESULTS --Of the 269 women , 31 were treated by surgeons who favoured mastectomy , 120 by surgeons who favoured breast conservation , and 118 by surgeons who offered a choice of treatment . Sixty two of the women treated by surgeons who offered a choice were eligible to choose their surgery , and 43 of these chose breast conserving surgery . The incidences of anxiety , depression , and sexual dysfunction were high in all treatment groups . There were no significant differences in the incidences of anxiety and depression between women who underwent mastectomy and those who underwent lumpectomy . A significant effect of surgeon type on the incidence of depression was observed , with patients treated by surgeons who offered a choice showing less depression than those treated by other surgeons ( p = 0.06 ) . There was no significant difference in psychiatric morbidity between women treated by surgeons who offered a choice who were eligible to choose their treatment and those in the same group who were not able to choose . Most of the women ( 159/244 ) gave fear of cancer as their primary fear rather than fear of losing a breast . The overall incidences of psychiatric morbidity in women who underwent mastectomy and those who underwent lumpectomy were similar to those found in the Cancer Research Campaign breast conservation study . At 12 months 28 % of women who underwent mastectomy in the present study were anxious compared with 26 % in the earlier study , and 27 % of women in the present study who underwent lumpectomy were anxious compared with 31 % in the earlier study . In both the present and earlier study 21 % of women who underwent mastectomy were depressed , and 19 % of women who underwent lumpectomy in the present study were depressed compared with 27 % in the earlier study . ) CONCLUSIONS --There is still no evidence that women with early breast cancer who undergo breast conservation surgery have less psychiatric morbidity after treatment than those who undergo mastectomy . Women who surrender autonomy for decision making by agreeing to participate in r and omised clinical trials do not experience any different psychological , sexual , or social problems from those women who are treated for breast cancer outside a clinical trial [22271538] OBJECTIVE To evaluate the efficacy of a brief cognitive-behavioral therapy ( CBT ) that is being developed for management of cognitive dysfunction following chemotherapy among breast cancer survivors . Memory and Attention Adaptation Training ( MAAT ) is a brief CBT design ed to improve the quality of life and function among cancer survivors with post-chemotherapy cognitive complaints . METHODS An initial , two-group ( MAAT versus waitlist , no treatment control ) , r and omized clinical trial ( RCT ) was conducted . Forty stage I and II female breast cancer survivors ( mean age = 50 ; SD = 6.4 ) were r and omized to conditions and assessed at baseline , post-treatment ( 8 weeks ) and 2-month follow-up assessment points on measures of : ( 1 ) self-reported daily cognitive failures ; ( 2 ) quality of life ; and ( 3 ) neuropsychological performance . Participants were also assessed for satisfaction with MAAT . RESULTS With education and IQ as covariates , MAAT participants made significant improvements relative to controls on the spiritual well-being subscale of the quality of life measure and on verbal memory , but statistical significance was not achieved on self-report of daily cognitive complaints . However , moderate-to-large effect sizes were observed on these outcomes . Participants gave MAAT high satisfaction ratings . CONCLUSIONS Although this initial RCT is a small study , MAAT participants appear to improve on one measure of quality of life and verbal memory performance relative to no treatment controls and rate MAAT with high satisfaction . These data are encouraging and support the continued development and evaluation of MAAT efficacy [19039808] BACKGROUND Many women with breast cancer need psychological help to cope more effectively after treatment . Cognitive and behavioural techniques are not yet well established in France . A multi-site r and omized study was conducted to evaluate the effects of a psycho-educational group intervention in this population . METHODS Two hundred and three patients , recruited after primary treatment , were r and omly assigned either to a treatment group ( psycho-educational intervention ) or to a waiting-list control group . The 8-week programme of 2 h sessions comprised of thematic discussion s , information and training in stress management techniques . Evaluation at baseline , after 8 sessions , and 1 month after programme completion , included evaluations using the STAI , POMS , MAC , EORTC QLQ-C30 and EORTC QLQ-BR23 breast module scales . RESULTS We observed a significant reduction in anxiety ( STAI , POMS ) among group participants , a reduction in anger , depression and fatigue ( POMS ) , a significant improvement in vigor and interpersonal relationships ( POMS ) , in emotional and role functioning , in health status and fatigue level ( EORTC QLQ-C30 ) . In contrast , coping strategies ( MAC ) were not significantly different between groups . No group-related negative effects were observed and the global satisfaction levels were very high . CONCLUSION This study demonstrates the feasibility and effectiveness of a psycho-educational intervention , which can accelerate the reduction of those negative affects which are present at the end of treatment . It represents an excellent complement or an alternative to individual psycho-oncologic therapeutic support , widely proposed in France , and should now be tested in groups with other types of cancer and at other disease phases [20044329] PURPOSE / OBJECTIVES To describe women 's unexpected and distressing symptom experiences after breast cancer treatment . RESEARCH APPROACH Qualitative and descriptive . SETTING Depending upon their preference , participants were interviewed in their homes or in a private office space in a nearby library . PARTICIPANTS Purposive sample of 13 women 1 - 18 years after breast cancer treatment . METHOD OLOGIC APPROACH Secondary analysis of phenomenologic data ( constant comparative method ) . MAIN RESEARCH VARIABLES Breast cancer symptom distress , ongoing symptoms , and unexpected experiences . FINDINGS Women described experiences of unexpected and distressing symptoms in the years following breast cancer treatment . Symptoms included pain , loss of energy , impaired limb movement , cognitive disturbance , changed sexual experience , and lymphedema . Four central themes were derived : living with lingering symptoms , confronting unexpected situations , losing precancer being , and feeling like a has-been . Distress intensified when women expected symptoms to disappear but symptoms persisted instead . Increased distress also was associated with sudden and unexpected situations or when symptoms elicited feelings of loss about precancer being and feelings of being a has been . Findings suggest that symptom distress has temporal , situational , and attributive dimensions . CONCLUSIONS Breast cancer survivors ' perceptions of ongoing and unexpected symptoms have important influences on quality of life . Underst and ing temporal , situational , and attributive dimensions of symptom distress empowers nurses and healthcare professionals to help breast cancer survivors prepare for subsequent ongoing or unexpected experiences in the years after breast cancer treatment . INTERPRETATION Follow-up care for breast cancer survivors should foster dialogue about ways that symptoms might emerge and that unexpected situations might occur . Prospect i ve studies are needed to examine symptom distress in terms of temporal , situational , and attributive dimensions and explore the relationship between symptom distress and psychological distress after breast cancer treatment [10197829] BACKGROUND We report a clinical trial comparing the effectiveness of education-based and peer discussion -based group interventions on adjustment to breast cancer . METHODS Women with stage I , II , or III breast cancer ( n = 312 ) were r and omly assigned to 1 of 4 group conditions : control , education , peer discussion , or education plus peer discussion ( combination ) . Seven groups ( each comprising 8 - 12 women ) were conducted in each of the 4 conditions ( 28 groups total ) . Adjustment was measured before the intervention , immediately after the intervention , and 6 months after the intervention . RESULTS Consistently positive effects on adjustment were seen in the education groups both immediately following and 6 months after the intervention . There were no benefits of participation in peer discussion groups , and some indications of adverse effects on adjustment at both follow-up examinations . The effects could be explained by changes in self-esteem , body image , and intrusive thoughts about the illness . CONCLUSIONS Education-based group interventions facilitated the initial adjustment of women diagnosed with early stage breast cancer . There was no evidence of benefits from peer discussion group interventions [23381060] Purpose Although patients receive information prior to commencing radiotherapy , they often experience anxiety and distress . We conducted a pilot r and omised controlled trial to determine whether a radiation therapist led psycho-educational intervention for breast cancer patients prior to radiotherapy is likely to be effective in reducing radiotherapy-related concerns , patient anxiety and depression . Methods The intervention comprised two face-to-face consultations with a radiation therapist ( one prior to radiation planning and the other prior to treatment ) . Patients completed surveys at baseline , prior to treatment planning and on the first day of treatment . Outcome measures included the Hospital Anxiety and Depression Scale , Radiation Therapy Related Patient Concerns and Radiation Therapy Knowledge Scales . Results One hundred and twenty two patients completed baseline measures . Fifty-eight patients received usual care , and 64 received the intervention . After the first consultation , patient anxiety was significantly lower in the intervention group ( p = 0.048 ) , as were concerns about radiotherapy ( p = 0.001 ) . There were no differences between groups for depression . Patient knowledge for the intervention group was higher after the first consultation ( p < 0.001 ) . Conclusion This intervention is likely to be effective in reducing patient anxiety and concerns and increasing knowledge . Future research is required to test this intervention with a larger population [17228986] In a 2 x 2 r and omized block repeated measure design , this study evaluated the follow-up efficacy of the uncertainty management intervention at 20 months . The sample included 483 recurrence-free women ( 342 White , 141 African American women ; mean age = 64 years ) who were 5 - 9 years posttreatment for breast cancer . Women were r and omly assigned to either the intervention or usual care control condition . The intervention was delivered during 4 weekly telephone sessions in which survivors were guided in the use of audiotaped cognitive-behavioral strategies and a self-help manual . Repeated measures MANOVAs evaluating treatment group , ethnic group , and treatment by ethnic interaction effects at 20 months indicated that training in uncertainty management result ed in improvements in cognitive reframing , cancer knowledge , and a variety of coping skills . Importantly , the 20-month outcomes also demonstrated benefits for women in the intervention condition in terms of declines in illness uncertainty and stable effects in personal growth over time [18490891] The purpose of this r and omized control trial was to verify the effectiveness of a brief group intervention that combines stress management psycho-education and physical activity ( ie , independent variable ) intervention in reducing fatigue and improving energy level , quality of life ( mental and physical ) , fitness ( VO2submax ) , and emotional distress ( ie , dependent variables ) in breast cancer survivors . This study applied Lazarus and Folkman stress-coping theoretical framework , as well as Salmon 's unifying theory of physical activity . Eighty-seven French-speaking women who had completed their treatments for nonmetastatic breast cancer at a university hospital in Quebec City , Canada , were r and omly assigned to either the group intervention ( experimental ) or the usual-care ( control ) condition . Data were collected at baseline , postintervention , and at 3-month follow-up . The 4-week group intervention was cofacilitated by 2 nurses . Results showed that participants in the intervention group showed greater improvement in fatigue , energy level , and emotional distress at 3-month follow-up , and physical quality of life at postintervention , compared with the participants in the control group . These results suggest that a brief psycho-educational group intervention focusing on active coping strategies and physical activity is beneficial to cancer survivors after breast cancer treatments [18020846] OBJECTIVE The purpose was to examine whether social-cognitive variables would moderate the efficacy of a couple-focused group intervention ( CG ) for women diagnosed with early stage breast cancer . DESIGN Participants ( N = 238 ) were r and omly assigned to 6 sessions of a couple-focused group versus usual care . Intent to treat growth curve modeling analyses indicated that emotional expression and emotional processing moderated CG effects on depression . MAIN OUTCOME MEASURES The primary outcome measures for this study were psychological distress and psychological well-being . RESULTS Treatment attrition analyses separating out participants assigned to but not attending CG indicated that emotional expression , emotional processing , and protective buffering moderated the effects of CG among those who attended CG with the most consistent effects noted for emotional processing on indicators of distress and well-being . CONCLUSION The CG intervention may be more effective for patients who begin the group experience using emotional approach coping strategies to deal with cancer [11879269] PURPOSE The purpose of this study was to determine whether participation in a group psychosocial intervention by patients with breast cancer would result in an improvement in psychological measures and in reduced billings in general medical expenses . DESCRIPTION OF STUDY Eligible women who had completed treatment for stage 0 , I , or II primary breast cancer were prospect ively and r and omly assigned to either the intervention ( n=46 ) or control ( n=43 ) group . Both groups received the usual psychosocial care ; however , the intervention group also participated in six weekly cognitive/behavioral psychosocial meetings . All were assessed on psychiatric symptoms , mood , depression , and coping strategies at four time periods : pre-intervention , post-intervention , 1-year follow-up , and 2-year follow-up . Alberta Healthcare billing records were obtained covering the 2-year follow-up period to determine the amount billed per person over the course of the study . RESULTS Women in the intervention group had less depression , less overall mood disturbance , better overall quality of life , and fewer psychiatric symptoms than those in the control group , beginning immediately post-intervention and remaining so at 2 years post-intervention . Billing in the intervention group was an average of $ 147 less than in the control group , a 23.5 % reduction . CLINICAL IMPLICATION S This is the first study to show that a psychosocial intervention can reduce direct healthcare billings in a sample of patients with cancer . Importantly , these findings help to justify the routine availability of such programs in cancer treatment facilities worldwide [22705939] Background : Older breast cancer survivors ( BCSs ) are at risk for late and long-term treatment effects on quality of life ( QOL ) , including lower physical functioning and fear of recurrence . Two promising approaches to address this include dance/movement therapy and mindfulness . Objective : The purpose of this 2-group r and omized controlled pilot feasibility study was to test short-term effects of a 12-week Mindful Movement Program ( MMP ) intervention combining mindfulness with self-directed movement on QOL and mindfulness in female BCSs 50 years or older and at 12 months or more following treatment . Methods : Consented participants were r and omized to an experimental group ( EG ) ( 12 weekly MMP sessions ) or a control group ( no sessions ) . All completed question naires 3 times . The EG participants kept home practice diaries . Analysis was conducted after intervention for immediate effects on outcome variables and 6 weeks later for maintenance of effects . Results : Participants ( n = 49 ) ranged in age from 50 to 90 years ( average , 65.6 years ) and were at 9.8 years since diagnosis ( range , 1–32 years ) , and the majority were white , unpartnered , and retired . After intervention , EG participants showed improved QOL via decreased fear of recurrence and increased mindfulness attitude . At 6 weeks , initial effects were retained . Conclusions : The MMP appears to benefit older BCSs by reducing fear of recurrence and improving mindfulness attitude . Although these findings are promising , a larger study is needed to determine more specifically what short- and long-term effects are possible . Implication s for Practice : The combination of self-directed movement and mindfulness , as tested here , may be a valuable tool for promoting health and well-being in older long-term survivors of breast cancer [20391072] The aim of this study was to evaluate a manualized cognitive behavioral group intervention for early-stage breast cancer patients . Sixty-nine women were recruited at an Irish specialist oncology hospital and assigned to a 6-week cognitive behavior therapy ( CBT ) program or an educational control group . Participants were assessed at baseline , 6 weeks , and 6-month follow-up . Groups × Time ( 2 × 3 ) ANOVAs showed that the program did not lead to greater improvement on st and ardized measures of coping , quality of life , or mood compared with the control group . Regression analyses showed that maladaptive coping and distress at baseline were predictive of psychological adjustment at follow-up . Level of distress was also predictive of quality of life at follow-up . Repeated measures ANOVAs of data from cases in the intervention group showed that patients who completed the program showed significant improvement in problem severity , impact of problems , coping ability , and goal attainment from pre- to posttreatment , and these gains were maintained at follow-up for problem severity and impact of problems , but not for coping ability or goal attainment . Participation in the program did not lead to less health service usage during the period from baseline to follow-up , compared with the educational control group . A controlled trial provided limited evidence for the effectiveness of brief cognitive behavior intervention in enhancing psychological adjustment of early-stage breast cancer patients with non clinical ly significant levels of psychological distress . Future research should evaluate the effectiveness of the program for patients with elevated levels of psychological distress and limited coping re sources [17467230] PURPOSE Psychological interventions are efficacious in reducing emotional distress for cancer patients . However , it is not clear whether psychological improvements are , in turn , related to improved health . A clinical trial tests whether a psychological intervention for cancer patients can do so , and also tests two routes to achieve better health : ( a ) reducing patients ' Emotional Distress , and /or ( b ) enhancing their functional immunity . METHODS Post-surgery , 227 breast cancer patients were r and omized to intervention or assessment only Study Arms . Conducted in small groups , intervention sessions were offered weekly for 4 months and followed by monthly sessions for 8 months . Measures included psychological ( distress ) , biological ( immune ) , and health outcomes ( performance status and evaluations of patient 's symptomatology , including toxicity from cancer treatment , lab values ) collected at baseline , 4 months , and 12 months . RESULTS A path model revealed that intervention participation directly improved health ( p<.05 ) at 12 months . These effects remained when statistically controlling for baseline levels of distress , immunity , and health as well as sociodemographic , disease , and cancer treatment variables . Regarding the mechanisms for achieving better health , support was found for an indirect effect of distress reduction . That is , by specifically lowering intervention patients ' distress at 4 months , their health was improved at 12 months ( p<.05 ) . Although the intervention simultaneously improved patients ' T-cell blastogenesis in response to phytohemagglutinin ( PHA ) , the latter increases were unrelated to improved health . CONCLUSION A convergence of biobehavioral effects and health improvements were observed . Behavioral change , rather than immunity change , was influential in achieving lower levels of symptomatology and higher functional status . Distress reduction is highlighted as an important mechanism by which health can be improved [22576981] Background When diagnosed with breast cancer , most women ’s lives change as well as their perspectives on and appreciation of life . The aim of the present study was to evaluate whether psychosocial support intervention could influence health-related quality of life ( HRQOL ) and fatigue during the first year after diagnosis . Material and methods Of 382 patients with newly diagnosed breast cancer , 191 patients were r and omized to an intervention group and 191 patients were r and omized to a routine control group . The intervention group received support intervention that lasted 1 week on a residential basis , followed by 4 days of follow-up 2 months later . The support intervention included informative educational parts , relaxation training , mental visualization , and nonverbal communication . HRQOL was measured using the European Organization for Research and Treatment of Cancer ( EORTC ) QLQ-C30 and QLQ-BR23 question naires and fatigue with the Norwegian version of the fatigue scale at baseline and at 2 , 6 , and 12 months after intervention . Result There was a time-dependent improvement in both functional and symptom scales between baseline and 12 months as measured by the EORTC QLQ-C30 and BR23 question naires and there was a decrease in fatigue between baseline and after 2 months with further improvement up to 12 months in both groups , but there were no differences between the intervention and control groups at any point in time . Conclusion HRQOL improves and symptoms of fatigue decrease over time , but we could not see any additional effect from the rehabilitation program in this setting [17523575] The study assessed whether a nursing intervention based on self-regulation theory , the Attentional Focus and Symptom Management Intervention ( AFSMI ) , could help women who underwent day surgery for breast cancer to achieve better pain management and decreased emotional distress . The sample consisted of 117 patients with breast cancer who were out patients and undergoing surgery as part of the initial treatment for their cancer . All subjects were interviewed at three different occasions . The subjects were r and omized into the experimental group ( n = 61 ) or the usual care group ( control , n = 56 ) . The subjects in the experimental group received the intervention in two sessions , 3 - 4 days and 10 - 11 days after surgery . The outcomes were the subjects ' pain and emotional distress . Results showed significant differences between the experimental and control group at post-test on home management , total mood disturbance , confusion and tension scores implying that the intervention was effective in achieving these outcomes . Clinical significance has illustrated that a nursing intervention applied during immediate recovery of breast cancer surgery is quite clinical ly relevant to reduce emotional distress . Self-regulation theory could effectively be used as a guide in developing nursing intervention programs in practice for patients with cancer undergoing day surgery as a primary treatment [9287446] BACKGROUND The pilot study used clinical trial methodology to differentiate the effects of imagery and support on coping , life attitudes , immune function , quality of life , and emotional well-being after breast cancer . METHODS Women ( N = 47 ) who completed treatment for primary breast cancer , excluding stage IV , were r and omly assigned to st and ard care ( n = 15 ) or six weekly support ( n = 16 ) or imagery ( n = 16 ) sessions . Self-report measures included Ways of Coping-Cancer , Life Attitude Profile , Quality of Life ( FACT-B ) , Profile of Mood States , and Functional Support . Immune measures included natural killer cell activity , plasma neopterin , interferon-gamma , interleukins 1 alpha , 1 beta , and 2 , and beta-endorphin levels . Differences between groups over time were tested using general linear models , adjusted for pretest score and covariates ( age , stage , and months posttreatment ) . RESULTS For all women , interferon-gamma increased , neopterin decreased , quality of life improved , and natural killer activity remained unchanged . Compared with st and ard care , both interventions improved coping skills ( seeking support ) and perceived social support , and tended to enhance meaning in life . Support boosted overall coping and death acceptance . When comparing imagery with support , imagery participants tended to have less stress , increased vigor , and improved functional and social quality of life . CONCLUSION Although imagery reduced stress and improved quality of life , both imagery and support improved coping , attitudes , and perception of support . The clinical implication s of these changes warrant further testing [22573418] OBJECTIVE This study aims to test two telephone-delivered interventions for their efficacy in improving quality of life ( QOL ) ( psychological , physical , social , and spiritual ) among Latinas with breast cancer and their family members or friends ( labeled supportive partners in this study ) . METHODS Latinas with breast cancer and their supportive partners ( SPs ) were r and omly assigned to one of two telephone delivered 8-week interventions : ( i ) telephone interpersonal counseling ( TIP-C ) or ( ii ) telephone health education ( THE ) . QOL assessment s were made at baseline , immediately after the 8-week interventions ended , and at an 8-week follow-up . Seventy Latinas and their 70 SPs completed all assessment s ( 36 in health education and 34 in counseling ) and were included in the final analysis . RESULTS Both Latinas with breast cancer and their SPs had significant improvements in virtually all dimensions of QOL over the 16 weeks of the investigation . However , there was no evidence documenting the superiority of either intervention for improving QOL . Preliminary cost analysis found that the counseling intervention cost about $ 164.68 for one dyad compared with $ 107.03 for health education . The majority of participants reported benefit from the intervention and liked that the intervention was in Spanish , included SPs , and was delivered by telephone . CONCLUSION The results of this study show that relatively brief , culturally appropriate , and highly accessible telephone-delivered interventions that provide emotional and information support can bring about substantial improvements in QOL for both Latinas with breast cancer and their SPs [24027211] BACKGROUND AND PURPOSE Previous literature s on young adult survivors of childhood cancer show inconsistent findings with regards to their psychological distress and health-related quality of life ( HRQOL ) . Much of the available data focus on negative patient outcomes following cancer treatments prescribed from 1970 to 1990 . In the present study , HRQOL and psychological distress of young adult survivors in Hong Kong was examined . It focused on subjects who had received cancer treatments prescribed in the last two decades . METHODS A structured telephone survey was conducted with 614 eligible survivors and 208 sibling controls in Hong Kong . RESULTS The survivors reported significantly lower mean scores in physical role and functioning , whereas their mental , social , and psychological well-being was similar to that of their sibling controls . Being female , older age , longer survival time , and specific cancer diagnoses were the factors associated with poorer physical and mental adaptation . HRQOL was negatively correlated with psychological distress . CONCLUSIONS Findings of the study suggest that most survivors adjusted fairly well in mental , psychological , and social aspects . Survivors with a higher risk of poor HRQOL could benefit from appropriate screening and counseling at an early stage to mitigate their survivorship difficulties . Prospect i ve follow-up studies on childhood cancer survivors are recommended to detect changes over longer survival periods [15452189] PURPOSE Cognitive-existential group therapy ( CEGT ) was developed to improve mood and mental attitude toward cancer in women with early-stage breast cancer receiving adjuvant chemotherapy . Given the debate about group therapy 's association with increased survival in women with metastatic breast cancer , we were curious to check its effect at a much earlier stage in the cancer journey . PATIENTS AND METHODS We r and omly assigned 303 women with early-stage breast cancer who were receiving adjuvant chemotherapy to either 20 sessions of weekly group therapy plus three relaxation classes ( n = 154 ) or to a control condition of three relaxation classes alone ( n = 149 ) . The primary outcome was survival . RESULTS CEGT did not extend survival ; the median survival time was 81.9 months ( 95 % CI , 64.8 to 99.0 months ) in the group-therapy women and 85.5 months ( 95 % CI , 67.5 to 103.6 months ) in the control arm . The hazard ratio for death was 1.35 ( 95 % CI , 0.76 to 2.39 ; P = .31 ) . In contrast , histology and axillary lymph node status were significant predictors of survival . Low- grade histology yielded a hazard ratio of 0.342 ( 95 % CI , 0.17 to 0.69 ) , and axillary lymph node-negative status yielded a hazard ratio of 0.397 ( 95 % CI , 0.20 to 0.78 ) . CONCLUSION CEGT does not prolong survival in women with early-stage breast cancer [17179873] Background : Psychosocial interventions can improve psychological quality of life ( symptoms of depression and anxiety ) of both women with breast cancer and their partners , but are not offered routinely to women and their partners . Objective : To test the hypotheses that telephone-delivered psychosocial interventions decrease depression and anxiety in women with breast cancer and their partners . Methods : The design of the study was a three-wave repeated measures with a between-subjects factor ( treatment group ) . Ninety-six women and their 96 partners were assigned r and omly to participate in one of three different 6-week programs : ( a ) telephone interpersonal counseling ( TIP-C ) ; ( b ) self-managed exercise ; or ( c ) attention control ( AC ) . Results : The mixed-model analysis of variance for symptoms of depression among women with breast cancer revealed women 's depressive symptom scores decreased over time in all groups . For anxiety , women 's symptoms of anxiety decreased in the TIP-C and exercise groups over time , but not in the AC group . A parallel set of analyses was conducted on partners ' depression and anxiety data . Symptoms of depression and anxiety among the partners decreased substantially over the course of the investigation . Similar to the women , partners ' symptoms of anxiety decreased significantly in the TIP-C and exercise groups , but not in the AC group . Discussion : Findings from this study support that these telephone-delivered psychosocial interventions were effective for decreasing symptoms of depression and anxiety to improve psychological quality of life when compared to an AC group [22964869] Background : At the time of diagnosis , patients with cancer are highly exposed to the risk of psychological morbidity . The effects of psychosocial intervention for newly diagnosed cancer patients have not been extensively studied . Objective : The objective of this study was to test the effects of a dyadic peer support intervention on self-efficacy , anxiety , depression , and mental adjustment among newly diagnosed breast cancer patients in Korea . Methods : This study used a r and omized controlled trial design . One hundred twenty-nine patients were recruited within 1 month of diagnosis with breast cancer in the National Cancer Center in Korea . The study participants were r and omly assigned to either experimental ( n = 64 ) or control ( n = 65 ) group . The experimental group underwent dyadic peer support intervention during the 6 weeks after surgery . The control group received the usual care . Results : There was a significant difference in changes in self-efficacy for self-management of breast cancer between the experimental and control groups ; however , no significant changes were observed in anxiety , depression , and mental adjustment between the 2 groups . Conclusions : A 6-week dyadic peer support intervention was feasible and effective for increasing self-efficacy for self-management among newly diagnosed breast cancer patients in Korea . However , this intervention did not improve other psychological outcomes . Implication s for Practice : Oncology nurses are optimally positioned to promote adjustment in patients with cancer . Trained peer support partners , supervised by skilled nurses , may be useful in improving self-efficacy of patients newly diagnosed with breast cancer [18835434] BACKGROUND A diagnosis of breast cancer and treatment are psychologically stressful events , particularly over the first year after diagnosis . Women undergo many dem and ing and anxiety-arousing treatments such as surgery , radiation and chemotherapy . Psychosocial interventions that promote psychosocial adaptation to these challenges may modulate physiological processes ( neuroendocrine and immune ) that are relevant for health outcomes in breast cancer patients . METHODS Women with Stages 1 - 3 breast cancer recruited 4 - 8 weeks after surgery were r and omized to either a 10-week group-based cognitive behavioral stress management ( CBSM ) intervention or a 1-day psychoeducational control group and completed question naires and late afternoon blood sample s at study entry and 6 and 12 months after assignment to experimental condition . RESULTS Of 128 women initially providing psychosocial question naire and blood sample s at study entry , 97 provided complete data for anxiety measures and cortisol analysis at all time points , and immune assays were run on a subset of 85 of these women . Those assigned to a 10-week group-based CBSM intervention evidence d better psychosocial adaptation ( lower reported cancer-specific anxiety and interviewer-rated general anxiety symptoms ) and physiological adaptation ( lower cortisol , greater Th1 cytokine [ interleukin-2 and interferon-gamma ] production and IL-2:IL-4 ratio ) after their adjuvant treatment compared to those in the control group . Effects on psychosocial adaptation indicators and cortisol appeared to hold across the entire 12-month observation period . Th1 cytokine regulation changes held only over the initial 6-month period . CONCLUSIONS This intervention may have facilitated a " recovery or maintenance " of Th1 cytokine regulation during or after the adjuvant therapy period . Behavioral interventions that address dysregulated neuroendocrine function could play a clinical ly significant role in optimizing host immunologic resistance during a vulnerable period [16594274] OBJECTIVE The purpose of this article is to evaluate an 8-week pilot intervention based on Social Cognitive Theory to improve quality of life for women with breast cancer . METHODS A total of 32 breast cancer patients were r and omized to either the intervention or st and ard care . Outcome variables included quality of life , mood , self-efficacy , outcome expectations , and self-regulation . RESULTS Effect sizes were calculated to examine the impact of the intervention , with moderate to large effect sizes found for several subscales of the outcome expectations variable : learning about cancer and treatment ( d = 0.85 ) , having a positive attitude ( d = 0.54 ) , talking about cancer ( d = 1.02 ) , engaging in relaxation ( d = 0.62 ) , and setting goals ( d = 1.58 ) . SIGNIFICANCE OF RESULTS A nonparametric sign test was conducted , indicating that women in the intervention condition either improved more or showed less decline than the women in st and ard care , p = .034 , two-tailed . Implication s and suggestions for the content and delivery of future psychosocial interventions with cancer patients are review ed [11824739] The feasibility of a r and omized clinical trial to implement and compare the effectiveness of three components of an intervention for women with breast cancer and their partners was tested . The intervention components , st and ardized education by videotape ( SE ) , telephone counseling ( TC ) , and education with telephone counseling ( SE + TC ) , were design ed with a complementary approach to disease management of breast cancer at each of four phases of the breast cancer experience : diagnostic , postsurgery , adjuvant therapy , and ongoing recovery . A st and ardized Telephone Counseling Training Manual was developed . A nonprobability sample of 12 patient-partner pairs was accrued . Four pairs were r and omly assigned to each of the three intervention components . A set of question naires was completed by each patient and partner at baseline and following each intervention for assessment of emotional , physical , and social adjustment , and perceived support . Attrition was minimal and return rate for the completed question naires at all five data - collection points was high . Validation of the SE and the TC , one of the objectives , was by data from the preliminary descriptive study ( Hoskins , 1990–1994 ) , pretests and posttests for st and ardized education , audiotapes for each phase-specific telephone counseling session , and evaluation forms for each intervention session . The positive findings included significant changes from pre- to postmeasurement in patients ' and partners ' scores for the st and ardized education in each of the four phases . Even with the limited statistical power , the effects were marked , lending support for a full-scale r and omized clinical trial , to underst and better the relative treatment efficacy and differential benefit of one or some interventions over others [10833696] PURPOSE / OBJECTIVES To test the value of telephone-administered cognitive-behavioral therapy in a study of patients with breast cancer . DESIGN Women were assigned r and omly to a therapy group or an assessment -only control group . SETTING A tertiary cancer treatment center serving rural areas of North Dakota and Minnesota . SAMPLE Women were recruited within three to four months of stage I ( n = 27 ) or stage II ( n = 26 ) breast cancer diagnosis . Age ranged from 30 - 82 ( mean = 51.5 years ) . Most participants ( n = 35 ) underwent a modified radical mastectomy ; 17 underwent a lumpectomy . METHODS Therapy involved 10 30-minute ( or less ) telephone sessions . Data that were collected from mailed question naires included psychological distress ( Profile of Mood States ) , perceived stress , coping ( Coping Response Indices-Revised ) , quality of life ( Medical Outcome Scale ) , and satisfaction with therapy . Measures were completed at baseline and at 4- and 10-month follow-up intervals . MAIN RESEARCH VARIABLES Telephone therapy , stress , coping , and quality of life . FINDINGS With time , women in the therapy and control groups reported reduced stress and improved quality of life . However , significant reductions in some kinds of distress ( anxiety , anger , depression , and confusion ) were not observed . Most therapy participants liked the telephone treatment sessions but showed only modest improvement ( less anxiety and confusion ) compared with women in the control group . CONCLUSIONS Most patients reported being comfortable with the telephone therapy and said that they felt better as a result of it . However , the outcome data showed that telephone therapy -- as carried out in this study --produced only modest benefits . Research ers need to consider who is best for delivering such therapy . IMPLICATION S FOR NURSING PRACTICE Providing telephone therapy to patients with breast cancer has potential benefits , and nurses may be the appropriate professionals to administer the therapy [10420420] PURPOSE / OBJECTIVES To examine the feasibility of using an emotional expression intervention with patients with cancer and test the hypothesis that emotional expression improves psychosocial adjustment . DESIGN Sequentially r and omized pretest/post-test design with repeated measures . SETTING Two radiation therapy ( RT ) facilities . SAMPLE Women completing RT for stage I or II breast cancer , who spoke and read English , were independent in self-care , and provided written consent . Subjects ( N = 44 ) were middle-aged ( mean = 53.6 years ) , Caucasian , married , and well educated . METHODS Following a baseline interview , subjects were sequentially r and omized to an attentional control group , a single dose , or a three-dose emotional expression writing group . Interventions were administered at the time of completion of RT . Follow-up telephone interviews were completed at 1 , 4 - 6 , 16 , and 28 weeks post-RT . MAIN RESEARCH VARIABLES Positive and negative affect , intrusiveness of thoughts , use of avoidant coping , side effect severity , trait negative affectivity , content of written essay , and themes derived from content analysis . FINDINGS A high level of acceptance and completion of emotional expression existed , but no effect of the intervention on psychosocial adjustment was evident . Process measures in the three-dose group changed as expected . No relationship existed between content changes and outcome measures . CONCLUSIONS Emotional expression is feasible for patients with cancer , but the efficacy of the intervention in improving mood and decreasing cognitive intrusion and avoidance was not supported . Emotional expression processes were consistent with those seen in other sample s and may influence outcomes that were not addressed in this study . IMPLICATION S FOR NURSING PRACTICE More extensive testing is needed , including additional outcome variables . Essays reveal concerns around communication , recurrence , and health behavior changes that should be considered in practice [12790260] The effectiveness of support group interventions for cancer patients has been established among White patients but has been virtually unstudied among minority patients . The current study represents the 1st r and omized support group intervention targeted to African American women with breast cancer . Participants ( N = 73 ) with nonmetastatic breast cancer were r and omly assigned to an 8-week group intervention or an assessment -only control condition At 12 months , the intervention result ed in improved mood as well as improved general and cancer-specific psychological functioning among women with greater baseline distress or lower income . Subsequent research is needed to address effective methods of enrolling and following women with fewer psychosocial and financial re sources , as they were the most likely to benefit from this particular intervention [15992569] OBJECTIVE The primary objective was to conduct a detailed analysis of individual variation in psychological morbidity in the year following surgery for breast cancer . The salience of the patients ' " illness perceptions " to morbidity was examined as a secondary objective . METHODS Psychological morbidity was assessed with the General Health Question naire ( GHQ-28 ) in a prospect i ve study of 371 women having surgery for primary breast cancer . Patients also completed the Illness Perception Question naire ( IPQ ) , Mental Adjustment to Cancer Scale ( MAC ) and the Eysenck Personality Scales ( EPS ) . Assessment s were made postoperatively and at 3 , 6 and 12 months after surgery . RESULTS Whilst descriptive statistics indicated a general reduction in mean distress over the 12-month follow-up , close analysis showed that a quarter of all patients maintained clinical ly significant levels of distress throughout the period . Patients with chronically elevated distress were characterised by higher levels of neuroticism , greater symptom awareness , more pain and poorer self-rated general health . In the regression analysis , psychological morbidity across the 1-year follow-up was predicted principally by the immediate postoperative state of distress , IPQ symptom awareness and the perceived time line of the illness , general health and , to a more minor extent , by neuroticism . CONCLUSION There is marked individual variation in psychological morbidity in the year following breast cancer surgery , which is reliably predicted by the patient 's immediate postoperative state of distress , her perception of the impact of the symptoms and the time line of the disease . Subgroups of patients with chronically high distress are characterised by factors including personality and negative perceptions and beliefs about their illness [20042336] Prospect i ve data are limited on the course of anxiety and depression and their determinants in women with early breast cancer . These parameters were assessed before adjuvant radiotherapy ( RT ) and over 5 years follow-up . Of 2208 women recruited to the START QOL study , 35 % reported clinical ly relevant levels of anxiety and /or depression pre-RT ; there was no significant change in these proportions over time . However , 75 % women with high baseline anxiety recorded further high scores over time whilst one in six had high scores at every follow-up point . Depression showed a similar pattern with lower frequencies at all time points ; very few with initial normal scores developed clinical ly relevant anxiety or depression over time . Lower educational level predicted worse anxiety and depression over time ; younger age predicted worse anxiety and chemotherapy predicted worse depression . Scores in the borderline or case range for anxiety or depression at baseline were both significantly associated with worse mood states over 5 years . These findings indicate the course of anxiety and depression in women with specific risk factors . This subgroup of patients requires greater clinical attention [12035205] PROBLEM Although research ers suggest treatments that provide patients with an active coping strategy may increase patients ' sense of self-efficacy , previous studies have not measured patients ' self-efficacy . METHODS Eighteen women receiving chemotherapy for breast cancer were r and omized to efficacy-enhancing experimental ( n = 10 ) and usual-care control ( n = 8) groups . The experimental group received five interventions delivered monthly . Variables-- quality of life , symptom distress , and self-care self-efficacy -- were measured at baseline and at 4 and 8 months later . FINDINGS At 4 and 8 months the interaction effects for the Functional Assessment of Cancer Treatment-Breast , used to measure quality of life , ranged from small for functional concerns to large for social concerns . Interaction effects for symptom distress , measured by the Symptom Distress Scale , were large . Interaction effects for self-care self-efficacy ranged from small for Enjoying Life and Stress Reduction , medium for Stress Reduction , and large for Making Decisions . CONCLUSIONS Interventions to promote self-efficacy may increase quality of life and decrease distress for women diagnosed with breast cancer [21901389] The aim of this study was determine the effectiveness of a mindfulness-based stress-reduction ( MBSR ) program on quality of life ( QOL ) and psychosocial outcomes in women with early-stage breast cancer , using a three-arm r and omized controlled clinical trial ( RCT ) . This RCT consisting of 172 women , aged 20–65 with stage I or II breast cancer consisted of the 8-week MBSR , which was compared to a nutrition education program ( NEP ) and usual supportive care ( UC ) . Follow-up was performed at three post-intervention points : 4 months , 1 , and 2 years . St and ardized , vali date d self-administered question naires were adopted to assess psychosocial variables . Statistical analysis included descriptive and regression analyses incorporating both intention-to-treat and post hoc multivariable approaches of the 163 women with complete data at baseline , those who were r and omized to MBSR experienced a significant improvement in the primary measures of QOL and coping outcomes compared to the NEP , UC , or both , including the spirituality subscale of the FACT-B as well as dealing with illness scale increases in active behavioral coping and active cognitive coping . Secondary outcome improvements result ing in significant between-group contrasts favoring the MBSR group at 4 months included meaningfulness , depression , paranoid ideation , hostility , anxiety , unhappiness , and emotional control . Results tended to decline at 12 months and even more at 24 months , though at all times , they were as robust in women with lower expectation of effect as in those with higher expectation . The MBSR intervention appears to benefit psychosocial adjustment in cancer patients , over and above the effects of usual care or a credible control condition . The universality of effects across levels of expectation indicates a potential to utilize this stress reduction approach as complementary therapy in oncologic practice [10964333] To the authors ' knowledge , there had been no evidence for the efficacy of psychosocial intervention among Japanese cancer patients . The objective of this study was to determine the effect of a psychosocial group intervention in reducing psychologic distress and enhancing coping in this population in a r and omized controlled trial [21308859] OBJECTIVE Rehabilitation programmes are intended to help cancer patients achieve optimal functioning and live independently . We evaluated whether a psychosocial rehabilitation course was effective in relieving cancer patients ' distress and improving their well-being . METHODS Patients with breast , prostate or colorectal cancer diagnosed within 2 years who had finished primary treatment were r and omised to usual care or a 6-day residential course of lectures , discussion s and peer groups on issues related to treatment and living with cancer . Changes in self-reported distress ( POMS-Sf ) and quality of life ( EORTC QLQ-C30 ) from baseline to 1 and 6 months ' follow-up were measured . Analyses were adjusted for baseline scores of outcome , cancer site , time since diagnosis , gender , age and education . RESULTS Of 507 patients , 452 were included in the analyses , 404 completed the 1-month and 394 the 6-month assessment . Patients in the control group showed greater decreases in total mood disturbance and subscales of the POMS-Sf and showed more improvement in emotional , cognitive and social functioning at both 1 and 6 months and in role functioning at 6 months than the intervention group . A similar pattern was observed in analyses of breast cancer patients only . CONCLUSION A 6-day residential rehabilitation course did not relieve cancer patients ' distress or improve their well-being [22399076] Background : Neuroendocrine dysregulation influenced by psychosocial stress is related to breast cancer recurrence . Very few studies examine the impacts of psychotherapy on diurnal cortisol patterns among breast cancer survivors . Methods : Forty-eight breast cancer patients who completed active cancer treatment were r and omly assigned to receive either 8 weekly body-mind-spirit ( BMS ) group therapy sessions or 1 educational ( EDU ) session . Self-report measures included the Beck Depression Inventory-II ( BDI-II ) , and the Meaning in Life question naire ( MLQ ) including two subscales : MLQ-Presence and MLQ- Search . Salivary cortisol levels were collected by the subjects in their homes at the time of awakening , 30 and 45 min after awakening , and at 12.00 , 17.00 , and 21.00 h. Measurement time points include baseline , the 2nd month ( completion of BMS therapy ) , the 5th month , and the 8th month . Results : There were no significant differences in BDI-II scores ( p>0.05 ) and MLQ-Presence scores ( p > 0.05 ) between BMS and EDU groups at baseline or across the three follow-ups . Nevertheless , greater MLQ- Search scores were found in the BMS group compared to the EDU group during the 5th month of follow-up ( p < 0.01 ) . The higher level of cortisol at 21.00 h ( p < 0.01 ) and a flatter diurnal cortisol pattern were more likely to occur in EDU than in BMS participants ( p < 0.05 ) at the 8th month of follow-up . Conclusion : BMS group therapy likely contributed to enhancing an active search for meaning in life toward more opportunities for personal growth and to maintaining stable cortisol responses to everyday life stress for breast cancer survivors [11336241] There has been much interest in the psychosocial issues faced by breast cancer patients because of the high prevalence of the disease and the severe psychological impact of the cancer itself , as well as its treatment . The objective of our study was to investigate the determinants of psychiatric morbidity among postoperative ambulatory breast cancer patients . The variables examined included the patients ' biomedical characteristics , demographic characteristics , current concerns , coping responses and social support factors . Patients Completed the Hospital Anxiety and Depression Scale ( HADS ) and the Mental Adjustment to Cancer scale ( MAC scale ) , and information pertaining to demographic variables , current concerns and social support factors was obtained by a specially design ed question naire . Available data were obtained from 148 r and omly selected postoperative ambulatory breast cancer patients . The prevalence of psychiatric morbidity ( including clinical anxiety and depression ) evaluated by using the HADS cut-off point was 23 % . The results of univariate analyses indicated that pain , dyspnea , having children with health problems , various other concerns ( about children , other family members , the patients ' own health and future treatment ) and poor coping responses ( low fighting spirit , high anxious preoccupation , high fatalism and high helplessness/hopelessness ) were significant determinants of the patients ' psychiatric morbidity . Additionally , in the logistic regression analysis , having children with health problems and having a low fighting spirit and a high helplessness/hopelessness were final significant determinants . Postoperative ambulatory breast cancer patients with these problems should be given careful attention , and psychosocial intervention may be beneficial for them [19941285] OBJECTIVE To determine whether a telephone counseling program can improve psychosocial outcomes among breast cancer patients post-treatment . METHODS A r and omized trial was conducted involving 21 hospitals and medical centers , with assessment s ( self-administered question naires ) at baseline , 12 and 18 months post-enrollment . Eligibility criteria included early stage diagnosis , enrollment during last treatment visit , and the ability to receive the intervention in English . Endpoints included distress ( Impact of Event Scale ) , depression ( Center for Epidemiologic Studies Depression Scale ) , and two study -specific measures : sexual dysfunction and personal growth . The control group ( n=152 ) received a re source directory for breast cancer ; the intervention group ( n=152 ) also received a one-year , 16 session telephone counseling program augmented with additional print material s. RESULTS Significant intervention effects were found for sexual dysfunction at 12 ( p=0.03 ) and 18 months ( p=0.04 ) and personal growth ( 12 months : p=0.005 ; 18 months : p=0.03 ) . No differences by group were found in mean scores for distress and depression , with both groups showing significant improvement at 12 and 18 months ( all p values for within-group change from baseline were < or=0.003 ) . However , when dichotomized at cutpoints suggestive of the need for a clinical referral , the control group showed virtually no change at 18 months , whereas the intervention group showed about a 50 % reduction in both distress ( p=0.07 ) and depression ( p=0.06 ) . CONCLUSIONS Telephone counseling may provide a viable method for extending psychosocial services to cancer survivors nationwide [10939175] Patients with breast cancer who undergo autologous bone marrow/peripheral blood stem cell transplantation ( ABMT ) cope not only with a life-threatening medical treatment , but also with multiple , interrelated symptoms including pain , fatigue , psychological distress , and nausea . The purpose of this study was to determine , in a r and omized controlled clinical trial , whether a comprehensive coping strategy program ( CCSP ) was effective in significantly reducing pain , fatigue , psychological distress , and nausea in patients with breast cancer who underwent ABMT . The CCSP was composed of preparatory information , cognitive restructuring , and relaxation with guided imagery . R and omization placed 52 patients in the CCSP treatment group and 58 patients in the control group . The CCSP was found to be effective in significantly reducing nausea as well as nausea combined with fatigue 7 days after the ABMT when the side effects of treatment were most severe . These results are important given the high incidence of nausea and fatigue in the ABMT population . The CCSP-treated group experienced mild anxiety as compared with the control group who reported moderate anxiety . The greatest effectiveness of CCSP may correspond to the time of the greatest morbidity for patients with breast cancer who have undergone ABM [90871] A prospect i ve , multidisciplinary , 5-year study of 69 consecutive female patients with early ( T0,1N0,1M0 ) breast cancer was conducted . Patients ' psychological responses to the diagnosis of cancer were assessed 3 months postoperatively . These responses were related to outcome 5 years after operation . Recurrence-free survival was significantly common among patients who had initially reacted to cancer by denial or who had a fighting spirit than among patients who had responded with stoic acceptance or feelings of helplessness and hopelessness [20974079] BACKGROUND Throughout the illness trajectory , women with breast cancer experience issues that are related to physical , emotional , and social adjustment . Despite a general consensus that state-of-the-art treatment for breast cancer should include educational and counseling interventions to reduce illness or treatment-related symptoms , there are few prospect i ve , theoretically based , phase-specific r and omized , controlled trials that have evaluated the effectiveness of such interventions in promoting adjustment . PURPOSE The aim of this study is to examine the physical , emotional , and social adjustment of women with early-stage breast cancer who received psychoeducation by videotapes , telephone counseling , or psychoeducation plus telephone counseling as interventions that address the specific needs of women during the diagnostic , postsurgery , adjuvant therapy , and ongoing recovery phases of breast cancer . DESIGN Primary data from a r and omized controlled clinical trial . SETTING Three major medical centers and one community hospital in New York City . METHODS A total of 249 patients were r and omly assigned to either the control group receiving usual care or to one of the three intervention groups . The interventions were administered at the diagnostic , postsurgery , adjuvant therapy , and ongoing recovery phases . Analyses were based on a mixed model analysis of variance . MAIN RESEARCH VARIABLES AND MEASUREMENT : Physical adjustment was measured by the side effects incidence and severity subscales of the Breast Cancer Treatment Response Inventory ( BCTRI ) and the overall health status score of the Self-Rated Health Subscale of the Multilevel Assessment Instrument . Emotional adjustment was measured using the psychological well-being subscale of the Profile of Adaptation to Life Clinical Scale and the side effect distress subscale of BCTRI . Social adjustment was measured by the domestic , vocational , and social environments subscales of the Psychosocial Adjustment to Illness Scale . FINDINGS Patients in all groups showed improvement over time in overall health , psychological well-being , and social adjustment . There were no significant group differences in physical adjustment , as measured by side effect incidence , severity , or overall health . There was poorer emotional adjustment over time in the usual care ( control ) group as compared to the intervention groups on the measure of side effect distress . For the telephone counseling group , there was a marked decline in psychological well-being from the adjuvant therapy phase through the ongoing recovery phase . There were no significant group differences in the dimensions of social adjustment . CONCLUSION The longitudinal design of this study has captured the dynamic process of adjustment to breast cancer , which in some aspects and at various phases has been different for the control and intervention groups . Although patients who received the study interventions improved in adjustment , the overall conclusion regarding physical , emotional , and social adjustment is that usual care , which was the st and ard of care for women in both the usual care ( control ) and intervention groups , supported their adjustment to breast cancer , with or without additional interventions . IMPLICATION S FOR NURSING The results are important to evidence -based practice and the determination of the efficacy and cost-effectiveness of interventions in improving patient outcomes . There is a need to further examine adjustment issues that continue during the ongoing recovery phase . KEY POINTS Psychoeducation by videotapes and telephone counseling decreased side effect distress and side effect severity and increased psychological well-being during the adjuvant therapy phase . All patients in the control and intervention groups improved in adjustment . Adjustment issues are still present in the ongoing recovery phase [18702064] OBJECTIVE Although women 's breast cancer affects both women and their male partners , as well as their relationships , few interventions have been developed to work with couples confronting breast cancer . The current investigation presents the pilot results from a new couple-based intervention program for breast cancer that teaches couples how to minimize negative effects and maximize positive functioning during this difficult time . METHOD In this pilot study , 14 couples in which the wife had early stage breast cancer were r and omly assigned to one of the two treatment conditions : Couple-based relationship enhancement ( RE ) or treatment-as-usual ( TAU ) . RESULTS The results from this study suggest that compared with couples receiving treatment-as-usual , both women and men in the RE condition experienced improved functioning on individual psychological variables as well as relationship functioning at posttest and 1-year follow-up . In addition , women in RE show fewer medical symptoms at both time periods . CONCLUSIONS In this pilot study , the couple-based intervention , RE , has shown promise in improving individual , medical , and relationship functioning for couples in which the woman is facing breast cancer , and therefore merits further investigation on a larger scale

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### Context: [3305975] Background : Despite thous and s of papers , the value of quality of life ( QoL ) in curing disease remains uncertain . Until now , we lacked tools for the diagnosis and specific treatment of diseased QoL. We approached this problem stepwise by theory building , modelling , an exploratory trial and now a definitive r and omised controlled trial ( RCT ) in breast cancer , whose results we report here . Methods : In all , 200 representative Bavarian primary breast cancer patients were recruited by five hospitals and treated by 146 care professionals . Patients were r and omised to either ( 1 ) a novel care pathway including diagnosis of ‘ diseased ’ QoL ( any QoL measure below 50 points ) using a QoL profile and expert report sent to the patient 's coordinating practitioner , who arranged QoL therapy consisting of up to five st and ardised treatments for specific QoL defects or ( 2 ) st and ard postoperative care adhering to the German national guideline for breast cancer . The primary end point was the proportion of patients in each group with diseased QoL 6 months after surgery . Patients were blinded to their allocated group . Results : At 0 and 3 months after surgery , diseased QoL was diagnosed in 70 % of patients . The QoL pathway reduced rates of diseased QoL to 56 % at 6 months , especially in emotion and coping , compared with 71 % in controls ( P=0.048 ) . Relative risk reduction was 21 % ( 95 % confidence interval ( CI ) : 0–37 ) , absolute risk reduction 15 % ( 95 % CI : 0.3–29 ) , number needed to treat (NNT)=7 ( 95 % CI : 3–37 ) . When QoL therapy finished after successful treatment , diseased QoL often returned again , indicating good responsiveness of the QoL pathway . Conclusion : A three-component outcome system including clinician-derived objective , patient-reported subjective end points and qualitative analysis of clinical relevance was developed in the last 10 years for cancer as a complex intervention . A separate QoL pathway was implemented for the diagnosis and treatment of diseased QoL and its effectiveness tested in a community-based , pragmatic , definitive RCT . While the pathway was active , it was effective with an NNT of 7 [15712339] In a r and omized controlled design , this study tested the efficacy of a theoretically based uncertainty management intervention delivered to older long-term breast cancer survivors . The sample included 509 recurrence-free women ( 360 Caucasian , 149 African-American women ) with a mean age of 64 years ( S.D.=8.9 years ) who were 5 - 9 years post-treated for breast cancer . Women were r and omly assigned to either the intervention or usual care control condition . The intervention was delivered during four weekly telephone sessions , in which study nurses guided cancer survivors in the use of audiotaped cognitive-behavioral strategies to manage uncertainty about recurrence , and a self-help manual design ed to help women underst and and manage long-term treatment side effects and other symptoms . Treatment outcome data on uncertainty management were gathered at pre-intervention and 10-months afterward . Repeated measures MANOVA evaluating treatment group , ethnic group , and treatment by ethnic interaction effects indicated that training in uncertainty management result ed in improvements in cognitive reframing , cancer knowledge , patient-health care provider communication , and a variety of coping skills . Results are discussed in terms of the importance of theory-based interventions for cancer survivors that target triggers of uncertainty about recurrence and in terms of ethnic differences in response to the intervention [3172715] Objectives : The internet offers new possibilities in psychosocial patient care . However , empirical data are lacking for oncological patients . A field-experimental study was conducted to obtain initial data to enable evaluation of the effectiveness of online counseling via e-mail for breast cancer patients . A secondary objective was to explore how patients reached by the service can be characterized on psychosocial status and illness . Methods : On a dedicated German- language website , 235 breast cancer patients registered for psychosocial counseling via e-mail . 133 registrants were r and omly assigned to a treatment group to receive immediate counseling or to a waiting list control group . The two-month counseling session took the form of a psychoeducation , individually tailored to each patient . Psychosocial outcome measures including psychological distress ( BSI ) and quality of life ( EORTC QLQ-C30 ) were assessed at registration and at a two-month follow-up . Descriptive data were recorded at registration . At the conclusion of the program , participants were asked to complete a patient satisfaction question naire ( ZUF-8 ) . Results : BSI responses showed that 85 % of all patients were initially diagnosable with comorbid psychopathology . Despite high severity of distress and attendant large reductions in quality of life , 72 % of all patients were not obtaining conventional assistance . Among counseling participants ( n=31 ) , no significant improvements in distress or quality of life were found in comparison to the control group ( n=34 ) , but patient satisfaction was nonetheless high . Conclusion : The study demonstrates that online counseling via e-mail reaches patients with unmet therapeutic needs , but also indicated its limitations , suggesting that the online setting may be most useful for prompting and supporting a transition to conventional counseling services [16135471] PURPOSE To evaluate the efficacy of a psychoeducational intervention in improving cancer-related fatigue . PATIENTS AND METHODS This r and omized controlled trial involved 109 women commencing adjuvant chemotherapy for stage I or II breast cancer in five chemotherapy treatment centers . Intervention group patients received an individualized fatigue education and support program delivered in the clinic and by phone over three 10- to 20-minute sessions 1 week apart . Instruments included a numeric rating scale assessing confidence with managing fatigue ; 11-point numeric rating scales measuring fatigue at worst , average , and best ; the Functional Assessment of Cancer Therapy-Fatigue and Piper Fatigue Scales ; the Cancer Self-Efficacy Scale ; the European Organisation for Research and Treatment of Cancer Quality of Life Question naire C30 ; and the Hospital Anxiety and Depression Scale . For each outcome , separate analyses of covariance of change scores between baseline ( T1 ) and the three follow-up time points ( T2 , T3 , and T4 ) were conducted , controlling for the variable 's corresponding baseline value . RESULTS Compared with the intervention group , mean difference scores between the baseline ( T1 ) and immediate after the test ( T2 ) assessment s increased significantly more for the control group for worst and average fatigue , Functional Assessment of Cancer Therapy-Fatigue , and Piper fatigue severity and interference measures . These differences were not observed between baseline and T3 and T4 assessment s. No significant differences were identified for any pre- or post-test change scores for confidence with managing fatigue , cancer self-efficacy , anxiety , depression , or quality of life . CONCLUSION Preparatory education and support has the potential to assist women to cope with cancer-related fatigue in the short term . However , further research is needed to identify ways to improve the potency and sustainability of psychoeducational interventions for managing cancer-related fatigue [17935144] OBJECTIVE The aim is to evaluate the effectiveness of a manualized 12-week supportive-expressive group therapy program among primary breast cancer patients treated in community setting s , to determine whether highly distressed patients were most likely to benefit and whether therapist 's training or experience was related to outcome . METHOD Three hundred and fifty-three women within one year of diagnosis with primary breast cancer were r and omly assigned to receive supportive-expressive group therapy or to an education control condition . Participants were recruited from two academic centers and nine oncology practice s , which were members of NCI 's Community Clinical Oncology Program ( CCOP ) and were followed over 2 years . RESULTS A 2x2x19 analysis of variance was conducted with main effects of treatment condition , cohort , and baseline distress and their interactions . There was no main effect for treatment condition after removing one subject with an extreme score . Highly distressed women did not derive a greater benefit from treatment . Therapist training and psychotherapy experience were not associated with a treatment effect . CONCLUSIONS This study provides no evidence of reduction in distress as the result of a brief supportive-expressive intervention for women with primary breast cancer . Future studies might productively focus on women with higher initial levels of distress [19016270] The question of whether stress poses a risk for cancer progression has been difficult to answer . A r and omized clinical trial tested the hypothesis that cancer patients coping with their recent diagnosis but receiving a psychologic intervention would have improved survival compared with patients who were only assessed [19235193] OBJECTIVES Considerable morbidity persists among survivors of breast cancer ( BC ) including high levels of psychological stress , anxiety , depression , fear of recurrence , and physical symptoms including pain , fatigue , and sleep disturbances , and impaired quality of life . Effective interventions are needed during this difficult transitional period . METHODS We conducted a r and omized controlled trial of 84 female BC survivors ( Stages 0-III ) recruited from the H. Lee Moffitt Cancer and Research Institute . All subjects were within 18 months of treatment completion with surgery and adjuvant radiation and /or chemotherapy . Subjects were r and omly assigned to a 6-week Mindfulness-Based Stress Reduction ( MBSR ) program design ed to self-regulate arousal to stressful circumstances or symptoms ( n=41 ) or to usual care ( n=43 ) . Outcome measures compared at 6 weeks by r and om assignment included vali date d measures of psychological status ( depression , anxiety , perceived stress , fear of recurrence , optimism , social support ) and psychological and physical subscales of quality of life ( SF-36 ) . RESULTS Compared with usual care , subjects assigned to MBSR(BC ) had significantly lower ( two-sided p<0.05 ) adjusted mean levels of depression ( 6.3 vs 9.6 ) , anxiety ( 28.3 vs 33.0 ) , and fear of recurrence ( 9.3 vs 11.6 ) at 6 weeks , along with higher energy ( 53.5 vs 49.2 ) , physical functioning ( 50.1 vs 47.0 ) , and physical role functioning ( 49.1 vs 42.8 ) . In stratified analyses , subjects more compliant with MBSR tended to experience greater improvements in measures of energy and physical functioning . CONCLUSIONS Among BC survivors within 18 months of treatment completion , a 6-week MBSR(BC ) program result ed in significant improvements in psychological status and quality of life compared with usual care [9024474] The effects of 8-week cancer support groups ( CSGs ) with and without coaching on adaptation were tested in a sample of 181 women with newly diagnosed early stage breast cancer . CSG participation with coaching result ed in higher quality of relationship with significant other at CSG conclusion ; this effect was not sustained 8 weeks later . CSG participation had no effect on symptom distress , emotional distress , or functional status . On average , symptom distress was low , emotional distress was moderate , and functional status was relatively high . Independent of CSGs , symptom distress decreased and functional status increased over time from entry into the study to 16 weeks later . Further research is needed to determine the optimal starting time and length for CSGs [23081984] OBJECTIVE The current report provides the result of a Phase II clinical trial regarding the effectiveness and feasibility of problem-solving therapy for psychological distress experienced by Japanese early-stage breast cancer patients . METHODS Participants were 36 post-surgery Japanese breast cancer patients in a university hospital located in Osaka Prefecture , Japan . After screening for psychological distress using the Distress and Impact Thermometer and the Hospital Anxiety and Depression Scale , highly distressed patients were exposed to 5 weekly sessions of the problem-solving therapy program . RESULTS Nineteen patients completed the intervention and follow-up . There was a significant difference between the pre-intervention and the 3-month follow-up in the total Hospital Anxiety and Depression Scale score ( P = 0.02 ) , and the mean change score from the pre-intervention to the follow-up was 6.05 ( SD = 1.94 ) . The intervention had a large effect size ( d = 0.82 ) . There were also significant changes in worry , self-efficacy and quality of life measures . CONCLUSIONS The findings of our study suggest that the problem-solving therapy program has potential to be effective for alleviating psychological distress experienced by Japanese early-stage breast cancer patients . The true effectiveness of the program should be confirmed by a future r and omized control trial [21458989] PURPOSE To test the effectiveness of a psycho-educational group intervention to improve psychological distress measured by POMS TMD , Quality of Life measured by European Organisation for Research and Treatment of Cancer ( EORTC ) , the core and breast cancer module , Mental Adjustment measured by MAC and marital relationship measured by BLRI in women with primary breast cancer conducted 10 weeks after surgery . A secondary outcome was 4-year survival . PATIENTS AND METHODS We r and omly assigned 210 patients with primary breast cancer to a control or an intervention group . Patients in the intervention group were offered two weekly 6-h sessions of psycho-education and eight weekly 2-h sessions of group psychotherapy . All participants were followed up for Quality of Life , coping ability and social relations 1 , 6 and 12 months after the intervention and on survival 4 years after surgical treatment . RESULTS No statistically significant effects of the intervention were found on any of the psychosocial question naire outcomes . There were not enough cases of death to analyse overall survival . The only statistically significant result was for patients who used anti depressive medication , for whom almost all measures improved over time , in both the control and intervention groups . CONCLUSION Psycho-education and group psychotherapy did not decrease psychological distress or increase Quality of Life , Mental Adjustment or improve marital relationship among patients with primary breast cancer [12424783] A Roy adaptation model-based support and education intervention for women with early-stage breast cancer was tested in a three-group , three-phase r and omized clinical trial of a sample of 125 women . The experimental group received 13 months of combined individual telephone and in-person group support and education , Control Group 1 received 13 months of telephone-only individual support and education , and Control Group 2 received one-time mailed educational information . The experimental group and Control Group 1 reported less mood disturbance at the end of all three phases , less loneliness at the end of Phases II and III , and a higher- quality relationship with a significant other at the end of Phase II than did Control Group 2 . No group differences were found for cancer-related worry or well-being . The findings suggest that individual telephone support may provide an effective alternative to in-person support groups . Further study of telephone interventions is recommended using ethnically and economically heterogeneous sample [19622708] Objectives : To test experimentally whether a psychological intervention reduces depression-related symptoms and markers of inflammation among cancer patients and to test one mechanism for the intervention effects . Depression and inflammation are common among cancer patients . Data suggest that inflammation can contribute to depressive symptoms , although the converse remains untested . Methods : As part of a r and omized clinical trial , newly diagnosed breast cancer patients ( n = 45 ) with clinical ly significant depressive symptoms were evaluated and r and omized to psychological intervention with assessment or assessment only study arms . The intervention spanned 12 months , with assessment s at baseline , 4 , 8 , and 12 months . Mixed-effects modeling tested the hypothesis that the intervention reduced self-reported depressive symptoms ( Center for Epidemiological Studies Depression scale , Profile of Mood States Depression and Fatigue subscales , and Medical Outcomes Study -Short Form 36 Bodily Pain subscale ) and immune cell numbers that are elevated in the presence of inflammation ( white blood cell count , neutrophil count , and helper/suppressor ratio ) . Mediation analyses tested whether change in depressive symptoms , pain , or fatigue predicted change in white blood cell count , neutrophil count , or the helper/suppressor ratio . Results : The intervention reduced significantly depressive symptoms , pain , fatigue , and inflammation markers . Moreover , the intervention effect on inflammation was mediated by its effect on depressive symptoms . Conclusions : This is the first experiment to test whether psychological treatment effective in reducing depressive symptoms would also reduce indicators of inflammation . Data show that the intervention reduced directly depressive symptoms and reduced indirectly inflammation . Psychological treatment may treat effectively depressive symptoms , pain , and fatigue among cancer patients . CES-D = Center for Epidemiological Studies -Depression scale , Iowa short form ; SF-36 = Medical Outcomes Study -Short Form 36 ; KPS = Karnofsky Performance Status [16442463] OBJECTIVE The importance of psychosocial counselling after a diagnosis of cancer has been acknowledged and many intervention studies have been carried out , with the aim to find out which types of intervention are most effective in enhancing quality of life in cancer patients . A factor which could be part of effective counselling could be the time of offering psychosocial counselling . The aim of this study was to research the effect of time of enrolment in a psychosocial group intervention on psychosocial adjustment . METHODS In the present study , 67 women with early stage breast cancer were r and omised in a psychosocial group intervention program starting within 4 months after surgery or in the same intervention program starting at least 3 months later . RESULTS The main conclusion of this study is that women who started with their intervention early were less distressed at 6 months follow-up than women who were in the delayed condition . Medical and demographic variables were predictive for some psychosocial adjustment indicators , but were not associated with time of enrolment . Regardless of time of enrolment , women improved in distress , body image and recreational activities , but showed a decrease in social interaction . CONCLUSION Though results are limited , based on these results we suggest that psychosocial counselling should be offered as soon after diagnosis or surgery for breast cancer . PRACTICE IMPLICATION S Women diagnosed with primary breast cancer should be able to start with psychological counselling soon after being diagnosed , to prevent them from becoming distressed at long term [14987957] OBJECTIVE This study examined the effect of a cognitive-behavioral stress management ( CBSM ) intervention on emotional well-being and immune function among women in the months following surgery for early-stage breast cancer . METHOD Twenty-nine women were r and omly assigned to receive either a 10-week CBSM intervention ( n=18 ) or a comparison experience ( n=11 ) . The primary psychological outcome measure was benefit finding . The primary immune function outcome measure was in vitro lymphocyte proliferative response to anti CD3 . RESULTS Women in the CBSM intervention reported greater perceptions of benefit from having breast cancer compared to the women in the comparison group . At 3-month follow-up , women in the CBSM group also had improved lymphocyte proliferation . Finally , increases in benefit finding after the 10-week intervention predicted increases in lymphocyte proliferation at the 3-month follow-up . CONCLUSION A CBSM intervention for women with early-stage breast cancer facilitated positive emotional responses to their breast cancer experience in parallel with later improvement in cellular immune function [18544286] In a phase I National Cancer Institute (NCI)-funded clinical trial , 34 breast cancer survivors , six weeks to one year post-treatment , were recruited to participate in a 6-class , 8-week long imagery stress reduction program entitled " Envision the Rhythms of Life . " Patients practice d imagery during and between sessions . Outcomes for quality of life and cortisol rhythm were assessed pre- to post-intervention , in two subsets of survivors ( intravenous [ IV ] chemotherapy , or no IV chemotherapy ) . Thirty survivors completed the 8-week program . Quality of life outcomes demonstrated statistically and clinical ly significant outcomes for the functional assessment of cancer therapy-general ( FACT-G ) global index ( p<.001 ) , representing improvements in survivor quality of life related to physical , social/family , emotional , and function well-being . Survivors also improved significantly on the breast cancer ( p<.001 ) and spiritual subscales ( p = .008 . ) Brief symptom inventory ( BSI ) assessment reported significant improvement for the global index ( p<.001 ) which included the categories of depression , somatization and anxiety . At eight weeks , cortisol rhythm , a biochemical indicator of stress and likelihood of cancer recurrence , produced a trend toward improvement for the fifth time point of the day ( p = .18 ) . Likert-based stress scales showed highly significant reductions in stress ( p<.0001 ) with subjects practicing imagery the most producing the best scores . Outcomes suggest the imagery program may significantly improve survivor quality of life and reduce stress [21831722] UNLABELLED This r and omized controlled trial assessed the effect of a SMART ( Stress Management and Resiliency Training ) program among 25 women diagnosed with breast cancer . Resilience , perceived stress , anxiety , and quality of life improved at 12 weeks in the active but not the control arm . A brief training in the SMART program can enhance resilience and quality of life and decrease stress and anxiety . INTRODUCTION Patients with breast cancer experience stress and anxiety related to their diagnosis , with result ing lower quality of life . The purpose of this study was to assess the effect of a SMART ( Stress Management and Resiliency Training ) program for increasing resiliency and for decreasing stress and anxiety among mentors who themselves were previously diagnosed with breast cancer . MATERIAL S AND METHODS The program consisted of two 90-minute group training sessions , a brief individual session , and 3 follow-up telephone calls . Twenty-four mentors at Mayo Clinic in Rochester , Minnesota , were r and omized in a single-blind , wait-list controlled clinical trial to either the SMART intervention or a control group for 12 weeks . Primary outcome measures assessed at baseline and at week 12 included the Connor Davidson Resilience Scale , Perceived Stress Scale , Smith Anxiety Scale , and Linear Analog Self Assessment Scale . RESULTS Twenty patients completed the study . A statistically significant improvement in resilience , perceived stress , anxiety , and overall quality of life at 12 weeks , compared with baseline was observed in the study arm . No significant difference in any of these measures was noted in the control group . CONCLUSION This study demonstrates that a brief , predominantly group-based resilience training intervention is feasible in patients with previous breast cancer ; also , it may be efficacious [18061756] OBJECTIVE Treatment of breast cancer is usually associated with significant psychological stress . In this study , we examined the effects of relaxation and visualization therapy ( RVT ) on psychological distress , cortisol levels , and immunological parameters of breast cancer patients undergoing radiotherapy . METHODS Participants were r and omly assigned to either the experimental ( n=20 ) who underwent group RVT for 24 consecutive days or control group ( n=14 ) who were on radiotherapy only . Psychological scores ( stress , anxiety , and depression ) were measured by structured clinical interviews . Salivary cortisol was assessed along the day . Lymphocytes were isolated and cultured to measure T-cell proliferation and sensitivity to glucocorticoids ( GCs ) . RESULTS RVT was effective to reduce stress , anxiety , and depression scores ( all P<.05 ) . However , cortisol levels as well as proliferation remained unchanged following RVT . Although T cells of experimental group were more sensitive to GCs than cells of controls at baseline , no changes were noted following RVT . Cortisol levels were positively correlated to anxiety and depression scores and inversely correlated to T-cell proliferation and sensitivity to GCs . CONCLUSION We conclude that the psychological intervention was capable to attenuate the emotional distress presented during radiotherapy treatment . A longer RVT or worse psychological morbidity at baseline may be necessary to translate psychological into biological changes [11570653] The authors report a 3-year follow-up of the effects of 8-week support group interventions on the quality of life of women with early stage breast cancer . Shortly after diagnosis , women were r and omly assigned to 1 of 4 conditions : control , education , peer discussion , and education plus peer discussion . The education group intervention focused on providing information to enhance control over the illness experience , whereas the peer discussion group intervention focused on providing emotional support through the expression of feelings . Consistent with the results that emerged 6 months after the interventions ( V. S. Helgeson , S. Cohen , R. Schulz , & J. Yasko , 1999 ) , the authors found that the benefits of the education intervention were maintained over a 3-year period ( N=252 ) , although effects dissipated with time . The authors continued to find no benefits of the peer discussion intervention , either alone or in combination with education [15337807] PURPOSE This r and omized clinical trial tests the hypothesis that a psychological intervention can reduce emotional distress , improve health behaviors and dose-intensity , and enhance immune responses . PATIENTS AND METHODS We studied 227 women who were surgically treated for regional breast cancer . Before adjuvant therapy , women completed interviews and question naires assessing emotional distress , social adjustment , and health behaviors . A 60-mL blood sample was drawn for immune assays . Patients were r and omly assigned to either the intervention group or assessment only group . The intervention was conducted in small patient groups , with one session per week for 4 months . The sessions included strategies to reduce stress , improve mood , alter health behaviors , and maintain adherence to cancer treatment and care . Re assessment occurred after completion of the intervention . RESULTS As predicted , patients receiving the intervention showed significant lowering of anxiety , improvements in perceived social support , improved dietary habits , and reduction in smoking ( all P < .05 ) . Analyses of adjuvant chemotherapy dose-intensity revealed significantly more variability ( ie , more dispersion in the dose-intensity values ) for the assessment arm ( P < .05 ) . Immune responses for the intervention patients paralleled their psychological and behavioral improvements . T-cell proliferation in response to phytohemagglutinin and concanavalin A remained stable or increased for the Intervention patients , whereas both responses declined for Assessment patients ; this effect was replicated across three concentrations for each assay ( all P < .01 ) . CONCLUSION These data show a convergence of significant psychological , health behavior , and biologic effects after a psychological intervention for cancer patients [16492649] Abstract The survivor uncertainty management intervention study is a r and omized controlled study design ed to test the efficacy of an intervention that combines training in audiotaped cognitive behavioral strategies to manage uncertainty about cancer recurrence with a self-help manual design ed to help women underst and and manage long-term treatment side effects and other symptoms . Specifically , women were taught to recognize their own personal triggers of uncertainty ( places , events or surroundings , that bring back memories , feelings , or concerns about breast cancer ) , and then use coping skills such as relaxation , distraction , and calming self-talk to deal with uncertainty . Also , women were taught to use the manual as a re source for dealing with fatigue , lymphedema , pain and other symptoms . Treatment outcome data ( Mishel et al. , in press ) indicated that the uncertainty management intervention result ed in improvements in cognitive reframing , cancer knowledge , social support , knowledge of symptoms and side effects , and coping skills when compared to a control condition . The purpose of the present paper was to report on the use and helpfulness of the intervention components by the 244 women who were in the intervention . Findings indicated that women regularly used the intervention components to deal with triggers of breast cancer recurrence and long-term treatment side effects and most women found the strategies very helpful [12923794] BACKGROUND We conducted a r and omised , controlled trial of cognitive-existential group therapy ( CEGT ) for women with early stage breast cancer receiving adjuvant chemotherapy with the aim of improving mood and mental attitude to cancer . METHODS Women were r and omised to 20 sessions of weekly group therapy plus 3 relaxation classes or to a control arm receiving 3 relaxation classes . Assessment s , independently done at baseline , 6 and 12 months , included a structured psychiatric interview and vali date d question naires covering mood , attitudes to cancer , family relationships , and satisfaction with therapy . RESULTS Three hundred and three of 491 ( 62 % ) eligible patients participated over 3 years . Distress was high pre-intervention : 10 % were diagnosed as suffering from major depression , 27 % from minor depression and 9 % from anxiety disorders . On an intention-to-treat analysis , there was a trend for those receiving group therapy ( n=154 ) to have reduced anxiety ( p=0.05 , 2-sided ) compared to controls ( n=149 ) . Women in group therapy also showed a trend towards improved family functioning compared to controls ( p=0.07 , 2-sided ) . The women in the groups reported greater satisfaction with their therapy ( p<0.001 , 2-sided ) , appreciating the support and citing better coping , self-growth and increased knowledge about cancer and its treatment . They valued the CEGT therapy . Overall effect size for the group intervention was small ( d=0.25 ) , with cancer recurrence having a deleterious effect in three of the 19 therapy groups . Psychologists as a discipline achieved a moderate mean effect size ( d=0.52 ) . CONCLUSION CEGT is a useful adjuvant psychological therapy for women with early stage breast cancer . Interaction effects between group members and therapists are relevant to outcome . Group-as-a-whole effects are powerful , but the training and experience of the therapist is especially critical to an efficacious outcome [17311247] PURPOSE The r and omized study aim ed to determine the efficacy of psychological intervention consisting of relaxation and guided imagery to reduce anxiety and depression in gynecologic and breast cancer patients undergoing brachytherapy during hospitalization . METHODS AND MATERIAL S Sixty-six patients programmed to receive brachytherapy in two hospitals in Barcelona ( Spain ) were included in this study . The patients were r and omly allocated to either the study group ( n=32 ) or the control group ( n=34 ) . Patients in both groups received training regarding brachytherapy , but only study group patients received training in relaxation and guided imagery . After collection of sociodemographic data , all patients were given a set of question naires on anxiety and depression : the Hospital Anxiety and Depression Scale ( HADS ) , and on quality of life : Cuestionario de Calidad de Vida QL-CA-AFex ( CCV ) , prior to , during and after brachytherapy . RESULTS The study group demonstrated a statistically significant reduction in anxiety ( p=0.008 ) , depression ( p=0.03 ) and body discomfort ( p=0.04 ) compared with the control group . CONCLUSIONS The use of relaxation techniques and guided imagery is effective in reducing the levels of anxiety , depression and body discomfort in patients who must remain isolated while undergoing brachytherapy . This simple and inexpensive intervention enhances the psychological wellness in patients undergoing brachytherapy . State : This study has passed Ethical Committee review [21988544] OBJECTIVE Major depression is the most common psychiatric disorder among breast cancer patients and is associated with substantial impairment . Although some research has explored the utility of psychotherapy with breast cancer patients , only 2 small trials have investigated the potential benefits of behavior therapy among patients with well-diagnosed depression . METHOD In a primarily Caucasian , well-educated sample of women ( age = 55.4 years , SD = 11.9 ) diagnosed with breast cancer and major depression ( n = 80 ) , this study was a r and omized clinical trial testing the efficacy of 8 sessions of behavioral activation treatment for depression ( BATD ) compared to problem-solving therapy . Primary outcome measures assessed depression , environmental reward , anxiety , quality of life , social support , and medical outcomes . RESULTS Across both treatments , results revealed strong treatment integrity , excellent patient satisfaction with treatment protocol s , and low patient attrition ( 19 % ) . Intent-to-treat analyses suggested both treatments were efficacious , with both evidencing significant pre-post treatment gains across all outcome measures . Across both treatments , gains were associated with strong effect sizes , and based on response and remission criteria , a reliable change index , and numbers-needed-to-treat analyses , approximately ¾ of patients exhibited clinical ly significant improvement . No significant group differences were found at posttreatment . Treatment gains were maintained at 12-month follow-up , with some support for stronger maintenance of gains in the BATD group . CONCLUSIONS BATD and problem-solving interventions represent practical interventions that may improve psychological outcomes and quality of life among depressed breast cancer patients . Study limitations and future research directions are discussed [22383279] OBJECTIVE This study evaluated the psychological effects of a pre-surgical stress management training ( SMT ) in cancer patients . METHODS Stress management training comprised four sessions in total : on 5 days and 1 day pre-surgery and on 2 days and 1 month post-surgery . Patients also received audio CDs with relaxation and coping skills exercises . Patients were r and omly assigned to the SMT ( N = 34 ) or a regular care condition ( N = 36 ) . Depression , anxiety , quality of life , perception of control , fatigue , pain , sleep problems , and surgery-related somatic symptoms were measured at Day 6 and Day 1 pre-surgery , and Day 2 , 5 , 30 and 90 post-surgery . RESULTS Depression and fatigue decreased in the intervention group and increased in the control group , leading to significant group differences at Day 2 ( fatigue ) and Day 5 post-surgery ( fatigue and depression ) . It also appeared that surgery-related symptoms had increased more in the control group 3 months post-surgery than in the SMT group . No intervention effects were observed for anxiety , pain , and sleep problems . CONCLUSION The use of a short psychological intervention is effective in reducing depression and fatigue in the post-surgical period , although the effects are of short duration [3236414] Background . Previous integrative literature review s and meta-analyses have yielded conflicting results regarding the effectiveness of psychosocial interventions for cancer patients . Methods . An integrative review of the literature focused on 19 r and omized , controlled trials ( 2006–2011 ) was completed to examine the effectiveness of psychosocial interventions for cancer patients . Eligibility criteria : Inclusion criteria were the study was an English language r and omized controlled clinical trial . Results . Seven studies involved nurses . Eleven studies result ed in positive outcomes . Overall , study quality was limited . In eight studies the intervention was not adequately described , 7 studies did not contain a hypothesis , 4 did not include clear eligibility criteria , 10 studies did not r and omize appropriately , 9 did not list recruitment date s , 11 did not include a power analysis , 14 did not include blinded patients or data collectors , 11 did not use an intent-to-treat analysis , 10 did not clarify reasons for drop outs , and 11 did not discuss treatment fidelity . Conclusions . Future studies should build on previous findings , use comparable outcome measures , and adhere to st and ards of quality research . Qualitative studies are needed to determine what cancer patients of varied ages , cancer stages , and racial/ethnic background s believe would be an effective intervention to manage their psychosocial needs [2242455] OBJECTIVES --To assess outside a clinical trial the psychological outcome of different treatment policies in women with early breast cancer who underwent either mastectomy or breast conservation surgery depending on the surgeon 's opinion or the patient 's choice . To determine whether the extent of psychiatric morbidity reported in women who underwent breast conservation surgery was associated with their participation in a r and omised clinical trial . DESIGN -- Prospect i ve , multicentre study capitalising on individual and motivational differences among patients and the different management policies among surgeons for treating patients with early breast cancer . SETTING --12 District general hospitals , three London teaching hospitals , and four private hospitals . PATIENTS --269 Women under 75 with a probable diagnosis of stage I or II breast cancer who were referred to 22 different surgeons . INTERVENTIONS --Surgery and radiotherapy or adjuvant chemotherapy , or both , depending on the individual surgeon 's stated preferences for managing early breast cancer . MAIN OUTCOME MEASURES --Anxiety and depression as assessed by st and ard methods two weeks , three months , and 12 months after surgery . RESULTS --Of the 269 women , 31 were treated by surgeons who favoured mastectomy , 120 by surgeons who favoured breast conservation , and 118 by surgeons who offered a choice of treatment . Sixty two of the women treated by surgeons who offered a choice were eligible to choose their surgery , and 43 of these chose breast conserving surgery . The incidences of anxiety , depression , and sexual dysfunction were high in all treatment groups . There were no significant differences in the incidences of anxiety and depression between women who underwent mastectomy and those who underwent lumpectomy . A significant effect of surgeon type on the incidence of depression was observed , with patients treated by surgeons who offered a choice showing less depression than those treated by other surgeons ( p = 0.06 ) . There was no significant difference in psychiatric morbidity between women treated by surgeons who offered a choice who were eligible to choose their treatment and those in the same group who were not able to choose . Most of the women ( 159/244 ) gave fear of cancer as their primary fear rather than fear of losing a breast . The overall incidences of psychiatric morbidity in women who underwent mastectomy and those who underwent lumpectomy were similar to those found in the Cancer Research Campaign breast conservation study . At 12 months 28 % of women who underwent mastectomy in the present study were anxious compared with 26 % in the earlier study , and 27 % of women in the present study who underwent lumpectomy were anxious compared with 31 % in the earlier study . In both the present and earlier study 21 % of women who underwent mastectomy were depressed , and 19 % of women who underwent lumpectomy in the present study were depressed compared with 27 % in the earlier study . ) CONCLUSIONS --There is still no evidence that women with early breast cancer who undergo breast conservation surgery have less psychiatric morbidity after treatment than those who undergo mastectomy . Women who surrender autonomy for decision making by agreeing to participate in r and omised clinical trials do not experience any different psychological , sexual , or social problems from those women who are treated for breast cancer outside a clinical trial [22271538] OBJECTIVE To evaluate the efficacy of a brief cognitive-behavioral therapy ( CBT ) that is being developed for management of cognitive dysfunction following chemotherapy among breast cancer survivors . Memory and Attention Adaptation Training ( MAAT ) is a brief CBT design ed to improve the quality of life and function among cancer survivors with post-chemotherapy cognitive complaints . METHODS An initial , two-group ( MAAT versus waitlist , no treatment control ) , r and omized clinical trial ( RCT ) was conducted . Forty stage I and II female breast cancer survivors ( mean age = 50 ; SD = 6.4 ) were r and omized to conditions and assessed at baseline , post-treatment ( 8 weeks ) and 2-month follow-up assessment points on measures of : ( 1 ) self-reported daily cognitive failures ; ( 2 ) quality of life ; and ( 3 ) neuropsychological performance . Participants were also assessed for satisfaction with MAAT . RESULTS With education and IQ as covariates , MAAT participants made significant improvements relative to controls on the spiritual well-being subscale of the quality of life measure and on verbal memory , but statistical significance was not achieved on self-report of daily cognitive complaints . However , moderate-to-large effect sizes were observed on these outcomes . Participants gave MAAT high satisfaction ratings . CONCLUSIONS Although this initial RCT is a small study , MAAT participants appear to improve on one measure of quality of life and verbal memory performance relative to no treatment controls and rate MAAT with high satisfaction . These data are encouraging and support the continued development and evaluation of MAAT efficacy [19039808] BACKGROUND Many women with breast cancer need psychological help to cope more effectively after treatment . Cognitive and behavioural techniques are not yet well established in France . A multi-site r and omized study was conducted to evaluate the effects of a psycho-educational group intervention in this population . METHODS Two hundred and three patients , recruited after primary treatment , were r and omly assigned either to a treatment group ( psycho-educational intervention ) or to a waiting-list control group . The 8-week programme of 2 h sessions comprised of thematic discussion s , information and training in stress management techniques . Evaluation at baseline , after 8 sessions , and 1 month after programme completion , included evaluations using the STAI , POMS , MAC , EORTC QLQ-C30 and EORTC QLQ-BR23 breast module scales . RESULTS We observed a significant reduction in anxiety ( STAI , POMS ) among group participants , a reduction in anger , depression and fatigue ( POMS ) , a significant improvement in vigor and interpersonal relationships ( POMS ) , in emotional and role functioning , in health status and fatigue level ( EORTC QLQ-C30 ) . In contrast , coping strategies ( MAC ) were not significantly different between groups . No group-related negative effects were observed and the global satisfaction levels were very high . CONCLUSION This study demonstrates the feasibility and effectiveness of a psycho-educational intervention , which can accelerate the reduction of those negative affects which are present at the end of treatment . It represents an excellent complement or an alternative to individual psycho-oncologic therapeutic support , widely proposed in France , and should now be tested in groups with other types of cancer and at other disease phases [20044329] PURPOSE / OBJECTIVES To describe women 's unexpected and distressing symptom experiences after breast cancer treatment . RESEARCH APPROACH Qualitative and descriptive . SETTING Depending upon their preference , participants were interviewed in their homes or in a private office space in a nearby library . PARTICIPANTS Purposive sample of 13 women 1 - 18 years after breast cancer treatment . METHOD OLOGIC APPROACH Secondary analysis of phenomenologic data ( constant comparative method ) . MAIN RESEARCH VARIABLES Breast cancer symptom distress , ongoing symptoms , and unexpected experiences . FINDINGS Women described experiences of unexpected and distressing symptoms in the years following breast cancer treatment . Symptoms included pain , loss of energy , impaired limb movement , cognitive disturbance , changed sexual experience , and lymphedema . Four central themes were derived : living with lingering symptoms , confronting unexpected situations , losing precancer being , and feeling like a has-been . Distress intensified when women expected symptoms to disappear but symptoms persisted instead . Increased distress also was associated with sudden and unexpected situations or when symptoms elicited feelings of loss about precancer being and feelings of being a has been . Findings suggest that symptom distress has temporal , situational , and attributive dimensions . CONCLUSIONS Breast cancer survivors ' perceptions of ongoing and unexpected symptoms have important influences on quality of life . Underst and ing temporal , situational , and attributive dimensions of symptom distress empowers nurses and healthcare professionals to help breast cancer survivors prepare for subsequent ongoing or unexpected experiences in the years after breast cancer treatment . INTERPRETATION Follow-up care for breast cancer survivors should foster dialogue about ways that symptoms might emerge and that unexpected situations might occur . Prospect i ve studies are needed to examine symptom distress in terms of temporal , situational , and attributive dimensions and explore the relationship between symptom distress and psychological distress after breast cancer treatment [10197829] BACKGROUND We report a clinical trial comparing the effectiveness of education-based and peer discussion -based group interventions on adjustment to breast cancer . METHODS Women with stage I , II , or III breast cancer ( n = 312 ) were r and omly assigned to 1 of 4 group conditions : control , education , peer discussion , or education plus peer discussion ( combination ) . Seven groups ( each comprising 8 - 12 women ) were conducted in each of the 4 conditions ( 28 groups total ) . Adjustment was measured before the intervention , immediately after the intervention , and 6 months after the intervention . RESULTS Consistently positive effects on adjustment were seen in the education groups both immediately following and 6 months after the intervention . There were no benefits of participation in peer discussion groups , and some indications of adverse effects on adjustment at both follow-up examinations . The effects could be explained by changes in self-esteem , body image , and intrusive thoughts about the illness . CONCLUSIONS Education-based group interventions facilitated the initial adjustment of women diagnosed with early stage breast cancer . There was no evidence of benefits from peer discussion group interventions [23381060] Purpose Although patients receive information prior to commencing radiotherapy , they often experience anxiety and distress . We conducted a pilot r and omised controlled trial to determine whether a radiation therapist led psycho-educational intervention for breast cancer patients prior to radiotherapy is likely to be effective in reducing radiotherapy-related concerns , patient anxiety and depression . Methods The intervention comprised two face-to-face consultations with a radiation therapist ( one prior to radiation planning and the other prior to treatment ) . Patients completed surveys at baseline , prior to treatment planning and on the first day of treatment . Outcome measures included the Hospital Anxiety and Depression Scale , Radiation Therapy Related Patient Concerns and Radiation Therapy Knowledge Scales . Results One hundred and twenty two patients completed baseline measures . Fifty-eight patients received usual care , and 64 received the intervention . After the first consultation , patient anxiety was significantly lower in the intervention group ( p = 0.048 ) , as were concerns about radiotherapy ( p = 0.001 ) . There were no differences between groups for depression . Patient knowledge for the intervention group was higher after the first consultation ( p < 0.001 ) . Conclusion This intervention is likely to be effective in reducing patient anxiety and concerns and increasing knowledge . Future research is required to test this intervention with a larger population [17228986] In a 2 x 2 r and omized block repeated measure design , this study evaluated the follow-up efficacy of the uncertainty management intervention at 20 months . The sample included 483 recurrence-free women ( 342 White , 141 African American women ; mean age = 64 years ) who were 5 - 9 years posttreatment for breast cancer . Women were r and omly assigned to either the intervention or usual care control condition . The intervention was delivered during 4 weekly telephone sessions in which survivors were guided in the use of audiotaped cognitive-behavioral strategies and a self-help manual . Repeated measures MANOVAs evaluating treatment group , ethnic group , and treatment by ethnic interaction effects at 20 months indicated that training in uncertainty management result ed in improvements in cognitive reframing , cancer knowledge , and a variety of coping skills . Importantly , the 20-month outcomes also demonstrated benefits for women in the intervention condition in terms of declines in illness uncertainty and stable effects in personal growth over time [18490891] The purpose of this r and omized control trial was to verify the effectiveness of a brief group intervention that combines stress management psycho-education and physical activity ( ie , independent variable ) intervention in reducing fatigue and improving energy level , quality of life ( mental and physical ) , fitness ( VO2submax ) , and emotional distress ( ie , dependent variables ) in breast cancer survivors . This study applied Lazarus and Folkman stress-coping theoretical framework , as well as Salmon 's unifying theory of physical activity . Eighty-seven French-speaking women who had completed their treatments for nonmetastatic breast cancer at a university hospital in Quebec City , Canada , were r and omly assigned to either the group intervention ( experimental ) or the usual-care ( control ) condition . Data were collected at baseline , postintervention , and at 3-month follow-up . The 4-week group intervention was cofacilitated by 2 nurses . Results showed that participants in the intervention group showed greater improvement in fatigue , energy level , and emotional distress at 3-month follow-up , and physical quality of life at postintervention , compared with the participants in the control group . These results suggest that a brief psycho-educational group intervention focusing on active coping strategies and physical activity is beneficial to cancer survivors after breast cancer treatments [18020846] OBJECTIVE The purpose was to examine whether social-cognitive variables would moderate the efficacy of a couple-focused group intervention ( CG ) for women diagnosed with early stage breast cancer . DESIGN Participants ( N = 238 ) were r and omly assigned to 6 sessions of a couple-focused group versus usual care . Intent to treat growth curve modeling analyses indicated that emotional expression and emotional processing moderated CG effects on depression . MAIN OUTCOME MEASURES The primary outcome measures for this study were psychological distress and psychological well-being . RESULTS Treatment attrition analyses separating out participants assigned to but not attending CG indicated that emotional expression , emotional processing , and protective buffering moderated the effects of CG among those who attended CG with the most consistent effects noted for emotional processing on indicators of distress and well-being . CONCLUSION The CG intervention may be more effective for patients who begin the group experience using emotional approach coping strategies to deal with cancer [11879269] PURPOSE The purpose of this study was to determine whether participation in a group psychosocial intervention by patients with breast cancer would result in an improvement in psychological measures and in reduced billings in general medical expenses . DESCRIPTION OF STUDY Eligible women who had completed treatment for stage 0 , I , or II primary breast cancer were prospect ively and r and omly assigned to either the intervention ( n=46 ) or control ( n=43 ) group . Both groups received the usual psychosocial care ; however , the intervention group also participated in six weekly cognitive/behavioral psychosocial meetings . All were assessed on psychiatric symptoms , mood , depression , and coping strategies at four time periods : pre-intervention , post-intervention , 1-year follow-up , and 2-year follow-up . Alberta Healthcare billing records were obtained covering the 2-year follow-up period to determine the amount billed per person over the course of the study . RESULTS Women in the intervention group had less depression , less overall mood disturbance , better overall quality of life , and fewer psychiatric symptoms than those in the control group , beginning immediately post-intervention and remaining so at 2 years post-intervention . Billing in the intervention group was an average of $ 147 less than in the control group , a 23.5 % reduction . CLINICAL IMPLICATION S This is the first study to show that a psychosocial intervention can reduce direct healthcare billings in a sample of patients with cancer . Importantly , these findings help to justify the routine availability of such programs in cancer treatment facilities worldwide [22705939] Background : Older breast cancer survivors ( BCSs ) are at risk for late and long-term treatment effects on quality of life ( QOL ) , including lower physical functioning and fear of recurrence . Two promising approaches to address this include dance/movement therapy and mindfulness . Objective : The purpose of this 2-group r and omized controlled pilot feasibility study was to test short-term effects of a 12-week Mindful Movement Program ( MMP ) intervention combining mindfulness with self-directed movement on QOL and mindfulness in female BCSs 50 years or older and at 12 months or more following treatment . Methods : Consented participants were r and omized to an experimental group ( EG ) ( 12 weekly MMP sessions ) or a control group ( no sessions ) . All completed question naires 3 times . The EG participants kept home practice diaries . Analysis was conducted after intervention for immediate effects on outcome variables and 6 weeks later for maintenance of effects . Results : Participants ( n = 49 ) ranged in age from 50 to 90 years ( average , 65.6 years ) and were at 9.8 years since diagnosis ( range , 1–32 years ) , and the majority were white , unpartnered , and retired . After intervention , EG participants showed improved QOL via decreased fear of recurrence and increased mindfulness attitude . At 6 weeks , initial effects were retained . Conclusions : The MMP appears to benefit older BCSs by reducing fear of recurrence and improving mindfulness attitude . Although these findings are promising , a larger study is needed to determine more specifically what short- and long-term effects are possible . Implication s for Practice : The combination of self-directed movement and mindfulness , as tested here , may be a valuable tool for promoting health and well-being in older long-term survivors of breast cancer [20391072] The aim of this study was to evaluate a manualized cognitive behavioral group intervention for early-stage breast cancer patients . Sixty-nine women were recruited at an Irish specialist oncology hospital and assigned to a 6-week cognitive behavior therapy ( CBT ) program or an educational control group . Participants were assessed at baseline , 6 weeks , and 6-month follow-up . Groups × Time ( 2 × 3 ) ANOVAs showed that the program did not lead to greater improvement on st and ardized measures of coping , quality of life , or mood compared with the control group . Regression analyses showed that maladaptive coping and distress at baseline were predictive of psychological adjustment at follow-up . Level of distress was also predictive of quality of life at follow-up . Repeated measures ANOVAs of data from cases in the intervention group showed that patients who completed the program showed significant improvement in problem severity , impact of problems , coping ability , and goal attainment from pre- to posttreatment , and these gains were maintained at follow-up for problem severity and impact of problems , but not for coping ability or goal attainment . Participation in the program did not lead to less health service usage during the period from baseline to follow-up , compared with the educational control group . A controlled trial provided limited evidence for the effectiveness of brief cognitive behavior intervention in enhancing psychological adjustment of early-stage breast cancer patients with non clinical ly significant levels of psychological distress . Future research should evaluate the effectiveness of the program for patients with elevated levels of psychological distress and limited coping re sources [17467230] PURPOSE Psychological interventions are efficacious in reducing emotional distress for cancer patients . However , it is not clear whether psychological improvements are , in turn , related to improved health . A clinical trial tests whether a psychological intervention for cancer patients can do so , and also tests two routes to achieve better health : ( a ) reducing patients ' Emotional Distress , and /or ( b ) enhancing their functional immunity . METHODS Post-surgery , 227 breast cancer patients were r and omized to intervention or assessment only Study Arms . Conducted in small groups , intervention sessions were offered weekly for 4 months and followed by monthly sessions for 8 months . Measures included psychological ( distress ) , biological ( immune ) , and health outcomes ( performance status and evaluations of patient 's symptomatology , including toxicity from cancer treatment , lab values ) collected at baseline , 4 months , and 12 months . RESULTS A path model revealed that intervention participation directly improved health ( p<.05 ) at 12 months . These effects remained when statistically controlling for baseline levels of distress , immunity , and health as well as sociodemographic , disease , and cancer treatment variables . Regarding the mechanisms for achieving better health , support was found for an indirect effect of distress reduction . That is , by specifically lowering intervention patients ' distress at 4 months , their health was improved at 12 months ( p<.05 ) . Although the intervention simultaneously improved patients ' T-cell blastogenesis in response to phytohemagglutinin ( PHA ) , the latter increases were unrelated to improved health . CONCLUSION A convergence of biobehavioral effects and health improvements were observed . Behavioral change , rather than immunity change , was influential in achieving lower levels of symptomatology and higher functional status . Distress reduction is highlighted as an important mechanism by which health can be improved [22576981] Background When diagnosed with breast cancer , most women ’s lives change as well as their perspectives on and appreciation of life . The aim of the present study was to evaluate whether psychosocial support intervention could influence health-related quality of life ( HRQOL ) and fatigue during the first year after diagnosis . Material and methods Of 382 patients with newly diagnosed breast cancer , 191 patients were r and omized to an intervention group and 191 patients were r and omized to a routine control group . The intervention group received support intervention that lasted 1 week on a residential basis , followed by 4 days of follow-up 2 months later . The support intervention included informative educational parts , relaxation training , mental visualization , and nonverbal communication . HRQOL was measured using the European Organization for Research and Treatment of Cancer ( EORTC ) QLQ-C30 and QLQ-BR23 question naires and fatigue with the Norwegian version of the fatigue scale at baseline and at 2 , 6 , and 12 months after intervention . Result There was a time-dependent improvement in both functional and symptom scales between baseline and 12 months as measured by the EORTC QLQ-C30 and BR23 question naires and there was a decrease in fatigue between baseline and after 2 months with further improvement up to 12 months in both groups , but there were no differences between the intervention and control groups at any point in time . Conclusion HRQOL improves and symptoms of fatigue decrease over time , but we could not see any additional effect from the rehabilitation program in this setting [17523575] The study assessed whether a nursing intervention based on self-regulation theory , the Attentional Focus and Symptom Management Intervention ( AFSMI ) , could help women who underwent day surgery for breast cancer to achieve better pain management and decreased emotional distress . The sample consisted of 117 patients with breast cancer who were out patients and undergoing surgery as part of the initial treatment for their cancer . All subjects were interviewed at three different occasions . The subjects were r and omized into the experimental group ( n = 61 ) or the usual care group ( control , n = 56 ) . The subjects in the experimental group received the intervention in two sessions , 3 - 4 days and 10 - 11 days after surgery . The outcomes were the subjects ' pain and emotional distress . Results showed significant differences between the experimental and control group at post-test on home management , total mood disturbance , confusion and tension scores implying that the intervention was effective in achieving these outcomes . Clinical significance has illustrated that a nursing intervention applied during immediate recovery of breast cancer surgery is quite clinical ly relevant to reduce emotional distress . Self-regulation theory could effectively be used as a guide in developing nursing intervention programs in practice for patients with cancer undergoing day surgery as a primary treatment [9287446] BACKGROUND The pilot study used clinical trial methodology to differentiate the effects of imagery and support on coping , life attitudes , immune function , quality of life , and emotional well-being after breast cancer . METHODS Women ( N = 47 ) who completed treatment for primary breast cancer , excluding stage IV , were r and omly assigned to st and ard care ( n = 15 ) or six weekly support ( n = 16 ) or imagery ( n = 16 ) sessions . Self-report measures included Ways of Coping-Cancer , Life Attitude Profile , Quality of Life ( FACT-B ) , Profile of Mood States , and Functional Support . Immune measures included natural killer cell activity , plasma neopterin , interferon-gamma , interleukins 1 alpha , 1 beta , and 2 , and beta-endorphin levels . Differences between groups over time were tested using general linear models , adjusted for pretest score and covariates ( age , stage , and months posttreatment ) . RESULTS For all women , interferon-gamma increased , neopterin decreased , quality of life improved , and natural killer activity remained unchanged . Compared with st and ard care , both interventions improved coping skills ( seeking support ) and perceived social support , and tended to enhance meaning in life . Support boosted overall coping and death acceptance . When comparing imagery with support , imagery participants tended to have less stress , increased vigor , and improved functional and social quality of life . CONCLUSION Although imagery reduced stress and improved quality of life , both imagery and support improved coping , attitudes , and perception of support . The clinical implication s of these changes warrant further testing [22573418] OBJECTIVE This study aims to test two telephone-delivered interventions for their efficacy in improving quality of life ( QOL ) ( psychological , physical , social , and spiritual ) among Latinas with breast cancer and their family members or friends ( labeled supportive partners in this study ) . METHODS Latinas with breast cancer and their supportive partners ( SPs ) were r and omly assigned to one of two telephone delivered 8-week interventions : ( i ) telephone interpersonal counseling ( TIP-C ) or ( ii ) telephone health education ( THE ) . QOL assessment s were made at baseline , immediately after the 8-week interventions ended , and at an 8-week follow-up . Seventy Latinas and their 70 SPs completed all assessment s ( 36 in health education and 34 in counseling ) and were included in the final analysis . RESULTS Both Latinas with breast cancer and their SPs had significant improvements in virtually all dimensions of QOL over the 16 weeks of the investigation . However , there was no evidence documenting the superiority of either intervention for improving QOL . Preliminary cost analysis found that the counseling intervention cost about $ 164.68 for one dyad compared with $ 107.03 for health education . The majority of participants reported benefit from the intervention and liked that the intervention was in Spanish , included SPs , and was delivered by telephone . CONCLUSION The results of this study show that relatively brief , culturally appropriate , and highly accessible telephone-delivered interventions that provide emotional and information support can bring about substantial improvements in QOL for both Latinas with breast cancer and their SPs [24027211] BACKGROUND AND PURPOSE Previous literature s on young adult survivors of childhood cancer show inconsistent findings with regards to their psychological distress and health-related quality of life ( HRQOL ) . Much of the available data focus on negative patient outcomes following cancer treatments prescribed from 1970 to 1990 . In the present study , HRQOL and psychological distress of young adult survivors in Hong Kong was examined . It focused on subjects who had received cancer treatments prescribed in the last two decades . METHODS A structured telephone survey was conducted with 614 eligible survivors and 208 sibling controls in Hong Kong . RESULTS The survivors reported significantly lower mean scores in physical role and functioning , whereas their mental , social , and psychological well-being was similar to that of their sibling controls . Being female , older age , longer survival time , and specific cancer diagnoses were the factors associated with poorer physical and mental adaptation . HRQOL was negatively correlated with psychological distress . CONCLUSIONS Findings of the study suggest that most survivors adjusted fairly well in mental , psychological , and social aspects . Survivors with a higher risk of poor HRQOL could benefit from appropriate screening and counseling at an early stage to mitigate their survivorship difficulties . Prospect i ve follow-up studies on childhood cancer survivors are recommended to detect changes over longer survival periods [15452189] PURPOSE Cognitive-existential group therapy ( CEGT ) was developed to improve mood and mental attitude toward cancer in women with early-stage breast cancer receiving adjuvant chemotherapy . Given the debate about group therapy 's association with increased survival in women with metastatic breast cancer , we were curious to check its effect at a much earlier stage in the cancer journey . PATIENTS AND METHODS We r and omly assigned 303 women with early-stage breast cancer who were receiving adjuvant chemotherapy to either 20 sessions of weekly group therapy plus three relaxation classes ( n = 154 ) or to a control condition of three relaxation classes alone ( n = 149 ) . The primary outcome was survival . RESULTS CEGT did not extend survival ; the median survival time was 81.9 months ( 95 % CI , 64.8 to 99.0 months ) in the group-therapy women and 85.5 months ( 95 % CI , 67.5 to 103.6 months ) in the control arm . The hazard ratio for death was 1.35 ( 95 % CI , 0.76 to 2.39 ; P = .31 ) . In contrast , histology and axillary lymph node status were significant predictors of survival . Low- grade histology yielded a hazard ratio of 0.342 ( 95 % CI , 0.17 to 0.69 ) , and axillary lymph node-negative status yielded a hazard ratio of 0.397 ( 95 % CI , 0.20 to 0.78 ) . CONCLUSION CEGT does not prolong survival in women with early-stage breast cancer [17179873] Background : Psychosocial interventions can improve psychological quality of life ( symptoms of depression and anxiety ) of both women with breast cancer and their partners , but are not offered routinely to women and their partners . Objective : To test the hypotheses that telephone-delivered psychosocial interventions decrease depression and anxiety in women with breast cancer and their partners . Methods : The design of the study was a three-wave repeated measures with a between-subjects factor ( treatment group ) . Ninety-six women and their 96 partners were assigned r and omly to participate in one of three different 6-week programs : ( a ) telephone interpersonal counseling ( TIP-C ) ; ( b ) self-managed exercise ; or ( c ) attention control ( AC ) . Results : The mixed-model analysis of variance for symptoms of depression among women with breast cancer revealed women 's depressive symptom scores decreased over time in all groups . For anxiety , women 's symptoms of anxiety decreased in the TIP-C and exercise groups over time , but not in the AC group . A parallel set of analyses was conducted on partners ' depression and anxiety data . Symptoms of depression and anxiety among the partners decreased substantially over the course of the investigation . Similar to the women , partners ' symptoms of anxiety decreased significantly in the TIP-C and exercise groups , but not in the AC group . Discussion : Findings from this study support that these telephone-delivered psychosocial interventions were effective for decreasing symptoms of depression and anxiety to improve psychological quality of life when compared to an AC group [22964869] Background : At the time of diagnosis , patients with cancer are highly exposed to the risk of psychological morbidity . The effects of psychosocial intervention for newly diagnosed cancer patients have not been extensively studied . Objective : The objective of this study was to test the effects of a dyadic peer support intervention on self-efficacy , anxiety , depression , and mental adjustment among newly diagnosed breast cancer patients in Korea . Methods : This study used a r and omized controlled trial design . One hundred twenty-nine patients were recruited within 1 month of diagnosis with breast cancer in the National Cancer Center in Korea . The study participants were r and omly assigned to either experimental ( n = 64 ) or control ( n = 65 ) group . The experimental group underwent dyadic peer support intervention during the 6 weeks after surgery . The control group received the usual care . Results : There was a significant difference in changes in self-efficacy for self-management of breast cancer between the experimental and control groups ; however , no significant changes were observed in anxiety , depression , and mental adjustment between the 2 groups . Conclusions : A 6-week dyadic peer support intervention was feasible and effective for increasing self-efficacy for self-management among newly diagnosed breast cancer patients in Korea . However , this intervention did not improve other psychological outcomes . Implication s for Practice : Oncology nurses are optimally positioned to promote adjustment in patients with cancer . Trained peer support partners , supervised by skilled nurses , may be useful in improving self-efficacy of patients newly diagnosed with breast cancer [18835434] BACKGROUND A diagnosis of breast cancer and treatment are psychologically stressful events , particularly over the first year after diagnosis . Women undergo many dem and ing and anxiety-arousing treatments such as surgery , radiation and chemotherapy . Psychosocial interventions that promote psychosocial adaptation to these challenges may modulate physiological processes ( neuroendocrine and immune ) that are relevant for health outcomes in breast cancer patients . METHODS Women with Stages 1 - 3 breast cancer recruited 4 - 8 weeks after surgery were r and omized to either a 10-week group-based cognitive behavioral stress management ( CBSM ) intervention or a 1-day psychoeducational control group and completed question naires and late afternoon blood sample s at study entry and 6 and 12 months after assignment to experimental condition . RESULTS Of 128 women initially providing psychosocial question naire and blood sample s at study entry , 97 provided complete data for anxiety measures and cortisol analysis at all time points , and immune assays were run on a subset of 85 of these women . Those assigned to a 10-week group-based CBSM intervention evidence d better psychosocial adaptation ( lower reported cancer-specific anxiety and interviewer-rated general anxiety symptoms ) and physiological adaptation ( lower cortisol , greater Th1 cytokine [ interleukin-2 and interferon-gamma ] production and IL-2:IL-4 ratio ) after their adjuvant treatment compared to those in the control group . Effects on psychosocial adaptation indicators and cortisol appeared to hold across the entire 12-month observation period . Th1 cytokine regulation changes held only over the initial 6-month period . CONCLUSIONS This intervention may have facilitated a " recovery or maintenance " of Th1 cytokine regulation during or after the adjuvant therapy period . Behavioral interventions that address dysregulated neuroendocrine function could play a clinical ly significant role in optimizing host immunologic resistance during a vulnerable period [16594274] OBJECTIVE The purpose of this article is to evaluate an 8-week pilot intervention based on Social Cognitive Theory to improve quality of life for women with breast cancer . METHODS A total of 32 breast cancer patients were r and omized to either the intervention or st and ard care . Outcome variables included quality of life , mood , self-efficacy , outcome expectations , and self-regulation . RESULTS Effect sizes were calculated to examine the impact of the intervention , with moderate to large effect sizes found for several subscales of the outcome expectations variable : learning about cancer and treatment ( d = 0.85 ) , having a positive attitude ( d = 0.54 ) , talking about cancer ( d = 1.02 ) , engaging in relaxation ( d = 0.62 ) , and setting goals ( d = 1.58 ) . SIGNIFICANCE OF RESULTS A nonparametric sign test was conducted , indicating that women in the intervention condition either improved more or showed less decline than the women in st and ard care , p = .034 , two-tailed . Implication s and suggestions for the content and delivery of future psychosocial interventions with cancer patients are review ed [11824739] The feasibility of a r and omized clinical trial to implement and compare the effectiveness of three components of an intervention for women with breast cancer and their partners was tested . The intervention components , st and ardized education by videotape ( SE ) , telephone counseling ( TC ) , and education with telephone counseling ( SE + TC ) , were design ed with a complementary approach to disease management of breast cancer at each of four phases of the breast cancer experience : diagnostic , postsurgery , adjuvant therapy , and ongoing recovery . A st and ardized Telephone Counseling Training Manual was developed . A nonprobability sample of 12 patient-partner pairs was accrued . Four pairs were r and omly assigned to each of the three intervention components . A set of question naires was completed by each patient and partner at baseline and following each intervention for assessment of emotional , physical , and social adjustment , and perceived support . Attrition was minimal and return rate for the completed question naires at all five data - collection points was high . Validation of the SE and the TC , one of the objectives , was by data from the preliminary descriptive study ( Hoskins , 1990–1994 ) , pretests and posttests for st and ardized education , audiotapes for each phase-specific telephone counseling session , and evaluation forms for each intervention session . The positive findings included significant changes from pre- to postmeasurement in patients ' and partners ' scores for the st and ardized education in each of the four phases . Even with the limited statistical power , the effects were marked , lending support for a full-scale r and omized clinical trial , to underst and better the relative treatment efficacy and differential benefit of one or some interventions over others [10833696] PURPOSE / OBJECTIVES To test the value of telephone-administered cognitive-behavioral therapy in a study of patients with breast cancer . DESIGN Women were assigned r and omly to a therapy group or an assessment -only control group . SETTING A tertiary cancer treatment center serving rural areas of North Dakota and Minnesota . SAMPLE Women were recruited within three to four months of stage I ( n = 27 ) or stage II ( n = 26 ) breast cancer diagnosis . Age ranged from 30 - 82 ( mean = 51.5 years ) . Most participants ( n = 35 ) underwent a modified radical mastectomy ; 17 underwent a lumpectomy . METHODS Therapy involved 10 30-minute ( or less ) telephone sessions . Data that were collected from mailed question naires included psychological distress ( Profile of Mood States ) , perceived stress , coping ( Coping Response Indices-Revised ) , quality of life ( Medical Outcome Scale ) , and satisfaction with therapy . Measures were completed at baseline and at 4- and 10-month follow-up intervals . MAIN RESEARCH VARIABLES Telephone therapy , stress , coping , and quality of life . FINDINGS With time , women in the therapy and control groups reported reduced stress and improved quality of life . However , significant reductions in some kinds of distress ( anxiety , anger , depression , and confusion ) were not observed . Most therapy participants liked the telephone treatment sessions but showed only modest improvement ( less anxiety and confusion ) compared with women in the control group . CONCLUSIONS Most patients reported being comfortable with the telephone therapy and said that they felt better as a result of it . However , the outcome data showed that telephone therapy -- as carried out in this study --produced only modest benefits . Research ers need to consider who is best for delivering such therapy . IMPLICATION S FOR NURSING PRACTICE Providing telephone therapy to patients with breast cancer has potential benefits , and nurses may be the appropriate professionals to administer the therapy [10420420] PURPOSE / OBJECTIVES To examine the feasibility of using an emotional expression intervention with patients with cancer and test the hypothesis that emotional expression improves psychosocial adjustment . DESIGN Sequentially r and omized pretest/post-test design with repeated measures . SETTING Two radiation therapy ( RT ) facilities . SAMPLE Women completing RT for stage I or II breast cancer , who spoke and read English , were independent in self-care , and provided written consent . Subjects ( N = 44 ) were middle-aged ( mean = 53.6 years ) , Caucasian , married , and well educated . METHODS Following a baseline interview , subjects were sequentially r and omized to an attentional control group , a single dose , or a three-dose emotional expression writing group . Interventions were administered at the time of completion of RT . Follow-up telephone interviews were completed at 1 , 4 - 6 , 16 , and 28 weeks post-RT . MAIN RESEARCH VARIABLES Positive and negative affect , intrusiveness of thoughts , use of avoidant coping , side effect severity , trait negative affectivity , content of written essay , and themes derived from content analysis . FINDINGS A high level of acceptance and completion of emotional expression existed , but no effect of the intervention on psychosocial adjustment was evident . Process measures in the three-dose group changed as expected . No relationship existed between content changes and outcome measures . CONCLUSIONS Emotional expression is feasible for patients with cancer , but the efficacy of the intervention in improving mood and decreasing cognitive intrusion and avoidance was not supported . Emotional expression processes were consistent with those seen in other sample s and may influence outcomes that were not addressed in this study . IMPLICATION S FOR NURSING PRACTICE More extensive testing is needed , including additional outcome variables . Essays reveal concerns around communication , recurrence , and health behavior changes that should be considered in practice [12790260] The effectiveness of support group interventions for cancer patients has been established among White patients but has been virtually unstudied among minority patients . The current study represents the 1st r and omized support group intervention targeted to African American women with breast cancer . Participants ( N = 73 ) with nonmetastatic breast cancer were r and omly assigned to an 8-week group intervention or an assessment -only control condition At 12 months , the intervention result ed in improved mood as well as improved general and cancer-specific psychological functioning among women with greater baseline distress or lower income . Subsequent research is needed to address effective methods of enrolling and following women with fewer psychosocial and financial re sources , as they were the most likely to benefit from this particular intervention [15992569] OBJECTIVE The primary objective was to conduct a detailed analysis of individual variation in psychological morbidity in the year following surgery for breast cancer . The salience of the patients ' " illness perceptions " to morbidity was examined as a secondary objective . METHODS Psychological morbidity was assessed with the General Health Question naire ( GHQ-28 ) in a prospect i ve study of 371 women having surgery for primary breast cancer . Patients also completed the Illness Perception Question naire ( IPQ ) , Mental Adjustment to Cancer Scale ( MAC ) and the Eysenck Personality Scales ( EPS ) . Assessment s were made postoperatively and at 3 , 6 and 12 months after surgery . RESULTS Whilst descriptive statistics indicated a general reduction in mean distress over the 12-month follow-up , close analysis showed that a quarter of all patients maintained clinical ly significant levels of distress throughout the period . Patients with chronically elevated distress were characterised by higher levels of neuroticism , greater symptom awareness , more pain and poorer self-rated general health . In the regression analysis , psychological morbidity across the 1-year follow-up was predicted principally by the immediate postoperative state of distress , IPQ symptom awareness and the perceived time line of the illness , general health and , to a more minor extent , by neuroticism . CONCLUSION There is marked individual variation in psychological morbidity in the year following breast cancer surgery , which is reliably predicted by the patient 's immediate postoperative state of distress , her perception of the impact of the symptoms and the time line of the disease . Subgroups of patients with chronically high distress are characterised by factors including personality and negative perceptions and beliefs about their illness [20042336] Prospect i ve data are limited on the course of anxiety and depression and their determinants in women with early breast cancer . These parameters were assessed before adjuvant radiotherapy ( RT ) and over 5 years follow-up . Of 2208 women recruited to the START QOL study , 35 % reported clinical ly relevant levels of anxiety and /or depression pre-RT ; there was no significant change in these proportions over time . However , 75 % women with high baseline anxiety recorded further high scores over time whilst one in six had high scores at every follow-up point . Depression showed a similar pattern with lower frequencies at all time points ; very few with initial normal scores developed clinical ly relevant anxiety or depression over time . Lower educational level predicted worse anxiety and depression over time ; younger age predicted worse anxiety and chemotherapy predicted worse depression . Scores in the borderline or case range for anxiety or depression at baseline were both significantly associated with worse mood states over 5 years . These findings indicate the course of anxiety and depression in women with specific risk factors . This subgroup of patients requires greater clinical attention [12035205] PROBLEM Although research ers suggest treatments that provide patients with an active coping strategy may increase patients ' sense of self-efficacy , previous studies have not measured patients ' self-efficacy . METHODS Eighteen women receiving chemotherapy for breast cancer were r and omized to efficacy-enhancing experimental ( n = 10 ) and usual-care control ( n = 8) groups . The experimental group received five interventions delivered monthly . Variables-- quality of life , symptom distress , and self-care self-efficacy -- were measured at baseline and at 4 and 8 months later . FINDINGS At 4 and 8 months the interaction effects for the Functional Assessment of Cancer Treatment-Breast , used to measure quality of life , ranged from small for functional concerns to large for social concerns . Interaction effects for symptom distress , measured by the Symptom Distress Scale , were large . Interaction effects for self-care self-efficacy ranged from small for Enjoying Life and Stress Reduction , medium for Stress Reduction , and large for Making Decisions . CONCLUSIONS Interventions to promote self-efficacy may increase quality of life and decrease distress for women diagnosed with breast cancer [21901389] The aim of this study was determine the effectiveness of a mindfulness-based stress-reduction ( MBSR ) program on quality of life ( QOL ) and psychosocial outcomes in women with early-stage breast cancer , using a three-arm r and omized controlled clinical trial ( RCT ) . This RCT consisting of 172 women , aged 20–65 with stage I or II breast cancer consisted of the 8-week MBSR , which was compared to a nutrition education program ( NEP ) and usual supportive care ( UC ) . Follow-up was performed at three post-intervention points : 4 months , 1 , and 2 years . St and ardized , vali date d self-administered question naires were adopted to assess psychosocial variables . Statistical analysis included descriptive and regression analyses incorporating both intention-to-treat and post hoc multivariable approaches of the 163 women with complete data at baseline , those who were r and omized to MBSR experienced a significant improvement in the primary measures of QOL and coping outcomes compared to the NEP , UC , or both , including the spirituality subscale of the FACT-B as well as dealing with illness scale increases in active behavioral coping and active cognitive coping . Secondary outcome improvements result ing in significant between-group contrasts favoring the MBSR group at 4 months included meaningfulness , depression , paranoid ideation , hostility , anxiety , unhappiness , and emotional control . Results tended to decline at 12 months and even more at 24 months , though at all times , they were as robust in women with lower expectation of effect as in those with higher expectation . The MBSR intervention appears to benefit psychosocial adjustment in cancer patients , over and above the effects of usual care or a credible control condition . The universality of effects across levels of expectation indicates a potential to utilize this stress reduction approach as complementary therapy in oncologic practice [10964333] To the authors ' knowledge , there had been no evidence for the efficacy of psychosocial intervention among Japanese cancer patients . The objective of this study was to determine the effect of a psychosocial group intervention in reducing psychologic distress and enhancing coping in this population in a r and omized controlled trial [21308859] OBJECTIVE Rehabilitation programmes are intended to help cancer patients achieve optimal functioning and live independently . We evaluated whether a psychosocial rehabilitation course was effective in relieving cancer patients ' distress and improving their well-being . METHODS Patients with breast , prostate or colorectal cancer diagnosed within 2 years who had finished primary treatment were r and omised to usual care or a 6-day residential course of lectures , discussion s and peer groups on issues related to treatment and living with cancer . Changes in self-reported distress ( POMS-Sf ) and quality of life ( EORTC QLQ-C30 ) from baseline to 1 and 6 months ' follow-up were measured . Analyses were adjusted for baseline scores of outcome , cancer site , time since diagnosis , gender , age and education . RESULTS Of 507 patients , 452 were included in the analyses , 404 completed the 1-month and 394 the 6-month assessment . Patients in the control group showed greater decreases in total mood disturbance and subscales of the POMS-Sf and showed more improvement in emotional , cognitive and social functioning at both 1 and 6 months and in role functioning at 6 months than the intervention group . A similar pattern was observed in analyses of breast cancer patients only . CONCLUSION A 6-day residential rehabilitation course did not relieve cancer patients ' distress or improve their well-being [22399076] Background : Neuroendocrine dysregulation influenced by psychosocial stress is related to breast cancer recurrence . Very few studies examine the impacts of psychotherapy on diurnal cortisol patterns among breast cancer survivors . Methods : Forty-eight breast cancer patients who completed active cancer treatment were r and omly assigned to receive either 8 weekly body-mind-spirit ( BMS ) group therapy sessions or 1 educational ( EDU ) session . Self-report measures included the Beck Depression Inventory-II ( BDI-II ) , and the Meaning in Life question naire ( MLQ ) including two subscales : MLQ-Presence and MLQ- Search . Salivary cortisol levels were collected by the subjects in their homes at the time of awakening , 30 and 45 min after awakening , and at 12.00 , 17.00 , and 21.00 h. Measurement time points include baseline , the 2nd month ( completion of BMS therapy ) , the 5th month , and the 8th month . Results : There were no significant differences in BDI-II scores ( p>0.05 ) and MLQ-Presence scores ( p > 0.05 ) between BMS and EDU groups at baseline or across the three follow-ups . Nevertheless , greater MLQ- Search scores were found in the BMS group compared to the EDU group during the 5th month of follow-up ( p < 0.01 ) . The higher level of cortisol at 21.00 h ( p < 0.01 ) and a flatter diurnal cortisol pattern were more likely to occur in EDU than in BMS participants ( p < 0.05 ) at the 8th month of follow-up . Conclusion : BMS group therapy likely contributed to enhancing an active search for meaning in life toward more opportunities for personal growth and to maintaining stable cortisol responses to everyday life stress for breast cancer survivors [11336241] There has been much interest in the psychosocial issues faced by breast cancer patients because of the high prevalence of the disease and the severe psychological impact of the cancer itself , as well as its treatment . The objective of our study was to investigate the determinants of psychiatric morbidity among postoperative ambulatory breast cancer patients . The variables examined included the patients ' biomedical characteristics , demographic characteristics , current concerns , coping responses and social support factors . Patients Completed the Hospital Anxiety and Depression Scale ( HADS ) and the Mental Adjustment to Cancer scale ( MAC scale ) , and information pertaining to demographic variables , current concerns and social support factors was obtained by a specially design ed question naire . Available data were obtained from 148 r and omly selected postoperative ambulatory breast cancer patients . The prevalence of psychiatric morbidity ( including clinical anxiety and depression ) evaluated by using the HADS cut-off point was 23 % . The results of univariate analyses indicated that pain , dyspnea , having children with health problems , various other concerns ( about children , other family members , the patients ' own health and future treatment ) and poor coping responses ( low fighting spirit , high anxious preoccupation , high fatalism and high helplessness/hopelessness ) were significant determinants of the patients ' psychiatric morbidity . Additionally , in the logistic regression analysis , having children with health problems and having a low fighting spirit and a high helplessness/hopelessness were final significant determinants . Postoperative ambulatory breast cancer patients with these problems should be given careful attention , and psychosocial intervention may be beneficial for them [19941285] OBJECTIVE To determine whether a telephone counseling program can improve psychosocial outcomes among breast cancer patients post-treatment . METHODS A r and omized trial was conducted involving 21 hospitals and medical centers , with assessment s ( self-administered question naires ) at baseline , 12 and 18 months post-enrollment . Eligibility criteria included early stage diagnosis , enrollment during last treatment visit , and the ability to receive the intervention in English . Endpoints included distress ( Impact of Event Scale ) , depression ( Center for Epidemiologic Studies Depression Scale ) , and two study -specific measures : sexual dysfunction and personal growth . The control group ( n=152 ) received a re source directory for breast cancer ; the intervention group ( n=152 ) also received a one-year , 16 session telephone counseling program augmented with additional print material s. RESULTS Significant intervention effects were found for sexual dysfunction at 12 ( p=0.03 ) and 18 months ( p=0.04 ) and personal growth ( 12 months : p=0.005 ; 18 months : p=0.03 ) . No differences by group were found in mean scores for distress and depression , with both groups showing significant improvement at 12 and 18 months ( all p values for within-group change from baseline were < or=0.003 ) . However , when dichotomized at cutpoints suggestive of the need for a clinical referral , the control group showed virtually no change at 18 months , whereas the intervention group showed about a 50 % reduction in both distress ( p=0.07 ) and depression ( p=0.06 ) . CONCLUSIONS Telephone counseling may provide a viable method for extending psychosocial services to cancer survivors nationwide [10939175] Patients with breast cancer who undergo autologous bone marrow/peripheral blood stem cell transplantation ( ABMT ) cope not only with a life-threatening medical treatment , but also with multiple , interrelated symptoms including pain , fatigue , psychological distress , and nausea . The purpose of this study was to determine , in a r and omized controlled clinical trial , whether a comprehensive coping strategy program ( CCSP ) was effective in significantly reducing pain , fatigue , psychological distress , and nausea in patients with breast cancer who underwent ABMT . The CCSP was composed of preparatory information , cognitive restructuring , and relaxation with guided imagery . R and omization placed 52 patients in the CCSP treatment group and 58 patients in the control group . The CCSP was found to be effective in significantly reducing nausea as well as nausea combined with fatigue 7 days after the ABMT when the side effects of treatment were most severe . These results are important given the high incidence of nausea and fatigue in the ABMT population . The CCSP-treated group experienced mild anxiety as compared with the control group who reported moderate anxiety . The greatest effectiveness of CCSP may correspond to the time of the greatest morbidity for patients with breast cancer who have undergone ABM [90871] A prospect i ve , multidisciplinary , 5-year study of 69 consecutive female patients with early ( T0,1N0,1M0 ) breast cancer was conducted . Patients ' psychological responses to the diagnosis of cancer were assessed 3 months postoperatively . These responses were related to outcome 5 years after operation . Recurrence-free survival was significantly common among patients who had initially reacted to cancer by denial or who had a fighting spirit than among patients who had responded with stoic acceptance or feelings of helplessness and hopelessness [20974079] BACKGROUND Throughout the illness trajectory , women with breast cancer experience issues that are related to physical , emotional , and social adjustment . Despite a general consensus that state-of-the-art treatment for breast cancer should include educational and counseling interventions to reduce illness or treatment-related symptoms , there are few prospect i ve , theoretically based , phase-specific r and omized , controlled trials that have evaluated the effectiveness of such interventions in promoting adjustment . PURPOSE The aim of this study is to examine the physical , emotional , and social adjustment of women with early-stage breast cancer who received psychoeducation by videotapes , telephone counseling , or psychoeducation plus telephone counseling as interventions that address the specific needs of women during the diagnostic , postsurgery , adjuvant therapy , and ongoing recovery phases of breast cancer . DESIGN Primary data from a r and omized controlled clinical trial . SETTING Three major medical centers and one community hospital in New York City . METHODS A total of 249 patients were r and omly assigned to either the control group receiving usual care or to one of the three intervention groups . The interventions were administered at the diagnostic , postsurgery , adjuvant therapy , and ongoing recovery phases . Analyses were based on a mixed model analysis of variance . MAIN RESEARCH VARIABLES AND MEASUREMENT : Physical adjustment was measured by the side effects incidence and severity subscales of the Breast Cancer Treatment Response Inventory ( BCTRI ) and the overall health status score of the Self-Rated Health Subscale of the Multilevel Assessment Instrument . Emotional adjustment was measured using the psychological well-being subscale of the Profile of Adaptation to Life Clinical Scale and the side effect distress subscale of BCTRI . Social adjustment was measured by the domestic , vocational , and social environments subscales of the Psychosocial Adjustment to Illness Scale . FINDINGS Patients in all groups showed improvement over time in overall health , psychological well-being , and social adjustment . There were no significant group differences in physical adjustment , as measured by side effect incidence , severity , or overall health . There was poorer emotional adjustment over time in the usual care ( control ) group as compared to the intervention groups on the measure of side effect distress . For the telephone counseling group , there was a marked decline in psychological well-being from the adjuvant therapy phase through the ongoing recovery phase . There were no significant group differences in the dimensions of social adjustment . CONCLUSION The longitudinal design of this study has captured the dynamic process of adjustment to breast cancer , which in some aspects and at various phases has been different for the control and intervention groups . Although patients who received the study interventions improved in adjustment , the overall conclusion regarding physical , emotional , and social adjustment is that usual care , which was the st and ard of care for women in both the usual care ( control ) and intervention groups , supported their adjustment to breast cancer , with or without additional interventions . IMPLICATION S FOR NURSING The results are important to evidence -based practice and the determination of the efficacy and cost-effectiveness of interventions in improving patient outcomes . There is a need to further examine adjustment issues that continue during the ongoing recovery phase . KEY POINTS Psychoeducation by videotapes and telephone counseling decreased side effect distress and side effect severity and increased psychological well-being during the adjuvant therapy phase . All patients in the control and intervention groups improved in adjustment . Adjustment issues are still present in the ongoing recovery phase [18702064] OBJECTIVE Although women 's breast cancer affects both women and their male partners , as well as their relationships , few interventions have been developed to work with couples confronting breast cancer . The current investigation presents the pilot results from a new couple-based intervention program for breast cancer that teaches couples how to minimize negative effects and maximize positive functioning during this difficult time . METHOD In this pilot study , 14 couples in which the wife had early stage breast cancer were r and omly assigned to one of the two treatment conditions : Couple-based relationship enhancement ( RE ) or treatment-as-usual ( TAU ) . RESULTS The results from this study suggest that compared with couples receiving treatment-as-usual , both women and men in the RE condition experienced improved functioning on individual psychological variables as well as relationship functioning at posttest and 1-year follow-up . In addition , women in RE show fewer medical symptoms at both time periods . CONCLUSIONS In this pilot study , the couple-based intervention , RE , has shown promise in improving individual , medical , and relationship functioning for couples in which the woman is facing breast cancer , and therefore merits further investigation on a larger scale Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND The prognosis and survival rate of women with breast cancer have significantly improved worldwide . Effective home-based multidimensional programmes for breast cancer survivors have gained an ever greater emphasis in survivorship care to maximise women 's quality of life for their successful transition to rehabilitation and normal life . It is important to summarise the best available evidence to evaluate the effects of home-based multidimensional survivorship programmes on quality of life in women within 10 years of the completion of surgery or adjuvant cancer therapy for breast cancer , or both . OBJECTIVES To assess the effects of home-based , multidimensional survivorship ( HBMS ) programmes on maintaining or improving the quality of life in breast cancer survivors . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

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[18696358] Objective . To test the hypothesis that calcium supplementation inhibits the underlying pathological processes in women with preeclampsia . Methods . Seven hundred and eight nulliparous women were enrolled in a WHO r and omized double-blind trial , who received 1.5 g of calcium or placebo from 20 weeks of pregnancy or earlier . Platelet count , serum urate , and urinary protein/creatinine ratio were measured at or near 35 gestational weeks . Results . No difference was detected in rates of abnormal platelet count ( relative risk [ RR ] 1.18 ; 95 % confidence interval [ CI ] , 0.63 to 2.18 ) , serum urate level ( 1.0 ; 0.64 to 1.57 ) or urine protein/creatinine ratio ( 1.01 ; 0.76 to 1.34 ) . This was consistent with the main trial finding of no difference in the incidence of ‘ dipstick ’ proteinuria between women receiving calcium and those receiving placebo ( 8312 women ; RR , 1.01 ; 95 % CI , 0.88 to 1.15 ) . Conclusions . An effect of calcium supplementation in the second half of pregnancy on the rate of abnormal laboratory measures associated with preeclampsia was not demonstrated [10511362] OBJECTIVE To determine the effect of maternal calcium supplementation during pregnancy on fetal bone mineralization . METHODS Healthy mothers with early ultrasound confirmation of date s and singleton pregnancies were enrolled in a double-masked study and r and omized before 22 weeks ' gestation to 2 g/day of elemental calcium or placebo until delivery . Maternal dietary intake at r and omization and at 32 - 33 weeks ' gestation was recorded with 24-hour dietary recalls . Dual-energy x-ray absorptiometry measurements of the whole body and lumbar spine of the neonates were performed before hospital discharge . RESULTS The infants of 256 women ( 128 per group ) had dual-energy x-ray absorptiometry measurements during the first week of life . There were no significant differences between treatment groups in gestational age , birth weight , or length of the infants , or in the total-body or lumbar spine bone mineral content . However , when bone mineral content was analyzed by treatment group within quintiles of maternal dietary calcium intake , total body bone mineral content ( mean + /- st and ard error of the mean ) was significantly greater in infants born to calcium-supplemented mothers ( 64.1+/-3.2 versus 55.7+/-2.7 g in the placebo group ) in the lowest quintile of dietary calcium intake ( less than 600 mg/day ) . The effect of calcium supplementation remained significant after adjustment for maternal age and maternal body mass index and after normalization for skeletal area and body length of the infant . CONCLUSION Maternal calcium supplementation of up to 2 g/day during the second and third trimesters can increase fetal bone mineralization in women with low dietary calcium intake . However , calcium supplementation in pregnant women with adequate dietary calcium intake is unlikely to result in major improvement in fetal bone mineralization [12657345] BACKGROUND Pregnancy is a time of increased need for calcium . The role of calcium supplements in altering maternal responses to fetal dem and for calcium is not fully understood . This article describes the results of a r and omized , crossover trial of calcium supplementation on bone resorption among pregnant women . DESIGN / SETTING PARTICIPANTS : Thirty-one Mexican women at 25 - 35 weeks gestation participated in the study for 20 days . Each woman received a 1200 mg calcium supplement on 10 consecutive days and a multivitamin without calcium for 10 days . Urine sample s were collected daily . Two pooled specimens from each subject ( representing urine from multivitamin days and from calcium days ) were preserved , and levels of cross-linked , N-telopeptides of type I collagen ( NTX ) , a biomarker of bone resorption , were measured . Dietary calcium intake was assessed using a food-frequency question naire . RESULTS Of the 31 participants , 27 ( 87.1 % ) showed reductions in urinary NTX levels while ingesting calcium supplements . When not ingesting calcium , NTX levels for the 31 subjects had a mean of 96.8 nM BCE/mM creatinine ; this was significantly higher ( p<0.001 ) than the mean urinary NTX levels of 83.2 nM BCE/mM creatinine during ingestion of the calcium supplements . Neither age nor dietary calcium intake was a significant predictor of treatment effect . CONCLUSION A bedtime , 1200-mg calcium supplement during the third trimester of pregnancy reduces maternal bone resorption by an average of 13.6 nM BCE/mM creatinine ( 14 % ) , as reflected by urinary NTX levels . These results suggest that calcium supplements reduce maternal skeletal-bone turnover during the third trimester of pregnancy [20078830] Calcium supplementation in mothers with low calcium intake has been of interest recently because of its association with optimal fetal growth and improved pre-eclampsia-related outcomes . While the effects of calcium supplementation have demonstrated benefits in prolonging gestation and subsequently improving birthweight , no specific studies have identified the longitudinal effects of supplementation on fetal growth in utero . Data were analysed in the context of the World Health Organization trial of calcium supplementation in calcium-deficient women . Five hundred and ten healthy , primiparous pregnant Argentinean women were r and omised ( at < 20 weeks gestation ) to either placebo ( n = 230 ) or calcium supplements ( 1500 mg calcium/day in 3 divided doses ; n = 231 ) . Growth parameters in utero were assessed with serial ultrasound scans . Birthweight , length , head , abdominal and thigh circumferences were recorded at delivery . No differences were found in fetal biometric measurements recorded at 20 , 24 , 28 , 32 and 36 weeks gestation between fetuses of women who were supplemented with calcium and those who were not . Similarly , neonatal characteristics and anthropometric measurements recorded at delivery were comparable in both groups . We conclude that calcium supplementation of 1500 mg calcium/day in pregnant women with low calcium intake does not appear to impact on fetal somatic or skeletal growth [23719547] BACKGROUND Pregnancy and lactation in adolescents with habitually low calcium intake may adversely affect maternal bone mass . OBJECTIVE We investigated the effect of calcium plus vitamin D supplementation during pregnancy on bone mass during lactation in Brazilian adolescent mothers with low-calcium diets ( ∼600 mg/d ) . DESIGN Pregnant adolescents ( 14 - 19 y ) r and omly received daily calcium ( 600 mg ) plus vitamin D3 ( 200 IU ) ( n = 30 ) or a placebo ( n = 26 ) from 26 wk of pregnancy ( baseline ) until parturition . The bone mineral content ( BMC ) , bone area ( BA ) , and bone mineral density ( BMD ) at the total body , lumbar spine , and hip ( total and femoral neck ) were evaluated by using dual-energy X-ray absorptiometry at 5 and 20 wk postpartum . Serum hormones and 25-hydroxyvitamin D [ 25(OH)D ] were measured . Group comparisons were adjusted for significant covariates . RESULTS The mean serum 25(OH)D concentration was 59 nmol/L at baseline . In comparison with the placebo , 25(OH)D tended to be 14 - 15 nmol/L higher postpartum in the supplemented group ( P = 0.08 ) . Total body and hip BMC and BMD decreased over time ( P ≤ 0.005 ) in both groups with a group × time interaction at the femoral neck ( P < 0.04 ) . Supplemented mothers had higher lumbar spine BA ( 6.7 % ; P = 0.002 ) and lumbar spine BMC ( 7.9 % , P = 0.08 ) than did mothers who consumed the placebo at 5 wk postpartum . At 20 wk postpartum , differences between groups were more evident , with higher lumbar spine BMC ( 13.9 % ) , lumbar spine BA ( 6.2 % ) , and lumbar spine BMD ( 10.6 % ) in the supplemented group ( P ≤ 0.008 ) . CONCLUSIONS Calcium plus vitamin D supplementation during pregnancy of adolescents with low calcium intake results in higher lumbar spine bone mass and a reduced rate of femoral neck bone loss during lactation . Additional studies are required to determine whether bone effects are temporary or long-lasting . This trial was registered at clinical trials.gov as NCT01732328 [16522914] BACKGROUND Growth and bone mineral accretion in Gambian infants are poorer than those in Western population s. The calcium intake of Gambian women is low , typically 300 - 400 mg Ca/d , and they have low breast-milk calcium concentrations , which result in low calcium intakes for their breastfed infants . A low maternal calcium supply in pregnancy may limit fetal mineral accretion and breast-milk calcium concentrations and thereby affect infant growth and bone mineral accretion . OBJECTIVE We investigated the effects of calcium supplementation in Gambian women during pregnancy on breast-milk calcium concentrations and infant birth weight , growth , and bone mineral accretion . DESIGN A r and omized , double-blind , placebo-controlled supplementation study was conducted in 125 Gambian women who received 1500 mg Ca/d ( as calcium carbonate ) or placebo from 20 wk of gestation until delivery . Infant birth weight and gestational age were recorded . Breast milk was collected , and infant anthropometric and bone measurements were performed at 2 , 13 , and 52 wk after delivery . Infant bone mineral status was assessed by using single-photon absorptiometry of the radius and whole-body dual-energy X-ray absorptiometry . RESULTS Compliance with the supplement was high . No significant differences were detected between the groups in breast-milk calcium concentration , infant birth weight , or growth or bone mineral status during the first year of life . A slower rate of increase in infant whole-body bone mineral content and bone area was found in the supplement group than in the placebo group ( group x time interaction : P = 0.03 and 0.02 , respectively ) . CONCLUSION Calcium supplementation of pregnant Gambian women had no significant benefit for breast-milk calcium concentrations or infant birth weight , growth , or bone mineral status in the first year of life [7598067] The calcium requirement for prolonged lactation was investigated in a r and omized supplementation study of Gambian mothers consuming a low-calcium diet ( 7.1 mmol/d , or 283 mg/d ) . Sixty women were studied from 10 d to 78 wk of lactation , receiving calcium or placebo for the first 12 mo . The supplement increased average calcium intake by 17.9 mmol/d ( 714 mg/d ) . Supplementation had no effect on breast-milk calcium concentration or on maternal bone mineral content . Urinary calcium output was higher in supplemented than in unsupplemented mothers by 1.18 mmol/d ( 47 mg/d ) , P < or = 0.005 . Longitudinal changes in urinary calcium output and bone mineral content made a substantial contribution to calcium requirements for lactation . This study suggests that , in women with low calcium intakes , there is no direct benefit from increasing calcium intake during lactation , and that physiological mechanisms operate to furnish calcium for breast-milk production [2627861] Background Prenatal lead exposure is associated with deficits in fetal growth and neurodevelopment . Calcium supplementation may attenuate fetal exposure by inhibiting mobilization of maternal bone lead and /or intestinal absorption of ingested lead . Objective Our goal was to evaluate the effect of 1,200 mg dietary calcium supplementation on maternal blood lead levels during pregnancy . Methods In a double-blind , r and omized , placebo-controlled trial conducted from 2001 through 2003 in Mexico City , we r and omly assigned 670 women in their first trimester of pregnancy to ingest calcium ( n = 334 ) or placebo ( n = 336 ) . We followed subjects through pregnancy and evaluated the effect of supplementation on maternal blood lead , using an intent-to-treat analysis by a mixed-effects regression model with r and om intercept , in 557 participants ( 83 % ) who completed follow-up . We then conducted as-treated analyses using similar models stratified by treatment compliance . Results Adjusting for baseline lead level , age , trimester of pregnancy , and dietary energy and calcium intake , calcium was associated with an average 11 % reduction ( 0.4 μg/dL ) in blood lead level relative to placebo ( p = 0.004 ) . This reduction was more evident in the second trimester ( −14 % , p < 0.001 ) than in the third ( −8 % , p = 0.107 ) and was strongest in women who were most compliant ( those who consumed ≥ 75 % calcium pills ; −24 % , p < 0.001 ) , had baseline blood lead > 5 μg/dL ( −17 % , p < 0.01 ) , or reported use of lead-glazed ceramics and high bone lead ( −31 % , p < 0.01 ) . Conclusion Calcium supplementation was associated with modest reductions in blood lead when administered during pregnancy and may constitute an important secondary prevention effort to reduce circulating maternal lead and , consequently , fetal exposure [3995154] Background : Evidence suggests that increased maternal calcium intake during pregnancy may result in lower offspring blood pressure , prompting calls for more robust data in this field , particularly in setting s of habitually low calcium intake . Objective : The objective was to investigate the effect of maternal calcium supplementation on blood pressure in offspring by recruiting children born after a r and omized , double-blind , placebo-controlled trial of calcium supplementation during pregnancy . Design : Children ( n = 389 ) from a rural area of The Gambia ( mean age : 7.4 ± 1.2 y ; range : 5–10 y ) , whose mothers received a calcium supplement ( 1500 mg Ca/d from 20 wk of gestation until delivery ) or placebo , were followed up in West Africa . Blood pressure was assessed under st and ardized conditions with use of the Omron 705IT automated oscillometric device ( Morton Medical Ltd , London , United Kingdom ) , and anthropometric and body composition ( bioelectrical impedance ) measurements were also made . Results : The analysis was restricted to 350 children born at term , which represented 64 % of original trial births . There was no difference in systolic ( adjusted mean difference : −0.04 mm Hg ; 95 % CI : −1.78 , 1.69 mm Hg ) or diastolic ( adjusted mean difference : 0.25 mm Hg ; 95 % CI : −1.27 , 1.77 mm Hg ) blood pressure between children whose mothers had received calcium and those who received placebo . No interaction between childhood body mass index ( in kg/m2 ; mean : 14.0 ) and maternal calcium supplementation was observed in this study . Conclusion : Calcium supplementation in the second half of pregnancy in Gambian women with very low habitual calcium intakes may not result in lower offspring blood pressure at 5–10 y of age [14553957] BACKGROUND The current study examined the relationship between calcium supplementation during pregnancy and blood pressure ( BP ) in the mother and offspring at 3 months and at 2 years postpartum . METHODS Nulliparous pregnant women were assigned to either receive 2 g of calcium or placebo daily beginning between weeks 13 to 21 of gestation and continuing until delivery . Blood pressure was measured in children and their mothers at 3 months ( n = 260 ) and ( n = 57 ) at 2 years postpartum . Systolic BP was measured in the infants using a sphygmomanometer with ultrasonic amplification . For the toddlers , three supine BP measurements were taken from the right arm using a Critikon automated sphygmomanometer just after measurement of left ventricular wall thickness . RESULTS Systolic BP in the calcium-supplemented infants was 2.2 mm Hg lower than in the placebo group ( P > .05 ) . At 2 years of age , systolic BP was 4.8 mm Hg lower in the calcium supplemented group ( P < .05 ) , whereas diastolic BP was 3 mm Hg lower ( P > .05 ) . There was no difference in left ventricular mass index between groups , although there was a significant correlation between systolic BP and wall thickness ( P < .05 ) . Maternal BP was positively correlated with circulating 1,25(OH)(2)D3 ( P < .001 ) but did not differ between calcium groups at 3 months postpartum . CONCLUSIONS The data on BP in the children are in agreement with previous studies and argue strongly for additional research into the effects of prenatal calcium supplementation on BP regulation in the offspring [20831450] Objectives . To evaluate if calcium supplementation during pregnancy could have any influence on primary dentition measured as the reduction of dental caries of the child . Design . Individual r and omized controlled trial . Setting . One hospital in Rosario , Argentina . Population . R and om sample of 195 12‐year‐old children from a follow‐up study of 614 women who were r and omized during pregnancy to calcium supplementation or placebo . Methods . An independent research er blinded to the group where the mothers were assigned performed a dental examination of the children . Main outcome measures . Proportion of children with at least one decayed , missing or filled teeth ( DMFT/dmft ) and mean number of decayed , missing or filled surfaces ( DMFS/dmfs ) per children . Results . Ninety‐eight children were assessed in the calcium supplementation group and 97 in the placebo group . 63.3 % of the children whose mother took calcium supplementation had at least one DMFT/dmft compared to 86.6 % in the placebo group ( < 0.001 ) . The children whose mother received the intervention had a 27 % reduction in the risk of developing at least one DMFT/dmft ( RR : 0.73 , CI 95 % : [ 0.62 ; 0.87 ] ) . Conclusions . This study shows a modeling effect of calcium intake during pregnancy on dental caries of the offspring . At around 12 years of age children whose mothers received calcium supplementation when pregnant showed a significant reduction in dental caries [11837466] OBJECTIVE The objective of this prospect i ve , open , r and omised trial was to determine the role of calcium supplementation in preventing pre-eclampsia . METHODS One hundred uncomplicated normotensive primigravidae were enrolled in the study before 20 weeks of pregnancy . Fifty each were r and omised to receive either two gram elemental calcium daily from 20 weeks of gestation to delivery ( study group ) or no calcium supplementation ( control group ) . Prior to 20 weeks of gestation each underwent a complete clinical and laboratory evaluation . Serum and urine calcium was measured first at 20 weeks of gestation and then at 24 - 28 weeks and at 32 - 36 weeks of pregnancy . RESULTS Patient characteristics at the start of therapy were similar in the two groups . Blood pressure profile was similar throughout pregnancy in the groups . The incidence of pre-eclampsia was similar ( 18 % in the study group and 16 % in the control group ) , but severe pre-eclampsia was significantly less in the study group . There was no significant difference between the two groups with regards to intra- and postpartum characteristics , perinatal outcome and maternal or fetal side effects . Serum and urinary calcium levels did not differ between the two groups . CONCLUSION While calcium supplementation did not lower the incidence of pre-eclampsia it did reduce its severity [9262495] BACKGROUND Women may lose bone during lactation because of calcium lost in breast milk . We studied whether calcium supplementation prevents bone loss during lactation or augments bone gain after weaning . METHODS We conducted two r and omized , placebo-controlled trials of calcium supplementation ( 1 g per day ) in postpartum women . In one trial ( the study of lactation ) , 97 lactating and 99 nonlactating women were enrolled a mean ( + /-SD ) of 16+/-2 days post partum . In the second trial ( the study of weaning ) , 95 lactating women who weaned their infants in the 2 months after enrollment and 92 nonlactating women were enrolled 5.6+/-0.8 months post partum . The bone density of the total body , lumbar spine , and forearm was measured at enrollment and after three and six months . RESULTS The bone density of the lumbar spine decreased by 4.2 percent in the lactating women receiving calcium and by 4.9 percent in those receiving placebo and increased by 2.2 and 0.4 percent , respectively , in the nonlactating women ( P<0.001 for the effect of lactation ; P= 0.01 for the effect of calcium ) . After weaning , the bone density of the lumbar spine increased by 5.9 percent in the lactating women receiving calcium and by 4.4 percent in those receiving placebo ; it increased by 2.5 and 1.6 percent , respectively , in the nonlactating women ( P<0.001 for the effects of lactation and calcium ) . There was no effect of either lactation or calcium supplementation on bone density in the forearm , and there was no effect of calcium supplementation on the calcium concentration in breast milk . CONCLUSIONS Calcium supplementation does not prevent bone loss during lactation and only slightly enhances the gain in bone density after weaning [18851852] OBJECTIVE To study the effect of calcium supplementation during pregnancy on blood pressure and maternal and neonatal outcomes . METHOD A total of 524 healthy primigravidas with a blood pressure less than 140/90 mm Hg were r and omly assigned between the 12th and 25th weeks to receive 2 g of elemental calcium or placebo and were followed-up until delivery . RESULTS The incidence of pre-eclampsia was significantly less in the calcium than in the placebo group ( 4.0 % vs 12.0 % ; odds ratio [ OR ] , 0.31 ; 95 % confidence interval [ CI ] , 0.15 - 0.63 ) ; the mean systolic and diastolic blood pressures at study completion were different in the calcium and placebo group ( P=0.007 and P=0.02 ) . The risk for preterm delivery was less in the calcium ( 7.0 % ) than in the placebo ( 12.7 % ) group ( OR , 0.51 ; 95 % CI , 0.28 - 0.93 ) . The mean baseline calcium intake was 313.83+/-203.25 mg/day ( range , 85.71 - 910.71 mg/day ) , which is lower than the recommended dietary intake of 1000 mg , and the 24-hour urinary calcium excretion was 130.82+/-67.44 mg/dL ( range , 40.5 - 387 mg/dL ) . CONCLUSION Calcium supplementation appears to reduce the occurrence of pre-eclampsia and preterm delivery in primigravidas who have a daily dietary calcium intake less than the recommended dietary allowances [3306493] Fifty-two healthy pregnant women were enrolled in a double-blind , r and omized , controlled clinical trial . After the 26th week of gestation , the women were given either 1.5 g of elemental calcium per day or a placebo . Subjects in the calcium group , after adjustment for race and initial blood pressure ( BP ) , had a term mean systolic and diastolic BP value of 4 - 5 mmHg lower than those in the placebo group ( P less than .05 ) . The incidence of pregnancy-induced hypertension was 11.1 % in the placebo group and 4.0 % in the calcium group , a nonsignificant difference . Combining these values with previous data , we found a dose-effect relationship between calcium intake and BP reduction during the third trimester of pregnancy . Further research should be directed at underst and ing the mechanism of this effect and trying to demonstrate a reduction in pregnancy-induced hypertension with calcium supplementation in a larger population [3778867] Background : Dietary calcium intake in rural Gambian women is very low ( ∼350 mg/d ) compared with international recommendations . Studies have suggested that calcium supplementation of women receiving low-calcium diets significantly reduces risk of pregnancy hypertension . Objective : We tested the effects on blood pressure ( BP ) of calcium carbonate supplementation ( 1500 mg Ca/d ) in pregnant , rural Gambian women . Design : The study was a r and omized , double-blind , parallel , placebo-controlled supplementation trial from 20 wk of gestation ( P20 ) until delivery ( calcium : n = 330 ; placebo ; n = 332 ) . BP and anthropometric measures were taken at P20 and then 4 weekly until 36 wk of gestation ( P36 ) , and infant anthropometric measures were taken at 2 , 13 , and 52 wk postdelivery . Results : A total of 525 ( calcium : n = 260 ; placebo : n = 265 ) women had BP measured at P36 and subsequently delivered a healthy term singleton infant . Mean compliance was 97 % , and urinary calcium measures confirmed the group allocation . At P20 , the mean ( ±SD ) systolic blood pressure ( SBP ) was 101.2 ± 9.0 and 102.1 ± 9.3 mm Hg , and diastolic blood pressure ( DBP ) was 54.5 ± 7.3 and 55.8 ± 7.8 mm Hg , in the calcium and placebo groups , respectively . The intention-to-treat analysis that was adjusted for confounders showed no significant effect of calcium supplementation on the change between P20 and P36 ( calcium compared with placebo ; mean ± SEM ) in SBP ( −0.64 ± 0.65 % ; P = 0.3 ) or DBP ( −0.22 ± 1.15 % ; P = 0.8 ) . There was no significant effect of supplementation on BP , pregnancy weight gain , weight postpartum , or infant weight , length , and other measures of growth . However , the comparability of the original r and omly assigned groups may have been compromised by the exclusion of 20.7 % of women from the final analysis . Conclusions : Calcium supplementation did not affect BP in pregnancy . This result may have been because the Gambian women were adapted to a low dietary calcium intake , and /or obesity , high gestational weight gain , high underlying BP , tobacco use , alcohol consumption , and sedentary lifestyles were rare . This trial was registered at the International St and ard R and omized Controlled Trial Register ( www.controlled-trials.com/m rct / ) as IS RCT N96502494 [3994635] Background : Mobilization of maternal bone mineral partly supplies calcium for fetal and neonatal bone growth and development . Objective : We investigated whether pregnant women with low calcium intakes may have a more extensive skeletal response postpartum that may compromise their short- or long-term bone health . Design : In a subset of participants ( n = 125 ) in a double-blind , r and omized , placebo-controlled trial ( International Trial Registry : IS RCT N96502494 ) in pregnant women in The Gambia , West Africa , with low calcium intakes ( ≈350 mg Ca/d ) , we measured bone mineral status of the whole body , lumbar spine , and hip by using dual-energy X-ray absorptiometry and measured bone mineral status of the forearm by using single-photon absorptiometry at 2 , 13 , and 52 wk lactation . We collected blood and urine from the subjects at 20 wk gestation and at 13 wk postpartum . Participants received calcium carbonate ( 1500 mg Ca/d ) or a matching placebo from 20 wk gestation to parturition ; participants did not consume supplements during lactation . Results : Women who received the calcium supplement in pregnancy had significantly lower bone mineral content ( BMC ) , bone area ( BA ) , and bone mineral density ( BMD ) at the hip throughout 12 mo lactation ( mean ± SE difference : BMC = −10.7 ± 3.7 % , P = 0.005 ; BA = −3.8 ± 1.9 % , P = 0.05 ; BMD = −6.9 ± 2.6 % , P = 0.01 ) . The women also experienced greater decreases in bone mineral during lactation at the lumbar spine and distal radius and had biochemical changes consistent with greater bone mineral mobilization . Conclusions : Calcium supplementation in pregnant women with low calcium intakes may disrupt metabolic adaptation and may not benefit maternal bone health . Further study is required to determine if such effects persist long term or elicit compensatory changes in bone structure [2721965] Maternal vitamin D deficiency during pregnancy is a recognized risk factor for rickets and osteomalacia in infancy ( 1 ) . The circulating plasma concentration of 25-hydroxyvitamin D ( 25OHD ) , a long-lived metabolite of vitamin D , is used to judge vitamin D status ; values below 25 nmol/L are associated with an increased risk of rickets and osteomalacia ( 1 ) . There is evidence that a low maternal plasma 25OHD in pregnancy may influence the growth and bone mineral accrual of the offspring during foetal life , infancy and childhood . Positive associations have been reported between maternal vitamin D status in pregnancy and birthweight , birth length , length at 1 year and bone mineral accretion at 9 years ( 2–6 ) , although evidence is conflicting ( 7,8 ) . These relationships have been observed at concentrations of 25OHD higher than those associated with rickets and osteomalacia , and there are calls to raise the accepted lower threshold of vitamin D sufficiency for pregnant women , most recently to 80 nmol/L ( 9 ) . On a population basis , plasma 25OHD concentrations above 80 nmol/L are relatively uncommon in countries at temperate latitudes but are more common among people living in the tropics who have abundant skin sunshine exposure ( 10 ) . To contribute to the debate on the definition of vitamin D sufficiency in pregnancy , we have investigated the influence of maternal plasma 25OHD concentration on foetal and infant growth in a rural area of The Gambia , West Africa ( 13 ° N ) . In this region , there is tropical sunshine all year , the women are farmers who work out-of-doors for much of each day , and local female dress does not restrict regular sunshine exposure to the face , neck , shoulders , arms and feet , especially during farm work and gardening . The study was a secondary analysis of biochemical , anthropometric and bone data from a subset of 125 women and infants collected during a calcium supplementation study of blood pressure in pregnant Gambian women ( International Trial Registry : IS RCT N96502494 ) . No significant benefits for foetal and infant growth of maternal calcium supplementation were identified despite the low customary calcium intake in The Gambia ( 11 ) . The protocol , methods , maternal characteristics and infant data from the detailed study have been published ( 11 ) . Briefly , women from the rural villages of Keneba and M and uar , West Kiang , The Gambia were recruited at 20 weeks of pregnancy ( P20 ) and r and omized to a daily calcium supplement or a matching placebo tablet until parturition ( 1500 mg Ca as calcium carbonate and microcellulose-lactose , respectively ; Nycomed Pharma AS , Asker , Norway ) . Fasting , early morning blood was collected and anthropometry performed at P20 and 36 weeks of pregnancy ( P36 ) . The mean ( ± SD ) age , weight , height and dietary calcium intake of the women at P20 were 27.4 ± 7.5 years , 56.3 ± 6.7 kg , 1.61 ± 0.05 m and 356 ± 190 mg/day , respectively . The median parity ( range ) was 3 ( 0–10 ) . Infant birthweight was measured within 24 h of delivery . Weight , crown-heel length and head circumference were measured at 2 , 13 and 52 weeks postpartum . In addition , infant bone mineral content ( BMC ) , bone mineral density ( BMD ) and bone width ( BW ) or bone area ( BA ) , were measured by single photon absorptiometry of the midshaft radius ( Lunar SP2 , Lunar Corporation , Madison , WI , USA ) and , for a subset ( n = 44 , 47 and 52 at 2 , 13 and 52 weeks , respectively ) , by whole-body dual-energy X-ray absorptiometry ( Lunar DPX+ , software version 4.7b , Lunar Corporation ) . Plasma 25OHD was measured a using radioimmunometric assay ( Diasorin Ltd , Wokingham , Berks , UK ) , with assay performance monitored through the Vitamin D External Quality Assessment Scheme ( DEQAS ; Endocrine/Oncology Laboratory , Charing Cross Hospital , London , UK ) . The intra- and inter-assay coefficients of variation were 4 % and 100 ) ; possible trends in the data with p = 0.01–0.1 were noted . The analysis was conducted on 123 mother – infant pairs ; blood sample s from two subjects were not available . Mean ± SD 25OHD ( range ) was : P20 = 103 ± 25 ( 53–167 ) nmol/L ; P36 = 111 ± 27 ( 51–189 ) nmol/L. No subject had a 25OHD value < 50 nmol/L , 20 % and 16 % had 25OHD < 80 nmol/L , at P20 and P36 , respectively . There was a high degree of within-subject consistency in 25OHD at P20 and P36 ( 25OHDP36 = 33.2 + [ 0.79 ± 0.07] × 25OHDP20 , p ≤ 0.001 , R2 adjusted 51.5 % , n = 121 ) ; 11 % of women had 25OHD < 80 nmol/L at both P20 and P36 . The mean birthweight of the infants was 2.99 ± 0.36 kg . The infant anthropometric and bone measures during the first year are given in Table 1 . No significant relationships or trends in the data were observed between maternal 25OHD concentration using the values at P20 , P36 or the mean of the two and any of the following infant measures : birthweight , infant weight , length , head circumference , BMC , BW ( or BA ) , BMD and size-adjusted BMC of the midshaft radius and whole body at any time postpartum . This is illustrated in Figure 1 for birthweight as a function of maternal 25OHD concentration at P20 . Comparing the results for mothers with 25OHD above and below 80 nmol/L did not alter this finding . Table 1 Anthropometric and bone measures of Gambian infants Figure 1 Lack of a significant relationship between infant birthweight and maternal vitamin D status at 20 weeks of pregnancy ( p = 0.8 ) . Multiple regression model included season , maternal height , weight , weight gain , supplement group and sex of the infant . No significant interaction between supplement group and maternal 25OHD concentration was observed for any infant variable . Trends in the data were observed in a few instances for a supplement group × 25OHD interaction among the bone measures but no consistent picture emerged and they were considered to have arisen by chance . We conclude that there is no evidence for an influence of vitamin D status during pregnancy on infant growth and bone mineral accrual in the conditions prevailing in The Gambia . The children in this study , as is common in this region of The Gambia ( 13 ) , were born small , grew well for the first months of life but experienced growth faltering during later infancy compared to Western children ( 11,14 ) , as demonstrated by their weight and length SDS . The 25OHD concentrations of the women were > 50 nmol/L in the second half of pregnancy , and no distinction could be drawn in infant outcomes between mothers with concentrations above or below 80 nmol/L. Thus , our study suggests that , for women with regular , adventitious UVB sunshine exposure and in situations where foetal and infant growth may be constrained by multiple factors , there would be no benefit for foetal and infant growth or bone mineral accrual in aim ing to increase the vitamin D status of individual mothers during pregnancy above 50 or 80 [19528561] Context Some data suggest that body weight is inversely associated with calcium intake , increasing the possibility that supplemental calcium might facilitate weight loss or prevent weight gain . Contribution Research ers r and omly assigned overweight and obese patients to supplemental calcium or placebo and found no between-group differences in measures of weight change . Caution Trial participants were almost all women . Implication Calcium supplementation is unlikely to prevent weight gain in persons who are overweight or obese . The Editors The high prevalence of overweight and obesity in the United States ( 1 ) has stimulated great interest in identifying approaches that may help to prevent weight gain or improve ability to lose weight . Increasing calcium intake is a potential means of weight management that has received much attention from both lay press ( 24 ) and the medical community ( 57 ) . This interest has been stimulated by a series of cross-sectional studies ( 817 ) reporting that children and adults with low reported consumption of dietary ( primarily dairy ) calcium have greater body weight , a higher degree of adiposity , and greater risk for having components of the metabolic syndrome than those who report that they consume more calcium . Some ( 1824 ) , although not all ( 2534 ) , longitudinal investigations have also suggested that children and adults who consume a lower calcium diet tend to gain more weight than those with greater dietary or supplemental calcium intake . These data , together with some small clinical trials suggesting that weight loss during dieting may be augmented by supplemental ( 35 ) or dairy calcium ( 3538 ) , have led to expectations that substantially augmenting calcium intake might diminish body weight by 0.5 kg or more each year ( 5 , 18 , 22 , 39 ) . Two possible mechanisms for an effect of dietary calcium on body weight have been suggested . First , calcium can combine with fatty acids in the intestine to form insoluble soaps that are therefore not absorbed ( 40 , 41 ) . Second , some research ers ( 4246 ) have proposed that low dietary calcium leads to increased adipocyte triglyceride deposition ( 4749 ) . If calcium substantially affects fat accumulation , calcium supplementation could prevent additional weight and fat gain among people with high body weight . To test this hypothesis , we measured the effect of calcium carbonate supplementation for 2 years on the weight and body fat of overweight and obese adults . Methods Setting and Participants We recruited participants through advertisements posted in Bethesda , Maryl and , and spontaneous reply to newspaper and radio advertising in the Washington , DC , metropolitan area seeking healthy adult volunteers for a project to study the health effects of calcium supplementation . Men and women age 18 to 80 years were eligible to enroll if they had a body mass index ( BMI ) of 25 kg/m2 or more and did not have cerebrovascular , cardiovascular , pulmonary , renal , hepatic , endocrinologic , or other substantial medical disease . Women were ineligible if they were pregnant , were breastfeeding , or had received a recommendation from a health care professional to take calcium supplements for any condition . We excluded persons who regularly used medications known to affect body weight , had a weight loss of 3 % or more in the preceding 3 months , reported total calcium intake in excess of 3.5 g/d , used supplemental calcium in excess of 300 mg/d , used vitamin D supplements in excess of 400 IU/d , or had a history of renal stones . The institutional review board of the National Institute of Child Health and Human Development , National Institutes of Health , approved the research protocol . Each participant provided signed consent . We provided financial compensation for participants ' time and inconvenience . Design Overview We conducted a single-center , r and omized , double-blind , placebo-controlled trial from March 2002 to April 2006 . After an outpatient visit to determine eligibility and obtain initial assessment s , participants entered a 2-year , double-blind treatment period . R and omization and Interventions We r and omly assigned participants , in a 1:1 ratio , to receive either elemental calcium , 1500 mg/d ( calcium carbonate , purchased from Particle Dynamics , St. Louis , Missouri ) , or placebo , administered as 2 divided doses with meals . Investigators assigned consecutive code numbers to participants from prespecified lists stratified by race or ethnicity , sex , and BMI ( 25 to 26.99 , 27 to 29.99 , 30 to 34.99 , and 35 kg/m2 ) . The National Institutes of Health Clinical Center Pharmaceutical Development Section used permuted blocks with stratification to generate the allocations that translated code numbers into study group assignments by using a pseudo-r and om number program . The Pharmaceutical Development Section prepared placebo and calcium capsules to appear identical . Pharmacy personnel , not otherwise involved with the conduct of the study , dispensed study capsules with medication placed in containers that appeared identical and differed only by the individual participant code number . No participant , investigator , or other medical or nursing staff interacting with participants was aware of study group assignments for the duration of the trial . Initial Assessment At their prer and omization evaluation , participants reported after an overnight fast and were weighed in hospital gowns by using a digital scale ( Life Measurement Instruments , Concord , California ) that was calibrated with a known weight before each participant 's measurement . We measured height by using a stadiometer calibrated before each measurement ( Holtain , Crymych , United Kingdom ) . Research dietitians assessed abdominal and hip circumferences in triplicate to the nearest 0.1 cm , as recommended ( 50 , 51 ) , and measured triceps skinfold thickness to the nearest 0.5 mm by using Lange calipers ( Cambridge Scientific Industries , Cambridge , Maryl and ) . We measured blood pressure , obtained after a 5-minute rest period , 3 times at 5-minute intervals from seated participants by using an automated sphygmomanometer ( Dinamap-Plus , Critikon , Tampa , Florida ) . We did whole-body dual-energy x-ray absorptiometry to estimate total body fat mass ( Delphi A , software version 11.2 , Hologic , Bedford , Massachusetts ) . We measured intact parathyroid hormone concentrations with 2-site immunochemiluminometric assays ( 52 ) , and serum 25-hydroxy vitamin D levels by using a competitive binding assay ( Nichols Advantage , Nichols Diagnostic , San Clemente , California ) ( 53 ) . We asked participants with substantial vitamin D deficiency ( serum 25-hydroxy vitamin D level < 25.0 nmol/L ) to take vitamin D , 400 IU/d ( ergocalciferol ) , in a multivitamin . We assessed baseline dietary calcium intake by using a 7-day food record that a registered dietitian review ed with each participant to maximize accuracy and completeness , and analyzed for dietary calcium intake by using the Nutrition Data System for Research software , versions 4.04_32 and 4.05_33 ( University of Minnesota , Minneapolis , Minnesota ) ( 54 ) . We measured calcium intake from multivitamins or calcium supplements with a vali date d calcium question naire ( 55 ) that was review ed for completeness through an interview with a registered dietitian . We recorded the calcium content as it was listed on the label of each multivitamin or calcium supplement . We measured dietary and supplemental vitamin D intakes in the same manner . We estimated energy intake at baseline and at 2 years by using a food-frequency question naire that assessed total diet ( 5557 ) . We measured socioeconomic status by using the Hollingshead score ( 58 ) . Outcomes and Follow-up Primary efficacy end points were change in body weight and body fat mass at the end of 2 years of treatment . Secondary outcomes were fasting anthropometric measurements , body composition by dual-energy x-ray absorptiometry , and change in blood pressure , assessed yearly , along with question naire data on dietary and supplemental calcium intake ( 55 ) . In addition , we contacted participants every 3 months to complete question naires about their adherence to the medication regimen ; assess their general health ; and obtain self-reports of mood , stress , physical activity , and hunger . Every 6 months , participants returned to the clinic to exchange their unused study medication for a new supply . We used the tally of returned capsules to assess adherence . To examine adequacy of the masking procedure , participants completed a question naire at the end of the study that requested they report their best guess about their study group assignment . Statistical Analysis All reported primary data analyses were prespecified . On the basis of our previous study of observed yearly changes in body weight over time ( 59 ) , we needed a total sample size of 256 participants to detect a 0.35-kg difference per year in weight change ( that is , 0.7 kg over 2 years ) between groups with 80 % power . Participant accrual was set at 340 participants to allow 25 % loss to follow-up . We analyzed data by using SPSS for Windows , version 14.0 ( SPSS , Chicago , Illinois ) . We assessed efficacy in the intention-to-treat sample of all r and omly assigned participants . We did 2 efficacy analyses . The primary analysis used a multiple imputation model for missing data under a missing-at-r and om assumption ( 60 ) . By using NORM , version 2.03 ( The Pennsylvania State University , State College , Pennsylvania ) ( 61 , 62 ) , we included all available baseline , 1-year , and 2-year outcome measures in an imputation model along with age , sex , race , baseline serum 25-hydroxy vitamin D concentration , baseline calcium intake , and study group . We then combined the coefficients from analyses of 20 imputed data sets into a single set of estimates according to Shafer ( 62 ) and the Rubin rules ( 63 ) . To assess sensitivity of these results to the missing-at-r and om assumption , we conducted 3 additional analyses : assuming that all participants who withdrew from the study had major weight gain ( [9241285] Objective To determine whether increased calcium intake ( 2 g/day ) in pregnancy is effective in reducing the risk of preeclampsia in pregnant teenagers . Methods The present study was a prospect i ve , r and omized , double-blind , controlled clinical trial . Two hundred sixty teenaged pregnant girls attending the Hospital Gíneco-Obstétrico Isidro Ayora in Quito , Ecuador , were included . Selection criteria were age less than 17.5 years , nulliparity , first prenatal visit before 20 weeks ' gestation , and residency in Quito ( 2800-m altitude ) . We used a table of r and om numbers to assign 125 girls to receive 2000 mg of elemental calcium daily , beginning at 20 weeks of gestation and continuing until delivery ; 135 women in the control group received a placebo . Blood pressure ( BP ) was measured twice every 4 weeks until delivery and at 48 hours after delivery . The diagnosis of preeclampsia was defined as BP greater than 140/90 mmHg on at least two occasions more than 6 hours apart and proteinuria greater than 30 mg/dL ( over one cross by dipstick on two occasions 4 - 24 hours apart ) . Results The average daily calcium intake in this population was approximately 51 % of the Recommended Dietary Allowance . Calcium supplementation was associated with a significantly decreased risk of preeclampsia ( risk reduction 12.35 % ; P < .001 ) , with 3.2 % ( n = 4 ) developing preeclampsia in the treatment group versus 15.5 % ( n = 21 ) in the placebo group . Moreover , calcium supplementation led to a reduction in systolic BP of 9.1 mmHg and in diastolic BP of 6.0 mmHg . Conclusion These results suggest that calcium supplementation during pregnancy in population s with low calcium intake is a safe , effective , and inexpensive preventive measure that significantly reduces the risk of preeclampsia [2220915] Results are presented of a r and omized , double-blinded controlled clinical trial of calcium supplementation ( 2.0 gm of elemental calcium as calcium carbonate ) and a placebo . All participants were 17 years of age or less and clinical ly healthy . Patients were enrolled by the twenty third week of gestation . The mean duration of calcium supplementation or placebo was approximately 14 weeks . Treatment consisted of 2.8 ( + /- 1.5 ) tablets per day in the placebo group ( N = 95 ) and 3.0 ( + /- 1.4 ) tablets per day in the calcium group ( N = 94 ) . Dietary calcium intake was similar in both groups at about 1200 mg/day . The calcium group had a lower incidence of preterm delivery ( less than 37 weeks ; 7.4 % vs 21.1 % ; p = 0.007 ) ; spontaneous labor and preterm delivery ( 6.4 % vs 17.9 % ; p = 0.01 ) ; and low birth weight ( 9.6 % vs 21.1 % ; p = 0.03 ) . This effect was also present after stratified analysis by level of treatment compliance , urinary tract infection , and chlamydial infection . Life-table analysis demonstrated an overall shift to a higher gestational age in the calcium group compared with the placebo group ( log-rank test , p = 0.02 ) . As suggested previously , the observed effect could be mediated by a reduction in uterine smooth muscle contractibility . If confirmed by future research , these results could represent an important preventive intervention for prematurity in high-risk population [8058229] Objective To evaluate the efficacy of oral supplemental calcium in reducing the incidence of pregnancy-induced hypertension ( gestational hypertension or preeclampsia ) in angiotensin-sensitive nulliparas [16946216] OBJECTIVE : To evaluate the effects of dietary calcium ( Ca ) intervention on adolescent pregnant mothers and their newborns . METHODS : Seventy-two pregnant adolescent mothers were r and omized into one of 3 groups : control , orange juice fortified with calcium , and dairy . The orange juice and dairy groups were required to take more than 1,200 mg Ca . Calcium tablets were added for those not able to meet required Ca . Maternal and infant weight , length , and blood pressure ( BP ) were recorded . Maternal dietary records were evaluated . Mother ’s blood was drawn for serum Ca , phosphate ( P ) , magnesium ( Mg ) , and vitamin 25-hydroxyvitamin D ( D ) . Cord blood was collected for serum Ca and D. Newborn total body Ca was determined . RESULTS : All mothers were similar in weight , height , and BP . Mothers in the orange juice plus calcium and dairy groups had higher intakes of Ca ( 1,472 mg and 1,771 mg ) than controls ( 862 mg ) . One half of the mothers in the orange juice plus calcium group required Ca tablets . Mothers in the dairy group had higher intakes of P , D , and Mg , higher serum folate and D , and higher cord D levels . Mothers in the orange juice plus calcium group had higher serum P but lower serum folate and D. Infants ( 3,517±273 g ) in the dairy group were heavier than infants in the control ( 3,277±177 g ) and orange juice plus calcium ( 3,292±165 g ) groups . Infants in the dairy group had higher total body calcium than control infants . CONCLUSION : Calcium diet supplemented with dairy products during adolescent pregnancy result ed in higher maternal vitamin D and folate serum levels and higher newborn weight and bone mineralization compared with controls . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00320125 LEVEL OF EVIDENCE : [16522392] OBJECTIVE The purpose of this trial was to determine whether calcium supplementation of pregnant women with low calcium intake reduces preeclampsia and preterm delivery . STUDY DESIGN R and omized placebo-controlled , double-blinded trial in nulliparous normotensive women from population s with dietary calcium < 600 mg/d . Women who were recruited before gestational week 20 received supplements ( 1.5 g calcium/d or placebo ) throughout pregnancy . Primary outcomes were preeclampsia and preterm delivery ; secondary outcomes focused on severe morbidity and maternal and neonatal mortality rates . RESULTS The groups comprised 8325 women who were assigned r and omly . Both groups had similar gestational ages , demographic characteristics , and blood pressure levels at entry . Compliance were both 85 % and follow-up losses ( calcium , 3.4 % ; placebo , 3.7 % ) . Calcium supplementation was associated with a non-statistically significant small reduction in preeclampsia ( 4.1 % vs 4.5 % ) that was evident by 35 weeks of gestation ( 1.2 % vs 2.8 % ; P = .04 ) . Eclampsia ( risk ratio , 0.68 : 95 % CI , 0.48 - 0.97 ) and severe gestational hypertension ( risk ratio , 0.71 ; 95 % CI , 0.61 - 0.82 ) were significantly lower in the calcium group . Overall , there was a reduction in the severe preeclamptic complications index ( risk ratio , 0.76 ; 95 % CI , 0.66 - 0.89 ; life-table analysis , log rank test ; P = .04 ) . The severe maternal morbidity and mortality index was also reduced in the supplementation group ( risk ratio , 0.80 ; 95 % CI , 0.70 - 0.91 ) . Preterm delivery ( the neonatal primary outcome ) and early preterm delivery tended to be reduced among women who were < or = 20 years of age ( risk ratio , 0.82 ; 95 % CI , 0.67 - 1.01 ; risk ratio , 0.64 ; 95 % CI , 0.42 - 0.98 , respectively ) . The neonatal mortality rate was lower ( risk ratio , 0.70 ; 95 % CI , 0.56 - 0.88 ) in the calcium group . CONCLUSION A 1.5-g calcium/day supplement did not prevent preeclampsia but did reduce its severity , maternal morbidity , and neonatal mortality , albeit these were secondary outcomes [8987323] In a r and omized controlled trial 201 healthy nulliparous women were r and omly allocated by means of a computer generated r and omization list . From 20 weeks of gestation until delivery they received either 2 g of oral elemental calcium ( n = 103 ) per day or an identical placebo ( n = 98 ) . Eleven women ( 5.47 % ) were lost to follow-up after r and omization . The study groups were very similar at the time of r and omization ; with respect to several clinical and demographic variables . Treatment compliance was very similar in both groups as was determined by pill count . The rate of pregnancy induced hypertension was lower in the calcium group than in the placebo group 8.24 % ; vs 29.03 % ; ( RR = 0.28 ; 95 % CI 0.14 - 0.59 ) . The incidence of gestational hypertension was 6.18 % in the calcium group and 17.20 % in the placebo group ( RR = 0.28 ; 95 % CI 0.08 - 0.80 ) , and the incidence of preeclampsia was 2.06 % in the calcium group and 11.82 % in the placebo group ( RR = 0.13 ; 95 % CI 0.01 - 0.64 ) . In conclusion calcium supplementation given in pregnancy to nulliparous women reduces the incidence of pregnancy induced hypertension [6846435] In this study the hypothesis that calcium supplementation during pregnancy can modify blood pressure patterns in a population of normal pregnant women was tested . Thirty-six women with normal single pregnancies , between 20 and 35 years of age , in the second trimester of gestation ( 15 weeks ) , were r and omly assigned to receive 1 gm of calcium per day ( n = 11 ) , 2 gm per day ( n = 11 ) , or a placebo ( n = 14 ) . No differences were observed at the times of admission into the study ( baseline ) in demographic and clinical variables or in the calcium intake of each group . Baseline blood pressure measures in several positions also were not different . After the initial blood pressure measures ( fifteenth week ) , five follow-up blood pressure measures were obtained . The supplemented groups had significantly lower diastolic blood pressure than the control subjects between the twentieth and twenty-fourth weeks of gestation . Thereafter , an increase in the control group and the group receiving 1 gm of calcium was observed , but levels were similar at term . On the contrary , patients receiving 2 gm of calcium had blood pressure values that remained significantly lower throughout the third trimester . No differences or clear patterns were observed in the blood levels of calcium , magnesium , phosphorus , and proteins between and within groups during gestation . A possible explanation involving parathyroid hormone is attempted [20044757] Objective Calcium dem and is increased during pregnancy . However , few r and omized controlled trials examined the effects of calcium supplementation on bone mass during pregnancy . This study determined effects of calcium and milk supplementation on maternal bone mineral density ( BMD ) and bone turnover in pregnant Chinese women with habitual low calcium intake . Methods In this r and omized controlled trial , 36 Chinese pregnant women ( 24–31 years , 18 gestational weeks ) were r and omly assigned to the following three arms ( 12 each ) : I , usual diet ; II , “ I ” + 45 g milk powder ( containing 350 mg calcium ) ; or III , “ II ” + 600 mg calcium/day from gestational age of 20 weeks to 6 weeks post-partum ( PP ) . BMD was measured post-treatment using dual-energy X-ray absorptiometry . Dietary intakes , 24-h urinary calcium , bone resorption ( urinary hydroxyproline ) and formation ( serum osteocalcin ) biomarkers were examined at the gestational age of 20 and 34 weeks , and 6 weeks PP . Results A dose-dependent relationship was observed between calcium intake and BMDs . The BMD values were significantly higher in subjects with calcium and milk supplementation than those in the controls at the whole body and spine ( p < 0.05 ) but not at the hip sites . We found significant decreases in changes of urinary hydroxyproline , and significant increases in serum osteocalcin during the intervention period in the calcium/milk intervention groups than those in the control group ( all p < 0.05 ) . Conclusion Calcium/milk supplementation during pregnancy is associated with greater BMD at the spine and whole body and suppresses bone resorption in Chinese women with habitual low calcium intake [19716540] OBJECTIVE We postulated that calcium supplementation of calcium-deficient pregnant women would lower vascular resistance in uteroplacental and fetoplacental circulations . STUDY DESIGN Pulsatility index ( PI ) and resistance index ( RI ) ( uterine and umbilical arteries ) and presence of bilateral uterine artery diastolic notching were assessed by Doppler ultrasound between 20 - 36 weeks ' gestation in 510 healthy , nulliparous Argentinean women with deficient calcium intake in a r and omized , placebo-controlled , double-blinded trial . RESULTS Average umbilical and uterine artery RI and PI tended to be lower in the supplemented group at each study week . Differences became statistically significant for umbilical artery RI and PI from 32 and 36 weeks , respectively . Estimated probabilities of bilateral uterine artery diastolic notching trended toward lower values in calcium-supplemented women . CONCLUSION Calcium supplementation of pregnant women with deficient calcium intake may affect uteroplacental and fetoplacental blood flow by preserving the vasodilation of normal gestation [8932976] The results of ten clinical trials suggest that supplemental calcium may prevent preeclampsia . However , method ologic problems and differences in study design limit the acceptance of the results and their relevance to other patient population s. Many of the trials were conducted in countries where , unlike the United States , the usual daily diet contained little calcium . Moreover , none of the trials has reported the outcome of systematic surveillance for urolithiasis , a potential complication of calcium supplementation . In response to the need for a thorough evaluation of the effects of calcium supplementation for the prevention of preeclampsia in the United States , the trial of Calcium for Preeclampsia Prevention ( CPEP ) was undertaken at five university medical centers . Healthy nulliparous patients were r and omly assigned to receive either 2 g supplemental calcium daily ( n = 2295 ) or placebo ( n = 2294 ) in a double-blind study . Study tablets were administered beginning from 13 to 21 completed weeks of gestation and continued until the termination of pregnancy . CPEP employed detailed diagnostic criteria , st and ardized techniques of measurement , and systematic surveillance for the major study endpoints and for urolithiasis . The nutrient intake of each patient was assessed at r and omization and at 32 - 33 weeks gestation . This report describes the study rationale , design , and methods [11864514] OBJECTIVE To research some effects of different levels of calcium intake in the mother 's bone mineral density . METHODS On the basis of insignificantly different among energy and other nutrition intake excepting calcium , 35 volunteers in pregnant 18 weeks healthy women were r and omly divided into I. II and III group [ calcium intake were ( 550 + /- 150 ) mg/d , ( 900 + /- 150 ) mg/d and ( 1,500 + /- 150 ) mg/d ] . The tracked study began from pregnant 20 weeks to postpartum 45 days . All over and different body of BMD ( Bone Mineral Density ) were assessed by dual-energy X-rays absorptiometry . RESULTS I group of many location BMD were below that of other groups ( P < 0 . 01 ) . As compared with the same age women 's lumbar spine BMD , I group was only maintained within the rang ( 85.14 + /- 6.61)% , and osteoporosis in some places of bone were found in some individual . II group was ( 90.74 + /- 6.53)% . III group was ( 100.44 + /- 5.19)% . Allover different body 's BMD were significantly correlated with the average BMD ( r > 0.8 , P < 0.1 ) , the most significant correlation was third lumbar spine . Calcium intake of women was positively correlated with different body 's BMD ( r > 0.5 , P < 0.01 ) . CONCLUSION III group , calcium intake was ( 30.68 + /- 3.56 ) mmol/d , pass through period of pregnancy , parturition and short-term breast-feed mother body remain the same BMD , and prevent osteoporosis . Reporting pregnant women calcium nutrition pass through BMD , lumbar spine is good representation [11430936] OBJECTIVE To study the effect of calcium supplementation on reduction of pre-eclampsia in Iranian women at high risk of pre-eclampsia . METHODS Thirty pregnant women at high risk of developing pre-eclampsia were r and omized to 2 g of daily calcium and placebo . Subjects and investigators were blinded to treatment allocation . The inclusion criteria were positive rollover test , having at least one risk factor for pre-eclampsia , between 28 and 32 weeks of pregnancy , and blood pressure less than 140/90 ( mm Hg ) . Exclusion criteria were having any chronic condition . Pre-eclampsia was defined as systolic/diastolic blood pressure over 140/90 plus proteinuria . All the subjects were followed up to delivery . RESULT A sevenfold reduction in the occurrence of pre-eclamsia were seen among the calcium group compared with the placebo group ( 7 out of 15 developed pre-eclampsia in control group vs. 1 out of 15 in calcium group , P=0.014 ) . No major effect on pregnancy induced hypertension was seen ( 66 % in placebo and 76 % in calcium group developed hypertension ) but the onset of hypertension was delayed 3 weeks in the calcium group . A longer duration of pregnancy was seen in calcium than placebo ( mean+/-S.D.=37+/-2 for calcium and 34+/-2 for placebo , P<0.05 ) . Infants born to the calcium group , on average , were 552 g heavier than infants born to the placebo group , P<0.05 . CONCLUSION Calcium supplementation is beneficial for preventing pre-eclampsia among Iranian women at high risk of developing pre-eclampsia [7770260] Objective To determine whether calcium supplementation prevents progression to severe disease in preterm nulliparous women with mild preeclampsia . Methods Seventy-five women hospitalized at 24–36 weeks ' gestation because of mild preeclampsia were r and omized to receive either 2 g/day of elemental calcium ( 36 women ) or placebo ( 39 ) . Both groups had similar demographic characteristics , initial blood pressure measurements , and amount of proteinuria . Diagnostic criteria and clinical management for severe preeclampsia were applied consistently . Results Eighteen of 36 calcium-treated subjects ( 50 % , 95 % confidence interval [ CI ] 33–67 ) developed severe preeclampsia , compared with 19 of 39 ( 48.7 % , 95 % CI 32–65 ) in the placebo group ( relative risk 1.03 , 95 % CI 0.64–1.03 ; P = 1.00 ) . Blood pressure values , gestational age at delivery , newborn weights , incidence of low Apgar scores , and umbilical arterial blood gases were similar for the two groups . Conclusion Calcium supplementation does not prevent severe preeclampsia in preterm patients with mild disease [18719672] Based on cell culture and studies in mice , increased dietary calcium appears to stimulate lipolysis and could possibly reduce body adiposity through hormonal influences on adipocyte calcium uptake . In this study , we investigated the effects of 1,500 mg supplemental calcium daily for 3 months on hormones regulating calcium and energy metabolism and rates of lipid oxidation and lipolysis in overweight women . Fifteen overweight ( BMI > 25 kg/m(2 ) ) premenopausal women were supplemented with 1,500 mg of calcium , as CaCO(3 ) , per day for 3 months while maintaining their usual diets and activity levels . Baseline and endpoint measurements were obtained after the subjects consumed a st and ardized 25 % fat diet for 4 days . Lipid oxidation was measured by indirect calorimetry , lipolysis by infusion of deuterated glycerol , and body fat by dual-energy X-ray absorptiometry . Urinary calcium , circulating levels of hormones involved in energy and lipid metabolism ( insulin , leptin , and adiponectin ) or calcium metabolism ( 25(OH)D , 1,25(OH)(2)D ) , and parathyroid hormone ( PTH ) ) were also measured . Urinary levels of calcium ( P = 0.005 ) increased and 1,25(OH)(2)D declined ( P = 0.03 ) . However other parameters , including body weight , body fat , PTH , insulin , leptin , adiponectin , 25(OH)D , as well as rates of lipid oxidation and lipolysis were not altered by calcium supplementation . Calcium supplementation for 3 months increased urinary calcium excretion , decreased circulating levels of 1,25(OH)(2)-D , but had no effect on rates of lipid oxidation or lipolysis , in these overweight women [10476618] OBJECTIVE The objectives of the study were to confirm the validity of using oscillometric measurement of MAP in the left lateral position to identify those at high risk for developing pregnancy-induced hypertension ( PIH ) , and to assess and compare the efficacy of prophylaxis with low-dose aspirin or calcium supplementation in high-risk patients . STUDY DESIGN A prospect i ve study in pregnancy ; 500 normotensive , primigravid Chinese women were recruited in the second trimester of pregnancy on the basis of 80 mm Hg > or = MAP < 106 mm Hg in the antenatal clinic . They were then screened by Dinamap in a research setting , measuring MAP in the left lateral position after rest and using a cutoff value of 60 mm Hg for inclusion in the r and omized study . R and omization was divided into three groups : control , low-dose aspirin , and calcium supplementation . After delivery , patients were classified as either having remained normotensive or having developed PIH , with or without proteinuria . RESULTS The incidence of both proteinuric and nonproteinuric PIH was significantly lower in patients screened out as low risk than in those selected as high risk using a critical value of 60 mm Hg for left lateral MAP ( p < 0.05 ) . The incidence of proteinuric PIH was significantly lower in patients given low-dose aspirin than in the control group ( p < 0.05 ) . However , the confidence intervals for the effect were wide , comparable with aspirin having no effect or leading to a 16-fold reduction in the risk of preeclampsia . For those given calcium supplementation , the reduction was not significant . There was no significant difference in the incidence of nonproteinuric PIH between the control group and the two groups receiving prophylaxis . CONCLUSION Oscillometric measurement of second-trimester left lateral MAP is a valid predictor of proteinuric PIH . Low-dose aspirin may offer a degree of protection from proteinuric PIH in these high-risk women . Calcium supplementation was not shown to significantly reduce the incidence of PIH [1600930] We investigated the inhibitory effect of calcium on iron absorption in 57 human subjects . Three studies suggested that the effect is not located in the gastrointestinal tract . The presence of phytate in a meal and formation of calcium-iron-phytate complexes is not a prerequisite for the inhibition . The relative increase in iron absorption by ascorbic acid was the same in meals with and without calcium , suggesting that calcium did not influence the balance between enhancing and inhibiting lig and s in the gastrointestinal lumen . No inhibiting effect on iron absorption was seen when adding 3 mg calcium to 0.01 mg iron ( molar ratio Ca/Fe = 420 ) . Previous studies showing a marked inhibition by calcium had a lower molar ratio , but greater amounts of calcium were given . This suggests that a minimal concentration of calcium is needed to achieve an effect . The present results indirectly support our original hypothesis that the inhibitory effect of calcium on iron absorption is situated within the intestinal mucosal cells . The practical nutritional implication s of the inhibitory effect of calcium are considerable since addition of milk , milkshake or cheese to common meals such as pizza or hamburger meals reduced iron absorption by 50 - 60 % . It is recommended to reduce the intake of dairy products with the main meals providing most of the dietary iron , especially for those having the highest iron requirements i.e. children , teenagers and women at childbearing age [15384598] Following our detailed studies of human milk calcium concentration , we hypothesized that calcium intake in pregnancy may determine human milk calcium concentration and hence the calcium intake of breastfed infants ( Prentice et al. 1994 ) . To test this , we conducted a controlled calcium supplementation study in pregnant women accustomed to a low calcium intake [9274547] Abstract Objective : To explore the long term effect of calcium supplementation during pregnancy on the offspring 's blood pressure during childhood . Design : Follow up of a population enrolled in a double blind , r and omised , placebo controlled trial . Setting : Perinatal research unit , World Health Organisation 's collaborative research centre . Subjects : 591 children at a mean age of 7 years whose mothers were r and omly assigned during pregnancy to receive 2 g/day of elemental calcium ( n=298 ) or placebo ( n=293 ) . Main outcome measures : Mean blood pressure and rate of high blood pressure of children . Results : Overall , systolic blood pressure was lower in the calcium group ( mean difference -1.4 mm Hg ; 95 % confidence interval -3.2 to 0.5 ) than in the placebo group . The effect was found predominantly among children whose body mass index at assessment was above the median for this population ( mean difference in systolic blood pressure -5.8 mm Hg ( -9.8 mm Hg to -1.7 mm Hg ) for children with an index > 17.5 and -3.2 mm Hg ( -6.3 mm Hg to -0.1 mm Hg ) for those with an index of > 15.7 to 17.5 ) . The risk of high systolic blood pressure was also lower in the calcium group than in the placebo group ( relative risk 0.59 ; 0.39 to 0.90 ) and particularly among children in the highest fourth of body mass index ( 0.43 ; 0.26 to 0.71 ) . Conclusion : Calcium supplementation during pregnancy is associated with lower systolic blood pressure in the offspring , particularly among overweight children . Key messages Impaired fetal and maternal nutrition seem to be associated with childhood blood pressure , but most of the evidence comes from uncontrolled studies Systolic blood pressure of children aged between 5 and 9 years was lower when mothers took calcium rather than placebo during pregnancy The effect is found predominantly among children with a body mass index above the median for this population Fetal life seems to be a period for programming blood pressure ; the magnitude of the effect observed has health implication s among overweight [2679864] Summary . Previous studies have suggested that increased dietary calcium is associated with a decreased occurrence of pregnancy‐induced hypertension . In this study 106 young healthy nulliparous women , residing in Quito , Ecuador , were enrolled in a double‐blind , r and omized , controlled clinical trial . From 24 weeks gestation until delivery they received either 2 g of elemental calcium per day or a placebo . Calcium supplementation was associated with a significantly decreased risk of pregnancy‐induced hypertension , with 4.1 % developing pregnancy‐induced hypertension in the treatment group versus 27.9 % in the placebo group . Treatment was associated with a decrease in both systolic and diastolic blood pressure over the course of pregnancy . In addition , there was a small but significant increase in serum ionized calcium levels in the calcium‐supplemented group during the treatment period [21677054] BACKGROUND Maternal nutritional intake during pregnancy may have important consequences for long-term health in offspring . OBJECTIVE The objective was to follow up the offspring in 2 r and omized trials of nutrient supplementation during pregnancy to investigate the effect on cardiovascular disease ( CVD ) risk in offspring . DESIGN We recruited offspring born during 2 trials in The Gambia , West Africa . One trial provided protein-energy-dense food supplements ( 1015 kcal and 22 g protein/d ) to pregnant ( intervention , from 20 wk gestation until delivery ) or lactating ( control , for 20 wk from birth ) women and was r and omized at the village level . The second was a double-blind , individually r and omized , placebo-controlled trial of calcium supplementation ( 1.5 g/d ) , which was also provided from 20 wk gestation until delivery . RESULTS Sixty-two percent ( n = 1267 ) of children ( aged 11 - 17 y ) born during the protein-energy trial were recruited and included in the analysis , and 64 % ( n = 350 ) of children ( aged 5 - 10 y ) born during the calcium trial were recruited and included in the analysis . Fasted plasma glucose was marginally lower in children born to mothers receiving protein-energy supplements during pregnancy than in those children of the lactating group ( adjusted mean difference : -0.05 mmol/L ; 95 % CI : -0.10 , -0.001 mmol/L ) . There were no other differences in CVD risk factors , including blood pressure , body composition , and cholesterol , between children born to intervention and control women from the protein-energy trial . Maternal calcium supplementation during pregnancy was unrelated to offspring blood pressure . CONCLUSION These data suggest that providing supplements to pregnant women in the second half of pregnancy may have little effect on the CVD risk of their offspring , at least in this setting and at the ages studied here . This trial was registered at www.controlled-trials.com as IS RCT N96502494 [2648839] In a study population that comprised 34 normal black pregnant women , biochemical changes are compared between a group of women who received 1.5 gm of calcium supplementation a day and a group of women who received placebos . The blood pressure-lowering effect of calcium supplementation appears to involve a mechanism that relates parathyroid hormone and plasma renin activity . Other alterations in calcium and magnesium metabolism , as reflected by increased urinary calcium excretion and serum magnesium levels , may also contribute to this effect . Subgroups of study participants with initial ( less than 26 weeks ' gestation ) low levels of serum calcium and plasma renin activity are the ones with the largest reductions in blood pressure . Whether these alterations can produce a reduction in the incidence of pregnancy-induced hypertension is the next question to be answered in this area [4596723] In an attempt to evaluate the aetiology and therapy of leg cramps during pregnancy . patients at an antenatal clinic were treated with calcium or a placebo [9241284] Objective To determine the effect of third-trimester calcium supplementation on maternal hemodynamic function . Methods Pregnant women were r and omized to receive either 1.5 g of elemental calcium or placebo for 6 weeks during the third trimester . Using Doppler technique , maternal hemodynamic characteristics were measured at baseline , at 2 hours after the first dose of study drug , and at the completion of 6 weeks . Serum , dietary , and urinary calcium levels were also assessed . Power calculation indicated the need to study ten subjects in each group to detect a 1.2 L ( 20 % ) difference in cardiac output between groups , assuming a mean of 6.2 ± 1.0 L/minute . Data were analyzed by analysis of variance for repeated measures , Student t test , Mann-Whitney U test , and Fisher exact test . Results Twenty-three women enrolled , and 18 completed the study . There were no statistically significant differences in demographic characteristics or in serum , dietary , or urinary calcium levels between the two groups . There were also no statistically significant differences in hemodynamic function over time within the calcium supplementation or placebo group ( P > .05 ; analysis of variance for repeated measures ) . After 6 weeks , there were no significant differences between the calcium- and placebo-treated subjects in any hemodynamic measurement . Specifically , there was not a statistically significant difference in cardiac output ( 7.3 ± 1.2 L/minute versus 8.0 ± 0.9 L/minute ; P = .09 ) between the calcium- and placebo-treated groups . Conclusions These findings suggest that third-trimester calcium supplementation does not significantly alter cardiac output . The mechanism by which calcium supplementation lowers blood pressure remains to be eluci date [3308737] 60 pregnant women underwent a double blind trial with calcium or ascorbic acid ( 1 g twice daily ) as treatment for leg cramps . There was no significant difference between the two treatment groups with respect to clinical improvement . In 14 out of 60 patients the symptoms were totally abolished and in another 27 patients the symptoms were significantly decreased by the treatment ( irrespective of drug used ) . In 17 patients the symptoms were unaffected while only two patients experienced an increase in frequency of their leg cramps during therapy . Serum total and ionized calcium concentrations , serum total magnesium and albumin concentrations were determined and were not significantly changed throughout therapy in any of the groups . No biochemical differences were found between the different treatment regimens or between those patients relieved or not relieved of their symptoms . Serum magnesium concentrations were at or just below the lower normal limit ( for non pregnant women ) in treated women and pregnant controls

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### Context: [18696358] Objective . To test the hypothesis that calcium supplementation inhibits the underlying pathological processes in women with preeclampsia . Methods . Seven hundred and eight nulliparous women were enrolled in a WHO r and omized double-blind trial , who received 1.5 g of calcium or placebo from 20 weeks of pregnancy or earlier . Platelet count , serum urate , and urinary protein/creatinine ratio were measured at or near 35 gestational weeks . Results . No difference was detected in rates of abnormal platelet count ( relative risk [ RR ] 1.18 ; 95 % confidence interval [ CI ] , 0.63 to 2.18 ) , serum urate level ( 1.0 ; 0.64 to 1.57 ) or urine protein/creatinine ratio ( 1.01 ; 0.76 to 1.34 ) . This was consistent with the main trial finding of no difference in the incidence of ‘ dipstick ’ proteinuria between women receiving calcium and those receiving placebo ( 8312 women ; RR , 1.01 ; 95 % CI , 0.88 to 1.15 ) . Conclusions . An effect of calcium supplementation in the second half of pregnancy on the rate of abnormal laboratory measures associated with preeclampsia was not demonstrated [10511362] OBJECTIVE To determine the effect of maternal calcium supplementation during pregnancy on fetal bone mineralization . METHODS Healthy mothers with early ultrasound confirmation of date s and singleton pregnancies were enrolled in a double-masked study and r and omized before 22 weeks ' gestation to 2 g/day of elemental calcium or placebo until delivery . Maternal dietary intake at r and omization and at 32 - 33 weeks ' gestation was recorded with 24-hour dietary recalls . Dual-energy x-ray absorptiometry measurements of the whole body and lumbar spine of the neonates were performed before hospital discharge . RESULTS The infants of 256 women ( 128 per group ) had dual-energy x-ray absorptiometry measurements during the first week of life . There were no significant differences between treatment groups in gestational age , birth weight , or length of the infants , or in the total-body or lumbar spine bone mineral content . However , when bone mineral content was analyzed by treatment group within quintiles of maternal dietary calcium intake , total body bone mineral content ( mean + /- st and ard error of the mean ) was significantly greater in infants born to calcium-supplemented mothers ( 64.1+/-3.2 versus 55.7+/-2.7 g in the placebo group ) in the lowest quintile of dietary calcium intake ( less than 600 mg/day ) . The effect of calcium supplementation remained significant after adjustment for maternal age and maternal body mass index and after normalization for skeletal area and body length of the infant . CONCLUSION Maternal calcium supplementation of up to 2 g/day during the second and third trimesters can increase fetal bone mineralization in women with low dietary calcium intake . However , calcium supplementation in pregnant women with adequate dietary calcium intake is unlikely to result in major improvement in fetal bone mineralization [12657345] BACKGROUND Pregnancy is a time of increased need for calcium . The role of calcium supplements in altering maternal responses to fetal dem and for calcium is not fully understood . This article describes the results of a r and omized , crossover trial of calcium supplementation on bone resorption among pregnant women . DESIGN / SETTING PARTICIPANTS : Thirty-one Mexican women at 25 - 35 weeks gestation participated in the study for 20 days . Each woman received a 1200 mg calcium supplement on 10 consecutive days and a multivitamin without calcium for 10 days . Urine sample s were collected daily . Two pooled specimens from each subject ( representing urine from multivitamin days and from calcium days ) were preserved , and levels of cross-linked , N-telopeptides of type I collagen ( NTX ) , a biomarker of bone resorption , were measured . Dietary calcium intake was assessed using a food-frequency question naire . RESULTS Of the 31 participants , 27 ( 87.1 % ) showed reductions in urinary NTX levels while ingesting calcium supplements . When not ingesting calcium , NTX levels for the 31 subjects had a mean of 96.8 nM BCE/mM creatinine ; this was significantly higher ( p<0.001 ) than the mean urinary NTX levels of 83.2 nM BCE/mM creatinine during ingestion of the calcium supplements . Neither age nor dietary calcium intake was a significant predictor of treatment effect . CONCLUSION A bedtime , 1200-mg calcium supplement during the third trimester of pregnancy reduces maternal bone resorption by an average of 13.6 nM BCE/mM creatinine ( 14 % ) , as reflected by urinary NTX levels . These results suggest that calcium supplements reduce maternal skeletal-bone turnover during the third trimester of pregnancy [20078830] Calcium supplementation in mothers with low calcium intake has been of interest recently because of its association with optimal fetal growth and improved pre-eclampsia-related outcomes . While the effects of calcium supplementation have demonstrated benefits in prolonging gestation and subsequently improving birthweight , no specific studies have identified the longitudinal effects of supplementation on fetal growth in utero . Data were analysed in the context of the World Health Organization trial of calcium supplementation in calcium-deficient women . Five hundred and ten healthy , primiparous pregnant Argentinean women were r and omised ( at < 20 weeks gestation ) to either placebo ( n = 230 ) or calcium supplements ( 1500 mg calcium/day in 3 divided doses ; n = 231 ) . Growth parameters in utero were assessed with serial ultrasound scans . Birthweight , length , head , abdominal and thigh circumferences were recorded at delivery . No differences were found in fetal biometric measurements recorded at 20 , 24 , 28 , 32 and 36 weeks gestation between fetuses of women who were supplemented with calcium and those who were not . Similarly , neonatal characteristics and anthropometric measurements recorded at delivery were comparable in both groups . We conclude that calcium supplementation of 1500 mg calcium/day in pregnant women with low calcium intake does not appear to impact on fetal somatic or skeletal growth [23719547] BACKGROUND Pregnancy and lactation in adolescents with habitually low calcium intake may adversely affect maternal bone mass . OBJECTIVE We investigated the effect of calcium plus vitamin D supplementation during pregnancy on bone mass during lactation in Brazilian adolescent mothers with low-calcium diets ( ∼600 mg/d ) . DESIGN Pregnant adolescents ( 14 - 19 y ) r and omly received daily calcium ( 600 mg ) plus vitamin D3 ( 200 IU ) ( n = 30 ) or a placebo ( n = 26 ) from 26 wk of pregnancy ( baseline ) until parturition . The bone mineral content ( BMC ) , bone area ( BA ) , and bone mineral density ( BMD ) at the total body , lumbar spine , and hip ( total and femoral neck ) were evaluated by using dual-energy X-ray absorptiometry at 5 and 20 wk postpartum . Serum hormones and 25-hydroxyvitamin D [ 25(OH)D ] were measured . Group comparisons were adjusted for significant covariates . RESULTS The mean serum 25(OH)D concentration was 59 nmol/L at baseline . In comparison with the placebo , 25(OH)D tended to be 14 - 15 nmol/L higher postpartum in the supplemented group ( P = 0.08 ) . Total body and hip BMC and BMD decreased over time ( P ≤ 0.005 ) in both groups with a group × time interaction at the femoral neck ( P < 0.04 ) . Supplemented mothers had higher lumbar spine BA ( 6.7 % ; P = 0.002 ) and lumbar spine BMC ( 7.9 % , P = 0.08 ) than did mothers who consumed the placebo at 5 wk postpartum . At 20 wk postpartum , differences between groups were more evident , with higher lumbar spine BMC ( 13.9 % ) , lumbar spine BA ( 6.2 % ) , and lumbar spine BMD ( 10.6 % ) in the supplemented group ( P ≤ 0.008 ) . CONCLUSIONS Calcium plus vitamin D supplementation during pregnancy of adolescents with low calcium intake results in higher lumbar spine bone mass and a reduced rate of femoral neck bone loss during lactation . Additional studies are required to determine whether bone effects are temporary or long-lasting . This trial was registered at clinical trials.gov as NCT01732328 [16522914] BACKGROUND Growth and bone mineral accretion in Gambian infants are poorer than those in Western population s. The calcium intake of Gambian women is low , typically 300 - 400 mg Ca/d , and they have low breast-milk calcium concentrations , which result in low calcium intakes for their breastfed infants . A low maternal calcium supply in pregnancy may limit fetal mineral accretion and breast-milk calcium concentrations and thereby affect infant growth and bone mineral accretion . OBJECTIVE We investigated the effects of calcium supplementation in Gambian women during pregnancy on breast-milk calcium concentrations and infant birth weight , growth , and bone mineral accretion . DESIGN A r and omized , double-blind , placebo-controlled supplementation study was conducted in 125 Gambian women who received 1500 mg Ca/d ( as calcium carbonate ) or placebo from 20 wk of gestation until delivery . Infant birth weight and gestational age were recorded . Breast milk was collected , and infant anthropometric and bone measurements were performed at 2 , 13 , and 52 wk after delivery . Infant bone mineral status was assessed by using single-photon absorptiometry of the radius and whole-body dual-energy X-ray absorptiometry . RESULTS Compliance with the supplement was high . No significant differences were detected between the groups in breast-milk calcium concentration , infant birth weight , or growth or bone mineral status during the first year of life . A slower rate of increase in infant whole-body bone mineral content and bone area was found in the supplement group than in the placebo group ( group x time interaction : P = 0.03 and 0.02 , respectively ) . CONCLUSION Calcium supplementation of pregnant Gambian women had no significant benefit for breast-milk calcium concentrations or infant birth weight , growth , or bone mineral status in the first year of life [7598067] The calcium requirement for prolonged lactation was investigated in a r and omized supplementation study of Gambian mothers consuming a low-calcium diet ( 7.1 mmol/d , or 283 mg/d ) . Sixty women were studied from 10 d to 78 wk of lactation , receiving calcium or placebo for the first 12 mo . The supplement increased average calcium intake by 17.9 mmol/d ( 714 mg/d ) . Supplementation had no effect on breast-milk calcium concentration or on maternal bone mineral content . Urinary calcium output was higher in supplemented than in unsupplemented mothers by 1.18 mmol/d ( 47 mg/d ) , P < or = 0.005 . Longitudinal changes in urinary calcium output and bone mineral content made a substantial contribution to calcium requirements for lactation . This study suggests that , in women with low calcium intakes , there is no direct benefit from increasing calcium intake during lactation , and that physiological mechanisms operate to furnish calcium for breast-milk production [2627861] Background Prenatal lead exposure is associated with deficits in fetal growth and neurodevelopment . Calcium supplementation may attenuate fetal exposure by inhibiting mobilization of maternal bone lead and /or intestinal absorption of ingested lead . Objective Our goal was to evaluate the effect of 1,200 mg dietary calcium supplementation on maternal blood lead levels during pregnancy . Methods In a double-blind , r and omized , placebo-controlled trial conducted from 2001 through 2003 in Mexico City , we r and omly assigned 670 women in their first trimester of pregnancy to ingest calcium ( n = 334 ) or placebo ( n = 336 ) . We followed subjects through pregnancy and evaluated the effect of supplementation on maternal blood lead , using an intent-to-treat analysis by a mixed-effects regression model with r and om intercept , in 557 participants ( 83 % ) who completed follow-up . We then conducted as-treated analyses using similar models stratified by treatment compliance . Results Adjusting for baseline lead level , age , trimester of pregnancy , and dietary energy and calcium intake , calcium was associated with an average 11 % reduction ( 0.4 μg/dL ) in blood lead level relative to placebo ( p = 0.004 ) . This reduction was more evident in the second trimester ( −14 % , p < 0.001 ) than in the third ( −8 % , p = 0.107 ) and was strongest in women who were most compliant ( those who consumed ≥ 75 % calcium pills ; −24 % , p < 0.001 ) , had baseline blood lead > 5 μg/dL ( −17 % , p < 0.01 ) , or reported use of lead-glazed ceramics and high bone lead ( −31 % , p < 0.01 ) . Conclusion Calcium supplementation was associated with modest reductions in blood lead when administered during pregnancy and may constitute an important secondary prevention effort to reduce circulating maternal lead and , consequently , fetal exposure [3995154] Background : Evidence suggests that increased maternal calcium intake during pregnancy may result in lower offspring blood pressure , prompting calls for more robust data in this field , particularly in setting s of habitually low calcium intake . Objective : The objective was to investigate the effect of maternal calcium supplementation on blood pressure in offspring by recruiting children born after a r and omized , double-blind , placebo-controlled trial of calcium supplementation during pregnancy . Design : Children ( n = 389 ) from a rural area of The Gambia ( mean age : 7.4 ± 1.2 y ; range : 5–10 y ) , whose mothers received a calcium supplement ( 1500 mg Ca/d from 20 wk of gestation until delivery ) or placebo , were followed up in West Africa . Blood pressure was assessed under st and ardized conditions with use of the Omron 705IT automated oscillometric device ( Morton Medical Ltd , London , United Kingdom ) , and anthropometric and body composition ( bioelectrical impedance ) measurements were also made . Results : The analysis was restricted to 350 children born at term , which represented 64 % of original trial births . There was no difference in systolic ( adjusted mean difference : −0.04 mm Hg ; 95 % CI : −1.78 , 1.69 mm Hg ) or diastolic ( adjusted mean difference : 0.25 mm Hg ; 95 % CI : −1.27 , 1.77 mm Hg ) blood pressure between children whose mothers had received calcium and those who received placebo . No interaction between childhood body mass index ( in kg/m2 ; mean : 14.0 ) and maternal calcium supplementation was observed in this study . Conclusion : Calcium supplementation in the second half of pregnancy in Gambian women with very low habitual calcium intakes may not result in lower offspring blood pressure at 5–10 y of age [14553957] BACKGROUND The current study examined the relationship between calcium supplementation during pregnancy and blood pressure ( BP ) in the mother and offspring at 3 months and at 2 years postpartum . METHODS Nulliparous pregnant women were assigned to either receive 2 g of calcium or placebo daily beginning between weeks 13 to 21 of gestation and continuing until delivery . Blood pressure was measured in children and their mothers at 3 months ( n = 260 ) and ( n = 57 ) at 2 years postpartum . Systolic BP was measured in the infants using a sphygmomanometer with ultrasonic amplification . For the toddlers , three supine BP measurements were taken from the right arm using a Critikon automated sphygmomanometer just after measurement of left ventricular wall thickness . RESULTS Systolic BP in the calcium-supplemented infants was 2.2 mm Hg lower than in the placebo group ( P > .05 ) . At 2 years of age , systolic BP was 4.8 mm Hg lower in the calcium supplemented group ( P < .05 ) , whereas diastolic BP was 3 mm Hg lower ( P > .05 ) . There was no difference in left ventricular mass index between groups , although there was a significant correlation between systolic BP and wall thickness ( P < .05 ) . Maternal BP was positively correlated with circulating 1,25(OH)(2)D3 ( P < .001 ) but did not differ between calcium groups at 3 months postpartum . CONCLUSIONS The data on BP in the children are in agreement with previous studies and argue strongly for additional research into the effects of prenatal calcium supplementation on BP regulation in the offspring [20831450] Objectives . To evaluate if calcium supplementation during pregnancy could have any influence on primary dentition measured as the reduction of dental caries of the child . Design . Individual r and omized controlled trial . Setting . One hospital in Rosario , Argentina . Population . R and om sample of 195 12‐year‐old children from a follow‐up study of 614 women who were r and omized during pregnancy to calcium supplementation or placebo . Methods . An independent research er blinded to the group where the mothers were assigned performed a dental examination of the children . Main outcome measures . Proportion of children with at least one decayed , missing or filled teeth ( DMFT/dmft ) and mean number of decayed , missing or filled surfaces ( DMFS/dmfs ) per children . Results . Ninety‐eight children were assessed in the calcium supplementation group and 97 in the placebo group . 63.3 % of the children whose mother took calcium supplementation had at least one DMFT/dmft compared to 86.6 % in the placebo group ( < 0.001 ) . The children whose mother received the intervention had a 27 % reduction in the risk of developing at least one DMFT/dmft ( RR : 0.73 , CI 95 % : [ 0.62 ; 0.87 ] ) . Conclusions . This study shows a modeling effect of calcium intake during pregnancy on dental caries of the offspring . At around 12 years of age children whose mothers received calcium supplementation when pregnant showed a significant reduction in dental caries [11837466] OBJECTIVE The objective of this prospect i ve , open , r and omised trial was to determine the role of calcium supplementation in preventing pre-eclampsia . METHODS One hundred uncomplicated normotensive primigravidae were enrolled in the study before 20 weeks of pregnancy . Fifty each were r and omised to receive either two gram elemental calcium daily from 20 weeks of gestation to delivery ( study group ) or no calcium supplementation ( control group ) . Prior to 20 weeks of gestation each underwent a complete clinical and laboratory evaluation . Serum and urine calcium was measured first at 20 weeks of gestation and then at 24 - 28 weeks and at 32 - 36 weeks of pregnancy . RESULTS Patient characteristics at the start of therapy were similar in the two groups . Blood pressure profile was similar throughout pregnancy in the groups . The incidence of pre-eclampsia was similar ( 18 % in the study group and 16 % in the control group ) , but severe pre-eclampsia was significantly less in the study group . There was no significant difference between the two groups with regards to intra- and postpartum characteristics , perinatal outcome and maternal or fetal side effects . Serum and urinary calcium levels did not differ between the two groups . CONCLUSION While calcium supplementation did not lower the incidence of pre-eclampsia it did reduce its severity [9262495] BACKGROUND Women may lose bone during lactation because of calcium lost in breast milk . We studied whether calcium supplementation prevents bone loss during lactation or augments bone gain after weaning . METHODS We conducted two r and omized , placebo-controlled trials of calcium supplementation ( 1 g per day ) in postpartum women . In one trial ( the study of lactation ) , 97 lactating and 99 nonlactating women were enrolled a mean ( + /-SD ) of 16+/-2 days post partum . In the second trial ( the study of weaning ) , 95 lactating women who weaned their infants in the 2 months after enrollment and 92 nonlactating women were enrolled 5.6+/-0.8 months post partum . The bone density of the total body , lumbar spine , and forearm was measured at enrollment and after three and six months . RESULTS The bone density of the lumbar spine decreased by 4.2 percent in the lactating women receiving calcium and by 4.9 percent in those receiving placebo and increased by 2.2 and 0.4 percent , respectively , in the nonlactating women ( P<0.001 for the effect of lactation ; P= 0.01 for the effect of calcium ) . After weaning , the bone density of the lumbar spine increased by 5.9 percent in the lactating women receiving calcium and by 4.4 percent in those receiving placebo ; it increased by 2.5 and 1.6 percent , respectively , in the nonlactating women ( P<0.001 for the effects of lactation and calcium ) . There was no effect of either lactation or calcium supplementation on bone density in the forearm , and there was no effect of calcium supplementation on the calcium concentration in breast milk . CONCLUSIONS Calcium supplementation does not prevent bone loss during lactation and only slightly enhances the gain in bone density after weaning [18851852] OBJECTIVE To study the effect of calcium supplementation during pregnancy on blood pressure and maternal and neonatal outcomes . METHOD A total of 524 healthy primigravidas with a blood pressure less than 140/90 mm Hg were r and omly assigned between the 12th and 25th weeks to receive 2 g of elemental calcium or placebo and were followed-up until delivery . RESULTS The incidence of pre-eclampsia was significantly less in the calcium than in the placebo group ( 4.0 % vs 12.0 % ; odds ratio [ OR ] , 0.31 ; 95 % confidence interval [ CI ] , 0.15 - 0.63 ) ; the mean systolic and diastolic blood pressures at study completion were different in the calcium and placebo group ( P=0.007 and P=0.02 ) . The risk for preterm delivery was less in the calcium ( 7.0 % ) than in the placebo ( 12.7 % ) group ( OR , 0.51 ; 95 % CI , 0.28 - 0.93 ) . The mean baseline calcium intake was 313.83+/-203.25 mg/day ( range , 85.71 - 910.71 mg/day ) , which is lower than the recommended dietary intake of 1000 mg , and the 24-hour urinary calcium excretion was 130.82+/-67.44 mg/dL ( range , 40.5 - 387 mg/dL ) . CONCLUSION Calcium supplementation appears to reduce the occurrence of pre-eclampsia and preterm delivery in primigravidas who have a daily dietary calcium intake less than the recommended dietary allowances [3306493] Fifty-two healthy pregnant women were enrolled in a double-blind , r and omized , controlled clinical trial . After the 26th week of gestation , the women were given either 1.5 g of elemental calcium per day or a placebo . Subjects in the calcium group , after adjustment for race and initial blood pressure ( BP ) , had a term mean systolic and diastolic BP value of 4 - 5 mmHg lower than those in the placebo group ( P less than .05 ) . The incidence of pregnancy-induced hypertension was 11.1 % in the placebo group and 4.0 % in the calcium group , a nonsignificant difference . Combining these values with previous data , we found a dose-effect relationship between calcium intake and BP reduction during the third trimester of pregnancy . Further research should be directed at underst and ing the mechanism of this effect and trying to demonstrate a reduction in pregnancy-induced hypertension with calcium supplementation in a larger population [3778867] Background : Dietary calcium intake in rural Gambian women is very low ( ∼350 mg/d ) compared with international recommendations . Studies have suggested that calcium supplementation of women receiving low-calcium diets significantly reduces risk of pregnancy hypertension . Objective : We tested the effects on blood pressure ( BP ) of calcium carbonate supplementation ( 1500 mg Ca/d ) in pregnant , rural Gambian women . Design : The study was a r and omized , double-blind , parallel , placebo-controlled supplementation trial from 20 wk of gestation ( P20 ) until delivery ( calcium : n = 330 ; placebo ; n = 332 ) . BP and anthropometric measures were taken at P20 and then 4 weekly until 36 wk of gestation ( P36 ) , and infant anthropometric measures were taken at 2 , 13 , and 52 wk postdelivery . Results : A total of 525 ( calcium : n = 260 ; placebo : n = 265 ) women had BP measured at P36 and subsequently delivered a healthy term singleton infant . Mean compliance was 97 % , and urinary calcium measures confirmed the group allocation . At P20 , the mean ( ±SD ) systolic blood pressure ( SBP ) was 101.2 ± 9.0 and 102.1 ± 9.3 mm Hg , and diastolic blood pressure ( DBP ) was 54.5 ± 7.3 and 55.8 ± 7.8 mm Hg , in the calcium and placebo groups , respectively . The intention-to-treat analysis that was adjusted for confounders showed no significant effect of calcium supplementation on the change between P20 and P36 ( calcium compared with placebo ; mean ± SEM ) in SBP ( −0.64 ± 0.65 % ; P = 0.3 ) or DBP ( −0.22 ± 1.15 % ; P = 0.8 ) . There was no significant effect of supplementation on BP , pregnancy weight gain , weight postpartum , or infant weight , length , and other measures of growth . However , the comparability of the original r and omly assigned groups may have been compromised by the exclusion of 20.7 % of women from the final analysis . Conclusions : Calcium supplementation did not affect BP in pregnancy . This result may have been because the Gambian women were adapted to a low dietary calcium intake , and /or obesity , high gestational weight gain , high underlying BP , tobacco use , alcohol consumption , and sedentary lifestyles were rare . This trial was registered at the International St and ard R and omized Controlled Trial Register ( www.controlled-trials.com/m rct / ) as IS RCT N96502494 [3994635] Background : Mobilization of maternal bone mineral partly supplies calcium for fetal and neonatal bone growth and development . Objective : We investigated whether pregnant women with low calcium intakes may have a more extensive skeletal response postpartum that may compromise their short- or long-term bone health . Design : In a subset of participants ( n = 125 ) in a double-blind , r and omized , placebo-controlled trial ( International Trial Registry : IS RCT N96502494 ) in pregnant women in The Gambia , West Africa , with low calcium intakes ( ≈350 mg Ca/d ) , we measured bone mineral status of the whole body , lumbar spine , and hip by using dual-energy X-ray absorptiometry and measured bone mineral status of the forearm by using single-photon absorptiometry at 2 , 13 , and 52 wk lactation . We collected blood and urine from the subjects at 20 wk gestation and at 13 wk postpartum . Participants received calcium carbonate ( 1500 mg Ca/d ) or a matching placebo from 20 wk gestation to parturition ; participants did not consume supplements during lactation . Results : Women who received the calcium supplement in pregnancy had significantly lower bone mineral content ( BMC ) , bone area ( BA ) , and bone mineral density ( BMD ) at the hip throughout 12 mo lactation ( mean ± SE difference : BMC = −10.7 ± 3.7 % , P = 0.005 ; BA = −3.8 ± 1.9 % , P = 0.05 ; BMD = −6.9 ± 2.6 % , P = 0.01 ) . The women also experienced greater decreases in bone mineral during lactation at the lumbar spine and distal radius and had biochemical changes consistent with greater bone mineral mobilization . Conclusions : Calcium supplementation in pregnant women with low calcium intakes may disrupt metabolic adaptation and may not benefit maternal bone health . Further study is required to determine if such effects persist long term or elicit compensatory changes in bone structure [2721965] Maternal vitamin D deficiency during pregnancy is a recognized risk factor for rickets and osteomalacia in infancy ( 1 ) . The circulating plasma concentration of 25-hydroxyvitamin D ( 25OHD ) , a long-lived metabolite of vitamin D , is used to judge vitamin D status ; values below 25 nmol/L are associated with an increased risk of rickets and osteomalacia ( 1 ) . There is evidence that a low maternal plasma 25OHD in pregnancy may influence the growth and bone mineral accrual of the offspring during foetal life , infancy and childhood . Positive associations have been reported between maternal vitamin D status in pregnancy and birthweight , birth length , length at 1 year and bone mineral accretion at 9 years ( 2–6 ) , although evidence is conflicting ( 7,8 ) . These relationships have been observed at concentrations of 25OHD higher than those associated with rickets and osteomalacia , and there are calls to raise the accepted lower threshold of vitamin D sufficiency for pregnant women , most recently to 80 nmol/L ( 9 ) . On a population basis , plasma 25OHD concentrations above 80 nmol/L are relatively uncommon in countries at temperate latitudes but are more common among people living in the tropics who have abundant skin sunshine exposure ( 10 ) . To contribute to the debate on the definition of vitamin D sufficiency in pregnancy , we have investigated the influence of maternal plasma 25OHD concentration on foetal and infant growth in a rural area of The Gambia , West Africa ( 13 ° N ) . In this region , there is tropical sunshine all year , the women are farmers who work out-of-doors for much of each day , and local female dress does not restrict regular sunshine exposure to the face , neck , shoulders , arms and feet , especially during farm work and gardening . The study was a secondary analysis of biochemical , anthropometric and bone data from a subset of 125 women and infants collected during a calcium supplementation study of blood pressure in pregnant Gambian women ( International Trial Registry : IS RCT N96502494 ) . No significant benefits for foetal and infant growth of maternal calcium supplementation were identified despite the low customary calcium intake in The Gambia ( 11 ) . The protocol , methods , maternal characteristics and infant data from the detailed study have been published ( 11 ) . Briefly , women from the rural villages of Keneba and M and uar , West Kiang , The Gambia were recruited at 20 weeks of pregnancy ( P20 ) and r and omized to a daily calcium supplement or a matching placebo tablet until parturition ( 1500 mg Ca as calcium carbonate and microcellulose-lactose , respectively ; Nycomed Pharma AS , Asker , Norway ) . Fasting , early morning blood was collected and anthropometry performed at P20 and 36 weeks of pregnancy ( P36 ) . The mean ( ± SD ) age , weight , height and dietary calcium intake of the women at P20 were 27.4 ± 7.5 years , 56.3 ± 6.7 kg , 1.61 ± 0.05 m and 356 ± 190 mg/day , respectively . The median parity ( range ) was 3 ( 0–10 ) . Infant birthweight was measured within 24 h of delivery . Weight , crown-heel length and head circumference were measured at 2 , 13 and 52 weeks postpartum . In addition , infant bone mineral content ( BMC ) , bone mineral density ( BMD ) and bone width ( BW ) or bone area ( BA ) , were measured by single photon absorptiometry of the midshaft radius ( Lunar SP2 , Lunar Corporation , Madison , WI , USA ) and , for a subset ( n = 44 , 47 and 52 at 2 , 13 and 52 weeks , respectively ) , by whole-body dual-energy X-ray absorptiometry ( Lunar DPX+ , software version 4.7b , Lunar Corporation ) . Plasma 25OHD was measured a using radioimmunometric assay ( Diasorin Ltd , Wokingham , Berks , UK ) , with assay performance monitored through the Vitamin D External Quality Assessment Scheme ( DEQAS ; Endocrine/Oncology Laboratory , Charing Cross Hospital , London , UK ) . The intra- and inter-assay coefficients of variation were 4 % and 100 ) ; possible trends in the data with p = 0.01–0.1 were noted . The analysis was conducted on 123 mother – infant pairs ; blood sample s from two subjects were not available . Mean ± SD 25OHD ( range ) was : P20 = 103 ± 25 ( 53–167 ) nmol/L ; P36 = 111 ± 27 ( 51–189 ) nmol/L. No subject had a 25OHD value < 50 nmol/L , 20 % and 16 % had 25OHD < 80 nmol/L , at P20 and P36 , respectively . There was a high degree of within-subject consistency in 25OHD at P20 and P36 ( 25OHDP36 = 33.2 + [ 0.79 ± 0.07] × 25OHDP20 , p ≤ 0.001 , R2 adjusted 51.5 % , n = 121 ) ; 11 % of women had 25OHD < 80 nmol/L at both P20 and P36 . The mean birthweight of the infants was 2.99 ± 0.36 kg . The infant anthropometric and bone measures during the first year are given in Table 1 . No significant relationships or trends in the data were observed between maternal 25OHD concentration using the values at P20 , P36 or the mean of the two and any of the following infant measures : birthweight , infant weight , length , head circumference , BMC , BW ( or BA ) , BMD and size-adjusted BMC of the midshaft radius and whole body at any time postpartum . This is illustrated in Figure 1 for birthweight as a function of maternal 25OHD concentration at P20 . Comparing the results for mothers with 25OHD above and below 80 nmol/L did not alter this finding . Table 1 Anthropometric and bone measures of Gambian infants Figure 1 Lack of a significant relationship between infant birthweight and maternal vitamin D status at 20 weeks of pregnancy ( p = 0.8 ) . Multiple regression model included season , maternal height , weight , weight gain , supplement group and sex of the infant . No significant interaction between supplement group and maternal 25OHD concentration was observed for any infant variable . Trends in the data were observed in a few instances for a supplement group × 25OHD interaction among the bone measures but no consistent picture emerged and they were considered to have arisen by chance . We conclude that there is no evidence for an influence of vitamin D status during pregnancy on infant growth and bone mineral accrual in the conditions prevailing in The Gambia . The children in this study , as is common in this region of The Gambia ( 13 ) , were born small , grew well for the first months of life but experienced growth faltering during later infancy compared to Western children ( 11,14 ) , as demonstrated by their weight and length SDS . The 25OHD concentrations of the women were > 50 nmol/L in the second half of pregnancy , and no distinction could be drawn in infant outcomes between mothers with concentrations above or below 80 nmol/L. Thus , our study suggests that , for women with regular , adventitious UVB sunshine exposure and in situations where foetal and infant growth may be constrained by multiple factors , there would be no benefit for foetal and infant growth or bone mineral accrual in aim ing to increase the vitamin D status of individual mothers during pregnancy above 50 or 80 [19528561] Context Some data suggest that body weight is inversely associated with calcium intake , increasing the possibility that supplemental calcium might facilitate weight loss or prevent weight gain . Contribution Research ers r and omly assigned overweight and obese patients to supplemental calcium or placebo and found no between-group differences in measures of weight change . Caution Trial participants were almost all women . Implication Calcium supplementation is unlikely to prevent weight gain in persons who are overweight or obese . The Editors The high prevalence of overweight and obesity in the United States ( 1 ) has stimulated great interest in identifying approaches that may help to prevent weight gain or improve ability to lose weight . Increasing calcium intake is a potential means of weight management that has received much attention from both lay press ( 24 ) and the medical community ( 57 ) . This interest has been stimulated by a series of cross-sectional studies ( 817 ) reporting that children and adults with low reported consumption of dietary ( primarily dairy ) calcium have greater body weight , a higher degree of adiposity , and greater risk for having components of the metabolic syndrome than those who report that they consume more calcium . Some ( 1824 ) , although not all ( 2534 ) , longitudinal investigations have also suggested that children and adults who consume a lower calcium diet tend to gain more weight than those with greater dietary or supplemental calcium intake . These data , together with some small clinical trials suggesting that weight loss during dieting may be augmented by supplemental ( 35 ) or dairy calcium ( 3538 ) , have led to expectations that substantially augmenting calcium intake might diminish body weight by 0.5 kg or more each year ( 5 , 18 , 22 , 39 ) . Two possible mechanisms for an effect of dietary calcium on body weight have been suggested . First , calcium can combine with fatty acids in the intestine to form insoluble soaps that are therefore not absorbed ( 40 , 41 ) . Second , some research ers ( 4246 ) have proposed that low dietary calcium leads to increased adipocyte triglyceride deposition ( 4749 ) . If calcium substantially affects fat accumulation , calcium supplementation could prevent additional weight and fat gain among people with high body weight . To test this hypothesis , we measured the effect of calcium carbonate supplementation for 2 years on the weight and body fat of overweight and obese adults . Methods Setting and Participants We recruited participants through advertisements posted in Bethesda , Maryl and , and spontaneous reply to newspaper and radio advertising in the Washington , DC , metropolitan area seeking healthy adult volunteers for a project to study the health effects of calcium supplementation . Men and women age 18 to 80 years were eligible to enroll if they had a body mass index ( BMI ) of 25 kg/m2 or more and did not have cerebrovascular , cardiovascular , pulmonary , renal , hepatic , endocrinologic , or other substantial medical disease . Women were ineligible if they were pregnant , were breastfeeding , or had received a recommendation from a health care professional to take calcium supplements for any condition . We excluded persons who regularly used medications known to affect body weight , had a weight loss of 3 % or more in the preceding 3 months , reported total calcium intake in excess of 3.5 g/d , used supplemental calcium in excess of 300 mg/d , used vitamin D supplements in excess of 400 IU/d , or had a history of renal stones . The institutional review board of the National Institute of Child Health and Human Development , National Institutes of Health , approved the research protocol . Each participant provided signed consent . We provided financial compensation for participants ' time and inconvenience . Design Overview We conducted a single-center , r and omized , double-blind , placebo-controlled trial from March 2002 to April 2006 . After an outpatient visit to determine eligibility and obtain initial assessment s , participants entered a 2-year , double-blind treatment period . R and omization and Interventions We r and omly assigned participants , in a 1:1 ratio , to receive either elemental calcium , 1500 mg/d ( calcium carbonate , purchased from Particle Dynamics , St. Louis , Missouri ) , or placebo , administered as 2 divided doses with meals . Investigators assigned consecutive code numbers to participants from prespecified lists stratified by race or ethnicity , sex , and BMI ( 25 to 26.99 , 27 to 29.99 , 30 to 34.99 , and 35 kg/m2 ) . The National Institutes of Health Clinical Center Pharmaceutical Development Section used permuted blocks with stratification to generate the allocations that translated code numbers into study group assignments by using a pseudo-r and om number program . The Pharmaceutical Development Section prepared placebo and calcium capsules to appear identical . Pharmacy personnel , not otherwise involved with the conduct of the study , dispensed study capsules with medication placed in containers that appeared identical and differed only by the individual participant code number . No participant , investigator , or other medical or nursing staff interacting with participants was aware of study group assignments for the duration of the trial . Initial Assessment At their prer and omization evaluation , participants reported after an overnight fast and were weighed in hospital gowns by using a digital scale ( Life Measurement Instruments , Concord , California ) that was calibrated with a known weight before each participant 's measurement . We measured height by using a stadiometer calibrated before each measurement ( Holtain , Crymych , United Kingdom ) . Research dietitians assessed abdominal and hip circumferences in triplicate to the nearest 0.1 cm , as recommended ( 50 , 51 ) , and measured triceps skinfold thickness to the nearest 0.5 mm by using Lange calipers ( Cambridge Scientific Industries , Cambridge , Maryl and ) . We measured blood pressure , obtained after a 5-minute rest period , 3 times at 5-minute intervals from seated participants by using an automated sphygmomanometer ( Dinamap-Plus , Critikon , Tampa , Florida ) . We did whole-body dual-energy x-ray absorptiometry to estimate total body fat mass ( Delphi A , software version 11.2 , Hologic , Bedford , Massachusetts ) . We measured intact parathyroid hormone concentrations with 2-site immunochemiluminometric assays ( 52 ) , and serum 25-hydroxy vitamin D levels by using a competitive binding assay ( Nichols Advantage , Nichols Diagnostic , San Clemente , California ) ( 53 ) . We asked participants with substantial vitamin D deficiency ( serum 25-hydroxy vitamin D level < 25.0 nmol/L ) to take vitamin D , 400 IU/d ( ergocalciferol ) , in a multivitamin . We assessed baseline dietary calcium intake by using a 7-day food record that a registered dietitian review ed with each participant to maximize accuracy and completeness , and analyzed for dietary calcium intake by using the Nutrition Data System for Research software , versions 4.04_32 and 4.05_33 ( University of Minnesota , Minneapolis , Minnesota ) ( 54 ) . We measured calcium intake from multivitamins or calcium supplements with a vali date d calcium question naire ( 55 ) that was review ed for completeness through an interview with a registered dietitian . We recorded the calcium content as it was listed on the label of each multivitamin or calcium supplement . We measured dietary and supplemental vitamin D intakes in the same manner . We estimated energy intake at baseline and at 2 years by using a food-frequency question naire that assessed total diet ( 5557 ) . We measured socioeconomic status by using the Hollingshead score ( 58 ) . Outcomes and Follow-up Primary efficacy end points were change in body weight and body fat mass at the end of 2 years of treatment . Secondary outcomes were fasting anthropometric measurements , body composition by dual-energy x-ray absorptiometry , and change in blood pressure , assessed yearly , along with question naire data on dietary and supplemental calcium intake ( 55 ) . In addition , we contacted participants every 3 months to complete question naires about their adherence to the medication regimen ; assess their general health ; and obtain self-reports of mood , stress , physical activity , and hunger . Every 6 months , participants returned to the clinic to exchange their unused study medication for a new supply . We used the tally of returned capsules to assess adherence . To examine adequacy of the masking procedure , participants completed a question naire at the end of the study that requested they report their best guess about their study group assignment . Statistical Analysis All reported primary data analyses were prespecified . On the basis of our previous study of observed yearly changes in body weight over time ( 59 ) , we needed a total sample size of 256 participants to detect a 0.35-kg difference per year in weight change ( that is , 0.7 kg over 2 years ) between groups with 80 % power . Participant accrual was set at 340 participants to allow 25 % loss to follow-up . We analyzed data by using SPSS for Windows , version 14.0 ( SPSS , Chicago , Illinois ) . We assessed efficacy in the intention-to-treat sample of all r and omly assigned participants . We did 2 efficacy analyses . The primary analysis used a multiple imputation model for missing data under a missing-at-r and om assumption ( 60 ) . By using NORM , version 2.03 ( The Pennsylvania State University , State College , Pennsylvania ) ( 61 , 62 ) , we included all available baseline , 1-year , and 2-year outcome measures in an imputation model along with age , sex , race , baseline serum 25-hydroxy vitamin D concentration , baseline calcium intake , and study group . We then combined the coefficients from analyses of 20 imputed data sets into a single set of estimates according to Shafer ( 62 ) and the Rubin rules ( 63 ) . To assess sensitivity of these results to the missing-at-r and om assumption , we conducted 3 additional analyses : assuming that all participants who withdrew from the study had major weight gain ( [9241285] Objective To determine whether increased calcium intake ( 2 g/day ) in pregnancy is effective in reducing the risk of preeclampsia in pregnant teenagers . Methods The present study was a prospect i ve , r and omized , double-blind , controlled clinical trial . Two hundred sixty teenaged pregnant girls attending the Hospital Gíneco-Obstétrico Isidro Ayora in Quito , Ecuador , were included . Selection criteria were age less than 17.5 years , nulliparity , first prenatal visit before 20 weeks ' gestation , and residency in Quito ( 2800-m altitude ) . We used a table of r and om numbers to assign 125 girls to receive 2000 mg of elemental calcium daily , beginning at 20 weeks of gestation and continuing until delivery ; 135 women in the control group received a placebo . Blood pressure ( BP ) was measured twice every 4 weeks until delivery and at 48 hours after delivery . The diagnosis of preeclampsia was defined as BP greater than 140/90 mmHg on at least two occasions more than 6 hours apart and proteinuria greater than 30 mg/dL ( over one cross by dipstick on two occasions 4 - 24 hours apart ) . Results The average daily calcium intake in this population was approximately 51 % of the Recommended Dietary Allowance . Calcium supplementation was associated with a significantly decreased risk of preeclampsia ( risk reduction 12.35 % ; P < .001 ) , with 3.2 % ( n = 4 ) developing preeclampsia in the treatment group versus 15.5 % ( n = 21 ) in the placebo group . Moreover , calcium supplementation led to a reduction in systolic BP of 9.1 mmHg and in diastolic BP of 6.0 mmHg . Conclusion These results suggest that calcium supplementation during pregnancy in population s with low calcium intake is a safe , effective , and inexpensive preventive measure that significantly reduces the risk of preeclampsia [2220915] Results are presented of a r and omized , double-blinded controlled clinical trial of calcium supplementation ( 2.0 gm of elemental calcium as calcium carbonate ) and a placebo . All participants were 17 years of age or less and clinical ly healthy . Patients were enrolled by the twenty third week of gestation . The mean duration of calcium supplementation or placebo was approximately 14 weeks . Treatment consisted of 2.8 ( + /- 1.5 ) tablets per day in the placebo group ( N = 95 ) and 3.0 ( + /- 1.4 ) tablets per day in the calcium group ( N = 94 ) . Dietary calcium intake was similar in both groups at about 1200 mg/day . The calcium group had a lower incidence of preterm delivery ( less than 37 weeks ; 7.4 % vs 21.1 % ; p = 0.007 ) ; spontaneous labor and preterm delivery ( 6.4 % vs 17.9 % ; p = 0.01 ) ; and low birth weight ( 9.6 % vs 21.1 % ; p = 0.03 ) . This effect was also present after stratified analysis by level of treatment compliance , urinary tract infection , and chlamydial infection . Life-table analysis demonstrated an overall shift to a higher gestational age in the calcium group compared with the placebo group ( log-rank test , p = 0.02 ) . As suggested previously , the observed effect could be mediated by a reduction in uterine smooth muscle contractibility . If confirmed by future research , these results could represent an important preventive intervention for prematurity in high-risk population [8058229] Objective To evaluate the efficacy of oral supplemental calcium in reducing the incidence of pregnancy-induced hypertension ( gestational hypertension or preeclampsia ) in angiotensin-sensitive nulliparas [16946216] OBJECTIVE : To evaluate the effects of dietary calcium ( Ca ) intervention on adolescent pregnant mothers and their newborns . METHODS : Seventy-two pregnant adolescent mothers were r and omized into one of 3 groups : control , orange juice fortified with calcium , and dairy . The orange juice and dairy groups were required to take more than 1,200 mg Ca . Calcium tablets were added for those not able to meet required Ca . Maternal and infant weight , length , and blood pressure ( BP ) were recorded . Maternal dietary records were evaluated . Mother ’s blood was drawn for serum Ca , phosphate ( P ) , magnesium ( Mg ) , and vitamin 25-hydroxyvitamin D ( D ) . Cord blood was collected for serum Ca and D. Newborn total body Ca was determined . RESULTS : All mothers were similar in weight , height , and BP . Mothers in the orange juice plus calcium and dairy groups had higher intakes of Ca ( 1,472 mg and 1,771 mg ) than controls ( 862 mg ) . One half of the mothers in the orange juice plus calcium group required Ca tablets . Mothers in the dairy group had higher intakes of P , D , and Mg , higher serum folate and D , and higher cord D levels . Mothers in the orange juice plus calcium group had higher serum P but lower serum folate and D. Infants ( 3,517±273 g ) in the dairy group were heavier than infants in the control ( 3,277±177 g ) and orange juice plus calcium ( 3,292±165 g ) groups . Infants in the dairy group had higher total body calcium than control infants . CONCLUSION : Calcium diet supplemented with dairy products during adolescent pregnancy result ed in higher maternal vitamin D and folate serum levels and higher newborn weight and bone mineralization compared with controls . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00320125 LEVEL OF EVIDENCE : [16522392] OBJECTIVE The purpose of this trial was to determine whether calcium supplementation of pregnant women with low calcium intake reduces preeclampsia and preterm delivery . STUDY DESIGN R and omized placebo-controlled , double-blinded trial in nulliparous normotensive women from population s with dietary calcium < 600 mg/d . Women who were recruited before gestational week 20 received supplements ( 1.5 g calcium/d or placebo ) throughout pregnancy . Primary outcomes were preeclampsia and preterm delivery ; secondary outcomes focused on severe morbidity and maternal and neonatal mortality rates . RESULTS The groups comprised 8325 women who were assigned r and omly . Both groups had similar gestational ages , demographic characteristics , and blood pressure levels at entry . Compliance were both 85 % and follow-up losses ( calcium , 3.4 % ; placebo , 3.7 % ) . Calcium supplementation was associated with a non-statistically significant small reduction in preeclampsia ( 4.1 % vs 4.5 % ) that was evident by 35 weeks of gestation ( 1.2 % vs 2.8 % ; P = .04 ) . Eclampsia ( risk ratio , 0.68 : 95 % CI , 0.48 - 0.97 ) and severe gestational hypertension ( risk ratio , 0.71 ; 95 % CI , 0.61 - 0.82 ) were significantly lower in the calcium group . Overall , there was a reduction in the severe preeclamptic complications index ( risk ratio , 0.76 ; 95 % CI , 0.66 - 0.89 ; life-table analysis , log rank test ; P = .04 ) . The severe maternal morbidity and mortality index was also reduced in the supplementation group ( risk ratio , 0.80 ; 95 % CI , 0.70 - 0.91 ) . Preterm delivery ( the neonatal primary outcome ) and early preterm delivery tended to be reduced among women who were < or = 20 years of age ( risk ratio , 0.82 ; 95 % CI , 0.67 - 1.01 ; risk ratio , 0.64 ; 95 % CI , 0.42 - 0.98 , respectively ) . The neonatal mortality rate was lower ( risk ratio , 0.70 ; 95 % CI , 0.56 - 0.88 ) in the calcium group . CONCLUSION A 1.5-g calcium/day supplement did not prevent preeclampsia but did reduce its severity , maternal morbidity , and neonatal mortality , albeit these were secondary outcomes [8987323] In a r and omized controlled trial 201 healthy nulliparous women were r and omly allocated by means of a computer generated r and omization list . From 20 weeks of gestation until delivery they received either 2 g of oral elemental calcium ( n = 103 ) per day or an identical placebo ( n = 98 ) . Eleven women ( 5.47 % ) were lost to follow-up after r and omization . The study groups were very similar at the time of r and omization ; with respect to several clinical and demographic variables . Treatment compliance was very similar in both groups as was determined by pill count . The rate of pregnancy induced hypertension was lower in the calcium group than in the placebo group 8.24 % ; vs 29.03 % ; ( RR = 0.28 ; 95 % CI 0.14 - 0.59 ) . The incidence of gestational hypertension was 6.18 % in the calcium group and 17.20 % in the placebo group ( RR = 0.28 ; 95 % CI 0.08 - 0.80 ) , and the incidence of preeclampsia was 2.06 % in the calcium group and 11.82 % in the placebo group ( RR = 0.13 ; 95 % CI 0.01 - 0.64 ) . In conclusion calcium supplementation given in pregnancy to nulliparous women reduces the incidence of pregnancy induced hypertension [6846435] In this study the hypothesis that calcium supplementation during pregnancy can modify blood pressure patterns in a population of normal pregnant women was tested . Thirty-six women with normal single pregnancies , between 20 and 35 years of age , in the second trimester of gestation ( 15 weeks ) , were r and omly assigned to receive 1 gm of calcium per day ( n = 11 ) , 2 gm per day ( n = 11 ) , or a placebo ( n = 14 ) . No differences were observed at the times of admission into the study ( baseline ) in demographic and clinical variables or in the calcium intake of each group . Baseline blood pressure measures in several positions also were not different . After the initial blood pressure measures ( fifteenth week ) , five follow-up blood pressure measures were obtained . The supplemented groups had significantly lower diastolic blood pressure than the control subjects between the twentieth and twenty-fourth weeks of gestation . Thereafter , an increase in the control group and the group receiving 1 gm of calcium was observed , but levels were similar at term . On the contrary , patients receiving 2 gm of calcium had blood pressure values that remained significantly lower throughout the third trimester . No differences or clear patterns were observed in the blood levels of calcium , magnesium , phosphorus , and proteins between and within groups during gestation . A possible explanation involving parathyroid hormone is attempted [20044757] Objective Calcium dem and is increased during pregnancy . However , few r and omized controlled trials examined the effects of calcium supplementation on bone mass during pregnancy . This study determined effects of calcium and milk supplementation on maternal bone mineral density ( BMD ) and bone turnover in pregnant Chinese women with habitual low calcium intake . Methods In this r and omized controlled trial , 36 Chinese pregnant women ( 24–31 years , 18 gestational weeks ) were r and omly assigned to the following three arms ( 12 each ) : I , usual diet ; II , “ I ” + 45 g milk powder ( containing 350 mg calcium ) ; or III , “ II ” + 600 mg calcium/day from gestational age of 20 weeks to 6 weeks post-partum ( PP ) . BMD was measured post-treatment using dual-energy X-ray absorptiometry . Dietary intakes , 24-h urinary calcium , bone resorption ( urinary hydroxyproline ) and formation ( serum osteocalcin ) biomarkers were examined at the gestational age of 20 and 34 weeks , and 6 weeks PP . Results A dose-dependent relationship was observed between calcium intake and BMDs . The BMD values were significantly higher in subjects with calcium and milk supplementation than those in the controls at the whole body and spine ( p < 0.05 ) but not at the hip sites . We found significant decreases in changes of urinary hydroxyproline , and significant increases in serum osteocalcin during the intervention period in the calcium/milk intervention groups than those in the control group ( all p < 0.05 ) . Conclusion Calcium/milk supplementation during pregnancy is associated with greater BMD at the spine and whole body and suppresses bone resorption in Chinese women with habitual low calcium intake [19716540] OBJECTIVE We postulated that calcium supplementation of calcium-deficient pregnant women would lower vascular resistance in uteroplacental and fetoplacental circulations . STUDY DESIGN Pulsatility index ( PI ) and resistance index ( RI ) ( uterine and umbilical arteries ) and presence of bilateral uterine artery diastolic notching were assessed by Doppler ultrasound between 20 - 36 weeks ' gestation in 510 healthy , nulliparous Argentinean women with deficient calcium intake in a r and omized , placebo-controlled , double-blinded trial . RESULTS Average umbilical and uterine artery RI and PI tended to be lower in the supplemented group at each study week . Differences became statistically significant for umbilical artery RI and PI from 32 and 36 weeks , respectively . Estimated probabilities of bilateral uterine artery diastolic notching trended toward lower values in calcium-supplemented women . CONCLUSION Calcium supplementation of pregnant women with deficient calcium intake may affect uteroplacental and fetoplacental blood flow by preserving the vasodilation of normal gestation [8932976] The results of ten clinical trials suggest that supplemental calcium may prevent preeclampsia . However , method ologic problems and differences in study design limit the acceptance of the results and their relevance to other patient population s. Many of the trials were conducted in countries where , unlike the United States , the usual daily diet contained little calcium . Moreover , none of the trials has reported the outcome of systematic surveillance for urolithiasis , a potential complication of calcium supplementation . In response to the need for a thorough evaluation of the effects of calcium supplementation for the prevention of preeclampsia in the United States , the trial of Calcium for Preeclampsia Prevention ( CPEP ) was undertaken at five university medical centers . Healthy nulliparous patients were r and omly assigned to receive either 2 g supplemental calcium daily ( n = 2295 ) or placebo ( n = 2294 ) in a double-blind study . Study tablets were administered beginning from 13 to 21 completed weeks of gestation and continued until the termination of pregnancy . CPEP employed detailed diagnostic criteria , st and ardized techniques of measurement , and systematic surveillance for the major study endpoints and for urolithiasis . The nutrient intake of each patient was assessed at r and omization and at 32 - 33 weeks gestation . This report describes the study rationale , design , and methods [11864514] OBJECTIVE To research some effects of different levels of calcium intake in the mother 's bone mineral density . METHODS On the basis of insignificantly different among energy and other nutrition intake excepting calcium , 35 volunteers in pregnant 18 weeks healthy women were r and omly divided into I. II and III group [ calcium intake were ( 550 + /- 150 ) mg/d , ( 900 + /- 150 ) mg/d and ( 1,500 + /- 150 ) mg/d ] . The tracked study began from pregnant 20 weeks to postpartum 45 days . All over and different body of BMD ( Bone Mineral Density ) were assessed by dual-energy X-rays absorptiometry . RESULTS I group of many location BMD were below that of other groups ( P < 0 . 01 ) . As compared with the same age women 's lumbar spine BMD , I group was only maintained within the rang ( 85.14 + /- 6.61)% , and osteoporosis in some places of bone were found in some individual . II group was ( 90.74 + /- 6.53)% . III group was ( 100.44 + /- 5.19)% . Allover different body 's BMD were significantly correlated with the average BMD ( r > 0.8 , P < 0.1 ) , the most significant correlation was third lumbar spine . Calcium intake of women was positively correlated with different body 's BMD ( r > 0.5 , P < 0.01 ) . CONCLUSION III group , calcium intake was ( 30.68 + /- 3.56 ) mmol/d , pass through period of pregnancy , parturition and short-term breast-feed mother body remain the same BMD , and prevent osteoporosis . Reporting pregnant women calcium nutrition pass through BMD , lumbar spine is good representation [11430936] OBJECTIVE To study the effect of calcium supplementation on reduction of pre-eclampsia in Iranian women at high risk of pre-eclampsia . METHODS Thirty pregnant women at high risk of developing pre-eclampsia were r and omized to 2 g of daily calcium and placebo . Subjects and investigators were blinded to treatment allocation . The inclusion criteria were positive rollover test , having at least one risk factor for pre-eclampsia , between 28 and 32 weeks of pregnancy , and blood pressure less than 140/90 ( mm Hg ) . Exclusion criteria were having any chronic condition . Pre-eclampsia was defined as systolic/diastolic blood pressure over 140/90 plus proteinuria . All the subjects were followed up to delivery . RESULT A sevenfold reduction in the occurrence of pre-eclamsia were seen among the calcium group compared with the placebo group ( 7 out of 15 developed pre-eclampsia in control group vs. 1 out of 15 in calcium group , P=0.014 ) . No major effect on pregnancy induced hypertension was seen ( 66 % in placebo and 76 % in calcium group developed hypertension ) but the onset of hypertension was delayed 3 weeks in the calcium group . A longer duration of pregnancy was seen in calcium than placebo ( mean+/-S.D.=37+/-2 for calcium and 34+/-2 for placebo , P<0.05 ) . Infants born to the calcium group , on average , were 552 g heavier than infants born to the placebo group , P<0.05 . CONCLUSION Calcium supplementation is beneficial for preventing pre-eclampsia among Iranian women at high risk of developing pre-eclampsia [7770260] Objective To determine whether calcium supplementation prevents progression to severe disease in preterm nulliparous women with mild preeclampsia . Methods Seventy-five women hospitalized at 24–36 weeks ' gestation because of mild preeclampsia were r and omized to receive either 2 g/day of elemental calcium ( 36 women ) or placebo ( 39 ) . Both groups had similar demographic characteristics , initial blood pressure measurements , and amount of proteinuria . Diagnostic criteria and clinical management for severe preeclampsia were applied consistently . Results Eighteen of 36 calcium-treated subjects ( 50 % , 95 % confidence interval [ CI ] 33–67 ) developed severe preeclampsia , compared with 19 of 39 ( 48.7 % , 95 % CI 32–65 ) in the placebo group ( relative risk 1.03 , 95 % CI 0.64–1.03 ; P = 1.00 ) . Blood pressure values , gestational age at delivery , newborn weights , incidence of low Apgar scores , and umbilical arterial blood gases were similar for the two groups . Conclusion Calcium supplementation does not prevent severe preeclampsia in preterm patients with mild disease [18719672] Based on cell culture and studies in mice , increased dietary calcium appears to stimulate lipolysis and could possibly reduce body adiposity through hormonal influences on adipocyte calcium uptake . In this study , we investigated the effects of 1,500 mg supplemental calcium daily for 3 months on hormones regulating calcium and energy metabolism and rates of lipid oxidation and lipolysis in overweight women . Fifteen overweight ( BMI > 25 kg/m(2 ) ) premenopausal women were supplemented with 1,500 mg of calcium , as CaCO(3 ) , per day for 3 months while maintaining their usual diets and activity levels . Baseline and endpoint measurements were obtained after the subjects consumed a st and ardized 25 % fat diet for 4 days . Lipid oxidation was measured by indirect calorimetry , lipolysis by infusion of deuterated glycerol , and body fat by dual-energy X-ray absorptiometry . Urinary calcium , circulating levels of hormones involved in energy and lipid metabolism ( insulin , leptin , and adiponectin ) or calcium metabolism ( 25(OH)D , 1,25(OH)(2)D ) , and parathyroid hormone ( PTH ) ) were also measured . Urinary levels of calcium ( P = 0.005 ) increased and 1,25(OH)(2)D declined ( P = 0.03 ) . However other parameters , including body weight , body fat , PTH , insulin , leptin , adiponectin , 25(OH)D , as well as rates of lipid oxidation and lipolysis were not altered by calcium supplementation . Calcium supplementation for 3 months increased urinary calcium excretion , decreased circulating levels of 1,25(OH)(2)-D , but had no effect on rates of lipid oxidation or lipolysis , in these overweight women [10476618] OBJECTIVE The objectives of the study were to confirm the validity of using oscillometric measurement of MAP in the left lateral position to identify those at high risk for developing pregnancy-induced hypertension ( PIH ) , and to assess and compare the efficacy of prophylaxis with low-dose aspirin or calcium supplementation in high-risk patients . STUDY DESIGN A prospect i ve study in pregnancy ; 500 normotensive , primigravid Chinese women were recruited in the second trimester of pregnancy on the basis of 80 mm Hg > or = MAP < 106 mm Hg in the antenatal clinic . They were then screened by Dinamap in a research setting , measuring MAP in the left lateral position after rest and using a cutoff value of 60 mm Hg for inclusion in the r and omized study . R and omization was divided into three groups : control , low-dose aspirin , and calcium supplementation . After delivery , patients were classified as either having remained normotensive or having developed PIH , with or without proteinuria . RESULTS The incidence of both proteinuric and nonproteinuric PIH was significantly lower in patients screened out as low risk than in those selected as high risk using a critical value of 60 mm Hg for left lateral MAP ( p < 0.05 ) . The incidence of proteinuric PIH was significantly lower in patients given low-dose aspirin than in the control group ( p < 0.05 ) . However , the confidence intervals for the effect were wide , comparable with aspirin having no effect or leading to a 16-fold reduction in the risk of preeclampsia . For those given calcium supplementation , the reduction was not significant . There was no significant difference in the incidence of nonproteinuric PIH between the control group and the two groups receiving prophylaxis . CONCLUSION Oscillometric measurement of second-trimester left lateral MAP is a valid predictor of proteinuric PIH . Low-dose aspirin may offer a degree of protection from proteinuric PIH in these high-risk women . Calcium supplementation was not shown to significantly reduce the incidence of PIH [1600930] We investigated the inhibitory effect of calcium on iron absorption in 57 human subjects . Three studies suggested that the effect is not located in the gastrointestinal tract . The presence of phytate in a meal and formation of calcium-iron-phytate complexes is not a prerequisite for the inhibition . The relative increase in iron absorption by ascorbic acid was the same in meals with and without calcium , suggesting that calcium did not influence the balance between enhancing and inhibiting lig and s in the gastrointestinal lumen . No inhibiting effect on iron absorption was seen when adding 3 mg calcium to 0.01 mg iron ( molar ratio Ca/Fe = 420 ) . Previous studies showing a marked inhibition by calcium had a lower molar ratio , but greater amounts of calcium were given . This suggests that a minimal concentration of calcium is needed to achieve an effect . The present results indirectly support our original hypothesis that the inhibitory effect of calcium on iron absorption is situated within the intestinal mucosal cells . The practical nutritional implication s of the inhibitory effect of calcium are considerable since addition of milk , milkshake or cheese to common meals such as pizza or hamburger meals reduced iron absorption by 50 - 60 % . It is recommended to reduce the intake of dairy products with the main meals providing most of the dietary iron , especially for those having the highest iron requirements i.e. children , teenagers and women at childbearing age [15384598] Following our detailed studies of human milk calcium concentration , we hypothesized that calcium intake in pregnancy may determine human milk calcium concentration and hence the calcium intake of breastfed infants ( Prentice et al. 1994 ) . To test this , we conducted a controlled calcium supplementation study in pregnant women accustomed to a low calcium intake [9274547] Abstract Objective : To explore the long term effect of calcium supplementation during pregnancy on the offspring 's blood pressure during childhood . Design : Follow up of a population enrolled in a double blind , r and omised , placebo controlled trial . Setting : Perinatal research unit , World Health Organisation 's collaborative research centre . Subjects : 591 children at a mean age of 7 years whose mothers were r and omly assigned during pregnancy to receive 2 g/day of elemental calcium ( n=298 ) or placebo ( n=293 ) . Main outcome measures : Mean blood pressure and rate of high blood pressure of children . Results : Overall , systolic blood pressure was lower in the calcium group ( mean difference -1.4 mm Hg ; 95 % confidence interval -3.2 to 0.5 ) than in the placebo group . The effect was found predominantly among children whose body mass index at assessment was above the median for this population ( mean difference in systolic blood pressure -5.8 mm Hg ( -9.8 mm Hg to -1.7 mm Hg ) for children with an index > 17.5 and -3.2 mm Hg ( -6.3 mm Hg to -0.1 mm Hg ) for those with an index of > 15.7 to 17.5 ) . The risk of high systolic blood pressure was also lower in the calcium group than in the placebo group ( relative risk 0.59 ; 0.39 to 0.90 ) and particularly among children in the highest fourth of body mass index ( 0.43 ; 0.26 to 0.71 ) . Conclusion : Calcium supplementation during pregnancy is associated with lower systolic blood pressure in the offspring , particularly among overweight children . Key messages Impaired fetal and maternal nutrition seem to be associated with childhood blood pressure , but most of the evidence comes from uncontrolled studies Systolic blood pressure of children aged between 5 and 9 years was lower when mothers took calcium rather than placebo during pregnancy The effect is found predominantly among children with a body mass index above the median for this population Fetal life seems to be a period for programming blood pressure ; the magnitude of the effect observed has health implication s among overweight [2679864] Summary . Previous studies have suggested that increased dietary calcium is associated with a decreased occurrence of pregnancy‐induced hypertension . In this study 106 young healthy nulliparous women , residing in Quito , Ecuador , were enrolled in a double‐blind , r and omized , controlled clinical trial . From 24 weeks gestation until delivery they received either 2 g of elemental calcium per day or a placebo . Calcium supplementation was associated with a significantly decreased risk of pregnancy‐induced hypertension , with 4.1 % developing pregnancy‐induced hypertension in the treatment group versus 27.9 % in the placebo group . Treatment was associated with a decrease in both systolic and diastolic blood pressure over the course of pregnancy . In addition , there was a small but significant increase in serum ionized calcium levels in the calcium‐supplemented group during the treatment period [21677054] BACKGROUND Maternal nutritional intake during pregnancy may have important consequences for long-term health in offspring . OBJECTIVE The objective was to follow up the offspring in 2 r and omized trials of nutrient supplementation during pregnancy to investigate the effect on cardiovascular disease ( CVD ) risk in offspring . DESIGN We recruited offspring born during 2 trials in The Gambia , West Africa . One trial provided protein-energy-dense food supplements ( 1015 kcal and 22 g protein/d ) to pregnant ( intervention , from 20 wk gestation until delivery ) or lactating ( control , for 20 wk from birth ) women and was r and omized at the village level . The second was a double-blind , individually r and omized , placebo-controlled trial of calcium supplementation ( 1.5 g/d ) , which was also provided from 20 wk gestation until delivery . RESULTS Sixty-two percent ( n = 1267 ) of children ( aged 11 - 17 y ) born during the protein-energy trial were recruited and included in the analysis , and 64 % ( n = 350 ) of children ( aged 5 - 10 y ) born during the calcium trial were recruited and included in the analysis . Fasted plasma glucose was marginally lower in children born to mothers receiving protein-energy supplements during pregnancy than in those children of the lactating group ( adjusted mean difference : -0.05 mmol/L ; 95 % CI : -0.10 , -0.001 mmol/L ) . There were no other differences in CVD risk factors , including blood pressure , body composition , and cholesterol , between children born to intervention and control women from the protein-energy trial . Maternal calcium supplementation during pregnancy was unrelated to offspring blood pressure . CONCLUSION These data suggest that providing supplements to pregnant women in the second half of pregnancy may have little effect on the CVD risk of their offspring , at least in this setting and at the ages studied here . This trial was registered at www.controlled-trials.com as IS RCT N96502494 [2648839] In a study population that comprised 34 normal black pregnant women , biochemical changes are compared between a group of women who received 1.5 gm of calcium supplementation a day and a group of women who received placebos . The blood pressure-lowering effect of calcium supplementation appears to involve a mechanism that relates parathyroid hormone and plasma renin activity . Other alterations in calcium and magnesium metabolism , as reflected by increased urinary calcium excretion and serum magnesium levels , may also contribute to this effect . Subgroups of study participants with initial ( less than 26 weeks ' gestation ) low levels of serum calcium and plasma renin activity are the ones with the largest reductions in blood pressure . Whether these alterations can produce a reduction in the incidence of pregnancy-induced hypertension is the next question to be answered in this area [4596723] In an attempt to evaluate the aetiology and therapy of leg cramps during pregnancy . patients at an antenatal clinic were treated with calcium or a placebo [9241284] Objective To determine the effect of third-trimester calcium supplementation on maternal hemodynamic function . Methods Pregnant women were r and omized to receive either 1.5 g of elemental calcium or placebo for 6 weeks during the third trimester . Using Doppler technique , maternal hemodynamic characteristics were measured at baseline , at 2 hours after the first dose of study drug , and at the completion of 6 weeks . Serum , dietary , and urinary calcium levels were also assessed . Power calculation indicated the need to study ten subjects in each group to detect a 1.2 L ( 20 % ) difference in cardiac output between groups , assuming a mean of 6.2 ± 1.0 L/minute . Data were analyzed by analysis of variance for repeated measures , Student t test , Mann-Whitney U test , and Fisher exact test . Results Twenty-three women enrolled , and 18 completed the study . There were no statistically significant differences in demographic characteristics or in serum , dietary , or urinary calcium levels between the two groups . There were also no statistically significant differences in hemodynamic function over time within the calcium supplementation or placebo group ( P > .05 ; analysis of variance for repeated measures ) . After 6 weeks , there were no significant differences between the calcium- and placebo-treated subjects in any hemodynamic measurement . Specifically , there was not a statistically significant difference in cardiac output ( 7.3 ± 1.2 L/minute versus 8.0 ± 0.9 L/minute ; P = .09 ) between the calcium- and placebo-treated groups . Conclusions These findings suggest that third-trimester calcium supplementation does not significantly alter cardiac output . The mechanism by which calcium supplementation lowers blood pressure remains to be eluci date [3308737] 60 pregnant women underwent a double blind trial with calcium or ascorbic acid ( 1 g twice daily ) as treatment for leg cramps . There was no significant difference between the two treatment groups with respect to clinical improvement . In 14 out of 60 patients the symptoms were totally abolished and in another 27 patients the symptoms were significantly decreased by the treatment ( irrespective of drug used ) . In 17 patients the symptoms were unaffected while only two patients experienced an increase in frequency of their leg cramps during therapy . Serum total and ionized calcium concentrations , serum total magnesium and albumin concentrations were determined and were not significantly changed throughout therapy in any of the groups . No biochemical differences were found between the different treatment regimens or between those patients relieved or not relieved of their symptoms . Serum magnesium concentrations were at or just below the lower normal limit ( for non pregnant women ) in treated women and pregnant controls Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Pre-eclampsia and eclampsia are common causes of serious morbidity and death . Calcium supplementation may reduce the risk of pre-eclampsia , and may help to prevent preterm birth . OBJECTIVES To assess the effects of calcium supplementation during pregnancy on hypertensive disorders of pregnancy and related maternal and child outcomes . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

22786531

[2025036] Previous studies have found that there is a correlation between mothers ' haemoglobin concentration or packed cell volume and infants ' birth weight , and that iron supplementation increases mothers ' haemoglobin concentration . The purpose of this study , using the data of a large r and omised trial on iron prophylaxis during pregnancy , was to find out whether iron supplementation causes fetal growth to deteriorate . At their first antenatal visit , 2912 pregnant women were r and omised into non-routine iron and routine iron supplementation . The mean length of gestation was shorter in the non-routine group . Birth weight did not differ between the groups , but due to longer gestations boys in the group receiving routine iron were taller than in the non-routine group . In both groups , whether studied by various values of packed cell volume or correlation coefficients , the lower the packed cell volume , the heavier and taller the infant and heavier the placenta . These negative correlations could be seen even with a packed cell volume measured early in pregnancy . St and ardising for blood pressure did not influence the correlation coefficients . The correlation between a high ratio for packed cell volume and poor fetal growth thus may not be caused by iron supplementation , nor mediated by blood pressure , but by some other mechanism [2405769] Background Gastrointestinal irritability can deter pregnant women from starting or continuing prenatal multivitamin supplementation . In a previous study , suboptimal tolerability was observed among pregnant women taking a large tablet ( 18 mm × 8 mm × 8 mm ) multivitamin with high elemental iron content ( 60 mg as ferrous fumarate ) . The objective of the present study was to compare rates of adherence and reported adverse events among pregnant women who were r and omized to commence supplementation with a small-tablet prenatal multivitamin , containing either low or high iron content . Methods Pregnant women who called the Motherisk Program ( Hospital for Sick Children , Toronto ) and had not started taking or had discontinued any multivitamin due to adverse events were included in this prospect i ve , r and omized , open-label , 2-arm study . Women were r and omized to take a small-size ( 16 mm × 9 mm × 4 mm ) , low elemental iron content ( 35 mg as ferrous fumarate ) multivitamin ( ' 35 mg ' group ) ; or a small-size ( 5 mm radius , 5 mm thickness ) , high elemental iron content ( 60 mg as ferrous sulphate ) multivitamin ( ' 60 mg ' group ) . Follow-up interviews documented pill intake and adverse events . Rates of adherence and adverse events were compared between groups using chi-squared tests and Kaplan-Meier survival curves . Results Of 167 r and omized women , 92 in the ' 35 mg ' group and 75 in the ' 60 mg ' group were included in the analysis . Despite ideal conditions and regular follow-ups , mean adherence based on pill intake recall , in both groups was approximately 50 % . No statistically significant difference was detected in proportions of women who actually started taking either multivitamin . Among those who started , no difference was detected in rates of adherence or reported adverse events . Conclusion The present results suggest that iron content is not a major determinant of adherence to prenatal multivitamins . Combined with our previous study , tablet size may be the more definitive factor affecting adherence [3530158] Two hundred Hausa primigravidae at Zaria were divided into five groups in a r and omized double-blind trial of antenatal oral antimalarial prophylaxis , and haematinic supplements . Group 1 received no active treatment . Groups 2 to 5 were given chloroquine 600 mg base once , followed by proguanil 100 mg per day . In addition , group 3 received iron 60 mg daily , group 4 folic acid 1 mg daily , and group 5 iron plus folic acid . Forty-five percent were anaemic ( haemoglobin ( Hb ) less than 11.0 g dl-1 ) at first attendance before 24 weeks of gestation , and malaria parasitaemia ( predominantly Plasmodium falciparum ) was seen in 27 % , of whom 60 % were anaemic . The mean Hb fell during pregnancy in group 1 , and seven patients in this group had to be removed from the trial and treated for severe anaemia ( packed cell volume ( PCV ) less than 0.26 ) . Only five patients in the other groups developed severe anaemia ( P = 0.006 ) , two of whom had malaria following failure to take treatment . Patients in group 1 had the lowest mean Hb at 28 and 36 weeks of gestation , and patients receiving antimalarials and iron ( groups 3 and 5 ) had the highest Hb at 28 weeks , but differences were not significant , possibly due to removal from the trial of patients with severe anaemia . Anaemia ( Hb less than 12.0 g dl-1 ) at six weeks after delivery was observed in 61 % of those not receiving active treatment ( group 1 ) , in 39 % of those protected against malaria but not receiving iron supplements ( groups 2 and 4 ) and in only 18 % of patients receiving both antimalarials and iron ( groups 3 and 5 ) . Folic acid had no significant effect on mean Hb . Proguanil was confirmed to be a highly effective causal prophylaxis . Prevention of malaria , without folic acid supplements , reduced the frequency of megaloblastic erythropoiesis from 56 % to 25 % . Folic acid supplements abolished megaloblastosis , except in three patients who were apparently not taking the treatment prescribed . Red cell folate ( RCF ) concentrations were higher in subjects with malaria , probably due to intracellular synthesis by plasmodia . Infants of mothers not receiving antimalarials appeared to have an erythroid hyperplasia . Maternal folate supplements raised infants ' serum folate and RCF . Fourteen per cent had low birth weight ( less than 2500 g ) , and the perinatal death rate was 11 % ; the greatest number were in group 1 , but not significantly . A regime is proposed for the prevention of malaria , iron deficiency , folate deficiency and anaemia in pregnancy in the guinea savanna of Nigeria [1481554] Background Prenatal micronutrient combinations with high iron content are associated with high rates of gastrointestinal symptoms . This coupled with nausea and vomiting of pregnancy results in women often discontinuing their multivitamins . A new prescription supplement ( PregVit ® ) that separates iron from calcium in two tablets – morning and evening , has lower elemental iron content ( 35 mg ) , but results in similar extent of iron absorption when compared to another supplement containing ( 60 mg ) of elemental iron ( Materna ® ) . The objectives of this study were to compare tolerability and compliance with PregVit ® vs. a supplement with high iron content ( Materna ® ) , in pregnant women . Methods R and omized , crossover open labeled study in 135 pregnant women attending outpatient clinics in Ontario and Quebec . Results Use of PregVit ® was associated with a 30 % reduction in constipation rate as compared to Materna ® . Both products demonstrated similar compliance rates . Compliance of Materna ® was negatively associated with the severity of nausea and vomiting of pregnancy . No such correlation was found for PregVvit ® . Conclusion PregVit ® , a supplement with lower iron content ( 35 mg ) , has significantly decreased constipation rates as compared to 60 mg iron- Materna and has similar compliance rates . High iron content in multivitamin supplements is associated with adverse effects in pregnancy [3217057] Background The purpose of this study was compare of daily iron supplementation in three time frames- daily , weekly and three time weekly supplementation in preventing anemia in healthy pregnant women . Method The present study was a prospect i ve simply r and omized clinical trial . During January 2006- January 2008 , 150 healthy pregnant women without anemia , in their 16th week of pregnancy were r and omly allocated into three equal groups . The first group ( n = 50 ) received a 50 mg-ferrous sulfate tablet daily , second group ( n = 50 ) received a 50 mg-ferrous sulfate tablet three times a week , and the third group ( n = 50 ) received two 50 mg-ferrous sulfate tablets ( 100 mg ) weekly , respectively for 12 consecutive weeks . Serum hemoglobin , ferritin , and iron were measured before and after the supplementation . Paired t and ANOVA tests were used as appropriated . Results There were no significant differences between the pre- and post-treatment hemoglobin levels with iron supplementation in the three group ( P = 0.518 , P = 0.276 , respectively ) . The mean serum iron level before and after treatment with iron supplementation in the three groups was not statistically significant ( P = 0.962 , P = 0.970 , respectively ) . Although the mean serum ferritin level before and after treatment with iron supplementation was statistically significant in the three groups , no significant differences were found comparing the three groups ( P = 0.827 , P = 0.635 respectively ) . Conclusions This results suggested , three times a week or weekly iron supplementation is as effective as daily supplementation for healthy pregnant women without anemia . Trial Registration IS RCT N : I RCT [7891047] OBJECTIVE To evaluate whether levels of iron status markers ( haemoglobin , serum transferrin saturation , serum ferritin ) in pregnant women , measured in the beginning of the second trimester , could be used to predict levels later in pregnancy , pre partum and post partum . DESIGN R and omized , double-blind , placebo-controlled parallel study . SETTING The Birth Clinic at the Department of Obstetrics , Herning Hospital , Herning , Denmark . SUBJECTS One hundred and twenty healthy pregnant women between 14 and 18 weeks of gestation . INTERVENTIONS Sixty-three women were allocated to treatment with tablets containing 66 mg ferrous iron ( as fumarate ) daily , and 57 women to treatment with placebo . MAIN OUTCOME MEASURES Haemoglobin , serum transferrin saturation , and serum ferritin were measured every 4th week during gestation , prior to delivery , and 1 and 8 weeks post partum . RESULTS Correlation matrices during pregnancy and post partum were calculated for each iron status marker separately in iron-treated and placebo-treated women . Haemoglobin , transferrin saturation and serum ferritin values at inclusion displayed steadily declining correlation coefficients with values obtained later in pregnancy . There were no clinical ly relevant correlations to values obtained 8 weeks or less prior to delivery , and no correlations to values post partum . Serum ferritin values at inclusion could not be used to predict values later in pregnancy or post partum . CONCLUSION Haemoglobin , transferrin saturation and serum ferritin values measured in the beginning of the second trimester appear to be unsuitable as guidelines for an individual iron prophylaxis in pregnant women [5926263] Bertino , J. R. , Ward , J. , Sartorelli , A. C. , and Silber , R. ( 1965 ) . 7 . clin . Invest . , 44 , 1028 . Bothwell , T. H. , Hurtardo , A. V. , Donohue , D. M. , and Finch , C. A. ( 1957 ) . Blood , 12 , 409 . Callender , S. T. , and Malpas , J. S. ( 1963 ) . Brit . med . 7 . , 2 , 1516 . Cockburn , F. , Sherman , J. D. , Ingall , D. , and Klein , R. ( 1965 ) . Proc . Soc . exp . Biol . ( N.Y. ) , 118 , 238 . Conrad , M. E. , Berman , A. , and Crosby , W. H. ( 1962 ) . Gastroenterology , 43 , 385 . Dacie , J. V. , and Lewis , S. M. ( 1963 ) . Practical Haematology , 3rd ed . London . Davis , A. E. , and Badenoch , J. ( 1962 ) . Lancet , 2 , 6 . Finch , C. A. , Coleman , D. H. , Motulsky , A. G. , Donohue , D. M. , and Reiff , R. H. ( 1956 ) . Blood , 11 , 807 . Herbert , V. ( 1963 ) . Amer . 7 . clan . Nutr . , 12 , 17 . Gottlieb , C. W. , and Altschule , M. D. ( 1965 ) . Lancet , 2 , 1052 [2724426] Background Deficiencies of iron and folic acid during pregnancy can lead to adverse outcomes for the fetus , thus supplements are recommended . Adherence to current tablet-based supplements is documented to be poor . Recently a powdered form of micronutrients has been developed which may decrease side-effects and thus improve adherence . However , before testing the efficacy of the supplement as an alternate choice for supplementation during pregnancy , the bioavailability of the iron needs to be determined . Our objective was to measure the relative bioavailability of iron and folic acid from a powdered supplement that can be sprinkled on semi-solid foods or beverages versus a traditional tablet supplement in pregnant women . Methods Eighteen healthy pregnant women ( 24 – 32 weeks gestation ) were r and omized to receive the supplements in a crossover design . Following ingestion of each supplement , the changes ( over baseline ) in serum iron and folate over 8 hours were determined . The powdered supplement contained 30 mg of iron as micronized dispersible ferric pyrophosphate with an emulsifier coating and 600 μg folic acid ; the tablet contained 27 mg iron from ferrous fumarate and 1000 μg folic acid . Results Overall absorption of iron from the powdered supplement was significantly lower than the tablet ( p = 0.003 ) . There was no difference in the overall absorption of folic acid between supplements . Based on the differences in the area under the curve and doses , the relative bioavailability of iron from powdered supplement was lower than from the tablet ( 0.22 ) . Conclusion The unexpected lower bioavailability of iron from the powdered supplement is contrary to previously published reports . However , since pills and capsules are known to be poorly accepted by some women during pregnancy , it is reasonable to continue to explore alternative micronutrient delivery systems and forms of iron for this purpose .Trial Registration Clinical Trials.gov [6881917] Iron and folate status of 203 pregnant women have been evaluated at 6 months gestation and on the same women and their newborn infants at delivery . The women who had , at 6 months gestation , a Hb level below 11 g/dl were systematic ally given iron supplements . Iron or placebo were r and omly allocated to the other women . At 6 months of pregnancy , one quarter of the women had a Hb level under 11 g/dl but one third had a serum ferritin level below 12 micrograms/l and more than half had low levels of serum and red cell folate . Iron supplements induced an increase both in Hb levels and in serum ferritin values ; however , no significant differences were observed in serum ferritin of the newborn infants , whether their mothers had received iron supplements or not . These results have led us to reconsider the value of ferritin levels at birth as an index of iron stores in the infant . Iron supplements had no effect on the folate status in mothers or infants or on the frequency of obstetrical complications . A significant relationship was found between maternal folate levels and length of gestation . Folate supplementation may reduce the incidence of premature delivery [9022526] Iron deficiency anemia is a serious health problem that affects the physical and cognitive development of children . Therefore , it is important to develop cost-effective interventions to improve the hematologic status of the millions of children affected by this condition worldwide . We studied 69 Guatemalan infants who had been r and omly assigned to one of three groups at the time of delivery : 1 ) cord clamping immediately after delivery ( n = 21 ) ; 2 ) clamping when the cord stopped pulsating , with the infant placed at the level of the placenta ( n = 26 ) ; or 3 ) clamping when the cord stopped pulsating , with the newborn placed below the level of the placenta ( n = 22 ) . Maternal and infant hematologic assessment s were performed at the time of delivery and 2 mo postpartum . At baseline the groups had similar socioeconomic , demographic , and biomedical characteristics and the newborns had similar hematocrit status . Two months after delivery , infants in the two groups with delayed cord clamping had significantly higher hematocrit values and hemoglobin concentrations than did those in the early-clamping group . The percentage with hematocrit values < 0.33 was 88 % in the control group compared with 42 % in group 2 and 55 % in group 3 ( P = 0.01 ) . These results suggest that waiting until the umbilical cord stops pulsating ( approximately 1 min after delivery ) is a feasible low-cost intervention that can reduce anemia in infants in developing countries [14608063] Iron deficiency is one of the main causes of anemia during pregnancy , although other micronutrient deficiencies may play a role . We examined the effects of daily antenatal and postnatal supplementation with four combinations of micronutrients on maternal hematologic indicators in a double-masked r and omized controlled community trial . Communities , called sectors , were r and omly assigned to supplementation with folic acid ( 400 microg ) , folic acid plus iron ( 60 mg ) , folic acid plus iron and zinc ( 30 mg ) and folic acid plus iron , zinc and 11 other micronutrients , each at the approximate recommended daily allowance for pregnancy all given with vitamin A as retinol acetate ( 1000 microg retinol equivalent ) , or vitamin A alone as the control group . Hemoglobin ( Hb ) and indicators of iron status were assessed at baseline and at 32 wk of gestation . At 6-wk postpartum , Hb assessment was repeated using a finger stick . Severely anemic women ( Hb < 70 g/L ) were treated according to WHO recommendations . Folic acid alone had no effect on maternal anemia or iron status . Hb concentrations were 14 g/L , [ 95 % confidence limits ( CL ) , 8.3 - 19.2 ] , 10.0 g/L ( CL , 5.2 - 14.8 ) and 9.4 g/L ( CL , 4.7 - 14.1 ) higher in the groups receiving folic acid plus iron , folic acid plus iron and zinc and folic acid plus iron , zinc and multiple micronutrients , respectively , relative to the control . Anemia in the third trimester was reduced by 54 % with folic acid plus iron , by 48 % with folic acid plus iron and zinc and by 36 % with folic acid plus iron , zinc and multiple micronutrients supplementation , relative to the control ( P < 0.05 ) . Thus , the combinations of folic acid plus iron and zinc and folic acid plus iron , zinc and multiple micronutrients provided no additional benefit in improving maternal hematologic status during pregnancy compared with folic acid plus iron . The level of compliance and baseline Hb concentrations modified the effect of iron [8644682] The effect of daily rather than weekly iron supplementation was compared in women who were 8 - 24 wk pregnant . One group ( n = 68 ) received 60 mg Fe/d , the second group ( n = 71 ) received 120 mg Fe/wk , given at once . Supplementation lasted 11.3 wk on average , depending on gestational date at entry , and was not supervised . Hemoglobin increased in both groups ( P < 0.001 ) ; serum ferritin did not change significantly . There was no significant difference between groups for changes in hemoglobin and serum ferritin . In a subgroup of women with a hemoglobin concentration < 110 g/L at baseline ( n = 45 daily ; n = 54 weekly ) no significant within-group changes occurred in serum ferritin , but the change in the daily group was 4.1 micrograms/L higher than in the weekly group ( P = 0.049 ) . Compliance , as indicated by two positive stool tests , was approximately equal to 54.3 % in the daily group and 62.2 % in the weekly group . We conclude that for the complete sample of subjects , the treatment effect of daily compared with weekly supplementation was similar under conditions resembling a normal antenatal care program [8237866] The present investigation was undertaken to assess the efficacy of oral iron supplementation during pregnancy by using a gastric delivery system ( GDS ) . Three hundred seventy-six pregnant women between 16 and 35 y of age and 14 and 22 wk gestation were selected if mild anemia was present ( hemoglobin concentration 80 - 110 g/L ) . The participants were r and omly assigned to one of three study groups given no iron , two FeSO4 tablets ( 100 mg Fe ) daily , or one GDS capsule ( 50 mg Fe ) daily . Blood was obtained initially and after 6 and 12 wk for measurement of red blood cell and iron indexes , including serum transferrin receptor . There was a significant and comparable improvement in hematologic and iron-status measurements in the two groups of women given iron whereas iron deficiency evolved in women given no iron supplement . We conclude that by eliminating gastrointestinal side effects and reducing the administration frequency of an iron supplement to once daily , a GDS offers significant advantages for iron supplementation of pregnant women [2963533] Studies on the treatment and prevention of iron deficiency anemia , in pregnant and nonpregnant women and in men , were conducted in Thail and and Burma . The effects of the dose of Fe , duration of Fe administration , additional supplementation with folate , mode of supplement delivery ( either supervised or unsupervised ) , and the presence of Hb(AE ) were studied . The frequency and severity of side effects were also recorded . Fe administration result ed in an increase in hemoglobin concentration in all anemic individuals but approximately 20 % failed to reach normality . The length of administration and the dose influenced the results . Frequency and severity of side effects increased with the dose of Fe administered . Folate supplementation did not affect the results . It appears possible to integrate a program of prevention and treatment of Fe deficiency anemia in a primary health-care system but the constraints and limitations of achievable results should be recognized [15113952] Daily iron supplementation programs for pregnant women recommend amounts of iron that are considered by some to be excessive , and either lower-dose or less frequent iron supplementation regimens have been proposed . A r and omized , placebo-controlled study was performed to assess and compare the relative effectiveness of a weekly ( WS ) or twice weekly ( TW ) iron supplementation schedule in maintaining or achieving hemoglobin ( Hb ) levels at term considered to carry minimal maternal and fetal risk ( 90 - 130 g/L ) . Pregnant women ( n = 116 ) at wk 10 - 30 of gestation ( 63 WS and 53 TW ) were enrolled in the study ( 52 in WS and 44 TW completed the study ) . Women were r and omly allocated to receive a 120-mg oral dose of iron as ferrous sulfate and 0.5 mg of folic acid weekly ( n = 52 ) or 60 mg iron and 0.25 mg folic acid and a placebo twice weekly ( n = 44 ) . Hb , hematocrit , serum ferritin , and transferrin saturation were estimated at baseline and at 36 - 39 wk of gestation . Baseline dietary data and the presence and intensity of intestinal helminthic infections were assessed . The duration of supplementation was 14 + /- 4 wk and the median level of adherence was 60.5 % . Hb concentrations improved in women following the TW regimen and in women following WS who had low baseline Hb levels . About 89 % of WS women and 95 % of TW women maintained Hb levels at term ( between 90 g/L and 130 g/L ) , a range associated with optimal pregnancy outcomes . One woman in the TW group exhibited higher Hb levels that potentially carried perinatal risk ( > 130 g/L ) . Intermittent iron and folic acid supplementation may be a valid strategy when used as a preventive intervention in prenatal care setting [15867287] In the United States , the prevalence of third trimester anemia among low-income pregnant women is 29 % and has not improved since the 1980s . Although low adherence has been linked to the ineffectiveness of iron supplementation programs , data regarding adherence to supplementation in low-income women are currently lacking . Hence this study was conducted to better underst and the factors associated with adherence to the use of iron-containing prenatal multivitamin/mineral supplements among low-income pregnant women . Adherence to supplement use was assessed by pill counts among 244 pregnant women of 867 women who were initially r and omized to receive 1 of 3 prenatal supplements . All women received care at a public prenatal clinic . Maternal characteristics associated with adherence were identified using predictive modeling . Women took 74 % of supplements as prescribed . Adherence was higher among non-Hispanic white women than among non-Hispanic black women ( 79 % vs. 72 % , P < /= 0.01 ) . Interactions of ethnicity with age group , smoking status , and prior supplement use were significant . Multivariate regression analysis stratified by ethnicity revealed that among the white women education beyond high school , unmarried status , nulligravidity , and smoking were positively associated with adherence . In contrast , among the black women , supplement use 3 mo prior to current pregnancy and no loss of appetite were positively associated with adherence . Further research investigating the influence of cultural factors is necessary to better underst and adherence to supplement use and the differences in adherence among ethnic groups [11053509] In the context of limited effectiveness of iron supplementation programs , intermittent iron supplementation is currently under debate as a possible alternative strategy that may enhance the effectiveness of operational programs . This field-based trial assessed the outcome of twice weekly iron supplementation compared to daily in Pakistan . A double-blind , r and omized , clinical trial was conducted in Northern Pakistan . Anemic pregnant women ( n = 191 ) were assigned to receive daily ( 200 mg ferrous sulfate ) or twice weekly ( 2 x 200 mg ferrous sulfate ) iron supplementation . Hemoglobin was measured at baseline and at 4-wk intervals for up to 12 wk . Serum ferritin was measured at baseline and 8 or 12 wk . Analysis was by intention to treat . The two groups did not differ in age , parity , sociodemographic characteristics , hemoglobin or serum ferritin concentrations at baseline . Women who received iron daily had a greater rise in hemoglobin compared with women who received iron twice weekly ( 17.8 + /- 1.8 vs. 3.8 + /- 1.2 g/L , P < 0.001 ) . The serum ferritin concentrations increased by 17.7 + /- 3.9 microgram/L ( P < 0.001 ) in the daily supplemented group and did not change in the twice weekly group . Daily iron supplementation remained superior to twice weekly supplementation after controlling initial hemoglobin Z-scores and duration of treatment . The body mass index ( BMI ) modified the effect of daily versus twice weekly iron supplementation . For every unit increase in BMI , the difference between the two treatment groups was reduced by 0.0014 ( final hemoglobin Z-score ; P = 0.027 ) . We recommend continuation of daily iron supplementation as opposed to intermittent iron supplementation in pregnant women in developing countries [16210715] BACKGROUND In Korea , it is customary to prescribe iron and folic acid supplements to pregnant women after the 20th wk of gestation ; however , little evidence exists to support this practice . OBJECTIVE The objective was to determine the effects of time of initiation and dose of prenatal iron and folic acid supplementation on the iron and folate nutriture of Korean women during pregnancy . DESIGN A total of 131 pregnant women were placed into 1 of 5 experimental groups , either the control group or 1 of 4 supplemented groups . The supplemented groups varied by time of initiation , which was either during the first trimester or at week 20 of gestation , and by dose of iron and folic acid supplements provided , which consisted of either 30 mg Fe plus 175 microg folic acid or 60 mg Fe plus 350 microg folic acid . All supplemented groups continued supplementation until delivery . RESULTS Improvements in iron and folate nutriture were highly dependent on when the supplement program was initiated , but both supplement doses were equally effective . In contrast , the influence of folic acid supplementation on maternal folate status was not as pronounced as was the influence of iron supplementation on iron status . CONCLUSION In pregnant Korean women , initiating iron and folic acid supplementation earlier during pregnancy may prevent the deterioration of iron and folate nutriture more than does increasing supplement doses in later stages of pregnancy [6461243] The usefulness of serum ferritin levels in assessing iron stores in pregnant women before and after supplementation with iron was studied . One hundred thirty-five healthy pregnant women between 22 to 28 wk were r and omly allotted to daily dose regimes of 60 , 120 , or 240 mg of ferrous sulphate . The tablets were given after meals under strict personal supervision . Before supplementation , iron deficiency ( ferritin level less than 10 micrograms/L ) was present in 54.8 % of the pregnant women , compared to an incidence of 17.8 % when assessed by serum iron concentration of less than 50 micrograms/dl . The mean ferritin level of pregnant women was 14.15 micrograms/L and was less than one-half that of healthy single women and one-sixth of that of healthy males . Supplementation with oral iron for 12 wk produced an increase in ferritin levels in all the groups , but significant increases were seen only in women given 120 and 240 mg of ferrous sulphate with or without folic acid . However , there were no differences in final Hb levels among the supplemented groups [9356536] We studied the effect of iron supplementation on the iron status of mothers and on biochemical iron status and clinical and anthropometric measures in their infants . The subjects were 197 pregnant women selected at 28 wk + /- 21 d of gestation at a mother- and -child health center in Niamey , Niger . Ninety-nine women received 100 mg elemental Fe/d throughout the remainder of their pregnancies and 98 received placebo . The prevalence of anemia and iron deficiency decreased markedly during the last trimester of pregnancy in the iron-supplemented group but remained constant in the placebo group . Three months after delivery , the prevalence of anemia was significantly higher in the placebo group . At delivery , there were no differences between the two groups in cord blood iron variables . Three months after delivery , serum ferritin concentrations were significantly higher in infants of women in the iron-supplemented group . Mean length and Apgar scores were significantly higher in infants with mothers in the iron group than in those with mothers in the placebo group [14668283] BACKGROUND We previously reported that maternal micronutrient supplementation in rural Nepal decreased low birth weight by approximately 15 % . OBJECTIVE We examined the effect of daily maternal micronutrient supplementation on fetal loss and infant mortality . DESIGN The study was a double-blind , cluster-r and omized , controlled trial among 4926 pregnant women and their 4130 infants in rural Nepal . In addition to vitamin A ( 1000 microg retinol equivalents ) , the intervention groups received either folic acid ( FA ; 400 microg ) , FA + iron ( 60 mg ) , FA + iron + zinc ( 30 mg ) , or multiple micronutrients ( MNs ; the foregoing plus 10 microg vitamin D , 10 mg vitamin E , 1.6 mg thiamine , 1.8 mg riboflavin , 2.2 mg vitamin B-6 , 2.6 microg vitamin B-12 , 100 mg vitamin C , 64 microg vitamin K , 20 mg niacin , 2 mg Cu , and 100 mg Mg ) . The control group received vitamin A only . RESULTS None of the supplements reduced fetal loss . Compared with control infants , infants whose mothers received FA alone or with iron or iron + zinc had a consistent pattern of 15 - 20 % lower 3-mo mortality ; this pattern was not observed with MNs . The effect on mortality was restricted to preterm infants , among whom the relative risks ( RRs ) were 0.36 ( 95 % CI : 0.18 , 0.75 ) for FA , 0.53 ( 0.30 , 0.92 ) for FA + iron , 0.77 ( 0.45 , 1.32 ) for FA + iron + zinc , and 0.70 ( 0.41 , 1.17 ) for MNs . Among term infants , the RR for mortality was close to 1 for all supplements except MNs ( RR : 1.74 ; 95 % CI : 1.00 , 3.04 ) . CONCLUSIONS Maternal micronutrient supplementation failed to reduce overall fetal loss or early infant mortality . Among preterm infants , FA alone or with iron reduced mortality in the first 3 mo of life . MNs may increase mortality risk among term infants , but this effect needs further evaluation [12600867] BACKGROUND Little is known about the benefits of prenatal multivitamin and mineral supplements in reducing low birth weight . OBJECTIVE We conducted a r and omized , double-blind clinical trial in semirural Mexico to compare the effects of multiple micronutrient ( MM ) supplements with those of iron supplements during pregnancy on birth size . DESIGN Pregnant women ( n = 873 ) were recruited before 13 wk of gestation and received supplements 6 d/wk at home , as well as routine antenatal care , until delivery . Both supplements contained 60 mg Fe , but the MM group also received 1 - 1.5 times the recommended dietary allowances of several micronutrients . RESULTS At recruitment , the women in the 2 groups were not significantly different in age , parity , economic status , height , or hemoglobin concentration but differed significantly in marital status ( 4.6 % and 2.0 % of women in the MM and iron-only groups , respectively , were single mothers ) and mean ( + /- SD ) body mass index ( in kg/m(2 ) ; 24.6 + /- 4.3 and 23.8 + /- 3.9 in the iron-only and MM groups , respectively ) . Losses to follow-up ( 25 % ) and compliance ( 95 % ) did not differ significantly between the groups . In intent-to-treat analyses ( MM group : n = 323 ; iron-only group : n = 322 ) , mean ( + /- SD ) birth weight ( 2.981 + /- 0.391 and 2.977 + /- 0.393 kg in the MM and iron-only groups , respectively ) and birth length ( 48.61 + /- 1.82 and 48.66 + /- 1.83 cm in the MM and iron-only groups , respectively ) did not differ significantly between the groups . CONCLUSION These findings suggest that MM supplementation during pregnancy does not lead to greater infant birth size than does iron-only supplementation [12450908] BACKGROUND According to our current underst and ing , iron absorption with weekly iron supplements is not higher than that with daily supplements ( ie , there is no mucosal block ) . However , community-based trials have repeatedly shown that a weekly regimen is as effective as a daily one . Furthermore , when differences in absorption are found , they are commonly smaller than would be expected on the basis of differences in the amount of iron provided . The possibility of differential compliance between the regimens needs to be evaluated to explain these findings . OBJECTIVE Taking compliance into account , we compared the efficacy and trial effectiveness of weekly and daily iron supplementation during pregnancy . DESIGN In Bangladesh , 50 antenatal centers were r and omly assigned to prescribe either 2 doses of 60 mg Fe once weekly or 1 dose of 60 mg Fe/d . Compliance was monitored by using a pill bottle equipped with an electronic counting device . Hemoglobin concentrations were measured at baseline and after 4 , 8 , and 12 wk of supplementation . RESULTS There was no differential effect per iron tablet between weekly and daily regimens . A 12-wk daily regimen ( 68 % compliance ) produced a small but significantly greater hemoglobin response than did the weekly regimen ( 104 % compliance ) . The first 20 tablets consumed produced most of the effect ; after 40 tablets , there was no further response . CONCLUSIONS There was no evidence of a mucosal block in the daily regimen . Over 12 wk , 50 % of the amount of iron in a daily regimen was sufficient for maximum hemoglobin effect . The weekly regimen provided a large part of this amount , explaining the limited difference in effect . It appears that the current international recommendation for iron supplementation in pregnancy is higher than necessary [16685054] BACKGROUND Iron supplements are often prescribed during pregnancy despite the lack of intervention trials that have assessed the effects of supplementation in pregnancy on childhood development . OBJECTIVE The objective was to determine whether iron supplementation during pregnancy influences childhood intelligence quotient ( IQ ) in an industrialized country . DESIGN Pregnant women ( n = 430 ) were r and omly allocated to receive iron ( 20 mg/d ) or placebo from 20 wk gestation until delivery , and the women and their children were followed up over the long term ( 4 y ) . Seventy percent of these families participated in the follow-up . The proportion of women with iron deficiency anemia at the end of pregnancy was 1 % ( 2 of 146 ) in the iron group and 11 % ( 15 of 141 ) in the placebo group . The primary outcome was the IQ of the children at 4 y of age , as assessed by the Stanford-Binet Intelligence Scale . Secondary outcomes included child behavior and the general health of the mothers . RESULTS The mean IQ was not significantly different ( P = 0.980 ) between the children of the iron-supplemented mothers ( 109 + /- 11 ; n = 153 ) and the children of the mothers in the placebo group ( 109 + /- 11 ; n = 149 ) . However , the percentage of children with an abnormal behavior score was higher in the iron group ( 24 of 151 , or 16 % ) than in the placebo group ( 12 of 149 , or 8 % ) ; the relative risk was 1.97 ( 95 % CI : 1.03 , 3.80 ; P = 0.037 ) . There was no significant difference in the health of the mothers between groups , as assessed by the SF-36 Health Survey . CONCLUSIONS Prenatal iron supplementation that reduces the incidence of iron deficiency anemia from 11 % to 1 % has no effect on the IQ of the offspring at 4 y of age [2596434] The use of hemoglobin as a predictor of response to iron therapy , for screening , and for prevalence estimates was studied . An Fe supplementation trial was performed in Quito , Ecuador , in which 412 pregnant women were r and omly assigned to treatment and control groups . Women in the treatment group received 390 mg ferrous sulfate/d for 2 mo . The prevalence of Fe deficiency as defined by response to therapy was found to be 60.8 % . Sensitivity and specificity were calculated at various cutoff points of hemoglobin . The estimates of sensitivity and specificity allow for the use of hemoglobin in screening for Fe deficiency anemia and in the estimation of the prevalence in population s with characteristics similar to those found in the sample of pregnant women in Quito . Hemoglobin was shown to be a good predictor of response to Fe treatment and a good estimate of prevalence of Fe deficiency when prevalence is high [8780347] Limited adherence to iron supplementation is thought to be a major reason for the low effectiveness of anemia-prevention programs . In rural Tanzania , women at 21 - 26 wk of gestation were r and omly given either 120 mg of a conventional ( Con ) iron supplement or 50 mg of a gastric-delivery-system ( GDS ) iron supplement for 12 wk . Adherence was assessed by using a pill bottle equipped with an electronic counting device . Adherence in the GDS group was 61 % compared with 42 % for the Con group . In both groups , women experiencing side effects had about one-third lower adherence . Fewer side effects were observed in the GDS group . In a subgroup of women with a low initial hemoglobin concentration ( < or = 120 g/L ) , the response to the iron supplements suggested that both of the applied doses were unnecessarily high for adequate hematologic response in a population with a marginal hemoglobin concentration . The GDS group appeared to require a dose one-fourth as high as that of the Con group for an equal effect on improving hemoglobin to normal concentrations [16600929] BACKGROUND Previously we showed that women in rural Nepal experience multiple micronutrient deficiencies in early pregnancy . OBJECTIVE This study examined the effects of daily antenatal micronutrient supplementation on changes in the biochemical status of several micronutrients during pregnancy . DESIGN In Nepal , we conducted a r and omized controlled trial in which 4 combinations of micronutrients ( folic acid , folic acid + iron , folic acid + iron + zinc , and a multiple micronutrient supplement containing folic acid , iron , zinc , and 11 other nutrients ) plus vitamin A , or vitamin A alone as a control , were given daily during pregnancy . In a sub sample of subjects ( n = 740 ) , blood was collected both before supplementation and at approximately 32 wk of gestation . RESULTS In the control group , serum concentrations of zinc , riboflavin , and vitamins B-12 and B-6 decreased , whereas those of copper and alpha-tocopherol increased , from the first to the third trimester . Concentrations of serum folate , 25-hydroxyvitamin D , and undercarboxylated prothrombin remained unchanged . Supplementation with folic acid alone or folic acid + iron decreased folate deficiency . However , the addition of zinc failed to increase serum folate , which suggests a negative inhibition ; multiple micronutrient supplementation increased serum folate . Folic acid + iron + zinc failed to improve zinc status but reduced sub clinical infection . Multiple micronutrient supplementation decreased the prevalence of serum riboflavin , vitamin B-6 , vitamin B-12 , folate , and vitamin D deficiencies but had no effect on infection . CONCLUSIONS In rural Nepal , antenatal supplementation with multiple micronutrients can ameliorate , to some extent , the burden of deficiency . The implication s of such biochemical improvements in the absence of functional and health benefits remain unclear [14522736] BACKGROUND The need for prophylactic iron during pregnancy is uncertain . OBJECTIVE We tested the hypothesis that administration of a daily iron supplement from enrollment to 28 wk of gestation to initially iron-replete , nonanemic pregnant women would reduce the prevalence of anemia at 28 wk and increase birth weight . DESIGN Between June 1995 and September 1998 , 513 low-income pregnant women in Clevel and were enrolled in the study before 20 wk of gestation . Of these , 275 had a hemoglobin concentration > /= 110 g/L and a ferritin concentration > /= 20 micro g/L and were r and omly assigned to receive a monthly supply of capsules containing either 30 mg Fe as ferrous sulfate or placebo until 28 wk of gestation . At 28 and 38 wk of gestation , women with a ferritin concentration of 12 to < 20 micro g/L or < 12 micro g/L received 30 and 60 mg Fe/d , respectively , regardless of initial assignment . Almost all the women received some supplemental iron during pregnancy . We obtained infant birth weight and gestational age at delivery for 117 and 96 of the 146 and 129 women r and omly assigned to receive iron and placebo , respectively . RESULTS Compared with placebo , iron supplementation from enrollment to 28 wk of gestation did not significantly affect the overall prevalence of anemia or the incidence of preterm births but led to a significantly higher mean ( + /- SD ) birth weight ( 206 + /- 565 g ; P = 0.010 ) , a significantly lower incidence of low-birth-weight infants ( 4 % compared with 17 % ; P = 0.003 ) , and a significantly lower incidence of preterm low-birth-weight infants ( 3 % compared with 10 % ; P = 0.017 ) . CONCLUSION Prenatal prophylactic iron supplementation deserves further examination as a measure to improve birth weight and potentially reduce health care costs [12816784] BACKGROUND Iron deficiency anemia ( IDA ) is common in pregnant women , but previous trials aim ed at preventing IDA used high-dose iron supplements that are known to cause gastrointestinal side effects . OBJECTIVE The objective was to assess the effect on maternal IDA and iron deficiency ( ID , without anemia ) of supplementing pregnant women with a low dosage ( 20 mg/d ) of iron . Effects on iron status were assessed at the time of delivery and at 6 mo postpartum . Gastrointestinal side effects were assessed at 24 and 36 wk of gestation . DESIGN This was a r and omized , double-blind , placebo-controlled trial of a 20-mg daily iron supplement ( ferrous sulfate ) given from 20 wk of gestation until delivery . RESULTS A total of 430 women were enrolled , and 386 ( 89.7 % ) completed the follow-up to 6 mo postpartum . At delivery , fewer women from the iron-supplemented group than from the placebo group had IDA [ 6/198 , or 3 % , compared with 20/185 , or 11 % ; relative risk ( RR ) : 0.28 ; 95 % CI : 0.12 , 0.68 ; P < 0.005 ] , and fewer women from the iron-supplemented group had ID ( 65/186 , or 35 % , compared with 102/176 , or 58 % ; RR : 0.60 ; 95 % CI : 0.48 , 0.76 ; P < 0.001 ) . There was no significant difference in gastrointestinal side effects between groups . At 6 mo postpartum , fewer women from the iron-supplemented group had ID ( 31/190 , or 16 % , compared with 51/177 , or 29 % ; RR : 0.57 ; 95 % CI : 0.38 , 0.84 ; P < 0.005 ) . The rate of IDA between the groups did not differ significantly at 6 mo postpartum . CONCLUSION Supplementing the diet of women with 20 mg Fe/d from week 20 of pregnancy until delivery is an effective strategy for preventing IDA and ID without side effects [19793860] BACKGROUND There is a growing interest in periconceptional iron supplementation in developing countries by research ers and policy makers ; however , there are no r and omized controlled trials that examine the effectiveness of this strategy in decreasing anemia during pregnancy . OBJECTIVE The aim was to determine whether periconceptional iron supplementation reduces anemia during pregnancy . DESIGN A r and omized , double-blind , controlled trial was conducted in rural Bangladesh . Married , nulliparous women were r and omly assigned to receive daily iron and folic acid ( IFA ; 60 mg ferrous fumarate and 400 microg folic acid ) ( n = 134 ) or folic acid ( FA ; 400 microg ) ( n = 138 ) in the form of a powdered supplement added to food . Women were followed until pregnancy or the end of 9 mo . Primary outcomes included hemoglobin , plasma ferritin , and plasma transferrin receptor concentrations . RESULTS Among 88 pregnant women , periconceptional IFA in comparison with FA did not affect anemia or iron status at 15 wk gestation . However , each 1 % increase in adherence was associated with a 10-g/L increase in change in hemoglobin from baseline ( P = 0.03 ) , and those who initiated supplementation at a mean ( + /-SD ) time of 72.9 + /- 57.8 d before conception showed a 7.3-g/L increase in change in hemoglobin from baseline compared with those who initiated supplementation at 26.3 + /- 12.3 d after conception ( P = 0.01 ) . Among 146 nonpregnant women , IFA decreased anemia ( odds ratio : 0.19 ; 95 % CI : 0.04 , 0.95 ) and improved iron stores ( P = 0.001 ) more than did FA . CONCLUSION Good adherence and initiation of supplementation before conception are needed to reduce anemia during early pregnancy . This trial was registered at www . clinical trials.gov as NCT00953134 [6824608] Summary . Serum iron , serum iron‐binding capacity , serum ferritin and erythrocyte protoporphyrin were determined during uncomplicated pregnancy in 45 healthy women ; 22 were given oral iron while the others were given a placebo . When iron was not given , 15 out of 23 women had exhausted iron stores and iron deficiency at term , as judged from low serum ferritin , low serum transferrin saturation and high erythrocyte protoporphyrin values . Only seven of them had a haemoglobin concentration between 10 and 11 g/dl at term but none had values < 10 g/dl . In the iron‐treated group ( n=22 ) none of the women developed iron deficiency . Serum ferritin was the most sensitive and specific test of iron deficiency . A practical procedure to detect iron deficiency and to control iron supplementation in pregnancy is suggested [12780424] Background . The aims of the present study were to evaluate the recommendations by comparing compliance and adequacy of iron status at 6 weeks postpartum between one group given advice only and one group given advice plus iron supplement . In the latter group the efficacies of two iron preparations of different strengths and types were compared [6726596] The known increased need for iron during pregnancy appears to be met only in part by increased iron absorption and amenorrhea . Considerable dem and s are made on maternal iron stores and , since many women lack sufficient storage iron , pregnancy may be expected to cause iron deficiency . This may lead to anemia in pregnancy and post partum and could also have a bearing on the iron status of the fetus and the neonate . Based on these considerations , prophylactic supplementation of dietary iron is advocated but remains a disputed issue . In the present controlled , prospect i ve and longitudinal study changes in hematologic status , and in particular in iron stores , during pregnancy were investigated in 44 healthy Caucasian women with uncomplicated pregnancies and deliveries . They were r and omly assigned to a study group ( n = 21 ) receiving oral iron supplements from the 16th week of amenorrhea until 6 weeks post partum , and a control group ( n = 23 ) without iron supplementation . Maternal concentrations of hemoglobin , serum iron , serum transferrin and serum ferritin were determined at 16 , 28 and 36 weeks of amenorrhea , at delivery , and 6 and 12 weeks post partum . The same variables were determined in cord blood . Iron supplementation appeared to prevent the physiologic fall in hemoglobin and serum iron concentrations which occurred in the control group , but had little influence on the observed rise in transferrin concentrations . Ferritin levels in serum , which are known to reflect mobilisable iron stores , fell to 30 % of the initial values in the control group and to 70 % in the study group . Six and 12 weeks post partum ferritin levels were still low in the nonsupplemented group ( Tab . I ) . ( ABSTRACT TRUNCATED AT 250 WORDS [1971872] A gastric delivery system ( GDS ) for iron supplementation was evaluated . Radioisotopic studies in 9 volunteers demonstrated a three-fold higher absorption of GDS iron compared with ferrous sulphate elixir . A double-blind placebo controlled trial was done in 200 women to compare the gastrointestinal side-effects associated with 50 mg iron daily given either as GDS or conventional ferrous sulphate . The conventional preparation was associated with a significantly higher frequency of nausea and anorexia , whereas there were no significant differences in reported side-effects between subjects receiving GDS or placebo . A single GDS capsule daily provides the same amount of absorbed iron as conventional ferrous sulphate given three times daily , and does not produce gastrointestinal side-effects [10696955] Background . The aim was to define reference values for hemoglobin , hematocrit and erythrocyte indices , i.e. erythrocyte count , mean corpuscular volume ( MCV ) , mean corpuscular hemoglobin ( MCH ) , mean corpuscular hemoglobin concentration ( MCHC ) , in normal pregnancy and after a normal delivery in non‐iron‐supplemented and iron supplemented women [12641613] Spatone Iron-Plus is a naturally occurring mineral water from Trefriw Wells Spa in Conwy County , North Wales , UK . It contains approximately 0.20 mg of iron per millilitre as ferrous sulphate and has been shown to provide iron in a highly bio-available form . A 24 ml sachet contains approximately 5 mg of iron . Iron deficiency is common in the obstetric population . However , compliance with traditional iron supplements is poor because of gastrointestinal side-effects . We design ed a r and omized , double-blind , placebo-controlled trial . A total of 102 low-risk antenatal patients , who were noncompliant with routinely prescribed ferrous sulphate tablets , were r and omized to receive 48 ml of Spatone water or placebo . The study was conducted between 22 and 28 weeks gestation . Primary outcome measures were compliance , gastrointestinal side-effects and changes in ferritin levels during the trial period . Compliance in the intervention group was 57 % compared with 67 % in the control group , P = 0.22 . Dyspepsia scores , as determined by a recognized and well-vali date d question naire , did not differ between the two groups . During the trial period , mean ferritin levels fell by 24 % in the Spatone Iron-Plus group compared with a mean fall of 51 % in ferritin levels among the control group , P = 0.016 [15777891] OBJECTIVE To compare the effect of daily oral iron supplementation with two injections of high dose parenteral iron . METHOD A total of 220 pregnant women with a singleton pregnancy and hemoglobin between 8 to 11 g% at 16 - 24 weeks gestation were identified and r and omly divided into two groups . Group A was started on daily oral iron therapy of 100 mg of elemental iron . Group B was given 250 mg of iron sorbitol intramuscularly and repeated at an interval of 4 - 6 weeks . Blood indices were evaluated at the beginning of study and at 36 weeks to see the effect after iron supplementation in the two groups . The data were analyzed using SPSS software , version 10.1 . RESULTS Definitive and comparable improvement in hemoglobin and all the blood indices ( hematocrit , MCH , MCHC , MCV , Serum iron and TIBC ) was observed . The absolute change in hemoglobin and hematocrit was 1.18+/-0.68 g% and 4.02+/-2.59 % in oral group , 1.34+/-0.77 g% and 4.93+/-3.65 % in parenteral group , respectively . Serum ferritin showed statistically significant absolute rise ( 10.43+/-7.92 microg/dl ) after parenteral iron supplementation as compared to oral iron supplementation ( 9.76+/-4.78 microg/dl ) . Obstetric outcome was comparable in two groups . CONCLUSION Two treatment regimens are biologically equivalent in terms of hematological response . Two high doses of intramuscular iron can be a good substitute to meet iron requirement in pregnancy [10878651] Objective : Intervention with iron supplementation , deworming , and information , education and communication ( IEC ) to improve the haematological status among each of the three trimesters of pregnant women in a rural community . Design : A community-based study was carried out using a two-group pre – post experimental design in a rural community . Setting : Two rural blocks in Vellore district were selected for the study . KV Kuppam block with a population of 120 , 000 and the adjacent Gudiyatham block with a population of 132 , 000 served as study and control areas for the study .Subjects : Using a multistage sampling , initially 50 % of the panchayats , the local village administrative units , were r and omly selected and all pregnant women were the subjects . In the pre-intervention survey 458 and 387 pregnant women had haemoglobin tested and the post-intervention survey covered 403 and 425 pregnant women in the study and control areas , respectively . Similarly serum ferritin was tested in a r and omly selected sub- sample with 254 and 191 pregnant women before intervention and in 216 and 223 pregnant women after intervention in both study and control areas , respectively . Intervention : Iron supplementation and deworming were provided to all pregnant women in the study area from the fourth month of their pregnancy . An intensive information , education and communication was carried out with facts on anaemia and diet modification to each pregnant woman , using a one-to-one approach in the community , and a group method in the mobile clinics . This was carried out for a period of 18 months . Results : A significant decrease in the prevalence of anaemia was found , from 56.1 % to 25.07 % ( P<0.001 ) , 73.4 % to 49.2 % ( P<0.001 ) and 68.8 % to 56.8 % ( P<0.01 ) among women in the first , second and third trimesters , respectively , in the intervention area . Significant ( P<0.001 ) increases in the mean haemoglobin of 0.85 g/dl ( 95 % CI 10.18–10.84 , 11.09–11.63 ) , 0.59 g/dl ( 95 % CI 9.98–10.34 , 10.55–10.95 ) and 0.36 g/dl ( 95 % CI 9.93–10.33 , 10.25–10.73 ) were also observed in each of the groups . Conclusion : A comprehensive community-based intervention with iron supplementation , helminthic treatment and increase in knowledge using IEC through effective strategies can improve the haematological status of pregnant women in each trimester . Sponsorship : Mother Care Project , John Snow Inc. , Funded by the United States Agency for International Development (USAID).European Journal of Clinical Nutrition ( 2000 ) 54 , [15766997] BACKGROUND Neonatal mortality is the biggest contributor to global mortality of children younger than 5 years , and low birthweight is a crucial underlying factor . We tested the hypotheses that antenatal multiple micronutrient supplementation would increase infant birthweight and gestational duration . METHODS We did a double-blind , r and omised controlled trial in Dhanusha district , Nepal . Women attending for antenatal care with singleton pregnancies at up to 20 weeks ' gestation were invited to participate . Participants were r and omly allocated either routine iron and folic acid supplements ( control ; n=600 ) or a multiple micronutrient supplement providing a recommended daily allowance of 15 vitamins and minerals ( intervention ; n=600 ) . Supplementation began at a minimum of 12 weeks ' gestation and continued until delivery . Primary outcome measures were birthweight and gestational duration . Analysis was by intention to treat . The study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N88625934 . FINDINGS Birthweight was available for 523/600 infants in the control group and 529/600 in the intervention group . Mean birthweight was 2733 g ( SD 422 ) in the control group and 2810 g ( 453 ) in the intervention group , representing a mean difference of 77 g ( 95 % CI 24 - 130 ; p=0.004 ) and a relative fall in the proportion of low birthweight by 25 % . No difference was recorded in the duration of gestation ( 0.2 weeks [ -0.1 to 0.4 ] ; p=0.12 ) , infant length ( 0.3 cm [ -0.1 to 0.6 ] ; p=0.16 ) , or head circumference ( 0.2 cm [ -0.1 to 0.4 ] ; p=0.18 ) . INTERPRETATION In a poor community in Nepal , consumption of a daily supplement containing a recommended daily allowance of 15 micronutrients in the second and third trimesters of pregnancy was associated with increased birthweight when compared with a st and ard iron and folic acid preparation . The effects on perinatal morbidity and mortality need further comparisons between studies . Published online March 3 , 2005 http://image.thelancet.com/extras/04art11045web.pdf [9351406] Background . The purpose of the present study was to evaluate the efficacy of low dose iron supplementation with and without a heme component , prescribed for women in the second half of pregnancy [17539886] Pregnancy during adolescence is associated with adverse birth outcomes , including preterm delivery and low birthweight . The nutrient availability to the fetus may be limited if the mother is still growing . This research aims to study the effects of pregnancy during adolescence in a nutritionally poor environment in rural Nepal . This study utilized data from a r and omized controlled trial of micronutrient supplementation during pregnancy in south-eastern Nepal . Women of parity 0 or 1 and of age < or= 25 years who gave birth to a singleton liveborn infant who was measured within 72 h of delivery were included ( n = 1393 ) . There was no difference in the risk of low birthweight ( OR = 0.96 ; 95 % CI = 0.90 - 1.02 ) or small for gestational age ( OR = 1.01 ; 95 % CI = 0.94 - 1.08 ) per year of increasing maternal age among primiparae . Young maternal age did not affect the anthropometry or gestational age of the offspring of parity 1 women . Each year of increasing maternal age among primiparae was associated with increases in birth length ( 0.07 cm ; 95 % CI = -0.01 to 0.16 ) , head ( 0.05 cm ; 95 % CI = 0.01 - 0.09 ) and chest circumference ( 0.07 cm ; 95 % CI = 0.01 - 0.12 ) , but not weight ( 9.0 g ; 95 % CI = -2.1 to 21.8 ) of their offspring . Young maternal age was associated with an increased risk of preterm delivery among primiparae ( OR = 2.07 ; 95 % CI = 1.26 - 3.38 ) that occurred at an age cut-off of < or=18 years relative to those 19 - 25 years . Thus , we conclude that young maternal age ( < or=18 years ) increased the risk of preterm delivery , but not intrauterine growth retardation , for the first but not second liveborn infant [19368922] OBJECTIVE To examine the effect of supplemental prenatal folic acid , folic acid-iron , folic acid-iron-zinc , and multiple micronutrients on maternal morbidity in rural Nepal . METHODS A cluster-r and omized double-masked controlled trial of pregnant women who received daily supplements from early pregnancy through 3 months post partum as per the treatment allocation . Women were interviewed at birth about labor and delivery complications and for 9 days post partum to obtain 24-hour histories of morbidity . RESULTS A total of 3986 ( 97.3 % ) women completed an interview regarding labor and delivery ; morbidity history was available for 3564 ( 87.0 % ) women . Folic acid-iron reduced the risk of postpartum hemorrhage ( relative risk [ RR ] 0.59 ; 95 % confidence interval [ CI ] 0.35 - 0.98 ) . Risk of dysfunctional labor increased with multiple micronutrient supplementation ( RR 1.28 ; 95 % CI , 1.01 - 1.60 ) , although preterm premature rupture of membrane decreased ( RR 0.40 ; 95 % CI , 0.21 - 0.79 ) . Puerperal sepsis was lower in those receiving folic acid-iron , folic acid-iron-zinc , and multiple micronutrients compared with controls ( P<0.05 ) . CONCLUSION Prenatal folic acid-iron supplementation reduced the risk of obstetric complications in this South Asian setting [17967217] Although routine Fe supplementation in pregnancy is a common practice , its clinical benefits or risks are uncertain . Children born to mothers in the Fe group in a trial of Fe supplementation in pregnancy have been found to have a significantly higher risk of abnormal behaviour at 4 years of age than those born to mothers in the placebo group . The objective of the present study therefore was to determine whether Fe supplementation in pregnancy influences child behaviour at early school age . The study was a follow-up of children at 6 - 8 years of age after women ( n 430 ) were r and omly allocated to receive a daily Fe supplement ( 20 mg ) or placebo from 20 weeks gestation until delivery . The supplement reduced the incidence of Fe-deficiency anaemia at delivery from 9 % to 1 % . Child behaviour and temperament were assessed using the Strengths and Difficulties Question naire and the Short Temperament Scale for Children . Of the children , 264 ( 61 % ) participated in the follow-up . Mean behaviour and temperament scores and the proportion of parent-rated and teacher-rated abnormal total difficulties scores did not differ between the Fe and placebo groups . However , the incidence of children with an abnormal teacher-rated peer problems subscale score was higher in the Fe group ( eleven of 112 subjects ; 8 % ) than in the placebo group ( three of 113 subjects ; 2 % ) ; the relative risk was 3.70 ( 95 % CI 1.06 , 12.91 ; P = 0.026 ) . We conclude that prenatal Fe supplementation had no consistent effect on child behaviour at early school age in this study population . Further investigation regarding the long-term effects of this common practice is warranted [19778983] The long-term benefits of antenatal iron supplementation in child survival are not known . In 1999 - 2001 , 4,926 pregnant women in rural Nepal participated in a cluster-r and omized , double-masked , controlled trial involving 4 alternative combinations of micronutrient supplements , each containing vitamin A. The authors examined the impact on birth weight and early infant mortality in comparison with controls , who received vitamin A only . They followed the surviving offspring of these women at approximately age 7 years to study effects of in utero supplementation on survival . Of 4,130 livebirths , 209 infants died in the first 3 months and 8 were lost to follow-up . Of those remaining , 3,761 were followed , 150 died between ages 3 months and 7 years , and 152 were lost to follow-up . Mortality rates per 1,000 child-years from birth to age 7 years differed by maternal supplementation group , as follows : folic acid , 13.4 ; folic acid-iron , 10.3 ; folic acid-iron-zinc , 12.0 ; multiple micronutrients ; 14.0 ; and controls , 15.2 . Hazard ratios were 0.90 ( 95 % confidence interval ( CI ) : 0.65 , 1.22 ) , 0.69 ( 95 % CI : 0.49 , 0.99 ) , 0.80 ( 95 % CI : 0.58 , 1.11 ) , and 0.93 ( 95 % CI : 0.66 , 1.31 ) , respectively , in the 4 supplementation groups . Maternal iron-folic acid supplementation reduced mortality among these children by 31 % between birth and age 7 years . These results provide additional motivation for strengthening antenatal iron-folic acid programs [19527380] OBJECTIVES To compare the effect of daily versus weekly iron supplementation on lipid peroxidation , hemoglobin levels and maternal and perinatal outcome in non-anemic pregnant women . METHODS Of 109 women r and omly allocated into three groups , 90 completed the study . Group I ( n = 30 ) received daily iron folic acid ; Group II ( n = 30 ) received weekly iron folic acid ; Group III ( n = 30 ) received daily iron (III)-hydroxide polymaltose complex . Hemoglobin levels , hematological indices , thiobarbituric acid reactive substances ( TBARS ) and glutathione levels were measured at baseline ( 14 - 16 weeks ) and at 30 - 34 weeks . Statistical analysis was done using the anova test . RESULTS Group I had a highly significant increase in TBARS level ( 0.61 + /- 0.26 micromol/L , P = 0.000 ) compared to groups II and III in which the change in TBARS was not significant ( 0.02 + /- 0.06 and 0.007 + /- 0.06 micromol/L , respectively ) . There was an insignificant fall in glutathione levels in all groups . There was no significant difference in the mean period of gestation , pregnancy complications and neonatal outcome between the three groups . Among 22.2 % of women who were non-compliant , Group I had significantly higher incidence of non-compliance ( P = 0.016 ) and side-effects ( P = 0.001 ) . Final hemoglobin was higher in Group I than II ( 11.9 + /- 1.2 , 11.3 + /- 0.9 , respectively , P = 0.041 ) . The TBARS level was not statistically different between preterm and term deliveries . Nine out of 11 patients who developed hypertension during pregnancy had preeclampsia . The final TBARS level was significantly higher in these women ( P = 0.000 ) . CONCLUSIONS Daily supplementation with ferrous sulphate results in greater lipid peroxidation than weekly supplementation , the latter is comparable with daily iron (III)-hydroxide polymaltose complex . Lipid peroxidation levels are significantly higher in preeclampsia [8846152] Blood manganese levels and iron status indices were determined each trimester in 66 healthy pregnant women . Twenty-five were r and omly assigned to iron supplementation , 19 to placebo and 22 received dietary advise aim ed at increasing their dietary intake of fibre . Iron supplemented women had significantly higher levels of blood haemoglobin compared to the levels of the two other groups , and higher serum ferritin levels compared to the placebo group . No significant difference in blood manganese levels was observed among the three groups of women . There was a significant increase in blood manganese levels from one trimester to the next , which was slightly more pronounced in non supplemented women . The median values in the three trimesters were 154 ( range 79 - 360 ) nmol/L , 190 ( range 98 - 408 ) nmol/L , and 230 ( range 133 - 481 ) nmol/L , respectively . Pregnancy seems to change manganese status or otherwise influence manganese metabolism irrespective of iron status and iron supplementation [2583756] This study was conducted to determine the optimum dose of supplemental iron for prophylaxis against pregnancy anemia . One hundred and ten pregnant women were r and omly allocated to three groups : Group A receiving equivalent of 60 mg , group B 120 mg and Group C 240 mg , elemental iron as ferrous sulphate daily ; the content of folic acid was constant in all the three groups ( 0·5 mg ) . These women had at least consumed 90 tablets in 100±10 days . Blood was drawn at the beginning and at the end of the treatment . Fifty percent were anemic ( < 11g/100 ml ) . The hemoglobin levels rose similarly in all groups and the differences were statistically not significant . Fifty-six percent had depleted iron stores ( serum ferritin value < 12 μg/1 ) at the beginning of the study . Following therapy a statistically significant increase in iron stores was observed in group B and C as compared to group A. The difference between group B and C was not significant . The side effects increased with increasing doses of iron ; 32·4 % , 40·3 % and 72 % in group A , B and C respectively . Based on these findings , the authors advocate that optimum dose of iron should be 120 mg instead of 60 mg as is currently being used in the National Nutritional Anemia Prophylaxis Programme . * * * DIRECT SUPPORT * * * A08BC044 [1858501] 192 pregnant women were consecutively r and omized to either a vitamin‐mineral pill or a vitamin mineral pill with a high iron content in a prospect i ve , open , r and omized investigation . The participants were advised about iron‐rich foodstuffs twice during pregnancy . Iron status of the mother proved to be without any significance for the outcome of pregnancy . A serum ferritin level of 80 pmol/l in mid‐pregnancy followed by a control in the last trimester was suggested as a guide in deciding of whether or not to prescribe supplementary iron during pregnancy [15566454] AIM To compare the hematological parameters and pregnancy outcome in women receiving daily versus weekly iron supplements during pregnancy . METHODS A prospect i ve r and omized controlled study was carried out at the Department of Obstetrics and Gynaecology of the All India Institute of Medical Sciences , New Delhi , India , during which 111 women were r and omized to receive either 100 mg elemental iron daily ( n=55 ) or 200 mg elemental iron weekly ( n=56 ) . Hemogram and serum ferritin level estimation were carried out at the beginning of pregnancy and within the 32 - 34-week period of gestation . Side-effects , compliance and the number of tablets consumed were noted for each group . The mean birth weight , period of gestation at delivery and mode of delivery were also compared between the two intervention groups . RESULTS There was no significant difference in the mean hemoglobin levels between the two intervention groups at the end of an average 17 weeks of iron supplementation . However , among anemic women who received daily supplementation , there was a greater rise in hemoglobin compared with those receiving supplementation weekly . The serum ferritin level was lower in the weekly supplemented group compared with that in the daily . There was no difference in the mean birth weight , period of gestation and mode of delivery between the two groups . Side-effects and non-compliance were significantly higher ( P<0.001 ) in the daily supplemented group . CONCLUSIONS Weekly iron supplementation is an effective option for prophylaxis in non-anemic pregnant women , but has less than optimal benefit in anemic women [16015266] Objectives : To assess the effects of daily prenatal multimicronutrient supplementation on birth weight ( BW ) and perinatal mortality . Design : R and omised , controlled , double masked trial . Setting : Urban Guinea-Bissau , West Africa . Subjects : A total of 2100 pregnant women ( 22±7 weeks pregnant at entry ) were recruited through antenatal clinics , of which 1670 ( 79.5 % ) completed the trial . BW was available for 1100 live born babies . Interventions : Identical-looking supplements containing one ( MN-1 ) or two ( MN-2 ) Recommended Dietary Allowances ( RDA ) of 15 micronutrients , or iron and folic acid ( control ) . Results : Mean BW among 1100 live born infants was 3050±498 g with 11.9 % being low birth weight ( LBW , BW<2500 g ) . Perinatal mortality was 82 per 1000 deliveries ( N=1670 ) , and neonatal mortality 45 per 1000 live births ( N=1599 ) . Mean BW in MN-1 ( n=360 ) and MN-2 ( n=374 ) groups were 53 [ −19 ; 125 ] and 95 [ 24 ; 166 ] g higher than controls ( n=366 ) . Proportion of LBW was 13.6 % in control , and 12.0 and 10.1 % in the MN-1 and MN-2 groups , respectively ( P=0.33 ) . Among anaemic women ( 30 % ) , MN-2 increased BW with 218 [ 81 ; 354 ] g compared to controls , with a decreased risk of LBW of 69 [ 27 ; 87]% . There were apparently no differences in perinatal mortality between groups . Conclusions : Prenatal micronutrient supplementation increased BW but did not reduce perinatal mortality in this study . Multimicronutrient supplementation with two RDA should be considered in future programmes to reduce the proportion of LBW [16424650] Background : It is a common belief among women that iron compounds have unpleasant gastrointestinal side effects . Objective : To assess the gastrointestinal side effects of iron prophylaxis in pregnancy . Methods : A r and omized , double-blind study comprising 404 healthy pregnant women allocated to four groups taking ferrous iron supplement ( as fumarate ) in doses of 20 ( n = 99 ) , 40 ( n = 100 ) , 60 ( n = 102 ) and 80 mg ( n = 103 ) daily from 18 weeks of gestation to delivery . Iron supplement was predominantly taken at bedtime . Gastrointestinal symptoms ( nausea , vomiting , epigastric pain , eructation , pyrosis , meteorism , borborygmi , colic pain , flatulence , constipation , thin feces , diarrhea ) , black feces , and use of laxatives were recorded by interview at 18 , 32 and 39 weeks of gestation . Results : The frequencies of gastrointestinal symptoms were not significantly different in the four iron supplement groups either at inclusion or at 32 and 39 weeks of gestation and thus not related to the iron dose . Conclusion : This study shows that a supplement of 20–80 mg ferrous iron ( as fumarate ) , taken between meals , has no clinical ly significant gastrointestinal side effects . The implementation of iron prophylaxis to pregnant women should not be compromised by undue concern of non-existing side effects [8141223] OBJECTIVE Our purpose was to study the effect of hematinic supplementation on the maternal erythropoietin response during singleton pregnancy . STUDY DESIGN In a r and omized , double-blind trial 97 patients with a first-trimester hemoglobin level > or = 14.0 gm/dl received either iron and folic acid ( hematinic group , n = 53 ) or a placebo ( n = 44 ) . Serial hemoglobin , hematocrit , and serum erythropoietin were recorded from maternal blood and from cord blood on delivery . Serum ferritin was measured in the first trimester , at 36 weeks ' gestation , and in cord blood . RESULTS In both groups ( 1 ) the mean hemoglobin was lower ( p < 0.01 ) at 40 weeks ' gestation than when first examined and ( 2 ) the mean serum erythropoietin was higher ( p < 0.01 ) . The mean serum ferritin was lower ( p < 0.001 ) in both groups at 36 weeks ' gestation than at presentation but higher ( p = 0.04 ) in the hematinic group than in the placebo group . The mean hemoglobin and hematocrit were similar in the two groups until the third trimester but thereafter were higher ( p < 0.05 ) in the hematinic group . The mean maternal serum erythropoietin was higher ( p < 0.05 ) in the placebo group than in the hematinic group after 24 weeks ' gestation . The mean cord blood hematologic values were similar in the two groups . CONCLUSION Maternal serum erythropoietin increased during pregnancy , but this response was reduced in the third trimester in the hematinic-supplemented group [19406557] OBJECTIVE To assess and compare the efficacy and safety of two and three doses of intravenous iron sucrose with daily oral ferrous sulphate in the prophylaxis of iron deficiency anaemia in pregnant women . STUDY DESIGN 260 women with singleton pregnancy who met inclusion criteria and who gave informed consent were r and omised between the 21st and 24th week into either the intravenous iron group or the oral iron group . Of 130 women in the intravenous iron group , 75 women received two doses of 200 mg iron sucrose and 55 three doses of 200 mg iron sucrose . The first dose was administered between the 21st and 24th gestational weeks , the second between the 28th and 32nd and the third between the 35th and 37th . The women of the oral group were given oral tablets of 80 mg ferrous sulphate daily , beginning on the day of study enrolment and stopping on the day of delivery . RESULTS There was a non-significant trend to a higher frequency of responders ( haemoglobin > or = 11 g/dl ) in the intravenous iron group ( 75 vs. 80 % ) . There was a significant difference of repleted iron stores before delivery ( ferritin>50 microg/l ) in the group with three intravenous iron doses in comparison to the oral iron group ( 49 vs. 14 % ; p<0.001 ) . No differences were observed in regard to maternal and perinatal outcomes . CONCLUSIONS There was no clinical ly significant difference in the haematological , maternal and foetal outcomes in the parenteral route of iron prophylaxis in pregnant women [19454124] OBJECTIVE We examined factors affecting compliance to antenatal micronutrient supplementation and women 's perceptions of supplement use . DESIGN R and omized controlled supplementation trial of four alternative combinations of micronutrients given during pregnancy through to 3 months postpartum . Women were visited twice weekly to monitor compliance and to replenish tablets by female study workers . At 6 weeks postpartum women with live births ( n 4096 ) were interviewed regarding their perceptions of the supplement . Median compliance calculated as percentage of total eligible doses received by women was high ( 84 % ) . SETTING Rural southern Nepal . SUBJECTS Pregnant women . RESULTS Women with high compliance ( above the median of 84 % ) were likely to be older , less educated , poorer , undernourished , belong to lower caste and of Pahadi ( hill ) ethnicity compared with women with low compliance ( at or below the median of 84 % ) . Smoking and drinking alcohol in the past week during pregnancy were strongly associated with low compliance . The major reason for irregular intake was forgetting to take supplements . A higher proportion of the high compliers liked taking the supplements but only half of them were willing to purchase them in the future . A large proportion of women ( 91 % ) perceived a benefit from taking the supplement such as improved strength and health , whereas only about 10 % perceived any side-effects which were not a major barrier to compliance . CONCLUSIONS The present analysis highlights that poor , undernourished , uneducated women can have high compliance to antenatal supplementation if they are supplied with the tablets and reminded to take them regularly , and counselled about side-effects [3511017] Recent studies suggest that infant behavior and psychological test performance are impaired by iron deficiency and may be improved by iron . Comparable studies have not been performed in older population s. Young women early in pregnancy whose nutritional intake may be impaired by poverty constitute a high-risk population . Women aged 14 - 24 years coming for prenatal care at or before 16 weeks gestation whose hematocrits were greater than or equal to 31 % were r and omized in a double-blind trial to receive vitamins supplemented with iron ( experimental group ) or vitamins alone ( controls ) . Hematologic status and tests of short-term memory and attention span were assessed at entry and conclusion of the one-month treatment period . The experimental group showed significant improvement on the most sensitive measure of short-term memory and three subtests . On comparison of the change between initial and final scores , the experimental group showed significant or borderline greater improvement than controls on three tests . These results indicated a beneficial effect of iron therapy on psychometric test-score performance [1062910] Abstract . Iron absorption , bone‐marrow smears and haematological parameters were repeatedly studied during pregnancy in 50 women . The same studies were repeated two months after delivery . The material was r and omly divided into two groups . Twenty‐four women were treated with 200 mg of ferrous iron daily while 26 were given placebo . The iron absorption was measured from radioiron‐labelled test doses of 100 mg ferrous iron in a whole‐body counter with high sensitivity [19474130] BACKGROUND We previously reported that a r and omized controlled trial of antenatal micronutrient supplements in rural Nepal decreased the risk of low birth weight by approximately 15 % . OBJECTIVE The objective was to examine the effects of micronutrient supplementation on growth and body composition in children of supplemented mothers through school age . DESIGN Mothers received 1 of 5 micronutrient supplements daily : folic acid , folic acid + iron , folic acid + iron + zinc , multiple micronutrients , or a control . All of the supplements contained vitamin A. Children born during this trial were revisited at age 6 - 8 y to measure height , weight , midupper arm circumference , waist circumference , and triceps and subscapular skinfold thicknesses . Arm fat and muscle area were estimated by using st and ard formulas , and height-for-age , weight-for-age , and body mass index-for-age z scores were calculated by using the World Health Organization growth st and ard . RESULTS Of the 3771 surviving children , 3324 were revisited and consented to anthropometric measurements . Maternal supplementation with folic acid + iron + zinc result ed in an increase in mean height ( 0.64 cm ; 95 % CI : 0.04 , 1.25 ) and a reduction in mean triceps skinfold thickness ( -0.25 mm ; 95 % CI : -0.44 , -0.06 ) , subscapular skinfold thickness ( -0.20 mm ; 95 % CI : -0.33 , -0.06 ) , and arm fat area ( -0.18 cm(2 ) ; -0.34 , -0.01 ) . No significant differences were found between groups in mean weight or body mass index-for-age z scores , waist circumference , or arm muscle area . Other micronutrient combinations including a multiple micronutrient formulation failed to show a growth benefit . CONCLUSION Antenatal supplementation with zinc may benefit child growth , particularly in areas where a deficiency of this nutrient is common [10422631] Abstract Assessment of the efficacy of iron therapy has usually been done in population s/ patients by monitoring changes in hemoglobin concentration , serum iron , percent transferrin saturation , and serum ferritin . In this study the protoporphyrin heme ( P/H ) ratio ( a measure of free erythrocyte protoporphyrin ) was measured before and after iron therapy in three groups of pregnant women , who received 60 mg ( group A ) , 120 mg ( group B ) , and 240 mg ( group C ) of elemental iron with folic acid ( 0.5 mg ) per day for a period of 12 weeks , to evaluate its efficacy to monitor iron therapy . The three groups were comparable regarding the initial mean Hb concentration and serum ferritin levels . The initial mean P/H ratios were markedly elevated in all three groups and were different in the three groups , being highest in group A ( 113.2±92.6 ) , intermediate in group B ( 87.5±62.5 ) , and lowest in group C ( 69.8±43.3 ) . The initial P/H ratio was significantly higher in group A than in group C ( p<0.05 ) . This probably affected the efficacy of iron therapy in the three groups . The P/H ratio decreased significantly in each of the three groups after iron therapy ( A and B : p<0.001 ; C p<0.01 ) . Mean Hb concentration and serum ferritin increased in all three groups post therapy ; however , the magnitude of change in P/H ratio in all three groups was much greater . This indicated that the predominant contributory factor for anemia was iron deficiency in this group of pregnant women . Serum iron and percent transferrin saturation are difficult to interpret in our population , as iron is freely available over the counter and is prescribed as soon as anemia is detected in patients ; therefore , the reduction in P/H ratio may be used to monitor response to iron therapy in population groups [8122498] In a r and omized , double‐blind , placebo controlled study of the effect of iron supplementation during pregnancy , iron status ( hemoglobin ( Hb ) , serum (S‐)transferrin saturation , S‐ferritin ) and S‐erythropoietin ( EPO ) were assessed in 120 healthy pregnant women at 14–16 weeks of gestation , and just before delivery ; 63 women were treated with 66 mg iron daily , and 57 with placebo . There were no differences in baseline values in the two groups . At term , the iron treated group had significantly higher Hb , transferrin saturation , S‐ferritin ( median 22 μg/1 vs. 14 μg/1 , ( p<0.0001 ) and lower S‐EPO compared to the placebo treated group . In the iron group , 30.2 % had exhausted iron stores ( i.e. S‐ferritin < 20 μg/1 ) , 6.3 % latent iron deficiency ( S‐ferritin < 20 μg/1 and transferrin saturation < 15 % ) , and no patients had iron deficiency anemia ( S‐ferritin < 20 μg/1 and transferrin saturation < 15 % and Hb < 110 g/1 ) . In the placebo group , 93.0 % had exhausted iron stores , 54.4 % latent iron deficiency , and 17.5 % iron deficiency anemia ; S‐EPO was inversely correlated to iron status markers : Hb , rs = −0.51,p<0.001 ; transferrin saturation , rs= −0.65,p<0.0001 ; S‐ferritin , rs= − 0.31 , R<0.01 , suggesting that the elevation in S‐EPO was secondary to iron deficient erythropoiesis . Newborns to iron treated mothers had higher cord S‐ferritin , median 155 μg/1 , than newborns to placebo treated mothers , median 118 ug/1 ( p<0.02 ) ; there were no differences in birth weight , transferrin saturation , or S‐EPO . Supplemental iron in a dose of 65 mg/day from the second trimester is sufficient to prevent iron deficiency in pregnant Danish women [16458655] OBJECTIVE The hypothesis that daily use of a prenatal supplement with iron from enrollment to third trimester to initially iron-replete , nonanemic pregnant women would reduce third-trimester anemia and improve birth outcomes was tested . STUDY DESIGN Eight hundred sixty-seven women in Raleigh , North Carolina , who were at < 20 weeks of gestation were enrolled ; 429 of these women had hemoglobin levels of > or = 110 g/L and ferritin levels of > or = 40 microg/L and were assigned r and omly to receive prenatal supplements with 30 mg of iron as ferrous sulfate ( n = 218 women ) or 0 mg of iron ( n = 211 women ) until 26 to 29 weeks of gestation . Intent-to-treat analysis was used for the outcomes of third-trimester iron status , birth weight , preterm birth , and small-for-gestational age . RESULTS Mean birth weight was higher by 108 g ( P = .03 ) , and the incidence of preterm delivery was lower ( 8 % vs 14 % ; P = .05 ) in the 30-mg group compared with the control group , respectively . Iron supplementation did not affect the prevalence of small-for-gestational age infants or third-trimester iron status . CONCLUSION Prophylactic iron supplementation that is begun early in pregnancy among low income women in the United States may have benefits beyond the reduction of iron deficiency anemia during pregnancy [19527383] AIM To determine the effect of an education program and /or pill count on the change in hemoglobin levels and the prevalence of anemia in pregnant women . METHODS A r and omized , factorial design controlled trial was conducted at the Tribhuvan University Teaching Hospital , Nepal . A total of 320 eligible pregnant women receiving prenatal care were r and omized into four groups ( control , education , pill count and education with pill count ) by block r and omization with allocation concealment . All recruited women received conventional routine prenatal care with a daily dose of 60 mg iron supplementation . In addition , the education group received an education program . Pill counting was done for the pill count group at their routine prenatal visits . The education with pill count group received both the education program plus pill counting . Baseline hemoglobin at the recruitment phase and follow-up hemoglobin after three months of recruitment were measured . Changes in hemoglobin levels and anemia prevalence were analyzed and compared between groups . RESULTS The education only and education with pill count groups had significantly higher hemoglobin changes ( 0.23 and 0.26 g/dL , respectively ) than the control group ( P < 0.01 ) . Anemia was reduced by 59 % in the education group and by 65 % in the education with pill count group , compared to the control group ( P < 0.05 ) . Pill count alone significantly improved neither the hemoglobin level nor anemia prevalence compared to the control group . CONCLUSION An education program along with routine iron supplementation can improve hemoglobin levels and reduce anemia prevalence in pregnant women . Pill count as a measure of compliance has no additional effect on improving hemoglobin status [2010577] This trial compares routine and selective iron supplementation during pregnancy to determine whether routine supplementation adversely affects fetal growth , increases infections and subjective adverse effects , and /or delays birth . At their first prenatal visit , 2912 pregnant women were r and omized into two groups ( 2694 gave birth ) . Compliance was satisfactory as measured by self-reports by mothers and hematocrit values in the third trimester . More women in the routinely supplemented group had subjected adverse effects . The groups were similar in regard to most of the other outcomes . In the selectively supplemented group , there was weak evidence for increase in sick-days , referrals to hospital outpatient clinic , cesarean section , blood transfusions , and infants who were diagnosed as having hyperviscosity . In the routine group , there were somewhat more women with gestations greater than or equal to 41 weeks and more dead infants . The subgroup analyses suggest that some of the apparently worse outcomes in the selective group were due to reactions of midwives and physicians to low hematocrit values [19336358] OBJECTIVE . We investigated the benefits of maternal multimicronutrient supplementation during gestation on the mental and psychomotor development of infants . METHODS . In a double-blind , r and omized , controlled trial , pregnant women ( N = 5828 ) in 2 rural counties in western China were assigned r and omly to receive multimicronutrient ( 5 minerals and 10 vitamins at levels approximating the recommended daily allowance ) , folic acid plus iron , or folic acid supplementation daily from ∼14 weeks of gestation until delivery . We assessed a subset of the newborns ( N = 1305 ) from the 3 supplementation groups by measuring their mental and psychomotor development with the Bayley Scales of Infant Development , at 3 , 6 , and 12 months of age . Multilevel analyses were used to compare the mental development and psychomotor development raw scores at 3 , 6 , and 12 months . RESULTS . Multimicronutrient supplementation was associated with mean increases in mental development raw scores for infants at 1 year of age of 1.00 and 1.22 points , compared with folic acid only and folic acid plus iron supplementation , respectively . However , supplementation did not increase significantly the psychomotor development raw scores up to 1 year of age . CONCLUSION . Compared with iron and folic acid supplementation , the administration of multimicronutrients to pregnant women improved the mental development of their children at 1 year of age [17928802] Background / Objectives : To compare the efficacy and side effects of low-dose vs high-dose iron supplements to correct anaemia in pregnancy . Subjects/ Methods : One hundred and eighty women with anaemia ( haemoglobin < 110 g l−1 ) in mid-pregnancy . The women were r and omly allocated to 20 ; 40 or 80 mg of iron daily for 8 weeks from mid-pregnancy . Results : One hundred and seventy-nine ( 99 % ) women completed the trial . At the end of treatment , there was a clear dose – response of increasing mean haemoglobin concentration with iron dose ( 111±13 g l−1 at 20 mg per day , 114±11 g l−1 at 40 mg per day and 119±12 g l−1 at 80 mg per day , P=0.006 ) . However , the incidence of anaemia did not differ statistically between groups . Compared with women in the 80 mg iron group , the odds ratio of anaemia was 1.9 ( 95 % CI : 0.8 , 4.3 , P=0.130 ) and 1.1 ( 95 % CI : 0.5 , 2.6 , P=0.827 ) , respectively , for women in the 20 mg iron group and the 40 mg iron group . The incidence of gastrointestinal side effects was significantly lower for women in the 20 mg iron group compared with women in the 80 mg iron group ; the odds ratio was 0.4 ( 95 % CI : 0.2 , 0.8 , P=0.014 ) for nausea , 0.3 ( 95 % CI : 0.2 , 0.7 , P=0.005 ) for stomach pain and 0.4 ( 95 % CI : 0.2 , 0.9 , P=0.023 ) for vomiting . Conclusions : Low-dose iron supplements may be effective at treating anaemia in pregnancy with less gastrointestinal side effects compared with high-dose supplements [7992349] A r and omized , double-blind , placebo-controlled community-based trial of oral iron supplementation ( 200 mg ferrous sulphate daily ) administered to multigravid pregnant women by traditional birth attendants ( TBAs ) was carried out in a rural area of The Gambia . Iron supplementation led to a significant reduction in the prevalence of anaemia and of iron deficiency . Iron supplementation was not accompanied by increased susceptibility to malaria infection ; there was no difference in the prevalence and severity of peripheral blood or placental malaria infection between the 2 groups of women . The birth weight of children born to women who received iron prophylaxis was increased by an average of 56 g. It is concluded that oral iron prophylaxis can be successfully delivered through TBAs integrated into a primary health care programme . This simple intervention can produce significant beneficial effects on the health of the mother without inducing increased susceptibility to malaria and has the potential for reducing perinatal mortality by increasing birth weight [7901636] Nutritional anaemia , thought to be caused by iron deficiency , affects 50 - 70 % of pregnant women in the developing world . The influence of vitamin A and iron supplementation was studied in anaemic pregnant women in West Java , in a r and omised , double-masked , placebo-controlled field trial . 251 women aged 17 - 35 years , parity 0 - 4 , gestation 16 - 24 weeks , and haemoglobin between 80 and 109 g/L were r and omly allocated to four groups : vitamin A ( 2.4 mg retinol ) and placebo iron tablets ; iron ( 60 mg elemental iron ) and placebo vitamin A ; vitamin A and iron ; or both placebos , all daily for 8 weeks . Maximum haemoglobin was achieved with both vitamin A and iron supplementation ( 12.78 g/L , 95 % Cl 10.86 to 14.70 ) , with one-third of the response attributable to vitamin A ( 3.68 g/L , 2.03 to 5.33 ) and two-thirds to iron ( 7.71 g/L , 5.97 to 9.45 ) . After supplementation , the proportion of women who became non-anaemic was 35 % in the vitamin-A-supplemented group , 68 % in the iron-supplemented group , 97 % in the group supplemented with both , and 16 % in the placebo group . Improvement in vitamin A status may contribute to the control of anaemic pregnant women [17764606] BACKGROUND Community iron supplementation programmes for pregnant women have lacked effectiveness , partly because of low compliance . OBJECTIVE To determine factors that influence compliance among pregnant women in Senegal . DESIGN Two hundred and twenty-one pregnant women , recruited from six health centres in Dakar during their first prenatal visit , were r and omly assigned to receive either a prescription to purchase iron/folic acid tablets ( control , n = 112 ) to be taken daily , according to official policy , or to receive free tablets ( treatment , n = 109 ) . Compliance was assessed 20 weeks after enrollment through interviews and pill count . Women with low or high compliance ( < 70 % or > or=70 % ) were asked to explain what influenced their adherence to supplementation . RESULTS Overall compliance was 69 % ; it was significantly higher in the treatment than in the control group ( 86 % vs. 48 % ; P < 0.0001 ) . Women with high compliance ( 58 % ) were motivated by : ( 1 ) the perception of improved health upon taking the tablets ( treatment = 24 % , control = 10 % ) ; ( 2 ) the insistence by midwives that they take the tablets ; and ( 3 ) the mention that the tablets would improve health . Women with low compliance ( 42 % ) reported : ( 1 ) the experience of side-effects that they associated with the tablets ( treatment = 13 % , control = 14 % ) ; ( 2 ) misunderst and ing that they needed to continue taking the tablets throughout pregnancy ( treatment = 0 % , control = 18 % ) ; and ( 3 ) forgetfulness . CONCLUSION Compliance with iron/folic acid supplementation in Senegal can be increased by providing women with clear instructions about tablet intake and educating them on the health benefits of the tablets [16760504] Folic acid is frequently given to pregnant women at the same time as intermittent preventive treatment ( IPTp ) with sulfadoxine/pyrimethamine ( SP ) , but it is not known if it interferes with the anti-malarial activity of SP . To investigate this concern , 1,035 Gambian primigravidae were r and omized to receive either folic acid ( 500 - 1,500 microg/day ) together with oral iron ( 522 ) or oral iron alone ( 513 ) for 14 days at the same time as they received IPTp with SP . On presentation , 261 women ( 25 % ) had Plasmodium falciparum asexual parasitemia . Prevalences of parasitemia on day 14 after treatment were similar in both groups : 5.7 % ( 26 of 458 ) in the iron plus folic acid group and 4.9 % ( 22 of 446 ) in the iron alone group ( risk difference = 0.74 % , 95 % confidence interval [ CI ] = -2.2 % to 3.7 % ) . Parasitologic cure was observed in 116 ( 91 % ) of 128 of women who were parasitemic on presentation and who received iron and folic acid and in 122 ( 92 % ) of 133 women who received iron alone ( difference = 1.1 % , 95 % CI = -5.6 % to 8.0 % ) . Women who received folic acid and iron had a slightly higher mean hemoglobin concentration at day 14 than women who had received iron alone ( difference = 0.14 g/dL , 95 % CI = 0.01 - 0.27 g/dL ) . The results of this study suggest that in an area of low SP resistance , administration of folic acid to pregnant women in a dose of 500 - 1,500 mug/day will not interfere with the protective effect of SP when used for IPTp [12637400] Abstract Objective : To assess the impact on birth size and risk of low birth weight of alternative combinations of micronutrients given to pregnant women . Design : Double blind cluster r and omised controlled trial . Setting : Rural community in south eastern Nepal . Participants : 4926 pregnant women and 4130 live born infants . Interventions : 426 communities were r and omised to five regimens in which pregnant women received daily supplements of folic acid , folic acid-iron , folic acid-iron-zinc , or multiple micronutrients all given with vitamin A , or vitamin A alone ( control ) . Main outcome measures : Birth weight , length , and head and chest circumference assessed within 72 hours of birth . Low birth weight was defined < 2500 g. Results : Supplementation with maternal folic acid alone had no effect on birth size . Folic acid-iron increased mean birth weight by 37 g ( 95 % confidence interval −16 g to 90 g ) and reduced the percentage of low birthweight babies ( < 2500 g ) from 43 % to 34 % ( 16 % ; relative risk=0.84 , 0.72 to 0.99 ) . Folic acid-iron-zinc had no effect on birth size compared with controls . Multiple micronutrient supplementation increased birth weight by 64 g ( 12 g to 115 g ) and reduced the percentage of low birthweight babies by 14 % ( 0.86 , 0.74 to 0.99 ) . None of the supplement combinations reduced the incidence of preterm births . Folic acid-iron and multiple micronutrients increased head and chest circumference of babies , but not length . Conclusions : Antenatal folic acid-iron supplements modestly reduce the risk of low birth weight . Multiple micronutrients confer no additional benefit over folic acid-iron in reducing this risk . What is already known on this topic Deficiencies in micronutrients are common in women in developing countries and have been associated with low birth weight and preterm delivery What this study adds In rural Nepal maternal supplementation with folic acid-iron reduced the incidence of low birth weight by 16 % A multiple micronutrient supplement of 14 micronutrients , including folic acid , iron , and zinc , reduced low birth weight by 14 % , thus conferring no advantage over folic [9704770] OBJECTIVE Our purpose was to demonstrate reduced blood volume in preeclampsia compared with nonproteinuric gestational hypertension and normal pregnancy by use of independent measures of red blood cell and plasma volumes . STUDY DESIGN Red blood cells labeled with a nonradioactive stable isotope of chromium and Evans ' blue were infused in subjects with preeclampsia or gestational hypertension and normotensive pregnant controls . Blood was sample d eight times over 60 minutes for dye concentration and at 30 minutes for chromium analysis . RESULTS Total blood and plasma volumes are decreased in preeclampsia ( 2660 + /- 382 mL/m2 and 1790 + /- 332 mL/m2 , respectively ) compared with normotensive subjects ( 3217 + /- 391 mL/m2 , P < 0.001 and 2279 + /- 325 mL/m2 , P < .001 ) and gestational hypertension ( 3139 + /- 272 mL/m2 , P < .001 and 2132 + /- 265 mL/m2 , P = .003 ) . Total body/peripheral hematocrit ratio is increased in preeclampsia . CONCLUSIONS Blood volume , by measurement of red blood cell and plasma volumes , is reduced and has altered distribution in preeclampsia but is normal in gestational hypertension [16733739] This study aims to evaluate iron prophylaxis in pregnant women from the individual aspect , i.e. according to serum ferritin levels at the beginning of pregnancy , and to assess which dose of iron would be adequate to prevent iron deficiency ( ID ) and iron deficiency anaemia ( IDA ) during pregnancy and postpartum . A r and omised , double-blind study comprising 301 healthy Danish pregnant women allocated into four groups taking ferrous iron ( as fumarate ) in doses of 20 mg ( n=74 ) , 40 mg ( n=76 ) , 60 mg ( n=77 ) and 80 mg ( n=75 ) from 18 weeks gestation ( inclusion ) to 8 weeks postpartum . Iron status markers [ serum ferritin , serum soluble transferrin receptor ( sTfR ) , haemoglobin ] were recorded at 18 , 32 and 39 weeks gestation and 8 weeks postpartum . Body iron was calculated using the serum sTfR/serum ferritin ratio . ID was defined by serum ferritin < 12 μg/l in pregnancy and < 15 μg/l postpartum ; IDA as serum ferritin < 12 μg/l and haemoglobin < 5th percentile in iron-replete pregnant women . Women in the iron supplement groups were stratified according to serum ferritin levels at inclusion ; 50.7 % had ferritin ≤30 μg/l , 37.7 % ferritin 30–70 μg/l and 11.6 % ferritin > 70 μg/l . At 32 weeks , women with ferritin ≤30 μg/l had an ID frequency of : 20-mg group 54.1 % , 40 mg 29.7 % , 60 mg 24.4 % , 80 mg 20.6 % ( p<0.001 ) ; women with ferritin > 30 μg/l had an ID frequency of : 20-mg group 20.0 % , 40 mg 13.9 % , 60 mg 5.7 % , 80 mg 5.1 % ( p<0.001 ) . Women with ferritin > 70 μg/l had no ID . Postpartum , ID was found in 4.7 % in 20-mg group , 2.9 % in group 40 mg and 0 % in group 60 and 80 mg . IDA : At 32 weeks , women with ferritin ≤30 μg/l had an IDA frequency of : 20-mg group 2.7 % , 40 mg 2.7 % , 60 and 80 mg 0 % ; none of the women with ferritin > 30 μg/l displayed IDA . Body iron at 18 weeks was 10.4 mg/kg , similar in the four iron groups . Later in pregnancy body iron declined significantly , being lower the 20 mg group , and similar in the 40 , 60 and 80-mg groups . Postpartum body iron rose to inclusion levels being 9.3 mg/kg in the 20-mg group and 10.5 mg/kg in the 40- , 60- and 80-mg groups . This study gives an estimate of iron dosage in individual iron prophylaxis adjusted to serum ferritin levels in early pregnancy . In the prevention of ID , we suggest 80–100 mg ferrous iron/day to women having ferritin ≤30 μg/l and 40 mg ferrous iron/day to women having ferritin 31–70 μg/l . In the prevention of IDA , we suggest 40 mg ferrous iron/day to women having ferritin ≤70 μg/l . Women with ferritin > 70 μg/l have no need for iron supplement [5551272] This study was planned to determine whether iron deficiency in pregnancy predisposed to the development of folate deficiency and also the smallest daily iron supplement that maintained haemoglobin levels in pregnancy . Three groups of women were given oral ferrous fumarate supplying 30 , 60 , and 120 mg of iron ; a fourth group was given 1 g of parenteral iron in early pregnancy followed by oral iron ( 60 mg ) ; a fifth group received a placebo . Tablets were taken once daily . Oral iron 30 mg once daily maintained haemoglobin levels throughout pregnancy . Women whose marrows lacked demonstrable iron at the 37th week had a significantly higher incidence of megaloblastic haemopoiesis ( 28·7 % ) than those with demonstrable iron stores ( 15·3 % ) ; women taking oral iron did not have a lower frequency of megaloblastosis than those given a placebo . We concluded that iron does not have a direct effect on folate status in pregnancy , that the association of iron deficiency and megaloblastic anaemia in pregnancy is the result of poor nutrition , and that there is no cause- and -effect relation between them [9277046] Serum erythropoietin ( EPO ) and its relationship to hemoglobin ( Hb ) , iron status markers and iron supplementation during normal pregnancy was assessed in a longitudinal , placebo-controlled study on 118 women , 61 took daily tablets containing 66 mg ferrous iron from the second trimester until delivery and 57 took placebo . Blood sample s were obtained at 4-week intervals until delivery as well as post-partum . In the placebo-treated women , median serum EPO rose from 22.5 U/l at inclusion to 35.0 U/l at delivery ( P = 0.0001 ) . In the iron-treated women , median serum EPO rose from 23.9 to 29.9 U/l ( P = 0.0001 ) . Serum EPO showed a steeper increase in the placebo-treated women than in the iron-treated women ( P < 0.05 ) . After delivery , serum EPO became normal in both groups ( P = 0.0001 ) . Median Hb was lower in placebo-treated ( iron depleted ) than in iron-treated ( iron repleted ) women ( P < 0.05 ) . In the placebo-treated women there was a negative correlation and in the iron-treated women a positive correlation between serum EPO and Hb . In the placebo-treated women , inverse correlations existed between serum EPO and serum transferrin saturation and serum ferritin , reflecting the consequences of iron deficiency , whereas the iron-treated women displayed no correlation . A physiological , nonhypoxia-induced increase in EPO production accounts for the basic expansion of the red cell mass during pregnancy . In placebo-treated women , iron deficient erythropoiesis constitutes an additional hypoxic stimulus , which induces a further increase in serum EPO [6029952] IN a previous investigation of the effects of grade d micro-doses of folic acid ( pteroyl glutamic acid ) in pregnancy suggestive evidence has been obtained that the minimal oral requirement may lie in the region of 300 pg./day . This conclusion was based largely upon the measurement of the fasting post-partum serum folate or L. casei activity in a group of patients from a population where poor dietary intake of folic acid was common . In patients receiving no prophylactic folic acid or IOO pg./day the median post-partum serum folate level was subnormal , in those receiving 3oo , ug./day it was normal and in those receiving 4sopg./day it was supranormal ( Willoughby and Jewell , 1966 ) . As an extension of this investigation the incidence of maternal anaemia has now been assessed among a population of 3599 patients r and omly allocated at their first ante-natal [8383415] Objective ‐ To determine : 1 ) if 18 mg iron daily is sufficient to cover the iron need during normal pregnancy , and 2 ) if women , who will not need iron supplementation during pregnancy , can be identified by early screening [7660438] The influence of haemoglobin genotype on the response to iron supplementation was studied in a r and omized , double blind , placebo-controlled trial involving 497 multigravid pregnant women from a rural area of The Gambia . Women were r and omly allocated to receive either oral iron ( 60 mg elemental iron per day ) or placebo . At 36 weeks of pregnancy , women who had received oral iron during pregnancy had higher mean haemoglobin , packed cell volume , plasma iron and ferritin levels than did women who received placebo . Iron supplementation of pregnant women with the AA haemoglobin genotype also result ed in increases in the packed cell volume ( PCV ) and haemoglobin level measured after delivery , and in the birth weight of the infant . However , in AS women PCV and haemoglobin level at delivery were lower in the supplemented group and supplementation was also associated with reduced birth weights . In malaria endemic areas , pregnant women with the haemoglobin genotype AS may not benefit from iron supplementation during pregnancy [2791561] This article reports the design and feasibility of a r and omized controlled trial of the benefits of routine iron prophylaxis during pregnancy . The multicenter trial , supported by a small budget , relied on health service personnel in Finnish maternity centers . Iron prophylaxis has had an established position in Finnish maternity care , and iron is freely available . This contributed to our decision to ask for informed consent after r and omization . During a year , 2960 mothers were recruited by midwives in 27 maternity health centers and r and omized into two groups : selective and routine iron supplementation . Mothers were followed until the postpartum checkup , and data were collected by five different question naires and abstract ed from the infant 's patient record . Adherence of the midwives to the study protocol was satisfactory , as was mothers ' compliance with recommended treatments . However , because the study was design ed to compare two treatment policies , problems of nonmasking hamper of the biologic effects of iron . This trial encourages the use of existing health services and their personnel in evaluation of medical technology [15715531] Objective . To determine the lowest dose of iron preventative of iron deficiency and iron deficiency anemia in pregnancy [16740440] BACKGROUND We undertook this study to compare the effectiveness and safety of antenatal daily and weekly supplementation with iron , folic acid , and vitamin B(12 ) in healthy , pregnant women who were not anemic at gestational week 20 . METHODS Women with singleton pregnancies and blood hemoglobin ( Hb ) > 115 g/L at gestational week 20 ( equivalent to 105 g/L at sea level ) were r and omly assigned to two groups , one consuming one tablet containing 60 mg iron , 200 mug folic acid and 1 mug vitamin B(12 ) daily ( DS , n = 56 ) ; the other consuming two tablets once weekly ( WS , n = 60 ) . Blood Hb and serum ferritin concentrations were measured every 4 weeks from weeks 20 to 36 , and pregnancy outcomes were evaluated . RESULTS Mild anemia and hypoferritinemia throughout pregnancy occurred less frequently in DS than WS . None of the 116 women had Hb concentrations < 103 g/L at any evaluation point . In contrast , hemoconcentration ( Hb > 145 g/L ) from gestational week 28 onwards occurred in 11 % in DS and 2 % in WS . We observed ex post facto that hemoconcentration at gestational week 28 was associated with a significantly higher relative risk of low birth weight ( RR 6.23 , 95 % CI 1.46 - 26.57 ) and premature delivery ( RR 7.78 , 95 % CI 1.45 - 24.74 ) . CONCLUSIONS In women who were nonanemic at gestational week 20 , both schemes ( DS and WS ) prevented the occurrence of Hb levels < 100 g/L. DS women had a higher incidence of hemoconcentration . Hemoconcentration was associated with increased risk of low birth weight and premature delivery [627303] The failure to prescribe in antenatal clinics a well tolerated form of supplementary oral iron that provides an adequate iron supply for the successful maintainance of active erythropoiesis in pregnant women largely accounts for the frequent development of latent iron deficiency in the child-bearing age . The potential value of Plexafer-F * , a slow release ferrous sulphate preparation supplemented with folic acid , in reducing the high incidence of latent iron deficiency in pregnancy was assessed by conducting a r and omized clinical trial of Plexafer-F and ordinary ferrous sulphate B.P. with folic acid in eighty women presenting early in pregnancy with latent iron deficiency . At the end of the trial , which was started at the sixteenth week of pregnancy and which lasted for twenty weeks , normal haematological values were obtained in thirty-eight out of forty patients ( 95 % ) taking Plexafer-F , but only in twenty-four out of forty patients ( 60 % ) taking ferrous sulphate . A simple screening test run on stool specimens provided during antenatal visits to check regular ingestion of the iron preparations prescribed , revealed regular drug intake and no intolerance in all the patients receiving Plexafer-F , against an intolerance leading to failure of regular drug intake in 37.5 % of patients receiving ordinary ferrous sulphate [5134472] The side-effects of a new sustained release oral ferrous sulphate preparation have been evaluated in three separate double-blind studies . Each tablet contained 100 mg of ferrous iron and the dosage employed in all studies was 2 tablets daily . In a large series of blood donors r and omly divided into three groups the frequency and type of side-effects were compared to ferrous sulphate tablets and placebo . In two series of pregnant women the side-effects were studied with a cross-over technique using ferrous sulphate tablets as reference . Placebo was also included as a reference in one of these studies . In all series the frequency of nausea and epigastric pain was about the same for the sustained release preparation as for placebo . In all series ferrous sulphate tablets gave a significantly higher frequency of nausea than the sustained release tablets and placebo . Also the frequency of epigastric pain was found to be higher in blood donors but this could not be verified in pregnant women [4668759] Summary The effect of small doses of iron and folic acid in a single tablet in preventing anaemia in pregnancy has been assessed . Fifty mg . elemental iron and 400μg . folic acid were found to be satisfactory daily supplements for both ‘ good ’ and ‘ bad ’ tablet takers . Tablet counting and an occasional chemical test for the presence of iron in the faeces were compared as indicators of tablet consumption and the latter found to be superior . The high incidence of faulty tablet consumption indicates the need for some check in anaemic patients in pregnancy [17889086] The iron status at 6 months and 4 years of children born to women who were r and omly allocated to receive 20 mg of iron daily in the second half of pregnancy did not differ from children of mothers in the control group . [17963760] OBJECTIVE To evaluate the effect of iron supplementation on serum copper and zinc levels . METHOD In a r and omized , double-blind , placebo-controlled trial , 66 pregnant women with hemoglobin 13.2 g/dL or greater between the 13th and 18th week of pregnancy were r and omized into case and control groups . From the 20th week until the end of pregnancy the case group received one ferrous sulfate tablet containing 50 mg elemental iron daily , while the control group received placebo . Hemoglobin , ferritin , copper , and zinc levels at 24 - 28 and 32 - 36 weeks of pregnancy were measured and compared . RESULTS In the case group , serum copper levels in the second and third trimester were significantly lower than the control group ( P<0.01 and P<0.001 , respectively ) . Serum zinc levels in the case group in the second and third trimester were also significantly lower than the control group ( P<0.001 ) . CONCLUSION Iron supplementation in pregnant women with hemoglobin greater than 13.2 g/dL reduces serum levels of copper and zinc [7631683] OBJECTIVE A r and omized trial comparing women who were given iron only if needed and those given iron prophylactically showed that routine prophylaxis is not crucial for mothers ' or infants ' health up to postpartum examination . This study investigated these infants ' and mothers ' subsequent health , as available in routine registers in a 7-year follow-up . STUDY DESIGN Original data ( N = 2693 ) were linked to the national population , birth , and hospital inpatient registers . RESULTS The outcomes in the two groups were very similar : there were no statistically significant differences in deaths after birth , number or timing of infants ' or mothers ' hospitalizations , reasons for mothers ' first hospitalization , number or timing of subsequent miscarriages or births , or problems or outcomes in the next birth . However , infants of the prophylactically supplemented group were more frequently hospitalized because of convulsions . CONCLUSION This study does not support routine iron prophylaxis for well-nourished pregnant women [17977537] OBJECTIVE To measure levels of markers of anemia before and after delivery in women who had high hemoglobin levels during the early stage of the second trimester of pregnancy and did not receive iron supplementation during their pregnancies . METHODS In a r and omized , double-blind , placebo-controlled trial 244 women who had a hemoglobin concentration of 13.2 g/dL or greater and a serum ferritin level higher than 15 microg/L between the 13th and 18th week of pregnancy took either one 150-mg tablet of ferrous sulfate daily or placebo during their pregnancies . Markers of anemia were measured at the time of delivery and 6 weeks postpartum . RESULTS There were statistically significant differences between the 2 groups in hematocrit as well as hemoglobin and ferritin levels both at the time of delivery and 6 weeks postpartum ( P<0.05 ) , but these differences were not clinical ly significant . CONCLUSION Not using iron supplementation did not cause a considerable decrease in markers of anemia in women with a hemoglobin concentration of 13.2 g/dL or greater in the second trimester of pregnancy [10842553] A weekly iron/folate supplement was compared with a st and ard daily iron/folate supplement in pregnant women living in rural Malawi . Women were enrolled as they attended the local antenatal clinic , stratified by grade of anaemia and then r and omized to receive either 60 mg iron/0.25 mg folate per day ( n=211 ) or 120 mg iron/0.50 mg folate once a week ( n=202 ) . Supplementation was continued for a minimum of 8 weeks ( 10 weeks on average ) and was self administered by the women at home . Initial haemoglobin values for the daily ( μ=105.7g/l ) and weekly ( μ=104.4g/l ) groups as well as final haemoglobin values ( 107.5 g/l and 105.6 g/l , respectively ) did not differ significantly between the two groups . Haemoglobin values increased by similar levels in both groups with the subset of anaemic women increasing by an average of 6.3 g/l in the daily group ( n=70 ) and 5.9 g/l in the weekly group ( n=66 ) for all women . For compliant , anaemic women , the increases were 7.4 g/l and 6.6 g/l for the daily and weekly groups , respectively . Compliance , as indicated by self reporting and by regular counts of remaining tablets , was significantly higher in the weekly group ( 76 % compared with 60 % , P < 0.05 ) , however compliance was identical in both groups when assessed by a stool test for elemental iron . Reported side effects were significantly reduced in the weekly group ( 6 % compared with 17 % , P < 0.05 ) . We conclude that a weekly iron supplement given to pregnant women in rural Malawi has similar haematologic effects , and an improved side effect profile , in comparison with a st and ard daily supplement when administered through an existing primary healthcare programme , although both regimens are relatively unsuccessful in the reduction of anaemia prevalence during pregnancy [11787984] In the present study 67 non-anaemic women were r and omly allocated to either 100 mg or 15 mg iron daily at about the 10 . week of pregnancy . At about week 18 , 30 and 36 of pregnancy , as well as 6 weeks after delivery , hemoglobin and the serum concentrations of ferritin , vitamin B12 , folates , Zn , Cu and Se were monitored . Dietary allowances of other minerals and vitamins are also increased in pregnancy , and the 15 mg iron tablet was enriched with Zn ( 10 mg ) , Cu ( 2 mg ) , Se ( 50 microg ) , vitamin B12 ( 3 microg ) , and folate ( 0.1 mg ) . Neither ferritin , nor Cu , Zn or Se concentrations differed statistically significantly between the treatment groups during pregnancy . Ferritin and Zn appeared to decrease approximately parallel to the hemodilution , whereas Cu concentrations increased from a non-pregnant reference mean of 18 micromol Cu/L to a maximum mean of nearly 33 micromol Cu/L during pregnancy . Se decreased concomitantly to about 1.0 micromol Se/L. Serum folate ( around 15 micromol/L ) was essentially unaffected by pregnancy in the group given multivitamin/mineral supplementation , whereas the mean concentration fell below 10 micromol/L in the group supplemented with 100 mg iron daily . Our results indicate that supplementation of 15 mg Fe daily during pregnancy results in a small reduction of hemoglobin . It is suggested that additional supplementation with folate might be of importance to maintain the serum folate concentration during pregnancy [15810797] Anemia is still the major nutritional problem among pregnant women in Southeast Asia . The objective of this study was to measure hemoglobin status and reduction of underweight in a group of pregnant women who received iron-fortified or nonfortified milk , and another group who received iron supplements ( tablets ) or placebo . The 44 women in the iron-fortified milk group received 15 mg of iron per day per 400 ml of milk , and 41 women received placebo . The 40 women in the iron supplement group received 60 mg of iron per day , and 43 women received nonfortified milk . During this intervention trial , all women were supervised from the 14th to the 18th week of gestation until delivery . Blood was sample d at 0 , 5 , 10 , and 16 weeks of intervention . After the 16th week of intervention , the changes in hemoglobin ( ΔHb ) concentrations in both treatment groups ( the iron-fortified milk and the iron tablet groups ) were not significantly different ( ΔHb : −0.5 ± 0.9 and −0.3 ± 0.9 g/L , respectively ) , but the changes were significantly greater in the nonfortified milk and placebo groups ( ΔHb : −1.2 ± 0.9 and −1.1 ± 0.8 g/L , respectively ; p < .01 ) . The change in transferrin saturation ( ΔTS ) in the iron-fortified milk group ( ΔTS : 3.4 ± 12.9 % ) was greater than that in the placebo and nonfortified milk groups ( ΔTS : −10.1 ± 9.8 % and −11.6 ± 10.7 % , respectively ) ( p < .01 ) . The weight gain of the subjects during intervention did not differ significantly in the fortified and nonfortified milk groups ( Δweight : 5.0 ± 2.0 and 5.8 ± 2.1 kg , respectively ) , but was higher than in the iron tablet group ( Δweight : 4.6 ± 3.1 kg p < .05 ) and the placebo group ( Δweight : 3.8 ± 2.5 kg ; p < .001 ) . Iron supplementation and fortification were seen to be effective in promoting weight gain in pregnant Vietnamese women . For women who are underweight , the administration of iron-fortified milk has additional benefits to those of supplementation , most likely due to additional energy and nutrient inputs [29120032] The effect of oral iron prophylaxis on haemoglobin concentration ( Hb ) and haematocrit ( Hct ) has been studied in 300 pregnant women . From the 3rd to 4th month of pregnancy and until term the women were r and omly treated with 100 mg or 200 mg ferrous iron daily respectively as sustained‐release tablets ( Duroferon ® Duretter ® ) or 200 mg ferrous iron as rapidly disintegrating tablets [5683581] The serial trends of the whole blood folate level in two groups of patients have been followed throughout pregnancy and up to six weeks postpartum . In those receiving iron alone the whole blood folate remained normal until the test at six weeks after delivery , at which time over half were in the deficient range . There appears to be a delay before this test reflects the current folate status when this changes rapidly . In those receiving iron plus 330 μg . of folic acid a day the results at this time were close to those at the beginning of pregnancy . Subnormal whole blood folate , red cell folate , and serum folate values occurred close to term in patients receiving iron alone , but were not found in those also receiving folic acid . Megaloblastic changes occurred at term in three patients receiving iron alone in whom the whole blood folate had repeatedly been low in early pregnancy . The observations are consistent with the previous suggestion that 300 μg . of folic acid daily is a suitable supplement to prevent deficiency in late pregnancy and the puerperium [7117682] Forty patients were given one of two iron-folic acid tablets starting from the first ante-natal visit and continuing to parturition . Haemoglobin levels were measured at the commencement , at the end of the study and on at least one other occasion . A comparison was made of haemoglobin levels and side-effects [19757261] Summary Prenatal multivitamin supplements ( PMS ) are recommended during pregnancy . Suboptimal adherence in women experiencing gastrointestinal ( GI ) conditions is thought to be attributed to the high elemental iron content in PMS . This study sought to quantify adherence and tolerability of iron-containing PMS in women with pre-existing GI conditions by recruiting women who called the Motherisk Helpline . Women with ( n = 36 ) and without ( n = 166 ) pre-existing GI conditions were r and omised to either PregVit ® ( n = 106 ) or Orifer F ® ( n = 96 ) . Monthly follow-up interviews were conducted to assess pill intake and GI adverse effects associated with PMS . The results of our study suggest that with the use of small size and low dose iron PMS , women with pre-existing GI conditions do not experience ( 1 ) more GI adverse effects , ( 2 ) lower adherence than women with no such conditions , and ( 3 ) may experience less severe nausea and vomiting of pregnancy . Supplementing with small tablets of low dose iron PMS should be considered [19203773] Iron ( Fe ) deficiency and anemia during pregnancy remain highly prevalent in Senegal because of low compliance with Fe supplementation . Improving women 's access to supplements may increase compliance . Six prenatal centers in Dakar were r and omly assigned to either a control group in which women received routine prenatal visits , including prescriptions to purchase iron/folic acid tablets ( IFA ) according to the guidelines of the current Senegalese supplementation program ( n=112 ) , or to an intervention group in which women received free IFA ( n=109 ) in addition to routine prenatal care . Compliance was assessed 20 weeks after enrollment by pill count and interviews . Hemoglobin , erythrocyte protoporphyrin and serum ferritin were measured at baseline and follow-up . Compliance was 48 % and 86 % in the control and intervention groups , respectively ( P<0.001 ) . After adjustment for confounding , prevalence of anemia was 62 % in the control group versus 31 % in the intervention group ( P<0.001 ) ; prevalence of Fe deficiency was 49 % and 21 % in the control and intervention groups , respectively ( P<0.001 ) . Improving access to IFA for pregnant women visiting health centers could dramatically increase their compliance , improve Fe status and decrease the incidence of anemia

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### Context: [2025036] Previous studies have found that there is a correlation between mothers ' haemoglobin concentration or packed cell volume and infants ' birth weight , and that iron supplementation increases mothers ' haemoglobin concentration . The purpose of this study , using the data of a large r and omised trial on iron prophylaxis during pregnancy , was to find out whether iron supplementation causes fetal growth to deteriorate . At their first antenatal visit , 2912 pregnant women were r and omised into non-routine iron and routine iron supplementation . The mean length of gestation was shorter in the non-routine group . Birth weight did not differ between the groups , but due to longer gestations boys in the group receiving routine iron were taller than in the non-routine group . In both groups , whether studied by various values of packed cell volume or correlation coefficients , the lower the packed cell volume , the heavier and taller the infant and heavier the placenta . These negative correlations could be seen even with a packed cell volume measured early in pregnancy . St and ardising for blood pressure did not influence the correlation coefficients . The correlation between a high ratio for packed cell volume and poor fetal growth thus may not be caused by iron supplementation , nor mediated by blood pressure , but by some other mechanism [2405769] Background Gastrointestinal irritability can deter pregnant women from starting or continuing prenatal multivitamin supplementation . In a previous study , suboptimal tolerability was observed among pregnant women taking a large tablet ( 18 mm × 8 mm × 8 mm ) multivitamin with high elemental iron content ( 60 mg as ferrous fumarate ) . The objective of the present study was to compare rates of adherence and reported adverse events among pregnant women who were r and omized to commence supplementation with a small-tablet prenatal multivitamin , containing either low or high iron content . Methods Pregnant women who called the Motherisk Program ( Hospital for Sick Children , Toronto ) and had not started taking or had discontinued any multivitamin due to adverse events were included in this prospect i ve , r and omized , open-label , 2-arm study . Women were r and omized to take a small-size ( 16 mm × 9 mm × 4 mm ) , low elemental iron content ( 35 mg as ferrous fumarate ) multivitamin ( ' 35 mg ' group ) ; or a small-size ( 5 mm radius , 5 mm thickness ) , high elemental iron content ( 60 mg as ferrous sulphate ) multivitamin ( ' 60 mg ' group ) . Follow-up interviews documented pill intake and adverse events . Rates of adherence and adverse events were compared between groups using chi-squared tests and Kaplan-Meier survival curves . Results Of 167 r and omized women , 92 in the ' 35 mg ' group and 75 in the ' 60 mg ' group were included in the analysis . Despite ideal conditions and regular follow-ups , mean adherence based on pill intake recall , in both groups was approximately 50 % . No statistically significant difference was detected in proportions of women who actually started taking either multivitamin . Among those who started , no difference was detected in rates of adherence or reported adverse events . Conclusion The present results suggest that iron content is not a major determinant of adherence to prenatal multivitamins . Combined with our previous study , tablet size may be the more definitive factor affecting adherence [3530158] Two hundred Hausa primigravidae at Zaria were divided into five groups in a r and omized double-blind trial of antenatal oral antimalarial prophylaxis , and haematinic supplements . Group 1 received no active treatment . Groups 2 to 5 were given chloroquine 600 mg base once , followed by proguanil 100 mg per day . In addition , group 3 received iron 60 mg daily , group 4 folic acid 1 mg daily , and group 5 iron plus folic acid . Forty-five percent were anaemic ( haemoglobin ( Hb ) less than 11.0 g dl-1 ) at first attendance before 24 weeks of gestation , and malaria parasitaemia ( predominantly Plasmodium falciparum ) was seen in 27 % , of whom 60 % were anaemic . The mean Hb fell during pregnancy in group 1 , and seven patients in this group had to be removed from the trial and treated for severe anaemia ( packed cell volume ( PCV ) less than 0.26 ) . Only five patients in the other groups developed severe anaemia ( P = 0.006 ) , two of whom had malaria following failure to take treatment . Patients in group 1 had the lowest mean Hb at 28 and 36 weeks of gestation , and patients receiving antimalarials and iron ( groups 3 and 5 ) had the highest Hb at 28 weeks , but differences were not significant , possibly due to removal from the trial of patients with severe anaemia . Anaemia ( Hb less than 12.0 g dl-1 ) at six weeks after delivery was observed in 61 % of those not receiving active treatment ( group 1 ) , in 39 % of those protected against malaria but not receiving iron supplements ( groups 2 and 4 ) and in only 18 % of patients receiving both antimalarials and iron ( groups 3 and 5 ) . Folic acid had no significant effect on mean Hb . Proguanil was confirmed to be a highly effective causal prophylaxis . Prevention of malaria , without folic acid supplements , reduced the frequency of megaloblastic erythropoiesis from 56 % to 25 % . Folic acid supplements abolished megaloblastosis , except in three patients who were apparently not taking the treatment prescribed . Red cell folate ( RCF ) concentrations were higher in subjects with malaria , probably due to intracellular synthesis by plasmodia . Infants of mothers not receiving antimalarials appeared to have an erythroid hyperplasia . Maternal folate supplements raised infants ' serum folate and RCF . Fourteen per cent had low birth weight ( less than 2500 g ) , and the perinatal death rate was 11 % ; the greatest number were in group 1 , but not significantly . A regime is proposed for the prevention of malaria , iron deficiency , folate deficiency and anaemia in pregnancy in the guinea savanna of Nigeria [1481554] Background Prenatal micronutrient combinations with high iron content are associated with high rates of gastrointestinal symptoms . This coupled with nausea and vomiting of pregnancy results in women often discontinuing their multivitamins . A new prescription supplement ( PregVit ® ) that separates iron from calcium in two tablets – morning and evening , has lower elemental iron content ( 35 mg ) , but results in similar extent of iron absorption when compared to another supplement containing ( 60 mg ) of elemental iron ( Materna ® ) . The objectives of this study were to compare tolerability and compliance with PregVit ® vs. a supplement with high iron content ( Materna ® ) , in pregnant women . Methods R and omized , crossover open labeled study in 135 pregnant women attending outpatient clinics in Ontario and Quebec . Results Use of PregVit ® was associated with a 30 % reduction in constipation rate as compared to Materna ® . Both products demonstrated similar compliance rates . Compliance of Materna ® was negatively associated with the severity of nausea and vomiting of pregnancy . No such correlation was found for PregVvit ® . Conclusion PregVit ® , a supplement with lower iron content ( 35 mg ) , has significantly decreased constipation rates as compared to 60 mg iron- Materna and has similar compliance rates . High iron content in multivitamin supplements is associated with adverse effects in pregnancy [3217057] Background The purpose of this study was compare of daily iron supplementation in three time frames- daily , weekly and three time weekly supplementation in preventing anemia in healthy pregnant women . Method The present study was a prospect i ve simply r and omized clinical trial . During January 2006- January 2008 , 150 healthy pregnant women without anemia , in their 16th week of pregnancy were r and omly allocated into three equal groups . The first group ( n = 50 ) received a 50 mg-ferrous sulfate tablet daily , second group ( n = 50 ) received a 50 mg-ferrous sulfate tablet three times a week , and the third group ( n = 50 ) received two 50 mg-ferrous sulfate tablets ( 100 mg ) weekly , respectively for 12 consecutive weeks . Serum hemoglobin , ferritin , and iron were measured before and after the supplementation . Paired t and ANOVA tests were used as appropriated . Results There were no significant differences between the pre- and post-treatment hemoglobin levels with iron supplementation in the three group ( P = 0.518 , P = 0.276 , respectively ) . The mean serum iron level before and after treatment with iron supplementation in the three groups was not statistically significant ( P = 0.962 , P = 0.970 , respectively ) . Although the mean serum ferritin level before and after treatment with iron supplementation was statistically significant in the three groups , no significant differences were found comparing the three groups ( P = 0.827 , P = 0.635 respectively ) . Conclusions This results suggested , three times a week or weekly iron supplementation is as effective as daily supplementation for healthy pregnant women without anemia . Trial Registration IS RCT N : I RCT [7891047] OBJECTIVE To evaluate whether levels of iron status markers ( haemoglobin , serum transferrin saturation , serum ferritin ) in pregnant women , measured in the beginning of the second trimester , could be used to predict levels later in pregnancy , pre partum and post partum . DESIGN R and omized , double-blind , placebo-controlled parallel study . SETTING The Birth Clinic at the Department of Obstetrics , Herning Hospital , Herning , Denmark . SUBJECTS One hundred and twenty healthy pregnant women between 14 and 18 weeks of gestation . INTERVENTIONS Sixty-three women were allocated to treatment with tablets containing 66 mg ferrous iron ( as fumarate ) daily , and 57 women to treatment with placebo . MAIN OUTCOME MEASURES Haemoglobin , serum transferrin saturation , and serum ferritin were measured every 4th week during gestation , prior to delivery , and 1 and 8 weeks post partum . RESULTS Correlation matrices during pregnancy and post partum were calculated for each iron status marker separately in iron-treated and placebo-treated women . Haemoglobin , transferrin saturation and serum ferritin values at inclusion displayed steadily declining correlation coefficients with values obtained later in pregnancy . There were no clinical ly relevant correlations to values obtained 8 weeks or less prior to delivery , and no correlations to values post partum . Serum ferritin values at inclusion could not be used to predict values later in pregnancy or post partum . CONCLUSION Haemoglobin , transferrin saturation and serum ferritin values measured in the beginning of the second trimester appear to be unsuitable as guidelines for an individual iron prophylaxis in pregnant women [5926263] Bertino , J. R. , Ward , J. , Sartorelli , A. C. , and Silber , R. ( 1965 ) . 7 . clin . Invest . , 44 , 1028 . Bothwell , T. H. , Hurtardo , A. V. , Donohue , D. M. , and Finch , C. A. ( 1957 ) . Blood , 12 , 409 . Callender , S. T. , and Malpas , J. S. ( 1963 ) . Brit . med . 7 . , 2 , 1516 . Cockburn , F. , Sherman , J. D. , Ingall , D. , and Klein , R. ( 1965 ) . Proc . Soc . exp . Biol . ( N.Y. ) , 118 , 238 . Conrad , M. E. , Berman , A. , and Crosby , W. H. ( 1962 ) . Gastroenterology , 43 , 385 . Dacie , J. V. , and Lewis , S. M. ( 1963 ) . Practical Haematology , 3rd ed . London . Davis , A. E. , and Badenoch , J. ( 1962 ) . Lancet , 2 , 6 . Finch , C. A. , Coleman , D. H. , Motulsky , A. G. , Donohue , D. M. , and Reiff , R. H. ( 1956 ) . Blood , 11 , 807 . Herbert , V. ( 1963 ) . Amer . 7 . clan . Nutr . , 12 , 17 . Gottlieb , C. W. , and Altschule , M. D. ( 1965 ) . Lancet , 2 , 1052 [2724426] Background Deficiencies of iron and folic acid during pregnancy can lead to adverse outcomes for the fetus , thus supplements are recommended . Adherence to current tablet-based supplements is documented to be poor . Recently a powdered form of micronutrients has been developed which may decrease side-effects and thus improve adherence . However , before testing the efficacy of the supplement as an alternate choice for supplementation during pregnancy , the bioavailability of the iron needs to be determined . Our objective was to measure the relative bioavailability of iron and folic acid from a powdered supplement that can be sprinkled on semi-solid foods or beverages versus a traditional tablet supplement in pregnant women . Methods Eighteen healthy pregnant women ( 24 – 32 weeks gestation ) were r and omized to receive the supplements in a crossover design . Following ingestion of each supplement , the changes ( over baseline ) in serum iron and folate over 8 hours were determined . The powdered supplement contained 30 mg of iron as micronized dispersible ferric pyrophosphate with an emulsifier coating and 600 μg folic acid ; the tablet contained 27 mg iron from ferrous fumarate and 1000 μg folic acid . Results Overall absorption of iron from the powdered supplement was significantly lower than the tablet ( p = 0.003 ) . There was no difference in the overall absorption of folic acid between supplements . Based on the differences in the area under the curve and doses , the relative bioavailability of iron from powdered supplement was lower than from the tablet ( 0.22 ) . Conclusion The unexpected lower bioavailability of iron from the powdered supplement is contrary to previously published reports . However , since pills and capsules are known to be poorly accepted by some women during pregnancy , it is reasonable to continue to explore alternative micronutrient delivery systems and forms of iron for this purpose .Trial Registration Clinical Trials.gov [6881917] Iron and folate status of 203 pregnant women have been evaluated at 6 months gestation and on the same women and their newborn infants at delivery . The women who had , at 6 months gestation , a Hb level below 11 g/dl were systematic ally given iron supplements . Iron or placebo were r and omly allocated to the other women . At 6 months of pregnancy , one quarter of the women had a Hb level under 11 g/dl but one third had a serum ferritin level below 12 micrograms/l and more than half had low levels of serum and red cell folate . Iron supplements induced an increase both in Hb levels and in serum ferritin values ; however , no significant differences were observed in serum ferritin of the newborn infants , whether their mothers had received iron supplements or not . These results have led us to reconsider the value of ferritin levels at birth as an index of iron stores in the infant . Iron supplements had no effect on the folate status in mothers or infants or on the frequency of obstetrical complications . A significant relationship was found between maternal folate levels and length of gestation . Folate supplementation may reduce the incidence of premature delivery [9022526] Iron deficiency anemia is a serious health problem that affects the physical and cognitive development of children . Therefore , it is important to develop cost-effective interventions to improve the hematologic status of the millions of children affected by this condition worldwide . We studied 69 Guatemalan infants who had been r and omly assigned to one of three groups at the time of delivery : 1 ) cord clamping immediately after delivery ( n = 21 ) ; 2 ) clamping when the cord stopped pulsating , with the infant placed at the level of the placenta ( n = 26 ) ; or 3 ) clamping when the cord stopped pulsating , with the newborn placed below the level of the placenta ( n = 22 ) . Maternal and infant hematologic assessment s were performed at the time of delivery and 2 mo postpartum . At baseline the groups had similar socioeconomic , demographic , and biomedical characteristics and the newborns had similar hematocrit status . Two months after delivery , infants in the two groups with delayed cord clamping had significantly higher hematocrit values and hemoglobin concentrations than did those in the early-clamping group . The percentage with hematocrit values < 0.33 was 88 % in the control group compared with 42 % in group 2 and 55 % in group 3 ( P = 0.01 ) . These results suggest that waiting until the umbilical cord stops pulsating ( approximately 1 min after delivery ) is a feasible low-cost intervention that can reduce anemia in infants in developing countries [14608063] Iron deficiency is one of the main causes of anemia during pregnancy , although other micronutrient deficiencies may play a role . We examined the effects of daily antenatal and postnatal supplementation with four combinations of micronutrients on maternal hematologic indicators in a double-masked r and omized controlled community trial . Communities , called sectors , were r and omly assigned to supplementation with folic acid ( 400 microg ) , folic acid plus iron ( 60 mg ) , folic acid plus iron and zinc ( 30 mg ) and folic acid plus iron , zinc and 11 other micronutrients , each at the approximate recommended daily allowance for pregnancy all given with vitamin A as retinol acetate ( 1000 microg retinol equivalent ) , or vitamin A alone as the control group . Hemoglobin ( Hb ) and indicators of iron status were assessed at baseline and at 32 wk of gestation . At 6-wk postpartum , Hb assessment was repeated using a finger stick . Severely anemic women ( Hb < 70 g/L ) were treated according to WHO recommendations . Folic acid alone had no effect on maternal anemia or iron status . Hb concentrations were 14 g/L , [ 95 % confidence limits ( CL ) , 8.3 - 19.2 ] , 10.0 g/L ( CL , 5.2 - 14.8 ) and 9.4 g/L ( CL , 4.7 - 14.1 ) higher in the groups receiving folic acid plus iron , folic acid plus iron and zinc and folic acid plus iron , zinc and multiple micronutrients , respectively , relative to the control . Anemia in the third trimester was reduced by 54 % with folic acid plus iron , by 48 % with folic acid plus iron and zinc and by 36 % with folic acid plus iron , zinc and multiple micronutrients supplementation , relative to the control ( P < 0.05 ) . Thus , the combinations of folic acid plus iron and zinc and folic acid plus iron , zinc and multiple micronutrients provided no additional benefit in improving maternal hematologic status during pregnancy compared with folic acid plus iron . The level of compliance and baseline Hb concentrations modified the effect of iron [8644682] The effect of daily rather than weekly iron supplementation was compared in women who were 8 - 24 wk pregnant . One group ( n = 68 ) received 60 mg Fe/d , the second group ( n = 71 ) received 120 mg Fe/wk , given at once . Supplementation lasted 11.3 wk on average , depending on gestational date at entry , and was not supervised . Hemoglobin increased in both groups ( P < 0.001 ) ; serum ferritin did not change significantly . There was no significant difference between groups for changes in hemoglobin and serum ferritin . In a subgroup of women with a hemoglobin concentration < 110 g/L at baseline ( n = 45 daily ; n = 54 weekly ) no significant within-group changes occurred in serum ferritin , but the change in the daily group was 4.1 micrograms/L higher than in the weekly group ( P = 0.049 ) . Compliance , as indicated by two positive stool tests , was approximately equal to 54.3 % in the daily group and 62.2 % in the weekly group . We conclude that for the complete sample of subjects , the treatment effect of daily compared with weekly supplementation was similar under conditions resembling a normal antenatal care program [8237866] The present investigation was undertaken to assess the efficacy of oral iron supplementation during pregnancy by using a gastric delivery system ( GDS ) . Three hundred seventy-six pregnant women between 16 and 35 y of age and 14 and 22 wk gestation were selected if mild anemia was present ( hemoglobin concentration 80 - 110 g/L ) . The participants were r and omly assigned to one of three study groups given no iron , two FeSO4 tablets ( 100 mg Fe ) daily , or one GDS capsule ( 50 mg Fe ) daily . Blood was obtained initially and after 6 and 12 wk for measurement of red blood cell and iron indexes , including serum transferrin receptor . There was a significant and comparable improvement in hematologic and iron-status measurements in the two groups of women given iron whereas iron deficiency evolved in women given no iron supplement . We conclude that by eliminating gastrointestinal side effects and reducing the administration frequency of an iron supplement to once daily , a GDS offers significant advantages for iron supplementation of pregnant women [2963533] Studies on the treatment and prevention of iron deficiency anemia , in pregnant and nonpregnant women and in men , were conducted in Thail and and Burma . The effects of the dose of Fe , duration of Fe administration , additional supplementation with folate , mode of supplement delivery ( either supervised or unsupervised ) , and the presence of Hb(AE ) were studied . The frequency and severity of side effects were also recorded . Fe administration result ed in an increase in hemoglobin concentration in all anemic individuals but approximately 20 % failed to reach normality . The length of administration and the dose influenced the results . Frequency and severity of side effects increased with the dose of Fe administered . Folate supplementation did not affect the results . It appears possible to integrate a program of prevention and treatment of Fe deficiency anemia in a primary health-care system but the constraints and limitations of achievable results should be recognized [15113952] Daily iron supplementation programs for pregnant women recommend amounts of iron that are considered by some to be excessive , and either lower-dose or less frequent iron supplementation regimens have been proposed . A r and omized , placebo-controlled study was performed to assess and compare the relative effectiveness of a weekly ( WS ) or twice weekly ( TW ) iron supplementation schedule in maintaining or achieving hemoglobin ( Hb ) levels at term considered to carry minimal maternal and fetal risk ( 90 - 130 g/L ) . Pregnant women ( n = 116 ) at wk 10 - 30 of gestation ( 63 WS and 53 TW ) were enrolled in the study ( 52 in WS and 44 TW completed the study ) . Women were r and omly allocated to receive a 120-mg oral dose of iron as ferrous sulfate and 0.5 mg of folic acid weekly ( n = 52 ) or 60 mg iron and 0.25 mg folic acid and a placebo twice weekly ( n = 44 ) . Hb , hematocrit , serum ferritin , and transferrin saturation were estimated at baseline and at 36 - 39 wk of gestation . Baseline dietary data and the presence and intensity of intestinal helminthic infections were assessed . The duration of supplementation was 14 + /- 4 wk and the median level of adherence was 60.5 % . Hb concentrations improved in women following the TW regimen and in women following WS who had low baseline Hb levels . About 89 % of WS women and 95 % of TW women maintained Hb levels at term ( between 90 g/L and 130 g/L ) , a range associated with optimal pregnancy outcomes . One woman in the TW group exhibited higher Hb levels that potentially carried perinatal risk ( > 130 g/L ) . Intermittent iron and folic acid supplementation may be a valid strategy when used as a preventive intervention in prenatal care setting [15867287] In the United States , the prevalence of third trimester anemia among low-income pregnant women is 29 % and has not improved since the 1980s . Although low adherence has been linked to the ineffectiveness of iron supplementation programs , data regarding adherence to supplementation in low-income women are currently lacking . Hence this study was conducted to better underst and the factors associated with adherence to the use of iron-containing prenatal multivitamin/mineral supplements among low-income pregnant women . Adherence to supplement use was assessed by pill counts among 244 pregnant women of 867 women who were initially r and omized to receive 1 of 3 prenatal supplements . All women received care at a public prenatal clinic . Maternal characteristics associated with adherence were identified using predictive modeling . Women took 74 % of supplements as prescribed . Adherence was higher among non-Hispanic white women than among non-Hispanic black women ( 79 % vs. 72 % , P < /= 0.01 ) . Interactions of ethnicity with age group , smoking status , and prior supplement use were significant . Multivariate regression analysis stratified by ethnicity revealed that among the white women education beyond high school , unmarried status , nulligravidity , and smoking were positively associated with adherence . In contrast , among the black women , supplement use 3 mo prior to current pregnancy and no loss of appetite were positively associated with adherence . Further research investigating the influence of cultural factors is necessary to better underst and adherence to supplement use and the differences in adherence among ethnic groups [11053509] In the context of limited effectiveness of iron supplementation programs , intermittent iron supplementation is currently under debate as a possible alternative strategy that may enhance the effectiveness of operational programs . This field-based trial assessed the outcome of twice weekly iron supplementation compared to daily in Pakistan . A double-blind , r and omized , clinical trial was conducted in Northern Pakistan . Anemic pregnant women ( n = 191 ) were assigned to receive daily ( 200 mg ferrous sulfate ) or twice weekly ( 2 x 200 mg ferrous sulfate ) iron supplementation . Hemoglobin was measured at baseline and at 4-wk intervals for up to 12 wk . Serum ferritin was measured at baseline and 8 or 12 wk . Analysis was by intention to treat . The two groups did not differ in age , parity , sociodemographic characteristics , hemoglobin or serum ferritin concentrations at baseline . Women who received iron daily had a greater rise in hemoglobin compared with women who received iron twice weekly ( 17.8 + /- 1.8 vs. 3.8 + /- 1.2 g/L , P < 0.001 ) . The serum ferritin concentrations increased by 17.7 + /- 3.9 microgram/L ( P < 0.001 ) in the daily supplemented group and did not change in the twice weekly group . Daily iron supplementation remained superior to twice weekly supplementation after controlling initial hemoglobin Z-scores and duration of treatment . The body mass index ( BMI ) modified the effect of daily versus twice weekly iron supplementation . For every unit increase in BMI , the difference between the two treatment groups was reduced by 0.0014 ( final hemoglobin Z-score ; P = 0.027 ) . We recommend continuation of daily iron supplementation as opposed to intermittent iron supplementation in pregnant women in developing countries [16210715] BACKGROUND In Korea , it is customary to prescribe iron and folic acid supplements to pregnant women after the 20th wk of gestation ; however , little evidence exists to support this practice . OBJECTIVE The objective was to determine the effects of time of initiation and dose of prenatal iron and folic acid supplementation on the iron and folate nutriture of Korean women during pregnancy . DESIGN A total of 131 pregnant women were placed into 1 of 5 experimental groups , either the control group or 1 of 4 supplemented groups . The supplemented groups varied by time of initiation , which was either during the first trimester or at week 20 of gestation , and by dose of iron and folic acid supplements provided , which consisted of either 30 mg Fe plus 175 microg folic acid or 60 mg Fe plus 350 microg folic acid . All supplemented groups continued supplementation until delivery . RESULTS Improvements in iron and folate nutriture were highly dependent on when the supplement program was initiated , but both supplement doses were equally effective . In contrast , the influence of folic acid supplementation on maternal folate status was not as pronounced as was the influence of iron supplementation on iron status . CONCLUSION In pregnant Korean women , initiating iron and folic acid supplementation earlier during pregnancy may prevent the deterioration of iron and folate nutriture more than does increasing supplement doses in later stages of pregnancy [6461243] The usefulness of serum ferritin levels in assessing iron stores in pregnant women before and after supplementation with iron was studied . One hundred thirty-five healthy pregnant women between 22 to 28 wk were r and omly allotted to daily dose regimes of 60 , 120 , or 240 mg of ferrous sulphate . The tablets were given after meals under strict personal supervision . Before supplementation , iron deficiency ( ferritin level less than 10 micrograms/L ) was present in 54.8 % of the pregnant women , compared to an incidence of 17.8 % when assessed by serum iron concentration of less than 50 micrograms/dl . The mean ferritin level of pregnant women was 14.15 micrograms/L and was less than one-half that of healthy single women and one-sixth of that of healthy males . Supplementation with oral iron for 12 wk produced an increase in ferritin levels in all the groups , but significant increases were seen only in women given 120 and 240 mg of ferrous sulphate with or without folic acid . However , there were no differences in final Hb levels among the supplemented groups [9356536] We studied the effect of iron supplementation on the iron status of mothers and on biochemical iron status and clinical and anthropometric measures in their infants . The subjects were 197 pregnant women selected at 28 wk + /- 21 d of gestation at a mother- and -child health center in Niamey , Niger . Ninety-nine women received 100 mg elemental Fe/d throughout the remainder of their pregnancies and 98 received placebo . The prevalence of anemia and iron deficiency decreased markedly during the last trimester of pregnancy in the iron-supplemented group but remained constant in the placebo group . Three months after delivery , the prevalence of anemia was significantly higher in the placebo group . At delivery , there were no differences between the two groups in cord blood iron variables . Three months after delivery , serum ferritin concentrations were significantly higher in infants of women in the iron-supplemented group . Mean length and Apgar scores were significantly higher in infants with mothers in the iron group than in those with mothers in the placebo group [14668283] BACKGROUND We previously reported that maternal micronutrient supplementation in rural Nepal decreased low birth weight by approximately 15 % . OBJECTIVE We examined the effect of daily maternal micronutrient supplementation on fetal loss and infant mortality . DESIGN The study was a double-blind , cluster-r and omized , controlled trial among 4926 pregnant women and their 4130 infants in rural Nepal . In addition to vitamin A ( 1000 microg retinol equivalents ) , the intervention groups received either folic acid ( FA ; 400 microg ) , FA + iron ( 60 mg ) , FA + iron + zinc ( 30 mg ) , or multiple micronutrients ( MNs ; the foregoing plus 10 microg vitamin D , 10 mg vitamin E , 1.6 mg thiamine , 1.8 mg riboflavin , 2.2 mg vitamin B-6 , 2.6 microg vitamin B-12 , 100 mg vitamin C , 64 microg vitamin K , 20 mg niacin , 2 mg Cu , and 100 mg Mg ) . The control group received vitamin A only . RESULTS None of the supplements reduced fetal loss . Compared with control infants , infants whose mothers received FA alone or with iron or iron + zinc had a consistent pattern of 15 - 20 % lower 3-mo mortality ; this pattern was not observed with MNs . The effect on mortality was restricted to preterm infants , among whom the relative risks ( RRs ) were 0.36 ( 95 % CI : 0.18 , 0.75 ) for FA , 0.53 ( 0.30 , 0.92 ) for FA + iron , 0.77 ( 0.45 , 1.32 ) for FA + iron + zinc , and 0.70 ( 0.41 , 1.17 ) for MNs . Among term infants , the RR for mortality was close to 1 for all supplements except MNs ( RR : 1.74 ; 95 % CI : 1.00 , 3.04 ) . CONCLUSIONS Maternal micronutrient supplementation failed to reduce overall fetal loss or early infant mortality . Among preterm infants , FA alone or with iron reduced mortality in the first 3 mo of life . MNs may increase mortality risk among term infants , but this effect needs further evaluation [12600867] BACKGROUND Little is known about the benefits of prenatal multivitamin and mineral supplements in reducing low birth weight . OBJECTIVE We conducted a r and omized , double-blind clinical trial in semirural Mexico to compare the effects of multiple micronutrient ( MM ) supplements with those of iron supplements during pregnancy on birth size . DESIGN Pregnant women ( n = 873 ) were recruited before 13 wk of gestation and received supplements 6 d/wk at home , as well as routine antenatal care , until delivery . Both supplements contained 60 mg Fe , but the MM group also received 1 - 1.5 times the recommended dietary allowances of several micronutrients . RESULTS At recruitment , the women in the 2 groups were not significantly different in age , parity , economic status , height , or hemoglobin concentration but differed significantly in marital status ( 4.6 % and 2.0 % of women in the MM and iron-only groups , respectively , were single mothers ) and mean ( + /- SD ) body mass index ( in kg/m(2 ) ; 24.6 + /- 4.3 and 23.8 + /- 3.9 in the iron-only and MM groups , respectively ) . Losses to follow-up ( 25 % ) and compliance ( 95 % ) did not differ significantly between the groups . In intent-to-treat analyses ( MM group : n = 323 ; iron-only group : n = 322 ) , mean ( + /- SD ) birth weight ( 2.981 + /- 0.391 and 2.977 + /- 0.393 kg in the MM and iron-only groups , respectively ) and birth length ( 48.61 + /- 1.82 and 48.66 + /- 1.83 cm in the MM and iron-only groups , respectively ) did not differ significantly between the groups . CONCLUSION These findings suggest that MM supplementation during pregnancy does not lead to greater infant birth size than does iron-only supplementation [12450908] BACKGROUND According to our current underst and ing , iron absorption with weekly iron supplements is not higher than that with daily supplements ( ie , there is no mucosal block ) . However , community-based trials have repeatedly shown that a weekly regimen is as effective as a daily one . Furthermore , when differences in absorption are found , they are commonly smaller than would be expected on the basis of differences in the amount of iron provided . The possibility of differential compliance between the regimens needs to be evaluated to explain these findings . OBJECTIVE Taking compliance into account , we compared the efficacy and trial effectiveness of weekly and daily iron supplementation during pregnancy . DESIGN In Bangladesh , 50 antenatal centers were r and omly assigned to prescribe either 2 doses of 60 mg Fe once weekly or 1 dose of 60 mg Fe/d . Compliance was monitored by using a pill bottle equipped with an electronic counting device . Hemoglobin concentrations were measured at baseline and after 4 , 8 , and 12 wk of supplementation . RESULTS There was no differential effect per iron tablet between weekly and daily regimens . A 12-wk daily regimen ( 68 % compliance ) produced a small but significantly greater hemoglobin response than did the weekly regimen ( 104 % compliance ) . The first 20 tablets consumed produced most of the effect ; after 40 tablets , there was no further response . CONCLUSIONS There was no evidence of a mucosal block in the daily regimen . Over 12 wk , 50 % of the amount of iron in a daily regimen was sufficient for maximum hemoglobin effect . The weekly regimen provided a large part of this amount , explaining the limited difference in effect . It appears that the current international recommendation for iron supplementation in pregnancy is higher than necessary [16685054] BACKGROUND Iron supplements are often prescribed during pregnancy despite the lack of intervention trials that have assessed the effects of supplementation in pregnancy on childhood development . OBJECTIVE The objective was to determine whether iron supplementation during pregnancy influences childhood intelligence quotient ( IQ ) in an industrialized country . DESIGN Pregnant women ( n = 430 ) were r and omly allocated to receive iron ( 20 mg/d ) or placebo from 20 wk gestation until delivery , and the women and their children were followed up over the long term ( 4 y ) . Seventy percent of these families participated in the follow-up . The proportion of women with iron deficiency anemia at the end of pregnancy was 1 % ( 2 of 146 ) in the iron group and 11 % ( 15 of 141 ) in the placebo group . The primary outcome was the IQ of the children at 4 y of age , as assessed by the Stanford-Binet Intelligence Scale . Secondary outcomes included child behavior and the general health of the mothers . RESULTS The mean IQ was not significantly different ( P = 0.980 ) between the children of the iron-supplemented mothers ( 109 + /- 11 ; n = 153 ) and the children of the mothers in the placebo group ( 109 + /- 11 ; n = 149 ) . However , the percentage of children with an abnormal behavior score was higher in the iron group ( 24 of 151 , or 16 % ) than in the placebo group ( 12 of 149 , or 8 % ) ; the relative risk was 1.97 ( 95 % CI : 1.03 , 3.80 ; P = 0.037 ) . There was no significant difference in the health of the mothers between groups , as assessed by the SF-36 Health Survey . CONCLUSIONS Prenatal iron supplementation that reduces the incidence of iron deficiency anemia from 11 % to 1 % has no effect on the IQ of the offspring at 4 y of age [2596434] The use of hemoglobin as a predictor of response to iron therapy , for screening , and for prevalence estimates was studied . An Fe supplementation trial was performed in Quito , Ecuador , in which 412 pregnant women were r and omly assigned to treatment and control groups . Women in the treatment group received 390 mg ferrous sulfate/d for 2 mo . The prevalence of Fe deficiency as defined by response to therapy was found to be 60.8 % . Sensitivity and specificity were calculated at various cutoff points of hemoglobin . The estimates of sensitivity and specificity allow for the use of hemoglobin in screening for Fe deficiency anemia and in the estimation of the prevalence in population s with characteristics similar to those found in the sample of pregnant women in Quito . Hemoglobin was shown to be a good predictor of response to Fe treatment and a good estimate of prevalence of Fe deficiency when prevalence is high [8780347] Limited adherence to iron supplementation is thought to be a major reason for the low effectiveness of anemia-prevention programs . In rural Tanzania , women at 21 - 26 wk of gestation were r and omly given either 120 mg of a conventional ( Con ) iron supplement or 50 mg of a gastric-delivery-system ( GDS ) iron supplement for 12 wk . Adherence was assessed by using a pill bottle equipped with an electronic counting device . Adherence in the GDS group was 61 % compared with 42 % for the Con group . In both groups , women experiencing side effects had about one-third lower adherence . Fewer side effects were observed in the GDS group . In a subgroup of women with a low initial hemoglobin concentration ( < or = 120 g/L ) , the response to the iron supplements suggested that both of the applied doses were unnecessarily high for adequate hematologic response in a population with a marginal hemoglobin concentration . The GDS group appeared to require a dose one-fourth as high as that of the Con group for an equal effect on improving hemoglobin to normal concentrations [16600929] BACKGROUND Previously we showed that women in rural Nepal experience multiple micronutrient deficiencies in early pregnancy . OBJECTIVE This study examined the effects of daily antenatal micronutrient supplementation on changes in the biochemical status of several micronutrients during pregnancy . DESIGN In Nepal , we conducted a r and omized controlled trial in which 4 combinations of micronutrients ( folic acid , folic acid + iron , folic acid + iron + zinc , and a multiple micronutrient supplement containing folic acid , iron , zinc , and 11 other nutrients ) plus vitamin A , or vitamin A alone as a control , were given daily during pregnancy . In a sub sample of subjects ( n = 740 ) , blood was collected both before supplementation and at approximately 32 wk of gestation . RESULTS In the control group , serum concentrations of zinc , riboflavin , and vitamins B-12 and B-6 decreased , whereas those of copper and alpha-tocopherol increased , from the first to the third trimester . Concentrations of serum folate , 25-hydroxyvitamin D , and undercarboxylated prothrombin remained unchanged . Supplementation with folic acid alone or folic acid + iron decreased folate deficiency . However , the addition of zinc failed to increase serum folate , which suggests a negative inhibition ; multiple micronutrient supplementation increased serum folate . Folic acid + iron + zinc failed to improve zinc status but reduced sub clinical infection . Multiple micronutrient supplementation decreased the prevalence of serum riboflavin , vitamin B-6 , vitamin B-12 , folate , and vitamin D deficiencies but had no effect on infection . CONCLUSIONS In rural Nepal , antenatal supplementation with multiple micronutrients can ameliorate , to some extent , the burden of deficiency . The implication s of such biochemical improvements in the absence of functional and health benefits remain unclear [14522736] BACKGROUND The need for prophylactic iron during pregnancy is uncertain . OBJECTIVE We tested the hypothesis that administration of a daily iron supplement from enrollment to 28 wk of gestation to initially iron-replete , nonanemic pregnant women would reduce the prevalence of anemia at 28 wk and increase birth weight . DESIGN Between June 1995 and September 1998 , 513 low-income pregnant women in Clevel and were enrolled in the study before 20 wk of gestation . Of these , 275 had a hemoglobin concentration > /= 110 g/L and a ferritin concentration > /= 20 micro g/L and were r and omly assigned to receive a monthly supply of capsules containing either 30 mg Fe as ferrous sulfate or placebo until 28 wk of gestation . At 28 and 38 wk of gestation , women with a ferritin concentration of 12 to < 20 micro g/L or < 12 micro g/L received 30 and 60 mg Fe/d , respectively , regardless of initial assignment . Almost all the women received some supplemental iron during pregnancy . We obtained infant birth weight and gestational age at delivery for 117 and 96 of the 146 and 129 women r and omly assigned to receive iron and placebo , respectively . RESULTS Compared with placebo , iron supplementation from enrollment to 28 wk of gestation did not significantly affect the overall prevalence of anemia or the incidence of preterm births but led to a significantly higher mean ( + /- SD ) birth weight ( 206 + /- 565 g ; P = 0.010 ) , a significantly lower incidence of low-birth-weight infants ( 4 % compared with 17 % ; P = 0.003 ) , and a significantly lower incidence of preterm low-birth-weight infants ( 3 % compared with 10 % ; P = 0.017 ) . CONCLUSION Prenatal prophylactic iron supplementation deserves further examination as a measure to improve birth weight and potentially reduce health care costs [12816784] BACKGROUND Iron deficiency anemia ( IDA ) is common in pregnant women , but previous trials aim ed at preventing IDA used high-dose iron supplements that are known to cause gastrointestinal side effects . OBJECTIVE The objective was to assess the effect on maternal IDA and iron deficiency ( ID , without anemia ) of supplementing pregnant women with a low dosage ( 20 mg/d ) of iron . Effects on iron status were assessed at the time of delivery and at 6 mo postpartum . Gastrointestinal side effects were assessed at 24 and 36 wk of gestation . DESIGN This was a r and omized , double-blind , placebo-controlled trial of a 20-mg daily iron supplement ( ferrous sulfate ) given from 20 wk of gestation until delivery . RESULTS A total of 430 women were enrolled , and 386 ( 89.7 % ) completed the follow-up to 6 mo postpartum . At delivery , fewer women from the iron-supplemented group than from the placebo group had IDA [ 6/198 , or 3 % , compared with 20/185 , or 11 % ; relative risk ( RR ) : 0.28 ; 95 % CI : 0.12 , 0.68 ; P < 0.005 ] , and fewer women from the iron-supplemented group had ID ( 65/186 , or 35 % , compared with 102/176 , or 58 % ; RR : 0.60 ; 95 % CI : 0.48 , 0.76 ; P < 0.001 ) . There was no significant difference in gastrointestinal side effects between groups . At 6 mo postpartum , fewer women from the iron-supplemented group had ID ( 31/190 , or 16 % , compared with 51/177 , or 29 % ; RR : 0.57 ; 95 % CI : 0.38 , 0.84 ; P < 0.005 ) . The rate of IDA between the groups did not differ significantly at 6 mo postpartum . CONCLUSION Supplementing the diet of women with 20 mg Fe/d from week 20 of pregnancy until delivery is an effective strategy for preventing IDA and ID without side effects [19793860] BACKGROUND There is a growing interest in periconceptional iron supplementation in developing countries by research ers and policy makers ; however , there are no r and omized controlled trials that examine the effectiveness of this strategy in decreasing anemia during pregnancy . OBJECTIVE The aim was to determine whether periconceptional iron supplementation reduces anemia during pregnancy . DESIGN A r and omized , double-blind , controlled trial was conducted in rural Bangladesh . Married , nulliparous women were r and omly assigned to receive daily iron and folic acid ( IFA ; 60 mg ferrous fumarate and 400 microg folic acid ) ( n = 134 ) or folic acid ( FA ; 400 microg ) ( n = 138 ) in the form of a powdered supplement added to food . Women were followed until pregnancy or the end of 9 mo . Primary outcomes included hemoglobin , plasma ferritin , and plasma transferrin receptor concentrations . RESULTS Among 88 pregnant women , periconceptional IFA in comparison with FA did not affect anemia or iron status at 15 wk gestation . However , each 1 % increase in adherence was associated with a 10-g/L increase in change in hemoglobin from baseline ( P = 0.03 ) , and those who initiated supplementation at a mean ( + /-SD ) time of 72.9 + /- 57.8 d before conception showed a 7.3-g/L increase in change in hemoglobin from baseline compared with those who initiated supplementation at 26.3 + /- 12.3 d after conception ( P = 0.01 ) . Among 146 nonpregnant women , IFA decreased anemia ( odds ratio : 0.19 ; 95 % CI : 0.04 , 0.95 ) and improved iron stores ( P = 0.001 ) more than did FA . CONCLUSION Good adherence and initiation of supplementation before conception are needed to reduce anemia during early pregnancy . This trial was registered at www . clinical trials.gov as NCT00953134 [6824608] Summary . Serum iron , serum iron‐binding capacity , serum ferritin and erythrocyte protoporphyrin were determined during uncomplicated pregnancy in 45 healthy women ; 22 were given oral iron while the others were given a placebo . When iron was not given , 15 out of 23 women had exhausted iron stores and iron deficiency at term , as judged from low serum ferritin , low serum transferrin saturation and high erythrocyte protoporphyrin values . Only seven of them had a haemoglobin concentration between 10 and 11 g/dl at term but none had values < 10 g/dl . In the iron‐treated group ( n=22 ) none of the women developed iron deficiency . Serum ferritin was the most sensitive and specific test of iron deficiency . A practical procedure to detect iron deficiency and to control iron supplementation in pregnancy is suggested [12780424] Background . The aims of the present study were to evaluate the recommendations by comparing compliance and adequacy of iron status at 6 weeks postpartum between one group given advice only and one group given advice plus iron supplement . In the latter group the efficacies of two iron preparations of different strengths and types were compared [6726596] The known increased need for iron during pregnancy appears to be met only in part by increased iron absorption and amenorrhea . Considerable dem and s are made on maternal iron stores and , since many women lack sufficient storage iron , pregnancy may be expected to cause iron deficiency . This may lead to anemia in pregnancy and post partum and could also have a bearing on the iron status of the fetus and the neonate . Based on these considerations , prophylactic supplementation of dietary iron is advocated but remains a disputed issue . In the present controlled , prospect i ve and longitudinal study changes in hematologic status , and in particular in iron stores , during pregnancy were investigated in 44 healthy Caucasian women with uncomplicated pregnancies and deliveries . They were r and omly assigned to a study group ( n = 21 ) receiving oral iron supplements from the 16th week of amenorrhea until 6 weeks post partum , and a control group ( n = 23 ) without iron supplementation . Maternal concentrations of hemoglobin , serum iron , serum transferrin and serum ferritin were determined at 16 , 28 and 36 weeks of amenorrhea , at delivery , and 6 and 12 weeks post partum . The same variables were determined in cord blood . Iron supplementation appeared to prevent the physiologic fall in hemoglobin and serum iron concentrations which occurred in the control group , but had little influence on the observed rise in transferrin concentrations . Ferritin levels in serum , which are known to reflect mobilisable iron stores , fell to 30 % of the initial values in the control group and to 70 % in the study group . Six and 12 weeks post partum ferritin levels were still low in the nonsupplemented group ( Tab . I ) . ( ABSTRACT TRUNCATED AT 250 WORDS [1971872] A gastric delivery system ( GDS ) for iron supplementation was evaluated . Radioisotopic studies in 9 volunteers demonstrated a three-fold higher absorption of GDS iron compared with ferrous sulphate elixir . A double-blind placebo controlled trial was done in 200 women to compare the gastrointestinal side-effects associated with 50 mg iron daily given either as GDS or conventional ferrous sulphate . The conventional preparation was associated with a significantly higher frequency of nausea and anorexia , whereas there were no significant differences in reported side-effects between subjects receiving GDS or placebo . A single GDS capsule daily provides the same amount of absorbed iron as conventional ferrous sulphate given three times daily , and does not produce gastrointestinal side-effects [10696955] Background . The aim was to define reference values for hemoglobin , hematocrit and erythrocyte indices , i.e. erythrocyte count , mean corpuscular volume ( MCV ) , mean corpuscular hemoglobin ( MCH ) , mean corpuscular hemoglobin concentration ( MCHC ) , in normal pregnancy and after a normal delivery in non‐iron‐supplemented and iron supplemented women [12641613] Spatone Iron-Plus is a naturally occurring mineral water from Trefriw Wells Spa in Conwy County , North Wales , UK . It contains approximately 0.20 mg of iron per millilitre as ferrous sulphate and has been shown to provide iron in a highly bio-available form . A 24 ml sachet contains approximately 5 mg of iron . Iron deficiency is common in the obstetric population . However , compliance with traditional iron supplements is poor because of gastrointestinal side-effects . We design ed a r and omized , double-blind , placebo-controlled trial . A total of 102 low-risk antenatal patients , who were noncompliant with routinely prescribed ferrous sulphate tablets , were r and omized to receive 48 ml of Spatone water or placebo . The study was conducted between 22 and 28 weeks gestation . Primary outcome measures were compliance , gastrointestinal side-effects and changes in ferritin levels during the trial period . Compliance in the intervention group was 57 % compared with 67 % in the control group , P = 0.22 . Dyspepsia scores , as determined by a recognized and well-vali date d question naire , did not differ between the two groups . During the trial period , mean ferritin levels fell by 24 % in the Spatone Iron-Plus group compared with a mean fall of 51 % in ferritin levels among the control group , P = 0.016 [15777891] OBJECTIVE To compare the effect of daily oral iron supplementation with two injections of high dose parenteral iron . METHOD A total of 220 pregnant women with a singleton pregnancy and hemoglobin between 8 to 11 g% at 16 - 24 weeks gestation were identified and r and omly divided into two groups . Group A was started on daily oral iron therapy of 100 mg of elemental iron . Group B was given 250 mg of iron sorbitol intramuscularly and repeated at an interval of 4 - 6 weeks . Blood indices were evaluated at the beginning of study and at 36 weeks to see the effect after iron supplementation in the two groups . The data were analyzed using SPSS software , version 10.1 . RESULTS Definitive and comparable improvement in hemoglobin and all the blood indices ( hematocrit , MCH , MCHC , MCV , Serum iron and TIBC ) was observed . The absolute change in hemoglobin and hematocrit was 1.18+/-0.68 g% and 4.02+/-2.59 % in oral group , 1.34+/-0.77 g% and 4.93+/-3.65 % in parenteral group , respectively . Serum ferritin showed statistically significant absolute rise ( 10.43+/-7.92 microg/dl ) after parenteral iron supplementation as compared to oral iron supplementation ( 9.76+/-4.78 microg/dl ) . Obstetric outcome was comparable in two groups . CONCLUSION Two treatment regimens are biologically equivalent in terms of hematological response . Two high doses of intramuscular iron can be a good substitute to meet iron requirement in pregnancy [10878651] Objective : Intervention with iron supplementation , deworming , and information , education and communication ( IEC ) to improve the haematological status among each of the three trimesters of pregnant women in a rural community . Design : A community-based study was carried out using a two-group pre – post experimental design in a rural community . Setting : Two rural blocks in Vellore district were selected for the study . KV Kuppam block with a population of 120 , 000 and the adjacent Gudiyatham block with a population of 132 , 000 served as study and control areas for the study .Subjects : Using a multistage sampling , initially 50 % of the panchayats , the local village administrative units , were r and omly selected and all pregnant women were the subjects . In the pre-intervention survey 458 and 387 pregnant women had haemoglobin tested and the post-intervention survey covered 403 and 425 pregnant women in the study and control areas , respectively . Similarly serum ferritin was tested in a r and omly selected sub- sample with 254 and 191 pregnant women before intervention and in 216 and 223 pregnant women after intervention in both study and control areas , respectively . Intervention : Iron supplementation and deworming were provided to all pregnant women in the study area from the fourth month of their pregnancy . An intensive information , education and communication was carried out with facts on anaemia and diet modification to each pregnant woman , using a one-to-one approach in the community , and a group method in the mobile clinics . This was carried out for a period of 18 months . Results : A significant decrease in the prevalence of anaemia was found , from 56.1 % to 25.07 % ( P<0.001 ) , 73.4 % to 49.2 % ( P<0.001 ) and 68.8 % to 56.8 % ( P<0.01 ) among women in the first , second and third trimesters , respectively , in the intervention area . Significant ( P<0.001 ) increases in the mean haemoglobin of 0.85 g/dl ( 95 % CI 10.18–10.84 , 11.09–11.63 ) , 0.59 g/dl ( 95 % CI 9.98–10.34 , 10.55–10.95 ) and 0.36 g/dl ( 95 % CI 9.93–10.33 , 10.25–10.73 ) were also observed in each of the groups . Conclusion : A comprehensive community-based intervention with iron supplementation , helminthic treatment and increase in knowledge using IEC through effective strategies can improve the haematological status of pregnant women in each trimester . Sponsorship : Mother Care Project , John Snow Inc. , Funded by the United States Agency for International Development (USAID).European Journal of Clinical Nutrition ( 2000 ) 54 , [15766997] BACKGROUND Neonatal mortality is the biggest contributor to global mortality of children younger than 5 years , and low birthweight is a crucial underlying factor . We tested the hypotheses that antenatal multiple micronutrient supplementation would increase infant birthweight and gestational duration . METHODS We did a double-blind , r and omised controlled trial in Dhanusha district , Nepal . Women attending for antenatal care with singleton pregnancies at up to 20 weeks ' gestation were invited to participate . Participants were r and omly allocated either routine iron and folic acid supplements ( control ; n=600 ) or a multiple micronutrient supplement providing a recommended daily allowance of 15 vitamins and minerals ( intervention ; n=600 ) . Supplementation began at a minimum of 12 weeks ' gestation and continued until delivery . Primary outcome measures were birthweight and gestational duration . Analysis was by intention to treat . The study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N88625934 . FINDINGS Birthweight was available for 523/600 infants in the control group and 529/600 in the intervention group . Mean birthweight was 2733 g ( SD 422 ) in the control group and 2810 g ( 453 ) in the intervention group , representing a mean difference of 77 g ( 95 % CI 24 - 130 ; p=0.004 ) and a relative fall in the proportion of low birthweight by 25 % . No difference was recorded in the duration of gestation ( 0.2 weeks [ -0.1 to 0.4 ] ; p=0.12 ) , infant length ( 0.3 cm [ -0.1 to 0.6 ] ; p=0.16 ) , or head circumference ( 0.2 cm [ -0.1 to 0.4 ] ; p=0.18 ) . INTERPRETATION In a poor community in Nepal , consumption of a daily supplement containing a recommended daily allowance of 15 micronutrients in the second and third trimesters of pregnancy was associated with increased birthweight when compared with a st and ard iron and folic acid preparation . The effects on perinatal morbidity and mortality need further comparisons between studies . Published online March 3 , 2005 http://image.thelancet.com/extras/04art11045web.pdf [9351406] Background . The purpose of the present study was to evaluate the efficacy of low dose iron supplementation with and without a heme component , prescribed for women in the second half of pregnancy [17539886] Pregnancy during adolescence is associated with adverse birth outcomes , including preterm delivery and low birthweight . The nutrient availability to the fetus may be limited if the mother is still growing . This research aims to study the effects of pregnancy during adolescence in a nutritionally poor environment in rural Nepal . This study utilized data from a r and omized controlled trial of micronutrient supplementation during pregnancy in south-eastern Nepal . Women of parity 0 or 1 and of age < or= 25 years who gave birth to a singleton liveborn infant who was measured within 72 h of delivery were included ( n = 1393 ) . There was no difference in the risk of low birthweight ( OR = 0.96 ; 95 % CI = 0.90 - 1.02 ) or small for gestational age ( OR = 1.01 ; 95 % CI = 0.94 - 1.08 ) per year of increasing maternal age among primiparae . Young maternal age did not affect the anthropometry or gestational age of the offspring of parity 1 women . Each year of increasing maternal age among primiparae was associated with increases in birth length ( 0.07 cm ; 95 % CI = -0.01 to 0.16 ) , head ( 0.05 cm ; 95 % CI = 0.01 - 0.09 ) and chest circumference ( 0.07 cm ; 95 % CI = 0.01 - 0.12 ) , but not weight ( 9.0 g ; 95 % CI = -2.1 to 21.8 ) of their offspring . Young maternal age was associated with an increased risk of preterm delivery among primiparae ( OR = 2.07 ; 95 % CI = 1.26 - 3.38 ) that occurred at an age cut-off of < or=18 years relative to those 19 - 25 years . Thus , we conclude that young maternal age ( < or=18 years ) increased the risk of preterm delivery , but not intrauterine growth retardation , for the first but not second liveborn infant [19368922] OBJECTIVE To examine the effect of supplemental prenatal folic acid , folic acid-iron , folic acid-iron-zinc , and multiple micronutrients on maternal morbidity in rural Nepal . METHODS A cluster-r and omized double-masked controlled trial of pregnant women who received daily supplements from early pregnancy through 3 months post partum as per the treatment allocation . Women were interviewed at birth about labor and delivery complications and for 9 days post partum to obtain 24-hour histories of morbidity . RESULTS A total of 3986 ( 97.3 % ) women completed an interview regarding labor and delivery ; morbidity history was available for 3564 ( 87.0 % ) women . Folic acid-iron reduced the risk of postpartum hemorrhage ( relative risk [ RR ] 0.59 ; 95 % confidence interval [ CI ] 0.35 - 0.98 ) . Risk of dysfunctional labor increased with multiple micronutrient supplementation ( RR 1.28 ; 95 % CI , 1.01 - 1.60 ) , although preterm premature rupture of membrane decreased ( RR 0.40 ; 95 % CI , 0.21 - 0.79 ) . Puerperal sepsis was lower in those receiving folic acid-iron , folic acid-iron-zinc , and multiple micronutrients compared with controls ( P<0.05 ) . CONCLUSION Prenatal folic acid-iron supplementation reduced the risk of obstetric complications in this South Asian setting [17967217] Although routine Fe supplementation in pregnancy is a common practice , its clinical benefits or risks are uncertain . Children born to mothers in the Fe group in a trial of Fe supplementation in pregnancy have been found to have a significantly higher risk of abnormal behaviour at 4 years of age than those born to mothers in the placebo group . The objective of the present study therefore was to determine whether Fe supplementation in pregnancy influences child behaviour at early school age . The study was a follow-up of children at 6 - 8 years of age after women ( n 430 ) were r and omly allocated to receive a daily Fe supplement ( 20 mg ) or placebo from 20 weeks gestation until delivery . The supplement reduced the incidence of Fe-deficiency anaemia at delivery from 9 % to 1 % . Child behaviour and temperament were assessed using the Strengths and Difficulties Question naire and the Short Temperament Scale for Children . Of the children , 264 ( 61 % ) participated in the follow-up . Mean behaviour and temperament scores and the proportion of parent-rated and teacher-rated abnormal total difficulties scores did not differ between the Fe and placebo groups . However , the incidence of children with an abnormal teacher-rated peer problems subscale score was higher in the Fe group ( eleven of 112 subjects ; 8 % ) than in the placebo group ( three of 113 subjects ; 2 % ) ; the relative risk was 3.70 ( 95 % CI 1.06 , 12.91 ; P = 0.026 ) . We conclude that prenatal Fe supplementation had no consistent effect on child behaviour at early school age in this study population . Further investigation regarding the long-term effects of this common practice is warranted [19778983] The long-term benefits of antenatal iron supplementation in child survival are not known . In 1999 - 2001 , 4,926 pregnant women in rural Nepal participated in a cluster-r and omized , double-masked , controlled trial involving 4 alternative combinations of micronutrient supplements , each containing vitamin A. The authors examined the impact on birth weight and early infant mortality in comparison with controls , who received vitamin A only . They followed the surviving offspring of these women at approximately age 7 years to study effects of in utero supplementation on survival . Of 4,130 livebirths , 209 infants died in the first 3 months and 8 were lost to follow-up . Of those remaining , 3,761 were followed , 150 died between ages 3 months and 7 years , and 152 were lost to follow-up . Mortality rates per 1,000 child-years from birth to age 7 years differed by maternal supplementation group , as follows : folic acid , 13.4 ; folic acid-iron , 10.3 ; folic acid-iron-zinc , 12.0 ; multiple micronutrients ; 14.0 ; and controls , 15.2 . Hazard ratios were 0.90 ( 95 % confidence interval ( CI ) : 0.65 , 1.22 ) , 0.69 ( 95 % CI : 0.49 , 0.99 ) , 0.80 ( 95 % CI : 0.58 , 1.11 ) , and 0.93 ( 95 % CI : 0.66 , 1.31 ) , respectively , in the 4 supplementation groups . Maternal iron-folic acid supplementation reduced mortality among these children by 31 % between birth and age 7 years . These results provide additional motivation for strengthening antenatal iron-folic acid programs [19527380] OBJECTIVES To compare the effect of daily versus weekly iron supplementation on lipid peroxidation , hemoglobin levels and maternal and perinatal outcome in non-anemic pregnant women . METHODS Of 109 women r and omly allocated into three groups , 90 completed the study . Group I ( n = 30 ) received daily iron folic acid ; Group II ( n = 30 ) received weekly iron folic acid ; Group III ( n = 30 ) received daily iron (III)-hydroxide polymaltose complex . Hemoglobin levels , hematological indices , thiobarbituric acid reactive substances ( TBARS ) and glutathione levels were measured at baseline ( 14 - 16 weeks ) and at 30 - 34 weeks . Statistical analysis was done using the anova test . RESULTS Group I had a highly significant increase in TBARS level ( 0.61 + /- 0.26 micromol/L , P = 0.000 ) compared to groups II and III in which the change in TBARS was not significant ( 0.02 + /- 0.06 and 0.007 + /- 0.06 micromol/L , respectively ) . There was an insignificant fall in glutathione levels in all groups . There was no significant difference in the mean period of gestation , pregnancy complications and neonatal outcome between the three groups . Among 22.2 % of women who were non-compliant , Group I had significantly higher incidence of non-compliance ( P = 0.016 ) and side-effects ( P = 0.001 ) . Final hemoglobin was higher in Group I than II ( 11.9 + /- 1.2 , 11.3 + /- 0.9 , respectively , P = 0.041 ) . The TBARS level was not statistically different between preterm and term deliveries . Nine out of 11 patients who developed hypertension during pregnancy had preeclampsia . The final TBARS level was significantly higher in these women ( P = 0.000 ) . CONCLUSIONS Daily supplementation with ferrous sulphate results in greater lipid peroxidation than weekly supplementation , the latter is comparable with daily iron (III)-hydroxide polymaltose complex . Lipid peroxidation levels are significantly higher in preeclampsia [8846152] Blood manganese levels and iron status indices were determined each trimester in 66 healthy pregnant women . Twenty-five were r and omly assigned to iron supplementation , 19 to placebo and 22 received dietary advise aim ed at increasing their dietary intake of fibre . Iron supplemented women had significantly higher levels of blood haemoglobin compared to the levels of the two other groups , and higher serum ferritin levels compared to the placebo group . No significant difference in blood manganese levels was observed among the three groups of women . There was a significant increase in blood manganese levels from one trimester to the next , which was slightly more pronounced in non supplemented women . The median values in the three trimesters were 154 ( range 79 - 360 ) nmol/L , 190 ( range 98 - 408 ) nmol/L , and 230 ( range 133 - 481 ) nmol/L , respectively . Pregnancy seems to change manganese status or otherwise influence manganese metabolism irrespective of iron status and iron supplementation [2583756] This study was conducted to determine the optimum dose of supplemental iron for prophylaxis against pregnancy anemia . One hundred and ten pregnant women were r and omly allocated to three groups : Group A receiving equivalent of 60 mg , group B 120 mg and Group C 240 mg , elemental iron as ferrous sulphate daily ; the content of folic acid was constant in all the three groups ( 0·5 mg ) . These women had at least consumed 90 tablets in 100±10 days . Blood was drawn at the beginning and at the end of the treatment . Fifty percent were anemic ( < 11g/100 ml ) . The hemoglobin levels rose similarly in all groups and the differences were statistically not significant . Fifty-six percent had depleted iron stores ( serum ferritin value < 12 μg/1 ) at the beginning of the study . Following therapy a statistically significant increase in iron stores was observed in group B and C as compared to group A. The difference between group B and C was not significant . The side effects increased with increasing doses of iron ; 32·4 % , 40·3 % and 72 % in group A , B and C respectively . Based on these findings , the authors advocate that optimum dose of iron should be 120 mg instead of 60 mg as is currently being used in the National Nutritional Anemia Prophylaxis Programme . * * * DIRECT SUPPORT * * * A08BC044 [1858501] 192 pregnant women were consecutively r and omized to either a vitamin‐mineral pill or a vitamin mineral pill with a high iron content in a prospect i ve , open , r and omized investigation . The participants were advised about iron‐rich foodstuffs twice during pregnancy . Iron status of the mother proved to be without any significance for the outcome of pregnancy . A serum ferritin level of 80 pmol/l in mid‐pregnancy followed by a control in the last trimester was suggested as a guide in deciding of whether or not to prescribe supplementary iron during pregnancy [15566454] AIM To compare the hematological parameters and pregnancy outcome in women receiving daily versus weekly iron supplements during pregnancy . METHODS A prospect i ve r and omized controlled study was carried out at the Department of Obstetrics and Gynaecology of the All India Institute of Medical Sciences , New Delhi , India , during which 111 women were r and omized to receive either 100 mg elemental iron daily ( n=55 ) or 200 mg elemental iron weekly ( n=56 ) . Hemogram and serum ferritin level estimation were carried out at the beginning of pregnancy and within the 32 - 34-week period of gestation . Side-effects , compliance and the number of tablets consumed were noted for each group . The mean birth weight , period of gestation at delivery and mode of delivery were also compared between the two intervention groups . RESULTS There was no significant difference in the mean hemoglobin levels between the two intervention groups at the end of an average 17 weeks of iron supplementation . However , among anemic women who received daily supplementation , there was a greater rise in hemoglobin compared with those receiving supplementation weekly . The serum ferritin level was lower in the weekly supplemented group compared with that in the daily . There was no difference in the mean birth weight , period of gestation and mode of delivery between the two groups . Side-effects and non-compliance were significantly higher ( P<0.001 ) in the daily supplemented group . CONCLUSIONS Weekly iron supplementation is an effective option for prophylaxis in non-anemic pregnant women , but has less than optimal benefit in anemic women [16015266] Objectives : To assess the effects of daily prenatal multimicronutrient supplementation on birth weight ( BW ) and perinatal mortality . Design : R and omised , controlled , double masked trial . Setting : Urban Guinea-Bissau , West Africa . Subjects : A total of 2100 pregnant women ( 22±7 weeks pregnant at entry ) were recruited through antenatal clinics , of which 1670 ( 79.5 % ) completed the trial . BW was available for 1100 live born babies . Interventions : Identical-looking supplements containing one ( MN-1 ) or two ( MN-2 ) Recommended Dietary Allowances ( RDA ) of 15 micronutrients , or iron and folic acid ( control ) . Results : Mean BW among 1100 live born infants was 3050±498 g with 11.9 % being low birth weight ( LBW , BW<2500 g ) . Perinatal mortality was 82 per 1000 deliveries ( N=1670 ) , and neonatal mortality 45 per 1000 live births ( N=1599 ) . Mean BW in MN-1 ( n=360 ) and MN-2 ( n=374 ) groups were 53 [ −19 ; 125 ] and 95 [ 24 ; 166 ] g higher than controls ( n=366 ) . Proportion of LBW was 13.6 % in control , and 12.0 and 10.1 % in the MN-1 and MN-2 groups , respectively ( P=0.33 ) . Among anaemic women ( 30 % ) , MN-2 increased BW with 218 [ 81 ; 354 ] g compared to controls , with a decreased risk of LBW of 69 [ 27 ; 87]% . There were apparently no differences in perinatal mortality between groups . Conclusions : Prenatal micronutrient supplementation increased BW but did not reduce perinatal mortality in this study . Multimicronutrient supplementation with two RDA should be considered in future programmes to reduce the proportion of LBW [16424650] Background : It is a common belief among women that iron compounds have unpleasant gastrointestinal side effects . Objective : To assess the gastrointestinal side effects of iron prophylaxis in pregnancy . Methods : A r and omized , double-blind study comprising 404 healthy pregnant women allocated to four groups taking ferrous iron supplement ( as fumarate ) in doses of 20 ( n = 99 ) , 40 ( n = 100 ) , 60 ( n = 102 ) and 80 mg ( n = 103 ) daily from 18 weeks of gestation to delivery . Iron supplement was predominantly taken at bedtime . Gastrointestinal symptoms ( nausea , vomiting , epigastric pain , eructation , pyrosis , meteorism , borborygmi , colic pain , flatulence , constipation , thin feces , diarrhea ) , black feces , and use of laxatives were recorded by interview at 18 , 32 and 39 weeks of gestation . Results : The frequencies of gastrointestinal symptoms were not significantly different in the four iron supplement groups either at inclusion or at 32 and 39 weeks of gestation and thus not related to the iron dose . Conclusion : This study shows that a supplement of 20–80 mg ferrous iron ( as fumarate ) , taken between meals , has no clinical ly significant gastrointestinal side effects . The implementation of iron prophylaxis to pregnant women should not be compromised by undue concern of non-existing side effects [8141223] OBJECTIVE Our purpose was to study the effect of hematinic supplementation on the maternal erythropoietin response during singleton pregnancy . STUDY DESIGN In a r and omized , double-blind trial 97 patients with a first-trimester hemoglobin level > or = 14.0 gm/dl received either iron and folic acid ( hematinic group , n = 53 ) or a placebo ( n = 44 ) . Serial hemoglobin , hematocrit , and serum erythropoietin were recorded from maternal blood and from cord blood on delivery . Serum ferritin was measured in the first trimester , at 36 weeks ' gestation , and in cord blood . RESULTS In both groups ( 1 ) the mean hemoglobin was lower ( p < 0.01 ) at 40 weeks ' gestation than when first examined and ( 2 ) the mean serum erythropoietin was higher ( p < 0.01 ) . The mean serum ferritin was lower ( p < 0.001 ) in both groups at 36 weeks ' gestation than at presentation but higher ( p = 0.04 ) in the hematinic group than in the placebo group . The mean hemoglobin and hematocrit were similar in the two groups until the third trimester but thereafter were higher ( p < 0.05 ) in the hematinic group . The mean maternal serum erythropoietin was higher ( p < 0.05 ) in the placebo group than in the hematinic group after 24 weeks ' gestation . The mean cord blood hematologic values were similar in the two groups . CONCLUSION Maternal serum erythropoietin increased during pregnancy , but this response was reduced in the third trimester in the hematinic-supplemented group [19406557] OBJECTIVE To assess and compare the efficacy and safety of two and three doses of intravenous iron sucrose with daily oral ferrous sulphate in the prophylaxis of iron deficiency anaemia in pregnant women . STUDY DESIGN 260 women with singleton pregnancy who met inclusion criteria and who gave informed consent were r and omised between the 21st and 24th week into either the intravenous iron group or the oral iron group . Of 130 women in the intravenous iron group , 75 women received two doses of 200 mg iron sucrose and 55 three doses of 200 mg iron sucrose . The first dose was administered between the 21st and 24th gestational weeks , the second between the 28th and 32nd and the third between the 35th and 37th . The women of the oral group were given oral tablets of 80 mg ferrous sulphate daily , beginning on the day of study enrolment and stopping on the day of delivery . RESULTS There was a non-significant trend to a higher frequency of responders ( haemoglobin > or = 11 g/dl ) in the intravenous iron group ( 75 vs. 80 % ) . There was a significant difference of repleted iron stores before delivery ( ferritin>50 microg/l ) in the group with three intravenous iron doses in comparison to the oral iron group ( 49 vs. 14 % ; p<0.001 ) . No differences were observed in regard to maternal and perinatal outcomes . CONCLUSIONS There was no clinical ly significant difference in the haematological , maternal and foetal outcomes in the parenteral route of iron prophylaxis in pregnant women [19454124] OBJECTIVE We examined factors affecting compliance to antenatal micronutrient supplementation and women 's perceptions of supplement use . DESIGN R and omized controlled supplementation trial of four alternative combinations of micronutrients given during pregnancy through to 3 months postpartum . Women were visited twice weekly to monitor compliance and to replenish tablets by female study workers . At 6 weeks postpartum women with live births ( n 4096 ) were interviewed regarding their perceptions of the supplement . Median compliance calculated as percentage of total eligible doses received by women was high ( 84 % ) . SETTING Rural southern Nepal . SUBJECTS Pregnant women . RESULTS Women with high compliance ( above the median of 84 % ) were likely to be older , less educated , poorer , undernourished , belong to lower caste and of Pahadi ( hill ) ethnicity compared with women with low compliance ( at or below the median of 84 % ) . Smoking and drinking alcohol in the past week during pregnancy were strongly associated with low compliance . The major reason for irregular intake was forgetting to take supplements . A higher proportion of the high compliers liked taking the supplements but only half of them were willing to purchase them in the future . A large proportion of women ( 91 % ) perceived a benefit from taking the supplement such as improved strength and health , whereas only about 10 % perceived any side-effects which were not a major barrier to compliance . CONCLUSIONS The present analysis highlights that poor , undernourished , uneducated women can have high compliance to antenatal supplementation if they are supplied with the tablets and reminded to take them regularly , and counselled about side-effects [3511017] Recent studies suggest that infant behavior and psychological test performance are impaired by iron deficiency and may be improved by iron . Comparable studies have not been performed in older population s. Young women early in pregnancy whose nutritional intake may be impaired by poverty constitute a high-risk population . Women aged 14 - 24 years coming for prenatal care at or before 16 weeks gestation whose hematocrits were greater than or equal to 31 % were r and omized in a double-blind trial to receive vitamins supplemented with iron ( experimental group ) or vitamins alone ( controls ) . Hematologic status and tests of short-term memory and attention span were assessed at entry and conclusion of the one-month treatment period . The experimental group showed significant improvement on the most sensitive measure of short-term memory and three subtests . On comparison of the change between initial and final scores , the experimental group showed significant or borderline greater improvement than controls on three tests . These results indicated a beneficial effect of iron therapy on psychometric test-score performance [1062910] Abstract . Iron absorption , bone‐marrow smears and haematological parameters were repeatedly studied during pregnancy in 50 women . The same studies were repeated two months after delivery . The material was r and omly divided into two groups . Twenty‐four women were treated with 200 mg of ferrous iron daily while 26 were given placebo . The iron absorption was measured from radioiron‐labelled test doses of 100 mg ferrous iron in a whole‐body counter with high sensitivity [19474130] BACKGROUND We previously reported that a r and omized controlled trial of antenatal micronutrient supplements in rural Nepal decreased the risk of low birth weight by approximately 15 % . OBJECTIVE The objective was to examine the effects of micronutrient supplementation on growth and body composition in children of supplemented mothers through school age . DESIGN Mothers received 1 of 5 micronutrient supplements daily : folic acid , folic acid + iron , folic acid + iron + zinc , multiple micronutrients , or a control . All of the supplements contained vitamin A. Children born during this trial were revisited at age 6 - 8 y to measure height , weight , midupper arm circumference , waist circumference , and triceps and subscapular skinfold thicknesses . Arm fat and muscle area were estimated by using st and ard formulas , and height-for-age , weight-for-age , and body mass index-for-age z scores were calculated by using the World Health Organization growth st and ard . RESULTS Of the 3771 surviving children , 3324 were revisited and consented to anthropometric measurements . Maternal supplementation with folic acid + iron + zinc result ed in an increase in mean height ( 0.64 cm ; 95 % CI : 0.04 , 1.25 ) and a reduction in mean triceps skinfold thickness ( -0.25 mm ; 95 % CI : -0.44 , -0.06 ) , subscapular skinfold thickness ( -0.20 mm ; 95 % CI : -0.33 , -0.06 ) , and arm fat area ( -0.18 cm(2 ) ; -0.34 , -0.01 ) . No significant differences were found between groups in mean weight or body mass index-for-age z scores , waist circumference , or arm muscle area . Other micronutrient combinations including a multiple micronutrient formulation failed to show a growth benefit . CONCLUSION Antenatal supplementation with zinc may benefit child growth , particularly in areas where a deficiency of this nutrient is common [10422631] Abstract Assessment of the efficacy of iron therapy has usually been done in population s/ patients by monitoring changes in hemoglobin concentration , serum iron , percent transferrin saturation , and serum ferritin . In this study the protoporphyrin heme ( P/H ) ratio ( a measure of free erythrocyte protoporphyrin ) was measured before and after iron therapy in three groups of pregnant women , who received 60 mg ( group A ) , 120 mg ( group B ) , and 240 mg ( group C ) of elemental iron with folic acid ( 0.5 mg ) per day for a period of 12 weeks , to evaluate its efficacy to monitor iron therapy . The three groups were comparable regarding the initial mean Hb concentration and serum ferritin levels . The initial mean P/H ratios were markedly elevated in all three groups and were different in the three groups , being highest in group A ( 113.2±92.6 ) , intermediate in group B ( 87.5±62.5 ) , and lowest in group C ( 69.8±43.3 ) . The initial P/H ratio was significantly higher in group A than in group C ( p<0.05 ) . This probably affected the efficacy of iron therapy in the three groups . The P/H ratio decreased significantly in each of the three groups after iron therapy ( A and B : p<0.001 ; C p<0.01 ) . Mean Hb concentration and serum ferritin increased in all three groups post therapy ; however , the magnitude of change in P/H ratio in all three groups was much greater . This indicated that the predominant contributory factor for anemia was iron deficiency in this group of pregnant women . Serum iron and percent transferrin saturation are difficult to interpret in our population , as iron is freely available over the counter and is prescribed as soon as anemia is detected in patients ; therefore , the reduction in P/H ratio may be used to monitor response to iron therapy in population groups [8122498] In a r and omized , double‐blind , placebo controlled study of the effect of iron supplementation during pregnancy , iron status ( hemoglobin ( Hb ) , serum (S‐)transferrin saturation , S‐ferritin ) and S‐erythropoietin ( EPO ) were assessed in 120 healthy pregnant women at 14–16 weeks of gestation , and just before delivery ; 63 women were treated with 66 mg iron daily , and 57 with placebo . There were no differences in baseline values in the two groups . At term , the iron treated group had significantly higher Hb , transferrin saturation , S‐ferritin ( median 22 μg/1 vs. 14 μg/1 , ( p<0.0001 ) and lower S‐EPO compared to the placebo treated group . In the iron group , 30.2 % had exhausted iron stores ( i.e. S‐ferritin < 20 μg/1 ) , 6.3 % latent iron deficiency ( S‐ferritin < 20 μg/1 and transferrin saturation < 15 % ) , and no patients had iron deficiency anemia ( S‐ferritin < 20 μg/1 and transferrin saturation < 15 % and Hb < 110 g/1 ) . In the placebo group , 93.0 % had exhausted iron stores , 54.4 % latent iron deficiency , and 17.5 % iron deficiency anemia ; S‐EPO was inversely correlated to iron status markers : Hb , rs = −0.51,p<0.001 ; transferrin saturation , rs= −0.65,p<0.0001 ; S‐ferritin , rs= − 0.31 , R<0.01 , suggesting that the elevation in S‐EPO was secondary to iron deficient erythropoiesis . Newborns to iron treated mothers had higher cord S‐ferritin , median 155 μg/1 , than newborns to placebo treated mothers , median 118 ug/1 ( p<0.02 ) ; there were no differences in birth weight , transferrin saturation , or S‐EPO . Supplemental iron in a dose of 65 mg/day from the second trimester is sufficient to prevent iron deficiency in pregnant Danish women [16458655] OBJECTIVE The hypothesis that daily use of a prenatal supplement with iron from enrollment to third trimester to initially iron-replete , nonanemic pregnant women would reduce third-trimester anemia and improve birth outcomes was tested . STUDY DESIGN Eight hundred sixty-seven women in Raleigh , North Carolina , who were at < 20 weeks of gestation were enrolled ; 429 of these women had hemoglobin levels of > or = 110 g/L and ferritin levels of > or = 40 microg/L and were assigned r and omly to receive prenatal supplements with 30 mg of iron as ferrous sulfate ( n = 218 women ) or 0 mg of iron ( n = 211 women ) until 26 to 29 weeks of gestation . Intent-to-treat analysis was used for the outcomes of third-trimester iron status , birth weight , preterm birth , and small-for-gestational age . RESULTS Mean birth weight was higher by 108 g ( P = .03 ) , and the incidence of preterm delivery was lower ( 8 % vs 14 % ; P = .05 ) in the 30-mg group compared with the control group , respectively . Iron supplementation did not affect the prevalence of small-for-gestational age infants or third-trimester iron status . CONCLUSION Prophylactic iron supplementation that is begun early in pregnancy among low income women in the United States may have benefits beyond the reduction of iron deficiency anemia during pregnancy [19527383] AIM To determine the effect of an education program and /or pill count on the change in hemoglobin levels and the prevalence of anemia in pregnant women . METHODS A r and omized , factorial design controlled trial was conducted at the Tribhuvan University Teaching Hospital , Nepal . A total of 320 eligible pregnant women receiving prenatal care were r and omized into four groups ( control , education , pill count and education with pill count ) by block r and omization with allocation concealment . All recruited women received conventional routine prenatal care with a daily dose of 60 mg iron supplementation . In addition , the education group received an education program . Pill counting was done for the pill count group at their routine prenatal visits . The education with pill count group received both the education program plus pill counting . Baseline hemoglobin at the recruitment phase and follow-up hemoglobin after three months of recruitment were measured . Changes in hemoglobin levels and anemia prevalence were analyzed and compared between groups . RESULTS The education only and education with pill count groups had significantly higher hemoglobin changes ( 0.23 and 0.26 g/dL , respectively ) than the control group ( P < 0.01 ) . Anemia was reduced by 59 % in the education group and by 65 % in the education with pill count group , compared to the control group ( P < 0.05 ) . Pill count alone significantly improved neither the hemoglobin level nor anemia prevalence compared to the control group . CONCLUSION An education program along with routine iron supplementation can improve hemoglobin levels and reduce anemia prevalence in pregnant women . Pill count as a measure of compliance has no additional effect on improving hemoglobin status [2010577] This trial compares routine and selective iron supplementation during pregnancy to determine whether routine supplementation adversely affects fetal growth , increases infections and subjective adverse effects , and /or delays birth . At their first prenatal visit , 2912 pregnant women were r and omized into two groups ( 2694 gave birth ) . Compliance was satisfactory as measured by self-reports by mothers and hematocrit values in the third trimester . More women in the routinely supplemented group had subjected adverse effects . The groups were similar in regard to most of the other outcomes . In the selectively supplemented group , there was weak evidence for increase in sick-days , referrals to hospital outpatient clinic , cesarean section , blood transfusions , and infants who were diagnosed as having hyperviscosity . In the routine group , there were somewhat more women with gestations greater than or equal to 41 weeks and more dead infants . The subgroup analyses suggest that some of the apparently worse outcomes in the selective group were due to reactions of midwives and physicians to low hematocrit values [19336358] OBJECTIVE . We investigated the benefits of maternal multimicronutrient supplementation during gestation on the mental and psychomotor development of infants . METHODS . In a double-blind , r and omized , controlled trial , pregnant women ( N = 5828 ) in 2 rural counties in western China were assigned r and omly to receive multimicronutrient ( 5 minerals and 10 vitamins at levels approximating the recommended daily allowance ) , folic acid plus iron , or folic acid supplementation daily from ∼14 weeks of gestation until delivery . We assessed a subset of the newborns ( N = 1305 ) from the 3 supplementation groups by measuring their mental and psychomotor development with the Bayley Scales of Infant Development , at 3 , 6 , and 12 months of age . Multilevel analyses were used to compare the mental development and psychomotor development raw scores at 3 , 6 , and 12 months . RESULTS . Multimicronutrient supplementation was associated with mean increases in mental development raw scores for infants at 1 year of age of 1.00 and 1.22 points , compared with folic acid only and folic acid plus iron supplementation , respectively . However , supplementation did not increase significantly the psychomotor development raw scores up to 1 year of age . CONCLUSION . Compared with iron and folic acid supplementation , the administration of multimicronutrients to pregnant women improved the mental development of their children at 1 year of age [17928802] Background / Objectives : To compare the efficacy and side effects of low-dose vs high-dose iron supplements to correct anaemia in pregnancy . Subjects/ Methods : One hundred and eighty women with anaemia ( haemoglobin < 110 g l−1 ) in mid-pregnancy . The women were r and omly allocated to 20 ; 40 or 80 mg of iron daily for 8 weeks from mid-pregnancy . Results : One hundred and seventy-nine ( 99 % ) women completed the trial . At the end of treatment , there was a clear dose – response of increasing mean haemoglobin concentration with iron dose ( 111±13 g l−1 at 20 mg per day , 114±11 g l−1 at 40 mg per day and 119±12 g l−1 at 80 mg per day , P=0.006 ) . However , the incidence of anaemia did not differ statistically between groups . Compared with women in the 80 mg iron group , the odds ratio of anaemia was 1.9 ( 95 % CI : 0.8 , 4.3 , P=0.130 ) and 1.1 ( 95 % CI : 0.5 , 2.6 , P=0.827 ) , respectively , for women in the 20 mg iron group and the 40 mg iron group . The incidence of gastrointestinal side effects was significantly lower for women in the 20 mg iron group compared with women in the 80 mg iron group ; the odds ratio was 0.4 ( 95 % CI : 0.2 , 0.8 , P=0.014 ) for nausea , 0.3 ( 95 % CI : 0.2 , 0.7 , P=0.005 ) for stomach pain and 0.4 ( 95 % CI : 0.2 , 0.9 , P=0.023 ) for vomiting . Conclusions : Low-dose iron supplements may be effective at treating anaemia in pregnancy with less gastrointestinal side effects compared with high-dose supplements [7992349] A r and omized , double-blind , placebo-controlled community-based trial of oral iron supplementation ( 200 mg ferrous sulphate daily ) administered to multigravid pregnant women by traditional birth attendants ( TBAs ) was carried out in a rural area of The Gambia . Iron supplementation led to a significant reduction in the prevalence of anaemia and of iron deficiency . Iron supplementation was not accompanied by increased susceptibility to malaria infection ; there was no difference in the prevalence and severity of peripheral blood or placental malaria infection between the 2 groups of women . The birth weight of children born to women who received iron prophylaxis was increased by an average of 56 g. It is concluded that oral iron prophylaxis can be successfully delivered through TBAs integrated into a primary health care programme . This simple intervention can produce significant beneficial effects on the health of the mother without inducing increased susceptibility to malaria and has the potential for reducing perinatal mortality by increasing birth weight [7901636] Nutritional anaemia , thought to be caused by iron deficiency , affects 50 - 70 % of pregnant women in the developing world . The influence of vitamin A and iron supplementation was studied in anaemic pregnant women in West Java , in a r and omised , double-masked , placebo-controlled field trial . 251 women aged 17 - 35 years , parity 0 - 4 , gestation 16 - 24 weeks , and haemoglobin between 80 and 109 g/L were r and omly allocated to four groups : vitamin A ( 2.4 mg retinol ) and placebo iron tablets ; iron ( 60 mg elemental iron ) and placebo vitamin A ; vitamin A and iron ; or both placebos , all daily for 8 weeks . Maximum haemoglobin was achieved with both vitamin A and iron supplementation ( 12.78 g/L , 95 % Cl 10.86 to 14.70 ) , with one-third of the response attributable to vitamin A ( 3.68 g/L , 2.03 to 5.33 ) and two-thirds to iron ( 7.71 g/L , 5.97 to 9.45 ) . After supplementation , the proportion of women who became non-anaemic was 35 % in the vitamin-A-supplemented group , 68 % in the iron-supplemented group , 97 % in the group supplemented with both , and 16 % in the placebo group . Improvement in vitamin A status may contribute to the control of anaemic pregnant women [17764606] BACKGROUND Community iron supplementation programmes for pregnant women have lacked effectiveness , partly because of low compliance . OBJECTIVE To determine factors that influence compliance among pregnant women in Senegal . DESIGN Two hundred and twenty-one pregnant women , recruited from six health centres in Dakar during their first prenatal visit , were r and omly assigned to receive either a prescription to purchase iron/folic acid tablets ( control , n = 112 ) to be taken daily , according to official policy , or to receive free tablets ( treatment , n = 109 ) . Compliance was assessed 20 weeks after enrollment through interviews and pill count . Women with low or high compliance ( < 70 % or > or=70 % ) were asked to explain what influenced their adherence to supplementation . RESULTS Overall compliance was 69 % ; it was significantly higher in the treatment than in the control group ( 86 % vs. 48 % ; P < 0.0001 ) . Women with high compliance ( 58 % ) were motivated by : ( 1 ) the perception of improved health upon taking the tablets ( treatment = 24 % , control = 10 % ) ; ( 2 ) the insistence by midwives that they take the tablets ; and ( 3 ) the mention that the tablets would improve health . Women with low compliance ( 42 % ) reported : ( 1 ) the experience of side-effects that they associated with the tablets ( treatment = 13 % , control = 14 % ) ; ( 2 ) misunderst and ing that they needed to continue taking the tablets throughout pregnancy ( treatment = 0 % , control = 18 % ) ; and ( 3 ) forgetfulness . CONCLUSION Compliance with iron/folic acid supplementation in Senegal can be increased by providing women with clear instructions about tablet intake and educating them on the health benefits of the tablets [16760504] Folic acid is frequently given to pregnant women at the same time as intermittent preventive treatment ( IPTp ) with sulfadoxine/pyrimethamine ( SP ) , but it is not known if it interferes with the anti-malarial activity of SP . To investigate this concern , 1,035 Gambian primigravidae were r and omized to receive either folic acid ( 500 - 1,500 microg/day ) together with oral iron ( 522 ) or oral iron alone ( 513 ) for 14 days at the same time as they received IPTp with SP . On presentation , 261 women ( 25 % ) had Plasmodium falciparum asexual parasitemia . Prevalences of parasitemia on day 14 after treatment were similar in both groups : 5.7 % ( 26 of 458 ) in the iron plus folic acid group and 4.9 % ( 22 of 446 ) in the iron alone group ( risk difference = 0.74 % , 95 % confidence interval [ CI ] = -2.2 % to 3.7 % ) . Parasitologic cure was observed in 116 ( 91 % ) of 128 of women who were parasitemic on presentation and who received iron and folic acid and in 122 ( 92 % ) of 133 women who received iron alone ( difference = 1.1 % , 95 % CI = -5.6 % to 8.0 % ) . Women who received folic acid and iron had a slightly higher mean hemoglobin concentration at day 14 than women who had received iron alone ( difference = 0.14 g/dL , 95 % CI = 0.01 - 0.27 g/dL ) . The results of this study suggest that in an area of low SP resistance , administration of folic acid to pregnant women in a dose of 500 - 1,500 mug/day will not interfere with the protective effect of SP when used for IPTp [12637400] Abstract Objective : To assess the impact on birth size and risk of low birth weight of alternative combinations of micronutrients given to pregnant women . Design : Double blind cluster r and omised controlled trial . Setting : Rural community in south eastern Nepal . Participants : 4926 pregnant women and 4130 live born infants . Interventions : 426 communities were r and omised to five regimens in which pregnant women received daily supplements of folic acid , folic acid-iron , folic acid-iron-zinc , or multiple micronutrients all given with vitamin A , or vitamin A alone ( control ) . Main outcome measures : Birth weight , length , and head and chest circumference assessed within 72 hours of birth . Low birth weight was defined < 2500 g. Results : Supplementation with maternal folic acid alone had no effect on birth size . Folic acid-iron increased mean birth weight by 37 g ( 95 % confidence interval −16 g to 90 g ) and reduced the percentage of low birthweight babies ( < 2500 g ) from 43 % to 34 % ( 16 % ; relative risk=0.84 , 0.72 to 0.99 ) . Folic acid-iron-zinc had no effect on birth size compared with controls . Multiple micronutrient supplementation increased birth weight by 64 g ( 12 g to 115 g ) and reduced the percentage of low birthweight babies by 14 % ( 0.86 , 0.74 to 0.99 ) . None of the supplement combinations reduced the incidence of preterm births . Folic acid-iron and multiple micronutrients increased head and chest circumference of babies , but not length . Conclusions : Antenatal folic acid-iron supplements modestly reduce the risk of low birth weight . Multiple micronutrients confer no additional benefit over folic acid-iron in reducing this risk . What is already known on this topic Deficiencies in micronutrients are common in women in developing countries and have been associated with low birth weight and preterm delivery What this study adds In rural Nepal maternal supplementation with folic acid-iron reduced the incidence of low birth weight by 16 % A multiple micronutrient supplement of 14 micronutrients , including folic acid , iron , and zinc , reduced low birth weight by 14 % , thus conferring no advantage over folic [9704770] OBJECTIVE Our purpose was to demonstrate reduced blood volume in preeclampsia compared with nonproteinuric gestational hypertension and normal pregnancy by use of independent measures of red blood cell and plasma volumes . STUDY DESIGN Red blood cells labeled with a nonradioactive stable isotope of chromium and Evans ' blue were infused in subjects with preeclampsia or gestational hypertension and normotensive pregnant controls . Blood was sample d eight times over 60 minutes for dye concentration and at 30 minutes for chromium analysis . RESULTS Total blood and plasma volumes are decreased in preeclampsia ( 2660 + /- 382 mL/m2 and 1790 + /- 332 mL/m2 , respectively ) compared with normotensive subjects ( 3217 + /- 391 mL/m2 , P < 0.001 and 2279 + /- 325 mL/m2 , P < .001 ) and gestational hypertension ( 3139 + /- 272 mL/m2 , P < .001 and 2132 + /- 265 mL/m2 , P = .003 ) . Total body/peripheral hematocrit ratio is increased in preeclampsia . CONCLUSIONS Blood volume , by measurement of red blood cell and plasma volumes , is reduced and has altered distribution in preeclampsia but is normal in gestational hypertension [16733739] This study aims to evaluate iron prophylaxis in pregnant women from the individual aspect , i.e. according to serum ferritin levels at the beginning of pregnancy , and to assess which dose of iron would be adequate to prevent iron deficiency ( ID ) and iron deficiency anaemia ( IDA ) during pregnancy and postpartum . A r and omised , double-blind study comprising 301 healthy Danish pregnant women allocated into four groups taking ferrous iron ( as fumarate ) in doses of 20 mg ( n=74 ) , 40 mg ( n=76 ) , 60 mg ( n=77 ) and 80 mg ( n=75 ) from 18 weeks gestation ( inclusion ) to 8 weeks postpartum . Iron status markers [ serum ferritin , serum soluble transferrin receptor ( sTfR ) , haemoglobin ] were recorded at 18 , 32 and 39 weeks gestation and 8 weeks postpartum . Body iron was calculated using the serum sTfR/serum ferritin ratio . ID was defined by serum ferritin < 12 μg/l in pregnancy and < 15 μg/l postpartum ; IDA as serum ferritin < 12 μg/l and haemoglobin < 5th percentile in iron-replete pregnant women . Women in the iron supplement groups were stratified according to serum ferritin levels at inclusion ; 50.7 % had ferritin ≤30 μg/l , 37.7 % ferritin 30–70 μg/l and 11.6 % ferritin > 70 μg/l . At 32 weeks , women with ferritin ≤30 μg/l had an ID frequency of : 20-mg group 54.1 % , 40 mg 29.7 % , 60 mg 24.4 % , 80 mg 20.6 % ( p<0.001 ) ; women with ferritin > 30 μg/l had an ID frequency of : 20-mg group 20.0 % , 40 mg 13.9 % , 60 mg 5.7 % , 80 mg 5.1 % ( p<0.001 ) . Women with ferritin > 70 μg/l had no ID . Postpartum , ID was found in 4.7 % in 20-mg group , 2.9 % in group 40 mg and 0 % in group 60 and 80 mg . IDA : At 32 weeks , women with ferritin ≤30 μg/l had an IDA frequency of : 20-mg group 2.7 % , 40 mg 2.7 % , 60 and 80 mg 0 % ; none of the women with ferritin > 30 μg/l displayed IDA . Body iron at 18 weeks was 10.4 mg/kg , similar in the four iron groups . Later in pregnancy body iron declined significantly , being lower the 20 mg group , and similar in the 40 , 60 and 80-mg groups . Postpartum body iron rose to inclusion levels being 9.3 mg/kg in the 20-mg group and 10.5 mg/kg in the 40- , 60- and 80-mg groups . This study gives an estimate of iron dosage in individual iron prophylaxis adjusted to serum ferritin levels in early pregnancy . In the prevention of ID , we suggest 80–100 mg ferrous iron/day to women having ferritin ≤30 μg/l and 40 mg ferrous iron/day to women having ferritin 31–70 μg/l . In the prevention of IDA , we suggest 40 mg ferrous iron/day to women having ferritin ≤70 μg/l . Women with ferritin > 70 μg/l have no need for iron supplement [5551272] This study was planned to determine whether iron deficiency in pregnancy predisposed to the development of folate deficiency and also the smallest daily iron supplement that maintained haemoglobin levels in pregnancy . Three groups of women were given oral ferrous fumarate supplying 30 , 60 , and 120 mg of iron ; a fourth group was given 1 g of parenteral iron in early pregnancy followed by oral iron ( 60 mg ) ; a fifth group received a placebo . Tablets were taken once daily . Oral iron 30 mg once daily maintained haemoglobin levels throughout pregnancy . Women whose marrows lacked demonstrable iron at the 37th week had a significantly higher incidence of megaloblastic haemopoiesis ( 28·7 % ) than those with demonstrable iron stores ( 15·3 % ) ; women taking oral iron did not have a lower frequency of megaloblastosis than those given a placebo . We concluded that iron does not have a direct effect on folate status in pregnancy , that the association of iron deficiency and megaloblastic anaemia in pregnancy is the result of poor nutrition , and that there is no cause- and -effect relation between them [9277046] Serum erythropoietin ( EPO ) and its relationship to hemoglobin ( Hb ) , iron status markers and iron supplementation during normal pregnancy was assessed in a longitudinal , placebo-controlled study on 118 women , 61 took daily tablets containing 66 mg ferrous iron from the second trimester until delivery and 57 took placebo . Blood sample s were obtained at 4-week intervals until delivery as well as post-partum . In the placebo-treated women , median serum EPO rose from 22.5 U/l at inclusion to 35.0 U/l at delivery ( P = 0.0001 ) . In the iron-treated women , median serum EPO rose from 23.9 to 29.9 U/l ( P = 0.0001 ) . Serum EPO showed a steeper increase in the placebo-treated women than in the iron-treated women ( P < 0.05 ) . After delivery , serum EPO became normal in both groups ( P = 0.0001 ) . Median Hb was lower in placebo-treated ( iron depleted ) than in iron-treated ( iron repleted ) women ( P < 0.05 ) . In the placebo-treated women there was a negative correlation and in the iron-treated women a positive correlation between serum EPO and Hb . In the placebo-treated women , inverse correlations existed between serum EPO and serum transferrin saturation and serum ferritin , reflecting the consequences of iron deficiency , whereas the iron-treated women displayed no correlation . A physiological , nonhypoxia-induced increase in EPO production accounts for the basic expansion of the red cell mass during pregnancy . In placebo-treated women , iron deficient erythropoiesis constitutes an additional hypoxic stimulus , which induces a further increase in serum EPO [6029952] IN a previous investigation of the effects of grade d micro-doses of folic acid ( pteroyl glutamic acid ) in pregnancy suggestive evidence has been obtained that the minimal oral requirement may lie in the region of 300 pg./day . This conclusion was based largely upon the measurement of the fasting post-partum serum folate or L. casei activity in a group of patients from a population where poor dietary intake of folic acid was common . In patients receiving no prophylactic folic acid or IOO pg./day the median post-partum serum folate level was subnormal , in those receiving 3oo , ug./day it was normal and in those receiving 4sopg./day it was supranormal ( Willoughby and Jewell , 1966 ) . As an extension of this investigation the incidence of maternal anaemia has now been assessed among a population of 3599 patients r and omly allocated at their first ante-natal [8383415] Objective ‐ To determine : 1 ) if 18 mg iron daily is sufficient to cover the iron need during normal pregnancy , and 2 ) if women , who will not need iron supplementation during pregnancy , can be identified by early screening [7660438] The influence of haemoglobin genotype on the response to iron supplementation was studied in a r and omized , double blind , placebo-controlled trial involving 497 multigravid pregnant women from a rural area of The Gambia . Women were r and omly allocated to receive either oral iron ( 60 mg elemental iron per day ) or placebo . At 36 weeks of pregnancy , women who had received oral iron during pregnancy had higher mean haemoglobin , packed cell volume , plasma iron and ferritin levels than did women who received placebo . Iron supplementation of pregnant women with the AA haemoglobin genotype also result ed in increases in the packed cell volume ( PCV ) and haemoglobin level measured after delivery , and in the birth weight of the infant . However , in AS women PCV and haemoglobin level at delivery were lower in the supplemented group and supplementation was also associated with reduced birth weights . In malaria endemic areas , pregnant women with the haemoglobin genotype AS may not benefit from iron supplementation during pregnancy [2791561] This article reports the design and feasibility of a r and omized controlled trial of the benefits of routine iron prophylaxis during pregnancy . The multicenter trial , supported by a small budget , relied on health service personnel in Finnish maternity centers . Iron prophylaxis has had an established position in Finnish maternity care , and iron is freely available . This contributed to our decision to ask for informed consent after r and omization . During a year , 2960 mothers were recruited by midwives in 27 maternity health centers and r and omized into two groups : selective and routine iron supplementation . Mothers were followed until the postpartum checkup , and data were collected by five different question naires and abstract ed from the infant 's patient record . Adherence of the midwives to the study protocol was satisfactory , as was mothers ' compliance with recommended treatments . However , because the study was design ed to compare two treatment policies , problems of nonmasking hamper of the biologic effects of iron . This trial encourages the use of existing health services and their personnel in evaluation of medical technology [15715531] Objective . To determine the lowest dose of iron preventative of iron deficiency and iron deficiency anemia in pregnancy [16740440] BACKGROUND We undertook this study to compare the effectiveness and safety of antenatal daily and weekly supplementation with iron , folic acid , and vitamin B(12 ) in healthy , pregnant women who were not anemic at gestational week 20 . METHODS Women with singleton pregnancies and blood hemoglobin ( Hb ) > 115 g/L at gestational week 20 ( equivalent to 105 g/L at sea level ) were r and omly assigned to two groups , one consuming one tablet containing 60 mg iron , 200 mug folic acid and 1 mug vitamin B(12 ) daily ( DS , n = 56 ) ; the other consuming two tablets once weekly ( WS , n = 60 ) . Blood Hb and serum ferritin concentrations were measured every 4 weeks from weeks 20 to 36 , and pregnancy outcomes were evaluated . RESULTS Mild anemia and hypoferritinemia throughout pregnancy occurred less frequently in DS than WS . None of the 116 women had Hb concentrations < 103 g/L at any evaluation point . In contrast , hemoconcentration ( Hb > 145 g/L ) from gestational week 28 onwards occurred in 11 % in DS and 2 % in WS . We observed ex post facto that hemoconcentration at gestational week 28 was associated with a significantly higher relative risk of low birth weight ( RR 6.23 , 95 % CI 1.46 - 26.57 ) and premature delivery ( RR 7.78 , 95 % CI 1.45 - 24.74 ) . CONCLUSIONS In women who were nonanemic at gestational week 20 , both schemes ( DS and WS ) prevented the occurrence of Hb levels < 100 g/L. DS women had a higher incidence of hemoconcentration . Hemoconcentration was associated with increased risk of low birth weight and premature delivery [627303] The failure to prescribe in antenatal clinics a well tolerated form of supplementary oral iron that provides an adequate iron supply for the successful maintainance of active erythropoiesis in pregnant women largely accounts for the frequent development of latent iron deficiency in the child-bearing age . The potential value of Plexafer-F * , a slow release ferrous sulphate preparation supplemented with folic acid , in reducing the high incidence of latent iron deficiency in pregnancy was assessed by conducting a r and omized clinical trial of Plexafer-F and ordinary ferrous sulphate B.P. with folic acid in eighty women presenting early in pregnancy with latent iron deficiency . At the end of the trial , which was started at the sixteenth week of pregnancy and which lasted for twenty weeks , normal haematological values were obtained in thirty-eight out of forty patients ( 95 % ) taking Plexafer-F , but only in twenty-four out of forty patients ( 60 % ) taking ferrous sulphate . A simple screening test run on stool specimens provided during antenatal visits to check regular ingestion of the iron preparations prescribed , revealed regular drug intake and no intolerance in all the patients receiving Plexafer-F , against an intolerance leading to failure of regular drug intake in 37.5 % of patients receiving ordinary ferrous sulphate [5134472] The side-effects of a new sustained release oral ferrous sulphate preparation have been evaluated in three separate double-blind studies . Each tablet contained 100 mg of ferrous iron and the dosage employed in all studies was 2 tablets daily . In a large series of blood donors r and omly divided into three groups the frequency and type of side-effects were compared to ferrous sulphate tablets and placebo . In two series of pregnant women the side-effects were studied with a cross-over technique using ferrous sulphate tablets as reference . Placebo was also included as a reference in one of these studies . In all series the frequency of nausea and epigastric pain was about the same for the sustained release preparation as for placebo . In all series ferrous sulphate tablets gave a significantly higher frequency of nausea than the sustained release tablets and placebo . Also the frequency of epigastric pain was found to be higher in blood donors but this could not be verified in pregnant women [4668759] Summary The effect of small doses of iron and folic acid in a single tablet in preventing anaemia in pregnancy has been assessed . Fifty mg . elemental iron and 400μg . folic acid were found to be satisfactory daily supplements for both ‘ good ’ and ‘ bad ’ tablet takers . Tablet counting and an occasional chemical test for the presence of iron in the faeces were compared as indicators of tablet consumption and the latter found to be superior . The high incidence of faulty tablet consumption indicates the need for some check in anaemic patients in pregnancy [17889086] The iron status at 6 months and 4 years of children born to women who were r and omly allocated to receive 20 mg of iron daily in the second half of pregnancy did not differ from children of mothers in the control group . [17963760] OBJECTIVE To evaluate the effect of iron supplementation on serum copper and zinc levels . METHOD In a r and omized , double-blind , placebo-controlled trial , 66 pregnant women with hemoglobin 13.2 g/dL or greater between the 13th and 18th week of pregnancy were r and omized into case and control groups . From the 20th week until the end of pregnancy the case group received one ferrous sulfate tablet containing 50 mg elemental iron daily , while the control group received placebo . Hemoglobin , ferritin , copper , and zinc levels at 24 - 28 and 32 - 36 weeks of pregnancy were measured and compared . RESULTS In the case group , serum copper levels in the second and third trimester were significantly lower than the control group ( P<0.01 and P<0.001 , respectively ) . Serum zinc levels in the case group in the second and third trimester were also significantly lower than the control group ( P<0.001 ) . CONCLUSION Iron supplementation in pregnant women with hemoglobin greater than 13.2 g/dL reduces serum levels of copper and zinc [7631683] OBJECTIVE A r and omized trial comparing women who were given iron only if needed and those given iron prophylactically showed that routine prophylaxis is not crucial for mothers ' or infants ' health up to postpartum examination . This study investigated these infants ' and mothers ' subsequent health , as available in routine registers in a 7-year follow-up . STUDY DESIGN Original data ( N = 2693 ) were linked to the national population , birth , and hospital inpatient registers . RESULTS The outcomes in the two groups were very similar : there were no statistically significant differences in deaths after birth , number or timing of infants ' or mothers ' hospitalizations , reasons for mothers ' first hospitalization , number or timing of subsequent miscarriages or births , or problems or outcomes in the next birth . However , infants of the prophylactically supplemented group were more frequently hospitalized because of convulsions . CONCLUSION This study does not support routine iron prophylaxis for well-nourished pregnant women [17977537] OBJECTIVE To measure levels of markers of anemia before and after delivery in women who had high hemoglobin levels during the early stage of the second trimester of pregnancy and did not receive iron supplementation during their pregnancies . METHODS In a r and omized , double-blind , placebo-controlled trial 244 women who had a hemoglobin concentration of 13.2 g/dL or greater and a serum ferritin level higher than 15 microg/L between the 13th and 18th week of pregnancy took either one 150-mg tablet of ferrous sulfate daily or placebo during their pregnancies . Markers of anemia were measured at the time of delivery and 6 weeks postpartum . RESULTS There were statistically significant differences between the 2 groups in hematocrit as well as hemoglobin and ferritin levels both at the time of delivery and 6 weeks postpartum ( P<0.05 ) , but these differences were not clinical ly significant . CONCLUSION Not using iron supplementation did not cause a considerable decrease in markers of anemia in women with a hemoglobin concentration of 13.2 g/dL or greater in the second trimester of pregnancy [10842553] A weekly iron/folate supplement was compared with a st and ard daily iron/folate supplement in pregnant women living in rural Malawi . Women were enrolled as they attended the local antenatal clinic , stratified by grade of anaemia and then r and omized to receive either 60 mg iron/0.25 mg folate per day ( n=211 ) or 120 mg iron/0.50 mg folate once a week ( n=202 ) . Supplementation was continued for a minimum of 8 weeks ( 10 weeks on average ) and was self administered by the women at home . Initial haemoglobin values for the daily ( μ=105.7g/l ) and weekly ( μ=104.4g/l ) groups as well as final haemoglobin values ( 107.5 g/l and 105.6 g/l , respectively ) did not differ significantly between the two groups . Haemoglobin values increased by similar levels in both groups with the subset of anaemic women increasing by an average of 6.3 g/l in the daily group ( n=70 ) and 5.9 g/l in the weekly group ( n=66 ) for all women . For compliant , anaemic women , the increases were 7.4 g/l and 6.6 g/l for the daily and weekly groups , respectively . Compliance , as indicated by self reporting and by regular counts of remaining tablets , was significantly higher in the weekly group ( 76 % compared with 60 % , P < 0.05 ) , however compliance was identical in both groups when assessed by a stool test for elemental iron . Reported side effects were significantly reduced in the weekly group ( 6 % compared with 17 % , P < 0.05 ) . We conclude that a weekly iron supplement given to pregnant women in rural Malawi has similar haematologic effects , and an improved side effect profile , in comparison with a st and ard daily supplement when administered through an existing primary healthcare programme , although both regimens are relatively unsuccessful in the reduction of anaemia prevalence during pregnancy [11787984] In the present study 67 non-anaemic women were r and omly allocated to either 100 mg or 15 mg iron daily at about the 10 . week of pregnancy . At about week 18 , 30 and 36 of pregnancy , as well as 6 weeks after delivery , hemoglobin and the serum concentrations of ferritin , vitamin B12 , folates , Zn , Cu and Se were monitored . Dietary allowances of other minerals and vitamins are also increased in pregnancy , and the 15 mg iron tablet was enriched with Zn ( 10 mg ) , Cu ( 2 mg ) , Se ( 50 microg ) , vitamin B12 ( 3 microg ) , and folate ( 0.1 mg ) . Neither ferritin , nor Cu , Zn or Se concentrations differed statistically significantly between the treatment groups during pregnancy . Ferritin and Zn appeared to decrease approximately parallel to the hemodilution , whereas Cu concentrations increased from a non-pregnant reference mean of 18 micromol Cu/L to a maximum mean of nearly 33 micromol Cu/L during pregnancy . Se decreased concomitantly to about 1.0 micromol Se/L. Serum folate ( around 15 micromol/L ) was essentially unaffected by pregnancy in the group given multivitamin/mineral supplementation , whereas the mean concentration fell below 10 micromol/L in the group supplemented with 100 mg iron daily . Our results indicate that supplementation of 15 mg Fe daily during pregnancy results in a small reduction of hemoglobin . It is suggested that additional supplementation with folate might be of importance to maintain the serum folate concentration during pregnancy [15810797] Anemia is still the major nutritional problem among pregnant women in Southeast Asia . The objective of this study was to measure hemoglobin status and reduction of underweight in a group of pregnant women who received iron-fortified or nonfortified milk , and another group who received iron supplements ( tablets ) or placebo . The 44 women in the iron-fortified milk group received 15 mg of iron per day per 400 ml of milk , and 41 women received placebo . The 40 women in the iron supplement group received 60 mg of iron per day , and 43 women received nonfortified milk . During this intervention trial , all women were supervised from the 14th to the 18th week of gestation until delivery . Blood was sample d at 0 , 5 , 10 , and 16 weeks of intervention . After the 16th week of intervention , the changes in hemoglobin ( ΔHb ) concentrations in both treatment groups ( the iron-fortified milk and the iron tablet groups ) were not significantly different ( ΔHb : −0.5 ± 0.9 and −0.3 ± 0.9 g/L , respectively ) , but the changes were significantly greater in the nonfortified milk and placebo groups ( ΔHb : −1.2 ± 0.9 and −1.1 ± 0.8 g/L , respectively ; p < .01 ) . The change in transferrin saturation ( ΔTS ) in the iron-fortified milk group ( ΔTS : 3.4 ± 12.9 % ) was greater than that in the placebo and nonfortified milk groups ( ΔTS : −10.1 ± 9.8 % and −11.6 ± 10.7 % , respectively ) ( p < .01 ) . The weight gain of the subjects during intervention did not differ significantly in the fortified and nonfortified milk groups ( Δweight : 5.0 ± 2.0 and 5.8 ± 2.1 kg , respectively ) , but was higher than in the iron tablet group ( Δweight : 4.6 ± 3.1 kg p < .05 ) and the placebo group ( Δweight : 3.8 ± 2.5 kg ; p < .001 ) . Iron supplementation and fortification were seen to be effective in promoting weight gain in pregnant Vietnamese women . For women who are underweight , the administration of iron-fortified milk has additional benefits to those of supplementation , most likely due to additional energy and nutrient inputs [29120032] The effect of oral iron prophylaxis on haemoglobin concentration ( Hb ) and haematocrit ( Hct ) has been studied in 300 pregnant women . From the 3rd to 4th month of pregnancy and until term the women were r and omly treated with 100 mg or 200 mg ferrous iron daily respectively as sustained‐release tablets ( Duroferon ® Duretter ® ) or 200 mg ferrous iron as rapidly disintegrating tablets [5683581] The serial trends of the whole blood folate level in two groups of patients have been followed throughout pregnancy and up to six weeks postpartum . In those receiving iron alone the whole blood folate remained normal until the test at six weeks after delivery , at which time over half were in the deficient range . There appears to be a delay before this test reflects the current folate status when this changes rapidly . In those receiving iron plus 330 μg . of folic acid a day the results at this time were close to those at the beginning of pregnancy . Subnormal whole blood folate , red cell folate , and serum folate values occurred close to term in patients receiving iron alone , but were not found in those also receiving folic acid . Megaloblastic changes occurred at term in three patients receiving iron alone in whom the whole blood folate had repeatedly been low in early pregnancy . The observations are consistent with the previous suggestion that 300 μg . of folic acid daily is a suitable supplement to prevent deficiency in late pregnancy and the puerperium [7117682] Forty patients were given one of two iron-folic acid tablets starting from the first ante-natal visit and continuing to parturition . Haemoglobin levels were measured at the commencement , at the end of the study and on at least one other occasion . A comparison was made of haemoglobin levels and side-effects [19757261] Summary Prenatal multivitamin supplements ( PMS ) are recommended during pregnancy . Suboptimal adherence in women experiencing gastrointestinal ( GI ) conditions is thought to be attributed to the high elemental iron content in PMS . This study sought to quantify adherence and tolerability of iron-containing PMS in women with pre-existing GI conditions by recruiting women who called the Motherisk Helpline . Women with ( n = 36 ) and without ( n = 166 ) pre-existing GI conditions were r and omised to either PregVit ® ( n = 106 ) or Orifer F ® ( n = 96 ) . Monthly follow-up interviews were conducted to assess pill intake and GI adverse effects associated with PMS . The results of our study suggest that with the use of small size and low dose iron PMS , women with pre-existing GI conditions do not experience ( 1 ) more GI adverse effects , ( 2 ) lower adherence than women with no such conditions , and ( 3 ) may experience less severe nausea and vomiting of pregnancy . Supplementing with small tablets of low dose iron PMS should be considered [19203773] Iron ( Fe ) deficiency and anemia during pregnancy remain highly prevalent in Senegal because of low compliance with Fe supplementation . Improving women 's access to supplements may increase compliance . Six prenatal centers in Dakar were r and omly assigned to either a control group in which women received routine prenatal visits , including prescriptions to purchase iron/folic acid tablets ( IFA ) according to the guidelines of the current Senegalese supplementation program ( n=112 ) , or to an intervention group in which women received free IFA ( n=109 ) in addition to routine prenatal care . Compliance was assessed 20 weeks after enrollment by pill count and interviews . Hemoglobin , erythrocyte protoporphyrin and serum ferritin were measured at baseline and follow-up . Compliance was 48 % and 86 % in the control and intervention groups , respectively ( P<0.001 ) . After adjustment for confounding , prevalence of anemia was 62 % in the control group versus 31 % in the intervention group ( P<0.001 ) ; prevalence of Fe deficiency was 49 % and 21 % in the control and intervention groups , respectively ( P<0.001 ) . Improving access to IFA for pregnant women visiting health centers could dramatically increase their compliance , improve Fe status and decrease the incidence of anemia Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Anaemia is a frequent condition during pregnancy , particularly among women in low- and middle-income countries . Traditionally , gestational anaemia has been prevented with daily iron supplements throughout pregnancy , but adherence to this regimen due to side effects , interrupted supply of the supplements , and concerns about safety among women with an adequate iron intake , have limited the use of this intervention . Intermittent ( i.e. two or three times a week on non-consecutive days ) supplementation has been proposed as an alternative to daily supplementation . OBJECTIVES To assess the benefits and harms of intermittent supplementation with iron alone or in combination with folic acid or other vitamins and minerals to pregnant women on neonatal and pregnancy outcomes . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

27562656

[15083445] OBJECTIVE To determine whether needle acupuncture may be useful in the reduction of leg spasticity in a chronic state . DESIGN Single-blind , r and omized , placebo-controlled trial . SETTING Neurologic outpatient department of a medical school in Germany . PARTICIPANTS Twenty-five patients ( 14 women ) suffering from chronic poststroke leg spasticity with pes equinovarus deformity ( Modified Ashworth Scale [ MAS ] score , > /=1 ) , aged 38 to 77 years ( mean + /- st and ard deviation , 58.5+/-10.4 y ) , were enrolled in the study . The mean time from stroke to inclusion in the study was approximately 5 years ( mean , 65.4+/-48.3 mo ; range , 7 - 180 mo ) . INTERVENTIONS Participants were r and omly assigned to placebo treatment ( n=12 ) by using a specially design ed placebo needling procedure , or verum treatment ( n=13 ) . MAIN OUTCOME MEASURES MAS score of the affected ankle , pain ( visual analog scale ) , and walking speed . RESULTS There was no demonstrated beneficial clinical effects from verum acupuncture . After 4 weeks of treatment , mean MAS score was 3.3+/-0.9 in the placebo group versus 3.3+/-1.1 in the verum group . The neurophysiologic measure of H-reflex indicated a significant increase of spinal motoneuron excitability after verum acupuncture ( H-response/M-response ratio : placebo,.39+/-.19 ; verum,.68+/-.41 ; P<.05 ) . CONCLUSIONS This effect might be explained by afferent input of A delta and C fibers to the spinal motoneuron . The results from our study indicate that needle acupuncture may not be helpful to patients with chronic poststroke spasticity . However , there was neurophysiologic evidence for specific acupuncture effects on a spinal ( segmental ) level involving nociceptive reflex mechanisms [3697148] An effective and safe remedy for shoulder pain is needed as shoulder pain is a common complication of stroke and restricts recovery of patients . This study was carried out to evaluate the effect of Ouhyul herbal acupuncture point injection ( O-API ) on shoulder pain in patients with stroke . Twenty-four participants with shoulder pain after stroke were recruited and r and omized to the O-API and control groups . Treatment was conducted for 2 weeks three times per week . We evaluated the effects of treatment with a numerical rating scale ( NRS ) , painless passive range of motion ( PROM ) of external shoulder rotation , and the Fugl-Meyer Motor Assessment ( FMMA ) at baseline , each week , and 1 week after the final treatment . All measures were similar between the O-API and control groups at baseline . The O-API group showed significant improvement on the NRS compared with that in the control group after 2 weeks of treatment , and the treatment effect was maintained until the follow-up period . PROM decreased significantly in both groups , but the reduction was maintained only in the O-API group . No significant difference was observed on the FMMA between the two groups . O-API result ed in significant improvement in shoulder pain after stroke , and its effect was maintained after termination of treatment without any severe side effects [20353105] OBJECTIVE To evaluate the therapeutic effect of comprehensive therapeutic protocol of electroacupuncture combined with active-blood- and -dissolve-stasis herbs and rehabilitation training for cerebral infa rct ion . METHODS A multi-center r and omized controlled trial was done , three hundred and twenty cases were divided into four groups : electroacupuncture combined with active-blood and dissolve-stasis herbs and rehabilitation training group ( group A ) , electroacupuncture combined with rehabilitation training group ( group B ) , herbs combined with rehabilitation training group ( group C ) and rehabilitation training group ( group D ) , 80 cases in each group . The following two groups of acupoints were used alternatively in electroacupuncture treatment : the first group including Vasomotor Area , Jianyu ( LI 15 ) , Biguan ( ST 31 ) , Hegu ( LI 4 ) and Taichong ( LR 3 ) ; the second group including Motor Area , Quchi ( LI 11 ) , Yanglingquan ( GB 34 ) and Shenshu ( BL 23 ) . 20 mL Xiangdan injection and 250 mL 5 % glucose injection or 250 mL 0.9 % sodium chloride injection were used by intravenous drip in herbs treatment once a day . The rehabilitation training was performed by the professional physical therapist . Each group was treated with corresponding treatment protocol . The therapeutic effect was evaluated by index of the mortality or disability rate 3 months after the onset of disease . The intention to treat analysis ( ITT ) was used in data . RESULTS The mortality or h and icap rate 3 months after the onset of disease of four groups were 17.5 % ( 14/80 ) in group A , 22.5 % ( 18/80 ) in group B , 40 . 0 % ( 32/80 ) in group C , and 31.3 % ( 25/80 ) in group D , respectively . The group A has a best therapeutic effect ( vs group C , group D , both P<0.05 ) , and there was no adverse event . CONCLUSION The combined application of electroacupuncture , active-blood and dissolve-stasis herbs and rehabilitation training is a better treatment for cerebral infa rct ion in clinic [8202976] Background and Purpose In a r and omized study of hemiparetic stroke patients with a median age of 75 years , functional recovery was significantly better in those who received additional sensory stimulation ( n=38 ) , including electrostimulation , than in control patients ( n=40 ) given the same physiotherapy and occupational therapy ; group differences for balance , mobility , and activities of daily living were significant . The present study was design ed to investigate postural control in patients who survived more than 2 years after stroke onset . Methods The 48 survivors ( mean , 2.7 years ; range , 2.0 to 3.8 years ) , 22 from the treatment group and 26 from the control group , were compared with 23 age-matched healthy subjects . Subjects were perturbed by vibrators applied to calf muscles or with galvanic vestibular stimulation . We evaluated postural control in terms of sway variances or sway velocities and the dynamics of postural control as a feedback system using system identification with a model previously vali date d for human postural control . Results Significantly more patients of the treatment group than of the control group maintained stance during perturbations ( P<.01 ) . Among patients capable of maintaining stance during perturbation , the control patients were characterized by significant divergence from normal values in two of the three characteristic parameters of dynamic postural control ( ie , swiftness and stiffness ; P<.05 ) compared with the treatment subgroup or age-matched subjects . Conclusions The course of sensory stimulation enhanced recovery of postural function , an enhancement still significant 2 years after the lesion and treatment . The differences and near normalization of characteristic parameters of dynamic postural control among treated patients suggest that improved recovery after sensory stimulation may be achieved by patients regaining normal or near normal dynamics of human postural control [18671899] Abstract Objective : To observe the effect of electro-acupuncture ( EA ) on dendritic spine and ephrin-A5 and to investigate the action of EA on neural plasticity after acute cerebral ischemic infa rct ion . Methods : Focal acute cerebral ischemia model was established by middle cerebral artery occlusion ( MCAO ) with electrocoagulation contralateral method . Ninety male Sprague – Dawley rats were r and omly divided into sham operation ( SO ) group , MCAO group and EA treatment ( ET ) group . Golgi dying , double immunofluorescence method and RT-PCR were used to detect dendritic spine density , expression patterns of ephrin-A5 and the effect of EA on them at the end of the first , second and fourth week after ischemia . Results : The dendritic spine density in MCAO group significantly decreased after ischemia ( p<0.01 ) . The dendritic spine density was raised in ET group in the corresponding time period ( p<0.01 ) and among the ET groups . It was higher at the end of the fourth week than before ( p<0.05 ) . The signal of ephrin-A5 was detected mainly in neuron cytoplasm , and the mRNA expression in MCAO group and ET group increased compared to that in SO group ( p<0.01 ) . The mRNA expression in ET group at the first week was much higher than that in MCAO group ( p<0.01 ) . In ET groups , the mRNA expression of ephrin-A5 was down-regulated along with the time going ( p<0.01 ) . Conclusion : It is possibly the regulation of the ephrin-A5 expression by which EA treatment improves the neural plasticity at the peri-infa rct cerebral cortex in acute cerebral ischemia rat . There may be a time window in EA treatment for acute cerebral ischemia [11498896] 63 patients with senile vascular dementia were r and omly divided into the treatment group ( treated by acupuncture ) and the control group ( treated with piracetam ) . The authors observed the changes in the score of Hasegawa 's dementia scale ( HDS ) , p300 , rheoencephalogram , topographic EEG , superoxide dismutase ( SOD ) activity in erythrocytes , and lipid peroxide ( LPO ) level in plasma before and after treatment . The statistical data showed that the total effective rate in the treatment group ( 80.6 % ) was significantly higher than that in the control group ( 25 % ) , and the differences in the observed indexes before and after treatment were significant ( P < 0.05 or P < 0.01 ) in the treatment group but not in the control group ( P > 0.05 ) , indicating that the acupuncture treatment was superior in immediate therapeutic effect on senile vascular dementia to drug treatment [11477855] OBJECTIVE To observe the clinical effect of electroacupuncture and acupuncture on vascular dementia ( VaD ) and the influence on superoxide dismutase ( SOD ) , lipid peroxide ( LPO ) and nitric oxide ( NO ) levels . METHODS Forty-six cases of VaD were r and omly divided into two groups , the electroacupuncture group ( EA group ) and the acupuncture group ( AP group ) . Assessment of Hasgawa 's dementia scale ( HDS ) , functional activities question naire ( FAQ ) and neurologic deficit scoring were done before and after treatment , and the changes on SOD , LPO and NO levels were observed . RESULTS After treatment , in the EA group , the HDS elevated , the FAQ lowered , SOD increased and LPO and NO decreased significantly , as compared with before treatment , P < 0.01 . But these parameters were not changed significantly in the AP group after treatment . The clinical symptoms were improved in both groups , but the reduction on neurologic deficit score was not significant . The total effective rate of the EA group was higher than that of the AP group . CONCLUSION The immediate effect of electroacupuncture was superior to that of acupuncture , suggesting that the electroacupuncture was more effective in promoting the intelligence recovery than acupuncture [19938212] This study is a double-blind r and omized controlled trial on the effect of intradermal acupuncture on insomnia after stroke . Hospitalized stroke patients with insomnia were enrolled in the study and were r and omly assigned to either a real intradermal acupuncture group ( RA group ) or a sham acupuncture group ( SA group ) . The RA group received intradermal acupuncture on Shen-Men ( He-7 ) and Nei-Kuan ( EH-6 ) for three days , and the SA group received sham acupuncture on the same points . The effect of acupuncture on insomnia was measured using Insomnia Severity Index ( ISI ) and Athens Insomnia Scale ( AIS ) at baseline and three days after treatment . To assess the effect of acupuncture on the autonomic nervous function , the subjects ' blood pressure and heart rate variability were monitored . Fifty-two subjects ( 27 in the RA group and 25 in the SA group ) were included in the final analysis . The insomnia-related scales ISI and AIS showed greater improvement of insomnia in the RA group than in the SA group . Moreover , there is a greater reduction of the number of non-dippers and a greater decrease of the LF/HF ratio ( heart rate variability ) in the RA group than in the SA group . These results indicate that sympathetic hyperactivities were stabilized in the RA group . It can thus be concluded that intradermal acupuncture on Shen-Men and Nei-Kuan is a useful therapeutic method for post stroke-onset insomnia as it reduces sympathetic hyperactivities [17585663] OBJECTIVE To observe clinical therapeutic effect of head point-through-point electroacupuncture ( EA ) on poststroke depression ( PSD ) and to study the mechanism . METHODS One hundred and eight cases of PSD were r and omly divided into a point-through-point EA group ( n = 38 ) , a non point-through-point group ( n = 36 ) and a western medicine group ( n = 34 ) . After treatment of 28 days , their therapeutic effects , scores of HAMD depression scale and SDS self-rating scale , and plasma 5-HT contents were compared before and after treatment among the 3 groups . RESULTS The effective rate of 86.84 % in the point-through-point EA group was better than 63.89 % in the non point-through-point group and 67.65 % in the western medicine group ( P < 0.05 or P < 0.01 ) . Plasma 5-HT content in the point-through-point EA group increased significantly , with a very significant difference as compared with that of the non point-through-point group ( P < 0.01 ) . CONCLUSION Head point-through-point therapy can obviously increase plasma 5-HT content of the patient with PSD , so as to cure poststroke depression , with a better therapeutic effect than other two groups [23885610] OBJECTIVE To assess the clinical efficacy of acupuncture at key acupoints combined with the routine rehabilitation training of limb function on spasmodic hemiplegia after cerebral infa rct ion . METHODS Eighty-six cases were r and omized into an acupuncture combined with rehabilitation group ( group A , 44 cases ) and a rehabilitation group ( group B , 42 cases ) . In group A , the key acupoints were selected from head , face , chest , abdomen , shoulder , back , h and s , feet and ankles such as Cuanzhu ( BL 2 ) , Danzhong ( CV 17 ) , Jianyu ( LI 15 ) and Yanglao ( SI 16 ) were stimulated with acupuncture . In combination , the routine limb rehabilitation training was applied , once every day . In group B , the routine limb rehabilitation training was applied alone . In both groups , 10 treatments made one session and 2 sessions were required totally . Before and after treatment , Fugl-Meyer scale and functional independent measurement ( FIM ) scale were adopted to assess the limb motor level and the activity of daily life in the patients respectively . The modified Ashworth scale was used to assess the effect of anti-spasm . RESULTS The total effective rate of anti-spasm was 90.9 % ( 40/44 ) in the group A , which was superior to 73.8 % ( 32/42 ) in the group B ( P < 0.05 ) . After 2 sessions of treatment , Fugl-Meyer score and FIM score were all improved in both groups ( all P < 0.05 ) and the results in the group A were better than those in the group B ( all P < 0.05 ) . Additionally , the improvement of FIM score after the 1st session of treatment in the group A was better as compared with the group B , indicating the significant difference ( P < 0.05 ) . CONCLUSION Acupuncture at key acupoints combined with rehabilitation therapy effectively relieves the spasmodic condition of the patients with post-stroke spasmodic hemiplegia , improves the limb function and the life activity of the patients [11239191] Background and Purpose — In small trials with control groups that receive no intervention , acupuncture has been reported to improve functional outcome after stroke . We studied effects of acupuncture and transcutaneous electrical nerve stimulation on functional outcome and quality of life after stroke versus a control group that received subliminal electrostimulation . Methods — In a multicenter r and omized controlled trial involving 7 university and district hospitals in Sweden , 150 patients with moderate or severe functional impairment were included . At days 5 to 10 after acute stroke , patients were r and omized to 1 of 3 intervention groups : ( a ) acupuncture , including electroacupuncture ; ( b ) sensory stimulation with high-intensity , low-frequency transcutaneous electrical nerve stimulation that induces muscle contractions ; and ( c ) low-intensity ( subliminal ) high-frequency electrostimulation ( control group ) . A total of 20 treatment sessions were performed over a 10-week period . Outcome variables included motor function , activities of daily living function , walking ability , social activities , and life satisfaction at 3-month and 1-year follow-up . Results — At baseline , patients in each group were closely similar in all important prognostic variables . At 3-month and 1-year follow-ups , no clinical ly important or statistically significant differences were observed between groups for any of the outcome variables . The 3 treatment modalities were all conducted without major adverse effects . Conclusions — When compared with a control group that received subliminal electrostimulation , treatment during the subacute phase of stroke with acupuncture or transcutaneous electrical nerve stimulation with muscle contractions had no beneficial effects on functional outcome or life satisfaction [23383459] OBJECTIVE To observe the effect of acupuncture stimulation of scalp- and body-acupoints on limb function in subacute stroke patients . METHODS A total of 110 stroke in patients were r and omly and equally divided into acupuncture group and control group . Patients of the acupuncture group were treated by acupuncture stimulation of scalp acupoint Dingnie Qianxiexian ( MS 6 ) and body acupoints Neiguan ( PC 6 ) , Jianyu ( LI 15 ) , Sanyinjiao ( SP 6 ) , etc . once daily for 20 days and routine neurological therapies , including drugs for controlling blood pressure , blood sugar , water-electrolyte balance , anticoagulation , encephaledema reduction , intracranial pressure reduction , anti-inflammation , neurofunction protection , etc . The stroke patients of the control group were treated with the routine neurological therapies only . The Fugl-Meyer assessment ( FMA ) , US National Institutes of Health Stroke Scale ( NIHSS ) were used to assess the patients ' limb function and nerve functional lesion severity before and after the treatment , and the ratio of mortality/disability and recurrence rate were used to assess the efficacy of acupuncture at the end of 3 and 6 months ' follow-up . RESULTS After the treatment , the FMA scores were increased significantly and NIHSS scores decreased considerably in both groups ( P < 0.01 ) , and the effects of acupuncture group were obviously superior to those of the control group ( P < 0.05 ) . There were no significant differences between two groups in the ratios of mortality/disability and recurrence rates at the end of 3 and 6 months ' follow-up ( P > 0.05 ) . CONCLUSION Scalp acupuncture combined with body acupuncture can evidently improve limb movement function and reduce the nerve function damage in stroke patients [18712644] Past studies have suggested that acupuncture may reduce spasticity in stroke survivors . We do not know , however , whether acupuncture may enhance the effect of strength training on motor function . This study compared upper-limb motor functional improvement in chronic stroke survivors who received a combination of acupuncture and strength training with that of subjects who received strength training alone . A total of 10 chronic stroke patients with moderate or severe wrist muscle spasticity were recruited for this study . The study used a crossover design with a r and om order of either combined electroacupuncture and strength training or strength training alone . Each subject received one of the two types of treatment twice a week for the first 6 weeks and switched to the other for another 6 weeks . Quantitative measurements of wrist spasticity , active wrist extension range of motion , isometric wrist strength , and clinical evaluation with Fugl-Meyer ( FM ) upper-limb motor scores were conducted before and after either treatment . After the combined treatment , the quantitative spasticity level , active wrist extension range of motion ( increased by a mean of 16.3 degrees ) , and FM upper-limb motor score ( increased by a mean of 4.9 points ) changed significantly ( p < 0.01 ) but no significant changes were noted in isometric wrist strength . The strength training alone result ed in no significant changes to any measured variable . The results of the current study indicate that the combined acupuncture and strength training treatment reduced muscle spasticity and may have improved motor function for chronic stroke survivors with moderate or severe muscle spasticity [24494280] OBJECTIVE To assess the clinical efficacy on post-stroke shoulder-h and syndrome ( SHS ) treated with acupuncture and rehabilitation and the impacts on patients ' nailfold microcirculation . METHODS One hundred and twenty patients were r and omized into an acupuncture rehabilitation group and a simple rehabilitation group , 60 cases in each one . In the simple rehabilitation group , OT ( comprehensive rehabilitation therapy ) training was adopted . In the acupuncture rehabilitation group , on the basis of the treatment as the simple rehabilitation , acu puncture was added at Taiyuan ( LU 9 ) , Zusanli ( ST 36 ) , Xuanzhong ( GB 39 ) , Waiguan ( TE 5 ) , Shousanli ( LI 10 ) , Quchi ( LI 11 ) and Jianyu ( LI 15 ) . Acupuncture was given once a day , 7 days made one session . Totally , 4 sessions of treatment were required . Fugl-Meyer score , upper limb pain score , the score of nerve function defect and the items of nailfold microcirculation of patients were assessed in the the two groups before and after treatment . The efficacy was compared between the two groups . RESULTS ( 1 ) The upper limb pain , the systematic motor function of the upper limbs , the nerve function defect , nailfold microcirculation and clinical symptoms were all improved after treatment in either the acupuncture rehabilitation group or the simple rehabilitation group as compared with those before treatment , indicating the significant difference ( P<0 . 05 , P<0 . 01 ) . ( 2 ) The i m provements in the upper limb pain ( 0 . 90+/-0.71 vs 1 . 80+/-0 . 66 ) , the systematic motor function of the upper limbs ( 42 . 43 13 . 57 vs 29 . 98+/-15 . 11 ) , the nerve function defect ( 8 . 60+/-11 . 61 vs 13 . 0+/-1 . 74 ) , nailfold microcirculation ( total score 3 . 18+/-1.32 vs 4.34+/-1.23 ) and clinical symptoms in the acupuncture rehabilitation group after treatment were different significantly as compared with those in the simple rehabilitation group ( PO0 . 05,P-O. 01 ) , and the results in the acupuncture rehabilitation group were superior to the simple rehabilitation group . ( 3 ) In the acupuncture rehabilitation group , the markedly effective rate was 50 . 0 % ( 30/60 ) and the total effective rate was 93.3 % ( 56/60 ) , which was better than 16.7 % ( 10/60 ) and 63 . 3 % ( 38/60 ) respectively in the simple rehabilitation group ( all P<0 . 05 ) . CONCLUSION Both the combined therapy of acupuncture and rehabilitation and the simple rehabilitation training are effective in the treatment of post-stroke SHS , and promote the status of nailfold microcirculation , the efficacy of the combined therapy is better than that of the latter [20578377] OBJECTIVE To verify the improvement function of warming-reinforcing acupuncture combined with rehabilitation training on the early motor function of hemiparalysis patients caused by ischemic brain stroke . METHODS Eighty cases were r and omly divided into a warming-reinforcing acupuncture combined with rehabilitation training group ( group A ) and a rehabilitation training group ( group B ) , 40 cases in each group . Both groups were treated with internal routine treatment . The Motor Relearning Program rehabilitation was used in group B , while warming-reinforcing acupuncture combined with Motor Relearning Program rehabilitation were used in group A. Jianyu ( LI 15 ) , Quchi ( LI 11 ) , Hegu ( LI 4 ) , Yanglingquan ( GB 34 ) , Yinlingquan ( SP 9 ) , Zusanli ( ST 36 ) , Sanyinjiao ( SP 6 ) were selected , and warming-reinforcing method was used in these points , they were treated for 3 weeks . The neurological functional deficits scores of hemiparalysis patients , Fugl-Meyer Score , Motor Function Assessment Score ( MAS ) , Barthel Index and Mini-mental State Examination ( MMSE ) were used to evaluate the condition of hemiparalysis patients before and after treatment . RESULTS The effective rate of group A ( 87.5 % , 35/40 ) superior to that of group B ( 67.5 % , 27/40 ) ( P < 0.05 ) . The neurological functional deficit scores , Fugl-Meyer score , MAS and Barthel Index of both groups were improved after treatment ( P < 0.01 , P < 0.05 ) , and the improved degree of group A was better than that of group B ( P < 0.01 , P < 0.05 ) . CONCLUSION There is obvious improvement function of warming-reinforcing acupuncture combined with rehabilitation training on the early motor function of hemiparalysis patients caused by ischemic brain stroke , and the function is better than that of simple rehabilitation training [11779909] Background and Purpose — A significant number of patients remain severely disabled after stroke despite rehabilitation with st and ard treatment modalities . Acupuncture has been reported as an alternative modality . This study aims to examine whether acupuncture has additional value to st and ard poststroke motor rehabilitation . Methods — A prospect i ve r and omized controlled trial ( RCT ) was carried out in a stroke rehabilitation unit in Hong Kong . One hundred six Chinese patients with moderate or severe functional impairment were included at days 3 to 15 after acute stroke . They were stratified into the moderate and the severe groups before r and omization into the control arm receiving st and ard modalities of treatment , which included physiotherapy , occupational and speech therapy , and skilled medical and nursing care , and the intervention arm receiving in addition traditional Chinese manual acupuncture . A mean of 35 acupuncture sessions on 10 main acupoints were performed over a 10-week period . Outcome measures included Fugl-Meyer assessment , Barthel Index , and Functional Independence Measure , respectively , at weeks 0 , 5 , and 10 , performed by blinded assessors . Results — At baseline , patients in each arm were comparable in all important prognostic characteristics . No statistically significant differences were observed between the 2 arms for any of the outcome measures at week 10 or outcome changes over time . Conclusions — Traditional Chinese manual acupuncture on the body has no additional value to st and ard poststroke motor rehabilitation [17604556] BACKGROUND Acupuncture may improve motor function in patients with chronic hemiparetic stroke , yet the neural mechanisms underlying such an effect are unknown . As part of a sham-controlled , r and omized clinical trial testing the efficacy of a 10-week acupuncture protocol in patients with chronic hemiparetic stroke , we examined the relationship between changes in function of the affected upper limb and brain activation using functional magnetic resonance imaging ( fMRI ) . METHODS Seven ( 7 ) chronic hemiparetic stroke patients underwent fMRI and testing of function of the affected upper limb ( spasticity and range-of-motion ) before and after a 10-week period of verum ( N=4 ) or sham ( N=3 ) acupuncture . The correlation between changes in function of the affected upper limb and brain activation after treatment was tested across patients . RESULTS We found a significant positive correlation between changes in function of the affected upper limb ( spasticity and range of motion ) and activation in a region of the ipsilesional motor cortex . Patients treated with verum acupuncture showed a trend toward a greater maximum activation change in this motor cortical area as compared to those treated with sham acupuncture . CONCLUSIONS Acupuncture may improve function of the affected upper limb in chronic hemiparetic stroke patients by increasing activity in the ipsilesional motor cortex [23057482] OBJECTIVES The aim of this study was to investigate whether acupuncture , especially Yamamoto 's New Scalp Acupuncture ( YNSA ) , is of value in additional to st and ard poststroke motor rehabilitation . DESIGN A prospect i ve , assessor-blinded r and omized control trial was carried out in an inpatient stroke rehabilitation unit with day hospital service . After inclusion , patients were stratified into control group and acupuncture group , r and omly . OUTCOME MEASURES The Barthel Index , the Rivermead Scale Index , and the Visual Analogue Scale were used to follow the efficacy of treatment . RESULTS In the acupuncture group , all the sensory , motor , and functional scores improved significantly during the examination period until 2 years after injury . The Barthel Index is increased from 4±2 to 95±4 in the acupuncture group . This index also increased in the control group ( from 4±2 to 75±4 ) , but the changes were significantly less than in the acupuncture group . A significant spontaneous recovery during the 2-year follow-up was found , but the YNSA treatment facilitated the functional recovery . Improved moving function and more flexible joints and ligaments were observed in comparison to the patients ' condition prior to treatment . CONCLUSIONS The data suggest that the YNSA is a useful method to treat stroke patients and enhance their quality of life [25199825] OBJECTIVE The purpose of this study was to determine the effects of deep dry needling ( DDN ) on spasticity , pressure sensitivity , and plantar pressure in patients who have had stroke . METHODS A r and omized controlled trial was conducted . Thirty-four patients who previously had a stroke were r and omly assigned either an experimental group that received a single session of DDN over the gastrocnemius and tibialis anterior muscles on the spastic leg or a control group that received no intervention . Spasticity ( evaluated with the Ashworth Scale ) ; pressure pain thresholds over the deltoid muscle , second metacarpal , and tibialis anterior muscle ; and plantar pressure ( baropodometry ) were collected by a blinded assessor before and 10 minutes after intervention . RESULTS A greater number of individuals receiving DDN exhibited decreased spasticity after the intervention ( P < .001 ) . The analysis of covariance showed that pressure pain thresholds increased bilaterally in patients receiving DDN compared with those who did not receive the intervention ( P < .001 ) . The analysis of covariance also found that patients receiving DDN experienced bilateral increases of support surface in the forefoot , unilateral increase of the support surface in the rear foot of the treated ( affected ) side , and bilateral decreases in mean pressure ( all , P < .02 ) as compared with those who did not receive DDN . CONCLUSIONS Our results suggest that a single session of DDN decreases spasticity and widespread pressure sensitivity in individuals with poststroke spasticity . Deep dry needling also induced changes in plantar pressure by increasing the support surface and decreasing the mean pressure [17955649] OBJECTIVE To observe the therapeutic effects of different acupuncture methods for spastic hemiparalysis due to cerebrovascular disorders . METHODS 90 cases of spastic hemiparalysis after wind-stroke were r and omly divided into a control group of 30 cases , a body acupuncture group of 30 cases and a point-penetrating acupuncture group of 30 cases . All the patients were given 4 courses of treatment , with 7 sessions constituting one therapeutic course and with a one-day interval between courses . The evaluations were made 3 times , i.e. once before treatment and once every 15 days during the treatment . RESULTS The therapeutic effects in the point-penetrating acupuncture group were obviously superior to those of both the control group and the body acupuncture group . CONCLUSION The point-penetrating acupuncture is an effective therapy for treating spastic hemiparalysis due to cerebrovascular disorders [21739685] OBJECTIVE To explore the impacts of acupuncture and rehabilitation on post-stroke abnormal patterns of limb movement and evaluate them via rehabilitation method . METHODS Ninety cases of post-stroke movement disorder were r and omly divided into an acupuncture-rehabilitation group , a body acupuncture group and a medication group , 30 cases in each group . In medication group , the conventional medication in neurological department was administered . In acupuncture-rehabilitation group and body acupuncture group , on the basis of the therapy as medication group , scalp acupuncture ( such as parietal area and anterior parietal area , etc . ) , rehabilitation training and traditional body acupuncture [ such as Jianyu ( LI 15 ) and Fengshi ( GB 31),etc . ] were supplemented . The continuous electric stimulation was applied in body acupuncture group . The treatment lasted for 8 weeks . The assessment of clinical efficacy , Fugl-Meyer score , Modified Ashworth scale ( MAS ) , range of motion ( ROM ) and shoulder pain score were taken as observation indices for rehabilitation evaluation before and after treatment in each group . RESULTS The effective rate was 93.1 % ( 27/29 ) in acupuncture-rehabilitation group , which was superior to 66.7 % ( 20/30 ) in body acupuncture group and 57.1 % ( 16/28 ) in control group ( both P<0.01 ) separately . After treatment , Fugl-Meyer score , MAS , ROM of the lower limbs and shoulder joint and shoulder pain score ( except medication group ) were all remarkably improved as compared with those before treatment in each group ( all P<0.01 ) . The improvements in Fugl-Meyer score , MAS , ROM of the upper limbs and shoulder pain score in acupuncture-rehabilitation group were significantly superior to those in body acupuncture group and medication group ( P<0.05 , P<0.01 ) . CONCLUSION Acupuncture and rehabilitation therapy and traditional body acupuncture remarkably improve in post-stroke movement disorder . But acupuncture and rehabilitation therapy is apparently superior to traditional body acupuncture . This therapy can effectively prevent and treat post-stroke abnormal patterns and it is greatly significant in the improvement of survival quality for the patients [21442809] OBJECTIVE To observe the curative effects of post-stroke h and dysfunction treated with acupuncture at Zhongzhu ( TE 3 ) and Waiguan ( TE 5 ) . METHODS Sixty cases of post-stroke h and dysfunction were r and omly divided into an observation group ( 30 cases ) and a control group ( 30 cases ) . Routine medicine , physical therapy , occupational therapy and other rehabilitation trainings were applied in both groups ; Zhongzhu ( TE 3 ) and Waiguan ( TE 5 ) were punctured in observation group . Scores of nervous functions deficit by the National Institutes of Health Stroke Scale ( NIHSS ) , h and function , walking ability , activities of daily living ( ADL ) by Modified Barthel Index Scale were e valuated in both groups before and after treatment . RESULTS After treatment , the scores of h and function , walking ability , ADL and NIHSS were improved in both groups ( all P < 0.01 ) , and the h and function , walking ability and ADL in observation group were superior to those in control group ( all P < 0.05 ) . CONCLUSION Routine medicine and rehabilitation trainings combined with acupuncture at Zhongzhu ( TE 3 ) and Waiguan ( TE 5 ) to treat post-stroke h and dysfunction can obviously improve the h and dysfunction after stroke , enhance the abilities of walking and daily living , and increase the curative effect [22489807] OBJECTIVES The majority of individuals who survive a stroke are disabled because of persisting neurological impairments . The objective of this study was to evaluate the efficacy of subcutaneous electrical stimulation of the scalp in spontaneous functional recovery of patients with chronic ischemic stroke , by evaluating clinical , neurological , and functional findings . SUBJECTS AND METHODS Sixty-two ( 62 ) subjects who were at least 18 months postdiagnosis of ischemic stroke were r and omized to receive 10 sessions of placebo or active low-frequency electrical stimulation ( 2/100 Hz ) using subcutaneous acupuncture needles over the scalp . Functional and neurological evaluations were indexed by the Barthel , Rankin , and National Institutes of Health Stroke Scale ( NIHSS ) . RESULTS Results show that there was a significant difference in functional improvement between the sham and active group as indexed by NIHSS scale . The active group had a larger functional improvement after 10 sessions of scalp electrical acupuncture . The other two functional scales ( Rankin and Barthel ) failed to show significant differences between the two treatment groups . CONCLUSIONS These results support further testing of scalp electrical acupuncture for the treatment of stroke as well further mechanistic studies to underst and mechanisms associated with the observed improvement . Further studies need to consider longer follow-up assessment s to investigate potential functional changes associated with electrical acupuncture [19288897] OBJECTIVE To observe the effect of electroacupuncture ( EA ) on hippocampal apoptosis and learning-memory ability in vascular dementia ( VD ) mice so as to investigate its underlying mechanism in the treatment of VD patients . METHODS Kunming mice were r and omly divided into sham-operation ( sham , n = 13 ) , model ( n = 15 ) , EA ( n = 16 ) and Nimodipine ( intragastric gavage , 30 mg/kg for 15 days , n = 15 ) groups . VD model was duplicated by occlusion of bilateral carotid arteries and reperfusion . EA ( 2 - 80 Hz , 2 mA ) was applied to " Dazhui " ( GV 14 ) , " Baihui " ( GV 20 ) , " Geshu " ( BL 17 ) and " Zusanli " ( ST 36 ) for 10 min , once daily for 15 days . Step-down and step-up tests were performed to assess the animal 's memory and learning abilities separately ; and the terminal deoxynucleotidyl transferase-mediated dUTP-nick end-labeling ( TUNEL ) method was used to display the apoptotic cells of the hippocampus tissue . RESULTS In comparison with sham group , the animals ' reaction time upon electric shock stimulation , both step-up and step-down error times , and hippocampal apoptosis number in model , EA and Nimodipine groups increased significantly ( P<0.01 ) , while the reaction latency upon electric shock of model , EA and Nimodipine groups decreased significantly ( P<0.01 ) . Compared with model group , the reaction time , both step-up and step-down error times and hippocampal apoptosis number of both EA and Nimodipine groups decreased significantly ( P<0.05 , P<0.01 ) ; while the reaction latency of EA and Nimodipine groups increased considerably ( P<0.01 ) . Comparison between EA and Nimodipine groups showed that the reaction latency of EA group was obviously longer than that of the later group ( P<0.01 ) , and the step-down error times of EA group was markedly lower than that of Nimodipine group ( P<0.05 ) . No significant differences were found between these two groups in other indexes ( P>0.05 ) . CONCLUSION EA can ameliorate VD mice 's learning-memory ability , which may be closely related to its effect in reducing hippocampal apoptosis [24298765] OBJECTIVE To observe the efficacy on post-stroke mild cognitive impairment ( MCI ) treated with acupuncture at Jing-well points on the differentiated meridians and temple-three-needle therapy . METHODS Seventy-three of stroke patients were r and omized into an acupuncture group ( 37 cases ) and a conventional treatment group ( 36 cases ) . Twenty healthy aged people in physical examination were collected as a control group . In the acupuncture group , on the basis of the conventional treatment of internal medication , the acupuncture at Jing-well points on the differentiated meridians and temple-three-needle therapy were applied . In the conventional treatment group , no any therapy was used except the conventional treatment of internal medication . In the control group , no any intervention was adopted . Neuroscan Nuamps electroencephalogram recording analysis system was used to determine the event-related potentials P300 , and the amplitude and mini mental state examination ( MMSE ) score was observed before and after treatment in both groups . RESULTS After treatment , in the acupuncture group , P300 latent stage was shortened , and the amplitude and the score of MMSE were increased ( P < 0.05 , P < 0.01 ) . In the conventional treatment group , above indices were not changed obviously as compared with that before treatment ( all P > 0.05 ) . Compared with the conventional treatment group , the differences in P300 latent stage , amplitude and MMSE score were remarkable in the acupuncture group ( P < 0.05 , P < 0.01 ) . CONCLUSION The acupuncture at Jing-well points on the differentiated meridians and temple-three-needle therapy improves the cognitive function of the patients with MCI [17432642] OBJECTIVE To search for an effective method for improving locomotor ability of upper limbs and ability of daily life in the patient of cerebral infa rct ion . METHODS Five hundred and seventy-eight cases of stroke were r and omly divided into 4 groups : an improved acupoints and rehabilitation exercise group ( group A , n = 148 ) , a rehabilitation exercise group ( group B , n = 142 ) , a routine acupoints and rehabilitation exercise group ( group C , n = 144 ) , and a medication group ( group D , n = 144 ) . The locomotor ability of the upper limbs and ability of daily life were evaluated respectively by Fugl-Meyer ( FMA ) and Barthel ( BMI ) . RESULTS There were significant differences in FMA and BMI scores in all the groups after treatment as compared with those before treatment ( P < 0.05 ) ; after treatment , the effect in the group A was significantly superior to those in group B and C ( P < 0.05 ) , with no significant difference between the group C and the group B. CONCLUSION The improved acupoints combined with rehabilitation exercise can improve locomotor ability of the upper limbs and ability of daily life in the patient of cerebral infa rct ion [18652322] OBJECTIVE To observe therapeutic effect of acupuncture combined with rehabilitation therapy on poststroke shoulder-h and syndrome . METHODS One hundred and twenty cases of poststroke shoulder-h and syndrome were r and omly divided into an acupuncture-rehabilitation group , an acupuncture group and a rehabilitation group , 40 cases in each group . The acupuncture-rehabilitation group were treated with acupuncture at Jianyu ( LI 15 ) , Jianqian , Jianliao ( TE 14 ) , etc . in combination with motor therapy ( rehabilitation training ) , the acupuncture group with simple acupuncture therapy , and the rehabilitation group with simple motor therapy . Upper extremity motor function , pain , joint activity were used for assessment of therapeutic effects . RESULTS The total effective rate of 87.5 % in the acupuncture-rehabilitation group was significantly better than 67.5 % in the acupuncture group and 65.0 % in the rehabilitation group ( P<0.01 ) ; acupuncture combined with rehabilitation therapy could significantly improve upper limb motor function , pain and joint activity with very significant differences as compared with the acupuncture group and the rehabilitation group ( P<0.01 ) . CONCLUSION Acupuncture combined with rehabilitation therapy has a high cured rate and an obvious therapeutic effect on poststroke shoulder-h and syndrome [22875557] CONTEXT Stroke is a leading cause of death and disability worldwide , being the third leading cause of death in the United States and the second and third most common causes of death in Chinese cities and rural areas , respectively . Evaluation of different rehabilitative modalities appears necessary to optimize treatment . OBJECTIVES To compare acupuncture and physiotherapy for effectiveness and reliability in treating hemiplegic patients after stroke . DESIGN The research team design ed a multicentered , three-arm , r and omized controlled trial . Power calculations revealed a targeted sample size of 310 participants . SETTING The study took place at seven in-patient hospitals in China . PARTICIPANTS The research team screened a total of 310 patients . Of that number , 274 completed the study , 15 did not meet the inclusion /exclusion criteria , and 21 dropped out . Adverse events were rare ( less than 1 % ) , mild , and temporary . INTERVENTION The research team r and omly divided participants into three groups that all received conventional care as needed-including psychological counseling , st and ard nursing care , and daily medical evaluation plus ( 1 ) acupuncture , ( 2 ) physiotherapy , or ( 3 ) acupuncture plus physiotherapy . The participants received treatments once a day , 6 days a week for 4 weeks . OUTCOME MEASURES The research team evaluated all patients at baseline , after 2 weeks , and after 4 weeks using the Fugl-Meyer Assessment of Physical Performance ( FMA ) , a modified Barthel Index ( BI ) , and the Neurologic Defect Scale ( NDS ) . RESULTS No significant differences existed between the three groups at baseline . Compared to baseline , participants in all groups improved their FMA , BI , and NDS scores by the end of week 2 ( P≤.05 ) and further improved by the end of week 4 ( P≤.05 ) The study found no statistically significant differences in outcomes between the three groups after treatment ( P>.05 ) . CONCLUSION Acupuncture plus conventional care was similar in effectiveness to physiotherapy treatment plus conventional care for poststroke rehabilitation . The study found no synergistic effects for the combination of acupuncture and physiotherapy in addition to conventional care ; that combination of treatments was no more effective than either treatment by itself . The effectiveness and lack of adverse events associated with acupuncture in this study suggest that it may represent an additional treatment option for stroke patients [20050300] OBJECTIVE The objective of this study was to investigate the effect of electroacupuncture on cognitive function and health-related quality of life in patients who have had a stroke . DESIGN This clinical trial employed a prospect i ve , r and omized , single-blind design . SETTING S/LOCATION The study was conducted at the department of rehabilitation medicine , Tri-Service General Hospital , Taipei , Taiwan . SUBJECTS Thirty-eight ( 38 ) participants were recruited , but only 33 completed the study . Seventeen ( 17 ) stroke participants with cognitive impairment were assigned to the treatment group and 16 were assigned to the control group . INTERVENTIONS Electroacupuncture was applied to acupuncture points PC6 and HT7 for 20 minutes twice a week for 8 weeks in the treatment group , while participants in each group continued rehabilitation . OUTCOME MEASURES Cognitive assessment ( LOTCA-G ) and quality -of-life assessment ( SF-36 and SS-QOL ) were carried out in each group at baseline and at 8 weeks after treatment . RESULTS Significant improvement was detected in four subtests of LOTCA-G : orientation , perception , praxis , and attention ( p<0.05 ) between treatment and control groups . Significant improvement was also indicated in subscales of SF-36 ( RP , VT , SF , RE , MH , MCS ) and SS-QOL ( language ) ( p<0.05 ) . No correlation was noted between the variables of LOTCA-G and SF-36/SS-QOL except four matches : Memory ( LOTCA-G ) and Mental Component Summary ( SF-36 ) : r=0.492 ; Memory ( LOTCA-G ) and Personality ( SS-QOL ) : r=0.485 ; Praxis ( LOTCA-G ) and Language ( SS-QOL ) : r=0.616 ; Orientation ( LOTCA-G ) , and Language ( SS-QOL ) : r=0.534 . CONCLUSIONS The results of this study confirm a positive effect of electroacupuncture on cognition and quality of life in patients who had a stroke . Future research will be required to evaluate potential mechanisms and potential long-term benefits [21793387] OBJECTIVE To assess the therapeutic effect of Jin 's " Sanzhen " therapy combined with rehabilitation training on limb-motor function of stroke patients by using Fugl-Meyer scale . METHODS A total of 254 hemiplegic stroke out patients and in patients from 7 hospitals were r and omly divided into Jin 's " Sanzhen " ( JSZ ) group ( n = 83 ) , rehabilitation group ( n = 84 ) and combination group ( n = 87 ) . Acupuncture was applied to acupoints of Jin 's " Sanzhen " including Quchi ( LI 11 ) , Waiguan ( SJ 5 ) and Hegu ( LI 4 ) ; Futu ( ST 32 ) . Zusanli ( ST 36 ) and Sanyinjiao ( SP 6 ) ; etc . The acupuncture needles were retained for 30 min after " Deqi " . Rehabilitation training included passive joint movement , st and ing-sitting training , tapping-pressing stimulation , walking training , etc . The treatment was conducted once daily , 5 sessions a week and for 4 weeks . Fugl-Meyer scale composed of 100-point motor domain of the upper- and lower-extremity sections was used to assess the patients ' motor function . RESULTS On day 28 after the treatment , of the 83.84 and 87 hemiplegic stroke patients in the JSZ , rehabilitation and combination groups , 48 ( 57.8 % ) , 31 ( 36.9 % ) and 50 ( 57.5 % ) experienced marked improvement in their clinical symptoms and signs , 26 ( 31.3 % ) , 44 ( 52.4 % ) and 31(35.6 % ) had an improvement , and 9 ( 10.8 % ) , 9 ( 10.7 % ) and 6 ( 6.9 % ) failed in the treatment , with the total effective rates being 89.2 % , 89.3 % and 93.1 % , respectively . The neurological deficit score ( NDS ) of the combination group was significantly lower than that of the rehabilitation group ( P < 0.05 ) . The Fugl-Meyer assessment score ( FMAS ) for extremity motor function of the combination group was apparently higher than those of the JSZ and rehabilitation groups ( P < 0.05 ) . No significant differences were found between the JSZ and rehabilitation groups in both NDS and FMAS ( P > 0.05 ) . CONCLUSION Jin 's " Sanzhen " therapy combined with rehabilitation training can significantly improve the limb motor function of hemiplegic stroke patients , and has a good synergistic effect [23600965] OBJECTIVE To assess the value of acupuncture for promoting the recovery of patients with ischemic stroke and to determine whether the outcomes of combined physiotherapy and acupuncture are superior to those with physiotherapy alone . DESIGN Prospect i ve r and omized controlled trial . SETTING Department of Rehabilitation Medicine , Huashan Hospital , Fudan University , P. R. China . PARTICIPANTS 120 in patients and out patients ( 84 men and 36 women ) . INTERVENTIONS Acupuncture , physiotherapy , and physiotherapy combined with acupuncture . MAIN OUTCOME MEASURES Motor function in the limbs was measured with the Fugl-Meyer assessment ( FMA ) . The modified Barthel index ( MBI ) was used to rate activities of daily living . All evaluations were performed by assessors blinded to treatment group . RESULTS On the first day of therapy ( day 0 , baseline ) , FMA and MBI scores did not significantly differ among the treatment groups . Compared with baseline , on the 28th day of therapy the mean FMA scores of the physiotherapy , acupuncture , and combined treatment groups had increased by 65.6 % , 57.7 % , and 67.2 % , respectively ; on the 56th day , FMA scores had increased by 88.1 % , 64.5 % , and 88.6 % , respectively ( p<0.05 ) . The respective MBI scores in the three groups increased by 85.2 % , 60.4 % , and 63.4 % at day 28 and by 108.0 % , 71.2 % , and 86.2 % at day 56 , respectively ( p<0.05 ) . However , FMA scores did not significantly differ among the three treatment groups on the 28th day . By the 56th day , the FMA and MBI scores of the physiotherapy group were 46.1 % and 33.2 % greater , respectively , than those in the acupuncture group p<0.05 ) . No significant differences were seen between the combined treatment group and the other groups . In addition , the FMA subscores for the upper extremities did not reflect any significant improvement in any group on the 56th day . Although the FMA subscores for the upper and lower extremities and the MBI score in the combined treatment group were higher than those in the acupuncture group , the differences were not statistically significant . CONCLUSIONS Acupuncture is less effective for the outcome measures studied than is physiotherapy . Moreover , the therapeutic effect of combining acupuncture with physiotherapy was not superior to that of physiotherapy alone . A larger-scale clinical trial is necessary to confirm these findings [8232703] The effectiveness of acupuncture in acute stroke remains largely untested and unproved . A r and omized , controlled trial was carried out to study the feasibility of acupuncture in combination with conventional supportive treatment for acute stroke patients . A total of 30 patients , aged 46 - 74 , with the onset of symptoms within 36 h were enrolled into the study after appropriate screening . All patients gave informed consent . Basing on the same supportive treatment , patients were r and omly assigned to a treatment with or without acupuncture . The procedure and acupoint selection were discussed and decided through several meetings of a group of senior acupuncture doctors in Taiwan . Acupuncture was applied 3 times/week for 4 weeks . During the study period , there were no problems in conducting this trial in terms of patient availability and acceptance , and physician cooperation . A significantly better neurologic outcome was observed in the acupuncture group on day 28 and day 90 . The improvement in neurologic status was greatest in patients with a poor neurologic score at baseline . There were no important side effects except for one episode of dizziness related to acupuncture treatment . The data and results of this study will be used as a guideline for planning a full-scale clinical trial , e.g. sample size calculation , method of r and omization with stratification of prognostic factors , choosing acupuncture points and technique of acupuncture [8232927] After obtaining informed consent , we r and omized 78 patients with severe hemiparesis of the left or right side within 10 days of stroke onset : 40 to a control group receiving daily physiotherapy and occupational therapy , and 38 to a group that , in addition , we treated with sensory stimulation ( acupuncture ) twice a week for 10 weeks . The median age was 76 years for both groups . Motor function , balance , and ADL ( Barthel 's Index ) were assessed before the start of treatment and at 1 and 3 months after stroke onset ; ADL was also assessed after 12 months . We assessed the quality of life ( QL ) using the Nottingham Health Profile 3 , 6 , and 12 months after stroke onset . Patients given sensory stimulation recovered faster and to a larger extent than the controls , with a significant difference for balance , mobility , ADL , QL , and days spent at hospitals/nursing homes . Whether acupuncture per se is responsible for the differences requires further study [16642607] OBJECTIVE To probe the best therapy for the patient after operation of hypertensive cerebral hemorrhage . METHODS One hundred cases were r and omly divided into a treatment group and a control group , 50 cases in each group . The control group were treated by routine western medicine ( Mannitol , Nifedipine and Caftriaxone sodium and so On ) , and the treatment group by the medication of the control group plus acupuncture 9 days after operation . Acupuncture was given at Neiguan ( PC 6 ) , Shuigou ( GV 26 ) , Sanyinjiso ( SP 6 ) , Jiquan ( HT 1 ) and Weizhong ( BL 40 ) and so on , combined with scalp acupuncture , with " restoring consciousness and inducing consciousness " needling method , for 10 days . The nervous function defect was assessed by Chinese Stroke Scale and the criteria for assessment of therapeutic effects . RESULTS Acupuncture could improve significantly nervous function defect . The total effective rate was 86.000 in the treatment group and 14.0 % in the control group with a significant difference between the two groups ( P < 0.01 ) . CONCLUSION The therapeutic effect of the treatment group is better than that of the control group . Acupuncture combined with western medicine has cooperation for treatment of hypertensive intracerebral hemorrhage with a better therapeutic effect [17526181] OBJECTIVE To observe the effect of scalp-acupuncture drawing method ( SADM ) on recovering motor function in hemiplegic patients following cerebral thrombosis at convalescent period . METHODS Adopting r and omized , single-blinded , controlled method , 93 patients suffering from hemiplegia following cerebral thrombosis were r and omly assigned to 3 groups , 31 in each group . All patients were treated based on neurological routine therapy , those in the treated group and the control group I were treated respectively with SADM and scalp-acupuncture twirling method ( SATM ) additionally , but for those in the control group II , no additional treatment was given . The treatment course for all was 4 weeks . RESULTS Before treatment , there were insignificant difference among 3 groups in the score of neural motor function deficits ( NFDS ) of limbs and activity of daily life ( ADL ) score ( P > 0.05 ) . After being treated for 4 weeks , the NFDS was significantly lower and in the control group II ( P < 0.01 , P < 0.05 ) and the change of the scores in the treated group was more than that in the control group I ( P < 0.05 ) . CONCLUSION SADM was superior to scalp-acupuncture twisting prove the ADL score and motor function of hemiplegia patients following cerebral thrombosis in the convalescent stage [25675557] OBJECTIVE To observe the impact on lower limbs balance function in treatment of yin-yang meridians acupuncture with respiratory reinforcing and reducing manipulation involved in the patients of stroke by applying B-PHY balance function test training system so as to provide the objective evidence in treatment of stroke ; with acupuncture . METHODS One hundred patients were r and omized into an observation group and a control group , 50 cases in each one . In the control group , the basic treatment was applied , without other relevant rehabilitation therapies associated . In the observation group , with the basic treatment as the control group 's , the therapy of the yin-yang meridians acupuncutre with respiratory reinforcing and reducing manipulation was adopted . On the yin meridians , Zuwuli ( LR 10 ) , Xuehai ( SP 10 ) , Yinlingquan ( SP 9 ) , Sanyinjiao ( SP 6 ) and the others were selected and stimulated with reducing manipulation achieved by the coordination of patient 's respiration . On the yang meridians , Biguan ( ST 31 ) , Liangqiu ( ST 34 ) , Yanglingquan ( GB 34 ) and the others were selected and stimulated with reinforcing manipulation achieved by the coordination of patient 's respiration . The treatment was given once a day and for 28 days totally . Before treatment and in 28 days of treatment , B-PHY balance function test training system was used to determine the weight shift track parameters ( track length , peripheral square , track length of per unit square , left-right offset and rectangle square ) , the weight shift track distance parameters [ mean of X axle weight shift distance ( Mean-X ) , mean of Y axle weight shift distance ( Mean-Y ) , maximum of X axle weight shift distance ( Max-X ) , maximum of Y axle weight shift distance ( Max-Y ) , weight shift distance ( LSKG ) , weight shift square ( SSKG ) , square ratio of weight shift ( LFS ) ] , stability coefficient ( SI ) and weight distribution coefficient ( WDI ) . RESULTS After treatment , the differences in the weight shift track parameters , SI and WDI were significant as compared with those before treatment in the patients of the two groups ( all P<0.01 ) ; while the differences in the weight shift distance parameters in the observation group were improved obviously after treatment as compared with those before treatment ( all P<0.01 ) , the differences of Mean-X , Max-Y and LFS in the control group were improved after treatment as compared with those before treatment ( all P<0.01 ) . Except SSKG , the improvements after treatment in the rest indices in the observation group were better than those in the control group ( all P<0.05 ) . CONCLUSION The yin-yang meridians acupuncture with respiratry reinforcing and re- ducing manipulation effectively improves the lower limbs balance function in the patients of stroke [23967632] OBJECTIVE To evaluate the efficacy and safety of acupuncture and moxibustion in the treatment of post-stroke depression ( PSD ) by regulating the liver and strengthening the root prescription . METHODS In light of the r and om controlled trial principle , 123 cases were r and omized into an acupuncture-moxibustion group ( 42 cases ) , a medication group ( 40 cases ) and an acupuncture + medication group ( 41 cases ) . In the acupuncture-moxibustion group , the therapy of regulating the liver and strengthening the root was applied . Acupuncture was given at Hegu ( LI 4 ) , Taichong ( LR 3 ) , Baihui ( GV 20 , Yintang ( GV 29 ) , etc . The granule moxibustion was applied at Zhongwan ( CV 12 ) , Xiawan ( CV 10 ) , Guanyuan ( CV 4 ) and Qihai ( CV 6 ) . The treatment was given once a day and stopped in weekend . In the medication group , paroxetine hydrochloride tablets were prescribed for oral administration , 20 mg each day after breakfast . In the acupuncture + medication group , the therapies were adopted as the acupuncture-moxibustion group and the medication group . In the 2nd and 4th week of treatment , HAMD was used as the primary index and Barthel index as the secondary one for the efficacy assessment in the three groups respectively . The spleen and stomach syndrome scale of TCM was used for the assessment of TCM syndrome efficacy . Treatment emergent symptom scale ( TESS ) was applied for the safety assessment . RESULTS In the 4th week of treatment , the markedly effective rates were 69.0 % ( 29/42 ) , 65.0 % ( 26/40 ) and 70.7 % ( 29/41 ) in the acupuncture-moxibustion group , the medication group and the acupuncture + medication group respectively . The efficacies of anti-depression were similar in comparison among groups ( P > 0.05 ) . In the 2nd week of treatment , the improvement of HAMD score was significant in the acupuncture + medication group as compared with that before treatment and in comparison with the medication group ( P < 0.05 , P < 0.01 ) . As for improving Barthel index , reducing the spleen and stomach symptom score of TCM and decreasing the score of TESS , the results in the acupuncture-moxibustion group and the acupuncture + medication group were superior to those in the medication group ( P < 0.05 , P < 0.01 ) . CONCLUSION The therapy of acupuncture and moxibustion with regulating the liver and strengthening the root achieves the definite efficacy of anti-depression and presents the quite high safety in treatment [21739683] OBJECTIVE To assess the clinical efficacy on post-stroke speech disorder treated with acupuncture and psychological intervention combined with rehabilitation training . METHODS The multi- central r and omized controlled study was adopted . One hundred and twenty cases of brain stroke were divided into a speech rehabilitation group ( control group ) , a speech rehabilitation plus acupuncture group ( observation group 1 ) and a speech rehabilitation plus acupuncture combined with psychotherapy group ( observation group 2 ) , 40 cases in each one . The rehabilitation training was conducted by a professional speech trainer . In acupuncture treatment , speech function area in scalp acupuncture , Jinjin ( EX-HN 12 ) and Yuye ( EX-HN 13 ) in tongue acupuncture and Lianquan ( CV 23 ) were the basic points . The supplementary points were selected according to syndrome differentiation . Bloodletting method was used in combination with acupuncture . Psychotherapy was applied by the physician in psychiatric department of the hospital . The corresponding programs were used in each group . Examination of Aphasia of Chinese of Beijing Hospital was adopted to observe the oral speech expression , listening comprehension and reading and writing ability . RESULTS After 21-day treatment , the total effective rate was 92.5 % ( 37/40 ) in observation group 1 , 97.5 % ( 39/40 ) in observation group 2 and 87.5 % ( 35/40 ) in control group . The efficacies were similar in comparison among 3 groups . The remarkable effective rate was 15.0 % ( 6/40 ) in observation group 1 , 50.0 % ( 20/40 ) in observation group 2 and 2.5 % ( 1/40 ) in control group . The result in observation group 2 was superior to the other two groups ( P<0.01 , P<0.001 ) . In comparison of the improvements of oral expression , listening comprehension , reading and writing ability , all of the 3 groups had achieved the improvements to different extents after treatment ( P<0.01 , P<0.001 ) . The results in observation group 2 were better than those in observation group 1 and control group . CONCLUSION Acupuncture and psychological intervention combined with rehabilitation training is obviously advantageous in the treatment of post-stroke speech disorder [21823415] OBJECTIVE To study the effect on the motor function of stroke patients by combination of needling at Back-shu point and trunk exercise . METHODS Ninety stroke hemiplegic patients were r and omly assigned to the conventional treatment group ( as the convention group ) , the Back-shu point needling group , and the combination of Back-shu point needling and the trunk exercise group , 30 patients in each group . They were treated with the conventional treatment , needling at Back-shu point , and the combination of needling at Back-shu point and trunk exercise . The Fugl-Meyer score ( FMA ) and modified Barthel index ( MBI ) score were assessed before treatment and two months after treatment . RESULTS The three rehabilitation treatment methods were all effective in improving the motor function of stroke hemiplegic patients ( P<0.05 ) . The effects in the Back-shu point needling group and the combination of Back-shu point needling and the trunk exercise group were respectively superior to that in the conventional treatment group ( P<0.05 ) . The effect in the combination of Back-shu point needling and the trunk exercise group was superior to that in the Back-shu point needling group ( P<0.05 ) . CONCLUSION The combination of Back-shu point needling and the trunk exercise could improve the motor function of stroke hemiplegic patients , and its effect was better than needling at Back-shu point alone [7750174] One hundred and eight cases of sequelae of cerebro-vascular accident were r and omly divided into two groups temporal point group ( TG , 58 cases ) and body acupuncture group ( BG , 50 cases ) . It was shown that after 30 treatments the therapeutic effects were significantly different statistically ( P < 0.01 ) between the two groups . The effect in TG was better than that in BG . It indicates that the two acupuncture therapies can improve blood rheology in patients . The ameliorative function in TG was better than that in BG [2844940] The CONSORT statement is used worldwide to improve the reporting of r and omised controlled trials . Kenneth Schulz and colleagues describe the latest version , CONSORT 2010 , which up date s the reporting guideline based on new method ological evidence and accumulating [18767580] OBJECTIVE To search for the best way to elevate the clinical therapeutic effect in the hemiplegic patient of cerebral thrombosis at convalescent period . METHODS Adopting single-blind , r and omized controlled method , 90 cases of cerebral thrombosis at convalescent period were assigned to 3 groups : a scalp acupuncture group ( group A ) , a rehabilitation therapy group ( group B ) and a scalp acupuncture combined with rehabilitation therapy group ( group C ) . Group A were treated with scalp acupuncture at the anterior oblique line of vertex-temporal and the posterior oblique line of vertex-temporal on the healthy side ; group B were treated with modern rehabilitation medical therapy , making limb function treatment ; group C were treated with the scalp acupuncture in the group A combined with the rehabilitation therapy in the group B. Improvement of neural function defect and activity of daily life ( ADL ) , and clinical therapeutic effect were observed . RESULTS After treatment , the scores of neural function defect of 6.14 + /- 0.36 in the group C was significantly lower than 8.94 + /- 0.56 in the group A and 8.64 + /- 0.49 in the group B ( P<0.05 ) ; the score of ADL of 88.39 + /- 10.02 and clinical therapeutic effect of 90.0 % in the group C were significantly higher than 74.19 + /- 12.12 and 76.7 % in the group A and 72.29 + /- 11.52 and 73.3 % in the group B ( P<0.05 ) . CONCLUSION The scalp acupuncture and rehabilitation therapy have synergistic action in improving motor function for the hemiplegic patient of cerebral thrombosis at convalescent period , and it is a better method for cerebral thrombosis at the convalescent stage [16344019] OBJECTIVE To compare the effects of traditional Chinese acupuncture with sham acupuncture on upper-extremity ( UE ) function and quality of life ( QOL ) in patients with chronic hemiparesis from stroke . DESIGN A prospect i ve , sham-controlled , r and omized controlled trial ( RCT ) . SETTING Patients recruited through a hospital stroke rehabilitation program . PARTICIPANTS Thirty-three subjects who incurred a stroke 0.8 to 24 years previously and had moderate to severe UE functional impairment . INTERVENTIONS Active acupuncture tailored to traditional Chinese medicine diagnoses , including electroacupuncture , or sham acupuncture . Up to 20 treatment sessions ( mean , 16.9 ) over a mean of 10.5 weeks . MAIN OUTCOME MEASURES UE motor function , spasticity , grip strength , range of motion ( ROM ) , activities of daily living , QOL , and mood . All outcomes were measured at baseline and after treatment . RESULTS Intention-to-treat ( ITT ) analyses found no statistically significant differences in outcomes between active and sham acupuncture groups . Analyses of protocol -compliant subjects revealed significant improvement in wrist spasticity ( P<.01 ) and both wrist ( P<.01 ) and shoulder ( P<.01 ) ROM in the active acupuncture group , and improvement trends in UE motor function ( P=.09 ) and digit ROM ( P=.06 ) . CONCLUSIONS Based on ITT analyses , we conclude that acupuncture does not improve UE function or QOL in patients with chronic stroke symptoms . However , gains in UE function observed in protocol -compliant subjects suggest traditional Chinese acupuncture may help patients with chronic stroke symptoms . These results must be interpreted cautiously because of small sample sizes and multiple , unadjusted , post hoc comparisons . A larger , more definitive RCT using a similar design is feasible and warranted [17378195] OBJECTIVE To observe effect of acupuncture combined witb byperbaric oxygenation on balance function of cerebral infa rct ion . METHODS Seventy-two cases were r and omly divided into a treatment group and a control group , 36 cases in each group . The control group were treated with routine medicine and hyperbaric oxygenation , and the treatment group with acupuncture on the basis of treatment method of the control group . Berg balance scale ( BBS ) was used for investigating changes of balance function before and after treatment in the patient of cerebral infa rct ion . RESULTS After treatment , the balance function improved in the two groups , with more significant improvement in the treatment group . And increase of motor function in the treatment group was more rapid than that in the control group ( P < O. 01 ) . CONCLUSION Acupuncture combined with hyperbaric oxygenation can overall and synchronously rehabilitate sense and motor functions , significantly improve balance disturbance in the patient of cerebral infa rct ion , with unique therapeutic effect on dysopia and dysacusis for the patient of cerebral infa rct ion at the early stage [18447213] OBJECTIVE To observe therapeutic effect of Tiaoshen Fuyin acupuncture therapy on cerebral infa rct ion-induced Broca aphasia . METHODS Sixty cases were r and omly divided into an observation group and a control group , 30 cases in each group . The observation group were treated with Tiaoshen Fuyin acupuncture therapy and language training , and the control group with simple language training . For the acupuncture treatment , Sishencong ( EX-HN 1 ) , Benshen ( GB 13 ) , Shenting ( GV 24 ) , Lianquan ( CV 23 ) , Xinshu ( BL 15 ) , Shentang ( BL 44 ) , Shendao ( GV 11 ) , Lingtao ( HT 4 ) were selected and language training included training of phonatory organs in mouth , the mouth shape , sound , spoken language expression and practical exchange ability . They were treated for 5 therapeutic courses . Language examination was conducted once each before and after treatment with " Aphasia Battery of Chinese " ( ABC method ) . RESULTS The therapeutic effect of Tiaoshen Fuyin acupuncture therapy combined with language training was better than that of simple language training . CONCLUSION Tiaoshen Fuyin acupuncture therapy combined with language training can significantly improve language function and increase life quality in the patient of cerebral infa rct ion-induced Broca aphasia [19803232] OBJECTIVE To provide reliable evidence of " J in three-needle therapy " for treatment of stroke . METHODS Multi- central r and omized controlled trials were adopted , 180 hemiplegia patients of ischemic stroke were r and omly divided into a fin three-needle group ( 90 cases ) and a routine acupuncture group ( 90 cases ) . Two groups were both treated with basic neurology therapies , and J in three-needle group was treated with J in three-needle therapy , three acupoints of tempora , h and and foot etc . were selected ; the routine acupuncture group was treated with traditional acupuncture , Quchi ( LI 11 ) , Huantiao ( GB 30 ) , Futu ( ST 32 ) etc . were selected . Both groups were treated with acupuncture for 5 weeks . The cognitive function score of functional comprehensive assessment scale ( FCA ) , the scores of mini-mental state examination scale ( MMSE ) and modified Barthel index ( BI ) were compared before and after treatment between two groups . Results After treatment , the scores of FCA , MMSE and BI in both groups were significantly improved compared to those before treatment ( P < 0.01 , P < 0.05 ) ; the improvement of FCA score , MMSE score and BI score in the J in three-needle group were superior to those of the routine acupuncture group after treatment ( P < 0.01 , P < 0.05 ) . The total effective rate of 85.4 % in the J in three-needle group was superior to tohat of 70.0 % in the routine acupuncture group ( P < 0.05 ) . CONCLUSION J in three-needle acupuncture treatment can obviously improve the cognitive function and activity ability of daily life of hemiplegia patients after stroke , and the therapeutic effect of J in three-needle therapy is superior to that of traditional acupuncture treatment [17691578] OBJECTIVE To observe the therapeutic effect of cluster-needle stimulation of scalp-points combined with rehabilitation training for apoplectic aphemia . METHODS A total of 56 out patients were r and omized into control ( medication , manicol/ beronald , Ca2 + antagonist , citicoline , etc . ) group . rehabilitation ( Rehab , visual-listening , articulation and speech training ) group and acupuncture [ Dingqu : 1 cun and 2 cun parallel to the line joining Baihui ( GV 20 ) and Qi and ing ( GV 21 ) respectively on the bilateral sides . Dingqianqu : 1 cun and 2 cun parallel to the line joining GV21 and Xinghui ( GV 22 ) separately on both sides . etc ] combined with rehabilitation ( Acup+ Rehab ) group . Aphasia Battery of Chinese ( ABC ) was used to assess the patient 's speech ability , i.e. , aphasia quocient ( AQ ) ; The Chinese functional communication ( CFCP ) test was used to evaluate the patient 's daily life speech communication ability , and Boston Diagnostic Aphasia Examination ( BDAE ) was also conducted to assess the severity of aphasia . RESULTS After the treatment , the speech ability , oral presentation , listening comprehension , writing ability , AQ index and CFCP were all improved significantly in 3 groups ( P < 0.005 , 0.01 ) ; the total effective rate ( 85.00 % ) of Acup+ Rehab group was significantly higher than those of Rehab group ( 77.78 % ) and control group ( 64.71 % , P < 0.05 , 0.01 ) . The scores of ABC , AQ index , CFCP and BDAE grade in Acup+ Rehab group were significantly higher than those of Rehab and control groups ( P < 0.05 , 0.01 ) , and those scores of Rehab group were also significantly higher than those of control group ( P < 0.05 , 0.01 ) . CONCLUSION The cluster-needle puncture of scalp-points combined with rehabilitation training is an effective therapy for improving apoplectic aphemia [9388311] VIP , SS and PP which exist in gastrointestinal tract and CNS might be to play an important role in nervous system as neurotransmitters of neuromediaters . There have been a few of reports about their changes in plasma and CSF in ICVD . The effects of acupuncture , which was used in treatment of ICVD with good efficiency , on VIP , SS and PP have not been known . For research ing their changes in ICVD and effects of electro-acupuncture on them , and finding the mechanism of acupuncture in treatment of ICVD , the study was performed . The levels of VIP , SS and PP in 64 patients with acute cerebral infa rct ion were determined . The points of acupuncture were Quchi ( LI 12 ) , Waiguan ( SJ 5 ) , Huantiao ( BG 30 ) , and Zusanli ( ST 36 ) . The routine treatment included dextran , nicotinic acid , aspirin , dipyridamole and radix salviae miltiorrhizae composita . The CSF and blood were taken before the begining of treatments and after a course of treatment . The level of VIP , SS and PP were measured by radiommunoassay . Results showed the level of CSF VIP in the patients was significantly lower as compared with controls . The level of plasma SS in the patients was lower , but the difference was not significant as compared with controls , and level of plasma PP in the patients was significantly increased when it was compared with controls . After electro-acupuncture treatment , in patients with good efficiency , CSF VIP recovered to normal level and the levels of plasma and CSF SS were significantly increased , while the level of plasma PP had no significant change . The results suggest that acupuncture might regulate the disturbances of metabolism of VIP and SS in CNS [20578378] OBJECTIVE To provide biomechanics basis for acupuncture improving motor function of stroke patients . METHODS With r and omized controlled trial method , 21 cases were r and omly divided into a control group ( n = 10 ) and an acupuncture group ( n = 10 ) . The control group was only treated with basic neurology therapies , and acupuncture at Shenshu ( BL 23 ) , Qihaishu ( BL 24 ) , Dachangshu ( BL 25 ) and Pishu ( BL 20 ) etc . were added in the acu-puncture group . After treatment for 2 weeks , the scores of Fugl-Meyer ( lower limb part ) and Barthel Index assessment before and after treatment were compared , and the changes of the single-foot supporting phase rate were observed . RESULTS After treatment , the scores of Fugl-Meyer ( lower limb part ) and Barthel Index assessment had no significant difference in the two groups as compared with those before treatment ( P > 0.05 ) , and the single-foot supporting phase rate in acupuncture group had very significant improvement as compared with both those before treatment and those in the control group ( P < 0.05 and P < 0.01 , respectively ) . CONCLUSION Acupuncture can increase the single-foot supporting phase rate of stroke patients and the biomechanics assessment is more sensitive than the rehabilitation scale assessment [9360031] Objective : We recently reported that acupuncture treatment of stroke patients in the subacute stage gave additive therapeutic benefit . The purpose of the present study was to determine , approximately one year after discharge from the rehabilitation hospital , whether the group differences still remained . Design : The patients were r and omized into two groups : one acupuncture group and one control group , considering gender and side of hemispheral localization of lesion . With regard to the main parameters the groups were comparable at baseline . Setting : Initially , 45 stroke patients admitted to Sunnaas Rehabilitation Hospital were included in the study : median 40 days post stroke . Subjects : Forty-one of the patients were available one year after the treatment period : 21 patients in the acupuncture group and 20 controls . Intervention : All subjects received an individually adapted , multidisciplinary rehabilitation programme . The acupuncture group received additional treatment with classical acupuncture for 30 min three to four times weekly for six weeks . Main outcome measures : The patients were evaluated at inclusion , after six weeks and approximately 12 months after discharge from the rehabilitation hospital . The Motor Assessment Scale ( MAS ) for stroke patients , Sunnaas Index of Activity of Daily Living ( ADL ) and Nottingham Health Profile ( NHP ) were used . In addition , the social situations of the patients were recorded at one year follow-up . Results : The results show that the acupuncture group improved significantly more than the controls , both during the treatment period of six weeks , and even more during the following year , both according to MAS , ADL , NHP and the social situation . Conclusion : Although the mechanism of the effects is debatable , there seems to be a positive long-term effect of acupuncture given in the subacute stage post stroke

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### Context: [15083445] OBJECTIVE To determine whether needle acupuncture may be useful in the reduction of leg spasticity in a chronic state . DESIGN Single-blind , r and omized , placebo-controlled trial . SETTING Neurologic outpatient department of a medical school in Germany . PARTICIPANTS Twenty-five patients ( 14 women ) suffering from chronic poststroke leg spasticity with pes equinovarus deformity ( Modified Ashworth Scale [ MAS ] score , > /=1 ) , aged 38 to 77 years ( mean + /- st and ard deviation , 58.5+/-10.4 y ) , were enrolled in the study . The mean time from stroke to inclusion in the study was approximately 5 years ( mean , 65.4+/-48.3 mo ; range , 7 - 180 mo ) . INTERVENTIONS Participants were r and omly assigned to placebo treatment ( n=12 ) by using a specially design ed placebo needling procedure , or verum treatment ( n=13 ) . MAIN OUTCOME MEASURES MAS score of the affected ankle , pain ( visual analog scale ) , and walking speed . RESULTS There was no demonstrated beneficial clinical effects from verum acupuncture . After 4 weeks of treatment , mean MAS score was 3.3+/-0.9 in the placebo group versus 3.3+/-1.1 in the verum group . The neurophysiologic measure of H-reflex indicated a significant increase of spinal motoneuron excitability after verum acupuncture ( H-response/M-response ratio : placebo,.39+/-.19 ; verum,.68+/-.41 ; P<.05 ) . CONCLUSIONS This effect might be explained by afferent input of A delta and C fibers to the spinal motoneuron . The results from our study indicate that needle acupuncture may not be helpful to patients with chronic poststroke spasticity . However , there was neurophysiologic evidence for specific acupuncture effects on a spinal ( segmental ) level involving nociceptive reflex mechanisms [3697148] An effective and safe remedy for shoulder pain is needed as shoulder pain is a common complication of stroke and restricts recovery of patients . This study was carried out to evaluate the effect of Ouhyul herbal acupuncture point injection ( O-API ) on shoulder pain in patients with stroke . Twenty-four participants with shoulder pain after stroke were recruited and r and omized to the O-API and control groups . Treatment was conducted for 2 weeks three times per week . We evaluated the effects of treatment with a numerical rating scale ( NRS ) , painless passive range of motion ( PROM ) of external shoulder rotation , and the Fugl-Meyer Motor Assessment ( FMMA ) at baseline , each week , and 1 week after the final treatment . All measures were similar between the O-API and control groups at baseline . The O-API group showed significant improvement on the NRS compared with that in the control group after 2 weeks of treatment , and the treatment effect was maintained until the follow-up period . PROM decreased significantly in both groups , but the reduction was maintained only in the O-API group . No significant difference was observed on the FMMA between the two groups . O-API result ed in significant improvement in shoulder pain after stroke , and its effect was maintained after termination of treatment without any severe side effects [20353105] OBJECTIVE To evaluate the therapeutic effect of comprehensive therapeutic protocol of electroacupuncture combined with active-blood- and -dissolve-stasis herbs and rehabilitation training for cerebral infa rct ion . METHODS A multi-center r and omized controlled trial was done , three hundred and twenty cases were divided into four groups : electroacupuncture combined with active-blood and dissolve-stasis herbs and rehabilitation training group ( group A ) , electroacupuncture combined with rehabilitation training group ( group B ) , herbs combined with rehabilitation training group ( group C ) and rehabilitation training group ( group D ) , 80 cases in each group . The following two groups of acupoints were used alternatively in electroacupuncture treatment : the first group including Vasomotor Area , Jianyu ( LI 15 ) , Biguan ( ST 31 ) , Hegu ( LI 4 ) and Taichong ( LR 3 ) ; the second group including Motor Area , Quchi ( LI 11 ) , Yanglingquan ( GB 34 ) and Shenshu ( BL 23 ) . 20 mL Xiangdan injection and 250 mL 5 % glucose injection or 250 mL 0.9 % sodium chloride injection were used by intravenous drip in herbs treatment once a day . The rehabilitation training was performed by the professional physical therapist . Each group was treated with corresponding treatment protocol . The therapeutic effect was evaluated by index of the mortality or disability rate 3 months after the onset of disease . The intention to treat analysis ( ITT ) was used in data . RESULTS The mortality or h and icap rate 3 months after the onset of disease of four groups were 17.5 % ( 14/80 ) in group A , 22.5 % ( 18/80 ) in group B , 40 . 0 % ( 32/80 ) in group C , and 31.3 % ( 25/80 ) in group D , respectively . The group A has a best therapeutic effect ( vs group C , group D , both P<0.05 ) , and there was no adverse event . CONCLUSION The combined application of electroacupuncture , active-blood and dissolve-stasis herbs and rehabilitation training is a better treatment for cerebral infa rct ion in clinic [8202976] Background and Purpose In a r and omized study of hemiparetic stroke patients with a median age of 75 years , functional recovery was significantly better in those who received additional sensory stimulation ( n=38 ) , including electrostimulation , than in control patients ( n=40 ) given the same physiotherapy and occupational therapy ; group differences for balance , mobility , and activities of daily living were significant . The present study was design ed to investigate postural control in patients who survived more than 2 years after stroke onset . Methods The 48 survivors ( mean , 2.7 years ; range , 2.0 to 3.8 years ) , 22 from the treatment group and 26 from the control group , were compared with 23 age-matched healthy subjects . Subjects were perturbed by vibrators applied to calf muscles or with galvanic vestibular stimulation . We evaluated postural control in terms of sway variances or sway velocities and the dynamics of postural control as a feedback system using system identification with a model previously vali date d for human postural control . Results Significantly more patients of the treatment group than of the control group maintained stance during perturbations ( P<.01 ) . Among patients capable of maintaining stance during perturbation , the control patients were characterized by significant divergence from normal values in two of the three characteristic parameters of dynamic postural control ( ie , swiftness and stiffness ; P<.05 ) compared with the treatment subgroup or age-matched subjects . Conclusions The course of sensory stimulation enhanced recovery of postural function , an enhancement still significant 2 years after the lesion and treatment . The differences and near normalization of characteristic parameters of dynamic postural control among treated patients suggest that improved recovery after sensory stimulation may be achieved by patients regaining normal or near normal dynamics of human postural control [18671899] Abstract Objective : To observe the effect of electro-acupuncture ( EA ) on dendritic spine and ephrin-A5 and to investigate the action of EA on neural plasticity after acute cerebral ischemic infa rct ion . Methods : Focal acute cerebral ischemia model was established by middle cerebral artery occlusion ( MCAO ) with electrocoagulation contralateral method . Ninety male Sprague – Dawley rats were r and omly divided into sham operation ( SO ) group , MCAO group and EA treatment ( ET ) group . Golgi dying , double immunofluorescence method and RT-PCR were used to detect dendritic spine density , expression patterns of ephrin-A5 and the effect of EA on them at the end of the first , second and fourth week after ischemia . Results : The dendritic spine density in MCAO group significantly decreased after ischemia ( p<0.01 ) . The dendritic spine density was raised in ET group in the corresponding time period ( p<0.01 ) and among the ET groups . It was higher at the end of the fourth week than before ( p<0.05 ) . The signal of ephrin-A5 was detected mainly in neuron cytoplasm , and the mRNA expression in MCAO group and ET group increased compared to that in SO group ( p<0.01 ) . The mRNA expression in ET group at the first week was much higher than that in MCAO group ( p<0.01 ) . In ET groups , the mRNA expression of ephrin-A5 was down-regulated along with the time going ( p<0.01 ) . Conclusion : It is possibly the regulation of the ephrin-A5 expression by which EA treatment improves the neural plasticity at the peri-infa rct cerebral cortex in acute cerebral ischemia rat . There may be a time window in EA treatment for acute cerebral ischemia [11498896] 63 patients with senile vascular dementia were r and omly divided into the treatment group ( treated by acupuncture ) and the control group ( treated with piracetam ) . The authors observed the changes in the score of Hasegawa 's dementia scale ( HDS ) , p300 , rheoencephalogram , topographic EEG , superoxide dismutase ( SOD ) activity in erythrocytes , and lipid peroxide ( LPO ) level in plasma before and after treatment . The statistical data showed that the total effective rate in the treatment group ( 80.6 % ) was significantly higher than that in the control group ( 25 % ) , and the differences in the observed indexes before and after treatment were significant ( P < 0.05 or P < 0.01 ) in the treatment group but not in the control group ( P > 0.05 ) , indicating that the acupuncture treatment was superior in immediate therapeutic effect on senile vascular dementia to drug treatment [11477855] OBJECTIVE To observe the clinical effect of electroacupuncture and acupuncture on vascular dementia ( VaD ) and the influence on superoxide dismutase ( SOD ) , lipid peroxide ( LPO ) and nitric oxide ( NO ) levels . METHODS Forty-six cases of VaD were r and omly divided into two groups , the electroacupuncture group ( EA group ) and the acupuncture group ( AP group ) . Assessment of Hasgawa 's dementia scale ( HDS ) , functional activities question naire ( FAQ ) and neurologic deficit scoring were done before and after treatment , and the changes on SOD , LPO and NO levels were observed . RESULTS After treatment , in the EA group , the HDS elevated , the FAQ lowered , SOD increased and LPO and NO decreased significantly , as compared with before treatment , P < 0.01 . But these parameters were not changed significantly in the AP group after treatment . The clinical symptoms were improved in both groups , but the reduction on neurologic deficit score was not significant . The total effective rate of the EA group was higher than that of the AP group . CONCLUSION The immediate effect of electroacupuncture was superior to that of acupuncture , suggesting that the electroacupuncture was more effective in promoting the intelligence recovery than acupuncture [19938212] This study is a double-blind r and omized controlled trial on the effect of intradermal acupuncture on insomnia after stroke . Hospitalized stroke patients with insomnia were enrolled in the study and were r and omly assigned to either a real intradermal acupuncture group ( RA group ) or a sham acupuncture group ( SA group ) . The RA group received intradermal acupuncture on Shen-Men ( He-7 ) and Nei-Kuan ( EH-6 ) for three days , and the SA group received sham acupuncture on the same points . The effect of acupuncture on insomnia was measured using Insomnia Severity Index ( ISI ) and Athens Insomnia Scale ( AIS ) at baseline and three days after treatment . To assess the effect of acupuncture on the autonomic nervous function , the subjects ' blood pressure and heart rate variability were monitored . Fifty-two subjects ( 27 in the RA group and 25 in the SA group ) were included in the final analysis . The insomnia-related scales ISI and AIS showed greater improvement of insomnia in the RA group than in the SA group . Moreover , there is a greater reduction of the number of non-dippers and a greater decrease of the LF/HF ratio ( heart rate variability ) in the RA group than in the SA group . These results indicate that sympathetic hyperactivities were stabilized in the RA group . It can thus be concluded that intradermal acupuncture on Shen-Men and Nei-Kuan is a useful therapeutic method for post stroke-onset insomnia as it reduces sympathetic hyperactivities [17585663] OBJECTIVE To observe clinical therapeutic effect of head point-through-point electroacupuncture ( EA ) on poststroke depression ( PSD ) and to study the mechanism . METHODS One hundred and eight cases of PSD were r and omly divided into a point-through-point EA group ( n = 38 ) , a non point-through-point group ( n = 36 ) and a western medicine group ( n = 34 ) . After treatment of 28 days , their therapeutic effects , scores of HAMD depression scale and SDS self-rating scale , and plasma 5-HT contents were compared before and after treatment among the 3 groups . RESULTS The effective rate of 86.84 % in the point-through-point EA group was better than 63.89 % in the non point-through-point group and 67.65 % in the western medicine group ( P < 0.05 or P < 0.01 ) . Plasma 5-HT content in the point-through-point EA group increased significantly , with a very significant difference as compared with that of the non point-through-point group ( P < 0.01 ) . CONCLUSION Head point-through-point therapy can obviously increase plasma 5-HT content of the patient with PSD , so as to cure poststroke depression , with a better therapeutic effect than other two groups [23885610] OBJECTIVE To assess the clinical efficacy of acupuncture at key acupoints combined with the routine rehabilitation training of limb function on spasmodic hemiplegia after cerebral infa rct ion . METHODS Eighty-six cases were r and omized into an acupuncture combined with rehabilitation group ( group A , 44 cases ) and a rehabilitation group ( group B , 42 cases ) . In group A , the key acupoints were selected from head , face , chest , abdomen , shoulder , back , h and s , feet and ankles such as Cuanzhu ( BL 2 ) , Danzhong ( CV 17 ) , Jianyu ( LI 15 ) and Yanglao ( SI 16 ) were stimulated with acupuncture . In combination , the routine limb rehabilitation training was applied , once every day . In group B , the routine limb rehabilitation training was applied alone . In both groups , 10 treatments made one session and 2 sessions were required totally . Before and after treatment , Fugl-Meyer scale and functional independent measurement ( FIM ) scale were adopted to assess the limb motor level and the activity of daily life in the patients respectively . The modified Ashworth scale was used to assess the effect of anti-spasm . RESULTS The total effective rate of anti-spasm was 90.9 % ( 40/44 ) in the group A , which was superior to 73.8 % ( 32/42 ) in the group B ( P < 0.05 ) . After 2 sessions of treatment , Fugl-Meyer score and FIM score were all improved in both groups ( all P < 0.05 ) and the results in the group A were better than those in the group B ( all P < 0.05 ) . Additionally , the improvement of FIM score after the 1st session of treatment in the group A was better as compared with the group B , indicating the significant difference ( P < 0.05 ) . CONCLUSION Acupuncture at key acupoints combined with rehabilitation therapy effectively relieves the spasmodic condition of the patients with post-stroke spasmodic hemiplegia , improves the limb function and the life activity of the patients [11239191] Background and Purpose — In small trials with control groups that receive no intervention , acupuncture has been reported to improve functional outcome after stroke . We studied effects of acupuncture and transcutaneous electrical nerve stimulation on functional outcome and quality of life after stroke versus a control group that received subliminal electrostimulation . Methods — In a multicenter r and omized controlled trial involving 7 university and district hospitals in Sweden , 150 patients with moderate or severe functional impairment were included . At days 5 to 10 after acute stroke , patients were r and omized to 1 of 3 intervention groups : ( a ) acupuncture , including electroacupuncture ; ( b ) sensory stimulation with high-intensity , low-frequency transcutaneous electrical nerve stimulation that induces muscle contractions ; and ( c ) low-intensity ( subliminal ) high-frequency electrostimulation ( control group ) . A total of 20 treatment sessions were performed over a 10-week period . Outcome variables included motor function , activities of daily living function , walking ability , social activities , and life satisfaction at 3-month and 1-year follow-up . Results — At baseline , patients in each group were closely similar in all important prognostic variables . At 3-month and 1-year follow-ups , no clinical ly important or statistically significant differences were observed between groups for any of the outcome variables . The 3 treatment modalities were all conducted without major adverse effects . Conclusions — When compared with a control group that received subliminal electrostimulation , treatment during the subacute phase of stroke with acupuncture or transcutaneous electrical nerve stimulation with muscle contractions had no beneficial effects on functional outcome or life satisfaction [23383459] OBJECTIVE To observe the effect of acupuncture stimulation of scalp- and body-acupoints on limb function in subacute stroke patients . METHODS A total of 110 stroke in patients were r and omly and equally divided into acupuncture group and control group . Patients of the acupuncture group were treated by acupuncture stimulation of scalp acupoint Dingnie Qianxiexian ( MS 6 ) and body acupoints Neiguan ( PC 6 ) , Jianyu ( LI 15 ) , Sanyinjiao ( SP 6 ) , etc . once daily for 20 days and routine neurological therapies , including drugs for controlling blood pressure , blood sugar , water-electrolyte balance , anticoagulation , encephaledema reduction , intracranial pressure reduction , anti-inflammation , neurofunction protection , etc . The stroke patients of the control group were treated with the routine neurological therapies only . The Fugl-Meyer assessment ( FMA ) , US National Institutes of Health Stroke Scale ( NIHSS ) were used to assess the patients ' limb function and nerve functional lesion severity before and after the treatment , and the ratio of mortality/disability and recurrence rate were used to assess the efficacy of acupuncture at the end of 3 and 6 months ' follow-up . RESULTS After the treatment , the FMA scores were increased significantly and NIHSS scores decreased considerably in both groups ( P < 0.01 ) , and the effects of acupuncture group were obviously superior to those of the control group ( P < 0.05 ) . There were no significant differences between two groups in the ratios of mortality/disability and recurrence rates at the end of 3 and 6 months ' follow-up ( P > 0.05 ) . CONCLUSION Scalp acupuncture combined with body acupuncture can evidently improve limb movement function and reduce the nerve function damage in stroke patients [18712644] Past studies have suggested that acupuncture may reduce spasticity in stroke survivors . We do not know , however , whether acupuncture may enhance the effect of strength training on motor function . This study compared upper-limb motor functional improvement in chronic stroke survivors who received a combination of acupuncture and strength training with that of subjects who received strength training alone . A total of 10 chronic stroke patients with moderate or severe wrist muscle spasticity were recruited for this study . The study used a crossover design with a r and om order of either combined electroacupuncture and strength training or strength training alone . Each subject received one of the two types of treatment twice a week for the first 6 weeks and switched to the other for another 6 weeks . Quantitative measurements of wrist spasticity , active wrist extension range of motion , isometric wrist strength , and clinical evaluation with Fugl-Meyer ( FM ) upper-limb motor scores were conducted before and after either treatment . After the combined treatment , the quantitative spasticity level , active wrist extension range of motion ( increased by a mean of 16.3 degrees ) , and FM upper-limb motor score ( increased by a mean of 4.9 points ) changed significantly ( p < 0.01 ) but no significant changes were noted in isometric wrist strength . The strength training alone result ed in no significant changes to any measured variable . The results of the current study indicate that the combined acupuncture and strength training treatment reduced muscle spasticity and may have improved motor function for chronic stroke survivors with moderate or severe muscle spasticity [24494280] OBJECTIVE To assess the clinical efficacy on post-stroke shoulder-h and syndrome ( SHS ) treated with acupuncture and rehabilitation and the impacts on patients ' nailfold microcirculation . METHODS One hundred and twenty patients were r and omized into an acupuncture rehabilitation group and a simple rehabilitation group , 60 cases in each one . In the simple rehabilitation group , OT ( comprehensive rehabilitation therapy ) training was adopted . In the acupuncture rehabilitation group , on the basis of the treatment as the simple rehabilitation , acu puncture was added at Taiyuan ( LU 9 ) , Zusanli ( ST 36 ) , Xuanzhong ( GB 39 ) , Waiguan ( TE 5 ) , Shousanli ( LI 10 ) , Quchi ( LI 11 ) and Jianyu ( LI 15 ) . Acupuncture was given once a day , 7 days made one session . Totally , 4 sessions of treatment were required . Fugl-Meyer score , upper limb pain score , the score of nerve function defect and the items of nailfold microcirculation of patients were assessed in the the two groups before and after treatment . The efficacy was compared between the two groups . RESULTS ( 1 ) The upper limb pain , the systematic motor function of the upper limbs , the nerve function defect , nailfold microcirculation and clinical symptoms were all improved after treatment in either the acupuncture rehabilitation group or the simple rehabilitation group as compared with those before treatment , indicating the significant difference ( P<0 . 05 , P<0 . 01 ) . ( 2 ) The i m provements in the upper limb pain ( 0 . 90+/-0.71 vs 1 . 80+/-0 . 66 ) , the systematic motor function of the upper limbs ( 42 . 43 13 . 57 vs 29 . 98+/-15 . 11 ) , the nerve function defect ( 8 . 60+/-11 . 61 vs 13 . 0+/-1 . 74 ) , nailfold microcirculation ( total score 3 . 18+/-1.32 vs 4.34+/-1.23 ) and clinical symptoms in the acupuncture rehabilitation group after treatment were different significantly as compared with those in the simple rehabilitation group ( PO0 . 05,P-O. 01 ) , and the results in the acupuncture rehabilitation group were superior to the simple rehabilitation group . ( 3 ) In the acupuncture rehabilitation group , the markedly effective rate was 50 . 0 % ( 30/60 ) and the total effective rate was 93.3 % ( 56/60 ) , which was better than 16.7 % ( 10/60 ) and 63 . 3 % ( 38/60 ) respectively in the simple rehabilitation group ( all P<0 . 05 ) . CONCLUSION Both the combined therapy of acupuncture and rehabilitation and the simple rehabilitation training are effective in the treatment of post-stroke SHS , and promote the status of nailfold microcirculation , the efficacy of the combined therapy is better than that of the latter [20578377] OBJECTIVE To verify the improvement function of warming-reinforcing acupuncture combined with rehabilitation training on the early motor function of hemiparalysis patients caused by ischemic brain stroke . METHODS Eighty cases were r and omly divided into a warming-reinforcing acupuncture combined with rehabilitation training group ( group A ) and a rehabilitation training group ( group B ) , 40 cases in each group . Both groups were treated with internal routine treatment . The Motor Relearning Program rehabilitation was used in group B , while warming-reinforcing acupuncture combined with Motor Relearning Program rehabilitation were used in group A. Jianyu ( LI 15 ) , Quchi ( LI 11 ) , Hegu ( LI 4 ) , Yanglingquan ( GB 34 ) , Yinlingquan ( SP 9 ) , Zusanli ( ST 36 ) , Sanyinjiao ( SP 6 ) were selected , and warming-reinforcing method was used in these points , they were treated for 3 weeks . The neurological functional deficits scores of hemiparalysis patients , Fugl-Meyer Score , Motor Function Assessment Score ( MAS ) , Barthel Index and Mini-mental State Examination ( MMSE ) were used to evaluate the condition of hemiparalysis patients before and after treatment . RESULTS The effective rate of group A ( 87.5 % , 35/40 ) superior to that of group B ( 67.5 % , 27/40 ) ( P < 0.05 ) . The neurological functional deficit scores , Fugl-Meyer score , MAS and Barthel Index of both groups were improved after treatment ( P < 0.01 , P < 0.05 ) , and the improved degree of group A was better than that of group B ( P < 0.01 , P < 0.05 ) . CONCLUSION There is obvious improvement function of warming-reinforcing acupuncture combined with rehabilitation training on the early motor function of hemiparalysis patients caused by ischemic brain stroke , and the function is better than that of simple rehabilitation training [11779909] Background and Purpose — A significant number of patients remain severely disabled after stroke despite rehabilitation with st and ard treatment modalities . Acupuncture has been reported as an alternative modality . This study aims to examine whether acupuncture has additional value to st and ard poststroke motor rehabilitation . Methods — A prospect i ve r and omized controlled trial ( RCT ) was carried out in a stroke rehabilitation unit in Hong Kong . One hundred six Chinese patients with moderate or severe functional impairment were included at days 3 to 15 after acute stroke . They were stratified into the moderate and the severe groups before r and omization into the control arm receiving st and ard modalities of treatment , which included physiotherapy , occupational and speech therapy , and skilled medical and nursing care , and the intervention arm receiving in addition traditional Chinese manual acupuncture . A mean of 35 acupuncture sessions on 10 main acupoints were performed over a 10-week period . Outcome measures included Fugl-Meyer assessment , Barthel Index , and Functional Independence Measure , respectively , at weeks 0 , 5 , and 10 , performed by blinded assessors . Results — At baseline , patients in each arm were comparable in all important prognostic characteristics . No statistically significant differences were observed between the 2 arms for any of the outcome measures at week 10 or outcome changes over time . Conclusions — Traditional Chinese manual acupuncture on the body has no additional value to st and ard poststroke motor rehabilitation [17604556] BACKGROUND Acupuncture may improve motor function in patients with chronic hemiparetic stroke , yet the neural mechanisms underlying such an effect are unknown . As part of a sham-controlled , r and omized clinical trial testing the efficacy of a 10-week acupuncture protocol in patients with chronic hemiparetic stroke , we examined the relationship between changes in function of the affected upper limb and brain activation using functional magnetic resonance imaging ( fMRI ) . METHODS Seven ( 7 ) chronic hemiparetic stroke patients underwent fMRI and testing of function of the affected upper limb ( spasticity and range-of-motion ) before and after a 10-week period of verum ( N=4 ) or sham ( N=3 ) acupuncture . The correlation between changes in function of the affected upper limb and brain activation after treatment was tested across patients . RESULTS We found a significant positive correlation between changes in function of the affected upper limb ( spasticity and range of motion ) and activation in a region of the ipsilesional motor cortex . Patients treated with verum acupuncture showed a trend toward a greater maximum activation change in this motor cortical area as compared to those treated with sham acupuncture . CONCLUSIONS Acupuncture may improve function of the affected upper limb in chronic hemiparetic stroke patients by increasing activity in the ipsilesional motor cortex [23057482] OBJECTIVES The aim of this study was to investigate whether acupuncture , especially Yamamoto 's New Scalp Acupuncture ( YNSA ) , is of value in additional to st and ard poststroke motor rehabilitation . DESIGN A prospect i ve , assessor-blinded r and omized control trial was carried out in an inpatient stroke rehabilitation unit with day hospital service . After inclusion , patients were stratified into control group and acupuncture group , r and omly . OUTCOME MEASURES The Barthel Index , the Rivermead Scale Index , and the Visual Analogue Scale were used to follow the efficacy of treatment . RESULTS In the acupuncture group , all the sensory , motor , and functional scores improved significantly during the examination period until 2 years after injury . The Barthel Index is increased from 4±2 to 95±4 in the acupuncture group . This index also increased in the control group ( from 4±2 to 75±4 ) , but the changes were significantly less than in the acupuncture group . A significant spontaneous recovery during the 2-year follow-up was found , but the YNSA treatment facilitated the functional recovery . Improved moving function and more flexible joints and ligaments were observed in comparison to the patients ' condition prior to treatment . CONCLUSIONS The data suggest that the YNSA is a useful method to treat stroke patients and enhance their quality of life [25199825] OBJECTIVE The purpose of this study was to determine the effects of deep dry needling ( DDN ) on spasticity , pressure sensitivity , and plantar pressure in patients who have had stroke . METHODS A r and omized controlled trial was conducted . Thirty-four patients who previously had a stroke were r and omly assigned either an experimental group that received a single session of DDN over the gastrocnemius and tibialis anterior muscles on the spastic leg or a control group that received no intervention . Spasticity ( evaluated with the Ashworth Scale ) ; pressure pain thresholds over the deltoid muscle , second metacarpal , and tibialis anterior muscle ; and plantar pressure ( baropodometry ) were collected by a blinded assessor before and 10 minutes after intervention . RESULTS A greater number of individuals receiving DDN exhibited decreased spasticity after the intervention ( P < .001 ) . The analysis of covariance showed that pressure pain thresholds increased bilaterally in patients receiving DDN compared with those who did not receive the intervention ( P < .001 ) . The analysis of covariance also found that patients receiving DDN experienced bilateral increases of support surface in the forefoot , unilateral increase of the support surface in the rear foot of the treated ( affected ) side , and bilateral decreases in mean pressure ( all , P < .02 ) as compared with those who did not receive DDN . CONCLUSIONS Our results suggest that a single session of DDN decreases spasticity and widespread pressure sensitivity in individuals with poststroke spasticity . Deep dry needling also induced changes in plantar pressure by increasing the support surface and decreasing the mean pressure [17955649] OBJECTIVE To observe the therapeutic effects of different acupuncture methods for spastic hemiparalysis due to cerebrovascular disorders . METHODS 90 cases of spastic hemiparalysis after wind-stroke were r and omly divided into a control group of 30 cases , a body acupuncture group of 30 cases and a point-penetrating acupuncture group of 30 cases . All the patients were given 4 courses of treatment , with 7 sessions constituting one therapeutic course and with a one-day interval between courses . The evaluations were made 3 times , i.e. once before treatment and once every 15 days during the treatment . RESULTS The therapeutic effects in the point-penetrating acupuncture group were obviously superior to those of both the control group and the body acupuncture group . CONCLUSION The point-penetrating acupuncture is an effective therapy for treating spastic hemiparalysis due to cerebrovascular disorders [21739685] OBJECTIVE To explore the impacts of acupuncture and rehabilitation on post-stroke abnormal patterns of limb movement and evaluate them via rehabilitation method . METHODS Ninety cases of post-stroke movement disorder were r and omly divided into an acupuncture-rehabilitation group , a body acupuncture group and a medication group , 30 cases in each group . In medication group , the conventional medication in neurological department was administered . In acupuncture-rehabilitation group and body acupuncture group , on the basis of the therapy as medication group , scalp acupuncture ( such as parietal area and anterior parietal area , etc . ) , rehabilitation training and traditional body acupuncture [ such as Jianyu ( LI 15 ) and Fengshi ( GB 31),etc . ] were supplemented . The continuous electric stimulation was applied in body acupuncture group . The treatment lasted for 8 weeks . The assessment of clinical efficacy , Fugl-Meyer score , Modified Ashworth scale ( MAS ) , range of motion ( ROM ) and shoulder pain score were taken as observation indices for rehabilitation evaluation before and after treatment in each group . RESULTS The effective rate was 93.1 % ( 27/29 ) in acupuncture-rehabilitation group , which was superior to 66.7 % ( 20/30 ) in body acupuncture group and 57.1 % ( 16/28 ) in control group ( both P<0.01 ) separately . After treatment , Fugl-Meyer score , MAS , ROM of the lower limbs and shoulder joint and shoulder pain score ( except medication group ) were all remarkably improved as compared with those before treatment in each group ( all P<0.01 ) . The improvements in Fugl-Meyer score , MAS , ROM of the upper limbs and shoulder pain score in acupuncture-rehabilitation group were significantly superior to those in body acupuncture group and medication group ( P<0.05 , P<0.01 ) . CONCLUSION Acupuncture and rehabilitation therapy and traditional body acupuncture remarkably improve in post-stroke movement disorder . But acupuncture and rehabilitation therapy is apparently superior to traditional body acupuncture . This therapy can effectively prevent and treat post-stroke abnormal patterns and it is greatly significant in the improvement of survival quality for the patients [21442809] OBJECTIVE To observe the curative effects of post-stroke h and dysfunction treated with acupuncture at Zhongzhu ( TE 3 ) and Waiguan ( TE 5 ) . METHODS Sixty cases of post-stroke h and dysfunction were r and omly divided into an observation group ( 30 cases ) and a control group ( 30 cases ) . Routine medicine , physical therapy , occupational therapy and other rehabilitation trainings were applied in both groups ; Zhongzhu ( TE 3 ) and Waiguan ( TE 5 ) were punctured in observation group . Scores of nervous functions deficit by the National Institutes of Health Stroke Scale ( NIHSS ) , h and function , walking ability , activities of daily living ( ADL ) by Modified Barthel Index Scale were e valuated in both groups before and after treatment . RESULTS After treatment , the scores of h and function , walking ability , ADL and NIHSS were improved in both groups ( all P < 0.01 ) , and the h and function , walking ability and ADL in observation group were superior to those in control group ( all P < 0.05 ) . CONCLUSION Routine medicine and rehabilitation trainings combined with acupuncture at Zhongzhu ( TE 3 ) and Waiguan ( TE 5 ) to treat post-stroke h and dysfunction can obviously improve the h and dysfunction after stroke , enhance the abilities of walking and daily living , and increase the curative effect [22489807] OBJECTIVES The majority of individuals who survive a stroke are disabled because of persisting neurological impairments . The objective of this study was to evaluate the efficacy of subcutaneous electrical stimulation of the scalp in spontaneous functional recovery of patients with chronic ischemic stroke , by evaluating clinical , neurological , and functional findings . SUBJECTS AND METHODS Sixty-two ( 62 ) subjects who were at least 18 months postdiagnosis of ischemic stroke were r and omized to receive 10 sessions of placebo or active low-frequency electrical stimulation ( 2/100 Hz ) using subcutaneous acupuncture needles over the scalp . Functional and neurological evaluations were indexed by the Barthel , Rankin , and National Institutes of Health Stroke Scale ( NIHSS ) . RESULTS Results show that there was a significant difference in functional improvement between the sham and active group as indexed by NIHSS scale . The active group had a larger functional improvement after 10 sessions of scalp electrical acupuncture . The other two functional scales ( Rankin and Barthel ) failed to show significant differences between the two treatment groups . CONCLUSIONS These results support further testing of scalp electrical acupuncture for the treatment of stroke as well further mechanistic studies to underst and mechanisms associated with the observed improvement . Further studies need to consider longer follow-up assessment s to investigate potential functional changes associated with electrical acupuncture [19288897] OBJECTIVE To observe the effect of electroacupuncture ( EA ) on hippocampal apoptosis and learning-memory ability in vascular dementia ( VD ) mice so as to investigate its underlying mechanism in the treatment of VD patients . METHODS Kunming mice were r and omly divided into sham-operation ( sham , n = 13 ) , model ( n = 15 ) , EA ( n = 16 ) and Nimodipine ( intragastric gavage , 30 mg/kg for 15 days , n = 15 ) groups . VD model was duplicated by occlusion of bilateral carotid arteries and reperfusion . EA ( 2 - 80 Hz , 2 mA ) was applied to " Dazhui " ( GV 14 ) , " Baihui " ( GV 20 ) , " Geshu " ( BL 17 ) and " Zusanli " ( ST 36 ) for 10 min , once daily for 15 days . Step-down and step-up tests were performed to assess the animal 's memory and learning abilities separately ; and the terminal deoxynucleotidyl transferase-mediated dUTP-nick end-labeling ( TUNEL ) method was used to display the apoptotic cells of the hippocampus tissue . RESULTS In comparison with sham group , the animals ' reaction time upon electric shock stimulation , both step-up and step-down error times , and hippocampal apoptosis number in model , EA and Nimodipine groups increased significantly ( P<0.01 ) , while the reaction latency upon electric shock of model , EA and Nimodipine groups decreased significantly ( P<0.01 ) . Compared with model group , the reaction time , both step-up and step-down error times and hippocampal apoptosis number of both EA and Nimodipine groups decreased significantly ( P<0.05 , P<0.01 ) ; while the reaction latency of EA and Nimodipine groups increased considerably ( P<0.01 ) . Comparison between EA and Nimodipine groups showed that the reaction latency of EA group was obviously longer than that of the later group ( P<0.01 ) , and the step-down error times of EA group was markedly lower than that of Nimodipine group ( P<0.05 ) . No significant differences were found between these two groups in other indexes ( P>0.05 ) . CONCLUSION EA can ameliorate VD mice 's learning-memory ability , which may be closely related to its effect in reducing hippocampal apoptosis [24298765] OBJECTIVE To observe the efficacy on post-stroke mild cognitive impairment ( MCI ) treated with acupuncture at Jing-well points on the differentiated meridians and temple-three-needle therapy . METHODS Seventy-three of stroke patients were r and omized into an acupuncture group ( 37 cases ) and a conventional treatment group ( 36 cases ) . Twenty healthy aged people in physical examination were collected as a control group . In the acupuncture group , on the basis of the conventional treatment of internal medication , the acupuncture at Jing-well points on the differentiated meridians and temple-three-needle therapy were applied . In the conventional treatment group , no any therapy was used except the conventional treatment of internal medication . In the control group , no any intervention was adopted . Neuroscan Nuamps electroencephalogram recording analysis system was used to determine the event-related potentials P300 , and the amplitude and mini mental state examination ( MMSE ) score was observed before and after treatment in both groups . RESULTS After treatment , in the acupuncture group , P300 latent stage was shortened , and the amplitude and the score of MMSE were increased ( P < 0.05 , P < 0.01 ) . In the conventional treatment group , above indices were not changed obviously as compared with that before treatment ( all P > 0.05 ) . Compared with the conventional treatment group , the differences in P300 latent stage , amplitude and MMSE score were remarkable in the acupuncture group ( P < 0.05 , P < 0.01 ) . CONCLUSION The acupuncture at Jing-well points on the differentiated meridians and temple-three-needle therapy improves the cognitive function of the patients with MCI [17432642] OBJECTIVE To search for an effective method for improving locomotor ability of upper limbs and ability of daily life in the patient of cerebral infa rct ion . METHODS Five hundred and seventy-eight cases of stroke were r and omly divided into 4 groups : an improved acupoints and rehabilitation exercise group ( group A , n = 148 ) , a rehabilitation exercise group ( group B , n = 142 ) , a routine acupoints and rehabilitation exercise group ( group C , n = 144 ) , and a medication group ( group D , n = 144 ) . The locomotor ability of the upper limbs and ability of daily life were evaluated respectively by Fugl-Meyer ( FMA ) and Barthel ( BMI ) . RESULTS There were significant differences in FMA and BMI scores in all the groups after treatment as compared with those before treatment ( P < 0.05 ) ; after treatment , the effect in the group A was significantly superior to those in group B and C ( P < 0.05 ) , with no significant difference between the group C and the group B. CONCLUSION The improved acupoints combined with rehabilitation exercise can improve locomotor ability of the upper limbs and ability of daily life in the patient of cerebral infa rct ion [18652322] OBJECTIVE To observe therapeutic effect of acupuncture combined with rehabilitation therapy on poststroke shoulder-h and syndrome . METHODS One hundred and twenty cases of poststroke shoulder-h and syndrome were r and omly divided into an acupuncture-rehabilitation group , an acupuncture group and a rehabilitation group , 40 cases in each group . The acupuncture-rehabilitation group were treated with acupuncture at Jianyu ( LI 15 ) , Jianqian , Jianliao ( TE 14 ) , etc . in combination with motor therapy ( rehabilitation training ) , the acupuncture group with simple acupuncture therapy , and the rehabilitation group with simple motor therapy . Upper extremity motor function , pain , joint activity were used for assessment of therapeutic effects . RESULTS The total effective rate of 87.5 % in the acupuncture-rehabilitation group was significantly better than 67.5 % in the acupuncture group and 65.0 % in the rehabilitation group ( P<0.01 ) ; acupuncture combined with rehabilitation therapy could significantly improve upper limb motor function , pain and joint activity with very significant differences as compared with the acupuncture group and the rehabilitation group ( P<0.01 ) . CONCLUSION Acupuncture combined with rehabilitation therapy has a high cured rate and an obvious therapeutic effect on poststroke shoulder-h and syndrome [22875557] CONTEXT Stroke is a leading cause of death and disability worldwide , being the third leading cause of death in the United States and the second and third most common causes of death in Chinese cities and rural areas , respectively . Evaluation of different rehabilitative modalities appears necessary to optimize treatment . OBJECTIVES To compare acupuncture and physiotherapy for effectiveness and reliability in treating hemiplegic patients after stroke . DESIGN The research team design ed a multicentered , three-arm , r and omized controlled trial . Power calculations revealed a targeted sample size of 310 participants . SETTING The study took place at seven in-patient hospitals in China . PARTICIPANTS The research team screened a total of 310 patients . Of that number , 274 completed the study , 15 did not meet the inclusion /exclusion criteria , and 21 dropped out . Adverse events were rare ( less than 1 % ) , mild , and temporary . INTERVENTION The research team r and omly divided participants into three groups that all received conventional care as needed-including psychological counseling , st and ard nursing care , and daily medical evaluation plus ( 1 ) acupuncture , ( 2 ) physiotherapy , or ( 3 ) acupuncture plus physiotherapy . The participants received treatments once a day , 6 days a week for 4 weeks . OUTCOME MEASURES The research team evaluated all patients at baseline , after 2 weeks , and after 4 weeks using the Fugl-Meyer Assessment of Physical Performance ( FMA ) , a modified Barthel Index ( BI ) , and the Neurologic Defect Scale ( NDS ) . RESULTS No significant differences existed between the three groups at baseline . Compared to baseline , participants in all groups improved their FMA , BI , and NDS scores by the end of week 2 ( P≤.05 ) and further improved by the end of week 4 ( P≤.05 ) The study found no statistically significant differences in outcomes between the three groups after treatment ( P>.05 ) . CONCLUSION Acupuncture plus conventional care was similar in effectiveness to physiotherapy treatment plus conventional care for poststroke rehabilitation . The study found no synergistic effects for the combination of acupuncture and physiotherapy in addition to conventional care ; that combination of treatments was no more effective than either treatment by itself . The effectiveness and lack of adverse events associated with acupuncture in this study suggest that it may represent an additional treatment option for stroke patients [20050300] OBJECTIVE The objective of this study was to investigate the effect of electroacupuncture on cognitive function and health-related quality of life in patients who have had a stroke . DESIGN This clinical trial employed a prospect i ve , r and omized , single-blind design . SETTING S/LOCATION The study was conducted at the department of rehabilitation medicine , Tri-Service General Hospital , Taipei , Taiwan . SUBJECTS Thirty-eight ( 38 ) participants were recruited , but only 33 completed the study . Seventeen ( 17 ) stroke participants with cognitive impairment were assigned to the treatment group and 16 were assigned to the control group . INTERVENTIONS Electroacupuncture was applied to acupuncture points PC6 and HT7 for 20 minutes twice a week for 8 weeks in the treatment group , while participants in each group continued rehabilitation . OUTCOME MEASURES Cognitive assessment ( LOTCA-G ) and quality -of-life assessment ( SF-36 and SS-QOL ) were carried out in each group at baseline and at 8 weeks after treatment . RESULTS Significant improvement was detected in four subtests of LOTCA-G : orientation , perception , praxis , and attention ( p<0.05 ) between treatment and control groups . Significant improvement was also indicated in subscales of SF-36 ( RP , VT , SF , RE , MH , MCS ) and SS-QOL ( language ) ( p<0.05 ) . No correlation was noted between the variables of LOTCA-G and SF-36/SS-QOL except four matches : Memory ( LOTCA-G ) and Mental Component Summary ( SF-36 ) : r=0.492 ; Memory ( LOTCA-G ) and Personality ( SS-QOL ) : r=0.485 ; Praxis ( LOTCA-G ) and Language ( SS-QOL ) : r=0.616 ; Orientation ( LOTCA-G ) , and Language ( SS-QOL ) : r=0.534 . CONCLUSIONS The results of this study confirm a positive effect of electroacupuncture on cognition and quality of life in patients who had a stroke . Future research will be required to evaluate potential mechanisms and potential long-term benefits [21793387] OBJECTIVE To assess the therapeutic effect of Jin 's " Sanzhen " therapy combined with rehabilitation training on limb-motor function of stroke patients by using Fugl-Meyer scale . METHODS A total of 254 hemiplegic stroke out patients and in patients from 7 hospitals were r and omly divided into Jin 's " Sanzhen " ( JSZ ) group ( n = 83 ) , rehabilitation group ( n = 84 ) and combination group ( n = 87 ) . Acupuncture was applied to acupoints of Jin 's " Sanzhen " including Quchi ( LI 11 ) , Waiguan ( SJ 5 ) and Hegu ( LI 4 ) ; Futu ( ST 32 ) . Zusanli ( ST 36 ) and Sanyinjiao ( SP 6 ) ; etc . The acupuncture needles were retained for 30 min after " Deqi " . Rehabilitation training included passive joint movement , st and ing-sitting training , tapping-pressing stimulation , walking training , etc . The treatment was conducted once daily , 5 sessions a week and for 4 weeks . Fugl-Meyer scale composed of 100-point motor domain of the upper- and lower-extremity sections was used to assess the patients ' motor function . RESULTS On day 28 after the treatment , of the 83.84 and 87 hemiplegic stroke patients in the JSZ , rehabilitation and combination groups , 48 ( 57.8 % ) , 31 ( 36.9 % ) and 50 ( 57.5 % ) experienced marked improvement in their clinical symptoms and signs , 26 ( 31.3 % ) , 44 ( 52.4 % ) and 31(35.6 % ) had an improvement , and 9 ( 10.8 % ) , 9 ( 10.7 % ) and 6 ( 6.9 % ) failed in the treatment , with the total effective rates being 89.2 % , 89.3 % and 93.1 % , respectively . The neurological deficit score ( NDS ) of the combination group was significantly lower than that of the rehabilitation group ( P < 0.05 ) . The Fugl-Meyer assessment score ( FMAS ) for extremity motor function of the combination group was apparently higher than those of the JSZ and rehabilitation groups ( P < 0.05 ) . No significant differences were found between the JSZ and rehabilitation groups in both NDS and FMAS ( P > 0.05 ) . CONCLUSION Jin 's " Sanzhen " therapy combined with rehabilitation training can significantly improve the limb motor function of hemiplegic stroke patients , and has a good synergistic effect [23600965] OBJECTIVE To assess the value of acupuncture for promoting the recovery of patients with ischemic stroke and to determine whether the outcomes of combined physiotherapy and acupuncture are superior to those with physiotherapy alone . DESIGN Prospect i ve r and omized controlled trial . SETTING Department of Rehabilitation Medicine , Huashan Hospital , Fudan University , P. R. China . PARTICIPANTS 120 in patients and out patients ( 84 men and 36 women ) . INTERVENTIONS Acupuncture , physiotherapy , and physiotherapy combined with acupuncture . MAIN OUTCOME MEASURES Motor function in the limbs was measured with the Fugl-Meyer assessment ( FMA ) . The modified Barthel index ( MBI ) was used to rate activities of daily living . All evaluations were performed by assessors blinded to treatment group . RESULTS On the first day of therapy ( day 0 , baseline ) , FMA and MBI scores did not significantly differ among the treatment groups . Compared with baseline , on the 28th day of therapy the mean FMA scores of the physiotherapy , acupuncture , and combined treatment groups had increased by 65.6 % , 57.7 % , and 67.2 % , respectively ; on the 56th day , FMA scores had increased by 88.1 % , 64.5 % , and 88.6 % , respectively ( p<0.05 ) . The respective MBI scores in the three groups increased by 85.2 % , 60.4 % , and 63.4 % at day 28 and by 108.0 % , 71.2 % , and 86.2 % at day 56 , respectively ( p<0.05 ) . However , FMA scores did not significantly differ among the three treatment groups on the 28th day . By the 56th day , the FMA and MBI scores of the physiotherapy group were 46.1 % and 33.2 % greater , respectively , than those in the acupuncture group p<0.05 ) . No significant differences were seen between the combined treatment group and the other groups . In addition , the FMA subscores for the upper extremities did not reflect any significant improvement in any group on the 56th day . Although the FMA subscores for the upper and lower extremities and the MBI score in the combined treatment group were higher than those in the acupuncture group , the differences were not statistically significant . CONCLUSIONS Acupuncture is less effective for the outcome measures studied than is physiotherapy . Moreover , the therapeutic effect of combining acupuncture with physiotherapy was not superior to that of physiotherapy alone . A larger-scale clinical trial is necessary to confirm these findings [8232703] The effectiveness of acupuncture in acute stroke remains largely untested and unproved . A r and omized , controlled trial was carried out to study the feasibility of acupuncture in combination with conventional supportive treatment for acute stroke patients . A total of 30 patients , aged 46 - 74 , with the onset of symptoms within 36 h were enrolled into the study after appropriate screening . All patients gave informed consent . Basing on the same supportive treatment , patients were r and omly assigned to a treatment with or without acupuncture . The procedure and acupoint selection were discussed and decided through several meetings of a group of senior acupuncture doctors in Taiwan . Acupuncture was applied 3 times/week for 4 weeks . During the study period , there were no problems in conducting this trial in terms of patient availability and acceptance , and physician cooperation . A significantly better neurologic outcome was observed in the acupuncture group on day 28 and day 90 . The improvement in neurologic status was greatest in patients with a poor neurologic score at baseline . There were no important side effects except for one episode of dizziness related to acupuncture treatment . The data and results of this study will be used as a guideline for planning a full-scale clinical trial , e.g. sample size calculation , method of r and omization with stratification of prognostic factors , choosing acupuncture points and technique of acupuncture [8232927] After obtaining informed consent , we r and omized 78 patients with severe hemiparesis of the left or right side within 10 days of stroke onset : 40 to a control group receiving daily physiotherapy and occupational therapy , and 38 to a group that , in addition , we treated with sensory stimulation ( acupuncture ) twice a week for 10 weeks . The median age was 76 years for both groups . Motor function , balance , and ADL ( Barthel 's Index ) were assessed before the start of treatment and at 1 and 3 months after stroke onset ; ADL was also assessed after 12 months . We assessed the quality of life ( QL ) using the Nottingham Health Profile 3 , 6 , and 12 months after stroke onset . Patients given sensory stimulation recovered faster and to a larger extent than the controls , with a significant difference for balance , mobility , ADL , QL , and days spent at hospitals/nursing homes . Whether acupuncture per se is responsible for the differences requires further study [16642607] OBJECTIVE To probe the best therapy for the patient after operation of hypertensive cerebral hemorrhage . METHODS One hundred cases were r and omly divided into a treatment group and a control group , 50 cases in each group . The control group were treated by routine western medicine ( Mannitol , Nifedipine and Caftriaxone sodium and so On ) , and the treatment group by the medication of the control group plus acupuncture 9 days after operation . Acupuncture was given at Neiguan ( PC 6 ) , Shuigou ( GV 26 ) , Sanyinjiso ( SP 6 ) , Jiquan ( HT 1 ) and Weizhong ( BL 40 ) and so on , combined with scalp acupuncture , with " restoring consciousness and inducing consciousness " needling method , for 10 days . The nervous function defect was assessed by Chinese Stroke Scale and the criteria for assessment of therapeutic effects . RESULTS Acupuncture could improve significantly nervous function defect . The total effective rate was 86.000 in the treatment group and 14.0 % in the control group with a significant difference between the two groups ( P < 0.01 ) . CONCLUSION The therapeutic effect of the treatment group is better than that of the control group . Acupuncture combined with western medicine has cooperation for treatment of hypertensive intracerebral hemorrhage with a better therapeutic effect [17526181] OBJECTIVE To observe the effect of scalp-acupuncture drawing method ( SADM ) on recovering motor function in hemiplegic patients following cerebral thrombosis at convalescent period . METHODS Adopting r and omized , single-blinded , controlled method , 93 patients suffering from hemiplegia following cerebral thrombosis were r and omly assigned to 3 groups , 31 in each group . All patients were treated based on neurological routine therapy , those in the treated group and the control group I were treated respectively with SADM and scalp-acupuncture twirling method ( SATM ) additionally , but for those in the control group II , no additional treatment was given . The treatment course for all was 4 weeks . RESULTS Before treatment , there were insignificant difference among 3 groups in the score of neural motor function deficits ( NFDS ) of limbs and activity of daily life ( ADL ) score ( P > 0.05 ) . After being treated for 4 weeks , the NFDS was significantly lower and in the control group II ( P < 0.01 , P < 0.05 ) and the change of the scores in the treated group was more than that in the control group I ( P < 0.05 ) . CONCLUSION SADM was superior to scalp-acupuncture twisting prove the ADL score and motor function of hemiplegia patients following cerebral thrombosis in the convalescent stage [25675557] OBJECTIVE To observe the impact on lower limbs balance function in treatment of yin-yang meridians acupuncture with respiratory reinforcing and reducing manipulation involved in the patients of stroke by applying B-PHY balance function test training system so as to provide the objective evidence in treatment of stroke ; with acupuncture . METHODS One hundred patients were r and omized into an observation group and a control group , 50 cases in each one . In the control group , the basic treatment was applied , without other relevant rehabilitation therapies associated . In the observation group , with the basic treatment as the control group 's , the therapy of the yin-yang meridians acupuncutre with respiratory reinforcing and reducing manipulation was adopted . On the yin meridians , Zuwuli ( LR 10 ) , Xuehai ( SP 10 ) , Yinlingquan ( SP 9 ) , Sanyinjiao ( SP 6 ) and the others were selected and stimulated with reducing manipulation achieved by the coordination of patient 's respiration . On the yang meridians , Biguan ( ST 31 ) , Liangqiu ( ST 34 ) , Yanglingquan ( GB 34 ) and the others were selected and stimulated with reinforcing manipulation achieved by the coordination of patient 's respiration . The treatment was given once a day and for 28 days totally . Before treatment and in 28 days of treatment , B-PHY balance function test training system was used to determine the weight shift track parameters ( track length , peripheral square , track length of per unit square , left-right offset and rectangle square ) , the weight shift track distance parameters [ mean of X axle weight shift distance ( Mean-X ) , mean of Y axle weight shift distance ( Mean-Y ) , maximum of X axle weight shift distance ( Max-X ) , maximum of Y axle weight shift distance ( Max-Y ) , weight shift distance ( LSKG ) , weight shift square ( SSKG ) , square ratio of weight shift ( LFS ) ] , stability coefficient ( SI ) and weight distribution coefficient ( WDI ) . RESULTS After treatment , the differences in the weight shift track parameters , SI and WDI were significant as compared with those before treatment in the patients of the two groups ( all P<0.01 ) ; while the differences in the weight shift distance parameters in the observation group were improved obviously after treatment as compared with those before treatment ( all P<0.01 ) , the differences of Mean-X , Max-Y and LFS in the control group were improved after treatment as compared with those before treatment ( all P<0.01 ) . Except SSKG , the improvements after treatment in the rest indices in the observation group were better than those in the control group ( all P<0.05 ) . CONCLUSION The yin-yang meridians acupuncture with respiratry reinforcing and re- ducing manipulation effectively improves the lower limbs balance function in the patients of stroke [23967632] OBJECTIVE To evaluate the efficacy and safety of acupuncture and moxibustion in the treatment of post-stroke depression ( PSD ) by regulating the liver and strengthening the root prescription . METHODS In light of the r and om controlled trial principle , 123 cases were r and omized into an acupuncture-moxibustion group ( 42 cases ) , a medication group ( 40 cases ) and an acupuncture + medication group ( 41 cases ) . In the acupuncture-moxibustion group , the therapy of regulating the liver and strengthening the root was applied . Acupuncture was given at Hegu ( LI 4 ) , Taichong ( LR 3 ) , Baihui ( GV 20 , Yintang ( GV 29 ) , etc . The granule moxibustion was applied at Zhongwan ( CV 12 ) , Xiawan ( CV 10 ) , Guanyuan ( CV 4 ) and Qihai ( CV 6 ) . The treatment was given once a day and stopped in weekend . In the medication group , paroxetine hydrochloride tablets were prescribed for oral administration , 20 mg each day after breakfast . In the acupuncture + medication group , the therapies were adopted as the acupuncture-moxibustion group and the medication group . In the 2nd and 4th week of treatment , HAMD was used as the primary index and Barthel index as the secondary one for the efficacy assessment in the three groups respectively . The spleen and stomach syndrome scale of TCM was used for the assessment of TCM syndrome efficacy . Treatment emergent symptom scale ( TESS ) was applied for the safety assessment . RESULTS In the 4th week of treatment , the markedly effective rates were 69.0 % ( 29/42 ) , 65.0 % ( 26/40 ) and 70.7 % ( 29/41 ) in the acupuncture-moxibustion group , the medication group and the acupuncture + medication group respectively . The efficacies of anti-depression were similar in comparison among groups ( P > 0.05 ) . In the 2nd week of treatment , the improvement of HAMD score was significant in the acupuncture + medication group as compared with that before treatment and in comparison with the medication group ( P < 0.05 , P < 0.01 ) . As for improving Barthel index , reducing the spleen and stomach symptom score of TCM and decreasing the score of TESS , the results in the acupuncture-moxibustion group and the acupuncture + medication group were superior to those in the medication group ( P < 0.05 , P < 0.01 ) . CONCLUSION The therapy of acupuncture and moxibustion with regulating the liver and strengthening the root achieves the definite efficacy of anti-depression and presents the quite high safety in treatment [21739683] OBJECTIVE To assess the clinical efficacy on post-stroke speech disorder treated with acupuncture and psychological intervention combined with rehabilitation training . METHODS The multi- central r and omized controlled study was adopted . One hundred and twenty cases of brain stroke were divided into a speech rehabilitation group ( control group ) , a speech rehabilitation plus acupuncture group ( observation group 1 ) and a speech rehabilitation plus acupuncture combined with psychotherapy group ( observation group 2 ) , 40 cases in each one . The rehabilitation training was conducted by a professional speech trainer . In acupuncture treatment , speech function area in scalp acupuncture , Jinjin ( EX-HN 12 ) and Yuye ( EX-HN 13 ) in tongue acupuncture and Lianquan ( CV 23 ) were the basic points . The supplementary points were selected according to syndrome differentiation . Bloodletting method was used in combination with acupuncture . Psychotherapy was applied by the physician in psychiatric department of the hospital . The corresponding programs were used in each group . Examination of Aphasia of Chinese of Beijing Hospital was adopted to observe the oral speech expression , listening comprehension and reading and writing ability . RESULTS After 21-day treatment , the total effective rate was 92.5 % ( 37/40 ) in observation group 1 , 97.5 % ( 39/40 ) in observation group 2 and 87.5 % ( 35/40 ) in control group . The efficacies were similar in comparison among 3 groups . The remarkable effective rate was 15.0 % ( 6/40 ) in observation group 1 , 50.0 % ( 20/40 ) in observation group 2 and 2.5 % ( 1/40 ) in control group . The result in observation group 2 was superior to the other two groups ( P<0.01 , P<0.001 ) . In comparison of the improvements of oral expression , listening comprehension , reading and writing ability , all of the 3 groups had achieved the improvements to different extents after treatment ( P<0.01 , P<0.001 ) . The results in observation group 2 were better than those in observation group 1 and control group . CONCLUSION Acupuncture and psychological intervention combined with rehabilitation training is obviously advantageous in the treatment of post-stroke speech disorder [21823415] OBJECTIVE To study the effect on the motor function of stroke patients by combination of needling at Back-shu point and trunk exercise . METHODS Ninety stroke hemiplegic patients were r and omly assigned to the conventional treatment group ( as the convention group ) , the Back-shu point needling group , and the combination of Back-shu point needling and the trunk exercise group , 30 patients in each group . They were treated with the conventional treatment , needling at Back-shu point , and the combination of needling at Back-shu point and trunk exercise . The Fugl-Meyer score ( FMA ) and modified Barthel index ( MBI ) score were assessed before treatment and two months after treatment . RESULTS The three rehabilitation treatment methods were all effective in improving the motor function of stroke hemiplegic patients ( P<0.05 ) . The effects in the Back-shu point needling group and the combination of Back-shu point needling and the trunk exercise group were respectively superior to that in the conventional treatment group ( P<0.05 ) . The effect in the combination of Back-shu point needling and the trunk exercise group was superior to that in the Back-shu point needling group ( P<0.05 ) . CONCLUSION The combination of Back-shu point needling and the trunk exercise could improve the motor function of stroke hemiplegic patients , and its effect was better than needling at Back-shu point alone [7750174] One hundred and eight cases of sequelae of cerebro-vascular accident were r and omly divided into two groups temporal point group ( TG , 58 cases ) and body acupuncture group ( BG , 50 cases ) . It was shown that after 30 treatments the therapeutic effects were significantly different statistically ( P < 0.01 ) between the two groups . The effect in TG was better than that in BG . It indicates that the two acupuncture therapies can improve blood rheology in patients . The ameliorative function in TG was better than that in BG [2844940] The CONSORT statement is used worldwide to improve the reporting of r and omised controlled trials . Kenneth Schulz and colleagues describe the latest version , CONSORT 2010 , which up date s the reporting guideline based on new method ological evidence and accumulating [18767580] OBJECTIVE To search for the best way to elevate the clinical therapeutic effect in the hemiplegic patient of cerebral thrombosis at convalescent period . METHODS Adopting single-blind , r and omized controlled method , 90 cases of cerebral thrombosis at convalescent period were assigned to 3 groups : a scalp acupuncture group ( group A ) , a rehabilitation therapy group ( group B ) and a scalp acupuncture combined with rehabilitation therapy group ( group C ) . Group A were treated with scalp acupuncture at the anterior oblique line of vertex-temporal and the posterior oblique line of vertex-temporal on the healthy side ; group B were treated with modern rehabilitation medical therapy , making limb function treatment ; group C were treated with the scalp acupuncture in the group A combined with the rehabilitation therapy in the group B. Improvement of neural function defect and activity of daily life ( ADL ) , and clinical therapeutic effect were observed . RESULTS After treatment , the scores of neural function defect of 6.14 + /- 0.36 in the group C was significantly lower than 8.94 + /- 0.56 in the group A and 8.64 + /- 0.49 in the group B ( P<0.05 ) ; the score of ADL of 88.39 + /- 10.02 and clinical therapeutic effect of 90.0 % in the group C were significantly higher than 74.19 + /- 12.12 and 76.7 % in the group A and 72.29 + /- 11.52 and 73.3 % in the group B ( P<0.05 ) . CONCLUSION The scalp acupuncture and rehabilitation therapy have synergistic action in improving motor function for the hemiplegic patient of cerebral thrombosis at convalescent period , and it is a better method for cerebral thrombosis at the convalescent stage [16344019] OBJECTIVE To compare the effects of traditional Chinese acupuncture with sham acupuncture on upper-extremity ( UE ) function and quality of life ( QOL ) in patients with chronic hemiparesis from stroke . DESIGN A prospect i ve , sham-controlled , r and omized controlled trial ( RCT ) . SETTING Patients recruited through a hospital stroke rehabilitation program . PARTICIPANTS Thirty-three subjects who incurred a stroke 0.8 to 24 years previously and had moderate to severe UE functional impairment . INTERVENTIONS Active acupuncture tailored to traditional Chinese medicine diagnoses , including electroacupuncture , or sham acupuncture . Up to 20 treatment sessions ( mean , 16.9 ) over a mean of 10.5 weeks . MAIN OUTCOME MEASURES UE motor function , spasticity , grip strength , range of motion ( ROM ) , activities of daily living , QOL , and mood . All outcomes were measured at baseline and after treatment . RESULTS Intention-to-treat ( ITT ) analyses found no statistically significant differences in outcomes between active and sham acupuncture groups . Analyses of protocol -compliant subjects revealed significant improvement in wrist spasticity ( P<.01 ) and both wrist ( P<.01 ) and shoulder ( P<.01 ) ROM in the active acupuncture group , and improvement trends in UE motor function ( P=.09 ) and digit ROM ( P=.06 ) . CONCLUSIONS Based on ITT analyses , we conclude that acupuncture does not improve UE function or QOL in patients with chronic stroke symptoms . However , gains in UE function observed in protocol -compliant subjects suggest traditional Chinese acupuncture may help patients with chronic stroke symptoms . These results must be interpreted cautiously because of small sample sizes and multiple , unadjusted , post hoc comparisons . A larger , more definitive RCT using a similar design is feasible and warranted [17378195] OBJECTIVE To observe effect of acupuncture combined witb byperbaric oxygenation on balance function of cerebral infa rct ion . METHODS Seventy-two cases were r and omly divided into a treatment group and a control group , 36 cases in each group . The control group were treated with routine medicine and hyperbaric oxygenation , and the treatment group with acupuncture on the basis of treatment method of the control group . Berg balance scale ( BBS ) was used for investigating changes of balance function before and after treatment in the patient of cerebral infa rct ion . RESULTS After treatment , the balance function improved in the two groups , with more significant improvement in the treatment group . And increase of motor function in the treatment group was more rapid than that in the control group ( P < O. 01 ) . CONCLUSION Acupuncture combined with hyperbaric oxygenation can overall and synchronously rehabilitate sense and motor functions , significantly improve balance disturbance in the patient of cerebral infa rct ion , with unique therapeutic effect on dysopia and dysacusis for the patient of cerebral infa rct ion at the early stage [18447213] OBJECTIVE To observe therapeutic effect of Tiaoshen Fuyin acupuncture therapy on cerebral infa rct ion-induced Broca aphasia . METHODS Sixty cases were r and omly divided into an observation group and a control group , 30 cases in each group . The observation group were treated with Tiaoshen Fuyin acupuncture therapy and language training , and the control group with simple language training . For the acupuncture treatment , Sishencong ( EX-HN 1 ) , Benshen ( GB 13 ) , Shenting ( GV 24 ) , Lianquan ( CV 23 ) , Xinshu ( BL 15 ) , Shentang ( BL 44 ) , Shendao ( GV 11 ) , Lingtao ( HT 4 ) were selected and language training included training of phonatory organs in mouth , the mouth shape , sound , spoken language expression and practical exchange ability . They were treated for 5 therapeutic courses . Language examination was conducted once each before and after treatment with " Aphasia Battery of Chinese " ( ABC method ) . RESULTS The therapeutic effect of Tiaoshen Fuyin acupuncture therapy combined with language training was better than that of simple language training . CONCLUSION Tiaoshen Fuyin acupuncture therapy combined with language training can significantly improve language function and increase life quality in the patient of cerebral infa rct ion-induced Broca aphasia [19803232] OBJECTIVE To provide reliable evidence of " J in three-needle therapy " for treatment of stroke . METHODS Multi- central r and omized controlled trials were adopted , 180 hemiplegia patients of ischemic stroke were r and omly divided into a fin three-needle group ( 90 cases ) and a routine acupuncture group ( 90 cases ) . Two groups were both treated with basic neurology therapies , and J in three-needle group was treated with J in three-needle therapy , three acupoints of tempora , h and and foot etc . were selected ; the routine acupuncture group was treated with traditional acupuncture , Quchi ( LI 11 ) , Huantiao ( GB 30 ) , Futu ( ST 32 ) etc . were selected . Both groups were treated with acupuncture for 5 weeks . The cognitive function score of functional comprehensive assessment scale ( FCA ) , the scores of mini-mental state examination scale ( MMSE ) and modified Barthel index ( BI ) were compared before and after treatment between two groups . Results After treatment , the scores of FCA , MMSE and BI in both groups were significantly improved compared to those before treatment ( P < 0.01 , P < 0.05 ) ; the improvement of FCA score , MMSE score and BI score in the J in three-needle group were superior to those of the routine acupuncture group after treatment ( P < 0.01 , P < 0.05 ) . The total effective rate of 85.4 % in the J in three-needle group was superior to tohat of 70.0 % in the routine acupuncture group ( P < 0.05 ) . CONCLUSION J in three-needle acupuncture treatment can obviously improve the cognitive function and activity ability of daily life of hemiplegia patients after stroke , and the therapeutic effect of J in three-needle therapy is superior to that of traditional acupuncture treatment [17691578] OBJECTIVE To observe the therapeutic effect of cluster-needle stimulation of scalp-points combined with rehabilitation training for apoplectic aphemia . METHODS A total of 56 out patients were r and omized into control ( medication , manicol/ beronald , Ca2 + antagonist , citicoline , etc . ) group . rehabilitation ( Rehab , visual-listening , articulation and speech training ) group and acupuncture [ Dingqu : 1 cun and 2 cun parallel to the line joining Baihui ( GV 20 ) and Qi and ing ( GV 21 ) respectively on the bilateral sides . Dingqianqu : 1 cun and 2 cun parallel to the line joining GV21 and Xinghui ( GV 22 ) separately on both sides . etc ] combined with rehabilitation ( Acup+ Rehab ) group . Aphasia Battery of Chinese ( ABC ) was used to assess the patient 's speech ability , i.e. , aphasia quocient ( AQ ) ; The Chinese functional communication ( CFCP ) test was used to evaluate the patient 's daily life speech communication ability , and Boston Diagnostic Aphasia Examination ( BDAE ) was also conducted to assess the severity of aphasia . RESULTS After the treatment , the speech ability , oral presentation , listening comprehension , writing ability , AQ index and CFCP were all improved significantly in 3 groups ( P < 0.005 , 0.01 ) ; the total effective rate ( 85.00 % ) of Acup+ Rehab group was significantly higher than those of Rehab group ( 77.78 % ) and control group ( 64.71 % , P < 0.05 , 0.01 ) . The scores of ABC , AQ index , CFCP and BDAE grade in Acup+ Rehab group were significantly higher than those of Rehab and control groups ( P < 0.05 , 0.01 ) , and those scores of Rehab group were also significantly higher than those of control group ( P < 0.05 , 0.01 ) . CONCLUSION The cluster-needle puncture of scalp-points combined with rehabilitation training is an effective therapy for improving apoplectic aphemia [9388311] VIP , SS and PP which exist in gastrointestinal tract and CNS might be to play an important role in nervous system as neurotransmitters of neuromediaters . There have been a few of reports about their changes in plasma and CSF in ICVD . The effects of acupuncture , which was used in treatment of ICVD with good efficiency , on VIP , SS and PP have not been known . For research ing their changes in ICVD and effects of electro-acupuncture on them , and finding the mechanism of acupuncture in treatment of ICVD , the study was performed . The levels of VIP , SS and PP in 64 patients with acute cerebral infa rct ion were determined . The points of acupuncture were Quchi ( LI 12 ) , Waiguan ( SJ 5 ) , Huantiao ( BG 30 ) , and Zusanli ( ST 36 ) . The routine treatment included dextran , nicotinic acid , aspirin , dipyridamole and radix salviae miltiorrhizae composita . The CSF and blood were taken before the begining of treatments and after a course of treatment . The level of VIP , SS and PP were measured by radiommunoassay . Results showed the level of CSF VIP in the patients was significantly lower as compared with controls . The level of plasma SS in the patients was lower , but the difference was not significant as compared with controls , and level of plasma PP in the patients was significantly increased when it was compared with controls . After electro-acupuncture treatment , in patients with good efficiency , CSF VIP recovered to normal level and the levels of plasma and CSF SS were significantly increased , while the level of plasma PP had no significant change . The results suggest that acupuncture might regulate the disturbances of metabolism of VIP and SS in CNS [20578378] OBJECTIVE To provide biomechanics basis for acupuncture improving motor function of stroke patients . METHODS With r and omized controlled trial method , 21 cases were r and omly divided into a control group ( n = 10 ) and an acupuncture group ( n = 10 ) . The control group was only treated with basic neurology therapies , and acupuncture at Shenshu ( BL 23 ) , Qihaishu ( BL 24 ) , Dachangshu ( BL 25 ) and Pishu ( BL 20 ) etc . were added in the acu-puncture group . After treatment for 2 weeks , the scores of Fugl-Meyer ( lower limb part ) and Barthel Index assessment before and after treatment were compared , and the changes of the single-foot supporting phase rate were observed . RESULTS After treatment , the scores of Fugl-Meyer ( lower limb part ) and Barthel Index assessment had no significant difference in the two groups as compared with those before treatment ( P > 0.05 ) , and the single-foot supporting phase rate in acupuncture group had very significant improvement as compared with both those before treatment and those in the control group ( P < 0.05 and P < 0.01 , respectively ) . CONCLUSION Acupuncture can increase the single-foot supporting phase rate of stroke patients and the biomechanics assessment is more sensitive than the rehabilitation scale assessment [9360031] Objective : We recently reported that acupuncture treatment of stroke patients in the subacute stage gave additive therapeutic benefit . The purpose of the present study was to determine , approximately one year after discharge from the rehabilitation hospital , whether the group differences still remained . Design : The patients were r and omized into two groups : one acupuncture group and one control group , considering gender and side of hemispheral localization of lesion . With regard to the main parameters the groups were comparable at baseline . Setting : Initially , 45 stroke patients admitted to Sunnaas Rehabilitation Hospital were included in the study : median 40 days post stroke . Subjects : Forty-one of the patients were available one year after the treatment period : 21 patients in the acupuncture group and 20 controls . Intervention : All subjects received an individually adapted , multidisciplinary rehabilitation programme . The acupuncture group received additional treatment with classical acupuncture for 30 min three to four times weekly for six weeks . Main outcome measures : The patients were evaluated at inclusion , after six weeks and approximately 12 months after discharge from the rehabilitation hospital . The Motor Assessment Scale ( MAS ) for stroke patients , Sunnaas Index of Activity of Daily Living ( ADL ) and Nottingham Health Profile ( NHP ) were used . In addition , the social situations of the patients were recorded at one year follow-up . Results : The results show that the acupuncture group improved significantly more than the controls , both during the treatment period of six weeks , and even more during the following year , both according to MAS , ADL , NHP and the social situation . Conclusion : Although the mechanism of the effects is debatable , there seems to be a positive long-term effect of acupuncture given in the subacute stage post stroke Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Various approaches to physical rehabilitation may be used after stroke , and considerable controversy and debate surround the effectiveness of relative approaches . Some physiotherapists base their treatments on a single approach ; others use a mixture of components from several different approaches . OBJECTIVES To determine whether physical rehabilitation approaches are effective in recovery of function and mobility in people with stroke , and to assess if any one physical rehabilitation approach is more effective than any other approach . For the previous versions of this review , the objective was to explore the effect of ' physiotherapy treatment approaches ' based on historical classifications of orthopaedic , neurophysiological or motor learning principles , or on a mixture of these treatment principles . For this up date of the review , the objective was to explore the effects of approaches that incorporate individual treatment components , categorised as functional task training , musculoskeletal intervention ( active ) , musculoskeletal intervention ( passive ) , neurophysiological intervention , cardiopulmonary intervention , assistive device or modality . In addition , we sought to explore the impact of time after stroke , geographical location of the study , dose of the intervention , provider of the intervention and treatment components included within an intervention . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

25227906

[22945403] BACKGROUND AND OBJECTIVE : Relative deficiency of dietary omega 3 polyunsaturated fatty acids ( n-3 PUFA ) has been implicated in the rising allergy prevalence in Westernized countries . Fish oil supplementation may provide an intervention strategy for primary allergy prevention . The objective of this study was to assess the effect of fish oil n-3 PUFA supplementation from birth to 6 months of age on infant allergic disease . METHODS : In a double-blind r and omized controlled trial , 420 infants at high atopic risk received a daily supplement of fish oil containing 280 mg docosahexaenoic acid and 110 mg eicosapentaenoic acid or a control ( olive oil ) , from birth to age 6 months . PUFA levels were measured in 6-month-old infants ’ erythrocytes and plasma and their mothers ’ breast milk . Eczema , food allergy , asthma and sensitization were assessed in 323 infants for whom clinical follow-up was completed at 12 months of age . RESULTS : At 6 months of age , infant docosahexaenoic acid and eicosapentaenoic acid levels were significantly higher ( both P < .05 ) and erythrocyte arachidonic acid levels were lower ( P = .003 ) in the fish oil group . Although n-3 PUFA levels at 6 months were associated with lower risk of eczema ( P = .033 ) and recurrent wheeze ( P = .027 ) , the association with eczema was not significant after multiple comparisons and there was no effect of the intervention per se on the primary study outcomes . Specifically , between-group comparisons revealed no differences in the occurrence of allergic outcomes including sensitization , eczema , asthma , or food allergy . CONCLUSIONS : Postnatal fish oil supplementation improved infant n-3 status but did not prevent childhood allergic disease [17431817] Summary Background Pre- and postnatal tissue accretion of long-chain polyunsaturated fatty acids ( LCPUFA ) has been related to visual and cognitive development in healthy children in several studies . Children with phenylketonuria ( PKU ) consume diets with very low contents of preformed LCPUFA . We studied prospect ively the LCPUFA status in infants with PKU without or with LCPUFA supplementation during the first year of life . Subjects and methods Infants with PKU were enrolled at diagnosis ( < 4 weeks of age ) and r and omized double blind to phenylalanine-free amino acid supplements without LCPUFA ( n=11 ) or with both arachidonic ( AA , 0.46 wt% ) and docosahexaenoic acids ( DHA , 0.27 wt% ) ( n=10 ) . At enrolment and again at 1 , 2 , 3 , 4 , 6 , 9 and 12 months , plasma phospholipid fatty acids were measured and dietary intakes were calculated from dietary protocol s. Results Unsupplemented patients showed a marked LCPUFA depletion to levels clearly below those observed in healthy breast-fed infants . In contrast , supplemented infants had stable and higher LCPUFA levels than unsupplemented infants , reaching significant differences for AA values at 3 , 4 and 6 months , and for DHA values at 1 , 3 , 4 , 6 , 9 and 12 months . Plasma phospholipid levels correlated closely with estimated dietary intakes of preformed LCPUFA . Conclusion Low LCPUFA intakes with PKU diets induce marked depletion of AA and particularly of DHA in the first year of life . Thus endogenous synthesis of LCPUFA from precursors supplied by diet seems unable to compensate for low LCPUFA intakes . LCPUFA supplementation of PKU diets during the first year of life effectively enhances LCPUFA status to levels comparable to those of healthy breast-fed infants [23340492] Background / Objective : Evidence is accumulating that the long-chain PUFA ( LCPUFA ) are associated with offspring growth and body composition . We investigated the relationship between LCPUFAs in red blood cells ( RBCs ) of pregnant women/breastfeeding mothers and umbilical cord RBCs of their neonates with infant growth and body composition ⩽1 year of age . Subjects/ Methods : In an open-label r and omized , controlled trial , 208 healthy pregnant women received a dietary intervention ( daily supplementation with 1200 mg n-3 LCPUFAs and dietary counseling to reduce arachidonic acid ( AA ) intake ) from the 15th week of gestation until 4 months of lactation or followed their habitual diet . Fatty acids of plasma phospholipids ( PLs ) and RBCs from maternal and cord blood were determined and associated with infant body weight , body mass index ( BMI ) , lean body mass and fat mass assessed by skinfold thickness measurements and ultrasonography . Results : Dietary intervention significantly reduced the n-6/n-3 LCPUFA ratio in maternal and cord-blood plasma PLs and RBCs . Maternal RBCs docosahexaenoic acid ( DHA ) , n-3 LCPUFAs and n-6 LCPUFAs at the 32nd week of gestation were positively related to birth weight . Maternal n-3 LCPUFAs , n-6 LCPUFAs and AA were positively associated with birth length . Maternal RBCs AA and n-6 LCPUFAs were significantly negatively related to BMI and Ponderal Index at 1 year postpartum , but not to fat mass . Conclusion : Maternal DHA , AA , total n-3 LCPUFAs and n-6 LCPUFAs might serve as prenatal growth factors , while n-6 LCPUFAs also seems to regulate postnatal growth . The maternal n-6/n-3 LCPUFA ratio does not appear to have a role in adipose tissue development during early postnatal life [21147707] Development of new infant formulas aims to replicate the benefits of breast milk . One benefit of breast milk over infant formulas is greater gastrointestinal comfort . We compared indicators of gastrointestinal comfort in infants fed a whey-predominant formula containing long-chain polyunsaturated fatty acids , galacto-oligo-saccharides and fructo-oligosaccharides , and infants fed a control casein-predominant formula without additional ingredients . The single-centre , prospect i ve , double-blind , controlled trial r and omly assigned healthy , full-term infants ( n=144 ) to receive exclusively either experimental or control formula from 30 days to 4 months of age . A group of exclusively breast-fed infants served as reference ( n=80 ) . At 1 , 2 , 3 , and 4 months , infants ' growth parameters were measured and their health assessed . Parents recorded frequency and physical characteristics of infants ' stool , frequency of regurgitation , vomiting , crying and colic . At 2-months , gastric emptying ( ultrasound ) and intestinal transit time ( H2 breath test ) were measured , and stool sample s collected for bacterial analysis . Compared to the control ( n=69 ) , fewer of the experimental group ( n=67 ) had hard stools ( 0.7 vs 7.5 % , p<0.001 ) and more had soft stools ( 90.8 vs 82.3 % , p<0.05 ) . Also compared to the control , the experimental group 's stool microbiota composition ( mean % bifidobacteria : 78.1 ( experimental , n=17 ) , 63.7 ( control , n=16 ) , 74.3 ( breast-fed , n=20 ) , gastric transit times ( 59.6 ( experimental , n=53 ) , 61.4 ( control , n=62 ) , 55.9 ( breast-fed , n=67 ) minutes ) and intestinal transit times ( data not shown ) were closer to that of the breast-fed group . Growth parameter values were similar for all groups . The data suggest that , in infants , the prebiotic-containing whey-based formula provides superior gastrointestinal comfort than a control formula [18951004] Formula supplemented with docosahexaenoic acid ( DHA ) improves retinal function of preterm infants but the optimal dose is unknown . In a r and omized controlled trial we examined the effect of increasing the DHA concentration of human milk and formula on circulating fatty acids of preterm infants . Infants born <33 weeks gestation were fed high-DHA milk ( 1 % total fat as DHA ) or st and ard-DHA milk ( 0.2 - 0.3 % DHA ) until reaching their estimated due date ( EDD ) . Milk arachidonic acid ( AA ) concentration was approximately 0.5 % for both groups . At EDD , erythrocyte membrane phospholipid DHA was elevated in the high-DHA group compared with st and ard-DHA ( mean+/-SD , high-DHA 6.8+/-1.2 , st and ard-DHA 5.2+/-0.7 , p<0.0005 ) but AA was lower ( high-DHA 14.9+/-1.3 , st and ard-DHA 16.0+/-1.2 , p<0.0005 ) . Feeding preterm infants human milk and formula with 1 % DHA raises but does not saturate erythrocyte phospholipids with DHA . Milk exceeding 1 % DHA may be required to increase DHA status to levels seen in term infants [20959577] CONTEXT Uncertainty about the benefits of dietary docosahexaenoic acid ( DHA ) for pregnant women and their children exists , despite international recommendations that pregnant women increase their DHA intakes . OBJECTIVE To determine whether increasing DHA during the last half of pregnancy will result in fewer women with high levels of depressive symptoms and enhance the neurodevelopmental outcome of their children . DESIGN , SETTING , AND PARTICIPANTS A double-blind , multicenter , r and omized controlled trial ( DHA to Optimize Mother Infant Outcome [ DOMInO ] trial ) in 5 Australian maternity hospitals of 2399 women who were less than 21 weeks ' gestation with singleton pregnancies and who were recruited between October 31 , 2005 , and January 11 , 2008 . Follow-up of children ( n = 726 ) was completed December 16 , 2009 . INTERVENTION Docosahexaenoic acid-rich fish oil capsules ( providing 800 mg/d of DHA ) or matched vegetable oil capsules without DHA from study entry to birth . MAIN OUTCOME MEASURES High levels of depressive symptoms in mothers as indicated by a score of more than 12 on the Edinburgh Postnatal Depression Scale at 6 weeks or 6 months postpartum . Cognitive and language development in children as assessed by the Bayley Scales of Infant and Toddler Development , Third Edition , at 18 months . RESULTS Of 2399 women enrolled , 96.7 % completed the trial . The percentage of women with high levels of depressive symptoms during the first 6 months postpartum did not differ between the DHA and control groups ( 9.67 % vs 11.19 % ; adjusted relative risk , 0.85 ; 95 % confidence interval [ CI ] , 0.70 - 1.02 ; P = .09 ) . Mean cognitive composite scores ( adjusted mean difference , 0.01 ; 95 % CI , -1.36 to 1.37 ; P = .99 ) and mean language composite scores ( adjusted mean difference , -1.42 ; 95 % CI , -3.07 to 0.22 ; P = .09 ) of children in the DHA group did not differ from children in the control group . CONCLUSION The use of DHA-rich fish oil capsules compared with vegetable oil capsules during pregnancy did not result in lower levels of postpartum depression in mothers or improved cognitive and language development in their offspring during early childhood . TRIAL REGISTRATION anzctr.org.au Identifier : ACTRN12605000569606 [23761484] BACKGROUND Early-life exposures to tobacco smoke and some dietary factors have been identified to induce epigenetic changes in genes involved in allergy and asthma development . Omega-3 ( n-3 ) polyunsaturated fatty acid ( PUFA ) intake during pregnancy could modulate key cytokines and T helper ( Th ) cell maturation ; however , little is known about the mechanism by which ω-3 PUFA could have a beneficial effect in preventing inflammatory disorders . OBJECTIVE We sought to test whether prenatal dietary supplementation with ω-3 PUFA during pregnancy may modulate epigenetic states in the infant immune system . DESIGN This study was based on a r and omized intervention trial conducted in Mexican pregnant women supplemented daily with 400 mg docosahexaenoic acid ( DHA ) or a placebo from 18 to 22 wk of gestation to parturition . We applied quantitative profiling of DNA methylation states in Th1 , Th2 , Th17 , and regulatory T-relevant genes as well as LINE1 repetitive elements of cord blood mononuclear cells ( n = 261 ) . RESULTS No significant difference in promoter methylation levels was shown between ω-3 PUFA-supplemented and control groups for the genes analyzed ; however , ω-3 PUFA supplementation was associated with changes in methylation levels in LINE1 repetitive elements ( P = 0.03 ) in infants of mothers who smoked during pregnancy . Furthermore , an association between the promoter methylation levels of IFNγ and IL13 was modulated by ω-3 PUFA supplementation ( P = 0.06 ) . CONCLUSIONS Our results indicate that maternal supplementation with ω-3 PUFA during pregnancy may modulate global methylation levels and the Th1/Th2 balance in infants . Therefore , the epigenetic mechanisms could provide attractive targets for prenatal modulation and prevention of inflammatory disorders and potentially other related diseases in childhood and adulthood [21705958] Conflicting evidence exists on the effect of long-chain polyunsaturated fatty acid ( LCPUFA ) formula supplementation on cardiovascular health in term infants . It is known that LCPUFA supplementation does not affect infant growth , but long term outcome data are not available . The current study investigates whether 2 mo LCPUFA formula supplementation affects cardiovascular and anthropometric development at 9 y. A prospect i ve , double-blind , r and omized trial was performed in healthy term infants : a st and ard formula control group ( CF , n = 169 ) and a LCPUFA-supplemented group [ LF , n = 145 ; 0.45 % ( by wt ) AA and 0.30 % ( by wt ) docosahexaenoic acid ( DHA ) ] . A breastfed group ( BF ; n = 159 ) served as reference . At the age of 9 y , systolic and diastolic blood pressure , heart rate , head circumference , weight , and height were measured . Univariate and multivariate analyses were performed ; 63 to 79 % of children were assessed . None of the cardiovascular or anthropometric measurements differed between the formula groups . Breastfed children had a marginally lower heart rate than formula-fed children , in particular compared with children fed control formula . Blood pressure and parameters of growth including BMI of breast and formula-fed children did not differ . In conclusion , the study suggests that short-term LCPUFA supplementation does not influence cardiovascular and anthropometric development at 9 [3522138] Background : Intestinal damage and malabsorption caused by chronic environmental enteropathy are associated with growth faltering seen in infants in less-developed countries . Evidence has suggested that supplementary omega-3 ( n−3 ) long-chain PUFAs ( LC-PUFAs ) might ameliorate this damage by reducing gastrointestinal inflammation . LC-PUFA supplementation may also benefit cognitive development . Objective : We tested whether early n−3 LC-PUFA supplementation improves infant intestinal integrity , growth , and cognitive function . Design : A r and omized , double-blind , controlled trial [ 200 mg DHA and 300 mg EPA or 2 mL olive oil/d for 6 mo ] was conducted in a population of 172 rural Gambian infants aged 3–9 mo . The primary endpoints were anthropometric measures and gut integrity [ assessed by using urinary lactulose : mannitol ratios ( LMRs ) ] . Plasma fatty acid status , intestinal mucosal inflammation ( fecal calprotectin ) , daily morbidity , and cognitive development ( 2-step means-end test and an attention assessment ) were secondary endpoints . Results : PUFA supplementation result ed in a significant increase in plasma n−3 LC-PUFA concentrations ( P < 0.001 for both DHA and EPA ) and midupper arm circumference ( MUAC ) ( effect size : 0.31 z scores ; 95 % CI : 0.06 , 0.56 ; P = 0.017 ) at 9 mo of age . At 12 mo , MUAC remained greater in the intervention group , and we observed significant increases in skinfold thicknesses ( P ≤ 0.022 for all ) . No other significant differences between treatment groups were detected for growth or LMRs at 9 mo or for secondary outcomes . Conclusions : Fish-oil supplementation successfully increased plasma n−3 fatty acid status . However , in young , breastfed Gambian infants , the intervention failed to improve linear growth , intestinal integrity , morbidity , or selected measures of cognitive development . The trial was registered at www.is rct n.org as IS RCT N66645725 [22218160] BACKGROUND Long-chain n-3 PUFAs found in oily fish may have a role in lowering the risk of allergic disease . OBJECTIVE The objective was to assess whether an increased intake of oily fish in pregnancy modifies neonatal immune responses and early markers of atopy . DESIGN Women ( n = 123 ) were r and omly assigned to continue their habitual diet , which was low in oily fish , or to consume 2 portions of salmon per week ( providing 3.45 g EPA plus DHA ) from 20 wk gestation until delivery . In umbilical cord blood sample s ( n = 101 ) , we measured n-3 fatty acids , IgE concentrations , and immunologic responses . Infants were clinical ly evaluated at age 6 mo ( n = 86 ) . RESULTS Cord blood mononuclear cell ( C BMC ) production of interleukin (IL)-2 , IL-4 , IL-5 , IL-10 , and tumor necrosis factor-α in response to phytohemagglutinin ( PHA ) and of IL-2 in response to Dermatophagoides pteronyssinus allergen 1 ( Derp1 ) was lower in the salmon group ( all P ≤ 0.03 ) . In the subgroup of C BMC s in which an allergic phenotype was confirmed in the mother or father , IL-10 production in response to Toll-like receptor 2 , 3 , and 4 agonists , ovalbumin , salmon parvalbumin , or Derp1 and prostagl and in E(2 ) production in response to lipopolysaccharide or PHA was lower in the salmon group ( all P ≤ 0.045 ) . Total IgE at birth and total IgE , incidence and severity of atopic dermatitis , and skin-prick-test positivity at 6 mo of age were not different between the 2 groups . CONCLUSION Oily fish intervention in pregnancy modifies neonatal immune responses but may not affect markers of infant atopy assessed at 6 mo of age . This trial is registered at clinical trials.gov as NCT00801502 [21332799] We have previously reported a protective effect of maternal omega-3 long-chain polyunsaturated fatty acids ( ω-3 LCPUFA ) supplementation in pregnancy and lactation on IgE-associated eczema and food allergy in the infant during the first year of life . Here we investigate whether the effects of the LCPUFA supplementation on IgE-associated diseases last up to 2 yr of age and assess the relationship between plasma proportions of ω-3 PUFAs and the frequency and severity of infant allergic disease . 145 pregnant women , at risk of having an allergic infant , were r and omized to daily supplementation with 1.6 g eicosapentaenoic acid ( EPA ) and 1.1 g docosahexaenoic acid ( DHA ) or placebo starting in the 25th gestational week and continuing through 3.5 months of breastfeeding . Clinical examinations , skin prick tests and analysis of maternal and infant plasma phospholipid fatty acids and infant specific IgE were performed . No difference in the prevalence of allergic symptoms was found between the intervention groups . The cumulative incidence of IgE-associated disease was lower in the ω-3-supplemented group ( 6/54 , 13 % ) compared with the placebo group ( 19/62 , 30 % , p=0.01 ) . Higher maternal and infant proportions of DHA and EPA were associated with lower prevalence of IgE associated disease ( p=0.01 - 0.05 ) in a dose-dependent manner . Higher maternal and infant proportions of DHA and EPA were found if the infants presented none , when compared with multiple allergic symptoms , ( p<0.05 ) regardless of sensitization . In summary , the ω-3 supplementation offered no obvious preventive effect on the prevalence of clinical symptoms of allergic disease , but the decrease in cumulative incidence of IgE-associated disease seen during the first year still remained until 2 yr of age . Furthermore , high proportions of DHA and EPA in maternal and infant plasma phospholipids were associated with less IgE-associated disease and a reduced severity of the allergic phenotype [16002810] BACKGROUND Normal brain and visual development is thought to require exogenous docosahexaenoic acid ( DHA ; 22:6n-3 ) intake , but the amount needed is debatable . Because the supplementation of breastfeeding mothers with DHA increases the DHA content of their infants ' plasma lipids , we hypothesized that it might also improve brain or visual function in the infants . OBJECTIVE The objective was to determine the effect of DHA supplementation of breastfeeding mothers on neurodevelopmental status and visual function in the recipient infant . DESIGN Breastfeeding women received capsules containing either a high-DHA algal oil ( approximately 200 mg DHA/d ) or a vegetable oil ( no DHA ) for 4 mo after delivery . Outcome variables included the fatty acid pattern of maternal plasma phospholipid and milk lipids 4 mo postpartum , the fatty acid pattern of plasma phospholipids and visual function in infants at 4 and 8 mo of age , and neurodevelopmental indexes of the infants at 12 and 30 mo of age . RESULTS Milk lipid and infant plasma phospholipid DHA contents of the supplemented and control groups were approximately 75 % and approximately 35 % higher , respectively , at 4 mo postpartum . However , neither the neurodevelopmental indexes of the infants at 12 mo of age nor the visual function at 4 or 8 mo of age differed significantly between groups . In contrast , the Bayley Psychomotor Development Index , but not the Mental Development Index , of the supplemented group was higher ( P < 0.01 ) at 30 mo of age . CONCLUSION DHA supplementation of breastfeeding mothers results in higher infant plasma phospholipid DHA contents during supplementation and a higher Bayley Psychomotor Development Index at 30 mo of age but results in no other advantages either at or before this age [21865979] Objectives : The aim of this study was to monitor changes in the fecal microbiota from 9 to 18 months and to investigate the effect of increasing dietary n-3 polyunsaturated fatty acids on the fecal microbiota . Patients and Methods : In a double-blind controlled trial with r and om allocation to daily supplementation with 5 mL of fish oil ( FO ) or sunflower oil ( SO ) from 9 to 18 months of age , stool sample s were collected from 132 healthy Danish infants . Molecular fingerprints of the bacterial DNA were obtained by terminal restriction fragment length polymorphism ( T-RFLP ) . Results : The T-RFLP profiles indicated that a few T-RFs became dominant with age ( bp100 and 102 , both presumed to be Bacteroidetes ) concomitantly with an overall increase in the microbial diversity ( P = 0.04 ) . Breast-feeding influenced both the T-RFLP profiles at 9 months and the changes from 9 to 18 months , and breast-feeding cessation during the trial modified the response to the dietary oils . In the FO group , the increase in bp102 was significantly reduced among children weaned before compared with those weaned during the trial ( P = 0.027 ) , whereas the increase in bp100 was reduced in the preweaned children of the SO group relative to those weaned during the trial ( P = 0.004 ) . This was supported by intervention group differences in the changes in bp102 and bp100 among the earlier weaned children ( P = 0.06 and P = 0.09 , respectively ) . Conclusions : Cessation of breast-feeding played a dominant role relative to developmental changes in the fecal microbiota from 9 to 18 months . FO compared with SO supplementation affected changes in large bacterial groups , but only among children who had stopped breast-feeding before 9 months of age [17688705] Dietary fat intake in pregnancy and lactation affects pregnancy outcomes and child growth , development and health . The European Commission charged the research project PERILIP , jointly with the Early Nutrition Programming Project , to develop recommendations on dietary fat intake in pregnancy and lactation . Literature review s were performed and a consensus conference held with international experts in the field , including representatives of international scientific associations . The adopted conclusions include : dietary fat intake in pregnancy and lactation ( energy% ) should be as recommended for the general population ; pregnant and lactating women should aim to achieve an average dietary intake of at least 200 mg DHA/d ; intakes of up to 1 g/d DHA or 2.7 g/d n-3 long-chain PUFA have been used in r and omized clinical trials without significant adverse effects ; women of childbearing age should aim to consume one to two portions of sea fish per week , including oily fish ; intake of the DHA precursor , alpha-linolenic acid , is far less effective with regard to DHA deposition in fetal brain than preformed DHA ; intake of fish or other sources of long-chain n-3 fatty acids results in a slightly longer pregnancy duration ; dietary inadequacies should be screened for during pregnancy and individual counselling be offered if needed [18614738] BACKGROUND Evidence suggests that asthma is rooted in the intrauterine environment and that intake of marine n-3 polyunsaturated fatty acids ( n-3 PUFAs ) in pregnancy may have immunomodulatory effects on the child . OBJECTIVE Our aim was to examine whether increasing maternal intake of n-3 PUFAs in pregnancy may affect offspring risk of asthma . DESIGN In 1990 , a population -based sample of 533 women with normal pregnancies were r and omly assigned 2:1:1 to receive four 1-g gelatin capsules/d with fish oil providing 2.7 g n-3 PUFAs ( n = 266 ) ; four 1-g , similar-looking capsules/d with olive oil ( n = 136 ) ; or no oil capsules ( n = 131 ) . Women were recruited and r and omly assigned around gestation week 30 and asked to take capsules until delivery . Among 531 live-born children , 528 were identified in registries and 523 were still alive by August 2006 . Diagnoses from the International Coding of Diseases version 10 were extracted from a m and atory registry that recorded diagnoses reported from hospital contacts . RESULTS During the 16 y that passed since childbirth , 19 children from the fish oil and olive oil groups had received an asthma-related diagnosis ; 10 had received the diagnosis allergic asthma . The hazard rate of asthma was reduced by 63 % ( 95 % CI : 8 % , 85 % ; P = 0.03 ) , whereas the hazard rate of allergic asthma was reduced by 87 % ( 95 % CI : 40 % , 97 % ; P = 0.01 ) in the fish oil compared with the olive oil group . CONCLUSION Under the assumption that intake of olive oil in the dose provided here was inert , our results support that increasing n-3 PUFAs in late pregnancy may carry an important prophylactic potential in relation to offspring asthma [21705959] A double-blind , r and omized , controlled , parallel-group prospect i ve trial was conducted to determine whether a dose-response existed for four different levels of docosahexaenoic acid ( DHA ) supplementation on the cognitive performance of infants . A total of 122 term infants were fed one of four different formulas varying in their DHA composition ( 0.00 , 0.32 , 0.64 , and 0.96 % of total fatty acids as DHA ) from birth to 12 mo . The three DHA-supplemented formulas also contained 0.64 % of total fatty acids as arachidonic acid ( ARA , 20:4n-6 ) . Infants were tested at 4 , 6 , and 9 mo of age on a visual habituation protocol that yielded both behavioral and psychophysiological indices of attention . Infants in all DHA+ARA-supplemented conditions had lower heart rates than those in the unsupplemented condition ; there was no dose-response for this effect . The distribution of time that infants spent in different phases of attention ( a cognitive index derived from the convergence of behavioral and cardiac responses ) varied as a function of dosage . Infants supplemented at the two lower DHA doses spent proportionately more time engaged in active stimulus processing than infants fed the unsupplemented formula , whereas infants fed the highest dose were intermediate and did not differ from any other group [3213334] Nutritional influences on cardiovascular disease operate throughout life . Studies in both experimental animals and humans have suggested that changes in the peri- and early post-natal nutrition can affect the development of the various components of the metabolic syndrome in adult life . This has lead to the hypothesis that n-3 fatty acid supplementation in pregnancy may have a beneficial effect on lipid profile in the offspring . The aim of the present study was to investigate the effect of supplementation with n-3 fatty acids during the third trimester of pregnancy on lipids and lipoproteins in the 19-year-old offspring . The study was based on the follow-up of a r and omized controlled trial from 1990 where 533 pregnant women were r and omized to fish oil ( n = 266 ) , olive oil ( n = 136 ) or no oil ( n = 131 ) . In 2009 , the offspring were invited to a physical examination including blood sampling . A total of 243 of the offspring participated . Lipid values did not differ between the fish oil and olive oil groups . The relative adjusted difference ( 95 % confidence intervals ) in lipid concentrations was −3 % ( −11 ; 7 ) for LDL cholesterol , 3 % ( −3 ; 10 ) for HDL cholesterol , −1 % ( −6 ; 5 ) for total cholesterol,−4 % ( −16 ; 10 ) for TAG concentrations , 2%(−2 ; 7 ) for apolipoprotein A1 , −1 % ( −9 ; 7 ) for apolipoprotein B and 3 % ( −7 ; 15 ) in relative abundance of small dense LDL . In conclusion , there was no effect of fish oil supplementation during the third trimester of pregnancy on offspring plasma lipids and lipoproteins in adolescence [21512889] Early accumulation of n-3 long-chain PUFA ( LCPUFA ) in the brain may contribute to differences in later cognitive abilities . In this study , our objective was to examine whether fish oil ( FO ) supplementation during lactation affects processing speed , working memory , inhibitory control , and socioemotional development at 7 years . Danish mothers ( n = 122 ) were r and omized to FO [ 1.5 g/d n-3 LCPUFA ] or olive oil ( OO ) supplementation during the first 4 months of lactation . The trial also included a high-fish intake ( HFI ) reference group ( n = 53 ) . Ninety-eight children were followed-up with an assessment of processing speed , an age-appropriate Stroop task , and the Strength and Difficulties Question naire at 7 year . A group effect of the intervention ( FO vs. OO ) was found in prosocial behavior scores ; this negative effect was carried by the boys . Exploratory analyses including all participants revealed the speed of processing scores were predicted by maternal n-3 LCPUFA intake during the intervention period ( negative relation ) and maternal education ( positive relation ) . Stroop scores indicative of working memory and inhibitory control were predicted by infant erythrocyte DHA status at 4 months of age ( negative relation ) . Early fish oil supplementation may have a negative effect on later cognitive abilities . Speed of processing and inhibitory control/working memory are differentially affected , with speed of processing showing effects of fish oil intake as a whole , whereas inhibitory control/working memory was related more specifically to DHA status [18842793] BACKGROUND Preterm infants have improved visual outcomes when fed a formula containing 0.2 - 0.4 % docosahexaenoic acid ( DHA ) compared with infants fed no DHA , but the optimal DHA dose is unknown . OBJECTIVE We assessed visual responses of preterm infants fed human milk ( HM ) and formula with a DHA concentration estimated to match the intrauterine accretion rate ( high-DHA group ) compared with infants fed HM and formula containing DHA at current concentrations . DESIGN A double-blind r and omized controlled trial studied preterm infants born at <33 wk gestation and fed HM or formula containing 1 % DHA ( high-DHA group ) or approximately 0.3 % DHA ( current practice ; control group ) until reaching their estimated due date ( EDD ) . Both groups received the same concentration of arachidonic acid . Sweep visual evoked potential ( VEP ) acuity and latency were assessed at 2 and 4 mo corrected age ( CA ) . Weight , length , and head circumference were assessed at EDD and at 2 and 4 mo CA . RESULTS At 2 mo CA , acuity of the high-DHA group did not differ from the control group [ high-DHA group ( x + /- SD ) : 5.6 + /- 2.4 cycles per degree ( cpd ) , n = 54 ; control group : 5.6 + /- 2.4 cpd , n = 61 ; P = 0.96 ] . By 4 mo CA , the high-DHA group exhibited an acuity that was 1.4 cpd higher than the control group ( high-DHA : 9.6 + /- 3.7 cpd , n = 44 ; control : 8.2 + /- 1.8 cpd ; n = 51 ; P = 0.025 ) . VEP latencies and anthropometric measurements were not different between the high-DHA and control groups . CONCLUSION The DHA requirement of preterm infants may be higher than currently provided by preterm formula or HM of Australian women [17284754] BACKGROUND Maternal diet during pregnancy might be one of the factors that influences fetal immune responses associated with childhood allergy . OBJECTIVE We analyzed the association between maternal diet during the last 4 wk of pregnancy and allergic sensitization and eczema in the offspring at 2 y of age . DESIGN Data from 2641 children at 2 y of age were analyzed within a German prospect i ve birth cohort study ( LISA ) . Maternal diet during the last 4 wk of pregnancy was assessed with a semiquantitative food-frequency question naire , which was administered shortly after childbirth . RESULTS High maternal intake of margarine [ adjusted odds ratio ( aOR ) : 1 . 49 ; 95 % CI : 1.08 , 2.04 ] and vegetable oils ( aOR : 1.48 ; 95 % CI : 1.14 , 1.91 ) during the last 4 wk of pregnancy was positively associated and high maternal fish intake ( aOR : 0.75 ; 95 % CI : 0.57 , 0.98 ) was inversely associated with eczema during the first 2 y in the offspring . High celery ( aOR : 1.85 ; 95 % CI : 1.18 , 2.89 ) and citrus fruit ( aOR : 1.73 ; 95 % CI : 1.18 , 2.53 ) intakes increased the risk of sensitization against food allergens . In turn , sensitization against inhalant allergens was positively related to a high maternal intake of deep-frying vegetable fat ( aOR : 1.61 ; 95 % CI : 1.02 , 2.54 ) , raw sweet pepper ( aOR : 2.16 ; 95 % CI : 1.20 , 3.90 ) , and citrus fruit ( aOR : 1.72 ; 95 % CI : 1.02 , 2.92 ) . CONCLUSIONS We suggest that the intake of allergenic foods and foods rich in n-6 polyunsaturated fatty acids during pregnancy may increase and foods rich in n-3 polyunsaturated fatty acids may decrease the risk of allergic diseases in the offspring [22805468] Maternal fish oil supplementation during pregnancy has been associated with altered infant immune responses and a reduced risk of infant sensitization and eczema [17204967] Background : Infants in developing countries require early dietary interventions to prevent nutritional deficiencies , above all protein , energy , iron and zinc . To what extent these interventions may affect the fatty acid ( FA ) status is still unknown . Objectives : To examine and compare the effects of 2 micronutrient “ sprinkles ” supplementations ( iron 12.5 mg + folic acid 150 μg , iron/folate and iron 12.5 mg + folic acid 150 μg + zinc 5 mg + vitamins A , C and D3 , mineral/micronutrient [ MMN ] ) versus placebo on the FA status of Cambodian infants . Methods : A total of 204 infants age 6 mo and living in Kompong Chhnang Province , Cambodia , were r and omly assigned to receive daily supplementation of MMN ( n = 68 ) and iron/folate ( n = 68 ) or placebo ( n = 68 ) for a 12-mo period in powder form as sprinkles . At the end of the intervention period , FAs in the range of 16 to 24 C were determined in blood drops absorbed on a strip collected from 182 subjects , and values among the 3 intervention subgroups and those of 21 Italian 18-mo-old , normal-growing infants as the reference group were compared . Results : At the end of the supplementation trial , higher levels of the 2 essential FAs ( EFAs ) ( linoleic acid , 18:2n-6 , and α-linolenic acid , 18:3n-3 ) were found in the MMN group . No differences occurred for the major longer chain derivatives of both EFAs arachidonic acid ( 20:4n-6 ) and docosahexaenoic acid ( 22:6n-3 ) . In MMN supplemented Cambodians , blood levels of linoleic acid approached those of Italian infants , and in addition their α-linolenic acid levels were improved . Cambodian infants , mostly still breast-fed through the second year of life , showed significantly higher levels of long-chain derivatives of both the n-6 and the n-3 series compared with Italians . Conclusions : Supplementation with iron , folic acid , zinc and vitamins was associated with an increase of linoleic acid and α-linolenic acid levels in Cambodian infants versus placebo , without significant changes in the concentrations of their longer chain derivatives , result ing in a FA status closer to Italian counterparts for the essential polyunsaturated FA levels . The iron/folate – treated infants showed no differences compared with the other 2 groups . Studies are needed to differentiate the potential effects of the supplemented micronutrients on the FA status [20227721] OBJECTIVE To investigate the incidence of allergic and respiratory diseases through age 3 years in children fed docosahexaenoic acid (DHA)- and arachidonic acid (ARA)-supplemented formula during infancy . STUDY DESIGN Children who completed r and omized , double-blind studies of DHA/ARA-supplemented ( 0.32%-0.36%/0.64%-0.72 % of total fatty acids , respectively ) versus nonsupplemented ( control ) formulas , fed during the first year of life , were eligible . Blinded study nurses review ed medical charts for upper respiratory infection ( URI ) , wheezing , asthma , bronchiolitis , bronchitis , allergic rhinitis , allergic conjunctivitis , otitis media , sinusitis , atopic dermatitis ( AD ) , and urticaria . RESULTS From the 2 original cohorts , 89/179 children participated ; 38/89 were fed DHA/ARA formula . The DHA/ARA group had significantly lower odds for developing URI ( odds ratio [ OR ] , 0.22 ; 95 % confidence interval [ CI ] , 0.08 - 0.58 ) , wheezing/asthma ( OR , 0.32 ; 95 % CI , 0.11 - 0.97 ) , wheezing/asthma/AD ( OR , 0.25 ; 95 % CI , 0.09 - 0.67 ) , or any allergy ( OR , 0.28 ; 95 % CI , 0.10 - 0.72 ) . The control group had significantly shorter time to first diagnosis of URI ( P = .006 ) , wheezing/asthma ( P = .03 ) , or any allergy ( P = .006 ) . CONCLUSIONS DHA/ARA supplementation was associated with delayed onset and reduced incidence of URIs and common allergic diseases up to 3 years of age [21443815] The effect of the dietary n-3 long-chain PUFA , DHA ( 22 : 6n-3 ) , on the growth of pre-term infants is controversial . We tested the effect of higher-dose DHA ( approximately 1 % dietary fatty acids ) on the growth of pre-term infants to 18 months corrected age compared with st and ard feeding practice ( 0·2 - 0·3 % DHA ) in a r and omised controlled trial . Infants born < 33 weeks gestation ( n 657 ) were r and omly allocated to receive breast milk and /or formula with higher DHA or st and ard DHA according to a concealed schedule stratified for sex and birth-weight ( < 1250 and ≥ 1250 g ) . The dietary arachidonic acid content of both diets was constant at approximately 0·4 % total fatty acids . The intervention was from day 2 to 5 of life until the infant 's expected date of delivery ( EDD ) . Growth was assessed at EDD , and at 4 , 12 and 18 months corrected age . There was no effect of higher DHA on weight or head circumference at any age , but infants fed higher DHA were 0·7 cm ( 95 % CI 0·1 , 1·4 cm ; P = 0·02 ) longer at 18 months corrected age . There was an interaction effect between treatment and birth weight strata for weight ( P = 0·01 ) and length ( P = 0·04 ) . Higher DHA result ed in increased length in infants born weighing ≥ 1250 g at 4 months corrected age and in both weight and length at 12 and 18 months corrected age . Our data show that DHA up to 1 % total dietary fatty acids does not adversely affect growth [16618358] It has been suggested that changes in dietary habits , particularly increased consumption of omega-6 polyunsaturated fatty acids ( PUFA ) and decreased consumption of omega-3 PUFAs may explain the increase in atopic disease seen in recent years . Furthermore , it seems possible that it is mainly prenatal or very early life environmental factors that influence the development of allergic diseases . It has also been suggested that intrauterine risk factors may act differently if mother themselves suffer from allergic disease . The aim of this study was to investigate whether the consumption of fish , butter and margarine during pregnancy might influence the development of allergic sensitizations in the offspring . The study population was divided into the offspring of allergic and non-allergic mothers . This was a retrospective cohort study enrolling 295 offspring of allergic mothers and 693 of non-allergic mothers . Information regarding maternal intake of fish , butter and margarine during pregnancy as well as other prenatal and perinatal confounding factors were retrospectively assessed by parental report via a st and ardized question naire . Atopy was determined by skin-prick tests ( SPT ) to eight prevalent inhalant allergens and two foods . In the allergic mothers ' group there is no clear correlation between maternal intakes of fish , butter and margarine and sensitizations to food or inhalants . In the non-allergic mothers ' group there was no correlation between butter and margarine intake and food or inhalant sensitizations . On the contrary , a protective effect of fish intake on SPT positivity was observed . In particular , frequent maternal intake ( ' 2 - 3 times/wk or more ' ) of fish reduced the risk of food sensitizations by over a third ( aOR 0.23 ; 95 % CI : 0.08 - 0.69 ) . A similar trend , even if not significant , was found for inhalants . Finally , even in the whole study population , i.e. allergic group plus non-allergic group , there was a similar trend between increased consumption of fish and decreased prevalence of SPT positivity for foods . This study shows that frequent intake of fish during pregnancy may contrast the development of SPT sensitizations for foods in the offspring of mothers without atopic disease . Therefore , larger prospect i ve studies are needed , enrolling mothers with and without allergic disease , to confirm these results [3175709] Background . It is currently recommended that diet of pregnant mothers contain 200–300 mg DHA/day . Aim . To determine whether DHA supplementation during pregnancy and lactation affects infants ' immune response . Methods . 60 women in ≥3rd pregnancy studied ; 30 r and omly assigned to receive DHA 400 mg/day from 12th week gestation until 4 months postpartum . From breast-fed infants , blood obtained for anti-HBs antibodies , immunoglobulins , lymphocyte subset phenotyping , and intracellular cytokine production . Results . CD4 + lymphocytes did not differ between groups , but CD4CD45RA/CD4 ( naïve cells ) significantly higher in infants in DHA+ group . Proportion of CD4 and CD8 cells producing IFNγ significantly lower in DHA+ group , with no differences in proportion of IL4-producing cells . Immunoglobulins and anti-HBs levels did not differ between groups . Conclusions . In infants of mothers receiving DHA supplementation , a higher percentage of CD4 naïve cells and decreased CD4 and CD8 IFNγ production is compatible with attenuation of a proinflammatory response [21490140] BACKGROUND The docosahexaenoic acid ( DHA ) intake of pregnant women is lower than estimates of the DHA accretion by the fetus , and recommendations were made to increase the DHA intake of pregnant women . OBJECTIVE The objective of this study was to determine whether the supplementation of pregnant women with DHA improved the visual acuity of infants at 4 mo . DESIGN We conducted a blinded assessment of a subset of healthy , full-term infants born to women enrolled in a double-blind , r and omized controlled trial called the DHA for Maternal and Infant Outcomes ( DOMInO ) trial . Women were r and omly assigned to consume DHA-rich fish-oil capsules ( ≈800 mg DHA/d in the treatment group ) or vegetable oil capsules ( control group ) from midpregnancy to delivery . The primary outcome was the sweep visual evoked potential ( VEP ) acuity at 4 mo . The VEP latency at 4 mo was a secondary outcome . RESULTS Mean ( ±SD ) VEP acuity did not differ between treatment and control groups [ treatment group : 8.37 ± 2.11 cycles per degree ( cpd ) , n = 89 ; control group : 8.55 ± 1.86 cpd , n = 93 ; P = 0.55 ] . VEP latencies also did not differ between groups . Irrespective of the group , maternal smoking in pregnancy was independently associated with poorer VEP acuity in the infant . CONCLUSIONS DHA supplementation in women with singleton pregnancies does not enhance infant visual acuity in infants at 4 mo of age . Visual acuity in infancy is adversely associated with maternal smoking in pregnancy . This trial was registered at www.anzctr.org.au as ACTRN12606000327583 . The DOMInO trial was registered at www.anzctr.org.au as ACTRN12605000569606 [22205307] BACKGROUND The composition of long-chain PUFAs ( LCPUFAs ) in the maternal diet may affect obesity risk in the mother 's offspring . OBJECTIVE We hypothesized that a reduction in the n-6 (omega-6):n-3 ( omega-3 ) LCPUFA ratio in the diet of pregnant women and breastfeeding mothers may prevent expansive adipose tissue growth in their infants during the first year of life . DESIGN In a r and omized controlled trial , 208 healthy pregnant women were r and omly assigned to an intervention ( 1200 mg n-3 LCPUFAs as a supplement per day and a concomitant reduction in arachidonic acid intake ) or a control diet from the 15th wk of pregnancy to 4 mo of lactation . The primary outcome was infant fat mass estimated by skinfold thickness ( SFT ) measurements at 4 body sites at 3 - 5 d , 6 wk , and 4 and 12 mo postpartum . Secondary endpoints included sonographic assessment of abdominal subcutaneous and preperitoneal fat , fat distribution , and child growth . RESULTS Infants did not differ in the sum of their 4 SFTs at ≤1 y of life [ intervention : 24.1 ± 4.4 mm ( n = 85 ) ; control : 24.1 ± 4.1 mm ( n = 80 ) ; mean difference : -0.0 mm ( 95 % CI : -1.3 , 1.3 mm ) ] or in growth . Likewise , longitudinal ultrasonography showed no significant differences in abdominal fat mass or fat distribution . CONCLUSIONS We showed no evidence that supplementation with n-3 fatty acids and instructions to reduce arachidonic acid intake during pregnancy and lactation relevantly affects fat mass in offspring during the first year of life . Prospect i ve long-term studies are needed to explore the efficacy of this dietary approach for primary prevention . This trial was registered at clinical trials.gov as NCT00362089 [21708809] BACKGROUND : Docosahexaenoic acid ( DHA ) has been associated with downregulation of inflammatory responses . OBJECTIVE : To report the effect of DHA supplementation on long-term atopic and respiratory outcomes in preterm infants . METHODS : This study is a multicenter , r and omized controlled trial comparing the outcomes for preterm infants <33 weeks ' gestation who consumed expressed breast milk from mothers taking either tuna oil ( high-DHA diet ) or soy oil ( st and ard-DHA ) capsules . Data collected included incidence of bronchopulmonary dysplasia ( BPD ) and parental reporting of atopic conditions over the first 18 months of life . RESULTS : Six hundred fifty-seven infants were enrolled ( 322 to high-DHA diet , 335 to st and ard ) , and 93.5 % completed the 18-month follow-up . There was a reduction in BPD in boys ( relative risk [ RR ] : 0.67 [ 95 % confidence interval ( CI ) : 0.47–0.96 ] ; P = .03 ) and in all infants with a birth weight of < 1250 g ( RR : 0.75 [ 95 % CI : 0.57–0.98 ] ; P = .04 ) . There was no effect on duration of respiratory support , admission length , or home oxygen requirement . There was a reduction in reported hay fever in all infants in the high-DHA group at either 12 or 18 months ( RR : 0.41 [ 95 % CI : 0.18–0.91 ] ; P = .03 ) and at either 12 or 18 months in boys ( RR : 0.15 [ 0.03–0.64 ] ; P = .01 ) . There was no effect on asthma , eczema , or food allergy . CONCLUSIONS : DHA supplementation for infants of <33 weeks ' gestation reduced the incidence of BPD in boys and in all infants with a birth weight of < 1250 g and reduced the incidence of reported hay fever in boys at either 12 or 18 months [19134240] Probiotics and long-chain PUFA ( LC-PUFA ) may be beneficial supplements for infants who are not breast-fed . The aim of the present study is to evaluate the safety of an infant formula containing the LC-PUFA DHA and arachidonic acid ( AA ) and the probiotic Bifidobacterium lactis by comparing the growth rate of infants fed the supplemented and unsupplemented formulas . One hundred and forty-two healthy , term infants were enrolled in a single-centre , r and omised , double-blind , controlled , parallel-group trial , and allocated to receive either st and ard or probiotic and LC-PUFA-containing experimental formulas . The infants were fed with their assigned formulas for 7 months . The primary outcome ( weight gain ) and the secondary outcomes ( length , head circumference and formula tolerance ) were measured throughout the study . LC-PUFA status was assessed at 4 months of age and immune response to childhood vaccines was measured at 7 months of age . There was no significant difference in growth between the two groups . The 90 % CI for the difference in mean weight gain was - 0.08 , 3.1 g in the intention-to-treat population and 0.1 - 3.8 g in the per protocol population , which lay within the predefined boundaries of equivalence , - 3.9 - 3.9 . There were no significant differences in mean length and head circumference . DHA and AA concentrations were higher in infants in the experimental formula group compared with the control formula group . No influence of the supplements on the response to vaccines was observed . Growth characteristics of term infants fed the starter formula containing a probiotic and LC-PUFA were similar to st and ard formula-fed infants [19091800] Early nutrition may program obesity and cardiovascular risk later in life , and one of the potential agents is ( n-3 ) long-chain PUFA ( LCPUFA ) . In this study , our objective was to examine whether fish oil ( FO ) supplementation during lactation affects blood pressure and body composition of children . Danish mothers ( n = 122 ) were r and omized to FO [ 1.5 g/d ( n-3 ) LCPUFA ] or olive oil ( OO ) supplementations during the first 4 mo of lactation . The trial also included a high-fish intake reference group ( n = 53 ) . Ninety-eight children were followed-up with blood pressure and anthropometry measurements at 7 y. Diet and physical activity level ( PAL ) were assessed by 4-d weighed dietary records and ActiReg . The PAL value was 4 % lower ( P = 0.048 ) and energy intake ( EI ) of the boys was 1.1 + /- 0.4 MJ/d higher ( P = 0.014 ) in the FO group than in the OO group . Starch intake was 15 + /- 6 g/d higher ( P = 0.012 ) in the FO group , but there were no other differences in diet . Body composition did not differ between the r and omized groups with or without adjustment for starch intake , EI , and PAL . FO boys had 6 mm Hg higher diastolic and mean arterial blood pressure than OO boys ( P < 0.01 ) , but girls did not differ . Within the r and omized groups , blood pressure was not correlated with maternal RBC ( n-3 ) LCPUFA after the intervention , but PAL values were ( r = -0.277 ; P = 0.038 ) . We previously found higher BMI at 2.5 y in the FO group , but the difference did not persist . The differences in blood pressure , EI , and PAL , particularly among boys , suggest that early ( n-3 ) LCPUFA intake may have adverse effects , which should be investigated in future studies [20130095] BACKGROUND The range of human milk docosahexaenoic acid ( DHA ) concentrations worldwide is much broader than the range explored in r and omized clinical trials to date . OBJECTIVE The primary objective was to determine the effect of 4 amounts of DHA supplementation on the visual acuity of formula-fed infants at 12 mo of age . Secondary objectives were to evaluate visual acuity maturation , red blood cell fatty acids , tolerance , anthropometric measures , and adverse events . DESIGN This double-masked , r and omized trial was conducted at 2 sites ( Dallas and Kansas City ) . Three hundred forty-three healthy , term , formula-fed infants were enrolled at 1 - 9 d of age and were r and omly assigned to be fed 1 of the following 4 infant formulas containing equivalent nutrient amounts , except for long-chain polyunsaturated fatty acids : control ( 0 % DHA ) , 0.32 % DHA , 0.64 % DHA , or 0.96 % DHA ; DHA-supplemented formulas also provided 0.64 % arachidonic acid . Visual acuity was measured by visual evoked potentials in 244 infants who completed the 12-mo primary outcome examination . RESULTS Infants fed control formula had significantly poorer visual evoked potential visual acuity at 12 mo of age than did infants who received any of the DHA-supplemented formulas ( P < 0.001 ) . There were no significant differences in visual evoked potential visual acuity between the 3 amounts of DHA supplementation for either site at any age tested . CONCLUSIONS DHA supplementation of infant formula at 0.32 % of total fatty acids improves visual acuity . Higher amounts of DHA supplementation were not associated with additional improvement of visual acuity . This trial was registered at clinical trials.gov as NCT00753818 [10974044] Docosahexaenoic acid ( DHA ) is important for infant development . The DHA transfer from maternal diet into human milk has not been investigated in detail . We studied the effects of DHA supplementation on the fatty acid composition of human milk and the secretion of dietary (13)C-labeled fatty acids , including DHA , into human milk . Ten lactating women were r and omized to consume , from 4 to 6 weeks postpartum , an oil rich in DHA ( DHASCO , 200 mg of DHA/day ) ( n = 5 ) or a placebo oil ( n = 5 ) . Dietary intakes were followed by 7-day protocol s. On study day 14 a single dose of [U-(13)C]DHASCO was given orally , milk sample s were collected over 48 h , and milk production was recorded . Milk fatty acid composition was determined by gas-liquid chromatography and isotopic enrichment was determined by gas chromatography- combustion-isotope ratio mass spectrometry ( GC-C-IRMS ) . Milk DHA content did not differ between the supplemented and placebo group at study entry ( 0.29 vs. 0.28 wt% , median ) . After 2 weeks of supplementation the milk DHA content was almost 2-fold higher in the supplemented versus placebo group ( 0.37 vs. 0.21 wt% , P = 0.003 ) . Cumulative recovery of [(13)C]palmitic , [(13)C]oleic , and [(13)C]docosahexaenoic acids in human milk at 48 h was similar between supplemented and placebo groups ( palmitic acid 7.40 vs. 8 . 14 % , oleic acid 9.14 vs. 9.97 % , and docosahexaenoic acid 9.09 vs. 8 . 03 % of dose , respectively ) . Notable lower recovery was observed for [(13)C]myristic acid in both the supplemented and placebo groups , 0 . 62 versus 0.77 % of dose . Dietary DHA supplementation increases the DHA content in human milk . DHA transfer from the diet into human milk is comparable to palmitic and oleic acid transfer [21775563] BACKGROUND It is well established that obesity tends to track from early childhood into adult life . Studies in experimental animals have suggested that changes in the peri- and early postnatal intake of n-3 ( omega-3 ) polyunsaturated acids can affect the development of obesity in adult life . OBJECTIVE The aim of the current study was to investigate the effect of daily supplementation with 2.7 g long-chain n-3 fatty acids during the third trimester of pregnancy on adiposity in 19-y-old offspring . DESIGN The study was based on follow-up of a r and omized controlled trial from 1990 , in which 533 pregnant women were r and omly assigned to receive fish oil , olive oil , or no oil . At ≈19 y of age , the offspring of subjects from the r and omized controlled trial were invited to undergo a physical examination , including anthropometric measurements and fasting blood sampling . The blood sample was analyzed for insulin , glucose , glycated hemoglobin , leptin , adiponectin , insulin-like growth factor I , and high-sensitivity C-reactive protein . Multiple linear regression modeling , adjusted for sex , smoking , and parental overweight , was used to estimate the effect of fish oil relative to that of olive oil on BMI ( in kg/m(2 ) ) , waist circumference , and biochemical measures . RESULTS A total of 243 of the offspring were followed up . We found no difference between the fish-oil and olive oil groups in BMI ( 0.13 ; -0.92 , 1.17 ) or waist circumference ( 0.7 cm ; -2.1 , 3.4 cm ) . Overall , results of the biochemical analyses supported the finding of no difference between the groups . CONCLUSION We detected no effect of fish-oil supplementation during pregnancy on offspring adiposity in adolescence [23066842] AIM Long-chain polyunsaturated fatty acid ( LCPUFA ) supplementation of infant formula may have a beneficial effect on cognitive development . This study aim ed to investigate the effect of LCPUFA formula supplementation primarily on cognition and secondarily on behaviour at age 9 years . Special attention was paid to the potentially modifying effect of maternal smoking during pregnancy . METHOD A double-blind , r and omized control study was performed in two groups of healthy infants born at term : one group , constituting the control group , received st and ard formula ( n=169 ) and another group received st and ard formula supplemented with LCPUFAs ( n=146 ) . A breastfed group ( n=159 ) served as an additional reference . At 9 years of age , 72 % of the children ( control group : n=123 ; 71 males , 52 females ; LCPUFA group : n=91 ; 42 males , 49 females ; breastfed group : n=127 , 64 males , 63 females ) underwent extensive cognitive and behavioural testing . RESULTS An interaction between infant nutrition and smoking during pregnancy was found . Among children exposed to smoking during pregnancy , LCPUFA supplementation was associated with higher mean verbal IQ scores ( p=0.007 ) and learning and memory ( p=0.006 ) . Among children not exposed to smoking during pregnancy , LCPUFA supplementation was associated with lower mean verbal memory scores ( p=0.003 ) . Executive function scores were significantly lower in the LCPUFA-supplemented group than in the control group ( p=0.001 ) . Breastfeeding was associated with better performance on IQ ( p=0.005 ) . INTERPRETATION No consistent beneficial effect of LCPUFA formula supplementation on cognitive development in term-born infants was found . The study confirmed that breastfeeding is associated with better cognition [23426033] BACKGROUND Observational studies associate higher intakes of n-3 ( omega-3 ) long-chain polyunsaturated fatty acids ( LCPUFAs ) during pregnancy with higher gestation duration and birth size . The results of r and omized supplementation trials using various n-3 LCPUFA sources and amounts are mixed . OBJECTIVE We tested the hypothesis that 600 mg/d of the n-3 LCPUFA docosahexaenoic acid ( DHA ) can increase maternal and newborn DHA status , gestation duration , birth weight , and length . Safety was assessed . DESIGN This phase III , double-blind , r and omized controlled trial was conducted between January 2006 and October 2011 . Women ( n = 350 ) consumed capsules ( placebo , DHA ) from < 20 wk of gestation to birth . Blood ( enrollment , birth , and cord ) was analyzed for red blood cell ( RBC ) phospholipid DHA . The statistical analysis was intent-to-treat . RESULTS Most of the capsules were consumed ( 76 % placebo ; 78 % DHA ) ; the mean DHA intake for the treated group was 469 mg/d . In comparison with placebo , DHA supplementation result ed in higher maternal and cord RBC-phospholipid-DHA ( 2.6 % ; P < 0.001 ) , longer gestation duration ( 2.9 d ; P = 0.041 ) , and greater birth weight ( 172 g ; P = 0.004 ) , length ( 0.7 cm ; P = 0.022 ) , and head circumference ( 0.5 cm ; P = 0.012 ) . In addition , the DHA group had fewer infants born at < 34 wk of gestation ( P = 0.025 ) and shorter hospital stays for infants born preterm ( 40.8 compared with 8.9 d ; P = 0.026 ) than did the placebo group . No safety concerns were identified . CONCLUSIONS A supplement of 600 mg DHA/d in the last half of gestation result ed in overall greater gestation duration and infant size . A reduction in early preterm and very-low birth weight could be important clinical and public health outcomes of DHA supplementation . This trial was registered at clinical trials.gov as NCT00266825 [21099447] We investigated whether the previously reported preventive effect of maternal ω-3 fatty acid supplementation on IgE-associated allergic disease in infancy may be mediated by facilitating a balanced circulating Th2/Th1 chemokine profile in the infant . Vaccine-induced immune responses at 2 y of age were also evaluated . Pregnant women , at risk of having an allergic infant , were r and omized to daily supplementation with 1.6 g eicosapentaenoic acid and 1.1 g docosahexaenoic acid or placebo from the 25th gestational week through 3.5 mo of breastfeeding . Infant plasma was analyzed for chemokines ( cord blood , 3 , 12 , 24 mo ) and anti-tetanus and anti-diphtheria IgG ( 24 mo ) . High Th2-associated CC-chemokine lig and 17 ( CCL17 ) levels were associated with infant allergic disease ( p < 0.05 ) . In infants without , but not with , maternal history of allergy , the ω-3 supplementation was related to lower CCL17/CXC-chemokine lig and 11 ( CXCL11 ) ( Th2/Th1 ) ratios ( p < 0.05 ) . Furthermore , in nonallergic , but not in allergic infants , ω-3 supplementation was linked with higher Th1-associated CXCL11 levels ( p < 0.05 ) , as well as increased IgG titers to diphtheria ( p = 0.01 ) and tetanus ( p = 0.05 ) toxins . Thus , the prospect of balancing the infant immune system toward a less Th2-dominated response , by maternal ω-3 fatty acid supplementation , seems to be influenced by allergic status [22269042] BACKGROUND Docosahexaenoic acid ( DHA ; 22:6n-3 ) is highly important during pregnancy for optimal development and functioning of fetal neural tissue . Infant ability to organize sleep and wake states following parturition is highly associated with later developmental outcomes . The impact of maternal DHA intake on sleep organization has not been previously investigated . AIMS To examine the effect of a DHA-containing functional food consumed during pregnancy on early neurobehavioral development as assessed by infant sleep patterning in the first 48 postnatal hours . STUDY DESIGN A longitudinal , r and omized , double-blinded , placebo-controlled design was used . SUBJECTS Women ( 18 - 35 y ) with no pregnancy complications consumed a cereal-based functional food ( 92 kcal ) containing 300 mg DHA an average of 5 d/week or placebo bars ( n=27 DHA , n=21 Placebo ) . The intervention began at 24 weeks gestation and continued until delivery ( 38 - 40 weeks ) . OUTCOME MEASURES Infant sleep/wake states were measured on postnatal days 1 ( D1 ) and 2 ( D2 ) using a pressure sensitive mattress recording respiration and body movements . RESULTS Using ANCOVA and controlling for ethnic variation , there were significant group differences in arousals in quiet sleep on D1 ( P=0.006 ) and D2 ( P=0.011 ) with fewer arousals in the DHA intervention group compared to the placebo group . Similarly , arousals in active sleep on D1 were significantly lower in the DHA-intervention group ( P=0.012 ) compared to the placebo group . CONCLUSIONS We conclude that increased prenatal supply of dietary DHA has a beneficial impact on infant sleep organization [17157660] BACKGROUND Early vitamin supplementation is given routinely to infants in many countries , but it is unclear whether this affects the risk of allergic diseases . OBJECTIVES We sought to study the association between early-life supplementation of vitamins A and D in water-soluble form or in peanut oil and allergic diseases up to 4 years of age . METHODS A prospect i ve birth cohort of 4089 newborn infants was followed for 4 years using parental question naires repeatedly to collect information on exposure and health . At 4 years , the response rate was 90 % , and allergen-specific IgE levels to food and airborne allergens were measured in 2614 of the participating children . RESULTS Vitamins A and D were given to 98 % of the children in infancy , and vitamins based in peanut oil dominated ( 90 % ) . Children supplemented with vitamins A and D in water-soluble form during the first year of life had an almost 2-fold increased risk of asthma ( adjusted odds ratio [ OD ] , 2.18 ; 95 % CI , 1.45 - 3.28 ) , food hypersensitivity ( adjusted OR , 1.89 ; 95 % CI , 1.33 - 2.65 ) , and sensitization to common food and airborne allergens ( adjusted OR , 1.88 ; 95 % CI , 1.34 - 2.64 ) at age 4 years compared with those receiving vitamins in peanut oil . No increased risk of IgE antibodies to peanut was seen in children receiving vitamins in peanut oil . CONCLUSION Supplementation of vitamins A and D in water-soluble form seems to increase the risk of allergic disease up to the age of 4 years compared with supplementation with the same vitamins given in peanut oil . CLINICAL IMPLICATION S Vitamins A and D in oil does not seem to increase the risk of allergic disease during childhood [22348468] n-3 Long-chain PUFA ( LC-PUFA ) intake during infancy is important for neurodevelopment ; however , previous studies of n-3 LC-PUFA supplementation have been inconclusive possibly due to an insufficient dose and limited methods of assessment . The present study aim ed to evaluate the effects of direct supplementation with high-dose fish oil ( FO ) on infant neurodevelopmental outcomes and language . In the present r and omised , double-blind , placebo-controlled trial , 420 healthy term infants were assigned to receive a DHA-enriched FO supplement ( containing at least 250 mg DHA/d and 60 mg EPA/d ) or a placebo ( olive oil ) from birth to 6 months . Assessment occurred at 18 months via the Bayley Scales of Infant and Toddler Development ( 3rd edition ; BSID-III ) and the Child Behavior Checklist . Language assessment occurred at 12 and 18 months via the Macarthur-Bates Communicative Development Inventory . The FO group had significantly higher erythrocyte DHA ( P = 0·03 ) and plasma phospholipid DHA ( P = 0·01 ) levels at 6 months of age relative to placebo . In a small subset analysis ( about 40 % of the total population ) , children in the FO group had significantly higher percentile ranks of both later developing gestures at 12 and 18 months ( P = 0·007 ; P = 0·002 , respectively ) and the total number of gestures ( P = 0·023 ; P = 0·006 , respectively ) . There was no significant difference between the groups in the st and ard or composite scores of the BSID-III . The results suggest that improved postnatal n-3 LC-PUFA intake in the first 6 months of life using high-dose infant FO supplementation was not beneficial to global infant neurodevelopment . However , some indication of benefits to early communicative development was observed [18679165] Polyunsaturated n-3 fatty acids ( n-3PUFA ) may improve brain development and prevent cardiovascular disease . Heart rhythm is autonomically controlled and among the affected cardiovascular risk markers in adults . The aim of the study was to examine whether fish oil supplementation in late infancy could modify heart rate ( HR ) and heart rate variability ( HRV ) . In a 2 × 2-intervention , 83 healthy Danish infants were r and omized to ± fish oil ( 3.4 ± 1.1 mL/d ) and cow 's milk or infant formula from 9 to 12 mo of age . In 57 infants , 0.5-h ECG recordings were successfully obtained before and after the intervention and erythrocyte fatty acid composition was determined in 30 of these . Fish oil supplementation raised erythrocyte n-3PUFA content ( p < 0.001 ) . No significant group differences were seen in HR or HRV . However , a fish-oil × gender interaction was observed on mean RR interval ( p = 0.001 ) with a 6 % longer mean RR interval in fish-oil-supplemented boys ( p = 0.007 ) . Irrespective of gender , there was a positive association between the 9- and 12-mo changes in RR interval and erythrocyte n-3PUFA ( p < 0.001 ) . In infants with confirmed changes in erythrocyte n-3PUFA , mean RR interval was found to be longer ( p = 0.011 ) in the fish-oil-supplemented groups . The study suggests that fish oil may affect heart rhythm in infants similar to that observed in adults . This may imply low n-3PUFA-status in late infancy and n-3PUFA influence on CNS function [20386325] Background and Objective : Feeding long-chain polyunsaturated fatty acids ( LCP ) influences immunity in adults ; however , less is known about their effect during development . The aim of the study was to determine the effect of feeding LCP on immunity in healthy infants during the first 4 months of life . Patients and Methods : Formula-fed infants were r and omized at ≤14 days of age to st and ard term formula ( Formula ) or formula containing LCP ( Formula+LCP ) . Infants exclusively fed human milk ( HM ) were included for comparison . At 16 weeks of age , blood was collected and phenotypes , the ability to proliferate and produce cytokines ( interleukin [IL]-2 , IL-4 , IL-6 , IL-10 , IL-12 , interferon [IFN]-γ , tumor necrosis factor [TNF]-α , TGF-β ) after incubation with phytohemaglutinin ( PHA ) , β-lactoglobulin , or soy protein were measured . Results : Feeding LCP result ed in a higher than and more similar proliferation rate to PHA in HM-fed infants , possibly because of a greater TH1 type cytokine response and a higher percentage of antigen mature ( CD45RO+ ) cells ( P < 0.05 ) . The response to β-lactoglobulin did not differ among groups . After incubation with soy protein Formula+LCP , compared with Formula produced less IL-2 and more TNF-α and had a higher percentage of CD8 + and a lower percentage of CD20 + ( CD20+CD54 + ) cells poststimulation ( P < 0.05 ) . Both formula groups produced less IL-2 after PHA , had a lower percentage of CD80 + cells , and a higher percentage of CD54 + cells after incubation with food proteins ( P < 0.05 ) . Conclusions : Formula-fed infants , at low risk for allergy , respond differently to mitogen and food proteins ex vivo than those fed HM . Feeding LCP altered some of these differences in the direction that is hypothesized to confer immune benefits [3269207] Objective To determine whether dietary n-3 long chain polyunsaturated fatty acid ( LCPUFA ) supplementation of pregnant women with a fetus at high risk of allergic disease reduces immunoglobulin E associated eczema or food allergy at 1 year of age . Design Follow-up of infants at high hereditary risk of allergic disease in the Docosahexaenoic Acid to Optimise Mother Infant Outcome ( DOMInO ) r and omised controlled trial . Setting Adelaide , South Australia . Participants 706 infants at high hereditary risk of developing allergic disease whose mothers were participating in the DOMInO trial . Interventions The intervention group ( n=368 ) was r and omly allocated to receive fish oil capsules ( providing 900 mg of n-3 LCPUFA daily ) from 21 weeks ’ gestation until birth ; the control group ( n=338 ) received matched vegetable oil capsules without n-3 LCPUFA . Main outcome measure Immunoglobulin E associated allergic disease ( eczema or food allergy with sensitisation ) at 1 year of age . Results No differences were seen in the overall percentage of infants with immunoglobulin E associated allergic disease between the n-3 LCPUFA and control groups ( 32/368 ( 9 % ) v 43/338 ( 13 % ) ; unadjusted relative risk 0.68 , 95 % confidence interval 0.43 to 1.05 , P=0.08 ; adjusted relative risk 0.70 , 0.45 to 1.09 , P=0.12 ) , although the percentage of infants diagnosed as having atopic eczema ( that is , eczema with associated sensitisation ) was lower in the n-3 LCPUFA group ( 26/368 ( 7 % ) v 39/338 ( 12 % ) ; unadjusted relative risk 0.61 , 0.38 to 0.98 , P=0.04 ; adjusted relative risk 0.64 , 0.40 to 1.02 , P=0.06 ) . Fewer infants were sensitised to egg in the n-3 LCPUFA group ( 34/368 ( 9 % ) v 52/338 ( 15 % ) ; unadjusted relative risk 0.61 , 0.40 to 0.91 , P=0.02 ; adjusted relative risk 0.62 , 0.41 to 0.93 , P=0.02 ) , but no difference between groups in immunoglobulin E associated food allergy was seen . Conclusion n-3 LCPUFA supplementation in pregnancy did not reduce the overall incidence of immunoglobulin E associated allergies in the first year of life , although atopic eczema and egg sensitisation were lower . Longer term follow-up is needed to determine if supplementation has an effect on respiratory allergic diseases and aeroallergen sensitisation in childhood . Trial registration Australian New Zeal and Clinical Trials Registry ACTRN12610000735055 ( DOMInO trial : ACTRN12605000569606 ) [19267292] This investigation evaluated variations in resting heart rate ( HR ) measures during the first half year of life in healthy , full-term infants who were either breast-fed ( BF ) , or fed formula with ( milk-based : MF ; soy-based : SF ) or without ( soy-based : SF− ) commercially supplemented DHA ( decosahexaenoic acid ) . In infants fed the DHA-deficient diet , higher HR and lower values for heart rate variability measures were observed , indicating decreased parasympathetic tone in this group . These effects , appearing at 4 months and continuing for the remainder of the study period , are consistent with suggestions that the 3–5-month postnatal interval may be an important period in the development of cardiovascular regulation . The absence of these effects in SF infants receiving the DHA-supplemented formula suggests that neither soy protein nor the associated phytochemicals in soy formula contribute to these effects to any appreciable extent . In general , the results do not indicate differences in any of the study variables attributable to soy formula per se [23433688] DHA ( 22:6n-3 ) supplementation during infancy has been associated with lower heart rate ( HR ) and improved neurobehavioral outcomes . We hypothesized that maternal DHA supplementation would improve fetal cardiac autonomic control and newborn neurobehavior . Pregnant women were r and omized to 600 mg/day of DHA or placebo oil capsules at 14.4 ( + /-4 ) weeks gestation . Fetal HR and HRV were calculated from magnetocardiograms ( MCGs ) at 24 , 32 and 36 weeks gestational age ( GA ) . Newborn neurobehavior was assessed using the Neonatal Behavioral Assessment Scale ( NBAS ) . Post-partum maternal and infant red blood cell ( RBC ) DHA was significantly higher in the supplemented group as were metrics of fetal HRV and newborn neurobehavior in the autonomic and motor clusters . Higher HRV is associated with more responsive and flexible autonomic nervous system ( ANS ) . Coupled with findings of improved autonomic and motor behavior , these data suggest that maternal DHA supplementation during pregnancy may impart an adaptive advantage to the fetus [21521543] DHA ( 22 : 6n-3 ) in pregnancy has previously been shown to benefit infant brain and retinal development . Fatty acid consumption during pregnancy may also have an impact on infant adipose tissue development . The objective of the present study was to assess the prenatal impact of a DHA-containing functional food ( DHA-FF ) on infant intra-uterine growth . This was a longitudinal , r and omised , double-blinded , placebo-controlled trial . Pregnant women were assigned to consume a DHA-FF or placebo bar from 24 weeks ' gestation until delivery . Blood sample s were collected from mothers at baseline and delivery and from the umbilical cord at delivery . Plasma and erythrocyte fatty acids were analysed by GLC and plasma insulin concentrations were analysed using a commercially available ELISA kit . Infant birth weight and length were obtained at delivery and ponderal index ( weight (g)/length (cm)3 × 100 ) was calculated . A total of forty-seven mothers completed the study . Infants of mothers consuming the DHA-FF during the last half of pregnancy had lower ponderal indices ( β = 0.198 , P < 0.05 ) and umbilical cord blood insulin concentrations ( β = 0.743 , P < 0.05 ) than infants of mothers consuming the placebo . Thus , DHA consumption during pregnancy may be advantageous with respect to infant body composition at birth and insulin sensitivity [17957193] BACKGROUND Inadequate consumption of fish could be a risk factor for low birth weight ( LBW ) . This study assessed fish intake and omega-3 LCPUFA intake and status for their association with LBW in a cohort of urban , south Indian pregnant women . SUBJECTS/ METHODS In a prospect i ve cohort study , data on maternal fish intake and omega-3 LCPUFA intake and status of 676 women were obtained at baseline ( first trimester ) , the second and third trimesters of pregnancy . Infant birth weight was measured immediately following hospital delivery . The dropout rate was 7.6 % . RESULTS Fifty-six percent of the study women consumed fish with low daily median intakes ( 3.4 , 4.1 and 3.8 g day(-1 ) at the three trimesters , respectively ) . Consequently , the median intakes of EPA and DHA during pregnancy were also low at 2.1 and 10.1 mg day(-1 ) , respectively . EPA and DHA intakes were associated with their status in erythrocyte membrane phospholipids during pregnancy ( r=0.40 and 0.36 , r=0.34 and 0.32 and r=0.37 and 0.41 , at the three trimesters , respectively , all P<0.001 ) . Women who did not eat fish during the third trimester had a significantly higher risk of LBW ( OR : 2.49 , P=0.019 ) . Similarly , low EPA intake during the third trimester had an association with a higher risk of LBW ( OR : 2.75 , P=0.011 ) . CONCLUSIONS Among low fish-eating pregnant women , fish intake in the third trimester was closely associated with birth weight . Supplementation with omega-3 LCPUFA during pregnancy may have important implication s for fetal development in India [21930549] OBJECTIVE : To test the hypothesis that long-chain polyunsaturated fatty acid ( LCPUFA ) supplementation in infancy would improve cognition into later childhood ( after 9 years ) at both general and specific levels . METHODS : A comprehensive cognitive battery was completed by 107 formerly preterm infants ( mean age : 128 months ) . As infants , they had been assigned r and omly to receive LCPUFA-supplemented ( N = 50 ) or control ( N = 57 ) formula , between birth and 9 months ; the docosahexaenoic acid level ( DHA ) in the supplemented formulas was 0.5 % . In addition to r and omized comparisons , we planned supplementary analyses to examine the effects of both gender and feeding group ( those receiving some maternal breast milk versus those receiving none ) . RESULTS : There were no significant differences between r and omized diet groups on any cognitive measure . There was significant interaction between gender and supplementation ; girls only showed beneficial effects of LCPUFAs on literacy . Significant interaction also occurred between feeding group and supplementation ; increases of 0.7 SD in verbal IQ , full-scale IQ , and memory scores were found for the LCPUFA group , but only for infants who received only formula and no maternal breast milk . CONCLUSIONS : The results of this post–9-year cognitive follow-up study in a r and omized trial of LCPUFA-supplemented formula for preterm infants suggest no overall group effects but indicate that gender-specific and diet-specific effects may exist . The data provide some evidence that LCPUFAs are a key factor in the cognitive benefits of breast milk . Caution is advised in data interpretation because of the small groups used [20093894] OBJECTIVE : To assess whether the addition of an omega-3 long-chain polyunsaturated fatty acid supplement would reduce preterm birth in women with at least one prior spontaneous preterm birth receiving 17&agr;-hydroxyprogesterone caproate . METHODS : We conducted a r and omized , double-masked , placebo-controlled trial in 13 centers . Women with a history of prior spontaneous singleton preterm birth and a current singleton gestation were assigned to either a daily omega-3 supplement ( 1,200 mg eicosapentaenoic acid and 800 mg docosahexaenoic acid ) or matching placebo from 16 - 22 through 36 weeks of gestation . All participants received weekly intramuscular 17&agr;-hydroxyprogesterone caproate ( 250 mg ) . The primary study outcome was delivery before 37 weeks of gestation . A sample size of 800 was necessary to have 80 % power to detect a 30 % reduction in the primary outcome from 30 % , assuming a type I error two-sided of 5 % . RESULTS : A total of 852 women were included , and none was lost to follow up . Delivery before 37 weeks of gestation occurred in 37.8 % ( 164/434 ) of women in the omega-3 group and 41.6 % ( 174/418 ) in the placebo group ( relative risk 0.91 , 95 % confidence interval 0.77 - 1.07 ) . CONCLUSION : Omega-3 long-chain polyunsaturated fatty acid supplementation offered no benefit in reducing preterm birth among women receiving 17&agr;-hydroxyprogesterone caproate who have a history of preterm delivery . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00135902 . LEVEL OF EVIDENCE : [19174829] Background / Objectives : High protein intake has been associated with increased growth . This may be linked to increased concentrations of insulin-like growth factor I ( IGF-I ) , which seems to be influenced by the diet , especially its protein component . The short-term effects of high protein intake in late infancy are not known . The objective was to investigate the effects of high protein intake in the form of whole milk ( WM ) on growth and IGF-I from 9 to 12 months of age . Subjects/ Methods : Healthy infants ( n=83 ) were r and omized to receive either WM or infant formula and fish oil or no fish oil ( 2 × 2 design ) . Anthropometric variables , IGF-I concentrations , serum urea nitrogen ( SUN ) and diet were recorded before and after the intervention . Results : Intake of WM significantly increased the protein energy percentage ( PE% ; P⩽0.001 ) and SUN ( P=0.01 ) , whereas there was no effect on size . The milk intervention increased IGF-I in boys ( P=0.034 ) but not in girls . Intake of fish oil had no effect on the outcomes . Including all infants in the analysis there was a significant correlation between weight and IGF-I at 12 months ( r=0.316 , P=0.017 ) , and PE% was positively associated with IGF-I after adjusting for sex and breastfeeding at both 9 ( r=0.329 , P=0.015 ) and 12 months ( r=0.272 , P=0.044 ) . Conclusions : R and omization to WM had no overall effect on growth . However , the positive effect of WM on IGF-I in boys and the positive association between PE% intake and IGF-I at 9 and 12 months is consistent with the hypothesis that a high milk intake stimulates growth [21691253] n-3 long-chain polyunsaturated fatty acids ( n-3 LCPUFA ) , from fish oil ( FO ) , in rodents have been shown to reduce adipogenesis . Evidence of an effect on adipose tissue mass in humans is limited , and no studies have specifically aim ed to eluci date this in infancy . To explore whether n-3 LCPUFA intake affects adipose tissue growth , we r and omly allocated 154 healthy infants to daily supplementation with FO or sunflower oil ( SO ) from 9 to 18 mo of age and measured z-score changes in various anthropometric assessment s of body size and skinfold thicknesses and plasma adipokine concentrations . Among the 133 completing infants , erythrocyte n-3 PUFA increased more in those receiving FO than in infants receiving SO [ 12.2 ± 0.7 ( mean ± SE ) versus 2.0 ± 0.4 fatty acid percentage ( FA% ) , p < 0.001 ] with a concomitant larger decrease in n-6 PUFA ( −8.9 ± 0.7 versus −0.9 ± 0.6 FA% , p < 0.001 ) . We found no association between FO consumption relative to SO consumption and any of the anthropometric measures related to the size of the fat mass , but infants in the FO group had a lower skinfold ratio ( triceps/subscapular ) at 18 mo than those in SO group ( p = 0.02 ) . Our findings do not support the hypothesis that dietary n-3 LCPUFA is important for infant fat mass , but future studies testing this specifically are warranted [21295417] BACKGROUND Studies investigating cognitive outcomes following docosahexaenoic acid ( DHA ) supplementation of infant formula yield conflicting results , perhaps due to inadequate dietary concentrations . AIM To determine the optimal DHA concentration in term formula to support cognitive maturation . DESIGN This was a double-masked , r and omized , controlled , prospect i ve trial . A total of 181 infants were enrolled at 1 - 9 days of age and assigned r and omly to receive one of four term infant formulas with one of four levels of docosahexaenoic acid : Control ( 0 % DHA ) , 0.32 % DHA , 0.64 % DHA , or 0.96 % DHA . All DHA-supplemented formulas contained 0.64 % arachidonic acid ( ARA ) . Infants were fed the assigned formulas until 12 months of age . One hundred forty-one children completed the 12-month feeding trial and were eligible for this study . Cognitive function was assessed in 131 children at 18 months of age using the Bayley Scales of Infant Development II ( BSID II ) . RESULTS There were no diet group differences on the Mental Development Index ( MDI ) , the Psychomotor Development Index ( PDI ) , or the Behavior Rating Scale ( BRS ) of the BSID II . However , when the scores of children who received any of the three DHA-supplemented formulas were combined and compared to control children , a significant difference emerged : the MDI scores of DHA-supplemented children were higher ( 104.1 v. 98.4 ; p=0.02 ) . CONCLUSIONS These results suggest that dietary supplementation of DHA during the first year of life leads to enhanced cognitive development at 18 months of age . DHA concentration of 0.32 % is adequate to improve cognitive function ; higher concentrations did not confer additional benefit [23803884] BACKGROUND The effect of long-chain polyunsaturated fatty acid ( LCPUFA ) intake on cognitive development is controversial . Most r and omized trials have assessed cognition at 18 mo , although significant development of cognitive abilities ( early executive function ) emerge later . OBJECTIVE The objective was to evaluate cognition beyond 18 mo and longitudinal cognitive change from 18 mo to 6 y in children who were fed variable amounts of docosahexaenoic acid ( 0.32 % , 0.64 % , and 0.96 % of total fatty acids ) and arachidonic acid ( ARA ; 0.64 % ) compared with children who were not fed LCPUFA as infants . DESIGN Eighty-one children ( 19 placebo , 62 LCPUFA ) who participated in a double-blind , r and omized trial of LCPUFA supplementation as infants were re-enrolled at 18 mo and tested every 6 mo until 6 y on age-appropriate st and ardized and specific cognitive tests . RESULTS LCPUFA supplementation did not influence performance on st and ardized tests of language and performance at 18 mo ; however , significant positive effects were observed from 3 to 5 y on rule-learning and inhibition tasks , the Peabody Picture Vocabulary Test at 5 y , and the Weschler Primary Preschool Scales of Intelligence at 6 y. Effects of LCPUFAs were not found on tasks of spatial memory , simple inhibition , or advanced problem solving . CONCLUSIONS The data from this relatively small trial suggest that , although the effects of LCPUFAs may not always be evident on st and ardized developmental tasks at 18 mo , significant effects may emerge later on more specific or fine-grained tasks . The results imply that studies of nutrition and cognitive development should be powered to continue through early childhood . This parent trial was registered at clinical trials.gov as NCT00266825 [19765006] This study examines whether feeding infants formula supplemented with long-chain polyunsaturated fatty acids ( LCPUFA ) improves cognitive function of 9-month-olds . Participants included 229 infants from 3 r and omized controlled trials . Children received either formula supplemented with docosahexaenoic acid and arachidonic acid , or a control formula beginning at 1 - 5 days ( 12-month feeding study ) , or following 6 weeks ( 6-week-weaning study ) or 4 - 6 months of breastfeeding ( 4-to 6-month weaning study ) . Infants were assessed with a 2-step problem solving task . In the 12-month feeding and 6-week weaning studies , supplemented children had more intentional solutions ( successful task completions ) and higher intention scores ( goal -directed behaviors ) than controls . These results suggest that LCPUFA supplementation improves means-end problem solving [20133326] Objective To investigate the relation between breastfeeding , use of docosahexaenoic acid (DHA)-fortified formula and neuropsychological function in children . Design Prospect i ve cohort study . Setting Southampton , UK . Subjects 241 children aged 4 years followed up from birth . Main outcome measures IQ measured by the Wechsler Pre-School and Primary Scale of Intelligence ( 3rd edn ) , visual attention , visuomotor precision , sentence repetition and verbal fluency measured by the NEPSY , and visual form-constancy measured by the Test of Visual-Perceptual Skills ( Non-Motor ) . Results In unadjusted analyses , children for whom breast milk or DHA-fortified formula was the main method of feeding throughout the first 6 months of life had higher mean full-scale and verbal IQ scores at age 4 years than those fed mainly unfortified formula . After adjustment for potential confounding factors , particularly maternal IQ and educational attainment , the differences in IQ between children in the breast milk and unfortified formula groups were severely attenuated , but children who were fed DHA-fortified formula had full-scale and verbal IQ scores that were respectively 5.62 ( 0.98 to 10.2 ) and 7.02 ( 1.56 to 12.4 ) points higher than children fed unfortified formula . However , estimated total intake of DHA in milk up to age 6 months was not associated with subsequent IQ or with score on any other test . Conclusions Differences in children 's intelligence according to type of milk fed in infancy may be due more to confounding by maternal or family characteristics than to the amount of long-chain polyunsaturated fatty acids they receive in milk [20515959] Objective To test the hypothesis that consumption of infant formulas containing long-chain polyunsaturated fatty acids ( LCPUFAs ) by preterm infants would favourably influence growth , body composition and blood pressure ( BP ) at age 10 years . Methods This was a follow-up study of a preterm cohort ( < 35 weeks and birth weight < 2000 g ) r and omly assigned to unsupplemented or LCPUFA-supplemented formulas to 9 months post term . The setting was a research clinic at Yorkhill Hospital for Sick Children , Glasgow , UK . A total of 107 children aged 9–11 years who participated in the original r and omised controlled trial ( 45 % follow-up ) took part . Main outcome measures were : ( 1 ) anthropometry , ( 2 ) body composition and ( 3 ) BP . Results There were no differences in growth or BP between r and omised groups for the whole cohort . However , girls who had received LCPUFA-supplemented formula were heavier ( 42.20 ( SD 9.61 ) vs 36.94 ( 9.46 ) kg , p=0.05 ) , had greater skin fold thicknesses ( biceps 10.7 ( 3.3 ) vs 8.5 ( 3.6 ) mm , p=0.03 ; suprailiac 16.7 ( 8.2 ) vs 12.0 ( 7.5 ) mm , p=0.03 ) and higher BP ( mean 82.2 ( 8.4 ) vs 78.1 ( 6.2 ) mm Hg , p=0.04 : systolic 111.4 ( 10.1 ) vs 105.9 ( 9.0 ) mm Hg , p=0.04 : diastolic 64.8 ( 8.4 ) vs 61.1 ( 5.4 ) mm Hg , p=0.05 ) . Differences in weight SD score ( 0.85 ( 95 % CI 0.13 to 1.58 ) , p=0.02 ) , Ln sum of skin fold thicknesses ( 0.27 ( 0.02 to 0.52 ) , p=0.04 ) and BP ( mean 4.6 mm Hg ( 0.43 to 8.84 ) , p=0.03 ; systolic 6.1 ( 0.45 to 11.7 ) , p=0.04 ) remained after adjustment for prer and omisation confounders . Differences in BP were not significant following adjustment for current weight . Conclusions Girls born preterm and r and omised to LCPUFA-supplemented formula showed increased weight , adiposity and BP at 9–11 years , which might have adverse consequences for later health . No effects were seen in boys . Long-term follow-up of other LCPUFA supplementation trials is required to further investigate this finding [21849596] BACKGROUND The influence of prenatal long-chain polyunsaturated fatty acids ( LC-PUFAs ) and folate on neurologic development remains controversial . OBJECTIVE The objective was to assess the long-term effects of n-3 ( omega-3 ) LC-PUFA supplementation , 5-methyltetrahydrofolate ( 5-MTHF ) supplementation , or both in pregnant women on cognitive development of offspring at 6.5 y of age . DESIGN This was a follow-up study of the NUHEAL ( Nutraceuticals for a Healthier Life ) cohort . Healthy pregnant women in 3 European centers were r and omly assigned to 4 intervention groups . From the 20th week of pregnancy until delivery , they received a daily supplement of 500 mg docosahexaenoic acid ( DHA ) + 150 mg eicosapentaenoic acid [ fish oil ( FO ) ] , 400 μg 5-MTHF , or both or a placebo . Infants received formula containing 0.5 % DHA and 0.4 % arachidonic acid ( AA ) if they were born to mothers receiving FO supplements or were virtually free of DHA and AA until the age of 6 mo if they belonged to the groups that were not supplemented with FO . Fatty acids and folate concentrations were determined in maternal blood at weeks 20 and 30 of pregnancy , at delivery , and in cord blood . Cognitive function was assessed at 6.5 y of age with the Kaufman Assessment Battery for Children ( K-ABC ) . RESULTS We observed no significant differences in K-ABC scores between intervention groups . Higher DHA in maternal erythrocytes at delivery was associated with a Mental Processing Composite Score higher than the 50th percentile in the offspring . CONCLUSION We observed no significant effect of supplementation on the cognitive function of children , but maternal DHA status may be related to later cognitive function in children . This trial was registered at clinical trials.gov as NCT01180933 [20053878] BACKGROUND The visual and mental development of preterm infants improved after feeding them milk enriched with docosahexaenoic acid ( DHA ) in amounts matching the fetal accretion rate . OBJECTIVE The objective was to evaluate whether feeding preterm infants milk with a higher DHA content than that used in current practice influences language or behavior in early childhood . DESIGN This was a follow-up study in a subgroup of infants enrolled in the DINO ( Docosahexaenoic acid for the Improvement in Neurodevelopmental Outcome ) trial . In a double-blind r and omized controlled trial , infants born at <33 wk of gestation were fed milk containing 1 % of total fatty acids as DHA ( higher-DHA group ) or approximately 0.3 % DHA ( control group ) until reaching full-term equivalent age . The longer-term effects of the intervention on language , behavior , and temperament were measured by using the MacArthur Communicative Development Inventory ( MCDI ) at 26-mo corrected age , the Strengths and Difficulties Question naire ( SDQ ) , and the Short Temperament Scale for Children ( STSC ) between 3- and 5-y corrected age . RESULTS Mean ( + /-SD ) MCDI scores did not differ significantly ( adjusted P = 0.8 ) between the higher-DHA group ( 308 + /- 179 , n = 60 ) and the control group ( 316 + /- 192 , n = 67 ) per the Vocabulary Production subscale . Composite scores on the SDQ and STSC did not differ between the higher-DHA group and the control group [ SDQ Total Difficulties : higher-DHA group ( 10.3 + /- 6.0 , n = 61 ) , control group ( 9.5 + /- 5.5 , n = 64 ) , adjusted P = 0.5 ; STSC score : higher-DHA group ( 3.1 + /- 0.7 , n = 61 ) , control group ( 3.0 + /- 0.7 , n = 64 ) , adjusted P = 0.3 ] . CONCLUSIONS Feeding preterm infants milk containing 3 times the st and ard amount of DHA did not result in any clinical ly meaningful change to language development or behavior when assessed in early childhood . Whether longer-term effects of dietary DHA supplementation can be detected remains to be assessed . This trial was registered with the Australia and New Zeal and Clinical Trial Registry at www.anzctr.org.au as 12606000327583 [19056592] BACKGROUND Docosahexaenoic acid ( DHA ) intake throughout the first year of life is associated with neurodevelopmental and neuropsychological benefits . Few studies have evaluated the role of DHA intakes on age at achievement of gross motor milestones . OBJECTIVE The objective was to assess the effects of DHA supplementation throughout the first year of life on the achievement of four gross motor milestones in healthy infants . DESIGN In this multicenter prospect i ve , r and omized , double-blind , placebo-controlled trial , 1160 healthy neonates were assigned to receive supplementation with either 20 mg liquid DHA ( n = 580 ) or placebo ( n = 580 ) orally once daily throughout the first year of life . The primary endpoint was the time at achievement of 4 gross motor milestones ( sitting without support , h and s- and -knees crawling , st and ing alone , and walking alone ) . All analyses were performed on an intention-to-treat basis . RESULTS The time to achievement of sitting without support was shorter ( P < 0.001 ) in infants who received DHA [ median : 26 wk ; interquartile range ( IQR ) : 24 - 29 wk ] than in those who received placebo ( 27 wk ; 26 - 31 wk ) . No significant difference between infants who received DHA or placebo was found for h and s- and -knees crawling [ 39 wk ( 34 - 44 wk ) compared with 40 wk ( 35 - 44 wk ) , respectively ] , st and ing alone [ 49 wk ( 43 - 55 wk ) compared with 49 wk ( 44 - 57 wk ) , respectively ] , and walking alone [ 55 wk ( 50 - 60 wk ) compared with 56 wk ( 52 - 61 wk ) , respectively ] . CONCLUSIONS Despite the 1-wk advance in sitting without support associated with DHA supplementation , no demonstrable persistent effects of DHA supplementation on later motor development milestones were found . Thus , the long-term clinical significance of the 1-wk change in sitting without support , if any , remains unknown . This trial is registered at ( clinical trials.gov ) as NCT00610922 [19515739] BACKGROUND n-3 Fatty acid supplementation in adults results in cardiovascular benefits . However , the cardiovascular effects of n-3 supplementation in early childhood are unknown . OBJECTIVE The objective was to evaluate blood pressure ( BP ) and arterial structure and function in 8-y-old children who had participated in a r and omized controlled trial of dietary n-3 and n-6 modification over the first 5 y of life . DESIGN The children ( n = 616 ; 49 % girls ) were r and omly assigned antenatally to active ( n = 312 ; increase in n-3 intake and decrease in n-6 intake ) or control ( n = 304 ) diet interventions implemented from the time of weaning or introduction of solids until 5 y of age . At age 8.0 + /- 0.1 y , BP , carotid intima-media thickness , carotid artery distensibility , augmentation index , and brachial pulse wave velocity were measured in 405 of these children . Venous blood was collected for measurement of plasma fatty acids , lipoproteins , high-sensitivity C-reactive protein , and asymmetric dimethylarginine . Plasma fatty acid concentrations were also assessed during the intervention . RESULTS Plasma concentrations of n-3 fatty acids were higher and of n-6 were lower in the active than in the control diet group at 18 mo and 3 and 5 y ( P < 0.0001 ) . Concentrations of n-3 and n-6 fatty acids were similar at 8 y. At 8 y of age , no significant differences were found in BP , carotid intima-media thickness , carotid artery distensibility , augmentation index , asymmetric dimethylarginine , high-sensitivity C-reactive protein , or lipoproteins between diet groups . CONCLUSION A dietary supplement intervention to increase n-3 and decrease n-6 intakes from infancy until 5 y does not result in significant improvements in arterial structure and function at age 8 y. This trial was registered at the Australian Clinical Trials Registry as ACTRN012605000042640 [22739364] The evidence relating prenatal supplementation with DHA to offspring neurological development is limited . We investigated the effect of prenatal DHA supplementation on infant brainstem auditory-evoked responses and visual- evoked potentials in a double-blind , r and omized controlled trial in Cuernavaca , Mexico . Pregnant women were supplemented daily with 400 mg DHA or placebo from gestation wk 18 - 22 through delivery . DHA and placebo groups did not differ in maternal characteristics at r and omization or infant characteristics at birth . Brainstem auditory-evoked responses were measured at 1 and 3 mo in 749 and 664 infants , respectively , and visual-evoked potentials were measured at 3 and 6 mo in 679 and 817 infants , respectively . Left-right brainstem auditory-evoked potentials were moderately correlated ( range , 0.26 - 0.43 ; all P < 0.001 ) and left-right visual-evoked potentials were strongly correlated ( range , 0.79 - 0.94 ; all P < 0.001 ) within any assessment . Correlations across visits were modest to moderate ( range , 0.09 - 0.38 ; all P < 0.01 ) . The offspring of DHA-supplemented women did not differ from those of control women with respect to any outcome measure ( all comparisons P > 0.10 ) . We conclude that DHA supplementation during pregnancy did not influence brainstem auditory-evoked responses at 1 and 3 mo or visual-evoked potentials at 3 and 6 mo [21807696] OBJECTIVE : Long-chain polyunsaturated fatty acids such as docosahexaenoic acid ( DHA ) influence immune function and inflammation ; however , the influence of maternal DHA supplementation on infant morbidity is unknown . We investigated the effects of prenatal DHA supplementation on infant morbidity . METHODS : In a double-blind r and omized controlled trial conducted in Mexico , pregnant women received daily supplementation with 400 mg of DHA or placebo from 18 to 22 weeks ' gestation through parturition . In infants aged 1 , 3 , and 6 months , caregivers reported the occurrence of common illness symptoms in the preceding 15 days . RESULTS : Data were available at 1 , 3 , and 6 months for 849 , 834 , and 834 infants , respectively . The occurrence of specific illness symptoms did not differ between groups ; however , the occurrence of a combined measure of cold symptoms was lower in the DHA group at 1 month ( OR : 0.76 ; 95 % CI : 0.58–1.00 ) . At 1 month , the DHA group experienced 26 % , 15 % , and 30 % shorter duration of cough , phlegm , and wheezing , respectively , but 22 % longer duration of rash ( all P ≤ .01 ) . At 3 months , infants in the DHA group spent 14 % less time ill ( P < .0001 ) . At 6 months , infants in the DHA group experienced 20 % , 13 % , 54 % , 23 % , and 25 % shorter duration of fever , nasal secretion , difficulty breathing , rash , and “ other illness , ” respectively , but 74 % longer duration of vomiting ( all P < .05 ) . CONCLUSIONS : DHA supplementation during pregnancy decreased the occurrence of colds in children at 1 month and influenced illness symptom duration at 1 , 3 , and 6 months [22835597] BACKGROUND Studies investigating the effects of docosahexaenoic acid ( DHA ) in infant formula on language development yield conflicting results . No study to date has investigated the effects of DHA in infant formula on school readiness . AIM To determine the effects of different dietary concentrations of DHA provided during the first 12 months of life on language development and school readiness . DESIGN This was a double-masked , r and omized , controlled , prospect i ve trial . A total of 182 infants were enrolled at 1 - 9 days of age and assigned r and omly to receive infant formula with one of four levels of DHA : control ( 0 % DHA ) , 0.32 % DHA , 0.64 % DHA , or 0.96 % DHA . All formulas with DHA also contained 0.64 % arachidonic acid . One hundred forty-one children completed the 12-month feeding trial and were eligible for this study . Consent was obtained from 131 participants . School readiness was assessed at 2.5 years using the Bracken Basic Concept Scale-Revised ( BBCS-R ) and receptive vocabulary was assessed at 2 and 3.5 years using the Peabody Picture Vocabulary Test-Third Edition ( PPVT-III ) . RESULTS There were no diet group differences on any of the BBCS-R subscales . On the PPVT-III , the control group had higher raw scores and st and ard scores than both the 0.32 % and 0.96 % groups at 2 years of age . These differences were not evident at 3.5 years . CONCLUSIONS Dietary DHA during the first year of life did not enhance school readiness or language development . Children who consumed infant formula with 0.32 % and 0.96 % DHA showed lower receptive vocabulary scores than controls at 2 but not 3.5 years of age [20211038] Maternal supplementation with long-chain PUFA , to improve infant neurological development , might cause additional increase of oxidative stress . Pregnant women aged 18 - 41 years were r and omised into one of four supplementation groups . From week 22 on , they received supplements containing either modified fish oil ( n 69 ) , 5-methyl-tetrahydro-folate ( n 65 ) , both ( n 64 ) , or placebo ( n 72 ) . Plasma Trolox-equivalent antioxidative capacity ( TEAC ) , concentrations of alpha-tocopherol , retinol , beta-carotene , free thiol groups , uric acid and thiobarbituric acid-reactive substances ( TBARS ) were determined at weeks 20 and 30 and at delivery . The studied antioxidants showed no significant differences between the four supplementation groups . At week 30 plasma TBARS levels were found to be significantly higher in the fish oil group ( 0.80 ( sem 0.04 ) micromol/l ) than in the folate ( 0.67 ( sem 0.03 ) micromol/l ; P = 0.024 ) and control ( 0.69 ( sem 0.04 ) micromol/l ; P = 0.01 ) groups . Concentrations of retinol and free thiol groups decreased during pregnancy , whereas uric acid increased and beta-carotene as well as TEAC showed only minor changes . Fish oil supplementation during the second half of pregnancy appears not to decrease antioxidant status . The increased TBARS levels at week 30 may indicate a period of increased oxidative stress in plasma at this time [18676533] OBJECTIVES . Arachidonic acid ( 20:4n-6 ) and docosahexaenoic acid ( 22:6n-3 ) are essential for brain growth and cognitive development . We have reported that supplementing pregnant and lactating women with n-3 very-long-chain polyunsaturated fatty acids promotes higher IQ scores at 4 years of age as compared with maternal supplementation with n-6 polyunsaturated fatty acids . In our present study , the children were examined at 7 years of age with the same cognitive tests as at 4 years of age . We also examined the relation between plasma fatty acid pattern and BMI in children , because an association between arachidonic acid and adipose tissue size has been suggested . METHODS . The study was r and omized and double-blinded . The mothers took 10 mL of cod liver oil or corn oil from week 18 of pregnancy until 3 months after delivery . Their children were tested with the Kaufman Assessment Battery for Children at 7 years of age , and their height and weight were measured . RESULTS . We did not find any significant differences in scores on the Kaufman Assessment Battery for Children test at 7 years of age between children whose mothers had taken cod liver oil ( n = 82 ) or corn oil ( n = 61 ) . We observed , however , that maternal plasma phospholipid concentrations of α-linolenic acid ( 18:3n-3 ) and docosahexaenoic acid during pregnancy were correlated to sequential processing at 7 years of age . We observed no correlation between fatty acid status at birth or during the first 3 months of life and BMI at 7 years of age . CONCLUSION . This study suggests that maternal concentration of n-3 very-long-chain polyunsaturated fatty acids during pregnancy might be of importance for later cognitive function , such as sequential processing , although we observed no significant effect of n-3 fatty acid intervention on global IQs . Neonatal fatty acid status had no influence on BMI at 7 years of age [17980419] BACKGROUND Altered intakes of n-3 and n-6 polyunsaturated fatty acids were suggested to modulate allergic disease , but intervention trials yielded inconclusive results . Because allergies are primed in early infancy and in utero , the fetus might be more accessible to nutritional intervention strategies . OBJECTIVE We sought to investigate how supplementation of pregnant women with a fish oil ( FO ) preparation modulates allergy-related immune parameters in mothers and offspring . METHODS We performed a multicenter , r and omized , double-blind , placebo-controlled trial . Three hundred eleven pregnant women received daily either FO with 0.5 g of docosahexaenoic acid and 0.15 g of eicosapentaenoic acid , 400 mug of methyl-tetra-hydrofolic acid , both , or placebo from the 22nd gestational week . T(H)1/T(H)2-related molecules were quantified in 197 maternal and 195 cord blood sample s by using real-time RT-PCR . Data are given as geometric means [ 95 % CIs ] . RESULTS FO supplementation was associated with increased TGF-beta mRNA in maternal ( 0.85 [ 0.8 - 0.89 ] ; placebo : 0.68 [ 0.64 - 0.72 ] ) and cord blood ( 0.85 [ 0.81 - 0.9 ] ; placebo : 0.75 [ 0.71 - 0.79 ] ) . IL-1 ( 0.69 [ 0.66 - 0.73 ] ; placebo : 0.83 [ 0.79 - 0.88 ] ) and IFN-gamma ( 0.54 [ 0.51 - 0.57 ] ; placebo : 0.65 [ 0.61 - 0.69 ] ) were decreased in mothers only ( P < .001 ) . Cord blood mRNA levels of IL-4 ( 0.54 [ 0.52 - 0.57 ] ; placebo : 0.64 [ 0.61 - 0.68 ] ) , IL-13 ( 0.61 [ 0.58 - 0.65 ] ; placebo : 0.85 [ 0.80 - 0.89 ] ) , CCR4 ( 0.70 [ 0.67 - 0.73 ] ; placebo : 0.88 [ 0.84 - 0.92 ] ; all P < .001 ) , and natural killer ( P < .001 ) and CCR3+CD8 + T cells ( P < .04 ) were decreased in the FO group . CONCLUSION Supplementation with FO during pregnancy is associated with decreased mRNA levels of T(H)2-related molecules in the fetus and decreased maternal inflammatory cytokines . We speculate that both effects are mediated by TGF-beta [22552037] BACKGROUND There is uncertainty regarding the efficacy of increasing n-3 long-chain PUFA ( LCPUFA ) intake during pregnancy in reducing the risk of gestational diabetes mellitus ( GDM ) and preeclampsia . OBJECTIVES The objective was to determine whether n-3 LCPUFA supplementation in pregnancy reduces the incidence of GDM or preeclampsia . A secondary objective was to assess the effect of n-3 LCPUFA supplementation on perinatal complications . DESIGN This was a double-blind , multicenter r and omized control trial-the DHA to Optimize Mother Infant Outcome ( DOMInO ) trial . Pregnant women ( n = 2399 ) of < 21 wk gestation were r and omly assigned to receive DHA-enriched fish oil ( 800 mg/d ) or vegetable oil capsules without DHA from trial entry to birth . The presence of GDM or preeclampsia was assessed through a blinded audit of medical records . Birth outcomes and prenatal complications were also assessed . RESULTS The overall incidences of GDM and preeclampsia were 8 % and 5 % , respectively , based on clinical diagnosis . The RR of GDM was 0.97 ( 95 % CI : 0.74 , 1.27 ) and of preeclampsia was 0.87 ( 95 % CI : 0.60 , 1.25 ) , and they did not differ significantly between the groups . Birth weight , length , and head circumference z scores also did not differ between the groups . There were 12 perinatal deaths and 5 neonatal convulsions in the control group compared with 3 perinatal deaths and no neonatal convulsions in the DHA group ( P = 0.03 in both cases ) . CONCLUSION DHA supplementation of 800 mg/d in the second half of pregnancy does not reduce the risk of GDM or preeclampsia . Whether supplementation reduces the risk of perinatal death and neonatal convulsions requires further investigation . The DOMInO trial was registered with the Australian New Zeal and Clinical Trials Registry as TRN12605000569606 [19193660] Objective : To study the effect of modified polyunsaturated fatty acid ( PUFA ) profiles of complementary food on long-chain ( LC ) PUFA composition in healthy infants . Design : Double blinded , r and omised , controlled intervention trial . Setting : Dortmund , Germany . Patients : Free-living sample of healthy term infants . Methods : Participants were r and omly assigned within the first 2 months of life . During the intervention period from 4 to 10 months , the control group ( n = 53 ) received commercial complementary meals with corn oil ( 3.4 g/meal ) rich in n-6 linoleic acid ( LA ) , the intervention group ( n = 49 ) received the same meals with rapeseed oil ( 1.6 g/meal ) rich in n-3 alpha-linolenic acid ( ALA ) . Fatty acid intake was assessed from dietary records throughout the intervention period . Fatty acid proportions ( % of total fatty acid ) in total plasma were analysed before and after the intervention . Results : Plasma fatty acid profiles did not differ between the intervention and control groups before the intervention . During the intervention , the only difference in fatty acid intake between the intervention and control groups was a higher intake of ALA in the intervention group , 21 % deriving from study food and a lower ratio of LA/ALA ( 10.7 vs 14.8 ) . At the end of the intervention , the plasma proportions of total n-3 fatty acids and of n-3 LC-PUFA , but not of ALA , were higher and the ratios of n-6/n-3 fatty acids were lower in the intervention group . Conclusions : Feasible dietary modifications of the precursor fatty acid profile via n-3 PUFA-rich vegetable oil favoured n-3 LC-PUFA synthesis in the complementary feeding period when LC-PUFA intake from breast milk and formula is decreasing [21130544] BACKGROUND & AIMS Canola oil is a variety of rapeseed oil low in erucic acid ( < 2 % ) . For many years , canola oil has been widely used as an ingredient in infant formula in Europe , but not in North America due to safety concerns . A number of studies have used variable canola content of infant formulas to investigate the effects of linoleic acid : α-linolenic acid ratio on visual function of infants . However , little published data is available to compare the safety of canola versus non-canola containing infant formula . The aim of this study is to investigate whether infant formulas containing canola oil support normal growth in infants as assessed by weight and length gain . METHODS Re-analyses of data on infant weight and length gain from a prospect i ve r and omized double-blind trial in full-term infants in the German Infant Nutritional Intervention study ( GINI ) . This analysis compared growth in infants receiving infant formulas with or without canola oil from week 4 to month 7 . Absolute weight and length , weight and length gain in gram or cm per day and st and ardized weight and length measurements were analyzed by analyses of variance and a longitudinal r and om effects model . St and ardization was conducted according to the new WHO 2006 age- and sex-specific child growth st and ards . RESULTS Absolute and st and ardized weight and length measures did not differ between the formula groups with or without canola oil . This was true for both , analyses within each of the three anthropometric measurement periods ( 4 - 6 weeks , 3 - 4 months , 6 - 7 months ) and for the longitudinal analyses over the whole period from 4 weeks to 7 months of life . Power analyses confirmed that sample size was sufficient to detect a difference of 3 g per day between 14 and 120 days between the two formula groups . CONCLUSIONS Infant formula containing canola oil supports normal infant growth as assessed by weight and length gain [23279074] AIM To determine the effect of neonatal docosahexaenoic acid ( DHA ) supplementation in preterm infants on later respiratory-related hospitalisations . METHODS We enrolled 657 infants in a multicentre , r and omised , controlled trial design ed to study the long-term efficacy of higher dose dietary DHA in infants born <33 weeks ' gestation . Treatment was with high DHA ( ∼1 % ) compared with st and ard DHA ( ∼0.3 % ) in breast milk or formula , given from the first week of life to term equivalent . Parent-reported hospital admissions to 18 months corrected age were recorded . The proportion of children hospitalised for lower respiratory tract ( LRT ) conditions and the mean number of hospitalisations per infant were determined . RESULTS Twenty-three per cent ( 154/657 ) of infants were hospitalised for LRT conditions . Seventy-three per cent ( 173/238 ) of admissions were for bronchiolitis . There was no significant effect of higher DHA on the proportion of infants admitted for LRT conditions ( high DHA 22 % vs. st and ard DHA 25 % , adjusted relative risk 0.92 , 95 % confidence interval ( CI ) 0.68 - 1.24 , P = 0.57 ) or in the mean number of admissions per infant ( high DHA 0.34 , st and ard DHA 0.38 , adjusted ratio of means 0.91 , 95 % CI 0.63 - 1.32 , P = 0.62 ) . The sexes responded differently to treatment ( interaction P = 0.046 ) , with reduced admissions in boys given high DHA , but this was not statistically significant ( high DHA 19 % , st and ard DHA 28 % , adjusted relative risk 0.69 , 95 % CI 0.46 - 1.04 , P = 0.08 ) . CONCLUSIONS Hospitalisation for LRT problems in the first 18 months for preterm infants was not reduced by neonatal supplementation with 1 % DHA [23531328] OBJECTIVES Maternal deficiency of the omega-3 fatty acid , docosahexaenoic acid ( DHA ) , has been associated with perinatal depression , but there is evidence that supplementation with eicosapentaenoic acid ( EPA ) may be more effective than DHA in treating depressive symptoms . This trial tested the relative effects of EPA- and DHA-rich fish oils on prevention of depressive symptoms among pregnant women at an increased risk of depression . STUDY DESIGN We enrolled 126 pregnant women at risk for depression ( Edinburgh Postnatal Depression Scale score 9 - 19 or a history of depression ) in early pregnancy and r and omly assigned them to receive EPA-rich fish oil ( 1060 mg EPA plus 274 mg DHA ) , DHA-rich fish oil ( 900 mg DHA plus 180 mg EPA ) , or soy oil placebo . Subjects completed the Beck Depression Inventory ( BDI ) and Mini-International Neuropsychiatric Interview at enrollment , 26 - 28 weeks , 34 - 36 weeks , and at 6 - 8 weeks ' postpartum . Serum fatty acids were analyzed at entry and at 34 - 36 weeks ' gestation . RESULTS One hundred eighteen women completed the trial . There were no differences between groups in BDI scores or other depression endpoints at any of the 3 time points after supplementation . The EPA- and DHA-rich fish oil groups exhibited significantly increased postsupplementation concentrations of serum EPA and serum DHA respectively . Serum DHA- concentrations at 34 - 36 weeks were inversely related to BDI scores in late pregnancy . CONCLUSION EPA-rich fish oil and DHA-rich fish oil supplementation did not prevent depressive symptoms during pregnancy or postpartum [20370943] Long-chain PUFA ( LCPUFA ) supplementation of formula can have beneficial effects on neurodevelopmental outcome in early infancy , but uncertainty exists regarding effects after 6 months . The present study is the first to investigate whether consumption by term infants of formula containing LCPUFA for the first 2 months after birth improves neurological condition of these children at 9 years of age . A prospect i ve , double-blind , r and omised control study was performed in two groups of healthy term infants : a control group with st and ard formula ( n 169 ) and a LCPUFA-supplemented group ( LF ; n 146 ) . A breast-fed group ( BF ; n 159 ) served as a reference . At age 9 years , children were neurologically assessed according to Touwen , result ing in a Neurological Optimality Score and information on severity and type of minor neurological dysfunction ( MND ) . Information on potential confounders was collected at enrollment and follow-up . Multivariate analyses were carried out to evaluate the effect of nutrition while adjusting for confounders . Attrition ( 28 % ) was selective : drop-outs in the LF group were more often boys and had a significantly lower mental developmental index at 18 months . Neurological optimality and severity and type of MND at 9 years did not differ between the two formula groups . Children in the BF group showed significantly less often fine manipulative dysfunction than formula-fed children . In conclusion , LCPUFA supplementation of formula during the first 2 postnatal months in healthy term infants does not alter neurological function at school age . The study confirmed that breast-fed infants have a slightly better neurodevelopmental outcome than formula-fed infants [22313729] Studies in experimental animals and human subjects have suggested that intake of n-3 fatty acids in early life can affect cardiovascular risk factors in adult life . Therefore , the aim of the present study was to investigate the effect of fish oil ( FO ) supplementation during the third trimester of pregnancy on blood pressure ( BP ) , heart rate ( HR ) and HR variability ( HRV ) in the 19-year-old offspring . The study was based on follow-up of a r and omised , controlled trial from 1990 , in which 533 pregnant women were r and omised to FO , olive oil ( OO ) or no oil ( NO ) during the last trimester of pregnancy . The offspring was invited to a physical examination including BP , HR and HRV measurements . A subgroup consisting of the offspring of mothers with a low baseline fish intake also had 24 h HRV determined . The OO group was used as reference and multiple linear regression modelling was used to compare the FO and OO groups . A total of 180 of the offspring from the FO and OO groups agreed to participate in the study ( 45 % ) . The adjusted difference between the FO and OO groups was 2 ( 95 % CI -1 , 4 ) mmHg in systolic and 1 ( 95 % CI 0 , 3 ) mmHg in diastolic BP . The difference in HR was 1 ( 95 % CI -2 , 4 ) . Also , HRV indices did not differ significantly between groups . Hence , FO supplementation during late pregnancy was not associated with offspring BP , HR and HRV during adolescence [18519483] OBJECTIVE . The objective of our study was to evaluate the effect of supplementation with docosahexaenoic acid and arachidonic acid for human milk-fed preterm infants . The primary end point was cognitive development at 6 months of age . METHODS . The study was a r and omized , double-blind , placebo-controlled study among 141 infants with birth weights of < 1500 g. The intervention with 32 mg of docosahexaenoic acid and 31 mg of arachidonic acid per 100 mL of human milk started 1 week after birth and lasted until discharge from the hospital ( on average , 9 weeks ) . Cognitive development was evaluated at 6 months of age by using the Ages and Stages Question naire and event-related potentials , a measure of brain correlates related to recognition memory . RESULTS . There was no difference in adverse events or growth between the 2 groups . At the 6-month follow-up evaluation , the intervention group performed better on the problem-solving subscore , compared with the control group ( 53.4 vs 49.5 points ) . There was also a nonsignificant higher total score ( 221 vs 215 points ) . The event-related potential data revealed that infants in the intervention group had significantly lower responses after the st and ard image , compared with the control group ( 8.6 vs 13.2 ) . There was no difference in responses to novel images . CONCLUSIONS . Supplementation with docosahexaenoic acid and arachidonic acid for very preterm infants fed human milk in the early neonatal period was associated with better recognition memory and higher problem-solving scores at 6 months [24045099] INTRODUCTION This intervention examined whether fish-oil-supplementation in late infancy modifies free-play test scores and if this is related to blood pressure ( BP ) and mean RR interval . PATIENTS AND METHODS 83 Danish 9-month-old infants were r and omized to ±fish oil ( FO ) ( 3.4±1.1mL/d ) for 3months and 61 of these completed the free-play-test before and after the intervention . RESULTS Most of the free-play scores changed during the intervention , but the intervention affected only the number of looks away from the toy , which was increased in + FO and decreased in -FO ( p=0.037 ) . The increased numbers of looks away were associated with an increase in erythrocyte eicosapentaenoic acid ( r=0.401 , p=0.017 , n=35 ) and were also associated with a decrease in systolic-BP ( r=-0.511 , p<0.001 , n=52 ) . CONCLUSIONS The results indicate that n-3 fatty acid intake also in late infancy can influence brain development and that the cognitive and cardiovascular effects may be related [22739373] Fish oil supplementation during pregnancy alters breast milk composition , but there is little information about the impact of oily fish consumption . We determined whether increased salmon consumption during pregnancy alters breast milk fatty acid composition and immune factors . Women ( n = 123 ) who rarely ate oily fish were r and omly assigned to consume their habitual diet or to consume 2 portions of farmed salmon per week from 20 wk of pregnancy until delivery . The salmon provided 3.45 g long-chain ( LC ) ( n-3 ) PUFA/wk . Breast milk fatty acid composition and immune factors [ soluble CD14 , transforming growth factor-β (TGFβ)1 , TGFβ2 , and secretory IgA ] were analyzed at 1 , 5 , 14 , and 28 d postpartum ( PP ) . Breast milk from the salmon group had higher proportions of EPA ( 80 % ) , docosapentaenoic acid ( 30 % ) , and DHA ( 90 % ) on d 5 PP compared with controls ( P < 0.01 ) . The LC ( n-6 ) PUFA : LC ( n-3 ) PUFA ratio was lower for the salmon group on all days of PP sampling ( P ≤ 0.004 ) , although individual ( n-6 ) PUFA proportions , including arachidonic acid , did not differ . All breast milk immune factors decreased between d 1 and 28 PP ( P < 0.001 ) . Breast milk secretory IgA ( sIgA ) was lower in the salmon group ( d 1 - 28 PP ; P = 0.006 ) . Salmon consumption during pregnancy , at the current recommended intakes , increases the LC ( n-3 ) PUFA concentration of breast milk in early lactation , thus improving the supply of these important fatty acids to the breast-fed neonate . The consequence of the lower breast milk concentration of sIgA in the salmon group is not clear

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### Context: [22945403] BACKGROUND AND OBJECTIVE : Relative deficiency of dietary omega 3 polyunsaturated fatty acids ( n-3 PUFA ) has been implicated in the rising allergy prevalence in Westernized countries . Fish oil supplementation may provide an intervention strategy for primary allergy prevention . The objective of this study was to assess the effect of fish oil n-3 PUFA supplementation from birth to 6 months of age on infant allergic disease . METHODS : In a double-blind r and omized controlled trial , 420 infants at high atopic risk received a daily supplement of fish oil containing 280 mg docosahexaenoic acid and 110 mg eicosapentaenoic acid or a control ( olive oil ) , from birth to age 6 months . PUFA levels were measured in 6-month-old infants ’ erythrocytes and plasma and their mothers ’ breast milk . Eczema , food allergy , asthma and sensitization were assessed in 323 infants for whom clinical follow-up was completed at 12 months of age . RESULTS : At 6 months of age , infant docosahexaenoic acid and eicosapentaenoic acid levels were significantly higher ( both P < .05 ) and erythrocyte arachidonic acid levels were lower ( P = .003 ) in the fish oil group . Although n-3 PUFA levels at 6 months were associated with lower risk of eczema ( P = .033 ) and recurrent wheeze ( P = .027 ) , the association with eczema was not significant after multiple comparisons and there was no effect of the intervention per se on the primary study outcomes . Specifically , between-group comparisons revealed no differences in the occurrence of allergic outcomes including sensitization , eczema , asthma , or food allergy . CONCLUSIONS : Postnatal fish oil supplementation improved infant n-3 status but did not prevent childhood allergic disease [17431817] Summary Background Pre- and postnatal tissue accretion of long-chain polyunsaturated fatty acids ( LCPUFA ) has been related to visual and cognitive development in healthy children in several studies . Children with phenylketonuria ( PKU ) consume diets with very low contents of preformed LCPUFA . We studied prospect ively the LCPUFA status in infants with PKU without or with LCPUFA supplementation during the first year of life . Subjects and methods Infants with PKU were enrolled at diagnosis ( < 4 weeks of age ) and r and omized double blind to phenylalanine-free amino acid supplements without LCPUFA ( n=11 ) or with both arachidonic ( AA , 0.46 wt% ) and docosahexaenoic acids ( DHA , 0.27 wt% ) ( n=10 ) . At enrolment and again at 1 , 2 , 3 , 4 , 6 , 9 and 12 months , plasma phospholipid fatty acids were measured and dietary intakes were calculated from dietary protocol s. Results Unsupplemented patients showed a marked LCPUFA depletion to levels clearly below those observed in healthy breast-fed infants . In contrast , supplemented infants had stable and higher LCPUFA levels than unsupplemented infants , reaching significant differences for AA values at 3 , 4 and 6 months , and for DHA values at 1 , 3 , 4 , 6 , 9 and 12 months . Plasma phospholipid levels correlated closely with estimated dietary intakes of preformed LCPUFA . Conclusion Low LCPUFA intakes with PKU diets induce marked depletion of AA and particularly of DHA in the first year of life . Thus endogenous synthesis of LCPUFA from precursors supplied by diet seems unable to compensate for low LCPUFA intakes . LCPUFA supplementation of PKU diets during the first year of life effectively enhances LCPUFA status to levels comparable to those of healthy breast-fed infants [23340492] Background / Objective : Evidence is accumulating that the long-chain PUFA ( LCPUFA ) are associated with offspring growth and body composition . We investigated the relationship between LCPUFAs in red blood cells ( RBCs ) of pregnant women/breastfeeding mothers and umbilical cord RBCs of their neonates with infant growth and body composition ⩽1 year of age . Subjects/ Methods : In an open-label r and omized , controlled trial , 208 healthy pregnant women received a dietary intervention ( daily supplementation with 1200 mg n-3 LCPUFAs and dietary counseling to reduce arachidonic acid ( AA ) intake ) from the 15th week of gestation until 4 months of lactation or followed their habitual diet . Fatty acids of plasma phospholipids ( PLs ) and RBCs from maternal and cord blood were determined and associated with infant body weight , body mass index ( BMI ) , lean body mass and fat mass assessed by skinfold thickness measurements and ultrasonography . Results : Dietary intervention significantly reduced the n-6/n-3 LCPUFA ratio in maternal and cord-blood plasma PLs and RBCs . Maternal RBCs docosahexaenoic acid ( DHA ) , n-3 LCPUFAs and n-6 LCPUFAs at the 32nd week of gestation were positively related to birth weight . Maternal n-3 LCPUFAs , n-6 LCPUFAs and AA were positively associated with birth length . Maternal RBCs AA and n-6 LCPUFAs were significantly negatively related to BMI and Ponderal Index at 1 year postpartum , but not to fat mass . Conclusion : Maternal DHA , AA , total n-3 LCPUFAs and n-6 LCPUFAs might serve as prenatal growth factors , while n-6 LCPUFAs also seems to regulate postnatal growth . The maternal n-6/n-3 LCPUFA ratio does not appear to have a role in adipose tissue development during early postnatal life [21147707] Development of new infant formulas aims to replicate the benefits of breast milk . One benefit of breast milk over infant formulas is greater gastrointestinal comfort . We compared indicators of gastrointestinal comfort in infants fed a whey-predominant formula containing long-chain polyunsaturated fatty acids , galacto-oligo-saccharides and fructo-oligosaccharides , and infants fed a control casein-predominant formula without additional ingredients . The single-centre , prospect i ve , double-blind , controlled trial r and omly assigned healthy , full-term infants ( n=144 ) to receive exclusively either experimental or control formula from 30 days to 4 months of age . A group of exclusively breast-fed infants served as reference ( n=80 ) . At 1 , 2 , 3 , and 4 months , infants ' growth parameters were measured and their health assessed . Parents recorded frequency and physical characteristics of infants ' stool , frequency of regurgitation , vomiting , crying and colic . At 2-months , gastric emptying ( ultrasound ) and intestinal transit time ( H2 breath test ) were measured , and stool sample s collected for bacterial analysis . Compared to the control ( n=69 ) , fewer of the experimental group ( n=67 ) had hard stools ( 0.7 vs 7.5 % , p<0.001 ) and more had soft stools ( 90.8 vs 82.3 % , p<0.05 ) . Also compared to the control , the experimental group 's stool microbiota composition ( mean % bifidobacteria : 78.1 ( experimental , n=17 ) , 63.7 ( control , n=16 ) , 74.3 ( breast-fed , n=20 ) , gastric transit times ( 59.6 ( experimental , n=53 ) , 61.4 ( control , n=62 ) , 55.9 ( breast-fed , n=67 ) minutes ) and intestinal transit times ( data not shown ) were closer to that of the breast-fed group . Growth parameter values were similar for all groups . The data suggest that , in infants , the prebiotic-containing whey-based formula provides superior gastrointestinal comfort than a control formula [18951004] Formula supplemented with docosahexaenoic acid ( DHA ) improves retinal function of preterm infants but the optimal dose is unknown . In a r and omized controlled trial we examined the effect of increasing the DHA concentration of human milk and formula on circulating fatty acids of preterm infants . Infants born <33 weeks gestation were fed high-DHA milk ( 1 % total fat as DHA ) or st and ard-DHA milk ( 0.2 - 0.3 % DHA ) until reaching their estimated due date ( EDD ) . Milk arachidonic acid ( AA ) concentration was approximately 0.5 % for both groups . At EDD , erythrocyte membrane phospholipid DHA was elevated in the high-DHA group compared with st and ard-DHA ( mean+/-SD , high-DHA 6.8+/-1.2 , st and ard-DHA 5.2+/-0.7 , p<0.0005 ) but AA was lower ( high-DHA 14.9+/-1.3 , st and ard-DHA 16.0+/-1.2 , p<0.0005 ) . Feeding preterm infants human milk and formula with 1 % DHA raises but does not saturate erythrocyte phospholipids with DHA . Milk exceeding 1 % DHA may be required to increase DHA status to levels seen in term infants [20959577] CONTEXT Uncertainty about the benefits of dietary docosahexaenoic acid ( DHA ) for pregnant women and their children exists , despite international recommendations that pregnant women increase their DHA intakes . OBJECTIVE To determine whether increasing DHA during the last half of pregnancy will result in fewer women with high levels of depressive symptoms and enhance the neurodevelopmental outcome of their children . DESIGN , SETTING , AND PARTICIPANTS A double-blind , multicenter , r and omized controlled trial ( DHA to Optimize Mother Infant Outcome [ DOMInO ] trial ) in 5 Australian maternity hospitals of 2399 women who were less than 21 weeks ' gestation with singleton pregnancies and who were recruited between October 31 , 2005 , and January 11 , 2008 . Follow-up of children ( n = 726 ) was completed December 16 , 2009 . INTERVENTION Docosahexaenoic acid-rich fish oil capsules ( providing 800 mg/d of DHA ) or matched vegetable oil capsules without DHA from study entry to birth . MAIN OUTCOME MEASURES High levels of depressive symptoms in mothers as indicated by a score of more than 12 on the Edinburgh Postnatal Depression Scale at 6 weeks or 6 months postpartum . Cognitive and language development in children as assessed by the Bayley Scales of Infant and Toddler Development , Third Edition , at 18 months . RESULTS Of 2399 women enrolled , 96.7 % completed the trial . The percentage of women with high levels of depressive symptoms during the first 6 months postpartum did not differ between the DHA and control groups ( 9.67 % vs 11.19 % ; adjusted relative risk , 0.85 ; 95 % confidence interval [ CI ] , 0.70 - 1.02 ; P = .09 ) . Mean cognitive composite scores ( adjusted mean difference , 0.01 ; 95 % CI , -1.36 to 1.37 ; P = .99 ) and mean language composite scores ( adjusted mean difference , -1.42 ; 95 % CI , -3.07 to 0.22 ; P = .09 ) of children in the DHA group did not differ from children in the control group . CONCLUSION The use of DHA-rich fish oil capsules compared with vegetable oil capsules during pregnancy did not result in lower levels of postpartum depression in mothers or improved cognitive and language development in their offspring during early childhood . TRIAL REGISTRATION anzctr.org.au Identifier : ACTRN12605000569606 [23761484] BACKGROUND Early-life exposures to tobacco smoke and some dietary factors have been identified to induce epigenetic changes in genes involved in allergy and asthma development . Omega-3 ( n-3 ) polyunsaturated fatty acid ( PUFA ) intake during pregnancy could modulate key cytokines and T helper ( Th ) cell maturation ; however , little is known about the mechanism by which ω-3 PUFA could have a beneficial effect in preventing inflammatory disorders . OBJECTIVE We sought to test whether prenatal dietary supplementation with ω-3 PUFA during pregnancy may modulate epigenetic states in the infant immune system . DESIGN This study was based on a r and omized intervention trial conducted in Mexican pregnant women supplemented daily with 400 mg docosahexaenoic acid ( DHA ) or a placebo from 18 to 22 wk of gestation to parturition . We applied quantitative profiling of DNA methylation states in Th1 , Th2 , Th17 , and regulatory T-relevant genes as well as LINE1 repetitive elements of cord blood mononuclear cells ( n = 261 ) . RESULTS No significant difference in promoter methylation levels was shown between ω-3 PUFA-supplemented and control groups for the genes analyzed ; however , ω-3 PUFA supplementation was associated with changes in methylation levels in LINE1 repetitive elements ( P = 0.03 ) in infants of mothers who smoked during pregnancy . Furthermore , an association between the promoter methylation levels of IFNγ and IL13 was modulated by ω-3 PUFA supplementation ( P = 0.06 ) . CONCLUSIONS Our results indicate that maternal supplementation with ω-3 PUFA during pregnancy may modulate global methylation levels and the Th1/Th2 balance in infants . Therefore , the epigenetic mechanisms could provide attractive targets for prenatal modulation and prevention of inflammatory disorders and potentially other related diseases in childhood and adulthood [21705958] Conflicting evidence exists on the effect of long-chain polyunsaturated fatty acid ( LCPUFA ) formula supplementation on cardiovascular health in term infants . It is known that LCPUFA supplementation does not affect infant growth , but long term outcome data are not available . The current study investigates whether 2 mo LCPUFA formula supplementation affects cardiovascular and anthropometric development at 9 y. A prospect i ve , double-blind , r and omized trial was performed in healthy term infants : a st and ard formula control group ( CF , n = 169 ) and a LCPUFA-supplemented group [ LF , n = 145 ; 0.45 % ( by wt ) AA and 0.30 % ( by wt ) docosahexaenoic acid ( DHA ) ] . A breastfed group ( BF ; n = 159 ) served as reference . At the age of 9 y , systolic and diastolic blood pressure , heart rate , head circumference , weight , and height were measured . Univariate and multivariate analyses were performed ; 63 to 79 % of children were assessed . None of the cardiovascular or anthropometric measurements differed between the formula groups . Breastfed children had a marginally lower heart rate than formula-fed children , in particular compared with children fed control formula . Blood pressure and parameters of growth including BMI of breast and formula-fed children did not differ . In conclusion , the study suggests that short-term LCPUFA supplementation does not influence cardiovascular and anthropometric development at 9 [3522138] Background : Intestinal damage and malabsorption caused by chronic environmental enteropathy are associated with growth faltering seen in infants in less-developed countries . Evidence has suggested that supplementary omega-3 ( n−3 ) long-chain PUFAs ( LC-PUFAs ) might ameliorate this damage by reducing gastrointestinal inflammation . LC-PUFA supplementation may also benefit cognitive development . Objective : We tested whether early n−3 LC-PUFA supplementation improves infant intestinal integrity , growth , and cognitive function . Design : A r and omized , double-blind , controlled trial [ 200 mg DHA and 300 mg EPA or 2 mL olive oil/d for 6 mo ] was conducted in a population of 172 rural Gambian infants aged 3–9 mo . The primary endpoints were anthropometric measures and gut integrity [ assessed by using urinary lactulose : mannitol ratios ( LMRs ) ] . Plasma fatty acid status , intestinal mucosal inflammation ( fecal calprotectin ) , daily morbidity , and cognitive development ( 2-step means-end test and an attention assessment ) were secondary endpoints . Results : PUFA supplementation result ed in a significant increase in plasma n−3 LC-PUFA concentrations ( P < 0.001 for both DHA and EPA ) and midupper arm circumference ( MUAC ) ( effect size : 0.31 z scores ; 95 % CI : 0.06 , 0.56 ; P = 0.017 ) at 9 mo of age . At 12 mo , MUAC remained greater in the intervention group , and we observed significant increases in skinfold thicknesses ( P ≤ 0.022 for all ) . No other significant differences between treatment groups were detected for growth or LMRs at 9 mo or for secondary outcomes . Conclusions : Fish-oil supplementation successfully increased plasma n−3 fatty acid status . However , in young , breastfed Gambian infants , the intervention failed to improve linear growth , intestinal integrity , morbidity , or selected measures of cognitive development . The trial was registered at www.is rct n.org as IS RCT N66645725 [22218160] BACKGROUND Long-chain n-3 PUFAs found in oily fish may have a role in lowering the risk of allergic disease . OBJECTIVE The objective was to assess whether an increased intake of oily fish in pregnancy modifies neonatal immune responses and early markers of atopy . DESIGN Women ( n = 123 ) were r and omly assigned to continue their habitual diet , which was low in oily fish , or to consume 2 portions of salmon per week ( providing 3.45 g EPA plus DHA ) from 20 wk gestation until delivery . In umbilical cord blood sample s ( n = 101 ) , we measured n-3 fatty acids , IgE concentrations , and immunologic responses . Infants were clinical ly evaluated at age 6 mo ( n = 86 ) . RESULTS Cord blood mononuclear cell ( C BMC ) production of interleukin (IL)-2 , IL-4 , IL-5 , IL-10 , and tumor necrosis factor-α in response to phytohemagglutinin ( PHA ) and of IL-2 in response to Dermatophagoides pteronyssinus allergen 1 ( Derp1 ) was lower in the salmon group ( all P ≤ 0.03 ) . In the subgroup of C BMC s in which an allergic phenotype was confirmed in the mother or father , IL-10 production in response to Toll-like receptor 2 , 3 , and 4 agonists , ovalbumin , salmon parvalbumin , or Derp1 and prostagl and in E(2 ) production in response to lipopolysaccharide or PHA was lower in the salmon group ( all P ≤ 0.045 ) . Total IgE at birth and total IgE , incidence and severity of atopic dermatitis , and skin-prick-test positivity at 6 mo of age were not different between the 2 groups . CONCLUSION Oily fish intervention in pregnancy modifies neonatal immune responses but may not affect markers of infant atopy assessed at 6 mo of age . This trial is registered at clinical trials.gov as NCT00801502 [21332799] We have previously reported a protective effect of maternal omega-3 long-chain polyunsaturated fatty acids ( ω-3 LCPUFA ) supplementation in pregnancy and lactation on IgE-associated eczema and food allergy in the infant during the first year of life . Here we investigate whether the effects of the LCPUFA supplementation on IgE-associated diseases last up to 2 yr of age and assess the relationship between plasma proportions of ω-3 PUFAs and the frequency and severity of infant allergic disease . 145 pregnant women , at risk of having an allergic infant , were r and omized to daily supplementation with 1.6 g eicosapentaenoic acid ( EPA ) and 1.1 g docosahexaenoic acid ( DHA ) or placebo starting in the 25th gestational week and continuing through 3.5 months of breastfeeding . Clinical examinations , skin prick tests and analysis of maternal and infant plasma phospholipid fatty acids and infant specific IgE were performed . No difference in the prevalence of allergic symptoms was found between the intervention groups . The cumulative incidence of IgE-associated disease was lower in the ω-3-supplemented group ( 6/54 , 13 % ) compared with the placebo group ( 19/62 , 30 % , p=0.01 ) . Higher maternal and infant proportions of DHA and EPA were associated with lower prevalence of IgE associated disease ( p=0.01 - 0.05 ) in a dose-dependent manner . Higher maternal and infant proportions of DHA and EPA were found if the infants presented none , when compared with multiple allergic symptoms , ( p<0.05 ) regardless of sensitization . In summary , the ω-3 supplementation offered no obvious preventive effect on the prevalence of clinical symptoms of allergic disease , but the decrease in cumulative incidence of IgE-associated disease seen during the first year still remained until 2 yr of age . Furthermore , high proportions of DHA and EPA in maternal and infant plasma phospholipids were associated with less IgE-associated disease and a reduced severity of the allergic phenotype [16002810] BACKGROUND Normal brain and visual development is thought to require exogenous docosahexaenoic acid ( DHA ; 22:6n-3 ) intake , but the amount needed is debatable . Because the supplementation of breastfeeding mothers with DHA increases the DHA content of their infants ' plasma lipids , we hypothesized that it might also improve brain or visual function in the infants . OBJECTIVE The objective was to determine the effect of DHA supplementation of breastfeeding mothers on neurodevelopmental status and visual function in the recipient infant . DESIGN Breastfeeding women received capsules containing either a high-DHA algal oil ( approximately 200 mg DHA/d ) or a vegetable oil ( no DHA ) for 4 mo after delivery . Outcome variables included the fatty acid pattern of maternal plasma phospholipid and milk lipids 4 mo postpartum , the fatty acid pattern of plasma phospholipids and visual function in infants at 4 and 8 mo of age , and neurodevelopmental indexes of the infants at 12 and 30 mo of age . RESULTS Milk lipid and infant plasma phospholipid DHA contents of the supplemented and control groups were approximately 75 % and approximately 35 % higher , respectively , at 4 mo postpartum . However , neither the neurodevelopmental indexes of the infants at 12 mo of age nor the visual function at 4 or 8 mo of age differed significantly between groups . In contrast , the Bayley Psychomotor Development Index , but not the Mental Development Index , of the supplemented group was higher ( P < 0.01 ) at 30 mo of age . CONCLUSION DHA supplementation of breastfeeding mothers results in higher infant plasma phospholipid DHA contents during supplementation and a higher Bayley Psychomotor Development Index at 30 mo of age but results in no other advantages either at or before this age [21865979] Objectives : The aim of this study was to monitor changes in the fecal microbiota from 9 to 18 months and to investigate the effect of increasing dietary n-3 polyunsaturated fatty acids on the fecal microbiota . Patients and Methods : In a double-blind controlled trial with r and om allocation to daily supplementation with 5 mL of fish oil ( FO ) or sunflower oil ( SO ) from 9 to 18 months of age , stool sample s were collected from 132 healthy Danish infants . Molecular fingerprints of the bacterial DNA were obtained by terminal restriction fragment length polymorphism ( T-RFLP ) . Results : The T-RFLP profiles indicated that a few T-RFs became dominant with age ( bp100 and 102 , both presumed to be Bacteroidetes ) concomitantly with an overall increase in the microbial diversity ( P = 0.04 ) . Breast-feeding influenced both the T-RFLP profiles at 9 months and the changes from 9 to 18 months , and breast-feeding cessation during the trial modified the response to the dietary oils . In the FO group , the increase in bp102 was significantly reduced among children weaned before compared with those weaned during the trial ( P = 0.027 ) , whereas the increase in bp100 was reduced in the preweaned children of the SO group relative to those weaned during the trial ( P = 0.004 ) . This was supported by intervention group differences in the changes in bp102 and bp100 among the earlier weaned children ( P = 0.06 and P = 0.09 , respectively ) . Conclusions : Cessation of breast-feeding played a dominant role relative to developmental changes in the fecal microbiota from 9 to 18 months . FO compared with SO supplementation affected changes in large bacterial groups , but only among children who had stopped breast-feeding before 9 months of age [17688705] Dietary fat intake in pregnancy and lactation affects pregnancy outcomes and child growth , development and health . The European Commission charged the research project PERILIP , jointly with the Early Nutrition Programming Project , to develop recommendations on dietary fat intake in pregnancy and lactation . Literature review s were performed and a consensus conference held with international experts in the field , including representatives of international scientific associations . The adopted conclusions include : dietary fat intake in pregnancy and lactation ( energy% ) should be as recommended for the general population ; pregnant and lactating women should aim to achieve an average dietary intake of at least 200 mg DHA/d ; intakes of up to 1 g/d DHA or 2.7 g/d n-3 long-chain PUFA have been used in r and omized clinical trials without significant adverse effects ; women of childbearing age should aim to consume one to two portions of sea fish per week , including oily fish ; intake of the DHA precursor , alpha-linolenic acid , is far less effective with regard to DHA deposition in fetal brain than preformed DHA ; intake of fish or other sources of long-chain n-3 fatty acids results in a slightly longer pregnancy duration ; dietary inadequacies should be screened for during pregnancy and individual counselling be offered if needed [18614738] BACKGROUND Evidence suggests that asthma is rooted in the intrauterine environment and that intake of marine n-3 polyunsaturated fatty acids ( n-3 PUFAs ) in pregnancy may have immunomodulatory effects on the child . OBJECTIVE Our aim was to examine whether increasing maternal intake of n-3 PUFAs in pregnancy may affect offspring risk of asthma . DESIGN In 1990 , a population -based sample of 533 women with normal pregnancies were r and omly assigned 2:1:1 to receive four 1-g gelatin capsules/d with fish oil providing 2.7 g n-3 PUFAs ( n = 266 ) ; four 1-g , similar-looking capsules/d with olive oil ( n = 136 ) ; or no oil capsules ( n = 131 ) . Women were recruited and r and omly assigned around gestation week 30 and asked to take capsules until delivery . Among 531 live-born children , 528 were identified in registries and 523 were still alive by August 2006 . Diagnoses from the International Coding of Diseases version 10 were extracted from a m and atory registry that recorded diagnoses reported from hospital contacts . RESULTS During the 16 y that passed since childbirth , 19 children from the fish oil and olive oil groups had received an asthma-related diagnosis ; 10 had received the diagnosis allergic asthma . The hazard rate of asthma was reduced by 63 % ( 95 % CI : 8 % , 85 % ; P = 0.03 ) , whereas the hazard rate of allergic asthma was reduced by 87 % ( 95 % CI : 40 % , 97 % ; P = 0.01 ) in the fish oil compared with the olive oil group . CONCLUSION Under the assumption that intake of olive oil in the dose provided here was inert , our results support that increasing n-3 PUFAs in late pregnancy may carry an important prophylactic potential in relation to offspring asthma [21705959] A double-blind , r and omized , controlled , parallel-group prospect i ve trial was conducted to determine whether a dose-response existed for four different levels of docosahexaenoic acid ( DHA ) supplementation on the cognitive performance of infants . A total of 122 term infants were fed one of four different formulas varying in their DHA composition ( 0.00 , 0.32 , 0.64 , and 0.96 % of total fatty acids as DHA ) from birth to 12 mo . The three DHA-supplemented formulas also contained 0.64 % of total fatty acids as arachidonic acid ( ARA , 20:4n-6 ) . Infants were tested at 4 , 6 , and 9 mo of age on a visual habituation protocol that yielded both behavioral and psychophysiological indices of attention . Infants in all DHA+ARA-supplemented conditions had lower heart rates than those in the unsupplemented condition ; there was no dose-response for this effect . The distribution of time that infants spent in different phases of attention ( a cognitive index derived from the convergence of behavioral and cardiac responses ) varied as a function of dosage . Infants supplemented at the two lower DHA doses spent proportionately more time engaged in active stimulus processing than infants fed the unsupplemented formula , whereas infants fed the highest dose were intermediate and did not differ from any other group [3213334] Nutritional influences on cardiovascular disease operate throughout life . Studies in both experimental animals and humans have suggested that changes in the peri- and early post-natal nutrition can affect the development of the various components of the metabolic syndrome in adult life . This has lead to the hypothesis that n-3 fatty acid supplementation in pregnancy may have a beneficial effect on lipid profile in the offspring . The aim of the present study was to investigate the effect of supplementation with n-3 fatty acids during the third trimester of pregnancy on lipids and lipoproteins in the 19-year-old offspring . The study was based on the follow-up of a r and omized controlled trial from 1990 where 533 pregnant women were r and omized to fish oil ( n = 266 ) , olive oil ( n = 136 ) or no oil ( n = 131 ) . In 2009 , the offspring were invited to a physical examination including blood sampling . A total of 243 of the offspring participated . Lipid values did not differ between the fish oil and olive oil groups . The relative adjusted difference ( 95 % confidence intervals ) in lipid concentrations was −3 % ( −11 ; 7 ) for LDL cholesterol , 3 % ( −3 ; 10 ) for HDL cholesterol , −1 % ( −6 ; 5 ) for total cholesterol,−4 % ( −16 ; 10 ) for TAG concentrations , 2%(−2 ; 7 ) for apolipoprotein A1 , −1 % ( −9 ; 7 ) for apolipoprotein B and 3 % ( −7 ; 15 ) in relative abundance of small dense LDL . In conclusion , there was no effect of fish oil supplementation during the third trimester of pregnancy on offspring plasma lipids and lipoproteins in adolescence [21512889] Early accumulation of n-3 long-chain PUFA ( LCPUFA ) in the brain may contribute to differences in later cognitive abilities . In this study , our objective was to examine whether fish oil ( FO ) supplementation during lactation affects processing speed , working memory , inhibitory control , and socioemotional development at 7 years . Danish mothers ( n = 122 ) were r and omized to FO [ 1.5 g/d n-3 LCPUFA ] or olive oil ( OO ) supplementation during the first 4 months of lactation . The trial also included a high-fish intake ( HFI ) reference group ( n = 53 ) . Ninety-eight children were followed-up with an assessment of processing speed , an age-appropriate Stroop task , and the Strength and Difficulties Question naire at 7 year . A group effect of the intervention ( FO vs. OO ) was found in prosocial behavior scores ; this negative effect was carried by the boys . Exploratory analyses including all participants revealed the speed of processing scores were predicted by maternal n-3 LCPUFA intake during the intervention period ( negative relation ) and maternal education ( positive relation ) . Stroop scores indicative of working memory and inhibitory control were predicted by infant erythrocyte DHA status at 4 months of age ( negative relation ) . Early fish oil supplementation may have a negative effect on later cognitive abilities . Speed of processing and inhibitory control/working memory are differentially affected , with speed of processing showing effects of fish oil intake as a whole , whereas inhibitory control/working memory was related more specifically to DHA status [18842793] BACKGROUND Preterm infants have improved visual outcomes when fed a formula containing 0.2 - 0.4 % docosahexaenoic acid ( DHA ) compared with infants fed no DHA , but the optimal DHA dose is unknown . OBJECTIVE We assessed visual responses of preterm infants fed human milk ( HM ) and formula with a DHA concentration estimated to match the intrauterine accretion rate ( high-DHA group ) compared with infants fed HM and formula containing DHA at current concentrations . DESIGN A double-blind r and omized controlled trial studied preterm infants born at <33 wk gestation and fed HM or formula containing 1 % DHA ( high-DHA group ) or approximately 0.3 % DHA ( current practice ; control group ) until reaching their estimated due date ( EDD ) . Both groups received the same concentration of arachidonic acid . Sweep visual evoked potential ( VEP ) acuity and latency were assessed at 2 and 4 mo corrected age ( CA ) . Weight , length , and head circumference were assessed at EDD and at 2 and 4 mo CA . RESULTS At 2 mo CA , acuity of the high-DHA group did not differ from the control group [ high-DHA group ( x + /- SD ) : 5.6 + /- 2.4 cycles per degree ( cpd ) , n = 54 ; control group : 5.6 + /- 2.4 cpd , n = 61 ; P = 0.96 ] . By 4 mo CA , the high-DHA group exhibited an acuity that was 1.4 cpd higher than the control group ( high-DHA : 9.6 + /- 3.7 cpd , n = 44 ; control : 8.2 + /- 1.8 cpd ; n = 51 ; P = 0.025 ) . VEP latencies and anthropometric measurements were not different between the high-DHA and control groups . CONCLUSION The DHA requirement of preterm infants may be higher than currently provided by preterm formula or HM of Australian women [17284754] BACKGROUND Maternal diet during pregnancy might be one of the factors that influences fetal immune responses associated with childhood allergy . OBJECTIVE We analyzed the association between maternal diet during the last 4 wk of pregnancy and allergic sensitization and eczema in the offspring at 2 y of age . DESIGN Data from 2641 children at 2 y of age were analyzed within a German prospect i ve birth cohort study ( LISA ) . Maternal diet during the last 4 wk of pregnancy was assessed with a semiquantitative food-frequency question naire , which was administered shortly after childbirth . RESULTS High maternal intake of margarine [ adjusted odds ratio ( aOR ) : 1 . 49 ; 95 % CI : 1.08 , 2.04 ] and vegetable oils ( aOR : 1.48 ; 95 % CI : 1.14 , 1.91 ) during the last 4 wk of pregnancy was positively associated and high maternal fish intake ( aOR : 0.75 ; 95 % CI : 0.57 , 0.98 ) was inversely associated with eczema during the first 2 y in the offspring . High celery ( aOR : 1.85 ; 95 % CI : 1.18 , 2.89 ) and citrus fruit ( aOR : 1.73 ; 95 % CI : 1.18 , 2.53 ) intakes increased the risk of sensitization against food allergens . In turn , sensitization against inhalant allergens was positively related to a high maternal intake of deep-frying vegetable fat ( aOR : 1.61 ; 95 % CI : 1.02 , 2.54 ) , raw sweet pepper ( aOR : 2.16 ; 95 % CI : 1.20 , 3.90 ) , and citrus fruit ( aOR : 1.72 ; 95 % CI : 1.02 , 2.92 ) . CONCLUSIONS We suggest that the intake of allergenic foods and foods rich in n-6 polyunsaturated fatty acids during pregnancy may increase and foods rich in n-3 polyunsaturated fatty acids may decrease the risk of allergic diseases in the offspring [22805468] Maternal fish oil supplementation during pregnancy has been associated with altered infant immune responses and a reduced risk of infant sensitization and eczema [17204967] Background : Infants in developing countries require early dietary interventions to prevent nutritional deficiencies , above all protein , energy , iron and zinc . To what extent these interventions may affect the fatty acid ( FA ) status is still unknown . Objectives : To examine and compare the effects of 2 micronutrient “ sprinkles ” supplementations ( iron 12.5 mg + folic acid 150 μg , iron/folate and iron 12.5 mg + folic acid 150 μg + zinc 5 mg + vitamins A , C and D3 , mineral/micronutrient [ MMN ] ) versus placebo on the FA status of Cambodian infants . Methods : A total of 204 infants age 6 mo and living in Kompong Chhnang Province , Cambodia , were r and omly assigned to receive daily supplementation of MMN ( n = 68 ) and iron/folate ( n = 68 ) or placebo ( n = 68 ) for a 12-mo period in powder form as sprinkles . At the end of the intervention period , FAs in the range of 16 to 24 C were determined in blood drops absorbed on a strip collected from 182 subjects , and values among the 3 intervention subgroups and those of 21 Italian 18-mo-old , normal-growing infants as the reference group were compared . Results : At the end of the supplementation trial , higher levels of the 2 essential FAs ( EFAs ) ( linoleic acid , 18:2n-6 , and α-linolenic acid , 18:3n-3 ) were found in the MMN group . No differences occurred for the major longer chain derivatives of both EFAs arachidonic acid ( 20:4n-6 ) and docosahexaenoic acid ( 22:6n-3 ) . In MMN supplemented Cambodians , blood levels of linoleic acid approached those of Italian infants , and in addition their α-linolenic acid levels were improved . Cambodian infants , mostly still breast-fed through the second year of life , showed significantly higher levels of long-chain derivatives of both the n-6 and the n-3 series compared with Italians . Conclusions : Supplementation with iron , folic acid , zinc and vitamins was associated with an increase of linoleic acid and α-linolenic acid levels in Cambodian infants versus placebo , without significant changes in the concentrations of their longer chain derivatives , result ing in a FA status closer to Italian counterparts for the essential polyunsaturated FA levels . The iron/folate – treated infants showed no differences compared with the other 2 groups . Studies are needed to differentiate the potential effects of the supplemented micronutrients on the FA status [20227721] OBJECTIVE To investigate the incidence of allergic and respiratory diseases through age 3 years in children fed docosahexaenoic acid (DHA)- and arachidonic acid (ARA)-supplemented formula during infancy . STUDY DESIGN Children who completed r and omized , double-blind studies of DHA/ARA-supplemented ( 0.32%-0.36%/0.64%-0.72 % of total fatty acids , respectively ) versus nonsupplemented ( control ) formulas , fed during the first year of life , were eligible . Blinded study nurses review ed medical charts for upper respiratory infection ( URI ) , wheezing , asthma , bronchiolitis , bronchitis , allergic rhinitis , allergic conjunctivitis , otitis media , sinusitis , atopic dermatitis ( AD ) , and urticaria . RESULTS From the 2 original cohorts , 89/179 children participated ; 38/89 were fed DHA/ARA formula . The DHA/ARA group had significantly lower odds for developing URI ( odds ratio [ OR ] , 0.22 ; 95 % confidence interval [ CI ] , 0.08 - 0.58 ) , wheezing/asthma ( OR , 0.32 ; 95 % CI , 0.11 - 0.97 ) , wheezing/asthma/AD ( OR , 0.25 ; 95 % CI , 0.09 - 0.67 ) , or any allergy ( OR , 0.28 ; 95 % CI , 0.10 - 0.72 ) . The control group had significantly shorter time to first diagnosis of URI ( P = .006 ) , wheezing/asthma ( P = .03 ) , or any allergy ( P = .006 ) . CONCLUSIONS DHA/ARA supplementation was associated with delayed onset and reduced incidence of URIs and common allergic diseases up to 3 years of age [21443815] The effect of the dietary n-3 long-chain PUFA , DHA ( 22 : 6n-3 ) , on the growth of pre-term infants is controversial . We tested the effect of higher-dose DHA ( approximately 1 % dietary fatty acids ) on the growth of pre-term infants to 18 months corrected age compared with st and ard feeding practice ( 0·2 - 0·3 % DHA ) in a r and omised controlled trial . Infants born < 33 weeks gestation ( n 657 ) were r and omly allocated to receive breast milk and /or formula with higher DHA or st and ard DHA according to a concealed schedule stratified for sex and birth-weight ( < 1250 and ≥ 1250 g ) . The dietary arachidonic acid content of both diets was constant at approximately 0·4 % total fatty acids . The intervention was from day 2 to 5 of life until the infant 's expected date of delivery ( EDD ) . Growth was assessed at EDD , and at 4 , 12 and 18 months corrected age . There was no effect of higher DHA on weight or head circumference at any age , but infants fed higher DHA were 0·7 cm ( 95 % CI 0·1 , 1·4 cm ; P = 0·02 ) longer at 18 months corrected age . There was an interaction effect between treatment and birth weight strata for weight ( P = 0·01 ) and length ( P = 0·04 ) . Higher DHA result ed in increased length in infants born weighing ≥ 1250 g at 4 months corrected age and in both weight and length at 12 and 18 months corrected age . Our data show that DHA up to 1 % total dietary fatty acids does not adversely affect growth [16618358] It has been suggested that changes in dietary habits , particularly increased consumption of omega-6 polyunsaturated fatty acids ( PUFA ) and decreased consumption of omega-3 PUFAs may explain the increase in atopic disease seen in recent years . Furthermore , it seems possible that it is mainly prenatal or very early life environmental factors that influence the development of allergic diseases . It has also been suggested that intrauterine risk factors may act differently if mother themselves suffer from allergic disease . The aim of this study was to investigate whether the consumption of fish , butter and margarine during pregnancy might influence the development of allergic sensitizations in the offspring . The study population was divided into the offspring of allergic and non-allergic mothers . This was a retrospective cohort study enrolling 295 offspring of allergic mothers and 693 of non-allergic mothers . Information regarding maternal intake of fish , butter and margarine during pregnancy as well as other prenatal and perinatal confounding factors were retrospectively assessed by parental report via a st and ardized question naire . Atopy was determined by skin-prick tests ( SPT ) to eight prevalent inhalant allergens and two foods . In the allergic mothers ' group there is no clear correlation between maternal intakes of fish , butter and margarine and sensitizations to food or inhalants . In the non-allergic mothers ' group there was no correlation between butter and margarine intake and food or inhalant sensitizations . On the contrary , a protective effect of fish intake on SPT positivity was observed . In particular , frequent maternal intake ( ' 2 - 3 times/wk or more ' ) of fish reduced the risk of food sensitizations by over a third ( aOR 0.23 ; 95 % CI : 0.08 - 0.69 ) . A similar trend , even if not significant , was found for inhalants . Finally , even in the whole study population , i.e. allergic group plus non-allergic group , there was a similar trend between increased consumption of fish and decreased prevalence of SPT positivity for foods . This study shows that frequent intake of fish during pregnancy may contrast the development of SPT sensitizations for foods in the offspring of mothers without atopic disease . Therefore , larger prospect i ve studies are needed , enrolling mothers with and without allergic disease , to confirm these results [3175709] Background . It is currently recommended that diet of pregnant mothers contain 200–300 mg DHA/day . Aim . To determine whether DHA supplementation during pregnancy and lactation affects infants ' immune response . Methods . 60 women in ≥3rd pregnancy studied ; 30 r and omly assigned to receive DHA 400 mg/day from 12th week gestation until 4 months postpartum . From breast-fed infants , blood obtained for anti-HBs antibodies , immunoglobulins , lymphocyte subset phenotyping , and intracellular cytokine production . Results . CD4 + lymphocytes did not differ between groups , but CD4CD45RA/CD4 ( naïve cells ) significantly higher in infants in DHA+ group . Proportion of CD4 and CD8 cells producing IFNγ significantly lower in DHA+ group , with no differences in proportion of IL4-producing cells . Immunoglobulins and anti-HBs levels did not differ between groups . Conclusions . In infants of mothers receiving DHA supplementation , a higher percentage of CD4 naïve cells and decreased CD4 and CD8 IFNγ production is compatible with attenuation of a proinflammatory response [21490140] BACKGROUND The docosahexaenoic acid ( DHA ) intake of pregnant women is lower than estimates of the DHA accretion by the fetus , and recommendations were made to increase the DHA intake of pregnant women . OBJECTIVE The objective of this study was to determine whether the supplementation of pregnant women with DHA improved the visual acuity of infants at 4 mo . DESIGN We conducted a blinded assessment of a subset of healthy , full-term infants born to women enrolled in a double-blind , r and omized controlled trial called the DHA for Maternal and Infant Outcomes ( DOMInO ) trial . Women were r and omly assigned to consume DHA-rich fish-oil capsules ( ≈800 mg DHA/d in the treatment group ) or vegetable oil capsules ( control group ) from midpregnancy to delivery . The primary outcome was the sweep visual evoked potential ( VEP ) acuity at 4 mo . The VEP latency at 4 mo was a secondary outcome . RESULTS Mean ( ±SD ) VEP acuity did not differ between treatment and control groups [ treatment group : 8.37 ± 2.11 cycles per degree ( cpd ) , n = 89 ; control group : 8.55 ± 1.86 cpd , n = 93 ; P = 0.55 ] . VEP latencies also did not differ between groups . Irrespective of the group , maternal smoking in pregnancy was independently associated with poorer VEP acuity in the infant . CONCLUSIONS DHA supplementation in women with singleton pregnancies does not enhance infant visual acuity in infants at 4 mo of age . Visual acuity in infancy is adversely associated with maternal smoking in pregnancy . This trial was registered at www.anzctr.org.au as ACTRN12606000327583 . The DOMInO trial was registered at www.anzctr.org.au as ACTRN12605000569606 [22205307] BACKGROUND The composition of long-chain PUFAs ( LCPUFAs ) in the maternal diet may affect obesity risk in the mother 's offspring . OBJECTIVE We hypothesized that a reduction in the n-6 (omega-6):n-3 ( omega-3 ) LCPUFA ratio in the diet of pregnant women and breastfeeding mothers may prevent expansive adipose tissue growth in their infants during the first year of life . DESIGN In a r and omized controlled trial , 208 healthy pregnant women were r and omly assigned to an intervention ( 1200 mg n-3 LCPUFAs as a supplement per day and a concomitant reduction in arachidonic acid intake ) or a control diet from the 15th wk of pregnancy to 4 mo of lactation . The primary outcome was infant fat mass estimated by skinfold thickness ( SFT ) measurements at 4 body sites at 3 - 5 d , 6 wk , and 4 and 12 mo postpartum . Secondary endpoints included sonographic assessment of abdominal subcutaneous and preperitoneal fat , fat distribution , and child growth . RESULTS Infants did not differ in the sum of their 4 SFTs at ≤1 y of life [ intervention : 24.1 ± 4.4 mm ( n = 85 ) ; control : 24.1 ± 4.1 mm ( n = 80 ) ; mean difference : -0.0 mm ( 95 % CI : -1.3 , 1.3 mm ) ] or in growth . Likewise , longitudinal ultrasonography showed no significant differences in abdominal fat mass or fat distribution . CONCLUSIONS We showed no evidence that supplementation with n-3 fatty acids and instructions to reduce arachidonic acid intake during pregnancy and lactation relevantly affects fat mass in offspring during the first year of life . Prospect i ve long-term studies are needed to explore the efficacy of this dietary approach for primary prevention . This trial was registered at clinical trials.gov as NCT00362089 [21708809] BACKGROUND : Docosahexaenoic acid ( DHA ) has been associated with downregulation of inflammatory responses . OBJECTIVE : To report the effect of DHA supplementation on long-term atopic and respiratory outcomes in preterm infants . METHODS : This study is a multicenter , r and omized controlled trial comparing the outcomes for preterm infants <33 weeks ' gestation who consumed expressed breast milk from mothers taking either tuna oil ( high-DHA diet ) or soy oil ( st and ard-DHA ) capsules . Data collected included incidence of bronchopulmonary dysplasia ( BPD ) and parental reporting of atopic conditions over the first 18 months of life . RESULTS : Six hundred fifty-seven infants were enrolled ( 322 to high-DHA diet , 335 to st and ard ) , and 93.5 % completed the 18-month follow-up . There was a reduction in BPD in boys ( relative risk [ RR ] : 0.67 [ 95 % confidence interval ( CI ) : 0.47–0.96 ] ; P = .03 ) and in all infants with a birth weight of < 1250 g ( RR : 0.75 [ 95 % CI : 0.57–0.98 ] ; P = .04 ) . There was no effect on duration of respiratory support , admission length , or home oxygen requirement . There was a reduction in reported hay fever in all infants in the high-DHA group at either 12 or 18 months ( RR : 0.41 [ 95 % CI : 0.18–0.91 ] ; P = .03 ) and at either 12 or 18 months in boys ( RR : 0.15 [ 0.03–0.64 ] ; P = .01 ) . There was no effect on asthma , eczema , or food allergy . CONCLUSIONS : DHA supplementation for infants of <33 weeks ' gestation reduced the incidence of BPD in boys and in all infants with a birth weight of < 1250 g and reduced the incidence of reported hay fever in boys at either 12 or 18 months [19134240] Probiotics and long-chain PUFA ( LC-PUFA ) may be beneficial supplements for infants who are not breast-fed . The aim of the present study is to evaluate the safety of an infant formula containing the LC-PUFA DHA and arachidonic acid ( AA ) and the probiotic Bifidobacterium lactis by comparing the growth rate of infants fed the supplemented and unsupplemented formulas . One hundred and forty-two healthy , term infants were enrolled in a single-centre , r and omised , double-blind , controlled , parallel-group trial , and allocated to receive either st and ard or probiotic and LC-PUFA-containing experimental formulas . The infants were fed with their assigned formulas for 7 months . The primary outcome ( weight gain ) and the secondary outcomes ( length , head circumference and formula tolerance ) were measured throughout the study . LC-PUFA status was assessed at 4 months of age and immune response to childhood vaccines was measured at 7 months of age . There was no significant difference in growth between the two groups . The 90 % CI for the difference in mean weight gain was - 0.08 , 3.1 g in the intention-to-treat population and 0.1 - 3.8 g in the per protocol population , which lay within the predefined boundaries of equivalence , - 3.9 - 3.9 . There were no significant differences in mean length and head circumference . DHA and AA concentrations were higher in infants in the experimental formula group compared with the control formula group . No influence of the supplements on the response to vaccines was observed . Growth characteristics of term infants fed the starter formula containing a probiotic and LC-PUFA were similar to st and ard formula-fed infants [19091800] Early nutrition may program obesity and cardiovascular risk later in life , and one of the potential agents is ( n-3 ) long-chain PUFA ( LCPUFA ) . In this study , our objective was to examine whether fish oil ( FO ) supplementation during lactation affects blood pressure and body composition of children . Danish mothers ( n = 122 ) were r and omized to FO [ 1.5 g/d ( n-3 ) LCPUFA ] or olive oil ( OO ) supplementations during the first 4 mo of lactation . The trial also included a high-fish intake reference group ( n = 53 ) . Ninety-eight children were followed-up with blood pressure and anthropometry measurements at 7 y. Diet and physical activity level ( PAL ) were assessed by 4-d weighed dietary records and ActiReg . The PAL value was 4 % lower ( P = 0.048 ) and energy intake ( EI ) of the boys was 1.1 + /- 0.4 MJ/d higher ( P = 0.014 ) in the FO group than in the OO group . Starch intake was 15 + /- 6 g/d higher ( P = 0.012 ) in the FO group , but there were no other differences in diet . Body composition did not differ between the r and omized groups with or without adjustment for starch intake , EI , and PAL . FO boys had 6 mm Hg higher diastolic and mean arterial blood pressure than OO boys ( P < 0.01 ) , but girls did not differ . Within the r and omized groups , blood pressure was not correlated with maternal RBC ( n-3 ) LCPUFA after the intervention , but PAL values were ( r = -0.277 ; P = 0.038 ) . We previously found higher BMI at 2.5 y in the FO group , but the difference did not persist . The differences in blood pressure , EI , and PAL , particularly among boys , suggest that early ( n-3 ) LCPUFA intake may have adverse effects , which should be investigated in future studies [20130095] BACKGROUND The range of human milk docosahexaenoic acid ( DHA ) concentrations worldwide is much broader than the range explored in r and omized clinical trials to date . OBJECTIVE The primary objective was to determine the effect of 4 amounts of DHA supplementation on the visual acuity of formula-fed infants at 12 mo of age . Secondary objectives were to evaluate visual acuity maturation , red blood cell fatty acids , tolerance , anthropometric measures , and adverse events . DESIGN This double-masked , r and omized trial was conducted at 2 sites ( Dallas and Kansas City ) . Three hundred forty-three healthy , term , formula-fed infants were enrolled at 1 - 9 d of age and were r and omly assigned to be fed 1 of the following 4 infant formulas containing equivalent nutrient amounts , except for long-chain polyunsaturated fatty acids : control ( 0 % DHA ) , 0.32 % DHA , 0.64 % DHA , or 0.96 % DHA ; DHA-supplemented formulas also provided 0.64 % arachidonic acid . Visual acuity was measured by visual evoked potentials in 244 infants who completed the 12-mo primary outcome examination . RESULTS Infants fed control formula had significantly poorer visual evoked potential visual acuity at 12 mo of age than did infants who received any of the DHA-supplemented formulas ( P < 0.001 ) . There were no significant differences in visual evoked potential visual acuity between the 3 amounts of DHA supplementation for either site at any age tested . CONCLUSIONS DHA supplementation of infant formula at 0.32 % of total fatty acids improves visual acuity . Higher amounts of DHA supplementation were not associated with additional improvement of visual acuity . This trial was registered at clinical trials.gov as NCT00753818 [10974044] Docosahexaenoic acid ( DHA ) is important for infant development . The DHA transfer from maternal diet into human milk has not been investigated in detail . We studied the effects of DHA supplementation on the fatty acid composition of human milk and the secretion of dietary (13)C-labeled fatty acids , including DHA , into human milk . Ten lactating women were r and omized to consume , from 4 to 6 weeks postpartum , an oil rich in DHA ( DHASCO , 200 mg of DHA/day ) ( n = 5 ) or a placebo oil ( n = 5 ) . Dietary intakes were followed by 7-day protocol s. On study day 14 a single dose of [U-(13)C]DHASCO was given orally , milk sample s were collected over 48 h , and milk production was recorded . Milk fatty acid composition was determined by gas-liquid chromatography and isotopic enrichment was determined by gas chromatography- combustion-isotope ratio mass spectrometry ( GC-C-IRMS ) . Milk DHA content did not differ between the supplemented and placebo group at study entry ( 0.29 vs. 0.28 wt% , median ) . After 2 weeks of supplementation the milk DHA content was almost 2-fold higher in the supplemented versus placebo group ( 0.37 vs. 0.21 wt% , P = 0.003 ) . Cumulative recovery of [(13)C]palmitic , [(13)C]oleic , and [(13)C]docosahexaenoic acids in human milk at 48 h was similar between supplemented and placebo groups ( palmitic acid 7.40 vs. 8 . 14 % , oleic acid 9.14 vs. 9.97 % , and docosahexaenoic acid 9.09 vs. 8 . 03 % of dose , respectively ) . Notable lower recovery was observed for [(13)C]myristic acid in both the supplemented and placebo groups , 0 . 62 versus 0.77 % of dose . Dietary DHA supplementation increases the DHA content in human milk . DHA transfer from the diet into human milk is comparable to palmitic and oleic acid transfer [21775563] BACKGROUND It is well established that obesity tends to track from early childhood into adult life . Studies in experimental animals have suggested that changes in the peri- and early postnatal intake of n-3 ( omega-3 ) polyunsaturated acids can affect the development of obesity in adult life . OBJECTIVE The aim of the current study was to investigate the effect of daily supplementation with 2.7 g long-chain n-3 fatty acids during the third trimester of pregnancy on adiposity in 19-y-old offspring . DESIGN The study was based on follow-up of a r and omized controlled trial from 1990 , in which 533 pregnant women were r and omly assigned to receive fish oil , olive oil , or no oil . At ≈19 y of age , the offspring of subjects from the r and omized controlled trial were invited to undergo a physical examination , including anthropometric measurements and fasting blood sampling . The blood sample was analyzed for insulin , glucose , glycated hemoglobin , leptin , adiponectin , insulin-like growth factor I , and high-sensitivity C-reactive protein . Multiple linear regression modeling , adjusted for sex , smoking , and parental overweight , was used to estimate the effect of fish oil relative to that of olive oil on BMI ( in kg/m(2 ) ) , waist circumference , and biochemical measures . RESULTS A total of 243 of the offspring were followed up . We found no difference between the fish-oil and olive oil groups in BMI ( 0.13 ; -0.92 , 1.17 ) or waist circumference ( 0.7 cm ; -2.1 , 3.4 cm ) . Overall , results of the biochemical analyses supported the finding of no difference between the groups . CONCLUSION We detected no effect of fish-oil supplementation during pregnancy on offspring adiposity in adolescence [23066842] AIM Long-chain polyunsaturated fatty acid ( LCPUFA ) supplementation of infant formula may have a beneficial effect on cognitive development . This study aim ed to investigate the effect of LCPUFA formula supplementation primarily on cognition and secondarily on behaviour at age 9 years . Special attention was paid to the potentially modifying effect of maternal smoking during pregnancy . METHOD A double-blind , r and omized control study was performed in two groups of healthy infants born at term : one group , constituting the control group , received st and ard formula ( n=169 ) and another group received st and ard formula supplemented with LCPUFAs ( n=146 ) . A breastfed group ( n=159 ) served as an additional reference . At 9 years of age , 72 % of the children ( control group : n=123 ; 71 males , 52 females ; LCPUFA group : n=91 ; 42 males , 49 females ; breastfed group : n=127 , 64 males , 63 females ) underwent extensive cognitive and behavioural testing . RESULTS An interaction between infant nutrition and smoking during pregnancy was found . Among children exposed to smoking during pregnancy , LCPUFA supplementation was associated with higher mean verbal IQ scores ( p=0.007 ) and learning and memory ( p=0.006 ) . Among children not exposed to smoking during pregnancy , LCPUFA supplementation was associated with lower mean verbal memory scores ( p=0.003 ) . Executive function scores were significantly lower in the LCPUFA-supplemented group than in the control group ( p=0.001 ) . Breastfeeding was associated with better performance on IQ ( p=0.005 ) . INTERPRETATION No consistent beneficial effect of LCPUFA formula supplementation on cognitive development in term-born infants was found . The study confirmed that breastfeeding is associated with better cognition [23426033] BACKGROUND Observational studies associate higher intakes of n-3 ( omega-3 ) long-chain polyunsaturated fatty acids ( LCPUFAs ) during pregnancy with higher gestation duration and birth size . The results of r and omized supplementation trials using various n-3 LCPUFA sources and amounts are mixed . OBJECTIVE We tested the hypothesis that 600 mg/d of the n-3 LCPUFA docosahexaenoic acid ( DHA ) can increase maternal and newborn DHA status , gestation duration , birth weight , and length . Safety was assessed . DESIGN This phase III , double-blind , r and omized controlled trial was conducted between January 2006 and October 2011 . Women ( n = 350 ) consumed capsules ( placebo , DHA ) from < 20 wk of gestation to birth . Blood ( enrollment , birth , and cord ) was analyzed for red blood cell ( RBC ) phospholipid DHA . The statistical analysis was intent-to-treat . RESULTS Most of the capsules were consumed ( 76 % placebo ; 78 % DHA ) ; the mean DHA intake for the treated group was 469 mg/d . In comparison with placebo , DHA supplementation result ed in higher maternal and cord RBC-phospholipid-DHA ( 2.6 % ; P < 0.001 ) , longer gestation duration ( 2.9 d ; P = 0.041 ) , and greater birth weight ( 172 g ; P = 0.004 ) , length ( 0.7 cm ; P = 0.022 ) , and head circumference ( 0.5 cm ; P = 0.012 ) . In addition , the DHA group had fewer infants born at < 34 wk of gestation ( P = 0.025 ) and shorter hospital stays for infants born preterm ( 40.8 compared with 8.9 d ; P = 0.026 ) than did the placebo group . No safety concerns were identified . CONCLUSIONS A supplement of 600 mg DHA/d in the last half of gestation result ed in overall greater gestation duration and infant size . A reduction in early preterm and very-low birth weight could be important clinical and public health outcomes of DHA supplementation . This trial was registered at clinical trials.gov as NCT00266825 [21099447] We investigated whether the previously reported preventive effect of maternal ω-3 fatty acid supplementation on IgE-associated allergic disease in infancy may be mediated by facilitating a balanced circulating Th2/Th1 chemokine profile in the infant . Vaccine-induced immune responses at 2 y of age were also evaluated . Pregnant women , at risk of having an allergic infant , were r and omized to daily supplementation with 1.6 g eicosapentaenoic acid and 1.1 g docosahexaenoic acid or placebo from the 25th gestational week through 3.5 mo of breastfeeding . Infant plasma was analyzed for chemokines ( cord blood , 3 , 12 , 24 mo ) and anti-tetanus and anti-diphtheria IgG ( 24 mo ) . High Th2-associated CC-chemokine lig and 17 ( CCL17 ) levels were associated with infant allergic disease ( p < 0.05 ) . In infants without , but not with , maternal history of allergy , the ω-3 supplementation was related to lower CCL17/CXC-chemokine lig and 11 ( CXCL11 ) ( Th2/Th1 ) ratios ( p < 0.05 ) . Furthermore , in nonallergic , but not in allergic infants , ω-3 supplementation was linked with higher Th1-associated CXCL11 levels ( p < 0.05 ) , as well as increased IgG titers to diphtheria ( p = 0.01 ) and tetanus ( p = 0.05 ) toxins . Thus , the prospect of balancing the infant immune system toward a less Th2-dominated response , by maternal ω-3 fatty acid supplementation , seems to be influenced by allergic status [22269042] BACKGROUND Docosahexaenoic acid ( DHA ; 22:6n-3 ) is highly important during pregnancy for optimal development and functioning of fetal neural tissue . Infant ability to organize sleep and wake states following parturition is highly associated with later developmental outcomes . The impact of maternal DHA intake on sleep organization has not been previously investigated . AIMS To examine the effect of a DHA-containing functional food consumed during pregnancy on early neurobehavioral development as assessed by infant sleep patterning in the first 48 postnatal hours . STUDY DESIGN A longitudinal , r and omized , double-blinded , placebo-controlled design was used . SUBJECTS Women ( 18 - 35 y ) with no pregnancy complications consumed a cereal-based functional food ( 92 kcal ) containing 300 mg DHA an average of 5 d/week or placebo bars ( n=27 DHA , n=21 Placebo ) . The intervention began at 24 weeks gestation and continued until delivery ( 38 - 40 weeks ) . OUTCOME MEASURES Infant sleep/wake states were measured on postnatal days 1 ( D1 ) and 2 ( D2 ) using a pressure sensitive mattress recording respiration and body movements . RESULTS Using ANCOVA and controlling for ethnic variation , there were significant group differences in arousals in quiet sleep on D1 ( P=0.006 ) and D2 ( P=0.011 ) with fewer arousals in the DHA intervention group compared to the placebo group . Similarly , arousals in active sleep on D1 were significantly lower in the DHA-intervention group ( P=0.012 ) compared to the placebo group . CONCLUSIONS We conclude that increased prenatal supply of dietary DHA has a beneficial impact on infant sleep organization [17157660] BACKGROUND Early vitamin supplementation is given routinely to infants in many countries , but it is unclear whether this affects the risk of allergic diseases . OBJECTIVES We sought to study the association between early-life supplementation of vitamins A and D in water-soluble form or in peanut oil and allergic diseases up to 4 years of age . METHODS A prospect i ve birth cohort of 4089 newborn infants was followed for 4 years using parental question naires repeatedly to collect information on exposure and health . At 4 years , the response rate was 90 % , and allergen-specific IgE levels to food and airborne allergens were measured in 2614 of the participating children . RESULTS Vitamins A and D were given to 98 % of the children in infancy , and vitamins based in peanut oil dominated ( 90 % ) . Children supplemented with vitamins A and D in water-soluble form during the first year of life had an almost 2-fold increased risk of asthma ( adjusted odds ratio [ OD ] , 2.18 ; 95 % CI , 1.45 - 3.28 ) , food hypersensitivity ( adjusted OR , 1.89 ; 95 % CI , 1.33 - 2.65 ) , and sensitization to common food and airborne allergens ( adjusted OR , 1.88 ; 95 % CI , 1.34 - 2.64 ) at age 4 years compared with those receiving vitamins in peanut oil . No increased risk of IgE antibodies to peanut was seen in children receiving vitamins in peanut oil . CONCLUSION Supplementation of vitamins A and D in water-soluble form seems to increase the risk of allergic disease up to the age of 4 years compared with supplementation with the same vitamins given in peanut oil . CLINICAL IMPLICATION S Vitamins A and D in oil does not seem to increase the risk of allergic disease during childhood [22348468] n-3 Long-chain PUFA ( LC-PUFA ) intake during infancy is important for neurodevelopment ; however , previous studies of n-3 LC-PUFA supplementation have been inconclusive possibly due to an insufficient dose and limited methods of assessment . The present study aim ed to evaluate the effects of direct supplementation with high-dose fish oil ( FO ) on infant neurodevelopmental outcomes and language . In the present r and omised , double-blind , placebo-controlled trial , 420 healthy term infants were assigned to receive a DHA-enriched FO supplement ( containing at least 250 mg DHA/d and 60 mg EPA/d ) or a placebo ( olive oil ) from birth to 6 months . Assessment occurred at 18 months via the Bayley Scales of Infant and Toddler Development ( 3rd edition ; BSID-III ) and the Child Behavior Checklist . Language assessment occurred at 12 and 18 months via the Macarthur-Bates Communicative Development Inventory . The FO group had significantly higher erythrocyte DHA ( P = 0·03 ) and plasma phospholipid DHA ( P = 0·01 ) levels at 6 months of age relative to placebo . In a small subset analysis ( about 40 % of the total population ) , children in the FO group had significantly higher percentile ranks of both later developing gestures at 12 and 18 months ( P = 0·007 ; P = 0·002 , respectively ) and the total number of gestures ( P = 0·023 ; P = 0·006 , respectively ) . There was no significant difference between the groups in the st and ard or composite scores of the BSID-III . The results suggest that improved postnatal n-3 LC-PUFA intake in the first 6 months of life using high-dose infant FO supplementation was not beneficial to global infant neurodevelopment . However , some indication of benefits to early communicative development was observed [18679165] Polyunsaturated n-3 fatty acids ( n-3PUFA ) may improve brain development and prevent cardiovascular disease . Heart rhythm is autonomically controlled and among the affected cardiovascular risk markers in adults . The aim of the study was to examine whether fish oil supplementation in late infancy could modify heart rate ( HR ) and heart rate variability ( HRV ) . In a 2 × 2-intervention , 83 healthy Danish infants were r and omized to ± fish oil ( 3.4 ± 1.1 mL/d ) and cow 's milk or infant formula from 9 to 12 mo of age . In 57 infants , 0.5-h ECG recordings were successfully obtained before and after the intervention and erythrocyte fatty acid composition was determined in 30 of these . Fish oil supplementation raised erythrocyte n-3PUFA content ( p < 0.001 ) . No significant group differences were seen in HR or HRV . However , a fish-oil × gender interaction was observed on mean RR interval ( p = 0.001 ) with a 6 % longer mean RR interval in fish-oil-supplemented boys ( p = 0.007 ) . Irrespective of gender , there was a positive association between the 9- and 12-mo changes in RR interval and erythrocyte n-3PUFA ( p < 0.001 ) . In infants with confirmed changes in erythrocyte n-3PUFA , mean RR interval was found to be longer ( p = 0.011 ) in the fish-oil-supplemented groups . The study suggests that fish oil may affect heart rhythm in infants similar to that observed in adults . This may imply low n-3PUFA-status in late infancy and n-3PUFA influence on CNS function [20386325] Background and Objective : Feeding long-chain polyunsaturated fatty acids ( LCP ) influences immunity in adults ; however , less is known about their effect during development . The aim of the study was to determine the effect of feeding LCP on immunity in healthy infants during the first 4 months of life . Patients and Methods : Formula-fed infants were r and omized at ≤14 days of age to st and ard term formula ( Formula ) or formula containing LCP ( Formula+LCP ) . Infants exclusively fed human milk ( HM ) were included for comparison . At 16 weeks of age , blood was collected and phenotypes , the ability to proliferate and produce cytokines ( interleukin [IL]-2 , IL-4 , IL-6 , IL-10 , IL-12 , interferon [IFN]-γ , tumor necrosis factor [TNF]-α , TGF-β ) after incubation with phytohemaglutinin ( PHA ) , β-lactoglobulin , or soy protein were measured . Results : Feeding LCP result ed in a higher than and more similar proliferation rate to PHA in HM-fed infants , possibly because of a greater TH1 type cytokine response and a higher percentage of antigen mature ( CD45RO+ ) cells ( P < 0.05 ) . The response to β-lactoglobulin did not differ among groups . After incubation with soy protein Formula+LCP , compared with Formula produced less IL-2 and more TNF-α and had a higher percentage of CD8 + and a lower percentage of CD20 + ( CD20+CD54 + ) cells poststimulation ( P < 0.05 ) . Both formula groups produced less IL-2 after PHA , had a lower percentage of CD80 + cells , and a higher percentage of CD54 + cells after incubation with food proteins ( P < 0.05 ) . Conclusions : Formula-fed infants , at low risk for allergy , respond differently to mitogen and food proteins ex vivo than those fed HM . Feeding LCP altered some of these differences in the direction that is hypothesized to confer immune benefits [3269207] Objective To determine whether dietary n-3 long chain polyunsaturated fatty acid ( LCPUFA ) supplementation of pregnant women with a fetus at high risk of allergic disease reduces immunoglobulin E associated eczema or food allergy at 1 year of age . Design Follow-up of infants at high hereditary risk of allergic disease in the Docosahexaenoic Acid to Optimise Mother Infant Outcome ( DOMInO ) r and omised controlled trial . Setting Adelaide , South Australia . Participants 706 infants at high hereditary risk of developing allergic disease whose mothers were participating in the DOMInO trial . Interventions The intervention group ( n=368 ) was r and omly allocated to receive fish oil capsules ( providing 900 mg of n-3 LCPUFA daily ) from 21 weeks ’ gestation until birth ; the control group ( n=338 ) received matched vegetable oil capsules without n-3 LCPUFA . Main outcome measure Immunoglobulin E associated allergic disease ( eczema or food allergy with sensitisation ) at 1 year of age . Results No differences were seen in the overall percentage of infants with immunoglobulin E associated allergic disease between the n-3 LCPUFA and control groups ( 32/368 ( 9 % ) v 43/338 ( 13 % ) ; unadjusted relative risk 0.68 , 95 % confidence interval 0.43 to 1.05 , P=0.08 ; adjusted relative risk 0.70 , 0.45 to 1.09 , P=0.12 ) , although the percentage of infants diagnosed as having atopic eczema ( that is , eczema with associated sensitisation ) was lower in the n-3 LCPUFA group ( 26/368 ( 7 % ) v 39/338 ( 12 % ) ; unadjusted relative risk 0.61 , 0.38 to 0.98 , P=0.04 ; adjusted relative risk 0.64 , 0.40 to 1.02 , P=0.06 ) . Fewer infants were sensitised to egg in the n-3 LCPUFA group ( 34/368 ( 9 % ) v 52/338 ( 15 % ) ; unadjusted relative risk 0.61 , 0.40 to 0.91 , P=0.02 ; adjusted relative risk 0.62 , 0.41 to 0.93 , P=0.02 ) , but no difference between groups in immunoglobulin E associated food allergy was seen . Conclusion n-3 LCPUFA supplementation in pregnancy did not reduce the overall incidence of immunoglobulin E associated allergies in the first year of life , although atopic eczema and egg sensitisation were lower . Longer term follow-up is needed to determine if supplementation has an effect on respiratory allergic diseases and aeroallergen sensitisation in childhood . Trial registration Australian New Zeal and Clinical Trials Registry ACTRN12610000735055 ( DOMInO trial : ACTRN12605000569606 ) [19267292] This investigation evaluated variations in resting heart rate ( HR ) measures during the first half year of life in healthy , full-term infants who were either breast-fed ( BF ) , or fed formula with ( milk-based : MF ; soy-based : SF ) or without ( soy-based : SF− ) commercially supplemented DHA ( decosahexaenoic acid ) . In infants fed the DHA-deficient diet , higher HR and lower values for heart rate variability measures were observed , indicating decreased parasympathetic tone in this group . These effects , appearing at 4 months and continuing for the remainder of the study period , are consistent with suggestions that the 3–5-month postnatal interval may be an important period in the development of cardiovascular regulation . The absence of these effects in SF infants receiving the DHA-supplemented formula suggests that neither soy protein nor the associated phytochemicals in soy formula contribute to these effects to any appreciable extent . In general , the results do not indicate differences in any of the study variables attributable to soy formula per se [23433688] DHA ( 22:6n-3 ) supplementation during infancy has been associated with lower heart rate ( HR ) and improved neurobehavioral outcomes . We hypothesized that maternal DHA supplementation would improve fetal cardiac autonomic control and newborn neurobehavior . Pregnant women were r and omized to 600 mg/day of DHA or placebo oil capsules at 14.4 ( + /-4 ) weeks gestation . Fetal HR and HRV were calculated from magnetocardiograms ( MCGs ) at 24 , 32 and 36 weeks gestational age ( GA ) . Newborn neurobehavior was assessed using the Neonatal Behavioral Assessment Scale ( NBAS ) . Post-partum maternal and infant red blood cell ( RBC ) DHA was significantly higher in the supplemented group as were metrics of fetal HRV and newborn neurobehavior in the autonomic and motor clusters . Higher HRV is associated with more responsive and flexible autonomic nervous system ( ANS ) . Coupled with findings of improved autonomic and motor behavior , these data suggest that maternal DHA supplementation during pregnancy may impart an adaptive advantage to the fetus [21521543] DHA ( 22 : 6n-3 ) in pregnancy has previously been shown to benefit infant brain and retinal development . Fatty acid consumption during pregnancy may also have an impact on infant adipose tissue development . The objective of the present study was to assess the prenatal impact of a DHA-containing functional food ( DHA-FF ) on infant intra-uterine growth . This was a longitudinal , r and omised , double-blinded , placebo-controlled trial . Pregnant women were assigned to consume a DHA-FF or placebo bar from 24 weeks ' gestation until delivery . Blood sample s were collected from mothers at baseline and delivery and from the umbilical cord at delivery . Plasma and erythrocyte fatty acids were analysed by GLC and plasma insulin concentrations were analysed using a commercially available ELISA kit . Infant birth weight and length were obtained at delivery and ponderal index ( weight (g)/length (cm)3 × 100 ) was calculated . A total of forty-seven mothers completed the study . Infants of mothers consuming the DHA-FF during the last half of pregnancy had lower ponderal indices ( β = 0.198 , P < 0.05 ) and umbilical cord blood insulin concentrations ( β = 0.743 , P < 0.05 ) than infants of mothers consuming the placebo . Thus , DHA consumption during pregnancy may be advantageous with respect to infant body composition at birth and insulin sensitivity [17957193] BACKGROUND Inadequate consumption of fish could be a risk factor for low birth weight ( LBW ) . This study assessed fish intake and omega-3 LCPUFA intake and status for their association with LBW in a cohort of urban , south Indian pregnant women . SUBJECTS/ METHODS In a prospect i ve cohort study , data on maternal fish intake and omega-3 LCPUFA intake and status of 676 women were obtained at baseline ( first trimester ) , the second and third trimesters of pregnancy . Infant birth weight was measured immediately following hospital delivery . The dropout rate was 7.6 % . RESULTS Fifty-six percent of the study women consumed fish with low daily median intakes ( 3.4 , 4.1 and 3.8 g day(-1 ) at the three trimesters , respectively ) . Consequently , the median intakes of EPA and DHA during pregnancy were also low at 2.1 and 10.1 mg day(-1 ) , respectively . EPA and DHA intakes were associated with their status in erythrocyte membrane phospholipids during pregnancy ( r=0.40 and 0.36 , r=0.34 and 0.32 and r=0.37 and 0.41 , at the three trimesters , respectively , all P<0.001 ) . Women who did not eat fish during the third trimester had a significantly higher risk of LBW ( OR : 2.49 , P=0.019 ) . Similarly , low EPA intake during the third trimester had an association with a higher risk of LBW ( OR : 2.75 , P=0.011 ) . CONCLUSIONS Among low fish-eating pregnant women , fish intake in the third trimester was closely associated with birth weight . Supplementation with omega-3 LCPUFA during pregnancy may have important implication s for fetal development in India [21930549] OBJECTIVE : To test the hypothesis that long-chain polyunsaturated fatty acid ( LCPUFA ) supplementation in infancy would improve cognition into later childhood ( after 9 years ) at both general and specific levels . METHODS : A comprehensive cognitive battery was completed by 107 formerly preterm infants ( mean age : 128 months ) . As infants , they had been assigned r and omly to receive LCPUFA-supplemented ( N = 50 ) or control ( N = 57 ) formula , between birth and 9 months ; the docosahexaenoic acid level ( DHA ) in the supplemented formulas was 0.5 % . In addition to r and omized comparisons , we planned supplementary analyses to examine the effects of both gender and feeding group ( those receiving some maternal breast milk versus those receiving none ) . RESULTS : There were no significant differences between r and omized diet groups on any cognitive measure . There was significant interaction between gender and supplementation ; girls only showed beneficial effects of LCPUFAs on literacy . Significant interaction also occurred between feeding group and supplementation ; increases of 0.7 SD in verbal IQ , full-scale IQ , and memory scores were found for the LCPUFA group , but only for infants who received only formula and no maternal breast milk . CONCLUSIONS : The results of this post–9-year cognitive follow-up study in a r and omized trial of LCPUFA-supplemented formula for preterm infants suggest no overall group effects but indicate that gender-specific and diet-specific effects may exist . The data provide some evidence that LCPUFAs are a key factor in the cognitive benefits of breast milk . Caution is advised in data interpretation because of the small groups used [20093894] OBJECTIVE : To assess whether the addition of an omega-3 long-chain polyunsaturated fatty acid supplement would reduce preterm birth in women with at least one prior spontaneous preterm birth receiving 17&agr;-hydroxyprogesterone caproate . METHODS : We conducted a r and omized , double-masked , placebo-controlled trial in 13 centers . Women with a history of prior spontaneous singleton preterm birth and a current singleton gestation were assigned to either a daily omega-3 supplement ( 1,200 mg eicosapentaenoic acid and 800 mg docosahexaenoic acid ) or matching placebo from 16 - 22 through 36 weeks of gestation . All participants received weekly intramuscular 17&agr;-hydroxyprogesterone caproate ( 250 mg ) . The primary study outcome was delivery before 37 weeks of gestation . A sample size of 800 was necessary to have 80 % power to detect a 30 % reduction in the primary outcome from 30 % , assuming a type I error two-sided of 5 % . RESULTS : A total of 852 women were included , and none was lost to follow up . Delivery before 37 weeks of gestation occurred in 37.8 % ( 164/434 ) of women in the omega-3 group and 41.6 % ( 174/418 ) in the placebo group ( relative risk 0.91 , 95 % confidence interval 0.77 - 1.07 ) . CONCLUSION : Omega-3 long-chain polyunsaturated fatty acid supplementation offered no benefit in reducing preterm birth among women receiving 17&agr;-hydroxyprogesterone caproate who have a history of preterm delivery . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00135902 . LEVEL OF EVIDENCE : [19174829] Background / Objectives : High protein intake has been associated with increased growth . This may be linked to increased concentrations of insulin-like growth factor I ( IGF-I ) , which seems to be influenced by the diet , especially its protein component . The short-term effects of high protein intake in late infancy are not known . The objective was to investigate the effects of high protein intake in the form of whole milk ( WM ) on growth and IGF-I from 9 to 12 months of age . Subjects/ Methods : Healthy infants ( n=83 ) were r and omized to receive either WM or infant formula and fish oil or no fish oil ( 2 × 2 design ) . Anthropometric variables , IGF-I concentrations , serum urea nitrogen ( SUN ) and diet were recorded before and after the intervention . Results : Intake of WM significantly increased the protein energy percentage ( PE% ; P⩽0.001 ) and SUN ( P=0.01 ) , whereas there was no effect on size . The milk intervention increased IGF-I in boys ( P=0.034 ) but not in girls . Intake of fish oil had no effect on the outcomes . Including all infants in the analysis there was a significant correlation between weight and IGF-I at 12 months ( r=0.316 , P=0.017 ) , and PE% was positively associated with IGF-I after adjusting for sex and breastfeeding at both 9 ( r=0.329 , P=0.015 ) and 12 months ( r=0.272 , P=0.044 ) . Conclusions : R and omization to WM had no overall effect on growth . However , the positive effect of WM on IGF-I in boys and the positive association between PE% intake and IGF-I at 9 and 12 months is consistent with the hypothesis that a high milk intake stimulates growth [21691253] n-3 long-chain polyunsaturated fatty acids ( n-3 LCPUFA ) , from fish oil ( FO ) , in rodents have been shown to reduce adipogenesis . Evidence of an effect on adipose tissue mass in humans is limited , and no studies have specifically aim ed to eluci date this in infancy . To explore whether n-3 LCPUFA intake affects adipose tissue growth , we r and omly allocated 154 healthy infants to daily supplementation with FO or sunflower oil ( SO ) from 9 to 18 mo of age and measured z-score changes in various anthropometric assessment s of body size and skinfold thicknesses and plasma adipokine concentrations . Among the 133 completing infants , erythrocyte n-3 PUFA increased more in those receiving FO than in infants receiving SO [ 12.2 ± 0.7 ( mean ± SE ) versus 2.0 ± 0.4 fatty acid percentage ( FA% ) , p < 0.001 ] with a concomitant larger decrease in n-6 PUFA ( −8.9 ± 0.7 versus −0.9 ± 0.6 FA% , p < 0.001 ) . We found no association between FO consumption relative to SO consumption and any of the anthropometric measures related to the size of the fat mass , but infants in the FO group had a lower skinfold ratio ( triceps/subscapular ) at 18 mo than those in SO group ( p = 0.02 ) . Our findings do not support the hypothesis that dietary n-3 LCPUFA is important for infant fat mass , but future studies testing this specifically are warranted [21295417] BACKGROUND Studies investigating cognitive outcomes following docosahexaenoic acid ( DHA ) supplementation of infant formula yield conflicting results , perhaps due to inadequate dietary concentrations . AIM To determine the optimal DHA concentration in term formula to support cognitive maturation . DESIGN This was a double-masked , r and omized , controlled , prospect i ve trial . A total of 181 infants were enrolled at 1 - 9 days of age and assigned r and omly to receive one of four term infant formulas with one of four levels of docosahexaenoic acid : Control ( 0 % DHA ) , 0.32 % DHA , 0.64 % DHA , or 0.96 % DHA . All DHA-supplemented formulas contained 0.64 % arachidonic acid ( ARA ) . Infants were fed the assigned formulas until 12 months of age . One hundred forty-one children completed the 12-month feeding trial and were eligible for this study . Cognitive function was assessed in 131 children at 18 months of age using the Bayley Scales of Infant Development II ( BSID II ) . RESULTS There were no diet group differences on the Mental Development Index ( MDI ) , the Psychomotor Development Index ( PDI ) , or the Behavior Rating Scale ( BRS ) of the BSID II . However , when the scores of children who received any of the three DHA-supplemented formulas were combined and compared to control children , a significant difference emerged : the MDI scores of DHA-supplemented children were higher ( 104.1 v. 98.4 ; p=0.02 ) . CONCLUSIONS These results suggest that dietary supplementation of DHA during the first year of life leads to enhanced cognitive development at 18 months of age . DHA concentration of 0.32 % is adequate to improve cognitive function ; higher concentrations did not confer additional benefit [23803884] BACKGROUND The effect of long-chain polyunsaturated fatty acid ( LCPUFA ) intake on cognitive development is controversial . Most r and omized trials have assessed cognition at 18 mo , although significant development of cognitive abilities ( early executive function ) emerge later . OBJECTIVE The objective was to evaluate cognition beyond 18 mo and longitudinal cognitive change from 18 mo to 6 y in children who were fed variable amounts of docosahexaenoic acid ( 0.32 % , 0.64 % , and 0.96 % of total fatty acids ) and arachidonic acid ( ARA ; 0.64 % ) compared with children who were not fed LCPUFA as infants . DESIGN Eighty-one children ( 19 placebo , 62 LCPUFA ) who participated in a double-blind , r and omized trial of LCPUFA supplementation as infants were re-enrolled at 18 mo and tested every 6 mo until 6 y on age-appropriate st and ardized and specific cognitive tests . RESULTS LCPUFA supplementation did not influence performance on st and ardized tests of language and performance at 18 mo ; however , significant positive effects were observed from 3 to 5 y on rule-learning and inhibition tasks , the Peabody Picture Vocabulary Test at 5 y , and the Weschler Primary Preschool Scales of Intelligence at 6 y. Effects of LCPUFAs were not found on tasks of spatial memory , simple inhibition , or advanced problem solving . CONCLUSIONS The data from this relatively small trial suggest that , although the effects of LCPUFAs may not always be evident on st and ardized developmental tasks at 18 mo , significant effects may emerge later on more specific or fine-grained tasks . The results imply that studies of nutrition and cognitive development should be powered to continue through early childhood . This parent trial was registered at clinical trials.gov as NCT00266825 [19765006] This study examines whether feeding infants formula supplemented with long-chain polyunsaturated fatty acids ( LCPUFA ) improves cognitive function of 9-month-olds . Participants included 229 infants from 3 r and omized controlled trials . Children received either formula supplemented with docosahexaenoic acid and arachidonic acid , or a control formula beginning at 1 - 5 days ( 12-month feeding study ) , or following 6 weeks ( 6-week-weaning study ) or 4 - 6 months of breastfeeding ( 4-to 6-month weaning study ) . Infants were assessed with a 2-step problem solving task . In the 12-month feeding and 6-week weaning studies , supplemented children had more intentional solutions ( successful task completions ) and higher intention scores ( goal -directed behaviors ) than controls . These results suggest that LCPUFA supplementation improves means-end problem solving [20133326] Objective To investigate the relation between breastfeeding , use of docosahexaenoic acid (DHA)-fortified formula and neuropsychological function in children . Design Prospect i ve cohort study . Setting Southampton , UK . Subjects 241 children aged 4 years followed up from birth . Main outcome measures IQ measured by the Wechsler Pre-School and Primary Scale of Intelligence ( 3rd edn ) , visual attention , visuomotor precision , sentence repetition and verbal fluency measured by the NEPSY , and visual form-constancy measured by the Test of Visual-Perceptual Skills ( Non-Motor ) . Results In unadjusted analyses , children for whom breast milk or DHA-fortified formula was the main method of feeding throughout the first 6 months of life had higher mean full-scale and verbal IQ scores at age 4 years than those fed mainly unfortified formula . After adjustment for potential confounding factors , particularly maternal IQ and educational attainment , the differences in IQ between children in the breast milk and unfortified formula groups were severely attenuated , but children who were fed DHA-fortified formula had full-scale and verbal IQ scores that were respectively 5.62 ( 0.98 to 10.2 ) and 7.02 ( 1.56 to 12.4 ) points higher than children fed unfortified formula . However , estimated total intake of DHA in milk up to age 6 months was not associated with subsequent IQ or with score on any other test . Conclusions Differences in children 's intelligence according to type of milk fed in infancy may be due more to confounding by maternal or family characteristics than to the amount of long-chain polyunsaturated fatty acids they receive in milk [20515959] Objective To test the hypothesis that consumption of infant formulas containing long-chain polyunsaturated fatty acids ( LCPUFAs ) by preterm infants would favourably influence growth , body composition and blood pressure ( BP ) at age 10 years . Methods This was a follow-up study of a preterm cohort ( < 35 weeks and birth weight < 2000 g ) r and omly assigned to unsupplemented or LCPUFA-supplemented formulas to 9 months post term . The setting was a research clinic at Yorkhill Hospital for Sick Children , Glasgow , UK . A total of 107 children aged 9–11 years who participated in the original r and omised controlled trial ( 45 % follow-up ) took part . Main outcome measures were : ( 1 ) anthropometry , ( 2 ) body composition and ( 3 ) BP . Results There were no differences in growth or BP between r and omised groups for the whole cohort . However , girls who had received LCPUFA-supplemented formula were heavier ( 42.20 ( SD 9.61 ) vs 36.94 ( 9.46 ) kg , p=0.05 ) , had greater skin fold thicknesses ( biceps 10.7 ( 3.3 ) vs 8.5 ( 3.6 ) mm , p=0.03 ; suprailiac 16.7 ( 8.2 ) vs 12.0 ( 7.5 ) mm , p=0.03 ) and higher BP ( mean 82.2 ( 8.4 ) vs 78.1 ( 6.2 ) mm Hg , p=0.04 : systolic 111.4 ( 10.1 ) vs 105.9 ( 9.0 ) mm Hg , p=0.04 : diastolic 64.8 ( 8.4 ) vs 61.1 ( 5.4 ) mm Hg , p=0.05 ) . Differences in weight SD score ( 0.85 ( 95 % CI 0.13 to 1.58 ) , p=0.02 ) , Ln sum of skin fold thicknesses ( 0.27 ( 0.02 to 0.52 ) , p=0.04 ) and BP ( mean 4.6 mm Hg ( 0.43 to 8.84 ) , p=0.03 ; systolic 6.1 ( 0.45 to 11.7 ) , p=0.04 ) remained after adjustment for prer and omisation confounders . Differences in BP were not significant following adjustment for current weight . Conclusions Girls born preterm and r and omised to LCPUFA-supplemented formula showed increased weight , adiposity and BP at 9–11 years , which might have adverse consequences for later health . No effects were seen in boys . Long-term follow-up of other LCPUFA supplementation trials is required to further investigate this finding [21849596] BACKGROUND The influence of prenatal long-chain polyunsaturated fatty acids ( LC-PUFAs ) and folate on neurologic development remains controversial . OBJECTIVE The objective was to assess the long-term effects of n-3 ( omega-3 ) LC-PUFA supplementation , 5-methyltetrahydrofolate ( 5-MTHF ) supplementation , or both in pregnant women on cognitive development of offspring at 6.5 y of age . DESIGN This was a follow-up study of the NUHEAL ( Nutraceuticals for a Healthier Life ) cohort . Healthy pregnant women in 3 European centers were r and omly assigned to 4 intervention groups . From the 20th week of pregnancy until delivery , they received a daily supplement of 500 mg docosahexaenoic acid ( DHA ) + 150 mg eicosapentaenoic acid [ fish oil ( FO ) ] , 400 μg 5-MTHF , or both or a placebo . Infants received formula containing 0.5 % DHA and 0.4 % arachidonic acid ( AA ) if they were born to mothers receiving FO supplements or were virtually free of DHA and AA until the age of 6 mo if they belonged to the groups that were not supplemented with FO . Fatty acids and folate concentrations were determined in maternal blood at weeks 20 and 30 of pregnancy , at delivery , and in cord blood . Cognitive function was assessed at 6.5 y of age with the Kaufman Assessment Battery for Children ( K-ABC ) . RESULTS We observed no significant differences in K-ABC scores between intervention groups . Higher DHA in maternal erythrocytes at delivery was associated with a Mental Processing Composite Score higher than the 50th percentile in the offspring . CONCLUSION We observed no significant effect of supplementation on the cognitive function of children , but maternal DHA status may be related to later cognitive function in children . This trial was registered at clinical trials.gov as NCT01180933 [20053878] BACKGROUND The visual and mental development of preterm infants improved after feeding them milk enriched with docosahexaenoic acid ( DHA ) in amounts matching the fetal accretion rate . OBJECTIVE The objective was to evaluate whether feeding preterm infants milk with a higher DHA content than that used in current practice influences language or behavior in early childhood . DESIGN This was a follow-up study in a subgroup of infants enrolled in the DINO ( Docosahexaenoic acid for the Improvement in Neurodevelopmental Outcome ) trial . In a double-blind r and omized controlled trial , infants born at <33 wk of gestation were fed milk containing 1 % of total fatty acids as DHA ( higher-DHA group ) or approximately 0.3 % DHA ( control group ) until reaching full-term equivalent age . The longer-term effects of the intervention on language , behavior , and temperament were measured by using the MacArthur Communicative Development Inventory ( MCDI ) at 26-mo corrected age , the Strengths and Difficulties Question naire ( SDQ ) , and the Short Temperament Scale for Children ( STSC ) between 3- and 5-y corrected age . RESULTS Mean ( + /-SD ) MCDI scores did not differ significantly ( adjusted P = 0.8 ) between the higher-DHA group ( 308 + /- 179 , n = 60 ) and the control group ( 316 + /- 192 , n = 67 ) per the Vocabulary Production subscale . Composite scores on the SDQ and STSC did not differ between the higher-DHA group and the control group [ SDQ Total Difficulties : higher-DHA group ( 10.3 + /- 6.0 , n = 61 ) , control group ( 9.5 + /- 5.5 , n = 64 ) , adjusted P = 0.5 ; STSC score : higher-DHA group ( 3.1 + /- 0.7 , n = 61 ) , control group ( 3.0 + /- 0.7 , n = 64 ) , adjusted P = 0.3 ] . CONCLUSIONS Feeding preterm infants milk containing 3 times the st and ard amount of DHA did not result in any clinical ly meaningful change to language development or behavior when assessed in early childhood . Whether longer-term effects of dietary DHA supplementation can be detected remains to be assessed . This trial was registered with the Australia and New Zeal and Clinical Trial Registry at www.anzctr.org.au as 12606000327583 [19056592] BACKGROUND Docosahexaenoic acid ( DHA ) intake throughout the first year of life is associated with neurodevelopmental and neuropsychological benefits . Few studies have evaluated the role of DHA intakes on age at achievement of gross motor milestones . OBJECTIVE The objective was to assess the effects of DHA supplementation throughout the first year of life on the achievement of four gross motor milestones in healthy infants . DESIGN In this multicenter prospect i ve , r and omized , double-blind , placebo-controlled trial , 1160 healthy neonates were assigned to receive supplementation with either 20 mg liquid DHA ( n = 580 ) or placebo ( n = 580 ) orally once daily throughout the first year of life . The primary endpoint was the time at achievement of 4 gross motor milestones ( sitting without support , h and s- and -knees crawling , st and ing alone , and walking alone ) . All analyses were performed on an intention-to-treat basis . RESULTS The time to achievement of sitting without support was shorter ( P < 0.001 ) in infants who received DHA [ median : 26 wk ; interquartile range ( IQR ) : 24 - 29 wk ] than in those who received placebo ( 27 wk ; 26 - 31 wk ) . No significant difference between infants who received DHA or placebo was found for h and s- and -knees crawling [ 39 wk ( 34 - 44 wk ) compared with 40 wk ( 35 - 44 wk ) , respectively ] , st and ing alone [ 49 wk ( 43 - 55 wk ) compared with 49 wk ( 44 - 57 wk ) , respectively ] , and walking alone [ 55 wk ( 50 - 60 wk ) compared with 56 wk ( 52 - 61 wk ) , respectively ] . CONCLUSIONS Despite the 1-wk advance in sitting without support associated with DHA supplementation , no demonstrable persistent effects of DHA supplementation on later motor development milestones were found . Thus , the long-term clinical significance of the 1-wk change in sitting without support , if any , remains unknown . This trial is registered at ( clinical trials.gov ) as NCT00610922 [19515739] BACKGROUND n-3 Fatty acid supplementation in adults results in cardiovascular benefits . However , the cardiovascular effects of n-3 supplementation in early childhood are unknown . OBJECTIVE The objective was to evaluate blood pressure ( BP ) and arterial structure and function in 8-y-old children who had participated in a r and omized controlled trial of dietary n-3 and n-6 modification over the first 5 y of life . DESIGN The children ( n = 616 ; 49 % girls ) were r and omly assigned antenatally to active ( n = 312 ; increase in n-3 intake and decrease in n-6 intake ) or control ( n = 304 ) diet interventions implemented from the time of weaning or introduction of solids until 5 y of age . At age 8.0 + /- 0.1 y , BP , carotid intima-media thickness , carotid artery distensibility , augmentation index , and brachial pulse wave velocity were measured in 405 of these children . Venous blood was collected for measurement of plasma fatty acids , lipoproteins , high-sensitivity C-reactive protein , and asymmetric dimethylarginine . Plasma fatty acid concentrations were also assessed during the intervention . RESULTS Plasma concentrations of n-3 fatty acids were higher and of n-6 were lower in the active than in the control diet group at 18 mo and 3 and 5 y ( P < 0.0001 ) . Concentrations of n-3 and n-6 fatty acids were similar at 8 y. At 8 y of age , no significant differences were found in BP , carotid intima-media thickness , carotid artery distensibility , augmentation index , asymmetric dimethylarginine , high-sensitivity C-reactive protein , or lipoproteins between diet groups . CONCLUSION A dietary supplement intervention to increase n-3 and decrease n-6 intakes from infancy until 5 y does not result in significant improvements in arterial structure and function at age 8 y. This trial was registered at the Australian Clinical Trials Registry as ACTRN012605000042640 [22739364] The evidence relating prenatal supplementation with DHA to offspring neurological development is limited . We investigated the effect of prenatal DHA supplementation on infant brainstem auditory-evoked responses and visual- evoked potentials in a double-blind , r and omized controlled trial in Cuernavaca , Mexico . Pregnant women were supplemented daily with 400 mg DHA or placebo from gestation wk 18 - 22 through delivery . DHA and placebo groups did not differ in maternal characteristics at r and omization or infant characteristics at birth . Brainstem auditory-evoked responses were measured at 1 and 3 mo in 749 and 664 infants , respectively , and visual-evoked potentials were measured at 3 and 6 mo in 679 and 817 infants , respectively . Left-right brainstem auditory-evoked potentials were moderately correlated ( range , 0.26 - 0.43 ; all P < 0.001 ) and left-right visual-evoked potentials were strongly correlated ( range , 0.79 - 0.94 ; all P < 0.001 ) within any assessment . Correlations across visits were modest to moderate ( range , 0.09 - 0.38 ; all P < 0.01 ) . The offspring of DHA-supplemented women did not differ from those of control women with respect to any outcome measure ( all comparisons P > 0.10 ) . We conclude that DHA supplementation during pregnancy did not influence brainstem auditory-evoked responses at 1 and 3 mo or visual-evoked potentials at 3 and 6 mo [21807696] OBJECTIVE : Long-chain polyunsaturated fatty acids such as docosahexaenoic acid ( DHA ) influence immune function and inflammation ; however , the influence of maternal DHA supplementation on infant morbidity is unknown . We investigated the effects of prenatal DHA supplementation on infant morbidity . METHODS : In a double-blind r and omized controlled trial conducted in Mexico , pregnant women received daily supplementation with 400 mg of DHA or placebo from 18 to 22 weeks ' gestation through parturition . In infants aged 1 , 3 , and 6 months , caregivers reported the occurrence of common illness symptoms in the preceding 15 days . RESULTS : Data were available at 1 , 3 , and 6 months for 849 , 834 , and 834 infants , respectively . The occurrence of specific illness symptoms did not differ between groups ; however , the occurrence of a combined measure of cold symptoms was lower in the DHA group at 1 month ( OR : 0.76 ; 95 % CI : 0.58–1.00 ) . At 1 month , the DHA group experienced 26 % , 15 % , and 30 % shorter duration of cough , phlegm , and wheezing , respectively , but 22 % longer duration of rash ( all P ≤ .01 ) . At 3 months , infants in the DHA group spent 14 % less time ill ( P < .0001 ) . At 6 months , infants in the DHA group experienced 20 % , 13 % , 54 % , 23 % , and 25 % shorter duration of fever , nasal secretion , difficulty breathing , rash , and “ other illness , ” respectively , but 74 % longer duration of vomiting ( all P < .05 ) . CONCLUSIONS : DHA supplementation during pregnancy decreased the occurrence of colds in children at 1 month and influenced illness symptom duration at 1 , 3 , and 6 months [22835597] BACKGROUND Studies investigating the effects of docosahexaenoic acid ( DHA ) in infant formula on language development yield conflicting results . No study to date has investigated the effects of DHA in infant formula on school readiness . AIM To determine the effects of different dietary concentrations of DHA provided during the first 12 months of life on language development and school readiness . DESIGN This was a double-masked , r and omized , controlled , prospect i ve trial . A total of 182 infants were enrolled at 1 - 9 days of age and assigned r and omly to receive infant formula with one of four levels of DHA : control ( 0 % DHA ) , 0.32 % DHA , 0.64 % DHA , or 0.96 % DHA . All formulas with DHA also contained 0.64 % arachidonic acid . One hundred forty-one children completed the 12-month feeding trial and were eligible for this study . Consent was obtained from 131 participants . School readiness was assessed at 2.5 years using the Bracken Basic Concept Scale-Revised ( BBCS-R ) and receptive vocabulary was assessed at 2 and 3.5 years using the Peabody Picture Vocabulary Test-Third Edition ( PPVT-III ) . RESULTS There were no diet group differences on any of the BBCS-R subscales . On the PPVT-III , the control group had higher raw scores and st and ard scores than both the 0.32 % and 0.96 % groups at 2 years of age . These differences were not evident at 3.5 years . CONCLUSIONS Dietary DHA during the first year of life did not enhance school readiness or language development . Children who consumed infant formula with 0.32 % and 0.96 % DHA showed lower receptive vocabulary scores than controls at 2 but not 3.5 years of age [20211038] Maternal supplementation with long-chain PUFA , to improve infant neurological development , might cause additional increase of oxidative stress . Pregnant women aged 18 - 41 years were r and omised into one of four supplementation groups . From week 22 on , they received supplements containing either modified fish oil ( n 69 ) , 5-methyl-tetrahydro-folate ( n 65 ) , both ( n 64 ) , or placebo ( n 72 ) . Plasma Trolox-equivalent antioxidative capacity ( TEAC ) , concentrations of alpha-tocopherol , retinol , beta-carotene , free thiol groups , uric acid and thiobarbituric acid-reactive substances ( TBARS ) were determined at weeks 20 and 30 and at delivery . The studied antioxidants showed no significant differences between the four supplementation groups . At week 30 plasma TBARS levels were found to be significantly higher in the fish oil group ( 0.80 ( sem 0.04 ) micromol/l ) than in the folate ( 0.67 ( sem 0.03 ) micromol/l ; P = 0.024 ) and control ( 0.69 ( sem 0.04 ) micromol/l ; P = 0.01 ) groups . Concentrations of retinol and free thiol groups decreased during pregnancy , whereas uric acid increased and beta-carotene as well as TEAC showed only minor changes . Fish oil supplementation during the second half of pregnancy appears not to decrease antioxidant status . The increased TBARS levels at week 30 may indicate a period of increased oxidative stress in plasma at this time [18676533] OBJECTIVES . Arachidonic acid ( 20:4n-6 ) and docosahexaenoic acid ( 22:6n-3 ) are essential for brain growth and cognitive development . We have reported that supplementing pregnant and lactating women with n-3 very-long-chain polyunsaturated fatty acids promotes higher IQ scores at 4 years of age as compared with maternal supplementation with n-6 polyunsaturated fatty acids . In our present study , the children were examined at 7 years of age with the same cognitive tests as at 4 years of age . We also examined the relation between plasma fatty acid pattern and BMI in children , because an association between arachidonic acid and adipose tissue size has been suggested . METHODS . The study was r and omized and double-blinded . The mothers took 10 mL of cod liver oil or corn oil from week 18 of pregnancy until 3 months after delivery . Their children were tested with the Kaufman Assessment Battery for Children at 7 years of age , and their height and weight were measured . RESULTS . We did not find any significant differences in scores on the Kaufman Assessment Battery for Children test at 7 years of age between children whose mothers had taken cod liver oil ( n = 82 ) or corn oil ( n = 61 ) . We observed , however , that maternal plasma phospholipid concentrations of α-linolenic acid ( 18:3n-3 ) and docosahexaenoic acid during pregnancy were correlated to sequential processing at 7 years of age . We observed no correlation between fatty acid status at birth or during the first 3 months of life and BMI at 7 years of age . CONCLUSION . This study suggests that maternal concentration of n-3 very-long-chain polyunsaturated fatty acids during pregnancy might be of importance for later cognitive function , such as sequential processing , although we observed no significant effect of n-3 fatty acid intervention on global IQs . Neonatal fatty acid status had no influence on BMI at 7 years of age [17980419] BACKGROUND Altered intakes of n-3 and n-6 polyunsaturated fatty acids were suggested to modulate allergic disease , but intervention trials yielded inconclusive results . Because allergies are primed in early infancy and in utero , the fetus might be more accessible to nutritional intervention strategies . OBJECTIVE We sought to investigate how supplementation of pregnant women with a fish oil ( FO ) preparation modulates allergy-related immune parameters in mothers and offspring . METHODS We performed a multicenter , r and omized , double-blind , placebo-controlled trial . Three hundred eleven pregnant women received daily either FO with 0.5 g of docosahexaenoic acid and 0.15 g of eicosapentaenoic acid , 400 mug of methyl-tetra-hydrofolic acid , both , or placebo from the 22nd gestational week . T(H)1/T(H)2-related molecules were quantified in 197 maternal and 195 cord blood sample s by using real-time RT-PCR . Data are given as geometric means [ 95 % CIs ] . RESULTS FO supplementation was associated with increased TGF-beta mRNA in maternal ( 0.85 [ 0.8 - 0.89 ] ; placebo : 0.68 [ 0.64 - 0.72 ] ) and cord blood ( 0.85 [ 0.81 - 0.9 ] ; placebo : 0.75 [ 0.71 - 0.79 ] ) . IL-1 ( 0.69 [ 0.66 - 0.73 ] ; placebo : 0.83 [ 0.79 - 0.88 ] ) and IFN-gamma ( 0.54 [ 0.51 - 0.57 ] ; placebo : 0.65 [ 0.61 - 0.69 ] ) were decreased in mothers only ( P < .001 ) . Cord blood mRNA levels of IL-4 ( 0.54 [ 0.52 - 0.57 ] ; placebo : 0.64 [ 0.61 - 0.68 ] ) , IL-13 ( 0.61 [ 0.58 - 0.65 ] ; placebo : 0.85 [ 0.80 - 0.89 ] ) , CCR4 ( 0.70 [ 0.67 - 0.73 ] ; placebo : 0.88 [ 0.84 - 0.92 ] ; all P < .001 ) , and natural killer ( P < .001 ) and CCR3+CD8 + T cells ( P < .04 ) were decreased in the FO group . CONCLUSION Supplementation with FO during pregnancy is associated with decreased mRNA levels of T(H)2-related molecules in the fetus and decreased maternal inflammatory cytokines . We speculate that both effects are mediated by TGF-beta [22552037] BACKGROUND There is uncertainty regarding the efficacy of increasing n-3 long-chain PUFA ( LCPUFA ) intake during pregnancy in reducing the risk of gestational diabetes mellitus ( GDM ) and preeclampsia . OBJECTIVES The objective was to determine whether n-3 LCPUFA supplementation in pregnancy reduces the incidence of GDM or preeclampsia . A secondary objective was to assess the effect of n-3 LCPUFA supplementation on perinatal complications . DESIGN This was a double-blind , multicenter r and omized control trial-the DHA to Optimize Mother Infant Outcome ( DOMInO ) trial . Pregnant women ( n = 2399 ) of < 21 wk gestation were r and omly assigned to receive DHA-enriched fish oil ( 800 mg/d ) or vegetable oil capsules without DHA from trial entry to birth . The presence of GDM or preeclampsia was assessed through a blinded audit of medical records . Birth outcomes and prenatal complications were also assessed . RESULTS The overall incidences of GDM and preeclampsia were 8 % and 5 % , respectively , based on clinical diagnosis . The RR of GDM was 0.97 ( 95 % CI : 0.74 , 1.27 ) and of preeclampsia was 0.87 ( 95 % CI : 0.60 , 1.25 ) , and they did not differ significantly between the groups . Birth weight , length , and head circumference z scores also did not differ between the groups . There were 12 perinatal deaths and 5 neonatal convulsions in the control group compared with 3 perinatal deaths and no neonatal convulsions in the DHA group ( P = 0.03 in both cases ) . CONCLUSION DHA supplementation of 800 mg/d in the second half of pregnancy does not reduce the risk of GDM or preeclampsia . Whether supplementation reduces the risk of perinatal death and neonatal convulsions requires further investigation . The DOMInO trial was registered with the Australian New Zeal and Clinical Trials Registry as TRN12605000569606 [19193660] Objective : To study the effect of modified polyunsaturated fatty acid ( PUFA ) profiles of complementary food on long-chain ( LC ) PUFA composition in healthy infants . Design : Double blinded , r and omised , controlled intervention trial . Setting : Dortmund , Germany . Patients : Free-living sample of healthy term infants . Methods : Participants were r and omly assigned within the first 2 months of life . During the intervention period from 4 to 10 months , the control group ( n = 53 ) received commercial complementary meals with corn oil ( 3.4 g/meal ) rich in n-6 linoleic acid ( LA ) , the intervention group ( n = 49 ) received the same meals with rapeseed oil ( 1.6 g/meal ) rich in n-3 alpha-linolenic acid ( ALA ) . Fatty acid intake was assessed from dietary records throughout the intervention period . Fatty acid proportions ( % of total fatty acid ) in total plasma were analysed before and after the intervention . Results : Plasma fatty acid profiles did not differ between the intervention and control groups before the intervention . During the intervention , the only difference in fatty acid intake between the intervention and control groups was a higher intake of ALA in the intervention group , 21 % deriving from study food and a lower ratio of LA/ALA ( 10.7 vs 14.8 ) . At the end of the intervention , the plasma proportions of total n-3 fatty acids and of n-3 LC-PUFA , but not of ALA , were higher and the ratios of n-6/n-3 fatty acids were lower in the intervention group . Conclusions : Feasible dietary modifications of the precursor fatty acid profile via n-3 PUFA-rich vegetable oil favoured n-3 LC-PUFA synthesis in the complementary feeding period when LC-PUFA intake from breast milk and formula is decreasing [21130544] BACKGROUND & AIMS Canola oil is a variety of rapeseed oil low in erucic acid ( < 2 % ) . For many years , canola oil has been widely used as an ingredient in infant formula in Europe , but not in North America due to safety concerns . A number of studies have used variable canola content of infant formulas to investigate the effects of linoleic acid : α-linolenic acid ratio on visual function of infants . However , little published data is available to compare the safety of canola versus non-canola containing infant formula . The aim of this study is to investigate whether infant formulas containing canola oil support normal growth in infants as assessed by weight and length gain . METHODS Re-analyses of data on infant weight and length gain from a prospect i ve r and omized double-blind trial in full-term infants in the German Infant Nutritional Intervention study ( GINI ) . This analysis compared growth in infants receiving infant formulas with or without canola oil from week 4 to month 7 . Absolute weight and length , weight and length gain in gram or cm per day and st and ardized weight and length measurements were analyzed by analyses of variance and a longitudinal r and om effects model . St and ardization was conducted according to the new WHO 2006 age- and sex-specific child growth st and ards . RESULTS Absolute and st and ardized weight and length measures did not differ between the formula groups with or without canola oil . This was true for both , analyses within each of the three anthropometric measurement periods ( 4 - 6 weeks , 3 - 4 months , 6 - 7 months ) and for the longitudinal analyses over the whole period from 4 weeks to 7 months of life . Power analyses confirmed that sample size was sufficient to detect a difference of 3 g per day between 14 and 120 days between the two formula groups . CONCLUSIONS Infant formula containing canola oil supports normal infant growth as assessed by weight and length gain [23279074] AIM To determine the effect of neonatal docosahexaenoic acid ( DHA ) supplementation in preterm infants on later respiratory-related hospitalisations . METHODS We enrolled 657 infants in a multicentre , r and omised , controlled trial design ed to study the long-term efficacy of higher dose dietary DHA in infants born <33 weeks ' gestation . Treatment was with high DHA ( ∼1 % ) compared with st and ard DHA ( ∼0.3 % ) in breast milk or formula , given from the first week of life to term equivalent . Parent-reported hospital admissions to 18 months corrected age were recorded . The proportion of children hospitalised for lower respiratory tract ( LRT ) conditions and the mean number of hospitalisations per infant were determined . RESULTS Twenty-three per cent ( 154/657 ) of infants were hospitalised for LRT conditions . Seventy-three per cent ( 173/238 ) of admissions were for bronchiolitis . There was no significant effect of higher DHA on the proportion of infants admitted for LRT conditions ( high DHA 22 % vs. st and ard DHA 25 % , adjusted relative risk 0.92 , 95 % confidence interval ( CI ) 0.68 - 1.24 , P = 0.57 ) or in the mean number of admissions per infant ( high DHA 0.34 , st and ard DHA 0.38 , adjusted ratio of means 0.91 , 95 % CI 0.63 - 1.32 , P = 0.62 ) . The sexes responded differently to treatment ( interaction P = 0.046 ) , with reduced admissions in boys given high DHA , but this was not statistically significant ( high DHA 19 % , st and ard DHA 28 % , adjusted relative risk 0.69 , 95 % CI 0.46 - 1.04 , P = 0.08 ) . CONCLUSIONS Hospitalisation for LRT problems in the first 18 months for preterm infants was not reduced by neonatal supplementation with 1 % DHA [23531328] OBJECTIVES Maternal deficiency of the omega-3 fatty acid , docosahexaenoic acid ( DHA ) , has been associated with perinatal depression , but there is evidence that supplementation with eicosapentaenoic acid ( EPA ) may be more effective than DHA in treating depressive symptoms . This trial tested the relative effects of EPA- and DHA-rich fish oils on prevention of depressive symptoms among pregnant women at an increased risk of depression . STUDY DESIGN We enrolled 126 pregnant women at risk for depression ( Edinburgh Postnatal Depression Scale score 9 - 19 or a history of depression ) in early pregnancy and r and omly assigned them to receive EPA-rich fish oil ( 1060 mg EPA plus 274 mg DHA ) , DHA-rich fish oil ( 900 mg DHA plus 180 mg EPA ) , or soy oil placebo . Subjects completed the Beck Depression Inventory ( BDI ) and Mini-International Neuropsychiatric Interview at enrollment , 26 - 28 weeks , 34 - 36 weeks , and at 6 - 8 weeks ' postpartum . Serum fatty acids were analyzed at entry and at 34 - 36 weeks ' gestation . RESULTS One hundred eighteen women completed the trial . There were no differences between groups in BDI scores or other depression endpoints at any of the 3 time points after supplementation . The EPA- and DHA-rich fish oil groups exhibited significantly increased postsupplementation concentrations of serum EPA and serum DHA respectively . Serum DHA- concentrations at 34 - 36 weeks were inversely related to BDI scores in late pregnancy . CONCLUSION EPA-rich fish oil and DHA-rich fish oil supplementation did not prevent depressive symptoms during pregnancy or postpartum [20370943] Long-chain PUFA ( LCPUFA ) supplementation of formula can have beneficial effects on neurodevelopmental outcome in early infancy , but uncertainty exists regarding effects after 6 months . The present study is the first to investigate whether consumption by term infants of formula containing LCPUFA for the first 2 months after birth improves neurological condition of these children at 9 years of age . A prospect i ve , double-blind , r and omised control study was performed in two groups of healthy term infants : a control group with st and ard formula ( n 169 ) and a LCPUFA-supplemented group ( LF ; n 146 ) . A breast-fed group ( BF ; n 159 ) served as a reference . At age 9 years , children were neurologically assessed according to Touwen , result ing in a Neurological Optimality Score and information on severity and type of minor neurological dysfunction ( MND ) . Information on potential confounders was collected at enrollment and follow-up . Multivariate analyses were carried out to evaluate the effect of nutrition while adjusting for confounders . Attrition ( 28 % ) was selective : drop-outs in the LF group were more often boys and had a significantly lower mental developmental index at 18 months . Neurological optimality and severity and type of MND at 9 years did not differ between the two formula groups . Children in the BF group showed significantly less often fine manipulative dysfunction than formula-fed children . In conclusion , LCPUFA supplementation of formula during the first 2 postnatal months in healthy term infants does not alter neurological function at school age . The study confirmed that breast-fed infants have a slightly better neurodevelopmental outcome than formula-fed infants [22313729] Studies in experimental animals and human subjects have suggested that intake of n-3 fatty acids in early life can affect cardiovascular risk factors in adult life . Therefore , the aim of the present study was to investigate the effect of fish oil ( FO ) supplementation during the third trimester of pregnancy on blood pressure ( BP ) , heart rate ( HR ) and HR variability ( HRV ) in the 19-year-old offspring . The study was based on follow-up of a r and omised , controlled trial from 1990 , in which 533 pregnant women were r and omised to FO , olive oil ( OO ) or no oil ( NO ) during the last trimester of pregnancy . The offspring was invited to a physical examination including BP , HR and HRV measurements . A subgroup consisting of the offspring of mothers with a low baseline fish intake also had 24 h HRV determined . The OO group was used as reference and multiple linear regression modelling was used to compare the FO and OO groups . A total of 180 of the offspring from the FO and OO groups agreed to participate in the study ( 45 % ) . The adjusted difference between the FO and OO groups was 2 ( 95 % CI -1 , 4 ) mmHg in systolic and 1 ( 95 % CI 0 , 3 ) mmHg in diastolic BP . The difference in HR was 1 ( 95 % CI -2 , 4 ) . Also , HRV indices did not differ significantly between groups . Hence , FO supplementation during late pregnancy was not associated with offspring BP , HR and HRV during adolescence [18519483] OBJECTIVE . The objective of our study was to evaluate the effect of supplementation with docosahexaenoic acid and arachidonic acid for human milk-fed preterm infants . The primary end point was cognitive development at 6 months of age . METHODS . The study was a r and omized , double-blind , placebo-controlled study among 141 infants with birth weights of < 1500 g. The intervention with 32 mg of docosahexaenoic acid and 31 mg of arachidonic acid per 100 mL of human milk started 1 week after birth and lasted until discharge from the hospital ( on average , 9 weeks ) . Cognitive development was evaluated at 6 months of age by using the Ages and Stages Question naire and event-related potentials , a measure of brain correlates related to recognition memory . RESULTS . There was no difference in adverse events or growth between the 2 groups . At the 6-month follow-up evaluation , the intervention group performed better on the problem-solving subscore , compared with the control group ( 53.4 vs 49.5 points ) . There was also a nonsignificant higher total score ( 221 vs 215 points ) . The event-related potential data revealed that infants in the intervention group had significantly lower responses after the st and ard image , compared with the control group ( 8.6 vs 13.2 ) . There was no difference in responses to novel images . CONCLUSIONS . Supplementation with docosahexaenoic acid and arachidonic acid for very preterm infants fed human milk in the early neonatal period was associated with better recognition memory and higher problem-solving scores at 6 months [24045099] INTRODUCTION This intervention examined whether fish-oil-supplementation in late infancy modifies free-play test scores and if this is related to blood pressure ( BP ) and mean RR interval . PATIENTS AND METHODS 83 Danish 9-month-old infants were r and omized to ±fish oil ( FO ) ( 3.4±1.1mL/d ) for 3months and 61 of these completed the free-play-test before and after the intervention . RESULTS Most of the free-play scores changed during the intervention , but the intervention affected only the number of looks away from the toy , which was increased in + FO and decreased in -FO ( p=0.037 ) . The increased numbers of looks away were associated with an increase in erythrocyte eicosapentaenoic acid ( r=0.401 , p=0.017 , n=35 ) and were also associated with a decrease in systolic-BP ( r=-0.511 , p<0.001 , n=52 ) . CONCLUSIONS The results indicate that n-3 fatty acid intake also in late infancy can influence brain development and that the cognitive and cardiovascular effects may be related [22739373] Fish oil supplementation during pregnancy alters breast milk composition , but there is little information about the impact of oily fish consumption . We determined whether increased salmon consumption during pregnancy alters breast milk fatty acid composition and immune factors . Women ( n = 123 ) who rarely ate oily fish were r and omly assigned to consume their habitual diet or to consume 2 portions of farmed salmon per week from 20 wk of pregnancy until delivery . The salmon provided 3.45 g long-chain ( LC ) ( n-3 ) PUFA/wk . Breast milk fatty acid composition and immune factors [ soluble CD14 , transforming growth factor-β (TGFβ)1 , TGFβ2 , and secretory IgA ] were analyzed at 1 , 5 , 14 , and 28 d postpartum ( PP ) . Breast milk from the salmon group had higher proportions of EPA ( 80 % ) , docosapentaenoic acid ( 30 % ) , and DHA ( 90 % ) on d 5 PP compared with controls ( P < 0.01 ) . The LC ( n-6 ) PUFA : LC ( n-3 ) PUFA ratio was lower for the salmon group on all days of PP sampling ( P ≤ 0.004 ) , although individual ( n-6 ) PUFA proportions , including arachidonic acid , did not differ . All breast milk immune factors decreased between d 1 and 28 PP ( P < 0.001 ) . Breast milk secretory IgA ( sIgA ) was lower in the salmon group ( d 1 - 28 PP ; P = 0.006 ) . Salmon consumption during pregnancy , at the current recommended intakes , increases the LC ( n-3 ) PUFA concentration of breast milk in early lactation , thus improving the supply of these important fatty acids to the breast-fed neonate . The consequence of the lower breast milk concentration of sIgA in the salmon group is not clear Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Allergies have become more prevalent globally over the last 20 years . Dietary consumption of n-3 ( or omega 3 ) long chain polyunsaturated fatty acids ( LCPUFA ) has declined over the same period of time . This , together with the known role of n-3 LCPUFA in inhibiting inflammation , has result ed in speculation that n-3 LCPUFA may prevent allergy development . Dietary n-3 fatty acids supplements may change the developing immune system of the newborn before allergic responses are established , particularly for those with a genetic predisposition to the production of the immunoglobulin E ( IgE ) antibody . Individuals with IgE-mediated allergies have both the signs and symptoms of the allergic disease and a positive skin prick test ( SPT ) to the allergen . OBJECTIVES To assess the effect of n-3 LCPUFA supplementation in pregnant and /or breastfeeding women on allergy outcomes ( food allergy , atopic dermatitis ( eczema ) , allergic rhinitis ( hay fever ) and asthma/wheeze ) in their children . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

28429603

[21255498] OBJECTIVE : In a cardiothoracic and vascular intensive care unit , to compare nasal high-flow ( NHF ) oxygen therapy and st and ard high-flow face mask ( HFFM ) oxygen therapy in patients with mild to moderate hypoxemic respiratory failure . METHODS : In a prospect i ve r and omized comparative study , 60 patients with mild to moderate hypoxemic respiratory failure were r and omized to receive NHF or HFFM . We analyzed the success of allocated therapy , noninvasive ventilation rate , and oxygenation . RESULTS : Significantly more NHF patients succeeded with their allocated therapy ( P = .006 ) . The rate of noninvasive ventilation in the NHF group was 3/29 ( 10 % ) , compared with 8/27 ( 30 % ) in the HFFM group ( P = .10 ) . The NHF patients also had significantly fewer desaturations ( P = .009 ) . CONCLUSIONS : NHF oxygen therapy may be more effective than HFFM in treating mild to moderate hypoxemic respiratory failure [3672522] Introduction Noninvasive ventilation ( NIV ) , as a weaning-facilitating strategy in predominantly chronic obstructive pulmonary disease ( COPD ) mechanically ventilated patients , is associated with reduced ventilator-associated pneumonia , total duration of mechanical ventilation , length of intensive care unit ( ICU ) and hospital stay , and mortality . However , this benefit after planned extubation in patients with acute respiratory failure of various etiologies remains to be eluci date d. The aim of this study was to determine the efficacy of NIV applied immediately after planned extubation in contrast to oxygen mask ( OM ) in patients with acute respiratory failure ( ARF ) . Methods A r and omized , prospect i ve , controlled , unblinded clinical study in a single center of a 24-bed adult general ICU in a university hospital was carried out in a 12-month period . Included patients met extubation criteria with at least 72 hours of mechanical ventilation due to acute respiratory failure , after following the ICU weaning protocol . Patients were r and omized immediately before elective extubation , being r and omly allocated to one of the study groups : NIV or OM . We compared both groups regarding gas exchange 15 minutes , 2 hours , and 24 hours after extubation , reintubation rate after 48 hours , duration of mechanical ventilation , ICU length of stay , and hospital mortality . Results Forty patients were r and omized to receive NIV ( 20 patients ) or OM ( 20 patients ) after the following extubation criteria were met : pressure support ( PSV ) of 7 cm H2O , positive end-expiratory pressure ( PEEP ) of 5 cm H2O , oxygen inspiratory fraction ( FiO2 ) ≤ 40 % , arterial oxygen saturation ( SaO2 ) ≥ 90 % , and ratio of respiratory rate and tidal volume in liters ( f/TV ) < 105 . Comparing the 20 patients ( NIV ) with the 18 patients ( OM ) that finished the study 48 hours after extubation , the rate of reintubation in NIV group was 5 % and 39 % in OM group ( P = 0.016 ) . Relative risk for reintubation was 0.13 ( CI = 0.017 to 0.946 ) . Absolute risk reduction for reintubation showed a decrease of 33.9 % , and analysis of the number needed to treat was three . No difference was found in the length of ICU stay ( P = 0.681 ) . Hospital mortality was zero in NIV group and 22.2 % in OM group ( P = 0.041 ) . Conclusions In this study population , NIV prevented 48 hours reintubation if applied immediately after elective extubation in patients with more than 3 days of ARF when compared with the OM group . Trial Registration numberIS RCT N : 41524441 [23602035] PURPOSE High flow nasal cannula ( HFNC ) may decrease preload being associated with beneficial hemodynamic and respiratory effects in adults with heart failure . METHODS This is a sequential intervention prospect i ve study including 10 adults with New York Heart Association ( NYHA ) class III and left ventricle ejection fraction 45 % or less . High flow gas was administered ( fraction of inspired oxygen , 0.21 ) through nasal cannula ( Optiflow(TM ) ; Fisher & Paykel , Auckl and , New Zeal and ) . Sequential echocardiographies were performed at baseline , using HFNC with 20 lpm and 40 lpm and post-HFNC . A reduction greater than 20 % in the estimated inspiratory collapse of the inferior vena cava ( IVC ) from baseline was considered clinical ly significant . RESULTS Ten patients were included , with median age of 57 ( 44 - 65 ) years ; 6 ( 60 % ) were female , and 8 ( 80 % ) had dilated cardiomyopathy . Median IVC inspiratory significantly ( P<.05 ) decreased from baseline ( 37 % ) to HFNC with 20 lpm ( 28 % ) and HFNC with 40 lpm ( 21 % ) , representing mean attributable reductions of 20 % ( 95 % confidence interval , 6 - 55 ) and 53 % ( 95 % confidence interval , 36 - 67 ) from baseline . Changes in the IVC inspiratory collapse were reversible after HFNC withdrawal . Respiratory rate was significantly reduced from 23 breaths per minute at baseline to 17 breaths per minute at HFNC with 20 lpm and 13 breaths per minute at HFNC with 40 lpm . In contrast , no significant changes in other echocardiographic or clinical variables were documented . CONCLUSION These findings suggest that patients with NYHA class III heart failure may benefit with HFNC supportive therapy [11066186] CONTEXT Continuous positive airway pressure ( CPAP ) is widely used in the belief that it may reduce the need for intubation and mechanical ventilation in patients with acute hypoxemic respiratory insufficiency . OBJECTIVE To compare the physiologic effects and the clinical efficacy of CPAP vs st and ard oxygen therapy in patients with acute hypoxemic , nonhypercapnic respiratory insufficiency . DESIGN , SETTING , AND PATIENTS R and omized , concealed , and unblinded trial of 123 consecutive adult patients who were admitted to 6 intensive care units between September 1997 and January 1999 with a PaO(2)/FIO(2 ) ratio of 300 mm Hg or less due to bilateral pulmonary edema ( n = 102 with acute lung injury and n = 21 with cardiac disease ) . INTERVENTIONS Patients were r and omly assigned to receive oxygen therapy alone ( n = 61 ) or oxygen therapy plus CPAP ( n = 62 ) . MAIN OUTCOME MEASURES Improvement in PaO(2)/FIO(2 ) ratio , rate of endotracheal intubation at any time during the study , adverse events , length of hospital stay , mortality , and duration of ventilatory assistance , compared between the CPAP and st and ard treatment groups . RESULTS Among the CPAP vs st and ard therapy groups , respectively , causes of respiratory failure ( pneumonia , 54 % and 55 % ) , presence of cardiac disease ( 33 % and 35 % ) , severity at admission , and hypoxemia ( median [ 5th-95th percentile ] PaO(2)/FIO(2 ) ratio , 140 [ 59 - 288 ] mm Hg vs 148 [ 62 - 283 ] mm Hg ; P = .43 ) were similarly distributed . After 1 hour of treatment , subjective responses to treatment ( P<.001 ) and median ( 5th-95th percentile ) PaO(2)/FIO(2 ) ratios were greater with CPAP ( 203 [ 45 - 431 ] mm Hg vs 151 [ 73 - 482 ] mm Hg ; P = .02 ) . No further difference in respiratory indices was observed between the groups . Treatment with CPAP failed to reduce the endotracheal intubation rate ( 21 [ 34 % ] vs 24 [ 39 % ] in the st and ard therapy group ; P = .53 ) , hospital mortality ( 19 [ 31 % ] vs 18 [ 30 % ] ; P = .89 ) , or median ( 5th-95th percentile ) intensive care unit length of stay ( 6.5 [ 1 - 57 ] days vs 6.0 [ 1 - 36 ] days ; P = .43 ) . A higher number of adverse events occurred with CPAP treatment ( 18 vs 6 ; P = .01 ) . CONCLUSION In this study , despite early physiologic improvement , CPAP neither reduced the need for intubation nor improved outcomes in patients with acute hypoxemic , nonhypercapnic respiratory insufficiency primarily due to acute lung injury . JAMA . 2000;284:2352 - 2360 [27706464] Importance High-flow conditioned oxygen therapy delivered through nasal cannulae and noninvasive mechanical ventilation ( NIV ) may reduce the need for reintubation . Among the advantages of high-flow oxygen therapy are comfort , availability , lower costs , and additional physiopathological mechanisms . Objective To test if high-flow conditioned oxygen therapy is noninferior to NIV for preventing postextubation respiratory failure and reintubation in patients at high risk of reintubation . Design , Setting , and Participants Multicenter r and omized clinical trial in 3 intensive care units in Spain ( September 2012-October 2014 ) including critically ill patients ready for planned extubation with at least 1 of the following high-risk factors for reintubation : older than 65 years ; Acute Physiology and Chronic Health Evaluation II score higher than 12 points on extubation day ; body mass index higher than 30 ; inadequate secretions management ; difficult or prolonged weaning ; more than 1 comorbidity ; heart failure as primary indication for mechanical ventilation ; moderate to severe chronic obstructive pulmonary disease ; airway patency problems ; or prolonged mechanical ventilation . Interventions Patients were r and omized to undergo either high-flow conditioned oxygen therapy or NIV for 24 hours after extubation . Main Outcomes and Measures Primary outcomes were reintubation and postextubation respiratory failure within 72 hours . Noninferiority margin was 10 percentage points . Secondary outcomes included respiratory infection , sepsis , and multiple organ failure , length of stay and mortality ; adverse events ; and time to reintubation . Results Of 604 patients ( mean age , 65 [ SD , 16 ] years ; 388 [ 64 % ] men ) , 314 received NIV and 290 high-flow oxygen . Sixty-six patients ( 22.8 % ) in the high-flow group vs 60 ( 19.1 % ) in the NIV group were reintubation ( absolute difference , -3.7 % ; 95 % CI , -9.1 % to ∞ ) ; 78 patients ( 26.9 % ) in the high-flow group vs 125 ( 39.8 % ) in the NIV group experienced postextubation respiratory failure ( risk difference , 12.9 % ; 95 % CI , 6.6 % to ∞ ) [ corrected ] . Median time to reintubation did not significantly differ : 26.5 hours ( IQR , 14 - 39 hours ) in the high-flow group vs 21.5 hours ( IQR , 10 - 47 hours ) in the NIV group ( absolute difference , -5 hours ; 95 % CI , -34 to 24 hours ) . Median postr and omization ICU length of stay was lower in the high-flow group , 3 days ( IQR , 2 - 7 ) vs 4 days ( IQR , 2 - 9 ; P=.048 ) . Other secondary outcomes were similar in the 2 groups . Adverse effects requiring withdrawal of the therapy were observed in none of patients in the high-flow group vs 42.9 % patients in the NIV group ( P < .001 ) . Conclusions and Relevance Among high-risk adults who have undergone extubation , high-flow conditioned oxygen therapy was not inferior to NIV for preventing reintubation and postextubation respiratory failure . High-flow conditioned oxygen therapy may offer advantages for these patients . Trial Registration clinical trials.gov Identifier : NCT01191489 [21958974] PURPOSE The purpose of this study was to determine the impact of high-flow nasal cannula oxygen ( HFNC ) on patients with acute respiratory failure ( ARF ) in comparison with conventional oxygen therapy . MATERIAL S AND METHODS This was a prospect i ve observational study . Patients with persistent ARF despite oxygen with conventional facemask without indication for immediate intubation were treated with HFNC oxygen . Clinical respiratory parameters and arterial blood gases were compared under conventional and HFNC oxygen therapy . RESULTS Twenty patients , aged 59 years ( 38 - 75 years ) and SAPS2 ( simplified acute physiology score ) 33 ( 26.5 - 38 ) , were included in the study . Etiology of ARF was mainly pneumonia ( n = 11 ) , sepsis ( n = 3 ) , and miscellaneous ( n = 6 ) . Use of HFNC enabled a significant reduction of respiratory rate , 28 ( 26 - 33 ) vs 24.5 ( 23 - 28.5 ) breath per minute ( P = .006 ) , and a significant increase in oxygen saturation , oxygen saturation as measured by pulse oximetry 93.5 % ( 90 - 98.5 ) vs 98.5 % ( 95.5 - 100 ) ( P = .0003 ) . Use of HFNC significantly increased Pao(2 ) from 8.73 ( 7.13 - 11.13 ) to 15.27 ( 9.66 - 25.6 ) kPa ( P = .001 ) and moderately increased Paco(2 ) , 5.26 ( 4.33 - 5.66 ) to 5.73 ( 4.8 - 6.2 ) kPa ( P = .005 ) without affecting pH. Median duration of HFNC was 26.5 ( 17 - 121 ) hours . Six patients were secondarily intubated , and 3 died in the intensive care unit . CONCLUSION Use of HFNC in patients with persistent ARF was associated with significant and sustained improvement of both clinical and biologic parameters [2777940] Background The aim of this prospect i ve study was to determine whether a level of positive airway pressure was generated in participants receiving nasal high flow ( NHF ) delivered by the Optiflow ™ system ( Fisher and Paykel Healthcare Ltd , Auckl and , New Zeal and ) in a cardiothoracic and vascular intensive care unit ( ICU ) . Methods Nasopharyngeal airway pressure was measured in 15 postoperative cardiac surgery adult patients who received both NHF and st and ard facemask therapy at a flow rate of 35 litre min−1 . Measurements were repeated in the open mouth and closed mouth positions . Mean airway pressure was determined by averaging the pressures at the peak of inspiration of each breath within a 1 min period , allowing the entire pressure profile of each breath to be included within the calculation . Results Low level positive pressure was demonstrated with NHF at 35 litre min−1 with mouth closed when compared with a facemask . NHF generated a mean nasopharyngeal airway pressure of mean ( sd ) 2.7 ( 1.04 ) cm H2O with the mouth closed . Airway pressure was significantly higher when breathing with mouth closed compared with mouth open ( P≤0.0001 ) . Conclusions This study demonstrated that a low level of positive pressure was generated with NHF at 35 litre min−1 of gas flow . This is consistent with results obtained in healthy volunteers . Australian Clinical Trials Registry www.actr.org.au ACTRN012606000139572 [24286408] Background Although noninvasive positive pressure ventilation ( NPPV ) has been successfully used for various kinds of acute respiratory failure , the data are limited regarding its application in postoperative respiratory failure after cardiac surgery . Therefore , we conducted a prospect i ve r and omized control study in a university surgical intensive care unit to evaluate the efficacy and safety of NPPV in the treatment of acute respiratory failure after cardiac surgery , and explore the predicting factors of NPPV failure . Methods From September 2011 to November 2012 patients with acute respiratory failure after cardiac surgery who had indication for the use of NPPV were r and omly divided into a NPPV treatment group ( NPPV group ) and the conventional treatment group ( control group ) . The between‐group differences in the patients ’ baseline characteristics , re‐intubation rate , tracheotomy rate , ventilator associated pneumonia ( VAP ) incidence , in‐hospital mortality , mechanical ventilation time after enrollment ( MV time ) , intensive care unit ( ICU ) and postoperative hospital stays were compared . The factors that predict NPPV failure were analyzed . Results During the study period , a total of 139 patients who had acute respiratory failure after cardiac surgery were recorded , and 95 of them met the inclusion criteria , which included 59 males and 36 females with a mean age of ( 61.5±11.2 ) years . Forty‐three patients underwent coronary artery bypass grafting ( CABG ) , 23 underwent valve surgery , 13 underwent CABG+valve surgery , 13 underwent major vascular surgery , and three underwent other surgeries . The NPPV group had 48 patients and the control group had 47 patients . In the NPPV group , the re‐intubation rate was 18.8 % , tracheotomy rate was 12.5 % , VAP incidence was 0 , and the in‐hospital mortality was 18.8 % , significantly lower than in the control group 80.9 % , 29.8 % , 17.0 % and 38.3 % respectively , P < 0.05 or P < 0.01 . The MV time and ICU stay ( expressed as the median ( P25 , P75 ) ) were 18.0 ( 9.2 , 35.0 ) hours and 4.0 ( 2.0 , 5.0 ) days , which were significantly shorter than in the control group , 96.0 ( 26.0 , 240.0 ) hours and 6.0 ( 4.0 , 9.0 ) days respectively , P < 0.05 or P < 0.01 . The postoperative hospital stays of the two groups were similar . The univariate analysis showed that the NPPV success subgroup had more patients with acute lung injury ( ALI ) ( 17 vs. 0 , P=0.038 ) , fewer patients with pneumonia ( 2 vs. 7 , P < 0.001 ) and lower acute physiology and chronic health evaluation II ( APACHE II ) scores ( 16.1±2.8 vs. 21.8±3.2 , P < 0.001 ) . Multivariate analysis showed that pneumonia ( P=0.027 ) and a high APACHE II score > 20 ( P=0.002 ) were the independent risk factors of NPPV failure . Conclusions We conclude that NPPV can be applied in selected patients with acute respiratory failure after cardiac surgery to reduce the need of re‐intubation and improve clinical outcome as compared with conventional treatment . Pneumonia and a high APACHE II score > 20 might be the independent risk factors of NPPV failure in this group of patients [16224108] RATIONALE Respiratory failure after extubation and reintubation is associated with increased morbidity and mortality . OBJECTIVES To assess the efficacy of noninvasive ventilation in averting respiratory failure after extubation in patients at increased risk . METHODS A prospect i ve r and omized controlled trial was conducted in 162 mechanically ventilated patients who tolerated a spontaneous breathing trial after recovery from the acute episode but had increased risk for respiratory failure after extubation . Patients were r and omly allocated after extubation to receive noninvasive ventilation for 24 h ( n = 79 ) , or conventional management with oxygen therapy ( control group , n = 83 ) . MEASUREMENTS AND MAIN RESULTS The primary end-point variable was the decrease in respiratory failure after extubation . In the noninvasive ventilation group , respiratory failure after extubation was less frequent ( 13 , 16 vs. 27 , 33 % ; p = 0.029 ) and the intensive care unit mortality was lower ( 2 , 3 versus 12 , 14 % ; p = 0.015 ) . However , 90-d survival did not change significantly between groups . Separate analyses of patients without and with hypercapnia ( arterial CO(2 ) tension greater than 45 mm Hg ) during the spontaneous breathing trial showed that noninvasive ventilation improved intensive care unit mortality ( 0 vs. 4 , 18 % ; p = 0.035 ) and 90-d survival ( p = 0.006 ) in hypercapnic patients only ; of them , 98 % had chronic respiratory disorders . CONCLUSIONS The early use of noninvasive ventilation averted respiratory failure after extubation and decreased intensive care unit mortality among patients at increased risk . The beneficial effect of noninvasive ventilation in improving survival of hypercapnic patients with chronic respiratory disorders warrants a new prospect i ve clinical trial [23050520] BACKGROUND : Electrical impedance tomography measures changes in lung impedance , which are mainly related to changes in lung volume . We used electrical impedance tomography to investigate the effects of high-flow nasal cannula ( HFNC ) and body position on global and regional end-expiratory lung impedance variation ( ΔEELI ) . METHODS : Prospect i ve study with 20 healthy adults . Two periods were defined : the first in supine position and the second in prone position . Each period was divided into 3 phases . In the first and the third phases the subjects were breathing ambient air , and in the second HFNC was implemented . Four regions of interest were defined : 2 ventral and 2 dorsal . For each respiratory cycle , global and regional ΔEELI were measured by electrical impedance tomography and were expressed as a function of the tidal variation of the first stable respiratory cycle ( units ) . RESULTS : HFNC increased global EELI by 1.26 units ( 95 % CI 1.20–1.31 , P < .001 ) in supine position , and by 0.87 units ( 95 % CI 0.82–0.91 , P < .001 ) in prone position . The distribution of ΔEELI was homogeneous in prone position , with no difference between ventral and dorsal lung regions ( −0.01 units , 95 % CI −0.01 to 0 , P = .18 ) , while in supine position a significant difference was found ( 0.22 units , 95 % CI 0.21–0.23 , P < .001 ) with increased EELI in ventral areas . CONCLUSIONS : HFNC increased global EELI in our population , regardless of body position , suggesting an increase in functional residual capacity . Prone positioning was related to a more homogeneous distribution of ΔEELI , while in supine position ΔEELI was higher in the ventral lung regions [20406507] OBJECTIVE To compare the comfort of oxygen therapy via high-flow nasal cannula ( HFNC ) versus via conventional face mask in patients with acute respiratory failure . Acute respiratory failure was defined as blood oxygen saturation < 96 % while receiving a fraction of inspired oxygen > or = 0.50 via face mask . METHODS Oxygen was first humidified with a bubble humidifier and delivered via face mask for 30 min , and then via HFNC with heated humidifier for another 30 min . At the end of each 30-min period we asked the patient to evaluate dyspnea , mouth dryness , and overall comfort , on a visual analog scale of 0 ( lowest ) to 10 ( highest ) . The results are expressed as median and interquartile range values . RESULTS We included 20 patients , with a median age of 57 ( 40 - 70 ) years . The total gas flow administered was higher with the HFNC than with the face mask ( 30 [ 21.3 - 38.7 ] L/min vs 15 [ 12 - 20 ] L/min , P < .001 ) . The HFNC was associated with less dyspnea ( 3.8 [ 1.3 - 5.8 ] vs 6.8 [ 4.1 - 7.9 ] , P = .001 ) and mouth dryness ( 5 [ 2.3 - 7 ] vs 9.5 [ 8 - 10 ] , P < .001 ) , and was more comfortable ( 9 [ 8 - 10 ] ) versus 5 [ 2.3 - 6.8 ] , P < .001 ) . HFNC was associated with higher P(aO(2 ) ) ( 127 [ 83 - 191 ] mm Hg vs 77 [ 64 - 88 ] mm Hg , P = .002 ) and lower respiratory rate ( 21 [ 18 - 27 ] breaths/min vs 28 [ 25 - 32 ] breaths/min , P < .001 ) , but no difference in P(aCO(2 ) ) . CONCLUSIONS HFNC was better tolerated and more comfortable than face mask . HFNC was associated with better oxygenation and lower respiratory rate . HFNC could have an important role in the treatment of patients with acute respiratory failure [25869405] Purpose Intubation of hypoxemic patients is associated with life-threatening adverse events . High-flow therapy by nasal cannula ( HFNC ) for preoxygenation before intubation has never been assessed by r and omized study . Our objective was to evaluate the efficiency of HFNC for preoxygenation , compared to high fraction-inspired oxygen facial mask ( HFFM ) . Methods Multicenter , r and omized , open-labelled , controlled PREOXYFLOW trial ( NCT 01747109 ) in six French intensive care units . Acute hypoxemic adults requiring intubation were r and omly allocated to HFNC or HFFM . Patients were eligible if PaO2/FiO2 ratio was below 300 mmHg , respiratory rate at least 30/min and if they required FiO2 50 % or more to obtain at least 90 % oxygen saturation . HFNC was maintained throughout the procedure , whereas HFFM was removed at the end of general anaesthesia induction . Primary outcome was the lowest saturation throughout intubation procedure . Secondary outcomes included adverse events related to intubation , duration of mechanical ventilation and death . Results A total of 124 patients were r and omized . In the intent-to-treat analysis , including 119 patients ( HFNC n = 62 ; HFFM n = 57 ) , the median ( interquartile range ) lowest saturation was 91.5 % ( 80–96 ) for HFNC and 89.5 % ( 81–95 ) for the HFFM group ( p = 0.44 ) . There was no difference for difficult intubation ( p = 0.18 ) , intubation difficulty scale , ventilation-free days ( p = 0.09 ) , intubation-related adverse events including desaturation < 80 % or mortality ( p = 0.46 ) . Conclusions Compared to HFFM , HFNC as a preoxygenation device did not reduce the lowest level of desaturation [25371400] BACKGROUND : Beneficial effects of high-flow nasal cannula ( HFNC ) oxygen on oxygenation and respiratory parameters have been reported in a small number of subjects with acute respiratory failure ( ARF ) . We aim ed to evaluate its effect in subjects with ARDS . METHODS : This was an observational single-center study . Prospect ively obtained data were retrospectively analyzed . All patients admitted over 1 y to a university hospital medicosurgical ICU were included . Classification was according to the highest ventilatory support required . HFNC indications were review ed , and demographics , clinical characteristics , and course of subjects with ARDS according to intubation need were compared . RESULTS : Of 607 subjects admitted , 560 required ventilatory or oxygen support , among whom 180 received noninvasive ventilatory support . HFNC was used in 87 subjects and as first-line treatment in 51 subjects ( 29 % of first-line noninvasively treated subjects ) , 45 of which had ARDS ( PaO2/FIO2 of 137 mm Hg ; 22 men , 57.9 y of age ) . Pneumonia accounted for 82 % of ARDS causes . The intubation rate in these subjects was 40 % . Higher Simplified Acute Physiology Score II ( SAPS II ; 46 vs 29 , P = .001 ) , occurrence of additional organ failure ( 76 % vs 26 % , P = .002 ) , mainly hemodynamic ( 50 % vs 7 % , P = .001 ) or neurological ( 22 % vs 0 , P = .01 ) , and trends toward lower PaO2/FIO2 and higher breathing frequency after HFNC initiation were evidence d in subjects who failed HFNC . Higher SAPS II scores were associated with HFNC failure in multivariate analysis . CONCLUSIONS : In daily care , over one fourth of subjects requiring noninvasive ventilatory support were treated via HFNC , with a high success rate in subjects with severe ARDS . We conclude that HFNC may be considered as first-line therapy in ARF , including patients with ARDS [25981908] BACKGROUND Whether noninvasive ventilation should be administered in patients with acute hypoxemic respiratory failure is debated . Therapy with high-flow oxygen through a nasal cannula may offer an alternative in patients with hypoxemia . METHODS We performed a multicenter , open-label trial in which we r and omly assigned patients without hypercapnia who had acute hypoxemic respiratory failure and a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of 300 mm Hg or less to high-flow oxygen therapy , st and ard oxygen therapy delivered through a face mask , or noninvasive positive-pressure ventilation . The primary outcome was the proportion of patients intubated at day 28 ; secondary outcomes included all-cause mortality in the intensive care unit and at 90 days and the number of ventilator-free days at day 28 . RESULTS A total of 310 patients were included in the analyses . The intubation rate ( primary outcome ) was 38 % ( 40 of 106 patients ) in the high-flow-oxygen group , 47 % ( 44 of 94 ) in the st and ard group , and 50 % ( 55 of 110 ) in the noninvasive-ventilation group ( P=0.18 for all comparisons ) . The number of ventilator-free days at day 28 was significantly higher in the high-flow-oxygen group ( 24±8 days , vs. 22±10 in the st and ard-oxygen group and 19±12 in the noninvasive-ventilation group ; P=0.02 for all comparisons ) . The hazard ratio for death at 90 days was 2.01 ( 95 % confidence interval [ CI ] , 1.01 to 3.99 ) with st and ard oxygen versus high-flow oxygen ( P=0.046 ) and 2.50 ( 95 % CI , 1.31 to 4.78 ) with noninvasive ventilation versus high-flow oxygen ( P=0.006 ) . CONCLUSIONS In patients with nonhypercapnic acute hypoxemic respiratory failure , treatment with high-flow oxygen , st and ard oxygen , or noninvasive ventilation did not result in significantly different intubation rates . There was a significant difference in favor of high-flow oxygen in 90-day mortality . ( Funded by the Programme Hospitalier de Recherche Clinique Interrégional 2010 of the French Ministry of Health ; FLORALI Clinical Trials.gov number , NCT01320384 . ) [3196245] Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more [21045639] Background : Current knowledge of the risk for postoperative pulmonary complications ( PPCs ) rests on studies that narrowly selected patients and procedures . Hypothesizing that PPC occurrence could be predicted from a reduced set of perioperative variables , we aim ed to develop a predictive index for a broad surgical population . Methods : Patients undergoing surgical procedures given general , neuraxial , or regional anesthesia in 59 hospitals were r and omly selected for this prospect i ve , multicenter study . The main outcome was the development of at least one of the following : respiratory infection , respiratory failure , bronchospasm , atelectasis , pleural effusion , pneumothorax , or aspiration pneumonitis . The cohort was r and omly divided into a development sub sample to construct a logistic regression model and a validation sub sample . A PPC predictive index was constructed . Results : Of 2,464 patients studied , 252 events were observed in 123 ( 5 % ) . Thirty-day mortality was higher in patients with a PPC ( 19.5 % ; 95 % [ CI ] , 12.5–26.5 % ) than in those without a PPC ( 0.5 % ; 95 % CI , 0.2–0.8 % ) . Regression modeling identified seven independent risk factors : low preoperative arterial oxygen saturation , acute respiratory infection during the previous month , age , preoperative anemia , upper abdominal or intrathoracic surgery , surgical duration of at least 2 h , and emergency surgery . The area under the receiver operating characteristic curve was 90 % ( 95 % CI , 85–94 % ) for the development sub sample and 88 % ( 95 % CI , 84–93 % ) for the validation sub sample . Conclusion : The risk index based on seven objective , easily assessed factors has excellent discriminative ability . The index can be used to assess individual risk of PPC and focus further research on measures to improve patient care [22417844] OBJECTIVE : Heated and humidified high flow nasal cannula oxygen therapy ( HFNC ) represents a new alternative to conventional oxygen therapy that has not been evaluated in the emergency department ( ED ) . We aim ed to study its feasibility and efficacy in patients exhibiting acute respiratory failure presenting to the ED . METHODS : Prospect i ve , observational study in a university hospital 's ED . Patients with acute respiratory failure requiring > 9 L/min oxygen or with ongoing clinical signs of respiratory distress despite oxygen therapy were included . The device of oxygen administration was then switched from non-rebreathing mask to HFNC . Dyspnea , rated by the Borg scale and a visual analog scale , respiratory rate , and SpO2 were collected before and 15 , 30 , and 60 min after beginning HFNC . Feasibility was assessed through caregivers ' acceptance of the device in terms of practicality and perceived effect on the subjects , evaluated by question naire . RESULTS : Seventeen subjects , median age 64 y ( 46–84.7 y ) , were studied . Pneumonia was the most common reason for oxygen therapy ( n = 9 ) . HFNC was associated with a significant decrease in both dyspnea scores : Borg scale from 6 ( 5–7 ) to 3 ( 2–4 ) ( P < .001 ) , and visual analog scale from 7 ( 5–8 ) to 3 ( 1–5 ) ( P < .01 ) . Respiratory rate decreased from 28 breaths/min ( 25–32 breaths/min ) to 25 breaths/min ( 21–28 breaths/min ) ( P < .001 ) , and SpO2 increased from 90 % ( 88.5–94 % ) to 97 % ( 92.5–100 % ) ( P < .001 ) . Fewer subjects exhibited clinical signs of respiratory distress ( 10/17 vs 3/17 , P = .03 ) . HFNC was well tolerated and no adverse event was noted . Altogether , 76 % of healthcare givers declared preferring HFNC , as compared to conventional oxygen therapy . CONCLUSIONS : HFNC is possible in the ED , and it alleviated dyspnea and improved respiratory parameters in subjects with acute hypoxemic respiratory failure [19781896] PURPOSE Oxygen delivery after extubation is critical to maintain adequate oxygenation and to avoid reintubation . The delivery of oxygen in such situations is usually by high-flow face mask ( HFFM ) . Yet , this may be uncomfortable for some patients . A recent advance in oxygen delivery technology is high-flow nasal prongs ( HFNP ) . There are no r and omized trials comparing these 2 modes . METHODS Patients were r and omized to either protocol A ( n = 25 ; HFFM followed by HFNP ) or protocol B ( n = 25 ; HFNP followed by HFFM ) after a stabilization period of 30 minutes after extubation . The primary objective was to compare the efficacy of HFNP to HFFM in maintaining gas exchange as measured by arterial blood gas . Secondary objective was to compare the relative effects on heart rate , blood pressure , respiratory rate , comfort , and tolerance . RESULTS Patients in both protocol s were comparable in terms of age , demographic , and physiologic variables including arterial blood gas , blood pressure , heart rate , respiratory rate , Glasgow Coma Score , sedation , and Acute Physiology and Chronic Health Evaluation ( APACHE ) III scores . There was no significant difference in gas exchange , respiratory rate , or hemodynamics . There was a significant difference ( P = .01 ) in tolerance , with nasal prongs being well tolerated . There was a trend ( P = .09 ) toward better patient comfort with HFNP . CONCLUSIONS High-flow nasal prongs are as effective as HFFM in delivering oxygen to extubated patients who require high-flow oxygen . The tolerance of HFNP was significantly better than in HFFM [4300050] Introduction Critically ill patients with respiratory failure undergoing bronchoscopy have an increased risk of hypoxaemia-related complications . Previous studies have shown that in awake , hypoxaemic patients non-invasive ventilation ( NIV ) is helpful in preventing gas exchange deterioration during bronchoscopy . An alternative and increasingly used means of oxygen delivery is its application via high-flow nasal cannula ( HFNC ) . This study was conducted to compare HFNC with NIV in patients with acute hypoxaemic respiratory failure undergoing flexible bronchoscopy . Methods Prospect i ve r and omised trial r and omising 40 critically ill patients with hypoxaemic respiratory failure to receive either NIV or HFNC during bronchoscopy in the intensive care unit . Results After the initiation of NIV and HFNC , oxygen levels were significantly higher in the NIV group compared to the HFNC group . Two patients were unable to proceed to bronchoscopy after the institution of HFNC due to progressive hypoxaemia . During bronchoscopy , one patient on HFNC deteriorated due to intravenous sedation requiring non-invasive ventilatory support . Bronchoscopy was well tolerated in all other patients . There were no significant differences between the two groups regarding heart rate , mean arterial pressure and respiratory rate . Three patients in the NIV group and one patient in the HFNC group were intubated within 24 hours after the end of bronchoscopy ( P = 0.29 ) . Conclusions The application of NIV was superior to HFNC with regard to oxygenation before , during and after bronchoscopy in patients with moderate to severe hypoxaemia . In patients with stable oxygenation under HFNC , subsequent bronchoscopy was well tolerated . Trial registration Clinical Trials.gov NCT01870765 . Registered 30 May 2013 [15190137] BACKGROUND The need for reintubation after extubation and discontinuation of mechanical ventilation is not uncommon and is associated with increased mortality . Noninvasive positive-pressure ventilation has been suggested as a promising therapy for patients with respiratory failure after extubation , but a single-center , r and omized trial recently found no benefit . We conducted a multicenter , r and omized trial to evaluate the effect of noninvasive positive-pressure ventilation on mortality in this clinical setting . METHODS Patients in 37 centers in eight countries who were electively extubated after at least 48 hours of mechanical ventilation and who had respiratory failure within the subsequent 48 hours were r and omly assigned to either noninvasive positive-pressure ventilation by face mask or st and ard medical therapy . RESULTS A total of 221 patients with similar baseline characteristics had been r and omly assigned to either noninvasive ventilation ( 114 patients ) or st and ard medical therapy ( 107 patients ) when the trial was stopped early , after an interim analysis . There was no difference between the noninvasive-ventilation group and the st and ard-therapy group in the need for reintubation ( rate of reintubation , 48 percent in both groups ; relative risk in the noninvasive-ventilation group , 0.99 ; 95 percent confidence interval , 0.76 to 1.30 ) . The rate of death in the intensive care unit was higher in the noninvasive-ventilation group than in the st and ard-therapy group ( 25 percent vs. 14 percent ; relative risk , 1.78 ; 95 percent confidence interval , 1.03 to 3.20 ; P=0.048 ) , and the median time from respiratory failure to reintubation was longer in the noninvasive-ventilation group ( 12 hours vs. 2 hours 30 minutes , P=0.02 ) . CONCLUSIONS Noninvasive positive-pressure ventilation does not prevent the need for reintubation or reduce mortality in unselected patients who have respiratory failure after extubation [27771739] Purpose High-flow nasal cannula ( HFNC ) oxygen therapy is attracting increasing interest in acute medicine as an alternative to st and ard oxygen therapy ; however , its use to prevent hypoxaemia after major abdominal surgery has not been evaluated . Our trial was design ed to close this evidence gap . Methods A multicentre r and omised controlled trial was carried out at three university hospitals in France . Adult patients at moderate to high risk of postoperative pulmonary complications who had undergone major abdominal surgery using lung-protective ventilation were r and omly assigned using a computer-generated sequence to receive either HFNC oxygen therapy or st and ard oxygen therapy ( low-flow oxygen delivered via nasal prongs or facemask ) directly after extubation . The primary endpoint was absolute risk reduction ( ARR ) for hypoxaemia at 1 h after extubation and after treatment discontinuation . Secondary outcomes included occurrence of postoperative pulmonary complications within 7 days after surgery , the duration of hospital stay , and in-hospital mortality . The analysis was performed on data from the modified intention-to-treat population . This trial was registered with Clinical Trials.gov ( NCT01887015 ) . Results Between 6 November 2013 and 1 March 2015 , 220 patients were r and omly assigned to receive either HFNC ( n = 108 ) or st and ard oxygen therapy ( n = 112 ) ; all of these patients completed follow-up . The median duration of the allocated treatment was 16 h ( interquartile range 14–18 h ) with st and ard oxygen therapy and 15 h ( interquartile range 12–18 ) with HFNC therapy . Twenty-three ( 21 % ) of the 108 patients treated with HFNC 1 h after extubation and 29 ( 27 % ) of the 108 patients after treatment discontinuation had postextubation hypoxaemia , compared with 27 ( 24 % ) and 34 ( 30 % ) of the 112 patients treated with st and ard oxygen ( ARR 4 , 95 % CI –8 to 15 % ; p = 0.57 ; adjusted relative risk [ RR ] 0.87 , 95 % CI 0.53–1.43 ; p = 0.58 ) . Over the 7-day postoperative follow-up period , there was no statistically significant difference between the groups in the proportion of patients who remained free of any pulmonary complication ( ARR 7 , 95 % CI –6 to 20 % ; p = 0.40 ) . Other secondary outcomes also did not differ significantly between the two groups . Conclusions Among patients undergoing major abdominal surgery , early preventive application of high-flow nasal cannula oxygen therapy after extubation did not result in improved pulmonary outcomes compared with st and ard oxygen therapy [19682735] BACKGROUND Non-invasive ventilation can prevent respiratory failure after extubation in individuals at increased risk of this complication , and enhanced survival in patients with hypercapnia has been recorded . We aim ed to assess prospect ively the effectiveness of non-invasive ventilation after extubation in patients with hypercapnia and as rescue therapy when respiratory failure develops . METHODS We undertook a r and omised controlled trial in three intensive-care units in Spain . We enrolled 106 mechanically ventilated patients with chronic respiratory disorders and hypercapnia after a successful spontaneous breathing trial . We r and omly allocated participants by computer to receive after extubation either non-invasive ventilation for 24 h ( n=54 ) or conventional oxygen treatment ( n=52 ) . The primary endpoint was avoidance of respiratory failure within 72 h after extubation . Analysis was by intention to treat . This trial is registered with clinical trials.gov , identifier NCT00539708 . FINDINGS Respiratory failure after extubation was less frequent in patients assigned non-invasive ventilation than in those allocated conventional oxygen therapy ( 8 [ 15 % ] vs 25 [ 48 % ] ; odds ratio 5.32 [ 95 % CI 2.11 - 13.46 ] ; p<0.0001 ) . In patients with respiratory failure , non-invasive ventilation as rescue therapy avoided reintubation in 17 of 27 patients . Non-invasive ventilation was independently associated with a lower risk of respiratory failure after extubation ( adjusted odds ratio 0.17 [ 95 % CI 0.06 - 0.44 ] ; p<0.0001 ) . 90-day mortality was lower in patients assigned non-invasive ventilation than in those allocated conventional oxygen ( p=0.0146 ) . INTERPRETATION Early non-invasive ventilation after extubation diminished risk of respiratory failure and lowered 90-day mortality in patients with hypercapnia during a spontaneous breathing trial . Routine implementation of this strategy for management of mechanically ventilated patients with chronic respiratory disorders is advisable . FUNDING IDIBAPS , CibeRes , Fondo de Investigaciones Sanitarias , European Respiratory Society [16276167] Objective : Compared with st and ard medical therapy ( SMT ) , noninvasive ventilation ( NIV ) does not reduce the need for reintubation in unselected patients who develop respiratory failure after extubation . The goal of this study was to assess whether early application of NIV , immediately after extubation , is effective in preventing postextubation respiratory failure in an at-risk population . Design : Multiple-center , r and omized controlled study . Setting : Multiple hospitals . Patients : Ninety-seven consecutive patients with similar baseline characteristics , requiring > 48 hrs of mechanical ventilation and considered at risk of developing postextubation respiratory failure ( i.e. , patients who had hypercapnia , congestive heart failure , ineffective cough and excessive tracheobronchial secretions , more than one failure of a weaning trial , more than one comorbid condition , and upper airway obstruction ) . Interventions : After a successful weaning trial , the patients were r and omized to receive NIV for ≥8 hrs a day in the first 48 hrs or SMT . Primary outcome was the need for reintubation according to st and ardized criteria . Secondary outcomes were intensive care unit and hospital mortality , as well as time spent in the intensive care unit and in hospital . Measurements and Main Results : Compared with the SMT group , the NIV group had a lower rate of reintubation ( four of 48 vs. 12 of 49 ; p = .027 ) . The need for reintubation was associated with a higher risk of mortality ( p < .01 ) . The use of NIV result ed in a reduction of risk of intensive care unit mortality ( −10 % , p < .01 ) , mediated by the reduction for the need of reintubation . Conclusions : NIV was more effective than SMT in preventing postextubation respiratory failure in a population considered at risk of developing this complication [25980660] IMPORTANCE Noninvasive ventilation delivered as bilevel positive airway pressure ( BiPAP ) is often used to avoid reintubation and improve outcomes of patients with hypoxemia after cardiothoracic surgery . High-flow nasal oxygen therapy is increasingly used to improve oxygenation because of its ease of implementation , tolerance , and clinical effectiveness . OBJECTIVE To determine whether high-flow nasal oxygen therapy was not inferior to BiPAP for preventing or resolving acute respiratory failure after cardiothoracic surgery . DESIGN AND SETTING Multicenter , r and omized , noninferiority trial ( BiPOP Study ) conducted between June 15 , 2011 , and January 15 , 2014 , at 6 French intensive care units . PARTICIPANTS A total of 830 patients who had undergone cardiothoracic surgery , of which coronary artery bypass , valvular repair , and pulmonary thromboendarterectomy were the most common , were included when they developed acute respiratory failure ( failure of a spontaneous breathing trial or successful breathing trial but failed extubation ) or were deemed at risk for respiratory failure after extubation due to preexisting risk factors . INTERVENTIONS Patients were r and omly assigned to receive high-flow nasal oxygen therapy delivered continuously through a nasal cannula ( flow , 50 L/min ; fraction of inspired oxygen [ FiO2 ] , 50 % ) ( n = 414 ) or BiPAP delivered with a full-face mask for at least 4 hours per day ( pressure support level , 8 cm H2O ; positive end-expiratory pressure , 4 cm H2O ; FiO2 , 50 % ) ( n = 416 ) . MAIN OUTCOMES AND MEASURES The primary outcome was treatment failure , defined as reintubation , switch to the other study treatment , or premature treatment discontinuation ( patient request or adverse effects , including gastric distention ) . Noninferiority of high-flow nasal oxygen therapy would be demonstrated if the lower boundary of the 95 % CI were less than 9 % . Secondary outcomes included mortality during intensive care unit stay , changes in respiratory variables , and respiratory complications . RESULTS High-flow nasal oxygen therapy was not inferior to BiPAP : the treatment failed in 87 of 414 patients with high-flow nasal oxygen therapy ( 21.0 % ) and 91 of 416 patients with BiPAP ( 21.9 % ) ( absolute difference , 0.9 % ; 95 % CI , -4.9 % to 6.6 % ; P = .003 ) . No significant differences were found for intensive care unit mortality ( 23 patients with BiPAP [ 5.5 % ] and 28 with high-flow nasal oxygen therapy [ 6.8 % ] ; P = .66 ) ( absolute difference , 1.2 % [ 95 % CI , -2.3 % to 4.8 % ] . Skin breakdown was significantly more common with BiPAP after 24 hours ( 10 % vs 3 % ; 95 % CI , 7.3%-13.4 % vs 1.8%-5.6 % ; P < .001 ) . CONCLUSIONS AND RELEVANCE Among cardiothoracic surgery patients with or at risk for respiratory failure , the use of high-flow nasal oxygen therapy compared with intermittent BiPAP did not result in a worse rate of treatment failure . The findings support the use of high-flow nasal oxygen therapy in similar patients . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01458444 [3362832] During bronchoscopy hypoxemia is commonly found and oxygen supply can be delivered by interfaces fed with high gas flows . Recently , the high-flow nasal cannula ( HFNC ) has been introduced for oxygen therapy in adults , but they have not been used so far during bronchoscopy in adults . Forty-five patients were r and omly assigned to 3 groups receiving oxygen : 40 L/min through a Venturi mask ( V40 , N = 15 ) , nasal cannula ( N40 , N = 15 ) , and 60 L/min through a nasal cannula ( N60 , N = 15 ) during bronchoscopy . Gas exchange and circulatory variables were sample d before ( FiO2 = 0.21 ) , at the end of bronchoscopy ( FiO2 = 0.5 ) , and thereafter ( V40 , FiO2 = 0.35 ) . In 8 healthy volunteers oxygen was r and omly delivered according to V40 , N40 , and N60 setting s , and airway pressure was measured . At the end of bronchoscopy , N60 presented higher PaO2 , PaO2/FiO2 , and SpO2 than V40 and N40 that did not differ between them . In the volunteers ( N60 ) median airway pressure amounted to 3.6 cmH2O . Under a flow rate of 40 L/min both the Venturi mask and HFNC behaved similarly , but nasal cannula associated with a 60 L/min flow produced the better results , thus indicating its use in mild respiratory dysfunctions [4126617] Background Aim of the study was to compare the short-term effects of oxygen therapy via a high-flow nasal cannula ( HFNC ) on functional and subjective respiratory parameters in patients with acute hypoxic respiratory failure in comparison to non-invasive ventilation ( NIV ) and st and ard treatment via a Venturi mask . Methods Fourteen patients with acute hypoxic respiratory failure were treated with HFNC ( FiO2 0.6 , gas flow 55 l/min ) , NIV ( FiO2 0.6 , PEEP 5 cm H2O Hg , tidal volume 6–8 ml/kg ideal body weight , ) and Venturi mask ( FiO2 0.6 , oxygen flow 15 l/min , ) in a r and omized order for 30 min each . Data collection included objective respiratory and circulatory parameters as well as a subjective rating of dyspnea and discomfort by the patients on a 10-point scale . In a final interview , all three methods were comparatively evaluated by each patient using a scale from 1 ( = very good ) to 6 ( = failed ) and the patients were asked to choose one method for further treatment . Results PaO2 was highest under NIV ( 129 ± 38 mmHg ) compared to HFNC ( 101 ± 34 mmHg , p < 0.01 vs. NIV ) and VM ( 85 ± 21 mmHg , p < 0.001 vs. NIV , p < 0.01 vs. HFNC , ANOVA ) . All other functional parameters showed no relevant differences . In contrast , dyspnea was significantly better using a HFNC ( 2.9 ± 2.1 , 10-point Borg scale ) compared to NIV ( 5.0 ± 3.3 , p < 0.05 ) , whereas dyspnea rating under HFNC and VM ( 3.3 ± 2.3 ) was not significantly different . A similar pattern was found when patients rated their overall discomfort on the 10 point scale : HFNC 2.7 ± 1.8 , VM 3.1 ± 2.8 ( ns vs. HFNC ) , NIV 5.4 ± 3.1 ( p < 0.05 vs. HFNC ) . In the final evaluation patients gave the best ratings to HFNC 2.3 ± 1.4 , followed by VM 3.2 ± 1.7 ( ns vs. HFNC ) and NIV 4.5 ± 1.7 ( p < 0.01 vs. HFNC and p < 0.05 vs. VM ) . For further treatment 10 patients chose HFNC , three VM and one NIV . Conclusions In hypoxic respiratory failure HFNC offers a good balance between oxygenation and comfort compared to NIV and Venturi mask and seems to be well tolerated by patients .Trial registration German clinical trials register : DRKS00005132 [4629403] Introduction In immunocompromised patients , acute respiratory failure ( ARF ) is associated with high mortality , particularly when invasive mechanical ventilation ( IMV ) is required . In patients with severe hypoxemia , high-flow nasal oxygen ( HFNO ) therapy has been used as an alternative to delivery of oxygen via a Venturi mask . Our objective in the present study was to compare HFNO and Venturi mask oxygen in immunocompromised patients with ARF . Methods We conducted a multicenter , parallel-group r and omized controlled trial in four intensive care units . Inclusion criteria were hypoxemic ARF and immunosuppression , defined as at least one of the following : solid or hematological malignancy , steroid or other immunosuppressant drug therapy , and HIV infection . Exclusion criteria were hypercapnia , previous IMV , and immediate need for IMV or noninvasive ventilation ( NIV ) . Patients were r and omized to 2 h of HFNO or Venturi mask oxygen . Results The primary endpoint was a need for IMV or NIV during the 2-h oxygen therapy period . Secondary endpoints were comfort , dyspnea , and thirst , as assessed hourly using a 0–10 visual analogue scale . We r and omized 100 consecutive patients , including 84 with malignancies , to HFNO ( n = 52 ) or Venturi mask oxygen ( n = 48 ) . During the 2-h study treatment period , 12 patients required IMV or NIV , and we found no significant difference between the two groups ( 15 % with HFNO and 8 % with the Venturi mask , P = 0.36 ) . None of the secondary endpoints differed significantly between the two groups . Conclusions In immunocompromised patients with hypoxemic ARF , a 2-h trial with HFNO improved neither mechanical ventilatory assistance nor patient comfort compared with oxygen delivered via a Venturi mask . However , the study was underpowered because of the low event rate and the one-sided hypothesis . Trial registration Clinical Trials.gov identifier : NCT02424773 . Registered 20 April 2015 [23921199] BACKGROUND Respiratory complications after cardiac surgery increase morbidity , mortality , and length of stay . Studies suggest that routine delivery of positive airway pressure after extubation may be beneficial . We sought to determine whether the routine administration of nasal high-flow oxygen therapy ( NHF ) improves pulmonary function after cardiac surgery . METHODS A pragmatic r and omized controlled trial ; participants received either NHF ( 45 litre min(-1 ) ) or usual care from extubation to Day 2 after surgery . The primary outcome was number of patients with / ratio ≥445 on Day 3 after surgery . The secondary outcomes included atelectasis score on chest X-ray ; spirometry ; intensive care and hospital length of stay ; mortality on Day 28 ; oxygenation indices ; escalation of respiratory support ; and patient comfort . RESULTS We r and omized 340 patients over 14 months . The number of patients with a / ratio of ≥445 on Day 3 was 78 ( 46.4 % ) in the NHF group vs 72 ( 42.4 % ) st and ard care [ odds ratio ( OR ) 1.18 , 95 % confidence interval ( CI ) 0.77 - 1.81 , P=0.45 ] . was reduced at both 4 h post-extubation and at 9 a.m. on Day 1 in the NHF group ( 5.3 vs 5.4 kPa , P=0.03 and 5.1 vs 5.3 kPa , P=0.03 , respectively ) . Escalation in respiratory support at any time in the study occurred in 47 patients ( 27.8 % ) allocated to NHF compared with 77 ( 45 % ) st and ard care ( OR 0.47 , 95 % CI 0.29 - 0.7 , P=0.001 ) . CONCLUSIONS Routine use of NHF did not increase / ratio on Day 3 but did reduce the requirement for escalation of respiratory support . TRIAL REGISTRATION Australia New Zeal and Clinical Trials Registry www.anzctr.org.au ( ACTRN12610000973011 ) [25390281] BACKGROUND : Effective O2 delivery and accurate end-tidal CO2 ( ETCO2 ) sampling are essential features of nasal cannulae ( NCs ) in patients with compromised respiratory status . We studied 4 NC design s : bifurcated nasal prongs ( NPs ) with O2 delivery and CO2 sensing in both NPs ( Hudson ) , separate O2/CO2 NPs ( Salter ) , and CO2 sensing in NPs with cloud O2 delivery outside the NPs via multi vents ( Oridion ) and dual vents ( Medline ) . We hypothesized that design differences between NCs would influence O2 delivery and ETCO2 detection . METHODS : Forty-five healthy volunteers , 18 to 35 years , participated in an unrestricted , r and omized block design , each subject serving as their own control in a 4-period crossover study design of 4 NCs during one session . Monitoring included electrocardiogram , posterior pharynx O2 sampling from a Hauge Airway ( Sharn Anesthesia Products , Tampa , FL ) , and NC ETCO2 . In 11 volunteers , radial artery blood was sample d from a catheter for partial pressures of O2 and carbon dioxide ( PaO2 and PaCO2 ) determination . Per r and omization , each NC was positioned , and data were collected over 2 minutes ( ETCO2 , pharyngeal O2 , PaO2 , and PaCO2 ) during room air and during O2 fresh gas flows ( FGFs ) of 2 , 4 , and 6 Lpm . Statistical analyses were performed with SAS Analytics Pro , Version 9.3 , and JMP Statistical Software , Version 11 ( SAS Institute Inc. , Cary , NC ) , significance at P < 0.05 . RESULTS : Blood gas analyses indicated PaCO2 during steady state at each experimental time period remained unchanged from physiologic baseline . PaO2 did not differ between NC devices at baseline or 2 Lpm O2 . The PaO2 at 4 Lpm from the separate NPs and bifurcated NCs was significantly higher than the multi-vented NC . Pharyngeal O2 with the NC with separate NPs was significantly higher than multivented and dual-vented cloud delivery NCs at 2 , 4 , and 6 Lpm FGF . Pharyngeal O2 with the NC with bifurcated NPs was significantly higher than the multi-vented NC at 2 Lpm , and higher than cloud delivery NCs at 4 and 6 Lpm FGF . ETCO2 was significantly lower with the NC with bifurcated NPs compared to the other 3 NCs , consistent with errant CO2 tracings at higher FGF . CONCLUSIONS : NCs provide supplemental inspired O2 concentrations for patients with impaired pulmonary function . Accurate measures of ETCO2 are helpful in assessing respiratory rate and determining whether CO2 retention is occurring from hypoventilation . These findings suggest the NC with separate NPs was the most effective in delivering O2 and the most consistent at providing reliable CO2 waveforms at higher FGFs [26577199] BACKGROUND : Humidified high-flow nasal cannula ( HFNC ) is a novel method of oxygen delivery with increasing use in emergency departments and intensive care setting s despite little evidence showing benefit over st and ard oxygen delivery methods ( st and ard O2 ) . The aim of this study was to determine whether HFNC compared with st and ard O2 given to subjects in acute respiratory distress would reduce the need for noninvasive ventilation or invasive ventilation . METHODS : This was a pragmatic open r and omized controlled trial in adult subjects with hypoxia and tachypnea presenting to a tertiary academic hospital emergency department . The primary outcome was the need for mechanical ventilation in the emergency department . RESULTS : We screened 1,287 patients , 322 met entry criteria and 19 were excluded from analysis . Of these , 165 r and omized to HFNC and 138 to st and ard O2 were analyzed . Baseline characteristics were similar . In the HFNC group , 3.6 % ( 95 % CI 1.5–7.9 % ) versus 7.2 % ( 95 % CI 3.8–13 % ) in the st and ard O2 group required mechanical ventilation in the emergency department ( P = .16 ) , and 5.5 % ( 95 % CI 2.8–10.2 % ) in HFNC versus 11.6 % ( 95 % CI 7.2–18.1 % ) in the st and ard O2 group required mechanical ventilation within 24 h of admission ( P = .053 ) . There was no difference in mortality or stay . Adverse effects were infrequent ; however , fewer subjects in the HFNC group had a fall in Glasgow coma score due to CO2 retention , 0 % ( 95 % CI 0–3 % ) versus 2.2 % ( 95 % CI 0.4–6 % ) . One in 12 subjects did not tolerate HFNC . CONCLUSIONS : HFNC was not shown to reduce the need for mechanical ventilation in the emergency department for subjects with acute respiratory distress compared with st and ard O2 , although it was safe and may reduce the need for escalation of oxygen therapy within the first 24 h of admission [25691263] Purpose Intubation in patients with respiratory failure can be avoided by high-flow nasal cannula ( HFNC ) use . However , it is unclear whether waiting until HFNC fails , which would delay intubation , has adverse effects . The present retrospective observational study assessed overall ICU mortality and other hospital outcomes of patients who received HFNC therapy that failed . Methods All consecutive patients in one tertiary hospital who received HFNC therapy that failed and who then required intubation between January 2013 and March 2014 were enrolled and classified according to whether intubation started early ( within 48 h ) or late ( at least 48 h ) after commencing HFNC . Results Of the 175 enrolled patients , 130 ( 74.3 % ) and 45 ( 25.7 % ) were intubated before and after 48 h of HFNC , respectively . The groups were similar in terms of most baseline characteristics . The early intubated patients had better overall ICU mortality ( 39.2 vs. 66.7 % ; P = 0.001 ) than late intubated patients . A similar pattern was seen with extubation success ( 37.7 vs. 15.6 % ; P = 0.006 ) , ventilator weaning ( 55.4 vs. 28.9 % ; P = 0.002 ) , and ventilator-free days ( 8.6 ± 10.1 vs. 3.6 ± 7.5 ; P = 0.011 ) . In propensity-adjusted and -matched analysis , early intubation was also associated with better overall ICU mortality [ adjusted odds ratio ( OR ) = 0.317 , P = 0.005 ; matched OR = 0.369 , P = 0.046 ] . Conclusions Failure of HFNC might cause delayed intubation and worse clinical outcomes in patients with respiratory failure . Large prospect i ve and r and omized controlled studies on HFNC failure are needed to draw a definitive conclusion [23739633] CONTEXT Dyspnea is one of the most distressing symptoms for cancer patients . The role of high-flow oxygen ( HFO ) and bilevel positive airway pressure ( BiPAP ) in the palliation of dyspnea has not been well characterized . OBJECTIVES To determine the feasibility of conducting a r and omized trial of HFO and BiPAP in cancer patients and examine the changes in dyspnea , physiologic parameters , and adverse effects with these modalities . METHODS In this r and omized study ( Clinical Trials.gov Identifier : NCT01518140 ) , we assigned hospitalized patients with advanced cancer and persistent dyspnea to either HFO or BiPAP for two hours . We assessed dyspnea with a numeric rating scale ( NRS ) and modified Borg scale ( MBS ) before and after the intervention . We also documented vital signs , transcutaneous carbon dioxide , and adverse effects . RESULTS Thirty patients were enrolled ( 1:1 ratio ) and 23 ( 77 % ) completed the assigned intervention . HFO was associated with improvements in both NRS ( mean 1.9 ; 95 % CI 0.4 - 3.4 ; P = 0.02 ) and MBS ( mean 2.1 ; 95 % CI 0.6 - 3.5 ; P = 0.007 ) . BiPAP also was associated with improvements in NRS ( mean 3.2 ; 95 % CI 1.3 - 5.1 ; P = 0.004 ) and MBS ( mean 1.5 ; 95 % CI -0.3 , 3.2 ; P = 0.13 ) . There were no significant differences between HFO and BiPAP in dyspnea NRS ( P = 0.14 ) and MBS ( P = 0.47 ) . Oxygen saturation improved with HFO ( 93 % vs. 99 % ; P = 0.003 ) , and respiratory rate had a nonstatistically significant decrease with both interventions ( HFO -3 , P = 0.11 ; BiPAP -2 , P = 0.11 ) . No significant adverse effects were observed . CONCLUSION HFO and BiPAP alleviated dyspnea , improved physiologic parameters , and were safe . Our results justify larger r and omized controlled trials to confirm these findings [21946925] Purpose To evaluate the efficiency , safety and outcome of high flow nasal cannula oxygen ( HFNC ) in ICU patients with acute respiratory failure . Methods Pilot prospect i ve monocentric study . Thirty-eight patients were included . Baseline demographic and clinical data , as well as respiratory variables at baseline and various times after HFNC initiation during 48 h , were recorded . Arterial blood gases were measured before and after the use of HFNC . Noise and discomfort were monitored along with outcome and need for invasive mechanical ventilation . Results HFNC significantly reduced the respiratory rate , heart rate , dyspnea score , supraclavicular retraction and thoracoabdominal asynchrony , and increased pulse oxymetry . These improvements were observed as early as 15 min after the beginning of HFNC for respiratory rate and pulse oxymetry . PaO2 and PaO2/FiO2 increased significantly after 1 h HFNC in comparison with baseline ( 141 ± 106 vs. 95 ± 40 mmHg , p = 0.009 and 169 ± 108 vs. 102 ± 23 , p = 0.036 ; respectively ) . These improvements lasted throughout the study period . HFNC was used for a mean duration of 2.8 days and a maximum of 7 days . It was never interrupted for intolerance . No nosocomial pneumonia occurred during HFNC . Nine patients required secondary invasive mechanical ventilation . Absence of a significant decrease in the respiratory rate , lower oxygenation and persistence of thoracoabdominal asynchrony after HFNC initiation were early indicators of HFNC failure . Conclusions HFNC has a beneficial effect on clinical signs and oxygenation in ICU patients with acute respiratory failure . These favorable results constitute a prerequisite to launching a r and omized controlled study to investigate whether HFNC reduces intubation in these patients [26060321] BACKGROUND : Acute dyspnea and hypoxemia are 2 of the most common problems in the emergency room . Oxygen therapy is an essential supportive treatment to correct these issues . In this study , we investigated the physiologic effects of high-flow nasal oxygen cannula ( HFNC ) compared with conventional oxygen therapy ( COT ) in subjects with acute dyspnea and hypoxemia in the emergency room . METHODS : A prospect i ve r and omized comparative study was conducted in the emergency department of a university hospital . Forty subjects were r and omized to receive HFNC or COT for 1 h. The primary outcome was level of dyspnea , and secondary outcomes included change in breathing frequency , subject comfort , adverse events , and rate of hospitalization . RESULTS : Common causes of acute dyspnea and hypoxemia were congestive heart failure , asthma exacerbation , COPD exacerbation , and pneumonia . HFNC significantly improved dyspnea ( 2.0 ± 1.8 vs 3.8 ± 2.3 , P = .01 ) and subject comfort ( 1.6 ± 1.7 vs 3.7 ± 2.4 , P = .01 ) compared with COT . No statistically significant difference in breathing frequency was found between the 2 groups at the end of the study . HFNC was well tolerated , and no serious adverse events were found . The rate of hospitalization in the HFNC group was lower than in the COT group , but there was no statistically significant difference ( 50 % vs 65 % , P = .34 ) . CONCLUSIONS : HFNC improved dyspnea and comfort in subjects presenting with acute dyspnea and hypoxemia in the emergency department . HFNC may benefit patients requiring oxygen therapy in the emergency room [22417569] BACKGROUND : Non-intubated critically ill patients are often treated by high-flow oxygen for acute respiratory failure . There is no current recommendation for humidification of oxygen devices . METHODS : We conducted a prospect i ve r and omized trial with a final crossover period to compare nasal airway caliber and respiratory comfort in patients with acute hypoxemic respiratory failure receiving either st and ard oxygen therapy with no humidification or heated and humidified high-flow oxygen therapy ( HHFO2 ) in a medical ICU . Nasal airway caliber was measured using acoustic rhinometry at baseline , after 4 and 24 hours ( H4 and H24 ) , and 4 hours after crossover ( H28 ) . Dryness of the nose , mouth , and throat was auto-evaluated and assessed blindly by an otorhinolaryngologist . After the crossover , the subjects were asked which system they preferred . RESULTS : Thirty subjects completed the protocol and were analyzed . Baseline median oxygen flow was 9 and 12 L/min in the st and ard and HHFO2 groups , respectively ( P = .21 ) . Acoustic rhinometry measurements showed no difference between the 2 systems . The dryness score was significantly lower in the HHFO2 group at H4 ( 2 vs 6 , P = .007 ) and H24 ( 0 vs 8 , P = .004 ) . During the crossover period , dryness increased promptly after switching to st and ard oxygen and decreased after switching to HHFO2 ( P = .008 ) . Sixteen subjects ( 53 % ) preferred HHFO2 ( P = .01 ) , especially those who required the highest flow of oxygen at admission ( P = .05 ) . CONCLUSIONS : Upper airway caliber was not significantly modified by HHFO2 , compared to st and ard oxygen therapy , but HHFO2 significantly reduced discomfort in critically ill patients with respiratory failure . The system is usually preferred over st and ard oxygen therapy [21762554] BACKGROUND : The effectiveness of noninvasive ventilation ( NIV ) after extubation in preventing post-extubation respiratory failure is still controversial . METHODS : We conducted a prospect i ve , multicenter r and omized controlled study involving patients on mechanical ventilation for > 48 hours who tolerated a 2-hour spontaneous breathing trial and were subsequently extubated . The patients were r and omized to NIV or st and ard medical therapy . Re-intubation rate within 72 hours was the primary outcome measure . Multivariable logistic regression analysis was used to determine predictors for extubation failure . RESULTS : We r and omized 406 patients to either NIV ( no. = 202 ) or st and ard medical therapy ( no. = 204 ) . The 2 groups had similar baseline clinical characteristics . There were no differences in extubation failure ( 13.2 % in control and 14.9 % in NIV ) , intensive care unit or hospital mortality . Cardiac failure was a more common cause of extubation failure in control than in NIV . There was no difference in rapid shallow breathing index ( RSBI ) in extubation failure patients between control ( 80 ) and NIV ( 73 ) . When using data from all patients , we found Acute Physiology and Chronic Health Evaluation ( APACHE II ) scores ( odds ratio [ OR ] 1.13 , 95 % CI 1.07–1.20 , P < .001 ) , maximal inspiratory pressure ( OR 1.04 , 95 % CI 1.00–1.08 , P = .03 ) , and RSBI ( OR 1.03 , 95 % CI 1.02–1.05 , P < .001 ) to be predictors of extubation failure . Abundant secretions were the most common reason ( 35.1 % ) for extubation failure identified by attending physicians . CONCLUSIONS : Preventive use of NIV after extubation in patients who passed spontaneous breathing trial did not show benefits in decreasing extubation failure rate or the mortality rate [28124736] Purpose Nasal continuous positive airway pressure ( nCPAP ) is currently the gold st and ard for respiratory support for moderate to severe acute viral bronchiolitis ( AVB ) . Although oxygen delivery via high flow nasal cannula ( HFNC ) is increasingly used , evidence of its efficacy and safety is lacking in infants . Methods A r and omized controlled trial was performed in five pediatric intensive care units ( PICUs ) to compare 7 cmH2O nCPAP with 2 L/kg/min oxygen therapy administered with HFNC in infants up to 6 months old with moderate to severe AVB . The primary endpoint was the percentage of failure within 24 h of r and omization using prespecified criteria . To satisfy noninferiority , the failure rate of HFNC had to lie within 15 % of the failure rate of nCPAP . Secondary outcomes included success rate after crossover , intubation rate , length of stay , and serious adverse events . Results From November 2014 to March 2015 , 142 infants were included and equally distributed into groups . The risk difference of −19 % ( 95 % CI −35 to −3 % ) did not allow the conclusion of HFNC noninferiority ( p = 0.707 ) . Superiority analysis suggested a relative risk of success 1.63 ( 95 % CI 1.02–2.63 ) higher with nCPAP . The success rate with the alternative respiratory support , intubation rate , duration s of noninvasive and invasive ventilation , skin lesions , and length of PICU stay were comparable between groups . No patient had air leak syndrome or died . Conclusion In young infants with moderate to severe AVB , initial management with HFNC did not have a failure rate similar to that of nCPAP . This clinical trial was recorded in the National Library of Medicine registry ( NCT 02457013 ) [24046462] OBJECTIVE : Compare the short-term benefit of high-flow nasal cannula ( HFNC ) with non-rebreathing mask in terms of change in dyspnea , physiologic variables , and patient comfort in subjects after endotracheal extubation . METHODS : A r and omized crossover study was conducted in a 10-bed respiratory care unit in a university hospital . Seventeen mechanically ventilated subjects were r and omized after extubation to either Protocol A ( applied HFNC for 30 min , followed by non-rebreathing mask for another 30 min ) or Protocol B ( applied non-rebreathing mask for 30 min , followed by HFNC for another 30 min ) . The level of dyspnea , breathing frequency , heart rate , blood pressure , oxygen saturation , and patient comfort were recorded . The results were expressed as mean ± SD , frequency , or percentage . Categorical variables were compared by chi-square test or Fisher exact test , and continuous variables were compared by dependent or paired t test . Statistical significance was defined as P < .05 . RESULTS : Seventeen subjects were divided into 2 groups : 9 subjects in Protocol A and 8 subjects in Protocol B. The baseline characteristics and physiologic parameters before extubation were not significantly different in each protocol . At the end of study , HFNC indicated less dyspnea ( P = .04 ) and lower breathing frequency ( P = .009 ) and heart rate ( P = .006 ) compared with non-rebreathing mask . Most of the subjects ( 88.2 % ) preferred HFNC to non-rebreathing mask . CONCLUSIONS : HFNC can improve dyspnea and physiologic parameters , including breathing frequency and heart rate , in extubated subjects compared with conventional oxygen therapy . This device may have a potential role for use after endotracheal extubation [25003980] RATIONALE Oxygen is commonly administered after extubation . Although several devices are available , data about their clinical efficacy are scarce . OBJECTIVES To compare the effects of the Venturi mask and the nasal high-flow ( NHF ) therapy on PaO2/FiO2SET ratio after extubation . Secondary endpoints were to assess effects on patient discomfort , adverse events , and clinical outcomes . METHODS R and omized , controlled , open-label trial on 105 patients with a PaO2/FiO2 ratio less than or equal to 300 immediately before extubation . The Venturi mask ( n = 52 ) or NHF ( n = 53 ) were applied for 48 hours postextubation . MEASUREMENTS AND MAIN RESULTS PaO2/FiO2SET , patient discomfort caused by the interface and by symptoms of airways dryness ( on a 10-point numerical rating scale ) , interface displacements , oxygen desaturations , need for ventilator support , and reintubation were assessed up to 48 hours after extubation . From the 24th hour , PaO2/FiO2SET was higher with the NHF ( 287 ± 74 vs. 247 ± 81 at 24 h ; P = 0.03 ) . Discomfort related both to the interface and to airways dryness was better with NHF ( respectively , 2.6 ± 2.2 vs. 5.1 ± 3.3 at 24 h , P = 0.006 ; 2.2 ± 1.8 vs. 3.7 ± 2.4 at 24 h , P = 0.002 ) . Fewer patients had interface displacements ( 32 % vs. 56 % ; P = 0.01 ) , oxygen desaturations ( 40 % vs. 75 % ; P < 0.001 ) , required reintubation ( 4 % vs. 21 % ; P = 0.01 ) , or any form of ventilator support ( 7 % vs. 35 % ; P < 0.001 ) in the NHF group . CONCLUSIONS Compared with the Venturi mask , NHF results in better oxygenation for the same set FiO2 after extubation . Use of NHF is associated with better comfort , fewer desaturations and interface displacements , and a lower reintubation rate . Clinical trial registered with www . clinical trials.gov ( NCT 01575353 ) [25479117] Objectives : Tracheal intubation of ICU patients is frequently associated with severe hypoxemia . Although noninvasive ventilation reduces desaturation during intubation of severely hypoxemic patients , it does not allow for per-procedure oxygenation and has not been evaluated in mild-to-moderate hypoxemic patients for whom high-flow nasal cannula oxygen may be an alternative . We sought to compare pre- and per-procedure oxygenation with either a nonrebreathing bag reservoir facemask or a high-flow nasal cannula oxygen during tracheal intubation of ICU patients . Design : Prospect i ve quasi-experimental before-after study ( Clinical Trials.gov : NCT01699880 ) . Setting : University hospital medico-surgical ICU . Patients : All adult patients requiring tracheal intubation in the ICU were eligible . Interventions : In the control ( before ) period , preoxygenation was performed with a nonrebreathing bag reservoir facemask and in the change of practice ( after ) period , with high-flow nasal cannula oxygen . Measurements and Main Results : Primary outcome was median lowest SpO2 during intubation , and secondary outcomes were SpO2 after preoxygenation and number of patients with saturation less than 80 % . One hundred one patients were included . Median lowest SpO2 during intubation were 94 % ( 83–98.5 ) with the nonrebreathing bag reservoir facemask versus 100 % ( 95–100 ) with high-flow nasal cannula oxygen ( p < 0.0001 ) . SpO2 values at the end of preoxygenation were higher with high-flow nasal cannula oxygen than with nonrebreathing bag reservoir facemask and were correlated with the lowest SpO2 reached during the intubation procedure ( r = 0.38 , p < 0.0001 ) . Patients in the nonrebreathing bag reservoir facemask group experienced more episodes of severe hypoxemia ( 2 % vs 14 % , p = 0.03 ) . In the multivariate analysis , preoxygenation with high-flow nasal cannula oxygen was an independent protective factor of the occurrence of severe hypoxemia ( odds ratio , 0.146 ; 95 % CI , 0.01–0.90 ; p = 0.037 ) . Conclusions : High-flow nasal cannula oxygen significantly improved preoxygenation and reduced prevalence of severe hypoxemia compared with nonrebreathing bag reservoir facemask . Its use could improve patient safety during intubation [27481760] PURPOSE The purpose of the study is to describe early predictors and to develop a prediction tool that accurately identifies the need for mechanical ventilation ( MV ) in pneumonia patients with hypoxemic acute respiratory failure ( ARF ) treated with high-flow nasal cannula ( HFNC ) . MATERIAL S AND METHODS This is a 4-year prospect i ve observational 2-center cohort study including patients with severe pneumonia treated with HFNC . High-flow nasal cannula failure was defined as need for MV . ROX index was defined as the ratio of pulse oximetry/fraction of inspired oxygen to respiratory rate . RESULTS One hundred fifty-seven patients were included , of whom 44 ( 28.0 % ) eventually required MV ( HFNC failure ) . After 12 hours of HFNC treatment , the ROX index demonstrated the best prediction accuracy ( area under the receiver operating characteristic curve 0.74 [ 95 % confidence interval , 0.64 - 0.84 ] ; P<.002 ) . The best cutoff point for the ROX index was estimated to be 4.88 . In the Cox proportional hazards model , a ROX index greater than or equal to 4.88 measured after 12 hours of HFNC was significantly associated with a lower risk for MV ( hazard ratio , 0.273 [ 95 % confidence interval , 0.121 - 0.618 ] ; P=.002 ) , even after adjusting for potential confounding . CONCLUSIONS In patients with ARF and pneumonia , the ROX index can identify patients at low risk for HFNC failure in whom therapy can be continued after 12 hours [22165366] In this study , we evaluated the performance of a humidified nasal high-flow system ( Optiflow ™ , Fisher and Paykel Healthcare ) by measuring delivered FiO2 and airway pressures . Oxygraphy , capnography and measurement of airway pressures were performed through a hypopharyngeal catheter in healthy volunteers receiving Optiflow ™ humidified nasal high flow therapy at rest and with exercise . The study was conducted in a non- clinical experimental setting . Ten healthy volunteers completed the study after giving informed written consent . Participants received a delivered oxygen fraction of 0.60 with gas flow rates of 10 , 20 , 30 , 40 and 50 l/minute in r and om order . FiO2 , FEO2 , FECO2 and airway pressures were measured . Calculation of FiO2 from FEO2 and FECO2 was later performed . Calculated FiO2 approached 0.60 as gas flow rates increased above 30 l/minute during nose breathing at rest . High peak inspiratory flow rates with exercise were associated with increased air entrainment . Hypopharyngeal pressure increased with increasing delivered gas flow rate . At 50 l/minute the system delivered a mean airway pressure of up to 7.1 cmH2O . We believe that the high gas flow rates delivered by this system enable an accurate inspired oxygen fraction to be delivered . The positive mean airway pressure created by the high flow increases the efficacy of this system and may serve as a bridge to formal positive pressure systems [25851385] Purpose Patients with a body mass index ( BMI ) ≥30 kg/m2 experience more severe atelectasis following cardiac surgery than those with normal BMI and its resolution is slower . This study aim ed to compare extubation of patients post-cardiac surgery with a BMI ≥30 kg/m2 onto high-flow nasal cannulae ( HFNC ) with st and ard care to determine whether HFNC could assist in minimising post-operative atelectasis and improve respiratory function . Methods In this r and omised controlled trial , patients received HFNC or st and ard oxygen therapy post-extubation . The primary outcome was atelectasis on chest X-ray . Secondary outcomes included oxygenation , respiratory rate ( RR ) , subjective dyspnoea , and failure of allocated treatment . Results One hundred and fifty-five patients were r and omised , 74 to control , 81 to HFNC . No difference was seen between groups in atelectasis scores on Days 1 or 5 ( median scores = 2 , p = 0.70 and p = 0.15 , respectively ) . In the 24-h post-extubation , there was no difference in mean PaO2/FiO2 ratio ( HFNC 227.9 , control 253.3 , p = 0.08 ) , or RR ( HFNC 17.2 , control 16.7 , p = 0.17 ) . However , low dyspnoea levels were observed in each group at 8 h post-extubation , median ( IQR ) scores were 0 ( 0–1 ) for control and 1 ( 0–3 ) for HFNC ( p = 0.008 ) . Five patients failed allocated treatment in the control group compared with three in the treatment group [ Odds ratio 0.53 , ( 95 % CI 0.11 , 2.24 ) , p = 0.40 ] . Conclusions In this study , prophylactic extubation onto HFNC post-cardiac surgery in patients with a BMI ≥30 kg/m2 did not lead to improvements in respiratory function . Larger studies assessing the role of HFNC in preventing worsening of respiratory function and intubation are required [25944940] INTRODUCTION : High-flow nasal cannula ( HFNC ) can deliver heated and humidified gas ( up to 100 % oxygen ) at a maximum flow of 60 L/min via nasal prongs or cannula . The aim of this study was to assess the short-term physiologic effects of HFNC . Inspiratory muscle effort , gas exchange , dyspnea score , and comfort were evaluated . METHODS : Twelve subjects admitted to the ICU for acute hypoxemic respiratory failure were prospect ively included . Four study sessions were performed . The first session consisted of oxygen therapy given through a high-FIO2 , non-rebreathing face mask . Recordings were then obtained during periods of HFNC and CPAP at 5 cm H2O in r and om order , and final measurements were performed during oxygen therapy delivered via a face mask . Each of these 4 periods lasted ∼20 min . RESULTS : Esophageal pressure signals , breathing pattern , gas exchange , comfort , and dyspnea were measured . Compared with the first session , HFNC reduced inspiratory effort ( pressure-time product of 156.0 [ 119.2–194.4 ] cm H2O × s/min vs 204.2 [ 149.6–324.7 ] cm H2O × s/min , P < .01 ) and breathing frequency ( P < .01 ) . No significant differences were observed between HFNC and CPAP for inspiratory effort and breathing frequency . Compared with the first session , PaO2/FIO2 increased significantly with HFNC ( 167 [ 157–184 ] mm Hg vs 156 [ 110–171 ] mm Hg , P < .01 ) . CPAP produced significantly greater PaO2/FIO2 improvement than did HFNC . Dyspnea improved with HFNC and CPAP , but this improvement was not significant . Subject comfort was not different across the 4 sessions . CONCLUSIONS : Compared with conventional oxygen therapy , HFNC improved inspiratory effort and oxygenation . In subjects with acute hypoxemic respiratory failure , HFNC is an alternative to conventional oxygen therapy . ( Clinical Trials.gov registration NCT01056952 . [26975498] IMPORTANCE Studies of mechanically ventilated critically ill patients that combine population s that are at high and low risk for reintubation suggest that conditioned high-flow nasal cannula oxygen therapy after extubation improves oxygenation compared with conventional oxygen therapy . However , conclusive data about reintubation are lacking . OBJECTIVE To determine whether high-flow nasal cannula oxygen therapy is superior to conventional oxygen therapy for preventing reintubation in mechanically ventilated patients at low risk for reintubation . DESIGN , SETTING , AND PARTICIPANTS Multicenter r and omized clinical trial conducted between September 2012 and October 2014 in 7 intensive care units ( ICUs ) in Spain . Participants were 527 adult critical patients at low risk for reintubation who fulfilled criteria for planned extubation . Low risk for reintubation was defined as younger than 65 years ; Acute Physiology and Chronic Health Evaluation II score less than 12 on day of extubation ; body mass index less than 30 ; adequate secretions management ; simple weaning ; 0 or 1 comorbidity ; and absence of heart failure , moderate-to-severe chronic obstructive pulmonary disease , airway patency problems , and prolonged mechanical ventilation . INTERVENTIONS Patients were r and omized to undergo either high-flow or conventional oxygen therapy for 24 hours after extubation . MAIN OUTCOMES AND MEASURES The primary outcome was reintubation within 72 hours , compared with the Cochran-Mantel-Haenszel χ2 test . Secondary outcomes included postextubation respiratory failure , respiratory infection , sepsis and multiorgan failure , ICU and hospital length of stay and mortality , adverse events , and time to reintubation . RESULTS Of 527 patients ( mean age , 51 years [ range , 18 - 64 ] ; 62 % men ) , 264 received high-flow therapy and 263 conventional oxygen therapy . Reintubation within 72 hours was less common in the high-flow group ( 13 patients [ 4.9 % ] vs 32 [ 12.2 % ] in the conventional group ; absolute difference , 7.2 % [ 95 % CI , 2.5 % to 12.2 % ] ; P = .004 ) . Postextubation respiratory failure was less common in the high-flow group ( 22/264 patients [ 8.3 % ] vs 38/263 [ 14.4 % ] in the conventional group ; absolute difference , 6.1 % [ 95 % CI , 0.7 % to 11.6 % ] ; P = .03 ) . Time to reintubation was not significantly different between groups ( 19 hours [ interquartile range , 12 - 28 ] in the high-flow group vs 15 hours [ interquartile range , 9 - 31 ] in the conventional group ; absolute difference , -4 [ 95 % CI , -54 to 46 ] ; P = .66 ] . No adverse effects were reported . CONCLUSIONS AND RELEVANCE Among extubated patients at low risk for reintubation , the use of high-flow nasal cannula oxygen compared with conventional oxygen therapy reduced the risk of reintubation within 72 hours . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01191489

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### Context: [21255498] OBJECTIVE : In a cardiothoracic and vascular intensive care unit , to compare nasal high-flow ( NHF ) oxygen therapy and st and ard high-flow face mask ( HFFM ) oxygen therapy in patients with mild to moderate hypoxemic respiratory failure . METHODS : In a prospect i ve r and omized comparative study , 60 patients with mild to moderate hypoxemic respiratory failure were r and omized to receive NHF or HFFM . We analyzed the success of allocated therapy , noninvasive ventilation rate , and oxygenation . RESULTS : Significantly more NHF patients succeeded with their allocated therapy ( P = .006 ) . The rate of noninvasive ventilation in the NHF group was 3/29 ( 10 % ) , compared with 8/27 ( 30 % ) in the HFFM group ( P = .10 ) . The NHF patients also had significantly fewer desaturations ( P = .009 ) . CONCLUSIONS : NHF oxygen therapy may be more effective than HFFM in treating mild to moderate hypoxemic respiratory failure [3672522] Introduction Noninvasive ventilation ( NIV ) , as a weaning-facilitating strategy in predominantly chronic obstructive pulmonary disease ( COPD ) mechanically ventilated patients , is associated with reduced ventilator-associated pneumonia , total duration of mechanical ventilation , length of intensive care unit ( ICU ) and hospital stay , and mortality . However , this benefit after planned extubation in patients with acute respiratory failure of various etiologies remains to be eluci date d. The aim of this study was to determine the efficacy of NIV applied immediately after planned extubation in contrast to oxygen mask ( OM ) in patients with acute respiratory failure ( ARF ) . Methods A r and omized , prospect i ve , controlled , unblinded clinical study in a single center of a 24-bed adult general ICU in a university hospital was carried out in a 12-month period . Included patients met extubation criteria with at least 72 hours of mechanical ventilation due to acute respiratory failure , after following the ICU weaning protocol . Patients were r and omized immediately before elective extubation , being r and omly allocated to one of the study groups : NIV or OM . We compared both groups regarding gas exchange 15 minutes , 2 hours , and 24 hours after extubation , reintubation rate after 48 hours , duration of mechanical ventilation , ICU length of stay , and hospital mortality . Results Forty patients were r and omized to receive NIV ( 20 patients ) or OM ( 20 patients ) after the following extubation criteria were met : pressure support ( PSV ) of 7 cm H2O , positive end-expiratory pressure ( PEEP ) of 5 cm H2O , oxygen inspiratory fraction ( FiO2 ) ≤ 40 % , arterial oxygen saturation ( SaO2 ) ≥ 90 % , and ratio of respiratory rate and tidal volume in liters ( f/TV ) < 105 . Comparing the 20 patients ( NIV ) with the 18 patients ( OM ) that finished the study 48 hours after extubation , the rate of reintubation in NIV group was 5 % and 39 % in OM group ( P = 0.016 ) . Relative risk for reintubation was 0.13 ( CI = 0.017 to 0.946 ) . Absolute risk reduction for reintubation showed a decrease of 33.9 % , and analysis of the number needed to treat was three . No difference was found in the length of ICU stay ( P = 0.681 ) . Hospital mortality was zero in NIV group and 22.2 % in OM group ( P = 0.041 ) . Conclusions In this study population , NIV prevented 48 hours reintubation if applied immediately after elective extubation in patients with more than 3 days of ARF when compared with the OM group . Trial Registration numberIS RCT N : 41524441 [23602035] PURPOSE High flow nasal cannula ( HFNC ) may decrease preload being associated with beneficial hemodynamic and respiratory effects in adults with heart failure . METHODS This is a sequential intervention prospect i ve study including 10 adults with New York Heart Association ( NYHA ) class III and left ventricle ejection fraction 45 % or less . High flow gas was administered ( fraction of inspired oxygen , 0.21 ) through nasal cannula ( Optiflow(TM ) ; Fisher & Paykel , Auckl and , New Zeal and ) . Sequential echocardiographies were performed at baseline , using HFNC with 20 lpm and 40 lpm and post-HFNC . A reduction greater than 20 % in the estimated inspiratory collapse of the inferior vena cava ( IVC ) from baseline was considered clinical ly significant . RESULTS Ten patients were included , with median age of 57 ( 44 - 65 ) years ; 6 ( 60 % ) were female , and 8 ( 80 % ) had dilated cardiomyopathy . Median IVC inspiratory significantly ( P<.05 ) decreased from baseline ( 37 % ) to HFNC with 20 lpm ( 28 % ) and HFNC with 40 lpm ( 21 % ) , representing mean attributable reductions of 20 % ( 95 % confidence interval , 6 - 55 ) and 53 % ( 95 % confidence interval , 36 - 67 ) from baseline . Changes in the IVC inspiratory collapse were reversible after HFNC withdrawal . Respiratory rate was significantly reduced from 23 breaths per minute at baseline to 17 breaths per minute at HFNC with 20 lpm and 13 breaths per minute at HFNC with 40 lpm . In contrast , no significant changes in other echocardiographic or clinical variables were documented . CONCLUSION These findings suggest that patients with NYHA class III heart failure may benefit with HFNC supportive therapy [11066186] CONTEXT Continuous positive airway pressure ( CPAP ) is widely used in the belief that it may reduce the need for intubation and mechanical ventilation in patients with acute hypoxemic respiratory insufficiency . OBJECTIVE To compare the physiologic effects and the clinical efficacy of CPAP vs st and ard oxygen therapy in patients with acute hypoxemic , nonhypercapnic respiratory insufficiency . DESIGN , SETTING , AND PATIENTS R and omized , concealed , and unblinded trial of 123 consecutive adult patients who were admitted to 6 intensive care units between September 1997 and January 1999 with a PaO(2)/FIO(2 ) ratio of 300 mm Hg or less due to bilateral pulmonary edema ( n = 102 with acute lung injury and n = 21 with cardiac disease ) . INTERVENTIONS Patients were r and omly assigned to receive oxygen therapy alone ( n = 61 ) or oxygen therapy plus CPAP ( n = 62 ) . MAIN OUTCOME MEASURES Improvement in PaO(2)/FIO(2 ) ratio , rate of endotracheal intubation at any time during the study , adverse events , length of hospital stay , mortality , and duration of ventilatory assistance , compared between the CPAP and st and ard treatment groups . RESULTS Among the CPAP vs st and ard therapy groups , respectively , causes of respiratory failure ( pneumonia , 54 % and 55 % ) , presence of cardiac disease ( 33 % and 35 % ) , severity at admission , and hypoxemia ( median [ 5th-95th percentile ] PaO(2)/FIO(2 ) ratio , 140 [ 59 - 288 ] mm Hg vs 148 [ 62 - 283 ] mm Hg ; P = .43 ) were similarly distributed . After 1 hour of treatment , subjective responses to treatment ( P<.001 ) and median ( 5th-95th percentile ) PaO(2)/FIO(2 ) ratios were greater with CPAP ( 203 [ 45 - 431 ] mm Hg vs 151 [ 73 - 482 ] mm Hg ; P = .02 ) . No further difference in respiratory indices was observed between the groups . Treatment with CPAP failed to reduce the endotracheal intubation rate ( 21 [ 34 % ] vs 24 [ 39 % ] in the st and ard therapy group ; P = .53 ) , hospital mortality ( 19 [ 31 % ] vs 18 [ 30 % ] ; P = .89 ) , or median ( 5th-95th percentile ) intensive care unit length of stay ( 6.5 [ 1 - 57 ] days vs 6.0 [ 1 - 36 ] days ; P = .43 ) . A higher number of adverse events occurred with CPAP treatment ( 18 vs 6 ; P = .01 ) . CONCLUSION In this study , despite early physiologic improvement , CPAP neither reduced the need for intubation nor improved outcomes in patients with acute hypoxemic , nonhypercapnic respiratory insufficiency primarily due to acute lung injury . JAMA . 2000;284:2352 - 2360 [27706464] Importance High-flow conditioned oxygen therapy delivered through nasal cannulae and noninvasive mechanical ventilation ( NIV ) may reduce the need for reintubation . Among the advantages of high-flow oxygen therapy are comfort , availability , lower costs , and additional physiopathological mechanisms . Objective To test if high-flow conditioned oxygen therapy is noninferior to NIV for preventing postextubation respiratory failure and reintubation in patients at high risk of reintubation . Design , Setting , and Participants Multicenter r and omized clinical trial in 3 intensive care units in Spain ( September 2012-October 2014 ) including critically ill patients ready for planned extubation with at least 1 of the following high-risk factors for reintubation : older than 65 years ; Acute Physiology and Chronic Health Evaluation II score higher than 12 points on extubation day ; body mass index higher than 30 ; inadequate secretions management ; difficult or prolonged weaning ; more than 1 comorbidity ; heart failure as primary indication for mechanical ventilation ; moderate to severe chronic obstructive pulmonary disease ; airway patency problems ; or prolonged mechanical ventilation . Interventions Patients were r and omized to undergo either high-flow conditioned oxygen therapy or NIV for 24 hours after extubation . Main Outcomes and Measures Primary outcomes were reintubation and postextubation respiratory failure within 72 hours . Noninferiority margin was 10 percentage points . Secondary outcomes included respiratory infection , sepsis , and multiple organ failure , length of stay and mortality ; adverse events ; and time to reintubation . Results Of 604 patients ( mean age , 65 [ SD , 16 ] years ; 388 [ 64 % ] men ) , 314 received NIV and 290 high-flow oxygen . Sixty-six patients ( 22.8 % ) in the high-flow group vs 60 ( 19.1 % ) in the NIV group were reintubation ( absolute difference , -3.7 % ; 95 % CI , -9.1 % to ∞ ) ; 78 patients ( 26.9 % ) in the high-flow group vs 125 ( 39.8 % ) in the NIV group experienced postextubation respiratory failure ( risk difference , 12.9 % ; 95 % CI , 6.6 % to ∞ ) [ corrected ] . Median time to reintubation did not significantly differ : 26.5 hours ( IQR , 14 - 39 hours ) in the high-flow group vs 21.5 hours ( IQR , 10 - 47 hours ) in the NIV group ( absolute difference , -5 hours ; 95 % CI , -34 to 24 hours ) . Median postr and omization ICU length of stay was lower in the high-flow group , 3 days ( IQR , 2 - 7 ) vs 4 days ( IQR , 2 - 9 ; P=.048 ) . Other secondary outcomes were similar in the 2 groups . Adverse effects requiring withdrawal of the therapy were observed in none of patients in the high-flow group vs 42.9 % patients in the NIV group ( P < .001 ) . Conclusions and Relevance Among high-risk adults who have undergone extubation , high-flow conditioned oxygen therapy was not inferior to NIV for preventing reintubation and postextubation respiratory failure . High-flow conditioned oxygen therapy may offer advantages for these patients . Trial Registration clinical trials.gov Identifier : NCT01191489 [21958974] PURPOSE The purpose of this study was to determine the impact of high-flow nasal cannula oxygen ( HFNC ) on patients with acute respiratory failure ( ARF ) in comparison with conventional oxygen therapy . MATERIAL S AND METHODS This was a prospect i ve observational study . Patients with persistent ARF despite oxygen with conventional facemask without indication for immediate intubation were treated with HFNC oxygen . Clinical respiratory parameters and arterial blood gases were compared under conventional and HFNC oxygen therapy . RESULTS Twenty patients , aged 59 years ( 38 - 75 years ) and SAPS2 ( simplified acute physiology score ) 33 ( 26.5 - 38 ) , were included in the study . Etiology of ARF was mainly pneumonia ( n = 11 ) , sepsis ( n = 3 ) , and miscellaneous ( n = 6 ) . Use of HFNC enabled a significant reduction of respiratory rate , 28 ( 26 - 33 ) vs 24.5 ( 23 - 28.5 ) breath per minute ( P = .006 ) , and a significant increase in oxygen saturation , oxygen saturation as measured by pulse oximetry 93.5 % ( 90 - 98.5 ) vs 98.5 % ( 95.5 - 100 ) ( P = .0003 ) . Use of HFNC significantly increased Pao(2 ) from 8.73 ( 7.13 - 11.13 ) to 15.27 ( 9.66 - 25.6 ) kPa ( P = .001 ) and moderately increased Paco(2 ) , 5.26 ( 4.33 - 5.66 ) to 5.73 ( 4.8 - 6.2 ) kPa ( P = .005 ) without affecting pH. Median duration of HFNC was 26.5 ( 17 - 121 ) hours . Six patients were secondarily intubated , and 3 died in the intensive care unit . CONCLUSION Use of HFNC in patients with persistent ARF was associated with significant and sustained improvement of both clinical and biologic parameters [2777940] Background The aim of this prospect i ve study was to determine whether a level of positive airway pressure was generated in participants receiving nasal high flow ( NHF ) delivered by the Optiflow ™ system ( Fisher and Paykel Healthcare Ltd , Auckl and , New Zeal and ) in a cardiothoracic and vascular intensive care unit ( ICU ) . Methods Nasopharyngeal airway pressure was measured in 15 postoperative cardiac surgery adult patients who received both NHF and st and ard facemask therapy at a flow rate of 35 litre min−1 . Measurements were repeated in the open mouth and closed mouth positions . Mean airway pressure was determined by averaging the pressures at the peak of inspiration of each breath within a 1 min period , allowing the entire pressure profile of each breath to be included within the calculation . Results Low level positive pressure was demonstrated with NHF at 35 litre min−1 with mouth closed when compared with a facemask . NHF generated a mean nasopharyngeal airway pressure of mean ( sd ) 2.7 ( 1.04 ) cm H2O with the mouth closed . Airway pressure was significantly higher when breathing with mouth closed compared with mouth open ( P≤0.0001 ) . Conclusions This study demonstrated that a low level of positive pressure was generated with NHF at 35 litre min−1 of gas flow . This is consistent with results obtained in healthy volunteers . Australian Clinical Trials Registry www.actr.org.au ACTRN012606000139572 [24286408] Background Although noninvasive positive pressure ventilation ( NPPV ) has been successfully used for various kinds of acute respiratory failure , the data are limited regarding its application in postoperative respiratory failure after cardiac surgery . Therefore , we conducted a prospect i ve r and omized control study in a university surgical intensive care unit to evaluate the efficacy and safety of NPPV in the treatment of acute respiratory failure after cardiac surgery , and explore the predicting factors of NPPV failure . Methods From September 2011 to November 2012 patients with acute respiratory failure after cardiac surgery who had indication for the use of NPPV were r and omly divided into a NPPV treatment group ( NPPV group ) and the conventional treatment group ( control group ) . The between‐group differences in the patients ’ baseline characteristics , re‐intubation rate , tracheotomy rate , ventilator associated pneumonia ( VAP ) incidence , in‐hospital mortality , mechanical ventilation time after enrollment ( MV time ) , intensive care unit ( ICU ) and postoperative hospital stays were compared . The factors that predict NPPV failure were analyzed . Results During the study period , a total of 139 patients who had acute respiratory failure after cardiac surgery were recorded , and 95 of them met the inclusion criteria , which included 59 males and 36 females with a mean age of ( 61.5±11.2 ) years . Forty‐three patients underwent coronary artery bypass grafting ( CABG ) , 23 underwent valve surgery , 13 underwent CABG+valve surgery , 13 underwent major vascular surgery , and three underwent other surgeries . The NPPV group had 48 patients and the control group had 47 patients . In the NPPV group , the re‐intubation rate was 18.8 % , tracheotomy rate was 12.5 % , VAP incidence was 0 , and the in‐hospital mortality was 18.8 % , significantly lower than in the control group 80.9 % , 29.8 % , 17.0 % and 38.3 % respectively , P < 0.05 or P < 0.01 . The MV time and ICU stay ( expressed as the median ( P25 , P75 ) ) were 18.0 ( 9.2 , 35.0 ) hours and 4.0 ( 2.0 , 5.0 ) days , which were significantly shorter than in the control group , 96.0 ( 26.0 , 240.0 ) hours and 6.0 ( 4.0 , 9.0 ) days respectively , P < 0.05 or P < 0.01 . The postoperative hospital stays of the two groups were similar . The univariate analysis showed that the NPPV success subgroup had more patients with acute lung injury ( ALI ) ( 17 vs. 0 , P=0.038 ) , fewer patients with pneumonia ( 2 vs. 7 , P < 0.001 ) and lower acute physiology and chronic health evaluation II ( APACHE II ) scores ( 16.1±2.8 vs. 21.8±3.2 , P < 0.001 ) . Multivariate analysis showed that pneumonia ( P=0.027 ) and a high APACHE II score > 20 ( P=0.002 ) were the independent risk factors of NPPV failure . Conclusions We conclude that NPPV can be applied in selected patients with acute respiratory failure after cardiac surgery to reduce the need of re‐intubation and improve clinical outcome as compared with conventional treatment . Pneumonia and a high APACHE II score > 20 might be the independent risk factors of NPPV failure in this group of patients [16224108] RATIONALE Respiratory failure after extubation and reintubation is associated with increased morbidity and mortality . OBJECTIVES To assess the efficacy of noninvasive ventilation in averting respiratory failure after extubation in patients at increased risk . METHODS A prospect i ve r and omized controlled trial was conducted in 162 mechanically ventilated patients who tolerated a spontaneous breathing trial after recovery from the acute episode but had increased risk for respiratory failure after extubation . Patients were r and omly allocated after extubation to receive noninvasive ventilation for 24 h ( n = 79 ) , or conventional management with oxygen therapy ( control group , n = 83 ) . MEASUREMENTS AND MAIN RESULTS The primary end-point variable was the decrease in respiratory failure after extubation . In the noninvasive ventilation group , respiratory failure after extubation was less frequent ( 13 , 16 vs. 27 , 33 % ; p = 0.029 ) and the intensive care unit mortality was lower ( 2 , 3 versus 12 , 14 % ; p = 0.015 ) . However , 90-d survival did not change significantly between groups . Separate analyses of patients without and with hypercapnia ( arterial CO(2 ) tension greater than 45 mm Hg ) during the spontaneous breathing trial showed that noninvasive ventilation improved intensive care unit mortality ( 0 vs. 4 , 18 % ; p = 0.035 ) and 90-d survival ( p = 0.006 ) in hypercapnic patients only ; of them , 98 % had chronic respiratory disorders . CONCLUSIONS The early use of noninvasive ventilation averted respiratory failure after extubation and decreased intensive care unit mortality among patients at increased risk . The beneficial effect of noninvasive ventilation in improving survival of hypercapnic patients with chronic respiratory disorders warrants a new prospect i ve clinical trial [23050520] BACKGROUND : Electrical impedance tomography measures changes in lung impedance , which are mainly related to changes in lung volume . We used electrical impedance tomography to investigate the effects of high-flow nasal cannula ( HFNC ) and body position on global and regional end-expiratory lung impedance variation ( ΔEELI ) . METHODS : Prospect i ve study with 20 healthy adults . Two periods were defined : the first in supine position and the second in prone position . Each period was divided into 3 phases . In the first and the third phases the subjects were breathing ambient air , and in the second HFNC was implemented . Four regions of interest were defined : 2 ventral and 2 dorsal . For each respiratory cycle , global and regional ΔEELI were measured by electrical impedance tomography and were expressed as a function of the tidal variation of the first stable respiratory cycle ( units ) . RESULTS : HFNC increased global EELI by 1.26 units ( 95 % CI 1.20–1.31 , P < .001 ) in supine position , and by 0.87 units ( 95 % CI 0.82–0.91 , P < .001 ) in prone position . The distribution of ΔEELI was homogeneous in prone position , with no difference between ventral and dorsal lung regions ( −0.01 units , 95 % CI −0.01 to 0 , P = .18 ) , while in supine position a significant difference was found ( 0.22 units , 95 % CI 0.21–0.23 , P < .001 ) with increased EELI in ventral areas . CONCLUSIONS : HFNC increased global EELI in our population , regardless of body position , suggesting an increase in functional residual capacity . Prone positioning was related to a more homogeneous distribution of ΔEELI , while in supine position ΔEELI was higher in the ventral lung regions [20406507] OBJECTIVE To compare the comfort of oxygen therapy via high-flow nasal cannula ( HFNC ) versus via conventional face mask in patients with acute respiratory failure . Acute respiratory failure was defined as blood oxygen saturation < 96 % while receiving a fraction of inspired oxygen > or = 0.50 via face mask . METHODS Oxygen was first humidified with a bubble humidifier and delivered via face mask for 30 min , and then via HFNC with heated humidifier for another 30 min . At the end of each 30-min period we asked the patient to evaluate dyspnea , mouth dryness , and overall comfort , on a visual analog scale of 0 ( lowest ) to 10 ( highest ) . The results are expressed as median and interquartile range values . RESULTS We included 20 patients , with a median age of 57 ( 40 - 70 ) years . The total gas flow administered was higher with the HFNC than with the face mask ( 30 [ 21.3 - 38.7 ] L/min vs 15 [ 12 - 20 ] L/min , P < .001 ) . The HFNC was associated with less dyspnea ( 3.8 [ 1.3 - 5.8 ] vs 6.8 [ 4.1 - 7.9 ] , P = .001 ) and mouth dryness ( 5 [ 2.3 - 7 ] vs 9.5 [ 8 - 10 ] , P < .001 ) , and was more comfortable ( 9 [ 8 - 10 ] ) versus 5 [ 2.3 - 6.8 ] , P < .001 ) . HFNC was associated with higher P(aO(2 ) ) ( 127 [ 83 - 191 ] mm Hg vs 77 [ 64 - 88 ] mm Hg , P = .002 ) and lower respiratory rate ( 21 [ 18 - 27 ] breaths/min vs 28 [ 25 - 32 ] breaths/min , P < .001 ) , but no difference in P(aCO(2 ) ) . CONCLUSIONS HFNC was better tolerated and more comfortable than face mask . HFNC was associated with better oxygenation and lower respiratory rate . HFNC could have an important role in the treatment of patients with acute respiratory failure [25869405] Purpose Intubation of hypoxemic patients is associated with life-threatening adverse events . High-flow therapy by nasal cannula ( HFNC ) for preoxygenation before intubation has never been assessed by r and omized study . Our objective was to evaluate the efficiency of HFNC for preoxygenation , compared to high fraction-inspired oxygen facial mask ( HFFM ) . Methods Multicenter , r and omized , open-labelled , controlled PREOXYFLOW trial ( NCT 01747109 ) in six French intensive care units . Acute hypoxemic adults requiring intubation were r and omly allocated to HFNC or HFFM . Patients were eligible if PaO2/FiO2 ratio was below 300 mmHg , respiratory rate at least 30/min and if they required FiO2 50 % or more to obtain at least 90 % oxygen saturation . HFNC was maintained throughout the procedure , whereas HFFM was removed at the end of general anaesthesia induction . Primary outcome was the lowest saturation throughout intubation procedure . Secondary outcomes included adverse events related to intubation , duration of mechanical ventilation and death . Results A total of 124 patients were r and omized . In the intent-to-treat analysis , including 119 patients ( HFNC n = 62 ; HFFM n = 57 ) , the median ( interquartile range ) lowest saturation was 91.5 % ( 80–96 ) for HFNC and 89.5 % ( 81–95 ) for the HFFM group ( p = 0.44 ) . There was no difference for difficult intubation ( p = 0.18 ) , intubation difficulty scale , ventilation-free days ( p = 0.09 ) , intubation-related adverse events including desaturation < 80 % or mortality ( p = 0.46 ) . Conclusions Compared to HFFM , HFNC as a preoxygenation device did not reduce the lowest level of desaturation [25371400] BACKGROUND : Beneficial effects of high-flow nasal cannula ( HFNC ) oxygen on oxygenation and respiratory parameters have been reported in a small number of subjects with acute respiratory failure ( ARF ) . We aim ed to evaluate its effect in subjects with ARDS . METHODS : This was an observational single-center study . Prospect ively obtained data were retrospectively analyzed . All patients admitted over 1 y to a university hospital medicosurgical ICU were included . Classification was according to the highest ventilatory support required . HFNC indications were review ed , and demographics , clinical characteristics , and course of subjects with ARDS according to intubation need were compared . RESULTS : Of 607 subjects admitted , 560 required ventilatory or oxygen support , among whom 180 received noninvasive ventilatory support . HFNC was used in 87 subjects and as first-line treatment in 51 subjects ( 29 % of first-line noninvasively treated subjects ) , 45 of which had ARDS ( PaO2/FIO2 of 137 mm Hg ; 22 men , 57.9 y of age ) . Pneumonia accounted for 82 % of ARDS causes . The intubation rate in these subjects was 40 % . Higher Simplified Acute Physiology Score II ( SAPS II ; 46 vs 29 , P = .001 ) , occurrence of additional organ failure ( 76 % vs 26 % , P = .002 ) , mainly hemodynamic ( 50 % vs 7 % , P = .001 ) or neurological ( 22 % vs 0 , P = .01 ) , and trends toward lower PaO2/FIO2 and higher breathing frequency after HFNC initiation were evidence d in subjects who failed HFNC . Higher SAPS II scores were associated with HFNC failure in multivariate analysis . CONCLUSIONS : In daily care , over one fourth of subjects requiring noninvasive ventilatory support were treated via HFNC , with a high success rate in subjects with severe ARDS . We conclude that HFNC may be considered as first-line therapy in ARF , including patients with ARDS [25981908] BACKGROUND Whether noninvasive ventilation should be administered in patients with acute hypoxemic respiratory failure is debated . Therapy with high-flow oxygen through a nasal cannula may offer an alternative in patients with hypoxemia . METHODS We performed a multicenter , open-label trial in which we r and omly assigned patients without hypercapnia who had acute hypoxemic respiratory failure and a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of 300 mm Hg or less to high-flow oxygen therapy , st and ard oxygen therapy delivered through a face mask , or noninvasive positive-pressure ventilation . The primary outcome was the proportion of patients intubated at day 28 ; secondary outcomes included all-cause mortality in the intensive care unit and at 90 days and the number of ventilator-free days at day 28 . RESULTS A total of 310 patients were included in the analyses . The intubation rate ( primary outcome ) was 38 % ( 40 of 106 patients ) in the high-flow-oxygen group , 47 % ( 44 of 94 ) in the st and ard group , and 50 % ( 55 of 110 ) in the noninvasive-ventilation group ( P=0.18 for all comparisons ) . The number of ventilator-free days at day 28 was significantly higher in the high-flow-oxygen group ( 24±8 days , vs. 22±10 in the st and ard-oxygen group and 19±12 in the noninvasive-ventilation group ; P=0.02 for all comparisons ) . The hazard ratio for death at 90 days was 2.01 ( 95 % confidence interval [ CI ] , 1.01 to 3.99 ) with st and ard oxygen versus high-flow oxygen ( P=0.046 ) and 2.50 ( 95 % CI , 1.31 to 4.78 ) with noninvasive ventilation versus high-flow oxygen ( P=0.006 ) . CONCLUSIONS In patients with nonhypercapnic acute hypoxemic respiratory failure , treatment with high-flow oxygen , st and ard oxygen , or noninvasive ventilation did not result in significantly different intubation rates . There was a significant difference in favor of high-flow oxygen in 90-day mortality . ( Funded by the Programme Hospitalier de Recherche Clinique Interrégional 2010 of the French Ministry of Health ; FLORALI Clinical Trials.gov number , NCT01320384 . ) [3196245] Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more [21045639] Background : Current knowledge of the risk for postoperative pulmonary complications ( PPCs ) rests on studies that narrowly selected patients and procedures . Hypothesizing that PPC occurrence could be predicted from a reduced set of perioperative variables , we aim ed to develop a predictive index for a broad surgical population . Methods : Patients undergoing surgical procedures given general , neuraxial , or regional anesthesia in 59 hospitals were r and omly selected for this prospect i ve , multicenter study . The main outcome was the development of at least one of the following : respiratory infection , respiratory failure , bronchospasm , atelectasis , pleural effusion , pneumothorax , or aspiration pneumonitis . The cohort was r and omly divided into a development sub sample to construct a logistic regression model and a validation sub sample . A PPC predictive index was constructed . Results : Of 2,464 patients studied , 252 events were observed in 123 ( 5 % ) . Thirty-day mortality was higher in patients with a PPC ( 19.5 % ; 95 % [ CI ] , 12.5–26.5 % ) than in those without a PPC ( 0.5 % ; 95 % CI , 0.2–0.8 % ) . Regression modeling identified seven independent risk factors : low preoperative arterial oxygen saturation , acute respiratory infection during the previous month , age , preoperative anemia , upper abdominal or intrathoracic surgery , surgical duration of at least 2 h , and emergency surgery . The area under the receiver operating characteristic curve was 90 % ( 95 % CI , 85–94 % ) for the development sub sample and 88 % ( 95 % CI , 84–93 % ) for the validation sub sample . Conclusion : The risk index based on seven objective , easily assessed factors has excellent discriminative ability . The index can be used to assess individual risk of PPC and focus further research on measures to improve patient care [22417844] OBJECTIVE : Heated and humidified high flow nasal cannula oxygen therapy ( HFNC ) represents a new alternative to conventional oxygen therapy that has not been evaluated in the emergency department ( ED ) . We aim ed to study its feasibility and efficacy in patients exhibiting acute respiratory failure presenting to the ED . METHODS : Prospect i ve , observational study in a university hospital 's ED . Patients with acute respiratory failure requiring > 9 L/min oxygen or with ongoing clinical signs of respiratory distress despite oxygen therapy were included . The device of oxygen administration was then switched from non-rebreathing mask to HFNC . Dyspnea , rated by the Borg scale and a visual analog scale , respiratory rate , and SpO2 were collected before and 15 , 30 , and 60 min after beginning HFNC . Feasibility was assessed through caregivers ' acceptance of the device in terms of practicality and perceived effect on the subjects , evaluated by question naire . RESULTS : Seventeen subjects , median age 64 y ( 46–84.7 y ) , were studied . Pneumonia was the most common reason for oxygen therapy ( n = 9 ) . HFNC was associated with a significant decrease in both dyspnea scores : Borg scale from 6 ( 5–7 ) to 3 ( 2–4 ) ( P < .001 ) , and visual analog scale from 7 ( 5–8 ) to 3 ( 1–5 ) ( P < .01 ) . Respiratory rate decreased from 28 breaths/min ( 25–32 breaths/min ) to 25 breaths/min ( 21–28 breaths/min ) ( P < .001 ) , and SpO2 increased from 90 % ( 88.5–94 % ) to 97 % ( 92.5–100 % ) ( P < .001 ) . Fewer subjects exhibited clinical signs of respiratory distress ( 10/17 vs 3/17 , P = .03 ) . HFNC was well tolerated and no adverse event was noted . Altogether , 76 % of healthcare givers declared preferring HFNC , as compared to conventional oxygen therapy . CONCLUSIONS : HFNC is possible in the ED , and it alleviated dyspnea and improved respiratory parameters in subjects with acute hypoxemic respiratory failure [19781896] PURPOSE Oxygen delivery after extubation is critical to maintain adequate oxygenation and to avoid reintubation . The delivery of oxygen in such situations is usually by high-flow face mask ( HFFM ) . Yet , this may be uncomfortable for some patients . A recent advance in oxygen delivery technology is high-flow nasal prongs ( HFNP ) . There are no r and omized trials comparing these 2 modes . METHODS Patients were r and omized to either protocol A ( n = 25 ; HFFM followed by HFNP ) or protocol B ( n = 25 ; HFNP followed by HFFM ) after a stabilization period of 30 minutes after extubation . The primary objective was to compare the efficacy of HFNP to HFFM in maintaining gas exchange as measured by arterial blood gas . Secondary objective was to compare the relative effects on heart rate , blood pressure , respiratory rate , comfort , and tolerance . RESULTS Patients in both protocol s were comparable in terms of age , demographic , and physiologic variables including arterial blood gas , blood pressure , heart rate , respiratory rate , Glasgow Coma Score , sedation , and Acute Physiology and Chronic Health Evaluation ( APACHE ) III scores . There was no significant difference in gas exchange , respiratory rate , or hemodynamics . There was a significant difference ( P = .01 ) in tolerance , with nasal prongs being well tolerated . There was a trend ( P = .09 ) toward better patient comfort with HFNP . CONCLUSIONS High-flow nasal prongs are as effective as HFFM in delivering oxygen to extubated patients who require high-flow oxygen . The tolerance of HFNP was significantly better than in HFFM [4300050] Introduction Critically ill patients with respiratory failure undergoing bronchoscopy have an increased risk of hypoxaemia-related complications . Previous studies have shown that in awake , hypoxaemic patients non-invasive ventilation ( NIV ) is helpful in preventing gas exchange deterioration during bronchoscopy . An alternative and increasingly used means of oxygen delivery is its application via high-flow nasal cannula ( HFNC ) . This study was conducted to compare HFNC with NIV in patients with acute hypoxaemic respiratory failure undergoing flexible bronchoscopy . Methods Prospect i ve r and omised trial r and omising 40 critically ill patients with hypoxaemic respiratory failure to receive either NIV or HFNC during bronchoscopy in the intensive care unit . Results After the initiation of NIV and HFNC , oxygen levels were significantly higher in the NIV group compared to the HFNC group . Two patients were unable to proceed to bronchoscopy after the institution of HFNC due to progressive hypoxaemia . During bronchoscopy , one patient on HFNC deteriorated due to intravenous sedation requiring non-invasive ventilatory support . Bronchoscopy was well tolerated in all other patients . There were no significant differences between the two groups regarding heart rate , mean arterial pressure and respiratory rate . Three patients in the NIV group and one patient in the HFNC group were intubated within 24 hours after the end of bronchoscopy ( P = 0.29 ) . Conclusions The application of NIV was superior to HFNC with regard to oxygenation before , during and after bronchoscopy in patients with moderate to severe hypoxaemia . In patients with stable oxygenation under HFNC , subsequent bronchoscopy was well tolerated . Trial registration Clinical Trials.gov NCT01870765 . Registered 30 May 2013 [15190137] BACKGROUND The need for reintubation after extubation and discontinuation of mechanical ventilation is not uncommon and is associated with increased mortality . Noninvasive positive-pressure ventilation has been suggested as a promising therapy for patients with respiratory failure after extubation , but a single-center , r and omized trial recently found no benefit . We conducted a multicenter , r and omized trial to evaluate the effect of noninvasive positive-pressure ventilation on mortality in this clinical setting . METHODS Patients in 37 centers in eight countries who were electively extubated after at least 48 hours of mechanical ventilation and who had respiratory failure within the subsequent 48 hours were r and omly assigned to either noninvasive positive-pressure ventilation by face mask or st and ard medical therapy . RESULTS A total of 221 patients with similar baseline characteristics had been r and omly assigned to either noninvasive ventilation ( 114 patients ) or st and ard medical therapy ( 107 patients ) when the trial was stopped early , after an interim analysis . There was no difference between the noninvasive-ventilation group and the st and ard-therapy group in the need for reintubation ( rate of reintubation , 48 percent in both groups ; relative risk in the noninvasive-ventilation group , 0.99 ; 95 percent confidence interval , 0.76 to 1.30 ) . The rate of death in the intensive care unit was higher in the noninvasive-ventilation group than in the st and ard-therapy group ( 25 percent vs. 14 percent ; relative risk , 1.78 ; 95 percent confidence interval , 1.03 to 3.20 ; P=0.048 ) , and the median time from respiratory failure to reintubation was longer in the noninvasive-ventilation group ( 12 hours vs. 2 hours 30 minutes , P=0.02 ) . CONCLUSIONS Noninvasive positive-pressure ventilation does not prevent the need for reintubation or reduce mortality in unselected patients who have respiratory failure after extubation [27771739] Purpose High-flow nasal cannula ( HFNC ) oxygen therapy is attracting increasing interest in acute medicine as an alternative to st and ard oxygen therapy ; however , its use to prevent hypoxaemia after major abdominal surgery has not been evaluated . Our trial was design ed to close this evidence gap . Methods A multicentre r and omised controlled trial was carried out at three university hospitals in France . Adult patients at moderate to high risk of postoperative pulmonary complications who had undergone major abdominal surgery using lung-protective ventilation were r and omly assigned using a computer-generated sequence to receive either HFNC oxygen therapy or st and ard oxygen therapy ( low-flow oxygen delivered via nasal prongs or facemask ) directly after extubation . The primary endpoint was absolute risk reduction ( ARR ) for hypoxaemia at 1 h after extubation and after treatment discontinuation . Secondary outcomes included occurrence of postoperative pulmonary complications within 7 days after surgery , the duration of hospital stay , and in-hospital mortality . The analysis was performed on data from the modified intention-to-treat population . This trial was registered with Clinical Trials.gov ( NCT01887015 ) . Results Between 6 November 2013 and 1 March 2015 , 220 patients were r and omly assigned to receive either HFNC ( n = 108 ) or st and ard oxygen therapy ( n = 112 ) ; all of these patients completed follow-up . The median duration of the allocated treatment was 16 h ( interquartile range 14–18 h ) with st and ard oxygen therapy and 15 h ( interquartile range 12–18 ) with HFNC therapy . Twenty-three ( 21 % ) of the 108 patients treated with HFNC 1 h after extubation and 29 ( 27 % ) of the 108 patients after treatment discontinuation had postextubation hypoxaemia , compared with 27 ( 24 % ) and 34 ( 30 % ) of the 112 patients treated with st and ard oxygen ( ARR 4 , 95 % CI –8 to 15 % ; p = 0.57 ; adjusted relative risk [ RR ] 0.87 , 95 % CI 0.53–1.43 ; p = 0.58 ) . Over the 7-day postoperative follow-up period , there was no statistically significant difference between the groups in the proportion of patients who remained free of any pulmonary complication ( ARR 7 , 95 % CI –6 to 20 % ; p = 0.40 ) . Other secondary outcomes also did not differ significantly between the two groups . Conclusions Among patients undergoing major abdominal surgery , early preventive application of high-flow nasal cannula oxygen therapy after extubation did not result in improved pulmonary outcomes compared with st and ard oxygen therapy [19682735] BACKGROUND Non-invasive ventilation can prevent respiratory failure after extubation in individuals at increased risk of this complication , and enhanced survival in patients with hypercapnia has been recorded . We aim ed to assess prospect ively the effectiveness of non-invasive ventilation after extubation in patients with hypercapnia and as rescue therapy when respiratory failure develops . METHODS We undertook a r and omised controlled trial in three intensive-care units in Spain . We enrolled 106 mechanically ventilated patients with chronic respiratory disorders and hypercapnia after a successful spontaneous breathing trial . We r and omly allocated participants by computer to receive after extubation either non-invasive ventilation for 24 h ( n=54 ) or conventional oxygen treatment ( n=52 ) . The primary endpoint was avoidance of respiratory failure within 72 h after extubation . Analysis was by intention to treat . This trial is registered with clinical trials.gov , identifier NCT00539708 . FINDINGS Respiratory failure after extubation was less frequent in patients assigned non-invasive ventilation than in those allocated conventional oxygen therapy ( 8 [ 15 % ] vs 25 [ 48 % ] ; odds ratio 5.32 [ 95 % CI 2.11 - 13.46 ] ; p<0.0001 ) . In patients with respiratory failure , non-invasive ventilation as rescue therapy avoided reintubation in 17 of 27 patients . Non-invasive ventilation was independently associated with a lower risk of respiratory failure after extubation ( adjusted odds ratio 0.17 [ 95 % CI 0.06 - 0.44 ] ; p<0.0001 ) . 90-day mortality was lower in patients assigned non-invasive ventilation than in those allocated conventional oxygen ( p=0.0146 ) . INTERPRETATION Early non-invasive ventilation after extubation diminished risk of respiratory failure and lowered 90-day mortality in patients with hypercapnia during a spontaneous breathing trial . Routine implementation of this strategy for management of mechanically ventilated patients with chronic respiratory disorders is advisable . FUNDING IDIBAPS , CibeRes , Fondo de Investigaciones Sanitarias , European Respiratory Society [16276167] Objective : Compared with st and ard medical therapy ( SMT ) , noninvasive ventilation ( NIV ) does not reduce the need for reintubation in unselected patients who develop respiratory failure after extubation . The goal of this study was to assess whether early application of NIV , immediately after extubation , is effective in preventing postextubation respiratory failure in an at-risk population . Design : Multiple-center , r and omized controlled study . Setting : Multiple hospitals . Patients : Ninety-seven consecutive patients with similar baseline characteristics , requiring > 48 hrs of mechanical ventilation and considered at risk of developing postextubation respiratory failure ( i.e. , patients who had hypercapnia , congestive heart failure , ineffective cough and excessive tracheobronchial secretions , more than one failure of a weaning trial , more than one comorbid condition , and upper airway obstruction ) . Interventions : After a successful weaning trial , the patients were r and omized to receive NIV for ≥8 hrs a day in the first 48 hrs or SMT . Primary outcome was the need for reintubation according to st and ardized criteria . Secondary outcomes were intensive care unit and hospital mortality , as well as time spent in the intensive care unit and in hospital . Measurements and Main Results : Compared with the SMT group , the NIV group had a lower rate of reintubation ( four of 48 vs. 12 of 49 ; p = .027 ) . The need for reintubation was associated with a higher risk of mortality ( p < .01 ) . The use of NIV result ed in a reduction of risk of intensive care unit mortality ( −10 % , p < .01 ) , mediated by the reduction for the need of reintubation . Conclusions : NIV was more effective than SMT in preventing postextubation respiratory failure in a population considered at risk of developing this complication [25980660] IMPORTANCE Noninvasive ventilation delivered as bilevel positive airway pressure ( BiPAP ) is often used to avoid reintubation and improve outcomes of patients with hypoxemia after cardiothoracic surgery . High-flow nasal oxygen therapy is increasingly used to improve oxygenation because of its ease of implementation , tolerance , and clinical effectiveness . OBJECTIVE To determine whether high-flow nasal oxygen therapy was not inferior to BiPAP for preventing or resolving acute respiratory failure after cardiothoracic surgery . DESIGN AND SETTING Multicenter , r and omized , noninferiority trial ( BiPOP Study ) conducted between June 15 , 2011 , and January 15 , 2014 , at 6 French intensive care units . PARTICIPANTS A total of 830 patients who had undergone cardiothoracic surgery , of which coronary artery bypass , valvular repair , and pulmonary thromboendarterectomy were the most common , were included when they developed acute respiratory failure ( failure of a spontaneous breathing trial or successful breathing trial but failed extubation ) or were deemed at risk for respiratory failure after extubation due to preexisting risk factors . INTERVENTIONS Patients were r and omly assigned to receive high-flow nasal oxygen therapy delivered continuously through a nasal cannula ( flow , 50 L/min ; fraction of inspired oxygen [ FiO2 ] , 50 % ) ( n = 414 ) or BiPAP delivered with a full-face mask for at least 4 hours per day ( pressure support level , 8 cm H2O ; positive end-expiratory pressure , 4 cm H2O ; FiO2 , 50 % ) ( n = 416 ) . MAIN OUTCOMES AND MEASURES The primary outcome was treatment failure , defined as reintubation , switch to the other study treatment , or premature treatment discontinuation ( patient request or adverse effects , including gastric distention ) . Noninferiority of high-flow nasal oxygen therapy would be demonstrated if the lower boundary of the 95 % CI were less than 9 % . Secondary outcomes included mortality during intensive care unit stay , changes in respiratory variables , and respiratory complications . RESULTS High-flow nasal oxygen therapy was not inferior to BiPAP : the treatment failed in 87 of 414 patients with high-flow nasal oxygen therapy ( 21.0 % ) and 91 of 416 patients with BiPAP ( 21.9 % ) ( absolute difference , 0.9 % ; 95 % CI , -4.9 % to 6.6 % ; P = .003 ) . No significant differences were found for intensive care unit mortality ( 23 patients with BiPAP [ 5.5 % ] and 28 with high-flow nasal oxygen therapy [ 6.8 % ] ; P = .66 ) ( absolute difference , 1.2 % [ 95 % CI , -2.3 % to 4.8 % ] . Skin breakdown was significantly more common with BiPAP after 24 hours ( 10 % vs 3 % ; 95 % CI , 7.3%-13.4 % vs 1.8%-5.6 % ; P < .001 ) . CONCLUSIONS AND RELEVANCE Among cardiothoracic surgery patients with or at risk for respiratory failure , the use of high-flow nasal oxygen therapy compared with intermittent BiPAP did not result in a worse rate of treatment failure . The findings support the use of high-flow nasal oxygen therapy in similar patients . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01458444 [3362832] During bronchoscopy hypoxemia is commonly found and oxygen supply can be delivered by interfaces fed with high gas flows . Recently , the high-flow nasal cannula ( HFNC ) has been introduced for oxygen therapy in adults , but they have not been used so far during bronchoscopy in adults . Forty-five patients were r and omly assigned to 3 groups receiving oxygen : 40 L/min through a Venturi mask ( V40 , N = 15 ) , nasal cannula ( N40 , N = 15 ) , and 60 L/min through a nasal cannula ( N60 , N = 15 ) during bronchoscopy . Gas exchange and circulatory variables were sample d before ( FiO2 = 0.21 ) , at the end of bronchoscopy ( FiO2 = 0.5 ) , and thereafter ( V40 , FiO2 = 0.35 ) . In 8 healthy volunteers oxygen was r and omly delivered according to V40 , N40 , and N60 setting s , and airway pressure was measured . At the end of bronchoscopy , N60 presented higher PaO2 , PaO2/FiO2 , and SpO2 than V40 and N40 that did not differ between them . In the volunteers ( N60 ) median airway pressure amounted to 3.6 cmH2O . Under a flow rate of 40 L/min both the Venturi mask and HFNC behaved similarly , but nasal cannula associated with a 60 L/min flow produced the better results , thus indicating its use in mild respiratory dysfunctions [4126617] Background Aim of the study was to compare the short-term effects of oxygen therapy via a high-flow nasal cannula ( HFNC ) on functional and subjective respiratory parameters in patients with acute hypoxic respiratory failure in comparison to non-invasive ventilation ( NIV ) and st and ard treatment via a Venturi mask . Methods Fourteen patients with acute hypoxic respiratory failure were treated with HFNC ( FiO2 0.6 , gas flow 55 l/min ) , NIV ( FiO2 0.6 , PEEP 5 cm H2O Hg , tidal volume 6–8 ml/kg ideal body weight , ) and Venturi mask ( FiO2 0.6 , oxygen flow 15 l/min , ) in a r and omized order for 30 min each . Data collection included objective respiratory and circulatory parameters as well as a subjective rating of dyspnea and discomfort by the patients on a 10-point scale . In a final interview , all three methods were comparatively evaluated by each patient using a scale from 1 ( = very good ) to 6 ( = failed ) and the patients were asked to choose one method for further treatment . Results PaO2 was highest under NIV ( 129 ± 38 mmHg ) compared to HFNC ( 101 ± 34 mmHg , p < 0.01 vs. NIV ) and VM ( 85 ± 21 mmHg , p < 0.001 vs. NIV , p < 0.01 vs. HFNC , ANOVA ) . All other functional parameters showed no relevant differences . In contrast , dyspnea was significantly better using a HFNC ( 2.9 ± 2.1 , 10-point Borg scale ) compared to NIV ( 5.0 ± 3.3 , p < 0.05 ) , whereas dyspnea rating under HFNC and VM ( 3.3 ± 2.3 ) was not significantly different . A similar pattern was found when patients rated their overall discomfort on the 10 point scale : HFNC 2.7 ± 1.8 , VM 3.1 ± 2.8 ( ns vs. HFNC ) , NIV 5.4 ± 3.1 ( p < 0.05 vs. HFNC ) . In the final evaluation patients gave the best ratings to HFNC 2.3 ± 1.4 , followed by VM 3.2 ± 1.7 ( ns vs. HFNC ) and NIV 4.5 ± 1.7 ( p < 0.01 vs. HFNC and p < 0.05 vs. VM ) . For further treatment 10 patients chose HFNC , three VM and one NIV . Conclusions In hypoxic respiratory failure HFNC offers a good balance between oxygenation and comfort compared to NIV and Venturi mask and seems to be well tolerated by patients .Trial registration German clinical trials register : DRKS00005132 [4629403] Introduction In immunocompromised patients , acute respiratory failure ( ARF ) is associated with high mortality , particularly when invasive mechanical ventilation ( IMV ) is required . In patients with severe hypoxemia , high-flow nasal oxygen ( HFNO ) therapy has been used as an alternative to delivery of oxygen via a Venturi mask . Our objective in the present study was to compare HFNO and Venturi mask oxygen in immunocompromised patients with ARF . Methods We conducted a multicenter , parallel-group r and omized controlled trial in four intensive care units . Inclusion criteria were hypoxemic ARF and immunosuppression , defined as at least one of the following : solid or hematological malignancy , steroid or other immunosuppressant drug therapy , and HIV infection . Exclusion criteria were hypercapnia , previous IMV , and immediate need for IMV or noninvasive ventilation ( NIV ) . Patients were r and omized to 2 h of HFNO or Venturi mask oxygen . Results The primary endpoint was a need for IMV or NIV during the 2-h oxygen therapy period . Secondary endpoints were comfort , dyspnea , and thirst , as assessed hourly using a 0–10 visual analogue scale . We r and omized 100 consecutive patients , including 84 with malignancies , to HFNO ( n = 52 ) or Venturi mask oxygen ( n = 48 ) . During the 2-h study treatment period , 12 patients required IMV or NIV , and we found no significant difference between the two groups ( 15 % with HFNO and 8 % with the Venturi mask , P = 0.36 ) . None of the secondary endpoints differed significantly between the two groups . Conclusions In immunocompromised patients with hypoxemic ARF , a 2-h trial with HFNO improved neither mechanical ventilatory assistance nor patient comfort compared with oxygen delivered via a Venturi mask . However , the study was underpowered because of the low event rate and the one-sided hypothesis . Trial registration Clinical Trials.gov identifier : NCT02424773 . Registered 20 April 2015 [23921199] BACKGROUND Respiratory complications after cardiac surgery increase morbidity , mortality , and length of stay . Studies suggest that routine delivery of positive airway pressure after extubation may be beneficial . We sought to determine whether the routine administration of nasal high-flow oxygen therapy ( NHF ) improves pulmonary function after cardiac surgery . METHODS A pragmatic r and omized controlled trial ; participants received either NHF ( 45 litre min(-1 ) ) or usual care from extubation to Day 2 after surgery . The primary outcome was number of patients with / ratio ≥445 on Day 3 after surgery . The secondary outcomes included atelectasis score on chest X-ray ; spirometry ; intensive care and hospital length of stay ; mortality on Day 28 ; oxygenation indices ; escalation of respiratory support ; and patient comfort . RESULTS We r and omized 340 patients over 14 months . The number of patients with a / ratio of ≥445 on Day 3 was 78 ( 46.4 % ) in the NHF group vs 72 ( 42.4 % ) st and ard care [ odds ratio ( OR ) 1.18 , 95 % confidence interval ( CI ) 0.77 - 1.81 , P=0.45 ] . was reduced at both 4 h post-extubation and at 9 a.m. on Day 1 in the NHF group ( 5.3 vs 5.4 kPa , P=0.03 and 5.1 vs 5.3 kPa , P=0.03 , respectively ) . Escalation in respiratory support at any time in the study occurred in 47 patients ( 27.8 % ) allocated to NHF compared with 77 ( 45 % ) st and ard care ( OR 0.47 , 95 % CI 0.29 - 0.7 , P=0.001 ) . CONCLUSIONS Routine use of NHF did not increase / ratio on Day 3 but did reduce the requirement for escalation of respiratory support . TRIAL REGISTRATION Australia New Zeal and Clinical Trials Registry www.anzctr.org.au ( ACTRN12610000973011 ) [25390281] BACKGROUND : Effective O2 delivery and accurate end-tidal CO2 ( ETCO2 ) sampling are essential features of nasal cannulae ( NCs ) in patients with compromised respiratory status . We studied 4 NC design s : bifurcated nasal prongs ( NPs ) with O2 delivery and CO2 sensing in both NPs ( Hudson ) , separate O2/CO2 NPs ( Salter ) , and CO2 sensing in NPs with cloud O2 delivery outside the NPs via multi vents ( Oridion ) and dual vents ( Medline ) . We hypothesized that design differences between NCs would influence O2 delivery and ETCO2 detection . METHODS : Forty-five healthy volunteers , 18 to 35 years , participated in an unrestricted , r and omized block design , each subject serving as their own control in a 4-period crossover study design of 4 NCs during one session . Monitoring included electrocardiogram , posterior pharynx O2 sampling from a Hauge Airway ( Sharn Anesthesia Products , Tampa , FL ) , and NC ETCO2 . In 11 volunteers , radial artery blood was sample d from a catheter for partial pressures of O2 and carbon dioxide ( PaO2 and PaCO2 ) determination . Per r and omization , each NC was positioned , and data were collected over 2 minutes ( ETCO2 , pharyngeal O2 , PaO2 , and PaCO2 ) during room air and during O2 fresh gas flows ( FGFs ) of 2 , 4 , and 6 Lpm . Statistical analyses were performed with SAS Analytics Pro , Version 9.3 , and JMP Statistical Software , Version 11 ( SAS Institute Inc. , Cary , NC ) , significance at P < 0.05 . RESULTS : Blood gas analyses indicated PaCO2 during steady state at each experimental time period remained unchanged from physiologic baseline . PaO2 did not differ between NC devices at baseline or 2 Lpm O2 . The PaO2 at 4 Lpm from the separate NPs and bifurcated NCs was significantly higher than the multi-vented NC . Pharyngeal O2 with the NC with separate NPs was significantly higher than multivented and dual-vented cloud delivery NCs at 2 , 4 , and 6 Lpm FGF . Pharyngeal O2 with the NC with bifurcated NPs was significantly higher than the multi-vented NC at 2 Lpm , and higher than cloud delivery NCs at 4 and 6 Lpm FGF . ETCO2 was significantly lower with the NC with bifurcated NPs compared to the other 3 NCs , consistent with errant CO2 tracings at higher FGF . CONCLUSIONS : NCs provide supplemental inspired O2 concentrations for patients with impaired pulmonary function . Accurate measures of ETCO2 are helpful in assessing respiratory rate and determining whether CO2 retention is occurring from hypoventilation . These findings suggest the NC with separate NPs was the most effective in delivering O2 and the most consistent at providing reliable CO2 waveforms at higher FGFs [26577199] BACKGROUND : Humidified high-flow nasal cannula ( HFNC ) is a novel method of oxygen delivery with increasing use in emergency departments and intensive care setting s despite little evidence showing benefit over st and ard oxygen delivery methods ( st and ard O2 ) . The aim of this study was to determine whether HFNC compared with st and ard O2 given to subjects in acute respiratory distress would reduce the need for noninvasive ventilation or invasive ventilation . METHODS : This was a pragmatic open r and omized controlled trial in adult subjects with hypoxia and tachypnea presenting to a tertiary academic hospital emergency department . The primary outcome was the need for mechanical ventilation in the emergency department . RESULTS : We screened 1,287 patients , 322 met entry criteria and 19 were excluded from analysis . Of these , 165 r and omized to HFNC and 138 to st and ard O2 were analyzed . Baseline characteristics were similar . In the HFNC group , 3.6 % ( 95 % CI 1.5–7.9 % ) versus 7.2 % ( 95 % CI 3.8–13 % ) in the st and ard O2 group required mechanical ventilation in the emergency department ( P = .16 ) , and 5.5 % ( 95 % CI 2.8–10.2 % ) in HFNC versus 11.6 % ( 95 % CI 7.2–18.1 % ) in the st and ard O2 group required mechanical ventilation within 24 h of admission ( P = .053 ) . There was no difference in mortality or stay . Adverse effects were infrequent ; however , fewer subjects in the HFNC group had a fall in Glasgow coma score due to CO2 retention , 0 % ( 95 % CI 0–3 % ) versus 2.2 % ( 95 % CI 0.4–6 % ) . One in 12 subjects did not tolerate HFNC . CONCLUSIONS : HFNC was not shown to reduce the need for mechanical ventilation in the emergency department for subjects with acute respiratory distress compared with st and ard O2 , although it was safe and may reduce the need for escalation of oxygen therapy within the first 24 h of admission [25691263] Purpose Intubation in patients with respiratory failure can be avoided by high-flow nasal cannula ( HFNC ) use . However , it is unclear whether waiting until HFNC fails , which would delay intubation , has adverse effects . The present retrospective observational study assessed overall ICU mortality and other hospital outcomes of patients who received HFNC therapy that failed . Methods All consecutive patients in one tertiary hospital who received HFNC therapy that failed and who then required intubation between January 2013 and March 2014 were enrolled and classified according to whether intubation started early ( within 48 h ) or late ( at least 48 h ) after commencing HFNC . Results Of the 175 enrolled patients , 130 ( 74.3 % ) and 45 ( 25.7 % ) were intubated before and after 48 h of HFNC , respectively . The groups were similar in terms of most baseline characteristics . The early intubated patients had better overall ICU mortality ( 39.2 vs. 66.7 % ; P = 0.001 ) than late intubated patients . A similar pattern was seen with extubation success ( 37.7 vs. 15.6 % ; P = 0.006 ) , ventilator weaning ( 55.4 vs. 28.9 % ; P = 0.002 ) , and ventilator-free days ( 8.6 ± 10.1 vs. 3.6 ± 7.5 ; P = 0.011 ) . In propensity-adjusted and -matched analysis , early intubation was also associated with better overall ICU mortality [ adjusted odds ratio ( OR ) = 0.317 , P = 0.005 ; matched OR = 0.369 , P = 0.046 ] . Conclusions Failure of HFNC might cause delayed intubation and worse clinical outcomes in patients with respiratory failure . Large prospect i ve and r and omized controlled studies on HFNC failure are needed to draw a definitive conclusion [23739633] CONTEXT Dyspnea is one of the most distressing symptoms for cancer patients . The role of high-flow oxygen ( HFO ) and bilevel positive airway pressure ( BiPAP ) in the palliation of dyspnea has not been well characterized . OBJECTIVES To determine the feasibility of conducting a r and omized trial of HFO and BiPAP in cancer patients and examine the changes in dyspnea , physiologic parameters , and adverse effects with these modalities . METHODS In this r and omized study ( Clinical Trials.gov Identifier : NCT01518140 ) , we assigned hospitalized patients with advanced cancer and persistent dyspnea to either HFO or BiPAP for two hours . We assessed dyspnea with a numeric rating scale ( NRS ) and modified Borg scale ( MBS ) before and after the intervention . We also documented vital signs , transcutaneous carbon dioxide , and adverse effects . RESULTS Thirty patients were enrolled ( 1:1 ratio ) and 23 ( 77 % ) completed the assigned intervention . HFO was associated with improvements in both NRS ( mean 1.9 ; 95 % CI 0.4 - 3.4 ; P = 0.02 ) and MBS ( mean 2.1 ; 95 % CI 0.6 - 3.5 ; P = 0.007 ) . BiPAP also was associated with improvements in NRS ( mean 3.2 ; 95 % CI 1.3 - 5.1 ; P = 0.004 ) and MBS ( mean 1.5 ; 95 % CI -0.3 , 3.2 ; P = 0.13 ) . There were no significant differences between HFO and BiPAP in dyspnea NRS ( P = 0.14 ) and MBS ( P = 0.47 ) . Oxygen saturation improved with HFO ( 93 % vs. 99 % ; P = 0.003 ) , and respiratory rate had a nonstatistically significant decrease with both interventions ( HFO -3 , P = 0.11 ; BiPAP -2 , P = 0.11 ) . No significant adverse effects were observed . CONCLUSION HFO and BiPAP alleviated dyspnea , improved physiologic parameters , and were safe . Our results justify larger r and omized controlled trials to confirm these findings [21946925] Purpose To evaluate the efficiency , safety and outcome of high flow nasal cannula oxygen ( HFNC ) in ICU patients with acute respiratory failure . Methods Pilot prospect i ve monocentric study . Thirty-eight patients were included . Baseline demographic and clinical data , as well as respiratory variables at baseline and various times after HFNC initiation during 48 h , were recorded . Arterial blood gases were measured before and after the use of HFNC . Noise and discomfort were monitored along with outcome and need for invasive mechanical ventilation . Results HFNC significantly reduced the respiratory rate , heart rate , dyspnea score , supraclavicular retraction and thoracoabdominal asynchrony , and increased pulse oxymetry . These improvements were observed as early as 15 min after the beginning of HFNC for respiratory rate and pulse oxymetry . PaO2 and PaO2/FiO2 increased significantly after 1 h HFNC in comparison with baseline ( 141 ± 106 vs. 95 ± 40 mmHg , p = 0.009 and 169 ± 108 vs. 102 ± 23 , p = 0.036 ; respectively ) . These improvements lasted throughout the study period . HFNC was used for a mean duration of 2.8 days and a maximum of 7 days . It was never interrupted for intolerance . No nosocomial pneumonia occurred during HFNC . Nine patients required secondary invasive mechanical ventilation . Absence of a significant decrease in the respiratory rate , lower oxygenation and persistence of thoracoabdominal asynchrony after HFNC initiation were early indicators of HFNC failure . Conclusions HFNC has a beneficial effect on clinical signs and oxygenation in ICU patients with acute respiratory failure . These favorable results constitute a prerequisite to launching a r and omized controlled study to investigate whether HFNC reduces intubation in these patients [26060321] BACKGROUND : Acute dyspnea and hypoxemia are 2 of the most common problems in the emergency room . Oxygen therapy is an essential supportive treatment to correct these issues . In this study , we investigated the physiologic effects of high-flow nasal oxygen cannula ( HFNC ) compared with conventional oxygen therapy ( COT ) in subjects with acute dyspnea and hypoxemia in the emergency room . METHODS : A prospect i ve r and omized comparative study was conducted in the emergency department of a university hospital . Forty subjects were r and omized to receive HFNC or COT for 1 h. The primary outcome was level of dyspnea , and secondary outcomes included change in breathing frequency , subject comfort , adverse events , and rate of hospitalization . RESULTS : Common causes of acute dyspnea and hypoxemia were congestive heart failure , asthma exacerbation , COPD exacerbation , and pneumonia . HFNC significantly improved dyspnea ( 2.0 ± 1.8 vs 3.8 ± 2.3 , P = .01 ) and subject comfort ( 1.6 ± 1.7 vs 3.7 ± 2.4 , P = .01 ) compared with COT . No statistically significant difference in breathing frequency was found between the 2 groups at the end of the study . HFNC was well tolerated , and no serious adverse events were found . The rate of hospitalization in the HFNC group was lower than in the COT group , but there was no statistically significant difference ( 50 % vs 65 % , P = .34 ) . CONCLUSIONS : HFNC improved dyspnea and comfort in subjects presenting with acute dyspnea and hypoxemia in the emergency department . HFNC may benefit patients requiring oxygen therapy in the emergency room [22417569] BACKGROUND : Non-intubated critically ill patients are often treated by high-flow oxygen for acute respiratory failure . There is no current recommendation for humidification of oxygen devices . METHODS : We conducted a prospect i ve r and omized trial with a final crossover period to compare nasal airway caliber and respiratory comfort in patients with acute hypoxemic respiratory failure receiving either st and ard oxygen therapy with no humidification or heated and humidified high-flow oxygen therapy ( HHFO2 ) in a medical ICU . Nasal airway caliber was measured using acoustic rhinometry at baseline , after 4 and 24 hours ( H4 and H24 ) , and 4 hours after crossover ( H28 ) . Dryness of the nose , mouth , and throat was auto-evaluated and assessed blindly by an otorhinolaryngologist . After the crossover , the subjects were asked which system they preferred . RESULTS : Thirty subjects completed the protocol and were analyzed . Baseline median oxygen flow was 9 and 12 L/min in the st and ard and HHFO2 groups , respectively ( P = .21 ) . Acoustic rhinometry measurements showed no difference between the 2 systems . The dryness score was significantly lower in the HHFO2 group at H4 ( 2 vs 6 , P = .007 ) and H24 ( 0 vs 8 , P = .004 ) . During the crossover period , dryness increased promptly after switching to st and ard oxygen and decreased after switching to HHFO2 ( P = .008 ) . Sixteen subjects ( 53 % ) preferred HHFO2 ( P = .01 ) , especially those who required the highest flow of oxygen at admission ( P = .05 ) . CONCLUSIONS : Upper airway caliber was not significantly modified by HHFO2 , compared to st and ard oxygen therapy , but HHFO2 significantly reduced discomfort in critically ill patients with respiratory failure . The system is usually preferred over st and ard oxygen therapy [21762554] BACKGROUND : The effectiveness of noninvasive ventilation ( NIV ) after extubation in preventing post-extubation respiratory failure is still controversial . METHODS : We conducted a prospect i ve , multicenter r and omized controlled study involving patients on mechanical ventilation for > 48 hours who tolerated a 2-hour spontaneous breathing trial and were subsequently extubated . The patients were r and omized to NIV or st and ard medical therapy . Re-intubation rate within 72 hours was the primary outcome measure . Multivariable logistic regression analysis was used to determine predictors for extubation failure . RESULTS : We r and omized 406 patients to either NIV ( no. = 202 ) or st and ard medical therapy ( no. = 204 ) . The 2 groups had similar baseline clinical characteristics . There were no differences in extubation failure ( 13.2 % in control and 14.9 % in NIV ) , intensive care unit or hospital mortality . Cardiac failure was a more common cause of extubation failure in control than in NIV . There was no difference in rapid shallow breathing index ( RSBI ) in extubation failure patients between control ( 80 ) and NIV ( 73 ) . When using data from all patients , we found Acute Physiology and Chronic Health Evaluation ( APACHE II ) scores ( odds ratio [ OR ] 1.13 , 95 % CI 1.07–1.20 , P < .001 ) , maximal inspiratory pressure ( OR 1.04 , 95 % CI 1.00–1.08 , P = .03 ) , and RSBI ( OR 1.03 , 95 % CI 1.02–1.05 , P < .001 ) to be predictors of extubation failure . Abundant secretions were the most common reason ( 35.1 % ) for extubation failure identified by attending physicians . CONCLUSIONS : Preventive use of NIV after extubation in patients who passed spontaneous breathing trial did not show benefits in decreasing extubation failure rate or the mortality rate [28124736] Purpose Nasal continuous positive airway pressure ( nCPAP ) is currently the gold st and ard for respiratory support for moderate to severe acute viral bronchiolitis ( AVB ) . Although oxygen delivery via high flow nasal cannula ( HFNC ) is increasingly used , evidence of its efficacy and safety is lacking in infants . Methods A r and omized controlled trial was performed in five pediatric intensive care units ( PICUs ) to compare 7 cmH2O nCPAP with 2 L/kg/min oxygen therapy administered with HFNC in infants up to 6 months old with moderate to severe AVB . The primary endpoint was the percentage of failure within 24 h of r and omization using prespecified criteria . To satisfy noninferiority , the failure rate of HFNC had to lie within 15 % of the failure rate of nCPAP . Secondary outcomes included success rate after crossover , intubation rate , length of stay , and serious adverse events . Results From November 2014 to March 2015 , 142 infants were included and equally distributed into groups . The risk difference of −19 % ( 95 % CI −35 to −3 % ) did not allow the conclusion of HFNC noninferiority ( p = 0.707 ) . Superiority analysis suggested a relative risk of success 1.63 ( 95 % CI 1.02–2.63 ) higher with nCPAP . The success rate with the alternative respiratory support , intubation rate , duration s of noninvasive and invasive ventilation , skin lesions , and length of PICU stay were comparable between groups . No patient had air leak syndrome or died . Conclusion In young infants with moderate to severe AVB , initial management with HFNC did not have a failure rate similar to that of nCPAP . This clinical trial was recorded in the National Library of Medicine registry ( NCT 02457013 ) [24046462] OBJECTIVE : Compare the short-term benefit of high-flow nasal cannula ( HFNC ) with non-rebreathing mask in terms of change in dyspnea , physiologic variables , and patient comfort in subjects after endotracheal extubation . METHODS : A r and omized crossover study was conducted in a 10-bed respiratory care unit in a university hospital . Seventeen mechanically ventilated subjects were r and omized after extubation to either Protocol A ( applied HFNC for 30 min , followed by non-rebreathing mask for another 30 min ) or Protocol B ( applied non-rebreathing mask for 30 min , followed by HFNC for another 30 min ) . The level of dyspnea , breathing frequency , heart rate , blood pressure , oxygen saturation , and patient comfort were recorded . The results were expressed as mean ± SD , frequency , or percentage . Categorical variables were compared by chi-square test or Fisher exact test , and continuous variables were compared by dependent or paired t test . Statistical significance was defined as P < .05 . RESULTS : Seventeen subjects were divided into 2 groups : 9 subjects in Protocol A and 8 subjects in Protocol B. The baseline characteristics and physiologic parameters before extubation were not significantly different in each protocol . At the end of study , HFNC indicated less dyspnea ( P = .04 ) and lower breathing frequency ( P = .009 ) and heart rate ( P = .006 ) compared with non-rebreathing mask . Most of the subjects ( 88.2 % ) preferred HFNC to non-rebreathing mask . CONCLUSIONS : HFNC can improve dyspnea and physiologic parameters , including breathing frequency and heart rate , in extubated subjects compared with conventional oxygen therapy . This device may have a potential role for use after endotracheal extubation [25003980] RATIONALE Oxygen is commonly administered after extubation . Although several devices are available , data about their clinical efficacy are scarce . OBJECTIVES To compare the effects of the Venturi mask and the nasal high-flow ( NHF ) therapy on PaO2/FiO2SET ratio after extubation . Secondary endpoints were to assess effects on patient discomfort , adverse events , and clinical outcomes . METHODS R and omized , controlled , open-label trial on 105 patients with a PaO2/FiO2 ratio less than or equal to 300 immediately before extubation . The Venturi mask ( n = 52 ) or NHF ( n = 53 ) were applied for 48 hours postextubation . MEASUREMENTS AND MAIN RESULTS PaO2/FiO2SET , patient discomfort caused by the interface and by symptoms of airways dryness ( on a 10-point numerical rating scale ) , interface displacements , oxygen desaturations , need for ventilator support , and reintubation were assessed up to 48 hours after extubation . From the 24th hour , PaO2/FiO2SET was higher with the NHF ( 287 ± 74 vs. 247 ± 81 at 24 h ; P = 0.03 ) . Discomfort related both to the interface and to airways dryness was better with NHF ( respectively , 2.6 ± 2.2 vs. 5.1 ± 3.3 at 24 h , P = 0.006 ; 2.2 ± 1.8 vs. 3.7 ± 2.4 at 24 h , P = 0.002 ) . Fewer patients had interface displacements ( 32 % vs. 56 % ; P = 0.01 ) , oxygen desaturations ( 40 % vs. 75 % ; P < 0.001 ) , required reintubation ( 4 % vs. 21 % ; P = 0.01 ) , or any form of ventilator support ( 7 % vs. 35 % ; P < 0.001 ) in the NHF group . CONCLUSIONS Compared with the Venturi mask , NHF results in better oxygenation for the same set FiO2 after extubation . Use of NHF is associated with better comfort , fewer desaturations and interface displacements , and a lower reintubation rate . Clinical trial registered with www . clinical trials.gov ( NCT 01575353 ) [25479117] Objectives : Tracheal intubation of ICU patients is frequently associated with severe hypoxemia . Although noninvasive ventilation reduces desaturation during intubation of severely hypoxemic patients , it does not allow for per-procedure oxygenation and has not been evaluated in mild-to-moderate hypoxemic patients for whom high-flow nasal cannula oxygen may be an alternative . We sought to compare pre- and per-procedure oxygenation with either a nonrebreathing bag reservoir facemask or a high-flow nasal cannula oxygen during tracheal intubation of ICU patients . Design : Prospect i ve quasi-experimental before-after study ( Clinical Trials.gov : NCT01699880 ) . Setting : University hospital medico-surgical ICU . Patients : All adult patients requiring tracheal intubation in the ICU were eligible . Interventions : In the control ( before ) period , preoxygenation was performed with a nonrebreathing bag reservoir facemask and in the change of practice ( after ) period , with high-flow nasal cannula oxygen . Measurements and Main Results : Primary outcome was median lowest SpO2 during intubation , and secondary outcomes were SpO2 after preoxygenation and number of patients with saturation less than 80 % . One hundred one patients were included . Median lowest SpO2 during intubation were 94 % ( 83–98.5 ) with the nonrebreathing bag reservoir facemask versus 100 % ( 95–100 ) with high-flow nasal cannula oxygen ( p < 0.0001 ) . SpO2 values at the end of preoxygenation were higher with high-flow nasal cannula oxygen than with nonrebreathing bag reservoir facemask and were correlated with the lowest SpO2 reached during the intubation procedure ( r = 0.38 , p < 0.0001 ) . Patients in the nonrebreathing bag reservoir facemask group experienced more episodes of severe hypoxemia ( 2 % vs 14 % , p = 0.03 ) . In the multivariate analysis , preoxygenation with high-flow nasal cannula oxygen was an independent protective factor of the occurrence of severe hypoxemia ( odds ratio , 0.146 ; 95 % CI , 0.01–0.90 ; p = 0.037 ) . Conclusions : High-flow nasal cannula oxygen significantly improved preoxygenation and reduced prevalence of severe hypoxemia compared with nonrebreathing bag reservoir facemask . Its use could improve patient safety during intubation [27481760] PURPOSE The purpose of the study is to describe early predictors and to develop a prediction tool that accurately identifies the need for mechanical ventilation ( MV ) in pneumonia patients with hypoxemic acute respiratory failure ( ARF ) treated with high-flow nasal cannula ( HFNC ) . MATERIAL S AND METHODS This is a 4-year prospect i ve observational 2-center cohort study including patients with severe pneumonia treated with HFNC . High-flow nasal cannula failure was defined as need for MV . ROX index was defined as the ratio of pulse oximetry/fraction of inspired oxygen to respiratory rate . RESULTS One hundred fifty-seven patients were included , of whom 44 ( 28.0 % ) eventually required MV ( HFNC failure ) . After 12 hours of HFNC treatment , the ROX index demonstrated the best prediction accuracy ( area under the receiver operating characteristic curve 0.74 [ 95 % confidence interval , 0.64 - 0.84 ] ; P<.002 ) . The best cutoff point for the ROX index was estimated to be 4.88 . In the Cox proportional hazards model , a ROX index greater than or equal to 4.88 measured after 12 hours of HFNC was significantly associated with a lower risk for MV ( hazard ratio , 0.273 [ 95 % confidence interval , 0.121 - 0.618 ] ; P=.002 ) , even after adjusting for potential confounding . CONCLUSIONS In patients with ARF and pneumonia , the ROX index can identify patients at low risk for HFNC failure in whom therapy can be continued after 12 hours [22165366] In this study , we evaluated the performance of a humidified nasal high-flow system ( Optiflow ™ , Fisher and Paykel Healthcare ) by measuring delivered FiO2 and airway pressures . Oxygraphy , capnography and measurement of airway pressures were performed through a hypopharyngeal catheter in healthy volunteers receiving Optiflow ™ humidified nasal high flow therapy at rest and with exercise . The study was conducted in a non- clinical experimental setting . Ten healthy volunteers completed the study after giving informed written consent . Participants received a delivered oxygen fraction of 0.60 with gas flow rates of 10 , 20 , 30 , 40 and 50 l/minute in r and om order . FiO2 , FEO2 , FECO2 and airway pressures were measured . Calculation of FiO2 from FEO2 and FECO2 was later performed . Calculated FiO2 approached 0.60 as gas flow rates increased above 30 l/minute during nose breathing at rest . High peak inspiratory flow rates with exercise were associated with increased air entrainment . Hypopharyngeal pressure increased with increasing delivered gas flow rate . At 50 l/minute the system delivered a mean airway pressure of up to 7.1 cmH2O . We believe that the high gas flow rates delivered by this system enable an accurate inspired oxygen fraction to be delivered . The positive mean airway pressure created by the high flow increases the efficacy of this system and may serve as a bridge to formal positive pressure systems [25851385] Purpose Patients with a body mass index ( BMI ) ≥30 kg/m2 experience more severe atelectasis following cardiac surgery than those with normal BMI and its resolution is slower . This study aim ed to compare extubation of patients post-cardiac surgery with a BMI ≥30 kg/m2 onto high-flow nasal cannulae ( HFNC ) with st and ard care to determine whether HFNC could assist in minimising post-operative atelectasis and improve respiratory function . Methods In this r and omised controlled trial , patients received HFNC or st and ard oxygen therapy post-extubation . The primary outcome was atelectasis on chest X-ray . Secondary outcomes included oxygenation , respiratory rate ( RR ) , subjective dyspnoea , and failure of allocated treatment . Results One hundred and fifty-five patients were r and omised , 74 to control , 81 to HFNC . No difference was seen between groups in atelectasis scores on Days 1 or 5 ( median scores = 2 , p = 0.70 and p = 0.15 , respectively ) . In the 24-h post-extubation , there was no difference in mean PaO2/FiO2 ratio ( HFNC 227.9 , control 253.3 , p = 0.08 ) , or RR ( HFNC 17.2 , control 16.7 , p = 0.17 ) . However , low dyspnoea levels were observed in each group at 8 h post-extubation , median ( IQR ) scores were 0 ( 0–1 ) for control and 1 ( 0–3 ) for HFNC ( p = 0.008 ) . Five patients failed allocated treatment in the control group compared with three in the treatment group [ Odds ratio 0.53 , ( 95 % CI 0.11 , 2.24 ) , p = 0.40 ] . Conclusions In this study , prophylactic extubation onto HFNC post-cardiac surgery in patients with a BMI ≥30 kg/m2 did not lead to improvements in respiratory function . Larger studies assessing the role of HFNC in preventing worsening of respiratory function and intubation are required [25944940] INTRODUCTION : High-flow nasal cannula ( HFNC ) can deliver heated and humidified gas ( up to 100 % oxygen ) at a maximum flow of 60 L/min via nasal prongs or cannula . The aim of this study was to assess the short-term physiologic effects of HFNC . Inspiratory muscle effort , gas exchange , dyspnea score , and comfort were evaluated . METHODS : Twelve subjects admitted to the ICU for acute hypoxemic respiratory failure were prospect ively included . Four study sessions were performed . The first session consisted of oxygen therapy given through a high-FIO2 , non-rebreathing face mask . Recordings were then obtained during periods of HFNC and CPAP at 5 cm H2O in r and om order , and final measurements were performed during oxygen therapy delivered via a face mask . Each of these 4 periods lasted ∼20 min . RESULTS : Esophageal pressure signals , breathing pattern , gas exchange , comfort , and dyspnea were measured . Compared with the first session , HFNC reduced inspiratory effort ( pressure-time product of 156.0 [ 119.2–194.4 ] cm H2O × s/min vs 204.2 [ 149.6–324.7 ] cm H2O × s/min , P < .01 ) and breathing frequency ( P < .01 ) . No significant differences were observed between HFNC and CPAP for inspiratory effort and breathing frequency . Compared with the first session , PaO2/FIO2 increased significantly with HFNC ( 167 [ 157–184 ] mm Hg vs 156 [ 110–171 ] mm Hg , P < .01 ) . CPAP produced significantly greater PaO2/FIO2 improvement than did HFNC . Dyspnea improved with HFNC and CPAP , but this improvement was not significant . Subject comfort was not different across the 4 sessions . CONCLUSIONS : Compared with conventional oxygen therapy , HFNC improved inspiratory effort and oxygenation . In subjects with acute hypoxemic respiratory failure , HFNC is an alternative to conventional oxygen therapy . ( Clinical Trials.gov registration NCT01056952 . [26975498] IMPORTANCE Studies of mechanically ventilated critically ill patients that combine population s that are at high and low risk for reintubation suggest that conditioned high-flow nasal cannula oxygen therapy after extubation improves oxygenation compared with conventional oxygen therapy . However , conclusive data about reintubation are lacking . OBJECTIVE To determine whether high-flow nasal cannula oxygen therapy is superior to conventional oxygen therapy for preventing reintubation in mechanically ventilated patients at low risk for reintubation . DESIGN , SETTING , AND PARTICIPANTS Multicenter r and omized clinical trial conducted between September 2012 and October 2014 in 7 intensive care units ( ICUs ) in Spain . Participants were 527 adult critical patients at low risk for reintubation who fulfilled criteria for planned extubation . Low risk for reintubation was defined as younger than 65 years ; Acute Physiology and Chronic Health Evaluation II score less than 12 on day of extubation ; body mass index less than 30 ; adequate secretions management ; simple weaning ; 0 or 1 comorbidity ; and absence of heart failure , moderate-to-severe chronic obstructive pulmonary disease , airway patency problems , and prolonged mechanical ventilation . INTERVENTIONS Patients were r and omized to undergo either high-flow or conventional oxygen therapy for 24 hours after extubation . MAIN OUTCOMES AND MEASURES The primary outcome was reintubation within 72 hours , compared with the Cochran-Mantel-Haenszel χ2 test . Secondary outcomes included postextubation respiratory failure , respiratory infection , sepsis and multiorgan failure , ICU and hospital length of stay and mortality , adverse events , and time to reintubation . RESULTS Of 527 patients ( mean age , 51 years [ range , 18 - 64 ] ; 62 % men ) , 264 received high-flow therapy and 263 conventional oxygen therapy . Reintubation within 72 hours was less common in the high-flow group ( 13 patients [ 4.9 % ] vs 32 [ 12.2 % ] in the conventional group ; absolute difference , 7.2 % [ 95 % CI , 2.5 % to 12.2 % ] ; P = .004 ) . Postextubation respiratory failure was less common in the high-flow group ( 22/264 patients [ 8.3 % ] vs 38/263 [ 14.4 % ] in the conventional group ; absolute difference , 6.1 % [ 95 % CI , 0.7 % to 11.6 % ] ; P = .03 ) . Time to reintubation was not significantly different between groups ( 19 hours [ interquartile range , 12 - 28 ] in the high-flow group vs 15 hours [ interquartile range , 9 - 31 ] in the conventional group ; absolute difference , -4 [ 95 % CI , -54 to 46 ] ; P = .66 ] . No adverse effects were reported . CONCLUSIONS AND RELEVANCE Among extubated patients at low risk for reintubation , the use of high-flow nasal cannula oxygen compared with conventional oxygen therapy reduced the risk of reintubation within 72 hours . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01191489 Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: The combination of an increasing number of new cancer cases and improving survival rates has led to a large and rapidly growing population with unique health-care requirements . Exercise has been proposed as a strategy to help address the issues faced by cancer patients . Supported by a growing body of research , major health organizations commonly identify the importance of incorporating exercise in cancer care and advise patients to be physically active . This systematic review comprehensively summarizes the available epidemiologic and r and omized controlled trial evidence investigating the role of exercise in the management of cancer . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

15609840

[10390311] BACKGROUND AND PURPOSE It has been suggested that cyclic neuromuscular electrical stimulation ( ES ) may enhance motor recovery after stroke . We have investigated the effects of ES of the wrist extensors on impairment of wrist function and on upper-limb disability in patients being rehabilitated after acute stroke . METHODS We recruited 60 hemiparetic patients ( mean age , 68 years ) 2 to 4 weeks after stroke into a r and omized , controlled , parallel-group study comparing st and ard rehabilitation treatment with st and ard treatment plus ES of wrist extensors ( 3 times 30 minutes daily for 8 weeks ) . Isometric strength of wrist extensors was measured using a device built for that purpose . Upper-limb disability was assessed with use of the Action Research Arm Test ( ARAT ) . Observations were continued for 32 weeks ( 24 weeks after the finish of ES or the control intervention phase ) . RESULTS The change in isometric strength of wrist extensors ( at an angle of 0 degrees extension ) was significantly greater in the ES group than the control group at both 8 and 32 weeks ( P=0.004 , P=0.014 by Mann Whitney U test ) . At week 8 the grasp and grip subscores of the ARAT increased significantly in the ES group compared with that in the control group ( P=0.013 and P=0.02 , respectively ) ; a similar trend was seen for the total ARAT score ( P=0.11 ) . In the subgroup of 33 patients with some residual wrist extensor strength at study entry ( moment at 0 degrees extension > 0 ) , the ARAT total score had increased at week 8 by a mean of 21.1 ( SD , 12.7 ) in the ES group compared with 10.3 ( SD , 9.0 ) in the control group ( P=0.024 , Mann Whitney U test ) ; however , at 32 weeks the differences between these 2 subgroups were no longer statistically significant . CONCLUSIONS ES of the wrist extensors enhances the recovery of isometric wrist extensor strength in hemiparetic stroke patients . Upper-limb disability was reduced after 8 weeks of ES therapy , with benefits most apparent in those with some residual motor function at the wrist . However , it is not clear how long the improvements in upper-limb disability are maintained after ES is discontinued [7149946] Poor prognosis for upper limb recovery of stroke survivors has not changed in at least 28 years ; only 4 % to 5 % of patients regain arm function during or after the active rehabilitation phase . This pilot study included 37 patients r and omly assigned to either an integrated behavioral-physical therapy treatment program including electromyographic feedback ( experimental group ) or a st and ard exercise physical therapy program of like duration and intensity ( control group ) . Both groups showed clinical ly significant improvements that exceeded previously reported experience . The experimental technique appears to be more effective when upper limb involvement is not severe in a late case , or when treatment is started early ( within 3 months poststroke ) in a severe case . The rehabilitation community should quickly investigate the improved prospect s of restoring a greater number of useful upper limbs in this often neglected group of hemiplegic patients [10084443] OBJECTIVE To determine the influence of functional electrical stimulation ( FES ) on subluxation and shoulder pain in hemiplegic patients . DESIGN Controlled study of 24 months ' duration beginning in the first month after onset of stroke . SUBJECTS AND SETTING One hundred twenty hemiplegic patients with both subluxed and painful shoulder were followed for rehabilitation before and after discharge between 1989 and 1993 . All subjects received conventional rehabilitation based on the Bobath concept . In addition , patients were alternately assigned to a control group or to receive additional FES for 5 weeks on muscles surrounding their subluxed and painful shoulder . MAIN MEASURES Clinical examinations , including range of motion , pain assessment , and x-rays , were performed at the start of the study , between the second and fourth weeks after onset of stroke , and subsequently at 6 , 12 , and 24 months . RESULTS The FES group showed significantly more improvement than the control group in both pain relief ( 80.7 % vs. 55.1 % , p<.01 ) and reduction of subluxation ( 78.9 % vs. 58.6 % , p<.05 ) . Furthermore , recovery of arm motion appeared to be significantly improved in the FES group ( 77.1 % vs. 60.3 % in the control group , p<.01 ) . CONCLUSION The FES program was significantly effective in reducing the severity of subluxation and pain and possibly may have facilitated recovery of the shoulder function in hemiplegic patients [11108760] Background and Purpose Motor dysfunction after unilateral deafferentation in primates can be overcome by restraining the unaffected limb . We asked whether a constraint-induced movement ( CIM ) program could be implemented within 2 weeks after stroke and whether CIM is more effective than traditional upper-extremity ( UE ) therapies during this period . Methods Twenty-three persons were enrolled in a pilot r and omized , controlled trial that compared CIM with traditional therapies . A blinded observer rated the primary end point , the Action Research Arm Test ( ARA ) . Inclusion criteria were the following : ischemic stroke within 14 days , persistent hemiparesis , evidence of preserved cognitive function , and presence of a protective motor response . Differences between the groups were compared by using Student ’s t tests , ANCOVA , and Mann-Whitney U tests . Results Twenty subjects completed the 14-day treatment . Two adverse outcomes , a recurrent stroke and a death , occurred in the traditional group ; 1 CIM subject met rehabilitation goals and was discharged before completing 14 inpatient days . The CIM treatment group had significantly higher scores on total ARA and pinch subscale scores ( P < 0.05 ) . Differences in the mean ARA grip , grasp , and gross movement subscale scores did not reach statistical significance . UE activities of daily living performance was not significantly different between groups , and no subject withdrew because of pain or frustration . Conclusions A clinical trial of CIM therapy during acute rehabilitation is feasible . CIM was associated with less arm impairment at the end of treatment . Long-term studies are needed to determine whether CIM early after stroke is superior to traditional therapies [9349677] Experimental and control groups of 10 hemiparetic stroke patients each underwent a 6 week , twice daily gait training program . The control group participated in a conventional physical therapy gait program . The experimental group trained in the same basic program with the addition of rhythmic auditory stimulation ( RAS ) . Patients entered the study as soon as they could complete 5 strides with h and -held assistance . The training program had to be completed within 3 months of the patients ' stroke . In the experimental group RAS was used as a timekeeper to synchronize step patterns and gradually entrain higher stride frequencies . Study groups were equated by gender , lesion site , and age . Motor function was assessed at pretest using Barthel , Fugl-Meyer , and Berg Scales . Walking patterns were assessed during pre- and post-test without RAS present . Pre- vs post-test measures revealed a statistically significant ( P<0.05 ) increase in velocity ( 164 % vs 107 % ) , stride length ( 88 % vs 34 % ) , and reduction in EMG amplitude variability of the gastrocnemius muscle ( 69 % vs 33 % ) for the RAS-training group compared to the control group . The difference in stride symmetry improvement ( 32 % in the RAS-group vs 16 % in the control group ) was statistically not significant . The data offer evidence that RAS is an efficient tool to enhance efforts in gait rehabilitation with acute stroke patients [8202978] Background and Purpose Alterations of gait cycle and foot-drop on the paretic limb are characteristic of stroke patients . Electromyographic biofeedback treatment has been used in rehabilitation of walking , but results are controversial . We performed gait analysis to evaluate the efficacy of electromyographic biofeedback compared with physical therapy . Methods Sixteen patients with ischemic stroke were enrolled in the study . The experimental group ( 4 men , 4 women ) received electromyographic biofeedback treatment together with physical therapy . The control group ( 5 men , 3 women ) was treated with physical therapy only . Clinical and functional evaluations before and after treatment were performed using Canadian Neurological , Adams , Ashworth , Basmajian , and Barthel Index scales . Computerized gait analysis was performed in all patients . Results Electromyographic biofeedback patients showed significantly increased scores on the Adams scale ( P<.05 ) and Basmajian scale ( P<.01 ) . Gait analysis in this group showed a recovery of foot-drop in the swing phase ( P<.02 ) after training . Conclusions Our data confirm that the electromyographic biofeedback technique increases muscle strength and improves recovery of functional locomotion in patients with hemiparesis and foot-drop after cerebral ischemia [12920254] BACKGROUND AND PURPOSE Rehabilitation care after stroke is highly variable and increasingly shorter in duration . The effect of therapeutic exercise on impairments and functional limitations after stroke is not clear . The objective of this study was to determine whether a structured , progressive , physiologically based exercise program for subacute stroke produces gains greater than those attributable to spontaneous recovery and usual care . METHODS This r and omized , controlled , single-blind clinical trial was conducted in a metropolitan area and 17 participating healthcare institutions . We included persons with stroke who were living in the community . One hundred patients ( mean age , 70 years ; mean Orpington score , 3.4 ) consented and were r and omized from a screened sample of 582 . Ninety-two subjects completed the trial . Intervention was a structured , progressive , physiologically based , therapist-supervised , in-home program of thirty-six 90-minute sessions over 12 weeks targeting flexibility , strength , balance , endurance , and upper-extremity function . Main outcome measures were postintervention strength ( ankle and knee isometric peak torque , grip strength ) , upper- and lower-extremity motor control ( Fugl Meyer ) , balance ( Berg and functional reach ) , endurance ( peak aerobic capacity and exercise duration ) , upper-extremity function ( Wolf Motor Function Test ) , and mobility ( timed 10-m walk and 6-minute walk distance ) . RESULTS In the intention-to-treat multivariate analysis of variance testing the overall effect , the intervention produced greater gains than usual care ( Wilk 's lambda=0.64 , P=0.0056 ) . Both intervention and usual care groups improved in strength , balance , upper- and lower-extremity motor control , upper-extremity function , and gait velocity . Gains for the intervention group exceeded those in the usual care group in balance , endurance , peak aerobic capacity , and mobility . Upper-extremity gains exceeded those in the usual care group only in patients with higher baseline function . CONCLUSIONS This structured , progressive program of therapeutic exercise in persons who had completed acute rehabilitation services produced gains in endurance , balance , and mobility beyond those attributable to spontaneous recovery and usual care [11552192] OBJECTIVES To identify the most responsive method of measuring gait speed , to estimate the responsiveness of other outcome measures , and to determine whether gait speed predicts discharge destination in acute stroke . DESIGN A prospect i ve cohort study . SETTING Five acute-care hospitals . PATIENTS Fifty subjects with residual gait deficits after a first-time stroke . INTERVENTIONS Five- ( 5mWT ) and 10-meter walk tests ( 10mWT ) at comfortable and maximum speeds , with 2 evaluations conducted an average + /- st and ard deviation ( SD ) of 8 + /- 3 and 38 + /- 5 days poststroke . MAIN OUTCOME MEASURE St and ardized response mean ( SRM = mean change/SD of change ) was used to estimate responsiveness for each walk test , the Berg Balance Scale , the Barthel Index , the Stroke Rehabilitation Assessment of Movement ( STREAM ) , and the Timed Up and Go ( TUG ) . RESULTS The SRMs were 1.22 and 1.00 for the 5mWT , and .92 and .83 for the 10mWT performed at a comfortable and maximum pace , respectively . The SRMs for the Berg Balance Scale , the Barthel Index , the STREAM , and the TUG were 1.04,.99,.89 , and .73 , respectively . The probability of discharge to a rehabilitation center for persons walking at < or = 0.3 m/s or > 0.6 m/s at the first evaluation was.95 and .22 , respectively . CONCLUSIONS The 5mWT at a comfortable pace is recommended as the measure of choice for clinicians and research ers who need to detect longitudinal change in walking disability in the first 5 weeks poststroke [11812553] BACKGROUND Community physiotherapy is often prescribed for stroke patients with long-term mobility problems . We aim ed to assess the effectiveness of this treatment in patients who had mobility problems 1 year after stroke . METHODS We screened 359 patients older than 50 years for a single-masked , r and omised controlled trial to assess the effects of community physiotherapy . Assessment s were made at baseline , 3 , 6 , and 9 months in 170 eligible patients assigned treatment or no intervention . The primary outcome measure was mobility measured by the Rivermead mobility index . Secondary outcome measures were gait speed , number of falls , daily activity ( Barthel index scores ) , social activity ( Frenchay activities index ) , hospital anxiety and depression scale , and emotional stress of carers ( general health question naire 28 ) . Analyses were by intention to treat . FINDINGS Follow-up was available for 146 patients ( 86 % ) . Changes in scores on the Rivermead mobility index ( score range 0 - 15 ) differed significantly between treatment and control groups at 3 months ( p=0.018 ) , but only by a median of 1 point ( 95 % CI 0 - 1 ) , with an interpolated value of 0.55 ( 0.08 - 1.04 ) . Gait speed was 2.6 m/min ( 0.30 - 4.95 ) higher in the treatment group at 3 months . Neither treatment effect persisted at 6-months ' and 9-months ' follow-up . Treatment had no effect on patients ' daily activity , social activity , anxiety , depression , and number of falls , or on emotional stress of carers . INTERPRETATION Community physiotherapy treatment for patients with mobility problems 1 year after stroke leads to significant , but clinical ly small , improvements in mobility and gait speed that are not sustained after treatment ends [10088589] A comparison was made of 113 consecutive patients who suffered a cerebrovascular accident and were hospitalized at a rehabilitation inpatient unit by dividing them into two groups : one group received the traditional 6-day/wk treatment regimen , and another group received treatment during the entire week ( 7 days/wk ) . When the patients were asked whether they had a preference ( which did not affect their group assignment ) , 82 % preferred a 6-day/wk program and 18 % preferred a 7-day/wk program . The length of inpatient stay for the 57 patients enrolled in the 6-day/wk program was 20.14 days ; for the 56 patients enrolled in the 7-day/wk program , the average length of stay was 20.11 days . This represents no significant difference . The functional recoveries were evaluated in areas that can affect length of stay , including dressing , bladder control , ambulation , and problem-solving . Both groups demonstrated significant gains in each domain when the intake and discharge ratings were compared . However , these gains were not significantly different when the 6- and 7-day/wk groups were compared . The results of the study contained herein , therefore , suggest that a 6-day/wk program for patients who have suffered a cardiovascular accident is just as effective as a 7-day/wk program [14617717] Objective : To investigate progress toward motor recovery in patients with chronic hemiparesis ( mean time since stroke 3.2 years ) , comparing different types of practice schedules . Design : To increase voluntary control of the upper extremity , active neuromuscular stimulation was administered during blocked and r and om practice schedules as patients performed three specific movements : wrist/finger extension , elbow joint extension , and shoulder joint abduction . Methods : 34 stroke subjects volunteered to participate and were r and omly assigned to one of three treatment groups : blocked practice ( the same movement was repetitively performed on successive trials ) combined with active neuromuscular stimulation ; r and om practice ( different movements on successive trials ) along with active stimulation ; or no active stimulation assistance control group . Subjects completed two days of 90 minute training for each of two weeks with at least 24 hours of rest between sessions . A session was three sets of 30 successful active neuromuscular stimulation trials with the three movements executed 10 times/set . Results : Mixed design analyses on three categories of behavioural measures indicated motor improvements for the blocked and r and om practice /stimulation groups in comparison with the control group during the post-test period , with a larger number of blocks moved , faster premotor and motor reaction times , and less variability in the sustained muscular contraction task . Conclusions : Upper extremity rehabilitation intervention of active stimulation and blocked practice performed as well as stimulation/r and om practice . Moreover , these purpose ful voluntary movement findings support and extend sensorimotor integration theory to both practice schedules [11129665] BACKGROUND AND PURPOSE The best treatment and management of stroke patients has been shown to be in stroke units by multidisciplinary rehabilitation teams . Since the composition of stroke units differs it is important to know the extent to which the different components contribute to this results . Physiotherapy is one component of most rehabilitation teams and recent systematic review s have shown that patients with stroke receiving more physiotherapy achieve more recovery from disability . However , information about the actual amounts of physiotherapy needed to achieve this result is not known . METHOD A pragmatic , r and omized , single-blind , controlled trial comparing recovery from disability in subjects receiving the current st and ard amount of 30 minutes ' physiotherapy with those receiving double that amount ( 60 minutes ) . The study included measures of physical performance and function , psychological aspects of anxiety and depression , and perceived control over recovery . RESULTS Some 114 subjects were recruited to the study ; full six-week data are available for 104 subjects and six-month data for 93 subjects . Comparison of initial to six-week difference scores in the control and intervention groups of the whole sample did not show a significant difference . Scrutiny of the recovery curves of the whole sample showed that , in half the sample , three distinct patterns of recovery were demonstrated . CONCLUSION These results suggest that doubling the physiotherapy time available for patients in a stroke unit will not provide a measurable benefit for all patients . The subgroup analysis of patterns of recovery must be regarded as speculative , but provides the basis for hypotheses about those likely to respond well to more intensive therapy [12971702] Objective : To determine whether an early increased-intensity upper limb therapy programme following acute stroke improves outcome . Design : A r and omized controlled trial . Setting : A stroke unit which provides acute care and rehabilitation for all stroke admissions . Subjects : One hundred and twenty-three patients who had had a stroke causing upper limb impairment within the previous 10 days . Intervention : The intervention group received stroke unit care plus enhanced upper limb rehabilitation provided jointly by a physiotherapist and occupational therapist , commencing within 10 days of stroke , and available up to 30 minutes/day , five days/week for six weeks . The control group received stroke unit care . Main outcome measures : The primary outcome measure was the Action Research Arm Test ( ARAT ) three months after stroke . Secondary outcome measures : Motricity Index ; Frenchay Arm Test ; upper limb pain ; Barthel ADL Index ; Nottingham E-ADL Scale ; and costs to health and social services at three and six months after stroke . Results : There were no differences in outcomes between the intervention and control groups three and six months after stroke . During the intervention period the intervention group received a median of 29 minutes of enhanced upper limb therapy per working day as in patients . The total amount of inpatient physiotherapy and occupational therapy received by the intervention group was a median of 52 minutes per working day during the intervention period and 38 minutes per working day for the control group ( p = 0.001 ) . There were no differences in service costs . Conclusions : An early increased-intensity interdisciplinary upper limb therapy programme jointly provided by a physiotherapist and occupational therapist did not improve outcome after stroke . The actual difference in the amount of therapy received by intervention and control groups was less than planned due to a competitive therapy bias [508075] Positional feedback ( PF ) and electrical stimulation were combined in a new treatment modality for facilitating wrist extension in stroke patients . Thirty adult hemiparetic patients lacking normal voluntary wrist extension were r and omly placed in control and study groups . The control group received conventional therapy while the study group received positional feedback stimulation training ( PFST ) in addition to conventional treatment . At the end of the 4-week program , study patients showed a 280 % increase in isometric extension torque when the wrist was positioned in 30 degrees of extension and 70 % increase when positioned in 30 degrees of flexion . Control patients showed no significant changes in torque . Study patients made an average 200 % gain in selective range of motion over their starting levels while controls made only a 50 % increase . Treatment using automated PFST equipment allows controlled repetitive isotonic exercise and facilitation of wrist extension without continuous one-on-one therapist/patient supervision [11732835] This case series examined the feasibility and efficacy of a modified constraint induced therapy ( CIT ) protocol administered on an outpatient basis . The Fugl-Meyer Assessment of Motor Recovery After Stroke ( Fugl ) , Action Research Arm Test ( ARA ) , Wolf Motor Function Test ( WMFT ) , and Motor Activity Log ( MAL ) were administered to six patients between 2 and 6 months poststroke ( CVA ) exhibiting stable motor deficits and learned nonuse of the affected limb . Two patients then participated in half-hour physical and occupational therapy sessions three times/week for 10 weeks . During the same period , their unaffected arms and h and s were restrained 5 days/week during 5 hours identified as times of frequent use . Two other patients received regular therapy and two control patients received no therapy . The ARA , Fugl , WMFT , and MAL were again administered after 10 weeks . Patients receiving modified CIT exhibited substantial improvements on the Fugl , ARA , and WMFT , as well as increases in amount and quality of use of the limb using the MAL . Patients receiving traditional or no therapy exhibited no improvements . Results suggest that modified CIT may be an efficacious method of improving function and use of the affected arms of patients exhibiting learned nonuse [10835457] BACKGROUND AND PURPOSE After stroke , many individuals have chronic unilateral motor dysfunction in the upper extremity that severely limits their functional movement control . The purpose of this study was to determine the effect of electromyography-triggered neuromuscular electrical stimulation on the wrist and finger extension muscles in individuals who had a stroke > or = 1 year earlier . METHODS Eleven individuals volunteered to participate and were r and omly assigned to either the electromyography-triggered neuromuscular stimulation experimental group ( 7 subjects ) or the control group ( 4 subjects ) . After completing a pretest involving 5 motor capability tests , the poststroke subjects completed 12 treatment sessions ( 30 minutes each ) according to group assignments . Once the control subjects completed 12 sessions attempting wrist and finger extension without any external assistance and were posttested , they were then given 12 sessions of the rehabilitation treatment . RESULTS The Box and Block test and the force-generation task ( sustained muscular contraction ) revealed significant findings ( P<0 . 05 ) . The experimental group moved significantly more blocks and displayed a higher isometric force impulse after the rehabilitation treatment . CONCLUSIONS Two lines of evidence clearly support the use of the electromyography-triggered neuromuscular electrical stimulation treatment to rehabilitate wrist and finger extension movements of hemiparetic individuals > or = 1 year after stroke . The treatment program decreased motor dysfunction and improved the motor capabilities in this group of poststroke individuals [10229728] BACKGROUND AND PURPOSE Subluxation is a significant problem in poststroke hemiplegia , result ing in pain and loss of function . Current treatments are not proved and not considered effective . It has been demonstrated that cyclical electrical stimulation of the shoulder muscles can reduce existing subluxation . The purpose of this study was to determine whether electrical stimulation could prevent subluxation in both the short and long terms . METHODS A prospect i ve , r and omized controlled study was used to determine the efficacy of electrical stimulation in preventing shoulder subluxation in patients after cerebrovascular accidents . Forty patients were selected and r and omly assigned to a control or treatment group . They had their first assessment within 48 hours of their stroke , and those in the treatment group were immediately put on a regimen of electrical stimulation for 4 weeks . All patients were assessed at 4 weeks after stroke and then again at 12 weeks after stroke . Assessment s were made of shoulder subluxation , pain , and motor control . RESULTS The treatment group had significantly less subluxation and pain after the treatment period , but at the end of the follow-up period there were no significant differences between the 2 groups . CONCLUSIONS Electrical stimulation can prevent shoulder subluxation , but this effect was not maintained after the withdrawal of treatment [9549021] Objective : To examine the effects of electromyographic ( EMG ) biofeedback training on the recovery of gait in the acute phase post stroke . Design : Patients were r and omly assigned to EMG biofeedback or control groups . They received treatment three times a week for six weeks . All patients were assessed prior to treatment , after 18 treatment sessions , and at three months follow-up . Setting : The study was carried out at Scunthorpe General Hospital in North Lincolnshire . The subjects were acute stroke patients who had been admitted on to the medical and elderly wards . Interventions : The EMG biofeedback group were treated using EMG as an adjunct to physiotherapy . The patients were encouraged to facilitate or inhibit abnormal muscle tone via auditory or visual signals transmitted from electrodes placed over the appropriate muscles . The control group were treated using the same techniques , electrodes were used with this group of patients , but the EMG machine was turned off and faced away from the patient and the therapist to control the placebo effect . Outcome measures : A large battery of outcome measures was used for physical and psychological assessment . The physical measures consisted of active movement , muscle tone , sensation , proprioception , mobility and activities of daily living ( ADL ) . The psychological measures included orientation , memory , spatial performance , language and IQ . Results : Twenty-one patients were included in the study . Scores were combined into four groups : mild EMG , severe EMG , mild control and severe control . Results showed that there was an improvement in physical scores for active movement , mobility and ADL over time , but there was no significant difference between the EMG and control groups . Scores on the psychological tests were within normal limits , and there was no difference in performance between the EMG and control groups . Conclusions : This study showed no significant differences in the rate of improvement after stroke between the two groups . Although EMG biofeed-back was used as an adjunct to physiotherapy and represented clinical practice , the results provide little evidence to support the clinical significance of using EMG biofeedback to improve gait in the acute phase after stroke [8630191] The effectiveness of ongoing rehabilitation services for postacute stroke survivors is poorly documented . We design ed a r and omized control , single-blinded study to demonstrate the effectiveness of intensive outpatient therapy . The treatment intervention consisted of 1 hr each of physical and occupational therapy , four times per week , for 12 wk ; therapy focused on neuromuscular facilitation and functional tasks . All subjects were screened before the therapies and after 3 mo and 9 mo . Forty-nine stroke survivors , who were at least l yr ( mean , 2.9 yr ) poststroke , were r and omized with two treated patients to each control ( no treatment supplied ) . All patients had received inpatient rehabilitation at the time of their acute stroke , but no patient had any ongoing therapy within the last 6 mo . The outcome measures included the Functional Independence Measure ( FIM ) , Brunnstrom stages of motor recovery , timed mobility tasks , and the Jebson h and evaluation . We also evaluated the level of depression , self-esteem , and socialization . The treated patients demonstrated an improvement of 6.6 points over the 3 mo of therapy compared with only 1.5 points in the control group in the FIM motor score transformed using Rasch analysis . The change from time 0 to 3 mo was significant in the treated group but not in the controls . Treated patients maintained their gains at the 9-mo follow-up , and controls lost ground . The treated group improved in terms of socialization and self-esteem as evidence d by a lower Sickness Impact Profile , whereas the controls tended to get worse . There was a trend toward less depression , but this did not reach a P = 0.05 level of significance . This study demonstrates that significant functional gains can still be attained in the postacute stroke survivor , despite prior inpatient rehabilitation services [10548673] BACKGROUND AND PURPOSE Of all stroke survivors , 30 % to 66 % are unable to use their affected arm in performing activities of daily living . Although forced use therapy appears to improve arm function in chronic stroke patients , there is no conclusive evidence . This study evaluates the effectiveness of forced use therapy . METHODS In an observer-blinded r and omized clinical trial , 66 chronic stroke patients were allocated to either forced use therapy ( immobilization of the unaffected arm combined with intensive training ) or a reference therapy of equally intensive bimanual training , based on Neuro-Developmental Treatment , for a period of 2 weeks . Outcomes were evaluated on the basis of the Rehabilitation Activities Profile ( activities ) , the Action Research Arm ( ARA ) test ( dexterity ) , the upper extremity section of the Fugl-Meyer Assessment scale , the Motor Activity Log ( MAL ) , and a Problem Score . The minimal clinical ly important difference ( MCID ) was determined at the onset of the study . RESULTS One week after the last treatment session , a significant difference in effectiveness in favor of the forced use group compared with the bimanual group ( corrected for baseline differences ) was found for the ARA score ( 3.0 points ; 95 % CI , 1.3 to 4.8 ; MCID , 5.7 points ) and the MAL amount of use score ( 0.52 points ; 95 % CI , 0.11 to 0.93 ; MCID , 0.50 ) . The other parameters revealed no significant differential effects . One-year follow-up effects were observed only for the ARA . The differences in treatment effect for the ARA and the MAL amount of use scores were clinical ly relevant for patients with sensory disorders and hemineglect , respectively . CONCLUSIONS The present study showed a small but lasting effect of forced use therapy on the dexterity of the affected arm ( ARA ) and a temporary clinical ly relevant effect on the amount of use of the affected arm during activities of daily living ( MAL amount of use ) . The effect of forced use therapy was clinical ly relevant in the subgroups of patients with sensory disorders and hemineglect , respectively [7770495] BACKGROUND AND PURPOSE Gait rehabilitation in patients with severe hemiplegia requires substantial effort . Preliminary studies indicate potential beneficial effects of using multichannel functional electrical stimulation ( MFES ) for gait rehabilitation in these patients . In this study , a new method of gait rehabilitation for nonambulatory patients with hemiplegia by means of MFES added to conventional therapy was introduced . The results of the method 's application were evaluated by comparing it with conventional therapeutic methods . SUBJECTS The proposed rehabilitation method was tested on a group of 20 patients with severe hemiplegia secondary to cerebrovascular accident . Subjects were r and omly assigned to one of two groups . One group received 3 weeks of MFES followed by 3 weeks of conventional therapy . The other group received 3 weeks of conventional therapy followed by 3 weeks of MFES . METHODS The effects of each therapeutic method were evaluated by measurements of temporal-distance variables and ground reaction forces and by assessment of each subject 's physical status according to the Fugl-Meyer evaluation scale . RESULTS There was improved performance of the subjects during MFES combined with conventional therapy as compared with conventional therapy alone . CONCLUSION AND DISCUSSION The superiority of the MFES method as compared with conventional therapy was mainly attributed to the enhanced motor learning accomplished by application of MFES . These results , however , are preliminary , and further research is needed [7041850] Electromyographic biofeedback was compared with simple exercise therapy as to its effectiveness in improving foot-drop in 22 stroke patients . The study was design ed to be a rigorous trial of biofeedback and the patients tested were aged and had stroke of long duration . One group of 11 patients underwent 6 weeks of exercise therapy 2 sessions per week for 15 minutes per session ; the 2nd group of 11 patients underwent similar therapy with EMG feedback . All therapy was conducted by a research assistant who was not a trained therapist . The groups were assessed blind before treatment , after treatment and a 6-week follow-up . The significantly greater improvements in the biofeedback group in terms of muscle strength at the end of treatment were maintained at follow-up . On the range of movement and gait analysis measures , both groups showed some improvement after treatment . However , at follow-up this improvement had relapsed for the exercise group while for the biofeedback group it had been maintained . It is argued that controlled trials are possible in biofeedback and that using patients as their own controls is not justified in view of the present findings and the previously reported literature [6391417] A long-term , comparison-group outcome trial with a partial crossover design was carried out on the effects of electromyographic biofeedback ( EMGBF ) plus physiotherapy ( PT ) versus PT alone in the treatment of the hemiplegic upper limb in stroke patients who were at least six months beyond the onset of their disability . Both the experimental and the control groups benefited from their treatment , but EMGBF was shown to have an additional effect , both in the experimental patients , and in the control patients when they switched over to the experimental treatment condition [3257300] The purpose of this study was to investigate , in a sample of patients with hemiparesis secondary to cerebrovascular accident , the relationship between the ratio of stimulus on time to off time and muscle fatigue using a commercial electrical stimulation unit . An experimental model was used to test the hypothesis that the smaller the stimulus off time relative to stimulus on time , the greater will be the muscle fatigue over time . The wrist extensor muscles of 18 patients with hemiparesis were stimulated electrically , and isometric force output was recorded continuously using an adapted strain gauge-recorder apparatus . For each testing session , peak on time of the electrical stimulus was set at 5 seconds , and off time was set at 5 , 15 , or 25 seconds . Six r and omly assigned treatment groups participated in three separate treatment sessions in a different order at 48-hour intervals . Treatment sessions were continued either until wrist extensor muscle force output decreased to 50 % of its initial value or for a maximum of 30 minutes . Data analysis revealed that significant differences in muscle tension developed among all duty cycles ( p less than .01 ) . Duty-cycle ratios of 1:1 , 1:3 , and 1:5 were shown to be progressively less fatiguing . Within the limits of this investigation , the 1:5 duty-cycle ratio was determined to be the best suited for initial use in programs of prolonged stimulation to the wrist extensor muscles of patients with hemiparesis . The hypothesis was accepted that the smaller the stimulus off time ( rest interval ) with respect to the stimulus on time , the greater will be the muscle fatigue over time [10698876] Abstract Objective : To establish if a brief programme of domiciliary occupational therapy could improve the recovery of patients with stroke discharged from hospital . Design : Single blind r and omised controlled trial . Setting : Two hospital sites within a UK teaching hospital . Subjects : 138 patients with stroke with a definite plan for discharge home from hospital . Intervention : Six week domiciliary occupational therapy or routine follow up . Main outcome measures : Nottingham extended activities of daily living score and “ global outcome ” ( deterioration according to the Barthel activities of daily living index , or death ) . Results : By eight weeks the mean Nottingham extended activities of daily living score in the intervention group was 4.8 points ( 95 % confidence interval −0.5 to 10.0 , P=0.08 ) greater than that of the control group . Overall , 16 ( 24 % ) intervention patients had a poor global outcome compared with 30 ( 42 % ) control patients ( odds ratio 0.43 , 0.21 to 0.89 , P=0.02 ) . These patterns persisted at six months but were not statistically significant . Patients in the intervention group were more likely to report satisfaction with a range of aspects of services . Conclusion : The functional outcome and satisfaction of patients with stroke can be improved by a brief occupational therapy programme carried out in the patient 's home immediately after discharge . Major benefits may not , however , be sustained [12370871] OBJECTIVE To evaluate and compare the effects of 3-hour versus 6-hour daily training sessions in constraint-induced movement therapy ( CIMT ) . DESIGN Intervention study , 2-group r and omized trial ; baseline , pretreatment , and posttreatment measures ; 1-month follow-up ( weekly measures ) . SETTING University department of psychology in Germany . PARTICIPANTS A convenience sample of 15 adults with chronic hemiparesis ( 13 stroke , 2 traumatic brain injury ) . INTERVENTION CIMT ( 14 consecutive days ; constraint of unaffected h and for a target of 90 % of waking hours ) with either 6 hours ( 6h/d group , n=7 ) or 3 hours ( 3h/d group , n=8 ) of shaping training with the affected h and per day . MAIN OUTCOME MEASURES The Motor Activity Log and Wolf Motor Function Test . RESULTS Significant improvements in motor function in the laboratory and increased use of the affected h and in the real-world environment were found in both groups . The beneficial effects were significantly greater in the 6h/d group than in the 3h/d group . CONCLUSION The 3-hour CIMT training schedule significantly improved motor function in chronic hemiparesis , but it was less effective than the 6-hour training schedule [6780105] Of 1094 patients with a confirmed stroke admitted to Northwick Park , a district general hospital , 364 ( 33 % ) died while in hospital , 215 ( 20 % ) were fully recovered when discharged , and 329 ( 30 % ) were too frail or too ill from diseases other than stroke to be considered for active rehabilitation . Only 121 ( 11 % ) were suitable for intensive treatment . They and 12 patients referred direct to out patients were allocated at r and om to one of three different courses of rehabilitation . Intensive was compared with conventional rehabilitation and with a third regimen which included no routine rehabilitation , but under which patients were encouraged to continue with exercises taught while in hospital and were regularly seen at home by a health visitor . Progress at three months and 12 months was measured by an index of activities of daily living . Improvement was greatest in those receiving intensive treatment , intermediate in those receiving conventional treatment , and least in those receiving no routine treatment . Decreasing intensity of treatment was associated with a significant increase in the proportions of patients who deteriorated and in the extent to which they deteriorated . Probably only a few stroke patients , mostly men , are suitable for intensive outpatient rehabilitation , but for those patients the treatment is effective and realistic [11101549] BACKGROUND Face-to-face assessment of research outcomes is expensive and may introduce bias . Postal question naires offer a cheaper alternative which avoids observer bias , but non-response and incomplete response reduce the effective sample size and may be equally serious sources of bias . This study examines the extent and potential effects of missing data in the postal collection of outcomes for a large rehabilitation trial . METHODS Question naires containing a number of established scales were posted to participants in a trial of occupational therapy after stroke . Response was maximized by telephone and postal reminders , and incomplete question naires were followed up by telephone . Scale scores obtained by imputing values to question naire items missing on return were compared with those achieved by telephone follow-up . FINDINGS Response to the initial posting was 60 % , rising to 85 % after reminders . Participants receiving the experimental treatment were more likely to respond without a reminder . There were no significant differences on any known factors between eventual responders and non-responders . Of the question naires , 43 % were incomplete on return : partial responders were significantly different to complete responders on baseline disability and home circumstances . Of the incomplete question naires , 71 % were resolved by telephone follow-up . In these , the scale scores achieved by telephone were generally higher than those derived by conventional imputation . CONCLUSION Postal outcome assessment achieved a good response rate , but considerable effort was needed to minimize non-response and incomplete response , both of which could have been serious sources of bias [9099186] BACKGROUND AND PURPOSE After stroke , the ability to balance in sitting is critical to independence . Although impairments in sitting balance are common , little is known about the effectiveness of rehabilitation strategies design ed to improve it . The purpose of this r and omized placebo-controlled study was to evaluate the effect of a 2-week task-related training program aim ed at increasing distance reached and the contribution of the affected lower leg to support and balance . METHODS Twenty subjects at least 1 year after stroke were r and omized into an experimental or control group . The experimental group participated in a st and ardized training program involving practice of reaching beyond arm 's length . The control group received sham training involving completion of cognitive-manipulative tasks within arm 's length . Performance of reaching in sitting was measured before and after training using electromyography , videotaping , and two force plates . Variables tested were movement time , distance reached , vertical ground reaction forces through the feet , and muscle activity . Subjects were also tested on sit-to-st and , walking , and cognitive tasks . Nineteen subjects completed the study . RESULTS After training , experimental subjects were able to reach faster and further , increase load through the affected foot , and increase activation of affected leg muscles compared with the control group ( P < .01 ) . The experimental group also improved in sit-to-st and . The control group did not improve in reaching or sit-to-st and . Neither group improved in walking . CONCLUSIONS This study provides strong evidence of the efficacy of task-related motor training in improving the ability to balance during seated reaching activities after stroke [3488280] Electromyographic biofeedback has been used with some success to treat patients with disturbances of muscle tone result ing from neurological disease . The aim of this study was to incorporate electrical myofeedback as an integral part of a physiotherapeutic regime design ed to improve quality of movement and function in limbs weakened or paralysed by stroke . A portable , inexpensive E. M. G. biofeedback machine was used . Stainless steel skin electrodes were applied which needed minimal skin preparation . Twelve adults , ( five male , seven female , mean age 44.2 years and 51.3 years respectively ) who were referred for treatment due to weakness of limb muscles due to disease of the brain or spinal cord , were treated . The mean time from onset of incidence to treatment was 75.5 days . Each patient received six weeks of treatment . This was divided into two phases . Phase 1 , ( weeks 1 , 2 , 3 ) and phase 2 ( weeks 4 , 5 , 6 ) . Physiotherapy , and physiotherapy with biofeedback was r and omly allocated to either phase . Each patient acted as his/her own control . A vali date d assessment was carried out by an independent therapist at the start of treatment , after three weeks and after six weeks of treatment . General function , knee function , range of movement of the affected side and timed tests were measured . Results show an overall improvement in general function . The second phase of treatment was slightly more favourable to improvement , but there was no indication that biofeedback significantly improved the outcome . In three tests it was equally significant to the physiotherapy applied ; in one test it improved the effectiveness of physiotherapy and in one test it reduced the effectiveness of physiotherapy . This suggests that a six week course of physiotherapy improved muscular function and range of movements in patients with weakness due to upper motor neurone disease , but that these effects are not enhanced by myofeedback [9360032] Objective : To measure the effect of the Odstock Dropped Foot Stimulator ( ODFS ) , a common peroneal stimulator , on the effort and speed of walking . Design : A r and omized controlled trial . Subjects : Hemiplegic patients who had suffered a single stroke at least six months prior to the start of the trial whose walking was impaired by a drop-foot . Interventions : The treatment , functional electrical stimulation ( FES ) group , used the stimulator and received a course of physiotherapy ; the control group received physiotherapy alone . Main outcome measures : Changes in walking speed measured over 10 m and the effort of walking measured by physiological cost index ( PCI ) . Results : Thirty-two subjects completed the trial , 16 in the FES group and 16 in the control group . Mean increase in walking speed between the beginning and end of the trial was 20.5 % in the FES group ( when the stimulator was used ) , and 5.2 % in the control group . Improvement was also measured in PCI with a reduction of 24.9 % in the FES group ( when the stimulator was used ) and 1 % in the control group . No improvement in these parameters was measured in the FES group when the stimulator was not used . Conclusion : Walking was statistically significantly improved when the ODFS was worn but no ' carry-over ' was measured . Physiotherapy alone , in this group of subjects with established stroke , did not improve walking [10203198] OBJECTIVE To evaluate the efficacy of intermittent pneumatic compression in treating oedema in the hemiplegic h and of stroke patients . DESIGN Single-blind r and omized control trial . SETTING acute and rehabilitation elderly care wards in a teaching district . SUBJECTS 37 Subjects with a first ever hemisphere stroke were r and omized to treatment with st and ard physiotherapy either alone or combined with intermittent pneumatic compression . MAIN OUTCOME MEASURES The effect of treatment on oedema was assessed using measures of the h and volume of the hemiplegic h and . The impact on function was assessed using the motricity index . RESULTS The treated group showed no change in the mean stroke h and volume . In the control group the mean stroke h and volume decreased by 3.2 ml . There was no statistically significant difference between the groups . The median scores for the motricity index increased for both groups but there was no significant difference between the groups and any improvement in motor function was independent of any treatment effects . CONCLUSION Intermittent pneumatic compression at the prescribed pressure and duration of this study is not an effective treatment for the oedematous stroke h and [6163362] Two treatment modalities for increasing active elbow extension with hemiplegic subjects were tested . Twenty subjects were r and omly assigned to one of two treatment groups -- an experimental treatment technique using kinesthetic biofeedback , or a control group consisting of an occupational therapy approach aim ed at increasing functional use of the envolved upper extremity . The results indicate that kinesthetic biofeedback was as beneficial as conventional occupational therapy . It was also demonstrated that an individual 's age , sex , or length of time beyond one-year post-CVA did not significantly affect treatment outcome . A majority of subjects in both treatment groups improved in ways not directly related to treatment , which suggests the need for long-term follow up of hemiplegic patients [6602993] Positional feedback stimulation training and cyclical electrical stimulation were used in combination as a treatment for facilitating knee extension in hemiparetic patients . Forty adult hemiparetic patients who demonstrated minimal active control of their quadriceps femoris muscles were r and omly assigned to control or study groups . The control patients received a program of physical therapy , and the study patients received the positional feedback stimulation training in addition to their therapy program . The stimulation training provided the patient with immediate auditory and visual feedback of his changing joint angle while he voluntarily extended his knee . When the patient reached a near maximal extension effort , electrical stimulation of the quadriceps femoris muscle was automatically triggered , completing the patient 's available range of motion in extension . The stimulation training was supplemented with two hours of cyclical electrical stimulation daily . At the end of four weeks , analysis revealed a statistically significant increase in knee extension torque and active synergistic range of motion in the study group . No change was noted in their ability to extend their knees using isolated quadriceps femoris muscle control . This study suggests that positional feedback stimulation training is effective when used to augment a facilitation program for improving knee extension control in hemiparetic patients [9596400] OBJECTIVE To assess the efficacy of electromyogram (EMG)-triggered neuromuscular stimulation ( EMG-stim ) in enhancing upper extremity motor and functional recovery of acute stroke survivors . DESIGN A pilot r and omized , single-blinded clinical trial . SETTING Freest and ing inpatient rehabilitation facility . PATIENTS Nine subjects who were within 6 weeks of their first unifocal , nonhemorrhagic stroke were r and omly assigned to either the EMG-stim ( n = 4 ) or control ( n = 5 ) group . All subjects had a detectable EMG signal ( > 5 microV ) from the surface of the paretic extensor carpi radialis and voluntary wrist extension in synergy or in isolation with muscle grade of < 3/5 . INTERVENTION All subjects received two 30-minute sessions per day of wrist strengthening exercises with EMG-stim ( experimental ) or without ( control ) for the duration of their rehabilitation stay . MAIN OUTCOME MEASURES Upper extremity Fugl-Meyer motor assessment and the feeding , grooming , and upper body dressing items of the Functional Independence Measure ( FIM ) were assessed at study entry and at discharge . RESULTS Subjects treated with EMG-stim exhibited significantly greater gains in Fugl-Meyer ( 27.0 vs 10.4 ; p = .05 ) , and FIM ( 6.0 vs 3.4 ; p = .02 ) scores compared with controls . CONCLUSION Data suggest that EMG-stim enhances the arm function of acute stroke survivors [2383382] One of the causes for shoulder pain associated with hemiplegia is thought to be vigorous range of motion to the involved upper extremity . The objective of this study was to analyze the occurrence of pain in patients treated with one of the three exercise programs commonly used in the rehabilitation of hemiplegia : 1 ) range of motion by the therapist , 2 ) skate board and 3 ) overhead pulley . Of the 48 hemiplegic patients evaluated , 28 were assigned to one of the three exercise groups . Comparing the number of patients who developed pain in each group , there was a significant difference , with 8 % of the patients in the range of motion by the therapist group , 12 % of the patients in the skate board group and 62 % of the patients in the overhead pulley group developing pain ( x2=8.44 ) ( P=0.014 ) . The three groups did not differ in the side of involvement ( P=0.57 ) , extent of hemiplegia ( P=0.25 ) or presence of subluxation ( P=0.84 ) . Use of overhead pulley has the highest risk of developing shoulder pain and should be avoided during rehabilitation of stroke patients [11237160] Objective : To evaluate the effects of leisure therapy and conventional occupational therapy ( OT ) on the mood , leisure participation and independence in activities of daily living ( ADL ) of stroke patients 6 and 12 months after hospital discharge . Design : Multicentre r and omized controlled trial . Setting and participants : Four hundred and sixty-six stroke patients from five UK centres . Main outcome measures : The General Health Question naire ( 12 item ) , the Nottingham Extended ADL Scale and the Nottingham Leisure Question naire , assessed by post , with telephone clarification . Results : Four hundred and forty ( 94 % ) and 426 ( 91 % ) subjects were alive at 6 and 12 months , respectively . Three hundred and seventy-four ( 85 % of survivors ) and 311 ( 78 % of survivors ) responded at 6 and 12 month follow-up respectively . At six months and compared to the control group , those allocated to leisure therapy had nonsignificantly better GHQ scores ( –1.2 : 95 % CI –2.9 , + 0.5 ) , leisure scores ( + 0.7 , 95 % CI –1.1 , + 2.5 ) and Extended ADL scores ( + 0.4 : 95 % CI –3.8 , + 4.5 ) : the ADL group had nonsignificantly better GHQ scores ( –0.1 : 95 % CI –1.8 , + 1.7 ) and Extended ADL scores ( + 1.4 : 95 % CI –2.9 , + 5.6 ) and nonsignificantly worse leisure scores ( –0.3 : 95 % CI –2.1 , + 1.6 ) . The results at 12 months were similar . Conclusion : In contrast to the findings of previous smaller trials , neither of the additional OT treatments showed a clear beneficial effect on mood , leisure activity or independence in ADL measured at 6 or 12 months [10440303] BACKGROUND Patients who have a stroke are not always admitted to hospital , and 22 - 60 % remain in the community , frequently without coordinated rehabilitation . We aim ed to assess the efficacy of an occupational therapy intervention for patients with stroke who were not admitted to hospital . METHODS In this single-blind r and omised controlled trial , consecutive stroke patients on a UK community register in Nottingham and Derbyshire were allocated r and omly to up to 5 months of occupational therapy at home or to no intervention ( control group ) 1 month after their stroke . The aim of the occupational therapy was to encourage independence in personal and instrumental activities of daily living . Patients were assessed on outcome measures at baseline ( before r and omisation ) and at 6 months . The primary outcome measure was the score on the extended activities of daily living ( EADL ) scale at 6 months . Other outcome measures included the Barthel index , the general health question naire 28 , the carer strain index , and the London h and icap scale . All assessment s were done by an independent assessor who was unaware of treatment allocation . The analysis included only data from completed question naires . FINDINGS 185 patients were included : 94 in the occupational therapy group and 91 in the control group . 22 patients were not assessed at 6 months . At follow-up , patients who had occupational therapy had significantly higher median scores than the controls on : the EADL scale ( 16 vs 12 , p<0.01 , estimated difference 3 [ 95 % CI 1 to 4 ] ) ; the Barthel index ( 20 vs 18 , p<0.01 , difference 1 , [ 0 - 1 ] ) ; the carer strain index ( 1 vs 3 , p<0.05 , difference 1 [ 0 to 2 ] ) ; and the London h and icap scale ( 76 vs 65 , p<0.05 , difference 7 , [ 0.3 to 13.5 ] ) . There were no significant differences on the general health question naire between the patient or carer . INTERPRETATION Occupational therapy significantly reduced disability and h and icap in patients with stroke who were not admitted to hospital [999485] The use of audiovisual displays of myoelectric potentials ( myofeedback ) has been suggested for retraining and strengthening of paretic muscles in patients with hemiplegia from stroke . This controlled study examines the specificity and efficiency of myofeedback in the strengthening of paretic muscles in hemiplegic patients . Eighteen patients with trace to fair-minus grade of deltoid muscle power result ing from strokes that had occurred at least six weeks earlier were r and omly assigned to the six possible orders of accurate ( true ) , positive noncontingent ( placebo ) and no feedback conditions . On three successive days , each patient received one session of each feedback condition , consisting of 20 isometric contractions of five seconds each with ten seconds of intervening rests . In addition , each patient 's motivational level was rated . Averaged myoelectric potentials were quantified for each contraction for analysis . When the data were analyzed without grouping , no statistical differences among the three feedback conditions were noted . However , when the subjects were grouped according to age and motivational level , during true and no feedback sessions , the older and the poorly motivated groups were found to show progressive increment of myoelectric output , whereas the younger and the better motivated showed the opposite results . With placebo feedback , both groups showed progressive decrement of myoelectric output . It is concluded that the effect of myofeedback is nonspecific at least in its short-term application for the retraining of hemiplegically paretic muscles [8215864] A computer-assisted feedback system was developed to present to walking subjects instantaneous feedback of their muscle activity or joint angular excursions during gait . Targets for muscle activity or joint motion were displayed on the feedback screen along with timing cues that prompted muscle activity or joint flexion/extension at specific times during the gait cycle . The purpose was to compare the effectiveness of joint angle and electromyographic ( EMG ) feedback to a focused program of physical therapy for gait . Eight hemiplegic stroke patients were treated with ankle joint angle feedback , EMG biofeedback from the soleus muscle , and conventional physical therapy for gait in a three-period crossover design . PT was given either first or last in the sequence of treatments . Gait analysis prior to and following each type of treatment revealed that the feedback treatments result ed in significant increases in stride length and walking velocity and in positive changes in push-off impulse , gait symmetry , and st and ing weight-bearing symmetry , as evaluated in a general linear model and paired t-tests . Overall , physical therapy produced no significant changes . However , when physical therapy was the first treatment of the sequence , significant increases in stride length and velocity were observed . When physical therapy was last , there were significant negative changes in gait symmetry and st and ing weight-bearing symmetry , and negative trends in stride length , walking velocity , and push-off impulse . It is concluded that computer-assisted feedback is an effective tool for retraining gait in stroke patients [1559090] OBJECTIVE --To determine whether the intervention of a physiotherapist improved mobility in patients seen more than one year after stroke . DESIGN --R and omised crossover trial comparing two groups offered intervention by a physiotherapist , one immediately after entry into the trial and the other after a delay of three months . The intervention consisted of identifying problems and offering advice and help to solve the problems . SETTING -- Patients ' homes in Oxfordshire . SUBJECTS-- Patients who had reduced mobility due to a stroke more than one year before entry ; 60 were recruited from a community stroke register and 34 in other ways . MAIN OUTCOME MEASURES --St and ard measures of mobility including gait speed , functional ambulation categories , the Nottingham extended activities of daily living index , and individual items from the Barthel activities of daily living index and the Frenchay activities index . Measures of manual dexterity , depression , and anxiety were used as controls . RESULTS --94 patients entered the trial and 49 were r and omised to immediate and 45 to delayed physiotherapy ; 89 were compared at the crossover point . At r and omisation the two groups were comparable . At three months the group given early therapy showed an improvement in gait speed whereas the untreated group had declined ( differences of -3.9 v 6.4 s to walk 10 m ; p less than 0.01 ) ; between three and six months the group given delayed therapy showed improvement and the previously treated group declined ( differences of 6.5 v -3.9 s to walk 10 m ; p less than 0.01 ) . A 9 % ( 95 % confidence interval 0 % to 18 % ) decrease in time taken to walk 10 m was associated with treatment and a 12 % ( 2 % to 19 % ) increase when patients were untreated . Other measures did not change significantly . CONCLUSION --Intervention of an experienced physiotherapist late after stroke specifically improves mobility , albeit by a small amount , but the effects do not seem to be maintained , perhaps because there is an underlying decline in mobility in these patients . Gait speed offers a simple and sensitive measure of outcome [10688340] Objective : To determine whether stroke patients with initial increases in arm motor recovery following low-frequency transcutaneous electrical nerve stimulation ( low TENS ) treatment go on to show long-term benefits . Also whether the same therapy results in long-term improvements in motor function , spasticity or activities of daily living ( ADL ) . Design : A three-year follow-up study . Subjects : Twenty-eight stroke patients , who had participated in a r and omized trial of daily treatment with low-frequency ( 1.7 Hz ) transcutaneous electrical nerve stimulation ( low TENS ) on the paretic arm for three months starting 6–12 months after stroke . Outcomes : Fugl-Meyer Motor Performance Scale for evaluation of changes in arm motor function . A 6-point Ashworth Scale to measure spasticity . Barthel Index to evaluate performance in ADL . Results : Motor function of the paretic arm had deteriorated in both treatment and control groups . Increased spasticity was seen in both groups . ADL score remained at a similar level in the low TENS group , whereas the control group had deteriorated during the same time period . Conclusions : Low TENS stimulation started 6–12 months after stroke may not have a specific effect on arm motor function years after completion of treatment [3288172] The study examined the efficacy of functional electric stimulation ( FES ) and biofeedback ( BFB ) treatment of gait dysfunction in patients with hemiplegia after stroke . These two therapeutic modalities were tested alone and in combination in a prospect i ve , controlled , r and omized trial . The authors hypothesized that in concurrent use , these two modalities would complement one another . Thirty-six hemiplegic patients undergoing rehabilitation after stroke were accepted for study and r and omized into four groups to receive either control , FES , BFB , or combined therapies . Each patient received 30 minutes of treatment three times per week for six weeks , in addition to their general rehabilitation program . Quantitative gait analysis was performed biweekly on each subject during the experimental therapy and for four weeks afterward . Thirty-two subjects completed the study . Combined therapy with BFB and FES result ed in improvements in both knee and ankle minimum flexion angles during swing phase that were statistically significant with p = 0.05 and p = 0.02 , respectively . Velocity of gait , cycle time , and symmetry of stance phases also improved . The length of time elapsed since the stroke did not prove to be a significant factor [11276182] BACKGROUND AND PURPOSE Visual biofeedback/forceplate systems are often used for treatment of balance disorders . In this study , the research ers investigated whether the addition of visual biofeedback/forceplate training could enhance the effects of other physical therapy interventions on balance and mobility following stroke . SUBJECTS The study included a sample of convenience of 13 out patients with hemiplegia who ranged in age from 30 to 77 years ( mean=60.4 , SD=15.4 ) and were 15 to 538 days poststroke . METHODS Subjects were assigned r and omly to either an experimental group or a control group when the study began , and their cognitive and visual-perceptual skills were tested by a psychologist . Subjects were also assessed using the Berg Balance Scale and the Timed " Up & Go " Test before and after 4 weeks of physical therapy . Both groups received physical therapy interventions design ed to improve balance and mobility 2 to 3 times per week . The experimental group trained on the NeuroCom Balance Master for 15 minutes of each 50-minute treatment session . The control group received other physical therapy for 50 minutes . RESULTS Following intervention , both groups scored higher on the Berg Balance Scale and required less time to perform the Timed " Up & Go " Test . These improvements corresponded to increased independence of balance and mobility in the study population . However , a comparison of mean changes revealed no differences between groups . DISCUSSION AND CONCLUSION Although both groups demonstrated improvement following 4 weeks of physical therapy interventions , no additional effects were found in the group that received visual biofeedback/forceplate training combined with other physical therapy [15293487] Objective : To discover if the provision of additional inpatient physiotherapy after stroke speeds the recovery of mobility . Design : A multisite single-blind r and omized controlled trial ( RCT ) comparing the effects of augmented physiotherapy input with normal input on the recovery of mobility after stroke . Setting : Three rehabilitation hospitals in North Glasgow , Scotl and . Subjects : Patients admitted to hospital with a clinical diagnosis of stroke , who were able to tolerate and benefit from mobility rehabilitation . Intervention : We aim ed to provide double the amount of physiotherapy to the augmented group . Main measures : Primary outcomes were mobility milestones ( ability to st and , step and walk ) , Rivermead Mobility Index ( RMI ) and walking speed . Results : Seventy patients were recruited . The augmented therapy group received more direct contact with a physiotherapist ( 62 versus 35 minutes per weekday ) and were more active ( 8.0 % versus 4.8 % time st and ing or walking ) than normal therapy controls . The augmented group tended to achieve independent walking earlier ( hazard ratio 1.48 , 95 % confidence interval 0.90–2.43 ; p=0.12 ) and had higher Rivermead Mobility Index scores at three months ( mean difference 1.6 ; 0.1 to 3.3 ; p=0.068 ) but these differences did not reach statistical significance . There was no significant difference in any other outcome . Conclusions : A modest augmented physiotherapy programme result ed in patients having more direct physiotherapy time and being more active . The inability to show statistically significant changes in outcome measures could indicate either that this intervention is ineffective or that our study could not detect modest changes [10945421] Objective : To determine whether strapping the shoulder in hemiplegic stroke patients : ( 1 ) prevents the development , or reduces the severity , of shoulder pain , ( 2 ) preserves range of movement in the shoulder , and ( 3 ) improves the functional outcomes for the arm and patient overall . Design : A prospect i ve , r and omized , single-blind controlled trial of shoulder strapping versus no strapping . Setting : Care of the elderly wards in a teaching hospital , Christchurch , New Zeal and . Subjects : All patients admitted with an acute hemiplegic stroke , who had persisting weakness of shoulder abduction . Intervention : The treatment group had their affected shoulder strapped for six weeks from r and omization in addition to st and ard physiotherapy . Main outcome measures : All subjects were assessed at entry ( week 0 ) , at end of the treatment phase ( week 6 ) and two months later ( week 14 ) . A visual analogue scale ( VAS ) was used to assess shoulder pain severity whereas shoulder range of movement to the point of pain ( SROMP ) assessed passive range of movement and pain . Functional Independence Measure ( FIM ) , Motor Assessment Scale ( MAS ) and Rankin Disability Index measured functional outcomes . Results : Ninety-eight subjects participated ( 49 strapped , 49 controls ) . Intention to treat analysis showed no significant difference in pain , range of movement or functional outcomes after the intervention phase or at the final assessment . However there were trends for less pain at six weeks ( VAS , p = 0.11 ) and better final upper limb function ( MAS , p = 0.16 ) in strapped patients . Skin reactions were uncommon ( 6.1 % ) . The presence of neglect or sensory loss , but not subluxation , at baseline was independently associated with poor outcome . Range of movement was lost early ( mean difference SROMP between hemiplegic and contralateral shoulders at baseline = 15.2 ° ( 95 % CI 10.9–19.5 ) ) and continued throughout the study . Shoulder strapping did not alter the rate at which range of movement was lost . Conclusions : No significant benefit with shoulder strapping was demonstrated and reasons for this are discussed . Range of movement in the hemiplegic shoulder is lost very early and any preventive treatments need to begin within the first 1–2 days after a stroke [1137478] The effectiveness of biofeedback training was compared to conventional physical therapy training in 20 adult hemiparetic patients with chronic foot-drop . They were r and omly placed into two groups of ten patients each : the first group treated over five weeks with therapeutic exercise and the second group treated over five weeks with therapeutic exercise plus biofeedback training . In the second group receiving the biofeedback training the increase in both strength and range of motion was approximately twice as great as in the first group . The improvement displayed by even the first group of patients suggests that a potential for functional improvement exists that is often unexploited . The addition of biofeedback facilitates the process . Four patients in the biofeedback group achieved and retained conscious control of dorsiflexion ; three of them are now able to walk without the use of the short leg brace [2701823] The study was design ed to evaluate the effect of electromyographic ( EMG ) biofeedback on the recovery of arm function after stroke . Patients who had impaired arm function and were between 2 and 8 weeks after stroke were r and omly allocated to receive either treatment incorporating EMG biofeedback or a control treatment in addition to their routine physiotherapy . The two groups of 20 patients were compared before and after 6 weeks of treatment and at follow-up 6 weeks later . There were no significant differences between the groups before treatment or at follow-up , but at the end of treatment those who received EMG biofeedback scored significantly higher on tests of arm function . Patients with severe impairment were shown to benefit most from EMG biofeedback but there was no difference in response to treatment according to patient 's age or side of stroke . Men had higher arm function scores than women before and at the end of treatment , but not at follow-up [14586909] OBJECTIVE To determine the effectiveness of progressive resistance strengthening exercises to improve gross motor function and walking in patients receiving intensive rehabilitation after stroke . DESIGN R and omized controlled trial . SETTING Five inpatient rehabilitation programs affiliated with teaching hospitals . PARTICIPANTS Inclusion criteria included less than 6 months poststroke and recovery of the leg stages 3 to 5 on the Chedoke-McMaster Stroke Assessment ( CMSA ) . INTERVENTIONS Both groups received conventional physical therapy programs . In addition , the experimental group performed 9 lower-extremity progressive resistance exercises 3 times a week for the duration of their stay , whereas the control group did the same exercises and for the same duration but without resistance . MAIN OUTCOME MEASURES The Disability Inventory of the CMSA and the 2-minute walk test ( 2MWT ) at baseline , 4 weeks , discharge , and 6 months after discharge . RESULTS Over the length of stay , the rate of change in the Disability Inventory was.27 points per day in the experimental group and .29 points per day in the control group ; the between-group difference was -.02 points per day ( 95 % confidence interval [ CI ] , -.10 to.06 ; P=.62 ) . At discharge , the rate of change in the 2MWT was -.01 m in the experimental group and .15 m in the control group ; the between-group difference was -.16 m ( 95 % CI , -.37 to.05 ; P=.14 ) . CONCLUSIONS Progressive resistance strengthening exercises as applied in our study were not effective when compared with the same exercises given without resistance [705282] A group of forty-nine hemiparetic patients with limited emotional , communication and sensibility involvement and with recent lesion of cerebrovascular aetiology was r and omly divided into two groups of twenty-four and twenty-five subjects . Both groups received traditional physiotherapy treatment for one hour/day , one group received twenty min/day of peroneal nerve stimulation . The maximum voluntary dorsal flexion moments of the ankle joint of the affected and non affected extremities were measured with an isometric brace twice a week for one month and for both groups . The recovery of moment in the stimulated group turned out to be about three times greater than in the control group and considerably less dependent upon age , time from lesion , initial value , side of lesion . Three patients using a peroneal brace at home as an assisting device were again evaluated two months later and a further improvement was observed . This work gives statistical support to previous observations based on very few cases and provides a statistically reliable answer concerning the entity of FES induced recovery of muscle force in hemiparetic subjects [14606736] Objective : To demonstrate the effect of rhythmical auditory stimulation in a musical context for gait therapy in hemiparetic stroke patients , when the stimulation is played back measure by measure initiated by the patient 's heel strikes ( musical motor feedback ) . Does this type of musical feedback improve walking more than a less specific gait therapy ? Design : The r and omized controlled trial considered 23 registered stroke patients . Two groups were created by r and omization : the control group received 15 sessions of conventional gait therapy and the test group received 15 therapy sessions with musical motor feedback . Setting : Inpatient rehabilitation hospital . Subjects : Median post-stroke interval was 44 days and the patients were able to walk without technical aids with a speed of approximately 0.71 m/s . Main outcome measures : Gait velocity , step duration , gait symmetry , stride length and foot rollover path length ( heel-on – toe-off distance ) . Result : The test group showed more mean improvement than the control group : stride length increased by 18 % versus 0 % , symmetry deviation decreased by 58 % versus 20 % , walking speed increased by 27 % versus 4 % and rollover path length increased by 28 % versus 11 % . Conclusion : Musical motor feedback improves the stroke patient 's walk in selected parameters more than conventional gait therapy . A fixed memory in the patient 's mind about the song and its timing may stimulate the improvement of gait even without the presence of an external pacemaker [11790899] PURPOSE A series of pilot studies were conducted to examine the effects of partial body weight ( PBW ) ambulation in people with chronic stroke . METHODS First , we compared gait characteristics during 3 modes of walking : level ground ambulation ; level ground ambulation with PBW ; and treadmill ambulation with PBW . Second , we examined the effects of repeated PBW treadmill training during level ground ambulation . RESULTS Improved symmetry in stance/swing times and sEMG activity of pre-tibialis and quadriceps muscle groups during PBW either over level ground or on the treadmill occurred in 10 chronic stroke subjects . Increased single limb support and decreased double limb support improved overall gait symmetry during level ground ambulation in 8 subjects following 6 - -8 weeks repeated PBW treadmill training . Tinetti Balance score also significantly improved . No changes in sEMG were observed . CONCLUSION These results suggest that PBW treadmill may help normalize gait and improve balance in the person with chronic stroke [12234091] Objective : To determine the efficacy of a modified constraint-induced therapy ( mCIT ) administered to patients with subacute stroke . Design : Prospect i ve , multiple-baseline , before-after , r and omized clinical trial . Setting : Subacute outpatient clinic . Subjects : Fourteen patients with subacute stroke who exhibited learned nonuse and stable motor deficits in their affected upper limbs . Intervention : Four patients participated in half-hour , structured physical and occupational therapy sessions that emphasized affected arm use in valued functional activities , 3 times per week for 10 weeks . Their less affected upper limbs were restrained 5 days per week during 5 hours identified as times of frequent use ( mCIT ) . Five patients received regular therapy ( TR ) with similar therapeutic contact time to mCIT , and 5 patients received no therapy ( CON ) . Main Outcome Measures : The Fugl-Meyer Assessment of Motor Recovery ( Fugl ) , Action Research Arm ( ARA ) test , and Motor Activity Log ( MAL ) . Results : After intervention , Fugl , ARA , and MAL scores remained virtually the same for TR and CON groups ; scores improved by 11.4 and 11.5 points , respectively , on the Fugl and ARA for the mCIT group . Amount and quality of arm use , as measured by the MAL , also improved for mCIT patients ( 2.49 and 0.47 , respectively ) . Conclusions : mCIT may be an efficacious method of improving affected arm function and use in stroke patients exhibiting learned nonuse [11991797] BACKGROUND AND PURPOSE The effects of different duration s of rehabilitation sessions for the upper extremities ( UEs ) and lower extremities ( LEs ) on the recovery of interlimb coordination in hemiplegic gait in patients who have had a stroke were investigated . SUBJECTS AND METHODS Fifty-three subjects who had strokes involving their middle cerebral arteries were assigned to rehabilitation programs with ( 1 ) an emphasis on the LEs , ( 2 ) an emphasis on the paretic UE , or ( 3 ) a condition in which the paretic arm ( UE ) and leg ( LE ) were immobilized with an inflatable pressure splint ( control treatment ) . The 3 treatment regimens were applied for 30 minutes , 5 days a week , during the first 20 weeks after onset of stroke . All subjects also participated in a rehabilitation program 5 days a week that consisted of 15 minutes of UE exercises and 15 minutes of LE exercises in addition to a weekly 11/2-hour session of training in activities of daily living . A repeated- measures design was used . Differences among the 3 treatment regimens were evaluated in terms of comfortable and maximal walking speeds . In addition , mean continuous relative phase ( CRP ) between paretic arm and leg ( PAL ) movements and nonparetic arm and leg ( NAL ) movements and st and ard deviations of CRP of both limb pairs as a measurement of stability ( variability ) were evaluated . RESULTS Comfortable walking speed improved in the group that received interventions involving the LEs compared with the group that received interventions involving the UEs and the group that received the control treatment . No differences among the 3 treatment conditions were found for the mean CRP of NAL and PAL as well as the st and ard deviation of CRP of both limb pairs . DISCUSSION AND CONCLUSION With the exception of an improved comfortable walking speed as a result of a longer duration of rehabilitation sessions , no differential effects of duration of rehabilitation sessions for the LEs and UEs on the variable we measured related to hemiplegic gait were found . Increasing walking speed , however , result ed in a larger mean CRP for both limb pairs , with increased stability and asymmetry of walking , indicating that walking speed influences interlimb coordination in hemiplegic gait [11237159] Objective : It is uncertain whether self-propulsion in a wheelchair should be encouraged or discouraged in the early stages of stroke rehabilitation . Design : A two-centre pilot study to assess the feasibility of performing a multicentre r and omized controlled trial on this subject . Setting : Clatterbridge and Aintree Stroke Rehabilitation Units , Merseyside , UK . Subjects : Forty early stroke patients ( mean age 67 years ) in whom it was uncertain whether self-propulsion in a wheelchair should be encouraged were studied . Intervention : A central r and omization service at Newcastle University was used to determine the policy about wheelchair provision and use for each patient . They were allocated to either an ‘ encouraged to self-propel ’ or a ‘ discouraged from self-propulsion group ’ . Outcome measures used : Independent outcome assessment was performed by postal question naire and telephone interview using the Barthel ADL Scale , Nottingham Extended ADL Scales and the shortened General Health Question naire ( GHQ-12 ) at 3 and 12 months . Patient 's length of stay and their Ashworth tone score were also measured either at three months or when they were discharged from hospital . Results : After considerable preparation time it was possible to conduct a trial on self-propulsion in early stroke rehabilitation in the two-pilot centres . No major differences were found between the pilot groups for any of the outcome measures . Conclusions : A multicentre r and omized controlled trial to assess this question is feasible but further work is being conducted before proceeding , to satisfy the concerns expressed to our group regarding the appropriateness of the intervention and the outcome measures . Address for correspondence : JA Barrett , Clatterbridge Hospital , Wirral , Merseyside CH69 4JY , UK . e-mail : [11518440] Objective : To explore the effects of weighted garments on the balance and gait of stroke patients . Design : A pilot r and omized controlled study with blinded measurement . Setting : Weighted garments were worn by patients living in the community and measurement was made in a hospital-based gait laboratory . Subjects : Twenty-four adults who were at least six months post stroke and were able to walk 10 metres with or without assistance or a walking aid . Intervention : The six-week treatment-phase subjects were given a set of weighted garments which they were shown how to apply and instructed to wear on their paretic side . Subjects r and omly allocated to the six-week control phase were not given any weighted garments . Main outcome measures : Balance was measured with the Berg Balance Scale . Gait was measured using GaitMat II , an instrumented walkway . Gait parameters of interest were velocity and symmetry of : step length ; single support time ; double support time ; and support base width . Measures were made at baseline before r and omization ( baseline ) and at the end of the six weeks of intervention ( outcome ) . Results : No statistically significant differences were found between the treatment and control groups at outcome for balance ( Mann – Whitney U-test ; p = 0.74 ) , gait velocity ( p = 0.68 ) or symmetry of gait parameters ( p = 0.33 to p = 0.75 ) . Conclusions : We found no evidence to support the clinical use of these weighted garments for stroke survivors [25026492] The effectiveness of biofeedback therapy , using the electromyograph , was compared with conventional physiotherapy treatments in eleven hemiparetic patients with severe disability of the upper limb . These were divided r and omly into two groups , a group of six patients receiving biofeedback treatments and five receiving physiotherapy treatments with conventional techniques . The results showed greater improvements in the biofeedback group in most fields of testing , and the patients in this group had a greater degree of control over the patterns of movement in the upper limb and the relaxation of spastic muscle groups . It was concluded that a wide range of hemiparetic patients should benefit in some degree by treatment of this form [26486052] Functional electrical stimulation ( FES ) may improve recovery after stroke . We studied its effects in 38 postcerebral infa rct patients . Twenty were r and omly assigned to receive FES producing ankle dorsiflexion on the affected side and physical therapy . The remaining 18 received physical therapy only . Subjects were evaluated prior to commencing therapy , at its completion after 4 weeks , and again 4 weeks later using functional and electrophysiological measures . Functional deficit in most patients improved ( p < 0.01 ) . Although no significant differences were observed when those treated with FES and those not treated were compared at 4 and 8 weeks , there was significant improvement in the rate of recovery using an ambulation score ( p < 0.05 ) , and there was a similar trend in the Barthel Index for FES-treated patients ( p < 0.1 ) . Our results indicate that FES may confer additional benefit in acute stroke rehabilitation . Further studies are needed to delineate how best to use it

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### Context: [10390311] BACKGROUND AND PURPOSE It has been suggested that cyclic neuromuscular electrical stimulation ( ES ) may enhance motor recovery after stroke . We have investigated the effects of ES of the wrist extensors on impairment of wrist function and on upper-limb disability in patients being rehabilitated after acute stroke . METHODS We recruited 60 hemiparetic patients ( mean age , 68 years ) 2 to 4 weeks after stroke into a r and omized , controlled , parallel-group study comparing st and ard rehabilitation treatment with st and ard treatment plus ES of wrist extensors ( 3 times 30 minutes daily for 8 weeks ) . Isometric strength of wrist extensors was measured using a device built for that purpose . Upper-limb disability was assessed with use of the Action Research Arm Test ( ARAT ) . Observations were continued for 32 weeks ( 24 weeks after the finish of ES or the control intervention phase ) . RESULTS The change in isometric strength of wrist extensors ( at an angle of 0 degrees extension ) was significantly greater in the ES group than the control group at both 8 and 32 weeks ( P=0.004 , P=0.014 by Mann Whitney U test ) . At week 8 the grasp and grip subscores of the ARAT increased significantly in the ES group compared with that in the control group ( P=0.013 and P=0.02 , respectively ) ; a similar trend was seen for the total ARAT score ( P=0.11 ) . In the subgroup of 33 patients with some residual wrist extensor strength at study entry ( moment at 0 degrees extension > 0 ) , the ARAT total score had increased at week 8 by a mean of 21.1 ( SD , 12.7 ) in the ES group compared with 10.3 ( SD , 9.0 ) in the control group ( P=0.024 , Mann Whitney U test ) ; however , at 32 weeks the differences between these 2 subgroups were no longer statistically significant . CONCLUSIONS ES of the wrist extensors enhances the recovery of isometric wrist extensor strength in hemiparetic stroke patients . Upper-limb disability was reduced after 8 weeks of ES therapy , with benefits most apparent in those with some residual motor function at the wrist . However , it is not clear how long the improvements in upper-limb disability are maintained after ES is discontinued [7149946] Poor prognosis for upper limb recovery of stroke survivors has not changed in at least 28 years ; only 4 % to 5 % of patients regain arm function during or after the active rehabilitation phase . This pilot study included 37 patients r and omly assigned to either an integrated behavioral-physical therapy treatment program including electromyographic feedback ( experimental group ) or a st and ard exercise physical therapy program of like duration and intensity ( control group ) . Both groups showed clinical ly significant improvements that exceeded previously reported experience . The experimental technique appears to be more effective when upper limb involvement is not severe in a late case , or when treatment is started early ( within 3 months poststroke ) in a severe case . The rehabilitation community should quickly investigate the improved prospect s of restoring a greater number of useful upper limbs in this often neglected group of hemiplegic patients [10084443] OBJECTIVE To determine the influence of functional electrical stimulation ( FES ) on subluxation and shoulder pain in hemiplegic patients . DESIGN Controlled study of 24 months ' duration beginning in the first month after onset of stroke . SUBJECTS AND SETTING One hundred twenty hemiplegic patients with both subluxed and painful shoulder were followed for rehabilitation before and after discharge between 1989 and 1993 . All subjects received conventional rehabilitation based on the Bobath concept . In addition , patients were alternately assigned to a control group or to receive additional FES for 5 weeks on muscles surrounding their subluxed and painful shoulder . MAIN MEASURES Clinical examinations , including range of motion , pain assessment , and x-rays , were performed at the start of the study , between the second and fourth weeks after onset of stroke , and subsequently at 6 , 12 , and 24 months . RESULTS The FES group showed significantly more improvement than the control group in both pain relief ( 80.7 % vs. 55.1 % , p<.01 ) and reduction of subluxation ( 78.9 % vs. 58.6 % , p<.05 ) . Furthermore , recovery of arm motion appeared to be significantly improved in the FES group ( 77.1 % vs. 60.3 % in the control group , p<.01 ) . CONCLUSION The FES program was significantly effective in reducing the severity of subluxation and pain and possibly may have facilitated recovery of the shoulder function in hemiplegic patients [11108760] Background and Purpose Motor dysfunction after unilateral deafferentation in primates can be overcome by restraining the unaffected limb . We asked whether a constraint-induced movement ( CIM ) program could be implemented within 2 weeks after stroke and whether CIM is more effective than traditional upper-extremity ( UE ) therapies during this period . Methods Twenty-three persons were enrolled in a pilot r and omized , controlled trial that compared CIM with traditional therapies . A blinded observer rated the primary end point , the Action Research Arm Test ( ARA ) . Inclusion criteria were the following : ischemic stroke within 14 days , persistent hemiparesis , evidence of preserved cognitive function , and presence of a protective motor response . Differences between the groups were compared by using Student ’s t tests , ANCOVA , and Mann-Whitney U tests . Results Twenty subjects completed the 14-day treatment . Two adverse outcomes , a recurrent stroke and a death , occurred in the traditional group ; 1 CIM subject met rehabilitation goals and was discharged before completing 14 inpatient days . The CIM treatment group had significantly higher scores on total ARA and pinch subscale scores ( P < 0.05 ) . Differences in the mean ARA grip , grasp , and gross movement subscale scores did not reach statistical significance . UE activities of daily living performance was not significantly different between groups , and no subject withdrew because of pain or frustration . Conclusions A clinical trial of CIM therapy during acute rehabilitation is feasible . CIM was associated with less arm impairment at the end of treatment . Long-term studies are needed to determine whether CIM early after stroke is superior to traditional therapies [9349677] Experimental and control groups of 10 hemiparetic stroke patients each underwent a 6 week , twice daily gait training program . The control group participated in a conventional physical therapy gait program . The experimental group trained in the same basic program with the addition of rhythmic auditory stimulation ( RAS ) . Patients entered the study as soon as they could complete 5 strides with h and -held assistance . The training program had to be completed within 3 months of the patients ' stroke . In the experimental group RAS was used as a timekeeper to synchronize step patterns and gradually entrain higher stride frequencies . Study groups were equated by gender , lesion site , and age . Motor function was assessed at pretest using Barthel , Fugl-Meyer , and Berg Scales . Walking patterns were assessed during pre- and post-test without RAS present . Pre- vs post-test measures revealed a statistically significant ( P<0.05 ) increase in velocity ( 164 % vs 107 % ) , stride length ( 88 % vs 34 % ) , and reduction in EMG amplitude variability of the gastrocnemius muscle ( 69 % vs 33 % ) for the RAS-training group compared to the control group . The difference in stride symmetry improvement ( 32 % in the RAS-group vs 16 % in the control group ) was statistically not significant . The data offer evidence that RAS is an efficient tool to enhance efforts in gait rehabilitation with acute stroke patients [8202978] Background and Purpose Alterations of gait cycle and foot-drop on the paretic limb are characteristic of stroke patients . Electromyographic biofeedback treatment has been used in rehabilitation of walking , but results are controversial . We performed gait analysis to evaluate the efficacy of electromyographic biofeedback compared with physical therapy . Methods Sixteen patients with ischemic stroke were enrolled in the study . The experimental group ( 4 men , 4 women ) received electromyographic biofeedback treatment together with physical therapy . The control group ( 5 men , 3 women ) was treated with physical therapy only . Clinical and functional evaluations before and after treatment were performed using Canadian Neurological , Adams , Ashworth , Basmajian , and Barthel Index scales . Computerized gait analysis was performed in all patients . Results Electromyographic biofeedback patients showed significantly increased scores on the Adams scale ( P<.05 ) and Basmajian scale ( P<.01 ) . Gait analysis in this group showed a recovery of foot-drop in the swing phase ( P<.02 ) after training . Conclusions Our data confirm that the electromyographic biofeedback technique increases muscle strength and improves recovery of functional locomotion in patients with hemiparesis and foot-drop after cerebral ischemia [12920254] BACKGROUND AND PURPOSE Rehabilitation care after stroke is highly variable and increasingly shorter in duration . The effect of therapeutic exercise on impairments and functional limitations after stroke is not clear . The objective of this study was to determine whether a structured , progressive , physiologically based exercise program for subacute stroke produces gains greater than those attributable to spontaneous recovery and usual care . METHODS This r and omized , controlled , single-blind clinical trial was conducted in a metropolitan area and 17 participating healthcare institutions . We included persons with stroke who were living in the community . One hundred patients ( mean age , 70 years ; mean Orpington score , 3.4 ) consented and were r and omized from a screened sample of 582 . Ninety-two subjects completed the trial . Intervention was a structured , progressive , physiologically based , therapist-supervised , in-home program of thirty-six 90-minute sessions over 12 weeks targeting flexibility , strength , balance , endurance , and upper-extremity function . Main outcome measures were postintervention strength ( ankle and knee isometric peak torque , grip strength ) , upper- and lower-extremity motor control ( Fugl Meyer ) , balance ( Berg and functional reach ) , endurance ( peak aerobic capacity and exercise duration ) , upper-extremity function ( Wolf Motor Function Test ) , and mobility ( timed 10-m walk and 6-minute walk distance ) . RESULTS In the intention-to-treat multivariate analysis of variance testing the overall effect , the intervention produced greater gains than usual care ( Wilk 's lambda=0.64 , P=0.0056 ) . Both intervention and usual care groups improved in strength , balance , upper- and lower-extremity motor control , upper-extremity function , and gait velocity . Gains for the intervention group exceeded those in the usual care group in balance , endurance , peak aerobic capacity , and mobility . Upper-extremity gains exceeded those in the usual care group only in patients with higher baseline function . CONCLUSIONS This structured , progressive program of therapeutic exercise in persons who had completed acute rehabilitation services produced gains in endurance , balance , and mobility beyond those attributable to spontaneous recovery and usual care [11552192] OBJECTIVES To identify the most responsive method of measuring gait speed , to estimate the responsiveness of other outcome measures , and to determine whether gait speed predicts discharge destination in acute stroke . DESIGN A prospect i ve cohort study . SETTING Five acute-care hospitals . PATIENTS Fifty subjects with residual gait deficits after a first-time stroke . INTERVENTIONS Five- ( 5mWT ) and 10-meter walk tests ( 10mWT ) at comfortable and maximum speeds , with 2 evaluations conducted an average + /- st and ard deviation ( SD ) of 8 + /- 3 and 38 + /- 5 days poststroke . MAIN OUTCOME MEASURE St and ardized response mean ( SRM = mean change/SD of change ) was used to estimate responsiveness for each walk test , the Berg Balance Scale , the Barthel Index , the Stroke Rehabilitation Assessment of Movement ( STREAM ) , and the Timed Up and Go ( TUG ) . RESULTS The SRMs were 1.22 and 1.00 for the 5mWT , and .92 and .83 for the 10mWT performed at a comfortable and maximum pace , respectively . The SRMs for the Berg Balance Scale , the Barthel Index , the STREAM , and the TUG were 1.04,.99,.89 , and .73 , respectively . The probability of discharge to a rehabilitation center for persons walking at < or = 0.3 m/s or > 0.6 m/s at the first evaluation was.95 and .22 , respectively . CONCLUSIONS The 5mWT at a comfortable pace is recommended as the measure of choice for clinicians and research ers who need to detect longitudinal change in walking disability in the first 5 weeks poststroke [11812553] BACKGROUND Community physiotherapy is often prescribed for stroke patients with long-term mobility problems . We aim ed to assess the effectiveness of this treatment in patients who had mobility problems 1 year after stroke . METHODS We screened 359 patients older than 50 years for a single-masked , r and omised controlled trial to assess the effects of community physiotherapy . Assessment s were made at baseline , 3 , 6 , and 9 months in 170 eligible patients assigned treatment or no intervention . The primary outcome measure was mobility measured by the Rivermead mobility index . Secondary outcome measures were gait speed , number of falls , daily activity ( Barthel index scores ) , social activity ( Frenchay activities index ) , hospital anxiety and depression scale , and emotional stress of carers ( general health question naire 28 ) . Analyses were by intention to treat . FINDINGS Follow-up was available for 146 patients ( 86 % ) . Changes in scores on the Rivermead mobility index ( score range 0 - 15 ) differed significantly between treatment and control groups at 3 months ( p=0.018 ) , but only by a median of 1 point ( 95 % CI 0 - 1 ) , with an interpolated value of 0.55 ( 0.08 - 1.04 ) . Gait speed was 2.6 m/min ( 0.30 - 4.95 ) higher in the treatment group at 3 months . Neither treatment effect persisted at 6-months ' and 9-months ' follow-up . Treatment had no effect on patients ' daily activity , social activity , anxiety , depression , and number of falls , or on emotional stress of carers . INTERPRETATION Community physiotherapy treatment for patients with mobility problems 1 year after stroke leads to significant , but clinical ly small , improvements in mobility and gait speed that are not sustained after treatment ends [10088589] A comparison was made of 113 consecutive patients who suffered a cerebrovascular accident and were hospitalized at a rehabilitation inpatient unit by dividing them into two groups : one group received the traditional 6-day/wk treatment regimen , and another group received treatment during the entire week ( 7 days/wk ) . When the patients were asked whether they had a preference ( which did not affect their group assignment ) , 82 % preferred a 6-day/wk program and 18 % preferred a 7-day/wk program . The length of inpatient stay for the 57 patients enrolled in the 6-day/wk program was 20.14 days ; for the 56 patients enrolled in the 7-day/wk program , the average length of stay was 20.11 days . This represents no significant difference . The functional recoveries were evaluated in areas that can affect length of stay , including dressing , bladder control , ambulation , and problem-solving . Both groups demonstrated significant gains in each domain when the intake and discharge ratings were compared . However , these gains were not significantly different when the 6- and 7-day/wk groups were compared . The results of the study contained herein , therefore , suggest that a 6-day/wk program for patients who have suffered a cardiovascular accident is just as effective as a 7-day/wk program [14617717] Objective : To investigate progress toward motor recovery in patients with chronic hemiparesis ( mean time since stroke 3.2 years ) , comparing different types of practice schedules . Design : To increase voluntary control of the upper extremity , active neuromuscular stimulation was administered during blocked and r and om practice schedules as patients performed three specific movements : wrist/finger extension , elbow joint extension , and shoulder joint abduction . Methods : 34 stroke subjects volunteered to participate and were r and omly assigned to one of three treatment groups : blocked practice ( the same movement was repetitively performed on successive trials ) combined with active neuromuscular stimulation ; r and om practice ( different movements on successive trials ) along with active stimulation ; or no active stimulation assistance control group . Subjects completed two days of 90 minute training for each of two weeks with at least 24 hours of rest between sessions . A session was three sets of 30 successful active neuromuscular stimulation trials with the three movements executed 10 times/set . Results : Mixed design analyses on three categories of behavioural measures indicated motor improvements for the blocked and r and om practice /stimulation groups in comparison with the control group during the post-test period , with a larger number of blocks moved , faster premotor and motor reaction times , and less variability in the sustained muscular contraction task . Conclusions : Upper extremity rehabilitation intervention of active stimulation and blocked practice performed as well as stimulation/r and om practice . Moreover , these purpose ful voluntary movement findings support and extend sensorimotor integration theory to both practice schedules [11129665] BACKGROUND AND PURPOSE The best treatment and management of stroke patients has been shown to be in stroke units by multidisciplinary rehabilitation teams . Since the composition of stroke units differs it is important to know the extent to which the different components contribute to this results . Physiotherapy is one component of most rehabilitation teams and recent systematic review s have shown that patients with stroke receiving more physiotherapy achieve more recovery from disability . However , information about the actual amounts of physiotherapy needed to achieve this result is not known . METHOD A pragmatic , r and omized , single-blind , controlled trial comparing recovery from disability in subjects receiving the current st and ard amount of 30 minutes ' physiotherapy with those receiving double that amount ( 60 minutes ) . The study included measures of physical performance and function , psychological aspects of anxiety and depression , and perceived control over recovery . RESULTS Some 114 subjects were recruited to the study ; full six-week data are available for 104 subjects and six-month data for 93 subjects . Comparison of initial to six-week difference scores in the control and intervention groups of the whole sample did not show a significant difference . Scrutiny of the recovery curves of the whole sample showed that , in half the sample , three distinct patterns of recovery were demonstrated . CONCLUSION These results suggest that doubling the physiotherapy time available for patients in a stroke unit will not provide a measurable benefit for all patients . The subgroup analysis of patterns of recovery must be regarded as speculative , but provides the basis for hypotheses about those likely to respond well to more intensive therapy [12971702] Objective : To determine whether an early increased-intensity upper limb therapy programme following acute stroke improves outcome . Design : A r and omized controlled trial . Setting : A stroke unit which provides acute care and rehabilitation for all stroke admissions . Subjects : One hundred and twenty-three patients who had had a stroke causing upper limb impairment within the previous 10 days . Intervention : The intervention group received stroke unit care plus enhanced upper limb rehabilitation provided jointly by a physiotherapist and occupational therapist , commencing within 10 days of stroke , and available up to 30 minutes/day , five days/week for six weeks . The control group received stroke unit care . Main outcome measures : The primary outcome measure was the Action Research Arm Test ( ARAT ) three months after stroke . Secondary outcome measures : Motricity Index ; Frenchay Arm Test ; upper limb pain ; Barthel ADL Index ; Nottingham E-ADL Scale ; and costs to health and social services at three and six months after stroke . Results : There were no differences in outcomes between the intervention and control groups three and six months after stroke . During the intervention period the intervention group received a median of 29 minutes of enhanced upper limb therapy per working day as in patients . The total amount of inpatient physiotherapy and occupational therapy received by the intervention group was a median of 52 minutes per working day during the intervention period and 38 minutes per working day for the control group ( p = 0.001 ) . There were no differences in service costs . Conclusions : An early increased-intensity interdisciplinary upper limb therapy programme jointly provided by a physiotherapist and occupational therapist did not improve outcome after stroke . The actual difference in the amount of therapy received by intervention and control groups was less than planned due to a competitive therapy bias [508075] Positional feedback ( PF ) and electrical stimulation were combined in a new treatment modality for facilitating wrist extension in stroke patients . Thirty adult hemiparetic patients lacking normal voluntary wrist extension were r and omly placed in control and study groups . The control group received conventional therapy while the study group received positional feedback stimulation training ( PFST ) in addition to conventional treatment . At the end of the 4-week program , study patients showed a 280 % increase in isometric extension torque when the wrist was positioned in 30 degrees of extension and 70 % increase when positioned in 30 degrees of flexion . Control patients showed no significant changes in torque . Study patients made an average 200 % gain in selective range of motion over their starting levels while controls made only a 50 % increase . Treatment using automated PFST equipment allows controlled repetitive isotonic exercise and facilitation of wrist extension without continuous one-on-one therapist/patient supervision [11732835] This case series examined the feasibility and efficacy of a modified constraint induced therapy ( CIT ) protocol administered on an outpatient basis . The Fugl-Meyer Assessment of Motor Recovery After Stroke ( Fugl ) , Action Research Arm Test ( ARA ) , Wolf Motor Function Test ( WMFT ) , and Motor Activity Log ( MAL ) were administered to six patients between 2 and 6 months poststroke ( CVA ) exhibiting stable motor deficits and learned nonuse of the affected limb . Two patients then participated in half-hour physical and occupational therapy sessions three times/week for 10 weeks . During the same period , their unaffected arms and h and s were restrained 5 days/week during 5 hours identified as times of frequent use . Two other patients received regular therapy and two control patients received no therapy . The ARA , Fugl , WMFT , and MAL were again administered after 10 weeks . Patients receiving modified CIT exhibited substantial improvements on the Fugl , ARA , and WMFT , as well as increases in amount and quality of use of the limb using the MAL . Patients receiving traditional or no therapy exhibited no improvements . Results suggest that modified CIT may be an efficacious method of improving function and use of the affected arms of patients exhibiting learned nonuse [10835457] BACKGROUND AND PURPOSE After stroke , many individuals have chronic unilateral motor dysfunction in the upper extremity that severely limits their functional movement control . The purpose of this study was to determine the effect of electromyography-triggered neuromuscular electrical stimulation on the wrist and finger extension muscles in individuals who had a stroke > or = 1 year earlier . METHODS Eleven individuals volunteered to participate and were r and omly assigned to either the electromyography-triggered neuromuscular stimulation experimental group ( 7 subjects ) or the control group ( 4 subjects ) . After completing a pretest involving 5 motor capability tests , the poststroke subjects completed 12 treatment sessions ( 30 minutes each ) according to group assignments . Once the control subjects completed 12 sessions attempting wrist and finger extension without any external assistance and were posttested , they were then given 12 sessions of the rehabilitation treatment . RESULTS The Box and Block test and the force-generation task ( sustained muscular contraction ) revealed significant findings ( P<0 . 05 ) . The experimental group moved significantly more blocks and displayed a higher isometric force impulse after the rehabilitation treatment . CONCLUSIONS Two lines of evidence clearly support the use of the electromyography-triggered neuromuscular electrical stimulation treatment to rehabilitate wrist and finger extension movements of hemiparetic individuals > or = 1 year after stroke . The treatment program decreased motor dysfunction and improved the motor capabilities in this group of poststroke individuals [10229728] BACKGROUND AND PURPOSE Subluxation is a significant problem in poststroke hemiplegia , result ing in pain and loss of function . Current treatments are not proved and not considered effective . It has been demonstrated that cyclical electrical stimulation of the shoulder muscles can reduce existing subluxation . The purpose of this study was to determine whether electrical stimulation could prevent subluxation in both the short and long terms . METHODS A prospect i ve , r and omized controlled study was used to determine the efficacy of electrical stimulation in preventing shoulder subluxation in patients after cerebrovascular accidents . Forty patients were selected and r and omly assigned to a control or treatment group . They had their first assessment within 48 hours of their stroke , and those in the treatment group were immediately put on a regimen of electrical stimulation for 4 weeks . All patients were assessed at 4 weeks after stroke and then again at 12 weeks after stroke . Assessment s were made of shoulder subluxation , pain , and motor control . RESULTS The treatment group had significantly less subluxation and pain after the treatment period , but at the end of the follow-up period there were no significant differences between the 2 groups . CONCLUSIONS Electrical stimulation can prevent shoulder subluxation , but this effect was not maintained after the withdrawal of treatment [9549021] Objective : To examine the effects of electromyographic ( EMG ) biofeedback training on the recovery of gait in the acute phase post stroke . Design : Patients were r and omly assigned to EMG biofeedback or control groups . They received treatment three times a week for six weeks . All patients were assessed prior to treatment , after 18 treatment sessions , and at three months follow-up . Setting : The study was carried out at Scunthorpe General Hospital in North Lincolnshire . The subjects were acute stroke patients who had been admitted on to the medical and elderly wards . Interventions : The EMG biofeedback group were treated using EMG as an adjunct to physiotherapy . The patients were encouraged to facilitate or inhibit abnormal muscle tone via auditory or visual signals transmitted from electrodes placed over the appropriate muscles . The control group were treated using the same techniques , electrodes were used with this group of patients , but the EMG machine was turned off and faced away from the patient and the therapist to control the placebo effect . Outcome measures : A large battery of outcome measures was used for physical and psychological assessment . The physical measures consisted of active movement , muscle tone , sensation , proprioception , mobility and activities of daily living ( ADL ) . The psychological measures included orientation , memory , spatial performance , language and IQ . Results : Twenty-one patients were included in the study . Scores were combined into four groups : mild EMG , severe EMG , mild control and severe control . Results showed that there was an improvement in physical scores for active movement , mobility and ADL over time , but there was no significant difference between the EMG and control groups . Scores on the psychological tests were within normal limits , and there was no difference in performance between the EMG and control groups . Conclusions : This study showed no significant differences in the rate of improvement after stroke between the two groups . Although EMG biofeed-back was used as an adjunct to physiotherapy and represented clinical practice , the results provide little evidence to support the clinical significance of using EMG biofeedback to improve gait in the acute phase after stroke [8630191] The effectiveness of ongoing rehabilitation services for postacute stroke survivors is poorly documented . We design ed a r and omized control , single-blinded study to demonstrate the effectiveness of intensive outpatient therapy . The treatment intervention consisted of 1 hr each of physical and occupational therapy , four times per week , for 12 wk ; therapy focused on neuromuscular facilitation and functional tasks . All subjects were screened before the therapies and after 3 mo and 9 mo . Forty-nine stroke survivors , who were at least l yr ( mean , 2.9 yr ) poststroke , were r and omized with two treated patients to each control ( no treatment supplied ) . All patients had received inpatient rehabilitation at the time of their acute stroke , but no patient had any ongoing therapy within the last 6 mo . The outcome measures included the Functional Independence Measure ( FIM ) , Brunnstrom stages of motor recovery , timed mobility tasks , and the Jebson h and evaluation . We also evaluated the level of depression , self-esteem , and socialization . The treated patients demonstrated an improvement of 6.6 points over the 3 mo of therapy compared with only 1.5 points in the control group in the FIM motor score transformed using Rasch analysis . The change from time 0 to 3 mo was significant in the treated group but not in the controls . Treated patients maintained their gains at the 9-mo follow-up , and controls lost ground . The treated group improved in terms of socialization and self-esteem as evidence d by a lower Sickness Impact Profile , whereas the controls tended to get worse . There was a trend toward less depression , but this did not reach a P = 0.05 level of significance . This study demonstrates that significant functional gains can still be attained in the postacute stroke survivor , despite prior inpatient rehabilitation services [10548673] BACKGROUND AND PURPOSE Of all stroke survivors , 30 % to 66 % are unable to use their affected arm in performing activities of daily living . Although forced use therapy appears to improve arm function in chronic stroke patients , there is no conclusive evidence . This study evaluates the effectiveness of forced use therapy . METHODS In an observer-blinded r and omized clinical trial , 66 chronic stroke patients were allocated to either forced use therapy ( immobilization of the unaffected arm combined with intensive training ) or a reference therapy of equally intensive bimanual training , based on Neuro-Developmental Treatment , for a period of 2 weeks . Outcomes were evaluated on the basis of the Rehabilitation Activities Profile ( activities ) , the Action Research Arm ( ARA ) test ( dexterity ) , the upper extremity section of the Fugl-Meyer Assessment scale , the Motor Activity Log ( MAL ) , and a Problem Score . The minimal clinical ly important difference ( MCID ) was determined at the onset of the study . RESULTS One week after the last treatment session , a significant difference in effectiveness in favor of the forced use group compared with the bimanual group ( corrected for baseline differences ) was found for the ARA score ( 3.0 points ; 95 % CI , 1.3 to 4.8 ; MCID , 5.7 points ) and the MAL amount of use score ( 0.52 points ; 95 % CI , 0.11 to 0.93 ; MCID , 0.50 ) . The other parameters revealed no significant differential effects . One-year follow-up effects were observed only for the ARA . The differences in treatment effect for the ARA and the MAL amount of use scores were clinical ly relevant for patients with sensory disorders and hemineglect , respectively . CONCLUSIONS The present study showed a small but lasting effect of forced use therapy on the dexterity of the affected arm ( ARA ) and a temporary clinical ly relevant effect on the amount of use of the affected arm during activities of daily living ( MAL amount of use ) . The effect of forced use therapy was clinical ly relevant in the subgroups of patients with sensory disorders and hemineglect , respectively [7770495] BACKGROUND AND PURPOSE Gait rehabilitation in patients with severe hemiplegia requires substantial effort . Preliminary studies indicate potential beneficial effects of using multichannel functional electrical stimulation ( MFES ) for gait rehabilitation in these patients . In this study , a new method of gait rehabilitation for nonambulatory patients with hemiplegia by means of MFES added to conventional therapy was introduced . The results of the method 's application were evaluated by comparing it with conventional therapeutic methods . SUBJECTS The proposed rehabilitation method was tested on a group of 20 patients with severe hemiplegia secondary to cerebrovascular accident . Subjects were r and omly assigned to one of two groups . One group received 3 weeks of MFES followed by 3 weeks of conventional therapy . The other group received 3 weeks of conventional therapy followed by 3 weeks of MFES . METHODS The effects of each therapeutic method were evaluated by measurements of temporal-distance variables and ground reaction forces and by assessment of each subject 's physical status according to the Fugl-Meyer evaluation scale . RESULTS There was improved performance of the subjects during MFES combined with conventional therapy as compared with conventional therapy alone . CONCLUSION AND DISCUSSION The superiority of the MFES method as compared with conventional therapy was mainly attributed to the enhanced motor learning accomplished by application of MFES . These results , however , are preliminary , and further research is needed [7041850] Electromyographic biofeedback was compared with simple exercise therapy as to its effectiveness in improving foot-drop in 22 stroke patients . The study was design ed to be a rigorous trial of biofeedback and the patients tested were aged and had stroke of long duration . One group of 11 patients underwent 6 weeks of exercise therapy 2 sessions per week for 15 minutes per session ; the 2nd group of 11 patients underwent similar therapy with EMG feedback . All therapy was conducted by a research assistant who was not a trained therapist . The groups were assessed blind before treatment , after treatment and a 6-week follow-up . The significantly greater improvements in the biofeedback group in terms of muscle strength at the end of treatment were maintained at follow-up . On the range of movement and gait analysis measures , both groups showed some improvement after treatment . However , at follow-up this improvement had relapsed for the exercise group while for the biofeedback group it had been maintained . It is argued that controlled trials are possible in biofeedback and that using patients as their own controls is not justified in view of the present findings and the previously reported literature [6391417] A long-term , comparison-group outcome trial with a partial crossover design was carried out on the effects of electromyographic biofeedback ( EMGBF ) plus physiotherapy ( PT ) versus PT alone in the treatment of the hemiplegic upper limb in stroke patients who were at least six months beyond the onset of their disability . Both the experimental and the control groups benefited from their treatment , but EMGBF was shown to have an additional effect , both in the experimental patients , and in the control patients when they switched over to the experimental treatment condition [3257300] The purpose of this study was to investigate , in a sample of patients with hemiparesis secondary to cerebrovascular accident , the relationship between the ratio of stimulus on time to off time and muscle fatigue using a commercial electrical stimulation unit . An experimental model was used to test the hypothesis that the smaller the stimulus off time relative to stimulus on time , the greater will be the muscle fatigue over time . The wrist extensor muscles of 18 patients with hemiparesis were stimulated electrically , and isometric force output was recorded continuously using an adapted strain gauge-recorder apparatus . For each testing session , peak on time of the electrical stimulus was set at 5 seconds , and off time was set at 5 , 15 , or 25 seconds . Six r and omly assigned treatment groups participated in three separate treatment sessions in a different order at 48-hour intervals . Treatment sessions were continued either until wrist extensor muscle force output decreased to 50 % of its initial value or for a maximum of 30 minutes . Data analysis revealed that significant differences in muscle tension developed among all duty cycles ( p less than .01 ) . Duty-cycle ratios of 1:1 , 1:3 , and 1:5 were shown to be progressively less fatiguing . Within the limits of this investigation , the 1:5 duty-cycle ratio was determined to be the best suited for initial use in programs of prolonged stimulation to the wrist extensor muscles of patients with hemiparesis . The hypothesis was accepted that the smaller the stimulus off time ( rest interval ) with respect to the stimulus on time , the greater will be the muscle fatigue over time [10698876] Abstract Objective : To establish if a brief programme of domiciliary occupational therapy could improve the recovery of patients with stroke discharged from hospital . Design : Single blind r and omised controlled trial . Setting : Two hospital sites within a UK teaching hospital . Subjects : 138 patients with stroke with a definite plan for discharge home from hospital . Intervention : Six week domiciliary occupational therapy or routine follow up . Main outcome measures : Nottingham extended activities of daily living score and “ global outcome ” ( deterioration according to the Barthel activities of daily living index , or death ) . Results : By eight weeks the mean Nottingham extended activities of daily living score in the intervention group was 4.8 points ( 95 % confidence interval −0.5 to 10.0 , P=0.08 ) greater than that of the control group . Overall , 16 ( 24 % ) intervention patients had a poor global outcome compared with 30 ( 42 % ) control patients ( odds ratio 0.43 , 0.21 to 0.89 , P=0.02 ) . These patterns persisted at six months but were not statistically significant . Patients in the intervention group were more likely to report satisfaction with a range of aspects of services . Conclusion : The functional outcome and satisfaction of patients with stroke can be improved by a brief occupational therapy programme carried out in the patient 's home immediately after discharge . Major benefits may not , however , be sustained [12370871] OBJECTIVE To evaluate and compare the effects of 3-hour versus 6-hour daily training sessions in constraint-induced movement therapy ( CIMT ) . DESIGN Intervention study , 2-group r and omized trial ; baseline , pretreatment , and posttreatment measures ; 1-month follow-up ( weekly measures ) . SETTING University department of psychology in Germany . PARTICIPANTS A convenience sample of 15 adults with chronic hemiparesis ( 13 stroke , 2 traumatic brain injury ) . INTERVENTION CIMT ( 14 consecutive days ; constraint of unaffected h and for a target of 90 % of waking hours ) with either 6 hours ( 6h/d group , n=7 ) or 3 hours ( 3h/d group , n=8 ) of shaping training with the affected h and per day . MAIN OUTCOME MEASURES The Motor Activity Log and Wolf Motor Function Test . RESULTS Significant improvements in motor function in the laboratory and increased use of the affected h and in the real-world environment were found in both groups . The beneficial effects were significantly greater in the 6h/d group than in the 3h/d group . CONCLUSION The 3-hour CIMT training schedule significantly improved motor function in chronic hemiparesis , but it was less effective than the 6-hour training schedule [6780105] Of 1094 patients with a confirmed stroke admitted to Northwick Park , a district general hospital , 364 ( 33 % ) died while in hospital , 215 ( 20 % ) were fully recovered when discharged , and 329 ( 30 % ) were too frail or too ill from diseases other than stroke to be considered for active rehabilitation . Only 121 ( 11 % ) were suitable for intensive treatment . They and 12 patients referred direct to out patients were allocated at r and om to one of three different courses of rehabilitation . Intensive was compared with conventional rehabilitation and with a third regimen which included no routine rehabilitation , but under which patients were encouraged to continue with exercises taught while in hospital and were regularly seen at home by a health visitor . Progress at three months and 12 months was measured by an index of activities of daily living . Improvement was greatest in those receiving intensive treatment , intermediate in those receiving conventional treatment , and least in those receiving no routine treatment . Decreasing intensity of treatment was associated with a significant increase in the proportions of patients who deteriorated and in the extent to which they deteriorated . Probably only a few stroke patients , mostly men , are suitable for intensive outpatient rehabilitation , but for those patients the treatment is effective and realistic [11101549] BACKGROUND Face-to-face assessment of research outcomes is expensive and may introduce bias . Postal question naires offer a cheaper alternative which avoids observer bias , but non-response and incomplete response reduce the effective sample size and may be equally serious sources of bias . This study examines the extent and potential effects of missing data in the postal collection of outcomes for a large rehabilitation trial . METHODS Question naires containing a number of established scales were posted to participants in a trial of occupational therapy after stroke . Response was maximized by telephone and postal reminders , and incomplete question naires were followed up by telephone . Scale scores obtained by imputing values to question naire items missing on return were compared with those achieved by telephone follow-up . FINDINGS Response to the initial posting was 60 % , rising to 85 % after reminders . Participants receiving the experimental treatment were more likely to respond without a reminder . There were no significant differences on any known factors between eventual responders and non-responders . Of the question naires , 43 % were incomplete on return : partial responders were significantly different to complete responders on baseline disability and home circumstances . Of the incomplete question naires , 71 % were resolved by telephone follow-up . In these , the scale scores achieved by telephone were generally higher than those derived by conventional imputation . CONCLUSION Postal outcome assessment achieved a good response rate , but considerable effort was needed to minimize non-response and incomplete response , both of which could have been serious sources of bias [9099186] BACKGROUND AND PURPOSE After stroke , the ability to balance in sitting is critical to independence . Although impairments in sitting balance are common , little is known about the effectiveness of rehabilitation strategies design ed to improve it . The purpose of this r and omized placebo-controlled study was to evaluate the effect of a 2-week task-related training program aim ed at increasing distance reached and the contribution of the affected lower leg to support and balance . METHODS Twenty subjects at least 1 year after stroke were r and omized into an experimental or control group . The experimental group participated in a st and ardized training program involving practice of reaching beyond arm 's length . The control group received sham training involving completion of cognitive-manipulative tasks within arm 's length . Performance of reaching in sitting was measured before and after training using electromyography , videotaping , and two force plates . Variables tested were movement time , distance reached , vertical ground reaction forces through the feet , and muscle activity . Subjects were also tested on sit-to-st and , walking , and cognitive tasks . Nineteen subjects completed the study . RESULTS After training , experimental subjects were able to reach faster and further , increase load through the affected foot , and increase activation of affected leg muscles compared with the control group ( P < .01 ) . The experimental group also improved in sit-to-st and . The control group did not improve in reaching or sit-to-st and . Neither group improved in walking . CONCLUSIONS This study provides strong evidence of the efficacy of task-related motor training in improving the ability to balance during seated reaching activities after stroke [3488280] Electromyographic biofeedback has been used with some success to treat patients with disturbances of muscle tone result ing from neurological disease . The aim of this study was to incorporate electrical myofeedback as an integral part of a physiotherapeutic regime design ed to improve quality of movement and function in limbs weakened or paralysed by stroke . A portable , inexpensive E. M. G. biofeedback machine was used . Stainless steel skin electrodes were applied which needed minimal skin preparation . Twelve adults , ( five male , seven female , mean age 44.2 years and 51.3 years respectively ) who were referred for treatment due to weakness of limb muscles due to disease of the brain or spinal cord , were treated . The mean time from onset of incidence to treatment was 75.5 days . Each patient received six weeks of treatment . This was divided into two phases . Phase 1 , ( weeks 1 , 2 , 3 ) and phase 2 ( weeks 4 , 5 , 6 ) . Physiotherapy , and physiotherapy with biofeedback was r and omly allocated to either phase . Each patient acted as his/her own control . A vali date d assessment was carried out by an independent therapist at the start of treatment , after three weeks and after six weeks of treatment . General function , knee function , range of movement of the affected side and timed tests were measured . Results show an overall improvement in general function . The second phase of treatment was slightly more favourable to improvement , but there was no indication that biofeedback significantly improved the outcome . In three tests it was equally significant to the physiotherapy applied ; in one test it improved the effectiveness of physiotherapy and in one test it reduced the effectiveness of physiotherapy . This suggests that a six week course of physiotherapy improved muscular function and range of movements in patients with weakness due to upper motor neurone disease , but that these effects are not enhanced by myofeedback [9360032] Objective : To measure the effect of the Odstock Dropped Foot Stimulator ( ODFS ) , a common peroneal stimulator , on the effort and speed of walking . Design : A r and omized controlled trial . Subjects : Hemiplegic patients who had suffered a single stroke at least six months prior to the start of the trial whose walking was impaired by a drop-foot . Interventions : The treatment , functional electrical stimulation ( FES ) group , used the stimulator and received a course of physiotherapy ; the control group received physiotherapy alone . Main outcome measures : Changes in walking speed measured over 10 m and the effort of walking measured by physiological cost index ( PCI ) . Results : Thirty-two subjects completed the trial , 16 in the FES group and 16 in the control group . Mean increase in walking speed between the beginning and end of the trial was 20.5 % in the FES group ( when the stimulator was used ) , and 5.2 % in the control group . Improvement was also measured in PCI with a reduction of 24.9 % in the FES group ( when the stimulator was used ) and 1 % in the control group . No improvement in these parameters was measured in the FES group when the stimulator was not used . Conclusion : Walking was statistically significantly improved when the ODFS was worn but no ' carry-over ' was measured . Physiotherapy alone , in this group of subjects with established stroke , did not improve walking [10203198] OBJECTIVE To evaluate the efficacy of intermittent pneumatic compression in treating oedema in the hemiplegic h and of stroke patients . DESIGN Single-blind r and omized control trial . SETTING acute and rehabilitation elderly care wards in a teaching district . SUBJECTS 37 Subjects with a first ever hemisphere stroke were r and omized to treatment with st and ard physiotherapy either alone or combined with intermittent pneumatic compression . MAIN OUTCOME MEASURES The effect of treatment on oedema was assessed using measures of the h and volume of the hemiplegic h and . The impact on function was assessed using the motricity index . RESULTS The treated group showed no change in the mean stroke h and volume . In the control group the mean stroke h and volume decreased by 3.2 ml . There was no statistically significant difference between the groups . The median scores for the motricity index increased for both groups but there was no significant difference between the groups and any improvement in motor function was independent of any treatment effects . CONCLUSION Intermittent pneumatic compression at the prescribed pressure and duration of this study is not an effective treatment for the oedematous stroke h and [6163362] Two treatment modalities for increasing active elbow extension with hemiplegic subjects were tested . Twenty subjects were r and omly assigned to one of two treatment groups -- an experimental treatment technique using kinesthetic biofeedback , or a control group consisting of an occupational therapy approach aim ed at increasing functional use of the envolved upper extremity . The results indicate that kinesthetic biofeedback was as beneficial as conventional occupational therapy . It was also demonstrated that an individual 's age , sex , or length of time beyond one-year post-CVA did not significantly affect treatment outcome . A majority of subjects in both treatment groups improved in ways not directly related to treatment , which suggests the need for long-term follow up of hemiplegic patients [6602993] Positional feedback stimulation training and cyclical electrical stimulation were used in combination as a treatment for facilitating knee extension in hemiparetic patients . Forty adult hemiparetic patients who demonstrated minimal active control of their quadriceps femoris muscles were r and omly assigned to control or study groups . The control patients received a program of physical therapy , and the study patients received the positional feedback stimulation training in addition to their therapy program . The stimulation training provided the patient with immediate auditory and visual feedback of his changing joint angle while he voluntarily extended his knee . When the patient reached a near maximal extension effort , electrical stimulation of the quadriceps femoris muscle was automatically triggered , completing the patient 's available range of motion in extension . The stimulation training was supplemented with two hours of cyclical electrical stimulation daily . At the end of four weeks , analysis revealed a statistically significant increase in knee extension torque and active synergistic range of motion in the study group . No change was noted in their ability to extend their knees using isolated quadriceps femoris muscle control . This study suggests that positional feedback stimulation training is effective when used to augment a facilitation program for improving knee extension control in hemiparetic patients [9596400] OBJECTIVE To assess the efficacy of electromyogram (EMG)-triggered neuromuscular stimulation ( EMG-stim ) in enhancing upper extremity motor and functional recovery of acute stroke survivors . DESIGN A pilot r and omized , single-blinded clinical trial . SETTING Freest and ing inpatient rehabilitation facility . PATIENTS Nine subjects who were within 6 weeks of their first unifocal , nonhemorrhagic stroke were r and omly assigned to either the EMG-stim ( n = 4 ) or control ( n = 5 ) group . All subjects had a detectable EMG signal ( > 5 microV ) from the surface of the paretic extensor carpi radialis and voluntary wrist extension in synergy or in isolation with muscle grade of < 3/5 . INTERVENTION All subjects received two 30-minute sessions per day of wrist strengthening exercises with EMG-stim ( experimental ) or without ( control ) for the duration of their rehabilitation stay . MAIN OUTCOME MEASURES Upper extremity Fugl-Meyer motor assessment and the feeding , grooming , and upper body dressing items of the Functional Independence Measure ( FIM ) were assessed at study entry and at discharge . RESULTS Subjects treated with EMG-stim exhibited significantly greater gains in Fugl-Meyer ( 27.0 vs 10.4 ; p = .05 ) , and FIM ( 6.0 vs 3.4 ; p = .02 ) scores compared with controls . CONCLUSION Data suggest that EMG-stim enhances the arm function of acute stroke survivors [2383382] One of the causes for shoulder pain associated with hemiplegia is thought to be vigorous range of motion to the involved upper extremity . The objective of this study was to analyze the occurrence of pain in patients treated with one of the three exercise programs commonly used in the rehabilitation of hemiplegia : 1 ) range of motion by the therapist , 2 ) skate board and 3 ) overhead pulley . Of the 48 hemiplegic patients evaluated , 28 were assigned to one of the three exercise groups . Comparing the number of patients who developed pain in each group , there was a significant difference , with 8 % of the patients in the range of motion by the therapist group , 12 % of the patients in the skate board group and 62 % of the patients in the overhead pulley group developing pain ( x2=8.44 ) ( P=0.014 ) . The three groups did not differ in the side of involvement ( P=0.57 ) , extent of hemiplegia ( P=0.25 ) or presence of subluxation ( P=0.84 ) . Use of overhead pulley has the highest risk of developing shoulder pain and should be avoided during rehabilitation of stroke patients [11237160] Objective : To evaluate the effects of leisure therapy and conventional occupational therapy ( OT ) on the mood , leisure participation and independence in activities of daily living ( ADL ) of stroke patients 6 and 12 months after hospital discharge . Design : Multicentre r and omized controlled trial . Setting and participants : Four hundred and sixty-six stroke patients from five UK centres . Main outcome measures : The General Health Question naire ( 12 item ) , the Nottingham Extended ADL Scale and the Nottingham Leisure Question naire , assessed by post , with telephone clarification . Results : Four hundred and forty ( 94 % ) and 426 ( 91 % ) subjects were alive at 6 and 12 months , respectively . Three hundred and seventy-four ( 85 % of survivors ) and 311 ( 78 % of survivors ) responded at 6 and 12 month follow-up respectively . At six months and compared to the control group , those allocated to leisure therapy had nonsignificantly better GHQ scores ( –1.2 : 95 % CI –2.9 , + 0.5 ) , leisure scores ( + 0.7 , 95 % CI –1.1 , + 2.5 ) and Extended ADL scores ( + 0.4 : 95 % CI –3.8 , + 4.5 ) : the ADL group had nonsignificantly better GHQ scores ( –0.1 : 95 % CI –1.8 , + 1.7 ) and Extended ADL scores ( + 1.4 : 95 % CI –2.9 , + 5.6 ) and nonsignificantly worse leisure scores ( –0.3 : 95 % CI –2.1 , + 1.6 ) . The results at 12 months were similar . Conclusion : In contrast to the findings of previous smaller trials , neither of the additional OT treatments showed a clear beneficial effect on mood , leisure activity or independence in ADL measured at 6 or 12 months [10440303] BACKGROUND Patients who have a stroke are not always admitted to hospital , and 22 - 60 % remain in the community , frequently without coordinated rehabilitation . We aim ed to assess the efficacy of an occupational therapy intervention for patients with stroke who were not admitted to hospital . METHODS In this single-blind r and omised controlled trial , consecutive stroke patients on a UK community register in Nottingham and Derbyshire were allocated r and omly to up to 5 months of occupational therapy at home or to no intervention ( control group ) 1 month after their stroke . The aim of the occupational therapy was to encourage independence in personal and instrumental activities of daily living . Patients were assessed on outcome measures at baseline ( before r and omisation ) and at 6 months . The primary outcome measure was the score on the extended activities of daily living ( EADL ) scale at 6 months . Other outcome measures included the Barthel index , the general health question naire 28 , the carer strain index , and the London h and icap scale . All assessment s were done by an independent assessor who was unaware of treatment allocation . The analysis included only data from completed question naires . FINDINGS 185 patients were included : 94 in the occupational therapy group and 91 in the control group . 22 patients were not assessed at 6 months . At follow-up , patients who had occupational therapy had significantly higher median scores than the controls on : the EADL scale ( 16 vs 12 , p<0.01 , estimated difference 3 [ 95 % CI 1 to 4 ] ) ; the Barthel index ( 20 vs 18 , p<0.01 , difference 1 , [ 0 - 1 ] ) ; the carer strain index ( 1 vs 3 , p<0.05 , difference 1 [ 0 to 2 ] ) ; and the London h and icap scale ( 76 vs 65 , p<0.05 , difference 7 , [ 0.3 to 13.5 ] ) . There were no significant differences on the general health question naire between the patient or carer . INTERPRETATION Occupational therapy significantly reduced disability and h and icap in patients with stroke who were not admitted to hospital [999485] The use of audiovisual displays of myoelectric potentials ( myofeedback ) has been suggested for retraining and strengthening of paretic muscles in patients with hemiplegia from stroke . This controlled study examines the specificity and efficiency of myofeedback in the strengthening of paretic muscles in hemiplegic patients . Eighteen patients with trace to fair-minus grade of deltoid muscle power result ing from strokes that had occurred at least six weeks earlier were r and omly assigned to the six possible orders of accurate ( true ) , positive noncontingent ( placebo ) and no feedback conditions . On three successive days , each patient received one session of each feedback condition , consisting of 20 isometric contractions of five seconds each with ten seconds of intervening rests . In addition , each patient 's motivational level was rated . Averaged myoelectric potentials were quantified for each contraction for analysis . When the data were analyzed without grouping , no statistical differences among the three feedback conditions were noted . However , when the subjects were grouped according to age and motivational level , during true and no feedback sessions , the older and the poorly motivated groups were found to show progressive increment of myoelectric output , whereas the younger and the better motivated showed the opposite results . With placebo feedback , both groups showed progressive decrement of myoelectric output . It is concluded that the effect of myofeedback is nonspecific at least in its short-term application for the retraining of hemiplegically paretic muscles [8215864] A computer-assisted feedback system was developed to present to walking subjects instantaneous feedback of their muscle activity or joint angular excursions during gait . Targets for muscle activity or joint motion were displayed on the feedback screen along with timing cues that prompted muscle activity or joint flexion/extension at specific times during the gait cycle . The purpose was to compare the effectiveness of joint angle and electromyographic ( EMG ) feedback to a focused program of physical therapy for gait . Eight hemiplegic stroke patients were treated with ankle joint angle feedback , EMG biofeedback from the soleus muscle , and conventional physical therapy for gait in a three-period crossover design . PT was given either first or last in the sequence of treatments . Gait analysis prior to and following each type of treatment revealed that the feedback treatments result ed in significant increases in stride length and walking velocity and in positive changes in push-off impulse , gait symmetry , and st and ing weight-bearing symmetry , as evaluated in a general linear model and paired t-tests . Overall , physical therapy produced no significant changes . However , when physical therapy was the first treatment of the sequence , significant increases in stride length and velocity were observed . When physical therapy was last , there were significant negative changes in gait symmetry and st and ing weight-bearing symmetry , and negative trends in stride length , walking velocity , and push-off impulse . It is concluded that computer-assisted feedback is an effective tool for retraining gait in stroke patients [1559090] OBJECTIVE --To determine whether the intervention of a physiotherapist improved mobility in patients seen more than one year after stroke . DESIGN --R and omised crossover trial comparing two groups offered intervention by a physiotherapist , one immediately after entry into the trial and the other after a delay of three months . The intervention consisted of identifying problems and offering advice and help to solve the problems . SETTING -- Patients ' homes in Oxfordshire . SUBJECTS-- Patients who had reduced mobility due to a stroke more than one year before entry ; 60 were recruited from a community stroke register and 34 in other ways . MAIN OUTCOME MEASURES --St and ard measures of mobility including gait speed , functional ambulation categories , the Nottingham extended activities of daily living index , and individual items from the Barthel activities of daily living index and the Frenchay activities index . Measures of manual dexterity , depression , and anxiety were used as controls . RESULTS --94 patients entered the trial and 49 were r and omised to immediate and 45 to delayed physiotherapy ; 89 were compared at the crossover point . At r and omisation the two groups were comparable . At three months the group given early therapy showed an improvement in gait speed whereas the untreated group had declined ( differences of -3.9 v 6.4 s to walk 10 m ; p less than 0.01 ) ; between three and six months the group given delayed therapy showed improvement and the previously treated group declined ( differences of 6.5 v -3.9 s to walk 10 m ; p less than 0.01 ) . A 9 % ( 95 % confidence interval 0 % to 18 % ) decrease in time taken to walk 10 m was associated with treatment and a 12 % ( 2 % to 19 % ) increase when patients were untreated . Other measures did not change significantly . CONCLUSION --Intervention of an experienced physiotherapist late after stroke specifically improves mobility , albeit by a small amount , but the effects do not seem to be maintained , perhaps because there is an underlying decline in mobility in these patients . Gait speed offers a simple and sensitive measure of outcome [10688340] Objective : To determine whether stroke patients with initial increases in arm motor recovery following low-frequency transcutaneous electrical nerve stimulation ( low TENS ) treatment go on to show long-term benefits . Also whether the same therapy results in long-term improvements in motor function , spasticity or activities of daily living ( ADL ) . Design : A three-year follow-up study . Subjects : Twenty-eight stroke patients , who had participated in a r and omized trial of daily treatment with low-frequency ( 1.7 Hz ) transcutaneous electrical nerve stimulation ( low TENS ) on the paretic arm for three months starting 6–12 months after stroke . Outcomes : Fugl-Meyer Motor Performance Scale for evaluation of changes in arm motor function . A 6-point Ashworth Scale to measure spasticity . Barthel Index to evaluate performance in ADL . Results : Motor function of the paretic arm had deteriorated in both treatment and control groups . Increased spasticity was seen in both groups . ADL score remained at a similar level in the low TENS group , whereas the control group had deteriorated during the same time period . Conclusions : Low TENS stimulation started 6–12 months after stroke may not have a specific effect on arm motor function years after completion of treatment [3288172] The study examined the efficacy of functional electric stimulation ( FES ) and biofeedback ( BFB ) treatment of gait dysfunction in patients with hemiplegia after stroke . These two therapeutic modalities were tested alone and in combination in a prospect i ve , controlled , r and omized trial . The authors hypothesized that in concurrent use , these two modalities would complement one another . Thirty-six hemiplegic patients undergoing rehabilitation after stroke were accepted for study and r and omized into four groups to receive either control , FES , BFB , or combined therapies . Each patient received 30 minutes of treatment three times per week for six weeks , in addition to their general rehabilitation program . Quantitative gait analysis was performed biweekly on each subject during the experimental therapy and for four weeks afterward . Thirty-two subjects completed the study . Combined therapy with BFB and FES result ed in improvements in both knee and ankle minimum flexion angles during swing phase that were statistically significant with p = 0.05 and p = 0.02 , respectively . Velocity of gait , cycle time , and symmetry of stance phases also improved . The length of time elapsed since the stroke did not prove to be a significant factor [11276182] BACKGROUND AND PURPOSE Visual biofeedback/forceplate systems are often used for treatment of balance disorders . In this study , the research ers investigated whether the addition of visual biofeedback/forceplate training could enhance the effects of other physical therapy interventions on balance and mobility following stroke . SUBJECTS The study included a sample of convenience of 13 out patients with hemiplegia who ranged in age from 30 to 77 years ( mean=60.4 , SD=15.4 ) and were 15 to 538 days poststroke . METHODS Subjects were assigned r and omly to either an experimental group or a control group when the study began , and their cognitive and visual-perceptual skills were tested by a psychologist . Subjects were also assessed using the Berg Balance Scale and the Timed " Up & Go " Test before and after 4 weeks of physical therapy . Both groups received physical therapy interventions design ed to improve balance and mobility 2 to 3 times per week . The experimental group trained on the NeuroCom Balance Master for 15 minutes of each 50-minute treatment session . The control group received other physical therapy for 50 minutes . RESULTS Following intervention , both groups scored higher on the Berg Balance Scale and required less time to perform the Timed " Up & Go " Test . These improvements corresponded to increased independence of balance and mobility in the study population . However , a comparison of mean changes revealed no differences between groups . DISCUSSION AND CONCLUSION Although both groups demonstrated improvement following 4 weeks of physical therapy interventions , no additional effects were found in the group that received visual biofeedback/forceplate training combined with other physical therapy [15293487] Objective : To discover if the provision of additional inpatient physiotherapy after stroke speeds the recovery of mobility . Design : A multisite single-blind r and omized controlled trial ( RCT ) comparing the effects of augmented physiotherapy input with normal input on the recovery of mobility after stroke . Setting : Three rehabilitation hospitals in North Glasgow , Scotl and . Subjects : Patients admitted to hospital with a clinical diagnosis of stroke , who were able to tolerate and benefit from mobility rehabilitation . Intervention : We aim ed to provide double the amount of physiotherapy to the augmented group . Main measures : Primary outcomes were mobility milestones ( ability to st and , step and walk ) , Rivermead Mobility Index ( RMI ) and walking speed . Results : Seventy patients were recruited . The augmented therapy group received more direct contact with a physiotherapist ( 62 versus 35 minutes per weekday ) and were more active ( 8.0 % versus 4.8 % time st and ing or walking ) than normal therapy controls . The augmented group tended to achieve independent walking earlier ( hazard ratio 1.48 , 95 % confidence interval 0.90–2.43 ; p=0.12 ) and had higher Rivermead Mobility Index scores at three months ( mean difference 1.6 ; 0.1 to 3.3 ; p=0.068 ) but these differences did not reach statistical significance . There was no significant difference in any other outcome . Conclusions : A modest augmented physiotherapy programme result ed in patients having more direct physiotherapy time and being more active . The inability to show statistically significant changes in outcome measures could indicate either that this intervention is ineffective or that our study could not detect modest changes [10945421] Objective : To determine whether strapping the shoulder in hemiplegic stroke patients : ( 1 ) prevents the development , or reduces the severity , of shoulder pain , ( 2 ) preserves range of movement in the shoulder , and ( 3 ) improves the functional outcomes for the arm and patient overall . Design : A prospect i ve , r and omized , single-blind controlled trial of shoulder strapping versus no strapping . Setting : Care of the elderly wards in a teaching hospital , Christchurch , New Zeal and . Subjects : All patients admitted with an acute hemiplegic stroke , who had persisting weakness of shoulder abduction . Intervention : The treatment group had their affected shoulder strapped for six weeks from r and omization in addition to st and ard physiotherapy . Main outcome measures : All subjects were assessed at entry ( week 0 ) , at end of the treatment phase ( week 6 ) and two months later ( week 14 ) . A visual analogue scale ( VAS ) was used to assess shoulder pain severity whereas shoulder range of movement to the point of pain ( SROMP ) assessed passive range of movement and pain . Functional Independence Measure ( FIM ) , Motor Assessment Scale ( MAS ) and Rankin Disability Index measured functional outcomes . Results : Ninety-eight subjects participated ( 49 strapped , 49 controls ) . Intention to treat analysis showed no significant difference in pain , range of movement or functional outcomes after the intervention phase or at the final assessment . However there were trends for less pain at six weeks ( VAS , p = 0.11 ) and better final upper limb function ( MAS , p = 0.16 ) in strapped patients . Skin reactions were uncommon ( 6.1 % ) . The presence of neglect or sensory loss , but not subluxation , at baseline was independently associated with poor outcome . Range of movement was lost early ( mean difference SROMP between hemiplegic and contralateral shoulders at baseline = 15.2 ° ( 95 % CI 10.9–19.5 ) ) and continued throughout the study . Shoulder strapping did not alter the rate at which range of movement was lost . Conclusions : No significant benefit with shoulder strapping was demonstrated and reasons for this are discussed . Range of movement in the hemiplegic shoulder is lost very early and any preventive treatments need to begin within the first 1–2 days after a stroke [1137478] The effectiveness of biofeedback training was compared to conventional physical therapy training in 20 adult hemiparetic patients with chronic foot-drop . They were r and omly placed into two groups of ten patients each : the first group treated over five weeks with therapeutic exercise and the second group treated over five weeks with therapeutic exercise plus biofeedback training . In the second group receiving the biofeedback training the increase in both strength and range of motion was approximately twice as great as in the first group . The improvement displayed by even the first group of patients suggests that a potential for functional improvement exists that is often unexploited . The addition of biofeedback facilitates the process . Four patients in the biofeedback group achieved and retained conscious control of dorsiflexion ; three of them are now able to walk without the use of the short leg brace [2701823] The study was design ed to evaluate the effect of electromyographic ( EMG ) biofeedback on the recovery of arm function after stroke . Patients who had impaired arm function and were between 2 and 8 weeks after stroke were r and omly allocated to receive either treatment incorporating EMG biofeedback or a control treatment in addition to their routine physiotherapy . The two groups of 20 patients were compared before and after 6 weeks of treatment and at follow-up 6 weeks later . There were no significant differences between the groups before treatment or at follow-up , but at the end of treatment those who received EMG biofeedback scored significantly higher on tests of arm function . Patients with severe impairment were shown to benefit most from EMG biofeedback but there was no difference in response to treatment according to patient 's age or side of stroke . Men had higher arm function scores than women before and at the end of treatment , but not at follow-up [14586909] OBJECTIVE To determine the effectiveness of progressive resistance strengthening exercises to improve gross motor function and walking in patients receiving intensive rehabilitation after stroke . DESIGN R and omized controlled trial . SETTING Five inpatient rehabilitation programs affiliated with teaching hospitals . PARTICIPANTS Inclusion criteria included less than 6 months poststroke and recovery of the leg stages 3 to 5 on the Chedoke-McMaster Stroke Assessment ( CMSA ) . INTERVENTIONS Both groups received conventional physical therapy programs . In addition , the experimental group performed 9 lower-extremity progressive resistance exercises 3 times a week for the duration of their stay , whereas the control group did the same exercises and for the same duration but without resistance . MAIN OUTCOME MEASURES The Disability Inventory of the CMSA and the 2-minute walk test ( 2MWT ) at baseline , 4 weeks , discharge , and 6 months after discharge . RESULTS Over the length of stay , the rate of change in the Disability Inventory was.27 points per day in the experimental group and .29 points per day in the control group ; the between-group difference was -.02 points per day ( 95 % confidence interval [ CI ] , -.10 to.06 ; P=.62 ) . At discharge , the rate of change in the 2MWT was -.01 m in the experimental group and .15 m in the control group ; the between-group difference was -.16 m ( 95 % CI , -.37 to.05 ; P=.14 ) . CONCLUSIONS Progressive resistance strengthening exercises as applied in our study were not effective when compared with the same exercises given without resistance [705282] A group of forty-nine hemiparetic patients with limited emotional , communication and sensibility involvement and with recent lesion of cerebrovascular aetiology was r and omly divided into two groups of twenty-four and twenty-five subjects . Both groups received traditional physiotherapy treatment for one hour/day , one group received twenty min/day of peroneal nerve stimulation . The maximum voluntary dorsal flexion moments of the ankle joint of the affected and non affected extremities were measured with an isometric brace twice a week for one month and for both groups . The recovery of moment in the stimulated group turned out to be about three times greater than in the control group and considerably less dependent upon age , time from lesion , initial value , side of lesion . Three patients using a peroneal brace at home as an assisting device were again evaluated two months later and a further improvement was observed . This work gives statistical support to previous observations based on very few cases and provides a statistically reliable answer concerning the entity of FES induced recovery of muscle force in hemiparetic subjects [14606736] Objective : To demonstrate the effect of rhythmical auditory stimulation in a musical context for gait therapy in hemiparetic stroke patients , when the stimulation is played back measure by measure initiated by the patient 's heel strikes ( musical motor feedback ) . Does this type of musical feedback improve walking more than a less specific gait therapy ? Design : The r and omized controlled trial considered 23 registered stroke patients . Two groups were created by r and omization : the control group received 15 sessions of conventional gait therapy and the test group received 15 therapy sessions with musical motor feedback . Setting : Inpatient rehabilitation hospital . Subjects : Median post-stroke interval was 44 days and the patients were able to walk without technical aids with a speed of approximately 0.71 m/s . Main outcome measures : Gait velocity , step duration , gait symmetry , stride length and foot rollover path length ( heel-on – toe-off distance ) . Result : The test group showed more mean improvement than the control group : stride length increased by 18 % versus 0 % , symmetry deviation decreased by 58 % versus 20 % , walking speed increased by 27 % versus 4 % and rollover path length increased by 28 % versus 11 % . Conclusion : Musical motor feedback improves the stroke patient 's walk in selected parameters more than conventional gait therapy . A fixed memory in the patient 's mind about the song and its timing may stimulate the improvement of gait even without the presence of an external pacemaker [11790899] PURPOSE A series of pilot studies were conducted to examine the effects of partial body weight ( PBW ) ambulation in people with chronic stroke . METHODS First , we compared gait characteristics during 3 modes of walking : level ground ambulation ; level ground ambulation with PBW ; and treadmill ambulation with PBW . Second , we examined the effects of repeated PBW treadmill training during level ground ambulation . RESULTS Improved symmetry in stance/swing times and sEMG activity of pre-tibialis and quadriceps muscle groups during PBW either over level ground or on the treadmill occurred in 10 chronic stroke subjects . Increased single limb support and decreased double limb support improved overall gait symmetry during level ground ambulation in 8 subjects following 6 - -8 weeks repeated PBW treadmill training . Tinetti Balance score also significantly improved . No changes in sEMG were observed . CONCLUSION These results suggest that PBW treadmill may help normalize gait and improve balance in the person with chronic stroke [12234091] Objective : To determine the efficacy of a modified constraint-induced therapy ( mCIT ) administered to patients with subacute stroke . Design : Prospect i ve , multiple-baseline , before-after , r and omized clinical trial . Setting : Subacute outpatient clinic . Subjects : Fourteen patients with subacute stroke who exhibited learned nonuse and stable motor deficits in their affected upper limbs . Intervention : Four patients participated in half-hour , structured physical and occupational therapy sessions that emphasized affected arm use in valued functional activities , 3 times per week for 10 weeks . Their less affected upper limbs were restrained 5 days per week during 5 hours identified as times of frequent use ( mCIT ) . Five patients received regular therapy ( TR ) with similar therapeutic contact time to mCIT , and 5 patients received no therapy ( CON ) . Main Outcome Measures : The Fugl-Meyer Assessment of Motor Recovery ( Fugl ) , Action Research Arm ( ARA ) test , and Motor Activity Log ( MAL ) . Results : After intervention , Fugl , ARA , and MAL scores remained virtually the same for TR and CON groups ; scores improved by 11.4 and 11.5 points , respectively , on the Fugl and ARA for the mCIT group . Amount and quality of arm use , as measured by the MAL , also improved for mCIT patients ( 2.49 and 0.47 , respectively ) . Conclusions : mCIT may be an efficacious method of improving affected arm function and use in stroke patients exhibiting learned nonuse [11991797] BACKGROUND AND PURPOSE The effects of different duration s of rehabilitation sessions for the upper extremities ( UEs ) and lower extremities ( LEs ) on the recovery of interlimb coordination in hemiplegic gait in patients who have had a stroke were investigated . SUBJECTS AND METHODS Fifty-three subjects who had strokes involving their middle cerebral arteries were assigned to rehabilitation programs with ( 1 ) an emphasis on the LEs , ( 2 ) an emphasis on the paretic UE , or ( 3 ) a condition in which the paretic arm ( UE ) and leg ( LE ) were immobilized with an inflatable pressure splint ( control treatment ) . The 3 treatment regimens were applied for 30 minutes , 5 days a week , during the first 20 weeks after onset of stroke . All subjects also participated in a rehabilitation program 5 days a week that consisted of 15 minutes of UE exercises and 15 minutes of LE exercises in addition to a weekly 11/2-hour session of training in activities of daily living . A repeated- measures design was used . Differences among the 3 treatment regimens were evaluated in terms of comfortable and maximal walking speeds . In addition , mean continuous relative phase ( CRP ) between paretic arm and leg ( PAL ) movements and nonparetic arm and leg ( NAL ) movements and st and ard deviations of CRP of both limb pairs as a measurement of stability ( variability ) were evaluated . RESULTS Comfortable walking speed improved in the group that received interventions involving the LEs compared with the group that received interventions involving the UEs and the group that received the control treatment . No differences among the 3 treatment conditions were found for the mean CRP of NAL and PAL as well as the st and ard deviation of CRP of both limb pairs . DISCUSSION AND CONCLUSION With the exception of an improved comfortable walking speed as a result of a longer duration of rehabilitation sessions , no differential effects of duration of rehabilitation sessions for the LEs and UEs on the variable we measured related to hemiplegic gait were found . Increasing walking speed , however , result ed in a larger mean CRP for both limb pairs , with increased stability and asymmetry of walking , indicating that walking speed influences interlimb coordination in hemiplegic gait [11237159] Objective : It is uncertain whether self-propulsion in a wheelchair should be encouraged or discouraged in the early stages of stroke rehabilitation . Design : A two-centre pilot study to assess the feasibility of performing a multicentre r and omized controlled trial on this subject . Setting : Clatterbridge and Aintree Stroke Rehabilitation Units , Merseyside , UK . Subjects : Forty early stroke patients ( mean age 67 years ) in whom it was uncertain whether self-propulsion in a wheelchair should be encouraged were studied . Intervention : A central r and omization service at Newcastle University was used to determine the policy about wheelchair provision and use for each patient . They were allocated to either an ‘ encouraged to self-propel ’ or a ‘ discouraged from self-propulsion group ’ . Outcome measures used : Independent outcome assessment was performed by postal question naire and telephone interview using the Barthel ADL Scale , Nottingham Extended ADL Scales and the shortened General Health Question naire ( GHQ-12 ) at 3 and 12 months . Patient 's length of stay and their Ashworth tone score were also measured either at three months or when they were discharged from hospital . Results : After considerable preparation time it was possible to conduct a trial on self-propulsion in early stroke rehabilitation in the two-pilot centres . No major differences were found between the pilot groups for any of the outcome measures . Conclusions : A multicentre r and omized controlled trial to assess this question is feasible but further work is being conducted before proceeding , to satisfy the concerns expressed to our group regarding the appropriateness of the intervention and the outcome measures . Address for correspondence : JA Barrett , Clatterbridge Hospital , Wirral , Merseyside CH69 4JY , UK . e-mail : [11518440] Objective : To explore the effects of weighted garments on the balance and gait of stroke patients . Design : A pilot r and omized controlled study with blinded measurement . Setting : Weighted garments were worn by patients living in the community and measurement was made in a hospital-based gait laboratory . Subjects : Twenty-four adults who were at least six months post stroke and were able to walk 10 metres with or without assistance or a walking aid . Intervention : The six-week treatment-phase subjects were given a set of weighted garments which they were shown how to apply and instructed to wear on their paretic side . Subjects r and omly allocated to the six-week control phase were not given any weighted garments . Main outcome measures : Balance was measured with the Berg Balance Scale . Gait was measured using GaitMat II , an instrumented walkway . Gait parameters of interest were velocity and symmetry of : step length ; single support time ; double support time ; and support base width . Measures were made at baseline before r and omization ( baseline ) and at the end of the six weeks of intervention ( outcome ) . Results : No statistically significant differences were found between the treatment and control groups at outcome for balance ( Mann – Whitney U-test ; p = 0.74 ) , gait velocity ( p = 0.68 ) or symmetry of gait parameters ( p = 0.33 to p = 0.75 ) . Conclusions : We found no evidence to support the clinical use of these weighted garments for stroke survivors [25026492] The effectiveness of biofeedback therapy , using the electromyograph , was compared with conventional physiotherapy treatments in eleven hemiparetic patients with severe disability of the upper limb . These were divided r and omly into two groups , a group of six patients receiving biofeedback treatments and five receiving physiotherapy treatments with conventional techniques . The results showed greater improvements in the biofeedback group in most fields of testing , and the patients in this group had a greater degree of control over the patterns of movement in the upper limb and the relaxation of spastic muscle groups . It was concluded that a wide range of hemiparetic patients should benefit in some degree by treatment of this form [26486052] Functional electrical stimulation ( FES ) may improve recovery after stroke . We studied its effects in 38 postcerebral infa rct patients . Twenty were r and omly assigned to receive FES producing ankle dorsiflexion on the affected side and physical therapy . The remaining 18 received physical therapy only . Subjects were evaluated prior to commencing therapy , at its completion after 4 weeks , and again 4 weeks later using functional and electrophysiological measures . Functional deficit in most patients improved ( p < 0.01 ) . Although no significant differences were observed when those treated with FES and those not treated were compared at 4 and 8 weeks , there was significant improvement in the rate of recovery using an ambulation score ( p < 0.05 ) , and there was a similar trend in the Barthel Index for FES-treated patients ( p < 0.1 ) . Our results indicate that FES may confer additional benefit in acute stroke rehabilitation . Further studies are needed to delineate how best to use it Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND With an increased focus on home-based stroke services and the undertaking of programmes , targeted at upper limb recovery within clinical practice , a systematic review of home-based therapy programmes for individuals with upper limb impairment following stroke was required . OBJECTIVES To determine the effects of home-based therapy programmes for upper limb recovery in patients with upper limb impairment following stroke . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

26509050

[3888622] Objectives To evaluate the efficacy and safety of certolizumab pegol ( CZP ) after 24 weeks in RAPID-PsA ( NCT01087788 ) , an ongoing Phase 3 trial in patients with psoriatic arthritis ( PsA ) . Methods Patients were r and omised 1:1:1 to placebo , 200 mg CZP every 2 weeks ( Q2W ) or 400 mg CZP every 4 weeks ( Q4W ) . Patients could have had exposure to one previous tumour necrosis factor ( TNF ) inhibitor therapy . Primary endpoints were American College of Rheumatology 20 % ( ACR20 ) response at week 12 and modified Total Sharp Score change from baseline at week 24 . Secondary endpoints included ; Psoriatic Arthritis Response Criteria ( PsARC ) score , Health Assessment Question naire Disability Index ( HAQ-DI ) , Psoriasis Area and Severity Index , Leeds Enthesitis Index , Leeds Dactylitis Index , and Modified Nail Psoriasis Severity Index . Results Of 409 patients r and omised , 368 completed 24 weeks of treatment . ACR20 response was significantly greater in CZP 200 mg Q2W and 400 mg Q4W-treated patients than placebo ( 58.0 % and 51.9 % vs 24.3 % ( p<0.001 ) ) at week 12 , with improvements observed by week 1 . There was a statistically significant improvement in physical function from baseline , measured by HAQ-DI in CZP patients compared with placebo ( −0.50 vs −0.19 , p<0.001 ) and more patients treated with CZP 200 mg Q2W and CZP 400 mg achieved an improvement in PsARC at week 24 than placebo ( 78.3 % and 77.0 % vs 33.1 % ( p<0.001 ) ) . Sustained improvements were observed in psoriatic skin involvement , enthesitis , dactylitis and nail disease . Higher ACR20 response with CZP was independent of prior TNF inhibitor exposure . No new safety signals were observed . Conclusions Rapid improvements in the signs and symptoms of PsA , including joints , skin , enthesitis , dactylitis and nail disease were observed across both CZP dosing regimens [2820265] Objective . Few data exist on the use of anti-TNF drugs for AS during routine clinical use in the UK . This report describes an improvement in Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI ) and Bath Ankylosing Spondylitis Functional Index ( BASFI ) after 6 months of therapy in 261 patients enrolled in a national prospect i ve observational register . Methods . The British Society for Rheumatology Biologics Register ( BSRBR ) recruited patients starting anti-TNF therapy for AS between 2002 and 2006 . Multivariable linear regression models were used to estimate the predictors of absolute improvement in BASDAI and BASFI at 6 months . Covariates included age , gender , disease duration , baseline BASDAI and BASFI , presence of raised inflammatory markers ( defined as twice the upper limit of normal ) and DMARD therapy . Results . The cohort was young ( median age 43 years ) and 82 % were males . Median baseline BASDAI was 7.6 and BASFI 7.9 . At 6 months , the mean improvements in BASDAI and BASFI were 3.6 and 2.6 U , respectively ; 52 % reached a BASDAI50 . Patients with raised inflammatory markers at the start of therapy had a 0.9-U ( 95 % CI 0.2 , 1.5 ) better improvement in BASDAI compared with those without . Lesser responses were seen in those with higher baseline BASFI scores . Women had a 1.1-U ( 95 % CI 0.3 , 2.0 ) greater improvement in BASFI at 6 months , as did those who were receiving concurrent DMARD therapy [ 0.9 U ( 95 % CI 0.2 , 1.7 ) ] . Conclusions . The majority of patients receiving anti-TNF therapy for AS during routine care demonstrated an improvement in disease activity . Raised inflammatory markers at the start of therapy predicted a greater improvement in BASDAI , identifying a group of patients who may be more responsive to anti-TNF therapies , although the results were not confined to this group [16549855] Prognosis studies are investigations of future events or the evaluation of associations between risk factors and health outcomes in population s of patients ( 1 ) . The results of such studies improve our underst and ing of the clinical course of a disease and assist clinicians in making informed decisions about how best to manage patients . Prognostic research also informs the design of intervention studies by helping define subgroups of patients who may benefit from a new treatment and by providing necessary information about the natural history of a disorder ( 2 ) . There has recently been a rapid increase in the use of systematic review methods to synthesize the evidence on research questions related to prognosis . It is essential that investigators conducting systematic review s thoroughly appraise the method ologic quality of included studies to be confident that a study 's design , conduct , analysis , and interpretation have adequately reduced the opportunity for bias ( 3 , 4 ) . Caution is warranted , however , because inclusion of method ologically weak studies can threaten the internal validity of a systematic review ( 4 ) . This follows abundant empirical evidence that inadequate attention to biases can cause invalid results and inferences ( 5 - 9 ) . However , there is limited consensus on how to appraise the quality of prognosis studies ( 1 ) . A useful framework to assess bias in such studies follows the basic principles of epidemiologic research ( 10 , 11 ) . We focus on 6 areas of potential bias : study participation , study attrition , prognostic factor measurement , confounding measurement and account , outcome measurement , and analysis . The main objectives of our review of review s are to describe methods used to assess the quality of prognosis studies and to describe how well current practice s assess potential biases . Our secondary objective is to develop recommendations to guide future quality appraisal , both within single studies of prognostic factors and within systematic review s of the evidence . We hope this work facilitates future discussion and research on biases in prognosis studies and systematic review s. Methods Literature Search and Study Selection We identified systematic review s of prognosis studies by search ing MEDLINE ( 1966 to October 2005 ) using the search strategy recommended by McKibbon and colleagues ( 12 ) . This strategy combines broad search terms for systematic review s ( systematic review .mp ; meta- analysis .mp ) and a sensitive search strategy for prognosis studies ( cohort , incidence , mortality , follow-up studies , prognos * , predict * , or course ) . We also search ed the reference lists of included review s and method ologic papers to identify other relevant publications . We restricted our search to English- language publications . One review er conducted the search and selected the studies . Systematic review s , defined as review s of published studies with a comprehensive search and systematic selection , were included if they assessed the method ologic quality of the included studies by using 1 or more explicit criteria . We excluded studies if they were meta-analyses of independent patient data only , if their primary goal was to investigate the effectiveness of an intervention or specific diagnostic or screening tests , or if they included studies that were not done on humans . Data Extraction and Synthesis Individual items included in the quality assessment of the systematic review s were recorded as they were reported in the publication ( that is , the information that would be available to readers and future review ers ) . We review ed journal Web sites and contacted the authors of the systematic review s for additional information when authors made such an offer in their original papers . When review s assessed different study design s by using different sets of quality items , we extracted only those items used to assess cohort studies . We constructed a comprehensive list of distinct items that the review s used to assess the quality of their included studies . The full text of each review was screened . All items used by the review authors to assess the quality of studies were extracted into a computerized spreadsheet by 1 review er . Two experienced review ers , a clinical epidemiologist and an epidemiologist , independently synthesized the quality items extracted from the prognosis review s to determine how well the systematic review s assessed potential biases . We did this in 3 steps : 1 ) identified distinct concepts or domains addressed by the quality items ; 2 ) grouped each extracted quality item into the appropriate domain or domains ; and 3 ) identified the domains necessary to assess potential biases in prognosis studies . We then used this information to assess how well the review s ' quality assessment included items from the domains necessary to assess potential biases . After completing each of the first 3 steps , the review ers met to attempt to reach a consensus . The consensus process involved each review er presenting his or her observations and results , followed by discussion and debate . A third review er was available in cases of persistent disagreement or uncertainty . In the first step , all domains addressed by the quality items were identified . The first review er iteratively and progressively defined the domains as items were extracted from the included review s. The second review er defined domains from a r and om list of all extracted quality items . Limited guidance was provided to the review ers so that their assessment s and definitions of domains would be independent . The review ers agreed on a final set of domains that adequately and completely defined all of the extracted items . In the second step , review ers independently grouped each extracted item into the appropriate domains . Review ers considered each extracted item by asking , What is each particular quality item addressing ? or What are the review 's authors getting at with the particular quality assessment item ? . Items were grouped into the domain or domains that best represented the concepts being addressed . For example , the extracted items at least 80 % of the group originally identified was located for follow-up and follow-up was sufficiently complete or does n't jeopardize validity were each independently classified by both review ers as assessing the domain completeness of follow-up adequate , whereas the extracted item quantification and description of all subjects lost to follow-up was classified as assessing the domain completeness of follow-up described . In the third step , we identified the domains necessary to assess potential biases . Each review er considered the ability of the identified domains to adequately address , at least in part , 1 of the following 6 potential biases : 1 ) study participation , 2 ) study attrition , 3 ) prognostic factor measurement , 4 ) confounding measurement and account , 5 ) outcome measurement , and 6 ) analysis . Domains were considered to adequately address part of the framework if information garnered from that domain would inform the assessment of potential bias . For example , both review ers judged that the identified domain study population represents source population or population of interest assessed potential bias in a prognosis study , whereas the domain research question definition did not , although the latter is an important consideration in assessing the inclusion of studies in a systematic review . Finally , on the basis of our previous ratings , we looked at whether each review included items from the domains necessary to assess the 6 potential biases . We calculated the frequency of systematic review s by assessing each potential bias and the number of review s that adequately assessed bias overall . From this systematic synthesis , we developed recommendations for improving quality appraisal in future systematic review s of prognosis studies . We used Microsoft Access and Excel 2002 ( Microsoft Corp. , Redmond , Washington ) for data management and SAS for Windows , version 9.1 ( SAS Institute , Inc. , Cary , North Carolina ) for descriptive statistics . Role of the Funding Sources The funding sources , the Canadian Institutes of Health Research , the Canadian Chiropractic Research Foundation , the Ontario Chiropractic Association , and the Ontario Ministry of Health and Long Term Care , did not have a role in the collection , analysis , or interpretation of the data or in the decision to su bmi t the manuscript for publication . Results We identified 1384 potentially relevant articles . Figure 1 shows a flow chart of studies that were included and excluded . Figure 2 shows the number of review s identified by year of publication . We excluded 131 systematic review s of prognosis studies that did not seem to include any quality assessment of the included studies ; this represented 44 % of prognosis review s. We included 163 review s of prognosis studies in our analysis ( 13 - 175 ) . The most common topics were cancer ( 15 % ) , musculoskeletal disorders and rheumatology ( 13 % ) , cardiovascular ( 10 % ) , neurology ( 10 % ) , and obstetrics ( 10 % ) . Other review s included a wide range of health and health care topics . Sixty-three percent of the review s investigated the association between a specific prognostic factor and a particular outcome ; the remainder investigated multiple prognostic factors or models . The number of primary studies included in each systematic review ranged from 3 to 167 ( median , 18 [ interquartile range , 12 to 31 ] ) . A complete description of the included review s is available from the authors on request . Figure 1 . Flow diagram of inclusion and exclusion criteria of systematic review s. Figure 2 . Number of systematic review s of prognosis studies identified over time . Quality Items One hundred fifty-three review s provided adequate detail to allow extraction of quality items . Eight hundred eighty-two distinct quality items were extracted from the review s. Most review s developed their own set of quality items , with only a few applying criteria from previous review s. Most quality items [3551220] Objective To determine serum biomarker associations with clinical response to golimumab treatment in patients with psoriatic arthritis ( PsA ) . Methods GO – REVEAL was a r and omised , placebo-controlled study of golimumab in patients with active PsA. Sample s were collected from 100 patients at baseline , week 4 and week 14 , and analysed for serum-based biomarkers and protein profiling ( total 92 markers ) ; data were correlated with clinical measures at week 14 . Results Serum levels of a subset of proteins ( apolipoprotein C III , ENRAGE , IL-16 , myeloperoxidase , vascular endothelial growth factor , pyridinoline , matrix metalloproteinase 3 , C-reactive protein ( CRP ) , carcinoembryonic antigen , intercellular adhesion molecule 1 and macrophage inflammatory protein 1α ) at baseline or week 4 were strongly associated with American College of Rheumatology 20 % improvement ( ACR20 ) response and /or disease activity score in 28 joints ( DAS28 ) at week 14 . A smaller subset of proteins was significantly associated with a 75 % improvement in the psoriasis area and severity index score ( PASI75 ) at week 14 , ( adiponectin , apolipoprotein CIII , serum glutamic oxaloacetic transaminase , and tumour necrosis factor α ) . Subsets of proteins were identified as potentially predictive of clinical response for each of the clinical measures , and the power of these biomarker panels to predict clinical response to golimumab treatment was stronger than for CRP alone . Conclusions This analysis provides insight into several panels of markers that may have utility in identifying PsA patients likely to have ACR20 , DAS28 , or PASI75 responses following golimumab treatment [3218893] Introduction Methotrexate ( MTX ) has been shown to modify infliximab pharmacokinetics in rheumatoid arthritis . However , its combination with infliximab in the treatment of ankylosing spondylitis ( AS ) is not recommended . The objective of this study was to examine the influence of MTX on infliximab exposure in patients with AS . Methods Patients with AS patients who had predominantly axial symptoms were r and omised to receive infliximab alone ( infusions of 5 mg/kg at weeks 0 , 2 , 6 , 12 and 18 ) or infliximab combined with MTX ( 10 mg/week ) . Infliximab concentrations were measured before and 2 hours after each infusion and at 1 , 3 , 4 , 5 , 8 , 10 , 14 and 18 weeks . We estimated individual cumulative area under the concentration versus time curves ( AUC ) for infliximab concentration between baseline and week 18 ( AUC0 - 18 ) . Clinical and laboratory evaluations were performed at each visit . The Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI ) score was the primary end point for clinical response . Results Twenty-six patients were included ( infliximab group : n = 12 , infliximab + MTX group : n = 14 ) , and 507 serum sample s were available for measurement of infliximab concentration . The two groups did not differ with regard to AUC0 - 18 or evolution of BASDAI scores and biomarkers of inflammation . Conclusions The combination of MTX and infliximab does not increase the exposure to infliximab over infliximab alone in patients with AS.Trial registration Clinical Trials.gov : [3823044] Abstract Rats transgenic for HLA-B27 and human β2microglobulin ( B27TR ) develop a multi-systemic disease resembling inflammatory bowel disease ( IBD ) and spondyloarthritis . TNFα has a crucial role in chronic inflammation . Our objective was to evaluate the effect of anti-TNFα treatment on spontaneous IBD in B27TR . Nine-week-old B27TR received monoclonal anti-TNFα or an isotypic IgG2a , k up to age of 18 weeks . A second group was monitored up to 18 weeks and then r and omly assigned to anti-TNFα or IgG2 a , k treatment . Each rat was monitored for clinical IBD manifestations . After sacrifice , the colon was examined for pathological changes . TNFα receptors ( TNF-R1 , TNF-R2 ) , Fas/Fas-L expression and apoptosis were evaluated . IgG2a , k-treated and untreated B27TR presented signs of IBD at 11 weeks , whereas in anti-TNFα-treated B27TR no IBD signs were detected . In the late treatment , IBD signs improved after 1 week . Histopathological analysis of IgG2a , k-treated B27TR colon showed inflammatory signs that were widely prevented by early anti-TNFα treatment . Late treatment did not significantly reduce inflammation . TNF-R1 was weakly expressed in intestinal epithelial cells of IgG2a , k-treated B27TR , while it was comparable to controls in anti-TNFα-treated animals . TNF-R2 immunopositivity was strongly evident in IgG2a , k-treated B27TR , whereas was absent in anti-TNFα-treated rats . RT-PCR confirmed these results . IgG2a , k-treated B27TR showed , at 18 weeks , few Fas-positive cells and an increase of Fas-L-positive cells . At 27 weeks , Fas-/Fas-L-positive cell number was significantly low . Anti-TNFα treatment increased Fas-L expression , whereas Fas increased only with the early treatment . TNFα blockade is effective in preventing inflammation in early phase of IBD , maintaining the homeostatic balance of apoptosis [19877087] OBJECTIVE To study the usefulness of erythrocyte sedimentation rate ( ESR ) , C-reactive protein ( CRP ) , and serum amyloid A ( SAA ) for response prediction and monitoring of anti-tumor necrosis factor ( anti-TNF ) treatment in ankylosing spondylitis ( AS ) patients . METHODS Patients were included consecutively before starting etanercept or infliximab treatment . ASsessment in Ankylosing Spondylitis ( ASAS ) response , defined as a 50 % improvement or an absolute improvement of 2 points of the Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI ; 0 - 10 scale ) , was assessed at 3 months . Inflammatory markers and the BASDAI were collected at baseline and 1 and 3 months . Longitudinal data analysis was performed to compare associations between inflammatory markers and the BASDAI over time by calculating st and ardized betas . Predictive values of baseline levels of inflammatory markers for ASAS response were calculated . RESULTS In total , 155 patients were included , of whom , after 3 months of treatment , 70 % in the etanercept cohort and 71 % in the infliximab cohort responded . All markers , notably SAA , decreased significantly ( P < 0.0001 ) . St and ardized betas were 0.49 for ESR , 0.43 for CRP , and 0.39 for SAA . Normal baseline levels of CRP and SAA were significantly associated with nonresponse . A combination of elevated CRP and SAA levels at baseline revealed the highest predictive value ( 81 % ) for ASAS response . CONCLUSION ESR , CRP , and SAA were significantly associated with the BASDAI over 3 months , and the association with ESR was the strongest . Elevated baseline CRP and SAA levels revealed the highest predictive value for response . Together , this study demonstrates that inflammatory markers , and notably CRP and SAA , may facilitate patient selection and monitoring of efficacy of anti-TNF treatment in AS , and could be added to response criteria [2911878] Introduction Since remission is now possible in psoriatic arthritis ( PsA ) we wished to examine remission rates in PsA patients following anti tumour necrosis factor alpha ( TNFα ) therapy and to examine possible predictors of response . Methods Analysis of a prospect i ve patient cohort attending a biologic clinic , between November 2004 and March 2008 , was performed prior to commencing therapy and at regular intervals . Baseline clinical characteristics including demographics , previous disease-modifying antirheumatic drug ( DMARD ) response , tender and swollen joint counts , early morning stiffness , pain visual analogue score , patient global assessment , C reactive protein ( CRP ) and health assessment question naire ( HAQ ) were collected . Results A total of 473 patients ( 152 PsA ; 321 rheumatoid arthritis ( RA ) ) were analyzed . At 12 months remission , defined according to the disease activity score using 28 joint count and CRP ( DAS28-CRP ) , was achieved in 58 % of PsA patients compared to 44 % of RA patients , significant improvement in outcome measures were noted in both groups ( P < 0.05 ) . Analysis of a subgroup of PsA and RA patients matched for DAS28-CRP at baseline also showed higher numbers of PsA patients achieving remission . Linear regression analysis identified the HAQ at baseline as the best predictor of remission in PsA patients ( P < 0.001 ) . Conclusions DAS28 remission is possible in PsA patients at one year following anti-TNF therapy , at higher rates than in RA patients and is predicted by baseline HAQ [3329231] Objective Identify serum biomarkers modulated by golimumab treatment and associated with clinical response in patients with ankylosing spondylitis ( AS ) . Methods Sera were collected at weeks 0 , 4 and 14 from 100 patients with active AS in the GO – RAISE study . Patients were r and omly assigned subcutaneous injections of placebo , golimumab 50 mg , or golimumab 100 mg every 4 weeks . Sample s were tested for select inflammatory , bone and cartilage markers , and protein profiling was also performed . Results Golimumab treatment result ed in significant decreases in several serum proteins at weeks 4 and 14 compared with placebo . Patients who achieved clinical response at week 14 , as assessed by a ≥20 % improvement in the Assessment in SpondyloArthitis international Society response criteria ( ASAS 20 ) , demonstrated a distinct biomarker profile with lower levels of acute phase reactants and inflammatory biomarkers compared with patients who did not . Notably , combinations of two or three biomarkers assessed at baseline were predictive of various clinical outcomes ( ASAS 20 , Bath ankylosing spondylitis disease activity index 50 or Bath ankylosing spondylitis functional index ) using a logistic regression analysis , and the overall predictive values for these combined biomarkers were greater than observed for C-reactive protein ( CRP ) alone . Conclusion Golimumab modulated acute phase reactants and inflammatory markers in patients with active AS . Specific combinations of biomarkers at baseline demonstrated a stronger prediction for clinical efficacy than CRP alone . These data provide insights into the mechanism of golimumab on inflammatory processes driving AS pathology , and may have utility in managing the treatment of patients with AS [17114188] Objective : To evaluate the efficacy and safety of infliximab through 1 year in patients with psoriatic arthritis ( PsA ) enrolled in the IMPACT 2 trial . Methods : In this double blind , placebo controlled , phase III study , 200 patients with active PsA were r and omised to receive infusions of infliximab 5 mg/kg or placebo at weeks 0 , 2 , 6 , and every 8 weeks thereafter through 1 year . Patients with persistent disease activity could enter early escape at week 16 , and all remaining placebo patients crossed over to infliximab at week 24 . Patients r and omised to infliximab who had no response or who lost response could escalate their dose to 10 mg/kg starting at week 38 . Clinical efficacy was assessed based on the proportion of patients achieving ACR 20 and PASI 75 responses . Major clinical response ( that is , maintenance of ACR 70 response for 24 continuous weeks ) was assessed for the first time in PsA. Results : Through 1 year of treatment , 58.9 % and 61.4 % of patients in the r and omised infliximab and placebo/infliximab groups , respectively , achieved ACR 20 ; corresponding figures for PASI 75 were 50.0 % and 60.3 % . At week 54 , major clinical response was achieved by 12.1 % of patients in the infliximab group . The safety profile of infliximab through week 54 was consistent with that seen through week 24 . Two malignancies occurred : basal cell skin cancer ( placebo ) and stage I Hodgkin ’s lymphoma ( infliximab ) . Conclusion : Infliximab maintains a high degree of clinical efficacy and continues to be well tolerated in patients with PsA through 1 year of treatment [15677701] OBJECTIVES To evaluate further in a phase III , double blind trial the efficacy of infliximab in patients with active psoriatic arthritis ( PsA ) , as observed in the smaller IMPACT trial . METHODS 200 patients with active PsA unresponsive to previous treatment were r and omised to infusions of infliximab 5 mg/kg or placebo at weeks 0 , 2 , 6 , 14 , and 22 . Patients with inadequate response entered early escape at week 16 . The primary measure of clinical response was ACR20 . Other measures included Psoriatic Arthritis Response Criteria ( PsARC ) , Psoriasis Area and Severity Index ( PASI ) , and dactylitis and enthesopathy assessment s. RESULTS At week 14 , 58 % of patients receiving infliximab and 11 % of those receiving placebo achieved an ACR20 response and 77 % of infliximab patients and 27 % of placebo patients achieved PsARC ( both p<0.001 ) . Among the 85 % of patients with at least 3 % body surface area psoriasis involvement at baseline , 53/83 ( 64 % ) patients receiving infliximab had at least 75 % improvement in PASI compared with 2/87 ( 2 % ) patients receiving placebo at week 14 ( p<0.001 ) . These therapeutic effects were maintained through the last evaluation ( week 24 ) . Fewer infliximab patients than placebo patients had dactylitis at week 14 ( 18 % v 30 % ; p = 0.025 ) and week 24 ( 12 % v 34 % ; p<0.001 ) . Fewer infliximab patients ( 22 % ) than placebo patients ( 34 % ) had active enthesopathy at week 14 ( p = 0.016 ) ; corresponding figures at week 24 were 20 % and 37 % ( p = 0.002 ) . Infliximab was generally well tolerated , with a similar incidence of adverse events in each group . CONCLUSIONS Infliximab 5 mg/kg through 24 weeks significantly improved active PsA , including dactylitis and enthesopathy , and associated psoriasis [22378566] OBJECTIVE Golimumab , administered subcutaneously every 4 weeks , has been shown to be effective in reducing the signs and symptoms of active psoriatic arthritis ( PsA ) through week 24 of the GO-REVEAL study . Herein we report 1-year clinical , radiographic , and safety findings . METHODS Adult patients with active PsA ( ≥3 swollen and ≥3 tender joints ) were r and omly assigned to receive subcutaneous placebo , golimumab 50 mg , or golimumab 100 mg every 4 weeks through week 20 . At week 16 , patients with < 10 % improvement from baseline in swollen and tender joint counts entered a blinded early escape phase , with placebo crossover to golimumab 50 mg , golimumab 50 mg increased to 100 mg , and golimumab 100 mg continued at 100 mg . Patients receiving placebo who did not enter the early escape phase crossed over to golimumab 50 mg at week 24 . Findings through 1 year are reported , including the second of 2 co primary end points ( i.e. , change from baseline to week 24 in PsA-modified Sharp/van der Heijde score [ SHS ] ) . RESULTS A total of 405 patients were r and omized : 113 to placebo and 146 each to the golimumab 50 mg and 100 mg groups . Mean changes in PsA-modified SHS from baseline to week 24 for the combined golimumab 50 mg and 100 mg group ( -0.09 ) and the golimumab 50 mg group ( -0.16 ) were significantly different versus placebo ( 0.27 ) ( P = 0.015 and P = 0.011 , respectively ) . Radiographic benefit was maintained through week 52 with golimumab . Clinical efficacy , including improvement in joint and skin responses and physical function , was maintained through 1 year . The frequency/types of adverse events were similar to those reported through week 24 . CONCLUSION Treatment of PsA with golimumab inhibited structural damage progression and demonstrated continued clinical efficacy and safety through 1 year [18316338] OBJECTIVE To identify factors predicting response to first TNF blocking treatment course in patients with established RA with a special focus on gender differences . METHODS Patients with active RA initiating their first treatment course of TNF-blocking therapy were enrolled . The study period was March 1999 through September 2006 . The prospect i ve protocol included information on demographics , clinical characteristics of patients and response measures . Fulfilment of ACR 50 - 70 % improvement and European League Against Rheumatism ( EULAR ) good response or remission [ 28-joint disease activity score ( DAS28 ) < 2.6 ] at 3 months were chosen as primary outcome measures . Potential predictors of responses were identified using multivariate binary logistic regression models . RESULTS In total , 1565 patients were included in the study . Gender did not influence treatment response . Consistently , concomitant methotrexate ( MTX ) was significantly associated with EULAR remission , EULAR good response , ACR50 response and ACR70 response with odds ratios ( ORs ) 1.97 , 2.13 , 2.10 and 1.75 , respectively . Concurrent treatment with other DMARDs was also significantly associated with EULAR remission , EULAR good response and ACR50 response ( OR : 1.96 , 2.24 and 1.94 , respectively ) . Likewise , low HAQ at baseline consistently predicted good clinical outcome . Disease activity at baseline was directly associated with favourable response when measured by ACR50 and ACR70 ( OR : 1.59 and 1.60 , respectively ) , whereas DAS28 score at baseline was inversely associated with EULAR remission ( OR : 0.78 ) . CONCLUSIONS In this observational study of patients with established RA , gender did not predict response to anti-TNF therapy , whereas treatment with concomitant DMARDs , especially MTX and low disability were associated with good response . Choice of outcome measures may influence the predictive value of baseline features [22514189] We prospect ively evaluated whether obesity impacts achievement of minimal disease activity ( MDA ) in subjects with psoriatic arthritis ( PsA ) [15692973] OBJECTIVE The signs and symptoms of ankylosing spondylitis ( AS ) respond inadequately to nonsteroidal antiinflammatory drugs , corticosteroids , and disease-modifying antirheumatic drugs in quite a number of patients . Tumor necrosis factor inhibitors have demonstrated success in reducing AS disease activity in a limited number of clinical trials . The objective of this multicenter , r and omized , placebo-controlled study was to evaluate the efficacy and safety of infliximab in patients with AS . METHODS Patients were r and omly assigned to receive infusions of placebo or 5 mg/kg infliximab at weeks 0 , 2 , 6 , 12 , and 18 . Efficacy was assessed using the ASsessment in Ankylosing Spondylitis ( ASAS ) International Working Group criteria , the Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI ) , night pain , patient 's global assessment , the Bath Ankylosing Spondylitis Functional Index ( BASFI ) , the Bath Ankylosing Spondylitis Metrology Index ( BASMI ) , chest expansion , the M and er enthesis index , the total swollen joint index , the C-reactive protein level , and the Short Form 36 ( SF-36 ) health survey question naire . The primary end point in this study was the proportion of patients with a 20 % improvement response according to the ASAS International Working Group criteria ( ASAS20 responders ) at week 24 . RESULTS Of the 357 patients screened , 201 were assigned to receive 5 mg/kg infliximab and 78 were assigned to receive placebo . After 24 weeks , 61.2 % of patients in the infliximab group were ASAS20 responders compared with 19.2 % of patients in the placebo group ( P < 0.001 ) . Clinical benefit was observed in patients receiving infliximab as early as week 2 and was maintained over the 24-week study period . Patients receiving infliximab also showed significant improvements in the BASDAI , BASFI , BASMI , chest expansion , and physical component summary score of the SF-36 . Adverse events were reported by 82.2 % of patients receiving infliximab and by 72.0 % of patients receiving placebo ; however , most adverse events in both treatment groups were mild or moderate in severity . CONCLUSION Infliximab was well tolerated and effective in a large cohort of patients with AS during a 24-week study period [2800202] Objectives : To evaluate the effectiveness of adalimumab in patients with psoriatic arthritis ( PsA ) and identify predictors of good clinical response for joint and skin lesions . Methods : Patients received adalimumab 40 mg every other week in addition to st and ard therapy in this prospect i ve , 12-week , open-label , uncontrolled study . Four definitions of good clinical response were used : ⩾50 % improvement in American College of Rheumatology response criteria ( ACR50 ) , good response according to European League Against Rheumatism ( EULAR ) guidelines , a ⩾3- grade improvement in Physician Global Assessment of psoriasis ( PGA ) and a ⩾50 % improvement in the Nail Psoriasis Severity Index ( NAPSI ) . Response predictors were determined by logistic regression with backward elimination ( selection level was 5 % ) . Results : Of 442 patients , 94 % completed 12 weeks of treatment . At week 12 , 74 % , 51 % and 32 % of the patients had achieved ACR20 , 50 and 70 , respectively ; 87 % and 61 % experienced moderate and good responses according to EULAR criteria , respectively . The percentage of patients with PGA results of “ clear/almost clear ” increased from 34 % ( baseline ) to 68 % . The mean NAPSI score was reduced by 44 % . No new safety signals were detected . A lower Health Assessment Question naire Disability Index ( HAQ-DI ) score , greater pain assessment , male sex and absence of systemic glucocorticoid therapy were strongly associated with achievement of ACR50 and good response according to EULAR criteria . In addition , greater C-reactive protein concentration and polyarthritis predicted ACR50 , and non-involvement of large joints predicted a good response according to EULAR criteria . Conclusions : Adalimumab was effective in patients with PsA. Lower impairment of physical function , greater pain , male sex and no systemic treatment with glucocorticoids were factors that increased the chance of achieving a good clinical response [3218909] Introduction Identifying ankylosing spondylitis ( AS ) patients who are likely to benefit from tumor necrosis factor-alpha ( TNF-α ) blocking therapy is important , especially in view of the costs and potential side effects of these agents . Recently , the AS Disease Activity Score ( ASDAS ) has been developed to assess both subjective and objective aspects of AS disease activity . However , data about the predictive value of the ASDAS with respect to clinical response to TNF-α blocking therapy are lacking . The aim of the present study was to identify baseline predictors of response and discontinuation of TNF-α blocking therapy in AS patients in daily clinical practice . Methods AS out patients who started TNF-α blocking therapy were included in the Groningen Leeuwarden Ankylosing Spondylitis ( GLAS ) study , an ongoing prospect i ve longitudinal observational cohort study with follow-up visits according to a fixed protocol . For the present analysis , patients were excluded if they had previously received anti-TNF-α treatment . Predictor analyses of response and treatment discontinuation were performed using logistic and Cox regression models , respectively . Results Between November 2004 and April 2010 , 220 patients started treatment with infliximab ( n = 32 ) , etanercept ( n = 137 ) , or adalimumab ( n = 51 ) . At three and six months , 68 % and 63 % of patients were Assessment s in Ankylosing Spondylitis (ASAS)20 responders , 49 % and 46 % ASAS40 responders , and 49 % and 50 % Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)50 responders , respectively . Baseline predictors of response were younger age , male gender , higher ASDAS score , higher erythrocyte sedimentation rate ( ESR ) level , higher C-reactive protein ( CRP ) level , presence of peripheral arthritis , higher patient 's global assessment of disease activity , and lower modified Schober test . In August 2010 , 64 % of patients were still using their TNF-α blocking agent with a median follow-up of 33.1 months ( range 2.4 to 68.2 ) . Baseline predictors of discontinuation of TNF-α blocking therapy were female gender , absence of peripheral arthritis , higher BASDAI , lower ESR level , and lower CRP level . Conclusions Besides younger age and male gender , objective variables such as higher inflammatory markers or ASDAS score were identified as independent baseline predictors of response and /or continuation of TNF-α blocking therapy . In contrast , higher baseline BASDAI score was independently associated with treatment discontinuation . Based on these results , it seems clinical ly relevant to include more objective variables in the evaluation of anti-TNF-α treatment [10972371] BACKGROUND Etanercept , a tumour-necrosis-factor inhibitor , has shown efficacy in the treatment of rheumatoid arthritis . Psoriatic arthritis and psoriasis are disease states in which tumour necrosis factor , a proinflammatory cytokine , is present in increased concentrations in joints and in the skin . Therefore , psoriatic arthritis and psoriasis may be appropriate therapeutic targets for etanercept . METHODS This r and omised , double-blind , placebo-controlled , 12 week study assessed the efficacy and safety of etanercept ( 25 mg twice-weekly subcutaneous injections ) or placebo in 60 patients with psoriatic arthritis and psoriasis . Psoriatic arthritis endpoints included the proportion of patients who met the Psoriatic Arthritis Response Criteria ( PsARC ) and who met the American College of Rheumatology preliminary criteria for improvement ( ACR20 ) . Psoriasis endpoints included improvement in the psoriasis area and severity index ( PASI ) and improvement in prospect ively-identified individual target lesions . FINDINGS In this 12 week study , 26 ( 87 % ) of etanercept-treated patients met the PsARC , compared with seven ( 23 % ) of placebo-controlled patients . The ARC20 was achieved by 22 ( 73 % ) of etanercept-treated patients compared with four ( 13 % ) of placebo-treated patients . Of the 19 patients in each treatment group who could be assessed for psoriasis ( > or = 3 % body surface area ) , five ( 26 % ) of etanercept-treated patients achieved a 75 % improvement in the PASI , compared with none of the placebo-treated patients ( p=0.015 ) . The median PASI improvement was 46 % in etanercept-treated patients versus 9 % in placebo-treated patients ; similarly , median target lesion improvements were 50 % and 0 , respectively . Etanercept was well tolerated . INTERPRETATION Etanercept offers patients with psoriatic arthritis and psoriasis a new therapeutic option for control of their disease [17179176] Objectives : To determine the predictive factors of clinical response to infliximab in patients with refractory psoriatic polyarthritis . Methods : A multicentre open study which included 69 patients with psoriatic polyarthritis refractory to methotrexate ( 15 mg/week at least for 8 weeks ) . Patients were treated with infliximab 5 mg/kg every 8 weeks in addition to their stable doses of methotrexate . A major clinical response was defined by the ACR50 at week 38 . Logistic regression analysis was performed to analyse which of the following measures at the start of treatment were associated with an ACR50 response : demographic and clinical characteristics , duration of disease , tender and swollen joint counts , involvement of large joints ( knee or hip , or both ) , erythrocyte sedimentation rate , C reactive protein ( CRP ) , Health Assessment Question naire disability index , axial involvement , and the presence of erosions at baseline . Results : In an intention to treat analysis 30/69 ( 44 % ) patients achieved an ACR50 response . In the univariate analysis both the presence of large joint involvement and severe disability were associated with a poor clinical response . In a multivariate logistic regression analysis high CRP values were independently associated with a good therapeutic response ( odds ratio ( OR ) = 18.7 ; 95 % confidence interval ( CI ) 1.8 to 181.6 ; p = 0.011 ) . In contrast , large joint involvement and severe disability were associated with a poor response , which reached significance for large joint involvement ( OR = 29.3 ; 95 % CI 3.2 to 266.3 ; p = 0.003 ) . Conclusion : A lower disability and , in particular , the absence of large joint involvement and higher CRP serum levels at the start of infliximab treatment are factors that seem to influence the probability of achieving a good therapeutic response in patients with psoriatic arthritis [16200601] OBJECTIVE Adalimumab , a fully human , anti-tumor necrosis factor monoclonal antibody , was evaluated for its safety and efficacy compared with placebo in the treatment of active psoriatic arthritis ( PsA ) . METHODS Patients with moderately to severely active PsA and a history of inadequate response to nonsteroidal antiinflammatory drugs were r and omized to receive 40 mg adalimumab or placebo subcutaneously every other week for 24 weeks . Study visits were at baseline , weeks 2 and 4 , and every 4 weeks thereafter . The primary efficacy end points were the American College of Rheumatology 20 % improvement ( ACR20 ) response at week 12 and the change in the modified total Sharp score of structural damage at week 24 . Secondary end points were measures of joint disease , disability , and quality of life in all patients , as well as the severity of skin disease in those patients with psoriasis involving at least 3 % of body surface area . RESULTS At week 12 , 58 % of the adalimumab-treated patients ( 87 of 151 ) achieved an ACR20 response , compared with 14 % of the placebo-treated patients ( 23 of 162 ) ( P < 0.001 ) . At week 24 , similar ACR20 response rates were maintained and the mean change in the modified total Sharp score was -0.2 in patients receiving adalimumab and 1.0 in those receiving placebo ( P < 0.001 ) . Among the 69 adalimumab-treated patients evaluated with the Psoriasis Area and Severity Index ( PASI ) , 59 % achieved a 75 % PASI improvement response at 24 weeks , compared with 1 % of the 69 placebo-treated patients evaluated ( P < 0.001 ) . Disability and quality of life measures were also significantly improved with adalimumab treatment compared with placebo . Adalimumab was generally safe and well-tolerated . CONCLUSION Adalimumab significantly improved joint and skin manifestations , inhibited structural changes on radiographs , lessened disability due to joint damage , and improved quality of life in patients with moderately to severely active [16142873] OBJECTIVE To examine the baseline demographic and disease characteristics that might influence improvement as measured by the Assessment in Ankylosing Spondylitis Response Criteria ( ASAS 20 ) in patients with ankylosing spondylitis ( AS ) . METHODS A multicenter Phase 3 study was performed to compare the safety and efficacy of 24 weeks of etanercept 25 mg subcutaneous injection twice weekly ( n = 138 ) and placebo ( n = 139 ) in patients with AS . The ASAS 20 was measured at multiple time points . Using a significance level of 0.05 , a repeated measures logistic regression model was used to determine which baseline factors influenced response in the etanercept-treated patients during the 24-week double blind portion of the trial . The following baseline factors were used in the model : demographic and disease severity variables , concomitant medications , extra-articular manifestations , and HLA-B27 status . The predictive capability of the model was then tested on the patients receiving placebo after they had received open-label etanercept treatment . RESULTS Baseline factors that were significant predictors of an ASAS 20 response in etanercept-treated patients were C-reactive protein ( CRP ) , back pain score , and Bath Ankylosing Spondylitis Functional Index ( BASFI ) score . Although clinical response to etanercept was seen at all levels of baseline disease activity , responses were consistently more likely with higher CRP levels or back pain scores and less likely with increased BASFI scores at baseline . CONCLUSIONS Higher CRP values and back pain scores and lower BASFI scores at baseline were significant predictors of a higher ASAS 20 response in patients with AS receiving etanercept but predictive value was of insufficient magnitude to determine treatment in individual patients [3446492] Introduction The excess of adipose tissue in obese individuals may have immunomodulating properties and pharmacokinetic consequences . The aim of this study was to determine whether body mass index ( BMI ) affects response to infliximab ( IFX ) in ankylosing spondylitis ( AS ) patients . Methods In 155 patients retrospectively included with active AS , the BMI was calculated before initiation of IFX treatment ( 5 mg/kg intravenously ) . After 6 months of treatment , changes from baseline in BASDAI , Visual Analogue Scale ( VAS ) pain , C-reactive protein ( CRP ) level , and total dose of nonsteroidal antiinflammatory drug ( NSAID ) were dichotomized with a threshold corresponding to a decrease of 50 % of initial level of the measure , into binary variables assessing response to IFX ( BASDAI50 , VAS50 , CRP50 , NSAID50 ) . Whether the BMI was predictive of the response to IFX therapy according to these definitions was assessed with logistic regression . Results Multivariate analysis found that a higher BMI was associated with a lower response for BASDAI50 ( P = 0.0003 ; OR , 0.87 ; 95 % CI ( 0.81 to 0.94 ) ) , VAS50 ( P < 0.0001 ; OR , 0.87 ; 95 % CI ( 0.80 to 0.93 ) ) ; CRP50 ( P = 0.0279 ; OR , 0.93 ; 95 % CI ( 0.88 to 0.99 ) ) , and NSAID50 ( P = 0.0077 ; OR , 0.91 ; 95 % CI ( 0.85 to 0.97 ) ) , criteria . According to the three WHO BMI categories , similar results were found for BASDAI50 ( 77.6 % , 48.9 % , and 26.5 % ; P < 0.0001 ) , VAS50 ( 72.6 % , 40.4 % , and 16.7 % ; P < 0.0001 ) ; CRP50 ( 87.5 % , 65.7 % , and 38.5 % ; P = 0.0001 ) , and NSAID50 ( 63.2 % , 51.5 % , and 34.6 % ; P = 0.06 ) . Conclusions This study provides the first evidence that a high BMI negatively influences the response to IFX in AS . Further prospect i ve studies , including assessment of the fat mass , pharmacokinetics , and adipokines dosages are m and atory to eluci date the role of obesity in AS IFX response [2911906] Introduction To identify independent predictors of radiographic progression in psoriatic arthritis ( PsA ) for patients treated with adalimumab or placebo in the Adalimumab Effectiveness in PsA Trial ( ADEPT ) . Methods Univariate analyses and multivariate linear regression analyses assessed risk for radiographic progression ( change in modified total Sharp score , ΔmTSS > 0.5 ) from baseline to week 24 for C-reactive protein ( CRP ) and other baseline variables , and for 24-week time-averaged CRP ( univariate analysis only ) . Subanalyses determined mean ΔmTSS for CRP subgroups . Analyses were post hoc , with observed data . Results One hundred and forty-four adalimumab-treated patients and 152 placebo-treated patients were assessed . Mean CRP was 64 % lower by week 2 with adalimumab and essentially unchanged with placebo . Univariate analyses indicated that elevated CRP at baseline and time-averaged CRP were strongly associated with radiographic progression for placebo-treated patients but not for adalimumab-treated patients . Multivariate analysis confirmed that elevated baseline CRP was the only strong independent risk factor for radiographic progression ( for CRP ≥1.0 mg/dl : odds ratio = 3.28 , 95 % confidence interval = 1.66 to 6.51 , P < 0.001 ) . Adalimumab treatment reduced risk of progression approximately fivefold . The difference between mean ΔmTSS for adalimumab versus placebo was greatest for patients with baseline CRP ≥2.0 mg/dl ( -0.5 vs. 2.6 ) . Conclusions Systemic inflammation in PsA , as indicated by elevated baseline CRP , was the only strong independent predictor of radiographic progression . This association was observed predominantly for placebo-treated patients . Adalimumab treatment substantially reduced the overall risk of radiographic progression , and provided greatest radiographic benefit for patients with the greatest CRP concentrations at baseline . Trial Registration Trial registration : NCT00195689 [3888598] Objectives To evaluate the efficacy and safety of certolizumab pegol ( CZP ) after 24 weeks in RAPID-axSpA ( NCT01087762 ) , an ongoing Phase 3 trial in patients with axial spondyloarthritis ( axSpA ) , including patients with ankylosing spondylitis ( AS ) and non-radiographic axSpA ( nr-axSpA ) . Methods Patients with active axSpA were r and omised 1:1:1 to placebo , CZP 200 mg every 2 weeks ( Q2W ) or CZP 400 mg every 4 weeks ( Q4W ) . In total 325 patients were r and omised . Primary endpoint was ASAS20 ( Assessment of SpondyloArthritis international Society 20 ) response at week 12 . Secondary outcomes included change from baseline in Bath Ankylosing Spondylitis Functional Index ( BASFI ) , Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI ) , and Bath Ankylosing Spondylitis Metrology Index ( BASMI ) linear . Results Baseline disease activity was similar between AS and nr-axSpA. At week 12 , ASAS20 response rates were significantly higher in CZP 200 mg Q2W and CZP 400 mg Q4W arms versus placebo ( 57.7 and 63.6 vs 38.3 , p≤0.004 ) . At week 24 , combined CZP arms showed significant ( p<0.001 ) differences in change from baseline versus placebo in BASFI ( −2.28 vs −0.40 ) , BASDAI ( −3.05 vs −1.05 ) , and BASMI ( −0.52 vs −0.07 ) . Improvements were observed as early as week 1 . Similar improvements were reported with CZP versus placebo in both AS and nr-axSpA sub population s. Adverse events were reported in 70.4 % vs 62.6 % , and serious adverse events in 4.7 % vs 4.7 % of All CZP versus placebo groups . No deaths or malignancies were reported . Conclusions CZP rapidly reduced the signs and symptoms of axSpA , with no new safety signals observed compared to the safety profile of CZP in RA . Similar improvements were observed across CZP dosing regimens , and in AS and nr-axSpA patients [11955536] UNLABELLED BACKGROUND Treatment options for patients with ankylosing spondylitis are few . We aim ed to assess the effectiveness of infliximab , an antibody to tumour necrosis factor (TNF)-alpha , in treatment of such patients . METHODS In this 12-week placebo-controlled multicentre study , we r and omly assigned 35 patients with active ankylosing spondylitis to intravenous infliximab ( 5 mg/kg ) and 35 to placebo at weeks 0 , 2 , and 6 . One patient in the infliximab group was withdrawn from the study . Our primary outcome was regression of disease activity of at least 50 % . To assess response , we used vali date d clinical criteria from the ankylosing spondylitis assessment working group , including disease activity ( BASDAI ) , functional indices ( BASFI ) , metrology ( BASMI ) , and quality of life ( short form 36 ) . Analyses were done by intention to treat . FINDINGS 18 ( 53 % ) of 34 patients on infliximab had a regression of disease activity at week 12 of at least 50 % compared with three ( 9 % ) of 35 on placebo ( difference 44 % [ 95 % CI 23 - 61 ] , p<0.0001 ) . Function and quality of life also improved significantly on infliximab but not on placebo ( p<0.0001 and p<0.0001 , respectively ) . Treatment with infliximab was generally well tolerated , but three patients had to stop treatment because of systemic tuberculosis , allergic granulomatosis of the lung , or mild leucopenia . INTERPRETATION Our results show that treatment with infliximab is effective in patients with active ankylosing spondylitis . Since there are some potentially serious adverse effects , we recommend that this treatment mainly be used in co-operation with rheumatological centres [17021665] The objective of this study was to evaluate if there are early clinical parameters in AS patients treated with three st and ard infusions of infliximab , which would predict whether a patient will derive a significant improvement at the tenth week , or whether there will be a lengthy clinical response after discontinuing the infusions . Sixty three AS patients were given three infusions of 5 mg/kg of infliximab at weeks 0 , 2 , and 6 and evaluated serially before each infusion and also at week 10 . Afterwards , patients were followed up by telephone interview until their disease activities were > 60 % of the baseline values . At that point , disease was considered to have relapsed . Clinical parameters at baseline as well as at week 2 were used for analysis to identify factors that might predict an improvement at week 10 , or predict a delayed relapse . A predictor is regarded as being useful if the area under the curve ( AUC ) when analyzed by receiver operator calculations ( ROC ) exceeds 0.75 . No parameters at baseline have sufficient predictive values . However , ASAS20 ( Assessment in Ankylosing Spondylitis International Working Group criteria ) at week 2 predicts improvement at week 10 , and also duration of clinical response after discontinuing the infliximab at week 6 . The response to one pulse of infliximab is the best predictor of subsequent response as well as rate of relapse after discontinuing the infliximab [17387031] OBJECTIVES The aims of this study were to assess the efficacy of infliximab ( IFX ) combined with methotrexate ( MTX ) versus IFX alone in the treatment of ankylosing spondylitis ( AS ) . METHODS The study was a 30weeks open label and prospect i ve study of parallel groups in 19 patients with active AS . These patients had shown incomplete therapeutic response to st and ard therapy ( full dose of non-steroidal anti-inflammatory drugs : NSAIDs ) and disease modifying antirheumatic drugs : DMARDs ( MTX or sulfasalazine : SLZ ) for a period of at least 12 weeks and were treated with IFX ( 5mg/kg ) . Patients were divided into two treatment groups according to the previous treatment : in Group A , 9 patients previously treated with 7.5mg/week of MTX were treated with IFX in addition to MTX ( IFX+MTX ) ; in Group B , 10 patients previously treated only with NSAIDs were treated with IFX ( 5mg/kg ) as monotherapy ( IFX ) . The primary outcome was improvement in disease activity shown by the BASDAI50 at week 30 ; the secondary outcome included comparison of the proportions of subjects in each group achieving response criteria proposed by the ASAS group . BASDAI , BASFI , ESR , CRP , pain , inflammation and Patient Global Assessment were also recorded . RESULTS Both groups were similar in sex ratio , clinical forms and B27 . Differences between groups occurred only in the disease duration and age of the patient . At 14 and 30 weeks only 50 % and 10 % respectively of the patients from the IFX group achieved BASDAI50 response compared to 89 % of patients from the IFX+MTX group . The difference between groups at 30 weeks was statistically significant ( p=0.001 ; percentage of difference : 79 % ; 95 % confidence interval ( CI ) : 26 - 93 % : ) . ASAS50 was reached in 67 % and 55.6 % of patients from the IFX+MTX group at 14 and 30 weeks respectively , compared with 30 % and 0 % of patients from the IFX group The difference between groups at 30 weeks was statistically significant ( p=0.011 ; percentage of difference : 57 % ; 95 % CI : 8 - 84.7 % ) . CONCLUSION Infliximab in combination with MTX seems to increase the efficacy of the therapeutic response in active AS patients , but more wide-ranging studies are necessary , mainly long-term studies [20385615] OBJECTIVE To determine predictors and time to response to treatment with TNF-alpha blockers in patients with PsA in a longitudinal observational cohort . METHODS We performed a cohort analysis of patients who were followed prospect ively in a large PsA clinic . Response to treatment was defined as an improvement of at least 40 % in active ( tender and /or swollen ) and swollen joint count ( SJC ) and 50 % improvement in the Psoriasis Area and Severity Index ( PASI ) score . RESULTS Ninety-five patients were included in the analysis . Of the total patients , 72.6 and 77.9 % demonstrated 40 % improvement in active joint counts at 3 and 12 months , respectively . Also , 80.5 and 87.4 % of the patients showed 40 % improvement in SJC at 3 and 12 months , respectively . A PASI50 was achieved by 54 and 60.4 % after 3 and 12 months of treatment , respectively . Of 17 patients who did not achieve 40 % improvement in total SJC at 3 months , 11 ( 64.7 % ) responded at 12 months . In multivariate analysis , the number of swollen joints at baseline predicted response of total active joints at 12 months [ odds ratio ( OR ) 1.34 ; P = 0.02 ] , whereas past use of TNF-alpha blocker decreased odds of response ( OR 0.05 ; P = 0.01 ) . CONCLUSION TNF-alpha blockers are effective in most PsA patients with the majority responding within 3 months of treatment . A significant proportion of the early non-responders will have a delayed response to treatment . Higher SJC at baseline and no prior use of TNF-alpha blockers predict response [22991950] Objectives : There is evidence that fat tissue may influence the response to therapy in patients with arthritis . The aim of this study was to assess whether the body mass index ( BMI ) affects rates of clinical remission in patients with psoriatic arthritis ( PsA ) treated with anti-tumour necrosis factor (TNF)-α biological drugs . Method : We retrospectively studied 135 patients with active peripheral PsA ( 45 obese , 47 overweight , and 43 normal-weight ) . Baseline BMI was correlated with the clinical response to adalimumab , etanercept , or infliximab . After 36 months ( median , range 6–79 ) of treatment , disease remission rates were assessed using the Disease Activity Score in 28 joints ( DAS28 ) or the Simplified Disease Activity Index ( SDAI ) . Possible predictors of clinical outcomes were assessed by multivariate analysis . Results : At baseline , BMI was significantly correlated only with the Health Assessment Question naire ( HAQ ) score ( r = 0.21 , p = 0.02 ) and not with disease activity . BMI did not predict disease remission or changes in HAQ score following anti-TNF-α therapy . Obese patients showed a significantly higher HAQ score and took significantly lower doses of prednisone than normal-weight or overweight patients , but their disease remission rates on the DAS28 ( 37 % ) or the SDAI ( 21 % ) were not significantly different from those of the other two groups ( 44 % and 21 % , respectively ) , regardless of the TNF-α inhibitor prescribed . Conclusions : In our retrospective analysis , disease activity and clinical response to anti-TNF-α therapy in PsA do not seem to be affected by BMI . Further prospect i ve studies are needed to confirm these preliminary results [20448079] OBJECTIVES To compare the clinical manifestations of spinal disease , peripheral arthritis and enthesitis , and to evaluate the effectiveness of adalimumab in a large cohort of patients with AS in relation to the presence or absence of psoriasis . METHODS Patients aged > or = 18 years with active AS were enrolled in an open-label study of adalimumab 40 mg every other week . Clinical symptoms were measured at baseline and Week 12 using st and ard assessment criteria . Differences between patients with and those without psoriasis were assessed . The relationship between changes in skin and AS symptoms was also analysed . RESULTS Of 1250 patients with AS who were enrolled in the study , 148 ( 11.8 % ) had a history of psoriasis , including 108 patients with current ( active ) psoriasis at entry . Baseline disease characteristics , including spinal structural damage , peripheral arthritis ( > or = 1 swollen joints ) and enthesitis ( > or = 1 inflamed entheses ) , were similar in both groups . At Week 12 , Assessment of SpondyloArthritis international Society 40 % response was achieved by 46.7 and 54.7 % and Bath AS Disease Activity Index 50 % response by 58.6 and 57.0 % of patients with and without psoriasis , respectively . Median changes in swollen joint scores and Maastricht AS Enthesitis Scores were similar in both groups . Skin changes during adalimumab treatment in AS patients with a history of psoriasis did not correlate with changes in AS symptoms . CONCLUSIONS The presence of psoriasis had no influence on the other clinical manifestations of patients with AS . Treatment with adalimumab markedly improved axial disease , peripheral arthritis and enthesitis , regardless of history of psoriasis [18006539] OBJECTIVE To evaluate the role of MRI in predicting a Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI ) improvement of at least 50 % ( BASDAI 50 ) upon anti-tumour necrosis factor ( TNF ) therapy of active ankylosing spondylitis ( AS ) . METHODS MRIs from patients with active AS who participated in r and omised controlled trials were analysed with respect to presence and extent of active inflammatory lesions as detected in the spine ( n = 46 ) , sacroiliac ( SI ) joints ( n = 42 ) and both sites ( n = 26 ) . Univariate and multivariate logistic regression analyses were applied to evaluate MRI and clinical data in predicting a BASDAI 50 response . RESULTS The Berlin MRI spine score ( odds ratio ( OR ) 1.16 , 95 % CI 1.02 to 1.33 ) and disease duration ( OR 0.9 , 95 % CI 0.63 to 0.97 ) were statistically significant predictors of a BASDAI 50 response using regression analysis while there was only a trend for C-reactive protein ( CRP ) . The likelihood ratio ( LR ) for achievement of BASDAI 50 was increased in patients with a Berlin MRI spine score > /=11 ( LR 6.7 ) , disease duration < 10 years ( LR 4.2 ) and CRP > /=40 mg/litre ( LR 3.4 ) . All patients with two or three of these predictors improved clinical ly ( as assessed by BASDAI ) by at least 45 % . Disease duration > 20 years , normal CRP and no active inflammatory lesion in the spine were highly predictive of not achieving BASDAI 50 . A trend was only found for the MRI score of SI joints to be predictive . CONCLUSIONS Widespread inflammation in the spine as detected by MRI contributes to predicting a BASDAI 50 response in active patients with AS treated with anti-TNF agents [18975305] OBJECTIVE To evaluate the efficacy and safety of golimumab in patients with ankylosing spondylitis ( AS ) in the GO-RAISE study . METHODS Patients with active AS , a Bath AS Disease Activity Index ( BASDAI ) score > or = 4 , and a back pain score of > or = 4 were r and omly assigned in a 1.8:1.8:1 ratio to receive subcutaneous injections of golimumab ( 50 mg or 100 mg ) or placebo every 4 weeks . The primary end point was the proportion of patients with at least 20 % improvement in the ASsessment in AS ( ASAS20 ) criteria at week 14 . RESULTS At r and omization , 138 , 140 , and 78 patients were assigned to the 50-mg , 100-mg , and placebo groups , respectively . After 14 weeks , 59.4 % , 60.0 % , and 21.8 % of patients , respectively , were ASAS20 responders ( P < 0.001 ) . A 40 % improvement in the ASAS criteria at week 24 occurred in 43.5 % , 54.3 % , and 15.4 % of patients , respectively . Patients receiving golimumab also showed significant improvement in the physical and mental component summary scores of the Short Form 36 Health Survey , the Jenkins Sleep Evaluation Question naire score , the BASDAI score , and the Bath AS Functional Index score , but not the Bath AS Metrology Index score . Through week 24 , 85.6 % of golimumab-treated patients and 76.6 % of patients in the placebo group had > or = 1 adverse event , and 5.4 % and 6.5 % of patients , respectively , had > or = 1 serious adverse event . Eight golimumab-treated patients and 1 placebo-treated patient had markedly abnormal liver enzyme values ( > or = 100 % increase from baseline and a value > 150 IU/liter ) , which were transient . CONCLUSION Golimumab was effective and well tolerated in a large cohort of patients with AS during a 24-week study period [15037444] BACKGROUND TNFalpha blockers have been shown to be highly efficacious in patients with active ankylosing spondylitis ( AS ) . OBJECTIVE To identify parameters predicting the clinical response to TNF blockers in AS . METHODS Patients with active AS participated in two placebo controlled , r and omised trials conducted in Germany with infliximab ( n = 69 ) and etanercept ( n = 30 ) , respectively . For inclusion in either trial patients had to have high disease activity ( BASDAI > or=4 ) and a spinal pain score ( numerical rating scale 0 - 10 ) > or=4 despite treatment with NSAIDs . A major clinical response was defined as a 50 % improvement of the initial BASDAI ( BASDAI 50 ) after 12 weeks ' treatment with active drug . Logistic regression likelihood ratio tests ( univariate and multivariate ) , Student 's t test , and chi(2 ) tests were performed . RESULTS Univariate analysis showed the following to be predictors of a major response ( BASDAI 50 ) to treatment : shorter disease duration ( p = 0.003 ) ; lower BASFI ( p = 0.007 ) ; younger age ( p = 0.009 ) ; raised ESR ( p = 0.033 ) ; raised CRP ( p = 0.035 ) . After adjustment for disease duration , BASFI , ESR , and CRP , but not age , remained significantly associated . After adjustment for disease duration and for BASFI , ESR , CRP , and in addition , a higher BASDAI were significantly associated with response . The best multivariate model built by stepwise regression contained the covariables disease duration , BASFI , BASDAI , and CRP . CONCLUSION A shorter disease duration , younger age , and a lower BASFI are predictors of a major clinical response to TNF blockers in active AS . Raised CRP and a higher BASDAI may also be valuable predictors . These data need to be confirmed in further studies [19273449] Objective . We evaluated the effectiveness and safety of adalimumab in a large cohort of patients with active ankylosing spondylitis ( AS ) and identified clinical predictors of good clinical response . Methods . Patients with active AS [ Bath AS Disease Activity Index ( BASDAI ) ≥4 ] received adalimumab 40 mg every other week in addition to their st and ard antirheumatic therapies in a multinational 12-week , open-label study . We used 3 definitions of good clinical response : 50 % improvement in the BASDAI ( BASDAI = 50 ) , 40 % improvement in the ASsessment s of SpondyloArthritis International Society criteria ( ASAS40 ) , or ASAS partial remission . Response predictors were determined by logistic regression with backward elimination ( selection level 5 % ) . Results . Of 1250 patients , 1159 ( 92.7 % ) completed 12 weeks of adalimumab treatment . At Week 12 , 57.2 % of patients achieved BASDAI 50 , 53.7 % achieved ASAS40 , and 27.7 % achieved ASAS partial remission . Important predictors of good clinical response ( BASDAI 50 , ASAS40 , and partial remission ) were younger age ( p < 0.001 ) , and greater C-reactive protein ( CRP ) concentration ( p ≤ 0.001 ) , HLA-B27 positivity ( p ≤ 0.01 ) , and tumor necrosis factor ( TNF ) antagonist naivety ( p < 0.001 ) . Conclusion . Adalimumab was effective in this large cohort of patients with AS , with more than half of patients achieving a BASDAI 50 or ASAS40 response and more than a quarter of patients reaching partial remission at Week 12.Younger age , greater CRP concentrations , HLA-B27 positivity , and TNF antagonist naivety were strongly associated with BASDAI 50 , ASAS40 , and partial remission responses . Clinical Trials.gov identifier : NCT00478660 [22806399] OBJECTIVE To evaluate the efficacy and safety of apremilast , a novel , orally available small molecule that specifically targets phosphodiesterase 4 , in the treatment of active psoriatic arthritis ( PsA ) . METHODS This phase II , multicenter , r and omized , double-blind , placebo-controlled study included the following : a 12-week treatment phase , with patients receiving placebo , apremilast 20 mg twice per day , or apremilast 40 mg once per day ; a 12-week treatment-extension phase , with patients in the placebo group re-r and omized to receive apremilast ; and a 4-week observational phase after treatment cessation . The primary end point was the proportion of patients achieving the American College of Rheumatology criteria for 20 % improvement ( ACR20 ) at week 12 . Safety assessment s included adverse events ( AEs ) , physical examinations , vital signs , laboratory parameters , and electrocardiograms . RESULTS Of the 204 patients with PsA who were r and omized to a treatment group , 165 completed the treatment phase . At the end of the treatment phase ( week 12 ) , 43.5 % of patients receiving apremilast 20 mg twice per day ( P < 0.001 ) and 35.8 % of those receiving 40 mg once per day ( P = 0.002 ) achieved an ACR20 response , compared with 11.8 % of those receiving placebo . At the end of the treatment-extension phase ( week 24 ) , > 40 % of patients in each group ( patients receiving apremilast 20 mg twice per day , patients receiving apremilast 40 mg once per day , and patients in the placebo group re-r and omized to receive apremilast ) achieved the ACR20 level of improvement . Most patients in the treatment phase ( 84.3 % ) and treatment-extension phase ( 68.3 % ) reported ≥ 1 AE . Diarrhea , headache , nausea , fatigue , and nasopharyngitis were reported most frequently ; most events were mild or moderate . No clinical ly relevant laboratory or electrocardiographic abnormalities were reported . CONCLUSION Treatment with apremilast at a dosage of 20 mg twice per day or 40 mg once per day demonstrated efficacy in comparison with placebo and was generally well tolerated in patients with active PsA. The balance of efficacy , tolerability , and safety supports further study of apremilast in [18576337] OBJECTIVE To evaluate the efficacy and safety of the tumor necrosis factor ( TNF ) antagonist adalimumab in patients with axial spondylarthritis ( SpA ) without radiographically defined sacroiliitis refractory to conventional treatment . METHODS Patients with active axial SpA ( n = 46 ) were r and omized to receive placebo or adalimumab at a dosage of 40 mg subcutaneously every other week for 12 weeks , followed by an open-label extension that continued up to week 52 . The diagnosis of axial SpA required the presence of 3 of 6 diagnostic criteria , including 2 of the following 3 criteria : inflammatory back pain , HLA-B27 positivity , or acute inflammation of the spine or sacroiliac joints on magnetic resonance imaging , in the absence of radiographic evidence of sacroiliitis . The primary end point was a 40 % response according to the improvement criteria of the Assessment of SpondyloArthritis international Society ( ASAS40 ) . RESULTS All 46 patients ( 22 receiving adalimumab and 24 receiving placebo ) completed the 12-week trial ; 38 patients completed the extension period to week 52 . At week 12 , an ASAS40 response was achieved by 54.5 % of the adalimumab-treated patients , as compared with 12.5 % of the placebo-treated patients ( P = 0.004 ) . After switching to adalimumab , a similar degree of efficacy was also achieved by the patients who were initially treated with placebo . Efficacy was maintained in all patients until week 52 . Young age at study entry and an elevated C-reactive protein concentration were the best predictors of achieving an ASAS40 response . Serious adverse events occurred in 5 patients , none of which was related to the study drug . CONCLUSION Adalimumab is the first TNF antagonist to demonstrate good clinical efficacy and safety in patients with axial SpA without radiographically defined sacroiliitis [17644547] Background : The use of tumour necrosis factor ( TNF ) blocking agents in psoriatic arthritis ( PsA ) is increasing , and the SSATG register has followed patients with PsA for more than 5 years . The aim of the present work therefore was to present efficacy and tolerability data of TNF-blocking agents on PsA in clinical practice , and to study potential predictors for drug survival ( the length of time a patient continues to take a particular drug ) . Material s and methods : Patients ( n = 261 ) with active PsA , starting anti-TNF therapy for the first time in southern Sweden , were included . Basal characteristics , disease activity measures , and termination reason for blockers were prospect ively collected during the period April 1999 to September 2006 . Cox proportional hazard models were used to investigate predictors for treatment termination . Results : Overall , response rates at 3–12 months for global visual analogue scale ( VASglobal50 ) and pain VAS ( VASpain50 ) were about 50 % , whereas response rates for European League Against Rheumatism ( EULAR ) scoring “ overall ” and EULAR “ good ” were around 75 % and 55 % , respectively . Concomitant methotrexate ( MTX ) ( hazard ratio ( HR ) 0.64 , 95 % CI 0.39–0.95 , p = 0.03 ) , etanercept ( HR 0.49 , 95 % CI 0.28–0.86 , p = 0.01 ) , and high C-reactive protein ( CRP ) levels ( HR 0.77 , 95 % CI 0.61–0.97 , p = 0.03 ) at treatment initiation were associated with better overall drug survival . The improved drug survival of concomitant MTX appeared to be related to significantly fewer dropouts because of adverse events ( HR = 0.24 ( 0.11–0.52 ) , p<0.01 ) . The blockers were well tolerated with a rate of serious adverse events of 5–6 % per year . No unexpected serious adverse events were observed . Conclusion : Concomitant MTX and high CRP levels are associated with treatment continuation of anti-TNF therapy in patients with PsA regardless of joint distribution . The positive effect of MTX was primarily linked to fewer dropouts because of adverse events [21632677] Objective . To investigate whether level of serum matrix metalloproteinase-3 ( MMP-3 ) can serve as a biomarker for monitoring and predicting response to etanercept treatment in patients with ankylosing spondylitis ( AS ) in daily clinical practice . Methods . Ninety-two consecutive AS out patients with active disease who started etanercept treatment were included in this longitudinal observational study . Clinical data were collected prospect ively at baseline and after 3 and 12 months of treatment . At the same timepoints , serum MMP-3 levels were measured retrospectively by ELISA . Results . Since baseline serum MMP-3 levels were significantly higher in male compared to female patients with AS , data analysis was split for gender . Changes in serum MMP-3 levels after etanercept treatment correlated positively with changes in clinical assessment s of disease activity and physical function in both male and female patients . Receiver operating characteristic analysis in male patients showed that baseline serum MMP-3 levels had poor accuracy ( AUC < 0.7 ) to discriminate between Assessment s in Ankylosing Spondylitis 20 ( ASAS20 ) or ASAS40 responders and nonresponders after 3 or 12 months of treatment . The accuracy of change in serum MMP-3 levels from baseline to 3 months in predicting response after 3 or 12 months of treatment was poor for ASAS40 ( AUC < 0.7 ) or moderate for ASAS20 ( AUC = 0.752 and 0.744 , respectively ) , and was not superior to the accuracy of change in the currently used objective biomarkers , erythrocyte sedimentation rate and C-reactive protein . Conclusion . Although significant changes in serum MMP-3 levels were found after etanercept treatment , data analysis indicates that serum MMP-3 levels are not very useful for monitoring and predicting response to etanercept treatment in patients with AS in daily clinical practice [20511613] Objectives To use prospect ively registered data from the Danish nationwide rheumatological data base ( DANBIO ) to describe disease activity , clinical response , treatment duration and predictors of drug survival ( ie , number of days individual patients maintained treatment ) and clinical response among patients with ankylosing spondylitis ( AS ) receiving their first treatment series with a tumour necrosis factor α ( TNFα ) inhibitor . Methods 842 TNFα inhibitor naive patients with AS were identified in DANBIO . Clinical response , drug survival and predictors thereof were investigated . ‘ Clinical response ’ was defined as a 50 % or 20 mm reduction in Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI ) within 6 months compared with baseline . Achievement of a BASDAI < 40 mm within 6 months was used as a second response parameter . Results 603 patients ( 72 % ) were men , disease duration 5 ( 1–13 ) years ( median ( IQR ) , age 41 ( 32–50 ) years . 445 ( 53 % ) received infliximab , 247 ( 29 % ) adalimumab and 150 ( 18 % ) etanercept . Parameters at baseline/1-year follow-up were : C-reactive protein ( CRP ) : 14 (7–27)/5 ( 2–10 ) mg/l , BASDAI 59 (44–72)/21 ( 8–39 ) mm , Bath Ankylosing Spondylitis Functional Index ( BASFI ) 50 (34–67)/24 ( 9–45 ) mm , Bath Ankylosing Spondylitis Metrology Index 40 (20–50)/20 ( 10–40 ) mm . Within 6 months , 407/644 patients ( 63 % ) achieved a clinical response . Median drug survival was 4.3 years . One- and 2-year survival rates were 74 % and 63 % , respectively . Baseline characteristics associated with longer drug survival were male gender , CRP > 14 mg/l and low visual analogue scale fatigue ( Cox regression analysis ) . Age , TNFα inhibitor and methotrexate use were insignificant . CRP > 14 mg/l , lower BASFI and younger age at baseline was associated with clinical response and achievement of a BASDAI < 40 mm ( logistic regression analysis ) . Conclusion TNFα inhibitors provide a rapid and sustained decrease of disease activity among patients with AS in clinical practice . Factors associated with continued treatment , clinical response and achievement of a BASDAI < 40 mm were identified [21551511] Objectives To investigate the relation between ankylosing spondylitis disease activity score ( ASDAS ) , Bath ankylosing spondylitis disease activity index ( BASDAI ) and treatment response and biomarkers of inflammation ( C-reactive protein ( CRP ) , interleukin-6 ( IL-6 ) , YKL-40 ) , angiogenesis ( vascular endothelial growth factor ( VEGF ) ) , cartilage ( C-terminal crosslinking telopeptide of type II collagen ( CTX-II ) , matrix metalloproteinase-3 ( MMP-3 ) , total aggrecan , cartilage oligomeric matrix protein ) and bone ( C-terminal crosslinking telopeptide of type I collagen , osteocalcin ) turnover in 60 patients with axial spondyloarthritis initiating tumour necrosis factor alpha ( TNFα ) inhibitor therapy . Methods ASDAS ( CRP-based ) , BASDAI and biomarkers were determined before and seven times during 46 weeks of TNFα inhibitor therapy . Results Very high ASDAS were associated with high levels of inflammatory biomarkers , while high BASDAI were not related to any biomarkers . Mixed modeling demonstrated significant longitudinal associations between ASDAS and IL-6 , VEGF , MMP-3 and osteocalcin and between BASDAI and CRP , IL-6 and VEGF . Major improvement in ASDAS was associated with larger percentage decreases in biomarkers of inflammation , angiogenesis , MMP-3 and increases in aggrecan and osteocalcin . BASDAI response was associated with larger decreases in CRP and IL-6 . Biomarkers with moderate/high differences in responsiveness for major versus no/ clinical ly important improvement in ASDAS were CRP , IL-6 , VEGF , aggrecan and osteocalcin , and VEGF and CTX-II for BASDAI response versus non-response . Conclusion Levels and changes of 10 biomarkers in patients with axial spondyloarthritis during anti-TNFα therapy were documented . Construct validity and responsiveness of IL-6 , VEGF , MMP-3 , total aggrecan and osteocalcin were demonstrated . ASDAS was more associated with these biomarkers than BASDAI , and may better reflect the inflammatory disease processes . Clinical Trials.gov identifier NCT00133315 [12794835] OBJECTIVE There is increasing evidence that tumor necrosis factor alpha ( TNFalpha ) is central ly involved in the pathogenesis of ankylosing spondylitis ( AS ) and other spondylarthritides . This study was design ed to investigate the efficacy of anti-TNFalpha therapy with etanercept , a 75-kd receptor fusion protein , in active AS . METHODS This multicenter trial had 2 phases : an initial placebo-controlled period of 6 weeks ' duration and an observational phase lasting 24 weeks . Thirty patients with active AS were included . They were r and omized into 2 groups , which received either etanercept ( 25 mg twice weekly ) ( n = 14 ) or placebo ( n = 16 ) for 6 weeks . Then both groups were treated with etanercept . Nonsteroidal antiinflammatory drug ( NSAID ) treatment could be continued , but disease-modifying antirheumatic drugs ( DMARDs ) and steroids had to be withdrawn prior to the study . All patients received etanercept for a total of 12 weeks and were followed up for at least 24 weeks . The Bath AS Disease Activity Index ( BASDAI ) , Bath AS Functional Index , Bath AS Metrology Index , pain level on a numeric rating scale , quality of life by the Short Form 36 , and C-reactive protein ( CRP ) level were assessed . The primary outcome parameter was a > or=50 % improvement in the BASDAI . RESULTS Treatment with etanercept result ed in at least a 50 % regression of disease activity in 57 % of these patients at week 6 , versus 6 % of the placebo-treated patients ( P = 0.004 ) . After the placebo-treated patients switched to etanercept , 56 % improved . The mean + /- SD BASDAI improved from 6.5 + /- 1.2 at baseline to 3.5 + /- 1.9 at week 6 in the etanercept group , with no improvement in the placebo group ( P = 0.003 between groups ) . Similarly , pain , function , mobility , and quality of life improved with etanercept but not with placebo at week 6 ( P < 0.05 ) . Mean CRP levels decreased significantly with etanercept but not with placebo ( P = 0.001 ) . There was ongoing improvement in all parameters in both groups until week 12 and week 18 , respectively ( i.e. , throughout the period of etanercept treatment ) . Disease relapses occurred a mean + /- SD of 6.2 + /- 3.0 weeks after cessation of etanercept . No severe adverse events , including major infections , were observed during the trial . CONCLUSION This study shows that on a short-term basis ( 3 months ) , treatment with etanercept is clearly efficacious in patients with active AS who are receiving NSAID therapy but not DMARDs or steroids . After cessation of therapy , almost all patients experienced a relapse within a few weeks . Thus , it seems probable that etanercept must be administered continuously in most AS patients to achieve permanent inhibition of the inflammatory process [19333944] OBJECTIVE To assess the efficacy and safety of golimumab in patients with active psoriatic arthritis ( PsA ) . METHODS Adult patients with PsA who had at least 3 swollen and 3 tender joints and active psoriasis were r and omly assigned to receive subcutaneous injections of placebo ( n = 113 ) , golimumab 50 mg ( n = 146 ) , or golimumab 100 mg ( n = 146 ) every 4 weeks through week 20 . Efficacy assessment s through week 24 included the American College of Rheumatology 20 % improvement criteria ( ACR20 ) , the Psoriasis Area and Severity Index ( PASI ) in patients in whom at least 3 % of the body surface area was affected by psoriasis at baseline , the Short Form 36 Health Survey ( SF-36 ) , the disability index of the Health Assessment Question naire ( HAQ ) , the Nail Psoriasis Severity Index ( NAPSI ) , the physician 's global assessment of psoriatic nail disease , and enthesitis ( using the PsA-modified Maastricht Ankylosing Spondylitis Enthesitis Score [ MASES ] index ) . RESULTS At week 14 , 48 % of all patients receiving golimumab , 51 % of patients receiving golimumab 50 mg , and 45 % of patients receiving golimumab 100 mg achieved an ACR20 response ( the primary end point ) , compared with 9 % of patients receiving placebo ( P < 0.001 for all comparisons ) . Among the 74 % of patients in whom at least 3 % of the body surface area was affected by psoriasis at baseline , 40 % of those in the golimumab 50 mg group and 58 % of those in the golimumab 100 mg group had at least 75 % improvement in the PASI at week 14 ( major secondary end point ) , compared with 3 % of placebo-treated patients ( P < 0.001 for both doses ) . Significant improvement was observed for other major secondary end points ( the HAQ and the SF-36 ) , the NAPSI , the physician 's global assessment of psoriatric nail disease , and the PsA-modified MASES index in each golimumab group compared with placebo . This efficacy was maintained through week 24 . Golimumab was generally well tolerated . CONCLUSION Treatment with golimumab at doses of 50 mg and 100 mg significantly improved active PsA and associated skin and nail psoriasis through week 24 [21885499] Objective . To assess the efficacy and safety of adalimumab or cyclosporine ( CYC ) as monotherapy or combination therapy for patients with active psoriatic arthritis ( PsA ) , despite methotrexate ( MTX ) therapy . Methods . A prospect i ve 12-month , nonr and omized , unblinded clinical trial of 57 , 58 , and 55 patients who received CYC ( 2.5–3.75 mg/kg/day ) , adalimumab ( 40 mg every other week ) , or combination , respectively . Lowering of concomitant nonsteroidal antiinflammatory drugs ( NSAID ) and corticosteroids and reductions of adalimumab and /or CYC doses in responding patients were not restricted . Results . Mean numbers of tender/swollen joints at baseline were 9.7/6.7 in CYC-treated , 13.0/7.8 in adalimumab-treated , and 14.5/9.4 in combination-treated patients , indicating lesser disease severity of patients assigned to the first group . The Psoriatic Arthritis Response Criteria at 12 months were met by 65 % of CYC-treated ( p = 0.0003 in favor of combination treatment ) , 85 % of adalimumab-treated ( p = 0.15 vs combination treatment ) , and 95 % of combination-treated patients , while the American College of Rheumatology-50 response rates were 36 % , 69 % , and 87 % , respectively ( p < 0.0001 and p = 0.03 in favor of combination treatment ) . A significantly greater mean improvement in Health Assessment Question naire Disability Index was achieved by combination treatment ( −1.11 ) vs CYC ( −0.41 ) or adalimumab alone ( −0.85 ) . Combination therapy significantly improved Psoriasis Area and Severity Index-50 response rates beyond adalimumab , but not beyond the effect of CYC monotherapy . Doses of NSAID and corticosteroids were reduced in combination-treated patients ; CYC doses and frequency of adalimumab injections were also reduced in 51 % and 10 % of them , respectively . No new safety signals were observed . Conclusion . The combination of adalimumab and CYC is safe and seemed to produce major improvement in both clinical and serological variables in patients with severely active PsA and inadequate response to MTX [16802350] OBJECTIVE To evaluate the safety and efficacy of adalimumab , a fully human recombinant IgG1 monoclonal antibody that specifically targets human tumor necrosis factor , in patients with active ankylosing spondylitis ( AS ) . METHODS This was a multicenter , r and omized ( 2:1 ratio ) , double-blind , placebo-controlled study to evaluate a subcutaneous injection of adalimumab , 40 mg every other week , compared with placebo for 24 weeks . The primary efficacy end point was the percentage of patients with a 20 % response according to the ASsessment in Ankylosing Spondylitis International Working Group criteria for improvement ( ASAS20 ) at week 12 . Secondary outcome measures included the ASAS20 at week 24 and multiple measures of disease activity , spinal mobility , and function , as well as ASAS partial remission . RESULTS At week 12 , 58.2 % of adalimumab-treated patients ( 121 of 208 ) achieved an ASAS20 response , compared with 20.6 % of placebo-treated patients ( 22 of 107 ) ( P < 0.001 ) . More patients in the adalimumab group ( 45.2 % [ 94 of 208 ] ) than in the placebo group ( 15.9 % [ 17 of 107 ] ) had at least a 50 % improvement in the Bath Ankylosing Spondylitis Disease Activity Index at week 12 ( P < 0.001 ) . Significant improvements in the ASAS40 response and the response according to the ASAS5/6 criteria at weeks 12 and 24 were also demonstrated ( P < 0.001 ) . Partial remission was achieved by more adalimumab-treated patients than placebo-treated patients ( 22.1 % versus 5.6 % ; P < 0.001 ) . Adalimumab-treated patients reported more adverse events ( 75.0 % versus 59.8 % of placebo-treated patients ; P < 0.05 ) , but there was no statistically significant difference in the incidence of infections . Most adverse events were mild or moderate in severity . CONCLUSION Adalimumab was well-tolerated during the 24-week study period and was associated with a significant and sustained reduction in the signs and symptoms of active AS [21279995] OBJECTIVE To investigate disease activity , treatment response , and drug survival , and predictors thereof , among Danish patients with psoriatic arthritis ( PsA ) receiving their first treatment series with a tumor necrosis factor α ( TNFα ) inhibitor . METHODS Patients with PsA were identified from a prospect i ve nationwide rheumatologic data base , the Danish biologics registry DANBIO , using data registered from 2000 - 2009 . Information was obtained on the patients ' clinical response to anti-TNFα treatment ( defined as achievement of the American College of Rheumatology 20 % [ ACR20 ] , ACR50 , and ACR70 improvement criteria or a European League Against Rheumatism [ EULAR ] good response at least once during the first 6 months of treatment ) and duration and rate of drug adherence ( referred to as drug survival ) , as well as predictors thereof . RESULTS Of 764 patients with PsA , 320 received adalimumab , 260 infliximab , and 184 etanercept . Median drug survival was 2.9 years , and 1-year and 2-year drug survival rates were 70 % and 57 % , respectively . Clinical parameters that showed improvement over 6 months were the C-reactive protein ( CRP ) level , Health Assessment Question naire score , and 28-joint Disease Activity Score . Male sex , CRP level > 10 mg/liter , concomitant methotrexate use , and low patient health visual analog scale score at baseline were associated with longer drug survival . Improvement was achieved by 59 % , 45 % , 24 % , and 54 % of patients according to the ACR20 , ACR50 , ACR70 response criteria and EULAR good response , respectively . A CRP level > 10 mg/liter was predictive of the improvement responses ( odds ratio [ OR ] 2.6 for ACR20 , OR 3.0 for ACR50 , OR 3.6 for ACR70 , and OR 2.2 for EULAR good response ) . CONCLUSION In these patients with PsA treated with their first TNFα inhibitor in clinical practice , high drug adherence and responder rates were observed . Moreover , increased levels of CRP at baseline were associated with both good treatment responses and continued treatment , which may be of clinical value in selecting the patients most likely to benefit from treatment with TNFα inhibitors

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### Context: [3888622] Objectives To evaluate the efficacy and safety of certolizumab pegol ( CZP ) after 24 weeks in RAPID-PsA ( NCT01087788 ) , an ongoing Phase 3 trial in patients with psoriatic arthritis ( PsA ) . Methods Patients were r and omised 1:1:1 to placebo , 200 mg CZP every 2 weeks ( Q2W ) or 400 mg CZP every 4 weeks ( Q4W ) . Patients could have had exposure to one previous tumour necrosis factor ( TNF ) inhibitor therapy . Primary endpoints were American College of Rheumatology 20 % ( ACR20 ) response at week 12 and modified Total Sharp Score change from baseline at week 24 . Secondary endpoints included ; Psoriatic Arthritis Response Criteria ( PsARC ) score , Health Assessment Question naire Disability Index ( HAQ-DI ) , Psoriasis Area and Severity Index , Leeds Enthesitis Index , Leeds Dactylitis Index , and Modified Nail Psoriasis Severity Index . Results Of 409 patients r and omised , 368 completed 24 weeks of treatment . ACR20 response was significantly greater in CZP 200 mg Q2W and 400 mg Q4W-treated patients than placebo ( 58.0 % and 51.9 % vs 24.3 % ( p<0.001 ) ) at week 12 , with improvements observed by week 1 . There was a statistically significant improvement in physical function from baseline , measured by HAQ-DI in CZP patients compared with placebo ( −0.50 vs −0.19 , p<0.001 ) and more patients treated with CZP 200 mg Q2W and CZP 400 mg achieved an improvement in PsARC at week 24 than placebo ( 78.3 % and 77.0 % vs 33.1 % ( p<0.001 ) ) . Sustained improvements were observed in psoriatic skin involvement , enthesitis , dactylitis and nail disease . Higher ACR20 response with CZP was independent of prior TNF inhibitor exposure . No new safety signals were observed . Conclusions Rapid improvements in the signs and symptoms of PsA , including joints , skin , enthesitis , dactylitis and nail disease were observed across both CZP dosing regimens [2820265] Objective . Few data exist on the use of anti-TNF drugs for AS during routine clinical use in the UK . This report describes an improvement in Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI ) and Bath Ankylosing Spondylitis Functional Index ( BASFI ) after 6 months of therapy in 261 patients enrolled in a national prospect i ve observational register . Methods . The British Society for Rheumatology Biologics Register ( BSRBR ) recruited patients starting anti-TNF therapy for AS between 2002 and 2006 . Multivariable linear regression models were used to estimate the predictors of absolute improvement in BASDAI and BASFI at 6 months . Covariates included age , gender , disease duration , baseline BASDAI and BASFI , presence of raised inflammatory markers ( defined as twice the upper limit of normal ) and DMARD therapy . Results . The cohort was young ( median age 43 years ) and 82 % were males . Median baseline BASDAI was 7.6 and BASFI 7.9 . At 6 months , the mean improvements in BASDAI and BASFI were 3.6 and 2.6 U , respectively ; 52 % reached a BASDAI50 . Patients with raised inflammatory markers at the start of therapy had a 0.9-U ( 95 % CI 0.2 , 1.5 ) better improvement in BASDAI compared with those without . Lesser responses were seen in those with higher baseline BASFI scores . Women had a 1.1-U ( 95 % CI 0.3 , 2.0 ) greater improvement in BASFI at 6 months , as did those who were receiving concurrent DMARD therapy [ 0.9 U ( 95 % CI 0.2 , 1.7 ) ] . Conclusions . The majority of patients receiving anti-TNF therapy for AS during routine care demonstrated an improvement in disease activity . Raised inflammatory markers at the start of therapy predicted a greater improvement in BASDAI , identifying a group of patients who may be more responsive to anti-TNF therapies , although the results were not confined to this group [16549855] Prognosis studies are investigations of future events or the evaluation of associations between risk factors and health outcomes in population s of patients ( 1 ) . The results of such studies improve our underst and ing of the clinical course of a disease and assist clinicians in making informed decisions about how best to manage patients . Prognostic research also informs the design of intervention studies by helping define subgroups of patients who may benefit from a new treatment and by providing necessary information about the natural history of a disorder ( 2 ) . There has recently been a rapid increase in the use of systematic review methods to synthesize the evidence on research questions related to prognosis . It is essential that investigators conducting systematic review s thoroughly appraise the method ologic quality of included studies to be confident that a study 's design , conduct , analysis , and interpretation have adequately reduced the opportunity for bias ( 3 , 4 ) . Caution is warranted , however , because inclusion of method ologically weak studies can threaten the internal validity of a systematic review ( 4 ) . This follows abundant empirical evidence that inadequate attention to biases can cause invalid results and inferences ( 5 - 9 ) . However , there is limited consensus on how to appraise the quality of prognosis studies ( 1 ) . A useful framework to assess bias in such studies follows the basic principles of epidemiologic research ( 10 , 11 ) . We focus on 6 areas of potential bias : study participation , study attrition , prognostic factor measurement , confounding measurement and account , outcome measurement , and analysis . The main objectives of our review of review s are to describe methods used to assess the quality of prognosis studies and to describe how well current practice s assess potential biases . Our secondary objective is to develop recommendations to guide future quality appraisal , both within single studies of prognostic factors and within systematic review s of the evidence . We hope this work facilitates future discussion and research on biases in prognosis studies and systematic review s. Methods Literature Search and Study Selection We identified systematic review s of prognosis studies by search ing MEDLINE ( 1966 to October 2005 ) using the search strategy recommended by McKibbon and colleagues ( 12 ) . This strategy combines broad search terms for systematic review s ( systematic review .mp ; meta- analysis .mp ) and a sensitive search strategy for prognosis studies ( cohort , incidence , mortality , follow-up studies , prognos * , predict * , or course ) . We also search ed the reference lists of included review s and method ologic papers to identify other relevant publications . We restricted our search to English- language publications . One review er conducted the search and selected the studies . Systematic review s , defined as review s of published studies with a comprehensive search and systematic selection , were included if they assessed the method ologic quality of the included studies by using 1 or more explicit criteria . We excluded studies if they were meta-analyses of independent patient data only , if their primary goal was to investigate the effectiveness of an intervention or specific diagnostic or screening tests , or if they included studies that were not done on humans . Data Extraction and Synthesis Individual items included in the quality assessment of the systematic review s were recorded as they were reported in the publication ( that is , the information that would be available to readers and future review ers ) . We review ed journal Web sites and contacted the authors of the systematic review s for additional information when authors made such an offer in their original papers . When review s assessed different study design s by using different sets of quality items , we extracted only those items used to assess cohort studies . We constructed a comprehensive list of distinct items that the review s used to assess the quality of their included studies . The full text of each review was screened . All items used by the review authors to assess the quality of studies were extracted into a computerized spreadsheet by 1 review er . Two experienced review ers , a clinical epidemiologist and an epidemiologist , independently synthesized the quality items extracted from the prognosis review s to determine how well the systematic review s assessed potential biases . We did this in 3 steps : 1 ) identified distinct concepts or domains addressed by the quality items ; 2 ) grouped each extracted quality item into the appropriate domain or domains ; and 3 ) identified the domains necessary to assess potential biases in prognosis studies . We then used this information to assess how well the review s ' quality assessment included items from the domains necessary to assess potential biases . After completing each of the first 3 steps , the review ers met to attempt to reach a consensus . The consensus process involved each review er presenting his or her observations and results , followed by discussion and debate . A third review er was available in cases of persistent disagreement or uncertainty . In the first step , all domains addressed by the quality items were identified . The first review er iteratively and progressively defined the domains as items were extracted from the included review s. The second review er defined domains from a r and om list of all extracted quality items . Limited guidance was provided to the review ers so that their assessment s and definitions of domains would be independent . The review ers agreed on a final set of domains that adequately and completely defined all of the extracted items . In the second step , review ers independently grouped each extracted item into the appropriate domains . Review ers considered each extracted item by asking , What is each particular quality item addressing ? or What are the review 's authors getting at with the particular quality assessment item ? . Items were grouped into the domain or domains that best represented the concepts being addressed . For example , the extracted items at least 80 % of the group originally identified was located for follow-up and follow-up was sufficiently complete or does n't jeopardize validity were each independently classified by both review ers as assessing the domain completeness of follow-up adequate , whereas the extracted item quantification and description of all subjects lost to follow-up was classified as assessing the domain completeness of follow-up described . In the third step , we identified the domains necessary to assess potential biases . Each review er considered the ability of the identified domains to adequately address , at least in part , 1 of the following 6 potential biases : 1 ) study participation , 2 ) study attrition , 3 ) prognostic factor measurement , 4 ) confounding measurement and account , 5 ) outcome measurement , and 6 ) analysis . Domains were considered to adequately address part of the framework if information garnered from that domain would inform the assessment of potential bias . For example , both review ers judged that the identified domain study population represents source population or population of interest assessed potential bias in a prognosis study , whereas the domain research question definition did not , although the latter is an important consideration in assessing the inclusion of studies in a systematic review . Finally , on the basis of our previous ratings , we looked at whether each review included items from the domains necessary to assess the 6 potential biases . We calculated the frequency of systematic review s by assessing each potential bias and the number of review s that adequately assessed bias overall . From this systematic synthesis , we developed recommendations for improving quality appraisal in future systematic review s of prognosis studies . We used Microsoft Access and Excel 2002 ( Microsoft Corp. , Redmond , Washington ) for data management and SAS for Windows , version 9.1 ( SAS Institute , Inc. , Cary , North Carolina ) for descriptive statistics . Role of the Funding Sources The funding sources , the Canadian Institutes of Health Research , the Canadian Chiropractic Research Foundation , the Ontario Chiropractic Association , and the Ontario Ministry of Health and Long Term Care , did not have a role in the collection , analysis , or interpretation of the data or in the decision to su bmi t the manuscript for publication . Results We identified 1384 potentially relevant articles . Figure 1 shows a flow chart of studies that were included and excluded . Figure 2 shows the number of review s identified by year of publication . We excluded 131 systematic review s of prognosis studies that did not seem to include any quality assessment of the included studies ; this represented 44 % of prognosis review s. We included 163 review s of prognosis studies in our analysis ( 13 - 175 ) . The most common topics were cancer ( 15 % ) , musculoskeletal disorders and rheumatology ( 13 % ) , cardiovascular ( 10 % ) , neurology ( 10 % ) , and obstetrics ( 10 % ) . Other review s included a wide range of health and health care topics . Sixty-three percent of the review s investigated the association between a specific prognostic factor and a particular outcome ; the remainder investigated multiple prognostic factors or models . The number of primary studies included in each systematic review ranged from 3 to 167 ( median , 18 [ interquartile range , 12 to 31 ] ) . A complete description of the included review s is available from the authors on request . Figure 1 . Flow diagram of inclusion and exclusion criteria of systematic review s. Figure 2 . Number of systematic review s of prognosis studies identified over time . Quality Items One hundred fifty-three review s provided adequate detail to allow extraction of quality items . Eight hundred eighty-two distinct quality items were extracted from the review s. Most review s developed their own set of quality items , with only a few applying criteria from previous review s. Most quality items [3551220] Objective To determine serum biomarker associations with clinical response to golimumab treatment in patients with psoriatic arthritis ( PsA ) . Methods GO – REVEAL was a r and omised , placebo-controlled study of golimumab in patients with active PsA. Sample s were collected from 100 patients at baseline , week 4 and week 14 , and analysed for serum-based biomarkers and protein profiling ( total 92 markers ) ; data were correlated with clinical measures at week 14 . Results Serum levels of a subset of proteins ( apolipoprotein C III , ENRAGE , IL-16 , myeloperoxidase , vascular endothelial growth factor , pyridinoline , matrix metalloproteinase 3 , C-reactive protein ( CRP ) , carcinoembryonic antigen , intercellular adhesion molecule 1 and macrophage inflammatory protein 1α ) at baseline or week 4 were strongly associated with American College of Rheumatology 20 % improvement ( ACR20 ) response and /or disease activity score in 28 joints ( DAS28 ) at week 14 . A smaller subset of proteins was significantly associated with a 75 % improvement in the psoriasis area and severity index score ( PASI75 ) at week 14 , ( adiponectin , apolipoprotein CIII , serum glutamic oxaloacetic transaminase , and tumour necrosis factor α ) . Subsets of proteins were identified as potentially predictive of clinical response for each of the clinical measures , and the power of these biomarker panels to predict clinical response to golimumab treatment was stronger than for CRP alone . Conclusions This analysis provides insight into several panels of markers that may have utility in identifying PsA patients likely to have ACR20 , DAS28 , or PASI75 responses following golimumab treatment [3218893] Introduction Methotrexate ( MTX ) has been shown to modify infliximab pharmacokinetics in rheumatoid arthritis . However , its combination with infliximab in the treatment of ankylosing spondylitis ( AS ) is not recommended . The objective of this study was to examine the influence of MTX on infliximab exposure in patients with AS . Methods Patients with AS patients who had predominantly axial symptoms were r and omised to receive infliximab alone ( infusions of 5 mg/kg at weeks 0 , 2 , 6 , 12 and 18 ) or infliximab combined with MTX ( 10 mg/week ) . Infliximab concentrations were measured before and 2 hours after each infusion and at 1 , 3 , 4 , 5 , 8 , 10 , 14 and 18 weeks . We estimated individual cumulative area under the concentration versus time curves ( AUC ) for infliximab concentration between baseline and week 18 ( AUC0 - 18 ) . Clinical and laboratory evaluations were performed at each visit . The Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI ) score was the primary end point for clinical response . Results Twenty-six patients were included ( infliximab group : n = 12 , infliximab + MTX group : n = 14 ) , and 507 serum sample s were available for measurement of infliximab concentration . The two groups did not differ with regard to AUC0 - 18 or evolution of BASDAI scores and biomarkers of inflammation . Conclusions The combination of MTX and infliximab does not increase the exposure to infliximab over infliximab alone in patients with AS.Trial registration Clinical Trials.gov : [3823044] Abstract Rats transgenic for HLA-B27 and human β2microglobulin ( B27TR ) develop a multi-systemic disease resembling inflammatory bowel disease ( IBD ) and spondyloarthritis . TNFα has a crucial role in chronic inflammation . Our objective was to evaluate the effect of anti-TNFα treatment on spontaneous IBD in B27TR . Nine-week-old B27TR received monoclonal anti-TNFα or an isotypic IgG2a , k up to age of 18 weeks . A second group was monitored up to 18 weeks and then r and omly assigned to anti-TNFα or IgG2 a , k treatment . Each rat was monitored for clinical IBD manifestations . After sacrifice , the colon was examined for pathological changes . TNFα receptors ( TNF-R1 , TNF-R2 ) , Fas/Fas-L expression and apoptosis were evaluated . IgG2a , k-treated and untreated B27TR presented signs of IBD at 11 weeks , whereas in anti-TNFα-treated B27TR no IBD signs were detected . In the late treatment , IBD signs improved after 1 week . Histopathological analysis of IgG2a , k-treated B27TR colon showed inflammatory signs that were widely prevented by early anti-TNFα treatment . Late treatment did not significantly reduce inflammation . TNF-R1 was weakly expressed in intestinal epithelial cells of IgG2a , k-treated B27TR , while it was comparable to controls in anti-TNFα-treated animals . TNF-R2 immunopositivity was strongly evident in IgG2a , k-treated B27TR , whereas was absent in anti-TNFα-treated rats . RT-PCR confirmed these results . IgG2a , k-treated B27TR showed , at 18 weeks , few Fas-positive cells and an increase of Fas-L-positive cells . At 27 weeks , Fas-/Fas-L-positive cell number was significantly low . Anti-TNFα treatment increased Fas-L expression , whereas Fas increased only with the early treatment . TNFα blockade is effective in preventing inflammation in early phase of IBD , maintaining the homeostatic balance of apoptosis [19877087] OBJECTIVE To study the usefulness of erythrocyte sedimentation rate ( ESR ) , C-reactive protein ( CRP ) , and serum amyloid A ( SAA ) for response prediction and monitoring of anti-tumor necrosis factor ( anti-TNF ) treatment in ankylosing spondylitis ( AS ) patients . METHODS Patients were included consecutively before starting etanercept or infliximab treatment . ASsessment in Ankylosing Spondylitis ( ASAS ) response , defined as a 50 % improvement or an absolute improvement of 2 points of the Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI ; 0 - 10 scale ) , was assessed at 3 months . Inflammatory markers and the BASDAI were collected at baseline and 1 and 3 months . Longitudinal data analysis was performed to compare associations between inflammatory markers and the BASDAI over time by calculating st and ardized betas . Predictive values of baseline levels of inflammatory markers for ASAS response were calculated . RESULTS In total , 155 patients were included , of whom , after 3 months of treatment , 70 % in the etanercept cohort and 71 % in the infliximab cohort responded . All markers , notably SAA , decreased significantly ( P < 0.0001 ) . St and ardized betas were 0.49 for ESR , 0.43 for CRP , and 0.39 for SAA . Normal baseline levels of CRP and SAA were significantly associated with nonresponse . A combination of elevated CRP and SAA levels at baseline revealed the highest predictive value ( 81 % ) for ASAS response . CONCLUSION ESR , CRP , and SAA were significantly associated with the BASDAI over 3 months , and the association with ESR was the strongest . Elevated baseline CRP and SAA levels revealed the highest predictive value for response . Together , this study demonstrates that inflammatory markers , and notably CRP and SAA , may facilitate patient selection and monitoring of efficacy of anti-TNF treatment in AS , and could be added to response criteria [2911878] Introduction Since remission is now possible in psoriatic arthritis ( PsA ) we wished to examine remission rates in PsA patients following anti tumour necrosis factor alpha ( TNFα ) therapy and to examine possible predictors of response . Methods Analysis of a prospect i ve patient cohort attending a biologic clinic , between November 2004 and March 2008 , was performed prior to commencing therapy and at regular intervals . Baseline clinical characteristics including demographics , previous disease-modifying antirheumatic drug ( DMARD ) response , tender and swollen joint counts , early morning stiffness , pain visual analogue score , patient global assessment , C reactive protein ( CRP ) and health assessment question naire ( HAQ ) were collected . Results A total of 473 patients ( 152 PsA ; 321 rheumatoid arthritis ( RA ) ) were analyzed . At 12 months remission , defined according to the disease activity score using 28 joint count and CRP ( DAS28-CRP ) , was achieved in 58 % of PsA patients compared to 44 % of RA patients , significant improvement in outcome measures were noted in both groups ( P < 0.05 ) . Analysis of a subgroup of PsA and RA patients matched for DAS28-CRP at baseline also showed higher numbers of PsA patients achieving remission . Linear regression analysis identified the HAQ at baseline as the best predictor of remission in PsA patients ( P < 0.001 ) . Conclusions DAS28 remission is possible in PsA patients at one year following anti-TNF therapy , at higher rates than in RA patients and is predicted by baseline HAQ [3329231] Objective Identify serum biomarkers modulated by golimumab treatment and associated with clinical response in patients with ankylosing spondylitis ( AS ) . Methods Sera were collected at weeks 0 , 4 and 14 from 100 patients with active AS in the GO – RAISE study . Patients were r and omly assigned subcutaneous injections of placebo , golimumab 50 mg , or golimumab 100 mg every 4 weeks . Sample s were tested for select inflammatory , bone and cartilage markers , and protein profiling was also performed . Results Golimumab treatment result ed in significant decreases in several serum proteins at weeks 4 and 14 compared with placebo . Patients who achieved clinical response at week 14 , as assessed by a ≥20 % improvement in the Assessment in SpondyloArthitis international Society response criteria ( ASAS 20 ) , demonstrated a distinct biomarker profile with lower levels of acute phase reactants and inflammatory biomarkers compared with patients who did not . Notably , combinations of two or three biomarkers assessed at baseline were predictive of various clinical outcomes ( ASAS 20 , Bath ankylosing spondylitis disease activity index 50 or Bath ankylosing spondylitis functional index ) using a logistic regression analysis , and the overall predictive values for these combined biomarkers were greater than observed for C-reactive protein ( CRP ) alone . Conclusion Golimumab modulated acute phase reactants and inflammatory markers in patients with active AS . Specific combinations of biomarkers at baseline demonstrated a stronger prediction for clinical efficacy than CRP alone . These data provide insights into the mechanism of golimumab on inflammatory processes driving AS pathology , and may have utility in managing the treatment of patients with AS [17114188] Objective : To evaluate the efficacy and safety of infliximab through 1 year in patients with psoriatic arthritis ( PsA ) enrolled in the IMPACT 2 trial . Methods : In this double blind , placebo controlled , phase III study , 200 patients with active PsA were r and omised to receive infusions of infliximab 5 mg/kg or placebo at weeks 0 , 2 , 6 , and every 8 weeks thereafter through 1 year . Patients with persistent disease activity could enter early escape at week 16 , and all remaining placebo patients crossed over to infliximab at week 24 . Patients r and omised to infliximab who had no response or who lost response could escalate their dose to 10 mg/kg starting at week 38 . Clinical efficacy was assessed based on the proportion of patients achieving ACR 20 and PASI 75 responses . Major clinical response ( that is , maintenance of ACR 70 response for 24 continuous weeks ) was assessed for the first time in PsA. Results : Through 1 year of treatment , 58.9 % and 61.4 % of patients in the r and omised infliximab and placebo/infliximab groups , respectively , achieved ACR 20 ; corresponding figures for PASI 75 were 50.0 % and 60.3 % . At week 54 , major clinical response was achieved by 12.1 % of patients in the infliximab group . The safety profile of infliximab through week 54 was consistent with that seen through week 24 . Two malignancies occurred : basal cell skin cancer ( placebo ) and stage I Hodgkin ’s lymphoma ( infliximab ) . Conclusion : Infliximab maintains a high degree of clinical efficacy and continues to be well tolerated in patients with PsA through 1 year of treatment [15677701] OBJECTIVES To evaluate further in a phase III , double blind trial the efficacy of infliximab in patients with active psoriatic arthritis ( PsA ) , as observed in the smaller IMPACT trial . METHODS 200 patients with active PsA unresponsive to previous treatment were r and omised to infusions of infliximab 5 mg/kg or placebo at weeks 0 , 2 , 6 , 14 , and 22 . Patients with inadequate response entered early escape at week 16 . The primary measure of clinical response was ACR20 . Other measures included Psoriatic Arthritis Response Criteria ( PsARC ) , Psoriasis Area and Severity Index ( PASI ) , and dactylitis and enthesopathy assessment s. RESULTS At week 14 , 58 % of patients receiving infliximab and 11 % of those receiving placebo achieved an ACR20 response and 77 % of infliximab patients and 27 % of placebo patients achieved PsARC ( both p<0.001 ) . Among the 85 % of patients with at least 3 % body surface area psoriasis involvement at baseline , 53/83 ( 64 % ) patients receiving infliximab had at least 75 % improvement in PASI compared with 2/87 ( 2 % ) patients receiving placebo at week 14 ( p<0.001 ) . These therapeutic effects were maintained through the last evaluation ( week 24 ) . Fewer infliximab patients than placebo patients had dactylitis at week 14 ( 18 % v 30 % ; p = 0.025 ) and week 24 ( 12 % v 34 % ; p<0.001 ) . Fewer infliximab patients ( 22 % ) than placebo patients ( 34 % ) had active enthesopathy at week 14 ( p = 0.016 ) ; corresponding figures at week 24 were 20 % and 37 % ( p = 0.002 ) . Infliximab was generally well tolerated , with a similar incidence of adverse events in each group . CONCLUSIONS Infliximab 5 mg/kg through 24 weeks significantly improved active PsA , including dactylitis and enthesopathy , and associated psoriasis [22378566] OBJECTIVE Golimumab , administered subcutaneously every 4 weeks , has been shown to be effective in reducing the signs and symptoms of active psoriatic arthritis ( PsA ) through week 24 of the GO-REVEAL study . Herein we report 1-year clinical , radiographic , and safety findings . METHODS Adult patients with active PsA ( ≥3 swollen and ≥3 tender joints ) were r and omly assigned to receive subcutaneous placebo , golimumab 50 mg , or golimumab 100 mg every 4 weeks through week 20 . At week 16 , patients with < 10 % improvement from baseline in swollen and tender joint counts entered a blinded early escape phase , with placebo crossover to golimumab 50 mg , golimumab 50 mg increased to 100 mg , and golimumab 100 mg continued at 100 mg . Patients receiving placebo who did not enter the early escape phase crossed over to golimumab 50 mg at week 24 . Findings through 1 year are reported , including the second of 2 co primary end points ( i.e. , change from baseline to week 24 in PsA-modified Sharp/van der Heijde score [ SHS ] ) . RESULTS A total of 405 patients were r and omized : 113 to placebo and 146 each to the golimumab 50 mg and 100 mg groups . Mean changes in PsA-modified SHS from baseline to week 24 for the combined golimumab 50 mg and 100 mg group ( -0.09 ) and the golimumab 50 mg group ( -0.16 ) were significantly different versus placebo ( 0.27 ) ( P = 0.015 and P = 0.011 , respectively ) . Radiographic benefit was maintained through week 52 with golimumab . Clinical efficacy , including improvement in joint and skin responses and physical function , was maintained through 1 year . The frequency/types of adverse events were similar to those reported through week 24 . CONCLUSION Treatment of PsA with golimumab inhibited structural damage progression and demonstrated continued clinical efficacy and safety through 1 year [18316338] OBJECTIVE To identify factors predicting response to first TNF blocking treatment course in patients with established RA with a special focus on gender differences . METHODS Patients with active RA initiating their first treatment course of TNF-blocking therapy were enrolled . The study period was March 1999 through September 2006 . The prospect i ve protocol included information on demographics , clinical characteristics of patients and response measures . Fulfilment of ACR 50 - 70 % improvement and European League Against Rheumatism ( EULAR ) good response or remission [ 28-joint disease activity score ( DAS28 ) < 2.6 ] at 3 months were chosen as primary outcome measures . Potential predictors of responses were identified using multivariate binary logistic regression models . RESULTS In total , 1565 patients were included in the study . Gender did not influence treatment response . Consistently , concomitant methotrexate ( MTX ) was significantly associated with EULAR remission , EULAR good response , ACR50 response and ACR70 response with odds ratios ( ORs ) 1.97 , 2.13 , 2.10 and 1.75 , respectively . Concurrent treatment with other DMARDs was also significantly associated with EULAR remission , EULAR good response and ACR50 response ( OR : 1.96 , 2.24 and 1.94 , respectively ) . Likewise , low HAQ at baseline consistently predicted good clinical outcome . Disease activity at baseline was directly associated with favourable response when measured by ACR50 and ACR70 ( OR : 1.59 and 1.60 , respectively ) , whereas DAS28 score at baseline was inversely associated with EULAR remission ( OR : 0.78 ) . CONCLUSIONS In this observational study of patients with established RA , gender did not predict response to anti-TNF therapy , whereas treatment with concomitant DMARDs , especially MTX and low disability were associated with good response . Choice of outcome measures may influence the predictive value of baseline features [22514189] We prospect ively evaluated whether obesity impacts achievement of minimal disease activity ( MDA ) in subjects with psoriatic arthritis ( PsA ) [15692973] OBJECTIVE The signs and symptoms of ankylosing spondylitis ( AS ) respond inadequately to nonsteroidal antiinflammatory drugs , corticosteroids , and disease-modifying antirheumatic drugs in quite a number of patients . Tumor necrosis factor inhibitors have demonstrated success in reducing AS disease activity in a limited number of clinical trials . The objective of this multicenter , r and omized , placebo-controlled study was to evaluate the efficacy and safety of infliximab in patients with AS . METHODS Patients were r and omly assigned to receive infusions of placebo or 5 mg/kg infliximab at weeks 0 , 2 , 6 , 12 , and 18 . Efficacy was assessed using the ASsessment in Ankylosing Spondylitis ( ASAS ) International Working Group criteria , the Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI ) , night pain , patient 's global assessment , the Bath Ankylosing Spondylitis Functional Index ( BASFI ) , the Bath Ankylosing Spondylitis Metrology Index ( BASMI ) , chest expansion , the M and er enthesis index , the total swollen joint index , the C-reactive protein level , and the Short Form 36 ( SF-36 ) health survey question naire . The primary end point in this study was the proportion of patients with a 20 % improvement response according to the ASAS International Working Group criteria ( ASAS20 responders ) at week 24 . RESULTS Of the 357 patients screened , 201 were assigned to receive 5 mg/kg infliximab and 78 were assigned to receive placebo . After 24 weeks , 61.2 % of patients in the infliximab group were ASAS20 responders compared with 19.2 % of patients in the placebo group ( P < 0.001 ) . Clinical benefit was observed in patients receiving infliximab as early as week 2 and was maintained over the 24-week study period . Patients receiving infliximab also showed significant improvements in the BASDAI , BASFI , BASMI , chest expansion , and physical component summary score of the SF-36 . Adverse events were reported by 82.2 % of patients receiving infliximab and by 72.0 % of patients receiving placebo ; however , most adverse events in both treatment groups were mild or moderate in severity . CONCLUSION Infliximab was well tolerated and effective in a large cohort of patients with AS during a 24-week study period [2800202] Objectives : To evaluate the effectiveness of adalimumab in patients with psoriatic arthritis ( PsA ) and identify predictors of good clinical response for joint and skin lesions . Methods : Patients received adalimumab 40 mg every other week in addition to st and ard therapy in this prospect i ve , 12-week , open-label , uncontrolled study . Four definitions of good clinical response were used : ⩾50 % improvement in American College of Rheumatology response criteria ( ACR50 ) , good response according to European League Against Rheumatism ( EULAR ) guidelines , a ⩾3- grade improvement in Physician Global Assessment of psoriasis ( PGA ) and a ⩾50 % improvement in the Nail Psoriasis Severity Index ( NAPSI ) . Response predictors were determined by logistic regression with backward elimination ( selection level was 5 % ) . Results : Of 442 patients , 94 % completed 12 weeks of treatment . At week 12 , 74 % , 51 % and 32 % of the patients had achieved ACR20 , 50 and 70 , respectively ; 87 % and 61 % experienced moderate and good responses according to EULAR criteria , respectively . The percentage of patients with PGA results of “ clear/almost clear ” increased from 34 % ( baseline ) to 68 % . The mean NAPSI score was reduced by 44 % . No new safety signals were detected . A lower Health Assessment Question naire Disability Index ( HAQ-DI ) score , greater pain assessment , male sex and absence of systemic glucocorticoid therapy were strongly associated with achievement of ACR50 and good response according to EULAR criteria . In addition , greater C-reactive protein concentration and polyarthritis predicted ACR50 , and non-involvement of large joints predicted a good response according to EULAR criteria . Conclusions : Adalimumab was effective in patients with PsA. Lower impairment of physical function , greater pain , male sex and no systemic treatment with glucocorticoids were factors that increased the chance of achieving a good clinical response [3218909] Introduction Identifying ankylosing spondylitis ( AS ) patients who are likely to benefit from tumor necrosis factor-alpha ( TNF-α ) blocking therapy is important , especially in view of the costs and potential side effects of these agents . Recently , the AS Disease Activity Score ( ASDAS ) has been developed to assess both subjective and objective aspects of AS disease activity . However , data about the predictive value of the ASDAS with respect to clinical response to TNF-α blocking therapy are lacking . The aim of the present study was to identify baseline predictors of response and discontinuation of TNF-α blocking therapy in AS patients in daily clinical practice . Methods AS out patients who started TNF-α blocking therapy were included in the Groningen Leeuwarden Ankylosing Spondylitis ( GLAS ) study , an ongoing prospect i ve longitudinal observational cohort study with follow-up visits according to a fixed protocol . For the present analysis , patients were excluded if they had previously received anti-TNF-α treatment . Predictor analyses of response and treatment discontinuation were performed using logistic and Cox regression models , respectively . Results Between November 2004 and April 2010 , 220 patients started treatment with infliximab ( n = 32 ) , etanercept ( n = 137 ) , or adalimumab ( n = 51 ) . At three and six months , 68 % and 63 % of patients were Assessment s in Ankylosing Spondylitis (ASAS)20 responders , 49 % and 46 % ASAS40 responders , and 49 % and 50 % Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)50 responders , respectively . Baseline predictors of response were younger age , male gender , higher ASDAS score , higher erythrocyte sedimentation rate ( ESR ) level , higher C-reactive protein ( CRP ) level , presence of peripheral arthritis , higher patient 's global assessment of disease activity , and lower modified Schober test . In August 2010 , 64 % of patients were still using their TNF-α blocking agent with a median follow-up of 33.1 months ( range 2.4 to 68.2 ) . Baseline predictors of discontinuation of TNF-α blocking therapy were female gender , absence of peripheral arthritis , higher BASDAI , lower ESR level , and lower CRP level . Conclusions Besides younger age and male gender , objective variables such as higher inflammatory markers or ASDAS score were identified as independent baseline predictors of response and /or continuation of TNF-α blocking therapy . In contrast , higher baseline BASDAI score was independently associated with treatment discontinuation . Based on these results , it seems clinical ly relevant to include more objective variables in the evaluation of anti-TNF-α treatment [10972371] BACKGROUND Etanercept , a tumour-necrosis-factor inhibitor , has shown efficacy in the treatment of rheumatoid arthritis . Psoriatic arthritis and psoriasis are disease states in which tumour necrosis factor , a proinflammatory cytokine , is present in increased concentrations in joints and in the skin . Therefore , psoriatic arthritis and psoriasis may be appropriate therapeutic targets for etanercept . METHODS This r and omised , double-blind , placebo-controlled , 12 week study assessed the efficacy and safety of etanercept ( 25 mg twice-weekly subcutaneous injections ) or placebo in 60 patients with psoriatic arthritis and psoriasis . Psoriatic arthritis endpoints included the proportion of patients who met the Psoriatic Arthritis Response Criteria ( PsARC ) and who met the American College of Rheumatology preliminary criteria for improvement ( ACR20 ) . Psoriasis endpoints included improvement in the psoriasis area and severity index ( PASI ) and improvement in prospect ively-identified individual target lesions . FINDINGS In this 12 week study , 26 ( 87 % ) of etanercept-treated patients met the PsARC , compared with seven ( 23 % ) of placebo-controlled patients . The ARC20 was achieved by 22 ( 73 % ) of etanercept-treated patients compared with four ( 13 % ) of placebo-treated patients . Of the 19 patients in each treatment group who could be assessed for psoriasis ( > or = 3 % body surface area ) , five ( 26 % ) of etanercept-treated patients achieved a 75 % improvement in the PASI , compared with none of the placebo-treated patients ( p=0.015 ) . The median PASI improvement was 46 % in etanercept-treated patients versus 9 % in placebo-treated patients ; similarly , median target lesion improvements were 50 % and 0 , respectively . Etanercept was well tolerated . INTERPRETATION Etanercept offers patients with psoriatic arthritis and psoriasis a new therapeutic option for control of their disease [17179176] Objectives : To determine the predictive factors of clinical response to infliximab in patients with refractory psoriatic polyarthritis . Methods : A multicentre open study which included 69 patients with psoriatic polyarthritis refractory to methotrexate ( 15 mg/week at least for 8 weeks ) . Patients were treated with infliximab 5 mg/kg every 8 weeks in addition to their stable doses of methotrexate . A major clinical response was defined by the ACR50 at week 38 . Logistic regression analysis was performed to analyse which of the following measures at the start of treatment were associated with an ACR50 response : demographic and clinical characteristics , duration of disease , tender and swollen joint counts , involvement of large joints ( knee or hip , or both ) , erythrocyte sedimentation rate , C reactive protein ( CRP ) , Health Assessment Question naire disability index , axial involvement , and the presence of erosions at baseline . Results : In an intention to treat analysis 30/69 ( 44 % ) patients achieved an ACR50 response . In the univariate analysis both the presence of large joint involvement and severe disability were associated with a poor clinical response . In a multivariate logistic regression analysis high CRP values were independently associated with a good therapeutic response ( odds ratio ( OR ) = 18.7 ; 95 % confidence interval ( CI ) 1.8 to 181.6 ; p = 0.011 ) . In contrast , large joint involvement and severe disability were associated with a poor response , which reached significance for large joint involvement ( OR = 29.3 ; 95 % CI 3.2 to 266.3 ; p = 0.003 ) . Conclusion : A lower disability and , in particular , the absence of large joint involvement and higher CRP serum levels at the start of infliximab treatment are factors that seem to influence the probability of achieving a good therapeutic response in patients with psoriatic arthritis [16200601] OBJECTIVE Adalimumab , a fully human , anti-tumor necrosis factor monoclonal antibody , was evaluated for its safety and efficacy compared with placebo in the treatment of active psoriatic arthritis ( PsA ) . METHODS Patients with moderately to severely active PsA and a history of inadequate response to nonsteroidal antiinflammatory drugs were r and omized to receive 40 mg adalimumab or placebo subcutaneously every other week for 24 weeks . Study visits were at baseline , weeks 2 and 4 , and every 4 weeks thereafter . The primary efficacy end points were the American College of Rheumatology 20 % improvement ( ACR20 ) response at week 12 and the change in the modified total Sharp score of structural damage at week 24 . Secondary end points were measures of joint disease , disability , and quality of life in all patients , as well as the severity of skin disease in those patients with psoriasis involving at least 3 % of body surface area . RESULTS At week 12 , 58 % of the adalimumab-treated patients ( 87 of 151 ) achieved an ACR20 response , compared with 14 % of the placebo-treated patients ( 23 of 162 ) ( P < 0.001 ) . At week 24 , similar ACR20 response rates were maintained and the mean change in the modified total Sharp score was -0.2 in patients receiving adalimumab and 1.0 in those receiving placebo ( P < 0.001 ) . Among the 69 adalimumab-treated patients evaluated with the Psoriasis Area and Severity Index ( PASI ) , 59 % achieved a 75 % PASI improvement response at 24 weeks , compared with 1 % of the 69 placebo-treated patients evaluated ( P < 0.001 ) . Disability and quality of life measures were also significantly improved with adalimumab treatment compared with placebo . Adalimumab was generally safe and well-tolerated . CONCLUSION Adalimumab significantly improved joint and skin manifestations , inhibited structural changes on radiographs , lessened disability due to joint damage , and improved quality of life in patients with moderately to severely active [16142873] OBJECTIVE To examine the baseline demographic and disease characteristics that might influence improvement as measured by the Assessment in Ankylosing Spondylitis Response Criteria ( ASAS 20 ) in patients with ankylosing spondylitis ( AS ) . METHODS A multicenter Phase 3 study was performed to compare the safety and efficacy of 24 weeks of etanercept 25 mg subcutaneous injection twice weekly ( n = 138 ) and placebo ( n = 139 ) in patients with AS . The ASAS 20 was measured at multiple time points . Using a significance level of 0.05 , a repeated measures logistic regression model was used to determine which baseline factors influenced response in the etanercept-treated patients during the 24-week double blind portion of the trial . The following baseline factors were used in the model : demographic and disease severity variables , concomitant medications , extra-articular manifestations , and HLA-B27 status . The predictive capability of the model was then tested on the patients receiving placebo after they had received open-label etanercept treatment . RESULTS Baseline factors that were significant predictors of an ASAS 20 response in etanercept-treated patients were C-reactive protein ( CRP ) , back pain score , and Bath Ankylosing Spondylitis Functional Index ( BASFI ) score . Although clinical response to etanercept was seen at all levels of baseline disease activity , responses were consistently more likely with higher CRP levels or back pain scores and less likely with increased BASFI scores at baseline . CONCLUSIONS Higher CRP values and back pain scores and lower BASFI scores at baseline were significant predictors of a higher ASAS 20 response in patients with AS receiving etanercept but predictive value was of insufficient magnitude to determine treatment in individual patients [3446492] Introduction The excess of adipose tissue in obese individuals may have immunomodulating properties and pharmacokinetic consequences . The aim of this study was to determine whether body mass index ( BMI ) affects response to infliximab ( IFX ) in ankylosing spondylitis ( AS ) patients . Methods In 155 patients retrospectively included with active AS , the BMI was calculated before initiation of IFX treatment ( 5 mg/kg intravenously ) . After 6 months of treatment , changes from baseline in BASDAI , Visual Analogue Scale ( VAS ) pain , C-reactive protein ( CRP ) level , and total dose of nonsteroidal antiinflammatory drug ( NSAID ) were dichotomized with a threshold corresponding to a decrease of 50 % of initial level of the measure , into binary variables assessing response to IFX ( BASDAI50 , VAS50 , CRP50 , NSAID50 ) . Whether the BMI was predictive of the response to IFX therapy according to these definitions was assessed with logistic regression . Results Multivariate analysis found that a higher BMI was associated with a lower response for BASDAI50 ( P = 0.0003 ; OR , 0.87 ; 95 % CI ( 0.81 to 0.94 ) ) , VAS50 ( P < 0.0001 ; OR , 0.87 ; 95 % CI ( 0.80 to 0.93 ) ) ; CRP50 ( P = 0.0279 ; OR , 0.93 ; 95 % CI ( 0.88 to 0.99 ) ) , and NSAID50 ( P = 0.0077 ; OR , 0.91 ; 95 % CI ( 0.85 to 0.97 ) ) , criteria . According to the three WHO BMI categories , similar results were found for BASDAI50 ( 77.6 % , 48.9 % , and 26.5 % ; P < 0.0001 ) , VAS50 ( 72.6 % , 40.4 % , and 16.7 % ; P < 0.0001 ) ; CRP50 ( 87.5 % , 65.7 % , and 38.5 % ; P = 0.0001 ) , and NSAID50 ( 63.2 % , 51.5 % , and 34.6 % ; P = 0.06 ) . Conclusions This study provides the first evidence that a high BMI negatively influences the response to IFX in AS . Further prospect i ve studies , including assessment of the fat mass , pharmacokinetics , and adipokines dosages are m and atory to eluci date the role of obesity in AS IFX response [2911906] Introduction To identify independent predictors of radiographic progression in psoriatic arthritis ( PsA ) for patients treated with adalimumab or placebo in the Adalimumab Effectiveness in PsA Trial ( ADEPT ) . Methods Univariate analyses and multivariate linear regression analyses assessed risk for radiographic progression ( change in modified total Sharp score , ΔmTSS > 0.5 ) from baseline to week 24 for C-reactive protein ( CRP ) and other baseline variables , and for 24-week time-averaged CRP ( univariate analysis only ) . Subanalyses determined mean ΔmTSS for CRP subgroups . Analyses were post hoc , with observed data . Results One hundred and forty-four adalimumab-treated patients and 152 placebo-treated patients were assessed . Mean CRP was 64 % lower by week 2 with adalimumab and essentially unchanged with placebo . Univariate analyses indicated that elevated CRP at baseline and time-averaged CRP were strongly associated with radiographic progression for placebo-treated patients but not for adalimumab-treated patients . Multivariate analysis confirmed that elevated baseline CRP was the only strong independent risk factor for radiographic progression ( for CRP ≥1.0 mg/dl : odds ratio = 3.28 , 95 % confidence interval = 1.66 to 6.51 , P < 0.001 ) . Adalimumab treatment reduced risk of progression approximately fivefold . The difference between mean ΔmTSS for adalimumab versus placebo was greatest for patients with baseline CRP ≥2.0 mg/dl ( -0.5 vs. 2.6 ) . Conclusions Systemic inflammation in PsA , as indicated by elevated baseline CRP , was the only strong independent predictor of radiographic progression . This association was observed predominantly for placebo-treated patients . Adalimumab treatment substantially reduced the overall risk of radiographic progression , and provided greatest radiographic benefit for patients with the greatest CRP concentrations at baseline . Trial Registration Trial registration : NCT00195689 [3888598] Objectives To evaluate the efficacy and safety of certolizumab pegol ( CZP ) after 24 weeks in RAPID-axSpA ( NCT01087762 ) , an ongoing Phase 3 trial in patients with axial spondyloarthritis ( axSpA ) , including patients with ankylosing spondylitis ( AS ) and non-radiographic axSpA ( nr-axSpA ) . Methods Patients with active axSpA were r and omised 1:1:1 to placebo , CZP 200 mg every 2 weeks ( Q2W ) or CZP 400 mg every 4 weeks ( Q4W ) . In total 325 patients were r and omised . Primary endpoint was ASAS20 ( Assessment of SpondyloArthritis international Society 20 ) response at week 12 . Secondary outcomes included change from baseline in Bath Ankylosing Spondylitis Functional Index ( BASFI ) , Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI ) , and Bath Ankylosing Spondylitis Metrology Index ( BASMI ) linear . Results Baseline disease activity was similar between AS and nr-axSpA. At week 12 , ASAS20 response rates were significantly higher in CZP 200 mg Q2W and CZP 400 mg Q4W arms versus placebo ( 57.7 and 63.6 vs 38.3 , p≤0.004 ) . At week 24 , combined CZP arms showed significant ( p<0.001 ) differences in change from baseline versus placebo in BASFI ( −2.28 vs −0.40 ) , BASDAI ( −3.05 vs −1.05 ) , and BASMI ( −0.52 vs −0.07 ) . Improvements were observed as early as week 1 . Similar improvements were reported with CZP versus placebo in both AS and nr-axSpA sub population s. Adverse events were reported in 70.4 % vs 62.6 % , and serious adverse events in 4.7 % vs 4.7 % of All CZP versus placebo groups . No deaths or malignancies were reported . Conclusions CZP rapidly reduced the signs and symptoms of axSpA , with no new safety signals observed compared to the safety profile of CZP in RA . Similar improvements were observed across CZP dosing regimens , and in AS and nr-axSpA patients [11955536] UNLABELLED BACKGROUND Treatment options for patients with ankylosing spondylitis are few . We aim ed to assess the effectiveness of infliximab , an antibody to tumour necrosis factor (TNF)-alpha , in treatment of such patients . METHODS In this 12-week placebo-controlled multicentre study , we r and omly assigned 35 patients with active ankylosing spondylitis to intravenous infliximab ( 5 mg/kg ) and 35 to placebo at weeks 0 , 2 , and 6 . One patient in the infliximab group was withdrawn from the study . Our primary outcome was regression of disease activity of at least 50 % . To assess response , we used vali date d clinical criteria from the ankylosing spondylitis assessment working group , including disease activity ( BASDAI ) , functional indices ( BASFI ) , metrology ( BASMI ) , and quality of life ( short form 36 ) . Analyses were done by intention to treat . FINDINGS 18 ( 53 % ) of 34 patients on infliximab had a regression of disease activity at week 12 of at least 50 % compared with three ( 9 % ) of 35 on placebo ( difference 44 % [ 95 % CI 23 - 61 ] , p<0.0001 ) . Function and quality of life also improved significantly on infliximab but not on placebo ( p<0.0001 and p<0.0001 , respectively ) . Treatment with infliximab was generally well tolerated , but three patients had to stop treatment because of systemic tuberculosis , allergic granulomatosis of the lung , or mild leucopenia . INTERPRETATION Our results show that treatment with infliximab is effective in patients with active ankylosing spondylitis . Since there are some potentially serious adverse effects , we recommend that this treatment mainly be used in co-operation with rheumatological centres [17021665] The objective of this study was to evaluate if there are early clinical parameters in AS patients treated with three st and ard infusions of infliximab , which would predict whether a patient will derive a significant improvement at the tenth week , or whether there will be a lengthy clinical response after discontinuing the infusions . Sixty three AS patients were given three infusions of 5 mg/kg of infliximab at weeks 0 , 2 , and 6 and evaluated serially before each infusion and also at week 10 . Afterwards , patients were followed up by telephone interview until their disease activities were > 60 % of the baseline values . At that point , disease was considered to have relapsed . Clinical parameters at baseline as well as at week 2 were used for analysis to identify factors that might predict an improvement at week 10 , or predict a delayed relapse . A predictor is regarded as being useful if the area under the curve ( AUC ) when analyzed by receiver operator calculations ( ROC ) exceeds 0.75 . No parameters at baseline have sufficient predictive values . However , ASAS20 ( Assessment in Ankylosing Spondylitis International Working Group criteria ) at week 2 predicts improvement at week 10 , and also duration of clinical response after discontinuing the infliximab at week 6 . The response to one pulse of infliximab is the best predictor of subsequent response as well as rate of relapse after discontinuing the infliximab [17387031] OBJECTIVES The aims of this study were to assess the efficacy of infliximab ( IFX ) combined with methotrexate ( MTX ) versus IFX alone in the treatment of ankylosing spondylitis ( AS ) . METHODS The study was a 30weeks open label and prospect i ve study of parallel groups in 19 patients with active AS . These patients had shown incomplete therapeutic response to st and ard therapy ( full dose of non-steroidal anti-inflammatory drugs : NSAIDs ) and disease modifying antirheumatic drugs : DMARDs ( MTX or sulfasalazine : SLZ ) for a period of at least 12 weeks and were treated with IFX ( 5mg/kg ) . Patients were divided into two treatment groups according to the previous treatment : in Group A , 9 patients previously treated with 7.5mg/week of MTX were treated with IFX in addition to MTX ( IFX+MTX ) ; in Group B , 10 patients previously treated only with NSAIDs were treated with IFX ( 5mg/kg ) as monotherapy ( IFX ) . The primary outcome was improvement in disease activity shown by the BASDAI50 at week 30 ; the secondary outcome included comparison of the proportions of subjects in each group achieving response criteria proposed by the ASAS group . BASDAI , BASFI , ESR , CRP , pain , inflammation and Patient Global Assessment were also recorded . RESULTS Both groups were similar in sex ratio , clinical forms and B27 . Differences between groups occurred only in the disease duration and age of the patient . At 14 and 30 weeks only 50 % and 10 % respectively of the patients from the IFX group achieved BASDAI50 response compared to 89 % of patients from the IFX+MTX group . The difference between groups at 30 weeks was statistically significant ( p=0.001 ; percentage of difference : 79 % ; 95 % confidence interval ( CI ) : 26 - 93 % : ) . ASAS50 was reached in 67 % and 55.6 % of patients from the IFX+MTX group at 14 and 30 weeks respectively , compared with 30 % and 0 % of patients from the IFX group The difference between groups at 30 weeks was statistically significant ( p=0.011 ; percentage of difference : 57 % ; 95 % CI : 8 - 84.7 % ) . CONCLUSION Infliximab in combination with MTX seems to increase the efficacy of the therapeutic response in active AS patients , but more wide-ranging studies are necessary , mainly long-term studies [20385615] OBJECTIVE To determine predictors and time to response to treatment with TNF-alpha blockers in patients with PsA in a longitudinal observational cohort . METHODS We performed a cohort analysis of patients who were followed prospect ively in a large PsA clinic . Response to treatment was defined as an improvement of at least 40 % in active ( tender and /or swollen ) and swollen joint count ( SJC ) and 50 % improvement in the Psoriasis Area and Severity Index ( PASI ) score . RESULTS Ninety-five patients were included in the analysis . Of the total patients , 72.6 and 77.9 % demonstrated 40 % improvement in active joint counts at 3 and 12 months , respectively . Also , 80.5 and 87.4 % of the patients showed 40 % improvement in SJC at 3 and 12 months , respectively . A PASI50 was achieved by 54 and 60.4 % after 3 and 12 months of treatment , respectively . Of 17 patients who did not achieve 40 % improvement in total SJC at 3 months , 11 ( 64.7 % ) responded at 12 months . In multivariate analysis , the number of swollen joints at baseline predicted response of total active joints at 12 months [ odds ratio ( OR ) 1.34 ; P = 0.02 ] , whereas past use of TNF-alpha blocker decreased odds of response ( OR 0.05 ; P = 0.01 ) . CONCLUSION TNF-alpha blockers are effective in most PsA patients with the majority responding within 3 months of treatment . A significant proportion of the early non-responders will have a delayed response to treatment . Higher SJC at baseline and no prior use of TNF-alpha blockers predict response [22991950] Objectives : There is evidence that fat tissue may influence the response to therapy in patients with arthritis . The aim of this study was to assess whether the body mass index ( BMI ) affects rates of clinical remission in patients with psoriatic arthritis ( PsA ) treated with anti-tumour necrosis factor (TNF)-α biological drugs . Method : We retrospectively studied 135 patients with active peripheral PsA ( 45 obese , 47 overweight , and 43 normal-weight ) . Baseline BMI was correlated with the clinical response to adalimumab , etanercept , or infliximab . After 36 months ( median , range 6–79 ) of treatment , disease remission rates were assessed using the Disease Activity Score in 28 joints ( DAS28 ) or the Simplified Disease Activity Index ( SDAI ) . Possible predictors of clinical outcomes were assessed by multivariate analysis . Results : At baseline , BMI was significantly correlated only with the Health Assessment Question naire ( HAQ ) score ( r = 0.21 , p = 0.02 ) and not with disease activity . BMI did not predict disease remission or changes in HAQ score following anti-TNF-α therapy . Obese patients showed a significantly higher HAQ score and took significantly lower doses of prednisone than normal-weight or overweight patients , but their disease remission rates on the DAS28 ( 37 % ) or the SDAI ( 21 % ) were not significantly different from those of the other two groups ( 44 % and 21 % , respectively ) , regardless of the TNF-α inhibitor prescribed . Conclusions : In our retrospective analysis , disease activity and clinical response to anti-TNF-α therapy in PsA do not seem to be affected by BMI . Further prospect i ve studies are needed to confirm these preliminary results [20448079] OBJECTIVES To compare the clinical manifestations of spinal disease , peripheral arthritis and enthesitis , and to evaluate the effectiveness of adalimumab in a large cohort of patients with AS in relation to the presence or absence of psoriasis . METHODS Patients aged > or = 18 years with active AS were enrolled in an open-label study of adalimumab 40 mg every other week . Clinical symptoms were measured at baseline and Week 12 using st and ard assessment criteria . Differences between patients with and those without psoriasis were assessed . The relationship between changes in skin and AS symptoms was also analysed . RESULTS Of 1250 patients with AS who were enrolled in the study , 148 ( 11.8 % ) had a history of psoriasis , including 108 patients with current ( active ) psoriasis at entry . Baseline disease characteristics , including spinal structural damage , peripheral arthritis ( > or = 1 swollen joints ) and enthesitis ( > or = 1 inflamed entheses ) , were similar in both groups . At Week 12 , Assessment of SpondyloArthritis international Society 40 % response was achieved by 46.7 and 54.7 % and Bath AS Disease Activity Index 50 % response by 58.6 and 57.0 % of patients with and without psoriasis , respectively . Median changes in swollen joint scores and Maastricht AS Enthesitis Scores were similar in both groups . Skin changes during adalimumab treatment in AS patients with a history of psoriasis did not correlate with changes in AS symptoms . CONCLUSIONS The presence of psoriasis had no influence on the other clinical manifestations of patients with AS . Treatment with adalimumab markedly improved axial disease , peripheral arthritis and enthesitis , regardless of history of psoriasis [18006539] OBJECTIVE To evaluate the role of MRI in predicting a Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI ) improvement of at least 50 % ( BASDAI 50 ) upon anti-tumour necrosis factor ( TNF ) therapy of active ankylosing spondylitis ( AS ) . METHODS MRIs from patients with active AS who participated in r and omised controlled trials were analysed with respect to presence and extent of active inflammatory lesions as detected in the spine ( n = 46 ) , sacroiliac ( SI ) joints ( n = 42 ) and both sites ( n = 26 ) . Univariate and multivariate logistic regression analyses were applied to evaluate MRI and clinical data in predicting a BASDAI 50 response . RESULTS The Berlin MRI spine score ( odds ratio ( OR ) 1.16 , 95 % CI 1.02 to 1.33 ) and disease duration ( OR 0.9 , 95 % CI 0.63 to 0.97 ) were statistically significant predictors of a BASDAI 50 response using regression analysis while there was only a trend for C-reactive protein ( CRP ) . The likelihood ratio ( LR ) for achievement of BASDAI 50 was increased in patients with a Berlin MRI spine score > /=11 ( LR 6.7 ) , disease duration < 10 years ( LR 4.2 ) and CRP > /=40 mg/litre ( LR 3.4 ) . All patients with two or three of these predictors improved clinical ly ( as assessed by BASDAI ) by at least 45 % . Disease duration > 20 years , normal CRP and no active inflammatory lesion in the spine were highly predictive of not achieving BASDAI 50 . A trend was only found for the MRI score of SI joints to be predictive . CONCLUSIONS Widespread inflammation in the spine as detected by MRI contributes to predicting a BASDAI 50 response in active patients with AS treated with anti-TNF agents [18975305] OBJECTIVE To evaluate the efficacy and safety of golimumab in patients with ankylosing spondylitis ( AS ) in the GO-RAISE study . METHODS Patients with active AS , a Bath AS Disease Activity Index ( BASDAI ) score > or = 4 , and a back pain score of > or = 4 were r and omly assigned in a 1.8:1.8:1 ratio to receive subcutaneous injections of golimumab ( 50 mg or 100 mg ) or placebo every 4 weeks . The primary end point was the proportion of patients with at least 20 % improvement in the ASsessment in AS ( ASAS20 ) criteria at week 14 . RESULTS At r and omization , 138 , 140 , and 78 patients were assigned to the 50-mg , 100-mg , and placebo groups , respectively . After 14 weeks , 59.4 % , 60.0 % , and 21.8 % of patients , respectively , were ASAS20 responders ( P < 0.001 ) . A 40 % improvement in the ASAS criteria at week 24 occurred in 43.5 % , 54.3 % , and 15.4 % of patients , respectively . Patients receiving golimumab also showed significant improvement in the physical and mental component summary scores of the Short Form 36 Health Survey , the Jenkins Sleep Evaluation Question naire score , the BASDAI score , and the Bath AS Functional Index score , but not the Bath AS Metrology Index score . Through week 24 , 85.6 % of golimumab-treated patients and 76.6 % of patients in the placebo group had > or = 1 adverse event , and 5.4 % and 6.5 % of patients , respectively , had > or = 1 serious adverse event . Eight golimumab-treated patients and 1 placebo-treated patient had markedly abnormal liver enzyme values ( > or = 100 % increase from baseline and a value > 150 IU/liter ) , which were transient . CONCLUSION Golimumab was effective and well tolerated in a large cohort of patients with AS during a 24-week study period [15037444] BACKGROUND TNFalpha blockers have been shown to be highly efficacious in patients with active ankylosing spondylitis ( AS ) . OBJECTIVE To identify parameters predicting the clinical response to TNF blockers in AS . METHODS Patients with active AS participated in two placebo controlled , r and omised trials conducted in Germany with infliximab ( n = 69 ) and etanercept ( n = 30 ) , respectively . For inclusion in either trial patients had to have high disease activity ( BASDAI > or=4 ) and a spinal pain score ( numerical rating scale 0 - 10 ) > or=4 despite treatment with NSAIDs . A major clinical response was defined as a 50 % improvement of the initial BASDAI ( BASDAI 50 ) after 12 weeks ' treatment with active drug . Logistic regression likelihood ratio tests ( univariate and multivariate ) , Student 's t test , and chi(2 ) tests were performed . RESULTS Univariate analysis showed the following to be predictors of a major response ( BASDAI 50 ) to treatment : shorter disease duration ( p = 0.003 ) ; lower BASFI ( p = 0.007 ) ; younger age ( p = 0.009 ) ; raised ESR ( p = 0.033 ) ; raised CRP ( p = 0.035 ) . After adjustment for disease duration , BASFI , ESR , and CRP , but not age , remained significantly associated . After adjustment for disease duration and for BASFI , ESR , CRP , and in addition , a higher BASDAI were significantly associated with response . The best multivariate model built by stepwise regression contained the covariables disease duration , BASFI , BASDAI , and CRP . CONCLUSION A shorter disease duration , younger age , and a lower BASFI are predictors of a major clinical response to TNF blockers in active AS . Raised CRP and a higher BASDAI may also be valuable predictors . These data need to be confirmed in further studies [19273449] Objective . We evaluated the effectiveness and safety of adalimumab in a large cohort of patients with active ankylosing spondylitis ( AS ) and identified clinical predictors of good clinical response . Methods . Patients with active AS [ Bath AS Disease Activity Index ( BASDAI ) ≥4 ] received adalimumab 40 mg every other week in addition to their st and ard antirheumatic therapies in a multinational 12-week , open-label study . We used 3 definitions of good clinical response : 50 % improvement in the BASDAI ( BASDAI = 50 ) , 40 % improvement in the ASsessment s of SpondyloArthritis International Society criteria ( ASAS40 ) , or ASAS partial remission . Response predictors were determined by logistic regression with backward elimination ( selection level 5 % ) . Results . Of 1250 patients , 1159 ( 92.7 % ) completed 12 weeks of adalimumab treatment . At Week 12 , 57.2 % of patients achieved BASDAI 50 , 53.7 % achieved ASAS40 , and 27.7 % achieved ASAS partial remission . Important predictors of good clinical response ( BASDAI 50 , ASAS40 , and partial remission ) were younger age ( p < 0.001 ) , and greater C-reactive protein ( CRP ) concentration ( p ≤ 0.001 ) , HLA-B27 positivity ( p ≤ 0.01 ) , and tumor necrosis factor ( TNF ) antagonist naivety ( p < 0.001 ) . Conclusion . Adalimumab was effective in this large cohort of patients with AS , with more than half of patients achieving a BASDAI 50 or ASAS40 response and more than a quarter of patients reaching partial remission at Week 12.Younger age , greater CRP concentrations , HLA-B27 positivity , and TNF antagonist naivety were strongly associated with BASDAI 50 , ASAS40 , and partial remission responses . Clinical Trials.gov identifier : NCT00478660 [22806399] OBJECTIVE To evaluate the efficacy and safety of apremilast , a novel , orally available small molecule that specifically targets phosphodiesterase 4 , in the treatment of active psoriatic arthritis ( PsA ) . METHODS This phase II , multicenter , r and omized , double-blind , placebo-controlled study included the following : a 12-week treatment phase , with patients receiving placebo , apremilast 20 mg twice per day , or apremilast 40 mg once per day ; a 12-week treatment-extension phase , with patients in the placebo group re-r and omized to receive apremilast ; and a 4-week observational phase after treatment cessation . The primary end point was the proportion of patients achieving the American College of Rheumatology criteria for 20 % improvement ( ACR20 ) at week 12 . Safety assessment s included adverse events ( AEs ) , physical examinations , vital signs , laboratory parameters , and electrocardiograms . RESULTS Of the 204 patients with PsA who were r and omized to a treatment group , 165 completed the treatment phase . At the end of the treatment phase ( week 12 ) , 43.5 % of patients receiving apremilast 20 mg twice per day ( P < 0.001 ) and 35.8 % of those receiving 40 mg once per day ( P = 0.002 ) achieved an ACR20 response , compared with 11.8 % of those receiving placebo . At the end of the treatment-extension phase ( week 24 ) , > 40 % of patients in each group ( patients receiving apremilast 20 mg twice per day , patients receiving apremilast 40 mg once per day , and patients in the placebo group re-r and omized to receive apremilast ) achieved the ACR20 level of improvement . Most patients in the treatment phase ( 84.3 % ) and treatment-extension phase ( 68.3 % ) reported ≥ 1 AE . Diarrhea , headache , nausea , fatigue , and nasopharyngitis were reported most frequently ; most events were mild or moderate . No clinical ly relevant laboratory or electrocardiographic abnormalities were reported . CONCLUSION Treatment with apremilast at a dosage of 20 mg twice per day or 40 mg once per day demonstrated efficacy in comparison with placebo and was generally well tolerated in patients with active PsA. The balance of efficacy , tolerability , and safety supports further study of apremilast in [18576337] OBJECTIVE To evaluate the efficacy and safety of the tumor necrosis factor ( TNF ) antagonist adalimumab in patients with axial spondylarthritis ( SpA ) without radiographically defined sacroiliitis refractory to conventional treatment . METHODS Patients with active axial SpA ( n = 46 ) were r and omized to receive placebo or adalimumab at a dosage of 40 mg subcutaneously every other week for 12 weeks , followed by an open-label extension that continued up to week 52 . The diagnosis of axial SpA required the presence of 3 of 6 diagnostic criteria , including 2 of the following 3 criteria : inflammatory back pain , HLA-B27 positivity , or acute inflammation of the spine or sacroiliac joints on magnetic resonance imaging , in the absence of radiographic evidence of sacroiliitis . The primary end point was a 40 % response according to the improvement criteria of the Assessment of SpondyloArthritis international Society ( ASAS40 ) . RESULTS All 46 patients ( 22 receiving adalimumab and 24 receiving placebo ) completed the 12-week trial ; 38 patients completed the extension period to week 52 . At week 12 , an ASAS40 response was achieved by 54.5 % of the adalimumab-treated patients , as compared with 12.5 % of the placebo-treated patients ( P = 0.004 ) . After switching to adalimumab , a similar degree of efficacy was also achieved by the patients who were initially treated with placebo . Efficacy was maintained in all patients until week 52 . Young age at study entry and an elevated C-reactive protein concentration were the best predictors of achieving an ASAS40 response . Serious adverse events occurred in 5 patients , none of which was related to the study drug . CONCLUSION Adalimumab is the first TNF antagonist to demonstrate good clinical efficacy and safety in patients with axial SpA without radiographically defined sacroiliitis [17644547] Background : The use of tumour necrosis factor ( TNF ) blocking agents in psoriatic arthritis ( PsA ) is increasing , and the SSATG register has followed patients with PsA for more than 5 years . The aim of the present work therefore was to present efficacy and tolerability data of TNF-blocking agents on PsA in clinical practice , and to study potential predictors for drug survival ( the length of time a patient continues to take a particular drug ) . Material s and methods : Patients ( n = 261 ) with active PsA , starting anti-TNF therapy for the first time in southern Sweden , were included . Basal characteristics , disease activity measures , and termination reason for blockers were prospect ively collected during the period April 1999 to September 2006 . Cox proportional hazard models were used to investigate predictors for treatment termination . Results : Overall , response rates at 3–12 months for global visual analogue scale ( VASglobal50 ) and pain VAS ( VASpain50 ) were about 50 % , whereas response rates for European League Against Rheumatism ( EULAR ) scoring “ overall ” and EULAR “ good ” were around 75 % and 55 % , respectively . Concomitant methotrexate ( MTX ) ( hazard ratio ( HR ) 0.64 , 95 % CI 0.39–0.95 , p = 0.03 ) , etanercept ( HR 0.49 , 95 % CI 0.28–0.86 , p = 0.01 ) , and high C-reactive protein ( CRP ) levels ( HR 0.77 , 95 % CI 0.61–0.97 , p = 0.03 ) at treatment initiation were associated with better overall drug survival . The improved drug survival of concomitant MTX appeared to be related to significantly fewer dropouts because of adverse events ( HR = 0.24 ( 0.11–0.52 ) , p<0.01 ) . The blockers were well tolerated with a rate of serious adverse events of 5–6 % per year . No unexpected serious adverse events were observed . Conclusion : Concomitant MTX and high CRP levels are associated with treatment continuation of anti-TNF therapy in patients with PsA regardless of joint distribution . The positive effect of MTX was primarily linked to fewer dropouts because of adverse events [21632677] Objective . To investigate whether level of serum matrix metalloproteinase-3 ( MMP-3 ) can serve as a biomarker for monitoring and predicting response to etanercept treatment in patients with ankylosing spondylitis ( AS ) in daily clinical practice . Methods . Ninety-two consecutive AS out patients with active disease who started etanercept treatment were included in this longitudinal observational study . Clinical data were collected prospect ively at baseline and after 3 and 12 months of treatment . At the same timepoints , serum MMP-3 levels were measured retrospectively by ELISA . Results . Since baseline serum MMP-3 levels were significantly higher in male compared to female patients with AS , data analysis was split for gender . Changes in serum MMP-3 levels after etanercept treatment correlated positively with changes in clinical assessment s of disease activity and physical function in both male and female patients . Receiver operating characteristic analysis in male patients showed that baseline serum MMP-3 levels had poor accuracy ( AUC < 0.7 ) to discriminate between Assessment s in Ankylosing Spondylitis 20 ( ASAS20 ) or ASAS40 responders and nonresponders after 3 or 12 months of treatment . The accuracy of change in serum MMP-3 levels from baseline to 3 months in predicting response after 3 or 12 months of treatment was poor for ASAS40 ( AUC < 0.7 ) or moderate for ASAS20 ( AUC = 0.752 and 0.744 , respectively ) , and was not superior to the accuracy of change in the currently used objective biomarkers , erythrocyte sedimentation rate and C-reactive protein . Conclusion . Although significant changes in serum MMP-3 levels were found after etanercept treatment , data analysis indicates that serum MMP-3 levels are not very useful for monitoring and predicting response to etanercept treatment in patients with AS in daily clinical practice [20511613] Objectives To use prospect ively registered data from the Danish nationwide rheumatological data base ( DANBIO ) to describe disease activity , clinical response , treatment duration and predictors of drug survival ( ie , number of days individual patients maintained treatment ) and clinical response among patients with ankylosing spondylitis ( AS ) receiving their first treatment series with a tumour necrosis factor α ( TNFα ) inhibitor . Methods 842 TNFα inhibitor naive patients with AS were identified in DANBIO . Clinical response , drug survival and predictors thereof were investigated . ‘ Clinical response ’ was defined as a 50 % or 20 mm reduction in Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI ) within 6 months compared with baseline . Achievement of a BASDAI < 40 mm within 6 months was used as a second response parameter . Results 603 patients ( 72 % ) were men , disease duration 5 ( 1–13 ) years ( median ( IQR ) , age 41 ( 32–50 ) years . 445 ( 53 % ) received infliximab , 247 ( 29 % ) adalimumab and 150 ( 18 % ) etanercept . Parameters at baseline/1-year follow-up were : C-reactive protein ( CRP ) : 14 (7–27)/5 ( 2–10 ) mg/l , BASDAI 59 (44–72)/21 ( 8–39 ) mm , Bath Ankylosing Spondylitis Functional Index ( BASFI ) 50 (34–67)/24 ( 9–45 ) mm , Bath Ankylosing Spondylitis Metrology Index 40 (20–50)/20 ( 10–40 ) mm . Within 6 months , 407/644 patients ( 63 % ) achieved a clinical response . Median drug survival was 4.3 years . One- and 2-year survival rates were 74 % and 63 % , respectively . Baseline characteristics associated with longer drug survival were male gender , CRP > 14 mg/l and low visual analogue scale fatigue ( Cox regression analysis ) . Age , TNFα inhibitor and methotrexate use were insignificant . CRP > 14 mg/l , lower BASFI and younger age at baseline was associated with clinical response and achievement of a BASDAI < 40 mm ( logistic regression analysis ) . Conclusion TNFα inhibitors provide a rapid and sustained decrease of disease activity among patients with AS in clinical practice . Factors associated with continued treatment , clinical response and achievement of a BASDAI < 40 mm were identified [21551511] Objectives To investigate the relation between ankylosing spondylitis disease activity score ( ASDAS ) , Bath ankylosing spondylitis disease activity index ( BASDAI ) and treatment response and biomarkers of inflammation ( C-reactive protein ( CRP ) , interleukin-6 ( IL-6 ) , YKL-40 ) , angiogenesis ( vascular endothelial growth factor ( VEGF ) ) , cartilage ( C-terminal crosslinking telopeptide of type II collagen ( CTX-II ) , matrix metalloproteinase-3 ( MMP-3 ) , total aggrecan , cartilage oligomeric matrix protein ) and bone ( C-terminal crosslinking telopeptide of type I collagen , osteocalcin ) turnover in 60 patients with axial spondyloarthritis initiating tumour necrosis factor alpha ( TNFα ) inhibitor therapy . Methods ASDAS ( CRP-based ) , BASDAI and biomarkers were determined before and seven times during 46 weeks of TNFα inhibitor therapy . Results Very high ASDAS were associated with high levels of inflammatory biomarkers , while high BASDAI were not related to any biomarkers . Mixed modeling demonstrated significant longitudinal associations between ASDAS and IL-6 , VEGF , MMP-3 and osteocalcin and between BASDAI and CRP , IL-6 and VEGF . Major improvement in ASDAS was associated with larger percentage decreases in biomarkers of inflammation , angiogenesis , MMP-3 and increases in aggrecan and osteocalcin . BASDAI response was associated with larger decreases in CRP and IL-6 . Biomarkers with moderate/high differences in responsiveness for major versus no/ clinical ly important improvement in ASDAS were CRP , IL-6 , VEGF , aggrecan and osteocalcin , and VEGF and CTX-II for BASDAI response versus non-response . Conclusion Levels and changes of 10 biomarkers in patients with axial spondyloarthritis during anti-TNFα therapy were documented . Construct validity and responsiveness of IL-6 , VEGF , MMP-3 , total aggrecan and osteocalcin were demonstrated . ASDAS was more associated with these biomarkers than BASDAI , and may better reflect the inflammatory disease processes . Clinical Trials.gov identifier NCT00133315 [12794835] OBJECTIVE There is increasing evidence that tumor necrosis factor alpha ( TNFalpha ) is central ly involved in the pathogenesis of ankylosing spondylitis ( AS ) and other spondylarthritides . This study was design ed to investigate the efficacy of anti-TNFalpha therapy with etanercept , a 75-kd receptor fusion protein , in active AS . METHODS This multicenter trial had 2 phases : an initial placebo-controlled period of 6 weeks ' duration and an observational phase lasting 24 weeks . Thirty patients with active AS were included . They were r and omized into 2 groups , which received either etanercept ( 25 mg twice weekly ) ( n = 14 ) or placebo ( n = 16 ) for 6 weeks . Then both groups were treated with etanercept . Nonsteroidal antiinflammatory drug ( NSAID ) treatment could be continued , but disease-modifying antirheumatic drugs ( DMARDs ) and steroids had to be withdrawn prior to the study . All patients received etanercept for a total of 12 weeks and were followed up for at least 24 weeks . The Bath AS Disease Activity Index ( BASDAI ) , Bath AS Functional Index , Bath AS Metrology Index , pain level on a numeric rating scale , quality of life by the Short Form 36 , and C-reactive protein ( CRP ) level were assessed . The primary outcome parameter was a > or=50 % improvement in the BASDAI . RESULTS Treatment with etanercept result ed in at least a 50 % regression of disease activity in 57 % of these patients at week 6 , versus 6 % of the placebo-treated patients ( P = 0.004 ) . After the placebo-treated patients switched to etanercept , 56 % improved . The mean + /- SD BASDAI improved from 6.5 + /- 1.2 at baseline to 3.5 + /- 1.9 at week 6 in the etanercept group , with no improvement in the placebo group ( P = 0.003 between groups ) . Similarly , pain , function , mobility , and quality of life improved with etanercept but not with placebo at week 6 ( P < 0.05 ) . Mean CRP levels decreased significantly with etanercept but not with placebo ( P = 0.001 ) . There was ongoing improvement in all parameters in both groups until week 12 and week 18 , respectively ( i.e. , throughout the period of etanercept treatment ) . Disease relapses occurred a mean + /- SD of 6.2 + /- 3.0 weeks after cessation of etanercept . No severe adverse events , including major infections , were observed during the trial . CONCLUSION This study shows that on a short-term basis ( 3 months ) , treatment with etanercept is clearly efficacious in patients with active AS who are receiving NSAID therapy but not DMARDs or steroids . After cessation of therapy , almost all patients experienced a relapse within a few weeks . Thus , it seems probable that etanercept must be administered continuously in most AS patients to achieve permanent inhibition of the inflammatory process [19333944] OBJECTIVE To assess the efficacy and safety of golimumab in patients with active psoriatic arthritis ( PsA ) . METHODS Adult patients with PsA who had at least 3 swollen and 3 tender joints and active psoriasis were r and omly assigned to receive subcutaneous injections of placebo ( n = 113 ) , golimumab 50 mg ( n = 146 ) , or golimumab 100 mg ( n = 146 ) every 4 weeks through week 20 . Efficacy assessment s through week 24 included the American College of Rheumatology 20 % improvement criteria ( ACR20 ) , the Psoriasis Area and Severity Index ( PASI ) in patients in whom at least 3 % of the body surface area was affected by psoriasis at baseline , the Short Form 36 Health Survey ( SF-36 ) , the disability index of the Health Assessment Question naire ( HAQ ) , the Nail Psoriasis Severity Index ( NAPSI ) , the physician 's global assessment of psoriatic nail disease , and enthesitis ( using the PsA-modified Maastricht Ankylosing Spondylitis Enthesitis Score [ MASES ] index ) . RESULTS At week 14 , 48 % of all patients receiving golimumab , 51 % of patients receiving golimumab 50 mg , and 45 % of patients receiving golimumab 100 mg achieved an ACR20 response ( the primary end point ) , compared with 9 % of patients receiving placebo ( P < 0.001 for all comparisons ) . Among the 74 % of patients in whom at least 3 % of the body surface area was affected by psoriasis at baseline , 40 % of those in the golimumab 50 mg group and 58 % of those in the golimumab 100 mg group had at least 75 % improvement in the PASI at week 14 ( major secondary end point ) , compared with 3 % of placebo-treated patients ( P < 0.001 for both doses ) . Significant improvement was observed for other major secondary end points ( the HAQ and the SF-36 ) , the NAPSI , the physician 's global assessment of psoriatric nail disease , and the PsA-modified MASES index in each golimumab group compared with placebo . This efficacy was maintained through week 24 . Golimumab was generally well tolerated . CONCLUSION Treatment with golimumab at doses of 50 mg and 100 mg significantly improved active PsA and associated skin and nail psoriasis through week 24 [21885499] Objective . To assess the efficacy and safety of adalimumab or cyclosporine ( CYC ) as monotherapy or combination therapy for patients with active psoriatic arthritis ( PsA ) , despite methotrexate ( MTX ) therapy . Methods . A prospect i ve 12-month , nonr and omized , unblinded clinical trial of 57 , 58 , and 55 patients who received CYC ( 2.5–3.75 mg/kg/day ) , adalimumab ( 40 mg every other week ) , or combination , respectively . Lowering of concomitant nonsteroidal antiinflammatory drugs ( NSAID ) and corticosteroids and reductions of adalimumab and /or CYC doses in responding patients were not restricted . Results . Mean numbers of tender/swollen joints at baseline were 9.7/6.7 in CYC-treated , 13.0/7.8 in adalimumab-treated , and 14.5/9.4 in combination-treated patients , indicating lesser disease severity of patients assigned to the first group . The Psoriatic Arthritis Response Criteria at 12 months were met by 65 % of CYC-treated ( p = 0.0003 in favor of combination treatment ) , 85 % of adalimumab-treated ( p = 0.15 vs combination treatment ) , and 95 % of combination-treated patients , while the American College of Rheumatology-50 response rates were 36 % , 69 % , and 87 % , respectively ( p < 0.0001 and p = 0.03 in favor of combination treatment ) . A significantly greater mean improvement in Health Assessment Question naire Disability Index was achieved by combination treatment ( −1.11 ) vs CYC ( −0.41 ) or adalimumab alone ( −0.85 ) . Combination therapy significantly improved Psoriasis Area and Severity Index-50 response rates beyond adalimumab , but not beyond the effect of CYC monotherapy . Doses of NSAID and corticosteroids were reduced in combination-treated patients ; CYC doses and frequency of adalimumab injections were also reduced in 51 % and 10 % of them , respectively . No new safety signals were observed . Conclusion . The combination of adalimumab and CYC is safe and seemed to produce major improvement in both clinical and serological variables in patients with severely active PsA and inadequate response to MTX [16802350] OBJECTIVE To evaluate the safety and efficacy of adalimumab , a fully human recombinant IgG1 monoclonal antibody that specifically targets human tumor necrosis factor , in patients with active ankylosing spondylitis ( AS ) . METHODS This was a multicenter , r and omized ( 2:1 ratio ) , double-blind , placebo-controlled study to evaluate a subcutaneous injection of adalimumab , 40 mg every other week , compared with placebo for 24 weeks . The primary efficacy end point was the percentage of patients with a 20 % response according to the ASsessment in Ankylosing Spondylitis International Working Group criteria for improvement ( ASAS20 ) at week 12 . Secondary outcome measures included the ASAS20 at week 24 and multiple measures of disease activity , spinal mobility , and function , as well as ASAS partial remission . RESULTS At week 12 , 58.2 % of adalimumab-treated patients ( 121 of 208 ) achieved an ASAS20 response , compared with 20.6 % of placebo-treated patients ( 22 of 107 ) ( P < 0.001 ) . More patients in the adalimumab group ( 45.2 % [ 94 of 208 ] ) than in the placebo group ( 15.9 % [ 17 of 107 ] ) had at least a 50 % improvement in the Bath Ankylosing Spondylitis Disease Activity Index at week 12 ( P < 0.001 ) . Significant improvements in the ASAS40 response and the response according to the ASAS5/6 criteria at weeks 12 and 24 were also demonstrated ( P < 0.001 ) . Partial remission was achieved by more adalimumab-treated patients than placebo-treated patients ( 22.1 % versus 5.6 % ; P < 0.001 ) . Adalimumab-treated patients reported more adverse events ( 75.0 % versus 59.8 % of placebo-treated patients ; P < 0.05 ) , but there was no statistically significant difference in the incidence of infections . Most adverse events were mild or moderate in severity . CONCLUSION Adalimumab was well-tolerated during the 24-week study period and was associated with a significant and sustained reduction in the signs and symptoms of active AS [21279995] OBJECTIVE To investigate disease activity , treatment response , and drug survival , and predictors thereof , among Danish patients with psoriatic arthritis ( PsA ) receiving their first treatment series with a tumor necrosis factor α ( TNFα ) inhibitor . METHODS Patients with PsA were identified from a prospect i ve nationwide rheumatologic data base , the Danish biologics registry DANBIO , using data registered from 2000 - 2009 . Information was obtained on the patients ' clinical response to anti-TNFα treatment ( defined as achievement of the American College of Rheumatology 20 % [ ACR20 ] , ACR50 , and ACR70 improvement criteria or a European League Against Rheumatism [ EULAR ] good response at least once during the first 6 months of treatment ) and duration and rate of drug adherence ( referred to as drug survival ) , as well as predictors thereof . RESULTS Of 764 patients with PsA , 320 received adalimumab , 260 infliximab , and 184 etanercept . Median drug survival was 2.9 years , and 1-year and 2-year drug survival rates were 70 % and 57 % , respectively . Clinical parameters that showed improvement over 6 months were the C-reactive protein ( CRP ) level , Health Assessment Question naire score , and 28-joint Disease Activity Score . Male sex , CRP level > 10 mg/liter , concomitant methotrexate use , and low patient health visual analog scale score at baseline were associated with longer drug survival . Improvement was achieved by 59 % , 45 % , 24 % , and 54 % of patients according to the ACR20 , ACR50 , ACR70 response criteria and EULAR good response , respectively . A CRP level > 10 mg/liter was predictive of the improvement responses ( odds ratio [ OR ] 2.6 for ACR20 , OR 3.0 for ACR50 , OR 3.6 for ACR70 , and OR 2.2 for EULAR good response ) . CONCLUSION In these patients with PsA treated with their first TNFα inhibitor in clinical practice , high drug adherence and responder rates were observed . Moreover , increased levels of CRP at baseline were associated with both good treatment responses and continued treatment , which may be of clinical value in selecting the patients most likely to benefit from treatment with TNFα inhibitors Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Tumour necrosis factor (TNF)-α inhibitors ( anti-TNFs ) are typically used when the inflammatory rheumatologic diseases ankylosing spondylitis ( AS ) and non-radiographic axial spondyloarthritis ( nr-AxSpA ) have not responded adequately to conventional therapy . Current National Institute for Health and Care Excellence ( NICE ) guidance recommends treatment with adalimumab , etanercept and golimumab in adults with active ( severe ) AS only if certain criteria are fulfilled but it does not recommend infliximab for AS . Anti-TNFs for patients with nr-AxSpA have not previously been appraised by NICE . OBJECTIVE To determine the clinical effectiveness , safety and cost-effectiveness within the NHS of adalimumab , certolizumab pegol , etanercept , golimumab and infliximab , within their licensed indications , for the treatment of severe active AS or severe nr-AxSpA ( but with objective signs of inflammation ) . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

12519617

[4056079] The bioavailability profiles of two sustained-release oral theophylline preparations , Respbid and Theo-Dur , were compared in 19 adults with obstructive airways disease . Intravenous aminophylline was used as the reference st and ard . No significant differences were detected in fraction absorbed , peak-trough fluctuations , or time to peak concentrations [7001056] Theophylline is commonly prescribed for chronic obstructive pulmonary disease ( COPD ) , although controlled studies do not exist to support this use . We administered theophylline and placebo orally to 40 ambulatory COPD patients in a double-blind , crossover manner . Pulmonary function tests were conducted before and after isoproterenol nebulization on the final day of each four-week study period . Theophylline therapy produced small , but significant , increases over placebo in mean values . However , only the forced expiratory volume in 1 s was " improved , " according to published criteria . There were no significant differences in subjective effects between treatment periods . Six patients were identified as " responders " ; responder status could be predicted on the basis of improvement in flow rates after isoproterenol nebulization . Theophylline therapy is not beneficial to most COPD patients , and potential responders should be given carefully monitored therapeutic trials rather than arbitrarily being given maintenance therapy [7387018] We studied ventilatory , hemodynamic , and subjective responses to different plasma theophylline concentrations in 10 patients with " irreversible " airflow obstruction . Subjects received theophylline at doses that produced low ( 9.0 to 12.5 micrograms/mL ) and high ( 17 to 22 micrograms/mL ) peak plasma concentrations ; subjects also received placebo . A significant ( P less than 0.05 ) dose-related difference in pulmonary function was observed between each treatment . The mean maximal increase in forced expiratory volume at 1 second over placebo was 21.3 % for high-dose theophylline and 6.0 % for low dose . Both treatments were well tolerated with respect to hemodynamic changes and other adverse effects . Despite improved findings in pulmonary function tests patients were unable to distinguish either treatment from placebo in terms of improvement in breathlessness [11399688] BACKGROUND Patients with COPD often require multiple therapies to improve lung function and decrease symptoms and exacerbations . Salmeterol and theophylline are indicated for the treatment of COPD , but the use of these agents in combination has not been extensively studied . OBJECTIVES To compare the efficacy and safety of salmeterol plus theophylline vs either agent alone in COPD . METHODS R and omized , double-blind , double-dummy , parallel-group trial in 943 patients with COPD . After an open-label theophylline titration period ( serum levels , 10 to 20 microg/mL ) , patients were r and omly assigned to receive salmeterol ( 42 microg bid ) plus theophylline , salmeterol ( 42 microg bid ) , or theophylline for 12 weeks . Serial pulmonary function tests were completed on day 1 and treatment week 12 . Patients kept diary cards and noted their peak flow rates , symptom scores , and albuterol use , and periodically completed quality -of-life and dyspnea question naires . RESULTS All three groups significantly improved compared with baseline . Combination treatment with salmeterol plus theophylline provided significantly ( p < or = 0.045 ) greater improvements in pulmonary function ; significantly ( p < or = 0.048 ) greater decreases in symptoms , dyspnea , and albuterol use ; and significantly fewer COPD exacerbations ( p = 0.023 vs theophylline ) . In general , treatment with salmeterol provided greater improvement in lung function and satisfaction with treatment compared with theophylline . Salmeterol treatment was also associated with significantly fewer drug-related adverse events ( p < or = 0.042 ) than either treatment that included theophylline . The safety profile ( adverse events , vital signs , and ECG findings ) of the two treatments that included theophylline were similar . CONCLUSION Patients with COPD may benefit from combination treatment with salmeterol plus theophylline , without a result ing increase in adverse events or other adverse sequelae [6127964] The acute ventilatory , cardiovascular and tremorogenic effect of a high oral dose of terbutaline ( 5 mg ) was compared with that of half the dose ( 2.5 mg ) combined with 280 mg anhydrous theophylline orally in a r and omized , double‐blind , cross‐over study in eight asthmatics . After 120 min . when steady‐state bronchodilation was achieved , five terbutaline inhalations ( 1.25 mg terbutaline sulphate ) were added to both treatment regimens . The mean maximum plasma concentration of theophylline was then 7 μg/ml ( 39 μmol/l ) [8678934] BACKGROUND Theophylline has been used to treat central apnea associated with Cheyne-Stokes respiration ( periodic breathing ) . We studied the effect of short-term oral theophylline therapy on periodic breathing associated with stable heart failure due to systolic dysfunction . METHODS Fifteen men with compensated heart failure ( left ventricular ejection fraction , 45 percent or less ) participated in the study . Their base-line polysomnograms showed periodic breathing , with more than 10 episodes of apnea and hypopnea per hour . In a double-blind crossover study , the patients received theophylline or placebo orally twice daily for five days , with one week of washout between the two periods . RESULTS After five days of treatment , the mean ( + /-SD ) plasma theophylline concentration was 11 + /- 2 microgram per milliliter . Theophylline therapy result ed in significant decreases in the number of episodes of apnea and hypopnea per hour ( 18 + /- 17 , vs. 37 + /- 23 with placebo and 47 + /- 21 at base line ; P<0.001 ) , the number of episodes of central apnea per hour ( 6 + /- 14 , vs. 26 + /- 21 and 26 + /- 20 , respectively ; P<0.001 ) , and the percentage of total sleep time during which the arterial oxyhemoglobin saturation was less than 90 percent ( 6 + /- 11 percent , vs. , 23 + /- 37 and 14 + /- 14 percent , respectively ; P<0.04 ) . There were no significant differences in the characteristics of sleep , the frequency of ventricular arrhythmias , daytime arterial-blood gas values , or the left ventricular ejection fraction during the base-line , placebo , and theophylline phases of the study . CONCLUSIONS In patients with stable heart failure , oral theophylline therapy reduced the number of episodes of apnea and hypopnea and the duration of arterial oxyhemoglobin desaturation during sleep [1792411] In two groups ( A and B ) of patients with severe chronic obstructive pulmonary disease ( COPD ) , matched for age and routine pulmonary function testing , we evaluated inspiratory muscle strength ( MIP ) , breathing pattern , mouth occlusion pressure ( P0.1 ) , inspiratory neural drive , assessed in terms of electromyographic activity of both diaphragm ( EMGd ) and intercostal ( EMGint ) muscles , and P0.1/EMGd ratio , an index of inspiratory neuromuscular coupling . Group A ( 8 patients ) was studied before and after a 7-day period of a new oral xanthine derivative ( bamiphylline , 1.2 g daily ) , and group B ( 7 patients ) was given a placebo . Under control conditions , compared with an age-matched normal control group , groups A and B both exhibited a decrease in MIP , more rapid ( increase in respiratory frequency RF ) and shallower ( decrease in tidal volume ; VT ) breathing ( RSB ) , a marked increase in both EMGd and EMGint and a lower P0.1/EMGd ratio . With bamiphylline FEV1 and PaO2 significantly increased , while a substantial increase in MIP was found in 5 out of the 8 patients . VT and inspiratory time ( Ti ) also significantly increased , and RF decreased . Both EMGd and EMGint significantly decreased , whereas P0.1/EMGd exhibited a substantial increase in 5 out of the 8 patients . Conversely , no significant changes were observed in group B during the study period . From these data we conclude that in patients with COPD , clinical manifestations , probably associated with inspiratory muscle overloading ( decrease in muscle strength , RSB , increase in respiratory neural drive , and derangement in neuromuscular coupling ) may benefit from a short-term treatment with bamiphylline [7025336] Twenty-four patients with reversible airflow obstruction under suboptimal control on conventional therapy entered a double-blind placebo-controlled trial of additional oral sustained release aminophylline . Assessment was by diary cards , twice daily PEFR , and weekly FEV1 . Nineteen patients completed the trial satisfactorily . Eleven were improved subjectively by addition of aminophylline . The mean PEFR for all 19 patients rose from 232 1 min-1 SEM + /- 5 , to 247 1 min-1 SEM + /- 4 ( p less than 0.0001 ) ; nine individuals showed a statistically significant improvement in mean PEFR and 10 showed an improvement of greater than 200 ml in their FEV1 . Improvement in PEFR on aminophylline was not at the expense of benefit from inhaled salbutamol . Unwanted effects of nausea , headache , and abdominal discomfort were recorded by 12 of the 24 patients entering the trial . Seventeen of the 19 patients completing the trial had plasma theophylline levels in the accepted therapeutic range of 10 - 20 mg 1(-1 ) . The drug doses required to achieve these levels varied from 8.6 - 30.8 mg kg-1 24 hr-1 in the patients with no clinical or biochemical evidence of liver disease . Oral aminophylline can improve control of airflow obstruction in patients with moderately severe disease who are already receiving multiple medication , but side-effects often limit its use . The wide dose range required to achieve therapeutic plasma levels indicates that measurements of plasma theophylline are necessary for adequate interpretation of trials of theophylline compounds [1592541] The bronchodilator , respiratory center and respiratory muscle effects of oral sustained release theophylline are investigated with a placebo controlled double-blind study in 34 patients with chronic obstructive lung disease ( COLD ) . The first 3 days were a theophylline washout period and the patients did not receive theophylline and on the 4th day , serum theophylline concentration was negligible . Initial pulmonary function tests were performed . Twenty-four of the patients took 350 mg oral sustained release theophylline twice a day . Ten of the patients were given placebo . On day 7 , serum theophylline concentrations of the study group were in therapeutic doses and the tests were repeated . Bronchodilator effect was assessed by spirometry , flow-volume loops and measuring airway resistance ( Raw ) . Respiratory muscle function was assessed by measuring maximal inspiratory ( PImax ) and expiratory pressures ( PEmax ) and the effect on respiratory center was evaluated by minute ventilation , mouth occlusion pressure index and inspiratory duty ratio . Forced vital capacity in one second ( p less than 0.001 ) , maximal mid expiratory flow rate ( p less than 0.05 ) , maximal expiratory flow at 50 percent of vital capacity ( p less than 0.001 ) , maximal inspiratory pressure ( p less than 0.01 ) increased , while airway resistance ( p less than 0.05 ) decreased significantly . Mouth occlusion pressure and minute ventilation mouth occlusion pressure index did not change after theophylline therapy . In placebo group , there was no significant change in airway obstruction assessed by spirometry and flow volume loops or in respiratory muscle function assessed by maximal respiratory pressures . It is therefore , concluded that oral sustained release theophylline has a bronchodilator effect in irreversible chronic obstructive lung disease , increases respiratory muscle function , but in therapeutic doses has no effect on respiratory center [7657856] The effects of famotidine ( 80 mg per day ) , cimetidine ( 1600 mg per day ) , and placebo on theophylline pharmacokinetic parameters in chronic obstructive pulmonary disease ( COPD ) patients were compared . This was an open-label , r and omized , three-period cross-over study , in which each subject first underwent a seven-day theophylline washout period , and thereafter received three single intravenous doses of theophylline ( 5 mg/kg infused over 30 minutes ) during the study . Each of the experimental treatments was administered orally every 12 hours for a total of 9.5 days ( 19 doses ) . Theophylline was infused after the 17th dose of each treatment . Fourteen serial blood sample s were collected before the start of each infusion , and for 30 hours after the end of each infusion . Plasma sample s were assayed for theophylline , pharmacokinetic parameters were estimated , and treatment effects on each parameter were compared . Fourteen COPD patients completed all three periods of the investigation . Famotidine treatment had virtually no effect on any of theophylline 's pharmacokinetic parameters . In contrast , cimetidine treatment significantly altered every pharmacokinetic parameter of theophylline as follows : Cimetidine decreased theophylline geometric mean CL from 2.74 L/h to 2.07 L/h ( P < .001 ) , and prolonged theophylline harmonic mean half-life from 6.6 to 9.6 hours ( P < .001 ) and mean residence time from 10.8 to 15.0 hours ( P < .001 ) . Cimetidine treatment slightly increased theophylline volume of distribution by approximately 10 % , and that change also was statistically significant ( P = .032 ) . The authors conclude that the treatment effects of cimetidine on theophylline pharmacokinetic parameters were in accord with those reported by others , and that famotidine treatment had no effect on any of theophylline 's pharmacokinetic parameters in COPD patients [2687897] A single-blind , placebo-controlled study was carried out in 30 patients with chronic obstructive bronchopneumopathy to assess the effectiveness and tolerability of the theophylline derivative , bamyphylline . On entry , patients were allocated to receive twice daily oral doses of either 600 mg bamyphylline or placebo for a period of 60 days . Spirometric measurements , blood pressure and respiratory rate recordings and blood gas analyses were made at baseline and after 10 , 30 and 60 days of treatment , as were assessment s of clinical and objective signs , such as sibili , rales and vesicular murmurs . Plasma concentrations of bamyphylline 1 hour after the first dose of the day were monitored at the same intervals . The results showed that there was a highly significant progressive improvement in pulmonary function which was already apparent after 10 days and this was accompanied by a marked improvement in cardiac dynamics and clinical signs . Plasma concentrations of bamyphylline remained stable throughout the study period and there were no reports of side-effects or significant variations in blood chemistry [2431838] Twenty-four patients ( five women ) aged 53 - 72 yr with both ischemic heart disease and asthma or chronic bronchitis receiving oral beta 2-agonists also received additional bronchodilating therapy with theophylline ( 600 mg daily ) , enprofylline ( 600 mg daily ) or placebo . The study was double-blind , r and omized , triple-crossover with each regimen given for two weeks . Holter monitoring was used during 48 consecutive hours in each period . Compared with placebo , addition of theophylline and enprofylline were associated with an increased mean hourly heart rate of 6 bpm ( p less than 0.001 ) . A small , but statistically significant ( p less than 0.05 ) increase in mean hourly frequency of premature ventricular beats ( PVBs ) occurred with enprofylline as compared with placebo . However , in only two patients with enprofylline ( and one patient with theophylline ) the increase in PVBs was such that a clinical ly relevant proarrhythmic effect seems possible . Furthermore , ventricular tachycardia was not more frequently observed with any xanthine than with placebo . Thus , combined oral bronchodilator therapy is not contraindicated in patients with obstructive lung disease and concomitant ischemic heart disease . Holter monitoring is recommended to assess the individual patient 's response to such therapy [389103] This study evaluated the effectiveness of oral bronchodilator therapy using theophylline in patients with nonreversible chronic obstructive pulmonary dis ease . Twelve chronic obstructive pulmonary disease patients were entered into a doubleblind crossover study using either active drug theophylline in 200 mg capsules ( Elixophyllin ) or placebo for 3 months , followed by 3 months of the alternate capsule . At baseline and monthly visits , data were recorded , including history , physical examination , and pulmonary function testing . Clinical ly , 7 of 11 patients responded favorably to theophylline , 3 were unchanged , and 1 improved on placebo . Comparison of each sign and symptom individually revealed no statistically significant differences . Pulmonary function ( FEV1 and FVC ) showed slight deterioration with placebo , but not with active drug therapy . These findings suggest that nonasthmatic patients may improve clinical ly during theophylline therapy whereas their pulmonary function may deteriorate during placebo therapy [6435664] We have compared the effects of oral theophylline and salbutamol on right and left ventricular function in twelve patients with chronic bronchitis and emphysema . Right and left ventricular ejection fraction ( RVEF and LVEF ) were measured using multiple gated radionuclide ventriculography . Theophylline 600 mg and salbutamol 4 mg both produced increases in RVEF and LVEF . There were no significant changes in blood gases after either drug . The clinical significance of the effects of oral bronchodilators on cardiac function in patients with chronic bronchitis and emphysema has yet to be determined [3046537] We conducted a four-period cross-over r and omized trial in which we found that patients with chronic airflow limitation demonstrated symptomatic improvement with both inhaled albuterol and oral theophylline . The response , however , was not uniform . We therefore tested the ability of acute change in forced expired volume in one second ( FEV1 ) following inhaled beta agonist to predict long-term symptomatic response to albuterol and theophylline . We found that the reproducibility of acute change in FEV1 over three repetitions was poor ( intraclass correlation 0.17 ) . Furthermore , the mean improvement FEV1 following inhaled albuterol across the three repetitions did not relate closely to symptomatic response to either albuterol or theophylline . We conclude that acute response to inhaled beta agonist is not useful for identifying patients with chronic airflow limitation who are likely to benefit from bronchodilator treatment [2778469] To test the relative merits of administering question naires with previous responses available ( the informed condition ) or unavailable ( the blind condition ) , we administered blind and informed versions of a quality of life question naire ( the Chronic Respiratory Disease Question naire , or CRQ ) in a r and omized , double-blind trial of bronchodilators in chronic airflow limitation . The responsiveness of the two methods , as reflected in the p-values associated with salbutamol and theophylline effects were comparable for three of the four dimensions of the CRQ . The data suggested possible increased responsiveness of the informed method for the emotional function dimension of the question naire . Changes in the informed CRQ dyspnea and fatigue dimensions showed stronger correlations with changes in spirometry , 6 minute walk distance , and rating of dyspnea after the walk test than did blind administration . Further , changes in all four CRQ dimensions showed stronger correlations with corresponding global ratings using the informed question naire . These results suggest that by letting study subjects see their previous responses the validity of subjective measures of health status in clinical trials can be improved [7874943] STUDY OBJECTIVE To determine the additive effect of oral theophylline in patients with stable COPD who received both inhaled salbutamol , 400 micrograms , and ipratropium bromide , 80 micrograms , four times daily administered with a metered-dose inhaler . DESIGN Twenty-four male patients with stable COPD ( FEV1 , 0.96 + /- 0.43 L ; 36.8 + /- 17.0 percent predicted [ % pred ] ) completed a r and omized , double-blind , placebo-controlled crossover trial with oral theophylline for 4 weeks . MEASUREMENTS AND RESULTS The average serum theophylline level was 15.0 + /- 5.5 micrograms/mL during treatment . On the whole , without inhalation of bronchodilators , FEV1 was 0.93 + /- 0.42 L during the placebo period and 1.00 + /- 0.43 L ( significantly different from placebo ; p < 0.01 ) during the theophylline period . At 15 and 60 min after inhalation of salbutamol , 400 micrograms , and ipratropium , 80 micrograms , the FEV1 with placebo was 1.12 + /- 0.43 L and 1.14 + /- 0.46 L , respectively , and the FEV1 with theophylline was 1.18 + /- 0.45 L ( p < 0.01 ) and 1.20 + /- 0.47 L ( p < 0.01 ) , respectively . Daily peak expiratory flow rate also improved . Daily symptom scores were not significantly different between theophylline and placebo periods . Nevertheless , eight patients reported a subjective benefit during the theophylline administration period , and they were thus considered subjective responders . While FEV1 after inhalation was significantly improved during the theophylline periods in subjective responders ( change in FEV1 between theophylline and placebo treatment 15 min after inhalation , 3.1 % pred ; 60 min , 3.5 % pred ) , postbronchodilator FEV1 was not significantly different between the placebo and theophylline periods in subjective nonresponders ( 15 min , 1.7 % pred ; 60 min , 1.6 % pred ) . CONCLUSIONS On the whole , theophylline has a small bronchodilating effect but does not improve the symptoms of patients with stable COPD . However , one third of patients with COPD may respond subjectively to theophylline . The additive bronchodilating effect of theophylline may be related to the symptomatic improvement in subjective responders [7040097] Using a double-blind , cross-over design the acute bronchodilating effect of 375 mg microcrystalline theophylline , 5 mg terbutaline , a combination of both drugs and placebo was studied in 11 patients suffering from moderate to severe chronic obstructive lung disease with partially reversible airway obstruction . Plasma concentrations both theophylline and terbutaline were measured . The bronchodilation produced by oral intake of 5 mg terbutaline and 375 mg theophylline was comparable . The maximal median value of terbutaline in plasma was 4.6 ng/ml 2 h after intake of medication , followed by a decline with a double peak in some patients . The maximal median increase of FEV1 was 37 % 3 h after intake of medication . The maximal median plasma level of theophylline reached 12.5 ng/ml 30 min after intake of the medication . The median maximal increase of FEV1 was 24 % . One hour after intake of medication and throughout the whole test period up to 7 h , the combination of 5 mg terbutaline and 375 mg theophylline produced a significantly greater bronchodilation than each drug alone . It is concluded that 375 mg microcrystalline theophylline produced a significantly greater bronchodilation than each drug alone . It is concluded that 375 mg microcrystalline theophylline and 5 mg terbutaline produces almost equal bronchodilating activity : a combination of both drugs , however , results in further bronchodilation [8797406] We compared the effects of evening administration of sustained-release theophylline ( Uniphyl ) and qid inhaled beta 2-agonist ( salbutamol , two 100-micrograms puffs ) on sleep quality and nocturnal oxygen saturation in 20 patients with COPD . Patients with FEV1 less than 70 % predicted and FEV1/FVC ratio less than 70 % were eligible to participate in this double-blind , crossover study , with 2-week treatment arms . Patients recorded morning and evening peak flow and symptoms in a daily diary . On the last day of each treatment period , overnight polysomnography was done . Spirometric indexes were measured before retiring and on awakening . Patients spent less time at less than 90 % oxygen saturation ( 51 + /- 92 min vs 72 + /- 105 min ; p = 0.03 ) during theophylline treatments than during salbutamol treatment . There was a smaller overnight decrease in FEV1 ( 0.04 L vs 0.13 L ; p = 0.04 ) after theophylline than after sallbutamol treatment . FEV1/FVC ratio and maximum expiratory flow at 50 % of vital capacity ( V50 ) increased overnight with theophylline and decreased with salbutamol ( p = 0.014 , 0.025 ) . Morning peak expiratory flow rate was higher with theophylline ( 4.0 + /- 1.7 L/s ) than with salbutamol ( 3.6 + /- 1.8 L/s ; p = 0.004 ) . The duration of patient-reported nocturnal wheezing was lower with theophylline than with salbutamol ( p = 0.006 ) . There were no differences between treatments in sleep quantity , efficiency , staging , or subjective quality . We conclude that , compared with salbutamol , evening administration of once-daily theophylline results in better nocturnal oxygen saturation and an improvement in the overnight change in pulmonary function , without affecting sleep architecture , in patients with COPD [3147048] OBJECTIVE --To evaluate measurement of the trapped gas volume as a measure of respiratory function in patients with chronic obstructive airways disease and their response to treatment with theophylline . DESIGN -- Patients able to produce consistent results on testing of respiratory function spent two weeks having dosage of theophylline adjusted to give individual pharmacokinetic data . This was followed by r and om assignment to four consecutive two month treatment periods -- placebo and low , medium , and high dose , as assessed by serum concentrations of theophylline . Respiratory function and exercise performance was assessed at the end of each two month period . SETTING --Chest unit in district hospital . PATIENTS --Thirty eight patients with chronic bronchitis and moderate to severe chronic obstruction to airflow were recruited ; 33 aged 53 - 73 years completed the study . INTERVENTIONS --Dosage of oral theophylline increased during two week optimisation period to 800 mg daily unless toxicity was predicted , when 400 mg was given . Targets for the steady state serum theophylline concentrations were 5 - 10 mg/l in the low dose period , 10 - 15 mg/l in the medium dose , and 15 - 20 mg/l in the high dose period . ENDPOINTS -- Respiratory function as measured by forced expiratory volume in one second , forced vital capacity , peak expiratory flow rate , slow vital capacity , and static lung volumes using helium dilution and body plethysmography from which trapped gas volume was derived . Exercise performance assessed by six minute walking test and diary cards using visual analogue scale . MEASUREMENTS AND MAIN RESULTS --The forced expiratory volume in one second , forced vital capacity , and peak expiratory flow rate changed only slightly ( about 13 % ) over the range of doses . There was a linear dose dependent fall of trapped gas volume from 1.84 l ( SE 0.157 ) to 1.42 l ( 0.152 ) , 1.05 l ( 0.128 ) , and 0.67 l ( 0.102 ) during the placebo and low , medium , and high dose treatment periods . Mean walking distance increased by up to 55.6 m ( 20 % ) . There was a modest improvement in dyspnoea as the dose of theophylline was increased . Side effects were mostly minor but they became more frequent as the dose was increased . CONCLUSION --The fall in trapped gas volume may reflect an improvement in peripheral ventilation ( associated with treatment with theophylline ) which is less apparent in the more common tests of lung function used in patients with chronic obstructive airways disease [7032378] We compared a 2-week course of 32 mg/d methylprednisolone with placebo in a double-blind crossover trial in 46 well-characterized patients with stable chronic obstructive pulmonary disease . Placebo and steroid trials were separated by 2 weeks when no tablets were given . Response was assessed by measuring forced expiratory volume in 1 second ( FEV1.0 ) . Placebo responses were normally distributed ( mean , 0.8 % change in FEV1.0 ; range , -30 % to 33 % ) . Six patients showed a greater than 50 % increase of FEV1.0 in response to steroid ; a seventh showed a 36 % increase and an eighth , a 29 % increase . Because of these patients the group as a whole showed a significantly greater FEV1.0 after steroid than after placebo . The eight steroid responders did not differ from nonresponders in age , sex , smoking history , or duration and intensity of symptoms including wheeze . Baseline lung function and eosinophilia of blood or sputum did not differ between the two groups . Patients who responded to steroids also responded to inhaled beta agonists : Acute bronchodilator response averaged 25 % in steroid responders and 13 % in nonresponders , a difference that was statistically significant although there was overlap between the two groups [1628722] Partial bronchodilator reversibility can be demonstrated in many patients with stable chronic obstructive pulmonary disease ( COPD ) , but its relevance to exercise capacity and symptoms is uncertain . Previous data suggest that anticholinergic bronchodilators do not improve exercise tolerance in such patients . We studied 32 patients with stable COPD , mean age 65 yrs , in a double-blind , placebo-controlled , cross-over trial of the inhaled anticholinergic drug , oxitropium bromide . From the within and between day placebo spirometry , we derived the spontaneous variation in forced expiratory volume in one second ( FEV1 ) and forced vital capacity ( FVC ) of this population ( FEV1 140 ml ; FVC 390 ml ) and considered responses beyond this to be significant . Oxitropium bromide increased baseline FEV1 from 0.70 ( 0.28 ) l ( mean ( SD ) ) to 0.88 ( 0.36 ) l. The 6 min walking distance increased by 7 % compared with placebo , whilst resting breathlessness scores fell from 2.0 to 1.23 at rest and 4.09 to 3.28 at the end of exercise after the active drug . Improvements in walking distances and symptoms were unrelated to changes in either FEV1 or FVC , indicating that routine reversibility testing is not a good predictor of symptomatic benefit in these patients [8202902] BACKGROUND --Theophylline is a well known bronchodilator which has been used for more than 50 years in the treatment of obstructive pulmonary diseases . In patients with severe chronic obstructive pulmonary disease whose cardiopulmonary performance is limited by their ventilatory capacity the administration of theophylline may improve exercise performance . METHODS --A r and omised , placebo controlled , double blind , crossover trial was conducted in 22 patients with severe but stable disease . The patients ( mean age 68 years ) were studied before and after one month of placebo and one month of treatment with a sustained release preparation of theophylline administered orally . The theophylline dose was adjusted until a blood level above 55.5 mumol/l was achieved . The two treatments were administered in r and om order and separated by a two week washout period . After theophylline was administered for one month a mean level of 68.2 mumol/l was achieved . Pulmonary function tests , arterial blood gas measurements , maximal voluntary ventilation ( MVV ) , and an incremental exercise test were performed before ( baseline ) and at the end of the first and second month of treatment . RESULTS --Pulmonary function tests showed no improvement in the flow parameters but showed an improvement in MVV after treatment with theophylline . Pulmonary gas exchange was improved after theophylline ( resting arterial PO2 8.91 v 8.59 kPa , PCO2 5.38 v 5.56 kPa ) . The incremental exercise study showed improvement in maximal work rate ( 86.5 v 75.0 watts ) and maximal ventilation ( VEmax ) ( 46.7 v 43.01/min ) . The dyspnoea index on maximal effort ( VEmax/MVV ) , anaerobic threshold , and oxygen pulse remained unchanged . Resting and exercise heart rate were higher after theophylline . CONCLUSIONS --Theophylline improved cardiorespiratory performance in these patients with severe chronic obstructive pulmonary disease mainly by increasing the ventilatory capacity [7982769] The effect of oral theophylline on clinical course , exercise , neuropsychological performance and bronchial reactivity was studied in chronic airflow obstruction . Twelve patients with chronic obstructive pulmonary disease ( COPD ) [ mean age 62.4 + /- 1.6 years ( SE ) , and forced expiratory volume in 1 sec of 1.15 + /- 0.1 l ] were r and omized to 4 weeks treatment with oral theophylline followed by 4 weeks of placebo , in a double-blind fashion . During each period , patients underwent clinical evaluation , incremental exercise , a battery of neuropsychological tests measuring a wide range of cognitive functions , and an inhaled methacholine provocation . On the active drug ( levels 9.5 + /- 1 mg/l ) , vital capacity and maximal breathing capacity were 16 + /- 7 % and 20 + /- 7 % respectively , higher relative to placebo ( P < 0.04 ) . Exercise capacity , as reflected by peak O2 uptake and the anaerobic threshold , improved 14 + /- 5 % and 18 + /- 5 % ( P < 0.04 ) . In contrast , bronchial responsiveness to inhaled methacholine and the mean scores on the neuropsychological tests were not significantly altered by the drug . Clinical symptoms were unaltered , but mild side effects were more common on theophylline . We concluded that in moderate to severe COPD , theophylline treatment , at the low range of the therapeutic dose , improves lung function and exercise capacity . This improvement is achieved with no detectable alteration of bronchial reactivity to methacholine and with no deleterious effect on cognitive functions [3717762] The effect of hypoxemia on the disposition of theophylline was examined in 10 stable patients with chronic obstructive pulmonary disease ( COPD ) receiving chronic theophylline and supplemental home oxygen therapy . Pharmacokinetics after intravenous theophylline were estimated on the second day of supplemental oxygen ( PaO2 , 69 + /- 4 mmHg ; mean + /- SEM ) and on the second day of room air breathing ( PaO2 , 43 + /- 3 ) using a r and omized cross-over design . On each occasion stable isotope-enriched theophylline ( 10 mg , m/z 183 ) was administered intravenously along with the regular oral dose of theophylline ( m/z 180 ) . Concentrations of both forms of theophylline in plasma sample s obtained over 24 h were measured using mass spectrometry . Theophylline clearance during oxygen therapy ( 0.048 + /- 0.005 L/h/kg ) was similar to that during room air breathing ( 0.050 + /- 0.004 L/h/kg ) . Values for elimination half-life ( 7.6 + /- 0.8 versus 6.8 + /- 0.6 h ) and volume of distribution at steady state ( 0.450 + /- 0.021 versus 0.429 + /- 0.024 L/kg ) were also unchanged . The volume of distribution of theophylline was inversely related to arterial pH during oxygen therapy ( pH range , 7.32 to 7.44 ) and during room air breathing ( pH range , 7.33 to 7.47 ) . Although hypoxemia does not alter theophylline clearance in patients with COPD , theophylline loading doses may need adjustment according to arterial pH because of an effect on volume of distribution [373776] The effect of theophylline ethylenediamine oblong tablets ( Euphyllin retard ) was tested in 40 patients by means of a double-blind trial , applying a dose of 2 X 350 mg/d and 2 X 700 mg/d . At the dose of 2 X 700 mg/d Euphyllin retard showed a good bronchodilatory effect . A reduction of the obstruction in the airways and an improvement of the arterial blood gases was statistically secured . At the dose of 2 X 350 mg/d a sufficient bronchodilation could not be recorded [2406328] To compare the efficacy and side effects of two xanthine derivatives in the maintenance therapy of reversible obstructive airway disease , 242 patients were assigned in r and omized , double-blind fashion to receive either oral enprofylline or theophylline for 5 weeks in addition to their usual maintenance regimens . After a week of placebo xanthine therapy , enprofylline-treated patients received 150 mg of this drug twice daily ( b.i.d . ) for 3 days , 300 mg b.i.d . for 2 weeks , and 450 mg b.i.d . for 2 weeks . Theophylline was administered in identical doses , except that the final dosage increase was not made if plasma theophylline was 12 mg/ml or higher . At 300 mg b.i.d . , both drugs significantly increased morning peak expiratory flow rate ( PEFR ) , the mean increase above baseline being significantly higher for theophylline-treated patients ( 29.9 + /- 37.2 L/min ) than for enprofylline-treated patients ( 17.4 + /- 36.9 L/min ) ( p = 0.023 ) . At 450 mg b.i.d . , improvement in morning PEFR was not significantly different between theophylline-treated ( 31.5 + /- 44.4 L/min ) and enprofylline-treated groups ( 23.5 + /- 48.4 L/min ) . Evening PEFR , FEV1 , and asthma symptom scores also improved significantly , demonstrating no significant difference between groups . The incidence of side effects was also similar between groups . We conclude that both enprofylline and theophylline offer useful bronchodilatation in the maintenance therapy of asthma , enprofylline , 450 mg b.i.d . , being approximately equivalent to theophylline , 300 or 450 mg b.i.d [7036401] In a double-blind placebo-controlled trial in 24 patients fulfilling the MRC criteria for chronic bronchitis , oral salbutamol 4 mg and slow-release aminophylline ( Phyllocontin ) 450 mg produced similar and significant ( p less than 0.05 ) mean increases in forced expiratory volume in one second ( FEV1 ) . A significantly greater increase in mean FEV1 and forced vital capacity ( FVC ) was seen when both drugs were given although there was no statistical evidence of synergistic interaction . Salbutamol significantly increased the mean distance walked in 12 minutes ( 12MD ) ( p less than 0.02 ) by 56 metres and a similar increase of 54 metres ( p less than 0.001 ) was seen after Phyllocontin . With both drugs in combination mean 12MD increased by 51 metres ( p less than 0.02 cf placebo ) , a change not significantly different from that observed with either drug alone . Oral salbutamol and Phyllocontin improve exercise tolerance in chronic bronchitis . The significantly greater changes in FEV1 and FVC result ing from simultaneous administration of the two drugs are not associated with further improvement in exercise tolerance [8630581] Dynamic hyperinflation ( DH ) is a major pathophysiologic consequence of airflow limitation during exercise in patients with chronic obstructive pulmonary disease ( COPD ) and an important contributing factor to breathlessness . In this study we aim ed to examine the effect of inhaled beta agonist therapy on DH during exercise in these patients and the relationship between changes in DH and breathlessness . In 13 COPD patients ( mean age 65.1 + /- 2.0 , FEV1 1.20 + /- 0.17 , FEV1/FVC 40 + /- 3 ) we measured pulmonary function tests , exercise breathlessness by Borg score , and exercise flow volume and pressure volume loops on two separate days . Prior to testing , patients r and omly received inhaled placebo or albuterol on the first test day and the alternative medication on the second test day . From measurements of exercise inspiratory capacity ( IC ) , we calculated the end-expiratory and end-inspiratory lung volumes ( EELV , EILV ) . We used esophageal pressure recordings to measure peak inspiratory esophageal pressure ( Pesins ) during exercise and this was related to the maximal capacity for pressure generation taking into account lung volume and airflow changes ( Pcapi ) . Bronchodilator caused significant increase in both FEV1 and FVC ( + 0.23 and + 0.51 , p<0.01 ) . Comparisons of breathlessness , exercise volumes , and pressures were made at the highest equivalent work load . There was a significant reduction in the peak exercise EELV/TLC ( 80 + /- 0.02 % to 76 + /- 0.02 % , p<0.05 ) while the peak EILV/TLC decreased by 2 % ( 97 + /- 1 % to 95 + /- 1 % , p<0.05 ) . The peak Pesins/Pcapi decreased ( 0.79 + /- 0.10 to 0.57 + /- 0.05 , p<0.05 ) , and the Pcapi - Pesins increased ( 7.4 + /- 3 to 13.0 + /- 3 cm H2O , p<0.05 ) . There was significant improvement in neuroventilatory coupling for volume change ( Pesins/Pcapi/VT/TLC 5.45 + /- 0.5 to 3.25 + /- 1.0 , p<0.05 ) . There was a significant reduction in breathlessness as measured by Borg score ( 4.5 + /- 0.7 to 3.1 + /- 0.5 , p<0.05 ) and there was a significant correlation between delta Borg and delta EILV/TLC ( r=0.771 , p<0.01 ) with a trend for Pesins/Pcapi/VT/TLC ( r=0.544 , p=0.067 ) . There was also a significant correlation between delta EELV/TLC and delta Pesins/Pcapi/VT/TLC ( r=0.772 , p<0.01 ) . The relationships between delta Borg , delta resting volumes , and flow rates were not significant . We conclude that in patients with COPD , inhaled bronchodilator reduces exercise DH and improves inspiratory pressure reserve and neuroventilatory coupling . Changes in DH and neuroventilatory coupling were the main determinants of reduced breathlessness [9358138] BACKGROUND Inhaled glucosteroids and oral theophylline are widely used to treat asthma . We compared the benefits of adding theophylline to inhaled glucosteroid with those of doubling the dose of inhaled glucosteroid in patients with persistent symptoms despite the use of inhaled glucosteroid . METHODS In a double-blind , placebo-controlled trial , we r and omly assigned 62 patients to receive either 400 microg of inhaled budesonide ( low-dose budesonide ) with 250 or 375 mg of theophylline ( depending on body weight ) or 800 microg of inhaled budesonide ( high-dose budesonide ) . All doses were given twice daily for three months . Lung function was measured serially , and patients kept records of peak expiratory flow , symptoms , and albuterol use . The effects of treatment on endogenous cortisol levels were also assessed . RESULTS Both treatments result ed in improvements in lung function that were sustained throughout the study . As compared with treatment with high-dose budesonide , treatment with low-dose budesonide plus theophylline result ed in greater improvements in forced vital capacity ( P=0.03 ) and forced expiratory volume in one second ( P= 0.03 ) . There were significant and similar reductions in beta2-agonist use and the variability of peak expiratory flow , a correlate of bronchial hyperresponsiveness and the severity of asthma . Serum cortisol concentrations were significantly reduced in the group given high-dose budesonide ( from a mean [ + /-SE ] of 18.4+/-2.4 microg per deciliter to 15.9+/-2.1 microg per deciliter , P=0.02 ) but were unchanged in the other group . The median serum theophylline concentration was 8.7 microg per milliliter ( therapeutic range , 10 to 20 ) among those who received theophylline . Both treatments were well tolerated . CONCLUSIONS For patients with moderate asthma and persistent symptoms , low-dose inhaled budesonide with theophylline and high-dose inhaled budesonide produced similar benefits . Effects were achieved at theophylline concentrations below the recommended therapeutic range . The addition of low-dose theophylline to inhaled glucosteroid may be preferable to and cheaper than increasing the dose of inhaled glucosteroid [1812479] 24 patients with COPD and delta FEV1 greater than 15 % were included in a double-blind crossover study . 7 dropouts due to deterioration of findings and incomplete data reduced the number of assessable patients to 17 . Most of the patients had been pretreated with a slightly higher theophylline dosage before initiation of the study . In the preliminary period a 24-hour profile of the peak flow was set up with a morning and evening theophylline level . During the 5-day treatment intervals a 24-hour profile of the serum theophylline levels and of the peak flow was recorded at two-hour intervals . A complete lung function test was performed in each phase . The pharmacokinetic data of both preparations are comparable . Euphylong showed a bioavailability of 83 % , the maximum of the serum level was attained at night . Serum level variations were only slightly higher than those of the reference drug . Euphylong had a night level of 24 % above the daily average ( reference drug 3 % ) . This was associated in a part of the group , about one-third of the total number of patients , with an improvement of the " morning dip " compared with the preliminary period or the reference drug . Over the entire group of patients there were no differences between both drugs or the preliminary period that could be ascribed to the theophylline premedication . An advantage shown by Euphylong was the better predictability of the serum levels . During the time period of the clinical routine the deviation of the serum level from the actual serum maximum was less than 15 % [10202315] Background : Chronic continuous airway inflammation caused by eosinophils has been noted to play critical roles in the pathophysiology of bronchial asthma , in addition to reversible obstruction and hypersensitivity of the respiratory tract . Therefore , suppression of chronic airway inflammation has become more important in asthma treatment . Although theophylline has been a conventionally used bronchodilator , it has been recently reported to have concurrent anti-inflammatory effects . Objective : Accordingly , we studied the effects of a slow-release theophylline preparation , Theolong ® , on airway inflammation . Methods : Administration of Theolong 400 mg/day to 24 patients with mild or moderate asthma and measuring eosinophil cationic protein ( ECP ) , a marker of airway inflammation , and eosinophils in sputum and peripheral blood at 4 and 8 weeks . Results : As a result , sputum ECP , serum ECP and sputum eosinophil count ( % ) were significantly lowered after 4 and 8 weeks . Conclusion : Thus , in the theophylline-administered group , slow-release theophylline , Theolong ® , was effective in treating asthma , with anti-inflammatory effects on inflammatory cells besides its bronchodilator action [10193252] OBJECTIVES To determine whether children with severe acute asthma treated with large doses of inhaled salbutamol , inhaled ipratropium , and intravenous steroids are conferred any further benefits by the addition of aminophylline given intravenously . STUDY DESIGN R and omised , double blind , placebo controlled trial of 163 children admitted to hospital with asthma who were unresponsive to nebulised salbutamol . RESULTS The placebo and treatment groups of children were similar at baseline . The 48 children in the aminophylline group had a greater improvement in spirometry at six hours and a higher oxygen saturation in the first 30 hours . Five subjects in the placebo group were intubated and ventilated after enrolment compared with none in the aminophylline group . CONCLUSIONS Aminophylline continues to have a place in the management of severe acute asthma in children unresponsive to initial treatment [9282234] Exercise tolerance in chronic obstructive pulmonary disease ( COPD ) patients treated with oral aminophylline may be different from those treated with high-dose inhaled ipratropium bromide . The purpose of this study was to compare the effects of therapeutic doses of oral aminophylline with high-dose ipratropium bromide on spirometry and exercise tolerance . The study was conducted on three consecutive days in a double-blind , r and omized , crossover fashion . Baseline studies obtained on each study day included vital signs , simple spirometry and a symptom-limited maximal cardiopulmonary stress test , after which patients received one of the following treatments on each day : Treatment 1 , inhaled ipratropium ( total dose of 144 micrograms ) with placebo tablets ; Treatment 2 , inhaled placebo with oral aminophylline ( 400 mg ) ; Treatment 3 , inhaled placebo and placebo tablets . Simple spirometry was repeated at 60 and 120 min after baseline . Vital signs and cardiopulmonary stress testing was repeated at 120 min . Eighteen patients were enrolled in the study , and 17 of these completed the study . There was a significant ( P < 0.05 ) increase in both forced expiratory volume in 1 s ( FEV1 ) , from 0.75 ( 0.21 ) to 0.92 ( 0.3 ) , and forced vital capacity ( FVC ) , from 1.8 ( 0.79 ) to 2.11 ( 0.84 ) , with high-dose ipratropium despite prior beta-agonist therapy . Lack of improvement in exercise capacity was noted with ipratropium despite improvement in spirometry . These results suggest that elderly patients with severe COPD may have exercise limitation that is not directly dependent on severity of airflow obstruction . Ipratropium bromide and aminophylline demonstrated no acute effects on exercise capacity [7788518] BACKGROUND Previous clinical therapeutic research has shown that inhaled nedocromil sodium can replace maintenance oral sustained release theophylline in the management of asthma patients . OBJECTIVE To compare directly the efficacy and safety of nedocromil sodium and sustained release theophylline . METHODS Using a r and omized , double-blind , double-dummy , parallel-group design , 105 patients with reversible obstructive airways disease ( 77 asthmatic patients ) recruited from four referred-care clinics received , in addition to their existing therapy , 4 mg nedocromil sodium four times daily or sustained release theophylline ( maximum daily dose 13 mg/kg ) for 6 weeks . Patients with serum theophylline levels within the therapeutic range of 10 to 20 micrograms/mL were retained for efficacy analysis . All were included in a tolerability analysis . Day and nighttime symptoms , inhaled bronchodilator use , morning tightness , cough , and twice daily peak flows were recorded on diary cards . Disease severity , lung function and unusual events were evaluated bi-weekly , and opinion of treatment after 6 weeks . RESULTS Both treatments improved symptoms , inhaled bronchodilator use and lung function to the same extent . Both treatments were very to moderately effective in > 70 % patients . The occurrence of gastrointestinal ( P < .05 ) and central nervous system ( P < .01 ) unusual events was significantly lower for nedocromil sodium compared with theophylline treated patients . CONCLUSIONS Nedocromil sodium and theophylline were equally effective in this group of patients but nedocromil sodium treatment was associated with significantly fewer side effects , and therefore may be the treatment of choice [6213382] In two groups of patients , 15 with asthma and 15 with chronic bronchitis , the bronchodilator effects of ipratropium bromide , of fenoterol plus theophylline , and of the combination of the three drugs , were compared using a double-blind , single-dose , placebo-controlled format . Ipratropium bromide caused rapid bronchodilatation which was not significantly different in asthmatic patients and patients with bronchitis ( delta FEV1 = .29 L in one hour in asthmatic patients , .18 L in patients with bronchitis ) . In contrast , fenoterol plus theophylline induced a considerably greater effect in asthmatic patients ( delta FEV1 = .41 L in one hour ) than in those with bronchitis ( delta FEV1 = .07 in one hour ) . The use of the three drugs in combination compared with ipratropium bromide alone , or fenoterol plus theophylline alone , result ed in a significant additional bronchodilatation in asthmatic patients . In the patients with bronchitis , the triple combination was clearly superior to fenoterol plus theophylline . A similar trend was present in comparing the triple combination to ipratropium bromide , but the difference did not reach statistical significance . There was no evidence of synergism when ipratropium bromide was combined with fenoterol plus theophylline in that the total bronchodilator effect was approximately additive . Asthmatic patients and the physician were able to distinguish the triple combination from placebo . No such ability was demonstrated with respect to those with bronchitis . All three drugs were well tolerated . Side effects were mostly mild , and none was related to the use of ipratropium [10588606] We tested the hypothesis that the decrease in dyspnea in patients with COPD with inhaled albuterol is in part due to increased diaphragmatic contractility . Eleven patients with COPD inhaled albuterol or placebo in a double-blind r and omized manner . Subsequently , dyspnea was measured while patients breathed through inspiratory resistors , and diaphragmatic contractility was quantified during maximal inspiratory efforts and after twitch stimulation of the phrenic nerves . Albuterol produced a decrease in dyspnea ( 5 + /- 2 to 4 + /- 2 [ SD ] Borg units , p < 0.01 ) , and increases in maximal transdiaphragmatic pressure ( 92.4 + /- 37.2 to 102.8 + /- 37.2 cm H(2)O , p < 0.03 ) and potentiated twitch transdiaphragmatic pressures ( 21.6 + /- 7.1 to 25.2 + /- 7.6 cm H(2)O , p < 0.02 ) . The decrease in dyspnea correlated with the increases in maximal and twitch transdiaphragmatic pressures : r = -0.64 ( p = 0 . 04 ) and r = -0.65 ( p = 0.04 ) , respectively . Compared with placebo , albuterol produced an increase in inspiratory capacity ( 1.87 + /- 0 . 71 to 2.26 + /- 0.74 L , p = 0.002 ) , which accounted for the increases in maximal and twitch transdiaphragmatic pressures . The decrease in dyspnea correlated with the increase in inspiratory capacity ( r = -0 . 62 , p = 0.04 ) , but not with the increase in FEV(1 ) ( r = -0.13 , p = 0 . 72 ) . In conclusion , albuterol relieves dyspnea and enhances respiratory muscle output in patients with COPD primarily by improving the length-tension relationship of the diaphragm rather than by improving its contractility [1899325] To investigate the effect of theophylline on sleep and sleep-disordered breathing in patients with chronic obstructive pulmonary disease ( COPD ) , we studied 12 male nonhypercapnic subjects with a mean + /- SEM age of 62.8 + /- 2.5 yr and a FEV1 of 1.36 + /- 0.11 L using a r and omized double-blind crossover protocol . Sustained-action theophylline ( 250 mg three times or four times a day ) or placebo was administered for 2 days , and the alternate drug was administered on the following 2 days . Sleep studies were performed on Nights 2 and 4 with spirometry at 9:00P.M. and 7:00A.M. Two puffs of metaproterenol or albuterol were administered at 10:00P.M. on both study nights . A theophylline level , drawn at bedtime ( 10:00 to 11:00P.M. ) , was 14.2 + /- 0.78 micrograms/ml on the theophylline nights and less than 2 on placebo nights . The morning FEV1 was significantly better during theophylline administration ( 1.27 + /- 0.12 versus 1.00 + /- 0.11 L , p less than 0.001 ) . The mean arterial oxygen saturation ( SaO2 ) and transcutaneous carbon dioxide pressure ( PCO2 ) were also better during NREM sleep on theophylline nights . Neither the mean SaO2 and transcutaneous PCO2 during REM sleep nor the apnea plus hypopnea index ( events per hour of sleep ) differed between placebo and theophylline nights . Theophylline administration did not impair the amount or architecture of sleep as neither total sleep time nor the fraction of time spent in Stages 1 , 2 , and 3/4 and REM differed between the two regimens . The number of arousals per hour of sleep was slightly less on theophylline nights ( 19.9 + /- 1.7 versus 24.9 + /- 2.7 , p less than 0.05 ) . ( ABSTRACT TRUNCATED AT 250 WORDS [1596003] The effect of theophylline on sleep quality and cognitive performance in patients with obstructive lung disease has been the subject of controversy . To examine the direct effects of theophylline on sleep quality and cognitive performance , without confounding effects from bronchodilatation , we have undertaken a study of the drug in healthy subjects . A double-blind , placebo-controlled crossover protocol was used to study the effect of oral sustained-release theophylline ( Theodur ) on subjective sleep quality , objective sleep quality , and cognitive performance . Overnight sleep studies were carried out on Nights 13 and 14 of each 2-wk study limb , and cognitive performance tests administered on Days 1 and 13 of each limb . A total of 18 subjects satisfactorily completed the study ( 8 males , median age 37 , range 24 to 67 yr ) . Theophylline levels were median 10.2 , range 2.3 to 13.3 micrograms/ml on Day 1 and 14.7 , range 9.6 to 17.5 micrograms/ml on Day 13 . No significant difference was observed between theophylline and placebo on subjective or objective sleep quality or on acute or medium-term cognitive performance . We conclude that theophylline does not affect sleep quality or cognitive performance in normal adults [2699466] A multicentre , double-blind , r and omized trial was carried out in 11 Italian Pneumologic Clinics to investigate the therapeutic efficacy and tolerability of doxofylline compared with slow-release theophylline in 139 patients ( 86 males , 53 females ) aged 17 - 77 years suffering from reversible chronic airways obstruction . The two groups of 69 patients on doxofylline and 70 patients on theophylline did not differ in their baseline clinical and functional parameters . After one week of wash-out , the two drugs were administered orally at a dose of 400 mg twice daily of doxofylline and 300 mg twice daily of theophylline . The treatment and follow-up lasted 28 days . Inhaled salbutamol on dem and was allowed in the wash-out week and throughout the trial . The average serum levels at day 14 and 28 were : doxofylline 7.5 and 8.5 micrograms/ml ; theophylline 10.4 and 7.95 micrograms/ml respectively . Both drugs significantly increased spirometric parameters ( p less than 0.001 for all tests ) and significantly reduced salbutamol consumption ( p less than 0.001 for both drugs ) . Doxofylline was better tolerated than theophylline considering either the number of unwanted side-effects : ( doxofylline 12 ; theophylline 37 ) or number of drop-outs due to side-effects ( doxofylline 5 ; theophylline 10 ) . From these results doxofylline seemed to be a good alternative to theophylline in the treatment of reversible chronic airway obstruction in view of its better safety profile [8989057] To determine the effect of theophylline on respiratory muscle efficiency ( RME ) , 12 normal subjects were given theophylline vs placebo in a double-blind , r and omized crossover protocol . Spirometry , resting energy expenditure , minute ventilation , RME and oxygen cost of breathing were measured at baseline , after taking theophylline , and after placebo . RME was calculated by dividing the added work required to breathe through a threshold load by the added energy consumed during loaded breathing . Oxygen cost of breathing was calculated by dividing the increase in oxygen consumption induced by breathing an air/carbon dioxide mixture by the associated increase in minute ventilation . RME increased from 3.3 + /- 1.6 % at baseline to 7.9 + /- 3.2 % after theophylline ( p < 0.01 ) but did not change significantly after placebo ( 4.8 + /- 2.4 % ) . Oxygen cost of breathing decreased from 3.9 + /- 2.4 mL O2 per liter at baseline to 1.7 + /- 0.7 mL O2 per liter after theophylline ( p < 0.05 ) but did not change significantly after placebo ( 2.8 + /- 1.3 mL O2 per liter ) . Theophylline use was also associated with an 18 % increase in minute ventilation ( p < 0.01 ) and a 15.7 % increase in resting energy expenditure ( p < 0.01 ) . Theophylline improves measured RME and reduces oxygen cost of breathing in normal subjects . These effects are offset by increases in resting energy expenditure and minute ventilation [9224226] BACKGROUND Patients with chronic obstructive pulmonary disease ( COPD ) tend to develop secondary erythrocytosis to compensate for their chronic hypoxia . Theophylline has recently been shown to reduce hematocrit and erythropoietin blood levels in normal subjects and in patients with erythrocytosis after renal transplantation . OBJECTIVE To determine whether theophylline may be used to lower the hematocrit in patients with COPD . METHODS Two hundred four patients with COPD were studied retrospectively and 10 patients prospect ively ( 8 starting treatment with the drug [ group 1 ] and 2 who suspended its long-term use [ group 2 ] ) for the correlation between theophylline therapy and hematocrit and erythropoietin level . RESULTS In the patients studied retrospectively , lower hematocrits were found in the theophylline-treated than in the untreated patients ( 0.43 + /- 0.006 vs 0.46 + /- 0.007 , respectively ; P < .002 ) . Twelve untreated patients and 2 of those treated with theophylline had hematocrits above 52 % . Oxygen saturation levels were similar in both groups , and exclusion of patients with oxygen saturation lower than 88 % did not change the pattern , suggesting that the effect of theophylline could not be entirely explained by improved oxygen availability . Seven of the 8 patients studied prospect ively in group 1 ( P < .02 ) and the 2 patients in group 2 showed inverse correlations between hematocrits and theophylline administration . A similar pattern was observed with serum erythropoietin levels in 5 of 7 patients studied . The effects were reproducible on rechallenge in 3 of the 4 patients in group 1 and the 2 patients in group 2 . CONCLUSIONS Theophylline may have a beneficial effect in treatment and prevention of erythrocytosis in patients with COPD [6738652] We studied the effects of theophylline on diaphragmatic strength and fatigue in 15 patients with severe chronic obstructive pulmonary disease . Diaphragmatic strength was assessed by measurement of the transdiaphragmatic pressure generated at functional residual capacity during a maximal inspiratory effort against closed airways . Diaphragmatic fatigue was induced by resistive loaded breathing . The electrical activity of the diaphragm was recorded with an esophageal electrode during the fatigue runs , and the high-low ratio of the electrical signal was analyzed to assess diaphragmatic fatigue . Studies were performed before and after 7 and 30 days of theophylline administration ( mean plasma level , 13 + /- 2 mg per liter ) . A control group received a placebo instead of theophylline . Theophylline increased maximal transdiaphragmatic pressure by 16 per cent after 7 days of administration ( P less than 0.01 ) , and this increase persisted after 30 days . No significant change in maximal transdiaphragmatic pressure was observed in the group given the placebo . Theophylline also suppressed diaphragmatic fatigue in all patients who received it . We conclude that theophylline has a potent and long-lasting effect on diaphragmatic strength and fatigue in patients with fixed airway obstruction [3966709] Although orally administered theophylline has been prescribed widely in patients with nonreversible airway obstruction , symptomatic benefit has not been established . To assess the effects of orally administered theophylline on dyspnea , we performed a r and omized , double-bind , crossover , placebo-theophylline clinical trial in 12 ambulatory male patients with moderate to severe nonreversible airway obstruction . Dyspnea was rated using 2 clinical indexes based on 3 components affecting breathlessness : functional impairment , magnitude of task that evokes dyspnea , and the associated magnitude of effort . Dyspnea and physiologic parameters were measured on 4 occasions : at baseline , 4 wk after initial treatment , a second baseline after a 2-wk washout period , and 4 wk after the second medication . For the 12 patients , mean age ( + /- SD ) was 60 + /- 7 yr , forced expiratory volume in one second was 1.36 + /- 0.67 L ( mean , 40 % of predicted ) , and arterial oxygen tension was 71 + /- 10 mmHg . During the treatment phase , all patients had a therapeutic theophylline blood level ( range , 12 to 19 micrograms/ml ) . Theophylline significantly decreased the components of functional impairment ( p = 0.02 ) and magnitude of task ( p = 0.02 ) relating to dyspnea , as well as the overall dyspnea rating ( p = 0.01 ) . There were no significant differences between placebo and theophylline therapy for spirometry , arterial blood gas tensions , and the 12-min walking distance . Thus , sustained-release theophylline significantly reduced dyspnea in these ambulatory patients with moderate to severe nonreversible airway obstruction without altering lung function , gas exchange , or exercise performance [6751178] Orally administered theophylline is commonly prescribed for patients with chronic obstructive pulmonary disease ( COPD ) . It would be advantageous to predict those patients who will or will not respond to this methylxanthine . Forty men with COPD received placebo and theophylline orally , each for 1 month in a double-blind , single cross-over fashion . The acute response of the forced expiratory volume in one second ( FEV1 ) to isoproterenol inhalation ( 015 mg ) during placebo therapy was determined . The subjective and objective responses after 1 month of therapeutic theophylline concentrations ( 15.1 + /- 4.2 microgram/ml ) , mean + /- SD ) in these clinical ly stable subjects also were measured . The sensitivity and specificity of isoproterenol aerosolization for predicting an objective response to theophylline was 75 and 96 % , respectively . We conclude that isoproterenol inhalation can predict the response to orally administered theophylline in patients with COPD [2681505] We compared the frequency and severity of cardiac arrhythmias during combined oral theophylline and inhaled salbutamol vs. salbutamol therapy alone in 18 patients with moderate to severe chronic obstructive pulmonary disease who had concurrent cardiac disease . Seventeen patients showed at least one supraventricular premature complex ( SVPC ) on the 24-h ECG recording when receiving salbutamol alone : eight patients had isolated SVPCs , less than 10/h ; five patients had greater than or equal to 10 SVPCs/h ; eight patients showed runs of supraventricular tachycardia or paroxysmal atrial fibrillation . Seventeen patients also had at least one ventricular premature complex : seven patients had less than 10 isolated PVCs/h , five patients greater than or equal to 10 PVCs/h ; eight patients had paired or multifocal PVCs and one patient a run of ventricular tachycardia . The addition of oral theophylline at an average dose of 600 mg in the evening ( blood concentrations showed a mean maximum of 13.4 + /- 4.0 ( SD ) and minimum of 5.5 + /- 2.9 mg/l ) had no influence on the frequency or severity of either ventricular or supraventricular arrhythmias . Thus , cardiac arrhythmias are very common in patients with chronic obstructive pulmonary disease and concomitant heart disease , but oral theophylline added to a regimen of salbutamol does not seem to affect the occurrence or severity of arrhythmias [7613555] Theophylline is known to alter sleep architecture because of its affinity to adenosine receptors . One of the consequences of disrupted sleep is impaired cognitive performance . A single-blind , r and omized cross-over study of eight male chronic obstructive pulmonary disease ( COPD ) patients was undertaken to evaluate the effects of theophylline versus doxofylline on sleep architecture . The patients , who were all ex-smokers , had been treated with theophylline . Mean age was 53 + /- 12 yrs , forced expiratory volume in one second ( FEV1 ) 50 + /- 22 % predicted and forced vital capacity ( FVC ) 70 + /- 18 % predicted . Following a wash-out period , four patients were given oral slow-release theophylline ( T ) ( 300 mg b.i.d . ) for one week , followed by a cross-over to doxofylline ( D ) ( 400 mg t.i.d . ) for a second week . The other four patients were given the drugs in the reverse order . All patients underwent polysomnography at baseline and at the end of each week of treatment . The number of arousals per hour was 5.5 + /- 2.9 at baseline , 9.4 + /- 5.2 during T treatment and 5.4 + /- 4.4 during D treatment . During T treatment , sleep efficiency was 60 + /- 19 % vs 75 + /- 13 % recorded at baseline trial and 68 + /- 25 recorded during D treatment . Sleep quality , during T treatment , was poorer than at baseline , with a greater increase in the percentage of wakefulness and more stage 2 sleep than at baseline . Slow wave sleep was reduced with both treatments , particularly D. Neither drug affected the arterial oxygen saturation ( Sao2 ) or respiratory rate during sleep . ( ABSTRACT TRUNCATED AT 250 WORDS [9741369] BACKGROUND The effects of theophylline or anticholinergic agents on exercise capacity in patients with chronic obstructive pulmonary disease ( COPD ) remain controversial . The aim of the present study was to compare the effect of an oral theophylline with an inhaled anticholinergic agent and to examine the effects of combined therapy on exercise performance using progressive cycle ergometry . METHODS Twenty one men with stable COPD and a mean ( SD ) forced expiratory volume in one second ( FEV1 ) of 1.00 ( 0.40 ) l were studied . Theophylline ( 600 or 800 mg daily ) , ipratropium bromide ( 160 μg ) , a combination of both drugs , and placebo were given in a r and omised , double blind , four period crossover design study . Spirometric data , pulse rate , and blood pressure were assessed before and at 90 and 120 minutes after inhalation . Symptom limited progressive cycle ergometer exercise tests ( 20 watts/min ) were performed 90 minutes after each inhalation , and dyspnoea was measured during exercise using the Borg scale . RESULTS The mean ( SD ) serum theophylline concentration was 18.3 ( 6.3 ) μg/ml , and seven patients had side effects during treatment with theophylline . Theophylline and ipratropium bromide produced greater increases in FEV1 , maximal oxygen consumption , maximal minute ventilation , and several dyspnoea ratios than placebo . There were no differences between theophylline and ipratropium bromide except in maximal heart rate . A combination of both drugs produced greater improvements in pulmonary function and exercise capacity than either drug alone . CONCLUSIONS Both high dose theophylline and high dose ipratropium bromide improved exercise capacity in patients with stable COPD . Although data based on short term effects can not be directly applied to long term therapy , theophylline added to an inhaled anticholinergic agent may have beneficial effects on exercise capacity in patients with COPD [10546469] A 1-yr multicentre two-tailed r and omized open study was conducted in 15 centres in Italy , with the aim of comparing the clinical efficacy ( over 3 months ) and tolerability ( over 1 yr ) of salmeterol with those of oral theophylline in patients with reversible chronic obstructive pulmonary disease ( COPD ) . Patients with reversible COPD ( forced expiratory volume in one second ( FEV1 ) 50 - 80 % , FEV1 after bronchodilator > 12 % , n = 138 ) were r and omized to receive salmeterol powder ( 50 micrograms b.i.d . with Diskhaler , n = 66 ) or individually dose-titrated slow-release oral theophylline capsules so as to obtain a serum concentration of theophylline ranging 10 - 20 micrograms.mL-1 ( n = 72 ) . During the 2-week run-in period , nonadmitted medications were discontinued and patients had to present with respiratory symptoms on at least four of the last seven days . Following r and omization , patients were required to monitor daytime and night-time symptoms , additional use of as-required salbutamol , and morning and evening peak expiratory flow ( PEF ) for 3 months . Spirometric measurements and assessment of the quality of life were performed every 3 months for 1 yr . Salmeterol was proven to be statistically more effective than theophylline in : 1 ) increasing the maximum value of morning PEF ; 2 ) increasing the percentages of days and nights without symptoms ; 3 ) reducing the need for additional salbutamol during daytime and night-time ; and 4 ) increasing quality of life in terms of physical and social activities , mental health and psychophysical energy , assessed 3 months after the beginning of treatment . Salmeterol was no more effective than theophylline in increasing : 1 ) forced vital capacity and FEV1 at the various measurements ; 2 ) maximum evening PEF value ; and 3 ) quality of life after the first 3 months of treatment . Neither treatment induced significant side-effects over the 1-yr treatment . This study confirms that inhaled salmeterol is more effective than oral theophylline in long term treatment of reversible obstructive pulmonary disease [1729064] To investigate the efficacy of bronchodilators in patients with irreversible chronic obstructive pulmonary disease ( COPD ) , we conducted a double-blind , r and omized , four-phase , crossover comparison between placebo , oral theophylline , inhaled salbutamol , and a combination of both drugs in 12 patients with stable COPD ( mean age , 63 years ) whose increase in forced expiratory volume in 1 s ( FEV1 ) was less than or equal to 15 percent following 200 micrograms of inhaled salbutamol . Patients received two weeks of therapy with each of the test regimens . Both theophylline and salbutamol result ed in statistically significant improvement in FEV1 , forced vital capacity ( FVC ) , slow vital capacity ( SVC ) , residual volume ( RV ) , airway resistance ( Raw ) , and maximum expiratory flow rate at 50 percent of vital capacity ( V50 ) . In most instances , there were no significant differences between theophylline and salbutamol . Combination therapy produced significantly greater improvement in FEV1 , FVC , V50 , Raw , and RV than either agent alone . The two drugs interacted in an additive fashion . Neither of the drugs , used singly , significantly reduced the severity or incidence of symptoms . The reduction in dyspnea and wheeze during combination therapy approached statistical significance ( p = 0.06 ) and patient preference was significantly in favor of the combination regimen . None of the active treatments produced significantly more side effects than placebo . We conclude that theophylline and inhaled salbutamol produce significant , and approximately equal , improvement in pulmonary function in patients traditionally classified as suffering from " irreversible " COPD . The combination of theophylline and inhaled salbutamol generally results in additional improvement over that obtained with either drug used alone and this improvement is reflected by reduced symptomatology and treatment preference [6641302] At rest and during exercise , noninvasive studies of cardiopulmonary physiology in patients with chronic obstructive pulmonary disease ( COPD ) were carried out to determine the objective benefits of commonly used oral bronchodilator drugs in 15 stable patients without cardiovascular disease or reversible obstruction of airflow . Theophylline , terbutaline , a combination of theophylline and terbutaline , and placebo were given for ten days each in a r and omly sequenced double-blind protocol for out patients . Spirometric values , the ratio of physiologic dead space to tidal volume ( VDp/VT ) , and the alveolar-arterial oxygen pressure difference ( P[A-a]O2 ) were studied at rest on each regimen . During steady-state exercise the changes in VDp/VT and P(A-a)O2 , as well as the ventilatory equivalent for oxygen and oxygen pulse , were measured . When compared with placebo , no significant change was noted in the previously mentioned measurements with any regimen , with the exception of a small improvement in the forced expiratory volume in one second , which was significant for all regimens . These findings suggest that commonly used oral bronchodilator drugs in usual doses may have small effects on airflow even in " irreversible " COPD but that the objective effect of these agents on gas exchange during rest and exercise is not significant [10430726] We wished to determine which resting spirometric parameters best reflect improvements in exercise tolerance and exertional dyspnea in response to acute high-dose anticholinergic therapy in advanced COPD . We studied 29 patients with stable COPD ( FEV(1 ) = 40 + /- 2 % predicted [ % pred ] ; mean + /- SEM ) and moderate to severe chronic dyspnea . In a double-blind placebo-controlled cross-over study , patients performed spirometry and symptom-limited constant-load cycle exercise before and 1 h after receiving 500 micrograms of nebulized ipratropium bromide ( IB ) or saline placebo . There were no significant changes in spirometry , exercise endurance , or exertional dyspnea after receiving placebo . In response to IB ( n = 58 ) : FEV(1 ) , FVC , and inspiratory capacity ( IC ) increased by 7 + /- 1%pred , 10 + /- 1%pred , and 14 + /- 2%pred , respectively ( p < 0.001 ) , with no change in the FEV(1)/FVC ratio . After receiving IB , exercise endurance time ( Tlim ) increased by 32 + /- 9 % ( p < 0.001 ) and slopes of Borg dyspnea ratings over time decreased by 11 + /- 6 % ( p < 0.05 ) . Percent change ( % Delta ) in Tlim correlated best with DeltaIC%pred ( p = 0.020 ) and change in inspiratory reserve volume ( DeltaTLC%pred ) ( p = 0.014 ) , but not with DeltaFVC%pred , DeltaPEFR%pred , or DeltaFEV(1)%pred . Change in Borg dyspnea ratings at isotime near end exercise also correlated with DeltaIC%pred ( p = 0.04 ) , but not with any other resting parameter . Changes in spirometric measurements are generally poor predictors of clinical improvement in response to bronchodilators in COPD . Of the available parameters , increased IC , which is an index of reduced resting lung hyperinflation , best reflected the improvements in exercise endurance and dyspnea after IB . IC should be used in conjunction with FEV(1 ) when evaluating therapeutic responses in COPD [2201960] The traditional role of theophylline as a bronchodilator has been exp and ed by recent findings that suggest this drug has more than smooth muscle relaxant properties . Several investigators indicate that theophylline has an inotropic effect on respiratory muscle , causing enhanced muscular contraction and prevention of muscle fatigue . In animal studies , the drug enhanced respiratory muscle contraction by 15 - 20 % , with levels in the upper end of the therapeutic range ( 15 - 20 mg/L ) . Results of studies in healthy volunteers and patients with lung disease , however , are conflicting . Five clinical trials demonstrated increased diaphragmatic contractility , whereas seven trials showed no effect , with five referring to the diaphragm and the remaining two to the sternomastoid muscle . Disparity in outcomes may be attributed to differences in patient population s , study design s , and techniques used to determine diaphragmatic contractility . Few long-term trials exist that document significant clinical benefit . Theophylline may prove to be of value in selected population s , such as adults with hypercapnic obstructive lung disease [11743900] AIM To investigate whether low dose theophylline has an anti-inflammatory effect in asthma . METHODS Nineteen asthmatic subjects were given 200 mg sustained-release theophylline preparation twice daily for 4 weeks . The mean serum concentration of theophylline was 7.9 mg/L. The percentage of eosinophils , EG2 + eosinophils , and the level of eosinophil cationic protein ( ECP ) in sputum pre- and post-administration were detected by Wright 's stain , immunocytochemistry , and immuno-CAP system , and the symptom scores and lung function were evaluated as well . The above indices for 10 healthy subjects were regarded as control . RESULTS Before using theophylline , sputum eosinophils , EG2 + eosinophils , and ECP in asthmatic group were much higher than those of healthy group . After four weeks administration , there were great decreases in percentage of total eosinophils ( 40 % + /- 17 % vs 29 % + /- 11 % , P < 0.01 ) , activated ( EG2 + ) eosinophils ( 28 % + /- 9 % vs 10 % + /- 8 % , P < 0.01 ) and in the concentration of sputum ECP [ ( 373 + /- 206 ) vs ( 220 + /- 132 ) microg/L , P < 0.01 ] . The symptom scores decreased greatly ( 7.1 + /- 1.2 vs 5.4 + /- 1.6 , P < 0.01 ) . There was a marked increased in forced expiratory volume one second ( FEV(1.0 ) ) after administration ( 2.2 + /- 0.6 vs 2.4 + /- 0.5 , P < 0.01 ) . The FEV(1.0 ) % of asthmatic subjects after administration increased ( 60 % + /- 13 % vs 65 % + /- 13 % , P < 0.01 ) , too . CONCLUSION These results indicated that low dose theophylline had inhibitory action on airway inflammation in asthma with noticeable improvement of the patients ' symptoms and lung function [1546832] Circadian alterations in lung function occur in respiratory disorders , with the nadir during the sleep-related hours . Higher therapeutic serum theophylline concentrations ( STC ) during the night have been shown to improve lung function in reversible airway disease . To determine what effect higher nocturnal STC would have in patients with chronic obstructive pulmonary disease ( COPD ) on overnight lung function , oxygen saturation , and sleep quality , two different theophylline products were used to give higher or lower STC during the night . We found that with a higher STC ( 15.0 + /- 1.0 versus 11.0 + /- 1.0 micrograms/ml , p = 0.005 ) at 7:00 A.M. , the overnight changes in FEV1 ( + 7.4 + /- 5.7 % versus -18.9 + /- 7.9 % , respectively ) and FVC ( + 1.8 + /- 7.5 % versus -17.2 + /- 3.9 % , respectively ) were significantly better . However , there was no apparent effect on oxygen saturation ( mean sleep values for higher STC were 85.3 + /- 1.2 % , and for lower STC they were 86.5 + /- 0.8 % ) . The higher STC did not adversely affect sleep latency , sleep efficiency , or sleep staging . We conclude that a higher therapeutic STC during sleep will improve lung function without altering oxygen saturation in patients with COPD . In this group of patients , the higher STC did not interfere with sleep characteristics [7224346] Because it is common to perform a bronchodilator challenge while a patient continues oral methylxanthines , we wanted to determine if this procedure might be misleading for subsequent therapy . Thirty-eight men with a long smoking history and a clinical diagnosis of chronic obstructive pulmonary disease ( COPD ) were given placebo and oral theophylline ( each for one month ) in a double-blind , single-crossover manner . Pulmonary functional tests were performed before and after isoproterenol nebulization on the final day of each 4-wk period . There were significantly larger increases in FVC ( p less than 0.001 ) and FEV1 ( p less than 0.01 ) after isoproterenol challenge when receiving placebo than when receiving theophylline . According to the intermountain Area rating criteria , only the results after isoproterenol challenge during placebo therapy would indicate improvement . These results suggested that isoproterenol inhalation challenge be performed after methylxanthines have been discontinued if used to predict which patients with COPD may respond to oral theophylline therapy [9088999] Doxophylline , or 2-(7'-theophyllinemethyl)1,3-dioxolane , is a theophylline derivative which has shown interesting bronchodilating activity , and it appears to determine few adverse effects . The aim of the present investigation was to evaluate clinical therapeutic effects of the drug in the treatment of 2 groups of patients suffering from moderate to severe chronic obstructive pulmonary disease differing in acute response to the inhaled beta 2-agonist salbutamol and to compare changes of lung function tests to serum concentration of doxophylline . We studied 67 patients with chronic obstructive pulmonary disease ( median age 63 years , 9 females and 58 males ) who were all clinical ly stable at the time of the study . Patients were separated into 2 groups on the basis of their reaction to inhalation of 200 micrograms of salbutamol : those with an increased FEV1 of more than 20 % from baseline value ( group 1 ) , and those with no increase ( group 2 ) . Doxophylline was administered orally at the dose of 400 mg 3 times daily . Serum levels of doxophylline were determined by high-pressure liquid chromatography . Spirometry and blood gas analysis were performed before and 10 days after treatment . Four patients stopped drug assumption because of side effects ( 3 for dyspepsia and 1 for anxiety ) . In group 1 ( 34 patients ) , a significant increase in SVC , FVC , FEV1 , FEF 25 - 75 % and PEFR was observed . In group 1 ( 29 patients ) , only PEFR significantly increased . No modifications in blood gas analysis were observed . The mean serum level of doxophylline was 14 micrograms/ml in group 1 and 9 micrograms/ml in group 2 : the difference was statistically significant . The relation between serum levels of doxophylline and FVC showed an increase in the parameter up to the concentration of 12 - 13 micrograms/ml , after which a plateau phase was observed . On the basis of our data , doxophylline appears to have an interesting bronchodilating effect in patients responsive to the inhaled beta 2-agonist salbutamol . The lower limit of the therapeutic range seems to be 12 - 13 micrograms/ml . The upper limit of the therapeutic range was not determined because it was not possible to obtain serum sample s when side effects occurred [4003919] The efficacy of bronchodilator therapy was assessed in the long-term management of patients with chronic bronchitis and varying degrees of reversible air-flow obstruction . Twenty-five patients with a mean forced expiratory volume in one second ( FEV1 ) 38.7 % predicted received : optimized doses of orally administered , sustained-release theophylline , inhaled salbutamol ( 200 micrograms 4 times a day ) , a combination of the 2 drugs , and identical placebo therapy for periods of 3 wk in a r and omized , double-blind , crossover trial . Patients who deteriorated during treatment were assessed immediately and design ated " treatment failures " if additional therapy proved necessary . Such " failures " occurred in 9 patients with placebo , in 8 with salbutamol , in 6 with theophylline , and in only 1 with combined therapy . Using a ranking system based on " treatment failures " and mean daily peak flow rates , first preference was given to combined therapy in 13 patients , theophylline in 6 , salbutamol in 4 , and placebo in 2 . Thus , both combined therapy ( p less than 0.001 ) and theophylline ( p less than 0.05 ) were better than placebo , but this was not so for inhaled salbutamol . Objective improvements in FEV1 and forced vital capacity were a consistent finding with combined therapy compared with placebo , although not with single agents , and additive effects were clearly demonstrated . In the subgroup of patients able to tolerate placebo therapy , no subjective benefit could be discerned during any of the 3 periods of active treatment . Thus , the combination of orally administered , sustained-release theophylline and inhaled salbutamol offered significant advantages in the clinical control of patients with chronic bronchitis with air-flow obstruction [2651178] A crossover pilot study was undertaken to compare the acceptability of controlled release salbutamol tablets ( 8 mg twice daily ) with a sustained release theophylline preparation ( 400–800 mg given once each night ) in patients with reversible obstructive airways disease . A 2-week run-in period was used to titrate the theophylline dosage . Patients were then allocated at r and om to one of the treatments before being immediately crossed over to the other for a further 4 weeks . Thirty-two patients , aged 17–66 years , entered the trial . Seventeen patients ( 53 % ) were withdrawn . The majority of the 13 withdrawals due to side-effects of theophylline occurred during the run-in period . There were no statistically significant differences between treatments for either lung function tests performed at the clinic or for peak expiratory flow rate recorded by the patients . The non-asthma symptom score was significantly higher with theophylline than with the salbutamol preparation . A preference for treatment with the controlled release salbutamol tablets was expressed by 11/15 patients [8214921] The effects of theophylline on pulmonary function and gas exchange during rest , sleep , and exercise were assessed in 10 patients with severe but stable chronic obstructive pulmonary disease ( COPD ; median FEV1 , 31 % of predicted ) . The study was r and omized , double blind , placebo controlled , and crossover in design , with each study period lasting 3 wk , and all other usual bronchodilator therapy was continued unchanged . All patients had detailed pulmonary function tests , in addition to exercise testing and overnight sleep studies by st and ard polysomnography . Theophylline significantly improved gas exchange during rest , exercise , and sleep . Awake resting arterial blood gases showed a higher PaO2 on theophylline ( 78 [ 53 to 93 ] mm Hg , median [ range ] ) than placebo ( 72 [ 47 to 83 ] mm Hg ; p < 0.01 by ANOVA ) , and PaCO2 was lower on theophylline ( 42 [ 38 to 54 ] ) compared with placebo ( 45 [ 40 to 51 ] , p < 0.05 by ANOVA ) . Arterial oxygen saturation ( SaO2 ) was significantly higher on theophylline than placebo during exercise and sleep ( p < 0.01 ) , and transcutaneous CO2 was lower during sleep ( p < 0.05 ) . Theophylline also result ed in significantly improved pulmonary function and reduced trapped gas volume ( p < 0.05 ) . Exercise performance was no different during theophylline or placebo phases of the study . Sleep quality , however , was significantly impaired on theophylline . We conclude that theophylline has clinical ly significant benefits in patients with severe COPD [2557274] 131 asthmatics aged 12 - 65 years , who still had symptoms despite inhaled or oral bronchodilators , were included in this double-blind group comparative study involving nedocromil sodium ( 2 puffs of 2 mg each twice daily ) and placebo ( 2 puffs twice daily ) . The study was carried out at 8 centers over six weeks . Under nedocromil sodium , cough , dyspnea and severity of attacks were reduced significantly . Overall patient assessment also clearly favoured the active substance . Nedocromil sodium was also superior to placebo in terms of the improvement of lung function ( FEV1 , FVC and PEFR ) . 26 patients complained of unusual symptoms ( 12 under nedocromil sodium , 14 under placebo ) . Nedocromil sodium proved to be an effective , safe and well-tolerated drug in the antiinflammatory long-term treatment of reversible obstructive airways disease [2498658] To assess the effects of theophylline in chronic obstructive pulmonary disease , we conducted a r and omized , placebo-controlled , double-blind , crossover trial in 60 patients with severe but stable disease . The patients ( mean age , 61 years ) were studied before and after two months of placebo and two months of treatment with a sustained-release preparation of theophylline ( 10 mg per kilogram of body weight per day ) , administered orally . The two treatments were administered in a r and om order and separated by an eight-day washout period . After taking theophylline for two months ( mean plasma concentration , 14.8 mg per liter ) , as compared with the two months of placebo , the patients had significant improvements in dyspnea , pulmonary gas exchange ( partial pressure of arterial oxygen , 66 vs. 61 mm Hg [ P less than 0.0001 ] ; partial pressure of arterial carbon dioxide , 44 vs. 49 mm Hg [ P less than 0.0001 ] ) , vital capacity ( 63 percent vs. 58 percent of the predicted value [ P less than 0.0001 ] ) , and forced expiratory volume in one second ( 36 percent vs. 32 percent of the predicted value [ P less than 0.0001 ] ) , with no significant change in airway resistance or functional residual capacity . Minute ventilation increased by a mean of 18 percent ( P less than 0.0001 ) in the patients taking theophylline because of increased tidal volume , with no change in respiratory frequency . The respiratory-muscle performance of the patients taking theophylline improved by approximately 29 percent ( P less than 0.0001 ) , as indicated by a decline in the ratio of inspiratory pleural pressure during quiet breathing to maximal pleural pressure . We conclude that theophylline improves respiratory function and dyspnea in patients with severe chronic obstructive pulmonary disease and that these improvements are probably due to better respiratory-muscle performance [7130553] Therapeutic response to theophylline in asthma is generally attributed to its effect in increasing intracellular 3',5 ' cyclic adenosine monophosphate ( cAMP ) by competitive inhibition of cAMP phosphodiesterase . However , because of discrepancies between therapeutic serum theophylline concentration achieved clinical ly and those required for in vitro phosphodiesterase inhibition , we explored the possibility that theophylline may act through adrenomedullary secretion of catecholamines . Five healthy , nonasthmatic male and female adults were studied with a double-blind , r and omized , crossover protocol . Theophylline ( 5 mg/kg ) and placebo were administered in a capsule dosage form . Plasma catecholamines epinephrine ( E ) , norepinephrine ( NE ) , and dopamine ( DA ) were measured by a radioenzymatic assay at baseline and after administration of theophylline at 1 , 2 , and 3 hr . Significant differences between theophylline- and placebo-treated groups ( p less than 0.05 ) were seen at 3 hr for mean percentage increase over baseline with E ( 120 % + /- 25.3 % ) and NE ( 48.02 % + /- 17.94 % ) after theophylline therapy ( mean peak level 7.2 + /- 0.48 micrograms/ml ) . Epinephrine plasma concentration was significantly greater ( p less than 0.001 ) at 3 hr compared with baseline ( 105 + /- 16 vs 56 + /- 18 pg/ml ) , while NE ( 448 + /- 52 vs 320 + /- 36 pg/ml ) did not attain significance ( p = 0.136 ) . A significant correlation ( p less than 0.05 ) was found between the percentage increase over basal for E ( r = 0.58 ) and NE ( r = 0.66 ) and serum theophylline levels . DA was not significantly increased at any time period . Thus theophylline in clinical ly relevant concentration appears to stimulate adrenomedullary secretion of catecholamine . Whether this is an important mechanism of action in asthma or explains some side effects of theophylline remains to be determined [6309542] Enprofylline is a potent bronchodilating xanthine derivative that has been shown to have little or no ability to antagonize adenosine in a variety of cell types . In eight patients with chronic obstructive lung disease , a single dose of enprofylline ( 3.5 mg/kg ) was given orally . A double blind , r and omized , crossover comparison was made with oral theophylline ( 9.5 mg/kg ) which is a potent and general adenosine receptor antagonist . Forced expiratory volume ( FEV1 ) , vital capacity , tremor of h and s , heart rate , and blood pressure were followed for 6 h. Plasma concentrations of both drugs were monitored . At doses producing significant bronchodilation , theophylline caused a significant increase in tremor of h and s whereas enprofylline did not . There were no significant changes in heart rate or blood pressure after either drug . It is suggested that the lack of tremorogenic effect of enprofylline is related to its lack of CNS-stimulating behavioural effects and , hence , may reflect its low tendency to antagonize neuro-depressant actions of adenosine . The adenosine-blocking mechanism may not be important for the bronchodilating effects of xanthines [1835291] The bronchodilator effects of a single dose of ipratropium bromide aerosol ( 36 micrograms ) and short-acting theophylline tablets ( dose titrated to produce serum levels of 10 - 20 micrograms/mL ) were compared in a double-blind , placebo-controlled crossover study in 21 patients with stable , chronic obstructive pulmonary disease . Mean peak forced expiratory volume in 1 second ( FEV1 ) increases over baseline and the proportion of patients attaining at least a 15 % increase in the FEV1 ( responders ) were 31 % and 90 % , respectively , for ipratropium and 17 % and 50 % , respectively , for theophylline . The average FEV1 increases during the 6-hour observation period were 18 % for ipratropium and 8 % for theophylline . The mean duration of action was 3.8 hours with ipratropium and 2.4 hours with theophylline . While side effects were rare , those experienced after theophylline use did involve the cardiovascular and gastrointestinal systems . These results show that ipratropium is a more potent bronchodilator than oral theophylline in patients with chronic airflow obstruction [23134] 1 . The bronchodilator effects of 500 microgram rimiterol by pressurized aerosol , 375 mg oral theophylline and both drugs in combination were compared in a r and omized , placebo-controlled , double-blind trial in eight patients with chronic , partially reversible airways obstruction . 2 . The four treatments were ( i ) oral theophylline , placebo aerosol ( TP ) ; ( ii ) oral placebo , rimiterol aerosol ( PR ) ; ( iii ) oral theophylline , rimiterol aerosol ( TR ) and ; ( iv ) oral placebo , placebo aerosol ( PP ) . The aerosol was administered 2 h after the oral treatment . 3 . Significant bronchodilatation ( % FEV1 change from control ) compared to PP occurred with TP from 60 to 480 min and with TR from 60 to 300 min , whereas with PR only for 45 min ( P less than 0.05 ) . 4 . The mean , peak % FEV1 increases from control were 51.8 % at 125 min , 31.7 % at 125 min , 26.1 % at 210 min and 0.9 % at 30 min for TR , PR , TP and PP respectively . 5 . At 125 min ( 5 min after aerosol inhalation ) the mean % FEV1 change from control with TR ( 51.8 % ) Was significantly greater than with PR ( 31.7 % ) , TP ( 22.2 % ) ( P less than 0.05 ) and PP ( -2.4 % ) ( P less than 0.01 ) . 6 . The mean , peak plasma theophylline levels were 10.19 microgram/ml at 120 min and 9.98 microgram/ml at 180 min with TR and TP respectively . Theophylline half-life ranged between 4.3 and 12.5 h ( mean + /- s.e . mean , 8.0 + /- 0.8 h ) . 7 . Additive bronchodilatation was produced when rimiterol was administered with theophylline at a time when therapeutic plasma theophylline levels were achieved [9925061] STUDY OBJECTIVE To compare quality of life and exercise capacity ( primary aim ) , and drug usage ( secondary aim ) , between groups of patients with irreversible chronic airflow limitation ( CAL ) who were undergoing theophylline Theo-Dur ; Key Pharmaceuticals ; Kenilworth , NJ ) therapy guided by n of 1 trials or st and ard practice . DESIGN R and omized study of n of 1 trials vs st and ard practice . SETTING Outpatient departments in two tertiary care centers . PATIENTS Sixty-eight patients with irreversible CAL who were symptomatic despite the use of inhaled bronchodilators , and who were unsure whether theophylline was helping them following open treatment , were r and omized into n of 1 trials ( N=34 ) or st and ard practice . INTERVENTIONS The n of 1 trials ( single-patient , r and omized , double-blind , multiple crossover comparisons of the effect on dyspnea of theophylline vs a placebo ) followed published guidelines . St and ard practice patients stopped taking theophylline but resumed it if their dyspnea worsened . If their dyspnea then improved , theophylline was continued . In both groups , a decision about continuing or stopping the use of theophylline was made within 3 months of r and omization . MEASUREMENTS AND RESULTS The primary outcomes ( the chronic respiratory disease question naire [ CRQ ] and 6-min walk ) were measured at baseline , 6 months , and 12 months by personnel blinded to treatment group allocation . No between-group differences ( n of 1 minus st and ard practice ) were seen in within-group changes over time ( 1 year minus baseline ) in the CRQ Physical Function score ( point estimate on the difference , -2.8 ; 95 % confidence limits [ CLs ] , -8.2 , 2.5 ) , CRQ Emotional Function score ( point estimate on the difference , 0.5 ; 95 % CLs , -4.7 , 5.7 ) , or 6-min walk ( point estimate on the difference , 8 m ; 95 % CLs , -26 , 44 m ) . No differences between groups were seen in the secondary outcome of the proportion of patients taking theophylline at 6 and 12 months . In 7 of 34 n of 1 trial patients ( 21 % ) , dyspnea improved during theophylline treatment compared with placebo treatment . CONCLUSIONS Using n of 1 trials to guide theophylline therapy in patients with irreversible CAL did not improve their quality of life or exercise capacity , or reduce drug usa e , over 1 year compared to st and ard practice . Under the objective conditions of an n of 1 trial , 21 % of patients with CAL responded to theophylline . There remains a rationale for considering theophylline in patients with irreversible CAL who remain symptomatic despite the use of inhaled bronchodilators , but the use of n of 1 trials to guide this decision did not yield clinical ly important advantages over st and ard practice [6751366] Twenty-one patients with chronic bronchitis entered a double-blind , cross-over study in which they received sustained-release theophylline ( ' Nuelin'SA ) 350 mg daily for 4 days followed by 700 mg daily for 4 days and matching placebo tablets for 8 days with one week separation . Seventeen patients completed the study . Three patients receiving higher doses for weight than the mean for the group were withdrawn because of side-effects . Mild side-effects only were reported in six other patients . Theophylline given twice daily produced a steady-state mean serum concentration of 13.9 micrograms/ml , 13 patients having concentrations inthe range of 10 - 20 micrograms/ml . There was no demonstrable improvement of symptoms but pulmonary function measurements in the clinic at the end of active treatment showed a statistically significant improvement in PEFR , 1-second forced expiratory volume and forced vital capacity [3069520] In a single-blind crossover study , two slow release theophylline preparations were evaluated in 18 patients with chronic bronchitis or asthma without cardiac , renal or liver disease . After r and omization into two groups , patients were treated , in a crossover study design , with 600 mg choline theophyllinate or 300 mg anhydrous theophylline administered orally every 12 h for 7 days . A 2-day washout period separated the two periods of treatment evaluation . Blood sample s in which plasma theophylline concentration was to be measured were taken at 7.30 a.m. , 2.00 p.m. and 7.30 p.m. during the last 5 days of therapy with each drug . The mean fluctuation in plasma theophylline concentration was ≤40 % in all 18 patients taking choline theophyllinate yet in only 15 ( 83 % ) patients administered anhydrous theophylline . Salbutamol inhaler was more frequently required for the relief of bronchospasm when taking anhydrous theophylline than when taking choline theophyllinate ( total of 41 vs 25 puffs , respectively , over 7 days ) . Drug-related adverse reactions occurred in four patients while taking anhydrous theophylline and in one patient while taking choline theophyllinate [2218006] Enprofylline , a recently developed xanthine derivative , is a more potent bronchodilator than theophylline . This study compares the efficacy and safety of enprofylline with theophylline for chronic obstructive airways disease ( COAD ) in elderly subjects . The study was of a r and omized double-blind parallel design and commenced with a 1-week reference period when oral bronchodilators were withdrawn . Patients were then treated with either enprofylline or theophylline 150 mg bd for 2 weeks ( period 1 ) followed by 300 mg bd for a further 3 weeks ( period 2 ) . Patients recorded peak expiratory flow rate ( PEFR ) and adverse experiences , if any , in a diary , daily . Of 111 patients recruited for the study , 85 entered active treatment ( theophylline , n = 44 ; enprofylline , n = 41 ) . Mean age was 72 years and mean bronchodilator reversibility was 22 % . Enprofylline increased mean morning PEFR by 11 % ( period 1 ) and 19 % ( period 2 ) whereas theophylline increased PEFR by 13 % and 19 % , respectively . From the enprofylline group 29 % were withdrawn from the study due mainly to headache and nausea/vomiting and from the theophylline group 7 % were withdrawn due mainly to nausea/vomiting . Mean plasma concentrations of enprofylline were 2.0 mg l-1 and 3.4 mg l-1 , and with theophylline 5.4 mg l-1 and 10.0 mg l-1 at the end of periods 1 and 2 , respectively . Enprofylline and theophylline produced similar improvements in lung functions and symptoms of chronic obstructive airways disease , but enprofylline was less well tolerated than theophylline [3297214] Fourteen patients with chronic obstructive airway disease participated in a r and omized , double-blind , placebo controlled , cross-over study to assess the effect of acutely administered aminophylline on respiratory muscle strength and exercise tolerance . An increase in the distance walked in 6 min occurred following aminophylline ( p less than 0.01 ) . There was no improvement in respiratory muscle strength , assessed by maximal static mouth pressures , and no increase in maximal ventilation or oxygen uptake during a progressive exercise test . The ventilatory response to inhaled CO2 was increased ( p less than 0.02 ) , suggesting a central stimulatory effect of aminophylline . The mean increase in walking distance was 5.7 % . In most cases , the change was small and unlikely to be of practical benefit [1854108] OBJECTIVE To assess the role of aminophylline in the treatment of acute exacerbations of bronchospastic disease when used in addition to inhaled beta-agonists and intravenous corticosteroids . DESIGN R and omized , double-blind , placebo-controlled intervention study . PATIENTS One hundred thirty-three adult patients with either asthma or chronic obstructive pulmonary disease who presented to the emergency department with asthma or wheezing . INTERVENTIONS All patients received therapy with both aerosolized metaproterenol and intravenous methyl-prednisolone . Patients were r and omly assigned to receive either a loading dose of aminophylline followed by a routine infusion ( n = 65 ) or an equal volume of placebo as a loading dose and infusion ( n = 68 ) . MEASUREMENTS AND MAIN RESULTS At discharge from the emergency department , the median serum theophylline concentration for the aminophylline group was 54 mumol/L ( 9.7 mg/L ) . The two groups showed no differences ( P greater than 0.2 ) in measurements of forced expiratory volume at 1 second ( FEV1 ) , forced vital capacity ( FVC ) , or peak expiratory flow rate ( PEFR ) at baseline or at 60 or 120 minutes after aminophylline administration . Neither patient satisfaction nor physician assessment of response to therapy differed between the two groups . There was no difference ( P greater than 0.2 ) in the frequency of side effects , except for a trend toward a higher frequency of nausea ( P = 0.13 ) in the aminophylline group . There was , however , a threefold decrease in the hospital admission rate for patients treated with aminophylline ( 6 % ) compared with placebo recipients ( 21 % ) ( P = 0.016 ) . CONCLUSION Aminophylline , in doses producing levels just below the commonly accepted therapeutic range , appears to decrease hospital admissions in patients with acute exacerbation of asthma or chronic obstructive pulmonary disease . This finding , if confirmed in larger studies , may represent a substantial cost savings [3087310] Thirteen clinical ly stable male patients aged 63 + /- 3 years with irreversible airway disease were given aminophylline and placebo in a r and omized crossover fashion on two consecutive days while receiving beta-agonists . During incremental exercise the maximal heart rate ( 139.0 + /- 22.1 vs 128.0 + /- 16.4 beats per minute ) and minute ventilation ( 41.9 + /- 6.9 vs 38.1 + /- 8.2 L/min ) were significantly higher and the arterial carbon dioxide pressure ( 34.6 + /- 5.0 vs 38.6 + /- 7.7 mm Hg ) was significantly lower during aminophylline administration than during placebo administration . However , spirometric findings , maximal inspiratory pressures , maximal oxygen consumption , work rate , and arterial oxygen pressure were similar on both regimens . We concluded that the major effect of aminophylline is to increase ventilatory drive in patients with irreversible airway obstruction . Unless an objective change in spirometric data or exercise capacity can be documented , we believe that aminophylline therapy is not warranted in these patients [8325065] To investigate the additive effect of oral theophylline on combined inhaled anticholinergic agent and beta 2-agonist therapy , 12 patients with stable COPD ( 64.6 + /- 5.9 years ) completed a r and omized , double-blind placebo-controlled crossover trial of oral theophylline for a 4-week period ( 400 mg for 2 weeks , followed by 600 mg for 2 weeks ) . All of the patients continued to inhale both salbutamol , 200 micrograms , and ipratropium bromide , 40 micrograms , using a metered-dose inhaler four times a day . Spirometry was assessed before , and 15 and 60 min after the inhalation of bronchodilators at 2-week intervals . Even after the inhalation of salbutamol and ipratropium , theophylline significantly improved FEV1 and daily peak expiratory flow rate compared with the placebo . No significant improvement in the daily symptom scores for cough , sputum , wheezing , or shortness of breath was observed throughout the different phases of treatment . This study shows that the additive bronchodilating effect of theophylline , when used in combination with salbutamol , 200 micrograms , and ipratropium , 40 micrograms , is significant but small in stable COPD . The addition of theophylline did not significantly improve the patient 's symptoms . Oral theophylline , when used in combination with an inhaled anticholinergic agent and an inhaled beta 2-agonist , may be of limited value in the treatment of stable COPD [3041826] Oxygen desaturation and sub clinical coronary artery disease may predispose older patients with chronic airflow obstruction to cardiac arrhythmias , especially when high concentrations of theophylline are present in the blood . To assess the safety and efficacy of Uniphyl tablets , an oral theophylline preparation formulated for once-daily dosing , in elderly patients with chronic airflow obstruction , we conducted a r and omized , three-phase , double-blind crossover study comparing evening dosing with Uniphyl tablets , Theo-Dur tablets administered twice daily , and placebo . The patients in the study were scheduled to receive each treatment for two weeks . Each day , symptoms , side effects , peak expiratory flow rates , and use of metered-dose inhalers were recorded . Near the end of each phase , serum theophylline concentrations were measured every two hours between 8:00 A.M. and 8:00 P.M. on two consecutive days . The patients underwent ambulatory Holter monitoring during the final 48 hours of each phase . Twelve patients completed the active-drug phases of the study , but seven of the 12 were removed from the placebo phase because of increasing symptom severity . The difference between the number of patients completing the active-drug and placebo phases was statistically significant ( p less than 0.001 ) . Treatment with Uniphyl tablets result ed in a significantly ( p less than 0.05 ) greater increase in peak expiratory flow rate than Theo-Dur tablet therapy , and both active drugs increased peak expiratory flow rate more than placebo . Circadian variation in peak expiratory flow rate was seen during the placebo and Theo-Dur tablet phases but not during the Uniphyl tablet phase . Symptoms and side effects were similar during the two active-drug phases . Cardiac ectopy was observed in most of the patients , but it was not significantly greater during the theophylline phases than during the placebo phase . Furthermore , ectopic activity was not directly related to the times of maximal serum theophylline concentration [8162730] To evaluate the role of inhaled ipratropium bromide alone vs oral theophylline plus inhaled beta-agonist or the combination of all three in patients with stable COPD , the following double-blind , placebo-controlled study was conducted . Forty-eight patients with stable COPD ( mean age , 61.8 years , with mean baseline FEV1 < 1.0 L ) were r and omized on four separate days to receive the following drug regimens : ( 1 ) theophylline tablets ( dose previously determined to result in blood level of 12 to 18 mg/L ) , followed by inhaled albuterol ( 2 puffs via metered-dose inhaler [ MDI ] ) , followed by inhaled placebo ( 2 puffs via MDI ) ; ( 2 ) oral placebo followed by ipratropium ( 2 puffs via MDI ; 36 micrograms ) , followed by inhaled placebo ; ( 3 ) oral theophylline , followed by albuterol , followed by ipratropium ; or ( 4 ) oral placebo followed by two inhaled placebos . On study days , spirometry and heart rate were measured at time 0 , 30 min , 60 min , and hourly for 6 h. The FEV1 peak change ( liters ) and area under the curve ( liter x hours ) for the treatment groups were compared . Ipratropium was more effective than placebo ( p = 0.001 and p = 0.0078 , respectively ) . The combination of albuterol and theophylline was superior to ipratropium alone ( p = 0.001 and p = 0.0001 , respectively ) , and all three drugs together were superior to the combination of albuterol and theophylline ( p = 0.0373 and p = 0.0289 ) , respectively ; one-sided test of hypotheses ) . Peak heart rates were significantly higher for treatment groups compared with placebo groups ( p = 0.0001 ) . However , theophylline and albuterol and the combination of all three drugs result ed in greater peak heart rates than did ipratropium alone ( p = 0.001 ) . These data suggest that for patients with stable COPD , combination therapy with ipratropium ( two puffs ) , theophylline , and albuterol ( two puffs ) is superior to ipratropium alone or the combination of theophylline and albuterol [4723589] Abstract Physiologic responses to intravenously administered theophylline were determined in nine hospitalized asthmatic subjects . In each patient incremental theophylline plasma concentration plateaus were attained at which pulmonary-function changes related to drug administration were examined . Continuous improvement in vital capacity and first-second forced expiratory volume was observed over the plasma range of theophylline concentration of 5 to 20 mg per liter . The improvement varied directly with the logarithm of the plasma concentration . A safe and effective dosage regimen for intravenous theophylline can be based on these observations . After a loading dose of aminophylline , 5.6 mg per kilogram given intravenously , 0.9 mg per kilogram per hour can be given as a maintenance dose . This amount will result in a plasma theophylline concentration of approximately 10 mg per liter for 95 per cent of patients and in recovery from some 30 to 40 per cent of reversible pulmonary-airway obstruction . ( N Engl J M [3345044] This study sought answers to 2 questions : ( 1 ) Is severe dyspnea to the point of exhaustion regularly accompanied by diaphragmatic fatigue in patients with moderately severe chronic obstructive pulmonary disease ( COPD ) ? ( 2 ) When diaphragmatic fatigue occurs in such patients , does theophylline prevent or delay its onset ? Eight eucapnic patients with moderately severe COPD were subjected to 2 different stresses to the point of severe dyspnea requiring cessation of the stress . The stresses were cycle exercise and inspiratory resistive breathing , the latter requiring a tidal Pdi equal to 60 % of Pdimax . Despite incapacitating dyspnea , objective evidence of diaphragmatic fatigue was not encountered during cycle exercise . During inspiratory resistive breathing , diaphragmatic fatigue was encountered in all patients as defined by consistent inability to attain a target Pdi during final moments of the resistance run . Patients were uniformly extremely dyspneic at this point . In neither stressful maneuver did oral sustained-release theophylline show a convincing or significant advantage over placebo when administered in a r and omized double-blind crossover protocol . These results suggest that the diaphragmatic fatigue encountered in this sort of COPD patient may be of predominantly central rather than peripheral ( myogenic ) origin and that theophylline may not be effective in this type of fatigue [9506004] Effects of theophylline administration on the respiratory drive were studied in seven patients with chronic obstructive pulmonary disease ( COPD ) . End tidal CO2 ( PetCO2 ) , minute ventilation ( Ve ) , forced expiratory volume in one second ( FEV1 ) , forced vital capacity ( FVC ) , oxygen consumption ( VO2 ) , carbon dioxide output ( VCO2 ) , serum theophylline level ( STL ) , ventilatory response ( VeR ) , and mouth occlusion pressure response ( OPR ) to rise in PetCO2 on rebreathing were measured before and at 2-hour intervals after oral administration of 5 mg/kg anydrous theophylline or placebo . Mouth occlusion pressure response and VeR showed c significant increase after theophylline but not after placebo . Significant positive correlation between changes ( delta ) in STL and OPR ( delta OPR = 0.025 + 0.8 delta STL ; SEE = 1 ; r = 0.4 ; P < 0.005 ) and between STL and VeR ( VeR = 0.82 + 0.055 STL + /- SEE = 0.7 ; r = 0.46 ; P < 0.01 ) and an inverse correlation between delta STL and delta PetCO2 ( delta PetCO2 = 13.8 - 0.59 delta STL ; SEE = 9.1 ; r = 0.61 ; P < 0.001 ) were noted . There was no correlation between the indices of respiratory drive and FEV1 , Ve , VO2 , or VCO2 . It is concluded that theophylline increases respiratory drive in clinical ly employed doses independently of its bronchodilator or metabolic effects [7985256] Even though the clinical efficacy is not well established , theophylline is commonly prescribed as a second or third line drug after inhaled beta 2-agonists and corticosteroids for patients with chronic obstructive pulmonary disease ( COPD ) . The therapeutic index is narrow , and therefore theophylline is often given in a " safe st and ard dose " , e.g. 300 mg b.i.d . We studied the long-term effect of sustained-release theophylline 300 mg b.i.d . over four weeks in 48 patients with severe irreversible COPD ( FEV1 : 0.99 + /- 0.45 l , FVC : 2.21 + /- 0.68 l ) in a r and omized , double-blind crossover study . During theophylline treatment there was significant improvements in dyspnoea score ( p < 0.001 ) and morning peak-flow ( p < 0.05 ) . In spite of this , there was no significant change in the patients ' " sense of well-being " or their daily use of inhaled beta-agonist . Spirometric tests or arterial blood gas values did not change significantly either . It is concluded that addition of theophylline in a " safe st and ard dose " ( i.e. 300 mg b.i.d . ) has only limited value in these patients

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### Context: [4056079] The bioavailability profiles of two sustained-release oral theophylline preparations , Respbid and Theo-Dur , were compared in 19 adults with obstructive airways disease . Intravenous aminophylline was used as the reference st and ard . No significant differences were detected in fraction absorbed , peak-trough fluctuations , or time to peak concentrations [7001056] Theophylline is commonly prescribed for chronic obstructive pulmonary disease ( COPD ) , although controlled studies do not exist to support this use . We administered theophylline and placebo orally to 40 ambulatory COPD patients in a double-blind , crossover manner . Pulmonary function tests were conducted before and after isoproterenol nebulization on the final day of each four-week study period . Theophylline therapy produced small , but significant , increases over placebo in mean values . However , only the forced expiratory volume in 1 s was " improved , " according to published criteria . There were no significant differences in subjective effects between treatment periods . Six patients were identified as " responders " ; responder status could be predicted on the basis of improvement in flow rates after isoproterenol nebulization . Theophylline therapy is not beneficial to most COPD patients , and potential responders should be given carefully monitored therapeutic trials rather than arbitrarily being given maintenance therapy [7387018] We studied ventilatory , hemodynamic , and subjective responses to different plasma theophylline concentrations in 10 patients with " irreversible " airflow obstruction . Subjects received theophylline at doses that produced low ( 9.0 to 12.5 micrograms/mL ) and high ( 17 to 22 micrograms/mL ) peak plasma concentrations ; subjects also received placebo . A significant ( P less than 0.05 ) dose-related difference in pulmonary function was observed between each treatment . The mean maximal increase in forced expiratory volume at 1 second over placebo was 21.3 % for high-dose theophylline and 6.0 % for low dose . Both treatments were well tolerated with respect to hemodynamic changes and other adverse effects . Despite improved findings in pulmonary function tests patients were unable to distinguish either treatment from placebo in terms of improvement in breathlessness [11399688] BACKGROUND Patients with COPD often require multiple therapies to improve lung function and decrease symptoms and exacerbations . Salmeterol and theophylline are indicated for the treatment of COPD , but the use of these agents in combination has not been extensively studied . OBJECTIVES To compare the efficacy and safety of salmeterol plus theophylline vs either agent alone in COPD . METHODS R and omized , double-blind , double-dummy , parallel-group trial in 943 patients with COPD . After an open-label theophylline titration period ( serum levels , 10 to 20 microg/mL ) , patients were r and omly assigned to receive salmeterol ( 42 microg bid ) plus theophylline , salmeterol ( 42 microg bid ) , or theophylline for 12 weeks . Serial pulmonary function tests were completed on day 1 and treatment week 12 . Patients kept diary cards and noted their peak flow rates , symptom scores , and albuterol use , and periodically completed quality -of-life and dyspnea question naires . RESULTS All three groups significantly improved compared with baseline . Combination treatment with salmeterol plus theophylline provided significantly ( p < or = 0.045 ) greater improvements in pulmonary function ; significantly ( p < or = 0.048 ) greater decreases in symptoms , dyspnea , and albuterol use ; and significantly fewer COPD exacerbations ( p = 0.023 vs theophylline ) . In general , treatment with salmeterol provided greater improvement in lung function and satisfaction with treatment compared with theophylline . Salmeterol treatment was also associated with significantly fewer drug-related adverse events ( p < or = 0.042 ) than either treatment that included theophylline . The safety profile ( adverse events , vital signs , and ECG findings ) of the two treatments that included theophylline were similar . CONCLUSION Patients with COPD may benefit from combination treatment with salmeterol plus theophylline , without a result ing increase in adverse events or other adverse sequelae [6127964] The acute ventilatory , cardiovascular and tremorogenic effect of a high oral dose of terbutaline ( 5 mg ) was compared with that of half the dose ( 2.5 mg ) combined with 280 mg anhydrous theophylline orally in a r and omized , double‐blind , cross‐over study in eight asthmatics . After 120 min . when steady‐state bronchodilation was achieved , five terbutaline inhalations ( 1.25 mg terbutaline sulphate ) were added to both treatment regimens . The mean maximum plasma concentration of theophylline was then 7 μg/ml ( 39 μmol/l ) [8678934] BACKGROUND Theophylline has been used to treat central apnea associated with Cheyne-Stokes respiration ( periodic breathing ) . We studied the effect of short-term oral theophylline therapy on periodic breathing associated with stable heart failure due to systolic dysfunction . METHODS Fifteen men with compensated heart failure ( left ventricular ejection fraction , 45 percent or less ) participated in the study . Their base-line polysomnograms showed periodic breathing , with more than 10 episodes of apnea and hypopnea per hour . In a double-blind crossover study , the patients received theophylline or placebo orally twice daily for five days , with one week of washout between the two periods . RESULTS After five days of treatment , the mean ( + /-SD ) plasma theophylline concentration was 11 + /- 2 microgram per milliliter . Theophylline therapy result ed in significant decreases in the number of episodes of apnea and hypopnea per hour ( 18 + /- 17 , vs. 37 + /- 23 with placebo and 47 + /- 21 at base line ; P<0.001 ) , the number of episodes of central apnea per hour ( 6 + /- 14 , vs. 26 + /- 21 and 26 + /- 20 , respectively ; P<0.001 ) , and the percentage of total sleep time during which the arterial oxyhemoglobin saturation was less than 90 percent ( 6 + /- 11 percent , vs. , 23 + /- 37 and 14 + /- 14 percent , respectively ; P<0.04 ) . There were no significant differences in the characteristics of sleep , the frequency of ventricular arrhythmias , daytime arterial-blood gas values , or the left ventricular ejection fraction during the base-line , placebo , and theophylline phases of the study . CONCLUSIONS In patients with stable heart failure , oral theophylline therapy reduced the number of episodes of apnea and hypopnea and the duration of arterial oxyhemoglobin desaturation during sleep [1792411] In two groups ( A and B ) of patients with severe chronic obstructive pulmonary disease ( COPD ) , matched for age and routine pulmonary function testing , we evaluated inspiratory muscle strength ( MIP ) , breathing pattern , mouth occlusion pressure ( P0.1 ) , inspiratory neural drive , assessed in terms of electromyographic activity of both diaphragm ( EMGd ) and intercostal ( EMGint ) muscles , and P0.1/EMGd ratio , an index of inspiratory neuromuscular coupling . Group A ( 8 patients ) was studied before and after a 7-day period of a new oral xanthine derivative ( bamiphylline , 1.2 g daily ) , and group B ( 7 patients ) was given a placebo . Under control conditions , compared with an age-matched normal control group , groups A and B both exhibited a decrease in MIP , more rapid ( increase in respiratory frequency RF ) and shallower ( decrease in tidal volume ; VT ) breathing ( RSB ) , a marked increase in both EMGd and EMGint and a lower P0.1/EMGd ratio . With bamiphylline FEV1 and PaO2 significantly increased , while a substantial increase in MIP was found in 5 out of the 8 patients . VT and inspiratory time ( Ti ) also significantly increased , and RF decreased . Both EMGd and EMGint significantly decreased , whereas P0.1/EMGd exhibited a substantial increase in 5 out of the 8 patients . Conversely , no significant changes were observed in group B during the study period . From these data we conclude that in patients with COPD , clinical manifestations , probably associated with inspiratory muscle overloading ( decrease in muscle strength , RSB , increase in respiratory neural drive , and derangement in neuromuscular coupling ) may benefit from a short-term treatment with bamiphylline [7025336] Twenty-four patients with reversible airflow obstruction under suboptimal control on conventional therapy entered a double-blind placebo-controlled trial of additional oral sustained release aminophylline . Assessment was by diary cards , twice daily PEFR , and weekly FEV1 . Nineteen patients completed the trial satisfactorily . Eleven were improved subjectively by addition of aminophylline . The mean PEFR for all 19 patients rose from 232 1 min-1 SEM + /- 5 , to 247 1 min-1 SEM + /- 4 ( p less than 0.0001 ) ; nine individuals showed a statistically significant improvement in mean PEFR and 10 showed an improvement of greater than 200 ml in their FEV1 . Improvement in PEFR on aminophylline was not at the expense of benefit from inhaled salbutamol . Unwanted effects of nausea , headache , and abdominal discomfort were recorded by 12 of the 24 patients entering the trial . Seventeen of the 19 patients completing the trial had plasma theophylline levels in the accepted therapeutic range of 10 - 20 mg 1(-1 ) . The drug doses required to achieve these levels varied from 8.6 - 30.8 mg kg-1 24 hr-1 in the patients with no clinical or biochemical evidence of liver disease . Oral aminophylline can improve control of airflow obstruction in patients with moderately severe disease who are already receiving multiple medication , but side-effects often limit its use . The wide dose range required to achieve therapeutic plasma levels indicates that measurements of plasma theophylline are necessary for adequate interpretation of trials of theophylline compounds [1592541] The bronchodilator , respiratory center and respiratory muscle effects of oral sustained release theophylline are investigated with a placebo controlled double-blind study in 34 patients with chronic obstructive lung disease ( COLD ) . The first 3 days were a theophylline washout period and the patients did not receive theophylline and on the 4th day , serum theophylline concentration was negligible . Initial pulmonary function tests were performed . Twenty-four of the patients took 350 mg oral sustained release theophylline twice a day . Ten of the patients were given placebo . On day 7 , serum theophylline concentrations of the study group were in therapeutic doses and the tests were repeated . Bronchodilator effect was assessed by spirometry , flow-volume loops and measuring airway resistance ( Raw ) . Respiratory muscle function was assessed by measuring maximal inspiratory ( PImax ) and expiratory pressures ( PEmax ) and the effect on respiratory center was evaluated by minute ventilation , mouth occlusion pressure index and inspiratory duty ratio . Forced vital capacity in one second ( p less than 0.001 ) , maximal mid expiratory flow rate ( p less than 0.05 ) , maximal expiratory flow at 50 percent of vital capacity ( p less than 0.001 ) , maximal inspiratory pressure ( p less than 0.01 ) increased , while airway resistance ( p less than 0.05 ) decreased significantly . Mouth occlusion pressure and minute ventilation mouth occlusion pressure index did not change after theophylline therapy . In placebo group , there was no significant change in airway obstruction assessed by spirometry and flow volume loops or in respiratory muscle function assessed by maximal respiratory pressures . It is therefore , concluded that oral sustained release theophylline has a bronchodilator effect in irreversible chronic obstructive lung disease , increases respiratory muscle function , but in therapeutic doses has no effect on respiratory center [7657856] The effects of famotidine ( 80 mg per day ) , cimetidine ( 1600 mg per day ) , and placebo on theophylline pharmacokinetic parameters in chronic obstructive pulmonary disease ( COPD ) patients were compared . This was an open-label , r and omized , three-period cross-over study , in which each subject first underwent a seven-day theophylline washout period , and thereafter received three single intravenous doses of theophylline ( 5 mg/kg infused over 30 minutes ) during the study . Each of the experimental treatments was administered orally every 12 hours for a total of 9.5 days ( 19 doses ) . Theophylline was infused after the 17th dose of each treatment . Fourteen serial blood sample s were collected before the start of each infusion , and for 30 hours after the end of each infusion . Plasma sample s were assayed for theophylline , pharmacokinetic parameters were estimated , and treatment effects on each parameter were compared . Fourteen COPD patients completed all three periods of the investigation . Famotidine treatment had virtually no effect on any of theophylline 's pharmacokinetic parameters . In contrast , cimetidine treatment significantly altered every pharmacokinetic parameter of theophylline as follows : Cimetidine decreased theophylline geometric mean CL from 2.74 L/h to 2.07 L/h ( P < .001 ) , and prolonged theophylline harmonic mean half-life from 6.6 to 9.6 hours ( P < .001 ) and mean residence time from 10.8 to 15.0 hours ( P < .001 ) . Cimetidine treatment slightly increased theophylline volume of distribution by approximately 10 % , and that change also was statistically significant ( P = .032 ) . The authors conclude that the treatment effects of cimetidine on theophylline pharmacokinetic parameters were in accord with those reported by others , and that famotidine treatment had no effect on any of theophylline 's pharmacokinetic parameters in COPD patients [2687897] A single-blind , placebo-controlled study was carried out in 30 patients with chronic obstructive bronchopneumopathy to assess the effectiveness and tolerability of the theophylline derivative , bamyphylline . On entry , patients were allocated to receive twice daily oral doses of either 600 mg bamyphylline or placebo for a period of 60 days . Spirometric measurements , blood pressure and respiratory rate recordings and blood gas analyses were made at baseline and after 10 , 30 and 60 days of treatment , as were assessment s of clinical and objective signs , such as sibili , rales and vesicular murmurs . Plasma concentrations of bamyphylline 1 hour after the first dose of the day were monitored at the same intervals . The results showed that there was a highly significant progressive improvement in pulmonary function which was already apparent after 10 days and this was accompanied by a marked improvement in cardiac dynamics and clinical signs . Plasma concentrations of bamyphylline remained stable throughout the study period and there were no reports of side-effects or significant variations in blood chemistry [2431838] Twenty-four patients ( five women ) aged 53 - 72 yr with both ischemic heart disease and asthma or chronic bronchitis receiving oral beta 2-agonists also received additional bronchodilating therapy with theophylline ( 600 mg daily ) , enprofylline ( 600 mg daily ) or placebo . The study was double-blind , r and omized , triple-crossover with each regimen given for two weeks . Holter monitoring was used during 48 consecutive hours in each period . Compared with placebo , addition of theophylline and enprofylline were associated with an increased mean hourly heart rate of 6 bpm ( p less than 0.001 ) . A small , but statistically significant ( p less than 0.05 ) increase in mean hourly frequency of premature ventricular beats ( PVBs ) occurred with enprofylline as compared with placebo . However , in only two patients with enprofylline ( and one patient with theophylline ) the increase in PVBs was such that a clinical ly relevant proarrhythmic effect seems possible . Furthermore , ventricular tachycardia was not more frequently observed with any xanthine than with placebo . Thus , combined oral bronchodilator therapy is not contraindicated in patients with obstructive lung disease and concomitant ischemic heart disease . Holter monitoring is recommended to assess the individual patient 's response to such therapy [389103] This study evaluated the effectiveness of oral bronchodilator therapy using theophylline in patients with nonreversible chronic obstructive pulmonary dis ease . Twelve chronic obstructive pulmonary disease patients were entered into a doubleblind crossover study using either active drug theophylline in 200 mg capsules ( Elixophyllin ) or placebo for 3 months , followed by 3 months of the alternate capsule . At baseline and monthly visits , data were recorded , including history , physical examination , and pulmonary function testing . Clinical ly , 7 of 11 patients responded favorably to theophylline , 3 were unchanged , and 1 improved on placebo . Comparison of each sign and symptom individually revealed no statistically significant differences . Pulmonary function ( FEV1 and FVC ) showed slight deterioration with placebo , but not with active drug therapy . These findings suggest that nonasthmatic patients may improve clinical ly during theophylline therapy whereas their pulmonary function may deteriorate during placebo therapy [6435664] We have compared the effects of oral theophylline and salbutamol on right and left ventricular function in twelve patients with chronic bronchitis and emphysema . Right and left ventricular ejection fraction ( RVEF and LVEF ) were measured using multiple gated radionuclide ventriculography . Theophylline 600 mg and salbutamol 4 mg both produced increases in RVEF and LVEF . There were no significant changes in blood gases after either drug . The clinical significance of the effects of oral bronchodilators on cardiac function in patients with chronic bronchitis and emphysema has yet to be determined [3046537] We conducted a four-period cross-over r and omized trial in which we found that patients with chronic airflow limitation demonstrated symptomatic improvement with both inhaled albuterol and oral theophylline . The response , however , was not uniform . We therefore tested the ability of acute change in forced expired volume in one second ( FEV1 ) following inhaled beta agonist to predict long-term symptomatic response to albuterol and theophylline . We found that the reproducibility of acute change in FEV1 over three repetitions was poor ( intraclass correlation 0.17 ) . Furthermore , the mean improvement FEV1 following inhaled albuterol across the three repetitions did not relate closely to symptomatic response to either albuterol or theophylline . We conclude that acute response to inhaled beta agonist is not useful for identifying patients with chronic airflow limitation who are likely to benefit from bronchodilator treatment [2778469] To test the relative merits of administering question naires with previous responses available ( the informed condition ) or unavailable ( the blind condition ) , we administered blind and informed versions of a quality of life question naire ( the Chronic Respiratory Disease Question naire , or CRQ ) in a r and omized , double-blind trial of bronchodilators in chronic airflow limitation . The responsiveness of the two methods , as reflected in the p-values associated with salbutamol and theophylline effects were comparable for three of the four dimensions of the CRQ . The data suggested possible increased responsiveness of the informed method for the emotional function dimension of the question naire . Changes in the informed CRQ dyspnea and fatigue dimensions showed stronger correlations with changes in spirometry , 6 minute walk distance , and rating of dyspnea after the walk test than did blind administration . Further , changes in all four CRQ dimensions showed stronger correlations with corresponding global ratings using the informed question naire . These results suggest that by letting study subjects see their previous responses the validity of subjective measures of health status in clinical trials can be improved [7874943] STUDY OBJECTIVE To determine the additive effect of oral theophylline in patients with stable COPD who received both inhaled salbutamol , 400 micrograms , and ipratropium bromide , 80 micrograms , four times daily administered with a metered-dose inhaler . DESIGN Twenty-four male patients with stable COPD ( FEV1 , 0.96 + /- 0.43 L ; 36.8 + /- 17.0 percent predicted [ % pred ] ) completed a r and omized , double-blind , placebo-controlled crossover trial with oral theophylline for 4 weeks . MEASUREMENTS AND RESULTS The average serum theophylline level was 15.0 + /- 5.5 micrograms/mL during treatment . On the whole , without inhalation of bronchodilators , FEV1 was 0.93 + /- 0.42 L during the placebo period and 1.00 + /- 0.43 L ( significantly different from placebo ; p < 0.01 ) during the theophylline period . At 15 and 60 min after inhalation of salbutamol , 400 micrograms , and ipratropium , 80 micrograms , the FEV1 with placebo was 1.12 + /- 0.43 L and 1.14 + /- 0.46 L , respectively , and the FEV1 with theophylline was 1.18 + /- 0.45 L ( p < 0.01 ) and 1.20 + /- 0.47 L ( p < 0.01 ) , respectively . Daily peak expiratory flow rate also improved . Daily symptom scores were not significantly different between theophylline and placebo periods . Nevertheless , eight patients reported a subjective benefit during the theophylline administration period , and they were thus considered subjective responders . While FEV1 after inhalation was significantly improved during the theophylline periods in subjective responders ( change in FEV1 between theophylline and placebo treatment 15 min after inhalation , 3.1 % pred ; 60 min , 3.5 % pred ) , postbronchodilator FEV1 was not significantly different between the placebo and theophylline periods in subjective nonresponders ( 15 min , 1.7 % pred ; 60 min , 1.6 % pred ) . CONCLUSIONS On the whole , theophylline has a small bronchodilating effect but does not improve the symptoms of patients with stable COPD . However , one third of patients with COPD may respond subjectively to theophylline . The additive bronchodilating effect of theophylline may be related to the symptomatic improvement in subjective responders [7040097] Using a double-blind , cross-over design the acute bronchodilating effect of 375 mg microcrystalline theophylline , 5 mg terbutaline , a combination of both drugs and placebo was studied in 11 patients suffering from moderate to severe chronic obstructive lung disease with partially reversible airway obstruction . Plasma concentrations both theophylline and terbutaline were measured . The bronchodilation produced by oral intake of 5 mg terbutaline and 375 mg theophylline was comparable . The maximal median value of terbutaline in plasma was 4.6 ng/ml 2 h after intake of medication , followed by a decline with a double peak in some patients . The maximal median increase of FEV1 was 37 % 3 h after intake of medication . The maximal median plasma level of theophylline reached 12.5 ng/ml 30 min after intake of the medication . The median maximal increase of FEV1 was 24 % . One hour after intake of medication and throughout the whole test period up to 7 h , the combination of 5 mg terbutaline and 375 mg theophylline produced a significantly greater bronchodilation than each drug alone . It is concluded that 375 mg microcrystalline theophylline produced a significantly greater bronchodilation than each drug alone . It is concluded that 375 mg microcrystalline theophylline and 5 mg terbutaline produces almost equal bronchodilating activity : a combination of both drugs , however , results in further bronchodilation [8797406] We compared the effects of evening administration of sustained-release theophylline ( Uniphyl ) and qid inhaled beta 2-agonist ( salbutamol , two 100-micrograms puffs ) on sleep quality and nocturnal oxygen saturation in 20 patients with COPD . Patients with FEV1 less than 70 % predicted and FEV1/FVC ratio less than 70 % were eligible to participate in this double-blind , crossover study , with 2-week treatment arms . Patients recorded morning and evening peak flow and symptoms in a daily diary . On the last day of each treatment period , overnight polysomnography was done . Spirometric indexes were measured before retiring and on awakening . Patients spent less time at less than 90 % oxygen saturation ( 51 + /- 92 min vs 72 + /- 105 min ; p = 0.03 ) during theophylline treatments than during salbutamol treatment . There was a smaller overnight decrease in FEV1 ( 0.04 L vs 0.13 L ; p = 0.04 ) after theophylline than after sallbutamol treatment . FEV1/FVC ratio and maximum expiratory flow at 50 % of vital capacity ( V50 ) increased overnight with theophylline and decreased with salbutamol ( p = 0.014 , 0.025 ) . Morning peak expiratory flow rate was higher with theophylline ( 4.0 + /- 1.7 L/s ) than with salbutamol ( 3.6 + /- 1.8 L/s ; p = 0.004 ) . The duration of patient-reported nocturnal wheezing was lower with theophylline than with salbutamol ( p = 0.006 ) . There were no differences between treatments in sleep quantity , efficiency , staging , or subjective quality . We conclude that , compared with salbutamol , evening administration of once-daily theophylline results in better nocturnal oxygen saturation and an improvement in the overnight change in pulmonary function , without affecting sleep architecture , in patients with COPD [3147048] OBJECTIVE --To evaluate measurement of the trapped gas volume as a measure of respiratory function in patients with chronic obstructive airways disease and their response to treatment with theophylline . DESIGN -- Patients able to produce consistent results on testing of respiratory function spent two weeks having dosage of theophylline adjusted to give individual pharmacokinetic data . This was followed by r and om assignment to four consecutive two month treatment periods -- placebo and low , medium , and high dose , as assessed by serum concentrations of theophylline . Respiratory function and exercise performance was assessed at the end of each two month period . SETTING --Chest unit in district hospital . PATIENTS --Thirty eight patients with chronic bronchitis and moderate to severe chronic obstruction to airflow were recruited ; 33 aged 53 - 73 years completed the study . INTERVENTIONS --Dosage of oral theophylline increased during two week optimisation period to 800 mg daily unless toxicity was predicted , when 400 mg was given . Targets for the steady state serum theophylline concentrations were 5 - 10 mg/l in the low dose period , 10 - 15 mg/l in the medium dose , and 15 - 20 mg/l in the high dose period . ENDPOINTS -- Respiratory function as measured by forced expiratory volume in one second , forced vital capacity , peak expiratory flow rate , slow vital capacity , and static lung volumes using helium dilution and body plethysmography from which trapped gas volume was derived . Exercise performance assessed by six minute walking test and diary cards using visual analogue scale . MEASUREMENTS AND MAIN RESULTS --The forced expiratory volume in one second , forced vital capacity , and peak expiratory flow rate changed only slightly ( about 13 % ) over the range of doses . There was a linear dose dependent fall of trapped gas volume from 1.84 l ( SE 0.157 ) to 1.42 l ( 0.152 ) , 1.05 l ( 0.128 ) , and 0.67 l ( 0.102 ) during the placebo and low , medium , and high dose treatment periods . Mean walking distance increased by up to 55.6 m ( 20 % ) . There was a modest improvement in dyspnoea as the dose of theophylline was increased . Side effects were mostly minor but they became more frequent as the dose was increased . CONCLUSION --The fall in trapped gas volume may reflect an improvement in peripheral ventilation ( associated with treatment with theophylline ) which is less apparent in the more common tests of lung function used in patients with chronic obstructive airways disease [7032378] We compared a 2-week course of 32 mg/d methylprednisolone with placebo in a double-blind crossover trial in 46 well-characterized patients with stable chronic obstructive pulmonary disease . Placebo and steroid trials were separated by 2 weeks when no tablets were given . Response was assessed by measuring forced expiratory volume in 1 second ( FEV1.0 ) . Placebo responses were normally distributed ( mean , 0.8 % change in FEV1.0 ; range , -30 % to 33 % ) . Six patients showed a greater than 50 % increase of FEV1.0 in response to steroid ; a seventh showed a 36 % increase and an eighth , a 29 % increase . Because of these patients the group as a whole showed a significantly greater FEV1.0 after steroid than after placebo . The eight steroid responders did not differ from nonresponders in age , sex , smoking history , or duration and intensity of symptoms including wheeze . Baseline lung function and eosinophilia of blood or sputum did not differ between the two groups . Patients who responded to steroids also responded to inhaled beta agonists : Acute bronchodilator response averaged 25 % in steroid responders and 13 % in nonresponders , a difference that was statistically significant although there was overlap between the two groups [1628722] Partial bronchodilator reversibility can be demonstrated in many patients with stable chronic obstructive pulmonary disease ( COPD ) , but its relevance to exercise capacity and symptoms is uncertain . Previous data suggest that anticholinergic bronchodilators do not improve exercise tolerance in such patients . We studied 32 patients with stable COPD , mean age 65 yrs , in a double-blind , placebo-controlled , cross-over trial of the inhaled anticholinergic drug , oxitropium bromide . From the within and between day placebo spirometry , we derived the spontaneous variation in forced expiratory volume in one second ( FEV1 ) and forced vital capacity ( FVC ) of this population ( FEV1 140 ml ; FVC 390 ml ) and considered responses beyond this to be significant . Oxitropium bromide increased baseline FEV1 from 0.70 ( 0.28 ) l ( mean ( SD ) ) to 0.88 ( 0.36 ) l. The 6 min walking distance increased by 7 % compared with placebo , whilst resting breathlessness scores fell from 2.0 to 1.23 at rest and 4.09 to 3.28 at the end of exercise after the active drug . Improvements in walking distances and symptoms were unrelated to changes in either FEV1 or FVC , indicating that routine reversibility testing is not a good predictor of symptomatic benefit in these patients [8202902] BACKGROUND --Theophylline is a well known bronchodilator which has been used for more than 50 years in the treatment of obstructive pulmonary diseases . In patients with severe chronic obstructive pulmonary disease whose cardiopulmonary performance is limited by their ventilatory capacity the administration of theophylline may improve exercise performance . METHODS --A r and omised , placebo controlled , double blind , crossover trial was conducted in 22 patients with severe but stable disease . The patients ( mean age 68 years ) were studied before and after one month of placebo and one month of treatment with a sustained release preparation of theophylline administered orally . The theophylline dose was adjusted until a blood level above 55.5 mumol/l was achieved . The two treatments were administered in r and om order and separated by a two week washout period . After theophylline was administered for one month a mean level of 68.2 mumol/l was achieved . Pulmonary function tests , arterial blood gas measurements , maximal voluntary ventilation ( MVV ) , and an incremental exercise test were performed before ( baseline ) and at the end of the first and second month of treatment . RESULTS --Pulmonary function tests showed no improvement in the flow parameters but showed an improvement in MVV after treatment with theophylline . Pulmonary gas exchange was improved after theophylline ( resting arterial PO2 8.91 v 8.59 kPa , PCO2 5.38 v 5.56 kPa ) . The incremental exercise study showed improvement in maximal work rate ( 86.5 v 75.0 watts ) and maximal ventilation ( VEmax ) ( 46.7 v 43.01/min ) . The dyspnoea index on maximal effort ( VEmax/MVV ) , anaerobic threshold , and oxygen pulse remained unchanged . Resting and exercise heart rate were higher after theophylline . CONCLUSIONS --Theophylline improved cardiorespiratory performance in these patients with severe chronic obstructive pulmonary disease mainly by increasing the ventilatory capacity [7982769] The effect of oral theophylline on clinical course , exercise , neuropsychological performance and bronchial reactivity was studied in chronic airflow obstruction . Twelve patients with chronic obstructive pulmonary disease ( COPD ) [ mean age 62.4 + /- 1.6 years ( SE ) , and forced expiratory volume in 1 sec of 1.15 + /- 0.1 l ] were r and omized to 4 weeks treatment with oral theophylline followed by 4 weeks of placebo , in a double-blind fashion . During each period , patients underwent clinical evaluation , incremental exercise , a battery of neuropsychological tests measuring a wide range of cognitive functions , and an inhaled methacholine provocation . On the active drug ( levels 9.5 + /- 1 mg/l ) , vital capacity and maximal breathing capacity were 16 + /- 7 % and 20 + /- 7 % respectively , higher relative to placebo ( P < 0.04 ) . Exercise capacity , as reflected by peak O2 uptake and the anaerobic threshold , improved 14 + /- 5 % and 18 + /- 5 % ( P < 0.04 ) . In contrast , bronchial responsiveness to inhaled methacholine and the mean scores on the neuropsychological tests were not significantly altered by the drug . Clinical symptoms were unaltered , but mild side effects were more common on theophylline . We concluded that in moderate to severe COPD , theophylline treatment , at the low range of the therapeutic dose , improves lung function and exercise capacity . This improvement is achieved with no detectable alteration of bronchial reactivity to methacholine and with no deleterious effect on cognitive functions [3717762] The effect of hypoxemia on the disposition of theophylline was examined in 10 stable patients with chronic obstructive pulmonary disease ( COPD ) receiving chronic theophylline and supplemental home oxygen therapy . Pharmacokinetics after intravenous theophylline were estimated on the second day of supplemental oxygen ( PaO2 , 69 + /- 4 mmHg ; mean + /- SEM ) and on the second day of room air breathing ( PaO2 , 43 + /- 3 ) using a r and omized cross-over design . On each occasion stable isotope-enriched theophylline ( 10 mg , m/z 183 ) was administered intravenously along with the regular oral dose of theophylline ( m/z 180 ) . Concentrations of both forms of theophylline in plasma sample s obtained over 24 h were measured using mass spectrometry . Theophylline clearance during oxygen therapy ( 0.048 + /- 0.005 L/h/kg ) was similar to that during room air breathing ( 0.050 + /- 0.004 L/h/kg ) . Values for elimination half-life ( 7.6 + /- 0.8 versus 6.8 + /- 0.6 h ) and volume of distribution at steady state ( 0.450 + /- 0.021 versus 0.429 + /- 0.024 L/kg ) were also unchanged . The volume of distribution of theophylline was inversely related to arterial pH during oxygen therapy ( pH range , 7.32 to 7.44 ) and during room air breathing ( pH range , 7.33 to 7.47 ) . Although hypoxemia does not alter theophylline clearance in patients with COPD , theophylline loading doses may need adjustment according to arterial pH because of an effect on volume of distribution [373776] The effect of theophylline ethylenediamine oblong tablets ( Euphyllin retard ) was tested in 40 patients by means of a double-blind trial , applying a dose of 2 X 350 mg/d and 2 X 700 mg/d . At the dose of 2 X 700 mg/d Euphyllin retard showed a good bronchodilatory effect . A reduction of the obstruction in the airways and an improvement of the arterial blood gases was statistically secured . At the dose of 2 X 350 mg/d a sufficient bronchodilation could not be recorded [2406328] To compare the efficacy and side effects of two xanthine derivatives in the maintenance therapy of reversible obstructive airway disease , 242 patients were assigned in r and omized , double-blind fashion to receive either oral enprofylline or theophylline for 5 weeks in addition to their usual maintenance regimens . After a week of placebo xanthine therapy , enprofylline-treated patients received 150 mg of this drug twice daily ( b.i.d . ) for 3 days , 300 mg b.i.d . for 2 weeks , and 450 mg b.i.d . for 2 weeks . Theophylline was administered in identical doses , except that the final dosage increase was not made if plasma theophylline was 12 mg/ml or higher . At 300 mg b.i.d . , both drugs significantly increased morning peak expiratory flow rate ( PEFR ) , the mean increase above baseline being significantly higher for theophylline-treated patients ( 29.9 + /- 37.2 L/min ) than for enprofylline-treated patients ( 17.4 + /- 36.9 L/min ) ( p = 0.023 ) . At 450 mg b.i.d . , improvement in morning PEFR was not significantly different between theophylline-treated ( 31.5 + /- 44.4 L/min ) and enprofylline-treated groups ( 23.5 + /- 48.4 L/min ) . Evening PEFR , FEV1 , and asthma symptom scores also improved significantly , demonstrating no significant difference between groups . The incidence of side effects was also similar between groups . We conclude that both enprofylline and theophylline offer useful bronchodilatation in the maintenance therapy of asthma , enprofylline , 450 mg b.i.d . , being approximately equivalent to theophylline , 300 or 450 mg b.i.d [7036401] In a double-blind placebo-controlled trial in 24 patients fulfilling the MRC criteria for chronic bronchitis , oral salbutamol 4 mg and slow-release aminophylline ( Phyllocontin ) 450 mg produced similar and significant ( p less than 0.05 ) mean increases in forced expiratory volume in one second ( FEV1 ) . A significantly greater increase in mean FEV1 and forced vital capacity ( FVC ) was seen when both drugs were given although there was no statistical evidence of synergistic interaction . Salbutamol significantly increased the mean distance walked in 12 minutes ( 12MD ) ( p less than 0.02 ) by 56 metres and a similar increase of 54 metres ( p less than 0.001 ) was seen after Phyllocontin . With both drugs in combination mean 12MD increased by 51 metres ( p less than 0.02 cf placebo ) , a change not significantly different from that observed with either drug alone . Oral salbutamol and Phyllocontin improve exercise tolerance in chronic bronchitis . The significantly greater changes in FEV1 and FVC result ing from simultaneous administration of the two drugs are not associated with further improvement in exercise tolerance [8630581] Dynamic hyperinflation ( DH ) is a major pathophysiologic consequence of airflow limitation during exercise in patients with chronic obstructive pulmonary disease ( COPD ) and an important contributing factor to breathlessness . In this study we aim ed to examine the effect of inhaled beta agonist therapy on DH during exercise in these patients and the relationship between changes in DH and breathlessness . In 13 COPD patients ( mean age 65.1 + /- 2.0 , FEV1 1.20 + /- 0.17 , FEV1/FVC 40 + /- 3 ) we measured pulmonary function tests , exercise breathlessness by Borg score , and exercise flow volume and pressure volume loops on two separate days . Prior to testing , patients r and omly received inhaled placebo or albuterol on the first test day and the alternative medication on the second test day . From measurements of exercise inspiratory capacity ( IC ) , we calculated the end-expiratory and end-inspiratory lung volumes ( EELV , EILV ) . We used esophageal pressure recordings to measure peak inspiratory esophageal pressure ( Pesins ) during exercise and this was related to the maximal capacity for pressure generation taking into account lung volume and airflow changes ( Pcapi ) . Bronchodilator caused significant increase in both FEV1 and FVC ( + 0.23 and + 0.51 , p<0.01 ) . Comparisons of breathlessness , exercise volumes , and pressures were made at the highest equivalent work load . There was a significant reduction in the peak exercise EELV/TLC ( 80 + /- 0.02 % to 76 + /- 0.02 % , p<0.05 ) while the peak EILV/TLC decreased by 2 % ( 97 + /- 1 % to 95 + /- 1 % , p<0.05 ) . The peak Pesins/Pcapi decreased ( 0.79 + /- 0.10 to 0.57 + /- 0.05 , p<0.05 ) , and the Pcapi - Pesins increased ( 7.4 + /- 3 to 13.0 + /- 3 cm H2O , p<0.05 ) . There was significant improvement in neuroventilatory coupling for volume change ( Pesins/Pcapi/VT/TLC 5.45 + /- 0.5 to 3.25 + /- 1.0 , p<0.05 ) . There was a significant reduction in breathlessness as measured by Borg score ( 4.5 + /- 0.7 to 3.1 + /- 0.5 , p<0.05 ) and there was a significant correlation between delta Borg and delta EILV/TLC ( r=0.771 , p<0.01 ) with a trend for Pesins/Pcapi/VT/TLC ( r=0.544 , p=0.067 ) . There was also a significant correlation between delta EELV/TLC and delta Pesins/Pcapi/VT/TLC ( r=0.772 , p<0.01 ) . The relationships between delta Borg , delta resting volumes , and flow rates were not significant . We conclude that in patients with COPD , inhaled bronchodilator reduces exercise DH and improves inspiratory pressure reserve and neuroventilatory coupling . Changes in DH and neuroventilatory coupling were the main determinants of reduced breathlessness [9358138] BACKGROUND Inhaled glucosteroids and oral theophylline are widely used to treat asthma . We compared the benefits of adding theophylline to inhaled glucosteroid with those of doubling the dose of inhaled glucosteroid in patients with persistent symptoms despite the use of inhaled glucosteroid . METHODS In a double-blind , placebo-controlled trial , we r and omly assigned 62 patients to receive either 400 microg of inhaled budesonide ( low-dose budesonide ) with 250 or 375 mg of theophylline ( depending on body weight ) or 800 microg of inhaled budesonide ( high-dose budesonide ) . All doses were given twice daily for three months . Lung function was measured serially , and patients kept records of peak expiratory flow , symptoms , and albuterol use . The effects of treatment on endogenous cortisol levels were also assessed . RESULTS Both treatments result ed in improvements in lung function that were sustained throughout the study . As compared with treatment with high-dose budesonide , treatment with low-dose budesonide plus theophylline result ed in greater improvements in forced vital capacity ( P=0.03 ) and forced expiratory volume in one second ( P= 0.03 ) . There were significant and similar reductions in beta2-agonist use and the variability of peak expiratory flow , a correlate of bronchial hyperresponsiveness and the severity of asthma . Serum cortisol concentrations were significantly reduced in the group given high-dose budesonide ( from a mean [ + /-SE ] of 18.4+/-2.4 microg per deciliter to 15.9+/-2.1 microg per deciliter , P=0.02 ) but were unchanged in the other group . The median serum theophylline concentration was 8.7 microg per milliliter ( therapeutic range , 10 to 20 ) among those who received theophylline . Both treatments were well tolerated . CONCLUSIONS For patients with moderate asthma and persistent symptoms , low-dose inhaled budesonide with theophylline and high-dose inhaled budesonide produced similar benefits . Effects were achieved at theophylline concentrations below the recommended therapeutic range . The addition of low-dose theophylline to inhaled glucosteroid may be preferable to and cheaper than increasing the dose of inhaled glucosteroid [1812479] 24 patients with COPD and delta FEV1 greater than 15 % were included in a double-blind crossover study . 7 dropouts due to deterioration of findings and incomplete data reduced the number of assessable patients to 17 . Most of the patients had been pretreated with a slightly higher theophylline dosage before initiation of the study . In the preliminary period a 24-hour profile of the peak flow was set up with a morning and evening theophylline level . During the 5-day treatment intervals a 24-hour profile of the serum theophylline levels and of the peak flow was recorded at two-hour intervals . A complete lung function test was performed in each phase . The pharmacokinetic data of both preparations are comparable . Euphylong showed a bioavailability of 83 % , the maximum of the serum level was attained at night . Serum level variations were only slightly higher than those of the reference drug . Euphylong had a night level of 24 % above the daily average ( reference drug 3 % ) . This was associated in a part of the group , about one-third of the total number of patients , with an improvement of the " morning dip " compared with the preliminary period or the reference drug . Over the entire group of patients there were no differences between both drugs or the preliminary period that could be ascribed to the theophylline premedication . An advantage shown by Euphylong was the better predictability of the serum levels . During the time period of the clinical routine the deviation of the serum level from the actual serum maximum was less than 15 % [10202315] Background : Chronic continuous airway inflammation caused by eosinophils has been noted to play critical roles in the pathophysiology of bronchial asthma , in addition to reversible obstruction and hypersensitivity of the respiratory tract . Therefore , suppression of chronic airway inflammation has become more important in asthma treatment . Although theophylline has been a conventionally used bronchodilator , it has been recently reported to have concurrent anti-inflammatory effects . Objective : Accordingly , we studied the effects of a slow-release theophylline preparation , Theolong ® , on airway inflammation . Methods : Administration of Theolong 400 mg/day to 24 patients with mild or moderate asthma and measuring eosinophil cationic protein ( ECP ) , a marker of airway inflammation , and eosinophils in sputum and peripheral blood at 4 and 8 weeks . Results : As a result , sputum ECP , serum ECP and sputum eosinophil count ( % ) were significantly lowered after 4 and 8 weeks . Conclusion : Thus , in the theophylline-administered group , slow-release theophylline , Theolong ® , was effective in treating asthma , with anti-inflammatory effects on inflammatory cells besides its bronchodilator action [10193252] OBJECTIVES To determine whether children with severe acute asthma treated with large doses of inhaled salbutamol , inhaled ipratropium , and intravenous steroids are conferred any further benefits by the addition of aminophylline given intravenously . STUDY DESIGN R and omised , double blind , placebo controlled trial of 163 children admitted to hospital with asthma who were unresponsive to nebulised salbutamol . RESULTS The placebo and treatment groups of children were similar at baseline . The 48 children in the aminophylline group had a greater improvement in spirometry at six hours and a higher oxygen saturation in the first 30 hours . Five subjects in the placebo group were intubated and ventilated after enrolment compared with none in the aminophylline group . CONCLUSIONS Aminophylline continues to have a place in the management of severe acute asthma in children unresponsive to initial treatment [9282234] Exercise tolerance in chronic obstructive pulmonary disease ( COPD ) patients treated with oral aminophylline may be different from those treated with high-dose inhaled ipratropium bromide . The purpose of this study was to compare the effects of therapeutic doses of oral aminophylline with high-dose ipratropium bromide on spirometry and exercise tolerance . The study was conducted on three consecutive days in a double-blind , r and omized , crossover fashion . Baseline studies obtained on each study day included vital signs , simple spirometry and a symptom-limited maximal cardiopulmonary stress test , after which patients received one of the following treatments on each day : Treatment 1 , inhaled ipratropium ( total dose of 144 micrograms ) with placebo tablets ; Treatment 2 , inhaled placebo with oral aminophylline ( 400 mg ) ; Treatment 3 , inhaled placebo and placebo tablets . Simple spirometry was repeated at 60 and 120 min after baseline . Vital signs and cardiopulmonary stress testing was repeated at 120 min . Eighteen patients were enrolled in the study , and 17 of these completed the study . There was a significant ( P < 0.05 ) increase in both forced expiratory volume in 1 s ( FEV1 ) , from 0.75 ( 0.21 ) to 0.92 ( 0.3 ) , and forced vital capacity ( FVC ) , from 1.8 ( 0.79 ) to 2.11 ( 0.84 ) , with high-dose ipratropium despite prior beta-agonist therapy . Lack of improvement in exercise capacity was noted with ipratropium despite improvement in spirometry . These results suggest that elderly patients with severe COPD may have exercise limitation that is not directly dependent on severity of airflow obstruction . Ipratropium bromide and aminophylline demonstrated no acute effects on exercise capacity [7788518] BACKGROUND Previous clinical therapeutic research has shown that inhaled nedocromil sodium can replace maintenance oral sustained release theophylline in the management of asthma patients . OBJECTIVE To compare directly the efficacy and safety of nedocromil sodium and sustained release theophylline . METHODS Using a r and omized , double-blind , double-dummy , parallel-group design , 105 patients with reversible obstructive airways disease ( 77 asthmatic patients ) recruited from four referred-care clinics received , in addition to their existing therapy , 4 mg nedocromil sodium four times daily or sustained release theophylline ( maximum daily dose 13 mg/kg ) for 6 weeks . Patients with serum theophylline levels within the therapeutic range of 10 to 20 micrograms/mL were retained for efficacy analysis . All were included in a tolerability analysis . Day and nighttime symptoms , inhaled bronchodilator use , morning tightness , cough , and twice daily peak flows were recorded on diary cards . Disease severity , lung function and unusual events were evaluated bi-weekly , and opinion of treatment after 6 weeks . RESULTS Both treatments improved symptoms , inhaled bronchodilator use and lung function to the same extent . Both treatments were very to moderately effective in > 70 % patients . The occurrence of gastrointestinal ( P < .05 ) and central nervous system ( P < .01 ) unusual events was significantly lower for nedocromil sodium compared with theophylline treated patients . CONCLUSIONS Nedocromil sodium and theophylline were equally effective in this group of patients but nedocromil sodium treatment was associated with significantly fewer side effects , and therefore may be the treatment of choice [6213382] In two groups of patients , 15 with asthma and 15 with chronic bronchitis , the bronchodilator effects of ipratropium bromide , of fenoterol plus theophylline , and of the combination of the three drugs , were compared using a double-blind , single-dose , placebo-controlled format . Ipratropium bromide caused rapid bronchodilatation which was not significantly different in asthmatic patients and patients with bronchitis ( delta FEV1 = .29 L in one hour in asthmatic patients , .18 L in patients with bronchitis ) . In contrast , fenoterol plus theophylline induced a considerably greater effect in asthmatic patients ( delta FEV1 = .41 L in one hour ) than in those with bronchitis ( delta FEV1 = .07 in one hour ) . The use of the three drugs in combination compared with ipratropium bromide alone , or fenoterol plus theophylline alone , result ed in a significant additional bronchodilatation in asthmatic patients . In the patients with bronchitis , the triple combination was clearly superior to fenoterol plus theophylline . A similar trend was present in comparing the triple combination to ipratropium bromide , but the difference did not reach statistical significance . There was no evidence of synergism when ipratropium bromide was combined with fenoterol plus theophylline in that the total bronchodilator effect was approximately additive . Asthmatic patients and the physician were able to distinguish the triple combination from placebo . No such ability was demonstrated with respect to those with bronchitis . All three drugs were well tolerated . Side effects were mostly mild , and none was related to the use of ipratropium [10588606] We tested the hypothesis that the decrease in dyspnea in patients with COPD with inhaled albuterol is in part due to increased diaphragmatic contractility . Eleven patients with COPD inhaled albuterol or placebo in a double-blind r and omized manner . Subsequently , dyspnea was measured while patients breathed through inspiratory resistors , and diaphragmatic contractility was quantified during maximal inspiratory efforts and after twitch stimulation of the phrenic nerves . Albuterol produced a decrease in dyspnea ( 5 + /- 2 to 4 + /- 2 [ SD ] Borg units , p < 0.01 ) , and increases in maximal transdiaphragmatic pressure ( 92.4 + /- 37.2 to 102.8 + /- 37.2 cm H(2)O , p < 0.03 ) and potentiated twitch transdiaphragmatic pressures ( 21.6 + /- 7.1 to 25.2 + /- 7.6 cm H(2)O , p < 0.02 ) . The decrease in dyspnea correlated with the increases in maximal and twitch transdiaphragmatic pressures : r = -0.64 ( p = 0 . 04 ) and r = -0.65 ( p = 0.04 ) , respectively . Compared with placebo , albuterol produced an increase in inspiratory capacity ( 1.87 + /- 0 . 71 to 2.26 + /- 0.74 L , p = 0.002 ) , which accounted for the increases in maximal and twitch transdiaphragmatic pressures . The decrease in dyspnea correlated with the increase in inspiratory capacity ( r = -0 . 62 , p = 0.04 ) , but not with the increase in FEV(1 ) ( r = -0.13 , p = 0 . 72 ) . In conclusion , albuterol relieves dyspnea and enhances respiratory muscle output in patients with COPD primarily by improving the length-tension relationship of the diaphragm rather than by improving its contractility [1899325] To investigate the effect of theophylline on sleep and sleep-disordered breathing in patients with chronic obstructive pulmonary disease ( COPD ) , we studied 12 male nonhypercapnic subjects with a mean + /- SEM age of 62.8 + /- 2.5 yr and a FEV1 of 1.36 + /- 0.11 L using a r and omized double-blind crossover protocol . Sustained-action theophylline ( 250 mg three times or four times a day ) or placebo was administered for 2 days , and the alternate drug was administered on the following 2 days . Sleep studies were performed on Nights 2 and 4 with spirometry at 9:00P.M. and 7:00A.M. Two puffs of metaproterenol or albuterol were administered at 10:00P.M. on both study nights . A theophylline level , drawn at bedtime ( 10:00 to 11:00P.M. ) , was 14.2 + /- 0.78 micrograms/ml on the theophylline nights and less than 2 on placebo nights . The morning FEV1 was significantly better during theophylline administration ( 1.27 + /- 0.12 versus 1.00 + /- 0.11 L , p less than 0.001 ) . The mean arterial oxygen saturation ( SaO2 ) and transcutaneous carbon dioxide pressure ( PCO2 ) were also better during NREM sleep on theophylline nights . Neither the mean SaO2 and transcutaneous PCO2 during REM sleep nor the apnea plus hypopnea index ( events per hour of sleep ) differed between placebo and theophylline nights . Theophylline administration did not impair the amount or architecture of sleep as neither total sleep time nor the fraction of time spent in Stages 1 , 2 , and 3/4 and REM differed between the two regimens . The number of arousals per hour of sleep was slightly less on theophylline nights ( 19.9 + /- 1.7 versus 24.9 + /- 2.7 , p less than 0.05 ) . ( ABSTRACT TRUNCATED AT 250 WORDS [1596003] The effect of theophylline on sleep quality and cognitive performance in patients with obstructive lung disease has been the subject of controversy . To examine the direct effects of theophylline on sleep quality and cognitive performance , without confounding effects from bronchodilatation , we have undertaken a study of the drug in healthy subjects . A double-blind , placebo-controlled crossover protocol was used to study the effect of oral sustained-release theophylline ( Theodur ) on subjective sleep quality , objective sleep quality , and cognitive performance . Overnight sleep studies were carried out on Nights 13 and 14 of each 2-wk study limb , and cognitive performance tests administered on Days 1 and 13 of each limb . A total of 18 subjects satisfactorily completed the study ( 8 males , median age 37 , range 24 to 67 yr ) . Theophylline levels were median 10.2 , range 2.3 to 13.3 micrograms/ml on Day 1 and 14.7 , range 9.6 to 17.5 micrograms/ml on Day 13 . No significant difference was observed between theophylline and placebo on subjective or objective sleep quality or on acute or medium-term cognitive performance . We conclude that theophylline does not affect sleep quality or cognitive performance in normal adults [2699466] A multicentre , double-blind , r and omized trial was carried out in 11 Italian Pneumologic Clinics to investigate the therapeutic efficacy and tolerability of doxofylline compared with slow-release theophylline in 139 patients ( 86 males , 53 females ) aged 17 - 77 years suffering from reversible chronic airways obstruction . The two groups of 69 patients on doxofylline and 70 patients on theophylline did not differ in their baseline clinical and functional parameters . After one week of wash-out , the two drugs were administered orally at a dose of 400 mg twice daily of doxofylline and 300 mg twice daily of theophylline . The treatment and follow-up lasted 28 days . Inhaled salbutamol on dem and was allowed in the wash-out week and throughout the trial . The average serum levels at day 14 and 28 were : doxofylline 7.5 and 8.5 micrograms/ml ; theophylline 10.4 and 7.95 micrograms/ml respectively . Both drugs significantly increased spirometric parameters ( p less than 0.001 for all tests ) and significantly reduced salbutamol consumption ( p less than 0.001 for both drugs ) . Doxofylline was better tolerated than theophylline considering either the number of unwanted side-effects : ( doxofylline 12 ; theophylline 37 ) or number of drop-outs due to side-effects ( doxofylline 5 ; theophylline 10 ) . From these results doxofylline seemed to be a good alternative to theophylline in the treatment of reversible chronic airway obstruction in view of its better safety profile [8989057] To determine the effect of theophylline on respiratory muscle efficiency ( RME ) , 12 normal subjects were given theophylline vs placebo in a double-blind , r and omized crossover protocol . Spirometry , resting energy expenditure , minute ventilation , RME and oxygen cost of breathing were measured at baseline , after taking theophylline , and after placebo . RME was calculated by dividing the added work required to breathe through a threshold load by the added energy consumed during loaded breathing . Oxygen cost of breathing was calculated by dividing the increase in oxygen consumption induced by breathing an air/carbon dioxide mixture by the associated increase in minute ventilation . RME increased from 3.3 + /- 1.6 % at baseline to 7.9 + /- 3.2 % after theophylline ( p < 0.01 ) but did not change significantly after placebo ( 4.8 + /- 2.4 % ) . Oxygen cost of breathing decreased from 3.9 + /- 2.4 mL O2 per liter at baseline to 1.7 + /- 0.7 mL O2 per liter after theophylline ( p < 0.05 ) but did not change significantly after placebo ( 2.8 + /- 1.3 mL O2 per liter ) . Theophylline use was also associated with an 18 % increase in minute ventilation ( p < 0.01 ) and a 15.7 % increase in resting energy expenditure ( p < 0.01 ) . Theophylline improves measured RME and reduces oxygen cost of breathing in normal subjects . These effects are offset by increases in resting energy expenditure and minute ventilation [9224226] BACKGROUND Patients with chronic obstructive pulmonary disease ( COPD ) tend to develop secondary erythrocytosis to compensate for their chronic hypoxia . Theophylline has recently been shown to reduce hematocrit and erythropoietin blood levels in normal subjects and in patients with erythrocytosis after renal transplantation . OBJECTIVE To determine whether theophylline may be used to lower the hematocrit in patients with COPD . METHODS Two hundred four patients with COPD were studied retrospectively and 10 patients prospect ively ( 8 starting treatment with the drug [ group 1 ] and 2 who suspended its long-term use [ group 2 ] ) for the correlation between theophylline therapy and hematocrit and erythropoietin level . RESULTS In the patients studied retrospectively , lower hematocrits were found in the theophylline-treated than in the untreated patients ( 0.43 + /- 0.006 vs 0.46 + /- 0.007 , respectively ; P < .002 ) . Twelve untreated patients and 2 of those treated with theophylline had hematocrits above 52 % . Oxygen saturation levels were similar in both groups , and exclusion of patients with oxygen saturation lower than 88 % did not change the pattern , suggesting that the effect of theophylline could not be entirely explained by improved oxygen availability . Seven of the 8 patients studied prospect ively in group 1 ( P < .02 ) and the 2 patients in group 2 showed inverse correlations between hematocrits and theophylline administration . A similar pattern was observed with serum erythropoietin levels in 5 of 7 patients studied . The effects were reproducible on rechallenge in 3 of the 4 patients in group 1 and the 2 patients in group 2 . CONCLUSIONS Theophylline may have a beneficial effect in treatment and prevention of erythrocytosis in patients with COPD [6738652] We studied the effects of theophylline on diaphragmatic strength and fatigue in 15 patients with severe chronic obstructive pulmonary disease . Diaphragmatic strength was assessed by measurement of the transdiaphragmatic pressure generated at functional residual capacity during a maximal inspiratory effort against closed airways . Diaphragmatic fatigue was induced by resistive loaded breathing . The electrical activity of the diaphragm was recorded with an esophageal electrode during the fatigue runs , and the high-low ratio of the electrical signal was analyzed to assess diaphragmatic fatigue . Studies were performed before and after 7 and 30 days of theophylline administration ( mean plasma level , 13 + /- 2 mg per liter ) . A control group received a placebo instead of theophylline . Theophylline increased maximal transdiaphragmatic pressure by 16 per cent after 7 days of administration ( P less than 0.01 ) , and this increase persisted after 30 days . No significant change in maximal transdiaphragmatic pressure was observed in the group given the placebo . Theophylline also suppressed diaphragmatic fatigue in all patients who received it . We conclude that theophylline has a potent and long-lasting effect on diaphragmatic strength and fatigue in patients with fixed airway obstruction [3966709] Although orally administered theophylline has been prescribed widely in patients with nonreversible airway obstruction , symptomatic benefit has not been established . To assess the effects of orally administered theophylline on dyspnea , we performed a r and omized , double-bind , crossover , placebo-theophylline clinical trial in 12 ambulatory male patients with moderate to severe nonreversible airway obstruction . Dyspnea was rated using 2 clinical indexes based on 3 components affecting breathlessness : functional impairment , magnitude of task that evokes dyspnea , and the associated magnitude of effort . Dyspnea and physiologic parameters were measured on 4 occasions : at baseline , 4 wk after initial treatment , a second baseline after a 2-wk washout period , and 4 wk after the second medication . For the 12 patients , mean age ( + /- SD ) was 60 + /- 7 yr , forced expiratory volume in one second was 1.36 + /- 0.67 L ( mean , 40 % of predicted ) , and arterial oxygen tension was 71 + /- 10 mmHg . During the treatment phase , all patients had a therapeutic theophylline blood level ( range , 12 to 19 micrograms/ml ) . Theophylline significantly decreased the components of functional impairment ( p = 0.02 ) and magnitude of task ( p = 0.02 ) relating to dyspnea , as well as the overall dyspnea rating ( p = 0.01 ) . There were no significant differences between placebo and theophylline therapy for spirometry , arterial blood gas tensions , and the 12-min walking distance . Thus , sustained-release theophylline significantly reduced dyspnea in these ambulatory patients with moderate to severe nonreversible airway obstruction without altering lung function , gas exchange , or exercise performance [6751178] Orally administered theophylline is commonly prescribed for patients with chronic obstructive pulmonary disease ( COPD ) . It would be advantageous to predict those patients who will or will not respond to this methylxanthine . Forty men with COPD received placebo and theophylline orally , each for 1 month in a double-blind , single cross-over fashion . The acute response of the forced expiratory volume in one second ( FEV1 ) to isoproterenol inhalation ( 015 mg ) during placebo therapy was determined . The subjective and objective responses after 1 month of therapeutic theophylline concentrations ( 15.1 + /- 4.2 microgram/ml ) , mean + /- SD ) in these clinical ly stable subjects also were measured . The sensitivity and specificity of isoproterenol aerosolization for predicting an objective response to theophylline was 75 and 96 % , respectively . We conclude that isoproterenol inhalation can predict the response to orally administered theophylline in patients with COPD [2681505] We compared the frequency and severity of cardiac arrhythmias during combined oral theophylline and inhaled salbutamol vs. salbutamol therapy alone in 18 patients with moderate to severe chronic obstructive pulmonary disease who had concurrent cardiac disease . Seventeen patients showed at least one supraventricular premature complex ( SVPC ) on the 24-h ECG recording when receiving salbutamol alone : eight patients had isolated SVPCs , less than 10/h ; five patients had greater than or equal to 10 SVPCs/h ; eight patients showed runs of supraventricular tachycardia or paroxysmal atrial fibrillation . Seventeen patients also had at least one ventricular premature complex : seven patients had less than 10 isolated PVCs/h , five patients greater than or equal to 10 PVCs/h ; eight patients had paired or multifocal PVCs and one patient a run of ventricular tachycardia . The addition of oral theophylline at an average dose of 600 mg in the evening ( blood concentrations showed a mean maximum of 13.4 + /- 4.0 ( SD ) and minimum of 5.5 + /- 2.9 mg/l ) had no influence on the frequency or severity of either ventricular or supraventricular arrhythmias . Thus , cardiac arrhythmias are very common in patients with chronic obstructive pulmonary disease and concomitant heart disease , but oral theophylline added to a regimen of salbutamol does not seem to affect the occurrence or severity of arrhythmias [7613555] Theophylline is known to alter sleep architecture because of its affinity to adenosine receptors . One of the consequences of disrupted sleep is impaired cognitive performance . A single-blind , r and omized cross-over study of eight male chronic obstructive pulmonary disease ( COPD ) patients was undertaken to evaluate the effects of theophylline versus doxofylline on sleep architecture . The patients , who were all ex-smokers , had been treated with theophylline . Mean age was 53 + /- 12 yrs , forced expiratory volume in one second ( FEV1 ) 50 + /- 22 % predicted and forced vital capacity ( FVC ) 70 + /- 18 % predicted . Following a wash-out period , four patients were given oral slow-release theophylline ( T ) ( 300 mg b.i.d . ) for one week , followed by a cross-over to doxofylline ( D ) ( 400 mg t.i.d . ) for a second week . The other four patients were given the drugs in the reverse order . All patients underwent polysomnography at baseline and at the end of each week of treatment . The number of arousals per hour was 5.5 + /- 2.9 at baseline , 9.4 + /- 5.2 during T treatment and 5.4 + /- 4.4 during D treatment . During T treatment , sleep efficiency was 60 + /- 19 % vs 75 + /- 13 % recorded at baseline trial and 68 + /- 25 recorded during D treatment . Sleep quality , during T treatment , was poorer than at baseline , with a greater increase in the percentage of wakefulness and more stage 2 sleep than at baseline . Slow wave sleep was reduced with both treatments , particularly D. Neither drug affected the arterial oxygen saturation ( Sao2 ) or respiratory rate during sleep . ( ABSTRACT TRUNCATED AT 250 WORDS [9741369] BACKGROUND The effects of theophylline or anticholinergic agents on exercise capacity in patients with chronic obstructive pulmonary disease ( COPD ) remain controversial . The aim of the present study was to compare the effect of an oral theophylline with an inhaled anticholinergic agent and to examine the effects of combined therapy on exercise performance using progressive cycle ergometry . METHODS Twenty one men with stable COPD and a mean ( SD ) forced expiratory volume in one second ( FEV1 ) of 1.00 ( 0.40 ) l were studied . Theophylline ( 600 or 800 mg daily ) , ipratropium bromide ( 160 μg ) , a combination of both drugs , and placebo were given in a r and omised , double blind , four period crossover design study . Spirometric data , pulse rate , and blood pressure were assessed before and at 90 and 120 minutes after inhalation . Symptom limited progressive cycle ergometer exercise tests ( 20 watts/min ) were performed 90 minutes after each inhalation , and dyspnoea was measured during exercise using the Borg scale . RESULTS The mean ( SD ) serum theophylline concentration was 18.3 ( 6.3 ) μg/ml , and seven patients had side effects during treatment with theophylline . Theophylline and ipratropium bromide produced greater increases in FEV1 , maximal oxygen consumption , maximal minute ventilation , and several dyspnoea ratios than placebo . There were no differences between theophylline and ipratropium bromide except in maximal heart rate . A combination of both drugs produced greater improvements in pulmonary function and exercise capacity than either drug alone . CONCLUSIONS Both high dose theophylline and high dose ipratropium bromide improved exercise capacity in patients with stable COPD . Although data based on short term effects can not be directly applied to long term therapy , theophylline added to an inhaled anticholinergic agent may have beneficial effects on exercise capacity in patients with COPD [10546469] A 1-yr multicentre two-tailed r and omized open study was conducted in 15 centres in Italy , with the aim of comparing the clinical efficacy ( over 3 months ) and tolerability ( over 1 yr ) of salmeterol with those of oral theophylline in patients with reversible chronic obstructive pulmonary disease ( COPD ) . Patients with reversible COPD ( forced expiratory volume in one second ( FEV1 ) 50 - 80 % , FEV1 after bronchodilator > 12 % , n = 138 ) were r and omized to receive salmeterol powder ( 50 micrograms b.i.d . with Diskhaler , n = 66 ) or individually dose-titrated slow-release oral theophylline capsules so as to obtain a serum concentration of theophylline ranging 10 - 20 micrograms.mL-1 ( n = 72 ) . During the 2-week run-in period , nonadmitted medications were discontinued and patients had to present with respiratory symptoms on at least four of the last seven days . Following r and omization , patients were required to monitor daytime and night-time symptoms , additional use of as-required salbutamol , and morning and evening peak expiratory flow ( PEF ) for 3 months . Spirometric measurements and assessment of the quality of life were performed every 3 months for 1 yr . Salmeterol was proven to be statistically more effective than theophylline in : 1 ) increasing the maximum value of morning PEF ; 2 ) increasing the percentages of days and nights without symptoms ; 3 ) reducing the need for additional salbutamol during daytime and night-time ; and 4 ) increasing quality of life in terms of physical and social activities , mental health and psychophysical energy , assessed 3 months after the beginning of treatment . Salmeterol was no more effective than theophylline in increasing : 1 ) forced vital capacity and FEV1 at the various measurements ; 2 ) maximum evening PEF value ; and 3 ) quality of life after the first 3 months of treatment . Neither treatment induced significant side-effects over the 1-yr treatment . This study confirms that inhaled salmeterol is more effective than oral theophylline in long term treatment of reversible obstructive pulmonary disease [1729064] To investigate the efficacy of bronchodilators in patients with irreversible chronic obstructive pulmonary disease ( COPD ) , we conducted a double-blind , r and omized , four-phase , crossover comparison between placebo , oral theophylline , inhaled salbutamol , and a combination of both drugs in 12 patients with stable COPD ( mean age , 63 years ) whose increase in forced expiratory volume in 1 s ( FEV1 ) was less than or equal to 15 percent following 200 micrograms of inhaled salbutamol . Patients received two weeks of therapy with each of the test regimens . Both theophylline and salbutamol result ed in statistically significant improvement in FEV1 , forced vital capacity ( FVC ) , slow vital capacity ( SVC ) , residual volume ( RV ) , airway resistance ( Raw ) , and maximum expiratory flow rate at 50 percent of vital capacity ( V50 ) . In most instances , there were no significant differences between theophylline and salbutamol . Combination therapy produced significantly greater improvement in FEV1 , FVC , V50 , Raw , and RV than either agent alone . The two drugs interacted in an additive fashion . Neither of the drugs , used singly , significantly reduced the severity or incidence of symptoms . The reduction in dyspnea and wheeze during combination therapy approached statistical significance ( p = 0.06 ) and patient preference was significantly in favor of the combination regimen . None of the active treatments produced significantly more side effects than placebo . We conclude that theophylline and inhaled salbutamol produce significant , and approximately equal , improvement in pulmonary function in patients traditionally classified as suffering from " irreversible " COPD . The combination of theophylline and inhaled salbutamol generally results in additional improvement over that obtained with either drug used alone and this improvement is reflected by reduced symptomatology and treatment preference [6641302] At rest and during exercise , noninvasive studies of cardiopulmonary physiology in patients with chronic obstructive pulmonary disease ( COPD ) were carried out to determine the objective benefits of commonly used oral bronchodilator drugs in 15 stable patients without cardiovascular disease or reversible obstruction of airflow . Theophylline , terbutaline , a combination of theophylline and terbutaline , and placebo were given for ten days each in a r and omly sequenced double-blind protocol for out patients . Spirometric values , the ratio of physiologic dead space to tidal volume ( VDp/VT ) , and the alveolar-arterial oxygen pressure difference ( P[A-a]O2 ) were studied at rest on each regimen . During steady-state exercise the changes in VDp/VT and P(A-a)O2 , as well as the ventilatory equivalent for oxygen and oxygen pulse , were measured . When compared with placebo , no significant change was noted in the previously mentioned measurements with any regimen , with the exception of a small improvement in the forced expiratory volume in one second , which was significant for all regimens . These findings suggest that commonly used oral bronchodilator drugs in usual doses may have small effects on airflow even in " irreversible " COPD but that the objective effect of these agents on gas exchange during rest and exercise is not significant [10430726] We wished to determine which resting spirometric parameters best reflect improvements in exercise tolerance and exertional dyspnea in response to acute high-dose anticholinergic therapy in advanced COPD . We studied 29 patients with stable COPD ( FEV(1 ) = 40 + /- 2 % predicted [ % pred ] ; mean + /- SEM ) and moderate to severe chronic dyspnea . In a double-blind placebo-controlled cross-over study , patients performed spirometry and symptom-limited constant-load cycle exercise before and 1 h after receiving 500 micrograms of nebulized ipratropium bromide ( IB ) or saline placebo . There were no significant changes in spirometry , exercise endurance , or exertional dyspnea after receiving placebo . In response to IB ( n = 58 ) : FEV(1 ) , FVC , and inspiratory capacity ( IC ) increased by 7 + /- 1%pred , 10 + /- 1%pred , and 14 + /- 2%pred , respectively ( p < 0.001 ) , with no change in the FEV(1)/FVC ratio . After receiving IB , exercise endurance time ( Tlim ) increased by 32 + /- 9 % ( p < 0.001 ) and slopes of Borg dyspnea ratings over time decreased by 11 + /- 6 % ( p < 0.05 ) . Percent change ( % Delta ) in Tlim correlated best with DeltaIC%pred ( p = 0.020 ) and change in inspiratory reserve volume ( DeltaTLC%pred ) ( p = 0.014 ) , but not with DeltaFVC%pred , DeltaPEFR%pred , or DeltaFEV(1)%pred . Change in Borg dyspnea ratings at isotime near end exercise also correlated with DeltaIC%pred ( p = 0.04 ) , but not with any other resting parameter . Changes in spirometric measurements are generally poor predictors of clinical improvement in response to bronchodilators in COPD . Of the available parameters , increased IC , which is an index of reduced resting lung hyperinflation , best reflected the improvements in exercise endurance and dyspnea after IB . IC should be used in conjunction with FEV(1 ) when evaluating therapeutic responses in COPD [2201960] The traditional role of theophylline as a bronchodilator has been exp and ed by recent findings that suggest this drug has more than smooth muscle relaxant properties . Several investigators indicate that theophylline has an inotropic effect on respiratory muscle , causing enhanced muscular contraction and prevention of muscle fatigue . In animal studies , the drug enhanced respiratory muscle contraction by 15 - 20 % , with levels in the upper end of the therapeutic range ( 15 - 20 mg/L ) . Results of studies in healthy volunteers and patients with lung disease , however , are conflicting . Five clinical trials demonstrated increased diaphragmatic contractility , whereas seven trials showed no effect , with five referring to the diaphragm and the remaining two to the sternomastoid muscle . Disparity in outcomes may be attributed to differences in patient population s , study design s , and techniques used to determine diaphragmatic contractility . Few long-term trials exist that document significant clinical benefit . Theophylline may prove to be of value in selected population s , such as adults with hypercapnic obstructive lung disease [11743900] AIM To investigate whether low dose theophylline has an anti-inflammatory effect in asthma . METHODS Nineteen asthmatic subjects were given 200 mg sustained-release theophylline preparation twice daily for 4 weeks . The mean serum concentration of theophylline was 7.9 mg/L. The percentage of eosinophils , EG2 + eosinophils , and the level of eosinophil cationic protein ( ECP ) in sputum pre- and post-administration were detected by Wright 's stain , immunocytochemistry , and immuno-CAP system , and the symptom scores and lung function were evaluated as well . The above indices for 10 healthy subjects were regarded as control . RESULTS Before using theophylline , sputum eosinophils , EG2 + eosinophils , and ECP in asthmatic group were much higher than those of healthy group . After four weeks administration , there were great decreases in percentage of total eosinophils ( 40 % + /- 17 % vs 29 % + /- 11 % , P < 0.01 ) , activated ( EG2 + ) eosinophils ( 28 % + /- 9 % vs 10 % + /- 8 % , P < 0.01 ) and in the concentration of sputum ECP [ ( 373 + /- 206 ) vs ( 220 + /- 132 ) microg/L , P < 0.01 ] . The symptom scores decreased greatly ( 7.1 + /- 1.2 vs 5.4 + /- 1.6 , P < 0.01 ) . There was a marked increased in forced expiratory volume one second ( FEV(1.0 ) ) after administration ( 2.2 + /- 0.6 vs 2.4 + /- 0.5 , P < 0.01 ) . The FEV(1.0 ) % of asthmatic subjects after administration increased ( 60 % + /- 13 % vs 65 % + /- 13 % , P < 0.01 ) , too . CONCLUSION These results indicated that low dose theophylline had inhibitory action on airway inflammation in asthma with noticeable improvement of the patients ' symptoms and lung function [1546832] Circadian alterations in lung function occur in respiratory disorders , with the nadir during the sleep-related hours . Higher therapeutic serum theophylline concentrations ( STC ) during the night have been shown to improve lung function in reversible airway disease . To determine what effect higher nocturnal STC would have in patients with chronic obstructive pulmonary disease ( COPD ) on overnight lung function , oxygen saturation , and sleep quality , two different theophylline products were used to give higher or lower STC during the night . We found that with a higher STC ( 15.0 + /- 1.0 versus 11.0 + /- 1.0 micrograms/ml , p = 0.005 ) at 7:00 A.M. , the overnight changes in FEV1 ( + 7.4 + /- 5.7 % versus -18.9 + /- 7.9 % , respectively ) and FVC ( + 1.8 + /- 7.5 % versus -17.2 + /- 3.9 % , respectively ) were significantly better . However , there was no apparent effect on oxygen saturation ( mean sleep values for higher STC were 85.3 + /- 1.2 % , and for lower STC they were 86.5 + /- 0.8 % ) . The higher STC did not adversely affect sleep latency , sleep efficiency , or sleep staging . We conclude that a higher therapeutic STC during sleep will improve lung function without altering oxygen saturation in patients with COPD . In this group of patients , the higher STC did not interfere with sleep characteristics [7224346] Because it is common to perform a bronchodilator challenge while a patient continues oral methylxanthines , we wanted to determine if this procedure might be misleading for subsequent therapy . Thirty-eight men with a long smoking history and a clinical diagnosis of chronic obstructive pulmonary disease ( COPD ) were given placebo and oral theophylline ( each for one month ) in a double-blind , single-crossover manner . Pulmonary functional tests were performed before and after isoproterenol nebulization on the final day of each 4-wk period . There were significantly larger increases in FVC ( p less than 0.001 ) and FEV1 ( p less than 0.01 ) after isoproterenol challenge when receiving placebo than when receiving theophylline . According to the intermountain Area rating criteria , only the results after isoproterenol challenge during placebo therapy would indicate improvement . These results suggested that isoproterenol inhalation challenge be performed after methylxanthines have been discontinued if used to predict which patients with COPD may respond to oral theophylline therapy [9088999] Doxophylline , or 2-(7'-theophyllinemethyl)1,3-dioxolane , is a theophylline derivative which has shown interesting bronchodilating activity , and it appears to determine few adverse effects . The aim of the present investigation was to evaluate clinical therapeutic effects of the drug in the treatment of 2 groups of patients suffering from moderate to severe chronic obstructive pulmonary disease differing in acute response to the inhaled beta 2-agonist salbutamol and to compare changes of lung function tests to serum concentration of doxophylline . We studied 67 patients with chronic obstructive pulmonary disease ( median age 63 years , 9 females and 58 males ) who were all clinical ly stable at the time of the study . Patients were separated into 2 groups on the basis of their reaction to inhalation of 200 micrograms of salbutamol : those with an increased FEV1 of more than 20 % from baseline value ( group 1 ) , and those with no increase ( group 2 ) . Doxophylline was administered orally at the dose of 400 mg 3 times daily . Serum levels of doxophylline were determined by high-pressure liquid chromatography . Spirometry and blood gas analysis were performed before and 10 days after treatment . Four patients stopped drug assumption because of side effects ( 3 for dyspepsia and 1 for anxiety ) . In group 1 ( 34 patients ) , a significant increase in SVC , FVC , FEV1 , FEF 25 - 75 % and PEFR was observed . In group 1 ( 29 patients ) , only PEFR significantly increased . No modifications in blood gas analysis were observed . The mean serum level of doxophylline was 14 micrograms/ml in group 1 and 9 micrograms/ml in group 2 : the difference was statistically significant . The relation between serum levels of doxophylline and FVC showed an increase in the parameter up to the concentration of 12 - 13 micrograms/ml , after which a plateau phase was observed . On the basis of our data , doxophylline appears to have an interesting bronchodilating effect in patients responsive to the inhaled beta 2-agonist salbutamol . The lower limit of the therapeutic range seems to be 12 - 13 micrograms/ml . The upper limit of the therapeutic range was not determined because it was not possible to obtain serum sample s when side effects occurred [4003919] The efficacy of bronchodilator therapy was assessed in the long-term management of patients with chronic bronchitis and varying degrees of reversible air-flow obstruction . Twenty-five patients with a mean forced expiratory volume in one second ( FEV1 ) 38.7 % predicted received : optimized doses of orally administered , sustained-release theophylline , inhaled salbutamol ( 200 micrograms 4 times a day ) , a combination of the 2 drugs , and identical placebo therapy for periods of 3 wk in a r and omized , double-blind , crossover trial . Patients who deteriorated during treatment were assessed immediately and design ated " treatment failures " if additional therapy proved necessary . Such " failures " occurred in 9 patients with placebo , in 8 with salbutamol , in 6 with theophylline , and in only 1 with combined therapy . Using a ranking system based on " treatment failures " and mean daily peak flow rates , first preference was given to combined therapy in 13 patients , theophylline in 6 , salbutamol in 4 , and placebo in 2 . Thus , both combined therapy ( p less than 0.001 ) and theophylline ( p less than 0.05 ) were better than placebo , but this was not so for inhaled salbutamol . Objective improvements in FEV1 and forced vital capacity were a consistent finding with combined therapy compared with placebo , although not with single agents , and additive effects were clearly demonstrated . In the subgroup of patients able to tolerate placebo therapy , no subjective benefit could be discerned during any of the 3 periods of active treatment . Thus , the combination of orally administered , sustained-release theophylline and inhaled salbutamol offered significant advantages in the clinical control of patients with chronic bronchitis with air-flow obstruction [2651178] A crossover pilot study was undertaken to compare the acceptability of controlled release salbutamol tablets ( 8 mg twice daily ) with a sustained release theophylline preparation ( 400–800 mg given once each night ) in patients with reversible obstructive airways disease . A 2-week run-in period was used to titrate the theophylline dosage . Patients were then allocated at r and om to one of the treatments before being immediately crossed over to the other for a further 4 weeks . Thirty-two patients , aged 17–66 years , entered the trial . Seventeen patients ( 53 % ) were withdrawn . The majority of the 13 withdrawals due to side-effects of theophylline occurred during the run-in period . There were no statistically significant differences between treatments for either lung function tests performed at the clinic or for peak expiratory flow rate recorded by the patients . The non-asthma symptom score was significantly higher with theophylline than with the salbutamol preparation . A preference for treatment with the controlled release salbutamol tablets was expressed by 11/15 patients [8214921] The effects of theophylline on pulmonary function and gas exchange during rest , sleep , and exercise were assessed in 10 patients with severe but stable chronic obstructive pulmonary disease ( COPD ; median FEV1 , 31 % of predicted ) . The study was r and omized , double blind , placebo controlled , and crossover in design , with each study period lasting 3 wk , and all other usual bronchodilator therapy was continued unchanged . All patients had detailed pulmonary function tests , in addition to exercise testing and overnight sleep studies by st and ard polysomnography . Theophylline significantly improved gas exchange during rest , exercise , and sleep . Awake resting arterial blood gases showed a higher PaO2 on theophylline ( 78 [ 53 to 93 ] mm Hg , median [ range ] ) than placebo ( 72 [ 47 to 83 ] mm Hg ; p < 0.01 by ANOVA ) , and PaCO2 was lower on theophylline ( 42 [ 38 to 54 ] ) compared with placebo ( 45 [ 40 to 51 ] , p < 0.05 by ANOVA ) . Arterial oxygen saturation ( SaO2 ) was significantly higher on theophylline than placebo during exercise and sleep ( p < 0.01 ) , and transcutaneous CO2 was lower during sleep ( p < 0.05 ) . Theophylline also result ed in significantly improved pulmonary function and reduced trapped gas volume ( p < 0.05 ) . Exercise performance was no different during theophylline or placebo phases of the study . Sleep quality , however , was significantly impaired on theophylline . We conclude that theophylline has clinical ly significant benefits in patients with severe COPD [2557274] 131 asthmatics aged 12 - 65 years , who still had symptoms despite inhaled or oral bronchodilators , were included in this double-blind group comparative study involving nedocromil sodium ( 2 puffs of 2 mg each twice daily ) and placebo ( 2 puffs twice daily ) . The study was carried out at 8 centers over six weeks . Under nedocromil sodium , cough , dyspnea and severity of attacks were reduced significantly . Overall patient assessment also clearly favoured the active substance . Nedocromil sodium was also superior to placebo in terms of the improvement of lung function ( FEV1 , FVC and PEFR ) . 26 patients complained of unusual symptoms ( 12 under nedocromil sodium , 14 under placebo ) . Nedocromil sodium proved to be an effective , safe and well-tolerated drug in the antiinflammatory long-term treatment of reversible obstructive airways disease [2498658] To assess the effects of theophylline in chronic obstructive pulmonary disease , we conducted a r and omized , placebo-controlled , double-blind , crossover trial in 60 patients with severe but stable disease . The patients ( mean age , 61 years ) were studied before and after two months of placebo and two months of treatment with a sustained-release preparation of theophylline ( 10 mg per kilogram of body weight per day ) , administered orally . The two treatments were administered in a r and om order and separated by an eight-day washout period . After taking theophylline for two months ( mean plasma concentration , 14.8 mg per liter ) , as compared with the two months of placebo , the patients had significant improvements in dyspnea , pulmonary gas exchange ( partial pressure of arterial oxygen , 66 vs. 61 mm Hg [ P less than 0.0001 ] ; partial pressure of arterial carbon dioxide , 44 vs. 49 mm Hg [ P less than 0.0001 ] ) , vital capacity ( 63 percent vs. 58 percent of the predicted value [ P less than 0.0001 ] ) , and forced expiratory volume in one second ( 36 percent vs. 32 percent of the predicted value [ P less than 0.0001 ] ) , with no significant change in airway resistance or functional residual capacity . Minute ventilation increased by a mean of 18 percent ( P less than 0.0001 ) in the patients taking theophylline because of increased tidal volume , with no change in respiratory frequency . The respiratory-muscle performance of the patients taking theophylline improved by approximately 29 percent ( P less than 0.0001 ) , as indicated by a decline in the ratio of inspiratory pleural pressure during quiet breathing to maximal pleural pressure . We conclude that theophylline improves respiratory function and dyspnea in patients with severe chronic obstructive pulmonary disease and that these improvements are probably due to better respiratory-muscle performance [7130553] Therapeutic response to theophylline in asthma is generally attributed to its effect in increasing intracellular 3',5 ' cyclic adenosine monophosphate ( cAMP ) by competitive inhibition of cAMP phosphodiesterase . However , because of discrepancies between therapeutic serum theophylline concentration achieved clinical ly and those required for in vitro phosphodiesterase inhibition , we explored the possibility that theophylline may act through adrenomedullary secretion of catecholamines . Five healthy , nonasthmatic male and female adults were studied with a double-blind , r and omized , crossover protocol . Theophylline ( 5 mg/kg ) and placebo were administered in a capsule dosage form . Plasma catecholamines epinephrine ( E ) , norepinephrine ( NE ) , and dopamine ( DA ) were measured by a radioenzymatic assay at baseline and after administration of theophylline at 1 , 2 , and 3 hr . Significant differences between theophylline- and placebo-treated groups ( p less than 0.05 ) were seen at 3 hr for mean percentage increase over baseline with E ( 120 % + /- 25.3 % ) and NE ( 48.02 % + /- 17.94 % ) after theophylline therapy ( mean peak level 7.2 + /- 0.48 micrograms/ml ) . Epinephrine plasma concentration was significantly greater ( p less than 0.001 ) at 3 hr compared with baseline ( 105 + /- 16 vs 56 + /- 18 pg/ml ) , while NE ( 448 + /- 52 vs 320 + /- 36 pg/ml ) did not attain significance ( p = 0.136 ) . A significant correlation ( p less than 0.05 ) was found between the percentage increase over basal for E ( r = 0.58 ) and NE ( r = 0.66 ) and serum theophylline levels . DA was not significantly increased at any time period . Thus theophylline in clinical ly relevant concentration appears to stimulate adrenomedullary secretion of catecholamine . Whether this is an important mechanism of action in asthma or explains some side effects of theophylline remains to be determined [6309542] Enprofylline is a potent bronchodilating xanthine derivative that has been shown to have little or no ability to antagonize adenosine in a variety of cell types . In eight patients with chronic obstructive lung disease , a single dose of enprofylline ( 3.5 mg/kg ) was given orally . A double blind , r and omized , crossover comparison was made with oral theophylline ( 9.5 mg/kg ) which is a potent and general adenosine receptor antagonist . Forced expiratory volume ( FEV1 ) , vital capacity , tremor of h and s , heart rate , and blood pressure were followed for 6 h. Plasma concentrations of both drugs were monitored . At doses producing significant bronchodilation , theophylline caused a significant increase in tremor of h and s whereas enprofylline did not . There were no significant changes in heart rate or blood pressure after either drug . It is suggested that the lack of tremorogenic effect of enprofylline is related to its lack of CNS-stimulating behavioural effects and , hence , may reflect its low tendency to antagonize neuro-depressant actions of adenosine . The adenosine-blocking mechanism may not be important for the bronchodilating effects of xanthines [1835291] The bronchodilator effects of a single dose of ipratropium bromide aerosol ( 36 micrograms ) and short-acting theophylline tablets ( dose titrated to produce serum levels of 10 - 20 micrograms/mL ) were compared in a double-blind , placebo-controlled crossover study in 21 patients with stable , chronic obstructive pulmonary disease . Mean peak forced expiratory volume in 1 second ( FEV1 ) increases over baseline and the proportion of patients attaining at least a 15 % increase in the FEV1 ( responders ) were 31 % and 90 % , respectively , for ipratropium and 17 % and 50 % , respectively , for theophylline . The average FEV1 increases during the 6-hour observation period were 18 % for ipratropium and 8 % for theophylline . The mean duration of action was 3.8 hours with ipratropium and 2.4 hours with theophylline . While side effects were rare , those experienced after theophylline use did involve the cardiovascular and gastrointestinal systems . These results show that ipratropium is a more potent bronchodilator than oral theophylline in patients with chronic airflow obstruction [23134] 1 . The bronchodilator effects of 500 microgram rimiterol by pressurized aerosol , 375 mg oral theophylline and both drugs in combination were compared in a r and omized , placebo-controlled , double-blind trial in eight patients with chronic , partially reversible airways obstruction . 2 . The four treatments were ( i ) oral theophylline , placebo aerosol ( TP ) ; ( ii ) oral placebo , rimiterol aerosol ( PR ) ; ( iii ) oral theophylline , rimiterol aerosol ( TR ) and ; ( iv ) oral placebo , placebo aerosol ( PP ) . The aerosol was administered 2 h after the oral treatment . 3 . Significant bronchodilatation ( % FEV1 change from control ) compared to PP occurred with TP from 60 to 480 min and with TR from 60 to 300 min , whereas with PR only for 45 min ( P less than 0.05 ) . 4 . The mean , peak % FEV1 increases from control were 51.8 % at 125 min , 31.7 % at 125 min , 26.1 % at 210 min and 0.9 % at 30 min for TR , PR , TP and PP respectively . 5 . At 125 min ( 5 min after aerosol inhalation ) the mean % FEV1 change from control with TR ( 51.8 % ) Was significantly greater than with PR ( 31.7 % ) , TP ( 22.2 % ) ( P less than 0.05 ) and PP ( -2.4 % ) ( P less than 0.01 ) . 6 . The mean , peak plasma theophylline levels were 10.19 microgram/ml at 120 min and 9.98 microgram/ml at 180 min with TR and TP respectively . Theophylline half-life ranged between 4.3 and 12.5 h ( mean + /- s.e . mean , 8.0 + /- 0.8 h ) . 7 . Additive bronchodilatation was produced when rimiterol was administered with theophylline at a time when therapeutic plasma theophylline levels were achieved [9925061] STUDY OBJECTIVE To compare quality of life and exercise capacity ( primary aim ) , and drug usage ( secondary aim ) , between groups of patients with irreversible chronic airflow limitation ( CAL ) who were undergoing theophylline Theo-Dur ; Key Pharmaceuticals ; Kenilworth , NJ ) therapy guided by n of 1 trials or st and ard practice . DESIGN R and omized study of n of 1 trials vs st and ard practice . SETTING Outpatient departments in two tertiary care centers . PATIENTS Sixty-eight patients with irreversible CAL who were symptomatic despite the use of inhaled bronchodilators , and who were unsure whether theophylline was helping them following open treatment , were r and omized into n of 1 trials ( N=34 ) or st and ard practice . INTERVENTIONS The n of 1 trials ( single-patient , r and omized , double-blind , multiple crossover comparisons of the effect on dyspnea of theophylline vs a placebo ) followed published guidelines . St and ard practice patients stopped taking theophylline but resumed it if their dyspnea worsened . If their dyspnea then improved , theophylline was continued . In both groups , a decision about continuing or stopping the use of theophylline was made within 3 months of r and omization . MEASUREMENTS AND RESULTS The primary outcomes ( the chronic respiratory disease question naire [ CRQ ] and 6-min walk ) were measured at baseline , 6 months , and 12 months by personnel blinded to treatment group allocation . No between-group differences ( n of 1 minus st and ard practice ) were seen in within-group changes over time ( 1 year minus baseline ) in the CRQ Physical Function score ( point estimate on the difference , -2.8 ; 95 % confidence limits [ CLs ] , -8.2 , 2.5 ) , CRQ Emotional Function score ( point estimate on the difference , 0.5 ; 95 % CLs , -4.7 , 5.7 ) , or 6-min walk ( point estimate on the difference , 8 m ; 95 % CLs , -26 , 44 m ) . No differences between groups were seen in the secondary outcome of the proportion of patients taking theophylline at 6 and 12 months . In 7 of 34 n of 1 trial patients ( 21 % ) , dyspnea improved during theophylline treatment compared with placebo treatment . CONCLUSIONS Using n of 1 trials to guide theophylline therapy in patients with irreversible CAL did not improve their quality of life or exercise capacity , or reduce drug usa e , over 1 year compared to st and ard practice . Under the objective conditions of an n of 1 trial , 21 % of patients with CAL responded to theophylline . There remains a rationale for considering theophylline in patients with irreversible CAL who remain symptomatic despite the use of inhaled bronchodilators , but the use of n of 1 trials to guide this decision did not yield clinical ly important advantages over st and ard practice [6751366] Twenty-one patients with chronic bronchitis entered a double-blind , cross-over study in which they received sustained-release theophylline ( ' Nuelin'SA ) 350 mg daily for 4 days followed by 700 mg daily for 4 days and matching placebo tablets for 8 days with one week separation . Seventeen patients completed the study . Three patients receiving higher doses for weight than the mean for the group were withdrawn because of side-effects . Mild side-effects only were reported in six other patients . Theophylline given twice daily produced a steady-state mean serum concentration of 13.9 micrograms/ml , 13 patients having concentrations inthe range of 10 - 20 micrograms/ml . There was no demonstrable improvement of symptoms but pulmonary function measurements in the clinic at the end of active treatment showed a statistically significant improvement in PEFR , 1-second forced expiratory volume and forced vital capacity [3069520] In a single-blind crossover study , two slow release theophylline preparations were evaluated in 18 patients with chronic bronchitis or asthma without cardiac , renal or liver disease . After r and omization into two groups , patients were treated , in a crossover study design , with 600 mg choline theophyllinate or 300 mg anhydrous theophylline administered orally every 12 h for 7 days . A 2-day washout period separated the two periods of treatment evaluation . Blood sample s in which plasma theophylline concentration was to be measured were taken at 7.30 a.m. , 2.00 p.m. and 7.30 p.m. during the last 5 days of therapy with each drug . The mean fluctuation in plasma theophylline concentration was ≤40 % in all 18 patients taking choline theophyllinate yet in only 15 ( 83 % ) patients administered anhydrous theophylline . Salbutamol inhaler was more frequently required for the relief of bronchospasm when taking anhydrous theophylline than when taking choline theophyllinate ( total of 41 vs 25 puffs , respectively , over 7 days ) . Drug-related adverse reactions occurred in four patients while taking anhydrous theophylline and in one patient while taking choline theophyllinate [2218006] Enprofylline , a recently developed xanthine derivative , is a more potent bronchodilator than theophylline . This study compares the efficacy and safety of enprofylline with theophylline for chronic obstructive airways disease ( COAD ) in elderly subjects . The study was of a r and omized double-blind parallel design and commenced with a 1-week reference period when oral bronchodilators were withdrawn . Patients were then treated with either enprofylline or theophylline 150 mg bd for 2 weeks ( period 1 ) followed by 300 mg bd for a further 3 weeks ( period 2 ) . Patients recorded peak expiratory flow rate ( PEFR ) and adverse experiences , if any , in a diary , daily . Of 111 patients recruited for the study , 85 entered active treatment ( theophylline , n = 44 ; enprofylline , n = 41 ) . Mean age was 72 years and mean bronchodilator reversibility was 22 % . Enprofylline increased mean morning PEFR by 11 % ( period 1 ) and 19 % ( period 2 ) whereas theophylline increased PEFR by 13 % and 19 % , respectively . From the enprofylline group 29 % were withdrawn from the study due mainly to headache and nausea/vomiting and from the theophylline group 7 % were withdrawn due mainly to nausea/vomiting . Mean plasma concentrations of enprofylline were 2.0 mg l-1 and 3.4 mg l-1 , and with theophylline 5.4 mg l-1 and 10.0 mg l-1 at the end of periods 1 and 2 , respectively . Enprofylline and theophylline produced similar improvements in lung functions and symptoms of chronic obstructive airways disease , but enprofylline was less well tolerated than theophylline [3297214] Fourteen patients with chronic obstructive airway disease participated in a r and omized , double-blind , placebo controlled , cross-over study to assess the effect of acutely administered aminophylline on respiratory muscle strength and exercise tolerance . An increase in the distance walked in 6 min occurred following aminophylline ( p less than 0.01 ) . There was no improvement in respiratory muscle strength , assessed by maximal static mouth pressures , and no increase in maximal ventilation or oxygen uptake during a progressive exercise test . The ventilatory response to inhaled CO2 was increased ( p less than 0.02 ) , suggesting a central stimulatory effect of aminophylline . The mean increase in walking distance was 5.7 % . In most cases , the change was small and unlikely to be of practical benefit [1854108] OBJECTIVE To assess the role of aminophylline in the treatment of acute exacerbations of bronchospastic disease when used in addition to inhaled beta-agonists and intravenous corticosteroids . DESIGN R and omized , double-blind , placebo-controlled intervention study . PATIENTS One hundred thirty-three adult patients with either asthma or chronic obstructive pulmonary disease who presented to the emergency department with asthma or wheezing . INTERVENTIONS All patients received therapy with both aerosolized metaproterenol and intravenous methyl-prednisolone . Patients were r and omly assigned to receive either a loading dose of aminophylline followed by a routine infusion ( n = 65 ) or an equal volume of placebo as a loading dose and infusion ( n = 68 ) . MEASUREMENTS AND MAIN RESULTS At discharge from the emergency department , the median serum theophylline concentration for the aminophylline group was 54 mumol/L ( 9.7 mg/L ) . The two groups showed no differences ( P greater than 0.2 ) in measurements of forced expiratory volume at 1 second ( FEV1 ) , forced vital capacity ( FVC ) , or peak expiratory flow rate ( PEFR ) at baseline or at 60 or 120 minutes after aminophylline administration . Neither patient satisfaction nor physician assessment of response to therapy differed between the two groups . There was no difference ( P greater than 0.2 ) in the frequency of side effects , except for a trend toward a higher frequency of nausea ( P = 0.13 ) in the aminophylline group . There was , however , a threefold decrease in the hospital admission rate for patients treated with aminophylline ( 6 % ) compared with placebo recipients ( 21 % ) ( P = 0.016 ) . CONCLUSION Aminophylline , in doses producing levels just below the commonly accepted therapeutic range , appears to decrease hospital admissions in patients with acute exacerbation of asthma or chronic obstructive pulmonary disease . This finding , if confirmed in larger studies , may represent a substantial cost savings [3087310] Thirteen clinical ly stable male patients aged 63 + /- 3 years with irreversible airway disease were given aminophylline and placebo in a r and omized crossover fashion on two consecutive days while receiving beta-agonists . During incremental exercise the maximal heart rate ( 139.0 + /- 22.1 vs 128.0 + /- 16.4 beats per minute ) and minute ventilation ( 41.9 + /- 6.9 vs 38.1 + /- 8.2 L/min ) were significantly higher and the arterial carbon dioxide pressure ( 34.6 + /- 5.0 vs 38.6 + /- 7.7 mm Hg ) was significantly lower during aminophylline administration than during placebo administration . However , spirometric findings , maximal inspiratory pressures , maximal oxygen consumption , work rate , and arterial oxygen pressure were similar on both regimens . We concluded that the major effect of aminophylline is to increase ventilatory drive in patients with irreversible airway obstruction . Unless an objective change in spirometric data or exercise capacity can be documented , we believe that aminophylline therapy is not warranted in these patients [8325065] To investigate the additive effect of oral theophylline on combined inhaled anticholinergic agent and beta 2-agonist therapy , 12 patients with stable COPD ( 64.6 + /- 5.9 years ) completed a r and omized , double-blind placebo-controlled crossover trial of oral theophylline for a 4-week period ( 400 mg for 2 weeks , followed by 600 mg for 2 weeks ) . All of the patients continued to inhale both salbutamol , 200 micrograms , and ipratropium bromide , 40 micrograms , using a metered-dose inhaler four times a day . Spirometry was assessed before , and 15 and 60 min after the inhalation of bronchodilators at 2-week intervals . Even after the inhalation of salbutamol and ipratropium , theophylline significantly improved FEV1 and daily peak expiratory flow rate compared with the placebo . No significant improvement in the daily symptom scores for cough , sputum , wheezing , or shortness of breath was observed throughout the different phases of treatment . This study shows that the additive bronchodilating effect of theophylline , when used in combination with salbutamol , 200 micrograms , and ipratropium , 40 micrograms , is significant but small in stable COPD . The addition of theophylline did not significantly improve the patient 's symptoms . Oral theophylline , when used in combination with an inhaled anticholinergic agent and an inhaled beta 2-agonist , may be of limited value in the treatment of stable COPD [3041826] Oxygen desaturation and sub clinical coronary artery disease may predispose older patients with chronic airflow obstruction to cardiac arrhythmias , especially when high concentrations of theophylline are present in the blood . To assess the safety and efficacy of Uniphyl tablets , an oral theophylline preparation formulated for once-daily dosing , in elderly patients with chronic airflow obstruction , we conducted a r and omized , three-phase , double-blind crossover study comparing evening dosing with Uniphyl tablets , Theo-Dur tablets administered twice daily , and placebo . The patients in the study were scheduled to receive each treatment for two weeks . Each day , symptoms , side effects , peak expiratory flow rates , and use of metered-dose inhalers were recorded . Near the end of each phase , serum theophylline concentrations were measured every two hours between 8:00 A.M. and 8:00 P.M. on two consecutive days . The patients underwent ambulatory Holter monitoring during the final 48 hours of each phase . Twelve patients completed the active-drug phases of the study , but seven of the 12 were removed from the placebo phase because of increasing symptom severity . The difference between the number of patients completing the active-drug and placebo phases was statistically significant ( p less than 0.001 ) . Treatment with Uniphyl tablets result ed in a significantly ( p less than 0.05 ) greater increase in peak expiratory flow rate than Theo-Dur tablet therapy , and both active drugs increased peak expiratory flow rate more than placebo . Circadian variation in peak expiratory flow rate was seen during the placebo and Theo-Dur tablet phases but not during the Uniphyl tablet phase . Symptoms and side effects were similar during the two active-drug phases . Cardiac ectopy was observed in most of the patients , but it was not significantly greater during the theophylline phases than during the placebo phase . Furthermore , ectopic activity was not directly related to the times of maximal serum theophylline concentration [8162730] To evaluate the role of inhaled ipratropium bromide alone vs oral theophylline plus inhaled beta-agonist or the combination of all three in patients with stable COPD , the following double-blind , placebo-controlled study was conducted . Forty-eight patients with stable COPD ( mean age , 61.8 years , with mean baseline FEV1 < 1.0 L ) were r and omized on four separate days to receive the following drug regimens : ( 1 ) theophylline tablets ( dose previously determined to result in blood level of 12 to 18 mg/L ) , followed by inhaled albuterol ( 2 puffs via metered-dose inhaler [ MDI ] ) , followed by inhaled placebo ( 2 puffs via MDI ) ; ( 2 ) oral placebo followed by ipratropium ( 2 puffs via MDI ; 36 micrograms ) , followed by inhaled placebo ; ( 3 ) oral theophylline , followed by albuterol , followed by ipratropium ; or ( 4 ) oral placebo followed by two inhaled placebos . On study days , spirometry and heart rate were measured at time 0 , 30 min , 60 min , and hourly for 6 h. The FEV1 peak change ( liters ) and area under the curve ( liter x hours ) for the treatment groups were compared . Ipratropium was more effective than placebo ( p = 0.001 and p = 0.0078 , respectively ) . The combination of albuterol and theophylline was superior to ipratropium alone ( p = 0.001 and p = 0.0001 , respectively ) , and all three drugs together were superior to the combination of albuterol and theophylline ( p = 0.0373 and p = 0.0289 ) , respectively ; one-sided test of hypotheses ) . Peak heart rates were significantly higher for treatment groups compared with placebo groups ( p = 0.0001 ) . However , theophylline and albuterol and the combination of all three drugs result ed in greater peak heart rates than did ipratropium alone ( p = 0.001 ) . These data suggest that for patients with stable COPD , combination therapy with ipratropium ( two puffs ) , theophylline , and albuterol ( two puffs ) is superior to ipratropium alone or the combination of theophylline and albuterol [4723589] Abstract Physiologic responses to intravenously administered theophylline were determined in nine hospitalized asthmatic subjects . In each patient incremental theophylline plasma concentration plateaus were attained at which pulmonary-function changes related to drug administration were examined . Continuous improvement in vital capacity and first-second forced expiratory volume was observed over the plasma range of theophylline concentration of 5 to 20 mg per liter . The improvement varied directly with the logarithm of the plasma concentration . A safe and effective dosage regimen for intravenous theophylline can be based on these observations . After a loading dose of aminophylline , 5.6 mg per kilogram given intravenously , 0.9 mg per kilogram per hour can be given as a maintenance dose . This amount will result in a plasma theophylline concentration of approximately 10 mg per liter for 95 per cent of patients and in recovery from some 30 to 40 per cent of reversible pulmonary-airway obstruction . ( N Engl J M [3345044] This study sought answers to 2 questions : ( 1 ) Is severe dyspnea to the point of exhaustion regularly accompanied by diaphragmatic fatigue in patients with moderately severe chronic obstructive pulmonary disease ( COPD ) ? ( 2 ) When diaphragmatic fatigue occurs in such patients , does theophylline prevent or delay its onset ? Eight eucapnic patients with moderately severe COPD were subjected to 2 different stresses to the point of severe dyspnea requiring cessation of the stress . The stresses were cycle exercise and inspiratory resistive breathing , the latter requiring a tidal Pdi equal to 60 % of Pdimax . Despite incapacitating dyspnea , objective evidence of diaphragmatic fatigue was not encountered during cycle exercise . During inspiratory resistive breathing , diaphragmatic fatigue was encountered in all patients as defined by consistent inability to attain a target Pdi during final moments of the resistance run . Patients were uniformly extremely dyspneic at this point . In neither stressful maneuver did oral sustained-release theophylline show a convincing or significant advantage over placebo when administered in a r and omized double-blind crossover protocol . These results suggest that the diaphragmatic fatigue encountered in this sort of COPD patient may be of predominantly central rather than peripheral ( myogenic ) origin and that theophylline may not be effective in this type of fatigue [9506004] Effects of theophylline administration on the respiratory drive were studied in seven patients with chronic obstructive pulmonary disease ( COPD ) . End tidal CO2 ( PetCO2 ) , minute ventilation ( Ve ) , forced expiratory volume in one second ( FEV1 ) , forced vital capacity ( FVC ) , oxygen consumption ( VO2 ) , carbon dioxide output ( VCO2 ) , serum theophylline level ( STL ) , ventilatory response ( VeR ) , and mouth occlusion pressure response ( OPR ) to rise in PetCO2 on rebreathing were measured before and at 2-hour intervals after oral administration of 5 mg/kg anydrous theophylline or placebo . Mouth occlusion pressure response and VeR showed c significant increase after theophylline but not after placebo . Significant positive correlation between changes ( delta ) in STL and OPR ( delta OPR = 0.025 + 0.8 delta STL ; SEE = 1 ; r = 0.4 ; P < 0.005 ) and between STL and VeR ( VeR = 0.82 + 0.055 STL + /- SEE = 0.7 ; r = 0.46 ; P < 0.01 ) and an inverse correlation between delta STL and delta PetCO2 ( delta PetCO2 = 13.8 - 0.59 delta STL ; SEE = 9.1 ; r = 0.61 ; P < 0.001 ) were noted . There was no correlation between the indices of respiratory drive and FEV1 , Ve , VO2 , or VCO2 . It is concluded that theophylline increases respiratory drive in clinical ly employed doses independently of its bronchodilator or metabolic effects [7985256] Even though the clinical efficacy is not well established , theophylline is commonly prescribed as a second or third line drug after inhaled beta 2-agonists and corticosteroids for patients with chronic obstructive pulmonary disease ( COPD ) . The therapeutic index is narrow , and therefore theophylline is often given in a " safe st and ard dose " , e.g. 300 mg b.i.d . We studied the long-term effect of sustained-release theophylline 300 mg b.i.d . over four weeks in 48 patients with severe irreversible COPD ( FEV1 : 0.99 + /- 0.45 l , FVC : 2.21 + /- 0.68 l ) in a r and omized , double-blind crossover study . During theophylline treatment there was significant improvements in dyspnoea score ( p < 0.001 ) and morning peak-flow ( p < 0.05 ) . In spite of this , there was no significant change in the patients ' " sense of well-being " or their daily use of inhaled beta-agonist . Spirometric tests or arterial blood gas values did not change significantly either . It is concluded that addition of theophylline in a " safe st and ard dose " ( i.e. 300 mg b.i.d . ) has only limited value in these patients Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND In the intrinsic system of controlling airway calibre , the cholinergic ( muscarinic ) sympathetic nervous system has an important role . Anticholinergic , anti muscarinic bronchodilators such as ipratropium bromide are frequently used in the management of childhood airway disease . In asthma , ipratropium is a less potent bronchodilator than beta-2 adrenergic agents but it is known to be a useful adjunct to other therapies , particularly in status asthmaticus . What remains unclear is the role of anticholinergic drugs in the maintenance treatment of chronic asthma . OBJECTIVES To determine the effectiveness of anticholinergic drugs in chronic asthma in children over the age of 2 years . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

30337465

[3120183] OBJECTIVE To pilot , among women with gestational diabetes mellitus ( GDM ) , the feasibility of a prenatal/postpartum intervention to modify diet and physical activity similar to the Diabetes Prevention Program . The intervention was delivered by telephone , and support for breastfeeding was addressed . RESEARCH DESIGN AND METHODS The goal was to help women return to their prepregnancy weight , if it was normal , or achieve a 5 % reduction from prepregnancy weight if overweight . Eligible participants were identified shortly after a GDM diagnosis ; 83.8 % consented to be r and omly assigned to intervention or usual medical care ( 96 and 101 women , respectively ) . The retention was 85.2 % at 12 months postpartum . RESULTS The proportion of women who reached the postpartum weight goal was higher , although not statistically significant , in the intervention condition than among usual care ( 37.5 vs. 21.4 % , absolute difference 16.1 % , P = 0.07 ) . The intervention was more effective among women who did not exceed the recommended gestational weight gain ( difference in the proportion of women meeting the weight goals : 22.5 % , P = 0.04 ) . The intervention condition decreased dietary fat intake more than the usual care ( condition difference in the mean change in percent of calories from fat : −3.6 % , P = 0.002 ) and increased breastfeeding , although not significantly ( condition difference in proportion : 15.0 % , P = 0.09 ) . No differences in postpartum physical activity were observed between conditions . CONCLUSIONS This study suggests that a lifestyle intervention that starts during pregnancy and continues postpartum is feasible and may prevent pregnancy weight retention and help overweight women lose weight . Strategies to help postpartum women overcome barriers to increasing physical activity are needed [27607876] OBJECTIVE : To investigate the effect of a supervised home-based exercise program on the recurrence and severity of gestational diabetes mellitus ( GDM ) together with other aspects of maternal health and obstetric and neonatal outcomes . METHODS : This r and omized controlled trial allocated women with a history of GDM to an exercise intervention ( 14-week supervised home-based stationary cycling program ) or to a control group ( st and ard care ) at 13±1 weeks of gestation . The primary outcome was a diagnosis of GDM . Secondary outcomes included maternal fitness , psychological well-being , and obstetric and neonatal outcomes . A sample size of 180 ( 90 in each group ) was required to attain 80 % power to detect a 40 % reduction in the incidence of GDM . RESULTS : Between June 2011 and July 2014 , 205 women provided written consent and completed baseline assessment s. Of these , 33 ( 16 % ) were subsequently excluded as a result of an elevated baseline oral glucose tolerance test ( OGTT ) , leaving 172 r and omized to exercise ( n=85 ) or control ( n=87 ) . Three women miscarried before the assessment of outcome measures ( control=2 ; exercise=1 ) . All remaining women completed the postintervention OGTT . The recurrence rate of GDM was similar between groups ( control 40 % [ n=34 ] ; exercise 40.5 % [ n=34 ] ; P=.95 ) and the severity of GDM at diagnosis was unaffected by the exercise program with similar glucose and insulin responses to the OGTT ( glucose 2 hours post-OGTT 7.7±1.5 compared with 7.6±1.6 mmol/L ; P>.05 ) . Maternal fitness was improved by the exercise program ( P<.01 ) and psychological distress was reduced ( P=.02 ) . There were no differences in obstetric and neonatal outcomes between groups ( P>.05 ) . CONCLUSION : Supervised home-based exercise started at 14 weeks of gestation did not prevent the recurrence of GDM ; however , it was associated with important benefits for maternal fitness and psychological well-being . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , https:// clinical trials.gov , NCT01283854 [29214130] To identify adherence required to achieve target health outcome ( s ) in nutrition and /or exercise interventions , a measurement tool that tracks objective and self-reported measures of adherence is necessary . The purpose of this study was to design an adherence measurement tool and test it retrospectively on the Nutrition and Exercise Lifestyle Intervention Program ( NELIP ; Ruchat et al. , Medicine and Science in Sports and Exercise , 44(8 ) , 1419–1426 , 2012 ; Mottola et al. , Medicine and Science in Sports and Exercise , 42(2 ) , 265–272 , 2010 ) , design ed to prevent excessive gestational weight gain ( EGWG ) . The tool was based on the goals of the NELIP and included a grading system for each behavior ( exercise and nutrition ) . It was used to determine whether adherence scores could differentiate excessive versus acceptable weight gain during pregnancy across pre-pregnancy body mass index ( BMI ) categories . Results showed irrespective of pre-pregnancy BMI , women with acceptable weight gain had significantly higher adherence ( p < 0.05 ) than women with excessive weight gain . It is recommended that this adherence tool be included in future prospect i ve lifestyle intervention studies [2628875] Background To evaluate the effectiveness and safety of water aerobics during pregnancy . Methods A r and omized controlled trial carried out in 71 low-risk sedentary pregnant women , r and omly allocated to water aerobics or no physical exercise . Maternal body composition and perinatal outcomes were evaluated . For statistical analysis Chi-square , Fisher 's or Student 's t-tests were applied . Risk ratios and their 95 % CI were estimated for main outcomes . Body composition was evaluated across time using MANOVA or Friedman multiple analysis . Results There were no significant differences between the groups regarding maternal weight gain , BMI or percentage of body fat during pregnancy . Incidence of preterm births ( RR = 0.84 ; 95%CI:0.28–2.53 ) , vaginal births ( RR = 1.24 ; 95%CI:0.73–2.09 ) , low birthweight ( RR = 1.30 ; 95%CI:0.61–2.79 ) and adequate weight for gestational age ( RR = 1.50 ; 95%CI:0.65–3.48 ) were also not significantly different between groups . There were no significant differences in systolic and diastolic blood pressure and heart rate between before and immediately after the water aerobics session . Conclusion Water aerobics for sedentary pregnant women proved to be safe and was not associated with any alteration in maternal body composition , type of delivery , preterm birth rate , neonatal well-being or weight [25412300] PURPOSE The purpose of the study was to determine the effect of a home-based cycling program for women with a recent diagnosis of gestational diabetes mellitus ( GDM ) on aerobic fitness , weight gain , self-reported mobility , attitude , and intentions toward maternal exercise , and obstetric and neonatal outcomes . METHODS Forty women ( mean ± SD , 28.8 ± 0.9-wk gestation ) were r and omized to either a supervised , home-based exercise program , combining continuous steady-state and interval cycling at various intensities , in combination with unsupervised moderate intensity aerobic activity and conventional diabetic management ( EX ; n = 20 ) or to conventional management alone ( CON ; n = 20 ) . The program began following diagnosis until week 34 of pregnancy ( mean ± SD duration of training , 6 ± 1 wk ) . RESULTS Mean compliance to the training program was 96 % . Maternal aerobic fitness , and attitude and intentions toward exercise were improved in response to the home-based exercise intervention compared with CON ( P < 0.05 ) . No differences were observed between the groups with respect to maternal weight gain or obstetric and neonatal outcomes ( P > 0.05 ) . CONCLUSION A home-based exercise program of 6 ± 1 wk in duration commenced after diagnosis of GDM can improve aerobic fitness and attitude and intentions toward exercise , with no adverse effect on maternal and neonatal pregnancy outcomes [24002348] INTRODUCTION Walking may be a strategy for increasing moderate-intensity physical activity ( MPA ) during pregnancy . PURPOSE This study aim ed to promote MPA among overweight and obese pregnant women , via walking , and to evaluate the effect of the intervention on maternal and birth outcomes . METHODS Thirty-seven overweight or obese pregnant women were r and omly assigned to a walking intervention or control group . Anthropometric and objective PA ( StepWatch ™ Activity Monitor ) data were collected for four 1-wk periods : weeks 10 - 14 ( V1 ) , weeks 17 - 19 ( V2 ) , weeks 27 - 29 ( V3 ) , and weeks 34 - 36 ( V4 ) of gestation . Participants provided information about maternal and birth outcomes . A cadence of ≥ 80 steps per minute was defined as MPA , and " meaningful walking " was defined as moderate walking in ≥ 8-min bouts . ANOVA was used to determine the differences in walking amount and meaningful walks , the Kolmogorov-Smirnov test was used for walking intensity distribution analysis , and Fisher 's exact test was used for maternal and infant outcomes analyses . Pearson correlation was used to examine the association between prepregnancy body mass index and gestational weight gain ( GWG ) . RESULTS There was significantly more MPA among women in the intervention group compared with those in the control group at V2 ( overweight , P < 0.0001 ; obese , P < 0.025 ) , V3 ( overweight , P < 0.0001 ) , and V4 ( overweight , P < 0.0001 ; obese , P < 0.025 ) . Women in the intervention group significantly increased their meaningful walks at V2 ( P = 0.054 ) , V3 ( P = 0.01 ) , and V4 ( P = 0.014 ) . There were trends for intervention group women to have more favorable maternal and birth outcomes compared with the control group . Rates of GWG at measurement points during pregnancy were significantly associated with preceding rates of GWG . CONCLUSION The pilot , unsupervised walking intervention increased the MPA of overweight and obese women during pregnancy [2467402] Background Previous publications indicate that acupuncture is efficient for the treatment of pelvic girdle pain , PGP , in pregnant women . However , the use of acupuncture for PGP is rare due to insufficient documentation of adverse effects of this treatment in this specific condition . The aim of the present work was to assess adverse effects of acupuncture on the pregnancy , mother , delivery and the fetus/neonate in comparison with women that received stabilising exercises as adjunct to st and ard treatment or st and ard treatment alone . Methods In all , 386 women with PGP entered this controlled , single-blind trial . They were r and omly assigned to st and ard treatment plus acupuncture ( n = 125 ) , st and ard treatment plus specific stabilising exercises ( n = 131 ) or to st and ard treatment alone ( n = 130 ) for 6 weeks . Acupuncture that may be considered strong was used and treatment was started as early as in the second trimester of pregnancy . Adverse effects were recorded during treatment and throughout the pregnancy . Influence on the fetus was measured with cardiotocography ( CTG ) before-during and after 43 acupuncture sessions in 43 women . A st and ardised computerized method to analyze the CTG reading numerically ( Oxford 8000 , Oxford , Engl and ) was used . After treatment , the women rated their overall experience of the treatment and listed adverse events if any in a question naire . Data of analgesia and oxytocin augmentation during labour , duration of labour , frequency of preterm birth , operative delivery , Apgar score , cord-blood gas/acid base balance and birth weight were also recorded . Results There were no serious adverse events after any of the treatments . Minor adverse events were common in the acupuncture group but women rated acupuncture favourably even despite this . The computerized or visually assessed CTG analyses of antenatal recordings in connection with acupuncture were all normal . Conclusion This study shows that acupuncture administered with a stimulation that may be considered strong led to minor adverse complaints from the mothers but had no observable severe adverse influences on the pregnancy , mother , delivery or the fetus/neonate [27935767] Context Lifestyle approaches for preventing gestational diabetes mellitus ( GDM ) have produced mixed results . Objective The aim of the present study was to compare the effectiveness of 3 lifestyle interventions [ healthy eating ( HE ) , physical activity ( PA ) , and both HE and PA ( HE+PA ) ] with usual care ( UC ) in reducing GDM risk . Design The present study was a multicenter r and omized controlled trial conducted from 2012 to 2014 [ the DALI ( vitamin D and lifestyle intervention for GDM prevention ) lifestyle study ] . Setting The study occurred at antenatal clinics across 11 centers in 9 European countries . Patients Consecutive pregnant women at < 20 weeks of gestation with a body mass index ( BMI ) of ≥29 kg/m2 and without GDM using the International Association of Diabetes and Pregnancy Study Group criteria ( n = 436 ) . For the intervention , women were r and omized , stratified by site , to UC , HE , PA , or HE+PA . The women received 5 face-to-face and ≤4 telephone coaching sessions using the principles of motivational interviewing . A gestational weight gain ( GWG ) < 5 kg was targeted . The coaches received st and ardized training and an intervention toolkit tailored to their culture and language . Main Outcome Measures The endpoints were the GWG at 35 to 37 weeks and the fasting glucose and insulin sensitivity [ homeostasis model assessment insulin resistance ( HOMA-IR ) ] at 24 to 28 weeks . Results We r and omized 108 women to HE+PA , 113 to HE , 110 to PA , and 105 to UC . In the HE+PA group , but not HE or PA alone , women achieved substantially less GWG than did the controls ( UC ) by 35 to 37 weeks ( -2.02 ; 95 % confidence interval , -3.58 to -0.46 kg ) . Despite this reduction , no improvements were seen in fasting or postload glucose levels , insulin concentrations , or HOMA-IR . The birthweights and large and small for gestational age rates were similar . Conclusions The combined HE+PA intervention was able to limit GWG but did not reduce fasting glycemia . Thus , lifestyle changes alone are unlikely to prevent GDM among women with a BMI of ≥29 kg/m2 [27622854] ABSTRACT Accumulating research indicates that the regular practice of physical exercise is beneficial to the human brain . From the improvement of academic achievement in children to the prevention of Alzheimer ’s disease in the elderly , exercise appears beneficial across the developmental spectrum . Recent work from animal studies also indicates that a pregnant mother can transfer the benefits of exercise during gestation to her offspring ’s brain . Exercising pregnant rats give birth to pups that have better memory and spatial learning as well as increased synaptic density . To investigate whether this transfer from the pregnant mother to her child also occurs in humans , we conducted a r and omized controlled trial ( n = 18 ) and measured the impact of exercise during pregnancy on the neuroelectric response of the neonatal brain with electroencephalography ( EEG ) . Here we show that , compared to the newborns of mothers who were inactive during their pregnancy , the children of exercising pregnant women are born with more mature brains . This was measured with the infant slow positive mismatch response ( SPMMR ) , an electroencephalographic potential known to decrease in amplitude with age . The SPMMR reflects processes associated with brain maturation via its response to sound discrimination and auditory memory . In this study , the children of the mothers who exercised throughout their pregnancy have a smaller SPMMR than the children of mothers who remained sedentary ( p = .019 ) . Our results demonstrate the impact regular exercise during pregnancy can have on the development of the human fetal brain [18396254] This study examined the effects of a yoga program during pregnancy , on maternal comfort , labor pain , and birth outcomes . A r and omized trial was conducted using 74-primigravid Thai women who were equally divided into two groups ( experimental and control ) . The yoga program involved six , 1-h sessions at prescribed weeks of gestation . A variety of instruments were used to assess maternal comfort , labor pain and birth outcomes . The experimental group was found to have higher levels of maternal comfort during labor and 2h post-labor , and experienced less subject evaluated labor pain than the control group . In each group , pain increased and maternal comfort decreased as labor progressed . No differences were found , between the groups , regarding pethidine usage , labor augmentation or newborn Apgar scores at 1 and 5 min . The experimental group was found to have a shorter duration of the first stage of labor , as well as the total time of labor [3718707] Background Excessive gestational weight gain ( GWG ) is associated with short- and long-term health problems among mothers and their offspring . There is a strong need for effective intervention strategies targeting excessive GWG to prevent adverse outcomes . Methods We performed a cluster-r and omized controlled intervention trial in eight gynecological practice s evaluating the feasibility and effectiveness of a lifestyle intervention presented to all pregnant women ; 250 healthy , pregnant women were recruited for the study . The intervention program consisted of two individually delivered counseling sessions focusing on diet , physical activity , and weight monitoring . The primary outcome was the proportion of pregnant women exceeding weight gain recommendations of the Institute of Medicine ( IOM ) . Secondary outcome variables were maternal weight retention and short-term obstetric and neonatal outcomes . Results The intervention result ed in a lower proportion of women exceeding IOM guidelines among women in the intervention group ( 38 % ) compared with the control group ( 60 % ) ( odds ratio ( OR ) : 0.5 ; 95 % confidence interval ( CI ) : 0.3 to 0.9 ) without prompting an increase in the proportion of pregnancies with suboptimal weight gain ( 19 % vs. 21 % ) . Participants in the intervention group gained significantly less weight than those in the control group . Only 17 % of the women in the intervention group showed substantial weight retention of more than 5 kg compared with 31 % of those in the control group at month four postpartum ( pp ) ( OR : 0.5 ; 95 % CI : 0.2 to 0.9 ) . There were no significant differences in obstetric and neonatal outcomes . Conclusions Lifestyle counseling given to pregnant women reduced the proportion of pregnancies with excessive GWG without increasing suboptimal weight gain , and may exert favorable effects on pp weight retention . Trial registration German Clinical Trials Register DRKS00003801 [22865627] BACKGROUND Exercise may influence glucose metabolism during pregnancy . We examined the effect of exercise intensity and duration on capillary glucose responses in pregnant women at low and high risk for gestational diabetes mellitus ( GDM ) who followed a modified GDM meal plan . METHODS R and omization occurred at study entry ( 16 - 20 weeks ' gestation ) into a low-intensity [ 30 % heart rate reserve , low risk-30%I , n = 12 ; high risk-30%I , n = 11 ] or vigorous-intensity ( 70 % heart rate reserve , low risk-70%I , n = 12 ; R-70%I , n = 11 ) exercise program with similar nutritional control . Exercise consisted of walking three to four times a week , gradually increasing time from 25 to 40 min/session . Free-living capillary glucose concentrations were measured once a week pre-exercise and post-exercise . RESULTS Capillary glucose responses to exercise were strongly influenced by an interaction between GDM risk , exercise duration and exercise intensity ( p = 0.006 ) . Decreases in glucose concentrations were observed after 25 ( 4 ± 13 % ) , 35 ( 21 ± 12 % ) and 40 min ( 15 ± 18 % ) of walking in high risk-30%I women , with the most noticeable decline after 35 and 40 min . In the high risk-70%I , glucose concentrations decreased significantly only after 25 ( 22 ± 14 % ) and 35 min ( 7 ± 23 % ) and increasing the exercise time attenuated glucose concentrations decline . In low risk women , regardless of exercise intensity and duration , decreases in glucose concentrations were significant and similar . CONCLUSION To achieve the best decline in glucose concentrations , pregnant women who follow a modified GDM meal plan should walk for 25 min/session at vigorous intensity or for 35 - 40 min/session at low intensity if they are at risk for GDM and for at least 25 min at either low or vigorous intensity if they are at low risk for GDM [25350037] AIM The effect of exercise training during the course of pregnancy on the newborn 's birth weight is unclear . This study examines the effect of aerobic and strength conditioning exercise performed during the second and the third trimester of pregnancy in nulliparous , previously inactive women on the newborn 's outcome . METHODS Sixty-three nulliparous , previously sedentary , were r and omly assigned to either an exercise ( N.=30 ) or a control ( N.=33 ) group . The subjects participated in the exercise group ( EG ) focused on aerobic and strength-conditioning exercise in three sessions for about 20 weeks . We registered the birth weight , birth length , gestational age at time of delivery , Apgar score and head circumference of the newborn . RESULTS There were no statistically significant differences between the two groups in mean birth weight , length , head circumference , and length of gestation . There was a significant difference between two groups in Apgar scores at 1 min ( P=0.036 ) and 5 min ( P=0.015 ) with newborns of the EG scoring higher than the CG . CONCLUSION Supervised , aerobic and strength conditioning exercise performed over the second and third trimester of pregnancy does not have a negative impact on the newborn 's body size and health [21459255] OBJECTIVE To determine if an interactive , computerized Video Doctor counseling tool improves self-reported diet and exercise in pregnant women . METHODS A r and omized trial comparing a Video Doctor intervention to usual care in ethnically diverse , low-income , English-speaking pregnant women was conducted . Brief messages about diet , exercise , and weight gain were delivered by an actor-portrayed Video Doctor twice during pregnancy . RESULTS In the Video Doctor group ( n=158 ) , there were statistically significant increases from baseline in exercise ( + 28 min ) , intake of fruits and vegetables , whole grains , fish , avocado and nuts , and significant decreases in intake of sugary foods , refined grains , high fat meats , fried foods , solid fats , and fast food . In contrast , there were no changes from baseline for any of these outcomes in the usual care group ( n=163 ) . Nutrition knowledge improved significantly over time in both groups but more so in the Video Doctor group . Clinician-patient discussion s about these topics occurred significantly more frequently in the Video Doctor group . There was no difference in weight gain between groups . CONCLUSION A brief Video Doctor intervention can improve exercise and dietary behaviors in pregnant women . PRACTICE IMPLICATION S The Video Doctor can be integrated into prenatal care to assist clinicians with effective diet and exercise counseling [26165396] BACKGROUND Behavioural interventions might improve clinical outcomes in pregnant women who are obese . We aim ed to investigate whether a complex intervention addressing diet and physical activity could reduce the incidence of gestational diabetes and large-for-gestational-age infants . METHODS The UK Pregnancies Better Eating and Activity Trial ( UPBEAT ) is a r and omised controlled trial done at antenatal clinics in eight hospitals in multi-ethnic , inner-city locations in the UK . We recruited pregnant women ( 15 - 18 weeks plus 6 days of gestation ) older than 16 years who were obese ( BMI ≥30 kg/m(2 ) ) . We r and omly assigned participants to either a behavioural intervention or st and ard antenatal care with an internet-based , computer-generated , r and omisation procedure , minimising by age , ethnic origin , centre , BMI , and parity . The intervention was delivered once a week through eight health trainer-led sessions . Primary outcomes were gestational diabetes ( diagnosed with an oral glucose tolerance test and by criteria from the International Association of Diabetes in Pregnancy Study Groups ) and large-for-gestational-age infants ( ≥90th customised birthweight centile ) . Analysis was by intention to treat . This trial is registered with Current Controlled Trials , ISCRTN89971375 . Recruitment and pregnancy outcomes are complete but childhood follow-up is ongoing . FINDINGS Between March 31 , 2009 , and June 2 , 2014 , we assessed 8820 women for eligibility and recruited 1555 , with a mean BMI of 36·3 kg/m(2 ) ( SD 4·8 ) . 772 were r and omly assigned to st and ard antenatal care and 783 were allocated the behavioural intervention , of which 651 and 629 women , respectively , completed an oral glucose tolerance test . Gestational diabetes was reported in 172 ( 26 % ) women in the st and ard care group compared with 160 ( 25 % ) in the intervention group ( risk ratio 0·96 , 95 % CI 0·79 - 1·16 ; p=0·68 ) . 61 ( 8 % ) of 751 babies in the st and ard care group were large for gestational age compared with 71 ( 9 % ) of 761 in the intervention group ( 1·15 , 0·83 - 1·59 ; p=0·40 ) . Thus , the primary outcomes did not differ between groups , despite improvements in some maternal secondary outcomes in the intervention group , including reduced dietary glycaemic load , gestational weight gain , and maternal sum-of-skinfold thicknesses , and increased physical activity . Adverse events included neonatal death ( two in the st and ard care group and three in the intervention group ) and fetal death in utero ( ten in the st and ard care group and six in the intervention group ) . No maternal deaths were reported . Incidence of miscarriage ( 2 % in the st and ard care group vs 2 % in the intervention group ) , major obstetric haemorrhage ( 1 % vs 3 % ) , and small-for-gestational-age infants ( ≤5th customised birthweight centile ; 6 % vs 5 % ) did not differ between groups . INTERPRETATION A behavioural intervention addressing diet and physical activity in women with obesity during pregnancy is not adequate to prevent gestational diabetes , or to reduce the incidence of large-for-gestational-age infants . FUNDING National Institute for Health Research , Guys and St Thomas ' Charity , Chief Scientist Office Scotl and , Tommy 's Charity [10647530] PURPOSE The present study examined the effects of exercise on physical and psychological variables in sedentary primigravidae ( PRA ) . METHODS A total of nine women r and omly assigned to an exercise ( E ) ( mean age = 31.3 + /- 3.1 yr ) and six subjects r and omly assigned to a control ( C ) group ( mean age = 27.8 + /- 3.1 yr ) fulfilled all requirements for the study . Exercise included a variety of exercise activities performed to a target heart rate of 150 - 156 beats x min(-1 ) , three times per week for 15 wk . RESULTS Results showed no significant differences between E and C groups in physical characteristics initially . A repeated measures ANOVA showed a significant group effect ( P < 0.05 ) and a significant group by time interaction ( P = 0.001 ) with the E group showing a significantly longer amount of time on the PWC150 test than the C group . There was no significant group , time , or group by time interaction for lactate accumulation . This occurred , despite the fact that the E group spent 56 % longer on the PWC150 test and the C group spent 30 % less time on the same test at the conclusion of the study . Finally , the E group in comparison to the C group showed more favorable improvements in several items related to health and well-being on the Body Cathexis Scale . There were no significant differences between E and C groups in any pregnancy outcome measures . All babies were delivered healthy at term . CONCLUSIONS These data suggest that a vigorous exercise program can lead to significant improvements in aerobic fitness at similar lactate concentrations compared to a control group and can be well tolerated by low risk sedentary PRA without any deleterious effects occurring to herself or unborn child [8990428] Objective To examine the effectiveness of a partially homebased , moderate-intensity aerobic exercise program for women with gestational diabetes . Methods This was a r and omized experimental design . Thirty-three women with gestational diabetes were r and omly assigned to the exercise or the no-exercise group . Subjects underwent hemoglobin A1C assay and submaximal cycle ergometer fitness tests at baseline and at study conclusion . Subjects kept diaries of home fasting and 2-hour postpr and ial blood glucose determinations . Exercise subjects were asked to exercise for 30 minutes three to four times weekly at 70 % of estimated maximal heart rate for the weeks of study participation . Two exercise sessions weekly were supervised by the investigator , and two were unsupervised at home . Control-group subjects were asked to maintain their current activity level . Results Daily fasting and postpr and ial blood glucose levels , hemoglobin A1C , incidence of exogenous insulin therapy , and incidence of newborn hypoglycemia were not different between the groups . There was a training effect in the exercise group ( P = .005 ) but not in the control group ( P = .25 ) . A significant decline in daily grams of carbohydrate consumed was observed in the control group ( P = .03 ) , but not in the exercise group ( P = .97 ) . No complications were found in the subjects who exercised . Conclusions A partially home-based exercise program did not reduce blood glucose levels , but did result in a modest increase in cardiorespiratory fitness . The intervention appeared safe [7771999] EDITORIAL COMMENT : When this paper was review ed the question was raised that the period of gestation is an obvious factor which can determine birth‐weight and the authors were asked how this may have affected their results The authors response was as follows [25823187] OBJECTIVE To assess the effect of aerobic exercise training on maternal and neonatal outcome METHODS The case-control study was conducted between January and July , 2011 . It was approved by the Research Ethics Committee of Toyserkan Azad University , and data was collected at prenatal clinics and delivery centres located in Hamedan , Iran . It comprised 80 pregnant women between 20 - 26 weeks of gestation r and omly assigned to two equal and matching groups of cases and controls . The intervention group did exercise continuously on a bicycle ergometre for 15 minutes , three times a week ; the intensity being 50 - 60 % of maximal heart rate . The control group did not do any exercise training . All information was obtained from the clinics , delivery centres , and from the reports of delivery room midwives . RESULTS No statistically significant difference was found between the two groups in gestational weight gain , pregnancy length , mode of delivery , first and second stage of labour , perineal tear , and 1st and 5th min Apgar score . Mean neonatal weight was significantly less in the intervention group than the control group ( p < 0.001 ) . CONCLUSION Exercising on a bicycle ergometer during pregnancy seems to be safe for the mother and the neonate [22017967] Please cite this paper as : Hui A , Back L , Ludwig S , Gardiner P , Sevenhuysen G , Dean H , Sellers E , McGavock J , Morris M , Bruce S , Murray R , Shen G. Lifestyle intervention on diet and exercise reduced excessive gestational weight gain in pregnant women under a r and omised controlled trial . BJOG 2012;119:70–77 [21247734] In the GRADE approach , r and omized trials start as high- quality evidence and observational studies as low- quality evidence , but both can be rated down if most of the relevant evidence comes from studies that suffer from a high risk of bias . Well-established limitations of r and omized trials include failure to conceal allocation , failure to blind , loss to follow-up , and failure to appropriately consider the intention-to-treat principle . More recently recognized limitations include stopping early for apparent benefit and selective reporting of outcomes according to the results . Key limitations of observational studies include use of inappropriate controls and failure to adequately adjust for prognostic imbalance . Risk of bias may vary across outcomes ( e.g. , loss to follow-up may be far less for all-cause mortality than for quality of life ) , a consideration that many systematic review s ignore . In deciding whether to rate down for risk of bias -- whether for r and omized trials or observational studies -- authors should not take an approach that averages across studies . Rather , for any individual outcome , when there are some studies with a high risk , and some with a low risk of bias , they should consider including only the studies with a lower risk of bias [23030765] Intrauterine Growth Retardation ( IUGR ) is defined as a rate of growth of a fetus that is less than normal for the growth potential of the fetus ( for that particular gestational age ) . Small for Gestational Age ( SGA ) is defined infant born following IUGR , with a weight at birth below the 10th percentile . Suboptimal fetal growth occurring in IUGR fetuses is an important cause of perinatal mortality and morbidity . The acute neonatal consequences of IUGR include metabolic and hematological disturbances , and disrupted thermoregulation ; in addition , respiratory distress ( RDS ) , necrotizing enterocolitis ( NEC ) , and retinopathy of prematurity ( ROP ) may contribute to perinatal morbidity . Metabolic disturbances are related to glucose and fatty acid metabolism . It is well-known that individuals who display poor growth in utero are at significantly increased risk for type 2 diabetes mellitus ( T2DM ) , obesity , hypertension , dyslipidemia , and insulin resistance ( the so-called metabolic syndrome , MS ) . MS ultimately leads to the premature development of cardiovascular diseases . In addition , short stature in children and adults , premature adrenarche , and the polycystic ovarian syndrome ( PCOS ) are endocrinological sequelae of IUGR . ( 8) Early onset growth delay and prematurity significantly increase the risk for neurological sequelae and motor and cognitive delay . Future prospect i ve studies need to investigate risk factors for infants who are SGA . If reliable prediction can be achieved , there is potential to reduce future perinatal morbidity and mortality , and long term consequences among SGA babies [2613131] Background To evaluate the association between water aerobics , maternal cardiovascular capacity during pregnancy , labor and neonatal outcomes . Methods A r and omized , controlled clinical trial was carried out in which 34 pregnant women were allocated to a water aerobics group and 37 to a control group . All women were su bmi tted to submaximal ergometric tests on a treadmill at 19 , 25 and 35 weeks of pregnancy and were followed up until delivery . Oxygen consumption ( VO2 max ) , cardiac output ( CO ) , physical fitness , skin temperature , data on labor and delivery , and neonate outcomes were evaluated . Frequency distributions of the baseline variables of both groups were initially performed and then analysis of the outcomes was carried out . Categorical data were compared using the chi-square test , and numerical using Student 's t or Mann-Whitney tests . Wilk 's Lambda or Friedman 's analysis of repeat measurements were applied for comparison of physical capacity , cardiovascular outcomes and maternal temperature . Results VO2 max and physical fitness were higher in both groups in the second trimester , returning to basal levels in the third trimester . In both groups , CO increased as pregnancy progressed and peak exercise temperature was higher than resting temperature , increasing further after five minutes of recovery and remaining at this level until 15 minutes after exercise completion . There was no difference between the two groups regarding duration ( 457.9 ± SD 249.6 vs 428.9 ± SD 203.2 minutes ) or type of delivery . Labor analgesia was requested by significantly fewer women in the water aerobics group ( 27 % vs 65 % ; RR = 0.42 95%CI 0.23–0.77 ) . Neonatal results were similar in both groups . Conclusion The regular practice of moderate water aerobics by sedentary and low risk pregnant women was not detrimental to the health of the mother or the child . There was no influence on maternal cardiovascular capacity , duration of labor or type of delivery ; however , there were fewer requests for analgesia during labor in the water aerobics group [10870784] Does strenuous antenatal exercise reduce birth‐weight ? Does reducing maternal exercise increase birthweight ? What to advise about exercise during pregnancy [25932848] OBJECTIVE : To examine the effect of an individually tailored , motivationally matched prenatal exercise intervention on gestational diabetes mellitus ( GDM ) and other measures of glucose intolerance among ethnically diverse prenatal care patients at increased risk for GDM . METHODS : The Behaviors Affecting Baby and You study r and omized eligible women at a mean ( st and ard deviation ) of 18.2 ( 4.1 ) weeks of gestation to a 12-week individually tailored , motivationally matched exercise intervention or a comparison health and wellness intervention . The goal of the exercise intervention was to achieve the American College of Obstetricians and Gynecologists ' guidelines for physical activity during pregnancy . Diagnosis of GDM , impaired glucose tolerance , abnormal glucose screen , and screening glucose values ( mg/dL ) were abstract ed from medical records . A sample size of 352 women ( 176 per group ) was planned to have 80 % power to detect reductions in risk of 35 % or larger . RESULTS : From July 2007 to December 2012 , a total of 251 ( 86.5 % ) women completed the intervention ; n=124 and 127 in the exercise and comparison interventions , respectively . Based on an intention-to-treat analysis , no statistically significant differences between the intervention groups were observed ; the relative odds of GDM in the exercise group was 0.61 ( 95 % confidence interval [ CI ] 0.28–1.32 ) as compared with the health and wellness comparison group . Odds ratios for impaired glucose tolerance and abnormal glucose screen were 0.68 ( 95 % CI 0.35–1.34 ) and 0.86 ( 95 % CI 0.51–1.47 ) , respectively . The intervention had no effect on birth outcomes . CONCLUSION : In this r and omized trial among ethnically diverse pregnant women at increased risk for GDM , we found that a prenatal exercise intervention implemented in the second trimester did not result in a statistically significant reduction in relative odds for GDM , impaired glucose tolerance , or abnormal glucose screen . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00728377 . LEVEL OF EVIDENCE : [4221718] Background Pregnancy is a recognised high risk period for excessive weight gain , contributing to postpartum weight retention and obesity development long-term . We aim ed to reduce postpartum weight retention following a low-intensity , self-management intervention integrated with routine antenatal care during pregnancy . Methods 228 women at increased risk of gestational diabetes , < 15 weeks gestation were r and omised to intervention ( 4 self-management sessions ) or control ( generic health information ) . Outcomes , collected at baseline and 6 weeks postpartum , included anthropometrics ( weight and height ) , physical activity ( pedometer ) and question naires ( health behaviours ) . Results Mean age ( 32.3 ± 4.7 and 31.7 ± 4.4 years ) and body mass index ( 30.4 ± 5.6 and 30.3 ± 5.9 kg/m2 ) were similar between intervention and control groups , respectively at baseline . By 6 weeks postpartum , weight change in the control group was significantly higher than the intervention group with a between group difference of 1.45 ± 5.1 kg ( 95 % CI : -2.86,-0.02 ; p < h0.05 ) overall , with a greater difference in weight found in overweight , but not obese women . Intervention group allocation , higher baseline BMI , GDM diagnosis , country of birth and higher age were all independent predictors of lower weight retention at 6 weeks postpartum on multivariable linear regression . Other factors related to weight including physical activity , did not differ between groups . Conclusions A low intensity intervention , integrated with st and ard antenatal care is effective in limiting postpartum weight retention . Implementation research is now required for scale-up to optimise antenatal health care . Trial registration Australian New Zeal and Clinical Trial Registry Number : ACTRN12608000233325 . Registered 7/5/2008 [4961392] Background The effectiveness of exercise training for preventing excessive gestational weight gain ( GWG ) and gestational diabetes mellitus ( GDM ) is still uncertain . As maternal obesity is associated with both GWG and GDM , there is a special need to assess whether prenatal exercise training programs provided to obese women reduce the risk of adverse pregnancy outcomes . Our primary aim was to assess whether regular supervised exercise training in pregnancy could reduce GWG in women with prepregnancy overweight/obesity . Secondary aims were to examine the effects of exercise in pregnancy on 30 outcomes including GDM incidence , blood pressure , blood measurements , skinfold thickness , and body composition . Methods and Findings This was a single-center study where we r and omized ( 1:1 ) 91 pregnant women with a prepregnancy body mass index ( BMI ) ≥ 28 kg/m2 to exercise training ( n = 46 ) or control ( st and ard maternity care ) ( n = 45 ) . Assessment s were done at baseline ( pregnancy week 12–18 ) and in late pregnancy ( week 34–37 ) , as well as at delivery . The exercise group was offered thrice weekly supervised sessions of 35 min of moderate intensity endurance exercise and 25 min of strength training . Seventeen women were lost to follow-up ( eight in the exercise group and nine in the control group ) . Our primary endpoint was GWG from baseline testing to delivery . The principal analyses were done as intention-to-treat analyses , with supplementary per protocol analyses where we assessed outcomes in the women who adhered to the exercise program ( n = 19 ) compared to the control group . Mean GWG from baseline to delivery was 10.5 kg in the exercise group and 9.2 kg in the control group , with a mean difference of 0.92 kg ( 95 % CI −1.35 , 3.18 ; p = 0.43 ) . Among the 30 secondary outcomes in late pregnancy , an apparent reduction was recorded in the incidence of GDM ( 2009 WHO definition ) in the exercise group ( 2 cases ; 6.1 % ) compared to the control group ( 9 cases ; 27.3 % ) , with an odds ratio of 0.1 ( 95 % CI 0.02 , 0.95 ; p = 0.04 ) . Systolic blood pressure was significantly lower in the exercise group ( mean 120.4 mm Hg ) compared to the control group ( mean 128.1 mm Hg ) , with a mean difference of −7.73 mm Hg ( 95 % CI −13.23 , −2.22 ; p = 0.006 ) . No significant between-group differences were seen in diastolic blood pressure , blood measurements , skinfold thickness , or body composition in late pregnancy . In per protocol analyses , late pregnancy systolic blood pressure was 115.7 ( 95 % CI 110.0 , 121.5 ) mm Hg in the exercise group ( significant between-group difference , p = 0.001 ) , and diastolic blood pressure was 75.1 ( 95 % CI 71.6 , 78.7 ) mm Hg ( significant between-group difference , p = 0.02 ) . We had planned to recruit 150 women into the trial ; hence , under-recruitment represents a major limitation of our results . Another limitation to our study was the low adherence to the exercise program , with only 50 % of the women included in the intention-to-treat analysis adhering as described in the study protocol . Conclusions In this trial we did not observe a reduction in GWG among overweight/obese women who received a supervised exercise training program during their pregnancy . The incidence of GDM in late pregnancy seemed to be lower in the women r and omized to exercise training than in the women receiving st and ard maternity care only . Systolic blood pressure in late pregnancy was also apparently lower in the exercise group than in the control group . These results indicate that supervised exercise training might be beneficial as a part of st and ard pregnancy care for overweight/obese women . Trial Registration Clinical Trials.gov [21948120] Objective The influence of an exercise programme performed by healthy pregnant women on maternal glucose tolerance was studied . Study design A physical activity ( PA , l and /aquatic activities ) programme during the entire pregnancy ( three sessions per week ) was conducted by a qualified instructor . 83 healthy pregnant women were r and omly assigned to either an exercise group ( EG , n=40 ) or a control ( CG , n=43 ) group . 50 g maternal glucose screen ( MGS ) , maternal weight gain and several pregnancy outcomes were recorded . Results Significant differences were found between study groups on the 50 g MGS . Values corresponding to the EG ( 103.8±20.4 mg/dl ) were better than those of the CG ( 126.9±29.5 mg/dl ) , p=0.000 . In addition , no differences in maternal weight gain and no cases of gestational diabetes in EG versus 3 in CG ( 7 % ) ( p>0.05 ) were found . Conclusion A moderate PA programme performed during pregnancy improves levels of maternal glucose tolerance [3750492] Background Antenatal preparation programmes are recommended worldwide to promote a healthy pregnancy and greater autonomy during labor and delivery , prevent physical discomfort and high levels of anxiety . The objective of this study was to evaluate effectiveness and safety of a birth preparation programme to minimize lumbopelvic pain , urinary incontinence , anxiety , and increase physical activity during pregnancy as well as to compare its effects on perinatal outcomes comparing two groups of nulliparous women . Methods A r and omized controlled trial was conducted with 197 low risk nulliparous women aged 16 to 40 years , with gestational age ≥ 18 weeks . Participants were r and omly allocated to participate in a birth preparation programme ( BPP ; n=97 ) or a control group ( CG ; n=100 ) . The intervention was performed on the days of prenatal visits , and consisted of physical exercises , educational activities and instructions on exercises to be performed at home . The control group followed a routine of prenatal care . Primary outcomes were urinary incontinence , lumbopelvic pain , physical activity , and anxiety . Secondary outcomes were perinatal variables . Results The risk of urinary incontinence in BPP participants was significantly lower at 30 weeks of pregnancy ( BPP 42.7 % , CG 62.2 % ; relative risk [ RR ] 0.69 ; 95 % confidence interval [ CI ] 0.51 - 0.93 ) and at 36 weeks of pregnancy ( BPP 41.2 % , CG 68.4 % ; RR 0.60 ; 95%CI 0.45 - 0.81 ) . Participation in the BPP encouraged women to exercise during pregnancy ( p=0.009 ) . No difference was found between the groups regarding to anxiety level , lumbopelvic pain , type or duration of delivery and weight or vitality of the newborn infant . Conclusions The BPP was effective in controlling urinary incontinence and to encourage the women to exercise during pregnancy with no adverse effects to pregnant women or the fetuses . Trial registration Clinical trials.gov , ( NCT01155804 [21354547] OBJECTIVE We have studied the effect of moderate physical activity that is performed by healthy women during their entire pregnancy on their perception of health status . STUDY DESIGN Eighty sedentary women were assigned r and omly to either an exercise group ( n = 40 ) or a control group ( n = 40 ) . Maternal perception of health status and several pregnancy outcomes were recorded . RESULTS Significant differences ( P = .03 ) were found between study groups in the percentage of women who perceived their health status as " very good " ; the values that corresponded to the exercise group ( n = 18 ; 54.5 % ) were better than those of the control group ( n = 9 ; 27.3 % ) . In addition , the women of the exercise group gained less weight ( 11,885 ± 3146 g ) than those of the control group ( 13,903 ± 2113 ; P = .03 ) . CONCLUSION A moderate physical activity program that is performed over the first , second , and third trimester of pregnancy improves the maternal perception of health status [26241428] OBJECTIVE : To compare , in an unselected population of nulliparous pregnant women , the postnatal effect of prenatal supervised pelvic floor muscle training with written instructions on postpartum urinary incontinence ( UI ) . METHODS : In a r and omized controlled trial in two parallel groups , 282 women were recruited from five university teaching hospitals in France and r and omized during the second trimester of pregnancy . The physiotherapy group received prenatal individually supervised exercises . Both groups received written instructions about how to perform exercises at home . Women were blindly assessed at baseline , end of pregnancy , and 2 and 12 months postpartum . The primary outcome measured was UI severity , assessed with an International Consultation on Incontinence Question naire-Urinary Incontinence Short Form score ( range 0–21 ; 1–5 is slight UI ) at 12 months postpartum ; other outcomes were UI prevalence and pelvic floor troubles assessed using self-administered question naires . To give a 1-point difference in UI severity score , we needed 91 women in each group ( st and ard deviation 2.4 , & agr;=0.05 , & bgr;=0.20 , and bilateral analysis ) . RESULTS : Between February 2008 and June 2010 , 140 women were r and omized in the physiotherapy group and 142 in the control group . No difference was observed between the two groups in UI severity , prevalence , or pelvic floor troubles at baseline , end of pregnancy , and at 2 and 12 months postpartum . At 12 months postpartum , the primary outcome was available for 190 women ( 67.4 % ) ; mean UI severity was 1.9 in the physiotherapy group compared with 2.1 in the control group ( P=.38 ) . CONCLUSION : Prenatal supervised pelvic floor training was not superior to written instructions in reducing postnatal UI . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov ; www . clinical trials.gov , NCT00551551 . LEVEL OF EVIDENCE : [10078577] OBJECTIVE To investigate if water-gymnastics during pregnancy may reduce the intensity of back/low back pain and the number of days on sick-leave . METHODS A prospect i ve , r and omized study . One hundred and twenty-nine women were r and omized to participate in water-gymnastics once a week during the second half of pregnancy and 129 were r and omized to a control group . The women in both groups filled in question naires in gestational weeks 18 , 34 and within the first postpartum week . Every day from week 18 to labor they assessed the intensity of back/low back pain . RESULTS Back pain intensity increased during pregnancy . No excess risk for the pregnancy associated with water-gymnastics was observed . The women participating in water-gymnastics recorded a lower intensity of back/low back pain . The total number of days on sick-leave because of back/low back pain was 982 in the water-gymnastics group ( 124 women ) compared with 1484 in the control group ( 120 women ) . After weeks 32 33 , seven women in the water-gymnastics group compared with 17 in the control group were on sickleave because of back/ low back pain ( p=0.031 ) . CONCLUSIONS Intensity of back/low back pain increased with advancing pregnancy . There was no excess risk for urinary or vaginal infections associated with water-gymnastics . Water-gymnastics during the second half of pregnancy significantly reduced the intensity of back/ low back pain . Water-gymnastics decreased the number of women on sick-leave because of back/low back pain . Water-gymnastics during pregnancy can be recommended as a method to relieve back pain and may reduce the need for sick-leave [12576255] OBJECTIVE Urinary incontinence is a chronic health complaint that severely reduces quality of life . Pregnancy and vaginal delivery are main risk factors in the development of urinary incontinence . The aim of this study was to assess whether intensive pelvic floor muscle training during pregnancy could prevent urinary incontinence . METHODS We conducted a single-blind r and omized controlled trial at Trondheim University Hospital and three outpatient physiotherapy clinics in a primary care setting . Three hundred one healthy nulliparous women were r and omly allocated to a training ( n = 148 ) or a control group ( n = 153 ) . The training group attended a 12-week intensive pelvic floor muscle training program during pregnancy , supervised by physiotherapists . The control group received the customary information . The primary outcome measure was self-reported symptoms of urinary incontinence . The secondary outcome measure was pelvic floor muscle strength . RESULTS At follow-up , significantly fewer women in the training group reported urinary incontinence : 48 of 148 ( 32 % ) versus 74 of 153 ( 48 % ) at 36 weeks ' pregnancy ( P = .007 ) and 29 of 148 ( 20 % ) versus 49 of 153 ( 32 % ) 3 months after delivery ( P = .018 ) . According to numbers needed to treat , intensive pelvic floor muscle training during pregnancy prevented urinary incontinence in about one in six women during pregnancy and one in eight women after delivery . Pelvic floor muscle strength was significantly higher in the training group at 36 weeks ' pregnancy ( P = .008 ) and 3 months after delivery ( P = .048 ) . CONCLUSION Intensive pelvic floor muscle training during pregnancy prevents urinary incontinence during pregnancy and after delivery . Pelvic floor muscle strength improved significantly after intensive pelvic floor muscle training [4573757] Objective To evaluate whether a 12-week supervised exercise program promotes an active lifestyle throughout pregnancy in pregnant women with obesity . Methods In this preliminary r and omised trial , pregnant women ( body mass index ≥ 30 kg/m2 ) were allocated to either st and ard care or supervised training , from 15 to 27 weeks of gestation . Physical activity was measured by accelerometry at 14 , 28 and 36 weeks , while fitness ( oxygen consumption ( VO2 ) at the anaerobic threshold ) , nutrition ( caloric intake and macronutrients percentage ) and anthropometry were assessed at 14 and 28 weeks of gestation . Analyses were performed using repeated measures ANOVA . Results A total of fifty ( 50 ) women were r and omised , 25 in each group . There was no time-group interaction for time spent at moderate and vigorous activity ( pinteraction = 0.064 ) , but the exercise group ’s levels were higher than controls ’ at all times ( pgroup effect = 0.014 ) . A significant time-group interaction was found for daily physical activity ( p = 0.023 ) ; similar at baseline ( ( 22.0 ± 6.7 vs 21.8 ± 7.3 ) x 104 counts/day ) the exercise group had higher levels than the control group following the intervention ( ( 22.8 ± 8.3 vs 19.2 ± 4.5 ) x 104 counts/day , p = 0.020 ) and at 36 weeks of gestation ( ( 19.2 ± 1.5 vs 14.9 ± 1.5 ) x 104 counts/day , p = 0.034 ) . Exercisers also gained less weight than controls during the intervention period despite similar nutritional intakes ( difference in weight change = -0.1 kg/week , 95 % CI -0.2 ; -0.02 , p = 0.016 ) and improved cardiorespiratory fitness ( difference in fitness change = 8.1 % , 95 % CI 0.7 ; 9.5 , p = 0.041 ) . Conclusions Compared with st and ard care , a supervised exercise program allows pregnant women with obesity to maintain fitness , limit weight gain and attenuate the decrease in physical activity levels observed in late pregnancy . Trial Registration Clinical Trials.gov [5934849] Background To develop effective health promotional and preventive prenatal programs , it is important to underst and perceived barriers to leisure-time physical activity during pregnancy , including exercise and sport participation . The aims of the present study was 1 ) to assess the effect of prenatal lifestyle intervention on the perceived barrier to leisure-time physical activity during pregnancy and the first year after delivery and 2 ) identify the most important perceived barriers to leisure-time physical activity at multiple time points during and after pregnancy . Methods This secondary analysis was part of the Norwegian Fit for Delivery study , a combined lifestyle intervention evaluated in a blinded , r and omized controlled trial . Healthy , nulliparous women with singleton pregnancy of ≤20 gestational weeks , age ≥ 18 years and body mass index ≥19 kg/m2 were recruited via healthcare clinics in southern Norway , including urban and rural setting s. Participants were r and omized to either twice-weekly supervised exercise sessions and nutritional counselling ( n = 303 ) or st and ard prenatal care ( n = 303 ) . The principal analysis was based on the participants who completed the st and ardized question naire assessing their perceived barriers to leisure-time physical activity at inclusion ( gestational week 16 , n = 589 ) and following intervention ( gestational week 36 , n = 509 ) , as well as six months ( n = 470 ) and 12 months ( n = 424 ) postpartum . Results Following intervention ( gestation week 35.4 ± 1.0 ) , a significant between-group difference in perceived barriers to leisure-time physical activity was found with respect to time constraints : “ ... I do not have the time ” ( intervention : 22 vs. control : 38 , p = 0.030 ) , mother-child safety concerns : “ ... afraid to harm the baby ” ( intervention : 8 vs. control : 25 , p = 0.002 ) and self-efficacy : “ ... I do not believe/think that I can do it ” ( intervention : 3 vs. control : 10 , p = 0.050 ) . No positive effect was seen at postpartum follow-up . Intrapersonal factors ( lack of time , energy and interest ) were the most frequently perceived barriers , and consistent over time among all participants . Conclusion The intervention had effect on intrapersonal perceived barriers in pregnancy , but not in the postpartum period . Perceived barriers to leisure-time physical activity were similar from early pregnancy to 12 months postpartum . Trial registration Clinical Trials.gov : NCT01001689 , registered July 2 , 2009 [4287470] Background The objectives of this study were to assess the efficacy of lifestyle intervention on gestational weight gain in pregnant women with normal and above normal body mass index ( BMI ) in a r and omized controlled trial . Methods A total of 116 pregnant women ( < 20 weeks of pregnancy ) without diabetes were enrolled and 113 pregnant women completed the program . Participants were r and omized into intervention and control groups . Women in the intervention group received weekly trainer-led group exercise sessions , instructed home exercise for 3 - 5-times/week during 20 - 36 weeks of gestation , and dietary counseling twice during pregnancy . Participants in the control group did not receive the intervention . All participants completed a physical activity question naire and a 3-day food record at enrolment and 2 months after enrolment . Results The participants in the intervention group with normal pre-pregnancy BMI ( ≤24.9 kg/M2 , n = 30 ) had lower gestational weight gain ( GWG ) , offspring birth weight and excessive gestational weight gain ( EGWG ) on pregnancy weight gain compared to the control group ( n = 27 , p < 0.05 ) . Those weight related-changes were not detected between the intervention ( n = 27 ) and control group ( n = 29 ) in the above normal pre-pregnancy BMI participants . Intervention reduced total calorie , total fat , saturated fat and cholesterol intake were detected in women with normal or above normal pre-pregnancy BMI compared to the control group ( p < 0.05 or 0.01 ) . Increased physical activity and reduced carbohydrate intake were detected in women with normal ( p < 0.05 ) , but not above normal , pre-pregnancy BMI at 2 months after the onset of the intervention compared to the control group . Conclusion The results of the present study demonstrated that the lifestyle intervention program decreased EGWG , GWG , offspring birth weight in pregnant women with normal , but not above normal , pre-pregnancy BMI , which was associated with increased physical activity and decreased carbohydrate intake . Trial registration [4431606] Objective To determine the effectiveness of a physical activity intervention for smoking cessation during pregnancy . Design Parallel group , r and omised controlled , multicentre trial . Setting 13 hospitals in Engl and , April 2009 to January 2014 . Participants 789 pregnant smokers , aged 16 - 50 years and at 10 - 24 weeks ’ gestation , who smoked at least one cigarette daily and were prepared to quit smoking one week after enrollment were r and omised ( 1:1 ) ; 785 were included in the intention to treat analyses , with 392 assigned to the physical activity group . Interventions Interventions began one week before a target quit date . Participants were r and omised to six weekly sessions of behavioural support for smoking cessation ( control ) or to this support plus 14 sessions combining supervised treadmill exercise and physical activity consultations . Main outcome measures The primary outcome was continuous smoking abstinence from the target quit date until end of pregnancy , vali date d by exhaled carbon monoxide or salivary cotinine levels . To assess adherence , levels of moderate-vigorous intensity physical activity were self reported and in a 11.5 % ( n=90 ) r and om sub sample of participants , physical activity was objective ly measured by an accelerometer . Results No significant difference was found in rates of smoking abstinence at end of pregnancy between the physical activity and control groups ( 8 % v 6 % ; odds ratio 1.21 , 95 % confidence interval 0.70 to 2.10 ) . For the physical activity group compared with the control group , there was a 40 % ( 95 % confidence interval 13 % to 73 % ) , 34 % ( 6 % to 69 % ) , and 46 % ( 12 % to 91 % ) greater increase in self reported minutes carrying out physical activity per week from baseline to one week , four weeks , and six weeks post-quit day , respectively . According to the accelerometer data there was no significant difference in physical activity levels between the groups . Participants attended a median of four treatment sessions in the intervention group and three in the control group . Adverse events and birth outcomes were similar between the two groups , except for significantly more caesarean births in the control group than in the physical activity group ( 29 % v 21 % , P=0.023 ) . Conclusion Adding a physical activity intervention to behavioural smoking cessation support for pregnant women did not increase cessation rates at end of pregnancy . During pregnancy , physical activity is not recommended for smoking cessation but remains indicated for general health benefits . Trial registration Current Controlled Trials IS RCT N48600346 [3753734] Objectives . To evaluate the association between physical exercise supervised in pregnant women with chronic hypertension and /or previous preeclampsia and maternal and neonatal outcomes . Method . R and omized controlled trial , which included 116 pregnant women with chronic hypertension and /or previous preeclampsia , considered risk of preeclampsia development . They were divided into two groups : study group that performed physical exercise with a stationary bicycle once a week , for 30 minutes ; the intensity was controlled ( heart rate 20 % above resting values ) , under professional supervision and a control group that was not engaged in any physical exercise . The data was retrieved from medical charts . Significance level assumed was 5 % . Results . Women from study group performed 9.24 ± 7.03 of physical exercise sessions . There were no differences between groups comparing type of delivery and maternal outcomes , including maternal morbidity and hospitalization in intensive unit care , and neonatal outcomes , including birth weight , adequacy of weight to gestational age , prematurity , Apgar scale at first and fifth minutes , hospitalization in intensive unit care , and neonatal morbidity . Conclusions . Physical exercise using a stationary bicycle in pregnant women with chronic hypertension and /or previous preeclampsia , once a week , under professional supervision , did not interfere in the delivery method and did not produce maternal and neonatal risks of the occurrence of morbidity . This trial is registered with Clinical Trials.gov NCT01395342 [19955397] BACKGROUND Maternal obesity and excessive gestational weight gain ( GWG ) are major short- and long-term risk factors for maternal and fetal complications . OBJECTIVE The objective was to study whether a lifestyle intervention based on a brochure or on active education can improve dietary habits , increase physical activity ( PA ) , and reduce GWG in obese pregnant women . DESIGN In this r and omized controlled trial , 195 white , obese pregnant women [ age : 29 + or - 4 y ; body mass index ( in kg/m(2 ) ) ; 33.6 + or - 4.2 ] were r and omly assigned into 3 groups : a group that received nutritional advice from a brochure , a group that received the brochure and lifestyle education by a nutritionist , and a control group . Nutritional habits were evaluated every trimester through 7-d food records . PA was evaluated with the Baecke question naire . RESULTS Energy intake did not change during pregnancy and was comparable in all groups . Fat intake , specifically saturated fat intake , decreased and protein intake increased from the first to the third trimester in the passive and active groups compared with an opposite change in the control group . Calcium intake and vegetable consumption increased during pregnancy in all groups . PA decreased in all groups , especially in the third trimester . No significant differences in GWG and obstetrical or neonatal outcome could be observed between the groups . CONCLUSIONS Both lifestyle interventions improved the nutritional habits of obese women during pregnancy . Neither PA nor GWG was affected [25306925] AIMS To pilot the feasibility of a prenatal lifestyle intervention to modify physical activity and diet among pregnant overweight and obese Hispanic women , with the aim of reducing risk factors for gestational diabetes mellitus . METHODS Women were r and omized either to a lifestyle intervention ( n = 33 , 48.5 % ) , consisting of a culturally and linguistically modified , motivationally targeted , individually tailored 6-month prenatal programme , or to st and ard care ( n = 35 , 51.5 % ) . Bilingual and bicultural health educators encouraged women to achieve guidelines for physical activity , decrease saturated fat and increase dietary fibre . Outcomes included gestational weight gain , infant birth weight and biomarkers associated with insulin resistance . RESULTS Patient retention up to delivery was 97 % in both study groups . The lifestyle intervention attenuated the pregnancy-associated decline in moderate-intensity physical activity , but differences between groups were not significant ( mean ± se -23.4 ± 16.6 vs -27.0 ± 16.2 metabolic equivalent of task h/week ; P = 0.88 ) . Vigorous-intensity activity increased during the course of pregnancy in the lifestyle intervention group ( mean ± se 1.6 ± 0.8 metabolic equivalent of task h/week ) and declined in the st and ard care group ( -0.8 ± 0.8 metabolic equivalent of task h/week ; P = 0.04 ) . The lifestyle intervention group also had slightly lower gestational weight gain and infant birth weights compared with the st and ard care group ; however , these differences were not statistically significant . There were no statistically significant differences in biomarkers of insulin resistance between groups . CONCLUSIONS Findings suggest that a motivationally matched lifestyle intervention is feasible and may help attenuate pregnancy-related decreases in vigorous physical activity in a population of overweight and obese Hispanic women . The intervention protocol can readily be translated into clinical practice in underserved and minority population [16055571] Objective : To evaluate the effects of aerobic training on submaximal cardiorespiratory capacity in overweight pregnant women . Methods : We conducted a r and omized clinical trial in a referral center prenatal clinic during the period 2000–2002 . Of 132 overweight ( body mass index 26–31 kg/m2 ) but otherwise healthy volunteers , at 20 years of age or older , with gestational age of 20 weeks or less , and without diabetes or hypertension , 92 consented to participate and were r and omized . Intervention consisted of 3 one-hour aerobic exercise sessions per week ; the control group received weekly relaxation and focus group discussion s. The main outcome measure was submaximal exercise capacity evaluated by oxygen uptake at the anaerobic ( first ventilatory ) threshold during cardiopulmonary treadmill testing 12 weeks after r and omization . Results : Oxygen uptake at the anaerobic threshold increased 18 % ( 15.9 ± 2.6 to 18.1 ± 3.1 mL · min−1 · kg−1 ) in the exercise group but decreased 16 % ( 16.9 ± 3.0 to 15.8 ± 2.6 mL · min−1 · kg−1 ) among the control group . Oxygen consumption at the anaerobic threshold , adjusted through analysis of covariance for baseline oxygen uptake , was 2.68 ( 95 % confidence interval 1.23 to 4.12 ) mL · min−1 · kg−1 greater in the exercise group . Women in the exercise group were approximately 5 times more likely than those in the control group to have regular or good cardiorespiratory capacity ( 12/38 versus 2/38 ; relative risk 5.2 , 95 % confidence interval 1.2 to 22.0 , number needed to treat 5 ) . Conclusion : Aerobic training in overweight pregnant women substantially increases submaximal exercise capacity , overcoming the otherwise negative effects of pregnancy in this regard . Additional studies are required to evaluate its effect on major clinical outcomes . LEVEL OF EVIDENCE : [12188409] A single center , prospect i ve , r and omized , single blinded , controlled study comparing the effects and safety of " sitting pelvic tilt exercise " in relieving back pain during the third trimester in primigravida was carried out . The sample s were composed of 67 primigravidas who attended the prenatal clinic at King Chulalongkorn Memorial Hospital . All subjects were selected by the r and om sampling technique and allocated into two groups for the experimental group and the control group ; for 32 and 35 pregnants , respectively . The experimental group received the pelvic tilt exercise program for 8 weeks during the third trimester . Pain intensity was measured by visual analogue scale ( VAS ) at day 0 and day 56 in both groups . The result of the study revealed 1 ) The mean VAS of back pain in the experimental group was significantly lower at day 56 than at day 0 and lower than the control group at day 56 ( p < 0.05 ) by unpaired t-test 2 ) There was no incidence of preterm labor , low birth weight or neonatal complication in the experimental group . In conclusion , the " sitting pelvic tilt exercise " during the third trimester in primigravidas could decrease back pain intensity without incidence of preterm labor , low birth weight or neonatal complication [24290112] OBJECTIVE To study the effect on maternal weight gain of a supervised light- to moderate-intensity exercise-based intervention performed from the ninth week of pregnancy . PARTICIPANTS AND METHODS A total of 962 healthy pregnant women were r and omly assigned to a st and ard care or exercise intervention group conducted between September 1 , 2007 , and January 31 , 2011 . The intervention included light- to moderate-intensity aerobic and resistance exercises performed 3 days a week ( 50 - 55 minutes per session ) . Excessive gestational weight gain was calculated on the basis of the 2009 Institute of Medicine ( IOM ) recommendations . Gestational body weight gain was calculated on the basis of the weight measured at the first prenatal visit ( fifth to sixth weeks of gestation ) and weight measured at the last visit to the clinic before delivery . Women were categorized into normal weight or overweight or obese . RESULTS Women in the intervention group gained less weight ( adjusted mean difference , 1.039 kg ; 95 % CI , 0.534 - 1.545 kg ; P<.001 ) and were less likely to gain weight above the IOM recommendations ( odds ratio , 0.625 ; 95 % CI , 0.461 - 0.847 ) compared with those in the st and ard care group . The main treatment effects according to body mass index category were that normal weight women in the intervention group gained less weight ( adjusted mean difference , 1.393 kg ; 95 % CI , 0.813 - 1.972 kg ; P<.001 ) and were less likely to gain weight above the IOM recommendations ( odds ratio , 0.508 ; 95 % CI , 0.334 - 0.774 ) than normal weight women who received st and ard care . No significant treatment effect was observed in overweight or obese women . CONCLUSION Supervised exercise of light to moderate intensity can be used to prevent excessive gestational weight gain , especially in normal weight women . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01790347 [21860990] BACKGROUND The use of the pelvic floor muscle training for urinary incontinence treatment is well established but little is known about its effects in labor and newborn outcomes . OBJECTIVES To evaluate the effects of antenatal pelvic floor muscle training and strength in labor and newborn outcomes in low-income pregnant women . METHODS This is a r and omized controlled trial that recruited forty-two nulliparous healthy pregnant women aged between 18 - 36 years old and able to contract the pelvic floor muscles . The participants were included in the study with 20 weeks of gestational age and had their pelvic floor muscles measured by vaginal squeeze pressure . They were r and omly allocated into two groups : training group and a non-intervention control group . Then , all participants had their labor and newborn outcomes evaluated through consultation of medical records by a blinded research er . RESULTS There were no statistically significant differences between the groups regarding gestational age at birth , type of labor , duration of the second stage of labor , total time of labor , prevalence of laceration , weight and size of the baby , and Apgar score . No correlation was observed between pelvic floor muscle strength and the second stage or the total length of labor . CONCLUSIONS This r and omized controlled trial did not find any effect of pelvic floor muscle training or pelvic floor muscle strength on labor and newborn outcomes [20737135] Introduction and hypothesisThe aim of the study was to evaluate the effect of antenatal pelvic floor muscle exercise ( PFME ) in the prevention and treatment of urinary incontinence during pregnancy and postpartum period . Methods Three hundred women were r and omly assigned to the PFME group and control group . Urinary symptoms were measured by Urogenital Distress Inventory-6 ( UDI-6 ) , Incontinence Impact Question naire-7 ( IIQ-7 ) , and question of self-reported urinary incontinence . Question naire scores of the PFME and the control groups were compared and analyzed . Results During late pregnancy and the postpartum period , the PFME group had significantly lower total UDI-6 and IIQ-7 scores ; their self-report rate of urinary incontinence was also less than the control group . Additionally , we found whether in PFME or control , women who delivered vaginally were more likely to develop postpartum urinary leakage than women who delivered by cesarean section . Conclusions PFME applied in pregnancy is effective in the treatment and prevention of urinary incontinence during pregnancy , and this effect may persist to postpartum period [12439652] BACKGROUND : The Institute of Medicine ( IOM ) recommends that normal‐weight women ( BMI ( body mass index ) of 19.8–26.0 ) gain 25–35 lb ( 11.4–15.9 kg ) during pregnancy , and that overweight women ( BMI of 26.1–29.0 ) gain 15–25 lbs ( 6.8–11.4 kg ) . A significant number of normal‐weight women and an even greater proportion of overweight women exceed these guidelines , which increases postpartum weight retention and may contribute to the development of obesity . OBJECTIVE : To determine whether a stepped care , behavioral intervention will decrease the percentage of women who gain more than the IOM recommendation . DESIGN : R and omized controlled trial comparing a stepped-care behavioral intervention with usual care . Women ( n=120 ) who had a BMI > 19.8 , age>18 and < 20 weeks gestation were recruited from a hospital-based clinic serving low-income women and r and omized by race and BMI category to the intervention or control group . The intervention group received education about weight gain , healthy eating , and exercise and individual graphs of their weight gain . Those exceeding weight gain goals were given more intensive intervention . Women were followed through pregnancy to their first postpartum clinic visit . The main outcome measure was weight gain during pregnancy categorized as above the IOM recommendations vs below or within the IOM recommendations . RESULTS : The intervention significantly decreased the percentage of normal-weight women who exceeded the IOM recommendations ( 33 vs 58 % , P<0.05 ) . There was a non-significant ( P=0.09 ) effect in the opposite direction among overweight women ( 59 % of intervention and 32 % of control gained more than recommended ) . Postpartum weight retention was strongly related to weight gain during pregnancy ( r=0.89 ) . CONCLUSIONS : The intervention reduced excessive weight gain during pregnancy among normal weight women [27272937] We examined the effects of home-based walking on sedentary Japanese women 's pregnancy outcomes and mood . A r and omized controlled trial was conducted , involving 118 women aged 22 - 36 years . Participants were r and omly assigned to walking intervention ( n = 60 ) or control ( n = 58 ) groups . The walking group was instructed to walk briskly for 30 min , three times weekly from 30 weeks ' gestation until delivery . Both groups counted their daily steps using pedometers . Pregnancy and delivery outcomes were assessed , participants completed the Profile of Mood States , and we used the intention-to-treat principle . Groups showed no differences regarding pregnancy or delivery outcomes . The walking group exhibited decreased scores on the depression-dejection and confusion subscales of the Profile of Mood States . Five of the 54 women in the intervention group who remained in the study ( 9.2 % ) completed 100 % of the prescribed walking program ; 32 ( 59.3 % ) women completed 80 % or more . Unsupervised walking improves sedentary pregnant women 's mood , indicating that regular walking during pregnancy should be promoted in this group [23365418] Objective To examine the effect of regular moderate-intensity exercise ( three training sessions/week ) on the incidence of gestational diabetes mellitus ( GDM , primary outcome ) . We also examined if the exercise intervention modifies the association between GDM and birth weight and risk of macrosomia , gestational age , risk of caesarean delivery and maternal weight gain ( secondary outcomes ) . Methods We r and omly assigned 510 healthy gravida to either an exercise intervention or a usual care ( control ) group ( n=255 each ) . The exercise programme focused on moderate-intensity resistance and aerobic exercises ( three times/week , 50–55 min/session ) . GDM diabetes was diagnosed according to the WHO criteria and the International Association for Diabetes in Pregnancy Study Group ( IADPSG ) . Results The intervention did not reduce the risk of developing GDM ( OR 0.84 , 95 % CI 0.50 to 1.40 ) when using the WHO criteria . We observed that the intervention reduced by 58 % the GDM-related risk ( WHO criteria ) of having a newborn with macrosomia ( OR 1.76 , 95 % CI 0.04 to 78.90 vs 4.22 , 95 % CI 1.35 to 13.19 ) in exercise and control groups , respectively ) , and by 34 % the GDM-related risk of having acute and elective caesarean delivery ( OR 1.30 , 95 % CI 0.44 to 3.84 vs 1.99 , 95 % CI 0.98 to 4.06 in exercise and control groups , respectively ) . Gestational age was similar across the treatment groups ( control , exercise ) and GDM category ( GDM or non-GDM ) , and maternal weight gain was ∼12 % lower in the exercise group independent of whether women developed GDM . The results were similar when the IADPSG criteria were used instead . Conclusions Regular moderate-intensity exercise performed over the second-third trimesters of pregnancy can be used to attenuate important GDM-related adverse outcomes [11120515] OBJECTIVE Our purpose was to test the null hypothesis that beginning regular , moderate-intensity exercise in early pregnancy has no effect on fetoplacental growth . STUDY DESIGN Forty-six women who did not exercise regularly were r and omly assigned at 8 weeks either to no exercise ( n = 24 ) or to weight-bearing exercise ( n = 22 ) 3 to 5 times a week for the remainder of pregnancy . Outcome variables included antenatal placental growth rate and neonatal and placental morphometric measurements . RESULTS The offspring of the exercising women were significantly heavier ( corrected birth weight : 3.75 + /- 0.08 kg vs 3.49 + /- 0.07 kg ) and longer ( 51.8 + /- 0.3 cm vs 50.6 + /- 0.3 cm ) than those born to control women . The difference in birth weight was the result of an increase in both lean body mass and fat mass . In addition , midtrimester placental growth rate was faster ( 26 + /- 2 cm(3)/wk vs 21 + /- 1 cm(3)/wk ) and morphometric indexes of placental function were greater in the exercise group . There were no significant differences in neonatal percentage body fat , head circumference , ponderal index , or maternal weight gain . CONCLUSIONS These data indicate that beginning a moderate regimen of weight-bearing exercise in early pregnancy enhances fetoplacental growth [22825089] OBJECTIVE : To estimate the effect of supervised physical exercise on maternal physical fitness , fetoplacental blood flow , and fetal growth . METHODS : This was a r and omized controlled trial comparing three groups of pregnant women . Groups were as follows : exercise initiated at 13 weeks ( group A ) ; exercise initiated at 20 weeks ( group B ) ; and a control group ( no supervised exercise ; group C ) . The women in groups A and B walked at moderate intensity three times weekly . Physical fitness level was evaluated at weeks 13 , 20 , and 28 . Fetal growth and uteroplacental blood flow were evaluated monthly . Birth weight was registered . Analysis of variance for repeat measures was used for outcomes evaluated throughout pregnancy . Risk ratio was used as a measure of the relative risk of preeclampsia , fetal growth restriction , macrosomia , small-for-gestational-age newborns , and large-for-gestational-age newborns . RESULTS : All the women analyzed completed more than 85 % of the program . According to the evaluation conducted at week 28 , physical fitness improved , with mean maximal oxygen consumptions ( VO2max ) of 27.3±4.3 ( group A ) , 28±3.3 ( group B ) , and 25.5±3.8 ( group C ; P=.03 ) . Mean birth weights were 3,279±453 g ( group A ) , 3,285±477 g ( group B ) , and 3,378±593 g ( group C ; P=.53 ) , with no difference in the frequency of large for gestational age or small for gestational age . No association was found between the practice of physical activity and the variables investigated ( preeclampsia , fetal weight , blood pressure , and pulsatility index of the uterine , umbilical , and middle cerebral arteries ) . CONCLUSION : Moderate-intensity walking improved the physical fitness level of healthy , pregnant , previously sedentary women without affecting fetoplacental blood flow or fetal growth . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00641550 . LEVEL OF EVIDENCE : [20864072] OBJECTIVE The objective of the study was to evaluate the effect of a resistance exercise program with an elastic b and on insulin requirement and glycemic control in patients with gestational diabetes mellitus ( GDM ) . STUDY DESIGN Sixty-four patients with gestational diabetes mellitus were r and omly assigned into 2 groups : an exercise group ( EG ; n = 32 ) and a control group not su bmi tted to the exercise program ( CG ; n = 32 ) . RESULTS A significant reduction in the number of patients who required insulin was observed in the EG ( 7/32 ) compared with the CG group ( 18/32 ) ( P = .005 ) . The percentage of time spent within the proposed target glucose range ( of at least 80 % of weekly measurements below the limits preestablished for the disease ) was significantly higher in EG compared with the CG group ( EG = 0.63 ± 0.30 ; CG = 0.41 ± 0.31 ; P = .006 ) . CONCLUSION The resistance exercise program was effective in reducing the number of patients with GDM who required insulin and in improving capillary glycemic control in this population [21208779] This article introduces the approach of GRADE to rating quality of evidence . GRADE specifies four categories-high , moderate , low , and very low-that are applied to a body of evidence , not to individual studies . In the context of a systematic review , quality reflects our confidence that the estimates of the effect are correct . In the context of recommendations , quality reflects our confidence that the effect estimates are adequate to support a particular recommendation . R and omized trials begin as high- quality evidence , observational studies as low quality . " Quality " as used in GRADE means more than risk of bias and so may also be compromised by imprecision , inconsistency , indirectness of study results , and publication bias . In addition , several factors can increase our confidence in an estimate of effect . GRADE provides a systematic approach for considering and reporting each of these factors . GRADE separates the process of assessing quality of evidence from the process of making recommendations . Judgments about the strength of a recommendation depend on more than just the quality of evidence [9704236] The objective of this study was to test the hypothesis that a woman 's dietary carbohydrate mix modifies the glucose and insulin response to both mixed caloric intake and exercise . Either a prospect i ve r and omized or a prospect i ve r and omized crossover design was used to examine the effects of two isocaloric , high-carbohydrate diets on the whole-blood glucose and insulin responses to mixed caloric intake and exercise in healthy nonpregnant ( n = 14 ) and pregnant ( n = 12 ) women . The diets differed only in the type of carbohydrate ingested . Those in one had low glycemic indexes and those in the other had high glycemic indexes . In nonpregnant women , the blood glucose response to a meal containing low-glycemic carbohydrate was half that seen with high-glycemic carbohydrate , and the effect of exercise on blood glucose was more pronounced while eating the high-glycemic carbohydrate diet . During pregnancy , women on the low-glycemic carbohydrate diet experienced no significant change in their glycemic response to mixed caloric intake , whereas those who switched to the high-glycemic carbohydrate diet experienced a 190 % increase in their response . In conclusion , the type of dietary carbohydrate in a healthy , physically active woman 's diet influences both her postpr and ial blood glucose profile and her blood sugar response to exercise [21895947] Please cite this paper as : Nascimento S , Surita F , Parpinelli M , Siani S , Pinto e Silva J. The effect of an antenatal physical exercise programme on maternal/perinatal outcomes and quality of life in overweight and obese pregnant women : a r and omised clinical trial . BJOG 2011;118:1455–1463 [26294205] Introduction and hypothesisThe objective was to assess foetal wellbeing in pregnant women subjected to pelvic floor muscle training ( PFMT ) by evaluating the acute and chronic effects of the procedure using the Doppler method . Methods Ninety-six primigravidae with singleton pregnancies and at a low risk of pregnancy complications were r and omised to either intervention with PFMT or no intervention . The final analysis included 26 women in the intervention group and 33 in the control group . Women from the intervention group were subjected to a daily PFMT program . Evidence of possible foetal risk was assessed by Doppler and the control group received st and ard care . The protocol was conducted from 20 to 36 weeks ’ gestation . The pulsatility indices ( PI ) of the uterine , umbilical and middle cerebral arteries were determined at 28 , 32 and 36 weeks ’ gestation . The acute effects were determined by comparing the values obtained before and after exercise in the group subjected to PFMT and the chronic effects were determined by comparing the resting values of the trained group with those of the control group . Results The results obtained showed normal values for the three gestational ages in both groups , with no difference between groups . Comparison before and after exercise showed a significant decline in the PI of uterine artery at 36 weeks without changes in the flow of umbilical and middle cerebral arteries . Conclusion Pelvic floor muscle training in low-risk primigravidae with singleton pregnancies was associated with a significant decline in PI of the uterine artery after exercise , while no significant changes in the flow of the middle cerebral and umbilical arteries were found . The PFMT may be recommended to women as a first-line measure to prevent of urinary incontinence during pregnancy [25518308] BACKGROUND Pelvic floor muscle exercises ( PFME ) are commonly recommended during pregnancy and after birth for both prevention and treatment of lower urinary tract symptoms ( LUTS ) . Stress urinary incontinence has long been presumed to be associated with urethral hypermobility . Pregnancy and delivery are known cause of increasing bladder neck descent ( BND ) . OBJECTIVE The present study aim ed to determine the effect of antenatal PFME on bladder neck descent in nulliparous pregnancy . MATERIAL AND METHOD 219 nulliparous women pregnant between 8 - 12 weeks were interviewed and then underwent transperineal ultrasound . Of the total , 108 women were r and omly assigned to a PFMT group , while 111 women to a control group . The latter group received routine antenatal care . For the intervention group , patients were taught about PFMT using visual biofeedback by transperineal ultrasound . The PFMT regimen comprised a series of 15 contractions , and each contraction was heldfor 5 seconds , with 5 seconds rest between each contraction . Patients were asked to repeat this regimen for 3 times after each meal . At second trimester , third trimester , 3-month postpartum and 6-month postpartum , the subjects in both groups were interviewed and then underwent another ultrasound assessment . Transperineal ultrasound was performed after bladder emptying , with the patient in the supine position . Bladder neck position was measured at rest and on maximal valsava , and the differences yielded a numerical valueforBND . The sample size was calculated with apower of80 % p<0.05 was considered significant . SPSS 15 . Ofor windows ( SPSS Inc. , Chicago , Illinois ) was used for statistical analyses . RESULTS Demographic characteristics did not differ significantly between PFMT and control groups , showing effective r and omization . Mean age was 26.95±3.94 and 26.51±5.41 years for PFMT and control group , respectively ( p = 0.49 ) . There were no significant differences in bladder symptoms between the two groups at the first visit . In the first trimester , the average BND of the PFMT group was slightly higher than BND of the control group ( 14.1±6.9 mm and 12.2±6.7 mm respectively ( p = 0.04 ) ) . When comparing delivery mode by using Pearson 's Chi-square test , there was no statistically significant difference between two groups ( p = 0.35 ) . The mean fetal birth weight of women in the PFMTgroup was 3,084 grams and in the control group was 3,093 grams ( p = 0.88 ) . At 6 monthspostpartum , 80 women of the PFMT group and 65 women of the control group returned for follow-up . There were no differences regarding the prevalence ofL UTS between the groups at 6 months after delivery . Women in the control group had a higher BND ( 16.4±6.6 mm ) than those in the PFMT group ( 13.9±7.3 mm , p = 0.03 ) . This difference was also found in the subgroup of the women who delivered vaginally ( BND = 17.5±6.7 mm in the control group and 13.2±7.4 mm in the PFMTgroup , p = 0.006 ) . CONCLUSION Although postpartum prevalence of LUTS was no different between groups , this study has demonstrated that antenatal pelvic floor muscle exercises may reduce bladder neck mobility at 6 months after childbirth . The significance of such an effect remains to be determined [7674866] To investigate the effects of participation in aerobic exercise on pregnancy outcome , 388 women ( mean age = 31.7 , range = 18 - 42 ) were followed from a mean 16.5-wk gestation through delivery . Frequency , duration , and mode of aerobic exercise prior to conception and during the first trimester were determined by in-person interviews . Activity patterns during the second and third trimesters were assessed by telephone interviews . For each time period , women were categorized into one of the following exercise groups : Level I = aerobic exercise , excluding vigorous walking , at least three times a week for at least 20 min a time ; Level II = aerobic exercise at least three times a week and 20 min at a time , if and only if vigorous walking is included ; Level III = aerobic exercise less than three times a week , 20 min a time ; and Level IV = aerobic exercise less than once a week . Mean birthweight was statistically unrelated to level of exercise preconceptionally or in any trimester . Gestational age , weight gain , and other pregnancy outcomes were also unassociated with exercise level . However , pregnancy symptoms were inversely associated with level of exercise ; women who exercised more earlier in pregnancy reported fewer discomforts later in pregnancy ( P = 0.01 ) . These data suggest that participation in aerobic exercise during pregnancy at a level great enough to produce or maintain a training effect does not adversely affect birthweight or other maternal and infant outcomes but may be associated temporally with fewer perceived pregnancy-associated discomforts [22183208] OBJECTIVE : To assess whether exercise during pregnancy can prevent gestational diabetes and improve insulin resistance . METHODS : A total of 855 women in gestational week 18–22 were r and omly assigned to receiving a 12-week st and ard exercise program ( intervention group ) or st and ard antenatal care ( control group ) . The exercise program followed st and ard recommendations and included moderate-intensity to high-intensity activity 3 or more days per week . Primary outcomes were gestational diabetes and insulin resistance estimated by the homeostasis model assessment method . For the power calculation , we assumed a gestational diabetes prevalence of 9 % in the control group and a prevalence of 4 % in the exercise group ( risk difference of 5 % ) . Under these assumptions , a two- sample comparison with a 5 % level of significance and power of 0.80 gave a study population of 381 patients in each group . RESULTS : At 32–36 weeks of gestation there were no differences between groups in prevalence of gestational diabetes : 25 of 375 ( 7 % ) in the intervention group compared with 18 of 327 ( 6 % ) in the control group ( P=.52 ) . There were no differences in insulin resistance between groups when adjusting for baseline values . Only 55 % of women in the intervention group managed to follow the recommended exercise protocol . No serious adverse events related to physical exercise were seen , and the outcomes of pregnancy were similar in the two groups . CONCLUSION : There was no evidence that offering women a 12-week st and ard exercise program during the second half of pregnancy prevents gestational diabetes or improves insulin resistance in healthy pregnant women with normal body mass indexes . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00476567 . LEVEL OF EVIDENCE : [26223239] OBJECTIVE To assess whether gestational diabetes mellitus ( GDM ) can be prevented by a moderate lifestyle intervention in pregnant women who are at high risk for the disease . RESEARCH DESIGN AND METHODS Two hundred ninety-three women with a history of GDM and /or a prepregnancy BMI of ≥30 kg/m2 were enrolled in the study at < 20 weeks of gestation and were r and omly allocated to the intervention group ( n = 155 ) or the control group ( n = 138 ) . Each subject in the intervention group received individualized counseling on diet , physical activity , and weight control from trained study nurses , and had one group meeting with a dietitian . The control group received st and ard antenatal care . The diagnosis of GDM was based on a 75-g , 2-h oral glucose tolerance test at 24–28 weeks of gestation . RESULTS A total of 269 women were included in the analyses . The incidence of GDM was 13.9 % in the intervention group and 21.6 % in the control group ( [ 95 % CI 0.40–0.98 % ] ; P = 0.044 , after adjustment for age , prepregnancy BMI , previous GDM status , and the number of weeks of gestation ) . Gestational weight gain was lower in the intervention group ( −0.58 kg [ 95 % CI −1.12 to −0.04 kg ] ; adjusted P = 0.037 ) . Women in the intervention group increased their leisure time physical activity more and improved their dietary quality compared with women in the control group . CONCLUSIONS A moderate individualized lifestyle intervention reduced the incidence of GDM by 39 % in high-risk pregnant women . These findings may have major health consequences for both the mother and the child [24652353] OBJECTIVE There is controversy concerning whether exercise during pregnancy may increase preterm delivery risk and type of delivery . The effect of pregnant Latin-American women engaging in vigorous exercise during the second and third trimester was examined regarding type of delivery and gestational age . MATERIAL S AND METHODS This was a secondary analysis of data from a controlled r and omized trial for determining the influence of physical exercise on pregnant women 's endothelial function . The study included 35 nulliparous women , gestational week 16 - 20 attending prenatal care at three tertiary hospitals in Colombia , who were r and omly assigned to one of two groups . The experimental group engaged in aerobic exercise involving 55 % - 75 % maximum heart rate for 60 min , three times a week for 12 weeks . The control group engaged in their usual physical activity . Maternal weight , height , weight gain , blood pressure and type of delivery were recorded ; gender , abdominal and head circumference ( cm ) , weight ( g ) , height ( cm ) , vitality ( Apgar score at 1 and 5 min ) and gestational age at the time of delivery ( in weeks , days ) were recorded for the newborn . RESULTS There was no difference in type of delivery by the end of the 12-week program ( p > 0.05 ) , nor regarding newborn anthropometric variables , Apgar score , or maternal variables concerning weight , height , relative weight gain , blood pressure or weeks of gestation ( p>0.05 ) . CONCLUSION The potential public health benefits of vigorous exercise were enormous . This study supported existing guidelines indicating that Latin-American women may begin or maintain an on-going exercise program during pregnancy . TRIAL REGISTRATION NCT00741312 [2890340] OBJECTIVE To examine the feasibility of an individualized exercise program to prevent gestational diabetes mellitus ( GDM ) in obese pregnant women . RESEARCH DESIGN AND METHODS The study was a pilot r and omized controlled trial with obese pregnant women ( intervention group , individualized exercise program [ n = 25 ] ; control group , usual care [ n = 25 ] ) . Average weekly energy expenditure ( MET hours per week and kilocalories per week ) of exercise-specific activity was assessed during pregnancy using the Pregnancy Physical Activity Question naire . Fasting glucose and insulin and homeostasis model assessment of insulin resistance ( HOMA-IR ) were assessed at baseline and 20 , 28 , and 36 weeks ' gestation . RESULTS Of the women in the intervention group , 16 of 22 ( 73 % ) achieved more than 900 kcal/week of exercise-based activity at 28 weeks compared with 8 of 19 women in the control group ( 42 % ) , P = 0.047 . However , insulin resistance ( HOMA-IR ) did not differ between the groups . CONCLUSION This intervention was feasible and prompted a modest increase in physical activity . However , we are not confident that this intervention would be sufficient to prevent GDM [21417561] Objectives To assess whether a 12-week supervised exercise-programme with an additional 30 min of moderate self-imposed physical activity on the non-supervised weekdays prevents excessive weight gain in pregnancy , as well as postpartum weight retention . Methods One hundred and five sedentary , nulliparous pregnant women with a mean age of 30.7 ± 4.0 years and a pre-pregnancy body mass index of 23.8 ± 4.3 kg/m2 were r and omised to either an exercise group ( EG , n = 52 ) or a control group ( CG , n = 53 ) . The exercise programme consisted of 60 min supervised aerobic dance and strength training for 60 min , at least twice per week for a minimum of 12 weeks . Results Drop-out rates were 19 % and 21 % in the EG and CG , respectively . Fewer women in the EG than in the CG exceeded the Institute of Medicine recommendations ; however , only EG participants who attended 24 exercise sessions ( n = 14 ) differed significantly from controls ( p = 0.006 ) with regard to weight gain during pregnancy ( 11.0 ± 2.3 vs. 13.8 ± 3.8 kg , p < 0.01 ) and postpartum weight retention ( 0.8 ± 1.7 vs. 3.3 ± 4.1 kg , p < 0.01 ) . Conclusions Regular participation in aerobic dance exercise can contribute to significantly reduce weight gain during pregnancy [8515355] Regular physical activity is an established therapeutic adjunct in diabetes , but has not been offered to pregnant diabetics in the past ; for sports might induce significant cardiovascular and hormonal changes that are able to reduce blood flow to the uterus and thus limit oxygen transfer to the fetus . Study ing the impact of a medically supervised exercise program on gestational diabetes mellitus [ GDM ) in a r and omised prospect i ve longitudinal study , this paper aims to assess the effects of maternal moderate and strenuous exercise on the fetus . By evaluating shortterm fetal responses as reflected in heart rate patterns ( FHR ) and longterm-pregnancy complications and neonatal outcome , our results suggest that -- in absence of ominous FHR changes or significant changes in uterine activity following the exercise sessions or increased diabetes-related peri- and neonatal morbidity -- regular physical activity seems to be a safe therapeutic option for the fetus of GDM mothers [25333246] PURPOSE The objective of this study is to assess the effectiveness of a maternal exercise program ( l and /aquatic activities , both aerobic and muscular conditioning ) in preventing gestational diabetes mellitus ( GDM ) . METHODS Three hundred and forty-two pregnant women from Spain ( age , 33.24 ± 4.3 yr ) without obstetric contraindications were recruited for a clinical r and omized controlled trial . The intervention group ( IG , n = 101 ) exercised for 60 and 50 min on l and and in water , respectively , three times per week . The control group ( n = 156 ) received usual st and ard care . RESULTS The prevalence of GDM was reduced in the IG group ( IG , 1 % , n = 1 , vs control group , 8.8 % , n = 13 ( χ1 = 6.84 , P = 0.009 ) ) with a significant risk estimate ( odds ratio = 0.103 ; 95 % confidence interval , 0.013 - 0.803 ) . CONCLUSION The exercise program performed during pregnancy reduced the prevalence of GDM by preserving glucose tolerance [15813473] BACKGROUND The main factor for the appearance of urinary stress incontinence in almost all women is pregnancy and vaginal childbirth . The pelvic floor exercises have been described for the treatment of urinary stress incontinence . OBJECTIVE To determine with a r and omized controlled trial if the pelvic floor exercises during pregnancy and late puerperium diminish the prevalence of urinary stress incontinence at 28 and 35 gestational week and at 6 weeks after childbirth . MATERIAL AND METHODS The study was made with nulliparous , pregnant women who realized pelvic floor exercises during pregnancy and after birth . 72 women were studied , 52.7 % realized pelvic floor exercises and 47.2 % did not . RESULTS The urinary stress incontinence frequency at the 28 gestational week in the no exercises group was 17.2 % , and at the 35 gestational week of 47 % and at 6 weeks after childbirth was of 47 % , while in the exercises group was 0 , 0 and 15 % , respectively . Moreover there were statistically significant differences between both groups regarding the presence of urinary stress incontinence , that is , the group that realized exercises presented less incontinence at the 28 and 35 gestational weeks and at 6 weeks after childbirth . CONCLUSIONS The results of this study concluded that the pelvic floor exercises during pregnancy and after childbirth prevent the urinary stress incontinence at this time [24200335] Purpose . The aim of the present study was to examine the influence of a program of moderate physical exercise throughout pregnancy on maternal and fetal parameters . Design . The study design was a r and omized controlled trial . Setting . The study took place at the Hospital of Fuenlabrada in Madrid , Spain . Sample . Analyzed were 200 pregnant women ( 31.54 ± 3.86 years ) , all of whom had uncomplicated and singleton gestation . Of these subjects , 107 were allocated to the exercise group ( EG ) and 93 to the control group ( CG ) . Intervention . Women from EG participated in a physical conditioning program throughout pregnancy , which included a total of 55- to 60-minute weekly sessions , 3 days per week . Measures . Pregnancy outcomes . Maternal : gestational age , weight gain , type of delivery , blood pressure during pregnancy , gestational diabetes ( n/% ) . Fetal : birth weight , birth size , head circumference , Apgar score , pH of umbilical cord . Analysis . Student 's unpaired t-test and χ2 test were used ; p values of ≤ .05 indicated statistical significance . Cohen 's d was used to determine the effect size . Results . There were significantly more pregnant women in the CG who gained excessive weight during their pregnancies than in the EG group ( CG : N = 31 , 35.6 % versus N = 22 , 21.2 % ; χ2 = 4.95 ; p = .02 ) . The effect size was small ( Phi value = .16 ) . Other pregnancy outcome showed no differences between groups . Conclusion . A regular and moderate physical exercise program throughout pregnancy is not a risk to maternal and fetal well-being , and it helps to control excessive weight gain [22616913] Please cite this paper as : Oostdam N , van Poppel M , Wouters M , Eekhoff E , Bekedam D , Kuchenbecker W , Quartero H , Heres M , van Mechelen W. No effect of the FitFor2 exercise programme on blood glucose , insulin sensitivity , and birthweight in pregnant women who were overweight and at risk for gestational diabetes : results of a r and omised controlled trial . BJOG 2012;119:1098–1107 [22464118] Eighty-four prenatally depressed women were r and omly assigned to yoga , massage therapy or st and ard prenatal care control groups to determine the relative effects of yoga and massage therapy on prenatal depression and neonatal outcomes . Following 12 weeks of twice weekly yoga or massage therapy sessions ( 20 min each ) both therapy groups versus the control group had a greater decrease on depression , anxiety and back and leg pain scales and a greater increase on a relationship scale . In addition , the yoga and massage therapy groups did not differ on neonatal outcomes including gestational age and birthweight , and those groups , in turn , had greater gestational age and birthweight than the control group [1750458] To assess the longitudinal changes in insulin release and insulin sensitivity in nonobese normal women during gestation , six women were evaluated with oral glucose tolerance testing , body composition analysis , intravenous glucose tolerance tests , and the hyperinsulinemic-euglycemic clamp before conception , at 12 to 14 weeks , and at 34 to 36 weeks ' gestation . There was a significant increase in the insulin/glucose ratio ( p = 0.028 ) during the oral glucose tolerance test during gestation . There was also a significant 3.0- to 3.5-fold increase throughout gestation in first-phase ( p = 0.001 ) and second-phase ( p = 0.0001 ) insulin release during the intravenous glucose tolerance test . Peripheral insulin sensitivity was estimated as the glucose infusion rate ( in milligrams per kilogram fat-free mass per minute ) during the hyperinsulinemic-euglycemic clamp . There was a significant ( p = 0.0003 ) 56 % decrease in insulin sensitivity through 36 weeks ' gestation . These results are the first to prospect ively evaluate the longitudinal changes in maternal carbohydrate metabolism from the time before conception through late gestation with newer methods such as the hyperinsulinemic-euglycemic clamp [26491878] BACKGROUND Smoking during pregnancy is the main preventable cause of poor birth outcomes . Improved methods are needed to help women to stop smoking during pregnancy . Pregnancy provides a compelling rationale for physical activity ( PA ) interventions as cessation medication is contraindicated or ineffective , and an effective PA intervention could be highly cost-effective . OBJECTIVE To examine the effectiveness and cost-effectiveness of a PA intervention plus st and ard behavioural support for smoking cessation relative to behavioural support alone for achieving smoking cessation at the end of pregnancy . DESIGN Multicentre , two-group , pragmatic r and omised controlled trial and economic evaluation with follow-up at the end of pregnancy and 6 months postnatally . R and omisation was stratified by centre and a computer-generated sequence was used to allocate participants using a 1 : 1 ratio . SETTING 13 hospitals offering antenatal care in the UK . PARTICIPANTS Women between 10 and 24 weeks ' gestation smoking five or more cigarettes a day before pregnancy and one or more during pregnancy . INTERVENTIONS Participants were r and omised to behavioural support for smoking cessation ( control ) or behavioural support plus a PA intervention consisting of supervised treadmill exercise plus PA consultations . Neither participants nor research ers were blinded to treatment allocation . MAIN OUTCOME MEASURES The primary outcome was self-reported , continuous smoking abstinence between a quit date and end of pregnancy , vali date d by expired carbon monoxide and /or salivary cotinine . Secondary outcomes were maternal weight , depression , birth outcomes , withdrawal symptoms and urges to smoke . The economic evaluation investigated the costs of the PA intervention compared with the control intervention . RESULTS In total , 789 women were r and omised ( n = 394 PA , n = 395 control ) . Four were excluded post r and omisation ( two had been enrolled twice in sequential pregnancies and two were ineligible and r and omised erroneously ) . The intention-to-treat analysis comprised 785 participants ( n = 392 PA , n = 393 control ) . There was no significant difference in the rate of abstinence at the end of pregnancy between the PA group ( 7.7 % ) and the control group ( 6.4 % ) [ odds ratio for PA group abstinence 1.21 , 95 % confidence interval ( CI ) 0.70 to 2.10 ] . For the PA group compared with the control group , there was a 33 % ( 95 % CI 14 % to 56 % ) , 28 % ( 95 % CI 7 % to 52 % ) and 36 % ( 95 % CI 12 % to 65 % ) significantly greater increase in self-reported minutes of moderate- and vigorous-intensity PA from baseline to 1 week , 4 weeks and 6 weeks respectively . Accelerometer data showed that there was no significant difference in PA levels between the groups . There were no significant differences between the groups for change in maternal weight , depression , withdrawal symptoms or urges to smoke . Adverse events and birth outcomes were similar between the groups except for there being significantly more caesarean births in the control group than in the PA group ( 28.7 % vs. 21.3 % ; p < 0.023 ) . The PA intervention was less costly than the control intervention by £ 35 per participant . This was mainly attributable to increased health-care usage in the control group . However , there was considerable statistical uncertainty around this estimate . CONCLUSIONS During pregnancy , offering an intervention combining supervised exercise and PA counselling does not add to the effectiveness of behavioural support for smoking cessation . Only 10 % of participants had PA levels accessed by accelerometer and it is , therefore , unclear whether or not the lack of an effect on the primary outcome is the result of insufficient increases in PA . Research is needed to identify the smoking population s most suitable for PA interventions and methods for increasing PA adherence . TRIAL REGISTRATION Current Controlled Trials IS RCT N48600346 . FUNDING This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol . 19 , No. 84 . See the NIHR Journals Library website for further project information [22843114] OBJECTIVE A prospect i ve r and omized controlled trial was design ed to assess the benefits and possible risks of aerobic exercise during pregnancy , using a fitness regimen based on the 2002 American College of Obstetricians and Gynecologists guidelines for exercise during pregnancy . METHODS Inactive women were r and omized at 12 - 14 wk gestation to a group that remained sedentary or to a group that performed moderate aerobic exercise 45 - 60 min , 4 d·wk , through 36 wk gestation . Thirty-one subjects in each group completed the study . RESULTS Compared with women who remained sedentary , active women improved aerobic fitness ( P < 0.05 ) and muscular strength ( P < 0.01 ) , delivered comparable size infants with significantly fewer cesarean deliveries ( P < 0.01 ) , and recovered faster postpartum ( P < 0.05 ) , at least related to the lower incidence of cesarean section . Active women developed no gestational hypertension ( P = 0.16 compared with controls ) and reported no injuries related to the exercise regimen . In the active group , there was one premature birth at 33 wk by a woman with a history of premature delivery of twins at 34 wk . There were no differences between groups in the incidence of gestational diabetes , musculoskeletal pains during pregnancy , flexibility on sit- and -reach test , mean length of pregnancy , neonatal Apgar scores , placenta weights , overall length of labor , weight gain during pregnancy , or weight retention postpartum . CONCLUSION Previously sedentary women who began exercising at 12 - 14 wk improved fitness and delivery outcomes [6513772] The interaction between maternal endurance exercise at or above a minimal conditioning level , prior to and during pregnancy , and pregnancy outcome was examined prospect ively in our obstetrical populace using epidemiologic techniques . Over a 3-month interval all women registering for antepartum care were interviewed . Those planning to continue exercise during pregnancy were re-interviewed between the 28th and 34th gestational weeks . A detailed review of clinical records was used for outcome assessment . Women who continued endurance exercise at or near preconceptual levels during pregnancy gained less weight ( -4.6 kg ) , delivered earlier (-8 d ) , and had lighter-weight offspring ( -500 g ) than those who stopped exercising prior to the 28th week . The latter group gained 2.2 kg more weight but delivered similar birthweight infants at a similar gestational age as their sedentary controls [30337348] Objective Theoretical concerns regarding the supine position at rest due to the gravid uterus obstructing aorta and vena caval flow may impinge uterine blood flow ( UBF ) to the fetus and maternal venous return . Design Systematic review . Data sources Online data bases up to 11 December 2017 . Study criteria Eligible population ( pregnant without contraindication to exercise ) , intervention ( frequency , intensity , duration , volume or type of supine exercise ) , comparator ( no exercise or exercise in left lateral rest position , upright posture or other supine exercise ) , outcomes ( potentially adverse effects on maternal blood pressure , cardiac output , heart rate , oxygen saturation , fetal movements , UBF , fetal heart rate ( FHR ) patterns ; adverse events such as bradycardia , low birth weight , intrauterine growth restriction , perinatal mortality and other adverse events as documented by study authors ) , and study design ( except case studies and review s ) published in English , Spanish , French or Portuguese . Results Seven studies ( n=1759 ) were included . ‘ Very low ’ to ‘ low ’ quality evidence from three r and omised controlled trials indicated no association between supervised exercise interventions that included supine exercise and low birth weight compared with no exercise . There was ‘ very low ’ to ‘ low ’ quality evidence from four observational studies that showed no adverse events in the mother ; however , there were abnormal FHR patterns ( as defined by study authors ) in 20 of 65 ( 31 % ) fetuses during an acute bout of supine exercise . UBF decreased ( 13 % ) when women moved from left lateral rest to acute dynamic supine exercise . Conclusion There was insufficient evidence to ascertain whether maternal exercise in the supine position is safe or should be avoided during pregnancy [23224059] Background — Preterm birth leads to an early switch from fetal to postnatal circulation before completion of left ventricular in utero development . In animal studies , this results in an adversely remodeled left ventricle . We determined whether preterm birth is associated with a distinct left ventricular structure and function in humans . Methods and Results — A total of 234 individuals 20 to 39 years of age underwent cardiovascular magnetic resonance . One hundred two had been followed prospect ively since preterm birth ( gestational age=30.3±2.5 week ; birth weight=1.3±0.3 kg ) , and 132 were born at term to uncomplicated pregnancies . Longitudinal and short-axis cine images were used to quantify left ventricular mass , 3-dimensional geometric variation by creation of a unique computational cardiac atlas , and myocardial function . We then determined whether perinatal factors modify these left ventricular parameters . Individuals born preterm had increased left ventricular mass ( 66.5±10.9 versus 55.4±11.4 g/m2 ; P<0.001 ) with greater prematurity associated with greater mass ( r = −0.22 , P=0.03 ) . Preterm-born individuals had short left ventricles with small internal diameters and a displaced apex . Ejection fraction was preserved ( P>0.99 ) , but both longitudinal systolic ( peak strain , strain rate , and velocity , P<0.001 ) and diastolic ( peak strain rate and velocity , P<0.001 ) function and rotational ( apical and basal peak systolic rotation rate , P = 0.05 and P = 0.006 ; net twist angle , P=0.02 ) movement were significantly reduced . A diagnosis of preeclampsia during the pregnancy was associated with further reductions in longitudinal peak systolic strain in the offspring ( P=0.02 , n=29 ) . Conclusions — Individuals born preterm have increased left ventricular mass in adult life . Furthermore , they exhibit a unique 3-dimensional left ventricular geometry and significant reductions in systolic and diastolic functional parameters . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT01487824 [24646172] The benefits of exercise and behavioural recommendations in gestational diabetes mellitus ( GDM ) are controversial . In a r and omized trial with a 2 × 2 factorial design , we examined the effect of exercise and behavioural recommendations on metabolic variables , and maternal/neonatal outcomes in 200 GDM patients . All women were given the same diet : group D received dietary recommendations only ; group E was advised to briskly walk 20‐min/day ; group B received behavioural dietary recommendations ; group BE was prescribed the same as B + E. Dietary habits improved in all groups . In a multivariable regression model , fasting glucose did not change . Exercise , but not behavioural recommendations , was associated with the reduction of postpr and ial glucose ( p < 0001 ) , glycated haemoglobin ( HbA1c ; p < 0.001 ) , triglycerides ( p = 0.02 ) and C‐reactive protein ( CRP ; p < 0.001 ) and reduced any maternal/neonatal complications ( OR = 0.50 ; 95%CI=0.28–0.89;p = 0.02 ) . In GDM patients a simple exercise programme reduced maternal postpr and ial glucose , HbA1c , CRP , triglycerides and any maternal/neonatal complications , but not fasting glucose values [24060449] OBJECTIVE The objective of the study was to assess physical activity intervention assessed by a pedometer with or without dietary intervention on gestational weight gain ( GWG ) in obese pregnant women by comparing with a control group . STUDY DESIGN This study was a r and omized controlled trial of 425 obese pregnant women comparing 3 groups : ( 1 ) PA plus D , physical activity and dietary intervention ( n = 142 ) ; ( 2 ) PA , physical activity intervention ( n = 142 ) ; and ( 3 ) C , a control group receiving st and ard care ( n = 141 ) . All participants routinely in gestational weeks 11 - 14 had an initial dietary counseling session and were advised to limit GWG to less than 5 kg . Physical activity intervention included encouragement to increase physical activity , aim ing at a daily step count of 11,000 , monitored by pedometer assessment on 7 consecutive days every 4 weeks . Dietary intervention included follow-up on a hypocaloric Mediterranean-style diet . Instruction was given by a dietician every 2 weeks . The primary outcome measure was GWG , and the secondary outcome measures were complications of pregnancy and delivery and neonatal outcome . RESULTS The study was completed by 389 patients ( 92 % ) . Median values of GWG ( ranges ) were lower in each of the intervention groups ( PA plus D , 8.6 [ -9.6 to 34.1 ] kg , and group PA , 9.4 [ -3.4 to 28.2 ] kg ) compared with the control group ( 10.9 [ -4.4 to 28.7 ] kg [ PA+D vs C ] ; P = .01 ; PA vs C ; P = .042 ) . No significant difference was found between the 2 intervention groups . In a multivariate analysis , physical activity intervention decreased GWG by a mean of 1.38 kg ( P = .040 ) . The Institute of Medicine 's recommendations for GWG were more frequently followed in the intervention groups . CONCLUSION Physical activity intervention assessed by pedometer with or without dietary follow-up reduced GWG compared with controls in obese pregnant women [22898328] OBJECTIVE The level of physical activity ( PA ) of pregnant women in Finl and is unknown . Even more limited is our knowledge of PA of women at high risk for gestational diabetes mellitus ( GDM ) . METHODS The women ( n=54 ) were r and omly assigned to a lifestyle intervention group ( n=27 ) including exercise advice by a physiotherapist six times during pregnancy or to a control group ( n=27 ) without additional exercise advice . Outcomes of the present study were required sample size , timing of counselling and change of PA . PA was retrospectively reported during 12 months before pregnancy and recorded one week monthly during pregnancy . RESULTS Individualized counselling by a physiotherapist result ed in small changes of recreational PA ( 2.7 MET hours/week , p=0.056 ) up to gestational week 25 compared with the similar decreasing tendency of PA in the control group . The women decreased recreational PA after week 30 . Sample size of 550 women at high risk for GDM per group would be needed for a PA study . CONCLUSIONS The optimal time window for increasing PA must be earlier than in the last trimester of pregnancy . Sample size for a study to increase PA by 2.7 MET hours/week on pregnant women at high risk of GDM should be about 550 per group [3096610] In a cluster-r and omized trial , Riitta Luoto and colleagues find that counseling on diet and activity can reduce the birthweight of babies born to women at risk of developing gestational diabetes mellitus ( GDM ) , but fail to find an effect on GDM [24175912] Abstract Objectives : To determine whether changes in lifestyle in women with BMI > 25 could decrease gestational weight gain and unfavorable pregnancy outcomes . Methods : Women with BMI > 25 were r and omized at 1st trimester to no intervention or a Therapeutic Lifestyle Changes ( TLC ) Program including diet ( overweight : 1700 kcal/day , obese : 1800 kcal/day ) and mild physical activity ( 30 min/day , 3 times/week ) . At baseline and at the 36th week women filled-in a Food Frequency Question naire . Outcomes : gestational weight gain , gestational diabetes mellitus , gestational hypertension , preterm delivery . Data stratified by BMI categories . Results : Socio-demographic features were similar between groups ( TLC : 33 cases , Controls : 28 cases ) . At term , gestational weight gain in obese women r and omized to TLC group was lower ( 6.7 ± 4.3 kg ) versus controls ( 10.1 ± 5.6 kg , p = 0.047 ) . Gestational diabetes mellitus , gestational hypertension and preterm delivery were also significantly lower . TLC was an independent factor in preventing gestational weight gain , gestational diabetes mellitus , gestational hypertension . Significant changes in eating habits occurred in the TLC group , which increased the number of snacks , the intake of fruits – vegetables and decreased the consumption of sugar . Conclusions : A caloric restriction associated to changes in eating behavior and constant physical activity , is able to reduce gestational weight gain and related pregnancy complications in obese women [21310836] BACKGROUND Excessive weight gain during pregnancy is a major risk factor for postpartum weight retention and future weight gain and obesity in women , but few adequately powered r and omized controlled trials have examined the efficacy of a behavioral weight-control intervention during pregnancy . OBJECTIVE This study examined whether a behavioral intervention during pregnancy could decrease the proportion of women who exceeded the 1990 Institute of Medicine ( IOM ) recommendations for gestational weight gains and increase the proportion of women who returned to pregravid weights by 6 mo postpartum . DESIGN This study was a r and omized , assessor-blind , controlled trial . Participants were pregnant ( 13.5 wk gestation ) , normal-weight ( NW ; n = 201 ) and overweight or obese ( OW/OB ; n = 200 ) women whose average age was 28.8 y. Participants were r and omly assigned within the 1990 IOM weight category ( NW compared with OW/OB ) to st and ard care ( n = 200 ) or to a behavioral intervention to prevent excessive gestational weight gain ( n = 201 ) . The intervention included one face-to-face visit ; weekly mailed material s that promoted an appropriate weight gain , healthy eating , and exercise ; individual graphs of weight gain ; and telephone-based feedback . The retention at the 6-mo postpartum assessment was 82 % . RESULTS Intent-to-treat analyses showed that the intervention , compared with st and ard care , decreased the percentage of NW women who exceeded IOM recommendations ( 40.2 % compared with 52.1 % ; P = 0.003 ) and increased the percentages of NW and OW/OB women who returned to their pregravid weights or below by 6 mo postpartum ( 30.7 % compared with 18.7 % ; P = 0.005 ) . CONCLUSION A low-intensity behavioral intervention during pregnancy reduced excessive gestational weight gains in NW women and prevented postpartum weight retention in NW and OW/OB women . This trial was registered at clinical trials.gov as NCT01117961

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### Context: [3120183] OBJECTIVE To pilot , among women with gestational diabetes mellitus ( GDM ) , the feasibility of a prenatal/postpartum intervention to modify diet and physical activity similar to the Diabetes Prevention Program . The intervention was delivered by telephone , and support for breastfeeding was addressed . RESEARCH DESIGN AND METHODS The goal was to help women return to their prepregnancy weight , if it was normal , or achieve a 5 % reduction from prepregnancy weight if overweight . Eligible participants were identified shortly after a GDM diagnosis ; 83.8 % consented to be r and omly assigned to intervention or usual medical care ( 96 and 101 women , respectively ) . The retention was 85.2 % at 12 months postpartum . RESULTS The proportion of women who reached the postpartum weight goal was higher , although not statistically significant , in the intervention condition than among usual care ( 37.5 vs. 21.4 % , absolute difference 16.1 % , P = 0.07 ) . The intervention was more effective among women who did not exceed the recommended gestational weight gain ( difference in the proportion of women meeting the weight goals : 22.5 % , P = 0.04 ) . The intervention condition decreased dietary fat intake more than the usual care ( condition difference in the mean change in percent of calories from fat : −3.6 % , P = 0.002 ) and increased breastfeeding , although not significantly ( condition difference in proportion : 15.0 % , P = 0.09 ) . No differences in postpartum physical activity were observed between conditions . CONCLUSIONS This study suggests that a lifestyle intervention that starts during pregnancy and continues postpartum is feasible and may prevent pregnancy weight retention and help overweight women lose weight . Strategies to help postpartum women overcome barriers to increasing physical activity are needed [27607876] OBJECTIVE : To investigate the effect of a supervised home-based exercise program on the recurrence and severity of gestational diabetes mellitus ( GDM ) together with other aspects of maternal health and obstetric and neonatal outcomes . METHODS : This r and omized controlled trial allocated women with a history of GDM to an exercise intervention ( 14-week supervised home-based stationary cycling program ) or to a control group ( st and ard care ) at 13±1 weeks of gestation . The primary outcome was a diagnosis of GDM . Secondary outcomes included maternal fitness , psychological well-being , and obstetric and neonatal outcomes . A sample size of 180 ( 90 in each group ) was required to attain 80 % power to detect a 40 % reduction in the incidence of GDM . RESULTS : Between June 2011 and July 2014 , 205 women provided written consent and completed baseline assessment s. Of these , 33 ( 16 % ) were subsequently excluded as a result of an elevated baseline oral glucose tolerance test ( OGTT ) , leaving 172 r and omized to exercise ( n=85 ) or control ( n=87 ) . Three women miscarried before the assessment of outcome measures ( control=2 ; exercise=1 ) . All remaining women completed the postintervention OGTT . The recurrence rate of GDM was similar between groups ( control 40 % [ n=34 ] ; exercise 40.5 % [ n=34 ] ; P=.95 ) and the severity of GDM at diagnosis was unaffected by the exercise program with similar glucose and insulin responses to the OGTT ( glucose 2 hours post-OGTT 7.7±1.5 compared with 7.6±1.6 mmol/L ; P>.05 ) . Maternal fitness was improved by the exercise program ( P<.01 ) and psychological distress was reduced ( P=.02 ) . There were no differences in obstetric and neonatal outcomes between groups ( P>.05 ) . CONCLUSION : Supervised home-based exercise started at 14 weeks of gestation did not prevent the recurrence of GDM ; however , it was associated with important benefits for maternal fitness and psychological well-being . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , https:// clinical trials.gov , NCT01283854 [29214130] To identify adherence required to achieve target health outcome ( s ) in nutrition and /or exercise interventions , a measurement tool that tracks objective and self-reported measures of adherence is necessary . The purpose of this study was to design an adherence measurement tool and test it retrospectively on the Nutrition and Exercise Lifestyle Intervention Program ( NELIP ; Ruchat et al. , Medicine and Science in Sports and Exercise , 44(8 ) , 1419–1426 , 2012 ; Mottola et al. , Medicine and Science in Sports and Exercise , 42(2 ) , 265–272 , 2010 ) , design ed to prevent excessive gestational weight gain ( EGWG ) . The tool was based on the goals of the NELIP and included a grading system for each behavior ( exercise and nutrition ) . It was used to determine whether adherence scores could differentiate excessive versus acceptable weight gain during pregnancy across pre-pregnancy body mass index ( BMI ) categories . Results showed irrespective of pre-pregnancy BMI , women with acceptable weight gain had significantly higher adherence ( p < 0.05 ) than women with excessive weight gain . It is recommended that this adherence tool be included in future prospect i ve lifestyle intervention studies [2628875] Background To evaluate the effectiveness and safety of water aerobics during pregnancy . Methods A r and omized controlled trial carried out in 71 low-risk sedentary pregnant women , r and omly allocated to water aerobics or no physical exercise . Maternal body composition and perinatal outcomes were evaluated . For statistical analysis Chi-square , Fisher 's or Student 's t-tests were applied . Risk ratios and their 95 % CI were estimated for main outcomes . Body composition was evaluated across time using MANOVA or Friedman multiple analysis . Results There were no significant differences between the groups regarding maternal weight gain , BMI or percentage of body fat during pregnancy . Incidence of preterm births ( RR = 0.84 ; 95%CI:0.28–2.53 ) , vaginal births ( RR = 1.24 ; 95%CI:0.73–2.09 ) , low birthweight ( RR = 1.30 ; 95%CI:0.61–2.79 ) and adequate weight for gestational age ( RR = 1.50 ; 95%CI:0.65–3.48 ) were also not significantly different between groups . There were no significant differences in systolic and diastolic blood pressure and heart rate between before and immediately after the water aerobics session . Conclusion Water aerobics for sedentary pregnant women proved to be safe and was not associated with any alteration in maternal body composition , type of delivery , preterm birth rate , neonatal well-being or weight [25412300] PURPOSE The purpose of the study was to determine the effect of a home-based cycling program for women with a recent diagnosis of gestational diabetes mellitus ( GDM ) on aerobic fitness , weight gain , self-reported mobility , attitude , and intentions toward maternal exercise , and obstetric and neonatal outcomes . METHODS Forty women ( mean ± SD , 28.8 ± 0.9-wk gestation ) were r and omized to either a supervised , home-based exercise program , combining continuous steady-state and interval cycling at various intensities , in combination with unsupervised moderate intensity aerobic activity and conventional diabetic management ( EX ; n = 20 ) or to conventional management alone ( CON ; n = 20 ) . The program began following diagnosis until week 34 of pregnancy ( mean ± SD duration of training , 6 ± 1 wk ) . RESULTS Mean compliance to the training program was 96 % . Maternal aerobic fitness , and attitude and intentions toward exercise were improved in response to the home-based exercise intervention compared with CON ( P < 0.05 ) . No differences were observed between the groups with respect to maternal weight gain or obstetric and neonatal outcomes ( P > 0.05 ) . CONCLUSION A home-based exercise program of 6 ± 1 wk in duration commenced after diagnosis of GDM can improve aerobic fitness and attitude and intentions toward exercise , with no adverse effect on maternal and neonatal pregnancy outcomes [24002348] INTRODUCTION Walking may be a strategy for increasing moderate-intensity physical activity ( MPA ) during pregnancy . PURPOSE This study aim ed to promote MPA among overweight and obese pregnant women , via walking , and to evaluate the effect of the intervention on maternal and birth outcomes . METHODS Thirty-seven overweight or obese pregnant women were r and omly assigned to a walking intervention or control group . Anthropometric and objective PA ( StepWatch ™ Activity Monitor ) data were collected for four 1-wk periods : weeks 10 - 14 ( V1 ) , weeks 17 - 19 ( V2 ) , weeks 27 - 29 ( V3 ) , and weeks 34 - 36 ( V4 ) of gestation . Participants provided information about maternal and birth outcomes . A cadence of ≥ 80 steps per minute was defined as MPA , and " meaningful walking " was defined as moderate walking in ≥ 8-min bouts . ANOVA was used to determine the differences in walking amount and meaningful walks , the Kolmogorov-Smirnov test was used for walking intensity distribution analysis , and Fisher 's exact test was used for maternal and infant outcomes analyses . Pearson correlation was used to examine the association between prepregnancy body mass index and gestational weight gain ( GWG ) . RESULTS There was significantly more MPA among women in the intervention group compared with those in the control group at V2 ( overweight , P < 0.0001 ; obese , P < 0.025 ) , V3 ( overweight , P < 0.0001 ) , and V4 ( overweight , P < 0.0001 ; obese , P < 0.025 ) . Women in the intervention group significantly increased their meaningful walks at V2 ( P = 0.054 ) , V3 ( P = 0.01 ) , and V4 ( P = 0.014 ) . There were trends for intervention group women to have more favorable maternal and birth outcomes compared with the control group . Rates of GWG at measurement points during pregnancy were significantly associated with preceding rates of GWG . CONCLUSION The pilot , unsupervised walking intervention increased the MPA of overweight and obese women during pregnancy [2467402] Background Previous publications indicate that acupuncture is efficient for the treatment of pelvic girdle pain , PGP , in pregnant women . However , the use of acupuncture for PGP is rare due to insufficient documentation of adverse effects of this treatment in this specific condition . The aim of the present work was to assess adverse effects of acupuncture on the pregnancy , mother , delivery and the fetus/neonate in comparison with women that received stabilising exercises as adjunct to st and ard treatment or st and ard treatment alone . Methods In all , 386 women with PGP entered this controlled , single-blind trial . They were r and omly assigned to st and ard treatment plus acupuncture ( n = 125 ) , st and ard treatment plus specific stabilising exercises ( n = 131 ) or to st and ard treatment alone ( n = 130 ) for 6 weeks . Acupuncture that may be considered strong was used and treatment was started as early as in the second trimester of pregnancy . Adverse effects were recorded during treatment and throughout the pregnancy . Influence on the fetus was measured with cardiotocography ( CTG ) before-during and after 43 acupuncture sessions in 43 women . A st and ardised computerized method to analyze the CTG reading numerically ( Oxford 8000 , Oxford , Engl and ) was used . After treatment , the women rated their overall experience of the treatment and listed adverse events if any in a question naire . Data of analgesia and oxytocin augmentation during labour , duration of labour , frequency of preterm birth , operative delivery , Apgar score , cord-blood gas/acid base balance and birth weight were also recorded . Results There were no serious adverse events after any of the treatments . Minor adverse events were common in the acupuncture group but women rated acupuncture favourably even despite this . The computerized or visually assessed CTG analyses of antenatal recordings in connection with acupuncture were all normal . Conclusion This study shows that acupuncture administered with a stimulation that may be considered strong led to minor adverse complaints from the mothers but had no observable severe adverse influences on the pregnancy , mother , delivery or the fetus/neonate [27935767] Context Lifestyle approaches for preventing gestational diabetes mellitus ( GDM ) have produced mixed results . Objective The aim of the present study was to compare the effectiveness of 3 lifestyle interventions [ healthy eating ( HE ) , physical activity ( PA ) , and both HE and PA ( HE+PA ) ] with usual care ( UC ) in reducing GDM risk . Design The present study was a multicenter r and omized controlled trial conducted from 2012 to 2014 [ the DALI ( vitamin D and lifestyle intervention for GDM prevention ) lifestyle study ] . Setting The study occurred at antenatal clinics across 11 centers in 9 European countries . Patients Consecutive pregnant women at < 20 weeks of gestation with a body mass index ( BMI ) of ≥29 kg/m2 and without GDM using the International Association of Diabetes and Pregnancy Study Group criteria ( n = 436 ) . For the intervention , women were r and omized , stratified by site , to UC , HE , PA , or HE+PA . The women received 5 face-to-face and ≤4 telephone coaching sessions using the principles of motivational interviewing . A gestational weight gain ( GWG ) < 5 kg was targeted . The coaches received st and ardized training and an intervention toolkit tailored to their culture and language . Main Outcome Measures The endpoints were the GWG at 35 to 37 weeks and the fasting glucose and insulin sensitivity [ homeostasis model assessment insulin resistance ( HOMA-IR ) ] at 24 to 28 weeks . Results We r and omized 108 women to HE+PA , 113 to HE , 110 to PA , and 105 to UC . In the HE+PA group , but not HE or PA alone , women achieved substantially less GWG than did the controls ( UC ) by 35 to 37 weeks ( -2.02 ; 95 % confidence interval , -3.58 to -0.46 kg ) . Despite this reduction , no improvements were seen in fasting or postload glucose levels , insulin concentrations , or HOMA-IR . The birthweights and large and small for gestational age rates were similar . Conclusions The combined HE+PA intervention was able to limit GWG but did not reduce fasting glycemia . Thus , lifestyle changes alone are unlikely to prevent GDM among women with a BMI of ≥29 kg/m2 [27622854] ABSTRACT Accumulating research indicates that the regular practice of physical exercise is beneficial to the human brain . From the improvement of academic achievement in children to the prevention of Alzheimer ’s disease in the elderly , exercise appears beneficial across the developmental spectrum . Recent work from animal studies also indicates that a pregnant mother can transfer the benefits of exercise during gestation to her offspring ’s brain . Exercising pregnant rats give birth to pups that have better memory and spatial learning as well as increased synaptic density . To investigate whether this transfer from the pregnant mother to her child also occurs in humans , we conducted a r and omized controlled trial ( n = 18 ) and measured the impact of exercise during pregnancy on the neuroelectric response of the neonatal brain with electroencephalography ( EEG ) . Here we show that , compared to the newborns of mothers who were inactive during their pregnancy , the children of exercising pregnant women are born with more mature brains . This was measured with the infant slow positive mismatch response ( SPMMR ) , an electroencephalographic potential known to decrease in amplitude with age . The SPMMR reflects processes associated with brain maturation via its response to sound discrimination and auditory memory . In this study , the children of the mothers who exercised throughout their pregnancy have a smaller SPMMR than the children of mothers who remained sedentary ( p = .019 ) . Our results demonstrate the impact regular exercise during pregnancy can have on the development of the human fetal brain [18396254] This study examined the effects of a yoga program during pregnancy , on maternal comfort , labor pain , and birth outcomes . A r and omized trial was conducted using 74-primigravid Thai women who were equally divided into two groups ( experimental and control ) . The yoga program involved six , 1-h sessions at prescribed weeks of gestation . A variety of instruments were used to assess maternal comfort , labor pain and birth outcomes . The experimental group was found to have higher levels of maternal comfort during labor and 2h post-labor , and experienced less subject evaluated labor pain than the control group . In each group , pain increased and maternal comfort decreased as labor progressed . No differences were found , between the groups , regarding pethidine usage , labor augmentation or newborn Apgar scores at 1 and 5 min . The experimental group was found to have a shorter duration of the first stage of labor , as well as the total time of labor [3718707] Background Excessive gestational weight gain ( GWG ) is associated with short- and long-term health problems among mothers and their offspring . There is a strong need for effective intervention strategies targeting excessive GWG to prevent adverse outcomes . Methods We performed a cluster-r and omized controlled intervention trial in eight gynecological practice s evaluating the feasibility and effectiveness of a lifestyle intervention presented to all pregnant women ; 250 healthy , pregnant women were recruited for the study . The intervention program consisted of two individually delivered counseling sessions focusing on diet , physical activity , and weight monitoring . The primary outcome was the proportion of pregnant women exceeding weight gain recommendations of the Institute of Medicine ( IOM ) . Secondary outcome variables were maternal weight retention and short-term obstetric and neonatal outcomes . Results The intervention result ed in a lower proportion of women exceeding IOM guidelines among women in the intervention group ( 38 % ) compared with the control group ( 60 % ) ( odds ratio ( OR ) : 0.5 ; 95 % confidence interval ( CI ) : 0.3 to 0.9 ) without prompting an increase in the proportion of pregnancies with suboptimal weight gain ( 19 % vs. 21 % ) . Participants in the intervention group gained significantly less weight than those in the control group . Only 17 % of the women in the intervention group showed substantial weight retention of more than 5 kg compared with 31 % of those in the control group at month four postpartum ( pp ) ( OR : 0.5 ; 95 % CI : 0.2 to 0.9 ) . There were no significant differences in obstetric and neonatal outcomes . Conclusions Lifestyle counseling given to pregnant women reduced the proportion of pregnancies with excessive GWG without increasing suboptimal weight gain , and may exert favorable effects on pp weight retention . Trial registration German Clinical Trials Register DRKS00003801 [22865627] BACKGROUND Exercise may influence glucose metabolism during pregnancy . We examined the effect of exercise intensity and duration on capillary glucose responses in pregnant women at low and high risk for gestational diabetes mellitus ( GDM ) who followed a modified GDM meal plan . METHODS R and omization occurred at study entry ( 16 - 20 weeks ' gestation ) into a low-intensity [ 30 % heart rate reserve , low risk-30%I , n = 12 ; high risk-30%I , n = 11 ] or vigorous-intensity ( 70 % heart rate reserve , low risk-70%I , n = 12 ; R-70%I , n = 11 ) exercise program with similar nutritional control . Exercise consisted of walking three to four times a week , gradually increasing time from 25 to 40 min/session . Free-living capillary glucose concentrations were measured once a week pre-exercise and post-exercise . RESULTS Capillary glucose responses to exercise were strongly influenced by an interaction between GDM risk , exercise duration and exercise intensity ( p = 0.006 ) . Decreases in glucose concentrations were observed after 25 ( 4 ± 13 % ) , 35 ( 21 ± 12 % ) and 40 min ( 15 ± 18 % ) of walking in high risk-30%I women , with the most noticeable decline after 35 and 40 min . In the high risk-70%I , glucose concentrations decreased significantly only after 25 ( 22 ± 14 % ) and 35 min ( 7 ± 23 % ) and increasing the exercise time attenuated glucose concentrations decline . In low risk women , regardless of exercise intensity and duration , decreases in glucose concentrations were significant and similar . CONCLUSION To achieve the best decline in glucose concentrations , pregnant women who follow a modified GDM meal plan should walk for 25 min/session at vigorous intensity or for 35 - 40 min/session at low intensity if they are at risk for GDM and for at least 25 min at either low or vigorous intensity if they are at low risk for GDM [25350037] AIM The effect of exercise training during the course of pregnancy on the newborn 's birth weight is unclear . This study examines the effect of aerobic and strength conditioning exercise performed during the second and the third trimester of pregnancy in nulliparous , previously inactive women on the newborn 's outcome . METHODS Sixty-three nulliparous , previously sedentary , were r and omly assigned to either an exercise ( N.=30 ) or a control ( N.=33 ) group . The subjects participated in the exercise group ( EG ) focused on aerobic and strength-conditioning exercise in three sessions for about 20 weeks . We registered the birth weight , birth length , gestational age at time of delivery , Apgar score and head circumference of the newborn . RESULTS There were no statistically significant differences between the two groups in mean birth weight , length , head circumference , and length of gestation . There was a significant difference between two groups in Apgar scores at 1 min ( P=0.036 ) and 5 min ( P=0.015 ) with newborns of the EG scoring higher than the CG . CONCLUSION Supervised , aerobic and strength conditioning exercise performed over the second and third trimester of pregnancy does not have a negative impact on the newborn 's body size and health [21459255] OBJECTIVE To determine if an interactive , computerized Video Doctor counseling tool improves self-reported diet and exercise in pregnant women . METHODS A r and omized trial comparing a Video Doctor intervention to usual care in ethnically diverse , low-income , English-speaking pregnant women was conducted . Brief messages about diet , exercise , and weight gain were delivered by an actor-portrayed Video Doctor twice during pregnancy . RESULTS In the Video Doctor group ( n=158 ) , there were statistically significant increases from baseline in exercise ( + 28 min ) , intake of fruits and vegetables , whole grains , fish , avocado and nuts , and significant decreases in intake of sugary foods , refined grains , high fat meats , fried foods , solid fats , and fast food . In contrast , there were no changes from baseline for any of these outcomes in the usual care group ( n=163 ) . Nutrition knowledge improved significantly over time in both groups but more so in the Video Doctor group . Clinician-patient discussion s about these topics occurred significantly more frequently in the Video Doctor group . There was no difference in weight gain between groups . CONCLUSION A brief Video Doctor intervention can improve exercise and dietary behaviors in pregnant women . PRACTICE IMPLICATION S The Video Doctor can be integrated into prenatal care to assist clinicians with effective diet and exercise counseling [26165396] BACKGROUND Behavioural interventions might improve clinical outcomes in pregnant women who are obese . We aim ed to investigate whether a complex intervention addressing diet and physical activity could reduce the incidence of gestational diabetes and large-for-gestational-age infants . METHODS The UK Pregnancies Better Eating and Activity Trial ( UPBEAT ) is a r and omised controlled trial done at antenatal clinics in eight hospitals in multi-ethnic , inner-city locations in the UK . We recruited pregnant women ( 15 - 18 weeks plus 6 days of gestation ) older than 16 years who were obese ( BMI ≥30 kg/m(2 ) ) . We r and omly assigned participants to either a behavioural intervention or st and ard antenatal care with an internet-based , computer-generated , r and omisation procedure , minimising by age , ethnic origin , centre , BMI , and parity . The intervention was delivered once a week through eight health trainer-led sessions . Primary outcomes were gestational diabetes ( diagnosed with an oral glucose tolerance test and by criteria from the International Association of Diabetes in Pregnancy Study Groups ) and large-for-gestational-age infants ( ≥90th customised birthweight centile ) . Analysis was by intention to treat . This trial is registered with Current Controlled Trials , ISCRTN89971375 . Recruitment and pregnancy outcomes are complete but childhood follow-up is ongoing . FINDINGS Between March 31 , 2009 , and June 2 , 2014 , we assessed 8820 women for eligibility and recruited 1555 , with a mean BMI of 36·3 kg/m(2 ) ( SD 4·8 ) . 772 were r and omly assigned to st and ard antenatal care and 783 were allocated the behavioural intervention , of which 651 and 629 women , respectively , completed an oral glucose tolerance test . Gestational diabetes was reported in 172 ( 26 % ) women in the st and ard care group compared with 160 ( 25 % ) in the intervention group ( risk ratio 0·96 , 95 % CI 0·79 - 1·16 ; p=0·68 ) . 61 ( 8 % ) of 751 babies in the st and ard care group were large for gestational age compared with 71 ( 9 % ) of 761 in the intervention group ( 1·15 , 0·83 - 1·59 ; p=0·40 ) . Thus , the primary outcomes did not differ between groups , despite improvements in some maternal secondary outcomes in the intervention group , including reduced dietary glycaemic load , gestational weight gain , and maternal sum-of-skinfold thicknesses , and increased physical activity . Adverse events included neonatal death ( two in the st and ard care group and three in the intervention group ) and fetal death in utero ( ten in the st and ard care group and six in the intervention group ) . No maternal deaths were reported . Incidence of miscarriage ( 2 % in the st and ard care group vs 2 % in the intervention group ) , major obstetric haemorrhage ( 1 % vs 3 % ) , and small-for-gestational-age infants ( ≤5th customised birthweight centile ; 6 % vs 5 % ) did not differ between groups . INTERPRETATION A behavioural intervention addressing diet and physical activity in women with obesity during pregnancy is not adequate to prevent gestational diabetes , or to reduce the incidence of large-for-gestational-age infants . FUNDING National Institute for Health Research , Guys and St Thomas ' Charity , Chief Scientist Office Scotl and , Tommy 's Charity [10647530] PURPOSE The present study examined the effects of exercise on physical and psychological variables in sedentary primigravidae ( PRA ) . METHODS A total of nine women r and omly assigned to an exercise ( E ) ( mean age = 31.3 + /- 3.1 yr ) and six subjects r and omly assigned to a control ( C ) group ( mean age = 27.8 + /- 3.1 yr ) fulfilled all requirements for the study . Exercise included a variety of exercise activities performed to a target heart rate of 150 - 156 beats x min(-1 ) , three times per week for 15 wk . RESULTS Results showed no significant differences between E and C groups in physical characteristics initially . A repeated measures ANOVA showed a significant group effect ( P < 0.05 ) and a significant group by time interaction ( P = 0.001 ) with the E group showing a significantly longer amount of time on the PWC150 test than the C group . There was no significant group , time , or group by time interaction for lactate accumulation . This occurred , despite the fact that the E group spent 56 % longer on the PWC150 test and the C group spent 30 % less time on the same test at the conclusion of the study . Finally , the E group in comparison to the C group showed more favorable improvements in several items related to health and well-being on the Body Cathexis Scale . There were no significant differences between E and C groups in any pregnancy outcome measures . All babies were delivered healthy at term . CONCLUSIONS These data suggest that a vigorous exercise program can lead to significant improvements in aerobic fitness at similar lactate concentrations compared to a control group and can be well tolerated by low risk sedentary PRA without any deleterious effects occurring to herself or unborn child [8990428] Objective To examine the effectiveness of a partially homebased , moderate-intensity aerobic exercise program for women with gestational diabetes . Methods This was a r and omized experimental design . Thirty-three women with gestational diabetes were r and omly assigned to the exercise or the no-exercise group . Subjects underwent hemoglobin A1C assay and submaximal cycle ergometer fitness tests at baseline and at study conclusion . Subjects kept diaries of home fasting and 2-hour postpr and ial blood glucose determinations . Exercise subjects were asked to exercise for 30 minutes three to four times weekly at 70 % of estimated maximal heart rate for the weeks of study participation . Two exercise sessions weekly were supervised by the investigator , and two were unsupervised at home . Control-group subjects were asked to maintain their current activity level . Results Daily fasting and postpr and ial blood glucose levels , hemoglobin A1C , incidence of exogenous insulin therapy , and incidence of newborn hypoglycemia were not different between the groups . There was a training effect in the exercise group ( P = .005 ) but not in the control group ( P = .25 ) . A significant decline in daily grams of carbohydrate consumed was observed in the control group ( P = .03 ) , but not in the exercise group ( P = .97 ) . No complications were found in the subjects who exercised . Conclusions A partially home-based exercise program did not reduce blood glucose levels , but did result in a modest increase in cardiorespiratory fitness . The intervention appeared safe [7771999] EDITORIAL COMMENT : When this paper was review ed the question was raised that the period of gestation is an obvious factor which can determine birth‐weight and the authors were asked how this may have affected their results The authors response was as follows [25823187] OBJECTIVE To assess the effect of aerobic exercise training on maternal and neonatal outcome METHODS The case-control study was conducted between January and July , 2011 . It was approved by the Research Ethics Committee of Toyserkan Azad University , and data was collected at prenatal clinics and delivery centres located in Hamedan , Iran . It comprised 80 pregnant women between 20 - 26 weeks of gestation r and omly assigned to two equal and matching groups of cases and controls . The intervention group did exercise continuously on a bicycle ergometre for 15 minutes , three times a week ; the intensity being 50 - 60 % of maximal heart rate . The control group did not do any exercise training . All information was obtained from the clinics , delivery centres , and from the reports of delivery room midwives . RESULTS No statistically significant difference was found between the two groups in gestational weight gain , pregnancy length , mode of delivery , first and second stage of labour , perineal tear , and 1st and 5th min Apgar score . Mean neonatal weight was significantly less in the intervention group than the control group ( p < 0.001 ) . CONCLUSION Exercising on a bicycle ergometer during pregnancy seems to be safe for the mother and the neonate [22017967] Please cite this paper as : Hui A , Back L , Ludwig S , Gardiner P , Sevenhuysen G , Dean H , Sellers E , McGavock J , Morris M , Bruce S , Murray R , Shen G. Lifestyle intervention on diet and exercise reduced excessive gestational weight gain in pregnant women under a r and omised controlled trial . BJOG 2012;119:70–77 [21247734] In the GRADE approach , r and omized trials start as high- quality evidence and observational studies as low- quality evidence , but both can be rated down if most of the relevant evidence comes from studies that suffer from a high risk of bias . Well-established limitations of r and omized trials include failure to conceal allocation , failure to blind , loss to follow-up , and failure to appropriately consider the intention-to-treat principle . More recently recognized limitations include stopping early for apparent benefit and selective reporting of outcomes according to the results . Key limitations of observational studies include use of inappropriate controls and failure to adequately adjust for prognostic imbalance . Risk of bias may vary across outcomes ( e.g. , loss to follow-up may be far less for all-cause mortality than for quality of life ) , a consideration that many systematic review s ignore . In deciding whether to rate down for risk of bias -- whether for r and omized trials or observational studies -- authors should not take an approach that averages across studies . Rather , for any individual outcome , when there are some studies with a high risk , and some with a low risk of bias , they should consider including only the studies with a lower risk of bias [23030765] Intrauterine Growth Retardation ( IUGR ) is defined as a rate of growth of a fetus that is less than normal for the growth potential of the fetus ( for that particular gestational age ) . Small for Gestational Age ( SGA ) is defined infant born following IUGR , with a weight at birth below the 10th percentile . Suboptimal fetal growth occurring in IUGR fetuses is an important cause of perinatal mortality and morbidity . The acute neonatal consequences of IUGR include metabolic and hematological disturbances , and disrupted thermoregulation ; in addition , respiratory distress ( RDS ) , necrotizing enterocolitis ( NEC ) , and retinopathy of prematurity ( ROP ) may contribute to perinatal morbidity . Metabolic disturbances are related to glucose and fatty acid metabolism . It is well-known that individuals who display poor growth in utero are at significantly increased risk for type 2 diabetes mellitus ( T2DM ) , obesity , hypertension , dyslipidemia , and insulin resistance ( the so-called metabolic syndrome , MS ) . MS ultimately leads to the premature development of cardiovascular diseases . In addition , short stature in children and adults , premature adrenarche , and the polycystic ovarian syndrome ( PCOS ) are endocrinological sequelae of IUGR . ( 8) Early onset growth delay and prematurity significantly increase the risk for neurological sequelae and motor and cognitive delay . Future prospect i ve studies need to investigate risk factors for infants who are SGA . If reliable prediction can be achieved , there is potential to reduce future perinatal morbidity and mortality , and long term consequences among SGA babies [2613131] Background To evaluate the association between water aerobics , maternal cardiovascular capacity during pregnancy , labor and neonatal outcomes . Methods A r and omized , controlled clinical trial was carried out in which 34 pregnant women were allocated to a water aerobics group and 37 to a control group . All women were su bmi tted to submaximal ergometric tests on a treadmill at 19 , 25 and 35 weeks of pregnancy and were followed up until delivery . Oxygen consumption ( VO2 max ) , cardiac output ( CO ) , physical fitness , skin temperature , data on labor and delivery , and neonate outcomes were evaluated . Frequency distributions of the baseline variables of both groups were initially performed and then analysis of the outcomes was carried out . Categorical data were compared using the chi-square test , and numerical using Student 's t or Mann-Whitney tests . Wilk 's Lambda or Friedman 's analysis of repeat measurements were applied for comparison of physical capacity , cardiovascular outcomes and maternal temperature . Results VO2 max and physical fitness were higher in both groups in the second trimester , returning to basal levels in the third trimester . In both groups , CO increased as pregnancy progressed and peak exercise temperature was higher than resting temperature , increasing further after five minutes of recovery and remaining at this level until 15 minutes after exercise completion . There was no difference between the two groups regarding duration ( 457.9 ± SD 249.6 vs 428.9 ± SD 203.2 minutes ) or type of delivery . Labor analgesia was requested by significantly fewer women in the water aerobics group ( 27 % vs 65 % ; RR = 0.42 95%CI 0.23–0.77 ) . Neonatal results were similar in both groups . Conclusion The regular practice of moderate water aerobics by sedentary and low risk pregnant women was not detrimental to the health of the mother or the child . There was no influence on maternal cardiovascular capacity , duration of labor or type of delivery ; however , there were fewer requests for analgesia during labor in the water aerobics group [10870784] Does strenuous antenatal exercise reduce birth‐weight ? Does reducing maternal exercise increase birthweight ? What to advise about exercise during pregnancy [25932848] OBJECTIVE : To examine the effect of an individually tailored , motivationally matched prenatal exercise intervention on gestational diabetes mellitus ( GDM ) and other measures of glucose intolerance among ethnically diverse prenatal care patients at increased risk for GDM . METHODS : The Behaviors Affecting Baby and You study r and omized eligible women at a mean ( st and ard deviation ) of 18.2 ( 4.1 ) weeks of gestation to a 12-week individually tailored , motivationally matched exercise intervention or a comparison health and wellness intervention . The goal of the exercise intervention was to achieve the American College of Obstetricians and Gynecologists ' guidelines for physical activity during pregnancy . Diagnosis of GDM , impaired glucose tolerance , abnormal glucose screen , and screening glucose values ( mg/dL ) were abstract ed from medical records . A sample size of 352 women ( 176 per group ) was planned to have 80 % power to detect reductions in risk of 35 % or larger . RESULTS : From July 2007 to December 2012 , a total of 251 ( 86.5 % ) women completed the intervention ; n=124 and 127 in the exercise and comparison interventions , respectively . Based on an intention-to-treat analysis , no statistically significant differences between the intervention groups were observed ; the relative odds of GDM in the exercise group was 0.61 ( 95 % confidence interval [ CI ] 0.28–1.32 ) as compared with the health and wellness comparison group . Odds ratios for impaired glucose tolerance and abnormal glucose screen were 0.68 ( 95 % CI 0.35–1.34 ) and 0.86 ( 95 % CI 0.51–1.47 ) , respectively . The intervention had no effect on birth outcomes . CONCLUSION : In this r and omized trial among ethnically diverse pregnant women at increased risk for GDM , we found that a prenatal exercise intervention implemented in the second trimester did not result in a statistically significant reduction in relative odds for GDM , impaired glucose tolerance , or abnormal glucose screen . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00728377 . LEVEL OF EVIDENCE : [4221718] Background Pregnancy is a recognised high risk period for excessive weight gain , contributing to postpartum weight retention and obesity development long-term . We aim ed to reduce postpartum weight retention following a low-intensity , self-management intervention integrated with routine antenatal care during pregnancy . Methods 228 women at increased risk of gestational diabetes , < 15 weeks gestation were r and omised to intervention ( 4 self-management sessions ) or control ( generic health information ) . Outcomes , collected at baseline and 6 weeks postpartum , included anthropometrics ( weight and height ) , physical activity ( pedometer ) and question naires ( health behaviours ) . Results Mean age ( 32.3 ± 4.7 and 31.7 ± 4.4 years ) and body mass index ( 30.4 ± 5.6 and 30.3 ± 5.9 kg/m2 ) were similar between intervention and control groups , respectively at baseline . By 6 weeks postpartum , weight change in the control group was significantly higher than the intervention group with a between group difference of 1.45 ± 5.1 kg ( 95 % CI : -2.86,-0.02 ; p < h0.05 ) overall , with a greater difference in weight found in overweight , but not obese women . Intervention group allocation , higher baseline BMI , GDM diagnosis , country of birth and higher age were all independent predictors of lower weight retention at 6 weeks postpartum on multivariable linear regression . Other factors related to weight including physical activity , did not differ between groups . Conclusions A low intensity intervention , integrated with st and ard antenatal care is effective in limiting postpartum weight retention . Implementation research is now required for scale-up to optimise antenatal health care . Trial registration Australian New Zeal and Clinical Trial Registry Number : ACTRN12608000233325 . Registered 7/5/2008 [4961392] Background The effectiveness of exercise training for preventing excessive gestational weight gain ( GWG ) and gestational diabetes mellitus ( GDM ) is still uncertain . As maternal obesity is associated with both GWG and GDM , there is a special need to assess whether prenatal exercise training programs provided to obese women reduce the risk of adverse pregnancy outcomes . Our primary aim was to assess whether regular supervised exercise training in pregnancy could reduce GWG in women with prepregnancy overweight/obesity . Secondary aims were to examine the effects of exercise in pregnancy on 30 outcomes including GDM incidence , blood pressure , blood measurements , skinfold thickness , and body composition . Methods and Findings This was a single-center study where we r and omized ( 1:1 ) 91 pregnant women with a prepregnancy body mass index ( BMI ) ≥ 28 kg/m2 to exercise training ( n = 46 ) or control ( st and ard maternity care ) ( n = 45 ) . Assessment s were done at baseline ( pregnancy week 12–18 ) and in late pregnancy ( week 34–37 ) , as well as at delivery . The exercise group was offered thrice weekly supervised sessions of 35 min of moderate intensity endurance exercise and 25 min of strength training . Seventeen women were lost to follow-up ( eight in the exercise group and nine in the control group ) . Our primary endpoint was GWG from baseline testing to delivery . The principal analyses were done as intention-to-treat analyses , with supplementary per protocol analyses where we assessed outcomes in the women who adhered to the exercise program ( n = 19 ) compared to the control group . Mean GWG from baseline to delivery was 10.5 kg in the exercise group and 9.2 kg in the control group , with a mean difference of 0.92 kg ( 95 % CI −1.35 , 3.18 ; p = 0.43 ) . Among the 30 secondary outcomes in late pregnancy , an apparent reduction was recorded in the incidence of GDM ( 2009 WHO definition ) in the exercise group ( 2 cases ; 6.1 % ) compared to the control group ( 9 cases ; 27.3 % ) , with an odds ratio of 0.1 ( 95 % CI 0.02 , 0.95 ; p = 0.04 ) . Systolic blood pressure was significantly lower in the exercise group ( mean 120.4 mm Hg ) compared to the control group ( mean 128.1 mm Hg ) , with a mean difference of −7.73 mm Hg ( 95 % CI −13.23 , −2.22 ; p = 0.006 ) . No significant between-group differences were seen in diastolic blood pressure , blood measurements , skinfold thickness , or body composition in late pregnancy . In per protocol analyses , late pregnancy systolic blood pressure was 115.7 ( 95 % CI 110.0 , 121.5 ) mm Hg in the exercise group ( significant between-group difference , p = 0.001 ) , and diastolic blood pressure was 75.1 ( 95 % CI 71.6 , 78.7 ) mm Hg ( significant between-group difference , p = 0.02 ) . We had planned to recruit 150 women into the trial ; hence , under-recruitment represents a major limitation of our results . Another limitation to our study was the low adherence to the exercise program , with only 50 % of the women included in the intention-to-treat analysis adhering as described in the study protocol . Conclusions In this trial we did not observe a reduction in GWG among overweight/obese women who received a supervised exercise training program during their pregnancy . The incidence of GDM in late pregnancy seemed to be lower in the women r and omized to exercise training than in the women receiving st and ard maternity care only . Systolic blood pressure in late pregnancy was also apparently lower in the exercise group than in the control group . These results indicate that supervised exercise training might be beneficial as a part of st and ard pregnancy care for overweight/obese women . Trial Registration Clinical Trials.gov [21948120] Objective The influence of an exercise programme performed by healthy pregnant women on maternal glucose tolerance was studied . Study design A physical activity ( PA , l and /aquatic activities ) programme during the entire pregnancy ( three sessions per week ) was conducted by a qualified instructor . 83 healthy pregnant women were r and omly assigned to either an exercise group ( EG , n=40 ) or a control ( CG , n=43 ) group . 50 g maternal glucose screen ( MGS ) , maternal weight gain and several pregnancy outcomes were recorded . Results Significant differences were found between study groups on the 50 g MGS . Values corresponding to the EG ( 103.8±20.4 mg/dl ) were better than those of the CG ( 126.9±29.5 mg/dl ) , p=0.000 . In addition , no differences in maternal weight gain and no cases of gestational diabetes in EG versus 3 in CG ( 7 % ) ( p>0.05 ) were found . Conclusion A moderate PA programme performed during pregnancy improves levels of maternal glucose tolerance [3750492] Background Antenatal preparation programmes are recommended worldwide to promote a healthy pregnancy and greater autonomy during labor and delivery , prevent physical discomfort and high levels of anxiety . The objective of this study was to evaluate effectiveness and safety of a birth preparation programme to minimize lumbopelvic pain , urinary incontinence , anxiety , and increase physical activity during pregnancy as well as to compare its effects on perinatal outcomes comparing two groups of nulliparous women . Methods A r and omized controlled trial was conducted with 197 low risk nulliparous women aged 16 to 40 years , with gestational age ≥ 18 weeks . Participants were r and omly allocated to participate in a birth preparation programme ( BPP ; n=97 ) or a control group ( CG ; n=100 ) . The intervention was performed on the days of prenatal visits , and consisted of physical exercises , educational activities and instructions on exercises to be performed at home . The control group followed a routine of prenatal care . Primary outcomes were urinary incontinence , lumbopelvic pain , physical activity , and anxiety . Secondary outcomes were perinatal variables . Results The risk of urinary incontinence in BPP participants was significantly lower at 30 weeks of pregnancy ( BPP 42.7 % , CG 62.2 % ; relative risk [ RR ] 0.69 ; 95 % confidence interval [ CI ] 0.51 - 0.93 ) and at 36 weeks of pregnancy ( BPP 41.2 % , CG 68.4 % ; RR 0.60 ; 95%CI 0.45 - 0.81 ) . Participation in the BPP encouraged women to exercise during pregnancy ( p=0.009 ) . No difference was found between the groups regarding to anxiety level , lumbopelvic pain , type or duration of delivery and weight or vitality of the newborn infant . Conclusions The BPP was effective in controlling urinary incontinence and to encourage the women to exercise during pregnancy with no adverse effects to pregnant women or the fetuses . Trial registration Clinical trials.gov , ( NCT01155804 [21354547] OBJECTIVE We have studied the effect of moderate physical activity that is performed by healthy women during their entire pregnancy on their perception of health status . STUDY DESIGN Eighty sedentary women were assigned r and omly to either an exercise group ( n = 40 ) or a control group ( n = 40 ) . Maternal perception of health status and several pregnancy outcomes were recorded . RESULTS Significant differences ( P = .03 ) were found between study groups in the percentage of women who perceived their health status as " very good " ; the values that corresponded to the exercise group ( n = 18 ; 54.5 % ) were better than those of the control group ( n = 9 ; 27.3 % ) . In addition , the women of the exercise group gained less weight ( 11,885 ± 3146 g ) than those of the control group ( 13,903 ± 2113 ; P = .03 ) . CONCLUSION A moderate physical activity program that is performed over the first , second , and third trimester of pregnancy improves the maternal perception of health status [26241428] OBJECTIVE : To compare , in an unselected population of nulliparous pregnant women , the postnatal effect of prenatal supervised pelvic floor muscle training with written instructions on postpartum urinary incontinence ( UI ) . METHODS : In a r and omized controlled trial in two parallel groups , 282 women were recruited from five university teaching hospitals in France and r and omized during the second trimester of pregnancy . The physiotherapy group received prenatal individually supervised exercises . Both groups received written instructions about how to perform exercises at home . Women were blindly assessed at baseline , end of pregnancy , and 2 and 12 months postpartum . The primary outcome measured was UI severity , assessed with an International Consultation on Incontinence Question naire-Urinary Incontinence Short Form score ( range 0–21 ; 1–5 is slight UI ) at 12 months postpartum ; other outcomes were UI prevalence and pelvic floor troubles assessed using self-administered question naires . To give a 1-point difference in UI severity score , we needed 91 women in each group ( st and ard deviation 2.4 , & agr;=0.05 , & bgr;=0.20 , and bilateral analysis ) . RESULTS : Between February 2008 and June 2010 , 140 women were r and omized in the physiotherapy group and 142 in the control group . No difference was observed between the two groups in UI severity , prevalence , or pelvic floor troubles at baseline , end of pregnancy , and at 2 and 12 months postpartum . At 12 months postpartum , the primary outcome was available for 190 women ( 67.4 % ) ; mean UI severity was 1.9 in the physiotherapy group compared with 2.1 in the control group ( P=.38 ) . CONCLUSION : Prenatal supervised pelvic floor training was not superior to written instructions in reducing postnatal UI . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov ; www . clinical trials.gov , NCT00551551 . LEVEL OF EVIDENCE : [10078577] OBJECTIVE To investigate if water-gymnastics during pregnancy may reduce the intensity of back/low back pain and the number of days on sick-leave . METHODS A prospect i ve , r and omized study . One hundred and twenty-nine women were r and omized to participate in water-gymnastics once a week during the second half of pregnancy and 129 were r and omized to a control group . The women in both groups filled in question naires in gestational weeks 18 , 34 and within the first postpartum week . Every day from week 18 to labor they assessed the intensity of back/low back pain . RESULTS Back pain intensity increased during pregnancy . No excess risk for the pregnancy associated with water-gymnastics was observed . The women participating in water-gymnastics recorded a lower intensity of back/low back pain . The total number of days on sick-leave because of back/low back pain was 982 in the water-gymnastics group ( 124 women ) compared with 1484 in the control group ( 120 women ) . After weeks 32 33 , seven women in the water-gymnastics group compared with 17 in the control group were on sickleave because of back/ low back pain ( p=0.031 ) . CONCLUSIONS Intensity of back/low back pain increased with advancing pregnancy . There was no excess risk for urinary or vaginal infections associated with water-gymnastics . Water-gymnastics during the second half of pregnancy significantly reduced the intensity of back/ low back pain . Water-gymnastics decreased the number of women on sick-leave because of back/low back pain . Water-gymnastics during pregnancy can be recommended as a method to relieve back pain and may reduce the need for sick-leave [12576255] OBJECTIVE Urinary incontinence is a chronic health complaint that severely reduces quality of life . Pregnancy and vaginal delivery are main risk factors in the development of urinary incontinence . The aim of this study was to assess whether intensive pelvic floor muscle training during pregnancy could prevent urinary incontinence . METHODS We conducted a single-blind r and omized controlled trial at Trondheim University Hospital and three outpatient physiotherapy clinics in a primary care setting . Three hundred one healthy nulliparous women were r and omly allocated to a training ( n = 148 ) or a control group ( n = 153 ) . The training group attended a 12-week intensive pelvic floor muscle training program during pregnancy , supervised by physiotherapists . The control group received the customary information . The primary outcome measure was self-reported symptoms of urinary incontinence . The secondary outcome measure was pelvic floor muscle strength . RESULTS At follow-up , significantly fewer women in the training group reported urinary incontinence : 48 of 148 ( 32 % ) versus 74 of 153 ( 48 % ) at 36 weeks ' pregnancy ( P = .007 ) and 29 of 148 ( 20 % ) versus 49 of 153 ( 32 % ) 3 months after delivery ( P = .018 ) . According to numbers needed to treat , intensive pelvic floor muscle training during pregnancy prevented urinary incontinence in about one in six women during pregnancy and one in eight women after delivery . Pelvic floor muscle strength was significantly higher in the training group at 36 weeks ' pregnancy ( P = .008 ) and 3 months after delivery ( P = .048 ) . CONCLUSION Intensive pelvic floor muscle training during pregnancy prevents urinary incontinence during pregnancy and after delivery . Pelvic floor muscle strength improved significantly after intensive pelvic floor muscle training [4573757] Objective To evaluate whether a 12-week supervised exercise program promotes an active lifestyle throughout pregnancy in pregnant women with obesity . Methods In this preliminary r and omised trial , pregnant women ( body mass index ≥ 30 kg/m2 ) were allocated to either st and ard care or supervised training , from 15 to 27 weeks of gestation . Physical activity was measured by accelerometry at 14 , 28 and 36 weeks , while fitness ( oxygen consumption ( VO2 ) at the anaerobic threshold ) , nutrition ( caloric intake and macronutrients percentage ) and anthropometry were assessed at 14 and 28 weeks of gestation . Analyses were performed using repeated measures ANOVA . Results A total of fifty ( 50 ) women were r and omised , 25 in each group . There was no time-group interaction for time spent at moderate and vigorous activity ( pinteraction = 0.064 ) , but the exercise group ’s levels were higher than controls ’ at all times ( pgroup effect = 0.014 ) . A significant time-group interaction was found for daily physical activity ( p = 0.023 ) ; similar at baseline ( ( 22.0 ± 6.7 vs 21.8 ± 7.3 ) x 104 counts/day ) the exercise group had higher levels than the control group following the intervention ( ( 22.8 ± 8.3 vs 19.2 ± 4.5 ) x 104 counts/day , p = 0.020 ) and at 36 weeks of gestation ( ( 19.2 ± 1.5 vs 14.9 ± 1.5 ) x 104 counts/day , p = 0.034 ) . Exercisers also gained less weight than controls during the intervention period despite similar nutritional intakes ( difference in weight change = -0.1 kg/week , 95 % CI -0.2 ; -0.02 , p = 0.016 ) and improved cardiorespiratory fitness ( difference in fitness change = 8.1 % , 95 % CI 0.7 ; 9.5 , p = 0.041 ) . Conclusions Compared with st and ard care , a supervised exercise program allows pregnant women with obesity to maintain fitness , limit weight gain and attenuate the decrease in physical activity levels observed in late pregnancy . Trial Registration Clinical Trials.gov [5934849] Background To develop effective health promotional and preventive prenatal programs , it is important to underst and perceived barriers to leisure-time physical activity during pregnancy , including exercise and sport participation . The aims of the present study was 1 ) to assess the effect of prenatal lifestyle intervention on the perceived barrier to leisure-time physical activity during pregnancy and the first year after delivery and 2 ) identify the most important perceived barriers to leisure-time physical activity at multiple time points during and after pregnancy . Methods This secondary analysis was part of the Norwegian Fit for Delivery study , a combined lifestyle intervention evaluated in a blinded , r and omized controlled trial . Healthy , nulliparous women with singleton pregnancy of ≤20 gestational weeks , age ≥ 18 years and body mass index ≥19 kg/m2 were recruited via healthcare clinics in southern Norway , including urban and rural setting s. Participants were r and omized to either twice-weekly supervised exercise sessions and nutritional counselling ( n = 303 ) or st and ard prenatal care ( n = 303 ) . The principal analysis was based on the participants who completed the st and ardized question naire assessing their perceived barriers to leisure-time physical activity at inclusion ( gestational week 16 , n = 589 ) and following intervention ( gestational week 36 , n = 509 ) , as well as six months ( n = 470 ) and 12 months ( n = 424 ) postpartum . Results Following intervention ( gestation week 35.4 ± 1.0 ) , a significant between-group difference in perceived barriers to leisure-time physical activity was found with respect to time constraints : “ ... I do not have the time ” ( intervention : 22 vs. control : 38 , p = 0.030 ) , mother-child safety concerns : “ ... afraid to harm the baby ” ( intervention : 8 vs. control : 25 , p = 0.002 ) and self-efficacy : “ ... I do not believe/think that I can do it ” ( intervention : 3 vs. control : 10 , p = 0.050 ) . No positive effect was seen at postpartum follow-up . Intrapersonal factors ( lack of time , energy and interest ) were the most frequently perceived barriers , and consistent over time among all participants . Conclusion The intervention had effect on intrapersonal perceived barriers in pregnancy , but not in the postpartum period . Perceived barriers to leisure-time physical activity were similar from early pregnancy to 12 months postpartum . Trial registration Clinical Trials.gov : NCT01001689 , registered July 2 , 2009 [4287470] Background The objectives of this study were to assess the efficacy of lifestyle intervention on gestational weight gain in pregnant women with normal and above normal body mass index ( BMI ) in a r and omized controlled trial . Methods A total of 116 pregnant women ( < 20 weeks of pregnancy ) without diabetes were enrolled and 113 pregnant women completed the program . Participants were r and omized into intervention and control groups . Women in the intervention group received weekly trainer-led group exercise sessions , instructed home exercise for 3 - 5-times/week during 20 - 36 weeks of gestation , and dietary counseling twice during pregnancy . Participants in the control group did not receive the intervention . All participants completed a physical activity question naire and a 3-day food record at enrolment and 2 months after enrolment . Results The participants in the intervention group with normal pre-pregnancy BMI ( ≤24.9 kg/M2 , n = 30 ) had lower gestational weight gain ( GWG ) , offspring birth weight and excessive gestational weight gain ( EGWG ) on pregnancy weight gain compared to the control group ( n = 27 , p < 0.05 ) . Those weight related-changes were not detected between the intervention ( n = 27 ) and control group ( n = 29 ) in the above normal pre-pregnancy BMI participants . Intervention reduced total calorie , total fat , saturated fat and cholesterol intake were detected in women with normal or above normal pre-pregnancy BMI compared to the control group ( p < 0.05 or 0.01 ) . Increased physical activity and reduced carbohydrate intake were detected in women with normal ( p < 0.05 ) , but not above normal , pre-pregnancy BMI at 2 months after the onset of the intervention compared to the control group . Conclusion The results of the present study demonstrated that the lifestyle intervention program decreased EGWG , GWG , offspring birth weight in pregnant women with normal , but not above normal , pre-pregnancy BMI , which was associated with increased physical activity and decreased carbohydrate intake . Trial registration [4431606] Objective To determine the effectiveness of a physical activity intervention for smoking cessation during pregnancy . Design Parallel group , r and omised controlled , multicentre trial . Setting 13 hospitals in Engl and , April 2009 to January 2014 . Participants 789 pregnant smokers , aged 16 - 50 years and at 10 - 24 weeks ’ gestation , who smoked at least one cigarette daily and were prepared to quit smoking one week after enrollment were r and omised ( 1:1 ) ; 785 were included in the intention to treat analyses , with 392 assigned to the physical activity group . Interventions Interventions began one week before a target quit date . Participants were r and omised to six weekly sessions of behavioural support for smoking cessation ( control ) or to this support plus 14 sessions combining supervised treadmill exercise and physical activity consultations . Main outcome measures The primary outcome was continuous smoking abstinence from the target quit date until end of pregnancy , vali date d by exhaled carbon monoxide or salivary cotinine levels . To assess adherence , levels of moderate-vigorous intensity physical activity were self reported and in a 11.5 % ( n=90 ) r and om sub sample of participants , physical activity was objective ly measured by an accelerometer . Results No significant difference was found in rates of smoking abstinence at end of pregnancy between the physical activity and control groups ( 8 % v 6 % ; odds ratio 1.21 , 95 % confidence interval 0.70 to 2.10 ) . For the physical activity group compared with the control group , there was a 40 % ( 95 % confidence interval 13 % to 73 % ) , 34 % ( 6 % to 69 % ) , and 46 % ( 12 % to 91 % ) greater increase in self reported minutes carrying out physical activity per week from baseline to one week , four weeks , and six weeks post-quit day , respectively . According to the accelerometer data there was no significant difference in physical activity levels between the groups . Participants attended a median of four treatment sessions in the intervention group and three in the control group . Adverse events and birth outcomes were similar between the two groups , except for significantly more caesarean births in the control group than in the physical activity group ( 29 % v 21 % , P=0.023 ) . Conclusion Adding a physical activity intervention to behavioural smoking cessation support for pregnant women did not increase cessation rates at end of pregnancy . During pregnancy , physical activity is not recommended for smoking cessation but remains indicated for general health benefits . Trial registration Current Controlled Trials IS RCT N48600346 [3753734] Objectives . To evaluate the association between physical exercise supervised in pregnant women with chronic hypertension and /or previous preeclampsia and maternal and neonatal outcomes . Method . R and omized controlled trial , which included 116 pregnant women with chronic hypertension and /or previous preeclampsia , considered risk of preeclampsia development . They were divided into two groups : study group that performed physical exercise with a stationary bicycle once a week , for 30 minutes ; the intensity was controlled ( heart rate 20 % above resting values ) , under professional supervision and a control group that was not engaged in any physical exercise . The data was retrieved from medical charts . Significance level assumed was 5 % . Results . Women from study group performed 9.24 ± 7.03 of physical exercise sessions . There were no differences between groups comparing type of delivery and maternal outcomes , including maternal morbidity and hospitalization in intensive unit care , and neonatal outcomes , including birth weight , adequacy of weight to gestational age , prematurity , Apgar scale at first and fifth minutes , hospitalization in intensive unit care , and neonatal morbidity . Conclusions . Physical exercise using a stationary bicycle in pregnant women with chronic hypertension and /or previous preeclampsia , once a week , under professional supervision , did not interfere in the delivery method and did not produce maternal and neonatal risks of the occurrence of morbidity . This trial is registered with Clinical Trials.gov NCT01395342 [19955397] BACKGROUND Maternal obesity and excessive gestational weight gain ( GWG ) are major short- and long-term risk factors for maternal and fetal complications . OBJECTIVE The objective was to study whether a lifestyle intervention based on a brochure or on active education can improve dietary habits , increase physical activity ( PA ) , and reduce GWG in obese pregnant women . DESIGN In this r and omized controlled trial , 195 white , obese pregnant women [ age : 29 + or - 4 y ; body mass index ( in kg/m(2 ) ) ; 33.6 + or - 4.2 ] were r and omly assigned into 3 groups : a group that received nutritional advice from a brochure , a group that received the brochure and lifestyle education by a nutritionist , and a control group . Nutritional habits were evaluated every trimester through 7-d food records . PA was evaluated with the Baecke question naire . RESULTS Energy intake did not change during pregnancy and was comparable in all groups . Fat intake , specifically saturated fat intake , decreased and protein intake increased from the first to the third trimester in the passive and active groups compared with an opposite change in the control group . Calcium intake and vegetable consumption increased during pregnancy in all groups . PA decreased in all groups , especially in the third trimester . No significant differences in GWG and obstetrical or neonatal outcome could be observed between the groups . CONCLUSIONS Both lifestyle interventions improved the nutritional habits of obese women during pregnancy . Neither PA nor GWG was affected [25306925] AIMS To pilot the feasibility of a prenatal lifestyle intervention to modify physical activity and diet among pregnant overweight and obese Hispanic women , with the aim of reducing risk factors for gestational diabetes mellitus . METHODS Women were r and omized either to a lifestyle intervention ( n = 33 , 48.5 % ) , consisting of a culturally and linguistically modified , motivationally targeted , individually tailored 6-month prenatal programme , or to st and ard care ( n = 35 , 51.5 % ) . Bilingual and bicultural health educators encouraged women to achieve guidelines for physical activity , decrease saturated fat and increase dietary fibre . Outcomes included gestational weight gain , infant birth weight and biomarkers associated with insulin resistance . RESULTS Patient retention up to delivery was 97 % in both study groups . The lifestyle intervention attenuated the pregnancy-associated decline in moderate-intensity physical activity , but differences between groups were not significant ( mean ± se -23.4 ± 16.6 vs -27.0 ± 16.2 metabolic equivalent of task h/week ; P = 0.88 ) . Vigorous-intensity activity increased during the course of pregnancy in the lifestyle intervention group ( mean ± se 1.6 ± 0.8 metabolic equivalent of task h/week ) and declined in the st and ard care group ( -0.8 ± 0.8 metabolic equivalent of task h/week ; P = 0.04 ) . The lifestyle intervention group also had slightly lower gestational weight gain and infant birth weights compared with the st and ard care group ; however , these differences were not statistically significant . There were no statistically significant differences in biomarkers of insulin resistance between groups . CONCLUSIONS Findings suggest that a motivationally matched lifestyle intervention is feasible and may help attenuate pregnancy-related decreases in vigorous physical activity in a population of overweight and obese Hispanic women . The intervention protocol can readily be translated into clinical practice in underserved and minority population [16055571] Objective : To evaluate the effects of aerobic training on submaximal cardiorespiratory capacity in overweight pregnant women . Methods : We conducted a r and omized clinical trial in a referral center prenatal clinic during the period 2000–2002 . Of 132 overweight ( body mass index 26–31 kg/m2 ) but otherwise healthy volunteers , at 20 years of age or older , with gestational age of 20 weeks or less , and without diabetes or hypertension , 92 consented to participate and were r and omized . Intervention consisted of 3 one-hour aerobic exercise sessions per week ; the control group received weekly relaxation and focus group discussion s. The main outcome measure was submaximal exercise capacity evaluated by oxygen uptake at the anaerobic ( first ventilatory ) threshold during cardiopulmonary treadmill testing 12 weeks after r and omization . Results : Oxygen uptake at the anaerobic threshold increased 18 % ( 15.9 ± 2.6 to 18.1 ± 3.1 mL · min−1 · kg−1 ) in the exercise group but decreased 16 % ( 16.9 ± 3.0 to 15.8 ± 2.6 mL · min−1 · kg−1 ) among the control group . Oxygen consumption at the anaerobic threshold , adjusted through analysis of covariance for baseline oxygen uptake , was 2.68 ( 95 % confidence interval 1.23 to 4.12 ) mL · min−1 · kg−1 greater in the exercise group . Women in the exercise group were approximately 5 times more likely than those in the control group to have regular or good cardiorespiratory capacity ( 12/38 versus 2/38 ; relative risk 5.2 , 95 % confidence interval 1.2 to 22.0 , number needed to treat 5 ) . Conclusion : Aerobic training in overweight pregnant women substantially increases submaximal exercise capacity , overcoming the otherwise negative effects of pregnancy in this regard . Additional studies are required to evaluate its effect on major clinical outcomes . LEVEL OF EVIDENCE : [12188409] A single center , prospect i ve , r and omized , single blinded , controlled study comparing the effects and safety of " sitting pelvic tilt exercise " in relieving back pain during the third trimester in primigravida was carried out . The sample s were composed of 67 primigravidas who attended the prenatal clinic at King Chulalongkorn Memorial Hospital . All subjects were selected by the r and om sampling technique and allocated into two groups for the experimental group and the control group ; for 32 and 35 pregnants , respectively . The experimental group received the pelvic tilt exercise program for 8 weeks during the third trimester . Pain intensity was measured by visual analogue scale ( VAS ) at day 0 and day 56 in both groups . The result of the study revealed 1 ) The mean VAS of back pain in the experimental group was significantly lower at day 56 than at day 0 and lower than the control group at day 56 ( p < 0.05 ) by unpaired t-test 2 ) There was no incidence of preterm labor , low birth weight or neonatal complication in the experimental group . In conclusion , the " sitting pelvic tilt exercise " during the third trimester in primigravidas could decrease back pain intensity without incidence of preterm labor , low birth weight or neonatal complication [24290112] OBJECTIVE To study the effect on maternal weight gain of a supervised light- to moderate-intensity exercise-based intervention performed from the ninth week of pregnancy . PARTICIPANTS AND METHODS A total of 962 healthy pregnant women were r and omly assigned to a st and ard care or exercise intervention group conducted between September 1 , 2007 , and January 31 , 2011 . The intervention included light- to moderate-intensity aerobic and resistance exercises performed 3 days a week ( 50 - 55 minutes per session ) . Excessive gestational weight gain was calculated on the basis of the 2009 Institute of Medicine ( IOM ) recommendations . Gestational body weight gain was calculated on the basis of the weight measured at the first prenatal visit ( fifth to sixth weeks of gestation ) and weight measured at the last visit to the clinic before delivery . Women were categorized into normal weight or overweight or obese . RESULTS Women in the intervention group gained less weight ( adjusted mean difference , 1.039 kg ; 95 % CI , 0.534 - 1.545 kg ; P<.001 ) and were less likely to gain weight above the IOM recommendations ( odds ratio , 0.625 ; 95 % CI , 0.461 - 0.847 ) compared with those in the st and ard care group . The main treatment effects according to body mass index category were that normal weight women in the intervention group gained less weight ( adjusted mean difference , 1.393 kg ; 95 % CI , 0.813 - 1.972 kg ; P<.001 ) and were less likely to gain weight above the IOM recommendations ( odds ratio , 0.508 ; 95 % CI , 0.334 - 0.774 ) than normal weight women who received st and ard care . No significant treatment effect was observed in overweight or obese women . CONCLUSION Supervised exercise of light to moderate intensity can be used to prevent excessive gestational weight gain , especially in normal weight women . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01790347 [21860990] BACKGROUND The use of the pelvic floor muscle training for urinary incontinence treatment is well established but little is known about its effects in labor and newborn outcomes . OBJECTIVES To evaluate the effects of antenatal pelvic floor muscle training and strength in labor and newborn outcomes in low-income pregnant women . METHODS This is a r and omized controlled trial that recruited forty-two nulliparous healthy pregnant women aged between 18 - 36 years old and able to contract the pelvic floor muscles . The participants were included in the study with 20 weeks of gestational age and had their pelvic floor muscles measured by vaginal squeeze pressure . They were r and omly allocated into two groups : training group and a non-intervention control group . Then , all participants had their labor and newborn outcomes evaluated through consultation of medical records by a blinded research er . RESULTS There were no statistically significant differences between the groups regarding gestational age at birth , type of labor , duration of the second stage of labor , total time of labor , prevalence of laceration , weight and size of the baby , and Apgar score . No correlation was observed between pelvic floor muscle strength and the second stage or the total length of labor . CONCLUSIONS This r and omized controlled trial did not find any effect of pelvic floor muscle training or pelvic floor muscle strength on labor and newborn outcomes [20737135] Introduction and hypothesisThe aim of the study was to evaluate the effect of antenatal pelvic floor muscle exercise ( PFME ) in the prevention and treatment of urinary incontinence during pregnancy and postpartum period . Methods Three hundred women were r and omly assigned to the PFME group and control group . Urinary symptoms were measured by Urogenital Distress Inventory-6 ( UDI-6 ) , Incontinence Impact Question naire-7 ( IIQ-7 ) , and question of self-reported urinary incontinence . Question naire scores of the PFME and the control groups were compared and analyzed . Results During late pregnancy and the postpartum period , the PFME group had significantly lower total UDI-6 and IIQ-7 scores ; their self-report rate of urinary incontinence was also less than the control group . Additionally , we found whether in PFME or control , women who delivered vaginally were more likely to develop postpartum urinary leakage than women who delivered by cesarean section . Conclusions PFME applied in pregnancy is effective in the treatment and prevention of urinary incontinence during pregnancy , and this effect may persist to postpartum period [12439652] BACKGROUND : The Institute of Medicine ( IOM ) recommends that normal‐weight women ( BMI ( body mass index ) of 19.8–26.0 ) gain 25–35 lb ( 11.4–15.9 kg ) during pregnancy , and that overweight women ( BMI of 26.1–29.0 ) gain 15–25 lbs ( 6.8–11.4 kg ) . A significant number of normal‐weight women and an even greater proportion of overweight women exceed these guidelines , which increases postpartum weight retention and may contribute to the development of obesity . OBJECTIVE : To determine whether a stepped care , behavioral intervention will decrease the percentage of women who gain more than the IOM recommendation . DESIGN : R and omized controlled trial comparing a stepped-care behavioral intervention with usual care . Women ( n=120 ) who had a BMI > 19.8 , age>18 and < 20 weeks gestation were recruited from a hospital-based clinic serving low-income women and r and omized by race and BMI category to the intervention or control group . The intervention group received education about weight gain , healthy eating , and exercise and individual graphs of their weight gain . Those exceeding weight gain goals were given more intensive intervention . Women were followed through pregnancy to their first postpartum clinic visit . The main outcome measure was weight gain during pregnancy categorized as above the IOM recommendations vs below or within the IOM recommendations . RESULTS : The intervention significantly decreased the percentage of normal-weight women who exceeded the IOM recommendations ( 33 vs 58 % , P<0.05 ) . There was a non-significant ( P=0.09 ) effect in the opposite direction among overweight women ( 59 % of intervention and 32 % of control gained more than recommended ) . Postpartum weight retention was strongly related to weight gain during pregnancy ( r=0.89 ) . CONCLUSIONS : The intervention reduced excessive weight gain during pregnancy among normal weight women [27272937] We examined the effects of home-based walking on sedentary Japanese women 's pregnancy outcomes and mood . A r and omized controlled trial was conducted , involving 118 women aged 22 - 36 years . Participants were r and omly assigned to walking intervention ( n = 60 ) or control ( n = 58 ) groups . The walking group was instructed to walk briskly for 30 min , three times weekly from 30 weeks ' gestation until delivery . Both groups counted their daily steps using pedometers . Pregnancy and delivery outcomes were assessed , participants completed the Profile of Mood States , and we used the intention-to-treat principle . Groups showed no differences regarding pregnancy or delivery outcomes . The walking group exhibited decreased scores on the depression-dejection and confusion subscales of the Profile of Mood States . Five of the 54 women in the intervention group who remained in the study ( 9.2 % ) completed 100 % of the prescribed walking program ; 32 ( 59.3 % ) women completed 80 % or more . Unsupervised walking improves sedentary pregnant women 's mood , indicating that regular walking during pregnancy should be promoted in this group [23365418] Objective To examine the effect of regular moderate-intensity exercise ( three training sessions/week ) on the incidence of gestational diabetes mellitus ( GDM , primary outcome ) . We also examined if the exercise intervention modifies the association between GDM and birth weight and risk of macrosomia , gestational age , risk of caesarean delivery and maternal weight gain ( secondary outcomes ) . Methods We r and omly assigned 510 healthy gravida to either an exercise intervention or a usual care ( control ) group ( n=255 each ) . The exercise programme focused on moderate-intensity resistance and aerobic exercises ( three times/week , 50–55 min/session ) . GDM diabetes was diagnosed according to the WHO criteria and the International Association for Diabetes in Pregnancy Study Group ( IADPSG ) . Results The intervention did not reduce the risk of developing GDM ( OR 0.84 , 95 % CI 0.50 to 1.40 ) when using the WHO criteria . We observed that the intervention reduced by 58 % the GDM-related risk ( WHO criteria ) of having a newborn with macrosomia ( OR 1.76 , 95 % CI 0.04 to 78.90 vs 4.22 , 95 % CI 1.35 to 13.19 ) in exercise and control groups , respectively ) , and by 34 % the GDM-related risk of having acute and elective caesarean delivery ( OR 1.30 , 95 % CI 0.44 to 3.84 vs 1.99 , 95 % CI 0.98 to 4.06 in exercise and control groups , respectively ) . Gestational age was similar across the treatment groups ( control , exercise ) and GDM category ( GDM or non-GDM ) , and maternal weight gain was ∼12 % lower in the exercise group independent of whether women developed GDM . The results were similar when the IADPSG criteria were used instead . Conclusions Regular moderate-intensity exercise performed over the second-third trimesters of pregnancy can be used to attenuate important GDM-related adverse outcomes [11120515] OBJECTIVE Our purpose was to test the null hypothesis that beginning regular , moderate-intensity exercise in early pregnancy has no effect on fetoplacental growth . STUDY DESIGN Forty-six women who did not exercise regularly were r and omly assigned at 8 weeks either to no exercise ( n = 24 ) or to weight-bearing exercise ( n = 22 ) 3 to 5 times a week for the remainder of pregnancy . Outcome variables included antenatal placental growth rate and neonatal and placental morphometric measurements . RESULTS The offspring of the exercising women were significantly heavier ( corrected birth weight : 3.75 + /- 0.08 kg vs 3.49 + /- 0.07 kg ) and longer ( 51.8 + /- 0.3 cm vs 50.6 + /- 0.3 cm ) than those born to control women . The difference in birth weight was the result of an increase in both lean body mass and fat mass . In addition , midtrimester placental growth rate was faster ( 26 + /- 2 cm(3)/wk vs 21 + /- 1 cm(3)/wk ) and morphometric indexes of placental function were greater in the exercise group . There were no significant differences in neonatal percentage body fat , head circumference , ponderal index , or maternal weight gain . CONCLUSIONS These data indicate that beginning a moderate regimen of weight-bearing exercise in early pregnancy enhances fetoplacental growth [22825089] OBJECTIVE : To estimate the effect of supervised physical exercise on maternal physical fitness , fetoplacental blood flow , and fetal growth . METHODS : This was a r and omized controlled trial comparing three groups of pregnant women . Groups were as follows : exercise initiated at 13 weeks ( group A ) ; exercise initiated at 20 weeks ( group B ) ; and a control group ( no supervised exercise ; group C ) . The women in groups A and B walked at moderate intensity three times weekly . Physical fitness level was evaluated at weeks 13 , 20 , and 28 . Fetal growth and uteroplacental blood flow were evaluated monthly . Birth weight was registered . Analysis of variance for repeat measures was used for outcomes evaluated throughout pregnancy . Risk ratio was used as a measure of the relative risk of preeclampsia , fetal growth restriction , macrosomia , small-for-gestational-age newborns , and large-for-gestational-age newborns . RESULTS : All the women analyzed completed more than 85 % of the program . According to the evaluation conducted at week 28 , physical fitness improved , with mean maximal oxygen consumptions ( VO2max ) of 27.3±4.3 ( group A ) , 28±3.3 ( group B ) , and 25.5±3.8 ( group C ; P=.03 ) . Mean birth weights were 3,279±453 g ( group A ) , 3,285±477 g ( group B ) , and 3,378±593 g ( group C ; P=.53 ) , with no difference in the frequency of large for gestational age or small for gestational age . No association was found between the practice of physical activity and the variables investigated ( preeclampsia , fetal weight , blood pressure , and pulsatility index of the uterine , umbilical , and middle cerebral arteries ) . CONCLUSION : Moderate-intensity walking improved the physical fitness level of healthy , pregnant , previously sedentary women without affecting fetoplacental blood flow or fetal growth . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00641550 . LEVEL OF EVIDENCE : [20864072] OBJECTIVE The objective of the study was to evaluate the effect of a resistance exercise program with an elastic b and on insulin requirement and glycemic control in patients with gestational diabetes mellitus ( GDM ) . STUDY DESIGN Sixty-four patients with gestational diabetes mellitus were r and omly assigned into 2 groups : an exercise group ( EG ; n = 32 ) and a control group not su bmi tted to the exercise program ( CG ; n = 32 ) . RESULTS A significant reduction in the number of patients who required insulin was observed in the EG ( 7/32 ) compared with the CG group ( 18/32 ) ( P = .005 ) . The percentage of time spent within the proposed target glucose range ( of at least 80 % of weekly measurements below the limits preestablished for the disease ) was significantly higher in EG compared with the CG group ( EG = 0.63 ± 0.30 ; CG = 0.41 ± 0.31 ; P = .006 ) . CONCLUSION The resistance exercise program was effective in reducing the number of patients with GDM who required insulin and in improving capillary glycemic control in this population [21208779] This article introduces the approach of GRADE to rating quality of evidence . GRADE specifies four categories-high , moderate , low , and very low-that are applied to a body of evidence , not to individual studies . In the context of a systematic review , quality reflects our confidence that the estimates of the effect are correct . In the context of recommendations , quality reflects our confidence that the effect estimates are adequate to support a particular recommendation . R and omized trials begin as high- quality evidence , observational studies as low quality . " Quality " as used in GRADE means more than risk of bias and so may also be compromised by imprecision , inconsistency , indirectness of study results , and publication bias . In addition , several factors can increase our confidence in an estimate of effect . GRADE provides a systematic approach for considering and reporting each of these factors . GRADE separates the process of assessing quality of evidence from the process of making recommendations . Judgments about the strength of a recommendation depend on more than just the quality of evidence [9704236] The objective of this study was to test the hypothesis that a woman 's dietary carbohydrate mix modifies the glucose and insulin response to both mixed caloric intake and exercise . Either a prospect i ve r and omized or a prospect i ve r and omized crossover design was used to examine the effects of two isocaloric , high-carbohydrate diets on the whole-blood glucose and insulin responses to mixed caloric intake and exercise in healthy nonpregnant ( n = 14 ) and pregnant ( n = 12 ) women . The diets differed only in the type of carbohydrate ingested . Those in one had low glycemic indexes and those in the other had high glycemic indexes . In nonpregnant women , the blood glucose response to a meal containing low-glycemic carbohydrate was half that seen with high-glycemic carbohydrate , and the effect of exercise on blood glucose was more pronounced while eating the high-glycemic carbohydrate diet . During pregnancy , women on the low-glycemic carbohydrate diet experienced no significant change in their glycemic response to mixed caloric intake , whereas those who switched to the high-glycemic carbohydrate diet experienced a 190 % increase in their response . In conclusion , the type of dietary carbohydrate in a healthy , physically active woman 's diet influences both her postpr and ial blood glucose profile and her blood sugar response to exercise [21895947] Please cite this paper as : Nascimento S , Surita F , Parpinelli M , Siani S , Pinto e Silva J. The effect of an antenatal physical exercise programme on maternal/perinatal outcomes and quality of life in overweight and obese pregnant women : a r and omised clinical trial . BJOG 2011;118:1455–1463 [26294205] Introduction and hypothesisThe objective was to assess foetal wellbeing in pregnant women subjected to pelvic floor muscle training ( PFMT ) by evaluating the acute and chronic effects of the procedure using the Doppler method . Methods Ninety-six primigravidae with singleton pregnancies and at a low risk of pregnancy complications were r and omised to either intervention with PFMT or no intervention . The final analysis included 26 women in the intervention group and 33 in the control group . Women from the intervention group were subjected to a daily PFMT program . Evidence of possible foetal risk was assessed by Doppler and the control group received st and ard care . The protocol was conducted from 20 to 36 weeks ’ gestation . The pulsatility indices ( PI ) of the uterine , umbilical and middle cerebral arteries were determined at 28 , 32 and 36 weeks ’ gestation . The acute effects were determined by comparing the values obtained before and after exercise in the group subjected to PFMT and the chronic effects were determined by comparing the resting values of the trained group with those of the control group . Results The results obtained showed normal values for the three gestational ages in both groups , with no difference between groups . Comparison before and after exercise showed a significant decline in the PI of uterine artery at 36 weeks without changes in the flow of umbilical and middle cerebral arteries . Conclusion Pelvic floor muscle training in low-risk primigravidae with singleton pregnancies was associated with a significant decline in PI of the uterine artery after exercise , while no significant changes in the flow of the middle cerebral and umbilical arteries were found . The PFMT may be recommended to women as a first-line measure to prevent of urinary incontinence during pregnancy [25518308] BACKGROUND Pelvic floor muscle exercises ( PFME ) are commonly recommended during pregnancy and after birth for both prevention and treatment of lower urinary tract symptoms ( LUTS ) . Stress urinary incontinence has long been presumed to be associated with urethral hypermobility . Pregnancy and delivery are known cause of increasing bladder neck descent ( BND ) . OBJECTIVE The present study aim ed to determine the effect of antenatal PFME on bladder neck descent in nulliparous pregnancy . MATERIAL AND METHOD 219 nulliparous women pregnant between 8 - 12 weeks were interviewed and then underwent transperineal ultrasound . Of the total , 108 women were r and omly assigned to a PFMT group , while 111 women to a control group . The latter group received routine antenatal care . For the intervention group , patients were taught about PFMT using visual biofeedback by transperineal ultrasound . The PFMT regimen comprised a series of 15 contractions , and each contraction was heldfor 5 seconds , with 5 seconds rest between each contraction . Patients were asked to repeat this regimen for 3 times after each meal . At second trimester , third trimester , 3-month postpartum and 6-month postpartum , the subjects in both groups were interviewed and then underwent another ultrasound assessment . Transperineal ultrasound was performed after bladder emptying , with the patient in the supine position . Bladder neck position was measured at rest and on maximal valsava , and the differences yielded a numerical valueforBND . The sample size was calculated with apower of80 % p<0.05 was considered significant . SPSS 15 . Ofor windows ( SPSS Inc. , Chicago , Illinois ) was used for statistical analyses . RESULTS Demographic characteristics did not differ significantly between PFMT and control groups , showing effective r and omization . Mean age was 26.95±3.94 and 26.51±5.41 years for PFMT and control group , respectively ( p = 0.49 ) . There were no significant differences in bladder symptoms between the two groups at the first visit . In the first trimester , the average BND of the PFMT group was slightly higher than BND of the control group ( 14.1±6.9 mm and 12.2±6.7 mm respectively ( p = 0.04 ) ) . When comparing delivery mode by using Pearson 's Chi-square test , there was no statistically significant difference between two groups ( p = 0.35 ) . The mean fetal birth weight of women in the PFMTgroup was 3,084 grams and in the control group was 3,093 grams ( p = 0.88 ) . At 6 monthspostpartum , 80 women of the PFMT group and 65 women of the control group returned for follow-up . There were no differences regarding the prevalence ofL UTS between the groups at 6 months after delivery . Women in the control group had a higher BND ( 16.4±6.6 mm ) than those in the PFMT group ( 13.9±7.3 mm , p = 0.03 ) . This difference was also found in the subgroup of the women who delivered vaginally ( BND = 17.5±6.7 mm in the control group and 13.2±7.4 mm in the PFMTgroup , p = 0.006 ) . CONCLUSION Although postpartum prevalence of LUTS was no different between groups , this study has demonstrated that antenatal pelvic floor muscle exercises may reduce bladder neck mobility at 6 months after childbirth . The significance of such an effect remains to be determined [7674866] To investigate the effects of participation in aerobic exercise on pregnancy outcome , 388 women ( mean age = 31.7 , range = 18 - 42 ) were followed from a mean 16.5-wk gestation through delivery . Frequency , duration , and mode of aerobic exercise prior to conception and during the first trimester were determined by in-person interviews . Activity patterns during the second and third trimesters were assessed by telephone interviews . For each time period , women were categorized into one of the following exercise groups : Level I = aerobic exercise , excluding vigorous walking , at least three times a week for at least 20 min a time ; Level II = aerobic exercise at least three times a week and 20 min at a time , if and only if vigorous walking is included ; Level III = aerobic exercise less than three times a week , 20 min a time ; and Level IV = aerobic exercise less than once a week . Mean birthweight was statistically unrelated to level of exercise preconceptionally or in any trimester . Gestational age , weight gain , and other pregnancy outcomes were also unassociated with exercise level . However , pregnancy symptoms were inversely associated with level of exercise ; women who exercised more earlier in pregnancy reported fewer discomforts later in pregnancy ( P = 0.01 ) . These data suggest that participation in aerobic exercise during pregnancy at a level great enough to produce or maintain a training effect does not adversely affect birthweight or other maternal and infant outcomes but may be associated temporally with fewer perceived pregnancy-associated discomforts [22183208] OBJECTIVE : To assess whether exercise during pregnancy can prevent gestational diabetes and improve insulin resistance . METHODS : A total of 855 women in gestational week 18–22 were r and omly assigned to receiving a 12-week st and ard exercise program ( intervention group ) or st and ard antenatal care ( control group ) . The exercise program followed st and ard recommendations and included moderate-intensity to high-intensity activity 3 or more days per week . Primary outcomes were gestational diabetes and insulin resistance estimated by the homeostasis model assessment method . For the power calculation , we assumed a gestational diabetes prevalence of 9 % in the control group and a prevalence of 4 % in the exercise group ( risk difference of 5 % ) . Under these assumptions , a two- sample comparison with a 5 % level of significance and power of 0.80 gave a study population of 381 patients in each group . RESULTS : At 32–36 weeks of gestation there were no differences between groups in prevalence of gestational diabetes : 25 of 375 ( 7 % ) in the intervention group compared with 18 of 327 ( 6 % ) in the control group ( P=.52 ) . There were no differences in insulin resistance between groups when adjusting for baseline values . Only 55 % of women in the intervention group managed to follow the recommended exercise protocol . No serious adverse events related to physical exercise were seen , and the outcomes of pregnancy were similar in the two groups . CONCLUSION : There was no evidence that offering women a 12-week st and ard exercise program during the second half of pregnancy prevents gestational diabetes or improves insulin resistance in healthy pregnant women with normal body mass indexes . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00476567 . LEVEL OF EVIDENCE : [26223239] OBJECTIVE To assess whether gestational diabetes mellitus ( GDM ) can be prevented by a moderate lifestyle intervention in pregnant women who are at high risk for the disease . RESEARCH DESIGN AND METHODS Two hundred ninety-three women with a history of GDM and /or a prepregnancy BMI of ≥30 kg/m2 were enrolled in the study at < 20 weeks of gestation and were r and omly allocated to the intervention group ( n = 155 ) or the control group ( n = 138 ) . Each subject in the intervention group received individualized counseling on diet , physical activity , and weight control from trained study nurses , and had one group meeting with a dietitian . The control group received st and ard antenatal care . The diagnosis of GDM was based on a 75-g , 2-h oral glucose tolerance test at 24–28 weeks of gestation . RESULTS A total of 269 women were included in the analyses . The incidence of GDM was 13.9 % in the intervention group and 21.6 % in the control group ( [ 95 % CI 0.40–0.98 % ] ; P = 0.044 , after adjustment for age , prepregnancy BMI , previous GDM status , and the number of weeks of gestation ) . Gestational weight gain was lower in the intervention group ( −0.58 kg [ 95 % CI −1.12 to −0.04 kg ] ; adjusted P = 0.037 ) . Women in the intervention group increased their leisure time physical activity more and improved their dietary quality compared with women in the control group . CONCLUSIONS A moderate individualized lifestyle intervention reduced the incidence of GDM by 39 % in high-risk pregnant women . These findings may have major health consequences for both the mother and the child [24652353] OBJECTIVE There is controversy concerning whether exercise during pregnancy may increase preterm delivery risk and type of delivery . The effect of pregnant Latin-American women engaging in vigorous exercise during the second and third trimester was examined regarding type of delivery and gestational age . MATERIAL S AND METHODS This was a secondary analysis of data from a controlled r and omized trial for determining the influence of physical exercise on pregnant women 's endothelial function . The study included 35 nulliparous women , gestational week 16 - 20 attending prenatal care at three tertiary hospitals in Colombia , who were r and omly assigned to one of two groups . The experimental group engaged in aerobic exercise involving 55 % - 75 % maximum heart rate for 60 min , three times a week for 12 weeks . The control group engaged in their usual physical activity . Maternal weight , height , weight gain , blood pressure and type of delivery were recorded ; gender , abdominal and head circumference ( cm ) , weight ( g ) , height ( cm ) , vitality ( Apgar score at 1 and 5 min ) and gestational age at the time of delivery ( in weeks , days ) were recorded for the newborn . RESULTS There was no difference in type of delivery by the end of the 12-week program ( p > 0.05 ) , nor regarding newborn anthropometric variables , Apgar score , or maternal variables concerning weight , height , relative weight gain , blood pressure or weeks of gestation ( p>0.05 ) . CONCLUSION The potential public health benefits of vigorous exercise were enormous . This study supported existing guidelines indicating that Latin-American women may begin or maintain an on-going exercise program during pregnancy . TRIAL REGISTRATION NCT00741312 [2890340] OBJECTIVE To examine the feasibility of an individualized exercise program to prevent gestational diabetes mellitus ( GDM ) in obese pregnant women . RESEARCH DESIGN AND METHODS The study was a pilot r and omized controlled trial with obese pregnant women ( intervention group , individualized exercise program [ n = 25 ] ; control group , usual care [ n = 25 ] ) . Average weekly energy expenditure ( MET hours per week and kilocalories per week ) of exercise-specific activity was assessed during pregnancy using the Pregnancy Physical Activity Question naire . Fasting glucose and insulin and homeostasis model assessment of insulin resistance ( HOMA-IR ) were assessed at baseline and 20 , 28 , and 36 weeks ' gestation . RESULTS Of the women in the intervention group , 16 of 22 ( 73 % ) achieved more than 900 kcal/week of exercise-based activity at 28 weeks compared with 8 of 19 women in the control group ( 42 % ) , P = 0.047 . However , insulin resistance ( HOMA-IR ) did not differ between the groups . CONCLUSION This intervention was feasible and prompted a modest increase in physical activity . However , we are not confident that this intervention would be sufficient to prevent GDM [21417561] Objectives To assess whether a 12-week supervised exercise-programme with an additional 30 min of moderate self-imposed physical activity on the non-supervised weekdays prevents excessive weight gain in pregnancy , as well as postpartum weight retention . Methods One hundred and five sedentary , nulliparous pregnant women with a mean age of 30.7 ± 4.0 years and a pre-pregnancy body mass index of 23.8 ± 4.3 kg/m2 were r and omised to either an exercise group ( EG , n = 52 ) or a control group ( CG , n = 53 ) . The exercise programme consisted of 60 min supervised aerobic dance and strength training for 60 min , at least twice per week for a minimum of 12 weeks . Results Drop-out rates were 19 % and 21 % in the EG and CG , respectively . Fewer women in the EG than in the CG exceeded the Institute of Medicine recommendations ; however , only EG participants who attended 24 exercise sessions ( n = 14 ) differed significantly from controls ( p = 0.006 ) with regard to weight gain during pregnancy ( 11.0 ± 2.3 vs. 13.8 ± 3.8 kg , p < 0.01 ) and postpartum weight retention ( 0.8 ± 1.7 vs. 3.3 ± 4.1 kg , p < 0.01 ) . Conclusions Regular participation in aerobic dance exercise can contribute to significantly reduce weight gain during pregnancy [8515355] Regular physical activity is an established therapeutic adjunct in diabetes , but has not been offered to pregnant diabetics in the past ; for sports might induce significant cardiovascular and hormonal changes that are able to reduce blood flow to the uterus and thus limit oxygen transfer to the fetus . Study ing the impact of a medically supervised exercise program on gestational diabetes mellitus [ GDM ) in a r and omised prospect i ve longitudinal study , this paper aims to assess the effects of maternal moderate and strenuous exercise on the fetus . By evaluating shortterm fetal responses as reflected in heart rate patterns ( FHR ) and longterm-pregnancy complications and neonatal outcome , our results suggest that -- in absence of ominous FHR changes or significant changes in uterine activity following the exercise sessions or increased diabetes-related peri- and neonatal morbidity -- regular physical activity seems to be a safe therapeutic option for the fetus of GDM mothers [25333246] PURPOSE The objective of this study is to assess the effectiveness of a maternal exercise program ( l and /aquatic activities , both aerobic and muscular conditioning ) in preventing gestational diabetes mellitus ( GDM ) . METHODS Three hundred and forty-two pregnant women from Spain ( age , 33.24 ± 4.3 yr ) without obstetric contraindications were recruited for a clinical r and omized controlled trial . The intervention group ( IG , n = 101 ) exercised for 60 and 50 min on l and and in water , respectively , three times per week . The control group ( n = 156 ) received usual st and ard care . RESULTS The prevalence of GDM was reduced in the IG group ( IG , 1 % , n = 1 , vs control group , 8.8 % , n = 13 ( χ1 = 6.84 , P = 0.009 ) ) with a significant risk estimate ( odds ratio = 0.103 ; 95 % confidence interval , 0.013 - 0.803 ) . CONCLUSION The exercise program performed during pregnancy reduced the prevalence of GDM by preserving glucose tolerance [15813473] BACKGROUND The main factor for the appearance of urinary stress incontinence in almost all women is pregnancy and vaginal childbirth . The pelvic floor exercises have been described for the treatment of urinary stress incontinence . OBJECTIVE To determine with a r and omized controlled trial if the pelvic floor exercises during pregnancy and late puerperium diminish the prevalence of urinary stress incontinence at 28 and 35 gestational week and at 6 weeks after childbirth . MATERIAL AND METHODS The study was made with nulliparous , pregnant women who realized pelvic floor exercises during pregnancy and after birth . 72 women were studied , 52.7 % realized pelvic floor exercises and 47.2 % did not . RESULTS The urinary stress incontinence frequency at the 28 gestational week in the no exercises group was 17.2 % , and at the 35 gestational week of 47 % and at 6 weeks after childbirth was of 47 % , while in the exercises group was 0 , 0 and 15 % , respectively . Moreover there were statistically significant differences between both groups regarding the presence of urinary stress incontinence , that is , the group that realized exercises presented less incontinence at the 28 and 35 gestational weeks and at 6 weeks after childbirth . CONCLUSIONS The results of this study concluded that the pelvic floor exercises during pregnancy and after childbirth prevent the urinary stress incontinence at this time [24200335] Purpose . The aim of the present study was to examine the influence of a program of moderate physical exercise throughout pregnancy on maternal and fetal parameters . Design . The study design was a r and omized controlled trial . Setting . The study took place at the Hospital of Fuenlabrada in Madrid , Spain . Sample . Analyzed were 200 pregnant women ( 31.54 ± 3.86 years ) , all of whom had uncomplicated and singleton gestation . Of these subjects , 107 were allocated to the exercise group ( EG ) and 93 to the control group ( CG ) . Intervention . Women from EG participated in a physical conditioning program throughout pregnancy , which included a total of 55- to 60-minute weekly sessions , 3 days per week . Measures . Pregnancy outcomes . Maternal : gestational age , weight gain , type of delivery , blood pressure during pregnancy , gestational diabetes ( n/% ) . Fetal : birth weight , birth size , head circumference , Apgar score , pH of umbilical cord . Analysis . Student 's unpaired t-test and χ2 test were used ; p values of ≤ .05 indicated statistical significance . Cohen 's d was used to determine the effect size . Results . There were significantly more pregnant women in the CG who gained excessive weight during their pregnancies than in the EG group ( CG : N = 31 , 35.6 % versus N = 22 , 21.2 % ; χ2 = 4.95 ; p = .02 ) . The effect size was small ( Phi value = .16 ) . Other pregnancy outcome showed no differences between groups . Conclusion . A regular and moderate physical exercise program throughout pregnancy is not a risk to maternal and fetal well-being , and it helps to control excessive weight gain [22616913] Please cite this paper as : Oostdam N , van Poppel M , Wouters M , Eekhoff E , Bekedam D , Kuchenbecker W , Quartero H , Heres M , van Mechelen W. No effect of the FitFor2 exercise programme on blood glucose , insulin sensitivity , and birthweight in pregnant women who were overweight and at risk for gestational diabetes : results of a r and omised controlled trial . BJOG 2012;119:1098–1107 [22464118] Eighty-four prenatally depressed women were r and omly assigned to yoga , massage therapy or st and ard prenatal care control groups to determine the relative effects of yoga and massage therapy on prenatal depression and neonatal outcomes . Following 12 weeks of twice weekly yoga or massage therapy sessions ( 20 min each ) both therapy groups versus the control group had a greater decrease on depression , anxiety and back and leg pain scales and a greater increase on a relationship scale . In addition , the yoga and massage therapy groups did not differ on neonatal outcomes including gestational age and birthweight , and those groups , in turn , had greater gestational age and birthweight than the control group [1750458] To assess the longitudinal changes in insulin release and insulin sensitivity in nonobese normal women during gestation , six women were evaluated with oral glucose tolerance testing , body composition analysis , intravenous glucose tolerance tests , and the hyperinsulinemic-euglycemic clamp before conception , at 12 to 14 weeks , and at 34 to 36 weeks ' gestation . There was a significant increase in the insulin/glucose ratio ( p = 0.028 ) during the oral glucose tolerance test during gestation . There was also a significant 3.0- to 3.5-fold increase throughout gestation in first-phase ( p = 0.001 ) and second-phase ( p = 0.0001 ) insulin release during the intravenous glucose tolerance test . Peripheral insulin sensitivity was estimated as the glucose infusion rate ( in milligrams per kilogram fat-free mass per minute ) during the hyperinsulinemic-euglycemic clamp . There was a significant ( p = 0.0003 ) 56 % decrease in insulin sensitivity through 36 weeks ' gestation . These results are the first to prospect ively evaluate the longitudinal changes in maternal carbohydrate metabolism from the time before conception through late gestation with newer methods such as the hyperinsulinemic-euglycemic clamp [26491878] BACKGROUND Smoking during pregnancy is the main preventable cause of poor birth outcomes . Improved methods are needed to help women to stop smoking during pregnancy . Pregnancy provides a compelling rationale for physical activity ( PA ) interventions as cessation medication is contraindicated or ineffective , and an effective PA intervention could be highly cost-effective . OBJECTIVE To examine the effectiveness and cost-effectiveness of a PA intervention plus st and ard behavioural support for smoking cessation relative to behavioural support alone for achieving smoking cessation at the end of pregnancy . DESIGN Multicentre , two-group , pragmatic r and omised controlled trial and economic evaluation with follow-up at the end of pregnancy and 6 months postnatally . R and omisation was stratified by centre and a computer-generated sequence was used to allocate participants using a 1 : 1 ratio . SETTING 13 hospitals offering antenatal care in the UK . PARTICIPANTS Women between 10 and 24 weeks ' gestation smoking five or more cigarettes a day before pregnancy and one or more during pregnancy . INTERVENTIONS Participants were r and omised to behavioural support for smoking cessation ( control ) or behavioural support plus a PA intervention consisting of supervised treadmill exercise plus PA consultations . Neither participants nor research ers were blinded to treatment allocation . MAIN OUTCOME MEASURES The primary outcome was self-reported , continuous smoking abstinence between a quit date and end of pregnancy , vali date d by expired carbon monoxide and /or salivary cotinine . Secondary outcomes were maternal weight , depression , birth outcomes , withdrawal symptoms and urges to smoke . The economic evaluation investigated the costs of the PA intervention compared with the control intervention . RESULTS In total , 789 women were r and omised ( n = 394 PA , n = 395 control ) . Four were excluded post r and omisation ( two had been enrolled twice in sequential pregnancies and two were ineligible and r and omised erroneously ) . The intention-to-treat analysis comprised 785 participants ( n = 392 PA , n = 393 control ) . There was no significant difference in the rate of abstinence at the end of pregnancy between the PA group ( 7.7 % ) and the control group ( 6.4 % ) [ odds ratio for PA group abstinence 1.21 , 95 % confidence interval ( CI ) 0.70 to 2.10 ] . For the PA group compared with the control group , there was a 33 % ( 95 % CI 14 % to 56 % ) , 28 % ( 95 % CI 7 % to 52 % ) and 36 % ( 95 % CI 12 % to 65 % ) significantly greater increase in self-reported minutes of moderate- and vigorous-intensity PA from baseline to 1 week , 4 weeks and 6 weeks respectively . Accelerometer data showed that there was no significant difference in PA levels between the groups . There were no significant differences between the groups for change in maternal weight , depression , withdrawal symptoms or urges to smoke . Adverse events and birth outcomes were similar between the groups except for there being significantly more caesarean births in the control group than in the PA group ( 28.7 % vs. 21.3 % ; p < 0.023 ) . The PA intervention was less costly than the control intervention by £ 35 per participant . This was mainly attributable to increased health-care usage in the control group . However , there was considerable statistical uncertainty around this estimate . CONCLUSIONS During pregnancy , offering an intervention combining supervised exercise and PA counselling does not add to the effectiveness of behavioural support for smoking cessation . Only 10 % of participants had PA levels accessed by accelerometer and it is , therefore , unclear whether or not the lack of an effect on the primary outcome is the result of insufficient increases in PA . Research is needed to identify the smoking population s most suitable for PA interventions and methods for increasing PA adherence . TRIAL REGISTRATION Current Controlled Trials IS RCT N48600346 . FUNDING This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol . 19 , No. 84 . See the NIHR Journals Library website for further project information [22843114] OBJECTIVE A prospect i ve r and omized controlled trial was design ed to assess the benefits and possible risks of aerobic exercise during pregnancy , using a fitness regimen based on the 2002 American College of Obstetricians and Gynecologists guidelines for exercise during pregnancy . METHODS Inactive women were r and omized at 12 - 14 wk gestation to a group that remained sedentary or to a group that performed moderate aerobic exercise 45 - 60 min , 4 d·wk , through 36 wk gestation . Thirty-one subjects in each group completed the study . RESULTS Compared with women who remained sedentary , active women improved aerobic fitness ( P < 0.05 ) and muscular strength ( P < 0.01 ) , delivered comparable size infants with significantly fewer cesarean deliveries ( P < 0.01 ) , and recovered faster postpartum ( P < 0.05 ) , at least related to the lower incidence of cesarean section . Active women developed no gestational hypertension ( P = 0.16 compared with controls ) and reported no injuries related to the exercise regimen . In the active group , there was one premature birth at 33 wk by a woman with a history of premature delivery of twins at 34 wk . There were no differences between groups in the incidence of gestational diabetes , musculoskeletal pains during pregnancy , flexibility on sit- and -reach test , mean length of pregnancy , neonatal Apgar scores , placenta weights , overall length of labor , weight gain during pregnancy , or weight retention postpartum . CONCLUSION Previously sedentary women who began exercising at 12 - 14 wk improved fitness and delivery outcomes [6513772] The interaction between maternal endurance exercise at or above a minimal conditioning level , prior to and during pregnancy , and pregnancy outcome was examined prospect ively in our obstetrical populace using epidemiologic techniques . Over a 3-month interval all women registering for antepartum care were interviewed . Those planning to continue exercise during pregnancy were re-interviewed between the 28th and 34th gestational weeks . A detailed review of clinical records was used for outcome assessment . Women who continued endurance exercise at or near preconceptual levels during pregnancy gained less weight ( -4.6 kg ) , delivered earlier (-8 d ) , and had lighter-weight offspring ( -500 g ) than those who stopped exercising prior to the 28th week . The latter group gained 2.2 kg more weight but delivered similar birthweight infants at a similar gestational age as their sedentary controls [30337348] Objective Theoretical concerns regarding the supine position at rest due to the gravid uterus obstructing aorta and vena caval flow may impinge uterine blood flow ( UBF ) to the fetus and maternal venous return . Design Systematic review . Data sources Online data bases up to 11 December 2017 . Study criteria Eligible population ( pregnant without contraindication to exercise ) , intervention ( frequency , intensity , duration , volume or type of supine exercise ) , comparator ( no exercise or exercise in left lateral rest position , upright posture or other supine exercise ) , outcomes ( potentially adverse effects on maternal blood pressure , cardiac output , heart rate , oxygen saturation , fetal movements , UBF , fetal heart rate ( FHR ) patterns ; adverse events such as bradycardia , low birth weight , intrauterine growth restriction , perinatal mortality and other adverse events as documented by study authors ) , and study design ( except case studies and review s ) published in English , Spanish , French or Portuguese . Results Seven studies ( n=1759 ) were included . ‘ Very low ’ to ‘ low ’ quality evidence from three r and omised controlled trials indicated no association between supervised exercise interventions that included supine exercise and low birth weight compared with no exercise . There was ‘ very low ’ to ‘ low ’ quality evidence from four observational studies that showed no adverse events in the mother ; however , there were abnormal FHR patterns ( as defined by study authors ) in 20 of 65 ( 31 % ) fetuses during an acute bout of supine exercise . UBF decreased ( 13 % ) when women moved from left lateral rest to acute dynamic supine exercise . Conclusion There was insufficient evidence to ascertain whether maternal exercise in the supine position is safe or should be avoided during pregnancy [23224059] Background — Preterm birth leads to an early switch from fetal to postnatal circulation before completion of left ventricular in utero development . In animal studies , this results in an adversely remodeled left ventricle . We determined whether preterm birth is associated with a distinct left ventricular structure and function in humans . Methods and Results — A total of 234 individuals 20 to 39 years of age underwent cardiovascular magnetic resonance . One hundred two had been followed prospect ively since preterm birth ( gestational age=30.3±2.5 week ; birth weight=1.3±0.3 kg ) , and 132 were born at term to uncomplicated pregnancies . Longitudinal and short-axis cine images were used to quantify left ventricular mass , 3-dimensional geometric variation by creation of a unique computational cardiac atlas , and myocardial function . We then determined whether perinatal factors modify these left ventricular parameters . Individuals born preterm had increased left ventricular mass ( 66.5±10.9 versus 55.4±11.4 g/m2 ; P<0.001 ) with greater prematurity associated with greater mass ( r = −0.22 , P=0.03 ) . Preterm-born individuals had short left ventricles with small internal diameters and a displaced apex . Ejection fraction was preserved ( P>0.99 ) , but both longitudinal systolic ( peak strain , strain rate , and velocity , P<0.001 ) and diastolic ( peak strain rate and velocity , P<0.001 ) function and rotational ( apical and basal peak systolic rotation rate , P = 0.05 and P = 0.006 ; net twist angle , P=0.02 ) movement were significantly reduced . A diagnosis of preeclampsia during the pregnancy was associated with further reductions in longitudinal peak systolic strain in the offspring ( P=0.02 , n=29 ) . Conclusions — Individuals born preterm have increased left ventricular mass in adult life . Furthermore , they exhibit a unique 3-dimensional left ventricular geometry and significant reductions in systolic and diastolic functional parameters . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT01487824 [24646172] The benefits of exercise and behavioural recommendations in gestational diabetes mellitus ( GDM ) are controversial . In a r and omized trial with a 2 × 2 factorial design , we examined the effect of exercise and behavioural recommendations on metabolic variables , and maternal/neonatal outcomes in 200 GDM patients . All women were given the same diet : group D received dietary recommendations only ; group E was advised to briskly walk 20‐min/day ; group B received behavioural dietary recommendations ; group BE was prescribed the same as B + E. Dietary habits improved in all groups . In a multivariable regression model , fasting glucose did not change . Exercise , but not behavioural recommendations , was associated with the reduction of postpr and ial glucose ( p < 0001 ) , glycated haemoglobin ( HbA1c ; p < 0.001 ) , triglycerides ( p = 0.02 ) and C‐reactive protein ( CRP ; p < 0.001 ) and reduced any maternal/neonatal complications ( OR = 0.50 ; 95%CI=0.28–0.89;p = 0.02 ) . In GDM patients a simple exercise programme reduced maternal postpr and ial glucose , HbA1c , CRP , triglycerides and any maternal/neonatal complications , but not fasting glucose values [24060449] OBJECTIVE The objective of the study was to assess physical activity intervention assessed by a pedometer with or without dietary intervention on gestational weight gain ( GWG ) in obese pregnant women by comparing with a control group . STUDY DESIGN This study was a r and omized controlled trial of 425 obese pregnant women comparing 3 groups : ( 1 ) PA plus D , physical activity and dietary intervention ( n = 142 ) ; ( 2 ) PA , physical activity intervention ( n = 142 ) ; and ( 3 ) C , a control group receiving st and ard care ( n = 141 ) . All participants routinely in gestational weeks 11 - 14 had an initial dietary counseling session and were advised to limit GWG to less than 5 kg . Physical activity intervention included encouragement to increase physical activity , aim ing at a daily step count of 11,000 , monitored by pedometer assessment on 7 consecutive days every 4 weeks . Dietary intervention included follow-up on a hypocaloric Mediterranean-style diet . Instruction was given by a dietician every 2 weeks . The primary outcome measure was GWG , and the secondary outcome measures were complications of pregnancy and delivery and neonatal outcome . RESULTS The study was completed by 389 patients ( 92 % ) . Median values of GWG ( ranges ) were lower in each of the intervention groups ( PA plus D , 8.6 [ -9.6 to 34.1 ] kg , and group PA , 9.4 [ -3.4 to 28.2 ] kg ) compared with the control group ( 10.9 [ -4.4 to 28.7 ] kg [ PA+D vs C ] ; P = .01 ; PA vs C ; P = .042 ) . No significant difference was found between the 2 intervention groups . In a multivariate analysis , physical activity intervention decreased GWG by a mean of 1.38 kg ( P = .040 ) . The Institute of Medicine 's recommendations for GWG were more frequently followed in the intervention groups . CONCLUSION Physical activity intervention assessed by pedometer with or without dietary follow-up reduced GWG compared with controls in obese pregnant women [22898328] OBJECTIVE The level of physical activity ( PA ) of pregnant women in Finl and is unknown . Even more limited is our knowledge of PA of women at high risk for gestational diabetes mellitus ( GDM ) . METHODS The women ( n=54 ) were r and omly assigned to a lifestyle intervention group ( n=27 ) including exercise advice by a physiotherapist six times during pregnancy or to a control group ( n=27 ) without additional exercise advice . Outcomes of the present study were required sample size , timing of counselling and change of PA . PA was retrospectively reported during 12 months before pregnancy and recorded one week monthly during pregnancy . RESULTS Individualized counselling by a physiotherapist result ed in small changes of recreational PA ( 2.7 MET hours/week , p=0.056 ) up to gestational week 25 compared with the similar decreasing tendency of PA in the control group . The women decreased recreational PA after week 30 . Sample size of 550 women at high risk for GDM per group would be needed for a PA study . CONCLUSIONS The optimal time window for increasing PA must be earlier than in the last trimester of pregnancy . Sample size for a study to increase PA by 2.7 MET hours/week on pregnant women at high risk of GDM should be about 550 per group [3096610] In a cluster-r and omized trial , Riitta Luoto and colleagues find that counseling on diet and activity can reduce the birthweight of babies born to women at risk of developing gestational diabetes mellitus ( GDM ) , but fail to find an effect on GDM [24175912] Abstract Objectives : To determine whether changes in lifestyle in women with BMI > 25 could decrease gestational weight gain and unfavorable pregnancy outcomes . Methods : Women with BMI > 25 were r and omized at 1st trimester to no intervention or a Therapeutic Lifestyle Changes ( TLC ) Program including diet ( overweight : 1700 kcal/day , obese : 1800 kcal/day ) and mild physical activity ( 30 min/day , 3 times/week ) . At baseline and at the 36th week women filled-in a Food Frequency Question naire . Outcomes : gestational weight gain , gestational diabetes mellitus , gestational hypertension , preterm delivery . Data stratified by BMI categories . Results : Socio-demographic features were similar between groups ( TLC : 33 cases , Controls : 28 cases ) . At term , gestational weight gain in obese women r and omized to TLC group was lower ( 6.7 ± 4.3 kg ) versus controls ( 10.1 ± 5.6 kg , p = 0.047 ) . Gestational diabetes mellitus , gestational hypertension and preterm delivery were also significantly lower . TLC was an independent factor in preventing gestational weight gain , gestational diabetes mellitus , gestational hypertension . Significant changes in eating habits occurred in the TLC group , which increased the number of snacks , the intake of fruits – vegetables and decreased the consumption of sugar . Conclusions : A caloric restriction associated to changes in eating behavior and constant physical activity , is able to reduce gestational weight gain and related pregnancy complications in obese women [21310836] BACKGROUND Excessive weight gain during pregnancy is a major risk factor for postpartum weight retention and future weight gain and obesity in women , but few adequately powered r and omized controlled trials have examined the efficacy of a behavioral weight-control intervention during pregnancy . OBJECTIVE This study examined whether a behavioral intervention during pregnancy could decrease the proportion of women who exceeded the 1990 Institute of Medicine ( IOM ) recommendations for gestational weight gains and increase the proportion of women who returned to pregravid weights by 6 mo postpartum . DESIGN This study was a r and omized , assessor-blind , controlled trial . Participants were pregnant ( 13.5 wk gestation ) , normal-weight ( NW ; n = 201 ) and overweight or obese ( OW/OB ; n = 200 ) women whose average age was 28.8 y. Participants were r and omly assigned within the 1990 IOM weight category ( NW compared with OW/OB ) to st and ard care ( n = 200 ) or to a behavioral intervention to prevent excessive gestational weight gain ( n = 201 ) . The intervention included one face-to-face visit ; weekly mailed material s that promoted an appropriate weight gain , healthy eating , and exercise ; individual graphs of weight gain ; and telephone-based feedback . The retention at the 6-mo postpartum assessment was 82 % . RESULTS Intent-to-treat analyses showed that the intervention , compared with st and ard care , decreased the percentage of NW women who exceeded IOM recommendations ( 40.2 % compared with 52.1 % ; P = 0.003 ) and increased the percentages of NW and OW/OB women who returned to their pregravid weights or below by 6 mo postpartum ( 30.7 % compared with 18.7 % ; P = 0.005 ) . CONCLUSION A low-intensity behavioral intervention during pregnancy reduced excessive gestational weight gains in NW women and prevented postpartum weight retention in NW and OW/OB women . This trial was registered at clinical trials.gov as NCT01117961 Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: Objective To perform a systematic review of the relationships between prenatal exercise and maternal harms including labour/delivery outcomes . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

28301050

[12480610] The aim of the study was to investigate the effect of addition of montelukast to inhaled fluticasone propionate ( FP ) therapy , compared with FP therapy alone ( 100 microg twice a day ) on airway immunopathology in individuals with mild asthma . Twenty-eight subjects received FP ( 100 microg twice a day ) or FP ( 100 microg twice a day ) plus montelukast ( 10 mg at night ) for 8 weeks and were then crossed over to the alternate treatment for a further 8 weeks . Physiological measurements and bronchial biopsies were obtained at + /- 2 days before treatment and + /- 2 days at the end of each treatment period . A two-period crossover analysis was performed and the mean and SE were calculated . There was no significant difference in percent predicted FEV1 ( p = 0.51 ) or PC20 mg/ml ( p = 0.81 ) between the two treatment regimes after 8 weeks of therapy . There was no difference in the efficacy of either treatment in decreasing T cell ( p = 0.97 ) , CD45RO+ ( p = 0.37 ) , mast cell ( p = 0.37 ) , or activated eosinophils ( p = 0.55 ) numbers in bronchial biopsies . There was no significant difference in the percentage area stained for IFN-gamma ( p = 0.76 ) or interleukin-4 ( p = 0.61 ) between treatments . Reduction of inflammatory cell numbers in the bronchial mucosa achieved with FP plus montelukast was not significantly different from the reduction observed with FP alone in individuals with mild asthma [15136378] STUDY OBJECTIVE Evidence for the anti-inflammatory activity of leukotriene receptor antagonists in humans is somewhat limited . There are also no data comparing the anti-inflammatory effects of leukotriene receptor antagonists with those of inhaled corticosteroids . This study was design ed to assess the clinical efficacy and anti-inflammatory effects of leukotriene receptor antagonist plus low-dose inhaled corticosteroids compared to those of a high-dose inhaled corticosteroid in patients with mild-to-moderate asthma . METHODS Forty-nine patients with newly diagnosed asthma were recruited . They were r and omly assigned to groups that received , for a 6-week period , either ( 1 ) budesonide , 600 microg bid ( 1,200 microg/d ) or ( 2 ) budesonide , 200 microg ( 400 microg/d ) , and zafirlukast , 20 mg bid . The variables of asthma control were recorded daily . Sputum induction and methacholine provocation tests were performed . RESULTS The results indicated that the administration of a low-dose inhaled corticosteroid plus zafirlukast was as effective as that of a high-dose inhaled corticosteroid regarding clinical improvement and anti-inflammatory effects ( ie , eosinophil percentage , and eosinophilic cationic protein [ ECP ] and cysteinyl leukotriene C4 levels in induced sputum ) . Nineteen ( group 1 , 8 patients ; group 2 , 11 patients ) of 49 patients ( 38.8 % ) had returned to normal airway responsiveness after treatment . Among these patients , 16 patients ( 84.2 % ) had normal ECP levels and 10 patients ( 52.6 % ) had normal percentages of eosinophils . ECP level , but not the eosinophil percentage , was significantly associated with symptom scores . The peak expiratory flow rate ( PEFR ) showed a significant correlation with the provocative concentration of methacholine causing a 20 % fall in FEV1 ( PC20 ) instead of with symptom scores . CONCLUSIONS The addition of a leukotriene modifier to treatment with low-dose inhaled corticosteroids is equivalent to treatment with high-dose inhaled corticosteroids in patients with newly diagnosed mild-to-moderate asthma . In addition to symptoms and PEFR , the monitoring of ECP and PC20 may be of great value in achieving optimal control of asthma [23380218] OBJECTIVE Many asthmatic patients are unable to quit cigarettes ; therefore information is needed on treatment options for smokers . This study evaluates 10 mg/d montelukast and 250 μg of fluticasone propionate twice daily , each compared with placebo , in patients with self-reported active smoking ( unable to quit ) and asthma . METHODS Patients ( ages 18 - 55 years , with asthma [ ≥1 year ] , FEV1 of 60 % to 90 % of predicted value , airway reversibility [ ≥12 % ] , and self-reported active smoking [ ≥0.5 to ≤2 packs per day ] ) were r and omized ( after a 3-week , single-blind , placebo , run-in period ) to 1 of 3 parallel , 6-month , double-blind treatment arms . The primary efficacy end point was the percentage of days with asthma control during treatment . Adverse experiences ( AEs ) were also evaluated . RESULTS There were 347 , 336 , and 336 patients r and omized to montelukast , fluticasone , and placebo , respectively . The mean percentage of days with asthma control over 6 months of treatment was 45 % ( montelukast , P < .05 vs placebo ) , 49 % ( fluticasone , P < .001 vs placebo ) , and 39 % ( placebo ) ; the difference between montelukast and fluticasone was not significant ( P = .14 ) . Patients with a smoking history of ≤11 pack years ( the median value ) tended to show more benefit with fluticasone , whereas those with a smoking history of > 11 pack years tended to show more benefit with montelukast . AEs occurred in similar proportions among treatment groups . CONCLUSIONS In a population of asthmatic patients actively smoking cigarettes , both 10 mg/d montelukast and 250 μg of fluticasone propionate twice daily significantly increased the mean percentage of days with asthma control compared with placebo [16407639] Background : The motive behind conducting this study was to determine if better control of asthma can be achieved by adding a second controller medication and to assess its use to reduce the dose of inhaled steroids . Objectives : The study aim ed to determine whether either oral sustained-release theophylline or montelukast added to inhaled steroids improved clinical symptoms and pulmonary function test parameters when compared to high-dose steroids alone . Methods : Ninety patients with incompletely controlled asthma were allocated , in a r and omised , double-blind fashion , to one of three treatment groups : group A : double dose of inhaled budesonide ( 400 µg b.i.d . ) , group B : 400 mg oral sustained-release theophylline plus budesonide ( 200 µg b.i.d . ) and group C : 10 mg montelukast plus budesonide ( 200 µg b.i.d . ) . The primary endpoints were forced expiratory volume in 1 s ( FEV1 ) and mean morning peak expiratory flow rate ( PEFR ) . Results : All three groups had improved FEV1 and PEFR at 8 weeks ( p < 0.001 ) . Group C increased their PEFR by 18.7 l/min ( 95 % confidence interval , CI , 12.4–25.1 ) more than group A and by 19.8 l/min ( 95 % CI 13.4–26.1 ) more than group B ( both p = 0.001 ) . Similarly , group C had a 114 ml ( 95 % CI 45–183 ml ) greater improvement in FEV1 than group A and a 95 ml ( 95 % CI 26–164 ml ) greater improvement than group B ( both p = 0.01 ) . Conclusions : Addition of montelukast to budesonide is safe and results in greater improvement in pulmonary function test parameters than high-dose budesonide treatment or addition of theophylline [21542741] BACKGROUND Most r and omized trials of treatment for asthma study highly selected patients under idealized conditions . METHODS We conducted two parallel , multicenter , pragmatic trials to evaluate the real-world effectiveness of a leukotriene-receptor antagonist ( LTRA ) as compared with either an inhaled glucocorticoid for first-line asthma-controller therapy or a long-acting beta(2)-agonist ( LABA ) as add-on therapy in patients already receiving inhaled glucocorticoid therapy . Eligible primary care patients 12 to 80 years of age had impaired asthma-related quality of life ( Mini Asthma Quality of Life Question naire [ MiniAQLQ ] score ≤6 ) or inadequate asthma control ( Asthma Control Question naire [ ACQ ] score ≥1 ) . We r and omly assigned patients to 2 years of open-label therapy , under the care of their usual physician , with LTRA ( 148 patients ) or an inhaled glucocorticoid ( 158 patients ) in the first-line controller therapy trial and LTRA ( 170 patients ) or LABA ( 182 patients ) added to an inhaled glucocorticoid in the add-on therapy trial . RESULTS Mean MiniAQLQ scores increased by 0.8 to 1.0 point over a period of 2 years in both trials . At 2 months , differences in the MiniAQLQ scores between the two treatment groups met our definition of equivalence ( 95 % confidence interval [ CI ] for an adjusted mean difference , -0.3 to 0.3 ) . At 2 years , mean MiniAQLQ scores approached equivalence , with an adjusted mean difference between treatment groups of -0.11 ( 95 % CI , -0.35 to 0.13 ) in the first-line controller therapy trial and of -0.11 ( 95 % CI , -0.32 to 0.11 ) in the add-on therapy trial . Exacerbation rates and ACQ scores did not differ significantly between the two groups . CONCLUSIONS Study results at 2 months suggest that LTRA was equivalent to an inhaled glucocorticoid as first-line controller therapy and to LABA as add-on therapy for diverse primary care patients . Equivalence was not proved at 2 years . The interpretation of results of pragmatic research may be limited by the crossover between treatment groups and lack of a placebo group . ( Funded by the National Coordinating Centre for Health Technology Assessment U.K. and others ; Controlled Clinical Trials number , IS RCT N99132811 . ) [12449158] The present study aim ed at comparing the effects of a dose reduction of inhaled corticosteroids on lung function , indirect measures of airway inflammation and clinical scores during treatment with a leucotriene receptor antagonist . In 50 patients ( mean forced expiratory volume in one second ( FEV1 ) 94 % predicted ) , steroid doses ( 800 µg beclomethasone dipropionate ) were first reduced to 50 % and then to 25 % , for 6 weeks each . One group received a placebo and the other group received montelukast ( 10 mg ) . The first reduction did not cause significant effects . During the second , FEV1 and peak expiratory flow decreased in both groups ( p<0.001 ) . Daytime symptoms were not altered with placebo but were reduced by montelukast ( p<0.05 ) . Night-time symptoms were slightly elevated with placebo ( p<0.05 ) but not montelukast , as well as the use of supplemental salbutamol . Changes in provocative concentration of methacholine causing a 20 % fall in FEV1 ( PC20 ) , sputum eosinophils and exhaled nitric oxide were mostly nonsignificant for both placebo and montelukast . These data demonstrate that a 75 % reduction in the dose of steroid given to patients with asthma led to a deterioration in lung function not prevented by montelukast , whereas changes in clinical state seemed to favour montelukast treatment . It therefore appears that potential effects of montelukast , in the presence of low-dose steroids , could not be attributed to single indices of lung function or airway inflammation [26460983] STUDY OBJECTIVE In acute exacerbations of asthma in children , corticosteroids reduce relapses , subsequent hospital admission , and the need for ß2-agonist bronchodilators . Prednisolone is the most commonly used corticosteroid , but prolonged treatment course , vomiting , and a bitter taste may reduce patient compliance . Dexamethasone has a longer half-life and has been used safely in other acute pediatric conditions . We examine whether a single dose of oral dexamethasone is noninferior to prednisolone in the emergency department ( ED ) treatment of asthma exacerbations in children , as measured by the Pediatric Respiratory Assessment Measure ( PRAM ) at day 4 . METHODS We conducted a r and omized , open-label , noninferiority trial comparing oral dexamethasone ( single dose of 0.3 mg/kg ) with prednisolone ( 1 mg/kg per day for 3 days ) in patients aged 2 to 16 years and with a known diagnosis of asthma or at least 1 previous episode of ß2-agonist-responsive wheeze who presented to a tertiary pediatric ED . The primary outcome measure was the mean PRAM score ( range of 0 to 12 points ) performed on day 4 . Secondary outcome measures included requirement for further steroids , vomiting of study medication , hospital admission , and unscheduled return visits to a health care practitioner within 14 days . RESULTS There were 245 enrollments involving 226 patients . There was no difference in mean PRAM scores at day 4 between the dexamethasone and prednisolone groups ( 0.91 versus 0.91 ; absolute difference 0.005 ; 95 % CI -0.35 to 0.34 ) . Fourteen patients vomited at least 1 dose of prednisolone compared with no patients in the dexamethasone group . Sixteen children ( 13.1 % ) in the dexamethasone group received further systemic steroids within 14 days after trial enrollment compared with 5 ( 4.2 % ) in the prednisolone group ( absolute difference 8.9 % ; 95 % CI 1.9 % to 16.0 % ) . There was no significant difference between the groups in hospital admission rates or the number of unscheduled return visits to a health care practitioner . CONCLUSION In children with acute exacerbations of asthma , a single dose of oral dexamethasone ( 0.3 mg/kg ) is noninferior to a 3-day course of oral prednisolone ( 1 mg/kg per day ) as measured by the mean PRAM score on day 4 [26786240] Abstract Introduction : Poor self-management by families is an important factor in explaining high rates of asthma morbidity in Puerto Rico , and for this reason we previously tested a family intervention called CALMA that was found effective in improving most asthma outcomes , but not effective in increasing the use of controller medications . CALMA-plus was developed to address this issue by adding to CALMA , components of provider training and screening for asthma in clinics . Methods : Study participants were selected from cl aims Medicaid data in San Juan , Puerto Rico . After screening , 404 children in eight clinics were selected after forming pairs of clinics and r and omizing the clinics ) to CALMA-only or CALMA-plus . Results : For all three primary outcomes at 12 months , the mean differences between treatment arms were small but in the predicted direction . However , after adjusting for clinic variation , the study failed to demonstrate that the CALMA-plus intervention was more efficacious than the CALMA-only intervention for increasing controller medication use , or decreasing asthma symptoms . Both groups had lower rates of asthma symptoms and service utilization , consistent with previous results of the CALMA-only intervention . Conclusions : Compliance of providers with the intervention and training , small number of clinics available and the multiple barriers experienced by providers for medicating may have been related to the lack of difference observed between the groups . Future interventions should respond to the limitations of the present study design and provide more re sources to providers that will increase provider participation in training and implementation of the intervention [12612294] Background : Proinflammatory leukotrienes , which are not completely inhibited by inhaled corticosteroids , may contribute to asthmatic problems . A 16 week multicentre , r and omised , double blind , controlled study was undertaken to study the efficacy of adding oral montelukast , a leukotriene receptor antagonist , to a constant dose of inhaled budesonide . Methods : A total of 639 patients aged 18–70 years with forced expiratory volume in 1 second ( FEV1 ) ≥55 % predicted and a minimum predefined level of asthma symptoms during a 2 week placebo run in period were r and omised to receive montelukast 10 mg ( n=326 ) or placebo ( n=313 ) once daily for 16 weeks . All patients received a constant dose of budesonide ( 400–1600 μg/day ) by Turbuhaler throughout the study . Results : Mean FEV1 at baseline was 81 % predicted . The median percentage of asthma exacerbation days was 35 % lower ( 3.1 % v 4.8 % ; p=0.03 ) and the median percentage of asthma free days was 56 % higher ( 66.1 % v 42.3 % ; p=0.001 ) in the montelukast group than in the placebo group . Patients receiving concomitant treatment with montelukast had significantly ( p<0.05 ) fewer nocturnal awakenings and significantly ( p<0.05 ) greater improvements in β agonist use and morning peak expiratory flow rate ( PEFR ) . Conclusions : For patients with mild airway obstruction and persistent asthma symptoms despite budesonide treatment , concomitant treatment with montelukast significantly improves asthma control [10355150] We undertook a community based case-control study to measure the effect of pranlukast on the reduction of inhaled steroid in adult asthmatics . Forty-one adults completed a run-in period of 4 weeks on 800 microgram of beclomethasone dipropionate ( BDP ) documenting twice daily peak expiratory flow ( PEF ) and symptom score and therapeutic score on a st and ard diary . Forced expiratory volume in one second ( FEV1.0 ) , V50 , V25 was measured once during the run-in period . Patients were then r and omized to receive either pranlukast with 400 microgram of BDP or 400 microgram alone for 8 weeks . There was no difference in the symptom score and therapeutic between the two groups at any time point . However , morning and evening % PEF run-in expressed as a % of the PEF average during the run-in period was significantly lower at 8 weeks in the groups without pranlukast . There were subjects in the group without pranlukast ( 35.3 % ) compared to those with ( 20.8 % ) who had a 10 % or more reduction in % PEF from the run-in period . The patients with an FEV1.0 < 80 % predicted who were r and omized to the control group were more likely ( 5 of 7 ) to have a fall in % PEF run-in and those r and omized to received pranlukast were less likely to have a fall in % PEF run-in though this was not significant ( 2 of 6 ) . In this study , pranlukast has demonstrated steroid sparing effect . Severe asthmatics ( FEV1.0 < 80 % ) who deteriorate after reduction of inhaled steroid may benefit most from pranlukast . Larger studies are now required to explore this important effect [4705626] Background Asthma affects more than 5 million patients in the United Kingdom . Nearly 500,000 of these patients have severe asthma with severe symptoms and frequent exacerbations that are inadequately controlled with available treatments . The burden of severe asthma on the NHS is enormous , accounting for 80 % of the total asthma cost ( £ 1 billion ) , with frequent exacerbations and expensive medications generating much of this cost . Of those patients with severe asthma , 70 % are sensitised to indoor aeroallergens , and the level of exposure to allergens determines the symptoms ; patients exposed to high levels are therefore most at risk of exacerbations and hospital admissions . The LASER trial aims to assess whether a new treatment , temperature controlled laminar airflow ( TLA ) delivered by the Airsonett ™ device , can reduce the frequency of exacerbations in patients with severe allergic asthma by reducing exposure to aeroallergens overnight . Methods This multicentre study is a placebo-controlled , blinded , r and omised controlled , parallel group trial . A total of 222 patients with a new or current diagnosis of severe allergic asthma will be assigned with a r and om element in a 1:1 ratio to receive either an active device for one year or a placebo device . The primary outcome is the frequency of severe asthma exacerbations occurring over a 12-month period , defined in accordance with the American Thoracic Society/European Respiratory Society ( ATS/ERS ) guidelines . Secondary outcomes include changes in asthma control , lung function , asthma-specific and global quality of life for participants and their carers , adherence to intervention , healthcare re source use and costs , and cost-effectiveness . Qualitative interviews will be conducted to elicit participant ’s and their partner ’s perceptions of the treatment . Discussion Effective measures of allergen avoidance have , to date , proved elusive . The LASER trial aims to address this . The study will ascertain whether home-based nocturnal TLA usage over a 12-month period can reduce the frequency of exacerbations and improve asthma control and quality of life as compared to placebo , whilst being cost-effective and acceptable to adults with poorly controlled , severe allergic asthma . The results of this study will be widely applicable to the many patients with allergic asthma both in the UK and internationally . Trial registration Current controlled trials IS RCT N46346208 ( Date assigned 22 January 2014 ) [12114351] STUDY OBJECTIVES To evaluate the effect of adding zafirlukast or low-dose theophylline to a beclomethasone dipropionate ( BDP ) extra-fine hydrofluoroalkane aerosol on bronchial hyperresponsiveness as the primary outcome variable . METHODS Twenty-four patients with mild-to-moderate asthma were studied using a r and omized crossover design with the following three treatment blocks : ( 1 ) beclomethasone , 100 microg/d , alone for the first 2 weeks followed by 400 microg/d alone for the next 2 weeks ; ( 2 ) beclomethasone , 100 microg/d , followed by 400 microg/d , with the addition of zafirlukast , 20 mg bid ; ( 3 ) beclomethasone , 100 microg/d , followed by 400 microg/d , with the addition of theophylline , 200 to 300 mg bid . Measurements were made after 2 and 4 weeks of each treatment and at pretreatment baseline . RESULTS The mean trough plasma theophylline concentration was 6.7 mg/L , coinciding with the anti-inflammatory target range ( ie , 5 to 10 mg/L ) . The provocative dose of methacholine causing a 20 % fall in FEV(1 ) ( as doubling dose difference from baseline ) was significantly ( p < 0.05 ) greater with beclomethasone , 100 microg , plus zafirlukast ( 1.1 doubling dose ) but not with beclomethasone , 100 microg , plus theophylline ( 0.7 doubling dose ) compared to beclomethasone , 100 microg alone ( 0.4 doubling dose ) , but not compared to beclomethasone , 400 microg alone ( 1.1 doubling dose ) . There were also significant ( p < 0.05 ) differences between beclomethasone , 100 microg , plus zafirlukast ( but not BDP , 100 microg , plus theophylline ) vs beclomethasone , 100 microg , alone in terms of nitric oxide level , midexpiratory phase of forced expiratory flow , and peak expiratory flow . There were no further significant improvements observed with the addition of zafirlukast or theophylline to beclomethasone , 400 microg . CONCLUSIONS A leukotriene receptor antagonist , but not low-dose theophylline , conferred significant additive anti-inflammatory effects to therapy with a low-dose inhaled corticosteroid but not to that with a medium dose of an inhaled corticosteroid . Thus , optimizing the dose of inhaled corticosteroid as monotherapy would seem to be the logical first step , which is in keeping with current guidelines [4878003] Abstract Background Bronchoprovocation challenges use direct or indirect acting stimuli to induce airflow obstruction . Indirect stimuli either non-allergic/non-IgE mediated ( e.g. exercise , mannitol ) or allergic/IgE mediated ( i.e. allergen ) trigger mast cells to release bronchoconstricting mediators ( e.g. cysteinyl leukotrienes , histamine ) . Performing repeat challenges within a short timeframe ( e.g. 3 h ) with non-allergic indirect stimuli results in a diminished , refractory response to the second challenge that is inhibited by non-steroidal anti-inflammatory medications . Cross refractoriness occurs between indirect stimuli . It follows that repeat bronchoprovocation with allergen might exhibit refractoriness that might be altered by ibuprofen . We assessed the response to a second allergen challenge performed 24 h after an initial allergen challenge to determine if the response is refractory . If refractoriness developed , the study aim ed to determine whether a single dose of ibuprofen would alter the refractory response to the second allergen challenge . In the absence of a refractory response , the study design allowed for the assessment of the effect of ibuprofen on allergen challenge outcomes , including indices of airway inflammation . Methods Thirteen mild atopic asthmatics were enrolled in a r and omized , double-blind , placebo controlled , cross-over study . Ibuprofen ( 400 mg ) or placebo was administered 1 h prior to the first of two allergen challenges , performed 24 h apart . Blood and sputum eosinophils , airway responsiveness to methacholine and levels of fractional exhaled nitric oxide were assessed before and 7 h after each allergen challenge . All data were log transformed and differences in geometric means were analyzed by paired t-tests . Results After placebo , early asthmatic responses for the two challenges were not significantly different ( p = 0.82 ) . A single 400 mg dose of ibuprofen decreased both the early ( p = 0.03 ; n = 12 ) and late asthmatic responses ( p = 0.03 ; n = 3 ) . Conclusion Allergen challenges conducted 24 h apart do not exhibit refractoriness . Single dose ibuprofen inhibits early and late asthmatic responses to allergen bronchoprovocation . Ibuprofen should be withheld for at least 24 h prior to investigations utilizing allergen bronchoprovocation . Trial registration clinical trials.gov # [15640321] Sputum eosinophilia is a sensitive predictor of benefit from corticosteroid treatment . Montelukast is a cysteinyl leukotriene antagonist , which also reduces sputum and blood eosinophils . The present study examined the possibility that montelukast has an added eosinophil-lowering effect in subjects with asthma who are corticosteroid responsive but relatively corticosteroid resistant . A total of 14 clinical ly stable adults with asthma requiring minimum treatment with a high-dose inhaled steroid or prednisone , with baseline sputum eosinophilia ( ≥5 % ) , were r and omised to receive 4 weeks of 10 mg montelukast or placebo daily in a double-blind crossover trial . The primary outcome was the effect of treatment on the percentage of sputum eosinophils . Secondary outcomes were changes in the blood eosinophil count , symptoms , forced expiratory volume in one second , peak expiratory flow and the need for salbutamol . The median ( interquartile range , i.e. 75th–25th centile ) for sputum eosinophils at baseline was 15.7 % ( 22 ) . The effect of adding montelukast was not significantly different from that of placebo , sputum eosinophils being 9.3 % ( 18.9 ) after montelukast and 11.3 % ( 22.8 ) after placebo . No difference was detected on secondary outcomes . No crossover interactions were observed . In conclusion , the addition of montelukast to existing high-dose corticosteroid therapy in subjects with asthma with elevated sputum eosinophils does not provide additional attenuation of airway eosinophilia [4509656] Purpose There have been few reports regarding the efficacy of antiasthmatics in older patients . To compare the efficacy of the addition of montelukast to low-dose inhaled budesonide ( MON-400BUD ) versus increasing the dose of inhaled steroid ( 800BUD ) on asthma control in older asthmatics . Methods A r and omized , open-label , parallel- design ed trial was conducted for 12 weeks . The primary endpoint was the rate of patients who reached " well-controlled asthma status " after the 12-week treatment period . Additionally , asthma exacerbations , sputum inflammatory cells , asthma control test ( ACT ) and physical functioning scale ( PFS ) , and adverse reactions were monitored . Results Twenty-four ( 36.9 % ) and 22 ( 34.9 % ) subjects in the MON-400BUD ( n=65 ) and 800BUD ( n=63 ) groups had well-controlled asthma at the end of the study , respectively . The numbers of asthma exacerbations requiring oral corticosteroid treatment ( 20 vs 9 , respectively , P=0.036 ) and the development of sore throat ( 22 vs 11 , respectively , P=0.045 ) were significantly higher in the 800BUD group than in the MON-400BUD group . Body mass index and changes in ACT , FEV1 % , 6-min walk distance and PFS from baseline were all significant determinants for distinguishing subjects with well-controlled and partly controlled asthma from those with uncontrolled asthma ( P<0.05 ) at the end of the study . Conclusions The efficacy of 12-week treatment with MON-400BUD in older asthmatics was comparable to that of 800BUD on asthma control but associated with reduced frequency of asthma exacerbations requiring oral steroids and sore throat events . Changes in ACT and PFS can be useful predictors of asthma control status in older patients [4736611] Background Influenza virus ( IFV ) infection is associated with increased morbidity and mortality in people with underlying lung disease . Treatment options for IFV are currently limited and antiviral resistance is a growing concern . DAS181 , an inhaled antiviral with a unique mechanism of action , has shown promise in early clinical trials involving generally healthy human subjects . This study was undertaken to assess the safety and tolerability of DAS181 in individuals with underlying reactive airway disease . Methods This was a r and omized , double-blind , placebo-controlled , crossover phase 1 study of DAS181-F02 . Dry particle inhaler administration of 10 mg was done on 3 consecutive days in ten adult volunteers with well-controlled asthma . The primary outcome was the frequency of adverse events ( AEs ) , grade 1 or higher that occurred during each study period . Results There were 280 AEs among ten evaluable subjects ( 56.8 % active ; 43.2 % placebo ) ; 90.7 % were grade 1 . No grade 3 or higher AEs occurred . A statistically significant association between exposure to DAS181 and experiencing any AE , a grade 1 AE , or a grade 2 AE was not detected . Overall , the majority of AEs were classified as possibly related ( 35.7 % ) , unlikely related ( 38.9 % ) , or unrelated ( 15.4 % ) to study drug administration . However , there was a statistically significant association between exposure to DAS181 and experiencing a definitely or probably related AE . Respiratory effects , including dyspnea , dry cough , and chest discomfort related to respirations , accounted for all of the definitely related AEs and one of the most common probably related AEs . Conclusions DAS181 was safe in this small study of otherwise healthy subjects with well-controlled asthma . However , the generalizability of these results is limited by the small sample size and generally mild nature of the subjects ’ asthma at baseline . The increased association of respiratory events classified as probably or definitely related to DAS181 administration suggests caution may need to be employed when administering DAS181 to individuals with less stable reactive airway disease . Further investigation in a controlled setting of the safety and efficacy of DAS181 in a larger population of asthmatic subjects with varying disease activity is warranted . Trial Registration Clinical Trials.gov NCT01113034Trial Registration Date : April 27 , [22536582] BACKGROUND In 2010 , the Canadian Thoracic Society ( CTS ) published a Consensus Summary for the diagnosis and management of asthma in children six years of age and older , and adults , including an up date d Asthma Management Continuum . The CTS Asthma Clinical Assembly subsequently began a formal clinical practice guideline up date process , focusing , in this first iteration , on topics of controversy and ⁄or gaps in the previous guidelines . METHODS Four clinical questions were identified as a focus for the up date d guideline : the role of noninvasive measurements of airway inflammation for the adjustment of anti-inflammatory therapy ; the initiation of adjunct therapy to inhaled corticosteroids ( ICS ) for uncontrolled asthma ; the role of a single inhaler of an ICS⁄long-acting beta(2)-agonist combination as a reliever , and as a reliever and a controller ; and the escalation of controller medication for acute loss of asthma control as part of a self-management action plan . The expert panel followed an adaptation process to identify and appraise existing guidelines on the specified topics . In addition , literature search es were performed to identify relevant systematic review s and r and omized controlled trials . The panel formally assessed and grade d the evidence , and made 34 recommendations . RESULTS The up date d guideline recommendations outline a role for inclusion of assessment of sputum eosinophils , in addition to st and ard measures of asthma control , to guide adjustment of controller therapy in adults with moderate to severe asthma . Appraisal of the evidence regarding which adjunct controller therapy to add to ICS and at what ICS dose to begin adjunct therapy in children and adults with poor asthma control supported the 2010 CTS Consensus Summary recommendations . New recommendations for the adjustment of controller medication within written action plans are provided . Finally , priority areas for future research were identified . CONCLUSIONS The present clinical practice guideline is the first up date of the CTS Asthma Guidelines following the Canadian Respiratory Guidelines Committee 's new guideline development process . Tools and strategies to support guideline implementation will be developed and the CTS will continue to regularly provide up date s reflecting new evidence [15182276] BACKGROUND Although current guidelines suggest the use of inhaled corticosteroids as the first line therapy in persistent asthma , the concerns about high-dose corticosteroids may limit their usage . We aim ed to investigate the efficacy of inhaled budesonide plus oral montelukast versus a double dose of inhaled budesonide . METHODOLOGY Thirty patients with moderate asthma took part in the study . Following a 2-week run in period , the patients were r and omized into two groups to receive 400 microg/day of inhaled budesonide plus 10 mg/day of montelukast ( BUD + M group ) or 800 microg/day of inhaled budesonide ( high BUD group ) . The patients were evaluated at 2-week intervals ( during a total treatment period of 6 weeks ) for symptom scores , asthma exacerbations , lung function , use of short-acting beta2 agonist , blood eosinophil counts and adverse events . RESULTS At the end of the study , morning and daytime symptom scores were significantly reduced within the groups . Although there was a significant decrease in the frequency of short-acting beta2 agonist use in the BUD + M group , the decrease in the high BUD group was not significant . During the study period , no patient in either group experienced an asthma exacerbation . Blood eosinophil levels significantly declined in both the BUD + M ( 0.87 + /- 0.31 % ) and high BUD groups ( 0.67 + /- 0.29 % ) as compared with baseline levels ( BUD + M = 2.60 + /- 0.65 % , high BUD group = 2.60 + /- 0.47 % ; P < 0.05 ) . CONCLUSION Our results suggest that the addition of montelukast to low-dose inhaled budesonide is as effective as a double dose of inhaled budesonide in asthma control [14584388] Eighty-one adult patients with bronchial asthma who suffered asthmatic episodes in spite of treatment with 400 mg/day of BDP were placed on pranlukast therapy for 4 weeks . Group I , which showed a 5 % or greater increase in PEFR , continued oral pranlukast medication for an additional two years . Those patients who did not show an increase of 5 % or greater in PEFR after 4 weeks of pranlukast therapy were instructed to continue the medication for another year . Group II , which exhibited a 5 % or greater increase in PEFR after a one-year period continued medication for one more year . Medication was suspended for Group III , which failed to show improvement in PEFR after one year , and the group was placed under observation for the following year . Group I improved significantly in PEFR and exhibited a reduction in the frequency of b2 inhalation , the number of night visits to a medical facility , the amount of steroids inhaled , and the quantity of oral steroids given at regular intervals ; and the Group I peripheral eosinophil count , serum ECP level , and FEV1.0 ameliorated . After one year , Group II also showed significant improvement in PEFR and a reduction in both the peripheral eosinophil count and the serum ECP level . This group 's PEFR continued to improve after two years . One year after medication was suspended , Group III showed a significant increase in the number of night visits to a medical facility and a rise in the serum ECP level . These findings indicated the efficacy of pranlukast [10934090] Not all asthma can be adequately controlled , despite the use of high-dose inhaled corticosteroids . Because cysteinyl-leukotrienes ( Cys-LT ) have been implicated in the pathogenesis of asthma , we hypothesized that the leukotriene receptor antagonist zafirlukast , in combination with high-doses of inhaled corticosteroids , might be efficacious in severe asthma . In a double-blind , parallel group study , 368 chronic adult asthmatic patients treated with inhaled corticosteroids ( 1,000 to 4,000 microgram/d ) , who had a predefined level of asthma symptoms during the run in period of the study , were r and omly assigned to receive additional treatment with a high dose of zafirlukast ( 80 mg twice daily ) ( n = 180 ) or placebo ( n = 188 ) for 6 wk . Compared with placebo , zafirlukast produced a significant improvement over baseline in the primary study endpoint of mean morning peak expiratory flow rate ( PEFR ) ( 18.7 L/min versus 1.5 L/min , p < 0.001 ) , as well as in evening PEFR ( p < 0.01 ) , FEV(1 ) ( p < 0.05 ) , daytime symptom score ( p < 0.001 ) , and beta(2)-agonist use ( p < 0.001 ) . Furthermore , zafirlukast significantly reduced the risk of an exacerbation of asthma ( odds ratio [ OR ] : 0.61 ; 95 % confidence interval [ CI ] : 0.38 to 0.99 ) and the risk of patients requiring a further increase in asthma controller therapy ( OR : 0.4 ; 95 % CI : 0.2 to 0.8 ) . In conclusion , in patients taking high-dose inhaled corticosteroids , zafirlukast improves pulmonary function and asthma symptoms , and reduces the risk of an asthma exacerbation , suggesting that the contribution of leukotrienes to asthma symptoms and exacerbations is not adequately controlled by high-dose inhaled corticosteroids [26615369] BACKGROUND Systemic reactions are related to the pathogenesis of Aspirin Exacerbated Respiratory Disease ( AERD ) . With this work we wanted to study the changes in the systemic levels of inflammatory mediators in both baseline and after oral aspirin challenge in patients with and without AERD . METHODS Patients with nasal polyposis and asthma with AERD ( n=20 ) and without ( n=18 ) were orally challenged with aspirin in a single-blind placebo controlled study . Serum sample s and urine were collected before and 6h after placebo and aspirin oral challenges . Serum levels of inflammatory mediators were assayed by using the Luminex technology and ELISA . The concentrations of 9-alpha , 11-beta prostagl and in F2 , and leukotriene E4 ( uLTE4 ) were measured in urine sample s by ELISA . The expression of T-cell surface markers was analyzed in peripheral blood mononuclear cells isolated before and after the challenges . RESULTS AERD patients showed significantly higher baseline levels of s-IL-5R-alpha , uLTE4 and percentage of CD4(+)CD25(+)CD127(pos ) and CD4(+)CD45RA(-)CD45RO(+ ) but decreased levels of TGF-β1 and number of CD4(+)CD25(+)CD127(neg ) cells . Aspirin challenge induced the release of uLTE4 , IL-6 and increased the number of CD4(+)CD45RA(-)CD45RO(+ ) memory T-cells only in AERD patients but failed to reduce the levels of sCD40L as observed in non-AERD subjects . Further , IL-8 and sIL-5R-alpha levels directly correlated with the PD20ASA and the effects of aspirin on IL-6 and number of memory T-cells was more pronounced in subjects showing more strong reaction ( bronchial and nasal ) . CONCLUSIONS AERD patients have a differential baseline inflammatory pattern that supports the role inflammation as underlying mechanism of the disease . Systemic response to oral aspirin challenge was related to an increase in serum IL-6 and the number of circulating memory T-cells in AERD patients [12590877] Insufficient data exist to evaluate the comparative effects of inhaled corticosteroids ( ICS ) versus leukotriene receptor antagonist ( LTRA ) on airway inflammation and quality of life ( QoL ) . The aim of the study was to compare the effectiveness of montelukast compared to budesonide at different doses on QoL and bronchial reactivity in mild-asthmatic adult patients . 45 subjects with bronchial asthma were r and omly assigned to a different treatment and divided in 3 treatment groups : A : 400 μg of budesonide twice a day ; B : 10 mg of montelukast daily ; C : 10 mg of montelukast daily plus 400 μg of budesonide twice a day . At the beginning of the study and at the end of the treatment period ( 16 weeks ) all patients underwent complete clinical evaluation , pulmonary function testing and methacholine challenge test ( MCHt ) . In group A the increase from baseline was 153.4 % , in group C was 133.2 % , and in group B 247.7 % , the latter increase being statistically significant compared to that in the other 2 groups ( p < 0.005 Wilcoxon test ) . In all domains the improvement in quality of life in the group treated with montelukast ( group B ) was significantly greater than that in the group treated with both medications ( group C ) : in particular , the improvement was consistent in the symptoms ( p < 0.01 ) and emotions ( p < 0.01 ) domains , and weaker in the physical activity ( p < 0.05 ) . A similar difference was observed between group B and A , but only in the symptoms ( p<0.01 ) , emotions ( p<0.01 ) , and environmental stimuli domains ( p<0.05 ) . The personal perception of their own disease is important for a correct therapeutic management of asthma . In order to optimize the treatment , a complete adherence of the patient to the treatment itself is required , to be achieved through simplification of therapeutic schedule and easy administration of medications . Montelukast may be considered a valid alternative in the treatment of mild-persistent asthma , both for the clinical and functional benefits and for the great advantage of the once-daily dosage , which consistently improves the compliance with the chronic treatment of the disease [11264758] OBJECTIVE Leukotriene antagonists are increasingly used in asthma management . Pranlukast is a new , orally active , selective inhibitor of CysLt1 leukotriene receptor . The present clinical trial was performed to study the effect and safety of pranlukast in mild-to-moderate asthma . METHODOLOGY A r and omized , double-blind , placebo-controlled , parallel group study was performed in eight medical centres in Korea . Mild-to-moderate asthma patients who had been treated with beta2-agonists and /or inhaled corticosteroids were studied . The patients ' symptoms were evaluated by asthma diary and twice-daily peak flow monitoring . RESULTS Of the 206 patients enrolled , 197 were eligible for analysis . The pranlukast group ( n = 98 ) showed statistically significant improvement in asthma symptoms , including asthma attack rate , daily living score , and morning and evening asthma scores . Pranlukast significantly reduced the consumption of beta2-agonist . Compared with the placebo group , forced vital capacity ( FVC ) and forced expiratory volume in 1 s ( FEV1 ) were not significantly higher in the pranlukast group . Morning and evening peak expiratory flow ( PEF ) were significantly increased after pranlukast treatment at weeks 2 and 4 ( 380.8 + /- 10.1 L/min at baseline , 394.5 + /- 10.1 at week 2 , 396.3 + /- 10.4 at week 4 ) . There were no serious adverse reactions . CONCLUSION Pranlukast , an oral leukotriene antagonist , was well tolerated and was effective for the management of mild-to-moderate asthma [14609035] BACKGROUND Zafirlukast is a leukotriene receptor antagonist that was invented to treat patients with chronic asthma . METHODS To evaluate whether the zafirlukast improved the peak expiratory flow rate ( PEFR ) and clinical symptoms , 31 asthmatic patients with moderate persistent asthma who received regular inhaled corticosteroid were r and omly divided into the study group ( N = 17 ) . They received the zafirlukast 20 mg bid for 4 weeks , and the control group ( N = 14 ) received a placebo . Daily morning and evening PEFR and St. George 's Respiratory Question naire ( SGRQ ) scoring were recorded respectively . The levels of serum IgE and urine leukotriene E4 before and after treatment were measured using enzyme linked immunosorbent assay and enzyme immunoassay kits . RESULTS In the zafirlukast treated group , the morning PEFR was significantly improved from 314.4 + /- 20.6 to 340.6 + /- 18.3 L/min ( N = 17 , p < 0.05 ) after 4 weeks of treatment , while the control group did not show any significant changes . The zafirlukast group had significant improvement in their symptom scores of SGRQ from 48.6 + /- 4.6 to 33.8 + /- 4.7 ( N = 17 , p < 0.05 ) . However , the placebo did not improve the symptom scores . CONCLUSION Leukotriene receptor antagonists effectively improved symptoms and benefited lung function for moderate persistent asthmatic patients who had received regular treatments with inhaled steroids [12153692] BACKGROUND Symptoms often deteriorate in well-controlled asthmatics after a step down in inhaled beclomethasone dipropionate ( iBDP ) therapy if the serum concentration of eosinophil cationic protein ( sECP ) is high . This deterioration is significantly abrogated by pranlukast , a leukotriene receptor antagonist , or by seratrodast , a thromboxane A2 receptor antagonist . However , these results were based on short-term ( less than 6 months ) observations . METHODS We studied 35 well-controlled adult asthmatics . We assigned the patients into different groups according to their sECP levels before the step down : ( i ) group A , sECP < 25 microg/L ; ( ii ) group B , sECP > or = 25 microg/L ; and ( iii ) group C , sECP > or = 25 microg/L but patients treated with pranlukast or seratrodast . We began the study with a step down in iBDP therapy ( initial step down ) , then followed the clinical course of the asthma for 2 years . During the study period , we decreased , increased or maintained the iBDP dose on the basis of the stepwise approach described in the National Institutes of Health guidelines . We monitored the time and frequency of exacerbation and evaluated the iBDP dose required to control the asthma symptoms . RESULTS The rates of exacerbation after the step down were high in groups A and B. In group A , the conditions were again qualified for the step down in all patients , but this was not the case for most group B patients . From 15 to 21 months after the initial step down , the average dose of iBDP required to control symptoms was significantly higher in group B than in group A patients ( P = 0.0127 - 0.0373 ) . The exacerbation rate in group C after 12 months tended to be lower than in the other two patient groups ( P = 0.0743 ) . In group C , the average dose of iBDP from 9 to 24 months after the initial step down was significantly lower than before the step down ( P < 0.0001 ) and was not significantly different from the mean dose of iBDP in groups A or B. CONCLUSIONS High sECP in well-controlled asthma may indicate the necessity for a higher iBDP dose over a long period than when the sECP concentration is not high . Even if sECP is high , pranlukast or seratrodast help to prevent exacerbation of asthma and enable successful step down in iBDP therapy for at least 2 years thereafter [17481879] Many patients with asthma remain symptomatic with impaired airway function on inhaled steroids . This study investigates the relationship between the clinical effect seen in response to additional treatment and the effect on airway inflammatory indices . Seventy-five adult asthmatic patients , incompletely controlled on 800 mcg budesonide/day , were r and omised following a 4 week run-in period , to a double-blind , multi-centre controlled clinical trial of doubling inhaled corticosteroid ( budesonide 1600 mcg/day ) or adding 10 mg montelukast for 12 weeks . Induced sputum was collected at baseline and end of treatment and analysed for eosinophil and neutrophil percentages , leukotrienes C4 , D4 and E4 , IL-8 , Eosinophil Cationic Protein ( ECP ) and histamine . Sputum evidence of inflammation ( 2.0 % eosinophils ) was seen in only 29 % of these patients and the percentage of eosinophils and other markers of airway inflammation did not change over the study period in either treatment group . There were significant improvements in am PEF ( montelukast : 31.7 L/min , budesonide : 32.3 L/min ) and quality of life with both treatments . We conclude that while both treatments showed similar improvements in lung function and quality of life , there was no evidence from these sputum markers measured that the effects were mediated via a reduction in airway inflammation or that the level of pre-treatment markers was associated with outcome [26915674] BACKGROUND Roflumilast , a selective phosphodiesterase 4 inhibitor , has been shown to provide modest improvements in lung function in patients with mild-to-moderate asthma , but its efficacy in patients with moderate-to-severe asthma has not been assessed . We hypothesized that this drug might provide benefit if combined with montelukast , a leukotriene receptor antagonist , in patients whose symptoms are uncontrolled by inhaled corticosteroids and long-acting β-agonists . OBJECTIVE We sought to examine the efficacy , safety , and mode of action of the addition of roflumilast and montelukast versus montelukast alone in patients with moderate-to-severe asthma . METHODS In a phase 2 , r and omized , double-blind , placebo-controlled , multiple-dose , 2-sequence , crossover study , 64 patients were r and omized to receive 500 μg of roflumilast plus montelukast followed by placebo plus 10 mg of montelukast ( sequence AB ) or placebo plus 10 mg of montelukast followed by 500 μg of roflumilast plus 10 mg of montelukast ( sequence BA ) . All patients had a diagnosis of bronchial asthma inadequately controlled by at least a medium-dose inhaled corticosteroid plus a long-acting β-agonist . RESULTS The analysis of FEV1 change from baseline to week 4 showed a statistically significant and clinical ly meaningful treatment difference of 100 mL for roflumilast plus montelukast versus placebo plus montelukast . Also , improvements in patient-reported outcomes and a reduction in urinary leukotriene E4 levels were observed during roflumilast plus montelukast treatment compared with placebo plus montelukast treatment . Adverse events were consistent with the known safety profile of roflumilast . CONCLUSION The combination of roflumilast with montelukast compared with montelukast alone improved lung function and asthma control in patients with moderate-to-severe asthma and deserves further study for this indication [12612295] Background : Inhaled corticosteroids ( ICS ) affect many inflammatory pathways in asthma but have little impact on cysteinyl leukotrienes . This may partly explain persistent airway inflammation during chronic ICS treatment and failure to achieve adequate asthma control in some patients . This double blind , r and omised , parallel group , non-inferiority , multicentre 16 week study compared the clinical benefits of adding montelukast to budesonide with doubling the budesonide dose in adults with asthma . Methods : After a 1 month single blind run in period , patients inadequately controlled on inhaled budesonide ( 800 μg/day ) were r and omised to receive montelukast 10 mg + inhaled budesonide 800 μg/day ( n=448 ) or budesonide 1600 μg/day ( n=441 ) for 12 weeks . Results : Both groups showed progressive improvement in several measures of asthma control compared with baseline . Mean morning peak expiratory flow ( AM PEF ) improved similarly in the last 10 weeks of treatment compared with baseline in both the montelukast + budesonide group and in the double dose budesonide group ( 33.5 v 30.1 l/min ) . During days 1–3 after start of treatment , the change in AM PEF from baseline was significantly greater in the montelukast + budesonide group than in the double dose budesonide group ( 20.1 v 9.6 l/min , p<0.001 ) , indicating faster onset of action in the montelukast group . Both groups showed similar improvements with respect to “ as needed ” β agonist use , mean daytime symptom score , nocturnal awakenings , exacerbations , asthma free days , peripheral eosinophil counts , and asthma specific quality of life . Both montelukast + budesonide and double dose budesonide were generally well tolerated . Conclusion : The addition of montelukast to inhaled budesonide is an effective and well tolerated alternative to doubling the dose of inhaled budesonide in adult asthma patients experiencing symptoms and inadequate control on budesonide alone [12638278] This paper presents the resulţs of Montelukast sodic therapy in 16 asthmatic patients , in a prospect i ve study . Montelukast sodic was given in severe chronic asthma treated by inhaled or systemic steroids before . Patients were followed up for three months regarding : clinical symptoms , respiratory function ( FEV ) , blood and sputum eozinophyls . Short term therapy showed a great improvement in day and night symptoms , a reduction of sputum and blood eozinophyls and an increased FEV . Long term therapy could be protective for asthma exacerbations and will provide constant good life quality of asthmatics [16998094] BACKGROUND Asthma treatment guidelines recommend addition of controller medications for patients with poorly controlled asthma . We compared the effectiveness of once-daily oral controller therapy with either an antileukotriene receptor antagonist ( montelukast ) or low-dose theophylline added to existing medications in patients with poorly controlled asthma . METHODS We conducted a r and omized , double-masked , placebo-controlled trial in 489 participants with poorly controlled asthma r and omly assigned to placebo , theophylline ( 300 mg/d ) , or montelukast ( 10 mg/d ) . Participants were monitored for 24 wk to measure the rate of episodes of poor asthma control ( EPACs ) defined by decreased peak flow , increased beta-agonist use , increased oral corticosteroid use , or unscheduled health care visits . OBSERVATIONS There was no significant difference in EPAC rates ( events/person/yr ) compared with placebo : low-dose theophylline , 4.9 ( 95 % confidence interval [ CI ] , 3.6 - 6.7 ; not significant ) ; montelukast , 4.0 ( 95 % CI , 3.0 - 5.4 ; not significant ) ; and placebo , 4.9 ( 95 % CI , 3.8 - 6.4 ) . Both montelukast and theophylline caused small improvements in prebronchodilator FEV(1 ) of borderline significance . Nausea was more common with theophylline only during the first 4 wk of treatment . Neither treatment improved asthma symptoms or quality of life . However , in patients not receiving inhaled corticosteroids , addition of low-dose theophylline significantly ( p < 0.002 ) improved asthma control and symptoms as well as lung function . CONCLUSIONS Neither montelukast nor low-dose theophylline lowered the EPAC rate of poor asthma control in patients with poorly controlled asthma despite improved lung function . For patients not using inhaled corticosteroids , low-dose theophylline improved asthma symptom control more than montelukast or placebo , and provides a safe and low-cost alternative asthma treatment [26960245] BACKGROUND Results from phase III clinical trials in adults and phase II clinical trials in children and adolescents demonstrate that tiotropium is an effective treatment when added to inhaled corticosteroid ( ICS ) maintenance therapy . OBJECTIVE We sought to assess the efficacy and safety of once-daily tiotropium Respimat added to ICSs with or without a leukotriene receptor antagonist in a phase III trial in adolescent patients with moderate symptomatic asthma . METHODS In this 48-week , double-blind , placebo-controlled , parallel-group study , 398 patients aged 12 to 17 years were r and omized to receive 5 μg ( 2 puffs of 2.5 μg ) or 2.5 μg ( 2 puffs of 1.25 μg ) of once-daily tiotropium or placebo ( 2 puffs ) administered through the Respimat device every evening , each as add-on treatment to ICS background therapy , with or without a leukotriene receptor antagonist ; long-acting β2-agonist therapy was not permitted during the study . RESULTS Improvement in peak FEV1 within 3 hours after dosing at 24 weeks ( primary end point ) was statistically significant with both tiotropium doses compared with placebo : 5 μg of tiotropium , 174 mL ( 95 % CI , 76 - 272 mL ) ; 2.5 μg of tiotropium , 134 mL ( 95 % CI , 34 - 234 mL ) . Significant improvements in trough FEV1 at week 24 ( a secondary end point ) were observed with the 5-μg dose only . Trends for improvement in asthma control and health-related quality of life over the 48-week treatment period were observed . CONCLUSIONS Once-daily tiotropium significantly improved lung function and was safe and well tolerated when added to at least ICS maintenance therapy in adolescent patients with moderate symptomatic asthma . Larger responses were observed with the 5-μg tiotropium dose [24941835] OBJECTIVE To observe the clinical efficacy of treating chronic persistent bronchial asthma ( CPBA ) children with abnormal myocardial enzyme spectrum ( AMES ) by Yupingfeng Powder ( YP ) combined routine therapy . METHODS From January 2010 to December 2012 , 156 CPBA children patients with AMES were r and omly assigned to the treatment group ( 80 cases ) and the control group ( 76 cases ) . All patients received routine treatment ( inhaled corticosteroids and /or leukotriene regulator ) . Besides , those in the treatment group took YP . The treatment duration was 3 months . The scores of children asthma control test ( C-ACT ) , pulmonary function ( FEV,% and PEF% ) , myocardial enzyme spectrum were observed before and after treatment , and 3 months before and after treatment . The myocardial enzyme spectrum of 40 healthy children at the baby clinics during the same period were recruited as the control . RESULTS Compared with the control group , creatine kinase isoenzyme ( CK-MB ) , creatine kinase(CK ) , and lactate dehydrogenase ( LDH ) increased in the two treatment groups ( P < 0.01 ) , but there was no statistical difference in AST ( P > 0.05 ) . Compared with before treatment in the same group , CK-MB , CK , LDH , and AST decreased in the treatment group after treatment and 3 months after treatment ( P < 0.01 ) . CK-MB , CK , LDH , and AST decreased in the control group 3 months after treatment ( P < 0.01 , P < 0.05).Compared with after treatment , CK decreased in the control group 3 months after treatment ( P < 0.01 ) . C-ACT score , FEV(1),% , and PEF% all increased in the two groups after treatment and 3 months after treatment ( P < 0.01 , P < 0.05 ) . Compared with after treatment in the same group , CK decreased in the control group 3 months after treatment ( P < 0 . 01 ) . Compared with the control group in the same period , post-treatment CK-MB and CK decreased ( P < 0 . 01 , P < 0 . 05 ) , while post-treatment C-ACT score , FEV , % , and PEF% increased ( P < 0.05 ) in the treatment group ( P < 0.05 ) . CONCLUSION YP could strengthen specific and non-specific immunity of the organism , and improve clinical symptoms and the level of myocardial enzyme spectrum [12670780] We studied 51 atopic non-smoking subjects who were divided to four treatments groups : ( A ) montelukast 10 mg daily , ( B ) budesonide 400 microg twice a day ( bid ) , ( C ) montelukast 10 mg daily plus budesonide 400 microg bid and ( D ) budesonide 800 microg bid . Bronchial responsiveness was assessed before and after 12 weeks of treatment . The bronchial responsiveness , evaluated by means of PC(20 ) values , showed a strong significant increase in groups B , C and D , and a weak but significant rise in group A , when compared to basal data . Regarding other pulmonary parameters ( FEV(1 ) , PEF ) there were no significant differences among the groups after 12 weeks of therapy . A statistical significance was founded after therapy between group A and C ( p < 0.05 ) , but not between the group B and D treated with only budesonide at different doses . No significant differences was observed in the side effect pattern among the various treatments . The study data demonstrated that administration of montelukast provided an important and additional effect on bronchial hyperresponsiveness . Oral administration represents a significant advantage over the majority of other anti-asthmatic drugs . Our results confirm the anti-inflammatory properties of both the inhaled corticosteroid ( ICS ) and montelukast and the possible role of these drugs can have on airway remodelling . While currently low dose ICS remains the reference drug as a controller in mild-moderate persistent asthma , montelukast may be viewed as a possible option , either in monotherapy or in association [16081585] Pharmacological therapy with inhaled steroids ( IS ) is currently considered the gold-st and ard of treatment for mild-persistent asthma . Leukotriene receptor antagonist drugs ( LTRAs ) play an important role associated with IS , allowing dose tapering and maintaining control of asthma symptoms . The aim of this study was to determine the effectiveness of montelukast ( MON ) to allow tapering of the inhaled dose of budesonide ( BUD ) in patients with mild-moderate persistent asthma . This 16-wk single-blind r and omized study included 40 asthmatic patients divided in 2 treatment groups . After a run-in period ( 4 wk ) , in which all patients inhaled 400 microg of BUD twice daily ( bid ) , group A ( 20 patients ) received MON ( oral , 10 mg/day ) combined with inhaled BUD ( 400 microg/bid ) , while group B ( 20 patients ) was treated with BUD for the whole period of the study . In both groups , at every 4 wk the dose of BUD was halved . After 12 wk of treatment the mean value of forced expiratory volume during the first sec ( FEV1 , as % of predicted value ) was significantly greater in group A compared with group B ( 94 + /- 7.5 vs 83.1 + /- 6.9 ; p<0.005 ) . The mean values of peak expiratory flow ( PEF ) , the percentages of asthmatic exacerbations , and the use of beta2-short-acting agonist ( SABA ) were similar in the 2 groups at 4 , 8 , and 12 wk . In conclusion , in patients with mild-moderate persistent asthma , MON therapy is useful in tapering the dose of IS in order to reduce its side effects and to maintain the clinical stability of the disease [12190656] Background Oral leukotriene receptor antagonists have been shown to have efficacy in chronic asthma [12536697] OBJECTIVES To explore the influence of zafirlukast on pulmonary functions and quality of life ( QOL ) in patients with mild-to-moderate asthma at the stage of attack and at the stable stage . METHODS Patients at the stage of attack were r and omly divided into two groups : Group one is zafirlukast 20 mg twice daily plus inhaled the half quantity of glucocorticoid(budelade ) of the Global Initiative for Asthma ( GINA ) st and ard quantity , long-effection aminophyllin 0.2 g twice daily and inhaled salbutamol when necessary ; Group two : inhaled budelade of GINA st and ard quantity , long-effection aminophyllin 0.2 g twice daily and inhaled salbutamol when necessary ) . Patients ' peak expiratory flow (PEF)/PEF predicted value % and delta PEFR% were determined at the second week and the forth week before and after the treatment . On the st and ard treatment , patients with the stable stage were added zafirlukast 20 mg twice a day . PEF values in the morning and evening and QOL were evaluated . RESULTS After treating with zafirlukast , the PEF/PEF predicted value % and delta PEFR% in Group one were higher and lower than those of Group two respevtively . These changes were appeared in two days and were peaked in two weeks and the peak had been gone on for more than 4 weeks , but these were no significant difference between the Groups ( P > 0.05 ) ; PEF values in the morning and evening in patients with the stable asthma increased 5.9 % and 4.6 % respectively and their QOL were improved in asthma symptoms , limitative activities , avoiding stimuli , and reacting on stimuli . CONCLUSION Zafirlukast can improve pulmonary function , reduce the inhalation quantity of steroid in patients with mild-to-moderate asthma , and play an important role in treating and improving QOL in patients with the stable asthma [10398629] Abstract Objective : To determine the ability of montelukast , a leukotriene receptor antagonist , to allow tapering of inhaled corticosteroids in clinical ly stable asthmatic patients . Design : Double blind , r and omised , placebo controlled , parallel group study . After a single blind placebo run in period , during which ( at most ) two inhaled corticosteroids dose decreases occurred , qualifying , clinical ly stable patients were allocated r and omly to receive montelukast ( 10 mg tablet ) or matching placebo once daily at bedtime for up to 12 weeks . Setting : 23 academic asthma centres in United States , Canada , and Europe . Participants : 226 clinical ly stable patients with chronic asthma receiving high doses of inhaled corticosteroids ( 113 r and omised to montelukast and 113 to placebo ) . Interventions : Every 2 weeks , the inhaled corticosteroids dose was tapered , maintained , or increased ( rescue ) based on a st and ardised clinical score . Main outcome measures : Last tolerated dose of inhaled corticosteroids . Results : Compared with placebo , montelukast allowed significant ( P=0.046 ) reduction in the inhaled corticosteroid dose ( montelukast 47 % v placebo 30 % ; least square mean difference 17.6 % , 95 % confidence interval 0.3 to 34.8 ) . Fewer patients on montelukast ( 18 ( 16 % ) v 34 ( 30 % ) placebo , P=0.01 ) required discontinuation because of failed rescue . Conclusions : Montelukast reduces the need for inhaled corticosteroids among patients requiring moderate to high doses of corticosteroid to maintain asthma control . Key messages Leukotriene receptor antagonists have complementary action to inhaled corticosteroids in asthma Many patients receive higher doses of inhaled corticosteroids than clinical ly required In this placebo controlled trial , montelukast allowed significant reduction of inhaled corticosteroid doses Fewer patients receiving montelukast had failed rescue than patients receiving [15526805] OBJECTIVES To compare the effects of addition of montelukast or salmeterol to inhaled corticosteroids ( ICS ) on the response to rescue beta2-agonist use after exercise-induced bronchoconstriction . METHODS A double-blind , placebo-controlled study was performed at 16 centers in the United States . Patients with asthma ( n = 122 , ages 15 - 58 ) whose symptoms were uncontrolled on Low-dose inhaled fluticasone and who had a history of exercise-induced worsening of asthma were r and omized to receive either montelukast ( 10 mg once daily ) , salmeterol ( 50microg twice daily ) , or placebo for 4 weeks . St and ardized spirometry after exercise challenge and beta2-agonist rescue was performed at baseline , week 1 and 4 . RESULTS Maximum achievable forced expiratory volume in 1 s ( FEV1 ) percent predicted after rescue beta2-agonist improved in the montelukast ( + 1.5 % ) and placebo ( + 1.2 % ) groups at 4 weeks , but diminished in the salmeterol ( -3.9 % ) group ( P < 0.001 ) . Although pre-exercise FEV1 was greatest with salmeterol ( P = 0.10 ) , patients taking montelukast had significantly greater protection from an exercise-induced decrease in FEV1 than those taking salmeterol ( P < 0.001 ) . Both the magnitude and rate of rescue bronchodilation were greater with montelukast compared with salmeterol ( P < 0.001 ) . Five minutes after rescue beta2-agonist , 92 % of patients taking montelukast and 68 % of those taking placebo had recovered to pre-exercise levels , whereas only 50 % of those taking salmeterol had recovered to pre-exercise levels . CONCLUSION In patients whose asthma symptoms remain uncontrolled using ICS , addition of montelukast permits a greater and more rapid rescue bronchodilation with a short-acting beta2-agonist than addition of salmeterol and provides consistent and clinical ly meaningful protection against exercise-induced bronchoconstriction [20471234] Bronchial hyperresponsiveness to 5-adenosine mono-phosphate ( AMP ) is a marker of airway inflammation . Inhaled corticosteroids and antileukotrienes are used as anti-inflammatory drugs for the treatment of asthma . To find out if these two drugs exert their protection in an additive fashion , we compared the effects of acute treatment with inhaled beclomethasone ( BDP ) and montelukast ( ML ) , alone or in combination , on methacholine and AMP induced bronchoconstriction . 15 asthmatic patients undertook methacholine and AMP challenges at baseline and after receiving ML or BDP , alone or in combination , in a r and omized , double-blind , double-dummy placebo-controlled , crossover design . BDP pretreatment significantly increased the AMP PC(20 ) value ( 68.34+/-15.9mg/mL ) as compared to placebo ( 22.87+/-5.7mg/mL ) . Combined treatment , BDP plus ML , afforded a further significant increase of AMP PC(20 ) ( 154.57+/-55.0mg/mL ) as compared to each single treatment . The significant protection exerted by combined treatment as compared to each single active treatment was also demonstrated by the change of AMP PC(20 ) doubling dose as compared to placebo and each single active treatment . Our findings suggest that these two agents exert their acute additive protection against AMP induced bronchoconstriction acting on distinct inflammatory pathways and their combined use might provide greater protection against inflammatory response elicited by AMP than either drug alone [15572850] Mild persistent asthma is most effectively controlled with inhaled corticosteroids . Leukotriene receptor antagonists have complementary effects to corticosteroids on inflammation control . The additional effect of a leukotriene receptor antagonist , zafirlukast , was investigated in stable asthma patients under control with inhaled budesonide . We conducted a r and omised , double-blind , placebo-controlled , single center trial to investigate the effects of add-on zafirlukast treatment to budesonide , on symptom score , pulmonary function , bronchial responsiveness , and serum levels of eosinophilic cationic protein ( ECP ) and antioxidant capacity in stable asthmatic patients under control with inhaled budesonide . The present study included 21 mild or moderate asthmatic patients ( 8 males and 13 females ) , who were stable at least for 6 weeks with inhaled budesonide ( 400 microg/day ) . Serum total antioxidant capacity ( TAC ) and ECP levels were measured , and symptom scoring , spirometry , and bronchial provocation with methacholine were performed . Then , the patients were r and omised to use either placebo or oral zafirlukast ( 40 mg/day ) in addition to budesonide for 6 weeks . At the 6th week , symptom scoring , spirometry , and bronchial provocation tests were repeated and serum TAC and ECP levels were measured again . After add-on zafirlukast treatment to budesonide , forced expiratory volume in 1 second ( FEV(1 ) ) , TAC and ECP values did not change significantly ( p > 0.05 ) but bronchial hyperresponsiveness and symptom score decreased significantly ( p = 0.022 ) compared to baseline . Thus , in stable asthmatic patients , add-on zafirlukast treatment to budesonide improves symptoms and decreases bronchial hyperresponsiveness [26634774] BACKGROUND AND OBJECTIVES : The use of written asthma action plans ( WAAPs ) has been associated with reduced asthma-related morbidity , but there are concerns about their complexity . We developed a health literacy – informed , pictogram- and photograph-based WAAP and examined whether providers who used it , with no training , would have better asthma counseling quality compared with those who used a st and ard plan . METHODS : Physicians at 2 academic centers r and omized to use a low-literacy or st and ard action plan ( American Academy of Allergy , Asthma and Immunology ) to counsel the hypothetical parent of child with moderate persistent asthma ( regimen : Flovent 110 μg 2 puffs twice daily , Singulair 5 mg daily , Albuterol 2 puffs every 4 hours as needed ) . Two blinded raters independently review ed counseling transcriptions . Primary outcome measures : medication instructions presented with times of day ( eg , morning and night vs number of times per day ) and inhaler color ; spacer use recommended ; need for everyday medications , even when sick , addressed ; and explicit symptoms used . RESULTS : 119 providers were r and omly assigned ( 61 low literacy , 58 st and ard ) . Providers who used the low-literacy plan were more likely to use times of day ( eg , Flovent morning and night , 96.7 % vs 51.7 % , P < .001 ; odds ratio [ OR ] = 27.5 ; 95 % confidence interval [ CI ] , 6.1–123.4 ) , recommend spacer use ( eg , Albuterol , 83.6 % vs 43.1 % , P < .001 ; OR = 6.7 ; 95 % CI , 2.9–15.8 ) , address need for daily medications when sick ( 93.4 % vs 34.5 % , P < .001 ; OR = 27.1 ; 95 % CI , 8.6–85.4 ) , use explicit symptoms ( eg , “ ribs show when breathing , ” 54.1 % vs 3.4 % , P < .001 ; OR = 33.0 ; 95 % CI , 7.4–147.5 ) . Few mentioned inhaler color . Mean ( SD ) counseling time was similar ( 3.9 [ 2.5 ] vs 3.8 [ 2.6 ] minutes , P = .8 ) . CONCLUSIONS : Use of a low-literacy WAAP improves the quality of asthma counseling by helping providers target key issues by using recommended clear communication principles [16270722] A few studies compared the additional effects of oral controller medicines on pulmonary function in asthmatic patients on a moderate dose of inhaled steroids . The aim of this study was to compare the additional effects of two oral asthma controllers , a leukotriene receptor antagonist and a sustained released theophylline ( Theo ) , with a moderate dose of inhaled steroid on peak expiratory flow ( PEF ) and asthma-related symptoms . A total of 67 adult asthmatic patients with PEF < 80 % predicted during a 2-week run-in period with 800 microg/day of beclomethasone dipropionate were r and omized to receive either pranlukast , 450 mg/day ( n = 33 ) , or sustained released Theo , 200 mg/day ( n = 34 ) , for 4 weeks . Pranlukast and Theo did not significantly alter the symptom scores , use of rescue beta2-agonist , and daily PEF variability . However , both agents significantly increased both morning and evening PEF compared with the run-in periods . The effects of both medications were comparable . For asthmatic patients even on a moderate dose of inhaled steroids , the addition of either leukotriene receptor antagonist or sustained released Theo does not improve asthma-related symptoms but significantly and equally increases PEF [18350399] The aim of this study was to investigate the effects of leukotriene receptor antagonists ( LTRAs ) on the premenstrual exacerbation of asthma ( PMA ) . Twenty-four female patients with mild asthma were enrolled in the study . Patients were followed for three menstrual cycles and separated into two groups based on whether they exibit premenstrual worsening of asthma symptoms ( n = 11 ) or not ( n = 13 ) . During the first month all were treated with only inhaled steroids ( IS ) ( run-in period ) ; during the second month they received IS plus placebo ; and during the third month they were given IS plus montelukast . Furthermore , they were advised to use beta 2 -agonists as needed . Peak expiratory flow rate ( PEFR ) and symptom scores were recorded during the 3 months . Pulmonary function tests ( PFT ) and the levels of oestrogen , progesterone , luteinizing hormone ( LH ) , and follicle-stimulating hormone ( FSH ) were measured a week before the begining of the menstrual period . At the end of the 3-month period , it was observed that following therapy with montelukast , the patients with PMA showed significant improvement in PEFR variability and symptom scores when compared with the placebo group . Baseline FSH levels were higher , but FSH and other hormone levels and PFTs did not change in these groups . However , in the group without PMA there was no difference between the montelukast or placebo groups in PEFR variability , symptom scores , PFTs , and hormone levels . Based on the data in h and , it could be stated that LTRAs have ensured the control of symptoms and improved PEFR variability in patients with PMA by supressing inflammation . We are of the view that LTRAs would be a right choice in the treatment of patients with PMA [11527250] BACKGROUND Although inhaled steroids are used as the first line of therapy in asthmatic patients , symptoms of asthma do not improve completely in some patients . OBJECTIVE To investigate the effects of pranlukast , a cysteinyl leukotriene receptor 1 antagonist , in patients with moderate/severe asthma , when combined with beclomethasone dipropionate ( BDP ) . METHODS Protocol 1 : After a 2-week observation period , 41 patients with moderate asthma were divided into those receiving BDP at 1,600 microg/day or 800 microg/day + pranlukast ( 450 mg/day ) . The effect of treatment was evaluated by measuring AM peak expiratory flow rate , symptom score , frequency of beta2-agonists , and daily variability of peak expiratory flow rate . Protocol 2 : 39 patients participated in this study including those with moderate asthma on 800 microg/day BDP ( group I ) , severe asthma on BDP at 1,600 microg/day ( group II ) , and severe asthma on 1,600 microg/day BDP + 5 to 20 mg prednisolone ( group III ) . Patients of all groups were additionally treated with pranlukast . RESULTS Protocol 1 : Both treatment regimens result ed in improvement in each clinical parameter . There were no significant differences in the effects of two treatment regimens . Protocol 2 : Pranlukast was effective in group I and II , but not in group III . In groups I and II , pranlukast tended to be more effective when BDP was introduced within the first year of onset of asthma . CONCLUSIONS Pranlukast is effective for patients with moderate asthma and those patients with severe asthma who are not treated with oral steroids . Pranlukast is more effective in patients treated with BDP early after onset [10588598] The primary objective of this study was to determine whether montelukast , an oral leukotriene receptor antagonist , provides additional clinical benefit to the effect of inhaled corticosteroids . A total of 642 patients with chronic asthma ( FEV(1 ) 50 to 85 % of predicted value and at least a predefined level of asthma symptoms ) incompletely controlled with inhaled beclomethasone , 200 microg twice daily using a spacer device , during the 4-wk run-in period were r and omly allocated , in a double-blind , double-dummy manner to one of four treatment groups : ( 1 ) montelukast 10 mg plus continuing inhaled beclomethasone ; ( 2 ) placebo tablet plus continuing inhaled beclomethasone ; ( 3 ) montelukast 10 mg and inhaled placebo ( after blind beclomethasone removal ) ; and ( 4 ) placebo tablet and inhaled placebo ( after blind beclomethasone removal ) . The primary endpoints were FEV(1 ) and daytime asthma symptoms score . Montelukast provided significant ( p < 0.05 ) clinical benefit in addition to inhaled beclomethasone by improving FEV(1 ) , daytime asthma symptom scores , and nocturnal awakenings . Blind removal of beclomethasone in the presence of placebo tablets caused worsening of asthma control , demonstrating that patients received clinical benefit from inhaled corticosteroids . Blind removal of beclomethasone in the presence of montelukast result ed in less asthma control but not to the level of the placebo group . All treatments were well tolerated ; clinical and laboratory adverse experiences were generally similar to placebo treatment in this study . In conclusion , montelukast provided additional asthma control to patients benefitting from , but incompletely controlled on , inhaled beclomethasone [9105060] To test whether the leukotriene antagonist ONO-1078 ( pranlukast ) prevents asthma exacerbations during reduction of high-dose inhaled corticosteroid , we conducted a r and omized , double-blind , placebo-controlled study in 79 asthma patients requiring high doses ( 1,500 microg/d or more ) of inhaled beclomethasone dipropionate ( BDI ) for clinical control ( duration of asthma , 11.0 + /- 3.1 yr ; duration of BDI treatment , 0.5 + /- 0.3 yr ; FEV1 percentage of predicted , 80.7 + /- 2.0 % ) . After a 2-wk run-in period , the doses of BDI were halved , while the patients were assigned to receive orally ONO-1078 , 450 mg twice daily , or placebo . In the placebo group FEV1 decreased by 0.33 + /- 0.20 L after 6 wk ( p < 0.001 ) . Likewise , morning and evening PEF decreased by 46 + /- 7 L/min and 18 + /- 6 L/min , respectively . By contrast these variables were sustained above baseline in the ONO-1078 group . The number of daytime and nighttime asthma symptoms and the use of beta2-agonist increased in the placebo group , whereas they remained unchanged in the ONO-1078 group . In the placebo group concentrations of serum eosinophil cationic protein and exhaled nitric oxide increased ( p = 0.007 and p = 0.025 , respectively ) , compared with no change in the ONO-1078 group . Therefore , the leukotriene antagonist ONO-1078 prevents the asthma deterioration provoked by a 6-wk reduction of the dose of inhaled BDI into half [26841365] In our prior r and omized trial on preventing influenza , asthma attacks as a secondary outcome occurred less often in the vitamin D group than in the placebo group . We aim ed to clarify whether low‐dose , short‐term vitamin D supplementation , in addition to st and ard treatments , improves control of childhood asthma [20550224] BACKGROUND Information is lacking on the relative effectiveness and cost effectiveness -- in a primary -care setting --of leukotriene receptor antagonists ( LTRAs ) as an alternative to inhaled corticosteroids ( ICS ) for initial asthma controller therapy . OBJECTIVE To compare the cost effectiveness of LTRAs versus ICS for patients initiating asthma controller therapy . METHODS An economic evaluation was conducted alongside a 2-year , pragmatic , r and omized controlled trial set in 53 primary -care practice s in the UK . Patients aged 12 - 80 years with asthma and symptoms requiring regular anti-inflammatory therapy ( n = 326 ) were r and omly assigned to LTRAs ( n = 162 ) or ICS ( n = 164 ) . The main outcome measures were the incremental costs per point improvement in the Mini Asthma Quality of Life Question naire , per point improvement in the Asthma Control Question naire and per QALY gained from the UK NHS and societal perspectives . RESULTS Over 2 years , re source use was similar between the two treatment groups , but the cost to society per patient was significantly higher for the LTRA group , at pounds sterling 711 versus pounds sterling 433 for the ICS group ( adjusted difference pounds sterling 204 ; 95 % CI 74 , 308 ) [ year 2005 values ] . Cost differences were driven primarily by differences in prescription drug costs , particularly study drug costs . There was a nonsignificant ( imputed , adjusted ) difference between treatment groups , favouring ICS , in QALYs gained at 2 years of -0.073 ( 95 % CI -0.143 , 0.010 ) . Therapy with LTRAs was , on average , a dominated strategy , and , at a threshold for willingness to pay of pounds sterling 30,000 per QALY gained , the probability of LTRAs being cost effective compared with ICS was approximately 3 % from both societal and NHS perspectives . CONCLUSIONS There is a very low probability of LTRAs being cost effective in the UK , at 2005 values , compared with ICS for initial asthma controller therapy . TRIAL REGISTRATION UK National Research Register N0547145240 ; Controlled Clinical Trials IS RCT N99132811 [20709517] BACKGROUND Airway inflammation is a key pathological feature of asthma which underlies its clinical presentation . OBJECTIVES To examine whether adding a leukotriene modifier to an inhaled corticosteroid produces further clinical and /or anti-inflammatory benefits in patients symptomatic on short-acting beta(2)-agonists . METHODS Patients uncontrolled on short-acting beta(2)-agonists were treated for 12 weeks with either fluticasone propionate ( 100mcg BD ) or fluticasone propionate ( 100mcg BD ) and montelukast ( 10 mg QD ) in a r and omized , double-blind , parallel group study . Bronchoscopy with endobronchial biopsy and bronchoalveolar lavage ( BAL ) was performed before and after treatment to compare effects on airway inflammation . RESULTS Of 103 subjects enrolled , 89 subjects completed treatment and 82 subjects had matched pair biopsy sample s. Submucosal eosinophil counts , the primary endpoint , and asthma control improved to similar extents after both treatments ( p < or=0.008 ) . Both treatments significantly reduced submucosal mast cell , CD3 + , CD4 + , CD8 + and CD25 + cell counts . Submucosal mast cell reduction was greater in the fluticasone propionate plus montelukast group . There were no differences between treatments in BAL markers of inflammation or thickness of sub-epithelial collagen . CONCLUSIONS Low-dose fluticasone propionate significantly improves clinical disease control and reduces airway inflammation in asthma patients uncontrolled with short-acting beta(2)-agonists without further improvement when montelukast is added to low-dose fluticasone propionate [23548532] BACKGROUND Eosinophilic inflammation of the small airways is a key process in asthma that often smolders in treated patients . The long-term effects of add-on therapy on the persistent inflammation in the small airways remain unknown . OBJECTIVE To examine the effects of add-on therapy with either ciclesonide , an inhaled corticosteroid with extrafine particles , or montelukast on small airway inflammation . METHODS Sixty patients with stable asthma receiving inhaled corticosteroid treatment were enrolled in a r and omized , open-label , parallel comparison study of 24-week add-on treatment with ciclesonide or montelukast . Patients were r and omly assigned to 3 groups : ciclesonide ( n = 19 ) , montelukast ( n = 22 ) , or no add-on as controls ( n = 19 ) . At baseline and at weeks 4 , 12 , and 24 , extended nitric oxide analysis ; pulmonary function tests , including impulse oscillometry ; blood eosinophil counts ; and asthma control tests ( ACTs ) were performed . RESULTS A total of 18 patients in the ciclesonide group , 19 in the montelukast group , and 15 in the control group completed the study and were analyzed . With repeated- measures analysis of variance , ciclesonide produced a significant decrease in alveolar nitric oxide and a significant improvement in ACT scores over time . Montelukast produced significant decreases in alveolar nitric oxide concentrations and blood eosinophil counts over time and slightly improved ACT scores , whereas no such changes were observed in the control group . Alveolar nitric oxide concentrations with ciclesonide and reactance area at low frequencies with montelukast produced greater improvements over time compared with control . CONCLUSION Ciclesonide add-on therapy and montelukast add-on therapy may act differently , but both separately can improve small airway abnormalities and provide better asthma control . TRIAL REGISTRATION umin.ac.jp/ctr Identifier : UMIN000001083 [26325232] Abstract Objective : Treatment guidelines for asthma recommend step-down therapy for well-controlled asthma patients . However , the precise strategy for step-down therapy has not been well defined . We investigated whether well-controlled patients with mild persistent asthma can tolerate a step-down therapy of either a reduced dose of inhaled corticosteroid ( ICS ) or a switch to a leukotriene receptor antagonist ( LTRA ) , pranlukast hydrate . Methods : We recruited 40 adult patients with mild persistent asthma who were well-controlled for at least 3 months with a low-dose ICS therapy . The patients were r and omly assigned to either an ICS dose reduction or a switch to pranlukast for 6 months . Results : FeNO levels in the pranlukast group were significantly increased over that in the ICS group . There were no significant differences between the two groups for lung function , FOT , at the endpoint . The percentage of patients with controlled asthma was 72.2 % in the pranlukast group and 90 % in the ICS group . No statistically significant difference between the two groups in the percentages of patients with treatment failure was observed . Conclusions : Patients with mild persistent asthma that is well-controlled by a low dose of ICS can be switched to pranlukast safely for at least 6 months . However , 27.8 % of the pranlukast group failed to maintain well-control , and FeNO levels increased with the switch to pranlukast at 6 months . This study was been limited by the small sample size and should therefore be considered preliminary . Further studies are needed to investigate the therapeutic efficacy of LTRA monotherapy as a step-down therapy

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### Context: [12480610] The aim of the study was to investigate the effect of addition of montelukast to inhaled fluticasone propionate ( FP ) therapy , compared with FP therapy alone ( 100 microg twice a day ) on airway immunopathology in individuals with mild asthma . Twenty-eight subjects received FP ( 100 microg twice a day ) or FP ( 100 microg twice a day ) plus montelukast ( 10 mg at night ) for 8 weeks and were then crossed over to the alternate treatment for a further 8 weeks . Physiological measurements and bronchial biopsies were obtained at + /- 2 days before treatment and + /- 2 days at the end of each treatment period . A two-period crossover analysis was performed and the mean and SE were calculated . There was no significant difference in percent predicted FEV1 ( p = 0.51 ) or PC20 mg/ml ( p = 0.81 ) between the two treatment regimes after 8 weeks of therapy . There was no difference in the efficacy of either treatment in decreasing T cell ( p = 0.97 ) , CD45RO+ ( p = 0.37 ) , mast cell ( p = 0.37 ) , or activated eosinophils ( p = 0.55 ) numbers in bronchial biopsies . There was no significant difference in the percentage area stained for IFN-gamma ( p = 0.76 ) or interleukin-4 ( p = 0.61 ) between treatments . Reduction of inflammatory cell numbers in the bronchial mucosa achieved with FP plus montelukast was not significantly different from the reduction observed with FP alone in individuals with mild asthma [15136378] STUDY OBJECTIVE Evidence for the anti-inflammatory activity of leukotriene receptor antagonists in humans is somewhat limited . There are also no data comparing the anti-inflammatory effects of leukotriene receptor antagonists with those of inhaled corticosteroids . This study was design ed to assess the clinical efficacy and anti-inflammatory effects of leukotriene receptor antagonist plus low-dose inhaled corticosteroids compared to those of a high-dose inhaled corticosteroid in patients with mild-to-moderate asthma . METHODS Forty-nine patients with newly diagnosed asthma were recruited . They were r and omly assigned to groups that received , for a 6-week period , either ( 1 ) budesonide , 600 microg bid ( 1,200 microg/d ) or ( 2 ) budesonide , 200 microg ( 400 microg/d ) , and zafirlukast , 20 mg bid . The variables of asthma control were recorded daily . Sputum induction and methacholine provocation tests were performed . RESULTS The results indicated that the administration of a low-dose inhaled corticosteroid plus zafirlukast was as effective as that of a high-dose inhaled corticosteroid regarding clinical improvement and anti-inflammatory effects ( ie , eosinophil percentage , and eosinophilic cationic protein [ ECP ] and cysteinyl leukotriene C4 levels in induced sputum ) . Nineteen ( group 1 , 8 patients ; group 2 , 11 patients ) of 49 patients ( 38.8 % ) had returned to normal airway responsiveness after treatment . Among these patients , 16 patients ( 84.2 % ) had normal ECP levels and 10 patients ( 52.6 % ) had normal percentages of eosinophils . ECP level , but not the eosinophil percentage , was significantly associated with symptom scores . The peak expiratory flow rate ( PEFR ) showed a significant correlation with the provocative concentration of methacholine causing a 20 % fall in FEV1 ( PC20 ) instead of with symptom scores . CONCLUSIONS The addition of a leukotriene modifier to treatment with low-dose inhaled corticosteroids is equivalent to treatment with high-dose inhaled corticosteroids in patients with newly diagnosed mild-to-moderate asthma . In addition to symptoms and PEFR , the monitoring of ECP and PC20 may be of great value in achieving optimal control of asthma [23380218] OBJECTIVE Many asthmatic patients are unable to quit cigarettes ; therefore information is needed on treatment options for smokers . This study evaluates 10 mg/d montelukast and 250 μg of fluticasone propionate twice daily , each compared with placebo , in patients with self-reported active smoking ( unable to quit ) and asthma . METHODS Patients ( ages 18 - 55 years , with asthma [ ≥1 year ] , FEV1 of 60 % to 90 % of predicted value , airway reversibility [ ≥12 % ] , and self-reported active smoking [ ≥0.5 to ≤2 packs per day ] ) were r and omized ( after a 3-week , single-blind , placebo , run-in period ) to 1 of 3 parallel , 6-month , double-blind treatment arms . The primary efficacy end point was the percentage of days with asthma control during treatment . Adverse experiences ( AEs ) were also evaluated . RESULTS There were 347 , 336 , and 336 patients r and omized to montelukast , fluticasone , and placebo , respectively . The mean percentage of days with asthma control over 6 months of treatment was 45 % ( montelukast , P < .05 vs placebo ) , 49 % ( fluticasone , P < .001 vs placebo ) , and 39 % ( placebo ) ; the difference between montelukast and fluticasone was not significant ( P = .14 ) . Patients with a smoking history of ≤11 pack years ( the median value ) tended to show more benefit with fluticasone , whereas those with a smoking history of > 11 pack years tended to show more benefit with montelukast . AEs occurred in similar proportions among treatment groups . CONCLUSIONS In a population of asthmatic patients actively smoking cigarettes , both 10 mg/d montelukast and 250 μg of fluticasone propionate twice daily significantly increased the mean percentage of days with asthma control compared with placebo [16407639] Background : The motive behind conducting this study was to determine if better control of asthma can be achieved by adding a second controller medication and to assess its use to reduce the dose of inhaled steroids . Objectives : The study aim ed to determine whether either oral sustained-release theophylline or montelukast added to inhaled steroids improved clinical symptoms and pulmonary function test parameters when compared to high-dose steroids alone . Methods : Ninety patients with incompletely controlled asthma were allocated , in a r and omised , double-blind fashion , to one of three treatment groups : group A : double dose of inhaled budesonide ( 400 µg b.i.d . ) , group B : 400 mg oral sustained-release theophylline plus budesonide ( 200 µg b.i.d . ) and group C : 10 mg montelukast plus budesonide ( 200 µg b.i.d . ) . The primary endpoints were forced expiratory volume in 1 s ( FEV1 ) and mean morning peak expiratory flow rate ( PEFR ) . Results : All three groups had improved FEV1 and PEFR at 8 weeks ( p < 0.001 ) . Group C increased their PEFR by 18.7 l/min ( 95 % confidence interval , CI , 12.4–25.1 ) more than group A and by 19.8 l/min ( 95 % CI 13.4–26.1 ) more than group B ( both p = 0.001 ) . Similarly , group C had a 114 ml ( 95 % CI 45–183 ml ) greater improvement in FEV1 than group A and a 95 ml ( 95 % CI 26–164 ml ) greater improvement than group B ( both p = 0.01 ) . Conclusions : Addition of montelukast to budesonide is safe and results in greater improvement in pulmonary function test parameters than high-dose budesonide treatment or addition of theophylline [21542741] BACKGROUND Most r and omized trials of treatment for asthma study highly selected patients under idealized conditions . METHODS We conducted two parallel , multicenter , pragmatic trials to evaluate the real-world effectiveness of a leukotriene-receptor antagonist ( LTRA ) as compared with either an inhaled glucocorticoid for first-line asthma-controller therapy or a long-acting beta(2)-agonist ( LABA ) as add-on therapy in patients already receiving inhaled glucocorticoid therapy . Eligible primary care patients 12 to 80 years of age had impaired asthma-related quality of life ( Mini Asthma Quality of Life Question naire [ MiniAQLQ ] score ≤6 ) or inadequate asthma control ( Asthma Control Question naire [ ACQ ] score ≥1 ) . We r and omly assigned patients to 2 years of open-label therapy , under the care of their usual physician , with LTRA ( 148 patients ) or an inhaled glucocorticoid ( 158 patients ) in the first-line controller therapy trial and LTRA ( 170 patients ) or LABA ( 182 patients ) added to an inhaled glucocorticoid in the add-on therapy trial . RESULTS Mean MiniAQLQ scores increased by 0.8 to 1.0 point over a period of 2 years in both trials . At 2 months , differences in the MiniAQLQ scores between the two treatment groups met our definition of equivalence ( 95 % confidence interval [ CI ] for an adjusted mean difference , -0.3 to 0.3 ) . At 2 years , mean MiniAQLQ scores approached equivalence , with an adjusted mean difference between treatment groups of -0.11 ( 95 % CI , -0.35 to 0.13 ) in the first-line controller therapy trial and of -0.11 ( 95 % CI , -0.32 to 0.11 ) in the add-on therapy trial . Exacerbation rates and ACQ scores did not differ significantly between the two groups . CONCLUSIONS Study results at 2 months suggest that LTRA was equivalent to an inhaled glucocorticoid as first-line controller therapy and to LABA as add-on therapy for diverse primary care patients . Equivalence was not proved at 2 years . The interpretation of results of pragmatic research may be limited by the crossover between treatment groups and lack of a placebo group . ( Funded by the National Coordinating Centre for Health Technology Assessment U.K. and others ; Controlled Clinical Trials number , IS RCT N99132811 . ) [12449158] The present study aim ed at comparing the effects of a dose reduction of inhaled corticosteroids on lung function , indirect measures of airway inflammation and clinical scores during treatment with a leucotriene receptor antagonist . In 50 patients ( mean forced expiratory volume in one second ( FEV1 ) 94 % predicted ) , steroid doses ( 800 µg beclomethasone dipropionate ) were first reduced to 50 % and then to 25 % , for 6 weeks each . One group received a placebo and the other group received montelukast ( 10 mg ) . The first reduction did not cause significant effects . During the second , FEV1 and peak expiratory flow decreased in both groups ( p<0.001 ) . Daytime symptoms were not altered with placebo but were reduced by montelukast ( p<0.05 ) . Night-time symptoms were slightly elevated with placebo ( p<0.05 ) but not montelukast , as well as the use of supplemental salbutamol . Changes in provocative concentration of methacholine causing a 20 % fall in FEV1 ( PC20 ) , sputum eosinophils and exhaled nitric oxide were mostly nonsignificant for both placebo and montelukast . These data demonstrate that a 75 % reduction in the dose of steroid given to patients with asthma led to a deterioration in lung function not prevented by montelukast , whereas changes in clinical state seemed to favour montelukast treatment . It therefore appears that potential effects of montelukast , in the presence of low-dose steroids , could not be attributed to single indices of lung function or airway inflammation [26460983] STUDY OBJECTIVE In acute exacerbations of asthma in children , corticosteroids reduce relapses , subsequent hospital admission , and the need for ß2-agonist bronchodilators . Prednisolone is the most commonly used corticosteroid , but prolonged treatment course , vomiting , and a bitter taste may reduce patient compliance . Dexamethasone has a longer half-life and has been used safely in other acute pediatric conditions . We examine whether a single dose of oral dexamethasone is noninferior to prednisolone in the emergency department ( ED ) treatment of asthma exacerbations in children , as measured by the Pediatric Respiratory Assessment Measure ( PRAM ) at day 4 . METHODS We conducted a r and omized , open-label , noninferiority trial comparing oral dexamethasone ( single dose of 0.3 mg/kg ) with prednisolone ( 1 mg/kg per day for 3 days ) in patients aged 2 to 16 years and with a known diagnosis of asthma or at least 1 previous episode of ß2-agonist-responsive wheeze who presented to a tertiary pediatric ED . The primary outcome measure was the mean PRAM score ( range of 0 to 12 points ) performed on day 4 . Secondary outcome measures included requirement for further steroids , vomiting of study medication , hospital admission , and unscheduled return visits to a health care practitioner within 14 days . RESULTS There were 245 enrollments involving 226 patients . There was no difference in mean PRAM scores at day 4 between the dexamethasone and prednisolone groups ( 0.91 versus 0.91 ; absolute difference 0.005 ; 95 % CI -0.35 to 0.34 ) . Fourteen patients vomited at least 1 dose of prednisolone compared with no patients in the dexamethasone group . Sixteen children ( 13.1 % ) in the dexamethasone group received further systemic steroids within 14 days after trial enrollment compared with 5 ( 4.2 % ) in the prednisolone group ( absolute difference 8.9 % ; 95 % CI 1.9 % to 16.0 % ) . There was no significant difference between the groups in hospital admission rates or the number of unscheduled return visits to a health care practitioner . CONCLUSION In children with acute exacerbations of asthma , a single dose of oral dexamethasone ( 0.3 mg/kg ) is noninferior to a 3-day course of oral prednisolone ( 1 mg/kg per day ) as measured by the mean PRAM score on day 4 [26786240] Abstract Introduction : Poor self-management by families is an important factor in explaining high rates of asthma morbidity in Puerto Rico , and for this reason we previously tested a family intervention called CALMA that was found effective in improving most asthma outcomes , but not effective in increasing the use of controller medications . CALMA-plus was developed to address this issue by adding to CALMA , components of provider training and screening for asthma in clinics . Methods : Study participants were selected from cl aims Medicaid data in San Juan , Puerto Rico . After screening , 404 children in eight clinics were selected after forming pairs of clinics and r and omizing the clinics ) to CALMA-only or CALMA-plus . Results : For all three primary outcomes at 12 months , the mean differences between treatment arms were small but in the predicted direction . However , after adjusting for clinic variation , the study failed to demonstrate that the CALMA-plus intervention was more efficacious than the CALMA-only intervention for increasing controller medication use , or decreasing asthma symptoms . Both groups had lower rates of asthma symptoms and service utilization , consistent with previous results of the CALMA-only intervention . Conclusions : Compliance of providers with the intervention and training , small number of clinics available and the multiple barriers experienced by providers for medicating may have been related to the lack of difference observed between the groups . Future interventions should respond to the limitations of the present study design and provide more re sources to providers that will increase provider participation in training and implementation of the intervention [12612294] Background : Proinflammatory leukotrienes , which are not completely inhibited by inhaled corticosteroids , may contribute to asthmatic problems . A 16 week multicentre , r and omised , double blind , controlled study was undertaken to study the efficacy of adding oral montelukast , a leukotriene receptor antagonist , to a constant dose of inhaled budesonide . Methods : A total of 639 patients aged 18–70 years with forced expiratory volume in 1 second ( FEV1 ) ≥55 % predicted and a minimum predefined level of asthma symptoms during a 2 week placebo run in period were r and omised to receive montelukast 10 mg ( n=326 ) or placebo ( n=313 ) once daily for 16 weeks . All patients received a constant dose of budesonide ( 400–1600 μg/day ) by Turbuhaler throughout the study . Results : Mean FEV1 at baseline was 81 % predicted . The median percentage of asthma exacerbation days was 35 % lower ( 3.1 % v 4.8 % ; p=0.03 ) and the median percentage of asthma free days was 56 % higher ( 66.1 % v 42.3 % ; p=0.001 ) in the montelukast group than in the placebo group . Patients receiving concomitant treatment with montelukast had significantly ( p<0.05 ) fewer nocturnal awakenings and significantly ( p<0.05 ) greater improvements in β agonist use and morning peak expiratory flow rate ( PEFR ) . Conclusions : For patients with mild airway obstruction and persistent asthma symptoms despite budesonide treatment , concomitant treatment with montelukast significantly improves asthma control [10355150] We undertook a community based case-control study to measure the effect of pranlukast on the reduction of inhaled steroid in adult asthmatics . Forty-one adults completed a run-in period of 4 weeks on 800 microgram of beclomethasone dipropionate ( BDP ) documenting twice daily peak expiratory flow ( PEF ) and symptom score and therapeutic score on a st and ard diary . Forced expiratory volume in one second ( FEV1.0 ) , V50 , V25 was measured once during the run-in period . Patients were then r and omized to receive either pranlukast with 400 microgram of BDP or 400 microgram alone for 8 weeks . There was no difference in the symptom score and therapeutic between the two groups at any time point . However , morning and evening % PEF run-in expressed as a % of the PEF average during the run-in period was significantly lower at 8 weeks in the groups without pranlukast . There were subjects in the group without pranlukast ( 35.3 % ) compared to those with ( 20.8 % ) who had a 10 % or more reduction in % PEF from the run-in period . The patients with an FEV1.0 < 80 % predicted who were r and omized to the control group were more likely ( 5 of 7 ) to have a fall in % PEF run-in and those r and omized to received pranlukast were less likely to have a fall in % PEF run-in though this was not significant ( 2 of 6 ) . In this study , pranlukast has demonstrated steroid sparing effect . Severe asthmatics ( FEV1.0 < 80 % ) who deteriorate after reduction of inhaled steroid may benefit most from pranlukast . Larger studies are now required to explore this important effect [4705626] Background Asthma affects more than 5 million patients in the United Kingdom . Nearly 500,000 of these patients have severe asthma with severe symptoms and frequent exacerbations that are inadequately controlled with available treatments . The burden of severe asthma on the NHS is enormous , accounting for 80 % of the total asthma cost ( £ 1 billion ) , with frequent exacerbations and expensive medications generating much of this cost . Of those patients with severe asthma , 70 % are sensitised to indoor aeroallergens , and the level of exposure to allergens determines the symptoms ; patients exposed to high levels are therefore most at risk of exacerbations and hospital admissions . The LASER trial aims to assess whether a new treatment , temperature controlled laminar airflow ( TLA ) delivered by the Airsonett ™ device , can reduce the frequency of exacerbations in patients with severe allergic asthma by reducing exposure to aeroallergens overnight . Methods This multicentre study is a placebo-controlled , blinded , r and omised controlled , parallel group trial . A total of 222 patients with a new or current diagnosis of severe allergic asthma will be assigned with a r and om element in a 1:1 ratio to receive either an active device for one year or a placebo device . The primary outcome is the frequency of severe asthma exacerbations occurring over a 12-month period , defined in accordance with the American Thoracic Society/European Respiratory Society ( ATS/ERS ) guidelines . Secondary outcomes include changes in asthma control , lung function , asthma-specific and global quality of life for participants and their carers , adherence to intervention , healthcare re source use and costs , and cost-effectiveness . Qualitative interviews will be conducted to elicit participant ’s and their partner ’s perceptions of the treatment . Discussion Effective measures of allergen avoidance have , to date , proved elusive . The LASER trial aims to address this . The study will ascertain whether home-based nocturnal TLA usage over a 12-month period can reduce the frequency of exacerbations and improve asthma control and quality of life as compared to placebo , whilst being cost-effective and acceptable to adults with poorly controlled , severe allergic asthma . The results of this study will be widely applicable to the many patients with allergic asthma both in the UK and internationally . Trial registration Current controlled trials IS RCT N46346208 ( Date assigned 22 January 2014 ) [12114351] STUDY OBJECTIVES To evaluate the effect of adding zafirlukast or low-dose theophylline to a beclomethasone dipropionate ( BDP ) extra-fine hydrofluoroalkane aerosol on bronchial hyperresponsiveness as the primary outcome variable . METHODS Twenty-four patients with mild-to-moderate asthma were studied using a r and omized crossover design with the following three treatment blocks : ( 1 ) beclomethasone , 100 microg/d , alone for the first 2 weeks followed by 400 microg/d alone for the next 2 weeks ; ( 2 ) beclomethasone , 100 microg/d , followed by 400 microg/d , with the addition of zafirlukast , 20 mg bid ; ( 3 ) beclomethasone , 100 microg/d , followed by 400 microg/d , with the addition of theophylline , 200 to 300 mg bid . Measurements were made after 2 and 4 weeks of each treatment and at pretreatment baseline . RESULTS The mean trough plasma theophylline concentration was 6.7 mg/L , coinciding with the anti-inflammatory target range ( ie , 5 to 10 mg/L ) . The provocative dose of methacholine causing a 20 % fall in FEV(1 ) ( as doubling dose difference from baseline ) was significantly ( p < 0.05 ) greater with beclomethasone , 100 microg , plus zafirlukast ( 1.1 doubling dose ) but not with beclomethasone , 100 microg , plus theophylline ( 0.7 doubling dose ) compared to beclomethasone , 100 microg alone ( 0.4 doubling dose ) , but not compared to beclomethasone , 400 microg alone ( 1.1 doubling dose ) . There were also significant ( p < 0.05 ) differences between beclomethasone , 100 microg , plus zafirlukast ( but not BDP , 100 microg , plus theophylline ) vs beclomethasone , 100 microg , alone in terms of nitric oxide level , midexpiratory phase of forced expiratory flow , and peak expiratory flow . There were no further significant improvements observed with the addition of zafirlukast or theophylline to beclomethasone , 400 microg . CONCLUSIONS A leukotriene receptor antagonist , but not low-dose theophylline , conferred significant additive anti-inflammatory effects to therapy with a low-dose inhaled corticosteroid but not to that with a medium dose of an inhaled corticosteroid . Thus , optimizing the dose of inhaled corticosteroid as monotherapy would seem to be the logical first step , which is in keeping with current guidelines [4878003] Abstract Background Bronchoprovocation challenges use direct or indirect acting stimuli to induce airflow obstruction . Indirect stimuli either non-allergic/non-IgE mediated ( e.g. exercise , mannitol ) or allergic/IgE mediated ( i.e. allergen ) trigger mast cells to release bronchoconstricting mediators ( e.g. cysteinyl leukotrienes , histamine ) . Performing repeat challenges within a short timeframe ( e.g. 3 h ) with non-allergic indirect stimuli results in a diminished , refractory response to the second challenge that is inhibited by non-steroidal anti-inflammatory medications . Cross refractoriness occurs between indirect stimuli . It follows that repeat bronchoprovocation with allergen might exhibit refractoriness that might be altered by ibuprofen . We assessed the response to a second allergen challenge performed 24 h after an initial allergen challenge to determine if the response is refractory . If refractoriness developed , the study aim ed to determine whether a single dose of ibuprofen would alter the refractory response to the second allergen challenge . In the absence of a refractory response , the study design allowed for the assessment of the effect of ibuprofen on allergen challenge outcomes , including indices of airway inflammation . Methods Thirteen mild atopic asthmatics were enrolled in a r and omized , double-blind , placebo controlled , cross-over study . Ibuprofen ( 400 mg ) or placebo was administered 1 h prior to the first of two allergen challenges , performed 24 h apart . Blood and sputum eosinophils , airway responsiveness to methacholine and levels of fractional exhaled nitric oxide were assessed before and 7 h after each allergen challenge . All data were log transformed and differences in geometric means were analyzed by paired t-tests . Results After placebo , early asthmatic responses for the two challenges were not significantly different ( p = 0.82 ) . A single 400 mg dose of ibuprofen decreased both the early ( p = 0.03 ; n = 12 ) and late asthmatic responses ( p = 0.03 ; n = 3 ) . Conclusion Allergen challenges conducted 24 h apart do not exhibit refractoriness . Single dose ibuprofen inhibits early and late asthmatic responses to allergen bronchoprovocation . Ibuprofen should be withheld for at least 24 h prior to investigations utilizing allergen bronchoprovocation . Trial registration clinical trials.gov # [15640321] Sputum eosinophilia is a sensitive predictor of benefit from corticosteroid treatment . Montelukast is a cysteinyl leukotriene antagonist , which also reduces sputum and blood eosinophils . The present study examined the possibility that montelukast has an added eosinophil-lowering effect in subjects with asthma who are corticosteroid responsive but relatively corticosteroid resistant . A total of 14 clinical ly stable adults with asthma requiring minimum treatment with a high-dose inhaled steroid or prednisone , with baseline sputum eosinophilia ( ≥5 % ) , were r and omised to receive 4 weeks of 10 mg montelukast or placebo daily in a double-blind crossover trial . The primary outcome was the effect of treatment on the percentage of sputum eosinophils . Secondary outcomes were changes in the blood eosinophil count , symptoms , forced expiratory volume in one second , peak expiratory flow and the need for salbutamol . The median ( interquartile range , i.e. 75th–25th centile ) for sputum eosinophils at baseline was 15.7 % ( 22 ) . The effect of adding montelukast was not significantly different from that of placebo , sputum eosinophils being 9.3 % ( 18.9 ) after montelukast and 11.3 % ( 22.8 ) after placebo . No difference was detected on secondary outcomes . No crossover interactions were observed . In conclusion , the addition of montelukast to existing high-dose corticosteroid therapy in subjects with asthma with elevated sputum eosinophils does not provide additional attenuation of airway eosinophilia [4509656] Purpose There have been few reports regarding the efficacy of antiasthmatics in older patients . To compare the efficacy of the addition of montelukast to low-dose inhaled budesonide ( MON-400BUD ) versus increasing the dose of inhaled steroid ( 800BUD ) on asthma control in older asthmatics . Methods A r and omized , open-label , parallel- design ed trial was conducted for 12 weeks . The primary endpoint was the rate of patients who reached " well-controlled asthma status " after the 12-week treatment period . Additionally , asthma exacerbations , sputum inflammatory cells , asthma control test ( ACT ) and physical functioning scale ( PFS ) , and adverse reactions were monitored . Results Twenty-four ( 36.9 % ) and 22 ( 34.9 % ) subjects in the MON-400BUD ( n=65 ) and 800BUD ( n=63 ) groups had well-controlled asthma at the end of the study , respectively . The numbers of asthma exacerbations requiring oral corticosteroid treatment ( 20 vs 9 , respectively , P=0.036 ) and the development of sore throat ( 22 vs 11 , respectively , P=0.045 ) were significantly higher in the 800BUD group than in the MON-400BUD group . Body mass index and changes in ACT , FEV1 % , 6-min walk distance and PFS from baseline were all significant determinants for distinguishing subjects with well-controlled and partly controlled asthma from those with uncontrolled asthma ( P<0.05 ) at the end of the study . Conclusions The efficacy of 12-week treatment with MON-400BUD in older asthmatics was comparable to that of 800BUD on asthma control but associated with reduced frequency of asthma exacerbations requiring oral steroids and sore throat events . Changes in ACT and PFS can be useful predictors of asthma control status in older patients [4736611] Background Influenza virus ( IFV ) infection is associated with increased morbidity and mortality in people with underlying lung disease . Treatment options for IFV are currently limited and antiviral resistance is a growing concern . DAS181 , an inhaled antiviral with a unique mechanism of action , has shown promise in early clinical trials involving generally healthy human subjects . This study was undertaken to assess the safety and tolerability of DAS181 in individuals with underlying reactive airway disease . Methods This was a r and omized , double-blind , placebo-controlled , crossover phase 1 study of DAS181-F02 . Dry particle inhaler administration of 10 mg was done on 3 consecutive days in ten adult volunteers with well-controlled asthma . The primary outcome was the frequency of adverse events ( AEs ) , grade 1 or higher that occurred during each study period . Results There were 280 AEs among ten evaluable subjects ( 56.8 % active ; 43.2 % placebo ) ; 90.7 % were grade 1 . No grade 3 or higher AEs occurred . A statistically significant association between exposure to DAS181 and experiencing any AE , a grade 1 AE , or a grade 2 AE was not detected . Overall , the majority of AEs were classified as possibly related ( 35.7 % ) , unlikely related ( 38.9 % ) , or unrelated ( 15.4 % ) to study drug administration . However , there was a statistically significant association between exposure to DAS181 and experiencing a definitely or probably related AE . Respiratory effects , including dyspnea , dry cough , and chest discomfort related to respirations , accounted for all of the definitely related AEs and one of the most common probably related AEs . Conclusions DAS181 was safe in this small study of otherwise healthy subjects with well-controlled asthma . However , the generalizability of these results is limited by the small sample size and generally mild nature of the subjects ’ asthma at baseline . The increased association of respiratory events classified as probably or definitely related to DAS181 administration suggests caution may need to be employed when administering DAS181 to individuals with less stable reactive airway disease . Further investigation in a controlled setting of the safety and efficacy of DAS181 in a larger population of asthmatic subjects with varying disease activity is warranted . Trial Registration Clinical Trials.gov NCT01113034Trial Registration Date : April 27 , [22536582] BACKGROUND In 2010 , the Canadian Thoracic Society ( CTS ) published a Consensus Summary for the diagnosis and management of asthma in children six years of age and older , and adults , including an up date d Asthma Management Continuum . The CTS Asthma Clinical Assembly subsequently began a formal clinical practice guideline up date process , focusing , in this first iteration , on topics of controversy and ⁄or gaps in the previous guidelines . METHODS Four clinical questions were identified as a focus for the up date d guideline : the role of noninvasive measurements of airway inflammation for the adjustment of anti-inflammatory therapy ; the initiation of adjunct therapy to inhaled corticosteroids ( ICS ) for uncontrolled asthma ; the role of a single inhaler of an ICS⁄long-acting beta(2)-agonist combination as a reliever , and as a reliever and a controller ; and the escalation of controller medication for acute loss of asthma control as part of a self-management action plan . The expert panel followed an adaptation process to identify and appraise existing guidelines on the specified topics . In addition , literature search es were performed to identify relevant systematic review s and r and omized controlled trials . The panel formally assessed and grade d the evidence , and made 34 recommendations . RESULTS The up date d guideline recommendations outline a role for inclusion of assessment of sputum eosinophils , in addition to st and ard measures of asthma control , to guide adjustment of controller therapy in adults with moderate to severe asthma . Appraisal of the evidence regarding which adjunct controller therapy to add to ICS and at what ICS dose to begin adjunct therapy in children and adults with poor asthma control supported the 2010 CTS Consensus Summary recommendations . New recommendations for the adjustment of controller medication within written action plans are provided . Finally , priority areas for future research were identified . CONCLUSIONS The present clinical practice guideline is the first up date of the CTS Asthma Guidelines following the Canadian Respiratory Guidelines Committee 's new guideline development process . Tools and strategies to support guideline implementation will be developed and the CTS will continue to regularly provide up date s reflecting new evidence [15182276] BACKGROUND Although current guidelines suggest the use of inhaled corticosteroids as the first line therapy in persistent asthma , the concerns about high-dose corticosteroids may limit their usage . We aim ed to investigate the efficacy of inhaled budesonide plus oral montelukast versus a double dose of inhaled budesonide . METHODOLOGY Thirty patients with moderate asthma took part in the study . Following a 2-week run in period , the patients were r and omized into two groups to receive 400 microg/day of inhaled budesonide plus 10 mg/day of montelukast ( BUD + M group ) or 800 microg/day of inhaled budesonide ( high BUD group ) . The patients were evaluated at 2-week intervals ( during a total treatment period of 6 weeks ) for symptom scores , asthma exacerbations , lung function , use of short-acting beta2 agonist , blood eosinophil counts and adverse events . RESULTS At the end of the study , morning and daytime symptom scores were significantly reduced within the groups . Although there was a significant decrease in the frequency of short-acting beta2 agonist use in the BUD + M group , the decrease in the high BUD group was not significant . During the study period , no patient in either group experienced an asthma exacerbation . Blood eosinophil levels significantly declined in both the BUD + M ( 0.87 + /- 0.31 % ) and high BUD groups ( 0.67 + /- 0.29 % ) as compared with baseline levels ( BUD + M = 2.60 + /- 0.65 % , high BUD group = 2.60 + /- 0.47 % ; P < 0.05 ) . CONCLUSION Our results suggest that the addition of montelukast to low-dose inhaled budesonide is as effective as a double dose of inhaled budesonide in asthma control [14584388] Eighty-one adult patients with bronchial asthma who suffered asthmatic episodes in spite of treatment with 400 mg/day of BDP were placed on pranlukast therapy for 4 weeks . Group I , which showed a 5 % or greater increase in PEFR , continued oral pranlukast medication for an additional two years . Those patients who did not show an increase of 5 % or greater in PEFR after 4 weeks of pranlukast therapy were instructed to continue the medication for another year . Group II , which exhibited a 5 % or greater increase in PEFR after a one-year period continued medication for one more year . Medication was suspended for Group III , which failed to show improvement in PEFR after one year , and the group was placed under observation for the following year . Group I improved significantly in PEFR and exhibited a reduction in the frequency of b2 inhalation , the number of night visits to a medical facility , the amount of steroids inhaled , and the quantity of oral steroids given at regular intervals ; and the Group I peripheral eosinophil count , serum ECP level , and FEV1.0 ameliorated . After one year , Group II also showed significant improvement in PEFR and a reduction in both the peripheral eosinophil count and the serum ECP level . This group 's PEFR continued to improve after two years . One year after medication was suspended , Group III showed a significant increase in the number of night visits to a medical facility and a rise in the serum ECP level . These findings indicated the efficacy of pranlukast [10934090] Not all asthma can be adequately controlled , despite the use of high-dose inhaled corticosteroids . Because cysteinyl-leukotrienes ( Cys-LT ) have been implicated in the pathogenesis of asthma , we hypothesized that the leukotriene receptor antagonist zafirlukast , in combination with high-doses of inhaled corticosteroids , might be efficacious in severe asthma . In a double-blind , parallel group study , 368 chronic adult asthmatic patients treated with inhaled corticosteroids ( 1,000 to 4,000 microgram/d ) , who had a predefined level of asthma symptoms during the run in period of the study , were r and omly assigned to receive additional treatment with a high dose of zafirlukast ( 80 mg twice daily ) ( n = 180 ) or placebo ( n = 188 ) for 6 wk . Compared with placebo , zafirlukast produced a significant improvement over baseline in the primary study endpoint of mean morning peak expiratory flow rate ( PEFR ) ( 18.7 L/min versus 1.5 L/min , p < 0.001 ) , as well as in evening PEFR ( p < 0.01 ) , FEV(1 ) ( p < 0.05 ) , daytime symptom score ( p < 0.001 ) , and beta(2)-agonist use ( p < 0.001 ) . Furthermore , zafirlukast significantly reduced the risk of an exacerbation of asthma ( odds ratio [ OR ] : 0.61 ; 95 % confidence interval [ CI ] : 0.38 to 0.99 ) and the risk of patients requiring a further increase in asthma controller therapy ( OR : 0.4 ; 95 % CI : 0.2 to 0.8 ) . In conclusion , in patients taking high-dose inhaled corticosteroids , zafirlukast improves pulmonary function and asthma symptoms , and reduces the risk of an asthma exacerbation , suggesting that the contribution of leukotrienes to asthma symptoms and exacerbations is not adequately controlled by high-dose inhaled corticosteroids [26615369] BACKGROUND Systemic reactions are related to the pathogenesis of Aspirin Exacerbated Respiratory Disease ( AERD ) . With this work we wanted to study the changes in the systemic levels of inflammatory mediators in both baseline and after oral aspirin challenge in patients with and without AERD . METHODS Patients with nasal polyposis and asthma with AERD ( n=20 ) and without ( n=18 ) were orally challenged with aspirin in a single-blind placebo controlled study . Serum sample s and urine were collected before and 6h after placebo and aspirin oral challenges . Serum levels of inflammatory mediators were assayed by using the Luminex technology and ELISA . The concentrations of 9-alpha , 11-beta prostagl and in F2 , and leukotriene E4 ( uLTE4 ) were measured in urine sample s by ELISA . The expression of T-cell surface markers was analyzed in peripheral blood mononuclear cells isolated before and after the challenges . RESULTS AERD patients showed significantly higher baseline levels of s-IL-5R-alpha , uLTE4 and percentage of CD4(+)CD25(+)CD127(pos ) and CD4(+)CD45RA(-)CD45RO(+ ) but decreased levels of TGF-β1 and number of CD4(+)CD25(+)CD127(neg ) cells . Aspirin challenge induced the release of uLTE4 , IL-6 and increased the number of CD4(+)CD45RA(-)CD45RO(+ ) memory T-cells only in AERD patients but failed to reduce the levels of sCD40L as observed in non-AERD subjects . Further , IL-8 and sIL-5R-alpha levels directly correlated with the PD20ASA and the effects of aspirin on IL-6 and number of memory T-cells was more pronounced in subjects showing more strong reaction ( bronchial and nasal ) . CONCLUSIONS AERD patients have a differential baseline inflammatory pattern that supports the role inflammation as underlying mechanism of the disease . Systemic response to oral aspirin challenge was related to an increase in serum IL-6 and the number of circulating memory T-cells in AERD patients [12590877] Insufficient data exist to evaluate the comparative effects of inhaled corticosteroids ( ICS ) versus leukotriene receptor antagonist ( LTRA ) on airway inflammation and quality of life ( QoL ) . The aim of the study was to compare the effectiveness of montelukast compared to budesonide at different doses on QoL and bronchial reactivity in mild-asthmatic adult patients . 45 subjects with bronchial asthma were r and omly assigned to a different treatment and divided in 3 treatment groups : A : 400 μg of budesonide twice a day ; B : 10 mg of montelukast daily ; C : 10 mg of montelukast daily plus 400 μg of budesonide twice a day . At the beginning of the study and at the end of the treatment period ( 16 weeks ) all patients underwent complete clinical evaluation , pulmonary function testing and methacholine challenge test ( MCHt ) . In group A the increase from baseline was 153.4 % , in group C was 133.2 % , and in group B 247.7 % , the latter increase being statistically significant compared to that in the other 2 groups ( p < 0.005 Wilcoxon test ) . In all domains the improvement in quality of life in the group treated with montelukast ( group B ) was significantly greater than that in the group treated with both medications ( group C ) : in particular , the improvement was consistent in the symptoms ( p < 0.01 ) and emotions ( p < 0.01 ) domains , and weaker in the physical activity ( p < 0.05 ) . A similar difference was observed between group B and A , but only in the symptoms ( p<0.01 ) , emotions ( p<0.01 ) , and environmental stimuli domains ( p<0.05 ) . The personal perception of their own disease is important for a correct therapeutic management of asthma . In order to optimize the treatment , a complete adherence of the patient to the treatment itself is required , to be achieved through simplification of therapeutic schedule and easy administration of medications . Montelukast may be considered a valid alternative in the treatment of mild-persistent asthma , both for the clinical and functional benefits and for the great advantage of the once-daily dosage , which consistently improves the compliance with the chronic treatment of the disease [11264758] OBJECTIVE Leukotriene antagonists are increasingly used in asthma management . Pranlukast is a new , orally active , selective inhibitor of CysLt1 leukotriene receptor . The present clinical trial was performed to study the effect and safety of pranlukast in mild-to-moderate asthma . METHODOLOGY A r and omized , double-blind , placebo-controlled , parallel group study was performed in eight medical centres in Korea . Mild-to-moderate asthma patients who had been treated with beta2-agonists and /or inhaled corticosteroids were studied . The patients ' symptoms were evaluated by asthma diary and twice-daily peak flow monitoring . RESULTS Of the 206 patients enrolled , 197 were eligible for analysis . The pranlukast group ( n = 98 ) showed statistically significant improvement in asthma symptoms , including asthma attack rate , daily living score , and morning and evening asthma scores . Pranlukast significantly reduced the consumption of beta2-agonist . Compared with the placebo group , forced vital capacity ( FVC ) and forced expiratory volume in 1 s ( FEV1 ) were not significantly higher in the pranlukast group . Morning and evening peak expiratory flow ( PEF ) were significantly increased after pranlukast treatment at weeks 2 and 4 ( 380.8 + /- 10.1 L/min at baseline , 394.5 + /- 10.1 at week 2 , 396.3 + /- 10.4 at week 4 ) . There were no serious adverse reactions . CONCLUSION Pranlukast , an oral leukotriene antagonist , was well tolerated and was effective for the management of mild-to-moderate asthma [14609035] BACKGROUND Zafirlukast is a leukotriene receptor antagonist that was invented to treat patients with chronic asthma . METHODS To evaluate whether the zafirlukast improved the peak expiratory flow rate ( PEFR ) and clinical symptoms , 31 asthmatic patients with moderate persistent asthma who received regular inhaled corticosteroid were r and omly divided into the study group ( N = 17 ) . They received the zafirlukast 20 mg bid for 4 weeks , and the control group ( N = 14 ) received a placebo . Daily morning and evening PEFR and St. George 's Respiratory Question naire ( SGRQ ) scoring were recorded respectively . The levels of serum IgE and urine leukotriene E4 before and after treatment were measured using enzyme linked immunosorbent assay and enzyme immunoassay kits . RESULTS In the zafirlukast treated group , the morning PEFR was significantly improved from 314.4 + /- 20.6 to 340.6 + /- 18.3 L/min ( N = 17 , p < 0.05 ) after 4 weeks of treatment , while the control group did not show any significant changes . The zafirlukast group had significant improvement in their symptom scores of SGRQ from 48.6 + /- 4.6 to 33.8 + /- 4.7 ( N = 17 , p < 0.05 ) . However , the placebo did not improve the symptom scores . CONCLUSION Leukotriene receptor antagonists effectively improved symptoms and benefited lung function for moderate persistent asthmatic patients who had received regular treatments with inhaled steroids [12153692] BACKGROUND Symptoms often deteriorate in well-controlled asthmatics after a step down in inhaled beclomethasone dipropionate ( iBDP ) therapy if the serum concentration of eosinophil cationic protein ( sECP ) is high . This deterioration is significantly abrogated by pranlukast , a leukotriene receptor antagonist , or by seratrodast , a thromboxane A2 receptor antagonist . However , these results were based on short-term ( less than 6 months ) observations . METHODS We studied 35 well-controlled adult asthmatics . We assigned the patients into different groups according to their sECP levels before the step down : ( i ) group A , sECP < 25 microg/L ; ( ii ) group B , sECP > or = 25 microg/L ; and ( iii ) group C , sECP > or = 25 microg/L but patients treated with pranlukast or seratrodast . We began the study with a step down in iBDP therapy ( initial step down ) , then followed the clinical course of the asthma for 2 years . During the study period , we decreased , increased or maintained the iBDP dose on the basis of the stepwise approach described in the National Institutes of Health guidelines . We monitored the time and frequency of exacerbation and evaluated the iBDP dose required to control the asthma symptoms . RESULTS The rates of exacerbation after the step down were high in groups A and B. In group A , the conditions were again qualified for the step down in all patients , but this was not the case for most group B patients . From 15 to 21 months after the initial step down , the average dose of iBDP required to control symptoms was significantly higher in group B than in group A patients ( P = 0.0127 - 0.0373 ) . The exacerbation rate in group C after 12 months tended to be lower than in the other two patient groups ( P = 0.0743 ) . In group C , the average dose of iBDP from 9 to 24 months after the initial step down was significantly lower than before the step down ( P < 0.0001 ) and was not significantly different from the mean dose of iBDP in groups A or B. CONCLUSIONS High sECP in well-controlled asthma may indicate the necessity for a higher iBDP dose over a long period than when the sECP concentration is not high . Even if sECP is high , pranlukast or seratrodast help to prevent exacerbation of asthma and enable successful step down in iBDP therapy for at least 2 years thereafter [17481879] Many patients with asthma remain symptomatic with impaired airway function on inhaled steroids . This study investigates the relationship between the clinical effect seen in response to additional treatment and the effect on airway inflammatory indices . Seventy-five adult asthmatic patients , incompletely controlled on 800 mcg budesonide/day , were r and omised following a 4 week run-in period , to a double-blind , multi-centre controlled clinical trial of doubling inhaled corticosteroid ( budesonide 1600 mcg/day ) or adding 10 mg montelukast for 12 weeks . Induced sputum was collected at baseline and end of treatment and analysed for eosinophil and neutrophil percentages , leukotrienes C4 , D4 and E4 , IL-8 , Eosinophil Cationic Protein ( ECP ) and histamine . Sputum evidence of inflammation ( 2.0 % eosinophils ) was seen in only 29 % of these patients and the percentage of eosinophils and other markers of airway inflammation did not change over the study period in either treatment group . There were significant improvements in am PEF ( montelukast : 31.7 L/min , budesonide : 32.3 L/min ) and quality of life with both treatments . We conclude that while both treatments showed similar improvements in lung function and quality of life , there was no evidence from these sputum markers measured that the effects were mediated via a reduction in airway inflammation or that the level of pre-treatment markers was associated with outcome [26915674] BACKGROUND Roflumilast , a selective phosphodiesterase 4 inhibitor , has been shown to provide modest improvements in lung function in patients with mild-to-moderate asthma , but its efficacy in patients with moderate-to-severe asthma has not been assessed . We hypothesized that this drug might provide benefit if combined with montelukast , a leukotriene receptor antagonist , in patients whose symptoms are uncontrolled by inhaled corticosteroids and long-acting β-agonists . OBJECTIVE We sought to examine the efficacy , safety , and mode of action of the addition of roflumilast and montelukast versus montelukast alone in patients with moderate-to-severe asthma . METHODS In a phase 2 , r and omized , double-blind , placebo-controlled , multiple-dose , 2-sequence , crossover study , 64 patients were r and omized to receive 500 μg of roflumilast plus montelukast followed by placebo plus 10 mg of montelukast ( sequence AB ) or placebo plus 10 mg of montelukast followed by 500 μg of roflumilast plus 10 mg of montelukast ( sequence BA ) . All patients had a diagnosis of bronchial asthma inadequately controlled by at least a medium-dose inhaled corticosteroid plus a long-acting β-agonist . RESULTS The analysis of FEV1 change from baseline to week 4 showed a statistically significant and clinical ly meaningful treatment difference of 100 mL for roflumilast plus montelukast versus placebo plus montelukast . Also , improvements in patient-reported outcomes and a reduction in urinary leukotriene E4 levels were observed during roflumilast plus montelukast treatment compared with placebo plus montelukast treatment . Adverse events were consistent with the known safety profile of roflumilast . CONCLUSION The combination of roflumilast with montelukast compared with montelukast alone improved lung function and asthma control in patients with moderate-to-severe asthma and deserves further study for this indication [12612295] Background : Inhaled corticosteroids ( ICS ) affect many inflammatory pathways in asthma but have little impact on cysteinyl leukotrienes . This may partly explain persistent airway inflammation during chronic ICS treatment and failure to achieve adequate asthma control in some patients . This double blind , r and omised , parallel group , non-inferiority , multicentre 16 week study compared the clinical benefits of adding montelukast to budesonide with doubling the budesonide dose in adults with asthma . Methods : After a 1 month single blind run in period , patients inadequately controlled on inhaled budesonide ( 800 μg/day ) were r and omised to receive montelukast 10 mg + inhaled budesonide 800 μg/day ( n=448 ) or budesonide 1600 μg/day ( n=441 ) for 12 weeks . Results : Both groups showed progressive improvement in several measures of asthma control compared with baseline . Mean morning peak expiratory flow ( AM PEF ) improved similarly in the last 10 weeks of treatment compared with baseline in both the montelukast + budesonide group and in the double dose budesonide group ( 33.5 v 30.1 l/min ) . During days 1–3 after start of treatment , the change in AM PEF from baseline was significantly greater in the montelukast + budesonide group than in the double dose budesonide group ( 20.1 v 9.6 l/min , p<0.001 ) , indicating faster onset of action in the montelukast group . Both groups showed similar improvements with respect to “ as needed ” β agonist use , mean daytime symptom score , nocturnal awakenings , exacerbations , asthma free days , peripheral eosinophil counts , and asthma specific quality of life . Both montelukast + budesonide and double dose budesonide were generally well tolerated . Conclusion : The addition of montelukast to inhaled budesonide is an effective and well tolerated alternative to doubling the dose of inhaled budesonide in adult asthma patients experiencing symptoms and inadequate control on budesonide alone [12638278] This paper presents the resulţs of Montelukast sodic therapy in 16 asthmatic patients , in a prospect i ve study . Montelukast sodic was given in severe chronic asthma treated by inhaled or systemic steroids before . Patients were followed up for three months regarding : clinical symptoms , respiratory function ( FEV ) , blood and sputum eozinophyls . Short term therapy showed a great improvement in day and night symptoms , a reduction of sputum and blood eozinophyls and an increased FEV . Long term therapy could be protective for asthma exacerbations and will provide constant good life quality of asthmatics [16998094] BACKGROUND Asthma treatment guidelines recommend addition of controller medications for patients with poorly controlled asthma . We compared the effectiveness of once-daily oral controller therapy with either an antileukotriene receptor antagonist ( montelukast ) or low-dose theophylline added to existing medications in patients with poorly controlled asthma . METHODS We conducted a r and omized , double-masked , placebo-controlled trial in 489 participants with poorly controlled asthma r and omly assigned to placebo , theophylline ( 300 mg/d ) , or montelukast ( 10 mg/d ) . Participants were monitored for 24 wk to measure the rate of episodes of poor asthma control ( EPACs ) defined by decreased peak flow , increased beta-agonist use , increased oral corticosteroid use , or unscheduled health care visits . OBSERVATIONS There was no significant difference in EPAC rates ( events/person/yr ) compared with placebo : low-dose theophylline , 4.9 ( 95 % confidence interval [ CI ] , 3.6 - 6.7 ; not significant ) ; montelukast , 4.0 ( 95 % CI , 3.0 - 5.4 ; not significant ) ; and placebo , 4.9 ( 95 % CI , 3.8 - 6.4 ) . Both montelukast and theophylline caused small improvements in prebronchodilator FEV(1 ) of borderline significance . Nausea was more common with theophylline only during the first 4 wk of treatment . Neither treatment improved asthma symptoms or quality of life . However , in patients not receiving inhaled corticosteroids , addition of low-dose theophylline significantly ( p < 0.002 ) improved asthma control and symptoms as well as lung function . CONCLUSIONS Neither montelukast nor low-dose theophylline lowered the EPAC rate of poor asthma control in patients with poorly controlled asthma despite improved lung function . For patients not using inhaled corticosteroids , low-dose theophylline improved asthma symptom control more than montelukast or placebo , and provides a safe and low-cost alternative asthma treatment [26960245] BACKGROUND Results from phase III clinical trials in adults and phase II clinical trials in children and adolescents demonstrate that tiotropium is an effective treatment when added to inhaled corticosteroid ( ICS ) maintenance therapy . OBJECTIVE We sought to assess the efficacy and safety of once-daily tiotropium Respimat added to ICSs with or without a leukotriene receptor antagonist in a phase III trial in adolescent patients with moderate symptomatic asthma . METHODS In this 48-week , double-blind , placebo-controlled , parallel-group study , 398 patients aged 12 to 17 years were r and omized to receive 5 μg ( 2 puffs of 2.5 μg ) or 2.5 μg ( 2 puffs of 1.25 μg ) of once-daily tiotropium or placebo ( 2 puffs ) administered through the Respimat device every evening , each as add-on treatment to ICS background therapy , with or without a leukotriene receptor antagonist ; long-acting β2-agonist therapy was not permitted during the study . RESULTS Improvement in peak FEV1 within 3 hours after dosing at 24 weeks ( primary end point ) was statistically significant with both tiotropium doses compared with placebo : 5 μg of tiotropium , 174 mL ( 95 % CI , 76 - 272 mL ) ; 2.5 μg of tiotropium , 134 mL ( 95 % CI , 34 - 234 mL ) . Significant improvements in trough FEV1 at week 24 ( a secondary end point ) were observed with the 5-μg dose only . Trends for improvement in asthma control and health-related quality of life over the 48-week treatment period were observed . CONCLUSIONS Once-daily tiotropium significantly improved lung function and was safe and well tolerated when added to at least ICS maintenance therapy in adolescent patients with moderate symptomatic asthma . Larger responses were observed with the 5-μg tiotropium dose [24941835] OBJECTIVE To observe the clinical efficacy of treating chronic persistent bronchial asthma ( CPBA ) children with abnormal myocardial enzyme spectrum ( AMES ) by Yupingfeng Powder ( YP ) combined routine therapy . METHODS From January 2010 to December 2012 , 156 CPBA children patients with AMES were r and omly assigned to the treatment group ( 80 cases ) and the control group ( 76 cases ) . All patients received routine treatment ( inhaled corticosteroids and /or leukotriene regulator ) . Besides , those in the treatment group took YP . The treatment duration was 3 months . The scores of children asthma control test ( C-ACT ) , pulmonary function ( FEV,% and PEF% ) , myocardial enzyme spectrum were observed before and after treatment , and 3 months before and after treatment . The myocardial enzyme spectrum of 40 healthy children at the baby clinics during the same period were recruited as the control . RESULTS Compared with the control group , creatine kinase isoenzyme ( CK-MB ) , creatine kinase(CK ) , and lactate dehydrogenase ( LDH ) increased in the two treatment groups ( P < 0.01 ) , but there was no statistical difference in AST ( P > 0.05 ) . Compared with before treatment in the same group , CK-MB , CK , LDH , and AST decreased in the treatment group after treatment and 3 months after treatment ( P < 0.01 ) . CK-MB , CK , LDH , and AST decreased in the control group 3 months after treatment ( P < 0.01 , P < 0.05).Compared with after treatment , CK decreased in the control group 3 months after treatment ( P < 0.01 ) . C-ACT score , FEV(1),% , and PEF% all increased in the two groups after treatment and 3 months after treatment ( P < 0.01 , P < 0.05 ) . Compared with after treatment in the same group , CK decreased in the control group 3 months after treatment ( P < 0 . 01 ) . Compared with the control group in the same period , post-treatment CK-MB and CK decreased ( P < 0 . 01 , P < 0 . 05 ) , while post-treatment C-ACT score , FEV , % , and PEF% increased ( P < 0.05 ) in the treatment group ( P < 0.05 ) . CONCLUSION YP could strengthen specific and non-specific immunity of the organism , and improve clinical symptoms and the level of myocardial enzyme spectrum [12670780] We studied 51 atopic non-smoking subjects who were divided to four treatments groups : ( A ) montelukast 10 mg daily , ( B ) budesonide 400 microg twice a day ( bid ) , ( C ) montelukast 10 mg daily plus budesonide 400 microg bid and ( D ) budesonide 800 microg bid . Bronchial responsiveness was assessed before and after 12 weeks of treatment . The bronchial responsiveness , evaluated by means of PC(20 ) values , showed a strong significant increase in groups B , C and D , and a weak but significant rise in group A , when compared to basal data . Regarding other pulmonary parameters ( FEV(1 ) , PEF ) there were no significant differences among the groups after 12 weeks of therapy . A statistical significance was founded after therapy between group A and C ( p < 0.05 ) , but not between the group B and D treated with only budesonide at different doses . No significant differences was observed in the side effect pattern among the various treatments . The study data demonstrated that administration of montelukast provided an important and additional effect on bronchial hyperresponsiveness . Oral administration represents a significant advantage over the majority of other anti-asthmatic drugs . Our results confirm the anti-inflammatory properties of both the inhaled corticosteroid ( ICS ) and montelukast and the possible role of these drugs can have on airway remodelling . While currently low dose ICS remains the reference drug as a controller in mild-moderate persistent asthma , montelukast may be viewed as a possible option , either in monotherapy or in association [16081585] Pharmacological therapy with inhaled steroids ( IS ) is currently considered the gold-st and ard of treatment for mild-persistent asthma . Leukotriene receptor antagonist drugs ( LTRAs ) play an important role associated with IS , allowing dose tapering and maintaining control of asthma symptoms . The aim of this study was to determine the effectiveness of montelukast ( MON ) to allow tapering of the inhaled dose of budesonide ( BUD ) in patients with mild-moderate persistent asthma . This 16-wk single-blind r and omized study included 40 asthmatic patients divided in 2 treatment groups . After a run-in period ( 4 wk ) , in which all patients inhaled 400 microg of BUD twice daily ( bid ) , group A ( 20 patients ) received MON ( oral , 10 mg/day ) combined with inhaled BUD ( 400 microg/bid ) , while group B ( 20 patients ) was treated with BUD for the whole period of the study . In both groups , at every 4 wk the dose of BUD was halved . After 12 wk of treatment the mean value of forced expiratory volume during the first sec ( FEV1 , as % of predicted value ) was significantly greater in group A compared with group B ( 94 + /- 7.5 vs 83.1 + /- 6.9 ; p<0.005 ) . The mean values of peak expiratory flow ( PEF ) , the percentages of asthmatic exacerbations , and the use of beta2-short-acting agonist ( SABA ) were similar in the 2 groups at 4 , 8 , and 12 wk . In conclusion , in patients with mild-moderate persistent asthma , MON therapy is useful in tapering the dose of IS in order to reduce its side effects and to maintain the clinical stability of the disease [12190656] Background Oral leukotriene receptor antagonists have been shown to have efficacy in chronic asthma [12536697] OBJECTIVES To explore the influence of zafirlukast on pulmonary functions and quality of life ( QOL ) in patients with mild-to-moderate asthma at the stage of attack and at the stable stage . METHODS Patients at the stage of attack were r and omly divided into two groups : Group one is zafirlukast 20 mg twice daily plus inhaled the half quantity of glucocorticoid(budelade ) of the Global Initiative for Asthma ( GINA ) st and ard quantity , long-effection aminophyllin 0.2 g twice daily and inhaled salbutamol when necessary ; Group two : inhaled budelade of GINA st and ard quantity , long-effection aminophyllin 0.2 g twice daily and inhaled salbutamol when necessary ) . Patients ' peak expiratory flow (PEF)/PEF predicted value % and delta PEFR% were determined at the second week and the forth week before and after the treatment . On the st and ard treatment , patients with the stable stage were added zafirlukast 20 mg twice a day . PEF values in the morning and evening and QOL were evaluated . RESULTS After treating with zafirlukast , the PEF/PEF predicted value % and delta PEFR% in Group one were higher and lower than those of Group two respevtively . These changes were appeared in two days and were peaked in two weeks and the peak had been gone on for more than 4 weeks , but these were no significant difference between the Groups ( P > 0.05 ) ; PEF values in the morning and evening in patients with the stable asthma increased 5.9 % and 4.6 % respectively and their QOL were improved in asthma symptoms , limitative activities , avoiding stimuli , and reacting on stimuli . CONCLUSION Zafirlukast can improve pulmonary function , reduce the inhalation quantity of steroid in patients with mild-to-moderate asthma , and play an important role in treating and improving QOL in patients with the stable asthma [10398629] Abstract Objective : To determine the ability of montelukast , a leukotriene receptor antagonist , to allow tapering of inhaled corticosteroids in clinical ly stable asthmatic patients . Design : Double blind , r and omised , placebo controlled , parallel group study . After a single blind placebo run in period , during which ( at most ) two inhaled corticosteroids dose decreases occurred , qualifying , clinical ly stable patients were allocated r and omly to receive montelukast ( 10 mg tablet ) or matching placebo once daily at bedtime for up to 12 weeks . Setting : 23 academic asthma centres in United States , Canada , and Europe . Participants : 226 clinical ly stable patients with chronic asthma receiving high doses of inhaled corticosteroids ( 113 r and omised to montelukast and 113 to placebo ) . Interventions : Every 2 weeks , the inhaled corticosteroids dose was tapered , maintained , or increased ( rescue ) based on a st and ardised clinical score . Main outcome measures : Last tolerated dose of inhaled corticosteroids . Results : Compared with placebo , montelukast allowed significant ( P=0.046 ) reduction in the inhaled corticosteroid dose ( montelukast 47 % v placebo 30 % ; least square mean difference 17.6 % , 95 % confidence interval 0.3 to 34.8 ) . Fewer patients on montelukast ( 18 ( 16 % ) v 34 ( 30 % ) placebo , P=0.01 ) required discontinuation because of failed rescue . Conclusions : Montelukast reduces the need for inhaled corticosteroids among patients requiring moderate to high doses of corticosteroid to maintain asthma control . Key messages Leukotriene receptor antagonists have complementary action to inhaled corticosteroids in asthma Many patients receive higher doses of inhaled corticosteroids than clinical ly required In this placebo controlled trial , montelukast allowed significant reduction of inhaled corticosteroid doses Fewer patients receiving montelukast had failed rescue than patients receiving [15526805] OBJECTIVES To compare the effects of addition of montelukast or salmeterol to inhaled corticosteroids ( ICS ) on the response to rescue beta2-agonist use after exercise-induced bronchoconstriction . METHODS A double-blind , placebo-controlled study was performed at 16 centers in the United States . Patients with asthma ( n = 122 , ages 15 - 58 ) whose symptoms were uncontrolled on Low-dose inhaled fluticasone and who had a history of exercise-induced worsening of asthma were r and omized to receive either montelukast ( 10 mg once daily ) , salmeterol ( 50microg twice daily ) , or placebo for 4 weeks . St and ardized spirometry after exercise challenge and beta2-agonist rescue was performed at baseline , week 1 and 4 . RESULTS Maximum achievable forced expiratory volume in 1 s ( FEV1 ) percent predicted after rescue beta2-agonist improved in the montelukast ( + 1.5 % ) and placebo ( + 1.2 % ) groups at 4 weeks , but diminished in the salmeterol ( -3.9 % ) group ( P < 0.001 ) . Although pre-exercise FEV1 was greatest with salmeterol ( P = 0.10 ) , patients taking montelukast had significantly greater protection from an exercise-induced decrease in FEV1 than those taking salmeterol ( P < 0.001 ) . Both the magnitude and rate of rescue bronchodilation were greater with montelukast compared with salmeterol ( P < 0.001 ) . Five minutes after rescue beta2-agonist , 92 % of patients taking montelukast and 68 % of those taking placebo had recovered to pre-exercise levels , whereas only 50 % of those taking salmeterol had recovered to pre-exercise levels . CONCLUSION In patients whose asthma symptoms remain uncontrolled using ICS , addition of montelukast permits a greater and more rapid rescue bronchodilation with a short-acting beta2-agonist than addition of salmeterol and provides consistent and clinical ly meaningful protection against exercise-induced bronchoconstriction [20471234] Bronchial hyperresponsiveness to 5-adenosine mono-phosphate ( AMP ) is a marker of airway inflammation . Inhaled corticosteroids and antileukotrienes are used as anti-inflammatory drugs for the treatment of asthma . To find out if these two drugs exert their protection in an additive fashion , we compared the effects of acute treatment with inhaled beclomethasone ( BDP ) and montelukast ( ML ) , alone or in combination , on methacholine and AMP induced bronchoconstriction . 15 asthmatic patients undertook methacholine and AMP challenges at baseline and after receiving ML or BDP , alone or in combination , in a r and omized , double-blind , double-dummy placebo-controlled , crossover design . BDP pretreatment significantly increased the AMP PC(20 ) value ( 68.34+/-15.9mg/mL ) as compared to placebo ( 22.87+/-5.7mg/mL ) . Combined treatment , BDP plus ML , afforded a further significant increase of AMP PC(20 ) ( 154.57+/-55.0mg/mL ) as compared to each single treatment . The significant protection exerted by combined treatment as compared to each single active treatment was also demonstrated by the change of AMP PC(20 ) doubling dose as compared to placebo and each single active treatment . Our findings suggest that these two agents exert their acute additive protection against AMP induced bronchoconstriction acting on distinct inflammatory pathways and their combined use might provide greater protection against inflammatory response elicited by AMP than either drug alone [15572850] Mild persistent asthma is most effectively controlled with inhaled corticosteroids . Leukotriene receptor antagonists have complementary effects to corticosteroids on inflammation control . The additional effect of a leukotriene receptor antagonist , zafirlukast , was investigated in stable asthma patients under control with inhaled budesonide . We conducted a r and omised , double-blind , placebo-controlled , single center trial to investigate the effects of add-on zafirlukast treatment to budesonide , on symptom score , pulmonary function , bronchial responsiveness , and serum levels of eosinophilic cationic protein ( ECP ) and antioxidant capacity in stable asthmatic patients under control with inhaled budesonide . The present study included 21 mild or moderate asthmatic patients ( 8 males and 13 females ) , who were stable at least for 6 weeks with inhaled budesonide ( 400 microg/day ) . Serum total antioxidant capacity ( TAC ) and ECP levels were measured , and symptom scoring , spirometry , and bronchial provocation with methacholine were performed . Then , the patients were r and omised to use either placebo or oral zafirlukast ( 40 mg/day ) in addition to budesonide for 6 weeks . At the 6th week , symptom scoring , spirometry , and bronchial provocation tests were repeated and serum TAC and ECP levels were measured again . After add-on zafirlukast treatment to budesonide , forced expiratory volume in 1 second ( FEV(1 ) ) , TAC and ECP values did not change significantly ( p > 0.05 ) but bronchial hyperresponsiveness and symptom score decreased significantly ( p = 0.022 ) compared to baseline . Thus , in stable asthmatic patients , add-on zafirlukast treatment to budesonide improves symptoms and decreases bronchial hyperresponsiveness [26634774] BACKGROUND AND OBJECTIVES : The use of written asthma action plans ( WAAPs ) has been associated with reduced asthma-related morbidity , but there are concerns about their complexity . We developed a health literacy – informed , pictogram- and photograph-based WAAP and examined whether providers who used it , with no training , would have better asthma counseling quality compared with those who used a st and ard plan . METHODS : Physicians at 2 academic centers r and omized to use a low-literacy or st and ard action plan ( American Academy of Allergy , Asthma and Immunology ) to counsel the hypothetical parent of child with moderate persistent asthma ( regimen : Flovent 110 μg 2 puffs twice daily , Singulair 5 mg daily , Albuterol 2 puffs every 4 hours as needed ) . Two blinded raters independently review ed counseling transcriptions . Primary outcome measures : medication instructions presented with times of day ( eg , morning and night vs number of times per day ) and inhaler color ; spacer use recommended ; need for everyday medications , even when sick , addressed ; and explicit symptoms used . RESULTS : 119 providers were r and omly assigned ( 61 low literacy , 58 st and ard ) . Providers who used the low-literacy plan were more likely to use times of day ( eg , Flovent morning and night , 96.7 % vs 51.7 % , P < .001 ; odds ratio [ OR ] = 27.5 ; 95 % confidence interval [ CI ] , 6.1–123.4 ) , recommend spacer use ( eg , Albuterol , 83.6 % vs 43.1 % , P < .001 ; OR = 6.7 ; 95 % CI , 2.9–15.8 ) , address need for daily medications when sick ( 93.4 % vs 34.5 % , P < .001 ; OR = 27.1 ; 95 % CI , 8.6–85.4 ) , use explicit symptoms ( eg , “ ribs show when breathing , ” 54.1 % vs 3.4 % , P < .001 ; OR = 33.0 ; 95 % CI , 7.4–147.5 ) . Few mentioned inhaler color . Mean ( SD ) counseling time was similar ( 3.9 [ 2.5 ] vs 3.8 [ 2.6 ] minutes , P = .8 ) . CONCLUSIONS : Use of a low-literacy WAAP improves the quality of asthma counseling by helping providers target key issues by using recommended clear communication principles [16270722] A few studies compared the additional effects of oral controller medicines on pulmonary function in asthmatic patients on a moderate dose of inhaled steroids . The aim of this study was to compare the additional effects of two oral asthma controllers , a leukotriene receptor antagonist and a sustained released theophylline ( Theo ) , with a moderate dose of inhaled steroid on peak expiratory flow ( PEF ) and asthma-related symptoms . A total of 67 adult asthmatic patients with PEF < 80 % predicted during a 2-week run-in period with 800 microg/day of beclomethasone dipropionate were r and omized to receive either pranlukast , 450 mg/day ( n = 33 ) , or sustained released Theo , 200 mg/day ( n = 34 ) , for 4 weeks . Pranlukast and Theo did not significantly alter the symptom scores , use of rescue beta2-agonist , and daily PEF variability . However , both agents significantly increased both morning and evening PEF compared with the run-in periods . The effects of both medications were comparable . For asthmatic patients even on a moderate dose of inhaled steroids , the addition of either leukotriene receptor antagonist or sustained released Theo does not improve asthma-related symptoms but significantly and equally increases PEF [18350399] The aim of this study was to investigate the effects of leukotriene receptor antagonists ( LTRAs ) on the premenstrual exacerbation of asthma ( PMA ) . Twenty-four female patients with mild asthma were enrolled in the study . Patients were followed for three menstrual cycles and separated into two groups based on whether they exibit premenstrual worsening of asthma symptoms ( n = 11 ) or not ( n = 13 ) . During the first month all were treated with only inhaled steroids ( IS ) ( run-in period ) ; during the second month they received IS plus placebo ; and during the third month they were given IS plus montelukast . Furthermore , they were advised to use beta 2 -agonists as needed . Peak expiratory flow rate ( PEFR ) and symptom scores were recorded during the 3 months . Pulmonary function tests ( PFT ) and the levels of oestrogen , progesterone , luteinizing hormone ( LH ) , and follicle-stimulating hormone ( FSH ) were measured a week before the begining of the menstrual period . At the end of the 3-month period , it was observed that following therapy with montelukast , the patients with PMA showed significant improvement in PEFR variability and symptom scores when compared with the placebo group . Baseline FSH levels were higher , but FSH and other hormone levels and PFTs did not change in these groups . However , in the group without PMA there was no difference between the montelukast or placebo groups in PEFR variability , symptom scores , PFTs , and hormone levels . Based on the data in h and , it could be stated that LTRAs have ensured the control of symptoms and improved PEFR variability in patients with PMA by supressing inflammation . We are of the view that LTRAs would be a right choice in the treatment of patients with PMA [11527250] BACKGROUND Although inhaled steroids are used as the first line of therapy in asthmatic patients , symptoms of asthma do not improve completely in some patients . OBJECTIVE To investigate the effects of pranlukast , a cysteinyl leukotriene receptor 1 antagonist , in patients with moderate/severe asthma , when combined with beclomethasone dipropionate ( BDP ) . METHODS Protocol 1 : After a 2-week observation period , 41 patients with moderate asthma were divided into those receiving BDP at 1,600 microg/day or 800 microg/day + pranlukast ( 450 mg/day ) . The effect of treatment was evaluated by measuring AM peak expiratory flow rate , symptom score , frequency of beta2-agonists , and daily variability of peak expiratory flow rate . Protocol 2 : 39 patients participated in this study including those with moderate asthma on 800 microg/day BDP ( group I ) , severe asthma on BDP at 1,600 microg/day ( group II ) , and severe asthma on 1,600 microg/day BDP + 5 to 20 mg prednisolone ( group III ) . Patients of all groups were additionally treated with pranlukast . RESULTS Protocol 1 : Both treatment regimens result ed in improvement in each clinical parameter . There were no significant differences in the effects of two treatment regimens . Protocol 2 : Pranlukast was effective in group I and II , but not in group III . In groups I and II , pranlukast tended to be more effective when BDP was introduced within the first year of onset of asthma . CONCLUSIONS Pranlukast is effective for patients with moderate asthma and those patients with severe asthma who are not treated with oral steroids . Pranlukast is more effective in patients treated with BDP early after onset [10588598] The primary objective of this study was to determine whether montelukast , an oral leukotriene receptor antagonist , provides additional clinical benefit to the effect of inhaled corticosteroids . A total of 642 patients with chronic asthma ( FEV(1 ) 50 to 85 % of predicted value and at least a predefined level of asthma symptoms ) incompletely controlled with inhaled beclomethasone , 200 microg twice daily using a spacer device , during the 4-wk run-in period were r and omly allocated , in a double-blind , double-dummy manner to one of four treatment groups : ( 1 ) montelukast 10 mg plus continuing inhaled beclomethasone ; ( 2 ) placebo tablet plus continuing inhaled beclomethasone ; ( 3 ) montelukast 10 mg and inhaled placebo ( after blind beclomethasone removal ) ; and ( 4 ) placebo tablet and inhaled placebo ( after blind beclomethasone removal ) . The primary endpoints were FEV(1 ) and daytime asthma symptoms score . Montelukast provided significant ( p < 0.05 ) clinical benefit in addition to inhaled beclomethasone by improving FEV(1 ) , daytime asthma symptom scores , and nocturnal awakenings . Blind removal of beclomethasone in the presence of placebo tablets caused worsening of asthma control , demonstrating that patients received clinical benefit from inhaled corticosteroids . Blind removal of beclomethasone in the presence of montelukast result ed in less asthma control but not to the level of the placebo group . All treatments were well tolerated ; clinical and laboratory adverse experiences were generally similar to placebo treatment in this study . In conclusion , montelukast provided additional asthma control to patients benefitting from , but incompletely controlled on , inhaled beclomethasone [9105060] To test whether the leukotriene antagonist ONO-1078 ( pranlukast ) prevents asthma exacerbations during reduction of high-dose inhaled corticosteroid , we conducted a r and omized , double-blind , placebo-controlled study in 79 asthma patients requiring high doses ( 1,500 microg/d or more ) of inhaled beclomethasone dipropionate ( BDI ) for clinical control ( duration of asthma , 11.0 + /- 3.1 yr ; duration of BDI treatment , 0.5 + /- 0.3 yr ; FEV1 percentage of predicted , 80.7 + /- 2.0 % ) . After a 2-wk run-in period , the doses of BDI were halved , while the patients were assigned to receive orally ONO-1078 , 450 mg twice daily , or placebo . In the placebo group FEV1 decreased by 0.33 + /- 0.20 L after 6 wk ( p < 0.001 ) . Likewise , morning and evening PEF decreased by 46 + /- 7 L/min and 18 + /- 6 L/min , respectively . By contrast these variables were sustained above baseline in the ONO-1078 group . The number of daytime and nighttime asthma symptoms and the use of beta2-agonist increased in the placebo group , whereas they remained unchanged in the ONO-1078 group . In the placebo group concentrations of serum eosinophil cationic protein and exhaled nitric oxide increased ( p = 0.007 and p = 0.025 , respectively ) , compared with no change in the ONO-1078 group . Therefore , the leukotriene antagonist ONO-1078 prevents the asthma deterioration provoked by a 6-wk reduction of the dose of inhaled BDI into half [26841365] In our prior r and omized trial on preventing influenza , asthma attacks as a secondary outcome occurred less often in the vitamin D group than in the placebo group . We aim ed to clarify whether low‐dose , short‐term vitamin D supplementation , in addition to st and ard treatments , improves control of childhood asthma [20550224] BACKGROUND Information is lacking on the relative effectiveness and cost effectiveness -- in a primary -care setting --of leukotriene receptor antagonists ( LTRAs ) as an alternative to inhaled corticosteroids ( ICS ) for initial asthma controller therapy . OBJECTIVE To compare the cost effectiveness of LTRAs versus ICS for patients initiating asthma controller therapy . METHODS An economic evaluation was conducted alongside a 2-year , pragmatic , r and omized controlled trial set in 53 primary -care practice s in the UK . Patients aged 12 - 80 years with asthma and symptoms requiring regular anti-inflammatory therapy ( n = 326 ) were r and omly assigned to LTRAs ( n = 162 ) or ICS ( n = 164 ) . The main outcome measures were the incremental costs per point improvement in the Mini Asthma Quality of Life Question naire , per point improvement in the Asthma Control Question naire and per QALY gained from the UK NHS and societal perspectives . RESULTS Over 2 years , re source use was similar between the two treatment groups , but the cost to society per patient was significantly higher for the LTRA group , at pounds sterling 711 versus pounds sterling 433 for the ICS group ( adjusted difference pounds sterling 204 ; 95 % CI 74 , 308 ) [ year 2005 values ] . Cost differences were driven primarily by differences in prescription drug costs , particularly study drug costs . There was a nonsignificant ( imputed , adjusted ) difference between treatment groups , favouring ICS , in QALYs gained at 2 years of -0.073 ( 95 % CI -0.143 , 0.010 ) . Therapy with LTRAs was , on average , a dominated strategy , and , at a threshold for willingness to pay of pounds sterling 30,000 per QALY gained , the probability of LTRAs being cost effective compared with ICS was approximately 3 % from both societal and NHS perspectives . CONCLUSIONS There is a very low probability of LTRAs being cost effective in the UK , at 2005 values , compared with ICS for initial asthma controller therapy . TRIAL REGISTRATION UK National Research Register N0547145240 ; Controlled Clinical Trials IS RCT N99132811 [20709517] BACKGROUND Airway inflammation is a key pathological feature of asthma which underlies its clinical presentation . OBJECTIVES To examine whether adding a leukotriene modifier to an inhaled corticosteroid produces further clinical and /or anti-inflammatory benefits in patients symptomatic on short-acting beta(2)-agonists . METHODS Patients uncontrolled on short-acting beta(2)-agonists were treated for 12 weeks with either fluticasone propionate ( 100mcg BD ) or fluticasone propionate ( 100mcg BD ) and montelukast ( 10 mg QD ) in a r and omized , double-blind , parallel group study . Bronchoscopy with endobronchial biopsy and bronchoalveolar lavage ( BAL ) was performed before and after treatment to compare effects on airway inflammation . RESULTS Of 103 subjects enrolled , 89 subjects completed treatment and 82 subjects had matched pair biopsy sample s. Submucosal eosinophil counts , the primary endpoint , and asthma control improved to similar extents after both treatments ( p < or=0.008 ) . Both treatments significantly reduced submucosal mast cell , CD3 + , CD4 + , CD8 + and CD25 + cell counts . Submucosal mast cell reduction was greater in the fluticasone propionate plus montelukast group . There were no differences between treatments in BAL markers of inflammation or thickness of sub-epithelial collagen . CONCLUSIONS Low-dose fluticasone propionate significantly improves clinical disease control and reduces airway inflammation in asthma patients uncontrolled with short-acting beta(2)-agonists without further improvement when montelukast is added to low-dose fluticasone propionate [23548532] BACKGROUND Eosinophilic inflammation of the small airways is a key process in asthma that often smolders in treated patients . The long-term effects of add-on therapy on the persistent inflammation in the small airways remain unknown . OBJECTIVE To examine the effects of add-on therapy with either ciclesonide , an inhaled corticosteroid with extrafine particles , or montelukast on small airway inflammation . METHODS Sixty patients with stable asthma receiving inhaled corticosteroid treatment were enrolled in a r and omized , open-label , parallel comparison study of 24-week add-on treatment with ciclesonide or montelukast . Patients were r and omly assigned to 3 groups : ciclesonide ( n = 19 ) , montelukast ( n = 22 ) , or no add-on as controls ( n = 19 ) . At baseline and at weeks 4 , 12 , and 24 , extended nitric oxide analysis ; pulmonary function tests , including impulse oscillometry ; blood eosinophil counts ; and asthma control tests ( ACTs ) were performed . RESULTS A total of 18 patients in the ciclesonide group , 19 in the montelukast group , and 15 in the control group completed the study and were analyzed . With repeated- measures analysis of variance , ciclesonide produced a significant decrease in alveolar nitric oxide and a significant improvement in ACT scores over time . Montelukast produced significant decreases in alveolar nitric oxide concentrations and blood eosinophil counts over time and slightly improved ACT scores , whereas no such changes were observed in the control group . Alveolar nitric oxide concentrations with ciclesonide and reactance area at low frequencies with montelukast produced greater improvements over time compared with control . CONCLUSION Ciclesonide add-on therapy and montelukast add-on therapy may act differently , but both separately can improve small airway abnormalities and provide better asthma control . TRIAL REGISTRATION umin.ac.jp/ctr Identifier : UMIN000001083 [26325232] Abstract Objective : Treatment guidelines for asthma recommend step-down therapy for well-controlled asthma patients . However , the precise strategy for step-down therapy has not been well defined . We investigated whether well-controlled patients with mild persistent asthma can tolerate a step-down therapy of either a reduced dose of inhaled corticosteroid ( ICS ) or a switch to a leukotriene receptor antagonist ( LTRA ) , pranlukast hydrate . Methods : We recruited 40 adult patients with mild persistent asthma who were well-controlled for at least 3 months with a low-dose ICS therapy . The patients were r and omly assigned to either an ICS dose reduction or a switch to pranlukast for 6 months . Results : FeNO levels in the pranlukast group were significantly increased over that in the ICS group . There were no significant differences between the two groups for lung function , FOT , at the endpoint . The percentage of patients with controlled asthma was 72.2 % in the pranlukast group and 90 % in the ICS group . No statistically significant difference between the two groups in the percentages of patients with treatment failure was observed . Conclusions : Patients with mild persistent asthma that is well-controlled by a low dose of ICS can be switched to pranlukast safely for at least 6 months . However , 27.8 % of the pranlukast group failed to maintain well-control , and FeNO levels increased with the switch to pranlukast at 6 months . This study was been limited by the small sample size and should therefore be considered preliminary . Further studies are needed to investigate the therapeutic efficacy of LTRA monotherapy as a step-down therapy Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND In the treatment of children with mild persistent asthma , low-dose inhaled corticosteroids ( ICS ) are recommended as the preferred monotherapy ( referred to as step 2 of therapy ) . In children with inadequate asthma control on low doses of ICS ( step 2 ) , asthma management guidelines recommend adding an anti-leukotriene agent to existing ICS as one of three therapeutic options to intensify therapy ( step 3 ) . OBJECTIVES To compare the efficacy and safety of the combination of anti-leukotriene agents and ICS to the use of the same , an increased , or a tapering dose of ICS in children and adolescents with persistent asthma who remain symptomatic despite the use of maintenance ICS . In addition , we wished to determine the characteristics of people or treatments , if any , that influenced the magnitude of response attributable to the addition of anti-leukotrienes . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

28762607

[2936444] Background Both low back pain ( LBP ) and neck pain ( NP ) are major occupational health problems . In the workplace , participatory ergonomics ( PE ) is frequently used on musculoskeletal disorders . However , evidence on the effectiveness of PE to prevent LBP and NP obtained from r and omised controlled trials ( RCTs ) is scarce . This study evaluates the process of the Stay@Work participatory ergonomics programme , including the perceived implementation of the prioritised ergonomic measures . Methods This cluster- RCT was conducted at the departments of four Dutch companies ( a railway transportation company , an airline company , a steel company , and a university including its university medical hospital ) . Directly after the r and omisation outcome , intervention departments formed a working group that followed the steps of PE during a six-hour working group meeting . Guided by an ergonomist , working groups identified and prioritised risk factors for LBP and NP , and composed and prioritised ergonomic measures . Within three months after the meeting , working groups had to implement the prioritised ergonomic measures at their department . Data on various process components ( recruitment , reach , fidelity , satisfaction , and implementation components , i.e. , dose delivered and dose received ) were collected and analysed on two levels : department ( i.e. , working group members from intervention departments ) and participant ( i.e. , workers from intervention departments ) . Results A total of 19 intervention departments ( n = 10 with mental workloads , n = 1 with a light physical workload , n = 4 departments with physical and mental workloads , and n = 4 with heavy physical workloads ) were recruited for participation , and the reach among working group members who participated was high ( 87 % ) . Fidelity and satisfaction towards the PE programme rated by the working group members was good ( 7.3 or higher ) . The same was found for the Stay@Work ergocoach training ( 7.5 or higher ) . In total , 66 ergonomic measures were prioritised by the working groups . Altogether , 34 % of all prioritised ergonomic measures were perceived as implemented ( dose delivered ) , while the workers at the intervention departments perceived 26 % as implemented ( dose received ) . Conclusions PE can be a successful method to develop and to prioritise ergonomic measures to prevent LBP and NP . Despite the positive rating of the PE programme the implementation of the prioritised ergonomic measures was lower than expected . Trial registration Current Controlled Trials IS RCT [18653261] AIMS quantitative description of adherence to motivational interviewing ( MI ) in smoking cessation sessions ; and examination of the relationships between client characteristics and adherence to MI , and between adherence to MI and future smoking status . METHODS 84 sessions were conducted during a r and omised controlled trial to test the effectiveness of a population -based smoking intervention in women during the postpartum period . Demographic and behaviour-related variables were included in a logistic regression to predict adherence to MI . MEASUREMENTS adherence was measured using the MI Treatment Integrity Scale . FINDINGS 38.1 % of sessions showed good adherence to MI . Receiving a good MI session was not related to any demographic or behavioural variables . The relationship between adherence and intervention outcome after six months was not statistically significant ( chi(2)=0.355 , p=0.551 ) . CONCLUSIONS the smoking cessation sessions examined in this study failed to adhere to MI . There was no relationship between adherence to MI and behavioural outcome six months after the intervention , indicating that women who smoke post partum may be a high-risk group for whom specific smoking cessation interventions need to be developed [4037760] Background Dementia affects 35 million people worldwide and is currently incurable . Many cases may be preventable because regular participation in physical , mental and social leisure activities during middle age is associated with up to 47 % dementia risk reduction . However , the majority of middle-aged adults are not active enough . MCI is therefore a clear target for activity interventions aim ed at reducing dementia risk . An active lifestyle during middle age reduces dementia risk but it remains to be determined if increased activity reduces dementia risk when MCI is already evident . Before this can be investigated conclusively , complex multimodal activity programmes are required that ( 1 ) combine multiple health promoting activities , ( 2 ) engage people with MCI , and ( 3 ) result in sufficient adherence rates . Methods We design ed the ThinkingFit programme to engage people with MCI in a complex intervention comprised of three activity components : physical activity , group-based cognitive stimulation ( GCST ) and individual cognitive stimulation ( ICST ) . Engagement and adherence was promoted by applying specific psychological techniques to enhance behavioural flexibility in an early pre-phase and during the course of the intervention . To pilot the intervention , participants served as their own controls during a 6- to 12-week run-in period , which was followed by 12 weeks of activity intervention . Results Out of 212 MCI patients screened , 163 were eligible , 70 consented and 67 completed the intervention ( mean age 74 years ) . Activity adherence rates were high : physical activity = 71 % ; GCST = 83 % ; ICST = 67 % . Significant treatment effects ( p < .05 ) were evident on physical health outcomes ( decreased BMI and systolic blood pressure , [ pre/post values of 26.3/25.9 kg/m2 and 145/136 mmHg respectively ] ) , fitness ( decreased resting and recovery heart rate [ 68/65 bpm and 75/69 bpm ] ) , and cognition ( improved working memory [ 5.3/6.3 items ] ) . Conclusions We found satisfactory recruitment , retention and engagement rates , coupled with significant treatment effects in elderly MCI patients . It appears feasible to conduct r and omized controlled trials of the dementia prevention potential of complex multimodal activity programmes like ThinkingFit . Trial registration Clinical Trials.gov registration nr : NCT01603862 ; date : 17/5/2012 [19487232] A recent special issue of the Journal of Pediatric Psychology included papers focused on evidence -based assessment across several broad domains of assessment in pediatric psychology ( e.g. , adherence , pediatric pain , and quality of life ) . In one of these papers , Holmbeck et al. ( 2008 ) review ed strengths and limitations of existing measures of psychosocial adjustment and psychopathology , concluding that many measures lacked supporting psychometric data ( e.g. , basic indices of reliability and validity ) that would permit a complete evaluation of these measures . Given that measure development and validation papers are frequently published in JPP ( Brown , 2007 ) , it is important that we attend to guiding psychometric principles when developing and disseminating data on new measures to be employed with pediatric population s ( Nunnally & Bernstein , 1994 ) . Thus , the purpose of this paper is to present and describe a checklist for authors to use when su bmi tting measure development papers to JPP . This checklist is included in the Appendix and is also included at the following link on the JPP website : http://www.oxfordjournals.org/our_journals/jpepsy/for _ authors /measure%20development%20checklist.pdf Findings presented by Holmbeck et al. ( 2008 ) indicated that 34 of the 37 measures review ed met pre-established “ evidence -based assessment ” ( EBA ) criteria for “ well-established ” measures ( Cohen et al. , 2008 ) . To be considered “ well-established , ” a measure had to have been presented in at least two peer- review ed journal articles by different investigatory teams , have demonstrated adequate levels of reliability and validity , and be accompanied by supporting information ( e.g. , a measure manual ) . Although most measures that we review ed met these criteria , we also found that most of the 34 “ well-established ” measures were hampered by at least one major psychometric flaw and /or lacked important psychometric data . We concluded that a more fine-grained EBA classification system is needed . One important distinction in this literature relates to differences between empirically supported assessment and evidence -based assessment . This type of distinction was first discussed in the literature on clinical interventions ( e.g. , Spring , 2007 ) . An empirically supported intervention is one that has demonstrated efficacy in r and omized clinical trials or clinic-based effectiveness trials . An evidence -based intervention has empirical support in the manner just described , but also “ integrates research evidence , clinical expertise , and patient preferences and characteristics … empirically-supported treatments ( ESTs ) are an important component of evidence -based practice ( EBP ) , but EBP can not be reduced to ESTs ” ( Spring , 2007 , p.611 ) . Applying these terms to the field of assessment and measure development efforts , an empirically supported assessment measure would be one that demonstrates satisfactory psychometric characteristics , broadly defined . To be evidence based , the measure should also demonstrate utility in clinical setting s , be useful in making diagnoses , be sensitive to treatment effects , and /or provide incremental validity above and beyond other similar measures . Although papers in the special issue of JPP frequently referred to “ evidence -based assessment ” ( Cohen et al. , 2009 ) , the articles included in the issue tended to evaluate the degree to which the measures were empirically-supported rather than evidence based . To be “ evidence -based , ” our review s would have needed to integrate an evaluation of clinical utility , diagnostic utility , and treatment sensitivity with the empirical psychometric data presented in each review . As noted , the published review s were more likely to focus on the latter rather than on the former . As suggested by Mash and Hunsley ( 2005 ) , detailed EBA profiles would provide a complete evaluation of evidence across each of several psychometric and clinical ly relevant dimensions , including : ( a ) internal consistency , ( b ) test – retest reliability , ( c ) the availability of normative data , ( d ) content validity , ( e ) construct validity , ( f ) convergent and discriminant validity , ( g ) criterion-related validity , ( h ) incremental validity , ( i ) clinical utility , ( j ) diagnostic utility , and ( k ) treatment sensitivity . The focus on incremental validity and clinical and diagnostic utility raises the bar from a focus on “ empirical support ” ( i.e. , where the focus would tend to be primarily on psychometric data ) to a broad focus on the “ evidence base ” for a measure . In developing the checklist that is the focus of this article , we attempted to provide a list of criteria relevant to establishing the evidence base ( and not just empirical support ) for a measure . In addition to shifting the focus from providing “ empirical support ” for a measure to providing an “ evidence base ” for our instruments , a checklist for measure development papers would permit JPP review ers to evaluate such papers in the same way that review ers of r and omized clinical trials make use of the Consoli date d St and ards of Reporting Trials ( CONSORT ) checklist and flowchart ( Altman et al. , 2001 ) . The CONSORT checklist contains reporting st and ards with respect to method ological features of and the manner in which results are reported in clinical trials . Moreover , authors are required to provide a flowchart that describes details of sample recruitment and attrition during the course of the study . Thus , a checklist for measure development papers would serve two interrelated purpose s : ( a ) it would provide guidance to authors as they embark on the measure development process and would provide a list of criteria authors can use as they develop an evidence base for their measures , and ( b ) it would begin to st and ardize the manner in which psychometric and other assessment -related data are presented in measure development papers for this journal . Before providing a more detailed overview of the checklist , it is important to note that this checklist is rather exhaustive ( see Appendix ) . As such , it represents what would “ ideally ” be expected for a measure development or validation manuscript rather than minimal criteria for such papers . No one paper can provide a complete evaluation of all important psychometric and clinical ly relevant dimensions that will establish once- and -for-all the evidence base for a measure . Instrument refinement is part of a measure development process that gradually builds an evidence base for a scale ( see Smith & McCarthy , 1995 , for suggestions on measure refinement ) . Indeed , the validation of any measure is a cumulative process that occurs across many different types of research studies and across research programs [11761203] BACKGROUND There is still only limited underst and ing of whether and why interventions to facilitate the implementation of guidelines for improving primary care are successful . It is therefore important to look inside the ' black box ' of the intervention , to ascertain which elements work well or less well . AIM To assess the associations of key elements of a nationwide multifaceted prevention programme with the successful implementation of cervical screening guidelines in general practice . DESIGN OF STUDY A nationwide prospect i ve cohort study . SETTING A r and om sample of one-third of all 4,758 general practice s in The Netherl and s ( n = 1,586 ) . METHOD General practitioners ( GPs ) in The Netherl and s were exposed to a two- and -a-half-year nationwide multifaceted prevention programme to improve the adherence to national guidelines for cervical cancer screening . Adherence to guidelines at baseline and after the intervention and actual exposure to programme elements were assessed in the sample using self-administered question naires . RESULTS Both baseline and post-measurement question naires were returned by 988 practice s ( response rate = 62 % ) . No major differences in baseline practice characteristics between study population , non-responders , and all Netherl and s practice s were observed . After the intervention all practice s improved markedly ( P<0.001 ) in their incorporation of nine out of 10 guideline indicators for effective cervical screening into practice . The most important elements for successful implementation were : specific software modules ( odds ratios and 95 % confidence intervalsfor all nine indicators ranged from OR = 1.85 [ 95 % CI = 1.24 - 2.77 ] to OR = 10.2 [ 95 % CI = 7.58 - 14.1 ] ) ; two or more ' practice visits ' by outreach visitors ( ORs and 95 % CIs for six indicators ranged from OR = 1.46 [ 95 % CI= 1.01 - 2.12 ] to OR = 2.35 [ 95 % CI = 1.63 - 3.38 ] ) ; and an educational programme for practice assistants ( ORs and 95 % CIs for four indicators ranged from OR = 1.57 [ 95 % CI = 1.00 - 1.92 ] to OR = 1.90 [ 95 % CI = 1.25 - 2.88 ] ) . CONCLUSION A multifaceted programme targeting GPs , including facilitating software modules , outreach visits , and educational sessions for PAs , contributes to the successful implementation of national guidelines for cervical screening [24469237] There is often wide variability in the reported effects of complex behavioral interventions . Effectiveness can vary across studies , sites , and providers . A factor that has been insufficiently considered is the fidelity of the behavioral treatment that was provided . Low quality practice could be likened to partial doses of a vaccine or antibiotic : the right idea but insufficient strength . Using motivational interviewing ( MI ) as an example , the authors describe three quality conditions that should be present for a study to be regarded as a trial of a complex behavioral intervention : ( 1 ) The treatment should clearly contain the components that are theoretically or empirically related to its efficacy ; ( 2 ) providers should be trained to an adequate and specified criterion of proficiency before treating trial patients ; and ( 3 ) the fidelity of treatment should be documented by reliable coding of practice throughout the study and reported in a manner that permits comparison with skill levels in other trials . The authors also discuss bona fide intervention failures despite strong clinical trial methodology , offering recommendations for future outcome research [24571932] BACKGROUND More evidence is needed on the potential role of ' booster ' interventions in the maintenance of increases in physical activity levels after a brief intervention in relatively sedentary population s. OBJECTIVES To determine whether objective ly measured physical activity , 6 months after a brief intervention , is increased in those receiving physical activity ' booster ' consultations delivered in a motivational interviewing ( MI ) style , either face to face or by telephone . DESIGN Three-arm , parallel-group , pragmatic , superiority r and omised controlled trial with nested qualitative research fidelity and geographical information systems and health economic sub studies . Treatment allocation was carried out using a web-based simple r and omisation procedure with equal allocation probabilities . Principal investigators and study statisticians were blinded to treatment allocation until after the final analysis only . SETTING Deprived areas of Sheffield , UK . PARTICIPANTS Previously sedentary people , aged 40 - 64 years , living in deprived areas of Sheffield , UK , who had increased their physical activity levels after receiving a brief intervention . INTERVENTIONS Participants were r and omised to the control group ( no further intervention ) or to two sessions of MI , either face to face ( ' full booster ' ) or by telephone ( ' mini booster ' ) . Sessions were delivered 1 and 2 months post-r and omisation . MAIN OUTCOME MEASURES The primary outcome was total energy expenditure ( TEE ) per day in kcal from 7-day accelerometry , measured using an Actiheart device ( CamNtech Ltd , Cambridge , UK ) . Independent evaluation of practitioner competence was carried out using the Motivational Interviewing Treatment Integrity assessment . An estimate of the per-participant intervention costs , re source use data collected by question naire and health-related quality of life data were analysed to produce a range of economic models from a short-term NHS perspective . An additional series of models were developed that used TEE values to estimate the long-term cost-effectiveness . RESULTS In total , 282 people were r and omised ( control = 96 ; mini booster = 92 , full booster = 94 ) of whom 160 had a minimum of 4 out of 7 days ' accelerometry data at 3 months ( control = 61 , mini booster = 47 , full booster = 52 ) . The mean difference in TEE per day between baseline and 3 months favoured the control arm over the combined booster arm but this was not statistically significant ( -39 kcal , 95 % confidence interval -173 to 95 , p = 0.57 ) . The autonomy-enabled MI communication style was generally acceptable , although some participants wanted a more paternalistic approach and most expressed enthusiasm for monitoring and feedback components of the intervention and research . Full boosters were more popular than mini boosters . Practitioners achieved and maintained a consistent level of MI competence . Walking distance to the nearest municipal green space or leisure facilities was not associated with physical activity levels . Two alternative modelling approaches both suggested that neither intervention was likely to be cost-effective . CONCLUSIONS Although some individuals do find a community-based , brief MI ' booster ' intervention supportive , the low levels of recruitment and retention and the lack of impact on objective ly measured physical activity levels in those with adequate outcome data suggest that it is unlikely to represent a clinical ly effective or cost-effective intervention for the maintenance of recently acquired physical activity increases in deprived middle-aged urban population s. Future research with middle-aged and relatively deprived population s should explore interventions to promote physical activity that require less proactive engagement from individuals , including environmental interventions . STUDY REGISTRATION Current Controlled Trials IS RCT N56495859 , Clinical Trials.gov NCT00836459 . FUNDING This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol . 18 , No. 13 . See the NIHR Journals Library website for further project information [1475568] Background Self-management programs for patients with heart failure can reduce hospitalizations and mortality . However , no programs have analyzed their usefulness for patients with low literacy . We compared the efficacy of a heart failure self-management program design ed for patients with low literacy versus usual care . Methods We performed a 12-month r and omized controlled trial . From November 2001 to April 2003 , we enrolled participants aged 30–80 , who had heart failure and took furosemide . Intervention patients received education on self-care emphasizing daily weight measurement , diuretic dose self-adjustment , and symptom recognition and response . Picture-based educational material s , a digital scale , and scheduled telephone follow-up were provided to reinforce adherence . Control patients received a generic heart failure brochure and usual care . Primary outcomes were combined hospitalization or death , and heart failure-related quality of life . Results 123 patients ( 64 control , 59 intervention ) participated ; 41 % had inadequate literacy . Patients in the intervention group had a lower rate of hospitalization or death ( crude incidence rate ratio ( IRR ) = 0.69 ; CI 0.4 , 1.2 ; adjusted IRR = 0.53 ; CI 0.32 , 0.89 ) . This difference was larger for patients with low literacy ( IRR = 0.39 ; CI 0.16 , 0.91 ) than for higher literacy ( IRR = 0.56 ; CI 0.3 , 1.04 ) , but the interaction was not statistically significant . At 12 months , more patients in the intervention group reported monitoring weights daily ( 79 % vs. 29 % , p < 0.0001 ) . After adjusting for baseline demographic and treatment differences , we found no difference in heart failure-related quality of life at 12 months ( difference = -2 ; CI -5 , + 9 ) . Conclusion A primary care-based heart failure self-management program design ed for patients with low literacy reduces the risk of hospitalizations or death [25159905] Developing more effective behavioural interventions requires an underst and ing of the mechanisms of behaviour change , and methods to rigorously test their theoretical basis . The delivery and theoretical basis of an intervention protocol were assessed in ProActive , a UK trial of an intervention to increase the physical activity of those at risk of Type 2 diabetes ( N = 365 ) . In 108 intervention sessions , behaviours of facilitators were mapped to four theories that informed intervention development and behaviours of participants were mapped to 17 theoretical components of these four theories . The theory base of the intervention specified by the protocol was different than that delivered by facilitators , and that received by participants . Of the intervention techniques delivered , 25 % were associated with theory of planned behaviour ( TPB ) , 42 % with self-regulation theory ( SRT ) , 24 % with operant learning theory ( OLT ) and 9 % with relapse prevention theory ( RPT ) . The theoretical classification of participant talk showed a different pattern , with twice the proportion associated with OLT ( 48 % ) , 21 % associated with TPB , 31 % with SRT and no talk associated with RPT . This study demonstrates one approach to assessing the extent to which the theories used to guide intervention development account for any changes observed [3656395] Abstract Objective . To study the effectiveness of a comprehensive diabetes programme in general practice that integrates patient-centred lifestyle counselling into structured diabetes care . Design and setting . Cluster r and omised trial in general practice s. Intervention . Nurse-led structured diabetes care with a protocol , record keeping , reminders , and feedback , plus training in motivational interviewing and agenda setting . Subjects . Primary care nurses in 58 general practice s and their 940 type 2 diabetes patients with an HbA1c concentration above 7 % , and a body mass index ( BMI ) above 25 kg/m2 . Main outcome measures . HbA1c , diet , and physical activity ( medical records and patient question naires ) . Results . Multilevel linear and logistic regression analyses adjusted for baseline outcomes showed that despite active nurse participation in the intervention , the comprehensive programme was no more effective than usual care after 14 months , as shown by HbA1c levels ( difference between groups = 0.13 ; CI 20.8–0.35 ) and diet ( fat ( difference between groups = 0.19 ; CI 20.82–1.21 ) ; vegetables ( difference between groups = 0.10 ; CI-0.21–0.41 ) ; fruit ( difference between groups = 20.02 ; CI 20.26–0.22 ) ) , and physical activity ( difference between groups = 21.15 ; CI 212.26–9.97 ) , or any of the other measures of clinical parameters , patient 's readiness to change , or quality of life . Conclusion . A comprehensive programme that integrated lifestyle counselling based on motivational interviewing principles integrated into structured diabetes care did not alter HbA1c or the lifestyle related to diet and physical activity . We thus question the impact of motivational interviewing in terms of its ability to improve routine diabetes care in general practice [23567399] OBJECTIVES To assess feasibility and to conduct a preliminary evaluation of outcomes following Peaceful Mind , a cognitive-behavioral therapy-based intervention for anxiety in dementia , relative to usual care . DESIGN Pilot r and omized controlled trial including assessment s at baseline and 3 and 6 months . SETTING Houston , TX . PARTICIPANTS Thirty-two out patients diagnosed with mild ( 47 % ) or moderate ( 53 % ) dementia receiving care through outpatient clinics at the Veterans Affairs medical center , Baylor College of Medicine , Harris County Hospital District , and community day centers for dementia , and their collaterals , who spent at least 8 hours a week with them . INTERVENTION Peaceful Mind included up to 12 weekly in-home sessions ( mean : 8.7 , SD : 2.27 ) during the initial 3 months and up to eight brief telephone sessions ( mean : 5.4 , SD : 3.17 ) during months 3 - 6 , involving self-monitoring for anxiety , deep breathing , and optional skills ( coping self-statements , behavioral activation , and sleep management ) . Patients learned skills , and collaterals served as coaches . In usual care , patients received diagnostic feedback , and providers were informed of inclusion status . MEASUREMENTS Neuropsychiatric Inventory-Anxiety subscale , Rating Anxiety in Dementia scale , Penn State Worry Question naire-Abbreviated , Geriatric Anxiety Inventory , Geriatric Depression Scale , Quality of Life in Alzheimer disease , Patient Health Question naire , and Client Satisfaction Question naire . RESULTS Feasibility was demonstrated with regard to recruitment , attrition , and treatment characteristics . At 3 months , clinicians rated patients receiving Peaceful Mind as less anxious , and patients rated themselves as having higher quality of life ; collaterals reported less distress related to loved ones ' anxiety . Although significant positive effects were not noted in other outcomes or at 6-month follow-up , the pilot nature of the trial prohibits conclusions about efficacy . CONCLUSIONS Results support that Peaceful Mind is ready for future comparative clinical trials [15193897] BACKGROUND This paper describes the implementation of the Healthy Directions-Health Centers intervention and examines the characteristics of participants associated with completion of intervention activities . Healthy Directions-Health Centers was design ed to address social context ual factors relevant to cancer prevention interventions for working class , multi-ethnic population s. METHODS Ten community health centers were paired and r and omly assigned to intervention or control . Patients who resided in low income , multi-ethnic neighborhoods were approached for participation . This study targeted fruit and vegetable consumption , red meat consumption , multi-vitamin intake , and physical activity . The intervention components consisted of : ( 1 ) a brief study endorsement from a clinician ; ( 2 ) an in-person counseling session with a health advisor ; ( 3 ) four follow-up telephone counseling sessions ; and ( 4 ) multiple distributions of tailored material s. RESULTS Among the 1,088 intervention group participants , 978 participants ( 90 % ) completed at least five out of six intervention activities . Participants who missed clinical appointments were less likely to complete all components of the intervention . Participant characteristics that predicted receipt of clinician endorsement differed from characteristics that predicted completion of health advisor activities . Low acculturation did not present a barrier to delivery of the intervention once the participant was enrolled . CONCLUSIONS Collection and reporting on process evaluation results can help explain variations in program implementation [9930042] Objective To evaluate whether nurse run clinics in general practice improve secondary prevention in patients with coronary heart disease . Design R and omised controlled trial . Setting A r and om sample of 19 general practice s in northeast Scotl and . Patients 1173 patients ( 685 men and 488 women ) under 80 years with working diagnoses of coronary heart disease , but without terminal illness or dementia and not housebound . Intervention Nurse run clinics promoted medical and lifestyle aspects of secondary prevention and offered regular follow up . Main outcome measures Components of secondary prevention assessed at baseline and one year were : aspirin use ; blood pressure management ; lipid management ; physical activity ; dietary fat ; and smoking status . A cumulative score was generated by counting the number of appropriate components of secondary prevention for each patient . Results There were significant improvements in aspirin management ( odds ratio 3.22 , 95 % confidence interval 2.15 to 4.80 ) , blood pressure management ( 5.32 , 3.01 to 9.41 ) , lipid management ( 3.19 , 2.39 to 4.26 ) , physical activity ( 1.67 , 1.23 to 2.26 ) and diet ( 1.47 , 1.10 to 1.96 ) . There was no effect on smoking cessation ( 0.78 , 0.47 to 1.28 ) . Of six possible components of secondary prevention , the baseline mean was 3.27 . The adjusted mean improvement attributable to intervention was 0.55 of a component ( 0.44 to 0.67 ) . Improvement was found regardless of practice baseline performance . Conclusions Nurse run clinics proved practical to implement in general practice and effectively increased secondary prevention in coronary heart disease . Most patients gained at least one effective component of secondary prevention and , for them , future cardiovascular events and mortality could be reduced by up to a third [12875144] The purpose of this study was to determine how an exercise adherence intervention affects the physiological , functional , and quality of life outcomes of patients with heart failure ( HF ) . Sixteen HF patients were r and omly assigned to an exercise-only group ( n = 8) or to an exercise-with-adherence group ( n = 8) . Two of the 16 people died from nonexercise related causes during the study and were not included in the analysis . The intervention was tested over a 24-week period in which patients participated in a 12-week supervised exercise program ( Phase 1 ) followed by 12 weeks of unsupervised home exercise ( Phase 2 ) . The intervention format was one of individualized graphic feedback on exercise goals and participation and problem-solving support by nurses . Results indicate that patients who received the intervention exercised more frequently and experienced improved outcomes during both phases . The adherence intervention may encourage HF patients to continue to exercise and thereby maintain the health benefits gained in both phases of an exercise program [17276321] OBJECTIVE To test if basic training for dietitians in motivational interviewing ( MI ) result ed in changes in dietitians ' counseling style and improvements in their patients ' diet and risk parameters . DESIGN A r and omized controlled trial . SETTING 9 home-care organizations in the Netherl and s. PARTICIPANTS 37 dietitians , 209 baseline patients , and 142 follow-up diabetes patients . INTERVENTION Dietitians were r and omly allocated to receive basic training in motivational interviewing ( MI dietitians , n=18 ) or not ( control dietitians , n=19 ) . MAIN OUTCOME MEASURES Counseling style of dietitians ; total self-reported saturated fat , fruit , and vegetable intake , measured body mass index ( BMI ) , waist circumference , and glycated hemoglobin ( Hemoglobin A(1c ) , HbA(1c ) ) of patients . ANALYSIS Analyses of variance and multiple linear regression analyses . Alpha = .05 RESULTS MI dietitians were significantly more empathetic , more often showed reflection during consultations , and were more likely than control dietitians to let their patients talk for the majority of the consultation . Patients of MI dietitians had significantly lower saturated fat intake levels at posttest compared to patients of control dietitians . No effects on HbA(1c ) , BMI , and waist circumference were found . CONCLUSIONS AND IMPLICATION S Basic training in MI changed the dietitians ' counseling style and result ed in lower saturated fat intakes in their patients [9028693] OBJECTIVE The aim of this r and omized pilot study was to examine whether the addition of motivational interviewing strategies to a behavioral obesity intervention enhances adherence and glucose control in older obese women with NIDDM . RESEARCH DESIGN AND METHODS Twenty-two older obese women ( 41 % black ) with NIDDM were r and omly assigned to 1 ) a st and ard 16-week group behavioral weight-control program that provided instruction in diet , exercise , and behavioral modification or 2 ) the same group behavioral program with three individualized motivational interviewing sessions added . RESULTS The motivational group attended significantly more group meetings ( 13.3 vs. 8.9 ) , completed significantly more food diaries ( 15.2 vs. 10.1 ) , and recorded blood glucose significantly more often ( 46.0 vs. 32.2 days ) than the st and ard group . Further , participants in the motivational group had significantly better glucose control post-treatment ( 9.8 vs. 10.8 % ) . Although both groups demonstrated significant weight loss , no differences were apparent between groups . CONCLUSIONS These results suggest that augmenting a st and ard behavioral treatment program for obese women with NIDDM with a motivational interviewing component may significantly enhance adherence to program recommendations and glycemic control . Preliminary data warrant further investigation with larger sample s and a longer follow-up [18395397] Cardiac pain arising from chronic stable angina ( CSA ) is a cardinal symptom of coronary artery disease and has a major negative impact on health-related quality of life ( HRQL ) , including pain , poor general health status , and inability to self-manage . Current secondary prevention approaches lack adequate scope to address CSA as a multidimensional ischemic and persistent pain problem . This trial evaluated the impact of a low-cost six-week angina psychoeducation program , entitled The Chronic Angina Self-Management Program ( CASMP ) , on HRQL , self-efficacy , and re source fulness to self-manage anginal pain . One hundred thirty participants were r and omized to the CASMP or three-month wait-list usual care ; 117 completed the study . Measures were taken at baseline and three months . General HRQL was measured using the Medical Outcomes Study 36-Item Short Form and the disease-specific Seattle Angina Question naire ( SAQ ) . Self-efficacy and re source fulness were measured using the Self-Efficacy Scale and the Self-Control Schedule , respectively . The mean age of participants was 68 years , 80 % were male . Analysis of variance of change scores yielded significant improvements in treatment group physical functioning [ F=11.75(1,114 ) , P<0.001 ] and general health [ F=10.94(1,114 ) , P=0.001 ] aspects of generic HRQL . Angina frequency [ F=5.57(1,115 ) , P=0.02 ] , angina stability [ F=7.37(1,115 ) , P=0.001 ] , and self-efficacy to manage disease [ F=8.45(1,115 ) , P=0.004 ] were also significantly improved at three months . The CASMP did not impact re source fulness . These data indicate that the CASMP was effective for improving physical functioning , general health , anginal pain symptoms , and self-efficacy to manage pain at three months and provide a basis for long-term evaluation of the program [17307300] OBJECTIVES 1 . Quantitative description of the adherence to the principles of Motivational Interviewing ( MI ) in smoking counseling sessions , 2 . Examination of the relation between clients ' characteristics and the adherence to the principles of MI , and between adherence to the principles of MI and future smoking status . METHODS A sample of n=163 sessions conducted during a r and omized controlled trial in testing the effectiveness of a population -based smoking intervention in women postpartum was investigated . Demographic and behavior-related variables were included in a logistic regression to predict adherence to MI . Adherence was measured using the Motivational Interviewing Treatment Integrity ( MITI ) scale . RESULTS Of the sessions , 49.4 % showed good adherence to MI . The OR of receiving a good MI session was 3.1 for non-smokers in comparison to daily smokers . No other demographic or behavioral variable gained statistical significance . The relation between adherence and intervention outcome after 6 months was statistically significant ( chi(2)=6.459 , p<0.05 ) . CONCLUSIONS This intervention study shows a satisfactory degree of adherence to and the effectiveness of MI . MI-adherence seems more likely in sessions concerned with smoking relapse prevention compared to smoking cessation sessions [11469475] OBJECTIVE To test the effects of a high intensity home-based progressive strength training program on the clinical signs and symptoms of osteoarthritis ( OA ) of the knee . METHODS Forty-six community dwelling patients , aged 55 years or older with knee pain and radiographic evidence of knee OA , were r and omized to a 4 month home based progressive strength training program or a nutrition education program ( attention control ) . Thirty-eight patients completed the trial with an adherence of 84 % to the intervention and 65 % to the attention control . The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis ( WOMAC ) index pain and physical function subscales . Secondary outcomes included clinical knee examination , muscle strength , physical performance measures , and question naires to measure quality of life variables . RESULTS Patients in the strength training group who completed the trial had a 71 % improvement in knee extension strength in the leg reported as most painful versus a 3 % improvement in the control group ( p < 0.01 ) . In a modified intent to treat analysis , self-reported pain improved by 36 % and physical function by 38 % in the strength training group versus 11 and 21 % , respectively , in the control group ( p = 0.01 for between group comparison ) . In addition , those patients in the strength training group who completed the trial had a 43 % mean reduction in pain ( p = 0.01 vs controls ) , a 44 % mean improvement in self-reported physical function ( p < 0.01 vs controls ) , and improvements in physical performance , quality of life , and self-efficacy when compared to the control group . CONCLUSION High intensity , home based strength training can produce substantial improvements in strength , pain , physical function and quality of life in patients with knee OA [20483968] CONTEXT Improving the quality of mental health care requires moving clinical interventions from controlled research setting s into real-world practice setting s. Although such advances have been made for depression , little work has been performed for anxiety disorders . OBJECTIVE To determine whether a flexible treatment-delivery model for multiple primary care anxiety disorders ( panic , generalized anxiety , social anxiety , and posttraumatic stress disorders ) would be better than usual care ( UC ) . DESIGN , SETTING , AND PATIENTS A r and omized controlled effectiveness trial of Coordinated Anxiety Learning and Management ( CALM ) compared with UC in 17 primary care clinics in 4 US cities . Between June 2006 and April 2008 , 1004 patients with anxiety disorders ( with or without major depression ) , aged 18 to 75 years , English- or Spanish-speaking , were enrolled and subsequently received treatment for 3 to 12 months . Blinded follow-up assessment s at 6 , 12 , and 18 months after baseline were completed in October 2009 . INTERVENTION CALM allowed choice of cognitive behavioral therapy ( CBT ) , medication , or both ; included real-time Web-based outcomes monitoring to optimize treatment decisions ; and a computer-assisted program to optimize delivery of CBT by nonexpert care managers who also assisted primary care clinicians in promoting adherence and optimizing medications . MAIN OUTCOME MEASURES Twelve-item Brief Symptom Inventory ( BSI-12 ) anxiety and somatic symptoms score . Secondary outcomes included proportion of responders ( > or = 50 % reduction from pretreatment BSI-12 score ) and remitters ( total BSI-12 score < 6 ) . RESULTS A significantly greater improvement for CALM vs UC in global anxiety symptoms was found ( BSI-12 group mean differences of -2.49 [ 95 % confidence interval { CI } , -3.59 to -1.40 ] , -2.63 [ 95 % CI , -3.73 to -1.54 ] , and -1.63 [ 95 % CI , -2.73 to -0.53 ] at 6 , 12 , and 18 months , respectively ) . At 12 months , response and remission rates ( CALM vs UC ) were 63.66 % ( 95 % CI , 58.95%-68.37 % ) vs 44.68 % ( 95 % CI , 39.76%-49.59 % ) , and 51.49 % ( 95 % CI , 46.60%-56.38 % ) vs 33.28 % ( 95 % CI , 28.62%-37.93 % ) , with a number needed to treat of 5.27 ( 95 % CI , 4.18 - 7.13 ) for response and 5.50 ( 95 % CI , 4.32 - 7.55 ) for remission . CONCLUSION For patients with anxiety disorders treated in primary care clinics , CALM compared with UC result ed in greater improvement in anxiety symptoms , depression symptoms , functional disability , and quality of care during 18 months of follow-up . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00347269 [21074887] AIM To determine whether glycemic control is improved when motivational interviewing ( MI ) , a patient-centered behavior change strategy , is used with diabetes self management education ( DSME ) as compared to DSME alone . METHODS poorly controlled type 2 diabetes ( T2DM ) patients ( n=234 ) were r and omized into 4 groups : MI+DSME or DSME alone , with or without use of a computerized summary of patient self management barriers . We compared HbA1c changes between groups at 6 months and investigated mediators of HbA1c change . RESULTS study patients attended the majority of the four intervention visits ( mean 3.4 ) , but drop-out rate was high at follow-up research visits ( 35 % ) . Multiple regression showed that groups receiving MI had a mean change in HbA1c that was significantly lower ( less improved ) than those not receiving MI ( t=2.10 ; p=0.037 ) . Mediators of HbA1c change for the total group were diabetes self-care behaviors and diabetes distress ; no between-group differences were found . CONCLUSIONS DSME improved blood glucose control , underlining its benefit for T2DM management . However , MI+DSME was less effective than DSME alone . Overall , weak support was found for the clinical utility of MI in the management of T2DM delivered by diabetes educators [12403802] Background . Counseling sedentary primary care patients can increase physical activity , but whether this approach will increase exercise and fitness in elderly adults with chronic diseases remains to be determined . Methods . After receiving individualized nurse counseling to begin a program of walking for health , 60- to 80-year-old primary care patients were r and omized to one of three levels of telephone contacts over 10 months : ( i ) 20 nurse-initiated calls , ( ii ) 10 nurse-initiated calls plus 10 motivational calls programmed through an automated phone calling system , or ( iii ) no program-initiated phone contacts . Self-reported ( diary ) walking adherence was the primary outcome ; other activity , social support , health quality of life , and measured walking performance , mobility , and body mass index and girths were also assessed during the initiation ( months 1 - 6 ) and maintenance ( months 7 - 10 ) phases of the trial . Results . Average adherence for the 181 participants to the goal of walking at least 20 minutes on 3 or more days per week was 44 % for initiation and 42 % for maintenance . Participants receiving the combination of nurse-initiated personal and automated phone calls walked significantly more frequently than those with no phone contacts . Fitness improved in all three groups ; changes were generally correlated with self-reported walking . Having a companion was associated with more frequent walking . Perceived quality of physical and mental health did not change . Conclusions . Simple and relatively inexpensive nurse contacts can motivate elderly primary care patients to walk for exercise , and this activity is associated with measurable health benefits [4180306] Background Many older adults are both highly sedentary ( that is , spend considerable amounts of time sitting ) and physically inactive ( that is , do little physical activity ) . This protocol describes an exploratory trial of a theory-based behaviour change intervention in the form of a booklet outlining simple activities ( ‘ tips ’ ) design ed both to reduce sedentary behaviour and to increase physical activity in older adults . The intervention is based on the ‘ habit formation ’ model , which proposes that consistent repetition leads to behaviour becoming automatic , sustaining activity gains over time . Methods The intervention is being developed iteratively , in line with Medical Research Council complex intervention guidelines . Selection of activity tips was informed by semi-structured interviews and focus groups with older adults , and input from a multidisciplinary expert panel . An ongoing preliminary field test of acceptability among 25 older adults will inform further refinement . An exploratory r and omized controlled trial will be conducted within a primary care setting , comparing the tips booklet with a control fact sheet . Retired , inactive and sedentary adults ( n = 120 ) aged 60 to 74 years , with no physical impairments precluding light physical activity , will be recruited from general practice s in north London , UK . The primary outcomes are recruitment and attrition rates . Secondary outcomes are changes in behaviour , habit , health and wellbeing over 12 weeks . Discussion Data will be used to inform study procedures for a future , larger-scale definitive r and omized controlled trial . Trial registration Current Controlled Trials IS RCT N47901994 [2942793] Background Evaluation of an implementation process and its fidelity can give insight into the ' black box ' of interventions . However , a lack of st and ardized methods for study ing fidelity and implementation process have been reported , which might be one reason for the fact that few prior studies in the field of health service research have systematic ally evaluated interventions ' implementation processes . The aim of this project is to systematic ally evaluate implementation fidelity and possible factors influencing fidelity of complex interventions in health and social care . Methods A modified version of The Conceptual Framework for Implementation Fidelity will be used as a conceptual model for the evaluation . The modification implies two additional moderating factors : context and recruitment . A systematic evaluation process was developed . Multiple case study method is used to investigate implementation of three complex health service interventions . Each case will be investigated in depth and longitudinally , using both quantitative and qualitative methods . Discussion This study is the first attempt to empirically test The Conceptual Framework for Implementation Fidelity . The study can highlight mechanism and factors of importance when implementing complex interventions . Especially the role of the moderating factors on implementation fidelity can be clarified . Trial Registration Supported Employment , SE , among people with severe mental illness -- a r and omized controlled trial : NCT00960024 [3534485] Background To examine the effects of a multicomponent exercise program on the cognitive function of older adults with amnestic mild cognitive impairment ( aMCI ) . Methods Design : Twelve months , r and omized controlled trial ; Setting : Community center in Japan ; Participants : Fifty older adults ( 27 men ) with aMCI ranging in age from 65 to 93 years ( mean age , 75 years ) ; Intervention : Subjects were r and omized into either a multicomponent exercise ( n = 25 ) or an education control group ( n = 25 ) . Subjects in the multicomponent exercise group exercised under the supervision of physiotherapists for 90 min/d , 2 d/wk , for a total of 80 times over 12 months . The exercises included aerobic exercises , muscle strength training , and postural balance retraining , and were conducted using multiple conditions to stimulate cognitive functions . Subjects in the control group attended three education classes regarding health during the 12-month period . Measurements were administered before , after the 6-month , and after the 12-month intervention period ; Measurements : The performance measures included the mini-mental state examination , logical memory subtest of the Wechsler memory scale-revised , digit symbol coding test , letter and categorical verbal fluency test , and the Stroop color word test . Results The mean adherence to the exercise program was 79.2 % . Improvements of cognitive function following multicomponent exercise were superior at treatment end ( group × time interactions for the mini-mental state examination ( P = 0.04 ) , logical memory of immediate recall ( P = 0.03 ) , and letter verbal fluency test ( P = 0.02 ) ) . The logical memory of delayed recall , digit symbol coding , and Stroop color word test showed main effects of time , although there were no group × time interactions . Conclusions This study indicates that exercise improves or supports , at least partly , cognitive performance in older adults with aMCI [1716168] Background Missing data present a challenge to many research projects . The problem is often pronounced in studies utilizing self-report scales , and literature addressing different strategies for dealing with missing data in such circumstances is scarce . The objective of this study was to compare six different imputation techniques for dealing with missing data in the Zung Self-reported Depression scale ( SDS ) . Methods 1580 participants from a surgical outcomes study completed the SDS . The SDS is a 20 question scale that respondents complete by circling a value of 1 to 4 for each question . The sum of the responses is calculated and respondents are classified as exhibiting depressive symptoms when their total score is over 40 . Missing values were simulated by r and omly selecting questions whose values were then deleted ( a missing completely at r and om simulation ) . Additionally , a missing at r and om and missing not at r and om simulation were completed . Six imputation methods were then considered ; 1 ) multiple imputation , 2 ) single regression , 3 ) individual mean , 4 ) overall mean , 5 ) participant 's preceding response , and 6 ) r and om selection of a value from 1 to 4 . For each method , the imputed mean SDS score and st and ard deviation were compared to the population statistics . The Spearman correlation coefficient , percent misclassified and the Kappa statistic were also calculated . Results When 10 % of values are missing , all the imputation methods except r and om selection produce Kappa statistics greater than 0.80 indicating ' near perfect ' agreement . MI produces the most valid imputed values with a high Kappa statistic ( 0.89 ) , although both single regression and individual mean imputation also produced favorable results . As the percent of missing information increased to 30 % , or when unbalanced missing data were introduced , MI maintained a high Kappa statistic . The individual mean and single regression method produced Kappas in the ' substantial agreement ' range ( 0.76 and 0.74 respectively ) . Conclusion Multiple imputation is the most accurate method for dealing with missing data in most of the missind data scenarios we assessed for the SDS . Imputing the individual 's mean is also an appropriate and simple method for dealing with missing data that may be more interpretable to the majority of medical readers . Research ers should consider conducting method ological assessment s such as this one when confronted with missing data . The optimal method should balance validity , ease of interpretability for readers , and analysis expertise of the research team [18314570] BACKGROUND Because preventing functional decline in older adults is a national priority and senior centers have been identified as potentially important venues for health-promotion activities , a trial of a multicomponent disability prevention program was conducted at a senior center . METHODS One hundred older adults were recruited for a 6-month r and omized clinical trial . All members of the experimental group received an exercise intervention , nutrition counseling , and a home safety assessment . Smoking and alcohol interventions were delivered to at-risk subjects . Outcome variables included the Medical Outcomes Study Short Form ( SF-36 ) health survey , the CES-Depression scale , bed days , and restricted-activity days . RESULTS A single study announcement result ed in a response sufficient to recruit 100 subjects . The exercise program was well received : 85 % of intervention subjects completed the 6-month program and adherence was excellent , with over 90 % attendance at exercise classes . After 6 months the intervention group had significantly better scores on 7 of 8 SF-36 subscales and fewer depressive symptoms than controls . CONCLUSIONS Senior centers may be excellent sites for community-based health promotion interventions : participation and adherence rates may be acceptable , interventions can be design ed that are feasible in this setting , and these interventions appear to affect health status positively . The study program improved physical and psychosocial functioning and is a promising model for preventing functional decline through activities based at senior centers [24113727] Objective : To examine the feasibility of a strategy training clinical trial in a small group of adults with stroke-related cognitive impairments in inpatient rehabilitation , and to explore the impact of strategy training on disability . Design : Non-r and omized two-group intervention pilot study . Setting : Two inpatient rehabilitation units within an academic health centre . Participants : Individuals with a primary diagnosis of acute stroke , who were admitted to inpatient rehabilitation and demonstrated cognitive impairments were included . Individuals with severe aphasia ; dementia ; major depressive disorder , bipolar , or psychotic disorder ; recent drug or alcohol abuse ; and anticipated length of stay less than five days were excluded . Intervention : Participants received strategy training or an attention control session in addition to usual rehabilitation care . Sessions in both groups were 30–40 minutes daily , five days per week , for the duration of inpatient rehabilitation . Main outcome measures : We assessed feasibility through participants ’ recruitment and retention ; research intervention session number and duration ; participants ’ comprehension and engagement ; intervention fidelity ; and participants ’ satisfaction . We assessed disability at study admission , inpatient rehabilitation discharge , 3 and 6 months using the Functional Independence Measure . Results : Participants in both groups ( 5 per group ) received the assigned intervention ( > 92 % planned sessions ; > 94 % fidelity ) and completed follow-up testing . Strategy training participants in this small sample demonstrated significantly less disability at six months ( M ( SE ) = 117 ( 3 ) ) than attention control participants ( M(SE ) = 96 ( 14 ) ; t8 = 7.87 , P = 0.02 ) . Conclusions : It is feasible and acceptable to administer both intervention protocol s as an adjunct to acute inpatient rehabilitation , and strategy training shows promise for reducing disability [8980206] OBJECTIVE To determine the effects of structured exercise programs on self-reported disability in older adults with knee osteoarthritis . SETTING AND DESIGN A r and omized , single-blind clinical trial lasting 18 months conducted at 2 academic medical centers . PARTICIPANTS A total of 439 community-dwelling adults , aged 60 years or older , with radiographically evident knee osteoarthritis , pain , and self-reported physical disability . INTERVENTIONS An aerobic exercise program , a resistance exercise program , and a health education program . MAIN OUTCOME MEASURES The primary outcome was self-reported disability score ( range , 1 - 5 ) . The secondary outcomes were knee pain score ( range , 1 - 6 ) , performance measures of physical function , x-ray score , aerobic capacity , and knee muscle strength . RESULTS A total of 365 ( 83 % ) participants completed the trial . Overall compliance with the exercise prescription was 68 % in the aerobic training group and 70 % in the resistance training group . Postr and omization , participants in the aerobic exercise group had a 10 % lower adjusted mean ( + /- SE ) score on the physical disability question naire ( 1.71 + /- 0.03 vs 1.90 + /- 0.04 units ; P<.001 ) , a 12 % lower score on the knee pain question naire ( 2.1 + /- 0.05 vs 2.4 + /- 0.05 units ; P=.001 ) , and performed better ( mean [ + /- SE ] ) on the 6-minute walk test ( 1507 + /- 16 vs 1349 + /- 16 ft ; P<.001 ) , mean ( + /-SE ) time to climb and descend stairs ( 12.7 + /- 0.4 vs 13.9 + /- 0.4 seconds ; P=.05 ) , time to lift and carry 10 pounds ( 9.1 + /- 0.2 vs 10.0 + /- 0.1 seconds ; P<.001 ) , and mean ( + /-SE ) time to get in and out of a car ( 8.7 + /- 0.3 vs 10.6 + /- 0.3 seconds ; P<.001 ) than the health education group . The resistance exercise group had an 8 % lower score on the physical disability question naire ( 1.74 + /- 0.04 vs 1.90 + /- 0.03 units ; P=.003 ) , 8 % lower pain score ( 2.2 + /- 0.06 vs 2.4 + /- 0.05 units ; P=.02 ) , greater distance on the 6-minute walk ( 1406 + /- 17 vs 1349 + /- 16 ft ; P=.02 ) , faster times on the lifting and carrying task ( 9.3 + /- 0.1 vs 10.0 + /- 0.16 seconds ; P=.001 ) , and the car task ( 9.0 + /- 0.3 vs 10.6 + /- 0.3 seconds ; P=.003 ) than the health education group . There were no differences in x-ray scores between either exercise group and the health education group . CONCLUSIONS Older disabled persons with osteoarthritis of the knee had modest improvements in measures of disability , physical performance , and pain from participating in either an aerobic or a resistance exercise program . These data suggest that exercise should be prescribed as part of the treatment for knee osteoarthritis [23368423] BACKGROUND The aim of the present study was to determine whether the addition of nurse case managers ( NCMs ) trained in motivational interviewing ( MI ) to usual care would result in improved outcomes in high-risk type 2 diabetes patients . METHODS A 2-year r and omized controlled pragmatic trial r and omized 545 patients to usual care control ( n=313 ) or those who received the intervention ( n=232 ) with additional practice -embedded NCM care , including MI-guided behavior change counseling . The NCMs received intensive MI training with ongoing fidelity assessment . RESULTS Systolic blood pressure ( SBP ) was better in the intervention than usual care group ( 131 ± 15 vs. 135 ± 18 mmHg , respectively ; P<0.05 ) . Improvements were seen in both the control and intervention groups in terms of HbA1c ( from 9.1 % to 8.0 % and from 8.8 % to 7.8 % , respectively ) , low-density lipoprotein ( LDL ; from 127 to 100 mg/dL and from 128 to 102 mg/dL , respectively ) , and diastolic blood pressure ( from 78 to 74 mmHg and from 80 to 74 mmHg , respectively ) . Depression symptom scores were better in the intervention group . The reduction in diabetes-related distress approached statistical significance . CONCLUSIONS The NCMs and MI improved SBP and complications screening . The large decrease in HbA1C and LDL in the control group may have obscured any further intervention effect . Although nurses prompted providers for medication titration , strategies to reduce provider clinical inertia may also be needed [22103957] OBJECTIVE Adherence to continuous positive airway pressure ( CPAP ) therapy for obstructive sleep apnoea ( OSA ) is poor . We assessed the effectiveness of a motivational interviewing intervention ( motivational interview nurse therapy [ MINT ] ) in addition to best practice st and ard care to improve acceptance and adherence to CPAP therapy in people with a new diagnosis of OSA . METHOD One hundred six Australian adults ( 69 % male ) with a new diagnosis of OSA and a clinical recommendation for CPAP treatment were recruited from a tertiary sleep disorders center . Participants were r and omly assigned to receive either 3 sessions of a motivational interviewing intervention ( MINT ; n = 53 ; mean age = 55.4 years ) or no intervention ( control ; n = 53 ; mean age = 57.74 years ) . The primary outcome was the difference between the groups in objective CPAP adherence at 1-month , 2-month , 3-month , and 12-month follow-ups . RESULTS Fifty ( 94 % ) participants in the MINT group and 50 ( 94 % ) participants in the control group met all inclusion and exclusion criteria and were included in the primary analysis . The number of hours of CPAP use per night in the MINT group at 3 months was 4.63 hr and was 3.16 hr in the control group ( p = .005 ) . This represents almost 50 % better adherence in the MINT group relative to the control group . Patients in the MINT group were substantially more likely to accept CPAP treatment . CONCLUSIONS MINT is a brief , manualized , effective intervention that improves CPAP acceptance and objective adherence rates compared to st and ard care alone [22367233] OBJECTIVES To investigate the feasibility of implementing a Sleep Education Program ( SEP ) for improving sleep in adult family home ( AFH ) residents with dementia , and the relative efficacy of SEP compared with usual care control in a pilot r and omized controlled trial . PARTICIPANTS Thirty-seven AFH staff-caregivers and 47 residents with comorbid dementia and sleep disturbances . INTERVENTION SEP consisted of four training sessions with staff-caregivers to develop and implement individualized resident behavioral sleep plans . MEASUREMENTS Treatment fidelity to the SEP was assessed following the National Institutes of Health ( NIH ) Behavior Change Consortium model utilizing trainer observations and staff-caregiver reports . Resident sleep was assessed by wrist actigraphy at baseline , 1-month posttreatment , and 6-month follow-up . Caregiver reports of resident daytime sleepiness , depression , and disruptive behaviors were also collected . RESULTS Each key area of treatment fidelity ( SEP delivery , receipt , enactment ) was identified , measured , and yielded significant outcomes . Staff-caregivers learned how to identify sleep scheduling , daily activity , and environmental factors that could contribute to nocturnal disturbances and developed and implemented strategies for modifying these factors . SEP decreased the frequency and disturbance level of target resident nocturnal behaviors and improved actigraphically measured sleep percent and total sleep time over the 6-month follow-up period compared with the control condition . CONCLUSION Results suggest behavioral interventions to improve sleep are feasible to implement in adult family homes and merit further investigation as a promising intervention for use with AFH residents with dementia [24238096] Venous thromboembolism ( VTE ) is a significant cause of morbidity and mortality in hospitalized medical patients . Evidence -based guidelines exist for preventing VTE ; unfortunately , these guidelines are not always adhered to by clinicians . The aim of this study was to evaluate the acceptability , utility and clinical impact of an educational outreach visit ( EOV ) on nurses ' provision of mechanical prophylaxis to hospitalized medical patients using a prospect i ve , uncontrolled , before- and -after design . Nurses received a 1-to-1 educational session on mechanical VTE prevention by a trained nurse facilitator . The EOV intervention was design ed by a multidisciplinary group of healthcare professionals using social marketing theory . Eighty-five of the 120 eligible nurses ( 71 % ) attended the EOV . The median length of each visit was 11.5 minutes ( interquartile range [ IQR ] , 10 - 15 ) and the median time spent arranging and conducting each visit was 63 minutes ( IQR , 49 - 85 ) . Eighty-four ( 99 % ) of the 85 participants gave a verbal commitment to trial the new evidence -based mechanical VTE prevention practice s. However , there were no measurable improvements in the proportion of patients risk assessed ( -1.7 % improvement ; 95 % confidence interval [ CI ] , -7.0 to 10.3 ; P = .68 ) or provided appropriate mechanical prophylaxis ( -0.3 % improvement ; 95 % CI , -13.4 to 14 ; P = .96 ) . Research ers conclude that EOV should not be used to improve nurses ' use of mechanical VTE prevention because it has no measurable impact on clinical practice and is re source intensive , requiring 4.5 minutes of preparation for every minute spent face to face with participants . Further research into the specific mechanism of action is required to explain the variability in clinical effect seen with this intervention [26360446] BACKGROUND Mental health policy in many countries is oriented around recovery , but the evidence base for service-level recovery-promotion interventions is lacking . METHODS We did a cluster , r and omised , controlled trial in two National Health Service Trusts in Engl and . REFOCUS is a 1-year team-level intervention targeting staff behaviour to increase focus on values , preferences , strengths , and goals of patients with psychosis , and staff-patient relationships , through coaching and partnership . Between April , 2011 , and May , 2012 , community-based adult mental health teams were r and omly allocated to provide usual treatment plus REFOCUS or usual treatment alone ( control ) . Baseline and 1-year follow-up outcomes were assessed in r and omly selected patients . The primary outcome was recovery and was assessed with the Question naire about Processes of Recovery ( QPR ) . We also calculated overall service costs . We used multiple imputation to estimate missing data , and the imputation model captured clustering at the team level . Analysis was by intention to treat . This trial is registered , number IS RCT N02507940 . FINDINGS 14 teams were included in the REFOCUS group and 13 in the control group . Outcomes were assessed in 403 patients ( 88 % of the target sample ) at baseline and in 297 at 1 year . Mean QPR total scores did not differ between the two groups ( REFOCUS group 40·6 [ SD 10·1 ] vs control 40·0 [ 10·2 ] , adjusted difference 0·68 , 95 % CI -1·7 to 3·1 , p=0·58 ) . High team participation was associated with higher staff-rated scores for recovery-promotion behaviour change ( adjusted difference -0·4 , 95 % CI -0·7 to -0·2 , p=0·001 ) and patient-rated QPR interpersonal scores ( -1·6 , -2·7 to -0·5 , p=0·005 ) at follow-up than low participation . Patients treated in the REFOCUS group incurred £ 1062 ( 95 % CI -1103 to 3017 ) lower adjusted costs than those in the control group . INTERPRETATION Although the primary endpoint was negative , supporting recovery might , from the staff perspective , improve functioning and reduce needs . Implementation of REFOCUS could increase staff recovery-promotion behaviours and improve patient-rated recovery . FUNDING National Institute for Health Research [19627913] OBJECTIVE The objectives are to describe for the first time a home-based exercise intervention for frail elderly hip fracture patients and to describe the feasibility of this exercise program . DESIGN A home-based exercise program was used in a r and omized controlled trial in which the authors investigated exercise intervention versus no exercise intervention in patients after hip fracture . SETTING This program was implemented at the patients ' own home or place of residence after discharge . PARTICIPANTS Women 65 years of age or older were recruited within 15 days of hip fracture . Eligible patients were those with a nonpathologic fracture who were admitted within 72 hours of injury , had surgical repair of the hip fracture , and met medical inclusion criteria . Participants initially were r and omized to exercise groups and then assigned to exercise trainers . INTERVENTION The exercise contained strength training and aerobic components . Participants were expected to exercise 5 days per week by performing a combination of supervised and independently performed exercise sessions . Intensity and duration were increased gradually by trainers in a st and ardized way . The frequency of the supervised sessions decreased as participants became more independent . Treatment fidelity visits ensured that the intervention was being delivered as intended across trainers and across participants . MAIN OUTCOME MEASUREMENT This work describes the feasibility and challenges of administering an intensive home-based exercise program in this population of older adults . RESULTS Of those patients r and omized to exercise , 82 % were followed by a trainer and almost all advanced to higher levels in both aerobic and strength programs . Overall , participants received an average of 44 ( 78.5 % ) of the prescribed visits by the trainer . CONCLUSIONS This study showed that it was possible to engage a frail older population of post-hip fracture patients in a program of aerobic and strength training exercise with a high rate of participation [2200380] The prevalence and impact of adult asthma are substantial , and poor self-management practice s , especially failures to adhere to treatment regimens , appear to be a significant problem . Desirable characteristics of an intervention program to improve self-management were identified through needs assessment and review of existing patient education re sources . A comprehensive program was developed that integrated a workbook with one-to-one counseling and adherence-enhancing strategies . A longitudinal 1-year study compared patients receiving this self-management program with " usual care " patients receiving st and ard asthma pamphlets . Patients were r and omly assigned to conditions . Baseline score and asthma severity were statistically controlled . Self-management patients had substantially better adherence than usual care patients , as well as improved functional status , at follow-up . Hospital and emergency department visits decreased in both groups but did not differ between groups [22390448] OBJECTIVES We tested the effectiveness of a community-based , literacy-sensitive , and culturally tailored lifestyle intervention on weight loss and diabetes risk reduction among low-income , Spanish-speaking Latinos at increased diabetes risk . METHODS Three hundred twelve participants from Lawrence , Massachusetts , were r and omly assigned to lifestyle intervention care ( IC ) or usual care ( UC ) between 2004 and 2007 . The intervention was implemented by trained Spanish-speaking individuals from the community . Each participant was followed for 1 year . RESULTS The participants ' mean age was 52 years ; 59 % had less than a high school education . The 1-year retention rate was 94 % . Compared with the UC group , the IC group had a modest but significant weight reduction ( -2.5 vs 0.63 lb ; P = .04 ) and a clinical ly meaningful reduction in hemoglobin A1c ( -0.10 % vs -0.04 % ; P = .009 ) . Likewise , insulin resistance improved significantly in the IC compared with the UC group . The IC group also had greater reductions in percentage of calories from total and saturated fat . CONCLUSIONS We developed an inexpensive , culturally sensitive diabetes prevention program that result ed in weight loss , improved HbA1c , and improved insulin resistance in a high-risk Latino population [9694180] AIM Our objective was to evaluate the effect of training in a patient-centred intervention for GPs and practice nurses on outcomes for patients with Type II diabetes . METHODS We carried out a r and omized controlled trial within general practice s as the basis for r and omization and a before- and -after design for measures of patient outcome . A parallel process study examined the use of the method by professionals . The study was carried out in 29 general practice s in South Glamorgan who had participated for at least 2 years in a local scheme of audit and CME in relation to Type II diabetes care . The subjects were 252 Type II diabetic patients recruited by 15 experimental and 14 control practice s. The main outcome measures were changes in glycosylated haemoglobin , patient satisfaction with care and treatment , functional health status and professional ability to apply the intervention . RESULTS Professionals adopted the innovative method with enthusiasm , but after 2 years only 19 % continued to apply the method systematic ally . The trial was , therefore , unable to demonstrate significant biochemical or functional improvements . This highlights the need to underst and the factors associated with professional uptake and subsequent ability to sustain changes in behaviour . CONCLUSIONS The efficacy of this behavioural intervention remains unproved , despite its acceptability to professional staff . Detailed and prolonged development and testing of behavioural interventions is an essential first step before embarking on r and omized controlled trials which involve complex behavioural changes in professionals or patients [24444847] Common mental disorders ( CMDs ) are a major cause of sickness absence . Twenty to 30 % of the workers who return to work after sickness absence due to CMDs experience recurrent sickness absence . We developed the Stimulating Healthy participation And Relapse Prevention (SHARP)-at work intervention , a problem solving intervention delivered by occupational physicians ( OPs ) , to prevent recurrent sickness absence in this worker population in The Netherl and s. A process evaluation was conducted alongside a cluster-r and omised controlled trial to ( 1 ) evaluate whether the SHARP-at work intervention was implemented according to the protocol and differed from treatment in the control group , and ( 2 ) to investigate the relationship between the key elements of the intervention and the effect outcome ( i.e. recurrent sickness absence ) . We collected process data for both the intervention and control group on recruitment , reach , dose delivered , dose received , fidelity , context and satisfaction . Data on recurrent sickness absence was collected through the registry system of the collaborating occupational health service . The study was performed in the Netherl and s , and between 2010 and 2012 , 154 OPs and 158 participants participated . Compared to the control group , participants in the intervention group more frequently had two or more consultations with the OP ( odds ratio [ OR ] = 3.2 , 95 % confidence interval [ CI ] = 1.2 - 8.8 ) and completed more assignments ( OR = 33.8 , 95 % CI = 10.4 - 109.5 ) as recommended in the intervention protocol . OPs and participants were satisfied with the intervention and rated it as applicable . Several individual intervention components were linked to the effect outcome . The process evaluation showed that the SHARP-at work intervention was conducted according to the protocol for the majority of the participants and well-received by OPs and participants . Furthermore , the intervention differed from treatment in the control group . Overall , the results provide support for implementing the intervention in practice [11493040] BACKGROUND We report process data on the feasibility of delivering a clinical preventive nutrition intervention that was effective in increasing participants ' consumption of fruits and vegetables . We also examine relationships between process variables and study outcomes . METHODS We r and omly assigned six practice sites in a managed care organization to a dietary intervention or control condition . We invited adults 18 years of age or older scheduled for routine health visits within the subsequent 2 months to participate . Of the 566 patients we contacted from the intervention sites , 230 ( 41 % ) enrolled . From the control sites , we contacted 617 , and 274 ( 44 % ) enrolled . Intervention participants received a tailored letter providing feedback on their consumption of target foods together with recommendations for improvement , stage-matched nutrition education booklets , a diet-health endorsement from their primary care providers ( PCPs ) , and two motivational counseling telephone calls . Of enrollees , 195 ( 85 % ) in the intervention group and 252 ( 92 % ) in the control group returned the final survey 3 months later . RESULTS Seventy-one percent of both participants and PCPs reported that the PCPs had discussed the relationship between diet and health at their visit . Fifty-seven percent of participants and 62 % of PCPs reported that they discussed the complete diet-health endorsement , which included : ( 1 ) acknowledgment of the relationship between diet and health and ( 2 ) tailored study recommendations . The inclusion of both parts of the diet-health endorsement , but not the length of time spent , appeared to correlate with healthful outcomes . CONCLUSIONS These process data suggest that the brief PCP diet-health endorsement contributed to the intervention effect on fruits and vegetables [21704360] BACKGROUND Improving inhaled corticosteroid ( ICS ) adherence should improve asthma outcomes . OBJECTIVE In a r and omized controlled trial we tested whether an individualized problem-solving ( PS ) intervention improves ICS adherence and asthma outcomes . METHODS Adults with moderate or severe asthma from clinics serving urban neighborhoods were r and omized to PS ( ie , defining specific barriers to adherence , proposing/weighing solutions , trying the best , assessing , and revising ) or st and ard asthma education ( AE ) for 3 months and then observed for 3 months . Adherence was monitored electronically . Outcomes included the following : asthma control , FEV(1 ) , asthma-related quality of life , emergency department ( ED ) visits , and hospitalizations . In an intention-to-treat- analysis longitudinal models using r and om effects and regression were used . RESULTS Three hundred thirty-three adults were r and omized : 49 ± 14 years of age , 72 % female , 68 % African American , 7 % Latino , mean FEV(1 ) of 66 % ± 19 % , and 103 ( 31 % ) with hospitalizations and 172 ( 52 % ) with ED visits for asthma in the prior year . There was no difference between groups in overall change in any outcome ( P > .20 ) . Mean adherence ( 61 % ± 27 % ) decreased significantly ( P = .0004 ) over time by 14 % and 10 % in the AE and PS groups , respectively . Asthma control improved overall by 15 % ( P = .002 ) . In both groups FEV(1 ) and quality of life improved by 6 % ( P = .01 ) and 18 % ( P < .0001 ) , respectively . However , the improvement in FEV(1 ) only occurred during monitoring but not subsequently after r and omization . Rates of ED visits and hospitalizations did not significantly decrease over the study period . CONCLUSION PS was not better than AE in improving adherence or asthma outcomes . However , monitoring ICS use with provision of medications and attention , which was imposed on both groups , was associated with improvement in FEV(1 ) and asthma control [23483412] This study evaluated the effectiveness of the Smoking Cessation and Reduction in Pregnancy Treatment ( SCRIPT ) Program selected by the West Virginia — Right From The Start Project for state-wide dissemination . A process evaluation documented the fidelity of SCRIPT delivery by Design ated Care Coordinators ( DCC ) , licensed nurses and social workers who provide home-based case management to Medicaid-eligible clients in all 55 counties . We implemented a quasi-experimental , non-r and omized , matched Comparison ( C ) Group design . The SCRIPT Experimental E Group ( N = 259 ) were all clients in 2009–2010 that wanted to quit , provided a screening carbon monoxide ( CO ) , and received a SCRIPT home visit . The ( C ) Group was derived from all clients in 2006–2007 who had the same CO assessment s as E Group clients and reported receiving cessation counseling . We stratified the baseline CO of E Group clients into 10 strata , and r and omly selected the same number of ( C ) Group clients ( N = 259 ) from each matched strata to evaluate the effectiveness of the SCRIPT Program . There were no significant baseline differences in the E and ( C ) Group . A Process Evaluation documented a significant increase in the fidelity of DCC delivery of SCRIPT Program procedures : from 63 % in 2006 to 74 % in 2010 . Significant increases were documented in the E Group cessation rate ( + 9.3 % ) and significant reduction rate ( + 4.5 % ) , a ≥50 % reduction from a baseline CO . Perinatal health case management staff can deliver the SCRIPT Program , and Medicaid-supported clients can change smoking behavior , even very late in pregnancy . When multiple biases were analyzed , we concluded the SCRIPT Dissemination Project was the most plausible reason for the significant changes in behavior [12350190] CONTEXT It is not known whether patient outcomes are enhanced by effective pharmacist-patient interactions . OBJECTIVE To assess the effectiveness of a pharmaceutical care program for patients with asthma or chronic obstructive pulmonary disease ( COPD ) . DESIGN , SETTING , AND PARTICIPANTS R and omized controlled trial conducted at 36 community drugstores in Indianapolis , Ind. We enrolled 1113 participants with active COPD or asthma from July 1998 to December 1999 . Outcomes were assessed in 947 ( 85.1 % ) participants at 6 months and 898 ( 80.7 % ) at 12 months . INTERVENTIONS The pharmaceutical care program ( n = 447 ) provided pharmacists with recent patient-specific clinical data ( peak expiratory flow rates [ PEFRs ] , emergency department [ ED ] visits , hospitalizations , and medication compliance ) , training , customized patient educational material s , and re sources to facilitate program implementation . The PEFR monitoring control group ( n = 363 ) received a peak flow meter , instructions about its use , and monthly calls to elicit PEFRs . However , PEFR data were not provided to the pharmacist . Patients in the usual care group ( n = 303 ) received neither peak flow meters nor instructions in their use ; during monthly telephone interviews , PEFR rates were not elicited . Pharmacists in both control groups had a training session but received no components of the pharmaceutical care intervention . MAIN OUTCOME MEASURES Peak expiratory flow rates , breathing-related ED or hospital visits , health-related quality of life ( HRQOL ) , medication compliance , and patient satisfaction . RESULTS At 12 months , patients receiving pharmaceutical care had significantly higher peak flow rates than the usual care group ( P = .02 ) but not than PEFR monitoring controls ( P = .28 ) . There were no significant between-group differences in medication compliance or HRQOL . Asthma patients receiving pharmaceutical care had significantly more breathing-related ED or hospital visits than the usual care group ( odds ratio , 2.16 ; 95 % confidence interval , 1.76 - 2.63 ; P<.001 ) . Patients receiving pharmaceutical care were more satisfied with their pharmacist than the usual care group ( P = .03 ) and the PEFR monitoring group ( P = .001 ) and were more satisfied with their health care than the usual care group at 6 months only ( P = .01 ) . Despite ample opportunities to implement the program , pharmacists accessed patient-specific data only about half of the time and documented actions about half of the time that records were accessed . CONCLUSIONS This pharmaceutical care program increased patients ' PEFRs compared with usual care but provided little benefit compared with peak flow monitoring alone . Pharmaceutical care increased patient satisfaction but also increased the amount of breathing-related medical care sought [10987780] R and omised controlled trials are widely accepted as the most reliable method of determining effectiveness , but most trials have evaluated the effects of a single intervention such as a drug . Recognition is increasing that other , non-pharmacological interventions should also be rigorously evaluated.1 - 3 This paper examines the design and execution of research required to address the additional problems result ing from evaluation of complex interventions —that is , those “ made up of various interconnecting parts.”4 The issues dealt with are discussed in a longer Medical Research Council paper ( www.mrc.ac.uk/complex_packages.html ) . We focus on r and omised trials but believe that this approach could be adapted to other design s when they are more appropriate . # # # # Summary points Complex interventions are those that include several components The evaluation of complex interventions is difficult because of problems of developing , identifying , documenting , and reproducing the intervention A phased approach to the development and evaluation of complex interventions is proposed to help research ers define clearly where they are in the research process Evaluation of complex interventions requires use of qualitative and quantitative evidence There are specific difficulties in defining , developing , documenting , and reproducing complex interventions that are subject to more variation than a drug . A typical example would be the design of a trial to evaluate the benefits of specialist stroke units . Such a trial would have to consider the expertise of various health professionals as well as investigations , drugs , treatment guidelines , and arrangements for discharge and follow up . Stroke units may also vary in terms of organisation , management , and skill mix . The active components of the stroke unit may be difficult to specify , making it difficult to replicate the intervention . The box gives other examples of complex interventions . # # # # Examples of complex interventions Service delivery and organisation : Stroke units Hospital at home Interventions directed at health professionals ' behaviour : Strategies for implementing guidelines Computerised decision support Community interventions : Community [25727114] OBJECTIVE The aim of this study was to test whether gender moderates intervention effects in the Coordinated Anxiety Learning and Management ( CALM ) intervention , a 12-month , r and omized controlled trial of a collaborative care intervention for anxiety disorders ( panic disorder , generalized anxiety disorder , posttraumatic stress disorder , and social anxiety disorder ) in 17 primary care clinics in California , Washington , and Arkansas . METHODS Participants ( N=1,004 ) completed measures of symptoms ( Brief Symptom Inventory [ BSI ] ) and functioning ( mental and physical health components of the 12-Item Short Form [ MCS and PCS ] and Healthy Days , Restricted Activity Days Scale ) at baseline , six , 12 , and 18 months . Data on dose , engagement , and beliefs about psychotherapy were collected for patients in the collaborative care group . RESULTS Gender moderated the relationship between treatment and its outcome on the BSI , MCS , and Healthy Days measures but not on the PCS . Women who received collaborative care showed clinical improvements on the BSI , MHC , and Healthy Days that were significantly different from outcomes for women in usual care . There were no differences for men in collaborative care compared with usual care on any measures . In the intervention group , women compared with men attended more sessions of psychotherapy , completed more modules of therapy , expressed more commitment , and viewed psychotherapy as more helpful . CONCLUSIONS These findings contribute to the broader literature on treatment heterogeneity , in particular the influence of gender , and may inform personalized care for people seeking anxiety treatment in primary care setting [11194695] Objectives . Physicians acknowledge the need to advise their patients about dietary habits , but they may not have the training or tools to do this efficiently . In the context of a r and omized trial , we investigated the feasibility of enlisting physicians to implement a dietary intervention in the primary care setting . Methods . Physicians from 14 primary care practice s were assigned via r and omization to introduce a self-help booklet to promote dietary change at routine appointments . Delivery of the booklet was recorded by these intervention physicians at the clinic appointment ; intervention participants were asked 3 months later in a telephone interview about whether they received and used the booklet . Results . According to physician documentation , 95 % of intervention participants who kept an appointment ( n = 935 ) received the booklet ; among participants completing a 3-month interview ( n = 890 ) , 96 % reported the same . However , only about 50 % of participants reported receiving the booklet from their physician ; the remainder received the booklet from other clinic staff . Overall , 93 % reported reading at least part of the booklet . Use of the booklet varied little whether it was delivered by a physician or staff person , but it was more likely to be read as time spent discussing the booklet increased . Conclusions . Physician cooperation and evidence of intervention effectiveness support the use of primary care for the delivery of interventions to change diet ; training the entire health team and repeating dietary advice at subsequent visits may improve the success of such interventions [3270575] Objective To evaluate the effectiveness and costs of a multifaceted flexible educational programme aim ed at reducing antibiotic dispensing at the practice level in primary care . Design R and omised controlled trial with general practice s as the unit of r and omisation and analysis . Clinicians and research ers were blinded to group allocation until after r and omisation . Setting 68 general practice s with about 480 000 patients in Wales , United Kingdom . Participants 34 practice s were r and omised to receive the educational programme and 34 practice s to be controls . 139 clinicians from the intervention practice s and 124 from control practice s had agreed to participate before r and omisation . Practice level data covering all the clinicians in the 68 practice s were analysed . Interventions Intervention practice s followed the Stemming the Tide of Antibiotic Resistance ( STAR ) educational programme , which included a practice based seminar reflecting on the practice s ’ own dispensing and resistance data , online educational elements , and practising consulting skills in routine care . Control practice s provided usual care . Main outcome measures Total numbers of oral antibiotic items dispensed for all causes per 1000 practice patients in the year after the intervention , adjusted for the previous year ’s dispensing . Secondary outcomes included reconsultations , admissions to hospital for selected causes , and costs . Results The rate of oral antibiotic dispensing ( items per 1000 registered patients ) decreased by 14.1 in the intervention group but increased by 12.1 in the control group , a net difference of 26.1 . After adjustment for baseline dispensing rate , this amounted to a 4.2 % ( 95 % confidence interval 0.6 % to 7.7 % ) reduction in total oral antibiotic dispensing for the year in the intervention group relative to the control group ( P=0.02 ) . Reductions were found for all classes of antibiotics other than penicillinase-resistant penicillins but were largest and significant individually for phenoxymethylpenicillins ( penicillin V ) ( 7.3 % , 0.4 % to 13.7 % ) and macrolides ( 7.7 % , 1.1 % to 13.8 % ) . There were no significant differences between intervention and control practice s in the number of admissions to hospital or in reconsultations for a respiratory tract infection within seven days of an index consultation . The mean cost of the programme was £ 2923 ( € 3491 , $ 4572 ) per practice ( SD £ 1187 ) . There was a 5.5 % reduction in the cost of dispensed antibiotics in the intervention group compared with the control group ( −0.4 % to 11.4 % ) , equivalent to a reduction of about £ 830 a year for an average intervention practice . Conclusion The STAR educational programme led to reductions in all cause oral antibiotic dispensing over the subsequent year with no significant change in admissions to hospital , reconsultations , or costs . Trial registration IS RCT No 63355948

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### Context: [2936444] Background Both low back pain ( LBP ) and neck pain ( NP ) are major occupational health problems . In the workplace , participatory ergonomics ( PE ) is frequently used on musculoskeletal disorders . However , evidence on the effectiveness of PE to prevent LBP and NP obtained from r and omised controlled trials ( RCTs ) is scarce . This study evaluates the process of the Stay@Work participatory ergonomics programme , including the perceived implementation of the prioritised ergonomic measures . Methods This cluster- RCT was conducted at the departments of four Dutch companies ( a railway transportation company , an airline company , a steel company , and a university including its university medical hospital ) . Directly after the r and omisation outcome , intervention departments formed a working group that followed the steps of PE during a six-hour working group meeting . Guided by an ergonomist , working groups identified and prioritised risk factors for LBP and NP , and composed and prioritised ergonomic measures . Within three months after the meeting , working groups had to implement the prioritised ergonomic measures at their department . Data on various process components ( recruitment , reach , fidelity , satisfaction , and implementation components , i.e. , dose delivered and dose received ) were collected and analysed on two levels : department ( i.e. , working group members from intervention departments ) and participant ( i.e. , workers from intervention departments ) . Results A total of 19 intervention departments ( n = 10 with mental workloads , n = 1 with a light physical workload , n = 4 departments with physical and mental workloads , and n = 4 with heavy physical workloads ) were recruited for participation , and the reach among working group members who participated was high ( 87 % ) . Fidelity and satisfaction towards the PE programme rated by the working group members was good ( 7.3 or higher ) . The same was found for the Stay@Work ergocoach training ( 7.5 or higher ) . In total , 66 ergonomic measures were prioritised by the working groups . Altogether , 34 % of all prioritised ergonomic measures were perceived as implemented ( dose delivered ) , while the workers at the intervention departments perceived 26 % as implemented ( dose received ) . Conclusions PE can be a successful method to develop and to prioritise ergonomic measures to prevent LBP and NP . Despite the positive rating of the PE programme the implementation of the prioritised ergonomic measures was lower than expected . Trial registration Current Controlled Trials IS RCT [18653261] AIMS quantitative description of adherence to motivational interviewing ( MI ) in smoking cessation sessions ; and examination of the relationships between client characteristics and adherence to MI , and between adherence to MI and future smoking status . METHODS 84 sessions were conducted during a r and omised controlled trial to test the effectiveness of a population -based smoking intervention in women during the postpartum period . Demographic and behaviour-related variables were included in a logistic regression to predict adherence to MI . MEASUREMENTS adherence was measured using the MI Treatment Integrity Scale . FINDINGS 38.1 % of sessions showed good adherence to MI . Receiving a good MI session was not related to any demographic or behavioural variables . The relationship between adherence and intervention outcome after six months was not statistically significant ( chi(2)=0.355 , p=0.551 ) . CONCLUSIONS the smoking cessation sessions examined in this study failed to adhere to MI . There was no relationship between adherence to MI and behavioural outcome six months after the intervention , indicating that women who smoke post partum may be a high-risk group for whom specific smoking cessation interventions need to be developed [4037760] Background Dementia affects 35 million people worldwide and is currently incurable . Many cases may be preventable because regular participation in physical , mental and social leisure activities during middle age is associated with up to 47 % dementia risk reduction . However , the majority of middle-aged adults are not active enough . MCI is therefore a clear target for activity interventions aim ed at reducing dementia risk . An active lifestyle during middle age reduces dementia risk but it remains to be determined if increased activity reduces dementia risk when MCI is already evident . Before this can be investigated conclusively , complex multimodal activity programmes are required that ( 1 ) combine multiple health promoting activities , ( 2 ) engage people with MCI , and ( 3 ) result in sufficient adherence rates . Methods We design ed the ThinkingFit programme to engage people with MCI in a complex intervention comprised of three activity components : physical activity , group-based cognitive stimulation ( GCST ) and individual cognitive stimulation ( ICST ) . Engagement and adherence was promoted by applying specific psychological techniques to enhance behavioural flexibility in an early pre-phase and during the course of the intervention . To pilot the intervention , participants served as their own controls during a 6- to 12-week run-in period , which was followed by 12 weeks of activity intervention . Results Out of 212 MCI patients screened , 163 were eligible , 70 consented and 67 completed the intervention ( mean age 74 years ) . Activity adherence rates were high : physical activity = 71 % ; GCST = 83 % ; ICST = 67 % . Significant treatment effects ( p < .05 ) were evident on physical health outcomes ( decreased BMI and systolic blood pressure , [ pre/post values of 26.3/25.9 kg/m2 and 145/136 mmHg respectively ] ) , fitness ( decreased resting and recovery heart rate [ 68/65 bpm and 75/69 bpm ] ) , and cognition ( improved working memory [ 5.3/6.3 items ] ) . Conclusions We found satisfactory recruitment , retention and engagement rates , coupled with significant treatment effects in elderly MCI patients . It appears feasible to conduct r and omized controlled trials of the dementia prevention potential of complex multimodal activity programmes like ThinkingFit . Trial registration Clinical Trials.gov registration nr : NCT01603862 ; date : 17/5/2012 [19487232] A recent special issue of the Journal of Pediatric Psychology included papers focused on evidence -based assessment across several broad domains of assessment in pediatric psychology ( e.g. , adherence , pediatric pain , and quality of life ) . In one of these papers , Holmbeck et al. ( 2008 ) review ed strengths and limitations of existing measures of psychosocial adjustment and psychopathology , concluding that many measures lacked supporting psychometric data ( e.g. , basic indices of reliability and validity ) that would permit a complete evaluation of these measures . Given that measure development and validation papers are frequently published in JPP ( Brown , 2007 ) , it is important that we attend to guiding psychometric principles when developing and disseminating data on new measures to be employed with pediatric population s ( Nunnally & Bernstein , 1994 ) . Thus , the purpose of this paper is to present and describe a checklist for authors to use when su bmi tting measure development papers to JPP . This checklist is included in the Appendix and is also included at the following link on the JPP website : http://www.oxfordjournals.org/our_journals/jpepsy/for _ authors /measure%20development%20checklist.pdf Findings presented by Holmbeck et al. ( 2008 ) indicated that 34 of the 37 measures review ed met pre-established “ evidence -based assessment ” ( EBA ) criteria for “ well-established ” measures ( Cohen et al. , 2008 ) . To be considered “ well-established , ” a measure had to have been presented in at least two peer- review ed journal articles by different investigatory teams , have demonstrated adequate levels of reliability and validity , and be accompanied by supporting information ( e.g. , a measure manual ) . Although most measures that we review ed met these criteria , we also found that most of the 34 “ well-established ” measures were hampered by at least one major psychometric flaw and /or lacked important psychometric data . We concluded that a more fine-grained EBA classification system is needed . One important distinction in this literature relates to differences between empirically supported assessment and evidence -based assessment . This type of distinction was first discussed in the literature on clinical interventions ( e.g. , Spring , 2007 ) . An empirically supported intervention is one that has demonstrated efficacy in r and omized clinical trials or clinic-based effectiveness trials . An evidence -based intervention has empirical support in the manner just described , but also “ integrates research evidence , clinical expertise , and patient preferences and characteristics … empirically-supported treatments ( ESTs ) are an important component of evidence -based practice ( EBP ) , but EBP can not be reduced to ESTs ” ( Spring , 2007 , p.611 ) . Applying these terms to the field of assessment and measure development efforts , an empirically supported assessment measure would be one that demonstrates satisfactory psychometric characteristics , broadly defined . To be evidence based , the measure should also demonstrate utility in clinical setting s , be useful in making diagnoses , be sensitive to treatment effects , and /or provide incremental validity above and beyond other similar measures . Although papers in the special issue of JPP frequently referred to “ evidence -based assessment ” ( Cohen et al. , 2009 ) , the articles included in the issue tended to evaluate the degree to which the measures were empirically-supported rather than evidence based . To be “ evidence -based , ” our review s would have needed to integrate an evaluation of clinical utility , diagnostic utility , and treatment sensitivity with the empirical psychometric data presented in each review . As noted , the published review s were more likely to focus on the latter rather than on the former . As suggested by Mash and Hunsley ( 2005 ) , detailed EBA profiles would provide a complete evaluation of evidence across each of several psychometric and clinical ly relevant dimensions , including : ( a ) internal consistency , ( b ) test – retest reliability , ( c ) the availability of normative data , ( d ) content validity , ( e ) construct validity , ( f ) convergent and discriminant validity , ( g ) criterion-related validity , ( h ) incremental validity , ( i ) clinical utility , ( j ) diagnostic utility , and ( k ) treatment sensitivity . The focus on incremental validity and clinical and diagnostic utility raises the bar from a focus on “ empirical support ” ( i.e. , where the focus would tend to be primarily on psychometric data ) to a broad focus on the “ evidence base ” for a measure . In developing the checklist that is the focus of this article , we attempted to provide a list of criteria relevant to establishing the evidence base ( and not just empirical support ) for a measure . In addition to shifting the focus from providing “ empirical support ” for a measure to providing an “ evidence base ” for our instruments , a checklist for measure development papers would permit JPP review ers to evaluate such papers in the same way that review ers of r and omized clinical trials make use of the Consoli date d St and ards of Reporting Trials ( CONSORT ) checklist and flowchart ( Altman et al. , 2001 ) . The CONSORT checklist contains reporting st and ards with respect to method ological features of and the manner in which results are reported in clinical trials . Moreover , authors are required to provide a flowchart that describes details of sample recruitment and attrition during the course of the study . Thus , a checklist for measure development papers would serve two interrelated purpose s : ( a ) it would provide guidance to authors as they embark on the measure development process and would provide a list of criteria authors can use as they develop an evidence base for their measures , and ( b ) it would begin to st and ardize the manner in which psychometric and other assessment -related data are presented in measure development papers for this journal . Before providing a more detailed overview of the checklist , it is important to note that this checklist is rather exhaustive ( see Appendix ) . As such , it represents what would “ ideally ” be expected for a measure development or validation manuscript rather than minimal criteria for such papers . No one paper can provide a complete evaluation of all important psychometric and clinical ly relevant dimensions that will establish once- and -for-all the evidence base for a measure . Instrument refinement is part of a measure development process that gradually builds an evidence base for a scale ( see Smith & McCarthy , 1995 , for suggestions on measure refinement ) . Indeed , the validation of any measure is a cumulative process that occurs across many different types of research studies and across research programs [11761203] BACKGROUND There is still only limited underst and ing of whether and why interventions to facilitate the implementation of guidelines for improving primary care are successful . It is therefore important to look inside the ' black box ' of the intervention , to ascertain which elements work well or less well . AIM To assess the associations of key elements of a nationwide multifaceted prevention programme with the successful implementation of cervical screening guidelines in general practice . DESIGN OF STUDY A nationwide prospect i ve cohort study . SETTING A r and om sample of one-third of all 4,758 general practice s in The Netherl and s ( n = 1,586 ) . METHOD General practitioners ( GPs ) in The Netherl and s were exposed to a two- and -a-half-year nationwide multifaceted prevention programme to improve the adherence to national guidelines for cervical cancer screening . Adherence to guidelines at baseline and after the intervention and actual exposure to programme elements were assessed in the sample using self-administered question naires . RESULTS Both baseline and post-measurement question naires were returned by 988 practice s ( response rate = 62 % ) . No major differences in baseline practice characteristics between study population , non-responders , and all Netherl and s practice s were observed . After the intervention all practice s improved markedly ( P<0.001 ) in their incorporation of nine out of 10 guideline indicators for effective cervical screening into practice . The most important elements for successful implementation were : specific software modules ( odds ratios and 95 % confidence intervalsfor all nine indicators ranged from OR = 1.85 [ 95 % CI = 1.24 - 2.77 ] to OR = 10.2 [ 95 % CI = 7.58 - 14.1 ] ) ; two or more ' practice visits ' by outreach visitors ( ORs and 95 % CIs for six indicators ranged from OR = 1.46 [ 95 % CI= 1.01 - 2.12 ] to OR = 2.35 [ 95 % CI = 1.63 - 3.38 ] ) ; and an educational programme for practice assistants ( ORs and 95 % CIs for four indicators ranged from OR = 1.57 [ 95 % CI = 1.00 - 1.92 ] to OR = 1.90 [ 95 % CI = 1.25 - 2.88 ] ) . CONCLUSION A multifaceted programme targeting GPs , including facilitating software modules , outreach visits , and educational sessions for PAs , contributes to the successful implementation of national guidelines for cervical screening [24469237] There is often wide variability in the reported effects of complex behavioral interventions . Effectiveness can vary across studies , sites , and providers . A factor that has been insufficiently considered is the fidelity of the behavioral treatment that was provided . Low quality practice could be likened to partial doses of a vaccine or antibiotic : the right idea but insufficient strength . Using motivational interviewing ( MI ) as an example , the authors describe three quality conditions that should be present for a study to be regarded as a trial of a complex behavioral intervention : ( 1 ) The treatment should clearly contain the components that are theoretically or empirically related to its efficacy ; ( 2 ) providers should be trained to an adequate and specified criterion of proficiency before treating trial patients ; and ( 3 ) the fidelity of treatment should be documented by reliable coding of practice throughout the study and reported in a manner that permits comparison with skill levels in other trials . The authors also discuss bona fide intervention failures despite strong clinical trial methodology , offering recommendations for future outcome research [24571932] BACKGROUND More evidence is needed on the potential role of ' booster ' interventions in the maintenance of increases in physical activity levels after a brief intervention in relatively sedentary population s. OBJECTIVES To determine whether objective ly measured physical activity , 6 months after a brief intervention , is increased in those receiving physical activity ' booster ' consultations delivered in a motivational interviewing ( MI ) style , either face to face or by telephone . DESIGN Three-arm , parallel-group , pragmatic , superiority r and omised controlled trial with nested qualitative research fidelity and geographical information systems and health economic sub studies . Treatment allocation was carried out using a web-based simple r and omisation procedure with equal allocation probabilities . Principal investigators and study statisticians were blinded to treatment allocation until after the final analysis only . SETTING Deprived areas of Sheffield , UK . PARTICIPANTS Previously sedentary people , aged 40 - 64 years , living in deprived areas of Sheffield , UK , who had increased their physical activity levels after receiving a brief intervention . INTERVENTIONS Participants were r and omised to the control group ( no further intervention ) or to two sessions of MI , either face to face ( ' full booster ' ) or by telephone ( ' mini booster ' ) . Sessions were delivered 1 and 2 months post-r and omisation . MAIN OUTCOME MEASURES The primary outcome was total energy expenditure ( TEE ) per day in kcal from 7-day accelerometry , measured using an Actiheart device ( CamNtech Ltd , Cambridge , UK ) . Independent evaluation of practitioner competence was carried out using the Motivational Interviewing Treatment Integrity assessment . An estimate of the per-participant intervention costs , re source use data collected by question naire and health-related quality of life data were analysed to produce a range of economic models from a short-term NHS perspective . An additional series of models were developed that used TEE values to estimate the long-term cost-effectiveness . RESULTS In total , 282 people were r and omised ( control = 96 ; mini booster = 92 , full booster = 94 ) of whom 160 had a minimum of 4 out of 7 days ' accelerometry data at 3 months ( control = 61 , mini booster = 47 , full booster = 52 ) . The mean difference in TEE per day between baseline and 3 months favoured the control arm over the combined booster arm but this was not statistically significant ( -39 kcal , 95 % confidence interval -173 to 95 , p = 0.57 ) . The autonomy-enabled MI communication style was generally acceptable , although some participants wanted a more paternalistic approach and most expressed enthusiasm for monitoring and feedback components of the intervention and research . Full boosters were more popular than mini boosters . Practitioners achieved and maintained a consistent level of MI competence . Walking distance to the nearest municipal green space or leisure facilities was not associated with physical activity levels . Two alternative modelling approaches both suggested that neither intervention was likely to be cost-effective . CONCLUSIONS Although some individuals do find a community-based , brief MI ' booster ' intervention supportive , the low levels of recruitment and retention and the lack of impact on objective ly measured physical activity levels in those with adequate outcome data suggest that it is unlikely to represent a clinical ly effective or cost-effective intervention for the maintenance of recently acquired physical activity increases in deprived middle-aged urban population s. Future research with middle-aged and relatively deprived population s should explore interventions to promote physical activity that require less proactive engagement from individuals , including environmental interventions . STUDY REGISTRATION Current Controlled Trials IS RCT N56495859 , Clinical Trials.gov NCT00836459 . FUNDING This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol . 18 , No. 13 . See the NIHR Journals Library website for further project information [1475568] Background Self-management programs for patients with heart failure can reduce hospitalizations and mortality . However , no programs have analyzed their usefulness for patients with low literacy . We compared the efficacy of a heart failure self-management program design ed for patients with low literacy versus usual care . Methods We performed a 12-month r and omized controlled trial . From November 2001 to April 2003 , we enrolled participants aged 30–80 , who had heart failure and took furosemide . Intervention patients received education on self-care emphasizing daily weight measurement , diuretic dose self-adjustment , and symptom recognition and response . Picture-based educational material s , a digital scale , and scheduled telephone follow-up were provided to reinforce adherence . Control patients received a generic heart failure brochure and usual care . Primary outcomes were combined hospitalization or death , and heart failure-related quality of life . Results 123 patients ( 64 control , 59 intervention ) participated ; 41 % had inadequate literacy . Patients in the intervention group had a lower rate of hospitalization or death ( crude incidence rate ratio ( IRR ) = 0.69 ; CI 0.4 , 1.2 ; adjusted IRR = 0.53 ; CI 0.32 , 0.89 ) . This difference was larger for patients with low literacy ( IRR = 0.39 ; CI 0.16 , 0.91 ) than for higher literacy ( IRR = 0.56 ; CI 0.3 , 1.04 ) , but the interaction was not statistically significant . At 12 months , more patients in the intervention group reported monitoring weights daily ( 79 % vs. 29 % , p < 0.0001 ) . After adjusting for baseline demographic and treatment differences , we found no difference in heart failure-related quality of life at 12 months ( difference = -2 ; CI -5 , + 9 ) . Conclusion A primary care-based heart failure self-management program design ed for patients with low literacy reduces the risk of hospitalizations or death [25159905] Developing more effective behavioural interventions requires an underst and ing of the mechanisms of behaviour change , and methods to rigorously test their theoretical basis . The delivery and theoretical basis of an intervention protocol were assessed in ProActive , a UK trial of an intervention to increase the physical activity of those at risk of Type 2 diabetes ( N = 365 ) . In 108 intervention sessions , behaviours of facilitators were mapped to four theories that informed intervention development and behaviours of participants were mapped to 17 theoretical components of these four theories . The theory base of the intervention specified by the protocol was different than that delivered by facilitators , and that received by participants . Of the intervention techniques delivered , 25 % were associated with theory of planned behaviour ( TPB ) , 42 % with self-regulation theory ( SRT ) , 24 % with operant learning theory ( OLT ) and 9 % with relapse prevention theory ( RPT ) . The theoretical classification of participant talk showed a different pattern , with twice the proportion associated with OLT ( 48 % ) , 21 % associated with TPB , 31 % with SRT and no talk associated with RPT . This study demonstrates one approach to assessing the extent to which the theories used to guide intervention development account for any changes observed [3656395] Abstract Objective . To study the effectiveness of a comprehensive diabetes programme in general practice that integrates patient-centred lifestyle counselling into structured diabetes care . Design and setting . Cluster r and omised trial in general practice s. Intervention . Nurse-led structured diabetes care with a protocol , record keeping , reminders , and feedback , plus training in motivational interviewing and agenda setting . Subjects . Primary care nurses in 58 general practice s and their 940 type 2 diabetes patients with an HbA1c concentration above 7 % , and a body mass index ( BMI ) above 25 kg/m2 . Main outcome measures . HbA1c , diet , and physical activity ( medical records and patient question naires ) . Results . Multilevel linear and logistic regression analyses adjusted for baseline outcomes showed that despite active nurse participation in the intervention , the comprehensive programme was no more effective than usual care after 14 months , as shown by HbA1c levels ( difference between groups = 0.13 ; CI 20.8–0.35 ) and diet ( fat ( difference between groups = 0.19 ; CI 20.82–1.21 ) ; vegetables ( difference between groups = 0.10 ; CI-0.21–0.41 ) ; fruit ( difference between groups = 20.02 ; CI 20.26–0.22 ) ) , and physical activity ( difference between groups = 21.15 ; CI 212.26–9.97 ) , or any of the other measures of clinical parameters , patient 's readiness to change , or quality of life . Conclusion . A comprehensive programme that integrated lifestyle counselling based on motivational interviewing principles integrated into structured diabetes care did not alter HbA1c or the lifestyle related to diet and physical activity . We thus question the impact of motivational interviewing in terms of its ability to improve routine diabetes care in general practice [23567399] OBJECTIVES To assess feasibility and to conduct a preliminary evaluation of outcomes following Peaceful Mind , a cognitive-behavioral therapy-based intervention for anxiety in dementia , relative to usual care . DESIGN Pilot r and omized controlled trial including assessment s at baseline and 3 and 6 months . SETTING Houston , TX . PARTICIPANTS Thirty-two out patients diagnosed with mild ( 47 % ) or moderate ( 53 % ) dementia receiving care through outpatient clinics at the Veterans Affairs medical center , Baylor College of Medicine , Harris County Hospital District , and community day centers for dementia , and their collaterals , who spent at least 8 hours a week with them . INTERVENTION Peaceful Mind included up to 12 weekly in-home sessions ( mean : 8.7 , SD : 2.27 ) during the initial 3 months and up to eight brief telephone sessions ( mean : 5.4 , SD : 3.17 ) during months 3 - 6 , involving self-monitoring for anxiety , deep breathing , and optional skills ( coping self-statements , behavioral activation , and sleep management ) . Patients learned skills , and collaterals served as coaches . In usual care , patients received diagnostic feedback , and providers were informed of inclusion status . MEASUREMENTS Neuropsychiatric Inventory-Anxiety subscale , Rating Anxiety in Dementia scale , Penn State Worry Question naire-Abbreviated , Geriatric Anxiety Inventory , Geriatric Depression Scale , Quality of Life in Alzheimer disease , Patient Health Question naire , and Client Satisfaction Question naire . RESULTS Feasibility was demonstrated with regard to recruitment , attrition , and treatment characteristics . At 3 months , clinicians rated patients receiving Peaceful Mind as less anxious , and patients rated themselves as having higher quality of life ; collaterals reported less distress related to loved ones ' anxiety . Although significant positive effects were not noted in other outcomes or at 6-month follow-up , the pilot nature of the trial prohibits conclusions about efficacy . CONCLUSIONS Results support that Peaceful Mind is ready for future comparative clinical trials [15193897] BACKGROUND This paper describes the implementation of the Healthy Directions-Health Centers intervention and examines the characteristics of participants associated with completion of intervention activities . Healthy Directions-Health Centers was design ed to address social context ual factors relevant to cancer prevention interventions for working class , multi-ethnic population s. METHODS Ten community health centers were paired and r and omly assigned to intervention or control . Patients who resided in low income , multi-ethnic neighborhoods were approached for participation . This study targeted fruit and vegetable consumption , red meat consumption , multi-vitamin intake , and physical activity . The intervention components consisted of : ( 1 ) a brief study endorsement from a clinician ; ( 2 ) an in-person counseling session with a health advisor ; ( 3 ) four follow-up telephone counseling sessions ; and ( 4 ) multiple distributions of tailored material s. RESULTS Among the 1,088 intervention group participants , 978 participants ( 90 % ) completed at least five out of six intervention activities . Participants who missed clinical appointments were less likely to complete all components of the intervention . Participant characteristics that predicted receipt of clinician endorsement differed from characteristics that predicted completion of health advisor activities . Low acculturation did not present a barrier to delivery of the intervention once the participant was enrolled . CONCLUSIONS Collection and reporting on process evaluation results can help explain variations in program implementation [9930042] Objective To evaluate whether nurse run clinics in general practice improve secondary prevention in patients with coronary heart disease . Design R and omised controlled trial . Setting A r and om sample of 19 general practice s in northeast Scotl and . Patients 1173 patients ( 685 men and 488 women ) under 80 years with working diagnoses of coronary heart disease , but without terminal illness or dementia and not housebound . Intervention Nurse run clinics promoted medical and lifestyle aspects of secondary prevention and offered regular follow up . Main outcome measures Components of secondary prevention assessed at baseline and one year were : aspirin use ; blood pressure management ; lipid management ; physical activity ; dietary fat ; and smoking status . A cumulative score was generated by counting the number of appropriate components of secondary prevention for each patient . Results There were significant improvements in aspirin management ( odds ratio 3.22 , 95 % confidence interval 2.15 to 4.80 ) , blood pressure management ( 5.32 , 3.01 to 9.41 ) , lipid management ( 3.19 , 2.39 to 4.26 ) , physical activity ( 1.67 , 1.23 to 2.26 ) and diet ( 1.47 , 1.10 to 1.96 ) . There was no effect on smoking cessation ( 0.78 , 0.47 to 1.28 ) . Of six possible components of secondary prevention , the baseline mean was 3.27 . The adjusted mean improvement attributable to intervention was 0.55 of a component ( 0.44 to 0.67 ) . Improvement was found regardless of practice baseline performance . Conclusions Nurse run clinics proved practical to implement in general practice and effectively increased secondary prevention in coronary heart disease . Most patients gained at least one effective component of secondary prevention and , for them , future cardiovascular events and mortality could be reduced by up to a third [12875144] The purpose of this study was to determine how an exercise adherence intervention affects the physiological , functional , and quality of life outcomes of patients with heart failure ( HF ) . Sixteen HF patients were r and omly assigned to an exercise-only group ( n = 8) or to an exercise-with-adherence group ( n = 8) . Two of the 16 people died from nonexercise related causes during the study and were not included in the analysis . The intervention was tested over a 24-week period in which patients participated in a 12-week supervised exercise program ( Phase 1 ) followed by 12 weeks of unsupervised home exercise ( Phase 2 ) . The intervention format was one of individualized graphic feedback on exercise goals and participation and problem-solving support by nurses . Results indicate that patients who received the intervention exercised more frequently and experienced improved outcomes during both phases . The adherence intervention may encourage HF patients to continue to exercise and thereby maintain the health benefits gained in both phases of an exercise program [17276321] OBJECTIVE To test if basic training for dietitians in motivational interviewing ( MI ) result ed in changes in dietitians ' counseling style and improvements in their patients ' diet and risk parameters . DESIGN A r and omized controlled trial . SETTING 9 home-care organizations in the Netherl and s. PARTICIPANTS 37 dietitians , 209 baseline patients , and 142 follow-up diabetes patients . INTERVENTION Dietitians were r and omly allocated to receive basic training in motivational interviewing ( MI dietitians , n=18 ) or not ( control dietitians , n=19 ) . MAIN OUTCOME MEASURES Counseling style of dietitians ; total self-reported saturated fat , fruit , and vegetable intake , measured body mass index ( BMI ) , waist circumference , and glycated hemoglobin ( Hemoglobin A(1c ) , HbA(1c ) ) of patients . ANALYSIS Analyses of variance and multiple linear regression analyses . Alpha = .05 RESULTS MI dietitians were significantly more empathetic , more often showed reflection during consultations , and were more likely than control dietitians to let their patients talk for the majority of the consultation . Patients of MI dietitians had significantly lower saturated fat intake levels at posttest compared to patients of control dietitians . No effects on HbA(1c ) , BMI , and waist circumference were found . CONCLUSIONS AND IMPLICATION S Basic training in MI changed the dietitians ' counseling style and result ed in lower saturated fat intakes in their patients [9028693] OBJECTIVE The aim of this r and omized pilot study was to examine whether the addition of motivational interviewing strategies to a behavioral obesity intervention enhances adherence and glucose control in older obese women with NIDDM . RESEARCH DESIGN AND METHODS Twenty-two older obese women ( 41 % black ) with NIDDM were r and omly assigned to 1 ) a st and ard 16-week group behavioral weight-control program that provided instruction in diet , exercise , and behavioral modification or 2 ) the same group behavioral program with three individualized motivational interviewing sessions added . RESULTS The motivational group attended significantly more group meetings ( 13.3 vs. 8.9 ) , completed significantly more food diaries ( 15.2 vs. 10.1 ) , and recorded blood glucose significantly more often ( 46.0 vs. 32.2 days ) than the st and ard group . Further , participants in the motivational group had significantly better glucose control post-treatment ( 9.8 vs. 10.8 % ) . Although both groups demonstrated significant weight loss , no differences were apparent between groups . CONCLUSIONS These results suggest that augmenting a st and ard behavioral treatment program for obese women with NIDDM with a motivational interviewing component may significantly enhance adherence to program recommendations and glycemic control . Preliminary data warrant further investigation with larger sample s and a longer follow-up [18395397] Cardiac pain arising from chronic stable angina ( CSA ) is a cardinal symptom of coronary artery disease and has a major negative impact on health-related quality of life ( HRQL ) , including pain , poor general health status , and inability to self-manage . Current secondary prevention approaches lack adequate scope to address CSA as a multidimensional ischemic and persistent pain problem . This trial evaluated the impact of a low-cost six-week angina psychoeducation program , entitled The Chronic Angina Self-Management Program ( CASMP ) , on HRQL , self-efficacy , and re source fulness to self-manage anginal pain . One hundred thirty participants were r and omized to the CASMP or three-month wait-list usual care ; 117 completed the study . Measures were taken at baseline and three months . General HRQL was measured using the Medical Outcomes Study 36-Item Short Form and the disease-specific Seattle Angina Question naire ( SAQ ) . Self-efficacy and re source fulness were measured using the Self-Efficacy Scale and the Self-Control Schedule , respectively . The mean age of participants was 68 years , 80 % were male . Analysis of variance of change scores yielded significant improvements in treatment group physical functioning [ F=11.75(1,114 ) , P<0.001 ] and general health [ F=10.94(1,114 ) , P=0.001 ] aspects of generic HRQL . Angina frequency [ F=5.57(1,115 ) , P=0.02 ] , angina stability [ F=7.37(1,115 ) , P=0.001 ] , and self-efficacy to manage disease [ F=8.45(1,115 ) , P=0.004 ] were also significantly improved at three months . The CASMP did not impact re source fulness . These data indicate that the CASMP was effective for improving physical functioning , general health , anginal pain symptoms , and self-efficacy to manage pain at three months and provide a basis for long-term evaluation of the program [17307300] OBJECTIVES 1 . Quantitative description of the adherence to the principles of Motivational Interviewing ( MI ) in smoking counseling sessions , 2 . Examination of the relation between clients ' characteristics and the adherence to the principles of MI , and between adherence to the principles of MI and future smoking status . METHODS A sample of n=163 sessions conducted during a r and omized controlled trial in testing the effectiveness of a population -based smoking intervention in women postpartum was investigated . Demographic and behavior-related variables were included in a logistic regression to predict adherence to MI . Adherence was measured using the Motivational Interviewing Treatment Integrity ( MITI ) scale . RESULTS Of the sessions , 49.4 % showed good adherence to MI . The OR of receiving a good MI session was 3.1 for non-smokers in comparison to daily smokers . No other demographic or behavioral variable gained statistical significance . The relation between adherence and intervention outcome after 6 months was statistically significant ( chi(2)=6.459 , p<0.05 ) . CONCLUSIONS This intervention study shows a satisfactory degree of adherence to and the effectiveness of MI . MI-adherence seems more likely in sessions concerned with smoking relapse prevention compared to smoking cessation sessions [11469475] OBJECTIVE To test the effects of a high intensity home-based progressive strength training program on the clinical signs and symptoms of osteoarthritis ( OA ) of the knee . METHODS Forty-six community dwelling patients , aged 55 years or older with knee pain and radiographic evidence of knee OA , were r and omized to a 4 month home based progressive strength training program or a nutrition education program ( attention control ) . Thirty-eight patients completed the trial with an adherence of 84 % to the intervention and 65 % to the attention control . The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis ( WOMAC ) index pain and physical function subscales . Secondary outcomes included clinical knee examination , muscle strength , physical performance measures , and question naires to measure quality of life variables . RESULTS Patients in the strength training group who completed the trial had a 71 % improvement in knee extension strength in the leg reported as most painful versus a 3 % improvement in the control group ( p < 0.01 ) . In a modified intent to treat analysis , self-reported pain improved by 36 % and physical function by 38 % in the strength training group versus 11 and 21 % , respectively , in the control group ( p = 0.01 for between group comparison ) . In addition , those patients in the strength training group who completed the trial had a 43 % mean reduction in pain ( p = 0.01 vs controls ) , a 44 % mean improvement in self-reported physical function ( p < 0.01 vs controls ) , and improvements in physical performance , quality of life , and self-efficacy when compared to the control group . CONCLUSION High intensity , home based strength training can produce substantial improvements in strength , pain , physical function and quality of life in patients with knee OA [20483968] CONTEXT Improving the quality of mental health care requires moving clinical interventions from controlled research setting s into real-world practice setting s. Although such advances have been made for depression , little work has been performed for anxiety disorders . OBJECTIVE To determine whether a flexible treatment-delivery model for multiple primary care anxiety disorders ( panic , generalized anxiety , social anxiety , and posttraumatic stress disorders ) would be better than usual care ( UC ) . DESIGN , SETTING , AND PATIENTS A r and omized controlled effectiveness trial of Coordinated Anxiety Learning and Management ( CALM ) compared with UC in 17 primary care clinics in 4 US cities . Between June 2006 and April 2008 , 1004 patients with anxiety disorders ( with or without major depression ) , aged 18 to 75 years , English- or Spanish-speaking , were enrolled and subsequently received treatment for 3 to 12 months . Blinded follow-up assessment s at 6 , 12 , and 18 months after baseline were completed in October 2009 . INTERVENTION CALM allowed choice of cognitive behavioral therapy ( CBT ) , medication , or both ; included real-time Web-based outcomes monitoring to optimize treatment decisions ; and a computer-assisted program to optimize delivery of CBT by nonexpert care managers who also assisted primary care clinicians in promoting adherence and optimizing medications . MAIN OUTCOME MEASURES Twelve-item Brief Symptom Inventory ( BSI-12 ) anxiety and somatic symptoms score . Secondary outcomes included proportion of responders ( > or = 50 % reduction from pretreatment BSI-12 score ) and remitters ( total BSI-12 score < 6 ) . RESULTS A significantly greater improvement for CALM vs UC in global anxiety symptoms was found ( BSI-12 group mean differences of -2.49 [ 95 % confidence interval { CI } , -3.59 to -1.40 ] , -2.63 [ 95 % CI , -3.73 to -1.54 ] , and -1.63 [ 95 % CI , -2.73 to -0.53 ] at 6 , 12 , and 18 months , respectively ) . At 12 months , response and remission rates ( CALM vs UC ) were 63.66 % ( 95 % CI , 58.95%-68.37 % ) vs 44.68 % ( 95 % CI , 39.76%-49.59 % ) , and 51.49 % ( 95 % CI , 46.60%-56.38 % ) vs 33.28 % ( 95 % CI , 28.62%-37.93 % ) , with a number needed to treat of 5.27 ( 95 % CI , 4.18 - 7.13 ) for response and 5.50 ( 95 % CI , 4.32 - 7.55 ) for remission . CONCLUSION For patients with anxiety disorders treated in primary care clinics , CALM compared with UC result ed in greater improvement in anxiety symptoms , depression symptoms , functional disability , and quality of care during 18 months of follow-up . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00347269 [21074887] AIM To determine whether glycemic control is improved when motivational interviewing ( MI ) , a patient-centered behavior change strategy , is used with diabetes self management education ( DSME ) as compared to DSME alone . METHODS poorly controlled type 2 diabetes ( T2DM ) patients ( n=234 ) were r and omized into 4 groups : MI+DSME or DSME alone , with or without use of a computerized summary of patient self management barriers . We compared HbA1c changes between groups at 6 months and investigated mediators of HbA1c change . RESULTS study patients attended the majority of the four intervention visits ( mean 3.4 ) , but drop-out rate was high at follow-up research visits ( 35 % ) . Multiple regression showed that groups receiving MI had a mean change in HbA1c that was significantly lower ( less improved ) than those not receiving MI ( t=2.10 ; p=0.037 ) . Mediators of HbA1c change for the total group were diabetes self-care behaviors and diabetes distress ; no between-group differences were found . CONCLUSIONS DSME improved blood glucose control , underlining its benefit for T2DM management . However , MI+DSME was less effective than DSME alone . Overall , weak support was found for the clinical utility of MI in the management of T2DM delivered by diabetes educators [12403802] Background . Counseling sedentary primary care patients can increase physical activity , but whether this approach will increase exercise and fitness in elderly adults with chronic diseases remains to be determined . Methods . After receiving individualized nurse counseling to begin a program of walking for health , 60- to 80-year-old primary care patients were r and omized to one of three levels of telephone contacts over 10 months : ( i ) 20 nurse-initiated calls , ( ii ) 10 nurse-initiated calls plus 10 motivational calls programmed through an automated phone calling system , or ( iii ) no program-initiated phone contacts . Self-reported ( diary ) walking adherence was the primary outcome ; other activity , social support , health quality of life , and measured walking performance , mobility , and body mass index and girths were also assessed during the initiation ( months 1 - 6 ) and maintenance ( months 7 - 10 ) phases of the trial . Results . Average adherence for the 181 participants to the goal of walking at least 20 minutes on 3 or more days per week was 44 % for initiation and 42 % for maintenance . Participants receiving the combination of nurse-initiated personal and automated phone calls walked significantly more frequently than those with no phone contacts . Fitness improved in all three groups ; changes were generally correlated with self-reported walking . Having a companion was associated with more frequent walking . Perceived quality of physical and mental health did not change . Conclusions . Simple and relatively inexpensive nurse contacts can motivate elderly primary care patients to walk for exercise , and this activity is associated with measurable health benefits [4180306] Background Many older adults are both highly sedentary ( that is , spend considerable amounts of time sitting ) and physically inactive ( that is , do little physical activity ) . This protocol describes an exploratory trial of a theory-based behaviour change intervention in the form of a booklet outlining simple activities ( ‘ tips ’ ) design ed both to reduce sedentary behaviour and to increase physical activity in older adults . The intervention is based on the ‘ habit formation ’ model , which proposes that consistent repetition leads to behaviour becoming automatic , sustaining activity gains over time . Methods The intervention is being developed iteratively , in line with Medical Research Council complex intervention guidelines . Selection of activity tips was informed by semi-structured interviews and focus groups with older adults , and input from a multidisciplinary expert panel . An ongoing preliminary field test of acceptability among 25 older adults will inform further refinement . An exploratory r and omized controlled trial will be conducted within a primary care setting , comparing the tips booklet with a control fact sheet . Retired , inactive and sedentary adults ( n = 120 ) aged 60 to 74 years , with no physical impairments precluding light physical activity , will be recruited from general practice s in north London , UK . The primary outcomes are recruitment and attrition rates . Secondary outcomes are changes in behaviour , habit , health and wellbeing over 12 weeks . Discussion Data will be used to inform study procedures for a future , larger-scale definitive r and omized controlled trial . Trial registration Current Controlled Trials IS RCT N47901994 [2942793] Background Evaluation of an implementation process and its fidelity can give insight into the ' black box ' of interventions . However , a lack of st and ardized methods for study ing fidelity and implementation process have been reported , which might be one reason for the fact that few prior studies in the field of health service research have systematic ally evaluated interventions ' implementation processes . The aim of this project is to systematic ally evaluate implementation fidelity and possible factors influencing fidelity of complex interventions in health and social care . Methods A modified version of The Conceptual Framework for Implementation Fidelity will be used as a conceptual model for the evaluation . The modification implies two additional moderating factors : context and recruitment . A systematic evaluation process was developed . Multiple case study method is used to investigate implementation of three complex health service interventions . Each case will be investigated in depth and longitudinally , using both quantitative and qualitative methods . Discussion This study is the first attempt to empirically test The Conceptual Framework for Implementation Fidelity . The study can highlight mechanism and factors of importance when implementing complex interventions . Especially the role of the moderating factors on implementation fidelity can be clarified . Trial Registration Supported Employment , SE , among people with severe mental illness -- a r and omized controlled trial : NCT00960024 [3534485] Background To examine the effects of a multicomponent exercise program on the cognitive function of older adults with amnestic mild cognitive impairment ( aMCI ) . Methods Design : Twelve months , r and omized controlled trial ; Setting : Community center in Japan ; Participants : Fifty older adults ( 27 men ) with aMCI ranging in age from 65 to 93 years ( mean age , 75 years ) ; Intervention : Subjects were r and omized into either a multicomponent exercise ( n = 25 ) or an education control group ( n = 25 ) . Subjects in the multicomponent exercise group exercised under the supervision of physiotherapists for 90 min/d , 2 d/wk , for a total of 80 times over 12 months . The exercises included aerobic exercises , muscle strength training , and postural balance retraining , and were conducted using multiple conditions to stimulate cognitive functions . Subjects in the control group attended three education classes regarding health during the 12-month period . Measurements were administered before , after the 6-month , and after the 12-month intervention period ; Measurements : The performance measures included the mini-mental state examination , logical memory subtest of the Wechsler memory scale-revised , digit symbol coding test , letter and categorical verbal fluency test , and the Stroop color word test . Results The mean adherence to the exercise program was 79.2 % . Improvements of cognitive function following multicomponent exercise were superior at treatment end ( group × time interactions for the mini-mental state examination ( P = 0.04 ) , logical memory of immediate recall ( P = 0.03 ) , and letter verbal fluency test ( P = 0.02 ) ) . The logical memory of delayed recall , digit symbol coding , and Stroop color word test showed main effects of time , although there were no group × time interactions . Conclusions This study indicates that exercise improves or supports , at least partly , cognitive performance in older adults with aMCI [1716168] Background Missing data present a challenge to many research projects . The problem is often pronounced in studies utilizing self-report scales , and literature addressing different strategies for dealing with missing data in such circumstances is scarce . The objective of this study was to compare six different imputation techniques for dealing with missing data in the Zung Self-reported Depression scale ( SDS ) . Methods 1580 participants from a surgical outcomes study completed the SDS . The SDS is a 20 question scale that respondents complete by circling a value of 1 to 4 for each question . The sum of the responses is calculated and respondents are classified as exhibiting depressive symptoms when their total score is over 40 . Missing values were simulated by r and omly selecting questions whose values were then deleted ( a missing completely at r and om simulation ) . Additionally , a missing at r and om and missing not at r and om simulation were completed . Six imputation methods were then considered ; 1 ) multiple imputation , 2 ) single regression , 3 ) individual mean , 4 ) overall mean , 5 ) participant 's preceding response , and 6 ) r and om selection of a value from 1 to 4 . For each method , the imputed mean SDS score and st and ard deviation were compared to the population statistics . The Spearman correlation coefficient , percent misclassified and the Kappa statistic were also calculated . Results When 10 % of values are missing , all the imputation methods except r and om selection produce Kappa statistics greater than 0.80 indicating ' near perfect ' agreement . MI produces the most valid imputed values with a high Kappa statistic ( 0.89 ) , although both single regression and individual mean imputation also produced favorable results . As the percent of missing information increased to 30 % , or when unbalanced missing data were introduced , MI maintained a high Kappa statistic . The individual mean and single regression method produced Kappas in the ' substantial agreement ' range ( 0.76 and 0.74 respectively ) . Conclusion Multiple imputation is the most accurate method for dealing with missing data in most of the missind data scenarios we assessed for the SDS . Imputing the individual 's mean is also an appropriate and simple method for dealing with missing data that may be more interpretable to the majority of medical readers . Research ers should consider conducting method ological assessment s such as this one when confronted with missing data . The optimal method should balance validity , ease of interpretability for readers , and analysis expertise of the research team [18314570] BACKGROUND Because preventing functional decline in older adults is a national priority and senior centers have been identified as potentially important venues for health-promotion activities , a trial of a multicomponent disability prevention program was conducted at a senior center . METHODS One hundred older adults were recruited for a 6-month r and omized clinical trial . All members of the experimental group received an exercise intervention , nutrition counseling , and a home safety assessment . Smoking and alcohol interventions were delivered to at-risk subjects . Outcome variables included the Medical Outcomes Study Short Form ( SF-36 ) health survey , the CES-Depression scale , bed days , and restricted-activity days . RESULTS A single study announcement result ed in a response sufficient to recruit 100 subjects . The exercise program was well received : 85 % of intervention subjects completed the 6-month program and adherence was excellent , with over 90 % attendance at exercise classes . After 6 months the intervention group had significantly better scores on 7 of 8 SF-36 subscales and fewer depressive symptoms than controls . CONCLUSIONS Senior centers may be excellent sites for community-based health promotion interventions : participation and adherence rates may be acceptable , interventions can be design ed that are feasible in this setting , and these interventions appear to affect health status positively . The study program improved physical and psychosocial functioning and is a promising model for preventing functional decline through activities based at senior centers [24113727] Objective : To examine the feasibility of a strategy training clinical trial in a small group of adults with stroke-related cognitive impairments in inpatient rehabilitation , and to explore the impact of strategy training on disability . Design : Non-r and omized two-group intervention pilot study . Setting : Two inpatient rehabilitation units within an academic health centre . Participants : Individuals with a primary diagnosis of acute stroke , who were admitted to inpatient rehabilitation and demonstrated cognitive impairments were included . Individuals with severe aphasia ; dementia ; major depressive disorder , bipolar , or psychotic disorder ; recent drug or alcohol abuse ; and anticipated length of stay less than five days were excluded . Intervention : Participants received strategy training or an attention control session in addition to usual rehabilitation care . Sessions in both groups were 30–40 minutes daily , five days per week , for the duration of inpatient rehabilitation . Main outcome measures : We assessed feasibility through participants ’ recruitment and retention ; research intervention session number and duration ; participants ’ comprehension and engagement ; intervention fidelity ; and participants ’ satisfaction . We assessed disability at study admission , inpatient rehabilitation discharge , 3 and 6 months using the Functional Independence Measure . Results : Participants in both groups ( 5 per group ) received the assigned intervention ( > 92 % planned sessions ; > 94 % fidelity ) and completed follow-up testing . Strategy training participants in this small sample demonstrated significantly less disability at six months ( M ( SE ) = 117 ( 3 ) ) than attention control participants ( M(SE ) = 96 ( 14 ) ; t8 = 7.87 , P = 0.02 ) . Conclusions : It is feasible and acceptable to administer both intervention protocol s as an adjunct to acute inpatient rehabilitation , and strategy training shows promise for reducing disability [8980206] OBJECTIVE To determine the effects of structured exercise programs on self-reported disability in older adults with knee osteoarthritis . SETTING AND DESIGN A r and omized , single-blind clinical trial lasting 18 months conducted at 2 academic medical centers . PARTICIPANTS A total of 439 community-dwelling adults , aged 60 years or older , with radiographically evident knee osteoarthritis , pain , and self-reported physical disability . INTERVENTIONS An aerobic exercise program , a resistance exercise program , and a health education program . MAIN OUTCOME MEASURES The primary outcome was self-reported disability score ( range , 1 - 5 ) . The secondary outcomes were knee pain score ( range , 1 - 6 ) , performance measures of physical function , x-ray score , aerobic capacity , and knee muscle strength . RESULTS A total of 365 ( 83 % ) participants completed the trial . Overall compliance with the exercise prescription was 68 % in the aerobic training group and 70 % in the resistance training group . Postr and omization , participants in the aerobic exercise group had a 10 % lower adjusted mean ( + /- SE ) score on the physical disability question naire ( 1.71 + /- 0.03 vs 1.90 + /- 0.04 units ; P<.001 ) , a 12 % lower score on the knee pain question naire ( 2.1 + /- 0.05 vs 2.4 + /- 0.05 units ; P=.001 ) , and performed better ( mean [ + /- SE ] ) on the 6-minute walk test ( 1507 + /- 16 vs 1349 + /- 16 ft ; P<.001 ) , mean ( + /-SE ) time to climb and descend stairs ( 12.7 + /- 0.4 vs 13.9 + /- 0.4 seconds ; P=.05 ) , time to lift and carry 10 pounds ( 9.1 + /- 0.2 vs 10.0 + /- 0.1 seconds ; P<.001 ) , and mean ( + /-SE ) time to get in and out of a car ( 8.7 + /- 0.3 vs 10.6 + /- 0.3 seconds ; P<.001 ) than the health education group . The resistance exercise group had an 8 % lower score on the physical disability question naire ( 1.74 + /- 0.04 vs 1.90 + /- 0.03 units ; P=.003 ) , 8 % lower pain score ( 2.2 + /- 0.06 vs 2.4 + /- 0.05 units ; P=.02 ) , greater distance on the 6-minute walk ( 1406 + /- 17 vs 1349 + /- 16 ft ; P=.02 ) , faster times on the lifting and carrying task ( 9.3 + /- 0.1 vs 10.0 + /- 0.16 seconds ; P=.001 ) , and the car task ( 9.0 + /- 0.3 vs 10.6 + /- 0.3 seconds ; P=.003 ) than the health education group . There were no differences in x-ray scores between either exercise group and the health education group . CONCLUSIONS Older disabled persons with osteoarthritis of the knee had modest improvements in measures of disability , physical performance , and pain from participating in either an aerobic or a resistance exercise program . These data suggest that exercise should be prescribed as part of the treatment for knee osteoarthritis [23368423] BACKGROUND The aim of the present study was to determine whether the addition of nurse case managers ( NCMs ) trained in motivational interviewing ( MI ) to usual care would result in improved outcomes in high-risk type 2 diabetes patients . METHODS A 2-year r and omized controlled pragmatic trial r and omized 545 patients to usual care control ( n=313 ) or those who received the intervention ( n=232 ) with additional practice -embedded NCM care , including MI-guided behavior change counseling . The NCMs received intensive MI training with ongoing fidelity assessment . RESULTS Systolic blood pressure ( SBP ) was better in the intervention than usual care group ( 131 ± 15 vs. 135 ± 18 mmHg , respectively ; P<0.05 ) . Improvements were seen in both the control and intervention groups in terms of HbA1c ( from 9.1 % to 8.0 % and from 8.8 % to 7.8 % , respectively ) , low-density lipoprotein ( LDL ; from 127 to 100 mg/dL and from 128 to 102 mg/dL , respectively ) , and diastolic blood pressure ( from 78 to 74 mmHg and from 80 to 74 mmHg , respectively ) . Depression symptom scores were better in the intervention group . The reduction in diabetes-related distress approached statistical significance . CONCLUSIONS The NCMs and MI improved SBP and complications screening . The large decrease in HbA1C and LDL in the control group may have obscured any further intervention effect . Although nurses prompted providers for medication titration , strategies to reduce provider clinical inertia may also be needed [22103957] OBJECTIVE Adherence to continuous positive airway pressure ( CPAP ) therapy for obstructive sleep apnoea ( OSA ) is poor . We assessed the effectiveness of a motivational interviewing intervention ( motivational interview nurse therapy [ MINT ] ) in addition to best practice st and ard care to improve acceptance and adherence to CPAP therapy in people with a new diagnosis of OSA . METHOD One hundred six Australian adults ( 69 % male ) with a new diagnosis of OSA and a clinical recommendation for CPAP treatment were recruited from a tertiary sleep disorders center . Participants were r and omly assigned to receive either 3 sessions of a motivational interviewing intervention ( MINT ; n = 53 ; mean age = 55.4 years ) or no intervention ( control ; n = 53 ; mean age = 57.74 years ) . The primary outcome was the difference between the groups in objective CPAP adherence at 1-month , 2-month , 3-month , and 12-month follow-ups . RESULTS Fifty ( 94 % ) participants in the MINT group and 50 ( 94 % ) participants in the control group met all inclusion and exclusion criteria and were included in the primary analysis . The number of hours of CPAP use per night in the MINT group at 3 months was 4.63 hr and was 3.16 hr in the control group ( p = .005 ) . This represents almost 50 % better adherence in the MINT group relative to the control group . Patients in the MINT group were substantially more likely to accept CPAP treatment . CONCLUSIONS MINT is a brief , manualized , effective intervention that improves CPAP acceptance and objective adherence rates compared to st and ard care alone [22367233] OBJECTIVES To investigate the feasibility of implementing a Sleep Education Program ( SEP ) for improving sleep in adult family home ( AFH ) residents with dementia , and the relative efficacy of SEP compared with usual care control in a pilot r and omized controlled trial . PARTICIPANTS Thirty-seven AFH staff-caregivers and 47 residents with comorbid dementia and sleep disturbances . INTERVENTION SEP consisted of four training sessions with staff-caregivers to develop and implement individualized resident behavioral sleep plans . MEASUREMENTS Treatment fidelity to the SEP was assessed following the National Institutes of Health ( NIH ) Behavior Change Consortium model utilizing trainer observations and staff-caregiver reports . Resident sleep was assessed by wrist actigraphy at baseline , 1-month posttreatment , and 6-month follow-up . Caregiver reports of resident daytime sleepiness , depression , and disruptive behaviors were also collected . RESULTS Each key area of treatment fidelity ( SEP delivery , receipt , enactment ) was identified , measured , and yielded significant outcomes . Staff-caregivers learned how to identify sleep scheduling , daily activity , and environmental factors that could contribute to nocturnal disturbances and developed and implemented strategies for modifying these factors . SEP decreased the frequency and disturbance level of target resident nocturnal behaviors and improved actigraphically measured sleep percent and total sleep time over the 6-month follow-up period compared with the control condition . CONCLUSION Results suggest behavioral interventions to improve sleep are feasible to implement in adult family homes and merit further investigation as a promising intervention for use with AFH residents with dementia [24238096] Venous thromboembolism ( VTE ) is a significant cause of morbidity and mortality in hospitalized medical patients . Evidence -based guidelines exist for preventing VTE ; unfortunately , these guidelines are not always adhered to by clinicians . The aim of this study was to evaluate the acceptability , utility and clinical impact of an educational outreach visit ( EOV ) on nurses ' provision of mechanical prophylaxis to hospitalized medical patients using a prospect i ve , uncontrolled , before- and -after design . Nurses received a 1-to-1 educational session on mechanical VTE prevention by a trained nurse facilitator . The EOV intervention was design ed by a multidisciplinary group of healthcare professionals using social marketing theory . Eighty-five of the 120 eligible nurses ( 71 % ) attended the EOV . The median length of each visit was 11.5 minutes ( interquartile range [ IQR ] , 10 - 15 ) and the median time spent arranging and conducting each visit was 63 minutes ( IQR , 49 - 85 ) . Eighty-four ( 99 % ) of the 85 participants gave a verbal commitment to trial the new evidence -based mechanical VTE prevention practice s. However , there were no measurable improvements in the proportion of patients risk assessed ( -1.7 % improvement ; 95 % confidence interval [ CI ] , -7.0 to 10.3 ; P = .68 ) or provided appropriate mechanical prophylaxis ( -0.3 % improvement ; 95 % CI , -13.4 to 14 ; P = .96 ) . Research ers conclude that EOV should not be used to improve nurses ' use of mechanical VTE prevention because it has no measurable impact on clinical practice and is re source intensive , requiring 4.5 minutes of preparation for every minute spent face to face with participants . Further research into the specific mechanism of action is required to explain the variability in clinical effect seen with this intervention [26360446] BACKGROUND Mental health policy in many countries is oriented around recovery , but the evidence base for service-level recovery-promotion interventions is lacking . METHODS We did a cluster , r and omised , controlled trial in two National Health Service Trusts in Engl and . REFOCUS is a 1-year team-level intervention targeting staff behaviour to increase focus on values , preferences , strengths , and goals of patients with psychosis , and staff-patient relationships , through coaching and partnership . Between April , 2011 , and May , 2012 , community-based adult mental health teams were r and omly allocated to provide usual treatment plus REFOCUS or usual treatment alone ( control ) . Baseline and 1-year follow-up outcomes were assessed in r and omly selected patients . The primary outcome was recovery and was assessed with the Question naire about Processes of Recovery ( QPR ) . We also calculated overall service costs . We used multiple imputation to estimate missing data , and the imputation model captured clustering at the team level . Analysis was by intention to treat . This trial is registered , number IS RCT N02507940 . FINDINGS 14 teams were included in the REFOCUS group and 13 in the control group . Outcomes were assessed in 403 patients ( 88 % of the target sample ) at baseline and in 297 at 1 year . Mean QPR total scores did not differ between the two groups ( REFOCUS group 40·6 [ SD 10·1 ] vs control 40·0 [ 10·2 ] , adjusted difference 0·68 , 95 % CI -1·7 to 3·1 , p=0·58 ) . High team participation was associated with higher staff-rated scores for recovery-promotion behaviour change ( adjusted difference -0·4 , 95 % CI -0·7 to -0·2 , p=0·001 ) and patient-rated QPR interpersonal scores ( -1·6 , -2·7 to -0·5 , p=0·005 ) at follow-up than low participation . Patients treated in the REFOCUS group incurred £ 1062 ( 95 % CI -1103 to 3017 ) lower adjusted costs than those in the control group . INTERPRETATION Although the primary endpoint was negative , supporting recovery might , from the staff perspective , improve functioning and reduce needs . Implementation of REFOCUS could increase staff recovery-promotion behaviours and improve patient-rated recovery . FUNDING National Institute for Health Research [19627913] OBJECTIVE The objectives are to describe for the first time a home-based exercise intervention for frail elderly hip fracture patients and to describe the feasibility of this exercise program . DESIGN A home-based exercise program was used in a r and omized controlled trial in which the authors investigated exercise intervention versus no exercise intervention in patients after hip fracture . SETTING This program was implemented at the patients ' own home or place of residence after discharge . PARTICIPANTS Women 65 years of age or older were recruited within 15 days of hip fracture . Eligible patients were those with a nonpathologic fracture who were admitted within 72 hours of injury , had surgical repair of the hip fracture , and met medical inclusion criteria . Participants initially were r and omized to exercise groups and then assigned to exercise trainers . INTERVENTION The exercise contained strength training and aerobic components . Participants were expected to exercise 5 days per week by performing a combination of supervised and independently performed exercise sessions . Intensity and duration were increased gradually by trainers in a st and ardized way . The frequency of the supervised sessions decreased as participants became more independent . Treatment fidelity visits ensured that the intervention was being delivered as intended across trainers and across participants . MAIN OUTCOME MEASUREMENT This work describes the feasibility and challenges of administering an intensive home-based exercise program in this population of older adults . RESULTS Of those patients r and omized to exercise , 82 % were followed by a trainer and almost all advanced to higher levels in both aerobic and strength programs . Overall , participants received an average of 44 ( 78.5 % ) of the prescribed visits by the trainer . CONCLUSIONS This study showed that it was possible to engage a frail older population of post-hip fracture patients in a program of aerobic and strength training exercise with a high rate of participation [2200380] The prevalence and impact of adult asthma are substantial , and poor self-management practice s , especially failures to adhere to treatment regimens , appear to be a significant problem . Desirable characteristics of an intervention program to improve self-management were identified through needs assessment and review of existing patient education re sources . A comprehensive program was developed that integrated a workbook with one-to-one counseling and adherence-enhancing strategies . A longitudinal 1-year study compared patients receiving this self-management program with " usual care " patients receiving st and ard asthma pamphlets . Patients were r and omly assigned to conditions . Baseline score and asthma severity were statistically controlled . Self-management patients had substantially better adherence than usual care patients , as well as improved functional status , at follow-up . Hospital and emergency department visits decreased in both groups but did not differ between groups [22390448] OBJECTIVES We tested the effectiveness of a community-based , literacy-sensitive , and culturally tailored lifestyle intervention on weight loss and diabetes risk reduction among low-income , Spanish-speaking Latinos at increased diabetes risk . METHODS Three hundred twelve participants from Lawrence , Massachusetts , were r and omly assigned to lifestyle intervention care ( IC ) or usual care ( UC ) between 2004 and 2007 . The intervention was implemented by trained Spanish-speaking individuals from the community . Each participant was followed for 1 year . RESULTS The participants ' mean age was 52 years ; 59 % had less than a high school education . The 1-year retention rate was 94 % . Compared with the UC group , the IC group had a modest but significant weight reduction ( -2.5 vs 0.63 lb ; P = .04 ) and a clinical ly meaningful reduction in hemoglobin A1c ( -0.10 % vs -0.04 % ; P = .009 ) . Likewise , insulin resistance improved significantly in the IC compared with the UC group . The IC group also had greater reductions in percentage of calories from total and saturated fat . CONCLUSIONS We developed an inexpensive , culturally sensitive diabetes prevention program that result ed in weight loss , improved HbA1c , and improved insulin resistance in a high-risk Latino population [9694180] AIM Our objective was to evaluate the effect of training in a patient-centred intervention for GPs and practice nurses on outcomes for patients with Type II diabetes . METHODS We carried out a r and omized controlled trial within general practice s as the basis for r and omization and a before- and -after design for measures of patient outcome . A parallel process study examined the use of the method by professionals . The study was carried out in 29 general practice s in South Glamorgan who had participated for at least 2 years in a local scheme of audit and CME in relation to Type II diabetes care . The subjects were 252 Type II diabetic patients recruited by 15 experimental and 14 control practice s. The main outcome measures were changes in glycosylated haemoglobin , patient satisfaction with care and treatment , functional health status and professional ability to apply the intervention . RESULTS Professionals adopted the innovative method with enthusiasm , but after 2 years only 19 % continued to apply the method systematic ally . The trial was , therefore , unable to demonstrate significant biochemical or functional improvements . This highlights the need to underst and the factors associated with professional uptake and subsequent ability to sustain changes in behaviour . CONCLUSIONS The efficacy of this behavioural intervention remains unproved , despite its acceptability to professional staff . Detailed and prolonged development and testing of behavioural interventions is an essential first step before embarking on r and omized controlled trials which involve complex behavioural changes in professionals or patients [24444847] Common mental disorders ( CMDs ) are a major cause of sickness absence . Twenty to 30 % of the workers who return to work after sickness absence due to CMDs experience recurrent sickness absence . We developed the Stimulating Healthy participation And Relapse Prevention (SHARP)-at work intervention , a problem solving intervention delivered by occupational physicians ( OPs ) , to prevent recurrent sickness absence in this worker population in The Netherl and s. A process evaluation was conducted alongside a cluster-r and omised controlled trial to ( 1 ) evaluate whether the SHARP-at work intervention was implemented according to the protocol and differed from treatment in the control group , and ( 2 ) to investigate the relationship between the key elements of the intervention and the effect outcome ( i.e. recurrent sickness absence ) . We collected process data for both the intervention and control group on recruitment , reach , dose delivered , dose received , fidelity , context and satisfaction . Data on recurrent sickness absence was collected through the registry system of the collaborating occupational health service . The study was performed in the Netherl and s , and between 2010 and 2012 , 154 OPs and 158 participants participated . Compared to the control group , participants in the intervention group more frequently had two or more consultations with the OP ( odds ratio [ OR ] = 3.2 , 95 % confidence interval [ CI ] = 1.2 - 8.8 ) and completed more assignments ( OR = 33.8 , 95 % CI = 10.4 - 109.5 ) as recommended in the intervention protocol . OPs and participants were satisfied with the intervention and rated it as applicable . Several individual intervention components were linked to the effect outcome . The process evaluation showed that the SHARP-at work intervention was conducted according to the protocol for the majority of the participants and well-received by OPs and participants . Furthermore , the intervention differed from treatment in the control group . Overall , the results provide support for implementing the intervention in practice [11493040] BACKGROUND We report process data on the feasibility of delivering a clinical preventive nutrition intervention that was effective in increasing participants ' consumption of fruits and vegetables . We also examine relationships between process variables and study outcomes . METHODS We r and omly assigned six practice sites in a managed care organization to a dietary intervention or control condition . We invited adults 18 years of age or older scheduled for routine health visits within the subsequent 2 months to participate . Of the 566 patients we contacted from the intervention sites , 230 ( 41 % ) enrolled . From the control sites , we contacted 617 , and 274 ( 44 % ) enrolled . Intervention participants received a tailored letter providing feedback on their consumption of target foods together with recommendations for improvement , stage-matched nutrition education booklets , a diet-health endorsement from their primary care providers ( PCPs ) , and two motivational counseling telephone calls . Of enrollees , 195 ( 85 % ) in the intervention group and 252 ( 92 % ) in the control group returned the final survey 3 months later . RESULTS Seventy-one percent of both participants and PCPs reported that the PCPs had discussed the relationship between diet and health at their visit . Fifty-seven percent of participants and 62 % of PCPs reported that they discussed the complete diet-health endorsement , which included : ( 1 ) acknowledgment of the relationship between diet and health and ( 2 ) tailored study recommendations . The inclusion of both parts of the diet-health endorsement , but not the length of time spent , appeared to correlate with healthful outcomes . CONCLUSIONS These process data suggest that the brief PCP diet-health endorsement contributed to the intervention effect on fruits and vegetables [21704360] BACKGROUND Improving inhaled corticosteroid ( ICS ) adherence should improve asthma outcomes . OBJECTIVE In a r and omized controlled trial we tested whether an individualized problem-solving ( PS ) intervention improves ICS adherence and asthma outcomes . METHODS Adults with moderate or severe asthma from clinics serving urban neighborhoods were r and omized to PS ( ie , defining specific barriers to adherence , proposing/weighing solutions , trying the best , assessing , and revising ) or st and ard asthma education ( AE ) for 3 months and then observed for 3 months . Adherence was monitored electronically . Outcomes included the following : asthma control , FEV(1 ) , asthma-related quality of life , emergency department ( ED ) visits , and hospitalizations . In an intention-to-treat- analysis longitudinal models using r and om effects and regression were used . RESULTS Three hundred thirty-three adults were r and omized : 49 ± 14 years of age , 72 % female , 68 % African American , 7 % Latino , mean FEV(1 ) of 66 % ± 19 % , and 103 ( 31 % ) with hospitalizations and 172 ( 52 % ) with ED visits for asthma in the prior year . There was no difference between groups in overall change in any outcome ( P > .20 ) . Mean adherence ( 61 % ± 27 % ) decreased significantly ( P = .0004 ) over time by 14 % and 10 % in the AE and PS groups , respectively . Asthma control improved overall by 15 % ( P = .002 ) . In both groups FEV(1 ) and quality of life improved by 6 % ( P = .01 ) and 18 % ( P < .0001 ) , respectively . However , the improvement in FEV(1 ) only occurred during monitoring but not subsequently after r and omization . Rates of ED visits and hospitalizations did not significantly decrease over the study period . CONCLUSION PS was not better than AE in improving adherence or asthma outcomes . However , monitoring ICS use with provision of medications and attention , which was imposed on both groups , was associated with improvement in FEV(1 ) and asthma control [23483412] This study evaluated the effectiveness of the Smoking Cessation and Reduction in Pregnancy Treatment ( SCRIPT ) Program selected by the West Virginia — Right From The Start Project for state-wide dissemination . A process evaluation documented the fidelity of SCRIPT delivery by Design ated Care Coordinators ( DCC ) , licensed nurses and social workers who provide home-based case management to Medicaid-eligible clients in all 55 counties . We implemented a quasi-experimental , non-r and omized , matched Comparison ( C ) Group design . The SCRIPT Experimental E Group ( N = 259 ) were all clients in 2009–2010 that wanted to quit , provided a screening carbon monoxide ( CO ) , and received a SCRIPT home visit . The ( C ) Group was derived from all clients in 2006–2007 who had the same CO assessment s as E Group clients and reported receiving cessation counseling . We stratified the baseline CO of E Group clients into 10 strata , and r and omly selected the same number of ( C ) Group clients ( N = 259 ) from each matched strata to evaluate the effectiveness of the SCRIPT Program . There were no significant baseline differences in the E and ( C ) Group . A Process Evaluation documented a significant increase in the fidelity of DCC delivery of SCRIPT Program procedures : from 63 % in 2006 to 74 % in 2010 . Significant increases were documented in the E Group cessation rate ( + 9.3 % ) and significant reduction rate ( + 4.5 % ) , a ≥50 % reduction from a baseline CO . Perinatal health case management staff can deliver the SCRIPT Program , and Medicaid-supported clients can change smoking behavior , even very late in pregnancy . When multiple biases were analyzed , we concluded the SCRIPT Dissemination Project was the most plausible reason for the significant changes in behavior [12350190] CONTEXT It is not known whether patient outcomes are enhanced by effective pharmacist-patient interactions . OBJECTIVE To assess the effectiveness of a pharmaceutical care program for patients with asthma or chronic obstructive pulmonary disease ( COPD ) . DESIGN , SETTING , AND PARTICIPANTS R and omized controlled trial conducted at 36 community drugstores in Indianapolis , Ind. We enrolled 1113 participants with active COPD or asthma from July 1998 to December 1999 . Outcomes were assessed in 947 ( 85.1 % ) participants at 6 months and 898 ( 80.7 % ) at 12 months . INTERVENTIONS The pharmaceutical care program ( n = 447 ) provided pharmacists with recent patient-specific clinical data ( peak expiratory flow rates [ PEFRs ] , emergency department [ ED ] visits , hospitalizations , and medication compliance ) , training , customized patient educational material s , and re sources to facilitate program implementation . The PEFR monitoring control group ( n = 363 ) received a peak flow meter , instructions about its use , and monthly calls to elicit PEFRs . However , PEFR data were not provided to the pharmacist . Patients in the usual care group ( n = 303 ) received neither peak flow meters nor instructions in their use ; during monthly telephone interviews , PEFR rates were not elicited . Pharmacists in both control groups had a training session but received no components of the pharmaceutical care intervention . MAIN OUTCOME MEASURES Peak expiratory flow rates , breathing-related ED or hospital visits , health-related quality of life ( HRQOL ) , medication compliance , and patient satisfaction . RESULTS At 12 months , patients receiving pharmaceutical care had significantly higher peak flow rates than the usual care group ( P = .02 ) but not than PEFR monitoring controls ( P = .28 ) . There were no significant between-group differences in medication compliance or HRQOL . Asthma patients receiving pharmaceutical care had significantly more breathing-related ED or hospital visits than the usual care group ( odds ratio , 2.16 ; 95 % confidence interval , 1.76 - 2.63 ; P<.001 ) . Patients receiving pharmaceutical care were more satisfied with their pharmacist than the usual care group ( P = .03 ) and the PEFR monitoring group ( P = .001 ) and were more satisfied with their health care than the usual care group at 6 months only ( P = .01 ) . Despite ample opportunities to implement the program , pharmacists accessed patient-specific data only about half of the time and documented actions about half of the time that records were accessed . CONCLUSIONS This pharmaceutical care program increased patients ' PEFRs compared with usual care but provided little benefit compared with peak flow monitoring alone . Pharmaceutical care increased patient satisfaction but also increased the amount of breathing-related medical care sought [10987780] R and omised controlled trials are widely accepted as the most reliable method of determining effectiveness , but most trials have evaluated the effects of a single intervention such as a drug . Recognition is increasing that other , non-pharmacological interventions should also be rigorously evaluated.1 - 3 This paper examines the design and execution of research required to address the additional problems result ing from evaluation of complex interventions —that is , those “ made up of various interconnecting parts.”4 The issues dealt with are discussed in a longer Medical Research Council paper ( www.mrc.ac.uk/complex_packages.html ) . We focus on r and omised trials but believe that this approach could be adapted to other design s when they are more appropriate . # # # # Summary points Complex interventions are those that include several components The evaluation of complex interventions is difficult because of problems of developing , identifying , documenting , and reproducing the intervention A phased approach to the development and evaluation of complex interventions is proposed to help research ers define clearly where they are in the research process Evaluation of complex interventions requires use of qualitative and quantitative evidence There are specific difficulties in defining , developing , documenting , and reproducing complex interventions that are subject to more variation than a drug . A typical example would be the design of a trial to evaluate the benefits of specialist stroke units . Such a trial would have to consider the expertise of various health professionals as well as investigations , drugs , treatment guidelines , and arrangements for discharge and follow up . Stroke units may also vary in terms of organisation , management , and skill mix . The active components of the stroke unit may be difficult to specify , making it difficult to replicate the intervention . The box gives other examples of complex interventions . # # # # Examples of complex interventions Service delivery and organisation : Stroke units Hospital at home Interventions directed at health professionals ' behaviour : Strategies for implementing guidelines Computerised decision support Community interventions : Community [25727114] OBJECTIVE The aim of this study was to test whether gender moderates intervention effects in the Coordinated Anxiety Learning and Management ( CALM ) intervention , a 12-month , r and omized controlled trial of a collaborative care intervention for anxiety disorders ( panic disorder , generalized anxiety disorder , posttraumatic stress disorder , and social anxiety disorder ) in 17 primary care clinics in California , Washington , and Arkansas . METHODS Participants ( N=1,004 ) completed measures of symptoms ( Brief Symptom Inventory [ BSI ] ) and functioning ( mental and physical health components of the 12-Item Short Form [ MCS and PCS ] and Healthy Days , Restricted Activity Days Scale ) at baseline , six , 12 , and 18 months . Data on dose , engagement , and beliefs about psychotherapy were collected for patients in the collaborative care group . RESULTS Gender moderated the relationship between treatment and its outcome on the BSI , MCS , and Healthy Days measures but not on the PCS . Women who received collaborative care showed clinical improvements on the BSI , MHC , and Healthy Days that were significantly different from outcomes for women in usual care . There were no differences for men in collaborative care compared with usual care on any measures . In the intervention group , women compared with men attended more sessions of psychotherapy , completed more modules of therapy , expressed more commitment , and viewed psychotherapy as more helpful . CONCLUSIONS These findings contribute to the broader literature on treatment heterogeneity , in particular the influence of gender , and may inform personalized care for people seeking anxiety treatment in primary care setting [11194695] Objectives . Physicians acknowledge the need to advise their patients about dietary habits , but they may not have the training or tools to do this efficiently . In the context of a r and omized trial , we investigated the feasibility of enlisting physicians to implement a dietary intervention in the primary care setting . Methods . Physicians from 14 primary care practice s were assigned via r and omization to introduce a self-help booklet to promote dietary change at routine appointments . Delivery of the booklet was recorded by these intervention physicians at the clinic appointment ; intervention participants were asked 3 months later in a telephone interview about whether they received and used the booklet . Results . According to physician documentation , 95 % of intervention participants who kept an appointment ( n = 935 ) received the booklet ; among participants completing a 3-month interview ( n = 890 ) , 96 % reported the same . However , only about 50 % of participants reported receiving the booklet from their physician ; the remainder received the booklet from other clinic staff . Overall , 93 % reported reading at least part of the booklet . Use of the booklet varied little whether it was delivered by a physician or staff person , but it was more likely to be read as time spent discussing the booklet increased . Conclusions . Physician cooperation and evidence of intervention effectiveness support the use of primary care for the delivery of interventions to change diet ; training the entire health team and repeating dietary advice at subsequent visits may improve the success of such interventions [3270575] Objective To evaluate the effectiveness and costs of a multifaceted flexible educational programme aim ed at reducing antibiotic dispensing at the practice level in primary care . Design R and omised controlled trial with general practice s as the unit of r and omisation and analysis . Clinicians and research ers were blinded to group allocation until after r and omisation . Setting 68 general practice s with about 480 000 patients in Wales , United Kingdom . Participants 34 practice s were r and omised to receive the educational programme and 34 practice s to be controls . 139 clinicians from the intervention practice s and 124 from control practice s had agreed to participate before r and omisation . Practice level data covering all the clinicians in the 68 practice s were analysed . Interventions Intervention practice s followed the Stemming the Tide of Antibiotic Resistance ( STAR ) educational programme , which included a practice based seminar reflecting on the practice s ’ own dispensing and resistance data , online educational elements , and practising consulting skills in routine care . Control practice s provided usual care . Main outcome measures Total numbers of oral antibiotic items dispensed for all causes per 1000 practice patients in the year after the intervention , adjusted for the previous year ’s dispensing . Secondary outcomes included reconsultations , admissions to hospital for selected causes , and costs . Results The rate of oral antibiotic dispensing ( items per 1000 registered patients ) decreased by 14.1 in the intervention group but increased by 12.1 in the control group , a net difference of 26.1 . After adjustment for baseline dispensing rate , this amounted to a 4.2 % ( 95 % confidence interval 0.6 % to 7.7 % ) reduction in total oral antibiotic dispensing for the year in the intervention group relative to the control group ( P=0.02 ) . Reductions were found for all classes of antibiotics other than penicillinase-resistant penicillins but were largest and significant individually for phenoxymethylpenicillins ( penicillin V ) ( 7.3 % , 0.4 % to 13.7 % ) and macrolides ( 7.7 % , 1.1 % to 13.8 % ) . There were no significant differences between intervention and control practice s in the number of admissions to hospital or in reconsultations for a respiratory tract infection within seven days of an index consultation . The mean cost of the programme was £ 2923 ( € 3491 , $ 4572 ) per practice ( SD £ 1187 ) . There was a 5.5 % reduction in the cost of dispensed antibiotics in the intervention group compared with the control group ( −0.4 % to 11.4 % ) , equivalent to a reduction of about £ 830 a year for an average intervention practice . Conclusion The STAR educational programme led to reductions in all cause oral antibiotic dispensing over the subsequent year with no significant change in admissions to hospital , reconsultations , or costs . Trial registration IS RCT No 63355948 Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Self-management programs have been widely reported to help patients manage symptoms and contain utilization of health care re sources for several chronic conditions , but to date no systematic review across multiple chronic diseases has been reported . We evaluated the efficacy of patient self-management educational programs for chronic diseases and critically review ed their methodology . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

21901680

[14512038] BACKGROUND Undernutrition and weight loss are important determinants of clinical outcome in older patients after hip fracture but the effectiveness of nutritional support programs in routine clinical practice remains controversial . AIMS OF THE PROJECT : To determine if oral nutritional supplements given daily for 28 days after hip fracture surgery could prevent weight loss and /or lead to improved clinical outcomes ( mortality rates , discharge destination , activities of daily living or length of hospital stay ) in non-malnourished community-dwelling older women with hip fracture . METHODS One hundred and nine women with BMI range 20 - 30 kg/m(2 ) were allocated to either nutritional supplements ( 352 kcal/day ) or usual hospital nutrition using a quasi-r and omisation technique . Body weight changes were monitored at 4 and 8 weeks and clinical outcomes were recorded at discharge and at 6 months . RESULTS No significant differences in weight change or clinical outcomes were seen between the two groups . Compliance with consuming the nutritional supplements was quite variable and there was a significant negative correlation between the amount of supplement consumed and subsequent weight change ( r=-0.36 , P=0.019 ) . CONCLUSIONS Poor compliance with oral nutritional supplements is an important determinant of the effectiveness of oral nutritional interventions in preventing weight loss after hip fracture . Whilst this may explain the lack of clinical improvements seen , our data do not support the routine use of oral nutritional supplements in non-malnourished hip fracture patients [8878142] There is a common perception that malnutrition is an inevitable manifestation of illness , that oral nutritional supplements are not taken or reduce the consumption of oral diet , and that nasogastric feeding is poorly tolerated . This study assessed the efficacy of supplemental enteral feeding on the nutritional status of malnourished patients , to compare oral supplements ( OS ) with overnight supplemental nasogastric feeding ( NG ) on nutritional status and to determine the effect of nutritional supplements on oral diet . Malnourished hospital patients were r and omized to one of three groups : control ( C ) , OS , or NG . All patients had access to hospital diet . Supplements were prescribed to meet estimated nutritional needs . Nutritional status was recorded at the start and the end of the feeding period . The total nutritional intake was recorded . Weight gain occurred in 64 % of the supplemented patients , whereas 73 % of the controls lost weight with mean weight changes of + 2.9 % OS . + 3.3 % NG , and -2.5 % C. There was no difference in the mean energy intake from food in the three groups . There were no documented complications of OS and three minor complications of NG . Both methods of supplementation allow weight gain without significantly affecting spontaneous oral intake [1802209] Ninety-three cancer patients about to undergo radiotherapy were studied . These patients were affected by cancer of the head and neck , breast cancer , and abdominopelvic cancer . They were r and omly distributed into control and experimental groups . The patients from the control group were allowed to eat ad libitum , whereas those from the experimental group followed a strict nutritional protocol that covered their needs while satisfying their particular tastes and habits . Data were collected the day before radiotherapy commenced and the day treatment ended . Anthropometric , analytical , and clinical parameters were determined . The results showed the benefit of dietetic treatment in experimental patients with head and neck or abdominopelvic cancer [17419798] AIMS To investigate whether a nutritional intervention in older women and men with femoral neck fracture had an effect on postoperative complications during hospitalization and on nutritional status at a four-month follow-up . METHODS The design was a r and omized controlled trial . The present study sample consisted of 157 patients aged 70 years and above with femoral neck fracture . The nutritional intervention included , among other things , a nutritional journal to detect nutrition deficiencies and protein-enriched meals for at least four days postoperatively . Further , at least two nutritional and protein drinks were served each day during the whole hospitalization and other factors that would influence the patient 's nutrition were also considered and dealt with . Postoperative complications were registered and patients were assessed using the Mini Nutritional Assessment ( MNA ) scale , including body mass index ( BMI ) , on admission and at a four-month follow-up . RESULTS Malnutrition was common and low MNA scores were associated with postoperative complications such as delirium and decubitus ulcers . There were significantly fewer days of delirium in the intervention group , seven patients in the intervention group developed decubitus ulcers vs. 14 patients in the control group and the total length of hospitalization was shorter . There were no detectable significant improvements regarding nutritional parameters between the intervention and the control group at the four-month follow-up but men improved their mean BMI , body weight and MNA scores in both the intervention and the control groups while women deteriorated in both groups . CONCLUSIONS Malnutrition was common among older people with hip fractures admitted to hospital . The nutritional intervention might have contributed to the patients suffering fewer days with delirium , fewer decubitus ulcers and shorter hospitalization but did not improve the long-term nutritional status , at least not in women . RELEVANCE TO CLINICAL PRACTICE This nutritional intervention , which was included in a multifactorial multidisciplinary intervention , is inexpensive and relatively easy to implement . It has significant effects on complications but no long-term effect on nutritional parameters , at least not in women [8467111] Malnutrition and cachexia are characteristic symptoms of human immunodeficiency virus (HIV)-1 infection and AIDS . To identify risk situations that might affect nutritional behavior and status and to evaluate the therapeutic effect of an intensified oral nutritional intervention , we analyzed 81 consecutively treated homosexual HIV-infected out patients with malnutrition retrospectively and could follow the outcome of a nutritional intervention prospect ively in 54 of them . Nutritional therapy was ineffective for only 5 of the 54 patients ; constant weight loss could be stopped in 31 of the patients , and 18 patients could even gain weight . We suggest intensified oral nutritional intervention should be an integral part of the treatment of HIV-infected patients to prevent or treat malnutrition [18514630] Decreases in whole-body lean mass can cause sarcopenia , a disease frequently found in the elderly . This condition is frequently associated with frailty and disability in aging as well as the onset and progression of several geriatric syndromes . Sarcopenia therefore must be managed with multidimensional approaches that include physical training , nutritional support , and metabolic and anabolic treatment . The purpose of our study was to assess the effect of an orally administered special mixture of amino acids ( AAs ) in elderly subjects with reduced lean body mass and sarcopenia . A r and omized , open-label , crossover study was conducted in 41 elderly subjects ( age range : 66 - 84 years ) with sarcopenia , assigned to 2 distinct treatments ( AAs and placebo ) . All subjects had normal body weight ( body mass index within 19 - 23 ) . The AA treatment consisted of 70.6 kcal/day ( 1 kcal = 4.2 kJ ) of 8 g of essential AA snacks , given at 10:00 am and 5:00 pm . Lean mass was measured with dual-energy x-ray absorptiometry in leg , arm , and trunk tissues . Significant increases in whole-body lean mass in all areas were seen after 6 months and more consistently after 18 months of oral nutritional supplementation with AAs . Fasting blood glucose , serum insulin , and homeostatic model assessment of insulin resistance ( an index of insulin resistance ) significantly decreased during AA treatment . Furthermore , a significant reduction in serum tumor necrosis factor-alpha ( TNF-alpha ) and a significant increase in both insulin-like growth factor-1 ( IGF-1 ) serum concentrations and in the IGF-1/TNF-alpha ratio were also found . No significant adverse effects were observed during AA treatment . These preliminary data indicate that nutritional supplements with the oral AA mixture significantly increased whole-body lean mass in elderly subjects with sarcopenia . The improvement in the amount of whole-body lean mass could be linked to increased insulin sensitivity and anabolic conditions related to IGF-1 availability [16182039] BACKGROUND AND AIMS In patients with liver cirrhosis , protein-energy malnutrition is a frequent finding and a risk factor influencing survival . The aim was to estimate the effects of an adequate diet on malnutrition and clinical outcome in patients with Child A or B HCV-related liver cirrhosis . METHODS We enrolled 90 consecutive out patients ( M/F=52/38 ) with liver cirrhosis , 30 in Child class A and 60 in class B. Patients were evaluated by anamnesis , clinical examination , estimation of daily caloric intake and measurement of anthropometrical and biochemical indexes . Patients were r and omized into two groups : group 1 with a 3-month oral controlled diet started one week after the first examination and this was followed by a 3-month of spontaneous dietary intake , and group 2 which started a 3-month spontaneous dietary intake followed by a 3-month of controlled diet . The follow-up was performed every month . RESULTS During the period of controlled diet in patients of both groups , protein malnutrition assessed by midarm muscle circumference , creatinine-height index and serum albumin significantly improved independently of the Child class . Lipid malnutrition , assessed by triceps skin fold thickness values , did not improve during the course of the study . The compliance to the prescribed diet was very high in both groups , and no carry over effect of the previous dietary intake was observed during the follow-up period . CONCLUSIONS The results emphasize the importance of both nutritional status evaluation and improvement in the Child A and B cirrhotic patients with HCV-related disease . The proposed nutritional approach was able to influence their protein malnutrition positively [6796711] In recent years , the concept of nutritional support as a part of a comprehensive cancer management program has gained increasing acceptability . However , little data is available in regard to the effect of nutritional support programs on the chronic disease state represented by recurrent or persistent cancer that characterizes patients undergoing systemic chemotherapy . In 1977 we undertook to study this problem in a r and omized prospect i ve study design ed to evaluate the effects of long-term ( 12 months ) enteral nutritional support in a group of ambulatory breast cancer patients undergoing a st and ard cytotoxic chemotherapy treatment program , in an adjuvant or therapeutic setting . The results of this study suggest that patients with breast cancer are overweight as compared to the general population and that any significant change in initial body weight , either a gain or a loss , is associated with an increased risk of recurrent disease . Data are presented which show little or no correlation between st and ard parameters of nutritional assessment and risk of disease recurrence and /or response to chemotherapy . These data also suggest that until we better underst and the relationship between tumor and host in breast cancer patients , we offer nutritional support programs only in situations where there are specific clinical indications for such interventions [16280442] BACKGROUND About 25 - 40 % of hospital patients are malnourished . With current clinical practice s , only 50 % of malnourished patients are identified by the medical and nursing staff . OBJECTIVE The objective of this study was to report the cost and effectiveness of early recognition and treatment of malnourished hospital patients with the use of the Short Nutritional Assessment Question naire ( SNAQ ) . DESIGN The intervention group consisted of 297 patients who were admitted to 2 mixed medical and surgical wards and who received both malnutrition screening at admission and st and ardized nutritional care . The control group consisted of a comparable group of 291 patients who received the usual hospital clinical care . Outcome measures were weight change , use of supplemental drinks , use of tube feeding , use of parenteral nutrition and in-between meals , number of consultations by the hospital dietitian , and length of hospital stay . RESULTS The recognition of malnutrition improved from 50 % to 80 % with the use of the SNAQ malnutrition screening tool during admission to the hospital . The st and ardized nutritional care protocol added approximately 600 kcal and 12 g protein to the daily intake of malnourished patients . Early screening and treatment of malnourished patients reduced the length of hospital stay in malnourished patients with low h and grip strength ( ie , frail patients ) . To shorten the mean length of hospital stay by 1 d for all malnourished patients , a mean investment of 76 euros ( 91 US dollars ) in nutritional screening and treatment was needed . The incremental costs were comparably low in the whole group and in the subgroup of malnourished patients with low h and grip strength . CONCLUSIONS Screening with the SNAQ and early st and ardized nutritional care improves the recognition of malnourished patients and provides the opportunity to start treatment at an early stage of hospitalization . The additional costs of early nutritional care are low , especially in frail malnourished patients [15277171] BACKGROUND Nutritional support is often recommended as part of the treatment of tuberculosis , but it has never been properly tested . OBJECTIVE We assessed the effects of early nutritional intervention on lean mass and physical function in patients with tuberculosis and wasting . DESIGN Patients who started antituberculous therapy within the previous 2 wk were r and omly assigned to receive st and ard nutritional counseling ( control group ) or nutritional counseling to increase their intake through diet and high-energy supplements ( nutritional supplement group ) for 6 wk . Body composition was measured by dual-energy X-ray absorptiometry , and physical function was assessed by maximum grip strength . RESULTS Patients in the nutritional supplement group ( n = 19 ) had a significantly greater increase in body weight ( 2.57 + /- 1.78 compared with 0.84 + /- 0.89 kg , P = 0.001 ) , total lean mass ( 1.17 + /- 0.93 compared with 0.04 + /- 1.26 kg , P = 0.006 ) , and grip strength ( 2.79 + /- 3.11 compared with -0.65 + /- 4.48 kg , P = 0.016 ) than did the control subjects ( n = 17 ) at week 6 . During subsequent follow-up , the increase in body weight remained greater in the nutritional supplement group , but this increase was due mainly to a greater gain in fat mass in the nutritional supplement group than in the control group . CONCLUSIONS Early intervention to increase nutritional intake increases lean mass and physical function . This adjunct to tuberculosis therapy could confer socioeconomic and survival benefits that deserve investigation in large-scale trials . Nutritional intervention after the initial phase of treatment could be less beneficial because it mainly increases fat [7500174] Nutritional deficiencies , frequently observed among the frail elderly , have been associated with increased morbidity and dependency . A r and omized clinical trial was conducted to assess the impact of nutritional supplementation on the functional status of frail elderly living at home . Subjects ( n = 50 ) over age 60 ( mean 78 y ) requiring community services and at elevated risk of undernutrition ( excessive weight loss or body mass index < 24 kg/m2 ) were r and omized to a high energy nutrient dense supplement provided by a dietitian or a control group receiving visits only . Outcome measures , including changes in h and grip strength , general well-being score , perception of health and number of falls , were measured by an investigator who was unaware of treatment assignment . After 12 wk , weight gain was greater in the supplemented group ( 2.1 + /- 2.3 vs. 0.6 + /- 1.6 kg ; P < 0.01 ) . Despite adequate statistical power , no functional measures differed except that the number of falls was lower among treated subjects vs. controls ( 0 % vs. 21 % ; P = 0.05 ) . Frail elderly can gain weight through oral supplementation , indicating the reversibility of weight loss in this group , but changes in functional status indicators may require a longer period of supplementation [17324657] BACKGROUND A r and omized controlled trial previously conducted in radiation oncology patients demonstrated that nutrition intervention had a beneficial impact on body weight , nutritional status , and quality of life compared with st and ard practice , but it did not report on dietary intake data . OBJECTIVE To determine the impact of nutrition intervention compared with st and ard practice on dietary intake in out patients receiving radiotherapy . DESIGN Prospect i ve , r and omized , controlled trial . SUBJECTS Sixty consecutive radiation oncology out patients ( 51 men and nine women ; age 61.9+/-14 years [ mean+/-st and ard deviation ] ) . SETTING Australian private radiotherapy facility . INTERVENTION Patients were r and omly assigned to receive either nutrition intervention ( n=29 ) ( nutrition counseling following the American Dietetic Association [ ADA ] medical nutrition therapy [ MNT ] protocol for radiation oncology ) or st and ard practice ( n=31 ) ( general nutrition talk and booklet ) . MAIN OUTCOME MEASURE Dietary intake ( protein , energy , fiber ) assessed at baseline and at 4 , 8 , and 12 weeks after starting radiotherapy . STATISTICAL ANALYSES Repeated- measures analysis of variance done on an intention to treat basis . RESULTS The nutrition intervention group had a higher mean total energy ( P=0.029 ) and protein intake ( P<0.001 ) compared with the st and ard practice group . Mean intake per kilogram of body weight for the nutrition intervention group ranged from 28 to 31 kcal/kg/day compared with 25 to 29 kcal/kg/day for the st and ard practice group ( P=0.022 ) . The nutrition intervention group had a higher mean protein intake ( 1.1 to 1.3 g/kg/day ) compared with the st and ard practice group ( 1.0 to 1.1 g/kg/day ) ( P=0.001 ) . Although the change in fiber intake between the groups was not significant , there was a trend in the anticipated direction ( P=0.083 ) . CONCLUSIONS Intensive nutrition intervention following the ADA MNT protocol results in improved dietary intake compared with st and ard practice and seems to beneficially impact nutrition-related outcomes previously observed in oncology out patients receiving radiotherapy . The ADA MNT protocol for radiation oncology is a useful guide to the level of nutrition support required [10807893] BACKGROUND Patients who undergo surgery are at risk of malnutrition due to periods of starvation , the stress of surgery , and subsequent increase in metabolic rate . There are limited data on nutritional outcome of surgical patients . AIMS To investigate changes in nutritional status and the influence of oral supplements on nutritional status , morbidity , and quality of life in postoperative surgical patients . METHODS Entry was determined by the presence of malnutrition , as defined by a body mass index ( BMI ) ⩽20 kg/m2 , anthropometric measurements ⩽15th percentile on admission , or initiation of oral diet postoperatively and /or a weight loss of 5 % or more during the operative period . We studied 101 patients : 52 were r and omised to the treatment group ( TG ) and prescribed a 1.5 kcal/ml nutritional supplement ; 49 patients were r and omised to the control group ( CG ) and continued with routine nutritional management . Nutritional status was assessed by weight , anthropometry , and grip strength , with measurements taken at two weekly intervals for 10 weeks . Complications , namely wound infection , chest infection , and antibiotic use were documented . Quality of life ( QOL ) was assessed using the UK SF-36 question naire . RESULTS Patients in the control group lost a maximum mean ( SD ) of 5.96 ( 4.21 ) kg in weight over a period of eight weeks while patients in group TG lost less weight overall ( maximum mean ( SD ) 3.40 ( 0.89 ) kg ( p<0.001 ) occurring at four weeks and progressively regained weight from week 4 ) . Anthropometry , grip strength , and QOL were similarly significantly different between groups ( p<0.001 ) . Fewer patients in the treatment group ( 7/52 ) required antibiotic prescriptions compared with the control group ( 15/49 ) . CONCLUSIONS Nutritional status declined for two months after discharge . Postoperative nutritional supplementation improved nutritional status , QOL , and morbidity in these patients [8598433] OBJECTIVE to evaluate the use of high-energy , high-protein , oral , liquid , nutrition supplementation and nutrition counseling on the weight status of patients infected with the human immunodeficiency virus ( HIV ) with and without secondary infections . DESIGN Prospect i ve , descriptive , intervention trial . Follow-up clinic visits were scheduled every 1 to 3 weeks for at least 6 weeks to monitor weight , gastrointestinal symptoms , number of supplements consumed , and incidence of secondary infections . SUBJECTS/ SETTING Community-based , HIV-infected patients , with and without an acquired immunodeficiency syndrome ( AIDS ) defining illness , who were receiving outpatient medical care at Deaconess Hospital . Twenty-two patients enrolled ; however , 4 dropped out and 1 died , so 17 were eligible for evaluation . INTERVENTION Dietary counseling consisted of recommendations to consume a high-protein diet ( 1.5 g/kg ideal body weight ) ; select foods that minimize gastrointestinal complications ; and take at least one high-energy , high-protein , oral , liquid , nutrition supplement daily . MAIN OUTCOME MEASURES Energy intake from the supplements and weight change over time in relation to whether a secondary infection occurred . STATISTICAL ANALYSIS Means , st and ard deviations , and frequency . RESULTS At the time of entry to the study , the patients with preexisting weight loss ( 16 of 17 ) were 14+/-8 % below their usual body weight . On average , patients consumed 11+/-4 supplements per week for 6+/-3 weeks . The majority ( 12 of 17 ) were able to gain or maintain weight . Overall weight change was 1.1+/-2.2 kg . Only 5 of 17 patients lost weight , 4 of whom developed a secondary infection during the study ( ie , after enrollment in the study ) . All of those who developed a secondary infection were classified as having AIDS and had lower mean CD4 counts at baseline than those who did not develop a secondary infection . Although those who developed a secondary infection had a higher incidence of weight loss , their consumption of oral supplements per week was greater than that of those without a secondary infection . APPLICATIONS/ CONCLUSIONS In patients with HIV infection and in the early stages of AIDS without a secondary infection , weight gain and /or maintenance was achievable with a high-energy , high-protein , oral , liquid , nutrition supplement in conjunction with nutrition counseling . The majority of the patients who developed a secondary infection , however , lost weight despite the use of supplements and counseling . Use of a high-energy , high-protein , oral , liquid , nutrition supplement , with intact nutrients , should be the first-line nutrition treatment for malnourished , HIV-infected patients without secondary infections [8909354] OBJECTIVE To evaluate the association of oral food intake with survival in very old demented nursing home patients . DESIGN A prospect i ve cohort study . SETTING A nursing home in northern Italy . MEASUREMENTS Anthropometric and laboratory nutritional indicators and nutrient intake were assessed in 33 demented ( age 85.7 + /- 5.7 years ) and 25 nondemented ( age 84.9 + /- 5.7 years ) patients . Mortality data were collected over a 28-month follow-up period . Association of survival with dementia was estimated by Kaplan-Meyer analysis and multivariate Cox proportional hazard models . RESULTS Nutrient intake and nutritional status were good compared with data in the literature and were similar in demented and nondemented patients , except for smaller triceps skinfold thickness in the demented . The cumulative annual death rate was 0.23 deaths per subject per year , similar in the demented ( 0.23 ) and the nondemented ( 0.22 ) . Unadjusted survival by Kaplan-Meyer analysis was similar in the two groups , and correction for-age , gender , cognition , triceps skinfold thickness , and number of drugs in a Cox model did not alter the relationship . CONCLUSIONS Dementia developing in very old age is not necessarily associated with malnutrition and decreased life expectancy [16679331] Abstract Objective To assess the effect of family style mealtimes on quality of life , physical performance , and body weight of nursing home residents without dementia . Design Cluster r and omised trial . Setting Five Dutch nursing homes . Participants 178 residents ( mean age 77 years ) . Two wards in each home were r and omised to intervention ( 95 participants ) or control groups ( 83 ) . Intervention During six months the intervention group took their meals family style and the control group received the usual individual pre-plated service . Main outcome measures Quality of life ( perceived safety ; autonomy ; and sensory , physical , and psychosocial functioning ) , gross and fine motor function , and body weight . Results The difference in change between the groups was significant for overall quality of life ( 6.1 units , 95 % confidence interval 2.1 to 10.3 ) , fine motor function ( 1.8 units , 0.6 to 3.0 ) , and body weight ( 1.5 kg , 0.6 to 2.4 ) . Conclusion Family style mealtimes maintain quality of life , physical performance , and body weight of nursing home residents without dementia . Trial registration Clinical trials [9309995] The impact of oral nutritional supplementation during an acute exacerbation of COPD on functional status was assessed through measuring change in lung function , strength testing , and general well-being . Subjects hospitalized for an acute exacerbation of COPD ( n = 33 ) were r and omized to extra nutritional support or the regular hospital care . They consumed an additional 10 kcal/kg/d . Outcome measures were measured at 2 wk as change scores . Forced vital capacity ( % predicted ) improved in the treatment group as compared with the control group ( + 8.7 % versus -3.5 % , p = 0.015 ) , and change in FEV1 was in the same direction but not significantly different ( p = 0.099 ) . There were no changes in h and grip strength or respiratory muscle strength , but there was a trend towards more improvement in the general well-being score ( + 11.96 versus -10.25 , p = 0.066 ) . Almost all subjects were in negative nitrogen balance , indicating muscle wasting . The degree of muscle wasting was strongly correlated with the dose of corticosteroids ( r = 0.73 , p < 0.005 ) . In conclusion , it is difficult to prevent important muscle wasting in patients with COPD treated with corticosteroids , but some small gains were observed with increased dietary intake [15788122] Since long-term weight maintenance ( WM ) is a major problem , interventions to improve WM are needed . The aim of the study was to investigate whether the addition of protein to the diet might limit weight regain after a weight loss of 5 - 10 % in overweight subjects . In a r and omised parallel study design , 113 overweight subjects ( BMI 29.3 ( SD 2.5 ) kg/m2 ) ; age 45.1 ( SD 10.4 ) years ) followed a very-low-energy diet for 4 weeks , after which there was a 6-month period of WM . During WM , subjects were r and omised into either a protein group or a control group . The protein group received 30 g/d protein in addition to their own usual diet . During the very-low-energy diet , no differences were observed between the groups . During WM , the protein group showed a higher protein intake ( 18 % v. 15 % ; P<0.05 ) , a lower weight regain ( 0.8 v. 3.0 kg ; P<0.05 ) , a decreased waist circumference ( -1.2 ( SD 0.7 ) v. 0.5 ( SD 0.5 ) cm ; P<0.05 ) and a smaller increase in respiratory quotient ( 0.03 ( SD 0.01 ) v. 0.07 0.01 ; (SD/)P < 0.05 ) compared with the control group . Weight regain in the protein group consisted of only fat-free mass , whereas the control group gained fat mass as well . Satiety in the fasted state before breakfast increased significantly more in the protein group than in the control group . After 6 months follow-up , body weight showed a significant group x time interaction . A protein intake of 18 % compared with 15 % result ed in improved WM in overweight subjects after a weight loss of 7.5 % . This improved WM implied several factors , i.e. improved body composition , fat distribution , substrate oxidation and satiety [12382215] OBJECTIVE This controlled trial was undertaken to evaluate the benefits of short-term enteral nutrient supplementation in maintenance hemodialysis ( MHD ) patients using a high-calorie and high-protein blend formula ( low-cost home-prepared [ HP ] blend or a commercially available supplement ) and to study its effect on selected parameters of nutritional status . The acceptability and palatability of the HP blend formula , ease of use , and cost were also assessed in comparison with the commercial nutritional supplement ( CNS ) . DESIGN R and omized controlled trial . SETTING Hemodialysis ( HD ) unit of a tertiary referral care hospital in Southern India . PATIENTS Nondiabetic adult MHD patients with no intercurrent illness , on regular thrice weekly MHD for at least 1 month before recruitment , with a body mass index ( BMI ) < 20 and a serum albumin level of < 4.0 g/dL. Patients were r and omized into control group and experimental group , the latter in turn to recieve either CNS or HP blend . INTERVENTION The control group received appropriate monitoring , including dietary recall and counselling for the prescribed diet ( protein intake of 1.2 g/kgIBW/d and energy of 35 to 45 kcal/kgIBW/d ) but no specific post-HD supplement . Patients in the supplement group received the respective supplement post-HD ( providing 500 kcal and 15 g protein ) for 1 month in addition to the monitored diet prescription . MAIN OUTCOME MEASURES ( 1 ) Nutritional status parameters , BMI and serum albumin ; ( 2 ) functional status on a 10-point Karnofsky scale ; ( 3 ) adverse metabolic effects , hyperphosphatemia at start and end of study ; and ( 4 ) subjective scoring for appetite , and acceptability of and tolerance to supplement . RESULTS Both groups showed an improvement in dry weight and BMI . In addition , the supplement group showed a significant increase in serum albumin level and functional scoring . Mild hyperphosphatemia occurred in the supplement group . An increase in baseline food intake was seen in the control group , but not in the supplemented group . No intolerance was reported to either supplement . CONCLUSION Enteral nutrient supplementation was shown to bring about a significant improvement in serum albumin level even in a short-term study . Use of an HP supplement was beneficial , acceptable , and inexpensive [8409181] OBJECTIVES To determine why elderly nursing home patients receive liquid oral protein supplements , what nutritional assessment is utilized , and whether there is evidence of effectiveness . DESIGN Retrospective , case control study comparing patients over 65 years of age , at two nursing homes , who were served oral supplements ( OS ) at least twice daily ( n = 56 ) , with a r and om sample of non-supplemented , non-tube fed patients ( n = 53 ) . Comparisons included medical diagnoses , medications , morbidity and mortality , weight changes , laboratory test results , and functional and behavioral status . RESULTS Nursing home patients were begun on OS ( median time after admission = 2 months , range = 0 - 72 months ) primarily because of weight loss ( 71 % ) and poor appetite ( 16 % ) . Supplemented patients were below an age-adjusted body weight on admission , unlike controls , and continued to lose weight until OS were started . On OS , weight was slowly regained over 9 - 10 months in a majority of patients to approximate admission weight . Some patients on OS showed improvement in albumin , total lymphocyte count , cholesterol , or hemoglobin , but too few patients had sufficient lab tests to verify any consistent effect . Mortality was higher in OS patients ( 8 vs 2 , P = 0.057 ) , who were also somewhat older ( 87.9 vs 84.5 years ) , but there was no statistical difference in infection or hospitalization rate . MEASUREMENTS Nutritional assessment in these nursing homes consisted almost exclusively of ( 1 ) serial measurement of weight , ( 2 ) comparison of weight to ( a ) " ideal body weight " and ( b ) previous weight , and ( 3 ) a subjective evaluation of food consumption . No other anthropometric evaluations or laboratory tests were conducted for nutritional assessment . CONCLUSIONS The diagnosis of and intervention in under-nutrition in nursing home patients is frequently disorganized . In addition , nutritional assessment , either for screening or for following intervention , is hampered by the lack of convenient and unambiguous assessment tools . OS use is associated with weight gain in many nursing home patients and also improves other nutritional parameters in selected individuals [565418] Seventeen patients undergoing 19 major urological operations for bladder cancer or rectal leiomyosarcoma ( 1 case ) were studied after r and omization for 3 hypocaloric dietary regimens , preoperative keto-adaptation by a carbohydrate-free , oral protein diet continued in the postoperative period by isotonic amino acid infusions , postoperative amino acid infusions only and 5 per cent dextrose infusions . In these normally nourished patients serum transferrin ( plus 13 mg./dl . minus 30 mg./dl . , minus 69 mg./dl . , p less than 0.05 for the first and combined amino acid groups against the third group ) and 2 other short half-life hepatic secretory proteins , prealbumin and retinol-binding protein , represented sensitive indexes of visceral protein and nutritional support , superior to nitrogen balance , anthropometric assays , delayed hypersensitivity skin test reactivity and serum albumin . Near isotonic amino acid infusions were more effective in preserving visceral protein status than 5 per cent dextrose but preoperative keto-adaptation was not shown to have any increased benefit over protein-sparing therapy given only after an operation [9195264] Summary . The objective of this prospect i ve study of matched controls was to find out whether supplementary nutrition would improve wound healing and decrease mortality in patients undergoing transtibial amputation for occlusive arterial disease . The nutritional status of 32 consecutive transtibial amputees was assessed and 28 were classified as malnourished . Supplementary nutrition was given reaching an average intake of 2098 kcal/day for a total of 11 days . In 24 patients , at least 5 days of preoperative supplementary nutrition were given , followed by postoperative treatment for a total of 11 days . Four patients who had an immediate operation were given only postoperative treatment , and 4 were excluded . The controls were 32 amputees in another hospital and matching procedures were carried out with corrections for diabetes , sex , age , smoking habits , previous vascular surgery and living conditions before amputation . Healing , including those healed before death in both groups , occurred in 26 of the nutrition group compared to 13 in the control group , which was statistically significant . Nine patients died within 6 months in the nutrition group compared to 14 of the controls ( not significant ) . Malnutrition was present in nearly 90 % of transtibial amputees and supplementary nutrition improved healing , but not mortality . Résumé . L’objectif de cette étude prospect i ve a été d’étudier si une augmentation de l’apport nutritionnel peut ameliorer la cicatrisation et réduire la mortalité chez les malades ayant subi une amputation de jambe en raison d’une maladie vasculaire . L’état nutritionnel de trente-deux patients consécutifs ayant subi une amputation de jambe a étéévalué . Vingt-huit ont été considérés comme malnutris . Une nutrition additionnelle leur a été donnée avec un apport moyen de 2098 kcal par jour pendant 11 jours . Chez 24 malades une nutrition additionnelle , de cinq jours au moins en préopératoire , a été suivie par un traitement postopératoire pour atteindre un total de 11 jours . Quatre malades necessitant une amputation en urgence n’ont re*u le traitement que postopératoire et quatre malades ont été exclus . Trente deux amputés de jambe venant d’un hopital universitaire voisin ont été utilisés comme contrôle , après associations des cas tenant compte de l’age , le sexe , du diabète , de la consommation de tabac , des opérations vasculaires précédentes et des conditions de vie antérieure à l’amputation . L’étude de la cicatrisation a montré que 26 amputés étaient cicatrisés dans le groupe ayant bénéficié d’un apport nutritionnel contre 13 dans le groupe de controle , P= 0.001 . Neuf patients sont morts dans les premier six mois dans le groupe ayant bénéficié d’un apport nutritionnel contre 14 dans le groupe de controle , ( n. s. ) . Cette étude montre clairement que près de 90 % des amputés de jambe étaient malnutris et qu’un apport nutritionnel a amelioré la cicatrisation du moignon sans pour autant augmenter la survie [15920748] BACKGROUND We aim ed to determine the effect of dietary counseling or oral supplements on outcome for patients with cancer , specifically , nutritional outcome , morbidity , and quality of life ( QOL ) , during and 3 months after radiotherapy . METHODS Seventy-five patients with head and neck cancer who were referred for radiotherapy ( RT ) were r and omized to the following groups : group 1 ( n = 25 ) , patients who received dietary counseling with regular foods ; group 2 ( n = 25 ) , patients who maintained usual diet plus supplements ; and group 3 ( n = 25 ) , patients who maintained intake ad lib . Nutritional intake ( determined by diet history ) and status ( determined by Ottery 's Subjective Global Assessment ) , and QOL ( determined by the European Organization for the Research and Treatment of Cancer Quality of Life Question naire version 3.0 [ EORTC QLQ-C30 ] ) were evaluated at baseline , at the end of RT , and at 3 months . RESULTS Energy intake after RT increased in both groups 1 and 2 ( p < or = .05 ) . Protein intake also increased in both groups 1 and 2 ( p < or = .006 ) . Both energy and protein intake decreased significantly in group 3 ( p < .01 ) . At 3 months , group 1 maintained intakes , whereas groups 2 and 3 returned to or below baseline levels . After RT , > 90 % of patients experienced RT toxicity ; this was not significantly different between groups , with a trend for reduced symptomatology in group 1 versus group 2/group 3 ( p < .07 ) . At 3 months , the reduction of incidence/severity of grade 1 + 2 anorexia , nausea/vomiting , xerostomia , and dysgeusia was different : 90 % of the patients improved in group 1 versus 67 % in group 2 versus 51 % in group 3 ( p < .0001 ) . After RT , QOL function scores improved ( p < .003 ) proportionally with improved nutritional intake and status in group 1/group 2 ( p < .05 ) and worsened in group 3 ( p < .05 ) ; at 3 months , patients in group 1 maintained or improved overall QOL , whereas patients in groups 2 and 3 maintained or worsened overall QOL . CONCLUSIONS During RT , nutritional interventions positively influenced outcomes , and counseling was of similar/higher benefit ; in the medium term , only counseling exerted a significant impact on patient outcomes [8029587] A body weight lower than 90 % of the optional value has an unfavorable influence on the prognosis of chronic obstructive pulmonary disease ( COPD ) . Short term studies of up to three months duration have shown improved function of respiratory muscle exercise tolerance and immunologic parameters by an increased caloric intake of 45 kcal/kg body weight . In a r and omized trial of twelve months 14 of 30 patients with an average FEV1 of 0.8 l were instructed to take a high calorie diet . For simplicity a part of the calories were administered as Fresubin , a fluid nutrient formula . Although a weight gain of 7 kg ( p = 0.003 ) was obtained the difference to the control group was statistically not significant ( p = 0.08 ) . The same was true for skin fold thickness ( 12.4 vs 5.7 mm ) , change of ventilatory parameters and the 6 minute walking distance ( -33 vs -86 m ) . Subjective improvement was , however , impressive in all patients with dietary intervention , explainable probably by increased attention . Dietary counselling for increased intake of calories , vitamins and also calcium is thus very important in the treatment of patients with COPD [2409852] Malnutrition occurs frequently in patients with cancer of the gastrointestinal ( GI ) or head and neck area and can lead to negative outcomes . The aim of this study is to determine the impact of early and intensive nutrition intervention ( NI ) on body weight , body composition , nutritional status , global quality of life ( QoL ) and physical function compared to usual practice in oncology out patients receiving radiotherapy to the GI or head and neck area . Out patients commencing at least 20 fractions of radiotherapy to the GI or head and neck area were r and omised to receive intensive , individualised nutrition counselling by a dietitian using a st and ard protocol and oral supplements if required , or the usual practice of the centre ( general advice and nutrition booklet ) . Outcome parameters were measured at baseline and 4 , 8 and 12 weeks after commencing radiotherapy using valid and reliable tools . A total of 60 patients ( 51 M : 9F ; mean age 61.9±14.0 years ) were r and omised to receive either NI ( n=29 ) or usual care ( UC ) ( n=31 ) . The NI group had statistically smaller deteriorations in weight ( P<0.001 ) , nutritional status ( P=0.020 ) and global QoL ( P=0.009 ) compared with those receiving UC . Clinical ly , but not statistically significant differences in fat-free mass were observed between the groups ( P=0.195 ) . Early and intensive NI appears beneficial in terms of minimising weight loss , deterioration in nutritional status , global QoL and physical function in oncology out patients receiving radiotherapy to the GI or head and neck area . Weight maintenance in this population leads to beneficial outcomes and suggests that this , rather than weight gain , may be a more appropriate aim of NI [16354710] OBJECTIVE To examine how improved attention to nutritional status and dietary intake , achieved through the employment of dietetic assistants ( DAs ) , will affect postoperative clinical outcome among elderly women with hip fracture . DESIGN Open prospect i ve r and omised controlled trial , comparing conventional nursing care with the additional nutritional support provided by DA . SETTING Thirty-eight bedded acute trauma ward in a teaching hospital . PARTICIPANTS All but 11 of 344 consecutive admissions with acute nonpathological hip fracture were approached . Three hundred and eighteen ( 93 % ) agreed to inclusion . Sixteen were ineligible as they were immediately transferred to another acute ward , were managed conservatively or died preoperatively . PRIMARY OUTCOME MEASURE Postoperative mortality in the acute trauma unit . SECONDARY OUTCOME MEASURES Postoperative mortality at 4 months after fracture , length of stay , energy intake and nutritional status . RESULTS DA-supported participants were less likely to die in the acute ward ( 4.1 versus 10.1 % , P = 0.048 ) . This effect was still apparent at 4 month follow-up ( 13.1 versus 22.9 % , P = 0.036 ) . DA-supported subjects had significantly better mean daily energy intake ( 1,105 kcal versus 756 kcal/24 h , 95 % CI 259 - 440 kcal/24 h , P<0.001 ) , significantly smaller reduction in mid-arm circumference during their inpatient stay ( 0.39 cm , P = 0.002 ) and nonsignificantly favourable results for other anthropometric and laboratory measurements . CONCLUSION Dietetic or nutrition assistants are being introduced in units across the UK . This , the largest ever study of nutritional support after hip fracture , shows that their employment significantly reduced patients ' risk of dying in the acute trauma unit ; an effect that persisted at 4 month follow-up [6799196] Nutritional intervention in the cancer patient [ e.g. , total parenteral nutrition ( TPN ) ] might improve durable survival because of increased tolerance to aggressive tumor therapy . To determine whether this assumption is correct , 42 patients with diffuse histiocytic lymphoma were induced with prednisone , high-dose methotrexate , Adriamycin , cyclophosphamide , and VP-16 ( ProMACE ) . Nitrogen mustard-vincristine-procarbazine-prednisone ( MOPP ) consolidation was then used , followed by late intensification with ProMACE . Patients were selected r and omly to receive adjuvant TPN or a st and ard diet during ProMACE-MOPP treatment . While TPN patients had a greater median weight gain than did control patients , lean body mass and degree of myelosuppression did not improved as a consequence of TPN . There was no significant difference in tumor response or survival between TPN and control patients , whether or not the patients were initially malnourished . In a second trial , 32 young patients with metastatic or other poor-prognosis sarcomas were r and omly allocated to receive TP or a st and ard diet as an adjunct to one very intensive course of combination chemotherapy or chemotherapy plus total body irradiation ; autologous marrow transplantation was used with gain than did controls but remained in a negative nitrogen balance . Response rates and median durable survival did not differ between the two groups . In both trials , the maximum nutritional support permitted by currently available technology was offered . Thus , the limiting factor may not be nutritional status but rather the intrinsic biology of the tumors and the limitations of their response to current therapy . In in vitro studies of the possible influence of nutrition on cancer treatment , we have compared sublines of P388 murine leukemia cells which are sensitive or resistant to Adriamycin . The difference in drug sensitivity correlated with differences in lipid composition , with more intracellular lipid , and with greater membrane rigidity in the resistant cells . Resistant cells have a relatively poor transport of drug into the cell ; moreover , intracellular Adriamycin is sequestered in lipid depots away from DNA . These results suggest one possible relationship between nutritional phenomena and drug sensitivity [17964008] BACKGROUND Malnutrition is a common problem in patients with digestive disease and is associated with impaired outcome . OBJECTIVE We investigated the effect of a three-month post-hospital nutritional intervention with high protein and energy supplements on body composition , muscle function and quality of life ( QoL ) in malnourished GI patients . PATIENTS AND INTERVENTION Eighty malnourished patients with benign digestive disease were r and omized to receive either oral nutritional supplements ( ONS ) for three months in addition to dietary counselling ( DC ) ( ONS patients ) or only dietary counselling ( DC patients ) . METHODS Nutritional status was determined with the subjective global assessment , body composition by bioelectrical impedance and anthropometry , muscle function with h and -grip strength and peak flow . QoL was assessed by the 36-item short-form question naire . RESULTS Age , body cell mass ( BCM ) , muscle function , gender distribution and QoL did not differ between ONS patients ( n=38 ) and DC patients ( n=42 ) at baseline . Body weight and BCM improved significantly in both groups after three months . However , h and -grip strength ( 26.1+/-11.3 - 31.5+/-10.1 kg , p<0.0001 ) and peak flow ( 329.2+/-124.0 - 388.9+/-108.4 l /min , p=0.004 ) improved only in the ONS patients and remained unchanged in the DC patients . Similarly , all eight scales of the QoL improved in the ONS patients compared with merely three in the DC patients . DC patients experienced significantly more readmissions ( n=20 ) than ONS patients ( n=10 ) during the study period ( p=0.041 ) . CONCLUSION A three month intervention with high protein oral supplements improves outcome in malnourished patients with digestive disease in terms of functional status , QoL and rehospitalization [16970646] OBJECTIVES To determine whether increases in caloric intake associated with consumption of a mid-morning nutritional supplement for 3 weeks were maintained in the week after stopping the supplement and to investigate the effects of body mass index ( BMI ) and cognitive and behavioral measures on this response . DESIGN Secondary analysis of a previously published r and omized , crossover , nonblinded clinical trial . SETTING A fully accredited geriatric care facility affiliated with the University of Toronto . PARTICIPANTS Thirty institutionalized seniors with probable Alzheimer 's disease ( AD ) who ate independently . MEASUREMENTS Investigator-weighed food intake , body weight , cognitive ( Severe Impairment Battery ; Global Deterioration Scale ) and behavioral ( Neuropsychiatric Inventory -- Nursing Home version ; London Psychogeriatric Rating Scale ) assessment s. RESULTS Individuals who responded successfully to supplementation as indicated by increases in daily energy intake were likely to maintain 58.8 % of that increase postsupplementation , although stopping the supplement was associated with decreased habitual energy intake in low- BMI individuals who reduced their daily intakes during supplementation in response to the extra calories . Cognitive/behavioral tests were not reliable predictors of postsupplement intake . CONCLUSION Institutionalized seniors with probable AD are likely to alter their usual energy intakes to maintain changes result ing from 3 weeks of supplementation . This effect may allow for rotating supplementation schedules in nursing homes that could reduce staff burden , but only for those individuals who are most likely to respond favorably . These data indicate that nutritional supplements and diet plans should be carefully prescribed in low- BMI individuals to limit variability in total energy provided and thus prevent lower-than-normal intake [2656603] Fifty ambulatory patients with head and neck cancer treated by definitive radiation therapy at the Fox Chase Cancer Center were prospect ively studied to determine the effect of oral nutritional supplements on both nutritional status and treatment response . Nutritional supplements maintained serum albumin during and post treatment . Nutritional supplements were shown to increase total protein and total calorie intake rather than displace these nutrients in usual food intake . Equal weight loss occurred in both the supplemented and non-supplemented groups during the observation period of 6 months , with the same or greater amount of weight loss registered 10 weeks after the start of treatment . Food supplements did not affect treatment response or complications , nor did they offer any survival advantage [12171453] OBJECTIVE To evaluate the impact of nutritional supplementation on nutritional status , muscle strength , perceived health , and functional status in a population of community-living , frail , undernourished elderly people . DESIGN A 16-week intervention study in which subjects were r and omized to an experimental or a control group and visited in their home on a monthly basis . Outcome variables were measured at the start and end of the study at subjects ' homes by a dietitian blinded to treatment assignment . SUBJECTS/ SETTING 83 elderly people ( experimental group : n=42 ; control group : n=41 ; mean age=80+/-7 years ) receiving community home-care services and at high risk for undernutrition . INTERVENTION Provision of a nutrient-dense protein-energy liquid supplement and encouragement to improve intake from other foods . OUTCOME MEASURES Anthropometric indexes , h and grip strength , isometric elbow flexion and leg extension strength , lower extremity function , perceived health , and functional status . STATISTICAL ANALYSES Study groups were compared on an " intention to treat " basis using analysis of variance for repeated measures and unpaired and paired t tests and their nonparametric equivalents where appropriate . RESULTS Total energy intake ( 1,772 vs 1,440 kcal ; P<.001 ) and weight gain ( 1.62 vs 0.04 kg ; P<.001 ) were higher in the supplemented group . No significant changes were observed with respect to other anthropometric indexes , muscle strength , or functional variables ; however , beneficial effects were observed in emotional role functioning ( P<0.01 ) and number of days spent in bed ( P=.04 ) . APPLICATIONS/ CONCLUSIONS Nutrition intervention is feasible in free-living , frail , undernourished elderly people and results in significant improvement of nutritional status with respect to energy and nutrient intake and weight gain . Weight loss can be stopped and in some cases reversed ; however , increased physical activity may also be required to improve health and functional status [15896431] RATIONALE Nutritional depletion is a common problem in chronic obstructive pulmonary disease ( COPD ) patients . It is caused , to a large extent , by an imbalance between low-energy intake and high-energy requirements . This problem adversely affects morbidity and mortality . However , the use of nutritional supplements to reach their energy necessities requires optimisation between positive and adverse effects on outcome before being used systematic ally as part of their comprehensive care . PURPOSE The aim of our study was to investigate the effects of oral nutritional repletion on quality of life in stable COPD patients . METHODS Prospect i ve , r and omised and multi-centre study . Stable COPD patients with a body mass index 22 , a fat-free mass index 16 , and /or a recent involuntary weight loss ( 5 % during last month , or 10 % during the last 3 months ) were studied . Exclusion criteria were to present signs of an airway infection , to have a cardiovascular , neurological , or endocrine disease , to be treated with oral steroids , immunosuppressors or oxygen therapy at home , and to receive nutritional supplements . During 12 weeks , patients were encouraged to ingest a total daily defined energy intake . R and omly , in patients from group A the total daily energy load was Resting Energy Expenditure (REE)x1.7 , and those from group B , REE x1.3 . Total daily energy intake was achieved with regular food plus , if necessary , oral nutritional supplement rich in proteins ( with 50 % of whey protein ) , with predominance of carbohydrates over fat , and enriched in antioxidants . Primary end-point variable was quality of life . Secondary end-point outcomes included body weight , body composition , lung function , h and grip strength , and compliance with the energy intake previously planned . Data were treated with a SAS System . Student 's test , Wilcoxon 's rank sum test , and Mann-Whitney 's test were used . RESULTS At baseline both groups of patients were comparable . All patients needed oral nutritional supplements to achieve total daily defined energy intake . After 12 weeks of follow-up , patients in both groups significantly increased energy intake . Patients in group A increased body weight ( P=0.001 ) , triceps skin fold thickness ( P=0.009 ) and body fat mass ( P=0.02 ) , and decreased body fat-free mass index ( P=0.02 ) . In this group a marked increase in airflow limitation was observed . A tendency to increase body weight and h and grip strength , and to decrease airflow limitation was observed in patients from group B. Furthermore , patients in the later group showed a significant improvement in the feeling of control over the disease ( P=0.007 ) and a tendency to better the other criteria in a quality of life scale . CONCLUSIONS According to our results , total daily energy intake of REE x 1.3 is preferable to REE x 1.7 in mild stable COPD patients . The administration of oral nutritional supplements , rich in proteins ( with 50 % of whey protein ) , with predominance of carbohydrates over fat , and enriched in antioxidants , to achieve total daily defined energy intake in patients in group B was followed by a significant improvement of one criteria ( mastery ) among many others in a quality of life scale [1425861] Abstract . A total of 29 patients with acute leukaemia were prospect ively r and omized before starting cytos‐tatic treatment to be nourished either with intensified oral nutrition ( intervention group ) or ad libitum nutritional intake during the whole tumour therapy ( median 22 weeks ) . All menus of free choice ( daily offer of 1.0–2.0 g protein , 30–50 kcal kg‐1 body weight ( BW ) ) . Beyond this , intervention patients nutrition education , daily visits by the dietician and record of food intake , as well as a weekly assessment of subjective well‐being ( linear analogue self assessment ‘ LASA ’ ) . From the LASA items , the factors : ‘ malaise ’ , ‘ psychological distress ’ , ‘ therapy side‐effects ’ were extracted by principal component analysis , and correlated to nutrient intake and nutritional status . At the end of antineoplastic induction therapy , after continuous hospitalization of 10 weeks ( median ) , 31.3 % of the controls had regained their initial nutritional status , and 68.8 % of the intervention group . Mean daily energy intake was 23.2 kcal kg‐1 BW during weeks with weight loss ( constant weight : 30.9 , weight gain : 39.3 kcal kg‐1 BW ) . Nutritional . behaviour correlated with subjective well‐being , low intake with complaints of tumour treatment side effects and weight loss with malaise [11463999] Background : No data is available on dietary intervention in c and i date s for lung transplantation and on the effect of different strategies for dietary support in this cohort . Aim : We therefore wanted to evaluate the effects of intensified nutritional support compared with simple support on energy intake and nutritional status . Method : Our participants were underweight ( n = 42 ) and normal-weight ( control group , n = 29 ) c and i date s for lung transplantation . The underweight patients were r and omized into two groups . Group A received intensified dietary counselling , ready-made liquid nutritional supplements free of charge and regular follow-ups , while group B received only one session of individual dietary counselling , no supplements and no follow-ups . Results : The mean intervention time was 21 weeks . Groups A and B both increased their energy intake and gained weight . Group A increased their energy intake from a median of 8.7 to 10.1 MJ ( p < 0.01 compared with the control group after intervention ) and gained a mean of 2.9 kg body weight ( 95 % CI 1.2 ; 4.7 , p = 0.005 compared with the control group ) , while group B increased from 7.4 to 10.8 MJ ( p = 0.005 ) and gained 2.3 kg ( 1.2 ; 3.3 , p = 0.002 ) . Only group B increased their fat-free mass . In this group , an increase in O2 saturation and a decrease in PaCO2 were suggested . None of the groups improved its physical performance . Conclusion : In c and i date s for lung transplantation we were unable to confirm the hypothesis that intensified nutritional support compared with a simple support increased compliance . Both groups achieved the goal for energy intake and gained weight [2691239] The effects of a nutritional support in hospitalized patients with alcoholic cirrhosis and liver failure were studied in a controlled protocol . Thirty-six patients were included , 17 were r and omly assigned to an experimental group and the rest to a control group . Experimentals received a diet aim ing at 50 kcal ( 209 kJ)/kg bodyweight/d and 1.5 g protein/kg bodyweight/d ( as proteins of high biological value ) . Controls received the st and ard diet prescribed by the attending physician . The severity of liver failure and the nutritional status on admission were similar in both groups . The measured energy intake in controls was 1813 + /- 121 kcal/d ( 7589 + /- 506 kJ/d ) and 2707 + /- 71 kcal/d ( 1131 + /- 297 kJ/d ) in experimentals ( P less than 0.001 ) . The protein intake in controls was 47 + /- 3.8 g/d and in experimentals 80 + /- 3 g/d ( P less than 0.001 ) . There were seven deaths during the study period ( two experimentals and five controls ) . No differences were observed in the evolution of liver failure , hepatic encephalopathy or nutritional status between both study groups . It is concluded that a higher energy and protein intake in these patients does not have adverse effects and is associated with a non-significant reduction in mortality [16889545] We report results of a r and omized clinical trial of a combined intervention of exercise and dietary counseling ( ExD ) after orthotopic liver transplantation ( OLT ) [15896425] AIMS To evaluate the effect of a whole formula diet on nutritional and cognitive status in Alzheimer 's disease patients . METHODS Patients were r and omly assigned to two interventions : a whole formula diet based on lyophilised foods ( Treatment Group , n=24 ) or nutritional advice ( Control Group , n=29 ) . Energy intake , body weight , biochemistry , Mini Nutritional Assessment ( MNA ) and Pfeiffer 's tests were determined at baseline and at 3 months of treatment . RESULTS No differences were observed between groups at baseline . Energy intake tended to increase in the Treatment Group and to decrease in the Control Group , although differences were not significant . The improvement in MNA and Pfeiffer test scores was not significantly different between groups . Body weight increased by 2.06+/-1.9 kg in the Treatment Group and by 0.32+/-3.04 kg in the Control Group ( P=0.007 ) . The increases in albumin ( P=0.007 ) , haemoglobin ( P=0.002 ) and serum ferritin ( P=0.009 ) were higher in the Treatment Group than in controls . A similar rate of serious adverse events ( hospitalisation or death ) was observed in both groups . CONCLUSIONS Administration of this whole formula has a positive impact on nutritional status . The great diversity in textures and tastes enable these formulations to be administered to a wide range of patients with or without liquid dysphagia [18431084] Background and aims : There are few studies published that combine the interventions of physical training and nutrition . The aim of the present study was to describe the impact of a physical and nutritional intervention program for frail community-dwelling elderly people over the age of 75 . Methods : Ninety-six community-dwelling elderly people ( 58 women ) were r and omized to four different groups : i ) a physical training program ( aerobic , muscle strength , balance ) , ii ) a nutritional intervention program ( individually targeted advice and group sessions ) , iii ) a combination of these interventions , and iv ) a control group . At baseline subjects were screened for physical performance such as muscle strength , balance , mobility and activities of daily living , as well as nutritional aspects such as energy intake , body weight and fat-free mass . These measurements were repeated immediately after the intervention , which lasted for 12 weeks , and after another 6 months . Results : The intention-to-treat analysis indicated significant improvements in lower-extremity muscle strength in both training groups compared with the nutrition group at 1st follow-up . There were small significant changes for some of the balance measurements in the training group without nutrition treatment . The nutrition intervention did not show any significant results . Conclusions : This study shows the positive effect on lower-extremity muscle strength directly after the intervention . Balance training most probably needs to be more individualized in order to be effective for frail elderly people . Further studies are needed , with larger sample sizes , to investigate the effects of these types of interventions before any further conclusions can be drawn [15669934] AIMS AND OBJECTIVES The purpose of the study was to test the effectiveness of nursing care based on active involvement of patients in their nutritional care . It was hypothesized that this type of care could improve energy and protein intake in elder orthopaedic patients . BACKGROUND Protein and energy malnutrition and deterioration in nutritional status is a common but neglected problem in hospital patients . METHODS The design was quasi-experimental with an intervention and control group . The study included 253 patients aged 65 and above admitted for hip fracture , hip or knee replacement . Food intake was recorded on a daily basis during the hospital stay . RESULTS The daily intake of energy increased with 23 % ( P = 0.001 ) and of protein with 45 % ( P = 0.001 ) . The intake increased from the very first day after the operation . The intake of energy and protein was not correlated with the patient 's age , body mass index or type of surgery . CONCLUSIONS The care based on patients ' active involvement in their own nutritional care and was found to be an effective method to raise the intake of energy and protein among elder orthopaedic patients . RELEVANCE TO CLINICAL PRACTICE This way of organizing the care identifies patients who do not consume enough energy and protein according to their current requirements and to take appropriate actions to prevent further malnutrition [18328440] BACKGROUND & AIMS Up to 50 % of patients with chronic pancreatitis ( CP ) are malnourished . There are limited data on the role of dietary intervention in improving the nutritional status of such patients . The aim was to compare the efficacy of medium chain triglyceride (MCT)-enriched commercial dietary supplements with dietary counseling for homemade food in the management of malnutrition in patients with CP . METHODS In a r and omized controlled trial , consecutive undernourished patients with CP ( body mass index [ BMI ] < 18.5 kg/m(2 ) ) at a tertiary care hospital were r and omized to receive either dietary counseling for regular homemade food or commercial MCT-enriched dietary supplements for a period of 3 months to compensate for the dietary calorie deficit . All patients received st and ard management for CP including pancreatic enzyme supplements . Primary outcome measure was improvement in BMI . RESULTS Sixty malnourished patients with CP were r and omized to counseling group ( n = 29 ; mean age , 32 + /- 10 years ; male , 83 % ) and supplementation group ( n = 31 ; mean age , 28 + /- 10 years ; male , 84 % ) . BMI increased in both the counseling group and supplementation group ( 17.2 + /- 1.7 vs 18.1 + /- 1.8 kg/m(2 ) , P = .001 ; 16.7 + /- 1.6 vs 18.2 + /- 1.6 kg/m(2 ) , P = .001 ) . There were similar improvements in triceps skinfold thickness , dietary intake , fecal fat , and pain score during a period of 3 months in both groups . There was , however , no significant difference between the counseling and supplementation groups with regard to any of the outcome measures . CONCLUSIONS Dietary counseling for a balanced homemade diet is as good as commercial food supplements in improving malnutrition in patients with CP [17275141] BACKGROUND & AIM Effects of combined nutritional treatment of patients at risk of protein-energy malnutrition ( PEM ) discharged from a geriatric service were evaluated . METHODS Patients ( n=108 , age 85+/-6 years ) at risk of malnutrition according to the short form of the mini nutritional assessment were r and omly allocated to dietary counseling , including liquid and multivitamin supplementation , i.e. intervention ( I , n=51 ) and to controls ( C , n=57 ) . Body weight , biochemical indices ( e.g. insulin-like growth factor I ( IGF-I ) ) , Katz activities of daily living ( ADL ) index , mini mental status examination ( MMSE ) and quality of life ( QoL ) by SF-36 were assessed at the start of the study and after 4 months . Statistical analyses were performed on " intention-to-treat " and on " treated-as- protocol " bases . RESULTS Fifty-four patients , 29 in the I-group ( 86+/-7 years , 66 % females ) and 25 in the C-group ( 85+/-7 years , 72 % females ) completed the study according to the protocol . Both modes of analysis revealed a significant positive effect of the combined nutritional intervention on weight maintenance . Treated-as- protocol analyses showed that Katz ADL index improved in the I-group ( p<0.001 ; p<0.05 between the groups ) . Serum IGF-I levels increased in the I-group ( p<0.001 ) , but were unchanged in the C-group ( p=0.07 between the groups ) . QoL was assessed to be low and had not changed after nutritional treatment . CONCLUSIONS Combined nutritional intervention prevented weight loss and improved ADL functions in discharged geriatric patients at risk of malnutrition [3027267] One hundred ninety-two patients with previously untreated metastatic cancer ( 102 non-small-cell lung cancer [ NSCLC ] ; 90 colorectal cancer ) were r and omized to receive either ad lib nutritional intake ( control group ) or specific nutritional intervention during a 12-week study period when chemotherapy was administered . Those patients r and omized to nutritional interventions were counselled to take oral nutrients with caloric intake equal to 1.7 to 1.95 times their basal energy expenditure , depending on their pretreatment nutritional status ( " st and ard " group ) . An augmented group was counselled to have a caloric intake equivalent to that of the st and ard group but with 25 % of calories provided as protein and additional supplements of zinc and magnesium . Counselling increased caloric intake in both tumor types but reduced weight loss in the short term only for lung cancer patients . Ninety-three NSCLC patients were evaluable for tumor response to vindesine and cisplatin . Overall , only 20.4 % of the patients responded , and there were no significant differences in response rates , median time to progression , or overall duration of survival between the nutrition intervention groups and the control group . The tumor response rate to time-sequenced 5-fluorouracil ( 5-FU ) and methotrexate in the 81 evaluable patients with colorectal cancer was only 14.8 % , and no significant differences in tumor response rates were noted between the three groups . Furthermore , the median time to progression and overall duration of survival were not different for the control , st and ard , and augmented groups . Nutritional interventions using dietary counselling had no impact on the percent of planned chemotherapy dose administered , the degree of toxicity experienced by patients , or the frequency of treatment delays . A multivariate prognostic factor analysis demonstrated that for lung cancer , the percent of weight loss , serum albumin concentration , and presence of liver metastases were significant ( P less than .05 ) and independent prognostic variables for survival duration . For colorectal cancer , serum albumin , alkaline phosphatase , lactic dehydrogenase ( LDH ) levels , and percent targeted caloric intake ( TCI ) were significant independent predictors of survival duration [9724503] OBJECTIVES To determine the effect of early intensive dietary intervention and follow-up on weight gains in newly transplanted renal patients . To provide appropriate dietary advice posttransplant that included advice to reduce weight gains . DESIGN Group A was studied prospect ively and group B was studied retrospectively over a period of 1 year posttransplant . SETTING Hospital transplant unit : inpatient ward and outpatient clinic . PATIENTS Thirty-three transplant patients were studied : Group A consisted of 11 patients ( 9 men , 2 women ) transplanted consecutively over 2 months , with a mean age of 39 years . Group B consisted of 22 patients ( 14 men , 8 women ) who had been transplanted consecutively 4 years before the study , with a mean age of 40 years . Both groups had functioning grafts ( serum creatinine < 200 micromol/L [ 2.2 mg/dL ] ) over the study period , and similar triple immunosuppressive therapy ( prednisolone , cyclosporine , and azathioprine ) . INTERVENTION Group A received intensive , individualized dietary advice in stages , with regular follow-up for the first 4 months posttransplant . Thereafter group A did not receive any dietary advice or follow-up for the 8 months leading up to 1 year posttransplant . Group B had not received any dietary advice or follow-up posttransplant . MAIN OUTCOME MEASURE Weight gained and body mass index ( BMI ) at 4 months and at 1 year posttransplant . RESULTS The mean weight ( BMI ) for group A at baseline , 4 months and at 1 year posttransplant was 67 + /- 13 kgs ( 24.1 + /- 3.9 kg/m2 ) , 69 + /- 12 kgs ( 24.6 + /- 3.5 kg/m2 ) , and 73 + /- 12 kgs ( 26.1 + /- 3.4 kg/m2 ) , respectively . The mean weight ( BMI ) for group B at baseline , 4 months and at 1 year posttransplant were 67 + /- 11 kgs ( 23.7 + /- 3.4 kg/m2 ) , 74 + /- 9 kgs ( 26.3 + /- 3.3 kg/m2 ) , and 79 + /- 12 kgs ( 27.9 + /- 4 kg/m2 ) , respectively . Analysis of group A showed no significant difference in weight gained and BMI with dietary advice and follow-up at 4 months posttransplant compared with baseline . There was a significant difference in weight gain and BMI at 1 year posttransplant compared with 4 months posttransplant ( P = .002 , P = .002 , respectively ) . Analysis between groups showed a significantly lower weight gain in group A compared with group B both at 4 months and at 1 year posttransplant ( P = .01 , P = .01 respectively ) . Group A had a significantly lower BMI than group B at 4 months and at 1 year posttransplant ( P = .003 , .006 , respectively ) . At 1 year posttransplant , group A had a mean weight gain of 5.5 kg per patient compared with a mean of 11.8 kg per patient in group B. CONCLUSION Early intensive dietary advice and follow-up is effective in controlling weight gains in the first year posttransplant . Dietary advice should be an important part of posttransplant treatment [16287132] BACKGROUND The aim was to evaluate the relationship between nutrition support ( NS ) on host toxicity and cancer outcome in patients with locally advanced head and neck squamous cell carcinoma ( HNSCC ) undergoing definitive radiotherapy ( XRT ) . METHODS We performed a secondary analysis of Radiation Therapy Oncology Group ( RTOG ) 90 - 03 , a prospect i ve r and omized trial evaluating four definitive XRT fractionation schedules in patients with locally advanced HNSCC , which prospect ively collected data on NS delivered before treatment ( BNS ) , during treatment ( TNS ) , and after definitive XRT . NS data and pretreatment characteristics of the 1073 evaluable patients were analyzed against therapy toxicity and outcome . RESULTS Patients receiving BNS experienced significantly less weight loss by the end of treatment and less grade 3 to 4 mucositis than patients not receiving BNS . However , patients receiving BNS had a poorer 5-year actuarial locoregional control rate than patients receiving TNS or no NS ( 29 % , 55 % , and 57 % , respectively , p < .0001 ) and a poorer 5-year overall survival rate ( 16 % , 36 % , and 49 % , respectively , p < .0001 ) . Patients receiving BNS were significantly more likely to have a higher T classification , N status , and overall American Joint Committee on Cancer ( AJCC ) stage and initial presentation with greater pretreatment weight loss , and a poorer Karnofsky Performance Status ( KPS ) than patients not receiving BNS . After adjusting for the impact of these prognostic factors through a recursive partition analysis , a multivariate analysis with a stratified Cox model found that BNS was still a highly significant independent prognostic factor for increased locoregional failure ( hazards ratio [ HR ] , 1.47 ; 95 % confidence interval [ CI ] , 1.21 - 1.79 ; p < .0001 ) and death ( HR , 1.41 ; 95 % CI , 1.19 - 1.67 ; p < .0001 ) . CONCLUSION In this study , the largest prospect i ve evaluation of nutrition data in treated patients with cancer , BNS was associated with inferior treatment outcome in the patients with HNSCC undergoing XRT . These results should be considered hypothesis generating and encourage prospect i ve clinical research and identification of the mechanisms underlying this finding [6841130] Ninety-seven patients with cancer , undergoing radiation treatment , were studied . Forty-two were given special dietary counseling and supplements of Sustagen or Isocal ; 42 controls received no special advice or supplements . Thirteen patients were excluded because of poor prognoses and the ethical need for food supplements . Nutrient intake of all groups was assessed by 3-d diet records in household measures in the first and the last week of treatment . Intake was significantly higher in the adjunctive than the control group . The excluded group , despite supplementation , had intakes similar to the control group . No difference was observed between the control and adjunctive groups in clinical status at the end of treatment or in long-term outcome [6387632] Cancer patients , assessed as nutritionally at risk , were r and omly assigned to a control group or to one of four intervention groups receiving ( a ) nutritional supplementation , ( b ) relaxation training , ( c ) both nutritional supplementation and relaxation training , or ( d ) neither nutritional supplementation nor relaxation training . Fifty-five subjects completed a four-month intervention period during which they were visited biweekly by a nurse ( except control subjects ) . In repeated measures analyses of variance , significant group-by-time interactions were obtained for weight and arm muscle circumference ( a measure of protein stores ) , indicating that for these measures the groups changed differentially during the intervention period . The group-by-time interaction approached significance on the Karnofsky Performance Status Scale . For all three variables , gain was greatest for the relaxation group ; the most severe loss occurred in the control group . These findings suggest that the cachexia of cancer may be slowed or reversed through noninvasive nursing interventions [16843999] The objective of this study was to determine the prevalence and correlates of malnutrition in patients living at home with cancer and chronic diseases . Patients ( 213 ) with cancer and 228 patients with chronic diseases were r and omly selected from general practice registers . Nutritional status was determined from body mass index ( BMI in kg/metre2 ) , triceps skinfold thickness ( TST ) , mid-arm muscle circumference ( MAMC ) and population centiles . Patients were classified as mildly malnourished if they had a BMI < 20 and TST or MAMC < 15th centile , moderately malnourished if they had a BMI < 18 and TST or MAMC < 5th centile , and severely malnourished if they had a BMI < 16 and TST or MAMC < 5th centile . Using these criteria , nearly 10 % of patients were malnourished : 24 ( 5.4 % ) mildly , 12 ( 2.7 % ) moderately and 4 ( 0.01 % ) severely . Malnutrition was more common in patients in social classes 3.2 , 4 and 5 than in social classes 1 , 2 and 3.1 ( P = 0.003 ) , and in patients receiving district nurse care ( P < 0.001 ) . Malnutrition was more prevalent in cancer patients who complained of chronic or severe pain ( 32 % vs 12 % , P = 0.021 ) and in patients with chronic disorders who experienced mental apathy ( 22 % vs 5 % , P = 0.014 ) . Clinicians need to be aware that malnutrition is common in patients living at home . In this study BMI proved to be a fairly good indicator of malnutrition and routine measurement of BMI would be one simple way of detecting patients who are at risk [16608139] Background and aims : Many elderly people with Alzheimer ’s disease experience weight loss . Illness and inadequate regain after a period of illness are considered as contributory causes of progressive weight loss in psychogeriatric patients . We studied whether early use of a liquid nutrition supplement immediately after onset of acute illness from infection can prevent weight loss in elderly psychogeriatric nursing home residents . Methods : R and omised controlled trial of 5 weeks after the onset of illness . Thirty-four psychogeriatric nursing home residents ( aged ±65 yrs ) completed the study period . A liquid nutrition supplement ( 200 ml ) once daily immediately after diagnosis of infection or st and ard treatment ( enriched food after referral to a dietician ) were provided . Body weight , mid-upper arm circumference , calf circumference , triceps skin fold thickness , dietary energy intake , and need for care were measured . Results : Weight change during the study period was significantly different between the st and ard ( −0.4 kg ) and supplement ( + 0.8 kg ) groups ( p=0.040 ) . No significant differences were observed in changes of midupper arm circumference , triceps skin fold thickness , calf circumference or energy intake between groups . Conclusions : Early provision of a liquid nutrition supplement immediately after onset of acute illness from infection leads to weight gain in elderly psychogeriatric nursing home residents [19074931] Background : Malnutrition in chronic obstructive pulmonary disease ( COPD ) is associated with a poor prognosis , yet evidence to support the role of dietary counselling and food fortification is lacking . A study was undertaken to assess the impact of dietary counselling and food fortification on outcome in out patients with COPD who are at risk of malnutrition . Methods : A r and omised controlled unblinded trial was performed in 59 out patients with COPD ( 6 months intervention and 6 months follow-up ) . The intervention group received dietary counselling and advice on food fortification and the controls received a dietary advice leaflet . Outcome measures were nutritional status , respiratory and skeletal muscle strength , respiratory function , perceived dyspnoea , activities of daily living ( ADL ) and quality of life . Results : The intervention group consumed more energy ( difference 194 kcal/day ; p = 0.02 ) and protein ( difference 11.8 g/day ; p<0.001 ) than controls . The intervention group gained weight during the intervention period and maintained weight during follow-up ; the controls lost weight throughout the study . Significant differences were observed between the groups in St George ’s Respiratory Question naire total score ( difference 10.1 ; p = 0.02 ) , Short Form-36 health change score ( difference 19.2 ; p = 0.029 ) and Medical Research Council dyspnoea score ( difference 1.0 ; p = 0.03 ) ; the difference in ADL score approached statistical significance ( difference 1.5 ; p = 0.06 ) . No differences were observed between groups in respiratory function or skeletal and respiratory muscle strength . Improvements in some variables persisted for 6 months beyond the intervention period . Conclusion : Dietary counselling and food fortification result ed in weight gain and improvements in outcome in nutritionally at-risk out patients with COPD , both during and beyond the intervention period [1456568] The association between severe nutritional depletion and chronic obstructive pulmonary disease ( COPD ) has long been recognized . A potential therapeutic benefit to nutritional support was previously suggested by us in a pilot investigation . Subsequent studies have reported conflicting results regarding the role of nutritional therapy in this clinical population . We report a r and omized controlled study of nutritional therapy in underweight patients with COPD that combines an initial inpatient investigation ( controlled nutritional support ) with a prolonged outpatient follow-up interval . Provision of adequate calorie and protein support , adjusted to metabolic requirements , result ed in weight gain ( intervention = + 2.4 kg versus control -0.5 kg ) , improved h and grip strength ( intervention = + 5.5 kg-force versus control -6.0 kg-force ) , expiratory muscle strength ( intervention = + 14.9 cm H2O versus control -9.2 cm H2O ) , and walking distance ( intervention = + 429 feet versus control -1.0 foot ) . Inspiratory muscle strength was also improved ( intervention = + 11.4 cm H2O versus control + 4.8 cm H2O ) although this did not quite reach statistical significance . We conclude that provision of adequate nutrient supply under controlled conditions results in significant clinical improvements in the COPD patient population . However , the intervention is costly , time-intensive , and of limited therapeutic magnitude . More detailed work of alternative outpatient strategies combined with additional rehabilitative measures is indicated to delineate the full therapeutic potential of nutritional support for this clinical population [8676539] BACKGROUND It was hypothesized that energy intake in hospitalized elderly patients could be improved by increasing the density of energy of the food and that the volume of food actually consumed , even with a higher energy content than the normal , would not change with servings of high energy-dense hospital food . METHODS Thirty-six elderly patients ( 52 to 96 years ) of both sexes , long-term treated at two comparable wards , participated in this study . The patients were given 6 weeks of regular hospital food ( RHF , 1670 kcal/d , 7.0 MJ ) and 6 weeks of high-energy food ( HE , 2520 kcal/d , 10.5 MJ ) . The volume of food was kept constant . A crossover study design was used . Food intake , energy intake , body weight , and modified functional condition ( Norton scale ) were measured . RESULTS Regardless of type of food ( RHF or HE ) and time of day ( lunch or dinner ) , he food portion size ( volume of food ) intake was the same , approximately 80 % of the portions consumed . HE led to a 40 % increase in energy intake ( from 25 + /- 1 during RHF to 35 + /- 2 kcal/kg/d , p < .0001 ) , which result ed in a 3.4 % increase in body weight ( p < .001 ) after 3 weeks of HE . Only minimal changes in functional condition were found . The cost of HE was substantially lower ( -85 % ) than any other mean available for improvement of energy intake . CONCLUSIONS A significant increase in energy intake can be achieved by higher energy density in regular hospital food and that HE does not cause a decrease in the volume of the food consumed . These findings suggest that it is the volume of food rather than the energy that limits voluntary energy intake of hospital food in elderly hospitalized patients [15796146] Background / Aim Malnutrition is highly prevalent in patients on continuous ambulatory peritoneal dialysis ( CAPD ) and is a strong predictor of increased morbidity and mortality . Therefore , the aim of this study was to evaluate the effect of oral administration of an egg albumin-based protein supplement on the nutritional status of CAPD patients . Methods In this r and omized , open label , controlled clinical trial , 28 CAPD patients were allocated to a study ( n = 13 ) or a control ( n = 15 ) group . Both groups received conventional nutritional counseling ; the study group received , additionally , an oral egg albumin-based supplement . During a 6-month follow-up , all patients had monthly clinical and biochemical evaluations and quarterly assessment s of adequacy of dialysis and nutrition . Results Serum albumin levels were not different between groups ; however , a significant increase ( baseline vs final ) was observed in the study group ( 2.64 ± 0.35 vs 3.05 ± 0.72 g/dL ) but not in the control group ( 2.66 ± 0.56 vs 2.80 ± 0.54 mg/dL ) . Calorie and protein intake increased more in the study group ( calories 1331 ± 432 vs 1872 ± 698 kcal ; proteins 1.0 ± 0.3 vs 1.7 ± 0.7 g/kg ) than in the control group ( calories 1423 ± 410 vs 1567 ± 381 kcal ; proteins 1.0 ± 0.4 vs 1.0 ± 0.3 g/kg ) . Similarly , non-protein nitrogen appearance rate ( nPNA ) increased significantly more in the study ( 1.00 ± 0.23 vs 1.18 ± 0.35 g/kg/day ) than in the control group ( 0.91 ± 0.11 vs 0.97 ± 0.14 g/kg/day ) . Triceps skinfold thickness ( TSF ) and midarm muscle area ( MAMA ) displayed a nonsignificant trend to a greater increase in the study group ( TSF 16.7 ± 8.7 vs 18.3 ± 10.7 mm ; MAMA 23.8 ± 6.2 vs 25.8 ± 5.9 cm2 ) than in controls ( TSF 16.4 ± 5.7 vs 16.9 ± 7.0 mm ; MAMA 28.7 ± 7.8 vs 30.0 ± 7.9 cm2 ) . At the end of follow-up , the frequency of patients with moderate or severe malnutrition decreased 6 % in the control group and decreased 28 % in the study group . At the final evaluation , the most important predictors of serum albumin were the oral egg albumin-based supplement administration and protein intake ( p < 0.05 ) ; secondary predictors ( p = 0.06 ) were peritoneal transport rate and MAMA . Conclusions In the study group , oral administration of the egg albumin-based supplement significantly improved serum albumin , calorie and protein intake , and nPNA , and , compared to controls , this maneuver was associated with a trend to increased anthropometric parameters and improved Subjective Global Assessment evaluation . Oral administration of the albumin supplement and protein intake were the most significant predictors of serum albumin at the end of follow-up . This oral supplement may be a safe , effective , and cheap method to improve nutritional status in peritoneal dialysis patients [12235650] Involuntary weight loss is often seen among patients with gastrointestinal ( GI ) cancer . Weight loss may influence quality of life ( QoL ) and is a predictor of survival . The present study is an attempt to improve body weight development in GI cancer patients by individual support ( IS ) , including nutritional measures . Patients were r and omized in a 2 × 2 design between 1 ) IS , including nutritional support , 2 ) group rehabilitation ( GR ) , 3 ) IS + GR ( ISGR ) , or 4 ) st and ard care ( SC ) . Data concerning dietary intake ( 24-h recalls ) , body weight , and QoL ( EORTC-QLQ C-30 ) were collected over 2 yr for 67 patients with colorectal or gastric cancer , r and omized to IS or ISGR . Data on weight and QoL were collected for 70 patients with the same diagnoses r and omized to GR or SC . Despite a tendency to greater weight loss at inclusion , the IS + ISGR group managed to gain weight significantly more rapidly and to a greater extent than the GR + SC group . The differences became statistically significant at 12 and 24 mo ( P < 0.05 ) . Patients with weight loss at baseline increased their energy intake and weight more than those without weight loss . No differences were seen in QoL ratings between r and omization groups , but there was a positive correlation between weight development and QoL and a negative correlation between fatigue and weight development . There was a numerical difference , not statistically significant ( P = 0.3 ) , indicating a shorter time of survival in patients in the GR + SC group . IS , including nutritional support , leads to more rapid weight gain than SC in patients with newly diagnosed GI cancer [14757395] BACKGROUND & AIMS Malnutrition is common in the elderly and increases morbidity and mortality . Most attempts to reverse malnutrition have used liquid supplements , but the findings are inconsistent . This study tests a new approach using a r and omised-controlled design . The aim was to examine whether health care assistants , trained to provide additional support with feeding , can improve acutely ill elderly in- patients ' clinical outcomes . METHODS The study was carried out on three acute medicine for the elderly wards at Hammersmith Hospitals NHS Trust , London . In all , 592 patients , all over 65 years old , were recruited . RESULTS The results showed that the median time patients received feeding support was 16 days , and the assisted group was given less intravenous antibiotics ( P=0.007 ) . However , the groups did not differ in markers of nutritional status , Barthel score , grip strength , length of stay or mortality . CONCLUSION It was concluded that the use of health care assistants in this specialised role , in an acute setting , without change to the food provision or without targeting higher risk patients , reduced the need for intravenous antibiotics . However , the intervention did not improve nutritional status or have an effect on length of stay in the time span studied . The results highlight the difficulties of improving the intake of acutely ill elderly patients during a hospital stay [19695832] OBJECTIVE Up to 60 % of hospitalized patients are undernourished . We studied the impact of nutritional therapy on quality of life and food intake . METHODS Undernourished patients were r and omized into two groups . The nutritional therapy group ( NT group ) received individual nutritional counseling and interventions , including oral nutritional supplements if appropriate , by a dietitian . The oral nutritional supplement group ( ONS group ) received oral nutritional supplements in addition to hospital meals without further instruction or counseling . Study duration was 10 to 15 d. At baseline and before discharge ( time point 1 ) we measured energy and protein intakes and quality of life . Quality of life was measured again 2 mo after discharge ( time point 2 ) . RESULTS Energy and protein intakes increased between baseline and time point 1 in both groups ( P=0.001 ) . The NT group ( n=18 ) met the energy requirements at time point 1 by 107 % and of protein by 94 % , the ONS group ( n=18 ) by 90 % and 88 % , respectively . Hospital meals alone did not cover the requirements . From baseline to time point 1 , quality of life increased in both groups . Quality of life increased further in the NT group from time point 1 to time point 2 ( P=0.016 ) , but not in the ONS group . CONCLUSION Both interventions caused a significant increase in energy and protein intakes and quality of life . In the NT group every patient received an efficacious individualized intervention . In contrast , the 7 of 18 patients in the ONS group who did not consume ONS had no intervention at all . Therefore , undernourished patients should be counseled individually by a dietitian [8173401] Abstract Objectives : To determine incidence of malnutrition among patients on admission to hospital , to monitor their changes in nutritional status during stay , and to determine awareness of nutrition in different clinical units . Design : Prospect i ve study of consecutive admissions . Setting : Acute teaching hospital . Subjects : 500 patients admitted to hospital : 100 each from general surgery , general medicine , respiratory medicine , orthopaedic surgery , and medicine for the elderly . Main outcome measures : Nutritional status of patients on admission and re assessment on discharge , review of case notes for information about nutritional status . Results : On admission , 200 of the 500 patients were undernourished ( body mass index less than 20 ) and 34 % were overweight ( body mass index > 25 ) . The 112 patients reassessed on discharge had mean weight loss of 5.4 % with greatest weight loss in those initially most undernourished . But the 10 patients referred for nutritional support showed mean weight gain of 7.9 % . Review of case notes revealed that , of the 200 undernourished patients , only 96 had any nutritional information documented . Conclusion : Malnutrition remains a largely unrecognised problem in hospital and highlights the need for education on clinical nutrition [17613583] Objective : To compare the effect of calcium/vitamin D supplements with a combination of calcium/vitamin D supplements and exercise/protein on risk of falling and postural balance . Design : R and omized clinical trial . Setting : University hospital physiotherapy department . Subjects : Twenty-four independently living elderly females aged 65 years and older with osteopenia or osteoporosis and mean total hip T-score ( SD ) of —1.8 ( 0.8 ) . Interventions : A three-month programme consisting of exercise/protein including training of muscular strength , co-ordination , balance and endurance . Calcium/ vitamin D was supplemented in all participants for a 12-month period . Outcome measures : Assessment took place prior to and following the months 3 , 6 , 9 and at the end of the study ; primary dependent variables assessed were risk of falling ( Berg Balance Test ) and postural balance ( forceplate ) . Secondary measures included body composition , strength , activity level , number of falls , bone mineral content , biochemical indices , nutritional status and general health . Results : Significant reductions of risk of falling ( repeated measures ANOVA F = 8.90 , P = 0.008 ) , an increase in muscular strength ( ANOVA F = 3.0 , P = 0.03 ) , and an increase in activity level ( ANOVA F = 3.38 , P = 0.02 ) were found in the experimental group as compared to the control group . Further on , there was 89 % reduction of falls reported in the experimental group ( experimental pre/post 8/1 falls ; control group pre/post 5/6 falls ) . Conclusion : This study provides support for our intervention programme aim ed at reducing the risk of falling in elderly participants diagnosed with osteopenia or osteoporosis . The data obtained from the pilot study allow the calculation of the actual sample size needed for a larger r and omized trial [15250845] To determine the feasibility of increasing the calcium , protein and calorie intake of osteoporotic fracture patients by repeated dietary counselling delivered by a dietitian , a r and omized controlled trial was conducted . Among 189 patients presenting with osteoporotic fractures to an Orthopaedics and Traumatology Department of a large regional hospital , 98 patients were r and omized to the intervention group and 91 were r and omized to the control group ( with usual care ) . Intervention group received three sessions of dietary counselling with tailored made recommendations over a period of 4 months , while the control group only received dietary assessment and pamphlets on the prevention of osteoporosis . Almost all subjects in both intervention and control groups had calcium intake below the recommended level of 1000 mg at baseline . Half and 60 % of subjects in both groups had total energy and protein intake below recommended levels respectively . The mean weights of control and intervention groups at baseline were 51.5 and 50.9 kg respectively , while the body mass index ( BMI ) were 22.6 ( kg m(-2 ) ) and 22.6 ( kg m(-2 ) ) respectively . After dietary intervention , significant increase of intake was seen in calcium intake ( P = 0.0095 by t-test ) in the intervention group . No significant increase was seen in protein or calorie intake . No significant change was observed in the body weight or BMI although there was a positive trend in the intervention group for all these parameters . We concluded that there was general malnutrition in Chinese elderly who presented with osteoporotic fractures . Dietary calcium could be increased by repeated professional dietary counselling . Future studies with longer duration and more objective clinical outcomes will be helpful to further demonstrate the long-term effects of dietary intervention on osteoporosis and other chronic diseases [16182685] The use of oral dietary supplements was compared with dietary counseling in 13 malnourished patients ( 3 males , mean age 18.1 years ) with cystic fibrosis . Energy intake and nutritional status were evaluated over 3 months . There was no significant change in energy intake or percent ideal body weight in either group [2737169] The potential nutritional and clinical benefits of sip-feed supplements were investigated by means of a controlled trial in elderly female patients admitted for orthopaedic surgery . A nutritional risk assessment procedure ( Nutritional Risk Question naire , NRQ ) was used to identify patients who might benefit from supplementation . Patients identified as high risk who did not receive supplements showed significant losses in triceps skinfold thickness ( TSF ) and mid-upper arm muscle circumference ( MUAMC ) measurements during hospitalization . Such changes were not observed in high-risk supplemented patients , but significant losses of MUAMC were also recorded in a group of patients who failed to comply with the supplement . No differences in biochemical parameters , muscle function , or clinical outcome were observed between supplemented and unsupplemented and non-compliant patients . The problems of poor compliance to sip-feed supplements and failure to observe clinical benefit in supplemented patients are discussed [16839988] Elderly long-term care patients ( n = 501 ) were r and omly allocated to receive dietary supplementation ( 400 kcal/day ) in addition to a normal hospital diet , or normal hospital diet only , for 26 weeks . The patients ' functional condition was assessed by a modified Norton scale comprising mental condition , activity , mobility , food intake , fluid intake , incontinence and general physical state . Nutritional status was assessed by anthropometry , serum protein analysis and delayed hypersensitivity skin tests . Improvements during the first 8 weeks were seen in activity and general physical condition in the supplemented group , and in mobility and general physical condition in the control group . After 8 weeks the supplemented group showed a significantly higher level of activity ( p < 0.05 ) compared to the control group . We conclude that in long-term geriatric care nutritional supplements help to maintain and improve the patients function [15788020] OBJECTIVE To study appetite and food choices in lean elderly women at the time of a femoral neck fracture and after 6 months of nutritional and anabolic intervention . SUBJECTS AND METHODS Forty-five nondemented women > 70 years of age ( mean + /- SD : 83 + /- 5 years ) with a recent hip fracture and body mass index < 24 kg/m2 ( mean : 20.5 + /- 2.3 ) were interviewed about their appetite and dietary habits prior to fracture . The patients were r and omized to treatment with a protein-rich liquid supplement ( PR ; 200 kcal and 20 g protein day(-1 ) ) alone or in combination with n and rolone decanoate injections ( PR/N ) 25 mg i.m . every third week or to a control group ( C ) . A second interview was conducted 6 months later . RESULTS Reduced appetite before the fracture was reported by 60 % . Half of the patients did not have dessert with any of their daily meals , one-third used low-fat margarines and one-third drank water with their meals . The estimated mean daily energy intake was 6.4 + /- 1.2 MJ ( 1541 + /- 304 kcal ) indicating that three of four subjects did not meet their energy needs . At 6 months , 40 % reported reduced appetite . There was no difference in the change of appetite between the three r and omized groups . Still , half of the subjects appeared to not meet their energy needs . Protein intake increased in the PR and PR/N groups , in contrast to the controls ( P = 0.002 ) . CONCLUSION Reduced appetite and insufficient energy intake was recorded in lean elderly women with a femoral neck fracture . Nutritional supplementation alone or in combination with an anabolic steroid increased protein intake without adversely affecting appetite [10634923] AIMS To compare nutritional counseling with and without oral supplements in HIV-infected patients with recent weight loss . DESIGN R and omized non-blinded controlled trial , stratified for change in antiretroviral treatment at baseline . PATIENTS HIV-infected patients with recent weight loss ( > 5 % of total , and > 3 % in the last month ) . INTERVENTION Nutritional counseling to increase dietary intake by 600 kcal/day over 8 weeks ; in group A ( n=24 ) by normal food , and in group B ( n=26 ) by a range of fortified drink supplements with a calorific value of 0.6 to 1.5 kcal/ml . METHODS Body composition by bioelectrical impedance analysis , dietary intake by 24 h recall . RESULTS Fat free mass increased from baseline to week 8 ( P<0.05 ) with no difference between groups A and B ( P=0.97 ) . Body cell mass and weight gain were not significant and equal between groups . Assessed at weeks 2 and 4 , group B patients consumed 11 + /- 6 kcal/kg as supplements , and their total energy intake was 6 kcal/kg higher than in group A ( P<0.01 ) . Total energy intake was not different between groups at weeks 6 and 8 . DISCUSSION Nutritional counseling and oral supplements are both feasible methods to restore food energy intake in malnourished HIV-infected patients . Although normal food intake is partially replaced , oral supplements may improve the adherence to a weight gain regimen [9135531] BACKGROUND : Previous work has shown that the administration of oral dietary supplements to patients who have undergone gastrointestinal surgery results in clinical ly significant short term benefits . AIMS : This study aim ed firstly to re-evaluate these short term effects , and secondly to establish whether there are any long term benefits . SUBJECTS : One hundred patients admitted for elective moderate or major gastrointestinal surgery . METHODS : In the inpatient phase , patients were r and omised to receive a normal ward diet postoperatively , or the same diet supplemented with an oral dietary supplement . In the outpatient phase , patients were further r and omised to receive their home diet , or their home diet supplemented with the oral dietary supplement for four months . RESULTS : During the inpatient phase , patients treated with oral supplements had a significantly improved nutritional intake and lost less weight ( 2.2 , 95 % confidence interval ( 95 % CI ) 0.9 kg ) compared with control patients ( 4.2 ( 0.78 ) kg , p < 0.001 ) . Supplemented patients maintained their h and grip strength whereas control patients showed a significant reduction in grip strength ( p < 0.01 ) . Subjective levels of fatigue increased significantly above preoperative levels in control patients ( p < 0.01 ) but not in the supplemented group . Twelve patients in the control group developed complications compared with four in the supplemented group ( p < 0.05 ) . In the outpatient phase , supplemented patients had improved nutrient intakes but there were no significant differences in indices of nutritional status or wellbeing between the groups . CONCLUSIONS : The prescription of oral dietary supplements to patients who have undergone gastrointestinal surgery results in clinical ly significant benefits . These benefits , however , are restricted to the inpatient phase [19812865] Objectives To determine whether in the current study the supply of a nutrient dense drink has a positive effect on mental and physical function of institutionalized elderly people . Design A 24-week , r and omized , double-blind , placebo-controlled , parallel-group , intervention trial . Setting Homes for the elderly and nursing homes in the Netherl and s. Participants Institutionalized elderly people older than 60 years , with a BMI ≤ 30 kg/m2 , and a Mini-Mental State Examination score of at least 10 points . InterventionIn addition to their usual diet the participants ( n=176 ) received either a nutrient dense drink or a placebo drink twice a day during 24 weeks . Measurements The functionality measures included cognitive function , mood , physical performance and the ability to perform activities of daily living . Results In the supplement group a favorable effect of the intervention drink on body weight ( 1.6 kg difference in change ; P = .035 ) , calf circumference ( 0.9 cm difference in change ; P = .048 ) , and blood values ( e.g. Hcy decreased from 16.8 to 11.2 µmol/L in the supplement group ) was found . In the total group no significant effect was found on functionality outcomes . However , a subgroup of participants with BMI at baseline below 24.4 kg/m2 performed better on the cognitive subscale of Alzheimer ’s Disease Assessment Scale ( P = .09 ) , and its language sub score ( P = .01 ) after 24 weeks of intervention . Conclusion The results in the total group of this trial suggest that the nutritional supplement used in this study improves nutritional status . Furthermore , the results of this trial suggest that it is effective as treatment for decreasing function in a subgroup of institutionalized elderly people with low BMI [8410128] PURPOSE This study examined the effect of frequent nutritional counseling on oral intake , body weight , response rate , survival , and quality of life in patients with cancer of the lung ( small-cell ) , ovary , or breast undergoing cyclic chemotherapy . PATIENTS AND METHODS Of 105 assessable patients , 57 were r and omized to receive nutritional counseling , and 48 to receive no nutritional counseling and consumption of an ad lib oral intake . The intervention group was counseled to achieve a daily energy and protein intake according to recommended dietary allowances . Counseling was st and ardized and performed by a trained dietitian , and took place twice monthly during a 5-month period from start of chemotherapy . RESULTS Dietary counseling increased daily energy intake by approximately 1 MJ and protein intake by 10 g over the entire study period . There was no change in the control group . Counseling led to an insignificant increase in body weight , but triceps skinfold measurement increased significantly after 5 months . Response rate and overall survival did not differ between the groups . Quality of life measured by the Quality -of-Life index ( QL-index ) increased significantly in both groups , but did not differ between groups . CONCLUSION No clinical benefit could be demonstrated despite long-term and continuous improved food intake in cancer patients with solid tumors undergoing aggressive chemotherapy [8010171] We examined changes in the nutritional status of elderly patients with chest infection for a period of 3 months after discharge from hospital , including the effects of nutritional supplementation on well-being and functional status as well as on nutritional indices . Eighty-one subjects admitted to an acute medical ward aged 65 years and over with chest infection were recruited consecutively , and r and omized to receive supplement ( 500 ml of Ensure liquid daily ) for 1 month , or no supplement , on discharge . Assessment at baseline , 1 , 2 and 3 months included a question naire to determine health , mental and functional status , and anthropometric measurements . Biochemical nutritional status was assessed at baseline , 1 and 3 months , and dietary intake ( 24 h recall method ) at 1 and 3 months . During recovery , both supplement and non-supplement groups showed improvement in various measures of well-being and biochemical status . In addition , the former group showed improvement in more anthropometric measurements , in thiamine and pyridoxine status , while the non-supplement group showed a lower level of functional ability after 3 months . Various measures of well-being and biochemical status of the water-soluble vitamins were better in the supplement groups . We conclude that nutritional supplementation may have a role in helping elderly patients to recover from chest infections [10382188] PURPOSE / OBJECTIVES To describe the effect of nutritional supplements on food intake in patients undergoing radiotherapy . DESIGN Experimental prospect i ve . SAMPLE 40 newly diagnosed patients with cancer beginning external beam radiation therapy . METHODS Weekly dietary counseling and recording of total daily dietary intake for three days a week for four weeks . One half of the subjects were r and omly assigned to ingest a liquid nutritional supplement between meals and at bedtime . MAIN RESEARCH VARIABLES Total daily protein and caloric intake , food-derived protein and caloric intake , and supplement-derived protein and caloric intake . FINDINGS Subjects ingesting nutritional supplements between meals significantly increased their total caloric and protein intake above that of controls and did not reduce their food-derived caloric or protein intake compared to controls . CONCLUSIONS Nutritional supplements can be used to increase total caloric and protein intake without causing a significant reduction in food intake . IMPLICATION S FOR NURSING PRACTICE In this patient sample , supplements were not substituted for food intake . Further research is needed to determine the effects of supplements on appetite in patients with advanced cancer [3057956] We carried out a prospect i ve , r and omized , controlled trial to investigate the effect of a 3-month period of supplementary oral nutrition in 14 poorly nourished out patients with COPD . Seven patients were r and omized into Group 1 who received their normal diet during Months 1 to 3 , a supplemented diet during Months 4 to 6 , and their original normal diet during Months 7 to 9 . The other 7 patients received their normal diet for the entire 9-month study period ( Group 2 ) . Seven well-nourished patients ( Group 3 ) matched for age and severity of air-flow obstruction served as control subjects ; they received their normal diet for the 9-month study period . Measurements of nutritional status , respiratory muscle and h and grip strength , sternomastoid muscle function ( including frequency/force curves , maximal relaxation rate , and a fatigability test ) , lung function , arterial blood gas tensions , general well-being and breathlessness scores , and 6-min walking distances were carried out monthly in all patients . At the start of the study , the poorly nourished patients had lower mean daily calorie and protein intakes than did the well-nourished patients . The poorly nourished patients had lower respiratory muscle and h and grip strength , and abnormal contractility and increased fatigability of the sternomastoid muscle compared with those in the well-nourished patients . After 3 months of supplementary oral nutrition , there was a significant improvement in the nutritional status of Group 1 patients , as evidence d by an increase in body weight , triceps skinfold thickness , and midarm muscle circumference . Respiratory muscle and h and grip strength increased in parallel with nutritional status , although there were no significant changes in lung function or arterial blood gas tensions . ( ABSTRACT TRUNCATED AT 250 WORDS [18407904] BACKGROUND Oral nutritional supplements have been recommended after orthopedic surgery in geriatric patients to reduce postoperative complications . However , tolerability of supplements could be a limitation , and their universal use is not supported by the heterogeneity of previous studies , especially in patients without malnutrition . METHODS This study is a r and omized , controlled , open , parallel , 3-arm clinical trial comparing supplementation with protein powder dissolved in liquids to aim at 36 g of protein per day , energy and protein supplements to aim at 37.6 g of protein and 500 kcal per day , or no intervention in normally nourished or mildly undernourished patients . Outcomes were serum albumin , prealbumin , retinol-binding globulin , and body mass index , among others . Postoperative complications were also recorded . RESULTS Ninety patients aged 83.8 + /- 6.6 years were included . The mean ingested amount of supplements was 41.1 % + /- 20.6 % in the protein powder supplement group and 51.4 % + /- 13.2 % in the energy protein supplement group ( t = 2.278 , P = .027 ) . Postoperative supplements had no effect on the nutrition status during in-hospital follow-up , as assessed by serum albumin ( P = .251 ) , prealbumin ( P = .530 ) , retinol-binding globulin ( P = .552 ) , or body mass index ( P = .582 ) . Multivariate analysis showed that length of hospital stay with an established complication until its resolution ( beta = .230 , P = .031 ) , total hospital stay ( beta = .450 , P < .001 ) , baseline body mass index ( beta = .204 , P = .045 ) , and total daily ingested proteins per body weight ( beta = .252 , P = .018 ) were predictive variables on the change in serum albumin ( R2 = 0.409 , F = 11.246 , P < .001 ) . CONCLUSIONS Oral nutritional supplements in normally nourished or only mildly undernourished geriatric patients with hip fracture su bmi tted to surgery may be of interest for patients with postoperative complications and long hospital stays [15684319] PURPOSE To investigate the impact of dietary counseling or nutritional supplements on outcomes in cancer patients : nutritional , morbidity , and quality of life ( QoL ) during and 3 months after radiotherapy . PATIENTS AND METHODS A total of 111 colorectal cancer out patients referred for radiotherapy , stratified by staging , were r and omly assigned : group 1 ( G1 ; n = 37 ) , dietary counseling ( regular foods ) ; group 2 ( G2 ; n = 37 ) , protein supplements ; and group 3 ( G3 ; n = 37 ) , ad libitum intake . Nutritional intake ( diet history ) , status ( Ottery 's Subjective Global Assessment ) , and QoL ( European Organisation for Research and Treatment of Cancer Quality of Life Question naire version 3.0 ) were evaluated at baseline , at the end , and 3 months after radiotherapy . RESULTS At radiotherapy completion , energy intake increased in G1/G2 ( P < or = .04 ) , G1 more than G2 ( P = .001 ) , and decreased in G3 ( P < .01 ) . Protein intake increased in G1/G2 ( P < or = .007 ) , G1 less than G2 ( not significant ) , and decreased in G3 ( P < .01 ) . At 3 months , G1 maintained nutritional intake and G2/G3 returned to baseline . After radiotherapy and at 3 months , rates of anorexia , nausea , vomiting , and diarrhea were higher in G3 ( P < .05 ) . At radiotherapy completion , in G1 all QoL function scores improved proportionally to adequate intake or nutritional status ( P < .05 ) ; whereas in G2 only three of six function scores improved proportionally to protein intake ( P = .04 ) , and in G3 all scores worsened ( P < .05 ) . At 3 months , G1 patients maintained/improved function , symptoms , and single-item scores ( P < .02 ) ; in G2 , only few function and symptom scales improved ( P < .05 ) ; in G3 , QoL remained as poor as after radiotherapy . In G1/G2 , respectively , improvement/deterioration of QoL correlated with better or poorer intake or nutritional status ( P < .003 ) . CONCLUSION During radiotherapy , both interventions positively influenced outcomes ; dietary counseling was of similar or higher benefit , whereas even 3 months after RT , it was the only method to sustain a significant impact on patient outcomes [9061125] The objective of this study , design ed as a r and omized controlled prospect i ve intervention study , was to evaluate the effect of nutritional supplementation on functional status and need of care in undernourished geriatric patients during hospitalization , and up to 6 months after discharge . Participants consisted of 46 undernourished geriatric patients from a geriatric acute care hospital aged 75 years or older without malignant disease , or need for tube feeding or parenteral nutrition . Patients in the supplement group ( SG , N=20 ) were offered 400 mL ( 2100 kJ ) daily of a liquid supplement during hospital stay and 200 mL ( 1050 kJ ) per day for the following 6 months at home . Patients in the control group ( CG , N=26 ) had usual care without supplements . The main outcome measure was functional status based on the Barthel Activities of Daily Living score ( ADL ) at hospital admission , discharge and after 6 months , with higher scores indicating greater independence and a maximum score of 100 points . In supplemented patients with good acceptance ( SG+ , N=11 ) , a median improvement of 20 points was observed between admission and discharge , and a further improvement of 5 points at home . Median changes were 0 and −10 points in supplemented patients with poor acceptance ( SG- , N=9 ) and 5 and 2.5 points in CG , respectively . In SG+ , the proportion of independent patients ( > 65 points ) increased continuously from 36 % at admission to 63 % at discharge , to 72 % after 6 months , and was significantly higher compared to CG at discharge ( 63 % vs 19 % , pš 0.05 ) and after 6 months ( 72 % vs 39 % , p<0.05 ) . 64 % of the patients in SG+ improved during hospitalization , compared to 23 % in CG ( p<0.05 ) . In the six months at home , 18 % of SG+ improved ; none of SG+ deteriorated in hospital or at home . In contrast , deterioration of the ADL score occurred in considerable proportions of SG− ( 22 % in hospital , 22 % at home ) and CG ( 4 % at hospital , 12 % at home ) patients . The proportion of patients who improved was smaller in SG− ( 44 % at hospital , 22 % at home ) as well as in CG ( 23 % at hospital , 35 % at home ) , compared to SG+ . In conclusion , a positive functional course was evident in supplemented patients with good acceptance during hospitalization , and further improvement was observed during the following 6 months at home . Nutritional support may contribute to reconvalescence and recovery of undernourished geriatric patients [16815130] Malnutrition and dehydration are potential consequences of dysphagia , a common swallowing disorder among elderly individuals . Providing smaller , more frequent meals has been suggested ( but not demonstrated ) to improve energy intake among this group . Accordingly , this study was design ed to assess whether the same energy content in five vs three daily meals would improve energy intake . Thirty-seven residents of an extended-care facility , aged older than 65 years , previously evaluated for dysphagia , and receiving a texture-modified diet , agreed to participate in a crossover study with r and om assignment to three or five meals during an initial 4-day study period , followed by the opposite meal pattern in a second period . Six were excluded from analysis , as their medical condition deteriorated before or during the study . Food and fluids consumed by participants during each study period were weighed before and after each meal . Average energy intakes were similar between the three- and five-meal patterns ( 1,325+/-207 kcal/day vs 1,342+/-177 kcal/day , respectively ; P=0.565 ) ; fluid intake was higher with five meals ( 698+/-156 mL/day ) vs three ( 612+/-176 mL/day ; P=0.003 ) . Because offering five daily feedings did not improve energy intakes when compared with three , dietitians caring for this vulnerable group might need to consider other nutrition intervention strategies [10620007] Weight loss and protein malnutrition are frequent complications in HIV‐infected patients . The effect of an oral nutritional supplement combined with nutritional counselling on whole body protein metabolism was assessed [18436085] BACKGROUND Progressive loss of kidney function results in an increased risk of malnutrition . Despite this , there is little evidence informing the impact of nutrition intervention on predialysis patients with chronic kidney disease ( CKD ; stages 4 and 5 ) . STUDY DESIGN R and omized controlled trial . SETTING & PARTICIPANTS 56 out patients ( men , 62 % ; mean age , 70.7 + /- 14.0 [ SD ] years ) with CKD were r and omly allocated to intervention ( n = 29 ) or control ( n = 27 ) by using a concealed computer-generated sequence . INTERVENTION The intervention group , provided with individualized dietary counseling with regular follow-up aim ed at achieving an intake of 0.8 to 1.0 g/kg of protein and greater than 125 kJ/kg of energy , or control , receiving written material only . OUTCOMES & MEASURES Change in body composition ( body cell mass , measured by means of total-body potassium , in 40 of 56 participants ) , nutritional status ( Subjective Global Assessment ) , and energy and protein intake ( 3-day food record ) . RESULTS During the 12 weeks , the intervention group had 3.5 % ( 95 % confidence interval , -2.1 to 9.1 ) less decrease in body cell mass , 17.7-kJ/kg/d ( 95 % confidence interval , 8.2 to 27.2 ) greater increase in energy intake , greater improvement in Subjective Global Assessment ( P < 0.01 ) , and no significant difference in protein intake compared with the control group ( -0.04 g/kg/d ; 95 % confidence interval , -0.73 to 0.16 ) . The intervention was associated with greater increases in energy and protein intake in women than men ( interaction P < 0.001 for both ) . LIMITATIONS Power to detect change in body cell mass , potential bias in ascertainment of Subjective Global Assessment . CONCLUSIONS In predialysis patients with CKD , structured nutrition intervention had a greater effect on energy and protein intake in women than men . Additional investigations are warranted to determine the impact on body composition [8733313] AIM To assess prospect ively the effects of a controlled program of inspiratory muscle training program and nutritional support in patients with chronic obstructive lung disease ( COPD ) . PATIENTS AND METHODS Twenty-three patients with COPD were r and omly assigned into four groups . Group I received a 1000 kcal/day nutritional supplement , given as a casein based enteral nutritional formula ; group III was subjected to inspiratory muscle training , using an inexpensive pressure threshold load valve constructed according to the Appropriate Technology principles of the WHO , adjusted at 30 % of Maximal Inspiratory Mouth Pressure and received also the nutritional supplement ; group IV was trained but did not receive the nutritional supplement and group II was not trained nor supplemented . Patients were studied during three months and monthly , inspiratory muscle function , exercise capacity and anthropometry were measured . RESULTS A significant improvement in exercise capacity , maximal inspiratory pressure and inspiratory muscle endurance was observed in the four groups throughout the study . Trained subjects had greater improvement in their inspiratory muscle endurance , compared to untrained subjects . Nutritional support had no effect in inspiratory muscle function or exercise capacity . No changes in anthropometric measures were observed . CONCLUSIONS The pressure threshold load valve used in this study , improved inspiratory muscle endurance and nutritional support had no effect in patients with COPD [8477961] A Veterans Affairs cooperative study involving 273 male patients was performed to evaluate efficacy of ox and rolone in combination with an enteral food supplement in severe alcoholic hepatitis . All patients had some degree of protein calorie malnutrition . On an intention-to-treat basis , only minimal changes in mortality were observed . However , in patients with moderate malnutrition mortality on active treatment at 1 mo was 9.4 % compared with 20.9 % in patients receiving placebo . This beneficial effect was maintained so that after 6 mo on active treatment 79.7 % of patients were still alive , compared with 62.7 % of placebo-treated patients ( p = 0.037 ) . Improvements in both the severity of the liver injury ( p = 0.03 ) and malnutrition ( p = 0.05 ) also occurred . No significant improvement was observed with severe malnutrition . To better determine the effect on therapeutic efficacy , we compared results with those from a nearly identical population ( cooperative study 119 ) treated with ox and rolone but not given the food supplement . Patients were stratified according to their caloric intake ( greater than 2,500 kcal/day was considered adequate to supply energy needs and promote anabolism ) . For patients with moderate malnutrition and adequate caloric intake , ox and rolone treatment reduced 6-mo mortality ( 4 % active treatment vs. 28 % placebo [ p = 0.002 ] ) . For patients with moderate malnutrition and inadequate calorie intake , ox and rolone had no effect on mortality ( 30 % active treatment vs. 33 % placebo ) . In cases of severe malnutrition , ox and rolone had no effect on survival . However , adequate caloric intake was associated with 19 % mortality , whereas patients with inadequate intake exhibited 51 % mortality ( p = 0.0001 ) . These results indicate that nutritional status should be evaluated in patients with alcoholic hepatitis . When malnutrition is present , vigorous nutrition therapy should be provided , and in patients with moderate malnutrition ox and rolone should be added to the regimen [3282825] We studied the effects of oral nutritional supplementation on respiratory muscle ( RM ) performance in 25 ambulatory patients with severe chronic obstructive pulmonary disease ( COPD ) . There was a relationship between body weight and anthropometric parameters of nutritional status ( triceps skinfold thickness [ r = 0.67 ; p less than 0.005 ] , midarm muscle circumference ( r = 0.53 ; p less than 0.005 ) , but body weight did not correlate with daily caloric intake , serum albumin , transferrin , or blood lymphocyte count . None of these measurements of nutritional status correlated with any measure of RM strength or endurance . In a r and omized observer-blinded crossover trial , patients were allocated to one of two groups . In the first eight weeks of the study , group A received nutritional supplementation , and patients in group B were control subjects . In the second eight weeks , patients in group A were control subjects , and group B received supplement . Mean daily caloric intake and body weight increased in both groups while receiving supplement ( both p less than 0.05 ) . Calories provided by the supplement were frequently substituted for normal dietary calories . Any increases in RM performance in the group receiving supplement were matched by increases ( due to learning ) in controls . We conclude that oral dietary supplements have no important effects on RM performance in ambulatory patients with COPD [6951009] Twenty-four orthognathic surgery patients were studied to determine the impact of a high-calorie liquid supplement on preventing or minimizing catabolism commonly associated with surgery . The experimental group of 12 subjects , chosen at r and om , consumed blenderized foods ad libitum and a high-calorie dietary supplement providing a minimum of 50 % of energy requirements . The remaining 12 subjects consumed only blenderized foods and served as the control group . The nutritional status of all patients was assessed one day before surgery and on Day 7 of the first , third , and sixth postoperative week . In general , nutrient intake in the experimental group remained similar to that before surgery , whereas intake in the control group decreased significantly , particularly at the one-week postoperative evaluation . It was concluded that the addition of a high-calorie liquid supplement to the dietary regimen of orthognathic surgery patients helped maintain nutrient intake at a level comparable to that before surgery . This result ed in better maintenance of body weight and somatic protein compartments compared with the control group [9225334] Little is known about nutritional intake after discharge though it takes months to regain preoperative weight after gastrointestinal surgery . We studied whether a 4-mo intervention with dietary advice and protein-rich supplements would increase nutritional intake and gain in lean body mass ( LBM ) in patients who had undergone gastrointestinal surgery . Patients admitted for gastrointestinal surgery were r and omized at discharge to serve as control patients ( n = 47 ) or to receive intervention ( n = 40 ) . One month after discharge , the control patients had a nutritional intake ( 3-d diet record ) comparable with the intake of the general population that did not increase further . During the 4 m , the intervention patients had an increased intake of protein ( + 22 % ) and energy ( + 16 % ) , and an enhanced gain of LBM after 2 mo ( control 0.8 kg versus intervention 2.1 kg ; P = 0.009 ) . After the 4-mo intervention , both LBM and fat were gained ( control 1.7 kg LBM and 0.2 kg fat versus intervention 3.1 kg LBM and 1.5 kg fat ; LBM : P = 0.029 and fat : P = 0.056 ) . At discharge patients should increase protein intake to 1.5 g.kg-1.d-1 for 2 mo , e.g. , by taking protein-rich liquid supplements [9550167] OBJECTIVE To evaluate the effects of nutrition counseling with or without oral supplementation in malnourished patients infected with the human immunodeficiency virus ( HIV ) . DESIGN R and omized controlled trial . SUBJECTS HIV-infected men ( n=118 ) who were less than 90 % of usual weight for height or who had lost more than 10 % of body weight . INTERVENTION Nutrition counseling alone ( control group ) vs nutrition counseling plus enteral supplementation ( supplement group ) for 6 weeks . All patients were instructed to consume a diet that exceeded estimated total energy expenditure by 960 kcal/day . MAIN OUTCOME MEASURES Weight , skinfold thickness , fat-free mass , grip strength , quality of life , and cognitive function ( Buschke test ) . STATISTICAL ANALYSES Differences in baseline variables and outcomes were evaluated using analysis of variance or the Wilcoxon rank sum test . RESULTS Ninety-nine men completed at least 4 weeks of treatment , 49 in the supplement group and 50 in the control group . Half the patients in each treatment group achieved at least 80 % of their energy target . No differences in weight , skinfold thickness measurements , or quality of life were observed . Compared with the control group , the supplement group had larger increases in fat-free mass and grip strength , although the differences did not reach statistical significance . APPLICATIONS In the short term , nutrition counseling with or without oral supplementation can achieve a substantial increase in energy intake in about 50 % of malnourished HIV-infected patients . Although further study is needed to evaluate long-term effects , these findings suggest that nutrition counseling has an important role in the management of malnourished HIV-infected patients [9043473] Background Postoperative fatigue and deterioration in functional capacity have been correlated to postoperative weight loss . This suggested that nutritional support to enhance the regain of weight might improve upon the convalescence [3536644] A prospect i ve controlled 6-month study was undertaken to compare the effect of Ensure , a defined formula dietary supplement , and diet counselling in 122 out patients with Crohn 's disease . The compliance to Ensure was poor due to a high incidence of side effects . Taking any amount of Ensure reduced the need for surgery and the amount of hospitalization . There was a trend for patients receiving Ensure to experience a decline in the value of their Crohn 's disease activity index ( p less than 0.10 ) . No consistent effects of Ensure were seen on the amount of work missed due to Crohn 's disease , in laboratory measurements , in the need for prednisone or Salazopyrin . The vitamin B12 intake was improved , but otherwise nutrient intake declined due to a decreased food intake . Thus , certain beneficial clinical trends were associated with taking Ensure , but larger numbers of compliant patients will need to be studied to better assess the long-term role of defined formula diets in the management of out patients with Crohn 's disease [2899528] A prospect i ve study was undertaken to establish the role of individualized diet counselling in the management of 137 out patients with Crohn 's disease . Individualized dietary counselling for 6 months was associated with a significant decrease in the Crohn 's disease activity index , an increased incidence of disease remission , a decreased need for prednisone and Salazopyrin therapy , a reduction in the number of days spent in hospital , and a reduction in the amount of time lost from work due to Crohn 's disease , when compared with control patients who did not receive dietary counselling but who were seen regularly in follow-up under similar circumstances . Improvement with diet counselling was more likely to occur in patients who had not previously been subjected to small bowel resection , and occurred in patients with active or inactive disease . The effect of counselling 58 patients was assessed over a further 6 months ( for a total 12-month period ) ; there was a persistently reduced Crohn 's disease activity index and a continued decreased number of lost days of work . The mechanism for these beneficial effects of diet counselling was not established . It is suggested that individualized diet counselling , aim ed at optimizing the patient 's nutritional status , may play a role in the management of patients with Crohn 's disease [18442509] Cystic fibrosis ( CF ) remains the most common genetically inherited disease in the white population and its prognosis is affected by nutritional status . Adults with the disease are now surviving longer and new strategies are required to ensure that they maintain optimal nutrition . This article reports preliminary data from a r and omized controlled trial of a 10-week home-based behavioral nutrition intervention , " Eat Well with CF . " Outcome measures of weight change over 6 and 12 months and changes in CF-specific nutrition knowledge score , self-efficacy score , reported dietary fat intake and health-related quality -of-life score were compared between the intervention group ( n=34 ) and a st and ard care control group ( n=34 ) . The hypotheses to be tested were that adults with CF completing " Eat Well with CF " would have an improved nutritional status , improvement in specific nutrition knowledge , and an improvement in self-efficacy regarding their ability to cope with a special diet , compared to those receiving st and ard care . There were substantial improvements in the intervention group 's specific CF nutrition knowledge score , self-efficacy score , and reported fat intake compared to control , but no substantial change in body mass index or health-related quality of life over time . Home-based nutrition education incorporating behavioral strategies can be an effective way to support adults with CF , enabling improvement in self-management skills in relation to diet and pancreatic enzyme replacement therapy . This study revealed gaps in basic nutrition knowledge and skills , inadequate knowledge of diet-disease links and pancreatic enzyme replacement therapy . These need to be identified when subjects progress from pediatric to adult care , and programs such as " Eat Well with CF " are a useful adjunct for registered dietitians trying to manage this diverse but growing population [18627001] UNLABELLED Patients with liver cirrhosis exhibit early onset of gluconeogenesis after short-term fasting . This accelerated metabolic reaction to starvation may underlie their increased protein requirements and muscle depletion . A r and omized controlled trial was conducted to test the hypothesis that provision of a late-evening nutritional supplement over a 12-month period would improve body protein stores in patients with cirrhosis . A total of 103 patients ( 68 male , 35 female ; median age 51 , range 28 - 74 ; Child-Pugh grading : 52A , 31B , 20C ) were r and omized to receive either daytime ( between 0900 and 1900 hours ) or nighttime ( between 2100 and 0700 hours ) supplementary nutrition ( 710 kcal/day ) . Primary etiology of liver disease was chronic viral hepatitis ( 67 ) , alcohol ( 15 ) , cholestatic ( 6 ) , and other ( 15 ) . Total body protein ( TBP ) was measured by neutron activation analysis at baseline , 3 , 6 , and 12 months . Total daily energy and protein intakes were assessed at baseline and at 3 months by comprehensive dietary recall . As a percentage of values predicted when well , TBP at baseline was similar for the daytime ( 85 + /- 2[st and ard error of the mean]% ) and nighttime ( 84 + /- 2 % ) groups . For the nighttime group , significant increases in TBP were measured at 3 ( 0.38 + /- 0.10 kg , P = 0.0004 ) , 6 ( 0.48 + /- 0.13 kg , P = 0.0007 ) , and 12 months ( 0.53 + /- 0.17 kg , P = 0.003 ) compared to baseline . For the daytime group , no significant changes in TBP were seen . Daily energy and protein intakes at 3 months were higher than at baseline in both groups ( P < 0.0001 ) , and these changes did not differ between the groups . CONCLUSION Provision of a nighttime feed to patients with cirrhosis results in body protein accretion equivalent to about 2 kg of lean tissue sustained over 12 months . This improved nutritional status may have important implication s for the clinical course of these patients [18586458] OBJECTIVE We tested the hypothesis that a multifaceted 11-wk intervention comprising nutrition , group exercise , and oral care would have a significant influence on nutrition and function in elderly ( > or=65 y ) nursing-home residents . METHODS The study was an 11-wk r and omized controlled intervention study with nutrition ( chocolate and homemade oral supplements ) , group exercise twice a week ( 45 - 60 min , moderate intensity ) , and oral care intervention one to two times a week , with the aim of improving nutritional status and function in elderly nursing-home residents . A follow-up visit was made 4 mo after the end of the intervention . Assessment s were weight , body mass index , dietary intake , h and grip strength , Senior Fitness Test , Berg 's Balance Scale , and the prevalence of plaque . RESULTS A total of 121 subjects ( 61 % ) accepted the invitation and 62 were r and omized to the intervention group . Six of these dropped out during the 11 wk . At the 4-mo follow-up there were 15 deaths in the intervention group and 8 in the control group . The nutrition and exercise were well tolerated . After 11 wk the change in percentage of weight ( P = 0.005 ) , percentage of body mass index ( P = 0.003 ) , energy intake ( P = 0.084 ) , protein intake ( P = 0.012 ) , and Berg 's Balance Scale ( P = 0.004 ) was higher in the intervention group than in the control group . In addition , the percentage of subjects whose functional tests improved was higher in the intervention group . Both groups lost the same percentage of weight after the intervention ( P = 0.908 ) . The total percentage of weight loss from baseline to follow-up was higher in the control group ( P = 0.019 ) . Oral care was not well accepted and the prevalence of plaque did not change . CONCLUSION It is possible to improve nutrition and function in elderly nursing-home residents by means of a multifaceted intervention consisting of chocolate , homemade supplements , group exercise , and oral care

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### Context: [14512038] BACKGROUND Undernutrition and weight loss are important determinants of clinical outcome in older patients after hip fracture but the effectiveness of nutritional support programs in routine clinical practice remains controversial . AIMS OF THE PROJECT : To determine if oral nutritional supplements given daily for 28 days after hip fracture surgery could prevent weight loss and /or lead to improved clinical outcomes ( mortality rates , discharge destination , activities of daily living or length of hospital stay ) in non-malnourished community-dwelling older women with hip fracture . METHODS One hundred and nine women with BMI range 20 - 30 kg/m(2 ) were allocated to either nutritional supplements ( 352 kcal/day ) or usual hospital nutrition using a quasi-r and omisation technique . Body weight changes were monitored at 4 and 8 weeks and clinical outcomes were recorded at discharge and at 6 months . RESULTS No significant differences in weight change or clinical outcomes were seen between the two groups . Compliance with consuming the nutritional supplements was quite variable and there was a significant negative correlation between the amount of supplement consumed and subsequent weight change ( r=-0.36 , P=0.019 ) . CONCLUSIONS Poor compliance with oral nutritional supplements is an important determinant of the effectiveness of oral nutritional interventions in preventing weight loss after hip fracture . Whilst this may explain the lack of clinical improvements seen , our data do not support the routine use of oral nutritional supplements in non-malnourished hip fracture patients [8878142] There is a common perception that malnutrition is an inevitable manifestation of illness , that oral nutritional supplements are not taken or reduce the consumption of oral diet , and that nasogastric feeding is poorly tolerated . This study assessed the efficacy of supplemental enteral feeding on the nutritional status of malnourished patients , to compare oral supplements ( OS ) with overnight supplemental nasogastric feeding ( NG ) on nutritional status and to determine the effect of nutritional supplements on oral diet . Malnourished hospital patients were r and omized to one of three groups : control ( C ) , OS , or NG . All patients had access to hospital diet . Supplements were prescribed to meet estimated nutritional needs . Nutritional status was recorded at the start and the end of the feeding period . The total nutritional intake was recorded . Weight gain occurred in 64 % of the supplemented patients , whereas 73 % of the controls lost weight with mean weight changes of + 2.9 % OS . + 3.3 % NG , and -2.5 % C. There was no difference in the mean energy intake from food in the three groups . There were no documented complications of OS and three minor complications of NG . Both methods of supplementation allow weight gain without significantly affecting spontaneous oral intake [1802209] Ninety-three cancer patients about to undergo radiotherapy were studied . These patients were affected by cancer of the head and neck , breast cancer , and abdominopelvic cancer . They were r and omly distributed into control and experimental groups . The patients from the control group were allowed to eat ad libitum , whereas those from the experimental group followed a strict nutritional protocol that covered their needs while satisfying their particular tastes and habits . Data were collected the day before radiotherapy commenced and the day treatment ended . Anthropometric , analytical , and clinical parameters were determined . The results showed the benefit of dietetic treatment in experimental patients with head and neck or abdominopelvic cancer [17419798] AIMS To investigate whether a nutritional intervention in older women and men with femoral neck fracture had an effect on postoperative complications during hospitalization and on nutritional status at a four-month follow-up . METHODS The design was a r and omized controlled trial . The present study sample consisted of 157 patients aged 70 years and above with femoral neck fracture . The nutritional intervention included , among other things , a nutritional journal to detect nutrition deficiencies and protein-enriched meals for at least four days postoperatively . Further , at least two nutritional and protein drinks were served each day during the whole hospitalization and other factors that would influence the patient 's nutrition were also considered and dealt with . Postoperative complications were registered and patients were assessed using the Mini Nutritional Assessment ( MNA ) scale , including body mass index ( BMI ) , on admission and at a four-month follow-up . RESULTS Malnutrition was common and low MNA scores were associated with postoperative complications such as delirium and decubitus ulcers . There were significantly fewer days of delirium in the intervention group , seven patients in the intervention group developed decubitus ulcers vs. 14 patients in the control group and the total length of hospitalization was shorter . There were no detectable significant improvements regarding nutritional parameters between the intervention and the control group at the four-month follow-up but men improved their mean BMI , body weight and MNA scores in both the intervention and the control groups while women deteriorated in both groups . CONCLUSIONS Malnutrition was common among older people with hip fractures admitted to hospital . The nutritional intervention might have contributed to the patients suffering fewer days with delirium , fewer decubitus ulcers and shorter hospitalization but did not improve the long-term nutritional status , at least not in women . RELEVANCE TO CLINICAL PRACTICE This nutritional intervention , which was included in a multifactorial multidisciplinary intervention , is inexpensive and relatively easy to implement . It has significant effects on complications but no long-term effect on nutritional parameters , at least not in women [8467111] Malnutrition and cachexia are characteristic symptoms of human immunodeficiency virus (HIV)-1 infection and AIDS . To identify risk situations that might affect nutritional behavior and status and to evaluate the therapeutic effect of an intensified oral nutritional intervention , we analyzed 81 consecutively treated homosexual HIV-infected out patients with malnutrition retrospectively and could follow the outcome of a nutritional intervention prospect ively in 54 of them . Nutritional therapy was ineffective for only 5 of the 54 patients ; constant weight loss could be stopped in 31 of the patients , and 18 patients could even gain weight . We suggest intensified oral nutritional intervention should be an integral part of the treatment of HIV-infected patients to prevent or treat malnutrition [18514630] Decreases in whole-body lean mass can cause sarcopenia , a disease frequently found in the elderly . This condition is frequently associated with frailty and disability in aging as well as the onset and progression of several geriatric syndromes . Sarcopenia therefore must be managed with multidimensional approaches that include physical training , nutritional support , and metabolic and anabolic treatment . The purpose of our study was to assess the effect of an orally administered special mixture of amino acids ( AAs ) in elderly subjects with reduced lean body mass and sarcopenia . A r and omized , open-label , crossover study was conducted in 41 elderly subjects ( age range : 66 - 84 years ) with sarcopenia , assigned to 2 distinct treatments ( AAs and placebo ) . All subjects had normal body weight ( body mass index within 19 - 23 ) . The AA treatment consisted of 70.6 kcal/day ( 1 kcal = 4.2 kJ ) of 8 g of essential AA snacks , given at 10:00 am and 5:00 pm . Lean mass was measured with dual-energy x-ray absorptiometry in leg , arm , and trunk tissues . Significant increases in whole-body lean mass in all areas were seen after 6 months and more consistently after 18 months of oral nutritional supplementation with AAs . Fasting blood glucose , serum insulin , and homeostatic model assessment of insulin resistance ( an index of insulin resistance ) significantly decreased during AA treatment . Furthermore , a significant reduction in serum tumor necrosis factor-alpha ( TNF-alpha ) and a significant increase in both insulin-like growth factor-1 ( IGF-1 ) serum concentrations and in the IGF-1/TNF-alpha ratio were also found . No significant adverse effects were observed during AA treatment . These preliminary data indicate that nutritional supplements with the oral AA mixture significantly increased whole-body lean mass in elderly subjects with sarcopenia . The improvement in the amount of whole-body lean mass could be linked to increased insulin sensitivity and anabolic conditions related to IGF-1 availability [16182039] BACKGROUND AND AIMS In patients with liver cirrhosis , protein-energy malnutrition is a frequent finding and a risk factor influencing survival . The aim was to estimate the effects of an adequate diet on malnutrition and clinical outcome in patients with Child A or B HCV-related liver cirrhosis . METHODS We enrolled 90 consecutive out patients ( M/F=52/38 ) with liver cirrhosis , 30 in Child class A and 60 in class B. Patients were evaluated by anamnesis , clinical examination , estimation of daily caloric intake and measurement of anthropometrical and biochemical indexes . Patients were r and omized into two groups : group 1 with a 3-month oral controlled diet started one week after the first examination and this was followed by a 3-month of spontaneous dietary intake , and group 2 which started a 3-month spontaneous dietary intake followed by a 3-month of controlled diet . The follow-up was performed every month . RESULTS During the period of controlled diet in patients of both groups , protein malnutrition assessed by midarm muscle circumference , creatinine-height index and serum albumin significantly improved independently of the Child class . Lipid malnutrition , assessed by triceps skin fold thickness values , did not improve during the course of the study . The compliance to the prescribed diet was very high in both groups , and no carry over effect of the previous dietary intake was observed during the follow-up period . CONCLUSIONS The results emphasize the importance of both nutritional status evaluation and improvement in the Child A and B cirrhotic patients with HCV-related disease . The proposed nutritional approach was able to influence their protein malnutrition positively [6796711] In recent years , the concept of nutritional support as a part of a comprehensive cancer management program has gained increasing acceptability . However , little data is available in regard to the effect of nutritional support programs on the chronic disease state represented by recurrent or persistent cancer that characterizes patients undergoing systemic chemotherapy . In 1977 we undertook to study this problem in a r and omized prospect i ve study design ed to evaluate the effects of long-term ( 12 months ) enteral nutritional support in a group of ambulatory breast cancer patients undergoing a st and ard cytotoxic chemotherapy treatment program , in an adjuvant or therapeutic setting . The results of this study suggest that patients with breast cancer are overweight as compared to the general population and that any significant change in initial body weight , either a gain or a loss , is associated with an increased risk of recurrent disease . Data are presented which show little or no correlation between st and ard parameters of nutritional assessment and risk of disease recurrence and /or response to chemotherapy . These data also suggest that until we better underst and the relationship between tumor and host in breast cancer patients , we offer nutritional support programs only in situations where there are specific clinical indications for such interventions [16280442] BACKGROUND About 25 - 40 % of hospital patients are malnourished . With current clinical practice s , only 50 % of malnourished patients are identified by the medical and nursing staff . OBJECTIVE The objective of this study was to report the cost and effectiveness of early recognition and treatment of malnourished hospital patients with the use of the Short Nutritional Assessment Question naire ( SNAQ ) . DESIGN The intervention group consisted of 297 patients who were admitted to 2 mixed medical and surgical wards and who received both malnutrition screening at admission and st and ardized nutritional care . The control group consisted of a comparable group of 291 patients who received the usual hospital clinical care . Outcome measures were weight change , use of supplemental drinks , use of tube feeding , use of parenteral nutrition and in-between meals , number of consultations by the hospital dietitian , and length of hospital stay . RESULTS The recognition of malnutrition improved from 50 % to 80 % with the use of the SNAQ malnutrition screening tool during admission to the hospital . The st and ardized nutritional care protocol added approximately 600 kcal and 12 g protein to the daily intake of malnourished patients . Early screening and treatment of malnourished patients reduced the length of hospital stay in malnourished patients with low h and grip strength ( ie , frail patients ) . To shorten the mean length of hospital stay by 1 d for all malnourished patients , a mean investment of 76 euros ( 91 US dollars ) in nutritional screening and treatment was needed . The incremental costs were comparably low in the whole group and in the subgroup of malnourished patients with low h and grip strength . CONCLUSIONS Screening with the SNAQ and early st and ardized nutritional care improves the recognition of malnourished patients and provides the opportunity to start treatment at an early stage of hospitalization . The additional costs of early nutritional care are low , especially in frail malnourished patients [15277171] BACKGROUND Nutritional support is often recommended as part of the treatment of tuberculosis , but it has never been properly tested . OBJECTIVE We assessed the effects of early nutritional intervention on lean mass and physical function in patients with tuberculosis and wasting . DESIGN Patients who started antituberculous therapy within the previous 2 wk were r and omly assigned to receive st and ard nutritional counseling ( control group ) or nutritional counseling to increase their intake through diet and high-energy supplements ( nutritional supplement group ) for 6 wk . Body composition was measured by dual-energy X-ray absorptiometry , and physical function was assessed by maximum grip strength . RESULTS Patients in the nutritional supplement group ( n = 19 ) had a significantly greater increase in body weight ( 2.57 + /- 1.78 compared with 0.84 + /- 0.89 kg , P = 0.001 ) , total lean mass ( 1.17 + /- 0.93 compared with 0.04 + /- 1.26 kg , P = 0.006 ) , and grip strength ( 2.79 + /- 3.11 compared with -0.65 + /- 4.48 kg , P = 0.016 ) than did the control subjects ( n = 17 ) at week 6 . During subsequent follow-up , the increase in body weight remained greater in the nutritional supplement group , but this increase was due mainly to a greater gain in fat mass in the nutritional supplement group than in the control group . CONCLUSIONS Early intervention to increase nutritional intake increases lean mass and physical function . This adjunct to tuberculosis therapy could confer socioeconomic and survival benefits that deserve investigation in large-scale trials . Nutritional intervention after the initial phase of treatment could be less beneficial because it mainly increases fat [7500174] Nutritional deficiencies , frequently observed among the frail elderly , have been associated with increased morbidity and dependency . A r and omized clinical trial was conducted to assess the impact of nutritional supplementation on the functional status of frail elderly living at home . Subjects ( n = 50 ) over age 60 ( mean 78 y ) requiring community services and at elevated risk of undernutrition ( excessive weight loss or body mass index < 24 kg/m2 ) were r and omized to a high energy nutrient dense supplement provided by a dietitian or a control group receiving visits only . Outcome measures , including changes in h and grip strength , general well-being score , perception of health and number of falls , were measured by an investigator who was unaware of treatment assignment . After 12 wk , weight gain was greater in the supplemented group ( 2.1 + /- 2.3 vs. 0.6 + /- 1.6 kg ; P < 0.01 ) . Despite adequate statistical power , no functional measures differed except that the number of falls was lower among treated subjects vs. controls ( 0 % vs. 21 % ; P = 0.05 ) . Frail elderly can gain weight through oral supplementation , indicating the reversibility of weight loss in this group , but changes in functional status indicators may require a longer period of supplementation [17324657] BACKGROUND A r and omized controlled trial previously conducted in radiation oncology patients demonstrated that nutrition intervention had a beneficial impact on body weight , nutritional status , and quality of life compared with st and ard practice , but it did not report on dietary intake data . OBJECTIVE To determine the impact of nutrition intervention compared with st and ard practice on dietary intake in out patients receiving radiotherapy . DESIGN Prospect i ve , r and omized , controlled trial . SUBJECTS Sixty consecutive radiation oncology out patients ( 51 men and nine women ; age 61.9+/-14 years [ mean+/-st and ard deviation ] ) . SETTING Australian private radiotherapy facility . INTERVENTION Patients were r and omly assigned to receive either nutrition intervention ( n=29 ) ( nutrition counseling following the American Dietetic Association [ ADA ] medical nutrition therapy [ MNT ] protocol for radiation oncology ) or st and ard practice ( n=31 ) ( general nutrition talk and booklet ) . MAIN OUTCOME MEASURE Dietary intake ( protein , energy , fiber ) assessed at baseline and at 4 , 8 , and 12 weeks after starting radiotherapy . STATISTICAL ANALYSES Repeated- measures analysis of variance done on an intention to treat basis . RESULTS The nutrition intervention group had a higher mean total energy ( P=0.029 ) and protein intake ( P<0.001 ) compared with the st and ard practice group . Mean intake per kilogram of body weight for the nutrition intervention group ranged from 28 to 31 kcal/kg/day compared with 25 to 29 kcal/kg/day for the st and ard practice group ( P=0.022 ) . The nutrition intervention group had a higher mean protein intake ( 1.1 to 1.3 g/kg/day ) compared with the st and ard practice group ( 1.0 to 1.1 g/kg/day ) ( P=0.001 ) . Although the change in fiber intake between the groups was not significant , there was a trend in the anticipated direction ( P=0.083 ) . CONCLUSIONS Intensive nutrition intervention following the ADA MNT protocol results in improved dietary intake compared with st and ard practice and seems to beneficially impact nutrition-related outcomes previously observed in oncology out patients receiving radiotherapy . The ADA MNT protocol for radiation oncology is a useful guide to the level of nutrition support required [10807893] BACKGROUND Patients who undergo surgery are at risk of malnutrition due to periods of starvation , the stress of surgery , and subsequent increase in metabolic rate . There are limited data on nutritional outcome of surgical patients . AIMS To investigate changes in nutritional status and the influence of oral supplements on nutritional status , morbidity , and quality of life in postoperative surgical patients . METHODS Entry was determined by the presence of malnutrition , as defined by a body mass index ( BMI ) ⩽20 kg/m2 , anthropometric measurements ⩽15th percentile on admission , or initiation of oral diet postoperatively and /or a weight loss of 5 % or more during the operative period . We studied 101 patients : 52 were r and omised to the treatment group ( TG ) and prescribed a 1.5 kcal/ml nutritional supplement ; 49 patients were r and omised to the control group ( CG ) and continued with routine nutritional management . Nutritional status was assessed by weight , anthropometry , and grip strength , with measurements taken at two weekly intervals for 10 weeks . Complications , namely wound infection , chest infection , and antibiotic use were documented . Quality of life ( QOL ) was assessed using the UK SF-36 question naire . RESULTS Patients in the control group lost a maximum mean ( SD ) of 5.96 ( 4.21 ) kg in weight over a period of eight weeks while patients in group TG lost less weight overall ( maximum mean ( SD ) 3.40 ( 0.89 ) kg ( p<0.001 ) occurring at four weeks and progressively regained weight from week 4 ) . Anthropometry , grip strength , and QOL were similarly significantly different between groups ( p<0.001 ) . Fewer patients in the treatment group ( 7/52 ) required antibiotic prescriptions compared with the control group ( 15/49 ) . CONCLUSIONS Nutritional status declined for two months after discharge . Postoperative nutritional supplementation improved nutritional status , QOL , and morbidity in these patients [8598433] OBJECTIVE to evaluate the use of high-energy , high-protein , oral , liquid , nutrition supplementation and nutrition counseling on the weight status of patients infected with the human immunodeficiency virus ( HIV ) with and without secondary infections . DESIGN Prospect i ve , descriptive , intervention trial . Follow-up clinic visits were scheduled every 1 to 3 weeks for at least 6 weeks to monitor weight , gastrointestinal symptoms , number of supplements consumed , and incidence of secondary infections . SUBJECTS/ SETTING Community-based , HIV-infected patients , with and without an acquired immunodeficiency syndrome ( AIDS ) defining illness , who were receiving outpatient medical care at Deaconess Hospital . Twenty-two patients enrolled ; however , 4 dropped out and 1 died , so 17 were eligible for evaluation . INTERVENTION Dietary counseling consisted of recommendations to consume a high-protein diet ( 1.5 g/kg ideal body weight ) ; select foods that minimize gastrointestinal complications ; and take at least one high-energy , high-protein , oral , liquid , nutrition supplement daily . MAIN OUTCOME MEASURES Energy intake from the supplements and weight change over time in relation to whether a secondary infection occurred . STATISTICAL ANALYSIS Means , st and ard deviations , and frequency . RESULTS At the time of entry to the study , the patients with preexisting weight loss ( 16 of 17 ) were 14+/-8 % below their usual body weight . On average , patients consumed 11+/-4 supplements per week for 6+/-3 weeks . The majority ( 12 of 17 ) were able to gain or maintain weight . Overall weight change was 1.1+/-2.2 kg . Only 5 of 17 patients lost weight , 4 of whom developed a secondary infection during the study ( ie , after enrollment in the study ) . All of those who developed a secondary infection were classified as having AIDS and had lower mean CD4 counts at baseline than those who did not develop a secondary infection . Although those who developed a secondary infection had a higher incidence of weight loss , their consumption of oral supplements per week was greater than that of those without a secondary infection . APPLICATIONS/ CONCLUSIONS In patients with HIV infection and in the early stages of AIDS without a secondary infection , weight gain and /or maintenance was achievable with a high-energy , high-protein , oral , liquid , nutrition supplement in conjunction with nutrition counseling . The majority of the patients who developed a secondary infection , however , lost weight despite the use of supplements and counseling . Use of a high-energy , high-protein , oral , liquid , nutrition supplement , with intact nutrients , should be the first-line nutrition treatment for malnourished , HIV-infected patients without secondary infections [8909354] OBJECTIVE To evaluate the association of oral food intake with survival in very old demented nursing home patients . DESIGN A prospect i ve cohort study . SETTING A nursing home in northern Italy . MEASUREMENTS Anthropometric and laboratory nutritional indicators and nutrient intake were assessed in 33 demented ( age 85.7 + /- 5.7 years ) and 25 nondemented ( age 84.9 + /- 5.7 years ) patients . Mortality data were collected over a 28-month follow-up period . Association of survival with dementia was estimated by Kaplan-Meyer analysis and multivariate Cox proportional hazard models . RESULTS Nutrient intake and nutritional status were good compared with data in the literature and were similar in demented and nondemented patients , except for smaller triceps skinfold thickness in the demented . The cumulative annual death rate was 0.23 deaths per subject per year , similar in the demented ( 0.23 ) and the nondemented ( 0.22 ) . Unadjusted survival by Kaplan-Meyer analysis was similar in the two groups , and correction for-age , gender , cognition , triceps skinfold thickness , and number of drugs in a Cox model did not alter the relationship . CONCLUSIONS Dementia developing in very old age is not necessarily associated with malnutrition and decreased life expectancy [16679331] Abstract Objective To assess the effect of family style mealtimes on quality of life , physical performance , and body weight of nursing home residents without dementia . Design Cluster r and omised trial . Setting Five Dutch nursing homes . Participants 178 residents ( mean age 77 years ) . Two wards in each home were r and omised to intervention ( 95 participants ) or control groups ( 83 ) . Intervention During six months the intervention group took their meals family style and the control group received the usual individual pre-plated service . Main outcome measures Quality of life ( perceived safety ; autonomy ; and sensory , physical , and psychosocial functioning ) , gross and fine motor function , and body weight . Results The difference in change between the groups was significant for overall quality of life ( 6.1 units , 95 % confidence interval 2.1 to 10.3 ) , fine motor function ( 1.8 units , 0.6 to 3.0 ) , and body weight ( 1.5 kg , 0.6 to 2.4 ) . Conclusion Family style mealtimes maintain quality of life , physical performance , and body weight of nursing home residents without dementia . Trial registration Clinical trials [9309995] The impact of oral nutritional supplementation during an acute exacerbation of COPD on functional status was assessed through measuring change in lung function , strength testing , and general well-being . Subjects hospitalized for an acute exacerbation of COPD ( n = 33 ) were r and omized to extra nutritional support or the regular hospital care . They consumed an additional 10 kcal/kg/d . Outcome measures were measured at 2 wk as change scores . Forced vital capacity ( % predicted ) improved in the treatment group as compared with the control group ( + 8.7 % versus -3.5 % , p = 0.015 ) , and change in FEV1 was in the same direction but not significantly different ( p = 0.099 ) . There were no changes in h and grip strength or respiratory muscle strength , but there was a trend towards more improvement in the general well-being score ( + 11.96 versus -10.25 , p = 0.066 ) . Almost all subjects were in negative nitrogen balance , indicating muscle wasting . The degree of muscle wasting was strongly correlated with the dose of corticosteroids ( r = 0.73 , p < 0.005 ) . In conclusion , it is difficult to prevent important muscle wasting in patients with COPD treated with corticosteroids , but some small gains were observed with increased dietary intake [15788122] Since long-term weight maintenance ( WM ) is a major problem , interventions to improve WM are needed . The aim of the study was to investigate whether the addition of protein to the diet might limit weight regain after a weight loss of 5 - 10 % in overweight subjects . In a r and omised parallel study design , 113 overweight subjects ( BMI 29.3 ( SD 2.5 ) kg/m2 ) ; age 45.1 ( SD 10.4 ) years ) followed a very-low-energy diet for 4 weeks , after which there was a 6-month period of WM . During WM , subjects were r and omised into either a protein group or a control group . The protein group received 30 g/d protein in addition to their own usual diet . During the very-low-energy diet , no differences were observed between the groups . During WM , the protein group showed a higher protein intake ( 18 % v. 15 % ; P<0.05 ) , a lower weight regain ( 0.8 v. 3.0 kg ; P<0.05 ) , a decreased waist circumference ( -1.2 ( SD 0.7 ) v. 0.5 ( SD 0.5 ) cm ; P<0.05 ) and a smaller increase in respiratory quotient ( 0.03 ( SD 0.01 ) v. 0.07 0.01 ; (SD/)P < 0.05 ) compared with the control group . Weight regain in the protein group consisted of only fat-free mass , whereas the control group gained fat mass as well . Satiety in the fasted state before breakfast increased significantly more in the protein group than in the control group . After 6 months follow-up , body weight showed a significant group x time interaction . A protein intake of 18 % compared with 15 % result ed in improved WM in overweight subjects after a weight loss of 7.5 % . This improved WM implied several factors , i.e. improved body composition , fat distribution , substrate oxidation and satiety [12382215] OBJECTIVE This controlled trial was undertaken to evaluate the benefits of short-term enteral nutrient supplementation in maintenance hemodialysis ( MHD ) patients using a high-calorie and high-protein blend formula ( low-cost home-prepared [ HP ] blend or a commercially available supplement ) and to study its effect on selected parameters of nutritional status . The acceptability and palatability of the HP blend formula , ease of use , and cost were also assessed in comparison with the commercial nutritional supplement ( CNS ) . DESIGN R and omized controlled trial . SETTING Hemodialysis ( HD ) unit of a tertiary referral care hospital in Southern India . PATIENTS Nondiabetic adult MHD patients with no intercurrent illness , on regular thrice weekly MHD for at least 1 month before recruitment , with a body mass index ( BMI ) < 20 and a serum albumin level of < 4.0 g/dL. Patients were r and omized into control group and experimental group , the latter in turn to recieve either CNS or HP blend . INTERVENTION The control group received appropriate monitoring , including dietary recall and counselling for the prescribed diet ( protein intake of 1.2 g/kgIBW/d and energy of 35 to 45 kcal/kgIBW/d ) but no specific post-HD supplement . Patients in the supplement group received the respective supplement post-HD ( providing 500 kcal and 15 g protein ) for 1 month in addition to the monitored diet prescription . MAIN OUTCOME MEASURES ( 1 ) Nutritional status parameters , BMI and serum albumin ; ( 2 ) functional status on a 10-point Karnofsky scale ; ( 3 ) adverse metabolic effects , hyperphosphatemia at start and end of study ; and ( 4 ) subjective scoring for appetite , and acceptability of and tolerance to supplement . RESULTS Both groups showed an improvement in dry weight and BMI . In addition , the supplement group showed a significant increase in serum albumin level and functional scoring . Mild hyperphosphatemia occurred in the supplement group . An increase in baseline food intake was seen in the control group , but not in the supplemented group . No intolerance was reported to either supplement . CONCLUSION Enteral nutrient supplementation was shown to bring about a significant improvement in serum albumin level even in a short-term study . Use of an HP supplement was beneficial , acceptable , and inexpensive [8409181] OBJECTIVES To determine why elderly nursing home patients receive liquid oral protein supplements , what nutritional assessment is utilized , and whether there is evidence of effectiveness . DESIGN Retrospective , case control study comparing patients over 65 years of age , at two nursing homes , who were served oral supplements ( OS ) at least twice daily ( n = 56 ) , with a r and om sample of non-supplemented , non-tube fed patients ( n = 53 ) . Comparisons included medical diagnoses , medications , morbidity and mortality , weight changes , laboratory test results , and functional and behavioral status . RESULTS Nursing home patients were begun on OS ( median time after admission = 2 months , range = 0 - 72 months ) primarily because of weight loss ( 71 % ) and poor appetite ( 16 % ) . Supplemented patients were below an age-adjusted body weight on admission , unlike controls , and continued to lose weight until OS were started . On OS , weight was slowly regained over 9 - 10 months in a majority of patients to approximate admission weight . Some patients on OS showed improvement in albumin , total lymphocyte count , cholesterol , or hemoglobin , but too few patients had sufficient lab tests to verify any consistent effect . Mortality was higher in OS patients ( 8 vs 2 , P = 0.057 ) , who were also somewhat older ( 87.9 vs 84.5 years ) , but there was no statistical difference in infection or hospitalization rate . MEASUREMENTS Nutritional assessment in these nursing homes consisted almost exclusively of ( 1 ) serial measurement of weight , ( 2 ) comparison of weight to ( a ) " ideal body weight " and ( b ) previous weight , and ( 3 ) a subjective evaluation of food consumption . No other anthropometric evaluations or laboratory tests were conducted for nutritional assessment . CONCLUSIONS The diagnosis of and intervention in under-nutrition in nursing home patients is frequently disorganized . In addition , nutritional assessment , either for screening or for following intervention , is hampered by the lack of convenient and unambiguous assessment tools . OS use is associated with weight gain in many nursing home patients and also improves other nutritional parameters in selected individuals [565418] Seventeen patients undergoing 19 major urological operations for bladder cancer or rectal leiomyosarcoma ( 1 case ) were studied after r and omization for 3 hypocaloric dietary regimens , preoperative keto-adaptation by a carbohydrate-free , oral protein diet continued in the postoperative period by isotonic amino acid infusions , postoperative amino acid infusions only and 5 per cent dextrose infusions . In these normally nourished patients serum transferrin ( plus 13 mg./dl . minus 30 mg./dl . , minus 69 mg./dl . , p less than 0.05 for the first and combined amino acid groups against the third group ) and 2 other short half-life hepatic secretory proteins , prealbumin and retinol-binding protein , represented sensitive indexes of visceral protein and nutritional support , superior to nitrogen balance , anthropometric assays , delayed hypersensitivity skin test reactivity and serum albumin . Near isotonic amino acid infusions were more effective in preserving visceral protein status than 5 per cent dextrose but preoperative keto-adaptation was not shown to have any increased benefit over protein-sparing therapy given only after an operation [9195264] Summary . The objective of this prospect i ve study of matched controls was to find out whether supplementary nutrition would improve wound healing and decrease mortality in patients undergoing transtibial amputation for occlusive arterial disease . The nutritional status of 32 consecutive transtibial amputees was assessed and 28 were classified as malnourished . Supplementary nutrition was given reaching an average intake of 2098 kcal/day for a total of 11 days . In 24 patients , at least 5 days of preoperative supplementary nutrition were given , followed by postoperative treatment for a total of 11 days . Four patients who had an immediate operation were given only postoperative treatment , and 4 were excluded . The controls were 32 amputees in another hospital and matching procedures were carried out with corrections for diabetes , sex , age , smoking habits , previous vascular surgery and living conditions before amputation . Healing , including those healed before death in both groups , occurred in 26 of the nutrition group compared to 13 in the control group , which was statistically significant . Nine patients died within 6 months in the nutrition group compared to 14 of the controls ( not significant ) . Malnutrition was present in nearly 90 % of transtibial amputees and supplementary nutrition improved healing , but not mortality . Résumé . L’objectif de cette étude prospect i ve a été d’étudier si une augmentation de l’apport nutritionnel peut ameliorer la cicatrisation et réduire la mortalité chez les malades ayant subi une amputation de jambe en raison d’une maladie vasculaire . L’état nutritionnel de trente-deux patients consécutifs ayant subi une amputation de jambe a étéévalué . Vingt-huit ont été considérés comme malnutris . Une nutrition additionnelle leur a été donnée avec un apport moyen de 2098 kcal par jour pendant 11 jours . Chez 24 malades une nutrition additionnelle , de cinq jours au moins en préopératoire , a été suivie par un traitement postopératoire pour atteindre un total de 11 jours . Quatre malades necessitant une amputation en urgence n’ont re*u le traitement que postopératoire et quatre malades ont été exclus . Trente deux amputés de jambe venant d’un hopital universitaire voisin ont été utilisés comme contrôle , après associations des cas tenant compte de l’age , le sexe , du diabète , de la consommation de tabac , des opérations vasculaires précédentes et des conditions de vie antérieure à l’amputation . L’étude de la cicatrisation a montré que 26 amputés étaient cicatrisés dans le groupe ayant bénéficié d’un apport nutritionnel contre 13 dans le groupe de controle , P= 0.001 . Neuf patients sont morts dans les premier six mois dans le groupe ayant bénéficié d’un apport nutritionnel contre 14 dans le groupe de controle , ( n. s. ) . Cette étude montre clairement que près de 90 % des amputés de jambe étaient malnutris et qu’un apport nutritionnel a amelioré la cicatrisation du moignon sans pour autant augmenter la survie [15920748] BACKGROUND We aim ed to determine the effect of dietary counseling or oral supplements on outcome for patients with cancer , specifically , nutritional outcome , morbidity , and quality of life ( QOL ) , during and 3 months after radiotherapy . METHODS Seventy-five patients with head and neck cancer who were referred for radiotherapy ( RT ) were r and omized to the following groups : group 1 ( n = 25 ) , patients who received dietary counseling with regular foods ; group 2 ( n = 25 ) , patients who maintained usual diet plus supplements ; and group 3 ( n = 25 ) , patients who maintained intake ad lib . Nutritional intake ( determined by diet history ) and status ( determined by Ottery 's Subjective Global Assessment ) , and QOL ( determined by the European Organization for the Research and Treatment of Cancer Quality of Life Question naire version 3.0 [ EORTC QLQ-C30 ] ) were evaluated at baseline , at the end of RT , and at 3 months . RESULTS Energy intake after RT increased in both groups 1 and 2 ( p < or = .05 ) . Protein intake also increased in both groups 1 and 2 ( p < or = .006 ) . Both energy and protein intake decreased significantly in group 3 ( p < .01 ) . At 3 months , group 1 maintained intakes , whereas groups 2 and 3 returned to or below baseline levels . After RT , > 90 % of patients experienced RT toxicity ; this was not significantly different between groups , with a trend for reduced symptomatology in group 1 versus group 2/group 3 ( p < .07 ) . At 3 months , the reduction of incidence/severity of grade 1 + 2 anorexia , nausea/vomiting , xerostomia , and dysgeusia was different : 90 % of the patients improved in group 1 versus 67 % in group 2 versus 51 % in group 3 ( p < .0001 ) . After RT , QOL function scores improved ( p < .003 ) proportionally with improved nutritional intake and status in group 1/group 2 ( p < .05 ) and worsened in group 3 ( p < .05 ) ; at 3 months , patients in group 1 maintained or improved overall QOL , whereas patients in groups 2 and 3 maintained or worsened overall QOL . CONCLUSIONS During RT , nutritional interventions positively influenced outcomes , and counseling was of similar/higher benefit ; in the medium term , only counseling exerted a significant impact on patient outcomes [8029587] A body weight lower than 90 % of the optional value has an unfavorable influence on the prognosis of chronic obstructive pulmonary disease ( COPD ) . Short term studies of up to three months duration have shown improved function of respiratory muscle exercise tolerance and immunologic parameters by an increased caloric intake of 45 kcal/kg body weight . In a r and omized trial of twelve months 14 of 30 patients with an average FEV1 of 0.8 l were instructed to take a high calorie diet . For simplicity a part of the calories were administered as Fresubin , a fluid nutrient formula . Although a weight gain of 7 kg ( p = 0.003 ) was obtained the difference to the control group was statistically not significant ( p = 0.08 ) . The same was true for skin fold thickness ( 12.4 vs 5.7 mm ) , change of ventilatory parameters and the 6 minute walking distance ( -33 vs -86 m ) . Subjective improvement was , however , impressive in all patients with dietary intervention , explainable probably by increased attention . Dietary counselling for increased intake of calories , vitamins and also calcium is thus very important in the treatment of patients with COPD [2409852] Malnutrition occurs frequently in patients with cancer of the gastrointestinal ( GI ) or head and neck area and can lead to negative outcomes . The aim of this study is to determine the impact of early and intensive nutrition intervention ( NI ) on body weight , body composition , nutritional status , global quality of life ( QoL ) and physical function compared to usual practice in oncology out patients receiving radiotherapy to the GI or head and neck area . Out patients commencing at least 20 fractions of radiotherapy to the GI or head and neck area were r and omised to receive intensive , individualised nutrition counselling by a dietitian using a st and ard protocol and oral supplements if required , or the usual practice of the centre ( general advice and nutrition booklet ) . Outcome parameters were measured at baseline and 4 , 8 and 12 weeks after commencing radiotherapy using valid and reliable tools . A total of 60 patients ( 51 M : 9F ; mean age 61.9±14.0 years ) were r and omised to receive either NI ( n=29 ) or usual care ( UC ) ( n=31 ) . The NI group had statistically smaller deteriorations in weight ( P<0.001 ) , nutritional status ( P=0.020 ) and global QoL ( P=0.009 ) compared with those receiving UC . Clinical ly , but not statistically significant differences in fat-free mass were observed between the groups ( P=0.195 ) . Early and intensive NI appears beneficial in terms of minimising weight loss , deterioration in nutritional status , global QoL and physical function in oncology out patients receiving radiotherapy to the GI or head and neck area . Weight maintenance in this population leads to beneficial outcomes and suggests that this , rather than weight gain , may be a more appropriate aim of NI [16354710] OBJECTIVE To examine how improved attention to nutritional status and dietary intake , achieved through the employment of dietetic assistants ( DAs ) , will affect postoperative clinical outcome among elderly women with hip fracture . DESIGN Open prospect i ve r and omised controlled trial , comparing conventional nursing care with the additional nutritional support provided by DA . SETTING Thirty-eight bedded acute trauma ward in a teaching hospital . PARTICIPANTS All but 11 of 344 consecutive admissions with acute nonpathological hip fracture were approached . Three hundred and eighteen ( 93 % ) agreed to inclusion . Sixteen were ineligible as they were immediately transferred to another acute ward , were managed conservatively or died preoperatively . PRIMARY OUTCOME MEASURE Postoperative mortality in the acute trauma unit . SECONDARY OUTCOME MEASURES Postoperative mortality at 4 months after fracture , length of stay , energy intake and nutritional status . RESULTS DA-supported participants were less likely to die in the acute ward ( 4.1 versus 10.1 % , P = 0.048 ) . This effect was still apparent at 4 month follow-up ( 13.1 versus 22.9 % , P = 0.036 ) . DA-supported subjects had significantly better mean daily energy intake ( 1,105 kcal versus 756 kcal/24 h , 95 % CI 259 - 440 kcal/24 h , P<0.001 ) , significantly smaller reduction in mid-arm circumference during their inpatient stay ( 0.39 cm , P = 0.002 ) and nonsignificantly favourable results for other anthropometric and laboratory measurements . CONCLUSION Dietetic or nutrition assistants are being introduced in units across the UK . This , the largest ever study of nutritional support after hip fracture , shows that their employment significantly reduced patients ' risk of dying in the acute trauma unit ; an effect that persisted at 4 month follow-up [6799196] Nutritional intervention in the cancer patient [ e.g. , total parenteral nutrition ( TPN ) ] might improve durable survival because of increased tolerance to aggressive tumor therapy . To determine whether this assumption is correct , 42 patients with diffuse histiocytic lymphoma were induced with prednisone , high-dose methotrexate , Adriamycin , cyclophosphamide , and VP-16 ( ProMACE ) . Nitrogen mustard-vincristine-procarbazine-prednisone ( MOPP ) consolidation was then used , followed by late intensification with ProMACE . Patients were selected r and omly to receive adjuvant TPN or a st and ard diet during ProMACE-MOPP treatment . While TPN patients had a greater median weight gain than did control patients , lean body mass and degree of myelosuppression did not improved as a consequence of TPN . There was no significant difference in tumor response or survival between TPN and control patients , whether or not the patients were initially malnourished . In a second trial , 32 young patients with metastatic or other poor-prognosis sarcomas were r and omly allocated to receive TP or a st and ard diet as an adjunct to one very intensive course of combination chemotherapy or chemotherapy plus total body irradiation ; autologous marrow transplantation was used with gain than did controls but remained in a negative nitrogen balance . Response rates and median durable survival did not differ between the two groups . In both trials , the maximum nutritional support permitted by currently available technology was offered . Thus , the limiting factor may not be nutritional status but rather the intrinsic biology of the tumors and the limitations of their response to current therapy . In in vitro studies of the possible influence of nutrition on cancer treatment , we have compared sublines of P388 murine leukemia cells which are sensitive or resistant to Adriamycin . The difference in drug sensitivity correlated with differences in lipid composition , with more intracellular lipid , and with greater membrane rigidity in the resistant cells . Resistant cells have a relatively poor transport of drug into the cell ; moreover , intracellular Adriamycin is sequestered in lipid depots away from DNA . These results suggest one possible relationship between nutritional phenomena and drug sensitivity [17964008] BACKGROUND Malnutrition is a common problem in patients with digestive disease and is associated with impaired outcome . OBJECTIVE We investigated the effect of a three-month post-hospital nutritional intervention with high protein and energy supplements on body composition , muscle function and quality of life ( QoL ) in malnourished GI patients . PATIENTS AND INTERVENTION Eighty malnourished patients with benign digestive disease were r and omized to receive either oral nutritional supplements ( ONS ) for three months in addition to dietary counselling ( DC ) ( ONS patients ) or only dietary counselling ( DC patients ) . METHODS Nutritional status was determined with the subjective global assessment , body composition by bioelectrical impedance and anthropometry , muscle function with h and -grip strength and peak flow . QoL was assessed by the 36-item short-form question naire . RESULTS Age , body cell mass ( BCM ) , muscle function , gender distribution and QoL did not differ between ONS patients ( n=38 ) and DC patients ( n=42 ) at baseline . Body weight and BCM improved significantly in both groups after three months . However , h and -grip strength ( 26.1+/-11.3 - 31.5+/-10.1 kg , p<0.0001 ) and peak flow ( 329.2+/-124.0 - 388.9+/-108.4 l /min , p=0.004 ) improved only in the ONS patients and remained unchanged in the DC patients . Similarly , all eight scales of the QoL improved in the ONS patients compared with merely three in the DC patients . DC patients experienced significantly more readmissions ( n=20 ) than ONS patients ( n=10 ) during the study period ( p=0.041 ) . CONCLUSION A three month intervention with high protein oral supplements improves outcome in malnourished patients with digestive disease in terms of functional status , QoL and rehospitalization [16970646] OBJECTIVES To determine whether increases in caloric intake associated with consumption of a mid-morning nutritional supplement for 3 weeks were maintained in the week after stopping the supplement and to investigate the effects of body mass index ( BMI ) and cognitive and behavioral measures on this response . DESIGN Secondary analysis of a previously published r and omized , crossover , nonblinded clinical trial . SETTING A fully accredited geriatric care facility affiliated with the University of Toronto . PARTICIPANTS Thirty institutionalized seniors with probable Alzheimer 's disease ( AD ) who ate independently . MEASUREMENTS Investigator-weighed food intake , body weight , cognitive ( Severe Impairment Battery ; Global Deterioration Scale ) and behavioral ( Neuropsychiatric Inventory -- Nursing Home version ; London Psychogeriatric Rating Scale ) assessment s. RESULTS Individuals who responded successfully to supplementation as indicated by increases in daily energy intake were likely to maintain 58.8 % of that increase postsupplementation , although stopping the supplement was associated with decreased habitual energy intake in low- BMI individuals who reduced their daily intakes during supplementation in response to the extra calories . Cognitive/behavioral tests were not reliable predictors of postsupplement intake . CONCLUSION Institutionalized seniors with probable AD are likely to alter their usual energy intakes to maintain changes result ing from 3 weeks of supplementation . This effect may allow for rotating supplementation schedules in nursing homes that could reduce staff burden , but only for those individuals who are most likely to respond favorably . These data indicate that nutritional supplements and diet plans should be carefully prescribed in low- BMI individuals to limit variability in total energy provided and thus prevent lower-than-normal intake [2656603] Fifty ambulatory patients with head and neck cancer treated by definitive radiation therapy at the Fox Chase Cancer Center were prospect ively studied to determine the effect of oral nutritional supplements on both nutritional status and treatment response . Nutritional supplements maintained serum albumin during and post treatment . Nutritional supplements were shown to increase total protein and total calorie intake rather than displace these nutrients in usual food intake . Equal weight loss occurred in both the supplemented and non-supplemented groups during the observation period of 6 months , with the same or greater amount of weight loss registered 10 weeks after the start of treatment . Food supplements did not affect treatment response or complications , nor did they offer any survival advantage [12171453] OBJECTIVE To evaluate the impact of nutritional supplementation on nutritional status , muscle strength , perceived health , and functional status in a population of community-living , frail , undernourished elderly people . DESIGN A 16-week intervention study in which subjects were r and omized to an experimental or a control group and visited in their home on a monthly basis . Outcome variables were measured at the start and end of the study at subjects ' homes by a dietitian blinded to treatment assignment . SUBJECTS/ SETTING 83 elderly people ( experimental group : n=42 ; control group : n=41 ; mean age=80+/-7 years ) receiving community home-care services and at high risk for undernutrition . INTERVENTION Provision of a nutrient-dense protein-energy liquid supplement and encouragement to improve intake from other foods . OUTCOME MEASURES Anthropometric indexes , h and grip strength , isometric elbow flexion and leg extension strength , lower extremity function , perceived health , and functional status . STATISTICAL ANALYSES Study groups were compared on an " intention to treat " basis using analysis of variance for repeated measures and unpaired and paired t tests and their nonparametric equivalents where appropriate . RESULTS Total energy intake ( 1,772 vs 1,440 kcal ; P<.001 ) and weight gain ( 1.62 vs 0.04 kg ; P<.001 ) were higher in the supplemented group . No significant changes were observed with respect to other anthropometric indexes , muscle strength , or functional variables ; however , beneficial effects were observed in emotional role functioning ( P<0.01 ) and number of days spent in bed ( P=.04 ) . APPLICATIONS/ CONCLUSIONS Nutrition intervention is feasible in free-living , frail , undernourished elderly people and results in significant improvement of nutritional status with respect to energy and nutrient intake and weight gain . Weight loss can be stopped and in some cases reversed ; however , increased physical activity may also be required to improve health and functional status [15896431] RATIONALE Nutritional depletion is a common problem in chronic obstructive pulmonary disease ( COPD ) patients . It is caused , to a large extent , by an imbalance between low-energy intake and high-energy requirements . This problem adversely affects morbidity and mortality . However , the use of nutritional supplements to reach their energy necessities requires optimisation between positive and adverse effects on outcome before being used systematic ally as part of their comprehensive care . PURPOSE The aim of our study was to investigate the effects of oral nutritional repletion on quality of life in stable COPD patients . METHODS Prospect i ve , r and omised and multi-centre study . Stable COPD patients with a body mass index 22 , a fat-free mass index 16 , and /or a recent involuntary weight loss ( 5 % during last month , or 10 % during the last 3 months ) were studied . Exclusion criteria were to present signs of an airway infection , to have a cardiovascular , neurological , or endocrine disease , to be treated with oral steroids , immunosuppressors or oxygen therapy at home , and to receive nutritional supplements . During 12 weeks , patients were encouraged to ingest a total daily defined energy intake . R and omly , in patients from group A the total daily energy load was Resting Energy Expenditure (REE)x1.7 , and those from group B , REE x1.3 . Total daily energy intake was achieved with regular food plus , if necessary , oral nutritional supplement rich in proteins ( with 50 % of whey protein ) , with predominance of carbohydrates over fat , and enriched in antioxidants . Primary end-point variable was quality of life . Secondary end-point outcomes included body weight , body composition , lung function , h and grip strength , and compliance with the energy intake previously planned . Data were treated with a SAS System . Student 's test , Wilcoxon 's rank sum test , and Mann-Whitney 's test were used . RESULTS At baseline both groups of patients were comparable . All patients needed oral nutritional supplements to achieve total daily defined energy intake . After 12 weeks of follow-up , patients in both groups significantly increased energy intake . Patients in group A increased body weight ( P=0.001 ) , triceps skin fold thickness ( P=0.009 ) and body fat mass ( P=0.02 ) , and decreased body fat-free mass index ( P=0.02 ) . In this group a marked increase in airflow limitation was observed . A tendency to increase body weight and h and grip strength , and to decrease airflow limitation was observed in patients from group B. Furthermore , patients in the later group showed a significant improvement in the feeling of control over the disease ( P=0.007 ) and a tendency to better the other criteria in a quality of life scale . CONCLUSIONS According to our results , total daily energy intake of REE x 1.3 is preferable to REE x 1.7 in mild stable COPD patients . The administration of oral nutritional supplements , rich in proteins ( with 50 % of whey protein ) , with predominance of carbohydrates over fat , and enriched in antioxidants , to achieve total daily defined energy intake in patients in group B was followed by a significant improvement of one criteria ( mastery ) among many others in a quality of life scale [1425861] Abstract . A total of 29 patients with acute leukaemia were prospect ively r and omized before starting cytos‐tatic treatment to be nourished either with intensified oral nutrition ( intervention group ) or ad libitum nutritional intake during the whole tumour therapy ( median 22 weeks ) . All menus of free choice ( daily offer of 1.0–2.0 g protein , 30–50 kcal kg‐1 body weight ( BW ) ) . Beyond this , intervention patients nutrition education , daily visits by the dietician and record of food intake , as well as a weekly assessment of subjective well‐being ( linear analogue self assessment ‘ LASA ’ ) . From the LASA items , the factors : ‘ malaise ’ , ‘ psychological distress ’ , ‘ therapy side‐effects ’ were extracted by principal component analysis , and correlated to nutrient intake and nutritional status . At the end of antineoplastic induction therapy , after continuous hospitalization of 10 weeks ( median ) , 31.3 % of the controls had regained their initial nutritional status , and 68.8 % of the intervention group . Mean daily energy intake was 23.2 kcal kg‐1 BW during weeks with weight loss ( constant weight : 30.9 , weight gain : 39.3 kcal kg‐1 BW ) . Nutritional . behaviour correlated with subjective well‐being , low intake with complaints of tumour treatment side effects and weight loss with malaise [11463999] Background : No data is available on dietary intervention in c and i date s for lung transplantation and on the effect of different strategies for dietary support in this cohort . Aim : We therefore wanted to evaluate the effects of intensified nutritional support compared with simple support on energy intake and nutritional status . Method : Our participants were underweight ( n = 42 ) and normal-weight ( control group , n = 29 ) c and i date s for lung transplantation . The underweight patients were r and omized into two groups . Group A received intensified dietary counselling , ready-made liquid nutritional supplements free of charge and regular follow-ups , while group B received only one session of individual dietary counselling , no supplements and no follow-ups . Results : The mean intervention time was 21 weeks . Groups A and B both increased their energy intake and gained weight . Group A increased their energy intake from a median of 8.7 to 10.1 MJ ( p < 0.01 compared with the control group after intervention ) and gained a mean of 2.9 kg body weight ( 95 % CI 1.2 ; 4.7 , p = 0.005 compared with the control group ) , while group B increased from 7.4 to 10.8 MJ ( p = 0.005 ) and gained 2.3 kg ( 1.2 ; 3.3 , p = 0.002 ) . Only group B increased their fat-free mass . In this group , an increase in O2 saturation and a decrease in PaCO2 were suggested . None of the groups improved its physical performance . Conclusion : In c and i date s for lung transplantation we were unable to confirm the hypothesis that intensified nutritional support compared with a simple support increased compliance . Both groups achieved the goal for energy intake and gained weight [2691239] The effects of a nutritional support in hospitalized patients with alcoholic cirrhosis and liver failure were studied in a controlled protocol . Thirty-six patients were included , 17 were r and omly assigned to an experimental group and the rest to a control group . Experimentals received a diet aim ing at 50 kcal ( 209 kJ)/kg bodyweight/d and 1.5 g protein/kg bodyweight/d ( as proteins of high biological value ) . Controls received the st and ard diet prescribed by the attending physician . The severity of liver failure and the nutritional status on admission were similar in both groups . The measured energy intake in controls was 1813 + /- 121 kcal/d ( 7589 + /- 506 kJ/d ) and 2707 + /- 71 kcal/d ( 1131 + /- 297 kJ/d ) in experimentals ( P less than 0.001 ) . The protein intake in controls was 47 + /- 3.8 g/d and in experimentals 80 + /- 3 g/d ( P less than 0.001 ) . There were seven deaths during the study period ( two experimentals and five controls ) . No differences were observed in the evolution of liver failure , hepatic encephalopathy or nutritional status between both study groups . It is concluded that a higher energy and protein intake in these patients does not have adverse effects and is associated with a non-significant reduction in mortality [16889545] We report results of a r and omized clinical trial of a combined intervention of exercise and dietary counseling ( ExD ) after orthotopic liver transplantation ( OLT ) [15896425] AIMS To evaluate the effect of a whole formula diet on nutritional and cognitive status in Alzheimer 's disease patients . METHODS Patients were r and omly assigned to two interventions : a whole formula diet based on lyophilised foods ( Treatment Group , n=24 ) or nutritional advice ( Control Group , n=29 ) . Energy intake , body weight , biochemistry , Mini Nutritional Assessment ( MNA ) and Pfeiffer 's tests were determined at baseline and at 3 months of treatment . RESULTS No differences were observed between groups at baseline . Energy intake tended to increase in the Treatment Group and to decrease in the Control Group , although differences were not significant . The improvement in MNA and Pfeiffer test scores was not significantly different between groups . Body weight increased by 2.06+/-1.9 kg in the Treatment Group and by 0.32+/-3.04 kg in the Control Group ( P=0.007 ) . The increases in albumin ( P=0.007 ) , haemoglobin ( P=0.002 ) and serum ferritin ( P=0.009 ) were higher in the Treatment Group than in controls . A similar rate of serious adverse events ( hospitalisation or death ) was observed in both groups . CONCLUSIONS Administration of this whole formula has a positive impact on nutritional status . The great diversity in textures and tastes enable these formulations to be administered to a wide range of patients with or without liquid dysphagia [18431084] Background and aims : There are few studies published that combine the interventions of physical training and nutrition . The aim of the present study was to describe the impact of a physical and nutritional intervention program for frail community-dwelling elderly people over the age of 75 . Methods : Ninety-six community-dwelling elderly people ( 58 women ) were r and omized to four different groups : i ) a physical training program ( aerobic , muscle strength , balance ) , ii ) a nutritional intervention program ( individually targeted advice and group sessions ) , iii ) a combination of these interventions , and iv ) a control group . At baseline subjects were screened for physical performance such as muscle strength , balance , mobility and activities of daily living , as well as nutritional aspects such as energy intake , body weight and fat-free mass . These measurements were repeated immediately after the intervention , which lasted for 12 weeks , and after another 6 months . Results : The intention-to-treat analysis indicated significant improvements in lower-extremity muscle strength in both training groups compared with the nutrition group at 1st follow-up . There were small significant changes for some of the balance measurements in the training group without nutrition treatment . The nutrition intervention did not show any significant results . Conclusions : This study shows the positive effect on lower-extremity muscle strength directly after the intervention . Balance training most probably needs to be more individualized in order to be effective for frail elderly people . Further studies are needed , with larger sample sizes , to investigate the effects of these types of interventions before any further conclusions can be drawn [15669934] AIMS AND OBJECTIVES The purpose of the study was to test the effectiveness of nursing care based on active involvement of patients in their nutritional care . It was hypothesized that this type of care could improve energy and protein intake in elder orthopaedic patients . BACKGROUND Protein and energy malnutrition and deterioration in nutritional status is a common but neglected problem in hospital patients . METHODS The design was quasi-experimental with an intervention and control group . The study included 253 patients aged 65 and above admitted for hip fracture , hip or knee replacement . Food intake was recorded on a daily basis during the hospital stay . RESULTS The daily intake of energy increased with 23 % ( P = 0.001 ) and of protein with 45 % ( P = 0.001 ) . The intake increased from the very first day after the operation . The intake of energy and protein was not correlated with the patient 's age , body mass index or type of surgery . CONCLUSIONS The care based on patients ' active involvement in their own nutritional care and was found to be an effective method to raise the intake of energy and protein among elder orthopaedic patients . RELEVANCE TO CLINICAL PRACTICE This way of organizing the care identifies patients who do not consume enough energy and protein according to their current requirements and to take appropriate actions to prevent further malnutrition [18328440] BACKGROUND & AIMS Up to 50 % of patients with chronic pancreatitis ( CP ) are malnourished . There are limited data on the role of dietary intervention in improving the nutritional status of such patients . The aim was to compare the efficacy of medium chain triglyceride (MCT)-enriched commercial dietary supplements with dietary counseling for homemade food in the management of malnutrition in patients with CP . METHODS In a r and omized controlled trial , consecutive undernourished patients with CP ( body mass index [ BMI ] < 18.5 kg/m(2 ) ) at a tertiary care hospital were r and omized to receive either dietary counseling for regular homemade food or commercial MCT-enriched dietary supplements for a period of 3 months to compensate for the dietary calorie deficit . All patients received st and ard management for CP including pancreatic enzyme supplements . Primary outcome measure was improvement in BMI . RESULTS Sixty malnourished patients with CP were r and omized to counseling group ( n = 29 ; mean age , 32 + /- 10 years ; male , 83 % ) and supplementation group ( n = 31 ; mean age , 28 + /- 10 years ; male , 84 % ) . BMI increased in both the counseling group and supplementation group ( 17.2 + /- 1.7 vs 18.1 + /- 1.8 kg/m(2 ) , P = .001 ; 16.7 + /- 1.6 vs 18.2 + /- 1.6 kg/m(2 ) , P = .001 ) . There were similar improvements in triceps skinfold thickness , dietary intake , fecal fat , and pain score during a period of 3 months in both groups . There was , however , no significant difference between the counseling and supplementation groups with regard to any of the outcome measures . CONCLUSIONS Dietary counseling for a balanced homemade diet is as good as commercial food supplements in improving malnutrition in patients with CP [17275141] BACKGROUND & AIM Effects of combined nutritional treatment of patients at risk of protein-energy malnutrition ( PEM ) discharged from a geriatric service were evaluated . METHODS Patients ( n=108 , age 85+/-6 years ) at risk of malnutrition according to the short form of the mini nutritional assessment were r and omly allocated to dietary counseling , including liquid and multivitamin supplementation , i.e. intervention ( I , n=51 ) and to controls ( C , n=57 ) . Body weight , biochemical indices ( e.g. insulin-like growth factor I ( IGF-I ) ) , Katz activities of daily living ( ADL ) index , mini mental status examination ( MMSE ) and quality of life ( QoL ) by SF-36 were assessed at the start of the study and after 4 months . Statistical analyses were performed on " intention-to-treat " and on " treated-as- protocol " bases . RESULTS Fifty-four patients , 29 in the I-group ( 86+/-7 years , 66 % females ) and 25 in the C-group ( 85+/-7 years , 72 % females ) completed the study according to the protocol . Both modes of analysis revealed a significant positive effect of the combined nutritional intervention on weight maintenance . Treated-as- protocol analyses showed that Katz ADL index improved in the I-group ( p<0.001 ; p<0.05 between the groups ) . Serum IGF-I levels increased in the I-group ( p<0.001 ) , but were unchanged in the C-group ( p=0.07 between the groups ) . QoL was assessed to be low and had not changed after nutritional treatment . CONCLUSIONS Combined nutritional intervention prevented weight loss and improved ADL functions in discharged geriatric patients at risk of malnutrition [3027267] One hundred ninety-two patients with previously untreated metastatic cancer ( 102 non-small-cell lung cancer [ NSCLC ] ; 90 colorectal cancer ) were r and omized to receive either ad lib nutritional intake ( control group ) or specific nutritional intervention during a 12-week study period when chemotherapy was administered . Those patients r and omized to nutritional interventions were counselled to take oral nutrients with caloric intake equal to 1.7 to 1.95 times their basal energy expenditure , depending on their pretreatment nutritional status ( " st and ard " group ) . An augmented group was counselled to have a caloric intake equivalent to that of the st and ard group but with 25 % of calories provided as protein and additional supplements of zinc and magnesium . Counselling increased caloric intake in both tumor types but reduced weight loss in the short term only for lung cancer patients . Ninety-three NSCLC patients were evaluable for tumor response to vindesine and cisplatin . Overall , only 20.4 % of the patients responded , and there were no significant differences in response rates , median time to progression , or overall duration of survival between the nutrition intervention groups and the control group . The tumor response rate to time-sequenced 5-fluorouracil ( 5-FU ) and methotrexate in the 81 evaluable patients with colorectal cancer was only 14.8 % , and no significant differences in tumor response rates were noted between the three groups . Furthermore , the median time to progression and overall duration of survival were not different for the control , st and ard , and augmented groups . Nutritional interventions using dietary counselling had no impact on the percent of planned chemotherapy dose administered , the degree of toxicity experienced by patients , or the frequency of treatment delays . A multivariate prognostic factor analysis demonstrated that for lung cancer , the percent of weight loss , serum albumin concentration , and presence of liver metastases were significant ( P less than .05 ) and independent prognostic variables for survival duration . For colorectal cancer , serum albumin , alkaline phosphatase , lactic dehydrogenase ( LDH ) levels , and percent targeted caloric intake ( TCI ) were significant independent predictors of survival duration [9724503] OBJECTIVES To determine the effect of early intensive dietary intervention and follow-up on weight gains in newly transplanted renal patients . To provide appropriate dietary advice posttransplant that included advice to reduce weight gains . DESIGN Group A was studied prospect ively and group B was studied retrospectively over a period of 1 year posttransplant . SETTING Hospital transplant unit : inpatient ward and outpatient clinic . PATIENTS Thirty-three transplant patients were studied : Group A consisted of 11 patients ( 9 men , 2 women ) transplanted consecutively over 2 months , with a mean age of 39 years . Group B consisted of 22 patients ( 14 men , 8 women ) who had been transplanted consecutively 4 years before the study , with a mean age of 40 years . Both groups had functioning grafts ( serum creatinine < 200 micromol/L [ 2.2 mg/dL ] ) over the study period , and similar triple immunosuppressive therapy ( prednisolone , cyclosporine , and azathioprine ) . INTERVENTION Group A received intensive , individualized dietary advice in stages , with regular follow-up for the first 4 months posttransplant . Thereafter group A did not receive any dietary advice or follow-up for the 8 months leading up to 1 year posttransplant . Group B had not received any dietary advice or follow-up posttransplant . MAIN OUTCOME MEASURE Weight gained and body mass index ( BMI ) at 4 months and at 1 year posttransplant . RESULTS The mean weight ( BMI ) for group A at baseline , 4 months and at 1 year posttransplant was 67 + /- 13 kgs ( 24.1 + /- 3.9 kg/m2 ) , 69 + /- 12 kgs ( 24.6 + /- 3.5 kg/m2 ) , and 73 + /- 12 kgs ( 26.1 + /- 3.4 kg/m2 ) , respectively . The mean weight ( BMI ) for group B at baseline , 4 months and at 1 year posttransplant were 67 + /- 11 kgs ( 23.7 + /- 3.4 kg/m2 ) , 74 + /- 9 kgs ( 26.3 + /- 3.3 kg/m2 ) , and 79 + /- 12 kgs ( 27.9 + /- 4 kg/m2 ) , respectively . Analysis of group A showed no significant difference in weight gained and BMI with dietary advice and follow-up at 4 months posttransplant compared with baseline . There was a significant difference in weight gain and BMI at 1 year posttransplant compared with 4 months posttransplant ( P = .002 , P = .002 , respectively ) . Analysis between groups showed a significantly lower weight gain in group A compared with group B both at 4 months and at 1 year posttransplant ( P = .01 , P = .01 respectively ) . Group A had a significantly lower BMI than group B at 4 months and at 1 year posttransplant ( P = .003 , .006 , respectively ) . At 1 year posttransplant , group A had a mean weight gain of 5.5 kg per patient compared with a mean of 11.8 kg per patient in group B. CONCLUSION Early intensive dietary advice and follow-up is effective in controlling weight gains in the first year posttransplant . Dietary advice should be an important part of posttransplant treatment [16287132] BACKGROUND The aim was to evaluate the relationship between nutrition support ( NS ) on host toxicity and cancer outcome in patients with locally advanced head and neck squamous cell carcinoma ( HNSCC ) undergoing definitive radiotherapy ( XRT ) . METHODS We performed a secondary analysis of Radiation Therapy Oncology Group ( RTOG ) 90 - 03 , a prospect i ve r and omized trial evaluating four definitive XRT fractionation schedules in patients with locally advanced HNSCC , which prospect ively collected data on NS delivered before treatment ( BNS ) , during treatment ( TNS ) , and after definitive XRT . NS data and pretreatment characteristics of the 1073 evaluable patients were analyzed against therapy toxicity and outcome . RESULTS Patients receiving BNS experienced significantly less weight loss by the end of treatment and less grade 3 to 4 mucositis than patients not receiving BNS . However , patients receiving BNS had a poorer 5-year actuarial locoregional control rate than patients receiving TNS or no NS ( 29 % , 55 % , and 57 % , respectively , p < .0001 ) and a poorer 5-year overall survival rate ( 16 % , 36 % , and 49 % , respectively , p < .0001 ) . Patients receiving BNS were significantly more likely to have a higher T classification , N status , and overall American Joint Committee on Cancer ( AJCC ) stage and initial presentation with greater pretreatment weight loss , and a poorer Karnofsky Performance Status ( KPS ) than patients not receiving BNS . After adjusting for the impact of these prognostic factors through a recursive partition analysis , a multivariate analysis with a stratified Cox model found that BNS was still a highly significant independent prognostic factor for increased locoregional failure ( hazards ratio [ HR ] , 1.47 ; 95 % confidence interval [ CI ] , 1.21 - 1.79 ; p < .0001 ) and death ( HR , 1.41 ; 95 % CI , 1.19 - 1.67 ; p < .0001 ) . CONCLUSION In this study , the largest prospect i ve evaluation of nutrition data in treated patients with cancer , BNS was associated with inferior treatment outcome in the patients with HNSCC undergoing XRT . These results should be considered hypothesis generating and encourage prospect i ve clinical research and identification of the mechanisms underlying this finding [6841130] Ninety-seven patients with cancer , undergoing radiation treatment , were studied . Forty-two were given special dietary counseling and supplements of Sustagen or Isocal ; 42 controls received no special advice or supplements . Thirteen patients were excluded because of poor prognoses and the ethical need for food supplements . Nutrient intake of all groups was assessed by 3-d diet records in household measures in the first and the last week of treatment . Intake was significantly higher in the adjunctive than the control group . The excluded group , despite supplementation , had intakes similar to the control group . No difference was observed between the control and adjunctive groups in clinical status at the end of treatment or in long-term outcome [6387632] Cancer patients , assessed as nutritionally at risk , were r and omly assigned to a control group or to one of four intervention groups receiving ( a ) nutritional supplementation , ( b ) relaxation training , ( c ) both nutritional supplementation and relaxation training , or ( d ) neither nutritional supplementation nor relaxation training . Fifty-five subjects completed a four-month intervention period during which they were visited biweekly by a nurse ( except control subjects ) . In repeated measures analyses of variance , significant group-by-time interactions were obtained for weight and arm muscle circumference ( a measure of protein stores ) , indicating that for these measures the groups changed differentially during the intervention period . The group-by-time interaction approached significance on the Karnofsky Performance Status Scale . For all three variables , gain was greatest for the relaxation group ; the most severe loss occurred in the control group . These findings suggest that the cachexia of cancer may be slowed or reversed through noninvasive nursing interventions [16843999] The objective of this study was to determine the prevalence and correlates of malnutrition in patients living at home with cancer and chronic diseases . Patients ( 213 ) with cancer and 228 patients with chronic diseases were r and omly selected from general practice registers . Nutritional status was determined from body mass index ( BMI in kg/metre2 ) , triceps skinfold thickness ( TST ) , mid-arm muscle circumference ( MAMC ) and population centiles . Patients were classified as mildly malnourished if they had a BMI < 20 and TST or MAMC < 15th centile , moderately malnourished if they had a BMI < 18 and TST or MAMC < 5th centile , and severely malnourished if they had a BMI < 16 and TST or MAMC < 5th centile . Using these criteria , nearly 10 % of patients were malnourished : 24 ( 5.4 % ) mildly , 12 ( 2.7 % ) moderately and 4 ( 0.01 % ) severely . Malnutrition was more common in patients in social classes 3.2 , 4 and 5 than in social classes 1 , 2 and 3.1 ( P = 0.003 ) , and in patients receiving district nurse care ( P < 0.001 ) . Malnutrition was more prevalent in cancer patients who complained of chronic or severe pain ( 32 % vs 12 % , P = 0.021 ) and in patients with chronic disorders who experienced mental apathy ( 22 % vs 5 % , P = 0.014 ) . Clinicians need to be aware that malnutrition is common in patients living at home . In this study BMI proved to be a fairly good indicator of malnutrition and routine measurement of BMI would be one simple way of detecting patients who are at risk [16608139] Background and aims : Many elderly people with Alzheimer ’s disease experience weight loss . Illness and inadequate regain after a period of illness are considered as contributory causes of progressive weight loss in psychogeriatric patients . We studied whether early use of a liquid nutrition supplement immediately after onset of acute illness from infection can prevent weight loss in elderly psychogeriatric nursing home residents . Methods : R and omised controlled trial of 5 weeks after the onset of illness . Thirty-four psychogeriatric nursing home residents ( aged ±65 yrs ) completed the study period . A liquid nutrition supplement ( 200 ml ) once daily immediately after diagnosis of infection or st and ard treatment ( enriched food after referral to a dietician ) were provided . Body weight , mid-upper arm circumference , calf circumference , triceps skin fold thickness , dietary energy intake , and need for care were measured . Results : Weight change during the study period was significantly different between the st and ard ( −0.4 kg ) and supplement ( + 0.8 kg ) groups ( p=0.040 ) . No significant differences were observed in changes of midupper arm circumference , triceps skin fold thickness , calf circumference or energy intake between groups . Conclusions : Early provision of a liquid nutrition supplement immediately after onset of acute illness from infection leads to weight gain in elderly psychogeriatric nursing home residents [19074931] Background : Malnutrition in chronic obstructive pulmonary disease ( COPD ) is associated with a poor prognosis , yet evidence to support the role of dietary counselling and food fortification is lacking . A study was undertaken to assess the impact of dietary counselling and food fortification on outcome in out patients with COPD who are at risk of malnutrition . Methods : A r and omised controlled unblinded trial was performed in 59 out patients with COPD ( 6 months intervention and 6 months follow-up ) . The intervention group received dietary counselling and advice on food fortification and the controls received a dietary advice leaflet . Outcome measures were nutritional status , respiratory and skeletal muscle strength , respiratory function , perceived dyspnoea , activities of daily living ( ADL ) and quality of life . Results : The intervention group consumed more energy ( difference 194 kcal/day ; p = 0.02 ) and protein ( difference 11.8 g/day ; p<0.001 ) than controls . The intervention group gained weight during the intervention period and maintained weight during follow-up ; the controls lost weight throughout the study . Significant differences were observed between the groups in St George ’s Respiratory Question naire total score ( difference 10.1 ; p = 0.02 ) , Short Form-36 health change score ( difference 19.2 ; p = 0.029 ) and Medical Research Council dyspnoea score ( difference 1.0 ; p = 0.03 ) ; the difference in ADL score approached statistical significance ( difference 1.5 ; p = 0.06 ) . No differences were observed between groups in respiratory function or skeletal and respiratory muscle strength . Improvements in some variables persisted for 6 months beyond the intervention period . Conclusion : Dietary counselling and food fortification result ed in weight gain and improvements in outcome in nutritionally at-risk out patients with COPD , both during and beyond the intervention period [1456568] The association between severe nutritional depletion and chronic obstructive pulmonary disease ( COPD ) has long been recognized . A potential therapeutic benefit to nutritional support was previously suggested by us in a pilot investigation . Subsequent studies have reported conflicting results regarding the role of nutritional therapy in this clinical population . We report a r and omized controlled study of nutritional therapy in underweight patients with COPD that combines an initial inpatient investigation ( controlled nutritional support ) with a prolonged outpatient follow-up interval . Provision of adequate calorie and protein support , adjusted to metabolic requirements , result ed in weight gain ( intervention = + 2.4 kg versus control -0.5 kg ) , improved h and grip strength ( intervention = + 5.5 kg-force versus control -6.0 kg-force ) , expiratory muscle strength ( intervention = + 14.9 cm H2O versus control -9.2 cm H2O ) , and walking distance ( intervention = + 429 feet versus control -1.0 foot ) . Inspiratory muscle strength was also improved ( intervention = + 11.4 cm H2O versus control + 4.8 cm H2O ) although this did not quite reach statistical significance . We conclude that provision of adequate nutrient supply under controlled conditions results in significant clinical improvements in the COPD patient population . However , the intervention is costly , time-intensive , and of limited therapeutic magnitude . More detailed work of alternative outpatient strategies combined with additional rehabilitative measures is indicated to delineate the full therapeutic potential of nutritional support for this clinical population [8676539] BACKGROUND It was hypothesized that energy intake in hospitalized elderly patients could be improved by increasing the density of energy of the food and that the volume of food actually consumed , even with a higher energy content than the normal , would not change with servings of high energy-dense hospital food . METHODS Thirty-six elderly patients ( 52 to 96 years ) of both sexes , long-term treated at two comparable wards , participated in this study . The patients were given 6 weeks of regular hospital food ( RHF , 1670 kcal/d , 7.0 MJ ) and 6 weeks of high-energy food ( HE , 2520 kcal/d , 10.5 MJ ) . The volume of food was kept constant . A crossover study design was used . Food intake , energy intake , body weight , and modified functional condition ( Norton scale ) were measured . RESULTS Regardless of type of food ( RHF or HE ) and time of day ( lunch or dinner ) , he food portion size ( volume of food ) intake was the same , approximately 80 % of the portions consumed . HE led to a 40 % increase in energy intake ( from 25 + /- 1 during RHF to 35 + /- 2 kcal/kg/d , p < .0001 ) , which result ed in a 3.4 % increase in body weight ( p < .001 ) after 3 weeks of HE . Only minimal changes in functional condition were found . The cost of HE was substantially lower ( -85 % ) than any other mean available for improvement of energy intake . CONCLUSIONS A significant increase in energy intake can be achieved by higher energy density in regular hospital food and that HE does not cause a decrease in the volume of the food consumed . These findings suggest that it is the volume of food rather than the energy that limits voluntary energy intake of hospital food in elderly hospitalized patients [15796146] Background / Aim Malnutrition is highly prevalent in patients on continuous ambulatory peritoneal dialysis ( CAPD ) and is a strong predictor of increased morbidity and mortality . Therefore , the aim of this study was to evaluate the effect of oral administration of an egg albumin-based protein supplement on the nutritional status of CAPD patients . Methods In this r and omized , open label , controlled clinical trial , 28 CAPD patients were allocated to a study ( n = 13 ) or a control ( n = 15 ) group . Both groups received conventional nutritional counseling ; the study group received , additionally , an oral egg albumin-based supplement . During a 6-month follow-up , all patients had monthly clinical and biochemical evaluations and quarterly assessment s of adequacy of dialysis and nutrition . Results Serum albumin levels were not different between groups ; however , a significant increase ( baseline vs final ) was observed in the study group ( 2.64 ± 0.35 vs 3.05 ± 0.72 g/dL ) but not in the control group ( 2.66 ± 0.56 vs 2.80 ± 0.54 mg/dL ) . Calorie and protein intake increased more in the study group ( calories 1331 ± 432 vs 1872 ± 698 kcal ; proteins 1.0 ± 0.3 vs 1.7 ± 0.7 g/kg ) than in the control group ( calories 1423 ± 410 vs 1567 ± 381 kcal ; proteins 1.0 ± 0.4 vs 1.0 ± 0.3 g/kg ) . Similarly , non-protein nitrogen appearance rate ( nPNA ) increased significantly more in the study ( 1.00 ± 0.23 vs 1.18 ± 0.35 g/kg/day ) than in the control group ( 0.91 ± 0.11 vs 0.97 ± 0.14 g/kg/day ) . Triceps skinfold thickness ( TSF ) and midarm muscle area ( MAMA ) displayed a nonsignificant trend to a greater increase in the study group ( TSF 16.7 ± 8.7 vs 18.3 ± 10.7 mm ; MAMA 23.8 ± 6.2 vs 25.8 ± 5.9 cm2 ) than in controls ( TSF 16.4 ± 5.7 vs 16.9 ± 7.0 mm ; MAMA 28.7 ± 7.8 vs 30.0 ± 7.9 cm2 ) . At the end of follow-up , the frequency of patients with moderate or severe malnutrition decreased 6 % in the control group and decreased 28 % in the study group . At the final evaluation , the most important predictors of serum albumin were the oral egg albumin-based supplement administration and protein intake ( p < 0.05 ) ; secondary predictors ( p = 0.06 ) were peritoneal transport rate and MAMA . Conclusions In the study group , oral administration of the egg albumin-based supplement significantly improved serum albumin , calorie and protein intake , and nPNA , and , compared to controls , this maneuver was associated with a trend to increased anthropometric parameters and improved Subjective Global Assessment evaluation . Oral administration of the albumin supplement and protein intake were the most significant predictors of serum albumin at the end of follow-up . This oral supplement may be a safe , effective , and cheap method to improve nutritional status in peritoneal dialysis patients [12235650] Involuntary weight loss is often seen among patients with gastrointestinal ( GI ) cancer . Weight loss may influence quality of life ( QoL ) and is a predictor of survival . The present study is an attempt to improve body weight development in GI cancer patients by individual support ( IS ) , including nutritional measures . Patients were r and omized in a 2 × 2 design between 1 ) IS , including nutritional support , 2 ) group rehabilitation ( GR ) , 3 ) IS + GR ( ISGR ) , or 4 ) st and ard care ( SC ) . Data concerning dietary intake ( 24-h recalls ) , body weight , and QoL ( EORTC-QLQ C-30 ) were collected over 2 yr for 67 patients with colorectal or gastric cancer , r and omized to IS or ISGR . Data on weight and QoL were collected for 70 patients with the same diagnoses r and omized to GR or SC . Despite a tendency to greater weight loss at inclusion , the IS + ISGR group managed to gain weight significantly more rapidly and to a greater extent than the GR + SC group . The differences became statistically significant at 12 and 24 mo ( P < 0.05 ) . Patients with weight loss at baseline increased their energy intake and weight more than those without weight loss . No differences were seen in QoL ratings between r and omization groups , but there was a positive correlation between weight development and QoL and a negative correlation between fatigue and weight development . There was a numerical difference , not statistically significant ( P = 0.3 ) , indicating a shorter time of survival in patients in the GR + SC group . IS , including nutritional support , leads to more rapid weight gain than SC in patients with newly diagnosed GI cancer [14757395] BACKGROUND & AIMS Malnutrition is common in the elderly and increases morbidity and mortality . Most attempts to reverse malnutrition have used liquid supplements , but the findings are inconsistent . This study tests a new approach using a r and omised-controlled design . The aim was to examine whether health care assistants , trained to provide additional support with feeding , can improve acutely ill elderly in- patients ' clinical outcomes . METHODS The study was carried out on three acute medicine for the elderly wards at Hammersmith Hospitals NHS Trust , London . In all , 592 patients , all over 65 years old , were recruited . RESULTS The results showed that the median time patients received feeding support was 16 days , and the assisted group was given less intravenous antibiotics ( P=0.007 ) . However , the groups did not differ in markers of nutritional status , Barthel score , grip strength , length of stay or mortality . CONCLUSION It was concluded that the use of health care assistants in this specialised role , in an acute setting , without change to the food provision or without targeting higher risk patients , reduced the need for intravenous antibiotics . However , the intervention did not improve nutritional status or have an effect on length of stay in the time span studied . The results highlight the difficulties of improving the intake of acutely ill elderly patients during a hospital stay [19695832] OBJECTIVE Up to 60 % of hospitalized patients are undernourished . We studied the impact of nutritional therapy on quality of life and food intake . METHODS Undernourished patients were r and omized into two groups . The nutritional therapy group ( NT group ) received individual nutritional counseling and interventions , including oral nutritional supplements if appropriate , by a dietitian . The oral nutritional supplement group ( ONS group ) received oral nutritional supplements in addition to hospital meals without further instruction or counseling . Study duration was 10 to 15 d. At baseline and before discharge ( time point 1 ) we measured energy and protein intakes and quality of life . Quality of life was measured again 2 mo after discharge ( time point 2 ) . RESULTS Energy and protein intakes increased between baseline and time point 1 in both groups ( P=0.001 ) . The NT group ( n=18 ) met the energy requirements at time point 1 by 107 % and of protein by 94 % , the ONS group ( n=18 ) by 90 % and 88 % , respectively . Hospital meals alone did not cover the requirements . From baseline to time point 1 , quality of life increased in both groups . Quality of life increased further in the NT group from time point 1 to time point 2 ( P=0.016 ) , but not in the ONS group . CONCLUSION Both interventions caused a significant increase in energy and protein intakes and quality of life . In the NT group every patient received an efficacious individualized intervention . In contrast , the 7 of 18 patients in the ONS group who did not consume ONS had no intervention at all . Therefore , undernourished patients should be counseled individually by a dietitian [8173401] Abstract Objectives : To determine incidence of malnutrition among patients on admission to hospital , to monitor their changes in nutritional status during stay , and to determine awareness of nutrition in different clinical units . Design : Prospect i ve study of consecutive admissions . Setting : Acute teaching hospital . Subjects : 500 patients admitted to hospital : 100 each from general surgery , general medicine , respiratory medicine , orthopaedic surgery , and medicine for the elderly . Main outcome measures : Nutritional status of patients on admission and re assessment on discharge , review of case notes for information about nutritional status . Results : On admission , 200 of the 500 patients were undernourished ( body mass index less than 20 ) and 34 % were overweight ( body mass index > 25 ) . The 112 patients reassessed on discharge had mean weight loss of 5.4 % with greatest weight loss in those initially most undernourished . But the 10 patients referred for nutritional support showed mean weight gain of 7.9 % . Review of case notes revealed that , of the 200 undernourished patients , only 96 had any nutritional information documented . Conclusion : Malnutrition remains a largely unrecognised problem in hospital and highlights the need for education on clinical nutrition [17613583] Objective : To compare the effect of calcium/vitamin D supplements with a combination of calcium/vitamin D supplements and exercise/protein on risk of falling and postural balance . Design : R and omized clinical trial . Setting : University hospital physiotherapy department . Subjects : Twenty-four independently living elderly females aged 65 years and older with osteopenia or osteoporosis and mean total hip T-score ( SD ) of —1.8 ( 0.8 ) . Interventions : A three-month programme consisting of exercise/protein including training of muscular strength , co-ordination , balance and endurance . Calcium/ vitamin D was supplemented in all participants for a 12-month period . Outcome measures : Assessment took place prior to and following the months 3 , 6 , 9 and at the end of the study ; primary dependent variables assessed were risk of falling ( Berg Balance Test ) and postural balance ( forceplate ) . Secondary measures included body composition , strength , activity level , number of falls , bone mineral content , biochemical indices , nutritional status and general health . Results : Significant reductions of risk of falling ( repeated measures ANOVA F = 8.90 , P = 0.008 ) , an increase in muscular strength ( ANOVA F = 3.0 , P = 0.03 ) , and an increase in activity level ( ANOVA F = 3.38 , P = 0.02 ) were found in the experimental group as compared to the control group . Further on , there was 89 % reduction of falls reported in the experimental group ( experimental pre/post 8/1 falls ; control group pre/post 5/6 falls ) . Conclusion : This study provides support for our intervention programme aim ed at reducing the risk of falling in elderly participants diagnosed with osteopenia or osteoporosis . The data obtained from the pilot study allow the calculation of the actual sample size needed for a larger r and omized trial [15250845] To determine the feasibility of increasing the calcium , protein and calorie intake of osteoporotic fracture patients by repeated dietary counselling delivered by a dietitian , a r and omized controlled trial was conducted . Among 189 patients presenting with osteoporotic fractures to an Orthopaedics and Traumatology Department of a large regional hospital , 98 patients were r and omized to the intervention group and 91 were r and omized to the control group ( with usual care ) . Intervention group received three sessions of dietary counselling with tailored made recommendations over a period of 4 months , while the control group only received dietary assessment and pamphlets on the prevention of osteoporosis . Almost all subjects in both intervention and control groups had calcium intake below the recommended level of 1000 mg at baseline . Half and 60 % of subjects in both groups had total energy and protein intake below recommended levels respectively . The mean weights of control and intervention groups at baseline were 51.5 and 50.9 kg respectively , while the body mass index ( BMI ) were 22.6 ( kg m(-2 ) ) and 22.6 ( kg m(-2 ) ) respectively . After dietary intervention , significant increase of intake was seen in calcium intake ( P = 0.0095 by t-test ) in the intervention group . No significant increase was seen in protein or calorie intake . No significant change was observed in the body weight or BMI although there was a positive trend in the intervention group for all these parameters . We concluded that there was general malnutrition in Chinese elderly who presented with osteoporotic fractures . Dietary calcium could be increased by repeated professional dietary counselling . Future studies with longer duration and more objective clinical outcomes will be helpful to further demonstrate the long-term effects of dietary intervention on osteoporosis and other chronic diseases [16182685] The use of oral dietary supplements was compared with dietary counseling in 13 malnourished patients ( 3 males , mean age 18.1 years ) with cystic fibrosis . Energy intake and nutritional status were evaluated over 3 months . There was no significant change in energy intake or percent ideal body weight in either group [2737169] The potential nutritional and clinical benefits of sip-feed supplements were investigated by means of a controlled trial in elderly female patients admitted for orthopaedic surgery . A nutritional risk assessment procedure ( Nutritional Risk Question naire , NRQ ) was used to identify patients who might benefit from supplementation . Patients identified as high risk who did not receive supplements showed significant losses in triceps skinfold thickness ( TSF ) and mid-upper arm muscle circumference ( MUAMC ) measurements during hospitalization . Such changes were not observed in high-risk supplemented patients , but significant losses of MUAMC were also recorded in a group of patients who failed to comply with the supplement . No differences in biochemical parameters , muscle function , or clinical outcome were observed between supplemented and unsupplemented and non-compliant patients . The problems of poor compliance to sip-feed supplements and failure to observe clinical benefit in supplemented patients are discussed [16839988] Elderly long-term care patients ( n = 501 ) were r and omly allocated to receive dietary supplementation ( 400 kcal/day ) in addition to a normal hospital diet , or normal hospital diet only , for 26 weeks . The patients ' functional condition was assessed by a modified Norton scale comprising mental condition , activity , mobility , food intake , fluid intake , incontinence and general physical state . Nutritional status was assessed by anthropometry , serum protein analysis and delayed hypersensitivity skin tests . Improvements during the first 8 weeks were seen in activity and general physical condition in the supplemented group , and in mobility and general physical condition in the control group . After 8 weeks the supplemented group showed a significantly higher level of activity ( p < 0.05 ) compared to the control group . We conclude that in long-term geriatric care nutritional supplements help to maintain and improve the patients function [15788020] OBJECTIVE To study appetite and food choices in lean elderly women at the time of a femoral neck fracture and after 6 months of nutritional and anabolic intervention . SUBJECTS AND METHODS Forty-five nondemented women > 70 years of age ( mean + /- SD : 83 + /- 5 years ) with a recent hip fracture and body mass index < 24 kg/m2 ( mean : 20.5 + /- 2.3 ) were interviewed about their appetite and dietary habits prior to fracture . The patients were r and omized to treatment with a protein-rich liquid supplement ( PR ; 200 kcal and 20 g protein day(-1 ) ) alone or in combination with n and rolone decanoate injections ( PR/N ) 25 mg i.m . every third week or to a control group ( C ) . A second interview was conducted 6 months later . RESULTS Reduced appetite before the fracture was reported by 60 % . Half of the patients did not have dessert with any of their daily meals , one-third used low-fat margarines and one-third drank water with their meals . The estimated mean daily energy intake was 6.4 + /- 1.2 MJ ( 1541 + /- 304 kcal ) indicating that three of four subjects did not meet their energy needs . At 6 months , 40 % reported reduced appetite . There was no difference in the change of appetite between the three r and omized groups . Still , half of the subjects appeared to not meet their energy needs . Protein intake increased in the PR and PR/N groups , in contrast to the controls ( P = 0.002 ) . CONCLUSION Reduced appetite and insufficient energy intake was recorded in lean elderly women with a femoral neck fracture . Nutritional supplementation alone or in combination with an anabolic steroid increased protein intake without adversely affecting appetite [10634923] AIMS To compare nutritional counseling with and without oral supplements in HIV-infected patients with recent weight loss . DESIGN R and omized non-blinded controlled trial , stratified for change in antiretroviral treatment at baseline . PATIENTS HIV-infected patients with recent weight loss ( > 5 % of total , and > 3 % in the last month ) . INTERVENTION Nutritional counseling to increase dietary intake by 600 kcal/day over 8 weeks ; in group A ( n=24 ) by normal food , and in group B ( n=26 ) by a range of fortified drink supplements with a calorific value of 0.6 to 1.5 kcal/ml . METHODS Body composition by bioelectrical impedance analysis , dietary intake by 24 h recall . RESULTS Fat free mass increased from baseline to week 8 ( P<0.05 ) with no difference between groups A and B ( P=0.97 ) . Body cell mass and weight gain were not significant and equal between groups . Assessed at weeks 2 and 4 , group B patients consumed 11 + /- 6 kcal/kg as supplements , and their total energy intake was 6 kcal/kg higher than in group A ( P<0.01 ) . Total energy intake was not different between groups at weeks 6 and 8 . DISCUSSION Nutritional counseling and oral supplements are both feasible methods to restore food energy intake in malnourished HIV-infected patients . Although normal food intake is partially replaced , oral supplements may improve the adherence to a weight gain regimen [9135531] BACKGROUND : Previous work has shown that the administration of oral dietary supplements to patients who have undergone gastrointestinal surgery results in clinical ly significant short term benefits . AIMS : This study aim ed firstly to re-evaluate these short term effects , and secondly to establish whether there are any long term benefits . SUBJECTS : One hundred patients admitted for elective moderate or major gastrointestinal surgery . METHODS : In the inpatient phase , patients were r and omised to receive a normal ward diet postoperatively , or the same diet supplemented with an oral dietary supplement . In the outpatient phase , patients were further r and omised to receive their home diet , or their home diet supplemented with the oral dietary supplement for four months . RESULTS : During the inpatient phase , patients treated with oral supplements had a significantly improved nutritional intake and lost less weight ( 2.2 , 95 % confidence interval ( 95 % CI ) 0.9 kg ) compared with control patients ( 4.2 ( 0.78 ) kg , p < 0.001 ) . Supplemented patients maintained their h and grip strength whereas control patients showed a significant reduction in grip strength ( p < 0.01 ) . Subjective levels of fatigue increased significantly above preoperative levels in control patients ( p < 0.01 ) but not in the supplemented group . Twelve patients in the control group developed complications compared with four in the supplemented group ( p < 0.05 ) . In the outpatient phase , supplemented patients had improved nutrient intakes but there were no significant differences in indices of nutritional status or wellbeing between the groups . CONCLUSIONS : The prescription of oral dietary supplements to patients who have undergone gastrointestinal surgery results in clinical ly significant benefits . These benefits , however , are restricted to the inpatient phase [19812865] Objectives To determine whether in the current study the supply of a nutrient dense drink has a positive effect on mental and physical function of institutionalized elderly people . Design A 24-week , r and omized , double-blind , placebo-controlled , parallel-group , intervention trial . Setting Homes for the elderly and nursing homes in the Netherl and s. Participants Institutionalized elderly people older than 60 years , with a BMI ≤ 30 kg/m2 , and a Mini-Mental State Examination score of at least 10 points . InterventionIn addition to their usual diet the participants ( n=176 ) received either a nutrient dense drink or a placebo drink twice a day during 24 weeks . Measurements The functionality measures included cognitive function , mood , physical performance and the ability to perform activities of daily living . Results In the supplement group a favorable effect of the intervention drink on body weight ( 1.6 kg difference in change ; P = .035 ) , calf circumference ( 0.9 cm difference in change ; P = .048 ) , and blood values ( e.g. Hcy decreased from 16.8 to 11.2 µmol/L in the supplement group ) was found . In the total group no significant effect was found on functionality outcomes . However , a subgroup of participants with BMI at baseline below 24.4 kg/m2 performed better on the cognitive subscale of Alzheimer ’s Disease Assessment Scale ( P = .09 ) , and its language sub score ( P = .01 ) after 24 weeks of intervention . Conclusion The results in the total group of this trial suggest that the nutritional supplement used in this study improves nutritional status . Furthermore , the results of this trial suggest that it is effective as treatment for decreasing function in a subgroup of institutionalized elderly people with low BMI [8410128] PURPOSE This study examined the effect of frequent nutritional counseling on oral intake , body weight , response rate , survival , and quality of life in patients with cancer of the lung ( small-cell ) , ovary , or breast undergoing cyclic chemotherapy . PATIENTS AND METHODS Of 105 assessable patients , 57 were r and omized to receive nutritional counseling , and 48 to receive no nutritional counseling and consumption of an ad lib oral intake . The intervention group was counseled to achieve a daily energy and protein intake according to recommended dietary allowances . Counseling was st and ardized and performed by a trained dietitian , and took place twice monthly during a 5-month period from start of chemotherapy . RESULTS Dietary counseling increased daily energy intake by approximately 1 MJ and protein intake by 10 g over the entire study period . There was no change in the control group . Counseling led to an insignificant increase in body weight , but triceps skinfold measurement increased significantly after 5 months . Response rate and overall survival did not differ between the groups . Quality of life measured by the Quality -of-Life index ( QL-index ) increased significantly in both groups , but did not differ between groups . CONCLUSION No clinical benefit could be demonstrated despite long-term and continuous improved food intake in cancer patients with solid tumors undergoing aggressive chemotherapy [8010171] We examined changes in the nutritional status of elderly patients with chest infection for a period of 3 months after discharge from hospital , including the effects of nutritional supplementation on well-being and functional status as well as on nutritional indices . Eighty-one subjects admitted to an acute medical ward aged 65 years and over with chest infection were recruited consecutively , and r and omized to receive supplement ( 500 ml of Ensure liquid daily ) for 1 month , or no supplement , on discharge . Assessment at baseline , 1 , 2 and 3 months included a question naire to determine health , mental and functional status , and anthropometric measurements . Biochemical nutritional status was assessed at baseline , 1 and 3 months , and dietary intake ( 24 h recall method ) at 1 and 3 months . During recovery , both supplement and non-supplement groups showed improvement in various measures of well-being and biochemical status . In addition , the former group showed improvement in more anthropometric measurements , in thiamine and pyridoxine status , while the non-supplement group showed a lower level of functional ability after 3 months . Various measures of well-being and biochemical status of the water-soluble vitamins were better in the supplement groups . We conclude that nutritional supplementation may have a role in helping elderly patients to recover from chest infections [10382188] PURPOSE / OBJECTIVES To describe the effect of nutritional supplements on food intake in patients undergoing radiotherapy . DESIGN Experimental prospect i ve . SAMPLE 40 newly diagnosed patients with cancer beginning external beam radiation therapy . METHODS Weekly dietary counseling and recording of total daily dietary intake for three days a week for four weeks . One half of the subjects were r and omly assigned to ingest a liquid nutritional supplement between meals and at bedtime . MAIN RESEARCH VARIABLES Total daily protein and caloric intake , food-derived protein and caloric intake , and supplement-derived protein and caloric intake . FINDINGS Subjects ingesting nutritional supplements between meals significantly increased their total caloric and protein intake above that of controls and did not reduce their food-derived caloric or protein intake compared to controls . CONCLUSIONS Nutritional supplements can be used to increase total caloric and protein intake without causing a significant reduction in food intake . IMPLICATION S FOR NURSING PRACTICE In this patient sample , supplements were not substituted for food intake . Further research is needed to determine the effects of supplements on appetite in patients with advanced cancer [3057956] We carried out a prospect i ve , r and omized , controlled trial to investigate the effect of a 3-month period of supplementary oral nutrition in 14 poorly nourished out patients with COPD . Seven patients were r and omized into Group 1 who received their normal diet during Months 1 to 3 , a supplemented diet during Months 4 to 6 , and their original normal diet during Months 7 to 9 . The other 7 patients received their normal diet for the entire 9-month study period ( Group 2 ) . Seven well-nourished patients ( Group 3 ) matched for age and severity of air-flow obstruction served as control subjects ; they received their normal diet for the 9-month study period . Measurements of nutritional status , respiratory muscle and h and grip strength , sternomastoid muscle function ( including frequency/force curves , maximal relaxation rate , and a fatigability test ) , lung function , arterial blood gas tensions , general well-being and breathlessness scores , and 6-min walking distances were carried out monthly in all patients . At the start of the study , the poorly nourished patients had lower mean daily calorie and protein intakes than did the well-nourished patients . The poorly nourished patients had lower respiratory muscle and h and grip strength , and abnormal contractility and increased fatigability of the sternomastoid muscle compared with those in the well-nourished patients . After 3 months of supplementary oral nutrition , there was a significant improvement in the nutritional status of Group 1 patients , as evidence d by an increase in body weight , triceps skinfold thickness , and midarm muscle circumference . Respiratory muscle and h and grip strength increased in parallel with nutritional status , although there were no significant changes in lung function or arterial blood gas tensions . ( ABSTRACT TRUNCATED AT 250 WORDS [18407904] BACKGROUND Oral nutritional supplements have been recommended after orthopedic surgery in geriatric patients to reduce postoperative complications . However , tolerability of supplements could be a limitation , and their universal use is not supported by the heterogeneity of previous studies , especially in patients without malnutrition . METHODS This study is a r and omized , controlled , open , parallel , 3-arm clinical trial comparing supplementation with protein powder dissolved in liquids to aim at 36 g of protein per day , energy and protein supplements to aim at 37.6 g of protein and 500 kcal per day , or no intervention in normally nourished or mildly undernourished patients . Outcomes were serum albumin , prealbumin , retinol-binding globulin , and body mass index , among others . Postoperative complications were also recorded . RESULTS Ninety patients aged 83.8 + /- 6.6 years were included . The mean ingested amount of supplements was 41.1 % + /- 20.6 % in the protein powder supplement group and 51.4 % + /- 13.2 % in the energy protein supplement group ( t = 2.278 , P = .027 ) . Postoperative supplements had no effect on the nutrition status during in-hospital follow-up , as assessed by serum albumin ( P = .251 ) , prealbumin ( P = .530 ) , retinol-binding globulin ( P = .552 ) , or body mass index ( P = .582 ) . Multivariate analysis showed that length of hospital stay with an established complication until its resolution ( beta = .230 , P = .031 ) , total hospital stay ( beta = .450 , P < .001 ) , baseline body mass index ( beta = .204 , P = .045 ) , and total daily ingested proteins per body weight ( beta = .252 , P = .018 ) were predictive variables on the change in serum albumin ( R2 = 0.409 , F = 11.246 , P < .001 ) . CONCLUSIONS Oral nutritional supplements in normally nourished or only mildly undernourished geriatric patients with hip fracture su bmi tted to surgery may be of interest for patients with postoperative complications and long hospital stays [15684319] PURPOSE To investigate the impact of dietary counseling or nutritional supplements on outcomes in cancer patients : nutritional , morbidity , and quality of life ( QoL ) during and 3 months after radiotherapy . PATIENTS AND METHODS A total of 111 colorectal cancer out patients referred for radiotherapy , stratified by staging , were r and omly assigned : group 1 ( G1 ; n = 37 ) , dietary counseling ( regular foods ) ; group 2 ( G2 ; n = 37 ) , protein supplements ; and group 3 ( G3 ; n = 37 ) , ad libitum intake . Nutritional intake ( diet history ) , status ( Ottery 's Subjective Global Assessment ) , and QoL ( European Organisation for Research and Treatment of Cancer Quality of Life Question naire version 3.0 ) were evaluated at baseline , at the end , and 3 months after radiotherapy . RESULTS At radiotherapy completion , energy intake increased in G1/G2 ( P < or = .04 ) , G1 more than G2 ( P = .001 ) , and decreased in G3 ( P < .01 ) . Protein intake increased in G1/G2 ( P < or = .007 ) , G1 less than G2 ( not significant ) , and decreased in G3 ( P < .01 ) . At 3 months , G1 maintained nutritional intake and G2/G3 returned to baseline . After radiotherapy and at 3 months , rates of anorexia , nausea , vomiting , and diarrhea were higher in G3 ( P < .05 ) . At radiotherapy completion , in G1 all QoL function scores improved proportionally to adequate intake or nutritional status ( P < .05 ) ; whereas in G2 only three of six function scores improved proportionally to protein intake ( P = .04 ) , and in G3 all scores worsened ( P < .05 ) . At 3 months , G1 patients maintained/improved function , symptoms , and single-item scores ( P < .02 ) ; in G2 , only few function and symptom scales improved ( P < .05 ) ; in G3 , QoL remained as poor as after radiotherapy . In G1/G2 , respectively , improvement/deterioration of QoL correlated with better or poorer intake or nutritional status ( P < .003 ) . CONCLUSION During radiotherapy , both interventions positively influenced outcomes ; dietary counseling was of similar or higher benefit , whereas even 3 months after RT , it was the only method to sustain a significant impact on patient outcomes [9061125] The objective of this study , design ed as a r and omized controlled prospect i ve intervention study , was to evaluate the effect of nutritional supplementation on functional status and need of care in undernourished geriatric patients during hospitalization , and up to 6 months after discharge . Participants consisted of 46 undernourished geriatric patients from a geriatric acute care hospital aged 75 years or older without malignant disease , or need for tube feeding or parenteral nutrition . Patients in the supplement group ( SG , N=20 ) were offered 400 mL ( 2100 kJ ) daily of a liquid supplement during hospital stay and 200 mL ( 1050 kJ ) per day for the following 6 months at home . Patients in the control group ( CG , N=26 ) had usual care without supplements . The main outcome measure was functional status based on the Barthel Activities of Daily Living score ( ADL ) at hospital admission , discharge and after 6 months , with higher scores indicating greater independence and a maximum score of 100 points . In supplemented patients with good acceptance ( SG+ , N=11 ) , a median improvement of 20 points was observed between admission and discharge , and a further improvement of 5 points at home . Median changes were 0 and −10 points in supplemented patients with poor acceptance ( SG- , N=9 ) and 5 and 2.5 points in CG , respectively . In SG+ , the proportion of independent patients ( > 65 points ) increased continuously from 36 % at admission to 63 % at discharge , to 72 % after 6 months , and was significantly higher compared to CG at discharge ( 63 % vs 19 % , pš 0.05 ) and after 6 months ( 72 % vs 39 % , p<0.05 ) . 64 % of the patients in SG+ improved during hospitalization , compared to 23 % in CG ( p<0.05 ) . In the six months at home , 18 % of SG+ improved ; none of SG+ deteriorated in hospital or at home . In contrast , deterioration of the ADL score occurred in considerable proportions of SG− ( 22 % in hospital , 22 % at home ) and CG ( 4 % at hospital , 12 % at home ) patients . The proportion of patients who improved was smaller in SG− ( 44 % at hospital , 22 % at home ) as well as in CG ( 23 % at hospital , 35 % at home ) , compared to SG+ . In conclusion , a positive functional course was evident in supplemented patients with good acceptance during hospitalization , and further improvement was observed during the following 6 months at home . Nutritional support may contribute to reconvalescence and recovery of undernourished geriatric patients [16815130] Malnutrition and dehydration are potential consequences of dysphagia , a common swallowing disorder among elderly individuals . Providing smaller , more frequent meals has been suggested ( but not demonstrated ) to improve energy intake among this group . Accordingly , this study was design ed to assess whether the same energy content in five vs three daily meals would improve energy intake . Thirty-seven residents of an extended-care facility , aged older than 65 years , previously evaluated for dysphagia , and receiving a texture-modified diet , agreed to participate in a crossover study with r and om assignment to three or five meals during an initial 4-day study period , followed by the opposite meal pattern in a second period . Six were excluded from analysis , as their medical condition deteriorated before or during the study . Food and fluids consumed by participants during each study period were weighed before and after each meal . Average energy intakes were similar between the three- and five-meal patterns ( 1,325+/-207 kcal/day vs 1,342+/-177 kcal/day , respectively ; P=0.565 ) ; fluid intake was higher with five meals ( 698+/-156 mL/day ) vs three ( 612+/-176 mL/day ; P=0.003 ) . Because offering five daily feedings did not improve energy intakes when compared with three , dietitians caring for this vulnerable group might need to consider other nutrition intervention strategies [10620007] Weight loss and protein malnutrition are frequent complications in HIV‐infected patients . The effect of an oral nutritional supplement combined with nutritional counselling on whole body protein metabolism was assessed [18436085] BACKGROUND Progressive loss of kidney function results in an increased risk of malnutrition . Despite this , there is little evidence informing the impact of nutrition intervention on predialysis patients with chronic kidney disease ( CKD ; stages 4 and 5 ) . STUDY DESIGN R and omized controlled trial . SETTING & PARTICIPANTS 56 out patients ( men , 62 % ; mean age , 70.7 + /- 14.0 [ SD ] years ) with CKD were r and omly allocated to intervention ( n = 29 ) or control ( n = 27 ) by using a concealed computer-generated sequence . INTERVENTION The intervention group , provided with individualized dietary counseling with regular follow-up aim ed at achieving an intake of 0.8 to 1.0 g/kg of protein and greater than 125 kJ/kg of energy , or control , receiving written material only . OUTCOMES & MEASURES Change in body composition ( body cell mass , measured by means of total-body potassium , in 40 of 56 participants ) , nutritional status ( Subjective Global Assessment ) , and energy and protein intake ( 3-day food record ) . RESULTS During the 12 weeks , the intervention group had 3.5 % ( 95 % confidence interval , -2.1 to 9.1 ) less decrease in body cell mass , 17.7-kJ/kg/d ( 95 % confidence interval , 8.2 to 27.2 ) greater increase in energy intake , greater improvement in Subjective Global Assessment ( P < 0.01 ) , and no significant difference in protein intake compared with the control group ( -0.04 g/kg/d ; 95 % confidence interval , -0.73 to 0.16 ) . The intervention was associated with greater increases in energy and protein intake in women than men ( interaction P < 0.001 for both ) . LIMITATIONS Power to detect change in body cell mass , potential bias in ascertainment of Subjective Global Assessment . CONCLUSIONS In predialysis patients with CKD , structured nutrition intervention had a greater effect on energy and protein intake in women than men . Additional investigations are warranted to determine the impact on body composition [8733313] AIM To assess prospect ively the effects of a controlled program of inspiratory muscle training program and nutritional support in patients with chronic obstructive lung disease ( COPD ) . PATIENTS AND METHODS Twenty-three patients with COPD were r and omly assigned into four groups . Group I received a 1000 kcal/day nutritional supplement , given as a casein based enteral nutritional formula ; group III was subjected to inspiratory muscle training , using an inexpensive pressure threshold load valve constructed according to the Appropriate Technology principles of the WHO , adjusted at 30 % of Maximal Inspiratory Mouth Pressure and received also the nutritional supplement ; group IV was trained but did not receive the nutritional supplement and group II was not trained nor supplemented . Patients were studied during three months and monthly , inspiratory muscle function , exercise capacity and anthropometry were measured . RESULTS A significant improvement in exercise capacity , maximal inspiratory pressure and inspiratory muscle endurance was observed in the four groups throughout the study . Trained subjects had greater improvement in their inspiratory muscle endurance , compared to untrained subjects . Nutritional support had no effect in inspiratory muscle function or exercise capacity . No changes in anthropometric measures were observed . CONCLUSIONS The pressure threshold load valve used in this study , improved inspiratory muscle endurance and nutritional support had no effect in patients with COPD [8477961] A Veterans Affairs cooperative study involving 273 male patients was performed to evaluate efficacy of ox and rolone in combination with an enteral food supplement in severe alcoholic hepatitis . All patients had some degree of protein calorie malnutrition . On an intention-to-treat basis , only minimal changes in mortality were observed . However , in patients with moderate malnutrition mortality on active treatment at 1 mo was 9.4 % compared with 20.9 % in patients receiving placebo . This beneficial effect was maintained so that after 6 mo on active treatment 79.7 % of patients were still alive , compared with 62.7 % of placebo-treated patients ( p = 0.037 ) . Improvements in both the severity of the liver injury ( p = 0.03 ) and malnutrition ( p = 0.05 ) also occurred . No significant improvement was observed with severe malnutrition . To better determine the effect on therapeutic efficacy , we compared results with those from a nearly identical population ( cooperative study 119 ) treated with ox and rolone but not given the food supplement . Patients were stratified according to their caloric intake ( greater than 2,500 kcal/day was considered adequate to supply energy needs and promote anabolism ) . For patients with moderate malnutrition and adequate caloric intake , ox and rolone treatment reduced 6-mo mortality ( 4 % active treatment vs. 28 % placebo [ p = 0.002 ] ) . For patients with moderate malnutrition and inadequate calorie intake , ox and rolone had no effect on mortality ( 30 % active treatment vs. 33 % placebo ) . In cases of severe malnutrition , ox and rolone had no effect on survival . However , adequate caloric intake was associated with 19 % mortality , whereas patients with inadequate intake exhibited 51 % mortality ( p = 0.0001 ) . These results indicate that nutritional status should be evaluated in patients with alcoholic hepatitis . When malnutrition is present , vigorous nutrition therapy should be provided , and in patients with moderate malnutrition ox and rolone should be added to the regimen [3282825] We studied the effects of oral nutritional supplementation on respiratory muscle ( RM ) performance in 25 ambulatory patients with severe chronic obstructive pulmonary disease ( COPD ) . There was a relationship between body weight and anthropometric parameters of nutritional status ( triceps skinfold thickness [ r = 0.67 ; p less than 0.005 ] , midarm muscle circumference ( r = 0.53 ; p less than 0.005 ) , but body weight did not correlate with daily caloric intake , serum albumin , transferrin , or blood lymphocyte count . None of these measurements of nutritional status correlated with any measure of RM strength or endurance . In a r and omized observer-blinded crossover trial , patients were allocated to one of two groups . In the first eight weeks of the study , group A received nutritional supplementation , and patients in group B were control subjects . In the second eight weeks , patients in group A were control subjects , and group B received supplement . Mean daily caloric intake and body weight increased in both groups while receiving supplement ( both p less than 0.05 ) . Calories provided by the supplement were frequently substituted for normal dietary calories . Any increases in RM performance in the group receiving supplement were matched by increases ( due to learning ) in controls . We conclude that oral dietary supplements have no important effects on RM performance in ambulatory patients with COPD [6951009] Twenty-four orthognathic surgery patients were studied to determine the impact of a high-calorie liquid supplement on preventing or minimizing catabolism commonly associated with surgery . The experimental group of 12 subjects , chosen at r and om , consumed blenderized foods ad libitum and a high-calorie dietary supplement providing a minimum of 50 % of energy requirements . The remaining 12 subjects consumed only blenderized foods and served as the control group . The nutritional status of all patients was assessed one day before surgery and on Day 7 of the first , third , and sixth postoperative week . In general , nutrient intake in the experimental group remained similar to that before surgery , whereas intake in the control group decreased significantly , particularly at the one-week postoperative evaluation . It was concluded that the addition of a high-calorie liquid supplement to the dietary regimen of orthognathic surgery patients helped maintain nutrient intake at a level comparable to that before surgery . This result ed in better maintenance of body weight and somatic protein compartments compared with the control group [9225334] Little is known about nutritional intake after discharge though it takes months to regain preoperative weight after gastrointestinal surgery . We studied whether a 4-mo intervention with dietary advice and protein-rich supplements would increase nutritional intake and gain in lean body mass ( LBM ) in patients who had undergone gastrointestinal surgery . Patients admitted for gastrointestinal surgery were r and omized at discharge to serve as control patients ( n = 47 ) or to receive intervention ( n = 40 ) . One month after discharge , the control patients had a nutritional intake ( 3-d diet record ) comparable with the intake of the general population that did not increase further . During the 4 m , the intervention patients had an increased intake of protein ( + 22 % ) and energy ( + 16 % ) , and an enhanced gain of LBM after 2 mo ( control 0.8 kg versus intervention 2.1 kg ; P = 0.009 ) . After the 4-mo intervention , both LBM and fat were gained ( control 1.7 kg LBM and 0.2 kg fat versus intervention 3.1 kg LBM and 1.5 kg fat ; LBM : P = 0.029 and fat : P = 0.056 ) . At discharge patients should increase protein intake to 1.5 g.kg-1.d-1 for 2 mo , e.g. , by taking protein-rich liquid supplements [9550167] OBJECTIVE To evaluate the effects of nutrition counseling with or without oral supplementation in malnourished patients infected with the human immunodeficiency virus ( HIV ) . DESIGN R and omized controlled trial . SUBJECTS HIV-infected men ( n=118 ) who were less than 90 % of usual weight for height or who had lost more than 10 % of body weight . INTERVENTION Nutrition counseling alone ( control group ) vs nutrition counseling plus enteral supplementation ( supplement group ) for 6 weeks . All patients were instructed to consume a diet that exceeded estimated total energy expenditure by 960 kcal/day . MAIN OUTCOME MEASURES Weight , skinfold thickness , fat-free mass , grip strength , quality of life , and cognitive function ( Buschke test ) . STATISTICAL ANALYSES Differences in baseline variables and outcomes were evaluated using analysis of variance or the Wilcoxon rank sum test . RESULTS Ninety-nine men completed at least 4 weeks of treatment , 49 in the supplement group and 50 in the control group . Half the patients in each treatment group achieved at least 80 % of their energy target . No differences in weight , skinfold thickness measurements , or quality of life were observed . Compared with the control group , the supplement group had larger increases in fat-free mass and grip strength , although the differences did not reach statistical significance . APPLICATIONS In the short term , nutrition counseling with or without oral supplementation can achieve a substantial increase in energy intake in about 50 % of malnourished HIV-infected patients . Although further study is needed to evaluate long-term effects , these findings suggest that nutrition counseling has an important role in the management of malnourished HIV-infected patients [9043473] Background Postoperative fatigue and deterioration in functional capacity have been correlated to postoperative weight loss . This suggested that nutritional support to enhance the regain of weight might improve upon the convalescence [3536644] A prospect i ve controlled 6-month study was undertaken to compare the effect of Ensure , a defined formula dietary supplement , and diet counselling in 122 out patients with Crohn 's disease . The compliance to Ensure was poor due to a high incidence of side effects . Taking any amount of Ensure reduced the need for surgery and the amount of hospitalization . There was a trend for patients receiving Ensure to experience a decline in the value of their Crohn 's disease activity index ( p less than 0.10 ) . No consistent effects of Ensure were seen on the amount of work missed due to Crohn 's disease , in laboratory measurements , in the need for prednisone or Salazopyrin . The vitamin B12 intake was improved , but otherwise nutrient intake declined due to a decreased food intake . Thus , certain beneficial clinical trends were associated with taking Ensure , but larger numbers of compliant patients will need to be studied to better assess the long-term role of defined formula diets in the management of out patients with Crohn 's disease [2899528] A prospect i ve study was undertaken to establish the role of individualized diet counselling in the management of 137 out patients with Crohn 's disease . Individualized dietary counselling for 6 months was associated with a significant decrease in the Crohn 's disease activity index , an increased incidence of disease remission , a decreased need for prednisone and Salazopyrin therapy , a reduction in the number of days spent in hospital , and a reduction in the amount of time lost from work due to Crohn 's disease , when compared with control patients who did not receive dietary counselling but who were seen regularly in follow-up under similar circumstances . Improvement with diet counselling was more likely to occur in patients who had not previously been subjected to small bowel resection , and occurred in patients with active or inactive disease . The effect of counselling 58 patients was assessed over a further 6 months ( for a total 12-month period ) ; there was a persistently reduced Crohn 's disease activity index and a continued decreased number of lost days of work . The mechanism for these beneficial effects of diet counselling was not established . It is suggested that individualized diet counselling , aim ed at optimizing the patient 's nutritional status , may play a role in the management of patients with Crohn 's disease [18442509] Cystic fibrosis ( CF ) remains the most common genetically inherited disease in the white population and its prognosis is affected by nutritional status . Adults with the disease are now surviving longer and new strategies are required to ensure that they maintain optimal nutrition . This article reports preliminary data from a r and omized controlled trial of a 10-week home-based behavioral nutrition intervention , " Eat Well with CF . " Outcome measures of weight change over 6 and 12 months and changes in CF-specific nutrition knowledge score , self-efficacy score , reported dietary fat intake and health-related quality -of-life score were compared between the intervention group ( n=34 ) and a st and ard care control group ( n=34 ) . The hypotheses to be tested were that adults with CF completing " Eat Well with CF " would have an improved nutritional status , improvement in specific nutrition knowledge , and an improvement in self-efficacy regarding their ability to cope with a special diet , compared to those receiving st and ard care . There were substantial improvements in the intervention group 's specific CF nutrition knowledge score , self-efficacy score , and reported fat intake compared to control , but no substantial change in body mass index or health-related quality of life over time . Home-based nutrition education incorporating behavioral strategies can be an effective way to support adults with CF , enabling improvement in self-management skills in relation to diet and pancreatic enzyme replacement therapy . This study revealed gaps in basic nutrition knowledge and skills , inadequate knowledge of diet-disease links and pancreatic enzyme replacement therapy . These need to be identified when subjects progress from pediatric to adult care , and programs such as " Eat Well with CF " are a useful adjunct for registered dietitians trying to manage this diverse but growing population [18627001] UNLABELLED Patients with liver cirrhosis exhibit early onset of gluconeogenesis after short-term fasting . This accelerated metabolic reaction to starvation may underlie their increased protein requirements and muscle depletion . A r and omized controlled trial was conducted to test the hypothesis that provision of a late-evening nutritional supplement over a 12-month period would improve body protein stores in patients with cirrhosis . A total of 103 patients ( 68 male , 35 female ; median age 51 , range 28 - 74 ; Child-Pugh grading : 52A , 31B , 20C ) were r and omized to receive either daytime ( between 0900 and 1900 hours ) or nighttime ( between 2100 and 0700 hours ) supplementary nutrition ( 710 kcal/day ) . Primary etiology of liver disease was chronic viral hepatitis ( 67 ) , alcohol ( 15 ) , cholestatic ( 6 ) , and other ( 15 ) . Total body protein ( TBP ) was measured by neutron activation analysis at baseline , 3 , 6 , and 12 months . Total daily energy and protein intakes were assessed at baseline and at 3 months by comprehensive dietary recall . As a percentage of values predicted when well , TBP at baseline was similar for the daytime ( 85 + /- 2[st and ard error of the mean]% ) and nighttime ( 84 + /- 2 % ) groups . For the nighttime group , significant increases in TBP were measured at 3 ( 0.38 + /- 0.10 kg , P = 0.0004 ) , 6 ( 0.48 + /- 0.13 kg , P = 0.0007 ) , and 12 months ( 0.53 + /- 0.17 kg , P = 0.003 ) compared to baseline . For the daytime group , no significant changes in TBP were seen . Daily energy and protein intakes at 3 months were higher than at baseline in both groups ( P < 0.0001 ) , and these changes did not differ between the groups . CONCLUSION Provision of a nighttime feed to patients with cirrhosis results in body protein accretion equivalent to about 2 kg of lean tissue sustained over 12 months . This improved nutritional status may have important implication s for the clinical course of these patients [18586458] OBJECTIVE We tested the hypothesis that a multifaceted 11-wk intervention comprising nutrition , group exercise , and oral care would have a significant influence on nutrition and function in elderly ( > or=65 y ) nursing-home residents . METHODS The study was an 11-wk r and omized controlled intervention study with nutrition ( chocolate and homemade oral supplements ) , group exercise twice a week ( 45 - 60 min , moderate intensity ) , and oral care intervention one to two times a week , with the aim of improving nutritional status and function in elderly nursing-home residents . A follow-up visit was made 4 mo after the end of the intervention . Assessment s were weight , body mass index , dietary intake , h and grip strength , Senior Fitness Test , Berg 's Balance Scale , and the prevalence of plaque . RESULTS A total of 121 subjects ( 61 % ) accepted the invitation and 62 were r and omized to the intervention group . Six of these dropped out during the 11 wk . At the 4-mo follow-up there were 15 deaths in the intervention group and 8 in the control group . The nutrition and exercise were well tolerated . After 11 wk the change in percentage of weight ( P = 0.005 ) , percentage of body mass index ( P = 0.003 ) , energy intake ( P = 0.084 ) , protein intake ( P = 0.012 ) , and Berg 's Balance Scale ( P = 0.004 ) was higher in the intervention group than in the control group . In addition , the percentage of subjects whose functional tests improved was higher in the intervention group . Both groups lost the same percentage of weight after the intervention ( P = 0.908 ) . The total percentage of weight loss from baseline to follow-up was higher in the control group ( P = 0.019 ) . Oral care was not well accepted and the prevalence of plaque did not change . CONCLUSION It is possible to improve nutrition and function in elderly nursing-home residents by means of a multifaceted intervention consisting of chocolate , homemade supplements , group exercise , and oral care Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Supportive interventions such as serving meals in a dining room environment or the use of assistants to feed patients are frequently recommended for the management of nutritionally vulnerable groups . Such interventions are included in many policy and guideline documents and have implication s for staff time but may incur additional costs , yet there appears to be a lack of evidence for their efficacy . OBJECTIVES To assess the effects of supportive interventions for enhancing dietary intake in malnourished or nutritionally at-risk adults . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

28376866

[25154822] PURPOSE Combining cisplatin or cetuximab with radiation improves overall survival ( OS ) of patients with stage III or IV head and neck carcinoma ( HNC ) . Cetuximab plus platinum regimens also increase OS in metastatic HNC . The Radiation Therapy Oncology Group launched a phase III trial to test the hypothesis that adding cetuximab to the radiation-cisplatin platform improves progression-free survival ( PFS ) . PATIENTS AND METHODS Eligible patients with stage III or IV HNC were r and omly assigned to receive radiation and cisplatin without ( arm A ) or with ( arm B ) cetuximab . Acute and late reactions were scored using Common Terminology Criteria for Adverse Events ( version 3 ) . Outcomes were correlated with patient and tumor features and markers . RESULTS Of 891 analyzed patients , 630 were alive at analysis ( median follow-up , 3.8 years ) . Cetuximab plus cisplatin-radiation , versus cisplatin-radiation alone , result ed in more frequent interruptions in radiation therapy ( 26.9 % v. 15.1 % , respectively ) ; similar cisplatin delivery ( mean , 185.7 mg/m2 v. 191.1 mg/m2 , respectively ) ; and more grade 3 to 4 radiation mucositis ( 43.2 % v. 33.3 % , respectively ) , rash , fatigue , anorexia , and hypokalemia , but not more late toxicity . No differences were found between arms A and B in 30-day mortality ( 1.8 % v. 2.0 % , respectively ; P = .81 ) , 3-year PFS ( 61.2 % v. 58.9 % , respectively ; P = .76 ) , 3-year OS ( 72.9 % v. 75.8 % , respectively ; P = .32 ) , locoregional failure ( 19.9 % v. 25.9 % , respectively ; P = .97 ) , or distant metastasis ( 13.0 % v. 9.7 % , respectively ; P = .08 ) . Patients with p16-positive oropharyngeal carcinoma ( OPC ) , compared with patients with p16-negative OPC , had better 3-year probability of PFS ( 72.8 % v. 49.2 % , respectively ; P < .001 ) and OS ( 85.6 % v. 60.1 % , respectively ; P < .001 ) , but tumor epidermal growth factor receptor ( EGFR ) expression did not distinguish outcome . CONCLUSION Adding cetuximab to radiation-cisplatin did not improve outcome and hence should not be prescribed routinely . PFS and OS were higher in patients with p16-positive OPC , but outcomes did not differ by EGFR expression [15625362] PURPOSE To select one of two chemoradiotherapy regimens for locally advanced squamous cell carcinoma ( SCC ) of the head and neck as the experimental arm for the next Trans-Tasman Radiation Oncology Group phase III trial . PATIENTS AND METHODS One hundred twenty-two previously untreated patients with stage III/IV SCC of the head and neck were r and omized to receive definitive radiotherapy ( 70 Gy in 7 weeks ) concurrently with either cisplatin ( 75 mg/m(2 ) ) plus tirapazamine ( 290 mg/m(2)/d ) on day 2 of weeks 1 , 4 , and 7 , and tirapazamine alone ( 160 mg/m(2)/d ) on days 1 , 3 , and 5 of weeks 2 and 3 ( TPZ/CIS ) , or cisplatin ( 50 mg/m(2 ) ) on day 1 and infusional fluorouracil ( 360 mg/m(2)/d ) on days 1 through 5 of weeks 6 and 7 ( chemoboost ) . RESULTS Three-year failure-free survival rates were 55 % with TPZ/CIS ( 95 % CI , 39 % to 70 % ) and 44 % with chemoboost ( 95 % CI , 30 % to 60 % ; log-rank P = .16 ) . Three-year locoregional failure-free rates were 84 % in the TPZ/CIS arm ( 95 % CI , 71 % to 92 % ) and 66 % in the chemoboost arm ( 95 % CI , 51 % to 79 % ; P = .069 ) . More febrile neutropenia and grade 3 or 4 late mucous membrane toxicity were observed with TPZ/CIS , while acute skin radiation reaction was more severe and prolonged with chemoboost . Compliance with protocol treatment was satisfactory on both arms . CONCLUSION Both regimens are feasible and are associated with significant but acceptable toxicity profiles in the cooperative group setting . Based on the promising efficacy seen in this trial , TPZ/CIS is being evaluated in a large phase III trial [17960013] BACKGROUND A r and omized phase 3 trial of the treatment of squamous-cell carcinoma of the head and neck compared induction chemotherapy with docetaxel plus cisplatin and fluorouracil ( TPF ) with cisplatin and fluorouracil ( PF ) , followed by chemoradiotherapy . METHODS We r and omly assigned 501 patients ( all of whom had stage III or IV disease with no distant metastases and tumors considered to be unresectable or were c and i date s for organ preservation ) to receive either TPF or PF induction chemotherapy , followed by chemoradiotherapy with weekly carboplatin therapy and radiotherapy for 5 days per week . The primary end point was overall survival . RESULTS With a minimum of 2 years of follow-up ( > or =3 years for 69 % of patients ) , significantly more patients survived in the TPF group than in the PF group ( hazard ratio for death , 0.70 ; P=0.006 ) . Estimates of overall survival at 3 years were 62 % in the TPF group and 48 % in the PF group ; the median overall survival was 71 months and 30 months , respectively ( P=0.006 ) . There was better locoregional control in the TPF group than in the PF group ( P=0.04 ) , but the incidence of distant metastases in the two groups did not differ significantly ( P=0.14 ) . Rates of neutropenia and febrile neutropenia were higher in the TPF group ; chemotherapy was more frequently delayed because of hematologic adverse events in the PF group . CONCLUSIONS Patients with squamous-cell carcinoma of the head and neck who received docetaxel plus cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy had a significantly longer survival than did patients who received cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy . ( Clinical Trials.gov number , NCT00273546 [ Clinical Trials.gov ] . ) [23041591] BACKGROUND Cetuximab combined with radiotherapy ( RT ) is a treatment option for head and neck cancer . The objectives of this r and omized , phase II trial were to evaluate the efficacy and safety of cetuximab maintenance therapy following definitive RT with concomitant cetuximab in patients with oropharyngeal cancer . PATIENTS AND METHODS Ninety-one patients with stage III-IV M0 oropharyngeal tumors were r and omly assigned to the treatment with accelerated concomitant boost RT ( 69.9 Gy ) + cetuximab or the same treatment with the addition of 12 consecutive weeks of cetuximab maintenance therapy . The primary end point was locoregional control ( LRC ) at 1 year . RESULTS LRC at 1 year was superior among patients in the experimental arm , treated with cetuximab maintenance ( 59 % versus 47 % ) . However , LRC was similar between both arms after 2 years of follow-up , as a result of increased locoregional recurrences after the first year in the maintenance group . Patients treated with adjuvant cetuximab do recover very soon from toxic effect after combined treatment . CONCLUSIONS Twelve weeks of cetuximab maintenance therapy after concomitant cetuximab + RT in locally advanced oropharyngeal carcinoma is feasible and improves clinical outcomes measured at 1 year . This improvement is not maintained after the second year suggesting that epidermal growth factor receptor blockade is not sufficient to completely eliminate the minimal residual disease [17197122] PURPOSE The long term results and patterns of failure in patients with squamous cell head and neck carcinoma ( SCHNC ) treated in a prospect i ve r and omized trial in which concomitant postoperative radiochemotherapy with Mitomycin C and Bleomycin ( CRT ) was compared with radiotherapy only ( RT ) , were analyzed . PATIENTS AND METHODS Between March 1997 and December 2001 , 114 eligible patients with Stage III or IV SCHNC were r and omized . Primary surgical treatment was performed with curative intent in all patients . Patients in both groups were postoperatively irradiated to the total dose of 56 - 70 Gy . Chemotherapy included Mitomycin C 15 mg/m2 after 10 Gy and 5 mg of Bleomycin twice weekly during irradiation . Median follow-up was 76 months ( 48 - 103 months ) . RESULTS At 5 years in the RT and CRT arms , the locoregional control was 65 % and 88 % ( p = 0.026 ) , disease-free survival 33 % and 53 % ( p = 0.035 ) , and overall survival 37 % and 55 % ( p = 0.091 ) respectively . Patients who benefited from chemotherapy were those with high-risk factors . The probability of distant metastases was 22 % in RT and 20 % in CRT arm ( p = 0.913 ) , of grade III or higher late toxicity 19 % in RT and 26 % in CRT arm ( p = 0.52 ) and of thyroid dysfunction 36 % in RT and 56 % in CRT arm ( p = 0.24 ) . The probability to develop a second primary malignancy ( SPM ) was 34 % in the RT and 8 % in the CRT arm ( p = 0.023 ) . One third of deaths were due to infection , but there was no difference between the 2 groups . CONCLUSION With concomitant radiochemotherapy , locoregional control and disease free survival were significantly improved . Second primary malignancies in the CRT arm compared to RT arm were significantly less frequent . The high probability of post treatment hypothyroidism in both arms warrants regular laboratory evaluation [20479425] PURPOSE Promising results in a r and omized phase II trial with the hypoxic cytotoxin tirapazamine ( TPZ ) combined with cisplatin ( CIS ) and radiation led to this phase III trial . PATIENTS AND METHODS Patients with previously untreated stage III or IV ( excluding T1 - 2N1 and M1 ) squamous cell carcinoma of the oral cavity , oropharynx , hypopharynx , or larynx were r and omly assigned to receive definitive radiotherapy ( 70 Gy in 7 weeks ) concurrently with either CIS ( 100 mg/m(2 ) ) on day 1 of weeks 1 , 4 , and 7 or CIS ( 75 mg/m(2 ) ) plus TPZ ( 290 mg/m(2)/d ) on day 1 of weeks 1 , 4 , and 7 and TPZ alone ( 160 mg/m(2)/d ) on days 1 , 3 , and 5 of weeks 2 and 3 ( TPZ/CIS ) . The primary end point was overall survival ( OS ) . The planned sample size was 850 , estimated to result in 334 deaths , which would provide 90 % power to detect a difference in 2-year survival rates of 60 % v 70 % for CIS versus TPZ/CIS , respectively ( hazard ratio = 0.69 ) . RESULTS Eight hundred sixty-one patients were accrued from 89 sites in 16 countries . In an intent-to-treat analysis , the 2-year OS rates were 65.7 % for CIS and 66.2 % for TPZ/CIS ( TPZ/CIS -- CIS : 95 % CI , -5.9 % to 6.9 % ) . There were no significant differences in failure-free survival , time to locoregional failure , or quality of life as measured by Functional Assessment of Cancer Therapy-Head and Neck . CONCLUSIONS We found no evidence that the addition of TPZ to chemoradiotherapy , in patients with advanced head and neck cancer not selected for the presence of hypoxia , improves OS [17960012] BACKGROUND Phase 2 studies suggest that the st and ard regimen of cisplatin and fluorouracil ( PF ) plus docetaxel ( TPF ) improves outcomes in squamous-cell carcinoma of the head and neck . We compared TPF with PF as induction chemotherapy in patients with locoregionally advanced , unresectable disease . METHODS We r and omly assigned eligible patients between the ages of 18 and 70 years who had stage III or stage IV disease and no distant metastases to receive either TPF ( docetaxel and cisplatin , day 1 ; fluorouracil by continuous infusion , days 1 to 5 ) or PF every 3 weeks for four cycles . Patients without progression of disease received radiotherapy within 4 to 7 weeks after completing chemotherapy . The primary end point was progression-free survival . RESULTS A total of 358 patients underwent r and omization , with 177 assigned to the TPF group and 181 to the PF group . At a median follow-up of 32.5 months , the median progression-free survival was 11.0 months in the TPF group and 8.2 months in the PF group ( hazard ratio for disease progression or death in the TPF group , 0.72 ; P=0.007 ) . Treatment with TPF result ed in a reduction in the risk of death of 27 % ( P=0.02 ) , with a median overall survival of 18.8 months , as compared with 14.5 months in the PF group . There were more grade 3 or 4 events of leukopenia and neutropenia in the TPF group and more grade 3 or 4 events of thrombocytopenia , nausea , vomiting , stomatitis , and hearing loss in the PF group . The rates of death from toxic effects were 2.3 % in the TPF group and 5.5 % in the PF group . CONCLUSIONS As compared with the st and ard regimen of cisplatin and fluorouracil , induction chemotherapy with the addition of docetaxel significantly improved progression-free and overall survival in patients with unresectable squamous-cell carcinoma of the head and neck . ( Clinical Trials.gov number , NCT00003888 [ Clinical Trials.gov ] . ) [20448462] The prognosis of patients with advanced head and neck cancer remain dismal . For this tumor type , elevated levels of EGFR are associated with a shorter disease free survival and time to treatment failure , reflecting a more aggressive phenotype . Nimotuzumab is a humanized monoclonal antibody that recognizes domain III of the extracellular region of the EGFR , within an area that overlaps with both the surface patch recognized by cetuximab and the binding site for EGF . In order to assess the efficacy of nimotuzumab in combination with radiotherapy , a controlled , double blind , r and omized clinical trial was conducted in 106 advanced squamous cell carcinoma of the head and neck patients , mostly , unfit for chemo-radiotherapy . Control patients received a placebo and radiotherapy . Treatment was safe and the most frequent adverse events consisted on grade I or II asthenia , fever , headache and chills . No skin rash was detected . A significant complete response rate improvement was found in the group of patients treated with nimotuzumab as compared to the placebo . In the intent to treat analysis , a trend towards survival benefit for nimotuzumab treated subjects was found . The survival benefit became significant when applying the Harrington-Fleming test , a weighted log-rank that underscores the detection of differences deferred on time . In addition , a preliminary biomarker investigation showed a significant survival improvement for nimotuzumab treated patients as compared to controls for subjects with EGFR positive tumors . All patients showed a quality of life improvement and a reduction of the general and specific symptoms of the disease [16467544] BACKGROUND We conducted a multinational , r and omized study to compare radiotherapy alone with radiotherapy plus cetuximab , a monoclonal antibody against the epidermal growth factor receptor , in the treatment of locoregionally advanced squamous-cell carcinoma of the head and neck . METHODS Patients with locoregionally advanced head and neck cancer were r and omly assigned to treatment with high-dose radiotherapy alone ( 213 patients ) or high-dose radiotherapy plus weekly cetuximab ( 211 patients ) at an initial dose of 400 mg per square meter of body-surface area , followed by 250 mg per square meter weekly for the duration of radiotherapy . The primary end point was the duration of control of locoregional disease ; secondary end points were overall survival , progression-free survival , the response rate , and safety . RESULTS The median duration of locoregional control was 24.4 months among patients treated with cetuximab plus radiotherapy and 14.9 months among those given radiotherapy alone ( hazard ratio for locoregional progression or death , 0.68 ; P=0.005 ) . With a median follow-up of 54.0 months , the median duration of overall survival was 49.0 months among patients treated with combined therapy and 29.3 months among those treated with radiotherapy alone ( hazard ratio for death , 0.74 ; P=0.03 ) . Radiotherapy plus cetuximab significantly prolonged progression-free survival ( hazard ratio for disease progression or death , 0.70 ; P=0.006 ) . With the exception of acneiform rash and infusion reactions , the incidence of grade 3 or greater toxic effects , including mucositis , did not differ significantly between the two groups . CONCLUSIONS Treatment of locoregionally advanced head and neck cancer with concomitant high-dose radiotherapy plus cetuximab improves locoregional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head and neck . ( Clinical Trials.gov number , NCT00004227 . [19179556] BACKGROUND Locally advanced laryngeal and hypopharyngeal cancers ( LHC ) represent a group of cancers for which surgery , laryngectomy-free survival ( LFS ) , overall survival ( OS ) , and progression-free survival ( PFS ) are clinical ly meaningful end points . PATIENTS AND METHODS These outcomes were analyzed in the subgroup of assessable LHC patients enrolled in TAX 324 , a phase III trial of sequential therapy comparing docetaxel plus cisplatin and fluorouracil ( TPF ) against cisplatin and fluorouracil ( PF ) , followed by chemoradiotherapy . RESULTS Among 501 patients enrolled in TAX 324 , 166 had LHC ( TPF , n = 90 ; PF , n = 76 ) . Patient characteristics were similar between subgroups . Median OS for TPF was 59 months [ 95 % confidence interval ( CI ) : 31-not reached ] versus 24 months ( 95 % CI : 13 - 42 ) for PF [ hazard ratio ( HR ) for death : 0.62 ; 95 % CI : 0.41 - 0.94 ; P = 0.024 ] . Median PFS for TPF was 21 months ( 95 % CI : 12 - 59 ) versus 11 months ( 95 % CI : 8 - 14 ) for PF ( HR : 0.66 ; 95 % CI : 0.45 - 0.97 ; P = 0.032 ) . Among operable patients ( TPF , n = 67 ; PF , n = 56 ) , LFS was significantly greater with TPF ( HR : 0.59 ; 95 % CI : 0.37 - 0.95 ; P = 0.030 ) . Three-year LFS with TPF was 52 % versus 32 % for PF . Fewer TPF patients had surgery ( 22 % versus 42 % ; P = 0.030 ) . CONCLUSIONS In locally advanced LHC , sequential therapy with induction TPF significantly improved survival and PFS versus PF . Among operable patients , TPF also significantly improved LFS and PFS . These results support the use of sequential TPF followed by carboplatin chemoradiotherapy as a treatment option for organ preservation or to improve survival in locally advanced LHC [15908196] A combination of cisplatin and 5-fluorouracil ( PF ) is considered the st and ard induction chemotherapy regimen for squamous cell carcinoma of the head and neck ( SCCHN ) . The present study compares the efficacy and safety of a new combination of cisplatin/docetaxel versus the PF regimen . A total of 83 chemotherapy-naive patients with locally advanced SCCHN were r and omised to receive every 21 d ( i ) docetaxel 85 mg/m2 i.v . on day 1 and cisplatin 40 mg/m2 i.v . on days 1 and 2 ( arm A ) or ( ii ) cisplatin 100 mg/m2 i.v . on day 1 followed by 5-fluorouracil 1000 mg/m2 in 24 h continuous infusion for 5 d ( arm B ) . A total of 287 cycles ( range 1 - 3 per patient ) were administered . Among 76 patients evaluable for response , the overall response rate in arm A was 70 % ( complete response ( CR ) 26 % , partial response ( PR ) 44 % ) and in arm B 69 % ( CR 16 % , PR 54 % ) , respectively . Median survival in arm A was 7.6 months ( 95 % CI : 5.8 - 11.1 ) and 9.9 months ( 95 % CI : 7.4 - 14.6 ) for arm B. The most frequent grade 3/4 toxicity in arm A was neutropaenia ( 34.1 % ) and diarrhoea ( 9.8 % ) versus mucositis ( 29.3 % ) and neutropaenia ( 19.5 % ) in arm B. Both schedules present a similar efficacy , with different but acceptable toxicity patterns [22749632] PURPOSE Previous analysis of this Intergroup trial demonstrated that with a median follow-up among surviving patients of 45.9 months , the concurrent postoperative administration of cisplatin and radiation therapy improved local-regional control and disease-free survival of patients who had high-risk resectable head- and -neck carcinomas . With a minimum of 10 years of follow-up potentially now available for all patients , these results are up date d here to examine long-term outcomes . METHODS AND MATERIAL S A total of 410 analyzable patients who had high-risk resected head- and -neck cancers were prospect ively r and omized to receive either radiation therapy ( RT : 60 Gy in 6 weeks ) or identical RT plus cisplatin , 100 mg/m(2)i.v . on days 1 , 22 , and 43 ( RT + CT ) . RESULTS At 10 years , the local-regional failure rates were 28.8 % vs 22.3 % ( P=.10 ) , disease-free survival was 19.1 % vs 20.1 % ( P=.25 ) , and overall survival was 27.0 % vs 29.1 % ( P=.31 ) for patients treated by RT vs RT + CT , respectively . In the unplanned subset analysis limited to patients who had microscopically involved resection margins and /or extracapsular spread of disease , local-regional failure occurred in 33.1 % vs 21.0 % ( P=.02 ) , disease-free survival was 12.3 % vs 18.4 % ( P=.05 ) , and overall survival was 19.6 % vs 27.1 % ( P=.07 ) , respectively . CONCLUSION At a median follow-up of 9.4 years for surviving patients , no significant differences in outcome were observed in the analysis of all r and omized eligible patients . However , analysis of the subgroup of patients who had either microscopically involved resection margins and /or extracapsular spread of disease showed improved local-regional control and disease-free survival with concurrent administration of chemotherapy . The remaining subgroup of patients who were enrolled only because they had tumor in 2 or more lymph nodes did not benefit from the addition of CT to RT [15128894] BACKGROUND We compared concomitant cisplatin and irradiation with radiotherapy alone as adjuvant treatment for stage III or IV head and neck cancer . METHODS After undergoing surgery with curative intent , 167 patients were r and omly assigned to receive radiotherapy alone ( 66 Gy over a period of 6 1/2 weeks ) and 167 to receive the same radiotherapy regimen combined with 100 mg of cisplatin per square meter of body-surface area on days 1 , 22 , and 43 of the radiotherapy regimen . RESULTS After a median follow-up of 60 months , the rate of progression-free survival was significantly higher in the combined-therapy group than in the group given radiotherapy alone ( P=0.04 by the log-rank test ; hazard ratio for disease progression , 0.75 ; 95 percent confidence interval , 0.56 to 0.99 ) , with 5-year Kaplan-Meier estimates of progression-free survival of 47 percent and 36 percent , respectively . The overall survival rate was also significantly higher in the combined-therapy group than in the radiotherapy group ( P=0.02 by the log-rank test ; hazard ratio for death , 0.70 ; 95 percent confidence interval , 0.52 to 0.95 ) , with five-year Kaplan-Meier estimates of overall survival of 53 percent and 40 percent , respectively . The cumulative incidence of local or regional relapses was significantly lower in the combined-therapy group ( P=0.007 ) . The estimated five-year cumulative incidence of local or regional relapses ( considering death from other causes as a competing risk ) was 31 percent after radiotherapy and 18 percent after combined therapy . Severe ( grade 3 or higher ) adverse effects were more frequent after combined therapy ( 41 percent ) than after radiotherapy ( 21 percent , P=0.001 ) ; the types of severe mucosal adverse effects were similar in the two groups , as was the incidence of late adverse effects . CONCLUSIONS Postoperative concurrent administration of high-dose cisplatin with radiotherapy is more efficacious than radiotherapy alone in patients with locally advanced head and neck cancer and does not cause an undue number of late complications [19318632] BACKGROUND Chemotherapy with cisplatin ( P ) and 5-fluorouracil ( F ) followed by radiotherapy in patients who respond to chemotherapy is an alternative to total laryngectomy for patients with locally advanced larynx and hypopharynx cancer . Data suggest that docetaxel ( T ) may add to the efficacy of PF . The objective of this trial was to determine whether adding T to PF could increase the larynx preservation rate . METHODS Patients who had larynx and hypopharynx cancer that required total laryngectomy were r and omly assigned to receive three cycles of TPF or PF . Patients who responded to chemotherapy received radiotherapy with or without additional chemotherapy . Patients who did not respond to chemotherapy underwent total laryngectomy followed by radiotherapy with or without additional chemotherapy . The primary endpoint was 3-year larynx preservation rate . Secondary endpoints included acute toxicities and overall response . All statistical tests were two-sided . RESULTS Baseline patient and tumor characteristics were well balanced between the TPF ( n = 110 ) and PF ( n = 103 ) groups . With a median follow-up of 36 months , the 3-year actuarial larynx preservation rate was 70.3 % with TPF vs 57.5 % with PF ( difference = 12.8 % ; P = .03 ) . Patients in the TPF group had more grade 2 alopecia , grade 4 neutropenia , and febrile neutropenia , whereas patients in the PF group had more grade 3 and 4 stomatitis , thrombocytopenia , and grade 4 creatinine elevation . The overall response was 80.0 % in the TPF group vs 59.2 % in the PF group ( difference = 20.8 % ; P = .002 ) . CONCLUSIONS In patients with advanced larynx and hypopharynx carcinomas , TPF induction chemotherapy was superior to the PF regimen in terms of overall response rate . These results suggest that larynx preservation could be achieved for a higher proportion of patients [19357741] BACKGROUND Management of advanced head and neck carcinoma is a challenging proposition . Presently concomitant chemo-irradiation has become the st and ard of care in such patients . Many chemotherapeutic drugs have shown radio-sensitising effects when used concomitantly along with radiation . The present study was carried out with the objective of assessing the feasibility and efficacy of low dose gemcitabine as radiosensitizer when used during radical radiotherapeutic management of patients with locally advanced head and neck carcinomas . PATIENTS AND METHODS From November 2000 to March 2003 , eighty histopathologically proven cases of squamous cell head and neck carcinoma were included in this trial , 40 patients were r and omly assigned to receive radiotherapy alone and 40 patients to receive gemcitabine along with radiotherapy . RESULTS All patients were assessable for toxicity and response . Severe mucositis ( WHO level 5 reactions were observed in 67 % patients in the CT/RT group vs 16 % patients in the RT only group . No severe hematological toxicity was seen . The rates of complete and partial responses were 42.5 % & 57.5 % respectively for RT only and 62.5 % & 37.5 % , respectively for CT/RT group . There was no significant difference in the response rates at the end of treatment but disease free survival at three years was better in the CT/RT group ( 63.3 % vs 20 % ) . Nine of the 17 patients with complete response in the radiation only group developed relapse while no relapses were seen in CT/RT group . CONCLUSION In the present study the combination of gemcitabine and radiotherapy has not shown any statistical difference in locoregional control but survival advantage was seen as compared to radiotherapy alone . At the same time more mucosal and skin toxicity was encountered when Gemcitabine is given concurrently with radiation [19176454] BACKGROUND Both induction chemotherapy followed by irradiation and concurrent chemotherapy and radiotherapy have been reported as valuable alternatives to total laryngectomy in patients with advanced larynx or hypopharynx cancer . We report results of the r and omized phase 3 trial 24954 from the European Organization for Research and Treatment of Cancer . METHODS Patients with resectable advanced squamous cell carcinoma of the larynx ( tumor stage T3-T4 ) or hypopharynx ( T2-T4 ) , with regional lymph nodes in the neck staged as N0-N2 and with no metastasis , were r and omly assigned to treatment in the sequential ( or control ) or the alternating ( or experimental ) arm . In the sequential arm , patients with a 50 % or more reduction in primary tumor size after two cycles of cisplatin and 5-fluorouracil received another two cycles , followed by radiotherapy ( 70 Gy total ) . In the alternating arm , a total of four cycles of cisplatin and 5-fluorouracil ( in weeks 1 , 4 , 7 , and 10 ) were alternated with radiotherapy with 20 Gy during the three 2-week intervals between chemotherapy cycles ( 60 Gy total ) . All nonresponders underwent salvage surgery and postoperative radiotherapy . The Kaplan-Meier method was used to obtain time-to-event data . RESULTS The 450 patients were r and omly assigned to treatment ( 224 to the sequential arm and 226 to the alternating arm ) . Median follow-up was 6.5 years . Survival with a functional larynx was similar in sequential and alternating arms ( hazard ratio of death and /or event = 0.85 , 95 % confidence interval = 0.68 to 1.06 ) , as were median overall survival ( 4.4 and 5.1 years , respectively ) and median progression-free interval ( 3.0 and 3.1 years , respectively ) . Grade 3 or 4 mucositis occurred in 64 ( 32 % ) of the 200 patients in the sequential arm who received radiotherapy and in 47 ( 21 % ) of the 220 patients in the alternating arm . Late severe edema and /or fibrosis was observed in 32 ( 16 % ) patients in the sequential arm and in 25 ( 11 % ) in the alternating arm . CONCLUSIONS Larynx preservation , progression-free interval , and overall survival were similar in both arms , as were acute and late toxic effects [10601378] BACKGROUND We design ed a r and omized clinical trial to test whether the addition of three cycles of chemotherapy during st and ard radiation therapy would improve disease-free survival in patients with stages III and IV ( i.e. , advanced oropharynx carcinoma ) . METHODS A total of 226 patients have been entered in a phase III multicenter , r and omized trial comparing radiotherapy alone ( arm A ) with radiotherapy with concomitant chemotherapy ( arm B ) . Radiotherapy was identical in the two arms , delivering , with conventional fractionation , 70 Gy in 35 fractions . In arm B , patients received during the period of radiotherapy three cycles of a 4-day regimen containing carboplatin ( 70 mg/m(2 ) per day ) and 5-fluorouracil ( 600 mg/m(2 ) per day ) by continuous infusion . The two arms were equally balanced with regard to age , sex , stage , performance status , histology , and primary tumor site . RESULTS Radiotherapy compliance was similar in the two arms with respect to total dose , treatment duration , and treatment interruption . The rate of grade s 3 and 4 mucositis was statistically significantly higher in arm B ( 71 % ; 95 % confidence interval [ CI ] = 54%-85 % ) than in arm A ( 39 % ; 95 % CI = 29%-56 % ) . Skin toxicity was not different between the two arms . Hematologic toxicity was higher in arm B as measured by neutrophil count and hemoglobin level . Three-year overall actuarial survival and disease-free survival rates were , respectively , 51 % ( 95 % CI = 39%-68 % ) versus 31 % ( 95 % CI = 18%-49 % ) and 42 % ( 95 % CI = 30%-57 % ) versus 20 % ( 95 % CI = 10%-33 % ) for patients treated with combined modality versus radiation therapy alone ( P = .02 and .04 , respectively ) . The locoregional control rate was improved in arm B ( 66 % ; 95 % CI = 51%-78 % ) versus arm A ( 42 % ; 95 % CI = 31%-56 % ) . CONCLUSION The statistically significant improvement in overall survival that was obtained supports the use of concomitant chemotherapy as an adjunct to radiotherapy in the management of carcinoma of the oropharynx [20032123] BACKGROUND Concomitant chemoradiotherapy ( CT/RT ) is the st and ard treatment of locally advanced squamous cell carcinoma of the head and neck ( SCCHN ) . We evaluated the efficacy of induction docetaxel ( Taxotere ) , cisplatin , and 5-fluorouracil ( TPF ) before CT/RT versus CT/RT alone . PATIENTS AND METHODS Patients with stage III-IVM0 SCCHN , Eastern Cooperative Oncology Group performance status of zero to one , were r and omly assigned to receive CT/RT alone ( arm A : two cycles of cisplatin 20 mg/m(2 ) , days1 - 4 , plus 5-fluorouracil 800 mg/m(2)/day 96 h continuous infusion , during weeks 1 and 6 of radiotherapy ) or three cycles of TPF ( arm B : docetaxel 75 mg/m(2 ) and cisplatin 80 mg/m(2 ) , day 1 , and 5-fluorouracil 800 mg/m(2)/day 96 h continuous infusion , every 3 weeks ) followed by the same CT/RT . The primary end point was the rate of radiologic complete response ( CR ) at 6 - 8 weeks after the end of CT/RT . RESULTS A total of 101 patients were r and omly allocated to the study ( 51 arm A ; 50 arm B ) . CR rates were 21.2 % ( arm A ) versus 50 % ( arm B ) . Median progression-free survival and overall survival were , respectively , 19.7 and 33.3 months ( arm A ) and 30.4 and 39.6 months ( arm B ) . Hematologic and non-hematologic toxic effects during CT/RT were similar in the two arms . CONCLUSION Induction TPF followed by CT/RT was associated with higher radiologic CR in patients with locally advanced SCCHN with no negative impact on CT/RT feasibility [26644536] PURPOSE No r and omized trials have been conducted to directly compare radiotherapy ( RT ) with concomitant cisplatin ( CDDP ) versus concomitant cetuximab ( CTX ) as first-line treatment of locally advanced squamous cell carcinoma of the head and neck . In this r and omized trial , we compared these two treatment regimens in terms of compliance , toxicity , and efficacy . PATIENTS AND METHODS Eligible patients were r and omly assigned in a 1:1 ratio to receive either CDDP 40 mg/m(2 ) once per week or CTX 400 mg/m(2 ) as loading dose followed by CTX 250 mg/m(2 ) once per week concomitant to radical RT . For primary end points , compliance to treatment was defined as number of days of treatment discontinuation and drug dosage reduction . The acute toxicity rate was defined according to the National Cancer Institute Common Toxicity Criteria . Efficacy end points were local recurrence-free survival , metastasis-free survival , cancer-specific survival , and overall survival . RESULTS The study was discontinued early because of slow accrual after the enrollment of 70 patients . RT discontinuation for more than 10 days occurred in 13 % of patients given CTX and 0 % given CDDP ( P = .05 ) . Drug dosage reduction occurred in 34 % given CTX and 53 % given CDDP ( difference not significant ) . Toxicity profiles differed between the two arms , with hematologic , renal , and GI toxicities more frequent in the CDDP arm , and cutaneous toxicity and the need for nutritional support more frequent in the CTX arm . Serious adverse events related to treatment , including four versus one toxic deaths , were higher in the CTX arm ( 19 % v 3 % , P = .044 ) . Locoregional control , patterns of failure , and survivals were similar between the treatment arms . CONCLUSION CTX concomitant to RT lowered compliance and increased acute toxicity rates . Efficacy outcomes were similar in both arms . These results raise the issue of appropriately selecting patients with head and neck cancer who can benefit from CTX in combination with RT [16275937] PURPOSE To compare the antitumor activity and toxicity of the two induction chemotherapy treatments of paclitaxel , cisplatin , and fluorouracil ( FU ; PCF ) versus st and ard cisplatin and FU ( CF ) , both followed by chemoradiotherapy ( CRT ) , in locally advanced head and neck cancer ( HNC ) . PATIENTS AND METHODS Eligibility criteria included biopsy-proven , previously untreated , stage III or IV locally advanced HNC . Patients received either CF ( cisplatin 100 mg/m2 on day 1 plus FU 1000 [ corrected ] mg/m2 continuous infusion on days 1 through 5 ) or PCF ( paclitaxel 175 mg/m2 on day 1 , cisplatin 100 mg/m2 on day 2 , and FU 500 mg/m2 continuous infusion on days 2 through 6 ) ; both regimens were administered for three cycles every 21 days . Patients with complete response ( CR ) or partial response of greater than 80 % in primary tumor received additional CRT ( cisplatin 100 mg/m2 on days 1 , 22 , and 43 plus 70 Gy ) . RESULTS A total of 382 eligible patients were r and omly assigned to CF ( n = 193 ) or PCF ( n = 189 ) . The CR rate was 14 % in the CF arm v 33 % in the PCF arm ( P < .001 ) . Median time to treatment failure was 12 months in the CF arm compared with 20 months in the PCF arm ( log-rank test , P = .006 ; Tarone-Ware , P = .003 ) . PCF patients had a trend to longer overall survival ( OS ; 37 months in CF arm v 43 months in PCF arm ; log-rank test , P = .06 ; Tarone-Ware , P = .03 ) . This difference was more evident in patients with unresectable disease ( OS : 26 months in CF arm v 36 months in PCF arm ; log-rank test , P = .04 ; Tarone-Ware , P = .03 ) . CF patients had a higher occurrence of grade 2 to 4 mucositis than PCF patients ( 53 % v 16 % , respectively ; P < .001 ) . CONCLUSION Induction chemotherapy with PCF was better tolerated and result ed in a higher CR rate than CF . However , new trials that compare induction chemotherapy plus CRT versus CRT alone are needed to better define the role of neoadjuvant treatment [17901953] Objectives We conducted a multicentric r and omized phase II trial comparing 5-FU continuous infusion ( PF ) and cisplatin , UFT and vinorelbine ( UFTVP ) as induction chemotherapy ( IC ) in locally advanced squamous cell head and neck cancer ( LA-SCHNC ) . Primary objective was complete response ( CR ) to IC and overall survival ( OS ) was a secondary objective . Material s and methods PF : cisplatin 100 mg/m2 i.v . Day 1 ( D1 ) and 5-FU 1,000 mg/m2 per day i.v . continous infusion D1–D5 , every 21 days . UFTVP : cisplatin 100 mg/m2 i.v . D1 ; UFT 200 mg/m2 per day p.o . D1–D21 and vinorelbine 25 mg/m2 i.v . D1 and D8 , every 21 days . Four IC courses were planned in both arms . Results A total of 206 patients ( pts ) were included ( PF/UFTVP : 99/107 ) : oral cavity : 8%/10 % , oropharynx : 20%/25 % , hypopharynx : 17%/14 % , larynx : 54%/50 % . Stage ( TNM , 2002 ) : III : 41%/35 % , IVA : 23%/27 % , IVB : 35%/38 % . Complete response to IC : PF:36%/UFTVP:31 % ( P : no significative ( NS ) ) . G 3–4 toxicity ( PF/UFTVP ) : neutropenia : 52%/72 % ; febrile neutropenia : 3%/20 % ( P < 0.001 ) ; anaemia:1%/14 % ( P < 0.001 ) ; trombocytopenia : 5%/0 % ( P = 0.02 ) ; mucositis : 15%/7 % ( P < 0.001 ) . Deaths during IC : 2(2%)/3(3 % ) . IC with UFTVP was associated with a favourable OS in the Cox analysis ( actuarial 5 year OS : 49 % vs. 34 % ; HR : 0.67 , 95 % CI : 0.47–0.95 , P : 0.03 ) . Conclusions Although clinical response is equal in both arms , overall survival ( Cox ) is better in the UFTVP arm . Febrile neutropenia and anaemia were more frequent with UFTVP while mucositis and trombocytopenia were more severe with PF [15629602] PURPOSE Previous r and omized trials have shown a benefit with concurrent use of the hypoxic cell cytotoxin mitomycin C ( MC ) and radiation ( RT ) in the management of squamous cell cancer of the head and neck ( SCCHN ) . We conducted a r and omized trial comparing MC with porfiromycin ( POR ) in combination with RT in the management of SCCHN . METHODS AND MATERIAL S Between 1992 and 1999 , 128 patients with SCCHN were enrolled in this prospect i ve r and omized trial . Patients were stratified by management intent , and balanced with respect to stage and site of disease . They were r and omized to receive MC ( 15 mg/M(2 ) ) or POR ( 40 mg/M(2 ) ) on Days 5 and 47 ( or last day ) of RT . Of 121 evaluable patients , 61 were r and omized to MC and 60 to POR . Patients were treated with st and ard daily RT to a total median dose of 64 Gy over 47 days . Patients were well balanced with respect to management intent , stage , site , age , sex , hemoglobin levels , tumor grade , radiation dose , and days on treatment . RESULTS There were no significant differences between the two arms with respect to acute hematologic or nonhematologic toxicities . As of January 2003 with a median follow-up of 6.3 years , there have been 19 local relapses ( 4 MC vs. 15 POR ) , 21 regional relapses ( 7 MC vs. 14 POR ) , 24 distant metastases ( 11 MC vs. 13 POR ) , and 66 deaths ( 33 MC vs. 33 POR ) . MC was superior to POR with respect to 5-year local relapse-free survival ( 91.6 % vs. 72.7 % , p = 0.01 ) , local-regional relapse-free survival ( 82 % vs. 65.3 % , p = 0.05 ) , and disease-free survival ( 72.8 % vs. 52.9 % , p = 0.026 ) . There were no significant differences between the two arms with respect to overall survival ( 49.2 % vs. 54.4 % ) or distant metastasis-free rate ( 79.9 % vs. 75.9 % ) . CONCLUSIONS Despite promising pre clinical data , and an acceptable toxicity profile , POR was inferior to MC as an adjunct to RT in the management of SCCHN . This r and omized trial emphasizes the need for r and omized studies to evaluate new agents in the management of SCCHN [23414589] BACKGROUND The relative efficacy of the addition of induction chemotherapy to chemoradiotherapy compared with chemoradiotherapy alone for patients with head and neck cancer is unclear . The PARADIGM study is a multicentre open-label phase 3 study comparing the use of docetaxel , cisplatin , and fluorouracil ( TPF ) induction chemotherapy followed by concurrent chemoradiotherapy with cisplatin-based concurrent chemoradiotherapy alone in patients with locally advanced head and neck cancer . METHODS Adult patients with previously untreated , non-metastatic , newly diagnosed head and neck cancer were eligible . Patients were eligible if their tumour was either unresectable or of low surgical curability on the basis of advanced tumour stage ( 3 or 4 ) or regional-node stage ( 2 or 3 , except T1N2 ) , or if they were a c and i date for organ preservation . Patients were r and omly assigned ( in a 1:1 ratio ) to receive either induction chemotherapy with three cycles of TPF followed by concurrent chemoradiotherapy with either docetaxel or carboplatin or concurrent chemoradiotherapy alone with two cycles of bolus cisplatin . A computer-generated r and omisation schedule using minimisation was prepared and the treatment assignment was done central ly at one of the study sites . Patients , study staff , and investigators were not masked to group assignment . Stratification factors were WHO performance status , primary disease site , and stage . The primary endpoint was overall survival . Analysis was by intention to treat . Patient accrual was terminated in December , 2008 , because of slow enrolment . The trial is registered with Clinical Trials.gov , number NCT00095875 . FINDINGS Between Aug 24 , 2004 , and Dec 29 , 2008 , we enrolled 145 patients across 16 sites . After a median follow-up of 49 months ( IQR 39 - 63 ) , 41 patients had died-20 in the induction chemotherapy followed by chemoradiotherapy group and 21 in the chemoradiotherapy alone group . 3-year overall survival was 73 % ( 95 % CI 60 - 82 ) in the induction therapy followed by chemoradiotherapy group and 78 % ( 66 - 86 ) in the chemoradiotherapy alone group ( hazard ratio 1·09 , 95 % CI 0·59 - 2·03 ; p=0·77 ) . More patients had febrile neutropenia in the induction chemotherapy followed by chemoradiotherapy group ( 16 patients ) than in the chemoradiotherapy alone group ( one patient ) . INTERPRETATION Although survival results were good in both groups there was no difference noted between those patients treated with induction chemotherapy followed by chemoradiotherapy and those who received chemoradiotherapy alone . We can not rule out the possibility of a difference in survival going undetected due to early termination of the trial . Clinicians should still use their best judgment , based on the available data , in the decision of how to best treat patients . The addition of induction chemotherapy remains an appropriate approach for advanced disease with high risk for local or distant failure . FUNDING Sanofi-Aventis [25049329] PURPOSE Induction chemotherapy ( IC ) before radiotherapy lowers distant failure ( DF ) rates in locally advanced squamous cell carcinoma of the head and neck ( SCCHN ) . The goal of this phase III trial was to determine whether IC before chemoradiotherapy ( CRT ) further improves survival compared with CRT alone in patients with N2 or N3 disease . PATIENTS AND METHODS Treatment-naive patients with nonmetastatic N2 or N3 SCCHN were r and omly assigned to CRT alone ( CRT arm ; docetaxel , fluorouracil , and hydroxyurea plus radiotherapy 0.15 Gy twice per day every other week ) versus two 21-day cycles of IC ( docetaxel 75 mg/m(2 ) on day 1 , cisplatin 75 mg/m(2 ) on day 1 , and fluorouracil 750 mg/m(2 ) on days 1 to 5 ) followed by the same CRT regimen ( IC + CRT arm ) . The primary end point was overall survival ( OS ) . Secondary end points included DF-free survival , failure pattern , and recurrence-free survival ( RFS ) . RESULTS A total of 285 patients were r and omly assigned . The most common grade 3 to 4 toxicities during IC were febrile neutropenia ( 11 % ) and mucositis ( 9 % ) ; during CRT ( both arms combined ) , they were mucositis ( 49 % ) , dermatitis ( 21 % ) , and leukopenia ( 18 % ) . Serious adverse events were more common in the IC arm ( 47 % v 28 % ; P = .002 ) . With a minimum follow-up of 30 months , there were no statistically significant differences in OS ( hazard ratio , 0.91 ; 95 % CI , 0.59 to 1.41 ) , RFS , or DF-free survival . CONCLUSION IC did not translate into improved OS compared with CRT alone . However , the study was underpowered because it did not meet the planned accrual target , and OS was higher than predicted in both arms . IC can not be recommended routinely in patients with N2 or N3 locally advanced SCCHN [18222010] BACKGROUND AND PURPOSE Post-operative radiotherapy is indicated for the treatment of head and neck cancers . In vitro , chemotherapy potentiates the cytotoxic effects of radiation . We report the results of a r and omized trial testing post-operative radiotherapy alone versus concomitant carboplatin and radiotherapy for head and neck cancers with lymph node involvement . MATERIAL S AND METHODS The study involved patients undergoing curative-intent surgery for head and neck cancers with histological evidence of lymph node involvement . Patients were r and omly assigned to receive radiotherapy alone ( 54 - 72Gy , 30 - 40 fractions , 6 - 8 weeks ) or identical treatment plus concomitant Carboplatin ( 50mg/m(2 ) administered by IV infusion twice weekly ) . RESULTS Between February 1994 and June 2002 , 144 patients were included . With a median follow-up of 106 months ( 95 % confidence interval ( CI ) [ 92 - 119 ] ) , the 2-year rate of loco-regional control was 73 % ( 95 % CI : 0.61 - 0.84 ) in the combined treatment group and 68 % ( 95 % CI : 0.57 - 0.80 ) in the radiotherapy group ( p=0.26 ) . Overall survival did not differ significantly between groups ( hazard ratio for death , 1.05 ; 95 % CI : 0.69 - 1.60 ; p=0.81 ) . CONCLUSIONS Twice-weekly administration of carboplatin concomitant to post-operative radiotherapy did not improve local control or overall survival rates in this population of patients with node-positive head and neck cancers [24256848] BACKGROUND Concurrent chemoradiotherapy ( CCRT ) is the st and ard treatment for patients with unresectable , nonmetastatic locoregionally advanced squamous-cell carcinoma of the head and neck ( LASCCHN ) . This r and omized , open-label , phase III clinical trial compared the efficacy between st and ard CCRT and two different induction chemotherapy ( ICT ) regimens followed by CCRT . PATIENTS AND METHODS Patients with untreated LASCCHN were r and omly assigned to ICT ( three cycles ) , with either docetaxel ( Taxotere ) , cisplatin and 5-fluorouracil ( TPF arm ) or cisplatin and 5-fluorouracil ( PF arm ) , followed by CCRT [ 7 weeks of radiotherapy ( RT ) with cisplatin 100 mg/m(2 ) on days 1 , 22 and 43 ] ; or 7 weeks of CCRT alone . The primary end points were progression-free survival ( PFS ) and time-to-treatment failure ( TTF ) . RESULTS In the intention-to-treat ( ITT ) population ( n = 439 ) , the median PFS times were 14.6 ( 95 % CI , 11.6 - 20.4 ) , 14.3 ( 95 % CI , 11.8 - 19.3 ) and 13.8 months ( 95 % CI , 11.0 - 17.5 ) at TPF-CCRT , PF-CCRT and CCRT arms , respectively ( log-rank P = 0.56 ) . The median TTF were 7.9 ( 95 % CI , 5.9 - 11.8 ) , 7.9 ( 95 % CI , 6.5 - 11.8 ) and 8.2 months ( 95 % CI , 6.7 - 12.6 ) for TPF-CCRT , PF-CCRT and CCRT alone , respectively ( log-rank P = 0.90 ) . There were no statistically significant differences for overall survival ( OS ) . Toxic effects from ICT-CCRT were manageable . CONCLUSION Overall , this trial failed to show any advantage of ICT-CCRT over CCRT alone in patients with unresectable LASCCHN [12758236] BACKGROUND AND PURPOSE Single agent mitomycin c ( MMC ) has been shown to improve the outcome of radiotherapy in single institution trials . In order to confirm these findings in a broader worldwide setting , the International Atomic Energy Agency ( IAEA ) initiated a multicentre trial r and omising between radiotherapy alone versus radiotherapy plus MMC . MATERIAL AND METHODS Patients with advanced head and neck cancer were treated with primary curative radiotherapy ( 66 Gy in 33 fractions with five fractions per week ) + /-a single injection ( 15 mg/m(2 ) ) of MMC at the end of the first week of radiotherapy . Stratification parameters were tumour localization , T-stage , N-stage , and institution . A total of 558 patients were recruited in the trial from February 1996 to December 1999 . Insufficient accrual and reporting led to the exclusion of three centres . The final study population consisted of 478 patients from seven centres . Patients had stage III ( n=223 ) or stage IV ( n=255 ) squamous cell carcinoma of the oral cavity ( n=230 ) , oropharynx ( n=140 ) , hypopharynx ( n=65 ) or larynx ( n=43 ) . Prognostic factors like age , gender , site , size , differentiation and stage were well balanced between the two arms . RESULTS The haematological side effects of MMC were very modest ( < 5 % grade 3 - 4 ) and did not require any specific interventions . Furthermore , MMC did not enhance the incidence or severity of acute and late radiation side effects . Confluent mucositis and dry skin desquamation was common , occurring in 56 % and 62 % of patients , respectively . The overall 3-year primary locoregional tumour control , disease-specific and overall survival rates were 19 , 36 and 30 % , respectively . Gender , haemoglobin drop , tumour site , tumour and nodal stage were significant parameters for loco-regional tumour control . There was no significant effect of MMC on locoregional control or survival , except for the 161 N0 patients , where MMC result ed in a better loco-regional control ( 3-year estimate 16 % vs. 29 % , P=0.01 ) . CONCLUSIONS The study did not show any major influence of MMC on loco-regional tumour control , survival or morbidity after primary radiotherapy in stage III-IV head and neck cancer except in N0 patients where loco-regional control was significantly improved [2363468] The objective of the study was to evaluate the effect of neoadjuvant chemotherapy on the survival of patients with oropharyngeal cancer . Patients with a squamous cell carcinoma of the oropharynx for whom curative radiotherapy or surgery was considered feasible were entered in a multicentric r and omized trial comparing neoadjuvant chemotherapy followed by loco-regional treatment to the same loco-regional treatment without chemotherapy . The loco-regional treatment consisted either of surgery plus radiotherapy or of radiotherapy alone . Three cycles of chemotherapy consisting of Cisplatin ( 100 mg/m2 ) on day 1 followed by a 24-hour i.v . infusion of fluorouracil ( 1000 mg/m2/day ) for 5 days were delivered every 21 days . 2–3 weeks after the end of chemotherapy , local treatment was performed . The trial was conducted by the Groupe d'Etude des Tumeurs de la Tête Et du Cou ( GETTEC ) . A total of 318 patients were enrolled in the study between 1986 and 1992 . Overall survival was significantly better ( P = 0.03 ) in the neoadjuvant chemotherapy group than in the control group , with a median survival of 5.1 years versus 3.3 years in the no chemotherapy group . The effect of neoadjuvant chemotherapy on event-free survival was smaller and of borderline significance ( P = 0.11 ) . Stratification of the results on the type of local treatment , surgery plus radiotherapy or radiotherapy alone , did not reveal any heterogeneity in the effect of chemotherapy . © 2000 Cancer Research Campaign [25002723] PURPOSE To report results of a r and omized phase II trial ( Radiation Therapy Oncology Group RTOG-0234 ) examining concurrent chemoradiotherapy and cetuximab in the postoperative treatment of patients with squamous cell carcinoma of the head and neck ( SCCHN ) with high-risk pathologic features . PATIENTS AND METHODS Eligibility required pathologic stage III to IV SCCHN with gross total resection showing positive margins and /or extracapsular nodal extension and /or two or more nodal metastases . Patients were r and omly assigned to 60 Gy radiation with cetuximab once per week plus either cisplatin 30 mg/m(2 ) or docetaxel 15 mg/m(2 ) once per week . RESULTS Between April 2004 and December 2006 , 238 patients were enrolled . With a median follow-up of 4.4 years , 2-year overall survival ( OS ) was 69 % for the cisplatin arm and 79 % for the docetaxel arm ; 2-year disease-free survival ( DFS ) was 57 % and 66 % , respectively . Patients with p16-positive oropharynx tumors showed markedly improved survival outcome relative to patients with p16-negative oropharynx tumors . Grade 3 to 4 myelosuppression was observed in 28 % of patients in the cisplatin arm and 14 % in the docetaxel arm ; mucositis was observed in 56 % and 54 % , respectively . DFS in this study was compared with that in the chemoradiotherapy arm of the RTOG-9501 trial ( Phase III Intergroup Trial of Surgery Followed by Radiotherapy Versus Radiochemotherapy for Resectable High Risk Squamous Cell Carcinoma of the Head and Neck ) , which had a hazard ratio of 0.76 for the cisplatin arm versus control ( P = .05 ) and 0.69 for the docetaxel arm versus control ( P = .01 ) , reflecting absolute improvement in 2-year DFS of 2.5 % and 11.1 % , respectively . CONCLUSION The delivery of postoperative chemoradiotherapy and cetuximab to patients with SCCHN is feasible and tolerated with predictable toxicity . The docetaxel regimen shows favorable outcome with improved DFS and OS relative to historical controls and has commenced formal testing in a phase II/III trial [14645636] BACKGROUND Induction chemotherapy with cisplatin plus fluorouracil followed by radiotherapy is the st and ard alternative to total laryngectomy for patients with locally advanced laryngeal cancer . The value of adding chemotherapy to radiotherapy and the optimal timing of chemotherapy are unknown . METHODS We r and omly assigned patients with locally advanced cancer of the larynx to one of three treatments : induction cisplatin plus fluorouracil followed by radiotherapy , radiotherapy with concurrent administration of cisplatin , or radiotherapy alone . The primary end point was preservation of the larynx . RESULTS A total of 547 patients were r and omly assigned to one of the three study groups . The median follow-up period was 3.8 years . At two years , the proportion of patients who had an intact larynx after radiotherapy with concurrent cisplatin ( 88 percent ) differed significantly from the proportions in the groups given induction chemotherapy followed by radiotherapy ( 75 percent , P=0.005 ) or radiotherapy alone ( 70 percent , P<0.001 ) . The rate of locoregional control was also significantly better with radiotherapy and concurrent cisplatin ( 78 percent , vs. 61 percent with induction cisplatin plus fluorouracil followed by radiotherapy and 56 percent with radiotherapy alone ) . Both of the chemotherapy-based regimens suppressed distant metastases and result ed in better disease-free survival than radiotherapy alone . However , overall survival rates were similar in all three groups . The rate of high- grade toxic effects was greater with the chemotherapy-based regimens ( 81 percent with induction cisplatin plus fluorouracil followed by radiotherapy and 82 percent with radiotherapy with concurrent cisplatin , vs. 61 percent with radiotherapy alone ) . The mucosal toxicity of concurrent radiotherapy and cisplatin was nearly twice as frequent as the mucosal toxicity of the other two treatments during radiotherapy . CONCLUSIONS In patients with laryngeal cancer , radiotherapy with concurrent administration of cisplatin is superior to induction chemotherapy followed by radiotherapy or radiotherapy alone for laryngeal preservation and locoregional control [21279703] The objective of this study was to compare concomitant chemoradiotherapy based on weekly low-dose gemcitabine versus weekly low-dose paclitaxel in locally advanced head and neck squamous cell carcinoma . Previously , untreated patients with locally advanced squamous cell carcinoma of the head and neck were r and omly assigned to one of the two concomitant chemoradiation regimens : ( 1 ) weekly gemcitabine at a dose of 100 mg/m2 over 30 min 1–2 h before radiotherapy and ( 2 ) weekly paclitaxal at a dose of 20 mg/m2 over 60 min 4–6 h before radiotherapy . The planned radiotherapy dose was 65 Gy over 6.5 weeks in 32 setting s. Two hundred and sixteen patients were r and omly divided into 2 groups : group A ( 110 patients ) and group B ( 106 patients ) who received concomitant weekly low-dose gemcitabine and low-dose paclitaxal , respectively , with the radiotherapy protocol . The hematological toxicity was generally mild . On the contrary , non-hematologic toxicities were severe . Grade III mucositis occurred in 36 % in group A and in 24 % in group B ( P = 0.04 ) . Moreover , grade III dermatitis were encountered in 24 % in group A and 13 % in group B ( P = 0.049 ) . Thirty-two ( 29 % ) of group A and 18(17 % ) of group B patients required enteral or parenteral feeding ( P = 0.01 ) . Sixteen ( 15 % ) of group A and 6 ( 6 % ) of group B required enteral or parenteral feeding that lasted for 6 months ( P = 0.03 ) . Regarding the late effect on swallowing , 8 % of patients in group A and 2 % of patients in group B required enteral or parenteral feeding for more than 6 months ( P = 0.035 ) . Response rates were 78 and 89 % in groups A and B , respectively ( P = 0.038 ) . The 2-year progression-free survival figures were 54 and 64 % of groups A and B , respectively ; however , the 2-year overall survival figures were 56 and 67 % , respectively . On the other h and , the 3-year progression-free survival figures were 39 and 48 % for groups A and B , respectively , while the 3-year overall survival figures were 45 and 49 % , respectively ( P = 0.05 ) . Both concomitant chemoradiotherapy regimens were easily given in the outpatient clinic . The regimen based on paclitaxel was significantly more tolerable and effective ; however , the difference was not enormous [25596659] BACKGROUND We aim ed to compare panitumumab , a fully human monoclonal antibody against EGFR , plus radiotherapy with chemoradiotherapy in patients with unresected , locally advanced squamous-cell carcinoma of the head and neck . METHODS In this international , open-label , r and omised , controlled , phase 2 trial , we recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 22 sites in eight countries worldwide . Patients aged 18 years and older with stage III , IVa , or IVb , previously untreated , measurable ( ≥ 10 mm for at least one dimension ) , locally advanced squamous-cell carcinoma of the head and neck ( non-nasopharygeal ) and an Eastern Cooperative Oncology Group performance status of 0 - 1 were r and omly assigned ( 2:3 ) by an independent vendor to open-label chemoradiotherapy ( two cycles of cisplatin 100 mg/m(2 ) during radiotherapy ) or to radiotherapy plus panitumumab ( three cycles of panitumumab 9 mg/kg every 3 weeks administered with radiotherapy ) using a stratified r and omisation with a block size of five . All patients received 70 - 72 Gy to gross tumour and 54 Gy to areas of sub clinical disease with accelerated fractionation radiotherapy . The primary endpoint was local-regional control at 2 years , analysed in all r and omly assigned patients who received at least one dose of their assigned protocol -specific treatment ( chemotherapy , radiation , or panitumumab ) . The trial is closed and this is the final analysis . This study is registered with Clinical Trials.gov , number NCT00547157 . FINDINGS Between Nov 30 , 2007 , and Nov 16 , 2009 , 152 patients were enrolled , and 151 received treatment ( 61 in the chemoradiotherapy group and 90 in the radiotherapy plus panitumumab group ) . Local-regional control at 2 years was 61 % ( 95 % CI 47 - 72 ) in the chemoradiotherapy group and 51 % ( 40 - 62 ) in the radiotherapy plus panitumumab group . The most frequent grade 3 - 4 adverse events were mucosal inflammation ( 25 [ 40 % ] of 62 patients in the chemoradiotherapy group vs 37 [ 42 % ] of 89 patients in the radiotherapy plus panitumumab group ) , dysphagia ( 20 [ 32 % ] vs 36 [ 40 % ] ) , and radiation skin injury ( seven [ 11 % ] vs 21 [ 24 % ] ) . Serious adverse events were reported in 25 ( 40 % ) of 62 patients in the chemoradiotherapy group and in 30 ( 34 % ) of 89 patients in the radiotherapy plus panitumumab group . INTERPRETATION Panitumumab can not replace cisplatin in the combined treatment with radiotherapy for unresected stage III-IVb squamous-cell carcinoma of the head and neck , and the role of EGFR inhibition in locally advanced squamous-cell carcinoma of the head and neck needs to be reassessed . FUNDING Amgen [11735172] AIMS A prospect i ve r and omized study was conducted to evaluate the benefit of adjuvant levamisole/UFT ( futraful and uracil ) chemotherapy in head and neck squamous cell carcinoma . METHODS Sixty-five patients with stage III and IV squamous cell carcinomas of oral cavity , oropharynx , hypopharynx and larynx with no distant metastasis were r and omized for the chemotherapy study . Thirty-one patients were r and omized for chemotherapy and two of them were subsequently excluded . In this study , a total of 29 patients on levamisole/UFT therapy and 34 patients on the control group were analysed . The main outcome was measured by the 5-year disease-free actuarial survival rate . RESULTS The rates of distant metastasis were 10 % for chemotherapy group and 32 % for control group ( P=0.06 ) . The 5-year disease-free actuarial survival rates for patients with and without adjuvant chemotherapy were 57 % and 39 % respectively ( P=0.207 ) . CONCLUSIONS A trend of better distant control in head and neck cancer patients with post-operative adjuvant oral chemotherapy was observed . The side effects were minimal . However , there was no statistically significant improvement in the overall long-term survival . It may be of value to conduct a large-scale multi-centre prospect i ve r and omized study to verify the efficacy of levamisole and UFT as post-operative adjuvant chemotherapy for the control of distant metastasis in high-risk population [20888709] PURPOSE The Head and Neck Intergroup conducted a Phase III r and omized trial to determine whether the addition weekly cisplatin to daily radiation therapy ( RT ) would improve survival in patients with unresectable squamous cell head- and -neck carcinoma . METHODS AND MATERIAL S Eligible patients were r and omized to RT ( 70 Gy at 1.8 - 2 Gy/day ) or to the identical RT with weekly cisplatin dosed at 20 mg/m(2 ) . Failure-free survival ( FFS ) and overall survival ( OS ) curves were estimated with the Kaplan-Meier method and compared with the log rank test . RESULTS Between 1982 and 1987 , 371 patients were accrued , and 308 patients were found eligible for analysis . Median follow-up was 62 months . The median FFS was 6.5 and 7.2 months for the RT and RT + cisplatin groups , respectively ( p = 0.30 ) . The p value for the treatment difference was p = 0.096 in multivariate modeling of FFS ( compared to a p = 0.30 in univariate analysis ) . Expected acute toxicities were significantly increased with the addition of cisplatin except for in-field RT toxicities . Late toxicities were not significantly different except for significantly more esophageal ( 9 % vs. 3 % , p = 0.03 ) and laryngeal ( 11 % vs. 4 % , p = 0.05 ) late toxicities in the RT + cisplatin group . CONCLUSION The addition of concurrent weekly cisplatin at 20 mg/m(2 ) to daily radiation did not improve survival , although there was evidence of activity . Low-dose weekly cisplatin seems to have modest tumor radiosensitization but can increase the risk of late swallowing complications [8985019] PURPOSE To report the final results of a prospect i ve r and omized trial that aim ed to evaluate efficacy and toxicity of concomitant postoperative radiotherapy and Cisplatin infusion in patients with Stage III or IV squamous cell carcinoma of the head and neck and histological evidence of extracapsular spread of tumor in lymph node metastase(s ) . METHODS AND MATERIAL S Radiotherapy was delivered using a daily dose of 1.7 Gy for the first 54 Gy and 1.8 to 2 Gy until the completion of the treatment . Cisplatin 50 mg i.v . with forced hydratation was given or not every week ( i.e. , seven to nine cycles ) concurrently with radiotherapy . A total of 44 patients were treated by irradiation only ( RT group ) and 39 by irradiation with chemotherapy ( CM group ) . RESULTS The RT group displayed a higher rate of loco-regional failures as compared to CM group ( 41 vs. 23 % ; p = 0.08 ) . The overall survival , the survival corrected for deaths by intercurrent disease , and the disease-free survival were better in CM group as compared to RT group with statistically significant differences . Survival without loco-regional treatment failure was better in the CM group , the difference being close to the level of significance ( p = 0.05 ) . Survival without distant metastases were comparable in the two therapeutic groups . Ten severe late complications were observed , four in the RT group ( 17 % ) and six in the CM group ( 22 % ) . Cox univariate analysis confirmed the importance of the therapeutic modality in predicting the overall survival , the survival corrected for deaths by intercurrent disease , and the disease-free survival . CONCLUSIONS The present final report of this phase III study confirms preliminary results . The concomitant use of 50 mg weekly Cisplatin infusion and postoperative radiation improved loco-regional control and survival . No significant increase of late radiation complications was observed in the CM group [28142468] 51 Background : To determine the efficacy , safety and tolerability of concurrent nimotuzumab ( monoclonal antibody against epidermal growth factor receptor ) used in combination with chemoradiation versus chemoradiation ( CRT ) alone in advanced inoperable squamous cell carcinoma of the head and neck ( SCCHN ) . METHODS 56 patients were r and omly assigned to either of the two treatment arms , nimotuzumab + CRT arm and CRT alone arm . Both arms received concurrent Cisplatin 30 mg/m2 repeated weekly for 6 - 7 cycles along with external beam radiotherapy 64 - 70 Gy ( 200cGy/day for 5 days a week for 6 - 7 weeks ) . Nimotuzumab arm additionally received nimotuzumab 200 mg weekly for 6 - 7 cycles . The patients were followed for 6 months after completion of CRT . The study end points were tumor response evaluation according to the RECIST Criteria version 1.1 and safety analysis using RTOG Acute Radiation Morbidity Scoring Criteria . Patients were evaluated weekly with hematologic tests and for adverse events like mucositis and dermatitis during the CRT . Tumor assessment was performed with clinical and endoscopic methods regularly during the CRT and then at 1 month , 3 months , and 6 months intervals after CRT . One MR imaging was done before starting the CRT to evaluate the baseline tumor characteristics , and another was done after the completion of CRT either at 3 months or 6 months or at both the intervals . RESULTS 25 patients each were evaluable in both the arms who completed the 6-month study . The overall response rate ( complete response + partial response ) was 96 % in nimotuzumab + CRT arm , whereas it was only 72 % in CRT alone arm after 6 months of completion of CRT , which is statistically significant ( p value = 0.0206 by Chi Square test ) . Additionally , nimotuzumab did not potentiate toxicities of CRT , and there was no significant difference in the acute radiation mucositis , dermatitis , or hematological toxicities in both the groups ( p value>>0.05 ) . CONCLUSIONS Nimotuzumab can be safely added to the st and ard CRT treatment for advanced inoperable SCCHN , to achieve better tumor response without potentiating toxicity [23182993] PURPOSE To report the long-term results of the Intergroup Radiation Therapy Oncology Group 91 - 11 study evaluating the contribution of chemotherapy added to radiation therapy ( RT ) for larynx preservation . PATIENTS AND METHODS Patients with stage III or IV glottic or supraglottic squamous cell cancer were r and omly assigned to induction cisplatin/fluorouracil ( PF ) followed by RT ( control arm ) , concomitant cisplatin/RT , or RT alone . The composite end point of laryngectomy-free survival ( LFS ) was the primary end point . RESULTS Five hundred twenty patients were analyzed . Median follow-up for surviving patients is 10.8 years . Both chemotherapy regimens significantly improved LFS compared with RT alone ( induction chemotherapy v RT alone : hazard ratio [ HR ] , 0.75 ; 95 % CI , 0.59 to 0.95 ; P = .02 ; concomitant chemotherapy v RT alone : HR , 0.78 ; 95 % CI , 0.78 to 0.98 ; P = .03 ) . Overall survival did not differ significantly , although there was a possibility of worse outcome with concomitant relative to induction chemotherapy ( HR , 1.25 ; 95 % CI , 0.98 to 1.61 ; P = .08 ) . Concomitant cisplatin/RT significantly improved the larynx preservation rate over induction PF followed by RT ( HR , 0.58 ; 95 % CI , 0.37 to 0.89 ; P = .0050 ) and over RT alone ( P < .001 ) , whereas induction PF followed by RT was not better than treatment with RT alone ( HR , 1.26 ; 95 % CI , 0.88 to 1.82 ; P = .35 ) . No difference in late effects was detected , but deaths not attributed to larynx cancer or treatment were higher with concomitant chemotherapy ( 30.8 % v 20.8 % with induction chemotherapy and 16.9 % with RT alone ) . CONCLUSION These 10-year results show that induction PF followed by RT and concomitant cisplatin/RT show similar efficacy for the composite end point of LFS . Locoregional control and larynx preservation were significantly improved with concomitant cisplatin/RT compared with the induction arm or RT alone . New strategies that improve organ preservation and function with less morbidity are needed [21300466] PURPOSE To compare the long-term outcome of treatment with concomitant cisplatin and hyperfractionated radiotherapy versus treatment with hyperfractionated radiotherapy alone in patients with locally advanced head and neck cancer . METHODS AND MATERIAL S From July 1994 to July 2000 , a total of 224 patients with squamous cell carcinoma of the head and neck were r and omized to receive either hyperfractionated radiotherapy alone ( median total dose , 74.4 Gy ; 1.2 Gy twice daily ; 5 days per week ) or the same radiotherapy combined with two cycles of cisplatin ( 20 mg/m(2 ) for 5 consecutive days during weeks 1 and 5 ) . The primary endpoint was the time to any treatment failure ; secondary endpoints were locoregional failure , metastatic failure , overall survival , and late toxicity assessed according to Radiation Therapy Oncology Group criteria . RESULTS Median follow-up was 9.5 years ( range , 0.1 - 15.4 years ) . Median time to any treatment failure was not significantly different between treatment arms ( hazard ratio [ HR ] , 1.2 [ 95 % confidence interval { CI } , 0.9 - 1.7 ; p = 0.17 ] ) . Rates of locoregional failure-free survival ( HR , 1.5 [ 95 % CI , 1.1 - 2.1 ; p = 0.02 ] ) , distant metastasis-free survival ( HR , 1.6 [ 95 % CI , 1.1 - 2.5 ; p = 0.02 ] ) , and cancer-specific survival ( HR , 1.6 [ 95 % CI , 1.0 - 2.5 ; p = 0.03 ] ) were significantly improved in the combined-treatment arm , with no difference in major late toxicity between treatment arms . However , overall survival was not significantly different ( HR , 1.3 [ 95 % CI , 0.9 - 1.8 ; p = 0.11 ] ) . CONCLUSIONS After long-term follow-up , combined-treatment with cisplatin and hyperfractionated radiotherapy maintained improved rates of locoregional control , distant metastasis-free survival , and cancer-specific survival compared to that of hyperfractionated radiotherapy alone , with no difference in major late toxicity [15128893] BACKGROUND Despite the use of resection and postoperative radiotherapy , high-risk squamous-cell carcinoma of the head and neck frequently recurs in the original tumor bed . We tested the hypothesis that concurrent postoperative administration of cisplatin and radiotherapy would improve the rate of local and regional control . METHODS Between September 9 , 1995 , and April 28 , 2000 , 459 patients were enrolled . After undergoing total resection of all visible and palpable disease , 231 patients were r and omly assigned to receive radiotherapy alone ( 60 to 66 Gy in 30 to 33 fractions over a period of 6 to 6.6 weeks ) and 228 patients to receive the identical treatment plus concurrent cisplatin ( 100 mg per square meter of body-surface area intravenously on days 1 , 22 , and 43 ) . RESULTS After a median follow-up of 45.9 months , the rate of local and regional control was significantly higher in the combined-therapy group than in the group given radiotherapy alone ( hazard ratio for local or regional recurrence , 0.61 ; 95 percent confidence interval , 0.41 to 0.91 ; P=0.01 ) . The estimated two-year rate of local and regional control was 82 percent in the combined-therapy group , as compared with 72 percent in the radiotherapy group . Disease-free survival was significantly longer in the combined-therapy group than in the radiotherapy group ( hazard ratio for disease or death , 0.78 ; 95 percent confidence interval , 0.61 to 0.99 ; P=0.04 ) , but overall survival was not ( hazard ratio for death , 0.84 ; 95 percent confidence interval , 0.65 to 1.09 ; P=0.19 ) . The incidence of acute adverse effects of grade 3 or greater was 34 percent in the radiotherapy group and 77 percent in the combined-therapy group ( P<0.001 ) . Four patients who received combined therapy died as a direct result of the treatment . CONCLUSIONS Among high-risk patients with resected head and neck cancer , concurrent postoperative chemotherapy and radiotherapy significantly improve the rates of local and regional control and disease-free survival . However , the combined treatment is associated with a substantial increase in adverse effects [19897418] BACKGROUND Previous results from our phase 3 r and omised trial showed that adding cetuximab to primary radiotherapy increased overall survival in patients with locoregionally advanced squamous-cell carcinoma of the head and neck ( LASCCHN ) at 3 years . Here we report the 5-year survival data , and investigate the relation between cetuximab-induced rash and survival . METHODS Patients with LASCCHN of the oropharynx , hypopharynx , or larynx with measurable disease were r and omly allocated in a 1:1 ratio to receive either comprehensive head and neck radiotherapy alone for 6 - 7 weeks or radiotherapy plus weekly doses of cetuximab : 400 mg/m(2 ) initial dose , followed by seven weekly doses at 250 mg/m(2 ) . R and omisation was done with an adaptive minimisation technique to balance assignments across stratification factors of Karnofsky performance score , T stage , N stage , and radiation fractionation . The trial was un-blinded . The primary endpoint was locoregional control , with a secondary endpoint of survival . Following discussion s with the US Food and Drug Administration , the data set was locked , except for queries to the sites about overall survival , before our previous report in 2006 , so that an independent review could be done . Analyses were done on an intention-to-treat basis . Following completion of treatment , patients underwent physical examination and radiographic imaging every 4 months for 2 years , and then every 6 months thereafter . The trial is registered at www . Clinical Trials.gov , number NCT00004227 . FINDINGS Patients were r and omly assigned to receive radiotherapy with ( n=211 ) or without ( n=213 ) cetuximab , and all patients were followed for survival . Up date d median overall survival for patients treated with cetuximab and radiotherapy was 49.0 months ( 95 % CI 32.8 - 69.5 ) versus 29.3 months ( 20.6 - 41.4 ) in the radiotherapy-alone group ( hazard ratio [ HR ] 0.73 , 95 % CI 0.56 - 0.95 ; p=0.018 ) . 5-year overall survival was 45.6 % in the cetuximab-plus-radiotherapy group and 36.4 % in the radiotherapy-alone group . Additionally , for the patients treated with cetuximab , overall survival was significantly improved in those who experienced an acneiform rash of at least grade 2 severity compared with patients with no rash or grade 1 rash ( HR 0.49 , 0.34 - 0.72 ; p=0.002 ) . INTERPRETATION For patients with LASCCHN , cetuximab plus radiotherapy significantly improves overall survival at 5 years compared with radiotherapy alone , confirming cetuximab plus radiotherapy as an important treatment option in this group of patients . Cetuximab-treated patients with prominent cetuximab-induced rash ( grade 2 or above ) have better survival than patients with no or grade 1 rash . FUNDING ImClone Systems , Merck KGaA , and Bristol-Myers Squibb [21233014] BACKGROUND At a minimum follow-up of 2 years , the TAX 324 study showed a significant survival benefit of induction chemotherapy with docetaxel , cisplatin , and fluorouracil ( TPF ) versus cisplatin and fluorouracil ( PF ) in locally advanced head and neck cancer . We report the long-term results at 5 years ' minimum follow-up . METHODS TAX 324 was a r and omised , open-label phase 3 trial comparing three cycles of TPF induction chemotherapy ( docetaxel 75 mg/m(2 ) , followed by intravenous cisplatin 100 mg/m(2 ) and fluorouracil 1000 mg/m(2 ) per day , administered as a continuous 24-h infusion for 4 days ) with three cycles of PF ( intravenous cisplatin 100 mg/m(2 ) , followed by fluorouracil 1000 mg/m(2 ) per day as a continuous 24-h infusion for 5 days ) in patients with stage III or IV squamous-cell carcinoma of the head or neck . Both regimens were followed by 7 weeks of chemoradiotherapy with concomitant weekly carboplatin . R and omisation was done central ly with the use of a biased-coin minimisation technique . At study entry , patients were stratified according to the site of the primary tumour , nodal status ( N0 or N1 vs N2 or N3 ) , and institution . For this long-term analysis , data as of Dec 1 , 2008 , were gathered retrospectively from patients ' medical records . Overall and progression-free survival were the primary endpoints . Tracheostomy and dependence on a gastric feeding tube were used as surrogate measures for treatment-related long-term toxicity . The intention-to-treat analysis included data from all 501 patients ( 255 TPF , 246 PF ) ; data from the initial analysis in 2005 were used for 61 patients who were lost to follow-up . TAX 324 was registered at Clinical Trials.gov , NCT00273546 . FINDINGS Median follow-up was 72·2 months ( 95 % CI 68·8 - 75·5 ) . Overall survival was significantly better after treatment with TPF versus PF ( hazard ratio [ HR ] 0·74 , 95 % CI 0·58 - 0·94 ) , with an estimated 5-year survival of 52 % in patients treated with TPF and 42 % in those receiving PF . Median survival was 70·6 months ( 95 % CI 49·0 - 89·0 ) in the TPF group versus 34·8 months ( 22·6 - 48·0 ) in the PF group ( p=0·014 ) . Progression-free survival was also significantly better in patients treated with TPF ( median 38·1 months , 95 % CI 19·3 - 66·1 , vs 13·2 months , 10·6 - 20·7 ; HR 0·75 , 95 % CI 0·60 - 0·94 ) . We detected no significant difference in dependence on gastric feeding tubes and tracheostomies between treatment groups . In the TPF group , three ( 3 % ) of 91 patients remained feeding-tube dependent , compared with eight ( 11 % ) of 71 patients in the PF group . Six ( 7 % ) of 92 patients had tracheostomies in the TPF group , versus eight ( 11 % ) of 71 in the PF group . INTERPRETATION Induction chemotherapy with TPF provides long-term survival benefit compared with PF in locally advanced head and neck cancer . Patients who are c and i date s for induction chemotherapy should be treated with TPF . FUNDING Sanofi-Aventis [28021429] 5519 Background : Cetuximab is commonly used in combination with either chemotherapy or radiation in the treatment of HNC , although the optimal way to integrate cetuximab with concurrent chemoradiation ( CRT ) remains unclear . We explored the addition of cetuximab to induction chemotherapy and two established CRT platforms in a r and omized phase II trial . METHODS Patients with locoregionally advanced HNC were treated with cetuximab , carboplatin , paclitaxel induction chemotherapy for 2 cycles . Patients were r and omized to A : cetuximab , 5-FU , hydroxyurea , and hyperfractionated week-on week-off RT ( 72 - 74Gy ) ( CetuxFHX ) , or B : cetuximab , cisplatin , accelerated radiation with concomitant boost (CetuxPX)(72Gy ) . Primary endpoints were 1- and 2-year progression-free ( PFS ) , and overall survival ( OS ) . RESULTS 110 patients with locoregionally advanced HNC ( 108 with Stage IV ) were enrolled . 57.3 % of patients had oropharyngeal ( OP ) primaries ( A : 49 % , B : 66 % , p16 staining is pending ) . Induction response rate was 91.8 % . 99.1 % of patients developed a rash ( ≥ grade 3 in 16.4 % ) ; ≥ grade 3 neutropenia developed in 36.3 % of patients . Overall 1- and 2-year survival rates were 98.3 % and 89.5 % in CetuxFHX , and 94.2 % and 91.4 % in CetuxPX arm , with 21.1months median follow-up ( not statistically significant , p=0.27 , logrank test ) . Progression free survival at 1 and 2 years was 86.0 % and 82.3 % in CetuxFHX , and 95.9 % and 89.7 % in CetuxPX ( p=0.18 ) . Grade ≥3 mucositis was present in 91.1%(A ) and 94.3%(B ) of patients ; grade ≥3 dermatitis in 82.1 % and 50.9 % of patients . 95 % of patients completed therapy . Treatment failures occurred in both OP and non-OP tumors . CONCLUSIONS Cetuximab-based induction chemotherapy is well tolerated and active . Cetuximab can safely be integrated with both FHX and cisplatin based CRT with acceptable toxicities . Survival is favorable on both study arms suggesting that either platform could be investigated further . Data on HPV versus non-HPV-related tumors will be available [17538164] PURPOSE In this r and omized , phase III study , quality of life ( QoL ) was assessed in patients with locoregionally advanced squamous cell carcinoma of the head and neck ( SCCHN ) after high-dose radiotherapy alone or in combination with cetuximab . PATIENTS AND METHODS Patients with stage III or IV nonmetastatic and measurable squamous cell carcinoma of the oropharynx , hypopharynx , or larynx were eligible . QoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Question naire C30 ( EORTC QLQ-C30 ) and EORTC QLQ Head and Neck Cancer-Specific Module at baseline , week 4 , and at months 4 , 8 , and 12 postbaseline . RESULTS In this study , one of the largest conducted in a population of patients with locoregionally advanced SCCHN , 424 patients received radiotherapy alone ( 213 patients ) or radiotherapy plus cetuximab ( 211 patients ) . Radiotherapy/cetuximab significantly improved locoregional control ( P = .005 ) and overall survival ( P = .03 ) compared with radiotherapy alone , without significantly increasing radiotherapy-associated adverse events . The current analysis focused on the impact of cetuximab on the QoL. Compliance with completion of QoL question naires was high in both arms . QoL worsened during treatment and improved after cessation of treatment , reaching baseline levels at 12 months . There were no significant differences in QoL scores between the treatment arms . This was particularly notable for global health status/QoL , social functioning , social eating , and social contact . Pretreatment global health status/QoL was identified as a significant prognostic variable in these patients . CONCLUSION The addition of cetuximab to radiotherapy significantly improved locoregional control and increased overall survival without adversely affecting [22261362] BACKGROUND Concomitant chemoradiotherapy and accelerated radiotherapy independently improve outcomes for patients with locally advanced head and neck squamous-cell carcinoma ( HNSCC ) . We aim ed to assess the efficacy and safety of a combination of these approaches . METHODS In our open-label phase 3 r and omised trial , we enrolled patients with locally advanced , stage III and IV ( non-metastatic ) HNSCC and an Eastern Cooperative Oncology Group performance status of 0 - 2 . We r and omly allocated patients central ly with a computer program ( with centre , T stage , N stage , and localisation as minimisation factors ) in a 1:1:1 ratio to receive conventional chemoradiotherapy ( 70 Gy in 7 weeks plus three cycles of 4 days ' concomitant carboplatin-fluorouracil ) , accelerated radiotherapy-chemotherapy ( 70 Gy in 6 weeks plus two cycles of 5 days ' concomitant carboplatin-fluorouracil ) , or very accelerated radiotherapy alone ( 64·8 Gy [ 1·8 Gy twice daily ] in 3·5 weeks ) . The primary endpoint , progression-free survival ( PFS ) , was assessed in all enrolled patients . This trial is completed . The trial is registered with Clinical Trials.gov , number NCT00828386 . FINDINGS Between Feb 29 , 2000 , and May 9 , 2007 , we r and omly allocated 279 patients to receive conventional chemoradiotherapy , 280 to accelerated radiotherapy-chemotherapy , and 281 to very accelerated radiotherapy . Median follow-up was 5·2 years ( IQR 4·9 - 6·2 ) ; rates of chemotherapy and radiotherapy compliance were good in all groups . Accelerated radiotherapy-chemotherapy offered no PFS benefit compared with conventional chemoradiotherapy ( HR 1·02 , 95 % CI 0·84 - 1·23 ; p=0·88 ) or very accelerated radiotherapy ( 0·83 , 0·69 - 1·01 ; p=0·060 ) ; conventional chemoradiotherapy improved PFS compared with very accelerated radiotherapy ( 0·82 , 0·67 - 0·99 ; p=0·041 ) . 3-year PFS was 37·6 % ( 95 % CI 32·1 - 43·4 ) after conventional chemoradiotherapy , 34·1 % ( 28·7 - 39·8 ) after accelerated radiotherapy-chemotherapy , and 32·2 % ( 27·0 - 37·9 ) after very accelerated radiotherapy . More patients in the very accelerated radiotherapy group had RTOG grade 3 - 4 acute mucosal toxicity ( 226 [ 84 % ] of 268 patients ) compared with accelerated radiotherapy-chemotherapy ( 205 [ 76 % ] of 271 patients ) or conventional chemoradiotherapy ( 180 [ 69 % ] of 262 ; p=0·0001 ) . 158 ( 60 % ) of 265 patients in the conventional chemoradiotherapy group , 176 ( 64 % ) of 276 patients in the accelerated radiotherapy-chemotherapy group , and 190 ( 70 % ) of 272 patients in the very accelerated radiotherapy group were intubated with feeding tubes during treatment ( p=0·045 ) . INTERPRETATION Chemotherapy has a substantial treatment effect given concomitantly with radiotherapy and acceleration of radiotherapy can not compensate for the absence of chemotherapy . We noted the most favourable outcomes for conventional chemoradiotherapy , suggesting that acceleration of radiotherapy is probably not beneficial in concomitant chemoradiotherapy schedules . FUNDING French Ministry of Health [24613543] OBJECTIVE Overexpression of epidermal growth factor receptor ( EGFR ) in many cancers makes it an attractive therapeutic target . This study evaluated the clinical utility of nimotuzumab , a monoclonal anti-EGFR antibody , used concurrently with radiotherapy ( RT ) and chemoradiotherapy ( CRT ) in squamous cell carcinoma of the head and neck ( SCCHN ) . METHODS This open-label study r and omized 92 treatment-naïve patients ( 1:1 ) with advanced SCCHN into chemoradiation ( CRT ± nimotuzumab ) or radiation ( RT ± nimotuzumab ) group by investigator 's discretion ; these were further r and omized into CRT + nimotuzumab or CRT and RT + nimotuzumab or RT groups , respectively . Treatment included 6 cycles each of cisplatin ( 50 mg/week ) , nimotuzumab ( 200 mg/week ) , and RT ( total dose , 60 - 66 Gy ) . Response ( tumor size reduction ) was assessed at Month 6 post-treatment and survival , at Month 60 . RESULTS Forty and 36 patients in the chemoradiation and radiation groups , respectively ( intent-to-treat population ) were evaluated . Overall response at Month 6 post-treatment was 100 % with CRT + nimotuzumab , 70 % with CRT , 76 % with RT + nimotuzumab , and 37 % with RT . At Month 60 , overall survival was 57 % with CRT + nimotuzumab , 26 % with CRT ( P = 0.03 ) , 39 % with RT + nimotuzumab , and 26 % with RT ( P > 0.05 ) . Median overall survival was not reached for CRT + nimotuzumab ; it was 21.94 months for CRT ( P = 0.0078 ) , 14.36 months for RT + nimotuzumab , and 12.78 months for RT ( P = 0.45 ) . Risk of death was 64 % lower with CRT + nimotuzumab than with CRT ( 95%CI : 0.37 , 1.56 ) , and 24 % lower with RT + nimotuzumab than with RT ( 95%CI : 0.16 , 0.79 ) . Thus nimotuzumab was safe and well tolerated with few mild to moderate self-limiting adverse events . CONCLUSION Concurrent use of nimotuzumab with CRT/RT is safe and provides long-term survival benefit [28490940] OBJECTIVE The aim of the present work was to make recommendations about the use of systemically administered drugs in combination or in sequence with radiation ( rt ) or surgery , or both , for cure or organ preservation , or both , in patients with locally advanced nonmetastatic ( stages iii-ivb ) squamous cell carcinoma of the head and neck ( lascchn ) . METHODS The Meta- analysis of Chemotherapy in Head and Neck Cancer ( mach-nc ) reports have , de facto , guided practice since 2000 , and so we search ed the literature for systematic review s published from January 2000 to February 2015 in reference to five research questions . A search was also conducted up to February 2015 for r and omized trials ( rcts ) not included in the meta-analyses . Recommendations were constructed using the Cancer Care Ontario Program in Evidence -Based Care practice guidelines development cycle . RESULTS In addition to up date d mach-nc reports , five additional meta-analyses and thirty rcts were identified . Five recommendations for lascchn treatment were generated based on those data . Concurrent chemoradiation ( ccrt ) is recommended to maximize the chance of cure in patients less than 71 years of age when rt is used as definitive treatment . The same recommendation also applies to patients with resected lascchn considered to be at high risk for locoregional recurrence . For lascchn patients who are c and i date s for organ preservation strategies and would otherwise require total laryngectomy , either ccrt or induction chemotherapy , followed by rt or surgery based on tumour response is recommended . The addition of cetuximab to intensified rt ( concomitant boost or hyperfractionated schedule ) is an alternative to ccrt . Routine use of induction chemotherapy to improve overall survival is not recommended . CONCLUSIONS We were able to use high-level evidence from patients receiving rt as definitive or postoperative treatment to generate recommendations for the use of systemic therapy in the treatment of lascchn . A limitation is a lack of stratification for human papillomavirus-related cancers of the oropharynx . One rct provided evidence for the use of cetuximab as an alternative to chemotherapy in the definitive rt setting . Concurrent chemoradiation provides one strategy for larynx preservation , but the best strategy is unclear . Use of induction chemotherapy does not improve overall survival , and its use should be limited to patients requiring immediate tumour downsizing before local therapy [25366680] PURPOSE We tested the efficacy and toxicity of cisplatin plus accelerated fractionation with a concomitant boost ( AFX-C ) versus st and ard fractionation ( SFX ) in locally advanced head and neck carcinoma ( LA-HNC ) . PATIENTS AND METHODS Patients had stage III to IV carcinoma of the oral cavity , oropharynx , hypopharynx , or larynx . Radiation therapy schedules were 70 Gy in 35 fractions over 7 weeks ( SFX ) or 72 Gy in 42 fractions over 6 weeks ( AFX-C ) . Cisplatin doses were 100 mg/m(2 ) once every 3 weeks for two ( AFX-C ) or three ( SFX ) cycles . Toxicities were scored by using National Cancer Institute Common Toxicity Criteria 2.0 and the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer criteria . Overall survival ( OS ) and progression-free survival ( PFS ) rates were estimated by using the Kaplan-Meier method and were compared by using the one-sided log-rank test . Locoregional failure ( LRF ) and distant metastasis ( DM ) rates were estimated by using the cumulative incidence method and Gray 's test . RESULTS In all , 721 of 743 patients were analyzable ( 361 , SFX ; 360 , AFX-C ) . At a median follow-up of 7.9 years ( range , 0.3 to 10.1 years ) for 355 surviving patients , no differences were observed in OS ( hazard ratio [ HR ] , 0.96 ; 95 % CI , 0.79 to 1.18 ; P = .37 ; 8-year survival , 48 % v 48 % ) , PFS ( HR , 1.02 ; 95 % CI , 0.84 to 1.24 ; P = .52 ; 8-year estimate , 42 % v 41 % ) , LRF ( HR , 1.08 ; 95 % CI , 0.84 to 1.38 ; P = .78 ; 8-year estimate , 37 % v 39 % ) , or DM ( HR , 0.83 ; 95 % CI , 0.56 to 1.24 ; P = .16 ; 8-year estimate , 15 % v 13 % ) . For oropharyngeal cancer , p16-positive patients had better OS than p16-negative patients ( HR , 0.30 ; 95 % CI , 0.21 to 0.42 ; P < .001 ; 8-year survival , 70.9 % v 30.2 % ) . There were no statistically significant differences in the grade 3 to 5 acute or late toxicities between the two arms and p-16 status . CONCLUSION When combined with cisplatin , AFX-C neither improved outcome nor increased late toxicity in patients with LA-HNC . Long-term high survival rates in p16-positive patients with oropharyngeal cancer support the ongoing efforts to explore deintensification [2806549] Summary Background Between 1990 and 2000 , we examined the effect of timing of non-platinum chemotherapy when combined with radiotherapy . We aim ed to determine whether giving chemotherapy concurrently with radiotherapy or as maintenance therapy , or both , affected clinical outcome . Here we report survival and recurrence after 10 years of follow-up . Methods Between Jan 15 , 1990 , and June 20 , 2000 , 966 patients were recruited from 34 centres in the UK and two centres from Malta and Turkey . Patients with locally advanced head and neck cancer , and who had not previously undergone surgery , were r and omly assigned to one of four groups in a 3:2:2:2 ratio , stratified by centre and chemotherapy regimen : radical radiotherapy alone ( n=233 ) ; radiotherapy with two courses of chemotherapy given simultaneously on days 1 and 14 of radiotherapy ( SIM alone ; n=166 ) ; or 14 and 28 days after completing radiotherapy ( SUB alone , n=160 ) ; or both ( SIM+SUB ; n=154 ) . Chemotherapy was either methotrexate alone , or vincristine , bleomycin , methotrexate , and fluorouracil . Patients who had previously undergone radical surgery to remove their tumour were only r and omised to radiotherapy alone ( n=135 ) or SIM alone ( n=118 ) , in a 3:2 ratio . The primary endpoints were overall survival ( from r and omisation ) , and event-free survival ( EFS ; recurrence , new tumour , or death ; whichever occurred first ) among patients who were disease-free 6 months after r and omisation . Analyses were by intention to treat . This trial is registered at www . Clinical trials.gov , number NCT00002476 . Findings All 966 patients were included in the analyses . Among patients who did not undergo surgery , the median overall survival was 2·6 years ( 99 % CI 1·9–4·2 ) in the radiotherapy alone group , 4·7 ( 2·6–7·8 ) years in the SIM alone group , 2·3 ( 1·6–3·5 ) years in the SUB alone group , and 2·7 ( 1·6–4·7 ) years in the SIM+SUB group ( p=0·10 ) . The corresponding median EFS were 1·0 ( 0·7–1·4 ) , 2·2 ( 1·1–6·0 ) , 1·0 ( 0·6–1·5 ) , and 1·0 ( 0·6–2·0 ) years ( p=0·005 ) , respectively . For every 100 patients given SIM alone , there are 11 fewer EFS events ( 99 % CI 1–21 ) , compared with 100 given radiotherapy , 10 years after treatment . Among the patients who had previously undergone surgery , median overall survival was 5·0 ( 99 % CI 1·8–8·0 ) and 4·6 ( 2·2–7·6 ) years in the radiotherapy alone and SIM alone groups ( p=0·70 ) , respectively , with corresponding median EFS of 3·7 ( 99 % CI 1·1–5·9 ) and 3·0 ( 1·2–5·6 ) years ( p=0·85 ) , respectively . The percentage of patients who had a significant toxicity during treatment were : 11 % ( radiotherapy alone , n=25 ) , 28 % ( SIM alone , n=47 ) , 12 % ( SUB alone , n=19 ) , and 36 % ( SIM+SUB , n=55 ) among patients without previous surgery ; and 9 % ( radiotherapy alone , n=12 ) and 20 % ( SIM alone , n=24 ) among those who had undergone previous surgery . The most common toxicity during treatment was mucositis . The percentage of patients who had a significant toxicity at least 6 months after r and omisation were : 6 % ( radiotherapy alone , n=13 ) , 6 % ( SIM alone , n=10 ) , 4 % ( SUB alone , n=7 ) , and 6 % ( SIM+SUB , n=9 ) among patients who had no previous surgery ; and 7 % ( radiotherapy alone , n=10 ) and 11 % ( SIM alone , n=13 ) among those who had undergone previous surgery . The most common toxicity 6 months after treatment was xerostomia , but this occurred in 3 % or less of patients in each group . Interpretation Concurrent non-platinum chemoradiotherapy reduces recurrences , new tumours , and deaths in patients who have not undergone previous surgery , even 10 years after starting treatment . Chemotherapy given after radiotherapy ( with or without concurrent chemotherapy ) is ineffective . Patients who have undergone previous surgery for head and neck cancer do not benefit from non-platinum chemotherapy . Funding Cancer Research UK , with support from University College London and University College London Hospital Comprehensive Biomedical Research Centre [21300455] PURPOSE To analyze the relationship between overall survival ( OS ) and radiation treatment time ( RTT ) and overall treatment time ( OTT ) in a well-described sequential therapy paradigm for locally advanced head- and -neck carcinoma ( LAHNC ) . METHODS AND MATERIAL S TAX 324 is a Phase III study comparing TPF ( docetaxel , cisplatin , and fluorouracil ) with PF ( cisplatin and fluorouracil ) induction chemotherapy ( IC ) in LAHNC patients ; both arms were followed by carboplatin-based chemoradiotherapy ( CRT ) . Prospect i ve radiotherapy quality assurance was performed . This analysis includes all patients who received three cycles of IC and a radiation dose of ≥70 Gy . Radiotherapy treatment time was analyzed as binary ( ≤8 weeks vs. longer ) and continuous ( number of days beyond 8 weeks ) functions . The primary analysis assessed the relationship between RTT , OTT , and OS , and the secondary analysis explored the association between treatment times and locoregional recurrence ( LRR ) . RESULTS A total of 333 ( of 501 ) TAX 324 patients met the criteria for inclusion in this analysis . There were no significant differences between the treatment arms in baseline or treatment characteristics . On multivariable analysis , PF IC , World Health Organization performance status of 1 , non-oropharynx site , T3/4 stage , N3 status , and prolonged RTT ( hazard ratio 1.63 , p=0.006 ) were associated with significantly inferior survival . Performance status , T3/4 disease , and prolonged RTT ( odds ratio 1.68 , p=0.047 ) were independently and negatively related to LRR on multivariable analysis , whereas PF was not . Overall treatment time was not independently associated with either OS or LRR . CONCLUSIONS In this secondary analysis of the TAX 324 trial , TPF IC remains superior to PF IC after controlling for radiotherapy delivery time . Even with optimal IC and concurrent chemotherapy , a non-prolonged RTT is a crucial determinant of treatment success . Appropriate delivery of radiotherapy after IC remains essential for optimizing OS in LAHNC [23265705] BACKGROUND This r and omised Phase II study assessed the activity and safety of concurrent chemoradiotherapy ( CRT ) and lapatinib followed by maintenance treatment in locally advanced , unresected stage III/IVA/IVB head and neck cancer . PATIENTS AND METHODS Patients were r and omised 1:1 to concurrent CRT and placebo followed by placebo or concurrent CRT and lapatinib followed by lapatinib . Treatment continued until disease progression or study withdrawal . Primary end-point was complete response rate ( CRR ) by independent review 6 months post-CRT . RESULTS Sixty-seven patients ( median age 56 years ; 97 % Eastern Cooperative Oncology Group performance status ≤1 ; 82 % stage IV ) were recruited . CRT dose intensities were unaffected by lapatinib : median radiation dose 70 Gy ( lapatinib , placebo ) , duration 49 ( lapatinib ) and 50 days ( placebo ) ; median cisplatin dose 260 mg/m(2 ) ( lapatinib ) and 280 mg/m(2 ) ( placebo ) . Lapatinib combined with CRT was well-tolerated . Grade 3/4 toxicities during CRT were balanced between arms , with the exception of an excess of grade 3 diarrhoea ( 6 % versus 0 % ) and rash ( 9 % versus 3 % ) and two grade 4 cardiac events in the lapatinib arm . CRR at 6 months post-CRT was 53 % with lapatinib versus 36 % with placebo in the intent-to-treat population . The progression-free survival ( PFS ) and overall survival rates at 18 months were 55 % versus 41 % and 68 % versus 57 % for the lapatinib and placebo arms , respectively . The difference between study arms was greatest in p16-negative disease ( median PFS > 20.4 months [ lapatinib ] versus 10.9 [ placebo ] ) . CONCLUSION Lapatinib combined with CRT is well-tolerated with numeric increases in CRR at 6 months post-CRT and median PFS in p16-negative disease [21295880] BACKGROUND AND PURPOSE Studies on accelerated fractionation ( AF ) in head and neck cancer have shown increased local control and survival compared with conventional fractionation ( CF ) , while others have been non-conclusive . In 1998 a national Swedish group decided to perform a r and omised controlled clinical study of AF . MATERIAL S AND METHODS Patients with verified squamous cell carcinoma of the oral cavity , oropharynx , larynx ( except glottic T1-T2 , N0 ) and hypopharynx were included . Patients with prior chemotherapy or surgery were excluded . Patients were r and omised to either CF ( 2Gy/day , 5days/week for 7 weeks , total dose 68Gy ) or to AF ( 1.1Gy+2.0Gy/day , 5days/week for 4.5weeks , total dose 68Gy ) . An extensive quality assurance protocol was followed throughout the study . The primary end point was loco-regional tumour control ( LRC ) at two years after treatment . RESULTS The study was closed in 2006 when 750 patients had been r and omised . Eighty-three percent of the patients had stages III-IV disease . Forty eight percent had oropharyngeal , 21 % laryngeal , 17 % hypopharyngeal and 14 % oral cancers . There were no significant differences regarding overall survival ( OS ) or LRC between the two regimens . The OS at two years was 68 % for AF and 67 % for CF . The corresponding figures for LRC were 71 % and 67 % , respectively . There was a trend towards improved LRC for oral cancers treated ( p=0.07 ) and for large tumours ( T3-T4 ) ( p=0.07 ) treated with AF . The AF group had significantly worse acute reactions , while there was no significant increase in late effects . CONCLUSION Overall the AF regimen did not prove to be more efficacious than CF . However , the trend towards improved results in AF for oral cancers needs to be further investigated

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### Context: [25154822] PURPOSE Combining cisplatin or cetuximab with radiation improves overall survival ( OS ) of patients with stage III or IV head and neck carcinoma ( HNC ) . Cetuximab plus platinum regimens also increase OS in metastatic HNC . The Radiation Therapy Oncology Group launched a phase III trial to test the hypothesis that adding cetuximab to the radiation-cisplatin platform improves progression-free survival ( PFS ) . PATIENTS AND METHODS Eligible patients with stage III or IV HNC were r and omly assigned to receive radiation and cisplatin without ( arm A ) or with ( arm B ) cetuximab . Acute and late reactions were scored using Common Terminology Criteria for Adverse Events ( version 3 ) . Outcomes were correlated with patient and tumor features and markers . RESULTS Of 891 analyzed patients , 630 were alive at analysis ( median follow-up , 3.8 years ) . Cetuximab plus cisplatin-radiation , versus cisplatin-radiation alone , result ed in more frequent interruptions in radiation therapy ( 26.9 % v. 15.1 % , respectively ) ; similar cisplatin delivery ( mean , 185.7 mg/m2 v. 191.1 mg/m2 , respectively ) ; and more grade 3 to 4 radiation mucositis ( 43.2 % v. 33.3 % , respectively ) , rash , fatigue , anorexia , and hypokalemia , but not more late toxicity . No differences were found between arms A and B in 30-day mortality ( 1.8 % v. 2.0 % , respectively ; P = .81 ) , 3-year PFS ( 61.2 % v. 58.9 % , respectively ; P = .76 ) , 3-year OS ( 72.9 % v. 75.8 % , respectively ; P = .32 ) , locoregional failure ( 19.9 % v. 25.9 % , respectively ; P = .97 ) , or distant metastasis ( 13.0 % v. 9.7 % , respectively ; P = .08 ) . Patients with p16-positive oropharyngeal carcinoma ( OPC ) , compared with patients with p16-negative OPC , had better 3-year probability of PFS ( 72.8 % v. 49.2 % , respectively ; P < .001 ) and OS ( 85.6 % v. 60.1 % , respectively ; P < .001 ) , but tumor epidermal growth factor receptor ( EGFR ) expression did not distinguish outcome . CONCLUSION Adding cetuximab to radiation-cisplatin did not improve outcome and hence should not be prescribed routinely . PFS and OS were higher in patients with p16-positive OPC , but outcomes did not differ by EGFR expression [15625362] PURPOSE To select one of two chemoradiotherapy regimens for locally advanced squamous cell carcinoma ( SCC ) of the head and neck as the experimental arm for the next Trans-Tasman Radiation Oncology Group phase III trial . PATIENTS AND METHODS One hundred twenty-two previously untreated patients with stage III/IV SCC of the head and neck were r and omized to receive definitive radiotherapy ( 70 Gy in 7 weeks ) concurrently with either cisplatin ( 75 mg/m(2 ) ) plus tirapazamine ( 290 mg/m(2)/d ) on day 2 of weeks 1 , 4 , and 7 , and tirapazamine alone ( 160 mg/m(2)/d ) on days 1 , 3 , and 5 of weeks 2 and 3 ( TPZ/CIS ) , or cisplatin ( 50 mg/m(2 ) ) on day 1 and infusional fluorouracil ( 360 mg/m(2)/d ) on days 1 through 5 of weeks 6 and 7 ( chemoboost ) . RESULTS Three-year failure-free survival rates were 55 % with TPZ/CIS ( 95 % CI , 39 % to 70 % ) and 44 % with chemoboost ( 95 % CI , 30 % to 60 % ; log-rank P = .16 ) . Three-year locoregional failure-free rates were 84 % in the TPZ/CIS arm ( 95 % CI , 71 % to 92 % ) and 66 % in the chemoboost arm ( 95 % CI , 51 % to 79 % ; P = .069 ) . More febrile neutropenia and grade 3 or 4 late mucous membrane toxicity were observed with TPZ/CIS , while acute skin radiation reaction was more severe and prolonged with chemoboost . Compliance with protocol treatment was satisfactory on both arms . CONCLUSION Both regimens are feasible and are associated with significant but acceptable toxicity profiles in the cooperative group setting . Based on the promising efficacy seen in this trial , TPZ/CIS is being evaluated in a large phase III trial [17960013] BACKGROUND A r and omized phase 3 trial of the treatment of squamous-cell carcinoma of the head and neck compared induction chemotherapy with docetaxel plus cisplatin and fluorouracil ( TPF ) with cisplatin and fluorouracil ( PF ) , followed by chemoradiotherapy . METHODS We r and omly assigned 501 patients ( all of whom had stage III or IV disease with no distant metastases and tumors considered to be unresectable or were c and i date s for organ preservation ) to receive either TPF or PF induction chemotherapy , followed by chemoradiotherapy with weekly carboplatin therapy and radiotherapy for 5 days per week . The primary end point was overall survival . RESULTS With a minimum of 2 years of follow-up ( > or =3 years for 69 % of patients ) , significantly more patients survived in the TPF group than in the PF group ( hazard ratio for death , 0.70 ; P=0.006 ) . Estimates of overall survival at 3 years were 62 % in the TPF group and 48 % in the PF group ; the median overall survival was 71 months and 30 months , respectively ( P=0.006 ) . There was better locoregional control in the TPF group than in the PF group ( P=0.04 ) , but the incidence of distant metastases in the two groups did not differ significantly ( P=0.14 ) . Rates of neutropenia and febrile neutropenia were higher in the TPF group ; chemotherapy was more frequently delayed because of hematologic adverse events in the PF group . CONCLUSIONS Patients with squamous-cell carcinoma of the head and neck who received docetaxel plus cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy had a significantly longer survival than did patients who received cisplatin and fluorouracil induction chemotherapy plus chemoradiotherapy . ( Clinical Trials.gov number , NCT00273546 [ Clinical Trials.gov ] . ) [23041591] BACKGROUND Cetuximab combined with radiotherapy ( RT ) is a treatment option for head and neck cancer . The objectives of this r and omized , phase II trial were to evaluate the efficacy and safety of cetuximab maintenance therapy following definitive RT with concomitant cetuximab in patients with oropharyngeal cancer . PATIENTS AND METHODS Ninety-one patients with stage III-IV M0 oropharyngeal tumors were r and omly assigned to the treatment with accelerated concomitant boost RT ( 69.9 Gy ) + cetuximab or the same treatment with the addition of 12 consecutive weeks of cetuximab maintenance therapy . The primary end point was locoregional control ( LRC ) at 1 year . RESULTS LRC at 1 year was superior among patients in the experimental arm , treated with cetuximab maintenance ( 59 % versus 47 % ) . However , LRC was similar between both arms after 2 years of follow-up , as a result of increased locoregional recurrences after the first year in the maintenance group . Patients treated with adjuvant cetuximab do recover very soon from toxic effect after combined treatment . CONCLUSIONS Twelve weeks of cetuximab maintenance therapy after concomitant cetuximab + RT in locally advanced oropharyngeal carcinoma is feasible and improves clinical outcomes measured at 1 year . This improvement is not maintained after the second year suggesting that epidermal growth factor receptor blockade is not sufficient to completely eliminate the minimal residual disease [17197122] PURPOSE The long term results and patterns of failure in patients with squamous cell head and neck carcinoma ( SCHNC ) treated in a prospect i ve r and omized trial in which concomitant postoperative radiochemotherapy with Mitomycin C and Bleomycin ( CRT ) was compared with radiotherapy only ( RT ) , were analyzed . PATIENTS AND METHODS Between March 1997 and December 2001 , 114 eligible patients with Stage III or IV SCHNC were r and omized . Primary surgical treatment was performed with curative intent in all patients . Patients in both groups were postoperatively irradiated to the total dose of 56 - 70 Gy . Chemotherapy included Mitomycin C 15 mg/m2 after 10 Gy and 5 mg of Bleomycin twice weekly during irradiation . Median follow-up was 76 months ( 48 - 103 months ) . RESULTS At 5 years in the RT and CRT arms , the locoregional control was 65 % and 88 % ( p = 0.026 ) , disease-free survival 33 % and 53 % ( p = 0.035 ) , and overall survival 37 % and 55 % ( p = 0.091 ) respectively . Patients who benefited from chemotherapy were those with high-risk factors . The probability of distant metastases was 22 % in RT and 20 % in CRT arm ( p = 0.913 ) , of grade III or higher late toxicity 19 % in RT and 26 % in CRT arm ( p = 0.52 ) and of thyroid dysfunction 36 % in RT and 56 % in CRT arm ( p = 0.24 ) . The probability to develop a second primary malignancy ( SPM ) was 34 % in the RT and 8 % in the CRT arm ( p = 0.023 ) . One third of deaths were due to infection , but there was no difference between the 2 groups . CONCLUSION With concomitant radiochemotherapy , locoregional control and disease free survival were significantly improved . Second primary malignancies in the CRT arm compared to RT arm were significantly less frequent . The high probability of post treatment hypothyroidism in both arms warrants regular laboratory evaluation [20479425] PURPOSE Promising results in a r and omized phase II trial with the hypoxic cytotoxin tirapazamine ( TPZ ) combined with cisplatin ( CIS ) and radiation led to this phase III trial . PATIENTS AND METHODS Patients with previously untreated stage III or IV ( excluding T1 - 2N1 and M1 ) squamous cell carcinoma of the oral cavity , oropharynx , hypopharynx , or larynx were r and omly assigned to receive definitive radiotherapy ( 70 Gy in 7 weeks ) concurrently with either CIS ( 100 mg/m(2 ) ) on day 1 of weeks 1 , 4 , and 7 or CIS ( 75 mg/m(2 ) ) plus TPZ ( 290 mg/m(2)/d ) on day 1 of weeks 1 , 4 , and 7 and TPZ alone ( 160 mg/m(2)/d ) on days 1 , 3 , and 5 of weeks 2 and 3 ( TPZ/CIS ) . The primary end point was overall survival ( OS ) . The planned sample size was 850 , estimated to result in 334 deaths , which would provide 90 % power to detect a difference in 2-year survival rates of 60 % v 70 % for CIS versus TPZ/CIS , respectively ( hazard ratio = 0.69 ) . RESULTS Eight hundred sixty-one patients were accrued from 89 sites in 16 countries . In an intent-to-treat analysis , the 2-year OS rates were 65.7 % for CIS and 66.2 % for TPZ/CIS ( TPZ/CIS -- CIS : 95 % CI , -5.9 % to 6.9 % ) . There were no significant differences in failure-free survival , time to locoregional failure , or quality of life as measured by Functional Assessment of Cancer Therapy-Head and Neck . CONCLUSIONS We found no evidence that the addition of TPZ to chemoradiotherapy , in patients with advanced head and neck cancer not selected for the presence of hypoxia , improves OS [17960012] BACKGROUND Phase 2 studies suggest that the st and ard regimen of cisplatin and fluorouracil ( PF ) plus docetaxel ( TPF ) improves outcomes in squamous-cell carcinoma of the head and neck . We compared TPF with PF as induction chemotherapy in patients with locoregionally advanced , unresectable disease . METHODS We r and omly assigned eligible patients between the ages of 18 and 70 years who had stage III or stage IV disease and no distant metastases to receive either TPF ( docetaxel and cisplatin , day 1 ; fluorouracil by continuous infusion , days 1 to 5 ) or PF every 3 weeks for four cycles . Patients without progression of disease received radiotherapy within 4 to 7 weeks after completing chemotherapy . The primary end point was progression-free survival . RESULTS A total of 358 patients underwent r and omization , with 177 assigned to the TPF group and 181 to the PF group . At a median follow-up of 32.5 months , the median progression-free survival was 11.0 months in the TPF group and 8.2 months in the PF group ( hazard ratio for disease progression or death in the TPF group , 0.72 ; P=0.007 ) . Treatment with TPF result ed in a reduction in the risk of death of 27 % ( P=0.02 ) , with a median overall survival of 18.8 months , as compared with 14.5 months in the PF group . There were more grade 3 or 4 events of leukopenia and neutropenia in the TPF group and more grade 3 or 4 events of thrombocytopenia , nausea , vomiting , stomatitis , and hearing loss in the PF group . The rates of death from toxic effects were 2.3 % in the TPF group and 5.5 % in the PF group . CONCLUSIONS As compared with the st and ard regimen of cisplatin and fluorouracil , induction chemotherapy with the addition of docetaxel significantly improved progression-free and overall survival in patients with unresectable squamous-cell carcinoma of the head and neck . ( Clinical Trials.gov number , NCT00003888 [ Clinical Trials.gov ] . ) [20448462] The prognosis of patients with advanced head and neck cancer remain dismal . For this tumor type , elevated levels of EGFR are associated with a shorter disease free survival and time to treatment failure , reflecting a more aggressive phenotype . Nimotuzumab is a humanized monoclonal antibody that recognizes domain III of the extracellular region of the EGFR , within an area that overlaps with both the surface patch recognized by cetuximab and the binding site for EGF . In order to assess the efficacy of nimotuzumab in combination with radiotherapy , a controlled , double blind , r and omized clinical trial was conducted in 106 advanced squamous cell carcinoma of the head and neck patients , mostly , unfit for chemo-radiotherapy . Control patients received a placebo and radiotherapy . Treatment was safe and the most frequent adverse events consisted on grade I or II asthenia , fever , headache and chills . No skin rash was detected . A significant complete response rate improvement was found in the group of patients treated with nimotuzumab as compared to the placebo . In the intent to treat analysis , a trend towards survival benefit for nimotuzumab treated subjects was found . The survival benefit became significant when applying the Harrington-Fleming test , a weighted log-rank that underscores the detection of differences deferred on time . In addition , a preliminary biomarker investigation showed a significant survival improvement for nimotuzumab treated patients as compared to controls for subjects with EGFR positive tumors . All patients showed a quality of life improvement and a reduction of the general and specific symptoms of the disease [16467544] BACKGROUND We conducted a multinational , r and omized study to compare radiotherapy alone with radiotherapy plus cetuximab , a monoclonal antibody against the epidermal growth factor receptor , in the treatment of locoregionally advanced squamous-cell carcinoma of the head and neck . METHODS Patients with locoregionally advanced head and neck cancer were r and omly assigned to treatment with high-dose radiotherapy alone ( 213 patients ) or high-dose radiotherapy plus weekly cetuximab ( 211 patients ) at an initial dose of 400 mg per square meter of body-surface area , followed by 250 mg per square meter weekly for the duration of radiotherapy . The primary end point was the duration of control of locoregional disease ; secondary end points were overall survival , progression-free survival , the response rate , and safety . RESULTS The median duration of locoregional control was 24.4 months among patients treated with cetuximab plus radiotherapy and 14.9 months among those given radiotherapy alone ( hazard ratio for locoregional progression or death , 0.68 ; P=0.005 ) . With a median follow-up of 54.0 months , the median duration of overall survival was 49.0 months among patients treated with combined therapy and 29.3 months among those treated with radiotherapy alone ( hazard ratio for death , 0.74 ; P=0.03 ) . Radiotherapy plus cetuximab significantly prolonged progression-free survival ( hazard ratio for disease progression or death , 0.70 ; P=0.006 ) . With the exception of acneiform rash and infusion reactions , the incidence of grade 3 or greater toxic effects , including mucositis , did not differ significantly between the two groups . CONCLUSIONS Treatment of locoregionally advanced head and neck cancer with concomitant high-dose radiotherapy plus cetuximab improves locoregional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head and neck . ( Clinical Trials.gov number , NCT00004227 . [19179556] BACKGROUND Locally advanced laryngeal and hypopharyngeal cancers ( LHC ) represent a group of cancers for which surgery , laryngectomy-free survival ( LFS ) , overall survival ( OS ) , and progression-free survival ( PFS ) are clinical ly meaningful end points . PATIENTS AND METHODS These outcomes were analyzed in the subgroup of assessable LHC patients enrolled in TAX 324 , a phase III trial of sequential therapy comparing docetaxel plus cisplatin and fluorouracil ( TPF ) against cisplatin and fluorouracil ( PF ) , followed by chemoradiotherapy . RESULTS Among 501 patients enrolled in TAX 324 , 166 had LHC ( TPF , n = 90 ; PF , n = 76 ) . Patient characteristics were similar between subgroups . Median OS for TPF was 59 months [ 95 % confidence interval ( CI ) : 31-not reached ] versus 24 months ( 95 % CI : 13 - 42 ) for PF [ hazard ratio ( HR ) for death : 0.62 ; 95 % CI : 0.41 - 0.94 ; P = 0.024 ] . Median PFS for TPF was 21 months ( 95 % CI : 12 - 59 ) versus 11 months ( 95 % CI : 8 - 14 ) for PF ( HR : 0.66 ; 95 % CI : 0.45 - 0.97 ; P = 0.032 ) . Among operable patients ( TPF , n = 67 ; PF , n = 56 ) , LFS was significantly greater with TPF ( HR : 0.59 ; 95 % CI : 0.37 - 0.95 ; P = 0.030 ) . Three-year LFS with TPF was 52 % versus 32 % for PF . Fewer TPF patients had surgery ( 22 % versus 42 % ; P = 0.030 ) . CONCLUSIONS In locally advanced LHC , sequential therapy with induction TPF significantly improved survival and PFS versus PF . Among operable patients , TPF also significantly improved LFS and PFS . These results support the use of sequential TPF followed by carboplatin chemoradiotherapy as a treatment option for organ preservation or to improve survival in locally advanced LHC [15908196] A combination of cisplatin and 5-fluorouracil ( PF ) is considered the st and ard induction chemotherapy regimen for squamous cell carcinoma of the head and neck ( SCCHN ) . The present study compares the efficacy and safety of a new combination of cisplatin/docetaxel versus the PF regimen . A total of 83 chemotherapy-naive patients with locally advanced SCCHN were r and omised to receive every 21 d ( i ) docetaxel 85 mg/m2 i.v . on day 1 and cisplatin 40 mg/m2 i.v . on days 1 and 2 ( arm A ) or ( ii ) cisplatin 100 mg/m2 i.v . on day 1 followed by 5-fluorouracil 1000 mg/m2 in 24 h continuous infusion for 5 d ( arm B ) . A total of 287 cycles ( range 1 - 3 per patient ) were administered . Among 76 patients evaluable for response , the overall response rate in arm A was 70 % ( complete response ( CR ) 26 % , partial response ( PR ) 44 % ) and in arm B 69 % ( CR 16 % , PR 54 % ) , respectively . Median survival in arm A was 7.6 months ( 95 % CI : 5.8 - 11.1 ) and 9.9 months ( 95 % CI : 7.4 - 14.6 ) for arm B. The most frequent grade 3/4 toxicity in arm A was neutropaenia ( 34.1 % ) and diarrhoea ( 9.8 % ) versus mucositis ( 29.3 % ) and neutropaenia ( 19.5 % ) in arm B. Both schedules present a similar efficacy , with different but acceptable toxicity patterns [22749632] PURPOSE Previous analysis of this Intergroup trial demonstrated that with a median follow-up among surviving patients of 45.9 months , the concurrent postoperative administration of cisplatin and radiation therapy improved local-regional control and disease-free survival of patients who had high-risk resectable head- and -neck carcinomas . With a minimum of 10 years of follow-up potentially now available for all patients , these results are up date d here to examine long-term outcomes . METHODS AND MATERIAL S A total of 410 analyzable patients who had high-risk resected head- and -neck cancers were prospect ively r and omized to receive either radiation therapy ( RT : 60 Gy in 6 weeks ) or identical RT plus cisplatin , 100 mg/m(2)i.v . on days 1 , 22 , and 43 ( RT + CT ) . RESULTS At 10 years , the local-regional failure rates were 28.8 % vs 22.3 % ( P=.10 ) , disease-free survival was 19.1 % vs 20.1 % ( P=.25 ) , and overall survival was 27.0 % vs 29.1 % ( P=.31 ) for patients treated by RT vs RT + CT , respectively . In the unplanned subset analysis limited to patients who had microscopically involved resection margins and /or extracapsular spread of disease , local-regional failure occurred in 33.1 % vs 21.0 % ( P=.02 ) , disease-free survival was 12.3 % vs 18.4 % ( P=.05 ) , and overall survival was 19.6 % vs 27.1 % ( P=.07 ) , respectively . CONCLUSION At a median follow-up of 9.4 years for surviving patients , no significant differences in outcome were observed in the analysis of all r and omized eligible patients . However , analysis of the subgroup of patients who had either microscopically involved resection margins and /or extracapsular spread of disease showed improved local-regional control and disease-free survival with concurrent administration of chemotherapy . The remaining subgroup of patients who were enrolled only because they had tumor in 2 or more lymph nodes did not benefit from the addition of CT to RT [15128894] BACKGROUND We compared concomitant cisplatin and irradiation with radiotherapy alone as adjuvant treatment for stage III or IV head and neck cancer . METHODS After undergoing surgery with curative intent , 167 patients were r and omly assigned to receive radiotherapy alone ( 66 Gy over a period of 6 1/2 weeks ) and 167 to receive the same radiotherapy regimen combined with 100 mg of cisplatin per square meter of body-surface area on days 1 , 22 , and 43 of the radiotherapy regimen . RESULTS After a median follow-up of 60 months , the rate of progression-free survival was significantly higher in the combined-therapy group than in the group given radiotherapy alone ( P=0.04 by the log-rank test ; hazard ratio for disease progression , 0.75 ; 95 percent confidence interval , 0.56 to 0.99 ) , with 5-year Kaplan-Meier estimates of progression-free survival of 47 percent and 36 percent , respectively . The overall survival rate was also significantly higher in the combined-therapy group than in the radiotherapy group ( P=0.02 by the log-rank test ; hazard ratio for death , 0.70 ; 95 percent confidence interval , 0.52 to 0.95 ) , with five-year Kaplan-Meier estimates of overall survival of 53 percent and 40 percent , respectively . The cumulative incidence of local or regional relapses was significantly lower in the combined-therapy group ( P=0.007 ) . The estimated five-year cumulative incidence of local or regional relapses ( considering death from other causes as a competing risk ) was 31 percent after radiotherapy and 18 percent after combined therapy . Severe ( grade 3 or higher ) adverse effects were more frequent after combined therapy ( 41 percent ) than after radiotherapy ( 21 percent , P=0.001 ) ; the types of severe mucosal adverse effects were similar in the two groups , as was the incidence of late adverse effects . CONCLUSIONS Postoperative concurrent administration of high-dose cisplatin with radiotherapy is more efficacious than radiotherapy alone in patients with locally advanced head and neck cancer and does not cause an undue number of late complications [19318632] BACKGROUND Chemotherapy with cisplatin ( P ) and 5-fluorouracil ( F ) followed by radiotherapy in patients who respond to chemotherapy is an alternative to total laryngectomy for patients with locally advanced larynx and hypopharynx cancer . Data suggest that docetaxel ( T ) may add to the efficacy of PF . The objective of this trial was to determine whether adding T to PF could increase the larynx preservation rate . METHODS Patients who had larynx and hypopharynx cancer that required total laryngectomy were r and omly assigned to receive three cycles of TPF or PF . Patients who responded to chemotherapy received radiotherapy with or without additional chemotherapy . Patients who did not respond to chemotherapy underwent total laryngectomy followed by radiotherapy with or without additional chemotherapy . The primary endpoint was 3-year larynx preservation rate . Secondary endpoints included acute toxicities and overall response . All statistical tests were two-sided . RESULTS Baseline patient and tumor characteristics were well balanced between the TPF ( n = 110 ) and PF ( n = 103 ) groups . With a median follow-up of 36 months , the 3-year actuarial larynx preservation rate was 70.3 % with TPF vs 57.5 % with PF ( difference = 12.8 % ; P = .03 ) . Patients in the TPF group had more grade 2 alopecia , grade 4 neutropenia , and febrile neutropenia , whereas patients in the PF group had more grade 3 and 4 stomatitis , thrombocytopenia , and grade 4 creatinine elevation . The overall response was 80.0 % in the TPF group vs 59.2 % in the PF group ( difference = 20.8 % ; P = .002 ) . CONCLUSIONS In patients with advanced larynx and hypopharynx carcinomas , TPF induction chemotherapy was superior to the PF regimen in terms of overall response rate . These results suggest that larynx preservation could be achieved for a higher proportion of patients [19357741] BACKGROUND Management of advanced head and neck carcinoma is a challenging proposition . Presently concomitant chemo-irradiation has become the st and ard of care in such patients . Many chemotherapeutic drugs have shown radio-sensitising effects when used concomitantly along with radiation . The present study was carried out with the objective of assessing the feasibility and efficacy of low dose gemcitabine as radiosensitizer when used during radical radiotherapeutic management of patients with locally advanced head and neck carcinomas . PATIENTS AND METHODS From November 2000 to March 2003 , eighty histopathologically proven cases of squamous cell head and neck carcinoma were included in this trial , 40 patients were r and omly assigned to receive radiotherapy alone and 40 patients to receive gemcitabine along with radiotherapy . RESULTS All patients were assessable for toxicity and response . Severe mucositis ( WHO level 5 reactions were observed in 67 % patients in the CT/RT group vs 16 % patients in the RT only group . No severe hematological toxicity was seen . The rates of complete and partial responses were 42.5 % & 57.5 % respectively for RT only and 62.5 % & 37.5 % , respectively for CT/RT group . There was no significant difference in the response rates at the end of treatment but disease free survival at three years was better in the CT/RT group ( 63.3 % vs 20 % ) . Nine of the 17 patients with complete response in the radiation only group developed relapse while no relapses were seen in CT/RT group . CONCLUSION In the present study the combination of gemcitabine and radiotherapy has not shown any statistical difference in locoregional control but survival advantage was seen as compared to radiotherapy alone . At the same time more mucosal and skin toxicity was encountered when Gemcitabine is given concurrently with radiation [19176454] BACKGROUND Both induction chemotherapy followed by irradiation and concurrent chemotherapy and radiotherapy have been reported as valuable alternatives to total laryngectomy in patients with advanced larynx or hypopharynx cancer . We report results of the r and omized phase 3 trial 24954 from the European Organization for Research and Treatment of Cancer . METHODS Patients with resectable advanced squamous cell carcinoma of the larynx ( tumor stage T3-T4 ) or hypopharynx ( T2-T4 ) , with regional lymph nodes in the neck staged as N0-N2 and with no metastasis , were r and omly assigned to treatment in the sequential ( or control ) or the alternating ( or experimental ) arm . In the sequential arm , patients with a 50 % or more reduction in primary tumor size after two cycles of cisplatin and 5-fluorouracil received another two cycles , followed by radiotherapy ( 70 Gy total ) . In the alternating arm , a total of four cycles of cisplatin and 5-fluorouracil ( in weeks 1 , 4 , 7 , and 10 ) were alternated with radiotherapy with 20 Gy during the three 2-week intervals between chemotherapy cycles ( 60 Gy total ) . All nonresponders underwent salvage surgery and postoperative radiotherapy . The Kaplan-Meier method was used to obtain time-to-event data . RESULTS The 450 patients were r and omly assigned to treatment ( 224 to the sequential arm and 226 to the alternating arm ) . Median follow-up was 6.5 years . Survival with a functional larynx was similar in sequential and alternating arms ( hazard ratio of death and /or event = 0.85 , 95 % confidence interval = 0.68 to 1.06 ) , as were median overall survival ( 4.4 and 5.1 years , respectively ) and median progression-free interval ( 3.0 and 3.1 years , respectively ) . Grade 3 or 4 mucositis occurred in 64 ( 32 % ) of the 200 patients in the sequential arm who received radiotherapy and in 47 ( 21 % ) of the 220 patients in the alternating arm . Late severe edema and /or fibrosis was observed in 32 ( 16 % ) patients in the sequential arm and in 25 ( 11 % ) in the alternating arm . CONCLUSIONS Larynx preservation , progression-free interval , and overall survival were similar in both arms , as were acute and late toxic effects [10601378] BACKGROUND We design ed a r and omized clinical trial to test whether the addition of three cycles of chemotherapy during st and ard radiation therapy would improve disease-free survival in patients with stages III and IV ( i.e. , advanced oropharynx carcinoma ) . METHODS A total of 226 patients have been entered in a phase III multicenter , r and omized trial comparing radiotherapy alone ( arm A ) with radiotherapy with concomitant chemotherapy ( arm B ) . Radiotherapy was identical in the two arms , delivering , with conventional fractionation , 70 Gy in 35 fractions . In arm B , patients received during the period of radiotherapy three cycles of a 4-day regimen containing carboplatin ( 70 mg/m(2 ) per day ) and 5-fluorouracil ( 600 mg/m(2 ) per day ) by continuous infusion . The two arms were equally balanced with regard to age , sex , stage , performance status , histology , and primary tumor site . RESULTS Radiotherapy compliance was similar in the two arms with respect to total dose , treatment duration , and treatment interruption . The rate of grade s 3 and 4 mucositis was statistically significantly higher in arm B ( 71 % ; 95 % confidence interval [ CI ] = 54%-85 % ) than in arm A ( 39 % ; 95 % CI = 29%-56 % ) . Skin toxicity was not different between the two arms . Hematologic toxicity was higher in arm B as measured by neutrophil count and hemoglobin level . Three-year overall actuarial survival and disease-free survival rates were , respectively , 51 % ( 95 % CI = 39%-68 % ) versus 31 % ( 95 % CI = 18%-49 % ) and 42 % ( 95 % CI = 30%-57 % ) versus 20 % ( 95 % CI = 10%-33 % ) for patients treated with combined modality versus radiation therapy alone ( P = .02 and .04 , respectively ) . The locoregional control rate was improved in arm B ( 66 % ; 95 % CI = 51%-78 % ) versus arm A ( 42 % ; 95 % CI = 31%-56 % ) . CONCLUSION The statistically significant improvement in overall survival that was obtained supports the use of concomitant chemotherapy as an adjunct to radiotherapy in the management of carcinoma of the oropharynx [20032123] BACKGROUND Concomitant chemoradiotherapy ( CT/RT ) is the st and ard treatment of locally advanced squamous cell carcinoma of the head and neck ( SCCHN ) . We evaluated the efficacy of induction docetaxel ( Taxotere ) , cisplatin , and 5-fluorouracil ( TPF ) before CT/RT versus CT/RT alone . PATIENTS AND METHODS Patients with stage III-IVM0 SCCHN , Eastern Cooperative Oncology Group performance status of zero to one , were r and omly assigned to receive CT/RT alone ( arm A : two cycles of cisplatin 20 mg/m(2 ) , days1 - 4 , plus 5-fluorouracil 800 mg/m(2)/day 96 h continuous infusion , during weeks 1 and 6 of radiotherapy ) or three cycles of TPF ( arm B : docetaxel 75 mg/m(2 ) and cisplatin 80 mg/m(2 ) , day 1 , and 5-fluorouracil 800 mg/m(2)/day 96 h continuous infusion , every 3 weeks ) followed by the same CT/RT . The primary end point was the rate of radiologic complete response ( CR ) at 6 - 8 weeks after the end of CT/RT . RESULTS A total of 101 patients were r and omly allocated to the study ( 51 arm A ; 50 arm B ) . CR rates were 21.2 % ( arm A ) versus 50 % ( arm B ) . Median progression-free survival and overall survival were , respectively , 19.7 and 33.3 months ( arm A ) and 30.4 and 39.6 months ( arm B ) . Hematologic and non-hematologic toxic effects during CT/RT were similar in the two arms . CONCLUSION Induction TPF followed by CT/RT was associated with higher radiologic CR in patients with locally advanced SCCHN with no negative impact on CT/RT feasibility [26644536] PURPOSE No r and omized trials have been conducted to directly compare radiotherapy ( RT ) with concomitant cisplatin ( CDDP ) versus concomitant cetuximab ( CTX ) as first-line treatment of locally advanced squamous cell carcinoma of the head and neck . In this r and omized trial , we compared these two treatment regimens in terms of compliance , toxicity , and efficacy . PATIENTS AND METHODS Eligible patients were r and omly assigned in a 1:1 ratio to receive either CDDP 40 mg/m(2 ) once per week or CTX 400 mg/m(2 ) as loading dose followed by CTX 250 mg/m(2 ) once per week concomitant to radical RT . For primary end points , compliance to treatment was defined as number of days of treatment discontinuation and drug dosage reduction . The acute toxicity rate was defined according to the National Cancer Institute Common Toxicity Criteria . Efficacy end points were local recurrence-free survival , metastasis-free survival , cancer-specific survival , and overall survival . RESULTS The study was discontinued early because of slow accrual after the enrollment of 70 patients . RT discontinuation for more than 10 days occurred in 13 % of patients given CTX and 0 % given CDDP ( P = .05 ) . Drug dosage reduction occurred in 34 % given CTX and 53 % given CDDP ( difference not significant ) . Toxicity profiles differed between the two arms , with hematologic , renal , and GI toxicities more frequent in the CDDP arm , and cutaneous toxicity and the need for nutritional support more frequent in the CTX arm . Serious adverse events related to treatment , including four versus one toxic deaths , were higher in the CTX arm ( 19 % v 3 % , P = .044 ) . Locoregional control , patterns of failure , and survivals were similar between the treatment arms . CONCLUSION CTX concomitant to RT lowered compliance and increased acute toxicity rates . Efficacy outcomes were similar in both arms . These results raise the issue of appropriately selecting patients with head and neck cancer who can benefit from CTX in combination with RT [16275937] PURPOSE To compare the antitumor activity and toxicity of the two induction chemotherapy treatments of paclitaxel , cisplatin , and fluorouracil ( FU ; PCF ) versus st and ard cisplatin and FU ( CF ) , both followed by chemoradiotherapy ( CRT ) , in locally advanced head and neck cancer ( HNC ) . PATIENTS AND METHODS Eligibility criteria included biopsy-proven , previously untreated , stage III or IV locally advanced HNC . Patients received either CF ( cisplatin 100 mg/m2 on day 1 plus FU 1000 [ corrected ] mg/m2 continuous infusion on days 1 through 5 ) or PCF ( paclitaxel 175 mg/m2 on day 1 , cisplatin 100 mg/m2 on day 2 , and FU 500 mg/m2 continuous infusion on days 2 through 6 ) ; both regimens were administered for three cycles every 21 days . Patients with complete response ( CR ) or partial response of greater than 80 % in primary tumor received additional CRT ( cisplatin 100 mg/m2 on days 1 , 22 , and 43 plus 70 Gy ) . RESULTS A total of 382 eligible patients were r and omly assigned to CF ( n = 193 ) or PCF ( n = 189 ) . The CR rate was 14 % in the CF arm v 33 % in the PCF arm ( P < .001 ) . Median time to treatment failure was 12 months in the CF arm compared with 20 months in the PCF arm ( log-rank test , P = .006 ; Tarone-Ware , P = .003 ) . PCF patients had a trend to longer overall survival ( OS ; 37 months in CF arm v 43 months in PCF arm ; log-rank test , P = .06 ; Tarone-Ware , P = .03 ) . This difference was more evident in patients with unresectable disease ( OS : 26 months in CF arm v 36 months in PCF arm ; log-rank test , P = .04 ; Tarone-Ware , P = .03 ) . CF patients had a higher occurrence of grade 2 to 4 mucositis than PCF patients ( 53 % v 16 % , respectively ; P < .001 ) . CONCLUSION Induction chemotherapy with PCF was better tolerated and result ed in a higher CR rate than CF . However , new trials that compare induction chemotherapy plus CRT versus CRT alone are needed to better define the role of neoadjuvant treatment [17901953] Objectives We conducted a multicentric r and omized phase II trial comparing 5-FU continuous infusion ( PF ) and cisplatin , UFT and vinorelbine ( UFTVP ) as induction chemotherapy ( IC ) in locally advanced squamous cell head and neck cancer ( LA-SCHNC ) . Primary objective was complete response ( CR ) to IC and overall survival ( OS ) was a secondary objective . Material s and methods PF : cisplatin 100 mg/m2 i.v . Day 1 ( D1 ) and 5-FU 1,000 mg/m2 per day i.v . continous infusion D1–D5 , every 21 days . UFTVP : cisplatin 100 mg/m2 i.v . D1 ; UFT 200 mg/m2 per day p.o . D1–D21 and vinorelbine 25 mg/m2 i.v . D1 and D8 , every 21 days . Four IC courses were planned in both arms . Results A total of 206 patients ( pts ) were included ( PF/UFTVP : 99/107 ) : oral cavity : 8%/10 % , oropharynx : 20%/25 % , hypopharynx : 17%/14 % , larynx : 54%/50 % . Stage ( TNM , 2002 ) : III : 41%/35 % , IVA : 23%/27 % , IVB : 35%/38 % . Complete response to IC : PF:36%/UFTVP:31 % ( P : no significative ( NS ) ) . G 3–4 toxicity ( PF/UFTVP ) : neutropenia : 52%/72 % ; febrile neutropenia : 3%/20 % ( P < 0.001 ) ; anaemia:1%/14 % ( P < 0.001 ) ; trombocytopenia : 5%/0 % ( P = 0.02 ) ; mucositis : 15%/7 % ( P < 0.001 ) . Deaths during IC : 2(2%)/3(3 % ) . IC with UFTVP was associated with a favourable OS in the Cox analysis ( actuarial 5 year OS : 49 % vs. 34 % ; HR : 0.67 , 95 % CI : 0.47–0.95 , P : 0.03 ) . Conclusions Although clinical response is equal in both arms , overall survival ( Cox ) is better in the UFTVP arm . Febrile neutropenia and anaemia were more frequent with UFTVP while mucositis and trombocytopenia were more severe with PF [15629602] PURPOSE Previous r and omized trials have shown a benefit with concurrent use of the hypoxic cell cytotoxin mitomycin C ( MC ) and radiation ( RT ) in the management of squamous cell cancer of the head and neck ( SCCHN ) . We conducted a r and omized trial comparing MC with porfiromycin ( POR ) in combination with RT in the management of SCCHN . METHODS AND MATERIAL S Between 1992 and 1999 , 128 patients with SCCHN were enrolled in this prospect i ve r and omized trial . Patients were stratified by management intent , and balanced with respect to stage and site of disease . They were r and omized to receive MC ( 15 mg/M(2 ) ) or POR ( 40 mg/M(2 ) ) on Days 5 and 47 ( or last day ) of RT . Of 121 evaluable patients , 61 were r and omized to MC and 60 to POR . Patients were treated with st and ard daily RT to a total median dose of 64 Gy over 47 days . Patients were well balanced with respect to management intent , stage , site , age , sex , hemoglobin levels , tumor grade , radiation dose , and days on treatment . RESULTS There were no significant differences between the two arms with respect to acute hematologic or nonhematologic toxicities . As of January 2003 with a median follow-up of 6.3 years , there have been 19 local relapses ( 4 MC vs. 15 POR ) , 21 regional relapses ( 7 MC vs. 14 POR ) , 24 distant metastases ( 11 MC vs. 13 POR ) , and 66 deaths ( 33 MC vs. 33 POR ) . MC was superior to POR with respect to 5-year local relapse-free survival ( 91.6 % vs. 72.7 % , p = 0.01 ) , local-regional relapse-free survival ( 82 % vs. 65.3 % , p = 0.05 ) , and disease-free survival ( 72.8 % vs. 52.9 % , p = 0.026 ) . There were no significant differences between the two arms with respect to overall survival ( 49.2 % vs. 54.4 % ) or distant metastasis-free rate ( 79.9 % vs. 75.9 % ) . CONCLUSIONS Despite promising pre clinical data , and an acceptable toxicity profile , POR was inferior to MC as an adjunct to RT in the management of SCCHN . This r and omized trial emphasizes the need for r and omized studies to evaluate new agents in the management of SCCHN [23414589] BACKGROUND The relative efficacy of the addition of induction chemotherapy to chemoradiotherapy compared with chemoradiotherapy alone for patients with head and neck cancer is unclear . The PARADIGM study is a multicentre open-label phase 3 study comparing the use of docetaxel , cisplatin , and fluorouracil ( TPF ) induction chemotherapy followed by concurrent chemoradiotherapy with cisplatin-based concurrent chemoradiotherapy alone in patients with locally advanced head and neck cancer . METHODS Adult patients with previously untreated , non-metastatic , newly diagnosed head and neck cancer were eligible . Patients were eligible if their tumour was either unresectable or of low surgical curability on the basis of advanced tumour stage ( 3 or 4 ) or regional-node stage ( 2 or 3 , except T1N2 ) , or if they were a c and i date for organ preservation . Patients were r and omly assigned ( in a 1:1 ratio ) to receive either induction chemotherapy with three cycles of TPF followed by concurrent chemoradiotherapy with either docetaxel or carboplatin or concurrent chemoradiotherapy alone with two cycles of bolus cisplatin . A computer-generated r and omisation schedule using minimisation was prepared and the treatment assignment was done central ly at one of the study sites . Patients , study staff , and investigators were not masked to group assignment . Stratification factors were WHO performance status , primary disease site , and stage . The primary endpoint was overall survival . Analysis was by intention to treat . Patient accrual was terminated in December , 2008 , because of slow enrolment . The trial is registered with Clinical Trials.gov , number NCT00095875 . FINDINGS Between Aug 24 , 2004 , and Dec 29 , 2008 , we enrolled 145 patients across 16 sites . After a median follow-up of 49 months ( IQR 39 - 63 ) , 41 patients had died-20 in the induction chemotherapy followed by chemoradiotherapy group and 21 in the chemoradiotherapy alone group . 3-year overall survival was 73 % ( 95 % CI 60 - 82 ) in the induction therapy followed by chemoradiotherapy group and 78 % ( 66 - 86 ) in the chemoradiotherapy alone group ( hazard ratio 1·09 , 95 % CI 0·59 - 2·03 ; p=0·77 ) . More patients had febrile neutropenia in the induction chemotherapy followed by chemoradiotherapy group ( 16 patients ) than in the chemoradiotherapy alone group ( one patient ) . INTERPRETATION Although survival results were good in both groups there was no difference noted between those patients treated with induction chemotherapy followed by chemoradiotherapy and those who received chemoradiotherapy alone . We can not rule out the possibility of a difference in survival going undetected due to early termination of the trial . Clinicians should still use their best judgment , based on the available data , in the decision of how to best treat patients . The addition of induction chemotherapy remains an appropriate approach for advanced disease with high risk for local or distant failure . FUNDING Sanofi-Aventis [25049329] PURPOSE Induction chemotherapy ( IC ) before radiotherapy lowers distant failure ( DF ) rates in locally advanced squamous cell carcinoma of the head and neck ( SCCHN ) . The goal of this phase III trial was to determine whether IC before chemoradiotherapy ( CRT ) further improves survival compared with CRT alone in patients with N2 or N3 disease . PATIENTS AND METHODS Treatment-naive patients with nonmetastatic N2 or N3 SCCHN were r and omly assigned to CRT alone ( CRT arm ; docetaxel , fluorouracil , and hydroxyurea plus radiotherapy 0.15 Gy twice per day every other week ) versus two 21-day cycles of IC ( docetaxel 75 mg/m(2 ) on day 1 , cisplatin 75 mg/m(2 ) on day 1 , and fluorouracil 750 mg/m(2 ) on days 1 to 5 ) followed by the same CRT regimen ( IC + CRT arm ) . The primary end point was overall survival ( OS ) . Secondary end points included DF-free survival , failure pattern , and recurrence-free survival ( RFS ) . RESULTS A total of 285 patients were r and omly assigned . The most common grade 3 to 4 toxicities during IC were febrile neutropenia ( 11 % ) and mucositis ( 9 % ) ; during CRT ( both arms combined ) , they were mucositis ( 49 % ) , dermatitis ( 21 % ) , and leukopenia ( 18 % ) . Serious adverse events were more common in the IC arm ( 47 % v 28 % ; P = .002 ) . With a minimum follow-up of 30 months , there were no statistically significant differences in OS ( hazard ratio , 0.91 ; 95 % CI , 0.59 to 1.41 ) , RFS , or DF-free survival . CONCLUSION IC did not translate into improved OS compared with CRT alone . However , the study was underpowered because it did not meet the planned accrual target , and OS was higher than predicted in both arms . IC can not be recommended routinely in patients with N2 or N3 locally advanced SCCHN [18222010] BACKGROUND AND PURPOSE Post-operative radiotherapy is indicated for the treatment of head and neck cancers . In vitro , chemotherapy potentiates the cytotoxic effects of radiation . We report the results of a r and omized trial testing post-operative radiotherapy alone versus concomitant carboplatin and radiotherapy for head and neck cancers with lymph node involvement . MATERIAL S AND METHODS The study involved patients undergoing curative-intent surgery for head and neck cancers with histological evidence of lymph node involvement . Patients were r and omly assigned to receive radiotherapy alone ( 54 - 72Gy , 30 - 40 fractions , 6 - 8 weeks ) or identical treatment plus concomitant Carboplatin ( 50mg/m(2 ) administered by IV infusion twice weekly ) . RESULTS Between February 1994 and June 2002 , 144 patients were included . With a median follow-up of 106 months ( 95 % confidence interval ( CI ) [ 92 - 119 ] ) , the 2-year rate of loco-regional control was 73 % ( 95 % CI : 0.61 - 0.84 ) in the combined treatment group and 68 % ( 95 % CI : 0.57 - 0.80 ) in the radiotherapy group ( p=0.26 ) . Overall survival did not differ significantly between groups ( hazard ratio for death , 1.05 ; 95 % CI : 0.69 - 1.60 ; p=0.81 ) . CONCLUSIONS Twice-weekly administration of carboplatin concomitant to post-operative radiotherapy did not improve local control or overall survival rates in this population of patients with node-positive head and neck cancers [24256848] BACKGROUND Concurrent chemoradiotherapy ( CCRT ) is the st and ard treatment for patients with unresectable , nonmetastatic locoregionally advanced squamous-cell carcinoma of the head and neck ( LASCCHN ) . This r and omized , open-label , phase III clinical trial compared the efficacy between st and ard CCRT and two different induction chemotherapy ( ICT ) regimens followed by CCRT . PATIENTS AND METHODS Patients with untreated LASCCHN were r and omly assigned to ICT ( three cycles ) , with either docetaxel ( Taxotere ) , cisplatin and 5-fluorouracil ( TPF arm ) or cisplatin and 5-fluorouracil ( PF arm ) , followed by CCRT [ 7 weeks of radiotherapy ( RT ) with cisplatin 100 mg/m(2 ) on days 1 , 22 and 43 ] ; or 7 weeks of CCRT alone . The primary end points were progression-free survival ( PFS ) and time-to-treatment failure ( TTF ) . RESULTS In the intention-to-treat ( ITT ) population ( n = 439 ) , the median PFS times were 14.6 ( 95 % CI , 11.6 - 20.4 ) , 14.3 ( 95 % CI , 11.8 - 19.3 ) and 13.8 months ( 95 % CI , 11.0 - 17.5 ) at TPF-CCRT , PF-CCRT and CCRT arms , respectively ( log-rank P = 0.56 ) . The median TTF were 7.9 ( 95 % CI , 5.9 - 11.8 ) , 7.9 ( 95 % CI , 6.5 - 11.8 ) and 8.2 months ( 95 % CI , 6.7 - 12.6 ) for TPF-CCRT , PF-CCRT and CCRT alone , respectively ( log-rank P = 0.90 ) . There were no statistically significant differences for overall survival ( OS ) . Toxic effects from ICT-CCRT were manageable . CONCLUSION Overall , this trial failed to show any advantage of ICT-CCRT over CCRT alone in patients with unresectable LASCCHN [12758236] BACKGROUND AND PURPOSE Single agent mitomycin c ( MMC ) has been shown to improve the outcome of radiotherapy in single institution trials . In order to confirm these findings in a broader worldwide setting , the International Atomic Energy Agency ( IAEA ) initiated a multicentre trial r and omising between radiotherapy alone versus radiotherapy plus MMC . MATERIAL AND METHODS Patients with advanced head and neck cancer were treated with primary curative radiotherapy ( 66 Gy in 33 fractions with five fractions per week ) + /-a single injection ( 15 mg/m(2 ) ) of MMC at the end of the first week of radiotherapy . Stratification parameters were tumour localization , T-stage , N-stage , and institution . A total of 558 patients were recruited in the trial from February 1996 to December 1999 . Insufficient accrual and reporting led to the exclusion of three centres . The final study population consisted of 478 patients from seven centres . Patients had stage III ( n=223 ) or stage IV ( n=255 ) squamous cell carcinoma of the oral cavity ( n=230 ) , oropharynx ( n=140 ) , hypopharynx ( n=65 ) or larynx ( n=43 ) . Prognostic factors like age , gender , site , size , differentiation and stage were well balanced between the two arms . RESULTS The haematological side effects of MMC were very modest ( < 5 % grade 3 - 4 ) and did not require any specific interventions . Furthermore , MMC did not enhance the incidence or severity of acute and late radiation side effects . Confluent mucositis and dry skin desquamation was common , occurring in 56 % and 62 % of patients , respectively . The overall 3-year primary locoregional tumour control , disease-specific and overall survival rates were 19 , 36 and 30 % , respectively . Gender , haemoglobin drop , tumour site , tumour and nodal stage were significant parameters for loco-regional tumour control . There was no significant effect of MMC on locoregional control or survival , except for the 161 N0 patients , where MMC result ed in a better loco-regional control ( 3-year estimate 16 % vs. 29 % , P=0.01 ) . CONCLUSIONS The study did not show any major influence of MMC on loco-regional tumour control , survival or morbidity after primary radiotherapy in stage III-IV head and neck cancer except in N0 patients where loco-regional control was significantly improved [2363468] The objective of the study was to evaluate the effect of neoadjuvant chemotherapy on the survival of patients with oropharyngeal cancer . Patients with a squamous cell carcinoma of the oropharynx for whom curative radiotherapy or surgery was considered feasible were entered in a multicentric r and omized trial comparing neoadjuvant chemotherapy followed by loco-regional treatment to the same loco-regional treatment without chemotherapy . The loco-regional treatment consisted either of surgery plus radiotherapy or of radiotherapy alone . Three cycles of chemotherapy consisting of Cisplatin ( 100 mg/m2 ) on day 1 followed by a 24-hour i.v . infusion of fluorouracil ( 1000 mg/m2/day ) for 5 days were delivered every 21 days . 2–3 weeks after the end of chemotherapy , local treatment was performed . The trial was conducted by the Groupe d'Etude des Tumeurs de la Tête Et du Cou ( GETTEC ) . A total of 318 patients were enrolled in the study between 1986 and 1992 . Overall survival was significantly better ( P = 0.03 ) in the neoadjuvant chemotherapy group than in the control group , with a median survival of 5.1 years versus 3.3 years in the no chemotherapy group . The effect of neoadjuvant chemotherapy on event-free survival was smaller and of borderline significance ( P = 0.11 ) . Stratification of the results on the type of local treatment , surgery plus radiotherapy or radiotherapy alone , did not reveal any heterogeneity in the effect of chemotherapy . © 2000 Cancer Research Campaign [25002723] PURPOSE To report results of a r and omized phase II trial ( Radiation Therapy Oncology Group RTOG-0234 ) examining concurrent chemoradiotherapy and cetuximab in the postoperative treatment of patients with squamous cell carcinoma of the head and neck ( SCCHN ) with high-risk pathologic features . PATIENTS AND METHODS Eligibility required pathologic stage III to IV SCCHN with gross total resection showing positive margins and /or extracapsular nodal extension and /or two or more nodal metastases . Patients were r and omly assigned to 60 Gy radiation with cetuximab once per week plus either cisplatin 30 mg/m(2 ) or docetaxel 15 mg/m(2 ) once per week . RESULTS Between April 2004 and December 2006 , 238 patients were enrolled . With a median follow-up of 4.4 years , 2-year overall survival ( OS ) was 69 % for the cisplatin arm and 79 % for the docetaxel arm ; 2-year disease-free survival ( DFS ) was 57 % and 66 % , respectively . Patients with p16-positive oropharynx tumors showed markedly improved survival outcome relative to patients with p16-negative oropharynx tumors . Grade 3 to 4 myelosuppression was observed in 28 % of patients in the cisplatin arm and 14 % in the docetaxel arm ; mucositis was observed in 56 % and 54 % , respectively . DFS in this study was compared with that in the chemoradiotherapy arm of the RTOG-9501 trial ( Phase III Intergroup Trial of Surgery Followed by Radiotherapy Versus Radiochemotherapy for Resectable High Risk Squamous Cell Carcinoma of the Head and Neck ) , which had a hazard ratio of 0.76 for the cisplatin arm versus control ( P = .05 ) and 0.69 for the docetaxel arm versus control ( P = .01 ) , reflecting absolute improvement in 2-year DFS of 2.5 % and 11.1 % , respectively . CONCLUSION The delivery of postoperative chemoradiotherapy and cetuximab to patients with SCCHN is feasible and tolerated with predictable toxicity . The docetaxel regimen shows favorable outcome with improved DFS and OS relative to historical controls and has commenced formal testing in a phase II/III trial [14645636] BACKGROUND Induction chemotherapy with cisplatin plus fluorouracil followed by radiotherapy is the st and ard alternative to total laryngectomy for patients with locally advanced laryngeal cancer . The value of adding chemotherapy to radiotherapy and the optimal timing of chemotherapy are unknown . METHODS We r and omly assigned patients with locally advanced cancer of the larynx to one of three treatments : induction cisplatin plus fluorouracil followed by radiotherapy , radiotherapy with concurrent administration of cisplatin , or radiotherapy alone . The primary end point was preservation of the larynx . RESULTS A total of 547 patients were r and omly assigned to one of the three study groups . The median follow-up period was 3.8 years . At two years , the proportion of patients who had an intact larynx after radiotherapy with concurrent cisplatin ( 88 percent ) differed significantly from the proportions in the groups given induction chemotherapy followed by radiotherapy ( 75 percent , P=0.005 ) or radiotherapy alone ( 70 percent , P<0.001 ) . The rate of locoregional control was also significantly better with radiotherapy and concurrent cisplatin ( 78 percent , vs. 61 percent with induction cisplatin plus fluorouracil followed by radiotherapy and 56 percent with radiotherapy alone ) . Both of the chemotherapy-based regimens suppressed distant metastases and result ed in better disease-free survival than radiotherapy alone . However , overall survival rates were similar in all three groups . The rate of high- grade toxic effects was greater with the chemotherapy-based regimens ( 81 percent with induction cisplatin plus fluorouracil followed by radiotherapy and 82 percent with radiotherapy with concurrent cisplatin , vs. 61 percent with radiotherapy alone ) . The mucosal toxicity of concurrent radiotherapy and cisplatin was nearly twice as frequent as the mucosal toxicity of the other two treatments during radiotherapy . CONCLUSIONS In patients with laryngeal cancer , radiotherapy with concurrent administration of cisplatin is superior to induction chemotherapy followed by radiotherapy or radiotherapy alone for laryngeal preservation and locoregional control [21279703] The objective of this study was to compare concomitant chemoradiotherapy based on weekly low-dose gemcitabine versus weekly low-dose paclitaxel in locally advanced head and neck squamous cell carcinoma . Previously , untreated patients with locally advanced squamous cell carcinoma of the head and neck were r and omly assigned to one of the two concomitant chemoradiation regimens : ( 1 ) weekly gemcitabine at a dose of 100 mg/m2 over 30 min 1–2 h before radiotherapy and ( 2 ) weekly paclitaxal at a dose of 20 mg/m2 over 60 min 4–6 h before radiotherapy . The planned radiotherapy dose was 65 Gy over 6.5 weeks in 32 setting s. Two hundred and sixteen patients were r and omly divided into 2 groups : group A ( 110 patients ) and group B ( 106 patients ) who received concomitant weekly low-dose gemcitabine and low-dose paclitaxal , respectively , with the radiotherapy protocol . The hematological toxicity was generally mild . On the contrary , non-hematologic toxicities were severe . Grade III mucositis occurred in 36 % in group A and in 24 % in group B ( P = 0.04 ) . Moreover , grade III dermatitis were encountered in 24 % in group A and 13 % in group B ( P = 0.049 ) . Thirty-two ( 29 % ) of group A and 18(17 % ) of group B patients required enteral or parenteral feeding ( P = 0.01 ) . Sixteen ( 15 % ) of group A and 6 ( 6 % ) of group B required enteral or parenteral feeding that lasted for 6 months ( P = 0.03 ) . Regarding the late effect on swallowing , 8 % of patients in group A and 2 % of patients in group B required enteral or parenteral feeding for more than 6 months ( P = 0.035 ) . Response rates were 78 and 89 % in groups A and B , respectively ( P = 0.038 ) . The 2-year progression-free survival figures were 54 and 64 % of groups A and B , respectively ; however , the 2-year overall survival figures were 56 and 67 % , respectively . On the other h and , the 3-year progression-free survival figures were 39 and 48 % for groups A and B , respectively , while the 3-year overall survival figures were 45 and 49 % , respectively ( P = 0.05 ) . Both concomitant chemoradiotherapy regimens were easily given in the outpatient clinic . The regimen based on paclitaxel was significantly more tolerable and effective ; however , the difference was not enormous [25596659] BACKGROUND We aim ed to compare panitumumab , a fully human monoclonal antibody against EGFR , plus radiotherapy with chemoradiotherapy in patients with unresected , locally advanced squamous-cell carcinoma of the head and neck . METHODS In this international , open-label , r and omised , controlled , phase 2 trial , we recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 22 sites in eight countries worldwide . Patients aged 18 years and older with stage III , IVa , or IVb , previously untreated , measurable ( ≥ 10 mm for at least one dimension ) , locally advanced squamous-cell carcinoma of the head and neck ( non-nasopharygeal ) and an Eastern Cooperative Oncology Group performance status of 0 - 1 were r and omly assigned ( 2:3 ) by an independent vendor to open-label chemoradiotherapy ( two cycles of cisplatin 100 mg/m(2 ) during radiotherapy ) or to radiotherapy plus panitumumab ( three cycles of panitumumab 9 mg/kg every 3 weeks administered with radiotherapy ) using a stratified r and omisation with a block size of five . All patients received 70 - 72 Gy to gross tumour and 54 Gy to areas of sub clinical disease with accelerated fractionation radiotherapy . The primary endpoint was local-regional control at 2 years , analysed in all r and omly assigned patients who received at least one dose of their assigned protocol -specific treatment ( chemotherapy , radiation , or panitumumab ) . The trial is closed and this is the final analysis . This study is registered with Clinical Trials.gov , number NCT00547157 . FINDINGS Between Nov 30 , 2007 , and Nov 16 , 2009 , 152 patients were enrolled , and 151 received treatment ( 61 in the chemoradiotherapy group and 90 in the radiotherapy plus panitumumab group ) . Local-regional control at 2 years was 61 % ( 95 % CI 47 - 72 ) in the chemoradiotherapy group and 51 % ( 40 - 62 ) in the radiotherapy plus panitumumab group . The most frequent grade 3 - 4 adverse events were mucosal inflammation ( 25 [ 40 % ] of 62 patients in the chemoradiotherapy group vs 37 [ 42 % ] of 89 patients in the radiotherapy plus panitumumab group ) , dysphagia ( 20 [ 32 % ] vs 36 [ 40 % ] ) , and radiation skin injury ( seven [ 11 % ] vs 21 [ 24 % ] ) . Serious adverse events were reported in 25 ( 40 % ) of 62 patients in the chemoradiotherapy group and in 30 ( 34 % ) of 89 patients in the radiotherapy plus panitumumab group . INTERPRETATION Panitumumab can not replace cisplatin in the combined treatment with radiotherapy for unresected stage III-IVb squamous-cell carcinoma of the head and neck , and the role of EGFR inhibition in locally advanced squamous-cell carcinoma of the head and neck needs to be reassessed . FUNDING Amgen [11735172] AIMS A prospect i ve r and omized study was conducted to evaluate the benefit of adjuvant levamisole/UFT ( futraful and uracil ) chemotherapy in head and neck squamous cell carcinoma . METHODS Sixty-five patients with stage III and IV squamous cell carcinomas of oral cavity , oropharynx , hypopharynx and larynx with no distant metastasis were r and omized for the chemotherapy study . Thirty-one patients were r and omized for chemotherapy and two of them were subsequently excluded . In this study , a total of 29 patients on levamisole/UFT therapy and 34 patients on the control group were analysed . The main outcome was measured by the 5-year disease-free actuarial survival rate . RESULTS The rates of distant metastasis were 10 % for chemotherapy group and 32 % for control group ( P=0.06 ) . The 5-year disease-free actuarial survival rates for patients with and without adjuvant chemotherapy were 57 % and 39 % respectively ( P=0.207 ) . CONCLUSIONS A trend of better distant control in head and neck cancer patients with post-operative adjuvant oral chemotherapy was observed . The side effects were minimal . However , there was no statistically significant improvement in the overall long-term survival . It may be of value to conduct a large-scale multi-centre prospect i ve r and omized study to verify the efficacy of levamisole and UFT as post-operative adjuvant chemotherapy for the control of distant metastasis in high-risk population [20888709] PURPOSE The Head and Neck Intergroup conducted a Phase III r and omized trial to determine whether the addition weekly cisplatin to daily radiation therapy ( RT ) would improve survival in patients with unresectable squamous cell head- and -neck carcinoma . METHODS AND MATERIAL S Eligible patients were r and omized to RT ( 70 Gy at 1.8 - 2 Gy/day ) or to the identical RT with weekly cisplatin dosed at 20 mg/m(2 ) . Failure-free survival ( FFS ) and overall survival ( OS ) curves were estimated with the Kaplan-Meier method and compared with the log rank test . RESULTS Between 1982 and 1987 , 371 patients were accrued , and 308 patients were found eligible for analysis . Median follow-up was 62 months . The median FFS was 6.5 and 7.2 months for the RT and RT + cisplatin groups , respectively ( p = 0.30 ) . The p value for the treatment difference was p = 0.096 in multivariate modeling of FFS ( compared to a p = 0.30 in univariate analysis ) . Expected acute toxicities were significantly increased with the addition of cisplatin except for in-field RT toxicities . Late toxicities were not significantly different except for significantly more esophageal ( 9 % vs. 3 % , p = 0.03 ) and laryngeal ( 11 % vs. 4 % , p = 0.05 ) late toxicities in the RT + cisplatin group . CONCLUSION The addition of concurrent weekly cisplatin at 20 mg/m(2 ) to daily radiation did not improve survival , although there was evidence of activity . Low-dose weekly cisplatin seems to have modest tumor radiosensitization but can increase the risk of late swallowing complications [8985019] PURPOSE To report the final results of a prospect i ve r and omized trial that aim ed to evaluate efficacy and toxicity of concomitant postoperative radiotherapy and Cisplatin infusion in patients with Stage III or IV squamous cell carcinoma of the head and neck and histological evidence of extracapsular spread of tumor in lymph node metastase(s ) . METHODS AND MATERIAL S Radiotherapy was delivered using a daily dose of 1.7 Gy for the first 54 Gy and 1.8 to 2 Gy until the completion of the treatment . Cisplatin 50 mg i.v . with forced hydratation was given or not every week ( i.e. , seven to nine cycles ) concurrently with radiotherapy . A total of 44 patients were treated by irradiation only ( RT group ) and 39 by irradiation with chemotherapy ( CM group ) . RESULTS The RT group displayed a higher rate of loco-regional failures as compared to CM group ( 41 vs. 23 % ; p = 0.08 ) . The overall survival , the survival corrected for deaths by intercurrent disease , and the disease-free survival were better in CM group as compared to RT group with statistically significant differences . Survival without loco-regional treatment failure was better in the CM group , the difference being close to the level of significance ( p = 0.05 ) . Survival without distant metastases were comparable in the two therapeutic groups . Ten severe late complications were observed , four in the RT group ( 17 % ) and six in the CM group ( 22 % ) . Cox univariate analysis confirmed the importance of the therapeutic modality in predicting the overall survival , the survival corrected for deaths by intercurrent disease , and the disease-free survival . CONCLUSIONS The present final report of this phase III study confirms preliminary results . The concomitant use of 50 mg weekly Cisplatin infusion and postoperative radiation improved loco-regional control and survival . No significant increase of late radiation complications was observed in the CM group [28142468] 51 Background : To determine the efficacy , safety and tolerability of concurrent nimotuzumab ( monoclonal antibody against epidermal growth factor receptor ) used in combination with chemoradiation versus chemoradiation ( CRT ) alone in advanced inoperable squamous cell carcinoma of the head and neck ( SCCHN ) . METHODS 56 patients were r and omly assigned to either of the two treatment arms , nimotuzumab + CRT arm and CRT alone arm . Both arms received concurrent Cisplatin 30 mg/m2 repeated weekly for 6 - 7 cycles along with external beam radiotherapy 64 - 70 Gy ( 200cGy/day for 5 days a week for 6 - 7 weeks ) . Nimotuzumab arm additionally received nimotuzumab 200 mg weekly for 6 - 7 cycles . The patients were followed for 6 months after completion of CRT . The study end points were tumor response evaluation according to the RECIST Criteria version 1.1 and safety analysis using RTOG Acute Radiation Morbidity Scoring Criteria . Patients were evaluated weekly with hematologic tests and for adverse events like mucositis and dermatitis during the CRT . Tumor assessment was performed with clinical and endoscopic methods regularly during the CRT and then at 1 month , 3 months , and 6 months intervals after CRT . One MR imaging was done before starting the CRT to evaluate the baseline tumor characteristics , and another was done after the completion of CRT either at 3 months or 6 months or at both the intervals . RESULTS 25 patients each were evaluable in both the arms who completed the 6-month study . The overall response rate ( complete response + partial response ) was 96 % in nimotuzumab + CRT arm , whereas it was only 72 % in CRT alone arm after 6 months of completion of CRT , which is statistically significant ( p value = 0.0206 by Chi Square test ) . Additionally , nimotuzumab did not potentiate toxicities of CRT , and there was no significant difference in the acute radiation mucositis , dermatitis , or hematological toxicities in both the groups ( p value>>0.05 ) . CONCLUSIONS Nimotuzumab can be safely added to the st and ard CRT treatment for advanced inoperable SCCHN , to achieve better tumor response without potentiating toxicity [23182993] PURPOSE To report the long-term results of the Intergroup Radiation Therapy Oncology Group 91 - 11 study evaluating the contribution of chemotherapy added to radiation therapy ( RT ) for larynx preservation . PATIENTS AND METHODS Patients with stage III or IV glottic or supraglottic squamous cell cancer were r and omly assigned to induction cisplatin/fluorouracil ( PF ) followed by RT ( control arm ) , concomitant cisplatin/RT , or RT alone . The composite end point of laryngectomy-free survival ( LFS ) was the primary end point . RESULTS Five hundred twenty patients were analyzed . Median follow-up for surviving patients is 10.8 years . Both chemotherapy regimens significantly improved LFS compared with RT alone ( induction chemotherapy v RT alone : hazard ratio [ HR ] , 0.75 ; 95 % CI , 0.59 to 0.95 ; P = .02 ; concomitant chemotherapy v RT alone : HR , 0.78 ; 95 % CI , 0.78 to 0.98 ; P = .03 ) . Overall survival did not differ significantly , although there was a possibility of worse outcome with concomitant relative to induction chemotherapy ( HR , 1.25 ; 95 % CI , 0.98 to 1.61 ; P = .08 ) . Concomitant cisplatin/RT significantly improved the larynx preservation rate over induction PF followed by RT ( HR , 0.58 ; 95 % CI , 0.37 to 0.89 ; P = .0050 ) and over RT alone ( P < .001 ) , whereas induction PF followed by RT was not better than treatment with RT alone ( HR , 1.26 ; 95 % CI , 0.88 to 1.82 ; P = .35 ) . No difference in late effects was detected , but deaths not attributed to larynx cancer or treatment were higher with concomitant chemotherapy ( 30.8 % v 20.8 % with induction chemotherapy and 16.9 % with RT alone ) . CONCLUSION These 10-year results show that induction PF followed by RT and concomitant cisplatin/RT show similar efficacy for the composite end point of LFS . Locoregional control and larynx preservation were significantly improved with concomitant cisplatin/RT compared with the induction arm or RT alone . New strategies that improve organ preservation and function with less morbidity are needed [21300466] PURPOSE To compare the long-term outcome of treatment with concomitant cisplatin and hyperfractionated radiotherapy versus treatment with hyperfractionated radiotherapy alone in patients with locally advanced head and neck cancer . METHODS AND MATERIAL S From July 1994 to July 2000 , a total of 224 patients with squamous cell carcinoma of the head and neck were r and omized to receive either hyperfractionated radiotherapy alone ( median total dose , 74.4 Gy ; 1.2 Gy twice daily ; 5 days per week ) or the same radiotherapy combined with two cycles of cisplatin ( 20 mg/m(2 ) for 5 consecutive days during weeks 1 and 5 ) . The primary endpoint was the time to any treatment failure ; secondary endpoints were locoregional failure , metastatic failure , overall survival , and late toxicity assessed according to Radiation Therapy Oncology Group criteria . RESULTS Median follow-up was 9.5 years ( range , 0.1 - 15.4 years ) . Median time to any treatment failure was not significantly different between treatment arms ( hazard ratio [ HR ] , 1.2 [ 95 % confidence interval { CI } , 0.9 - 1.7 ; p = 0.17 ] ) . Rates of locoregional failure-free survival ( HR , 1.5 [ 95 % CI , 1.1 - 2.1 ; p = 0.02 ] ) , distant metastasis-free survival ( HR , 1.6 [ 95 % CI , 1.1 - 2.5 ; p = 0.02 ] ) , and cancer-specific survival ( HR , 1.6 [ 95 % CI , 1.0 - 2.5 ; p = 0.03 ] ) were significantly improved in the combined-treatment arm , with no difference in major late toxicity between treatment arms . However , overall survival was not significantly different ( HR , 1.3 [ 95 % CI , 0.9 - 1.8 ; p = 0.11 ] ) . CONCLUSIONS After long-term follow-up , combined-treatment with cisplatin and hyperfractionated radiotherapy maintained improved rates of locoregional control , distant metastasis-free survival , and cancer-specific survival compared to that of hyperfractionated radiotherapy alone , with no difference in major late toxicity [15128893] BACKGROUND Despite the use of resection and postoperative radiotherapy , high-risk squamous-cell carcinoma of the head and neck frequently recurs in the original tumor bed . We tested the hypothesis that concurrent postoperative administration of cisplatin and radiotherapy would improve the rate of local and regional control . METHODS Between September 9 , 1995 , and April 28 , 2000 , 459 patients were enrolled . After undergoing total resection of all visible and palpable disease , 231 patients were r and omly assigned to receive radiotherapy alone ( 60 to 66 Gy in 30 to 33 fractions over a period of 6 to 6.6 weeks ) and 228 patients to receive the identical treatment plus concurrent cisplatin ( 100 mg per square meter of body-surface area intravenously on days 1 , 22 , and 43 ) . RESULTS After a median follow-up of 45.9 months , the rate of local and regional control was significantly higher in the combined-therapy group than in the group given radiotherapy alone ( hazard ratio for local or regional recurrence , 0.61 ; 95 percent confidence interval , 0.41 to 0.91 ; P=0.01 ) . The estimated two-year rate of local and regional control was 82 percent in the combined-therapy group , as compared with 72 percent in the radiotherapy group . Disease-free survival was significantly longer in the combined-therapy group than in the radiotherapy group ( hazard ratio for disease or death , 0.78 ; 95 percent confidence interval , 0.61 to 0.99 ; P=0.04 ) , but overall survival was not ( hazard ratio for death , 0.84 ; 95 percent confidence interval , 0.65 to 1.09 ; P=0.19 ) . The incidence of acute adverse effects of grade 3 or greater was 34 percent in the radiotherapy group and 77 percent in the combined-therapy group ( P<0.001 ) . Four patients who received combined therapy died as a direct result of the treatment . CONCLUSIONS Among high-risk patients with resected head and neck cancer , concurrent postoperative chemotherapy and radiotherapy significantly improve the rates of local and regional control and disease-free survival . However , the combined treatment is associated with a substantial increase in adverse effects [19897418] BACKGROUND Previous results from our phase 3 r and omised trial showed that adding cetuximab to primary radiotherapy increased overall survival in patients with locoregionally advanced squamous-cell carcinoma of the head and neck ( LASCCHN ) at 3 years . Here we report the 5-year survival data , and investigate the relation between cetuximab-induced rash and survival . METHODS Patients with LASCCHN of the oropharynx , hypopharynx , or larynx with measurable disease were r and omly allocated in a 1:1 ratio to receive either comprehensive head and neck radiotherapy alone for 6 - 7 weeks or radiotherapy plus weekly doses of cetuximab : 400 mg/m(2 ) initial dose , followed by seven weekly doses at 250 mg/m(2 ) . R and omisation was done with an adaptive minimisation technique to balance assignments across stratification factors of Karnofsky performance score , T stage , N stage , and radiation fractionation . The trial was un-blinded . The primary endpoint was locoregional control , with a secondary endpoint of survival . Following discussion s with the US Food and Drug Administration , the data set was locked , except for queries to the sites about overall survival , before our previous report in 2006 , so that an independent review could be done . Analyses were done on an intention-to-treat basis . Following completion of treatment , patients underwent physical examination and radiographic imaging every 4 months for 2 years , and then every 6 months thereafter . The trial is registered at www . Clinical Trials.gov , number NCT00004227 . FINDINGS Patients were r and omly assigned to receive radiotherapy with ( n=211 ) or without ( n=213 ) cetuximab , and all patients were followed for survival . Up date d median overall survival for patients treated with cetuximab and radiotherapy was 49.0 months ( 95 % CI 32.8 - 69.5 ) versus 29.3 months ( 20.6 - 41.4 ) in the radiotherapy-alone group ( hazard ratio [ HR ] 0.73 , 95 % CI 0.56 - 0.95 ; p=0.018 ) . 5-year overall survival was 45.6 % in the cetuximab-plus-radiotherapy group and 36.4 % in the radiotherapy-alone group . Additionally , for the patients treated with cetuximab , overall survival was significantly improved in those who experienced an acneiform rash of at least grade 2 severity compared with patients with no rash or grade 1 rash ( HR 0.49 , 0.34 - 0.72 ; p=0.002 ) . INTERPRETATION For patients with LASCCHN , cetuximab plus radiotherapy significantly improves overall survival at 5 years compared with radiotherapy alone , confirming cetuximab plus radiotherapy as an important treatment option in this group of patients . Cetuximab-treated patients with prominent cetuximab-induced rash ( grade 2 or above ) have better survival than patients with no or grade 1 rash . FUNDING ImClone Systems , Merck KGaA , and Bristol-Myers Squibb [21233014] BACKGROUND At a minimum follow-up of 2 years , the TAX 324 study showed a significant survival benefit of induction chemotherapy with docetaxel , cisplatin , and fluorouracil ( TPF ) versus cisplatin and fluorouracil ( PF ) in locally advanced head and neck cancer . We report the long-term results at 5 years ' minimum follow-up . METHODS TAX 324 was a r and omised , open-label phase 3 trial comparing three cycles of TPF induction chemotherapy ( docetaxel 75 mg/m(2 ) , followed by intravenous cisplatin 100 mg/m(2 ) and fluorouracil 1000 mg/m(2 ) per day , administered as a continuous 24-h infusion for 4 days ) with three cycles of PF ( intravenous cisplatin 100 mg/m(2 ) , followed by fluorouracil 1000 mg/m(2 ) per day as a continuous 24-h infusion for 5 days ) in patients with stage III or IV squamous-cell carcinoma of the head or neck . Both regimens were followed by 7 weeks of chemoradiotherapy with concomitant weekly carboplatin . R and omisation was done central ly with the use of a biased-coin minimisation technique . At study entry , patients were stratified according to the site of the primary tumour , nodal status ( N0 or N1 vs N2 or N3 ) , and institution . For this long-term analysis , data as of Dec 1 , 2008 , were gathered retrospectively from patients ' medical records . Overall and progression-free survival were the primary endpoints . Tracheostomy and dependence on a gastric feeding tube were used as surrogate measures for treatment-related long-term toxicity . The intention-to-treat analysis included data from all 501 patients ( 255 TPF , 246 PF ) ; data from the initial analysis in 2005 were used for 61 patients who were lost to follow-up . TAX 324 was registered at Clinical Trials.gov , NCT00273546 . FINDINGS Median follow-up was 72·2 months ( 95 % CI 68·8 - 75·5 ) . Overall survival was significantly better after treatment with TPF versus PF ( hazard ratio [ HR ] 0·74 , 95 % CI 0·58 - 0·94 ) , with an estimated 5-year survival of 52 % in patients treated with TPF and 42 % in those receiving PF . Median survival was 70·6 months ( 95 % CI 49·0 - 89·0 ) in the TPF group versus 34·8 months ( 22·6 - 48·0 ) in the PF group ( p=0·014 ) . Progression-free survival was also significantly better in patients treated with TPF ( median 38·1 months , 95 % CI 19·3 - 66·1 , vs 13·2 months , 10·6 - 20·7 ; HR 0·75 , 95 % CI 0·60 - 0·94 ) . We detected no significant difference in dependence on gastric feeding tubes and tracheostomies between treatment groups . In the TPF group , three ( 3 % ) of 91 patients remained feeding-tube dependent , compared with eight ( 11 % ) of 71 patients in the PF group . Six ( 7 % ) of 92 patients had tracheostomies in the TPF group , versus eight ( 11 % ) of 71 in the PF group . INTERPRETATION Induction chemotherapy with TPF provides long-term survival benefit compared with PF in locally advanced head and neck cancer . Patients who are c and i date s for induction chemotherapy should be treated with TPF . FUNDING Sanofi-Aventis [28021429] 5519 Background : Cetuximab is commonly used in combination with either chemotherapy or radiation in the treatment of HNC , although the optimal way to integrate cetuximab with concurrent chemoradiation ( CRT ) remains unclear . We explored the addition of cetuximab to induction chemotherapy and two established CRT platforms in a r and omized phase II trial . METHODS Patients with locoregionally advanced HNC were treated with cetuximab , carboplatin , paclitaxel induction chemotherapy for 2 cycles . Patients were r and omized to A : cetuximab , 5-FU , hydroxyurea , and hyperfractionated week-on week-off RT ( 72 - 74Gy ) ( CetuxFHX ) , or B : cetuximab , cisplatin , accelerated radiation with concomitant boost (CetuxPX)(72Gy ) . Primary endpoints were 1- and 2-year progression-free ( PFS ) , and overall survival ( OS ) . RESULTS 110 patients with locoregionally advanced HNC ( 108 with Stage IV ) were enrolled . 57.3 % of patients had oropharyngeal ( OP ) primaries ( A : 49 % , B : 66 % , p16 staining is pending ) . Induction response rate was 91.8 % . 99.1 % of patients developed a rash ( ≥ grade 3 in 16.4 % ) ; ≥ grade 3 neutropenia developed in 36.3 % of patients . Overall 1- and 2-year survival rates were 98.3 % and 89.5 % in CetuxFHX , and 94.2 % and 91.4 % in CetuxPX arm , with 21.1months median follow-up ( not statistically significant , p=0.27 , logrank test ) . Progression free survival at 1 and 2 years was 86.0 % and 82.3 % in CetuxFHX , and 95.9 % and 89.7 % in CetuxPX ( p=0.18 ) . Grade ≥3 mucositis was present in 91.1%(A ) and 94.3%(B ) of patients ; grade ≥3 dermatitis in 82.1 % and 50.9 % of patients . 95 % of patients completed therapy . Treatment failures occurred in both OP and non-OP tumors . CONCLUSIONS Cetuximab-based induction chemotherapy is well tolerated and active . Cetuximab can safely be integrated with both FHX and cisplatin based CRT with acceptable toxicities . Survival is favorable on both study arms suggesting that either platform could be investigated further . Data on HPV versus non-HPV-related tumors will be available [17538164] PURPOSE In this r and omized , phase III study , quality of life ( QoL ) was assessed in patients with locoregionally advanced squamous cell carcinoma of the head and neck ( SCCHN ) after high-dose radiotherapy alone or in combination with cetuximab . PATIENTS AND METHODS Patients with stage III or IV nonmetastatic and measurable squamous cell carcinoma of the oropharynx , hypopharynx , or larynx were eligible . QoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Question naire C30 ( EORTC QLQ-C30 ) and EORTC QLQ Head and Neck Cancer-Specific Module at baseline , week 4 , and at months 4 , 8 , and 12 postbaseline . RESULTS In this study , one of the largest conducted in a population of patients with locoregionally advanced SCCHN , 424 patients received radiotherapy alone ( 213 patients ) or radiotherapy plus cetuximab ( 211 patients ) . Radiotherapy/cetuximab significantly improved locoregional control ( P = .005 ) and overall survival ( P = .03 ) compared with radiotherapy alone , without significantly increasing radiotherapy-associated adverse events . The current analysis focused on the impact of cetuximab on the QoL. Compliance with completion of QoL question naires was high in both arms . QoL worsened during treatment and improved after cessation of treatment , reaching baseline levels at 12 months . There were no significant differences in QoL scores between the treatment arms . This was particularly notable for global health status/QoL , social functioning , social eating , and social contact . Pretreatment global health status/QoL was identified as a significant prognostic variable in these patients . CONCLUSION The addition of cetuximab to radiotherapy significantly improved locoregional control and increased overall survival without adversely affecting [22261362] BACKGROUND Concomitant chemoradiotherapy and accelerated radiotherapy independently improve outcomes for patients with locally advanced head and neck squamous-cell carcinoma ( HNSCC ) . We aim ed to assess the efficacy and safety of a combination of these approaches . METHODS In our open-label phase 3 r and omised trial , we enrolled patients with locally advanced , stage III and IV ( non-metastatic ) HNSCC and an Eastern Cooperative Oncology Group performance status of 0 - 2 . We r and omly allocated patients central ly with a computer program ( with centre , T stage , N stage , and localisation as minimisation factors ) in a 1:1:1 ratio to receive conventional chemoradiotherapy ( 70 Gy in 7 weeks plus three cycles of 4 days ' concomitant carboplatin-fluorouracil ) , accelerated radiotherapy-chemotherapy ( 70 Gy in 6 weeks plus two cycles of 5 days ' concomitant carboplatin-fluorouracil ) , or very accelerated radiotherapy alone ( 64·8 Gy [ 1·8 Gy twice daily ] in 3·5 weeks ) . The primary endpoint , progression-free survival ( PFS ) , was assessed in all enrolled patients . This trial is completed . The trial is registered with Clinical Trials.gov , number NCT00828386 . FINDINGS Between Feb 29 , 2000 , and May 9 , 2007 , we r and omly allocated 279 patients to receive conventional chemoradiotherapy , 280 to accelerated radiotherapy-chemotherapy , and 281 to very accelerated radiotherapy . Median follow-up was 5·2 years ( IQR 4·9 - 6·2 ) ; rates of chemotherapy and radiotherapy compliance were good in all groups . Accelerated radiotherapy-chemotherapy offered no PFS benefit compared with conventional chemoradiotherapy ( HR 1·02 , 95 % CI 0·84 - 1·23 ; p=0·88 ) or very accelerated radiotherapy ( 0·83 , 0·69 - 1·01 ; p=0·060 ) ; conventional chemoradiotherapy improved PFS compared with very accelerated radiotherapy ( 0·82 , 0·67 - 0·99 ; p=0·041 ) . 3-year PFS was 37·6 % ( 95 % CI 32·1 - 43·4 ) after conventional chemoradiotherapy , 34·1 % ( 28·7 - 39·8 ) after accelerated radiotherapy-chemotherapy , and 32·2 % ( 27·0 - 37·9 ) after very accelerated radiotherapy . More patients in the very accelerated radiotherapy group had RTOG grade 3 - 4 acute mucosal toxicity ( 226 [ 84 % ] of 268 patients ) compared with accelerated radiotherapy-chemotherapy ( 205 [ 76 % ] of 271 patients ) or conventional chemoradiotherapy ( 180 [ 69 % ] of 262 ; p=0·0001 ) . 158 ( 60 % ) of 265 patients in the conventional chemoradiotherapy group , 176 ( 64 % ) of 276 patients in the accelerated radiotherapy-chemotherapy group , and 190 ( 70 % ) of 272 patients in the very accelerated radiotherapy group were intubated with feeding tubes during treatment ( p=0·045 ) . INTERPRETATION Chemotherapy has a substantial treatment effect given concomitantly with radiotherapy and acceleration of radiotherapy can not compensate for the absence of chemotherapy . We noted the most favourable outcomes for conventional chemoradiotherapy , suggesting that acceleration of radiotherapy is probably not beneficial in concomitant chemoradiotherapy schedules . FUNDING French Ministry of Health [24613543] OBJECTIVE Overexpression of epidermal growth factor receptor ( EGFR ) in many cancers makes it an attractive therapeutic target . This study evaluated the clinical utility of nimotuzumab , a monoclonal anti-EGFR antibody , used concurrently with radiotherapy ( RT ) and chemoradiotherapy ( CRT ) in squamous cell carcinoma of the head and neck ( SCCHN ) . METHODS This open-label study r and omized 92 treatment-naïve patients ( 1:1 ) with advanced SCCHN into chemoradiation ( CRT ± nimotuzumab ) or radiation ( RT ± nimotuzumab ) group by investigator 's discretion ; these were further r and omized into CRT + nimotuzumab or CRT and RT + nimotuzumab or RT groups , respectively . Treatment included 6 cycles each of cisplatin ( 50 mg/week ) , nimotuzumab ( 200 mg/week ) , and RT ( total dose , 60 - 66 Gy ) . Response ( tumor size reduction ) was assessed at Month 6 post-treatment and survival , at Month 60 . RESULTS Forty and 36 patients in the chemoradiation and radiation groups , respectively ( intent-to-treat population ) were evaluated . Overall response at Month 6 post-treatment was 100 % with CRT + nimotuzumab , 70 % with CRT , 76 % with RT + nimotuzumab , and 37 % with RT . At Month 60 , overall survival was 57 % with CRT + nimotuzumab , 26 % with CRT ( P = 0.03 ) , 39 % with RT + nimotuzumab , and 26 % with RT ( P > 0.05 ) . Median overall survival was not reached for CRT + nimotuzumab ; it was 21.94 months for CRT ( P = 0.0078 ) , 14.36 months for RT + nimotuzumab , and 12.78 months for RT ( P = 0.45 ) . Risk of death was 64 % lower with CRT + nimotuzumab than with CRT ( 95%CI : 0.37 , 1.56 ) , and 24 % lower with RT + nimotuzumab than with RT ( 95%CI : 0.16 , 0.79 ) . Thus nimotuzumab was safe and well tolerated with few mild to moderate self-limiting adverse events . CONCLUSION Concurrent use of nimotuzumab with CRT/RT is safe and provides long-term survival benefit [28490940] OBJECTIVE The aim of the present work was to make recommendations about the use of systemically administered drugs in combination or in sequence with radiation ( rt ) or surgery , or both , for cure or organ preservation , or both , in patients with locally advanced nonmetastatic ( stages iii-ivb ) squamous cell carcinoma of the head and neck ( lascchn ) . METHODS The Meta- analysis of Chemotherapy in Head and Neck Cancer ( mach-nc ) reports have , de facto , guided practice since 2000 , and so we search ed the literature for systematic review s published from January 2000 to February 2015 in reference to five research questions . A search was also conducted up to February 2015 for r and omized trials ( rcts ) not included in the meta-analyses . Recommendations were constructed using the Cancer Care Ontario Program in Evidence -Based Care practice guidelines development cycle . RESULTS In addition to up date d mach-nc reports , five additional meta-analyses and thirty rcts were identified . Five recommendations for lascchn treatment were generated based on those data . Concurrent chemoradiation ( ccrt ) is recommended to maximize the chance of cure in patients less than 71 years of age when rt is used as definitive treatment . The same recommendation also applies to patients with resected lascchn considered to be at high risk for locoregional recurrence . For lascchn patients who are c and i date s for organ preservation strategies and would otherwise require total laryngectomy , either ccrt or induction chemotherapy , followed by rt or surgery based on tumour response is recommended . The addition of cetuximab to intensified rt ( concomitant boost or hyperfractionated schedule ) is an alternative to ccrt . Routine use of induction chemotherapy to improve overall survival is not recommended . CONCLUSIONS We were able to use high-level evidence from patients receiving rt as definitive or postoperative treatment to generate recommendations for the use of systemic therapy in the treatment of lascchn . A limitation is a lack of stratification for human papillomavirus-related cancers of the oropharynx . One rct provided evidence for the use of cetuximab as an alternative to chemotherapy in the definitive rt setting . Concurrent chemoradiation provides one strategy for larynx preservation , but the best strategy is unclear . Use of induction chemotherapy does not improve overall survival , and its use should be limited to patients requiring immediate tumour downsizing before local therapy [25366680] PURPOSE We tested the efficacy and toxicity of cisplatin plus accelerated fractionation with a concomitant boost ( AFX-C ) versus st and ard fractionation ( SFX ) in locally advanced head and neck carcinoma ( LA-HNC ) . PATIENTS AND METHODS Patients had stage III to IV carcinoma of the oral cavity , oropharynx , hypopharynx , or larynx . Radiation therapy schedules were 70 Gy in 35 fractions over 7 weeks ( SFX ) or 72 Gy in 42 fractions over 6 weeks ( AFX-C ) . Cisplatin doses were 100 mg/m(2 ) once every 3 weeks for two ( AFX-C ) or three ( SFX ) cycles . Toxicities were scored by using National Cancer Institute Common Toxicity Criteria 2.0 and the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer criteria . Overall survival ( OS ) and progression-free survival ( PFS ) rates were estimated by using the Kaplan-Meier method and were compared by using the one-sided log-rank test . Locoregional failure ( LRF ) and distant metastasis ( DM ) rates were estimated by using the cumulative incidence method and Gray 's test . RESULTS In all , 721 of 743 patients were analyzable ( 361 , SFX ; 360 , AFX-C ) . At a median follow-up of 7.9 years ( range , 0.3 to 10.1 years ) for 355 surviving patients , no differences were observed in OS ( hazard ratio [ HR ] , 0.96 ; 95 % CI , 0.79 to 1.18 ; P = .37 ; 8-year survival , 48 % v 48 % ) , PFS ( HR , 1.02 ; 95 % CI , 0.84 to 1.24 ; P = .52 ; 8-year estimate , 42 % v 41 % ) , LRF ( HR , 1.08 ; 95 % CI , 0.84 to 1.38 ; P = .78 ; 8-year estimate , 37 % v 39 % ) , or DM ( HR , 0.83 ; 95 % CI , 0.56 to 1.24 ; P = .16 ; 8-year estimate , 15 % v 13 % ) . For oropharyngeal cancer , p16-positive patients had better OS than p16-negative patients ( HR , 0.30 ; 95 % CI , 0.21 to 0.42 ; P < .001 ; 8-year survival , 70.9 % v 30.2 % ) . There were no statistically significant differences in the grade 3 to 5 acute or late toxicities between the two arms and p-16 status . CONCLUSION When combined with cisplatin , AFX-C neither improved outcome nor increased late toxicity in patients with LA-HNC . Long-term high survival rates in p16-positive patients with oropharyngeal cancer support the ongoing efforts to explore deintensification [2806549] Summary Background Between 1990 and 2000 , we examined the effect of timing of non-platinum chemotherapy when combined with radiotherapy . We aim ed to determine whether giving chemotherapy concurrently with radiotherapy or as maintenance therapy , or both , affected clinical outcome . Here we report survival and recurrence after 10 years of follow-up . Methods Between Jan 15 , 1990 , and June 20 , 2000 , 966 patients were recruited from 34 centres in the UK and two centres from Malta and Turkey . Patients with locally advanced head and neck cancer , and who had not previously undergone surgery , were r and omly assigned to one of four groups in a 3:2:2:2 ratio , stratified by centre and chemotherapy regimen : radical radiotherapy alone ( n=233 ) ; radiotherapy with two courses of chemotherapy given simultaneously on days 1 and 14 of radiotherapy ( SIM alone ; n=166 ) ; or 14 and 28 days after completing radiotherapy ( SUB alone , n=160 ) ; or both ( SIM+SUB ; n=154 ) . Chemotherapy was either methotrexate alone , or vincristine , bleomycin , methotrexate , and fluorouracil . Patients who had previously undergone radical surgery to remove their tumour were only r and omised to radiotherapy alone ( n=135 ) or SIM alone ( n=118 ) , in a 3:2 ratio . The primary endpoints were overall survival ( from r and omisation ) , and event-free survival ( EFS ; recurrence , new tumour , or death ; whichever occurred first ) among patients who were disease-free 6 months after r and omisation . Analyses were by intention to treat . This trial is registered at www . Clinical trials.gov , number NCT00002476 . Findings All 966 patients were included in the analyses . Among patients who did not undergo surgery , the median overall survival was 2·6 years ( 99 % CI 1·9–4·2 ) in the radiotherapy alone group , 4·7 ( 2·6–7·8 ) years in the SIM alone group , 2·3 ( 1·6–3·5 ) years in the SUB alone group , and 2·7 ( 1·6–4·7 ) years in the SIM+SUB group ( p=0·10 ) . The corresponding median EFS were 1·0 ( 0·7–1·4 ) , 2·2 ( 1·1–6·0 ) , 1·0 ( 0·6–1·5 ) , and 1·0 ( 0·6–2·0 ) years ( p=0·005 ) , respectively . For every 100 patients given SIM alone , there are 11 fewer EFS events ( 99 % CI 1–21 ) , compared with 100 given radiotherapy , 10 years after treatment . Among the patients who had previously undergone surgery , median overall survival was 5·0 ( 99 % CI 1·8–8·0 ) and 4·6 ( 2·2–7·6 ) years in the radiotherapy alone and SIM alone groups ( p=0·70 ) , respectively , with corresponding median EFS of 3·7 ( 99 % CI 1·1–5·9 ) and 3·0 ( 1·2–5·6 ) years ( p=0·85 ) , respectively . The percentage of patients who had a significant toxicity during treatment were : 11 % ( radiotherapy alone , n=25 ) , 28 % ( SIM alone , n=47 ) , 12 % ( SUB alone , n=19 ) , and 36 % ( SIM+SUB , n=55 ) among patients without previous surgery ; and 9 % ( radiotherapy alone , n=12 ) and 20 % ( SIM alone , n=24 ) among those who had undergone previous surgery . The most common toxicity during treatment was mucositis . The percentage of patients who had a significant toxicity at least 6 months after r and omisation were : 6 % ( radiotherapy alone , n=13 ) , 6 % ( SIM alone , n=10 ) , 4 % ( SUB alone , n=7 ) , and 6 % ( SIM+SUB , n=9 ) among patients who had no previous surgery ; and 7 % ( radiotherapy alone , n=10 ) and 11 % ( SIM alone , n=13 ) among those who had undergone previous surgery . The most common toxicity 6 months after treatment was xerostomia , but this occurred in 3 % or less of patients in each group . Interpretation Concurrent non-platinum chemoradiotherapy reduces recurrences , new tumours , and deaths in patients who have not undergone previous surgery , even 10 years after starting treatment . Chemotherapy given after radiotherapy ( with or without concurrent chemotherapy ) is ineffective . Patients who have undergone previous surgery for head and neck cancer do not benefit from non-platinum chemotherapy . Funding Cancer Research UK , with support from University College London and University College London Hospital Comprehensive Biomedical Research Centre [21300455] PURPOSE To analyze the relationship between overall survival ( OS ) and radiation treatment time ( RTT ) and overall treatment time ( OTT ) in a well-described sequential therapy paradigm for locally advanced head- and -neck carcinoma ( LAHNC ) . METHODS AND MATERIAL S TAX 324 is a Phase III study comparing TPF ( docetaxel , cisplatin , and fluorouracil ) with PF ( cisplatin and fluorouracil ) induction chemotherapy ( IC ) in LAHNC patients ; both arms were followed by carboplatin-based chemoradiotherapy ( CRT ) . Prospect i ve radiotherapy quality assurance was performed . This analysis includes all patients who received three cycles of IC and a radiation dose of ≥70 Gy . Radiotherapy treatment time was analyzed as binary ( ≤8 weeks vs. longer ) and continuous ( number of days beyond 8 weeks ) functions . The primary analysis assessed the relationship between RTT , OTT , and OS , and the secondary analysis explored the association between treatment times and locoregional recurrence ( LRR ) . RESULTS A total of 333 ( of 501 ) TAX 324 patients met the criteria for inclusion in this analysis . There were no significant differences between the treatment arms in baseline or treatment characteristics . On multivariable analysis , PF IC , World Health Organization performance status of 1 , non-oropharynx site , T3/4 stage , N3 status , and prolonged RTT ( hazard ratio 1.63 , p=0.006 ) were associated with significantly inferior survival . Performance status , T3/4 disease , and prolonged RTT ( odds ratio 1.68 , p=0.047 ) were independently and negatively related to LRR on multivariable analysis , whereas PF was not . Overall treatment time was not independently associated with either OS or LRR . CONCLUSIONS In this secondary analysis of the TAX 324 trial , TPF IC remains superior to PF IC after controlling for radiotherapy delivery time . Even with optimal IC and concurrent chemotherapy , a non-prolonged RTT is a crucial determinant of treatment success . Appropriate delivery of radiotherapy after IC remains essential for optimizing OS in LAHNC [23265705] BACKGROUND This r and omised Phase II study assessed the activity and safety of concurrent chemoradiotherapy ( CRT ) and lapatinib followed by maintenance treatment in locally advanced , unresected stage III/IVA/IVB head and neck cancer . PATIENTS AND METHODS Patients were r and omised 1:1 to concurrent CRT and placebo followed by placebo or concurrent CRT and lapatinib followed by lapatinib . Treatment continued until disease progression or study withdrawal . Primary end-point was complete response rate ( CRR ) by independent review 6 months post-CRT . RESULTS Sixty-seven patients ( median age 56 years ; 97 % Eastern Cooperative Oncology Group performance status ≤1 ; 82 % stage IV ) were recruited . CRT dose intensities were unaffected by lapatinib : median radiation dose 70 Gy ( lapatinib , placebo ) , duration 49 ( lapatinib ) and 50 days ( placebo ) ; median cisplatin dose 260 mg/m(2 ) ( lapatinib ) and 280 mg/m(2 ) ( placebo ) . Lapatinib combined with CRT was well-tolerated . Grade 3/4 toxicities during CRT were balanced between arms , with the exception of an excess of grade 3 diarrhoea ( 6 % versus 0 % ) and rash ( 9 % versus 3 % ) and two grade 4 cardiac events in the lapatinib arm . CRR at 6 months post-CRT was 53 % with lapatinib versus 36 % with placebo in the intent-to-treat population . The progression-free survival ( PFS ) and overall survival rates at 18 months were 55 % versus 41 % and 68 % versus 57 % for the lapatinib and placebo arms , respectively . The difference between study arms was greatest in p16-negative disease ( median PFS > 20.4 months [ lapatinib ] versus 10.9 [ placebo ] ) . CONCLUSION Lapatinib combined with CRT is well-tolerated with numeric increases in CRR at 6 months post-CRT and median PFS in p16-negative disease [21295880] BACKGROUND AND PURPOSE Studies on accelerated fractionation ( AF ) in head and neck cancer have shown increased local control and survival compared with conventional fractionation ( CF ) , while others have been non-conclusive . In 1998 a national Swedish group decided to perform a r and omised controlled clinical study of AF . MATERIAL S AND METHODS Patients with verified squamous cell carcinoma of the oral cavity , oropharynx , larynx ( except glottic T1-T2 , N0 ) and hypopharynx were included . Patients with prior chemotherapy or surgery were excluded . Patients were r and omised to either CF ( 2Gy/day , 5days/week for 7 weeks , total dose 68Gy ) or to AF ( 1.1Gy+2.0Gy/day , 5days/week for 4.5weeks , total dose 68Gy ) . An extensive quality assurance protocol was followed throughout the study . The primary end point was loco-regional tumour control ( LRC ) at two years after treatment . RESULTS The study was closed in 2006 when 750 patients had been r and omised . Eighty-three percent of the patients had stages III-IV disease . Forty eight percent had oropharyngeal , 21 % laryngeal , 17 % hypopharyngeal and 14 % oral cancers . There were no significant differences regarding overall survival ( OS ) or LRC between the two regimens . The OS at two years was 68 % for AF and 67 % for CF . The corresponding figures for LRC were 71 % and 67 % , respectively . There was a trend towards improved LRC for oral cancers treated ( p=0.07 ) and for large tumours ( T3-T4 ) ( p=0.07 ) treated with AF . The AF group had significantly worse acute reactions , while there was no significant increase in late effects . CONCLUSION Overall the AF regimen did not prove to be more efficacious than CF . However , the trend towards improved results in AF for oral cancers needs to be further investigated Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND There are still many unresolved questions in the management of locally advanced Head and Neck Cancer ( HNC ) . Many chemotherapeutic drugs and radiotherapy fractionation schemes are available and not all have been evaluated in head-to-head clinical trials . This systematic review and Bayesian network meta- analysis aims to compare the available treatment strategies and chemotherapeutic options for locally advanced HNC . Altered fractionation increases the risk of developing grade 3 - 4 mucositis compared to conventional RT ( OR 3.74 95 % 1.64 - 8.67 ) INTERPRETATION : CCRT with cisplatin remains the gold st and ard of treatment . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

17409887

[12377323] PURPOSE This multi-institutional Phase III r and omized study compared 10 Gy single-fraction radiotherapy ( RT ) with 20 Gy in five fractions in the palliation of thoracic symptoms from lung cancer . METHODS AND MATERIAL S The primary end point was palliation of thoracic symptoms at 1 month after RT , evaluated by a patient-completed daily diary card . Secondary end points included quality of life , toxicity , and survival . RESULTS Most ( 69 % ) of 230 patients r and omized had locally advanced disease unsuitable for curative treatment . The treatment arms were well balanced with respect to the known prognostic factors . At 1 month after RT , no difference was found in symptom control between the two arms , as judged by the daily diary scores . The changes in the scores on the Lung Cancer Symptom Scale indicated that the fractionated RT ( five fractions ) group had greater improvement in symptoms related to lung cancer ( p = 0.009 ) , pain ( p = 0.0008 ) , ability to carry out normal activities ( p = 0.037 ) , and better global quality of life ( p = 0.039 ) . The European Organization for Research and Treatment of Cancer QLQ-C30 scores showed that patients receiving five fractions had a greater improvement in scores with respect to pain ( p = 0.04 ) . No significant difference was found in treatment-related toxicity . Patients who received five fractions survived on average 2 months longer ( p = 0.0305 ) than patients who received one fraction . CONCLUSION Although the two treatment strategies provided a similar degree of palliation of thoracic symptoms , the difference in survival between the two study arms was of a clinical ly relevant magnitude [12040280] A phase III r and omized trial was conducted to investigate whether induction chemotherapy followed by radiation can influence survival as compared with radiation alone in unresectable , locally advanced non-small-cell lung cancer ( LADNSCLC ) . A total of 101 patients with unresectable stage IIIA or IIIB NSCLC were enrolled . Patients were stratified by performance status , weight loss , histology and stage , and then r and omized to receive combined chemoradiotherapy or radiotherapy alone . Radiotherapy was administered in 1.8 Gy to 2.0 Gy st and ard fractions daily 5 times weekly for a total dose of 60 Gy to 65 Gy . The combined group received induction of cisplatin , etoposide , and vinblastine ( PEV ) chemotherapy with cisplatin 20 mg/m2 on days 1 to 5 , etoposide 100 mg/m2 on days 2 to 4 , and vinblastine 6 mg/m2 on day 1 , which wasrepeated every 3 weeks for 3 courses , after which time the patients underwent radiotherapy . Of 101 patients registered , 89 patients ( 43 combined , 46 radiotherapy alone ) were eligible for analysis . The response rates for the combined and radiotherapy groups were 65 % ( 28/43 ) and 70 % ( 32/46 ) , respectively . The median survival time ( MST ) showed a tendency to be more prolonged in the combined group than in the group receiving radiotherapy alone ( 13.8 vs. 8.5 months ) . The MST in patients with nonsquamous histology was strikingly prolonged in the combined group as compared with the radiotherapy group ( 14 vs. 3.6 months , p 0.027 ) . Likewise , the MST in patients with stage IIIB was significantly prolonged in the combined group as compared with the radiotherapy group ( 11.1 vs. 7.2 months , p 0.045 ) . Together , the MST of the high-risk group with nonsquamous or stage IIIB was significantly higher in the combined group than that seen in the radiotherapy group ( 11.6 vs. 8 months , p 0.046 ) , whereas the MST of the low-risk group , defined as having both squamous histology and stage IIIA , was similar in the two treatment groups ( 18.3 vs. 20.8 months , p = 0.293 ) . In conclusion , induction PEV chemotherapy plus radiotherapy is superior to radiotherapy alone in high-risk subsets of unresectable LAD-NSCLC and therapeutic strategy should be based on the identification of prognostic factors [1971762] Two policies of palliative thoracic radiotherapy for non-small-cell lung cancer have been compared in a r and omised multicentre controlled trial . A total of 369 patients with inoperable , histologically or cytologically confirmed disease , too advanced for radical ' curative ' radiotherapy , and with their main symptoms related to the primary intrathoracic tumour even if metastases were present , were studied . They were allocated at r and om either to a regimen of 17 Gy given in two fractions of 8.5 Gy 1 week apart ( F2 regimen ) , or to a conventional multifractionated regimen of either 30 Gy in ten fractions or 27 Gy in six fractions ( a biologically equivalent dose ) , given daily except at weekends ( FM regimen ) . On admission , 93 % of the patients had cough , 47 % haemoptysis , 57 % chest pain , 58 % anorexia , and 11 % dysphagia . As assessed by the clinicians , palliation of the main symptoms was achieved in high proportions of patients ranging in the F2 group from 65 % for cough to 81 % for haemoptysis and in the FM group from 56 % for cough to 86 % for haemoptysis . Haemoptysis , chest pain , and anorexia disappeared for a time in well over half the patients with these symptoms , and cough in 37 % . For all the main symptoms , the median duration of palliation was 50 % or more of survival . Performance status improved in approximately half of the patients with a poor status on admission . All these results were similar in the two treatment groups . As assessed daily by the patients using a diary card , the quality of life deteriorated slightly during treatment but then improved steadily during the next 5 weeks . The proportion of patients with dysphagia increased considerably during treatment , but fell to the pretreatment level during the next 2 weeks . The results were similar in the two groups . Radiation myelopathy was suspected in one ( F2 ) patient . There was no difference in survival between the two groups ( log-rank test ) , the median survival time from the date of allocation being 179 days in the F2 and 177 days in the FM group . In the light of all the findings , the regimen of two fractions of 8.5 Gy given 1 week apart is recommended [16087956] PURPOSE We conducted a phase III study to compare the survival impact of concurrent versus sequential treatment with radiotherapy ( RT ) and chemotherapy ( CT ) in unresectable stage III non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Patients were r and omly assigned to one of the two treatment arms . In the sequential arm , patients received induction CT with cisplatin ( 120 mg/m2 ) on days 1 , 29 , and 57 , and vinorelbine ( 30 mg/m2/wk ) from day 1 to day 78 , followed by thoracic RT at a dose of 66 Gy in 33 fractions ( 2 Gy per fraction and 5 fractions per week ) . In the concurrent arm , the same RT was started on day 1 with two concurrent cycles of cisplatin 20 mg/m2/d and etoposide 50 mg/m2/d ( days 1 to 5 and days 29 to 33 ) ; patients then received consolidation therapy with cisplatin 80 mg/m2 on days 78 and 106 and vinorelbine 30 mg/m2/wk from days 78 to 127 . RESULTS Two hundred five patients were r and omly assigned . Pretreatment characteristics were well balanced between the two arms . There were six toxic deaths in the sequential arm and 10 in the concurrent arm . Median survival was 14.5 months in the sequential arm and 16.3 months in the concurrent arm ( log-rank test P = .24 ) . Two- , 3- , and 4-year survival rates were better in the concurrent arm ( 39 % , 25 % , and 21 % , respectively ) than in the sequential arm ( 26 % , 19 % , and 14 % , respectively ) . Esophageal toxicity was significantly more frequent in the concurrent arm than in the sequential arm ( 32 % v 3 % ) . CONCLUSION Although not statistically significant , clinical ly important differences in the median , 2- , 3- , and 4-year survival rates were observed , with a trend in favor of concurrent chemoradiation therapy , suggesting that is the optimal strategy for patients with locally advanced NSCLC [9626216] PURPOSE The cisplatin-vinorelbine regimen has superior activity in advanced non-small-cell lung cancer ( NSCLC ) . We conducted a phase I trial to identify the maximum-tolerated dose ( MTD ) and dose-limiting toxicities ( DLTs ) of this regimen with concomitant thoracic radiation ( RT ) in patients with advanced chest malignancies . PATIENTS AND METHODS Patients with advanced chest malignancies that required RT were enrolled onto this phase I study of st and ard chest radiation ( 30 daily 2-Gy fractions for a total of 60 Gy ) and concurrent chemotherapy with cisplatin starting at 100 mg/m2 every 3 weeks and vinorelbine starting at 20 mg/m2/wk . RESULTS Thirty-seven patients were treated on this study . Two of three patients treated at the maximum-administered dose of cisplatin 100 mg/m2 per cycle and vinorelbine 25 mg/m2/wk experienced acute DLT ( neutropenia ) , which required deescalation . The dose level of cisplatin 100 mg/m2 and vinorelbine 20 mg/m2/wk , although tolerated acutely , produced delayed esophagitis , which proved dose-limiting . The recommended phase II dose was cisplatin 80 mg/m2 every 3 weeks and vinorelbine 15 mg/m2 given 2 of every 3 weeks with concomitant chest RT . CONCLUSION Concomitant chemoradiotherapy with cisplatin and vinorelbine is feasible . The recommended phase II dose is cisplatin 80 mg/m2 every 3 weeks with vinorelbine 15 mg/m2 given twice over 3 weeks on a day 1/day 8 schedule . Esophagitis is the DLT , with neutropenia occurring at higher dose levels . A Cancer and Leukemia Group B ( CALGB ) phase II trial is currently underway to evaluate further the efficacy and toxicities of this regimen in unresectable stage III NSCLC [14998844] PURPOSE To determine the radiosensitizing effect of prolonged exposure of carboplatin in patients with locally unresectable non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Patients with histologically proven NSCLC , performance score < 2 , weight loss < 10 % , and normal organ functions were r and omized between carboplatin 840 mg/m2 administered continuously during 6 weeks of radiotherapy or thoracic radiotherapy alone ( both 60 Gy ) . Toxicity was evaluated with National Cancer Institute Common Toxicity Criteria ( NCI CTC ) and the Radiation Therapy Oncology Group ( RTOG ) criteria . Quality of life was measured with European Organization for Research and Treatment of Cancer ( EORTC ) QLQ-C30/LC13 question naires . RESULTS One-hundred and sixty patients were included . Pathologically confirmed persistent tumor was present in 53 % of patients in the combination arm versus 58 % in the radiotherapy alone arm ( P=0.5 ) . Median survival in the combination arm was 11.8 [ 95 % confidence interval ( CI ) 9.3 - 14.2 ] months and in the radiotherapy alone arm 11.7 ( 95 % CI 8.1 - 15.5 ) months ; progression-free survival was not different between arms [ 6.8 and 7.5 months , respectively ( P=0.28 ) ] . Acute toxicity was mild , late toxicity was radiation-induced cardiomyopathy ( three patients ) and pulmonary fibrosis ( five patients ) . Quality of life was not different between arms , but in all measured patients cough and dyspnea improved , pain became less , and slight paresthesia developed 3 months after treatment . CONCLUSION Addition of continuously administered carboplatin as radiosensitizer for locally unresectable NSCLC does not improve local tumor control or overall survival [3033751] Eighty one patients with inoperable non-small cell lung carcinoma ( NSCLC ) were entered in a r and omized phase II trial comparing split-dose irradiation alone to combined treatment radiotherapy and polychemotherapy ( C.A.P. + V.D.S. ) . The quality of life and the survival of the patients were studied . We have defined three classes of quality of life responses based on the time elapsed before the performance status index drops . A higher quality of life failure rate was observed in the combined treatment group ( p non-significant ) but the time elapsed before the Karnofsky index drops is longer in the combined treatment group for the quality of life " no change " subgroup ( p = 0.15 ) . Survival and quality adjusted survival are similar in both treatment groups . The same conclusion holds for retrospective stratified treatment groups . The results of the study are presented according to the decision tree theory . We conclude that as far as the quality of life is concerned , polychemotherapy combined with the particular split-dose irradiation schedule used is an effective treatment of inoperable NSCLC . Its efficiency is comparable to , but not better than , the same radiotherapy schedule alone taken as a reference baseline [15364136] PURPOSE The superiority of chemoradiotherapy ( CRT ) over radiation alone in locally advanced non-small cell lung cancer ( NSCLC ) has been proven , but the relative merits of a concurrent schedule versus their sequential administration are less clear . This study compared the safety and efficacy of concurrent and sequential CRT , with chemotherapy ( CT ) consisting of a cisplatin and vinorelbine regimen , in patients with locally advanced NSCLC . PATIENTS AND METHODS One hundred and two previously untreated patients ( aged 42 - 75 years ) with locally advanced , stage IIIA ( n = 15 ) or stage IIIB ( n = 87 ) NSCLC were entered into the study . The CT schedule consisted of up to four cycles of cisplatin 80 mg/m(2 ) on day 1 , and vinorelbine 25 mg/m(2 ) at the first and fourth cycles ( 12.5 mg/m(2 ) during the 2nd/3rd cycles ) on days 1 , 8 , 15 of a 28-day cycle . Radiotherapy ( RT ) was prescribed at a dose of 60 Gy/30 fractions , given as five fractions per week for 6 weeks . In the concurrent arm ( arm A ) , RT was started on day 4 of cycle 2 ; whilst in the sequential arm ( arm B ) , RT started within 2 weeks after completion of CT . Fifty-two patients were r and omized to concurrent treatment and 50 to the sequential schedule . RESULTS Overall survival was significantly longer in arm A ( median survival 16.6 months ) versus arm B ( median survival 12.9 months ) ( P = 0.023 by means of log-rank test ; hazard ratio HR = 0.61 , 95 % CI of HR ( 0.39 - 0.93 ) ) , and time to progression ( TTP ) was also significantly longer in arm A ( median time to progression 11.9 months ) versus arm B ( median time to progression 8.5 months ) ( P = 0.024 by means of log-rank test ; HR = 0.62 , 95 % CI of HR ( 0.38 - 0.93 ) ) . Ninety-eight patients were evaluable for response and 101 for toxicity . The overall response rate was significantly higher in arm A , 80 % ( with 21 % complete response ( CR ) ) compared with 47 % ( with 17 % CR ) in arm B ( P = 0.001 by means of chi(2)-test ) . WHO grade 3 or 4 toxicity was more frequent in arm A than in arm B , with a significantly greater incidence of leucopenia ( 53 % versus 19 % , P = 0.009 by means of chi(2 ) test ) and nausea/vomiting ( 39 % versus 15 % , P = 0.044 by means of chi(2 ) test ) . There were no treatment related deaths . CONCLUSION In this study population , concurrent CRT demonstrated significant benefit in terms of response rate , overall survival and time to progression over sequential CRT . The concurrent CRT schedule was associated with higher toxicity ; however , the adverse event profile was acceptable in both arms [12377962] PURPOSE To evaluate new drugs in combination with cisplatin in unresectable stage III non-small-cell lung cancer , Cancer and Leukemia Group B ( CALGB ) conducted a r and omized phase II study of two cycles of induction chemotherapy followed by two additional cycles of the same drugs with concomitant radiotherapy . PATIENTS AND METHODS Eligible patients received four cycles of cisplatin at 80 mg/m(2 ) on days 1 , 22 , 43 , and 64 with arm 1 : gemcitabine 1,250 mg/m(2 ) on days 1 , 8 , 22 , and 29 and 600 mg/m(2 ) on days 43 , 50 , 64 , and 71 ; arm 2 : paclitaxel 225 mg/m(2 ) for 3 hours on days 1 and 22 and 135 mg/m(2 ) on days 43 and 64 ; and arm 3 : vinorelbine 25 mg/m(2 ) on days 1 , 8 , 15 , 22 , and 29 and 15 mg/m(2 ) on days 43 , 50 , 64 , and 71 . Radiotherapy was initiated on day 43 at 2 Gy/d ( total dose , 66 Gy ) . RESULTS One hundred seventy-five eligible patients were analyzed . Toxicities during induction chemotherapy consisted primarily of grade 3 or 4 granulocytopenia . Grade 3 or 4 toxicities during concomitant chemoradiotherapy consisted of thrombocytopenia , granulo-cytopenia , and esophagitis . Response rates after completion of radiotherapy were 74 % , 67 % , and 73 % for arms 1 , 2 , and 3 , respectively . Median survival for all patients was 17 months . One- , 2- , and 3-year survival rates for the patients on the three arms were 68%/37%/28 % , 62%/29%/19 % , and 65%/40%/23 % . CONCLUSION Four cycles of gemcitabine , vinorelbine , or paclitaxel in combination with cisplatin can be administered at these doses and schedules . The observed survival rates exceed those of previous CALGB trials and may be attributable to the use of concomitant chemoradiotherapy . Induction chemotherapy added to concomitant chemoradiotherapy is being evaluated in a phase III r and omized trial [2361948] A prospect i ve r and omised study compared two palliative radiotherapy schedules for inoperable symptomatic non-small-cell lung cancer ( NSCLC ) . After stratification , 100 patients were r and omly assigned to 20 Gy/5 fractions (fr)/5 days ( arm A ) or 16 Gy/2 fr/day 1 and 8 ( arm B ) . There were 90 men and 10 women aged 47–81 years ( mean 66 ) , performance status 1–4 ( median 2 ) . The major clinical characteristics and incidence and degree of initial disease-related symptoms were similar in both groups . Treatment effects were assessed using patient 's chart , doctor 's scoring of symptomatic change and chest X-ray . Study end points included degree and duration of symptomatic relief , treatment side effects , objective response rates and overall survival . A total of 55 patients were assigned to arm A and 45 to arm B. In all , 98 patients received assigned treatment , whereas two patients died before its termination . Treatment tolerance was good and did not differ between study arms . No significant differences between study arms were observed in the degree of relief of all analysed symptoms . Overall survival time differed significantly in favour of arm B ( median 8.0 vs 5.3 months ; P=0.016 ) . Both irradiation schedules provided comparable , effective palliation of tumour-related symptoms . The improved overall survival and treatment convenience of 2-fraction schedule suggest its usefulness in the routine management of symptomatic inoperable NSCLC [12177106] PURPOSE There are no published survival data after chemoradiotherapy ( chemoRT ) in pathologically documented stage IIIB non-small-cell lung cancer . Studies of radiotherapy ( RT ) alone or chemotherapy followed by RT yield 5-year survivals less than 10 % . The Southwest Oncology Group ( SWOG ) employed the same concurrent chemoRT induction regimen used in its predecessor trimodality trial to determine the efficacy , safety , and long-term outcome of replacing postinduction surgery with additional chemoRT . PATIENTS AND METHODS Eligible patients for SWOG-9019 had pathologic documentation of T4N0/1 , T4N2 , or N3 stage IIIB non-small-cell lung cancer . They had pulmonary function adequate to withst and combined-modality therapy , identical to the requirements of the previous trial with postchemoRT surgery . Induction therapy was two cycles of cisplatin plus etoposide ( PE ) concurrent with once-daily thoracic RT ( 45 Gy ) . In the absence of progressive disease , RT was completed to 61 Gy , with two additional cycles of cisplatin plus etoposide . RESULTS Fifty eligible patients were accrued with tumor-node ( TN ) substage confirmed on central review : 18 , T4N0/1 ; 12 , T4N2 ; and 20 , N3 . Grade 4 neutropenia was the most common toxicity ( 32 % ) . Grade 3/4 esophagitis occurred in 12 % and 8 % . Median follow-up was 52 months , and overall median survival was 15 months ( 10 to 22 , 95 % confidence interval ) . Three- and 5-year survivals were 17 % and 15 % ( 5-year T4N0/1 , 17 % ; T4N2 , 13 % ; and N3 , 15 % ) . CONCLUSION Feasibility and long-term survival support the application of these results as a st and ard against which mature outcomes of chemoRT trials with new chemotherapy agents can be compared . These results also justify use of the SWOG-9019 approach as a control arm in ongoing phase III trials [8581393] Eighty four patients from Groote Schuur Hospital and Frere Hospital East London were entered into a prospect i ve r and omised trial between January 1990 and December 1993 . All the patients possessed non-small cell carcinoma ( NSCLC ) of the lung too extensive for radical irradiation and World Health Organization performance status 0 - 2 . The patients were r and omised to receive either 35 Gy in 10 fractions ( 43 patients ) or 45 Gy in 15 fractions ( 41 patients ) . In the patients treated to 35 Gy and 45 Gy , the median survival was 8.5 months in both groups , the symptomatic response rate was 68 % and 76 % and the incidence of moderate to severe radiation oesophagitis was 23 % and 41 % respectively . The latter approached statistical significance ( P = 0.07 , chi square ) . There was no evidence of a dose response effect on survival in the moderate dose range in patients treated palliatively for locally advanced NSCLC [10506617] PURPOSE Chemotherapy for non-small-cell lung cancer ( NSCLC ) remains controversial . We describe the two largest reported , r and omized , parallel trials design ed to determine whether the addition of chemotherapy influences duration and quality of life in localized , unresectable ( mitomycin , ifosfamide , cisplatin [MIC]1 trial ) and extensive ( MIC2 trial ) disease . PATIENTS AND METHODS Ambulatory patients with NSCLC , aged 75 years or younger , with localized disease , were r and omized in MIC1 to receive up to four cycles of chemotherapy ( CT : mitomycin 6 mg/m(2 ) , ifosfamide 3 g/m(2 ) , and cisplatin 50 mg/m(2 ) ) every 21 days , followed by radical radiotherapy ( CT + RT ) or radiotherapy ( RT ) alone . Extensive-stage patients were r and omized in MIC2 to identical chemotherapy plus palliative care ( CT + PC ) or palliative care ( PC ) alone . Short-term change in quality of life ( QOL ) was assessed in a subgroup of patients . Data from the two trials were combined to allow multivariate and stratified survival analyses . RESULTS Seven hundred ninety-seven eligible patients were r and omized , 446 in MIC1 and 351 in MIC2 . MIC CT improved survival in both trials ( significantly in MIC2 ) . The median survival time in MIC1 was 11.7 months ( CT + RT ) versus 9.7 months ( RT alone ) ( P = .14 ) ; whereas in MIC2 , median survival time was 6.7 months ( CT + PC ) compared with 4 . 8 months ( PC alone ) ( P = .03 ) . QOL , assessed in 134 patients from start of trial to week 6 , showed improvement with chemotherapy and deterioration with st and ard treatment . In the combined analysis of 797 r and omized patients , the positive effect of MIC on survival was significant overall ( P = .01 ) and after adjusting for prognostic factors ( P = .01 ) . CONCLUSION MIC chemotherapy prolongs survival in unresectable NSCLC without compromising QOL [231024] Sixty-eight evaluable patients with unresectable adenocarcinoma and large cell carcinoma of the lung were treated on a prospect i ve r and omized trial comparing thoracic radiation therapy ( TRT ) plus combination chemotherapy with either cyclophosphamide , Adriamycin and cis-platinum ( CAP ) or cyclophosphamide , Adriamycin ( same dosages ) and DTIC ( CAD ) , 34 on each arm . Patients treated with TRT plus CAP had a better overall regression rate ( 59 % vs 47 % ) and a statistically significant superiority in time to disease progression ( 147 days vs 303 days ) and survival ( 217 days vs 504 days ) [9135893] The aim of this prospect i ve r and omized trial was to compare the symptomatic effects of two different regimens of palliative radiotherapy for lung cancer . Two hundred and sixteen patients needing palliation were r and omized to receive either a 17 Gy mid-point dose in two fractions 1 week apart or 22.5 Gy in five daily fractions . Both toxicity and efficacy were evaluated by postal question naires . This small study was intended to identify any clinical ly important differences in toxicity or efficacy between the two regimens . We detected no such difference , although there was a tendency for iatrogenic dysphagia and improvement in chest pain and cough to be more common with the two-fraction regimen . The only symptom that was improved in over 50 % of patients for 8 weeks or more was haemoptysis . Haemoptysis and chest pain appeared to be the best indications for treatment . The relief of other symptoms was disappointing in both degree and duration [2452146] Between October 1981 and November 1984 , 291 patients with inoperable advanced non-small cell carcinoma of the lung ( NSCLC ) were r and omized to a two-arm study . Eighteen of 291 defaulted treatment and were excluded from the study . Twenty-seven of 273 died during treatment ; they were invaluable for treatment response but were included in survival analysis . Without correction for lung attenuation 45 Gy/18 fractions/4 1/2 weeks were given in arm 1 and 31.2 Gy/4 fractions/4 weeks were given in arm 2 . One hundred twenty-eight of 273 were included in arm 1 and 145/273 in arm 2 . The two arms were comparable in patient age , sex , performance status and symptoms , primary tumor site , histology , stage of the disease , and distribution of metastases and radiation portal size used . Prognosis was poor with an overall median survival of 20 weeks and was similar in both arms . Radiological tumor response was also similar : 53 % in arm 1 and 50 % in arm 2 . However arm 1 was superior than arm 2 in achieving symptom palliation , 71 % vs 54 % , p less than 0.02 . Treatment complications were mild and included mainly radiation oesophagitis and pneumonitis and pulmonary fibrosis . Treatments in both arms were equally well tolerated [15860852] PURPOSE A national multicenter r and omized study compared the efficacy of 2 x 8 Gy versus our st and ard 10 x 3 Gy in patients with inoperable stage IIIA/B ( with an Eastern Cooperative Oncology Group score of 3 to 4 and /or substantial weight loss ) and stage IV non-small-cell lung cancer . PATIENTS AND METHODS Between January 1999 and June 2002 , 297 patients were eligible and r and omized to receive either 10 x 3 Gy or 2 x 8 Gy by external-beam irradiation . The primary end point was a patient-assessed score of treatment effect on seven thoracic symptoms using an adapted Rotterdam Symptom Checklist . Study sample size was determined based on an average total symptom score difference of more than one point over the initial 39 weeks post-treatment . The time course of symptom scores were also evaluated , and other secondary end points were toxicity and survival . RESULTS Both treatment arms were equally effective , as the average total symptom score over the initial 39 weeks did not differ . However , the pattern in time of these scores differed significantly ( P < .001 ) . Palliation in the 10 x 3-Gy arm was more prolonged ( until week 22 ) with less worsening symptoms than in 2 x 8-Gy . Survival in the 10 x 3-Gy arm was significantly ( P = .03 ) better than in the 2 x 8-Gy arm with 1-year survival of 19.6 % ( 95%CI , 14.1 % to 27.3 % ) v 10.9 % ( 95%CI , 6.9 % to 17.3 % ) . CONCLUSION The 10 x 3-Gy radiotherapy schedule is preferred over the 2 x 8-Gy schedule for palliative treatment , as it improves survival and results in a longer duration of the palliative response [1977779] Two policies of palliative thoracic radiotherapy for NSCLC have been compared in a r and omised multicentre controlled trial aim ed at simplifying the palliative treatment of patients with poor performance status . A total of 235 patients were entered . They had inoperable , microscopically confirmed disease , too advanced for ' curative ' radiotherapy . Their main symptoms were related to the primary intrathoracic tumour even if metastases were present , and they had a poor performance status . Patients were allocated at r and om to regimens of either 17 Gy given in two fractions of 8.5 Gy 1 week apart ( F2 regimen , 117 patients ) , or a single fraction of 10 Gy ( F1 regimen , 118 patients ) . Two patients ( one in each group ) were excluded from all analyses because they were found to have had previously treated malignant disease and had been admitted in error . On admission , 95 % of the 233 eligible patients had cough , 47 % haemoptysis , 59 % chest pain , 64 % anorexia , and 16 % dysphagia . As assessed by the clinicians , these symptoms were palliated in high proportions of patients , ranging in the F2 group from 48 % for cough to 75 % for haemoptysis , and in the F1 group from 55 % for anorexia to 72 % for haemoptysis and chest pain . For all five symptoms the median duration of palliation was 50 % or more of survival . All these results were similar in the two treatment groups . In contrast , on daily assessment by the patients using a diary card , those treated with the F2 regimen experienced substantially more dysphagia , which was recorded in 56 % of the patients compared with 23 % in the F1 group ( difference 33 % : 95 % confidence interval 17 - 48 % ) . The median survival from r and omisation was 100 days in the F2 group and 122 days in the F1 group . The F1 regimen , as it requires only a single attendance for treatment , is recommended as a palliative regimen for patients with inoperable NSCLC and a poor performance status [15845568] BACKGROUND The purpose of this study was to evaluate whether radiotherapy with carboplatin would result in longer survival than radiotherapy alone in elderly patients with unresectable stage III non-small cell lung cancer ( NSCLC ) . METHODS Eligible patients were 71 years of age or older with unresectable stage III NSCLC . Patients were r and omly assigned to the radiotherapy alone ( RT ) arm , irradiation with 60 Gy ; or the chemoradiotherapy ( CRT ) arm , the same radiotherapy and additional concurrent use of carboplatin 30 mg/m(2 ) per fraction up to the first 20 fractions . RESULTS This study was terminated early when 46 patients were registered from November 1999 to February 2001 . Four patients ( one in the RT arm , three in the CRT arm ) were considered to have died due to treatment-related causes . The JCOG Radiotherapy Committee assessed these treatment-related deaths ( TRDs ) and the compliance with radiotherapy in this trial . They found that 60 % of the cases corresponded to protocol deviation and 7 % were protocol violation in dose constraint to the normal lung , two of whom died due to radiation pneumonitis . As to the effectiveness for the 46 patients enrolled , the median survival time was 428 days [ 95 % confidence interval ( CI ) = 212 - 680 days ] in the RT arm versus 554 days ( 95 % CI = 331 to not estimable ) in the CRT arm . CONCLUSIONS Due to the early termination of this study , the effectiveness of concurrent use of carboplatin remains unclear . We re-planned and started a study with an active quality control program which was developed by the JCOG Radiotherapy Committee [16087941] PURPOSE This phase II noncomparative r and omized trial was conducted to determine the optimal sequencing and integration of paclitaxel/carboplatin with st and ard daily thoracic radiation therapy ( TRT ) , in patients with locally advanced unresected stage III non-small-cell lung cancer ( NSCLC ) . Survival data were compared with historical st and ard sequential chemoradiotherapy data from the Radiation Therapy Oncology Group . PATIENTS AND METHODS Patients with unresected stages IIIA and IIIB NSCLC , with Karnofsky performance status > or = 70 % and weight loss < or = 10 % , received two cycles of induction paclitaxel ( 200 mg/m2)/carboplatin ( area under the plasma concentration time curve [ AUC ] = 6 ) followed by TRT 63.0 Gy ( arm 1 , sequential ) or two cycles of induction paclitaxel ( 200 mg/m2)/carboplatin ( AUC = 6 ) followed by weekly paclitaxel ( 45 mg/m2)/carboplatin ( AUC = 2 ) with concurrent TRT 63.0 Gy ( arm 2 , induction/concurrent ) , or weekly paclitaxel ( 45 mg/m2)/carboplatin ( AUC = 2)/TRT ( 63.0 Gy ) followed by two cycles of paclitaxel ( 200 mg/m2)/carboplatin ( AUC = 6 ; arm 3 , concurrent/consolidation ) . RESULTS With a median follow-up time of 39.6 months , median overall survival was 13.0 , 12.7 , and 16.3 months for arms 1 , 2 , and 3 , respectively . During induction chemotherapy , grade 3/4 granulocytopenia occurred in 32 % and 38 % of patients on study arms 1 and 2 , respectively . The most common locoregional grade 3/4 toxicity during and after TRT was esophagitis , which was more pronounced with the administration of concurrent chemoradiotherapy on study arms 2 and 3 ( 19 % and 28 % , respectively ) . CONCLUSION Concurrent weekly paclitaxel , carboplatin , and TRT followed by consolidation seems to be associated with the best outcome , although this schedule was associated with greater toxicity [2557304] From October 1979 to December 1982 , 126 patients with locally advanced unresectable or inoperable Stage II ( 7 patients ) , Stage IIIA ( 81 patients ) , and Stage IIIB ( 38 patients ) non-small cell carcinoma of the lung were treated in a prospect i ve r and omized trial using five cycles of CAP ( Cytoxan , Adriamycin , and cisplatin ) , T-CAP ( triazinate plus CAP ) , or V-CAP ( VP-16 plus CAP ) chemotherapy with thoracic radiation therapy ( TRT ) . TRT consisted of 40 Gy in 10 fractions ( split-course ) with cycles 3 and 4 of chemotherapy . The treatment field included the primary tumor , ipsilateral hilum , mediastinum , and ipsilateral supraclavicular fossa . All patients were followed until death or for a minimum of 5 years for survivors . The evaluable subgroup consisted of 102 patients who completed TRT . Median and 5-year survivals for the entire group were 14.0 months and 10 % , respectively ; for the evaluable subgroup , they were 14.8 months and 12 % , respectively . There was a trend toward better survival with V-CAP plus TRT than with CAP plus TRT ( p = 0.08 ) . Median and 5-year survivals were 16.2 months and 18 % , respectively , with V-CAP plus TRT . Of eight prognostic variables analyzed for their association with survival , only Eastern Cooperative Oncology Group performance status ( 0,1 versus 2 ) ( p = 0.02 ) and weight loss ( less than or equal to 10 % versus greater than 10 % ) ( p = 0.05 ) were significant . Sex , age , T stage , N stage , overall stage , and histologic type were not significantly associated with survival . Failure analysis revealed 83 patients ( 81 % ) with identifiable first failures . The median time to first failure was 9.8 months , and the median survival after first failure was 4.7 months . Failure patterns included local failure alone ( 19 % ) , local and distant ( 20 % ) , and distant alone ( 43 % ) . Nineteen percent of patients had no documented progression . Total failure patterns were local in 39 % and distant in 63 % . Twenty-three patients ( 23 % ) had failure in the brain ; they accounted for 31 % of all distant failures . In 20 of these patients ( 20 % of all patients ) , this was the only site of failure . There were eight ( 8 % ) initial nodal failures in 96 untreated contralateral supraclavicular fossae . No initial failures were seen in any of 101 untreated contralateral hila . The data suggest the following : ( a ) Combined treatment with V-CAP and TRT yielded excellent results ( median survival , 16.2 months ; 5-year survival , 18 % ) . ( ABSTRACT TRUNCATED AT 400 WORDS [2851172] Cis-Dichlorodiammine platinum ( II ) ( cis-DDP ) was demonstrated to be a potentiator of radiation therapy ( RT ) in experimental tumor models and in cultured cells . To assess the effectiveness of a combined modality treatment including RT and a weekly low-dose administration of cis-DDP , from January 1986 to June 1987 , 95 patients with unresectable locally advanced non-small cell carcinoma of the lung ( stage IIIa , b ) were r and omized for study . Fifty patients received RT alone at doses of 50 Gy ; 45 patients received the same RT plus cis-DDP 15 mg/m2 IV weekly . An overall response rate of 50 % and 64 % was observed in the RT and RT + cis-DDP group , respectively . No statistically significant differences were detected with regard to median survival time ( 11 months for RT v 16 months for RT + cis-DDP ) and progression-free interval ( 7 months in the RT arm v 9 months in the RT + cis-DDP arm ) , but the patterns of the first failure appeared to be affected by treatment . In fact , a lower number of intrathoracic relapses was observed in the RT + cis-DDP arm ( 12 in the RT + cis-DDP v 23 in the RT arm ) . Toxicity was mild and the feasibility of this schedule must be remarked . A better local control of disease can be obtained using cis-DDP as a radiation potentiator , but the true influence of this combined modality treatment on the length of survival , and the optimal cis-DDP timing and dosage are still to be evaluated in further clinical trials [6286087] An analysis of intrathoracic tumor control was carried out in 378 patients with histologically proven unresectable non‐oat cell carcinoma of the lung treated with definitive radiotherapy , r and omized to one of four treatment regimens : 4000 rad split course ( 2000 rad in five fractions in one week , two weeks rest and additional 2000 rad in five fractions in one week ) or 4000 , 5000 or 6000 rad continuous courses , five fractions per week . Between 85 and 101 patients are analyzed in each treatment group . The complete plus partial response was 46–51 % in the 4000 rad groups in contrast to 61–66 % in the 5000 to 6000 rad groups ( P = 0.008 ) . The overall two year survival rate was 10–11 % for the patients treated with 4000 rad split or continuous course , and 19 % in the patients treated with 5000 to 6000 rad . The complete response in patients with tumors 3 cm or less in diameter was 16 % when treated with 4000 rad in contrast to 20–31 % in those treated with 5000–6000 rad . In the patients with lesions from 4 to 6 cm in diameter , complete and partial tumor regression was 48 % in the 4000 rad group , 67 % with 5000 rad , and 71 % with 6000 rad . These differences are statistically significant ( P = 0.033 ) . Intrathoracic recurrences were correlated with the dose of irradiation given : 52 % with 4000 rad , 41 % with 5000 rad , and 30 % with 6000 rad ( P = 0.006 ) . An analysis of protocol compliance was carried out in 301 patients with available data , irradiated at the primary site according to protocol instruction ( none or minor variation ) . Median survival for patients treated to the ipsilateral or contralateral hilar lymph nodes according to the protocol varied from 46–50 weeks in contrast to 20–30 weeks for those with major protocol variations in nodal irradiation . Variations in ipsilateral and contralateral nodal irradiation correlated with significant reductions in tumor control ( P = 0.02 and P = 0.009 , respectively ) . In addition to patient and tumor characteristics , the technical factors of irradiation are critical parameters that affect tumor control and survival in patients with non‐oat cell bronchogenic carcinoma . Strict quality assurance criteria in radiotherapy are necessary to achieve optimal treatment results and a careful program to evaluate techniques of irradiation and protocol compliance should be maintained in cooperative group studies in order to enhance the validity of clinical trials [10458211] PURPOSE To determine whether the administration of carboplatin concurrently with radiation treatment improves survival in patients with inoperable stage III non-small-cell lung cancer . PATIENTS AND METHODS Two hundred eighty-three patients with inoperable stage III non-small-cell lung cancer were entered onto a r and omized trial by the Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group . R and omization was performed before initiation of any therapy . All patients received an induction chemotherapy program with vinblastine and cisplatin for 5 weeks , followed by 6,000 cGy of radiation therapy over 6 weeks . One hundred thirty-seven patients were r and omized to this therapy regimen alone ; 146 patients were r and omized to receive carboplatin at 100 mg/m2/wk concurrent with the radiation therapy . RESULTS The complete response was 18 % with concurrent carboplatin versus 10 % with radiotherapy alone ( P = .101 ) . There was no difference with respect to failure-free survival ( 10 % with carboplatin and 9 % with radiotherapy alone ) or overall survival ( 13 % with carboplatin and 10 % with radiotherapy alone ) at 4 years . In patients not receiving carboplatin , the relapse rate was 69 % within the field of radiation and 53 % in the boost volume . In patients receiving carboplatin , the relapse rate was 59 % within the field of radiation and 43 % in the boost volume . Patients with cancers more than 70 cm2 in size had significantly poorer survival ( P = .01 ) . CONCLUSION Carboplatin at the dose and schedule used did not significantly impact on disease control or survival . The relapse rate within the chest remained more than 50 % . More effective regimens will be required to impact on local disease control and survival [15165089] This study was design ed to compare high-dose fractionated radiotherapy alone versus the same radiotherapy plus cisplatin in stage III non-small cell lung cancer ( NSCLC ) . We r and omly assigned 176 patients with stage III non-small cell lung cancer to one of two treatments ; fractionated radiotherapy alone at dose of 64 Gy for 6 - 7 weeks ( 2 Gy given 32 times , in five fractions a week ) or radiotherapy in the same schedule , combined with 20mg/m2 cisplatin 1 h before radiotherapy , given on days 1 - 5 of the second and sixth treatment weeks . The frequency of loco-regional progression was 68 % among the patients who received radiotherapy plus cisplatin and 86 % among those who received radiotherapy alone ( P = 0.0001 ) . The probability of survival free of disease after 3 years was 10 % among the patients assigned to radiotherapy plus cisplatin and 0 % among those treated only with radiotherapy ( P = 0.0006 ) . Overall survival at 3 years was 10 % among those given radiotherapy plus cisplatin and 2 % among those who received radiotherapy alone ( P = 0.00001 ) . Multivariate analysis demonstrated that radiotherapy plus cisplatin significantly improved loco-regional progression-free survival and overall survival , irrespective of radiation dose . The addition of cisplatin to fractionated radiotherapy prolongs loco-regional progression-free interval and survival in stage III non-small cell lung cancer [8648358] PURPOSE To investigate the efficacy of concurrent hyperfractionated radiation therapy ( HFX RT ) and low-dose daily chemotherapy ( CHT ) in stage III non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Between January 1990 and December 1991 , 131 patients with histologically or cytologically confirmed stage III NSCLC , Karnofsky performance status ( KPS ) > or = 50 , and no previous therapy were r and omly treated as follows : group I , HFX RT with 1.2 Gy twice daily to a total dose of 69.6 Gy ( n = 66 ) ; and group II , same HFX RT with CHT consisting of 50 mg of carboplatin ( CBDCA ) and 50 mg of etoposide ( VP-16 ) given on each RT day ( n = 65 ) . RESULTS Group II patients had a significantly longer survival time than group I patients , with a median survival of 22 versus 14 months and 4-year survival rates of 23 % versus 9 % ( P = .021 ) . The median time to local recurrence and 4-year local recurrence-free survival rate were also significantly higher in group II than in group I ( 25 v 20 months and 42 % v 19 % respectively , P = .015 ) . In contrast , the distant metastasis-free survival rate did not significantly differ in the two groups ( P = .33 ) . The two groups showed similar incidence of acute and late high- grade toxicity ( P = .44 and .75 , respectively ) . No treatment-related toxicity was observed . CONCLUSION The combination of HFX RT and low-dose daily CBDCA plus VP-16 was tolerable and improved the survival of patients with stage III NSCLC as a result of improved local control [12202326] Abstract Objective : To determine whether patients with locally advanced non-small cell lung cancer unsuitable for resection or radical radiotherapy , and with minimal thoracic symptoms , should be given palliative thoracic radiotherapy immediately or as needed to treat symptoms . Design : Multicentre r and omised controlled trial . Setting : 23 centres in the United Kingdom , Irel and , and South Africa . Participants : 230 patients with previously untreated , non-small cell lung cancer that is locally too advanced for resection or radical radiotherapy with curative intent , with minimal thoracic symptoms , and with no indication for immediate thoracic radiotherapy . Interventions : All patients were given supportive treatment and were r and omised to receive palliative thoracic radiotherapy either immediately or delayed until needed to treat symptoms . The recommended regimens were 17 Gy in two fractions one week apart or 10 Gy as a single dose . Main outcome measures : Primary — patients alive and without moderate or severe cough , chest pain , haemoptysis , or dyspnoea six months from r and omisation , as recorded by clinicians . Secondary — quality of life , adverse events , survival . Results : From December 1992 to May 1999 , 230 patients were r and omised . 104/115 of the patients in the immediate treatment group received thoracic radiotherapy ( 90 received one of the recommended regimens ) . In the delayed treatment group , 48/115 ( 42 % ) patients received thoracic radiotherapy ( 29 received one of the recommended regimens ) ; 64 ( 56 % ) died without receiving thoracic radiotherapy ; the remaining three ( 3 % ) were alive at the end of the study without having received the treatment . For patients who received thoracic radiotherapy , the median time to start was 15 days in the immediate treatment group and 125 days in the delayed treatment group . The primary outcome measure was achieved in 28 % of the immediate treatment group and 26 % of patients from the delayed treatment group ( 27/97 and 27/103 , respectively ; absolute difference 1.6 % , 95 % confidence interval -10.7 % to 13.9 % ) . No evidence of a difference was observed between the two treatment groups in terms of activity level , anxiety , depression , and psychological distress , as recorded by the patients . Adverse events were more common in the immediate treatment group . Neither group had a survival advantage ( hazard ratio 0.95 , 0.73to 1.24 ; P=0.71 ) . Median survival was 8.3 months and 7.9 months , and the survival rates were 31 % and 29 % at 12 months , for the immediate and delayed treatment groups , respectively . Conclusion : In minimally symptomatic patients with locally advanced non-small cell lung cancer , no persuasive evidence was found to indicate that giving immediate palliative thoracic radiotherapy improves symptom control , quality of life , or survival when compared with delaying until symptoms require treatment [11316542] PURPOSE To investigate whether the addition of weekend chemotherapy consisting of carboplatin/etoposide to hyperfractionated radiation therapy ( Hfx RT ) and concurrent daily carboplatin/etoposide offers an advantage over the same Hfx RT/daily carboplatin/etoposide . METHODS AND MATERIAL S A total of 195 patients ( Group I , 98 ; Group II , 97 ) were treated with either Hfx RT to a total tumor dose of 69.6 Gy via 1.2 Gy b.i.d . fractionation and daily 50 mg each of carboplatin and etoposide during the RT course ( Group I ) or the same Hfx RT with daily carboplatin/etoposide consisting of 30 mg each of carboplatin and etoposide and with weekend ( Saturdays and Sundays ) 100 mg each of carboplatin and etoposide during the RT course ( Group II ) . RESULTS No difference was found regarding median survival time and 5-year survival rates ( 20 vs. 22 months and 20 % vs. 23 % ; p = 0.57 ) . Median time to local progression was 20 and 19 months , respectively , while 5-year local progression-free survival rates were 28 % and 27 % , respectively ( p = 0.66 ) . Also , there was no difference regarding either median time to distant metastasis and 5-year distant metastasis-free survival ( 21 vs. 25 months and 29 % vs. 34 % , p = 0.29 ) . There was no difference in the incidence of various nonhematologic toxicities between the two treatment groups , but patients treated with the weekend CHT had significantly more high- grade ( > or = 3 ) hematologic toxicity ( p = 0.0046 ) . Late high- grade toxicity was not different between the two treatment groups . CONCLUSION The addition of weekend carboplatin/etoposide did not improve results over those obtained with Hfx RT and concurrent low-dose , daily carboplatin/etoposide , but it led to a higher incidence of acute high- grade hematologic toxicity [9506347] A three‐arm Phase III r and omized trial was performed to compare response rates , time to local or distant progression , and survival for patients with unresectable ( Stage IIIA or IIIB ) nonsmall cell lung carcinoma treated with st and ard fractionated thoracic radiotherapy ( SFTRT ) versus accelerated hyperfractionated thoracic radiotherapy ( AHTRT ) with or without combination etoposide and cisplatin chemotherapy [2851173] One hundred sixteen patients with unresectable locally advanced non-small cell lung cancer ( NSCLC ) were accrued in a prospect i ve r and omized trial comparing ( A ) , chemotherapy ( cisplatin and etoposide [ VP-16 ] ) for two courses plus radiation therapy ( 30 + 20 Gy split course ) , followed by an additional two courses to ( B ) , the same regimen plus the addition of lonidamine ( LND ) . There were 93 patients evaluable for response ( 46 in the chemotherapy/radiation arm and 47 in the chemotherapy/radiation/LND arm ) . One hundred fifteen patients were evaluable for toxicity . The overall response rates , median time to progression , and median survival time were similar in both arms . For the group of patients with squamous cell histology , time to progression was 27 weeks on arm A and 38 weeks on arm B ( P = 0.01 ) . Two-year survival in the squamous cell group in arm A was 9 % , in arm B , 39 % . LND does not give rise to additional toxicity , although myalgia and testicular pain are characteristic side effects [12618901] Purpose . In this study our objective was to evaluate the therapeutic significance of concurrent paclitaxel and radiotherapy compared with radiotherapy alone . Patients and methods . Patients with stage III A/B NSCLC were r and omly assigned to receive either radiotherapy alone ( group 2 ) or concurrent weekly paclitaxel with radiotherapy ( group 1 ) in GMMA . Radiotherapy was given as a split-course schedule with the total dose of 56 Gy . Paclitaxel , 60 mg/m2 , was administered only to group 1 on the first day of each radiotherapy week . To assess differences between values , P values were calculated with the χ2 test . A Mann Whitney U-test was used to assess significant differences between the two values . Actuarial survival curves were calculated by the Kaplan-Meier method . Results . There were 25 patients who underwent chemoradiotherapy and 26 who underwent radiotherapy only . Median follow-up was 14 months . The overall response rate was 92 % and 70 % for groups 1 and 2 , respectively ( P= 0.003 ) . Median survival was 15.2 months for group 1 , and 12.0 months for group 2 ( P= 0.027 ) . Conclusion . Based on this response and the toxicity profile , outpatient split-course radiotherapy and weekly paclitaxel seems to be feasible and safe [14990635] PURPOSE To investigate whether the effect of hypofractionated thoracic radiotherapy ( TRT ) is comparable to more st and ard fractionated radiotherapy ( RT ) in advanced non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS A total of 421 patients with locally advanced stage III or stage IV NSCLC tumors were included . Inclusion criteria were inoperable , disease too advanced for curative radiotherapy , and chest symptoms or central tumor threatening the airways . Patients were r and omly assigned to three arms : A , 17 Gy per two fractions ( n = 146 ) ; B , 42 Gy per 15 fractions ( n = 145 ) ; and C , 50 Gy per 25 fractions ( n = 130 ) . Four hundred seven patients were eligible for the study ; 395 patients ( 97 % ) participated in the health-related quality -of-life ( HRQOL ) study . The European Organization for Research and Treatment of Cancer ( EORTC ) Quality of Life Question naire (QLQ)-C30 and EORTC QLQ-lung cancer-specific module ( LC13 ) were used to investigate airway symptom relief and changes in HRQOL . Assessment s were performed before TRT and until week 54 . Clinicians ' assessment s of symptom improvement were at 2 , 6 , and 14 weeks after completion of TRT . The patients were observed for a minimum of 3 years . Results Baseline prognostic data were equally distributed in the treatment groups . Patient compliance with respect to the HRQOL investigation was minimum 74 % . HRQOL and symptom relief were equivalent in the treatment arms . No significant difference in survival among arms A , B , and C was found , with median survival 8.2 , 7.0 , and 6.8 months , respectively . CONCLUSION Our data indicate that protracted palliative TRT renders no improvement in symptom relief , HRQOL , or survival when compared with short-term hypofractionated treatment in advanced NSCLC [7844608] PURPOSE To investigate the efficacy of combined hyperfractionated radiation therapy ( HFX RT ) and concurrent chemotherapy ( CHT ) in stage IIIA or IIIB non-small-cell lung cancer ( NSCLC ) compared with that of HFX RT alone . PATIENTS AND METHODS Between January 1988 and December 1989 , 169 patients were divided r and omly into the following groups : group I , HFX RT with 1.2 Gy twice daily to a total dose of 64.8 Gy ( n = 61 ) ; group II , same HFX RT with CHT consisting of 100 mg of carboplatin ( CBDCA ) on days 1 and 2 and 100 mg of etoposide ( VP-16 ) on days 1 to 3 of each week during the RT course ( n = 52 ) ; and group III , same HFX RT with CHT consisting of 200 mg of CBDCA on days 1 and 2 and 100 mg of VP-16 on days 1 to 5 of the first , third , and fifth weeks of the RT course ( n = 56 ) . RESULTS The median survival time ( MST ) was 8 months for group I , 18 months for group II , and 13 months for group III . The 3-year survival rates were 6.6 % , 23 % , and 16 % , respectively . There was a significant difference in the survival rate between groups I and II ( P = .0027 , log-rank test ) , but not between groups I and III ( P = .17 ) or between groups II and III ( P = .14 ) . The relapse-free survival rate in group II was also higher than that in group I ( P = .0024 ) , which was largely due to improved local control in group II patients . Patients in groups II and III showed a higher incidence of acute and /or late high- grade toxicity compared with group I patients , but no patient died of treatment-related toxicity . CONCLUSION The combination of HFX RT and continuous CBDCA/VP-16 CHT was tolerable and substantially increased the survival rate [10577698] PURPOSE To investigate the effects separately and together of ( a ) shortening overall treatment time and ( b ) giving concurrent carboplatin in patients having radical radiotherapy for inoperable non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Between April 1989 and May 1995 , 204 patients with medically inoperable or technically unresectable NSCLC localised to the primary site and regional lymph nodes were r and omised to receive one of four treatments using a 2 x 2 factorial design : st and ard radiotherapy , 60 Gy in 30 fractions in 6 weeks ( R6 ) ; accelerated radiotherapy , 60 Gy in 30 fractions in 3 weeks ( R3 ) ; st and ard radiotherapy as in R6 with carboplatin 70 mg/m2/day for 5 days during weeks 1 and 5 of radiotherapy ( R6C ) ; accelerated radiotherapy as in R3 with carboplatin 70 mg/m2/day for 5 days during week 1 of radiotherapy ( R3C ) . RESULTS The estimated median survival of all r and omised patients was 15.7 months and estimated 2-year survival was 31 % . The longest survival was seen in patients r and omised to R6C ( median 20.3 months , 41 % surviving at 2 years ) but there were no statistically significant differences between treatment arms or treatment factors ( carboplatin versus no carboplatin , accelerated versus conventional radiotherapy ) . Haematological toxicity was significantly greater in patients treated with carboplatin and oesophageal toxicity was significantly greater and more protracted in patients treated with accelerated radiotherapy . CONCLUSIONS This study failed to show a significant survival advantage for any of the treatment arms or factors . Halving overall treatment time result ed in significantly greater oesophageal toxicity with no suggestion of a survival advantage [17357188] PURPOSE This r and omized phase II trial was conducted to compare the overall response rate ( ORR ) of gemcitabine plus cisplatin combination followed by sequential radiotherapy ( RT ) ( arm A ) versus RT alone ( arm B ) in chemonaive patients with stage IIIA or IIIB non-small cell lung cancer ( NSCLC ) . Secondary objectives were to evaluate time to progressive disease ( TTPD ) , overall survival , and treatment tolerability in both arms . PATIENTS AND METHODS Eligible patients were required to have stage IIIA or stage IIIB NSCLC , no previous chemotherapy , ECOG performance status of 0 - 2 , bidimensionally measurable disease , and age 18 to 75 years . Patients r and omized in arm A were given 3 cycles of induction chemotherapy with gemcitabine 1250 mg/m(2 ) on days 1 and 8 , plus cisplatin 80 mg/m(2 ) on day 1 , every 21 days , followed by RT . In both arms , total dosage of RT was 63 Gy given in 34 fractions . Treatment continued until disease progression or unacceptable toxicity . RESULTS Enrolled patients in both arms ( 30 in each arm ) were well balanced for demographics and disease characteristics . The ORR , median TTPD and overall survival duration were 46.6/26.6 % , 9.9/7.1 months and 12.5/10.0 months for arm A and arm B , respectively . The chemoradiation arm ( arm A ) was associated with significantly higher hematologic toxicities ( anemia , neutropenia and thrombocytopenia ) and nonhematologic toxicities ( nausea , vomiting , paresthesias and alopecia ) . CONCLUSION Sequential chemoradiation seems to be more effective than radiation alone , with acceptable toxicity profile . Confirmation phase III studies are warranted [1310160] BACKGROUND AND METHODS Cisplatin ( cis-diamminedichloroplatinum ) has been reported to enhance the cell-killing effect of radiation , an effect whose intensity varies with the schedule of administration . We r and omly assigned 331 patients with nonmetastatic inoperable non-small-cell lung cancer to one of three treatments : radiotherapy for two weeks ( 3 Gy given 10 times , in five fractions a week ) , followed by a three-week rest period and then radiotherapy for two more weeks ( 2.5 Gy given 10 times , five fractions a week ) ; radiotherapy on the same schedule , combined with 30 mg of cisplatin per square meter of body-surface area , given on the first day of each treatment week ; or radiotherapy on the same schedule , combined with 6 mg of cisplatin per square meter , given daily before radiotherapy . RESULTS Survival was significantly improved in the radiotherapy-daily-cisplatin group as compared with the radiotherapy group ( P = 0.009 ) : survival in the radiotherapy-daily-cisplatin group was 54 percent at one year , 26 percent at two years , and 16 percent at three years , as compared with 46 percent , 13 percent , and 2 percent , respectively , in the radiotherapy group . Survival in the radiotherapy-weekly-cisplatin group was intermediate ( 44 percent , 19 percent , and 13 percent ) and not significantly different from survival in either of the other two groups . The survival benefit of daily combined treatment was due to improved control of local disease ( P = 0.003 ) . Survival without local recurrence was 59 percent at one year and 31 percent at two years in the radiotherapy-daily-cisplatin group ; 42 percent and 30 percent , respectively , in the radiotherapy-weekly-cisplatin group ; and 41 percent and 19 percent , respectively , in the radiotherapy group . Cisplatin induced nausea and vomiting in 86 percent of the patients given it weekly and in 78 percent of those given it daily ; these effects were severe in 26 percent and 28 percent , respectively . CONCLUSIONS Cisplatin , given daily in combination with the radiotherapy described here to patients with nonmetastatic but inoperable non-small-cell lung cancer , improved rates of survival and control of local disease at the price of substantial side effects [8777169] BACKGROUND The treatment results of radiotherapy in stage III non-small-cell lung cancer are very poor . Several phase II studies showed that neoadjuvant chemotherapy followed by radiotherapy was feasible in this patient group and suggested that treatment outcome might improve . A r and omized phase II study was performed addressing the response rate and morbidity of high-dose split course radiotherapy ( RT ) versus the same radiotherapy preceded by high-dose chemotherapy ( CT ) in patients with stage III non-small-cell lung cancer . PATIENTS AND METHODS Seventy eligible patients were r and omized in this study . CT consisted of cisplatin 100 mg/m2 days 1 and 22 , and vindesine 3 mg/m2 on days 1 , 8 , 22 and 29 . Radiotherapy started on day 43 in the combined arm and immediately in the RT-only arm . The primary tumour and the regional nodes were treated by 30 Gy/10 fractions/2 weeks and after the split by a second course of 25 Gy/10 fractions/2 weeks . In the combined arm a third CT cycle was planned during the split between RT courses . RESULTS In the CT + RT arm 34 patients were evaluable for response and toxicity and 30 patients in the RT only arm . After completion of treatment 7 patients had a complete response ( 2 in the CT plus RT arm , 5 in the RT alone arm ) and 26 patients a partial response ( 13 in the CT plus RT arm , 13 in the RT alone arm ) for an overall response rate of 52 % ( 95 % CI 39%-65 % ) . Acute toxicity was worse in the combined treatment arm with grade 4 leucocytopenia in 8 patients and thrombocytopenia grade 4 in one patient . Three patients had reversible renal toxicity grade 2 . There was one toxic death in the RT plus CT arm . There was no enhancement of acute or late radiation pulmonary or oesophageal toxicity . Time to progressive disease ( median 30 vs. 35 weeks ) and overall survival time ( median 12 months ) were equal in both treatment arms . CONCLUSION High-dose radiotherapy preceded by high-dose chemotherapy was more toxic than radiotherapy alone and did not result in this study in any benefit in terms of response rate , time to progressive disease and overall survival [8187005] The purpose of this study was to determine the feasibility of additional chemotherapy beyond 5 weeks of vinblastine-cisplatin followed by radiation therapy for patients with stage III non-small cell lung cancer . In this r and omized phase II trial , the goal was to determine , in a similar population of patients , the toxicity of either of two additional chemotherapy programs . Ninety-one patients with stage III non-small cell lung cancer received the same induction regime of vinblastine/cisplatin/radiotherapy . In patients r and omized to regime 1 , an additional four cycles of vinblastine/cisplatin were given after the radiotherapy . In regimen 2 , six weekly doses of carboplatin were given concurrent with the radiotherapy . The additional four cycles of vinblastine and cisplatin were completed by 34 % of patients ; the concurrent carboplatin program was completed by 70 % of patients . Grade 3 or 4 granulocytopenia occurred in 53 % of patients on regime 1 versus 17 % on regime 2 ( p < 0.003 ) ; grade 3 or 4 nausea/vomiting occurred in 20 % of those on regime 1 versus 7 % on regimen 2 ( p = 0.175 ) . Response rates and survival were similar for the two regimens , with approximately 30 % of patients surviving at 2 years . Given the reduced toxicity and the improved capacity to complete the planned therapy with the concurrent carboplatin treatment , this regimen will be further examined in a phase III trial [10561343] PURPOSE A phase III study was performed to determine whether concurrent or sequential treatment with radiotherapy ( RT ) and chemotherapy ( CT ) improves survival in unresectable stage III non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Patients were assigned to the two treatment arms . In the concurrent arm , chemotherapy consisted of cisplatin ( 80 mg/m(2 ) on days 1 and 29 ) , vindesine ( 3 mg/m(2 ) on days 1 , 8 , 29 , and 36 ) , and mitomycin ( 8 mg/m(2 ) on days 1 and 29 ) . RT began on day 2 at a dose of 28 Gy ( 2 Gy per fraction and 5 fractions per week for a total of 14 fractions ) followed by a rest period of 10 days , and then repeated . In the sequential arm , the same CT was given , but RT was initiated after completing CT and consisted of 56 Gy ( 2 Gy per fraction and 5 fractions per week for a total of 28 fractions ) . RESULTS Three hundred twenty patients were entered onto the study . Pretreatment characteristics were well balanced between the treatment arms . The response rate for the concurrent arm was significantly higher ( 84 . 0 % ) than that of the sequential arm ( 66 % ) ( P = .0002 ) . The median survival duration was significantly superior in patients receiving concurrent therapy ( 16.5 months ) , as compared with those receiving sequential therapy ( 13.3 months ) ( P = .03998 ) . Two- , 3- , 4- , and 5-year survival rates in the concurrent group ( 34.6 % , 22.3 % , 16.9 % , and 15.8 % , respectively ) were better than those in the sequential group ( 27.4 % , 14.7 % , 10.1 % , and 8.9 % , respectively ) . Myelosuppression was significantly greater among patients on the concurrent arm than on the sequential arm ( P = .0001 ) . CONCLUSION In selected patients with unresectable stage III NSCLC , the concurrent approach yields a significantly increased response rate and enhanced median survival duration when compared with the sequential approach [28016284] 7005 Background : St and ard therapy for unresectable stage III NSCLC includes concomitant chemoradiotherapy . In CALGB 39801 , we evaluated whether the addition of induction chemotherapy prior to CT/XRT would result in improved survival . METHODS Between 10/1998 and 5/2002 , 366 stage III patients ( pts ) were r and omized to either immediate CT/XRT [ carboplatin AUC of 2 and paclitaxel 50 mg/m2 each given weekly during 66 Gy chest XRT to ; arm 1 ( 182 pts ) ] or two cycles of carboplatin AUC 6 and paclitaxel 200 mg/m2 given q 21 days x 2 cycles followed by identical CT/XRT ; arm 2 ( 184 pts ) . The accrual goal was 360 patients . 290 deaths were required to have 80 % power to detect a 40 % increase in median survival assuming a one-tailed log-rank test conducted at the 0.025 level of significance . RESULTS 34 % of pts were female , 66 % male and 63 % were age 60 or older . Grade 3 or 4 toxicities during induction chemotherapy consisted mainly of neutropenia ( 17%/21 % ) . During CT/XRT , grade 3/4 neutropenia was noted in 11%/4 % ( arm 1 ) versus 21%/6 % ( arm 2 ) , grade 3 anemia was 5 % vs 11 % , grade 3/4 fatigue 16%/1 % vs 16%/4 % , esophagitis 30%/1 % vs 28%/7 % , and dyspnea 9%/3 % vs 15%/4 % . Overall , 4 toxicities were experienced by 24 % of patients on arm 1 versus 41 % on arm 2 ( p=0.001 ) . With 254 of 290 targeted deaths , median survival on arm 1 is 11.4 months versus 14 months on arm 2 ( p=0.154 ) . One year survival estimates are 48 % ( 41%-57 % ) and 54 % ( 47%-62 % ) respectively . CONCLUSION The median survival achieved in each of the treatment groups is low compared to other recent experiences in the literature . The reason(s ) for this are uncertain . The addition of induction chemotherapy to immediate concurrent CT/XRT is associated with a 2.6 month increase in median survival . However these findings are not sufficient to reject the null hypothesis of no treatment difference between the two study arms . Further follow up of this data set is required . Our results do not support the use of induction chemotherapy followed by CT/XRT as evidence based st and ard of care for patients with unresectable stage III NSCLC . [ Table : see text ] [8780630] BACKGROUND For many years , high dose radiation therapy was the st and ard treatment for patients with locally or regionally advanced non-small-cell lung cancer ( NSCLC ) , despite a 5-year survival rate of only 3%-10 % following such therapy . From May 1984 through May 1987 , the Cancer and Leukemia Group B ( CALGB ) conducted a r and omized trial that showed that induction chemotherapy before radiation therapy improved survival during the first 3 years of follow-up . PURPOSE This report provides data for 7 years of follow-up of patients enrolled in the CALGB trial . METHODS The patient population consisted of individuals who had clinical or surgical stage III , histologically documented NSCLC ; a CALGB performance status of 0 - 1 ; less than 5 % loss of body weight in the 3 months preceding diagnosis ; and radiographically visible disease . Patients were r and omly assigned to receive either 1 ) cisplatin ( 100 mg/m2 body surface area intravenously on days 1 and 29 ) and vinblastine ( 5 mg/m2 body surface area intravenously weekly on days 1 , 8 , 15 , 22 , and 29 ) followed by radiation therapy with 6000 cGy given in 30 fractions beginning on day 50 ( CT-RT group ) or 2 ) radiation therapy with 6000 cGy alone beginning on day 1 ( RT group ) for a maximum duration of 6 - 7 weeks . Patients were evaluated for tumor regression if they had measurable or evaluable disease and were monitored for toxic effects , disease progression , and date of death . RESULTS There were 78 eligible patients r and omly assigned to the CT-RT group and 77 r and omly assigned to the RT group . Both groups were similar in terms of sex , age , histologic cell type , performance status , substage of disease , and whether staging had been clinical or surgical . All patients had measurable or evaluable disease at the time of r and om assignment to treatment groups . Both groups received a similar quantity and quality of radiation therapy . As previously reported , the rate of tumor response , as determined radiographically , was 56 % for the CT-RT group and 43 % for the RT group ( P = .092 ) . After more than 7 years of follow-up , the median survival remains greater for the CT-RT group ( 13.7 months ) than for the RT group ( 9.6 months ) ( P = .012 ) as ascertained by the logrank test ( two-sided ) . The percentages of patients surviving after years 1 through 7 were 54 , 26 , 24 , 19 , 17 , 13 , and 13 for the CT-RT group and 40 , 13 , 10 , 7 , 6 , 6 , and 6 for the RT group . CONCLUSIONS Long-term follow-up confirms that patients with stage III NSCLC who receive 5 weeks of chemotherapy with cisplatin and vinblastine before radiation therapy have a 4.1-month increase in median survival . The use of sequential chemotherapy-radiotherapy increases the projected proportion of 5-year survivors by a factor of 2.8 compared with that of radiotherapy alone . However , inasmuch as 80%-85 % of such patients still die within 5 years and because treatment failure occurs both in the irradiated field and at distant sites in patients receiving either sequential chemotherapy-radiotherapy or radiotherapy alone , the need for further improvements in both the local and systemic treatment of this disease persists [12772814] This prospect i ve r and omized trial compared neoadjuvant chemotherapy followed by local-regional radiotherapy ( study group ) with radiotherapy alone ( control group ) in 506 patients with locally advanced non-small-cell lung cancer . The study group received three cycles of cisplatin , ifosfamide with Mesna , and mitomycin C at 21-day intervals . Radiotherapy was delivered up to a dose of 60 Gy . Evaluable patients numbered 460 . In the study group , 228 patients were assessed for tumor response after chemotherapy : 13 ( 5.7 % ) had a complete response ; 103 ( 43.2 % ) , a partial response ; 48 ( 21 % ) showed no change ; and 74 patients ( 31.1 % ) had progressive disease . These patients then received chest irradiation , which was well tolerated . On completion of radiotherapy , 16.2 % of the study group and 6 % of the control group had a complete response . No change was seen in 10.1 % of study patients and 15.5 % of control patients . Respective rates for disease progression were 27.6 % and 42.3 % . Actuarial 2-year survival was 20 % in the study group and 7.4 % in the control group [12743155] PURPOSE To test the concept of taxane sequencing in combined-modality therapy , this phase II trial ( S9504 ) evaluated consolidation docetaxel after concurrent chemoradiotherapy in patients with pathologically documented stage IIIB non-small-cell lung cancer ( NSCLC ) . Results were compared with those of the predecessor study ( S9019 ) with identical eligibility , staging criteria , and treatment , excepting docetaxel consolidation . PATIENTS AND METHODS Treatment consisted of cisplatin 50 mg/m2 on days 1 , 8 , 29 , and 36 , etoposide 50 mg/m2 on days 1 through 5 and 29 through 33 , and concurrent thoracic radiotherapy ( total dose of 61 Gy ) . Consolidation docetaxel started 4 to 6 weeks after chemoradiotherapy at an initial dose of 75 mg/m2 . RESULTS Stage subsets ( tumor-node-metastasis system ) in 83 eligible patients were as follows : T4N0/1 , 31 patients ( 37 % ) ; T4N2 , 22 patients ( 27 % ) , and T1 - 3N3 , 30 patients ( 36 % ) . Concurrent chemoradiotherapy was generally well tolerated , but two patients died from probable radiation-associated pneumonitis . Neutropenia during consolidation docetaxel was common ( 57 % with grade 4 ) and most frequent during escalation to 100 mg/m2 . Median progression-free survival was 16 months , median survival was 26 months , and 1- , 2- , and 3-year survival rates were 76 % , 54 % , and 37 % , respectively . Brain metastasis was the most common site of failure . In S9019 , median survival was 15 months and 1- , 2- , and 3-year survival rates were 58 % , 34 % , and 17 % , respectively . CONCLUSION Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB NSCLC is feasible and generally tolerable , and results compare favorably with the predecessor trial S9019 . Nevertheless , this study remains hypothesis-generating and does not provide definitive evidence of the benefit of this approach . Phase III trials evaluating the S9504 regimen have been initiated to vali date these results [11241082] OBJECTIVE The rate of complete resection ( 50 % ) and the 5-year survival ( 30 % ) for non-small cell lung carcinomas of the superior sulcus have not changed for 40 years . Recently , combined modality therapy has improved outcome in other subsets of locally advanced non-small cell lung carcinoma . This trial tested the feasibility of induction chemoradiation and surgical resection in non-small cell lung carcinoma of the superior sulcus with the ultimate aim of improving resectability and survival . METHODS Patients with mediastinoscopy-negative T3 - 4 N0 - 1 superior sulcus non-small cell lung carcinoma received 2 cycles of cisplatin and etoposide chemotherapy concurrent with 45 Gy of radiation . Patients with stable or responding disease underwent thoracotomy 3 to 5 weeks later . All patients received 2 more cycles of chemotherapy and were followed up by serial radiographs and scans . Survival was calculated by the Kaplan-Meier method and prognostic factors were assessed for significance by Cox regression analysis . RESULTS From April 1995 to September 1999 , 111 eligible patients ( 77 men , 34 women ) were entered in the study , including 80 ( 72.1 % ) with T3 and 31 with T4 tumors . Induction therapy was completed as planned in 102 ( 92 % ) patients . There were 3 treatment-related deaths ( 2.7 % ) . Cytopenia was the main grade 3 to 4 toxicity . Of 95 patients eligible for surgery , 83 underwent thoracotomy , 2 ( 2.4 % ) died postoperatively , and 76 ( 92 % ) had a complete resection . Fifty-four ( 65 % ) thoracotomy specimens showed either a pathologic complete response or minimal microscopic disease . The 2-year survival was 55 % for all eligible patients and 70 % for patients who had a complete resection . To date , survival is not significantly influenced by patient sex , T status , or pathologic response . CONCLUSIONS ( 1 ) This combined modality treatment is feasible in a multi-institutional setting ; ( 2 ) the pathologic complete response rates were high ; and ( 3 ) resectability and overall survival were improved compared with historical experience , especially for T4 tumors , which usually have a grim prognosis [8943671] The aim of this r and omised trial was to investigate the effect of induction chemotherapy before radiotherapy on survival in 302 patients with non-resectable squamous cell carcinoma of the lung . Radiotherapy , 56 Gy to the chest , was given to 154 patients and combined treatment , with chemotherapy preceding the radiotherapy , to 148 patients . Chemotherapy consisted of three courses of cisplatin ( 120 mg/m2 ) and etoposide ( 100 mg/m2 i.v . for 3 days ) administered every fourth week . Median survival was 10.5 months in the radiotherapy arm and 11 months in the combined treatment arm . The 2-year survival rate was 17 % in the radiotherapy arm and 21 % in the combined treatment arm . Addition of chemotherapy seemed to significantly improve survival , according to the Cox multivariate analysis ( P = 0.04 ) , but as only a trend according to life-table analysis ( P = 0.11 ) . Chemotherapy also accomplished a trend towards improved local control ( P = 0.08 ) and towards decreased metastatic disease ( P = 0.10 ) . 2 patients in the combined treatment arm , but none in the radiotherapy arm , died from toxicity . The conclusion was that the value of the chemotherapy used in this study was very modest , but the results strongly support further research for more efficient drugs and combinations [9549815] Assessment of health related quality of life has become an important endpoint in many cancer clinical trials . Because the participants of these trials often experience disease and treatment related morbidity and mortality , non-r and om missing assessment s are inevitable . Examples are presented from several such trials that illustrate the impact of missing data on the analysis of QOL in these trials . The sensitivity of different analyses depends on the proportion of assessment s that are missing and the strength of the association of the underlying reasons for missing data with disease and treatment related morbidity and mortality . In the setting of clinical trials of cancer therapy , the assumption that the data are missing completely at r and om ( MCAR ) and analyses of complete cases is usually unjustified . Further , the assumption of missing at r and om ( MAR ) may also be violated in many trials and models appropriate for non-ignorable missing data should be explored . Recommendations are presented to minimize missing data , to obtain useful documentation concerning the reasons for missing data and to perform sensitivity analyses [8814371] In patients with non-metastatic but inoperable non-small cell lung cancer that is locally too extensive for radical radiotherapy ( RT ) , but who have good performance status , it is important to determine whether thoracic RT should be the minimum that is required to palliate thoracic symptoms or whether treatment should be more intensive , with the aim of prolonging survival . A total of 509 such patients from 11 centres in the UK between November 1989 and October 1992 were admitted to a trial comparing palliative versus more intensive RT with respect to survival and quality of life . They were allocated at r and om to receive thoracic RT with either 17 Gy in two fractions ( F2 ) 1 week apart ( 255 patients ) or 39 Gy in 13 fractions ( F13 ) 5 days per week ( 254 patients ) . Survival was better in the F13 group , the median survival periods being 7 months in the F2 group compared with 9 months in the F13 group , and the survival rates 31 % and 36 % at one year and 9 % and 12 % at 2 years , respectively ( hazard ratio = 0.82 ; 95 % CI0.69 - 0.99 ) . There was a suggestion of a trend towards greater benefit in fitter patients . Metastases appeared earlier in the F2 group . As recorded by patients using the Rotterdam Symptom Checklist , the commonest symptoms on admission were cough , shortness of breath , tiredness , lack of energy , worrying and chest pain . These were more rapidly palliated by the F2 regimen . Psychological distress was generally lower in the F13 group . Three patients ( two F13 , one F2 ) exhibited evidence of myelopathy . As recorded by patients using a diary card , 76 % of the F2 compared with 81 % of the F13 patients had dysphagia associated with their RT . This was transient , lasting for a median of 6.5 days in the F2 group compared with 14 days in the F13 group . In conclusion , the F2 regimen had a more rapid palliative effect . In the F13 group , although treatment-related dysphagia was worse , survival was longer

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### Context: [12377323] PURPOSE This multi-institutional Phase III r and omized study compared 10 Gy single-fraction radiotherapy ( RT ) with 20 Gy in five fractions in the palliation of thoracic symptoms from lung cancer . METHODS AND MATERIAL S The primary end point was palliation of thoracic symptoms at 1 month after RT , evaluated by a patient-completed daily diary card . Secondary end points included quality of life , toxicity , and survival . RESULTS Most ( 69 % ) of 230 patients r and omized had locally advanced disease unsuitable for curative treatment . The treatment arms were well balanced with respect to the known prognostic factors . At 1 month after RT , no difference was found in symptom control between the two arms , as judged by the daily diary scores . The changes in the scores on the Lung Cancer Symptom Scale indicated that the fractionated RT ( five fractions ) group had greater improvement in symptoms related to lung cancer ( p = 0.009 ) , pain ( p = 0.0008 ) , ability to carry out normal activities ( p = 0.037 ) , and better global quality of life ( p = 0.039 ) . The European Organization for Research and Treatment of Cancer QLQ-C30 scores showed that patients receiving five fractions had a greater improvement in scores with respect to pain ( p = 0.04 ) . No significant difference was found in treatment-related toxicity . Patients who received five fractions survived on average 2 months longer ( p = 0.0305 ) than patients who received one fraction . CONCLUSION Although the two treatment strategies provided a similar degree of palliation of thoracic symptoms , the difference in survival between the two study arms was of a clinical ly relevant magnitude [12040280] A phase III r and omized trial was conducted to investigate whether induction chemotherapy followed by radiation can influence survival as compared with radiation alone in unresectable , locally advanced non-small-cell lung cancer ( LADNSCLC ) . A total of 101 patients with unresectable stage IIIA or IIIB NSCLC were enrolled . Patients were stratified by performance status , weight loss , histology and stage , and then r and omized to receive combined chemoradiotherapy or radiotherapy alone . Radiotherapy was administered in 1.8 Gy to 2.0 Gy st and ard fractions daily 5 times weekly for a total dose of 60 Gy to 65 Gy . The combined group received induction of cisplatin , etoposide , and vinblastine ( PEV ) chemotherapy with cisplatin 20 mg/m2 on days 1 to 5 , etoposide 100 mg/m2 on days 2 to 4 , and vinblastine 6 mg/m2 on day 1 , which wasrepeated every 3 weeks for 3 courses , after which time the patients underwent radiotherapy . Of 101 patients registered , 89 patients ( 43 combined , 46 radiotherapy alone ) were eligible for analysis . The response rates for the combined and radiotherapy groups were 65 % ( 28/43 ) and 70 % ( 32/46 ) , respectively . The median survival time ( MST ) showed a tendency to be more prolonged in the combined group than in the group receiving radiotherapy alone ( 13.8 vs. 8.5 months ) . The MST in patients with nonsquamous histology was strikingly prolonged in the combined group as compared with the radiotherapy group ( 14 vs. 3.6 months , p 0.027 ) . Likewise , the MST in patients with stage IIIB was significantly prolonged in the combined group as compared with the radiotherapy group ( 11.1 vs. 7.2 months , p 0.045 ) . Together , the MST of the high-risk group with nonsquamous or stage IIIB was significantly higher in the combined group than that seen in the radiotherapy group ( 11.6 vs. 8 months , p 0.046 ) , whereas the MST of the low-risk group , defined as having both squamous histology and stage IIIA , was similar in the two treatment groups ( 18.3 vs. 20.8 months , p = 0.293 ) . In conclusion , induction PEV chemotherapy plus radiotherapy is superior to radiotherapy alone in high-risk subsets of unresectable LAD-NSCLC and therapeutic strategy should be based on the identification of prognostic factors [1971762] Two policies of palliative thoracic radiotherapy for non-small-cell lung cancer have been compared in a r and omised multicentre controlled trial . A total of 369 patients with inoperable , histologically or cytologically confirmed disease , too advanced for radical ' curative ' radiotherapy , and with their main symptoms related to the primary intrathoracic tumour even if metastases were present , were studied . They were allocated at r and om either to a regimen of 17 Gy given in two fractions of 8.5 Gy 1 week apart ( F2 regimen ) , or to a conventional multifractionated regimen of either 30 Gy in ten fractions or 27 Gy in six fractions ( a biologically equivalent dose ) , given daily except at weekends ( FM regimen ) . On admission , 93 % of the patients had cough , 47 % haemoptysis , 57 % chest pain , 58 % anorexia , and 11 % dysphagia . As assessed by the clinicians , palliation of the main symptoms was achieved in high proportions of patients ranging in the F2 group from 65 % for cough to 81 % for haemoptysis and in the FM group from 56 % for cough to 86 % for haemoptysis . Haemoptysis , chest pain , and anorexia disappeared for a time in well over half the patients with these symptoms , and cough in 37 % . For all the main symptoms , the median duration of palliation was 50 % or more of survival . Performance status improved in approximately half of the patients with a poor status on admission . All these results were similar in the two treatment groups . As assessed daily by the patients using a diary card , the quality of life deteriorated slightly during treatment but then improved steadily during the next 5 weeks . The proportion of patients with dysphagia increased considerably during treatment , but fell to the pretreatment level during the next 2 weeks . The results were similar in the two groups . Radiation myelopathy was suspected in one ( F2 ) patient . There was no difference in survival between the two groups ( log-rank test ) , the median survival time from the date of allocation being 179 days in the F2 and 177 days in the FM group . In the light of all the findings , the regimen of two fractions of 8.5 Gy given 1 week apart is recommended [16087956] PURPOSE We conducted a phase III study to compare the survival impact of concurrent versus sequential treatment with radiotherapy ( RT ) and chemotherapy ( CT ) in unresectable stage III non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Patients were r and omly assigned to one of the two treatment arms . In the sequential arm , patients received induction CT with cisplatin ( 120 mg/m2 ) on days 1 , 29 , and 57 , and vinorelbine ( 30 mg/m2/wk ) from day 1 to day 78 , followed by thoracic RT at a dose of 66 Gy in 33 fractions ( 2 Gy per fraction and 5 fractions per week ) . In the concurrent arm , the same RT was started on day 1 with two concurrent cycles of cisplatin 20 mg/m2/d and etoposide 50 mg/m2/d ( days 1 to 5 and days 29 to 33 ) ; patients then received consolidation therapy with cisplatin 80 mg/m2 on days 78 and 106 and vinorelbine 30 mg/m2/wk from days 78 to 127 . RESULTS Two hundred five patients were r and omly assigned . Pretreatment characteristics were well balanced between the two arms . There were six toxic deaths in the sequential arm and 10 in the concurrent arm . Median survival was 14.5 months in the sequential arm and 16.3 months in the concurrent arm ( log-rank test P = .24 ) . Two- , 3- , and 4-year survival rates were better in the concurrent arm ( 39 % , 25 % , and 21 % , respectively ) than in the sequential arm ( 26 % , 19 % , and 14 % , respectively ) . Esophageal toxicity was significantly more frequent in the concurrent arm than in the sequential arm ( 32 % v 3 % ) . CONCLUSION Although not statistically significant , clinical ly important differences in the median , 2- , 3- , and 4-year survival rates were observed , with a trend in favor of concurrent chemoradiation therapy , suggesting that is the optimal strategy for patients with locally advanced NSCLC [9626216] PURPOSE The cisplatin-vinorelbine regimen has superior activity in advanced non-small-cell lung cancer ( NSCLC ) . We conducted a phase I trial to identify the maximum-tolerated dose ( MTD ) and dose-limiting toxicities ( DLTs ) of this regimen with concomitant thoracic radiation ( RT ) in patients with advanced chest malignancies . PATIENTS AND METHODS Patients with advanced chest malignancies that required RT were enrolled onto this phase I study of st and ard chest radiation ( 30 daily 2-Gy fractions for a total of 60 Gy ) and concurrent chemotherapy with cisplatin starting at 100 mg/m2 every 3 weeks and vinorelbine starting at 20 mg/m2/wk . RESULTS Thirty-seven patients were treated on this study . Two of three patients treated at the maximum-administered dose of cisplatin 100 mg/m2 per cycle and vinorelbine 25 mg/m2/wk experienced acute DLT ( neutropenia ) , which required deescalation . The dose level of cisplatin 100 mg/m2 and vinorelbine 20 mg/m2/wk , although tolerated acutely , produced delayed esophagitis , which proved dose-limiting . The recommended phase II dose was cisplatin 80 mg/m2 every 3 weeks and vinorelbine 15 mg/m2 given 2 of every 3 weeks with concomitant chest RT . CONCLUSION Concomitant chemoradiotherapy with cisplatin and vinorelbine is feasible . The recommended phase II dose is cisplatin 80 mg/m2 every 3 weeks with vinorelbine 15 mg/m2 given twice over 3 weeks on a day 1/day 8 schedule . Esophagitis is the DLT , with neutropenia occurring at higher dose levels . A Cancer and Leukemia Group B ( CALGB ) phase II trial is currently underway to evaluate further the efficacy and toxicities of this regimen in unresectable stage III NSCLC [14998844] PURPOSE To determine the radiosensitizing effect of prolonged exposure of carboplatin in patients with locally unresectable non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Patients with histologically proven NSCLC , performance score < 2 , weight loss < 10 % , and normal organ functions were r and omized between carboplatin 840 mg/m2 administered continuously during 6 weeks of radiotherapy or thoracic radiotherapy alone ( both 60 Gy ) . Toxicity was evaluated with National Cancer Institute Common Toxicity Criteria ( NCI CTC ) and the Radiation Therapy Oncology Group ( RTOG ) criteria . Quality of life was measured with European Organization for Research and Treatment of Cancer ( EORTC ) QLQ-C30/LC13 question naires . RESULTS One-hundred and sixty patients were included . Pathologically confirmed persistent tumor was present in 53 % of patients in the combination arm versus 58 % in the radiotherapy alone arm ( P=0.5 ) . Median survival in the combination arm was 11.8 [ 95 % confidence interval ( CI ) 9.3 - 14.2 ] months and in the radiotherapy alone arm 11.7 ( 95 % CI 8.1 - 15.5 ) months ; progression-free survival was not different between arms [ 6.8 and 7.5 months , respectively ( P=0.28 ) ] . Acute toxicity was mild , late toxicity was radiation-induced cardiomyopathy ( three patients ) and pulmonary fibrosis ( five patients ) . Quality of life was not different between arms , but in all measured patients cough and dyspnea improved , pain became less , and slight paresthesia developed 3 months after treatment . CONCLUSION Addition of continuously administered carboplatin as radiosensitizer for locally unresectable NSCLC does not improve local tumor control or overall survival [3033751] Eighty one patients with inoperable non-small cell lung carcinoma ( NSCLC ) were entered in a r and omized phase II trial comparing split-dose irradiation alone to combined treatment radiotherapy and polychemotherapy ( C.A.P. + V.D.S. ) . The quality of life and the survival of the patients were studied . We have defined three classes of quality of life responses based on the time elapsed before the performance status index drops . A higher quality of life failure rate was observed in the combined treatment group ( p non-significant ) but the time elapsed before the Karnofsky index drops is longer in the combined treatment group for the quality of life " no change " subgroup ( p = 0.15 ) . Survival and quality adjusted survival are similar in both treatment groups . The same conclusion holds for retrospective stratified treatment groups . The results of the study are presented according to the decision tree theory . We conclude that as far as the quality of life is concerned , polychemotherapy combined with the particular split-dose irradiation schedule used is an effective treatment of inoperable NSCLC . Its efficiency is comparable to , but not better than , the same radiotherapy schedule alone taken as a reference baseline [15364136] PURPOSE The superiority of chemoradiotherapy ( CRT ) over radiation alone in locally advanced non-small cell lung cancer ( NSCLC ) has been proven , but the relative merits of a concurrent schedule versus their sequential administration are less clear . This study compared the safety and efficacy of concurrent and sequential CRT , with chemotherapy ( CT ) consisting of a cisplatin and vinorelbine regimen , in patients with locally advanced NSCLC . PATIENTS AND METHODS One hundred and two previously untreated patients ( aged 42 - 75 years ) with locally advanced , stage IIIA ( n = 15 ) or stage IIIB ( n = 87 ) NSCLC were entered into the study . The CT schedule consisted of up to four cycles of cisplatin 80 mg/m(2 ) on day 1 , and vinorelbine 25 mg/m(2 ) at the first and fourth cycles ( 12.5 mg/m(2 ) during the 2nd/3rd cycles ) on days 1 , 8 , 15 of a 28-day cycle . Radiotherapy ( RT ) was prescribed at a dose of 60 Gy/30 fractions , given as five fractions per week for 6 weeks . In the concurrent arm ( arm A ) , RT was started on day 4 of cycle 2 ; whilst in the sequential arm ( arm B ) , RT started within 2 weeks after completion of CT . Fifty-two patients were r and omized to concurrent treatment and 50 to the sequential schedule . RESULTS Overall survival was significantly longer in arm A ( median survival 16.6 months ) versus arm B ( median survival 12.9 months ) ( P = 0.023 by means of log-rank test ; hazard ratio HR = 0.61 , 95 % CI of HR ( 0.39 - 0.93 ) ) , and time to progression ( TTP ) was also significantly longer in arm A ( median time to progression 11.9 months ) versus arm B ( median time to progression 8.5 months ) ( P = 0.024 by means of log-rank test ; HR = 0.62 , 95 % CI of HR ( 0.38 - 0.93 ) ) . Ninety-eight patients were evaluable for response and 101 for toxicity . The overall response rate was significantly higher in arm A , 80 % ( with 21 % complete response ( CR ) ) compared with 47 % ( with 17 % CR ) in arm B ( P = 0.001 by means of chi(2)-test ) . WHO grade 3 or 4 toxicity was more frequent in arm A than in arm B , with a significantly greater incidence of leucopenia ( 53 % versus 19 % , P = 0.009 by means of chi(2 ) test ) and nausea/vomiting ( 39 % versus 15 % , P = 0.044 by means of chi(2 ) test ) . There were no treatment related deaths . CONCLUSION In this study population , concurrent CRT demonstrated significant benefit in terms of response rate , overall survival and time to progression over sequential CRT . The concurrent CRT schedule was associated with higher toxicity ; however , the adverse event profile was acceptable in both arms [12377962] PURPOSE To evaluate new drugs in combination with cisplatin in unresectable stage III non-small-cell lung cancer , Cancer and Leukemia Group B ( CALGB ) conducted a r and omized phase II study of two cycles of induction chemotherapy followed by two additional cycles of the same drugs with concomitant radiotherapy . PATIENTS AND METHODS Eligible patients received four cycles of cisplatin at 80 mg/m(2 ) on days 1 , 22 , 43 , and 64 with arm 1 : gemcitabine 1,250 mg/m(2 ) on days 1 , 8 , 22 , and 29 and 600 mg/m(2 ) on days 43 , 50 , 64 , and 71 ; arm 2 : paclitaxel 225 mg/m(2 ) for 3 hours on days 1 and 22 and 135 mg/m(2 ) on days 43 and 64 ; and arm 3 : vinorelbine 25 mg/m(2 ) on days 1 , 8 , 15 , 22 , and 29 and 15 mg/m(2 ) on days 43 , 50 , 64 , and 71 . Radiotherapy was initiated on day 43 at 2 Gy/d ( total dose , 66 Gy ) . RESULTS One hundred seventy-five eligible patients were analyzed . Toxicities during induction chemotherapy consisted primarily of grade 3 or 4 granulocytopenia . Grade 3 or 4 toxicities during concomitant chemoradiotherapy consisted of thrombocytopenia , granulo-cytopenia , and esophagitis . Response rates after completion of radiotherapy were 74 % , 67 % , and 73 % for arms 1 , 2 , and 3 , respectively . Median survival for all patients was 17 months . One- , 2- , and 3-year survival rates for the patients on the three arms were 68%/37%/28 % , 62%/29%/19 % , and 65%/40%/23 % . CONCLUSION Four cycles of gemcitabine , vinorelbine , or paclitaxel in combination with cisplatin can be administered at these doses and schedules . The observed survival rates exceed those of previous CALGB trials and may be attributable to the use of concomitant chemoradiotherapy . Induction chemotherapy added to concomitant chemoradiotherapy is being evaluated in a phase III r and omized trial [2361948] A prospect i ve r and omised study compared two palliative radiotherapy schedules for inoperable symptomatic non-small-cell lung cancer ( NSCLC ) . After stratification , 100 patients were r and omly assigned to 20 Gy/5 fractions (fr)/5 days ( arm A ) or 16 Gy/2 fr/day 1 and 8 ( arm B ) . There were 90 men and 10 women aged 47–81 years ( mean 66 ) , performance status 1–4 ( median 2 ) . The major clinical characteristics and incidence and degree of initial disease-related symptoms were similar in both groups . Treatment effects were assessed using patient 's chart , doctor 's scoring of symptomatic change and chest X-ray . Study end points included degree and duration of symptomatic relief , treatment side effects , objective response rates and overall survival . A total of 55 patients were assigned to arm A and 45 to arm B. In all , 98 patients received assigned treatment , whereas two patients died before its termination . Treatment tolerance was good and did not differ between study arms . No significant differences between study arms were observed in the degree of relief of all analysed symptoms . Overall survival time differed significantly in favour of arm B ( median 8.0 vs 5.3 months ; P=0.016 ) . Both irradiation schedules provided comparable , effective palliation of tumour-related symptoms . The improved overall survival and treatment convenience of 2-fraction schedule suggest its usefulness in the routine management of symptomatic inoperable NSCLC [12177106] PURPOSE There are no published survival data after chemoradiotherapy ( chemoRT ) in pathologically documented stage IIIB non-small-cell lung cancer . Studies of radiotherapy ( RT ) alone or chemotherapy followed by RT yield 5-year survivals less than 10 % . The Southwest Oncology Group ( SWOG ) employed the same concurrent chemoRT induction regimen used in its predecessor trimodality trial to determine the efficacy , safety , and long-term outcome of replacing postinduction surgery with additional chemoRT . PATIENTS AND METHODS Eligible patients for SWOG-9019 had pathologic documentation of T4N0/1 , T4N2 , or N3 stage IIIB non-small-cell lung cancer . They had pulmonary function adequate to withst and combined-modality therapy , identical to the requirements of the previous trial with postchemoRT surgery . Induction therapy was two cycles of cisplatin plus etoposide ( PE ) concurrent with once-daily thoracic RT ( 45 Gy ) . In the absence of progressive disease , RT was completed to 61 Gy , with two additional cycles of cisplatin plus etoposide . RESULTS Fifty eligible patients were accrued with tumor-node ( TN ) substage confirmed on central review : 18 , T4N0/1 ; 12 , T4N2 ; and 20 , N3 . Grade 4 neutropenia was the most common toxicity ( 32 % ) . Grade 3/4 esophagitis occurred in 12 % and 8 % . Median follow-up was 52 months , and overall median survival was 15 months ( 10 to 22 , 95 % confidence interval ) . Three- and 5-year survivals were 17 % and 15 % ( 5-year T4N0/1 , 17 % ; T4N2 , 13 % ; and N3 , 15 % ) . CONCLUSION Feasibility and long-term survival support the application of these results as a st and ard against which mature outcomes of chemoRT trials with new chemotherapy agents can be compared . These results also justify use of the SWOG-9019 approach as a control arm in ongoing phase III trials [8581393] Eighty four patients from Groote Schuur Hospital and Frere Hospital East London were entered into a prospect i ve r and omised trial between January 1990 and December 1993 . All the patients possessed non-small cell carcinoma ( NSCLC ) of the lung too extensive for radical irradiation and World Health Organization performance status 0 - 2 . The patients were r and omised to receive either 35 Gy in 10 fractions ( 43 patients ) or 45 Gy in 15 fractions ( 41 patients ) . In the patients treated to 35 Gy and 45 Gy , the median survival was 8.5 months in both groups , the symptomatic response rate was 68 % and 76 % and the incidence of moderate to severe radiation oesophagitis was 23 % and 41 % respectively . The latter approached statistical significance ( P = 0.07 , chi square ) . There was no evidence of a dose response effect on survival in the moderate dose range in patients treated palliatively for locally advanced NSCLC [10506617] PURPOSE Chemotherapy for non-small-cell lung cancer ( NSCLC ) remains controversial . We describe the two largest reported , r and omized , parallel trials design ed to determine whether the addition of chemotherapy influences duration and quality of life in localized , unresectable ( mitomycin , ifosfamide , cisplatin [MIC]1 trial ) and extensive ( MIC2 trial ) disease . PATIENTS AND METHODS Ambulatory patients with NSCLC , aged 75 years or younger , with localized disease , were r and omized in MIC1 to receive up to four cycles of chemotherapy ( CT : mitomycin 6 mg/m(2 ) , ifosfamide 3 g/m(2 ) , and cisplatin 50 mg/m(2 ) ) every 21 days , followed by radical radiotherapy ( CT + RT ) or radiotherapy ( RT ) alone . Extensive-stage patients were r and omized in MIC2 to identical chemotherapy plus palliative care ( CT + PC ) or palliative care ( PC ) alone . Short-term change in quality of life ( QOL ) was assessed in a subgroup of patients . Data from the two trials were combined to allow multivariate and stratified survival analyses . RESULTS Seven hundred ninety-seven eligible patients were r and omized , 446 in MIC1 and 351 in MIC2 . MIC CT improved survival in both trials ( significantly in MIC2 ) . The median survival time in MIC1 was 11.7 months ( CT + RT ) versus 9.7 months ( RT alone ) ( P = .14 ) ; whereas in MIC2 , median survival time was 6.7 months ( CT + PC ) compared with 4 . 8 months ( PC alone ) ( P = .03 ) . QOL , assessed in 134 patients from start of trial to week 6 , showed improvement with chemotherapy and deterioration with st and ard treatment . In the combined analysis of 797 r and omized patients , the positive effect of MIC on survival was significant overall ( P = .01 ) and after adjusting for prognostic factors ( P = .01 ) . CONCLUSION MIC chemotherapy prolongs survival in unresectable NSCLC without compromising QOL [231024] Sixty-eight evaluable patients with unresectable adenocarcinoma and large cell carcinoma of the lung were treated on a prospect i ve r and omized trial comparing thoracic radiation therapy ( TRT ) plus combination chemotherapy with either cyclophosphamide , Adriamycin and cis-platinum ( CAP ) or cyclophosphamide , Adriamycin ( same dosages ) and DTIC ( CAD ) , 34 on each arm . Patients treated with TRT plus CAP had a better overall regression rate ( 59 % vs 47 % ) and a statistically significant superiority in time to disease progression ( 147 days vs 303 days ) and survival ( 217 days vs 504 days ) [9135893] The aim of this prospect i ve r and omized trial was to compare the symptomatic effects of two different regimens of palliative radiotherapy for lung cancer . Two hundred and sixteen patients needing palliation were r and omized to receive either a 17 Gy mid-point dose in two fractions 1 week apart or 22.5 Gy in five daily fractions . Both toxicity and efficacy were evaluated by postal question naires . This small study was intended to identify any clinical ly important differences in toxicity or efficacy between the two regimens . We detected no such difference , although there was a tendency for iatrogenic dysphagia and improvement in chest pain and cough to be more common with the two-fraction regimen . The only symptom that was improved in over 50 % of patients for 8 weeks or more was haemoptysis . Haemoptysis and chest pain appeared to be the best indications for treatment . The relief of other symptoms was disappointing in both degree and duration [2452146] Between October 1981 and November 1984 , 291 patients with inoperable advanced non-small cell carcinoma of the lung ( NSCLC ) were r and omized to a two-arm study . Eighteen of 291 defaulted treatment and were excluded from the study . Twenty-seven of 273 died during treatment ; they were invaluable for treatment response but were included in survival analysis . Without correction for lung attenuation 45 Gy/18 fractions/4 1/2 weeks were given in arm 1 and 31.2 Gy/4 fractions/4 weeks were given in arm 2 . One hundred twenty-eight of 273 were included in arm 1 and 145/273 in arm 2 . The two arms were comparable in patient age , sex , performance status and symptoms , primary tumor site , histology , stage of the disease , and distribution of metastases and radiation portal size used . Prognosis was poor with an overall median survival of 20 weeks and was similar in both arms . Radiological tumor response was also similar : 53 % in arm 1 and 50 % in arm 2 . However arm 1 was superior than arm 2 in achieving symptom palliation , 71 % vs 54 % , p less than 0.02 . Treatment complications were mild and included mainly radiation oesophagitis and pneumonitis and pulmonary fibrosis . Treatments in both arms were equally well tolerated [15860852] PURPOSE A national multicenter r and omized study compared the efficacy of 2 x 8 Gy versus our st and ard 10 x 3 Gy in patients with inoperable stage IIIA/B ( with an Eastern Cooperative Oncology Group score of 3 to 4 and /or substantial weight loss ) and stage IV non-small-cell lung cancer . PATIENTS AND METHODS Between January 1999 and June 2002 , 297 patients were eligible and r and omized to receive either 10 x 3 Gy or 2 x 8 Gy by external-beam irradiation . The primary end point was a patient-assessed score of treatment effect on seven thoracic symptoms using an adapted Rotterdam Symptom Checklist . Study sample size was determined based on an average total symptom score difference of more than one point over the initial 39 weeks post-treatment . The time course of symptom scores were also evaluated , and other secondary end points were toxicity and survival . RESULTS Both treatment arms were equally effective , as the average total symptom score over the initial 39 weeks did not differ . However , the pattern in time of these scores differed significantly ( P < .001 ) . Palliation in the 10 x 3-Gy arm was more prolonged ( until week 22 ) with less worsening symptoms than in 2 x 8-Gy . Survival in the 10 x 3-Gy arm was significantly ( P = .03 ) better than in the 2 x 8-Gy arm with 1-year survival of 19.6 % ( 95%CI , 14.1 % to 27.3 % ) v 10.9 % ( 95%CI , 6.9 % to 17.3 % ) . CONCLUSION The 10 x 3-Gy radiotherapy schedule is preferred over the 2 x 8-Gy schedule for palliative treatment , as it improves survival and results in a longer duration of the palliative response [1977779] Two policies of palliative thoracic radiotherapy for NSCLC have been compared in a r and omised multicentre controlled trial aim ed at simplifying the palliative treatment of patients with poor performance status . A total of 235 patients were entered . They had inoperable , microscopically confirmed disease , too advanced for ' curative ' radiotherapy . Their main symptoms were related to the primary intrathoracic tumour even if metastases were present , and they had a poor performance status . Patients were allocated at r and om to regimens of either 17 Gy given in two fractions of 8.5 Gy 1 week apart ( F2 regimen , 117 patients ) , or a single fraction of 10 Gy ( F1 regimen , 118 patients ) . Two patients ( one in each group ) were excluded from all analyses because they were found to have had previously treated malignant disease and had been admitted in error . On admission , 95 % of the 233 eligible patients had cough , 47 % haemoptysis , 59 % chest pain , 64 % anorexia , and 16 % dysphagia . As assessed by the clinicians , these symptoms were palliated in high proportions of patients , ranging in the F2 group from 48 % for cough to 75 % for haemoptysis , and in the F1 group from 55 % for anorexia to 72 % for haemoptysis and chest pain . For all five symptoms the median duration of palliation was 50 % or more of survival . All these results were similar in the two treatment groups . In contrast , on daily assessment by the patients using a diary card , those treated with the F2 regimen experienced substantially more dysphagia , which was recorded in 56 % of the patients compared with 23 % in the F1 group ( difference 33 % : 95 % confidence interval 17 - 48 % ) . The median survival from r and omisation was 100 days in the F2 group and 122 days in the F1 group . The F1 regimen , as it requires only a single attendance for treatment , is recommended as a palliative regimen for patients with inoperable NSCLC and a poor performance status [15845568] BACKGROUND The purpose of this study was to evaluate whether radiotherapy with carboplatin would result in longer survival than radiotherapy alone in elderly patients with unresectable stage III non-small cell lung cancer ( NSCLC ) . METHODS Eligible patients were 71 years of age or older with unresectable stage III NSCLC . Patients were r and omly assigned to the radiotherapy alone ( RT ) arm , irradiation with 60 Gy ; or the chemoradiotherapy ( CRT ) arm , the same radiotherapy and additional concurrent use of carboplatin 30 mg/m(2 ) per fraction up to the first 20 fractions . RESULTS This study was terminated early when 46 patients were registered from November 1999 to February 2001 . Four patients ( one in the RT arm , three in the CRT arm ) were considered to have died due to treatment-related causes . The JCOG Radiotherapy Committee assessed these treatment-related deaths ( TRDs ) and the compliance with radiotherapy in this trial . They found that 60 % of the cases corresponded to protocol deviation and 7 % were protocol violation in dose constraint to the normal lung , two of whom died due to radiation pneumonitis . As to the effectiveness for the 46 patients enrolled , the median survival time was 428 days [ 95 % confidence interval ( CI ) = 212 - 680 days ] in the RT arm versus 554 days ( 95 % CI = 331 to not estimable ) in the CRT arm . CONCLUSIONS Due to the early termination of this study , the effectiveness of concurrent use of carboplatin remains unclear . We re-planned and started a study with an active quality control program which was developed by the JCOG Radiotherapy Committee [16087941] PURPOSE This phase II noncomparative r and omized trial was conducted to determine the optimal sequencing and integration of paclitaxel/carboplatin with st and ard daily thoracic radiation therapy ( TRT ) , in patients with locally advanced unresected stage III non-small-cell lung cancer ( NSCLC ) . Survival data were compared with historical st and ard sequential chemoradiotherapy data from the Radiation Therapy Oncology Group . PATIENTS AND METHODS Patients with unresected stages IIIA and IIIB NSCLC , with Karnofsky performance status > or = 70 % and weight loss < or = 10 % , received two cycles of induction paclitaxel ( 200 mg/m2)/carboplatin ( area under the plasma concentration time curve [ AUC ] = 6 ) followed by TRT 63.0 Gy ( arm 1 , sequential ) or two cycles of induction paclitaxel ( 200 mg/m2)/carboplatin ( AUC = 6 ) followed by weekly paclitaxel ( 45 mg/m2)/carboplatin ( AUC = 2 ) with concurrent TRT 63.0 Gy ( arm 2 , induction/concurrent ) , or weekly paclitaxel ( 45 mg/m2)/carboplatin ( AUC = 2)/TRT ( 63.0 Gy ) followed by two cycles of paclitaxel ( 200 mg/m2)/carboplatin ( AUC = 6 ; arm 3 , concurrent/consolidation ) . RESULTS With a median follow-up time of 39.6 months , median overall survival was 13.0 , 12.7 , and 16.3 months for arms 1 , 2 , and 3 , respectively . During induction chemotherapy , grade 3/4 granulocytopenia occurred in 32 % and 38 % of patients on study arms 1 and 2 , respectively . The most common locoregional grade 3/4 toxicity during and after TRT was esophagitis , which was more pronounced with the administration of concurrent chemoradiotherapy on study arms 2 and 3 ( 19 % and 28 % , respectively ) . CONCLUSION Concurrent weekly paclitaxel , carboplatin , and TRT followed by consolidation seems to be associated with the best outcome , although this schedule was associated with greater toxicity [2557304] From October 1979 to December 1982 , 126 patients with locally advanced unresectable or inoperable Stage II ( 7 patients ) , Stage IIIA ( 81 patients ) , and Stage IIIB ( 38 patients ) non-small cell carcinoma of the lung were treated in a prospect i ve r and omized trial using five cycles of CAP ( Cytoxan , Adriamycin , and cisplatin ) , T-CAP ( triazinate plus CAP ) , or V-CAP ( VP-16 plus CAP ) chemotherapy with thoracic radiation therapy ( TRT ) . TRT consisted of 40 Gy in 10 fractions ( split-course ) with cycles 3 and 4 of chemotherapy . The treatment field included the primary tumor , ipsilateral hilum , mediastinum , and ipsilateral supraclavicular fossa . All patients were followed until death or for a minimum of 5 years for survivors . The evaluable subgroup consisted of 102 patients who completed TRT . Median and 5-year survivals for the entire group were 14.0 months and 10 % , respectively ; for the evaluable subgroup , they were 14.8 months and 12 % , respectively . There was a trend toward better survival with V-CAP plus TRT than with CAP plus TRT ( p = 0.08 ) . Median and 5-year survivals were 16.2 months and 18 % , respectively , with V-CAP plus TRT . Of eight prognostic variables analyzed for their association with survival , only Eastern Cooperative Oncology Group performance status ( 0,1 versus 2 ) ( p = 0.02 ) and weight loss ( less than or equal to 10 % versus greater than 10 % ) ( p = 0.05 ) were significant . Sex , age , T stage , N stage , overall stage , and histologic type were not significantly associated with survival . Failure analysis revealed 83 patients ( 81 % ) with identifiable first failures . The median time to first failure was 9.8 months , and the median survival after first failure was 4.7 months . Failure patterns included local failure alone ( 19 % ) , local and distant ( 20 % ) , and distant alone ( 43 % ) . Nineteen percent of patients had no documented progression . Total failure patterns were local in 39 % and distant in 63 % . Twenty-three patients ( 23 % ) had failure in the brain ; they accounted for 31 % of all distant failures . In 20 of these patients ( 20 % of all patients ) , this was the only site of failure . There were eight ( 8 % ) initial nodal failures in 96 untreated contralateral supraclavicular fossae . No initial failures were seen in any of 101 untreated contralateral hila . The data suggest the following : ( a ) Combined treatment with V-CAP and TRT yielded excellent results ( median survival , 16.2 months ; 5-year survival , 18 % ) . ( ABSTRACT TRUNCATED AT 400 WORDS [2851172] Cis-Dichlorodiammine platinum ( II ) ( cis-DDP ) was demonstrated to be a potentiator of radiation therapy ( RT ) in experimental tumor models and in cultured cells . To assess the effectiveness of a combined modality treatment including RT and a weekly low-dose administration of cis-DDP , from January 1986 to June 1987 , 95 patients with unresectable locally advanced non-small cell carcinoma of the lung ( stage IIIa , b ) were r and omized for study . Fifty patients received RT alone at doses of 50 Gy ; 45 patients received the same RT plus cis-DDP 15 mg/m2 IV weekly . An overall response rate of 50 % and 64 % was observed in the RT and RT + cis-DDP group , respectively . No statistically significant differences were detected with regard to median survival time ( 11 months for RT v 16 months for RT + cis-DDP ) and progression-free interval ( 7 months in the RT arm v 9 months in the RT + cis-DDP arm ) , but the patterns of the first failure appeared to be affected by treatment . In fact , a lower number of intrathoracic relapses was observed in the RT + cis-DDP arm ( 12 in the RT + cis-DDP v 23 in the RT arm ) . Toxicity was mild and the feasibility of this schedule must be remarked . A better local control of disease can be obtained using cis-DDP as a radiation potentiator , but the true influence of this combined modality treatment on the length of survival , and the optimal cis-DDP timing and dosage are still to be evaluated in further clinical trials [6286087] An analysis of intrathoracic tumor control was carried out in 378 patients with histologically proven unresectable non‐oat cell carcinoma of the lung treated with definitive radiotherapy , r and omized to one of four treatment regimens : 4000 rad split course ( 2000 rad in five fractions in one week , two weeks rest and additional 2000 rad in five fractions in one week ) or 4000 , 5000 or 6000 rad continuous courses , five fractions per week . Between 85 and 101 patients are analyzed in each treatment group . The complete plus partial response was 46–51 % in the 4000 rad groups in contrast to 61–66 % in the 5000 to 6000 rad groups ( P = 0.008 ) . The overall two year survival rate was 10–11 % for the patients treated with 4000 rad split or continuous course , and 19 % in the patients treated with 5000 to 6000 rad . The complete response in patients with tumors 3 cm or less in diameter was 16 % when treated with 4000 rad in contrast to 20–31 % in those treated with 5000–6000 rad . In the patients with lesions from 4 to 6 cm in diameter , complete and partial tumor regression was 48 % in the 4000 rad group , 67 % with 5000 rad , and 71 % with 6000 rad . These differences are statistically significant ( P = 0.033 ) . Intrathoracic recurrences were correlated with the dose of irradiation given : 52 % with 4000 rad , 41 % with 5000 rad , and 30 % with 6000 rad ( P = 0.006 ) . An analysis of protocol compliance was carried out in 301 patients with available data , irradiated at the primary site according to protocol instruction ( none or minor variation ) . Median survival for patients treated to the ipsilateral or contralateral hilar lymph nodes according to the protocol varied from 46–50 weeks in contrast to 20–30 weeks for those with major protocol variations in nodal irradiation . Variations in ipsilateral and contralateral nodal irradiation correlated with significant reductions in tumor control ( P = 0.02 and P = 0.009 , respectively ) . In addition to patient and tumor characteristics , the technical factors of irradiation are critical parameters that affect tumor control and survival in patients with non‐oat cell bronchogenic carcinoma . Strict quality assurance criteria in radiotherapy are necessary to achieve optimal treatment results and a careful program to evaluate techniques of irradiation and protocol compliance should be maintained in cooperative group studies in order to enhance the validity of clinical trials [10458211] PURPOSE To determine whether the administration of carboplatin concurrently with radiation treatment improves survival in patients with inoperable stage III non-small-cell lung cancer . PATIENTS AND METHODS Two hundred eighty-three patients with inoperable stage III non-small-cell lung cancer were entered onto a r and omized trial by the Cancer and Leukemia Group B and the Eastern Cooperative Oncology Group . R and omization was performed before initiation of any therapy . All patients received an induction chemotherapy program with vinblastine and cisplatin for 5 weeks , followed by 6,000 cGy of radiation therapy over 6 weeks . One hundred thirty-seven patients were r and omized to this therapy regimen alone ; 146 patients were r and omized to receive carboplatin at 100 mg/m2/wk concurrent with the radiation therapy . RESULTS The complete response was 18 % with concurrent carboplatin versus 10 % with radiotherapy alone ( P = .101 ) . There was no difference with respect to failure-free survival ( 10 % with carboplatin and 9 % with radiotherapy alone ) or overall survival ( 13 % with carboplatin and 10 % with radiotherapy alone ) at 4 years . In patients not receiving carboplatin , the relapse rate was 69 % within the field of radiation and 53 % in the boost volume . In patients receiving carboplatin , the relapse rate was 59 % within the field of radiation and 43 % in the boost volume . Patients with cancers more than 70 cm2 in size had significantly poorer survival ( P = .01 ) . CONCLUSION Carboplatin at the dose and schedule used did not significantly impact on disease control or survival . The relapse rate within the chest remained more than 50 % . More effective regimens will be required to impact on local disease control and survival [15165089] This study was design ed to compare high-dose fractionated radiotherapy alone versus the same radiotherapy plus cisplatin in stage III non-small cell lung cancer ( NSCLC ) . We r and omly assigned 176 patients with stage III non-small cell lung cancer to one of two treatments ; fractionated radiotherapy alone at dose of 64 Gy for 6 - 7 weeks ( 2 Gy given 32 times , in five fractions a week ) or radiotherapy in the same schedule , combined with 20mg/m2 cisplatin 1 h before radiotherapy , given on days 1 - 5 of the second and sixth treatment weeks . The frequency of loco-regional progression was 68 % among the patients who received radiotherapy plus cisplatin and 86 % among those who received radiotherapy alone ( P = 0.0001 ) . The probability of survival free of disease after 3 years was 10 % among the patients assigned to radiotherapy plus cisplatin and 0 % among those treated only with radiotherapy ( P = 0.0006 ) . Overall survival at 3 years was 10 % among those given radiotherapy plus cisplatin and 2 % among those who received radiotherapy alone ( P = 0.00001 ) . Multivariate analysis demonstrated that radiotherapy plus cisplatin significantly improved loco-regional progression-free survival and overall survival , irrespective of radiation dose . The addition of cisplatin to fractionated radiotherapy prolongs loco-regional progression-free interval and survival in stage III non-small cell lung cancer [8648358] PURPOSE To investigate the efficacy of concurrent hyperfractionated radiation therapy ( HFX RT ) and low-dose daily chemotherapy ( CHT ) in stage III non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Between January 1990 and December 1991 , 131 patients with histologically or cytologically confirmed stage III NSCLC , Karnofsky performance status ( KPS ) > or = 50 , and no previous therapy were r and omly treated as follows : group I , HFX RT with 1.2 Gy twice daily to a total dose of 69.6 Gy ( n = 66 ) ; and group II , same HFX RT with CHT consisting of 50 mg of carboplatin ( CBDCA ) and 50 mg of etoposide ( VP-16 ) given on each RT day ( n = 65 ) . RESULTS Group II patients had a significantly longer survival time than group I patients , with a median survival of 22 versus 14 months and 4-year survival rates of 23 % versus 9 % ( P = .021 ) . The median time to local recurrence and 4-year local recurrence-free survival rate were also significantly higher in group II than in group I ( 25 v 20 months and 42 % v 19 % respectively , P = .015 ) . In contrast , the distant metastasis-free survival rate did not significantly differ in the two groups ( P = .33 ) . The two groups showed similar incidence of acute and late high- grade toxicity ( P = .44 and .75 , respectively ) . No treatment-related toxicity was observed . CONCLUSION The combination of HFX RT and low-dose daily CBDCA plus VP-16 was tolerable and improved the survival of patients with stage III NSCLC as a result of improved local control [12202326] Abstract Objective : To determine whether patients with locally advanced non-small cell lung cancer unsuitable for resection or radical radiotherapy , and with minimal thoracic symptoms , should be given palliative thoracic radiotherapy immediately or as needed to treat symptoms . Design : Multicentre r and omised controlled trial . Setting : 23 centres in the United Kingdom , Irel and , and South Africa . Participants : 230 patients with previously untreated , non-small cell lung cancer that is locally too advanced for resection or radical radiotherapy with curative intent , with minimal thoracic symptoms , and with no indication for immediate thoracic radiotherapy . Interventions : All patients were given supportive treatment and were r and omised to receive palliative thoracic radiotherapy either immediately or delayed until needed to treat symptoms . The recommended regimens were 17 Gy in two fractions one week apart or 10 Gy as a single dose . Main outcome measures : Primary — patients alive and without moderate or severe cough , chest pain , haemoptysis , or dyspnoea six months from r and omisation , as recorded by clinicians . Secondary — quality of life , adverse events , survival . Results : From December 1992 to May 1999 , 230 patients were r and omised . 104/115 of the patients in the immediate treatment group received thoracic radiotherapy ( 90 received one of the recommended regimens ) . In the delayed treatment group , 48/115 ( 42 % ) patients received thoracic radiotherapy ( 29 received one of the recommended regimens ) ; 64 ( 56 % ) died without receiving thoracic radiotherapy ; the remaining three ( 3 % ) were alive at the end of the study without having received the treatment . For patients who received thoracic radiotherapy , the median time to start was 15 days in the immediate treatment group and 125 days in the delayed treatment group . The primary outcome measure was achieved in 28 % of the immediate treatment group and 26 % of patients from the delayed treatment group ( 27/97 and 27/103 , respectively ; absolute difference 1.6 % , 95 % confidence interval -10.7 % to 13.9 % ) . No evidence of a difference was observed between the two treatment groups in terms of activity level , anxiety , depression , and psychological distress , as recorded by the patients . Adverse events were more common in the immediate treatment group . Neither group had a survival advantage ( hazard ratio 0.95 , 0.73to 1.24 ; P=0.71 ) . Median survival was 8.3 months and 7.9 months , and the survival rates were 31 % and 29 % at 12 months , for the immediate and delayed treatment groups , respectively . Conclusion : In minimally symptomatic patients with locally advanced non-small cell lung cancer , no persuasive evidence was found to indicate that giving immediate palliative thoracic radiotherapy improves symptom control , quality of life , or survival when compared with delaying until symptoms require treatment [11316542] PURPOSE To investigate whether the addition of weekend chemotherapy consisting of carboplatin/etoposide to hyperfractionated radiation therapy ( Hfx RT ) and concurrent daily carboplatin/etoposide offers an advantage over the same Hfx RT/daily carboplatin/etoposide . METHODS AND MATERIAL S A total of 195 patients ( Group I , 98 ; Group II , 97 ) were treated with either Hfx RT to a total tumor dose of 69.6 Gy via 1.2 Gy b.i.d . fractionation and daily 50 mg each of carboplatin and etoposide during the RT course ( Group I ) or the same Hfx RT with daily carboplatin/etoposide consisting of 30 mg each of carboplatin and etoposide and with weekend ( Saturdays and Sundays ) 100 mg each of carboplatin and etoposide during the RT course ( Group II ) . RESULTS No difference was found regarding median survival time and 5-year survival rates ( 20 vs. 22 months and 20 % vs. 23 % ; p = 0.57 ) . Median time to local progression was 20 and 19 months , respectively , while 5-year local progression-free survival rates were 28 % and 27 % , respectively ( p = 0.66 ) . Also , there was no difference regarding either median time to distant metastasis and 5-year distant metastasis-free survival ( 21 vs. 25 months and 29 % vs. 34 % , p = 0.29 ) . There was no difference in the incidence of various nonhematologic toxicities between the two treatment groups , but patients treated with the weekend CHT had significantly more high- grade ( > or = 3 ) hematologic toxicity ( p = 0.0046 ) . Late high- grade toxicity was not different between the two treatment groups . CONCLUSION The addition of weekend carboplatin/etoposide did not improve results over those obtained with Hfx RT and concurrent low-dose , daily carboplatin/etoposide , but it led to a higher incidence of acute high- grade hematologic toxicity [9506347] A three‐arm Phase III r and omized trial was performed to compare response rates , time to local or distant progression , and survival for patients with unresectable ( Stage IIIA or IIIB ) nonsmall cell lung carcinoma treated with st and ard fractionated thoracic radiotherapy ( SFTRT ) versus accelerated hyperfractionated thoracic radiotherapy ( AHTRT ) with or without combination etoposide and cisplatin chemotherapy [2851173] One hundred sixteen patients with unresectable locally advanced non-small cell lung cancer ( NSCLC ) were accrued in a prospect i ve r and omized trial comparing ( A ) , chemotherapy ( cisplatin and etoposide [ VP-16 ] ) for two courses plus radiation therapy ( 30 + 20 Gy split course ) , followed by an additional two courses to ( B ) , the same regimen plus the addition of lonidamine ( LND ) . There were 93 patients evaluable for response ( 46 in the chemotherapy/radiation arm and 47 in the chemotherapy/radiation/LND arm ) . One hundred fifteen patients were evaluable for toxicity . The overall response rates , median time to progression , and median survival time were similar in both arms . For the group of patients with squamous cell histology , time to progression was 27 weeks on arm A and 38 weeks on arm B ( P = 0.01 ) . Two-year survival in the squamous cell group in arm A was 9 % , in arm B , 39 % . LND does not give rise to additional toxicity , although myalgia and testicular pain are characteristic side effects [12618901] Purpose . In this study our objective was to evaluate the therapeutic significance of concurrent paclitaxel and radiotherapy compared with radiotherapy alone . Patients and methods . Patients with stage III A/B NSCLC were r and omly assigned to receive either radiotherapy alone ( group 2 ) or concurrent weekly paclitaxel with radiotherapy ( group 1 ) in GMMA . Radiotherapy was given as a split-course schedule with the total dose of 56 Gy . Paclitaxel , 60 mg/m2 , was administered only to group 1 on the first day of each radiotherapy week . To assess differences between values , P values were calculated with the χ2 test . A Mann Whitney U-test was used to assess significant differences between the two values . Actuarial survival curves were calculated by the Kaplan-Meier method . Results . There were 25 patients who underwent chemoradiotherapy and 26 who underwent radiotherapy only . Median follow-up was 14 months . The overall response rate was 92 % and 70 % for groups 1 and 2 , respectively ( P= 0.003 ) . Median survival was 15.2 months for group 1 , and 12.0 months for group 2 ( P= 0.027 ) . Conclusion . Based on this response and the toxicity profile , outpatient split-course radiotherapy and weekly paclitaxel seems to be feasible and safe [14990635] PURPOSE To investigate whether the effect of hypofractionated thoracic radiotherapy ( TRT ) is comparable to more st and ard fractionated radiotherapy ( RT ) in advanced non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS A total of 421 patients with locally advanced stage III or stage IV NSCLC tumors were included . Inclusion criteria were inoperable , disease too advanced for curative radiotherapy , and chest symptoms or central tumor threatening the airways . Patients were r and omly assigned to three arms : A , 17 Gy per two fractions ( n = 146 ) ; B , 42 Gy per 15 fractions ( n = 145 ) ; and C , 50 Gy per 25 fractions ( n = 130 ) . Four hundred seven patients were eligible for the study ; 395 patients ( 97 % ) participated in the health-related quality -of-life ( HRQOL ) study . The European Organization for Research and Treatment of Cancer ( EORTC ) Quality of Life Question naire (QLQ)-C30 and EORTC QLQ-lung cancer-specific module ( LC13 ) were used to investigate airway symptom relief and changes in HRQOL . Assessment s were performed before TRT and until week 54 . Clinicians ' assessment s of symptom improvement were at 2 , 6 , and 14 weeks after completion of TRT . The patients were observed for a minimum of 3 years . Results Baseline prognostic data were equally distributed in the treatment groups . Patient compliance with respect to the HRQOL investigation was minimum 74 % . HRQOL and symptom relief were equivalent in the treatment arms . No significant difference in survival among arms A , B , and C was found , with median survival 8.2 , 7.0 , and 6.8 months , respectively . CONCLUSION Our data indicate that protracted palliative TRT renders no improvement in symptom relief , HRQOL , or survival when compared with short-term hypofractionated treatment in advanced NSCLC [7844608] PURPOSE To investigate the efficacy of combined hyperfractionated radiation therapy ( HFX RT ) and concurrent chemotherapy ( CHT ) in stage IIIA or IIIB non-small-cell lung cancer ( NSCLC ) compared with that of HFX RT alone . PATIENTS AND METHODS Between January 1988 and December 1989 , 169 patients were divided r and omly into the following groups : group I , HFX RT with 1.2 Gy twice daily to a total dose of 64.8 Gy ( n = 61 ) ; group II , same HFX RT with CHT consisting of 100 mg of carboplatin ( CBDCA ) on days 1 and 2 and 100 mg of etoposide ( VP-16 ) on days 1 to 3 of each week during the RT course ( n = 52 ) ; and group III , same HFX RT with CHT consisting of 200 mg of CBDCA on days 1 and 2 and 100 mg of VP-16 on days 1 to 5 of the first , third , and fifth weeks of the RT course ( n = 56 ) . RESULTS The median survival time ( MST ) was 8 months for group I , 18 months for group II , and 13 months for group III . The 3-year survival rates were 6.6 % , 23 % , and 16 % , respectively . There was a significant difference in the survival rate between groups I and II ( P = .0027 , log-rank test ) , but not between groups I and III ( P = .17 ) or between groups II and III ( P = .14 ) . The relapse-free survival rate in group II was also higher than that in group I ( P = .0024 ) , which was largely due to improved local control in group II patients . Patients in groups II and III showed a higher incidence of acute and /or late high- grade toxicity compared with group I patients , but no patient died of treatment-related toxicity . CONCLUSION The combination of HFX RT and continuous CBDCA/VP-16 CHT was tolerable and substantially increased the survival rate [10577698] PURPOSE To investigate the effects separately and together of ( a ) shortening overall treatment time and ( b ) giving concurrent carboplatin in patients having radical radiotherapy for inoperable non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Between April 1989 and May 1995 , 204 patients with medically inoperable or technically unresectable NSCLC localised to the primary site and regional lymph nodes were r and omised to receive one of four treatments using a 2 x 2 factorial design : st and ard radiotherapy , 60 Gy in 30 fractions in 6 weeks ( R6 ) ; accelerated radiotherapy , 60 Gy in 30 fractions in 3 weeks ( R3 ) ; st and ard radiotherapy as in R6 with carboplatin 70 mg/m2/day for 5 days during weeks 1 and 5 of radiotherapy ( R6C ) ; accelerated radiotherapy as in R3 with carboplatin 70 mg/m2/day for 5 days during week 1 of radiotherapy ( R3C ) . RESULTS The estimated median survival of all r and omised patients was 15.7 months and estimated 2-year survival was 31 % . The longest survival was seen in patients r and omised to R6C ( median 20.3 months , 41 % surviving at 2 years ) but there were no statistically significant differences between treatment arms or treatment factors ( carboplatin versus no carboplatin , accelerated versus conventional radiotherapy ) . Haematological toxicity was significantly greater in patients treated with carboplatin and oesophageal toxicity was significantly greater and more protracted in patients treated with accelerated radiotherapy . CONCLUSIONS This study failed to show a significant survival advantage for any of the treatment arms or factors . Halving overall treatment time result ed in significantly greater oesophageal toxicity with no suggestion of a survival advantage [17357188] PURPOSE This r and omized phase II trial was conducted to compare the overall response rate ( ORR ) of gemcitabine plus cisplatin combination followed by sequential radiotherapy ( RT ) ( arm A ) versus RT alone ( arm B ) in chemonaive patients with stage IIIA or IIIB non-small cell lung cancer ( NSCLC ) . Secondary objectives were to evaluate time to progressive disease ( TTPD ) , overall survival , and treatment tolerability in both arms . PATIENTS AND METHODS Eligible patients were required to have stage IIIA or stage IIIB NSCLC , no previous chemotherapy , ECOG performance status of 0 - 2 , bidimensionally measurable disease , and age 18 to 75 years . Patients r and omized in arm A were given 3 cycles of induction chemotherapy with gemcitabine 1250 mg/m(2 ) on days 1 and 8 , plus cisplatin 80 mg/m(2 ) on day 1 , every 21 days , followed by RT . In both arms , total dosage of RT was 63 Gy given in 34 fractions . Treatment continued until disease progression or unacceptable toxicity . RESULTS Enrolled patients in both arms ( 30 in each arm ) were well balanced for demographics and disease characteristics . The ORR , median TTPD and overall survival duration were 46.6/26.6 % , 9.9/7.1 months and 12.5/10.0 months for arm A and arm B , respectively . The chemoradiation arm ( arm A ) was associated with significantly higher hematologic toxicities ( anemia , neutropenia and thrombocytopenia ) and nonhematologic toxicities ( nausea , vomiting , paresthesias and alopecia ) . CONCLUSION Sequential chemoradiation seems to be more effective than radiation alone , with acceptable toxicity profile . Confirmation phase III studies are warranted [1310160] BACKGROUND AND METHODS Cisplatin ( cis-diamminedichloroplatinum ) has been reported to enhance the cell-killing effect of radiation , an effect whose intensity varies with the schedule of administration . We r and omly assigned 331 patients with nonmetastatic inoperable non-small-cell lung cancer to one of three treatments : radiotherapy for two weeks ( 3 Gy given 10 times , in five fractions a week ) , followed by a three-week rest period and then radiotherapy for two more weeks ( 2.5 Gy given 10 times , five fractions a week ) ; radiotherapy on the same schedule , combined with 30 mg of cisplatin per square meter of body-surface area , given on the first day of each treatment week ; or radiotherapy on the same schedule , combined with 6 mg of cisplatin per square meter , given daily before radiotherapy . RESULTS Survival was significantly improved in the radiotherapy-daily-cisplatin group as compared with the radiotherapy group ( P = 0.009 ) : survival in the radiotherapy-daily-cisplatin group was 54 percent at one year , 26 percent at two years , and 16 percent at three years , as compared with 46 percent , 13 percent , and 2 percent , respectively , in the radiotherapy group . Survival in the radiotherapy-weekly-cisplatin group was intermediate ( 44 percent , 19 percent , and 13 percent ) and not significantly different from survival in either of the other two groups . The survival benefit of daily combined treatment was due to improved control of local disease ( P = 0.003 ) . Survival without local recurrence was 59 percent at one year and 31 percent at two years in the radiotherapy-daily-cisplatin group ; 42 percent and 30 percent , respectively , in the radiotherapy-weekly-cisplatin group ; and 41 percent and 19 percent , respectively , in the radiotherapy group . Cisplatin induced nausea and vomiting in 86 percent of the patients given it weekly and in 78 percent of those given it daily ; these effects were severe in 26 percent and 28 percent , respectively . CONCLUSIONS Cisplatin , given daily in combination with the radiotherapy described here to patients with nonmetastatic but inoperable non-small-cell lung cancer , improved rates of survival and control of local disease at the price of substantial side effects [8777169] BACKGROUND The treatment results of radiotherapy in stage III non-small-cell lung cancer are very poor . Several phase II studies showed that neoadjuvant chemotherapy followed by radiotherapy was feasible in this patient group and suggested that treatment outcome might improve . A r and omized phase II study was performed addressing the response rate and morbidity of high-dose split course radiotherapy ( RT ) versus the same radiotherapy preceded by high-dose chemotherapy ( CT ) in patients with stage III non-small-cell lung cancer . PATIENTS AND METHODS Seventy eligible patients were r and omized in this study . CT consisted of cisplatin 100 mg/m2 days 1 and 22 , and vindesine 3 mg/m2 on days 1 , 8 , 22 and 29 . Radiotherapy started on day 43 in the combined arm and immediately in the RT-only arm . The primary tumour and the regional nodes were treated by 30 Gy/10 fractions/2 weeks and after the split by a second course of 25 Gy/10 fractions/2 weeks . In the combined arm a third CT cycle was planned during the split between RT courses . RESULTS In the CT + RT arm 34 patients were evaluable for response and toxicity and 30 patients in the RT only arm . After completion of treatment 7 patients had a complete response ( 2 in the CT plus RT arm , 5 in the RT alone arm ) and 26 patients a partial response ( 13 in the CT plus RT arm , 13 in the RT alone arm ) for an overall response rate of 52 % ( 95 % CI 39%-65 % ) . Acute toxicity was worse in the combined treatment arm with grade 4 leucocytopenia in 8 patients and thrombocytopenia grade 4 in one patient . Three patients had reversible renal toxicity grade 2 . There was one toxic death in the RT plus CT arm . There was no enhancement of acute or late radiation pulmonary or oesophageal toxicity . Time to progressive disease ( median 30 vs. 35 weeks ) and overall survival time ( median 12 months ) were equal in both treatment arms . CONCLUSION High-dose radiotherapy preceded by high-dose chemotherapy was more toxic than radiotherapy alone and did not result in this study in any benefit in terms of response rate , time to progressive disease and overall survival [8187005] The purpose of this study was to determine the feasibility of additional chemotherapy beyond 5 weeks of vinblastine-cisplatin followed by radiation therapy for patients with stage III non-small cell lung cancer . In this r and omized phase II trial , the goal was to determine , in a similar population of patients , the toxicity of either of two additional chemotherapy programs . Ninety-one patients with stage III non-small cell lung cancer received the same induction regime of vinblastine/cisplatin/radiotherapy . In patients r and omized to regime 1 , an additional four cycles of vinblastine/cisplatin were given after the radiotherapy . In regimen 2 , six weekly doses of carboplatin were given concurrent with the radiotherapy . The additional four cycles of vinblastine and cisplatin were completed by 34 % of patients ; the concurrent carboplatin program was completed by 70 % of patients . Grade 3 or 4 granulocytopenia occurred in 53 % of patients on regime 1 versus 17 % on regime 2 ( p < 0.003 ) ; grade 3 or 4 nausea/vomiting occurred in 20 % of those on regime 1 versus 7 % on regimen 2 ( p = 0.175 ) . Response rates and survival were similar for the two regimens , with approximately 30 % of patients surviving at 2 years . Given the reduced toxicity and the improved capacity to complete the planned therapy with the concurrent carboplatin treatment , this regimen will be further examined in a phase III trial [10561343] PURPOSE A phase III study was performed to determine whether concurrent or sequential treatment with radiotherapy ( RT ) and chemotherapy ( CT ) improves survival in unresectable stage III non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Patients were assigned to the two treatment arms . In the concurrent arm , chemotherapy consisted of cisplatin ( 80 mg/m(2 ) on days 1 and 29 ) , vindesine ( 3 mg/m(2 ) on days 1 , 8 , 29 , and 36 ) , and mitomycin ( 8 mg/m(2 ) on days 1 and 29 ) . RT began on day 2 at a dose of 28 Gy ( 2 Gy per fraction and 5 fractions per week for a total of 14 fractions ) followed by a rest period of 10 days , and then repeated . In the sequential arm , the same CT was given , but RT was initiated after completing CT and consisted of 56 Gy ( 2 Gy per fraction and 5 fractions per week for a total of 28 fractions ) . RESULTS Three hundred twenty patients were entered onto the study . Pretreatment characteristics were well balanced between the treatment arms . The response rate for the concurrent arm was significantly higher ( 84 . 0 % ) than that of the sequential arm ( 66 % ) ( P = .0002 ) . The median survival duration was significantly superior in patients receiving concurrent therapy ( 16.5 months ) , as compared with those receiving sequential therapy ( 13.3 months ) ( P = .03998 ) . Two- , 3- , 4- , and 5-year survival rates in the concurrent group ( 34.6 % , 22.3 % , 16.9 % , and 15.8 % , respectively ) were better than those in the sequential group ( 27.4 % , 14.7 % , 10.1 % , and 8.9 % , respectively ) . Myelosuppression was significantly greater among patients on the concurrent arm than on the sequential arm ( P = .0001 ) . CONCLUSION In selected patients with unresectable stage III NSCLC , the concurrent approach yields a significantly increased response rate and enhanced median survival duration when compared with the sequential approach [28016284] 7005 Background : St and ard therapy for unresectable stage III NSCLC includes concomitant chemoradiotherapy . In CALGB 39801 , we evaluated whether the addition of induction chemotherapy prior to CT/XRT would result in improved survival . METHODS Between 10/1998 and 5/2002 , 366 stage III patients ( pts ) were r and omized to either immediate CT/XRT [ carboplatin AUC of 2 and paclitaxel 50 mg/m2 each given weekly during 66 Gy chest XRT to ; arm 1 ( 182 pts ) ] or two cycles of carboplatin AUC 6 and paclitaxel 200 mg/m2 given q 21 days x 2 cycles followed by identical CT/XRT ; arm 2 ( 184 pts ) . The accrual goal was 360 patients . 290 deaths were required to have 80 % power to detect a 40 % increase in median survival assuming a one-tailed log-rank test conducted at the 0.025 level of significance . RESULTS 34 % of pts were female , 66 % male and 63 % were age 60 or older . Grade 3 or 4 toxicities during induction chemotherapy consisted mainly of neutropenia ( 17%/21 % ) . During CT/XRT , grade 3/4 neutropenia was noted in 11%/4 % ( arm 1 ) versus 21%/6 % ( arm 2 ) , grade 3 anemia was 5 % vs 11 % , grade 3/4 fatigue 16%/1 % vs 16%/4 % , esophagitis 30%/1 % vs 28%/7 % , and dyspnea 9%/3 % vs 15%/4 % . Overall , 4 toxicities were experienced by 24 % of patients on arm 1 versus 41 % on arm 2 ( p=0.001 ) . With 254 of 290 targeted deaths , median survival on arm 1 is 11.4 months versus 14 months on arm 2 ( p=0.154 ) . One year survival estimates are 48 % ( 41%-57 % ) and 54 % ( 47%-62 % ) respectively . CONCLUSION The median survival achieved in each of the treatment groups is low compared to other recent experiences in the literature . The reason(s ) for this are uncertain . The addition of induction chemotherapy to immediate concurrent CT/XRT is associated with a 2.6 month increase in median survival . However these findings are not sufficient to reject the null hypothesis of no treatment difference between the two study arms . Further follow up of this data set is required . Our results do not support the use of induction chemotherapy followed by CT/XRT as evidence based st and ard of care for patients with unresectable stage III NSCLC . [ Table : see text ] [8780630] BACKGROUND For many years , high dose radiation therapy was the st and ard treatment for patients with locally or regionally advanced non-small-cell lung cancer ( NSCLC ) , despite a 5-year survival rate of only 3%-10 % following such therapy . From May 1984 through May 1987 , the Cancer and Leukemia Group B ( CALGB ) conducted a r and omized trial that showed that induction chemotherapy before radiation therapy improved survival during the first 3 years of follow-up . PURPOSE This report provides data for 7 years of follow-up of patients enrolled in the CALGB trial . METHODS The patient population consisted of individuals who had clinical or surgical stage III , histologically documented NSCLC ; a CALGB performance status of 0 - 1 ; less than 5 % loss of body weight in the 3 months preceding diagnosis ; and radiographically visible disease . Patients were r and omly assigned to receive either 1 ) cisplatin ( 100 mg/m2 body surface area intravenously on days 1 and 29 ) and vinblastine ( 5 mg/m2 body surface area intravenously weekly on days 1 , 8 , 15 , 22 , and 29 ) followed by radiation therapy with 6000 cGy given in 30 fractions beginning on day 50 ( CT-RT group ) or 2 ) radiation therapy with 6000 cGy alone beginning on day 1 ( RT group ) for a maximum duration of 6 - 7 weeks . Patients were evaluated for tumor regression if they had measurable or evaluable disease and were monitored for toxic effects , disease progression , and date of death . RESULTS There were 78 eligible patients r and omly assigned to the CT-RT group and 77 r and omly assigned to the RT group . Both groups were similar in terms of sex , age , histologic cell type , performance status , substage of disease , and whether staging had been clinical or surgical . All patients had measurable or evaluable disease at the time of r and om assignment to treatment groups . Both groups received a similar quantity and quality of radiation therapy . As previously reported , the rate of tumor response , as determined radiographically , was 56 % for the CT-RT group and 43 % for the RT group ( P = .092 ) . After more than 7 years of follow-up , the median survival remains greater for the CT-RT group ( 13.7 months ) than for the RT group ( 9.6 months ) ( P = .012 ) as ascertained by the logrank test ( two-sided ) . The percentages of patients surviving after years 1 through 7 were 54 , 26 , 24 , 19 , 17 , 13 , and 13 for the CT-RT group and 40 , 13 , 10 , 7 , 6 , 6 , and 6 for the RT group . CONCLUSIONS Long-term follow-up confirms that patients with stage III NSCLC who receive 5 weeks of chemotherapy with cisplatin and vinblastine before radiation therapy have a 4.1-month increase in median survival . The use of sequential chemotherapy-radiotherapy increases the projected proportion of 5-year survivors by a factor of 2.8 compared with that of radiotherapy alone . However , inasmuch as 80%-85 % of such patients still die within 5 years and because treatment failure occurs both in the irradiated field and at distant sites in patients receiving either sequential chemotherapy-radiotherapy or radiotherapy alone , the need for further improvements in both the local and systemic treatment of this disease persists [12772814] This prospect i ve r and omized trial compared neoadjuvant chemotherapy followed by local-regional radiotherapy ( study group ) with radiotherapy alone ( control group ) in 506 patients with locally advanced non-small-cell lung cancer . The study group received three cycles of cisplatin , ifosfamide with Mesna , and mitomycin C at 21-day intervals . Radiotherapy was delivered up to a dose of 60 Gy . Evaluable patients numbered 460 . In the study group , 228 patients were assessed for tumor response after chemotherapy : 13 ( 5.7 % ) had a complete response ; 103 ( 43.2 % ) , a partial response ; 48 ( 21 % ) showed no change ; and 74 patients ( 31.1 % ) had progressive disease . These patients then received chest irradiation , which was well tolerated . On completion of radiotherapy , 16.2 % of the study group and 6 % of the control group had a complete response . No change was seen in 10.1 % of study patients and 15.5 % of control patients . Respective rates for disease progression were 27.6 % and 42.3 % . Actuarial 2-year survival was 20 % in the study group and 7.4 % in the control group [12743155] PURPOSE To test the concept of taxane sequencing in combined-modality therapy , this phase II trial ( S9504 ) evaluated consolidation docetaxel after concurrent chemoradiotherapy in patients with pathologically documented stage IIIB non-small-cell lung cancer ( NSCLC ) . Results were compared with those of the predecessor study ( S9019 ) with identical eligibility , staging criteria , and treatment , excepting docetaxel consolidation . PATIENTS AND METHODS Treatment consisted of cisplatin 50 mg/m2 on days 1 , 8 , 29 , and 36 , etoposide 50 mg/m2 on days 1 through 5 and 29 through 33 , and concurrent thoracic radiotherapy ( total dose of 61 Gy ) . Consolidation docetaxel started 4 to 6 weeks after chemoradiotherapy at an initial dose of 75 mg/m2 . RESULTS Stage subsets ( tumor-node-metastasis system ) in 83 eligible patients were as follows : T4N0/1 , 31 patients ( 37 % ) ; T4N2 , 22 patients ( 27 % ) , and T1 - 3N3 , 30 patients ( 36 % ) . Concurrent chemoradiotherapy was generally well tolerated , but two patients died from probable radiation-associated pneumonitis . Neutropenia during consolidation docetaxel was common ( 57 % with grade 4 ) and most frequent during escalation to 100 mg/m2 . Median progression-free survival was 16 months , median survival was 26 months , and 1- , 2- , and 3-year survival rates were 76 % , 54 % , and 37 % , respectively . Brain metastasis was the most common site of failure . In S9019 , median survival was 15 months and 1- , 2- , and 3-year survival rates were 58 % , 34 % , and 17 % , respectively . CONCLUSION Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB NSCLC is feasible and generally tolerable , and results compare favorably with the predecessor trial S9019 . Nevertheless , this study remains hypothesis-generating and does not provide definitive evidence of the benefit of this approach . Phase III trials evaluating the S9504 regimen have been initiated to vali date these results [11241082] OBJECTIVE The rate of complete resection ( 50 % ) and the 5-year survival ( 30 % ) for non-small cell lung carcinomas of the superior sulcus have not changed for 40 years . Recently , combined modality therapy has improved outcome in other subsets of locally advanced non-small cell lung carcinoma . This trial tested the feasibility of induction chemoradiation and surgical resection in non-small cell lung carcinoma of the superior sulcus with the ultimate aim of improving resectability and survival . METHODS Patients with mediastinoscopy-negative T3 - 4 N0 - 1 superior sulcus non-small cell lung carcinoma received 2 cycles of cisplatin and etoposide chemotherapy concurrent with 45 Gy of radiation . Patients with stable or responding disease underwent thoracotomy 3 to 5 weeks later . All patients received 2 more cycles of chemotherapy and were followed up by serial radiographs and scans . Survival was calculated by the Kaplan-Meier method and prognostic factors were assessed for significance by Cox regression analysis . RESULTS From April 1995 to September 1999 , 111 eligible patients ( 77 men , 34 women ) were entered in the study , including 80 ( 72.1 % ) with T3 and 31 with T4 tumors . Induction therapy was completed as planned in 102 ( 92 % ) patients . There were 3 treatment-related deaths ( 2.7 % ) . Cytopenia was the main grade 3 to 4 toxicity . Of 95 patients eligible for surgery , 83 underwent thoracotomy , 2 ( 2.4 % ) died postoperatively , and 76 ( 92 % ) had a complete resection . Fifty-four ( 65 % ) thoracotomy specimens showed either a pathologic complete response or minimal microscopic disease . The 2-year survival was 55 % for all eligible patients and 70 % for patients who had a complete resection . To date , survival is not significantly influenced by patient sex , T status , or pathologic response . CONCLUSIONS ( 1 ) This combined modality treatment is feasible in a multi-institutional setting ; ( 2 ) the pathologic complete response rates were high ; and ( 3 ) resectability and overall survival were improved compared with historical experience , especially for T4 tumors , which usually have a grim prognosis [8943671] The aim of this r and omised trial was to investigate the effect of induction chemotherapy before radiotherapy on survival in 302 patients with non-resectable squamous cell carcinoma of the lung . Radiotherapy , 56 Gy to the chest , was given to 154 patients and combined treatment , with chemotherapy preceding the radiotherapy , to 148 patients . Chemotherapy consisted of three courses of cisplatin ( 120 mg/m2 ) and etoposide ( 100 mg/m2 i.v . for 3 days ) administered every fourth week . Median survival was 10.5 months in the radiotherapy arm and 11 months in the combined treatment arm . The 2-year survival rate was 17 % in the radiotherapy arm and 21 % in the combined treatment arm . Addition of chemotherapy seemed to significantly improve survival , according to the Cox multivariate analysis ( P = 0.04 ) , but as only a trend according to life-table analysis ( P = 0.11 ) . Chemotherapy also accomplished a trend towards improved local control ( P = 0.08 ) and towards decreased metastatic disease ( P = 0.10 ) . 2 patients in the combined treatment arm , but none in the radiotherapy arm , died from toxicity . The conclusion was that the value of the chemotherapy used in this study was very modest , but the results strongly support further research for more efficient drugs and combinations [9549815] Assessment of health related quality of life has become an important endpoint in many cancer clinical trials . Because the participants of these trials often experience disease and treatment related morbidity and mortality , non-r and om missing assessment s are inevitable . Examples are presented from several such trials that illustrate the impact of missing data on the analysis of QOL in these trials . The sensitivity of different analyses depends on the proportion of assessment s that are missing and the strength of the association of the underlying reasons for missing data with disease and treatment related morbidity and mortality . In the setting of clinical trials of cancer therapy , the assumption that the data are missing completely at r and om ( MCAR ) and analyses of complete cases is usually unjustified . Further , the assumption of missing at r and om ( MAR ) may also be violated in many trials and models appropriate for non-ignorable missing data should be explored . Recommendations are presented to minimize missing data , to obtain useful documentation concerning the reasons for missing data and to perform sensitivity analyses [8814371] In patients with non-metastatic but inoperable non-small cell lung cancer that is locally too extensive for radical radiotherapy ( RT ) , but who have good performance status , it is important to determine whether thoracic RT should be the minimum that is required to palliate thoracic symptoms or whether treatment should be more intensive , with the aim of prolonging survival . A total of 509 such patients from 11 centres in the UK between November 1989 and October 1992 were admitted to a trial comparing palliative versus more intensive RT with respect to survival and quality of life . They were allocated at r and om to receive thoracic RT with either 17 Gy in two fractions ( F2 ) 1 week apart ( 255 patients ) or 39 Gy in 13 fractions ( F13 ) 5 days per week ( 254 patients ) . Survival was better in the F13 group , the median survival periods being 7 months in the F2 group compared with 9 months in the F13 group , and the survival rates 31 % and 36 % at one year and 9 % and 12 % at 2 years , respectively ( hazard ratio = 0.82 ; 95 % CI0.69 - 0.99 ) . There was a suggestion of a trend towards greater benefit in fitter patients . Metastases appeared earlier in the F2 group . As recorded by patients using the Rotterdam Symptom Checklist , the commonest symptoms on admission were cough , shortness of breath , tiredness , lack of energy , worrying and chest pain . These were more rapidly palliated by the F2 regimen . Psychological distress was generally lower in the F13 group . Three patients ( two F13 , one F2 ) exhibited evidence of myelopathy . As recorded by patients using a diary card , 76 % of the F2 compared with 81 % of the F13 patients had dysphagia associated with their RT . This was transient , lasting for a median of 6.5 days in the F2 group compared with 14 days in the F13 group . In conclusion , the F2 regimen had a more rapid palliative effect . In the F13 group , although treatment-related dysphagia was worse , survival was longer Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: Aim Several drugs have been used for treating non-alcoholic fatty liver disease ( NAFLD ) . The present study is a network meta- analysis of such drugs . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

24627325

[16291467] BACKGROUND AND OBJECTIVE To develop a checklist of items measuring the quality of reports of r and omized clinical trials ( RCTs ) assessing nonpharmacological treatments ( NPTs ) . STUDY DESIGN AND SETTING The Delphi consensus method was used to select and reduce the number of items in the checklist . A total of 154 individuals were invited to participate : epidemiologists and statisticians involved in the field of methodology of RCTs ( n = 55 ) , members of the Cochrane Collaboration ( n = 41 ) , and clinicians involved in planning NPT clinical trials ( n = 58 ) . Participants ranked on a 10-point Likert scale whether an item should be included in the checklist . RESULTS Fifty-five experts ( 36 % ) participated in the survey . They were experienced in systematic review s ( 68 % were involved in the Cochrane Collaboration ) and in planning RCTs ( 76 % ) . Three rounds of the Delphi method were conducted to achieve consensus . The final checklist contains 10 items and 5 subitems , with items related to the st and ardization of the intervention , care provider influence , and additional measures to minimize the potential bias from lack of blinding of participants , care providers , and outcome assessors . CONCLUSIONS This tool can be used to critically appraise the medical literature , design NPT studies , and assess the quality of trial reports included in systematic review [7895394] OBJECTIVE We performed a r and omised trial to evaluate if intensive supervised training of the back should be offered to all patients after a first lumbar diskectomy . METHODS Forty consecutive patients were , after a first lumbar diskectomy , r and omly allocated to 2 groups undergoing " supervised training " twice a week for 3 months in an outpatient clinic or " home training " after 2 hours of instruction . RESULTS The two rehabilitation models both showed a significant effect on spinal mobility , isokinetic trunk flexion strength , isokinetic trunk extension strength and daily function . These improvements were unchanged at follow up 3 months later . The pain score remained unchanged , however , throughout the trial in both groups . No differences in effect between the two rehabilitation models could be found for any of the assessed parameters . Thirteen patients did not complete the trial , including 9 from the supervised endurance trained group , mainly because of increased pain and reprolaps ( n = 4 ) . Four patients dropped out of the home trained group , only one because of increased pain . The differences in drop-out rate and training side effects were , however , not statistically significant . CONCLUSION We conclude that it is not worthwhile to implement 3 months of supervised intensive endurance training as opposed to home training in all cases of first lumbar diskectomy , although a beneficial effect and better compliance might be found for a selected group of such patients [20680372] As the average life expectancy of the population increases , surgical decompression of the lumbar spine is being performed with increasing frequency . It now constitutes the most common type of lumbar spinal surgery in older patients . The present prospect i ve study examined the 5-year outcome of lumbar decompression surgery without fusion . The group comprised 159 patients undergoing decompression for degenerative spinal disorders who had been participants in a r and omised controlled trial of post-operative rehabilitation that had shown no between-group differences at 2 years . Leg pain and back pain intensity ( 0–10 graphic rating scale ) , self-rated disability ( Rol and Morris ) , global outcome of surgery ( 5-point Likert scale ) and re-operation rates were assessed 5 years post-operatively . Ten patients had died before the 5-year follow-up . Of the remaining 149 patients , 143 returned a 5-year follow-up ( FU ) question naire ( effective return rate excluding deaths , 96 % ) . Their mean age was 64 ( SD 11 ) years and 92/143 ( 64 % ) were men . In the 5-year follow-up period , 34/143 patients ( 24 % ) underwent re-operation ( 17 further decompressions , 17 fusions and 1 intradural drainage/debridement ) . In patients who were not re-operated , leg pain decreased significantly ( p < 0.05 ) from before surgery to 2 months FU , after which there was no significant change up to 5 years . Low back pain also decreased significantly by 2 months FU , but then showed a slight , but significant ( p < 0.05 ) , gradual increase of < 1 point by 5-year FU . Disability decreased significantly from pre-operative to 2 months FU and showed a further significant decrease at 5 months FU . Thereafter , it remained stable up to the 5-year FU . Pain and disability scores recorded after 5 years showed a significant correlation with those at earlier follow-ups ( r = 0.53–0.82 ; p < 0.05 ) . Patients who were re-operated at some stage over the 5-year period showed significantly worse final outcomes for leg pain and disability ( p < 0.05 ) . In conclusion , pain and disability showed minimal change in the 5-year period after surgery , but the re-operation rate was relatively high . Re-operation result ed in worse final outcomes in terms of leg pain and disability . At the 5-year follow-up , the “ average ” patient experienced frequent , but relatively low levels of , pain and moderate disability . This knowledge on the long-term outcome should be incorporated into the pre-operative patient information process [17119140] CONTEXT Lumbar diskectomy is the most common surgical procedure performed for back and leg symptoms in US patients , but the efficacy of the procedure relative to nonoperative care remains controversial . OBJECTIVE To assess the efficacy of surgery for lumbar intervertebral disk herniation . DESIGN , SETTING , AND PATIENTS The Spine Patient Outcomes Research Trial , a r and omized clinical trial enrolling patients between March 2000 and November 2004 from 13 multidisciplinary spine clinics in 11 US states . Patients were 501 surgical c and i date s ( mean age , 42 years ; 42 % women ) with imaging-confirmed lumbar intervertebral disk herniation and persistent signs and symptoms of radiculopathy for at least 6 weeks . INTERVENTIONS St and ard open diskectomy vs nonoperative treatment individualized to the patient . MAIN OUTCOME MEASURES Primary outcomes were changes from baseline for the Medical Outcomes Study 36-item Short-Form Health Survey bodily pain and physical function scales and the modified Oswestry Disability Index ( American Academy of Orthopaedic Surgeons MODEMS version ) at 6 weeks , 3 months , 6 months , and 1 and 2 years from enrollment . Secondary outcomes included sciatica severity as measured by the Sciatica Bothersomeness Index , satisfaction with symptoms , self-reported improvement , and employment status . RESULTS Adherence to assigned treatment was limited : 50 % of patients assigned to surgery received surgery within 3 months of enrollment , while 30 % of those assigned to nonoperative treatment received surgery in the same period . Intent-to-treat analyses demonstrated substantial improvements for all primary and secondary outcomes in both treatment groups . Between-group differences in improvements were consistently in favor of surgery for all periods but were small and not statistically significant for the primary outcomes . CONCLUSIONS Patients in both the surgery and the nonoperative treatment groups improved substantially over a 2-year period . Because of the large numbers of patients who crossed over in both directions , conclusions about the superiority or equivalence of the treatments are not warranted based on the intent-to-treat analysis . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00000410 [7997919] Study Design This was a study of a st and ardized functional restoration program that included 11 centers in saven states , involving 303 patients in the treatment group and 94 patients in the comparison group . Objective To illustrative the positive effect a functional restoration program has on return to work rates and work retention regardless of previous surgical intervention . Summary of Background Data Data were obtained from the initial and discharge evaluations as well as at 6− and 12-month follow-up . Methods Patients received a st and ardized work capacity assessment upon entrance and were recommended to the program if they adhered to specific entrance criteria . Treatment patients received the same evaluation at discharge . Results Significant improvement in functional abilities , actual return to work , and work retention were noted in the treatment group regardless of treatment intervention . Conclusions This study demonstrated improved return to work rates and work retention with surgical and nonsurgical patients after their participation in a functional restoration program [17538084] BACKGROUND Lumbar-disk surgery often is performed in patients who have sciatica that does not resolve within 6 weeks , but the optimal timing of surgery is not known . METHODS We r and omly assigned 283 patients who had had severe sciatica for 6 to 12 weeks to early surgery or to prolonged conservative treatment with surgery if needed . The primary outcomes were the score on the Rol and Disability Question naire , the score on the visual-analogue scale for leg pain , and the patient 's report of perceived recovery during the first year after r and omization . Repeated- measures analysis according to the intention-to-treat principle was used to estimate the outcome curves for both groups . RESULTS Of 141 patients assigned to undergo early surgery , 125 ( 89 % ) underwent microdiskectomy after a mean of 2.2 weeks . Of 142 patients design ated for conservative treatment , 55 ( 39 % ) were treated surgically after a mean of 18.7 weeks . There was no significant overall difference in disability scores during the first year ( P=0.13 ) . Relief of leg pain was faster for patients assigned to early surgery ( P<0.001 ) . Patients assigned to early surgery also reported a faster rate of perceived recovery ( hazard ratio , 1.97 ; 95 % confidence interval , 1.72 to 2.22 ; P<0.001 ) . In both groups , however , the probability of perceived recovery after 1 year of follow-up was 95 % . CONCLUSIONS The 1-year outcomes were similar for patients assigned to early surgery and those assigned to conservative treatment with eventual surgery if needed , but the rates of pain relief and of perceived recovery were faster for those assigned to early surgery . ( Current Controlled Trials number , IS RCT N26872154 [ controlled-trials.com ] . ) [18758356] Study Design . We r and omized 200 patients after lumbar discectomy to receive epidural steroid or none with a 2-year follow-up . Objective . To evaluate the outcome , neurologic impairment and safety of epidural steroid following lumbar discectomy for herniated disc disease . Summary of Background Data . Convalescence after discectomy for herniated disc disease is dependent on pain and the inflammatory response . Previous studies in arthroscopic and abdominal surgery demonstrate steroids , which reduce the inflammatory response and enhance recovery . Here we report a 2-year follow-up of a r and omized trial of epidural steroid following lumbar discectomy . Methods . Through 2001 and 2003 200 patients undergoing discectomy for herniated disc disease were r and omly allocated to receive epidural methylprednisolone 40 mg or none . In the control group ( 62 males and 38 females , median age 41 years , 18–66 ) 48 L5 , 50 L4 , and 6 L3 discectomies were performed and in the intervention group ( 60 males and 40 females , median age 45 years , 15–53 ) 56 L5 , 46 L4 , and 3 L3 discectomies . Contemporary with r and omization to epidural steroid or none both groups received preoperative prophylactic antibiotics and the same multimodal pain treatment . Results . Hospital stay was reduced from 8 to 6 days ( P = 0.0001 ) and the number of patients with neurologic signs were reduced more ( 70 % vs. 44 % , P = 0.0004 ) by epidural steroid . Incidence of reoperation at 1 year was 6 % in both groups and 8 % in the control group and 7 % in the intervention group after 2 years . No infections were registered . Conclusion . Epidural methylprednisolone enhances recovery after discectomy for herniated disc disease without apparent side effects [17762803] Study Design . Three-group , r and omized , single blinded , controlled trial . Objective . To test the effectiveness of physiotherapy-based rehabilitation starting 1 week after lumbar disc surgery . In addition , we tried to estimate the contribution of specific effects to the observed outcome ( efficacy ) . Summary of Background Data . Physiotherapy-based rehabilitation is usually recommended for patients following lumbar disc surgery . Few and conflicting data exist for the relative effectiveness of this intervention . Methods . A total of 120 patients following first-time , uncomplicated lumbar disc surgery were r and omly assigned to “ comprehensive ” physiotherapy , “ sham ” neck massage , or no therapy . Before enrollment , all subjects completed a minimal physiotherapeutic intervention . Physiotherapy was administered by experienced physiotherapists and consisted of 20 sessions per patient over 12 weeks . Masseurs administered “ sham massage ” to the neck . The amount of treatment time was equal to that of physiotherapy . The main outcome measure was the Low Back Pain Rating Score ( LBPRS ) at 6 and 12 weeks , and 1.5 years after r and omization . Secondary parameters were patients ' overall satisfaction with treatment outcome and socioeconomic and psychologic measures . Results . At the end of therapy ( 12 weeks ) , the LBPRS revealed a significantly better improvement in the physiotherapy group than in the untreated group . LBPRS outcome , however , did not significantly differ between physiotherapy and “ sham ” therapy . There was a tendency toward significance between the sham therapy and no therapy . Within the 1.5-year follow-up , LBP rating scales remained significantly improved compared with baseline , but there were no significant outcome differences . No statistically significant between-group differences were found for the secondary outcome parameters . Conclusion . As compared with no therapy , physiotherapy following first-time disc herniation operation is effective in the short-term . Because of the limited benefits of physiotherapy relative to “ sham ” therapy , it is open to question whether this treatment acts primarily physiologically in patients following first-time lumbar disc surgery , but psychological factors may contribute substantially to the benefits observed [16239890] OBJECTIVE : To determine the effects of a postoperative early isolated lumbar extension muscle-strengthening program on pain , disability , return to work , and power of back muscle after operation for herniated lumbar disc . METHODS : Seventy-five patients were r and omized into an exercise group ( 20 men , 15 women ) and a control group ( 18 men , 22 women ) to perform a prospect i ve controlled trial of a lumbar extension exercise program in patients who underwent lumbar microdiscectomy or percutaneous endoscopic discectomy . Six weeks after surgery , patients in the exercise group undertook a 12-week lumbar extension exercise program . The assessment included measures of lumbar extensor power by the MedX ( Ocala , FL ) lumbar extension machine , muscle mass of multifidus and longissimus ( L4–L5 cross-sectional area ) by computed tomography . All patients completed the visual analog scale and the Oswestry disability index to assess pain and disability , respectively . Return to work data were also investigated . RESULTS : After the exercise program , significant improvements were observed in the exercise group versus the control group for lumbar extensor power ( 51.67 % versus 17.55 % , respectively ; P < 0.05 ) , the cross-sectional area of multifidus and longissimus muscle ( 29.23 % versus 7.2 % , respectively ; P < 0.05 ) , and the visual analog scale score ( 2.51 versus 4.30 , respectively ; P < 0.05 ) . The percentages of returning to work within 4 months after surgery were significantly greater in the exercise group than in the control group ( 87 % versus 24 % , respectively ) . Although this was not statistically significant ( P > 0.05 ) , the Oswestry disability index scores in the exercise group were better than that in control group ( 24.6 versus 30.6 , respectively ) . CONCLUSION : These results support the positive effects of the postoperative early lumbar extension muscle-strengthening program on pain , return to work , and strength of back muscles in patients after operation of herniated lumbar disc [16421747] A prospect i ve and controlled study of training after surgery for lumbar disc herniation ( LDH ) . The objective was to determine the effect of early neuromuscular customized training after LDH surgery . No consensus exists on the type and timing of physical rehabilitation after LDH surgery . Patients aged 15–50 years , disc prolapse at L4–L5 or L5–S1 . Before surgery , at 6 weeks , 4 , and 12 months postoperatively , the following evaluations were performed : low back pain and leg pain estimated on a visual analog scale , disability according to the Rol and –Morris question naire ( RMQ ) and disability rating index ( DRI ) . Clinical examination , including the SLR test , was performed using a single blind method . Consumption of analgesics was registered . Twenty-five patients started neuromuscular customized training 2 weeks after surgery ( early training group = ETG ) . Thirty-one patients formed a control group ( CG ) and started traditional training after 6 weeks . There was no significant difference in pain and disability between the two training groups before surgery . Median preoperative leg pain was 63 mm in ETG and 70 mm in the CG . Preoperative median disability according to RMQ was 14 in the ETG and 14.5 in the CG . Disability according to DRI ( 33/56 patients ) was 5.3 in the ETG vs. 4.6 in the CG . At 6 weeks , 4 months , and 12 months , pain was significantly reduced in both groups , to the same extent . Disability scores were lower in the ETG at all follow-ups , and after 12 months , the difference was significant ( RMQ P=.034 , DRI P=.015 ) . The results of the present study show early neuromuscular customized training to have a superior effect on disability , with a significant difference compared to traditional training at a follow-up 12 months after surgery . No adverse effects of the early training were seen . A prospect i ve , r and omized study with a larger patient sample is warranted to ultimately demonstrate that early training as described is beneficial for patients undergoing LDH surgery [11728081] In a r and omized study , using psychometric assessment , we evaluated two training programs before and after surgical treatment of lumbar disc herniation . 26 patients were treated according to an early active training program ( treatment group ) . 24 patients followed a traditional less active training program ( control group ) . Before surgery , the patients filled in the following question naires 3 and 12 months after surgery : Multidimensional Pain Inventory ( MPI ) , State and Trait Anxiety Inventory , and Beck Depression Inventory . Pain was assessed by the patient 's pain drawing and a visual analog scale . Both groups improved as regards pain severity and state of anxiety . The MPI parameter , pain interference , improved more in the early active treatment group than in the control group . This suggests that the early active training program has a positive effect on the way patients cope with pain in their daily lives [15704503] Objective : To compare two different exercise programmes versus a control group , after lumbar disc surgery . Design : A prospect i ve , single-blind , r and omized controlled study . Setting : Outpatient clinic of Istanbul Faculty of Medicine , Department of Physical Medicine and Rehabilitation . Subjects : Sixty patients diagnosed as having single level lumbar disc herniation with clinical examination and MRI evaluation and who had undergone lumbar discectomy ( post-operative first month ) at a single level . Patients with serious pathologies involving the cardiac and respiratory systems that could prevent them from doing exercises were excluded . Intervention : The patients were r and omly split into three groups . The first group received an intensive exercise programme and back school education while the second group received a home exercise programme and back school education . The third group was defined as the control group and did not receive education or exercise . Main measures : The patients were evaluated at the beginning and end of the treatment with clinical parameters , pain levels , endurance tests and weight-lifting tests , modified Oswestry Disability Index , Beck Depression Inventory , Low Back Pain Rating Scale and return to work . Results : The groups doing exercises experienced a decrease in the severity of pain and disability , also functional parameters showed better improvement than the control group . The intensive exercise programme was better than the home exercise programme . Conclusions : It seems that intensive exercise is more effective in reduction of pain and disability , but whether it is cost-effective is not clear [10214482] Summary Objective . Lumbar discectomy is a common elective surgical procedure but many patients still experience postoperative back pain which may delay hospital discharge . We therefore evaluated the efficacy of a parenteral non-steroidal antiinflammatory agent , ketorolac , for the management of post-surgical pain . Methods . Fifty three patients undergoing lumbar discectomy at a Medical School affiliated Veterans Administration hospital were r and omly assigned to receive either : 1 ) 30 mg intramuscular ketorolac upon surgical closure and every 6 hours for 36 hours and narcotic analgesics as needed ( PRN ) ; or 2 ) only narcotic analgesics as needed . A blinded observer recorded the average , minimum and maximum postoperative pain intensity using a Numeric Pain Intensity Scale ; total postoperative narcotic consumption , complications , length of hospitalization ( from surgery to discharge ) and outcome at 6 weeks . Results . The patients who received ketorolac reported significantly lower average ( p<0.001 ) , minimum ( p<0.001 ) , and maximum ( p<0.001 ) pain scores than patients receiving only narcotic analgesics . Cumulative narcotic doses ( st and ardized to parenteral morphine ) were significantly lower in the ketorolac group ( p < 0.001 ) . There was no significant difference between groups in the frequency of side effects , and no complication specifically associated with ketorolac use was observed . Mean length of hospitalization was significantly shorter ( p=0.05 ) in patients receiving ketorolac than in patients receiving only narcotics . Six weeks after surgery 5 ( 19.2 % ) patients who received only narcotics were troubled by persistent back pain . By contrast , all patients who received ketorolac were free of back pain at follow-up ( p=0.03 ) . Conclusions . These results suggest that ketorolac , when used with PRN narcotics , is more effective than PRN narcotics alone for postoperative pain following lumbar disc surgery . In addition , this strategy also may contribute to early discharge from hospital after lumbar disc surgery [18427312] Study Design . Prospect i ve , r and omized , controlled study of patients with lumbar disc herniations , operated either in a full-endoscopic or microsurgical technique . Objective . Comparison of results of lumbar discectomies in full-endoscopic interlaminar and transforaminal technique with the conventional microsurgical technique . Summary of Background Data . Even with good results , conventional disc operations may result in subsequent damage due to trauma . Endoscopic techniques have become the st and ard in many areas because of the advantages they offer intraoperatively and after surgery . With the transforaminal and interlaminar techniques , 2 full-endoscopic procedures are available for lumbar disc operations . Methods . One hundred seventy-eight patients with full-endoscopic or microsurgical discectomy underwent follow-up for 2 years . In addition to general and specific parameters , the following measuring instruments were used : VAS , German version North American Spine Society Instrument , Oswestry Low-Back Pain Disability Question naire . Results . After surgery 82 % of the patients no longer had leg pain , and 14 % had occasional pain . The clinical results were the same in both groups . The recurrence rate was 6.2 % with no difference between the groups . The full-endoscopic techniques brought significant advantages in the following areas : back pain , rehabilitation , complications , and traumatization . Conclusion . The clinical results of the full-endoscopic technique are equal to those of the microsurgical technique . At the same time , there are advantages in the operation technique and reduced traumatization . With the surgical devices and the possibility of selecting an interlaminar or posterolateral to lateral transforaminal procedure , lumbar disc herniations outside and insidethe spinal canal can be sufficiently removed using the full-endoscopic technique , when taking the appropriate criteria into account . Full-endoscopic surgery is a sufficient and safe supplementation and alternative to microsurgical procedures [19892091] OBJECTIVE To investigate whether immediate commencement of exercises after lumbar microdiscectomy enabled patients to become independently mobile more rapidly with no increase in risk of complications . STUDY DESIGN R and omised , single-blind , controlled trial . SETTING One secondary care teaching hospital in the UK . PARTICIPANTS Thirty patients were recruited . The follow-up rate was 28 ( 93 % ) at 4 weeks and 23 ( 77 % ) at 3 months . INTERVENTIONS Patients were r and omised to an intervention group commencing exercises within 2 hours after surgery , or a control group commencing exercises on the first postoperative day . MAIN OUTCOME MEASURES Primary outcome measures included the time taken for the patient to become independently mobile and attain discharge criteria following surgery . Secondary outcome measures were disability and pain scores collected before surgery , and 4 weeks and 3 months after surgery ; and return to work rates . RESULTS The two groups were similar at baseline . The results indicated significantly reduced time to independent mobility [ median 7 vs 19 hours , median difference 9 hours , 95 % confidence interval ( CI ) 1.25 to 14.5 , P=0.009 ] and return to work ( median 6 vs 8 weeks , median difference 2 weeks , 95 % CI 0 to 6 , P=0.002 ) in the intervention group compared with the control group . At 15 hours after surgery , independent mobility was attained in 80 and 40 % of the intervention and control groups , respectively . There were no significant differences in disability and pain scores at 4 weeks and 3 months . CONCLUSIONS Immediate commencement of exercises following first-time single-level lumbar microdiscectomy enabled patients to become independently mobile more rapidly and return to work sooner . Immediate commencement of exercises may enable patients to be discharged earlier , with associated cost benefits to health care and no increase in the rate of revision surgery [20639806] AIM A considerable number of patients who undergo surgery for a lumbosacral radicular syndrome ( LRS ) continue to experience disability , pain , and loss of work capacity . The goal of the study is to develop a brief screening instrument to identify these patients at risk of residual complaints . METHODS In a prospect i ve study of 277 patients , the predictors for the outcomes disability , pain , and loss of work capacity were investigated . The best predictive model was constructed using a stepwise selection procedure ( forward selection ) , which calculates the discriminative power of the model . Based on the relationship between regression coefficients , a clinical prediction rule was derived that predicted the probability of residual complaints after surgery for LRS . RESULTS At 6 month follow-up 141 patients ( 51 % ) had residual complaints . The discriminative power of the instrument was .78 ( AUC ) . The " Nijmegen Outcome of Lumbar Disc surgery Screening-instrument " ( NOLDS ) was based on the variables " lower education level " , " younger age " , " pain 3 days postoperatively " , " passive pain coping " , and " fear of movement/(re)injury " . CONCLUSION The results of the study are promising , showing that a brief clinical screening instrument can be used to identify patients at risk of residual complaints at 6 months after surgery for LRS . The early identification of patients at risk having residual complaints may make it possible to start tailored treatment early in the rehabilitation process [1599723] Background Low back pain remains a costly quality -of-life-related health problem . Microdiscectomy is often the surgical procedure of choice for a symptomatic , single-level , lumbar disc herniation in younger and middle-aged adults . The question of whether a post-microdiscectomy exercise program enhances function , quality of life , and disability status has not been systematic ally explored . Thus , the overall purpose of this study is to assess immediate and long-term outcomes of an exercise program , developed at University of Southern California ( USC ) , targeting the trunk and lower extremities ( USC Spine Exercise Program ) for persons who have undergone a single-level microdiscectomy for the first time . Methods / design One hundred individuals between the ages of 18 and 60 who consent to undergo lumbar microdiscectomy will be recruited to participate in this study . Subjects will be r and omly assigned to one of two groups : 1 ) one session of back care education , or 2 ) a back care education session followed by the 12-week USC Spine Exercise Program . The outcome examiners ( evaluators ) , as well as the data managers , will be blinded to group allocation . Education will consist of a one-hour " one-on-one " session with the intervention therapist , guided by an educational booklet specifically design ed for post-microdiscectomy care . This session will occur four to six weeks after surgery . The USC Spine Exercise Program consists of two parts : back extensor strength and endurance , and mat and upright therapeutic exercises . This exercise program is goal -oriented , performance-based , and periodized . It will begin two to three days after the education session , and will occur three times a week for 12 weeks . Primary outcome measures include the Oswestry Disability Question naire , Rol and -Morris Disability Question naire , SF-36 ® quality of life assessment , Subjective Quality of Life Scale , 50-foot Walk , Repeated Sit-to-St and , and a modified Sorensen test . The outcome measures in the study will be assessed before and after the 12-week post-surgical intervention program . Long-term follow up assessment s will occur every six months beginning one year after surgery and ending five years after surgery . Immediate and long-term effects will be assessed using repeated measures multivariate analysis of variance ( MANOVA ) . If significant interactions are found , one-way ANOVAs will be performed followed by post-hoc testing to determine statistically significant pairwise comparisons . Discussion We have presented the rationale and design for a r and omized controlled trial evaluating the effectiveness of a treatment regimen for people who have undergone a single-level lumbar microdiscectomy [20159123] OBJECTIVE To compare the effects of aquatic backward locomotion exercise and progressive resistance exercise with a machine on lumbar extension strength in patients who have undergone diskectomy for a lumbar disk herniation . DESIGN Prospect i ve comparative study . SETTING Department of Kinesiology at a state university . PARTICIPANTS Male patients ( N=30 ) with disk herniation at spinal levels L3 to S1 completed this study as subjects . INTERVENTION After the diskectomy for a lumbar disk herniation , all patients had 6 weeks of rest time . At the end of the rest period , the aquatic backward locomotion exercise and progressive resistance exercise groups , respectively , started first 6 weeks of underwater training and lumbar extension training twice per week . After completion of the first 6-week training , subjects participated in a second 6-week training . After the whole 12-week training , subjects had no training for 6 weeks ( detraining ) and a follow-up 6-week training ( retraining ) . The control ( CON ) group did not undergo any training . MAIN OUTCOME MEASURES For each test , maximum voluntary isometric lumbar extension strength was measured in 7 trunk positions ( 72 degrees , 60 degrees , 48 degrees , 36 degrees , 24 degrees , 12 degrees , and 0 degrees of the trunk angle ) . RESULTS The progressive resistance exercise and aquatic backward locomotion exercise groups showed increases in lumbar extension strength after the first 6-week training , although they were not statistically different from the CON group . After a second 6-week training , the progressive resistance exercise and aquatic backward locomotion exercise groups showed statistically significant increases in their strength levels as compared with the CON group . After the detraining period , the strength levels of the progressive resistance exercise and aquatic backward locomotion exercise groups did not statistically differ from the CON group . After the retraining period , the progressive resistance exercise and aquatic backward locomotion exercise groups showed increases in their strength levels , which were different from that of the CON group . CONCLUSIONS The results obtained suggested that the aquatic backward locomotion exercise is as beneficial as progressive resistance exercise for improving lumbar extension strength in patients after lumbar diskectomy surgery [2586633] Abstract During the recent years improved operation techniques and administrative procedures have been developed for early rehabilitation . At the same time preoperative lifestyle intervention ( prehabilitation ) has revealed a large potential for additional risk reduction . The aim was to assess the quality of life and to estimate the cost-effectiveness of st and ard care versus an integrated programme including prehabilitation and early rehabilitation . Methods The analyses were based on the results from 60 patients undergoing lumbar fusion for degenerative lumbar disease ; 28 patients were r and omised to the integrated programme and 32 to the st and ard care programme . Data on cost and health related quality of life was collected preoperatively , during hospitalisation and postoperatively . The cost was estimated from multiplication of the re source consumption and price per unit . Results Overall there was no difference in health related quality of life scores . The patients from the integrated programme obtained their postoperative milestones sooner , returned to work and soaked less primary care after discharge . The integrated programme was 1,625 € ( direct costs 494 € + indirect costs 1,131 € ) less costly per patient compared to the st and ard care programme . Conclusion The integrated programme of prehabilitation and early rehabilitation in spine surgery is more cost-effective compared to st and ard care programme alone [10327508] STUDY DESIGN An intervention study by the medical advisers of a social security sickness fund on a m and atorily insured patient population after open discectomy for herniated lumbar intervertebral disc . The medical advisers were r and omized into two groups : a control group ( n = 30 ) and an intervention group ( n = 30 ) . OBJECTIVES To compare a rehabilitation-oriented approach in insurance medicine focused primarily on early mobilization and early resumption of professional activities with the usual cl aim -based practice . SUMMARY OF BACKGROUND DATA This study included 710 patients , with a mean age of 39.2 years , who underwent surgery for herniated lumbar disc . METHODS Medical advisers in the rehabilitation-oriented group examined the patients monthly , starting at 6 weeks after the surgical intervention . They used a newly developed protocol to motivate the patients and treating physicians toward social and professional reintegration . RESULTS At 52 weeks , 10.1 % of the patients guided by medical advisers from the rehabilitation-oriented group had not resumed work in contrast to 18.1 % of the patients in the control group . It was statistically proven that this effect also holds during the follow-up period . CONCLUSIONS A rehabilitation-oriented approach by the medical advisers of social security can increase the probability of a return to work for patients after lumbar disc herniation surgery [11740347] STUDY DESIGN R and omized controlled trial with 12-month follow-up . OBJECTIVES To determine whether the addition of neural mobilization to st and ard postoperative care improved the outcome of lumbar spinal surgery . SUMMARY OF BACKGROUND DATA It has been suggested that neural mobilization should be performed after spinal surgery to prevent nerve root adhesions and improve outcome . However , to date , there is no convincing evidence of the value of neural mobilization . METHODS Eighty-one patients undergoing lumbar discectomy , fusion , or laminectomy at a private hospital in Sydney were r and omly allocated to st and ard postoperative care or st and ard care plus neural mobilization . Neural mobilization included passive movements and active exercises design ed to mobilize the lumbosacral nerve roots and sciatic tract . Primary outcome measures were global perceived effect measured on a 7-point scale , pain measured using visual analogue scales and the McGill Pain Question naire , and disability measured with the Quebec Disability Scale . RESULTS All patients received the treatment as allocated with 12-month follow-up data available for 76 patients ( 94 % of those r and omized ) . There were no statistically significant or clinical ly significant benefits provided by the neural mobilization treatment for any outcome . CONCLUSIONS The neural mobilization protocol evaluated in this study did not provide an additional benefit to st and ard postoperative care for patients undergoing spinal surgery . The authors advocate that this protocol not be used in clinical practice [19020904] The effectiveness of physiotherapy after first-time lumbar disc surgery is still largely unknown . Studies in this field are heterogeneous and behavioural treatment principles have only been evaluated in one earlier study . The aim of this r and omised study was to compare clinic-based physiotherapy with a behavioural approach to a home-based training programme regarding back disability , activity level , behavioural aspects , pain and global health measures . A total of 59 lumbar disc patients without any previous spine surgery or comorbidity participated in the study . Clinic-based physiotherapy with a behavioural approach was compared to home-based training 3 and 12 months after surgery . Additionally , the home training group was followed up 3 months after surgery by a structured telephone interview evaluating adherence to the exercise programme . Outcome measures were : Oswestry Disability Index ( ODI ) , physical activity level , kinesiophobia , coping , pain , quality of life and patient satisfaction . Treatment compliance was high in both groups . There were no differences between the two groups regarding back pain disability measured by ODI 3 and 12 months after surgery . However , back pain reduction and increase in quality of life were significantly higher in the home-based training group . The patients in the clinic-based training group had significantly higher activity levels 12 months after surgery and were significantly more satisfied with physiotherapy care 3 months after surgery compared to the home-based training group . Rehabilitation after first-time lumbar disc surgery can be based on home training as long as the patients receive both careful instructions from a physiotherapist and strategies for active pain coping , and have access to the physiotherapist if questions regarding training arise . This might be a convenient treatment arrangement for most patients [1607978] Intraoperative epidural corticosteroids have been used by some surgeons to decrease pain following surgery for a herniated lumbar disc . In this study , 84 consecutively treated , comparable patients with unilateral lumbar disc herniation were prospect ively assigned r and omly to receive either epidural corticosteroids ( 40 mg methylprednisolone acetate ) or saline at the conclusion of the operative procedure . The postoperative morbidity of these two groups was evaluated by tabulating the following parameters : pain relief as measured by consumption of postoperative pain medications ; the length of hospital stay ; postoperative functional status ; and the time interval from surgery until return to work . The mean postoperative analgesic medications consumed was 12.2 + /- 1.9 mg of morphine equivalents in the corticosteroid group versus 12.2 + /- 1.8 mg of morphine equivalents in the control group . The mean hospital stay was less than 2 days in each group , and the mean interval until return to work was 21.2 + /- 2.7 days in the corticosteroid group versus 25.4 + /- 3.1 days in the control group . Moreover , no statistically significant difference was measured between the steroid-treated and control groups when the data were stratified for sex , age , and site of disc herniation . The mean outcome scores , which are derived from a postoperative assessment of pain relief result ing from surgery , functional status , and interval until return to work , were identical in the corticosteroid and control groups . This study concludes that epidural corticosteroid administration after microsurgical lumbar discectomy for unilateral disc herniation does not lessen postoperative morbidity or improve functional recovery [14505118] Behavioral approaches to treating patients following lumbar disc surgery are becoming increasingly popular . The treatment method is based on the assumption that pain and pain disability are not only influenced by somatic pathology , if found , but also by psychological and social factors . A recent study highlighted the effectiveness of cognitive-behavioral interventions , as compared to no treatment , for chronic low back patients . However , to the authors ' knowledge , there is no r and omized controlled trial that evaluates a behavioral program for patients following lumbar disc surgery . The purpose of this study was to assess the effectiveness of a behavioral grade d activity ( BGA ) program compared to usual care ( UC ) in physiotherapy following first-time lumbar disc surgery . The BGA program was a patient-tailored intervention based upon operant therapy . The essence of the BGA is to teach patients that it is safe to increase activity levels . The study was design ed as a r and omized controlled trial . Assessment s were carried out before and after treatment by an observer blinded to treatment allocation . Patients suffering residual symptoms restricting their activities of daily living and /or work at the 6 weeks post-surgery consultation by the neurosurgeon were included . The exclusion criteria were : complications during surgery , any relevant underlying pathology , and any contraindication to physiotherapy or the BGA program . Primary outcome measures were the patient 's Global Perceived Effect and the functional status . Secondary measures were : fear of movement , viewing pain as extremely threatening , pain , severity of the main complaint , range of motion , and relapses . Physiotherapists in the BGA group received proper training . Between November 1997 and December 1999 , 105 patients were r and omized ; 53 into the UC group and 52 into the BGA group . The unadjusted analysis shows a 19.3 % ( 95 % CI : 0.1 to 38.5 ) statistically significant difference to the advantage of the UC group on Global Perceived Effect . This result , however , is not robust , as the adjusted analyses reveal a difference of 15.7 % ( 95 % CI : −3.9 to 35.2 ) , which is not statistically significant . For all other outcome measures there were no statistically significant or clinical ly relevant differences between the two intervention groups . In general , the physiotherapists ' compliance with the BGA program was satisfactory , although not all treatments , either in the BGA or the UC group , were delivered exactly as planned , result ing in less contrast between the two interventions than had been planned for . There was one re-operation in each group . The BGA program was not more effective than UC in patients following first-time lumbar disc surgery . For Global Perceived Effect there was a borderline statistically significant difference to the advantage of the UC group . On functional status and all other outcome measures there were no relevant differences between interventions . The number of re-operations was negligible , indicating that it is safe to exercise after first-time disc surgery [8434331] Ninety-six patients who had undergone first-time discectomy for herniated lumbar intervertebral discs were consecutively r and omized to two physical rehabilitation programs : a program of high-intensity , dynamic back extension and abdominal exercises with occurrence of low back pain being the limiting factor or a traditional program of mild , generally mobilityimproving exercises within pain limits . Both groups underwent 14 hours of treatment during a 6-week period 5 weeks after surgery . At 26 weeks ' follow-up , results indicated that patients who did the high-intensity exercises experienced greater success with regard to the patient disabilityindex and work capabilities . After 1 year , a trend that favored the use of intensive exercises could be observed . No differences were found in pain or objective measurements . A rehabilitation program of intensive exercises with occurrence of back pain being the limiting factor appears to increase patient behavioral support , result ing in work capacity improvements and patient self-rated disability levels . The results indicate that a 6-wk , 14-hr postoperative rehabilitation program is inadequate if objective postoperative deficit improvements are the desired goal [19584344] CONTEXT Conventional microdiskectomy is the most frequently performed surgery for patients with sciatica due to lumbar disk herniation . Transmuscular tubular diskectomy has been introduced to increase the rate of recovery , although evidence is lacking of its efficacy . OBJECTIVE To determine outcomes and time to recovery in patients treated with tubular diskectomy compared with conventional microdiskectomy . DESIGN , SETTING , AND PATIENTS The Sciatica Micro-Endoscopic Diskectomy r and omized controlled trial was conducted among 328 patients aged 18 to 70 years who had persistent leg pain ( > 8 weeks ) due to lumbar disk herniations at 7 general hospitals in The Netherl and s from January 2005 to October 2006 . Patients and observers were blinded during the follow-up , which ended 1 year after final enrollment . INTERVENTIONS Tubular diskectomy ( n = 167 ) vs conventional microdiskectomy ( n = 161 ) . MAIN OUTCOME MEASURES The primary outcome was functional assessment on the Rol and -Morris Disability Question naire ( RDQ ) for sciatica ( score range : 0 - 23 , with higher scores indicating worse functional status ) at 8 weeks and 1 year after r and omization . Secondary outcomes were scores on the visual analog scale for leg pain and back pain ( score range : 0 - 100 mm ) and patient 's self-report of recovery ( measured on a Likert 7-point scale ) . RESULTS Based on intention-to-treat analysis , the mean RDQ score during the first year after surgery was 6.2 ( 95 % confidence interval [ CI ] , 5.6 to 6.8 ) for tubular diskectomy and 5.4 ( 95 % CI , 4.6 to 6.2 ) for conventional microdiskectomy ( between-group mean difference , 0.8 ; 95 % CI , -0.2 to 1.7 ) . At 8 weeks after surgery , the RDQ mean ( SE ) score was 5.8 ( 0.4 ) for tubular diskectomy and 4.9 ( 0.5 ) for conventional microdiskectomy ( between-group mean difference , 0.8 ; 95 % CI , -0.4 to 2.1 ) . At 1 year , the RDQ mean ( SE ) score was 4.7 ( 0.5 ) for tubular diskectomy and 3.4 ( 0.5 ) for conventional microdiskectomy ( between-group mean difference , 1.3 ; 95 % CI , 0.03 to 2.6 ) in favor of conventional microdiskectomy . On the visual analog scale , the 1-year between-group mean difference in improvement was 4.2 mm ( 95 % CI , 0.9 to 7.5 mm ) for leg pain and 3.5 mm ( 95 % CI , 0.1 to 6.9 mm ) for back pain in favor of conventional microdiskectomy . At 1 year , 107 of 156 patients ( 69 % ) assigned to tubular diskectomy reported a good recovery vs 120 of 151 patients ( 79 % ) assigned to conventional microdiskectomy ( odds ratio , 0.59 [ 95 % CI , 0.35 to 0.99 ] ; P = .05 ) . CONCLUSIONS Use of tubular diskectomy compared with conventional microdiskectomy did not result in a statistically significant improvement in the Rol and -Morris Disability Question naire score . Tubular diskectomy result ed in less favorable results for patient self-reported leg pain , back pain , and recovery . TRIAL REGISTRATION is rct n.org Identifier : IS RCT N51857546 [20103575] Objective : To evaluate the outcome after spinal surgery when adding prehabilitation to the early rehabilitation . Design : A r and omized clinical study . Setting : Orthopaedic surgery department . Subject : Sixty patients scheduled for surgery followed by inpatient rehabilitation for degenerative lumbar disease . Interventions : The patients were computer r and omized to prehabilitation and early rehabilitation ( 28 patients ) or to st and ard care exclusively ( 32 patients ) . The intervention began two months prior to the operation . The prehabilitation included an intensive exercise programme and optimization of the analgesic treatment . Protein drinks were given the day before surgery . The early postoperative rehabilitation included balanced pain therapy with self-administered epidural analgesia , doubled intensified mobilization and protein supplements . Main measures : The outcome measurements were postoperative stay , complications , functionality , pain and satisfaction . Results : At operation the intervention group had improved function , assessed by Rol and Morris Question naire ( P = 0.001 ) . After surgery the intervention group reached the recovery milestones faster than the control group ( 1—6 days versus 3—13 , P = 0.001 ) , and left hospital earlier ( 5 ( 3—9 ) versus 7 ( 5—15 ) days , P = 0.007 ) . There was no difference in postoperative complications , adverse events , low back pain and radiating pain , timed up and go , sit-to-st and or in life quality . Patient satisfaction was significantly higher in the intervention group compared with the control group . Conclusion : The integrated programme of prehabilitation and early rehabilitation improved the outcome and shortened the hospital stay — without more complications , pain or dissatisfaction [8484146] Sixty-two patients with chronic low back pain occurring 14 - 60 months after undergoing discectomy for the first time were r and omized to two physical treatment groups : 24 sessions of intensive dynamic back exercises with hyperextension or 24 sessions of intensive dynamic back exercises without hyperextension . At the conclusion of therapy and at one-year follow-up , no difference was seen between the r and omized groups , with regard to the combined assessment s of pain , disability and objective measurements . A difference for back exercises without hyperextension to be superior to the other treatment regimen was statistically significant at the three-month follow-up . In the patient 's qualitative assessment of treatment outcome there were seen no significant differences between back exercises with or without hyperextension . There was a similar and significant improvement of the isometric endurance of back muscles in both groups , but the flexibility of the spine was significantly improved only in the group using hyperextension exercises . The overall response rate of an earlier published investigation was reproduced . It is concluded that chronic back patients after first time discectomy may benefit from an intensive rehabilitation protocol including intensive exercises . The added use of hyperextension exercises does not confer any independent benefit . Furthermore , the training had to continue for more than 2 - 3 months before a statistical significant decrease in back pain was reported in the patient pain diary [17108817] Study Design . A prospect i ve r and omized study involving 280 consecutive cases of lumbar disc herniation managed either by an endoscopic discectomy alone or an endoscopic discectomy combined with an intradiscal injection of a low dose ( 1000 U ) of chymopapain . Objective . To compare outcome , complications , and reherniations of both techniques . Summary of Background Data . Despite a low complication rate , posterolateral endoscopic nucleotomy has made a lengthy evolution because of an assumed limited indication . Chemonucleolysis , however , proven to be safe and effective , has not continued to be accepted by the majority in the spinal community as microdiscectomy is considered to be more reliable . Method . A total of 280 consecutive patients with a primary herniated , including sequestrated , lumbar disc with predominant leg pain , was r and omized . A clinical follow-up was performed at 3 months , and at 1 and 2 years after the index operation with an extensive question naire , including the visual analog scale for pain and the MacNab criteria . The cohort integrity at 3 months was 100 % , at 1 year 96 % , and at 2 years 92 % . Results . At the 3-month evaluation , only minor complications were registered . At 1-year postoperatively , group 1 ( endoscopy alone ) had a recurrence rate of 6.9 % compared to group 2 ( the combination therapy ) , with a recurrence rate of 1.6 % , which was a statistically significant difference in favor of the combination therapy ( P = 0045 ) . At the 2-year follow-up , group 1 reported that 85.4 % had an excellent or good result , 6.9 % a fair result , and 7.7 % were not satisfied . At the 2-year follow-up , group 2 reported that 93.3 % had an excellent or good result , 2.5 % a fair result , and 4.2 % were not satisfied . This outcome was statistically significant in favor of the group including chymopapain . There were no infections or patients with any form of permanent iatrogenic nerve damage , and no patients had a major complication . Conclusions . A high percentage of patient satisfaction could be obtained with a posterior lateral endoscopic discectomy for lumbar disc herniation , and a statistically significant improvement of the results was obtained when an intradiscal injection of 1000 U of chymopapain was added . There was a low recurrence rate with no major complications . The method can be applied in any type of lumbar disc herniation , including the L5−S1 level [17593405] Spinal decompression is the most common type of spinal surgery carried out in the older patient , and is being performed with increasing frequency . Physiotherapy ( rehabilitation ) is often prescribed after surgery , although its benefits compared with no formal rehabilitation have yet to be demonstrated in r and omised control trials . The aim of this r and omised controlled trial was to examine the effects on outcome up to 2 years after spinal decompression surgery of two types of postoperative physiotherapy compared with no postoperative therapy ( self-management ) . Hundred and fifty-nine patients ( 100 men , 59 women ; 65 ± 11 years ) undergoing decompression surgery for spinal stenosis/herniated disc were r and omised to one of the following programmes beginning 2 months post-op : recommended to “ keep active ” ( CONTROL ; n = 54 ) ; physiotherapy , spine stabilisation exercises ( PT-StabEx ; n = 56 ) ; physiotherapy , mixed techniques ( PT-Mixed ; n = 49 ) . Both PT programmes involved 2 × 30 min sessions/week for up to 12 weeks , with home exercises . Pain intensity ( 0–10 graphic rating scale , for back and leg pain separately ) and self-rated disability ( Rol and Morris ) were assessed before surgery , before and after the rehabilitation phase ( approx . 2 and 5 months post-op ) , and at 12 and 24 months after the operation . ‘ Intention to treat ’ analyses were used . At 24 months , 151 patients returned question naires ( effective return rate , excluding 4 deaths , 97 % ) . Significant reductions in leg and back pain and self-rated disability were recorded after surgery ( P < 0.05 ) . Pain showed no further changes in any group up to 24 months later , whereas disability declined further during the “ rehabilitation ” phase ( P < 0.05 ) then stabilised , but with no significant group differences . 12 weeks of post-operative physiotherapy did not influence the course of change in pain or disability up to 24 months after decompression surgery . Advising patients to keep active by carrying out the type of physical activities that they most enjoy appears to be just as good as administering a supervised rehabilitation program , and at no cost to the health-care provider [12394665] A prospect i ve and r and omized study was conducted of 52 patients who were treated by two home training programs after surgical treatment of lumbar disc herniation . Twenty-six patients followed an early active treatment program , and 26 patients followed a less active training program ( control group ) . Forty-nine patients ( 82 % ) answered a question naire 5–7 years postoperatively . The reoperation rate was two of 49 patients . None of these patients had followed the early active treatment program . Patients with signs of depression before surgery were not significantly less satisfied with the outcome than patients with no signs of depression before surgery [15895329] OBJECTIVE To assess the adherence to and effects of a 12-month combined strength and stretching home exercise regimen versus stretching alone , on patient outcome after lumbar disk surgery . DESIGN R and omized controlled trial . SETTING Departments of physical medicine and rehabilitation and orthopedics at a Finnish hospital . PARTICIPANTS Patients ( N=126 ) were r and omized into either a combined strength training and stretching group ( STG , n=65 ) or a control group ( CG , n=61 ) . INTERVENTION The STG was instructed to perform strength training and both the STG and CG were instructed in the same stretching and stabilization exercises for 12 months . MAIN OUTCOME MEASURES Pain on the visual analog scale ( VAS ) , the Oswestry and the Million disability indexes , isometric and dynamic trunk muscle strength , mobility in the lumbar spine , and straight-leg raising were measured . RESULTS The trial was completed by 71 % and 77 % of the patients from the STG and the CG , respectively . The mean strength training frequency decreased from 1.5 to 0.6 times a week in the STG during the intervention . The mean stretching frequency decreased from 3.7 to 1.6 times a week in both groups . Median back and leg pain varied between 17 and 23 mm ( VAS ) , and the Million and Oswestry indices varied between 14 and 23 points 2 months postoperatively . No statistically significant changes took place in these outcome measures during the 12-month follow-up in both groups . The changes in isometric trunk extension favored the STG ( P = .016 ) during the first 2 months . However , during the whole 12-month training period , both dynamic and isometric back extension and flexion strength , as well as mobility of the spine and repetitive squat-test results , improved significantly in both groups , and no differences were found in any of the physical function parameters between the STG and CG . CONCLUSIONS At the 12-month follow-up , no statistically significant changes were found in the physical function , pain , or disability measures between the groups . In the STG , training adherence with regard to training frequency and intensity remained too low to lead to specific training-induced adaptations in the neuromuscular system . Progressive loading , supervision of training , and psychosocial support is needed in long-term rehabilitation programs to maintain patient motivation [15014270] Study Design . An economic evaluation was conducted alongside a r and omized controlled trial . Summary of Background Data . Little is known about the effectiveness of cognitive-behavioral treatment options for patients following lumbar disc surgery . If the knowledge available was supported by an economic evaluation , the information could then be used to make recommendations for the implementation of cognitive-behavioral treatment in the routine of rehabilitation following lumbar disc surgery . Objective . To examine the cost-effectiveness of a behavioral- grade d activity program , which is an operant treatment , compared to usual care as delivered by a physical therapist for patients following first-time lumbar disc surgery . Methods . For the economic evaluation , a societal viewpoint was applied . The primary outcome measures ( measured at the 12-month follow-up ) were global perceived effect and functional status . To evaluate the economic consequences of the treatments , direct health care and non-health care costs were considered , as well as indirect costs . Results . The clinical outcomes showed no relevant differences between behavioral- grade d activity ( n = 52 ) and UC ( n = 53 ) . Treatment costs were almost identical in the two intervention groups . The difference in direct health care costs was , although not statistically significant , 264 EURO [ 95 % CI : −3–525 ] higher in behavioral- grade d activity than in usual care per patient-year . It was mainly the excess cost of visiting the physiotherapist in the behavioral- grade d activity group that accounted for this difference . The difference in direct non-health care costs , although not statistically significant , was 388 EURO [ 95 % CI : −217 ; 992 ] lower in the usual care group due to unpaid help by friends or family . Consequently , although again not statistically significant , the total direct costs in behavioral- grade d activity are 639 EURO [ 95 % CI : −91 ; 1368 ] higherthan in usual care . For the indirect costs , there was a statistically significant difference , behavioral- grade d activity being more expensive . The sensitivity analysis showed that these results are fairly robust . Conclusions . This study concludes that there are no differences between the two treatment conditions on any of the clinical outcome measures but that behavioral- grade d activity is associated with higher costs . Consequently , there is no reason for the implementation of behavioral- grade d activity as the st and ard treatment for patients following lumbar disc surgery [12892241] OBJECTIVE The aim of this study was to determine the efficacy of dynamic lumbar stabilization exercises in patients with lumbar microdiscectomy . DESIGN A prospect i ve , r and omized , controlled study . SUBJECTS Forty-two patients who were diagnosed as having lumbar disc herniation and had been operated on using the microdiscectomy method were divided r and omly into 3 groups . METHODS Dynamic lumbar stabilization exercises were set for the first group and a home exercise programme for the second . The third group given no exercises was considered as a control group . All patients were examined twice , once before the exercise programme and once 8 weeks later . RESULTS Improvement in the first group was highly significant after the treatment ( p < 0.0001 ) . The second group improved significantly more in some parameters ( pain , functional disability , lumbar Schober , progressive isoinertial lifting evaluation ( neck ) , trunk endurance ( flexion-extension ) ) than did the third group . The third group of patients showed some improvement in fingertip-floor distance , functional disability , modified lumbar Schober and left rotation in 8 weeks , but there were no significant improvements in the other parameters . CONCLUSION Dynamic lumbar stabilization exercises are an efficient and useful technique in the rehabilitation of patients who have undergone microdiscectomy . They relieve pain , improve functional parameters and strengthen trunk , abdominal and low back muscles [10767815] Study Design . A r and omized clinical trial of postoperative medical exercise therapy in patients after operation for lumbar disc herniation with blind assessment of clinical outcomes . Objective . To assess the effect of an early regimen of vigorous medical exercise compared with an ordinary care program . Summary of Background Data . Methods . Patients offered an operation for lumbar disc herniation were consecutively r and omized to a training group or to a control group . The training consisted of an 8-week active rehabilitation program including a regimen of vigorous lumbar stabilizing exercises . The control subjects participated in a mild program of 2 to 3 back exercises at home , after relaxing and resting their backs for 2 months after the surgery . The outcomes were evaluated 6 and 12 months after the operation . The results are based on intention-to-treat analyses . Results . Sixty-three of 65 eligible patients agreed to participate in the trial . Fifty-eight and 53 patients attended for evaluation at 6 and 12 months , respectively . There was a significantly larger improvement in the mean Rol and ’s disability index ( from 8.9 to 5.4 [ P = 0.02 ] at 6 months and from 8.7 to 5.3 [ P = 0.03 ] at 12 months ) and in reported pain ( from 3.7 to 2.0 [ P = 0.04 ] at 6 months and from 3.2 to 1.8 [ P = 0.09 ] at 12 months ) in the training group . A significantly ( P = 0.05 ) higher proportion of the training group reported that they participated in daily activities as usual . There were more patients in the training group who reported improvement in self-evaluated health after surgery at both 6 ( P = 0.02 ) and at 12 months ( P = 0.05 ) . Finally , no differences in clinical end points were observed between the groups . Conclusions . Vigorous medical exercise therapy , started 4 weeks after surgery for lumbar disc herniation , reduced disability and pain after surgery . Because no differences in clinical end points were observed , there is hardly any danger associated with early and vigorous training after operation for disc herniation [15662744] Study Design and Objectives . In a r and omized clinical trial , the effectiveness of behavioral grade d activity was assessed as compared to usual care provided by physiotherapists for patients after first-time lumbar disc surgery ( n = 105 ) . Summary of Background Data . Little is known about the effectiveness of rehabilitation programs following lumbar disc surgery . Most programs focus on biomechanical aspects , whereas psychosocial factors are hardly addressed . The aim of the behavioral grade d activity program , which is an operant treatment , is to alter psycho-social factors such as fear of movement and pain catastrophizing , which might subsequently lead to improved functional status and higher rates of recovery . Behavioral treatments for patients following lumbar disc surgery have not yet been assessed in a r and omized clinical trial . Methods . Inclusion criteria : age between 18 and 65 years ; first-time lumbar disc surgery ; restrictions in normal activities of daily living . Exclusion criteria : surgical complications and confirmed and relevant underlying diseases . Outcome assessment took place at 6 and 12 months after r and omization . Results . Six months after r and omization , 62 % of the patients had recovered following usual care versus 65 % of the patients following behavioral grade d activity . After 12 months , 73 % and 75 % , respectively , had recovered . Differences between intervention groups , 3 % and 2 % respectively , after 6 and 12 months are not statistically significant . Furthermore , there were no differences between the two groups regarding functional status , pain , pain catastrophizing , fear of movement , range of motion , general health , social functioning or return to work . After 1 year , 4 of the behavioral grade d activity cases had undergone another operation versus 2 of usual care cases . Conclusion . Both fear of movement and pain catastrophizing seem to be unaffected by either treatment in these patients . It is concluded that treatment principles derived from theories within the field of chronic low back pain might not apply to these patients . After 1 year of follow-up , there were no statistically significant or clinical ly relevant differences between the behavioral grade d activity program and usual care as provided by physiotherapists for patients following first-time lumbar disc surgery [8875722] Study Design A prospect i ve clinical trial was conducted . Objectives To determine if removing activity restrictions after surgery and encouraging early return to work would affect clinical outcomes after lumbar discectomy . Summary of Background Information Current practice usually recommends several weeks to months of restricted activities after lumbar discectomy . No formal studies have been done to determine the optimal period of restriction , if any , after surgery . Methods Fifty consecutive patients undergoing limited open discectomy for herniated lumbar intervertebral disc were prospect ively treated with no restrictions at all after surgery and were urged to return to full activities as soon as possible . The patients were followed for a minimum of 2 years . At follow‐up evaluation , an independent examiner evaluated each patient . Results The mean time from surgery to return to work was 1.7 weeks . Eleven of 44 ( 25 % ) patients returned to work on the next work day . Ninety‐seven percent of patients who were working before surgery returned to their previous work . Forty‐three of 44 ( 97 % ) patients had returned to full duty by 8 weeks after surgery . At follow‐up evaluation ( 3.8 years ) , five patients had changed work ; three patients increased their work level , and two decreased their work level . No patient changed employment because of back or leg pain . There were three reherniations at the operative level ( 6 % ) , all occurring more than 1 year after surgery . One patent required reoperation . Back and leg pain scores at follow‐up evaluation were very low . Conclusion Lifting of postoperative restrictions after limited discectomy allowed shortened sick leave without increased complications . Postoperative pre caution s in these patients may not be necessary [3536770] The aim of this prospect i ve study was to examine the one-year postoperative results in patients operated on for lumbar disc herniation r and omized in two groups : one with comprehensive rehabilitation and the other taken care of by normal care facilities . A total of 212 patients without any previous spinal operations comprised the final study group . The physiatrist , the surgeon , the social worker , and the psychologist performed the h and icap evaluation according to the occupation h and icap scales of the WHO . The h and icap was evaluated for two phases : before the onset of acute sciatica leading to operation and one year after operation . No significant differences in h and icap distribution between the intervention and normal care groups were seen . The postoperative h and icap correlated highly significantly with preoperative h and icap for both groups . More than half ( 57 % ) of all the patients returned to work within two months of the operation . The amount of sick leaves did not differ significantly between the intervention and normal care groups . A total of 15 persons ( 7 % ) retired during the postoperative year [3441840] The prospect i ve study was undertaken to find out preoperative or perioperative factors predicting the results of the first surgery for lumbar disc herniation . The results were evaluated 1 and 6 months postoperatively using , in addition to the patient evaluation , indices for pain , activities of daily living ( ADL ) , and working capacity . The best result was achieved if the patient was operated on before 2 months ' duration of disabling sciatica . The operative finding grade d as protrusion predicted poor result . The social and psychological factors influenced the outcome more than the findings in the preoperative physical examination or the grade of operative finding . It is recommended to add indices for pain and ADL and a psychological test to the preoperative examinations of patients with lumbar disc herniation [16825039] BACKGROUND CONTEXT Discectomy is the surgery of choice for the lumbosacral radicular syndrome . Previous studies on the postsurgical management of these cases compare one exercise regime to another . This study compares an exercise-based group with a control group involving no formal exercise or rehabilitation . PURPOSE The outcomes of a formal postsurgical exercise-based rehabilitation when compared with the usual rehabilitative surgical advice were evaluated . STUDY DESIGN A r and omized clinical trial comparing management regimes after lumbar discectomies . PATIENT SAMPLE Ninety-three lumbar discectomy patients were r and omized to two groups . OUTCOME MEASURES The following postoperative outcomes were used : levels of pain ; levels of function ; psychological well-being ; time off work ; levels of medication ; and number of doctor/therapist visits . METHODS Ninety-three lumbar discectomy patients were r and omized to two groups . The treatment group undertook a 6-month supervised nonaggravating exercise program . The control group followed the usual surgical advice to resume normal activities as soon as the pain allowed . Both groups were followed for 1 year by using vali date d outcome measures . RESULTS The results are based on an intention-to-treat analysis . Patients in both groups improved during the 1-year follow-up ( p=.001 ) . There was no statistical significance between the groups at the clinical endpoint . The treatment group returned to work 7 days earlier and had fewer days off work in the 1-year follow-up period . CONCLUSION There was no statistical advantage gained by the group that performed the 6-month supervised nonaggravating exercise program at 1-year follow-up . They did , however , have fewer days off work [7849747] The professional literature contains relatively few r and omized-control studies that have assessed the efficacy of physical therapy approaches to the management of patients with chronic low back pain ( CLBP ) . The purpose s of this study were : 1 ) to investigate the effects of physical agents , joint manipulation , low-tech exercise , and high-tech exercise on objective measures of CLBP ; 2 ) to track the length of CLBP relief ; and 3 ) to determine treatment cost-effectiveness . Two-hundred-fifty subjects ( 68 females , 182 males ; ages 34 - 51 years ) with CLBP following an L5 laminectomy were r and omly assigned into five separate groups for a treatment period of 8 weeks . Chronic low back pain status was measured by modified-modified Schober , Cybex Liftask , and Oswestry procedures . Results revealed that : 1 ) only low-tech and high-tech exercise produced significant improvements ( p < .05 ) in CLBP , 2 ) the mean period of CLBP relief ranged from 1.6 weeks ( control ) to 91.4 weeks ( low-tech exercise ) , and 3 ) low-tech exercise was most cost-effective . It was concluded that : 1 ) low-tech and high-tech exercise were the only effective treatments for CLBP , 2 ) low-tech exercise produced the longest period of CLBP relief , and 3 ) low-tech exercise was the most cost-effective form of treatment . Clinical ly , low-tech exercise may be the treatment method of choice for the effective management of chronic low back pain [21505377] Study Design . Cost-effectiveness analysis alongside a factorial r and omized controlled trial . Objective . To assess the cost-effectiveness of a rehabilitation program and /or an education booklet each compared with usual care for the postoperative management of patients undergoing discectomy or lateral nerve root decompression surgery . Summary of Background Data . There is little knowledge about the cost-effectiveness of postoperative management of patients after spinal surgery . Methods . A total of 338 patients were recruited into the study between June 2005 and March 2009 . Patients were r and omized to rehabilitation only , booklet only , rehabilitation plus booklet , or usual care only . Interactions between booklet and rehabilitation were nonsignificant ; hence , we compare booklet versus no booklet and rehabilitation versus no rehabilitation . We adopt an English National Health Service and personal social services perspective . Data on outcomes and costs are based on patient level data from the trial . A 1-year time horizon was used . Outcomes were measured in terms of quality -adjusted life years . Health-related quality of life was reported by patients using the EuroQol-5D ( EQ-5D ) . A comprehensive range of health service contacts were included in the cost analysis . Results . There were no significant differences in costs or outcomes associated with either intervention . Mean incremental costs and mean quality -adjusted life years gained per patient of booklet versus no booklet were −£87 ( 95 % CI : −£1221 to £ 1047 ) and −0.023 ( 95 % CI : −0.068 to 0.023 ) , respectively . Figures for rehabilitation versus no rehabilitation were £ 160 ( 95 % CI : −£984 to £ 1304 ) and 0.002 ( 95 % CI : −0.044 to 0.048 ) , respectively . Neither intervention was cost-effective when compared with the threshold range commonly used to judge whether or not an intervention is cost-effective in the English National Health Service . Conclusion . Cost-effectiveness evidence does not support use of booklet over no booklet or rehabilitation over no rehabilitation for the postoperative management of patients after spinal surgery [431682] This paper proposes a new method for planning r and omized clinical trials . This method is especially suited to comparison of a best st and ard or control treatment with an experimental treatment . Patients are allocated into two groups by a r and om or chance mechanism . Patients in the first group receive st and ard treatment ; those in the second group are asked if they will accept the experimental therapy ; if they decline , they receive the best st and ard treatment . In the analyses of results , all those in the second group , regardless of treatment , are compared with those in the first group . Any loss of statistical efficiency can be overcome by increased numbers . This experimental plan is indeed a r and omized clinical trial and has the advantage that , before providing consent , a patient will know whether an experimental treatment is to be used [10851101] Study Design . A prospect i ve r and omized controlled trial of exercise therapy in patients who underwent microdiscectomy for prolapsed lumbar intervertebral disc . Results of a pilot study are presented . Objective . To determine the effects of a postoperative exercise program on pain , disability , psychological status , and spinal function . Summary of Background Data . Microdiscectomy is often used successfully to treat prolapsed lumbar intervertebral disc . However , some patients do not have a good outcome and many continue to have low back pain . The reasons for this are unclear but impairment of back muscle function due to months of inactivity before surgery may be a contributing factor . A postoperative exercise program may improve outcome in such patients . Methods . Twenty patients who underwent lumbar microdiscectomy were r and omized into EXERCISE and CONTROL groups . After surgery , all patients received normal postoperative care that included advice from a physiotherapist about exercise and a return to normal activities . Six weeks after surgery , patients in the EXERCISE group undertook a 4-week exercise program that concentrated on improving strength and endurance of the back and abdominal muscles and mobility of the spine and hips . Assessment s of spinal function were performed in all patients during the week before surgery and at 6 , 10 , 26 , and 52 weeks after . The assessment included measures of posture , hip and lumbar mobility , back muscle endurance capacity and electromyographic measures of back muscle fatigue . On each occasion , patients completed question naires inquiring about pain , disability and psychological status . Results . Surgery improved pain , disability , back muscle endurance capacity and hip and lumbar mobility in both groups of patients . After the exercise program , the EXERCISE group showed further improvements in these measures and also in electromyographic measures of back muscle fatigability . All these improvements were maintained 12 months after surgery . The only further improvement showed by the CONTROL group between 6 and 52 weeks was an increase in back muscle endurance capacity . Conclusion . A 4-week postoperative exercise program can improve pain , disability , and spinal function in patients who undergo microdiscectomy [9820916] Study Design . A prospect i ve , r and omized , and controlled study was conducted . Objectives . To evaluate two training programs , both of which started immediately after lumbar discectomy . Summary of Background Data . In previous studies , patients began physiotherapy between 4 weeks and 60 months after surgery . No studies have been conducted to evaluate a physiotherapy program that begins immediately after surgery . Method . Twenty‐six patients were treated according to an early active training program . Twenty‐six patients were treated with a traditional , less active training program ( control group ) . All patients were examined immediately before and after surgery and 3 , 6 , 12 , and 52 weeks after surgery by an unbiased observer . Two years after surgery , patients completed a question naire . Range of motion of the lumbar spine and straight leg raising were measured . Pain intensity and location was measured by a visual analog scale . The duration of sick leave was documented . Results . Six and 12 weeks after surgery , patients with dominating residual leg pain had significantly less intense pain in the early active training group than those in the control group ( P < 0.05 ) . Twelve weeks after surgery , range of motion of the lumbar spine was significantly more increased in the early active training group ( P < 0.01 ) . One year after surgery , there was no significant difference between the groups regarding the duration of sick leave , results in a positive straight leg raising , or pain intensity . Twenty‐two ( 88 % ) patients in the early active training group and 16 ( 67 % ) in the control group were satisfied with the treatment outcome 2 years after surgery ( P < 0.10 ) . Conclusions . Patients rehabilitated according to the early active training program had a better short‐term outcome of objective values . At 2 years ' follow‐up , more patients were satisfied with the result of the operation . The early active treatment program is recommended [20878044] OBJECTIVE To determine the effects of lumbar extension exercise on strength , disability index , and pain scores in patients after lumbar discectomy surgery . DESIGN Prospect i ve comparative study . SUBJECTS Forty patients experiencing a herniated disc at lumbar levels were divided into 4 subgroups for different training frequencies : twice/week ( group 1 ) , once/week ( group 2 ) , once/2 weeks ( group 3 ) , and no training ( control ) . METHODS After completing the initial 12-week training , all subjects participated in a 12-week follow-up training . RESULTS Groups 1 and 2 showed significant increases in lumbar extension strength ( 26 Nm and 7 Nm , respectively ) , while group 3 and the control group showed significant decreases in lumbar extension strength . Groups 1 and 2 showed significant decreases in disability index ( 1.4 and 0.8 Oswestry Disability Index points , respectively ) , and group 1 showed significant decreases in back and leg pain scores ( both 0.5 units on a 10-cm visual analog scale ) . CONCLUSION Lumbar extension strength and disability index improve with training frequencies of once and twice per week , while back and leg pain improve with a training frequency of twice per week . The clinical importance of these improvements is question able , as the scores were already very low after the discectomy and the magnitude of absolute improvements were small [12673431] To comprehend the results of a r and omised controlled trial ( RCT ) , readers must underst and its design , conduct , analysis , and interpretation . That goal can be achieved only through total transparency from authors . Despite several decades of educational efforts , the reporting of RCTs needs improvement . Investigators and editors developed the original CONSORT ( Consoli date d St and ards of Reporting Trials ) statement to help authors improve reporting by use of a checklist and flow diagram . The revised CONSORT statement presented here incorporates new evidence and addresses some criticisms of the original statement . The checklist items pertain to the content of the Title , Abstract , Introduction , Methods , Results , and Discussion . The revised checklist includes 22 items selected because empirical evidence indicates that not reporting this information is associated with biased estimates of treatment effect , or because the information is essential to judge the reliability or relevance of the findings . We intended the flow diagram to depict the passage of participants through an RCT . The revised flow diagram depicts information from four stages of a trial ( enrollment , intervention allocation , follow- up , and analysis ) . The diagram explicitly shows the number of participants , for each intervention group , included in the primary data analysis . Inclusion of these numbers allows the reader to judge whether the authors have done an intention- to-treat analysis . In sum , the CONSORT statement is intended to improve the reporting of an RCT , enabling readers to underst and a trial 's conduct and to assess the validity of its results [23484826] BACKGROUND Magnetic resonance imaging ( MRI ) is frequently performed during follow-up in patients with known lumbar-disk herniation and persistent symptoms of sciatica . The association between findings on MRI and clinical outcome is controversial . METHODS We studied 283 patients in a r and omized trial comparing surgery and prolonged conservative care for sciatica and lumbar-disk herniation . Patients underwent MRI at baseline and after 1 year . We used a 4-point scale to assess disk herniation on MRI , ranging from 1 for " definitely present " to 4 for " definitely absent . " A favorable clinical outcome was defined as complete or nearly complete disappearance of symptoms at 1 year . We compared proportions of patients with a favorable outcome among those with a definite absence of disk herniation and those with a definite , probable , or possible presence of disk herniation at 1 year . The area under the receiver-operating-characteristic ( ROC ) curve was used to assess the prognostic accuracy of the 4-point scores regarding a favorable or unfavorable outcome , with 1 indicating perfect discriminatory value and 0.5 or less indicating no discriminatory value . RESULTS At 1 year , 84 % of the patients reported having a favorable outcome . Disk herniation was visible in 35 % with a favorable outcome and in 33 % with an unfavorable outcome ( P=0.70 ) . A favorable outcome was reported in 85 % of patients with disk herniation and 83 % without disk herniation ( P=0.70 ) . MRI assessment of disk herniation did not distinguish between patients with a favorable outcome and those with an unfavorable outcome ( area under ROC curve , 0.48 ) . CONCLUSIONS MRI performed at 1-year follow-up in patients who had been treated for sciatica and lumbar-disk herniation did not distinguish between those with a favorable outcome and those with an unfavorable outcome . ( Funded by the Netherl and s Organization for Health Research and Development and the Hoelen Foundation ; Controlled Clinical Trials number , IS RCT N26872154 . ) [21378603] Study Design . This was a multicenter , factorial , r and omized , controlled trial on the postoperative management of spinal surgery patients , with r and omization stratified by surgeon and operative procedure . Objective . This study sought to determine whether the functional outcome of two common spinal operations could be improved by a program of postoperative rehabilitation that combines professional support and advice with grade d active exercise commencing 6 weeks after surgery and /or an educational booklet based on evidence -based messages and advice received at discharge from hospital , each compared with usual care . Summary of Background Data . Surgical interventions on the spine are increasing , and while surgery for spinal stenosis and disc prolapse have been shown to be superior to conservative management , functional outcome , and patient satisfaction are not optimal . Methods . The study compared the effectiveness of a rehabilitation program and an education booklet for the postoperative management of patients undergoing discectomy or lateral nerve root decompression surgery , each compared with “ usual care ” using a 2 × 2 factorial design , r and omizing patient to four groups ; rehabilitation-only , booklet-only , rehabilitation-plus-booklet , and usual care only . The primary outcome measure was the Oswestry Disability Index ( ODI ) at 12 months , with secondary outcomes including visual analog scale measures of back and leg pain . Results . Three hundred thirty-eight patients were recruited into the study and measurements were obtained preoperatively and then repeated at 6 weeks , 3 , 6 , 9 and 12 months postoperatively . Twelve months postoperatively the observed effect of rehabilitation on ODI was −2.7 ( 95 % CI : −6.8 to 1.5 ) and the effect of booklet was 2.7 ( 95 % CI : −1.5 to 6.9 ) . Conclusion . This study found that neither intervention had a significant impact on long-term outcome [19778981] Background Restoration of physical function following lumbar microdiskectomy may be influenced by the postoperative care provided . Objective The purpose of this study was to examine the effectiveness of a new interventional protocol to improve functional performance in patients who have undergone a single-level lumbar microdiskectomy . Setting The study was conducted in physical therapy outpatient clinics . Design and Participants Ninety-eight participants ( 53 male , 45 female ) who had undergone a single-level lumbar microdiskectomy were r and omly allocated to receive education only or exercise and education . Intervention and Measurements The exercise intervention consisted of a 12-week periodized program of back extensor strength ( force-generating capacity ) and endurance training and mat and upright therapeutic exercises . The Oswestry Disability Index ( ODI ) and physical measures of functional performance were tested 4 to 6 weeks postsurgery and 12 weeks later , following completion of the intervention program . Because some participants sought physical therapy outside of the study , postintervention scores were analyzed for both an as-r and omized ( 2-group ) design and an as-treated ( 3-group ) design . Results In the 2-group analyses , exercise and education result ed in a greater reduction in ODI scores and a greater improvement in distance walked . In the 3-group analyses , post hoc comparisons showed a significantly greater reduction in ODI scores following exercise and education compared with the education-only and usual physical therapy groups . Limitations The limitations of this study include a lack of adherence to group assignment , disproportionate therapist contact time among treatment groups , and multiple use of univariate analyses . Conclusions An intensive , progressive exercise program combined with education reduces disability and improves function in patients who have undergone a single-level lumbar microdiskectomy

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### Context: [16291467] BACKGROUND AND OBJECTIVE To develop a checklist of items measuring the quality of reports of r and omized clinical trials ( RCTs ) assessing nonpharmacological treatments ( NPTs ) . STUDY DESIGN AND SETTING The Delphi consensus method was used to select and reduce the number of items in the checklist . A total of 154 individuals were invited to participate : epidemiologists and statisticians involved in the field of methodology of RCTs ( n = 55 ) , members of the Cochrane Collaboration ( n = 41 ) , and clinicians involved in planning NPT clinical trials ( n = 58 ) . Participants ranked on a 10-point Likert scale whether an item should be included in the checklist . RESULTS Fifty-five experts ( 36 % ) participated in the survey . They were experienced in systematic review s ( 68 % were involved in the Cochrane Collaboration ) and in planning RCTs ( 76 % ) . Three rounds of the Delphi method were conducted to achieve consensus . The final checklist contains 10 items and 5 subitems , with items related to the st and ardization of the intervention , care provider influence , and additional measures to minimize the potential bias from lack of blinding of participants , care providers , and outcome assessors . CONCLUSIONS This tool can be used to critically appraise the medical literature , design NPT studies , and assess the quality of trial reports included in systematic review [7895394] OBJECTIVE We performed a r and omised trial to evaluate if intensive supervised training of the back should be offered to all patients after a first lumbar diskectomy . METHODS Forty consecutive patients were , after a first lumbar diskectomy , r and omly allocated to 2 groups undergoing " supervised training " twice a week for 3 months in an outpatient clinic or " home training " after 2 hours of instruction . RESULTS The two rehabilitation models both showed a significant effect on spinal mobility , isokinetic trunk flexion strength , isokinetic trunk extension strength and daily function . These improvements were unchanged at follow up 3 months later . The pain score remained unchanged , however , throughout the trial in both groups . No differences in effect between the two rehabilitation models could be found for any of the assessed parameters . Thirteen patients did not complete the trial , including 9 from the supervised endurance trained group , mainly because of increased pain and reprolaps ( n = 4 ) . Four patients dropped out of the home trained group , only one because of increased pain . The differences in drop-out rate and training side effects were , however , not statistically significant . CONCLUSION We conclude that it is not worthwhile to implement 3 months of supervised intensive endurance training as opposed to home training in all cases of first lumbar diskectomy , although a beneficial effect and better compliance might be found for a selected group of such patients [20680372] As the average life expectancy of the population increases , surgical decompression of the lumbar spine is being performed with increasing frequency . It now constitutes the most common type of lumbar spinal surgery in older patients . The present prospect i ve study examined the 5-year outcome of lumbar decompression surgery without fusion . The group comprised 159 patients undergoing decompression for degenerative spinal disorders who had been participants in a r and omised controlled trial of post-operative rehabilitation that had shown no between-group differences at 2 years . Leg pain and back pain intensity ( 0–10 graphic rating scale ) , self-rated disability ( Rol and Morris ) , global outcome of surgery ( 5-point Likert scale ) and re-operation rates were assessed 5 years post-operatively . Ten patients had died before the 5-year follow-up . Of the remaining 149 patients , 143 returned a 5-year follow-up ( FU ) question naire ( effective return rate excluding deaths , 96 % ) . Their mean age was 64 ( SD 11 ) years and 92/143 ( 64 % ) were men . In the 5-year follow-up period , 34/143 patients ( 24 % ) underwent re-operation ( 17 further decompressions , 17 fusions and 1 intradural drainage/debridement ) . In patients who were not re-operated , leg pain decreased significantly ( p < 0.05 ) from before surgery to 2 months FU , after which there was no significant change up to 5 years . Low back pain also decreased significantly by 2 months FU , but then showed a slight , but significant ( p < 0.05 ) , gradual increase of < 1 point by 5-year FU . Disability decreased significantly from pre-operative to 2 months FU and showed a further significant decrease at 5 months FU . Thereafter , it remained stable up to the 5-year FU . Pain and disability scores recorded after 5 years showed a significant correlation with those at earlier follow-ups ( r = 0.53–0.82 ; p < 0.05 ) . Patients who were re-operated at some stage over the 5-year period showed significantly worse final outcomes for leg pain and disability ( p < 0.05 ) . In conclusion , pain and disability showed minimal change in the 5-year period after surgery , but the re-operation rate was relatively high . Re-operation result ed in worse final outcomes in terms of leg pain and disability . At the 5-year follow-up , the “ average ” patient experienced frequent , but relatively low levels of , pain and moderate disability . This knowledge on the long-term outcome should be incorporated into the pre-operative patient information process [17119140] CONTEXT Lumbar diskectomy is the most common surgical procedure performed for back and leg symptoms in US patients , but the efficacy of the procedure relative to nonoperative care remains controversial . OBJECTIVE To assess the efficacy of surgery for lumbar intervertebral disk herniation . DESIGN , SETTING , AND PATIENTS The Spine Patient Outcomes Research Trial , a r and omized clinical trial enrolling patients between March 2000 and November 2004 from 13 multidisciplinary spine clinics in 11 US states . Patients were 501 surgical c and i date s ( mean age , 42 years ; 42 % women ) with imaging-confirmed lumbar intervertebral disk herniation and persistent signs and symptoms of radiculopathy for at least 6 weeks . INTERVENTIONS St and ard open diskectomy vs nonoperative treatment individualized to the patient . MAIN OUTCOME MEASURES Primary outcomes were changes from baseline for the Medical Outcomes Study 36-item Short-Form Health Survey bodily pain and physical function scales and the modified Oswestry Disability Index ( American Academy of Orthopaedic Surgeons MODEMS version ) at 6 weeks , 3 months , 6 months , and 1 and 2 years from enrollment . Secondary outcomes included sciatica severity as measured by the Sciatica Bothersomeness Index , satisfaction with symptoms , self-reported improvement , and employment status . RESULTS Adherence to assigned treatment was limited : 50 % of patients assigned to surgery received surgery within 3 months of enrollment , while 30 % of those assigned to nonoperative treatment received surgery in the same period . Intent-to-treat analyses demonstrated substantial improvements for all primary and secondary outcomes in both treatment groups . Between-group differences in improvements were consistently in favor of surgery for all periods but were small and not statistically significant for the primary outcomes . CONCLUSIONS Patients in both the surgery and the nonoperative treatment groups improved substantially over a 2-year period . Because of the large numbers of patients who crossed over in both directions , conclusions about the superiority or equivalence of the treatments are not warranted based on the intent-to-treat analysis . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00000410 [7997919] Study Design This was a study of a st and ardized functional restoration program that included 11 centers in saven states , involving 303 patients in the treatment group and 94 patients in the comparison group . Objective To illustrative the positive effect a functional restoration program has on return to work rates and work retention regardless of previous surgical intervention . Summary of Background Data Data were obtained from the initial and discharge evaluations as well as at 6− and 12-month follow-up . Methods Patients received a st and ardized work capacity assessment upon entrance and were recommended to the program if they adhered to specific entrance criteria . Treatment patients received the same evaluation at discharge . Results Significant improvement in functional abilities , actual return to work , and work retention were noted in the treatment group regardless of treatment intervention . Conclusions This study demonstrated improved return to work rates and work retention with surgical and nonsurgical patients after their participation in a functional restoration program [17538084] BACKGROUND Lumbar-disk surgery often is performed in patients who have sciatica that does not resolve within 6 weeks , but the optimal timing of surgery is not known . METHODS We r and omly assigned 283 patients who had had severe sciatica for 6 to 12 weeks to early surgery or to prolonged conservative treatment with surgery if needed . The primary outcomes were the score on the Rol and Disability Question naire , the score on the visual-analogue scale for leg pain , and the patient 's report of perceived recovery during the first year after r and omization . Repeated- measures analysis according to the intention-to-treat principle was used to estimate the outcome curves for both groups . RESULTS Of 141 patients assigned to undergo early surgery , 125 ( 89 % ) underwent microdiskectomy after a mean of 2.2 weeks . Of 142 patients design ated for conservative treatment , 55 ( 39 % ) were treated surgically after a mean of 18.7 weeks . There was no significant overall difference in disability scores during the first year ( P=0.13 ) . Relief of leg pain was faster for patients assigned to early surgery ( P<0.001 ) . Patients assigned to early surgery also reported a faster rate of perceived recovery ( hazard ratio , 1.97 ; 95 % confidence interval , 1.72 to 2.22 ; P<0.001 ) . In both groups , however , the probability of perceived recovery after 1 year of follow-up was 95 % . CONCLUSIONS The 1-year outcomes were similar for patients assigned to early surgery and those assigned to conservative treatment with eventual surgery if needed , but the rates of pain relief and of perceived recovery were faster for those assigned to early surgery . ( Current Controlled Trials number , IS RCT N26872154 [ controlled-trials.com ] . ) [18758356] Study Design . We r and omized 200 patients after lumbar discectomy to receive epidural steroid or none with a 2-year follow-up . Objective . To evaluate the outcome , neurologic impairment and safety of epidural steroid following lumbar discectomy for herniated disc disease . Summary of Background Data . Convalescence after discectomy for herniated disc disease is dependent on pain and the inflammatory response . Previous studies in arthroscopic and abdominal surgery demonstrate steroids , which reduce the inflammatory response and enhance recovery . Here we report a 2-year follow-up of a r and omized trial of epidural steroid following lumbar discectomy . Methods . Through 2001 and 2003 200 patients undergoing discectomy for herniated disc disease were r and omly allocated to receive epidural methylprednisolone 40 mg or none . In the control group ( 62 males and 38 females , median age 41 years , 18–66 ) 48 L5 , 50 L4 , and 6 L3 discectomies were performed and in the intervention group ( 60 males and 40 females , median age 45 years , 15–53 ) 56 L5 , 46 L4 , and 3 L3 discectomies . Contemporary with r and omization to epidural steroid or none both groups received preoperative prophylactic antibiotics and the same multimodal pain treatment . Results . Hospital stay was reduced from 8 to 6 days ( P = 0.0001 ) and the number of patients with neurologic signs were reduced more ( 70 % vs. 44 % , P = 0.0004 ) by epidural steroid . Incidence of reoperation at 1 year was 6 % in both groups and 8 % in the control group and 7 % in the intervention group after 2 years . No infections were registered . Conclusion . Epidural methylprednisolone enhances recovery after discectomy for herniated disc disease without apparent side effects [17762803] Study Design . Three-group , r and omized , single blinded , controlled trial . Objective . To test the effectiveness of physiotherapy-based rehabilitation starting 1 week after lumbar disc surgery . In addition , we tried to estimate the contribution of specific effects to the observed outcome ( efficacy ) . Summary of Background Data . Physiotherapy-based rehabilitation is usually recommended for patients following lumbar disc surgery . Few and conflicting data exist for the relative effectiveness of this intervention . Methods . A total of 120 patients following first-time , uncomplicated lumbar disc surgery were r and omly assigned to “ comprehensive ” physiotherapy , “ sham ” neck massage , or no therapy . Before enrollment , all subjects completed a minimal physiotherapeutic intervention . Physiotherapy was administered by experienced physiotherapists and consisted of 20 sessions per patient over 12 weeks . Masseurs administered “ sham massage ” to the neck . The amount of treatment time was equal to that of physiotherapy . The main outcome measure was the Low Back Pain Rating Score ( LBPRS ) at 6 and 12 weeks , and 1.5 years after r and omization . Secondary parameters were patients ' overall satisfaction with treatment outcome and socioeconomic and psychologic measures . Results . At the end of therapy ( 12 weeks ) , the LBPRS revealed a significantly better improvement in the physiotherapy group than in the untreated group . LBPRS outcome , however , did not significantly differ between physiotherapy and “ sham ” therapy . There was a tendency toward significance between the sham therapy and no therapy . Within the 1.5-year follow-up , LBP rating scales remained significantly improved compared with baseline , but there were no significant outcome differences . No statistically significant between-group differences were found for the secondary outcome parameters . Conclusion . As compared with no therapy , physiotherapy following first-time disc herniation operation is effective in the short-term . Because of the limited benefits of physiotherapy relative to “ sham ” therapy , it is open to question whether this treatment acts primarily physiologically in patients following first-time lumbar disc surgery , but psychological factors may contribute substantially to the benefits observed [16239890] OBJECTIVE : To determine the effects of a postoperative early isolated lumbar extension muscle-strengthening program on pain , disability , return to work , and power of back muscle after operation for herniated lumbar disc . METHODS : Seventy-five patients were r and omized into an exercise group ( 20 men , 15 women ) and a control group ( 18 men , 22 women ) to perform a prospect i ve controlled trial of a lumbar extension exercise program in patients who underwent lumbar microdiscectomy or percutaneous endoscopic discectomy . Six weeks after surgery , patients in the exercise group undertook a 12-week lumbar extension exercise program . The assessment included measures of lumbar extensor power by the MedX ( Ocala , FL ) lumbar extension machine , muscle mass of multifidus and longissimus ( L4–L5 cross-sectional area ) by computed tomography . All patients completed the visual analog scale and the Oswestry disability index to assess pain and disability , respectively . Return to work data were also investigated . RESULTS : After the exercise program , significant improvements were observed in the exercise group versus the control group for lumbar extensor power ( 51.67 % versus 17.55 % , respectively ; P < 0.05 ) , the cross-sectional area of multifidus and longissimus muscle ( 29.23 % versus 7.2 % , respectively ; P < 0.05 ) , and the visual analog scale score ( 2.51 versus 4.30 , respectively ; P < 0.05 ) . The percentages of returning to work within 4 months after surgery were significantly greater in the exercise group than in the control group ( 87 % versus 24 % , respectively ) . Although this was not statistically significant ( P > 0.05 ) , the Oswestry disability index scores in the exercise group were better than that in control group ( 24.6 versus 30.6 , respectively ) . CONCLUSION : These results support the positive effects of the postoperative early lumbar extension muscle-strengthening program on pain , return to work , and strength of back muscles in patients after operation of herniated lumbar disc [16421747] A prospect i ve and controlled study of training after surgery for lumbar disc herniation ( LDH ) . The objective was to determine the effect of early neuromuscular customized training after LDH surgery . No consensus exists on the type and timing of physical rehabilitation after LDH surgery . Patients aged 15–50 years , disc prolapse at L4–L5 or L5–S1 . Before surgery , at 6 weeks , 4 , and 12 months postoperatively , the following evaluations were performed : low back pain and leg pain estimated on a visual analog scale , disability according to the Rol and –Morris question naire ( RMQ ) and disability rating index ( DRI ) . Clinical examination , including the SLR test , was performed using a single blind method . Consumption of analgesics was registered . Twenty-five patients started neuromuscular customized training 2 weeks after surgery ( early training group = ETG ) . Thirty-one patients formed a control group ( CG ) and started traditional training after 6 weeks . There was no significant difference in pain and disability between the two training groups before surgery . Median preoperative leg pain was 63 mm in ETG and 70 mm in the CG . Preoperative median disability according to RMQ was 14 in the ETG and 14.5 in the CG . Disability according to DRI ( 33/56 patients ) was 5.3 in the ETG vs. 4.6 in the CG . At 6 weeks , 4 months , and 12 months , pain was significantly reduced in both groups , to the same extent . Disability scores were lower in the ETG at all follow-ups , and after 12 months , the difference was significant ( RMQ P=.034 , DRI P=.015 ) . The results of the present study show early neuromuscular customized training to have a superior effect on disability , with a significant difference compared to traditional training at a follow-up 12 months after surgery . No adverse effects of the early training were seen . A prospect i ve , r and omized study with a larger patient sample is warranted to ultimately demonstrate that early training as described is beneficial for patients undergoing LDH surgery [11728081] In a r and omized study , using psychometric assessment , we evaluated two training programs before and after surgical treatment of lumbar disc herniation . 26 patients were treated according to an early active training program ( treatment group ) . 24 patients followed a traditional less active training program ( control group ) . Before surgery , the patients filled in the following question naires 3 and 12 months after surgery : Multidimensional Pain Inventory ( MPI ) , State and Trait Anxiety Inventory , and Beck Depression Inventory . Pain was assessed by the patient 's pain drawing and a visual analog scale . Both groups improved as regards pain severity and state of anxiety . The MPI parameter , pain interference , improved more in the early active treatment group than in the control group . This suggests that the early active training program has a positive effect on the way patients cope with pain in their daily lives [15704503] Objective : To compare two different exercise programmes versus a control group , after lumbar disc surgery . Design : A prospect i ve , single-blind , r and omized controlled study . Setting : Outpatient clinic of Istanbul Faculty of Medicine , Department of Physical Medicine and Rehabilitation . Subjects : Sixty patients diagnosed as having single level lumbar disc herniation with clinical examination and MRI evaluation and who had undergone lumbar discectomy ( post-operative first month ) at a single level . Patients with serious pathologies involving the cardiac and respiratory systems that could prevent them from doing exercises were excluded . Intervention : The patients were r and omly split into three groups . The first group received an intensive exercise programme and back school education while the second group received a home exercise programme and back school education . The third group was defined as the control group and did not receive education or exercise . Main measures : The patients were evaluated at the beginning and end of the treatment with clinical parameters , pain levels , endurance tests and weight-lifting tests , modified Oswestry Disability Index , Beck Depression Inventory , Low Back Pain Rating Scale and return to work . Results : The groups doing exercises experienced a decrease in the severity of pain and disability , also functional parameters showed better improvement than the control group . The intensive exercise programme was better than the home exercise programme . Conclusions : It seems that intensive exercise is more effective in reduction of pain and disability , but whether it is cost-effective is not clear [10214482] Summary Objective . Lumbar discectomy is a common elective surgical procedure but many patients still experience postoperative back pain which may delay hospital discharge . We therefore evaluated the efficacy of a parenteral non-steroidal antiinflammatory agent , ketorolac , for the management of post-surgical pain . Methods . Fifty three patients undergoing lumbar discectomy at a Medical School affiliated Veterans Administration hospital were r and omly assigned to receive either : 1 ) 30 mg intramuscular ketorolac upon surgical closure and every 6 hours for 36 hours and narcotic analgesics as needed ( PRN ) ; or 2 ) only narcotic analgesics as needed . A blinded observer recorded the average , minimum and maximum postoperative pain intensity using a Numeric Pain Intensity Scale ; total postoperative narcotic consumption , complications , length of hospitalization ( from surgery to discharge ) and outcome at 6 weeks . Results . The patients who received ketorolac reported significantly lower average ( p<0.001 ) , minimum ( p<0.001 ) , and maximum ( p<0.001 ) pain scores than patients receiving only narcotic analgesics . Cumulative narcotic doses ( st and ardized to parenteral morphine ) were significantly lower in the ketorolac group ( p < 0.001 ) . There was no significant difference between groups in the frequency of side effects , and no complication specifically associated with ketorolac use was observed . Mean length of hospitalization was significantly shorter ( p=0.05 ) in patients receiving ketorolac than in patients receiving only narcotics . Six weeks after surgery 5 ( 19.2 % ) patients who received only narcotics were troubled by persistent back pain . By contrast , all patients who received ketorolac were free of back pain at follow-up ( p=0.03 ) . Conclusions . These results suggest that ketorolac , when used with PRN narcotics , is more effective than PRN narcotics alone for postoperative pain following lumbar disc surgery . In addition , this strategy also may contribute to early discharge from hospital after lumbar disc surgery [18427312] Study Design . Prospect i ve , r and omized , controlled study of patients with lumbar disc herniations , operated either in a full-endoscopic or microsurgical technique . Objective . Comparison of results of lumbar discectomies in full-endoscopic interlaminar and transforaminal technique with the conventional microsurgical technique . Summary of Background Data . Even with good results , conventional disc operations may result in subsequent damage due to trauma . Endoscopic techniques have become the st and ard in many areas because of the advantages they offer intraoperatively and after surgery . With the transforaminal and interlaminar techniques , 2 full-endoscopic procedures are available for lumbar disc operations . Methods . One hundred seventy-eight patients with full-endoscopic or microsurgical discectomy underwent follow-up for 2 years . In addition to general and specific parameters , the following measuring instruments were used : VAS , German version North American Spine Society Instrument , Oswestry Low-Back Pain Disability Question naire . Results . After surgery 82 % of the patients no longer had leg pain , and 14 % had occasional pain . The clinical results were the same in both groups . The recurrence rate was 6.2 % with no difference between the groups . The full-endoscopic techniques brought significant advantages in the following areas : back pain , rehabilitation , complications , and traumatization . Conclusion . The clinical results of the full-endoscopic technique are equal to those of the microsurgical technique . At the same time , there are advantages in the operation technique and reduced traumatization . With the surgical devices and the possibility of selecting an interlaminar or posterolateral to lateral transforaminal procedure , lumbar disc herniations outside and insidethe spinal canal can be sufficiently removed using the full-endoscopic technique , when taking the appropriate criteria into account . Full-endoscopic surgery is a sufficient and safe supplementation and alternative to microsurgical procedures [19892091] OBJECTIVE To investigate whether immediate commencement of exercises after lumbar microdiscectomy enabled patients to become independently mobile more rapidly with no increase in risk of complications . STUDY DESIGN R and omised , single-blind , controlled trial . SETTING One secondary care teaching hospital in the UK . PARTICIPANTS Thirty patients were recruited . The follow-up rate was 28 ( 93 % ) at 4 weeks and 23 ( 77 % ) at 3 months . INTERVENTIONS Patients were r and omised to an intervention group commencing exercises within 2 hours after surgery , or a control group commencing exercises on the first postoperative day . MAIN OUTCOME MEASURES Primary outcome measures included the time taken for the patient to become independently mobile and attain discharge criteria following surgery . Secondary outcome measures were disability and pain scores collected before surgery , and 4 weeks and 3 months after surgery ; and return to work rates . RESULTS The two groups were similar at baseline . The results indicated significantly reduced time to independent mobility [ median 7 vs 19 hours , median difference 9 hours , 95 % confidence interval ( CI ) 1.25 to 14.5 , P=0.009 ] and return to work ( median 6 vs 8 weeks , median difference 2 weeks , 95 % CI 0 to 6 , P=0.002 ) in the intervention group compared with the control group . At 15 hours after surgery , independent mobility was attained in 80 and 40 % of the intervention and control groups , respectively . There were no significant differences in disability and pain scores at 4 weeks and 3 months . CONCLUSIONS Immediate commencement of exercises following first-time single-level lumbar microdiscectomy enabled patients to become independently mobile more rapidly and return to work sooner . Immediate commencement of exercises may enable patients to be discharged earlier , with associated cost benefits to health care and no increase in the rate of revision surgery [20639806] AIM A considerable number of patients who undergo surgery for a lumbosacral radicular syndrome ( LRS ) continue to experience disability , pain , and loss of work capacity . The goal of the study is to develop a brief screening instrument to identify these patients at risk of residual complaints . METHODS In a prospect i ve study of 277 patients , the predictors for the outcomes disability , pain , and loss of work capacity were investigated . The best predictive model was constructed using a stepwise selection procedure ( forward selection ) , which calculates the discriminative power of the model . Based on the relationship between regression coefficients , a clinical prediction rule was derived that predicted the probability of residual complaints after surgery for LRS . RESULTS At 6 month follow-up 141 patients ( 51 % ) had residual complaints . The discriminative power of the instrument was .78 ( AUC ) . The " Nijmegen Outcome of Lumbar Disc surgery Screening-instrument " ( NOLDS ) was based on the variables " lower education level " , " younger age " , " pain 3 days postoperatively " , " passive pain coping " , and " fear of movement/(re)injury " . CONCLUSION The results of the study are promising , showing that a brief clinical screening instrument can be used to identify patients at risk of residual complaints at 6 months after surgery for LRS . The early identification of patients at risk having residual complaints may make it possible to start tailored treatment early in the rehabilitation process [1599723] Background Low back pain remains a costly quality -of-life-related health problem . Microdiscectomy is often the surgical procedure of choice for a symptomatic , single-level , lumbar disc herniation in younger and middle-aged adults . The question of whether a post-microdiscectomy exercise program enhances function , quality of life , and disability status has not been systematic ally explored . Thus , the overall purpose of this study is to assess immediate and long-term outcomes of an exercise program , developed at University of Southern California ( USC ) , targeting the trunk and lower extremities ( USC Spine Exercise Program ) for persons who have undergone a single-level microdiscectomy for the first time . Methods / design One hundred individuals between the ages of 18 and 60 who consent to undergo lumbar microdiscectomy will be recruited to participate in this study . Subjects will be r and omly assigned to one of two groups : 1 ) one session of back care education , or 2 ) a back care education session followed by the 12-week USC Spine Exercise Program . The outcome examiners ( evaluators ) , as well as the data managers , will be blinded to group allocation . Education will consist of a one-hour " one-on-one " session with the intervention therapist , guided by an educational booklet specifically design ed for post-microdiscectomy care . This session will occur four to six weeks after surgery . The USC Spine Exercise Program consists of two parts : back extensor strength and endurance , and mat and upright therapeutic exercises . This exercise program is goal -oriented , performance-based , and periodized . It will begin two to three days after the education session , and will occur three times a week for 12 weeks . Primary outcome measures include the Oswestry Disability Question naire , Rol and -Morris Disability Question naire , SF-36 ® quality of life assessment , Subjective Quality of Life Scale , 50-foot Walk , Repeated Sit-to-St and , and a modified Sorensen test . The outcome measures in the study will be assessed before and after the 12-week post-surgical intervention program . Long-term follow up assessment s will occur every six months beginning one year after surgery and ending five years after surgery . Immediate and long-term effects will be assessed using repeated measures multivariate analysis of variance ( MANOVA ) . If significant interactions are found , one-way ANOVAs will be performed followed by post-hoc testing to determine statistically significant pairwise comparisons . Discussion We have presented the rationale and design for a r and omized controlled trial evaluating the effectiveness of a treatment regimen for people who have undergone a single-level lumbar microdiscectomy [20159123] OBJECTIVE To compare the effects of aquatic backward locomotion exercise and progressive resistance exercise with a machine on lumbar extension strength in patients who have undergone diskectomy for a lumbar disk herniation . DESIGN Prospect i ve comparative study . SETTING Department of Kinesiology at a state university . PARTICIPANTS Male patients ( N=30 ) with disk herniation at spinal levels L3 to S1 completed this study as subjects . INTERVENTION After the diskectomy for a lumbar disk herniation , all patients had 6 weeks of rest time . At the end of the rest period , the aquatic backward locomotion exercise and progressive resistance exercise groups , respectively , started first 6 weeks of underwater training and lumbar extension training twice per week . After completion of the first 6-week training , subjects participated in a second 6-week training . After the whole 12-week training , subjects had no training for 6 weeks ( detraining ) and a follow-up 6-week training ( retraining ) . The control ( CON ) group did not undergo any training . MAIN OUTCOME MEASURES For each test , maximum voluntary isometric lumbar extension strength was measured in 7 trunk positions ( 72 degrees , 60 degrees , 48 degrees , 36 degrees , 24 degrees , 12 degrees , and 0 degrees of the trunk angle ) . RESULTS The progressive resistance exercise and aquatic backward locomotion exercise groups showed increases in lumbar extension strength after the first 6-week training , although they were not statistically different from the CON group . After a second 6-week training , the progressive resistance exercise and aquatic backward locomotion exercise groups showed statistically significant increases in their strength levels as compared with the CON group . After the detraining period , the strength levels of the progressive resistance exercise and aquatic backward locomotion exercise groups did not statistically differ from the CON group . After the retraining period , the progressive resistance exercise and aquatic backward locomotion exercise groups showed increases in their strength levels , which were different from that of the CON group . CONCLUSIONS The results obtained suggested that the aquatic backward locomotion exercise is as beneficial as progressive resistance exercise for improving lumbar extension strength in patients after lumbar diskectomy surgery [2586633] Abstract During the recent years improved operation techniques and administrative procedures have been developed for early rehabilitation . At the same time preoperative lifestyle intervention ( prehabilitation ) has revealed a large potential for additional risk reduction . The aim was to assess the quality of life and to estimate the cost-effectiveness of st and ard care versus an integrated programme including prehabilitation and early rehabilitation . Methods The analyses were based on the results from 60 patients undergoing lumbar fusion for degenerative lumbar disease ; 28 patients were r and omised to the integrated programme and 32 to the st and ard care programme . Data on cost and health related quality of life was collected preoperatively , during hospitalisation and postoperatively . The cost was estimated from multiplication of the re source consumption and price per unit . Results Overall there was no difference in health related quality of life scores . The patients from the integrated programme obtained their postoperative milestones sooner , returned to work and soaked less primary care after discharge . The integrated programme was 1,625 € ( direct costs 494 € + indirect costs 1,131 € ) less costly per patient compared to the st and ard care programme . Conclusion The integrated programme of prehabilitation and early rehabilitation in spine surgery is more cost-effective compared to st and ard care programme alone [10327508] STUDY DESIGN An intervention study by the medical advisers of a social security sickness fund on a m and atorily insured patient population after open discectomy for herniated lumbar intervertebral disc . The medical advisers were r and omized into two groups : a control group ( n = 30 ) and an intervention group ( n = 30 ) . OBJECTIVES To compare a rehabilitation-oriented approach in insurance medicine focused primarily on early mobilization and early resumption of professional activities with the usual cl aim -based practice . SUMMARY OF BACKGROUND DATA This study included 710 patients , with a mean age of 39.2 years , who underwent surgery for herniated lumbar disc . METHODS Medical advisers in the rehabilitation-oriented group examined the patients monthly , starting at 6 weeks after the surgical intervention . They used a newly developed protocol to motivate the patients and treating physicians toward social and professional reintegration . RESULTS At 52 weeks , 10.1 % of the patients guided by medical advisers from the rehabilitation-oriented group had not resumed work in contrast to 18.1 % of the patients in the control group . It was statistically proven that this effect also holds during the follow-up period . CONCLUSIONS A rehabilitation-oriented approach by the medical advisers of social security can increase the probability of a return to work for patients after lumbar disc herniation surgery [11740347] STUDY DESIGN R and omized controlled trial with 12-month follow-up . OBJECTIVES To determine whether the addition of neural mobilization to st and ard postoperative care improved the outcome of lumbar spinal surgery . SUMMARY OF BACKGROUND DATA It has been suggested that neural mobilization should be performed after spinal surgery to prevent nerve root adhesions and improve outcome . However , to date , there is no convincing evidence of the value of neural mobilization . METHODS Eighty-one patients undergoing lumbar discectomy , fusion , or laminectomy at a private hospital in Sydney were r and omly allocated to st and ard postoperative care or st and ard care plus neural mobilization . Neural mobilization included passive movements and active exercises design ed to mobilize the lumbosacral nerve roots and sciatic tract . Primary outcome measures were global perceived effect measured on a 7-point scale , pain measured using visual analogue scales and the McGill Pain Question naire , and disability measured with the Quebec Disability Scale . RESULTS All patients received the treatment as allocated with 12-month follow-up data available for 76 patients ( 94 % of those r and omized ) . There were no statistically significant or clinical ly significant benefits provided by the neural mobilization treatment for any outcome . CONCLUSIONS The neural mobilization protocol evaluated in this study did not provide an additional benefit to st and ard postoperative care for patients undergoing spinal surgery . The authors advocate that this protocol not be used in clinical practice [19020904] The effectiveness of physiotherapy after first-time lumbar disc surgery is still largely unknown . Studies in this field are heterogeneous and behavioural treatment principles have only been evaluated in one earlier study . The aim of this r and omised study was to compare clinic-based physiotherapy with a behavioural approach to a home-based training programme regarding back disability , activity level , behavioural aspects , pain and global health measures . A total of 59 lumbar disc patients without any previous spine surgery or comorbidity participated in the study . Clinic-based physiotherapy with a behavioural approach was compared to home-based training 3 and 12 months after surgery . Additionally , the home training group was followed up 3 months after surgery by a structured telephone interview evaluating adherence to the exercise programme . Outcome measures were : Oswestry Disability Index ( ODI ) , physical activity level , kinesiophobia , coping , pain , quality of life and patient satisfaction . Treatment compliance was high in both groups . There were no differences between the two groups regarding back pain disability measured by ODI 3 and 12 months after surgery . However , back pain reduction and increase in quality of life were significantly higher in the home-based training group . The patients in the clinic-based training group had significantly higher activity levels 12 months after surgery and were significantly more satisfied with physiotherapy care 3 months after surgery compared to the home-based training group . Rehabilitation after first-time lumbar disc surgery can be based on home training as long as the patients receive both careful instructions from a physiotherapist and strategies for active pain coping , and have access to the physiotherapist if questions regarding training arise . This might be a convenient treatment arrangement for most patients [1607978] Intraoperative epidural corticosteroids have been used by some surgeons to decrease pain following surgery for a herniated lumbar disc . In this study , 84 consecutively treated , comparable patients with unilateral lumbar disc herniation were prospect ively assigned r and omly to receive either epidural corticosteroids ( 40 mg methylprednisolone acetate ) or saline at the conclusion of the operative procedure . The postoperative morbidity of these two groups was evaluated by tabulating the following parameters : pain relief as measured by consumption of postoperative pain medications ; the length of hospital stay ; postoperative functional status ; and the time interval from surgery until return to work . The mean postoperative analgesic medications consumed was 12.2 + /- 1.9 mg of morphine equivalents in the corticosteroid group versus 12.2 + /- 1.8 mg of morphine equivalents in the control group . The mean hospital stay was less than 2 days in each group , and the mean interval until return to work was 21.2 + /- 2.7 days in the corticosteroid group versus 25.4 + /- 3.1 days in the control group . Moreover , no statistically significant difference was measured between the steroid-treated and control groups when the data were stratified for sex , age , and site of disc herniation . The mean outcome scores , which are derived from a postoperative assessment of pain relief result ing from surgery , functional status , and interval until return to work , were identical in the corticosteroid and control groups . This study concludes that epidural corticosteroid administration after microsurgical lumbar discectomy for unilateral disc herniation does not lessen postoperative morbidity or improve functional recovery [14505118] Behavioral approaches to treating patients following lumbar disc surgery are becoming increasingly popular . The treatment method is based on the assumption that pain and pain disability are not only influenced by somatic pathology , if found , but also by psychological and social factors . A recent study highlighted the effectiveness of cognitive-behavioral interventions , as compared to no treatment , for chronic low back patients . However , to the authors ' knowledge , there is no r and omized controlled trial that evaluates a behavioral program for patients following lumbar disc surgery . The purpose of this study was to assess the effectiveness of a behavioral grade d activity ( BGA ) program compared to usual care ( UC ) in physiotherapy following first-time lumbar disc surgery . The BGA program was a patient-tailored intervention based upon operant therapy . The essence of the BGA is to teach patients that it is safe to increase activity levels . The study was design ed as a r and omized controlled trial . Assessment s were carried out before and after treatment by an observer blinded to treatment allocation . Patients suffering residual symptoms restricting their activities of daily living and /or work at the 6 weeks post-surgery consultation by the neurosurgeon were included . The exclusion criteria were : complications during surgery , any relevant underlying pathology , and any contraindication to physiotherapy or the BGA program . Primary outcome measures were the patient 's Global Perceived Effect and the functional status . Secondary measures were : fear of movement , viewing pain as extremely threatening , pain , severity of the main complaint , range of motion , and relapses . Physiotherapists in the BGA group received proper training . Between November 1997 and December 1999 , 105 patients were r and omized ; 53 into the UC group and 52 into the BGA group . The unadjusted analysis shows a 19.3 % ( 95 % CI : 0.1 to 38.5 ) statistically significant difference to the advantage of the UC group on Global Perceived Effect . This result , however , is not robust , as the adjusted analyses reveal a difference of 15.7 % ( 95 % CI : −3.9 to 35.2 ) , which is not statistically significant . For all other outcome measures there were no statistically significant or clinical ly relevant differences between the two intervention groups . In general , the physiotherapists ' compliance with the BGA program was satisfactory , although not all treatments , either in the BGA or the UC group , were delivered exactly as planned , result ing in less contrast between the two interventions than had been planned for . There was one re-operation in each group . The BGA program was not more effective than UC in patients following first-time lumbar disc surgery . For Global Perceived Effect there was a borderline statistically significant difference to the advantage of the UC group . On functional status and all other outcome measures there were no relevant differences between interventions . The number of re-operations was negligible , indicating that it is safe to exercise after first-time disc surgery [8434331] Ninety-six patients who had undergone first-time discectomy for herniated lumbar intervertebral discs were consecutively r and omized to two physical rehabilitation programs : a program of high-intensity , dynamic back extension and abdominal exercises with occurrence of low back pain being the limiting factor or a traditional program of mild , generally mobilityimproving exercises within pain limits . Both groups underwent 14 hours of treatment during a 6-week period 5 weeks after surgery . At 26 weeks ' follow-up , results indicated that patients who did the high-intensity exercises experienced greater success with regard to the patient disabilityindex and work capabilities . After 1 year , a trend that favored the use of intensive exercises could be observed . No differences were found in pain or objective measurements . A rehabilitation program of intensive exercises with occurrence of back pain being the limiting factor appears to increase patient behavioral support , result ing in work capacity improvements and patient self-rated disability levels . The results indicate that a 6-wk , 14-hr postoperative rehabilitation program is inadequate if objective postoperative deficit improvements are the desired goal [19584344] CONTEXT Conventional microdiskectomy is the most frequently performed surgery for patients with sciatica due to lumbar disk herniation . Transmuscular tubular diskectomy has been introduced to increase the rate of recovery , although evidence is lacking of its efficacy . OBJECTIVE To determine outcomes and time to recovery in patients treated with tubular diskectomy compared with conventional microdiskectomy . DESIGN , SETTING , AND PATIENTS The Sciatica Micro-Endoscopic Diskectomy r and omized controlled trial was conducted among 328 patients aged 18 to 70 years who had persistent leg pain ( > 8 weeks ) due to lumbar disk herniations at 7 general hospitals in The Netherl and s from January 2005 to October 2006 . Patients and observers were blinded during the follow-up , which ended 1 year after final enrollment . INTERVENTIONS Tubular diskectomy ( n = 167 ) vs conventional microdiskectomy ( n = 161 ) . MAIN OUTCOME MEASURES The primary outcome was functional assessment on the Rol and -Morris Disability Question naire ( RDQ ) for sciatica ( score range : 0 - 23 , with higher scores indicating worse functional status ) at 8 weeks and 1 year after r and omization . Secondary outcomes were scores on the visual analog scale for leg pain and back pain ( score range : 0 - 100 mm ) and patient 's self-report of recovery ( measured on a Likert 7-point scale ) . RESULTS Based on intention-to-treat analysis , the mean RDQ score during the first year after surgery was 6.2 ( 95 % confidence interval [ CI ] , 5.6 to 6.8 ) for tubular diskectomy and 5.4 ( 95 % CI , 4.6 to 6.2 ) for conventional microdiskectomy ( between-group mean difference , 0.8 ; 95 % CI , -0.2 to 1.7 ) . At 8 weeks after surgery , the RDQ mean ( SE ) score was 5.8 ( 0.4 ) for tubular diskectomy and 4.9 ( 0.5 ) for conventional microdiskectomy ( between-group mean difference , 0.8 ; 95 % CI , -0.4 to 2.1 ) . At 1 year , the RDQ mean ( SE ) score was 4.7 ( 0.5 ) for tubular diskectomy and 3.4 ( 0.5 ) for conventional microdiskectomy ( between-group mean difference , 1.3 ; 95 % CI , 0.03 to 2.6 ) in favor of conventional microdiskectomy . On the visual analog scale , the 1-year between-group mean difference in improvement was 4.2 mm ( 95 % CI , 0.9 to 7.5 mm ) for leg pain and 3.5 mm ( 95 % CI , 0.1 to 6.9 mm ) for back pain in favor of conventional microdiskectomy . At 1 year , 107 of 156 patients ( 69 % ) assigned to tubular diskectomy reported a good recovery vs 120 of 151 patients ( 79 % ) assigned to conventional microdiskectomy ( odds ratio , 0.59 [ 95 % CI , 0.35 to 0.99 ] ; P = .05 ) . CONCLUSIONS Use of tubular diskectomy compared with conventional microdiskectomy did not result in a statistically significant improvement in the Rol and -Morris Disability Question naire score . Tubular diskectomy result ed in less favorable results for patient self-reported leg pain , back pain , and recovery . TRIAL REGISTRATION is rct n.org Identifier : IS RCT N51857546 [20103575] Objective : To evaluate the outcome after spinal surgery when adding prehabilitation to the early rehabilitation . Design : A r and omized clinical study . Setting : Orthopaedic surgery department . Subject : Sixty patients scheduled for surgery followed by inpatient rehabilitation for degenerative lumbar disease . Interventions : The patients were computer r and omized to prehabilitation and early rehabilitation ( 28 patients ) or to st and ard care exclusively ( 32 patients ) . The intervention began two months prior to the operation . The prehabilitation included an intensive exercise programme and optimization of the analgesic treatment . Protein drinks were given the day before surgery . The early postoperative rehabilitation included balanced pain therapy with self-administered epidural analgesia , doubled intensified mobilization and protein supplements . Main measures : The outcome measurements were postoperative stay , complications , functionality , pain and satisfaction . Results : At operation the intervention group had improved function , assessed by Rol and Morris Question naire ( P = 0.001 ) . After surgery the intervention group reached the recovery milestones faster than the control group ( 1—6 days versus 3—13 , P = 0.001 ) , and left hospital earlier ( 5 ( 3—9 ) versus 7 ( 5—15 ) days , P = 0.007 ) . There was no difference in postoperative complications , adverse events , low back pain and radiating pain , timed up and go , sit-to-st and or in life quality . Patient satisfaction was significantly higher in the intervention group compared with the control group . Conclusion : The integrated programme of prehabilitation and early rehabilitation improved the outcome and shortened the hospital stay — without more complications , pain or dissatisfaction [8484146] Sixty-two patients with chronic low back pain occurring 14 - 60 months after undergoing discectomy for the first time were r and omized to two physical treatment groups : 24 sessions of intensive dynamic back exercises with hyperextension or 24 sessions of intensive dynamic back exercises without hyperextension . At the conclusion of therapy and at one-year follow-up , no difference was seen between the r and omized groups , with regard to the combined assessment s of pain , disability and objective measurements . A difference for back exercises without hyperextension to be superior to the other treatment regimen was statistically significant at the three-month follow-up . In the patient 's qualitative assessment of treatment outcome there were seen no significant differences between back exercises with or without hyperextension . There was a similar and significant improvement of the isometric endurance of back muscles in both groups , but the flexibility of the spine was significantly improved only in the group using hyperextension exercises . The overall response rate of an earlier published investigation was reproduced . It is concluded that chronic back patients after first time discectomy may benefit from an intensive rehabilitation protocol including intensive exercises . The added use of hyperextension exercises does not confer any independent benefit . Furthermore , the training had to continue for more than 2 - 3 months before a statistical significant decrease in back pain was reported in the patient pain diary [17108817] Study Design . A prospect i ve r and omized study involving 280 consecutive cases of lumbar disc herniation managed either by an endoscopic discectomy alone or an endoscopic discectomy combined with an intradiscal injection of a low dose ( 1000 U ) of chymopapain . Objective . To compare outcome , complications , and reherniations of both techniques . Summary of Background Data . Despite a low complication rate , posterolateral endoscopic nucleotomy has made a lengthy evolution because of an assumed limited indication . Chemonucleolysis , however , proven to be safe and effective , has not continued to be accepted by the majority in the spinal community as microdiscectomy is considered to be more reliable . Method . A total of 280 consecutive patients with a primary herniated , including sequestrated , lumbar disc with predominant leg pain , was r and omized . A clinical follow-up was performed at 3 months , and at 1 and 2 years after the index operation with an extensive question naire , including the visual analog scale for pain and the MacNab criteria . The cohort integrity at 3 months was 100 % , at 1 year 96 % , and at 2 years 92 % . Results . At the 3-month evaluation , only minor complications were registered . At 1-year postoperatively , group 1 ( endoscopy alone ) had a recurrence rate of 6.9 % compared to group 2 ( the combination therapy ) , with a recurrence rate of 1.6 % , which was a statistically significant difference in favor of the combination therapy ( P = 0045 ) . At the 2-year follow-up , group 1 reported that 85.4 % had an excellent or good result , 6.9 % a fair result , and 7.7 % were not satisfied . At the 2-year follow-up , group 2 reported that 93.3 % had an excellent or good result , 2.5 % a fair result , and 4.2 % were not satisfied . This outcome was statistically significant in favor of the group including chymopapain . There were no infections or patients with any form of permanent iatrogenic nerve damage , and no patients had a major complication . Conclusions . A high percentage of patient satisfaction could be obtained with a posterior lateral endoscopic discectomy for lumbar disc herniation , and a statistically significant improvement of the results was obtained when an intradiscal injection of 1000 U of chymopapain was added . There was a low recurrence rate with no major complications . The method can be applied in any type of lumbar disc herniation , including the L5−S1 level [17593405] Spinal decompression is the most common type of spinal surgery carried out in the older patient , and is being performed with increasing frequency . Physiotherapy ( rehabilitation ) is often prescribed after surgery , although its benefits compared with no formal rehabilitation have yet to be demonstrated in r and omised control trials . The aim of this r and omised controlled trial was to examine the effects on outcome up to 2 years after spinal decompression surgery of two types of postoperative physiotherapy compared with no postoperative therapy ( self-management ) . Hundred and fifty-nine patients ( 100 men , 59 women ; 65 ± 11 years ) undergoing decompression surgery for spinal stenosis/herniated disc were r and omised to one of the following programmes beginning 2 months post-op : recommended to “ keep active ” ( CONTROL ; n = 54 ) ; physiotherapy , spine stabilisation exercises ( PT-StabEx ; n = 56 ) ; physiotherapy , mixed techniques ( PT-Mixed ; n = 49 ) . Both PT programmes involved 2 × 30 min sessions/week for up to 12 weeks , with home exercises . Pain intensity ( 0–10 graphic rating scale , for back and leg pain separately ) and self-rated disability ( Rol and Morris ) were assessed before surgery , before and after the rehabilitation phase ( approx . 2 and 5 months post-op ) , and at 12 and 24 months after the operation . ‘ Intention to treat ’ analyses were used . At 24 months , 151 patients returned question naires ( effective return rate , excluding 4 deaths , 97 % ) . Significant reductions in leg and back pain and self-rated disability were recorded after surgery ( P < 0.05 ) . Pain showed no further changes in any group up to 24 months later , whereas disability declined further during the “ rehabilitation ” phase ( P < 0.05 ) then stabilised , but with no significant group differences . 12 weeks of post-operative physiotherapy did not influence the course of change in pain or disability up to 24 months after decompression surgery . Advising patients to keep active by carrying out the type of physical activities that they most enjoy appears to be just as good as administering a supervised rehabilitation program , and at no cost to the health-care provider [12394665] A prospect i ve and r and omized study was conducted of 52 patients who were treated by two home training programs after surgical treatment of lumbar disc herniation . Twenty-six patients followed an early active treatment program , and 26 patients followed a less active training program ( control group ) . Forty-nine patients ( 82 % ) answered a question naire 5–7 years postoperatively . The reoperation rate was two of 49 patients . None of these patients had followed the early active treatment program . Patients with signs of depression before surgery were not significantly less satisfied with the outcome than patients with no signs of depression before surgery [15895329] OBJECTIVE To assess the adherence to and effects of a 12-month combined strength and stretching home exercise regimen versus stretching alone , on patient outcome after lumbar disk surgery . DESIGN R and omized controlled trial . SETTING Departments of physical medicine and rehabilitation and orthopedics at a Finnish hospital . PARTICIPANTS Patients ( N=126 ) were r and omized into either a combined strength training and stretching group ( STG , n=65 ) or a control group ( CG , n=61 ) . INTERVENTION The STG was instructed to perform strength training and both the STG and CG were instructed in the same stretching and stabilization exercises for 12 months . MAIN OUTCOME MEASURES Pain on the visual analog scale ( VAS ) , the Oswestry and the Million disability indexes , isometric and dynamic trunk muscle strength , mobility in the lumbar spine , and straight-leg raising were measured . RESULTS The trial was completed by 71 % and 77 % of the patients from the STG and the CG , respectively . The mean strength training frequency decreased from 1.5 to 0.6 times a week in the STG during the intervention . The mean stretching frequency decreased from 3.7 to 1.6 times a week in both groups . Median back and leg pain varied between 17 and 23 mm ( VAS ) , and the Million and Oswestry indices varied between 14 and 23 points 2 months postoperatively . No statistically significant changes took place in these outcome measures during the 12-month follow-up in both groups . The changes in isometric trunk extension favored the STG ( P = .016 ) during the first 2 months . However , during the whole 12-month training period , both dynamic and isometric back extension and flexion strength , as well as mobility of the spine and repetitive squat-test results , improved significantly in both groups , and no differences were found in any of the physical function parameters between the STG and CG . CONCLUSIONS At the 12-month follow-up , no statistically significant changes were found in the physical function , pain , or disability measures between the groups . In the STG , training adherence with regard to training frequency and intensity remained too low to lead to specific training-induced adaptations in the neuromuscular system . Progressive loading , supervision of training , and psychosocial support is needed in long-term rehabilitation programs to maintain patient motivation [15014270] Study Design . An economic evaluation was conducted alongside a r and omized controlled trial . Summary of Background Data . Little is known about the effectiveness of cognitive-behavioral treatment options for patients following lumbar disc surgery . If the knowledge available was supported by an economic evaluation , the information could then be used to make recommendations for the implementation of cognitive-behavioral treatment in the routine of rehabilitation following lumbar disc surgery . Objective . To examine the cost-effectiveness of a behavioral- grade d activity program , which is an operant treatment , compared to usual care as delivered by a physical therapist for patients following first-time lumbar disc surgery . Methods . For the economic evaluation , a societal viewpoint was applied . The primary outcome measures ( measured at the 12-month follow-up ) were global perceived effect and functional status . To evaluate the economic consequences of the treatments , direct health care and non-health care costs were considered , as well as indirect costs . Results . The clinical outcomes showed no relevant differences between behavioral- grade d activity ( n = 52 ) and UC ( n = 53 ) . Treatment costs were almost identical in the two intervention groups . The difference in direct health care costs was , although not statistically significant , 264 EURO [ 95 % CI : −3–525 ] higher in behavioral- grade d activity than in usual care per patient-year . It was mainly the excess cost of visiting the physiotherapist in the behavioral- grade d activity group that accounted for this difference . The difference in direct non-health care costs , although not statistically significant , was 388 EURO [ 95 % CI : −217 ; 992 ] lower in the usual care group due to unpaid help by friends or family . Consequently , although again not statistically significant , the total direct costs in behavioral- grade d activity are 639 EURO [ 95 % CI : −91 ; 1368 ] higherthan in usual care . For the indirect costs , there was a statistically significant difference , behavioral- grade d activity being more expensive . The sensitivity analysis showed that these results are fairly robust . Conclusions . This study concludes that there are no differences between the two treatment conditions on any of the clinical outcome measures but that behavioral- grade d activity is associated with higher costs . Consequently , there is no reason for the implementation of behavioral- grade d activity as the st and ard treatment for patients following lumbar disc surgery [12892241] OBJECTIVE The aim of this study was to determine the efficacy of dynamic lumbar stabilization exercises in patients with lumbar microdiscectomy . DESIGN A prospect i ve , r and omized , controlled study . SUBJECTS Forty-two patients who were diagnosed as having lumbar disc herniation and had been operated on using the microdiscectomy method were divided r and omly into 3 groups . METHODS Dynamic lumbar stabilization exercises were set for the first group and a home exercise programme for the second . The third group given no exercises was considered as a control group . All patients were examined twice , once before the exercise programme and once 8 weeks later . RESULTS Improvement in the first group was highly significant after the treatment ( p < 0.0001 ) . The second group improved significantly more in some parameters ( pain , functional disability , lumbar Schober , progressive isoinertial lifting evaluation ( neck ) , trunk endurance ( flexion-extension ) ) than did the third group . The third group of patients showed some improvement in fingertip-floor distance , functional disability , modified lumbar Schober and left rotation in 8 weeks , but there were no significant improvements in the other parameters . CONCLUSION Dynamic lumbar stabilization exercises are an efficient and useful technique in the rehabilitation of patients who have undergone microdiscectomy . They relieve pain , improve functional parameters and strengthen trunk , abdominal and low back muscles [10767815] Study Design . A r and omized clinical trial of postoperative medical exercise therapy in patients after operation for lumbar disc herniation with blind assessment of clinical outcomes . Objective . To assess the effect of an early regimen of vigorous medical exercise compared with an ordinary care program . Summary of Background Data . Methods . Patients offered an operation for lumbar disc herniation were consecutively r and omized to a training group or to a control group . The training consisted of an 8-week active rehabilitation program including a regimen of vigorous lumbar stabilizing exercises . The control subjects participated in a mild program of 2 to 3 back exercises at home , after relaxing and resting their backs for 2 months after the surgery . The outcomes were evaluated 6 and 12 months after the operation . The results are based on intention-to-treat analyses . Results . Sixty-three of 65 eligible patients agreed to participate in the trial . Fifty-eight and 53 patients attended for evaluation at 6 and 12 months , respectively . There was a significantly larger improvement in the mean Rol and ’s disability index ( from 8.9 to 5.4 [ P = 0.02 ] at 6 months and from 8.7 to 5.3 [ P = 0.03 ] at 12 months ) and in reported pain ( from 3.7 to 2.0 [ P = 0.04 ] at 6 months and from 3.2 to 1.8 [ P = 0.09 ] at 12 months ) in the training group . A significantly ( P = 0.05 ) higher proportion of the training group reported that they participated in daily activities as usual . There were more patients in the training group who reported improvement in self-evaluated health after surgery at both 6 ( P = 0.02 ) and at 12 months ( P = 0.05 ) . Finally , no differences in clinical end points were observed between the groups . Conclusions . Vigorous medical exercise therapy , started 4 weeks after surgery for lumbar disc herniation , reduced disability and pain after surgery . Because no differences in clinical end points were observed , there is hardly any danger associated with early and vigorous training after operation for disc herniation [15662744] Study Design and Objectives . In a r and omized clinical trial , the effectiveness of behavioral grade d activity was assessed as compared to usual care provided by physiotherapists for patients after first-time lumbar disc surgery ( n = 105 ) . Summary of Background Data . Little is known about the effectiveness of rehabilitation programs following lumbar disc surgery . Most programs focus on biomechanical aspects , whereas psychosocial factors are hardly addressed . The aim of the behavioral grade d activity program , which is an operant treatment , is to alter psycho-social factors such as fear of movement and pain catastrophizing , which might subsequently lead to improved functional status and higher rates of recovery . Behavioral treatments for patients following lumbar disc surgery have not yet been assessed in a r and omized clinical trial . Methods . Inclusion criteria : age between 18 and 65 years ; first-time lumbar disc surgery ; restrictions in normal activities of daily living . Exclusion criteria : surgical complications and confirmed and relevant underlying diseases . Outcome assessment took place at 6 and 12 months after r and omization . Results . Six months after r and omization , 62 % of the patients had recovered following usual care versus 65 % of the patients following behavioral grade d activity . After 12 months , 73 % and 75 % , respectively , had recovered . Differences between intervention groups , 3 % and 2 % respectively , after 6 and 12 months are not statistically significant . Furthermore , there were no differences between the two groups regarding functional status , pain , pain catastrophizing , fear of movement , range of motion , general health , social functioning or return to work . After 1 year , 4 of the behavioral grade d activity cases had undergone another operation versus 2 of usual care cases . Conclusion . Both fear of movement and pain catastrophizing seem to be unaffected by either treatment in these patients . It is concluded that treatment principles derived from theories within the field of chronic low back pain might not apply to these patients . After 1 year of follow-up , there were no statistically significant or clinical ly relevant differences between the behavioral grade d activity program and usual care as provided by physiotherapists for patients following first-time lumbar disc surgery [8875722] Study Design A prospect i ve clinical trial was conducted . Objectives To determine if removing activity restrictions after surgery and encouraging early return to work would affect clinical outcomes after lumbar discectomy . Summary of Background Information Current practice usually recommends several weeks to months of restricted activities after lumbar discectomy . No formal studies have been done to determine the optimal period of restriction , if any , after surgery . Methods Fifty consecutive patients undergoing limited open discectomy for herniated lumbar intervertebral disc were prospect ively treated with no restrictions at all after surgery and were urged to return to full activities as soon as possible . The patients were followed for a minimum of 2 years . At follow‐up evaluation , an independent examiner evaluated each patient . Results The mean time from surgery to return to work was 1.7 weeks . Eleven of 44 ( 25 % ) patients returned to work on the next work day . Ninety‐seven percent of patients who were working before surgery returned to their previous work . Forty‐three of 44 ( 97 % ) patients had returned to full duty by 8 weeks after surgery . At follow‐up evaluation ( 3.8 years ) , five patients had changed work ; three patients increased their work level , and two decreased their work level . No patient changed employment because of back or leg pain . There were three reherniations at the operative level ( 6 % ) , all occurring more than 1 year after surgery . One patent required reoperation . Back and leg pain scores at follow‐up evaluation were very low . Conclusion Lifting of postoperative restrictions after limited discectomy allowed shortened sick leave without increased complications . Postoperative pre caution s in these patients may not be necessary [3536770] The aim of this prospect i ve study was to examine the one-year postoperative results in patients operated on for lumbar disc herniation r and omized in two groups : one with comprehensive rehabilitation and the other taken care of by normal care facilities . A total of 212 patients without any previous spinal operations comprised the final study group . The physiatrist , the surgeon , the social worker , and the psychologist performed the h and icap evaluation according to the occupation h and icap scales of the WHO . The h and icap was evaluated for two phases : before the onset of acute sciatica leading to operation and one year after operation . No significant differences in h and icap distribution between the intervention and normal care groups were seen . The postoperative h and icap correlated highly significantly with preoperative h and icap for both groups . More than half ( 57 % ) of all the patients returned to work within two months of the operation . The amount of sick leaves did not differ significantly between the intervention and normal care groups . A total of 15 persons ( 7 % ) retired during the postoperative year [3441840] The prospect i ve study was undertaken to find out preoperative or perioperative factors predicting the results of the first surgery for lumbar disc herniation . The results were evaluated 1 and 6 months postoperatively using , in addition to the patient evaluation , indices for pain , activities of daily living ( ADL ) , and working capacity . The best result was achieved if the patient was operated on before 2 months ' duration of disabling sciatica . The operative finding grade d as protrusion predicted poor result . The social and psychological factors influenced the outcome more than the findings in the preoperative physical examination or the grade of operative finding . It is recommended to add indices for pain and ADL and a psychological test to the preoperative examinations of patients with lumbar disc herniation [16825039] BACKGROUND CONTEXT Discectomy is the surgery of choice for the lumbosacral radicular syndrome . Previous studies on the postsurgical management of these cases compare one exercise regime to another . This study compares an exercise-based group with a control group involving no formal exercise or rehabilitation . PURPOSE The outcomes of a formal postsurgical exercise-based rehabilitation when compared with the usual rehabilitative surgical advice were evaluated . STUDY DESIGN A r and omized clinical trial comparing management regimes after lumbar discectomies . PATIENT SAMPLE Ninety-three lumbar discectomy patients were r and omized to two groups . OUTCOME MEASURES The following postoperative outcomes were used : levels of pain ; levels of function ; psychological well-being ; time off work ; levels of medication ; and number of doctor/therapist visits . METHODS Ninety-three lumbar discectomy patients were r and omized to two groups . The treatment group undertook a 6-month supervised nonaggravating exercise program . The control group followed the usual surgical advice to resume normal activities as soon as the pain allowed . Both groups were followed for 1 year by using vali date d outcome measures . RESULTS The results are based on an intention-to-treat analysis . Patients in both groups improved during the 1-year follow-up ( p=.001 ) . There was no statistical significance between the groups at the clinical endpoint . The treatment group returned to work 7 days earlier and had fewer days off work in the 1-year follow-up period . CONCLUSION There was no statistical advantage gained by the group that performed the 6-month supervised nonaggravating exercise program at 1-year follow-up . They did , however , have fewer days off work [7849747] The professional literature contains relatively few r and omized-control studies that have assessed the efficacy of physical therapy approaches to the management of patients with chronic low back pain ( CLBP ) . The purpose s of this study were : 1 ) to investigate the effects of physical agents , joint manipulation , low-tech exercise , and high-tech exercise on objective measures of CLBP ; 2 ) to track the length of CLBP relief ; and 3 ) to determine treatment cost-effectiveness . Two-hundred-fifty subjects ( 68 females , 182 males ; ages 34 - 51 years ) with CLBP following an L5 laminectomy were r and omly assigned into five separate groups for a treatment period of 8 weeks . Chronic low back pain status was measured by modified-modified Schober , Cybex Liftask , and Oswestry procedures . Results revealed that : 1 ) only low-tech and high-tech exercise produced significant improvements ( p < .05 ) in CLBP , 2 ) the mean period of CLBP relief ranged from 1.6 weeks ( control ) to 91.4 weeks ( low-tech exercise ) , and 3 ) low-tech exercise was most cost-effective . It was concluded that : 1 ) low-tech and high-tech exercise were the only effective treatments for CLBP , 2 ) low-tech exercise produced the longest period of CLBP relief , and 3 ) low-tech exercise was the most cost-effective form of treatment . Clinical ly , low-tech exercise may be the treatment method of choice for the effective management of chronic low back pain [21505377] Study Design . Cost-effectiveness analysis alongside a factorial r and omized controlled trial . Objective . To assess the cost-effectiveness of a rehabilitation program and /or an education booklet each compared with usual care for the postoperative management of patients undergoing discectomy or lateral nerve root decompression surgery . Summary of Background Data . There is little knowledge about the cost-effectiveness of postoperative management of patients after spinal surgery . Methods . A total of 338 patients were recruited into the study between June 2005 and March 2009 . Patients were r and omized to rehabilitation only , booklet only , rehabilitation plus booklet , or usual care only . Interactions between booklet and rehabilitation were nonsignificant ; hence , we compare booklet versus no booklet and rehabilitation versus no rehabilitation . We adopt an English National Health Service and personal social services perspective . Data on outcomes and costs are based on patient level data from the trial . A 1-year time horizon was used . Outcomes were measured in terms of quality -adjusted life years . Health-related quality of life was reported by patients using the EuroQol-5D ( EQ-5D ) . A comprehensive range of health service contacts were included in the cost analysis . Results . There were no significant differences in costs or outcomes associated with either intervention . Mean incremental costs and mean quality -adjusted life years gained per patient of booklet versus no booklet were −£87 ( 95 % CI : −£1221 to £ 1047 ) and −0.023 ( 95 % CI : −0.068 to 0.023 ) , respectively . Figures for rehabilitation versus no rehabilitation were £ 160 ( 95 % CI : −£984 to £ 1304 ) and 0.002 ( 95 % CI : −0.044 to 0.048 ) , respectively . Neither intervention was cost-effective when compared with the threshold range commonly used to judge whether or not an intervention is cost-effective in the English National Health Service . Conclusion . Cost-effectiveness evidence does not support use of booklet over no booklet or rehabilitation over no rehabilitation for the postoperative management of patients after spinal surgery [431682] This paper proposes a new method for planning r and omized clinical trials . This method is especially suited to comparison of a best st and ard or control treatment with an experimental treatment . Patients are allocated into two groups by a r and om or chance mechanism . Patients in the first group receive st and ard treatment ; those in the second group are asked if they will accept the experimental therapy ; if they decline , they receive the best st and ard treatment . In the analyses of results , all those in the second group , regardless of treatment , are compared with those in the first group . Any loss of statistical efficiency can be overcome by increased numbers . This experimental plan is indeed a r and omized clinical trial and has the advantage that , before providing consent , a patient will know whether an experimental treatment is to be used [10851101] Study Design . A prospect i ve r and omized controlled trial of exercise therapy in patients who underwent microdiscectomy for prolapsed lumbar intervertebral disc . Results of a pilot study are presented . Objective . To determine the effects of a postoperative exercise program on pain , disability , psychological status , and spinal function . Summary of Background Data . Microdiscectomy is often used successfully to treat prolapsed lumbar intervertebral disc . However , some patients do not have a good outcome and many continue to have low back pain . The reasons for this are unclear but impairment of back muscle function due to months of inactivity before surgery may be a contributing factor . A postoperative exercise program may improve outcome in such patients . Methods . Twenty patients who underwent lumbar microdiscectomy were r and omized into EXERCISE and CONTROL groups . After surgery , all patients received normal postoperative care that included advice from a physiotherapist about exercise and a return to normal activities . Six weeks after surgery , patients in the EXERCISE group undertook a 4-week exercise program that concentrated on improving strength and endurance of the back and abdominal muscles and mobility of the spine and hips . Assessment s of spinal function were performed in all patients during the week before surgery and at 6 , 10 , 26 , and 52 weeks after . The assessment included measures of posture , hip and lumbar mobility , back muscle endurance capacity and electromyographic measures of back muscle fatigue . On each occasion , patients completed question naires inquiring about pain , disability and psychological status . Results . Surgery improved pain , disability , back muscle endurance capacity and hip and lumbar mobility in both groups of patients . After the exercise program , the EXERCISE group showed further improvements in these measures and also in electromyographic measures of back muscle fatigability . All these improvements were maintained 12 months after surgery . The only further improvement showed by the CONTROL group between 6 and 52 weeks was an increase in back muscle endurance capacity . Conclusion . A 4-week postoperative exercise program can improve pain , disability , and spinal function in patients who undergo microdiscectomy [9820916] Study Design . A prospect i ve , r and omized , and controlled study was conducted . Objectives . To evaluate two training programs , both of which started immediately after lumbar discectomy . Summary of Background Data . In previous studies , patients began physiotherapy between 4 weeks and 60 months after surgery . No studies have been conducted to evaluate a physiotherapy program that begins immediately after surgery . Method . Twenty‐six patients were treated according to an early active training program . Twenty‐six patients were treated with a traditional , less active training program ( control group ) . All patients were examined immediately before and after surgery and 3 , 6 , 12 , and 52 weeks after surgery by an unbiased observer . Two years after surgery , patients completed a question naire . Range of motion of the lumbar spine and straight leg raising were measured . Pain intensity and location was measured by a visual analog scale . The duration of sick leave was documented . Results . Six and 12 weeks after surgery , patients with dominating residual leg pain had significantly less intense pain in the early active training group than those in the control group ( P < 0.05 ) . Twelve weeks after surgery , range of motion of the lumbar spine was significantly more increased in the early active training group ( P < 0.01 ) . One year after surgery , there was no significant difference between the groups regarding the duration of sick leave , results in a positive straight leg raising , or pain intensity . Twenty‐two ( 88 % ) patients in the early active training group and 16 ( 67 % ) in the control group were satisfied with the treatment outcome 2 years after surgery ( P < 0.10 ) . Conclusions . Patients rehabilitated according to the early active training program had a better short‐term outcome of objective values . At 2 years ' follow‐up , more patients were satisfied with the result of the operation . The early active treatment program is recommended [20878044] OBJECTIVE To determine the effects of lumbar extension exercise on strength , disability index , and pain scores in patients after lumbar discectomy surgery . DESIGN Prospect i ve comparative study . SUBJECTS Forty patients experiencing a herniated disc at lumbar levels were divided into 4 subgroups for different training frequencies : twice/week ( group 1 ) , once/week ( group 2 ) , once/2 weeks ( group 3 ) , and no training ( control ) . METHODS After completing the initial 12-week training , all subjects participated in a 12-week follow-up training . RESULTS Groups 1 and 2 showed significant increases in lumbar extension strength ( 26 Nm and 7 Nm , respectively ) , while group 3 and the control group showed significant decreases in lumbar extension strength . Groups 1 and 2 showed significant decreases in disability index ( 1.4 and 0.8 Oswestry Disability Index points , respectively ) , and group 1 showed significant decreases in back and leg pain scores ( both 0.5 units on a 10-cm visual analog scale ) . CONCLUSION Lumbar extension strength and disability index improve with training frequencies of once and twice per week , while back and leg pain improve with a training frequency of twice per week . The clinical importance of these improvements is question able , as the scores were already very low after the discectomy and the magnitude of absolute improvements were small [12673431] To comprehend the results of a r and omised controlled trial ( RCT ) , readers must underst and its design , conduct , analysis , and interpretation . That goal can be achieved only through total transparency from authors . Despite several decades of educational efforts , the reporting of RCTs needs improvement . Investigators and editors developed the original CONSORT ( Consoli date d St and ards of Reporting Trials ) statement to help authors improve reporting by use of a checklist and flow diagram . The revised CONSORT statement presented here incorporates new evidence and addresses some criticisms of the original statement . The checklist items pertain to the content of the Title , Abstract , Introduction , Methods , Results , and Discussion . The revised checklist includes 22 items selected because empirical evidence indicates that not reporting this information is associated with biased estimates of treatment effect , or because the information is essential to judge the reliability or relevance of the findings . We intended the flow diagram to depict the passage of participants through an RCT . The revised flow diagram depicts information from four stages of a trial ( enrollment , intervention allocation , follow- up , and analysis ) . The diagram explicitly shows the number of participants , for each intervention group , included in the primary data analysis . Inclusion of these numbers allows the reader to judge whether the authors have done an intention- to-treat analysis . In sum , the CONSORT statement is intended to improve the reporting of an RCT , enabling readers to underst and a trial 's conduct and to assess the validity of its results [23484826] BACKGROUND Magnetic resonance imaging ( MRI ) is frequently performed during follow-up in patients with known lumbar-disk herniation and persistent symptoms of sciatica . The association between findings on MRI and clinical outcome is controversial . METHODS We studied 283 patients in a r and omized trial comparing surgery and prolonged conservative care for sciatica and lumbar-disk herniation . Patients underwent MRI at baseline and after 1 year . We used a 4-point scale to assess disk herniation on MRI , ranging from 1 for " definitely present " to 4 for " definitely absent . " A favorable clinical outcome was defined as complete or nearly complete disappearance of symptoms at 1 year . We compared proportions of patients with a favorable outcome among those with a definite absence of disk herniation and those with a definite , probable , or possible presence of disk herniation at 1 year . The area under the receiver-operating-characteristic ( ROC ) curve was used to assess the prognostic accuracy of the 4-point scores regarding a favorable or unfavorable outcome , with 1 indicating perfect discriminatory value and 0.5 or less indicating no discriminatory value . RESULTS At 1 year , 84 % of the patients reported having a favorable outcome . Disk herniation was visible in 35 % with a favorable outcome and in 33 % with an unfavorable outcome ( P=0.70 ) . A favorable outcome was reported in 85 % of patients with disk herniation and 83 % without disk herniation ( P=0.70 ) . MRI assessment of disk herniation did not distinguish between patients with a favorable outcome and those with an unfavorable outcome ( area under ROC curve , 0.48 ) . CONCLUSIONS MRI performed at 1-year follow-up in patients who had been treated for sciatica and lumbar-disk herniation did not distinguish between those with a favorable outcome and those with an unfavorable outcome . ( Funded by the Netherl and s Organization for Health Research and Development and the Hoelen Foundation ; Controlled Clinical Trials number , IS RCT N26872154 . ) [21378603] Study Design . This was a multicenter , factorial , r and omized , controlled trial on the postoperative management of spinal surgery patients , with r and omization stratified by surgeon and operative procedure . Objective . This study sought to determine whether the functional outcome of two common spinal operations could be improved by a program of postoperative rehabilitation that combines professional support and advice with grade d active exercise commencing 6 weeks after surgery and /or an educational booklet based on evidence -based messages and advice received at discharge from hospital , each compared with usual care . Summary of Background Data . Surgical interventions on the spine are increasing , and while surgery for spinal stenosis and disc prolapse have been shown to be superior to conservative management , functional outcome , and patient satisfaction are not optimal . Methods . The study compared the effectiveness of a rehabilitation program and an education booklet for the postoperative management of patients undergoing discectomy or lateral nerve root decompression surgery , each compared with “ usual care ” using a 2 × 2 factorial design , r and omizing patient to four groups ; rehabilitation-only , booklet-only , rehabilitation-plus-booklet , and usual care only . The primary outcome measure was the Oswestry Disability Index ( ODI ) at 12 months , with secondary outcomes including visual analog scale measures of back and leg pain . Results . Three hundred thirty-eight patients were recruited into the study and measurements were obtained preoperatively and then repeated at 6 weeks , 3 , 6 , 9 and 12 months postoperatively . Twelve months postoperatively the observed effect of rehabilitation on ODI was −2.7 ( 95 % CI : −6.8 to 1.5 ) and the effect of booklet was 2.7 ( 95 % CI : −1.5 to 6.9 ) . Conclusion . This study found that neither intervention had a significant impact on long-term outcome [19778981] Background Restoration of physical function following lumbar microdiskectomy may be influenced by the postoperative care provided . Objective The purpose of this study was to examine the effectiveness of a new interventional protocol to improve functional performance in patients who have undergone a single-level lumbar microdiskectomy . Setting The study was conducted in physical therapy outpatient clinics . Design and Participants Ninety-eight participants ( 53 male , 45 female ) who had undergone a single-level lumbar microdiskectomy were r and omly allocated to receive education only or exercise and education . Intervention and Measurements The exercise intervention consisted of a 12-week periodized program of back extensor strength ( force-generating capacity ) and endurance training and mat and upright therapeutic exercises . The Oswestry Disability Index ( ODI ) and physical measures of functional performance were tested 4 to 6 weeks postsurgery and 12 weeks later , following completion of the intervention program . Because some participants sought physical therapy outside of the study , postintervention scores were analyzed for both an as-r and omized ( 2-group ) design and an as-treated ( 3-group ) design . Results In the 2-group analyses , exercise and education result ed in a greater reduction in ODI scores and a greater improvement in distance walked . In the 3-group analyses , post hoc comparisons showed a significantly greater reduction in ODI scores following exercise and education compared with the education-only and usual physical therapy groups . Limitations The limitations of this study include a lack of adherence to group assignment , disproportionate therapist contact time among treatment groups , and multiple use of univariate analyses . Conclusions An intensive , progressive exercise program combined with education reduces disability and improves function in patients who have undergone a single-level lumbar microdiskectomy Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: The purpose of this systematic review was to assess the effects of spinal manipulative therapy ( SMT ) , acupuncture and herbal medicine for chronic non-specific LBP . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

29168569

[22801933] OBJECTIVE To evaluate the effectiveness of Sprinkles alongside infant and young child feeding ( IYCF ) education compared with IYCF education alone on anemia , deficiencies in iron , vitamin A , and zinc , and growth in Cambodian infants . DESIGN Cluster-r and omized effectiveness study . SETTING Cambodian rural health district . PARTICIPANTS Among 3112 infants aged 6 months , a r and om sub sample ( n = 1350 ) was surveyed at baseline and 6-month intervals to age 24 months . INTERVENTION Daily micronutrient Sprinkles alongside IYCF education vs IYCF education alone for 6 months from ages 6 to 11 months . MAIN OUTCOME MEASURES Prevalence of anemia ; iron , vitamin A , and zinc deficiencies ; and growth via biomarkers and anthropometry . RESULTS Anemia prevalence ( hemoglobin level < 11.0 g/dL [ to convert to grams per liter , multiply by 10.0 ] ) was reduced in the intervention arm compared with the control arm by 20.6 % at 12 months ( 95 % CI , 9.4 - 30.2 ; P = .001 ) , and the prevalence of moderate anemia ( hemoglobin level < 10.0 g/dL ) was reduced by 27.1 % ( 95 % CI , 21.0 - 31.8 ; P < .001 ) . At 12 and 18 months , iron deficiency prevalence was reduced by 23.5 % ( 95 % CI , 15.6 - 29.1 ; P < .001 ) and 11.6 % ( 95 % CI , 2.6 - 17.9 ; P = .02 ) , respectively . The mean serum zinc concentration was increased at 12 months ( 2.88 μg/dL [ to convert to micromoles per liter , multiply by 0.153 ] ; 95 % CI , 0.26 - 5.42 ; P = .03 ) . There was no statistically significant difference in the prevalence of zinc and vitamin A deficiencies or in growth at any time . CONCLUSIONS Sprinkles reduced anemia and iron deficiency and increased the mean serum zinc concentration in Cambodian infants . Anemia and zinc effects did not persist beyond the intervention period . TRIAL REGISTRATION anzctr.org.au Identifier : ACTRN12608000069358 [9192196] Objective : To compare the efficacy of a daily and a weekly iron supplementation on the hematological status of anemic children living at high altitude . Design : Double blind iron supplementation trial including a placebo control group . Setting : A socioeconomically disadvantaged district of La Paz , Bolivia ( altitude of 4000 m ) . Subjects : Anemic ( hemoglobin concentration≤144 g/L ) , 3.3–8.3 y old children of both sexes . Intervention : Children received a placebo ( n=57 ) or a dose of 3–4 mg of elemental iron per kg body weight ( FeSO4 tablets ) 1 d per week ( n=58 ) or 5 d per week ( n=58 ) for 16 weeks . Results : Hemoglobin and zinc erythrocyte protoporphyrin concentrations improved significantly in supplemented groups but not in the placebo group . Changes in hemoglobin during the study were not significantly different between supplemented groups ( weekly group : 15.2±6.9 g/L and daily group : 18.6±11.1 g/L ) but were different from the placebo group ( 0.5±7.1 g/L , P<0.001 ) . At the end of the supplementation period , the hemoglobin distribution was Gaussian , and similar in both supplemented groups . Adjusting for the initial hemoglobin concentration , final hemoglobin and its changes were similar in both supplemented groups . Conclusion : Weekly iron supplementation is as efficacious as daily iron supplementation in improving iron status and correcting moderate iron deficiency anemia in Bolivian school children living at high altitude . Sponsorship : Program supported in part by ORSTROM , the French Ministry of Foreign Affairs and the National Secretary 's Office of Health , Bolivia [22810982] Few studies have evaluated the impact of fortification with iron-rich foods such as amaranth grain and multi-micronutrient powder ( MNP ) containing low doses of highly bioavailable iron to control iron deficiency anemia ( IDA ) in children . We assessed the efficacy of maize porridge enriched with amaranth grain or MNP to reduce IDA in Kenyan preschool children . In a 16-wk intervention trial , children ( n = 279 ; 12 - 59 mo ) were r and omly assigned to : unrefined maize porridge ( control ; 4.1 mg of iron/meal ; phytate : iron molar ratio 5:1 ) ; unrefined maize ( 30 % ) and amaranth grain ( 70 % ) porridge ( amaranth group ; 23 mg of iron/meal ; phytate : iron molar ratio 3:1 ) ; or unrefined maize porridge with MNP ( MNP group ; 6.6 mg iron/meal ; phytate : iron molar ratio 2.6:1 ; 2.5 mg iron as NaFeEDTA ) . Primary outcomes were anemia and iron status with treatment effects estimated relative to control . At baseline , 38 % were anemic and 30 % iron deficient . Consumption of MNP reduced the prevalence of anemia [ -46 % ( 95 % CI : -67 , -12 ) ] , iron deficiency [ -70 % ( 95 % CI : -89 , -16 ) ] , and IDA [ -75 % ( 95 % CI : -92 , -20 ) ] . The soluble transferrin receptor [ -10 % ( 95 % CI : -16 , -4 ) ] concentration was lower , whereas the hemoglobin ( Hb ) [ 2.7 g/L ( 95 % CI : 0.4 , 5.1 ) ] and plasma ferritin [ 40 % ( 95 % CI : 10 , 95 ) ] concentrations increased in the MNP group . There was no significant change in Hb or iron status in the amaranth group . Consumption of maize porridge fortified with low-dose , highly bioavailable iron MNP can reduce the prevalence of IDA in preschool children . In contrast , fortification with amaranth grain did not improve iron status despite a large increase in iron intake , likely due to high ratio of phytic acid : iron in the meal [17413115] BACKGROUND Children participating in the Integrated Child Development Service ( ICDS ) in India have high rates of iron and vitamin A deficiency . OBJECTIVE The objective was to assess the efficacy of a premix fortified with iron and vitamin A and added at the community level to prepared khichdi , a rice and dal mixture , in increasing iron and vitamin A stores and decreasing the prevalence of iron deficiency , anemia , and vitamin A deficiency . DESIGN This cluster , r and omized , double-blind , controlled trial was initiated in 30 Anganwadi centers ( daycare centers ) in West Bengal state , India . Children aged 36 - 66 mo ( n = 516 ) attending village-based ICDS centers were r and omly assigned to receive either a fortified or a nonfortified premix for 24 wk . Blood was drawn at 0 and 24 wk by venipuncture for the measurement of hemoglobin , serum ferritin , and serum retinol . RESULTS The change in the hemoglobin concentration of anemic children was significantly different between fortified and nonfortified khichdi groups ( P < 0.001 ) . Prevalence rates of anemia , iron deficiency , and iron deficiency anemia were significantly lower after 24 wk in the fortified-khichdi group than in the nonfortified-khichdi group ( P < 0.001 ) . There were no significant differences in serum retinol concentrations or in the prevalence of vitamin A deficiency between the fortified- and nonfortified-khichdi groups . CONCLUSION A premix fortified with iron , vitamin A , and folic acid and added to supplementary food at the community level can be effective at increasing iron stores and reducing the prevalence of iron deficiency and anemia [22705425] To assess the impact of intensive nutrition education ( INE ) with or without the provision of micronutrient powder ( MNP ) on the nutritional status of mildly wasted children in Nias , Indonesia , two groups of mildly wasted ( > = -1.5 to < -1.0 WHZ ) children aged > = 6 to < 60 months in the Church World Service ( CWS ) project areas were assigned by village r and omization to receive INE ( n=64 ) or INE+MNP ( n=51 ) in a weekly program . Another two groups of mildly wasted children who were living at a clear distance from INE and INE+MNP villages were selected to receive a monthly non-intensive nutrition education program ( NNE ) with or without MNP ( n=50 both respectively ) . WHZ , weight , height , haemoglobin ( Hb ) level , and morbidity data were assessed at admission , during the study , and at individual discharge . Children 's weight gain ( g/kg body weight/day ) was highest in INE+MNP group ( 2.2±2.1 ) , followed by INE ( 1.1±0.9 ) , NNE+MNP ( 0.3±0.5 ) and NNE ( 0.3±0.4 ) group . In both MNP intervention groups ( INE+MNP , NNE+MNP ) , supplements significantly increased Hb value ( g/L ) of respective children ( 10.0±10.0 ; p<0.001 and 3.0±8.0 ; p<0.05 respectively ) . Proportion of children who reached discharge criterion was highest among the INE+MNP ( 70.6 % ; n=36 ) , followed by INE ( 64.1 % ; n=41 ) , NNE+MNP ( 26.0 % ; n=13 ) , and NNE ( 20.0 % ; n=10 ) groups ( p<0.001 ) . Shortest length of stay until recovery was observed among children in the INE+MNP group ( 29.9 days ) , followed by INE ( 40.0 days ) , NNE+MNP ( 80.6 days ) , and NNE ( 86.2 days ) respectively ( p<0.001 ) . Weekly intensive nutrition education supported by MNP supplementation produced the best results regarding weight gain and haemoglobin status of mildly wasted children [9846856] BACKGROUND Despite ample food supplies , the incidence of childhood underweight and stunting remains high in Ug and a. Many factors contribute to this situation , but the role of low zinc intakes has not been adequately explored . OBJECTIVE Our objective was to study the effect of zinc supplementation on growth and body composition of preschool children by using the outcome measures of weight , height , and midupper arm circumference ( MUAC ) . DESIGN The study was r and omized , double-blind , placebo-controlled , parallel , and 8 mo long , and incorporated 6 mo of zinc supplementation . Children ( n = 153 ) aged 55.8 + /- 11.2 mo from 3 r and omly selected nursery schools of medium , low , and very low socioeconomic status in a suburb of Kampala took part . The intervention comprised 10 mg Zn ( as ZnSO4 ) or placebo daily in freshly prepared fruit juice , Monday to Friday inclusive . RESULTS Zinc supplementation increased MUAC by the end of the study ( P = 0.029 ) and led to greater weight gain in children from the school of medium socioeconomic status at 3 and 8 mo ( P = 0.019 and P = 0.038 , respectively ) . There was no effect on weight gain of the children from the other schools . Zinc supplementation had no influence on height . Infection rates ( of which 82 % were recorded as malaria ) were lower in the zinc-supplemented group than in control subjects ( P = 0.063 ) . CONCLUSIONS Zinc supplementation may counter the age-related decrease in MUAC often observed in preschool children in developing countries . The study provides evidence that zinc may not be the most limiting nutrient for weight gain in children of poor nutritional status , but may become so as nutritional status improves [15735110] Growth faltering , anemia , and multiple micronutrient deficiency are common during infancy in developing countries . This South African trial was part of a multicenter study aim ed at testing the efficacy of multiple micronutrient supplementation on growth , anemia , micronutrient status , and morbidity during infancy across 4 countries . A total of 265 infants aged 6 - 12 mo were individually r and omized to 1 of 4 intervention groups : a daily multiple micronutrient supplement ( DMM ) , a daily placebo supplement ( P ) ; a multiple micronutrient supplement 1 d of the week and placebo supplement on the other days of the week ( WMM ) , and a daily iron supplement ( DI ) . For 6 mo , the blinded supplements were provided to mothers at monthly health clinic sessions , and consumption was verified during weekly household visits by community health workers , when morbidity was also checked . Weight and height of the infants were measured monthly , and blood sample s were taken at the beginning and at the end for assessing the infants micronutrient status . There were no significant differences in nutritional status of the groups at baseline with 40 % of infants with anemia ( hemoglobin < 110 g/L ) , 16 % vitamin A deficiency ( plasma retinol < 0.7 micromol/L ) , 47 % zinc deficiency ( plasma zinc < 10.7 micromol/L ) , 2 % underweight , and 11 % stunting . There was no difference in growth or morbidity between the micronutrient supplemented groups and the P group during the 6-mo study . The DMM was the most effective intervention tested , not only for improving anemia but also for improving iron , zinc , riboflavin , and tocopherol status [16702330] Anemia and co-existing deficiencies of zinc , iron , iodine , and vitamin A occur among children in many developing countries including NE Thail and , probably contributing to impairments in growth , immune competence , and cognition . Sustainable strategies are urgently required to combat these deficiencies . We assessed the efficacy of a micronutrient-fortified seasoning powder served with a school lunch on reducing anemia and improving the micronutrient status of rural NE Thai children . Children ( n = 569 ) aged 5.5 - 13.4y from 10 schools were r and omly assigned to receive a seasoning powder either unfortified or fortified with zinc ( 5 mg ) , iron ( 5 mg ) , vitamin A ( 270 microg ) , and iodine ( 50 microg ) ( per serving ) and incorporated into a school lunch prepared central ly and delivered 5 d/wk for 31 wk . Teachers monitored school lunch consumption . Baseline and final micronutrient status , hemoglobinopathies , and infection or inflammation were assessed from blood and urine sample s. For the primary outcome , anemia ( based on hemoglobin ) , no intervention effect was apparent ( odds ratio : 1.02 95 % CI : 0.69 , 1.51 ) after adjustment for design strata . The odds of zinc ( based on serum zinc ) and urinary iodine deficiency in the fortified group were 0.63 ( 0.42 , 0.94 ) and 0.52 ( 0.38 , 0.71 ) times those in the unfortified group , respectively . Fortification had no effect on serum retinol ( 0.61 : 0.25,1.51 ) , ferritin ( 1.12 : 0.43 , 2.96 ) , or mean red cell volume ( 1.16 : 0.82 , 1.64 ) . Therefore , a micronutrient-fortified seasoning powder is a promising vehicle for improving zinc , iodine , and hemoglobin status , and its potential for incorporation into lunch programs in day care centers and schools in NE Thail and warrants investigation [18065586] BACKGROUND There is still uncertainty about the best procedure to alleviate iron deficiency . Additionally more reliable methods are needed to assess the effect of iron intervention . OBJECTIVE We examined the efficacy of daily iron ( 10 mg ) , daily and weekly multiple-micronutrient supplementation ( 10 and 20 mg Fe , respectively ) in improving body iron stores of Indonesian infants . DESIGN Infants aged 6 - 12 mo were r and omly allocated to 1 of 4 groups : daily multiple-micronutrients ( DMM ) foodlike tablets ( foodLETs ) , weekly multiple-micronutrient ( WMM ) foodLETs , daily iron ( DI ) foodLETs , or daily placebo . Hemoglobin , ferritin , transferrin receptors , and C-reactive protein data were obtained at baseline and 23 wk . RESULTS Body iron estimated from the ratio of transferrin receptors to ferritin was analyzed for 244 infants . At baseline , mean iron stores ( 0.5 + /- 4.1 mg/kg ) did not differ among the groups , and 45.5 % infants had deficits in tissue iron ( body iron < 0 ) . At week 23 , the group DI had the highest increment in mean body iron ( 4.0 mg/kg ) , followed by the DMM group ( 2.3 mg/kg ; P < 0.001 for both ) . The iron stores in the WMM group did not change , whereas the mean body iron declined in the daily placebo group ( -2.2 mg/kg ; P < 0.001 ) . Compared with the daily placebo group , the DMM group gained 4.55 mg Fe/kg , the DI group gained 6.23 mg Fe/kg ( both P < 0.001 ) , and the WMM group gained 2.54 mg Fe/kg ( P = 0.001 ) . CONCLUSIONS When compliance can be ensured , DI and DMM foodLETs are efficacious in improving and WMM is efficacious in maintaining iron stores among Indonesian infants [18541560] BACKGROUND Reductions in iodine and zinc deficiencies and improvements in hemoglobin were achieved from a micronutrient-fortified seasoning powder consumed in school lunches by children in northeast Thail and . OBJECTIVE The objective was to determine whether fortification with 4 micronutrients in a school lunch results in changes in children 's growth , morbidity , and cognitive function compared with no fortification . DESIGN In a r and omized controlled trial of 569 children aged 5.5 - 13.4 y from 10 schools , we compared the efficacy of a seasoning powder fortified with or without 5 mg Fe , 5 mg Zn , 50 mug I , and 270 mug vitamin A per serving consumed with a school lunch 5 d/wk . Here we report on results of the secondary functional outcomes . RESULTS The groups were comparable concerning compliance and loss to follow-up . The intervention had no statistically significant effect on anthropometric measures over 31 wk , but reduced the incidence of respiratory-related illnesses [ rate ratio ( RR ) : 0.83 ; 95 % CI : 0.73 , 0.94 ] , symptoms of runny nose ( RR : 0.80 ; 95 % CI : 0.70 , 0.92 ) , cough ( RR : 0.80 ; 95 % CI : 0.66 , 0.96 ) , and diarrhea ( RR : 0.38 ; 95 % CI : 0.16 , 0.90 ) . For the visual recall test , those in the fortified group recalled 0.5 more items ( 95 % CI : 0.1 , 0.9 ) than did the controls . There were no statistically significant differences between groups in the results of the digits forward and backward tests or in school grade s at the conclusion of the 2 semesters . CONCLUSION The beneficial effects on morbidity and visual recall over a short period , in addition to some biochemical improvements , highlight the potential of this micronutrient-fortified seasoning powder supplied in a school lunch . This trial was registered at clinical trials.gov as ACTRN12605000341628 [17921387] BACKGROUND Little is known about the combined effect of micronutrients and essential fatty acids on cognitive function in school-aged children . OBJECTIVE We assessed the effect of micronutrients , long-chain n-3 fatty acids , or both on indicators of cognitive performance in well-nourished and marginally nourished school-aged children . DESIGN Two 2-by-2 factorial r and omized controlled double-blind trials were performed home-based in Adelaide , South Australia , and at 6 primary schools in Jakarta , Indonesia . A total of 396 children ( aged 6 - 10 y ) in Australia and 384 children in Indonesia were r and omly allocated to receive a drink with a micronutrient mix ( iron , zinc , folate , and vitamins A , B-6 , B-12 , and C ) , with docosahexanoic acid ( DHA , 88 mg/d ) and eicosapentaenoic acid ( EPA , 22 mg/d ) , or with both or placebo 6 d/wk for 12 mo . Biochemical indicators were determined at baseline and 12 mo . Cognitive performance was measured at baseline , 6 mo , and 12 mo . RESULTS The micronutrient treatment significantly improved plasma micronutrient concentrations in Australian and Indonesian children . DHA+EPA treatment increased plasma DHA and total plasma n-3 fatty acids in both countries . The micronutrient treatment result ed in significant increases in scores on tests representing verbal learning and memory in Australia ( estimated effect size : 0.23 ; 95 % CI : 0.01 , 0.46 ) . A similar effect was observed among Indonesian girls ( estimated effect size : 0.32 ; 95 % CI : -0.01 , 0.64 ) . No effects were found on tests measuring general intelligence or attention . No effects of DHA+EPA on the factors of cognitive tests were observed . CONCLUSION In well-nourished school-aged children , fortification with multiple micronutrients can result in improvements in verbal learning and memory [17374671] We evaluated the effectiveness of a 2-mo treatment of Sprinkles containing 12.5 mg iron , 5 mg zinc , 400 microg vitamin A , 160 microg folic acid , and 30 mg vitamin C in reducing anemia among children 9- to 24 mo old in Haiti . Ten food distribution points ( FDP ) where children received take-home rations of fortified wheat-soy blend ( WSB ) were r and omly allocated into 2 groups : 1 ) Sprinkles-WSB ( S-WSB ) ( 6 FDP ; n = 254 ) , receiving 30 sachets of Sprinkles monthly for 2 mo ; and 2 ) WSB only ( WSB ) ( 4 FDP ; n = 161 ) , not receiving Sprinkles . At baseline , anemia prevalence [ hemoglobin ( Hb ) < 100 g/L ] , adjusted for age and sex , was 54 and 39 % in S-WSB and WSB groups , respectively . After the 2-mo intervention ( 1st follow-up ) , anemia , adjusted for baseline prevalence , age , and sex dropped to 24 % in S-WSB ( P < 0.001 ) and increased to 43 % in WSB ( P = 0.07 ) . At 7 mo postintervention , anemia in S-WSB declined to 14 % ; 92 % of children who were nonanemic at 1st follow-up remained so without further Sprinkles consumption . From baseline to 1st follow-up , mean Hb increased by 5.5 g/L and dropped by 1.0 g/L in the S-WSB and WSB groups , respectively ( P < 0.001 ) . From baseline to 2nd follow-up , mean Hb increased by 10.9 g/L in S-WSB ( P < 0.001 ) . Changes in mean Hb were greater for younger children ( < 21 mo at onset of intervention ) ( P < 0.05 ) and for children who were anemic at baseline ( P < 0.001 ) . In population s with a high prevalence of anemia , such as rural Haiti , 2 mo of Sprinkles are effective in reducing anemia among 9- to 24-mo-old children [11722961] BACKGROUND St and ard therapy for anemia in infants is ferrous sulfate drops administered 3 times/d . Adherence to treatment , however , is often poor . One likely reason for poor adherence is the unpleasant side effects associated with drops . OBJECTIVE The objective was to evaluate the use of a new form of iron and a delivery system to treat anemia in infants that is likely to produce better adherence to treatment . DESIGN Using a prospect i ve , r and omized , controlled design , we studied 557 anemic children aged 6 - 18 mo ( hemoglobin : 70 - 99 g/L ) in rural Ghana . One group received a daily sachet of microencapsulated ferrous fumarate ( 80 mg elemental Fe ) in powder form plus ascorbic acid to be sprinkled onto any complementary food eaten ( sprinkles group ) ; a control group received ferrous sulfate drops 3 times/d for 2 mo ( total dose : 40 mg elemental Fe ) . Hemoglobin and serum ferritin concentrations were measured at baseline and at the end of treatment . RESULTS Successful treatment of anemia ( hemoglobin > 100 g/L ) occurred in 58 % of the sprinkles group and in 56 % of the drops group , with minimal side effects in both groups . Geometric mean ferritin concentrations increased significantly in each group from baseline to the end of treatment ( P < 0.001 ) . CONCLUSION Use of ferrous sulfate drops or a single daily dose of microencapsulated ferrous fumarate sprinkles plus ascorbic acid result ed in a similar rate of successful treatment of anemia without side effects . To our knowledge , this is the first demonstration of the use of microencapsulated iron sprinkles to treat anemia . Improved ease of use may favor the use of sprinkles to deliver iron [12672922] Although iron deficiency is the most common single-nutrient deficiency in infants and children , other deficiencies may develop concurrently , including zinc deficiency . In previous studies , we used home-fortification with " Sprinkles , " single-serve sachets containing microencapsulated ferrous fumarate added to weaning foods , to successfully treat anemia . This mode of micronutrient delivery is amenable to the delivery of other micronutrients . However , the relative efficacy of multiple micronutrient supplements for the treatment of anemia requires evaluation due to possible nutrient interactions . Thus , we evaluated the relative efficacy of Sprinkles formulated with iron and zinc in anemic infants , compared with Sprinkles formulated with iron alone . We studied 304 anemic infants ( mean age 10.3 + /- 2.5 mo ; hemoglobin 87.4 + /- 8.4 g/L ) in rural Ghana . A combined supplementation group ( FeZn ) received daily Sprinkles containing 80 mg iron and 10 mg zinc ; a comparison group ( Fe ) received Sprinkles ( 80 mg iron ) without zinc for 2 mo . The rate of recovery from anemia was higher in the Fe group compared with the FeZn group ( 74.8 vs. 62.9 % ; P = 0.048 ) . The plasma zinc concentration decreased significantly in both groups ( P < 0.05 ) . A significant decline in the height for age Z-score was observed in the FeZn group ( P = 0.0011 ) , but there was no change in the Fe group . These results suggest that in a controlled setting , home-fortification using micronutrient Sprinkles with iron , or iron and zinc , was very successful in treating anemia ; however , this intervention alone was insufficient to improve zinc status or promote catch-up growth in this stunted and wasted population [11976161] BACKGROUND In rural Vietnam , vitamin A deficiency is a concern . Among the indigenous fruit and vegetables , Momordica cochinchinensis ( gac ) fruit has been identified as having the highest beta-carotene concentration . Locally , it is mixed with rice in a preparation called xoi gac . OBJECTIVE The purpose of this study was to assess this beta-carotene- rich rice preparation as a source of provitamin A for children in rural Vietnam . DESIGN Preschoolers ( n = 185 ) participated in a 30-d controlled supplementation trial . Children with low hemoglobin concentrations were assigned to 1 of 3 groups : a fruit group , who received xoi gac that contained 3.5 mg beta-carotene per serving ; a powder group , who received rice mixed with 5.0 mg synthetic beta-carotene powder ; and a control group , who received rice without fortification . RESULTS The mean increase in plasma beta-carotene concentrations in the fruit and powder groups was significantly greater than that in the control group ( P < 0.0001 ) . After supplementation , the mean plasma retinol concentration in the fruit group was significantly higher than that in the control ( P = 0.006 ) and powder ( P = 0.0053 ) groups . Among the children with initial hemoglobin concentrations < or=110 g/L , the mean increase in hemoglobin concentrations in the fruit group was marginally higher than that in the control group ( P = 0.017 ) but was not significantly different from that in the powder group . CONCLUSIONS beta-Carotene from xoi gac is a good source of provitamin A carotenoids . Severely anemic children might particularly benefit from routine xoi gac [24002280] IMPORTANCE In sub-Saharan Africa , malaria is a leading cause of childhood morbidity and iron deficiency is among the most prevalent nutritional deficiencies . In 2006 , the World Health Organization and the United Nations Children 's Fund released a joint statement that recommended limiting use of iron supplements ( tablets or liquids ) among children in malaria-endemic areas because of concern about increased malaria risk . As a result , anemia control programs were either not initiated or stopped in these areas . OBJECTIVE To determine the effect of providing a micronutrient powder ( MNP ) with or without iron on the incidence of malaria among children living in a high malaria-burden area . DESIGN , SETTING , AND PARTICIPANTS Double-blind , cluster r and omized trial of children aged 6 to 35 months ( n = 1958 living in 1552 clusters ) conducted over 6 months in 2010 in a rural community setting in central Ghana , West Africa . A cluster was defined as a compound including 1 or more households . Children were excluded if iron supplement use occurred within the past 6 months , they had severe anemia ( hemoglobin level < 7 g/dL ) , or severe wasting ( weight-for-length z score < -3 ) . INTERVENTIONS Children were r and omized by cluster to receive a MNP with iron ( iron group ; 12.5 mg/d of iron ) or without iron ( no iron group ) . The MNP with and without iron were added to semiliquid home-prepared foods daily for 5 months followed by 1-month of further monitoring . Insecticide-treated bed nets were provided at enrollment , as well as malaria treatment when indicated . MAIN OUTCOMES AND MEASURES Malaria episodes in the iron group compared with the no iron group during the 5-month intervention period . RESULTS In intention-to-treat analyses , malaria incidence overall was significantly lower in the iron group compared with the no iron group ( 76.1 and 86.1 episodes/100 child-years , respectively ; risk ratio ( RR ) , 0.87 [ 95 % CI , 0.79 - 0.97 ] ) , and during the intervention period ( 79.4 and 90.7 episodes/100 child-years , respectively ; RR , 0.87 [ 95 % CI , 0.78 - 0.96 ] ) . In secondary analyses , these differences were no longer statistically significant after adjusting for baseline iron deficiency and anemia status overall ( adjusted RR , 0.87 ; 95 % CI , 0.75 - 1.01 ) and during the intervention period ( adjusted RR , 0.86 ; 95 % CI , 0.74 - 1.00 ) . CONCLUSION AND RELEVANCE In a malaria-endemic setting in which insecticide-treated bed nets were provided and appropriate malaria treatment was available , daily use of a MNP with iron did not result in an increased incidence of malaria among young children . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01001871 [23664200] OBJECTIVE To evaluate the incidence of diarrheal disease ( DD ) and acute respiratory infection ( ARI ) in children undergoing supplementation of zinc and other micronutrients through the use of sprinkles , as well as their acceptance by these patients . METHOD This was a r and omized double-blinded clinical trial of 143 healthy institutionalized children , aged 6 to 48 months . They were r and omized into two groups and received daily zinc and micronutrients - test group ( sprinkles ) , or micronutrients without zinc - control group . Children were supplemented for 90 days and followed regarding the outcomes of DD and ARI . RESULTS Of the r and omized children , 52.45 % belonged to the test and 47.55 % to the control group . The incidence of DD in the test group was 14.7 % and was 19.1 % in the control group . The test group showed a lower risk of developing DD when compared to controls , but this finding was not statistically significant ( RR=0.77 [ 0.37 to 1.6 ] , p=0.5088 ) . ARI had high incidence in both groups , 60 % in the test group and 48.5 % in the control group , with an increased risk of developing the disease in the test group , but with no statistical significance ( RR=1.24 [ 0.91 to 1.68 ] , p=0.1825 ) . Regarding acceptance , the mean percentage of consumption , in days , of the entire content of the sachets containing sprinkles was 95.72 % ( SD=4.9 ) and 96.4 % ( SD=6.2 ) for the test and control groups , respectively . CONCLUSIONS Zinc supplementation through the use of sprinkles did not reduce the incidence of DD or ARI among the evaluated children . The sprinkles were well accepted by all study participants [12756979] OBJECTIVE To compare the effectiveness of microencapsulated iron(II ) fumarate sprinkles ( with and without vitamin A ) , iron(II ) sulfate drops , and placebo sprinkles in preventing recurrence of anaemia and to determine the long-term haematological outcomes in children at high risk of recurrence of anaemia 12 months after the end of supplementation . METHODS A prospect i ve , r and omized , placebo-controlled design was used to study 437 Ghanaian children aged 8 - 20 months who were not anaemic ( haemoglobin > or = 100 g/l ) . Four groups were given microencapsulated iron(II ) fumarate sprinkles , microencapsulated iron(II ) fumarate sprinkles with vitamin A , iron(II ) sulfate drops or placebo sprinkles daily for six months . Primary outcome measures were change in haemoglobin and anaemic status at baseline and study end . Non-anaemic children at the end of the supplementation period were reassessed 12 months after supplementation ended . FINDINGS Overall , 324 children completed the supplementation period . Among the four groups , no significant changes were seen in mean haemoglobin , ferritin or serum retinol values from baseline to the end of the supplementation period . During the trial , 82.4 % ( 267/324 ) of children maintained their non-anaemic status . Sprinkles were well accepted without complications . At 12 months post-supplementation , 77.1 % ( 162/210 ) of children with no intervention remained non-anaemic . This proportion was similar for children among the four groups . CONCLUSION In most children previously treated for anaemia , further supplementation was not needed to maintain their non-anaemic status . These results may have important implication s for community intervention programmes in which initial high-dose treatment is needed because of a high prevalence of anaemia [18811792] Responsive complementary feeding , whereby the mother feeds her child in response to child cues of hunger state and psychomotor abilities , is a problem in some countries , and likely contributes to malnutrition . Interventions are needed to evaluate whether promoting responsive feeding would add any benefit . Using a cluster r and omized field trial , we evaluated a six-session educational programme that emphasized practice of two key behaviours , namely child self-feeding and maternal responsiveness . One hundred mothers and their 12- to 24-month-olds attended the sessions as part of village clusters r and omly assigned to the intervention group . A similar number of controls received sessions on foods to feed and nutritional disorders . Outcomes assessed at pre-test , 2-week post-intervention and again 5-months post-intervention included weight , mouthfuls of food taken , self-feeding and maternal responsiveness . Research assistants , blind to group assignment , observed and coded mother and child behaviours during the midday meal . Secondary measures included foods fed and feeding messages recalled . Analysis was based on intention to treat and accounted for clustering . Only 10 % of each group was lost to follow-up . Weight ( d = 0.28 ) , weight gain ( d = 0.48 ) and child self-feeding ( d = 0.30 ) were significantly higher in the responsive feeding group . Mouthfuls of food eaten and maternal responsiveness were not significantly increased by the intervention . Mothers in the intervention gave their children more vegetables , and spontaneously recalled more feeding messages at the 5-month follow-up . These results provide evidence that self-feeding and weight gain can improve by targeting specific behaviours , while maternal responsiveness may require more intensive strategies [3266642] Background Multiple micronutrient deficiencies , in particular iron deficiency anaemia ( IDA ) is a severe public health problem in Lao People 's Democratic Republic ( Lao PDR ) . Because of the practical difficulties encountered in improving the nutritional adequacy of traditional complementary foods and the limitations associated with the use of liquid iron supplementation for the treatment and prevention of IDA in infants and young children , recently , home-fortification with multivitamins and minerals sprinkles was recommended . This study aims to compare the effect of twice weekly versus daily supplementation with multivitamins and minerals powder ( MMP ) on anaemia prevalence , haemoglobin concentration , and growth in infants and young children in a rural community in Lao PDR . Methods A r and omized trial was conducted in six rural communities . Children aged 6 to 52 months ( n = 336 ) were r and omly assigned to a control group ( n = 110 ) or to one of two intervention groups receiving either two sachets per week ( n = 115 ) or a daily sachet ( n = 111 ) of MMP for 24 weeks ; 331 children completed the study . A finger prick of blood was taken at baseline , at week 12 , and again at week 24 to determine haemoglobin concentration . Anthropometric measurements were taken every 4 weeks . The McNemar test was used to assess within group differences at three time points in the study subjects with anaemia and one-way ANOVA was used to assess changes in mean haemoglobin concentration in the treatment groups . Results MMP supplementation result ed in significant improvements in haemoglobin concentration and in the reduction of anaemia prevalence in the two treatment groups compared with the control group ( p < 0.001 ) . The severely to moderately anaemic children ( Hb < 100 g/L ) on daily supplementation recovered faster than those on twice weekly supplementation . MMP was well accepted and compliance was high in both treatment groups . Overall , the improvement in the weight for age Z-score was very small and not statistically significant across the three study groups . Conclusions MMP supplementation had positive effects in reduction of anaemia prevalence and in improving haemoglobin concentration . For severely to moderately anaemic children , daily MMP supplementation was more effective in improving haemoglobin concentration and reducing anaemia prevalence . A longer intervention period is probably needed to have a positive effect on growth [5079648] Background Despite recommendations supporting optimal breastfeeding , the number of women practicing exclusive breastfeeding ( EBF ) remains low , and few interventions have demonstrated implementation and impact at scale . Alive & Thrive was implemented over a period of 6 y ( 2009–2014 ) and aim ed to improve breastfeeding practice s through intensified interpersonal counseling ( IPC ) , mass media ( MM ) , and community mobilization ( CM ) intervention components delivered at scale in the context of policy advocacy ( PA ) in Bangladesh and Viet Nam . In Bangladesh , IPC was delivered through a large non-governmental health program ; in Viet Nam , it was integrated into government health facilities . This study evaluated the population -level impact of intensified IPC , MM , CM , and PA ( intensive ) compared to st and ard nutrition counseling and less intensive MM , CM , and PA ( non-intensive ) on breastfeeding practice s in these two countries . Methods and Findings A cluster-r and omized evaluation design was employed in each country . For the evaluation sample , 20 sub-districts in Bangladesh and 40 communes in Viet Nam were r and omized to either the intensive or the non-intensive group . Cross-sectional surveys ( n ~ 500 children 0–5.9 mo old per group per country ) were implemented at baseline ( June 7–August 29 , 2010 , in Viet Nam ; April 28–June 26 , 2010 , in Bangladesh ) and endline ( June 16–August 30 , 2014 , in Viet Nam ; April 20–June 23 , 2014 , in Bangladesh ) . Difference-in-differences estimates ( DDEs ) of impact were calculated , adjusting for clustering . In Bangladesh , improvements were significantly greater in the intensive compared to the non-intensive group for the proportion of women who reported practicing EBF in the previous 24 h ( DDE 36.2 percentage points [ pp ] , 95 % CI 21.0–51.5 , p < 0.001 ; prevalence in intensive group rose from 48.5 % to 87.6 % ) and engaging in early initiation of breastfeeding ( EIBF ) ( 16.7 pp , 95 % CI 2.8–30.6 , p = 0.021 ; 63.7 % to 94.2 % ) . In Viet Nam , EBF increases were greater in the intensive group ( 27.9 pp , 95 % CI 17.7–38.1 , p < 0.001 ; 18.9 % to 57.8 % ) ; EIBF declined ( 60.0 % to 53.2 % ) in the intensive group , but less than in the non-intensive group ( 57.4 % to 40.6 % ; DDE 10.0 pp , 95 % CI −1.3 to 21.4 , p = 0.072 ) . Our impact estimates may underestimate the full potential of such a multipronged intervention because the evaluation lacked a “ pure control ” area with no MM or national/provincial PA . Conclusions At-scale interventions combining intensive IPC with MM , CM , and PA had greater positive impacts on breastfeeding practice s in Bangladesh and Viet Nam than st and ard counseling with less intensive MM , CM , and PA . To our knowledge , this study is the first to document implementation and impacts of breastfeeding promotion at scale using rigorous evaluation design s. Strategies to design and deliver similar programs could improve breastfeeding practice s in other context s. Trial registration Clinical Trials.gov NCT01678716 ( Bangladesh ) and NCT01676623 ( Viet Nam [24683674] Background The effectiveness of commonly suggested public health interventions to control childhood iron- deficiency anemia has been low . Objective To determine whether iron provided in Sprinkles daily or in a higher dose once weekly affected hemoglobin , serum ferritin levels , and serum transferrin receptor levels , and to determine whether there were dif- ferences in the effects of the two regimens . Methods In this cluster-r and omized , community- based trial conducted in rural areas of Bangladesh , 136 children aged 12 to 24 months with mild to moderate anemia ( hemoglobin 70–109 g/L ) were r and omly allo- cated to receive Sprinkles daily ( 12.5 mg of elemental iron , n = 79 ) or once weekly ( 30 mg of elemental iron , n = 73 ) for 8 weeks . Hemoglobin , serum ferritin , and serum transferrin receptor were assessed at the start and end of the intervention . Results In both groups , there were significant increases in hemoglobin and serum ferritin and a significant decrease in serum transferrin receptor ( p < .01 ) . There were no significant differences between the groups in the increases in hemoglobin ( 16.1 ± 13.2 g/L for the group receiving Sprinkles daily and 12.3 ± 13.3 g/L for the group receiving Sprinkles once weekly ) and serum ferritin ( 10.6 and 5.7 μg/L , respectively ) . The decrease in serum transferrin receptor also did not significantly differ between the groups ( median , −2.5 and −1 . 8 mg/L , respectively ) . The prevalence rates of iron-deficiency anemia , depleted iron stores , and tissue iron deficiency decreased significantly within each group ( p < .01 ) , with no significant differences between the groups . Conclusions Home fortification of complementary foods with Sprinkles given either daily or once weekly improved iron-deficiency anemia and iron status among young children [19155581] Preschool children in developing countries are likely to have multiple , concurrent micronutrient deficiencies . This study was design ed to evaluate the effectiveness of different combinations of nutritional fortified diet to improve the blood levels of iron , vitamin A and other essential micronutrients in the preschool population of Banan District of Chongqing , China . From December 2005 to June 2006 , a total of 226 2 - 6 y old preschool children were recruited from three nurseries in the area , and they were r and omly assigned to three different fortified diet groups for 6 mo . Group I was fortified with vitamin A ; groups II and III were fortified with vitamin A plus iron and vitamin A plus iron , thiamine , riboflavin , folic acid , niacinamide , zinc and calcium , respectively . Subjects ' weight and height were measured for assessing the children 's growth and development . Blood sample s were taken at the beginning and the end of the 6-mo study period for measuring serum levels of micronutrients . Group III with the multiple micronutrient fortified diet was the most effective to improve the serum level of retinol from [ media ( P25 , P75 ) : 1.06 ( 0.89 , 1.32 ) ] micromol/L to 1.29 ( 1.04 , 1.39 ) micromol/L ( p<0.05 ) and retinol binding protein from 17.0 ( 12.6 , 25.6 ) mg/L to 31.6 ( 24.4 , 44.0 ) mg/L ( p<0.05 ) and to mobilize the stored iron in the liver ( p<0.05 ) . In addition , the three groups ' hemoglobin levels were elevated from 117.0 ( 109.0 , 124.1 ) g/L , 114.0 ( 109.2 , 119.7 ) g/L and 115.0 ( 109.5 , 122.7 ) g/L to 125.7 ( 119.2 , 133.1 ) g/L , 126.5 ( 122.2 , 135.9 ) g/L and 125.1 ( 119.8 , 131.6 ) g/L over the 6 mo of intervention period , but there were no difference among the three groups ( p>0.05 ) . Nevertheless , unexpected results were obtained when comparing the effects on growth status among the different supplement groups . Our study has demonstrated that a multiple micronutrient fortified diet for 6 mo is more effective to improve the levels of hemoglobin , serum retinol , and RBP as well as to facilitate the mobilization of iron storage in preschool children [21178093] Micronutrient powders ( MNP ) are often added to complementary foods high in inhibitors of iron and zinc absorption . Most MNP therefore include high amounts of iron and zinc , but it is no longer recommended in malarial areas to use untargeted MNP that contain the Reference Nutrient Intake for iron in a single serving . The aim was to test the efficacy of a low-iron and -zinc ( each 2.5 mg ) MNP containing iron as NaFeEDTA , ascorbic acid ( AA ) , and an exogenous phytase active at gut pH. In a double-blind controlled trial , South African school children with low iron status ( n = 200 ) were r and omized to receive either the MNP or the unfortified carrier added just before consumption to a high-phytate maize porridge 5 d/wk for 23 wk ; primary outcomes were iron and zinc status and a secondary outcome was somatic growth . Compared with the control , the MNP increased serum ferritin ( P < 0.05 ) , body iron stores ( P < 0.01 ) and weight-for-age Z-scores ( P < 0.05 ) and decreased transferrin receptor ( P < 0.05 ) . The prevalence of iron deficiency fell by 30.6 % ( P < 0.01 ) and the prevalence of zinc deficiency decreased by 11.8 % ( P < 0.05 ) . Absorption of iron from the MNP was estimated to be 7 - 8 % . Inclusion of an exogenous phytase combined with NaFeEDTA and AA may allow a substantial reduction in the iron dose from existing MNP while still delivering adequate iron and zinc . In addition , the MNP is likely to enhance absorption of the high native iron content of complementary foods based on cereals and /or legumes [18586646] The aim of this study was to determine the iron status of infants who consumed porridge cooked in water with added ferrous sulphate . A total of 234 infants , aged 6 - 12 months , were recruited from 36 nurseries in the Democratic Peoples Republic of Korea ( DPRK North Korea ) and r and omly divided into iron ( Fe ) and placebo groups . At baseline , almost half the children had Hb<110 g/L and no significant differences between the two groups were found with regard to hemoglobin concentration and anemia prevalence . The Fe group received rice porridge fortified with 10 mg of iron ( as ferrous sulfate ) per day , added to the water in which the rice was cooked and the placebo group non-fortified cereal for 6 months . After which , the hemoglobin ( Hb ) , serum ferritin ( SF ) and packed cell volume ( PCV ) were measured and it was found that the proportion of children with anemia ( Hb<110 g/L ) was lower ( 24.3 % v 48.1 % p<0.01 ) , the Hb levels ( 117.6 g/L v 109.8 g/L p<0.001 ) and serum ferritin were higher ( 40.7 v 26.8 mcg/L p<0.001 ) ; and iron deficiency anemia ( Hb<110 g/L , SF<12 mcg/L ) was lower in the Fe group ( 3 % v 22 % p<0.001 ) when compared to the placebo group . Ferrous sulphate , added to the water in which rice was cooked , lowered the prevalence of iron deficiency anemia of infants in the DPRK with no adverse reactions . This simple fortification would be suitable as a nationwide program in the DPRK and other countries with large infant nurseries [12362781] To improve the iron status of infants an effort was made to increase the iron content of complementary foods by adding 12.5 mg of elemental iron to the meal in the form of micro-encapsulated ferrous fumarate coated with a lipid . The contents of the packet were sprinkled directly on to infant foods . Relative absorption of iron from this supplement was determined in a prospect i ve r and omized study with 39 infants ( mean age 33.6 ± 5.2 weeks ) with initial hemoglobin values greater than 100 g/L. They were fed two complementary foods ( rice-based and wheat-based ) in which the supplement labeled with stable isotopes of iron 57Fe and 58 Fe was incorporated . The erythrocyte iron incorporation was measured in the blood by inductively coupled plasma mass spectrophotometry . The incorporation of iron was significantly higher 11.9 % p < .001 and 13.3 % p < .001 and no difference was observed with the type of cereal in complementary foods . The use of ferrous fumarate sprinkles has proved to be efficacious in increasing the available iron intake of the infants [5037872] Background : Complementary feeding ( CF ) contributes to child growth and development , but few CF programs are delivered at scale . Alive & Thrive addressed this in Bangladesh through intensified interpersonal counseling ( IPC ) , mass media ( MM ) , and community mobilization ( CM ) . Objective : The objective was to evaluate the impact of providing IPC + MM + CM ( intensive ) compared with st and ard nutrition counseling + less intensive MM + CM ( nonintensive ) on CF practice s and anthropometric measurements . Methods : We used a cluster-r and omized , nonblinded evaluation with cross-sectional surveys [ n = ∼600 and 1090 children 6–23.9 mo and 24–47.9 mo/group , respectively , at baseline ( 2010 ) and n = ∼500 and 1100 children of the same age , respectively , at endline ( 2014 ) ] . We derived difference-in-difference impact estimates ( DDEs ) , adjusting for geographic clustering , infant age , sex , differences in baseline characteristics , and differential change in characteristics over time . Results : Groups were similar at baseline . CF improvements were significantly greater in the intensive than in the nonintensive group [ DDEs : 16.3 , 14.7 , 22.0 , and 24.6 percentage points ( pp ) for minimum dietary diversity , minimum meal frequency , minimum acceptable diet , and consumption of iron-rich foods , respectively ] . In the intensive group , CF practice s were high : 50.4 % for minimum acceptable diet , 63.8 % for minimum diet diversity , 75.1 % for minimum meal frequency , and 78.5 % for consumption of iron-rich foods . Timely introduction of foods improved . Significant , nondifferential stunting declines occurred in intensive ( 6.2 pp ) and nonintensive ( 5.2 pp ) groups in children 24–47.9 mo . Conclusions : The intensive program substantially improved CF practice s compared with the nonintensive program . Large-scale program delivery was feasible and , with the use of multiple platforms , reached 1.7 million households . Nondifferential impacts on stunting were likely due to rapid positive secular trends in Bangladesh . Accelerating linear growth further could require accompanying interventions . This study establishes proof of concept for large-scale behavior change interventions to improve child feeding . This trial was registered at clinical trials.gov as NCT01678716 [20701549] This current pilot trial assessed the feasibility of implementing a point-of-use ( PoU ) micronutrient fortification in preschool setting s. Preschool children ( n = 151 ) aged 36–79 months were r and omized into intervention ( n = 76 ) and control ( n = 75 ) groups , both receiving breakfast maize-porridge with added micronutrient or placebo powder for 52 school days . Process evaluation and early childhood development indicators were used to assess trial feasibility . Process evaluation results showed that the implementation components were feasible and could be delivered with high fidelity . The improvement in hemoglobin concentration in intervention and control groups were not significantly different ( P = 0.250 ) . There was medium likelihood for practical significance for the two global cognitive scores assessed : non-verbal index ( intervention effects : 7.20 ; 95 % confidence interval : 2.60 , 11.81 ; P = 0.002 , effect size : 0.55 ) and mental processing index ( intervention effects : 2.73 ; 95 % confidence interval : 0.25 , 5.70 ; P = 0.072 , effect size : 0.36 ) on the Kaufman Assessment Battery for Children , Second Edition . The lessons from this trial could help in planning/implementing future PoU micronutrient fortification trial among South African preschool children [16684385] OBJECTIVES To examine consumption rates and serum ferritin ( SF ) concentrations ( as a marker of safety ) among schoolchildren ( 3 - 6 years ) provided with daily and weekly micronutrients . DESIGN AND METHODS Micronutrients were provided for one school term ( 13 weeks ) to a kindergarten in northern China as single-dose Sprinkles sachets containing 30 mg of iron as encapsulated ferrous fumarate , 5 mg zinc gluconate , 50 mg vitamin C , 300 microg vitamin A , 7.5 microg vitamin D3 and 150 microg folic acid . Sixteen classrooms were r and omly assigned to : ( 1 ) daily supplements for 5 days a week ( daily group ) ; ( 2 ) weekly supplements ( weekly group ) ; or ( 3 ) no supplements ( control group ) . Consumption of sachets was monitored for each child and SF concentrations were measured at the end of study . R and om effects general linear models and graphs were used to compare the groups . RESULTS A total of 415 children from 16 classrooms entered the study . At the end of the study , mean consumption rates per child were 86 % ( daily group ; st and ard deviation ( SD ) 12 % ) and 87 % ( weekly group ; SD 16 % ) . Median SF concentrations were 71 microg l(-1 ) ( range 27 - 292 microg l(-1 ) ; daily group ) , 55 microg l(-1 ) ( range 11 - 299 microg l(-1 ) ; weekly group ) and 54 microg l(-1 ) ( range 7 - 327 microg l(-1 ) ; control group ) ; the overall difference was not significant ( P=0.06 ) . However , the daily group was significantly different from the control ( P=0.02 ) ; daily and weekly groups had higher SF at lower percentiles and similar SF at higher percentiles compared with the control group . CONCLUSION The high consumption rates and appropriate SF concentrations in the supplemented groups suggest that a short-term school programme with Sprinkles is an efficient and safe way to provide micronutrients ( including iron ) [23167586] To evaluate the sustainability of market-based community distribution of micronutrient powders ( Sprinkles ( ® ) , Hexagon Nutrition , Mumbai , India . ) among pre-school children in Kenya , we conducted in August 2010 a follow-up survey , 18 months after study -related marketing and household monitoring ended . We surveyed 849 children aged 6 - 35 months r and omly selected from 60 study villages . Nutritional biomarkers were measured by fingerstick ; demographic characteristics , Sprinkles purchases and use were assessed through household question naires . We compared Sprinkles use , marketing efforts and biomarker levels with the data from surveys conducted in March 2007 , March 2008 and March 2009 . We used logistic regression to evaluate associations between marketing activities and Sprinkles use in the 2010 survey . At the 2010 follow-up , 21.9 % of children used Sprinkles in the previous 7 days , compared with 64.9 % in 2008 ( P < 0.001 ) . Average intake was 3.2 sachets week(-1 ) in 2008 , 1.6 sachets week(-1 ) in 2009 and 1.1 sachets week(-1 ) in 2010 ( P < 0.001 ) . Factors associated with recent Sprinkles use in 2010 included young age [ 6 - 23 months vs. 24 - 35 months , adjusted odds ratio ( aOR ) = 1.5 , P = 0.02 ] , lowest 2 quintiles of socio-economic status ( aOR = 1.7 , P = 0.004 ) , household attendance at trainings or launches ( aOR = 2.8 , P < 0.001 ) and ever receiving promotional items including free Sprinkles , calendars , cups and t-shirts ( aOR = 1.7 , P = 0.04 ) . In 2010 , there was increased prevalence of anaemia and malaria ( P < 0.001 ) , but not iron deficiency ( P = 0.44 ) , compared with that in 2008 . Sprinkles use in 2010 was associated with decreased iron deficiency ( P = 0.03 ) . Sprinkles coverage reduced after stopping household monitoring and reducing marketing activities . Continued promotion and monitoring of Sprinkles usage may be important components to sustain the programme [17895911] Background / Objectives : Despite repeated public commitments and availability of various forms of iron supplements , rates of anaemia in developing countries remain high . A major reason for this lack of success has been poor adherence . The objective of this study was to compare the effectiveness of daily and flexible administration of micronutrient Sprinkles on adherence , acceptability and haematological status among young children in rural Bangladesh . Subjects/ Methods : A sample of 362 children ( haemoglobin (Hb)⩾70 g l−1 ) aged 6–24 months were cluster-r and omized to receive 60 sachets of Sprinkles either ( i ) daily over 2 months ; ( ii ) flexibly over 3 months ; or ( iii ) flexibly over 4 months . With a flexible regimen , mothers/caregivers decided how frequently to use Sprinkles without exceeding one sachet per day . Adherence was assessed monthly by counting the number of sachets used and acceptability was evaluated through focus group discussion s. Haemoglobin was measured at baseline , at the end of each intervention period and 6 months post-intervention . Results : Mean percent adherence was significantly higher in the flexible-4-month group ( 98 % ) compared to the flexible-3-month ( 93 % ) and daily-2-month ( 88 % ) groups ( P<0.01 ) . Most mothers found flexible administration to be more acceptable than daily due to perceived benefits of use . Hb at the end of intervention was significantly higher in the flexible-4-month group compared to the daily group ( P=0.03 ) . Anaemia prevalence decreased by 65 % in the flexible-4-month group compared to 54 % in the flexible-3-month and 51 % in the daily-2-month groups . Percent of cured children who maintained a non-anaemic status 6 months post-intervention was significantly higher in the flexible-4-month ( 82 % ) and flexible-3-month ( 80 % ) groups than the daily-2-month ( 53 % ) group ( P<0.05 ) . Conclusions : The adherence , acceptability and haematological response to flexible administration over 4 months were found preferable to daily [21750564] Background / Objectives : Multiple micronutrient supplementation with Sprinkles powder and crushable Foodlets tablets may be effective means of controlling micronutrient deficiencies in infants . Their efficacy has not been tested in countries like Iran where wheat as the staple food may affect nutrient bioavailability . This study aim ed to compare the efficacy of Sprinkles , Foodlets and the current supplement ( Drops ) for improving micronutrient status and growth among Iranian infants . Subjects/ Methods : Infants of 6–18 months of age , living in an urban district of Iran were r and omised to receive daily Sprinkles ( n=120 ) , Foodlets ( n=121 ) or Drops ( n=121 ) for 4 months . Haemoglobin ( Hb ) , serum ferritin , serum retinol , serum zinc , 25(OH ) D concentration and anthropometry were assessed at baseline and at 4 months . Results : Iron status improved with all treatments . Drops showed significantly greater changes in Hb and serum ferritin , though changes in anaemia prevalence were not different across groups . Infants having Foodlets and Sprinkles had significantly greater reductions in proportion of children with zinc deficiency compared with Drops . No significant differences in treatment effects were observed for mean serum 25(OH ) D and retinol , or for growth of infants across groups . Conclusion : The study was the first efficacy trial with Sprinkles and Foodlets in the Middle East where wheat or rice is the principal complementary foods . Differences across treatment groups were largely consistent with supplement micronutrient composition for iron and zinc , with no benefit in this population for serum retinol , 25(OH ) D , growth or anthropometric status . The trial identified trade-offs in combining multiple micronutrients in a single delivery mechanism [12887843] OBJECTIVE To evaluate and compare the response between food supplemented with iron in powdered and iron in syrup forms for the treatment of iron deficiency anemia in children aged 1 - 5 years . DESIGN Quasi-experimental study . PLACE AND DURATION OF STUDY This study was conducted at Combined Military Hospital , Multan , from January 2000 to December 2000 . PATIENTS AND METHODS Consecutive 200 cases of iron deficiency anemia , aged 1 - 5 years , were included in the study . Diagnosis was based on history , physical examination , complete blood counts ( CBC ) and serum ferritin levels . The patients were r and omized to receive either iron in syrup form ( Group A ) or equivalent doses of iron powder sprinkled over food ( Group B ) . The patients were followed up with hemoglobin estimation ( Hb ) and reticulocyte response at 2 weeks , 4 weeks and 6 weeks . CBC and serum ferritin were repeated at 6 weeks . RESULTS Over half ( 51 % ) of the patients were between 1 - 2 years of age . One hundred thirty-two were males and 68 females . Most of the patients belonged to poor socioeconomic class . The iron in powder form was better tolerated than iron syrup as this group witnessed fewer episodes of gastrointestinal disturbances . The rise in mean Hb level after 6 weeks of treatment in group A and B was 1.6 g/dl and 1.9 g/dl respectively . Hemoglobin rise in group B was more than group A but this was statistically non-significant ( p > 0.05 ) . There was small but significant ( p < 0.05 ) rise in serum ferritin in both the groups . There was no significant difference between the two groups for response to the two forms of iron administration . CONCLUSION The powdered form of iron is a cost-effective and better tolerated method of iron administration in children and can be considered as an alternate option for the treatment of iron deficiency anemia in children [21208779] This article introduces the approach of GRADE to rating quality of evidence . GRADE specifies four categories-high , moderate , low , and very low-that are applied to a body of evidence , not to individual studies . In the context of a systematic review , quality reflects our confidence that the estimates of the effect are correct . In the context of recommendations , quality reflects our confidence that the effect estimates are adequate to support a particular recommendation . R and omized trials begin as high- quality evidence , observational studies as low quality . " Quality " as used in GRADE means more than risk of bias and so may also be compromised by imprecision , inconsistency , indirectness of study results , and publication bias . In addition , several factors can increase our confidence in an estimate of effect . GRADE provides a systematic approach for considering and reporting each of these factors . GRADE separates the process of assessing quality of evidence from the process of making recommendations . Judgments about the strength of a recommendation depend on more than just the quality of evidence [23602230] BACKGROUND Powders containing iron and other micronutrients are recommended as a strategy to prevent nutritional anaemia and other micronutrient deficiencies in children . We assessed the effects of provision of two micronutrient powder formulations , with or without zinc , to children in Pakistan . METHODS We did a cluster r and omised trial in urban and rural sites in Sindh , Pakistan . A baseline survey identified 256 clusters , which were r and omly assigned ( within urban and rural strata , by computer-generated r and om numbers ) to one of three groups : non-supplemented control ( group A ) , micronutrient powder without zinc ( group B ) , or micronutrient powder with 10 mg zinc ( group C ) . Children in the clusters aged 6 months were eligible for inclusion in the study . Powders were to be given daily between 6 and 18 months of age ; follow-up was to age 2 years . Micronutrient powder sachets for groups B and C were identical except for colour ; investigators and field and supervisory staff were masked to composition of the micronutrient powders until trial completion . Parents knew whether their child was receiving supplementation , but did not know whether the powder contained zinc . Primary outcomes were growth , episodes of diarrhoea , acute lower respiratory tract infection , fever , and incidence of admission to hospital . This trial is registered with Clinical Trials.gov , number NCT00705445 . RESULTS The trial was done between Nov 1 , 2008 , and Dec 31 , 2011 . 947 children were enrolled in group A clusters , 910 in group B clusters , and 889 in group C clusters . Micronutrient powder administration was associated with lower risk of iron-deficiency anaemia at 18 months compared with the control group ( odds ratio [ OR ] for micronutrient powder without zinc=0·20 , 95 % CI 0·11 - 0·36 ; OR for micronutrient powder with zinc=0·25 , 95 % CI 0·14 - 0·44 ) . Compared with the control group , children in the group receiving micronutrient powder without zinc gained an extra 0·31 cm ( 95 % CI 0·03 - 0·59 ) between 6 and 18 months of age and children receiving micronutrient powder with zinc an extra 0·56 cm ( 0·29 - 0·84 ) . We recorded strong evidence of an increased proportion of days with diarrhoea ( p=0·001 ) and increased incidence of bloody diarrhoea ( p=0·003 ) between 6 and 18 months in the two micronutrient powder groups , and reported chest indrawing ( p=0·03 ) . Incidence of febrile episodes or admission to hospital for diarrhoea , respiratory problems , or febrile episodes did not differ between the three groups . INTERPRETATION Use of micronutrient powders reduces iron-deficiency anaemia in young children . However , the excess burden of diarrhoea and respiratory morbidities associated with micronutrient powder use and the very small effect on growth recorded suggest that a careful assessment of risks and benefits must be done in population s with malnourished children and high diarrhoea burdens . FUNDING Bill & Melinda Gates Foundation [16881929] Home-fortification of complementary foods with micronutrients ( including iron ) as Sprinkles is a new strategy to control iron deficiency and anaemia in developing countries . However , the most effective dose and form of iron is not known . The purpose of this study was to compare the efficacy of various doses ( 12.5 , 20 or 30 mg ) and treatment methods ( multi-micronutrient Sprinkles vs. ferrous sulphate drops ) on haemoglobin ( Hb ) concentration after 8 weeks of treatment in anaemic children . In total , 133 anaemic Ghanaian children ( Hb 70 - 99 g L(-1 ) ) aged 6 - 18 months were r and omly assigned to one of five daily interventions for 8 weeks . Out of the five interventions , four used Sprinkles , and one used iron drops . Of the four Sprinkles groups , three included 12.5 , 20 or 30 mg of iron as ferrous fumarate , and one included 20 mg of iron as ferric pyrophosphate . The iron drops group included 12.5 mg of iron as liquid ferrous sulphate . Hb concentrations were measured at baseline , week 3 and week 8 . The primary outcome measure was Hb concentration at 8 weeks after treatment . We compared differences in Hb and ferritin concentrations and prevalence of iron deficiency anaemia ( Hb < 100 g L(-1 ) and soluble transferrin receptor concentrations > 8.5 mg L(-1 ) ) from baseline to 8 weeks within and between groups . Adherence and reporting of side effects ( staining of the teeth , ease of use , diarrhoea and darkening of stools ) were compared between groups . Mean change in Hb was 1.4 g L(-1 ) ( SD = 1.8 ) ( P = 0.0001 ) . Change in Hb concentrations from baseline to 8 weeks was significant in all groups ( P = 0.0001 - 0.0007 ) , with no differences across groups . Geometric means of serum ferritin varied from 18.6 to 44.0 microg L(-1 ) at baseline . At week 8 , these means were in the interval of 48.0 - 78.3 microg L(-1 ) , with no group differences . Prevalence of iron deficiency anaemia decreased significantly from baseline to 8 weeks in all groups with the exception of the iron drops group , with no group differences . Adherence was lower in the drops group ( 64 % ) as compared with Sprinkles groups ( 84 % ) . Greater staining of the teeth and less ease of use were reported in the drops group as compared with Sprinkles groups . A dose as low as 12.5 mg of iron as ferrous fumarate when provided as Sprinkles may be effective in anaemic children [19111318] OBJECTIVE To determine whether low-income infants ' adherence to nutritional supplementation with ferrous fumarate sprinkles was better than that with ferrous sulfate drops . STUDY DESIGN The study was a r and omized clinical trial of healthy 6-month-old infants . Each infant received either a daily packet of sprinkles or a dropperful of liquid . Follow-up included alternating telephone and home visits biweekly for 3 months . Adherence was defined as high if the infant 's caregiver reported supplement use on 5 to 7 days during the week before assessment . Side effects and caregiver attitude about supplements were secondary outcomes . Analyses were conducted using generalized estimating equations and chi(2 ) and Wilcoxon rank-sum tests . RESULTS A total of 150 of 225 eligible infants were enrolled . Adherence to supplementation was generally poor . High adherence ranged from 32 % to 63 % at any assessment in the subjects receiving drops , compared with 30 % to 46 % in those receiving sprinkles . The drops group was more likely to have at least four assessment s with high adherence ( 22 % vs 9.5 % ; P = .03 ) . Caregivers of the drops infants were more likely to report greater than usual fussiness ( P < .01 ) ; however , fussiness had no consistent impact on adherence . CONCLUSIONS The use of ferrous fumarate sprinkles rather than traditional ferrous sulfate drops did not improve adherence with daily iron supplementation in low-income infants [23723079] Objective To assess the effectiveness of micronutrient powder ( MNP ) supplementation in reducing anemia levels in children aged 6 mo to 6 y in India . Methods Sixty sachets of MNP ( Sprinkles Plus ) were administered flexibly over a 4 mo period to 17,124 children at anganwadi centers or at home through Integrated Child Development Services ( ICDS ) . Compliance was monitored using compliance cards and an assessment of mother ’s recall at post-intervention survey . Hemoglobin was measured in separate r and om sample s of 1,786 children before and 1,782 children after MNP supplementation . Results Mean compliance rate was estimated at 56.4 % ( based on mother ’s recall ) and 91.7 % ( based on compliance cards ) for children who received MNP at home . Mean compliance was 96.9 % ( based on compliance cards ) for children who received MNP at anganwadis . A significant reduction in anemia ( 50 % to 33 % in boys ; p-value < .000 ; 47.4 % to 34.2 % in girls ) was seen following MNP supplementation . Conclusions Integration of a flexibly administered MNP supplementation into the ICDS is effective in reducing and treating anemia in children 6 mo to 6 y age [17351300] UNLABELLED Iron supplementation programs using pediatric tablets or drops have not been successful in the control of anemia amongst infants and children in India . Sprinkles is an innovative multi-micronutrient home fortification strategy to control iron deficiency and anemia . OBJECTIVE We aim ed to determine the hematologic response to different doses and forms of iron in Sprinkles and iron drops . SETTING Twenty two villages of Vadu Rural Health Program , KEM Hospital , Pune . DESIGN Double blind clustered r and omized community-based trial . SUBJECTS Children ( n=432 ) aged 6 to 18 mo age with Hb between 70 to 100 g/L were enrolled . METHODS Selected villages were r and omized into 5 groups : Sprinkles 12.5 , 20 or 30 mg ferrous fumarate , Sprinkles 20 mg micronized ferric pyrophosphate or drops 20 mg ferrous glycine sulphate ( DROPS ) for 8 weeks . Household socio-demographic information was collected at baseline . Side effects and compliance were monitored through weekly visits . Hemoglobin was estimated at baseline , 3 and 8 weeks . Ferritin was assessed at baseline and 8 weeks . RESULTS Baseline characteristics were similar across all groups . Hemoglobin increased significantly ( P<0.0001 ) in all groups at 8 weeks with no difference between groups . Ferritin increased ( P<0.0001 ) significantly in all groups with no difference across the groups . Compliance ( overall range : 42 to 62 % ) was lowest for DROPS . Side effects were significantly higher among DROPS compared to Sprinkles ( p>0.05 ) . CONCLUSIONS Sprinkles 12.5 mg FF dose is as efficacious as higher doses of iron in Sprinkles or DROPS in increasing hemoglobin . Sprinkles FF 12.5 mg is recommended as it has fewer reported side effects and better compliance compared to DROPS [20973465] Background Iron-deficiency anemia is widespread among young children in the Kyrgyz Republic , and there is an urgent need to identify an effective intervention to address this significant public health problem . Objective To test the effectiveness of a 2-month intervention with daily home fortification of complementary food using micronutrient powder ( Sprinkles ) in reducing anemia among children 6 to 36 months of age in the Kyrgyz Republic . Methods In this cluster-r and omized , community-based effectiveness trial conducted in three regions of the Kyrgyz Republic , 24 clusters of children aged 6 to 36 months were r and omly assigned to two groups . The intervention group ( 12 clusters , n = 1,103 ) received 60 sachets of micronutrient powder ( 12.5 mg elemental iron ) , which were taken as one sachet daily for 2 months . The control group ( 12 clusters , n = 1,090 ) did not receive micronutrient powder until after the study period . Blood hemoglobin concentration was assessed at the start and end of the intervention . Results From baseline to follow-up , the mean hemoglobin concentration in the intervention group increased by 7 g/L , whereas it decreased by 2 g/L in the control group ( p < .001 ) . The prevalence of anemia ( hemoglobin < 110 g/L ) in the intervention group decreased from 72 % at baseline to 52 % at follow-up , whereas it increased from 72 % to 75 % in the control group ( p < .001 ) . Compliance with the intervention was high , with children consuming on average 45 of the 60 sachets given . Conclusions A course of 60 Sprinkles micronutrient powder sachets taken daily for 2 months is effective in improving hemoglobin levels and reducing the prevalence of anemia among young children in the Kyrgyz Republic [22492366] BACKGROUND Although the efficacy of micronutrient powders [ MNPs ; eg , Sprinkles MNP ( Sprinkles Global Health Initiative ) ] in the reduction of anemia has been established , the effectiveness of these powders in real-world programs has seldom been assessed . OBJECTIVE In this study , we evaluated the effect of community-based marketing and distribution of Sprinkles MNP on childhood rates of anemia and iron and vitamin A deficiency . DESIGN In a cluster-r and omized trial in children aged 6 - 35 mo in Western Kenya , 60 villages were r and omly assigned to either intervention or control groups . Community vendors marketed and sold sachets of Sprinkles MNP in intervention villages . Biweekly household visits monitored the use of Sprinkles MNP . Hemoglobin , ferritin , retinol binding protein , malaria , and anthropometric measures were assessed at baseline ( n = 1063 ) and 12 mo of follow-up ( n = 862 ) . Data were analyzed by using an intention-to-treat analysis and generalized linear mixed models . RESULTS On average , 33 % of households in intervention villages purchased Sprinkles MNP ; the average weekly intake per child was 0.9 sachets ( ∼11.3 mg Fe and ∼328 μg vitamin A ) . Compared with control subjects , intervention children had greater improvements in hemoglobin concentrations ( increase of 0.9 compared with 0.6 g/dL , respectively ; P = 0.02 ) , iron deficiency ( decrease of 19.3 % compared with 5.3 % , respectively ; P = 0.001 ) , and vitamin A deficiency ( decrease of 7.5 % compared with an increase of 2.5 % , respectively ; P = 0.01 ) . Results adjusted for age , sex , socioeconomic status , and maternal education showed a significant association between the hemoglobin , iron , and vitamin A concentrations of children and the number of Sprinkles MNP sachets the children consumed . The prevalence of malaria , wasting , and stunting did not change significantly in either group . CONCLUSION Even with relatively low and infrequent use , Sprinkles MNP sales through community vendors were associated with decreased rates of anemia and iron and vitamin A deficiency in children in a re source -poor setting . This trial was registered at clinical trials.gov as NCT01088958 [19219236] This was a double-blind , placebo-controlled , community-based trial . For 16 weeks , children in the intervention group ( n = 180 ) received iron-fortified rice , while children in the control group ( n = 174 ) received rice with placebo . Anemia was defined as hemoglobin < 11.0g/dL. Student 's t-test was used to compare mean variation in hemoglobin between the groups . Hemoglobin concentration improved in both groups , with a mean increase of 0.42g/ dL in the intervention group ( 11.28+/-1.23g/dL to 11.75+/-1.16g/dL , p < 0.001 ) , and 0.49g/dL in controls ( 11.06+/-1.13g/dL to 11.51+/-1.16g/dL , p < 0.001 ) . Anemia decreased ( p < 0.01 ) in both groups ( 37.8 % to 23.3 % in the intervention group and 45.4 % to 33.3 % in controls ) , with no significant difference between the two . Hemoglobin increase was significantly higher in children that received total iron = 53.76 mg from fortified rice , compared to those who received less than this cut-off value ( 0.94g/dl vs. 0.39g/dl , p = 0.03 ) . The findings suggest that this type of intervention can be useful in anemia control as long as fortified food intake is adequate [19927606] Objective Multiple micronutrient deficiencies exist in many developing countries . We conducted a study to test the efficacy of ferrous glycine phosphate in reducing anemia and of riboflavin in reducing angular stomatitis when these micronutrients were added to the noon meal for schoolchildren . Methods A pre- and post-test design was used to study children 5 to 9 years of age , with an experimental and a control group . Two schools in the same locality in Chennai were chosen for the study . The experimental school had 65 children and the control school had 71 children , all of whom consumed a noon meal at the school daily . The children in the experimental school received a powder containing ferrous glycine phosphate and riboflavin , which was added to the meal during cooking every day for 6 months . The dosage was 28 mg of elemental iron and 1 mg of riboflavin per child per day . The children attended school for 5 days each week from Monday to Friday , except for holidays ; they received the fortificants on 100 days during the 6-month period . There was no intervention in the control school . Children in the experimental and control groups were matched by socioeconomic status , age , and eating habits at baseline . All the children in the experimental and control schools were dewormed at baseline and at endline after 6 months . Hemoglobin was measured by the cynamethemoglobin method at baseline and endline . Results Binary logistic regression showed a significant ( p < .001 ) time x group interaction for anemia . The prevalence of anemia in the experimental school was 69.0 % at baseline and 32.8 % after 100 days of intervention over 6 months , a statistically significant change ( p < .001 ) . The prevalence of anemia in the control school was 91.5 % at baseline and increased to 97.2 % at endline ; the increase was not statistically significant . The prevalence of angular stomatitis was reduced from 21 % at baseline to 0 % at endline in the experimental school , whereas it was 23 % at baseline and 20 % at endline in the control school . Conclusions The added fortificants reduced the prevalence of the micronutrient deficiencies [16556612] Aims : To examine the effect of the daily use of micronutrients ( including zinc ) or the same micronutrients plus heat inactivated lactic acid bacteria ( LAB ) , on diarrhoea in children compared to placebo . Methods : A triple blind r and omised clinical trial in an urban slum of Karachi , Pakistan . Micronutrients ( including zinc ) , micronutrients ( including zinc and LAB ) , or placebo , were provided daily for two months to 75 young children ( aged 6–12 months ) identified at high risk for diarrhoea related mortality on the basis of history of at least one episode of diarrhoea in the preceding two weeks . The longitudinal prevalence of diarrhoea was defined as the percentage of days a child had diarrhoea out of the days the child was observed . Results : Mean longitudinal prevalence of diarrhoea in the micronutrient – zinc group was 15 % ( SD = 10 % ) child-days compared to 26 % ( SD = 20 % ) child-days in the placebo group and 26 % ( SD = 19 % ) child-days in the micronutrient – zinc – LAB group . The difference between the micronutrient – zinc – LAB and placebo groups was not significant . Conclusion : The daily provision of micronutrients ( including zinc ) reduces the longitudinal prevalence of diarrhoea and thus may also reduce diarrhoea related mortality in young children ; heat inactivated LAB has negative effects in these children [21502222] OBJECTIVES : The goal of this study was to determine if a responsive stimulation and feeding intervention improved developmental and nutritional outcomes compared with a regular information-based parenting program . The hypothesis was that mothers in the intervention would exhibit better parenting skills and children would exhibit better developmental and nutritional outcomes than controls . METHODS : A cluster-r and omized field trial was conducted with 302 children aged 8 to 20 months and their mothers in rural Bangladesh who were r and omly assigned according to village to 1 of 3 groups . The control mothers received 12 informational sessions on health and nutrition . The intervention groups received an additional 6 sessions delivered by peer educators who included modeling and coached practice in self-feeding and verbal responsiveness with the child during play . A second intervention group received , along with the sessions , 6 months of a food powder fortified with minerals and vitamins . Developmental outcomes included the Home Observation for Measurement of the Environment ( HOME ) Inventory , mother-child responsive talk , and language development . Nutritional outcomes included weight , height , self-feeding , and mouthfuls eaten . We used analysis of covariance to compare the 3 groups at the posttest and at follow-up , covarying the pretest levels and confounders . RESULTS : At follow-up , responsive stimulation-feeding groups had better HOME inventory scores , responsive talking , language , mouthfuls eaten , and h and -washing . Micronutrient fortification result ed in more weight gain . CONCLUSIONS : A brief behavior-change program that focused on modeling and practice in stimulation and feeding was found to benefit children 's nutrition and language development . Micronutrients benefited children 's weight but not length [20715602] Background There is a lack of peer- review ed literature describing in detail the formative research to develop Sprinkles interventions . Objective To describe community members ' reactions to and experiences using Sprinkles , with an emphasis on acceptability , utilization , and promotion . Methods Fourteen initial focus group discussion s on Sprinkles and a 25-family home study were conducted . For the home study , each child 6 to 59 months of age in the household received 30 sachets ( 1 per day ) . The initial 14 focus group discussion s included mothers , gr and mothers , vendors , women who purchased from vendors , and adults in the general population . Home study families were recruited from participants in the initial 14 focus group discussion s who had at least one child 6 to 59 months of age . Results Sprinkles were highly acceptable to adults and most children ; some children thought Sprinkles were sugar . Most home study families prepared and used Sprinkles correctly . All families reported positive effects , particularly increased appetite , and recommended Sprinkles ; none experienced major problems . Potential barriers identified were lack of knowledge of and experience with Sprinkles , availability of Sprinkles , and cost . Promotional messages targeted to mothers , fathers , all child-care providers , and doctors focused on the positive health effects of Sprinkles . Conclusions Issues related to Sprinkles preparation , use , and barriers required attention before implementation . Locally appropriate visual and written instructions were developed for dissemination . Intervention training sessions and promotions were tailored to answer frequently asked questions , increase knowledge of Sprinkles , and provide tangible evidence of health benefits . Information needs and perceptions changed quickly after use of Sprinkles . Existing levels of Sprinkles awareness and knowledge should be considered when design ing interventions [18803728] This cross-sectional r and omized controlled study assessed the social acceptability of micronutrient fortified cooked lunch meals by schoolchildren in rural Himalayan villages of India , in a program where the cooking and the micronutrient fortification were done at school . Subjects were r and omly assigned to treatment ( 91 ) and control ( 90 ) groups . The treatment group consumed a weighed amount of cooked lunch meals fortified with locally produced multi-micronutrient premix and the control group consumed a weighed amount of the same meals but without added micronutrient premix . After having eaten , subjects were asked to rate , on a 3-point Likert scale using " smiley " faces , the pleasantness of smell , taste , and overall satisfaction with the food . The mean age of study children was 7.96 + /- 1.64 y and 48.6 % were males . The average amounts of food consumed by the treatment and control groups were 345 + /- 114 and 360 + /- 102.4 g , respectively . Addition of the multi-micronutrient premix to school meals did not significantly affect the mean amount of food consumed by the schoolchildren ( P > 0.05 ; independent sample t-test ) . No significant differences were seen between treatment and control groups in terms of ratings for taste , smell , and the general acceptance of the micronutrient fortified or the unfortified school meals . In conclusion , the addition of a multiple micronutrient premix to school meals was well liked by schoolchildren and did not adversely affect their food consumption [19587124] Responsive complementary feeding , whereby the mother feeds her child in response to child cues and psychomotor abilities , is low in some countries and likely contributes to malnutrition . Interventions are needed to evaluate whether promoting responsive feeding would add any benefit . Using a cluster-r and omized field trial , we evaluated a 6-session educational program that emphasized the practice of child self-feeding and maternal responsiveness . A total of 108 mothers and their 8- to 20-mo-old children in 19 clusters were r and omly assigned to the intervention group and 95 in 18 clusters were assigned to the informational control group . Outcomes were assessed at pretest , postintervention , and follow-up . Research assistants , who were unaware of group assignment , observed and coded mother and child midday meal behaviors . At follow-up , the percent of self-fed mouthfuls was 47.8 + /- 42.4 ( mean + /- SD ) in the responsive feeding group children compared with 32.2 + /- 41.0 in the controls ( P = 0.01 ) ; likewise , the number of responsive verbalizations was 6.55 + /- 5.9 in the responsive feeding mothers and 4.62 + /- 4.5 in controls ( P = 0.01 ) . Intervention mothers recalled more messages . Mouthfuls of food eaten by children and weight were equivalent in the 2 groups . Lack of change in foods eaten and small quantities may explain the similarly low levels of weight gain . These results provide evidence that self-feeding and maternal verbal responsiveness , two developmentally important behaviors , can be increased by targeting specific behaviors with appropriate behavior change strategies of modeling and coached practice . Weight gain may require more nutritional input , especially in areas of high food insecurity [25143342] Background In-home iron fortification for infants in developing countries is recommended for control of anaemia , but low absorption typically results in > 80 % of the iron passing into the colon . Iron is essential for growth and virulence of many pathogenic enterobacteria . We determined the effect of high and low dose in-home iron fortification on the infant gut microbiome and intestinal inflammation . Methods We performed two double-blind r and omised controlled trials in 6-month-old Kenyan infants ( n=115 ) consuming home-fortified maize porridge daily for 4 months . In the first , infants received a micronutrient powder ( MNP ) containing 2.5 mg iron as NaFeEDTA or the MNP without iron . In the second , they received a different MNP containing 12.5 mg iron as ferrous fumarate or the MNP without the iron . The primary outcome was gut microbiome composition analysed by 16S pyrosequencing and targeted real-time PCR ( qPCR ) . Secondary outcomes included faecal calprotectin ( marker of intestinal inflammation ) and incidence of diarrhoea . We analysed the trials separately and combined . Results At baseline , 63 % of the total microbial 16S rRNA could be assigned to Bifidobacteriaceae but there were high prevalences of pathogens , including Salmonella Clostridium difficile , Clostridium perfringens , and pathogenic Escherichia coli . Using pyrosequencing , + FeMNPs increased enterobacteria , particularly Escherichia/Shigella ( p=0.048 ) , the enterobacteria/bifidobacteria ratio ( p=0.020 ) , and Clostridium ( p=0.030 ) . Most of these effects were confirmed using qPCR ; for example , + FeMNPs increased pathogenic E. coli strains ( p=0.029 ) . + FeMNPs also increased faecal calprotectin ( p=0.002 ) . During the trial , 27.3 % of infants in + 12.5 mgFeMNP required treatment for diarrhoea versus 8.3 % in −12.5 mgFeMNP ( p=0.092 ) . There were no study -related serious adverse events in either group . Conclusions In this setting , provision of iron-containing MNPs to weaning infants adversely affects the gut microbiome , increasing pathogen abundance and causing intestinal inflammation . Trial registration number NCT01111864 [20605698] OBJECTIVE Improvement of hemoglobin and serum retinol and facilitation of the mobilization of iron storage were achieved with a multiple-micronutrient-fortified diet in preschoolers for 6 mo in a suburb of Chongqing , China . We investigated whether fortification with multiple micronutrients in a diet for preschool children results in changes in children 's infectious morbidity compared with diets fortified solely with vitamin A and with vitamin A plus iron . METHODS From December 2005 to June 2006 , 226 2- to 6-y-old preschool children were recruited from three nurseries r and omly assigned to three different fortified-diet groups for 6 mo . Group I was fortified with vitamin A ; groups II and III were fortified with vitamin A plus iron and vitamin A plus iron , thiamine , riboflavin , folic acid , niacinamide , zinc , and calcium , respectively . The secondary functional outcomes , morbidity of diarrhea and respiratory infection , were collected during supplementation . RESULTS The groups were comparable concerning compliance and loss to follow-up . There was evidence of a lower incidence rate of respiratory-related illnesses , diarrhea-related illness , fewer symptoms of runny nose , cough , and fever , and shorter duration of respiratory-related illnesses and cough for children in group III compared with children in groups I and II . However , there was no significantly or clinical ly important difference between children in groups I and II . CONCLUSION The beneficial effects on infectious morbidity over 6 mo , in addition to some biochemical improvements , highlight the potential of this micronutrient-fortified seasoning powder supplied in a diet for preschool children [28031374] BACKGROUND Promoting adequate nutrition through interventions to improve infant and young child feeding ( IYCF ) has the potential to contribute to child development . OBJECTIVE We examined whether an intensive intervention package that was aim ed at improving IYCF at scale through the Alive & Thrive initiative in Bangladesh also advanced language and gross motor development , and whether advancements in language and gross motor development were explained through improved complementary feeding . METHODS A cluster-r and omized design compared 2 intervention packages : intensive interpersonal counseling on IYCF , mass media campaign , and community mobilization ( intensive ) compared with usual nutrition counseling and mass media campaign ( nonintensive ) . Twenty subdistricts were r and omly assigned to receive either the intensive or the nonintensive intervention . Household surveys were conducted at baseline ( 2010 ) and at endline ( 2014 ) in the same communities ( n = ∼4000 children aged 0 - 47.9 mo for each round ) . Child development was measured by asking mothers if their child had reached each of multiple milestones , with some observed . Linear regression accounting for clustering was used to derive difference-in-differences ( DID ) impact estimates , and path analysis was used to examine developmental advancement through indicators of improved IYCF and other factors . RESULTS The DID in language development between intensive and nonintensive groups was 1.05 milestones ( P = 0.001 ) among children aged 6 - 23.9 mo and 0.76 milestones ( P = 0.038 ) among children aged 24 - 47.9 mo . For gross motor development , the DID was 0.85 milestones ( P = 0.035 ) among children aged 6 - 23.9 mo . The differences observed corresponded to age- and sex-adjusted effect sizes of 0.35 for language and 0.23 for gross motor development . Developmental advancement at 6 - 23.9 mo was partially explained through improved minimum dietary diversity and the consumption of iron-rich food . CONCLUSIONS Intensive IYCF intervention differentially advanced language and gross motor development , which was partially explained through improved complementary feeding . Measuring a diverse set of child outcomes , including functional outcomes such as child development , is important when evaluating integrated nutrition programs . This trial was registered at clinical trials.gov as NCT01678716 [20410083] Anemia and micronutrient deficiencies are common among Indian schoolchildren . We assessed the effectiveness of micronutrient fortification of meals cooked and fortified at school on anemia and micronutrient status of schoolchildren in Himalayan villages of India . In this placebo-controlled , cluster-r and omized study , 499 schoolchildren ( 6 - 10 y ) received either multiple micronutrients ( treatment group ) or placebo ( control group ) as part of school meals ( 6 d/wk ) for 8 mo . Both groups were dewormed at the beginning of the study . The micronutrient premix provided 10 mg iron , 375 microg vitamin A , 4.2 mg zinc , 225 microg folic acid , and 1.35 microg vitamin B-12 for each child per day ( approximately 75 % recommended dietary allowance ) . Blood sample s drawn before and after the intervention were analyzed for hemoglobin , ferritin , retinol , zinc , folate , and vitamin B-12 . Baseline prevalence of anemia ( 37 % ) , iron deficiency anemia ( 10 % ) , low serum ferritin ( 24 % ) , retinol ( 56 % ) , zinc ( 74 % ) , folate ( 68 % ) , and vitamin B-12 ( 17 % ) did not differ between groups . Postintervention , fewer in the treatment group had lower serum retinol [ odds ratio ( OR ) ( 95 % CI ) : 0.57 ( 0.33 - 0.97 ) ] and folate [ OR ( 95 % CI ) : 0.47 ( 0.26 - 0.84 ) ] than the control group . The serum vitamin B-12 concentration decreased in both groups , but the magnitude of change was less in the treatment than in the control group ( P < 0.05 ) . Total body iron ( TBI ) increased in both groups ; however , the change was greater in the treatment than in the control group ( P < 0.05 ) . Micronutrient fortification of school meals by trained school personnel was effective in improving vitamin A , folate , and TBI status while also reducing the magnitude of a decrease in vitamin B-12 status

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### Context: [22801933] OBJECTIVE To evaluate the effectiveness of Sprinkles alongside infant and young child feeding ( IYCF ) education compared with IYCF education alone on anemia , deficiencies in iron , vitamin A , and zinc , and growth in Cambodian infants . DESIGN Cluster-r and omized effectiveness study . SETTING Cambodian rural health district . PARTICIPANTS Among 3112 infants aged 6 months , a r and om sub sample ( n = 1350 ) was surveyed at baseline and 6-month intervals to age 24 months . INTERVENTION Daily micronutrient Sprinkles alongside IYCF education vs IYCF education alone for 6 months from ages 6 to 11 months . MAIN OUTCOME MEASURES Prevalence of anemia ; iron , vitamin A , and zinc deficiencies ; and growth via biomarkers and anthropometry . RESULTS Anemia prevalence ( hemoglobin level < 11.0 g/dL [ to convert to grams per liter , multiply by 10.0 ] ) was reduced in the intervention arm compared with the control arm by 20.6 % at 12 months ( 95 % CI , 9.4 - 30.2 ; P = .001 ) , and the prevalence of moderate anemia ( hemoglobin level < 10.0 g/dL ) was reduced by 27.1 % ( 95 % CI , 21.0 - 31.8 ; P < .001 ) . At 12 and 18 months , iron deficiency prevalence was reduced by 23.5 % ( 95 % CI , 15.6 - 29.1 ; P < .001 ) and 11.6 % ( 95 % CI , 2.6 - 17.9 ; P = .02 ) , respectively . The mean serum zinc concentration was increased at 12 months ( 2.88 μg/dL [ to convert to micromoles per liter , multiply by 0.153 ] ; 95 % CI , 0.26 - 5.42 ; P = .03 ) . There was no statistically significant difference in the prevalence of zinc and vitamin A deficiencies or in growth at any time . CONCLUSIONS Sprinkles reduced anemia and iron deficiency and increased the mean serum zinc concentration in Cambodian infants . Anemia and zinc effects did not persist beyond the intervention period . TRIAL REGISTRATION anzctr.org.au Identifier : ACTRN12608000069358 [9192196] Objective : To compare the efficacy of a daily and a weekly iron supplementation on the hematological status of anemic children living at high altitude . Design : Double blind iron supplementation trial including a placebo control group . Setting : A socioeconomically disadvantaged district of La Paz , Bolivia ( altitude of 4000 m ) . Subjects : Anemic ( hemoglobin concentration≤144 g/L ) , 3.3–8.3 y old children of both sexes . Intervention : Children received a placebo ( n=57 ) or a dose of 3–4 mg of elemental iron per kg body weight ( FeSO4 tablets ) 1 d per week ( n=58 ) or 5 d per week ( n=58 ) for 16 weeks . Results : Hemoglobin and zinc erythrocyte protoporphyrin concentrations improved significantly in supplemented groups but not in the placebo group . Changes in hemoglobin during the study were not significantly different between supplemented groups ( weekly group : 15.2±6.9 g/L and daily group : 18.6±11.1 g/L ) but were different from the placebo group ( 0.5±7.1 g/L , P<0.001 ) . At the end of the supplementation period , the hemoglobin distribution was Gaussian , and similar in both supplemented groups . Adjusting for the initial hemoglobin concentration , final hemoglobin and its changes were similar in both supplemented groups . Conclusion : Weekly iron supplementation is as efficacious as daily iron supplementation in improving iron status and correcting moderate iron deficiency anemia in Bolivian school children living at high altitude . Sponsorship : Program supported in part by ORSTROM , the French Ministry of Foreign Affairs and the National Secretary 's Office of Health , Bolivia [22810982] Few studies have evaluated the impact of fortification with iron-rich foods such as amaranth grain and multi-micronutrient powder ( MNP ) containing low doses of highly bioavailable iron to control iron deficiency anemia ( IDA ) in children . We assessed the efficacy of maize porridge enriched with amaranth grain or MNP to reduce IDA in Kenyan preschool children . In a 16-wk intervention trial , children ( n = 279 ; 12 - 59 mo ) were r and omly assigned to : unrefined maize porridge ( control ; 4.1 mg of iron/meal ; phytate : iron molar ratio 5:1 ) ; unrefined maize ( 30 % ) and amaranth grain ( 70 % ) porridge ( amaranth group ; 23 mg of iron/meal ; phytate : iron molar ratio 3:1 ) ; or unrefined maize porridge with MNP ( MNP group ; 6.6 mg iron/meal ; phytate : iron molar ratio 2.6:1 ; 2.5 mg iron as NaFeEDTA ) . Primary outcomes were anemia and iron status with treatment effects estimated relative to control . At baseline , 38 % were anemic and 30 % iron deficient . Consumption of MNP reduced the prevalence of anemia [ -46 % ( 95 % CI : -67 , -12 ) ] , iron deficiency [ -70 % ( 95 % CI : -89 , -16 ) ] , and IDA [ -75 % ( 95 % CI : -92 , -20 ) ] . The soluble transferrin receptor [ -10 % ( 95 % CI : -16 , -4 ) ] concentration was lower , whereas the hemoglobin ( Hb ) [ 2.7 g/L ( 95 % CI : 0.4 , 5.1 ) ] and plasma ferritin [ 40 % ( 95 % CI : 10 , 95 ) ] concentrations increased in the MNP group . There was no significant change in Hb or iron status in the amaranth group . Consumption of maize porridge fortified with low-dose , highly bioavailable iron MNP can reduce the prevalence of IDA in preschool children . In contrast , fortification with amaranth grain did not improve iron status despite a large increase in iron intake , likely due to high ratio of phytic acid : iron in the meal [17413115] BACKGROUND Children participating in the Integrated Child Development Service ( ICDS ) in India have high rates of iron and vitamin A deficiency . OBJECTIVE The objective was to assess the efficacy of a premix fortified with iron and vitamin A and added at the community level to prepared khichdi , a rice and dal mixture , in increasing iron and vitamin A stores and decreasing the prevalence of iron deficiency , anemia , and vitamin A deficiency . DESIGN This cluster , r and omized , double-blind , controlled trial was initiated in 30 Anganwadi centers ( daycare centers ) in West Bengal state , India . Children aged 36 - 66 mo ( n = 516 ) attending village-based ICDS centers were r and omly assigned to receive either a fortified or a nonfortified premix for 24 wk . Blood was drawn at 0 and 24 wk by venipuncture for the measurement of hemoglobin , serum ferritin , and serum retinol . RESULTS The change in the hemoglobin concentration of anemic children was significantly different between fortified and nonfortified khichdi groups ( P < 0.001 ) . Prevalence rates of anemia , iron deficiency , and iron deficiency anemia were significantly lower after 24 wk in the fortified-khichdi group than in the nonfortified-khichdi group ( P < 0.001 ) . There were no significant differences in serum retinol concentrations or in the prevalence of vitamin A deficiency between the fortified- and nonfortified-khichdi groups . CONCLUSION A premix fortified with iron , vitamin A , and folic acid and added to supplementary food at the community level can be effective at increasing iron stores and reducing the prevalence of iron deficiency and anemia [22705425] To assess the impact of intensive nutrition education ( INE ) with or without the provision of micronutrient powder ( MNP ) on the nutritional status of mildly wasted children in Nias , Indonesia , two groups of mildly wasted ( > = -1.5 to < -1.0 WHZ ) children aged > = 6 to < 60 months in the Church World Service ( CWS ) project areas were assigned by village r and omization to receive INE ( n=64 ) or INE+MNP ( n=51 ) in a weekly program . Another two groups of mildly wasted children who were living at a clear distance from INE and INE+MNP villages were selected to receive a monthly non-intensive nutrition education program ( NNE ) with or without MNP ( n=50 both respectively ) . WHZ , weight , height , haemoglobin ( Hb ) level , and morbidity data were assessed at admission , during the study , and at individual discharge . Children 's weight gain ( g/kg body weight/day ) was highest in INE+MNP group ( 2.2±2.1 ) , followed by INE ( 1.1±0.9 ) , NNE+MNP ( 0.3±0.5 ) and NNE ( 0.3±0.4 ) group . In both MNP intervention groups ( INE+MNP , NNE+MNP ) , supplements significantly increased Hb value ( g/L ) of respective children ( 10.0±10.0 ; p<0.001 and 3.0±8.0 ; p<0.05 respectively ) . Proportion of children who reached discharge criterion was highest among the INE+MNP ( 70.6 % ; n=36 ) , followed by INE ( 64.1 % ; n=41 ) , NNE+MNP ( 26.0 % ; n=13 ) , and NNE ( 20.0 % ; n=10 ) groups ( p<0.001 ) . Shortest length of stay until recovery was observed among children in the INE+MNP group ( 29.9 days ) , followed by INE ( 40.0 days ) , NNE+MNP ( 80.6 days ) , and NNE ( 86.2 days ) respectively ( p<0.001 ) . Weekly intensive nutrition education supported by MNP supplementation produced the best results regarding weight gain and haemoglobin status of mildly wasted children [9846856] BACKGROUND Despite ample food supplies , the incidence of childhood underweight and stunting remains high in Ug and a. Many factors contribute to this situation , but the role of low zinc intakes has not been adequately explored . OBJECTIVE Our objective was to study the effect of zinc supplementation on growth and body composition of preschool children by using the outcome measures of weight , height , and midupper arm circumference ( MUAC ) . DESIGN The study was r and omized , double-blind , placebo-controlled , parallel , and 8 mo long , and incorporated 6 mo of zinc supplementation . Children ( n = 153 ) aged 55.8 + /- 11.2 mo from 3 r and omly selected nursery schools of medium , low , and very low socioeconomic status in a suburb of Kampala took part . The intervention comprised 10 mg Zn ( as ZnSO4 ) or placebo daily in freshly prepared fruit juice , Monday to Friday inclusive . RESULTS Zinc supplementation increased MUAC by the end of the study ( P = 0.029 ) and led to greater weight gain in children from the school of medium socioeconomic status at 3 and 8 mo ( P = 0.019 and P = 0.038 , respectively ) . There was no effect on weight gain of the children from the other schools . Zinc supplementation had no influence on height . Infection rates ( of which 82 % were recorded as malaria ) were lower in the zinc-supplemented group than in control subjects ( P = 0.063 ) . CONCLUSIONS Zinc supplementation may counter the age-related decrease in MUAC often observed in preschool children in developing countries . The study provides evidence that zinc may not be the most limiting nutrient for weight gain in children of poor nutritional status , but may become so as nutritional status improves [15735110] Growth faltering , anemia , and multiple micronutrient deficiency are common during infancy in developing countries . This South African trial was part of a multicenter study aim ed at testing the efficacy of multiple micronutrient supplementation on growth , anemia , micronutrient status , and morbidity during infancy across 4 countries . A total of 265 infants aged 6 - 12 mo were individually r and omized to 1 of 4 intervention groups : a daily multiple micronutrient supplement ( DMM ) , a daily placebo supplement ( P ) ; a multiple micronutrient supplement 1 d of the week and placebo supplement on the other days of the week ( WMM ) , and a daily iron supplement ( DI ) . For 6 mo , the blinded supplements were provided to mothers at monthly health clinic sessions , and consumption was verified during weekly household visits by community health workers , when morbidity was also checked . Weight and height of the infants were measured monthly , and blood sample s were taken at the beginning and at the end for assessing the infants micronutrient status . There were no significant differences in nutritional status of the groups at baseline with 40 % of infants with anemia ( hemoglobin < 110 g/L ) , 16 % vitamin A deficiency ( plasma retinol < 0.7 micromol/L ) , 47 % zinc deficiency ( plasma zinc < 10.7 micromol/L ) , 2 % underweight , and 11 % stunting . There was no difference in growth or morbidity between the micronutrient supplemented groups and the P group during the 6-mo study . The DMM was the most effective intervention tested , not only for improving anemia but also for improving iron , zinc , riboflavin , and tocopherol status [16702330] Anemia and co-existing deficiencies of zinc , iron , iodine , and vitamin A occur among children in many developing countries including NE Thail and , probably contributing to impairments in growth , immune competence , and cognition . Sustainable strategies are urgently required to combat these deficiencies . We assessed the efficacy of a micronutrient-fortified seasoning powder served with a school lunch on reducing anemia and improving the micronutrient status of rural NE Thai children . Children ( n = 569 ) aged 5.5 - 13.4y from 10 schools were r and omly assigned to receive a seasoning powder either unfortified or fortified with zinc ( 5 mg ) , iron ( 5 mg ) , vitamin A ( 270 microg ) , and iodine ( 50 microg ) ( per serving ) and incorporated into a school lunch prepared central ly and delivered 5 d/wk for 31 wk . Teachers monitored school lunch consumption . Baseline and final micronutrient status , hemoglobinopathies , and infection or inflammation were assessed from blood and urine sample s. For the primary outcome , anemia ( based on hemoglobin ) , no intervention effect was apparent ( odds ratio : 1.02 95 % CI : 0.69 , 1.51 ) after adjustment for design strata . The odds of zinc ( based on serum zinc ) and urinary iodine deficiency in the fortified group were 0.63 ( 0.42 , 0.94 ) and 0.52 ( 0.38 , 0.71 ) times those in the unfortified group , respectively . Fortification had no effect on serum retinol ( 0.61 : 0.25,1.51 ) , ferritin ( 1.12 : 0.43 , 2.96 ) , or mean red cell volume ( 1.16 : 0.82 , 1.64 ) . Therefore , a micronutrient-fortified seasoning powder is a promising vehicle for improving zinc , iodine , and hemoglobin status , and its potential for incorporation into lunch programs in day care centers and schools in NE Thail and warrants investigation [18065586] BACKGROUND There is still uncertainty about the best procedure to alleviate iron deficiency . Additionally more reliable methods are needed to assess the effect of iron intervention . OBJECTIVE We examined the efficacy of daily iron ( 10 mg ) , daily and weekly multiple-micronutrient supplementation ( 10 and 20 mg Fe , respectively ) in improving body iron stores of Indonesian infants . DESIGN Infants aged 6 - 12 mo were r and omly allocated to 1 of 4 groups : daily multiple-micronutrients ( DMM ) foodlike tablets ( foodLETs ) , weekly multiple-micronutrient ( WMM ) foodLETs , daily iron ( DI ) foodLETs , or daily placebo . Hemoglobin , ferritin , transferrin receptors , and C-reactive protein data were obtained at baseline and 23 wk . RESULTS Body iron estimated from the ratio of transferrin receptors to ferritin was analyzed for 244 infants . At baseline , mean iron stores ( 0.5 + /- 4.1 mg/kg ) did not differ among the groups , and 45.5 % infants had deficits in tissue iron ( body iron < 0 ) . At week 23 , the group DI had the highest increment in mean body iron ( 4.0 mg/kg ) , followed by the DMM group ( 2.3 mg/kg ; P < 0.001 for both ) . The iron stores in the WMM group did not change , whereas the mean body iron declined in the daily placebo group ( -2.2 mg/kg ; P < 0.001 ) . Compared with the daily placebo group , the DMM group gained 4.55 mg Fe/kg , the DI group gained 6.23 mg Fe/kg ( both P < 0.001 ) , and the WMM group gained 2.54 mg Fe/kg ( P = 0.001 ) . CONCLUSIONS When compliance can be ensured , DI and DMM foodLETs are efficacious in improving and WMM is efficacious in maintaining iron stores among Indonesian infants [18541560] BACKGROUND Reductions in iodine and zinc deficiencies and improvements in hemoglobin were achieved from a micronutrient-fortified seasoning powder consumed in school lunches by children in northeast Thail and . OBJECTIVE The objective was to determine whether fortification with 4 micronutrients in a school lunch results in changes in children 's growth , morbidity , and cognitive function compared with no fortification . DESIGN In a r and omized controlled trial of 569 children aged 5.5 - 13.4 y from 10 schools , we compared the efficacy of a seasoning powder fortified with or without 5 mg Fe , 5 mg Zn , 50 mug I , and 270 mug vitamin A per serving consumed with a school lunch 5 d/wk . Here we report on results of the secondary functional outcomes . RESULTS The groups were comparable concerning compliance and loss to follow-up . The intervention had no statistically significant effect on anthropometric measures over 31 wk , but reduced the incidence of respiratory-related illnesses [ rate ratio ( RR ) : 0.83 ; 95 % CI : 0.73 , 0.94 ] , symptoms of runny nose ( RR : 0.80 ; 95 % CI : 0.70 , 0.92 ) , cough ( RR : 0.80 ; 95 % CI : 0.66 , 0.96 ) , and diarrhea ( RR : 0.38 ; 95 % CI : 0.16 , 0.90 ) . For the visual recall test , those in the fortified group recalled 0.5 more items ( 95 % CI : 0.1 , 0.9 ) than did the controls . There were no statistically significant differences between groups in the results of the digits forward and backward tests or in school grade s at the conclusion of the 2 semesters . CONCLUSION The beneficial effects on morbidity and visual recall over a short period , in addition to some biochemical improvements , highlight the potential of this micronutrient-fortified seasoning powder supplied in a school lunch . This trial was registered at clinical trials.gov as ACTRN12605000341628 [17921387] BACKGROUND Little is known about the combined effect of micronutrients and essential fatty acids on cognitive function in school-aged children . OBJECTIVE We assessed the effect of micronutrients , long-chain n-3 fatty acids , or both on indicators of cognitive performance in well-nourished and marginally nourished school-aged children . DESIGN Two 2-by-2 factorial r and omized controlled double-blind trials were performed home-based in Adelaide , South Australia , and at 6 primary schools in Jakarta , Indonesia . A total of 396 children ( aged 6 - 10 y ) in Australia and 384 children in Indonesia were r and omly allocated to receive a drink with a micronutrient mix ( iron , zinc , folate , and vitamins A , B-6 , B-12 , and C ) , with docosahexanoic acid ( DHA , 88 mg/d ) and eicosapentaenoic acid ( EPA , 22 mg/d ) , or with both or placebo 6 d/wk for 12 mo . Biochemical indicators were determined at baseline and 12 mo . Cognitive performance was measured at baseline , 6 mo , and 12 mo . RESULTS The micronutrient treatment significantly improved plasma micronutrient concentrations in Australian and Indonesian children . DHA+EPA treatment increased plasma DHA and total plasma n-3 fatty acids in both countries . The micronutrient treatment result ed in significant increases in scores on tests representing verbal learning and memory in Australia ( estimated effect size : 0.23 ; 95 % CI : 0.01 , 0.46 ) . A similar effect was observed among Indonesian girls ( estimated effect size : 0.32 ; 95 % CI : -0.01 , 0.64 ) . No effects were found on tests measuring general intelligence or attention . No effects of DHA+EPA on the factors of cognitive tests were observed . CONCLUSION In well-nourished school-aged children , fortification with multiple micronutrients can result in improvements in verbal learning and memory [17374671] We evaluated the effectiveness of a 2-mo treatment of Sprinkles containing 12.5 mg iron , 5 mg zinc , 400 microg vitamin A , 160 microg folic acid , and 30 mg vitamin C in reducing anemia among children 9- to 24 mo old in Haiti . Ten food distribution points ( FDP ) where children received take-home rations of fortified wheat-soy blend ( WSB ) were r and omly allocated into 2 groups : 1 ) Sprinkles-WSB ( S-WSB ) ( 6 FDP ; n = 254 ) , receiving 30 sachets of Sprinkles monthly for 2 mo ; and 2 ) WSB only ( WSB ) ( 4 FDP ; n = 161 ) , not receiving Sprinkles . At baseline , anemia prevalence [ hemoglobin ( Hb ) < 100 g/L ] , adjusted for age and sex , was 54 and 39 % in S-WSB and WSB groups , respectively . After the 2-mo intervention ( 1st follow-up ) , anemia , adjusted for baseline prevalence , age , and sex dropped to 24 % in S-WSB ( P < 0.001 ) and increased to 43 % in WSB ( P = 0.07 ) . At 7 mo postintervention , anemia in S-WSB declined to 14 % ; 92 % of children who were nonanemic at 1st follow-up remained so without further Sprinkles consumption . From baseline to 1st follow-up , mean Hb increased by 5.5 g/L and dropped by 1.0 g/L in the S-WSB and WSB groups , respectively ( P < 0.001 ) . From baseline to 2nd follow-up , mean Hb increased by 10.9 g/L in S-WSB ( P < 0.001 ) . Changes in mean Hb were greater for younger children ( < 21 mo at onset of intervention ) ( P < 0.05 ) and for children who were anemic at baseline ( P < 0.001 ) . In population s with a high prevalence of anemia , such as rural Haiti , 2 mo of Sprinkles are effective in reducing anemia among 9- to 24-mo-old children [11722961] BACKGROUND St and ard therapy for anemia in infants is ferrous sulfate drops administered 3 times/d . Adherence to treatment , however , is often poor . One likely reason for poor adherence is the unpleasant side effects associated with drops . OBJECTIVE The objective was to evaluate the use of a new form of iron and a delivery system to treat anemia in infants that is likely to produce better adherence to treatment . DESIGN Using a prospect i ve , r and omized , controlled design , we studied 557 anemic children aged 6 - 18 mo ( hemoglobin : 70 - 99 g/L ) in rural Ghana . One group received a daily sachet of microencapsulated ferrous fumarate ( 80 mg elemental Fe ) in powder form plus ascorbic acid to be sprinkled onto any complementary food eaten ( sprinkles group ) ; a control group received ferrous sulfate drops 3 times/d for 2 mo ( total dose : 40 mg elemental Fe ) . Hemoglobin and serum ferritin concentrations were measured at baseline and at the end of treatment . RESULTS Successful treatment of anemia ( hemoglobin > 100 g/L ) occurred in 58 % of the sprinkles group and in 56 % of the drops group , with minimal side effects in both groups . Geometric mean ferritin concentrations increased significantly in each group from baseline to the end of treatment ( P < 0.001 ) . CONCLUSION Use of ferrous sulfate drops or a single daily dose of microencapsulated ferrous fumarate sprinkles plus ascorbic acid result ed in a similar rate of successful treatment of anemia without side effects . To our knowledge , this is the first demonstration of the use of microencapsulated iron sprinkles to treat anemia . Improved ease of use may favor the use of sprinkles to deliver iron [12672922] Although iron deficiency is the most common single-nutrient deficiency in infants and children , other deficiencies may develop concurrently , including zinc deficiency . In previous studies , we used home-fortification with " Sprinkles , " single-serve sachets containing microencapsulated ferrous fumarate added to weaning foods , to successfully treat anemia . This mode of micronutrient delivery is amenable to the delivery of other micronutrients . However , the relative efficacy of multiple micronutrient supplements for the treatment of anemia requires evaluation due to possible nutrient interactions . Thus , we evaluated the relative efficacy of Sprinkles formulated with iron and zinc in anemic infants , compared with Sprinkles formulated with iron alone . We studied 304 anemic infants ( mean age 10.3 + /- 2.5 mo ; hemoglobin 87.4 + /- 8.4 g/L ) in rural Ghana . A combined supplementation group ( FeZn ) received daily Sprinkles containing 80 mg iron and 10 mg zinc ; a comparison group ( Fe ) received Sprinkles ( 80 mg iron ) without zinc for 2 mo . The rate of recovery from anemia was higher in the Fe group compared with the FeZn group ( 74.8 vs. 62.9 % ; P = 0.048 ) . The plasma zinc concentration decreased significantly in both groups ( P < 0.05 ) . A significant decline in the height for age Z-score was observed in the FeZn group ( P = 0.0011 ) , but there was no change in the Fe group . These results suggest that in a controlled setting , home-fortification using micronutrient Sprinkles with iron , or iron and zinc , was very successful in treating anemia ; however , this intervention alone was insufficient to improve zinc status or promote catch-up growth in this stunted and wasted population [11976161] BACKGROUND In rural Vietnam , vitamin A deficiency is a concern . Among the indigenous fruit and vegetables , Momordica cochinchinensis ( gac ) fruit has been identified as having the highest beta-carotene concentration . Locally , it is mixed with rice in a preparation called xoi gac . OBJECTIVE The purpose of this study was to assess this beta-carotene- rich rice preparation as a source of provitamin A for children in rural Vietnam . DESIGN Preschoolers ( n = 185 ) participated in a 30-d controlled supplementation trial . Children with low hemoglobin concentrations were assigned to 1 of 3 groups : a fruit group , who received xoi gac that contained 3.5 mg beta-carotene per serving ; a powder group , who received rice mixed with 5.0 mg synthetic beta-carotene powder ; and a control group , who received rice without fortification . RESULTS The mean increase in plasma beta-carotene concentrations in the fruit and powder groups was significantly greater than that in the control group ( P < 0.0001 ) . After supplementation , the mean plasma retinol concentration in the fruit group was significantly higher than that in the control ( P = 0.006 ) and powder ( P = 0.0053 ) groups . Among the children with initial hemoglobin concentrations < or=110 g/L , the mean increase in hemoglobin concentrations in the fruit group was marginally higher than that in the control group ( P = 0.017 ) but was not significantly different from that in the powder group . CONCLUSIONS beta-Carotene from xoi gac is a good source of provitamin A carotenoids . Severely anemic children might particularly benefit from routine xoi gac [24002280] IMPORTANCE In sub-Saharan Africa , malaria is a leading cause of childhood morbidity and iron deficiency is among the most prevalent nutritional deficiencies . In 2006 , the World Health Organization and the United Nations Children 's Fund released a joint statement that recommended limiting use of iron supplements ( tablets or liquids ) among children in malaria-endemic areas because of concern about increased malaria risk . As a result , anemia control programs were either not initiated or stopped in these areas . OBJECTIVE To determine the effect of providing a micronutrient powder ( MNP ) with or without iron on the incidence of malaria among children living in a high malaria-burden area . DESIGN , SETTING , AND PARTICIPANTS Double-blind , cluster r and omized trial of children aged 6 to 35 months ( n = 1958 living in 1552 clusters ) conducted over 6 months in 2010 in a rural community setting in central Ghana , West Africa . A cluster was defined as a compound including 1 or more households . Children were excluded if iron supplement use occurred within the past 6 months , they had severe anemia ( hemoglobin level < 7 g/dL ) , or severe wasting ( weight-for-length z score < -3 ) . INTERVENTIONS Children were r and omized by cluster to receive a MNP with iron ( iron group ; 12.5 mg/d of iron ) or without iron ( no iron group ) . The MNP with and without iron were added to semiliquid home-prepared foods daily for 5 months followed by 1-month of further monitoring . Insecticide-treated bed nets were provided at enrollment , as well as malaria treatment when indicated . MAIN OUTCOMES AND MEASURES Malaria episodes in the iron group compared with the no iron group during the 5-month intervention period . RESULTS In intention-to-treat analyses , malaria incidence overall was significantly lower in the iron group compared with the no iron group ( 76.1 and 86.1 episodes/100 child-years , respectively ; risk ratio ( RR ) , 0.87 [ 95 % CI , 0.79 - 0.97 ] ) , and during the intervention period ( 79.4 and 90.7 episodes/100 child-years , respectively ; RR , 0.87 [ 95 % CI , 0.78 - 0.96 ] ) . In secondary analyses , these differences were no longer statistically significant after adjusting for baseline iron deficiency and anemia status overall ( adjusted RR , 0.87 ; 95 % CI , 0.75 - 1.01 ) and during the intervention period ( adjusted RR , 0.86 ; 95 % CI , 0.74 - 1.00 ) . CONCLUSION AND RELEVANCE In a malaria-endemic setting in which insecticide-treated bed nets were provided and appropriate malaria treatment was available , daily use of a MNP with iron did not result in an increased incidence of malaria among young children . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01001871 [23664200] OBJECTIVE To evaluate the incidence of diarrheal disease ( DD ) and acute respiratory infection ( ARI ) in children undergoing supplementation of zinc and other micronutrients through the use of sprinkles , as well as their acceptance by these patients . METHOD This was a r and omized double-blinded clinical trial of 143 healthy institutionalized children , aged 6 to 48 months . They were r and omized into two groups and received daily zinc and micronutrients - test group ( sprinkles ) , or micronutrients without zinc - control group . Children were supplemented for 90 days and followed regarding the outcomes of DD and ARI . RESULTS Of the r and omized children , 52.45 % belonged to the test and 47.55 % to the control group . The incidence of DD in the test group was 14.7 % and was 19.1 % in the control group . The test group showed a lower risk of developing DD when compared to controls , but this finding was not statistically significant ( RR=0.77 [ 0.37 to 1.6 ] , p=0.5088 ) . ARI had high incidence in both groups , 60 % in the test group and 48.5 % in the control group , with an increased risk of developing the disease in the test group , but with no statistical significance ( RR=1.24 [ 0.91 to 1.68 ] , p=0.1825 ) . Regarding acceptance , the mean percentage of consumption , in days , of the entire content of the sachets containing sprinkles was 95.72 % ( SD=4.9 ) and 96.4 % ( SD=6.2 ) for the test and control groups , respectively . CONCLUSIONS Zinc supplementation through the use of sprinkles did not reduce the incidence of DD or ARI among the evaluated children . The sprinkles were well accepted by all study participants [12756979] OBJECTIVE To compare the effectiveness of microencapsulated iron(II ) fumarate sprinkles ( with and without vitamin A ) , iron(II ) sulfate drops , and placebo sprinkles in preventing recurrence of anaemia and to determine the long-term haematological outcomes in children at high risk of recurrence of anaemia 12 months after the end of supplementation . METHODS A prospect i ve , r and omized , placebo-controlled design was used to study 437 Ghanaian children aged 8 - 20 months who were not anaemic ( haemoglobin > or = 100 g/l ) . Four groups were given microencapsulated iron(II ) fumarate sprinkles , microencapsulated iron(II ) fumarate sprinkles with vitamin A , iron(II ) sulfate drops or placebo sprinkles daily for six months . Primary outcome measures were change in haemoglobin and anaemic status at baseline and study end . Non-anaemic children at the end of the supplementation period were reassessed 12 months after supplementation ended . FINDINGS Overall , 324 children completed the supplementation period . Among the four groups , no significant changes were seen in mean haemoglobin , ferritin or serum retinol values from baseline to the end of the supplementation period . During the trial , 82.4 % ( 267/324 ) of children maintained their non-anaemic status . Sprinkles were well accepted without complications . At 12 months post-supplementation , 77.1 % ( 162/210 ) of children with no intervention remained non-anaemic . This proportion was similar for children among the four groups . CONCLUSION In most children previously treated for anaemia , further supplementation was not needed to maintain their non-anaemic status . These results may have important implication s for community intervention programmes in which initial high-dose treatment is needed because of a high prevalence of anaemia [18811792] Responsive complementary feeding , whereby the mother feeds her child in response to child cues of hunger state and psychomotor abilities , is a problem in some countries , and likely contributes to malnutrition . Interventions are needed to evaluate whether promoting responsive feeding would add any benefit . Using a cluster r and omized field trial , we evaluated a six-session educational programme that emphasized practice of two key behaviours , namely child self-feeding and maternal responsiveness . One hundred mothers and their 12- to 24-month-olds attended the sessions as part of village clusters r and omly assigned to the intervention group . A similar number of controls received sessions on foods to feed and nutritional disorders . Outcomes assessed at pre-test , 2-week post-intervention and again 5-months post-intervention included weight , mouthfuls of food taken , self-feeding and maternal responsiveness . Research assistants , blind to group assignment , observed and coded mother and child behaviours during the midday meal . Secondary measures included foods fed and feeding messages recalled . Analysis was based on intention to treat and accounted for clustering . Only 10 % of each group was lost to follow-up . Weight ( d = 0.28 ) , weight gain ( d = 0.48 ) and child self-feeding ( d = 0.30 ) were significantly higher in the responsive feeding group . Mouthfuls of food eaten and maternal responsiveness were not significantly increased by the intervention . Mothers in the intervention gave their children more vegetables , and spontaneously recalled more feeding messages at the 5-month follow-up . These results provide evidence that self-feeding and weight gain can improve by targeting specific behaviours , while maternal responsiveness may require more intensive strategies [3266642] Background Multiple micronutrient deficiencies , in particular iron deficiency anaemia ( IDA ) is a severe public health problem in Lao People 's Democratic Republic ( Lao PDR ) . Because of the practical difficulties encountered in improving the nutritional adequacy of traditional complementary foods and the limitations associated with the use of liquid iron supplementation for the treatment and prevention of IDA in infants and young children , recently , home-fortification with multivitamins and minerals sprinkles was recommended . This study aims to compare the effect of twice weekly versus daily supplementation with multivitamins and minerals powder ( MMP ) on anaemia prevalence , haemoglobin concentration , and growth in infants and young children in a rural community in Lao PDR . Methods A r and omized trial was conducted in six rural communities . Children aged 6 to 52 months ( n = 336 ) were r and omly assigned to a control group ( n = 110 ) or to one of two intervention groups receiving either two sachets per week ( n = 115 ) or a daily sachet ( n = 111 ) of MMP for 24 weeks ; 331 children completed the study . A finger prick of blood was taken at baseline , at week 12 , and again at week 24 to determine haemoglobin concentration . Anthropometric measurements were taken every 4 weeks . The McNemar test was used to assess within group differences at three time points in the study subjects with anaemia and one-way ANOVA was used to assess changes in mean haemoglobin concentration in the treatment groups . Results MMP supplementation result ed in significant improvements in haemoglobin concentration and in the reduction of anaemia prevalence in the two treatment groups compared with the control group ( p < 0.001 ) . The severely to moderately anaemic children ( Hb < 100 g/L ) on daily supplementation recovered faster than those on twice weekly supplementation . MMP was well accepted and compliance was high in both treatment groups . Overall , the improvement in the weight for age Z-score was very small and not statistically significant across the three study groups . Conclusions MMP supplementation had positive effects in reduction of anaemia prevalence and in improving haemoglobin concentration . For severely to moderately anaemic children , daily MMP supplementation was more effective in improving haemoglobin concentration and reducing anaemia prevalence . A longer intervention period is probably needed to have a positive effect on growth [5079648] Background Despite recommendations supporting optimal breastfeeding , the number of women practicing exclusive breastfeeding ( EBF ) remains low , and few interventions have demonstrated implementation and impact at scale . Alive & Thrive was implemented over a period of 6 y ( 2009–2014 ) and aim ed to improve breastfeeding practice s through intensified interpersonal counseling ( IPC ) , mass media ( MM ) , and community mobilization ( CM ) intervention components delivered at scale in the context of policy advocacy ( PA ) in Bangladesh and Viet Nam . In Bangladesh , IPC was delivered through a large non-governmental health program ; in Viet Nam , it was integrated into government health facilities . This study evaluated the population -level impact of intensified IPC , MM , CM , and PA ( intensive ) compared to st and ard nutrition counseling and less intensive MM , CM , and PA ( non-intensive ) on breastfeeding practice s in these two countries . Methods and Findings A cluster-r and omized evaluation design was employed in each country . For the evaluation sample , 20 sub-districts in Bangladesh and 40 communes in Viet Nam were r and omized to either the intensive or the non-intensive group . Cross-sectional surveys ( n ~ 500 children 0–5.9 mo old per group per country ) were implemented at baseline ( June 7–August 29 , 2010 , in Viet Nam ; April 28–June 26 , 2010 , in Bangladesh ) and endline ( June 16–August 30 , 2014 , in Viet Nam ; April 20–June 23 , 2014 , in Bangladesh ) . Difference-in-differences estimates ( DDEs ) of impact were calculated , adjusting for clustering . In Bangladesh , improvements were significantly greater in the intensive compared to the non-intensive group for the proportion of women who reported practicing EBF in the previous 24 h ( DDE 36.2 percentage points [ pp ] , 95 % CI 21.0–51.5 , p < 0.001 ; prevalence in intensive group rose from 48.5 % to 87.6 % ) and engaging in early initiation of breastfeeding ( EIBF ) ( 16.7 pp , 95 % CI 2.8–30.6 , p = 0.021 ; 63.7 % to 94.2 % ) . In Viet Nam , EBF increases were greater in the intensive group ( 27.9 pp , 95 % CI 17.7–38.1 , p < 0.001 ; 18.9 % to 57.8 % ) ; EIBF declined ( 60.0 % to 53.2 % ) in the intensive group , but less than in the non-intensive group ( 57.4 % to 40.6 % ; DDE 10.0 pp , 95 % CI −1.3 to 21.4 , p = 0.072 ) . Our impact estimates may underestimate the full potential of such a multipronged intervention because the evaluation lacked a “ pure control ” area with no MM or national/provincial PA . Conclusions At-scale interventions combining intensive IPC with MM , CM , and PA had greater positive impacts on breastfeeding practice s in Bangladesh and Viet Nam than st and ard counseling with less intensive MM , CM , and PA . To our knowledge , this study is the first to document implementation and impacts of breastfeeding promotion at scale using rigorous evaluation design s. Strategies to design and deliver similar programs could improve breastfeeding practice s in other context s. Trial registration Clinical Trials.gov NCT01678716 ( Bangladesh ) and NCT01676623 ( Viet Nam [24683674] Background The effectiveness of commonly suggested public health interventions to control childhood iron- deficiency anemia has been low . Objective To determine whether iron provided in Sprinkles daily or in a higher dose once weekly affected hemoglobin , serum ferritin levels , and serum transferrin receptor levels , and to determine whether there were dif- ferences in the effects of the two regimens . Methods In this cluster-r and omized , community- based trial conducted in rural areas of Bangladesh , 136 children aged 12 to 24 months with mild to moderate anemia ( hemoglobin 70–109 g/L ) were r and omly allo- cated to receive Sprinkles daily ( 12.5 mg of elemental iron , n = 79 ) or once weekly ( 30 mg of elemental iron , n = 73 ) for 8 weeks . Hemoglobin , serum ferritin , and serum transferrin receptor were assessed at the start and end of the intervention . Results In both groups , there were significant increases in hemoglobin and serum ferritin and a significant decrease in serum transferrin receptor ( p < .01 ) . There were no significant differences between the groups in the increases in hemoglobin ( 16.1 ± 13.2 g/L for the group receiving Sprinkles daily and 12.3 ± 13.3 g/L for the group receiving Sprinkles once weekly ) and serum ferritin ( 10.6 and 5.7 μg/L , respectively ) . The decrease in serum transferrin receptor also did not significantly differ between the groups ( median , −2.5 and −1 . 8 mg/L , respectively ) . The prevalence rates of iron-deficiency anemia , depleted iron stores , and tissue iron deficiency decreased significantly within each group ( p < .01 ) , with no significant differences between the groups . Conclusions Home fortification of complementary foods with Sprinkles given either daily or once weekly improved iron-deficiency anemia and iron status among young children [19155581] Preschool children in developing countries are likely to have multiple , concurrent micronutrient deficiencies . This study was design ed to evaluate the effectiveness of different combinations of nutritional fortified diet to improve the blood levels of iron , vitamin A and other essential micronutrients in the preschool population of Banan District of Chongqing , China . From December 2005 to June 2006 , a total of 226 2 - 6 y old preschool children were recruited from three nurseries in the area , and they were r and omly assigned to three different fortified diet groups for 6 mo . Group I was fortified with vitamin A ; groups II and III were fortified with vitamin A plus iron and vitamin A plus iron , thiamine , riboflavin , folic acid , niacinamide , zinc and calcium , respectively . Subjects ' weight and height were measured for assessing the children 's growth and development . Blood sample s were taken at the beginning and the end of the 6-mo study period for measuring serum levels of micronutrients . Group III with the multiple micronutrient fortified diet was the most effective to improve the serum level of retinol from [ media ( P25 , P75 ) : 1.06 ( 0.89 , 1.32 ) ] micromol/L to 1.29 ( 1.04 , 1.39 ) micromol/L ( p<0.05 ) and retinol binding protein from 17.0 ( 12.6 , 25.6 ) mg/L to 31.6 ( 24.4 , 44.0 ) mg/L ( p<0.05 ) and to mobilize the stored iron in the liver ( p<0.05 ) . In addition , the three groups ' hemoglobin levels were elevated from 117.0 ( 109.0 , 124.1 ) g/L , 114.0 ( 109.2 , 119.7 ) g/L and 115.0 ( 109.5 , 122.7 ) g/L to 125.7 ( 119.2 , 133.1 ) g/L , 126.5 ( 122.2 , 135.9 ) g/L and 125.1 ( 119.8 , 131.6 ) g/L over the 6 mo of intervention period , but there were no difference among the three groups ( p>0.05 ) . Nevertheless , unexpected results were obtained when comparing the effects on growth status among the different supplement groups . Our study has demonstrated that a multiple micronutrient fortified diet for 6 mo is more effective to improve the levels of hemoglobin , serum retinol , and RBP as well as to facilitate the mobilization of iron storage in preschool children [21178093] Micronutrient powders ( MNP ) are often added to complementary foods high in inhibitors of iron and zinc absorption . Most MNP therefore include high amounts of iron and zinc , but it is no longer recommended in malarial areas to use untargeted MNP that contain the Reference Nutrient Intake for iron in a single serving . The aim was to test the efficacy of a low-iron and -zinc ( each 2.5 mg ) MNP containing iron as NaFeEDTA , ascorbic acid ( AA ) , and an exogenous phytase active at gut pH. In a double-blind controlled trial , South African school children with low iron status ( n = 200 ) were r and omized to receive either the MNP or the unfortified carrier added just before consumption to a high-phytate maize porridge 5 d/wk for 23 wk ; primary outcomes were iron and zinc status and a secondary outcome was somatic growth . Compared with the control , the MNP increased serum ferritin ( P < 0.05 ) , body iron stores ( P < 0.01 ) and weight-for-age Z-scores ( P < 0.05 ) and decreased transferrin receptor ( P < 0.05 ) . The prevalence of iron deficiency fell by 30.6 % ( P < 0.01 ) and the prevalence of zinc deficiency decreased by 11.8 % ( P < 0.05 ) . Absorption of iron from the MNP was estimated to be 7 - 8 % . Inclusion of an exogenous phytase combined with NaFeEDTA and AA may allow a substantial reduction in the iron dose from existing MNP while still delivering adequate iron and zinc . In addition , the MNP is likely to enhance absorption of the high native iron content of complementary foods based on cereals and /or legumes [18586646] The aim of this study was to determine the iron status of infants who consumed porridge cooked in water with added ferrous sulphate . A total of 234 infants , aged 6 - 12 months , were recruited from 36 nurseries in the Democratic Peoples Republic of Korea ( DPRK North Korea ) and r and omly divided into iron ( Fe ) and placebo groups . At baseline , almost half the children had Hb<110 g/L and no significant differences between the two groups were found with regard to hemoglobin concentration and anemia prevalence . The Fe group received rice porridge fortified with 10 mg of iron ( as ferrous sulfate ) per day , added to the water in which the rice was cooked and the placebo group non-fortified cereal for 6 months . After which , the hemoglobin ( Hb ) , serum ferritin ( SF ) and packed cell volume ( PCV ) were measured and it was found that the proportion of children with anemia ( Hb<110 g/L ) was lower ( 24.3 % v 48.1 % p<0.01 ) , the Hb levels ( 117.6 g/L v 109.8 g/L p<0.001 ) and serum ferritin were higher ( 40.7 v 26.8 mcg/L p<0.001 ) ; and iron deficiency anemia ( Hb<110 g/L , SF<12 mcg/L ) was lower in the Fe group ( 3 % v 22 % p<0.001 ) when compared to the placebo group . Ferrous sulphate , added to the water in which rice was cooked , lowered the prevalence of iron deficiency anemia of infants in the DPRK with no adverse reactions . This simple fortification would be suitable as a nationwide program in the DPRK and other countries with large infant nurseries [12362781] To improve the iron status of infants an effort was made to increase the iron content of complementary foods by adding 12.5 mg of elemental iron to the meal in the form of micro-encapsulated ferrous fumarate coated with a lipid . The contents of the packet were sprinkled directly on to infant foods . Relative absorption of iron from this supplement was determined in a prospect i ve r and omized study with 39 infants ( mean age 33.6 ± 5.2 weeks ) with initial hemoglobin values greater than 100 g/L. They were fed two complementary foods ( rice-based and wheat-based ) in which the supplement labeled with stable isotopes of iron 57Fe and 58 Fe was incorporated . The erythrocyte iron incorporation was measured in the blood by inductively coupled plasma mass spectrophotometry . The incorporation of iron was significantly higher 11.9 % p < .001 and 13.3 % p < .001 and no difference was observed with the type of cereal in complementary foods . The use of ferrous fumarate sprinkles has proved to be efficacious in increasing the available iron intake of the infants [5037872] Background : Complementary feeding ( CF ) contributes to child growth and development , but few CF programs are delivered at scale . Alive & Thrive addressed this in Bangladesh through intensified interpersonal counseling ( IPC ) , mass media ( MM ) , and community mobilization ( CM ) . Objective : The objective was to evaluate the impact of providing IPC + MM + CM ( intensive ) compared with st and ard nutrition counseling + less intensive MM + CM ( nonintensive ) on CF practice s and anthropometric measurements . Methods : We used a cluster-r and omized , nonblinded evaluation with cross-sectional surveys [ n = ∼600 and 1090 children 6–23.9 mo and 24–47.9 mo/group , respectively , at baseline ( 2010 ) and n = ∼500 and 1100 children of the same age , respectively , at endline ( 2014 ) ] . We derived difference-in-difference impact estimates ( DDEs ) , adjusting for geographic clustering , infant age , sex , differences in baseline characteristics , and differential change in characteristics over time . Results : Groups were similar at baseline . CF improvements were significantly greater in the intensive than in the nonintensive group [ DDEs : 16.3 , 14.7 , 22.0 , and 24.6 percentage points ( pp ) for minimum dietary diversity , minimum meal frequency , minimum acceptable diet , and consumption of iron-rich foods , respectively ] . In the intensive group , CF practice s were high : 50.4 % for minimum acceptable diet , 63.8 % for minimum diet diversity , 75.1 % for minimum meal frequency , and 78.5 % for consumption of iron-rich foods . Timely introduction of foods improved . Significant , nondifferential stunting declines occurred in intensive ( 6.2 pp ) and nonintensive ( 5.2 pp ) groups in children 24–47.9 mo . Conclusions : The intensive program substantially improved CF practice s compared with the nonintensive program . Large-scale program delivery was feasible and , with the use of multiple platforms , reached 1.7 million households . Nondifferential impacts on stunting were likely due to rapid positive secular trends in Bangladesh . Accelerating linear growth further could require accompanying interventions . This study establishes proof of concept for large-scale behavior change interventions to improve child feeding . This trial was registered at clinical trials.gov as NCT01678716 [20701549] This current pilot trial assessed the feasibility of implementing a point-of-use ( PoU ) micronutrient fortification in preschool setting s. Preschool children ( n = 151 ) aged 36–79 months were r and omized into intervention ( n = 76 ) and control ( n = 75 ) groups , both receiving breakfast maize-porridge with added micronutrient or placebo powder for 52 school days . Process evaluation and early childhood development indicators were used to assess trial feasibility . Process evaluation results showed that the implementation components were feasible and could be delivered with high fidelity . The improvement in hemoglobin concentration in intervention and control groups were not significantly different ( P = 0.250 ) . There was medium likelihood for practical significance for the two global cognitive scores assessed : non-verbal index ( intervention effects : 7.20 ; 95 % confidence interval : 2.60 , 11.81 ; P = 0.002 , effect size : 0.55 ) and mental processing index ( intervention effects : 2.73 ; 95 % confidence interval : 0.25 , 5.70 ; P = 0.072 , effect size : 0.36 ) on the Kaufman Assessment Battery for Children , Second Edition . The lessons from this trial could help in planning/implementing future PoU micronutrient fortification trial among South African preschool children [16684385] OBJECTIVES To examine consumption rates and serum ferritin ( SF ) concentrations ( as a marker of safety ) among schoolchildren ( 3 - 6 years ) provided with daily and weekly micronutrients . DESIGN AND METHODS Micronutrients were provided for one school term ( 13 weeks ) to a kindergarten in northern China as single-dose Sprinkles sachets containing 30 mg of iron as encapsulated ferrous fumarate , 5 mg zinc gluconate , 50 mg vitamin C , 300 microg vitamin A , 7.5 microg vitamin D3 and 150 microg folic acid . Sixteen classrooms were r and omly assigned to : ( 1 ) daily supplements for 5 days a week ( daily group ) ; ( 2 ) weekly supplements ( weekly group ) ; or ( 3 ) no supplements ( control group ) . Consumption of sachets was monitored for each child and SF concentrations were measured at the end of study . R and om effects general linear models and graphs were used to compare the groups . RESULTS A total of 415 children from 16 classrooms entered the study . At the end of the study , mean consumption rates per child were 86 % ( daily group ; st and ard deviation ( SD ) 12 % ) and 87 % ( weekly group ; SD 16 % ) . Median SF concentrations were 71 microg l(-1 ) ( range 27 - 292 microg l(-1 ) ; daily group ) , 55 microg l(-1 ) ( range 11 - 299 microg l(-1 ) ; weekly group ) and 54 microg l(-1 ) ( range 7 - 327 microg l(-1 ) ; control group ) ; the overall difference was not significant ( P=0.06 ) . However , the daily group was significantly different from the control ( P=0.02 ) ; daily and weekly groups had higher SF at lower percentiles and similar SF at higher percentiles compared with the control group . CONCLUSION The high consumption rates and appropriate SF concentrations in the supplemented groups suggest that a short-term school programme with Sprinkles is an efficient and safe way to provide micronutrients ( including iron ) [23167586] To evaluate the sustainability of market-based community distribution of micronutrient powders ( Sprinkles ( ® ) , Hexagon Nutrition , Mumbai , India . ) among pre-school children in Kenya , we conducted in August 2010 a follow-up survey , 18 months after study -related marketing and household monitoring ended . We surveyed 849 children aged 6 - 35 months r and omly selected from 60 study villages . Nutritional biomarkers were measured by fingerstick ; demographic characteristics , Sprinkles purchases and use were assessed through household question naires . We compared Sprinkles use , marketing efforts and biomarker levels with the data from surveys conducted in March 2007 , March 2008 and March 2009 . We used logistic regression to evaluate associations between marketing activities and Sprinkles use in the 2010 survey . At the 2010 follow-up , 21.9 % of children used Sprinkles in the previous 7 days , compared with 64.9 % in 2008 ( P < 0.001 ) . Average intake was 3.2 sachets week(-1 ) in 2008 , 1.6 sachets week(-1 ) in 2009 and 1.1 sachets week(-1 ) in 2010 ( P < 0.001 ) . Factors associated with recent Sprinkles use in 2010 included young age [ 6 - 23 months vs. 24 - 35 months , adjusted odds ratio ( aOR ) = 1.5 , P = 0.02 ] , lowest 2 quintiles of socio-economic status ( aOR = 1.7 , P = 0.004 ) , household attendance at trainings or launches ( aOR = 2.8 , P < 0.001 ) and ever receiving promotional items including free Sprinkles , calendars , cups and t-shirts ( aOR = 1.7 , P = 0.04 ) . In 2010 , there was increased prevalence of anaemia and malaria ( P < 0.001 ) , but not iron deficiency ( P = 0.44 ) , compared with that in 2008 . Sprinkles use in 2010 was associated with decreased iron deficiency ( P = 0.03 ) . Sprinkles coverage reduced after stopping household monitoring and reducing marketing activities . Continued promotion and monitoring of Sprinkles usage may be important components to sustain the programme [17895911] Background / Objectives : Despite repeated public commitments and availability of various forms of iron supplements , rates of anaemia in developing countries remain high . A major reason for this lack of success has been poor adherence . The objective of this study was to compare the effectiveness of daily and flexible administration of micronutrient Sprinkles on adherence , acceptability and haematological status among young children in rural Bangladesh . Subjects/ Methods : A sample of 362 children ( haemoglobin (Hb)⩾70 g l−1 ) aged 6–24 months were cluster-r and omized to receive 60 sachets of Sprinkles either ( i ) daily over 2 months ; ( ii ) flexibly over 3 months ; or ( iii ) flexibly over 4 months . With a flexible regimen , mothers/caregivers decided how frequently to use Sprinkles without exceeding one sachet per day . Adherence was assessed monthly by counting the number of sachets used and acceptability was evaluated through focus group discussion s. Haemoglobin was measured at baseline , at the end of each intervention period and 6 months post-intervention . Results : Mean percent adherence was significantly higher in the flexible-4-month group ( 98 % ) compared to the flexible-3-month ( 93 % ) and daily-2-month ( 88 % ) groups ( P<0.01 ) . Most mothers found flexible administration to be more acceptable than daily due to perceived benefits of use . Hb at the end of intervention was significantly higher in the flexible-4-month group compared to the daily group ( P=0.03 ) . Anaemia prevalence decreased by 65 % in the flexible-4-month group compared to 54 % in the flexible-3-month and 51 % in the daily-2-month groups . Percent of cured children who maintained a non-anaemic status 6 months post-intervention was significantly higher in the flexible-4-month ( 82 % ) and flexible-3-month ( 80 % ) groups than the daily-2-month ( 53 % ) group ( P<0.05 ) . Conclusions : The adherence , acceptability and haematological response to flexible administration over 4 months were found preferable to daily [21750564] Background / Objectives : Multiple micronutrient supplementation with Sprinkles powder and crushable Foodlets tablets may be effective means of controlling micronutrient deficiencies in infants . Their efficacy has not been tested in countries like Iran where wheat as the staple food may affect nutrient bioavailability . This study aim ed to compare the efficacy of Sprinkles , Foodlets and the current supplement ( Drops ) for improving micronutrient status and growth among Iranian infants . Subjects/ Methods : Infants of 6–18 months of age , living in an urban district of Iran were r and omised to receive daily Sprinkles ( n=120 ) , Foodlets ( n=121 ) or Drops ( n=121 ) for 4 months . Haemoglobin ( Hb ) , serum ferritin , serum retinol , serum zinc , 25(OH ) D concentration and anthropometry were assessed at baseline and at 4 months . Results : Iron status improved with all treatments . Drops showed significantly greater changes in Hb and serum ferritin , though changes in anaemia prevalence were not different across groups . Infants having Foodlets and Sprinkles had significantly greater reductions in proportion of children with zinc deficiency compared with Drops . No significant differences in treatment effects were observed for mean serum 25(OH ) D and retinol , or for growth of infants across groups . Conclusion : The study was the first efficacy trial with Sprinkles and Foodlets in the Middle East where wheat or rice is the principal complementary foods . Differences across treatment groups were largely consistent with supplement micronutrient composition for iron and zinc , with no benefit in this population for serum retinol , 25(OH ) D , growth or anthropometric status . The trial identified trade-offs in combining multiple micronutrients in a single delivery mechanism [12887843] OBJECTIVE To evaluate and compare the response between food supplemented with iron in powdered and iron in syrup forms for the treatment of iron deficiency anemia in children aged 1 - 5 years . DESIGN Quasi-experimental study . PLACE AND DURATION OF STUDY This study was conducted at Combined Military Hospital , Multan , from January 2000 to December 2000 . PATIENTS AND METHODS Consecutive 200 cases of iron deficiency anemia , aged 1 - 5 years , were included in the study . Diagnosis was based on history , physical examination , complete blood counts ( CBC ) and serum ferritin levels . The patients were r and omized to receive either iron in syrup form ( Group A ) or equivalent doses of iron powder sprinkled over food ( Group B ) . The patients were followed up with hemoglobin estimation ( Hb ) and reticulocyte response at 2 weeks , 4 weeks and 6 weeks . CBC and serum ferritin were repeated at 6 weeks . RESULTS Over half ( 51 % ) of the patients were between 1 - 2 years of age . One hundred thirty-two were males and 68 females . Most of the patients belonged to poor socioeconomic class . The iron in powder form was better tolerated than iron syrup as this group witnessed fewer episodes of gastrointestinal disturbances . The rise in mean Hb level after 6 weeks of treatment in group A and B was 1.6 g/dl and 1.9 g/dl respectively . Hemoglobin rise in group B was more than group A but this was statistically non-significant ( p > 0.05 ) . There was small but significant ( p < 0.05 ) rise in serum ferritin in both the groups . There was no significant difference between the two groups for response to the two forms of iron administration . CONCLUSION The powdered form of iron is a cost-effective and better tolerated method of iron administration in children and can be considered as an alternate option for the treatment of iron deficiency anemia in children [21208779] This article introduces the approach of GRADE to rating quality of evidence . GRADE specifies four categories-high , moderate , low , and very low-that are applied to a body of evidence , not to individual studies . In the context of a systematic review , quality reflects our confidence that the estimates of the effect are correct . In the context of recommendations , quality reflects our confidence that the effect estimates are adequate to support a particular recommendation . R and omized trials begin as high- quality evidence , observational studies as low quality . " Quality " as used in GRADE means more than risk of bias and so may also be compromised by imprecision , inconsistency , indirectness of study results , and publication bias . In addition , several factors can increase our confidence in an estimate of effect . GRADE provides a systematic approach for considering and reporting each of these factors . GRADE separates the process of assessing quality of evidence from the process of making recommendations . Judgments about the strength of a recommendation depend on more than just the quality of evidence [23602230] BACKGROUND Powders containing iron and other micronutrients are recommended as a strategy to prevent nutritional anaemia and other micronutrient deficiencies in children . We assessed the effects of provision of two micronutrient powder formulations , with or without zinc , to children in Pakistan . METHODS We did a cluster r and omised trial in urban and rural sites in Sindh , Pakistan . A baseline survey identified 256 clusters , which were r and omly assigned ( within urban and rural strata , by computer-generated r and om numbers ) to one of three groups : non-supplemented control ( group A ) , micronutrient powder without zinc ( group B ) , or micronutrient powder with 10 mg zinc ( group C ) . Children in the clusters aged 6 months were eligible for inclusion in the study . Powders were to be given daily between 6 and 18 months of age ; follow-up was to age 2 years . Micronutrient powder sachets for groups B and C were identical except for colour ; investigators and field and supervisory staff were masked to composition of the micronutrient powders until trial completion . Parents knew whether their child was receiving supplementation , but did not know whether the powder contained zinc . Primary outcomes were growth , episodes of diarrhoea , acute lower respiratory tract infection , fever , and incidence of admission to hospital . This trial is registered with Clinical Trials.gov , number NCT00705445 . RESULTS The trial was done between Nov 1 , 2008 , and Dec 31 , 2011 . 947 children were enrolled in group A clusters , 910 in group B clusters , and 889 in group C clusters . Micronutrient powder administration was associated with lower risk of iron-deficiency anaemia at 18 months compared with the control group ( odds ratio [ OR ] for micronutrient powder without zinc=0·20 , 95 % CI 0·11 - 0·36 ; OR for micronutrient powder with zinc=0·25 , 95 % CI 0·14 - 0·44 ) . Compared with the control group , children in the group receiving micronutrient powder without zinc gained an extra 0·31 cm ( 95 % CI 0·03 - 0·59 ) between 6 and 18 months of age and children receiving micronutrient powder with zinc an extra 0·56 cm ( 0·29 - 0·84 ) . We recorded strong evidence of an increased proportion of days with diarrhoea ( p=0·001 ) and increased incidence of bloody diarrhoea ( p=0·003 ) between 6 and 18 months in the two micronutrient powder groups , and reported chest indrawing ( p=0·03 ) . Incidence of febrile episodes or admission to hospital for diarrhoea , respiratory problems , or febrile episodes did not differ between the three groups . INTERPRETATION Use of micronutrient powders reduces iron-deficiency anaemia in young children . However , the excess burden of diarrhoea and respiratory morbidities associated with micronutrient powder use and the very small effect on growth recorded suggest that a careful assessment of risks and benefits must be done in population s with malnourished children and high diarrhoea burdens . FUNDING Bill & Melinda Gates Foundation [16881929] Home-fortification of complementary foods with micronutrients ( including iron ) as Sprinkles is a new strategy to control iron deficiency and anaemia in developing countries . However , the most effective dose and form of iron is not known . The purpose of this study was to compare the efficacy of various doses ( 12.5 , 20 or 30 mg ) and treatment methods ( multi-micronutrient Sprinkles vs. ferrous sulphate drops ) on haemoglobin ( Hb ) concentration after 8 weeks of treatment in anaemic children . In total , 133 anaemic Ghanaian children ( Hb 70 - 99 g L(-1 ) ) aged 6 - 18 months were r and omly assigned to one of five daily interventions for 8 weeks . Out of the five interventions , four used Sprinkles , and one used iron drops . Of the four Sprinkles groups , three included 12.5 , 20 or 30 mg of iron as ferrous fumarate , and one included 20 mg of iron as ferric pyrophosphate . The iron drops group included 12.5 mg of iron as liquid ferrous sulphate . Hb concentrations were measured at baseline , week 3 and week 8 . The primary outcome measure was Hb concentration at 8 weeks after treatment . We compared differences in Hb and ferritin concentrations and prevalence of iron deficiency anaemia ( Hb < 100 g L(-1 ) and soluble transferrin receptor concentrations > 8.5 mg L(-1 ) ) from baseline to 8 weeks within and between groups . Adherence and reporting of side effects ( staining of the teeth , ease of use , diarrhoea and darkening of stools ) were compared between groups . Mean change in Hb was 1.4 g L(-1 ) ( SD = 1.8 ) ( P = 0.0001 ) . Change in Hb concentrations from baseline to 8 weeks was significant in all groups ( P = 0.0001 - 0.0007 ) , with no differences across groups . Geometric means of serum ferritin varied from 18.6 to 44.0 microg L(-1 ) at baseline . At week 8 , these means were in the interval of 48.0 - 78.3 microg L(-1 ) , with no group differences . Prevalence of iron deficiency anaemia decreased significantly from baseline to 8 weeks in all groups with the exception of the iron drops group , with no group differences . Adherence was lower in the drops group ( 64 % ) as compared with Sprinkles groups ( 84 % ) . Greater staining of the teeth and less ease of use were reported in the drops group as compared with Sprinkles groups . A dose as low as 12.5 mg of iron as ferrous fumarate when provided as Sprinkles may be effective in anaemic children [19111318] OBJECTIVE To determine whether low-income infants ' adherence to nutritional supplementation with ferrous fumarate sprinkles was better than that with ferrous sulfate drops . STUDY DESIGN The study was a r and omized clinical trial of healthy 6-month-old infants . Each infant received either a daily packet of sprinkles or a dropperful of liquid . Follow-up included alternating telephone and home visits biweekly for 3 months . Adherence was defined as high if the infant 's caregiver reported supplement use on 5 to 7 days during the week before assessment . Side effects and caregiver attitude about supplements were secondary outcomes . Analyses were conducted using generalized estimating equations and chi(2 ) and Wilcoxon rank-sum tests . RESULTS A total of 150 of 225 eligible infants were enrolled . Adherence to supplementation was generally poor . High adherence ranged from 32 % to 63 % at any assessment in the subjects receiving drops , compared with 30 % to 46 % in those receiving sprinkles . The drops group was more likely to have at least four assessment s with high adherence ( 22 % vs 9.5 % ; P = .03 ) . Caregivers of the drops infants were more likely to report greater than usual fussiness ( P < .01 ) ; however , fussiness had no consistent impact on adherence . CONCLUSIONS The use of ferrous fumarate sprinkles rather than traditional ferrous sulfate drops did not improve adherence with daily iron supplementation in low-income infants [23723079] Objective To assess the effectiveness of micronutrient powder ( MNP ) supplementation in reducing anemia levels in children aged 6 mo to 6 y in India . Methods Sixty sachets of MNP ( Sprinkles Plus ) were administered flexibly over a 4 mo period to 17,124 children at anganwadi centers or at home through Integrated Child Development Services ( ICDS ) . Compliance was monitored using compliance cards and an assessment of mother ’s recall at post-intervention survey . Hemoglobin was measured in separate r and om sample s of 1,786 children before and 1,782 children after MNP supplementation . Results Mean compliance rate was estimated at 56.4 % ( based on mother ’s recall ) and 91.7 % ( based on compliance cards ) for children who received MNP at home . Mean compliance was 96.9 % ( based on compliance cards ) for children who received MNP at anganwadis . A significant reduction in anemia ( 50 % to 33 % in boys ; p-value < .000 ; 47.4 % to 34.2 % in girls ) was seen following MNP supplementation . Conclusions Integration of a flexibly administered MNP supplementation into the ICDS is effective in reducing and treating anemia in children 6 mo to 6 y age [17351300] UNLABELLED Iron supplementation programs using pediatric tablets or drops have not been successful in the control of anemia amongst infants and children in India . Sprinkles is an innovative multi-micronutrient home fortification strategy to control iron deficiency and anemia . OBJECTIVE We aim ed to determine the hematologic response to different doses and forms of iron in Sprinkles and iron drops . SETTING Twenty two villages of Vadu Rural Health Program , KEM Hospital , Pune . DESIGN Double blind clustered r and omized community-based trial . SUBJECTS Children ( n=432 ) aged 6 to 18 mo age with Hb between 70 to 100 g/L were enrolled . METHODS Selected villages were r and omized into 5 groups : Sprinkles 12.5 , 20 or 30 mg ferrous fumarate , Sprinkles 20 mg micronized ferric pyrophosphate or drops 20 mg ferrous glycine sulphate ( DROPS ) for 8 weeks . Household socio-demographic information was collected at baseline . Side effects and compliance were monitored through weekly visits . Hemoglobin was estimated at baseline , 3 and 8 weeks . Ferritin was assessed at baseline and 8 weeks . RESULTS Baseline characteristics were similar across all groups . Hemoglobin increased significantly ( P<0.0001 ) in all groups at 8 weeks with no difference between groups . Ferritin increased ( P<0.0001 ) significantly in all groups with no difference across the groups . Compliance ( overall range : 42 to 62 % ) was lowest for DROPS . Side effects were significantly higher among DROPS compared to Sprinkles ( p>0.05 ) . CONCLUSIONS Sprinkles 12.5 mg FF dose is as efficacious as higher doses of iron in Sprinkles or DROPS in increasing hemoglobin . Sprinkles FF 12.5 mg is recommended as it has fewer reported side effects and better compliance compared to DROPS [20973465] Background Iron-deficiency anemia is widespread among young children in the Kyrgyz Republic , and there is an urgent need to identify an effective intervention to address this significant public health problem . Objective To test the effectiveness of a 2-month intervention with daily home fortification of complementary food using micronutrient powder ( Sprinkles ) in reducing anemia among children 6 to 36 months of age in the Kyrgyz Republic . Methods In this cluster-r and omized , community-based effectiveness trial conducted in three regions of the Kyrgyz Republic , 24 clusters of children aged 6 to 36 months were r and omly assigned to two groups . The intervention group ( 12 clusters , n = 1,103 ) received 60 sachets of micronutrient powder ( 12.5 mg elemental iron ) , which were taken as one sachet daily for 2 months . The control group ( 12 clusters , n = 1,090 ) did not receive micronutrient powder until after the study period . Blood hemoglobin concentration was assessed at the start and end of the intervention . Results From baseline to follow-up , the mean hemoglobin concentration in the intervention group increased by 7 g/L , whereas it decreased by 2 g/L in the control group ( p < .001 ) . The prevalence of anemia ( hemoglobin < 110 g/L ) in the intervention group decreased from 72 % at baseline to 52 % at follow-up , whereas it increased from 72 % to 75 % in the control group ( p < .001 ) . Compliance with the intervention was high , with children consuming on average 45 of the 60 sachets given . Conclusions A course of 60 Sprinkles micronutrient powder sachets taken daily for 2 months is effective in improving hemoglobin levels and reducing the prevalence of anemia among young children in the Kyrgyz Republic [22492366] BACKGROUND Although the efficacy of micronutrient powders [ MNPs ; eg , Sprinkles MNP ( Sprinkles Global Health Initiative ) ] in the reduction of anemia has been established , the effectiveness of these powders in real-world programs has seldom been assessed . OBJECTIVE In this study , we evaluated the effect of community-based marketing and distribution of Sprinkles MNP on childhood rates of anemia and iron and vitamin A deficiency . DESIGN In a cluster-r and omized trial in children aged 6 - 35 mo in Western Kenya , 60 villages were r and omly assigned to either intervention or control groups . Community vendors marketed and sold sachets of Sprinkles MNP in intervention villages . Biweekly household visits monitored the use of Sprinkles MNP . Hemoglobin , ferritin , retinol binding protein , malaria , and anthropometric measures were assessed at baseline ( n = 1063 ) and 12 mo of follow-up ( n = 862 ) . Data were analyzed by using an intention-to-treat analysis and generalized linear mixed models . RESULTS On average , 33 % of households in intervention villages purchased Sprinkles MNP ; the average weekly intake per child was 0.9 sachets ( ∼11.3 mg Fe and ∼328 μg vitamin A ) . Compared with control subjects , intervention children had greater improvements in hemoglobin concentrations ( increase of 0.9 compared with 0.6 g/dL , respectively ; P = 0.02 ) , iron deficiency ( decrease of 19.3 % compared with 5.3 % , respectively ; P = 0.001 ) , and vitamin A deficiency ( decrease of 7.5 % compared with an increase of 2.5 % , respectively ; P = 0.01 ) . Results adjusted for age , sex , socioeconomic status , and maternal education showed a significant association between the hemoglobin , iron , and vitamin A concentrations of children and the number of Sprinkles MNP sachets the children consumed . The prevalence of malaria , wasting , and stunting did not change significantly in either group . CONCLUSION Even with relatively low and infrequent use , Sprinkles MNP sales through community vendors were associated with decreased rates of anemia and iron and vitamin A deficiency in children in a re source -poor setting . This trial was registered at clinical trials.gov as NCT01088958 [19219236] This was a double-blind , placebo-controlled , community-based trial . For 16 weeks , children in the intervention group ( n = 180 ) received iron-fortified rice , while children in the control group ( n = 174 ) received rice with placebo . Anemia was defined as hemoglobin < 11.0g/dL. Student 's t-test was used to compare mean variation in hemoglobin between the groups . Hemoglobin concentration improved in both groups , with a mean increase of 0.42g/ dL in the intervention group ( 11.28+/-1.23g/dL to 11.75+/-1.16g/dL , p < 0.001 ) , and 0.49g/dL in controls ( 11.06+/-1.13g/dL to 11.51+/-1.16g/dL , p < 0.001 ) . Anemia decreased ( p < 0.01 ) in both groups ( 37.8 % to 23.3 % in the intervention group and 45.4 % to 33.3 % in controls ) , with no significant difference between the two . Hemoglobin increase was significantly higher in children that received total iron = 53.76 mg from fortified rice , compared to those who received less than this cut-off value ( 0.94g/dl vs. 0.39g/dl , p = 0.03 ) . The findings suggest that this type of intervention can be useful in anemia control as long as fortified food intake is adequate [19927606] Objective Multiple micronutrient deficiencies exist in many developing countries . We conducted a study to test the efficacy of ferrous glycine phosphate in reducing anemia and of riboflavin in reducing angular stomatitis when these micronutrients were added to the noon meal for schoolchildren . Methods A pre- and post-test design was used to study children 5 to 9 years of age , with an experimental and a control group . Two schools in the same locality in Chennai were chosen for the study . The experimental school had 65 children and the control school had 71 children , all of whom consumed a noon meal at the school daily . The children in the experimental school received a powder containing ferrous glycine phosphate and riboflavin , which was added to the meal during cooking every day for 6 months . The dosage was 28 mg of elemental iron and 1 mg of riboflavin per child per day . The children attended school for 5 days each week from Monday to Friday , except for holidays ; they received the fortificants on 100 days during the 6-month period . There was no intervention in the control school . Children in the experimental and control groups were matched by socioeconomic status , age , and eating habits at baseline . All the children in the experimental and control schools were dewormed at baseline and at endline after 6 months . Hemoglobin was measured by the cynamethemoglobin method at baseline and endline . Results Binary logistic regression showed a significant ( p < .001 ) time x group interaction for anemia . The prevalence of anemia in the experimental school was 69.0 % at baseline and 32.8 % after 100 days of intervention over 6 months , a statistically significant change ( p < .001 ) . The prevalence of anemia in the control school was 91.5 % at baseline and increased to 97.2 % at endline ; the increase was not statistically significant . The prevalence of angular stomatitis was reduced from 21 % at baseline to 0 % at endline in the experimental school , whereas it was 23 % at baseline and 20 % at endline in the control school . Conclusions The added fortificants reduced the prevalence of the micronutrient deficiencies [16556612] Aims : To examine the effect of the daily use of micronutrients ( including zinc ) or the same micronutrients plus heat inactivated lactic acid bacteria ( LAB ) , on diarrhoea in children compared to placebo . Methods : A triple blind r and omised clinical trial in an urban slum of Karachi , Pakistan . Micronutrients ( including zinc ) , micronutrients ( including zinc and LAB ) , or placebo , were provided daily for two months to 75 young children ( aged 6–12 months ) identified at high risk for diarrhoea related mortality on the basis of history of at least one episode of diarrhoea in the preceding two weeks . The longitudinal prevalence of diarrhoea was defined as the percentage of days a child had diarrhoea out of the days the child was observed . Results : Mean longitudinal prevalence of diarrhoea in the micronutrient – zinc group was 15 % ( SD = 10 % ) child-days compared to 26 % ( SD = 20 % ) child-days in the placebo group and 26 % ( SD = 19 % ) child-days in the micronutrient – zinc – LAB group . The difference between the micronutrient – zinc – LAB and placebo groups was not significant . Conclusion : The daily provision of micronutrients ( including zinc ) reduces the longitudinal prevalence of diarrhoea and thus may also reduce diarrhoea related mortality in young children ; heat inactivated LAB has negative effects in these children [21502222] OBJECTIVES : The goal of this study was to determine if a responsive stimulation and feeding intervention improved developmental and nutritional outcomes compared with a regular information-based parenting program . The hypothesis was that mothers in the intervention would exhibit better parenting skills and children would exhibit better developmental and nutritional outcomes than controls . METHODS : A cluster-r and omized field trial was conducted with 302 children aged 8 to 20 months and their mothers in rural Bangladesh who were r and omly assigned according to village to 1 of 3 groups . The control mothers received 12 informational sessions on health and nutrition . The intervention groups received an additional 6 sessions delivered by peer educators who included modeling and coached practice in self-feeding and verbal responsiveness with the child during play . A second intervention group received , along with the sessions , 6 months of a food powder fortified with minerals and vitamins . Developmental outcomes included the Home Observation for Measurement of the Environment ( HOME ) Inventory , mother-child responsive talk , and language development . Nutritional outcomes included weight , height , self-feeding , and mouthfuls eaten . We used analysis of covariance to compare the 3 groups at the posttest and at follow-up , covarying the pretest levels and confounders . RESULTS : At follow-up , responsive stimulation-feeding groups had better HOME inventory scores , responsive talking , language , mouthfuls eaten , and h and -washing . Micronutrient fortification result ed in more weight gain . CONCLUSIONS : A brief behavior-change program that focused on modeling and practice in stimulation and feeding was found to benefit children 's nutrition and language development . Micronutrients benefited children 's weight but not length [20715602] Background There is a lack of peer- review ed literature describing in detail the formative research to develop Sprinkles interventions . Objective To describe community members ' reactions to and experiences using Sprinkles , with an emphasis on acceptability , utilization , and promotion . Methods Fourteen initial focus group discussion s on Sprinkles and a 25-family home study were conducted . For the home study , each child 6 to 59 months of age in the household received 30 sachets ( 1 per day ) . The initial 14 focus group discussion s included mothers , gr and mothers , vendors , women who purchased from vendors , and adults in the general population . Home study families were recruited from participants in the initial 14 focus group discussion s who had at least one child 6 to 59 months of age . Results Sprinkles were highly acceptable to adults and most children ; some children thought Sprinkles were sugar . Most home study families prepared and used Sprinkles correctly . All families reported positive effects , particularly increased appetite , and recommended Sprinkles ; none experienced major problems . Potential barriers identified were lack of knowledge of and experience with Sprinkles , availability of Sprinkles , and cost . Promotional messages targeted to mothers , fathers , all child-care providers , and doctors focused on the positive health effects of Sprinkles . Conclusions Issues related to Sprinkles preparation , use , and barriers required attention before implementation . Locally appropriate visual and written instructions were developed for dissemination . Intervention training sessions and promotions were tailored to answer frequently asked questions , increase knowledge of Sprinkles , and provide tangible evidence of health benefits . Information needs and perceptions changed quickly after use of Sprinkles . Existing levels of Sprinkles awareness and knowledge should be considered when design ing interventions [18803728] This cross-sectional r and omized controlled study assessed the social acceptability of micronutrient fortified cooked lunch meals by schoolchildren in rural Himalayan villages of India , in a program where the cooking and the micronutrient fortification were done at school . Subjects were r and omly assigned to treatment ( 91 ) and control ( 90 ) groups . The treatment group consumed a weighed amount of cooked lunch meals fortified with locally produced multi-micronutrient premix and the control group consumed a weighed amount of the same meals but without added micronutrient premix . After having eaten , subjects were asked to rate , on a 3-point Likert scale using " smiley " faces , the pleasantness of smell , taste , and overall satisfaction with the food . The mean age of study children was 7.96 + /- 1.64 y and 48.6 % were males . The average amounts of food consumed by the treatment and control groups were 345 + /- 114 and 360 + /- 102.4 g , respectively . Addition of the multi-micronutrient premix to school meals did not significantly affect the mean amount of food consumed by the schoolchildren ( P > 0.05 ; independent sample t-test ) . No significant differences were seen between treatment and control groups in terms of ratings for taste , smell , and the general acceptance of the micronutrient fortified or the unfortified school meals . In conclusion , the addition of a multiple micronutrient premix to school meals was well liked by schoolchildren and did not adversely affect their food consumption [19587124] Responsive complementary feeding , whereby the mother feeds her child in response to child cues and psychomotor abilities , is low in some countries and likely contributes to malnutrition . Interventions are needed to evaluate whether promoting responsive feeding would add any benefit . Using a cluster-r and omized field trial , we evaluated a 6-session educational program that emphasized the practice of child self-feeding and maternal responsiveness . A total of 108 mothers and their 8- to 20-mo-old children in 19 clusters were r and omly assigned to the intervention group and 95 in 18 clusters were assigned to the informational control group . Outcomes were assessed at pretest , postintervention , and follow-up . Research assistants , who were unaware of group assignment , observed and coded mother and child midday meal behaviors . At follow-up , the percent of self-fed mouthfuls was 47.8 + /- 42.4 ( mean + /- SD ) in the responsive feeding group children compared with 32.2 + /- 41.0 in the controls ( P = 0.01 ) ; likewise , the number of responsive verbalizations was 6.55 + /- 5.9 in the responsive feeding mothers and 4.62 + /- 4.5 in controls ( P = 0.01 ) . Intervention mothers recalled more messages . Mouthfuls of food eaten by children and weight were equivalent in the 2 groups . Lack of change in foods eaten and small quantities may explain the similarly low levels of weight gain . These results provide evidence that self-feeding and maternal verbal responsiveness , two developmentally important behaviors , can be increased by targeting specific behaviors with appropriate behavior change strategies of modeling and coached practice . Weight gain may require more nutritional input , especially in areas of high food insecurity [25143342] Background In-home iron fortification for infants in developing countries is recommended for control of anaemia , but low absorption typically results in > 80 % of the iron passing into the colon . Iron is essential for growth and virulence of many pathogenic enterobacteria . We determined the effect of high and low dose in-home iron fortification on the infant gut microbiome and intestinal inflammation . Methods We performed two double-blind r and omised controlled trials in 6-month-old Kenyan infants ( n=115 ) consuming home-fortified maize porridge daily for 4 months . In the first , infants received a micronutrient powder ( MNP ) containing 2.5 mg iron as NaFeEDTA or the MNP without iron . In the second , they received a different MNP containing 12.5 mg iron as ferrous fumarate or the MNP without the iron . The primary outcome was gut microbiome composition analysed by 16S pyrosequencing and targeted real-time PCR ( qPCR ) . Secondary outcomes included faecal calprotectin ( marker of intestinal inflammation ) and incidence of diarrhoea . We analysed the trials separately and combined . Results At baseline , 63 % of the total microbial 16S rRNA could be assigned to Bifidobacteriaceae but there were high prevalences of pathogens , including Salmonella Clostridium difficile , Clostridium perfringens , and pathogenic Escherichia coli . Using pyrosequencing , + FeMNPs increased enterobacteria , particularly Escherichia/Shigella ( p=0.048 ) , the enterobacteria/bifidobacteria ratio ( p=0.020 ) , and Clostridium ( p=0.030 ) . Most of these effects were confirmed using qPCR ; for example , + FeMNPs increased pathogenic E. coli strains ( p=0.029 ) . + FeMNPs also increased faecal calprotectin ( p=0.002 ) . During the trial , 27.3 % of infants in + 12.5 mgFeMNP required treatment for diarrhoea versus 8.3 % in −12.5 mgFeMNP ( p=0.092 ) . There were no study -related serious adverse events in either group . Conclusions In this setting , provision of iron-containing MNPs to weaning infants adversely affects the gut microbiome , increasing pathogen abundance and causing intestinal inflammation . Trial registration number NCT01111864 [20605698] OBJECTIVE Improvement of hemoglobin and serum retinol and facilitation of the mobilization of iron storage were achieved with a multiple-micronutrient-fortified diet in preschoolers for 6 mo in a suburb of Chongqing , China . We investigated whether fortification with multiple micronutrients in a diet for preschool children results in changes in children 's infectious morbidity compared with diets fortified solely with vitamin A and with vitamin A plus iron . METHODS From December 2005 to June 2006 , 226 2- to 6-y-old preschool children were recruited from three nurseries r and omly assigned to three different fortified-diet groups for 6 mo . Group I was fortified with vitamin A ; groups II and III were fortified with vitamin A plus iron and vitamin A plus iron , thiamine , riboflavin , folic acid , niacinamide , zinc , and calcium , respectively . The secondary functional outcomes , morbidity of diarrhea and respiratory infection , were collected during supplementation . RESULTS The groups were comparable concerning compliance and loss to follow-up . There was evidence of a lower incidence rate of respiratory-related illnesses , diarrhea-related illness , fewer symptoms of runny nose , cough , and fever , and shorter duration of respiratory-related illnesses and cough for children in group III compared with children in groups I and II . However , there was no significantly or clinical ly important difference between children in groups I and II . CONCLUSION The beneficial effects on infectious morbidity over 6 mo , in addition to some biochemical improvements , highlight the potential of this micronutrient-fortified seasoning powder supplied in a diet for preschool children [28031374] BACKGROUND Promoting adequate nutrition through interventions to improve infant and young child feeding ( IYCF ) has the potential to contribute to child development . OBJECTIVE We examined whether an intensive intervention package that was aim ed at improving IYCF at scale through the Alive & Thrive initiative in Bangladesh also advanced language and gross motor development , and whether advancements in language and gross motor development were explained through improved complementary feeding . METHODS A cluster-r and omized design compared 2 intervention packages : intensive interpersonal counseling on IYCF , mass media campaign , and community mobilization ( intensive ) compared with usual nutrition counseling and mass media campaign ( nonintensive ) . Twenty subdistricts were r and omly assigned to receive either the intensive or the nonintensive intervention . Household surveys were conducted at baseline ( 2010 ) and at endline ( 2014 ) in the same communities ( n = ∼4000 children aged 0 - 47.9 mo for each round ) . Child development was measured by asking mothers if their child had reached each of multiple milestones , with some observed . Linear regression accounting for clustering was used to derive difference-in-differences ( DID ) impact estimates , and path analysis was used to examine developmental advancement through indicators of improved IYCF and other factors . RESULTS The DID in language development between intensive and nonintensive groups was 1.05 milestones ( P = 0.001 ) among children aged 6 - 23.9 mo and 0.76 milestones ( P = 0.038 ) among children aged 24 - 47.9 mo . For gross motor development , the DID was 0.85 milestones ( P = 0.035 ) among children aged 6 - 23.9 mo . The differences observed corresponded to age- and sex-adjusted effect sizes of 0.35 for language and 0.23 for gross motor development . Developmental advancement at 6 - 23.9 mo was partially explained through improved minimum dietary diversity and the consumption of iron-rich food . CONCLUSIONS Intensive IYCF intervention differentially advanced language and gross motor development , which was partially explained through improved complementary feeding . Measuring a diverse set of child outcomes , including functional outcomes such as child development , is important when evaluating integrated nutrition programs . This trial was registered at clinical trials.gov as NCT01678716 [20410083] Anemia and micronutrient deficiencies are common among Indian schoolchildren . We assessed the effectiveness of micronutrient fortification of meals cooked and fortified at school on anemia and micronutrient status of schoolchildren in Himalayan villages of India . In this placebo-controlled , cluster-r and omized study , 499 schoolchildren ( 6 - 10 y ) received either multiple micronutrients ( treatment group ) or placebo ( control group ) as part of school meals ( 6 d/wk ) for 8 mo . Both groups were dewormed at the beginning of the study . The micronutrient premix provided 10 mg iron , 375 microg vitamin A , 4.2 mg zinc , 225 microg folic acid , and 1.35 microg vitamin B-12 for each child per day ( approximately 75 % recommended dietary allowance ) . Blood sample s drawn before and after the intervention were analyzed for hemoglobin , ferritin , retinol , zinc , folate , and vitamin B-12 . Baseline prevalence of anemia ( 37 % ) , iron deficiency anemia ( 10 % ) , low serum ferritin ( 24 % ) , retinol ( 56 % ) , zinc ( 74 % ) , folate ( 68 % ) , and vitamin B-12 ( 17 % ) did not differ between groups . Postintervention , fewer in the treatment group had lower serum retinol [ odds ratio ( OR ) ( 95 % CI ) : 0.57 ( 0.33 - 0.97 ) ] and folate [ OR ( 95 % CI ) : 0.47 ( 0.26 - 0.84 ) ] than the control group . The serum vitamin B-12 concentration decreased in both groups , but the magnitude of change was less in the treatment than in the control group ( P < 0.05 ) . Total body iron ( TBI ) increased in both groups ; however , the change was greater in the treatment than in the control group ( P < 0.05 ) . Micronutrient fortification of school meals by trained school personnel was effective in improving vitamin A , folate , and TBI status while also reducing the magnitude of a decrease in vitamin B-12 status Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: Background Vitamins and minerals are essential for growth and metabolism . The World Health Organization estimates that more than 2 billion people are deficient in key vitamins and minerals . Groups most vulnerable to these micronutrient deficiencies are pregnant and lactating women and young children , given their increased dem and s. Food fortification is one of the strategies that has been used safely and effectively to prevent vitamin and mineral deficiencies . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

27087396

[25582309] The objective was to determine the effect of daily supplementation with 30 mg of iron ( Fe ) plus 30 mg of zinc ( Zn ) for 3 months on Fe status of women of childbearing age . This was a r and omized double-blind , placebo-controlled trial . Eighty-one women ( 18–45 years ) were r and omly assigned to receive either a daily single dose of 30 mg of Fe ( group 1 ; n = 28 ) and 30 mg of Fe plus 30 mg of Zn ( group 2 ; n = 26 ) or placebo ( n = 27 ) for 3 months . Hemoglobin ( Hb ) , mean corpuscular volume , serum Fe , total iron-binding capacity , transferrin saturation , erythrocyte Zn protoporphyrin , serum ferritin ( SF ) , serum transferrin receptor ( TfR ) , total body Fe , serum Zn , and high-sensitivity C-reactive protein were measured at baseline and at the end of the study . At baseline , 3.7 , 28.4 , and 3.7 % of women had iron-deficiency anemia ( IDA ) , Fe deficiency without anemia , and depleted Fe stores , respectively . No significant differences on Fe status were found between groups before supplementation . After supplementation , group 2 showed a significant increase of Hb and total body Fe and a significant decrease of TfR compared with placebo ( p < 0.05 ) . Moreover , serum Zn increased significantly in group 2 compared with group 1 ( p < 0.01 ) and placebo ( p < 0.01 ) . In conclusion , daily supplementation with 30 mg of Fe plus 30 mg of Zn for 3 months improved significantly the Fe and Zn status of women , compared with those who received placebo . The positive effect of Fe supplementation on Fe status is enhanced by combined Zn supplementation [5338945] In a study published elsewhere ( Wood and Elwood , 1966 ) the associations between the severity of various symptoms and haemoglobin levels in subjects who took part in a community survey is described . The present paper describes a double-blind r and omized clinical trial of the effects on these symptoms of oral iron therapy in a sample of the women seen during the community survey . In addition some limited data relating to a separate trial conducted in severely anaemic women identified in a hospital out-patient clinic are presented [10710409] Our objective was to investigate the effects of iron depletion on adaptation to aerobic exercise , assessed by time to complete a 15-km cycle ergometer test . Forty-two iron-depleted ( serum ferritin < 16 microg/l ) , nonanemic ( Hb > 12 g/dl ) women ( 18 - 33 yr old ) received 100 mg of ferrous sulfate ( S ) or placebo ( P ) per day for 6 wk in a r and omized , double-blind trial . Subjects trained for 30 min/day , 5 days/wk at 75 - 85 % of maximum heart rate for the final 4 wk of the study . There were no group differences in baseline iron status or in 15-km time . Iron supplementation increased serum ferritin and decreased transferrin receptors in the S compared with the P group . The S and P groups decreased 15-km time and respiratory exchange ratio and increased work rate during the 15-km time trial after training . The decrease in 15-km time was greater in the S than in the P group ( P = 0.04 ) and could be partially attributed to increases in serum ferritin and Hb . These results indicate that iron deficiency without anemia impairs favorable adaptation to aerobic exercise [8286880] We examined changes in iron status in 25 female varsity collegiate swimmers over the course of a competitive season via weekly capillary blood sampling . We also studied the effectiveness of moderate iron supplementation ( 39 mg/day ) in preventing expected changes in iron status via a double-blinded crossover design . On entry into the study , 17 of the swimmers had depleted iron stores ( plasma ferritin < 12 micrograms/L ) and 5 were anemic ( Hb < 120 g/L ) . After 5 wk of placebo treatment , hemoglobin decreased ( > or = 6 g/L ) in 44 % and increased in 12 % of the subjects . After 5 wk of iron supplementation , hemoglobin decreased in 16 % and increased in 24 % of the subjects . Likewise , after placebo treatment , plasma ferritin decreased ( > or = 5 micrograms/L ) in 24 % and increased in 4 % of the subjects , whereas iron supplementation result ed in decreases in 4 % and increases in 68 % of the subjects . In the absence of iron supplementation , hemoglobin levels decreased despite mean dietary iron intakes of 16.3 mg/day . These results show that moderate iron supplementation is effective in preventing decline in the iron status of female collegiate swimmers during a competitive season , but a higher dose of iron may be necessary to reverse their iron-deficient state [25668261] IMPORTANCE Although blood donation is allowed every 8 weeks in the United States , recovery of hemoglobin to the currently accepted st and ard ( 12.5 g/dL ) is frequently delayed , and some donors become anemic . OBJECTIVE To determine the effect of oral iron supplementation on hemoglobin recovery time ( days to recovery of 80 % of hemoglobin removed ) and recovery of iron stores in iron-depleted ( " low ferritin , " ≤26 ng/mL ) and iron-replete ( " higher ferritin , " > 26 ng/mL ) blood donors . DESIGN , SETTING , AND PARTICIPANTS R and omized , nonblinded clinical trial of blood donors stratified by ferritin level , sex , and age conducted in 4 regional blood centers in the United States in 2012 . Included were 215 eligible participants aged 18 to 79 years who had not donated whole blood or red blood cells within 4 months . INTERVENTIONS One tablet of ferrous gluconate ( 37.5 mg of elemental iron ) daily or no iron for 24 weeks ( 168 days ) after donating a unit of whole blood ( 500 mL ) . MAIN OUTCOMES AND MEASURES Time to recovery of 80 % of the postdonation decrease in hemoglobin and recovery of ferritin level to baseline as a measure of iron stores . RESULTS The mean baseline hemoglobin levels were comparable in the iron and no-iron groups and declined from a mean ( SD ) of 13.4 ( 1.1 ) g/dL to 12.0 ( 1.2 ) g/dL after donation in the low-ferritin group and from 14.2 ( 1.1 ) g/dL to 12.9 ( 1.2 ) g/dL in the higher-ferritin group . Compared with participants who did not receive iron supplementation , those who received iron supplementation had shortened time to 80 % hemoglobin recovery in both the low-ferritin ( mean , 32 days , interquartile range [ IQR ] , 30 - 34 , vs 158 days , IQR , 126->168 ) and higher-ferritin groups ( 31 days , IQR , 29 - 33 , vs 78 days , IQR , 66 - 95 ) . Median time to recovery to baseline ferritin levels in the low-ferritin group taking iron was 21 days ( IQR , 12 - 84 ) . For participants not taking iron , recovery to baseline was longer than 168 days ( IQR , 128->168 ) . Median time to recovery to baseline in the higher-ferritin group taking iron was 107 days ( IQR , 75 - 141 ) , and for participants not taking iron , recovery to baseline was longer than 168 days ( IQR , > 168->168 ) . Recovery of iron stores in all participants who received supplements took a median of 76 days ( IQR , 20 - 126 ) ; for participants not taking iron , median recovery time was longer than 168 days ( IQR , 147->168 days ; P < .001 ) . Without iron supplements , 67 % of participants did not recover iron stores by 168 days . CONCLUSIONS AND RELEVANCE Among blood donors with normal hemoglobin levels , low-dose iron supplementation , compared with no supplementation , reduced time to 80 % recovery of the postdonation decrease in hemoglobin concentration in donors with low ferritin ( ≤26 ng/mL ) or higher ferritin ( > 26 ng/mL ) . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01555060 [11916761] BACKGROUND Iron deficiency without anemia has been shown to reduce both muscle-tissue oxidative capacity and endurance in animals . However , the consequences of iron deficiency in humans remain unclear . OBJECTIVE We investigated the effects of iron supplementation on adaptation to aerobic training among marginally iron-depleted women . We hypothesized that iron supplementation for 6 wk would significantly improve iron status and maximal oxygen uptake ( VO(2)max ) after 4 wk of concurrent aerobic training . DESIGN Forty-one untrained , iron-depleted , nonanemic women were r and omly assigned to receive either 50 mg FeSO(4 ) or a placebo twice daily for 6 wk in a double-blind trial . All subjects trained on cycle ergometers 5 d/wk for 4 wk , beginning on week 3 of the study . RESULTS Six weeks of iron supplementation significantly improved serum ferritin and serum transferrin receptor ( sTfR ) concentrations and transferrin saturation without affecting hemoglobin concentrations or hematocrit . Average VO(2)max and maximal respiratory exchange ratio improved in both the placebo and iron groups after training ; however , the iron group experienced significantly greater improvements in VO(2)max . Both iron-status and fitness outcomes were analyzed after stratifying by baseline sTfR concentration ( > and < or = 8.0 mg/L ) , which showed that the previously observed treatment effects were due to iron-status and fitness improvements among subjects with poor baseline iron status . CONCLUSIONS Our findings strongly suggest that iron deficiency without anemia but with elevated sTfR status impairs aerobic adaptation among previously untrained women and that this can be corrected with iron supplementation [2963533] Studies on the treatment and prevention of iron deficiency anemia , in pregnant and nonpregnant women and in men , were conducted in Thail and and Burma . The effects of the dose of Fe , duration of Fe administration , additional supplementation with folate , mode of supplement delivery ( either supervised or unsupervised ) , and the presence of Hb(AE ) were studied . The frequency and severity of side effects were also recorded . Fe administration result ed in an increase in hemoglobin concentration in all anemic individuals but approximately 20 % failed to reach normality . The length of administration and the dose influenced the results . Frequency and severity of side effects increased with the dose of Fe administered . Folate supplementation did not affect the results . It appears possible to integrate a program of prevention and treatment of Fe deficiency anemia in a primary health-care system but the constraints and limitations of achievable results should be recognized [2912000] Response of iron , copper , and zinc status to supplementation with Zn or a combination of Zn and Fe was assessed in adult females in a 10-wk study . Group Z received 50 mg Zn/d as Zn gluconate ; group F-Z received 50 mg Fe as ferrous sulfate monohydrate in addition to the Zn . For Group Z , serum ferritin , hematocrit , and erythrocyte Cu , Zn-superoxide dismutase ( ESOD ) were significantly lower ( p less than 0.05 ) after 10 wk supplementation compared with pretreatment levels . Serum Zn increased ( p less than 0.01 ) but no change occurred in serum ceruloplasmin , hemoglobin , or salivary sediment Zn with treatment . For Group F-Z ESOD decreased with treatment as did salivary sediment Zn ( p less than 0.05 ) . Serum ferritin and serum Zn increased significantly , but hemoglobin , hematocrit , and ceruloplasmin were not affected by this treatment . Supplementation with Zn poses a risk to Fe and Cu status . Inclusion of Fe with Zn ameliorates the effect on Fe but not on Cu status [14985219] BACKGROUND We previously showed that iron supplementation significantly improves iron status and maximal work capacity in previously untrained , marginally iron-deficient women with a baseline serum transferrin receptor concentration > 8.0 mg/L. However , the effect of transferrin receptor status on adaptation in endurance capacity after aerobic training in these subjects has not been fully explored . OBJECTIVE Our objective was to examine the effect of baseline serum transferrin receptor status on adaptations in endurance capacity . DESIGN Forty-one untrained , iron-depleted , nonanemic women were r and omly assigned to receive either 100 mg FeSO(4 ) or a placebo for 6 wk in a double-blind trial . All subjects trained on cycle ergometers 5 d/wk for the last 4 wk of the study . Endurance capacity was assessed at baseline and after treatment by using a 15-km time trial conducted on a cycle ergometer . RESULTS Significant treatment effects were observed for time to complete the 15-km time trial , work rate , and percentage of maximal oxygen uptake in subjects with a baseline serum transferrin receptor concentration > 8.0 mg/L. No significant treatment effects were observed in subjects with a normal baseline transferrin receptor concentration . CONCLUSIONS Our findings suggest that , in the presence of overt tissue iron deficiency , iron deficiency without anemia impairs adaptation in endurance capacity after aerobic training in previously untrained women . This impairment can be corrected with iron supplementation [17311950] Commercial elemental iron powders ( electrolytic and reduced iron ) , as well as heme iron supplements , were tested for efficacy in improving the iron status of women . In a r and omized , double-blind trial , 51 women with moderate to low iron stores received daily for 12 wk : 1 ) placebo , 2 ) 5 mg iron as heme iron or 50 mg iron as 3 ) electrolytic iron , 4 ) reduced iron , or 5 ) FeSO(4 ) . Treatments were provided in 2 capsules ( heme carrier ) and 3 wheat rolls ( other iron sources ) . Differences in iron status , food nonheme iron absorption , and fecal properties were evaluated . Body iron , assessed from the serum transferrin receptor : ferritin ratio , increased significantly more in subjects administered FeSO(4 ) ( 127 + /- 29 mg ; mean + /- SEM ) and electrolytic ( 115 + /- 37 mg ) , but not the reduced ( 74 + /- 32 mg ) or heme ( 65 + /- 26 mg ) iron forms , compared with those given placebo ( 2 + /- 19 mg ) . Based on body iron determinations , retention of the added iron was estimated as 3.0 , 2.7 , 1.8 , and 15.5 % , in the 4 iron-treated groups , respectively . Iron treatments did not affect food iron absorption . The 50 mg/d iron treatments increased fecal iron and free radical-generating capacity in vitro , but did not affect fecal water cytotoxicity . In subjects administered FeSO(4 ) , fecal water content was increased slightly but significantly more than in the placebo group . In conclusion , electrolytic iron was approximately 86 % as efficacious as FeSO(4 ) for improving body iron , but the power of this study was insufficient to detect any efficacy of the reduced or heme iron within 12 wk . With modification , this methodology of testing higher levels of food fortification for several weeks in healthy women with low iron stores has the potential for economically assessing the efficiency of iron compounds to improve iron status [8147338] Eighty iron-deficient , nonpregnant female workers were r and omly assigned to ferrous sulphate ( 60 or 120 mg Fe/d ) or placebo treatment for 12 wk . Energy expenditure was estimated during 3 d by heart rate ( HR ) recording . Production efficiency ( PE ) was calculated as the ratio of productivity to energy expenditure . In the iron-treated group mean hemoglobin ( Hb ) increased from 114 to 127 g/L ( P < 0.001 ) , mean serum ferritin increased from 9.7 to 30.0 micrograms/L ( P < 0.001 ) , and mean free erythrocyte protoporphyrin decreased from 1.01 to 0.49 mumol/L ( P < 0.001 ) . Mean HR at work decreased from 95.5 to 91.1 beats/min ( P < 0.001 ) , which was inversely correlated with the change in Hb ( r = -0.60 , P < 0.001 ) . PE increased significantly in the iron-treated group ( P < 0.001 ) and its change paralleled the change in Hb ( r = 0.58 , P < 0.001 ) . The results show that iron supplementation enabled these women to do the same work at a lower energy cost [17344500] BACKGROUND Evidence suggests that brain iron deficiency at any time in life may disrupt metabolic processes and subsequently change cognitive and behavioral functioning . Women of reproductive age are among those most vulnerable to iron deficiency and may be at high risk for cognitive alterations due to iron deficiency . OBJECTIVE We aim ed to examine the relation between iron status and cognitive abilities in young women . DESIGN A blinded , placebo-controlled , stratified intervention study was conducted in women aged 18 - 35 y of varied iron status who were r and omly assigned to receive iron supplements or a placebo . Cognition was assessed by using 8 cognitive performance tasks ( from Detterman 's Cognitive Abilities Test ) at baseline ( n = 149 ) and after 16 wk of treatment ( n = 113 ) . RESULTS At baseline , the iron-sufficient women ( n = 42 ) performed better on cognitive tasks ( P = 0.011 ) and completed them faster ( P = 0.038 ) than did the women with iron deficiency anemia ( n = 34 ) . Factors representing performance accuracy and the time needed to complete the tasks by the iron-deficient but nonanemic women ( n = 73 ) were intermediate between the 2 extremes of iron status . After treatment , a significant improvement in serum ferritin was associated with a 5 - 7-fold improvement in cognitive performance , whereas a significant improvement in hemoglobin was related to improved speed in completing the cognitive tasks . CONCLUSIONS Iron status is a significant factor in cognitive performance in women of reproductive age . Severity of anemia primarily affects processing speed , and severity of iron deficiency affects accuracy of cognitive function over a broad range of tasks . Thus , the effects of iron deficiency on cognition are not limited to the developing brain [12540406] BACKGROUND Tissue iron depletion may negatively affect endurance performance and muscle fatigability . OBJECTIVE We investigated tissue-level iron depletion and progressive fatigue of the quadriceps during dynamic knee-extension exercise in young women . DESIGN Twenty iron-depleted ( serum ferritin < 20 micro g/L ) , nonanemic ( hemoglobin > 110 g/L ) women ( macro x + /- SEM age : 29.1 + /- 1.2 y ) received iron ( iron group ) or placebo ( placebo group ) for 6 wk in a r and omized , double-blind trial ( n = 10 per group ) . A protocol integrating 2 - 3-s maximal voluntary static contractions ( MVCs ) with dynamic knee extensions was used to assess fatigue . RESULTS No significant differences between the groups in baseline iron status , MVC at rest , or MVC at the end of the protocol were observed . After treatment , serum iron and transferrin saturation increased significantly in the iron group ( P = 0.02 and P = 0.03 , respectively ) . Serum transferrin receptor concentrations increased significantly in the placebo group ( P < 0.01 ) but not in the iron group . After treatment , the rate of decrease in MVC was attenuated in the iron group but not in the placebo group ( P = 0.01 ) . In the iron group , MVC at the sixth minute of the fatigue protocol and MVC at the end of the protocol were approximately 15 % ( P = 0.04 ) and approximately 27 % higher ( P < 0.01 ) , respectively , after treatment . These improvements were not related to changes in iron-status indexes or tissue iron stores , although power was low ( < 0.50 ) to detect these relations . CONCLUSIONS Iron supplementation was associated with a significant improvement in muscle fatigability . Interpretation regarding the direct role of tissue iron status is limited by the study 's low power to detect relations between tissue iron improvement and decreased muscle fatigue [1442656] Forty-seven previously sedentary women participating in a 12-wk moderate aerobic-exercise program were r and omly assigned to one of four dietary groups : 50-mg/d iron supplement and a low food-iron diet ( 50 FE + EX ) , 10-mg/d iron supplement and a low food-iron diet ( 10 FE + EX ) , placebo and unrestricted diet ( P + EX ) , and meat supplement and high food-iron diet ( M + EX ) . A sedentary control group ( n = 13 ) received no dietary interventions . Hematocrit , total iron-binding capacity , and hemoglobin , serum iron , serum ferritin , and serum albumin concentrations were measured every 4 wk . Hemoglobin values decreased at the end of 4 wk in all exercising groups compared with the control group . Iron status in the 50 FE + EX and M + EX groups improved after week 4 as indicated by an increase in serum ferritin , serum iron , and hemoglobin concentrations , and a decline in total iron-binding capacity . Thus , short-term , moderate aerobic exercise result ed in compromised iron status that was offset to varying degrees by ingesting iron or meat supplements . However , meat supplements were more effective in protecting hemoglobin and ferritin status than were iron supplements [14704300] Elevated iron stores may or may not promote atherogenesis by increasing free radical formation and oxidative stress , but controlled diet and supplement trials are lacking . We tested the hypothesis that iron supplementation does not increase the susceptibility of LDL to undergo oxidative modification in women with low iron status . A r and omized , double-blind , 2-period crossover study design ( n=26 ) was used to examine the effects of the following diets on measures of LDL oxidation : average American diet ( AAD ) [ 36 % of energy as fat ; 15 % saturated fatty acids ( SFA ) ] , and a Step 2 diet ( 26 % fat ; 7 % SFA ) . In addition , subjects received either a supplement containing 160 mg of ferrous sulfate ( 50 mg elemental iron ) or a placebo twice daily [ supplement group received a total of 320 mg ferrous sulfate ( 100 mg elemental iron ) daily ] . After supplementation , serum ferritin differed between the supplement and placebo groups ( P=0.008 ) . Measures of LDL oxidation were not affected by supplement intake ; however , they were affected by diet . Lag time was shorter after the women consumed the AAD diet than after the Step 2 diet ( P<0.0001 ) . The diets did not affect the rate of oxidation or total dienes . Although iron status was improved by aggressive iron supplementation , LDL oxidative susceptibility was not affected . As expected , lag time was increased after the women consumed the low fat , low SFA diet . Therefore , the results of this study do not support a relationship between iron status and LDL oxidation [10539778] This 7-mo double-blind study compared the efficacy of two iron supplementation schemes in improving iron nutrition among 116 healthy fertile-age women . They were r and omly distributed in three groups , receiving : Group 1 , iron + folate ( 60 mg and 250 microg , respectively ) daily for 3 mo ( currently recommended scheme ) , and folate ( 250 microg ) weekly the subsequent 4 mo . Group 2 , folate daily , and 60 mg iron only once weekly for 3 mo , and then weekly iron + folate for 4 mo . Group 3 , folate daily for 3 mo and then weekly for 4 mo . At baseline , 16 % had depleted stores ( plasma ferritin < 15 microg/L ) and 16 % had hemoglobin levels < 125 g/L. Eight percent had hemoglobin levels < 120 g/L. In Group 1 hemoglobin and ferritin increased at 3 mo but returned to near basal conditions after 4 mo of weekly folate . In Group 2 , hemoglobin and ferritin increased progressively throughout the 7 mo but mostly after 3 mo . Group 3 did not change . Side effects were highest with daily iron . Weekly iron supplementation over 7 mo ( 30 doses ) improved and sustained iron nutrition at least as effectively and was better tolerated than 90 daily iron supplements consumed during 3 mo [10721929] To assess the efficacy and acceptability of a daily and intermittent iron supplementation , a double-blind , placebo-controlled trial was conducted in a public school located in periurban Lima , Peru . Adolescent girls ( n = 312 ) , 12 - 18 y old , were r and omly assigned to one of the following three groups : 1 ) 60 mg iron as ferrous sulfate daily from Monday to Friday ; 2 ) 60 mg iron as ferrous sulfate 2 d/wk and 3 d placebo ( intermittent ) ; 3 ) placebo , from Monday to Friday . Field workers gave the girls supplements during school hours for 17 wk ; 296 girls completed the trial . Girls took 94 % of the expected dose of 85 pills . Few side effects were reported . Postintervention , hemoglobin ( Hb ) , serum ferritin ( SF ) and free erythrocyte protoporphyrin ( FEP ) were improved significantly in the iron-supplemented groups compared with placebo ( P<0.05 ) . Daily supplements led to higher Hb increases than intermittent supplements ( P<0.05 ) , but SF and FEP were similar between the two groups . Thus , both iron supplementation schedules were efficacious in preventing iron deficiency in adolescent girls through the school system , and the daily schedule was better than the intermittent schedule at increasing Hb values and reducing anemia [3292842] Background Iron deficiency without anemia is related to adverse symptoms that can be relieved by supplementation . Since a blood donation can induce such an iron deficiency , we investigated the clinical impact of iron treatment after a blood donation . Methods One week after donation , we r and omly assigned 154 female donors with iron deficiency without anemia , aged below 50 years , to a four-week oral treatment of ferrous sulfate versus a placebo . The main outcome was the change in the level of fatigue before and after the intervention . Aerobic capacity , mood disorder , quality of life , compliance and adverse events were also evaluated . Hemoglobin and ferritin were used as biological markers . Results The effect of the treatment from baseline to four weeks of iron treatment was an increase in hemoglobin and ferritin levels to 5.2 g/L ( P < 0.01 ) and 14.8 ng/mL ( P < 0.01 ) , respectively . No significant clinical effect was observed for fatigue ( -0.15 points , 95 % confidence interval -0.9 points to 0.6 points , P = 0.697 ) or for other outcomes . Compliance and interruption for side effects was similar in both groups . Additionally , blood donation did not induce overt symptoms of fatigue in spite of the significant biological changes it produces . Conclusions These data are valuable as they enable us to conclude that donors with iron deficiency without anemia after a blood donation would not clinical ly benefit from iron supplementation . Trial Registration Clinical Trials.gov : [24660763] BACKGROUND Blood donation is known to contribute to iron deficiency in regular blood donors . This study investigated the safety and efficacy of postdonation iron replacement to mitigate iron deficiency in blood donors . STUDY DESIGN AND METHODS A total of 282 female whole blood donors aged 18 to 45 were prospect ively r and omized in a double-blinded placebo controlled trial to receive an 8-week postdonation course of carbonyl iron ( 45 mg daily ) or placebo . The primary endpoint was prevalence of iron deficiency ( ferritin < 15 ng/mL ) at 12 weeks postdonation . Secondary endpoints were eligibility to donate based on capillary hemoglobin ( Hb ) and incidence of gastrointestinal ( GI ) complaints . RESULTS Ferritin levels at Week 12 were significantly higher in donors receiving carbonyl iron ( 17.0 ± 10.9 ng/mL ) compared with those receiving placebo ( 10.6 ± 8.4 ng/mL ; p < 0.001 ) . The proportion of iron-deficient donors was significantly lower in the carbonyl iron group ( 51.9 % ) compared to the placebo ( 80.5 % ; p < 0.001 ) . The mean Hb level in the carbonyl iron group ( 134.6 ± 8.7 g/L ) was significantly higher than in the placebo arm ( 130.0 ± 9.9 g/L ; p < 0.001 ) , significantly improving eligibility to donate at Week 12 . Significantly more donors receiving carbonyl iron had at least one GI side effect ( p < 0.001 ) . Importantly , 86.7 % of donors receiving carbonyl iron indicated that they would take iron on an ongoing basis . CONCLUSION An 8-week postdonation course of 45 mg of carbonyl iron significantly reduced iron deficiency and was well tolerated in female whole blood donors . Postdonation iron replacement may have a role in a broader strategy to optimize donor iron status [7299507] This study was conducted to examine the relationship between anemia , supplementation with iron and vitamin C , and productivity . Using the cyanmethemoglobin method , 671 female garment factory workers were examined . On the basis of the World Health Organization ( WHO ) st and ard , 98 were found to be mildly or moderately/severely anemic . An equal number was r and omly chosen from the nonanemic workers . The subjects were then r and omly assigned to either the placebo group or the group receiving 525 mg of ferrous sulfate ( 105 mg elemental iron ) and 500 mg ascorbic acid . Only 118 of the 196 subjects completed the three-month study . The mean hemoglobin ( Hb ) and work output , as indicated by efficiency rating ( ER ) , of the placebo group did not change significantly . Mildly anemic workers with supplements showed a significant improvement in mean Hb , but not in mean ER . The moderately/severely anemic group receiving supplements had significant increases in both Hb and ER [1919803] In 781 female college students , there were 41 cases of iron deficiency anemia , 209 of latent iron deficiency , 3 of other anemias , and 528 normal cases . Fifty-four volunteers recruited from the iron deficiency anemia and severe latent iron deficiency groups were r and omly divided into 4 study groups . Groups I and III received 500 mg of vitamin C daily , and groups II and IV received ferric ammonium citrate ( FeAC ; equivalent to 6 mg iron ) in addition to vitamin C for 9 weeks . Groups I and II were loaded by aerobic exercise at 50 % VO2 max . Significant differences between groups were noted in serum ferritin ( SF ) in III/IV , hematocrit ( Ht ) in II/III and III/IV , and reticulocytes ( RET ) in I/II , I/IV , and III/IV . Hemoglobin ( Hb ) and other iron-related blood indices tended to normalize in groups II and IV when compared with the pre-values . VO2 max was elevated in groups I and II regardless of iron treatment , but was augmented more in group II than group [16968234] BACKGROUND No treatment is known to permanently increase salivary flow in patients with hyposalivation . The objective of this study was to investigate the effect of iron supplementation on salivary flow rate . METHODS A double-blind , r and omized , placebo-controlled trial was carried out on 50 individuals with a low unstimulated whole salivary flow rate and low serum ferritin . Half the individuals received 60 mg iron orally twice a day for 3 months , while the other half received placebo . RESULTS No statistically significant difference was found between the groups after treatment for the unstimulated flow rate and in the subjective assessment s of oral dryness . The serum ferritin values increased significantly in the iron group but not in the placebo group . CONCLUSION Oral supplementation with iron for 3 months has no effect on salivary flow rate among individuals with hyposalivation and low serum ferritin values [10221325] The authors estimated components of variance and intraclass correlation coefficients ( ICCs ) to aid in the design of complex surveys and community intervention studies by analyzing data from the Health Survey for Engl and 1994 . This cross-sectional survey of English adults included data on a range of lifestyle risk factors and health outcomes . For the survey , households were sample d in 720 postal code sectors nested within 177 district health authorities and 14 regional health authorities . Study subjects were adults aged 16 years or more . ICCs and components of variance were estimated from a nested r and om-effects analysis of variance . Results are presented at the district health authority , postal code sector , and household levels . Between-cluster variation was evident at each level of clustering . In these data , ICCs were inversely related to cluster size , but design effects could be substantial when the cluster size was large . Most ICCs were below 0.01 at the district health authority level , and they were mostly below 0.05 at the postal code sector level . At the household level , many ICCs were in the range of 0.0 - 0.3 . These data may provide useful information for the design of epidemiologic studies in which the units sample d or allocated range in size from households to large administrative areas [24195864] PURPOSE Studies in both animals and humans show a relationship between iron depletion without anemia ( IDNA ) and physical performance . Compared with their sedentary counterparts , female endurance athletes are at greater risk of IDNA , and consequences relevant to endurance athletes include reduced work capacity and energetic efficiency ( EF ) . We conducted a r and omized placebo-controlled trial to investigate the effects of iron ( Fe ) supplementation on Fe status and performance in nonanemic female rowers during training . METHODS At the beginning of a training season , 40 rowers were r and omized to receive either 100 mg·d FeSO4 ( n = 21 ) or placebo ( n = 19 ) using a double-blind design . Thirty-one ( n = 15 Fe , 16 placebo ) completed the 6-wk trial . Fe status ( hemoglobin , serum ferritin , soluble transferrin receptor ) , body composition , and laboratory tests of physical performance ( 4-km time trial , V˙O2peak , energetic EF , and blood lactate ) were assessed at baseline and after training . RESULTS Rowers in both groups increased their fat-free mass ( P < 0.001 ) and V˙O2peak ( P < 0.001 ) after training . Multiple regression analyses revealed improvements in Fe stores ( serum ferritin ) in the Fe treatment group after controlling for baseline Fe stores ( P = 0.07 ) . Rowers in the Fe group had slower lactate response during the first half of the time trial and after 5 min of recovery ( P = 0.05 ) and showed greater improvements in energy expenditure ( P = 0.01 for group-by time ) and energetic EF compared with placebo ( P = 0.03 for group-by time ) . CONCLUSIONS Female rowers with depleted Fe stores who consumed supplemental Fe during training improved their Fe status and energetic EF during endurance exercise . These results are important for endurance athletes whose dietary patterns and physical training increase their risk of IDNA and suggest that Fe supplementation may maximize the benefits of endurance training [1496946] OBJECTIVE To document a subjective response to iron therapy in female adolescents . DESIGN Double-blind , placebo-controlled prospect i ve study . SETTING High school classes in an urban community in Israel . PARTICIPANTS Twenty-nine girls , aged 16 and 17 years , who ingested syrup containing iron ( daily for 2 months ) and 30 girls who received a placebo . MAIN RESULTS By the end of the study , a statistically significant improvement in three subjective parameters , ie , lassitude , the ability to concentrate in school , and mood was reported by the girls who ingested iron compared with the controls . Sixty-five percent , 100 % , and 65 % of the girls , respectively , who reported improvement in the above-mentioned parameters were hypoferremic initially and became normoferremic by the end of the study . CONCLUSION Iron supplementation may be of benefit to female adolescents , as evidence d by their responses to subjective parameters [4073160] Rates of iron deficiency are high amongst healthy young women . Cognitive impairment occurs secondary to iron deficiency in infants and children , but evaluation of the impact on cognition among young women is inconsistent . The aim was to determine the suitability of the IntegNeuro test battery for assessing cognitive function in iron-deficient and iron-sufficient young women . A pilot double-blinded , placebo-controlled intervention trial was conducted in iron-deficient ( serum ferritin ≤ 20 μg/L and haemoglobin > 120 g/L ) and iron-sufficient young women ( 18–35 years ) . Cognitive function and haematological markers of iron status were measured at baseline and follow-up . Iron-deficient participants ( n = 24 ) were r and omised to receive placebo , 60 mg or 80 mg elemental iron daily supplements for 16 weeks . A control group of iron-sufficient participants ( n = 8) was allocated to placebo . Change scores for Impulsivity and Attention were significantly greater in plasma ferritin improvers than in non-improvers ( p = 0.004 , p = 0.026 ) . IntegNeuro was easy to administer and acceptable to young women . Based on the differences in Memory and Attention scores between iron-deficient participants on iron treatment and those on placebo , it was decided that between 26 and 84 participants would be required in each iron treatment group for an adequately powered extension of this pilot RCT [4082414] Background Oral iron supplementation is often associated with rapid onset of gastrointestinal side-effects . The aim of this study was to develop and trial a short , simple question naire to capture these early side-effects and to determine which symptoms are more discriminating . Methods The study was a double-blind placebo-controlled r and omized parallel trial with one week treatment followed by one week wash-out . Subjects were r and omized into two treatment groups ( n = 10/group ) to receive either ferrous sulphate ( 200 mg capsules containing 65 mg of iron ) or placebo , both to be taken at mealtimes twice daily during the treatment period . Subjects completed the question naires daily for 14 days . The question naire included gastrointestinal symptoms commonly reported to be associated with the oral intake of ferrous iron salts ( i.e. nausea , vomiting , heartburn , abdominal pain , diarrhoea , and constipation ) . Results Seventy five per cent of participants reporting the presence of one or more symptoms in the first week of the study were in the ferrous sulphate group . In the second week of the study ( i.e. wash-out ) , 67 % of the participants reporting one or more symptom(s ) were in the ferrous sulphate group . In the first week of the study ( treatment ) the number of symptoms reported by participants in the ferrous sulphate group ( mean ± SEM = 6.7 ± 1.7 ) was significantly higher than that for participants in the placebo group ( 1.2 ± 0.5 ) ( p = 0.01 ) . In the second week of the study ( wash-out ) the number of symptoms reported by participants in the ferrous sulphate group ( 4.6 ± 2.0 ) appeared higher than for participants in the placebo group ( 1.0 ± 0.7 ) although this did not reach significance ( p = 0.12 ) . Events for which the gastrointestinal symptom question naire was most discriminatory between ferrous sulphate and placebo groups were : heartburn , abdominal pain and the presence of black stools ( all p ≤ 0.03 ) . Conclusions A tool for the detection of commonly-occurring side effects should not require large study numbers to be effective . With just 10 subjects per group ( iron or placebo ) , this simple question naire measures gastrointestinal side-effects associated with oral iron ( ferrous sulphate ) supplementation , and would be appropriate for use in intervention studies or clinical trials . Trial registration Clinical Trials.gov Identifier : NCT02146053 ( 21/05/2014 ) [4011041] Adherence to iron supplementation can be compromised due to side effects , and these limit blinding in studies of iron deficiency . No studies have reported an efficacious iron dose that allows participants to remain blinded . This pilot study aim ed to determine a ferrous sulfate dose that improves iron stores , while minimising side effects and enabling blinding . A double-blinded RCT was conducted in 32 women ( 18–35 years ) : 24 with latent iron deficiency ( serum ferritin < 20 µg/L ) and 8 iron sufficient controls . Participants with latent iron deficiency were r and omised to 60 mg or 80 mg elemental iron or to placebo , for 16 weeks . The iron sufficient control group took placebo . Treatment groups ( 60 mg n = 7 and 80 mg n = 6 ) had significantly higher ferritin change scores than placebo groups ( iron deficient n = 5 and iron sufficient n = 6 ) , F(1 , 23 ) = 8.46 , p ≤ 0.01 . Of the 24 who completed the trial , 10 participants ( 77 % ) on iron reported side effects , compared with 5 ( 45 % ) on placebo , but there were no differences in side effects ( p = 0.29 ) , or compliance ( p = 0.60 ) between iron groups . Nine ( 69 % ) participants on iron , and 11 ( 56 % ) on placebo correctly guessed their treatment allocation . Both iron doses were equally effective in normalising ferritin levels . Although reported side-effects were similar for both groups , a majority of participants correctly guessed their treatment group [534861] The effects of iron-deficiency anaemia on workers productivity were studied in a tea plantation in Sri Lanka . The quantity of tea picked per day was studied before and after iron supplementation or placebo treatment . After one month 's treatment significantly more tea was picked when the haemoglobin ( Hb ) concentration was increased by iron supplementation than when it was not . The degree of improvement was greater in more-anaemic subjects ( those with concentrations of 6.0 - 9.0 g Hb/dl ) . The level of physical activity of anaemic subjects in their everyday environment was also recorded for four or 24 hours continuously both before and after treatment . After three weeks these levels was significantly greater in the iron-treated than matched placebo-treated subjects . The economic implication s of increased work productively with iron treatment are evident , particularly in developing countries . These results also provide strong evidence for the clinical impression that people with iron-deficiency anaemia suffer from tiredness and weakness [12763985] Abstract Objective To determine the subjective response to iron therapy in non-anaemic women with unexplained fatigue . Design Double blind r and omised placebo controlled trial . Setting Academic primary care centre and eight general practice s in western Switzerl and . Participants 144 women aged 18 to 55 , assigned to either oral ferrous sulphate ( 80 mg/day of elemental iron daily ; n=75 ) or placebo ( n=69 ) for four weeks . Main outcome measures Level of fatigue , measured by a 10 point visual analogue scale . Results 136 ( 94 % ) women completed the study . Most had a low serum ferritin concentration ; ≤ 20 μg/l in 69 ( 51 % ) women . Mean age , haemoglobin concentration , serum ferritin concentration , level of fatigue , depression , and anxiety were similar in both groups at baseline . Both groups were also similar for compliance and dropout rates . The level of fatigue after one month decreased by −1.82/6.37 points ( 29 % ) in the iron group compared with −0.85/6.46 points ( 13 % ) in the placebo group ( difference 0.95 points , 95 % confidence interval 0.32 to 1.62 ; P=0.004 ) . Subgroups analysis showed that only women with ferritin concentrations ≤ 50 μg/l improved with oral supplementation . Conclusion Non-anaemic women with unexplained fatigue may benefit from iron supplementation . The effect may be restricted to women with low or borderline serum ferritin concentrations [5448798] A variety of aspects of psychomotor function were assessed in 47 women before and after iron therapy . These women , all of whom had initial haemoglobin levels below 10·5 g./100 ml . , had been drawn from a population sample of 2,283 women seen at a haematological screening survey . There was no evidence of any beneficial effect of a rise in haemoglobin level on psychomotor function or on symptoms . Possibly this is because if an effect does occur it is unlikely to be apparent unless the haemoglobin level is very low . If this is true then anaemia is probably a rare cause of symptoms or impairment in psychomotor function in the community [12736400] OBJECTIVE To examine the benefits of anemia prophylaxis in adolescent school.girls by weekly or daily iron-folate supplementation . DESIGN Prospect i ve study . SETTING Government girl schools of northeast Delhi . SUBJECTS 2088 subjects ( with hemoglobin greater than 7.9 g/dL ) , including 702 on daily and 695 on weekly iron-folate administration ; 691 girls served as controls . RESULTS About 85 % girls were iron deficient out of which 49.3 % were anemic . Weekly administration took longer time to raise hemoglobin but was effective as well as practical . Plasma ferritin estimation in girls showed rise in level in both the treated groups . CONCLUSION Weekly administration of iron-folate was a practical and effective strategy for anemia prophylaxis in adolescent school girls [1501568] The purpose of this investigation was to examine the effects of oral iron supplementation on endurance performance in initially iron-depleted , nonanemic female distance runners . Eighteen iron-depleted ( serum ferritin less than 20 ng.ml-1 , hemoglobin greater than or equal to 12 g.dl-1 ) women ( 22 - 39 yr ) performed a VO2max test and an endurance run to exhaustion . Subjects were pair-matched on the basis of endurance time and then r and omly assigned to an iron supplement or a placebo group . Following supplementation , the iron group had a significantly higher ( P = 0.03 ) mean serum ferritin concentration ( 23.4 vs 15.7 ng.ml-1 ) and lower ( P = 0.04 ) mean total iron-binding capacity than the placebo group . Both groups increased their time to exhaustion ( 25.5 % and 22.2 % for the iron and placebo groups , respectively ) but were not significantly different ( P = 0.72 ) from each other . There were also no differences ( P greater than 0.05 ) between the groups with respect to lactate concentrations and physiological measures taken during the two exercise tests . The results of this study suggest that 8 wk of oral iron supplementation improves iron status in iron-depleted female distance runners , but does not enhance endurance capacity [23204154] Objectives : Limited information is available on the role of pork meat in influencing iron status . The aim of this study was to determine the effect of consuming pork meat as compared to iron supplementation on nutritional status and feeling of well-being . Methods : Young women were r and omly assigned to a control diet ( CG ) , a pork-containing diet ( PG ) , or a control diet with iron supplementation ( SG ) for 12 weeks . Sixty-five women aged 24.6 ± 4.4 years ( mean ± SD ) completed the trial . Results : Serum ferritin concentrations were increased significantly ( p = 0.001 ) in participants assigned to the SG as compared with the other groups , as assessed by repeated- measures analysis of variance . At week 12 , hemoglobin concentrations were significantly higher in PG and SG as compared with CG . Plasma zinc concentrations at the end of the intervention were similar to baseline concentrations for individuals in the CG and PG but were decreased significantly ( p < 0.05 ) in SG . Plasma- , erythrocyte-folate , and serum vitamin B6 and B12 concentrations were not significantly affected by the intervention , although the concentrations of vitamins B6 and B12 tended to increase in PG . Well-being , as measured using the Health Survey Short Form ( SF-36 ) and its 8 multi-item scales , showed significant improvement in vitality in SG ( p < 0.05 ) and bodily pain in PG ( p < 0.05 ) . No significant relationships were observed between these health concept scores and biomarkers of nutritional status . Conclusions : Consumption of pork meat by young women maintains hemoglobin levels to the same extent as low-dose iron supplementation and enhances the components of well-being , mainly their perception of bodily pain [9279061] This paper discusses the effect that high altitudes have on iron metabolism and summarizes the results of an iron-folate supplementation trial . The two main objectives of the trial were to determine hemoglobin cut-off values for the diagnosis of anemia in Bolivian women of childbearing age living at high altitudes , and to estimate the prevalence of anemia in this population . The study showed that nutritional anemia is an important public health problem in such population s and that many methods of assessing it lead to an underestimation of prevalence . The cut-off values defined through this study , one of the few iron supplementation trials conducted at high altitudes , confirm the need to establish revised hemoglobin values for the diagnosis of anemia in population s living at high altitudes [6506175] Depletion of body iron stores is a major factor limiting regular blood donations by menstruating females . To determine if regular iron supplementation would solve this problem , we conducted a double-blind study in which menstruating female donors were r and omly placed into one of three groups : one taking 39 mg elemental iron , a second taking 39 mg of iron plus 75 mg vitamin C , and a third taking 100 mg vitamin C daily . The women were requested to donate every 8 weeks for at least 1 year . Blood sample s were taken on each donation for measurements of hemoglobin , total iron binding capacity ( TIBC ) , and ferritin . In the two groups taking iron supplements hemoglobin and ferritin increased from baseline values and the TIBC decreased . The vitamin C control group showed decreases from baseline for hemoglobin and ferritin and increases in TIBC . Differences between groups taking iron supplements and the group not taking supplements were highly significant . Drop-out from the study was due to various causes ; however , iron intolerance was uncommon . Minimal daily iron supplementation was beneficial in maintaining body iron stores and hemoglobin levels in menstruating females on a schedule of blood donation as often as every 8 weeks [6864076] We studied the effect of 2 weeks of iron therapy on exercise performance and exercise-induced lactate production in trained women athletes : six control subjects with normal parameters of iron status and nine with mild iron-deficiency anemia defined by low Fe/TIBC , ferritin , and minimally decreased Hgb values . Iron therapy improved the abnormal measures of iron status and low Hgb in the second group to normal . Exercise performance in a progressive work-exercise protocol on a bicycle ergometer to exhaustion was unchanged after iron therapy in both groups ; however , blood lactate levels at maximum exercise in the iron-deficient group decreased significantly from 10.3 + /- 0.6 mmol/L before therapy to 8.42 + /- 0.7 after therapy ( p less than 0.03 ) . The control subjects did not significantly alter lactate levels after maximal exercise on iron compared to placebo : 8.3 + /- 0.8 mmol/L vs. 8.5 + /- 0.7 . Although there was not a significant difference in maximum exercise performance after iron therapy , these data support animal experiments implying that iron may play a role in oxidative metabolism and that minimal decreases in Hgb may impair arterial oxygen content enough to affect aerobic metabolism . In addition , these findings may have important implication s for competitive women athletes in whom mild iron deficiency may go unnoticed [16835600] Objective : To determine the effect of iron supplementation on iron status and endurance capacity . Design : R and omized , double-blind iron supplementation . Setting : University of Missouri-Columbia and surrounding community . Subjects : Twenty iron-deficient ( serum ferritin , sFer<16 μg/l ; serum transferrin receptor , sTfR>8.0 mg/l ; or sTfR/log sFer index > 4.5 ) , nonanemic ( hemoglobin , Hb>120 g/l , women ; > 130 g/l , men ) men and women ( 18–41 years ) were recruited via fliers and newspaper advertisements ; 20 of 31 eligible subjects participated . Interventions : A 30 mg measure of elemental iron as ferrous sulfate or placebo daily for 6 weeks . Results : Dietary iron intake and physical activity did not differ between groups before or after supplementation . Iron supplementation significantly increased sFer compared to placebo ( P=0.01 ) , but did not affect Hb or hematocrit . Iron supplementation prevented the decline in ventilatory threshold ( VT ) observed in the placebo group from pre- to post-supplementation ( P=0.01 ) ; this effect was greater in individuals with lower sFer before intervention ( P<0.05 ) . Changes in sFer from pre- to post-treatment were positively correlated with changes in VT ( P=0.03 ) , independent of supplementation . The iron group significantly increased gross energetic efficiency during the submaximal test ( P=0.04 ) . Changes in sFer were negatively correlated with changes in average respiratory exchange ratio during the submaximal test ( P<0.05 ) . Conclusions : Iron supplementation significantly improves iron status and endurance capacity in iron-deficient , nonanemic trained male and female subjects . Sponsorship : Missouri University Alumni Association , by the Elizabeth Hegarty Foundation and by the Department of Nutritional Sciences [1874236] Summary Serum iron deficiency has a high incidence in female athletes . We investigated the effects of a daily oral iron supplement , ( 160 mg ) administered during an intensive 7-week physical training programme , on body iron status , and the maximal aerobic capacity ( VO2max ) of 13 women ( group A ) compared to 15 who took a placebo ( group B ) . The subjects were 19 years old . Blood sample s were obtained before training began and on days 1 , 7 , 21 and 42 of training . They were analysed for packed cell volume ( PVC ) and for haemoglobin ( Hb ) , 2,3-diphosphoglycerate ( 2,3-DPG ) , haptoglobin , iron and ferritin concentrations . TheVO2max was measured on days 0 , 21 and 42 of training . Following 21 days of training Hb , PCV and ferritin were significantly higher ( P⩽0.01 ) in group A compared to group B. Over the training period Hb rose by 9.3 % and 2.4 % in groups A and B , respectively . At the end of training 66 % of group B exhibited ferritin concentrations below 10 ng·ml−1 , while none of group A had such low values . MeanVO2max of group A had increased by 7.5 % following 21 days of training ( P⩽0.01 ) and by 15.3 % after 42 days . No appreciable increase inVO2max had occurred in group B by day 21 ( significantly lower thanVO2max of group A;P⩽0.05 ) , however by day 42 it had increased by 14.3 % ( P⩽0.05 ) . In both groups 2,3-DPG·g Hb−1 had increased significantly ( P⩽0.005 ) by day 7 ( 22 % ) and remained at that level for an additional 35 days . We concluded that a daily oral iron supplement given to young women during intensive training improved several haematological variables and their body iron status . This improvement was associated with an increasedVO2max only during the early stages of their training ( day 21 ) compared with the placebo group [11814373] OBJECTIVE To compare the effectiveness of weekly vs daily iron and folic acid supplementation for control of anemia in adolescent Nepalese girls . DESIGN R and omized controlled trial . SETTING A Government Girl School in Dharan , Nepal , an urban foothill town that is 305 m above sea level . SUBJECTS Consecutive healthy adolescent girls ( n = 209 , median age 15 years ) r and omized to 3 groups matched for age , anthropometry , and personal and sociodemographic characteristics . Of 209 subjects , 181 completed the trial . Two girls had adverse reactions to treatment and were excluded . INTERVENTION Group A ( n = 70 ) received a 350-mg ferrous sulfate and 1.5-mg folic acid combination once daily for 90 to 100 days . Group B ( n = 67 ) received the tablet under supervision once a week for 14 weeks . Group C ( n = 72 ) did not receive any drugs . OUTCOME VARIABLE Presupplementation and postsupplementation differences in prevalence of anemia and change in hematocrit . RESULTS Prevalence of anemia ( defined as hematocrit < 36 % ) declined from 68.6 % and 70.1 % in groups A and B to 20 % and 13.4 % , respectively , postsupplementation ( P<.001 ) , whereas the prevalence in group C changed little ( 68.1 % to 65.3 % , P = .81 ) . There was a significant rise in the mean hematocrit of both supplemented groups ( group A , 32.9 % + /- 3.5 % to 41.0 % + /- 5.6 % , P<.001 ; group B , 33.2 % + /- 3.6 % to 40.4 % + /- 4.9 % , P<.001 ) but no appreciable change in controls ( 34.2 % + /- 2.9 % to 34.1 % + /- 3.3 % , P = .91 ) . Net change in mean hematocrit in both the supplementation groups was comparable ( P = .57 ) . CONCLUSIONS The prevalence of anemia in adolescent Nepalese girls is high . Supervised iron and folic acid therapy once a week is an effective alternative to daily administration and helps lower the prevalence of anemia in adolescent girls [9459375] Serum transferrin receptor ( sTfR ) concentration has been recognized recently as a reliable indicator of functional iron deficiency , but its response to iron supplementation has not been investigated in marginally iron-deficient women . In this r and omized , double-blinded trial , 37 female subjects aged 19 - 35 y with iron depletion without anemia ( hemoglobin > 120 g/L and serum ferritin < 16 microg/L ) received an iron supplement or placebo for 8 wk . Iron status was measured before treatment , after 4 wk of treatment , and posttreatment ( ie , after 8 wk of treatment ) . Iron supplementation of these iron-depleted , nonanemic women result ed in a progressive and significant decrease in sTfR and a significant increase in serum ferritin , and prevented a fall in hemoglobin . The responsiveness of sTfR to iron treatment indicated that sTfR is a sensitive indicator of marginal iron deficiency in iron-depleted , nonanemic women , even when their body iron stores were being replenished [8107547] To determine the effects of an 8-wk dietary iron supplementation ( 100 mg.d-1 ) on low plasma ferritin concentration ( < 20 ng.ml-1 ) and endurance , 20 active women ( 19 - 35 yr ) were studied while performing a VO2max test and an endurance test ( 80 % VO2max ) on a cycle ergometer . Subjects were r and omly placed in an iron supplement ( IG ) or a placebo group ( PG ) using a double-blind method . After treatment in the IG , ferritin levels were higher ( 22.5 + /- 3.4 vs 14.3 + /- 2.2 ng.ml-1 ; P < 0.05 ) , Hb increased ( 12.8 + /- 0.4 to 14.1 + /- 0.2 g.dl-1 ; P < 0.05 ) , and TIBC decreased ( 366.2 + /- 24.8 to 293.8 + /- 14.0 micrograms.dl-1 ; P < 0.05 ) . Also after treatment the IG 's VO2max was significantly greater ( P < 0.05 ) than the PG value and their postendurance blood lactate decreased ( 5.03 + /- 0.44 to 3.85 + /- 0.6 mM.l-1 ; P < 0.05 ) . Endurance time to exhaustion increased 38 % ( 37.28 + /- 5.03 to 51.4 + /- 7.45 min ) following iron treatment ; however , this change was not statistically significant . The results suggest that this level of iron supplementation can reverse mild anemia , increase VO2max , and reduce blood lactate concentration after submaximal exercise [22443058] OBJECTIVE To investigate the effect of iron supplementation on iron deficiency anemia of childbearing age women , and to find out the optimal amount of iron intake for maintaining their health . METHODS 74 childbearing age women aged 21 to 45 years with anemia were r and omly assigned to intervention or control group by hemoglobin content , and a iron nutrition packet ( mainly composed of ferric pyrophosphate and ferrous fumarate , containing iron 8 mg ) or a placebo packet was given daily for six months , respectively . Hemoglobin , serum ferritin , food frequency and 24h dietary recall survey were performed before intervention and three and six months after intervention . RESULTS Hemoglobin and serum ferritin of the intervention group were significantly higher ( P < 0.01 ) than that in control group after six months . The number of women with hemoglobin > or = 120 g/L in intervention and control group was 15 ( 44.1 % ) and 5 ( 14.3 % ) , respectively ( P < 0.01 ) . The number of women with serum ferritin > or = 15 micro g/L in intervention and control group was 11 ( 34.4 % ) and 4 ( 12.5 % ) , respectively ( P < 0.05 ) . The average dietary iron intake was 14.0 mg/d , mainly from plant foods . There was a positive correlation of total iron intake ( dietary iron plus iron supplements ) with hemoglobin ( r = 0.57 , P < 0.01 ) . More menstrual blood and dietary fiber were the risk factors for iron deficiency anemia ( P < 0.05 ) . CONCLUSION The anemic status in childbearing age women could be improved by providing iron 8 mg daily for six months consecutively . Daily dietary intake of iron 23.2 mg can meet the requirement of maintaining normal iron storage for childbearing age women [1752712] The purpose of this study was to determine the effects of two weeks of high dosage iron supplementation on various blood iron indices and metabolic parameters in non-anemic , iron-depleted competitive female cross-country runners . The subjects were highly trained members of the Colorado State University cross-country team and were completing 40 to 50 miles of training weekly . A pretest , post-test single-blind crossover design was employed . Upon collection of baseline exercise blood and metabolic data , five subjects were r and omly assigned to iron supplementation ( 650 mg ferrous sulfate ; 130 mg elemental iron ) and five subjects to placebo treatment . At two weeks the treatments were reversed . Exercise blood and metabolic data were collected at two-week intervals . Dietary iron intake was assessed using a three-day dietary survey . Dietary analysis revealed deficiencies in vitamin B-6 , iron , magnesium , and zinc according to USRDA st and ards . Baseline blood sample s revealed no deficiencies in iron storage or transport proteins . Two weeks of iron supplementation result ed in no significant increases in blood iron indices . Metabolic parameters related to running performance were also unchanged after iron supplementation . High dosage , short-term iron supplementation appears to have no effect on blood or metabolic parameters in iron-depleted but non-anemic female cross-country runners [1555906] Low serum ferritin concentrations are commonly found in female athletes . By study ing the effects of an 8-week iron or placebo supplementation in 31 female athletes ( aged 17 - 31 years ) , with an initial serum ferritin concentration less than or equal to 25 micrograms/l and blood hemoglobin 120 g/l , we investigated whether low serum ferritin values hinder aerobic performance . Serum ferritin concentration increased from 14 ( 25th and 75th percentile : 11 , 21 ) to 26 ( 18 , 36 ) micrograms/l in the iron-supplemented group , but remained at a low 11 ( 9 , 17 ) micrograms/l in the placebo group ( group difference after supplementation : p = 0.001 ) . Before supplementation , blood hemoglobin concentration was not different in the two groups . After supplementation , however , the concentration in the iron group was 139 ( 135 , 144 ) g/l and 128 ( 126 , 134 ) g/l in the placebo group ( group difference : p = 0.001 ) . Iron supplementation did not affect blood lactate concentration or VO2max during an incremental ergometer test . Hence , aerobic performance was not impaired in nonanemic female athletes with serum ferritin 25 micrograms/l [11601562] Objective : To investigate the efficacy of , first , a dietary regimen involving increased consumption of iron-rich foods and enhancers of iron absorption and decreased consumption of inhibitors of iron absorption and , second , a low dose iron chelate iron supplement , for increasing iron stores in young adult New Zeal and women with mild iron deficiency ( MID ) . Methods : The study was a 16 week r and omized placebo-controlled intervention . Seventy-five women aged 18 to 40 years with MID ( serum ferritin < 20 μg/L and hemoglobin ≥120 g/L ) were assigned to one of three groups : Placebo , Supplement ( 50 mg iron/day as amino acid chelate ) or Diet . Participants in the Diet Group were given individual dietary counseling to increase the intake and bioavailability of dietary iron . Dietary changes were monitored by a previously vali date d computer-administered iron food frequency question naire . Results : Diet Group members significantly increased their intake of flesh foods , heme iron , vitamin C and foods cooked using cast-iron cookware and significantly decreased their phytate and calcium intakes . Serum ferritin increased in the Supplement and Diet Groups by 59 % ( p=0.001 ) and 26 % ( p=0.068 ) , respectively , in comparison to the Placebo Group . The serum transferrin receptor : serum ferritin ratio decreased by 51 % in the Supplement Group ( p=0.0001 ) , and there was a non-significant decrease of 22 % ( p=0.1232 ) in the Diet Group . Conclusions : This study is the first , to our knowledge , to demonstrate that an intensive dietary program has the potential to improve the iron status of women with iron deficiency [20416130] Interventions to combat mild Fe deficiency in women of childbearing age may affect Zn nutriture . We used dietary and laboratory indices to assess change in Zn status during a 4-month partially blinded placebo-controlled Fe intervention in women with low Fe stores ( serum ferritin < 20 microg/l and Hb > or = 120 g/l ) from Dunedin , New Zeal and . Subjects aged 18 - 40 years were r and omly assigned to three groups : dietary advice ( diet group ; DG ; n 29 ) , daily Fe supplement with meals ( supplement group ; SG ; n 23 ; 50 mg Fe as amino acid chelate ) and placebo ( placebo group ; PG , n 26 ) . A vali date d semi-quantitative FFQ ( SFFQ ) was administered at baseline , and at 4 , 8 and 15 weeks ; fasting morning blood sample s were assayed for serum Zn , alkaline phosphatase ( ALP ) and C-reactive protein at baseline , and at 4 , 8 , 12 and 16 weeks ; hair Zn and taste detection thresholds by electrogustometry were measured at baseline and at 16 weeks . Intakes of flesh foods and vitamin C but not Zn or Fe increased , whereas phytate and phytate : Zn molar ratios decreased ( all P < or = 0.01 ) in the DG compared with the PG and SG , based on three SFFQ . Serum Zn increased in both the DG and PG ( adjusted , P < or = 0.002 ) , so the between-group difference was not significant ; the lack of a parallel rise in the SG was significant when compared with the PG ( P = 0.02 ) . ALP activity ( but not hair Zn or taste acuity ) followed a similar trend . In conclusion , Zn status was not improved compared with placebo by an Fe-based dietary intervention . However , a daily moderate-dose Fe supplement with meals appeared to lower Zn status in these young adult women [3341317] Iron-deficiency anemia impairs exercise capacity , but whether nonanemic iron depletion decreases endurance performance is unclear . In 14 iron-deficient ( serum ferritin level , less than 20 micrograms/L [ less than 20 ng/L])nonanemic runners , hematologic and treadmill running values were followed up during a competitive season . Following a four-week control period , runners were treated for one month in a double-blind protocol with ferrous sulfate ( 975 mg/d ) or placebo . During treatment , the mean ferritin level rose from 8.7 to 26.6 micrograms/L ( 8.7 to 26.6 ng/mL ) in those patients taking iron and fell from 10.6 to 8.6 micrograms/L ( 10.7 to 8.6 ng/mL ) in the placebo group . Treadmill endurance times improved significantly in the iron-treated runners compared with controls . Endurance time declined in all seven controls ( range , 0.07 to 1.30 minutes ) , while six of seven iron-treated subjects improved their performance ( range , 0.03 to 1.92 minutes ) . No significant differences in maximal or submaximal oxygen consumption , ventilation , or heart rate were observed between the groups except for a 4 % increase in maximum oxygen consumption during placebo treatment . These data indicate that nonanemic iron deficiency impairs exercise performance but does not influence gas exchange or cardiac measures [18363581] BACKGROUND Iron deficiency is a public problem in women , which contributes to the high percentage of deferred blood donations in this group . This study evaluated the effect of iron supplementation in improving iron stores to promote safe blood donation in women . STUDY DESIGN AND METHODS A total of 412 female blood donors were r and omly recruited for the study . The volunteers were scheduled for an initial visit and three subsequent visits at 4-month intervals for possible repeat donation . Each volunteer was given 21 tablets of 150 mg of ferrous sulfate or placebo to be taken three times daily for 1 week after each blood donation . Their hemoglobin ( Hb ) concentration , hematocrit ( Hct ) , serum ferritin , total iron-binding capacity ( TIBC ) , and percent saturation of the TIBC were tested throughout the course of the study . RESULTS The group taking ferrous sulfate showed no significant difference between the mean initial and final result for any of the values other than Hb values , whereas there was a significant decline in mean Hb , Hct , serum iron , serum ferritin , and percent saturation in the group taking placebo . Hb concentrations declined significantly in both groups ; however , it was more severe in the placebo group when compared to the ferrous sulfate group . The relative risk of iron deficiency in placebo group was 3.6 ( 95 % confidence interval = 1.73 - 7.74 ) . CONCLUSION The results indicate that supplementation therapy can be considered as one of the strategies to promote safe blood donation in women . A quantity of 150 mg of elemental iron per day as ferrous sulfate , however , is not the correct dose for Iranian female donors [4408096] Objective Women ’s nutritional status during conception and early pregnancy can influence maternal and infant outcomes . This study examined the efficacy of pre-pregnancy supplementation with iron and multivitamins to reduce the prevalence of anemia during the periconceptional period among rural Tanzanian women and adolescent girls . Design A double-blind , r and omized controlled trial was conducted in which participants were individually r and omized to receive daily oral supplements of folic acid alone , folic acid and iron , or folic acid , iron , and vitamins A , B-complex , C , and E at approximately single recommended dietary allowance ( RDA ) doses for six months . Setting Rural Rufiji District , Tanzania . Subjects Non-pregnant women and adolescent girls aged 15–29 years ( n = 802 ) . Results The study arms were comparable in demographic and socioeconomic characteristics , food security , nutritional status , pregnancy history , and compliance with the regimen ( p>0.05 ) . In total , 561 participants ( 70 % ) completed the study and were included in the intention-to-treat analysis . Hemoglobin levels were not different across treatments ( median : 11.1 g/dL , Q1-Q3 : 10.0–12.4 g/dL , p = 0.65 ) . However , compared with the folic acid arm ( 28 % ) , there was a significant reduction in the risk of hypochromic microcytic anemia in the folic acid and iron arm ( 17 % , RR : 0.61 , 95 % CI : 0.42–0.90 , p = 0.01 ) and the folic acid , iron , and multivitamin arm ( 19 % , RR : 0.66 , 95 % CI : 0.45–0.96 , p = 0.03 ) . Inverse probability of treatment weighting ( IPTW ) to adjust for potential selection bias due to loss to follow-up did not material ly change these results . The effect of the regimens was not modified by frequency of household meat consumption , baseline underweight status , parity , breastfeeding status , or level of compliance ( in all cases , p for interaction>0.2 ) . Conclusions Daily oral supplementation with iron and folic acid among women and adolescents prior to pregnancy reduces risk of anemia . The potential benefits of supplementation on the risk of periconceptional anemia and adverse pregnancy outcomes warrant investigation in larger studies . Trial Registration Clinical Trials.gov [3810831] A r and omized , double-blind trial of iron replacement after repeated blood donation was conducted in 75 menstruating women ; 51 completed the study . Volunteers were assigned r and omly to one of three treatment groups : 1 ) carbonyl iron ( nontoxic elemental iron powder ) , 600 mg ; 2 ) ferrous sulfate , 300 mg ( 60 mg Fe++ ) ; or 3 ) placebo , each given three times daily for 1 week immediately after blood donation . Blood sample s obtained initially and 56 days later were tested for hemoglobin , mean corpuscular volume ( MCV ) , free erythrocyte protoporphyrin , serum ferritin , serum iron , total iron binding capacity ( TIBC ) , and percent saturation of TIBC . The prevalence of gastrointestinal side effects was similar in both groups taking iron . At the end of the study there was no laboratory evidence of change in iron status in women who received carbonyl iron ( n = 15 ) . In those treated with ferrous sulfate ( n = 17 ) the mean TIBC increased ( p less than 0.001 ) , and in the placebo group ( n = 19 ) there were decreases in mean MCV ( p less than 0.01 ) , serum ferritin ( p less than 0.001 ) , and percent saturation ( p = 0.027 ) with an increase in mean TIBC ( p = 0.004 ) . Carbonyl iron seems to be effective for short-term iron replacement in repeat blood donors and may have the advantage of decreased or absent risk of poisoning if accidentally ingested by children [16340950] Objective : To investigate whether iron supplementation can improve thyroid hormone function in iron-deficient adolescent girls . Design : A double-blind r and omized intervention study . Setting : The study was performed from 2002 through 2003 in the Islamic Republic of Iran . Subjects:103 iron-deficient non-anaemic girls who fulfilled all inclusion criteria were included , and 94 subjects successfully completed the study . Interventions : Patients were r and omly assigned to one of four groups and treated with a single oral dose of 190 mg iodine plus 300 mg ferrous sulphate 5 times/week ( n=24 ) , 300 mg ferrous sulphate 5 times/week ( n=23 ) , a single oral dose of 190 mg iodine ( n=25 ) , or a placebo ( n=22 ) for 12 weeks . Results : All groups were comparable at baseline . After the intervention , there was a significant increase in ferritin and transferrin saturation in the iron+iodine group ( 17.6 vs 8.7 μg/dl , and 18.8 vs 7.2 % , respectively , P<0.001 for both ) and in the iron group ( P<0.001 for both ) . Urinary iodine doubled in the iron+iodine group and in the iodine group ( P<0.001 for both ) . Thyroid indices tT4 , tT3 and T3RU increased and reverse RT3 decreased in the iron+iodine group ( 10 vs 8.9 μg/dl , P < 0.001 ; 143 vs 138 μg/dl , P<0.05 ; 32.3 vs 28.4 % , P<0.001 and 24.8 vs 44.2 ng/dl , P<0.001 , respectively ) and in the iron group . These two groups did not differ for any of the four indices , but both differed significantly from the iodine and placebo groups . Conclusions : Our results indicate that improvement of iron status was accompanied by an improvement in some indices of thyroid hormones . Sponsorship : This study was supported by the Dean of Research Affairs of the Tehran University of Medical Sciences [19874572] INTRODUCTION Frequent blood donations may lead to a negative iron balance . Iron depletion may be prevented by iron supplementation after whole blood donations . The aim of this study was to compare the short time changes in iron status after donation in two groups r and omized to iron supplementation or no additional iron . A second objective was to evaluate the effect of iron supplementation in donors having HFE-variants compared to HFE wild types . METHODS Subjects of both genders ( 199 women , 200 men ) were r and omised to receive iron supplementation or no additional iron after donation . Iron status , defined by the concentration of haemoglobin , serum ferritin , soluble transferrin receptor , concentration of haemoglobin in reticulocytes ( CHr ) and percent hypochrome mature red blood cells , was determined at the start of donation and 8 + /- 2 days after donation . HFE genotyping was performed at reappearance . RESULTS There was a significant difference between the two study groups on all the iron status parameters . CHr was an efficient , early marker of ongoing synthesis of haemoglobin . Heterozygosity for the HFE variants C282Y and H63D had no statistically significant influence on the iron status . The donor 's baseline serum ferritin value may be basis for an individual iron supplementation regimen , as donors with serum ferritin > 50 microg/l do not seem to utilize the iron supplementation , but prefer endogenous iron to restore the loss of haemoglobin . CONCLUSION Iron supplementation had a significant positive impact on the restoration of iron status one week after donation [3250868] Sixty-nine boys and girls between 10 and 14 years , with evidence of sub clinical vitamin deficiencies and poor iron status were enrolled into the study at the beginning of the rainy season . Children were allocated to three treatment groups to receive five times weekly either a placebo , 200 mg ferrous sulphate or 5 mg riboflavin and 150 mg ascorbic acid . Before receiving the supplement , and 9 weeks later , children performed an exercise regimen on a treadmill during which expired air was collected and heart rate measured . There was a general deterioration in the running performance of the children during the study period which was not affected by either the iron or the vitamin supplement [19474138] BACKGROUND Decrements in iron status have been reported in female soldiers during military training . Diminished iron status adversely affects physical and cognitive performance . OBJECTIVE We wanted to determine whether iron supplementation could prevent decrements in iron status and improve measures of physical performance and cognitive status in female soldiers during basic combat training ( BCT ) . DESIGN In this 8-wk r and omized , double-blind , placebo-controlled trial , soldier volunteers ( n = 219 ) were provided with capsules containing either 100 mg ferrous sulfate or a placebo . Iron status indicator assays were performed pre- and post-BCT . Two-mile running time was assessed post-BCT ; mood was assessed by using the Profile of Mood States question naire pre- and post-BCT . RESULTS The BCT course affected iron status : red blood cell distribution width and soluble transferrin receptor were elevated ( P < 0.05 ) , and serum ferritin was lowered ( P < 0.05 ) post-BCT . Iron supplementation attenuated the decrement in iron status ; group-by-time interactions ( P < 0.01 ) were observed for serum ferritin and soluble transferrin receptor . Iron supplementation result ed in improved ( P < 0.05 ) vigor scores on the Profile of Mood States post-BCT and in faster running time ( P < 0.05 ) in volunteers reporting to BCT with iron deficiency anemia . CONCLUSIONS Iron status is affected by BCT , and iron supplementation attenuates the decrement in indicators of iron status in female soldiers . Furthermore , iron supplementation may prove to be beneficial for mood and physical performance during the training period . Future efforts should identify and treat female soldiers or athletes who begin training regimens with iron deficiency or iron deficiency anemia [2733574] In order to examine the effects of mild iron deficiency on physical work capacity , 40 prelatent iron-deficient female endurance runners were studied before and after 8 wk of supplementation with either oral iron ( 320 mg ferrous sulfate ) or a matching placebo . Subjects underwent the following physical work capacity tests : the Wingate cycle ergometer test , the anaerobic speed test , the ventilatory threshold , VO2max , and maximal treadmill velocity during the VO2max test . Muscle biopsy sample s pre- and post-treatment were obtained from 17 of the subjects , and these were assayed for citrate synthase and cytoplasmic alpha-glycerophosphate dehydrogenase activity . Subjects were r and omly assigned to one of the treatment groups , and a double-blind method of administration of the supplements was used . The differences in improvement scores between the two groups on the work capacity and enzyme activity variables were statistically nonsignificant ( P greater than 0.05 ) . Serum ferritin values rose from a mean of 12.4 + /- 4.5 to 37.7 + /- 19.7 ng.ml-1 for the experimental group and from 12.2 + /- 4.3 to 17.2 + /- 8.9 ng.ml-1 for the controls ( P = 0.0025 ) , whereas hemoglobin levels remained fairly constant for both groups ( P = 0.6 ) . Eight weeks of iron supplementation to prelatent/latent iron-deficient , physically active females did not significantly enhance work capacity . Within the limitations of this study , the presence of a serum ferritin below 20 ng.ml-1 does not pose a significant h and icap to physical work capacity [15563440] The effects of 4 weeks iron supplementation on haematological and immunological status were studied in 25 elite female soccer players aged 20 - 28 years . The subjects were r and omized and assigned to one of the following two groups ; subjects given 40 mg/day iron supplementation ( S group ) or those given placebo ( C group ) . The oral iron supplementation ( 40 mg elemental iron ) was taken in 15 ml solution once a day by the S group , and the C group took a placebo for 4 weeks . Daily energy and protein intakes met the Korean Recommended Dietary Allowances . Blood haemoglobin concentration did not change in the S group , but decreased significantly ( P<0.05 ) in the C group over the 4-week experimental period . Haematocrit , mean cell volume , mean cell haemoglobin and total iron binding capacity decreased significantly , and mean cell haemoglobin concentration increased significantly ( P<0.05 ) in both the S and C groups . Plasma ferritin concentration increased significantly ( P<0.05 ) in the S group , but did not change in the C group . The change of plasma immunological parameters and erythrocyte anti-oxidative enzyme activities were almost the same between the S and C groups . These results suggest that 4 weeks of iron supplementation by elite female soccer players significantly increased body iron stores and inhibited decrease of haemoglobin concentration induced by soccer training [7835330] We studied effects of dose and treatment duration during low-dose iron supplementation in premenopausal , non-pregnant women , with initial serum ferritin and haemoglobin concentrations < 20 micrograms x l-1 and > or = 120 g x l-1 , respectively . The study was r and omized , double-blind and placebo-controlled . Three groups completed a 6-month study : placebo ( n = 27 ) , FE-9 ( 9 mg iron x day-1 , n = 18 ) and FE-27 group ( 27 mg iron x day-1 , n = 19 ) . The supplement consisted of 11 % heme and 89 % inorganic iron . In FE-27 , serum ferritin increased from ( mean , 95 % confidence interval ) 11.8 ( 9.7 ; 14.4 ) to 25.3 ( 18.6 ; 34.4 ) micrograms x l-1 in 1 month , and remained stable after that ( ANOVA : group effect , P = 0.0003 ) . In both FE-9 and FE-27 , blood haemoglobin levels increased from 136 ( 132 ; 140 ) to 142 ( 139 ; 145 ) g x l-1 in 1 month , remaining constant after that ( group effect , P = 0.001 ) . Hence , the 27 mg daily dose of organic/inorganic iron corrected both mild anaemia and storage iron depletion , whereas the 9 mg dose did not affect iron stores . Elongation of treatment duration above 1 month brought about only minor changes [7091036] The effects of energy supplementation ( group I received 200 kcal/day and group II received 1000/kcal day ) were examined on road workers in Kenya . Anthropometric , dietary , worker productivity , clinical hematology , and parasitology data were collected from 224 workers of both sexes or , sub sample s of these workers at base-line , midpoint , and final measurement periods . Sixty-seven percent of the work force was less than 85 % of weight for height . Females tended to be better nourished than males . Multiple regression analysis showed that increases in arm circumference and Hb levels were associated with significant productivity gains of about 4 % . At the midpoint , group II males gained 1.10 kg ( p less than 0.0003 ) while group I males showed no change . Weight loss during the latter part of the study result ed in no significant final weight change for males . " Successful " supplementation was weakly associated with a productivity increase for group II workers of 12.5 % ( p less than 0.10 ) [7476052] The impact of long-term ( 6-month ) moderate exercise on the iron status of previously sedentary women was determined by r and omly assigning 62 college-age women into one of the following four groups : 1 ) 50 mg.d-1 iron supplement , low iron diet ( N = 16 ) ; 2 ) Placebo , free choice diet ( N = 13 ) ; 3 ) Meat supplement to achieve 15 mg.d-1 iron intake ( N = 13 ) ; and 4 ) Control , free choice diet ( N = 20 ) . All groups except the Control group exercised 3 d.wk-1 at 60%-75 % of their heart rate reserve . VO2max was measured at baseline and week 24 . Blood was sample d at baseline and every 4 wk thereafter for 24 wk to measure iron status and to eluci date the causes for alterations in iron status . Subjects had depleted iron stores throughout the study as indicated by their serum ferritin levels ( < 15 ng.ml-1 ) . Serum iron , total iron binding capacity and transferrin saturation were not compromised with exercise . Mean hemoglobin level in the Placebo/Ex group was significantly ( P < 0.05 ) lower than the 50 Fe/Ex and the Meat/Ex groups by week 24 . However , changes in serum albumin , haptoglobin , and erythropoietin data from the study can not explain these changes [3047920] Female blood donors with low hematocrit levels detected by copper sulfate screening were selected r and omly to receive either 75 mg of iron per day , as ferrous gluconate , or a calcium phosphate placebo . Their ferritin , serum iron , total iron-binding capacity , zinc protoporphyrin , and hemoglobin values , as well as their suitability to donate blood , were determined initially ( Visit 1 ) and at four follow-up visits ( Visits 2 - 5 ) . By the second visit , the serum ferritin and iron values of donors receiving iron supplementation differed significantly from those of donors receiving placebo . By the fifth visit , a less marked but significant increase in hemoglobin had occurred in the iron group , but not in the placebo group . At no time was there a significant difference between the groups ' suitability to donate blood , with each group donating at almost half of their visits . The authors conclude that iron supplementation at this dose level in deferred female blood donors improves their iron status and hemoglobin levels , but does not significantly increase their suitability to donate blood as compared with the suitability of placebo-treated donors [2180144] The effectiveness of elemental , nontoxic carbonyl iron in replacing iron lost at blood donation was examined . In a r and omized double-blind design , 99 women , aged 18 to 40 , were given placebo or low-dose carbonyl iron ( 100 mg orally ) at bedtime for 56 days after phlebotomy . Compliance was equivalent for the two regimens . Mild side effects were slightly greater with carbonyl iron . At Day 56 , estimated net iron absorption from therapy or diet , or both , was sufficient to replace iron in 85 percent of those receiving carbonyl iron but in only 29 percent of those taking placebo ( p less than 0.001 ) . The rates of deferral from repeat donation were 8 percent in the carbonyl iron group and 36 percent in the placebo group ( p less than 0.01 ) , and the positive predictive value of routine screening in identifying participants without iron deficiency was 83 versus 13 percent ( p less than 0.01 ) . It can be concluded that short-term carbonyl iron supplementation in female blood donors can replace the iron lost at phlebotomy , protect the women against iron deficiency , and enhance their ability to give blood [10989766] This experimental study was design ed to investigate the effects of daily versus intermittent iron supplementation on iron status of high school girls in Zahedan and Rasht cities in 1996 - 1997 . The subjects were selected r and omly from among students of grade s 1 - 3 of four high schools in each city . Anemia was determined by measuring hematological indices . 260 anemic and a similar number of non-anemic subjects of 4 high schools were selected and allocated r and omly to 4 treatment groups . During a 3-month period , the test groups were given 150 mg ferrous sulfate tablets ( 50 mg Fe ) . Subjects in group 1 received a daily dose , groups 2 & 3 received twice or once weekly doses respectively . The control group received no iron supplement . For these subjects , in addition to hematological indices biochemical iron indices were measured in the beginning and at the end of the study . The increases in hemoglobin concentration in anemic subjects were not significantly different among supplemented groups but were different from the control group ( p < 0.00001 ) . Among anemic subjects , changes in serum ferritin levels in 3 supplemented groups were significantly different from the control group . Serum ferritin in Group 1 was also increased to a greater extent than groups 2 and 3 ( P < 0.00001 ) . It is concluded that over the study period a weekly iron dose was as effective as a daily dose in treating anemia but the daily dose was more effective in improving iron stores than a weekly dose in the short run [8855856] BACKGROUND Up to 25 % of adolescent girls in the USA are iron deficient . This double-blind , placebo-controlled clinical trial assessed the effects of iron supplementation on cognitive function in adolescent girls with non-anaemic iron deficiency . METHODS 716 girls who enrolled at four Baltimore high schools were screened for non-anaemic iron deficiency ( serum ferritin < or = 12 micrograms/L with normal haemoglobin ) . 98 ( 13.7 % ) girls had non-anaemic iron deficiency of whom 81 were enrolled in the trial . Participants were r and omly assigned oral ferrous sulphate ( 650 mg twice daily ) or placebo for 8 weeks . The effect of iron treatment was assessed by question naires and haematological and cognitive tests , which were done before treatment started and repeated after the intervention . We used four tests of attention and memory to measure cognitive functioning . Intention-to-treat and per- protocol analyses were done . FINDINGS Of the 81 enrolled girls with non-anaemic iron deficiency , 78 ( 96 % ) completed the study ( 39 in each group ) . Five girls ( three control , two treatment ) developed anaemia during the intervention and were excluded from the analyses . Thus , 73 girls were included in the per- protocol analysis . Ethnic distribution , mean age , serum ferritin concentrations , haemoglobin concentrations , and cognitive test scores of the groups did not differ significantly at baseline . Postintervention haematological measures of iron status were significantly improved in the treatment group ( serum ferritin 27.3 vs 12.1 micrograms/L , p < 0.001 ) . Regression analysis showed that girls who received iron performed better on a test of verbal learning and memory than girls in the control group ( p < 0.02 ) . INTERPRETATION In this urban population of non-anaemic iron-deficient adolescent girls , iron supplementation improved verbal learning and memory [4587790] Pregnant women with anaemia due to combined iron and folate deficiencies were r and omly divided into 3 groups receiving either combination therapy with iron and pteroylglutamic acid , or treatment with iron or pteroylglutamic acid olone . A fourth group of pregnant women with levels of Hb above 10 g/100 ml received placebo . Combined iron and folate administration result ed in a marked therapeutic response , while mild or insignificant improvement was associated with either iron or folic acid teratment alone . The Hb concentration of the women receiving placebo dropped gradually in most instances . The results reported here suggest that in population s with a high prevalence of iron and folate deficiencies both these compounds should be supplied in order to prevent anaemia . The possible causal relationship between iron and folate deficiencies are discussed in the light of the present results and relevant literature [10721926] The prevalence of anemia is high in adolescent girls in India , with over 70 % anemic . Iron-folic acid ( IFA ) supplements have been shown to enhance adolescent growth elsewhere in the world . To confirm these results in India , a study was conducted in urban areas of Vadodora , India to investigate the effect of IFA supplements on hemoglobin , hunger and growth in adolescent girls 10 - 18 y of age . Results show that there was a high dem and for IFA supplements and > 90 % of the girls consumed 85 out of 90 tablets provided . There was an increment of 17.3 g/L hemoglobin in the group of girls receiving IFA supplements , whereas hemoglobin decreased slightly in girls in the control group . Girls and parents reported that girls increased their food intake . A significant weight gain of 0.83 kg was seen in the intervention group , whereas girls in the control group showed little weight gain . The growth increment was greater in the 10- to 14-y-old age group than in the 15- to 18-y-old group , as expected , due to rapid growth during the adolescent spurt . IFA supplementation is recommended for growth promotion among adolescents who are underweight [23602244] Limited information is available on the role of iron in fatty acid metabolism in humans . We hypothesized that iron supplementation will increase desaturase activity , and so , the aim of this study was to determine the effect of iron supplementation on fatty acid desaturase activity in young women . Participants were r and omly assigned to a control group ( CG ) or supplementation group ( SG ) who were provided with 37.4 mg of elemental iron daily for 12 weeks . Forty women completed the trial , n = 19 in CG and n = 21 in SG . The mean ages were 25.2 and 24.6 years , and body mass indices were 21.8 and 21.2 ( kg/m(2 ) ) in CG and SG , respectively . Serum ferritin concentrations increased significantly ( P < .01 ) in subjects assigned to SG but were unchanged in CG . Serum iron concentrations were not significantly changed . Plasma zinc concentrations at the end of the intervention were similar to baseline values for individuals in CG but were decreased significantly ( P = .004 ) in SG . Plasma fatty acids , phospholipid fatty acids , and desaturase activities , expressed as precursor-to-product ratios , were not significantly affected by the intervention , although in SG the concentration of serum ferritin was correlated positively ( P < .05 ) with Δ6-desaturase activity . Supplementing non-anemic women with low dose iron improves iron status but has no significant effect on desaturase activity . The lack of a clear effect on an indirect indicator of desaturase activity may be related to the antagonism between iron and zinc , as illustrated by the decrease in plasma zinc concentrations in women who were supplemented with iron

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### Context: [25582309] The objective was to determine the effect of daily supplementation with 30 mg of iron ( Fe ) plus 30 mg of zinc ( Zn ) for 3 months on Fe status of women of childbearing age . This was a r and omized double-blind , placebo-controlled trial . Eighty-one women ( 18–45 years ) were r and omly assigned to receive either a daily single dose of 30 mg of Fe ( group 1 ; n = 28 ) and 30 mg of Fe plus 30 mg of Zn ( group 2 ; n = 26 ) or placebo ( n = 27 ) for 3 months . Hemoglobin ( Hb ) , mean corpuscular volume , serum Fe , total iron-binding capacity , transferrin saturation , erythrocyte Zn protoporphyrin , serum ferritin ( SF ) , serum transferrin receptor ( TfR ) , total body Fe , serum Zn , and high-sensitivity C-reactive protein were measured at baseline and at the end of the study . At baseline , 3.7 , 28.4 , and 3.7 % of women had iron-deficiency anemia ( IDA ) , Fe deficiency without anemia , and depleted Fe stores , respectively . No significant differences on Fe status were found between groups before supplementation . After supplementation , group 2 showed a significant increase of Hb and total body Fe and a significant decrease of TfR compared with placebo ( p < 0.05 ) . Moreover , serum Zn increased significantly in group 2 compared with group 1 ( p < 0.01 ) and placebo ( p < 0.01 ) . In conclusion , daily supplementation with 30 mg of Fe plus 30 mg of Zn for 3 months improved significantly the Fe and Zn status of women , compared with those who received placebo . The positive effect of Fe supplementation on Fe status is enhanced by combined Zn supplementation [5338945] In a study published elsewhere ( Wood and Elwood , 1966 ) the associations between the severity of various symptoms and haemoglobin levels in subjects who took part in a community survey is described . The present paper describes a double-blind r and omized clinical trial of the effects on these symptoms of oral iron therapy in a sample of the women seen during the community survey . In addition some limited data relating to a separate trial conducted in severely anaemic women identified in a hospital out-patient clinic are presented [10710409] Our objective was to investigate the effects of iron depletion on adaptation to aerobic exercise , assessed by time to complete a 15-km cycle ergometer test . Forty-two iron-depleted ( serum ferritin < 16 microg/l ) , nonanemic ( Hb > 12 g/dl ) women ( 18 - 33 yr old ) received 100 mg of ferrous sulfate ( S ) or placebo ( P ) per day for 6 wk in a r and omized , double-blind trial . Subjects trained for 30 min/day , 5 days/wk at 75 - 85 % of maximum heart rate for the final 4 wk of the study . There were no group differences in baseline iron status or in 15-km time . Iron supplementation increased serum ferritin and decreased transferrin receptors in the S compared with the P group . The S and P groups decreased 15-km time and respiratory exchange ratio and increased work rate during the 15-km time trial after training . The decrease in 15-km time was greater in the S than in the P group ( P = 0.04 ) and could be partially attributed to increases in serum ferritin and Hb . These results indicate that iron deficiency without anemia impairs favorable adaptation to aerobic exercise [8286880] We examined changes in iron status in 25 female varsity collegiate swimmers over the course of a competitive season via weekly capillary blood sampling . We also studied the effectiveness of moderate iron supplementation ( 39 mg/day ) in preventing expected changes in iron status via a double-blinded crossover design . On entry into the study , 17 of the swimmers had depleted iron stores ( plasma ferritin < 12 micrograms/L ) and 5 were anemic ( Hb < 120 g/L ) . After 5 wk of placebo treatment , hemoglobin decreased ( > or = 6 g/L ) in 44 % and increased in 12 % of the subjects . After 5 wk of iron supplementation , hemoglobin decreased in 16 % and increased in 24 % of the subjects . Likewise , after placebo treatment , plasma ferritin decreased ( > or = 5 micrograms/L ) in 24 % and increased in 4 % of the subjects , whereas iron supplementation result ed in decreases in 4 % and increases in 68 % of the subjects . In the absence of iron supplementation , hemoglobin levels decreased despite mean dietary iron intakes of 16.3 mg/day . These results show that moderate iron supplementation is effective in preventing decline in the iron status of female collegiate swimmers during a competitive season , but a higher dose of iron may be necessary to reverse their iron-deficient state [25668261] IMPORTANCE Although blood donation is allowed every 8 weeks in the United States , recovery of hemoglobin to the currently accepted st and ard ( 12.5 g/dL ) is frequently delayed , and some donors become anemic . OBJECTIVE To determine the effect of oral iron supplementation on hemoglobin recovery time ( days to recovery of 80 % of hemoglobin removed ) and recovery of iron stores in iron-depleted ( " low ferritin , " ≤26 ng/mL ) and iron-replete ( " higher ferritin , " > 26 ng/mL ) blood donors . DESIGN , SETTING , AND PARTICIPANTS R and omized , nonblinded clinical trial of blood donors stratified by ferritin level , sex , and age conducted in 4 regional blood centers in the United States in 2012 . Included were 215 eligible participants aged 18 to 79 years who had not donated whole blood or red blood cells within 4 months . INTERVENTIONS One tablet of ferrous gluconate ( 37.5 mg of elemental iron ) daily or no iron for 24 weeks ( 168 days ) after donating a unit of whole blood ( 500 mL ) . MAIN OUTCOMES AND MEASURES Time to recovery of 80 % of the postdonation decrease in hemoglobin and recovery of ferritin level to baseline as a measure of iron stores . RESULTS The mean baseline hemoglobin levels were comparable in the iron and no-iron groups and declined from a mean ( SD ) of 13.4 ( 1.1 ) g/dL to 12.0 ( 1.2 ) g/dL after donation in the low-ferritin group and from 14.2 ( 1.1 ) g/dL to 12.9 ( 1.2 ) g/dL in the higher-ferritin group . Compared with participants who did not receive iron supplementation , those who received iron supplementation had shortened time to 80 % hemoglobin recovery in both the low-ferritin ( mean , 32 days , interquartile range [ IQR ] , 30 - 34 , vs 158 days , IQR , 126->168 ) and higher-ferritin groups ( 31 days , IQR , 29 - 33 , vs 78 days , IQR , 66 - 95 ) . Median time to recovery to baseline ferritin levels in the low-ferritin group taking iron was 21 days ( IQR , 12 - 84 ) . For participants not taking iron , recovery to baseline was longer than 168 days ( IQR , 128->168 ) . Median time to recovery to baseline in the higher-ferritin group taking iron was 107 days ( IQR , 75 - 141 ) , and for participants not taking iron , recovery to baseline was longer than 168 days ( IQR , > 168->168 ) . Recovery of iron stores in all participants who received supplements took a median of 76 days ( IQR , 20 - 126 ) ; for participants not taking iron , median recovery time was longer than 168 days ( IQR , 147->168 days ; P < .001 ) . Without iron supplements , 67 % of participants did not recover iron stores by 168 days . CONCLUSIONS AND RELEVANCE Among blood donors with normal hemoglobin levels , low-dose iron supplementation , compared with no supplementation , reduced time to 80 % recovery of the postdonation decrease in hemoglobin concentration in donors with low ferritin ( ≤26 ng/mL ) or higher ferritin ( > 26 ng/mL ) . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01555060 [11916761] BACKGROUND Iron deficiency without anemia has been shown to reduce both muscle-tissue oxidative capacity and endurance in animals . However , the consequences of iron deficiency in humans remain unclear . OBJECTIVE We investigated the effects of iron supplementation on adaptation to aerobic training among marginally iron-depleted women . We hypothesized that iron supplementation for 6 wk would significantly improve iron status and maximal oxygen uptake ( VO(2)max ) after 4 wk of concurrent aerobic training . DESIGN Forty-one untrained , iron-depleted , nonanemic women were r and omly assigned to receive either 50 mg FeSO(4 ) or a placebo twice daily for 6 wk in a double-blind trial . All subjects trained on cycle ergometers 5 d/wk for 4 wk , beginning on week 3 of the study . RESULTS Six weeks of iron supplementation significantly improved serum ferritin and serum transferrin receptor ( sTfR ) concentrations and transferrin saturation without affecting hemoglobin concentrations or hematocrit . Average VO(2)max and maximal respiratory exchange ratio improved in both the placebo and iron groups after training ; however , the iron group experienced significantly greater improvements in VO(2)max . Both iron-status and fitness outcomes were analyzed after stratifying by baseline sTfR concentration ( > and < or = 8.0 mg/L ) , which showed that the previously observed treatment effects were due to iron-status and fitness improvements among subjects with poor baseline iron status . CONCLUSIONS Our findings strongly suggest that iron deficiency without anemia but with elevated sTfR status impairs aerobic adaptation among previously untrained women and that this can be corrected with iron supplementation [2963533] Studies on the treatment and prevention of iron deficiency anemia , in pregnant and nonpregnant women and in men , were conducted in Thail and and Burma . The effects of the dose of Fe , duration of Fe administration , additional supplementation with folate , mode of supplement delivery ( either supervised or unsupervised ) , and the presence of Hb(AE ) were studied . The frequency and severity of side effects were also recorded . Fe administration result ed in an increase in hemoglobin concentration in all anemic individuals but approximately 20 % failed to reach normality . The length of administration and the dose influenced the results . Frequency and severity of side effects increased with the dose of Fe administered . Folate supplementation did not affect the results . It appears possible to integrate a program of prevention and treatment of Fe deficiency anemia in a primary health-care system but the constraints and limitations of achievable results should be recognized [2912000] Response of iron , copper , and zinc status to supplementation with Zn or a combination of Zn and Fe was assessed in adult females in a 10-wk study . Group Z received 50 mg Zn/d as Zn gluconate ; group F-Z received 50 mg Fe as ferrous sulfate monohydrate in addition to the Zn . For Group Z , serum ferritin , hematocrit , and erythrocyte Cu , Zn-superoxide dismutase ( ESOD ) were significantly lower ( p less than 0.05 ) after 10 wk supplementation compared with pretreatment levels . Serum Zn increased ( p less than 0.01 ) but no change occurred in serum ceruloplasmin , hemoglobin , or salivary sediment Zn with treatment . For Group F-Z ESOD decreased with treatment as did salivary sediment Zn ( p less than 0.05 ) . Serum ferritin and serum Zn increased significantly , but hemoglobin , hematocrit , and ceruloplasmin were not affected by this treatment . Supplementation with Zn poses a risk to Fe and Cu status . Inclusion of Fe with Zn ameliorates the effect on Fe but not on Cu status [14985219] BACKGROUND We previously showed that iron supplementation significantly improves iron status and maximal work capacity in previously untrained , marginally iron-deficient women with a baseline serum transferrin receptor concentration > 8.0 mg/L. However , the effect of transferrin receptor status on adaptation in endurance capacity after aerobic training in these subjects has not been fully explored . OBJECTIVE Our objective was to examine the effect of baseline serum transferrin receptor status on adaptations in endurance capacity . DESIGN Forty-one untrained , iron-depleted , nonanemic women were r and omly assigned to receive either 100 mg FeSO(4 ) or a placebo for 6 wk in a double-blind trial . All subjects trained on cycle ergometers 5 d/wk for the last 4 wk of the study . Endurance capacity was assessed at baseline and after treatment by using a 15-km time trial conducted on a cycle ergometer . RESULTS Significant treatment effects were observed for time to complete the 15-km time trial , work rate , and percentage of maximal oxygen uptake in subjects with a baseline serum transferrin receptor concentration > 8.0 mg/L. No significant treatment effects were observed in subjects with a normal baseline transferrin receptor concentration . CONCLUSIONS Our findings suggest that , in the presence of overt tissue iron deficiency , iron deficiency without anemia impairs adaptation in endurance capacity after aerobic training in previously untrained women . This impairment can be corrected with iron supplementation [17311950] Commercial elemental iron powders ( electrolytic and reduced iron ) , as well as heme iron supplements , were tested for efficacy in improving the iron status of women . In a r and omized , double-blind trial , 51 women with moderate to low iron stores received daily for 12 wk : 1 ) placebo , 2 ) 5 mg iron as heme iron or 50 mg iron as 3 ) electrolytic iron , 4 ) reduced iron , or 5 ) FeSO(4 ) . Treatments were provided in 2 capsules ( heme carrier ) and 3 wheat rolls ( other iron sources ) . Differences in iron status , food nonheme iron absorption , and fecal properties were evaluated . Body iron , assessed from the serum transferrin receptor : ferritin ratio , increased significantly more in subjects administered FeSO(4 ) ( 127 + /- 29 mg ; mean + /- SEM ) and electrolytic ( 115 + /- 37 mg ) , but not the reduced ( 74 + /- 32 mg ) or heme ( 65 + /- 26 mg ) iron forms , compared with those given placebo ( 2 + /- 19 mg ) . Based on body iron determinations , retention of the added iron was estimated as 3.0 , 2.7 , 1.8 , and 15.5 % , in the 4 iron-treated groups , respectively . Iron treatments did not affect food iron absorption . The 50 mg/d iron treatments increased fecal iron and free radical-generating capacity in vitro , but did not affect fecal water cytotoxicity . In subjects administered FeSO(4 ) , fecal water content was increased slightly but significantly more than in the placebo group . In conclusion , electrolytic iron was approximately 86 % as efficacious as FeSO(4 ) for improving body iron , but the power of this study was insufficient to detect any efficacy of the reduced or heme iron within 12 wk . With modification , this methodology of testing higher levels of food fortification for several weeks in healthy women with low iron stores has the potential for economically assessing the efficiency of iron compounds to improve iron status [8147338] Eighty iron-deficient , nonpregnant female workers were r and omly assigned to ferrous sulphate ( 60 or 120 mg Fe/d ) or placebo treatment for 12 wk . Energy expenditure was estimated during 3 d by heart rate ( HR ) recording . Production efficiency ( PE ) was calculated as the ratio of productivity to energy expenditure . In the iron-treated group mean hemoglobin ( Hb ) increased from 114 to 127 g/L ( P < 0.001 ) , mean serum ferritin increased from 9.7 to 30.0 micrograms/L ( P < 0.001 ) , and mean free erythrocyte protoporphyrin decreased from 1.01 to 0.49 mumol/L ( P < 0.001 ) . Mean HR at work decreased from 95.5 to 91.1 beats/min ( P < 0.001 ) , which was inversely correlated with the change in Hb ( r = -0.60 , P < 0.001 ) . PE increased significantly in the iron-treated group ( P < 0.001 ) and its change paralleled the change in Hb ( r = 0.58 , P < 0.001 ) . The results show that iron supplementation enabled these women to do the same work at a lower energy cost [17344500] BACKGROUND Evidence suggests that brain iron deficiency at any time in life may disrupt metabolic processes and subsequently change cognitive and behavioral functioning . Women of reproductive age are among those most vulnerable to iron deficiency and may be at high risk for cognitive alterations due to iron deficiency . OBJECTIVE We aim ed to examine the relation between iron status and cognitive abilities in young women . DESIGN A blinded , placebo-controlled , stratified intervention study was conducted in women aged 18 - 35 y of varied iron status who were r and omly assigned to receive iron supplements or a placebo . Cognition was assessed by using 8 cognitive performance tasks ( from Detterman 's Cognitive Abilities Test ) at baseline ( n = 149 ) and after 16 wk of treatment ( n = 113 ) . RESULTS At baseline , the iron-sufficient women ( n = 42 ) performed better on cognitive tasks ( P = 0.011 ) and completed them faster ( P = 0.038 ) than did the women with iron deficiency anemia ( n = 34 ) . Factors representing performance accuracy and the time needed to complete the tasks by the iron-deficient but nonanemic women ( n = 73 ) were intermediate between the 2 extremes of iron status . After treatment , a significant improvement in serum ferritin was associated with a 5 - 7-fold improvement in cognitive performance , whereas a significant improvement in hemoglobin was related to improved speed in completing the cognitive tasks . CONCLUSIONS Iron status is a significant factor in cognitive performance in women of reproductive age . Severity of anemia primarily affects processing speed , and severity of iron deficiency affects accuracy of cognitive function over a broad range of tasks . Thus , the effects of iron deficiency on cognition are not limited to the developing brain [12540406] BACKGROUND Tissue iron depletion may negatively affect endurance performance and muscle fatigability . OBJECTIVE We investigated tissue-level iron depletion and progressive fatigue of the quadriceps during dynamic knee-extension exercise in young women . DESIGN Twenty iron-depleted ( serum ferritin < 20 micro g/L ) , nonanemic ( hemoglobin > 110 g/L ) women ( macro x + /- SEM age : 29.1 + /- 1.2 y ) received iron ( iron group ) or placebo ( placebo group ) for 6 wk in a r and omized , double-blind trial ( n = 10 per group ) . A protocol integrating 2 - 3-s maximal voluntary static contractions ( MVCs ) with dynamic knee extensions was used to assess fatigue . RESULTS No significant differences between the groups in baseline iron status , MVC at rest , or MVC at the end of the protocol were observed . After treatment , serum iron and transferrin saturation increased significantly in the iron group ( P = 0.02 and P = 0.03 , respectively ) . Serum transferrin receptor concentrations increased significantly in the placebo group ( P < 0.01 ) but not in the iron group . After treatment , the rate of decrease in MVC was attenuated in the iron group but not in the placebo group ( P = 0.01 ) . In the iron group , MVC at the sixth minute of the fatigue protocol and MVC at the end of the protocol were approximately 15 % ( P = 0.04 ) and approximately 27 % higher ( P < 0.01 ) , respectively , after treatment . These improvements were not related to changes in iron-status indexes or tissue iron stores , although power was low ( < 0.50 ) to detect these relations . CONCLUSIONS Iron supplementation was associated with a significant improvement in muscle fatigability . Interpretation regarding the direct role of tissue iron status is limited by the study 's low power to detect relations between tissue iron improvement and decreased muscle fatigue [1442656] Forty-seven previously sedentary women participating in a 12-wk moderate aerobic-exercise program were r and omly assigned to one of four dietary groups : 50-mg/d iron supplement and a low food-iron diet ( 50 FE + EX ) , 10-mg/d iron supplement and a low food-iron diet ( 10 FE + EX ) , placebo and unrestricted diet ( P + EX ) , and meat supplement and high food-iron diet ( M + EX ) . A sedentary control group ( n = 13 ) received no dietary interventions . Hematocrit , total iron-binding capacity , and hemoglobin , serum iron , serum ferritin , and serum albumin concentrations were measured every 4 wk . Hemoglobin values decreased at the end of 4 wk in all exercising groups compared with the control group . Iron status in the 50 FE + EX and M + EX groups improved after week 4 as indicated by an increase in serum ferritin , serum iron , and hemoglobin concentrations , and a decline in total iron-binding capacity . Thus , short-term , moderate aerobic exercise result ed in compromised iron status that was offset to varying degrees by ingesting iron or meat supplements . However , meat supplements were more effective in protecting hemoglobin and ferritin status than were iron supplements [14704300] Elevated iron stores may or may not promote atherogenesis by increasing free radical formation and oxidative stress , but controlled diet and supplement trials are lacking . We tested the hypothesis that iron supplementation does not increase the susceptibility of LDL to undergo oxidative modification in women with low iron status . A r and omized , double-blind , 2-period crossover study design ( n=26 ) was used to examine the effects of the following diets on measures of LDL oxidation : average American diet ( AAD ) [ 36 % of energy as fat ; 15 % saturated fatty acids ( SFA ) ] , and a Step 2 diet ( 26 % fat ; 7 % SFA ) . In addition , subjects received either a supplement containing 160 mg of ferrous sulfate ( 50 mg elemental iron ) or a placebo twice daily [ supplement group received a total of 320 mg ferrous sulfate ( 100 mg elemental iron ) daily ] . After supplementation , serum ferritin differed between the supplement and placebo groups ( P=0.008 ) . Measures of LDL oxidation were not affected by supplement intake ; however , they were affected by diet . Lag time was shorter after the women consumed the AAD diet than after the Step 2 diet ( P<0.0001 ) . The diets did not affect the rate of oxidation or total dienes . Although iron status was improved by aggressive iron supplementation , LDL oxidative susceptibility was not affected . As expected , lag time was increased after the women consumed the low fat , low SFA diet . Therefore , the results of this study do not support a relationship between iron status and LDL oxidation [10539778] This 7-mo double-blind study compared the efficacy of two iron supplementation schemes in improving iron nutrition among 116 healthy fertile-age women . They were r and omly distributed in three groups , receiving : Group 1 , iron + folate ( 60 mg and 250 microg , respectively ) daily for 3 mo ( currently recommended scheme ) , and folate ( 250 microg ) weekly the subsequent 4 mo . Group 2 , folate daily , and 60 mg iron only once weekly for 3 mo , and then weekly iron + folate for 4 mo . Group 3 , folate daily for 3 mo and then weekly for 4 mo . At baseline , 16 % had depleted stores ( plasma ferritin < 15 microg/L ) and 16 % had hemoglobin levels < 125 g/L. Eight percent had hemoglobin levels < 120 g/L. In Group 1 hemoglobin and ferritin increased at 3 mo but returned to near basal conditions after 4 mo of weekly folate . In Group 2 , hemoglobin and ferritin increased progressively throughout the 7 mo but mostly after 3 mo . Group 3 did not change . Side effects were highest with daily iron . Weekly iron supplementation over 7 mo ( 30 doses ) improved and sustained iron nutrition at least as effectively and was better tolerated than 90 daily iron supplements consumed during 3 mo [10721929] To assess the efficacy and acceptability of a daily and intermittent iron supplementation , a double-blind , placebo-controlled trial was conducted in a public school located in periurban Lima , Peru . Adolescent girls ( n = 312 ) , 12 - 18 y old , were r and omly assigned to one of the following three groups : 1 ) 60 mg iron as ferrous sulfate daily from Monday to Friday ; 2 ) 60 mg iron as ferrous sulfate 2 d/wk and 3 d placebo ( intermittent ) ; 3 ) placebo , from Monday to Friday . Field workers gave the girls supplements during school hours for 17 wk ; 296 girls completed the trial . Girls took 94 % of the expected dose of 85 pills . Few side effects were reported . Postintervention , hemoglobin ( Hb ) , serum ferritin ( SF ) and free erythrocyte protoporphyrin ( FEP ) were improved significantly in the iron-supplemented groups compared with placebo ( P<0.05 ) . Daily supplements led to higher Hb increases than intermittent supplements ( P<0.05 ) , but SF and FEP were similar between the two groups . Thus , both iron supplementation schedules were efficacious in preventing iron deficiency in adolescent girls through the school system , and the daily schedule was better than the intermittent schedule at increasing Hb values and reducing anemia [3292842] Background Iron deficiency without anemia is related to adverse symptoms that can be relieved by supplementation . Since a blood donation can induce such an iron deficiency , we investigated the clinical impact of iron treatment after a blood donation . Methods One week after donation , we r and omly assigned 154 female donors with iron deficiency without anemia , aged below 50 years , to a four-week oral treatment of ferrous sulfate versus a placebo . The main outcome was the change in the level of fatigue before and after the intervention . Aerobic capacity , mood disorder , quality of life , compliance and adverse events were also evaluated . Hemoglobin and ferritin were used as biological markers . Results The effect of the treatment from baseline to four weeks of iron treatment was an increase in hemoglobin and ferritin levels to 5.2 g/L ( P < 0.01 ) and 14.8 ng/mL ( P < 0.01 ) , respectively . No significant clinical effect was observed for fatigue ( -0.15 points , 95 % confidence interval -0.9 points to 0.6 points , P = 0.697 ) or for other outcomes . Compliance and interruption for side effects was similar in both groups . Additionally , blood donation did not induce overt symptoms of fatigue in spite of the significant biological changes it produces . Conclusions These data are valuable as they enable us to conclude that donors with iron deficiency without anemia after a blood donation would not clinical ly benefit from iron supplementation . Trial Registration Clinical Trials.gov : [24660763] BACKGROUND Blood donation is known to contribute to iron deficiency in regular blood donors . This study investigated the safety and efficacy of postdonation iron replacement to mitigate iron deficiency in blood donors . STUDY DESIGN AND METHODS A total of 282 female whole blood donors aged 18 to 45 were prospect ively r and omized in a double-blinded placebo controlled trial to receive an 8-week postdonation course of carbonyl iron ( 45 mg daily ) or placebo . The primary endpoint was prevalence of iron deficiency ( ferritin < 15 ng/mL ) at 12 weeks postdonation . Secondary endpoints were eligibility to donate based on capillary hemoglobin ( Hb ) and incidence of gastrointestinal ( GI ) complaints . RESULTS Ferritin levels at Week 12 were significantly higher in donors receiving carbonyl iron ( 17.0 ± 10.9 ng/mL ) compared with those receiving placebo ( 10.6 ± 8.4 ng/mL ; p < 0.001 ) . The proportion of iron-deficient donors was significantly lower in the carbonyl iron group ( 51.9 % ) compared to the placebo ( 80.5 % ; p < 0.001 ) . The mean Hb level in the carbonyl iron group ( 134.6 ± 8.7 g/L ) was significantly higher than in the placebo arm ( 130.0 ± 9.9 g/L ; p < 0.001 ) , significantly improving eligibility to donate at Week 12 . Significantly more donors receiving carbonyl iron had at least one GI side effect ( p < 0.001 ) . Importantly , 86.7 % of donors receiving carbonyl iron indicated that they would take iron on an ongoing basis . CONCLUSION An 8-week postdonation course of 45 mg of carbonyl iron significantly reduced iron deficiency and was well tolerated in female whole blood donors . Postdonation iron replacement may have a role in a broader strategy to optimize donor iron status [7299507] This study was conducted to examine the relationship between anemia , supplementation with iron and vitamin C , and productivity . Using the cyanmethemoglobin method , 671 female garment factory workers were examined . On the basis of the World Health Organization ( WHO ) st and ard , 98 were found to be mildly or moderately/severely anemic . An equal number was r and omly chosen from the nonanemic workers . The subjects were then r and omly assigned to either the placebo group or the group receiving 525 mg of ferrous sulfate ( 105 mg elemental iron ) and 500 mg ascorbic acid . Only 118 of the 196 subjects completed the three-month study . The mean hemoglobin ( Hb ) and work output , as indicated by efficiency rating ( ER ) , of the placebo group did not change significantly . Mildly anemic workers with supplements showed a significant improvement in mean Hb , but not in mean ER . The moderately/severely anemic group receiving supplements had significant increases in both Hb and ER [1919803] In 781 female college students , there were 41 cases of iron deficiency anemia , 209 of latent iron deficiency , 3 of other anemias , and 528 normal cases . Fifty-four volunteers recruited from the iron deficiency anemia and severe latent iron deficiency groups were r and omly divided into 4 study groups . Groups I and III received 500 mg of vitamin C daily , and groups II and IV received ferric ammonium citrate ( FeAC ; equivalent to 6 mg iron ) in addition to vitamin C for 9 weeks . Groups I and II were loaded by aerobic exercise at 50 % VO2 max . Significant differences between groups were noted in serum ferritin ( SF ) in III/IV , hematocrit ( Ht ) in II/III and III/IV , and reticulocytes ( RET ) in I/II , I/IV , and III/IV . Hemoglobin ( Hb ) and other iron-related blood indices tended to normalize in groups II and IV when compared with the pre-values . VO2 max was elevated in groups I and II regardless of iron treatment , but was augmented more in group II than group [16968234] BACKGROUND No treatment is known to permanently increase salivary flow in patients with hyposalivation . The objective of this study was to investigate the effect of iron supplementation on salivary flow rate . METHODS A double-blind , r and omized , placebo-controlled trial was carried out on 50 individuals with a low unstimulated whole salivary flow rate and low serum ferritin . Half the individuals received 60 mg iron orally twice a day for 3 months , while the other half received placebo . RESULTS No statistically significant difference was found between the groups after treatment for the unstimulated flow rate and in the subjective assessment s of oral dryness . The serum ferritin values increased significantly in the iron group but not in the placebo group . CONCLUSION Oral supplementation with iron for 3 months has no effect on salivary flow rate among individuals with hyposalivation and low serum ferritin values [10221325] The authors estimated components of variance and intraclass correlation coefficients ( ICCs ) to aid in the design of complex surveys and community intervention studies by analyzing data from the Health Survey for Engl and 1994 . This cross-sectional survey of English adults included data on a range of lifestyle risk factors and health outcomes . For the survey , households were sample d in 720 postal code sectors nested within 177 district health authorities and 14 regional health authorities . Study subjects were adults aged 16 years or more . ICCs and components of variance were estimated from a nested r and om-effects analysis of variance . Results are presented at the district health authority , postal code sector , and household levels . Between-cluster variation was evident at each level of clustering . In these data , ICCs were inversely related to cluster size , but design effects could be substantial when the cluster size was large . Most ICCs were below 0.01 at the district health authority level , and they were mostly below 0.05 at the postal code sector level . At the household level , many ICCs were in the range of 0.0 - 0.3 . These data may provide useful information for the design of epidemiologic studies in which the units sample d or allocated range in size from households to large administrative areas [24195864] PURPOSE Studies in both animals and humans show a relationship between iron depletion without anemia ( IDNA ) and physical performance . Compared with their sedentary counterparts , female endurance athletes are at greater risk of IDNA , and consequences relevant to endurance athletes include reduced work capacity and energetic efficiency ( EF ) . We conducted a r and omized placebo-controlled trial to investigate the effects of iron ( Fe ) supplementation on Fe status and performance in nonanemic female rowers during training . METHODS At the beginning of a training season , 40 rowers were r and omized to receive either 100 mg·d FeSO4 ( n = 21 ) or placebo ( n = 19 ) using a double-blind design . Thirty-one ( n = 15 Fe , 16 placebo ) completed the 6-wk trial . Fe status ( hemoglobin , serum ferritin , soluble transferrin receptor ) , body composition , and laboratory tests of physical performance ( 4-km time trial , V˙O2peak , energetic EF , and blood lactate ) were assessed at baseline and after training . RESULTS Rowers in both groups increased their fat-free mass ( P < 0.001 ) and V˙O2peak ( P < 0.001 ) after training . Multiple regression analyses revealed improvements in Fe stores ( serum ferritin ) in the Fe treatment group after controlling for baseline Fe stores ( P = 0.07 ) . Rowers in the Fe group had slower lactate response during the first half of the time trial and after 5 min of recovery ( P = 0.05 ) and showed greater improvements in energy expenditure ( P = 0.01 for group-by time ) and energetic EF compared with placebo ( P = 0.03 for group-by time ) . CONCLUSIONS Female rowers with depleted Fe stores who consumed supplemental Fe during training improved their Fe status and energetic EF during endurance exercise . These results are important for endurance athletes whose dietary patterns and physical training increase their risk of IDNA and suggest that Fe supplementation may maximize the benefits of endurance training [1496946] OBJECTIVE To document a subjective response to iron therapy in female adolescents . DESIGN Double-blind , placebo-controlled prospect i ve study . SETTING High school classes in an urban community in Israel . PARTICIPANTS Twenty-nine girls , aged 16 and 17 years , who ingested syrup containing iron ( daily for 2 months ) and 30 girls who received a placebo . MAIN RESULTS By the end of the study , a statistically significant improvement in three subjective parameters , ie , lassitude , the ability to concentrate in school , and mood was reported by the girls who ingested iron compared with the controls . Sixty-five percent , 100 % , and 65 % of the girls , respectively , who reported improvement in the above-mentioned parameters were hypoferremic initially and became normoferremic by the end of the study . CONCLUSION Iron supplementation may be of benefit to female adolescents , as evidence d by their responses to subjective parameters [4073160] Rates of iron deficiency are high amongst healthy young women . Cognitive impairment occurs secondary to iron deficiency in infants and children , but evaluation of the impact on cognition among young women is inconsistent . The aim was to determine the suitability of the IntegNeuro test battery for assessing cognitive function in iron-deficient and iron-sufficient young women . A pilot double-blinded , placebo-controlled intervention trial was conducted in iron-deficient ( serum ferritin ≤ 20 μg/L and haemoglobin > 120 g/L ) and iron-sufficient young women ( 18–35 years ) . Cognitive function and haematological markers of iron status were measured at baseline and follow-up . Iron-deficient participants ( n = 24 ) were r and omised to receive placebo , 60 mg or 80 mg elemental iron daily supplements for 16 weeks . A control group of iron-sufficient participants ( n = 8) was allocated to placebo . Change scores for Impulsivity and Attention were significantly greater in plasma ferritin improvers than in non-improvers ( p = 0.004 , p = 0.026 ) . IntegNeuro was easy to administer and acceptable to young women . Based on the differences in Memory and Attention scores between iron-deficient participants on iron treatment and those on placebo , it was decided that between 26 and 84 participants would be required in each iron treatment group for an adequately powered extension of this pilot RCT [4082414] Background Oral iron supplementation is often associated with rapid onset of gastrointestinal side-effects . The aim of this study was to develop and trial a short , simple question naire to capture these early side-effects and to determine which symptoms are more discriminating . Methods The study was a double-blind placebo-controlled r and omized parallel trial with one week treatment followed by one week wash-out . Subjects were r and omized into two treatment groups ( n = 10/group ) to receive either ferrous sulphate ( 200 mg capsules containing 65 mg of iron ) or placebo , both to be taken at mealtimes twice daily during the treatment period . Subjects completed the question naires daily for 14 days . The question naire included gastrointestinal symptoms commonly reported to be associated with the oral intake of ferrous iron salts ( i.e. nausea , vomiting , heartburn , abdominal pain , diarrhoea , and constipation ) . Results Seventy five per cent of participants reporting the presence of one or more symptoms in the first week of the study were in the ferrous sulphate group . In the second week of the study ( i.e. wash-out ) , 67 % of the participants reporting one or more symptom(s ) were in the ferrous sulphate group . In the first week of the study ( treatment ) the number of symptoms reported by participants in the ferrous sulphate group ( mean ± SEM = 6.7 ± 1.7 ) was significantly higher than that for participants in the placebo group ( 1.2 ± 0.5 ) ( p = 0.01 ) . In the second week of the study ( wash-out ) the number of symptoms reported by participants in the ferrous sulphate group ( 4.6 ± 2.0 ) appeared higher than for participants in the placebo group ( 1.0 ± 0.7 ) although this did not reach significance ( p = 0.12 ) . Events for which the gastrointestinal symptom question naire was most discriminatory between ferrous sulphate and placebo groups were : heartburn , abdominal pain and the presence of black stools ( all p ≤ 0.03 ) . Conclusions A tool for the detection of commonly-occurring side effects should not require large study numbers to be effective . With just 10 subjects per group ( iron or placebo ) , this simple question naire measures gastrointestinal side-effects associated with oral iron ( ferrous sulphate ) supplementation , and would be appropriate for use in intervention studies or clinical trials . Trial registration Clinical Trials.gov Identifier : NCT02146053 ( 21/05/2014 ) [4011041] Adherence to iron supplementation can be compromised due to side effects , and these limit blinding in studies of iron deficiency . No studies have reported an efficacious iron dose that allows participants to remain blinded . This pilot study aim ed to determine a ferrous sulfate dose that improves iron stores , while minimising side effects and enabling blinding . A double-blinded RCT was conducted in 32 women ( 18–35 years ) : 24 with latent iron deficiency ( serum ferritin < 20 µg/L ) and 8 iron sufficient controls . Participants with latent iron deficiency were r and omised to 60 mg or 80 mg elemental iron or to placebo , for 16 weeks . The iron sufficient control group took placebo . Treatment groups ( 60 mg n = 7 and 80 mg n = 6 ) had significantly higher ferritin change scores than placebo groups ( iron deficient n = 5 and iron sufficient n = 6 ) , F(1 , 23 ) = 8.46 , p ≤ 0.01 . Of the 24 who completed the trial , 10 participants ( 77 % ) on iron reported side effects , compared with 5 ( 45 % ) on placebo , but there were no differences in side effects ( p = 0.29 ) , or compliance ( p = 0.60 ) between iron groups . Nine ( 69 % ) participants on iron , and 11 ( 56 % ) on placebo correctly guessed their treatment allocation . Both iron doses were equally effective in normalising ferritin levels . Although reported side-effects were similar for both groups , a majority of participants correctly guessed their treatment group [534861] The effects of iron-deficiency anaemia on workers productivity were studied in a tea plantation in Sri Lanka . The quantity of tea picked per day was studied before and after iron supplementation or placebo treatment . After one month 's treatment significantly more tea was picked when the haemoglobin ( Hb ) concentration was increased by iron supplementation than when it was not . The degree of improvement was greater in more-anaemic subjects ( those with concentrations of 6.0 - 9.0 g Hb/dl ) . The level of physical activity of anaemic subjects in their everyday environment was also recorded for four or 24 hours continuously both before and after treatment . After three weeks these levels was significantly greater in the iron-treated than matched placebo-treated subjects . The economic implication s of increased work productively with iron treatment are evident , particularly in developing countries . These results also provide strong evidence for the clinical impression that people with iron-deficiency anaemia suffer from tiredness and weakness [12763985] Abstract Objective To determine the subjective response to iron therapy in non-anaemic women with unexplained fatigue . Design Double blind r and omised placebo controlled trial . Setting Academic primary care centre and eight general practice s in western Switzerl and . Participants 144 women aged 18 to 55 , assigned to either oral ferrous sulphate ( 80 mg/day of elemental iron daily ; n=75 ) or placebo ( n=69 ) for four weeks . Main outcome measures Level of fatigue , measured by a 10 point visual analogue scale . Results 136 ( 94 % ) women completed the study . Most had a low serum ferritin concentration ; ≤ 20 μg/l in 69 ( 51 % ) women . Mean age , haemoglobin concentration , serum ferritin concentration , level of fatigue , depression , and anxiety were similar in both groups at baseline . Both groups were also similar for compliance and dropout rates . The level of fatigue after one month decreased by −1.82/6.37 points ( 29 % ) in the iron group compared with −0.85/6.46 points ( 13 % ) in the placebo group ( difference 0.95 points , 95 % confidence interval 0.32 to 1.62 ; P=0.004 ) . Subgroups analysis showed that only women with ferritin concentrations ≤ 50 μg/l improved with oral supplementation . Conclusion Non-anaemic women with unexplained fatigue may benefit from iron supplementation . The effect may be restricted to women with low or borderline serum ferritin concentrations [5448798] A variety of aspects of psychomotor function were assessed in 47 women before and after iron therapy . These women , all of whom had initial haemoglobin levels below 10·5 g./100 ml . , had been drawn from a population sample of 2,283 women seen at a haematological screening survey . There was no evidence of any beneficial effect of a rise in haemoglobin level on psychomotor function or on symptoms . Possibly this is because if an effect does occur it is unlikely to be apparent unless the haemoglobin level is very low . If this is true then anaemia is probably a rare cause of symptoms or impairment in psychomotor function in the community [12736400] OBJECTIVE To examine the benefits of anemia prophylaxis in adolescent school.girls by weekly or daily iron-folate supplementation . DESIGN Prospect i ve study . SETTING Government girl schools of northeast Delhi . SUBJECTS 2088 subjects ( with hemoglobin greater than 7.9 g/dL ) , including 702 on daily and 695 on weekly iron-folate administration ; 691 girls served as controls . RESULTS About 85 % girls were iron deficient out of which 49.3 % were anemic . Weekly administration took longer time to raise hemoglobin but was effective as well as practical . Plasma ferritin estimation in girls showed rise in level in both the treated groups . CONCLUSION Weekly administration of iron-folate was a practical and effective strategy for anemia prophylaxis in adolescent school girls [1501568] The purpose of this investigation was to examine the effects of oral iron supplementation on endurance performance in initially iron-depleted , nonanemic female distance runners . Eighteen iron-depleted ( serum ferritin less than 20 ng.ml-1 , hemoglobin greater than or equal to 12 g.dl-1 ) women ( 22 - 39 yr ) performed a VO2max test and an endurance run to exhaustion . Subjects were pair-matched on the basis of endurance time and then r and omly assigned to an iron supplement or a placebo group . Following supplementation , the iron group had a significantly higher ( P = 0.03 ) mean serum ferritin concentration ( 23.4 vs 15.7 ng.ml-1 ) and lower ( P = 0.04 ) mean total iron-binding capacity than the placebo group . Both groups increased their time to exhaustion ( 25.5 % and 22.2 % for the iron and placebo groups , respectively ) but were not significantly different ( P = 0.72 ) from each other . There were also no differences ( P greater than 0.05 ) between the groups with respect to lactate concentrations and physiological measures taken during the two exercise tests . The results of this study suggest that 8 wk of oral iron supplementation improves iron status in iron-depleted female distance runners , but does not enhance endurance capacity [23204154] Objectives : Limited information is available on the role of pork meat in influencing iron status . The aim of this study was to determine the effect of consuming pork meat as compared to iron supplementation on nutritional status and feeling of well-being . Methods : Young women were r and omly assigned to a control diet ( CG ) , a pork-containing diet ( PG ) , or a control diet with iron supplementation ( SG ) for 12 weeks . Sixty-five women aged 24.6 ± 4.4 years ( mean ± SD ) completed the trial . Results : Serum ferritin concentrations were increased significantly ( p = 0.001 ) in participants assigned to the SG as compared with the other groups , as assessed by repeated- measures analysis of variance . At week 12 , hemoglobin concentrations were significantly higher in PG and SG as compared with CG . Plasma zinc concentrations at the end of the intervention were similar to baseline concentrations for individuals in the CG and PG but were decreased significantly ( p < 0.05 ) in SG . Plasma- , erythrocyte-folate , and serum vitamin B6 and B12 concentrations were not significantly affected by the intervention , although the concentrations of vitamins B6 and B12 tended to increase in PG . Well-being , as measured using the Health Survey Short Form ( SF-36 ) and its 8 multi-item scales , showed significant improvement in vitality in SG ( p < 0.05 ) and bodily pain in PG ( p < 0.05 ) . No significant relationships were observed between these health concept scores and biomarkers of nutritional status . Conclusions : Consumption of pork meat by young women maintains hemoglobin levels to the same extent as low-dose iron supplementation and enhances the components of well-being , mainly their perception of bodily pain [9279061] This paper discusses the effect that high altitudes have on iron metabolism and summarizes the results of an iron-folate supplementation trial . The two main objectives of the trial were to determine hemoglobin cut-off values for the diagnosis of anemia in Bolivian women of childbearing age living at high altitudes , and to estimate the prevalence of anemia in this population . The study showed that nutritional anemia is an important public health problem in such population s and that many methods of assessing it lead to an underestimation of prevalence . The cut-off values defined through this study , one of the few iron supplementation trials conducted at high altitudes , confirm the need to establish revised hemoglobin values for the diagnosis of anemia in population s living at high altitudes [6506175] Depletion of body iron stores is a major factor limiting regular blood donations by menstruating females . To determine if regular iron supplementation would solve this problem , we conducted a double-blind study in which menstruating female donors were r and omly placed into one of three groups : one taking 39 mg elemental iron , a second taking 39 mg of iron plus 75 mg vitamin C , and a third taking 100 mg vitamin C daily . The women were requested to donate every 8 weeks for at least 1 year . Blood sample s were taken on each donation for measurements of hemoglobin , total iron binding capacity ( TIBC ) , and ferritin . In the two groups taking iron supplements hemoglobin and ferritin increased from baseline values and the TIBC decreased . The vitamin C control group showed decreases from baseline for hemoglobin and ferritin and increases in TIBC . Differences between groups taking iron supplements and the group not taking supplements were highly significant . Drop-out from the study was due to various causes ; however , iron intolerance was uncommon . Minimal daily iron supplementation was beneficial in maintaining body iron stores and hemoglobin levels in menstruating females on a schedule of blood donation as often as every 8 weeks [6864076] We studied the effect of 2 weeks of iron therapy on exercise performance and exercise-induced lactate production in trained women athletes : six control subjects with normal parameters of iron status and nine with mild iron-deficiency anemia defined by low Fe/TIBC , ferritin , and minimally decreased Hgb values . Iron therapy improved the abnormal measures of iron status and low Hgb in the second group to normal . Exercise performance in a progressive work-exercise protocol on a bicycle ergometer to exhaustion was unchanged after iron therapy in both groups ; however , blood lactate levels at maximum exercise in the iron-deficient group decreased significantly from 10.3 + /- 0.6 mmol/L before therapy to 8.42 + /- 0.7 after therapy ( p less than 0.03 ) . The control subjects did not significantly alter lactate levels after maximal exercise on iron compared to placebo : 8.3 + /- 0.8 mmol/L vs. 8.5 + /- 0.7 . Although there was not a significant difference in maximum exercise performance after iron therapy , these data support animal experiments implying that iron may play a role in oxidative metabolism and that minimal decreases in Hgb may impair arterial oxygen content enough to affect aerobic metabolism . In addition , these findings may have important implication s for competitive women athletes in whom mild iron deficiency may go unnoticed [16835600] Objective : To determine the effect of iron supplementation on iron status and endurance capacity . Design : R and omized , double-blind iron supplementation . Setting : University of Missouri-Columbia and surrounding community . Subjects : Twenty iron-deficient ( serum ferritin , sFer<16 μg/l ; serum transferrin receptor , sTfR>8.0 mg/l ; or sTfR/log sFer index > 4.5 ) , nonanemic ( hemoglobin , Hb>120 g/l , women ; > 130 g/l , men ) men and women ( 18–41 years ) were recruited via fliers and newspaper advertisements ; 20 of 31 eligible subjects participated . Interventions : A 30 mg measure of elemental iron as ferrous sulfate or placebo daily for 6 weeks . Results : Dietary iron intake and physical activity did not differ between groups before or after supplementation . Iron supplementation significantly increased sFer compared to placebo ( P=0.01 ) , but did not affect Hb or hematocrit . Iron supplementation prevented the decline in ventilatory threshold ( VT ) observed in the placebo group from pre- to post-supplementation ( P=0.01 ) ; this effect was greater in individuals with lower sFer before intervention ( P<0.05 ) . Changes in sFer from pre- to post-treatment were positively correlated with changes in VT ( P=0.03 ) , independent of supplementation . The iron group significantly increased gross energetic efficiency during the submaximal test ( P=0.04 ) . Changes in sFer were negatively correlated with changes in average respiratory exchange ratio during the submaximal test ( P<0.05 ) . Conclusions : Iron supplementation significantly improves iron status and endurance capacity in iron-deficient , nonanemic trained male and female subjects . Sponsorship : Missouri University Alumni Association , by the Elizabeth Hegarty Foundation and by the Department of Nutritional Sciences [1874236] Summary Serum iron deficiency has a high incidence in female athletes . We investigated the effects of a daily oral iron supplement , ( 160 mg ) administered during an intensive 7-week physical training programme , on body iron status , and the maximal aerobic capacity ( VO2max ) of 13 women ( group A ) compared to 15 who took a placebo ( group B ) . The subjects were 19 years old . Blood sample s were obtained before training began and on days 1 , 7 , 21 and 42 of training . They were analysed for packed cell volume ( PVC ) and for haemoglobin ( Hb ) , 2,3-diphosphoglycerate ( 2,3-DPG ) , haptoglobin , iron and ferritin concentrations . TheVO2max was measured on days 0 , 21 and 42 of training . Following 21 days of training Hb , PCV and ferritin were significantly higher ( P⩽0.01 ) in group A compared to group B. Over the training period Hb rose by 9.3 % and 2.4 % in groups A and B , respectively . At the end of training 66 % of group B exhibited ferritin concentrations below 10 ng·ml−1 , while none of group A had such low values . MeanVO2max of group A had increased by 7.5 % following 21 days of training ( P⩽0.01 ) and by 15.3 % after 42 days . No appreciable increase inVO2max had occurred in group B by day 21 ( significantly lower thanVO2max of group A;P⩽0.05 ) , however by day 42 it had increased by 14.3 % ( P⩽0.05 ) . In both groups 2,3-DPG·g Hb−1 had increased significantly ( P⩽0.005 ) by day 7 ( 22 % ) and remained at that level for an additional 35 days . We concluded that a daily oral iron supplement given to young women during intensive training improved several haematological variables and their body iron status . This improvement was associated with an increasedVO2max only during the early stages of their training ( day 21 ) compared with the placebo group [11814373] OBJECTIVE To compare the effectiveness of weekly vs daily iron and folic acid supplementation for control of anemia in adolescent Nepalese girls . DESIGN R and omized controlled trial . SETTING A Government Girl School in Dharan , Nepal , an urban foothill town that is 305 m above sea level . SUBJECTS Consecutive healthy adolescent girls ( n = 209 , median age 15 years ) r and omized to 3 groups matched for age , anthropometry , and personal and sociodemographic characteristics . Of 209 subjects , 181 completed the trial . Two girls had adverse reactions to treatment and were excluded . INTERVENTION Group A ( n = 70 ) received a 350-mg ferrous sulfate and 1.5-mg folic acid combination once daily for 90 to 100 days . Group B ( n = 67 ) received the tablet under supervision once a week for 14 weeks . Group C ( n = 72 ) did not receive any drugs . OUTCOME VARIABLE Presupplementation and postsupplementation differences in prevalence of anemia and change in hematocrit . RESULTS Prevalence of anemia ( defined as hematocrit < 36 % ) declined from 68.6 % and 70.1 % in groups A and B to 20 % and 13.4 % , respectively , postsupplementation ( P<.001 ) , whereas the prevalence in group C changed little ( 68.1 % to 65.3 % , P = .81 ) . There was a significant rise in the mean hematocrit of both supplemented groups ( group A , 32.9 % + /- 3.5 % to 41.0 % + /- 5.6 % , P<.001 ; group B , 33.2 % + /- 3.6 % to 40.4 % + /- 4.9 % , P<.001 ) but no appreciable change in controls ( 34.2 % + /- 2.9 % to 34.1 % + /- 3.3 % , P = .91 ) . Net change in mean hematocrit in both the supplementation groups was comparable ( P = .57 ) . CONCLUSIONS The prevalence of anemia in adolescent Nepalese girls is high . Supervised iron and folic acid therapy once a week is an effective alternative to daily administration and helps lower the prevalence of anemia in adolescent girls [9459375] Serum transferrin receptor ( sTfR ) concentration has been recognized recently as a reliable indicator of functional iron deficiency , but its response to iron supplementation has not been investigated in marginally iron-deficient women . In this r and omized , double-blinded trial , 37 female subjects aged 19 - 35 y with iron depletion without anemia ( hemoglobin > 120 g/L and serum ferritin < 16 microg/L ) received an iron supplement or placebo for 8 wk . Iron status was measured before treatment , after 4 wk of treatment , and posttreatment ( ie , after 8 wk of treatment ) . Iron supplementation of these iron-depleted , nonanemic women result ed in a progressive and significant decrease in sTfR and a significant increase in serum ferritin , and prevented a fall in hemoglobin . The responsiveness of sTfR to iron treatment indicated that sTfR is a sensitive indicator of marginal iron deficiency in iron-depleted , nonanemic women , even when their body iron stores were being replenished [8107547] To determine the effects of an 8-wk dietary iron supplementation ( 100 mg.d-1 ) on low plasma ferritin concentration ( < 20 ng.ml-1 ) and endurance , 20 active women ( 19 - 35 yr ) were studied while performing a VO2max test and an endurance test ( 80 % VO2max ) on a cycle ergometer . Subjects were r and omly placed in an iron supplement ( IG ) or a placebo group ( PG ) using a double-blind method . After treatment in the IG , ferritin levels were higher ( 22.5 + /- 3.4 vs 14.3 + /- 2.2 ng.ml-1 ; P < 0.05 ) , Hb increased ( 12.8 + /- 0.4 to 14.1 + /- 0.2 g.dl-1 ; P < 0.05 ) , and TIBC decreased ( 366.2 + /- 24.8 to 293.8 + /- 14.0 micrograms.dl-1 ; P < 0.05 ) . Also after treatment the IG 's VO2max was significantly greater ( P < 0.05 ) than the PG value and their postendurance blood lactate decreased ( 5.03 + /- 0.44 to 3.85 + /- 0.6 mM.l-1 ; P < 0.05 ) . Endurance time to exhaustion increased 38 % ( 37.28 + /- 5.03 to 51.4 + /- 7.45 min ) following iron treatment ; however , this change was not statistically significant . The results suggest that this level of iron supplementation can reverse mild anemia , increase VO2max , and reduce blood lactate concentration after submaximal exercise [22443058] OBJECTIVE To investigate the effect of iron supplementation on iron deficiency anemia of childbearing age women , and to find out the optimal amount of iron intake for maintaining their health . METHODS 74 childbearing age women aged 21 to 45 years with anemia were r and omly assigned to intervention or control group by hemoglobin content , and a iron nutrition packet ( mainly composed of ferric pyrophosphate and ferrous fumarate , containing iron 8 mg ) or a placebo packet was given daily for six months , respectively . Hemoglobin , serum ferritin , food frequency and 24h dietary recall survey were performed before intervention and three and six months after intervention . RESULTS Hemoglobin and serum ferritin of the intervention group were significantly higher ( P < 0.01 ) than that in control group after six months . The number of women with hemoglobin > or = 120 g/L in intervention and control group was 15 ( 44.1 % ) and 5 ( 14.3 % ) , respectively ( P < 0.01 ) . The number of women with serum ferritin > or = 15 micro g/L in intervention and control group was 11 ( 34.4 % ) and 4 ( 12.5 % ) , respectively ( P < 0.05 ) . The average dietary iron intake was 14.0 mg/d , mainly from plant foods . There was a positive correlation of total iron intake ( dietary iron plus iron supplements ) with hemoglobin ( r = 0.57 , P < 0.01 ) . More menstrual blood and dietary fiber were the risk factors for iron deficiency anemia ( P < 0.05 ) . CONCLUSION The anemic status in childbearing age women could be improved by providing iron 8 mg daily for six months consecutively . Daily dietary intake of iron 23.2 mg can meet the requirement of maintaining normal iron storage for childbearing age women [1752712] The purpose of this study was to determine the effects of two weeks of high dosage iron supplementation on various blood iron indices and metabolic parameters in non-anemic , iron-depleted competitive female cross-country runners . The subjects were highly trained members of the Colorado State University cross-country team and were completing 40 to 50 miles of training weekly . A pretest , post-test single-blind crossover design was employed . Upon collection of baseline exercise blood and metabolic data , five subjects were r and omly assigned to iron supplementation ( 650 mg ferrous sulfate ; 130 mg elemental iron ) and five subjects to placebo treatment . At two weeks the treatments were reversed . Exercise blood and metabolic data were collected at two-week intervals . Dietary iron intake was assessed using a three-day dietary survey . Dietary analysis revealed deficiencies in vitamin B-6 , iron , magnesium , and zinc according to USRDA st and ards . Baseline blood sample s revealed no deficiencies in iron storage or transport proteins . Two weeks of iron supplementation result ed in no significant increases in blood iron indices . Metabolic parameters related to running performance were also unchanged after iron supplementation . High dosage , short-term iron supplementation appears to have no effect on blood or metabolic parameters in iron-depleted but non-anemic female cross-country runners [1555906] Low serum ferritin concentrations are commonly found in female athletes . By study ing the effects of an 8-week iron or placebo supplementation in 31 female athletes ( aged 17 - 31 years ) , with an initial serum ferritin concentration less than or equal to 25 micrograms/l and blood hemoglobin 120 g/l , we investigated whether low serum ferritin values hinder aerobic performance . Serum ferritin concentration increased from 14 ( 25th and 75th percentile : 11 , 21 ) to 26 ( 18 , 36 ) micrograms/l in the iron-supplemented group , but remained at a low 11 ( 9 , 17 ) micrograms/l in the placebo group ( group difference after supplementation : p = 0.001 ) . Before supplementation , blood hemoglobin concentration was not different in the two groups . After supplementation , however , the concentration in the iron group was 139 ( 135 , 144 ) g/l and 128 ( 126 , 134 ) g/l in the placebo group ( group difference : p = 0.001 ) . Iron supplementation did not affect blood lactate concentration or VO2max during an incremental ergometer test . Hence , aerobic performance was not impaired in nonanemic female athletes with serum ferritin 25 micrograms/l [11601562] Objective : To investigate the efficacy of , first , a dietary regimen involving increased consumption of iron-rich foods and enhancers of iron absorption and decreased consumption of inhibitors of iron absorption and , second , a low dose iron chelate iron supplement , for increasing iron stores in young adult New Zeal and women with mild iron deficiency ( MID ) . Methods : The study was a 16 week r and omized placebo-controlled intervention . Seventy-five women aged 18 to 40 years with MID ( serum ferritin < 20 μg/L and hemoglobin ≥120 g/L ) were assigned to one of three groups : Placebo , Supplement ( 50 mg iron/day as amino acid chelate ) or Diet . Participants in the Diet Group were given individual dietary counseling to increase the intake and bioavailability of dietary iron . Dietary changes were monitored by a previously vali date d computer-administered iron food frequency question naire . Results : Diet Group members significantly increased their intake of flesh foods , heme iron , vitamin C and foods cooked using cast-iron cookware and significantly decreased their phytate and calcium intakes . Serum ferritin increased in the Supplement and Diet Groups by 59 % ( p=0.001 ) and 26 % ( p=0.068 ) , respectively , in comparison to the Placebo Group . The serum transferrin receptor : serum ferritin ratio decreased by 51 % in the Supplement Group ( p=0.0001 ) , and there was a non-significant decrease of 22 % ( p=0.1232 ) in the Diet Group . Conclusions : This study is the first , to our knowledge , to demonstrate that an intensive dietary program has the potential to improve the iron status of women with iron deficiency [20416130] Interventions to combat mild Fe deficiency in women of childbearing age may affect Zn nutriture . We used dietary and laboratory indices to assess change in Zn status during a 4-month partially blinded placebo-controlled Fe intervention in women with low Fe stores ( serum ferritin < 20 microg/l and Hb > or = 120 g/l ) from Dunedin , New Zeal and . Subjects aged 18 - 40 years were r and omly assigned to three groups : dietary advice ( diet group ; DG ; n 29 ) , daily Fe supplement with meals ( supplement group ; SG ; n 23 ; 50 mg Fe as amino acid chelate ) and placebo ( placebo group ; PG , n 26 ) . A vali date d semi-quantitative FFQ ( SFFQ ) was administered at baseline , and at 4 , 8 and 15 weeks ; fasting morning blood sample s were assayed for serum Zn , alkaline phosphatase ( ALP ) and C-reactive protein at baseline , and at 4 , 8 , 12 and 16 weeks ; hair Zn and taste detection thresholds by electrogustometry were measured at baseline and at 16 weeks . Intakes of flesh foods and vitamin C but not Zn or Fe increased , whereas phytate and phytate : Zn molar ratios decreased ( all P < or = 0.01 ) in the DG compared with the PG and SG , based on three SFFQ . Serum Zn increased in both the DG and PG ( adjusted , P < or = 0.002 ) , so the between-group difference was not significant ; the lack of a parallel rise in the SG was significant when compared with the PG ( P = 0.02 ) . ALP activity ( but not hair Zn or taste acuity ) followed a similar trend . In conclusion , Zn status was not improved compared with placebo by an Fe-based dietary intervention . However , a daily moderate-dose Fe supplement with meals appeared to lower Zn status in these young adult women [3341317] Iron-deficiency anemia impairs exercise capacity , but whether nonanemic iron depletion decreases endurance performance is unclear . In 14 iron-deficient ( serum ferritin level , less than 20 micrograms/L [ less than 20 ng/L])nonanemic runners , hematologic and treadmill running values were followed up during a competitive season . Following a four-week control period , runners were treated for one month in a double-blind protocol with ferrous sulfate ( 975 mg/d ) or placebo . During treatment , the mean ferritin level rose from 8.7 to 26.6 micrograms/L ( 8.7 to 26.6 ng/mL ) in those patients taking iron and fell from 10.6 to 8.6 micrograms/L ( 10.7 to 8.6 ng/mL ) in the placebo group . Treadmill endurance times improved significantly in the iron-treated runners compared with controls . Endurance time declined in all seven controls ( range , 0.07 to 1.30 minutes ) , while six of seven iron-treated subjects improved their performance ( range , 0.03 to 1.92 minutes ) . No significant differences in maximal or submaximal oxygen consumption , ventilation , or heart rate were observed between the groups except for a 4 % increase in maximum oxygen consumption during placebo treatment . These data indicate that nonanemic iron deficiency impairs exercise performance but does not influence gas exchange or cardiac measures [18363581] BACKGROUND Iron deficiency is a public problem in women , which contributes to the high percentage of deferred blood donations in this group . This study evaluated the effect of iron supplementation in improving iron stores to promote safe blood donation in women . STUDY DESIGN AND METHODS A total of 412 female blood donors were r and omly recruited for the study . The volunteers were scheduled for an initial visit and three subsequent visits at 4-month intervals for possible repeat donation . Each volunteer was given 21 tablets of 150 mg of ferrous sulfate or placebo to be taken three times daily for 1 week after each blood donation . Their hemoglobin ( Hb ) concentration , hematocrit ( Hct ) , serum ferritin , total iron-binding capacity ( TIBC ) , and percent saturation of the TIBC were tested throughout the course of the study . RESULTS The group taking ferrous sulfate showed no significant difference between the mean initial and final result for any of the values other than Hb values , whereas there was a significant decline in mean Hb , Hct , serum iron , serum ferritin , and percent saturation in the group taking placebo . Hb concentrations declined significantly in both groups ; however , it was more severe in the placebo group when compared to the ferrous sulfate group . The relative risk of iron deficiency in placebo group was 3.6 ( 95 % confidence interval = 1.73 - 7.74 ) . CONCLUSION The results indicate that supplementation therapy can be considered as one of the strategies to promote safe blood donation in women . A quantity of 150 mg of elemental iron per day as ferrous sulfate , however , is not the correct dose for Iranian female donors [4408096] Objective Women ’s nutritional status during conception and early pregnancy can influence maternal and infant outcomes . This study examined the efficacy of pre-pregnancy supplementation with iron and multivitamins to reduce the prevalence of anemia during the periconceptional period among rural Tanzanian women and adolescent girls . Design A double-blind , r and omized controlled trial was conducted in which participants were individually r and omized to receive daily oral supplements of folic acid alone , folic acid and iron , or folic acid , iron , and vitamins A , B-complex , C , and E at approximately single recommended dietary allowance ( RDA ) doses for six months . Setting Rural Rufiji District , Tanzania . Subjects Non-pregnant women and adolescent girls aged 15–29 years ( n = 802 ) . Results The study arms were comparable in demographic and socioeconomic characteristics , food security , nutritional status , pregnancy history , and compliance with the regimen ( p>0.05 ) . In total , 561 participants ( 70 % ) completed the study and were included in the intention-to-treat analysis . Hemoglobin levels were not different across treatments ( median : 11.1 g/dL , Q1-Q3 : 10.0–12.4 g/dL , p = 0.65 ) . However , compared with the folic acid arm ( 28 % ) , there was a significant reduction in the risk of hypochromic microcytic anemia in the folic acid and iron arm ( 17 % , RR : 0.61 , 95 % CI : 0.42–0.90 , p = 0.01 ) and the folic acid , iron , and multivitamin arm ( 19 % , RR : 0.66 , 95 % CI : 0.45–0.96 , p = 0.03 ) . Inverse probability of treatment weighting ( IPTW ) to adjust for potential selection bias due to loss to follow-up did not material ly change these results . The effect of the regimens was not modified by frequency of household meat consumption , baseline underweight status , parity , breastfeeding status , or level of compliance ( in all cases , p for interaction>0.2 ) . Conclusions Daily oral supplementation with iron and folic acid among women and adolescents prior to pregnancy reduces risk of anemia . The potential benefits of supplementation on the risk of periconceptional anemia and adverse pregnancy outcomes warrant investigation in larger studies . Trial Registration Clinical Trials.gov [3810831] A r and omized , double-blind trial of iron replacement after repeated blood donation was conducted in 75 menstruating women ; 51 completed the study . Volunteers were assigned r and omly to one of three treatment groups : 1 ) carbonyl iron ( nontoxic elemental iron powder ) , 600 mg ; 2 ) ferrous sulfate , 300 mg ( 60 mg Fe++ ) ; or 3 ) placebo , each given three times daily for 1 week immediately after blood donation . Blood sample s obtained initially and 56 days later were tested for hemoglobin , mean corpuscular volume ( MCV ) , free erythrocyte protoporphyrin , serum ferritin , serum iron , total iron binding capacity ( TIBC ) , and percent saturation of TIBC . The prevalence of gastrointestinal side effects was similar in both groups taking iron . At the end of the study there was no laboratory evidence of change in iron status in women who received carbonyl iron ( n = 15 ) . In those treated with ferrous sulfate ( n = 17 ) the mean TIBC increased ( p less than 0.001 ) , and in the placebo group ( n = 19 ) there were decreases in mean MCV ( p less than 0.01 ) , serum ferritin ( p less than 0.001 ) , and percent saturation ( p = 0.027 ) with an increase in mean TIBC ( p = 0.004 ) . Carbonyl iron seems to be effective for short-term iron replacement in repeat blood donors and may have the advantage of decreased or absent risk of poisoning if accidentally ingested by children [16340950] Objective : To investigate whether iron supplementation can improve thyroid hormone function in iron-deficient adolescent girls . Design : A double-blind r and omized intervention study . Setting : The study was performed from 2002 through 2003 in the Islamic Republic of Iran . Subjects:103 iron-deficient non-anaemic girls who fulfilled all inclusion criteria were included , and 94 subjects successfully completed the study . Interventions : Patients were r and omly assigned to one of four groups and treated with a single oral dose of 190 mg iodine plus 300 mg ferrous sulphate 5 times/week ( n=24 ) , 300 mg ferrous sulphate 5 times/week ( n=23 ) , a single oral dose of 190 mg iodine ( n=25 ) , or a placebo ( n=22 ) for 12 weeks . Results : All groups were comparable at baseline . After the intervention , there was a significant increase in ferritin and transferrin saturation in the iron+iodine group ( 17.6 vs 8.7 μg/dl , and 18.8 vs 7.2 % , respectively , P<0.001 for both ) and in the iron group ( P<0.001 for both ) . Urinary iodine doubled in the iron+iodine group and in the iodine group ( P<0.001 for both ) . Thyroid indices tT4 , tT3 and T3RU increased and reverse RT3 decreased in the iron+iodine group ( 10 vs 8.9 μg/dl , P < 0.001 ; 143 vs 138 μg/dl , P<0.05 ; 32.3 vs 28.4 % , P<0.001 and 24.8 vs 44.2 ng/dl , P<0.001 , respectively ) and in the iron group . These two groups did not differ for any of the four indices , but both differed significantly from the iodine and placebo groups . Conclusions : Our results indicate that improvement of iron status was accompanied by an improvement in some indices of thyroid hormones . Sponsorship : This study was supported by the Dean of Research Affairs of the Tehran University of Medical Sciences [19874572] INTRODUCTION Frequent blood donations may lead to a negative iron balance . Iron depletion may be prevented by iron supplementation after whole blood donations . The aim of this study was to compare the short time changes in iron status after donation in two groups r and omized to iron supplementation or no additional iron . A second objective was to evaluate the effect of iron supplementation in donors having HFE-variants compared to HFE wild types . METHODS Subjects of both genders ( 199 women , 200 men ) were r and omised to receive iron supplementation or no additional iron after donation . Iron status , defined by the concentration of haemoglobin , serum ferritin , soluble transferrin receptor , concentration of haemoglobin in reticulocytes ( CHr ) and percent hypochrome mature red blood cells , was determined at the start of donation and 8 + /- 2 days after donation . HFE genotyping was performed at reappearance . RESULTS There was a significant difference between the two study groups on all the iron status parameters . CHr was an efficient , early marker of ongoing synthesis of haemoglobin . Heterozygosity for the HFE variants C282Y and H63D had no statistically significant influence on the iron status . The donor 's baseline serum ferritin value may be basis for an individual iron supplementation regimen , as donors with serum ferritin > 50 microg/l do not seem to utilize the iron supplementation , but prefer endogenous iron to restore the loss of haemoglobin . CONCLUSION Iron supplementation had a significant positive impact on the restoration of iron status one week after donation [3250868] Sixty-nine boys and girls between 10 and 14 years , with evidence of sub clinical vitamin deficiencies and poor iron status were enrolled into the study at the beginning of the rainy season . Children were allocated to three treatment groups to receive five times weekly either a placebo , 200 mg ferrous sulphate or 5 mg riboflavin and 150 mg ascorbic acid . Before receiving the supplement , and 9 weeks later , children performed an exercise regimen on a treadmill during which expired air was collected and heart rate measured . There was a general deterioration in the running performance of the children during the study period which was not affected by either the iron or the vitamin supplement [19474138] BACKGROUND Decrements in iron status have been reported in female soldiers during military training . Diminished iron status adversely affects physical and cognitive performance . OBJECTIVE We wanted to determine whether iron supplementation could prevent decrements in iron status and improve measures of physical performance and cognitive status in female soldiers during basic combat training ( BCT ) . DESIGN In this 8-wk r and omized , double-blind , placebo-controlled trial , soldier volunteers ( n = 219 ) were provided with capsules containing either 100 mg ferrous sulfate or a placebo . Iron status indicator assays were performed pre- and post-BCT . Two-mile running time was assessed post-BCT ; mood was assessed by using the Profile of Mood States question naire pre- and post-BCT . RESULTS The BCT course affected iron status : red blood cell distribution width and soluble transferrin receptor were elevated ( P < 0.05 ) , and serum ferritin was lowered ( P < 0.05 ) post-BCT . Iron supplementation attenuated the decrement in iron status ; group-by-time interactions ( P < 0.01 ) were observed for serum ferritin and soluble transferrin receptor . Iron supplementation result ed in improved ( P < 0.05 ) vigor scores on the Profile of Mood States post-BCT and in faster running time ( P < 0.05 ) in volunteers reporting to BCT with iron deficiency anemia . CONCLUSIONS Iron status is affected by BCT , and iron supplementation attenuates the decrement in indicators of iron status in female soldiers . Furthermore , iron supplementation may prove to be beneficial for mood and physical performance during the training period . Future efforts should identify and treat female soldiers or athletes who begin training regimens with iron deficiency or iron deficiency anemia [2733574] In order to examine the effects of mild iron deficiency on physical work capacity , 40 prelatent iron-deficient female endurance runners were studied before and after 8 wk of supplementation with either oral iron ( 320 mg ferrous sulfate ) or a matching placebo . Subjects underwent the following physical work capacity tests : the Wingate cycle ergometer test , the anaerobic speed test , the ventilatory threshold , VO2max , and maximal treadmill velocity during the VO2max test . Muscle biopsy sample s pre- and post-treatment were obtained from 17 of the subjects , and these were assayed for citrate synthase and cytoplasmic alpha-glycerophosphate dehydrogenase activity . Subjects were r and omly assigned to one of the treatment groups , and a double-blind method of administration of the supplements was used . The differences in improvement scores between the two groups on the work capacity and enzyme activity variables were statistically nonsignificant ( P greater than 0.05 ) . Serum ferritin values rose from a mean of 12.4 + /- 4.5 to 37.7 + /- 19.7 ng.ml-1 for the experimental group and from 12.2 + /- 4.3 to 17.2 + /- 8.9 ng.ml-1 for the controls ( P = 0.0025 ) , whereas hemoglobin levels remained fairly constant for both groups ( P = 0.6 ) . Eight weeks of iron supplementation to prelatent/latent iron-deficient , physically active females did not significantly enhance work capacity . Within the limitations of this study , the presence of a serum ferritin below 20 ng.ml-1 does not pose a significant h and icap to physical work capacity [15563440] The effects of 4 weeks iron supplementation on haematological and immunological status were studied in 25 elite female soccer players aged 20 - 28 years . The subjects were r and omized and assigned to one of the following two groups ; subjects given 40 mg/day iron supplementation ( S group ) or those given placebo ( C group ) . The oral iron supplementation ( 40 mg elemental iron ) was taken in 15 ml solution once a day by the S group , and the C group took a placebo for 4 weeks . Daily energy and protein intakes met the Korean Recommended Dietary Allowances . Blood haemoglobin concentration did not change in the S group , but decreased significantly ( P<0.05 ) in the C group over the 4-week experimental period . Haematocrit , mean cell volume , mean cell haemoglobin and total iron binding capacity decreased significantly , and mean cell haemoglobin concentration increased significantly ( P<0.05 ) in both the S and C groups . Plasma ferritin concentration increased significantly ( P<0.05 ) in the S group , but did not change in the C group . The change of plasma immunological parameters and erythrocyte anti-oxidative enzyme activities were almost the same between the S and C groups . These results suggest that 4 weeks of iron supplementation by elite female soccer players significantly increased body iron stores and inhibited decrease of haemoglobin concentration induced by soccer training [7835330] We studied effects of dose and treatment duration during low-dose iron supplementation in premenopausal , non-pregnant women , with initial serum ferritin and haemoglobin concentrations < 20 micrograms x l-1 and > or = 120 g x l-1 , respectively . The study was r and omized , double-blind and placebo-controlled . Three groups completed a 6-month study : placebo ( n = 27 ) , FE-9 ( 9 mg iron x day-1 , n = 18 ) and FE-27 group ( 27 mg iron x day-1 , n = 19 ) . The supplement consisted of 11 % heme and 89 % inorganic iron . In FE-27 , serum ferritin increased from ( mean , 95 % confidence interval ) 11.8 ( 9.7 ; 14.4 ) to 25.3 ( 18.6 ; 34.4 ) micrograms x l-1 in 1 month , and remained stable after that ( ANOVA : group effect , P = 0.0003 ) . In both FE-9 and FE-27 , blood haemoglobin levels increased from 136 ( 132 ; 140 ) to 142 ( 139 ; 145 ) g x l-1 in 1 month , remaining constant after that ( group effect , P = 0.001 ) . Hence , the 27 mg daily dose of organic/inorganic iron corrected both mild anaemia and storage iron depletion , whereas the 9 mg dose did not affect iron stores . Elongation of treatment duration above 1 month brought about only minor changes [7091036] The effects of energy supplementation ( group I received 200 kcal/day and group II received 1000/kcal day ) were examined on road workers in Kenya . Anthropometric , dietary , worker productivity , clinical hematology , and parasitology data were collected from 224 workers of both sexes or , sub sample s of these workers at base-line , midpoint , and final measurement periods . Sixty-seven percent of the work force was less than 85 % of weight for height . Females tended to be better nourished than males . Multiple regression analysis showed that increases in arm circumference and Hb levels were associated with significant productivity gains of about 4 % . At the midpoint , group II males gained 1.10 kg ( p less than 0.0003 ) while group I males showed no change . Weight loss during the latter part of the study result ed in no significant final weight change for males . " Successful " supplementation was weakly associated with a productivity increase for group II workers of 12.5 % ( p less than 0.10 ) [7476052] The impact of long-term ( 6-month ) moderate exercise on the iron status of previously sedentary women was determined by r and omly assigning 62 college-age women into one of the following four groups : 1 ) 50 mg.d-1 iron supplement , low iron diet ( N = 16 ) ; 2 ) Placebo , free choice diet ( N = 13 ) ; 3 ) Meat supplement to achieve 15 mg.d-1 iron intake ( N = 13 ) ; and 4 ) Control , free choice diet ( N = 20 ) . All groups except the Control group exercised 3 d.wk-1 at 60%-75 % of their heart rate reserve . VO2max was measured at baseline and week 24 . Blood was sample d at baseline and every 4 wk thereafter for 24 wk to measure iron status and to eluci date the causes for alterations in iron status . Subjects had depleted iron stores throughout the study as indicated by their serum ferritin levels ( < 15 ng.ml-1 ) . Serum iron , total iron binding capacity and transferrin saturation were not compromised with exercise . Mean hemoglobin level in the Placebo/Ex group was significantly ( P < 0.05 ) lower than the 50 Fe/Ex and the Meat/Ex groups by week 24 . However , changes in serum albumin , haptoglobin , and erythropoietin data from the study can not explain these changes [3047920] Female blood donors with low hematocrit levels detected by copper sulfate screening were selected r and omly to receive either 75 mg of iron per day , as ferrous gluconate , or a calcium phosphate placebo . Their ferritin , serum iron , total iron-binding capacity , zinc protoporphyrin , and hemoglobin values , as well as their suitability to donate blood , were determined initially ( Visit 1 ) and at four follow-up visits ( Visits 2 - 5 ) . By the second visit , the serum ferritin and iron values of donors receiving iron supplementation differed significantly from those of donors receiving placebo . By the fifth visit , a less marked but significant increase in hemoglobin had occurred in the iron group , but not in the placebo group . At no time was there a significant difference between the groups ' suitability to donate blood , with each group donating at almost half of their visits . The authors conclude that iron supplementation at this dose level in deferred female blood donors improves their iron status and hemoglobin levels , but does not significantly increase their suitability to donate blood as compared with the suitability of placebo-treated donors [2180144] The effectiveness of elemental , nontoxic carbonyl iron in replacing iron lost at blood donation was examined . In a r and omized double-blind design , 99 women , aged 18 to 40 , were given placebo or low-dose carbonyl iron ( 100 mg orally ) at bedtime for 56 days after phlebotomy . Compliance was equivalent for the two regimens . Mild side effects were slightly greater with carbonyl iron . At Day 56 , estimated net iron absorption from therapy or diet , or both , was sufficient to replace iron in 85 percent of those receiving carbonyl iron but in only 29 percent of those taking placebo ( p less than 0.001 ) . The rates of deferral from repeat donation were 8 percent in the carbonyl iron group and 36 percent in the placebo group ( p less than 0.01 ) , and the positive predictive value of routine screening in identifying participants without iron deficiency was 83 versus 13 percent ( p less than 0.01 ) . It can be concluded that short-term carbonyl iron supplementation in female blood donors can replace the iron lost at phlebotomy , protect the women against iron deficiency , and enhance their ability to give blood [10989766] This experimental study was design ed to investigate the effects of daily versus intermittent iron supplementation on iron status of high school girls in Zahedan and Rasht cities in 1996 - 1997 . The subjects were selected r and omly from among students of grade s 1 - 3 of four high schools in each city . Anemia was determined by measuring hematological indices . 260 anemic and a similar number of non-anemic subjects of 4 high schools were selected and allocated r and omly to 4 treatment groups . During a 3-month period , the test groups were given 150 mg ferrous sulfate tablets ( 50 mg Fe ) . Subjects in group 1 received a daily dose , groups 2 & 3 received twice or once weekly doses respectively . The control group received no iron supplement . For these subjects , in addition to hematological indices biochemical iron indices were measured in the beginning and at the end of the study . The increases in hemoglobin concentration in anemic subjects were not significantly different among supplemented groups but were different from the control group ( p < 0.00001 ) . Among anemic subjects , changes in serum ferritin levels in 3 supplemented groups were significantly different from the control group . Serum ferritin in Group 1 was also increased to a greater extent than groups 2 and 3 ( P < 0.00001 ) . It is concluded that over the study period a weekly iron dose was as effective as a daily dose in treating anemia but the daily dose was more effective in improving iron stores than a weekly dose in the short run [8855856] BACKGROUND Up to 25 % of adolescent girls in the USA are iron deficient . This double-blind , placebo-controlled clinical trial assessed the effects of iron supplementation on cognitive function in adolescent girls with non-anaemic iron deficiency . METHODS 716 girls who enrolled at four Baltimore high schools were screened for non-anaemic iron deficiency ( serum ferritin < or = 12 micrograms/L with normal haemoglobin ) . 98 ( 13.7 % ) girls had non-anaemic iron deficiency of whom 81 were enrolled in the trial . Participants were r and omly assigned oral ferrous sulphate ( 650 mg twice daily ) or placebo for 8 weeks . The effect of iron treatment was assessed by question naires and haematological and cognitive tests , which were done before treatment started and repeated after the intervention . We used four tests of attention and memory to measure cognitive functioning . Intention-to-treat and per- protocol analyses were done . FINDINGS Of the 81 enrolled girls with non-anaemic iron deficiency , 78 ( 96 % ) completed the study ( 39 in each group ) . Five girls ( three control , two treatment ) developed anaemia during the intervention and were excluded from the analyses . Thus , 73 girls were included in the per- protocol analysis . Ethnic distribution , mean age , serum ferritin concentrations , haemoglobin concentrations , and cognitive test scores of the groups did not differ significantly at baseline . Postintervention haematological measures of iron status were significantly improved in the treatment group ( serum ferritin 27.3 vs 12.1 micrograms/L , p < 0.001 ) . Regression analysis showed that girls who received iron performed better on a test of verbal learning and memory than girls in the control group ( p < 0.02 ) . INTERPRETATION In this urban population of non-anaemic iron-deficient adolescent girls , iron supplementation improved verbal learning and memory [4587790] Pregnant women with anaemia due to combined iron and folate deficiencies were r and omly divided into 3 groups receiving either combination therapy with iron and pteroylglutamic acid , or treatment with iron or pteroylglutamic acid olone . A fourth group of pregnant women with levels of Hb above 10 g/100 ml received placebo . Combined iron and folate administration result ed in a marked therapeutic response , while mild or insignificant improvement was associated with either iron or folic acid teratment alone . The Hb concentration of the women receiving placebo dropped gradually in most instances . The results reported here suggest that in population s with a high prevalence of iron and folate deficiencies both these compounds should be supplied in order to prevent anaemia . The possible causal relationship between iron and folate deficiencies are discussed in the light of the present results and relevant literature [10721926] The prevalence of anemia is high in adolescent girls in India , with over 70 % anemic . Iron-folic acid ( IFA ) supplements have been shown to enhance adolescent growth elsewhere in the world . To confirm these results in India , a study was conducted in urban areas of Vadodora , India to investigate the effect of IFA supplements on hemoglobin , hunger and growth in adolescent girls 10 - 18 y of age . Results show that there was a high dem and for IFA supplements and > 90 % of the girls consumed 85 out of 90 tablets provided . There was an increment of 17.3 g/L hemoglobin in the group of girls receiving IFA supplements , whereas hemoglobin decreased slightly in girls in the control group . Girls and parents reported that girls increased their food intake . A significant weight gain of 0.83 kg was seen in the intervention group , whereas girls in the control group showed little weight gain . The growth increment was greater in the 10- to 14-y-old age group than in the 15- to 18-y-old group , as expected , due to rapid growth during the adolescent spurt . IFA supplementation is recommended for growth promotion among adolescents who are underweight [23602244] Limited information is available on the role of iron in fatty acid metabolism in humans . We hypothesized that iron supplementation will increase desaturase activity , and so , the aim of this study was to determine the effect of iron supplementation on fatty acid desaturase activity in young women . Participants were r and omly assigned to a control group ( CG ) or supplementation group ( SG ) who were provided with 37.4 mg of elemental iron daily for 12 weeks . Forty women completed the trial , n = 19 in CG and n = 21 in SG . The mean ages were 25.2 and 24.6 years , and body mass indices were 21.8 and 21.2 ( kg/m(2 ) ) in CG and SG , respectively . Serum ferritin concentrations increased significantly ( P < .01 ) in subjects assigned to SG but were unchanged in CG . Serum iron concentrations were not significantly changed . Plasma zinc concentrations at the end of the intervention were similar to baseline values for individuals in CG but were decreased significantly ( P = .004 ) in SG . Plasma fatty acids , phospholipid fatty acids , and desaturase activities , expressed as precursor-to-product ratios , were not significantly affected by the intervention , although in SG the concentration of serum ferritin was correlated positively ( P < .05 ) with Δ6-desaturase activity . Supplementing non-anemic women with low dose iron improves iron status but has no significant effect on desaturase activity . The lack of a clear effect on an indirect indicator of desaturase activity may be related to the antagonism between iron and zinc , as illustrated by the decrease in plasma zinc concentrations in women who were supplemented with iron Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: Adolescence is a critical stage in the life cycle , and adequate nutrition is necessary for the proper growth and development of individuals and their offspring . Here , we comprehensively review all published systematic review s ( through October 2016 ) on adolescents ( 10 - 19 years ) and women of reproductive age , including pregnant women , which targeted interventions related to nutrition . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

10732935

[8281590] It is often necessary to adjust a patient ’s sedation level while they are in the intensive care unit . The purpose of this study was to compare propofol with midazolam for controlling short-term alterations in sedation . Twenty-three patients undergoing an interactive procedure , physiotherapy , during mechanical ventilation of the lungs were studied . The patients were r and omly assigned to receive infusions of propofol or midazolam for sedation . Sedation was assessed using the method of Ramsay , where 3 is drowsy responding only to comm and s ; and 5 is asleep with a slow response to light glabellar tap . Prior to physiotherapy sedation was deepened from 3 to 5 by increasing the sedative infusion rate , and level 5 was maintained during physiotherapy by adjusting the infusion rate whenever necessary . After physiotherapy , the sedative dose was reduced until level 3 was again achieved . During physiotherapy , sedation level 5 was achieved for 53.9 % of the time with propofol but for only 25.7 % with midazolam ( P < 0.01 ) . After physiotherapy , those patients se date d with propofol re-awakened to level 3 faster ( 8.3 ± 2.3 min , mean ±SE ) than those receiving midazolam ( 92.8 ± 35.0 min , P < 0.05 ) . After physiotherapy , a further 1.8 ± 0.5 dose adjustments were required to the midazolam infusion while only 0.4 ± 0.2 adjustments were required to the propofol infusion ( P < 0.05 ) . During physiotherapy 3.0 ± 0.5 dose adjustments to the propofol dose were required compared with 3.6 ± 0.5 adjustments to the midazolam dose ( NS ) . It is concluded that , during a st and ardized stimulus , physiotherapy , propofol infusion allowed a desired sedation score to be maintained for more of the time than did infusion of midazolam . Subsequently , when the infusion rates were reduced , less time was taken to re-awaken to baseline levels after physiotherapy , with fewer adjustments to the infusion rate , in those patients receiving propofol than midazolam . RésuméAux soins intensifs , il faut fréquemment modifier le niveau de sédation ; cette étude compare le propofol au midazolam pour contrôler ces changements de courte durée . Vingt-trois patients sous ventilateur mécanique soumis à des manoeuvres de physiothérapie interactive sont inclus dans l’étude . Ils reçoivent au hasard en sédation une perfusion de profopol ou de midazolam . La sédation est évaluée selon l’échelle de Ramsey ; on accorde 3 pour la somnolence avec réponse aux ordres et 5 au sommeil avec réponse lente à la légère percussion de la glabelle . Avant la physiothérapie , la sédation est approfondie du niveau 3 au niveau 5 en augmentant la perfusion au besoin . Après la physiothérapie , on réduit la perfusion jusqu’au retour au niveau 3 . Pendant la physiothérapie , le niveau 5 est atteint pendant 53,9 % de la durée du traitement avec le propofol contre seulement 25,7 % avec le midazolam ( P < 0,01 ) . Après la physiothérapie , les patients sous propofol reviennent au niveau 3 plus rapidement ( 8,3 ± 2,3 min , moyenne ± SD ) que ceux qui reçoivent du midazolam ( 92,8 ± 35,0 min , P < 0,05 ) . Après la physiothérapie , le dosage de midazolam nécessite 1,8 ± 0.5 ajustements comparativement à 0,4 ± 0,2 pour le propofol ( P < 0,05 ) . Pendant la physiothérapie , la posologie du propofol doit être ajustée 3,0 ± 0,5 fois comparativement à 3,6 ± 0,5 pour celle du midazolam ( NS ) . En conclusion , pendant une stimulation st and ardisée , la perfusion de propofol permet de maintenir le niveau de sédation désiré plus souvent que la perfusion de midazolam . Par la suite , lorsqu’on diminue la perfusion , le temps requis pour le retour à la ligne de base nécessite moins d’ajustements pour le propofol que pour le midazolam [2841885] UNLABELLED It was the aim of this study to compare two regimens for sedation and analgesia during ventilator treatment in intensive care patients . Special regard was given to endocrine stress response , neuro-monitoring , hemodynamic parameters and clinical practicability . METHODS A total number of 16 patients of an operative ICU were r and omly allocated to the following groups : ( 1 ) Fentanyl-group , approximately 0.2 mg/h fentanyl , 2.5 mg/h midazolam and 2 mg/h pancuronium in intermittent doses , ( 2 ) ketamine-group , about 50 mg/h ketamine and 2.5 mg/h midazolam by syringe pump , in addition 2 mg/h pancuronium . During a period of 2 days and in intervalls of 6 h , plasma levels of epinephrine and norepinephrine ( by HPLC/ECD ) , ADH , ACTH and cortisol ( by RIA ) , ketamine ( by GC ) and stress-metabolites ( glucose , lactate , free glycerol ) were determined . Hemodynamic parameters were investigated in intervalls of 12 h , EEG ( Compressed Spectral Array , CSA ) in intervalls of 24 h. In addition , routine laboratory data , vigilance and adaptation to the respirator were observed . RESULTS Plasma levels of adrenaline , noradrenaline , dopamine , ADH , ACTH , cortisol and stress-metabolites were comparable in both groups . Levels of ADH , ACTH , cortisol and free glycerol did not leave the normal range . In three patients , in which epinephrine- or norepinephrine-infusions were necessary to improve cardiocirculatory stability , this treatment could be finished after beginning of the ketamine application . In both groups , CSA showed a dominant delta- und theta-activity according to the clinical aspects of sufficient sedation and analgesia . Hemodynamic parameters were comparable in both groups . ( ABSTRACT TRUNCATED AT 250 WORDS [1539785] A 2 % solution of propofol has been compared with the 1 % formulation for sedation in patients whose lungs were being mechanically ventilated in an intensive care unit following coronary artery bypass surgery . There were no significant differences in the amount of propofol used in the two groups , the rate of propofol infusion or the number of changes made to the infusion rate to maintain the desired level of sedation . Recovery times and times to tracheal extubation were similar . The mean heart rates of those receiving 2 % propofol were significantly higher throughout the period of the study for no apparent reason . Propofol 2 % was found to be safe , easy to administer and a practical alternative to the 1 % solution for sedating cardiac surgical patients [10150550] A r and omised crossover study was undertaken to compare the quality and cost of controlled versus empirical sedation with midazolam in critically ill patients . Patients ( n = 40 ) entering the ICU were enrolled provided they satisfied the strict entry criteria . During 90 hours of midazolam sedation , patients received r and omly allocated 10-hour periods of controlled or empirical sedation . With empirical sedation , the mean dose of midazolam and the cost of sedation were almost double those with controlled sedation . The quality of sedation was superior with the controlled method . In a separate study on 352 patients , a cost-benefit analysis of controlled sedation with midazolam or propofol infusion or bolus injections of morphine plus diazepam showed that the quality of sedation achieved with propofol was superior to the other two regimens and that , with morphine plus diazepam , the quality of sedation was unacceptably poor . Although the direct purchase price of propofol was higher than that of other agents , the total cost of sedation with propofol was lower than that for midazolam for short-term intensive care ( less than 24 hours ) and comparable to midazolam for longer-term use . However , indirect benefits of sedation with propofol include a much shorter ICU stay with the attendant reduced nursing costs and greater throughout the patients , and this more than compensates for the higher purchase price of the agent [9142583] Objective : The assessment of propofol to produce diurnal sedation in critically ill patients Design : Prospect i ve clinical study Setting : Intensive Care Unit , University Hospital Patients and participants : Thirty consecutive patients admitted to the Intensive Care Unit older than 18 years who were expected to be se date d for more than 50 h Interventions : The patients were r and omised into two groups . All received sedation with a constant background infusion of morphine and a variable infusion rate of propofol , which was altered hourly to maintain the intended sedation score . The first group received constant light sedation ( CLS ) over 50 h aim ing for a Ramsay score of 2–3 . The second group received CLS between 0600 h and 2200 h and additional night sedation ( ANS ) with propofol between 2200 h and 0600 h , aim ing for a sedation score of 4–5 . Measurements and results : Patients were studied for 50 h from 1800 h on the first day of admission . Recordings of heart rate , blood pressure , sedation scores and propofol and morphine infusion rates were made hourly . An APACHE II score was recorded for each patient . Sedation scores were analysed by blind visual assessment and cosinor analysis , which is used in chronobiology to examine the correlation of data with a cosine curve . Patients in the ANS group had significantly better rhythmicity of sedation levels using cosinor analysis ( r = 26 % v 8 % ) p < 0.01 . There was no difference between the CLS and ANS groups with respect to age , sex or APACHE II scores . Nine out of 15 patients in the ANS group achieved diurnal sedation . Three patients in the CLS group showed diurnal rhythmicity of sedation , which can be attributed to natural sleep , and had a median APACHE II score of 12 . Five patients in the CLS group and three in the ANS group showed a deep constant sedation pattern . They had high APACHE II scores ( median 21.5 ) and an obtunded conscious level on admission due to severe sepsis . Conclusion : Propofol can safely provide diurnal sedation in the critically ill when titrated against the Ramsay score . Sedation levels can not be manipulated in some severely ill patients [2876719] Sedation was studied in 30 patients requiring overnight ventilation in the intensive therapy unit ( ITU ) . Patients received an infusion of either alfentanil or pethidine , supplemented with midazolam . The infusion rates were adjusted to provide optimal sedation as judged by a nurse , and measurements were made of quality of sedation , recovery and serum cortisol concentration . In addition , blood concentrations of alfentanil were measured to permit pharmacokinetic and pharmacodynamic analysis . Satisfactory sedation was achieved in both groups . The required infusion rate for alfentanil was between 0.4 and 0.5 micrograms kg-1 min-1 . Recovery was good in both groups , apart from one patient in the alfentanil group , in whom recovery was greatly prolonged and alfentanil pharmacokinetics were abnormal . A difference was found in the metabolic response to surgery between the two groups , the response in the alfentanil group being significantly less marked [8630539] Propofol ( P ) and midazolam ( M ) are frequently given by continuous infusion for sedation in critically ill , mechanically ventilated patients . We compared these drugs with regard to : ( 1 ) time-to-awaken ; ( 2 ) reproducibility of bedside assessment s of level of sedation ; ( 3 ) time-to-sedation ; and ( 4 ) change in oxygen consumption ( V O2 ) from awake to se date d state . Seventy-three patients were prospect ively r and omized to receive either P ( n=37 ) or M ( n=36 ) . Wake-up times after stopping the drug were assessed by blinded and unblinded observers , by asking patients to perform simple tasks . Times to se date were assessed by consensus agreement among nurses and investigators . Demographics and APACHE II scores were not different between P and M. The P group had a significantly narrower range of wake-up times with a higher likelihood of waking in less than 60 min . Blinded versus unblinded observations had excellent correlation . Average time to se date and decrease in V O2 were not different . We conclude that in this patient population : ( 1 ) both P and M achieved optimal sedation in a large fraction of patients when administered by specified dosing protocol s ; ( 2 ) P had a faster , more reliable , wake-up time ; ( 3 ) assessment s of time-to-awaken were objective and reproducible ; ( 4 ) time to sedation was not significantly different ; ( 5 ) V O2 decreased similarly with both [9187783] Purpose The purpose of this r and omized , double-blind study was to evaluate the efficacy of midazolam and propofol for postoperative sedation and early extubation following cardiac surgery . Methods ASA physical status II-III patients scheduled to undergo elective first-time cardiac surgery with an ejection fraction > 45 % were eligible . All patients received a st and ardized sufentanil/isoflurane anaesthesa . Dunng cardiopulmonary bypass 100 μg · kg−1 · mm−1 propofol was substituted for isoflurane . Upon amval in the Intensive Care Unit ( ICU ) . patients were r and omized to either 10 μg · kg · min−1 propofol ( n = 21 ) or 0.25 μg · kg · mm−1 midazolam ( n = 20 ) . Infusion rates were adjusted to maintain sedation within a predetermined range ( Ramsay 2–4 ) . The infuson was terminated after four hours . Patients were weaned from mechanical ventilation and their tracheas extubated when haemodynamic stability , haemostasis , normothermia and mental orientation were confirmed . Haemodynamic measurements , artenal blood gas tensions and pulmonary function tests were recorded at specified times . Results There were no differences between the two groups for the time spent at each level of sedation , number of infusion rate adjustments , amount of analgesic and vasoactive drugs , times to awakening and extubation . The costs of propofol were higher than those of midazolam . There were no differences in haemodynamic values , artenal blood gas tensions and pulmonary function . Conclusion We conclude that midazolam and propofol are safe and effective sedative agents permitting early extubation in this selected cardiac patient population but propofol costs were higher . RésuméButLe but de cette étude r and omisée , à double insu était d’évaluer l’efficacité du midazolam et du propofol pour sédation postopératoire en vue d’une extubation précoce postchirurgie cardiaqueMéthodologieTout patient ASA II-III admis pour une première chirurgie cardiaque élective ayant une fraction d’éjection > 45 % était éligible . Tous les patients ont reçu une anesthésie st and ard à base de sufentanil/isoflurane . Durant la circulation extracorporelle , le propofol ( 100μg · kg−1 · min−1 ) a été substitué à l’isoflurane . Dès l’arnvée aux soins intensifs , les patients furent r and omisés soit au propofol ( n = 21)à 10 μg · kg−1 · mm−1 sort au midazolam ( n = 20 ) 0.25 μg · kg−1 · mm−1 . Les débits de perfusion étaient ajustés pour maintenir un niveau de sédation prédéterminée ( Ramsay 2–4 ) . La perfusion était cessée après quatre heures . Les patients étaient sevrés de la ventilation mécanique et extubés lorsque la stabilité hémodynamique , l’hémostase , la normothermie et l’orientation mentale étaient confirmées . Des bilans hémodynamiques , gaz arténels et fonction pulmonaire furent enregistrés à des intervalles spécifiques . RésultatsIl n’y avait pas de différence entre les groupes pour le temps occupé aux différents niveaux de sédation , d’ajustement de perfusion , le temps d’éveil et d’extubation . Le coût du propofol était plus élevé que celui du midazolam . La dem and e d’analgésique et l’utilisation d’agents vasoactifs étaient similaires . Aucune différence de fonction pulmonaire , gaz arténels et hémodynamique n’a été décelée . Conclusion Nous concluons que le midazolam et le propofol sont sécuritaires et efficaces comme agents de sédation permettant une extubation précoce pour ce groupe de patients cardiaques sélectionnés mais le coût du propofol est plus élevé [8205830] Objectives To describe the variety of medications prescribed along with the doses administered and routes of administration , and to delineate the clarity of orders written and the accuracy of transcription of drugs used for sedation , anxiety , pain , and neuromuscular blockade in a surgical intensive care unit ( ICU ) . Design A prospect i ve , observational study of drug-related information collected from forms used by physicians and nurses . Setting Three adult surgical ICUs at an academic medical center . Patients were admitted to a surgical service and co-managed by the surgical ICU team and primary surgical service . Patients Consecutive patients admitted to all of these units from September 1992 to January 1993 . Interventions None . Measurements and Main Results Information on prescribing and administering sedatives , analgesics , and neuromuscular blocking drugs was obtained from data collected on 221 patients . A total of 202 ( 91 % ) patients received , on average , 1.9 ± 1.4 study drugs ( range 0 to 9 ) in a wide variety of combinations . There were 2,103 total doses administered from 448 drug orders . Ninety percent of study drug orders were written for administration on an “ as-needed ” basis ; in 42 % of these orders , the indication for use was not specified . On average , only 27 % of the maximal allowable daily dose was administered ; this number ranged from 15 % for hydromorphone to 77 % for chlordiazepoxide . Morphine sulfate , the most commonly prescribed drug , was ordered primarily for intravenous administration in 84 % of patients . Morphine sulfate was prescribed using 19 different doses ( written as a range of doses ) and 13 different dosing intervals . Transcription discrepancies were observed in 17 % of orders . In 2.7 % of doses , the actual dose that was administered could not be determined . Conclusions A wide variety of sedatives and analgesics are frequently used in surgical ICU patients . These agents are often ordered on an “ as-needed ” basis using a range of doses , sometimes without adequate directions about the indication for their use . Daily doses received are significantly less than their maximum allowable daily doses . Orders for these medications are sometimes transcribed and charted incorrectly . In contrast , neuromuscular blocking agents are not commonly prescribed . Future studies are needed to improve order writing of these agents , and to determine the criteria used by physicians and nurses in the selection and administration of these agents , the outcomes of therapy , and the most cost-effective regimen . ( Crit Care Med 1994 ; 22:974–980 [8681594] OBJECTIVES To compare the effectiveness , characteristics , duration of action , hemodynamic and biochemical effects , and side effects of propofol and midazolam used for continuous intravenous sedation of ventilated critically ill patients . DESIGN Multicenter , prospect i ve , r and omized , nonblinded study . SETTING Nine Spanish general intensive care units ( ICUs ) . PATIENTS Ninety-eight patients admitted to the ICU who were mechanically ventilated and required sedation for a minimum of 48 hrs . INTERVENTIONS Propofol or midazolam was used for induction and maintenance of continuous intravenous sedation for a maximum of 5 days . The effectiveness of those two regimens was assessed according to their effects on ventilatory management and the presence of agitation . MEASUREMENTS AND MAIN RESULTS In 93 % of the patients studied , there was a medical cause necessitating mechanical ventilation . The mean ( + /-SD ) duration of sedation was 81 + /- 25 hrs and 88 + /- 27 hrs for the propofol and midazolam groups , respectively . The induction dose was 2.24 + /- 0.43 mg/kg over 318 + /- 363 secs for propofol , and 0.22 + /-0.07 mg/kg over 33 + /-29 secs for midazolam . The maintenance dose was 2.8 + /-1.1 mg/kg/hr for propofol and 0.14 + /- 0.10 mg/kg/hr for midazolam . There was no difference regarding the opiate and muscle relaxant requirements between the two groups . Sedation with propofol was more effective in achieving patient-ventilator synchrony than that with midazolam after the first hour of treatment ( p < .01 ) . Patients se date d with propofol awoke more rapidly and with less variability that those patients se date d with midazolam ( 23 + /- 16 mins vs. 137 + /- 185 mins , respectively , p < .05 ) , particularly in those patients requiring deep sedation ( 27 + /- 16 mins vs. 237 + /- 222 mins , respectively , p < .01 ) . No hemodynamic or biochemical changes were detected in any of the treatment groups . During induction , five patients in the propofol group and two patients in the midazolam group had hypotension . CONCLUSIONS In this population of critically ill patients , propofol is an effective and safe alternative for sedation , with some advantages , such as short duration of action and high effectiveness over the conventional regimen with benzodiazepines and opiates [2570958] 101 critically ill patients admitted to five intensive-care units were allocated r and omly to receive a continuous intravenous infusion of either propofol or midazolam for sedation for up to 24 h. In addition , morphine was given to provide analgesia . The mean duration of infusion was 20.2 h ( range 3.0 - 24.5 ) in the propofol group and 21.3 h ( 4.0 - 47.0 ) in the midazolam group and infusion rates were 1.77 mg/kg/h ( range 0.40 - 5.00 ) and 0.10 mg/kg/h ( 0.01 - 0.26 ) , respectively . The infusion rates were adjusted as necessary , and the desired level of sedation was achieved easily in most patients in both groups . There were slight falls in arterial pressure , but there were no significant differences between the groups . Heart rate was lower in patients who received propofol . Some small changes occurred in biochemical and haematological variables in both groups , but they were not clinical ly significant . There was no indication that either drug substantially impaired adrenal steroidogenesis . When the infusion was discontinued , there was less variability in recovery of consciousness in patients who had received propofol . In a subgroup of patients , weaning from mechanical ventilation was achieved significantly faster after discontinuation of propofol than of midazolam . Propofol proved to be a satisfactory agent for sedation of these critically ill patients and compared favourably with midazolam [1418278] Propofol infusion was found to provide excellent sedation and rapid recovery in intensive care . The present study compared Propofol with lytic solution ( lytic solution = mixture of 100 mg Pethidine , 50 mg Promethazine and 0.6 mg Dihydroergotamine ) during 6 hours of postoperative artificial ventilation . 60 patients after major abdominal surgical procedures were studied with ethical committee approval and informed consent . Patients were r and omly allocated to receive either Propofol or lytic solution . We aim ed at a sedation level of stage 5 according to the Ramsey score . The mean drug dosages were 3.9 mg/kg/h of Propofol and 4.2 ml/h of lytic solution . Hemodynamic values , blood gases as well as various biochemical measures did not show any difference between the groups . At the end of the sedation period triglyceride concentrations were significantly higher in patients receiving Propofol ( 166 + 79 mg/dl ) compared to the control group ( 97 + 60 mg/dl ) . Significant and relevant differences were found for the times of recovery after discontinuation of the sedative . These times were very short in the Propofol group . Furthermore , in view of a longer recovery time after lytic solution in this group the respiratory rate was significantly slower up to the end of the observation period . We conclude that a major advantage of Propofol in the present study was the rapid recovery after 6 hour sedation . Patients gain vigilance rapidly and sufficient spontaneous respiration within minutes . Not at least thanks to these facts patient 's safety can be improved in the recovery period [8062564] Objective To compare the safety and effectiveness of propofol ( 2,6-diisopropylphenol ) to midazolam for sedation of mechanically ventilated patients after coronary artery bypass grafting . Design Open , r and omized , prospect i ve trial . Setting Cardiothoracic intensive care unit ( ICU ) , Clevel and Clinic Foundation . Patients Eighty-four patients with normal or moderately impaired left ventricular function who underwent elective coronary artery bypass graft surgery under high-dose opioid anesthesia . Interventions Patients were r and omly selected to receive either propofol ( mean loading dose 0.24 mg/kg ; mean maintenance dose 0.76 mg/kg/hr ) or midazolam ( mean loading dose 0.012 mg/kg ; mean maintenance dose 0.018 mg/kg/hr ) . Infusion rates were titrated to keep patients comfortable , drowsy , and responsive to verbal stimulation . Study duration , 8 to 12 hrs ; infusions were started in the ICU when patients were awake and hemodynamically stable . Measurements and Main Results During therapy , both groups had lower mean arterial pressures and heart rates compared with baseline measurements ; however , the propofol group had significantly lower heart rates than the midazolam group during the first 2 hrs of infusion . The propofol group also had significantly lower blood pressure measurements 5 and 10 mins after the initial dose , although there was no difference during infusion . Baseline cardiac output was measured before starting the infusion , and measurements were repeated during continuous infusion at 4 , 8 , and 12 hrs . Cardiac output values were similar . Propofol maintenance infusions ranged from 3 to 30 μg/kg/min and midazolam infusions ranged from 0.1 to 0.7 μg/kg/min . At these infusion rates . both groups had adequate sedation , based on nurse and patient evaluations ; however , the propofol group used significantly lower total doses of sodium nitroprusside and supplemental opioids . Conclusions Both propofol and midazolam provided safe and effective sedation of coronary artery bypass graft patients recovering from high-dose opioid anesthesia . The reduced need for both antihypertensive medication and opioids seen in the propofol group may be advantageous . However , the hypotension seen after the initial bolus dose of propofol may be a concern . No difference between the two drugs could be demonstrated in time to extubation or ICU discharge , although it is probable that time to extubation was governed more by residual operative opioids than the study agents . ( Crit Care Med 1994 ; 22:1415–1423 [7867354] OBJECTIVES To evaluate the comparative safety and effectiveness of intravenous infusion of propofol or midazolam when used for 12 to 24 hrs of sedation and to evaluate the quality of sedation during stimulation . DESIGN An open , comparative , prospect i ve , r and omized study . SETTING Surgical intensive care unit ( ICU ) in a university hospital . PATIENTS Postoperative , intubated , general surgical , and orthopedic patients requiring mechanical ventilation ( n = 60 ) . INTERVENTIONS None . MEASUREMENTS Assessment s were made at baseline ( 0 time ) , 5 , 10 , 15 , 30 , 45 , and 60 mins ; at 2 , 4 , 6 , 8 , 10 , 12 , 14 , 16 , 18 , 20 , 22 , and 24 hrs ; and at the end of sedation . The assessment s included systolic , mean , and diastolic blood pressures , heart rate , two-lead electrocardiogram , pulse oximetry oxygen saturation , FIO2 , end-tidal CO2 , respiratory rate , ventilator rate , tidal volume , and sedation scale . Vital signs and the sedation scale were obtained at 30 , 60 , and 90 mins and at 2 , 4 , 12 , and 24 hrs after the end of sedation . At approximately 8 hrs and 24 hrs ( or at the end of sedation ) , the patient 's CO2 production was calculated over a 5-min interval . Every 4 hrs , the nurse would summarize and rate patient response during stimulation as well as the overall rating of the sedation and patient ability to tolerate the ICU setting . MAIN RESULTS There were no significant differences in pulse oximetry , arterial blood gas values , or respiratory measurements during sedation with propofol or midazolam . The mean heart rate was slower in the propofol group throughout the sedation and postsedation periods . The rating of sedation and tolerance of the ICU environment were significantly better for the propofol-treated group . Postsedation , the propofol group woke up faster on discontinuation of the sedative . CONCLUSIONS Propofol was as safe and as efficacious as midazolam for continuous intravenous sedation . The quality of sedation was better in the propofol group [8045143] To evaluate the efficacy of continuous infusions of lorazepam vs. midazolam for sedation in the intensive care unit ( ICU ) . Design : Prospect i ve , r and omized study . Setting : Large , urban university hospital . Patients : Twenty adult medical ICU patients receiving mechanical ventilatory support . Interventions : Patients were r and omized to receive either lorazepam or midazolam . The infusion rate was adjusted at the bedside by the ICU nurse according to a st and ardized study protocol to achieve and maintain sedation at Ramsay 's sedation level 2 or 3 . Measurements and Main Results : Ten patients were r and omized to receive lorazepam and ten to receive midazolam . The groups were similar in demographics , Acute Physiology and Chronic Health Evaluation ( APACHE ) II scores , ICU admission diagnosis , underlying disease processes , and supplemental analgesic administration . The mean time to achieve initial adequate sedation was 124 mins for lorazepam and 105 mins for midazolam . The mean infusion rate at the point of initial sedation was 0.06 mg/kg/hr for lorazepam and 0.15 mg/kg/hr for midazolam . The maximum and mean infusion rates for the entire study period were 0.1 and 0.06 mg/kg/hr , respectively , for lorazepam and 0.29 and 0.24 mg/kg/hr , respectively , for midazolam . The number of infusion rate adjustments per day was 1.9 mg/kg/hr for lorazepam and 3.6 mg/kg/hr for midazolam . Of the surviving patients , the mean time to return to baseline mental status after discontinuation of the benzodiazepine infusion was 261 mins for lorazepam and 1815 mins for midazolam . The mean volume of fluid per day required to deliver the maximum dose of benzodiazepine was 1.2 L for lorazepam ( maximum 2.4 L ) and 1.3 L for midazolam ( maximum 3.6 L ) . Conclusions : While there was a tendency to a longer time required for return to baseline mental status in patients receiving midazolam , this was not statistically signficant . Findings of interest concerning both midazolam and lorazepam were : a ) time to achieve sedation in medical ICU patients is often prolonged ; b ) actual dose requirements necessary to maintain sedation in this patient population are larger than the current literature describes ; c ) time to awaken after discontinuation of the infusion was occasionally delayed for > 24 hrs ; d ) large volumes of fluid were required to deliver these doses of drug via this route of administration . ( Crit Care Med 1994 ; 22:1241–1247 [8329251] We have compared the sedative and amnesic effects of midazolam and propofol in 35 volunteers . Sedation was measured by simple reaction time immediately before and after a bolus injection and 1 h after the commencement of a subsequent continuous infusion . Memory was measured three times using two memory tests : perceptual facilitation provided an implicit memory measure and recognition provided an explicit memory measure . Propofol and midazolam had similar sedative effects both immediately after bolus doses and after 1-h continuous infusions of the drugs . In contrast , midazolam had a more profound amnesic effect than propofol on the recognition memory test . The drugs had little effect on performance with the implicit memory test . Performance on the memory tests was unrelated to sedation [8686815] A comparison was made of the drug costs and nursing dependency of patients undergoing elective cardiac surgery and routine postoperative recovery for two anaesthetic techniques using either propofol with low dose fentanyl or midazolam with high dose fentanyl . Estimates of re source use were based on a r and omised clinical trial undertaken at the Northern General Hospital , Sheffield . Times from entry to the intensive care unit until extubation and discharge were recorded for 70 patients and were transformed to nursing shifts . Nursing dependency was calculated on the basis of one nurse per ventilated patient and 0.5 nurse from the start of the shift after extubation . Nursing costs were allocated on the basis of the patient 's status at the beginning of each shift in line with the hospital 's staffing policy . All drugs used from the morning of the operation until discharge were recorded . Costs of nursing and drugs were calculated . The total cost of patients in the propofol group was 13.3 % less than midazolam patients ( p = 0.043 , for geometric means Cl 0.4 % to 27.8 % ) . The clinical study was not design ed for economic endpoints ; however , it demonstrated achievable savings in propofol‐treated patients [8432154] The purpose of this study was to evaluate and compare the clinical effects , safety , and economic cost of propofol and midazolam in the sedation of patients undergoing mechanical ventilation in the ICU . Eighty-eight critically ill patients were studied and r and omly allocated to receive short-term ( less than 24 h ) , medium-term ( 24 h to 7 days ) , and prolonged ( more than 7 days ) continuous sedation with propofol ( n = 46 ) or midazolam ( n = 42 ) . Mean doses required were 2.36 mg/kg/h for propofol and 0.17 mg/kg/h for midazolam . Patients in the group receiving propofol showed a percentage of hours of sedation at the desired level ( grade 2 , 3 , 4 , or 5 on the Ramsay scale ) of 93 percent , compared with 82 percent ( p < 0.05 ) in the group receiving midazolam . Both agents were considered safe with respect to the induction of adverse reactions during their use in prolonged sedation . Recovery after interrupting sedation was significantly faster in patients treated with propofol than in those se date d with midazolam ( p < 0.05 ) . Recovery of total consciousness was predictable according to sedation time in propofol-treated subgroups ( r = 0.98 , 0.88 , and 0.92 , respectively ) , while this correlation was not observed in the midazolam-treated group . In the subgroup with sedation of less than 24 h , propofol provided a cost savings of approximately 2,000 pesetas ( pts ) per patient , due to shorter stays in the ICU . We conclude that propofol is a sedative agent with the same safety , higher clinical effectiveness , and a better cost-benefit ratio than midazolam in the continuous sedation of critically ill patients [9590313] OBJECTIVES To evaluate and compare the clinical efficacy , impact on hemodynamics , safety profiles , and cost of combined administration of propofol and midazolam ( synergistic sedation ) vs. midazolam and propofol administered as sole agents , for sedation of mechanically ventilated patients after coronary artery bypass grafting . DESIGN Prospect i ve , controlled , r and omized , double-blind clinical trial . SETTING Intensive care unit of SCIAS-Hospital de Barcelona . PATIENTS Seventy-five mechanically ventilated patients who underwent coronary artery bypass graft surgery under low-dose opioid anesthesia . INTERVENTIONS According to the double-blind method , patients were r and omly assigned to receive propofol ( n = 25 ) , midazolam ( n = 25 ) , or propofol combined with midazolam ( n = 25 ) . Infusion rates were adjusted to stay between 8 and 11 points on Glasgow Coma Score modified by Cook and Palma . MEASUREMENTS AND MAIN RESULTS Mean + /- SD duration of sedation was 14.4 + /- 1.5 hrs , 14.1 + /- 1.1 hrs , and 14.7 + /- 1.9 hrs for the propofol , midazolam , and synergistic groups , respectively . The induction dose was 0.55 + /- 0.05 mg/kg for propofol as sole agent , 0.05 + /- 0.01 mg/kg for midazolam as sole agent , and 0.22 + /- 0.03 mg/kg for propofol administered in combination with 0.02 + /- 0.00 mg/kg of midazolam ( p = .001 ) . The maintenance dose was 1.20 + /- 0.03 mg/kg/hr for propofol as sole agent , 0.08 + /- 0.01 mg/kg/hr for midazolam as sole agent , and 0.50 + /- 0.09 mg/kg/hr for propofol administered in combination with 0.03 + /- 0.01 mg/kg/hr of midazolam ( p < .001 ) . All sedative regimens achieved similar efficacy in percentage of hours of adequate sedation ( 93 % for propofol , 88 % for midazolam , and 90 % for the synergistic group , respectively ) . After induction , both propofol and midazolam groups had significant decreases in systolic blood pressure , diastolic blood pressure , left atrial pressure , and heart rate . Patients in the synergistic group had significant bradycardia throughout the study , without impairment in other hemodynamic parameters . Patients se date d with propofol or synergistic regimen awoke sooner and could be extubated before those patients se date d with midazolam ( 0.9 + /- 0.3 hrs and 1.2 + /- 0.6 hrs vs. 2.3 + /- 0.8 hrs , respectively , p = .01 ) . Synergistic sedation produced cost savings of 28 % with respect to midazolam and 68 % with respect to propofol . CONCLUSIONS In the study conditions , the new synergistic treatment with propofol and midazolam administered together is an effective and safe alternative for sedation , with some advantages over the conventional regimen with propofol or midazolam administered as sole agents , such as absence of hemodynamic impairment , > 68 % reduction in maintenance dose , and lower pharmaceutical cost [8605792] OBJECTIVES To evaluate and compare the clinical efficacy , impact on hemodynamic and oxygen transport variables , safety profiles , and cost efficiency of sedation and anxiolysis with lorazepam vs. continuous infusion of midazolam in critically ill , intensive care unit patients . DESIGN Multicenter , prospect i ve , r and omized , open-label study . SETTING Teaching hospitals . PATIENTS Ninety-five critically ill , mechanically ventilated patients with fiberoptic pulmonary artery catheters in place were r and omly assigned to receive short-term ( 8 hrs ) sedation with either intermittent intravenous injection lorazepam ( group A , n = 50 ) or continuous intravenous infusion midazolam ( group B , n = 45 ) titrated to clinical response . MEASUREMENTS AND MAIN RESULTS The severity of illness , demographic characteristics , levels of anxiety and agitation , hemodynamic parameters , oxygen transport variables , quality of sedation , nursing acceptance , and laboratory chemistries reflecting drug safety were recorded . There were no significant differences with regard to demographic data , hemodynamic and oxygen transport variables , or levels of anxiety/agitation between the two groups at baseline , 5 mins , 30 mins , and 4 and 8 hrs after administration of sedation . There were no significant differences in the quality of sedation or anxiolysis . Midazolam-treated patients used significantly larger amounts of drug for similar levels of sedation and anxiolysis ( 14.4 + /- 1.2 mg/8 hrs vs. 1.6 + /- 0.1 mg/8 hrs , p = .001 ) . Both drugs were safely administered and patient and nurse satisfaction was similar . CONCLUSIONS Sedation and anxiolysis with lorazepam and midazolam in critically ill patients is safe and clinical ly effective . Hemodynamic and oxygen transport variables are similarly affected by both drugs . The dose of midazolam required for sedation is much larger than the dose of lorazepam required for sedation , and midazolam is therefore less cost-efficient [2192570] Thirty‐seven patients with a wide range of illnesses were studied during mechanical ventilation of the lungs in an intensive care unit . Fifteen were se date d with a continuous propofol infusion , with analgesia provided by bolus doses of papaveretum . Twelve received a continuous infusion of papaveretum , supplemented by bolus doses of midazolam . The level of sedation was assessed every four hours and measurements were made of haemodynamic and respiratory variables . Levels of sedation were generally satisfactory in both groups . Six patients who received propofol required the use of muscle relaxants , because of their strong respiratory drives , to achieve synchronisation with the ventilator . There was no significant difference in respiratory or haemodynamic variables between the groups , but several patients required inotropic support because of their disease . There was no evidence of inhibition of adrenal steroidogenesis in the propofol group . Propofol can be a useful sedative agent in the intensive care unit , but sedative regimens should be tailored to individual patient requirements [10170449] Morphine + midazolam and alfentanil + propofol are regimens offering well tolerated and effective sedation for critically ill patients . However , morphine + midazolam is associated with accumulation in these patients , result ing in prolonged recovery characteristics . Alfentanil+propofol , although more expensive , has a shorter elimination half-life , is not associated with accumulation problems and results in a rapid recovery . This study compared sedation quality , patient recovery characteristics and the cost of alfentanil + propofol and morphine + midazolam for sedating critically ill patients in the intensive care setting . 26 patients were r and omly allocated to receive sedation with alfentanil + propofol ( n = 17 ) or morphine + midazolam ( n = 9 ) . Outcome measures were the times until extubation , intensive care unit ( ICU ) transfer and final hospital discharge . Cost analysis assessed both drug-related costs , including drug acquisition and administration , and non-drug-related costs , including bed occupancy . Age , gender , diagnosis , Acute Physiological and Chronic Health Evaluation ( APACHE ) II scores and sedation quality did not differ significantly between groups . The times to extubation and until patients were fit for transfer from ICU were significantly shorter for patients se date d with alfentanil + propofol than for those se date d with morphine + midazolam . The total costs ( at the time of the study Pounds 1 was equivalent to $ US1.59 ) for ICU hospital stay per patient for alfentanil + propofol and morphine + midazolam were 3063 Pounds and 9511 Pounds , respectively , because the shorter recovery characteristics of alfentanil + propofol led to a reduction in ICU stay . Corresponding costss for total hospital stay were 6063 Pounds and 13735 Pounds , respectively . In conclusion , alfentanil + propofol has a better pharmacoeconomic profile than morphine + midazolam for sedating critically ill patients in the ICU setting [2186650] One hundred adult patients who required mechanical ventilation after open heart surgery for coronary revascularisation were studied . All received a st and ard premedication and a high dose opioid anaesthetic . On arrival in the intensive care unit they were allocated r and omly to receive either propofol or midazolam to maintain sedation within a predetermined range . Patients who received propofol underwent extubation of the trachea , using st and ard criteria , after a mean time ( log‐transformed ) of 7.6 minutes after sedation for approximately 17 hours . The corresponding time was 125 minutes in those given midazolam . There were significantly higher morphine requirements during sedation , and higher arterial carbon dioxide tensions 30 minutes after extubation of the trachea , in patients who received midazolam . Pharmacokinetic analysis in 20 patients showed that the elimination half‐life of propofol was prolonged ( 470 minutes ) and clearance was reduced ( 1.14 litres/minute ) compared with subjects who had not undergone cardiopulmonary bypass . The rapid clinical recovery was reflected in a rapid redistribution half‐life ( 13.4 minutes ) , but this was also longer than the redistribution time of 2–4 minutes in other patients [7762918] Preamble Although economic outcomes research is an evolving field in health services research , there are correct and incorrect ways to conduct and report on economic outcomes studies . Research practice s that help to minimize real or perceived bias will increase the quality and usefulness of such studies for those who sponsor , publish , and use them . Because of public concerns about the potential for bias in the design , analysis , and reporting of economic analyses of health care technology , we formed a task force to develop principles to enhance the credibility of these studies . The Task Force on Principles for Economic Analysis of Health Care Technology included participants from academia , the pharmaceutical industry , the public sector , and private research organizations . As health care re sources become increasingly constrained , the information used to make re source allocation decisions must be as reliable , valid , and free of bias as possible . Getting it right at the level at which economic results are produced will help to protect consumers and will advance the health of the public . Bias stems from two broad categories : lack of appropriate independence for research ers and lack of consensus about methods . We focused heavily on the first of these categories for two major reasons . First , few have yet considered the unique issues of research er independence in economic outcomes research [ 1 , 2 ] . Second , other investigators have begun to consider and define proper methods for economic outcomes work ( an area of considerable controversy ) [ 3 - 5 ] . We also looked closely at the requirements for the reporting of economic analyses , which are intended to ensure method ologic transparency and accountability . The Need for Voluntary Guidelines Widespread use of economic analysis as part of the development of pharmaceutical , biotechnologic , and medical devices is relatively new . To date , many economic analyses of health care have focused on pharmaceutical agents , and many such studies have been funded by pharmaceutical companies . Results of these economic outcomes studies are used by medical technology firms to support the pricing and marketing of new interventions and to influence national health care systems and third-party payers in their development of coverage and payment decisions . Managed care organizations , hospitals , and government-subsidized health care programs rely on economic analysis of medical technology to help make formulary purchasing and utilization decisions . Physicians may use the results of these analyses to help guide treatment and prescription decisions . Health care economic outcomes projects are sponsored and conducted by pharmaceutical , biotechnologic , and medical device companies ; government agencies ; nonprofit foundations ; academic investigators ; and private research and consulting firms . The st and ards and methods used to evaluate the safety and efficacy of pharmaceutical products in r and omized , controlled trials have evolved over 50 years of collaboration among research ers in private , public , and academic setting s. Compared with those established to ensure the safety and efficacy of clinical trials , the principles and methods for the conduct of economic studies of health care technology are far less developed . Problems of conduct , reporting , and bias exist in all types of research [ 6 - 14 ] . In response , codes of conduct , such as those developed by the American Federation for Clinical Research and the Institute of Medicine , have been developed for many scientific disciplines [ 15 - 24 ] . These are good models on which to base principles of conduct for economic outcomes analysis . Although many published principles apply to economic studies , others should be modified and new ones should be developed to guide the conduct and reporting of economic outcomes analyses . Economic outcomes research requires unique guidelines for the following reasons : 1 ) As a field , it continues to evolve and is often misunderstood by end users ; 2 ) peer review of it requires special expertise that often exceeds the capabilities of review ers and scientific journals ; 3 ) it often uses secondary data and requires that many assumptions be made [ for example , attribution of a dollar cost to a unit of re source use ] ; 4 ) it offers unique method ologic choices , such as which types of costs to include ( direct , indirect , intangible , induced ) , which perspective to apply ( that of society , payer , provider , patient ) , which design to adopt ( cost- identification , costbenefit , cost-effectiveness , costutility ) , from where to obtain costs [ indemnity data base , managed care or capitated data base , hospital cost systems , Medicare , Medicaid ] , and whether to collect re source consumption data prospect ively or retrospectively through various modeling techniques ; and 5 ) economic studies play an increasingly important role in health care decision making because of increasing financial constraints throughout the health care industry . The financial and medical implication s of decision making done on the basis of these studies , coupled with the lack of widely accepted guidelines about the conduct and reporting of economic analyses , undermine the credibility of this research . A major issue is that the primary source of funding for this research is often the primary financial beneficiary of positive study results . Unfortunately , even valid studies done under the best of circumstances may be suspect [ 25 - 29 ] . This has led at least one major journal to conclude that these analyses should be viewed much like editorials or review articles are viewed in terms of potential for conflicts of interest [ 30 ] . We developed the guidelines reported here after extensive consultation with experts from the public , private , and academic sectors . We recommend that research ers and sponsors adhere to these guidelines , and we suggest they state publicly within their manuscripts that they have done so . End users , including journal editors and readers , consumers , and social decision makers , may then feel more secure in accepting the results of the research , while recognizing that intensive critique of the research will always be necessary . Operations of the Task Force The Task Force on Principles for Economic Analysis of Health Care Technology was initiated and organized by faculty from the Leonard Davis Institute ( LDI ) Center for Health Policy of the University of Pennsylvania . However , because not all LDI faculty were involved , this paper does not represent an official LDI position statement . The Task Force was funded by a coalition of pharmaceutical companies ( Appendix A ) . Funding was also requested ( but not obtained ) from various government and private foundations . All funding was provided in the form of unrestricted research grants or gifts to the University of Pennsylvania . Guidelines derive their credibility in part from the composition of the panel that creates them and the process by which they are developed . C and i date s for participation in the Task Force from the private sector and the academic research community were identified by the frequency with which they were cited in the health economics literature , which was obtained using a MEDLINE search of literature related to economic analyses of medical technology published between 1983 and 1992 . Approximately 15 members attended each meeting . Minutes were distributed after each meeting and approved by all members present . Members from the sponsoring pharmaceutical companies and the academic organizers rotated so that they numbered three and one , respectively , at the table for each formal Task Force meeting . Several professional and governmental organizations , including the Institute of Medicine , the Agency for Health Care Policy and Research , the Food and Drug Administration ( FDA ) , the Health Care Financing Administration , the Centers for Disease Control and Prevention , and a managed care organization , were asked to suggest persons who might participate . In addition , other organizations with a stake in economic analyses were each asked to suggest a person who , because of his or her professional background , had extensive knowledge of or experience with economic analyses . An academic pharmacist , an academic research er , a private research er , an ethicist and patient advocate , and an attorney specializing in medical ethics rounded out the Task Force ( Appendix B ) . Two members withdrew from participation . A small audience consisting of industry sponsors , academic organizers , staff , and a few other interested parties were invited to each meeting and allowed to comment . Four formal meetings of the Task Force were held in Philadelphia during 1993 and 1994 , and the most substantial work was done by various subcommittees between these meetings . The three main subcommittees were titled Ethical Conduct , Responsibility and Control ( the findings of these two subcommittees were later merged into one report ) , and Reporting Requirements for Economic Evaluations ( Appendix C ) . The Task Force was assisted by a professional facilitator . Although Task Force members sought consensus wherever possible on the key issues , consensus was not forced and recommendations were issued only when substantial agreement existed among the members . Task Force members were not asked to formally represent any organization . Formal endorsement of the final document was not sought . Copies of this report will be distributed to all organizations that were asked to suggest a participant and to other parties who responded to announcements placed in The New Engl and Journal of Medicine , Scrip , and the Pink Sheet . The Task Force findings will also be reported at academic conferences , medical profession meetings , and appropriate trade conventions . Findings and Recommendations Valid approaches to economic analyses can be defined ; acceptable methods can be differentiated from unacceptable ones . Bias in economic research stems from two major sources : lack of appropriate independence for [8989173] OBJECTIVE To compare the effectiveness of sedation , the time required for weaning , and the costs of prolonged sedation of critically ill mechanically ventilated patients with midazolam and propofol . DESIGN Open-label , r and omized , prospect i ve , phase IV clinical trial . SETTING Medical and surgical intensive care unit ( ICU ) in a community hospital . PATIENTS All ICU admissions ( medical , surgical and trauma ) requiring mechanical ventilation for > 24 hrs . A total of 108 patients were included in the study . INTERVENTIONS Patients were r and omized to receive midazolam or propofol . The dose range allowed for each drug was 0.1 to 0.5 mg/kg/hr for midazolam and 1 to 6 mg/kg/hr for propofol . The lowest dose that achieved an adequate patient-ventilator synchrony was infused . All patients received 0.5 mg/kg/24 hrs of morphine chloride . MEASUREMENTS AND MAIN RESULTS The level of sedation was quantified by the Ramsay scale every 2 hrs until weaning from mechanical ventilation was started . If sedation could not be achieved by infusing the highest dose of midazolam or propofol , the case was recorded as a therapeutic failure . In the propofol group , serum triglycerides were determined every 72 hrs . Concentrations of > 500 mg/dL were also recorded as a therapeutic failure . When the patient was ready for weaning according to defined criteria , sedation was interrupted abruptly and the time from interruption of sedation to the first T-bridge trial and to extubation was measured . Cost analysis was performed based on the cost of intensive care in our unit ( $ 54/hr ) . In the midazolam group ( n = 54 ) , 15 ( 27.8 % ) patients died ; 11 ( 20.4 % ) patients had therapeutic failure ; and 28 ( 51.8 % ) patients were subjected to a T-bridge trial . In the propofol group ( n = 54 ) , these proportions were 11 ( 20.4 % ) , 18 ( 33.4 % [ including seven due to inadequate sedation , and 11 due to hypertriglyceridemia ] ) , and 25 ( 46.2 % ) , respectively . None of these values was significantly different between the two groups . Duration of sedation was 141.7 + /- 89.4 ( SD ) hrs and 139.7 + /- 84.7 hrs ( p = NS ) , and cost ( US dollars ) attributed to sedation was $ 378 + /- 342 and $ 1,047 + /- 794 ( p = .0001 ) for the midazolam and propofol groups , respectively . In the midazolam group , time from discontinuation of the drug infusion to extubation was 97.9 + /- 54.6 hrs ( 48.9 + /- 47.2 hrs to the first disconnection , and 49.0 + /- 23.7 hrs to extubation ) . In the propofol group , time from discontinuation of the drug infusion to extubation was 34.8 + /- 29.4 hrs ( 4.0 + /- 3.9 hrs to the first disconnection , and 30.8 + /- 29.2 hrs to extubation ) . The difference between the two groups in the weaning time was 63.1 + /- 12.5 ( SEM ) hrs ( p < .0001 ) . Cost per patient in the midazolam group ( including ICU therapy and sedation with midazolam ) was $ 10,828 + /- 5,734 . Cost per patient in the propofol group was $ 9,466 + /- 5,820 , $ 1,362 less than in the midazolam group . CONCLUSIONS In our population of critically ill patients se date d with midazolam or propofol over prolonged periods , midazolam and propofol were equally effective as sedative agents . However , despite remarkable differences in the cost of sedation with these two agents , the economic profile is more favorable for propofol than for midazolam due to a shorter weaning time associated with propofol administration [8669676] Background Propofol sedation offers advantages for titration and rapid emergence in the critically ill patient , but concern for adverse hemodynamic effects potentially limits its use in these patients . The current study compares the cardiovascular effects of sedation with propofol versus midazolam during the first 12 h after coronary revascularization . Methods Three hundred fifty‐one patients undergoing coronary revascularization were anesthetized using a st and ardized sufentanil/midazolam regimen , and assigned r and omly to 12 h of sedation with either propofol or midazolam while tracheally intubated . The incidence and characteristics of hemodynamic episodes , defined as heart rate less than 60 or greater than 100 beats/min or systolic blood pressure greater than 140 or less than 90 mmHg , were determined using data electronically recorded at 1‐min intervals . The presence of myocardial ischemia was determined using continuous three‐channel Holter electrocardiography ( ECG ) and of myocardial infa rct ions ( MI ) using 12‐lead ECG ( Q wave MI , Minnesota Code ) or creatine kinase isoenzymes ( CK‐MB ) analysis ( non‐Q wave MI , peak CK‐MB > 70 ng/ml , or CK‐MB > 70 IU/l ) . Results Ninety‐three percent of patients in both treatment groups had at least one hemodynamic episode during the period of postoperative sedation . Propofol sedation result ed in a 17 % lower incidence of tachycardia ( 58 % vs. 70 % , propofol vs. midazolam ; P = 0.04 ) , a 28 % lower incidence of hypertension ( 39 % vs. 54 % ; P = 0.02 ) , and a greater incidence of hypotension ( 68 % vs. 51 % ; P = 0.01 ) . Despite these hemodynamic effects , the incidence of myocardial ischemia did not differ between treatment groups ( 12 % propofol vs. 13 % midazolam ; P = 0.66 ) , nor did its severity , as measured by ischemic minutes per hour monitored ( 8.7+/‐5.8 vs. 6.2+/‐4.6 min/h , propofol vs. midazolam ; P = 0.19 ) or ischemic area under the curve ( 6.8+/‐4.0 vs. 5.3+/‐4.2 ; P = 0.37 ) . The incidence of cardiac death ( one per group ) , Q wave MI ( propofol , n = 7 ; midazolam , n = 3 ; P = 0.27 ) , or non Q wave MI ( propofol , n = 16 ; midazolam , n = 18 ; P = 0.81 ) did not differ between treatment groups . Conclusions Hemodynamic episodes occur frequently in the first 12 h after coronary revascularization . Compared with a st and ard sedation regimen ( midazolam ) , propofol sedation appears to modulate postoperative hemodynamic responses by reducing the incidence and severity of tachycardia and hypertension and increasing the incidence of hypotension . Both sedation regimens appear similarly safe with respect to myocardial ischemia . These findings indicate that propofol infusion provides effective sedation without deleterious hemodynamic effects in patients recovering from cardiac surgery [1874212] Forty-four patients , with admission APACHE II scores between 5 and 24 , undergoing mechanical ventilation in the intensive therapy unit , received a sedative regimen consisting of continuous infusions of propofol and alfentanil . Patients were r and omly allocated to one of three groups to receive either alfentanil 0.25 microgram kg-1 min-1 ( 10 patients ) , 0.50 microgram kg-1 min-1 ( 15 patients ) or 0.75 microgram kg-1 min-1 ( 18 patients ) for analgesia . An infusion of propofol 20 - 200 mg h-1 ran concurrently to maintain a satisfactory level of sedation . Patients received the infusions for between 4 and 260 h and 38 patients spent more than 90 % of this time at satisfactory sedation levels . After stopping the infusions all patients had short times to wakening ( mean 3 - 18 min ) and to establish spontaneous respiration ( mean 8 - 28 min ) , suggesting no significant cumulation . Some depression of blood pressure was seen on starting the infusions , which was in general easily treated with fluids or small increases in inotropic agents . One patient , however , was withdrawn from the trial because of haemodynamic instability . This combination of drugs can be recommended for sedation of general intensive-therapy patients , provided the cost is not felt to be prohibitive [9620508] Previous studies have compared sedation profiles with midazolam ( Mz ) and propofol ( Pf ) , particularly in heterogeneous population s of patients .Decreases in blood pressure and heart rate have been reported after the administration of propofol . These side effects are potentially deleterious in severe trauma patients , particularly in patients with head trauma . To assess the safety and efficacy of Mz and Pf , alone or in combination , in the prolonged sedation of severe trauma patients , we design ed a prospect i ve , controlled , r and omized , study . One hundred consecutively admitted trauma patients requiring mechanical ventilation and sedation for more than 48 h were studied . Patients were se date d according to three different protocol s based on the continuous IV administration of Mz alone , Pf alone , and Mz in combination with Pf . All patients received morphine chloride . Safety and efficacy were assessed during the sedation and wake-up periods according to clinical and laboratory variables . Cerebral hemodynamics were also studied in patients with head trauma . Patients were se date d for 6.3 + /- 4.0 days ( mean + /- SD ) . All three sedation regimens were equally efficacious in achieving the desired sedation goal . The incidence of adverse events during the sedation period was also similar . In head trauma patients with intracranial pressure ( ICP ) monitoring , we did not find differences in ICP , cerebral perfusion pressure , or jugular venous oxygen saturation among the three groups . The serum triglyceride concentration was significantly higher in the Pf group . Wake-up time was significantly shorter in the Pf group . We conclude that both Mz and Pf are safe and efficacious in the sedation of severe trauma patients . The use of Pf in these patients is associated with a high incidence of hypertriglyceridemia and a shorter wake-up time . Implication s : In a prospect i ve , controlled , r and omized study , we confirmed the safety and efficacy of midazolam and propofol , alone or in combination , in the prolonged sedation of a homogeneous group of severe trauma patients , particularly in patients with head trauma . The propofol group had shorter wake-up times and higher triglyceride levels . ( Anesth Analg 1998;86:1219 - 24 [2058827] This study was undertaken to compare two regimens for analgesic sedation in intensive care patients with exogenous catecholamine therapy , giving special regard to catecholamine dem and and hemodynamic parameters . A total of 20 ventilated patients in a surgical intensive care unit were investigated in a prospect ively r and omized design . Exogenous catecholamine therapy with epinephrine and /or norepinephrine was started at systolic pressure ( SAP ) less than 85 mmHg or mean arterial pressure ( MAP ) less than 65 mmHg to maintain cardiovascular function . For analgesic sedation , patients received bolus injections of about 0.2 mg/h fentanyl and 2.5 mg/h midazolam ( fentanyl group , n = 10 ) or an infusion of about 50 mg/h ketamine and 2.5 mg/h midazolam by syringe pump ( ketamine group , n = 10 ) . Before the investigation , all patients received fentanyl and midazolam . The study period was 48 h. During the course of the study , mean catecholamine dosage increased significantly in the fentanyl group from 12.1 to 16.3 micrograms/min ( + 33 % , P = 0.003 ) . In the ketamine group , mean catecholamine dosage decreased from 43.9 to 38 micrograms/min ( -13 % , P = 0.19 ) . No significant differences in group levels or time course were observed with regard to MAP , heart rate , cardiac index , pulmonary capillary wedge pressure , and shunt volume . Levels of pulmonary artery pressure ( PAP ) were comparable in both groups ( ketamine group 29 mmHg , fentanyl group 26 mmHg ) . In time course , PAP increased by about 5 mmHg in the ketamine group but not in the fentanyl group ( P = 0.009 ) . The average central venous pressure ( CVP ) was 12 mmHg in both groups . At the end of the investigation , CVP decreased in the fentanyl group and increased in the ketamine group ( P = 0.0001 ) . ( ABSTRACT TRUNCATED AT 250 WORDS [9356086] The influence of light versus heavy sedation after coronary artery bypass graft ( CABG ) surgery on the development of postoperative myocardial ischemia has not been described . After uncomplicated CABG surgery , 50 patients were r and omly assigned to receive LOW ( n = 24 ; target Ramsay Sedation Score [ RSS ] = 2 ) or HIGH ( n = 26 ; target RSS = 4 ) sedation with propofol . Analgesia was provided to maintain a visual analog scale ( VAS ) pain score < 7 . Myocardial ischemia was identified perioperatively using continuous 3-lead Holter monitoring . By measuring creatine kinase ( CK ) MB levels preoperatively , at entry to the intensive care unit ( ICU ) , and every 12 h for 48 h ; and by obtaining serial 12-lead electrocardiograms ( ECG ) ( preoperatively ; 2 , 4 , 12 , 24 , and 48 h after ICU admission , 8:00 AM the morning after surgery ; and 5 min pre- and postextubation ) , myocardial infa rct ion was identified . Endocrine stress response was assessed by measuring serum cortisol levels preoperatively , on admission to the ICU , and 24 h postoperatively . In a subset of patients ( LOW n = 10 , HIGH n = 11 ) , plasma and urinary catecholamine levels were also measured . There were no between-group differences in demographics , operative course , hemodynamic variables , or cortisol levels while in the ICU . The VAS pain score and target RSS were achieved and sustained , and they differed between groups . There were three myocardial infa rct ions in each group by CKMB criteria alone . No ECG-identifiable myocardial infa rct ion occurred . The ST segment versus time curve ( LOW 187 + /- 295 versus HIGH 1071 + /- 2137 mm/min ) differed between groups . Urinary and plasma catecholamine levels were similar between groups over the observation period . We conclude that the use of a reduced sedation regimen in combination with adequate analgesia did not result in an increased endocrine stress response or risk of myocardial ischemia . Implication s : This r and omized study of patients after coronary artery bypass surgery examined whether light ( versus heavy ) sedation with propofol in the intensive care unit was associated with an increased degree of myocardial ischemia . Using techniques to detect myocardial ischemia , including Holter monitoring , electrocardiogram , and myocardial enzyme measurements , no differences were found . We conclude that light sedation does not increase the endocrine stress response or the risk of myocardial infa rct ion . ( Anesth Analg 1997;85:971 - 8 [3580237] Midazolam given as hourly intermittent injections was compared with the same dose given by infusion for postoperative sedation in patients after cardiopulmonary bypass . A stable concentration was rapidly attained with the infusion whereas 6 - 8 h was required to attain stable plasma ( trough ) concentrations in the intermittent injection group . Plasma concentrations decreased rapidly to low values within 6 h of discontinuation of therapy . High plasma concentrations and a long ( 16 h ) half-life were noted in one patient who may be a slow metabolizer of the drug [2500195] OBJECTIVE --To compare isoflurane with midazolam for sedation of ventilated patients . DESIGN --R and omised control study . Setting --Intensive care unit in university teaching hospital . PATIENTS --Sixty patients aged 18 - 76 who required mechanical ventilation . INTERVENTIONS --Sedation with either 0.1 - 0.6 % isoflurane in an air-oxygen mixture ( 30 patients ) or a continuous intravenous infusion of midazolam 0.01 - 0.20 mg/kg/h ( 30 patients ) . Sedation was assessed initially and hourly thereafter on a six point scale . Incremental intravenous doses of morphine 0.05 mg/kg were given for analgesia as required . The trial sedative was stopped when the patient was judged ready for weaning from ventilatory support or at 24 hours ( whichever was earlier ) . END POINT -- Achievement of a predetermined level of sedation for as much of the time as possible . MAIN RESULTS --Isoflurane produced satisfactory sedation for a greater proportion of time ( 86 % ) than midazolam ( 64 % ) , and patients se date d with isoflurane recovered more rapidly from sedation . CONCLUSION --Isoflurane is a promising alternative technique for sedation of ventilated patients in the intensive care unit [1636917] Sedative-analgesic treatment of patients on long-term artificial ventilation aims at protection from stress related to their disease or therapy . By stabilising both the patient 's vital functions and psychological state this treatment may contribute to therapeutic success . The choice of drugs depends primarily on the nature and course of the underlying disease . Midazolam and propofol are available as hypnotics for short-term sedation during the post-operative period . The purpose of this study was to evaluate the effects of both agents on cardiovascular function , cortisol production , lipometabolism , and the recovery period following 24-h sedation . METHODS . Twenty female patients ( mean body weight : 72 kg , mean age : 60 years ) were r and omly assigned to receive either midazolam or propofol over 24 h following major abdominal surgery . Balanced anaesthesia ( halothane/O2/N2O/fentanyl ) was administered for the surgical procedure . Assisted ventilation was used in all patients during the post-operative sedation period . Sedation depth was maintained at III-IV on the Ramsey scale . On arrival in the intensive care unit ( ICU ) , an initial i.v . bolus of midazolam 0.1 mg/kg or propofol 1 mg/kg was followed by a continuous infusion ( midazolam : 0.1 mg/kg.h ; propofol : 2 mg/kg.h ) . Supplementary boluses of one-half the initial dose were given if required . Post-operative analgesia was achieved with 3 mg intravenous piritramide at 2-h intervals . A 7F Swan-Ganz catheter was inserted in the pulmonary artery and haemodynamic and biochemical parameters were monitored at 4-h intervals over 24 h starting 2 h after arrival in the ICU . Catecholamines were measured by high-pressure lipid chromatography ( HPLC ) , cortisol by radioimmunoassay , midazolam by HPLC and ultraviolet detection , and propofol by HPLC and fluorescence detection . Data were calculated as means . The statistical analysis was performed according to the Mann-Whitney test , and significance was accepted for P less than 0.05 . RESULTS . On administration of the propofol bolus at the onset of sedation , a decrease in blood pressure was particularly observed in patients with masked hypovolaemia , however , this decrease was easily controlled by volume administration . Independent of the type of sedation , the haemodynamic parameters remained unchanged throughout the observation period . At all times of measurement the mean heart rate was lower in the propofol group ( 90/min ) when compared with the midazolam group ( 100/min ) , however , this difference did not reach significance . There were also no significant differences in cardiac index at all times of measurement , although it increased in both groups within the first 12 h by 0.6 l/min.min2 . In both groups this increase was associated with a reduction in peripheral resistance and an increase in rectal temperature . To achieve the desired sedation depth , midazolam was administered at a mean dosage of 0.11 mg/kg.h and propofol at 1.9 mg/kg.h . Catecholamine levels decreased in both groups within the first 8 h : after 8 h of sedation the plasma levels of noradrenaline and adrenaline were 525 and 65 pg/ml , respectively , in the midazolam group and 327 and 51 pg/ml in the propofol group . ( ABSTRACT TRUNCATED AT 400 WORDS [9105222] Background : Cardiopulmonary bypass is associated with substantial release of catecholamines and cortisol for 12 or more h. A technique was assessed that may mitigate the responses with continuous 12‐h postoperative sedation using propofol . Methods : One hundred twenty‐one patients having primary elective cardiopulmonary bypass graft ( CABG ) surgery were enrolled in a double‐blind , r and omized trial and anesthetized using a st and ardized sufentanil‐midazolam regimen . When arriving at the intensive care unit ( ICU ) , patients were r and omly assigned to either group SC ( st and ard care ) , in which intermittent bolus administration of midazolam and morphine were given as required to keep patients comfortable ; or group CP ( continuous propofol ) , in which 12 h of continuous postoperative infusion of propofol was titrated to keep patients deeply se date d. Serial perioperative measurements of plasma and urine cortisol , epinephrine , norepinephrine , and dopamine were obtained ; heart rate and blood pressure were recorded continuously , and medication use , including requirements for opioids and vasoactive drugs , was recorded . Repeated‐ measures analysis was used to assess differences between study groups for plasma catecholamine and cortisol levels at each measurement time . Results : In the control state‐before the initiation of postoperative sedation in the ICU‐no significant differences between study groups were observed for urine or plasma catecholamine or cortisol concentrations . During the ICU study period , for the first 6–8 h , significant differences were found between study groups SC and CP in plasma cortisol ( SC = 28 + /‐ 15 mg/dl ; CP = 19 + /‐ 12 mg/dl ; estimated mean difference [ EMD ] = 9 mg/dl ; P = 0.0004 ) , plasma epinephrine ( SC = 132 + /‐ 120 micro gram/ml ; CP = 77 + /‐ 122 micro gram/ml ; EMD = 69 micro gram/ml ; P = 0.009 ) , urine cortisol ( SC = 216 + /‐ 313 micro gram/ml ; CP = 93 + /‐ 129 micro gram/ml ; EMD = 127 micro gram/ml ; P = 0.007 ) , urine dopamine ( SC = 85 + /‐ 48 micro gram ; CP = 52 + /‐ 43 micro gram ; EMD = 32 micro gram ; P = 0.002 ) , urine epinephrine ( SC = 7 + /‐ 8 micro gram ; CP = 4 + /‐ 5 micro gram ; EMD = 3 micro gram ; P = 0.009 ) , and urine norepinephrine ( SC = 24 + /‐ 14 mg ; CP = 13 + /‐ 9 mg ; EMD = 11 mg ; P = 0.0004 ) . Reductions in urine and plasma catecholamine and cortisol concentrations found for the CP group generally persisted during the 12‐h propofol infusion period and then rapidly returned toward control ( SC group ) values after propofol was discontinued . Postoperative opioid use was reduced in the CP group ( SC = 97 % ; CP = 49 % ; P = 0.001 ) , as was the incidence of ( SC = 79 % ; CP = 60 % ; P = 0.04 ) and hypertension ( SC = 58 % ; CP = 33 % ; P = 0.01 ) , but the incidence of hypotension was increased ( SC = 49 % ; CP = 81 % ; P = 0.001 ) . Conclusions : Cardiopulmonary bypass graft surgery is associated with substantial increases in plasma and urine catecholamine and cortisol concentrations , which persist for 12 or more h. This hormonal response may be mitigated by a technique of intensive continuous 12‐h postoperative sedation with propofol , which is associated with a decrease in tachycardia and hypertension and an increase in hypotension

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### Context: [8281590] It is often necessary to adjust a patient ’s sedation level while they are in the intensive care unit . The purpose of this study was to compare propofol with midazolam for controlling short-term alterations in sedation . Twenty-three patients undergoing an interactive procedure , physiotherapy , during mechanical ventilation of the lungs were studied . The patients were r and omly assigned to receive infusions of propofol or midazolam for sedation . Sedation was assessed using the method of Ramsay , where 3 is drowsy responding only to comm and s ; and 5 is asleep with a slow response to light glabellar tap . Prior to physiotherapy sedation was deepened from 3 to 5 by increasing the sedative infusion rate , and level 5 was maintained during physiotherapy by adjusting the infusion rate whenever necessary . After physiotherapy , the sedative dose was reduced until level 3 was again achieved . During physiotherapy , sedation level 5 was achieved for 53.9 % of the time with propofol but for only 25.7 % with midazolam ( P < 0.01 ) . After physiotherapy , those patients se date d with propofol re-awakened to level 3 faster ( 8.3 ± 2.3 min , mean ±SE ) than those receiving midazolam ( 92.8 ± 35.0 min , P < 0.05 ) . After physiotherapy , a further 1.8 ± 0.5 dose adjustments were required to the midazolam infusion while only 0.4 ± 0.2 adjustments were required to the propofol infusion ( P < 0.05 ) . During physiotherapy 3.0 ± 0.5 dose adjustments to the propofol dose were required compared with 3.6 ± 0.5 adjustments to the midazolam dose ( NS ) . It is concluded that , during a st and ardized stimulus , physiotherapy , propofol infusion allowed a desired sedation score to be maintained for more of the time than did infusion of midazolam . Subsequently , when the infusion rates were reduced , less time was taken to re-awaken to baseline levels after physiotherapy , with fewer adjustments to the infusion rate , in those patients receiving propofol than midazolam . RésuméAux soins intensifs , il faut fréquemment modifier le niveau de sédation ; cette étude compare le propofol au midazolam pour contrôler ces changements de courte durée . Vingt-trois patients sous ventilateur mécanique soumis à des manoeuvres de physiothérapie interactive sont inclus dans l’étude . Ils reçoivent au hasard en sédation une perfusion de profopol ou de midazolam . La sédation est évaluée selon l’échelle de Ramsey ; on accorde 3 pour la somnolence avec réponse aux ordres et 5 au sommeil avec réponse lente à la légère percussion de la glabelle . Avant la physiothérapie , la sédation est approfondie du niveau 3 au niveau 5 en augmentant la perfusion au besoin . Après la physiothérapie , on réduit la perfusion jusqu’au retour au niveau 3 . Pendant la physiothérapie , le niveau 5 est atteint pendant 53,9 % de la durée du traitement avec le propofol contre seulement 25,7 % avec le midazolam ( P < 0,01 ) . Après la physiothérapie , les patients sous propofol reviennent au niveau 3 plus rapidement ( 8,3 ± 2,3 min , moyenne ± SD ) que ceux qui reçoivent du midazolam ( 92,8 ± 35,0 min , P < 0,05 ) . Après la physiothérapie , le dosage de midazolam nécessite 1,8 ± 0.5 ajustements comparativement à 0,4 ± 0,2 pour le propofol ( P < 0,05 ) . Pendant la physiothérapie , la posologie du propofol doit être ajustée 3,0 ± 0,5 fois comparativement à 3,6 ± 0,5 pour celle du midazolam ( NS ) . En conclusion , pendant une stimulation st and ardisée , la perfusion de propofol permet de maintenir le niveau de sédation désiré plus souvent que la perfusion de midazolam . Par la suite , lorsqu’on diminue la perfusion , le temps requis pour le retour à la ligne de base nécessite moins d’ajustements pour le propofol que pour le midazolam [2841885] UNLABELLED It was the aim of this study to compare two regimens for sedation and analgesia during ventilator treatment in intensive care patients . Special regard was given to endocrine stress response , neuro-monitoring , hemodynamic parameters and clinical practicability . METHODS A total number of 16 patients of an operative ICU were r and omly allocated to the following groups : ( 1 ) Fentanyl-group , approximately 0.2 mg/h fentanyl , 2.5 mg/h midazolam and 2 mg/h pancuronium in intermittent doses , ( 2 ) ketamine-group , about 50 mg/h ketamine and 2.5 mg/h midazolam by syringe pump , in addition 2 mg/h pancuronium . During a period of 2 days and in intervalls of 6 h , plasma levels of epinephrine and norepinephrine ( by HPLC/ECD ) , ADH , ACTH and cortisol ( by RIA ) , ketamine ( by GC ) and stress-metabolites ( glucose , lactate , free glycerol ) were determined . Hemodynamic parameters were investigated in intervalls of 12 h , EEG ( Compressed Spectral Array , CSA ) in intervalls of 24 h. In addition , routine laboratory data , vigilance and adaptation to the respirator were observed . RESULTS Plasma levels of adrenaline , noradrenaline , dopamine , ADH , ACTH , cortisol and stress-metabolites were comparable in both groups . Levels of ADH , ACTH , cortisol and free glycerol did not leave the normal range . In three patients , in which epinephrine- or norepinephrine-infusions were necessary to improve cardiocirculatory stability , this treatment could be finished after beginning of the ketamine application . In both groups , CSA showed a dominant delta- und theta-activity according to the clinical aspects of sufficient sedation and analgesia . Hemodynamic parameters were comparable in both groups . ( ABSTRACT TRUNCATED AT 250 WORDS [1539785] A 2 % solution of propofol has been compared with the 1 % formulation for sedation in patients whose lungs were being mechanically ventilated in an intensive care unit following coronary artery bypass surgery . There were no significant differences in the amount of propofol used in the two groups , the rate of propofol infusion or the number of changes made to the infusion rate to maintain the desired level of sedation . Recovery times and times to tracheal extubation were similar . The mean heart rates of those receiving 2 % propofol were significantly higher throughout the period of the study for no apparent reason . Propofol 2 % was found to be safe , easy to administer and a practical alternative to the 1 % solution for sedating cardiac surgical patients [10150550] A r and omised crossover study was undertaken to compare the quality and cost of controlled versus empirical sedation with midazolam in critically ill patients . Patients ( n = 40 ) entering the ICU were enrolled provided they satisfied the strict entry criteria . During 90 hours of midazolam sedation , patients received r and omly allocated 10-hour periods of controlled or empirical sedation . With empirical sedation , the mean dose of midazolam and the cost of sedation were almost double those with controlled sedation . The quality of sedation was superior with the controlled method . In a separate study on 352 patients , a cost-benefit analysis of controlled sedation with midazolam or propofol infusion or bolus injections of morphine plus diazepam showed that the quality of sedation achieved with propofol was superior to the other two regimens and that , with morphine plus diazepam , the quality of sedation was unacceptably poor . Although the direct purchase price of propofol was higher than that of other agents , the total cost of sedation with propofol was lower than that for midazolam for short-term intensive care ( less than 24 hours ) and comparable to midazolam for longer-term use . However , indirect benefits of sedation with propofol include a much shorter ICU stay with the attendant reduced nursing costs and greater throughout the patients , and this more than compensates for the higher purchase price of the agent [9142583] Objective : The assessment of propofol to produce diurnal sedation in critically ill patients Design : Prospect i ve clinical study Setting : Intensive Care Unit , University Hospital Patients and participants : Thirty consecutive patients admitted to the Intensive Care Unit older than 18 years who were expected to be se date d for more than 50 h Interventions : The patients were r and omised into two groups . All received sedation with a constant background infusion of morphine and a variable infusion rate of propofol , which was altered hourly to maintain the intended sedation score . The first group received constant light sedation ( CLS ) over 50 h aim ing for a Ramsay score of 2–3 . The second group received CLS between 0600 h and 2200 h and additional night sedation ( ANS ) with propofol between 2200 h and 0600 h , aim ing for a sedation score of 4–5 . Measurements and results : Patients were studied for 50 h from 1800 h on the first day of admission . Recordings of heart rate , blood pressure , sedation scores and propofol and morphine infusion rates were made hourly . An APACHE II score was recorded for each patient . Sedation scores were analysed by blind visual assessment and cosinor analysis , which is used in chronobiology to examine the correlation of data with a cosine curve . Patients in the ANS group had significantly better rhythmicity of sedation levels using cosinor analysis ( r = 26 % v 8 % ) p < 0.01 . There was no difference between the CLS and ANS groups with respect to age , sex or APACHE II scores . Nine out of 15 patients in the ANS group achieved diurnal sedation . Three patients in the CLS group showed diurnal rhythmicity of sedation , which can be attributed to natural sleep , and had a median APACHE II score of 12 . Five patients in the CLS group and three in the ANS group showed a deep constant sedation pattern . They had high APACHE II scores ( median 21.5 ) and an obtunded conscious level on admission due to severe sepsis . Conclusion : Propofol can safely provide diurnal sedation in the critically ill when titrated against the Ramsay score . Sedation levels can not be manipulated in some severely ill patients [2876719] Sedation was studied in 30 patients requiring overnight ventilation in the intensive therapy unit ( ITU ) . Patients received an infusion of either alfentanil or pethidine , supplemented with midazolam . The infusion rates were adjusted to provide optimal sedation as judged by a nurse , and measurements were made of quality of sedation , recovery and serum cortisol concentration . In addition , blood concentrations of alfentanil were measured to permit pharmacokinetic and pharmacodynamic analysis . Satisfactory sedation was achieved in both groups . The required infusion rate for alfentanil was between 0.4 and 0.5 micrograms kg-1 min-1 . Recovery was good in both groups , apart from one patient in the alfentanil group , in whom recovery was greatly prolonged and alfentanil pharmacokinetics were abnormal . A difference was found in the metabolic response to surgery between the two groups , the response in the alfentanil group being significantly less marked [8630539] Propofol ( P ) and midazolam ( M ) are frequently given by continuous infusion for sedation in critically ill , mechanically ventilated patients . We compared these drugs with regard to : ( 1 ) time-to-awaken ; ( 2 ) reproducibility of bedside assessment s of level of sedation ; ( 3 ) time-to-sedation ; and ( 4 ) change in oxygen consumption ( V O2 ) from awake to se date d state . Seventy-three patients were prospect ively r and omized to receive either P ( n=37 ) or M ( n=36 ) . Wake-up times after stopping the drug were assessed by blinded and unblinded observers , by asking patients to perform simple tasks . Times to se date were assessed by consensus agreement among nurses and investigators . Demographics and APACHE II scores were not different between P and M. The P group had a significantly narrower range of wake-up times with a higher likelihood of waking in less than 60 min . Blinded versus unblinded observations had excellent correlation . Average time to se date and decrease in V O2 were not different . We conclude that in this patient population : ( 1 ) both P and M achieved optimal sedation in a large fraction of patients when administered by specified dosing protocol s ; ( 2 ) P had a faster , more reliable , wake-up time ; ( 3 ) assessment s of time-to-awaken were objective and reproducible ; ( 4 ) time to sedation was not significantly different ; ( 5 ) V O2 decreased similarly with both [9187783] Purpose The purpose of this r and omized , double-blind study was to evaluate the efficacy of midazolam and propofol for postoperative sedation and early extubation following cardiac surgery . Methods ASA physical status II-III patients scheduled to undergo elective first-time cardiac surgery with an ejection fraction > 45 % were eligible . All patients received a st and ardized sufentanil/isoflurane anaesthesa . Dunng cardiopulmonary bypass 100 μg · kg−1 · mm−1 propofol was substituted for isoflurane . Upon amval in the Intensive Care Unit ( ICU ) . patients were r and omized to either 10 μg · kg · min−1 propofol ( n = 21 ) or 0.25 μg · kg · mm−1 midazolam ( n = 20 ) . Infusion rates were adjusted to maintain sedation within a predetermined range ( Ramsay 2–4 ) . The infuson was terminated after four hours . Patients were weaned from mechanical ventilation and their tracheas extubated when haemodynamic stability , haemostasis , normothermia and mental orientation were confirmed . Haemodynamic measurements , artenal blood gas tensions and pulmonary function tests were recorded at specified times . Results There were no differences between the two groups for the time spent at each level of sedation , number of infusion rate adjustments , amount of analgesic and vasoactive drugs , times to awakening and extubation . The costs of propofol were higher than those of midazolam . There were no differences in haemodynamic values , artenal blood gas tensions and pulmonary function . Conclusion We conclude that midazolam and propofol are safe and effective sedative agents permitting early extubation in this selected cardiac patient population but propofol costs were higher . RésuméButLe but de cette étude r and omisée , à double insu était d’évaluer l’efficacité du midazolam et du propofol pour sédation postopératoire en vue d’une extubation précoce postchirurgie cardiaqueMéthodologieTout patient ASA II-III admis pour une première chirurgie cardiaque élective ayant une fraction d’éjection > 45 % était éligible . Tous les patients ont reçu une anesthésie st and ard à base de sufentanil/isoflurane . Durant la circulation extracorporelle , le propofol ( 100μg · kg−1 · min−1 ) a été substitué à l’isoflurane . Dès l’arnvée aux soins intensifs , les patients furent r and omisés soit au propofol ( n = 21)à 10 μg · kg−1 · mm−1 sort au midazolam ( n = 20 ) 0.25 μg · kg−1 · mm−1 . Les débits de perfusion étaient ajustés pour maintenir un niveau de sédation prédéterminée ( Ramsay 2–4 ) . La perfusion était cessée après quatre heures . Les patients étaient sevrés de la ventilation mécanique et extubés lorsque la stabilité hémodynamique , l’hémostase , la normothermie et l’orientation mentale étaient confirmées . Des bilans hémodynamiques , gaz arténels et fonction pulmonaire furent enregistrés à des intervalles spécifiques . RésultatsIl n’y avait pas de différence entre les groupes pour le temps occupé aux différents niveaux de sédation , d’ajustement de perfusion , le temps d’éveil et d’extubation . Le coût du propofol était plus élevé que celui du midazolam . La dem and e d’analgésique et l’utilisation d’agents vasoactifs étaient similaires . Aucune différence de fonction pulmonaire , gaz arténels et hémodynamique n’a été décelée . Conclusion Nous concluons que le midazolam et le propofol sont sécuritaires et efficaces comme agents de sédation permettant une extubation précoce pour ce groupe de patients cardiaques sélectionnés mais le coût du propofol est plus élevé [8205830] Objectives To describe the variety of medications prescribed along with the doses administered and routes of administration , and to delineate the clarity of orders written and the accuracy of transcription of drugs used for sedation , anxiety , pain , and neuromuscular blockade in a surgical intensive care unit ( ICU ) . Design A prospect i ve , observational study of drug-related information collected from forms used by physicians and nurses . Setting Three adult surgical ICUs at an academic medical center . Patients were admitted to a surgical service and co-managed by the surgical ICU team and primary surgical service . Patients Consecutive patients admitted to all of these units from September 1992 to January 1993 . Interventions None . Measurements and Main Results Information on prescribing and administering sedatives , analgesics , and neuromuscular blocking drugs was obtained from data collected on 221 patients . A total of 202 ( 91 % ) patients received , on average , 1.9 ± 1.4 study drugs ( range 0 to 9 ) in a wide variety of combinations . There were 2,103 total doses administered from 448 drug orders . Ninety percent of study drug orders were written for administration on an “ as-needed ” basis ; in 42 % of these orders , the indication for use was not specified . On average , only 27 % of the maximal allowable daily dose was administered ; this number ranged from 15 % for hydromorphone to 77 % for chlordiazepoxide . Morphine sulfate , the most commonly prescribed drug , was ordered primarily for intravenous administration in 84 % of patients . Morphine sulfate was prescribed using 19 different doses ( written as a range of doses ) and 13 different dosing intervals . Transcription discrepancies were observed in 17 % of orders . In 2.7 % of doses , the actual dose that was administered could not be determined . Conclusions A wide variety of sedatives and analgesics are frequently used in surgical ICU patients . These agents are often ordered on an “ as-needed ” basis using a range of doses , sometimes without adequate directions about the indication for their use . Daily doses received are significantly less than their maximum allowable daily doses . Orders for these medications are sometimes transcribed and charted incorrectly . In contrast , neuromuscular blocking agents are not commonly prescribed . Future studies are needed to improve order writing of these agents , and to determine the criteria used by physicians and nurses in the selection and administration of these agents , the outcomes of therapy , and the most cost-effective regimen . ( Crit Care Med 1994 ; 22:974–980 [8681594] OBJECTIVES To compare the effectiveness , characteristics , duration of action , hemodynamic and biochemical effects , and side effects of propofol and midazolam used for continuous intravenous sedation of ventilated critically ill patients . DESIGN Multicenter , prospect i ve , r and omized , nonblinded study . SETTING Nine Spanish general intensive care units ( ICUs ) . PATIENTS Ninety-eight patients admitted to the ICU who were mechanically ventilated and required sedation for a minimum of 48 hrs . INTERVENTIONS Propofol or midazolam was used for induction and maintenance of continuous intravenous sedation for a maximum of 5 days . The effectiveness of those two regimens was assessed according to their effects on ventilatory management and the presence of agitation . MEASUREMENTS AND MAIN RESULTS In 93 % of the patients studied , there was a medical cause necessitating mechanical ventilation . The mean ( + /-SD ) duration of sedation was 81 + /- 25 hrs and 88 + /- 27 hrs for the propofol and midazolam groups , respectively . The induction dose was 2.24 + /- 0.43 mg/kg over 318 + /- 363 secs for propofol , and 0.22 + /-0.07 mg/kg over 33 + /-29 secs for midazolam . The maintenance dose was 2.8 + /-1.1 mg/kg/hr for propofol and 0.14 + /- 0.10 mg/kg/hr for midazolam . There was no difference regarding the opiate and muscle relaxant requirements between the two groups . Sedation with propofol was more effective in achieving patient-ventilator synchrony than that with midazolam after the first hour of treatment ( p < .01 ) . Patients se date d with propofol awoke more rapidly and with less variability that those patients se date d with midazolam ( 23 + /- 16 mins vs. 137 + /- 185 mins , respectively , p < .05 ) , particularly in those patients requiring deep sedation ( 27 + /- 16 mins vs. 237 + /- 222 mins , respectively , p < .01 ) . No hemodynamic or biochemical changes were detected in any of the treatment groups . During induction , five patients in the propofol group and two patients in the midazolam group had hypotension . CONCLUSIONS In this population of critically ill patients , propofol is an effective and safe alternative for sedation , with some advantages , such as short duration of action and high effectiveness over the conventional regimen with benzodiazepines and opiates [2570958] 101 critically ill patients admitted to five intensive-care units were allocated r and omly to receive a continuous intravenous infusion of either propofol or midazolam for sedation for up to 24 h. In addition , morphine was given to provide analgesia . The mean duration of infusion was 20.2 h ( range 3.0 - 24.5 ) in the propofol group and 21.3 h ( 4.0 - 47.0 ) in the midazolam group and infusion rates were 1.77 mg/kg/h ( range 0.40 - 5.00 ) and 0.10 mg/kg/h ( 0.01 - 0.26 ) , respectively . The infusion rates were adjusted as necessary , and the desired level of sedation was achieved easily in most patients in both groups . There were slight falls in arterial pressure , but there were no significant differences between the groups . Heart rate was lower in patients who received propofol . Some small changes occurred in biochemical and haematological variables in both groups , but they were not clinical ly significant . There was no indication that either drug substantially impaired adrenal steroidogenesis . When the infusion was discontinued , there was less variability in recovery of consciousness in patients who had received propofol . In a subgroup of patients , weaning from mechanical ventilation was achieved significantly faster after discontinuation of propofol than of midazolam . Propofol proved to be a satisfactory agent for sedation of these critically ill patients and compared favourably with midazolam [1418278] Propofol infusion was found to provide excellent sedation and rapid recovery in intensive care . The present study compared Propofol with lytic solution ( lytic solution = mixture of 100 mg Pethidine , 50 mg Promethazine and 0.6 mg Dihydroergotamine ) during 6 hours of postoperative artificial ventilation . 60 patients after major abdominal surgical procedures were studied with ethical committee approval and informed consent . Patients were r and omly allocated to receive either Propofol or lytic solution . We aim ed at a sedation level of stage 5 according to the Ramsey score . The mean drug dosages were 3.9 mg/kg/h of Propofol and 4.2 ml/h of lytic solution . Hemodynamic values , blood gases as well as various biochemical measures did not show any difference between the groups . At the end of the sedation period triglyceride concentrations were significantly higher in patients receiving Propofol ( 166 + 79 mg/dl ) compared to the control group ( 97 + 60 mg/dl ) . Significant and relevant differences were found for the times of recovery after discontinuation of the sedative . These times were very short in the Propofol group . Furthermore , in view of a longer recovery time after lytic solution in this group the respiratory rate was significantly slower up to the end of the observation period . We conclude that a major advantage of Propofol in the present study was the rapid recovery after 6 hour sedation . Patients gain vigilance rapidly and sufficient spontaneous respiration within minutes . Not at least thanks to these facts patient 's safety can be improved in the recovery period [8062564] Objective To compare the safety and effectiveness of propofol ( 2,6-diisopropylphenol ) to midazolam for sedation of mechanically ventilated patients after coronary artery bypass grafting . Design Open , r and omized , prospect i ve trial . Setting Cardiothoracic intensive care unit ( ICU ) , Clevel and Clinic Foundation . Patients Eighty-four patients with normal or moderately impaired left ventricular function who underwent elective coronary artery bypass graft surgery under high-dose opioid anesthesia . Interventions Patients were r and omly selected to receive either propofol ( mean loading dose 0.24 mg/kg ; mean maintenance dose 0.76 mg/kg/hr ) or midazolam ( mean loading dose 0.012 mg/kg ; mean maintenance dose 0.018 mg/kg/hr ) . Infusion rates were titrated to keep patients comfortable , drowsy , and responsive to verbal stimulation . Study duration , 8 to 12 hrs ; infusions were started in the ICU when patients were awake and hemodynamically stable . Measurements and Main Results During therapy , both groups had lower mean arterial pressures and heart rates compared with baseline measurements ; however , the propofol group had significantly lower heart rates than the midazolam group during the first 2 hrs of infusion . The propofol group also had significantly lower blood pressure measurements 5 and 10 mins after the initial dose , although there was no difference during infusion . Baseline cardiac output was measured before starting the infusion , and measurements were repeated during continuous infusion at 4 , 8 , and 12 hrs . Cardiac output values were similar . Propofol maintenance infusions ranged from 3 to 30 μg/kg/min and midazolam infusions ranged from 0.1 to 0.7 μg/kg/min . At these infusion rates . both groups had adequate sedation , based on nurse and patient evaluations ; however , the propofol group used significantly lower total doses of sodium nitroprusside and supplemental opioids . Conclusions Both propofol and midazolam provided safe and effective sedation of coronary artery bypass graft patients recovering from high-dose opioid anesthesia . The reduced need for both antihypertensive medication and opioids seen in the propofol group may be advantageous . However , the hypotension seen after the initial bolus dose of propofol may be a concern . No difference between the two drugs could be demonstrated in time to extubation or ICU discharge , although it is probable that time to extubation was governed more by residual operative opioids than the study agents . ( Crit Care Med 1994 ; 22:1415–1423 [7867354] OBJECTIVES To evaluate the comparative safety and effectiveness of intravenous infusion of propofol or midazolam when used for 12 to 24 hrs of sedation and to evaluate the quality of sedation during stimulation . DESIGN An open , comparative , prospect i ve , r and omized study . SETTING Surgical intensive care unit ( ICU ) in a university hospital . PATIENTS Postoperative , intubated , general surgical , and orthopedic patients requiring mechanical ventilation ( n = 60 ) . INTERVENTIONS None . MEASUREMENTS Assessment s were made at baseline ( 0 time ) , 5 , 10 , 15 , 30 , 45 , and 60 mins ; at 2 , 4 , 6 , 8 , 10 , 12 , 14 , 16 , 18 , 20 , 22 , and 24 hrs ; and at the end of sedation . The assessment s included systolic , mean , and diastolic blood pressures , heart rate , two-lead electrocardiogram , pulse oximetry oxygen saturation , FIO2 , end-tidal CO2 , respiratory rate , ventilator rate , tidal volume , and sedation scale . Vital signs and the sedation scale were obtained at 30 , 60 , and 90 mins and at 2 , 4 , 12 , and 24 hrs after the end of sedation . At approximately 8 hrs and 24 hrs ( or at the end of sedation ) , the patient 's CO2 production was calculated over a 5-min interval . Every 4 hrs , the nurse would summarize and rate patient response during stimulation as well as the overall rating of the sedation and patient ability to tolerate the ICU setting . MAIN RESULTS There were no significant differences in pulse oximetry , arterial blood gas values , or respiratory measurements during sedation with propofol or midazolam . The mean heart rate was slower in the propofol group throughout the sedation and postsedation periods . The rating of sedation and tolerance of the ICU environment were significantly better for the propofol-treated group . Postsedation , the propofol group woke up faster on discontinuation of the sedative . CONCLUSIONS Propofol was as safe and as efficacious as midazolam for continuous intravenous sedation . The quality of sedation was better in the propofol group [8045143] To evaluate the efficacy of continuous infusions of lorazepam vs. midazolam for sedation in the intensive care unit ( ICU ) . Design : Prospect i ve , r and omized study . Setting : Large , urban university hospital . Patients : Twenty adult medical ICU patients receiving mechanical ventilatory support . Interventions : Patients were r and omized to receive either lorazepam or midazolam . The infusion rate was adjusted at the bedside by the ICU nurse according to a st and ardized study protocol to achieve and maintain sedation at Ramsay 's sedation level 2 or 3 . Measurements and Main Results : Ten patients were r and omized to receive lorazepam and ten to receive midazolam . The groups were similar in demographics , Acute Physiology and Chronic Health Evaluation ( APACHE ) II scores , ICU admission diagnosis , underlying disease processes , and supplemental analgesic administration . The mean time to achieve initial adequate sedation was 124 mins for lorazepam and 105 mins for midazolam . The mean infusion rate at the point of initial sedation was 0.06 mg/kg/hr for lorazepam and 0.15 mg/kg/hr for midazolam . The maximum and mean infusion rates for the entire study period were 0.1 and 0.06 mg/kg/hr , respectively , for lorazepam and 0.29 and 0.24 mg/kg/hr , respectively , for midazolam . The number of infusion rate adjustments per day was 1.9 mg/kg/hr for lorazepam and 3.6 mg/kg/hr for midazolam . Of the surviving patients , the mean time to return to baseline mental status after discontinuation of the benzodiazepine infusion was 261 mins for lorazepam and 1815 mins for midazolam . The mean volume of fluid per day required to deliver the maximum dose of benzodiazepine was 1.2 L for lorazepam ( maximum 2.4 L ) and 1.3 L for midazolam ( maximum 3.6 L ) . Conclusions : While there was a tendency to a longer time required for return to baseline mental status in patients receiving midazolam , this was not statistically signficant . Findings of interest concerning both midazolam and lorazepam were : a ) time to achieve sedation in medical ICU patients is often prolonged ; b ) actual dose requirements necessary to maintain sedation in this patient population are larger than the current literature describes ; c ) time to awaken after discontinuation of the infusion was occasionally delayed for > 24 hrs ; d ) large volumes of fluid were required to deliver these doses of drug via this route of administration . ( Crit Care Med 1994 ; 22:1241–1247 [8329251] We have compared the sedative and amnesic effects of midazolam and propofol in 35 volunteers . Sedation was measured by simple reaction time immediately before and after a bolus injection and 1 h after the commencement of a subsequent continuous infusion . Memory was measured three times using two memory tests : perceptual facilitation provided an implicit memory measure and recognition provided an explicit memory measure . Propofol and midazolam had similar sedative effects both immediately after bolus doses and after 1-h continuous infusions of the drugs . In contrast , midazolam had a more profound amnesic effect than propofol on the recognition memory test . The drugs had little effect on performance with the implicit memory test . Performance on the memory tests was unrelated to sedation [8686815] A comparison was made of the drug costs and nursing dependency of patients undergoing elective cardiac surgery and routine postoperative recovery for two anaesthetic techniques using either propofol with low dose fentanyl or midazolam with high dose fentanyl . Estimates of re source use were based on a r and omised clinical trial undertaken at the Northern General Hospital , Sheffield . Times from entry to the intensive care unit until extubation and discharge were recorded for 70 patients and were transformed to nursing shifts . Nursing dependency was calculated on the basis of one nurse per ventilated patient and 0.5 nurse from the start of the shift after extubation . Nursing costs were allocated on the basis of the patient 's status at the beginning of each shift in line with the hospital 's staffing policy . All drugs used from the morning of the operation until discharge were recorded . Costs of nursing and drugs were calculated . The total cost of patients in the propofol group was 13.3 % less than midazolam patients ( p = 0.043 , for geometric means Cl 0.4 % to 27.8 % ) . The clinical study was not design ed for economic endpoints ; however , it demonstrated achievable savings in propofol‐treated patients [8432154] The purpose of this study was to evaluate and compare the clinical effects , safety , and economic cost of propofol and midazolam in the sedation of patients undergoing mechanical ventilation in the ICU . Eighty-eight critically ill patients were studied and r and omly allocated to receive short-term ( less than 24 h ) , medium-term ( 24 h to 7 days ) , and prolonged ( more than 7 days ) continuous sedation with propofol ( n = 46 ) or midazolam ( n = 42 ) . Mean doses required were 2.36 mg/kg/h for propofol and 0.17 mg/kg/h for midazolam . Patients in the group receiving propofol showed a percentage of hours of sedation at the desired level ( grade 2 , 3 , 4 , or 5 on the Ramsay scale ) of 93 percent , compared with 82 percent ( p < 0.05 ) in the group receiving midazolam . Both agents were considered safe with respect to the induction of adverse reactions during their use in prolonged sedation . Recovery after interrupting sedation was significantly faster in patients treated with propofol than in those se date d with midazolam ( p < 0.05 ) . Recovery of total consciousness was predictable according to sedation time in propofol-treated subgroups ( r = 0.98 , 0.88 , and 0.92 , respectively ) , while this correlation was not observed in the midazolam-treated group . In the subgroup with sedation of less than 24 h , propofol provided a cost savings of approximately 2,000 pesetas ( pts ) per patient , due to shorter stays in the ICU . We conclude that propofol is a sedative agent with the same safety , higher clinical effectiveness , and a better cost-benefit ratio than midazolam in the continuous sedation of critically ill patients [9590313] OBJECTIVES To evaluate and compare the clinical efficacy , impact on hemodynamics , safety profiles , and cost of combined administration of propofol and midazolam ( synergistic sedation ) vs. midazolam and propofol administered as sole agents , for sedation of mechanically ventilated patients after coronary artery bypass grafting . DESIGN Prospect i ve , controlled , r and omized , double-blind clinical trial . SETTING Intensive care unit of SCIAS-Hospital de Barcelona . PATIENTS Seventy-five mechanically ventilated patients who underwent coronary artery bypass graft surgery under low-dose opioid anesthesia . INTERVENTIONS According to the double-blind method , patients were r and omly assigned to receive propofol ( n = 25 ) , midazolam ( n = 25 ) , or propofol combined with midazolam ( n = 25 ) . Infusion rates were adjusted to stay between 8 and 11 points on Glasgow Coma Score modified by Cook and Palma . MEASUREMENTS AND MAIN RESULTS Mean + /- SD duration of sedation was 14.4 + /- 1.5 hrs , 14.1 + /- 1.1 hrs , and 14.7 + /- 1.9 hrs for the propofol , midazolam , and synergistic groups , respectively . The induction dose was 0.55 + /- 0.05 mg/kg for propofol as sole agent , 0.05 + /- 0.01 mg/kg for midazolam as sole agent , and 0.22 + /- 0.03 mg/kg for propofol administered in combination with 0.02 + /- 0.00 mg/kg of midazolam ( p = .001 ) . The maintenance dose was 1.20 + /- 0.03 mg/kg/hr for propofol as sole agent , 0.08 + /- 0.01 mg/kg/hr for midazolam as sole agent , and 0.50 + /- 0.09 mg/kg/hr for propofol administered in combination with 0.03 + /- 0.01 mg/kg/hr of midazolam ( p < .001 ) . All sedative regimens achieved similar efficacy in percentage of hours of adequate sedation ( 93 % for propofol , 88 % for midazolam , and 90 % for the synergistic group , respectively ) . After induction , both propofol and midazolam groups had significant decreases in systolic blood pressure , diastolic blood pressure , left atrial pressure , and heart rate . Patients in the synergistic group had significant bradycardia throughout the study , without impairment in other hemodynamic parameters . Patients se date d with propofol or synergistic regimen awoke sooner and could be extubated before those patients se date d with midazolam ( 0.9 + /- 0.3 hrs and 1.2 + /- 0.6 hrs vs. 2.3 + /- 0.8 hrs , respectively , p = .01 ) . Synergistic sedation produced cost savings of 28 % with respect to midazolam and 68 % with respect to propofol . CONCLUSIONS In the study conditions , the new synergistic treatment with propofol and midazolam administered together is an effective and safe alternative for sedation , with some advantages over the conventional regimen with propofol or midazolam administered as sole agents , such as absence of hemodynamic impairment , > 68 % reduction in maintenance dose , and lower pharmaceutical cost [8605792] OBJECTIVES To evaluate and compare the clinical efficacy , impact on hemodynamic and oxygen transport variables , safety profiles , and cost efficiency of sedation and anxiolysis with lorazepam vs. continuous infusion of midazolam in critically ill , intensive care unit patients . DESIGN Multicenter , prospect i ve , r and omized , open-label study . SETTING Teaching hospitals . PATIENTS Ninety-five critically ill , mechanically ventilated patients with fiberoptic pulmonary artery catheters in place were r and omly assigned to receive short-term ( 8 hrs ) sedation with either intermittent intravenous injection lorazepam ( group A , n = 50 ) or continuous intravenous infusion midazolam ( group B , n = 45 ) titrated to clinical response . MEASUREMENTS AND MAIN RESULTS The severity of illness , demographic characteristics , levels of anxiety and agitation , hemodynamic parameters , oxygen transport variables , quality of sedation , nursing acceptance , and laboratory chemistries reflecting drug safety were recorded . There were no significant differences with regard to demographic data , hemodynamic and oxygen transport variables , or levels of anxiety/agitation between the two groups at baseline , 5 mins , 30 mins , and 4 and 8 hrs after administration of sedation . There were no significant differences in the quality of sedation or anxiolysis . Midazolam-treated patients used significantly larger amounts of drug for similar levels of sedation and anxiolysis ( 14.4 + /- 1.2 mg/8 hrs vs. 1.6 + /- 0.1 mg/8 hrs , p = .001 ) . Both drugs were safely administered and patient and nurse satisfaction was similar . CONCLUSIONS Sedation and anxiolysis with lorazepam and midazolam in critically ill patients is safe and clinical ly effective . Hemodynamic and oxygen transport variables are similarly affected by both drugs . The dose of midazolam required for sedation is much larger than the dose of lorazepam required for sedation , and midazolam is therefore less cost-efficient [2192570] Thirty‐seven patients with a wide range of illnesses were studied during mechanical ventilation of the lungs in an intensive care unit . Fifteen were se date d with a continuous propofol infusion , with analgesia provided by bolus doses of papaveretum . Twelve received a continuous infusion of papaveretum , supplemented by bolus doses of midazolam . The level of sedation was assessed every four hours and measurements were made of haemodynamic and respiratory variables . Levels of sedation were generally satisfactory in both groups . Six patients who received propofol required the use of muscle relaxants , because of their strong respiratory drives , to achieve synchronisation with the ventilator . There was no significant difference in respiratory or haemodynamic variables between the groups , but several patients required inotropic support because of their disease . There was no evidence of inhibition of adrenal steroidogenesis in the propofol group . Propofol can be a useful sedative agent in the intensive care unit , but sedative regimens should be tailored to individual patient requirements [10170449] Morphine + midazolam and alfentanil + propofol are regimens offering well tolerated and effective sedation for critically ill patients . However , morphine + midazolam is associated with accumulation in these patients , result ing in prolonged recovery characteristics . Alfentanil+propofol , although more expensive , has a shorter elimination half-life , is not associated with accumulation problems and results in a rapid recovery . This study compared sedation quality , patient recovery characteristics and the cost of alfentanil + propofol and morphine + midazolam for sedating critically ill patients in the intensive care setting . 26 patients were r and omly allocated to receive sedation with alfentanil + propofol ( n = 17 ) or morphine + midazolam ( n = 9 ) . Outcome measures were the times until extubation , intensive care unit ( ICU ) transfer and final hospital discharge . Cost analysis assessed both drug-related costs , including drug acquisition and administration , and non-drug-related costs , including bed occupancy . Age , gender , diagnosis , Acute Physiological and Chronic Health Evaluation ( APACHE ) II scores and sedation quality did not differ significantly between groups . The times to extubation and until patients were fit for transfer from ICU were significantly shorter for patients se date d with alfentanil + propofol than for those se date d with morphine + midazolam . The total costs ( at the time of the study Pounds 1 was equivalent to $ US1.59 ) for ICU hospital stay per patient for alfentanil + propofol and morphine + midazolam were 3063 Pounds and 9511 Pounds , respectively , because the shorter recovery characteristics of alfentanil + propofol led to a reduction in ICU stay . Corresponding costss for total hospital stay were 6063 Pounds and 13735 Pounds , respectively . In conclusion , alfentanil + propofol has a better pharmacoeconomic profile than morphine + midazolam for sedating critically ill patients in the ICU setting [2186650] One hundred adult patients who required mechanical ventilation after open heart surgery for coronary revascularisation were studied . All received a st and ard premedication and a high dose opioid anaesthetic . On arrival in the intensive care unit they were allocated r and omly to receive either propofol or midazolam to maintain sedation within a predetermined range . Patients who received propofol underwent extubation of the trachea , using st and ard criteria , after a mean time ( log‐transformed ) of 7.6 minutes after sedation for approximately 17 hours . The corresponding time was 125 minutes in those given midazolam . There were significantly higher morphine requirements during sedation , and higher arterial carbon dioxide tensions 30 minutes after extubation of the trachea , in patients who received midazolam . Pharmacokinetic analysis in 20 patients showed that the elimination half‐life of propofol was prolonged ( 470 minutes ) and clearance was reduced ( 1.14 litres/minute ) compared with subjects who had not undergone cardiopulmonary bypass . The rapid clinical recovery was reflected in a rapid redistribution half‐life ( 13.4 minutes ) , but this was also longer than the redistribution time of 2–4 minutes in other patients [7762918] Preamble Although economic outcomes research is an evolving field in health services research , there are correct and incorrect ways to conduct and report on economic outcomes studies . Research practice s that help to minimize real or perceived bias will increase the quality and usefulness of such studies for those who sponsor , publish , and use them . Because of public concerns about the potential for bias in the design , analysis , and reporting of economic analyses of health care technology , we formed a task force to develop principles to enhance the credibility of these studies . The Task Force on Principles for Economic Analysis of Health Care Technology included participants from academia , the pharmaceutical industry , the public sector , and private research organizations . As health care re sources become increasingly constrained , the information used to make re source allocation decisions must be as reliable , valid , and free of bias as possible . Getting it right at the level at which economic results are produced will help to protect consumers and will advance the health of the public . Bias stems from two broad categories : lack of appropriate independence for research ers and lack of consensus about methods . We focused heavily on the first of these categories for two major reasons . First , few have yet considered the unique issues of research er independence in economic outcomes research [ 1 , 2 ] . Second , other investigators have begun to consider and define proper methods for economic outcomes work ( an area of considerable controversy ) [ 3 - 5 ] . We also looked closely at the requirements for the reporting of economic analyses , which are intended to ensure method ologic transparency and accountability . The Need for Voluntary Guidelines Widespread use of economic analysis as part of the development of pharmaceutical , biotechnologic , and medical devices is relatively new . To date , many economic analyses of health care have focused on pharmaceutical agents , and many such studies have been funded by pharmaceutical companies . Results of these economic outcomes studies are used by medical technology firms to support the pricing and marketing of new interventions and to influence national health care systems and third-party payers in their development of coverage and payment decisions . Managed care organizations , hospitals , and government-subsidized health care programs rely on economic analysis of medical technology to help make formulary purchasing and utilization decisions . Physicians may use the results of these analyses to help guide treatment and prescription decisions . Health care economic outcomes projects are sponsored and conducted by pharmaceutical , biotechnologic , and medical device companies ; government agencies ; nonprofit foundations ; academic investigators ; and private research and consulting firms . The st and ards and methods used to evaluate the safety and efficacy of pharmaceutical products in r and omized , controlled trials have evolved over 50 years of collaboration among research ers in private , public , and academic setting s. Compared with those established to ensure the safety and efficacy of clinical trials , the principles and methods for the conduct of economic studies of health care technology are far less developed . Problems of conduct , reporting , and bias exist in all types of research [ 6 - 14 ] . In response , codes of conduct , such as those developed by the American Federation for Clinical Research and the Institute of Medicine , have been developed for many scientific disciplines [ 15 - 24 ] . These are good models on which to base principles of conduct for economic outcomes analysis . Although many published principles apply to economic studies , others should be modified and new ones should be developed to guide the conduct and reporting of economic outcomes analyses . Economic outcomes research requires unique guidelines for the following reasons : 1 ) As a field , it continues to evolve and is often misunderstood by end users ; 2 ) peer review of it requires special expertise that often exceeds the capabilities of review ers and scientific journals ; 3 ) it often uses secondary data and requires that many assumptions be made [ for example , attribution of a dollar cost to a unit of re source use ] ; 4 ) it offers unique method ologic choices , such as which types of costs to include ( direct , indirect , intangible , induced ) , which perspective to apply ( that of society , payer , provider , patient ) , which design to adopt ( cost- identification , costbenefit , cost-effectiveness , costutility ) , from where to obtain costs [ indemnity data base , managed care or capitated data base , hospital cost systems , Medicare , Medicaid ] , and whether to collect re source consumption data prospect ively or retrospectively through various modeling techniques ; and 5 ) economic studies play an increasingly important role in health care decision making because of increasing financial constraints throughout the health care industry . The financial and medical implication s of decision making done on the basis of these studies , coupled with the lack of widely accepted guidelines about the conduct and reporting of economic analyses , undermine the credibility of this research . A major issue is that the primary source of funding for this research is often the primary financial beneficiary of positive study results . Unfortunately , even valid studies done under the best of circumstances may be suspect [ 25 - 29 ] . This has led at least one major journal to conclude that these analyses should be viewed much like editorials or review articles are viewed in terms of potential for conflicts of interest [ 30 ] . We developed the guidelines reported here after extensive consultation with experts from the public , private , and academic sectors . We recommend that research ers and sponsors adhere to these guidelines , and we suggest they state publicly within their manuscripts that they have done so . End users , including journal editors and readers , consumers , and social decision makers , may then feel more secure in accepting the results of the research , while recognizing that intensive critique of the research will always be necessary . Operations of the Task Force The Task Force on Principles for Economic Analysis of Health Care Technology was initiated and organized by faculty from the Leonard Davis Institute ( LDI ) Center for Health Policy of the University of Pennsylvania . However , because not all LDI faculty were involved , this paper does not represent an official LDI position statement . The Task Force was funded by a coalition of pharmaceutical companies ( Appendix A ) . Funding was also requested ( but not obtained ) from various government and private foundations . All funding was provided in the form of unrestricted research grants or gifts to the University of Pennsylvania . Guidelines derive their credibility in part from the composition of the panel that creates them and the process by which they are developed . C and i date s for participation in the Task Force from the private sector and the academic research community were identified by the frequency with which they were cited in the health economics literature , which was obtained using a MEDLINE search of literature related to economic analyses of medical technology published between 1983 and 1992 . Approximately 15 members attended each meeting . Minutes were distributed after each meeting and approved by all members present . Members from the sponsoring pharmaceutical companies and the academic organizers rotated so that they numbered three and one , respectively , at the table for each formal Task Force meeting . Several professional and governmental organizations , including the Institute of Medicine , the Agency for Health Care Policy and Research , the Food and Drug Administration ( FDA ) , the Health Care Financing Administration , the Centers for Disease Control and Prevention , and a managed care organization , were asked to suggest persons who might participate . In addition , other organizations with a stake in economic analyses were each asked to suggest a person who , because of his or her professional background , had extensive knowledge of or experience with economic analyses . An academic pharmacist , an academic research er , a private research er , an ethicist and patient advocate , and an attorney specializing in medical ethics rounded out the Task Force ( Appendix B ) . Two members withdrew from participation . A small audience consisting of industry sponsors , academic organizers , staff , and a few other interested parties were invited to each meeting and allowed to comment . Four formal meetings of the Task Force were held in Philadelphia during 1993 and 1994 , and the most substantial work was done by various subcommittees between these meetings . The three main subcommittees were titled Ethical Conduct , Responsibility and Control ( the findings of these two subcommittees were later merged into one report ) , and Reporting Requirements for Economic Evaluations ( Appendix C ) . The Task Force was assisted by a professional facilitator . Although Task Force members sought consensus wherever possible on the key issues , consensus was not forced and recommendations were issued only when substantial agreement existed among the members . Task Force members were not asked to formally represent any organization . Formal endorsement of the final document was not sought . Copies of this report will be distributed to all organizations that were asked to suggest a participant and to other parties who responded to announcements placed in The New Engl and Journal of Medicine , Scrip , and the Pink Sheet . The Task Force findings will also be reported at academic conferences , medical profession meetings , and appropriate trade conventions . Findings and Recommendations Valid approaches to economic analyses can be defined ; acceptable methods can be differentiated from unacceptable ones . Bias in economic research stems from two major sources : lack of appropriate independence for [8989173] OBJECTIVE To compare the effectiveness of sedation , the time required for weaning , and the costs of prolonged sedation of critically ill mechanically ventilated patients with midazolam and propofol . DESIGN Open-label , r and omized , prospect i ve , phase IV clinical trial . SETTING Medical and surgical intensive care unit ( ICU ) in a community hospital . PATIENTS All ICU admissions ( medical , surgical and trauma ) requiring mechanical ventilation for > 24 hrs . A total of 108 patients were included in the study . INTERVENTIONS Patients were r and omized to receive midazolam or propofol . The dose range allowed for each drug was 0.1 to 0.5 mg/kg/hr for midazolam and 1 to 6 mg/kg/hr for propofol . The lowest dose that achieved an adequate patient-ventilator synchrony was infused . All patients received 0.5 mg/kg/24 hrs of morphine chloride . MEASUREMENTS AND MAIN RESULTS The level of sedation was quantified by the Ramsay scale every 2 hrs until weaning from mechanical ventilation was started . If sedation could not be achieved by infusing the highest dose of midazolam or propofol , the case was recorded as a therapeutic failure . In the propofol group , serum triglycerides were determined every 72 hrs . Concentrations of > 500 mg/dL were also recorded as a therapeutic failure . When the patient was ready for weaning according to defined criteria , sedation was interrupted abruptly and the time from interruption of sedation to the first T-bridge trial and to extubation was measured . Cost analysis was performed based on the cost of intensive care in our unit ( $ 54/hr ) . In the midazolam group ( n = 54 ) , 15 ( 27.8 % ) patients died ; 11 ( 20.4 % ) patients had therapeutic failure ; and 28 ( 51.8 % ) patients were subjected to a T-bridge trial . In the propofol group ( n = 54 ) , these proportions were 11 ( 20.4 % ) , 18 ( 33.4 % [ including seven due to inadequate sedation , and 11 due to hypertriglyceridemia ] ) , and 25 ( 46.2 % ) , respectively . None of these values was significantly different between the two groups . Duration of sedation was 141.7 + /- 89.4 ( SD ) hrs and 139.7 + /- 84.7 hrs ( p = NS ) , and cost ( US dollars ) attributed to sedation was $ 378 + /- 342 and $ 1,047 + /- 794 ( p = .0001 ) for the midazolam and propofol groups , respectively . In the midazolam group , time from discontinuation of the drug infusion to extubation was 97.9 + /- 54.6 hrs ( 48.9 + /- 47.2 hrs to the first disconnection , and 49.0 + /- 23.7 hrs to extubation ) . In the propofol group , time from discontinuation of the drug infusion to extubation was 34.8 + /- 29.4 hrs ( 4.0 + /- 3.9 hrs to the first disconnection , and 30.8 + /- 29.2 hrs to extubation ) . The difference between the two groups in the weaning time was 63.1 + /- 12.5 ( SEM ) hrs ( p < .0001 ) . Cost per patient in the midazolam group ( including ICU therapy and sedation with midazolam ) was $ 10,828 + /- 5,734 . Cost per patient in the propofol group was $ 9,466 + /- 5,820 , $ 1,362 less than in the midazolam group . CONCLUSIONS In our population of critically ill patients se date d with midazolam or propofol over prolonged periods , midazolam and propofol were equally effective as sedative agents . However , despite remarkable differences in the cost of sedation with these two agents , the economic profile is more favorable for propofol than for midazolam due to a shorter weaning time associated with propofol administration [8669676] Background Propofol sedation offers advantages for titration and rapid emergence in the critically ill patient , but concern for adverse hemodynamic effects potentially limits its use in these patients . The current study compares the cardiovascular effects of sedation with propofol versus midazolam during the first 12 h after coronary revascularization . Methods Three hundred fifty‐one patients undergoing coronary revascularization were anesthetized using a st and ardized sufentanil/midazolam regimen , and assigned r and omly to 12 h of sedation with either propofol or midazolam while tracheally intubated . The incidence and characteristics of hemodynamic episodes , defined as heart rate less than 60 or greater than 100 beats/min or systolic blood pressure greater than 140 or less than 90 mmHg , were determined using data electronically recorded at 1‐min intervals . The presence of myocardial ischemia was determined using continuous three‐channel Holter electrocardiography ( ECG ) and of myocardial infa rct ions ( MI ) using 12‐lead ECG ( Q wave MI , Minnesota Code ) or creatine kinase isoenzymes ( CK‐MB ) analysis ( non‐Q wave MI , peak CK‐MB > 70 ng/ml , or CK‐MB > 70 IU/l ) . Results Ninety‐three percent of patients in both treatment groups had at least one hemodynamic episode during the period of postoperative sedation . Propofol sedation result ed in a 17 % lower incidence of tachycardia ( 58 % vs. 70 % , propofol vs. midazolam ; P = 0.04 ) , a 28 % lower incidence of hypertension ( 39 % vs. 54 % ; P = 0.02 ) , and a greater incidence of hypotension ( 68 % vs. 51 % ; P = 0.01 ) . Despite these hemodynamic effects , the incidence of myocardial ischemia did not differ between treatment groups ( 12 % propofol vs. 13 % midazolam ; P = 0.66 ) , nor did its severity , as measured by ischemic minutes per hour monitored ( 8.7+/‐5.8 vs. 6.2+/‐4.6 min/h , propofol vs. midazolam ; P = 0.19 ) or ischemic area under the curve ( 6.8+/‐4.0 vs. 5.3+/‐4.2 ; P = 0.37 ) . The incidence of cardiac death ( one per group ) , Q wave MI ( propofol , n = 7 ; midazolam , n = 3 ; P = 0.27 ) , or non Q wave MI ( propofol , n = 16 ; midazolam , n = 18 ; P = 0.81 ) did not differ between treatment groups . Conclusions Hemodynamic episodes occur frequently in the first 12 h after coronary revascularization . Compared with a st and ard sedation regimen ( midazolam ) , propofol sedation appears to modulate postoperative hemodynamic responses by reducing the incidence and severity of tachycardia and hypertension and increasing the incidence of hypotension . Both sedation regimens appear similarly safe with respect to myocardial ischemia . These findings indicate that propofol infusion provides effective sedation without deleterious hemodynamic effects in patients recovering from cardiac surgery [1874212] Forty-four patients , with admission APACHE II scores between 5 and 24 , undergoing mechanical ventilation in the intensive therapy unit , received a sedative regimen consisting of continuous infusions of propofol and alfentanil . Patients were r and omly allocated to one of three groups to receive either alfentanil 0.25 microgram kg-1 min-1 ( 10 patients ) , 0.50 microgram kg-1 min-1 ( 15 patients ) or 0.75 microgram kg-1 min-1 ( 18 patients ) for analgesia . An infusion of propofol 20 - 200 mg h-1 ran concurrently to maintain a satisfactory level of sedation . Patients received the infusions for between 4 and 260 h and 38 patients spent more than 90 % of this time at satisfactory sedation levels . After stopping the infusions all patients had short times to wakening ( mean 3 - 18 min ) and to establish spontaneous respiration ( mean 8 - 28 min ) , suggesting no significant cumulation . Some depression of blood pressure was seen on starting the infusions , which was in general easily treated with fluids or small increases in inotropic agents . One patient , however , was withdrawn from the trial because of haemodynamic instability . This combination of drugs can be recommended for sedation of general intensive-therapy patients , provided the cost is not felt to be prohibitive [9620508] Previous studies have compared sedation profiles with midazolam ( Mz ) and propofol ( Pf ) , particularly in heterogeneous population s of patients .Decreases in blood pressure and heart rate have been reported after the administration of propofol . These side effects are potentially deleterious in severe trauma patients , particularly in patients with head trauma . To assess the safety and efficacy of Mz and Pf , alone or in combination , in the prolonged sedation of severe trauma patients , we design ed a prospect i ve , controlled , r and omized , study . One hundred consecutively admitted trauma patients requiring mechanical ventilation and sedation for more than 48 h were studied . Patients were se date d according to three different protocol s based on the continuous IV administration of Mz alone , Pf alone , and Mz in combination with Pf . All patients received morphine chloride . Safety and efficacy were assessed during the sedation and wake-up periods according to clinical and laboratory variables . Cerebral hemodynamics were also studied in patients with head trauma . Patients were se date d for 6.3 + /- 4.0 days ( mean + /- SD ) . All three sedation regimens were equally efficacious in achieving the desired sedation goal . The incidence of adverse events during the sedation period was also similar . In head trauma patients with intracranial pressure ( ICP ) monitoring , we did not find differences in ICP , cerebral perfusion pressure , or jugular venous oxygen saturation among the three groups . The serum triglyceride concentration was significantly higher in the Pf group . Wake-up time was significantly shorter in the Pf group . We conclude that both Mz and Pf are safe and efficacious in the sedation of severe trauma patients . The use of Pf in these patients is associated with a high incidence of hypertriglyceridemia and a shorter wake-up time . Implication s : In a prospect i ve , controlled , r and omized study , we confirmed the safety and efficacy of midazolam and propofol , alone or in combination , in the prolonged sedation of a homogeneous group of severe trauma patients , particularly in patients with head trauma . The propofol group had shorter wake-up times and higher triglyceride levels . ( Anesth Analg 1998;86:1219 - 24 [2058827] This study was undertaken to compare two regimens for analgesic sedation in intensive care patients with exogenous catecholamine therapy , giving special regard to catecholamine dem and and hemodynamic parameters . A total of 20 ventilated patients in a surgical intensive care unit were investigated in a prospect ively r and omized design . Exogenous catecholamine therapy with epinephrine and /or norepinephrine was started at systolic pressure ( SAP ) less than 85 mmHg or mean arterial pressure ( MAP ) less than 65 mmHg to maintain cardiovascular function . For analgesic sedation , patients received bolus injections of about 0.2 mg/h fentanyl and 2.5 mg/h midazolam ( fentanyl group , n = 10 ) or an infusion of about 50 mg/h ketamine and 2.5 mg/h midazolam by syringe pump ( ketamine group , n = 10 ) . Before the investigation , all patients received fentanyl and midazolam . The study period was 48 h. During the course of the study , mean catecholamine dosage increased significantly in the fentanyl group from 12.1 to 16.3 micrograms/min ( + 33 % , P = 0.003 ) . In the ketamine group , mean catecholamine dosage decreased from 43.9 to 38 micrograms/min ( -13 % , P = 0.19 ) . No significant differences in group levels or time course were observed with regard to MAP , heart rate , cardiac index , pulmonary capillary wedge pressure , and shunt volume . Levels of pulmonary artery pressure ( PAP ) were comparable in both groups ( ketamine group 29 mmHg , fentanyl group 26 mmHg ) . In time course , PAP increased by about 5 mmHg in the ketamine group but not in the fentanyl group ( P = 0.009 ) . The average central venous pressure ( CVP ) was 12 mmHg in both groups . At the end of the investigation , CVP decreased in the fentanyl group and increased in the ketamine group ( P = 0.0001 ) . ( ABSTRACT TRUNCATED AT 250 WORDS [9356086] The influence of light versus heavy sedation after coronary artery bypass graft ( CABG ) surgery on the development of postoperative myocardial ischemia has not been described . After uncomplicated CABG surgery , 50 patients were r and omly assigned to receive LOW ( n = 24 ; target Ramsay Sedation Score [ RSS ] = 2 ) or HIGH ( n = 26 ; target RSS = 4 ) sedation with propofol . Analgesia was provided to maintain a visual analog scale ( VAS ) pain score < 7 . Myocardial ischemia was identified perioperatively using continuous 3-lead Holter monitoring . By measuring creatine kinase ( CK ) MB levels preoperatively , at entry to the intensive care unit ( ICU ) , and every 12 h for 48 h ; and by obtaining serial 12-lead electrocardiograms ( ECG ) ( preoperatively ; 2 , 4 , 12 , 24 , and 48 h after ICU admission , 8:00 AM the morning after surgery ; and 5 min pre- and postextubation ) , myocardial infa rct ion was identified . Endocrine stress response was assessed by measuring serum cortisol levels preoperatively , on admission to the ICU , and 24 h postoperatively . In a subset of patients ( LOW n = 10 , HIGH n = 11 ) , plasma and urinary catecholamine levels were also measured . There were no between-group differences in demographics , operative course , hemodynamic variables , or cortisol levels while in the ICU . The VAS pain score and target RSS were achieved and sustained , and they differed between groups . There were three myocardial infa rct ions in each group by CKMB criteria alone . No ECG-identifiable myocardial infa rct ion occurred . The ST segment versus time curve ( LOW 187 + /- 295 versus HIGH 1071 + /- 2137 mm/min ) differed between groups . Urinary and plasma catecholamine levels were similar between groups over the observation period . We conclude that the use of a reduced sedation regimen in combination with adequate analgesia did not result in an increased endocrine stress response or risk of myocardial ischemia . Implication s : This r and omized study of patients after coronary artery bypass surgery examined whether light ( versus heavy ) sedation with propofol in the intensive care unit was associated with an increased degree of myocardial ischemia . Using techniques to detect myocardial ischemia , including Holter monitoring , electrocardiogram , and myocardial enzyme measurements , no differences were found . We conclude that light sedation does not increase the endocrine stress response or the risk of myocardial infa rct ion . ( Anesth Analg 1997;85:971 - 8 [3580237] Midazolam given as hourly intermittent injections was compared with the same dose given by infusion for postoperative sedation in patients after cardiopulmonary bypass . A stable concentration was rapidly attained with the infusion whereas 6 - 8 h was required to attain stable plasma ( trough ) concentrations in the intermittent injection group . Plasma concentrations decreased rapidly to low values within 6 h of discontinuation of therapy . High plasma concentrations and a long ( 16 h ) half-life were noted in one patient who may be a slow metabolizer of the drug [2500195] OBJECTIVE --To compare isoflurane with midazolam for sedation of ventilated patients . DESIGN --R and omised control study . Setting --Intensive care unit in university teaching hospital . PATIENTS --Sixty patients aged 18 - 76 who required mechanical ventilation . INTERVENTIONS --Sedation with either 0.1 - 0.6 % isoflurane in an air-oxygen mixture ( 30 patients ) or a continuous intravenous infusion of midazolam 0.01 - 0.20 mg/kg/h ( 30 patients ) . Sedation was assessed initially and hourly thereafter on a six point scale . Incremental intravenous doses of morphine 0.05 mg/kg were given for analgesia as required . The trial sedative was stopped when the patient was judged ready for weaning from ventilatory support or at 24 hours ( whichever was earlier ) . END POINT -- Achievement of a predetermined level of sedation for as much of the time as possible . MAIN RESULTS --Isoflurane produced satisfactory sedation for a greater proportion of time ( 86 % ) than midazolam ( 64 % ) , and patients se date d with isoflurane recovered more rapidly from sedation . CONCLUSION --Isoflurane is a promising alternative technique for sedation of ventilated patients in the intensive care unit [1636917] Sedative-analgesic treatment of patients on long-term artificial ventilation aims at protection from stress related to their disease or therapy . By stabilising both the patient 's vital functions and psychological state this treatment may contribute to therapeutic success . The choice of drugs depends primarily on the nature and course of the underlying disease . Midazolam and propofol are available as hypnotics for short-term sedation during the post-operative period . The purpose of this study was to evaluate the effects of both agents on cardiovascular function , cortisol production , lipometabolism , and the recovery period following 24-h sedation . METHODS . Twenty female patients ( mean body weight : 72 kg , mean age : 60 years ) were r and omly assigned to receive either midazolam or propofol over 24 h following major abdominal surgery . Balanced anaesthesia ( halothane/O2/N2O/fentanyl ) was administered for the surgical procedure . Assisted ventilation was used in all patients during the post-operative sedation period . Sedation depth was maintained at III-IV on the Ramsey scale . On arrival in the intensive care unit ( ICU ) , an initial i.v . bolus of midazolam 0.1 mg/kg or propofol 1 mg/kg was followed by a continuous infusion ( midazolam : 0.1 mg/kg.h ; propofol : 2 mg/kg.h ) . Supplementary boluses of one-half the initial dose were given if required . Post-operative analgesia was achieved with 3 mg intravenous piritramide at 2-h intervals . A 7F Swan-Ganz catheter was inserted in the pulmonary artery and haemodynamic and biochemical parameters were monitored at 4-h intervals over 24 h starting 2 h after arrival in the ICU . Catecholamines were measured by high-pressure lipid chromatography ( HPLC ) , cortisol by radioimmunoassay , midazolam by HPLC and ultraviolet detection , and propofol by HPLC and fluorescence detection . Data were calculated as means . The statistical analysis was performed according to the Mann-Whitney test , and significance was accepted for P less than 0.05 . RESULTS . On administration of the propofol bolus at the onset of sedation , a decrease in blood pressure was particularly observed in patients with masked hypovolaemia , however , this decrease was easily controlled by volume administration . Independent of the type of sedation , the haemodynamic parameters remained unchanged throughout the observation period . At all times of measurement the mean heart rate was lower in the propofol group ( 90/min ) when compared with the midazolam group ( 100/min ) , however , this difference did not reach significance . There were also no significant differences in cardiac index at all times of measurement , although it increased in both groups within the first 12 h by 0.6 l/min.min2 . In both groups this increase was associated with a reduction in peripheral resistance and an increase in rectal temperature . To achieve the desired sedation depth , midazolam was administered at a mean dosage of 0.11 mg/kg.h and propofol at 1.9 mg/kg.h . Catecholamine levels decreased in both groups within the first 8 h : after 8 h of sedation the plasma levels of noradrenaline and adrenaline were 525 and 65 pg/ml , respectively , in the midazolam group and 327 and 51 pg/ml in the propofol group . ( ABSTRACT TRUNCATED AT 400 WORDS [9105222] Background : Cardiopulmonary bypass is associated with substantial release of catecholamines and cortisol for 12 or more h. A technique was assessed that may mitigate the responses with continuous 12‐h postoperative sedation using propofol . Methods : One hundred twenty‐one patients having primary elective cardiopulmonary bypass graft ( CABG ) surgery were enrolled in a double‐blind , r and omized trial and anesthetized using a st and ardized sufentanil‐midazolam regimen . When arriving at the intensive care unit ( ICU ) , patients were r and omly assigned to either group SC ( st and ard care ) , in which intermittent bolus administration of midazolam and morphine were given as required to keep patients comfortable ; or group CP ( continuous propofol ) , in which 12 h of continuous postoperative infusion of propofol was titrated to keep patients deeply se date d. Serial perioperative measurements of plasma and urine cortisol , epinephrine , norepinephrine , and dopamine were obtained ; heart rate and blood pressure were recorded continuously , and medication use , including requirements for opioids and vasoactive drugs , was recorded . Repeated‐ measures analysis was used to assess differences between study groups for plasma catecholamine and cortisol levels at each measurement time . Results : In the control state‐before the initiation of postoperative sedation in the ICU‐no significant differences between study groups were observed for urine or plasma catecholamine or cortisol concentrations . During the ICU study period , for the first 6–8 h , significant differences were found between study groups SC and CP in plasma cortisol ( SC = 28 + /‐ 15 mg/dl ; CP = 19 + /‐ 12 mg/dl ; estimated mean difference [ EMD ] = 9 mg/dl ; P = 0.0004 ) , plasma epinephrine ( SC = 132 + /‐ 120 micro gram/ml ; CP = 77 + /‐ 122 micro gram/ml ; EMD = 69 micro gram/ml ; P = 0.009 ) , urine cortisol ( SC = 216 + /‐ 313 micro gram/ml ; CP = 93 + /‐ 129 micro gram/ml ; EMD = 127 micro gram/ml ; P = 0.007 ) , urine dopamine ( SC = 85 + /‐ 48 micro gram ; CP = 52 + /‐ 43 micro gram ; EMD = 32 micro gram ; P = 0.002 ) , urine epinephrine ( SC = 7 + /‐ 8 micro gram ; CP = 4 + /‐ 5 micro gram ; EMD = 3 micro gram ; P = 0.009 ) , and urine norepinephrine ( SC = 24 + /‐ 14 mg ; CP = 13 + /‐ 9 mg ; EMD = 11 mg ; P = 0.0004 ) . Reductions in urine and plasma catecholamine and cortisol concentrations found for the CP group generally persisted during the 12‐h propofol infusion period and then rapidly returned toward control ( SC group ) values after propofol was discontinued . Postoperative opioid use was reduced in the CP group ( SC = 97 % ; CP = 49 % ; P = 0.001 ) , as was the incidence of ( SC = 79 % ; CP = 60 % ; P = 0.04 ) and hypertension ( SC = 58 % ; CP = 33 % ; P = 0.01 ) , but the incidence of hypotension was increased ( SC = 49 % ; CP = 81 % ; P = 0.001 ) . Conclusions : Cardiopulmonary bypass graft surgery is associated with substantial increases in plasma and urine catecholamine and cortisol concentrations , which persist for 12 or more h. This hormonal response may be mitigated by a technique of intensive continuous 12‐h postoperative sedation with propofol , which is associated with a decrease in tachycardia and hypertension and an increase in hypotension Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: Sedatives are commonly used for mechanically ventilated patients in intensive care units ( ICU ) . However , a variety of sedatives are available and their efficacy and safety have been compared in numerous trials with inconsistent results . To resolve uncertainties regarding usefulness of these sedatives , we performed a systematic review and network meta- analysis . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

24127118

[17311843] Background : TORCH ( Towards a Revolution in COPD Health ) is an international multicentre , r and omised , placebo-controlled clinical trial of inhaled fluticasone propionate/salmeterol combination treatment and its monotherapy components for maintenance treatment of moderately to severely impaired patients with chronic obstructive pulmonary disease ( COPD ) . The primary outcome is all-cause mortality . Cause-specific mortality and deaths related to COPD are additional outcome measures , but systematic methods for ascertainment of these outcomes have not previously been described . Methods : A Clinical Endpoint Committee ( CEC ) was tasked with categorising the cause of death and the relationship of deaths to COPD in a systematic , unbiased and independent manner . The key elements of the operation of the committee were the use of predefined principles of operation and definitions of cause of death and COPD -relatedness ; the independent review of cases by all members with development of a consensus opinion ; and a substantial infrastructure to collect medical information . Results : 911 deaths were review ed and consensus was reached in all . Cause-specific mortality was : cardiovascular 27 % , respiratory 35 % , cancer 21 % , other 10 % and unknown 8 % . 40 % of deaths were definitely or probably related to COPD . Adjudications were identical in 83 % of blindly re-adjudicated cases ( κ = 0.80 ) . COPD -relatedness was reproduced 84 % of the time ( κ = 0.73 ) . The CEC adjudication was equivalent to the primary cause of death recorded by the site investigator in 52 % of cases . Conclusion : A CEC can provide st and ardised , reliable and informative adjudication of COPD mortality that provides information which frequently differs from data collected from assessment by site investigators [22383665] BACKGROUND Effects of β(2)-adrenergic receptor gene ( ADRB2 ) polymorphism on therapeutic responses to long-acting β(2)-adrenergic agonists have not been evaluated in long-term COPD trials . We aim ed to investigate the effects of the ADRB2 Gly16Arg polymorphism on response to formoterol alone or in combination with the inhaled corticosteroid budesonide in patients with COPD . METHODS Patients ≥ 40 years of age with moderate to very severe COPD from the 12-month trial I ( NCT00206167 ) or the 6-month trial II ( NCT00206154 ) were r and omly assigned to bid budesonide/formoterol pressurized metered-dose inhaler ( pMDI ) 320/9 μg or 160/9 μg , budesonide pMDI 320 μg + formoterol dry powder inhaler 9 μg ( trial II ) , budesonide pMDI 320 μg ( trial II ) , formoterol dry powder inhaler 9 μg , or placebo . The effect of Gly16Arg on predose FEV(1 ) and 1-h postdose FEV(1 ) , exacerbations , diary variables , and adverse events were analyzed . RESULTS No significant interaction between genotype and treatment response was observed for predose ( P ≥ .197 ) or postdose FEV(1 ) ( P ≥ .125 ) in either pharmacogenetic study ( n = 2,866 ) . The number of COPD exacerbations per patient-treatment year was low and similar across genotypes for the active treatment groups ( both studies ) . Percentages of patients with adverse events were similar across Gly16Arg genotype groups for each treatment . CONCLUSION Therapeutic response and tolerability to long-term treatment with formoterol alone or in combination with budesonide was not modified by ADRB2 Gly16Arg genotype in two large independent pharmacogenetic studies in patients with moderate to very severe COPD [2707163] Guidelines recommend that patients with COPD are stratified arbitrarily by baseline severity ( FEV1 ) to decide when to initiate combination treatment with a long-acting β2-agonist and an inhaled corticosteroid . Assessment of baseline FEV1 as a continuous variable may provide a more reliable prediction of treatment effects . Patients from a 1-year , parallel-group , r and omized controlled trial comparing 50 μg salmeterol ( Sal ) , 500 μg fluticasone propionate ( FP ) , the combination ( Sal/FP ) and placebo , ( bid ) , were categorized post hoc into FEV1 < 50 % and FEV1 ≥50 % predicted subgroups ( n=949/513 respectively ) . Treatment effects on clinical outcomes – lung function , exacerbations , health status , diary card symptoms , and adverse events – were investigated . Treatment responses based on a pre-specified analysis explored treatment differences by severity as a continuous variable . Lung function improved with active treatment irrespective of FEV1 ; Sal/FP had greatest effect . This improvement appeared additive in milder disease ; synergistic in severe disease . Active therapy significantly reduced exacerbation rate in patients with FEV1 < 50 % predicted , not in milder disease . Health status and breathlessness improved with Sal/FP irrespective of baseline FEV1 ; adverse events were similar across subgroups . The spirometric response to Sal/FP varied with baseline FEV1 , and clinical benefits were not restricted to patients with severe disease . These data have implication s for COPD management decisions , suggesting that arbitrary stratifications of baseline severity are not necessarily indicative of treatment efficacy and that the benefits of assessing baseline severity as a continuous variable should be assessed in future trials [12637127] BACKGROUND Chronic obstructive pulmonary disease ( COPD ) is debilitating and costly to manage . A recent clinical trial concluded that formoterol , a long-acting beta(2)-adrenoceptor agonist , was more clinical ly effective than inpratropium bromide in the management of COPD . OBJECTIVE The aim of this study was to perform an economic assessment of the management of COPD with formeterol versus ipratropium bromide . METHODS Assessment were based on the results of a previously published 12-week , multicenter , double-masked , r and omized , parallel-group , placebo-controlled clinical trial comparing inhaled formoterol dry powder 12 and 24 microg BID with ipratropium bromide 40 microg QID pressurized metered dose inhaler and with placebo in 780 COPD patients . Treatment costs for study drugs and rescue medications were estimated from re source utilization and average wholesale prices . Costs were assessed with respect to forced expiratory lung volume in 1 second ( FEV(1 ) ) and patient-reported quality of life ( QOL ) as assessed via the St. George 's Respiratory Question naire . Cost-effectiveness ratios were calculated for each treatment arm and incremental cost-effectiveness ratios ( ICERs ) were calculated for each treatment relative to the next best alternative . Economic efficiency frontiers were identified . Sensitivity analysis was conducted . RESULTS Cost analysis with respect to FEV(1 ) revealed an economic efficiency frontier formed by placebo , ipratropium bromide 40 microg , and formoterol 12 microg at their respective FEV(1 ) levels , with cost-effectiveness ratios of $ 30.18 , $ 53.50 , and $ 142.04 , respectively , per FEV(1 ) . The ICER for ipratropium over placebo was $ 273.03 ; for formoterol 12 microg over ipratropium , $ 1611.32 . Cost analysis with respect to QOL showed an economic efficiency frontier formed by placebo and formoterol 12 microg at their respective QOL outcomes , with cost-effectiveness ratios of $ 25.96 and $ 32.56 , respectively , per QOL score change . The cost-effectiveness ratio for ipratropium was $ 69.40,which was not on the QOL economic efficiency frontier . The ICER for formoterol 12 microg over placebo was $ 34.51 per QOL score point . CONCLUSIONS Formoterol 12 microg provided greater QOL outcome than ipratropium bromide at an additional cost of $ 554.28 per year . Further research would be necessary to assess whether the differences in outcomes , particularly QOL , observed in the short term with formoterol would lead to favorable long-term health and economic outcomes [3580134] Background : Combination therapy with a long-acting bronchodilator and an inhaled corticosteroid ( ICS ) is recommended in patients with chronic obstructive pulmonary disease ( COPD ) who have frequent exacerbations . The efficacy and tolerability of the combination of budesonide/formoterol have been demonstrated in patients with COPD when administered via the dry powder inhaler ( DPI ) in a 1-year study and when administered via the hydrofluoroalkane ( HFA ) pressurized metered-dose inhaler ( pMDI ) in a 6-month study . Objective : This study assessed the long-term efficacy and tolerability of budesonide/formoterol HFA pMDI in patients with moderate to very severe COPD . Methods : This was a 12-month , r and omized , double-blind , double-dummy , parallel-group , active- and placebo-controlled , multicentre study ( NCT00206167 ) of 1964 patients aged ≥40 years with moderate to very severe COPD conducted from 2005 to 2007 at 237 sites in the US , Europe and Mexico . After 2 weeks of treatment based on previous therapy ( ICSs , short-acting bronchodilators allowed ) , patients received one of the following treatments twice daily : budesonide/formoterol pMDI 160/4.5 μg × two inhalations ( 320/9 μg ) ; budesonide/formoterol pMDI 80/4.5 μg × two inhalations ( 160/9 μg ) ; formoterol DPI 4.5 μg × two inhalations ( 9 μg ) ; or placebo . Main outcome measures : The co- primary efficacy variables were pre-dose forced expiratory volume in 1 second ( FEV1 ) and 1-hour post-dose FEV1 . Results : Budesonide/formoterol 320/9 μg demonstrated greater improvements in pre-dose FEV1 versus formoterol ( p = 0.008 ) , and both budesonide/formoterol doses demonstrated greater improvements in 1-hour post-dose FEV1 versus placebo ( p < 0.001 ) . The rate of COPD exacerbations was lower in both budesonide/formoterol groups compared with formoterol and placebo ( p ≤ 0.004 ) . Both budesonide/formoterol doses were more effective than placebo ( p ≤ 0.006 ) for controlling dyspnoea and improving health status ( St George ’s Respiratory Question naire ) . All treatments were generally well tolerated . The incidence of pneumonia was not different for active ( 3.4–4.0 % ) and placebo ( 5.0 % ) groups . Conclusions : Budesonide/formoterol pMDI ( 320/9 μg and 160/9 μg ) improved pulmonary function and reduced symptoms and exacerbations over 1 year in patients with moderate to very severe COPD . Only budesonide/formoterol pMDI 320/9 μg demonstrated greater efficacy for both co- primary variables compared with formoterol DPI 9 μg . Both budesonide/formoterol pMDI dosages were well tolerated relative to formoterol and placebo [18511702] RATIONALE Chronic obstructive pulmonary disease ( COPD ) is characterized by an accelerated decline in lung function . No drug has been shown conclusively to reduce this decline . OBJECTIVES In a post hoc analysis of the Toward a Revolution in COPD Health ( TORCH ) study , we investigated the effects of combined salmeterol 50 microg plus fluticasone propionate 500 microg , either component alone or placebo , on the rate of post-bronchodilator FEV(1 ) decline in patients with moderate or severe COPD . METHODS A r and omized , double-blind , placebo-controlled study was conducted from September 2000 to November 2005 in 42 countries . Of 6,112 patients from the efficacy population , 5,343 were included in this analysis . MEASUREMENTS AND MAIN RESULTS Spirometry was measured every 24 weeks for 3 years . There were 26,539 on-treatment observations . The adjusted rate of decline in FEV(1 ) was 55 ml/year for placebo , 42 ml/year for salmeterol , 42 ml/year for fluticasone propionate , and 39 ml/year for salmeterol plus fluticasone propionate . Salmeterol plus fluticasone propionate reduced the rate of FEV(1 ) decline by 16 ml/year compared with placebo ( 95 % confidence interval [ CI ] , 7 - 25 ; P < 0.001 ) . The difference was smaller for fluticasone propionate and salmeterol compared with placebo ( 13 ml/year ; 95 % CI , 5 - 22 ; P = 0.003 ) . Rates of decline were similar among the active treatment arms . FEV(1 ) declined faster in current smokers and patients with a lower body mass index , and varied between world regions . Patients who exacerbated more frequently had a faster FEV(1 ) decline . CONCLUSIONS Pharmacotherapy with salmeterol plus fluticasone propionate , or the components , reduces the rate of decline of FEV(1 ) in patients with moderate-to-severe COPD , thus slowing disease progression . Clinical trial ( GSK Study Code SCO30003 ) registered with www . clinical trials.gov ( NCT00268216 ) [15332386] Only long-term home oxygen therapy has been shown in r and omised controlled trials to increase survival in chronic obstructive pulmonary disease ( COPD ) . There have been no trials assessing the effect of inhaled corticosteroids and long-acting bronchodilators , alone or in combination , on mortality in patients with COPD , despite their known benefit in reducing symptoms and exacerbations . The “ TOwards a Revolution in COPD Health ” ( TORCH ) survival study is aim ing to determine the impact of salmeterol/fluticasone propionate ( SFC ) combination and the individual components on the survival of COPD patients . TORCH is a multicentre , r and omised , double-blind , parallel-group , placebo-controlled study . Approximately 6,200 patients with moderate-to-severe COPD were r and omly assigned to b.i.d . treatment with either SFC ( 50/500 µg ) , fluticasone propionate ( 500 µg ) , salmeterol ( 50 µg ) or placebo for 3 yrs . The primary end-point is all-cause mortality ; secondary end-points are COPD morbidity relating to rate of exacerbations and health status , using the St George 's Respiratory Question naire . Other end-points include other mortality and exacerbation end-points , requirement for long-term oxygen therapy , and clinic lung function . Safety end-points include adverse events , with additional information on bone fractures . The first patient was recruited in September 2000 and results should be available in 2006 . This paper describes the “ TOwards a Revolution in COPD Health ” study and explains the rationale behind it [20693243] Indacaterol is a novel , inhaled , once-daily , ultra-long-acting & bgr;2-agonist bronchodilator recently approved in Europe for the treatment of chronic obstructive pulmonary disease ( COPD ) . The aim of the present study was to investigate the efficacy and safety of indacaterol compared with placebo and the twice-daily & bgr;2-agonist , salmeterol , as an active control . Patients with moderate-to-severe COPD were r and omised to 6 months double-blind treatment with indacaterol ( 150 & mgr;g once daily ) , salmeterol ( 50 & mgr;g twice daily ) or placebo . The primary efficacy end-point was trough ( 24 h post-dose ) forced expiratory volume in 1 s ( FEV1 ) after 12 weeks . 1,002 patients were r and omised and 838 ( 84 % ) completed the study . Indacaterol increased trough FEV1 at week 12 by 170 mL over placebo ( p<0.001 ) and by 60 mL over salmeterol ( p<0.001 ) . Both active treatments improved health status ( St George 's Respiratory Question naire ) and dyspnoea ( transition dyspnoea index ) compared with placebo , with differences between them favouring indacaterol . Safety profiles were similar across the treatment groups , and both indacaterol and salmeterol were well tolerated . Once-daily treatment with 150 & mgr;g indacaterol had a significant and clinical ly relevant bronchodilator effect over 24 h post-dose and improved health status and dyspnoea to a greater extent than twice-daily 50 & mgr;g salmeterol . Indacaterol should prove a useful additional treatment for patients with COPD [12796155] BACKGROUND Patients with COPD have an increased risk of cardiovascular disease . Despite the clinical benefits of long-acting beta-agonist agents in the treatment of COPD , patients may be at an increased risk of cardiovascular toxicity , including tachyarrhythmia due to beta-adrenergic stimulation . OBJECTIVE To evaluate the cardiovascular safety of salmeterol in COPD patients by conducting a pooled analysis of cardiovascular safety data . DESIGN R and omized , double-blind , parallel group , multiple-dose studies , which included salmeterol , 50 micro g bid , and placebo arms . STUDY SELECTION Seven of a total of 17 studies met the predefined inclusion requirements and were pooled . A total of 1,443 patients received placebo , while 1,410 patients received salmeterol , 50 micro g bid . The median duration of treatment was 24 weeks ( range , 12 to 52 weeks ) . RESULTS Treatment with salmeterol , 50 micro g bid , showed no increased risk of cardiovascular adverse events ( AEs ) compared with placebo ( relative risk , 1.03 ; 95 % confidence interval , 0.8 to 1.3 ; p = 0.838 ) . Both groups had a similar incidence of cardiovascular events ( 8 % ) , including cardiovascular deaths . The incidence of cardiovascular AEs increased with age , concurrent cardiovascular conditions , and treatment with antiarrhythmic/bradycardic agents , although increases were comparable in both treatment groups . There were no episodes of sustained ventricular tachycardia , and no clinical ly significant differences were observed in 24-h heart rate , ventricular and supraventricular ectopic events , qualitative ECGs , QT intervals , or vital signs between the salmeterol , 50 micro g bid , group and the placebo group . Similar findings were observed when patients were stratified for age of > 65 years or the known presence of cardiovascular disease . CONCLUSIONS Treatment with salmeterol , 50 micro g bid , does not increase the risk of cardiovascular AEs in this population of COPD patients compared with placebo [11549532] We compared the effectiveness of inhaled formoterol with that of ipratropium in the treatment of chronic obstructive pulmonary disease ( COPD ) . After a 2-wk run-in period , 780 patients with COPD were r and omized to receive for 12 wk formoterol dry powder 12 or 24 microg twice daily , ipratropium bromide 40 microg four times daily , or placebo in a multicenter , double-blind , parallel-group study . The primary efficacy variable was the area under the curve for forced expiratory volume in 1 s ( FEV(1 ) ) measured over 12 h after 12 wk of treatment . Secondary variables included diary symptoms and quality of life . Both doses of formoterol and ipratropium significantly increased the area under the curve for FEV(1 ) in comparison with placebo ( all p < 0.001 ) . Both doses of formoterol were also significantly superior to ipratropium ( all p < 0.025 ) . Compared with placebo , both doses of formoterol significantly improved symptoms ( all p < or = 0.007 ) and quality of life ( p < 0.01 for total scores ) whereas ipratropium did not show significant effects ( all p > or = 0.3 ) . All study treatments exhibited a similar safety profile . We conclude that formoterol is more effective than ipratropium bromide in the treatment of COPD , as the efficacy of ipratropium on airflow obstruction does not translate into a clinical benefit that patients can perceive [20180870] BACKGROUND In 2003 , chronic obstructive pulmonary disease ( COPD ) accounted for 46 % of the burden of chronic respiratory disease in the Australian community . In the 65 - 74-year-old age group , COPD was the sixth leading cause of disability for men and the seventh for women . AIMS To measure the influence of disease severity , COPD phenotype and comorbidities on acute health service utilization and direct acute care costs in patients admitted with COPD . METHODS Prospect i ve cohort study of 80 patients admitted to the Royal Melbourne Hospital in 2001 - 2002 for an exacerbation of COPD . Patients were followed for 12 months and data were collected on acute care utilization . Direct hospital costs were derived using Transition II , an activity-based costing system . Individual patient costs were then modelled to ascertain which patient factors influenced total direct hospital costs . RESULTS Direct costs were calculated for 225 episodes of care , the median cost per admission was AU$3124 ( interquartile range $ 1393 to $ 5045 ) . The median direct cost of acute care management per patient per year was AU$7273 ( interquartile range $ 3957 to $ 14 448 ) . In a multivariate analysis using linear regression modelling , factors predictive of higher annual costs were increasing age ( P= 0.041 ) , use of domiciliary oxygen ( P= 0.008 ) and the presence of chronic heart failure ( P= 0.006 ) . CONCLUSION This model has identified a number of patient factors that predict higher acute care costs and awareness of these can be used for service planning to meet the needs of patients admitted with COPD [11948033] STUDY OBJECTIVE To compare the efficacy , tolerability , and safety of therapy with formoterol and oral slow-release theophylline ( THEO ) in patients with COPD . DESIGN A r and omized , parallel-group study , with double-blind arms for formoterol and placebo ( PL ) and an open arm for oral slow-release THEO administered in individual doses on the basis of plasma concentrations . SETTING Eighty-one centers worldwide . PATIENTS Eight hundred fifty-four patients with symptomatic COPD . INTERVENTION Comparison of twice-daily inhaled formoterol dry powder ( 12 or 24 microg ) , PL , and THEO ( individualized doses ) over 12 months . MEASUREMENTS AND RESULTS Compared to PL , doses of formoterol and THEO both significantly improved the area under the curve for FEV(1 ) measured over a period of 12 h following the morning dose of study medication at 3 and 12 months ( p < 0.001 for all comparisons ) . Therapy with formoterol , 12 microg , was significantly more effective than that with THEO ( p < or = 0.026 ) . Formoterol significantly reduced the percentage of " bad days " ( i.e. , days with at least two individual symptom scores > or = 2 and /or a reduction in peak expiratory flow from a baseline of > 20 % ; p < or = 0.035 vs. PL and THEO ) , and the use of salbutamol rescue medication ( p < or = 0.003 vs PL ) over the whole treatment period , while the effect of THEO was similar to that of PL . Therapy with formoterol and THEO was more effective than PL at improving quality of life for > 12 months ( p < or = 0.030 ) . Treatment-related adverse events and discontinuations were more frequent among patients receiving THEO than among those receiving formoterol . CONCLUSIONS Long-term treatment with inhaled formoterol dry powder is more effective and better tolerated than treatment with therapeutically appropriate doses of oral slow-release THEO in symptomatic patients with COPD [20522841] Background Indacaterol is a long-acting inhaled β2-agonist ( LABA ) for the treatment of chronic obstructive pulmonary disease ( COPD ) . In previous studies , indacaterol provided 24 h bronchodilation on once-daily dosing with a fast onset of action . This study compared the efficacy and safety of indacaterol with the twice-daily LABA formoterol and placebo over 1 year . Methods Patients with moderate to severe COPD were r and omised to receive once-daily indacaterol 300 μg ( n=437 ) or 600 μg ( n=428 ) , twice-daily formoterol 12 μg ( n=435 ) or placebo ( n=432 ) for 52 weeks in a double-blind double-dummy parallel group study . The primary efficacy variable was forced expiratory volume in 1 s ( FEV1 ) measured 24 h postdose after 12 weeks ( indacaterol vs placebo ) . Other outcomes included dyspnoea ( transition dyspnoea index , TDI ) , use of as-needed salbutamol , symptom-based measures recorded on diary cards , exacerbations , health status ( St George 's Respiratory Question naire ) , BODE index ( body mass index , obstruction , dyspnoea , exercise ) , safety and tolerability . Results Indacaterol increased 24 h postdose FEV1 after 12 weeks by 170 ml ( both doses ) versus placebo and by 100 ml versus formoterol ( all p<0.001 ) . These significant differences were maintained at 52 weeks . Symptomatic outcomes were improved compared with placebo with all active treatments , and indacaterol was more effective than formoterol in improving TDI score and reducing the need for as-needed salbutamol . Indacaterol was well tolerated and had a good overall safety profile , including minimal impact on QTc interval and systemic β2-mediated events . Conclusions Once-daily indacaterol is an effective 24 h bronchodilator that improves symptoms and health status and confers clinical improvements over a twice-daily 12 h LABA as a treatment for patients with moderate to severe COPD . Trial registration number NCT 00393458 [12570112] The efficacy and safety of budesonide/formoterol in a single inhaler compared with placebo , budesonide and formoterol were evaluated in patients with moderate-to-severe chronic obstructive pulmonary disease ( COPD ) . In a 12-month , r and omised , double-blind , placebo-controlled , parallel-group study in 812 adults ( mean age 64 yrs , mean forced expiratory volume in one second ( FEV1 ) 36 % predicted normal ) , patients received two inhalations twice daily of either budesonide/formoterol ( Symbicort ® ) 160/4.5 µg ( delivered dose ) , budesonide 200 µg ( metered dose ) , formoterol 4.5 µg or placebo . Severe exacerbations and FEV1 ( primary variables ) , peak expiratory flow ( PEF ) , COPD symptoms , health-related quality of life ( HRQL ) , mild exacerbations , use of reliever β2‐agonist and safety variables were recorded . Budesonide/formoterol reduced the mean number of severe exacerbations per patient per year by 24 % versus placebo and 23 % versus formoterol . FEV1 increased by 15 % versus placebo and 9 % versus budesonide . Morning PEF improved significantly on day 1 versus placebo and budesonide ; after 1 week , morning PEF was improved versus placebo , budesonide and formoterol . Improvements in morning and evening PEF versus comparators were maintained over 12 months . Budesonide/formoterol decreased all symptom scores and use of reliever β2‐agonists significantly versus placebo and budesonide , and improved HRQL versus placebo . All treatments were well tolerated . These results suggest a role for budesonide/formoterol in the long-term management of moderate-to-severe chronic obstructive pulmonary disease [12583942] BACKGROUND Inhaled long-acting beta2 agonists improve lung function and health status in symptomatic chronic obstructive pulmonary disease ( COPD ) , whereas inhaled corticosteroids reduce the frequency of acute episodes of symptom exacerbation and delay deterioration in health status . We postulated that a combination of these treatments would be better than each component used alone . METHODS 1465 patients with COPD were recruited from outpatient departments in 25 countries . They were treated in a r and omised , double-blind , parallel-group , placebo-controlled study with either 50 microg salmeterol twice daily ( n=372 ) , 500 microg fluticasone twice daily ( n=374 ) , 50 microg salmeterol and 500 microg fluticasone twice daily ( n=358 ) , or placebo ( n=361 ) for 12 months . The primary outcome was the pretreatment forced expiratory volume in 1s ( FEV1 ) after 12 months treatment ' and after patients had abstained from all bronchodilators for at least 6h and from study medication for at least 12h . Secondary outcomes were other lung function measurements , symptoms and rescue treatment use , the number of exacerbations , patient withdrawals , and disease-specific health status . We assessed adverse events , serum cortisol concentrations , skin bruising , and electrocardiograms . Analysis was as predefined in the study protocol . FINDINGS All active treatments improved lung function , symptoms , and health status and reduced use of rescue medication and frequency of exacerbations . Combination therapy improved pretreatment FEV1 significantly more than did placebo ( treatment difference 133 mL , 95 % CI 105 - 161 , p<0.0001 ) , salmeterol ( 73 mL , 46 - 101 , p<0.0001 ) , or fluticasone alone ( 95 mL , 67 - 122 , p<0.0001 ) . Combination treatment produced a clinical ly significant improvement in health status and the greatest reduction in daily symptoms . All treatments were well tolerated with no difference in the frequency of adverse events , bruising , or clinical ly significant falls in serum cortisol concentration . INTERPRETATION Because inhaled long-acting beta2 agonists and corticosteroid combination treatment produces better control of symptoms and lung function , with no greater risk of side-effects than that with use of either component alone , this combination treatment should be considered for patients with COPD [9150318] The objectives of this study were to compare the efficacy and safety of salmeterol xinafoate ( 50 and 100 microg b.i.d . ) with that of placebo , when added to existing therapy , in the treatment of patients with chronic obstructive pulmonary disease ( COPD ) . Six hundred and seventy four patients were r and omized to receive either salmeterol 50 microg b.i.d . , salmeterol 100 microg b.i.d . , or placebo treatment for a period of 16 weeks . The results showed a significant improvement in daily symptom scores noted for patients taking either 50 microg ( p=0.043 ) or 100 microg b.i.d . salmeterol ( p=0.01 ) compared with placebo , with a corresponding decrease in additional daytime salbutamol requirements for both salmeterol groups . The same pattern was reflected for night-time symptoms and additional salbutamol use . During treatment , forced expiratory volume in one second ( FEV1 ) measurements improved significantly in each salmeterol group , with up to a 7 % improvement observed at the end of the study . Although no difference was observed between treatment groups for the distance walked in 6 min , patients treated with salmeterol 50 microg b.i.d . were significantly less breathless than those treated with placebo after their 6 min walk , after 8 weeks ( p=0.024 ) and 16 weeks ( p=0.004 ) of therapy . Adverse events were similar in all three groups except for tremor , which was significantly higher in the 100 microg b.i.d . salmeterol group ( p=0.005 ) compared both with 50 microg b.i.d . salmeterol and placebo . Salmeterol offered further positive improvement to the effect of therapy in patients with chronic obstructive pulmonary disease when added to their existing regimens . This clinical improvement was similar both with 50 and 100 microg b.i.d . dosage , although the group receiving 50 microg b.i.d . tolerated the drug better than those receiving 100 microg b.i.d . salmeterol [12030736] The aim of this study was to investigate formoterol , an inhaled long-acting β2-agonist , in patients with chronic obstructive pulmonary disease ( COPD ) . Six-hundred and ninety-two COPD patients , mean baseline forced expiratory volume in one second ( FEV1 ) 54 % , FEV1/forced vital capacity 75 % of predicted , reversibility 6.4 % pred , were treated with formoterol ( 4.5 , 9 or 18 µg b.i.d . ) or placebo via Turbuhaler ® for 12 weeks . Symptoms were recorded daily . Spirometry and the incremental shuttle walking test ( SWT ) were performed at clinic visits . Compared with placebo , 18 µg b.i.d . formoterol reduced the mean total symptom score by 13 % and increased the percentage of nights without awakenings by 15 % . Formoterol ( 9 and 18 µg b.i.d . ) significantly reduced symptom scores for breathlessness ( −7 % and −9 % , respectively ) and chest tightness ( −11 % and −8 % , respectively ) , reduced the need for rescue medication ( −25 % and −18 % , respectively ) , and increased symptom-free days ( 71 % and 86 % , respectively ) . FEV1 improved significantly after all three doses of formoterol ( versus placebo ) . No differences were found between groups in SWT walking distance . No unexpected adverse events were seen . In conclusion , 9 and 18 µg b.i.d . formoterol reduced symptoms and increased the number of symptom-free days in a dose-dependent manner in chronic obstructive pulmonary disease patients . Formoterol improved lung function at a dose of 4.5 µg b.i.d . and higher [14680078] Lung function in chronic obstructive pulmonary disease ( COPD ) can be improved acutely by oral corticosteroids and bronchodilators . Whether clinical improvement can be maintained by subsequent inhaled therapy is unknown . COPD patients ( n=1,022 , mean prebronchodilator forced expiratory volume in one second ( FEV1 ) 36 % predicted ) initially received formoterol ( 9 µg b.i.d . ) and oral prednisolone ( 30 mg o.d . ) for 2 weeks . After this time , patients were r and omised to b.i.d . inhaled budesonide/formoterol 320/9 µg , budesonide 400 µg , formoterol 9 µg or placebo for 12 months . Postmedication FEV1 improved by 0.21 L and health-related quality of life using the St George 's Respiratory Question naire ( SGRQ ) by 4.5 units after run-in . Fewer patients receiving budesonide/formoterol withdrew from the study than those receiving budesonide , formoterol or placebo . Budesonide/formoterol patients had a prolonged time to first exacerbation ( 254 versus 96 days ) and maintained higher FEV1 ( 99 % versus 87 % of baseline ) , both primary variables versus placebo . They had fewer exacerbations ( 1.38 versus 1.80 exacerbations per patient per year ) , had higher prebronchodilator peak expiratory flow , and showed clinical ly relevant improvements in SGRQ versus placebo ( −7.5 units ) . Budesonide/formoterol was more effective than either monocomponent in both primary variables . Budesonide/formoterol in a single inhaler ( Symbicort ® ) maintains the benefit of treatment optimisation , stabilising lung function and delaying exacerbations more effectively than either component drug alone or placebo [3233513] Background This study evaluated the efficacy and safety of the long-acting β2-agonist formoterol in patients with moderate-to-severe COPD . Methods This double-blind , placebo-controlled , parallel-group , multinational phase III study r and omized patients ≥ 40 years of age with moderate-to-severe COPD to inhaled formoterol 4.5 or 9 μg twice daily ( bid ) via Turbuhaler ® or placebo for 12 weeks . Salbutamol 100 μg/actuation via pMDI was permitted as reliever medication . The primary outcome variable was change ( ratio ) from baseline to treatment period in FEV1 60-min post-dose . Results 613 patients received treatment ( formoterol 4.5 μg n = 206 ; 9 μg n = 199 ; placebo n = 208 ) ; 539 ( 87.9 % ) male ; 324 ( 52.9 % ) Japanese and 289 ( 47.1 % ) European . End of study increases in FEV1 60-min post-dose were significantly greater ( p < 0.001 for both ) with formoterol 4.5 and 9 μg bid ( 113 % of baseline for both ) than with placebo , as were all secondary outcome measures . The proportion of patients with an improvement in St George 's Respiratory Question naire score of ≥ 4 was 50.2 % for formoterol 4.5 μg ( p = 0.0682 vs. placebo ) , 59.2 % ( p = 0.0004 ) for 9 μg , and 41.3 % for placebo . Reduction in reliever medication use was significantly greater with formoterol vs. placebo ( 9 μg : -0.548 , p < 0.001 ; 4.5 μg : -0.274 , p = 0.027 ) , with 9 μg being significantly superior to 4.5 μg ( -0.274 , p = 0.029 ) . Formoterol was well tolerated with the incidence and type of adverse events not being different for the three groups . Conclusions Formoterol 4.5 μg and 9 μg bid was effective and well tolerated in patients with COPD ; there was no difference between formoterol doses for the primary endpoint ; however , an added value of formoterol 9 μg over 4.5 μg bid was observed for some secondary endpoints . Trial registration NCT00628862 ( Clinical Trials.gov ) ; D5122C00001 ( AstraZeneca Study code ) [10208192] STUDY OBJECTIVES To examine and compare the efficacy and safety of salmeterol xinafoate , a long-acting inhaled beta2-adrenergic agonist , with inhaled ipratropium bromide and inhaled placebo in patients with COPD . DESIGN A stratified , r and omized , double-blind , double-dummy , placebo-controlled , parallel group clinical trial . SETTING Multiple sites at clinics and university medical centers throughout the United States . PATIENTS Four hundred eleven symptomatic patients with COPD with FEV1 < or = 65 % predicted and no clinical ly significant concurrent disease . INTERVENTIONS Comparison of inhaled salmeterol ( 42 microg twice daily ) , inhaled ipratropium bromide ( 36 microg four times a day ) , and inhaled placebo ( 2 puffs four times a day ) over 12 weeks . RESULTS Salmeterol xinafoate was significantly ( p < 0.0001 ) better than placebo and ipratropium in improving lung function at the recommended doses over the 12-week trial . Both salmeterol and ipratropium reduced dyspnea related to activities of daily living compared with placebo ; this improvement was associated with reduced use of supplemental albuterol . Analyses of time to first COPD exacerbation revealed salmeterol to be superior to placebo and ipratropium ( p < 0.05 ) . Adverse effects were similar among the three treatments . CONCLUSIONS These collective data support the use of salmeterol as first-line bronchodilator therapy for the long-term treatment of airflow obstruction in patients with COPD [12449166] The aim of this study was to compare the effects of formoterol , ipratropium bromide and a placebo on walking distance , lung function , symptoms and quality of life ( QoL ) in chronic obstructive pulmonary disease ( COPD ) patients . A total of 183 patients ( mean age 64 yrs , 86 female ) with moderate-to-severe nonreversible COPD participated in this r and omised , double-blind , parallel-group study . After a 2-week placebo run-in , patients were r and omised to formoterol Turbuhaler ® 18 μg b.i.d . ( delivered dose ) , ipratropium bromide 80 μg t.i.d . via a pressurised metered dose inhaler , or placebo for 12 weeks . Inhaled short-acting β2-agonists were allowed as relief medication and inhaled glucocorticosteroids were allowed at a constant dose . The primary variable was walking distance in the shuttle walking test ( SWT ) . Baseline mean SWT distance was 325 m , mean forced expiratory volume in one second ( FEV1 ) was 40 % predicted . Clinical ly significant improvements in SWT ( > 30 m ) were seen in 41 , 38 and 30 % of formoterol , ipratropium and placebo patients , respectively ( not significant ) . Mean increases from run-in were 19 , 17 and 5 m in the formoterol , ipratropium and placebo groups , respectively . Both active treatments significantly improved FEV1 , forced vital capacity , peak expiratory flow and daytime dyspnoea score compared with placebo . Formoterol reduced relief medication use compared with placebo . Neither active treatment improved QoL. Formoterol and ipratropium improved airway function and symptoms , without significant improvements in the shuttle walking test [14555565] OBJECTIVES To investigate the determinants of patient withdrawal from our study , and the effect of these withdrawals on the outcome of treatment with inhaled corticosteroids in patients with COPD . DESIGN A double-blind , placebo-controlled , r and omized trial . SETTING Eighteen outpatient centers in the United Kingdom . PARTICIPANTS Seven hundred fifty-one patients with stable COPD defined clinical ly and as baseline postbronchodilator FEV(1 ) > or = 0.8 L and < 85 % predicted , FEV(1)/FVC ratio < 70 % , and FEV(1 ) change after albuterol < 10 % of predicted . INTERVENTION R and om assignment of either 500 microg bid of inhaled fluticasone propionate ( FP ) using a spacer device or an identical placebo inhaler . Treatment was continued for 3 years or until patients withdrew from follow-up . MEASUREMENTS AND RESULTS Postbronchodilator FEV(1 ) was measured on three occasions before r and omization and every 3 months thereafter . Health status was assessed by the disease-specific St. George Respiratory Question naire ( SGRQ ) and the modified short-form 36 question naire ( SF-36 ) at baseline and every 6 months . Three hundred thirty-nine patients withdrew , of whom 156 patients received FP . Prescription of frequent courses of oral prednisolone was the most common reason for withdrawing as specified in the protocol ( 69 patients in the FP group withdrew due to respiratory symptoms , compared with 93 patients in the placebo group ) . This explained the significantly greater dropout of placebo-treated patients that was most evident when FEV(1 ) was < 50 % predicted . Patients withdrawing had a significantly more rapid decline in health status , measured by both the SGRQ and the SF-36 ( p < 0.001 ) . Those withdrawing from the placebo group had a more rapid decline in FEV(1 ) and more exacerbations than the FP-treated groups . Baseline FEV(1 ) was lower in dropouts than in patients completing the study receiving placebo , but there was no difference between the respective groups receiving FP . CONCLUSIONS Patients who withdrew from follow-up were those with the most rapidly deteriorating health status and lung function . Losing these patients from the final analysis can reduce the power of a study to achieve its primary end point [19717476] The TOwards a Revolution in COPD Health ( TORCH ) study was a 3-yr multicentre trial of 6,112 patients r and omised to salmeterol ( Salm ) , fluticasone propionate ( FP ) , a Salm/FP combination ( SFC ) or placebo ( P ) . Here the cost-effectiveness of treatments evaluated in the TORCH study is assessed . For four regions , 3-yr all-cause hospitalisation , medication and outpatient care costs were calculated . The sample was restricted to the 21 countries ( n = 4,237 ) in which European quality of life five-dimension ( EQ-5D ) data were collected in order to estimate the number of quality -adjusted life years ( QALYs ) . Regression models were fitted to survival , study medication cost , other medication cost and EQ-5D data in order to estimate total cost , number of QALYs and cost per QALY , adjusted for missing data and region . SFC had a trial-wide estimate of cost per QALY of 43,600 US dollars ( USD ) compared with P ( 95 % confidence interval 21,400–123,500 USD ) . Estimates for Salm versus P ( 197,000 USD ) and FP versus P ( 78,000 USD ) were less favourable . The US estimates were greater than those from other regions ; for SFC versus P , the cost per QALY was 77,100 ( 46,200–241,700 ) USD compared to 24,200 ( 15,200–56,100 ) USD in Western Europe . Compared with P , SFC has a lower incremental cost-effectiveness ratio than either FP or Salm used alone , and is , therefore , preferred to these monotherapies on the grounds of cost-effectiveness [12556006] Chronic obstructive pulmonary disease ( COPD ) is associated with a large economic and social burden . Few economic studies have examined the benefits of inhaled therapy for patients with COPD . This 16-week study examined the cost-effectiveness of salmeterol in this patient group . Patients with a history of COPD were r and omised to treatment with salmetrol 50 mcg ( 229 patients ) or placebo ( 227 patients ) twice daily administered by metered-dose inhaler in addition to normal therapy . Forced expiratory volume ( FEV1 ) was measured and patients recorded the impact of their symptoms in a daily diary . Health status was assessed using the St Georges Respiratory Question naire . A significantly higher proportion of salmeterol-treated patients had an increase of > 15 % in FEV1 . Salmeterol patients had a higher mean proportion of symptom-free days and nights than those in the placebo group . More salmeterol patients had a clinical ly significant improvement in health status . Total healthcare costs were increased in the salmeterol group , but hospital and GP visit costs and concurrent COPD medication costs were lower . The reduction in hospital costs was sufficient to offset a substantial portion of the acquisition cost of salmeterol . Addition of salmeterol to COPD patients ' current therapy improved lung function , health status at the expense of a modest increase in costs compared with usual therapy [21397482] BACKGROUND Indacaterol is a novel , inhaled , ultra-long-acting β(2)-agonist bronchodilator for maintenance use in patients with COPD . The aim of this paper is to assess the effect of indacaterol on dyspnoea and health status , using pooled study data to evaluate the relative efficacy of indacaterol and existing bronchodilators . METHODS Individual patient data were pooled from three r and omized , placebo-controlled studies ( NCT00393458 ; NCT00567996 ; NCT00463567 ) , conducted in patients with moderate-to-severe COPD . Treatments were double-blind indacaterol 150 μg ( n = 746 ) or 300 μg ( n = 853 ) once-daily , formoterol 12 μg twice-daily ( n = 556 ) , salmeterol 50 μg twice-daily ( n = 333 ) and placebo ( n = 1185 ) ; and open-label tiotropium 18 μg once-daily ( n = 415 ) . Evaluation after 6 months ' treatment was by transition dyspnoea index ( TDI ; minimum clinical ly important difference [ MCID ] ≥1 point ) , and St George 's Respiratory Question naire ( SGRQ ; MCID ≥4 units ) . RESULTS Differences from placebo in TDI total score were 1.01 ( indacaterol 150 μg ) 1.28 ( indacaterol 300 μg ) , 0.74 ( formoterol ) , 0.92 ( salmeterol ) and 0.88 ( tiotropium ) ( all p < 0.05 ) , with corresponding odds ratios versus placebo for exceeding the MCID from baseline of 1.91 , 2.69 , 2.02 , 1.79 and 1.49 ( all p < 0.05 ) . Differences versus placebo in SGRQ total score were -4.4 ( indacaterol 150 μg ) , -3.4 ( indacaterol 300 μg ) , -2.8 ( formoterol ) , -4.0 ( salmeterol ) and -1.7 ( tiotropium ) ( all p < 0.05 ) , with corresponding odds ratios versus placebo for exceeding the MCID of 1.95 , 1.63 , 1.54 , 1.82 and 1.29 ( all p < 0.05 apart from tiotropium ) . CONCLUSIONS Indacaterol provided clinical ly important improvements in dyspnoea and health status that were at least as good as and often better than those observed with existing bronchodilator treatments for COPD [20685748] Background Previous studies have suggested that long-term use of β agonists to treat chronic obstructive pulmonary disease ( COPD ) may increase the risk of cardiovascular adverse events . In this post hoc analysis , data from the TOwards a Revolution in COPD Health ( TORCH ) study were used to investigate whether use of the long-acting β2 agonist salmeterol over 3 years increased the risk of cardiovascular adverse events in patients with moderate to severe COPD . Methods TORCH was a r and omised , double-blind , placebo controlled study conducted at 444 centres in 42 countries . Patients ( n=6184 ; safety population ) received twice daily combined salmeterol 50 μg plus fluticasone propionate 500 μg ( SFC ) , either component alone , or placebo . Adverse events were recorded every 12 weeks for 3 years . Results The probability of having a cardiovascular adverse event by 3 years was 24.2 % for placebo , 22.7 % for salmeterol , 24.3 % for fluticasone propionate and 20.8 % for SFC . Although a history of myocardial infa rct ion doubled the probability of cardiovascular adverse events , the event rates remained similar across treatment groups . Conclusion Post hoc analysis of the 3-year TORCH data set showed that salmeterol alone or in combination ( SFC ) did not increase the risk of cardiovascular events in patients with moderate to severe COPD [12068339] BACKGROUND In the past , the role of long-acting beta(2- ) agonists in chronic obstructive pulmonary disease ( COPD ) relative to other agents has been unclear . OBJECTIVES To compare the effect of adding salmeterol ( 50 microg bid ) or placebo to concurrent anticholinergic therapy on symptom scores , quality of life , prebronchodilator lung function and exacerbations in patients with moderately severe COPD . METHODS This was a double-blind , r and omized , parallel-group study in patients aged 40 years or older receiving anticholinergic medication . Patients were r and omly assigned to treatment with placebo ( n=207 ) or salmeterol ( n=201 ) via a Diskus/Accuhaler inhaler for 24 weeks . RESULTS The morning trough ( pre study drug ) forced expiratory volume in 1 s ( FEV(1 ) ) increased significantly above baseline levels among the salmeterol-treated patients . Improvement in FEV(1 ) was greater in the salmeterol group than in the placebo group at four weeks ( difference 0.06 L , P<0.005 ) , eight weeks ( 0.06 L , P<0.005 ) and 16 weeks ( 0.05 L , P<0.05 ) after the start of treatment . There was a nonsignificant trend in favour of salmeterol after 24 weeks of treatment ( P=0.198 ) . Improvements in morning peak flow were significantly greater in the salmeterol group over 24 weeks ( P<0.01 ) . Although symptom scores were numerically higher in the salmeterol group than in the placebo group and there was less requirement for rescue bronchodilator use , these differences were not statistically significant . In the salmeterol group , fewer patients had exacerbations of COPD , and there was a trend toward an improved quality of life . The safety profile of the two groups was similar . CONCLUSIONS Salmeterol has a beneficial effect when added to existing anticholinergic therapy in patients with COPD . The regular use of salmeterol for six months was not associated with worsening of the underlying airflow obstruction ; rather , there was a tendency for the trough FEV1 to improve above the baseline levels over the treatment period [19011503] Beta-adrenergic stimulation may increase heart rate and the potential for cardiac arrhythmias . The effect of inhaled long-acting beta2-agonists ( LABAs ) on these outcomes was evaluated in patients with chronic obstructive pulmonary disease ( COPD ) in 2 double-blind r and omized clinical trials . The pretreatment arrhythmia occurrence frequency in these patients was also described . In this analysis , 24-hour Holter monitoring data were pooled from 2 identically design ed Phase III trials . Patients were r and omized to LABA treatment or placebo for 12 weeks : a ) nebulized arformoterol 15 & mgr;g BID , b ) 25 & mgr;g BID , or c ) 50 & mgr;g QD ; d ) salmeterol metered dose inhaler 42 & mgr;g BID ; or e ) placebo . The 24-hour Holter monitoring was performed pretreatment and at Weeks 0 ( first day of dosing ) , 6 , and 12 . We assessed the proportion of patients with each of 4 arrhythmias : atrial tachycardia , atrial fibrillation/flutter , and " nonsustained " ; ( 4 - 10 beats ) and " sustained " ; ( > 10 beats ) ventricular tachycardia . There were 5226 Holter recordings in 1429 treated patients . At baseline , there was a low frequency of occurrence of atrial fibrillation/flutter ( 0.1 % ) , nonsustained ventricular tachycardia ( 3.1 % ) , and > 10 beat ventricular tachycardia ( 0.3 % ) . Atrial tachycardia occurred frequently ( 41.8 % ) . The proportion of patients with treatment-emergent atrial tachycardia ranged from 27 % to 32 % and was non-significantly higher , by ∼2%-5 % ( p = 0.70 ) , in the LABA groups compared with the placebo group . The rates of the other more serious arrhythmias did not increase with LABA treatment and were similar to placebo . All treatment groups ( LABA and placebo ) had consistent small decreases from baseline in mean 24-hour and maximum hourly heart rate . In conclusion , in this large cohort of COPD patients with no or stable cardiac comorbidities , a high proportion ( ∼40 % ) of patients were observed to have atrial tachycardia before treatment , which increased by 2%-5 % with LABA treatment . More serious arrhythmias were infrequent and did not increase with inhaled LABA therapy . LABA administration did not increase mean heart rate . Abbreviations : bpm = beats per minute , CI = confidence interval , COPD = chronic obstructive pulmonary disease , FEV1 = forced expiratory volume in 1 second , FVC = forced vital capacity , ITT = intent-to-treat , LABA = long-acting beta2-agonist , MedDRA = Medical Dictionary for Regulatory [18804362] Although guidelines recommend combining long-acting bronchodilators in COPD , data are limited . We examined the clinical efficacy and safety of formoterol , tiotropium and the combination in patients with COPD . Eight hundred and forty-seven patients with COPD ( mean FEV(1 ) 52 % predicted ; FEV(1)/FVC 53 % ) were r and omized to receive one of the following four treatments for 24 weeks : formoterol 10 microg b.i.d . plus tiotropium 18 microg o.d . ; formoterol 10 microg b.i.d . ; tiotropium 18 microg o.d . , or placebo . The study was partially blinded ( formoterol and placebo ) . For the primary endpoint , FEV(1 ) 2h post-dose after 24 weeks , there were small differences in favour of the combination therapy versus formoterol ( 0.07 L , p=0.044 ) or tiotropium ( 0.06 L , p=0.066 ) . All three treatments were superior to placebo ( p<0.001 ) . The combination was statistically superior to monotherapy for : the primary endpoint ( p=0.044 vs. formoterol ) ; FEV(1 ) 5 min after the first dose ( p<0.001 ) and at 12 weeks ( p<0.05 vs. tiotropium ) ; and peak expiratory flow averaged over the first 6 weeks ( p<0.001 vs. both ) . The three active treatments were significantly more effective than placebo for secondary endpoints : COPD -related ' bad days ' , symptoms , use of rescue medication and peak expiratory flow , and aspects of health-related quality of life . The overall incidence of adverse events was similar with all active treatments , although COPD -related adverse events were more common with tiotropium . Combined bronchodilator therapy may be a valuable treatment option for patients with COPD [15790985] Background : Combined treatment with inhaled corticosteroids and long acting β2 agonists is approved for the treatment of chronic obstructive pulmonary disease ( COPD ) , but little is known about the onset of effect of the combination . Methods : Data were used from 1465 patients with COPD entered into a large 1 year double blind trial with daily measurements of peak expiratory flow ( PEF ) and symptom scores . Results : PEF was significantly higher after 1 day in patients treated with salmeterol 50 μg twice daily or the salmeterol/fluticasone propionate combination 50/500 μg twice daily than placebo . In patients treated with fluticasone propionate 500 μg twice daily alone , PEF differed from placebo after 2 days . The differences after 2 weeks compared with placebo were 16 l/min ( 95 % confidence interval ( CI ) 11 to 21 ) , 11 l/min ( 95 % CI 6 to 16 ) , and 27 l/min ( 95 % CI 22 to 33 ) for salmeterol , fluticasone propionate , and the salmeterol/fluticasone propionate combination , respectively . For all treatments the effect on PEF after 2 weeks was comparable to that seen at the end of the study . The difference between the salmeterol/fluticasone propionate combination and placebo after 2 weeks as a percentage of baseline was similar for PEF and clinic forced expiratory volume in 1 second ( FEV1 ) . Differences in breathlessness scores were statistically significant after 1 day for the group treated with salmeterol alone and after 2 days for the combination group . The 2 week change in FEV1 was only partly indicative of a long term response in individual patients . Conclusions : The effects of salmeterol and fluticasone propionate , alone or in combination , on PEF and breathlessness are seen within days and most of the obtainable effect on these parameters is reached within 2 weeks [12379552] This r and omized controlled trial examined the benefits of combining an inhaled corticosteroid , fluticasone propionate ( F ) , with an inhaled long-acting beta(2)-agonist , salmeterol ( S ) , to treat the inflammatory and bronchoconstrictive components of chronic obstructive pulmonary disease ( COPD ) . A total of 691 patients with COPD received the combination of F and S ( FSC ) , S ( 50 mcg ) , F ( 500 mcg ) , or placebo twice daily via the Diskus device for 24 weeks . A significantly greater increase in predose FEV(1 ) at the endpoint was observed after FSC ( 156 ml ) compared with S ( 107 ml , p = 0.012 ) and placebo ( -4 ml , p < 0.0001 ) . A significantly greater increase in 2-hour postdose FEV(1 ) at the endpoint was observed after treatment with FSC ( 261 ml ) compared with F ( 138 ml , p < 0.001 ) and placebo ( 28 ml , p < 0.001 ) . There were greater improvements in the Transition Dyspnea Index with FSC ( 2.1 ) compared with F ( 1.3 , p = 0.033 ) , S ( 0.9 , p < 0.001 ) , and placebo ( 0.4 , p < 0.0001 ) . The incidence of adverse effects ( except for an increase in oral c and idiasis with FSC and F ) was similar among the treatment groups . We conclude that FSC improved lung function and reduced the severity of dyspnea compared with individual components and placebo [14509555] Loss of bronchodilator effectiveness or tolerance has been observed with inhaled beta-agonists but not with inhaled anticholinergic medications . Initially , tolerance is reflected in loss of bronchial protection against stimuli followed by loss of bronchodilator properties . However , generally such observations have been reported in asthma . A 6-month r and omized , double-dummy placebo-controlled trial comparing tiotropium to salmeterol provided the opportunity to examine spirometric tolerance to long-acting beta-agonists in patients with COPD . Spirometry was measured over 12h at baseline and at days 15 , 57 , 116 and 169 . Changes over time from baseline were compared relative to changes observed with placebo . A total of 623 patients participated ( tiotropium = 209 , salmeterol = 213 , placebo = 201 ) . The groups were similar in age ( mean = 65 years ) , gender ( 75 % men ) , and baseline FEV1 ( mean = 1.08 + /- 0.37l [ 40 + /- 12 % predicted ] ) . Relative to placebo , both active drugs improved morning pre-drug , peak and average FEV1 and FVC throughout the trial . However , from day 1 to 169 , salmeterol was associated with a higher decline in average FEV1 and FVC ( 0 - 12h ) ( difference from placebo : -36 and -115 ml , P < 0.05 ) , which was most prominent over the 8 - 12 h period ( difference from placebo : -45 and -138 ml , P < 0.01 ) . Significant declines in peak FVC relative to placebo ( -83 ml , P < 0.05 ) but not FEV1 ( -12ml ) were observed with salmeterol . Tiotropium was associated with further improvements in spirometry from days 1 to 15 and no evidence of tolerance from day 15 to the end of the trial . In conclusion , tolerance to pharmacologic bronchodilation occurs with long-acting beta-agonists such as salmeterol and not with inhaled anticholinergics [18259972] Rationale : Arformoterol , a single isomer long-acting β2-agonist , was developed as an inhalation solution for the maintenance treatment of bronchoconstriction in COPD . Methods : The pulmonary function efficacy of nebulized arformoterol ( 15 μ g BID , 25 μ g BID , 50 μ g QD ) and salmeterol MDI ( 42 μ g BID ) versus placebo was assessed in 1456 subjects ( mean FEV1 1.2L , mean predicted 41 % ) . Data were pooled from 2 identical , 12-week , double-blind , r and omized trials . The percent change in trough FEV1 , percent change in FEV1 average AUC(0 - 12 hrs ) and peak percent change FEV1 from predose were analyzed . Results : Improvement in trough FEV1 averaged over 12 weeks was greater for arformoterol and salmeterol versus placebo ( mean differences from placebo [ 95 % CI ] arformoterol–15 μ g BID : 11.4 % [ 8.4 , 14.3 ] ; 25 μ g BID : 15.4 % [ 12.2 , 18.6 ] ; 50 μ g QD : 10.9 % [ 7.9 , 13.9 ] ) ; salmeterol : ( 11.6 % [ 8.8 , 14.4 ] ) . Greater improvements versus placebo occurred after the first dose ( mean differences between arformoterol and placebo for trough FEV1 : 13–19 % ; FEV1 AUC(0 - 12 hrs ) : 19–24 % ; peak percent change : 20–25 % ) and at week 12 ( trough FEV1 : 10–13 % ; FEV1 AUC(0 - 12 hrs ) : 6–13 % ; peak percent change : 7–14 % ) ; all 95 % CIs excluded zero . Increases in FEV1 AUC(0 - 12 hrs ) and peak percent change were greater for arformoterol than for salmeterol ( 95 % CIs excluded zero ) . After 12 weeks , 78–87 % of arformoterol subjects had ≥ 10 % increases in FEV1 from pre-dose ( 56 % salmeterol , 44 % placebo ) ; the median time to response was 3–13 minutes ( 142 minutes salmeterol ) . Conclusions : In these trials , COPD subjects administered nebulized arformoterol demonstrated significant and sustained improvement in lung function over 12 weeks [16199148] Formoterol is a long-acting beta2-agonist with a rapid onset of effect in patients with chronic obstructive pulmonary disease ( COPD ) , making it potentially suitable for both maintenance and as-needed bronchodilator treatment . To evaluate the efficacy and tolerability of maintenance formoterol in patients with COPD and to compare the effects of additional formoterol as needed with terbutaline . In this 6-month , double-blind study , 657 patients with COPD ( 40 years , forced expiratory volume in 1s [ FEV1 ] 40 - 70 % predicted normal ) were r and omized to formoterol 9 microg twice daily ( bid ) plus terbutaline 0.5 mg as needed ( FORM bid ) , formoterol 9 microg bid plus formoterol 4.5 microg as needed ( FORM bid+prn ) , or placebo bid plus terbutaline 0.5 mg as needed ( placebo ) , all administered via Turbuhaler . Primary efficacy variables were FEV1 and the sum of breathlessness and chest tightness scores combined symptom score . Formoterol significantly ( P<0.01 ) increased FEV(1 ) compared with placebo : FORM bid 6.5 % ( 95 % CI : 2.5 , 10.7 % ) ; FORM bid+prn 11.8 % ( 95 % CI : 7.7 , 16.2 % ) . Combined symptom score decreased significantly in both formoterol groups compared with placebo : FORM bid -0.27 ( 95 % CI : -0.49 , -0.06 ; P=0.012 ) ; FORM bid+prn -0.32 ( 95 % CI : -0.53 , -0.11 ; P=0.0026 ) . Similar significant ( P<0.05 ) improvements were seen in both formoterol groups for morning peak expiratory flow , cough and sleep scores , and reliever use . In this study , formoterol 9 microg bid via Turbuhaler as maintenance therapy , with either formoterol or terbutaline as rescue medication , provided sustained improvements in lung function and COPD symptoms . Both formoterol regimens were well tolerated with no differences in adverse events or electrocardiogram profiles [15853436] Abstract Objective : To compare the healthcare costs and effects of budesonide/formoterol in a single inhaler with those of budesonide and formoterol monotherapies , and placebo , in a multinational study in patients with chronic obstructive pulmonary disease ( COPD ) , National Heart , Lung and Blood Institute (NHLBI)/WHO Global Initiative for Chronic Obstructive Lung Disease ( GOLD ) stages III or IV . Previous analysis of the clinical data from the study had shown that budesonide/formoterol was associated with better lung function and improved health-related QOL compared with the monocomponents or placebo and lower frequency of exacerbations compared with formoterol and placebo . Method : Patients ( n = 1022 ) were r and omised to twice-daily treatment with two inhalations of budesonide/formoterol ( 160μg/4.5μg ) in a single inhaler , budesonide 200μg , formoterol 4.5μg or placebo for 12 months . Data on medication and healthcare use were combined with Swedish unit cost data to estimate the total annual healthcare cost per patient from the Swedish healthcare payer perspective . Costs were valued in Swedish kronor ( SEK ) [ 2001 values ] and converted to euros ( SEK1 = € 0.11 , 25th April 2003 ) . Results : This evaluation estimated the total annual healthcare costs per patient to be numerically lower for budesonide/formoterol ( € 2518 ) than for budesonide ( € 3194 ) , formoterol ( € 3653 ) or placebo ( € 3213 ) . Cost-effectiveness acceptability curves suggest that budesonide/formoterol may be cost effective compared with formoterol , even if the decision maker is not willing to pay anything for the additional clinical effects , and that budesonide/formoterol is cost effective compared with placebo if a decision maker is willing to pay about € 2 per day , per avoided exacerbation . Conclusion : This economic analysis suggests that the clinical benefits of using budesonide/formoterol in a single inhaler are achieved at a numerically lower total healthcare cost than either monocomponent or placebo . Budesonide/formoterol in patients with severe COPD ( GOLD stages III or IV ) may be cost effective , from the healthcare provider perspective , compared with either monocomponent [19581353] BACKGROUND Osteoporosis is common in patients with COPD , but its prevalence and progression are not well characterized . Concerns have been raised over the possible deleterious effect of long-term therapy with inhaled corticosteroids ( ICSs ) on bone density in this population . Here , we investigated the long-term effects of therapy with fluticasone propionate ( FP ) alone , salmeterol ( SAL ) alone , and a SAL/FP combination ( SFC ) on bone mineral density ( BMD ) and bone fractures in patients with moderate-to-severe COPD in the TOwards a Revolution in COPD Health ( TORCH ) study . METHODS A r and omized , double-blind , parallel-group , placebo-controlled study conducted at 88 US centers involving 658 patients ( a subset of 6,184 international subjects in TORCH ) . Therapy with placebo , SAL ( 50 microg ) , FP ( 500 microg ) , or SFC ( SAL 50 microg/FP 500 microg ) twice daily was administered for 3 years . Baseline and yearly measurements of BMD at the hip and lumbar spine were performed . The incidence of traumatic and nontraumatic bone fractures was recorded . RESULTS At baseline , 18 % of men and 30 % of women had osteoporosis , and 42 % of men and 41 % of women had osteopenia based on BMD assessment s. Forty-three percent of subjects completed all testing . The changes in BMD at the hip and lumbar spine over 3 years were small . No significant differences were observed between treatment arms ( adjusted mean percent change from baseline at hip was -3.1 % for placebo , -1.7 % for SAL , -2.9 % for FP , and -3.2 % for SFC therapy , respectively ; while , the corresponding changes for the lumbar spine were 0 , 1.5 % , -0.3 % , and -0.3 % for placebo , respectively , SAL , FP , and SFC therapy ) . The incidence of fractures was low and was similar for all treatments ( 5.1 % to 6.3 % ) . CONCLUSIONS Osteoporosis is highly prevalent in patients with COPD , irrespective of gender . In the TORCH study , no significant effect on BMD was detected for ICS therapy compared with placebo . TRIAL REGISTRATION Clinical Trials.gov Identifier : NTC00268216 [10525558] BACKGROUND The Chronic Respiratory Question naire ( CRQ ) and the St George 's Respiratory Question naire ( SGRQ ) are the two most widely used quality of life question naires in chronic obstructive pulmonary disease ( COPD ) . A study was undertaken to compare directly the self-administered version of the CRQ and the SGRQ with respect to feasibility , internal consistency , validity , and sensitivity to changes result ing from bronchodilator therapy . METHODS One hundred and forty four patients with moderate or severe COPD were r and omly assigned to receive three months of treatment with either salmeterol , salmeterol + ipratropium bromide , or placebo . Quality of life was measured at baseline and after 12 weeks of treatment . RESULTS The proportions of missing values per patient were low for both question naires ( 0.54 % for the CRQ and 2 % for the SGRQ ) . The internal consistency was good for both question naires ( Cronbach 's alpha coefficients > /= 0.84 for the CRQ and > /= 0.76 for the SGRQ ) . Factor analysis confirmed the original domain structure of the CRQ but not of the SGRQ . Correlations with forced expiratory volume in one second ( FEV(1 ) ) % predicted and peak expiratory flow rate ( PEFR ) were low for both question naires but better for the SGRQ than for the CRQ . The ability to discriminate between subjects with different levels of FEV(1 ) was somewhat better for the SGRQ . The correlations with symptom scores were comparable for both question naires . Cross sectionally , the scores of the two question naires were moderately to highly correlated ( coefficients ranged from 0.35 to 0.72 ) . Longitudinally , these correlations were lower ( coefficients ranged from 0.17 to 0.54 ) but were still significant . The CRQ total and emotions score and the SGRQ symptoms score were the most responsive to change . The SGRQ symptoms domain was the only domain where the improvement in patients receiving combination treatment crossed the threshold for clinical relevance . CONCLUSIONS Since this analysis of reliability , validity , and responsiveness to change did not clearly favour one instrument above the other , the choice between the CRQ and the SGRQ can be based on other considerations such as the required sample size or the availability of reference values [18363201] Nebulized solutions of long-acting bronchodilators provide an alternative to DPI and MDI delivery , particularly for COPD patients unable to use h and -held devices easily or correctly . The long-acting beta2-agonist , formoterol fumarate , is differentiated by its onset of significant bronchodilation within 5 min of administration . In a r and omized , double-blind , double-dummy trial , COPD subjects ( n=351 , mean forced expiratory volume FEV1=1.3 L , 44 % predicted ) received nebulized formoterol fumarate ( Perforomist inhalation solution ; FFIS 20 microg ) or DPI ( Foradil Aerolizer ; FA 12 microg ) , or placebo twice daily for 12 weeks . Efficacy was assessed with 12-h pulmonary function tests , and quality of life was assessed before and after treatment with the St. George 's Respiratory Question naire ( SGRQ ) . At the 12-week endpoint , FFIS significantly increased FEV1 AUC0 - 12h relative to placebo ( p<0.0001 ) . No evidence of tachyphylaxis was observed as indicated by maintained FEV1 AUC and reduced rescue albuterol use throughout treatment . FFIS also significantly increased peak FEV1 , trough FEV1 , and st and ardized FVC AUC0 - 12h compared with placebo . SGRQ assessment at Week 12 demonstrated significant and clinical ly meaningful improvements in total score ( FFIS vs placebo , -4.9 , p=0.0067 ) , symptom , and impact scores . No significant differences in efficacy were observed between the two active treatments . Drug related AEs in the FFIS arm with a frequency > or = 1 % and exceeding placebo were dry mouth , nausea , and insomnia . Nebulized FFIS provided significant improvement in respiratory status and quality of life in subjects with COPD relative to placebo and was well tolerated . The efficacy and safety profile of FFIS was comparable to FA DPI [7503401] Inhaled formoterol is a potent selective β2‐agonist with rapid onset and at least 12‐h duration of bronchodilation . The aim of the study was to compare the bronchodilating effect of inhaled formoterol dry powder ‘ dp ) 12 μg b.i.d . with salbutamol dp 400 μg q.i.d . and placebo in patients with reversible obstructive airway disease ‘ ROAD ) . The study design consisted of a closed 12‐week double‐blind , placebo‐controlled , multicenter trial followed by an open noncomparative , multicenter , 12‐month follow‐up trial , in which the tolerability of formoterol dp was assessed . A total of 304 patients ‘ 146 men , 158 women ) aged 18‐79 years , ill during 0.1‐64 years , were r and omized . No demographic or baseline differences were found among the different treatment groups . The bronchodilating effect of formoterol , assessed by morning premedication PEFR , was significantly superior to placebo ‘ P < 0.0001 ) and salbutamol ‘ P < 0.0001 ) . Efficacy was maintained during the open follow‐up study with 12 μg b.i.d . in most of the patients . A few patients , however , needed 24 μg b.i.d . to control their ROAD . Formoterol 12 μg b.i.d . significantly reduced morning and evening asthma symptoms and sleep disturbances , and reduced significantly the need for rescue medication . The tolerability of the three treatment groups was comparable . In conclusion , formoterol 12 μg dp b.i.d . was significantly superior to both salbutamol 400 μg dp q.i.d . and placebo , and reduced asthma symptoms significantly . Overall , formoterol showed a tolerability profile comparable to that of salbutamol , and no tachyphylaxis was observed during 1 year of treatment [18042473] BACKGROUND Recently , there have been concerns about the tolerability of long-acting (2)-agonists , including possible adverse cardiovascular effects-a particular concern in patients with chronic obstructive pulmonary disease ( COPD ) , who are at elevated risk for cardiovascular disease . OBJECTIVE The aim of this study was to assess the cardiac safety profile of nebulized formoterol fumarate inhalation solution . METHODS Cardiac safety was assessed as part of a 12-week , r and omized , double-blind , double-dummy , placebo- and active-controlled trial that was conducted at 38 centers across the United States . Male and female patients aged > /=40 years with COPD and without other significant disease were enrolled . After a 4- to 14-day , single-blind placebo run-in period , patients with COPD were r and omly assigned to receive formoterol fumarate inhalation solution 20 microg BID via nebulizer ( FFIS group ) , formoterol fumarate 12 microg BID via dry powder inhaler ( FA group ) , or placebo . Cardiac effects-measured by changes in heart rate ( HR ) and ventricular premature beats ; incidence of proarrhythmic events ; change in corrected QT ( QTc ) interval ; and incidence of maximum mean change in QTc > /=60 ms-were assessed using 24-hour Holter monitoring at baseline and 12 weeks ; 12-lead electrocardiography at screening and weeks 4 , 8 , and 12 ; and patient diary cards . RESULTS A total of 351 patients with COPD were r and omized ( mean age , 62.8 years ; 56.1 % male ; mean postbronchodilator forced expiratory volume in 1 second , 1.5 L ) . Holter monitoring found no clinical ly meaningful effects of FFIS or FA treatment on mean or maximum HR , ventricular premature beats , or inci dence of arrhythmic events compared with placebo . At week 12 , mean ( SD ) changes from baseline in mean HR were -0.6 ( 10.9 ) , + 0.1 ( 11.6 ) , and -1.4 ( 9.4 ) bpm in the FFIS , FA , and placebo groups , respectively . The incidence of mean maximum changes in QTc > /=60 ms at any time during the 12-week treatment period were 1.6 % , 1.8 % , and 1.8 % with FFIS , FA , and placebo , respectively . Treatment-emergent cardiac adverse events ( AEs ) occurred in 4.1 % , 3.5 % , and 4.4 % of patients in the FFIS , FA , and placebo groups ; withdrawals due to possible cardiac AEs occurred in 1 patient per treatment group . No deaths or serious cardiac AEs occurred during the treatment period . CONCLUSION In this COPD population , no clinical ly significant cardiac effects were found with twicedaily treatment with nebulized formoterol fumarate inhalation solution [15526804] The prevalence of chronic obstructive pulmonary disease ( COPD ) in women is increasing worldwide . Women may have greater susceptibility to COPD progression than men , and differences in efficacy and safety of respiratory medications by gender are largely unexplored . We aim ed to determine whether the response to treatment in women with COPD differed from men in a large , 1-year double-blind trial ( ' TRISTAN ' ) . In a sensitivity analysis , we compared 539 male and 180 female COPD patients , who were r and omized to the saLmeterol/fluticasone combination 50/500mcg bid or placebo for 12 months . Combination therapy improved pre-treatment FEV1 significantly more than placebo in women by 152 ml ( 95 % confidence interval 95 - 208 ) and in men by 127 ml ( 94 - 159 ) . Similarly , a reduction in COPD exacerbation rates of 31 % in women ( 9 - 48 % ) and of 23 % in men ( 8 - 35 % ) was observed . Combination therapy reduced COPD exacerbations requiring treatment with oral corticosteroids by 36 % in women and by 41 % in men . Finally , combination treatment produced a better improvement in health status than placebo with a decrease in the SGRQ scores in women by -2.3 ( -4.6 - 0.1 ) and in men by -2.1 ( -3.5 to -0.8 ) . No gender interaction was found for any outcome . Treatments were well tolerated with no difference in the frequency of adverse events in women and men . In this trial , therapy with the salmeterol/fluticasone combination produced significant improvements compared to placebo on all main endpoints and the magnitude of these improvements was similar for both men and women [12114338] BACKGROUND Tiotropium , a once-daily anticholinergic , and salmeterol represent two inhaled , long-acting bronchodilators from different pharmacologic classes . A trial was design ed to examine the efficacy and safety of both compounds with multiple outcome measures , including lung function , dyspnea , and health-related quality of life ( HRQoL ) in patients with COPD . METHODS A 6-month , r and omized , placebo-controlled , double-blind , double-dummy , parallel-group study of tiotropium , 18 microg once daily via dry-powder inhaler , compared with salmeterol , 50 microg bid via metered-dose inhaler , was conducted in patients with COPD . Efficacy was assessed by 12-h monitoring of spirometry , transition dyspnea index ( TDI ) , and the St. George 's Respiratory Question naire ( SGRQ ) . RESULTS A total of 623 patients participated ( tiotropium , n= 209 ; salmeterol , n = 213 ; and placebo , n = 201 ) . The groups were similar in age ( mean , 65 years ) , gender ( 75 % men ) , and baseline FEV(1 ) ( mean , 1.08 + /- 0.37 L ; percent predicted , 40 + /- 12 % [ + /- SD ] ) . Compared with placebo treatment , the mean predose morning FEV(1 ) following 6 months of therapy increased significantly more for the tiotropium group ( 0.14 L ) than the salmeterol group ( 0.09 L ; p < 0.01 ) . The average FEV(1 ) ( 0 to 12 h ) for tiotropium was statistically superior to salmeterol ( difference , 0.08 L ; p < 0.001 ) . Tiotropium improved TDI focal score by 1.02 U compared with placebo ( p = 0.01 ) , whereas there was no significant change in TDI focal score with salmeterol ( 0.24 U ) . Tiotropium was superior to salmeterol in improving TDI focal score ( p < 0.05 ) . At 6 months , the mean improvement in SGRQ total score vs baseline was tiotropium , - 5.14 U ( p < 0.05 vs placebo ) ; salmeterol , - 3.54 U ( p = 0.4 vs placebo ) ; and placebo , - 2.43 U. A statistically higher proportion of patients receiving tiotropium achieved at least a 4-U change in SGRQ score compared to patients receiving placebo . Both active drugs reduced the need for rescue albuterol ( p < 0.0001 ) . CONCLUSIONS Tiotropium once daily produces superior bronchodilation , improvements in dyspnea , and proportion of patients achieving meaningful changes in HRQoL compared to twice-daily salmeterol in patients with COPD [8999618] This article is based on a study first published in Allergy . The bronchodilating effect of the long acting beta 2-agonist formoterol dey powder ( dp ) 12 micrograms twice daily was compared to salbutamol 400 micrograms four times daily and placebo in patients with reversible obstructive airway disease . The study design consisted of a closed 12-week double-blind , placebo-controlled , multicentre trial followed by an open noncomparative , multicentre 12-month follow-up trial , in which tolerability of formoterol dp was assessed . A total of 304 patients aged 18 - 79 years were r and omized . The bronchodilating effect of formoterol , assessed by morning premedication peak flow rate , was significantly superior to placebo ( p < 0.0001 ) and salbutamol ( p < 0.001 ) . Efficacy was maintained during the open follow-up study . Formoterol 12 micrograms twice daily significantly reduced morning and evening asthma symptoms and sleep disturbances , and significantly reduced the need for rescue medication . In conclusion , formoterol 12 micrograms dp twice daily was significantly superior to both salbutamol 400 micrograms dp four times daily and placebo , and reduced asthma symptoms significantly . Overall , formoterol showed a tolerability profile comparable to that of salbutamol , and no tachyphylaxis was observed during one year of treatment [10853852] The efficacy and safety of salmeterol alone was compared with the combination of salmeterol plus ipratropium and with placebo during long-term treatment in patients with stable chronic obstructive pulmonary disease . In addition , the single-dose effect in response to the first dose of treatment was studied over 12 h. The patients ( n=144 ; age 64+/-7 yrs , forced expiratory volume in one second ( FEV1 ) 44+/-11 % pred ) participated in a three-centre double-blind double-placebo parallel group study and were r and omized after a run-in period of 2 weeks to receive either salmeterol 50 microg b.i.d . , salmeterol 5 microg b.i.d . plus ipratropium 40 microg q.i.d . or placebo for a period of 12 weeks . The single-dose study demonstrated that salmeterol produced a significant increase in FEV1 ( peak of 7 % pred ) and specific airway conductance ( sGaw ) ( maximum of 60 % baseline ) for > or = 12 h. The combination of salmeterol plus ipratropium elicited a greater bronchodilator response ( 11 % and 94 % increases respectively ) than salmeterol alone during the first 6 h after inhalation . During treatment there were significant improvements in daytime symptom scores and morning peak expiratory flow in both the salmeterol and the salmeterol plus ipratropium groups ( p<0.001 ) , with an associated decrease in the use of rescue salbutamol . Improvements in FEV1 and sGaw were greater in the salmeterol plus ipratropium group than in the patients receiving only salmeterol . Thirty-five patients had an exacerbation ; 11 ( 23 % ) in the salmeterol group ( versus placebo NS ) , six ( 13 % ) in the salmeterol plus ipratropium group ( versus placebo p<0.01 ) and 18 ( 36 % ) in the placebo group . In conclusion , in patients with severe stable chronic obstructive pulmonary disease , long-term treatment with either salmeterol alone or salmeterol plus ipratropium is safe and effective . There was added benefit from the combination therapy in terms of improvement in airways obstruction , but not for improvement in symptom control or need for rescue salbutamol [12564609] The need to manage the key symptoms of chronic obstructive pulmonary disease ( COPD ) ( breathlessness , cough and sputum ) is an important treatment objective . Viozan ( sibenadet HCl , AR-C68397AA ) is a novel dual D2 dopamine receptor , beta2-adrenoceptor agonist , which combines conventional bronchodilatory activity with the sensory nerve modulation afforded by dopamine agonism . The efficacy of this agent in relieving patient symptoms has been determined in a series of large-scale clinical studies ; the results of a 3-month , placebo-controlled multi-centre study are reported . Effect on patient symptoms was determined using a novel patient-reported assessment instrument , the Breathlessness , Cough and Sputum Scale ( BCSS ) . Patients with smoking-related COPD were required to complete a 2-week baseline period before being r and omized to one of three treatment groups ; sibenadet ( 500 microg three times daily ) plus placebo ( twice daily ) ; salmeterol ( 50 microg twice daily ) plus placebo ( three times daily ) ; placebo ( twice daily ) plus a second placebo ( three times daily ) . All treatments were delivered via pressurized metered dose inhaler ( pMDI ) for 12 weeks . From enrolment , patients were required to complete daily diary cards to record symptoms of breathlessness , cough and sputum , medication use and adverse events . The primary outcome measure was the difference between the mean BCSS total score measured over the baseline period and the mean BCSS total score in the final 4 weeks of the treatment period . Secondary measures included assessment of lung function , rescue medication use , exacerbations , health-related quality of life , opinion of efficacy and safety . Although an initial reduction in BCSS total score ( indicating symptom improvement ) was seen with sibenadet therapy , this effect was not maintained for the study duration . Salmeterol therapy , however , result ed in a sustained reduction in BCSS total score . No notable benefit over placebo was seen in lung function , exacerbations or health-related quality of life with either active treatment . While the results of this study failed to demonstrate sustained efficacy with sibenadet therapy , they do indicate the value of symptom assessment in the clinical evaluation of new drugs for the treatment of COPD [19880616] The TORCH ( Towards a Revolution in COPD Health ) trial has highlighted some important issues in the design and analysis of long term trials in chronic obstructive pulmonary disease . These include collection of off-treatment exacerbation data , analysis of exacerbation rates and the effect of inclusion of patients receiving inhaled corticosteroids ( ICS ) prior to r and omisation . When effective medications are available to patients who withdraw , inclusion of off-treatment data can mask important treatment effects on exacerbation rates . Analysis of on-treatment data avoids this bias but it needs to be combined with careful analysis of withdrawal patterns across treatments . The negative binomial model is currently the best approach to statistical analysis of exacerbation rates , while analysis of time to exacerbation can supplement this approach . In the TORCH trial , exacerbation rates were higher among patients with previous use of ICS compared to those with no prior use on all study treatments . Retrospective subgroup analysis suggests ICS reduced exacerbation rates compared with placebo , regardless of prior use of ICS before entry to the study . Factorial analysis provides an alternative analysis for trials with combinations of treatments , but assumes no interaction between treatments , an assumption which can not be verified by a significance test . No definitive conclusions can yet be drawn on whether ICS treatment has an effect on mortality [17314337] BACKGROUND Long-acting beta-agonists and inhaled corticosteroids are used to treat chronic obstructive pulmonary disease ( COPD ) , but their effect on survival is unknown . METHODS We conducted a r and omized , double-blind trial comparing salmeterol at a dose of 50 microg plus fluticasone propionate at a dose of 500 microg twice daily ( combination regimen ) , administered with a single inhaler , with placebo , salmeterol alone , or fluticasone propionate alone for a period of 3 years . The primary outcome was death from any cause for the comparison between the combination regimen and placebo ; the frequency of exacerbations , health status , and spirometric values were also assessed . RESULTS Of 6112 patients in the efficacy population , 875 died within 3 years after the start of the study treatment . All-cause mortality rates were 12.6 % in the combination-therapy group , 15.2 % in the placebo group , 13.5 % in the salmeterol group , and 16.0 % in the fluticasone group . The hazard ratio for death in the combination-therapy group , as compared with the placebo group , was 0.825 ( 95 % confidence interval [ CI ] , 0.681 to 1.002 ; P=0.052 , adjusted for the interim analyses ) , corresponding to a difference of 2.6 percentage points or a reduction in the risk of death of 17.5 % . The mortality rate for salmeterol alone or fluticasone propionate alone did not differ significantly from that for placebo . As compared with placebo , the combination regimen reduced the annual rate of exacerbations from 1.13 to 0.85 and improved health status and spirometric values ( P<0.001 for all comparisons with placebo ) . There was no difference in the incidence of ocular or bone side effects . The probability of having pneumonia reported as an adverse event was higher among patients receiving medications containing fluticasone propionate ( 19.6 % in the combination-therapy group and 18.3 % in the fluticasone group ) than in the placebo group ( 12.3 % , P<0.001 for comparisons between these treatments and placebo ) . CONCLUSIONS The reduction in death from all causes among patients with COPD in the combination-therapy group did not reach the predetermined level of statistical significance . There were significant benefits in all other outcomes among these patients . ( Clinical Trials.gov number , NCT00268216 [ Clinical Trials.gov ] . ) [9105068] Changes in health-related quality of life ( HRQoL ) were evaluated in patients with chronic obstructive pulmonary disease ( COPD ) following treatment with placebo , salmeterol 50 microg twice a day or 100 microg twice a day by metered-dose inhaler . Patients completed the disease-specific St. George 's Respiratory Question naire ( SGRQ ) and the Medical Outcomes Study Short Form 36 ( SF-36 ) at baseline and after 16 wk of treatment . Data from 283 patients ( 95 patients in the placebo group and 94 in each salmeterol group ) were available for HRQoL analysis . Apart from a small difference in ages , all treatment groups were well matched at baseline in terms of forced expiratory volume in one second ( FEV1 ) and HRQoL scores . Compared with placebo , salmeterol 50 microg twice a day was associated with significant improvements in SGRQ " Total " and " Impacts " scores which exceeded the threshold for a clinical ly significant change . This was not seen with salmeterol 100 microg twice a day . Changes in SGRQ and SF-36 scores correlated . They also showed a weak but significant relationship with FEV1 . This study has shown that a modest change in lung function may be associated with clinical ly significant gain in health and well-being in COPD patients [17472819] OBJECTIVE The aim of this study was to assess the efficacy and tolerability of nebulized arformoterol tartrate ( a selective , long-acting beta(2)-adrenergic agonist that is the [ R , R ] isomer of formoterol ) and salmeterol xinafoate versus placebo in patients with chronic obstructive pulmonary disease ( COPD ) . METHODS This 12-week , multicenter , r and omized , double-blind , double-dummy , placebo- and active-controlled trial was conducted at 60 centers across the United States . Male and female patients aged > or=35 years with physician-diagnosed COPD received arformoterol ( 15 microg BID , 25 microg BID , or 50 microg QD via nebulizer ) , salmeterol ( 42 microg BID via metered dose inhaler ) , or placebo . Pulmonary function was assessed by spirometry ; dyspnea , by the Transitional Dyspnea Index ( TDI ) ; and health status , by the St. George 's Respiratory Question naire ( SGRQ ) . Adverse events ( AEs ) were assessed by site personnel at all clinic visits ( screening , first dose at week 0 , and at weeks 3 , 6 , 9 , 12 , and follow-up ) . COPD exacerbations were defined as worsening respiratory status requiring a change in medication or an unscheduled provider visit . RESULTS A total of 717 patients received study medication . The demographic composition of all treatment arms was similar . The mean age was 62.9 years , 58 % were men , and mean baseline forced expiratory volume in 1 second ( FEV(1 ) ) was 1.2 L ( 41 % predicted ) . Mean improvement in trough FEV(1 ) over 12 weeks was significantly greater with all 3 arformoterol doses ( 15 microg BID , + 16.9 % ; 25 microg BID , + 18.9 % ; 50 microg QD , + 14.9 % ) and for salmeterol ( + 17.4 % ) relative to placebo ( + 6.0 % ; P < 0.001 ) . There were significantly greater improvements in the mean percentage change in FEV(1 ) AUC(0 - 12h ) from the predose value over 12 weeks ( 15 microg BID , 12.7 % , 25 microg BID , 13.9 % , 50 microg QD , 18.9 % ; salmeterol , 9.8 % ) versus placebo ( 2.7 % ; P < or= 0.001 ) ; all doses of arformoterol were statistically different from salmeterol for this end point ( P < or= 0.024 ) . At week 12 , TDI focal scores were significantly greater with all arformoterol doses compared with placebo ( mean [ 95 % CI ] : 15 microg BID , 0.97 [ 0.25 - 1.69 ] ; 25 microg BID , 1.08 [ 0.3 - 1.86 ] ; 50 microg QD , 1.04 [ 0.32 - 1.771 ) , suggesting treatment-associated improvement in dyspnea , however , the difference between salmeterol and placebo was not statistically significant ( 0.36 [ -0.40 to 1.12 ] ) . Improvements in health status , as measured using SGRQ total scores , were -2.6 to -3.6 U in the arformoterol groups , -4.4 U for salmeterol , and -1.2 U for placebo ; 95 % CI of differences versus placebo suggested significant improvement for the arformoterol 25 microg BID and salmeterol groups . There was a similar frequency of AEs and COPD exacerbations across all groups , including placebo . CONCLUSIONS In this trial , patients with moderate to severe COPD administered nebulized arformoterol over 12 weeks were observed to have significant and sustained improvements in airway function and dyspnea compared with placebo . The results also suggest that all doses of arformoterol , including the lowest dose ( 15 microg BID ) , were effective . Overall , nebulized arformoterol was well tolerated [21531124] BACKGROUND Chronic obstructive pulmonary disease ( COPD ) patients are thought to have limited bronchodilator response , determined by changes in forced expiratory volume in 1s ( FEV(1 ) ) . In this study , we assessed bronchodilator response in patients with COPD using not only FEV(1 ) but also changes in lung volume expressed as forced vital capacity ( FVC ) and inspiratory capacity ( IC ) . We also evaluated the speed of onset of bronchodilation . METHODS Data were from 2 r and omized , double-blind , placebo-controlled studies ( 6-months [ NCT00206154 ] ; 12-months [ NCT00206167 ] ) in patients with moderate to very severe COPD . TREATMENTS twice daily budesonide/formoterol pressurized metered-dose inhaler ( pMDI ) 320/9μg , budesonide/formoterol pMDI 160/9μg , formoterol dry powder inhaler ( DPI ) 9μg , placebo . RESULTS The percentage of patients with FEV(1 ) improvement ( ≥12 % and ≥200mL ; American Thoracic Society [ ATS ] criterion ) was 34 - 39 % post-albuterol ( screening ) . On day of r and omization ( DOR ) , a larger proportion receiving formoterol-containing treatment exhibited reversibility within 60min : FEV(1 ) ( 57 - 59 % ) . Similar results were seen for IC ( 50 - 61 % ) and FVC ( 57 - 67 % ) using the same improvement criteria . The time to ≥15 % FEV(1 ) improvement on DOR was 5.0 , 4.8 , and 7.3min for budesonide/formoterol 320/9 , budesonide/formoterol 160/9 , and formoterol , respectively . Time to ≥15 % FEV(1 ) improvement was better maintained with budesonide/formoterol than formoterol at treatment end ( 6 and 12 months ) . CONCLUSIONS Most patients with moderate to very severe COPD exhibit ATS-defined bronchodilator reversibility based on flow and lung volume measures after budesonide/formoterol pMDI or formoterol treatment . Budesonide/formoterol pMDI also has a rapid ( within 5min ) onset of bronchodilation that is maintained over time compared with formoterol alone [21159140] Introduction : R and omised controlled trials ( RCTs ) are considered the least biased method for evaluating drug efficacy and several large long‐term RCTs in chronic obstructive pulmonary disease have been published . These usually include drugs with symptomatic benefits and have significant withdrawal rates

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### Context: [17311843] Background : TORCH ( Towards a Revolution in COPD Health ) is an international multicentre , r and omised , placebo-controlled clinical trial of inhaled fluticasone propionate/salmeterol combination treatment and its monotherapy components for maintenance treatment of moderately to severely impaired patients with chronic obstructive pulmonary disease ( COPD ) . The primary outcome is all-cause mortality . Cause-specific mortality and deaths related to COPD are additional outcome measures , but systematic methods for ascertainment of these outcomes have not previously been described . Methods : A Clinical Endpoint Committee ( CEC ) was tasked with categorising the cause of death and the relationship of deaths to COPD in a systematic , unbiased and independent manner . The key elements of the operation of the committee were the use of predefined principles of operation and definitions of cause of death and COPD -relatedness ; the independent review of cases by all members with development of a consensus opinion ; and a substantial infrastructure to collect medical information . Results : 911 deaths were review ed and consensus was reached in all . Cause-specific mortality was : cardiovascular 27 % , respiratory 35 % , cancer 21 % , other 10 % and unknown 8 % . 40 % of deaths were definitely or probably related to COPD . Adjudications were identical in 83 % of blindly re-adjudicated cases ( κ = 0.80 ) . COPD -relatedness was reproduced 84 % of the time ( κ = 0.73 ) . The CEC adjudication was equivalent to the primary cause of death recorded by the site investigator in 52 % of cases . Conclusion : A CEC can provide st and ardised , reliable and informative adjudication of COPD mortality that provides information which frequently differs from data collected from assessment by site investigators [22383665] BACKGROUND Effects of β(2)-adrenergic receptor gene ( ADRB2 ) polymorphism on therapeutic responses to long-acting β(2)-adrenergic agonists have not been evaluated in long-term COPD trials . We aim ed to investigate the effects of the ADRB2 Gly16Arg polymorphism on response to formoterol alone or in combination with the inhaled corticosteroid budesonide in patients with COPD . METHODS Patients ≥ 40 years of age with moderate to very severe COPD from the 12-month trial I ( NCT00206167 ) or the 6-month trial II ( NCT00206154 ) were r and omly assigned to bid budesonide/formoterol pressurized metered-dose inhaler ( pMDI ) 320/9 μg or 160/9 μg , budesonide pMDI 320 μg + formoterol dry powder inhaler 9 μg ( trial II ) , budesonide pMDI 320 μg ( trial II ) , formoterol dry powder inhaler 9 μg , or placebo . The effect of Gly16Arg on predose FEV(1 ) and 1-h postdose FEV(1 ) , exacerbations , diary variables , and adverse events were analyzed . RESULTS No significant interaction between genotype and treatment response was observed for predose ( P ≥ .197 ) or postdose FEV(1 ) ( P ≥ .125 ) in either pharmacogenetic study ( n = 2,866 ) . The number of COPD exacerbations per patient-treatment year was low and similar across genotypes for the active treatment groups ( both studies ) . Percentages of patients with adverse events were similar across Gly16Arg genotype groups for each treatment . CONCLUSION Therapeutic response and tolerability to long-term treatment with formoterol alone or in combination with budesonide was not modified by ADRB2 Gly16Arg genotype in two large independent pharmacogenetic studies in patients with moderate to very severe COPD [2707163] Guidelines recommend that patients with COPD are stratified arbitrarily by baseline severity ( FEV1 ) to decide when to initiate combination treatment with a long-acting β2-agonist and an inhaled corticosteroid . Assessment of baseline FEV1 as a continuous variable may provide a more reliable prediction of treatment effects . Patients from a 1-year , parallel-group , r and omized controlled trial comparing 50 μg salmeterol ( Sal ) , 500 μg fluticasone propionate ( FP ) , the combination ( Sal/FP ) and placebo , ( bid ) , were categorized post hoc into FEV1 < 50 % and FEV1 ≥50 % predicted subgroups ( n=949/513 respectively ) . Treatment effects on clinical outcomes – lung function , exacerbations , health status , diary card symptoms , and adverse events – were investigated . Treatment responses based on a pre-specified analysis explored treatment differences by severity as a continuous variable . Lung function improved with active treatment irrespective of FEV1 ; Sal/FP had greatest effect . This improvement appeared additive in milder disease ; synergistic in severe disease . Active therapy significantly reduced exacerbation rate in patients with FEV1 < 50 % predicted , not in milder disease . Health status and breathlessness improved with Sal/FP irrespective of baseline FEV1 ; adverse events were similar across subgroups . The spirometric response to Sal/FP varied with baseline FEV1 , and clinical benefits were not restricted to patients with severe disease . These data have implication s for COPD management decisions , suggesting that arbitrary stratifications of baseline severity are not necessarily indicative of treatment efficacy and that the benefits of assessing baseline severity as a continuous variable should be assessed in future trials [12637127] BACKGROUND Chronic obstructive pulmonary disease ( COPD ) is debilitating and costly to manage . A recent clinical trial concluded that formoterol , a long-acting beta(2)-adrenoceptor agonist , was more clinical ly effective than inpratropium bromide in the management of COPD . OBJECTIVE The aim of this study was to perform an economic assessment of the management of COPD with formeterol versus ipratropium bromide . METHODS Assessment were based on the results of a previously published 12-week , multicenter , double-masked , r and omized , parallel-group , placebo-controlled clinical trial comparing inhaled formoterol dry powder 12 and 24 microg BID with ipratropium bromide 40 microg QID pressurized metered dose inhaler and with placebo in 780 COPD patients . Treatment costs for study drugs and rescue medications were estimated from re source utilization and average wholesale prices . Costs were assessed with respect to forced expiratory lung volume in 1 second ( FEV(1 ) ) and patient-reported quality of life ( QOL ) as assessed via the St. George 's Respiratory Question naire . Cost-effectiveness ratios were calculated for each treatment arm and incremental cost-effectiveness ratios ( ICERs ) were calculated for each treatment relative to the next best alternative . Economic efficiency frontiers were identified . Sensitivity analysis was conducted . RESULTS Cost analysis with respect to FEV(1 ) revealed an economic efficiency frontier formed by placebo , ipratropium bromide 40 microg , and formoterol 12 microg at their respective FEV(1 ) levels , with cost-effectiveness ratios of $ 30.18 , $ 53.50 , and $ 142.04 , respectively , per FEV(1 ) . The ICER for ipratropium over placebo was $ 273.03 ; for formoterol 12 microg over ipratropium , $ 1611.32 . Cost analysis with respect to QOL showed an economic efficiency frontier formed by placebo and formoterol 12 microg at their respective QOL outcomes , with cost-effectiveness ratios of $ 25.96 and $ 32.56 , respectively , per QOL score change . The cost-effectiveness ratio for ipratropium was $ 69.40,which was not on the QOL economic efficiency frontier . The ICER for formoterol 12 microg over placebo was $ 34.51 per QOL score point . CONCLUSIONS Formoterol 12 microg provided greater QOL outcome than ipratropium bromide at an additional cost of $ 554.28 per year . Further research would be necessary to assess whether the differences in outcomes , particularly QOL , observed in the short term with formoterol would lead to favorable long-term health and economic outcomes [3580134] Background : Combination therapy with a long-acting bronchodilator and an inhaled corticosteroid ( ICS ) is recommended in patients with chronic obstructive pulmonary disease ( COPD ) who have frequent exacerbations . The efficacy and tolerability of the combination of budesonide/formoterol have been demonstrated in patients with COPD when administered via the dry powder inhaler ( DPI ) in a 1-year study and when administered via the hydrofluoroalkane ( HFA ) pressurized metered-dose inhaler ( pMDI ) in a 6-month study . Objective : This study assessed the long-term efficacy and tolerability of budesonide/formoterol HFA pMDI in patients with moderate to very severe COPD . Methods : This was a 12-month , r and omized , double-blind , double-dummy , parallel-group , active- and placebo-controlled , multicentre study ( NCT00206167 ) of 1964 patients aged ≥40 years with moderate to very severe COPD conducted from 2005 to 2007 at 237 sites in the US , Europe and Mexico . After 2 weeks of treatment based on previous therapy ( ICSs , short-acting bronchodilators allowed ) , patients received one of the following treatments twice daily : budesonide/formoterol pMDI 160/4.5 μg × two inhalations ( 320/9 μg ) ; budesonide/formoterol pMDI 80/4.5 μg × two inhalations ( 160/9 μg ) ; formoterol DPI 4.5 μg × two inhalations ( 9 μg ) ; or placebo . Main outcome measures : The co- primary efficacy variables were pre-dose forced expiratory volume in 1 second ( FEV1 ) and 1-hour post-dose FEV1 . Results : Budesonide/formoterol 320/9 μg demonstrated greater improvements in pre-dose FEV1 versus formoterol ( p = 0.008 ) , and both budesonide/formoterol doses demonstrated greater improvements in 1-hour post-dose FEV1 versus placebo ( p < 0.001 ) . The rate of COPD exacerbations was lower in both budesonide/formoterol groups compared with formoterol and placebo ( p ≤ 0.004 ) . Both budesonide/formoterol doses were more effective than placebo ( p ≤ 0.006 ) for controlling dyspnoea and improving health status ( St George ’s Respiratory Question naire ) . All treatments were generally well tolerated . The incidence of pneumonia was not different for active ( 3.4–4.0 % ) and placebo ( 5.0 % ) groups . Conclusions : Budesonide/formoterol pMDI ( 320/9 μg and 160/9 μg ) improved pulmonary function and reduced symptoms and exacerbations over 1 year in patients with moderate to very severe COPD . Only budesonide/formoterol pMDI 320/9 μg demonstrated greater efficacy for both co- primary variables compared with formoterol DPI 9 μg . Both budesonide/formoterol pMDI dosages were well tolerated relative to formoterol and placebo [18511702] RATIONALE Chronic obstructive pulmonary disease ( COPD ) is characterized by an accelerated decline in lung function . No drug has been shown conclusively to reduce this decline . OBJECTIVES In a post hoc analysis of the Toward a Revolution in COPD Health ( TORCH ) study , we investigated the effects of combined salmeterol 50 microg plus fluticasone propionate 500 microg , either component alone or placebo , on the rate of post-bronchodilator FEV(1 ) decline in patients with moderate or severe COPD . METHODS A r and omized , double-blind , placebo-controlled study was conducted from September 2000 to November 2005 in 42 countries . Of 6,112 patients from the efficacy population , 5,343 were included in this analysis . MEASUREMENTS AND MAIN RESULTS Spirometry was measured every 24 weeks for 3 years . There were 26,539 on-treatment observations . The adjusted rate of decline in FEV(1 ) was 55 ml/year for placebo , 42 ml/year for salmeterol , 42 ml/year for fluticasone propionate , and 39 ml/year for salmeterol plus fluticasone propionate . Salmeterol plus fluticasone propionate reduced the rate of FEV(1 ) decline by 16 ml/year compared with placebo ( 95 % confidence interval [ CI ] , 7 - 25 ; P < 0.001 ) . The difference was smaller for fluticasone propionate and salmeterol compared with placebo ( 13 ml/year ; 95 % CI , 5 - 22 ; P = 0.003 ) . Rates of decline were similar among the active treatment arms . FEV(1 ) declined faster in current smokers and patients with a lower body mass index , and varied between world regions . Patients who exacerbated more frequently had a faster FEV(1 ) decline . CONCLUSIONS Pharmacotherapy with salmeterol plus fluticasone propionate , or the components , reduces the rate of decline of FEV(1 ) in patients with moderate-to-severe COPD , thus slowing disease progression . Clinical trial ( GSK Study Code SCO30003 ) registered with www . clinical trials.gov ( NCT00268216 ) [15332386] Only long-term home oxygen therapy has been shown in r and omised controlled trials to increase survival in chronic obstructive pulmonary disease ( COPD ) . There have been no trials assessing the effect of inhaled corticosteroids and long-acting bronchodilators , alone or in combination , on mortality in patients with COPD , despite their known benefit in reducing symptoms and exacerbations . The “ TOwards a Revolution in COPD Health ” ( TORCH ) survival study is aim ing to determine the impact of salmeterol/fluticasone propionate ( SFC ) combination and the individual components on the survival of COPD patients . TORCH is a multicentre , r and omised , double-blind , parallel-group , placebo-controlled study . Approximately 6,200 patients with moderate-to-severe COPD were r and omly assigned to b.i.d . treatment with either SFC ( 50/500 µg ) , fluticasone propionate ( 500 µg ) , salmeterol ( 50 µg ) or placebo for 3 yrs . The primary end-point is all-cause mortality ; secondary end-points are COPD morbidity relating to rate of exacerbations and health status , using the St George 's Respiratory Question naire . Other end-points include other mortality and exacerbation end-points , requirement for long-term oxygen therapy , and clinic lung function . Safety end-points include adverse events , with additional information on bone fractures . The first patient was recruited in September 2000 and results should be available in 2006 . This paper describes the “ TOwards a Revolution in COPD Health ” study and explains the rationale behind it [20693243] Indacaterol is a novel , inhaled , once-daily , ultra-long-acting & bgr;2-agonist bronchodilator recently approved in Europe for the treatment of chronic obstructive pulmonary disease ( COPD ) . The aim of the present study was to investigate the efficacy and safety of indacaterol compared with placebo and the twice-daily & bgr;2-agonist , salmeterol , as an active control . Patients with moderate-to-severe COPD were r and omised to 6 months double-blind treatment with indacaterol ( 150 & mgr;g once daily ) , salmeterol ( 50 & mgr;g twice daily ) or placebo . The primary efficacy end-point was trough ( 24 h post-dose ) forced expiratory volume in 1 s ( FEV1 ) after 12 weeks . 1,002 patients were r and omised and 838 ( 84 % ) completed the study . Indacaterol increased trough FEV1 at week 12 by 170 mL over placebo ( p<0.001 ) and by 60 mL over salmeterol ( p<0.001 ) . Both active treatments improved health status ( St George 's Respiratory Question naire ) and dyspnoea ( transition dyspnoea index ) compared with placebo , with differences between them favouring indacaterol . Safety profiles were similar across the treatment groups , and both indacaterol and salmeterol were well tolerated . Once-daily treatment with 150 & mgr;g indacaterol had a significant and clinical ly relevant bronchodilator effect over 24 h post-dose and improved health status and dyspnoea to a greater extent than twice-daily 50 & mgr;g salmeterol . Indacaterol should prove a useful additional treatment for patients with COPD [12796155] BACKGROUND Patients with COPD have an increased risk of cardiovascular disease . Despite the clinical benefits of long-acting beta-agonist agents in the treatment of COPD , patients may be at an increased risk of cardiovascular toxicity , including tachyarrhythmia due to beta-adrenergic stimulation . OBJECTIVE To evaluate the cardiovascular safety of salmeterol in COPD patients by conducting a pooled analysis of cardiovascular safety data . DESIGN R and omized , double-blind , parallel group , multiple-dose studies , which included salmeterol , 50 micro g bid , and placebo arms . STUDY SELECTION Seven of a total of 17 studies met the predefined inclusion requirements and were pooled . A total of 1,443 patients received placebo , while 1,410 patients received salmeterol , 50 micro g bid . The median duration of treatment was 24 weeks ( range , 12 to 52 weeks ) . RESULTS Treatment with salmeterol , 50 micro g bid , showed no increased risk of cardiovascular adverse events ( AEs ) compared with placebo ( relative risk , 1.03 ; 95 % confidence interval , 0.8 to 1.3 ; p = 0.838 ) . Both groups had a similar incidence of cardiovascular events ( 8 % ) , including cardiovascular deaths . The incidence of cardiovascular AEs increased with age , concurrent cardiovascular conditions , and treatment with antiarrhythmic/bradycardic agents , although increases were comparable in both treatment groups . There were no episodes of sustained ventricular tachycardia , and no clinical ly significant differences were observed in 24-h heart rate , ventricular and supraventricular ectopic events , qualitative ECGs , QT intervals , or vital signs between the salmeterol , 50 micro g bid , group and the placebo group . Similar findings were observed when patients were stratified for age of > 65 years or the known presence of cardiovascular disease . CONCLUSIONS Treatment with salmeterol , 50 micro g bid , does not increase the risk of cardiovascular AEs in this population of COPD patients compared with placebo [11549532] We compared the effectiveness of inhaled formoterol with that of ipratropium in the treatment of chronic obstructive pulmonary disease ( COPD ) . After a 2-wk run-in period , 780 patients with COPD were r and omized to receive for 12 wk formoterol dry powder 12 or 24 microg twice daily , ipratropium bromide 40 microg four times daily , or placebo in a multicenter , double-blind , parallel-group study . The primary efficacy variable was the area under the curve for forced expiratory volume in 1 s ( FEV(1 ) ) measured over 12 h after 12 wk of treatment . Secondary variables included diary symptoms and quality of life . Both doses of formoterol and ipratropium significantly increased the area under the curve for FEV(1 ) in comparison with placebo ( all p < 0.001 ) . Both doses of formoterol were also significantly superior to ipratropium ( all p < 0.025 ) . Compared with placebo , both doses of formoterol significantly improved symptoms ( all p < or = 0.007 ) and quality of life ( p < 0.01 for total scores ) whereas ipratropium did not show significant effects ( all p > or = 0.3 ) . All study treatments exhibited a similar safety profile . We conclude that formoterol is more effective than ipratropium bromide in the treatment of COPD , as the efficacy of ipratropium on airflow obstruction does not translate into a clinical benefit that patients can perceive [20180870] BACKGROUND In 2003 , chronic obstructive pulmonary disease ( COPD ) accounted for 46 % of the burden of chronic respiratory disease in the Australian community . In the 65 - 74-year-old age group , COPD was the sixth leading cause of disability for men and the seventh for women . AIMS To measure the influence of disease severity , COPD phenotype and comorbidities on acute health service utilization and direct acute care costs in patients admitted with COPD . METHODS Prospect i ve cohort study of 80 patients admitted to the Royal Melbourne Hospital in 2001 - 2002 for an exacerbation of COPD . Patients were followed for 12 months and data were collected on acute care utilization . Direct hospital costs were derived using Transition II , an activity-based costing system . Individual patient costs were then modelled to ascertain which patient factors influenced total direct hospital costs . RESULTS Direct costs were calculated for 225 episodes of care , the median cost per admission was AU$3124 ( interquartile range $ 1393 to $ 5045 ) . The median direct cost of acute care management per patient per year was AU$7273 ( interquartile range $ 3957 to $ 14 448 ) . In a multivariate analysis using linear regression modelling , factors predictive of higher annual costs were increasing age ( P= 0.041 ) , use of domiciliary oxygen ( P= 0.008 ) and the presence of chronic heart failure ( P= 0.006 ) . CONCLUSION This model has identified a number of patient factors that predict higher acute care costs and awareness of these can be used for service planning to meet the needs of patients admitted with COPD [11948033] STUDY OBJECTIVE To compare the efficacy , tolerability , and safety of therapy with formoterol and oral slow-release theophylline ( THEO ) in patients with COPD . DESIGN A r and omized , parallel-group study , with double-blind arms for formoterol and placebo ( PL ) and an open arm for oral slow-release THEO administered in individual doses on the basis of plasma concentrations . SETTING Eighty-one centers worldwide . PATIENTS Eight hundred fifty-four patients with symptomatic COPD . INTERVENTION Comparison of twice-daily inhaled formoterol dry powder ( 12 or 24 microg ) , PL , and THEO ( individualized doses ) over 12 months . MEASUREMENTS AND RESULTS Compared to PL , doses of formoterol and THEO both significantly improved the area under the curve for FEV(1 ) measured over a period of 12 h following the morning dose of study medication at 3 and 12 months ( p < 0.001 for all comparisons ) . Therapy with formoterol , 12 microg , was significantly more effective than that with THEO ( p < or = 0.026 ) . Formoterol significantly reduced the percentage of " bad days " ( i.e. , days with at least two individual symptom scores > or = 2 and /or a reduction in peak expiratory flow from a baseline of > 20 % ; p < or = 0.035 vs. PL and THEO ) , and the use of salbutamol rescue medication ( p < or = 0.003 vs PL ) over the whole treatment period , while the effect of THEO was similar to that of PL . Therapy with formoterol and THEO was more effective than PL at improving quality of life for > 12 months ( p < or = 0.030 ) . Treatment-related adverse events and discontinuations were more frequent among patients receiving THEO than among those receiving formoterol . CONCLUSIONS Long-term treatment with inhaled formoterol dry powder is more effective and better tolerated than treatment with therapeutically appropriate doses of oral slow-release THEO in symptomatic patients with COPD [20522841] Background Indacaterol is a long-acting inhaled β2-agonist ( LABA ) for the treatment of chronic obstructive pulmonary disease ( COPD ) . In previous studies , indacaterol provided 24 h bronchodilation on once-daily dosing with a fast onset of action . This study compared the efficacy and safety of indacaterol with the twice-daily LABA formoterol and placebo over 1 year . Methods Patients with moderate to severe COPD were r and omised to receive once-daily indacaterol 300 μg ( n=437 ) or 600 μg ( n=428 ) , twice-daily formoterol 12 μg ( n=435 ) or placebo ( n=432 ) for 52 weeks in a double-blind double-dummy parallel group study . The primary efficacy variable was forced expiratory volume in 1 s ( FEV1 ) measured 24 h postdose after 12 weeks ( indacaterol vs placebo ) . Other outcomes included dyspnoea ( transition dyspnoea index , TDI ) , use of as-needed salbutamol , symptom-based measures recorded on diary cards , exacerbations , health status ( St George 's Respiratory Question naire ) , BODE index ( body mass index , obstruction , dyspnoea , exercise ) , safety and tolerability . Results Indacaterol increased 24 h postdose FEV1 after 12 weeks by 170 ml ( both doses ) versus placebo and by 100 ml versus formoterol ( all p<0.001 ) . These significant differences were maintained at 52 weeks . Symptomatic outcomes were improved compared with placebo with all active treatments , and indacaterol was more effective than formoterol in improving TDI score and reducing the need for as-needed salbutamol . Indacaterol was well tolerated and had a good overall safety profile , including minimal impact on QTc interval and systemic β2-mediated events . Conclusions Once-daily indacaterol is an effective 24 h bronchodilator that improves symptoms and health status and confers clinical improvements over a twice-daily 12 h LABA as a treatment for patients with moderate to severe COPD . Trial registration number NCT 00393458 [12570112] The efficacy and safety of budesonide/formoterol in a single inhaler compared with placebo , budesonide and formoterol were evaluated in patients with moderate-to-severe chronic obstructive pulmonary disease ( COPD ) . In a 12-month , r and omised , double-blind , placebo-controlled , parallel-group study in 812 adults ( mean age 64 yrs , mean forced expiratory volume in one second ( FEV1 ) 36 % predicted normal ) , patients received two inhalations twice daily of either budesonide/formoterol ( Symbicort ® ) 160/4.5 µg ( delivered dose ) , budesonide 200 µg ( metered dose ) , formoterol 4.5 µg or placebo . Severe exacerbations and FEV1 ( primary variables ) , peak expiratory flow ( PEF ) , COPD symptoms , health-related quality of life ( HRQL ) , mild exacerbations , use of reliever β2‐agonist and safety variables were recorded . Budesonide/formoterol reduced the mean number of severe exacerbations per patient per year by 24 % versus placebo and 23 % versus formoterol . FEV1 increased by 15 % versus placebo and 9 % versus budesonide . Morning PEF improved significantly on day 1 versus placebo and budesonide ; after 1 week , morning PEF was improved versus placebo , budesonide and formoterol . Improvements in morning and evening PEF versus comparators were maintained over 12 months . Budesonide/formoterol decreased all symptom scores and use of reliever β2‐agonists significantly versus placebo and budesonide , and improved HRQL versus placebo . All treatments were well tolerated . These results suggest a role for budesonide/formoterol in the long-term management of moderate-to-severe chronic obstructive pulmonary disease [12583942] BACKGROUND Inhaled long-acting beta2 agonists improve lung function and health status in symptomatic chronic obstructive pulmonary disease ( COPD ) , whereas inhaled corticosteroids reduce the frequency of acute episodes of symptom exacerbation and delay deterioration in health status . We postulated that a combination of these treatments would be better than each component used alone . METHODS 1465 patients with COPD were recruited from outpatient departments in 25 countries . They were treated in a r and omised , double-blind , parallel-group , placebo-controlled study with either 50 microg salmeterol twice daily ( n=372 ) , 500 microg fluticasone twice daily ( n=374 ) , 50 microg salmeterol and 500 microg fluticasone twice daily ( n=358 ) , or placebo ( n=361 ) for 12 months . The primary outcome was the pretreatment forced expiratory volume in 1s ( FEV1 ) after 12 months treatment ' and after patients had abstained from all bronchodilators for at least 6h and from study medication for at least 12h . Secondary outcomes were other lung function measurements , symptoms and rescue treatment use , the number of exacerbations , patient withdrawals , and disease-specific health status . We assessed adverse events , serum cortisol concentrations , skin bruising , and electrocardiograms . Analysis was as predefined in the study protocol . FINDINGS All active treatments improved lung function , symptoms , and health status and reduced use of rescue medication and frequency of exacerbations . Combination therapy improved pretreatment FEV1 significantly more than did placebo ( treatment difference 133 mL , 95 % CI 105 - 161 , p<0.0001 ) , salmeterol ( 73 mL , 46 - 101 , p<0.0001 ) , or fluticasone alone ( 95 mL , 67 - 122 , p<0.0001 ) . Combination treatment produced a clinical ly significant improvement in health status and the greatest reduction in daily symptoms . All treatments were well tolerated with no difference in the frequency of adverse events , bruising , or clinical ly significant falls in serum cortisol concentration . INTERPRETATION Because inhaled long-acting beta2 agonists and corticosteroid combination treatment produces better control of symptoms and lung function , with no greater risk of side-effects than that with use of either component alone , this combination treatment should be considered for patients with COPD [9150318] The objectives of this study were to compare the efficacy and safety of salmeterol xinafoate ( 50 and 100 microg b.i.d . ) with that of placebo , when added to existing therapy , in the treatment of patients with chronic obstructive pulmonary disease ( COPD ) . Six hundred and seventy four patients were r and omized to receive either salmeterol 50 microg b.i.d . , salmeterol 100 microg b.i.d . , or placebo treatment for a period of 16 weeks . The results showed a significant improvement in daily symptom scores noted for patients taking either 50 microg ( p=0.043 ) or 100 microg b.i.d . salmeterol ( p=0.01 ) compared with placebo , with a corresponding decrease in additional daytime salbutamol requirements for both salmeterol groups . The same pattern was reflected for night-time symptoms and additional salbutamol use . During treatment , forced expiratory volume in one second ( FEV1 ) measurements improved significantly in each salmeterol group , with up to a 7 % improvement observed at the end of the study . Although no difference was observed between treatment groups for the distance walked in 6 min , patients treated with salmeterol 50 microg b.i.d . were significantly less breathless than those treated with placebo after their 6 min walk , after 8 weeks ( p=0.024 ) and 16 weeks ( p=0.004 ) of therapy . Adverse events were similar in all three groups except for tremor , which was significantly higher in the 100 microg b.i.d . salmeterol group ( p=0.005 ) compared both with 50 microg b.i.d . salmeterol and placebo . Salmeterol offered further positive improvement to the effect of therapy in patients with chronic obstructive pulmonary disease when added to their existing regimens . This clinical improvement was similar both with 50 and 100 microg b.i.d . dosage , although the group receiving 50 microg b.i.d . tolerated the drug better than those receiving 100 microg b.i.d . salmeterol [12030736] The aim of this study was to investigate formoterol , an inhaled long-acting β2-agonist , in patients with chronic obstructive pulmonary disease ( COPD ) . Six-hundred and ninety-two COPD patients , mean baseline forced expiratory volume in one second ( FEV1 ) 54 % , FEV1/forced vital capacity 75 % of predicted , reversibility 6.4 % pred , were treated with formoterol ( 4.5 , 9 or 18 µg b.i.d . ) or placebo via Turbuhaler ® for 12 weeks . Symptoms were recorded daily . Spirometry and the incremental shuttle walking test ( SWT ) were performed at clinic visits . Compared with placebo , 18 µg b.i.d . formoterol reduced the mean total symptom score by 13 % and increased the percentage of nights without awakenings by 15 % . Formoterol ( 9 and 18 µg b.i.d . ) significantly reduced symptom scores for breathlessness ( −7 % and −9 % , respectively ) and chest tightness ( −11 % and −8 % , respectively ) , reduced the need for rescue medication ( −25 % and −18 % , respectively ) , and increased symptom-free days ( 71 % and 86 % , respectively ) . FEV1 improved significantly after all three doses of formoterol ( versus placebo ) . No differences were found between groups in SWT walking distance . No unexpected adverse events were seen . In conclusion , 9 and 18 µg b.i.d . formoterol reduced symptoms and increased the number of symptom-free days in a dose-dependent manner in chronic obstructive pulmonary disease patients . Formoterol improved lung function at a dose of 4.5 µg b.i.d . and higher [14680078] Lung function in chronic obstructive pulmonary disease ( COPD ) can be improved acutely by oral corticosteroids and bronchodilators . Whether clinical improvement can be maintained by subsequent inhaled therapy is unknown . COPD patients ( n=1,022 , mean prebronchodilator forced expiratory volume in one second ( FEV1 ) 36 % predicted ) initially received formoterol ( 9 µg b.i.d . ) and oral prednisolone ( 30 mg o.d . ) for 2 weeks . After this time , patients were r and omised to b.i.d . inhaled budesonide/formoterol 320/9 µg , budesonide 400 µg , formoterol 9 µg or placebo for 12 months . Postmedication FEV1 improved by 0.21 L and health-related quality of life using the St George 's Respiratory Question naire ( SGRQ ) by 4.5 units after run-in . Fewer patients receiving budesonide/formoterol withdrew from the study than those receiving budesonide , formoterol or placebo . Budesonide/formoterol patients had a prolonged time to first exacerbation ( 254 versus 96 days ) and maintained higher FEV1 ( 99 % versus 87 % of baseline ) , both primary variables versus placebo . They had fewer exacerbations ( 1.38 versus 1.80 exacerbations per patient per year ) , had higher prebronchodilator peak expiratory flow , and showed clinical ly relevant improvements in SGRQ versus placebo ( −7.5 units ) . Budesonide/formoterol was more effective than either monocomponent in both primary variables . Budesonide/formoterol in a single inhaler ( Symbicort ® ) maintains the benefit of treatment optimisation , stabilising lung function and delaying exacerbations more effectively than either component drug alone or placebo [3233513] Background This study evaluated the efficacy and safety of the long-acting β2-agonist formoterol in patients with moderate-to-severe COPD . Methods This double-blind , placebo-controlled , parallel-group , multinational phase III study r and omized patients ≥ 40 years of age with moderate-to-severe COPD to inhaled formoterol 4.5 or 9 μg twice daily ( bid ) via Turbuhaler ® or placebo for 12 weeks . Salbutamol 100 μg/actuation via pMDI was permitted as reliever medication . The primary outcome variable was change ( ratio ) from baseline to treatment period in FEV1 60-min post-dose . Results 613 patients received treatment ( formoterol 4.5 μg n = 206 ; 9 μg n = 199 ; placebo n = 208 ) ; 539 ( 87.9 % ) male ; 324 ( 52.9 % ) Japanese and 289 ( 47.1 % ) European . End of study increases in FEV1 60-min post-dose were significantly greater ( p < 0.001 for both ) with formoterol 4.5 and 9 μg bid ( 113 % of baseline for both ) than with placebo , as were all secondary outcome measures . The proportion of patients with an improvement in St George 's Respiratory Question naire score of ≥ 4 was 50.2 % for formoterol 4.5 μg ( p = 0.0682 vs. placebo ) , 59.2 % ( p = 0.0004 ) for 9 μg , and 41.3 % for placebo . Reduction in reliever medication use was significantly greater with formoterol vs. placebo ( 9 μg : -0.548 , p < 0.001 ; 4.5 μg : -0.274 , p = 0.027 ) , with 9 μg being significantly superior to 4.5 μg ( -0.274 , p = 0.029 ) . Formoterol was well tolerated with the incidence and type of adverse events not being different for the three groups . Conclusions Formoterol 4.5 μg and 9 μg bid was effective and well tolerated in patients with COPD ; there was no difference between formoterol doses for the primary endpoint ; however , an added value of formoterol 9 μg over 4.5 μg bid was observed for some secondary endpoints . Trial registration NCT00628862 ( Clinical Trials.gov ) ; D5122C00001 ( AstraZeneca Study code ) [10208192] STUDY OBJECTIVES To examine and compare the efficacy and safety of salmeterol xinafoate , a long-acting inhaled beta2-adrenergic agonist , with inhaled ipratropium bromide and inhaled placebo in patients with COPD . DESIGN A stratified , r and omized , double-blind , double-dummy , placebo-controlled , parallel group clinical trial . SETTING Multiple sites at clinics and university medical centers throughout the United States . PATIENTS Four hundred eleven symptomatic patients with COPD with FEV1 < or = 65 % predicted and no clinical ly significant concurrent disease . INTERVENTIONS Comparison of inhaled salmeterol ( 42 microg twice daily ) , inhaled ipratropium bromide ( 36 microg four times a day ) , and inhaled placebo ( 2 puffs four times a day ) over 12 weeks . RESULTS Salmeterol xinafoate was significantly ( p < 0.0001 ) better than placebo and ipratropium in improving lung function at the recommended doses over the 12-week trial . Both salmeterol and ipratropium reduced dyspnea related to activities of daily living compared with placebo ; this improvement was associated with reduced use of supplemental albuterol . Analyses of time to first COPD exacerbation revealed salmeterol to be superior to placebo and ipratropium ( p < 0.05 ) . Adverse effects were similar among the three treatments . CONCLUSIONS These collective data support the use of salmeterol as first-line bronchodilator therapy for the long-term treatment of airflow obstruction in patients with COPD [12449166] The aim of this study was to compare the effects of formoterol , ipratropium bromide and a placebo on walking distance , lung function , symptoms and quality of life ( QoL ) in chronic obstructive pulmonary disease ( COPD ) patients . A total of 183 patients ( mean age 64 yrs , 86 female ) with moderate-to-severe nonreversible COPD participated in this r and omised , double-blind , parallel-group study . After a 2-week placebo run-in , patients were r and omised to formoterol Turbuhaler ® 18 μg b.i.d . ( delivered dose ) , ipratropium bromide 80 μg t.i.d . via a pressurised metered dose inhaler , or placebo for 12 weeks . Inhaled short-acting β2-agonists were allowed as relief medication and inhaled glucocorticosteroids were allowed at a constant dose . The primary variable was walking distance in the shuttle walking test ( SWT ) . Baseline mean SWT distance was 325 m , mean forced expiratory volume in one second ( FEV1 ) was 40 % predicted . Clinical ly significant improvements in SWT ( > 30 m ) were seen in 41 , 38 and 30 % of formoterol , ipratropium and placebo patients , respectively ( not significant ) . Mean increases from run-in were 19 , 17 and 5 m in the formoterol , ipratropium and placebo groups , respectively . Both active treatments significantly improved FEV1 , forced vital capacity , peak expiratory flow and daytime dyspnoea score compared with placebo . Formoterol reduced relief medication use compared with placebo . Neither active treatment improved QoL. Formoterol and ipratropium improved airway function and symptoms , without significant improvements in the shuttle walking test [14555565] OBJECTIVES To investigate the determinants of patient withdrawal from our study , and the effect of these withdrawals on the outcome of treatment with inhaled corticosteroids in patients with COPD . DESIGN A double-blind , placebo-controlled , r and omized trial . SETTING Eighteen outpatient centers in the United Kingdom . PARTICIPANTS Seven hundred fifty-one patients with stable COPD defined clinical ly and as baseline postbronchodilator FEV(1 ) > or = 0.8 L and < 85 % predicted , FEV(1)/FVC ratio < 70 % , and FEV(1 ) change after albuterol < 10 % of predicted . INTERVENTION R and om assignment of either 500 microg bid of inhaled fluticasone propionate ( FP ) using a spacer device or an identical placebo inhaler . Treatment was continued for 3 years or until patients withdrew from follow-up . MEASUREMENTS AND RESULTS Postbronchodilator FEV(1 ) was measured on three occasions before r and omization and every 3 months thereafter . Health status was assessed by the disease-specific St. George Respiratory Question naire ( SGRQ ) and the modified short-form 36 question naire ( SF-36 ) at baseline and every 6 months . Three hundred thirty-nine patients withdrew , of whom 156 patients received FP . Prescription of frequent courses of oral prednisolone was the most common reason for withdrawing as specified in the protocol ( 69 patients in the FP group withdrew due to respiratory symptoms , compared with 93 patients in the placebo group ) . This explained the significantly greater dropout of placebo-treated patients that was most evident when FEV(1 ) was < 50 % predicted . Patients withdrawing had a significantly more rapid decline in health status , measured by both the SGRQ and the SF-36 ( p < 0.001 ) . Those withdrawing from the placebo group had a more rapid decline in FEV(1 ) and more exacerbations than the FP-treated groups . Baseline FEV(1 ) was lower in dropouts than in patients completing the study receiving placebo , but there was no difference between the respective groups receiving FP . CONCLUSIONS Patients who withdrew from follow-up were those with the most rapidly deteriorating health status and lung function . Losing these patients from the final analysis can reduce the power of a study to achieve its primary end point [19717476] The TOwards a Revolution in COPD Health ( TORCH ) study was a 3-yr multicentre trial of 6,112 patients r and omised to salmeterol ( Salm ) , fluticasone propionate ( FP ) , a Salm/FP combination ( SFC ) or placebo ( P ) . Here the cost-effectiveness of treatments evaluated in the TORCH study is assessed . For four regions , 3-yr all-cause hospitalisation , medication and outpatient care costs were calculated . The sample was restricted to the 21 countries ( n = 4,237 ) in which European quality of life five-dimension ( EQ-5D ) data were collected in order to estimate the number of quality -adjusted life years ( QALYs ) . Regression models were fitted to survival , study medication cost , other medication cost and EQ-5D data in order to estimate total cost , number of QALYs and cost per QALY , adjusted for missing data and region . SFC had a trial-wide estimate of cost per QALY of 43,600 US dollars ( USD ) compared with P ( 95 % confidence interval 21,400–123,500 USD ) . Estimates for Salm versus P ( 197,000 USD ) and FP versus P ( 78,000 USD ) were less favourable . The US estimates were greater than those from other regions ; for SFC versus P , the cost per QALY was 77,100 ( 46,200–241,700 ) USD compared to 24,200 ( 15,200–56,100 ) USD in Western Europe . Compared with P , SFC has a lower incremental cost-effectiveness ratio than either FP or Salm used alone , and is , therefore , preferred to these monotherapies on the grounds of cost-effectiveness [12556006] Chronic obstructive pulmonary disease ( COPD ) is associated with a large economic and social burden . Few economic studies have examined the benefits of inhaled therapy for patients with COPD . This 16-week study examined the cost-effectiveness of salmeterol in this patient group . Patients with a history of COPD were r and omised to treatment with salmetrol 50 mcg ( 229 patients ) or placebo ( 227 patients ) twice daily administered by metered-dose inhaler in addition to normal therapy . Forced expiratory volume ( FEV1 ) was measured and patients recorded the impact of their symptoms in a daily diary . Health status was assessed using the St Georges Respiratory Question naire . A significantly higher proportion of salmeterol-treated patients had an increase of > 15 % in FEV1 . Salmeterol patients had a higher mean proportion of symptom-free days and nights than those in the placebo group . More salmeterol patients had a clinical ly significant improvement in health status . Total healthcare costs were increased in the salmeterol group , but hospital and GP visit costs and concurrent COPD medication costs were lower . The reduction in hospital costs was sufficient to offset a substantial portion of the acquisition cost of salmeterol . Addition of salmeterol to COPD patients ' current therapy improved lung function , health status at the expense of a modest increase in costs compared with usual therapy [21397482] BACKGROUND Indacaterol is a novel , inhaled , ultra-long-acting β(2)-agonist bronchodilator for maintenance use in patients with COPD . The aim of this paper is to assess the effect of indacaterol on dyspnoea and health status , using pooled study data to evaluate the relative efficacy of indacaterol and existing bronchodilators . METHODS Individual patient data were pooled from three r and omized , placebo-controlled studies ( NCT00393458 ; NCT00567996 ; NCT00463567 ) , conducted in patients with moderate-to-severe COPD . Treatments were double-blind indacaterol 150 μg ( n = 746 ) or 300 μg ( n = 853 ) once-daily , formoterol 12 μg twice-daily ( n = 556 ) , salmeterol 50 μg twice-daily ( n = 333 ) and placebo ( n = 1185 ) ; and open-label tiotropium 18 μg once-daily ( n = 415 ) . Evaluation after 6 months ' treatment was by transition dyspnoea index ( TDI ; minimum clinical ly important difference [ MCID ] ≥1 point ) , and St George 's Respiratory Question naire ( SGRQ ; MCID ≥4 units ) . RESULTS Differences from placebo in TDI total score were 1.01 ( indacaterol 150 μg ) 1.28 ( indacaterol 300 μg ) , 0.74 ( formoterol ) , 0.92 ( salmeterol ) and 0.88 ( tiotropium ) ( all p < 0.05 ) , with corresponding odds ratios versus placebo for exceeding the MCID from baseline of 1.91 , 2.69 , 2.02 , 1.79 and 1.49 ( all p < 0.05 ) . Differences versus placebo in SGRQ total score were -4.4 ( indacaterol 150 μg ) , -3.4 ( indacaterol 300 μg ) , -2.8 ( formoterol ) , -4.0 ( salmeterol ) and -1.7 ( tiotropium ) ( all p < 0.05 ) , with corresponding odds ratios versus placebo for exceeding the MCID of 1.95 , 1.63 , 1.54 , 1.82 and 1.29 ( all p < 0.05 apart from tiotropium ) . CONCLUSIONS Indacaterol provided clinical ly important improvements in dyspnoea and health status that were at least as good as and often better than those observed with existing bronchodilator treatments for COPD [20685748] Background Previous studies have suggested that long-term use of β agonists to treat chronic obstructive pulmonary disease ( COPD ) may increase the risk of cardiovascular adverse events . In this post hoc analysis , data from the TOwards a Revolution in COPD Health ( TORCH ) study were used to investigate whether use of the long-acting β2 agonist salmeterol over 3 years increased the risk of cardiovascular adverse events in patients with moderate to severe COPD . Methods TORCH was a r and omised , double-blind , placebo controlled study conducted at 444 centres in 42 countries . Patients ( n=6184 ; safety population ) received twice daily combined salmeterol 50 μg plus fluticasone propionate 500 μg ( SFC ) , either component alone , or placebo . Adverse events were recorded every 12 weeks for 3 years . Results The probability of having a cardiovascular adverse event by 3 years was 24.2 % for placebo , 22.7 % for salmeterol , 24.3 % for fluticasone propionate and 20.8 % for SFC . Although a history of myocardial infa rct ion doubled the probability of cardiovascular adverse events , the event rates remained similar across treatment groups . Conclusion Post hoc analysis of the 3-year TORCH data set showed that salmeterol alone or in combination ( SFC ) did not increase the risk of cardiovascular events in patients with moderate to severe COPD [12068339] BACKGROUND In the past , the role of long-acting beta(2- ) agonists in chronic obstructive pulmonary disease ( COPD ) relative to other agents has been unclear . OBJECTIVES To compare the effect of adding salmeterol ( 50 microg bid ) or placebo to concurrent anticholinergic therapy on symptom scores , quality of life , prebronchodilator lung function and exacerbations in patients with moderately severe COPD . METHODS This was a double-blind , r and omized , parallel-group study in patients aged 40 years or older receiving anticholinergic medication . Patients were r and omly assigned to treatment with placebo ( n=207 ) or salmeterol ( n=201 ) via a Diskus/Accuhaler inhaler for 24 weeks . RESULTS The morning trough ( pre study drug ) forced expiratory volume in 1 s ( FEV(1 ) ) increased significantly above baseline levels among the salmeterol-treated patients . Improvement in FEV(1 ) was greater in the salmeterol group than in the placebo group at four weeks ( difference 0.06 L , P<0.005 ) , eight weeks ( 0.06 L , P<0.005 ) and 16 weeks ( 0.05 L , P<0.05 ) after the start of treatment . There was a nonsignificant trend in favour of salmeterol after 24 weeks of treatment ( P=0.198 ) . Improvements in morning peak flow were significantly greater in the salmeterol group over 24 weeks ( P<0.01 ) . Although symptom scores were numerically higher in the salmeterol group than in the placebo group and there was less requirement for rescue bronchodilator use , these differences were not statistically significant . In the salmeterol group , fewer patients had exacerbations of COPD , and there was a trend toward an improved quality of life . The safety profile of the two groups was similar . CONCLUSIONS Salmeterol has a beneficial effect when added to existing anticholinergic therapy in patients with COPD . The regular use of salmeterol for six months was not associated with worsening of the underlying airflow obstruction ; rather , there was a tendency for the trough FEV1 to improve above the baseline levels over the treatment period [19011503] Beta-adrenergic stimulation may increase heart rate and the potential for cardiac arrhythmias . The effect of inhaled long-acting beta2-agonists ( LABAs ) on these outcomes was evaluated in patients with chronic obstructive pulmonary disease ( COPD ) in 2 double-blind r and omized clinical trials . The pretreatment arrhythmia occurrence frequency in these patients was also described . In this analysis , 24-hour Holter monitoring data were pooled from 2 identically design ed Phase III trials . Patients were r and omized to LABA treatment or placebo for 12 weeks : a ) nebulized arformoterol 15 & mgr;g BID , b ) 25 & mgr;g BID , or c ) 50 & mgr;g QD ; d ) salmeterol metered dose inhaler 42 & mgr;g BID ; or e ) placebo . The 24-hour Holter monitoring was performed pretreatment and at Weeks 0 ( first day of dosing ) , 6 , and 12 . We assessed the proportion of patients with each of 4 arrhythmias : atrial tachycardia , atrial fibrillation/flutter , and " nonsustained " ; ( 4 - 10 beats ) and " sustained " ; ( > 10 beats ) ventricular tachycardia . There were 5226 Holter recordings in 1429 treated patients . At baseline , there was a low frequency of occurrence of atrial fibrillation/flutter ( 0.1 % ) , nonsustained ventricular tachycardia ( 3.1 % ) , and > 10 beat ventricular tachycardia ( 0.3 % ) . Atrial tachycardia occurred frequently ( 41.8 % ) . The proportion of patients with treatment-emergent atrial tachycardia ranged from 27 % to 32 % and was non-significantly higher , by ∼2%-5 % ( p = 0.70 ) , in the LABA groups compared with the placebo group . The rates of the other more serious arrhythmias did not increase with LABA treatment and were similar to placebo . All treatment groups ( LABA and placebo ) had consistent small decreases from baseline in mean 24-hour and maximum hourly heart rate . In conclusion , in this large cohort of COPD patients with no or stable cardiac comorbidities , a high proportion ( ∼40 % ) of patients were observed to have atrial tachycardia before treatment , which increased by 2%-5 % with LABA treatment . More serious arrhythmias were infrequent and did not increase with inhaled LABA therapy . LABA administration did not increase mean heart rate . Abbreviations : bpm = beats per minute , CI = confidence interval , COPD = chronic obstructive pulmonary disease , FEV1 = forced expiratory volume in 1 second , FVC = forced vital capacity , ITT = intent-to-treat , LABA = long-acting beta2-agonist , MedDRA = Medical Dictionary for Regulatory [18804362] Although guidelines recommend combining long-acting bronchodilators in COPD , data are limited . We examined the clinical efficacy and safety of formoterol , tiotropium and the combination in patients with COPD . Eight hundred and forty-seven patients with COPD ( mean FEV(1 ) 52 % predicted ; FEV(1)/FVC 53 % ) were r and omized to receive one of the following four treatments for 24 weeks : formoterol 10 microg b.i.d . plus tiotropium 18 microg o.d . ; formoterol 10 microg b.i.d . ; tiotropium 18 microg o.d . , or placebo . The study was partially blinded ( formoterol and placebo ) . For the primary endpoint , FEV(1 ) 2h post-dose after 24 weeks , there were small differences in favour of the combination therapy versus formoterol ( 0.07 L , p=0.044 ) or tiotropium ( 0.06 L , p=0.066 ) . All three treatments were superior to placebo ( p<0.001 ) . The combination was statistically superior to monotherapy for : the primary endpoint ( p=0.044 vs. formoterol ) ; FEV(1 ) 5 min after the first dose ( p<0.001 ) and at 12 weeks ( p<0.05 vs. tiotropium ) ; and peak expiratory flow averaged over the first 6 weeks ( p<0.001 vs. both ) . The three active treatments were significantly more effective than placebo for secondary endpoints : COPD -related ' bad days ' , symptoms , use of rescue medication and peak expiratory flow , and aspects of health-related quality of life . The overall incidence of adverse events was similar with all active treatments , although COPD -related adverse events were more common with tiotropium . Combined bronchodilator therapy may be a valuable treatment option for patients with COPD [15790985] Background : Combined treatment with inhaled corticosteroids and long acting β2 agonists is approved for the treatment of chronic obstructive pulmonary disease ( COPD ) , but little is known about the onset of effect of the combination . Methods : Data were used from 1465 patients with COPD entered into a large 1 year double blind trial with daily measurements of peak expiratory flow ( PEF ) and symptom scores . Results : PEF was significantly higher after 1 day in patients treated with salmeterol 50 μg twice daily or the salmeterol/fluticasone propionate combination 50/500 μg twice daily than placebo . In patients treated with fluticasone propionate 500 μg twice daily alone , PEF differed from placebo after 2 days . The differences after 2 weeks compared with placebo were 16 l/min ( 95 % confidence interval ( CI ) 11 to 21 ) , 11 l/min ( 95 % CI 6 to 16 ) , and 27 l/min ( 95 % CI 22 to 33 ) for salmeterol , fluticasone propionate , and the salmeterol/fluticasone propionate combination , respectively . For all treatments the effect on PEF after 2 weeks was comparable to that seen at the end of the study . The difference between the salmeterol/fluticasone propionate combination and placebo after 2 weeks as a percentage of baseline was similar for PEF and clinic forced expiratory volume in 1 second ( FEV1 ) . Differences in breathlessness scores were statistically significant after 1 day for the group treated with salmeterol alone and after 2 days for the combination group . The 2 week change in FEV1 was only partly indicative of a long term response in individual patients . Conclusions : The effects of salmeterol and fluticasone propionate , alone or in combination , on PEF and breathlessness are seen within days and most of the obtainable effect on these parameters is reached within 2 weeks [12379552] This r and omized controlled trial examined the benefits of combining an inhaled corticosteroid , fluticasone propionate ( F ) , with an inhaled long-acting beta(2)-agonist , salmeterol ( S ) , to treat the inflammatory and bronchoconstrictive components of chronic obstructive pulmonary disease ( COPD ) . A total of 691 patients with COPD received the combination of F and S ( FSC ) , S ( 50 mcg ) , F ( 500 mcg ) , or placebo twice daily via the Diskus device for 24 weeks . A significantly greater increase in predose FEV(1 ) at the endpoint was observed after FSC ( 156 ml ) compared with S ( 107 ml , p = 0.012 ) and placebo ( -4 ml , p < 0.0001 ) . A significantly greater increase in 2-hour postdose FEV(1 ) at the endpoint was observed after treatment with FSC ( 261 ml ) compared with F ( 138 ml , p < 0.001 ) and placebo ( 28 ml , p < 0.001 ) . There were greater improvements in the Transition Dyspnea Index with FSC ( 2.1 ) compared with F ( 1.3 , p = 0.033 ) , S ( 0.9 , p < 0.001 ) , and placebo ( 0.4 , p < 0.0001 ) . The incidence of adverse effects ( except for an increase in oral c and idiasis with FSC and F ) was similar among the treatment groups . We conclude that FSC improved lung function and reduced the severity of dyspnea compared with individual components and placebo [14509555] Loss of bronchodilator effectiveness or tolerance has been observed with inhaled beta-agonists but not with inhaled anticholinergic medications . Initially , tolerance is reflected in loss of bronchial protection against stimuli followed by loss of bronchodilator properties . However , generally such observations have been reported in asthma . A 6-month r and omized , double-dummy placebo-controlled trial comparing tiotropium to salmeterol provided the opportunity to examine spirometric tolerance to long-acting beta-agonists in patients with COPD . Spirometry was measured over 12h at baseline and at days 15 , 57 , 116 and 169 . Changes over time from baseline were compared relative to changes observed with placebo . A total of 623 patients participated ( tiotropium = 209 , salmeterol = 213 , placebo = 201 ) . The groups were similar in age ( mean = 65 years ) , gender ( 75 % men ) , and baseline FEV1 ( mean = 1.08 + /- 0.37l [ 40 + /- 12 % predicted ] ) . Relative to placebo , both active drugs improved morning pre-drug , peak and average FEV1 and FVC throughout the trial . However , from day 1 to 169 , salmeterol was associated with a higher decline in average FEV1 and FVC ( 0 - 12h ) ( difference from placebo : -36 and -115 ml , P < 0.05 ) , which was most prominent over the 8 - 12 h period ( difference from placebo : -45 and -138 ml , P < 0.01 ) . Significant declines in peak FVC relative to placebo ( -83 ml , P < 0.05 ) but not FEV1 ( -12ml ) were observed with salmeterol . Tiotropium was associated with further improvements in spirometry from days 1 to 15 and no evidence of tolerance from day 15 to the end of the trial . In conclusion , tolerance to pharmacologic bronchodilation occurs with long-acting beta-agonists such as salmeterol and not with inhaled anticholinergics [18259972] Rationale : Arformoterol , a single isomer long-acting β2-agonist , was developed as an inhalation solution for the maintenance treatment of bronchoconstriction in COPD . Methods : The pulmonary function efficacy of nebulized arformoterol ( 15 μ g BID , 25 μ g BID , 50 μ g QD ) and salmeterol MDI ( 42 μ g BID ) versus placebo was assessed in 1456 subjects ( mean FEV1 1.2L , mean predicted 41 % ) . Data were pooled from 2 identical , 12-week , double-blind , r and omized trials . The percent change in trough FEV1 , percent change in FEV1 average AUC(0 - 12 hrs ) and peak percent change FEV1 from predose were analyzed . Results : Improvement in trough FEV1 averaged over 12 weeks was greater for arformoterol and salmeterol versus placebo ( mean differences from placebo [ 95 % CI ] arformoterol–15 μ g BID : 11.4 % [ 8.4 , 14.3 ] ; 25 μ g BID : 15.4 % [ 12.2 , 18.6 ] ; 50 μ g QD : 10.9 % [ 7.9 , 13.9 ] ) ; salmeterol : ( 11.6 % [ 8.8 , 14.4 ] ) . Greater improvements versus placebo occurred after the first dose ( mean differences between arformoterol and placebo for trough FEV1 : 13–19 % ; FEV1 AUC(0 - 12 hrs ) : 19–24 % ; peak percent change : 20–25 % ) and at week 12 ( trough FEV1 : 10–13 % ; FEV1 AUC(0 - 12 hrs ) : 6–13 % ; peak percent change : 7–14 % ) ; all 95 % CIs excluded zero . Increases in FEV1 AUC(0 - 12 hrs ) and peak percent change were greater for arformoterol than for salmeterol ( 95 % CIs excluded zero ) . After 12 weeks , 78–87 % of arformoterol subjects had ≥ 10 % increases in FEV1 from pre-dose ( 56 % salmeterol , 44 % placebo ) ; the median time to response was 3–13 minutes ( 142 minutes salmeterol ) . Conclusions : In these trials , COPD subjects administered nebulized arformoterol demonstrated significant and sustained improvement in lung function over 12 weeks [16199148] Formoterol is a long-acting beta2-agonist with a rapid onset of effect in patients with chronic obstructive pulmonary disease ( COPD ) , making it potentially suitable for both maintenance and as-needed bronchodilator treatment . To evaluate the efficacy and tolerability of maintenance formoterol in patients with COPD and to compare the effects of additional formoterol as needed with terbutaline . In this 6-month , double-blind study , 657 patients with COPD ( 40 years , forced expiratory volume in 1s [ FEV1 ] 40 - 70 % predicted normal ) were r and omized to formoterol 9 microg twice daily ( bid ) plus terbutaline 0.5 mg as needed ( FORM bid ) , formoterol 9 microg bid plus formoterol 4.5 microg as needed ( FORM bid+prn ) , or placebo bid plus terbutaline 0.5 mg as needed ( placebo ) , all administered via Turbuhaler . Primary efficacy variables were FEV1 and the sum of breathlessness and chest tightness scores combined symptom score . Formoterol significantly ( P<0.01 ) increased FEV(1 ) compared with placebo : FORM bid 6.5 % ( 95 % CI : 2.5 , 10.7 % ) ; FORM bid+prn 11.8 % ( 95 % CI : 7.7 , 16.2 % ) . Combined symptom score decreased significantly in both formoterol groups compared with placebo : FORM bid -0.27 ( 95 % CI : -0.49 , -0.06 ; P=0.012 ) ; FORM bid+prn -0.32 ( 95 % CI : -0.53 , -0.11 ; P=0.0026 ) . Similar significant ( P<0.05 ) improvements were seen in both formoterol groups for morning peak expiratory flow , cough and sleep scores , and reliever use . In this study , formoterol 9 microg bid via Turbuhaler as maintenance therapy , with either formoterol or terbutaline as rescue medication , provided sustained improvements in lung function and COPD symptoms . Both formoterol regimens were well tolerated with no differences in adverse events or electrocardiogram profiles [15853436] Abstract Objective : To compare the healthcare costs and effects of budesonide/formoterol in a single inhaler with those of budesonide and formoterol monotherapies , and placebo , in a multinational study in patients with chronic obstructive pulmonary disease ( COPD ) , National Heart , Lung and Blood Institute (NHLBI)/WHO Global Initiative for Chronic Obstructive Lung Disease ( GOLD ) stages III or IV . Previous analysis of the clinical data from the study had shown that budesonide/formoterol was associated with better lung function and improved health-related QOL compared with the monocomponents or placebo and lower frequency of exacerbations compared with formoterol and placebo . Method : Patients ( n = 1022 ) were r and omised to twice-daily treatment with two inhalations of budesonide/formoterol ( 160μg/4.5μg ) in a single inhaler , budesonide 200μg , formoterol 4.5μg or placebo for 12 months . Data on medication and healthcare use were combined with Swedish unit cost data to estimate the total annual healthcare cost per patient from the Swedish healthcare payer perspective . Costs were valued in Swedish kronor ( SEK ) [ 2001 values ] and converted to euros ( SEK1 = € 0.11 , 25th April 2003 ) . Results : This evaluation estimated the total annual healthcare costs per patient to be numerically lower for budesonide/formoterol ( € 2518 ) than for budesonide ( € 3194 ) , formoterol ( € 3653 ) or placebo ( € 3213 ) . Cost-effectiveness acceptability curves suggest that budesonide/formoterol may be cost effective compared with formoterol , even if the decision maker is not willing to pay anything for the additional clinical effects , and that budesonide/formoterol is cost effective compared with placebo if a decision maker is willing to pay about € 2 per day , per avoided exacerbation . Conclusion : This economic analysis suggests that the clinical benefits of using budesonide/formoterol in a single inhaler are achieved at a numerically lower total healthcare cost than either monocomponent or placebo . Budesonide/formoterol in patients with severe COPD ( GOLD stages III or IV ) may be cost effective , from the healthcare provider perspective , compared with either monocomponent [19581353] BACKGROUND Osteoporosis is common in patients with COPD , but its prevalence and progression are not well characterized . Concerns have been raised over the possible deleterious effect of long-term therapy with inhaled corticosteroids ( ICSs ) on bone density in this population . Here , we investigated the long-term effects of therapy with fluticasone propionate ( FP ) alone , salmeterol ( SAL ) alone , and a SAL/FP combination ( SFC ) on bone mineral density ( BMD ) and bone fractures in patients with moderate-to-severe COPD in the TOwards a Revolution in COPD Health ( TORCH ) study . METHODS A r and omized , double-blind , parallel-group , placebo-controlled study conducted at 88 US centers involving 658 patients ( a subset of 6,184 international subjects in TORCH ) . Therapy with placebo , SAL ( 50 microg ) , FP ( 500 microg ) , or SFC ( SAL 50 microg/FP 500 microg ) twice daily was administered for 3 years . Baseline and yearly measurements of BMD at the hip and lumbar spine were performed . The incidence of traumatic and nontraumatic bone fractures was recorded . RESULTS At baseline , 18 % of men and 30 % of women had osteoporosis , and 42 % of men and 41 % of women had osteopenia based on BMD assessment s. Forty-three percent of subjects completed all testing . The changes in BMD at the hip and lumbar spine over 3 years were small . No significant differences were observed between treatment arms ( adjusted mean percent change from baseline at hip was -3.1 % for placebo , -1.7 % for SAL , -2.9 % for FP , and -3.2 % for SFC therapy , respectively ; while , the corresponding changes for the lumbar spine were 0 , 1.5 % , -0.3 % , and -0.3 % for placebo , respectively , SAL , FP , and SFC therapy ) . The incidence of fractures was low and was similar for all treatments ( 5.1 % to 6.3 % ) . CONCLUSIONS Osteoporosis is highly prevalent in patients with COPD , irrespective of gender . In the TORCH study , no significant effect on BMD was detected for ICS therapy compared with placebo . TRIAL REGISTRATION Clinical Trials.gov Identifier : NTC00268216 [10525558] BACKGROUND The Chronic Respiratory Question naire ( CRQ ) and the St George 's Respiratory Question naire ( SGRQ ) are the two most widely used quality of life question naires in chronic obstructive pulmonary disease ( COPD ) . A study was undertaken to compare directly the self-administered version of the CRQ and the SGRQ with respect to feasibility , internal consistency , validity , and sensitivity to changes result ing from bronchodilator therapy . METHODS One hundred and forty four patients with moderate or severe COPD were r and omly assigned to receive three months of treatment with either salmeterol , salmeterol + ipratropium bromide , or placebo . Quality of life was measured at baseline and after 12 weeks of treatment . RESULTS The proportions of missing values per patient were low for both question naires ( 0.54 % for the CRQ and 2 % for the SGRQ ) . The internal consistency was good for both question naires ( Cronbach 's alpha coefficients > /= 0.84 for the CRQ and > /= 0.76 for the SGRQ ) . Factor analysis confirmed the original domain structure of the CRQ but not of the SGRQ . Correlations with forced expiratory volume in one second ( FEV(1 ) ) % predicted and peak expiratory flow rate ( PEFR ) were low for both question naires but better for the SGRQ than for the CRQ . The ability to discriminate between subjects with different levels of FEV(1 ) was somewhat better for the SGRQ . The correlations with symptom scores were comparable for both question naires . Cross sectionally , the scores of the two question naires were moderately to highly correlated ( coefficients ranged from 0.35 to 0.72 ) . Longitudinally , these correlations were lower ( coefficients ranged from 0.17 to 0.54 ) but were still significant . The CRQ total and emotions score and the SGRQ symptoms score were the most responsive to change . The SGRQ symptoms domain was the only domain where the improvement in patients receiving combination treatment crossed the threshold for clinical relevance . CONCLUSIONS Since this analysis of reliability , validity , and responsiveness to change did not clearly favour one instrument above the other , the choice between the CRQ and the SGRQ can be based on other considerations such as the required sample size or the availability of reference values [18363201] Nebulized solutions of long-acting bronchodilators provide an alternative to DPI and MDI delivery , particularly for COPD patients unable to use h and -held devices easily or correctly . The long-acting beta2-agonist , formoterol fumarate , is differentiated by its onset of significant bronchodilation within 5 min of administration . In a r and omized , double-blind , double-dummy trial , COPD subjects ( n=351 , mean forced expiratory volume FEV1=1.3 L , 44 % predicted ) received nebulized formoterol fumarate ( Perforomist inhalation solution ; FFIS 20 microg ) or DPI ( Foradil Aerolizer ; FA 12 microg ) , or placebo twice daily for 12 weeks . Efficacy was assessed with 12-h pulmonary function tests , and quality of life was assessed before and after treatment with the St. George 's Respiratory Question naire ( SGRQ ) . At the 12-week endpoint , FFIS significantly increased FEV1 AUC0 - 12h relative to placebo ( p<0.0001 ) . No evidence of tachyphylaxis was observed as indicated by maintained FEV1 AUC and reduced rescue albuterol use throughout treatment . FFIS also significantly increased peak FEV1 , trough FEV1 , and st and ardized FVC AUC0 - 12h compared with placebo . SGRQ assessment at Week 12 demonstrated significant and clinical ly meaningful improvements in total score ( FFIS vs placebo , -4.9 , p=0.0067 ) , symptom , and impact scores . No significant differences in efficacy were observed between the two active treatments . Drug related AEs in the FFIS arm with a frequency > or = 1 % and exceeding placebo were dry mouth , nausea , and insomnia . Nebulized FFIS provided significant improvement in respiratory status and quality of life in subjects with COPD relative to placebo and was well tolerated . The efficacy and safety profile of FFIS was comparable to FA DPI [7503401] Inhaled formoterol is a potent selective β2‐agonist with rapid onset and at least 12‐h duration of bronchodilation . The aim of the study was to compare the bronchodilating effect of inhaled formoterol dry powder ‘ dp ) 12 μg b.i.d . with salbutamol dp 400 μg q.i.d . and placebo in patients with reversible obstructive airway disease ‘ ROAD ) . The study design consisted of a closed 12‐week double‐blind , placebo‐controlled , multicenter trial followed by an open noncomparative , multicenter , 12‐month follow‐up trial , in which the tolerability of formoterol dp was assessed . A total of 304 patients ‘ 146 men , 158 women ) aged 18‐79 years , ill during 0.1‐64 years , were r and omized . No demographic or baseline differences were found among the different treatment groups . The bronchodilating effect of formoterol , assessed by morning premedication PEFR , was significantly superior to placebo ‘ P < 0.0001 ) and salbutamol ‘ P < 0.0001 ) . Efficacy was maintained during the open follow‐up study with 12 μg b.i.d . in most of the patients . A few patients , however , needed 24 μg b.i.d . to control their ROAD . Formoterol 12 μg b.i.d . significantly reduced morning and evening asthma symptoms and sleep disturbances , and reduced significantly the need for rescue medication . The tolerability of the three treatment groups was comparable . In conclusion , formoterol 12 μg dp b.i.d . was significantly superior to both salbutamol 400 μg dp q.i.d . and placebo , and reduced asthma symptoms significantly . Overall , formoterol showed a tolerability profile comparable to that of salbutamol , and no tachyphylaxis was observed during 1 year of treatment [18042473] BACKGROUND Recently , there have been concerns about the tolerability of long-acting (2)-agonists , including possible adverse cardiovascular effects-a particular concern in patients with chronic obstructive pulmonary disease ( COPD ) , who are at elevated risk for cardiovascular disease . OBJECTIVE The aim of this study was to assess the cardiac safety profile of nebulized formoterol fumarate inhalation solution . METHODS Cardiac safety was assessed as part of a 12-week , r and omized , double-blind , double-dummy , placebo- and active-controlled trial that was conducted at 38 centers across the United States . Male and female patients aged > /=40 years with COPD and without other significant disease were enrolled . After a 4- to 14-day , single-blind placebo run-in period , patients with COPD were r and omly assigned to receive formoterol fumarate inhalation solution 20 microg BID via nebulizer ( FFIS group ) , formoterol fumarate 12 microg BID via dry powder inhaler ( FA group ) , or placebo . Cardiac effects-measured by changes in heart rate ( HR ) and ventricular premature beats ; incidence of proarrhythmic events ; change in corrected QT ( QTc ) interval ; and incidence of maximum mean change in QTc > /=60 ms-were assessed using 24-hour Holter monitoring at baseline and 12 weeks ; 12-lead electrocardiography at screening and weeks 4 , 8 , and 12 ; and patient diary cards . RESULTS A total of 351 patients with COPD were r and omized ( mean age , 62.8 years ; 56.1 % male ; mean postbronchodilator forced expiratory volume in 1 second , 1.5 L ) . Holter monitoring found no clinical ly meaningful effects of FFIS or FA treatment on mean or maximum HR , ventricular premature beats , or inci dence of arrhythmic events compared with placebo . At week 12 , mean ( SD ) changes from baseline in mean HR were -0.6 ( 10.9 ) , + 0.1 ( 11.6 ) , and -1.4 ( 9.4 ) bpm in the FFIS , FA , and placebo groups , respectively . The incidence of mean maximum changes in QTc > /=60 ms at any time during the 12-week treatment period were 1.6 % , 1.8 % , and 1.8 % with FFIS , FA , and placebo , respectively . Treatment-emergent cardiac adverse events ( AEs ) occurred in 4.1 % , 3.5 % , and 4.4 % of patients in the FFIS , FA , and placebo groups ; withdrawals due to possible cardiac AEs occurred in 1 patient per treatment group . No deaths or serious cardiac AEs occurred during the treatment period . CONCLUSION In this COPD population , no clinical ly significant cardiac effects were found with twicedaily treatment with nebulized formoterol fumarate inhalation solution [15526804] The prevalence of chronic obstructive pulmonary disease ( COPD ) in women is increasing worldwide . Women may have greater susceptibility to COPD progression than men , and differences in efficacy and safety of respiratory medications by gender are largely unexplored . We aim ed to determine whether the response to treatment in women with COPD differed from men in a large , 1-year double-blind trial ( ' TRISTAN ' ) . In a sensitivity analysis , we compared 539 male and 180 female COPD patients , who were r and omized to the saLmeterol/fluticasone combination 50/500mcg bid or placebo for 12 months . Combination therapy improved pre-treatment FEV1 significantly more than placebo in women by 152 ml ( 95 % confidence interval 95 - 208 ) and in men by 127 ml ( 94 - 159 ) . Similarly , a reduction in COPD exacerbation rates of 31 % in women ( 9 - 48 % ) and of 23 % in men ( 8 - 35 % ) was observed . Combination therapy reduced COPD exacerbations requiring treatment with oral corticosteroids by 36 % in women and by 41 % in men . Finally , combination treatment produced a better improvement in health status than placebo with a decrease in the SGRQ scores in women by -2.3 ( -4.6 - 0.1 ) and in men by -2.1 ( -3.5 to -0.8 ) . No gender interaction was found for any outcome . Treatments were well tolerated with no difference in the frequency of adverse events in women and men . In this trial , therapy with the salmeterol/fluticasone combination produced significant improvements compared to placebo on all main endpoints and the magnitude of these improvements was similar for both men and women [12114338] BACKGROUND Tiotropium , a once-daily anticholinergic , and salmeterol represent two inhaled , long-acting bronchodilators from different pharmacologic classes . A trial was design ed to examine the efficacy and safety of both compounds with multiple outcome measures , including lung function , dyspnea , and health-related quality of life ( HRQoL ) in patients with COPD . METHODS A 6-month , r and omized , placebo-controlled , double-blind , double-dummy , parallel-group study of tiotropium , 18 microg once daily via dry-powder inhaler , compared with salmeterol , 50 microg bid via metered-dose inhaler , was conducted in patients with COPD . Efficacy was assessed by 12-h monitoring of spirometry , transition dyspnea index ( TDI ) , and the St. George 's Respiratory Question naire ( SGRQ ) . RESULTS A total of 623 patients participated ( tiotropium , n= 209 ; salmeterol , n = 213 ; and placebo , n = 201 ) . The groups were similar in age ( mean , 65 years ) , gender ( 75 % men ) , and baseline FEV(1 ) ( mean , 1.08 + /- 0.37 L ; percent predicted , 40 + /- 12 % [ + /- SD ] ) . Compared with placebo treatment , the mean predose morning FEV(1 ) following 6 months of therapy increased significantly more for the tiotropium group ( 0.14 L ) than the salmeterol group ( 0.09 L ; p < 0.01 ) . The average FEV(1 ) ( 0 to 12 h ) for tiotropium was statistically superior to salmeterol ( difference , 0.08 L ; p < 0.001 ) . Tiotropium improved TDI focal score by 1.02 U compared with placebo ( p = 0.01 ) , whereas there was no significant change in TDI focal score with salmeterol ( 0.24 U ) . Tiotropium was superior to salmeterol in improving TDI focal score ( p < 0.05 ) . At 6 months , the mean improvement in SGRQ total score vs baseline was tiotropium , - 5.14 U ( p < 0.05 vs placebo ) ; salmeterol , - 3.54 U ( p = 0.4 vs placebo ) ; and placebo , - 2.43 U. A statistically higher proportion of patients receiving tiotropium achieved at least a 4-U change in SGRQ score compared to patients receiving placebo . Both active drugs reduced the need for rescue albuterol ( p < 0.0001 ) . CONCLUSIONS Tiotropium once daily produces superior bronchodilation , improvements in dyspnea , and proportion of patients achieving meaningful changes in HRQoL compared to twice-daily salmeterol in patients with COPD [8999618] This article is based on a study first published in Allergy . The bronchodilating effect of the long acting beta 2-agonist formoterol dey powder ( dp ) 12 micrograms twice daily was compared to salbutamol 400 micrograms four times daily and placebo in patients with reversible obstructive airway disease . The study design consisted of a closed 12-week double-blind , placebo-controlled , multicentre trial followed by an open noncomparative , multicentre 12-month follow-up trial , in which tolerability of formoterol dp was assessed . A total of 304 patients aged 18 - 79 years were r and omized . The bronchodilating effect of formoterol , assessed by morning premedication peak flow rate , was significantly superior to placebo ( p < 0.0001 ) and salbutamol ( p < 0.001 ) . Efficacy was maintained during the open follow-up study . Formoterol 12 micrograms twice daily significantly reduced morning and evening asthma symptoms and sleep disturbances , and significantly reduced the need for rescue medication . In conclusion , formoterol 12 micrograms dp twice daily was significantly superior to both salbutamol 400 micrograms dp four times daily and placebo , and reduced asthma symptoms significantly . Overall , formoterol showed a tolerability profile comparable to that of salbutamol , and no tachyphylaxis was observed during one year of treatment [10853852] The efficacy and safety of salmeterol alone was compared with the combination of salmeterol plus ipratropium and with placebo during long-term treatment in patients with stable chronic obstructive pulmonary disease . In addition , the single-dose effect in response to the first dose of treatment was studied over 12 h. The patients ( n=144 ; age 64+/-7 yrs , forced expiratory volume in one second ( FEV1 ) 44+/-11 % pred ) participated in a three-centre double-blind double-placebo parallel group study and were r and omized after a run-in period of 2 weeks to receive either salmeterol 50 microg b.i.d . , salmeterol 5 microg b.i.d . plus ipratropium 40 microg q.i.d . or placebo for a period of 12 weeks . The single-dose study demonstrated that salmeterol produced a significant increase in FEV1 ( peak of 7 % pred ) and specific airway conductance ( sGaw ) ( maximum of 60 % baseline ) for > or = 12 h. The combination of salmeterol plus ipratropium elicited a greater bronchodilator response ( 11 % and 94 % increases respectively ) than salmeterol alone during the first 6 h after inhalation . During treatment there were significant improvements in daytime symptom scores and morning peak expiratory flow in both the salmeterol and the salmeterol plus ipratropium groups ( p<0.001 ) , with an associated decrease in the use of rescue salbutamol . Improvements in FEV1 and sGaw were greater in the salmeterol plus ipratropium group than in the patients receiving only salmeterol . Thirty-five patients had an exacerbation ; 11 ( 23 % ) in the salmeterol group ( versus placebo NS ) , six ( 13 % ) in the salmeterol plus ipratropium group ( versus placebo p<0.01 ) and 18 ( 36 % ) in the placebo group . In conclusion , in patients with severe stable chronic obstructive pulmonary disease , long-term treatment with either salmeterol alone or salmeterol plus ipratropium is safe and effective . There was added benefit from the combination therapy in terms of improvement in airways obstruction , but not for improvement in symptom control or need for rescue salbutamol [12564609] The need to manage the key symptoms of chronic obstructive pulmonary disease ( COPD ) ( breathlessness , cough and sputum ) is an important treatment objective . Viozan ( sibenadet HCl , AR-C68397AA ) is a novel dual D2 dopamine receptor , beta2-adrenoceptor agonist , which combines conventional bronchodilatory activity with the sensory nerve modulation afforded by dopamine agonism . The efficacy of this agent in relieving patient symptoms has been determined in a series of large-scale clinical studies ; the results of a 3-month , placebo-controlled multi-centre study are reported . Effect on patient symptoms was determined using a novel patient-reported assessment instrument , the Breathlessness , Cough and Sputum Scale ( BCSS ) . Patients with smoking-related COPD were required to complete a 2-week baseline period before being r and omized to one of three treatment groups ; sibenadet ( 500 microg three times daily ) plus placebo ( twice daily ) ; salmeterol ( 50 microg twice daily ) plus placebo ( three times daily ) ; placebo ( twice daily ) plus a second placebo ( three times daily ) . All treatments were delivered via pressurized metered dose inhaler ( pMDI ) for 12 weeks . From enrolment , patients were required to complete daily diary cards to record symptoms of breathlessness , cough and sputum , medication use and adverse events . The primary outcome measure was the difference between the mean BCSS total score measured over the baseline period and the mean BCSS total score in the final 4 weeks of the treatment period . Secondary measures included assessment of lung function , rescue medication use , exacerbations , health-related quality of life , opinion of efficacy and safety . Although an initial reduction in BCSS total score ( indicating symptom improvement ) was seen with sibenadet therapy , this effect was not maintained for the study duration . Salmeterol therapy , however , result ed in a sustained reduction in BCSS total score . No notable benefit over placebo was seen in lung function , exacerbations or health-related quality of life with either active treatment . While the results of this study failed to demonstrate sustained efficacy with sibenadet therapy , they do indicate the value of symptom assessment in the clinical evaluation of new drugs for the treatment of COPD [19880616] The TORCH ( Towards a Revolution in COPD Health ) trial has highlighted some important issues in the design and analysis of long term trials in chronic obstructive pulmonary disease . These include collection of off-treatment exacerbation data , analysis of exacerbation rates and the effect of inclusion of patients receiving inhaled corticosteroids ( ICS ) prior to r and omisation . When effective medications are available to patients who withdraw , inclusion of off-treatment data can mask important treatment effects on exacerbation rates . Analysis of on-treatment data avoids this bias but it needs to be combined with careful analysis of withdrawal patterns across treatments . The negative binomial model is currently the best approach to statistical analysis of exacerbation rates , while analysis of time to exacerbation can supplement this approach . In the TORCH trial , exacerbation rates were higher among patients with previous use of ICS compared to those with no prior use on all study treatments . Retrospective subgroup analysis suggests ICS reduced exacerbation rates compared with placebo , regardless of prior use of ICS before entry to the study . Factorial analysis provides an alternative analysis for trials with combinations of treatments , but assumes no interaction between treatments , an assumption which can not be verified by a significance test . No definitive conclusions can yet be drawn on whether ICS treatment has an effect on mortality [17314337] BACKGROUND Long-acting beta-agonists and inhaled corticosteroids are used to treat chronic obstructive pulmonary disease ( COPD ) , but their effect on survival is unknown . METHODS We conducted a r and omized , double-blind trial comparing salmeterol at a dose of 50 microg plus fluticasone propionate at a dose of 500 microg twice daily ( combination regimen ) , administered with a single inhaler , with placebo , salmeterol alone , or fluticasone propionate alone for a period of 3 years . The primary outcome was death from any cause for the comparison between the combination regimen and placebo ; the frequency of exacerbations , health status , and spirometric values were also assessed . RESULTS Of 6112 patients in the efficacy population , 875 died within 3 years after the start of the study treatment . All-cause mortality rates were 12.6 % in the combination-therapy group , 15.2 % in the placebo group , 13.5 % in the salmeterol group , and 16.0 % in the fluticasone group . The hazard ratio for death in the combination-therapy group , as compared with the placebo group , was 0.825 ( 95 % confidence interval [ CI ] , 0.681 to 1.002 ; P=0.052 , adjusted for the interim analyses ) , corresponding to a difference of 2.6 percentage points or a reduction in the risk of death of 17.5 % . The mortality rate for salmeterol alone or fluticasone propionate alone did not differ significantly from that for placebo . As compared with placebo , the combination regimen reduced the annual rate of exacerbations from 1.13 to 0.85 and improved health status and spirometric values ( P<0.001 for all comparisons with placebo ) . There was no difference in the incidence of ocular or bone side effects . The probability of having pneumonia reported as an adverse event was higher among patients receiving medications containing fluticasone propionate ( 19.6 % in the combination-therapy group and 18.3 % in the fluticasone group ) than in the placebo group ( 12.3 % , P<0.001 for comparisons between these treatments and placebo ) . CONCLUSIONS The reduction in death from all causes among patients with COPD in the combination-therapy group did not reach the predetermined level of statistical significance . There were significant benefits in all other outcomes among these patients . ( Clinical Trials.gov number , NCT00268216 [ Clinical Trials.gov ] . ) [9105068] Changes in health-related quality of life ( HRQoL ) were evaluated in patients with chronic obstructive pulmonary disease ( COPD ) following treatment with placebo , salmeterol 50 microg twice a day or 100 microg twice a day by metered-dose inhaler . Patients completed the disease-specific St. George 's Respiratory Question naire ( SGRQ ) and the Medical Outcomes Study Short Form 36 ( SF-36 ) at baseline and after 16 wk of treatment . Data from 283 patients ( 95 patients in the placebo group and 94 in each salmeterol group ) were available for HRQoL analysis . Apart from a small difference in ages , all treatment groups were well matched at baseline in terms of forced expiratory volume in one second ( FEV1 ) and HRQoL scores . Compared with placebo , salmeterol 50 microg twice a day was associated with significant improvements in SGRQ " Total " and " Impacts " scores which exceeded the threshold for a clinical ly significant change . This was not seen with salmeterol 100 microg twice a day . Changes in SGRQ and SF-36 scores correlated . They also showed a weak but significant relationship with FEV1 . This study has shown that a modest change in lung function may be associated with clinical ly significant gain in health and well-being in COPD patients [17472819] OBJECTIVE The aim of this study was to assess the efficacy and tolerability of nebulized arformoterol tartrate ( a selective , long-acting beta(2)-adrenergic agonist that is the [ R , R ] isomer of formoterol ) and salmeterol xinafoate versus placebo in patients with chronic obstructive pulmonary disease ( COPD ) . METHODS This 12-week , multicenter , r and omized , double-blind , double-dummy , placebo- and active-controlled trial was conducted at 60 centers across the United States . Male and female patients aged > or=35 years with physician-diagnosed COPD received arformoterol ( 15 microg BID , 25 microg BID , or 50 microg QD via nebulizer ) , salmeterol ( 42 microg BID via metered dose inhaler ) , or placebo . Pulmonary function was assessed by spirometry ; dyspnea , by the Transitional Dyspnea Index ( TDI ) ; and health status , by the St. George 's Respiratory Question naire ( SGRQ ) . Adverse events ( AEs ) were assessed by site personnel at all clinic visits ( screening , first dose at week 0 , and at weeks 3 , 6 , 9 , 12 , and follow-up ) . COPD exacerbations were defined as worsening respiratory status requiring a change in medication or an unscheduled provider visit . RESULTS A total of 717 patients received study medication . The demographic composition of all treatment arms was similar . The mean age was 62.9 years , 58 % were men , and mean baseline forced expiratory volume in 1 second ( FEV(1 ) ) was 1.2 L ( 41 % predicted ) . Mean improvement in trough FEV(1 ) over 12 weeks was significantly greater with all 3 arformoterol doses ( 15 microg BID , + 16.9 % ; 25 microg BID , + 18.9 % ; 50 microg QD , + 14.9 % ) and for salmeterol ( + 17.4 % ) relative to placebo ( + 6.0 % ; P < 0.001 ) . There were significantly greater improvements in the mean percentage change in FEV(1 ) AUC(0 - 12h ) from the predose value over 12 weeks ( 15 microg BID , 12.7 % , 25 microg BID , 13.9 % , 50 microg QD , 18.9 % ; salmeterol , 9.8 % ) versus placebo ( 2.7 % ; P < or= 0.001 ) ; all doses of arformoterol were statistically different from salmeterol for this end point ( P < or= 0.024 ) . At week 12 , TDI focal scores were significantly greater with all arformoterol doses compared with placebo ( mean [ 95 % CI ] : 15 microg BID , 0.97 [ 0.25 - 1.69 ] ; 25 microg BID , 1.08 [ 0.3 - 1.86 ] ; 50 microg QD , 1.04 [ 0.32 - 1.771 ) , suggesting treatment-associated improvement in dyspnea , however , the difference between salmeterol and placebo was not statistically significant ( 0.36 [ -0.40 to 1.12 ] ) . Improvements in health status , as measured using SGRQ total scores , were -2.6 to -3.6 U in the arformoterol groups , -4.4 U for salmeterol , and -1.2 U for placebo ; 95 % CI of differences versus placebo suggested significant improvement for the arformoterol 25 microg BID and salmeterol groups . There was a similar frequency of AEs and COPD exacerbations across all groups , including placebo . CONCLUSIONS In this trial , patients with moderate to severe COPD administered nebulized arformoterol over 12 weeks were observed to have significant and sustained improvements in airway function and dyspnea compared with placebo . The results also suggest that all doses of arformoterol , including the lowest dose ( 15 microg BID ) , were effective . Overall , nebulized arformoterol was well tolerated [21531124] BACKGROUND Chronic obstructive pulmonary disease ( COPD ) patients are thought to have limited bronchodilator response , determined by changes in forced expiratory volume in 1s ( FEV(1 ) ) . In this study , we assessed bronchodilator response in patients with COPD using not only FEV(1 ) but also changes in lung volume expressed as forced vital capacity ( FVC ) and inspiratory capacity ( IC ) . We also evaluated the speed of onset of bronchodilation . METHODS Data were from 2 r and omized , double-blind , placebo-controlled studies ( 6-months [ NCT00206154 ] ; 12-months [ NCT00206167 ] ) in patients with moderate to very severe COPD . TREATMENTS twice daily budesonide/formoterol pressurized metered-dose inhaler ( pMDI ) 320/9μg , budesonide/formoterol pMDI 160/9μg , formoterol dry powder inhaler ( DPI ) 9μg , placebo . RESULTS The percentage of patients with FEV(1 ) improvement ( ≥12 % and ≥200mL ; American Thoracic Society [ ATS ] criterion ) was 34 - 39 % post-albuterol ( screening ) . On day of r and omization ( DOR ) , a larger proportion receiving formoterol-containing treatment exhibited reversibility within 60min : FEV(1 ) ( 57 - 59 % ) . Similar results were seen for IC ( 50 - 61 % ) and FVC ( 57 - 67 % ) using the same improvement criteria . The time to ≥15 % FEV(1 ) improvement on DOR was 5.0 , 4.8 , and 7.3min for budesonide/formoterol 320/9 , budesonide/formoterol 160/9 , and formoterol , respectively . Time to ≥15 % FEV(1 ) improvement was better maintained with budesonide/formoterol than formoterol at treatment end ( 6 and 12 months ) . CONCLUSIONS Most patients with moderate to very severe COPD exhibit ATS-defined bronchodilator reversibility based on flow and lung volume measures after budesonide/formoterol pMDI or formoterol treatment . Budesonide/formoterol pMDI also has a rapid ( within 5min ) onset of bronchodilation that is maintained over time compared with formoterol alone [21159140] Introduction : R and omised controlled trials ( RCTs ) are considered the least biased method for evaluating drug efficacy and several large long‐term RCTs in chronic obstructive pulmonary disease have been published . These usually include drugs with symptomatic benefits and have significant withdrawal rates Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Pharmacological therapy for chronic obstructive pulmonary disease ( COPD ) is aim ed at relieving symptoms , improving quality of life and preventing or treating exacerbations . Treatment tends to begin with one inhaler , and additional therapies are introduced as necessary . For persistent or worsening symptoms , long-acting inhaled therapies taken once or twice daily are preferred over short-acting inhalers . Several Cochrane review s have looked at the risks and benefits of specific long-acting inhaled therapies compared with placebo or other treatments . However for patients and clinicians , it is important to underst and the merits of these treatments relative to each other , and whether a particular class of inhaled therapies is more beneficial than the others . OBJECTIVES To assess the efficacy of treatment options for patients whose chronic obstructive pulmonary disease can not be controlled by short-acting therapies alone . The review will not look at combination therapies usually considered later in the course of the disease . How does long-term efficacy compare between different pharmacological treatments for COPD ? 2 . Are there limitations in the current evidence base that may compromise the conclusions drawn by this network meta- analysis ? If so , what are the implication s for future research ? AUTHORS ' CONCLUSIONS This network meta- analysis compares four different classes of long-acting inhalers for people with COPD who need more than short-acting bronchodilators . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

17443522

[4890375] One hundred and three antenatal patients with initial haemoglobin levels of 10.7 g./100 ml . or less at their first antenatal visit were treated with either ferrous gluconate , Ferrogradumet or intravenous Astrafer . A significant rise in haemoglobin level occurred in the first month in those groups receiving iron therapy compared with the control group . From the end of the first month until 36 weeks gestation , there was no significant difference between the treatment groups [19506383] Objective : To evaluate the effectiveness of a stepwise use of recombinant human erythropoietin ( rhEPO ) in pregnant patients with severe anemia or nonresponsive to intravenously administered iron only . Methods : All subjects had iron deficiency anemia , i.e. , a hemoglobin ( Hb ) level < 10.0 g/dl and ferritin ≤15 μg/l . Patients with an Hb level ≥9.0 g/dl and < 10.0 g/dl received 200 mg iron sucrose intravenously twice weekly . If response to therapy was poor , patients additionally received 10,000 U rhEPO twice weekly . Patients with an Hb level < 9.0 g/dl primarily received iron sucrose and rhEPO likewise . Results : Of the 84 patients , 59 had a baseline Hb level between 9.0 and 9.9 g/dl , of whom 32 responded poorly , thus receiving additional rhEPO . Twenty-five patients had a baseline Hb level < 9.0 g/dl . The overall Hb level after therapy was 11.0 g/dl ( ±0.5 , range 10.0–12.6 g/dl ) . Mean duration of therapy was 3.5 weeks ( 7 infusions ) . Conclusion : This study shows an effective treatment regimen for patients with various degrees of anemia in pregnancy . Iron sucrose is a safe and effective treatment option . In cases of severe iron deficiency anemia or poor response to parenteral iron therapy additional administration of rhEPO might be considered . However , the mechanism for not responding to intravenous iron therapy despite iron deficiency anemia still remains unclear to a large extent [16319260] OBJECTIVE : The aim of this study was to compare the efficacy of intravenous iron to oral iron in the treatment of anemia in pregnancy . METHODS : In this r and omized open-label study , 90 women with hemoglobin levels between 8 and 10.5 g/dL and ferritin values less than 13 & mgr;g/L received either oral iron polymaltose complex ( 300 mg elemental iron per day ) or intravenous iron sucrose . The iron sucrose dose was calculated from the following formula : weight before pregnancy ( kg ) × ( 110 g/L – actual hemoglobin [ g/L ] ) × 0.24 + 500 mg . Treatment efficacy was assessed by measuring hemoglobin and ferritin on the 14th and 28th days and at delivery , and the hemoglobin on the first postpartum day . Adverse drug reactions , fetal weight , hospitalization time , and blood transfusions were also recorded . RESULTS : Hemoglobin values varied significantly with time between groups ( interaction effect , P < .001 ) . The change in hemoglobin from baseline was significantly higher in the intravenous group than the oral group at each measurement ; the changes with respect to subsequent hemoglobin were significantly higher on the 14th ( P = .004 ) and 28th ( P = .031 ) days . Ferritin values were higher in patients receiving intravenous iron throughout pregnancy . No serious adverse drug reactions were observed . Fetal weight and hospitalization time were similar in the 2 groups . Blood transfusion was required for only one patient in the oral group . CONCLUSION : Intravenous iron treated iron-deficiency anemia of pregnancy and restored iron stores faster and more effectively than oral iron , with no serious adverse reactions . LEVEL OF EVIDENCE : [12532571] OBJECTIVE ( 1 ) To determine an alternative iron supplementation with better efficacy , compliance & safety in treatment of iron deficiency anemia during pregnancy , ( 2 ) to reduce blood transfusion during pregnancy , labor and puerperium . MATERIAL AND METHOD A prospect i ve comparative study . A total number of 60 pregnant women with the gestational age of 12 - 34 weeks were included in the study who were suffering from iron deficiency anemia . They were divided in 3 groups ( A , B and C ) . Group A ( n = 15 ) received intravenous iron sucrose according to recommended dose containing 500 mg of iron sucrose for storage , in group B ( n = 20 ) iron sucrose was administered according to deficit calculated as per formula but 200 mg of iron was given for storage instead of 500 mg , to reduce cost . While group C received intra muscular iron Sorbitol in the dose used as practice . RESULTS Mean hemoglobin in group A and B was 8.0 + /- 1.1 g/dl and 8.9 + /- 0.7 respectively , in group C , it was 8.8 + /- 0.9 g/dl . In group A & B initial hemoglobin was assessed 3 weeks post therapy which showed an average rise of 2.8 g/dl ( group A ) and 1.9 g/dl ( group B ) and second assessment of Hemoglobin was done prior to delivery ( ave : 6.6 weeks ) showed a total rise of 3.8 g/dl ( group A ) and 2.4 g/dl ( group B ) . Pre delivery mean Hemoglobin in group A and B was 11.8 g/dl and 11.3 g/dl respectively . In group C , the Hemoglobin was assessed only prior to delivery ( average : 8.4 weeks from the start of therapy ) , and a rise of 1.4 g/dl was observed with pre delivery mean Hemoglobin of 10.2 g/dl . Target hemoglobin levels i.e. 11 g/dl was achieved by 80 % in Group A , 70 % in Group B and 28 % in Group C by the time of delivery . Blood transfusion was not required in any group . In group A and B one patient had moderate abdominal pain , 2 had weakness and shivering and 3 had phlebitis at the site where intravenous canula was retained . None of patient discontinued the therapy due to any adverse effect . In group C majority complained of pain at injection site while 5 patients dropped out from the study due to intolerance . CONCLUSION Intravenous iron therapy is safe , convenient and more effective then intramuscular iron therapy in treatment of iron deficiency anemia during pregnancy . The intravenous iron therapy can replace blood transfusion in antenatal period [14684407] BACKGROUND Daily oral iron supplementation during pregnancy fails to reduce the prevalence of anemia . However , 2 or 3 intramuscular doses of iron given at monthly intervals were recently found to be effective . OBJECTIVE We compared the safety and efficacy in treating pregnancy anemia of 3 intramuscular doses of iron given at monthly intervals with those of daily oral iron supplementation . DESIGN In a prospect i ve , partially r and omized study , 148 pregnant women received daily oral doses of 100 mg elemental Fe and 500 micro g folic acid , and 106 pregnant women received 3 intramuscular doses of 250 mg elemental Fe as iron dextran at 1-mo intervals and oral doses of 5 mg folic acid twice weekly . One hundred women in each group completed the study . Changes in hemoglobin , iron indicators , pregnancy outcomes , and birth weight were compared between the 2 groups . RESULTS Hemoglobin and iron indicators improved significantly with both treatments . The increase in serum ferritin concentration after parenteral iron treatment was significantly higher than that after oral iron treatment . No significant differences between the 2 groups in pregnancy outcomes and birth weight were observed . Systemic side effects were more common in the parenteral iron group , whereas gastrointestinal side effects were more common in the oral iron group . CONCLUSIONS The intramuscular administration of 3 doses of 250 mg Fe at monthly intervals appears to have good compliance and efficacy and may be used in women who can not tolerate oral administration of iron . However , intramuscular administration of iron is appropriate only in hospital setting s well equipped to treat anaphylactic crises [8644682] The effect of daily rather than weekly iron supplementation was compared in women who were 8 - 24 wk pregnant . One group ( n = 68 ) received 60 mg Fe/d , the second group ( n = 71 ) received 120 mg Fe/wk , given at once . Supplementation lasted 11.3 wk on average , depending on gestational date at entry , and was not supervised . Hemoglobin increased in both groups ( P < 0.001 ) ; serum ferritin did not change significantly . There was no significant difference between groups for changes in hemoglobin and serum ferritin . In a subgroup of women with a hemoglobin concentration < 110 g/L at baseline ( n = 45 daily ; n = 54 weekly ) no significant within-group changes occurred in serum ferritin , but the change in the daily group was 4.1 micrograms/L higher than in the weekly group ( P = 0.049 ) . Compliance , as indicated by two positive stool tests , was approximately equal to 54.3 % in the daily group and 62.2 % in the weekly group . We conclude that for the complete sample of subjects , the treatment effect of daily compared with weekly supplementation was similar under conditions resembling a normal antenatal care program [18806105] In rural China , many pregnant women in their third trimester suffer from anemia ( 48 % ) and iron deficiency ( ID ; 42 % ) , often with coexisting deficiencies of retinol and riboflavin . We investigated the effect of retinol and riboflavin supplementation in addition to iron plus folic acid on anemia and subjective well-being in pregnant women . The study was a 2-mo , double-blind , r and omized trial . Subjects ( n = 366 ) with anemia [ hemoglobin ( Hb ) < /= 105 g/L ] were r and omly assigned to 4 groups , all receiving 60 mg/d iron and 400 mug/d folic acid . The iron+folic acid ( IF ) group ( n = 93 ) served as reference , the iron+folic acid+retinol group ( IFA ) ( n = 91 ) was treated with 2000 mug retinol , the iron+folic acid+riboflavin group ( IFB ) ( n = 91 ) with 1.0 mg riboflavin , and the iron+folic acid+retinol+riboflavin group ( IFAB ) ( n = 91 ) with retinol and riboflavin . After the 2-mo intervention , the Hb concentration increased in all 4 groups ( P < 0.001 ) . The increase in the IFAB group was 5.4 + /- 1.1 g/L greater than in the IF group ( P < 0.001 ) . The reduced prevalence of anemia ( Hb < 110g/L ) and ID anemia were significantly greater in the groups supplemented with retinol and /or riboflavin than in the IF group . Moreover , gastrointestinal symptoms were less prevalent in the IFA group than in the IF group ( P < 0.05 ) and improved well-being was more prevalent in the groups receiving additional retinol and /or riboflavin than in the IF group ( P < 0.05 ) . Thus , a combination of iron , folic acid , retinol , and riboflavin was more effective than iron plus folic acid alone . Multimicronutrient supplementation may be worthwhile for pregnant women in rural China [11053509] In the context of limited effectiveness of iron supplementation programs , intermittent iron supplementation is currently under debate as a possible alternative strategy that may enhance the effectiveness of operational programs . This field-based trial assessed the outcome of twice weekly iron supplementation compared to daily in Pakistan . A double-blind , r and omized , clinical trial was conducted in Northern Pakistan . Anemic pregnant women ( n = 191 ) were assigned to receive daily ( 200 mg ferrous sulfate ) or twice weekly ( 2 x 200 mg ferrous sulfate ) iron supplementation . Hemoglobin was measured at baseline and at 4-wk intervals for up to 12 wk . Serum ferritin was measured at baseline and 8 or 12 wk . Analysis was by intention to treat . The two groups did not differ in age , parity , sociodemographic characteristics , hemoglobin or serum ferritin concentrations at baseline . Women who received iron daily had a greater rise in hemoglobin compared with women who received iron twice weekly ( 17.8 + /- 1.8 vs. 3.8 + /- 1.2 g/L , P < 0.001 ) . The serum ferritin concentrations increased by 17.7 + /- 3.9 microgram/L ( P < 0.001 ) in the daily supplemented group and did not change in the twice weekly group . Daily iron supplementation remained superior to twice weekly supplementation after controlling initial hemoglobin Z-scores and duration of treatment . The body mass index ( BMI ) modified the effect of daily versus twice weekly iron supplementation . For every unit increase in BMI , the difference between the two treatment groups was reduced by 0.0014 ( final hemoglobin Z-score ; P = 0.027 ) . We recommend continuation of daily iron supplementation as opposed to intermittent iron supplementation in pregnant women in developing countries [17490976] BACKGROUND Nightblindness affects 16 - 52 % of pregnant women in areas of Nepal and in some cases persists after vitamin A treatment . Iron and riboflavin affect vitamin A utilization and photoreceptor function , respectively , and pilot data in the study population showed a high prevalence of iron and riboflavin deficiencies . OBJECTIVE The objective was to assess the effect of supplemental iron and riboflavin on pupillary threshold ( PT ) and plasma retinol in nightblind , pregnant Nepali women given vitamin A-fortified rice . DESIGN Nightblind pregnant women were r and omly assigned to receive , 6 d/wk under supervision for 6 wk , a vitamin A-fortified rice curry dish providing 850 microg retinal activity equivalents/d with either a 30-mg Fe and 6-mg riboflavin ( FeR + VA ) capsule or a placebo control ( VA only ) capsule . Hemoglobin , erythrocyte riboflavin , and plasma ferritin and retinol were measured before and after the intervention . Dark adaptation was assessed by PT score . RESULTS Women who were iron deficient at baseline ( n=38 ) had significantly greater improvement in PT score with iron and riboflavin supplementation than without ( P=0.05 ) . Iron and riboflavin supplements significantly reduced the prevalences of riboflavin deficiency ( from 60 % to 6 % ; P<0.0001 ) , iron deficiency anemia ( from 35 % to 15 % ; P<0.007 ) , and abnormal PT ( from 87 % to 30 % ; P<0.05 ) from baseline . Mean increases in erythrocyte riboflavin ( P<0.0001 ) and plasma ferritin ( P=0.01 ) were greater in the FeR + VA group than in the VA only group . CONCLUSIONS Iron deficiency may limit the efficacy of vitamin A to normalize dark adaptation in pregnant Nepali women . Further studies are needed to assess the effect of simultaneous delivery of iron and vitamin A for the treatment of nightblindness [4575153] One hundred twelve pregnant women at 26 ± 2 weeks of gestation and with hemoglobin levels of less than 11 g/100 ml were investigated for level of hematocrit , serum iron , iron-binding capacity , serum vitamin B 12 , and serum folates . They were r and omly divided into eight groups receiving as follows : I , placebo ; II , iron ; III , vitamin B 12 ; IV , folic acid ; V , iron + vitamin B 12 ; VI , iron + folic acid ; VII , vitamin B 12 + folic acid ; and VIII , iron , vitamin B 12 , and folic acid . The treatment was given for a period of 4 weeks . The women receiving iron singly or in combination showed a significant rise in hemoglobin . Vitamin B 12 and /or folic acid did not enhance the effect of iron supplementation . The response to therapy was not related to initial level of serum iron , vitamin B 12 , or folic acid . The study clearly demonstrates that iron deficiency is the most important factor in causation of anemia in these women [9356536] We studied the effect of iron supplementation on the iron status of mothers and on biochemical iron status and clinical and anthropometric measures in their infants . The subjects were 197 pregnant women selected at 28 wk + /- 21 d of gestation at a mother- and -child health center in Niamey , Niger . Ninety-nine women received 100 mg elemental Fe/d throughout the remainder of their pregnancies and 98 received placebo . The prevalence of anemia and iron deficiency decreased markedly during the last trimester of pregnancy in the iron-supplemented group but remained constant in the placebo group . Three months after delivery , the prevalence of anemia was significantly higher in the placebo group . At delivery , there were no differences between the two groups in cord blood iron variables . Three months after delivery , serum ferritin concentrations were significantly higher in infants of women in the iron-supplemented group . Mean length and Apgar scores were significantly higher in infants with mothers in the iron group than in those with mothers in the placebo group [12450908] BACKGROUND According to our current underst and ing , iron absorption with weekly iron supplements is not higher than that with daily supplements ( ie , there is no mucosal block ) . However , community-based trials have repeatedly shown that a weekly regimen is as effective as a daily one . Furthermore , when differences in absorption are found , they are commonly smaller than would be expected on the basis of differences in the amount of iron provided . The possibility of differential compliance between the regimens needs to be evaluated to explain these findings . OBJECTIVE Taking compliance into account , we compared the efficacy and trial effectiveness of weekly and daily iron supplementation during pregnancy . DESIGN In Bangladesh , 50 antenatal centers were r and omly assigned to prescribe either 2 doses of 60 mg Fe once weekly or 1 dose of 60 mg Fe/d . Compliance was monitored by using a pill bottle equipped with an electronic counting device . Hemoglobin concentrations were measured at baseline and after 4 , 8 , and 12 wk of supplementation . RESULTS There was no differential effect per iron tablet between weekly and daily regimens . A 12-wk daily regimen ( 68 % compliance ) produced a small but significantly greater hemoglobin response than did the weekly regimen ( 104 % compliance ) . The first 20 tablets consumed produced most of the effect ; after 40 tablets , there was no further response . CONCLUSIONS There was no evidence of a mucosal block in the daily regimen . Over 12 wk , 50 % of the amount of iron in a daily regimen was sufficient for maximum hemoglobin effect . The weekly regimen provided a large part of this amount , explaining the limited difference in effect . It appears that the current international recommendation for iron supplementation in pregnancy is higher than necessary [16685054] BACKGROUND Iron supplements are often prescribed during pregnancy despite the lack of intervention trials that have assessed the effects of supplementation in pregnancy on childhood development . OBJECTIVE The objective was to determine whether iron supplementation during pregnancy influences childhood intelligence quotient ( IQ ) in an industrialized country . DESIGN Pregnant women ( n = 430 ) were r and omly allocated to receive iron ( 20 mg/d ) or placebo from 20 wk gestation until delivery , and the women and their children were followed up over the long term ( 4 y ) . Seventy percent of these families participated in the follow-up . The proportion of women with iron deficiency anemia at the end of pregnancy was 1 % ( 2 of 146 ) in the iron group and 11 % ( 15 of 141 ) in the placebo group . The primary outcome was the IQ of the children at 4 y of age , as assessed by the Stanford-Binet Intelligence Scale . Secondary outcomes included child behavior and the general health of the mothers . RESULTS The mean IQ was not significantly different ( P = 0.980 ) between the children of the iron-supplemented mothers ( 109 + /- 11 ; n = 153 ) and the children of the mothers in the placebo group ( 109 + /- 11 ; n = 149 ) . However , the percentage of children with an abnormal behavior score was higher in the iron group ( 24 of 151 , or 16 % ) than in the placebo group ( 12 of 149 , or 8 % ) ; the relative risk was 1.97 ( 95 % CI : 1.03 , 3.80 ; P = 0.037 ) . There was no significant difference in the health of the mothers between groups , as assessed by the SF-36 Health Survey . CONCLUSIONS Prenatal iron supplementation that reduces the incidence of iron deficiency anemia from 11 % to 1 % has no effect on the IQ of the offspring at 4 y of age [7072624] Research was conducted in Liberia , West Africa to ascertain which hematinics produce the best Hb response in women during the 3rd trimester of pregnancy . After obtaining background information , each of the 621 subjects was r and omly assigned to one of four treatment groups . Group 1 was given 60 mg iron once daily , group 2 was given 60 mg iron 3 times daily , group 3 was given 60 mg iron 3 times daily plus a 5-mg folic acid tablet once daily , and group 4 was given the same treatment as group 3 but also a weekly antimalarial prophylactic . For comparison , 58 untreated women in their 3rd trimester were also studied . Before therapy the five groups were similar with respect to selected socioeconomic status , health , and dietary variables . Hb response to therapy was measured at 4-wk intervals from the 24th wk of gestation until term . The Hb rises in all four treatment groups were significantly ( p less than 0.001 ) higher than the base-line values at 4 , 8 , and 12 wk after the interventions . The percentage of anemic women was reduced from 78 to 45 % over the 12 wk of supplementation . Hb rises in groups 3 and 4 were not significantly different from those in groups receiving iron alone . It is concluded that iron deficiency is the main cause of anemia in this population [4176866] Abstract Sternal bone-marrow aspirates from pregnant women were stained for storage iron . Haematological indicators of iron nutrition were examined throughout the remainder of pregnancy in three groups of women : those with latent or prelatent iron deficiency ( as judged by stainable marrow iron ) whose iron stores were replenished with parenteral iron and who subsequently were given no supplementary haematinics ( A ) or oral folic acid ( B ) ; and those with satisfactory iron stores ( C ) . In group C , low levels of serum-iron developed during pregnancy , and iron-deficiency anaemia developed in some . Haematological indicators remained satisfactory in groups A and B , so iron re sources in these patients were much greater than the iron content of the bone-marrow indicated . It is suggested that storage iron in the marrow is mobilised early in pregnancy to provide a source of immediately available iron ; this mobilisation is achieved , perhaps , by an increase in serum total iron-binding capacity [15777891] OBJECTIVE To compare the effect of daily oral iron supplementation with two injections of high dose parenteral iron . METHOD A total of 220 pregnant women with a singleton pregnancy and hemoglobin between 8 to 11 g% at 16 - 24 weeks gestation were identified and r and omly divided into two groups . Group A was started on daily oral iron therapy of 100 mg of elemental iron . Group B was given 250 mg of iron sorbitol intramuscularly and repeated at an interval of 4 - 6 weeks . Blood indices were evaluated at the beginning of study and at 36 weeks to see the effect after iron supplementation in the two groups . The data were analyzed using SPSS software , version 10.1 . RESULTS Definitive and comparable improvement in hemoglobin and all the blood indices ( hematocrit , MCH , MCHC , MCV , Serum iron and TIBC ) was observed . The absolute change in hemoglobin and hematocrit was 1.18+/-0.68 g% and 4.02+/-2.59 % in oral group , 1.34+/-0.77 g% and 4.93+/-3.65 % in parenteral group , respectively . Serum ferritin showed statistically significant absolute rise ( 10.43+/-7.92 microg/dl ) after parenteral iron supplementation as compared to oral iron supplementation ( 9.76+/-4.78 microg/dl ) . Obstetric outcome was comparable in two groups . CONCLUSION Two treatment regimens are biologically equivalent in terms of hematological response . Two high doses of intramuscular iron can be a good substitute to meet iron requirement in pregnancy [16544716] OBJECTIVE To study the effect of different therapeutical regimens of Ferro-Folgamma , in pregnant patients with iron deficiency anemia . MATERIAL S AND METHODS 22 pregnant patients between 20 and 35 week of gestation ( mean 29 gestational week ) with hemoglobin levels between 83.1 - 106 g/l were included . They were divided in two groups : group 1 included patients with hemoglobin levels up to 100g/l and group 2 - -with hemoglobin levels between 100 and 110 . The dosage of the preparation in group 1 was 1 tablet Ferro-Folgamma tid for 40 days , and 1 tablet Ferro-Folgamma bid for the same period . Blood sample s were taken four times during the study on day 0 , 10th day , 20th day and in the week after the 40th completed day of therapy . The sample s were tested for CBC , iron , transferine , feritine , folic acid . All patients were given complete information about the possible risks of iron deficiency anemia during pregnancy and parturition . DISCUSSION AND RESULTS The mean hemoglobin level at initiation of treatment was 91.22 g/l ( day 0 ) . After initiation of treatment the the following rise in hemoglobin levels was detected 10th day - 103.8 g/l , 20th day - 112.6 g/l , after the 40th completed day - 136.0 g/l . The mean levels of the rest of hematological parameters were , day 0 - Er - 3.25 mln/microl , Fe - 7.53 micromol/l , transferine - 3.65 gr/l , feritine - 15.02 ngr/ml , folic acid - 14.08 ng/ml , vit . B12 - 219.68 pg/ml ; 10th day - Er- 3.5 mln/microl , Fe - 14 . 12 micromol/l ; 20th day - Er - 4.10 mln/microl , Fe - 20.46 micromol/l ; 40th completed day - Er- 4.69 mln/microl , Fe - 13.12 micromol/l , transferine - 3.82 gr/l , feritine - 27.42 ngr/ml , folic acid - 15.67 ng/ml , vit . B12 - 484.52 pg/ml respectively . CONCLUSIONS Oral treatment with Ferro-Folgamma , according the described dosage regimen , demonstrates its fast and stable effect in treatment of moderate iron deficiency and recovery of depleted iron pool in pregnant patients as well . It could be administered as a prophylactic preparation for borderline anemic states [10682464] OBJECTIVE To study the efficacy of iron supplementation during pregnancy and its influences on the outcome of pregnancy . METHODS A total of 369 pregnant women were enrolled in this study . According to the hemoglbin levels at recruitment , there were 2 groups : preventive ( Hb > or = 110 g/L ) and treatment ( Hb < 110 g/L ) groups . In the preventive group , women entered the study from 20 - 24 gestational weeks and were r and omly assigned to materna treatment ( n = 96 ) who took materna 1 tablet daily or control group ( n = 95 ) who took no other supplementation . In the treatment groups , women less than 36 gestational weeks were accepted . They were r and omly divided as materna ( n = 93 ) 1 tablet/d , ferrous sulfate 0.3 g tid/d ( n = 50 ) or Ferroids 1 tablet/d ( n = 35 ) groups . Both Hb and serum ferritin concentrations were determined at admission and immediately after delivery . In some cases serum ferritin in the umbilical vein were measured as well . Hemoglobin levels were examined every 4 weeks during the observational period . RESULTS In the preventive groups , maternal serum ferritin levels after materna treatment were significantly higher than that before treatment and the control group ( P < 0.05 ) . As for the anemia women , compared the serum ferritin concentration , materna treatment had significantly higher levels than that at admission ( P < 0.05 ) , and also higher than that in the ferrous sulfate or ferroids tratment groups ( P < 0.05 ) . The s-ferritin in the umbilical vein had no correlation with the paired maternal levels . There were no significant differences in the pregnancy outcomes among all the groups . CONCLUSION Materna can increase the iron storage and effectively improve the iron deficiency during pregnancy , and has no impact on the prgnancy outcomes [19503953] The objective of this study was to analyze adherence and side effects of three iron supplement regimens ( ferrous sulfate ) on anemic pregnant women . The clinical trial involved 150 women between the 16th and 20th gestational weeks , at low obstetric risk and with hemoglobin concentration of between 8.0 and 11.0 g/dL. Treatment was provided by ferrous sulfate with 60 mg of elemental iron during 16 ( + /- 1 ) weeks , in three regimens : single tablet a week ( n = 48 ) ; single tablet twice a week ( n = 53 ) or single tablet a day ( n = 49 ) . The outcomes were adherence , assessed through interviews and by counting tablets , and side effects , according to patient information . The adherence showed a declining trend ( 92 % , 83 % and 71 % ; p = 0.010 ) and the side effects revealed a growing trend ( 40 % , 45 % and 71 % ; p = 0.002 ) as the dosage increased . Diarrhea and epigastric pain were significantly associated with the dose administered ( p = 0.002 ) . These results suggest that in anemic pregnant women , complaints are directly proportional and the compliance is inversely proportional to the amount of medicinal iron [19527380] OBJECTIVES To compare the effect of daily versus weekly iron supplementation on lipid peroxidation , hemoglobin levels and maternal and perinatal outcome in non-anemic pregnant women . METHODS Of 109 women r and omly allocated into three groups , 90 completed the study . Group I ( n = 30 ) received daily iron folic acid ; Group II ( n = 30 ) received weekly iron folic acid ; Group III ( n = 30 ) received daily iron (III)-hydroxide polymaltose complex . Hemoglobin levels , hematological indices , thiobarbituric acid reactive substances ( TBARS ) and glutathione levels were measured at baseline ( 14 - 16 weeks ) and at 30 - 34 weeks . Statistical analysis was done using the anova test . RESULTS Group I had a highly significant increase in TBARS level ( 0.61 + /- 0.26 micromol/L , P = 0.000 ) compared to groups II and III in which the change in TBARS was not significant ( 0.02 + /- 0.06 and 0.007 + /- 0.06 micromol/L , respectively ) . There was an insignificant fall in glutathione levels in all groups . There was no significant difference in the mean period of gestation , pregnancy complications and neonatal outcome between the three groups . Among 22.2 % of women who were non-compliant , Group I had significantly higher incidence of non-compliance ( P = 0.016 ) and side-effects ( P = 0.001 ) . Final hemoglobin was higher in Group I than II ( 11.9 + /- 1.2 , 11.3 + /- 0.9 , respectively , P = 0.041 ) . The TBARS level was not statistically different between preterm and term deliveries . Nine out of 11 patients who developed hypertension during pregnancy had preeclampsia . The final TBARS level was significantly higher in these women ( P = 0.000 ) . CONCLUSIONS Daily supplementation with ferrous sulphate results in greater lipid peroxidation than weekly supplementation , the latter is comparable with daily iron (III)-hydroxide polymaltose complex . Lipid peroxidation levels are significantly higher in preeclampsia [15566454] AIM To compare the hematological parameters and pregnancy outcome in women receiving daily versus weekly iron supplements during pregnancy . METHODS A prospect i ve r and omized controlled study was carried out at the Department of Obstetrics and Gynaecology of the All India Institute of Medical Sciences , New Delhi , India , during which 111 women were r and omized to receive either 100 mg elemental iron daily ( n=55 ) or 200 mg elemental iron weekly ( n=56 ) . Hemogram and serum ferritin level estimation were carried out at the beginning of pregnancy and within the 32 - 34-week period of gestation . Side-effects , compliance and the number of tablets consumed were noted for each group . The mean birth weight , period of gestation at delivery and mode of delivery were also compared between the two intervention groups . RESULTS There was no significant difference in the mean hemoglobin levels between the two intervention groups at the end of an average 17 weeks of iron supplementation . However , among anemic women who received daily supplementation , there was a greater rise in hemoglobin compared with those receiving supplementation weekly . The serum ferritin level was lower in the weekly supplemented group compared with that in the daily . There was no difference in the mean birth weight , period of gestation and mode of delivery between the two groups . Side-effects and non-compliance were significantly higher ( P<0.001 ) in the daily supplemented group . CONCLUSIONS Weekly iron supplementation is an effective option for prophylaxis in non-anemic pregnant women , but has less than optimal benefit in anemic women [12890161] The absorption of iron from Spatone Iron-Plus has been investigated in pregnant women with iron deficiency anaemia . A total of 25 mg Fe was taken and absorption determined from the increase in serum iron concentration during a period of 3 h. Mean absorption was 28 % , significantly higher than in nonpregnant , nonanaemic women ( 14 % ) . These studies demonstrate that Spatone provides an alternative to the st and ard ferrous sulphate tablet for prevention of iron deficiency in pregnancy . As only lower doses of iron are required , the unpleasant side-effects of iron therapy are largely avoided [1103213] A W.H.O. sponsored collaborative study of the effects of iron supplementation to pregnant women was carried out in Delhi ( northern India ) and Vellore ( southern India ) . Supplementation was given under supervision from the 26th to the 36th or 38th week of pregnancy . A control group received only placebo ; one group received vitamin B12 and folic acid alone ; four groups received vitamin B12 , folate and a daily iron supplement ranging from 30 to 240 mg of elemental iron as ferrous fumerate , and one further group received 120 mg of iron without B12 or folate . Groups receiving no iron showed a fall in mean stet concentration . Those receiving iron showed a rise in haemoglobin , the best results being in the groups receiving 120 and 240 mg of iron together with vitamin B12 and folate . Even in these groups however there was still a high prevalence of anaemia and iron deficiency at the end of the trial period . Iron alone did not produce as good results as iron plus vitamin B12 and folate . The supplementation had no detectable effect on the birth weight of the children , nor on the haemoglobin concentration of the infants at three months of age . The daily absorption of iron in the pregnant women , as judged from the increase in haemoglobin mass , was not as satisfactory as expected . Possible reasons for this are discussed . It is concluded that to provide these women with adequate iron a daily oral supplementation of 120 mg of elemental iron or more is needed . This can only be achieved by medicinal means . Before supplementation can be recommended on a public health scale , further information regarding the cost and expected benefits of such measures must be obtained [16424650] Background : It is a common belief among women that iron compounds have unpleasant gastrointestinal side effects . Objective : To assess the gastrointestinal side effects of iron prophylaxis in pregnancy . Methods : A r and omized , double-blind study comprising 404 healthy pregnant women allocated to four groups taking ferrous iron supplement ( as fumarate ) in doses of 20 ( n = 99 ) , 40 ( n = 100 ) , 60 ( n = 102 ) and 80 mg ( n = 103 ) daily from 18 weeks of gestation to delivery . Iron supplement was predominantly taken at bedtime . Gastrointestinal symptoms ( nausea , vomiting , epigastric pain , eructation , pyrosis , meteorism , borborygmi , colic pain , flatulence , constipation , thin feces , diarrhea ) , black feces , and use of laxatives were recorded by interview at 18 , 32 and 39 weeks of gestation . Results : The frequencies of gastrointestinal symptoms were not significantly different in the four iron supplement groups either at inclusion or at 32 and 39 weeks of gestation and thus not related to the iron dose . Conclusion : This study shows that a supplement of 20–80 mg ferrous iron ( as fumarate ) , taken between meals , has no clinical ly significant gastrointestinal side effects . The implementation of iron prophylaxis to pregnant women should not be compromised by undue concern of non-existing side effects [11904617] OBJECTIVE The aim of this study was to compare intravenous iron sucrose versus oral iron sulfate in anemia at 6 months of pregnancy . STUDY DESIGN A r and om , prospect i ve , open study with individual benefit was performed involving 50 patients with hemoglobin levels between 8 and 10 g/dL and a ferritin value of < 50 microg/L. In the intravenous group ( IV group ) , the iron dose was calculated from the following formula : Weight before pregnancy ( kg ) x ( 120 g/L - Actual hemoglobin [ g/L ] ) x 0.24 + 500 mg . The oral group ( PO group ) received 240 mg of iron sulfate per day for 4 weeks . Treatment efficacy was assessed by measurement of hemoglobin and reticulocytes on days 8 , 15 , 21 , and 30 and at delivery and of ferritin on day 30 and at delivery . The baby 's birth weight and iron stores were noted . Results were expressed as median + /- interquartile range . Mann-Whitney and Wilcoxon tests were used for the analysis , with P < .05 considered significant . RESULTS An increase in hemoglobin was observed , rising from 9.6 + /- 0.79 g/dL to 11.11 + /- 1.3 g/dL on day 30 in the IV group and from 9.7 + /- 0.5 g/dL to 11 + /- 1.25 g/dL on day 30 in the PO group ( not significant ) . On day 30 ( P < .0001 ) and at delivery ( P = .01 ) ferritin was higher in the IV group . A mean higher birth weight of 250 g was noted in the IV group ( not significant ) . CONCLUSION Iron sucrose appears to be a treatment without serious side effects indicated in correction of pregnancy anemia or iron stores depletion [19406557] OBJECTIVE To assess and compare the efficacy and safety of two and three doses of intravenous iron sucrose with daily oral ferrous sulphate in the prophylaxis of iron deficiency anaemia in pregnant women . STUDY DESIGN 260 women with singleton pregnancy who met inclusion criteria and who gave informed consent were r and omised between the 21st and 24th week into either the intravenous iron group or the oral iron group . Of 130 women in the intravenous iron group , 75 women received two doses of 200 mg iron sucrose and 55 three doses of 200 mg iron sucrose . The first dose was administered between the 21st and 24th gestational weeks , the second between the 28th and 32nd and the third between the 35th and 37th . The women of the oral group were given oral tablets of 80 mg ferrous sulphate daily , beginning on the day of study enrolment and stopping on the day of delivery . RESULTS There was a non-significant trend to a higher frequency of responders ( haemoglobin > or = 11 g/dl ) in the intravenous iron group ( 75 vs. 80 % ) . There was a significant difference of repleted iron stores before delivery ( ferritin>50 microg/l ) in the group with three intravenous iron doses in comparison to the oral iron group ( 49 vs. 14 % ; p<0.001 ) . No differences were observed in regard to maternal and perinatal outcomes . CONCLUSIONS There was no clinical ly significant difference in the haematological , maternal and foetal outcomes in the parenteral route of iron prophylaxis in pregnant women [8379860] Pregnant women between 14 and 20 weeks were r and omly recruited in 2 groups , 50 to each . One group received iron with folic acid orally , other group was given 5 injections of iron dextran spaced 4 weekly . Mean haemoglobin was same for both the groups at the beginning ( p > 0.05 ) . At 36 weeks intramuscular group has shown statistically more haemoglobin rise than oral group ( p < 0.001 ) . This new intramuscular schedule is found to be convenient , cheap and acceptable to pregnant women . It also assures at least 5 antenatal checkups to a pregnant woman [16458655] OBJECTIVE The hypothesis that daily use of a prenatal supplement with iron from enrollment to third trimester to initially iron-replete , nonanemic pregnant women would reduce third-trimester anemia and improve birth outcomes was tested . STUDY DESIGN Eight hundred sixty-seven women in Raleigh , North Carolina , who were at < 20 weeks of gestation were enrolled ; 429 of these women had hemoglobin levels of > or = 110 g/L and ferritin levels of > or = 40 microg/L and were assigned r and omly to receive prenatal supplements with 30 mg of iron as ferrous sulfate ( n = 218 women ) or 0 mg of iron ( n = 211 women ) until 26 to 29 weeks of gestation . Intent-to-treat analysis was used for the outcomes of third-trimester iron status , birth weight , preterm birth , and small-for-gestational age . RESULTS Mean birth weight was higher by 108 g ( P = .03 ) , and the incidence of preterm delivery was lower ( 8 % vs 14 % ; P = .05 ) in the 30-mg group compared with the control group , respectively . Iron supplementation did not affect the prevalence of small-for-gestational age infants or third-trimester iron status . CONCLUSION Prophylactic iron supplementation that is begun early in pregnancy among low income women in the United States may have benefits beyond the reduction of iron deficiency anemia during pregnancy [17928802] Background / Objectives : To compare the efficacy and side effects of low-dose vs high-dose iron supplements to correct anaemia in pregnancy . Subjects/ Methods : One hundred and eighty women with anaemia ( haemoglobin < 110 g l−1 ) in mid-pregnancy . The women were r and omly allocated to 20 ; 40 or 80 mg of iron daily for 8 weeks from mid-pregnancy . Results : One hundred and seventy-nine ( 99 % ) women completed the trial . At the end of treatment , there was a clear dose – response of increasing mean haemoglobin concentration with iron dose ( 111±13 g l−1 at 20 mg per day , 114±11 g l−1 at 40 mg per day and 119±12 g l−1 at 80 mg per day , P=0.006 ) . However , the incidence of anaemia did not differ statistically between groups . Compared with women in the 80 mg iron group , the odds ratio of anaemia was 1.9 ( 95 % CI : 0.8 , 4.3 , P=0.130 ) and 1.1 ( 95 % CI : 0.5 , 2.6 , P=0.827 ) , respectively , for women in the 20 mg iron group and the 40 mg iron group . The incidence of gastrointestinal side effects was significantly lower for women in the 20 mg iron group compared with women in the 80 mg iron group ; the odds ratio was 0.4 ( 95 % CI : 0.2 , 0.8 , P=0.014 ) for nausea , 0.3 ( 95 % CI : 0.2 , 0.7 , P=0.005 ) for stomach pain and 0.4 ( 95 % CI : 0.2 , 0.9 , P=0.023 ) for vomiting . Conclusions : Low-dose iron supplements may be effective at treating anaemia in pregnancy with less gastrointestinal side effects compared with high-dose supplements [12057549] BACKGROUND Anticonvulsants are used for pre-eclampsia in the belief they prevent eclamptic convulsions , and so improve outcome . Evidence supported magnesium sulphate as the drug to evaluate . METHODS Eligible women ( n=10141 ) had not given birth or were 24 h or less postpartum ; blood pressure of 140/90 mm Hg or more , and proteinuria of 1 + ( 30 mg/dL ) or more ; and there was clinical uncertainty about magnesium sulphate . Women were r and omised in 33 countries to either magnesium sulphate ( n=5071 ) or placebo ( n=5070 ) . Primary outcomes were eclampsia and , for women r and omised before delivery , death of the baby . Follow up was until discharge from hospital after delivery . Analyses were by intention to treat . FINDINGS Follow-up data were available for 10,110 ( 99.7 % ) women , 9992 ( 99 % ) of whom received the allocated treatment . 1201 of 4999 ( 24 % ) women given magnesium sulphate reported side-effects versus 228 of 4993 ( 5 % ) given placebo . Women allocated magnesium sulphate had a 58 % lower risk of eclampsia ( 95 % CI 40 - 71 ) than those allocated placebo ( 40 , 0.8 % , vs 96 , 1.9 % ; 11 fewer women with eclampsia per 1000 women ) . Maternal mortality was also lower among women allocated magnesium sulphate ( relative risk 0.55 , 0.26 - 1.14 ) . For women r and omised before delivery , there was no clear difference in the risk of the baby dying ( 576 , 12.7 % , vs 558 , 12.4 % ; relative risk 1.02 , 99 % CI 0.92 - 1.14 ) . The only notable difference in maternal or neonatal morbidity was for placental abruption ( relative risk 0.67 , 99 % CI 0.45 - 0.89 ) . INTERPRETATION Magnesium sulphate halves the risk of eclampsia , and probably reduces the risk of maternal death . There do not appear to be substantive harmful effects to mother or baby in the short term [14617464] A comparative study was conducted to demonstrate the difference , if any , in effectiveness of treatment of iron deficiency anaemia in pregnancy with either iron dextran or ferrous sulphate . Sixty pregnant women with iron deficiency anaemia were assigned r and omly to either group and treated for 6 weeks . The age and parity distributions with mean packed cell volumes ( PCVs ) and gestational age at onset of treatment in the two groups were comparable . Comparing the mean PCVs at week 2 , week 4 and week 6 of treatment the iron dextran group recorded higher and statistically significant mean PCVs ( P < 0.001 ) . Thirty-six per cent of patients in the iron dextran group compared to 3.3 % in the oral iron group ( P = 0.004 ) had their anaemia corrected by the sixth week . No significant side effects accompanied the use of intramuscular iron dextran . It was concluded that iron dextran corrects iron deficiency anaemia faster than ferrous sulphate . Parenteral iron should be considered in pregnant woman with moderate and asymptomatic severe anaemia between gestation ages of 28 weeks and 34 weeks ; this may reduce the frequency of blood transfusion both in the antenatal and postnatal periods in these patients [17435611] BACKGROUND The efficacy of iron polymaltose complex ( IPC ) in the treatment of iron deficiency anemia ( IDA ) during pregnancy has not been well established , and the evidence is inconclusive . AIMS The aim of the study was to compare efficacy , safety , compliance , and cost-effectiveness of IPC with ferrous sulphate ( FS ) in pregnant patients . SETTING S AND DESIGN S The r and omized , double-blind , parallel-group study was conducted in the Department of Pharmacology in collaboration with the Department of Obstetrics and Gynaecology Postgraduate Institute of Medical Education and Research , Ch and igarh , India . METHODS One hundred pregnant women aged 20 - 40 years at 14 to 27 weeks ' gestation , with hemoglobin ( Hb ) < 9 g/dL , and serum ferritin < 12 mcg/L , were classified into 2 groups . One group received IPC ( 100 mg elemental iron ) , and the other group received FS ( 120 mg elemental iron ) daily for 8 weeks . At Week 0 and Week 8 , Hb , packed cell volume ( PCV ) , mean corpuscular volume ( MCV ) , mean corpuscular hemoglobin ( MCH ) , mean corpuscular hemoglobin concentration ( MCHC ) , serum iron , and serum ferritin were measured . Compliance with study medication was determined by pill counting at each visit . Cost minimization analysis was done to compare the costs of the 2 treatments . STATISTICAL ANALYSIS Data are expressed as mean -/+ SD . Paired and unpaired ' t ' test were used to analyze differences within groups and between groups . Chi-square ( x2 ) test was used to analyze primary efficacy parameters and adverse drug reactions ( ADR ) . RESULTS Statistically significant increases in Hb , PCV , MCV , MCH , MCHC , serum iron , and serum ferritin levels were seen at the end of 8 weeks of treatment in both groups . The overall adverse effects were more common in the FS group compared with the IPC group [ 41 ( 78 % ) vs 15 ( 31 % ) , P < .001 ] . The compliance rate was significantly ( P < .05 ) higher for the IPC ( 91 % ) group than for the FS ( 87 % ) group . The average total cost ( direct + indirect ) of treatment of anemia was comparable between the 2 groups . CONCLUSION The results of the present study suggest that IPC can be considered as a useful alternative formulation for the treatment of IDA during pregnancy for those patients who can not tolerate other iron preparations ( ferrous form ) ; this is an important finding , as compliance is a significant concern during pregnancy [7901636] Nutritional anaemia , thought to be caused by iron deficiency , affects 50 - 70 % of pregnant women in the developing world . The influence of vitamin A and iron supplementation was studied in anaemic pregnant women in West Java , in a r and omised , double-masked , placebo-controlled field trial . 251 women aged 17 - 35 years , parity 0 - 4 , gestation 16 - 24 weeks , and haemoglobin between 80 and 109 g/L were r and omly allocated to four groups : vitamin A ( 2.4 mg retinol ) and placebo iron tablets ; iron ( 60 mg elemental iron ) and placebo vitamin A ; vitamin A and iron ; or both placebos , all daily for 8 weeks . Maximum haemoglobin was achieved with both vitamin A and iron supplementation ( 12.78 g/L , 95 % Cl 10.86 to 14.70 ) , with one-third of the response attributable to vitamin A ( 3.68 g/L , 2.03 to 5.33 ) and two-thirds to iron ( 7.71 g/L , 5.97 to 9.45 ) . After supplementation , the proportion of women who became non-anaemic was 35 % in the vitamin-A-supplemented group , 68 % in the iron-supplemented group , 97 % in the group supplemented with both , and 16 % in the placebo group . Improvement in vitamin A status may contribute to the control of anaemic pregnant women [9508353] Abstract : Anaemia is the most common medical disorder in pregnancy with iron deficiency anaemia accounting for the majority of cases . Over 90 % of the iron deficiency anaemia is due to red cell iron deficiency associated with depleted iron stores and deficient intake . The two main modalities of treating iron deficiency anaemia are oral or parenteral iron . Ferrous Hausmann ® ( iron dextrin ) is the latest iron preparation which can be used for intravenous parenteral administration as a total dose infusion . This study compares the efficacy of Ferrum Hausmann ® with oral ferrous fumarate therapy in the treatment of iron deficiency anaemia in pregnancy . Our study shows that treatment with intravenous Ferrum Hausmann ® ( iron dextrin ) result ed in a significantly better level and rate of increase of haemoglobin ( p<0.001 ) . Serum ferritin , which is the best indicator of iron stores , was significantly higher ( p<0.001 ) in the intravenous group . Other indices of iron status such as serum iron , serum transferrin and zinc protoporphyrin also showed a significant improvement in the intravenous group compared to those given oral iron . The results suggest that intravenous iron as a total dose infusion is able to replenish iron stores more efficiently , completely and at a faster rate than oral iron therapy , thus providing the fuel for stimulation of full erythopoiesis compared to oral iron . There were also no reports of any adverse reactions with intravenous iron dextrin , whereas there were a considerable proportion of women on oral iron therapy who reported side effects . In conclusion , intravenous iron therapy with Ferrous Hausmann ® ( iron dextrin ) is a suitable , effective and safe alternative to oral iron therapy in the treatment of iron deficiency anaemia in pregnancy [856693] In a therapeutic comparative study two trial-groups ( 1 and 2 ) of 30 pregnant women each suffering from iron deficiency anemia of light degree received r and omly selected a combination of ferrous succinate and multivitamins ( Multibionta-Eisen ) or a combination of ferrous sulfate and folic acid ( preparations ES ) . By both medications the decrease of hemoglobin , red blood count and hematocrit could be stopped and a re-increase of these values was seen afterwards . There was no significant differences in response between Multibionta-Eisen and ES . A significant increase of Hb , RBC and Hc as compared prior to treatment was limited to group 2 . Possible causes for the non-significant results of group 1 are discussed . The results of the study are demonstrating a certain superiority of preparation ME . This combination showed at least equal efficiency as preparation ES in spite of a smaller iron dosage and was well tolerated without exception . Subjective complaints may be better improved by Multibionta-Eisen [15936423] MRC CRASH is a r and omised controlled trial ( IS RCT N74459797 ) of the effect of corticosteroids on death and disability after head injury . We r and omly allocated 10,008 adults with head injury and a Glasgow Coma Scale score of 14 or less , within 8 h of injury , to a 48-h infusion of corticosteroid ( methylprednisolone ) or placebo . Data at 6 months were obtained for 9673 ( 96.7 % ) patients . The risk of death was higher in the corticosteroid group than in the placebo group ( 1248 [ 25.7 % ] vs 1075 [ 22.3 % ] deaths ; relative risk 1.15 , 95 % CI 1.07 - 1.24 ; p=0.0001 ) , as was the risk of death or severe disability ( 1828 [ 38.1 % ] vs 1728 [ 36.3 % ] dead or severely disabled ; 1.05 , 0.99 - 1.10 ; p=0.079 ) . There was no evidence that the effect of corticosteroids differed by injury severity or time since injury . These results lend support to our earlier conclusion that corticosteroids should not be used routinely in the treatment of head injury [508702] 1 . The relative efficacy of oral and parenteral iron administration in the prophylaxis and treatment of Fe-deficiency anaemia of pregnancy has been studied . 2 . Intravenous administration of Fe by total dose infusion of Fe dextran was not superior to oral Fe 120 mg/d , 6 d/week for 10 - 12 weeks . 3 . Intramuscular Fe dextran , 100 mg twice per week for 10 - 12 weeks , produced a significantly greater rise in mean haemoglobin concentration than oral Fe therapy . 4 . The superiority of intramuscular Fe as compared with intravenous Fe is probably related to the different h and ling of the Fe dextran by the reticulo-endothelial system . 5 . In spite of the better response to intramuscular Fe dextran , it is not recommended for public health practice because of the risks associated with its use and the much higher cost of the preparation and its delivery [8819662] Iron deficiency occurs when the rate of loss of utilization exceeds its assimilation . Treatment is based on iron supplementation but due to side effects compliance to iron therapy is poor . A double blind comparative study was done using a novel time release preparation of ferrous sulphate ( Code A ) v.s. sustained release ferrous sulphate preparation ( Code B ) on 60 pregnant women in mid or late pregnancy with anaemia . The amount of ferrous sulphate in Code A was less than half of Code B. The patients were sequentially r and omised as Code A or Code B recipient . The non compliance rate was 33 % , and for both Code A & Code B. The mean improvement in hemoglobin after 4 weeks of therapy was 2.01 gm% for Code A and 2.3 gm% for Code B. Iron absorption as evidence d by improvement in S. Iron , TIBC and ferritin levels was better with Code A. The improvement in subjective symptoms of anaemia was better than average in Code B preparation . Code A group had comparatively more side effects both major and minor , this may have been the reason for a slightly higher drop out rate in this group . In conclusion the timed release preparation has a comparable haematological response and better absorption with significantly lower doses as compared to the sustained release preparation [4099313] Summary An investigation was planned to establish whether direct transfusion of packed cells with added ethacrynic acid was as safe and effective as exchange transfusion in the management of severe an˦mia in pregnancy , when cardiac failure caused by an˦mia is either present or imminent . 93 pregnant Nigerian women with h˦matocrit readings between 5 % and 13 % were allocated at r and om to two treatment groups . One group received exchange transfusion and the other was managed by direct transfusion of packed cells to which ethacrynic acid had been added . Subsequent treatment was the same for both groups . Analysis of maternal and fetal outcome showed that the results achieved by the two methods of treatment was similar . In the 46 patients treated by exchange transfusion 1 mother and 12 fetuses were lost , compared with no maternal death and the loss of 11 fetuses in the 47 treated by direct transfusion and ethacrynic acid . Apart from its simplicity , the ethacrynic acid technique has the advantage that less donor blood is required . Direct blood-transfusion combined with ethacrynic acid is , therefore , recommended for the initial treatment of very severe an˦mia in pregnancy , except for patients who require emergency surgery and those in advanced labour , for whom exchange transfusion is still preferred [3920093] The authors conducted a clinical investigation on sixty-nine pregnant women , anaemic and non-anaemic , the purpose being to assess the effect of 50 days treatment with four different medicinal iron preparations , namely , ferrous sulphate , iron chondroitinsulfuric acid complex , and ferritin alone or associated with folinic acid and cobamamide , on various haematological parameters ( Hb , RCC , Ht , CV , Iron , and Transferrin IBC ) . The four products demonstrated a similar efficacy in maintaining anaemic conditions under control ; moreover , the results confirmed our hypothesis of the absorption of iron ferritin . While three products were well tolerated , ferrous sulphate induced , in some cases , side-effects [18760066] OBJECTIVE To determine the efficacy and safety of Total Dose Infusion ( TDI ) of low molecular weight iron dextran for the treatment of iron deficiency anemia compared to oral iron replacement during pregnancy through improvement in hemoglobin ( Hb ) after intervention . STUDY DESIGN Non-r and omized control trial . PLACE AND DURATION OF STUDY Section of Gynaecology and Obstetrics , Shifa International Hospital and Shifa Community Health Centre , Islamabad during January 2005 to January 2006 . PATIENTS AND METHODS A group of 100 pregnant women with gestational age greater than 12 weeks with confirmed diagnosis of iron deficiency anemia attending the antenatal clinics were enrolled in this study . Total dose iron infusion of low molecular iron dextran was given to these patients after calculating iron deficit , in a monitored in-patient setting . Control comprised of a second group of 50 pregnant females matched for age , parity and baseline hemoglobin , tolerant to oral iron supplementation ( ferrous sulphate 200 mg three times a day ) attending the antenatal clinics during the same period . Post-treatment hemoglobin levels of study group as well as the oral control group were determined between 3 to 4 weeks . RESULTS In the intervention group , mean pre-infusion hemoglobin level was 8.57 + /- 0.9 gm/dl ( range 5 - 10.5 gm/dl ) and mean post-infusion Hb was 11.0 + /- 1.1 ( range 8.4 - 14.3 gm/dl ) . In control group , mean pre-oral intake Hb level was 9.5 + /- 0.9 gm/dl ( range 7 - 10.5 gm/dl ) and mean post-oral intake Hb was 10.2 + /- 1.2 gm/dl ( range 6.4 - 12.8 gm/dl ) . Mean increase of Hb in intervention group was 2.43 gm/dl ( 95 % CI 2.4 - 3.8 ) and for controls it was 0.7 gm/dl ( 95 % CI 0.6 - 2.3 ) . Flushing and palpitations were observed in 4 % of interventional group patients and none in the control group . No significant adverse reactions were observed in either group . CONCLUSION We conclude that the total parenteral iron replacement with low molecular weight iron dextran is an effective and safe method for the treatment of iron deficiency anemia in a selected group of pregnant women [8902444] OBJECTIVE To evaluate the safety and efficacy of intravenous iron sucrose complex ( ISC ) as compared with oral ferrous sulfate in the treatment of iron deficiency anemia during pregnancy . STUDY DESIGN prospect i ve , open , controlled study in which pregnant women with iron deficiency anemia were sequentially selected from the antenatal clinic and assigned either to ISC ( study group ) or to ferrous sulfate ( control group ) . METHODS Each study patient was given the total calculated amount of ICS ( Hb deficit ( g/l ) x body weight ( kg ) x 0.3 ) in divided doses ( 200 mg ( elemental iron ) in 100 ml normal saline intravenously over 1 h daily ) followed by 10 mg/kg to replenish iron stores . Each patient of the control group was given ferrous sulfate 300 mg ( 60 mg elemental iron ) orally three times a day . All patients were monitored for adverse effects , clinical and laboratory response . RESULTS There were 52 patients and 59 controls . ISC group achieved a significantly higher Hb level ( 128.5 + /- 6.6 g/l vs. 111.4 + /- 12.4 g/l in the control group P < or = 0.001 ) in a shorter period ( 6.9 + /- 1.8 weeks vs. 14.9 + /- 3.1 weeks in the control group , P < or = 0.001 ) . ISC complex group showed no major side effects while 4 ( 6 % ) of the control group could not tolerate ferrous sulfate , 18 ( 30 % ) complained of disturbing gastrointestinal symptoms and 18 ( 30 % ) had poor compliance . CONCLUSION We conclude that ISC is safe and effective in the treatment of iron deficiency anemia during pregnancy [11262469] OBJECTIVE This study was undertaken to determine the efficacy and safety of intravenously administered iron sucrose with versus without adjuvant recombinant human erythropoietin in the treatment of gestational iron-deficiency anemia resistant to therapy with orally administered iron alone . STUDY DESIGN Forty patients with gestational iron-deficiency anemia were r and omly assigned to receive intravenously iron sucrose plus recombinant human erythropoietin or iron sucrose alone twice weekly . Target hemoglobin value was 11.0 g/dL. Efficacy measures were reticulocyte count , increase in hematocrit , and time to target hemoglobin level ( treatment duration in weeks and need for continued therapy after 4 weeks ) . RESULTS Both regimens were effective , but with adjuvant recombinant human erythropoietin the reticulocyte counts were higher from day 4 ( P<.01 ) , increases in hematocrit were greater from day 11 ( P < .01 ) , and the median duration of therapy was shorter ( 18 vs 25 days ) , with more patients reaching the target hemoglobin level by 4 weeks of treatment ( n = 19 vs. n = 15 ) . The groups did not differ with respect to maternal-fetal safety parameters . CONCLUSION Adjuvant recombinant human erythropoietin safely enhanced the efficacy of iron sucrose in the treatment of gestational iron-deficiency anemia resistant to orally administered iron alone [15253399] BACKGROUND Erythrocyte indices change in pregnancy , mainly due to physiological haemodilution and iron-deficient erythropoiesis . The present study was undertaken to determine the haematological indices during different periods of gestation in women receiving daily iron supplements and compare them with those in women receiving weekly iron supplements . METHODS Pregnant women < 20 weeks of gestation attending the antenatal clinic at the All India Institute of Medical Sciences were r and omized to receive either 100 mg elemental iron daily or 200 mg elemental iron weekly . The haemoglobin , haematocrit , mean corpuscular volume , mean corpuscular haemoglobin and mean corpuscular haemoglobin concentration were estimated at baseline , after 1 month , 3 months and at 34 weeks of gestation . RESULTS Changes consistent with physiological haemodilution in mid-term pregnancy were noted and the values at 34 weeks of gestation were not significantly different between the two groups . CONCLUSION The effects of intermittent iron supplementation on the erythrocyte indices in pregnancy are comparable with those observed with daily supplementation [12269674] Objective To evaluate whether folate supplementation to iron is able to accelerate solving of iron deficiency anaemia in pregnancy [1996436] Sixty pregnant patients with a haemoglobin ( Hb ) less than 8 g/dl and proven iron-deficiency anaemia were r and omly allocated to two treatment groups . Group A received the usual recommended dose of iron dextran ( Imferon ; Fisons ) and group B received two-thirds of the recommended dose . A further 30 patients received oral iron ( group C ) . There was no difference in Hb value between the three groups 4 weeks after treatment or 3 months after delivery . At 6 months after delivery , a higher mean Hb value was found in the patients in group A than those in groups B and C. Significantly higher serum ferritin levels were found in group A and this difference was still present 6 months postnatally . There was no significant difference in the incidence of delayed reactions between the two groups who received iron dextran [7079905] Forty-one pregnant patients with severe iron deficiency anaemia were treated with either intravenous iron-dextran ( Imferon ; Fisons ) or intravenous iron plus folic acid . There was no difference in the rate of response or the eventual total response in the two groups , suggesting that iron therapy does not unmask or produce a relative folic acid deficiency [7888886] Abstract Objective : To assess the relation of the lowest haemoglobin concentration in pregnancy with birth weight and the rates of low birth weight and preterm delivery in different ethnic groups . Design : Retrospective analysis of 153602 pregnancies with ethnic group and birth weight recorded on a regional pregnancy data base during 1988 - 91 . The haemoglobin measurement used was the lowest recorded during pregnancy . Setting : North West Thames region . Subjects : 115262 white women , 22206 Indo-Pakistanis , 4570 Afro-Caribbeans , 2642 mediterraneans , 3905 black Africans , 2351 orientals , and 2666 others . Main outcome measures : Birth weight and rates of low birth weight ( < 2500 g ) and preterm delivery ( < 37 completed weeks ) . Results : Maximum mean birth weight in white women was achieved with a lowest haemoglobin concentration in pregnancy of 85 - 95 g/l ; the lowest incidence of low birth weight and preterm labour occurred with a lowest haemoglobin of 95 - 105 g/l . A similar pattern occurred in all ethnic groups . Conclusions : The magnitude of the fall in haemoglobin concentration in pregnancy is related to birth weight ; failure of the haemoglobin concentration to fall below 105 g/l indicates an increased risk of low birth weight and preterm delivery . This phenomenon is seen in all ethnic groups . Some ethnic groups have higher rates of low birth weight and preterm delivery than white women , and they also have higher rates of low haemoglobin concentrations . This increased rate of “ anaemia , ” however , does not account for their higher rates of low birth weight , which occurs at all haemoglobin concentrations . Key messages Key messages Failure of the haemoglobin concentration to fall during pregnancy was associated with a five to sevenfold increase in the incidence of low birth weight and preterm birth Routine haematinic administration in pregnancy is unnecessary on fetal grounds for most pregnancies The mean corpuscular volume may be a better indicator of maternal iron deficiency , but this needs prospect i ve [2898400] Six hundred twenty-three pregnant women with iron deficiency anemia received iron dextran Imferon by total dose infusion ( TDI ) . Two dose levels were compared in respect of tolerance and hemoglobin response . The incidence of delayed reactions was significantly higher in the high dose group ( P less than 0.01 ) but there was no significant difference in the incidence of reactions occurring during the infusion . These findings are discussed in relation to the hemoglobin response [17889086] The iron status at 6 months and 4 years of children born to women who were r and omly allocated to receive 20 mg of iron daily in the second half of pregnancy did not differ from children of mothers in the control group . [3577453] 39 pregnant women , hemoglobin in serum less than or equal to 6,80 mmol/l were treated with Vitaferro , Folicombin and additional vitamins . Test groups were formed by means of r and omisation . Hematological and clinicochemical parameters were measured before , as well as 2 and 6 weeks after starting treatment and the results were evaluated .-- In the diagnosis of iron deficiency anemia in pregnancy serum iron concentration and iron-binding capacity are sufficient . The diagnosis is proved by an increase of the serum hemoglobin 2 weeks after starting therapy . For the total number of patients an increase of hemoglobin could be proved 2- and 6 weeks after starting therapy . However , the 3 chosen therapeutic methods did not show any differences in statistically proved values in form of therapeutic results . This is , in our view , due to given deviation and the specific character of the test group . During pregnancy iron deficiency anemia should be treated by doses more than 100 mg iron per day . Normalization of the hemoglobin under iron substitution is no indication for immediate interruption of the treatment [4587790] Pregnant women with anaemia due to combined iron and folate deficiencies were r and omly divided into 3 groups receiving either combination therapy with iron and pteroylglutamic acid , or treatment with iron or pteroylglutamic acid olone . A fourth group of pregnant women with levels of Hb above 10 g/100 ml received placebo . Combined iron and folate administration result ed in a marked therapeutic response , while mild or insignificant improvement was associated with either iron or folic acid teratment alone . The Hb concentration of the women receiving placebo dropped gradually in most instances . The results reported here suggest that in population s with a high prevalence of iron and folate deficiencies both these compounds should be supplied in order to prevent anaemia . The possible causal relationship between iron and folate deficiencies are discussed in the light of the present results and relevant literature [10842553] A weekly iron/folate supplement was compared with a st and ard daily iron/folate supplement in pregnant women living in rural Malawi . Women were enrolled as they attended the local antenatal clinic , stratified by grade of anaemia and then r and omized to receive either 60 mg iron/0.25 mg folate per day ( n=211 ) or 120 mg iron/0.50 mg folate once a week ( n=202 ) . Supplementation was continued for a minimum of 8 weeks ( 10 weeks on average ) and was self administered by the women at home . Initial haemoglobin values for the daily ( μ=105.7g/l ) and weekly ( μ=104.4g/l ) groups as well as final haemoglobin values ( 107.5 g/l and 105.6 g/l , respectively ) did not differ significantly between the two groups . Haemoglobin values increased by similar levels in both groups with the subset of anaemic women increasing by an average of 6.3 g/l in the daily group ( n=70 ) and 5.9 g/l in the weekly group ( n=66 ) for all women . For compliant , anaemic women , the increases were 7.4 g/l and 6.6 g/l for the daily and weekly groups , respectively . Compliance , as indicated by self reporting and by regular counts of remaining tablets , was significantly higher in the weekly group ( 76 % compared with 60 % , P < 0.05 ) , however compliance was identical in both groups when assessed by a stool test for elemental iron . Reported side effects were significantly reduced in the weekly group ( 6 % compared with 17 % , P < 0.05 ) . We conclude that a weekly iron supplement given to pregnant women in rural Malawi has similar haematologic effects , and an improved side effect profile , in comparison with a st and ard daily supplement when administered through an existing primary healthcare programme , although both regimens are relatively unsuccessful in the reduction of anaemia prevalence during pregnancy [19639462] Objective . To compare the effects of bovine lactoferrin with ferrous sulfate on iron nutritional status and to evaluate their tolerability in 100 pregnant women with iron deficiency anemia . Design . Prospect i ve , r and omized , controlled , double blind trial . Setting . Obstetrics clinic of a University Department of Obstetrics and Gynecology . Population . One‐hundred pregnant , healthy women to be treated either with one capsule of 100 mg bovine lactoferrin twice a day ( Group A ; n = 49 ) and 520 mg ferrous sulfate once a day ( Group B ; n = 48 ) . Methods . After 30 days , we evaluated hemoglobin ( Hb ) , serum ferritin , serum iron and total iron‐ binding capacity ( TIBC ) values . All women were asked to keep a diary of five potential gastrointestinal side effects ( abdominal pain , nausea , vomiting , diarrhea and constipation ) . For each symptom , patients had to rate its severity according to a scale ranging from 0 ( absent ) to 3 ( severe ) . Main outcome measures . Hb level before and after treatment . Secondary outcomes were serum ferritin , serum iron and TIBC levels and the difference in symptom scores between groups . Results . In Groups A and B , Hb , serum ferritin and iron were significantly increased while TIBC was significantly reduced in comparison with basal values . No significant differences were observed between Groups A and B. The median scores of abdominal pain and constipation were significantly higher in patients treated with ferrous sulfate in comparison with those treated with bovine lactoferrin . Conclusions . The results show that bovine lactoferrin has the same efficacy as ferrous sulfate in restoring iron deposits with significantly fewer gastrointestinal side effects [15231078] OBJECTIVE To evaluate the effectiveness of three regimens employing ferrous sulfate to treat pregnant women with anemia . METHODS The study was carried out at the Women 's Health Center of the Pernambuco Institute of Maternal and Child Health in the city of Recife , Pernambuco , Brazil , from May 2000 to December 2001 . A r and omized clinical trial with blinded laboratory analysis was conducted . Iron ( 60 mg ) was administered as 300-mg ferrous sulfate tablets . The women were allocated to three treatment groups , according to the frequency of ingesting the tablets : once a week ( 48 women ) , twice a week ( 53 women ) , and once a day ( 49 women ) . The groups were compared for the values for hemoglobin ( Hb ) concentration , mean corpuscular volume , and ferritin before and after the treatment . RESULTS Before the intervention , the groups were homogeneous . They had the following mean ( + /- st and ard deviation ) concentrations of hemoglobin : 10.2 + /- 0.5 g/dL for the group receiving iron once a week , 10.2 + /- 0.6 g/dL for the group receiving iron twice a week , and 10.1 + /- 0.6 g/dL for the group receiving iron once a day . The means of corpuscular volume were , respectively : 88.5 + /- 5.0 fL , 87.6 + /- 5.9 fL , and 88.7 + /- 5.1 fL. The respective medians for ferritin were 30.2 ng/mL , 37.1 ng/mL , and 52.9 ng/mL. The cure rate ( Hb > 11 g/dL ) was 27 % in the patients treated once a week , 34 % in those treated twice a week , and 47 % in the women treated daily . Treatment failure ( hemoglobin < 10 g/dL ) was seen in 41.6 % , 13.2 % , and 2.0 % of the patients in the respective groups . Interruption of treatment due to diarrhea or epigastric pain occurred only among the patients treated daily . CONCLUSION The regimen with iron administered daily is still the best option for treating anemia . However , treatment with ferrous sulfate administered twice a week is an alternative for patients who are unable to adhere to daily treatment

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### Context: [4890375] One hundred and three antenatal patients with initial haemoglobin levels of 10.7 g./100 ml . or less at their first antenatal visit were treated with either ferrous gluconate , Ferrogradumet or intravenous Astrafer . A significant rise in haemoglobin level occurred in the first month in those groups receiving iron therapy compared with the control group . From the end of the first month until 36 weeks gestation , there was no significant difference between the treatment groups [19506383] Objective : To evaluate the effectiveness of a stepwise use of recombinant human erythropoietin ( rhEPO ) in pregnant patients with severe anemia or nonresponsive to intravenously administered iron only . Methods : All subjects had iron deficiency anemia , i.e. , a hemoglobin ( Hb ) level < 10.0 g/dl and ferritin ≤15 μg/l . Patients with an Hb level ≥9.0 g/dl and < 10.0 g/dl received 200 mg iron sucrose intravenously twice weekly . If response to therapy was poor , patients additionally received 10,000 U rhEPO twice weekly . Patients with an Hb level < 9.0 g/dl primarily received iron sucrose and rhEPO likewise . Results : Of the 84 patients , 59 had a baseline Hb level between 9.0 and 9.9 g/dl , of whom 32 responded poorly , thus receiving additional rhEPO . Twenty-five patients had a baseline Hb level < 9.0 g/dl . The overall Hb level after therapy was 11.0 g/dl ( ±0.5 , range 10.0–12.6 g/dl ) . Mean duration of therapy was 3.5 weeks ( 7 infusions ) . Conclusion : This study shows an effective treatment regimen for patients with various degrees of anemia in pregnancy . Iron sucrose is a safe and effective treatment option . In cases of severe iron deficiency anemia or poor response to parenteral iron therapy additional administration of rhEPO might be considered . However , the mechanism for not responding to intravenous iron therapy despite iron deficiency anemia still remains unclear to a large extent [16319260] OBJECTIVE : The aim of this study was to compare the efficacy of intravenous iron to oral iron in the treatment of anemia in pregnancy . METHODS : In this r and omized open-label study , 90 women with hemoglobin levels between 8 and 10.5 g/dL and ferritin values less than 13 & mgr;g/L received either oral iron polymaltose complex ( 300 mg elemental iron per day ) or intravenous iron sucrose . The iron sucrose dose was calculated from the following formula : weight before pregnancy ( kg ) × ( 110 g/L – actual hemoglobin [ g/L ] ) × 0.24 + 500 mg . Treatment efficacy was assessed by measuring hemoglobin and ferritin on the 14th and 28th days and at delivery , and the hemoglobin on the first postpartum day . Adverse drug reactions , fetal weight , hospitalization time , and blood transfusions were also recorded . RESULTS : Hemoglobin values varied significantly with time between groups ( interaction effect , P < .001 ) . The change in hemoglobin from baseline was significantly higher in the intravenous group than the oral group at each measurement ; the changes with respect to subsequent hemoglobin were significantly higher on the 14th ( P = .004 ) and 28th ( P = .031 ) days . Ferritin values were higher in patients receiving intravenous iron throughout pregnancy . No serious adverse drug reactions were observed . Fetal weight and hospitalization time were similar in the 2 groups . Blood transfusion was required for only one patient in the oral group . CONCLUSION : Intravenous iron treated iron-deficiency anemia of pregnancy and restored iron stores faster and more effectively than oral iron , with no serious adverse reactions . LEVEL OF EVIDENCE : [12532571] OBJECTIVE ( 1 ) To determine an alternative iron supplementation with better efficacy , compliance & safety in treatment of iron deficiency anemia during pregnancy , ( 2 ) to reduce blood transfusion during pregnancy , labor and puerperium . MATERIAL AND METHOD A prospect i ve comparative study . A total number of 60 pregnant women with the gestational age of 12 - 34 weeks were included in the study who were suffering from iron deficiency anemia . They were divided in 3 groups ( A , B and C ) . Group A ( n = 15 ) received intravenous iron sucrose according to recommended dose containing 500 mg of iron sucrose for storage , in group B ( n = 20 ) iron sucrose was administered according to deficit calculated as per formula but 200 mg of iron was given for storage instead of 500 mg , to reduce cost . While group C received intra muscular iron Sorbitol in the dose used as practice . RESULTS Mean hemoglobin in group A and B was 8.0 + /- 1.1 g/dl and 8.9 + /- 0.7 respectively , in group C , it was 8.8 + /- 0.9 g/dl . In group A & B initial hemoglobin was assessed 3 weeks post therapy which showed an average rise of 2.8 g/dl ( group A ) and 1.9 g/dl ( group B ) and second assessment of Hemoglobin was done prior to delivery ( ave : 6.6 weeks ) showed a total rise of 3.8 g/dl ( group A ) and 2.4 g/dl ( group B ) . Pre delivery mean Hemoglobin in group A and B was 11.8 g/dl and 11.3 g/dl respectively . In group C , the Hemoglobin was assessed only prior to delivery ( average : 8.4 weeks from the start of therapy ) , and a rise of 1.4 g/dl was observed with pre delivery mean Hemoglobin of 10.2 g/dl . Target hemoglobin levels i.e. 11 g/dl was achieved by 80 % in Group A , 70 % in Group B and 28 % in Group C by the time of delivery . Blood transfusion was not required in any group . In group A and B one patient had moderate abdominal pain , 2 had weakness and shivering and 3 had phlebitis at the site where intravenous canula was retained . None of patient discontinued the therapy due to any adverse effect . In group C majority complained of pain at injection site while 5 patients dropped out from the study due to intolerance . CONCLUSION Intravenous iron therapy is safe , convenient and more effective then intramuscular iron therapy in treatment of iron deficiency anemia during pregnancy . The intravenous iron therapy can replace blood transfusion in antenatal period [14684407] BACKGROUND Daily oral iron supplementation during pregnancy fails to reduce the prevalence of anemia . However , 2 or 3 intramuscular doses of iron given at monthly intervals were recently found to be effective . OBJECTIVE We compared the safety and efficacy in treating pregnancy anemia of 3 intramuscular doses of iron given at monthly intervals with those of daily oral iron supplementation . DESIGN In a prospect i ve , partially r and omized study , 148 pregnant women received daily oral doses of 100 mg elemental Fe and 500 micro g folic acid , and 106 pregnant women received 3 intramuscular doses of 250 mg elemental Fe as iron dextran at 1-mo intervals and oral doses of 5 mg folic acid twice weekly . One hundred women in each group completed the study . Changes in hemoglobin , iron indicators , pregnancy outcomes , and birth weight were compared between the 2 groups . RESULTS Hemoglobin and iron indicators improved significantly with both treatments . The increase in serum ferritin concentration after parenteral iron treatment was significantly higher than that after oral iron treatment . No significant differences between the 2 groups in pregnancy outcomes and birth weight were observed . Systemic side effects were more common in the parenteral iron group , whereas gastrointestinal side effects were more common in the oral iron group . CONCLUSIONS The intramuscular administration of 3 doses of 250 mg Fe at monthly intervals appears to have good compliance and efficacy and may be used in women who can not tolerate oral administration of iron . However , intramuscular administration of iron is appropriate only in hospital setting s well equipped to treat anaphylactic crises [8644682] The effect of daily rather than weekly iron supplementation was compared in women who were 8 - 24 wk pregnant . One group ( n = 68 ) received 60 mg Fe/d , the second group ( n = 71 ) received 120 mg Fe/wk , given at once . Supplementation lasted 11.3 wk on average , depending on gestational date at entry , and was not supervised . Hemoglobin increased in both groups ( P < 0.001 ) ; serum ferritin did not change significantly . There was no significant difference between groups for changes in hemoglobin and serum ferritin . In a subgroup of women with a hemoglobin concentration < 110 g/L at baseline ( n = 45 daily ; n = 54 weekly ) no significant within-group changes occurred in serum ferritin , but the change in the daily group was 4.1 micrograms/L higher than in the weekly group ( P = 0.049 ) . Compliance , as indicated by two positive stool tests , was approximately equal to 54.3 % in the daily group and 62.2 % in the weekly group . We conclude that for the complete sample of subjects , the treatment effect of daily compared with weekly supplementation was similar under conditions resembling a normal antenatal care program [18806105] In rural China , many pregnant women in their third trimester suffer from anemia ( 48 % ) and iron deficiency ( ID ; 42 % ) , often with coexisting deficiencies of retinol and riboflavin . We investigated the effect of retinol and riboflavin supplementation in addition to iron plus folic acid on anemia and subjective well-being in pregnant women . The study was a 2-mo , double-blind , r and omized trial . Subjects ( n = 366 ) with anemia [ hemoglobin ( Hb ) < /= 105 g/L ] were r and omly assigned to 4 groups , all receiving 60 mg/d iron and 400 mug/d folic acid . The iron+folic acid ( IF ) group ( n = 93 ) served as reference , the iron+folic acid+retinol group ( IFA ) ( n = 91 ) was treated with 2000 mug retinol , the iron+folic acid+riboflavin group ( IFB ) ( n = 91 ) with 1.0 mg riboflavin , and the iron+folic acid+retinol+riboflavin group ( IFAB ) ( n = 91 ) with retinol and riboflavin . After the 2-mo intervention , the Hb concentration increased in all 4 groups ( P < 0.001 ) . The increase in the IFAB group was 5.4 + /- 1.1 g/L greater than in the IF group ( P < 0.001 ) . The reduced prevalence of anemia ( Hb < 110g/L ) and ID anemia were significantly greater in the groups supplemented with retinol and /or riboflavin than in the IF group . Moreover , gastrointestinal symptoms were less prevalent in the IFA group than in the IF group ( P < 0.05 ) and improved well-being was more prevalent in the groups receiving additional retinol and /or riboflavin than in the IF group ( P < 0.05 ) . Thus , a combination of iron , folic acid , retinol , and riboflavin was more effective than iron plus folic acid alone . Multimicronutrient supplementation may be worthwhile for pregnant women in rural China [11053509] In the context of limited effectiveness of iron supplementation programs , intermittent iron supplementation is currently under debate as a possible alternative strategy that may enhance the effectiveness of operational programs . This field-based trial assessed the outcome of twice weekly iron supplementation compared to daily in Pakistan . A double-blind , r and omized , clinical trial was conducted in Northern Pakistan . Anemic pregnant women ( n = 191 ) were assigned to receive daily ( 200 mg ferrous sulfate ) or twice weekly ( 2 x 200 mg ferrous sulfate ) iron supplementation . Hemoglobin was measured at baseline and at 4-wk intervals for up to 12 wk . Serum ferritin was measured at baseline and 8 or 12 wk . Analysis was by intention to treat . The two groups did not differ in age , parity , sociodemographic characteristics , hemoglobin or serum ferritin concentrations at baseline . Women who received iron daily had a greater rise in hemoglobin compared with women who received iron twice weekly ( 17.8 + /- 1.8 vs. 3.8 + /- 1.2 g/L , P < 0.001 ) . The serum ferritin concentrations increased by 17.7 + /- 3.9 microgram/L ( P < 0.001 ) in the daily supplemented group and did not change in the twice weekly group . Daily iron supplementation remained superior to twice weekly supplementation after controlling initial hemoglobin Z-scores and duration of treatment . The body mass index ( BMI ) modified the effect of daily versus twice weekly iron supplementation . For every unit increase in BMI , the difference between the two treatment groups was reduced by 0.0014 ( final hemoglobin Z-score ; P = 0.027 ) . We recommend continuation of daily iron supplementation as opposed to intermittent iron supplementation in pregnant women in developing countries [17490976] BACKGROUND Nightblindness affects 16 - 52 % of pregnant women in areas of Nepal and in some cases persists after vitamin A treatment . Iron and riboflavin affect vitamin A utilization and photoreceptor function , respectively , and pilot data in the study population showed a high prevalence of iron and riboflavin deficiencies . OBJECTIVE The objective was to assess the effect of supplemental iron and riboflavin on pupillary threshold ( PT ) and plasma retinol in nightblind , pregnant Nepali women given vitamin A-fortified rice . DESIGN Nightblind pregnant women were r and omly assigned to receive , 6 d/wk under supervision for 6 wk , a vitamin A-fortified rice curry dish providing 850 microg retinal activity equivalents/d with either a 30-mg Fe and 6-mg riboflavin ( FeR + VA ) capsule or a placebo control ( VA only ) capsule . Hemoglobin , erythrocyte riboflavin , and plasma ferritin and retinol were measured before and after the intervention . Dark adaptation was assessed by PT score . RESULTS Women who were iron deficient at baseline ( n=38 ) had significantly greater improvement in PT score with iron and riboflavin supplementation than without ( P=0.05 ) . Iron and riboflavin supplements significantly reduced the prevalences of riboflavin deficiency ( from 60 % to 6 % ; P<0.0001 ) , iron deficiency anemia ( from 35 % to 15 % ; P<0.007 ) , and abnormal PT ( from 87 % to 30 % ; P<0.05 ) from baseline . Mean increases in erythrocyte riboflavin ( P<0.0001 ) and plasma ferritin ( P=0.01 ) were greater in the FeR + VA group than in the VA only group . CONCLUSIONS Iron deficiency may limit the efficacy of vitamin A to normalize dark adaptation in pregnant Nepali women . Further studies are needed to assess the effect of simultaneous delivery of iron and vitamin A for the treatment of nightblindness [4575153] One hundred twelve pregnant women at 26 ± 2 weeks of gestation and with hemoglobin levels of less than 11 g/100 ml were investigated for level of hematocrit , serum iron , iron-binding capacity , serum vitamin B 12 , and serum folates . They were r and omly divided into eight groups receiving as follows : I , placebo ; II , iron ; III , vitamin B 12 ; IV , folic acid ; V , iron + vitamin B 12 ; VI , iron + folic acid ; VII , vitamin B 12 + folic acid ; and VIII , iron , vitamin B 12 , and folic acid . The treatment was given for a period of 4 weeks . The women receiving iron singly or in combination showed a significant rise in hemoglobin . Vitamin B 12 and /or folic acid did not enhance the effect of iron supplementation . The response to therapy was not related to initial level of serum iron , vitamin B 12 , or folic acid . The study clearly demonstrates that iron deficiency is the most important factor in causation of anemia in these women [9356536] We studied the effect of iron supplementation on the iron status of mothers and on biochemical iron status and clinical and anthropometric measures in their infants . The subjects were 197 pregnant women selected at 28 wk + /- 21 d of gestation at a mother- and -child health center in Niamey , Niger . Ninety-nine women received 100 mg elemental Fe/d throughout the remainder of their pregnancies and 98 received placebo . The prevalence of anemia and iron deficiency decreased markedly during the last trimester of pregnancy in the iron-supplemented group but remained constant in the placebo group . Three months after delivery , the prevalence of anemia was significantly higher in the placebo group . At delivery , there were no differences between the two groups in cord blood iron variables . Three months after delivery , serum ferritin concentrations were significantly higher in infants of women in the iron-supplemented group . Mean length and Apgar scores were significantly higher in infants with mothers in the iron group than in those with mothers in the placebo group [12450908] BACKGROUND According to our current underst and ing , iron absorption with weekly iron supplements is not higher than that with daily supplements ( ie , there is no mucosal block ) . However , community-based trials have repeatedly shown that a weekly regimen is as effective as a daily one . Furthermore , when differences in absorption are found , they are commonly smaller than would be expected on the basis of differences in the amount of iron provided . The possibility of differential compliance between the regimens needs to be evaluated to explain these findings . OBJECTIVE Taking compliance into account , we compared the efficacy and trial effectiveness of weekly and daily iron supplementation during pregnancy . DESIGN In Bangladesh , 50 antenatal centers were r and omly assigned to prescribe either 2 doses of 60 mg Fe once weekly or 1 dose of 60 mg Fe/d . Compliance was monitored by using a pill bottle equipped with an electronic counting device . Hemoglobin concentrations were measured at baseline and after 4 , 8 , and 12 wk of supplementation . RESULTS There was no differential effect per iron tablet between weekly and daily regimens . A 12-wk daily regimen ( 68 % compliance ) produced a small but significantly greater hemoglobin response than did the weekly regimen ( 104 % compliance ) . The first 20 tablets consumed produced most of the effect ; after 40 tablets , there was no further response . CONCLUSIONS There was no evidence of a mucosal block in the daily regimen . Over 12 wk , 50 % of the amount of iron in a daily regimen was sufficient for maximum hemoglobin effect . The weekly regimen provided a large part of this amount , explaining the limited difference in effect . It appears that the current international recommendation for iron supplementation in pregnancy is higher than necessary [16685054] BACKGROUND Iron supplements are often prescribed during pregnancy despite the lack of intervention trials that have assessed the effects of supplementation in pregnancy on childhood development . OBJECTIVE The objective was to determine whether iron supplementation during pregnancy influences childhood intelligence quotient ( IQ ) in an industrialized country . DESIGN Pregnant women ( n = 430 ) were r and omly allocated to receive iron ( 20 mg/d ) or placebo from 20 wk gestation until delivery , and the women and their children were followed up over the long term ( 4 y ) . Seventy percent of these families participated in the follow-up . The proportion of women with iron deficiency anemia at the end of pregnancy was 1 % ( 2 of 146 ) in the iron group and 11 % ( 15 of 141 ) in the placebo group . The primary outcome was the IQ of the children at 4 y of age , as assessed by the Stanford-Binet Intelligence Scale . Secondary outcomes included child behavior and the general health of the mothers . RESULTS The mean IQ was not significantly different ( P = 0.980 ) between the children of the iron-supplemented mothers ( 109 + /- 11 ; n = 153 ) and the children of the mothers in the placebo group ( 109 + /- 11 ; n = 149 ) . However , the percentage of children with an abnormal behavior score was higher in the iron group ( 24 of 151 , or 16 % ) than in the placebo group ( 12 of 149 , or 8 % ) ; the relative risk was 1.97 ( 95 % CI : 1.03 , 3.80 ; P = 0.037 ) . There was no significant difference in the health of the mothers between groups , as assessed by the SF-36 Health Survey . CONCLUSIONS Prenatal iron supplementation that reduces the incidence of iron deficiency anemia from 11 % to 1 % has no effect on the IQ of the offspring at 4 y of age [7072624] Research was conducted in Liberia , West Africa to ascertain which hematinics produce the best Hb response in women during the 3rd trimester of pregnancy . After obtaining background information , each of the 621 subjects was r and omly assigned to one of four treatment groups . Group 1 was given 60 mg iron once daily , group 2 was given 60 mg iron 3 times daily , group 3 was given 60 mg iron 3 times daily plus a 5-mg folic acid tablet once daily , and group 4 was given the same treatment as group 3 but also a weekly antimalarial prophylactic . For comparison , 58 untreated women in their 3rd trimester were also studied . Before therapy the five groups were similar with respect to selected socioeconomic status , health , and dietary variables . Hb response to therapy was measured at 4-wk intervals from the 24th wk of gestation until term . The Hb rises in all four treatment groups were significantly ( p less than 0.001 ) higher than the base-line values at 4 , 8 , and 12 wk after the interventions . The percentage of anemic women was reduced from 78 to 45 % over the 12 wk of supplementation . Hb rises in groups 3 and 4 were not significantly different from those in groups receiving iron alone . It is concluded that iron deficiency is the main cause of anemia in this population [4176866] Abstract Sternal bone-marrow aspirates from pregnant women were stained for storage iron . Haematological indicators of iron nutrition were examined throughout the remainder of pregnancy in three groups of women : those with latent or prelatent iron deficiency ( as judged by stainable marrow iron ) whose iron stores were replenished with parenteral iron and who subsequently were given no supplementary haematinics ( A ) or oral folic acid ( B ) ; and those with satisfactory iron stores ( C ) . In group C , low levels of serum-iron developed during pregnancy , and iron-deficiency anaemia developed in some . Haematological indicators remained satisfactory in groups A and B , so iron re sources in these patients were much greater than the iron content of the bone-marrow indicated . It is suggested that storage iron in the marrow is mobilised early in pregnancy to provide a source of immediately available iron ; this mobilisation is achieved , perhaps , by an increase in serum total iron-binding capacity [15777891] OBJECTIVE To compare the effect of daily oral iron supplementation with two injections of high dose parenteral iron . METHOD A total of 220 pregnant women with a singleton pregnancy and hemoglobin between 8 to 11 g% at 16 - 24 weeks gestation were identified and r and omly divided into two groups . Group A was started on daily oral iron therapy of 100 mg of elemental iron . Group B was given 250 mg of iron sorbitol intramuscularly and repeated at an interval of 4 - 6 weeks . Blood indices were evaluated at the beginning of study and at 36 weeks to see the effect after iron supplementation in the two groups . The data were analyzed using SPSS software , version 10.1 . RESULTS Definitive and comparable improvement in hemoglobin and all the blood indices ( hematocrit , MCH , MCHC , MCV , Serum iron and TIBC ) was observed . The absolute change in hemoglobin and hematocrit was 1.18+/-0.68 g% and 4.02+/-2.59 % in oral group , 1.34+/-0.77 g% and 4.93+/-3.65 % in parenteral group , respectively . Serum ferritin showed statistically significant absolute rise ( 10.43+/-7.92 microg/dl ) after parenteral iron supplementation as compared to oral iron supplementation ( 9.76+/-4.78 microg/dl ) . Obstetric outcome was comparable in two groups . CONCLUSION Two treatment regimens are biologically equivalent in terms of hematological response . Two high doses of intramuscular iron can be a good substitute to meet iron requirement in pregnancy [16544716] OBJECTIVE To study the effect of different therapeutical regimens of Ferro-Folgamma , in pregnant patients with iron deficiency anemia . MATERIAL S AND METHODS 22 pregnant patients between 20 and 35 week of gestation ( mean 29 gestational week ) with hemoglobin levels between 83.1 - 106 g/l were included . They were divided in two groups : group 1 included patients with hemoglobin levels up to 100g/l and group 2 - -with hemoglobin levels between 100 and 110 . The dosage of the preparation in group 1 was 1 tablet Ferro-Folgamma tid for 40 days , and 1 tablet Ferro-Folgamma bid for the same period . Blood sample s were taken four times during the study on day 0 , 10th day , 20th day and in the week after the 40th completed day of therapy . The sample s were tested for CBC , iron , transferine , feritine , folic acid . All patients were given complete information about the possible risks of iron deficiency anemia during pregnancy and parturition . DISCUSSION AND RESULTS The mean hemoglobin level at initiation of treatment was 91.22 g/l ( day 0 ) . After initiation of treatment the the following rise in hemoglobin levels was detected 10th day - 103.8 g/l , 20th day - 112.6 g/l , after the 40th completed day - 136.0 g/l . The mean levels of the rest of hematological parameters were , day 0 - Er - 3.25 mln/microl , Fe - 7.53 micromol/l , transferine - 3.65 gr/l , feritine - 15.02 ngr/ml , folic acid - 14.08 ng/ml , vit . B12 - 219.68 pg/ml ; 10th day - Er- 3.5 mln/microl , Fe - 14 . 12 micromol/l ; 20th day - Er - 4.10 mln/microl , Fe - 20.46 micromol/l ; 40th completed day - Er- 4.69 mln/microl , Fe - 13.12 micromol/l , transferine - 3.82 gr/l , feritine - 27.42 ngr/ml , folic acid - 15.67 ng/ml , vit . B12 - 484.52 pg/ml respectively . CONCLUSIONS Oral treatment with Ferro-Folgamma , according the described dosage regimen , demonstrates its fast and stable effect in treatment of moderate iron deficiency and recovery of depleted iron pool in pregnant patients as well . It could be administered as a prophylactic preparation for borderline anemic states [10682464] OBJECTIVE To study the efficacy of iron supplementation during pregnancy and its influences on the outcome of pregnancy . METHODS A total of 369 pregnant women were enrolled in this study . According to the hemoglbin levels at recruitment , there were 2 groups : preventive ( Hb > or = 110 g/L ) and treatment ( Hb < 110 g/L ) groups . In the preventive group , women entered the study from 20 - 24 gestational weeks and were r and omly assigned to materna treatment ( n = 96 ) who took materna 1 tablet daily or control group ( n = 95 ) who took no other supplementation . In the treatment groups , women less than 36 gestational weeks were accepted . They were r and omly divided as materna ( n = 93 ) 1 tablet/d , ferrous sulfate 0.3 g tid/d ( n = 50 ) or Ferroids 1 tablet/d ( n = 35 ) groups . Both Hb and serum ferritin concentrations were determined at admission and immediately after delivery . In some cases serum ferritin in the umbilical vein were measured as well . Hemoglobin levels were examined every 4 weeks during the observational period . RESULTS In the preventive groups , maternal serum ferritin levels after materna treatment were significantly higher than that before treatment and the control group ( P < 0.05 ) . As for the anemia women , compared the serum ferritin concentration , materna treatment had significantly higher levels than that at admission ( P < 0.05 ) , and also higher than that in the ferrous sulfate or ferroids tratment groups ( P < 0.05 ) . The s-ferritin in the umbilical vein had no correlation with the paired maternal levels . There were no significant differences in the pregnancy outcomes among all the groups . CONCLUSION Materna can increase the iron storage and effectively improve the iron deficiency during pregnancy , and has no impact on the prgnancy outcomes [19503953] The objective of this study was to analyze adherence and side effects of three iron supplement regimens ( ferrous sulfate ) on anemic pregnant women . The clinical trial involved 150 women between the 16th and 20th gestational weeks , at low obstetric risk and with hemoglobin concentration of between 8.0 and 11.0 g/dL. Treatment was provided by ferrous sulfate with 60 mg of elemental iron during 16 ( + /- 1 ) weeks , in three regimens : single tablet a week ( n = 48 ) ; single tablet twice a week ( n = 53 ) or single tablet a day ( n = 49 ) . The outcomes were adherence , assessed through interviews and by counting tablets , and side effects , according to patient information . The adherence showed a declining trend ( 92 % , 83 % and 71 % ; p = 0.010 ) and the side effects revealed a growing trend ( 40 % , 45 % and 71 % ; p = 0.002 ) as the dosage increased . Diarrhea and epigastric pain were significantly associated with the dose administered ( p = 0.002 ) . These results suggest that in anemic pregnant women , complaints are directly proportional and the compliance is inversely proportional to the amount of medicinal iron [19527380] OBJECTIVES To compare the effect of daily versus weekly iron supplementation on lipid peroxidation , hemoglobin levels and maternal and perinatal outcome in non-anemic pregnant women . METHODS Of 109 women r and omly allocated into three groups , 90 completed the study . Group I ( n = 30 ) received daily iron folic acid ; Group II ( n = 30 ) received weekly iron folic acid ; Group III ( n = 30 ) received daily iron (III)-hydroxide polymaltose complex . Hemoglobin levels , hematological indices , thiobarbituric acid reactive substances ( TBARS ) and glutathione levels were measured at baseline ( 14 - 16 weeks ) and at 30 - 34 weeks . Statistical analysis was done using the anova test . RESULTS Group I had a highly significant increase in TBARS level ( 0.61 + /- 0.26 micromol/L , P = 0.000 ) compared to groups II and III in which the change in TBARS was not significant ( 0.02 + /- 0.06 and 0.007 + /- 0.06 micromol/L , respectively ) . There was an insignificant fall in glutathione levels in all groups . There was no significant difference in the mean period of gestation , pregnancy complications and neonatal outcome between the three groups . Among 22.2 % of women who were non-compliant , Group I had significantly higher incidence of non-compliance ( P = 0.016 ) and side-effects ( P = 0.001 ) . Final hemoglobin was higher in Group I than II ( 11.9 + /- 1.2 , 11.3 + /- 0.9 , respectively , P = 0.041 ) . The TBARS level was not statistically different between preterm and term deliveries . Nine out of 11 patients who developed hypertension during pregnancy had preeclampsia . The final TBARS level was significantly higher in these women ( P = 0.000 ) . CONCLUSIONS Daily supplementation with ferrous sulphate results in greater lipid peroxidation than weekly supplementation , the latter is comparable with daily iron (III)-hydroxide polymaltose complex . Lipid peroxidation levels are significantly higher in preeclampsia [15566454] AIM To compare the hematological parameters and pregnancy outcome in women receiving daily versus weekly iron supplements during pregnancy . METHODS A prospect i ve r and omized controlled study was carried out at the Department of Obstetrics and Gynaecology of the All India Institute of Medical Sciences , New Delhi , India , during which 111 women were r and omized to receive either 100 mg elemental iron daily ( n=55 ) or 200 mg elemental iron weekly ( n=56 ) . Hemogram and serum ferritin level estimation were carried out at the beginning of pregnancy and within the 32 - 34-week period of gestation . Side-effects , compliance and the number of tablets consumed were noted for each group . The mean birth weight , period of gestation at delivery and mode of delivery were also compared between the two intervention groups . RESULTS There was no significant difference in the mean hemoglobin levels between the two intervention groups at the end of an average 17 weeks of iron supplementation . However , among anemic women who received daily supplementation , there was a greater rise in hemoglobin compared with those receiving supplementation weekly . The serum ferritin level was lower in the weekly supplemented group compared with that in the daily . There was no difference in the mean birth weight , period of gestation and mode of delivery between the two groups . Side-effects and non-compliance were significantly higher ( P<0.001 ) in the daily supplemented group . CONCLUSIONS Weekly iron supplementation is an effective option for prophylaxis in non-anemic pregnant women , but has less than optimal benefit in anemic women [12890161] The absorption of iron from Spatone Iron-Plus has been investigated in pregnant women with iron deficiency anaemia . A total of 25 mg Fe was taken and absorption determined from the increase in serum iron concentration during a period of 3 h. Mean absorption was 28 % , significantly higher than in nonpregnant , nonanaemic women ( 14 % ) . These studies demonstrate that Spatone provides an alternative to the st and ard ferrous sulphate tablet for prevention of iron deficiency in pregnancy . As only lower doses of iron are required , the unpleasant side-effects of iron therapy are largely avoided [1103213] A W.H.O. sponsored collaborative study of the effects of iron supplementation to pregnant women was carried out in Delhi ( northern India ) and Vellore ( southern India ) . Supplementation was given under supervision from the 26th to the 36th or 38th week of pregnancy . A control group received only placebo ; one group received vitamin B12 and folic acid alone ; four groups received vitamin B12 , folate and a daily iron supplement ranging from 30 to 240 mg of elemental iron as ferrous fumerate , and one further group received 120 mg of iron without B12 or folate . Groups receiving no iron showed a fall in mean stet concentration . Those receiving iron showed a rise in haemoglobin , the best results being in the groups receiving 120 and 240 mg of iron together with vitamin B12 and folate . Even in these groups however there was still a high prevalence of anaemia and iron deficiency at the end of the trial period . Iron alone did not produce as good results as iron plus vitamin B12 and folate . The supplementation had no detectable effect on the birth weight of the children , nor on the haemoglobin concentration of the infants at three months of age . The daily absorption of iron in the pregnant women , as judged from the increase in haemoglobin mass , was not as satisfactory as expected . Possible reasons for this are discussed . It is concluded that to provide these women with adequate iron a daily oral supplementation of 120 mg of elemental iron or more is needed . This can only be achieved by medicinal means . Before supplementation can be recommended on a public health scale , further information regarding the cost and expected benefits of such measures must be obtained [16424650] Background : It is a common belief among women that iron compounds have unpleasant gastrointestinal side effects . Objective : To assess the gastrointestinal side effects of iron prophylaxis in pregnancy . Methods : A r and omized , double-blind study comprising 404 healthy pregnant women allocated to four groups taking ferrous iron supplement ( as fumarate ) in doses of 20 ( n = 99 ) , 40 ( n = 100 ) , 60 ( n = 102 ) and 80 mg ( n = 103 ) daily from 18 weeks of gestation to delivery . Iron supplement was predominantly taken at bedtime . Gastrointestinal symptoms ( nausea , vomiting , epigastric pain , eructation , pyrosis , meteorism , borborygmi , colic pain , flatulence , constipation , thin feces , diarrhea ) , black feces , and use of laxatives were recorded by interview at 18 , 32 and 39 weeks of gestation . Results : The frequencies of gastrointestinal symptoms were not significantly different in the four iron supplement groups either at inclusion or at 32 and 39 weeks of gestation and thus not related to the iron dose . Conclusion : This study shows that a supplement of 20–80 mg ferrous iron ( as fumarate ) , taken between meals , has no clinical ly significant gastrointestinal side effects . The implementation of iron prophylaxis to pregnant women should not be compromised by undue concern of non-existing side effects [11904617] OBJECTIVE The aim of this study was to compare intravenous iron sucrose versus oral iron sulfate in anemia at 6 months of pregnancy . STUDY DESIGN A r and om , prospect i ve , open study with individual benefit was performed involving 50 patients with hemoglobin levels between 8 and 10 g/dL and a ferritin value of < 50 microg/L. In the intravenous group ( IV group ) , the iron dose was calculated from the following formula : Weight before pregnancy ( kg ) x ( 120 g/L - Actual hemoglobin [ g/L ] ) x 0.24 + 500 mg . The oral group ( PO group ) received 240 mg of iron sulfate per day for 4 weeks . Treatment efficacy was assessed by measurement of hemoglobin and reticulocytes on days 8 , 15 , 21 , and 30 and at delivery and of ferritin on day 30 and at delivery . The baby 's birth weight and iron stores were noted . Results were expressed as median + /- interquartile range . Mann-Whitney and Wilcoxon tests were used for the analysis , with P < .05 considered significant . RESULTS An increase in hemoglobin was observed , rising from 9.6 + /- 0.79 g/dL to 11.11 + /- 1.3 g/dL on day 30 in the IV group and from 9.7 + /- 0.5 g/dL to 11 + /- 1.25 g/dL on day 30 in the PO group ( not significant ) . On day 30 ( P < .0001 ) and at delivery ( P = .01 ) ferritin was higher in the IV group . A mean higher birth weight of 250 g was noted in the IV group ( not significant ) . CONCLUSION Iron sucrose appears to be a treatment without serious side effects indicated in correction of pregnancy anemia or iron stores depletion [19406557] OBJECTIVE To assess and compare the efficacy and safety of two and three doses of intravenous iron sucrose with daily oral ferrous sulphate in the prophylaxis of iron deficiency anaemia in pregnant women . STUDY DESIGN 260 women with singleton pregnancy who met inclusion criteria and who gave informed consent were r and omised between the 21st and 24th week into either the intravenous iron group or the oral iron group . Of 130 women in the intravenous iron group , 75 women received two doses of 200 mg iron sucrose and 55 three doses of 200 mg iron sucrose . The first dose was administered between the 21st and 24th gestational weeks , the second between the 28th and 32nd and the third between the 35th and 37th . The women of the oral group were given oral tablets of 80 mg ferrous sulphate daily , beginning on the day of study enrolment and stopping on the day of delivery . RESULTS There was a non-significant trend to a higher frequency of responders ( haemoglobin > or = 11 g/dl ) in the intravenous iron group ( 75 vs. 80 % ) . There was a significant difference of repleted iron stores before delivery ( ferritin>50 microg/l ) in the group with three intravenous iron doses in comparison to the oral iron group ( 49 vs. 14 % ; p<0.001 ) . No differences were observed in regard to maternal and perinatal outcomes . CONCLUSIONS There was no clinical ly significant difference in the haematological , maternal and foetal outcomes in the parenteral route of iron prophylaxis in pregnant women [8379860] Pregnant women between 14 and 20 weeks were r and omly recruited in 2 groups , 50 to each . One group received iron with folic acid orally , other group was given 5 injections of iron dextran spaced 4 weekly . Mean haemoglobin was same for both the groups at the beginning ( p > 0.05 ) . At 36 weeks intramuscular group has shown statistically more haemoglobin rise than oral group ( p < 0.001 ) . This new intramuscular schedule is found to be convenient , cheap and acceptable to pregnant women . It also assures at least 5 antenatal checkups to a pregnant woman [16458655] OBJECTIVE The hypothesis that daily use of a prenatal supplement with iron from enrollment to third trimester to initially iron-replete , nonanemic pregnant women would reduce third-trimester anemia and improve birth outcomes was tested . STUDY DESIGN Eight hundred sixty-seven women in Raleigh , North Carolina , who were at < 20 weeks of gestation were enrolled ; 429 of these women had hemoglobin levels of > or = 110 g/L and ferritin levels of > or = 40 microg/L and were assigned r and omly to receive prenatal supplements with 30 mg of iron as ferrous sulfate ( n = 218 women ) or 0 mg of iron ( n = 211 women ) until 26 to 29 weeks of gestation . Intent-to-treat analysis was used for the outcomes of third-trimester iron status , birth weight , preterm birth , and small-for-gestational age . RESULTS Mean birth weight was higher by 108 g ( P = .03 ) , and the incidence of preterm delivery was lower ( 8 % vs 14 % ; P = .05 ) in the 30-mg group compared with the control group , respectively . Iron supplementation did not affect the prevalence of small-for-gestational age infants or third-trimester iron status . CONCLUSION Prophylactic iron supplementation that is begun early in pregnancy among low income women in the United States may have benefits beyond the reduction of iron deficiency anemia during pregnancy [17928802] Background / Objectives : To compare the efficacy and side effects of low-dose vs high-dose iron supplements to correct anaemia in pregnancy . Subjects/ Methods : One hundred and eighty women with anaemia ( haemoglobin < 110 g l−1 ) in mid-pregnancy . The women were r and omly allocated to 20 ; 40 or 80 mg of iron daily for 8 weeks from mid-pregnancy . Results : One hundred and seventy-nine ( 99 % ) women completed the trial . At the end of treatment , there was a clear dose – response of increasing mean haemoglobin concentration with iron dose ( 111±13 g l−1 at 20 mg per day , 114±11 g l−1 at 40 mg per day and 119±12 g l−1 at 80 mg per day , P=0.006 ) . However , the incidence of anaemia did not differ statistically between groups . Compared with women in the 80 mg iron group , the odds ratio of anaemia was 1.9 ( 95 % CI : 0.8 , 4.3 , P=0.130 ) and 1.1 ( 95 % CI : 0.5 , 2.6 , P=0.827 ) , respectively , for women in the 20 mg iron group and the 40 mg iron group . The incidence of gastrointestinal side effects was significantly lower for women in the 20 mg iron group compared with women in the 80 mg iron group ; the odds ratio was 0.4 ( 95 % CI : 0.2 , 0.8 , P=0.014 ) for nausea , 0.3 ( 95 % CI : 0.2 , 0.7 , P=0.005 ) for stomach pain and 0.4 ( 95 % CI : 0.2 , 0.9 , P=0.023 ) for vomiting . Conclusions : Low-dose iron supplements may be effective at treating anaemia in pregnancy with less gastrointestinal side effects compared with high-dose supplements [12057549] BACKGROUND Anticonvulsants are used for pre-eclampsia in the belief they prevent eclamptic convulsions , and so improve outcome . Evidence supported magnesium sulphate as the drug to evaluate . METHODS Eligible women ( n=10141 ) had not given birth or were 24 h or less postpartum ; blood pressure of 140/90 mm Hg or more , and proteinuria of 1 + ( 30 mg/dL ) or more ; and there was clinical uncertainty about magnesium sulphate . Women were r and omised in 33 countries to either magnesium sulphate ( n=5071 ) or placebo ( n=5070 ) . Primary outcomes were eclampsia and , for women r and omised before delivery , death of the baby . Follow up was until discharge from hospital after delivery . Analyses were by intention to treat . FINDINGS Follow-up data were available for 10,110 ( 99.7 % ) women , 9992 ( 99 % ) of whom received the allocated treatment . 1201 of 4999 ( 24 % ) women given magnesium sulphate reported side-effects versus 228 of 4993 ( 5 % ) given placebo . Women allocated magnesium sulphate had a 58 % lower risk of eclampsia ( 95 % CI 40 - 71 ) than those allocated placebo ( 40 , 0.8 % , vs 96 , 1.9 % ; 11 fewer women with eclampsia per 1000 women ) . Maternal mortality was also lower among women allocated magnesium sulphate ( relative risk 0.55 , 0.26 - 1.14 ) . For women r and omised before delivery , there was no clear difference in the risk of the baby dying ( 576 , 12.7 % , vs 558 , 12.4 % ; relative risk 1.02 , 99 % CI 0.92 - 1.14 ) . The only notable difference in maternal or neonatal morbidity was for placental abruption ( relative risk 0.67 , 99 % CI 0.45 - 0.89 ) . INTERPRETATION Magnesium sulphate halves the risk of eclampsia , and probably reduces the risk of maternal death . There do not appear to be substantive harmful effects to mother or baby in the short term [14617464] A comparative study was conducted to demonstrate the difference , if any , in effectiveness of treatment of iron deficiency anaemia in pregnancy with either iron dextran or ferrous sulphate . Sixty pregnant women with iron deficiency anaemia were assigned r and omly to either group and treated for 6 weeks . The age and parity distributions with mean packed cell volumes ( PCVs ) and gestational age at onset of treatment in the two groups were comparable . Comparing the mean PCVs at week 2 , week 4 and week 6 of treatment the iron dextran group recorded higher and statistically significant mean PCVs ( P < 0.001 ) . Thirty-six per cent of patients in the iron dextran group compared to 3.3 % in the oral iron group ( P = 0.004 ) had their anaemia corrected by the sixth week . No significant side effects accompanied the use of intramuscular iron dextran . It was concluded that iron dextran corrects iron deficiency anaemia faster than ferrous sulphate . Parenteral iron should be considered in pregnant woman with moderate and asymptomatic severe anaemia between gestation ages of 28 weeks and 34 weeks ; this may reduce the frequency of blood transfusion both in the antenatal and postnatal periods in these patients [17435611] BACKGROUND The efficacy of iron polymaltose complex ( IPC ) in the treatment of iron deficiency anemia ( IDA ) during pregnancy has not been well established , and the evidence is inconclusive . AIMS The aim of the study was to compare efficacy , safety , compliance , and cost-effectiveness of IPC with ferrous sulphate ( FS ) in pregnant patients . SETTING S AND DESIGN S The r and omized , double-blind , parallel-group study was conducted in the Department of Pharmacology in collaboration with the Department of Obstetrics and Gynaecology Postgraduate Institute of Medical Education and Research , Ch and igarh , India . METHODS One hundred pregnant women aged 20 - 40 years at 14 to 27 weeks ' gestation , with hemoglobin ( Hb ) < 9 g/dL , and serum ferritin < 12 mcg/L , were classified into 2 groups . One group received IPC ( 100 mg elemental iron ) , and the other group received FS ( 120 mg elemental iron ) daily for 8 weeks . At Week 0 and Week 8 , Hb , packed cell volume ( PCV ) , mean corpuscular volume ( MCV ) , mean corpuscular hemoglobin ( MCH ) , mean corpuscular hemoglobin concentration ( MCHC ) , serum iron , and serum ferritin were measured . Compliance with study medication was determined by pill counting at each visit . Cost minimization analysis was done to compare the costs of the 2 treatments . STATISTICAL ANALYSIS Data are expressed as mean -/+ SD . Paired and unpaired ' t ' test were used to analyze differences within groups and between groups . Chi-square ( x2 ) test was used to analyze primary efficacy parameters and adverse drug reactions ( ADR ) . RESULTS Statistically significant increases in Hb , PCV , MCV , MCH , MCHC , serum iron , and serum ferritin levels were seen at the end of 8 weeks of treatment in both groups . The overall adverse effects were more common in the FS group compared with the IPC group [ 41 ( 78 % ) vs 15 ( 31 % ) , P < .001 ] . The compliance rate was significantly ( P < .05 ) higher for the IPC ( 91 % ) group than for the FS ( 87 % ) group . The average total cost ( direct + indirect ) of treatment of anemia was comparable between the 2 groups . CONCLUSION The results of the present study suggest that IPC can be considered as a useful alternative formulation for the treatment of IDA during pregnancy for those patients who can not tolerate other iron preparations ( ferrous form ) ; this is an important finding , as compliance is a significant concern during pregnancy [7901636] Nutritional anaemia , thought to be caused by iron deficiency , affects 50 - 70 % of pregnant women in the developing world . The influence of vitamin A and iron supplementation was studied in anaemic pregnant women in West Java , in a r and omised , double-masked , placebo-controlled field trial . 251 women aged 17 - 35 years , parity 0 - 4 , gestation 16 - 24 weeks , and haemoglobin between 80 and 109 g/L were r and omly allocated to four groups : vitamin A ( 2.4 mg retinol ) and placebo iron tablets ; iron ( 60 mg elemental iron ) and placebo vitamin A ; vitamin A and iron ; or both placebos , all daily for 8 weeks . Maximum haemoglobin was achieved with both vitamin A and iron supplementation ( 12.78 g/L , 95 % Cl 10.86 to 14.70 ) , with one-third of the response attributable to vitamin A ( 3.68 g/L , 2.03 to 5.33 ) and two-thirds to iron ( 7.71 g/L , 5.97 to 9.45 ) . After supplementation , the proportion of women who became non-anaemic was 35 % in the vitamin-A-supplemented group , 68 % in the iron-supplemented group , 97 % in the group supplemented with both , and 16 % in the placebo group . Improvement in vitamin A status may contribute to the control of anaemic pregnant women [9508353] Abstract : Anaemia is the most common medical disorder in pregnancy with iron deficiency anaemia accounting for the majority of cases . Over 90 % of the iron deficiency anaemia is due to red cell iron deficiency associated with depleted iron stores and deficient intake . The two main modalities of treating iron deficiency anaemia are oral or parenteral iron . Ferrous Hausmann ® ( iron dextrin ) is the latest iron preparation which can be used for intravenous parenteral administration as a total dose infusion . This study compares the efficacy of Ferrum Hausmann ® with oral ferrous fumarate therapy in the treatment of iron deficiency anaemia in pregnancy . Our study shows that treatment with intravenous Ferrum Hausmann ® ( iron dextrin ) result ed in a significantly better level and rate of increase of haemoglobin ( p<0.001 ) . Serum ferritin , which is the best indicator of iron stores , was significantly higher ( p<0.001 ) in the intravenous group . Other indices of iron status such as serum iron , serum transferrin and zinc protoporphyrin also showed a significant improvement in the intravenous group compared to those given oral iron . The results suggest that intravenous iron as a total dose infusion is able to replenish iron stores more efficiently , completely and at a faster rate than oral iron therapy , thus providing the fuel for stimulation of full erythopoiesis compared to oral iron . There were also no reports of any adverse reactions with intravenous iron dextrin , whereas there were a considerable proportion of women on oral iron therapy who reported side effects . In conclusion , intravenous iron therapy with Ferrous Hausmann ® ( iron dextrin ) is a suitable , effective and safe alternative to oral iron therapy in the treatment of iron deficiency anaemia in pregnancy [856693] In a therapeutic comparative study two trial-groups ( 1 and 2 ) of 30 pregnant women each suffering from iron deficiency anemia of light degree received r and omly selected a combination of ferrous succinate and multivitamins ( Multibionta-Eisen ) or a combination of ferrous sulfate and folic acid ( preparations ES ) . By both medications the decrease of hemoglobin , red blood count and hematocrit could be stopped and a re-increase of these values was seen afterwards . There was no significant differences in response between Multibionta-Eisen and ES . A significant increase of Hb , RBC and Hc as compared prior to treatment was limited to group 2 . Possible causes for the non-significant results of group 1 are discussed . The results of the study are demonstrating a certain superiority of preparation ME . This combination showed at least equal efficiency as preparation ES in spite of a smaller iron dosage and was well tolerated without exception . Subjective complaints may be better improved by Multibionta-Eisen [15936423] MRC CRASH is a r and omised controlled trial ( IS RCT N74459797 ) of the effect of corticosteroids on death and disability after head injury . We r and omly allocated 10,008 adults with head injury and a Glasgow Coma Scale score of 14 or less , within 8 h of injury , to a 48-h infusion of corticosteroid ( methylprednisolone ) or placebo . Data at 6 months were obtained for 9673 ( 96.7 % ) patients . The risk of death was higher in the corticosteroid group than in the placebo group ( 1248 [ 25.7 % ] vs 1075 [ 22.3 % ] deaths ; relative risk 1.15 , 95 % CI 1.07 - 1.24 ; p=0.0001 ) , as was the risk of death or severe disability ( 1828 [ 38.1 % ] vs 1728 [ 36.3 % ] dead or severely disabled ; 1.05 , 0.99 - 1.10 ; p=0.079 ) . There was no evidence that the effect of corticosteroids differed by injury severity or time since injury . These results lend support to our earlier conclusion that corticosteroids should not be used routinely in the treatment of head injury [508702] 1 . The relative efficacy of oral and parenteral iron administration in the prophylaxis and treatment of Fe-deficiency anaemia of pregnancy has been studied . 2 . Intravenous administration of Fe by total dose infusion of Fe dextran was not superior to oral Fe 120 mg/d , 6 d/week for 10 - 12 weeks . 3 . Intramuscular Fe dextran , 100 mg twice per week for 10 - 12 weeks , produced a significantly greater rise in mean haemoglobin concentration than oral Fe therapy . 4 . The superiority of intramuscular Fe as compared with intravenous Fe is probably related to the different h and ling of the Fe dextran by the reticulo-endothelial system . 5 . In spite of the better response to intramuscular Fe dextran , it is not recommended for public health practice because of the risks associated with its use and the much higher cost of the preparation and its delivery [8819662] Iron deficiency occurs when the rate of loss of utilization exceeds its assimilation . Treatment is based on iron supplementation but due to side effects compliance to iron therapy is poor . A double blind comparative study was done using a novel time release preparation of ferrous sulphate ( Code A ) v.s. sustained release ferrous sulphate preparation ( Code B ) on 60 pregnant women in mid or late pregnancy with anaemia . The amount of ferrous sulphate in Code A was less than half of Code B. The patients were sequentially r and omised as Code A or Code B recipient . The non compliance rate was 33 % , and for both Code A & Code B. The mean improvement in hemoglobin after 4 weeks of therapy was 2.01 gm% for Code A and 2.3 gm% for Code B. Iron absorption as evidence d by improvement in S. Iron , TIBC and ferritin levels was better with Code A. The improvement in subjective symptoms of anaemia was better than average in Code B preparation . Code A group had comparatively more side effects both major and minor , this may have been the reason for a slightly higher drop out rate in this group . In conclusion the timed release preparation has a comparable haematological response and better absorption with significantly lower doses as compared to the sustained release preparation [4099313] Summary An investigation was planned to establish whether direct transfusion of packed cells with added ethacrynic acid was as safe and effective as exchange transfusion in the management of severe an˦mia in pregnancy , when cardiac failure caused by an˦mia is either present or imminent . 93 pregnant Nigerian women with h˦matocrit readings between 5 % and 13 % were allocated at r and om to two treatment groups . One group received exchange transfusion and the other was managed by direct transfusion of packed cells to which ethacrynic acid had been added . Subsequent treatment was the same for both groups . Analysis of maternal and fetal outcome showed that the results achieved by the two methods of treatment was similar . In the 46 patients treated by exchange transfusion 1 mother and 12 fetuses were lost , compared with no maternal death and the loss of 11 fetuses in the 47 treated by direct transfusion and ethacrynic acid . Apart from its simplicity , the ethacrynic acid technique has the advantage that less donor blood is required . Direct blood-transfusion combined with ethacrynic acid is , therefore , recommended for the initial treatment of very severe an˦mia in pregnancy , except for patients who require emergency surgery and those in advanced labour , for whom exchange transfusion is still preferred [3920093] The authors conducted a clinical investigation on sixty-nine pregnant women , anaemic and non-anaemic , the purpose being to assess the effect of 50 days treatment with four different medicinal iron preparations , namely , ferrous sulphate , iron chondroitinsulfuric acid complex , and ferritin alone or associated with folinic acid and cobamamide , on various haematological parameters ( Hb , RCC , Ht , CV , Iron , and Transferrin IBC ) . The four products demonstrated a similar efficacy in maintaining anaemic conditions under control ; moreover , the results confirmed our hypothesis of the absorption of iron ferritin . While three products were well tolerated , ferrous sulphate induced , in some cases , side-effects [18760066] OBJECTIVE To determine the efficacy and safety of Total Dose Infusion ( TDI ) of low molecular weight iron dextran for the treatment of iron deficiency anemia compared to oral iron replacement during pregnancy through improvement in hemoglobin ( Hb ) after intervention . STUDY DESIGN Non-r and omized control trial . PLACE AND DURATION OF STUDY Section of Gynaecology and Obstetrics , Shifa International Hospital and Shifa Community Health Centre , Islamabad during January 2005 to January 2006 . PATIENTS AND METHODS A group of 100 pregnant women with gestational age greater than 12 weeks with confirmed diagnosis of iron deficiency anemia attending the antenatal clinics were enrolled in this study . Total dose iron infusion of low molecular iron dextran was given to these patients after calculating iron deficit , in a monitored in-patient setting . Control comprised of a second group of 50 pregnant females matched for age , parity and baseline hemoglobin , tolerant to oral iron supplementation ( ferrous sulphate 200 mg three times a day ) attending the antenatal clinics during the same period . Post-treatment hemoglobin levels of study group as well as the oral control group were determined between 3 to 4 weeks . RESULTS In the intervention group , mean pre-infusion hemoglobin level was 8.57 + /- 0.9 gm/dl ( range 5 - 10.5 gm/dl ) and mean post-infusion Hb was 11.0 + /- 1.1 ( range 8.4 - 14.3 gm/dl ) . In control group , mean pre-oral intake Hb level was 9.5 + /- 0.9 gm/dl ( range 7 - 10.5 gm/dl ) and mean post-oral intake Hb was 10.2 + /- 1.2 gm/dl ( range 6.4 - 12.8 gm/dl ) . Mean increase of Hb in intervention group was 2.43 gm/dl ( 95 % CI 2.4 - 3.8 ) and for controls it was 0.7 gm/dl ( 95 % CI 0.6 - 2.3 ) . Flushing and palpitations were observed in 4 % of interventional group patients and none in the control group . No significant adverse reactions were observed in either group . CONCLUSION We conclude that the total parenteral iron replacement with low molecular weight iron dextran is an effective and safe method for the treatment of iron deficiency anemia in a selected group of pregnant women [8902444] OBJECTIVE To evaluate the safety and efficacy of intravenous iron sucrose complex ( ISC ) as compared with oral ferrous sulfate in the treatment of iron deficiency anemia during pregnancy . STUDY DESIGN prospect i ve , open , controlled study in which pregnant women with iron deficiency anemia were sequentially selected from the antenatal clinic and assigned either to ISC ( study group ) or to ferrous sulfate ( control group ) . METHODS Each study patient was given the total calculated amount of ICS ( Hb deficit ( g/l ) x body weight ( kg ) x 0.3 ) in divided doses ( 200 mg ( elemental iron ) in 100 ml normal saline intravenously over 1 h daily ) followed by 10 mg/kg to replenish iron stores . Each patient of the control group was given ferrous sulfate 300 mg ( 60 mg elemental iron ) orally three times a day . All patients were monitored for adverse effects , clinical and laboratory response . RESULTS There were 52 patients and 59 controls . ISC group achieved a significantly higher Hb level ( 128.5 + /- 6.6 g/l vs. 111.4 + /- 12.4 g/l in the control group P < or = 0.001 ) in a shorter period ( 6.9 + /- 1.8 weeks vs. 14.9 + /- 3.1 weeks in the control group , P < or = 0.001 ) . ISC complex group showed no major side effects while 4 ( 6 % ) of the control group could not tolerate ferrous sulfate , 18 ( 30 % ) complained of disturbing gastrointestinal symptoms and 18 ( 30 % ) had poor compliance . CONCLUSION We conclude that ISC is safe and effective in the treatment of iron deficiency anemia during pregnancy [11262469] OBJECTIVE This study was undertaken to determine the efficacy and safety of intravenously administered iron sucrose with versus without adjuvant recombinant human erythropoietin in the treatment of gestational iron-deficiency anemia resistant to therapy with orally administered iron alone . STUDY DESIGN Forty patients with gestational iron-deficiency anemia were r and omly assigned to receive intravenously iron sucrose plus recombinant human erythropoietin or iron sucrose alone twice weekly . Target hemoglobin value was 11.0 g/dL. Efficacy measures were reticulocyte count , increase in hematocrit , and time to target hemoglobin level ( treatment duration in weeks and need for continued therapy after 4 weeks ) . RESULTS Both regimens were effective , but with adjuvant recombinant human erythropoietin the reticulocyte counts were higher from day 4 ( P<.01 ) , increases in hematocrit were greater from day 11 ( P < .01 ) , and the median duration of therapy was shorter ( 18 vs 25 days ) , with more patients reaching the target hemoglobin level by 4 weeks of treatment ( n = 19 vs. n = 15 ) . The groups did not differ with respect to maternal-fetal safety parameters . CONCLUSION Adjuvant recombinant human erythropoietin safely enhanced the efficacy of iron sucrose in the treatment of gestational iron-deficiency anemia resistant to orally administered iron alone [15253399] BACKGROUND Erythrocyte indices change in pregnancy , mainly due to physiological haemodilution and iron-deficient erythropoiesis . The present study was undertaken to determine the haematological indices during different periods of gestation in women receiving daily iron supplements and compare them with those in women receiving weekly iron supplements . METHODS Pregnant women < 20 weeks of gestation attending the antenatal clinic at the All India Institute of Medical Sciences were r and omized to receive either 100 mg elemental iron daily or 200 mg elemental iron weekly . The haemoglobin , haematocrit , mean corpuscular volume , mean corpuscular haemoglobin and mean corpuscular haemoglobin concentration were estimated at baseline , after 1 month , 3 months and at 34 weeks of gestation . RESULTS Changes consistent with physiological haemodilution in mid-term pregnancy were noted and the values at 34 weeks of gestation were not significantly different between the two groups . CONCLUSION The effects of intermittent iron supplementation on the erythrocyte indices in pregnancy are comparable with those observed with daily supplementation [12269674] Objective To evaluate whether folate supplementation to iron is able to accelerate solving of iron deficiency anaemia in pregnancy [1996436] Sixty pregnant patients with a haemoglobin ( Hb ) less than 8 g/dl and proven iron-deficiency anaemia were r and omly allocated to two treatment groups . Group A received the usual recommended dose of iron dextran ( Imferon ; Fisons ) and group B received two-thirds of the recommended dose . A further 30 patients received oral iron ( group C ) . There was no difference in Hb value between the three groups 4 weeks after treatment or 3 months after delivery . At 6 months after delivery , a higher mean Hb value was found in the patients in group A than those in groups B and C. Significantly higher serum ferritin levels were found in group A and this difference was still present 6 months postnatally . There was no significant difference in the incidence of delayed reactions between the two groups who received iron dextran [7079905] Forty-one pregnant patients with severe iron deficiency anaemia were treated with either intravenous iron-dextran ( Imferon ; Fisons ) or intravenous iron plus folic acid . There was no difference in the rate of response or the eventual total response in the two groups , suggesting that iron therapy does not unmask or produce a relative folic acid deficiency [7888886] Abstract Objective : To assess the relation of the lowest haemoglobin concentration in pregnancy with birth weight and the rates of low birth weight and preterm delivery in different ethnic groups . Design : Retrospective analysis of 153602 pregnancies with ethnic group and birth weight recorded on a regional pregnancy data base during 1988 - 91 . The haemoglobin measurement used was the lowest recorded during pregnancy . Setting : North West Thames region . Subjects : 115262 white women , 22206 Indo-Pakistanis , 4570 Afro-Caribbeans , 2642 mediterraneans , 3905 black Africans , 2351 orientals , and 2666 others . Main outcome measures : Birth weight and rates of low birth weight ( < 2500 g ) and preterm delivery ( < 37 completed weeks ) . Results : Maximum mean birth weight in white women was achieved with a lowest haemoglobin concentration in pregnancy of 85 - 95 g/l ; the lowest incidence of low birth weight and preterm labour occurred with a lowest haemoglobin of 95 - 105 g/l . A similar pattern occurred in all ethnic groups . Conclusions : The magnitude of the fall in haemoglobin concentration in pregnancy is related to birth weight ; failure of the haemoglobin concentration to fall below 105 g/l indicates an increased risk of low birth weight and preterm delivery . This phenomenon is seen in all ethnic groups . Some ethnic groups have higher rates of low birth weight and preterm delivery than white women , and they also have higher rates of low haemoglobin concentrations . This increased rate of “ anaemia , ” however , does not account for their higher rates of low birth weight , which occurs at all haemoglobin concentrations . Key messages Key messages Failure of the haemoglobin concentration to fall during pregnancy was associated with a five to sevenfold increase in the incidence of low birth weight and preterm birth Routine haematinic administration in pregnancy is unnecessary on fetal grounds for most pregnancies The mean corpuscular volume may be a better indicator of maternal iron deficiency , but this needs prospect i ve [2898400] Six hundred twenty-three pregnant women with iron deficiency anemia received iron dextran Imferon by total dose infusion ( TDI ) . Two dose levels were compared in respect of tolerance and hemoglobin response . The incidence of delayed reactions was significantly higher in the high dose group ( P less than 0.01 ) but there was no significant difference in the incidence of reactions occurring during the infusion . These findings are discussed in relation to the hemoglobin response [17889086] The iron status at 6 months and 4 years of children born to women who were r and omly allocated to receive 20 mg of iron daily in the second half of pregnancy did not differ from children of mothers in the control group . [3577453] 39 pregnant women , hemoglobin in serum less than or equal to 6,80 mmol/l were treated with Vitaferro , Folicombin and additional vitamins . Test groups were formed by means of r and omisation . Hematological and clinicochemical parameters were measured before , as well as 2 and 6 weeks after starting treatment and the results were evaluated .-- In the diagnosis of iron deficiency anemia in pregnancy serum iron concentration and iron-binding capacity are sufficient . The diagnosis is proved by an increase of the serum hemoglobin 2 weeks after starting therapy . For the total number of patients an increase of hemoglobin could be proved 2- and 6 weeks after starting therapy . However , the 3 chosen therapeutic methods did not show any differences in statistically proved values in form of therapeutic results . This is , in our view , due to given deviation and the specific character of the test group . During pregnancy iron deficiency anemia should be treated by doses more than 100 mg iron per day . Normalization of the hemoglobin under iron substitution is no indication for immediate interruption of the treatment [4587790] Pregnant women with anaemia due to combined iron and folate deficiencies were r and omly divided into 3 groups receiving either combination therapy with iron and pteroylglutamic acid , or treatment with iron or pteroylglutamic acid olone . A fourth group of pregnant women with levels of Hb above 10 g/100 ml received placebo . Combined iron and folate administration result ed in a marked therapeutic response , while mild or insignificant improvement was associated with either iron or folic acid teratment alone . The Hb concentration of the women receiving placebo dropped gradually in most instances . The results reported here suggest that in population s with a high prevalence of iron and folate deficiencies both these compounds should be supplied in order to prevent anaemia . The possible causal relationship between iron and folate deficiencies are discussed in the light of the present results and relevant literature [10842553] A weekly iron/folate supplement was compared with a st and ard daily iron/folate supplement in pregnant women living in rural Malawi . Women were enrolled as they attended the local antenatal clinic , stratified by grade of anaemia and then r and omized to receive either 60 mg iron/0.25 mg folate per day ( n=211 ) or 120 mg iron/0.50 mg folate once a week ( n=202 ) . Supplementation was continued for a minimum of 8 weeks ( 10 weeks on average ) and was self administered by the women at home . Initial haemoglobin values for the daily ( μ=105.7g/l ) and weekly ( μ=104.4g/l ) groups as well as final haemoglobin values ( 107.5 g/l and 105.6 g/l , respectively ) did not differ significantly between the two groups . Haemoglobin values increased by similar levels in both groups with the subset of anaemic women increasing by an average of 6.3 g/l in the daily group ( n=70 ) and 5.9 g/l in the weekly group ( n=66 ) for all women . For compliant , anaemic women , the increases were 7.4 g/l and 6.6 g/l for the daily and weekly groups , respectively . Compliance , as indicated by self reporting and by regular counts of remaining tablets , was significantly higher in the weekly group ( 76 % compared with 60 % , P < 0.05 ) , however compliance was identical in both groups when assessed by a stool test for elemental iron . Reported side effects were significantly reduced in the weekly group ( 6 % compared with 17 % , P < 0.05 ) . We conclude that a weekly iron supplement given to pregnant women in rural Malawi has similar haematologic effects , and an improved side effect profile , in comparison with a st and ard daily supplement when administered through an existing primary healthcare programme , although both regimens are relatively unsuccessful in the reduction of anaemia prevalence during pregnancy [19639462] Objective . To compare the effects of bovine lactoferrin with ferrous sulfate on iron nutritional status and to evaluate their tolerability in 100 pregnant women with iron deficiency anemia . Design . Prospect i ve , r and omized , controlled , double blind trial . Setting . Obstetrics clinic of a University Department of Obstetrics and Gynecology . Population . One‐hundred pregnant , healthy women to be treated either with one capsule of 100 mg bovine lactoferrin twice a day ( Group A ; n = 49 ) and 520 mg ferrous sulfate once a day ( Group B ; n = 48 ) . Methods . After 30 days , we evaluated hemoglobin ( Hb ) , serum ferritin , serum iron and total iron‐ binding capacity ( TIBC ) values . All women were asked to keep a diary of five potential gastrointestinal side effects ( abdominal pain , nausea , vomiting , diarrhea and constipation ) . For each symptom , patients had to rate its severity according to a scale ranging from 0 ( absent ) to 3 ( severe ) . Main outcome measures . Hb level before and after treatment . Secondary outcomes were serum ferritin , serum iron and TIBC levels and the difference in symptom scores between groups . Results . In Groups A and B , Hb , serum ferritin and iron were significantly increased while TIBC was significantly reduced in comparison with basal values . No significant differences were observed between Groups A and B. The median scores of abdominal pain and constipation were significantly higher in patients treated with ferrous sulfate in comparison with those treated with bovine lactoferrin . Conclusions . The results show that bovine lactoferrin has the same efficacy as ferrous sulfate in restoring iron deposits with significantly fewer gastrointestinal side effects [15231078] OBJECTIVE To evaluate the effectiveness of three regimens employing ferrous sulfate to treat pregnant women with anemia . METHODS The study was carried out at the Women 's Health Center of the Pernambuco Institute of Maternal and Child Health in the city of Recife , Pernambuco , Brazil , from May 2000 to December 2001 . A r and omized clinical trial with blinded laboratory analysis was conducted . Iron ( 60 mg ) was administered as 300-mg ferrous sulfate tablets . The women were allocated to three treatment groups , according to the frequency of ingesting the tablets : once a week ( 48 women ) , twice a week ( 53 women ) , and once a day ( 49 women ) . The groups were compared for the values for hemoglobin ( Hb ) concentration , mean corpuscular volume , and ferritin before and after the treatment . RESULTS Before the intervention , the groups were homogeneous . They had the following mean ( + /- st and ard deviation ) concentrations of hemoglobin : 10.2 + /- 0.5 g/dL for the group receiving iron once a week , 10.2 + /- 0.6 g/dL for the group receiving iron twice a week , and 10.1 + /- 0.6 g/dL for the group receiving iron once a day . The means of corpuscular volume were , respectively : 88.5 + /- 5.0 fL , 87.6 + /- 5.9 fL , and 88.7 + /- 5.1 fL. The respective medians for ferritin were 30.2 ng/mL , 37.1 ng/mL , and 52.9 ng/mL. The cure rate ( Hb > 11 g/dL ) was 27 % in the patients treated once a week , 34 % in those treated twice a week , and 47 % in the women treated daily . Treatment failure ( hemoglobin < 10 g/dL ) was seen in 41.6 % , 13.2 % , and 2.0 % of the patients in the respective groups . Interruption of treatment due to diarrhea or epigastric pain occurred only among the patients treated daily . CONCLUSION The regimen with iron administered daily is still the best option for treating anemia . However , treatment with ferrous sulfate administered twice a week is an alternative for patients who are unable to adhere to daily treatment Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Iron and folic acid supplementation has been the preferred intervention to improve iron stores and prevent anaemia among pregnant women , and it is thought to improve other maternal and birth outcomes . OBJECTIVES To assess the effects of daily oral iron supplements for pregnant women , either alone or in conjunction with folic acid , or with other vitamins and minerals as a public health intervention in antenatal care . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

30637590

[19644849] OBJECTIVE To assess the safety and efficacy of golimumab in methotrexate (MTX)-naive patients with active rheumatoid arthritis ( RA ) . METHODS MTX-naive patients with RA ( n = 637 ) were r and omized to receive placebo plus MTX ( group 1 ) , golimumab 100 mg plus placebo ( group 2 ) , golimumab 50 mg plus MTX ( group 3 ) , or golimumab 100 mg plus MTX ( group 4 ) . Subcutaneous injections of golimumab or placebo were administered every 4 weeks . The dosage of MTX/placebo capsules started at 10 mg/week and escalated to 20 mg/week . The primary end point , the proportion of patients meeting the American College of Rheumatology 50 % improvement criteria ( achieving an ACR50 response ) at week 24 , required significant differences between groups 3 and 4 combined ( combined group ) versus group 1 and significant differences in a pairwise comparison ( group 3 or group 4 versus group 1 ) . RESULTS An intent-to-treat ( ITT ) analysis of the ACR50 response at week 24 did not show a significant difference between the combined group and group 1 ( 38.4 % and 29.4 % , respectively ; P=0.053 ) , while a post hoc modified ITT analysis ( excluding 3 untreated patients ) of the ACR50 response showed statistically significant differences between the combined group and group 1 ( 38.5 % versus 29.4 % ; P=0.049 ) and between group 3 ( 40.5 % ; P=0.038 ) but not group 4 ( 36.5 % ; P=0.177 ) and group 1 . Group 2 was noninferior to group 1 for the ACR50 response at week 24 ( 33.1 % ; 95 % confidence interval lower bound -5.2 % ; predefined delta value for noninferiority -10 % ) . The combination of golimumab plus MTX demonstrated a significantly better response compared with placebo plus MTX in most other efficacy parameters , including response/remission according to the Disease Activity Score in 28 joints . Serious adverse events occurred in 7 % , 3 % , 6 % , and 6 % of patients in groups 1 , 2 , 3 , and 4 , respectively . CONCLUSION Although the primary end point was not met , the modified ITT analysis of the primary end point and other prespecified efficacy measures demonstrated that the efficacy of golimumab plus MTX is better than , and the efficacy of golimumab alone is similar to , the efficacy of MTX alone in reducing RA signs and symptoms in MTX-naive patients , with no unexpected safety concerns [27190098] Objective To compare the value that rheumatologists across Europe attach to patients ' preferences and economic aspects when choosing treatments for patients with rheumatoid arthritis . Methods In a discrete choice experiment , European rheumatologists chose between two hypothetical drug treatments for a patient with moderate disease activity . Treatments differed in five attributes : efficacy ( improvement and achieved state on disease activity ) , safety ( probability of serious adverse events ) , patient 's preference ( level of agreement ) , medication costs and cost-effectiveness ( incremental cost-effectiveness ratio ( ICER ) ) . A Bayesian efficient design defined 14 choice sets , and a r and om parameter logit model was used to estimate relative preferences for rheumatologists across countries . Cluster analyses and latent class models were applied to underst and preference patterns across countries and among individual rheumatologists . Results Responses of 559 rheumatologists from 12 European countries were included in the analysis ( 49 % females , mean age 48 years ) . In all countries , efficacy dominated treatment decisions followed by economic considerations and patients ’ preferences . Across countries , rheumatologists avoided selecting a treatment that patients disliked . Latent class models revealed four respondent profiles : one traded off all attributes except safety , and the remaining three classes disregarded ICER . Among individual rheumatologists , 57 % disregarded ICER and these were more likely from Italy , Romania , Portugal or France , whereas 43 % disregarded uncommon/rare side effects and were more likely from Belgium , Germany , Hungary , the Netherl and s , Norway , Spain , Sweden or UK . Conclusions Overall , European rheumatologists are willing to trade between treatment efficacy , patients ' treatment preferences and economic considerations . However , the degree of trade-off differs between countries and among individuals [4151516] Objectives To evaluate the efficacy and safety of adalimumab+methotrexate ( MTX ) in Japanese patients with early rheumatoid arthritis ( RA ) who had not previously received MTX or biologics . Methods This r and omised , double-blind , placebo-controlled , multicentre study evaluated adalimumab 40 mg every other week+MTX 6–8 mg every week versus MTX 6–8 mg every week alone for 26 weeks in patients with RA ( ≤2-year duration ) . The primary endpoint was inhibition of radiographic progression ( change ( Δ ) from baseline in modified total Sharp score ( mTSS ) ) at week 26 . Results A total of 171 patients received adalimumab+MTX ( mean dose , 6.2±0.8 mg/week ) and 163 patients received MTX alone ( mean dose , 6.6±0.6 mg/week , p<0.001 ) . The mean RA duration was 0.3 years and 315 ( 94.3 % ) had high disease activity ( DAS28>5.1 ) . Adalimumab+MTX significantly inhibited radiographic progression at week 26 versus MTX alone ( ΔmTSS , 1.5±6.1 vs 2.4±3.2 , respectively ; p<0.001 ) . Significantly more patients in the adalimumab+MTX group ( 62.0 % ) did not show radiographic progression ( ΔmTSS≤0.5 ) versus the MTX alone group ( 35.4 % ; p<0.001 ) . Patients treated with adalimumab+MTX were significantly more likely to achieve American College of Rheumatology responses and achieve clinical remission , using various definitions , at 26 weeks versus MTX alone . Combination therapy was well tolerated , and no new safety signals were observed . Conclusions Adalimumab in combination with low-dose MTX was well tolerated and efficacious in suppressing radiographic progression and improving clinical outcomes in Japanese patients with early RA and high disease activity [22753402] Objective Early treatment of patients with rheumatoid arthritis ( RA ) with combination treatment starting with methotrexate , sulfasalazine , hydroxychloroquine and prednisolone ( FIN-RACo strategy ) is superior to monotherapy . A study was undertaken to determine whether infliximab ( INFL ) added to intensified FIN-RACo treatment for the initial 6 months improves the 2-year outcome . Methods 99 patients with early untreated active RA were enrolled in an investigator-initiated , r and omised , double-blind , multicentre , parallel-group trial . Primary outcomes were remission and radiological changes at 2 years . All patients started with FIN-RACo . In addition , they were r and omised to receive INFL or placebo ( Pla ) from weeks 4 to 26 . Results At 24 months , 66 % and 53 % , respectively , of the patients in the FIN-RACo+INFL and FIN-RACo+Pla groups were in remission according to the modified American College of Rheumatology ( ACR ) criteria ( p=0.19 ) , 26 % and 10 % were in sustained modified ACR remission ( p=0.042 ) and 82 % in both groups were in remission by 28-joint disease activity score ( not significant ) . Mean changes in the total Sharp-van der Heijde score were 0.2 and 1.4 , respectively ( p=0.0058 ) . Conclusions Most patients with early active RA achieve clinical remission and develop negligible joint damage with the intensified FIN-RACo regimen . Adding INFL for the first 6 months delays radiological progression [24618266] Objective To compare the efficacy of etanercept ( ETN ) and methotrexate ( MTX ) versus MTX monotherapy for remission induction in patients with early inflammatory arthritis . Methods In a 78-week multicentre r and omised placebo-controlled superiority trial , 110 DMARD-naïve patients with early clinical synovitis ( ≥1 tender and swollen joint , and within 3 months of diagnosis ) and either rheumatoid factor , anticitrullinated protein antibodies or shared epitope positive were r and omised 1:1 to receive MTX+ETN or MTX+placebo ( PBO ) for 52 weeks . Injections ( ETN or PBO ) were stopped in all patients at week 52 . In those with no tender or swollen joints ( NTSJ ) for > 26 weeks , injections were stopped early . If patients had NTSJ > 12 weeks after stopping the injections , MTX was weaned . The primary endpoint was NTSJ at week 52 . Results No statistically significant difference was seen for the primary endpoint ( NTSJ at week 52 ( 32.5 % vs 28.1 % [ adjusted OR 1.32 ( 0.56 to 3.09 ) , p=0.522 ] ) in the MTX+ETN and MTX+PBO groups , respectively ) . The secondary endpoints did not differ between groups at week 52 or 78 . Exploratory analyses showed a higher proportions of patients with DAS28-CRP<2.6 in the MTX+ETN group at week 2 ( 38.5 % vs 9.2 % , adjusted OR 8.87 ( 2.53 to 31.17 ) , p=0.001 ) and week 12 ( 65.1 % vs 43.8 % , adjusted OR 2.49 ( 1.12 to 5.54 ) , p=0.026 ) . Conclusions In this group of patients with early inflammatory arthritis , almost a third had no tender , swollen joints after 1 year . MTX+ETN was not superior to MTX monotherapy in achieving this outcome . Clinical responses , however , including DAS28-CRP<2.6 , were achieved earlier with MTX+ETN combination therapy . Trial registration number The EMPIRE trial is registered on the following trial registries : Eudract-2005 - 005467 - 29 ; IS RCT N 55428162 ( http://www.controlled-trials.com/IS RCT N55428162/EMPIRE ) . The full trial protocol can be obtained from the corresponding author [28267648] HighlightsEarly rheumatoid arthritis patients have increased levels of soluble CD83 in plasma . The release of soluble CD83 is independent of TNF‐&agr;.In rheumatoid arthritis sCD83 levels are higher in synovial fluid than in plasma . The level of soluble CD83 in plasma does not correlate with disease activity . CD83 is mainly expressed intracellularly in a variety of different cell types . Abstract Rheumatoid arthritis ( RA ) is an autoimmune disease which may lead to severe disabilities due to structural joint damage and extraarticular manifestations The dendritic cell marker CD83 belongs to the immunoglobulin superfamily and has previously been associated with autoimmune diseases . In RA the levels of soluble CD83 ( sCD83 ) are elevated in synovial fluid , however little is known about CD83 expression and regulation in RA . Therefore , we studied how CD83 is expressed in RA and further evaluated the effect of anti‐TNF‐&agr ; therapy hereon . Early RA patients were r and omized to conventional disease modifying anti‐rheumatic drugs with or without additional anti‐TNF‐&agr ; therapy . Rheumatoid arthritis patients had increased levels of sCD83 in plasma compared with healthy volunteers . The increase in sCD83 plasma levels were unaffected by anti‐TNF‐&agr ; therapy . In chronic RA patients the levels of sCD83 were higher in synovial fluid than in plasma , and only a limited amount of membrane bound CD83 expression was detected on the surface of cells from peripheral blood and synovial fluid . Finally , confocal microscopy of RA synovial membranes revealed that CD83 was mainly localized intracellularly in a group of cells with diverse morphology including both antigen‐presenting cells and non‐antigen‐presenting cells . Our findings demonstrate that early‐stage RA patients have elevated levels of sCD83 in plasma and that anti‐TNF‐&agr ; treatment has no effect on the sCD83 plasma level . This suggest that in RA patients sCD83 regulation is beyond control of [17158431] BACKGROUND Tumor necrosis factor ( TNF ) is an important mediator of cachexia , and its blockade prevents catabolism in animal models . However , little evidence shows that anti-TNF therapy is effective in treating cachexia in humans . OBJECTIVE The main aim of this study was to investigate the effect of etanercept , a synthetic soluble TNF receptor , on body composition in patients with early rheumatoid arthritis ( RA ) . DESIGN Twenty-six patients were r and omly assigned to 24 wk of treatment with etanercept or methotrexate ; the latter is the first-line therapy for RA . Body composition , physical function , disease activity , systemic inflammation , and the circulating insulin-like growth factor ( IGF ) system were measured at baseline ( week 0 ) and at follow-up ( weeks 12 and 24 ) . Twelve patients in each treatment group ( 9 F , 3 M ) completed the study . RESULTS Overall , no important changes in body composition were observed , despite a transient increase in IGF-I at week 12 ( P < 0.01 ) . However , the secondary analysis of those patients ( 6/treatment group ) who gained weight during follow-up showed a significant effect of etanercept on the composition of the weight gained : 44 % of weight gained in the etanercept group was fat-free mass , as compared with only 14 % in the methotrexate group ( P = 0.04 ) . Etanercept and methotrexate were equally effective in controlling the disease and improving physical function . CONCLUSIONS Anti-TNF therapy with etanercept is not superior to that with methotrexate for the treatment of rheumatoid cachexia over a period of 6 mo . However , TNF blockade seems to normalize the anabolic response to overfeeding and , if these findings are confirmed , may be useful in conditions characterized by anorexia and weight loss [28598681] Abstract Rheumatoid arthritis ( RA ) is characterized by chronic joint inflammation and infiltration by activated macrophages . TNFα is a central mediator in this process . The mannose receptor , CD206 , is a scavenger receptor expressed by M2A-macrophages and dendritic cells . It is involved in collagen internalization and degradation . The soluble form has been suggested as a biomarker of M2A-macrophage activation . The aim of this study was to investigate sCD206 plasma levels in early RA patients initiating anti-TNFα treatment . Plasma levels of sCD206 were measured by ELISA in sample s from 155 early RA patients with an average symptom duration of 3 months . Patients were r and omized to 12 months ’ methotrexate and placebo ( PLA ) or methotrexate and adalimumab ( ADA ) treatment , followed by open-label treatment with disease-modifying anti-rheumatic drugs ( DMARD ) and if needed , ADA . Disease activity was assessed at baseline and after 3 , 6 , 12 and 24 months . Baseline plasma level of sCD206 in treatment naïve RA patients was 0.33 mg/L ( CI : 0.33–0.38 mg/L ) corresponding to the upper part of the reference interval for healthy controls ( 0.10–0.43 mg/L ) . In the PLA group , sCD206 levels decreased after 3 months , but did not differ from baseline after 6 months . In the ADA group , however , levels remained lower than baseline throughout the treatment period . In conclusion , initially , plasma sCD206 in early RA patients decreased in accordance with disease activity and initiation of DMARD treatment . Treatment with anti-TNFα preserved this decrease throughout the study period [22739990] Objective To investigate the long-term effects of induction therapy with adalimumab ( ADA ) plus methotrexate ( MTX ) in comparison with placebo ( PBO ) plus MTX in DMARD-naïve patients with active early rheumatoid arthritis ( RA ) . Methods Patients with active early RA ( disease duration of ≤12 months ) were r and omly assigned to receive 40 mg ADA subcutaneously every other week ( eow ) plus MTX 15 mg/week subcutaneously or PBO plus MTX subcutaneously at 15 mg/week over 24 weeks . Thereafter , all patients received MTX monotherapy up to week 48 . The primary outcome was the Disease Activity Score 28 ( DAS28 ) at week 48 . Secondary outcomes included proportions of patients in remission ( DAS28<2.6 ) , ACR responses , Health Assessment Question naire ( HAQ ) score and radiographic progression . Results 87 patients were assigned to ADA/MTX and 85 patients to PBO/MTX . At baseline , DAS28 was 6.2±0.8 in the ADA/MTX and 6.3±0.9 in the PBO/MTX groups . At week 24 , treatment with ADA/MTX compared with PBO/MTX result ed in a greater reduction in DAS28 ( 3.0±1.2 vs 3.6±1.4 ; p=0.009 ) and other secondary outcomes such as DAS28 remission rate ( 47.9 % vs 29.5 % ; p=0.021 ) and HAQ ( 0.49±0.6 vs 0.72±0.6 ; p=0.0014 ) . At week 48 , the difference in clinical outcomes between groups was not statistically significant ( DAS28 : 3.2±1.4 vs 3.4±1.6 ; p=0.41 ) . Radiographic progression at week 48 was significantly greater in patients administered PBO/MTX ( Sharp/van der Heijde score : ADA/MTX 2.6 vs PBO/MTX 6.4 ; p=0.03 , Ratingen score : 1.7 vs 4.2 ; p=0.01 ) . Conclusions A greater reduction in radiographic progression after initial combination therapy with ADA and MTX was seen at week 48 , even after discontinuation of ADA treatment at week 24 . This sustained effect was not found at the primary endpoint ( DAS28 reduction ) [18662933] Objectives : To compare the occurrence of drug-free remission , functional ability and radiological damage after 4 years of response-driven treatment according to four different treatment strategies for rheumatoid arthritis ( RA ) . Methods : Patients with recent-onset , active RA ( n = 508 ) were r and omly assigned to four different treatment strategies : ( 1 ) sequential monotherapy ; ( 2 ) step-up combination therapy ; ( 3 ) initial combination therapy with prednisone and ( 4 ) initial combination therapy with infliximab . Treatment was adjusted based on 3-monthly disease activity score ( DAS ) assessment s , aim ing at a DAS ⩽2.4 . From the third year , patients with a sustained DAS < 1.6 discontinued treatment . Results : In total , 43 % of patients were in remission ( DAS < 1.6 ) at 4 years and 13 % were in drug-free remission : 14 % , 12 % , 8 % and 18 % of patients in groups 1–4 , respectively . The absence of anti-cyclic citrullinated peptide antibodies , male gender and short symptom duration were independently associated with drug-free remission . Functional ability and remission were maintained in all four groups with the continuation of DAS-driven treatment , without significant differences between the groups . Significant progression of joint damage was observed in 38 % and 31 % of patients in groups 3 and 4 versus 51 % and 54 % of patients in groups 1 and 2 ( p<0.05 , group 4 versus groups 1 and 2 , group 3 versus group 2 ) . Conclusions : In patients with recent-onset active RA , drug-free remission was achieved in up to 18 % of patients . DAS-driven treatment maintained clinical and functional improvement , independent of the treatment strategy . Joint damage progression remained significantly lower after initial combination therapy compared with initial monotherapy [5738604] Objectives To investigate the clinical impact of 1-year certolizumab pegol ( CZP ) therapy added to the first year of 2-year methotrexate ( MTX ) therapy , compared with 2-year therapy with MTX alone . Methods MTX-naïve patients with early rheumatoid arthritis ( RA ) with poor prognostic factors were eligible to enter Certolizumab-Optimal Prevention of joint damage for Early RA ( C-OPERA ) , a multicentre , r and omised , controlled study , which consisted of a 52-week double-blind ( DB ) period and subsequent 52-week post treatment ( PT ) period . Patients were r and omised to optimised MTX+CZP ( n=159 ) or optimised MTX+placebo ( PBO ; n=157 ) . Following the DB period , patients entered the PT period , receiving MTX alone ( CZP+MTX→MTX ; n=108 , PBO+MTX→MTX ; n=71 ) . Patients who flared could receive rescue treatment with open-label CZP . Results 34 CZP+MTX→MTX patients and 14 PBO+MTX→MTX patients discontinued during the PT period . From week 52 through week 104 , significant inhibition of total modified total Sharp score progression was observed for CZP+MTX versus PBO+MTX ( week 104 : 84.2 % vs 67.5 % ( p<0.001 ) ) . Remission rates decreased after CZP discontinuation ; however , higher rates were maintained through week 104 in CZP+MTX→MTX versus PBO+MTX→MTX ( 41.5 % vs 29.3 % ( p=0.026 ) , 34.6 % vs 24.2 % ( p=0.049 ) and 41.5 % vs 33.1 % ( p=0.132 ) at week 104 in SDAI , Boolean and DAS28(erythrocyte sedimentation rate ) remission . CZP retreated patients due to flare ( n=28 ) showed rapid clinical improvement . The incidence of overall adverse events was similar between groups . Conclusions In MTX-naïve patients with early RA with poor prognostic factors , an initial 1 year of add-on CZP to 2-year optimised MTX therapy brings radiographic and clinical benefit through 2 years , even after stopping CZP . Trial registration number NCT01451203 [5264210] Objectives To assess the efficacy and safety of certolizumab pegol (CZP)+dose-optimised methotrexate ( MTX ) versus placebo (PBO)+dose-optimised MTX in inducing and sustaining clinical remission in DMARD-naïve patients with moderate-to-severe , active , progressive rheumatoid arthritis ( RA ) , with poor prognostic factors over 52 weeks . Methods DMARD-naïve patients with ≤1 year of active RA were r and omised ( 3:1 ) in a double-blind manner to CZP ( 400 mg Weeks 0 , 2 , 4 , then 200 mg Q2W to Week 52)+MTX or PBO+MTX ( the mean optimised-MTX dose=21 and 22 mg/week , respectively ) . Sustained remission ( sREM ) and sustained low disease activity ( sLDA ; DAS28(ESR)<2.6 and DAS28(ESR)≤3.2 , respectively , at both Weeks 40 and 52 ) were the primary and secondary endpoints . Results Patients were r and omised to CZP+MTX ( n=660 ) and PBO+MTX ( n=219 ) . At Week 52 , significantly more patients assigned to CZP+MTX compared with PBO+MTX achieved sREM ( 28.9 % vs 15.0 % , p<0.001 ) and sLDA ( 43.8 % vs 28.6 % , p<0.001 ) . Inhibition of radiographic progression and improvements in physical functioning were significantly greater for CZP+MTX versus PBO+MTX ( van der Heijde modified total Sharp score ( mTSS ) mean absolute change from baseline ( CFB ) : 0.2 vs 1.8 , p<0.001 , rate of mTSS non-progressors : 70.3 % vs 49.7 % , p<0.001 ; least squares ( LS ) mean CFB in Health Assessment Question naire-Disability Index ( HAQ-DI ) : −1.00 vs −0.82 , p<0.001 ) . Incidence of adverse events ( AEs ) and serious AEs was similar between treatment groups . Infection was the most frequent AE , with higher incidence for CZP+MTX ( 71.8/100 patient-years ( PY ) ) versus PBO+MTX ( 52.7/100 PY ) ; the rate of serious infection was similar between CZP+MTX ( 3.3/100 PY ) and PBO+MTX ( 3.7/100 PY ) . Conclusions CZP+dose-optimised MTX treatment of DMARD-naïve early RA result ed in significantly more patients achieving sREM and sLDA , improved physical function and inhibited structural damage compared with PBO+dose-optimised MTX . Trial registration number NCT01519791 [4440309] Introduction Clinical synovitis is often associated with damage to bone and cartilage . Previous data have suggested that joint erosions ( JE ) are more prevalent than joint space narrowing ( JSN ) and that the two processes are partly independent of each other . The objective of this study was to evaluate whether the presence of JE in an individual joint can lead to development of JSN and if existing JSN leads to new onset of JE , in the absence of synovitis . Methods The Prospect i ve Multi-Centre R and omised , Double-Blind , Active Comparator-Controlled , Parallel-Groups Study Comparing the Fully Human Monoclonal Anti-TNFα Antibody Adalimumab Given Every Second Week With Methotrexate Given Weekly and the Combination of Adalimumab and Methotrexate Administered Over 2 Years in Patients With Early Rheumatoid Arthritis ( PREMIER ) enrolled early rheumatoid arthritis ( RA ) patients who were r and omized to one of three treatments : methotrexate ( MTX ) , adalimumab ( ADA ) , or ADA + MTX . All evaluable joints with JE and JSN measures at 26 and 52 weeks and synovitis assessment s from week 26 to 52 were included . Synovitis was assessed every 2–8 weeks by swollen joint counts between weeks 26 and 52 . Radiographs were taken at week 26 and 52 . Two readers , blinded to time and sequence , scored 14 bilateral joints individually for JE and JSN . Multivariate logistic modeling was used to characterize the dependence of JE/JSN onset at 52 weeks . Analyses were performed based on treatment arm and were also performed within individual joints . Results JE and swelling were independently and comparably associated with onset of JSN at week 52 . Assessment by individual joints indicated that existing JE , independent of swelling , was significantly associated with JSN onset in higher proportions of metatarsophalangeal ( MTP ; 7/10 ) than proximal interphalangeal ( PIP ; 1/8 ) or metacarpophalangeal ( MCP ; 1/10 ) joints . Treatment with ADA + MTX prevents JE/JSN progression independently of its ability to suppress synovitis and limits JE/JSN onset and progression in joints with existing damage . Conclusions Existing JE predisposes individual joints to development of JSN independently of synovitis in the same joint . Weight-bearing MTP joints with JE may be at increased risk for JSN when compared with MCPs and PIPs . Trial registration Clinical trials.gov NCT00195663 . Registered 13 September 2005 [29280011] Adverse events ( AEs ) are common during disease-modifying antirheumatic drug ( DMARD ) treatment , but their influence on treatment results is unclear . We studied AEs in relation to disease activity in early rheumatoid arthritis ( RA ) . Ninety-nine patients started intensive treatment with three conventional synthetic DMARDs ( csDMARDs ) and oral prednisolone , and were r and omized to a 6-month induction treatment with infliximab or placebo . All AEs during the first 12 months of treatment were recorded . We scored each AE based on severity ( scale 1–4 ) and defined the burden of AEs as the sum of these scores . Patients were divided into tertiles according to the burden of AEs . As outcomes , we assessed 28-joint disease activity score ( DAS28 ) levels and remission rates at 12 and 24 months . Three hundred thirty-one AEs in 99 patients were reported , and 27 ( 8 % ) were categorized as severe or serious . Mean burden of AEs per patient was 5.4 ± 4.3 . Seventy-nine AEs ( 24 % ) led to temporary ( n = 52 ) or permanent ( n = 27 ) csDMARD discontinuation . Of discontinuations , 1 , 21 , and 57 were detected in the first , second , and third tertiles , respectively . DAS28 remission rates decreased across tertiles at 12 months ( 94 , 94 , and 76 % ; p for linearity 0.029 ) and at 24 months ( 90 , 86 , and 70 % ; p for linearity 0.021 ) . Mean DAS28 levels increased across tertiles at 12 months ( 1.5 ± 1.0 , 1.7 ± 0.9 , and 1.9 ± 1.2 ; p for linearity 0.021 ) and at 24 months ( 1.4 ± 0.8 , 1.6 ± 1.0 , and 1.9 ± 1.1 ; p for linearity 0.007 ) . High burden of AEs is associated with higher disease activity and lower likelihood of remission in early RA [3551224] Objective To assess the efficacy and safety of adalimumab plus methotrexate ( ADA+MTX ) compared with methotrexate monotherapy in achieving stable low disease activity ( LDA ; disease activity score ( DAS28(CRP ) ) < 3.2 at weeks 22 and 26 ) and clinical , radiographic and functional outcomes in methotrexate-naive patients with early rheumatoid arthritis ( RA ) . Methods 1032 patients with active RA were r and omly assigned 1:1 to ADA+MTX or placebo plus methotrexate ( PBO+MTX ) for 26 weeks . Treatment modifications were to be made in a subsequent study period based on the achievement of DAS28(CRP ) < 3.2 at weeks 22 and 26 . Post-hoc analyses compared patients achieving stable remission using DAS28 and 2010 ACR/EULAR criteria with those achieving LDA but not remission . Results Among patients completing 6 months , 44 % ( 207/466 ) ADA+MTX versus 24 % ( 112/460 ) PBO+MTX patients achieved stable LDA at weeks 22 and 26 ( p<0.001 ) . Combination therapy was statistically superior to methotrexate in obtaining higher ACR20/50/70 responses , more clinical remissions , greater mean reductions in DAS28(CRP ) , no radiographic progression , and normal functional status at week 26 ( p<0.001 for all ) . The only factor predicting stable LDA was disease activity at week 12 . Patients achieving ACR/EULAR remission , particularly in the PBO+MTX group , had some advantage in radiographic outcomes compared with patients who only achieved LDA ( but not remission ) . The overall frequency of adverse events was comparable between groups . There were more serious infections and deaths in the ADA+MTX group , with a possible age effect . Conclusions Treatment with ADA+MTX was significantly superior to methotrexate alone with respect to clinical , radiographic and functional outcomes in patients with early active RA . Before initiating treatment with adalimumab , individual patient evaluation of the benefit/risk ratio should be carefully considered [27638812] OBJECTIVES To determine the change in established biomarkers of cardiovascular ( CV ) risk , namely , total cholesterol/high-density lipoprotein cholesterol ratio ( TC/HDL-C ) , N-terminal pro-brain natriuretic peptide ( NT-proBNP ) and insulin resistance ( IR ) in patients with early RA treated with two different treat-to-target strategies . METHODS Fasting glucose , lipids , insulin and NT-proBNP were measured at baseline , weeks 26 and 78 in 79 DMARD-naïve RA patients , free of CV disease , as part of a double-blind r and omized controlled trial of MTX with either infliximab ( IFX ) or methylprednisolone as induction therapy . Homeostasis model assessment -estimated IR ( HOMA-IR ) ( glucose*insulin/405 ) was used to measure IR . Multiple imputation was employed , and linear regression analyses were adjusted for baseline values . RESULTS Changes in DAS44-CRP did not differ between the treatment arms at weeks 26 and 78 . Mean TC/HDL-C , HOMA-IR and NT-proBNP improved in both groups at weeks 26 and 78 , although change in NT-proBNP was not statistically significant at week 78 . Changes in TC/HDL-C and NT-proBNP were similar between treatment arms , but HOMA-IR values in the IFX + MTX arm were 42 % lower than those treated with MTX + methylprednisolone at week 78 ( P = 0.003 ) ; the difference remained significant after adjustment for baseline BMI , ACPA positivity , smoking status and intramuscular glucocorticoid use ( P = 0.007 ) . CONCLUSION When implementing a treat-to-target approach , treatment of early RA was associated with improvement in TC/HDL-C , HOMA-IR and NT-proBNP , and a greater long-term improvement in HOMA-IR was seen in those treated with IFX . TRIAL REGISTRATION EU Clinical Trials Register , http://www . clinical trialsregister.eu , Eudract-2005 - 005013 - 37 ; ISRTCNregisrty , http://www.is rct n.com , IS RCT N48638981 [4823586] Objective To determine the most effective treatment strategy among anticitrullinated protein antibodies (ACPA)-negative patients with early rheumatoid arthritis . Methods In the BeSt study , 184 ACPA-negative patients were r and omised to : ( 1 ) sequential monotherapy , ( 2 ) step-up therapy , ( 3 ) initial combination including prednisone , ( 4 ) initial combination including infliximab . Treatment was targeted at the disease activity score ( DAS ) ≤2.4 . Early response and 10-year outcomes were compared between the four strategy -arms in ACPA-negative patients . Results ACPA-negative patients achieved more short-term functional improvement from initial combination therapy than when on monotherapy ( at month 3 , mean Health Assessment Question naire ( HAQ ) 0.71 vs 0.98 , p=0.006 ; at month 6 , 0.59 vs 0.87 , p=0.004 ) . Functional ability over time was comparable between the strategy -arms ( p=0.551 ) with a mean HAQ of 0.6 at year 10 ( p=0.580 for comparison across the strategy -arms ) . 10-year radiographic progression was negligible ( median 0.5 ) and comparable between the 4 strategy -arms ( p=0.082 ) . At year 10 , remission was achieved by 11/40 ( 28 % ) , 9/45 ( 20 % ) , 17/56 ( 30 % ) and 17/43 patients ( 40 % ) in strategy -arms 1–4 , respectively ( p=0.434 ) . Over time , similar remission percentages were achieved in all strategy -arms ( p=0.815 ) . 18 % , 16 % , 20 % and 21 % in strategy -arms 1 to 4 ( p=0.742 ) were in drug-free remission at year 10 , with a median duration of 60 months across the arms . Conclusions Initial combination therapy with methotrexate , sulfasalazine and prednisone , or methotrexate and infliximab , is the most effective treatment strategy for ACPA-negative patients , result ing in earlier functional improvement than when on initial methotrexate monotherapy . After 10 years of targeted treatment , in all strategy -arms favourable clinical outcomes were achieved and radiographic progression was limited . Trial registration number NTR262 , NTR265 [3988871] Objective . The aim of this study was to compare efficacy outcomes of initial treatment with adalimumab + MTX vs adalimumab addition following 26 weeks of MTX monotherapy in Japanese early RA patients naive to MTX with high disease activity . Methods . Patients completing the 26-week , r and omized , placebo-controlled trial of adalimumab + MTX were eligible to receive 26 weeks of open-label adalimumab + MTX . Patients were assessed for mean change from baseline in the 28-joint DAS with ESR ( DAS28-ESR ) and modified total Sharp score ( mTSS ) , and for the proportions of patients achieving clinical , functional or radiographic remission . Results . Of 333 patients assessed , 278 ( 137 from the initial adalimumab + MTX and 141 from the initial placebo + MTX groups ) completed the 52-week study . Significant differences in clinical and functional parameters observed during the 26-week blinded period were not apparent following the addition of open-label adalimumab to MTX . Open-label adalimumab + MTX slowed radiographic progression through week 52 in both groups , but patients who received adalimumab + MTX throughout the study exhibited less radiographic progression than those who received placebo + MTX during the first 26 weeks ( mean ΔmTSS at week 52 = 2.56 vs 3.30 , P < 0.001 ) . Conclusion . Delayed addition of adalimumab in Japanese MTX-naive early RA patients did not impact clinical and functional outcomes at week 52 compared with the earlier addition of adalimumab . However , the accrual of significant structural damage during blinded placebo + MTX therapy contributed to the persistence of differences between the treatment strategies , suggesting that Japanese patients at risk for aggressive disease should benefit from the early inclusion of adalimumab + MTX combination therapy . Trial registration . Clinical Trials.gov ( http:// clinical trials.gov/ ) , NCT00870467 [4717398] Objectives To evaluate efficacy and safety of combination therapy using certolizumab pegol ( CZP ) and methotrexate ( MTX ) as first-line treatment for MTX-naive , early rheumatoid arthritis ( RA ) with poor prognostic factors , compared with MTX alone . Methods MTX-naive , early RA patients with ≤12 months persistent disease , high anti-cyclic citrullinated peptide , and either rheumatoid factor positive and /or presence of bone erosions were enrolled in this multicentre , double-blind , r and omised placebo (PBO)-controlled study . Patients were r and omised 1:1 to CZP+MTX or PBO+MTX for 52 weeks . Primary endpoint was inhibition of radiographic progression ( change from baseline in modified Total Sharp Score ( mTSS CFB ) ) at week 52 . Secondary endpoints were mTSS CFB at week 24 , and clinical remission rates at weeks 24 and 52 . Results 316 patients r and omised to CZP+MTX ( n=159 ) or PBO+MTX ( n=157 ) had comparable baseline characteristics reflecting features of early RA ( mean disease duration : 4.0 vs 4.3 months ; Disease Activity Score 28-joint assessment ( DAS28 ) ) ( erythrocyte sedimentation rate ( ESR ) ) : 5.4 vs 5.5 ; mTSS : 5.2 vs 6.0 ) . CZP+MTX group showed significantly greater inhibition of radiographic progression relative to PBO+MTX at week 52 ( mTSS CFB=0.36 vs 1.58 ; p<0.001 ) and week 24 ( mTSS CFB=0.26 vs 0.86 ; p=0.003 ) . Clinical remission rates ( Simple Disease Activity Index , Boolean and DAS28 ( ESR ) ) of the CZP+MTX group were significantly higher compared with those of the PBO+MTX group , at weeks 24 and 52 . Safety results in both groups were similar , with no new safety signals observed with addition of CZP to MTX . Conclusions In MTX-naive early RA patients with poor prognostic factors , CZP+MTX significantly inhibited structural damage and reduced RA signs and symptoms , demonstrating the efficacy of CZP in these patients . Trial registration number ( NCT01451203 ) [19741011] OBJECTIVES In early and active RA despite MTX , continuous treatment with TNF blockers in combination with MTX is recommended . To compare this strategy with an initial combination of MTX and adalimumab ( ADA ) given for 3 months and then adjusted based on the disease activity status . METHODS Prospect i ve unblinded r and omized multicentre controlled 1-year trial in which 65 patients with early ( < 6 months ) and active [ disease activity score ( DAS28(ESR ) ) > 5.1 ] RA were assigned to Group 1 ( 32 patients ): MTX ( 0.3 mg/kg/week , maximum of 20 mg/week , without escalating dose regimen ) or to Group 2 ( 33 patients ): initial combination therapy with MTX ( as in Group 1 ) and ADA ( 40 mg eow ) . In both groups , treatment was adjusted every 3 months . The aim was to achieve a low DAS ( DAS28(ESR ) < 3.2 ) . RESULTS From Week 12 until Week 52 , seven patients in Group 1 and 11 patients in Group 2 remained in low disease activity state while receiving MTX monotherapy ( P = 0.28 ) . The 1-year area under the curve ( AUC ) of DAS28 was lower in Group 2 owing to an initial better response . The total intake of anti-TNF-alpha and the mean increase in total modified Sharp score was similar in the two groups . CONCLUSIONS Initial combination of MTX and ADA and then an adjusted based on the disease activity status achieved a faster control of disease activity but did not increase the number of patients for whom anti-TNF-alpha treatment was not needed after 12 weeks nor a better subsequent clinical or radiological outcome than a 3-month delayed initiation of anti-TNF in patients with still active disease despite MTX [27432355] Purpose We assessed whether MRI measures of synovitis , osteitis and bone erosion were associated with patient-reported outcomes ( PROs ) in a longitudinal clinical trial setting among patients with rheumatoid arthritis ( RA ) . Methods This longitudinal cohort of 291 patients with RA was derived from the MRI sub study of the GO-BEFORE r and omised controlled trial of golimumab among methotrexate-naïve patients . Correlations between RAMRIS scores ( synovitis , osteitis , bone erosion ) and physical function ( Health Assessment Question naire ( HAQ ) ) , pain and global patient scores were determined at 0 , 12 , 24 and 52 weeks . Correlations between interval changes were also assessed . Multivariable regression models using robust generalised estimating equations evaluated associations over all time-points and their relationship to other clinical disease activity measures . Results Greater synovitis , osteitis and bone erosion scores were positively associated with HAQ at all time-points ( all p<0.05 ) and with pain and patient global scores at 24 and 52 weeks . Over all visits , synovitis was associated with HAQ , pain and patient global scores ( p≤0.03 ) independent of clinical disease activity measures . Improvements in synovitis and bone erosion were also associated with improvements in PROs . Less improvement in synovitis and progression in MRI erosion at 52 weeks were both independently associated with worsening in all PROs at 52 weeks while progression on X-ray was not associated . Similar associations were observed across treatment groups . Conclusions MRI measures of inflammation and structural damage correlate independently with physical function , pain and patient global assessment s. These observations support the validity of MRI biomarkers . Trial registration number NCT00264537 ; Post- results [12115173] OBJECTIVE To compare the clinical and radiographic outcomes in patients with rheumatoid arthritis ( RA ) who received monotherapy with either etanercept or methotrexate ( MTX ) for 2 years and to assess the safety of this therapy . METHODS In the Enbrel ERA ( early rheumatoid arthritis ) trial , 632 patients with early , active RA were r and omized to receive either twice-weekly subcutaneous etanercept ( 10 mg or 25 mg ) or weekly oral MTX ( mean dosage 19 mg per week ) for at least 1 year in a double-blind manner . Following the blinded phase of the trial , 512 patients continued to receive the therapy to which they had been r and omized for up to 1 additional year , in an open-label manner . Radiograph readers remained blinded to treatment group assignment and the chronologic order of images . RESULTS At 24 months , more 25-mg etanercept patients than MTX patients met American College of Rheumatology 20 % improvement criteria ( 72 % and 59 % , respectively ; P = 0.005 ) , and more had no increase in total score and erosion scores on the Sharp scale ( P = 0.017 and P = 0.012 , respectively ) . The mean changes in total Sharp score and erosion score in the 25-mg etanercept group ( 1.3 and 0.66 units , respectively ) were significantly lower than those in the MTX group ( 3.2 and 1.86 units , respectively ; P = 0.001 ) . Significantly more patients in the 25-mg etanercept group ( 55 % ) than in the MTX group ( 37 % ) had at least 0.5 units of improvement in the Health Assessment Question naire disability index ( P < 0.001 ) . Fewer patients in the etanercept group than in the MTX group experienced adverse events or discontinued treatment because of adverse events . CONCLUSION Etanercept as monotherapy was safe and was superior to MTX in reducing disease activity , arresting structural damage , and decreasing disability over 2 years in patients with early , aggressive RA [23912798] Objectives In disease modifying antirheumatic drug (DMARD)-naive early rheumatoid arthritis ( RA ) , to compare the efficacy of methotrexate ( MTX ) and infliximab ( IFX ) with MTX and intravenous corticosteroid for remission induction . Methods In a 78-week multicentre r and omised controlled trial , double-blinded to week 26 , 112 treatment-naive RA patients ( 1987 American College of Rheumatology classification criteria ) with disease activity score 44 (DAS44)>2.4 were r and omised to MTX + IFX or MTX + single dose intravenous methylprednisolone 250 mg . A treat-to-target approach was used with treatment escalation if DAS44>2.4 . In the IFX group , IFX was discontinued for sustained remission ( DAS44<1.6 for 6 months ) . The primary outcome was change in modified total Sharp-van der Heijde score ( mTSS ) at week 50 . Results The mean changes in mTSS score at week 50 in the IFX and intravenous steroid groups were 1.20 units and 2.81 units , respectively ( adjusted difference ( 95 % CI ) −1.45 ( −3.35 to 0.45 ) ; p=0.132 ) . Radiographic non-progression ( mTSS<2.0 ) occurred in 81 % vs 71 % ( OR 1.77 ( 0.56 to 5.61 ) ; p=0.328 ) . DAS44 remission was achieved at week 50 in 49 % and 36 % ( OR 2.13 ( 0.91 to 5.00 ) ; p=0.082 ) , and at week 78 in 48 % and 50 % ( OR 1.12 ( 0.47 to 2.68 ) ; p=0.792 ) . Exploratory analyses suggested higher DAS28 remission at week 6 and less ultrasound synovitis at week 50 in the IFX group . Of the IFX group , 25 % ( 14/55 ) achieved sustained remission and stopped IFX . No substantive differences in adverse events were seen . Conclusions In DMARD-naive early RA patients , initial therapy with MTX+high-dose intravenous steroid result ed in good disease control with little structural damage . MTX+IFX was not statistically superior to MTX+intravenous steroid when combined with a treat-to-target approach [18821658] OBJECTIVE To compare work disability and job loss in early rheumatoid arthritis ( RA ) patients receiving adalimumab plus methotrexate ( adalimumab + MTX ) versus MTX alone . METHODS In this multicenter , r and omized , controlled trial , patients with RA for < 2 years who had never taken MTX and who self-reported work impairment were r and omized to adalimumab + MTX or placebo + MTX for 56 weeks . Primary outcome was job loss of any cause and /or imminent job loss at or after week 16 . Secondary outcomes included disease activity , function ( Health Assessment Question naire [ HAQ ] score ) , and RA quality of life ( RAQoL ) question naire score . Work was evaluated with work diaries and the RA Work Instability Scale . RESULTS Although job loss during the 56-week study was significantly lower with adalimumab + MTX ( 14 of 75 patients ) compared with MTX alone ( 29 of 73 patients ; P=0.005 ) , the primary end point was not met ( 12 of 75 versus 20 of 73 patients ; P=0.092 ) , likely owing to early drop out in the MTX group . There were significant improvements in American College of Rheumatology 20 % response criteria , 28-joint Disease Activity Score , DeltaHAQ , DeltaRAQoL , and working time lost in the adalimumab + MTX group . Twenty-four serious adverse events were reported in 17 participants , with no differences between groups . CONCLUSION Adalimumab + MTX reduced job loss and improved productivity in early RA when compared with MTX alone , which supports the early use of anti-tumor necrosis factor therapy and suggests its cost efficacy [25939484] At least 30 % of patients with rheumatoid arthritis ( RA ) do not respond to biologic agents , which emphasizes the need of predictive biomarkers . We aim ed to identify microRNAs ( miRNAs ) predictive of response to adalimumab in 180 treatment-naïve RA patients enrolled in the OPtimized treatment algorithm for patients with early RA ( OPERA ) Study , an investigator-initiated , prospect i ve , double-blind placebo-controlled study . Patients were r and omized to adalimumab 40 mg ( n=89 ) or placebo – adalimumab ( n=91 ) subcutaneously in combination with methotrexate . Expressions of 377 miRNAs were determined using TaqMan Human MicroRNA LDA , A Card v2.0 ( Applied Biosystems ) . Associations between miRNAs and treatment response were tested using interaction analyses . MiRNAs with a P-value < 0.05 using three different normalizations were included in a multivariate model . After backwards elimination , the combination of low expression of miR-22 and high expression of miR-886.3p was associated with EULAR good response . Future studies to assess the utility of these miRNAs as predictive biomarkers are needed [15529377] OBJECTIVE To compare the benefits of initiating treatment with methotrexate ( MTX ) and infliximab ( anti-tumor necrosis factor alpha [ anti-TNFalpha ] monoclonal antibody ) with those of MTX treatment alone in patients with rheumatoid arthritis ( RA ) of < or =3 years ' duration . METHODS RA patients were eligible if they had active disease and no prior treatment with MTX or a TNFalpha inhibitor . One thous and forty-nine patients were r and omly assigned in a 4:5:5 ratio to 3 treatment groups : MTX-placebo , MTX-3 mg/kg infliximab , and MTX-6 mg/kg infliximab . MTX dosages were rapidly escalated to 20 mg/week , and infliximab or placebo infusions were given at weeks 0 , 2 , and 6 , and every 8 weeks thereafter through week 46 . RESULTS At week 54 , the median percentage of American College of Rheumatology improvement ( ACR-N ) was higher for the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups than for the MTX-placebo group ( 38.9 % and 46.7 % versus 26.4 % , respectively ; P < 0.001 for both comparisons ) . Patients in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups also showed less radiographic progression than those receiving MTX alone ( mean + /- SD changes in van der Heijde modification of the total Sharp score at week 54 : 0.4 + /- 5.8 and 0.5 + /- 5.6 versus 3.7 + /- 9.6 , respectively ; P < 0.001 for each comparison ) . In addition , physical function improved significantly more in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups than in the MTX-placebo group . Infliximab therapy was associated with a significantly higher incidence of serious infections , especially pneumonia . CONCLUSION For patients with active RA in its early stages , combination therapy with MTX and infliximab provides greater clinical , radiographic , and functional benefits than treatment with MTX alone [5571914] Objective YKL-40 , a chitinase-like glycoprotein associated with inflammation and tissue remodeling , is produced by joint tissues and recognized as a c and i date auto-antigen in rheumatoid arthritis ( RA ) . In the present study , we investigated YKL-40 as a potential biomarker of disease activity in patients with early RA at baseline and during intensive treatment aim ing for early remission . Methods Ninety-nine patients with early DMARD-naïve RA participated in the NEO-RACo study . For the first four weeks , the patients were treated with the combination of sulphasalazine , methotrexate , hydroxychloroquine and low dose prednisolone ( FIN-RACo DMARD combination ) , and subsequently r and omized to receive placebo or infliximab added on the treatment for further 22 weeks . Disease activity was evaluated using the 28-joint disease activity score and plasma YKL-40 concentrations were measured by immunoassay . Results At the baseline , plasma YKL-40 concentration was 57 ± 37 ( mean ± SD ) ng/ml . YKL-40 was significantly associated with the disease activity score , interleukin-6 and erythrocyte sedimentation rate both at the baseline and during the 26 weeks ’ treatment . The csDMARD combination decreased YKL-40 levels already during the first four weeks of treatment , and there was no further reduction when the tumour necrosis factor-α antagonist infliximab was added on the combination treatment . Conclusions High YKL-40 levels were found to be associated with disease activity in early DMARD-naïve RA and during intensive treat-to-target therapy . The present results suggest YKL-40 as a useful biomarker of disease activity in RA to be used to steer treatment towards remission [21415052] Objective To compare clinical and radiological outcomes of four dynamic treatment strategies in recent-onset rheumatoid arthritis ( RA ) after 5 years follow-up . Methods 508 patients with recent-onset RA were r and omly assigned into four treatment strategies : sequential monotherapy ; step-up combination therapy ; initial combination with prednisone ; initial combination with infliximab . Treatment adjustments were made based on 3-monthly disease activity score ( DAS ) measurements ( if DAS > 2.4 next treatment step ; if DAS ≤2.4 during ≥6 months taper to maintenance dose ; if DAS < 1.6 during ≥6 months stop antirheumatic treatment ) . Primary and secondary outcomes were functional ability , joint damage progression , health-related quality of life and ( drug-free ) remission percentages . Results After 5 years , 48 % of patients were in clinical remission ( DAS < 1.6 ) and 14 % in drug-free remission , irrespective of initial treatment . After an earlier improvement in functional ability and quality of life with initial combination therapy , from 1 year onwards clinical outcomes were comparable across the groups and stable during 5 years . The initial combination groups showed less joint damage in year 1 . In years 2–5 annual progression was comparable across the groups . After 5 years , initial combination therapy result ed in significantly less joint damage progression , reflecting the earlier clinical response . Conclusion Irrespective of initial treatment , an impressive improvement in clinical and radiological outcomes of RA patients can be achieved with dynamic treatment aim ed at reducing disease activity , leading to 48 % remission , 14 % drug-free remission and sustained functional improvement . Starting with combination therapy result ed in earlier clinical improvement and less joint damage without more toxicity [25962601] OBJECTIVES Rheumatoid arthritis ( RA ) is a chronic autoimmune disease where TNF-α is a central mediator of inflammation , and is cleaved from the cell surface by TACE/ADAM17 . This metalloproteinase is also responsible for the release of soluble ( s ) CD163 . Soluble CD163 reflects macrophage activation . In RA , sCD163 has been suggested as a marker of disease activity and progression . Our aim is to investigate sCD163 levels in early RA patients . METHODS Soluble CD163 was measured by ELISA from 150 RA plasma sample s from the OPERA trial . Averaged disease duration was three months , prior to r and omisation with methotrexate ( MTX ) and adalimumab ( DMARD+ADA ) or MTX and placebo ( DMARD+PLA ) . Soluble CD163 levels were evaluated in relation to clinical disease parameters . RESULTS Plasma sCD163 at baseline was 2.39 mg/l ( 1.74 mg/l-3.18 mg/l ) , mean ( 95 % CI ) , vs healthy controls : 1.63 mg/l ( 1.54 mg/l - 1.73 mg/l ) , ( p<0.001 ) . After three months of treatment sCD163 levels decreased significantly ( average 23.5 % ) in both treatment groups . Significant incremental sCD163 levels followed withdrawal of ADA after 12 months of treatment . Baseline sCD163 correlated with CRP and all investigated disease activity markers ( ρ=0.16 - 0.28 , p<0.05 ) . In the DMARD+PLA group baseline sCD163 also correlated with CRP during the follow-up period . CONCLUSIONS Soluble CD163 correlated with disease activity markers in early RA before treatment . Plasma sCD163 may add to currently available disease measures by specifically reflecting changes in macrophage activity as evidence d by increasing levels following anti-TNF withdrawal , despite maintenance of a stable clinical condition achieved by conventional remedies . It remains to be determined whether sCD163 is an early predictor of disease flare [20889601] Objective . To evaluate the efficacy and safety of initial combination treatment with adalimumab ( ADA ) and methotrexate ( MTX ) versus monotherapy with ADA or MTX during an open-label extension of PREMIER . Methods . Patients with early rheumatoid arthritis ( RA ) received blinded ADA plus MTX , ADA alone , or MTX alone for 2 years in PREMIER . At Year 2 , patients could enroll in an open-label extension and receive ADA monotherapy ; MTX could be added at the investigator ’s discretion . Longterm efficacy results are presented as observed data . Results . In the open-label period , 497 of the original 799 r and omized patients had ≥ 1 dose of ADA ( by original r and omization : ADA plus MTX , n = 183 ; ADA , n = 159 ; MTX , n = 155 ) . In the completers cohort [ patients with available Year-5 ACR responses and modified total Sharp scores ( mTSS ) ] , the Year-5 mean change from baseline in mTSS for the ADA+MTX arm ( n = 124 ) was 2.9 , compared with 8.7 and 9.7 in the ADA ( n = 115 ) and MTX ( n = 115 ) arms . Comprehensive disease remission , defined as the combination of DAS28 remission , normal function ( Health Assessment Question naire ≤ 0.5 ) , and radiographic nonprogression ( ΔmTSS ≤ 0.5 ) , was achieved by more patients in the initial ADA+MTX arm ( 35 % ) than in the ADA ( 13 % ) or MTX ( 14 % ) arms . Conclusion . Initial combination treatment with ADA plus MTX , followed by open-label ADA , led to better longterm clinical , functional , and radiographic outcomes than either initial ADA or MTX monotherapy during 5 years of treatment [28289873] Identifying prognostic factors for remission in early rheumatoid arthritis ( ERA ) patients is of key clinical importance . We studied patient-reported outcomes ( PROs ) as predictors of remission in a clinical trial . We r and omized 99 untreated ERA patients to receive remission-targeted treatment with three disease-modifying antirheumatic drugs and prednisolone for 24 months , and infliximab or placebo for the initial 6 months . At baseline , we measured following PROs : eight Short Form 36 question naire ( SF-36 ) dimensions , patient ’s global assessment [ PGA , visual analogue scale ( VAS ) ] , Health Assessment Question naire ( HAQ ) , and pain VAS . We used multivariable-adjusted regression models to identify PROs that independently predicted modified American College of Rheumatology remission at 2 years . Follow-up data at 2 years were available for 93 patients ( 92 % ) , and 58 patients ( 62 % ) were in remission . At baseline , patients who achieved remission had higher radiological score ( p = 0.04 ) , lower tender joint count ( p = 0.001 ) , lower PGA ( p = 0.005 ) and physician ’s global assessment ( p = 0.019 ) , lower HAQ ( p = 0.016 ) , less morning stiffness ( p = 0.009 ) , and significantly higher scores in seven out of eight SF-36 dimensions compared with patients who did not . In multivariable models that included all PROs , remission was associated with SF-36 dimensions higher vitality ( odds ratio 2.01 ; 95 % confidence interval 1.19–3.39 ) and better emotional role functioning ( odds ratio 1.64 ; 95 % confidence interval 1.01–2.68 ) . PGA , pain VAS , HAQ , and other SF-36 dimensions were not associated with remission . We conclude that self-reported vitality and better emotional role functioning are among the most important PROs for the prediction of remission in ERA [18635256] BACKGROUND Remission and radiographic non-progression are goals in the treatment of early rheumatoid arthritis . The aim of the combination of methotrexate and etanercept in active early rheumatoid arthritis ( COMET ) trial is to compare remission and radiographic non-progression in patients treated with methotrexate monotherapy or with methotrexate plus etanercept . METHODS 542 out patients who were methotrexate-naive and had had early moderate-to-severe rheumatoid arthritis for 3 - 24 months were r and omly assigned to receive either methotrexate alone titrated up from 7.5 mg a week to a maximum of 20 mg a week by week 8 or methotrexate ( same titration ) plus etanercept 50 mg a week . Co primary endpoints at 52 weeks were remission measured with the disease activity score in 28 joints ( DAS28 ) and radiographic non-progression measured with modified total Sharp score . Treatment was allocated with a computerised r and omisation and enrolment system , which masked both participants and carers . Analysis was done by modified intention to treat with last observation carried forward for missing data . This study is registered with Clinical Trials.gov , number NCT00195494 ) . FINDINGS 274 participants were r and omly assigned to receive combined treatment and 268 methotrexate alone . 132 of 265 ( 50 % , 95 % CI 44 - 56 % ) patients who took combined treatment and were available for assessment achieved clinical remission compared with 73 of 263 ( 28 % , 23 - 33 % ) taking methotrexate alone ( effect difference 22.05 % , 95%CI 13.96 - 30.15 % , p<0.0001 ) . 487 evaluable patients had severe disease ( DAS28>5.1 ) . 196 of 246 ( 80 % , 75 - 85 % ) and 135 of 230 ( 59 % , 53 - 65 % ) , respectively , achieved radiographic non-progression ( 20.98 % , 12.97 - 29.09 % , p<0.0001 ) . Serious adverse events were similar between groups . INTERPRETATION Both clinical remission and radiographic non-progression are achievable goals in patients with early severe rheumatoid arthritis within 1 year of combined treatment with etanercept plus methotrexate . FUNDING Wyeth Research [18050189] OBJECTIVE To compare the effects of methotrexate ( MTX ) , alone or in combination with intravenous ( IV ) methylprednisolone ( MP ) or infliximab , on magnetic resonance imaging (MRI)-detected synovitis , bone edema , and erosive changes in patients with early rheumatoid arthritis ( RA ) . METHODS Forty-four patients with early RA were r and omized to receive MTX alone ( MTX group ) , MTX plus IV MP ( IV MP group ) , or MTX plus infliximab ( infliximab group ) , infused on day 0 and weeks 2 , 6 , 14 , 22 , 30 , 38 , and 46 . Gadolinium-enhanced MRI scans of the metacarpophalangeal joints , wrists , and metatarsophalangeal joints were performed at baseline , week 18 , and week 52 . RESULTS Scores for MRI-detected synovitis and bone edema improved over time in the 3 groups , with significantly lower synovitis scores in the infliximab group compared with the MTX group and significantly lower bone edema scores in the infliximab group compared with the MTX and the IV MP groups . Scores for MRI-detected erosion significantly increased over time in all groups . There were no differences in erosion scores between the MTX group and the other groups . It is of note that patients treated with IV MP showed more significant progression in MRI-detected erosions compared with patients treated with infliximab . At week 22 , response rates according to the American College of Rheumatology 20 % improvement criteria ( ACR20 ) , the ACR50 , and the ACR70 were significantly higher in both the IV MP group and the infliximab group compared with the MTX group . At week 52 , remission was achieved in 40 % of patients in the MTX group and in 70 % of patients in the IV MP and infliximab groups . Health Assessment Question naire scores improved significantly over time in all groups , with patients receiving IV MP experiencing significantly more improvement compared with patients treated with MTX alone . No severe side effects were observed , except 1 case of MTX-related pneumonitis . CONCLUSION The combination of MTX and infliximab is superior to MTX alone for reducing MRI-detected signs of synovitis and bone edema in patients with early RA . Progression of MRI-detected erosion was greater in patients treated with MTX plus IV MP compared with that in patients who received MTX plus infliximab [23908187] Objective To study whether adding initial infliximab to remission-targeted initial combination-DMARD treatment improves the long-term outcomes in patients with early rheumatoid arthritis ( RA ) . Methods Ninety-nine patients with early , DMARD-naïve RA were treated with a triple combination of DMARDs , starting with methotrexate ( max 25 mg/week ) , sulfasalazine ( max 2 g/day ) , hydroxychloroquine ( 35 mg/kg/week ) , and with prednisolone ( 7.5 mg/day ) , and r and omised to double blindly receive either infliximab ( 3 mg/kg ; FIN-RACo+INFL ) or placebo ( FIN-RACo+PLA ) infusions during the first 6 months . After 2 years the treatment strategies became unrestricted , but the treatment goal was strict ACR remission . At 5 years the clinical and radiographic outcomes were assessed . Results Ninety-one patients ( 92 % ) were followed up to 5 years , 45 in the FIN-RACo+INFL and 46 in the FIN-RACo+PLA groups . At 5 years , the respective proportions of patients in strict ACR and in disease activity score 28 remissions in the FIN-RACo+INFL and FIN-RACo+PLA groups were 60 % ( 95 % CI 44 % to 74 % ) and 61 % ( 95 % CI 45 % to 75 % ) ( p=0.87 ) , and 84 % ( 95 % CI 71 % to 94 % ) and 89 % ( 95 % CI 76 % to 96 % ) ( p=0.51 ) . The corresponding mean ( SD ) total Sharp/van der Heijde scores at 5 years were 4.3 ( 7.6 ) , and 5.3 ( 7.3 ) , while the respective mean Sharp/van der Heijde scores changes from baseline to 5 years were 1.6 ( 95 % CI 0.0 to 3.4 ) and 3.7 ( 95 % CI 2.2 to 5.8 ) ( p=0.13 ) . Conclusions In early RA , targeted treatment with a combination of traditional DMARDs and prednisolone induces remission and minimises radiographic progression in most patients up to 5 years ; adding initial infliximab for 6 months does not improve these outcomes [5656933] In disease‐modifying antirheumatic drug – naive patients with early rheumatoid arthritis ( RA ) who had achieved sustained low disease activity ( a Disease Activity Score in 28 joints using the erythrocyte sedimentation rate of ≤3.2 at both week 40 and week 52 ) after 1 year of treatment with certolizumab pegol ( CZP ) at a st and ard dose ( 200 mg every 2 weeks plus optimized methotrexate [ MTX ] ) , we evaluated whether continuation of CZP treatment at a st and ard dose or at a reduced frequency ( 200 mg every 4 weeks plus MTX ) was superior to stopping CZP ( placebo plus MTX ) in maintaining low disease activity for 1 additional year [24412895] Objectives To investigate whether a treat-to-target strategy with methotrexate and intra-articular glucocorticosteroid injections suppresses MRI inflammation and halts structural damage progression in patients with early rheumatoid arthritis ( ERA ) , and whether adalimumab provides an additional effect . Methods In a double-blind , placebo-controlled trial , 85 disease-modifying antirheumatic drug-naïve patients with ERA were r and omised to receive methotrexate , intra-articular glucocorticosteroid injections and placebo/adalimumab ( 43/42 ) . Contrast-enhanced MRI of the right h and was performed at months 0 , 6 and 12 . Synovitis , osteitis , tenosynovitis , MRI bone erosion and joint space narrowing ( JSN ) were scored with vali date d methods . Dynamic contrast-enhanced MRI ( DCE-MRI ) was carried out in 14 patients . Results Synovitis , osteitis and tenosynovitis scores decreased highly significantly ( p<0.0001 ) during the 12-months ’ follow-up , with mean change scores of −3.7 ( median −3.0 ) , −2.2 ( −1 ) and −5.3 ( −4.0 ) , respectively . No overall change in MRI bone erosion and JSN scores was seen , with change scores of 0.1 ( 0 ) and 0.2 ( 0 ) . The tenosynovitis score at month 6 was significantly lower in the adalimumab group , 1.3 ( 0 ) , than in the placebo group , 3.9 ( 2 ) , Mann – Whitney : p<0.035 . Furthermore , the osteitis score decreased significantly during the 12-months ’ follow-up in the adalimumab group , but not in the placebo group , Wilcoxon : p=0.001–0.002 and p=0.062–0.146 . DCE-MRI parameters correlated closely with conventional MRI inflammatory parameters . Clinical measures decreased highly significantly during follow-up . Conclusions A treat-to-target strategy with methotrexate and intra-articular glucocorticosteroid in patients with ERA effectively decreased synovitis , osteitis and tenosynovitis and halted structural damage progression as judged by MRI . The findings suggest that addition of adalimumab is associated with further suppression of osteitis and tenosynovitis [24168956] BACKGROUND Biological agents offer good control of rheumatoid arthritis , but the long-term benefits of achieving low disease activity with a biological agent plus methotrexate or methotrexate alone are unclear . The OPTIMA trial assessed different treatment adjustment strategies in patients with early rheumatoid arthritis attaining ( or not ) stable low disease activity with adalimumab plus methotrexate or methotrexate monotherapy . METHODS This trial was done at 161 sites worldwide . Patients with early ( < 1 year duration ) rheumatoid arthritis naive to methotrexate were r and omly allocated ( by interactive voice response system , in a 1:1 ratio , block size four ) to adalimumab ( 40 mg every other week ) plus methotrexate ( initiated at 7·5 mg/week , increased by 2·5 mg every 1 - 2 weeks to a maximum weekly dose of 20 mg by week 8) or placebo plus methotrexate for 26 weeks ( period 1 ) . Patients in the adalimumab plus methotrexate group who completed period 1 and achieved the stable low disease activity target ( 28-joint disease activity score with C-reactive protein [DAS28]<3·2 at weeks 22 and 26 ) were r and omised to adalimumab-continuation or adalimumab-withdrawal for an additional 52 weeks ( period 2 ) . Patients achieving the target with initial methotrexate continued methotrexate-monotherapy . Inadequate responders were offered adalimumab plus methotrexate . All patients and investigators were masked to treatment allocation in period 1 . During period 2 , treatment reallocation of patients who achieved the target was masked to patients and investigators ; patients who did not achieve the target remained masked to original r and omisation , but were aware of the subsequent assignment . The primary endpoint was a composite measure of DAS28 of less than 3·2 at week 78 and radiographic non-progression from baseline to week 78 , compared between adalimumab-continuation and methotrexate-monotherapy . Adverse events were monitored throughout period 2 . This trial is registered with Clinical Trials.gov , number NCT00420927 . FINDINGS The study was done between Dec 28 , 2006 , and Aug 3 , 2010 . 1636 patients were assessed and 1032 were r and omised in period 1 ( 515 to adalimumab plus methotrexate ; 517 to placebo plus methotrexate ) . 466 patients in the adalimumab plus methotrexate group completed period 1 ; 207 achieved the stable low disease activity target , of whom 105 were rer and omised to adalimumab-continuation . 460 patients in the placebo plus methotrexate group completed period 1 ; 112 achieved the stable low disease activity target and continued methotrexate-monotherapy . 73 of 105 ( 70 % ) patients in the adalimumab-continuation group and 61 of 112 ( 54 % ) patients in the methotrexate-monotherapy group achieved the primary endpoint at week 78 ( mean difference 15 % [ 95 % CI 2 - 28 % ] , p=0·0225 ) . Patients achieving the stable low disease activity target on adalimumab plus methotrexate who withdrew adalimumab mostly maintained their good responses . Overall , 706 of 926 patients in period 2 had an adverse event , of which 82 were deemed serious ; however , distribution of adverse events did not differ between groups . INTERPRETATION Treatment to a stable low disease activity target result ed in improved clinical , functional , and structural outcomes , with both adalimumab-continuation and methotrexate-monotherapy . However , a higher proportion of patients treated with initial adalimumab plus methotrexate achieved the low disease activity target compared with those initially treated with methotrexate alone . Outcomes were much the same whether adalimumab was continued or withdrawn in patients who initially responded to adalimumab plus methotrexate . FUNDING AbbVie [15996057] OBJECTIVE To evaluate safety , efficacy , and radiographic progression in patients with early rheumatoid arthritis ( RA ) undergoing longterm treatment with etanercept . METHODS Patients with early RA ( disease duration of 3 years or less ) who had completed a 2-year efficacy study comparing etanercept and methotrexate ( MTX ) were followed in an extension where they received 25 mg etanercept twice weekly . Safety was summarized descriptively and compared with data from the efficacy study . Efficacy and radiographic progression were assessed using American College of Rheumatology response criteria , disease activity scores , and Total Sharp Score ( TSS ) . RESULTS Rates of serious adverse events and serious infections did not increase with longterm exposure to etanercept , and were similar to rates reported for the blinded portion of the efficacy study . Efficacy was sustained in patients who completed 5 years of etanercept treatment at the time of this report ( N = 201 ) , even in those who decreased or discontinued use of MTX or corticosteroids . No radiographic progression ( change in TSS < or = 0 ) was seen in 55 % of patients with 5-year radiographs ; negative change ( TSS < 0 ) was seen in 11 % . CONCLUSION Etanercept treatment in patients with early RA was generally well tolerated for up to 5 years . The results indicate sustained efficacy and decreased rate of radiographic progression . The rate of radiographic progression was low compared with other studies , emphasizing the benefit gained in patients with early aggressive RA who undergo longterm treatment with etanercept [26324784] Objectives : It is well recognized that medication adherence of rheumatoid arthritis ( RA ) patients is often poor . As less attention has been paid to physicians ’ adherence to targeted treatment , we aim ed to investigate how it affects outcomes in aggressively treated early RA patients . Method : In the new Finnish RA Combination Therapy ( NEO-RACo ) trial , 99 patients with early active RA were treated , targeting remission , with a combination of methotrexate , sulfasalazine , hydroxychloroquine , and low-dose prednisolone for 2 years , and r and omized to receive infliximab or placebo for the initial 6 months . After 2 years , therapy was unrestricted while remission was still targeted . Patients were divided into tertiles by physicians ’ adherence to treat-to-target , which was evaluated with a scoring system during the initial 2 years . After 5 years of follow-up , the between-tertile differences in remission rates , 28-joint Disease Activity Score ( DAS28 ) levels , radiological changes , cumulative days off work , and the use of anti-rheumatic medication were assessed . Results : Follow-up data were available for 93 patients . Physicians ’ good adherence was associated with improved remission rates at 2–4 years and lower DAS28 levels throughout the follow-up . In a multivariable model , physicians ’ adherence was the most important predictor of remission at 3 months and 2 years ( p < 0.001 for both ) . Between 2 and 5 years , biologics were used more often in the tertile of low adherence compared with the other two groups ( p = 0.024 ) . No significant differences were observed in radiological progression and cumulative days off work . Conclusions : Physicians ’ good adherence is associated with improved remission rates and lesser use of biologics in early RA [27494516] OBJECTIVES To study the effects of neglecting intra-articular glucocorticoid injections ( IAGCIs ) into swollen joints in early rheumatoid arthritis ( RA ) . METHODS Ninety-nine patients with early , DMARD naive RA were treated , aim ing at remission , with methotrexate , sulfasalazine , hydroxychloroquine , low-dose oral prednisolone and , when needed , IAGCIs for 2 years , and r and omised to receive infliximab or placebo from weeks 4 to 26 . During each of the 15 study visits , patients were scored retrospectively 0.2 - 0.4 points ( depending on the number of non-injected joints ) if IAGCIs to all swollen joints were not given . Patients were divided into tertiles by their cumulative scores for neglected injections ( CSNI ) over 24 months . 28-joint disease activity score ( DAS28 ) area under the curve ( AUC ) between 0 - 24 months , remission rates , changes in quality of life , and radiological changes during the follow-up were assessed . Trends across tertiles of CSNI were tested with generalised linear models . RESULTS Higher CSNI was associated with lower strict remission rates ( p=0.005 ) , and lower quality of life ( p=0.004 ) at 24 months , and higher DAS28 AUC ( p<0.001 ) during the follow-up . At 24 months , DAS28 remission rates were 90 % , 93 % and 76 % ( p=0.081 ) , and strict remission rates were 74 % , 77 % and 39 % by tertiles of CSNI . No significant differences were observed in radiological progression ( p=0.089 ) . IAGCIs were well tolerated . CONCLUSIONS Neglecting IAGCIs into swollen joints is associated with lower remission rates , higher disease activity , and lower quality of life . Hence , IAGCIs should be used as an integral part of the targeted treatment of early RA [11096165] BACKGROUND Etanercept , which blocks the action of tumor necrosis factor , reduces disease activity in patients with long-st and ing rheumatoid arthritis . Its efficacy in reducing disease activity and preventing joint damage in patients with active early rheumatoid arthritis is unknown . METHODS We treated 632 patients with early rheumatoid arthritis with either twice-weekly subcutaneous etanercept ( 10 or 25 mg ) or weekly oral methotrexate ( mean , 19 mg per week ) for 12 months . Clinical response was defined as the percent improvement in disease activity according to the criteria of the American College of Rheumatology . Bone erosion and joint-space narrowing were measured radiographically and scored with use of the Sharp scale . On this scale , an increase of 1 point represents one new erosion or minimal narrowing . RESULTS As compared with patients who received methotrexate , patients who received the 25-mg dose of etanercept had a more rapid rate of improvement , with significantly more patients having 20 percent , 50 percent , and 70 percent improvement in disease activity during the first six months ( P<0.05 ) . The mean increase in the erosion score during the first 6 months was 0.30 in the group assigned to receive 25 mg of etanercept and 0.68 in the methotrexate group ( P= 0.001 ) , and the respective increases during the first 12 months were 0.47 and 1.03 ( P=0.002 ) . Among patients who received the 25-mg dose of etanercept , 72 percent had no increase in the erosion score , as compared with 60 percent of patients in the methotrexate group ( P=0.007 ) . This group of patients also had fewer adverse events ( P=0.02 ) and fewer infections ( P= 0.006 ) than the group that was treated with methotrexate . CONCLUSIONS As compared with oral methotrexate , subcutaneous [ corrected ] etanercept acted more rapidly to decrease symptoms and slow joint damage in patients with early active rheumatoid arthritis [26489704] Objectives To study clinical and radiographic outcomes after withdrawing 1 year 's adalimumab induction therapy for early rheumatoid arthritis ( eRA ) added to a methotrexate and intra-articular triamcinolone hexacetonide treat-to-target strategy ( NCT00660647 ) . Methods Disease-modifying antirheumatic drug (DMARD)-naive patients with eRA started methotrexate ( 20 mg/week ) and intra-articular triamcinolone ( 20 mg/ml ) for 2 years . In addition , they were r and omised to receive placebo adalimumab ( DMARD group , n=91 ) or adalimumab ( 40 mg/every other week ) ( DMARD+adalimumab group , n=89 ) during the first year . Sulfasalazine and hydroxychloroquine were added if disease activity persisted after 3 months . During year 2 , synthetic DMARDs continued . Adalimumab was (re)initiated if active disease reoccurred . Clinical response , remission , disability , quality of life and radiographic changes were assessed . Results One year after adalimumab withdrawal , treatment profiles and clinical responses did not differ between groups . In the DMARD/DMARD+adalimumab groups , the median 2-year methotrexate dose was 20/20 mg/week ( p=0.45 ) , triple DMARD therapy had been initiated in 33/27 patients ( p=0.49 ) , adalimumab was (re)initiated in 12/12 patients and cumulative triamcinolone dose was 160/120 mg ( p=0.15 ) . The treatment target ( disease activity score , 4 variables , C-reactive protein ( DAS28CRP ) ≤3.2 or DAS28>3.2 without swollen joints ) was achieved at all visits in ≥85 % of patients in year 2 ; remission rates were DAS28CRP<2.6:69%/66 % ; Clinical Disease Activity Index ≤2.8:55%/57 % ; Simplified Disease Activity Index < 3.3:54%/49 % ; American College of Rheumatology/European League against Rheumatism ( 28 joints):44%/45 % ( p=0.66–1.00 ) . Radiographic progression ( Δtotal Sharp score/year ) was similar 1.31/0.53 ( p=0.12 ) . Erosive progression ( Δerosion score (ES)/year ) was year 1:0.57/0.06 ( p=0.02 ) ; year 2:0.38/0.05 ( p=0.005 ) . Proportion of patients without erosive progression ( ΔES≤0 ) was year 1 : 59%/76 % ( p=0.03 ) ; year 2:64%/79 % ( p=0.04 ) . Conclusions An aggressive triamcinolone and synthetic DMARD treat-to-target strategy in eRA provided excellent 2-year clinical and radiographic disease control independent of adalimumab induction therapy . ES progression was slightly less during and following adalimumab induction therapy . Trial registration number NCT00660647 [22045836] Objective . Rheumatoid arthritis ( RA ) is associated with significant impairments in health-related quality of life ( HRQOL ) . We evaluated patient-reported outcomes including HRQOL outcomes following adalimumab plus methotrexate ( MTX ) therapy in patients with early RA . Methods . PREMIER was a phase III , multicenter , r and omized , double-blind , active-comparator clinical trial in early RA . Patients aged ≥ 18 years were r and omly assigned to receive adalimumab 40 mg every other week ( eow ) plus weekly MTX , weekly MTX , or adalimumab 40 mg eow for 104 weeks . American College of Rheumatology ( ACR ) criteria were used to evaluate clinical efficacy and response . Outcomes were assessed using the Health Assessment Question naire Disability Index ( HAQ-DI ) , Short-Form 36 Health Survey ( SF-36 ) , Short-Form 6 Dimension ( SF-6D ) , visual analog scale ( VAS ) assessment s of global disease activity ( patient ’s global assessment ; PtGA ) and pain , Functional Assessment of Chronic Illness Therapy-Fatigue ( FACIT-F ) , and Health Utility Index Mark 3 ( HUI-3 ) . Results . Of 799 patients enrolled , 268 received adalimumab plus MTX , 257 received MTX monotherapy , and 274 received adalimumab monotherapy . Patients treated with adalimumab plus MTX demonstrated significant baseline to Week 104 improvements in HAQ-DI ( p < 0.0001 ) , SF-36 Physical Component Summary ( p < 0.0001 ) , 4 SF-36 domains [ physical function ( p < 0.0001 ) , bodily pain ( p < 0.0001 ) , vitality ( p = 0.0139 ) , role limitations -physical ( p = 0.0005 ) ] , SF-6D ( p = 0.0152 ) , VAS-PtGA ( p < 0.0001 ) , VAS-pain ( p < 0.0001 ) , FACIT-F ( p < 0.0001 ) , and HUI-3 ( p = 0.0034 ) scores versus patients treated with MTX monotherapy . Both SF-6D and HUI-3 were found to be sensitive preference-based measures for assessing the effects of treatment on multidimensional function . No clinical ly meaningful differences between adalimumab and MTX monotherapy groups were observed for most measures . For each measure , there was significant association between HRQOL improvement and ACR clinical response . Conclusion . Adalimumab plus MTX significantly improved physical functioning and HRQOL in patients with early RA over 2 years of treatment . ( Clinical Trials.gov identifier NCT00195663 ) [26087654] Objectives : To investigate the levels of interleukin (IL)-23 in patients with early rheumatoid arthritis ( eRA ) and the effect of anti-tumour necrosis factor (anti-TNF)-α treatment on IL-23 levels . Method : Treatment-naïve eRA patients from the OPERA cohort were included ( n = 151 ) . Patients were r and omized to methotrexate ( MTX ) plus adalimumab ( ADA ; n = 75 ) or MTX plus placebo-ADA ( PLA ; n = 76 ) . Plasma sample s were obtained at baseline and at months 3 , 6 , and 12 together with values for C-reactive protein ( CRP ) , the 28-joint Disease Activity Score based on CRP ( DAS28CRP ) , scores on the Clinical Disease Activity Index ( CDAI ) and the Simplified Disease Activity Index ( SDAI ) , visual analogue scale ( VAS ) for pain/fatigue/physician global and total Sharp/van der Heijde score ( TSS ) . IL-23 was measured at each time point . Results : IL-23 levels decreased significantly in the ADA group from 20.6 pg/mL ( IQR 13.1–32.7 pg/mL ) at baseline to 18 pg/mL ( IQR 7.2–25.0 pg/mL ) at 12 months ( p < 0.01 ) . No significant decrease in IL-23 level was observed in the PLA group . No associations between baseline IL-23 levels and measures of disease activity ( DAS28CRP , CRP , CDAI , or SDAI ) at 12 or 24 months were present in the treatment groups . Baseline IL-23 correlated inversely with changes in TSS and symptom duration before diagnosis . Conclusions : Our data show increased baseline levels and a significant decrease in IL-23 levels in eRA patients treated with anti-TNF-α . The inverse correlation with duration of symptoms before diagnosis supports the importance of IL-23 in the pre clinical disease development of RA [27089068] Context A treat-to-target strategy , or treatment to achieve low disease activity , has been associated with improved outcomes among patients with early active rheumatoid arthritis ( RA ) . Long-term data on this approach are lacking . Contribution This r and omized , controlled trial compared 4 treat-to-target strategies for early active RA over 10 years . Most patients had persistently reduced disease activity scores , improved functional status , and limited joint damage during follow-up . They had survival similar to that of the general Dutch population . Caution The trial lacked a nontargeted treatment strategy . Implication Potential outcomes of a treat-to-target approach for early RA include sustained clinical improvement , drug-free remission , and normalized survival . Suppression of inflammation in patients with rheumatoid arthritis ( RA ) is associated with clinical improvement and prevention of radiographic joint damage . Rapid suppression can be achieved with initial combination therapy , including synthetic disease-modifying antirheumatic drugs and corticosteroids or a tumor necrosis factor- inhibitor ( 17 ) . In addition , tightly controlled targeted treatment ( that is , frequent measurements of disease activity with treatment adjustments aim ing to achieve a predefined target ) results in better outcomes than routine care ( 8 , 9 ) . The BeSt ( Beh and elStrategien in reumatode artritis ) study integrated a treat-to-target concept to achieve low disease activity ( defined as a disease activity score [ DAS ] 2.4 ) with a comparison of 4 dynamic treatment strategies . Patients with early active RA were r and omly assigned to sequential monotherapy , step-up combination therapy , or initial combination therapy with either prednisone or an antitumor necrosis factor- agent ( infliximab ) . Based on measurements of disease activity every 3 months , the medication dosage was increased when the DAS was higher than 2.4 and tapered if DAS was persistently 2.4 or less . The study compared the clinical , radiographic , and toxicity outcomes of these strategies over time . We report on these outcomes among participants during 10-year follow-up and compare their survival with that of the general population . Methods Design Overview The r and omized , multicenter , assessor-blinded BeSt study ( 2 ) was design ed by Dutch rheumatologists to determine in which order available antirheumatic medication could best be used to treat patients with newly diagnosed RA , aim ing at low disease activity over 10 years . The original study protocol and amendments for study extension after 2 and 5 years ( Supplements 1 through 3 ) were approved by the medical ethics committees of all participating hospitals . All patients gave written informed consent . Supplement . Data Supplement Setting and Participants The study enrolled 508 patients aged 18 years or older with early active RA according to the revised 1987 American College of Rheumatology criteria for RA ( 10 ) , with symptom duration of fewer than 2 years . They were recruited in 18 nonuniversity and 2 university hospitals in the Netherl and s between 2000 and 2002 . Exclusion criteria encompassed contraindications to the antirheumatic medications used in the study protocol ( Appendix 1 ) ( 2 , 11 ) . R and omization and Interventions Patients were allocated to 1 of 4 dynamic treatment strategies by variable block r and omization , stratified by center : strategy 1 , sequential monotherapy ; strategy 2 , step-up combination therapy ( both starting with methotrexate monotherapy ) ; strategy 3 ; initial combination therapy with methotrexate , sulfasalazine , and prednisone ; and strategy 4 , initial combination therapy with methotrexate and infliximab . For all strategies , subsequent treatment adjustments were specified in the study protocol for patients with an inadequate response ( Appendix Figure 1 ) . Over 10 years , treatment response was measured every 3 months using the DAS ( 12 ) based on a swollen joint count in 44 joints , a tender joint count in 53 joints ( Ritchie articular index ) ( 13 ) , erythrocyte sedimentation rate , and patient 's assessment of global health on a visual analogue scale ( 0 to 100 mm ) ( 12 ) . A DAS of 2.4 or less , indicating low disease activity ( 14 ) , was set as the treatment goal . Treatment was intensified ( medication changed or dosage increased , according to the treatment strategy ) at each study visit that the DAS was greater than 2.4 ( Appendix Figure 1 ) . In case of a continued good response ( DAS 2.4 for 6 months ) , dosage was tapered to a maintenance dose ( if DAS remained < 1.6 for 6 months ; defined as remission ) ( 15 ) and eventually discontinued ( defined as drug-free remission [ DFR ] ) ( Appendix 2 ) . Appendix Figure 1 . Flow diagram of treatment steps per strategy . The figure shows the required treatment intensification steps for each strategy as long as the DAS remained > 2.4 when measured every 3 mo . In all 4 strategies , patients may progress from one treatment step to the next at different times , depending on individual DAS results determined at observation every 3 mo . Patients receiving infliximab ( who receive their dose every 8 wk ) had additional DAS measurements 1 wk before each infusion . These measurements dictated if the next dose needed to be increased . Doses started at 3 mg/kg of body weight . If the DAS was greater than 2.4 , the dose was increased in a stepwise manner to 6 mg/kg , then 7.5 mg/kg , and finally 10 mg/kg ( always rounded to the nearest hundredth ) . The dosage could be tapered if DAS calculations determined every 3 mo were 2.4 or less for at least 6 mo consecutively . Medication dosages were as follows : azathioprine , 2 mg/kg to 3 mg/kg per day ; cyclosporine A , 2.5 mg/kg per day ; methylprednisolone , 3 doses of 120 mg in weeks 1 , 4 , and 8 ; gold , 50 mg/wk ; hydroxychloroquine , 200 mg/d ; infliximab , dose as indicated every 8 wk ; leflunomide , 20 mg/d ; methotrexate , dose as indicated every week ; prednisone , 7.5 mg/d unless indicated otherwise ; sulfasalazine , 2000 mg/d . DAS= disease activity score . Outcomes and Follow-up The patients were clinical ly assessed every 3 months at study visits during the 10-year follow-up . Functional status , laboratory tests , and adverse events ( AEs ) were assessed . Functional ability was measured using the Health Assessment Question naire ( HAQ ) ( range , 0 [ best ] to 3 [ worst ] ) ( 16 ) . Conventional radiography of h and s and feet were performed annually to assess joint damage progression . All radiographs from baseline to year 10 were scored by 2 independent blinded readers using the modified Sharpvan der Heijde score ( SHS ) ( range 0 [ best ] to 448 [ worst ] ) ( 17 ) in 1 session in r and om order . The intraclass correlation coefficient between the 2 readers was 0.96 ( 95 % CI , 0.95 to 0.97 ) . The mean score of the 2 readers was used for the analysis . The AEs , either reported during visits or apparent in continued laboratory assessment s every 3 months , and serious AEs ( SAEs ) , which also included death during follow-up , were recorded during the trial . For patients who dropped out of the study , life and death status from inclusion to year 10 was obtained from the hospital ( where they enrolled ) , general practitioner , or municipality of the patient 's residence . Those who emigrated and could not be traced thereafter were censored from the date of emigration ( n= 6 ) . One patient could not be located after loss to follow-up and was also censored from the last moment of contact . Survival data of the general Dutch population were acquired from Statistics Netherl and s. Statistical Analysis For each analysis , patients were analyzed in their allocated treatment strategy at baseline , regardless of the number of treatment steps during follow-up . Time to dropout was compared among the treatment strategies with the log-rank test . The HAQ score , low disease activity , remission rate , DFR , SHS , and initial treatment step at year 10 ( intention-to-treat and completer analyses ) were reported separately for each strategy . After multiple imputation of the DAS , the percentages of low disease activity ( DAS 2.4 ) and remission ( DAS < 1.6 ) at year 10 were estimated and compared among the strategies . The imputation model included terms for observed DAS , HAQ score , r and omization strategy , age , sex , anticitrullinated peptide antibody , rheumatoid factor , SHS , and treatment step ; 10 data sets were imputed ( Supplement 4 ) . The imputation method assumed the missing values to be missing at r and om . Sensitivity analyses using controlled imputation methods ( 18 ) tested the robustness of this assumption against violations ( Supplement 4 ) . The HAQ score was analyzed over time using a linear mixed model , taking into account repeated measurements , with a Toeplitz covariance type under the assumption of equally spaced visits ( scheduled every 3 months ) . This model included time as a continuous variable , treatment , and a time-by-treatment interaction term . Sensitivity analyses were also performed for this outcome ( Supplement 4 ) . Radiographic progression at 10 years ( defined as an increase in SHS from baseline to year 10 ) was observed in patients who completed the study using a cumulative probability plot . Radiographic progression over time was analyzed by using a weighted generalized estimating equation ( GEE ) with a negative binomial working distribution , AR1 ( that is , autoregressive ) working correlation , and robust estimation of SEs . This analysis is valid under the missing-at-r and om assumption and was chosen because of the skewed nature of the SHS ( 18 ) . Weights per patient per year were found by using a logistic regression that modeled the inverse probability of a patient having radiographic data available at that measurement time ( Supplement 5 ) . Survival in the study population was compared with the general population ( matched by sex , age , and calendar year ) using the st and ardized mortality ratio : ( observed deathsexpected deaths ) ( 19 ) . KaplanMeier curves and the log-rank test were used to compare survival among the treatment strategies . Cox regression analysis was used to identify [29142030] Objective . The aim was to identify plasma ( i.e. , cell-free ) microRNA ( miRNA ) predicting antitumor necrosis and /or methotrexate ( MTX ) treatment response in patients enrolled in an investigator-initiated , prospect i ve , double-blinded , placebo-controlled trial ( The OPERA study , NCT00660647 ) . Methods . We included 180 disease-modifying antirheumatic drug – naive patients with early rheumatoid arthritis ( RA ) r and omized to adalimumab ( ADA ; n = 89 ) or placebo ( n = 91 ) in combination with MTX . Plasma sample s before and 3 months after treatment initiation were analyzed for 91 specific miRNA by quantitative reverse transcriptase-polymerase chain reaction on microfluidic dynamic arrays . A linear mixed-effects model was used to test for associations between pretreatment miRNA and changes in miRNA expression and American College of Rheumatology/European League Against Rheumatism ( ACR/EULAR ) Boolean ( 28 joints ) remission at 3 and 12 months , applying false discovery rate correction for multiple testing . Using leave-one-out cross validation , we built predictive multivariate miRNA models and estimated classification performances using receiver-operating characteristics ( ROC ) curves . Results . In the ADA group , a higher pretreatment level of miR-27a-3p was significantly associated with remission at 12 months . The level decreased in remitting patients between pretreatment and 3 months , and increased in nonremitting patients . No associations were found in the placebo group receiving only MTX . Two multivariate miRNA models were able to predict response to ADA treatment after 3 and 12 months , with 63 % and 82 % area under the ROC curves , respectively . Conclusion . We identified miR-27a-3p as a potential predictive biomarker of ACR/EULAR remission in patients with early RA treated with ADA in combination with MTX . We conclude that pretreatment plasma-miRNA profiles may be of predictive value , but the results need confirmation in independent cohorts [29985080] Objectives : Measurement of serum biomarkers at disease onset may improve prediction of disease course in patients with early rheumatoid arthritis ( RA ) . We evaluated the multi-biomarker disease activity ( MBDA ) score and early changes in MBDA score for prediction of 28-joint Disease Activity Score based on C-reactive protein ( DAS28-CRP ) remission and radiographic progression in the double-blinded OPERA trial . Method : Treatment-naïve RA patients ( N = 180 ) with moderate or high DAS28 were r and omized to methotrexate ( MTX ) + adalimumab ( n = 89 ) or MTX + placebo ( n = 91 ) in combination with glucocorticoid injection into swollen joints . X-rays of h and s and feet were evaluated at months 0 and 12 ( n = 164 ) by the total Sharp van der Heijde score ( TSS ) . The smallest detectable change ( 1.8 TSS units ) defined radiographic progression ( ∆TSS ≥ 2 ) . Clinical remission ( DAS28-CRP < 2.6 ) was assessed at baseline and 6 months . MBDA score was determined at 0 and 3 months and tested in a multivariable logistic regression model for predicting DAS28 remission at 6 months and radiographic progression at 1 year . Results : Baseline MBDA score was independently associated with radiographic progression at 1 year [ odds ratio ( OR ) = 1.03/unit , 95 % confidence interval ( CI ) = 1.01–1.06 ] , and changes in MBDA score from baseline to 3 months with clinical remission at 6 months [ OR = 0.98/unit , 95 % CI 0.96–1.00 ) . In anti-cyclic citrullinated peptide antibody (anti-CCP)-positive patients , 35 of 89 with high MBDA score ( > 44 ) showed radiographic progression ( PPV = 39 % ) , compared with 0 of 15 patients ( NPV = 100 % ) with low/moderate MBDA score ( ≤ 44 ) ( p = 0.003 ) . Conclusion : Early changes in MBDA score were associated with clinical remission based on DAS28-CRP at 6 months . In anti-CCP-positive patients , a non-high baseline MBDA score ( ≤ 44 ) had a clinical value by predicting very low risk of radiographic progression at 12 months [6085639] Background In the present study , we explored the effects of immediate induction therapy with the anti-tumour necrosis factor (TNF)α antibody infliximab ( IFX ) plus methotrexate ( MTX ) compared with MTX alone and with placebo ( PL ) in patients with very early inflammatory arthritis . Methods In an investigator-initiated , double-blind , r and omised , placebo-controlled , multi-centre trial ( IS RCT N21272423 , http://www.is rct n.com/IS RCT N21272423 ) , patients with synovitis of 12 weeks duration in at least two joints underwent 1 year of treatment with IFX in combination with MTX , MTX monotherapy , or PL r and omised in a 2:2:1 ratio . The primary endpoint was clinical remission after 1 year ( sustained for at least two consecutive visits 8 weeks apart ) with remission defined as no swollen joints , 0–2 tender joints , and an acute-phase reactant within the normal range . Results Ninety patients participated in the present study . At week 54 ( primary endpoint ) , 32 % of the patients in the IFX + MTX group achieved sustained remission compared with 14 % on MTX alone and 0 % on PL . This difference ( p < 0.05 over all three groups ) was statistically significant for IFX + MTX vs PL ( p < 0.05 ) , but not for IFX + MTX vs MTX ( p = 0.10 ) , nor for MTX vs PL ( p = 0.31 ) . Remission was maintained during the second year on no therapy in 75 % of the IFX + MTX patients compared with 20 % of the MTX-only patients . Conclusions These results indicate that patients with early arthritis can benefit from induction therapy with anti-TNF plus MTX compared with MTX alone , suggesting that intensive treatment can alter the disease evolution . Trial registration The trial was registered at http://www.is rct n.com/IS RCT N21272423 on 4 October 2007 ( date applied)/12 December 2007 ( date assigned ) . The first patient was included on 24 October 2007 [27114561] OBJECTIVES To evaluate the effects of adalimumab plus MTX ( ADA + MTX ) vs MTX monotherapy on work-related outcomes in early RA patients with elevated risk of employment loss . METHODS A post hoc analysis at weeks 26 and 24 from the Optimal Protocol for Treatment Initiation with Methotrexate and Adalimumab ( OPTIMA ) and PRevention Of Work Disability ( PROWD ) trials , respectively , was conducted in MTX-naïve RA patients r and omized to ADA + MTX or placebo ( PBO ) + MTX . Work instability was assessed using the RA-Work Instability Scale ( RA-WIS ) and work productivity was measured with the Work Productivity and Activity Impairment Question naire . Employed patients with a baseline RA-WIS score ⩾10 , indicating medium to high risk for job loss , were included ( OPTIMA , n = 320 ; PROWD , n = 124 ) . RESULTS Patients receiving ADA + MTX in OPTIMA had significantly greater improvements in RA-WIS compared with PBO + MTX ( mean change -7.22 vs -5.23 , respectively ) . Significantly higher percentages of patients in the ADA + MTX group experienced improvements in one or more risk category ( 58 vs 47 % ) and ⩾5 ( 55 vs 43 % ) , ⩾7 ( 47 vs 35 % ) and ⩾9 ( 42 % vs 26 % ) points in their RA-WIS score . These trends were seen in PROWD but were not significant . In OPTIMA , patients receiving ADA + MTX showed significant changes in percentage points from baseline vs PBO + MTX in activity impairment , presenteeism and overall work impairment ( -32.0 vs -23.7 , -24.6 vs -17.1 , -27.3 vs -18.3 , respectively ) . CONCLUSIONS Among early RA patients with elevated risk of employment loss , ADA + MTX therapy was associated with a significant reduction in work instability vs PBO + MTX . Significantly greater percentages of patients receiving ADA + MTX therapy achieved clinical ly meaningful improvements in their RA-WIS scores [26091907] Objective To evaluate the construct validity of the rheumatoid arthritis MRI score ( RAMRIS ) erosion evaluation as structural damage end point and to assess the potential impact of incorporation in clinical trials . Methods In a r and omised trial of early methotrexate-naïve RA ( GO-BEFORE ) , RAMRIS scores were determined from MRIs and van der Heijde-Sharp ( vdHS ) scores from radiographs , at baseline , week 12 , week 24 and week 52 . Progression in damage scores was defined as change > 0.5 . Associations of X-ray and MRI outcomes with clinical features were evaluated for convergent validity . Iterative Wilcoxon rank sum tests and tests of proportion estimated the sample size required to detect differences between combination therapy ( methotrexate+golimumab ) and methotrexate-monotherapy arms in ( A ) change in damage score and ( B ) proportion of patients progressing . Results Patients with early MRI progression had higher DAS28 , C reactive protein ( CRP ) and vdHS at baseline , and higher 2-year HAQ . Associations were similar to those with 1-year vdHS progression . Differences in change in structural damage between treatment arms achieved significance with fewer subjects when 12-week or 24-week MRI erosion score was the outcome ( 150 patients ; 100 among an enriched sample with baseline-synovitis > 5 ) compared with the 52-week vdHS ( 275 patients ) . Differences in the proportion progressing could be detected in 234 total subjects with 12-week MRI in an enriched sample whereas 1-year X-ray required between 468 and 1160 subjects . Conclusions Early MRI erosion progression is a valid measure of structural damage that could substantially decrease sample size and study duration if used as structural damage end point in RA clinical trials

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### Context: [19644849] OBJECTIVE To assess the safety and efficacy of golimumab in methotrexate (MTX)-naive patients with active rheumatoid arthritis ( RA ) . METHODS MTX-naive patients with RA ( n = 637 ) were r and omized to receive placebo plus MTX ( group 1 ) , golimumab 100 mg plus placebo ( group 2 ) , golimumab 50 mg plus MTX ( group 3 ) , or golimumab 100 mg plus MTX ( group 4 ) . Subcutaneous injections of golimumab or placebo were administered every 4 weeks . The dosage of MTX/placebo capsules started at 10 mg/week and escalated to 20 mg/week . The primary end point , the proportion of patients meeting the American College of Rheumatology 50 % improvement criteria ( achieving an ACR50 response ) at week 24 , required significant differences between groups 3 and 4 combined ( combined group ) versus group 1 and significant differences in a pairwise comparison ( group 3 or group 4 versus group 1 ) . RESULTS An intent-to-treat ( ITT ) analysis of the ACR50 response at week 24 did not show a significant difference between the combined group and group 1 ( 38.4 % and 29.4 % , respectively ; P=0.053 ) , while a post hoc modified ITT analysis ( excluding 3 untreated patients ) of the ACR50 response showed statistically significant differences between the combined group and group 1 ( 38.5 % versus 29.4 % ; P=0.049 ) and between group 3 ( 40.5 % ; P=0.038 ) but not group 4 ( 36.5 % ; P=0.177 ) and group 1 . Group 2 was noninferior to group 1 for the ACR50 response at week 24 ( 33.1 % ; 95 % confidence interval lower bound -5.2 % ; predefined delta value for noninferiority -10 % ) . The combination of golimumab plus MTX demonstrated a significantly better response compared with placebo plus MTX in most other efficacy parameters , including response/remission according to the Disease Activity Score in 28 joints . Serious adverse events occurred in 7 % , 3 % , 6 % , and 6 % of patients in groups 1 , 2 , 3 , and 4 , respectively . CONCLUSION Although the primary end point was not met , the modified ITT analysis of the primary end point and other prespecified efficacy measures demonstrated that the efficacy of golimumab plus MTX is better than , and the efficacy of golimumab alone is similar to , the efficacy of MTX alone in reducing RA signs and symptoms in MTX-naive patients , with no unexpected safety concerns [27190098] Objective To compare the value that rheumatologists across Europe attach to patients ' preferences and economic aspects when choosing treatments for patients with rheumatoid arthritis . Methods In a discrete choice experiment , European rheumatologists chose between two hypothetical drug treatments for a patient with moderate disease activity . Treatments differed in five attributes : efficacy ( improvement and achieved state on disease activity ) , safety ( probability of serious adverse events ) , patient 's preference ( level of agreement ) , medication costs and cost-effectiveness ( incremental cost-effectiveness ratio ( ICER ) ) . A Bayesian efficient design defined 14 choice sets , and a r and om parameter logit model was used to estimate relative preferences for rheumatologists across countries . Cluster analyses and latent class models were applied to underst and preference patterns across countries and among individual rheumatologists . Results Responses of 559 rheumatologists from 12 European countries were included in the analysis ( 49 % females , mean age 48 years ) . In all countries , efficacy dominated treatment decisions followed by economic considerations and patients ’ preferences . Across countries , rheumatologists avoided selecting a treatment that patients disliked . Latent class models revealed four respondent profiles : one traded off all attributes except safety , and the remaining three classes disregarded ICER . Among individual rheumatologists , 57 % disregarded ICER and these were more likely from Italy , Romania , Portugal or France , whereas 43 % disregarded uncommon/rare side effects and were more likely from Belgium , Germany , Hungary , the Netherl and s , Norway , Spain , Sweden or UK . Conclusions Overall , European rheumatologists are willing to trade between treatment efficacy , patients ' treatment preferences and economic considerations . However , the degree of trade-off differs between countries and among individuals [4151516] Objectives To evaluate the efficacy and safety of adalimumab+methotrexate ( MTX ) in Japanese patients with early rheumatoid arthritis ( RA ) who had not previously received MTX or biologics . Methods This r and omised , double-blind , placebo-controlled , multicentre study evaluated adalimumab 40 mg every other week+MTX 6–8 mg every week versus MTX 6–8 mg every week alone for 26 weeks in patients with RA ( ≤2-year duration ) . The primary endpoint was inhibition of radiographic progression ( change ( Δ ) from baseline in modified total Sharp score ( mTSS ) ) at week 26 . Results A total of 171 patients received adalimumab+MTX ( mean dose , 6.2±0.8 mg/week ) and 163 patients received MTX alone ( mean dose , 6.6±0.6 mg/week , p<0.001 ) . The mean RA duration was 0.3 years and 315 ( 94.3 % ) had high disease activity ( DAS28>5.1 ) . Adalimumab+MTX significantly inhibited radiographic progression at week 26 versus MTX alone ( ΔmTSS , 1.5±6.1 vs 2.4±3.2 , respectively ; p<0.001 ) . Significantly more patients in the adalimumab+MTX group ( 62.0 % ) did not show radiographic progression ( ΔmTSS≤0.5 ) versus the MTX alone group ( 35.4 % ; p<0.001 ) . Patients treated with adalimumab+MTX were significantly more likely to achieve American College of Rheumatology responses and achieve clinical remission , using various definitions , at 26 weeks versus MTX alone . Combination therapy was well tolerated , and no new safety signals were observed . Conclusions Adalimumab in combination with low-dose MTX was well tolerated and efficacious in suppressing radiographic progression and improving clinical outcomes in Japanese patients with early RA and high disease activity [22753402] Objective Early treatment of patients with rheumatoid arthritis ( RA ) with combination treatment starting with methotrexate , sulfasalazine , hydroxychloroquine and prednisolone ( FIN-RACo strategy ) is superior to monotherapy . A study was undertaken to determine whether infliximab ( INFL ) added to intensified FIN-RACo treatment for the initial 6 months improves the 2-year outcome . Methods 99 patients with early untreated active RA were enrolled in an investigator-initiated , r and omised , double-blind , multicentre , parallel-group trial . Primary outcomes were remission and radiological changes at 2 years . All patients started with FIN-RACo . In addition , they were r and omised to receive INFL or placebo ( Pla ) from weeks 4 to 26 . Results At 24 months , 66 % and 53 % , respectively , of the patients in the FIN-RACo+INFL and FIN-RACo+Pla groups were in remission according to the modified American College of Rheumatology ( ACR ) criteria ( p=0.19 ) , 26 % and 10 % were in sustained modified ACR remission ( p=0.042 ) and 82 % in both groups were in remission by 28-joint disease activity score ( not significant ) . Mean changes in the total Sharp-van der Heijde score were 0.2 and 1.4 , respectively ( p=0.0058 ) . Conclusions Most patients with early active RA achieve clinical remission and develop negligible joint damage with the intensified FIN-RACo regimen . Adding INFL for the first 6 months delays radiological progression [24618266] Objective To compare the efficacy of etanercept ( ETN ) and methotrexate ( MTX ) versus MTX monotherapy for remission induction in patients with early inflammatory arthritis . Methods In a 78-week multicentre r and omised placebo-controlled superiority trial , 110 DMARD-naïve patients with early clinical synovitis ( ≥1 tender and swollen joint , and within 3 months of diagnosis ) and either rheumatoid factor , anticitrullinated protein antibodies or shared epitope positive were r and omised 1:1 to receive MTX+ETN or MTX+placebo ( PBO ) for 52 weeks . Injections ( ETN or PBO ) were stopped in all patients at week 52 . In those with no tender or swollen joints ( NTSJ ) for > 26 weeks , injections were stopped early . If patients had NTSJ > 12 weeks after stopping the injections , MTX was weaned . The primary endpoint was NTSJ at week 52 . Results No statistically significant difference was seen for the primary endpoint ( NTSJ at week 52 ( 32.5 % vs 28.1 % [ adjusted OR 1.32 ( 0.56 to 3.09 ) , p=0.522 ] ) in the MTX+ETN and MTX+PBO groups , respectively ) . The secondary endpoints did not differ between groups at week 52 or 78 . Exploratory analyses showed a higher proportions of patients with DAS28-CRP<2.6 in the MTX+ETN group at week 2 ( 38.5 % vs 9.2 % , adjusted OR 8.87 ( 2.53 to 31.17 ) , p=0.001 ) and week 12 ( 65.1 % vs 43.8 % , adjusted OR 2.49 ( 1.12 to 5.54 ) , p=0.026 ) . Conclusions In this group of patients with early inflammatory arthritis , almost a third had no tender , swollen joints after 1 year . MTX+ETN was not superior to MTX monotherapy in achieving this outcome . Clinical responses , however , including DAS28-CRP<2.6 , were achieved earlier with MTX+ETN combination therapy . Trial registration number The EMPIRE trial is registered on the following trial registries : Eudract-2005 - 005467 - 29 ; IS RCT N 55428162 ( http://www.controlled-trials.com/IS RCT N55428162/EMPIRE ) . The full trial protocol can be obtained from the corresponding author [28267648] HighlightsEarly rheumatoid arthritis patients have increased levels of soluble CD83 in plasma . The release of soluble CD83 is independent of TNF‐&agr;.In rheumatoid arthritis sCD83 levels are higher in synovial fluid than in plasma . The level of soluble CD83 in plasma does not correlate with disease activity . CD83 is mainly expressed intracellularly in a variety of different cell types . Abstract Rheumatoid arthritis ( RA ) is an autoimmune disease which may lead to severe disabilities due to structural joint damage and extraarticular manifestations The dendritic cell marker CD83 belongs to the immunoglobulin superfamily and has previously been associated with autoimmune diseases . In RA the levels of soluble CD83 ( sCD83 ) are elevated in synovial fluid , however little is known about CD83 expression and regulation in RA . Therefore , we studied how CD83 is expressed in RA and further evaluated the effect of anti‐TNF‐&agr ; therapy hereon . Early RA patients were r and omized to conventional disease modifying anti‐rheumatic drugs with or without additional anti‐TNF‐&agr ; therapy . Rheumatoid arthritis patients had increased levels of sCD83 in plasma compared with healthy volunteers . The increase in sCD83 plasma levels were unaffected by anti‐TNF‐&agr ; therapy . In chronic RA patients the levels of sCD83 were higher in synovial fluid than in plasma , and only a limited amount of membrane bound CD83 expression was detected on the surface of cells from peripheral blood and synovial fluid . Finally , confocal microscopy of RA synovial membranes revealed that CD83 was mainly localized intracellularly in a group of cells with diverse morphology including both antigen‐presenting cells and non‐antigen‐presenting cells . Our findings demonstrate that early‐stage RA patients have elevated levels of sCD83 in plasma and that anti‐TNF‐&agr ; treatment has no effect on the sCD83 plasma level . This suggest that in RA patients sCD83 regulation is beyond control of [17158431] BACKGROUND Tumor necrosis factor ( TNF ) is an important mediator of cachexia , and its blockade prevents catabolism in animal models . However , little evidence shows that anti-TNF therapy is effective in treating cachexia in humans . OBJECTIVE The main aim of this study was to investigate the effect of etanercept , a synthetic soluble TNF receptor , on body composition in patients with early rheumatoid arthritis ( RA ) . DESIGN Twenty-six patients were r and omly assigned to 24 wk of treatment with etanercept or methotrexate ; the latter is the first-line therapy for RA . Body composition , physical function , disease activity , systemic inflammation , and the circulating insulin-like growth factor ( IGF ) system were measured at baseline ( week 0 ) and at follow-up ( weeks 12 and 24 ) . Twelve patients in each treatment group ( 9 F , 3 M ) completed the study . RESULTS Overall , no important changes in body composition were observed , despite a transient increase in IGF-I at week 12 ( P < 0.01 ) . However , the secondary analysis of those patients ( 6/treatment group ) who gained weight during follow-up showed a significant effect of etanercept on the composition of the weight gained : 44 % of weight gained in the etanercept group was fat-free mass , as compared with only 14 % in the methotrexate group ( P = 0.04 ) . Etanercept and methotrexate were equally effective in controlling the disease and improving physical function . CONCLUSIONS Anti-TNF therapy with etanercept is not superior to that with methotrexate for the treatment of rheumatoid cachexia over a period of 6 mo . However , TNF blockade seems to normalize the anabolic response to overfeeding and , if these findings are confirmed , may be useful in conditions characterized by anorexia and weight loss [28598681] Abstract Rheumatoid arthritis ( RA ) is characterized by chronic joint inflammation and infiltration by activated macrophages . TNFα is a central mediator in this process . The mannose receptor , CD206 , is a scavenger receptor expressed by M2A-macrophages and dendritic cells . It is involved in collagen internalization and degradation . The soluble form has been suggested as a biomarker of M2A-macrophage activation . The aim of this study was to investigate sCD206 plasma levels in early RA patients initiating anti-TNFα treatment . Plasma levels of sCD206 were measured by ELISA in sample s from 155 early RA patients with an average symptom duration of 3 months . Patients were r and omized to 12 months ’ methotrexate and placebo ( PLA ) or methotrexate and adalimumab ( ADA ) treatment , followed by open-label treatment with disease-modifying anti-rheumatic drugs ( DMARD ) and if needed , ADA . Disease activity was assessed at baseline and after 3 , 6 , 12 and 24 months . Baseline plasma level of sCD206 in treatment naïve RA patients was 0.33 mg/L ( CI : 0.33–0.38 mg/L ) corresponding to the upper part of the reference interval for healthy controls ( 0.10–0.43 mg/L ) . In the PLA group , sCD206 levels decreased after 3 months , but did not differ from baseline after 6 months . In the ADA group , however , levels remained lower than baseline throughout the treatment period . In conclusion , initially , plasma sCD206 in early RA patients decreased in accordance with disease activity and initiation of DMARD treatment . Treatment with anti-TNFα preserved this decrease throughout the study period [22739990] Objective To investigate the long-term effects of induction therapy with adalimumab ( ADA ) plus methotrexate ( MTX ) in comparison with placebo ( PBO ) plus MTX in DMARD-naïve patients with active early rheumatoid arthritis ( RA ) . Methods Patients with active early RA ( disease duration of ≤12 months ) were r and omly assigned to receive 40 mg ADA subcutaneously every other week ( eow ) plus MTX 15 mg/week subcutaneously or PBO plus MTX subcutaneously at 15 mg/week over 24 weeks . Thereafter , all patients received MTX monotherapy up to week 48 . The primary outcome was the Disease Activity Score 28 ( DAS28 ) at week 48 . Secondary outcomes included proportions of patients in remission ( DAS28<2.6 ) , ACR responses , Health Assessment Question naire ( HAQ ) score and radiographic progression . Results 87 patients were assigned to ADA/MTX and 85 patients to PBO/MTX . At baseline , DAS28 was 6.2±0.8 in the ADA/MTX and 6.3±0.9 in the PBO/MTX groups . At week 24 , treatment with ADA/MTX compared with PBO/MTX result ed in a greater reduction in DAS28 ( 3.0±1.2 vs 3.6±1.4 ; p=0.009 ) and other secondary outcomes such as DAS28 remission rate ( 47.9 % vs 29.5 % ; p=0.021 ) and HAQ ( 0.49±0.6 vs 0.72±0.6 ; p=0.0014 ) . At week 48 , the difference in clinical outcomes between groups was not statistically significant ( DAS28 : 3.2±1.4 vs 3.4±1.6 ; p=0.41 ) . Radiographic progression at week 48 was significantly greater in patients administered PBO/MTX ( Sharp/van der Heijde score : ADA/MTX 2.6 vs PBO/MTX 6.4 ; p=0.03 , Ratingen score : 1.7 vs 4.2 ; p=0.01 ) . Conclusions A greater reduction in radiographic progression after initial combination therapy with ADA and MTX was seen at week 48 , even after discontinuation of ADA treatment at week 24 . This sustained effect was not found at the primary endpoint ( DAS28 reduction ) [18662933] Objectives : To compare the occurrence of drug-free remission , functional ability and radiological damage after 4 years of response-driven treatment according to four different treatment strategies for rheumatoid arthritis ( RA ) . Methods : Patients with recent-onset , active RA ( n = 508 ) were r and omly assigned to four different treatment strategies : ( 1 ) sequential monotherapy ; ( 2 ) step-up combination therapy ; ( 3 ) initial combination therapy with prednisone and ( 4 ) initial combination therapy with infliximab . Treatment was adjusted based on 3-monthly disease activity score ( DAS ) assessment s , aim ing at a DAS ⩽2.4 . From the third year , patients with a sustained DAS < 1.6 discontinued treatment . Results : In total , 43 % of patients were in remission ( DAS < 1.6 ) at 4 years and 13 % were in drug-free remission : 14 % , 12 % , 8 % and 18 % of patients in groups 1–4 , respectively . The absence of anti-cyclic citrullinated peptide antibodies , male gender and short symptom duration were independently associated with drug-free remission . Functional ability and remission were maintained in all four groups with the continuation of DAS-driven treatment , without significant differences between the groups . Significant progression of joint damage was observed in 38 % and 31 % of patients in groups 3 and 4 versus 51 % and 54 % of patients in groups 1 and 2 ( p<0.05 , group 4 versus groups 1 and 2 , group 3 versus group 2 ) . Conclusions : In patients with recent-onset active RA , drug-free remission was achieved in up to 18 % of patients . DAS-driven treatment maintained clinical and functional improvement , independent of the treatment strategy . Joint damage progression remained significantly lower after initial combination therapy compared with initial monotherapy [5738604] Objectives To investigate the clinical impact of 1-year certolizumab pegol ( CZP ) therapy added to the first year of 2-year methotrexate ( MTX ) therapy , compared with 2-year therapy with MTX alone . Methods MTX-naïve patients with early rheumatoid arthritis ( RA ) with poor prognostic factors were eligible to enter Certolizumab-Optimal Prevention of joint damage for Early RA ( C-OPERA ) , a multicentre , r and omised , controlled study , which consisted of a 52-week double-blind ( DB ) period and subsequent 52-week post treatment ( PT ) period . Patients were r and omised to optimised MTX+CZP ( n=159 ) or optimised MTX+placebo ( PBO ; n=157 ) . Following the DB period , patients entered the PT period , receiving MTX alone ( CZP+MTX→MTX ; n=108 , PBO+MTX→MTX ; n=71 ) . Patients who flared could receive rescue treatment with open-label CZP . Results 34 CZP+MTX→MTX patients and 14 PBO+MTX→MTX patients discontinued during the PT period . From week 52 through week 104 , significant inhibition of total modified total Sharp score progression was observed for CZP+MTX versus PBO+MTX ( week 104 : 84.2 % vs 67.5 % ( p<0.001 ) ) . Remission rates decreased after CZP discontinuation ; however , higher rates were maintained through week 104 in CZP+MTX→MTX versus PBO+MTX→MTX ( 41.5 % vs 29.3 % ( p=0.026 ) , 34.6 % vs 24.2 % ( p=0.049 ) and 41.5 % vs 33.1 % ( p=0.132 ) at week 104 in SDAI , Boolean and DAS28(erythrocyte sedimentation rate ) remission . CZP retreated patients due to flare ( n=28 ) showed rapid clinical improvement . The incidence of overall adverse events was similar between groups . Conclusions In MTX-naïve patients with early RA with poor prognostic factors , an initial 1 year of add-on CZP to 2-year optimised MTX therapy brings radiographic and clinical benefit through 2 years , even after stopping CZP . Trial registration number NCT01451203 [5264210] Objectives To assess the efficacy and safety of certolizumab pegol (CZP)+dose-optimised methotrexate ( MTX ) versus placebo (PBO)+dose-optimised MTX in inducing and sustaining clinical remission in DMARD-naïve patients with moderate-to-severe , active , progressive rheumatoid arthritis ( RA ) , with poor prognostic factors over 52 weeks . Methods DMARD-naïve patients with ≤1 year of active RA were r and omised ( 3:1 ) in a double-blind manner to CZP ( 400 mg Weeks 0 , 2 , 4 , then 200 mg Q2W to Week 52)+MTX or PBO+MTX ( the mean optimised-MTX dose=21 and 22 mg/week , respectively ) . Sustained remission ( sREM ) and sustained low disease activity ( sLDA ; DAS28(ESR)<2.6 and DAS28(ESR)≤3.2 , respectively , at both Weeks 40 and 52 ) were the primary and secondary endpoints . Results Patients were r and omised to CZP+MTX ( n=660 ) and PBO+MTX ( n=219 ) . At Week 52 , significantly more patients assigned to CZP+MTX compared with PBO+MTX achieved sREM ( 28.9 % vs 15.0 % , p<0.001 ) and sLDA ( 43.8 % vs 28.6 % , p<0.001 ) . Inhibition of radiographic progression and improvements in physical functioning were significantly greater for CZP+MTX versus PBO+MTX ( van der Heijde modified total Sharp score ( mTSS ) mean absolute change from baseline ( CFB ) : 0.2 vs 1.8 , p<0.001 , rate of mTSS non-progressors : 70.3 % vs 49.7 % , p<0.001 ; least squares ( LS ) mean CFB in Health Assessment Question naire-Disability Index ( HAQ-DI ) : −1.00 vs −0.82 , p<0.001 ) . Incidence of adverse events ( AEs ) and serious AEs was similar between treatment groups . Infection was the most frequent AE , with higher incidence for CZP+MTX ( 71.8/100 patient-years ( PY ) ) versus PBO+MTX ( 52.7/100 PY ) ; the rate of serious infection was similar between CZP+MTX ( 3.3/100 PY ) and PBO+MTX ( 3.7/100 PY ) . Conclusions CZP+dose-optimised MTX treatment of DMARD-naïve early RA result ed in significantly more patients achieving sREM and sLDA , improved physical function and inhibited structural damage compared with PBO+dose-optimised MTX . Trial registration number NCT01519791 [4440309] Introduction Clinical synovitis is often associated with damage to bone and cartilage . Previous data have suggested that joint erosions ( JE ) are more prevalent than joint space narrowing ( JSN ) and that the two processes are partly independent of each other . The objective of this study was to evaluate whether the presence of JE in an individual joint can lead to development of JSN and if existing JSN leads to new onset of JE , in the absence of synovitis . Methods The Prospect i ve Multi-Centre R and omised , Double-Blind , Active Comparator-Controlled , Parallel-Groups Study Comparing the Fully Human Monoclonal Anti-TNFα Antibody Adalimumab Given Every Second Week With Methotrexate Given Weekly and the Combination of Adalimumab and Methotrexate Administered Over 2 Years in Patients With Early Rheumatoid Arthritis ( PREMIER ) enrolled early rheumatoid arthritis ( RA ) patients who were r and omized to one of three treatments : methotrexate ( MTX ) , adalimumab ( ADA ) , or ADA + MTX . All evaluable joints with JE and JSN measures at 26 and 52 weeks and synovitis assessment s from week 26 to 52 were included . Synovitis was assessed every 2–8 weeks by swollen joint counts between weeks 26 and 52 . Radiographs were taken at week 26 and 52 . Two readers , blinded to time and sequence , scored 14 bilateral joints individually for JE and JSN . Multivariate logistic modeling was used to characterize the dependence of JE/JSN onset at 52 weeks . Analyses were performed based on treatment arm and were also performed within individual joints . Results JE and swelling were independently and comparably associated with onset of JSN at week 52 . Assessment by individual joints indicated that existing JE , independent of swelling , was significantly associated with JSN onset in higher proportions of metatarsophalangeal ( MTP ; 7/10 ) than proximal interphalangeal ( PIP ; 1/8 ) or metacarpophalangeal ( MCP ; 1/10 ) joints . Treatment with ADA + MTX prevents JE/JSN progression independently of its ability to suppress synovitis and limits JE/JSN onset and progression in joints with existing damage . Conclusions Existing JE predisposes individual joints to development of JSN independently of synovitis in the same joint . Weight-bearing MTP joints with JE may be at increased risk for JSN when compared with MCPs and PIPs . Trial registration Clinical trials.gov NCT00195663 . Registered 13 September 2005 [29280011] Adverse events ( AEs ) are common during disease-modifying antirheumatic drug ( DMARD ) treatment , but their influence on treatment results is unclear . We studied AEs in relation to disease activity in early rheumatoid arthritis ( RA ) . Ninety-nine patients started intensive treatment with three conventional synthetic DMARDs ( csDMARDs ) and oral prednisolone , and were r and omized to a 6-month induction treatment with infliximab or placebo . All AEs during the first 12 months of treatment were recorded . We scored each AE based on severity ( scale 1–4 ) and defined the burden of AEs as the sum of these scores . Patients were divided into tertiles according to the burden of AEs . As outcomes , we assessed 28-joint disease activity score ( DAS28 ) levels and remission rates at 12 and 24 months . Three hundred thirty-one AEs in 99 patients were reported , and 27 ( 8 % ) were categorized as severe or serious . Mean burden of AEs per patient was 5.4 ± 4.3 . Seventy-nine AEs ( 24 % ) led to temporary ( n = 52 ) or permanent ( n = 27 ) csDMARD discontinuation . Of discontinuations , 1 , 21 , and 57 were detected in the first , second , and third tertiles , respectively . DAS28 remission rates decreased across tertiles at 12 months ( 94 , 94 , and 76 % ; p for linearity 0.029 ) and at 24 months ( 90 , 86 , and 70 % ; p for linearity 0.021 ) . Mean DAS28 levels increased across tertiles at 12 months ( 1.5 ± 1.0 , 1.7 ± 0.9 , and 1.9 ± 1.2 ; p for linearity 0.021 ) and at 24 months ( 1.4 ± 0.8 , 1.6 ± 1.0 , and 1.9 ± 1.1 ; p for linearity 0.007 ) . High burden of AEs is associated with higher disease activity and lower likelihood of remission in early RA [3551224] Objective To assess the efficacy and safety of adalimumab plus methotrexate ( ADA+MTX ) compared with methotrexate monotherapy in achieving stable low disease activity ( LDA ; disease activity score ( DAS28(CRP ) ) < 3.2 at weeks 22 and 26 ) and clinical , radiographic and functional outcomes in methotrexate-naive patients with early rheumatoid arthritis ( RA ) . Methods 1032 patients with active RA were r and omly assigned 1:1 to ADA+MTX or placebo plus methotrexate ( PBO+MTX ) for 26 weeks . Treatment modifications were to be made in a subsequent study period based on the achievement of DAS28(CRP ) < 3.2 at weeks 22 and 26 . Post-hoc analyses compared patients achieving stable remission using DAS28 and 2010 ACR/EULAR criteria with those achieving LDA but not remission . Results Among patients completing 6 months , 44 % ( 207/466 ) ADA+MTX versus 24 % ( 112/460 ) PBO+MTX patients achieved stable LDA at weeks 22 and 26 ( p<0.001 ) . Combination therapy was statistically superior to methotrexate in obtaining higher ACR20/50/70 responses , more clinical remissions , greater mean reductions in DAS28(CRP ) , no radiographic progression , and normal functional status at week 26 ( p<0.001 for all ) . The only factor predicting stable LDA was disease activity at week 12 . Patients achieving ACR/EULAR remission , particularly in the PBO+MTX group , had some advantage in radiographic outcomes compared with patients who only achieved LDA ( but not remission ) . The overall frequency of adverse events was comparable between groups . There were more serious infections and deaths in the ADA+MTX group , with a possible age effect . Conclusions Treatment with ADA+MTX was significantly superior to methotrexate alone with respect to clinical , radiographic and functional outcomes in patients with early active RA . Before initiating treatment with adalimumab , individual patient evaluation of the benefit/risk ratio should be carefully considered [27638812] OBJECTIVES To determine the change in established biomarkers of cardiovascular ( CV ) risk , namely , total cholesterol/high-density lipoprotein cholesterol ratio ( TC/HDL-C ) , N-terminal pro-brain natriuretic peptide ( NT-proBNP ) and insulin resistance ( IR ) in patients with early RA treated with two different treat-to-target strategies . METHODS Fasting glucose , lipids , insulin and NT-proBNP were measured at baseline , weeks 26 and 78 in 79 DMARD-naïve RA patients , free of CV disease , as part of a double-blind r and omized controlled trial of MTX with either infliximab ( IFX ) or methylprednisolone as induction therapy . Homeostasis model assessment -estimated IR ( HOMA-IR ) ( glucose*insulin/405 ) was used to measure IR . Multiple imputation was employed , and linear regression analyses were adjusted for baseline values . RESULTS Changes in DAS44-CRP did not differ between the treatment arms at weeks 26 and 78 . Mean TC/HDL-C , HOMA-IR and NT-proBNP improved in both groups at weeks 26 and 78 , although change in NT-proBNP was not statistically significant at week 78 . Changes in TC/HDL-C and NT-proBNP were similar between treatment arms , but HOMA-IR values in the IFX + MTX arm were 42 % lower than those treated with MTX + methylprednisolone at week 78 ( P = 0.003 ) ; the difference remained significant after adjustment for baseline BMI , ACPA positivity , smoking status and intramuscular glucocorticoid use ( P = 0.007 ) . CONCLUSION When implementing a treat-to-target approach , treatment of early RA was associated with improvement in TC/HDL-C , HOMA-IR and NT-proBNP , and a greater long-term improvement in HOMA-IR was seen in those treated with IFX . TRIAL REGISTRATION EU Clinical Trials Register , http://www . clinical trialsregister.eu , Eudract-2005 - 005013 - 37 ; ISRTCNregisrty , http://www.is rct n.com , IS RCT N48638981 [4823586] Objective To determine the most effective treatment strategy among anticitrullinated protein antibodies (ACPA)-negative patients with early rheumatoid arthritis . Methods In the BeSt study , 184 ACPA-negative patients were r and omised to : ( 1 ) sequential monotherapy , ( 2 ) step-up therapy , ( 3 ) initial combination including prednisone , ( 4 ) initial combination including infliximab . Treatment was targeted at the disease activity score ( DAS ) ≤2.4 . Early response and 10-year outcomes were compared between the four strategy -arms in ACPA-negative patients . Results ACPA-negative patients achieved more short-term functional improvement from initial combination therapy than when on monotherapy ( at month 3 , mean Health Assessment Question naire ( HAQ ) 0.71 vs 0.98 , p=0.006 ; at month 6 , 0.59 vs 0.87 , p=0.004 ) . Functional ability over time was comparable between the strategy -arms ( p=0.551 ) with a mean HAQ of 0.6 at year 10 ( p=0.580 for comparison across the strategy -arms ) . 10-year radiographic progression was negligible ( median 0.5 ) and comparable between the 4 strategy -arms ( p=0.082 ) . At year 10 , remission was achieved by 11/40 ( 28 % ) , 9/45 ( 20 % ) , 17/56 ( 30 % ) and 17/43 patients ( 40 % ) in strategy -arms 1–4 , respectively ( p=0.434 ) . Over time , similar remission percentages were achieved in all strategy -arms ( p=0.815 ) . 18 % , 16 % , 20 % and 21 % in strategy -arms 1 to 4 ( p=0.742 ) were in drug-free remission at year 10 , with a median duration of 60 months across the arms . Conclusions Initial combination therapy with methotrexate , sulfasalazine and prednisone , or methotrexate and infliximab , is the most effective treatment strategy for ACPA-negative patients , result ing in earlier functional improvement than when on initial methotrexate monotherapy . After 10 years of targeted treatment , in all strategy -arms favourable clinical outcomes were achieved and radiographic progression was limited . Trial registration number NTR262 , NTR265 [3988871] Objective . The aim of this study was to compare efficacy outcomes of initial treatment with adalimumab + MTX vs adalimumab addition following 26 weeks of MTX monotherapy in Japanese early RA patients naive to MTX with high disease activity . Methods . Patients completing the 26-week , r and omized , placebo-controlled trial of adalimumab + MTX were eligible to receive 26 weeks of open-label adalimumab + MTX . Patients were assessed for mean change from baseline in the 28-joint DAS with ESR ( DAS28-ESR ) and modified total Sharp score ( mTSS ) , and for the proportions of patients achieving clinical , functional or radiographic remission . Results . Of 333 patients assessed , 278 ( 137 from the initial adalimumab + MTX and 141 from the initial placebo + MTX groups ) completed the 52-week study . Significant differences in clinical and functional parameters observed during the 26-week blinded period were not apparent following the addition of open-label adalimumab to MTX . Open-label adalimumab + MTX slowed radiographic progression through week 52 in both groups , but patients who received adalimumab + MTX throughout the study exhibited less radiographic progression than those who received placebo + MTX during the first 26 weeks ( mean ΔmTSS at week 52 = 2.56 vs 3.30 , P < 0.001 ) . Conclusion . Delayed addition of adalimumab in Japanese MTX-naive early RA patients did not impact clinical and functional outcomes at week 52 compared with the earlier addition of adalimumab . However , the accrual of significant structural damage during blinded placebo + MTX therapy contributed to the persistence of differences between the treatment strategies , suggesting that Japanese patients at risk for aggressive disease should benefit from the early inclusion of adalimumab + MTX combination therapy . Trial registration . Clinical Trials.gov ( http:// clinical trials.gov/ ) , NCT00870467 [4717398] Objectives To evaluate efficacy and safety of combination therapy using certolizumab pegol ( CZP ) and methotrexate ( MTX ) as first-line treatment for MTX-naive , early rheumatoid arthritis ( RA ) with poor prognostic factors , compared with MTX alone . Methods MTX-naive , early RA patients with ≤12 months persistent disease , high anti-cyclic citrullinated peptide , and either rheumatoid factor positive and /or presence of bone erosions were enrolled in this multicentre , double-blind , r and omised placebo (PBO)-controlled study . Patients were r and omised 1:1 to CZP+MTX or PBO+MTX for 52 weeks . Primary endpoint was inhibition of radiographic progression ( change from baseline in modified Total Sharp Score ( mTSS CFB ) ) at week 52 . Secondary endpoints were mTSS CFB at week 24 , and clinical remission rates at weeks 24 and 52 . Results 316 patients r and omised to CZP+MTX ( n=159 ) or PBO+MTX ( n=157 ) had comparable baseline characteristics reflecting features of early RA ( mean disease duration : 4.0 vs 4.3 months ; Disease Activity Score 28-joint assessment ( DAS28 ) ) ( erythrocyte sedimentation rate ( ESR ) ) : 5.4 vs 5.5 ; mTSS : 5.2 vs 6.0 ) . CZP+MTX group showed significantly greater inhibition of radiographic progression relative to PBO+MTX at week 52 ( mTSS CFB=0.36 vs 1.58 ; p<0.001 ) and week 24 ( mTSS CFB=0.26 vs 0.86 ; p=0.003 ) . Clinical remission rates ( Simple Disease Activity Index , Boolean and DAS28 ( ESR ) ) of the CZP+MTX group were significantly higher compared with those of the PBO+MTX group , at weeks 24 and 52 . Safety results in both groups were similar , with no new safety signals observed with addition of CZP to MTX . Conclusions In MTX-naive early RA patients with poor prognostic factors , CZP+MTX significantly inhibited structural damage and reduced RA signs and symptoms , demonstrating the efficacy of CZP in these patients . Trial registration number ( NCT01451203 ) [19741011] OBJECTIVES In early and active RA despite MTX , continuous treatment with TNF blockers in combination with MTX is recommended . To compare this strategy with an initial combination of MTX and adalimumab ( ADA ) given for 3 months and then adjusted based on the disease activity status . METHODS Prospect i ve unblinded r and omized multicentre controlled 1-year trial in which 65 patients with early ( < 6 months ) and active [ disease activity score ( DAS28(ESR ) ) > 5.1 ] RA were assigned to Group 1 ( 32 patients ): MTX ( 0.3 mg/kg/week , maximum of 20 mg/week , without escalating dose regimen ) or to Group 2 ( 33 patients ): initial combination therapy with MTX ( as in Group 1 ) and ADA ( 40 mg eow ) . In both groups , treatment was adjusted every 3 months . The aim was to achieve a low DAS ( DAS28(ESR ) < 3.2 ) . RESULTS From Week 12 until Week 52 , seven patients in Group 1 and 11 patients in Group 2 remained in low disease activity state while receiving MTX monotherapy ( P = 0.28 ) . The 1-year area under the curve ( AUC ) of DAS28 was lower in Group 2 owing to an initial better response . The total intake of anti-TNF-alpha and the mean increase in total modified Sharp score was similar in the two groups . CONCLUSIONS Initial combination of MTX and ADA and then an adjusted based on the disease activity status achieved a faster control of disease activity but did not increase the number of patients for whom anti-TNF-alpha treatment was not needed after 12 weeks nor a better subsequent clinical or radiological outcome than a 3-month delayed initiation of anti-TNF in patients with still active disease despite MTX [27432355] Purpose We assessed whether MRI measures of synovitis , osteitis and bone erosion were associated with patient-reported outcomes ( PROs ) in a longitudinal clinical trial setting among patients with rheumatoid arthritis ( RA ) . Methods This longitudinal cohort of 291 patients with RA was derived from the MRI sub study of the GO-BEFORE r and omised controlled trial of golimumab among methotrexate-naïve patients . Correlations between RAMRIS scores ( synovitis , osteitis , bone erosion ) and physical function ( Health Assessment Question naire ( HAQ ) ) , pain and global patient scores were determined at 0 , 12 , 24 and 52 weeks . Correlations between interval changes were also assessed . Multivariable regression models using robust generalised estimating equations evaluated associations over all time-points and their relationship to other clinical disease activity measures . Results Greater synovitis , osteitis and bone erosion scores were positively associated with HAQ at all time-points ( all p<0.05 ) and with pain and patient global scores at 24 and 52 weeks . Over all visits , synovitis was associated with HAQ , pain and patient global scores ( p≤0.03 ) independent of clinical disease activity measures . Improvements in synovitis and bone erosion were also associated with improvements in PROs . Less improvement in synovitis and progression in MRI erosion at 52 weeks were both independently associated with worsening in all PROs at 52 weeks while progression on X-ray was not associated . Similar associations were observed across treatment groups . Conclusions MRI measures of inflammation and structural damage correlate independently with physical function , pain and patient global assessment s. These observations support the validity of MRI biomarkers . Trial registration number NCT00264537 ; Post- results [12115173] OBJECTIVE To compare the clinical and radiographic outcomes in patients with rheumatoid arthritis ( RA ) who received monotherapy with either etanercept or methotrexate ( MTX ) for 2 years and to assess the safety of this therapy . METHODS In the Enbrel ERA ( early rheumatoid arthritis ) trial , 632 patients with early , active RA were r and omized to receive either twice-weekly subcutaneous etanercept ( 10 mg or 25 mg ) or weekly oral MTX ( mean dosage 19 mg per week ) for at least 1 year in a double-blind manner . Following the blinded phase of the trial , 512 patients continued to receive the therapy to which they had been r and omized for up to 1 additional year , in an open-label manner . Radiograph readers remained blinded to treatment group assignment and the chronologic order of images . RESULTS At 24 months , more 25-mg etanercept patients than MTX patients met American College of Rheumatology 20 % improvement criteria ( 72 % and 59 % , respectively ; P = 0.005 ) , and more had no increase in total score and erosion scores on the Sharp scale ( P = 0.017 and P = 0.012 , respectively ) . The mean changes in total Sharp score and erosion score in the 25-mg etanercept group ( 1.3 and 0.66 units , respectively ) were significantly lower than those in the MTX group ( 3.2 and 1.86 units , respectively ; P = 0.001 ) . Significantly more patients in the 25-mg etanercept group ( 55 % ) than in the MTX group ( 37 % ) had at least 0.5 units of improvement in the Health Assessment Question naire disability index ( P < 0.001 ) . Fewer patients in the etanercept group than in the MTX group experienced adverse events or discontinued treatment because of adverse events . CONCLUSION Etanercept as monotherapy was safe and was superior to MTX in reducing disease activity , arresting structural damage , and decreasing disability over 2 years in patients with early , aggressive RA [23912798] Objectives In disease modifying antirheumatic drug (DMARD)-naive early rheumatoid arthritis ( RA ) , to compare the efficacy of methotrexate ( MTX ) and infliximab ( IFX ) with MTX and intravenous corticosteroid for remission induction . Methods In a 78-week multicentre r and omised controlled trial , double-blinded to week 26 , 112 treatment-naive RA patients ( 1987 American College of Rheumatology classification criteria ) with disease activity score 44 (DAS44)>2.4 were r and omised to MTX + IFX or MTX + single dose intravenous methylprednisolone 250 mg . A treat-to-target approach was used with treatment escalation if DAS44>2.4 . In the IFX group , IFX was discontinued for sustained remission ( DAS44<1.6 for 6 months ) . The primary outcome was change in modified total Sharp-van der Heijde score ( mTSS ) at week 50 . Results The mean changes in mTSS score at week 50 in the IFX and intravenous steroid groups were 1.20 units and 2.81 units , respectively ( adjusted difference ( 95 % CI ) −1.45 ( −3.35 to 0.45 ) ; p=0.132 ) . Radiographic non-progression ( mTSS<2.0 ) occurred in 81 % vs 71 % ( OR 1.77 ( 0.56 to 5.61 ) ; p=0.328 ) . DAS44 remission was achieved at week 50 in 49 % and 36 % ( OR 2.13 ( 0.91 to 5.00 ) ; p=0.082 ) , and at week 78 in 48 % and 50 % ( OR 1.12 ( 0.47 to 2.68 ) ; p=0.792 ) . Exploratory analyses suggested higher DAS28 remission at week 6 and less ultrasound synovitis at week 50 in the IFX group . Of the IFX group , 25 % ( 14/55 ) achieved sustained remission and stopped IFX . No substantive differences in adverse events were seen . Conclusions In DMARD-naive early RA patients , initial therapy with MTX+high-dose intravenous steroid result ed in good disease control with little structural damage . MTX+IFX was not statistically superior to MTX+intravenous steroid when combined with a treat-to-target approach [18821658] OBJECTIVE To compare work disability and job loss in early rheumatoid arthritis ( RA ) patients receiving adalimumab plus methotrexate ( adalimumab + MTX ) versus MTX alone . METHODS In this multicenter , r and omized , controlled trial , patients with RA for < 2 years who had never taken MTX and who self-reported work impairment were r and omized to adalimumab + MTX or placebo + MTX for 56 weeks . Primary outcome was job loss of any cause and /or imminent job loss at or after week 16 . Secondary outcomes included disease activity , function ( Health Assessment Question naire [ HAQ ] score ) , and RA quality of life ( RAQoL ) question naire score . Work was evaluated with work diaries and the RA Work Instability Scale . RESULTS Although job loss during the 56-week study was significantly lower with adalimumab + MTX ( 14 of 75 patients ) compared with MTX alone ( 29 of 73 patients ; P=0.005 ) , the primary end point was not met ( 12 of 75 versus 20 of 73 patients ; P=0.092 ) , likely owing to early drop out in the MTX group . There were significant improvements in American College of Rheumatology 20 % response criteria , 28-joint Disease Activity Score , DeltaHAQ , DeltaRAQoL , and working time lost in the adalimumab + MTX group . Twenty-four serious adverse events were reported in 17 participants , with no differences between groups . CONCLUSION Adalimumab + MTX reduced job loss and improved productivity in early RA when compared with MTX alone , which supports the early use of anti-tumor necrosis factor therapy and suggests its cost efficacy [25939484] At least 30 % of patients with rheumatoid arthritis ( RA ) do not respond to biologic agents , which emphasizes the need of predictive biomarkers . We aim ed to identify microRNAs ( miRNAs ) predictive of response to adalimumab in 180 treatment-naïve RA patients enrolled in the OPtimized treatment algorithm for patients with early RA ( OPERA ) Study , an investigator-initiated , prospect i ve , double-blind placebo-controlled study . Patients were r and omized to adalimumab 40 mg ( n=89 ) or placebo – adalimumab ( n=91 ) subcutaneously in combination with methotrexate . Expressions of 377 miRNAs were determined using TaqMan Human MicroRNA LDA , A Card v2.0 ( Applied Biosystems ) . Associations between miRNAs and treatment response were tested using interaction analyses . MiRNAs with a P-value < 0.05 using three different normalizations were included in a multivariate model . After backwards elimination , the combination of low expression of miR-22 and high expression of miR-886.3p was associated with EULAR good response . Future studies to assess the utility of these miRNAs as predictive biomarkers are needed [15529377] OBJECTIVE To compare the benefits of initiating treatment with methotrexate ( MTX ) and infliximab ( anti-tumor necrosis factor alpha [ anti-TNFalpha ] monoclonal antibody ) with those of MTX treatment alone in patients with rheumatoid arthritis ( RA ) of < or =3 years ' duration . METHODS RA patients were eligible if they had active disease and no prior treatment with MTX or a TNFalpha inhibitor . One thous and forty-nine patients were r and omly assigned in a 4:5:5 ratio to 3 treatment groups : MTX-placebo , MTX-3 mg/kg infliximab , and MTX-6 mg/kg infliximab . MTX dosages were rapidly escalated to 20 mg/week , and infliximab or placebo infusions were given at weeks 0 , 2 , and 6 , and every 8 weeks thereafter through week 46 . RESULTS At week 54 , the median percentage of American College of Rheumatology improvement ( ACR-N ) was higher for the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups than for the MTX-placebo group ( 38.9 % and 46.7 % versus 26.4 % , respectively ; P < 0.001 for both comparisons ) . Patients in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups also showed less radiographic progression than those receiving MTX alone ( mean + /- SD changes in van der Heijde modification of the total Sharp score at week 54 : 0.4 + /- 5.8 and 0.5 + /- 5.6 versus 3.7 + /- 9.6 , respectively ; P < 0.001 for each comparison ) . In addition , physical function improved significantly more in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups than in the MTX-placebo group . Infliximab therapy was associated with a significantly higher incidence of serious infections , especially pneumonia . CONCLUSION For patients with active RA in its early stages , combination therapy with MTX and infliximab provides greater clinical , radiographic , and functional benefits than treatment with MTX alone [5571914] Objective YKL-40 , a chitinase-like glycoprotein associated with inflammation and tissue remodeling , is produced by joint tissues and recognized as a c and i date auto-antigen in rheumatoid arthritis ( RA ) . In the present study , we investigated YKL-40 as a potential biomarker of disease activity in patients with early RA at baseline and during intensive treatment aim ing for early remission . Methods Ninety-nine patients with early DMARD-naïve RA participated in the NEO-RACo study . For the first four weeks , the patients were treated with the combination of sulphasalazine , methotrexate , hydroxychloroquine and low dose prednisolone ( FIN-RACo DMARD combination ) , and subsequently r and omized to receive placebo or infliximab added on the treatment for further 22 weeks . Disease activity was evaluated using the 28-joint disease activity score and plasma YKL-40 concentrations were measured by immunoassay . Results At the baseline , plasma YKL-40 concentration was 57 ± 37 ( mean ± SD ) ng/ml . YKL-40 was significantly associated with the disease activity score , interleukin-6 and erythrocyte sedimentation rate both at the baseline and during the 26 weeks ’ treatment . The csDMARD combination decreased YKL-40 levels already during the first four weeks of treatment , and there was no further reduction when the tumour necrosis factor-α antagonist infliximab was added on the combination treatment . Conclusions High YKL-40 levels were found to be associated with disease activity in early DMARD-naïve RA and during intensive treat-to-target therapy . The present results suggest YKL-40 as a useful biomarker of disease activity in RA to be used to steer treatment towards remission [21415052] Objective To compare clinical and radiological outcomes of four dynamic treatment strategies in recent-onset rheumatoid arthritis ( RA ) after 5 years follow-up . Methods 508 patients with recent-onset RA were r and omly assigned into four treatment strategies : sequential monotherapy ; step-up combination therapy ; initial combination with prednisone ; initial combination with infliximab . Treatment adjustments were made based on 3-monthly disease activity score ( DAS ) measurements ( if DAS > 2.4 next treatment step ; if DAS ≤2.4 during ≥6 months taper to maintenance dose ; if DAS < 1.6 during ≥6 months stop antirheumatic treatment ) . Primary and secondary outcomes were functional ability , joint damage progression , health-related quality of life and ( drug-free ) remission percentages . Results After 5 years , 48 % of patients were in clinical remission ( DAS < 1.6 ) and 14 % in drug-free remission , irrespective of initial treatment . After an earlier improvement in functional ability and quality of life with initial combination therapy , from 1 year onwards clinical outcomes were comparable across the groups and stable during 5 years . The initial combination groups showed less joint damage in year 1 . In years 2–5 annual progression was comparable across the groups . After 5 years , initial combination therapy result ed in significantly less joint damage progression , reflecting the earlier clinical response . Conclusion Irrespective of initial treatment , an impressive improvement in clinical and radiological outcomes of RA patients can be achieved with dynamic treatment aim ed at reducing disease activity , leading to 48 % remission , 14 % drug-free remission and sustained functional improvement . Starting with combination therapy result ed in earlier clinical improvement and less joint damage without more toxicity [25962601] OBJECTIVES Rheumatoid arthritis ( RA ) is a chronic autoimmune disease where TNF-α is a central mediator of inflammation , and is cleaved from the cell surface by TACE/ADAM17 . This metalloproteinase is also responsible for the release of soluble ( s ) CD163 . Soluble CD163 reflects macrophage activation . In RA , sCD163 has been suggested as a marker of disease activity and progression . Our aim is to investigate sCD163 levels in early RA patients . METHODS Soluble CD163 was measured by ELISA from 150 RA plasma sample s from the OPERA trial . Averaged disease duration was three months , prior to r and omisation with methotrexate ( MTX ) and adalimumab ( DMARD+ADA ) or MTX and placebo ( DMARD+PLA ) . Soluble CD163 levels were evaluated in relation to clinical disease parameters . RESULTS Plasma sCD163 at baseline was 2.39 mg/l ( 1.74 mg/l-3.18 mg/l ) , mean ( 95 % CI ) , vs healthy controls : 1.63 mg/l ( 1.54 mg/l - 1.73 mg/l ) , ( p<0.001 ) . After three months of treatment sCD163 levels decreased significantly ( average 23.5 % ) in both treatment groups . Significant incremental sCD163 levels followed withdrawal of ADA after 12 months of treatment . Baseline sCD163 correlated with CRP and all investigated disease activity markers ( ρ=0.16 - 0.28 , p<0.05 ) . In the DMARD+PLA group baseline sCD163 also correlated with CRP during the follow-up period . CONCLUSIONS Soluble CD163 correlated with disease activity markers in early RA before treatment . Plasma sCD163 may add to currently available disease measures by specifically reflecting changes in macrophage activity as evidence d by increasing levels following anti-TNF withdrawal , despite maintenance of a stable clinical condition achieved by conventional remedies . It remains to be determined whether sCD163 is an early predictor of disease flare [20889601] Objective . To evaluate the efficacy and safety of initial combination treatment with adalimumab ( ADA ) and methotrexate ( MTX ) versus monotherapy with ADA or MTX during an open-label extension of PREMIER . Methods . Patients with early rheumatoid arthritis ( RA ) received blinded ADA plus MTX , ADA alone , or MTX alone for 2 years in PREMIER . At Year 2 , patients could enroll in an open-label extension and receive ADA monotherapy ; MTX could be added at the investigator ’s discretion . Longterm efficacy results are presented as observed data . Results . In the open-label period , 497 of the original 799 r and omized patients had ≥ 1 dose of ADA ( by original r and omization : ADA plus MTX , n = 183 ; ADA , n = 159 ; MTX , n = 155 ) . In the completers cohort [ patients with available Year-5 ACR responses and modified total Sharp scores ( mTSS ) ] , the Year-5 mean change from baseline in mTSS for the ADA+MTX arm ( n = 124 ) was 2.9 , compared with 8.7 and 9.7 in the ADA ( n = 115 ) and MTX ( n = 115 ) arms . Comprehensive disease remission , defined as the combination of DAS28 remission , normal function ( Health Assessment Question naire ≤ 0.5 ) , and radiographic nonprogression ( ΔmTSS ≤ 0.5 ) , was achieved by more patients in the initial ADA+MTX arm ( 35 % ) than in the ADA ( 13 % ) or MTX ( 14 % ) arms . Conclusion . Initial combination treatment with ADA plus MTX , followed by open-label ADA , led to better longterm clinical , functional , and radiographic outcomes than either initial ADA or MTX monotherapy during 5 years of treatment [28289873] Identifying prognostic factors for remission in early rheumatoid arthritis ( ERA ) patients is of key clinical importance . We studied patient-reported outcomes ( PROs ) as predictors of remission in a clinical trial . We r and omized 99 untreated ERA patients to receive remission-targeted treatment with three disease-modifying antirheumatic drugs and prednisolone for 24 months , and infliximab or placebo for the initial 6 months . At baseline , we measured following PROs : eight Short Form 36 question naire ( SF-36 ) dimensions , patient ’s global assessment [ PGA , visual analogue scale ( VAS ) ] , Health Assessment Question naire ( HAQ ) , and pain VAS . We used multivariable-adjusted regression models to identify PROs that independently predicted modified American College of Rheumatology remission at 2 years . Follow-up data at 2 years were available for 93 patients ( 92 % ) , and 58 patients ( 62 % ) were in remission . At baseline , patients who achieved remission had higher radiological score ( p = 0.04 ) , lower tender joint count ( p = 0.001 ) , lower PGA ( p = 0.005 ) and physician ’s global assessment ( p = 0.019 ) , lower HAQ ( p = 0.016 ) , less morning stiffness ( p = 0.009 ) , and significantly higher scores in seven out of eight SF-36 dimensions compared with patients who did not . In multivariable models that included all PROs , remission was associated with SF-36 dimensions higher vitality ( odds ratio 2.01 ; 95 % confidence interval 1.19–3.39 ) and better emotional role functioning ( odds ratio 1.64 ; 95 % confidence interval 1.01–2.68 ) . PGA , pain VAS , HAQ , and other SF-36 dimensions were not associated with remission . We conclude that self-reported vitality and better emotional role functioning are among the most important PROs for the prediction of remission in ERA [18635256] BACKGROUND Remission and radiographic non-progression are goals in the treatment of early rheumatoid arthritis . The aim of the combination of methotrexate and etanercept in active early rheumatoid arthritis ( COMET ) trial is to compare remission and radiographic non-progression in patients treated with methotrexate monotherapy or with methotrexate plus etanercept . METHODS 542 out patients who were methotrexate-naive and had had early moderate-to-severe rheumatoid arthritis for 3 - 24 months were r and omly assigned to receive either methotrexate alone titrated up from 7.5 mg a week to a maximum of 20 mg a week by week 8 or methotrexate ( same titration ) plus etanercept 50 mg a week . Co primary endpoints at 52 weeks were remission measured with the disease activity score in 28 joints ( DAS28 ) and radiographic non-progression measured with modified total Sharp score . Treatment was allocated with a computerised r and omisation and enrolment system , which masked both participants and carers . Analysis was done by modified intention to treat with last observation carried forward for missing data . This study is registered with Clinical Trials.gov , number NCT00195494 ) . FINDINGS 274 participants were r and omly assigned to receive combined treatment and 268 methotrexate alone . 132 of 265 ( 50 % , 95 % CI 44 - 56 % ) patients who took combined treatment and were available for assessment achieved clinical remission compared with 73 of 263 ( 28 % , 23 - 33 % ) taking methotrexate alone ( effect difference 22.05 % , 95%CI 13.96 - 30.15 % , p<0.0001 ) . 487 evaluable patients had severe disease ( DAS28>5.1 ) . 196 of 246 ( 80 % , 75 - 85 % ) and 135 of 230 ( 59 % , 53 - 65 % ) , respectively , achieved radiographic non-progression ( 20.98 % , 12.97 - 29.09 % , p<0.0001 ) . Serious adverse events were similar between groups . INTERPRETATION Both clinical remission and radiographic non-progression are achievable goals in patients with early severe rheumatoid arthritis within 1 year of combined treatment with etanercept plus methotrexate . FUNDING Wyeth Research [18050189] OBJECTIVE To compare the effects of methotrexate ( MTX ) , alone or in combination with intravenous ( IV ) methylprednisolone ( MP ) or infliximab , on magnetic resonance imaging (MRI)-detected synovitis , bone edema , and erosive changes in patients with early rheumatoid arthritis ( RA ) . METHODS Forty-four patients with early RA were r and omized to receive MTX alone ( MTX group ) , MTX plus IV MP ( IV MP group ) , or MTX plus infliximab ( infliximab group ) , infused on day 0 and weeks 2 , 6 , 14 , 22 , 30 , 38 , and 46 . Gadolinium-enhanced MRI scans of the metacarpophalangeal joints , wrists , and metatarsophalangeal joints were performed at baseline , week 18 , and week 52 . RESULTS Scores for MRI-detected synovitis and bone edema improved over time in the 3 groups , with significantly lower synovitis scores in the infliximab group compared with the MTX group and significantly lower bone edema scores in the infliximab group compared with the MTX and the IV MP groups . Scores for MRI-detected erosion significantly increased over time in all groups . There were no differences in erosion scores between the MTX group and the other groups . It is of note that patients treated with IV MP showed more significant progression in MRI-detected erosions compared with patients treated with infliximab . At week 22 , response rates according to the American College of Rheumatology 20 % improvement criteria ( ACR20 ) , the ACR50 , and the ACR70 were significantly higher in both the IV MP group and the infliximab group compared with the MTX group . At week 52 , remission was achieved in 40 % of patients in the MTX group and in 70 % of patients in the IV MP and infliximab groups . Health Assessment Question naire scores improved significantly over time in all groups , with patients receiving IV MP experiencing significantly more improvement compared with patients treated with MTX alone . No severe side effects were observed , except 1 case of MTX-related pneumonitis . CONCLUSION The combination of MTX and infliximab is superior to MTX alone for reducing MRI-detected signs of synovitis and bone edema in patients with early RA . Progression of MRI-detected erosion was greater in patients treated with MTX plus IV MP compared with that in patients who received MTX plus infliximab [23908187] Objective To study whether adding initial infliximab to remission-targeted initial combination-DMARD treatment improves the long-term outcomes in patients with early rheumatoid arthritis ( RA ) . Methods Ninety-nine patients with early , DMARD-naïve RA were treated with a triple combination of DMARDs , starting with methotrexate ( max 25 mg/week ) , sulfasalazine ( max 2 g/day ) , hydroxychloroquine ( 35 mg/kg/week ) , and with prednisolone ( 7.5 mg/day ) , and r and omised to double blindly receive either infliximab ( 3 mg/kg ; FIN-RACo+INFL ) or placebo ( FIN-RACo+PLA ) infusions during the first 6 months . After 2 years the treatment strategies became unrestricted , but the treatment goal was strict ACR remission . At 5 years the clinical and radiographic outcomes were assessed . Results Ninety-one patients ( 92 % ) were followed up to 5 years , 45 in the FIN-RACo+INFL and 46 in the FIN-RACo+PLA groups . At 5 years , the respective proportions of patients in strict ACR and in disease activity score 28 remissions in the FIN-RACo+INFL and FIN-RACo+PLA groups were 60 % ( 95 % CI 44 % to 74 % ) and 61 % ( 95 % CI 45 % to 75 % ) ( p=0.87 ) , and 84 % ( 95 % CI 71 % to 94 % ) and 89 % ( 95 % CI 76 % to 96 % ) ( p=0.51 ) . The corresponding mean ( SD ) total Sharp/van der Heijde scores at 5 years were 4.3 ( 7.6 ) , and 5.3 ( 7.3 ) , while the respective mean Sharp/van der Heijde scores changes from baseline to 5 years were 1.6 ( 95 % CI 0.0 to 3.4 ) and 3.7 ( 95 % CI 2.2 to 5.8 ) ( p=0.13 ) . Conclusions In early RA , targeted treatment with a combination of traditional DMARDs and prednisolone induces remission and minimises radiographic progression in most patients up to 5 years ; adding initial infliximab for 6 months does not improve these outcomes [5656933] In disease‐modifying antirheumatic drug – naive patients with early rheumatoid arthritis ( RA ) who had achieved sustained low disease activity ( a Disease Activity Score in 28 joints using the erythrocyte sedimentation rate of ≤3.2 at both week 40 and week 52 ) after 1 year of treatment with certolizumab pegol ( CZP ) at a st and ard dose ( 200 mg every 2 weeks plus optimized methotrexate [ MTX ] ) , we evaluated whether continuation of CZP treatment at a st and ard dose or at a reduced frequency ( 200 mg every 4 weeks plus MTX ) was superior to stopping CZP ( placebo plus MTX ) in maintaining low disease activity for 1 additional year [24412895] Objectives To investigate whether a treat-to-target strategy with methotrexate and intra-articular glucocorticosteroid injections suppresses MRI inflammation and halts structural damage progression in patients with early rheumatoid arthritis ( ERA ) , and whether adalimumab provides an additional effect . Methods In a double-blind , placebo-controlled trial , 85 disease-modifying antirheumatic drug-naïve patients with ERA were r and omised to receive methotrexate , intra-articular glucocorticosteroid injections and placebo/adalimumab ( 43/42 ) . Contrast-enhanced MRI of the right h and was performed at months 0 , 6 and 12 . Synovitis , osteitis , tenosynovitis , MRI bone erosion and joint space narrowing ( JSN ) were scored with vali date d methods . Dynamic contrast-enhanced MRI ( DCE-MRI ) was carried out in 14 patients . Results Synovitis , osteitis and tenosynovitis scores decreased highly significantly ( p<0.0001 ) during the 12-months ’ follow-up , with mean change scores of −3.7 ( median −3.0 ) , −2.2 ( −1 ) and −5.3 ( −4.0 ) , respectively . No overall change in MRI bone erosion and JSN scores was seen , with change scores of 0.1 ( 0 ) and 0.2 ( 0 ) . The tenosynovitis score at month 6 was significantly lower in the adalimumab group , 1.3 ( 0 ) , than in the placebo group , 3.9 ( 2 ) , Mann – Whitney : p<0.035 . Furthermore , the osteitis score decreased significantly during the 12-months ’ follow-up in the adalimumab group , but not in the placebo group , Wilcoxon : p=0.001–0.002 and p=0.062–0.146 . DCE-MRI parameters correlated closely with conventional MRI inflammatory parameters . Clinical measures decreased highly significantly during follow-up . Conclusions A treat-to-target strategy with methotrexate and intra-articular glucocorticosteroid in patients with ERA effectively decreased synovitis , osteitis and tenosynovitis and halted structural damage progression as judged by MRI . The findings suggest that addition of adalimumab is associated with further suppression of osteitis and tenosynovitis [24168956] BACKGROUND Biological agents offer good control of rheumatoid arthritis , but the long-term benefits of achieving low disease activity with a biological agent plus methotrexate or methotrexate alone are unclear . The OPTIMA trial assessed different treatment adjustment strategies in patients with early rheumatoid arthritis attaining ( or not ) stable low disease activity with adalimumab plus methotrexate or methotrexate monotherapy . METHODS This trial was done at 161 sites worldwide . Patients with early ( < 1 year duration ) rheumatoid arthritis naive to methotrexate were r and omly allocated ( by interactive voice response system , in a 1:1 ratio , block size four ) to adalimumab ( 40 mg every other week ) plus methotrexate ( initiated at 7·5 mg/week , increased by 2·5 mg every 1 - 2 weeks to a maximum weekly dose of 20 mg by week 8) or placebo plus methotrexate for 26 weeks ( period 1 ) . Patients in the adalimumab plus methotrexate group who completed period 1 and achieved the stable low disease activity target ( 28-joint disease activity score with C-reactive protein [DAS28]<3·2 at weeks 22 and 26 ) were r and omised to adalimumab-continuation or adalimumab-withdrawal for an additional 52 weeks ( period 2 ) . Patients achieving the target with initial methotrexate continued methotrexate-monotherapy . Inadequate responders were offered adalimumab plus methotrexate . All patients and investigators were masked to treatment allocation in period 1 . During period 2 , treatment reallocation of patients who achieved the target was masked to patients and investigators ; patients who did not achieve the target remained masked to original r and omisation , but were aware of the subsequent assignment . The primary endpoint was a composite measure of DAS28 of less than 3·2 at week 78 and radiographic non-progression from baseline to week 78 , compared between adalimumab-continuation and methotrexate-monotherapy . Adverse events were monitored throughout period 2 . This trial is registered with Clinical Trials.gov , number NCT00420927 . FINDINGS The study was done between Dec 28 , 2006 , and Aug 3 , 2010 . 1636 patients were assessed and 1032 were r and omised in period 1 ( 515 to adalimumab plus methotrexate ; 517 to placebo plus methotrexate ) . 466 patients in the adalimumab plus methotrexate group completed period 1 ; 207 achieved the stable low disease activity target , of whom 105 were rer and omised to adalimumab-continuation . 460 patients in the placebo plus methotrexate group completed period 1 ; 112 achieved the stable low disease activity target and continued methotrexate-monotherapy . 73 of 105 ( 70 % ) patients in the adalimumab-continuation group and 61 of 112 ( 54 % ) patients in the methotrexate-monotherapy group achieved the primary endpoint at week 78 ( mean difference 15 % [ 95 % CI 2 - 28 % ] , p=0·0225 ) . Patients achieving the stable low disease activity target on adalimumab plus methotrexate who withdrew adalimumab mostly maintained their good responses . Overall , 706 of 926 patients in period 2 had an adverse event , of which 82 were deemed serious ; however , distribution of adverse events did not differ between groups . INTERPRETATION Treatment to a stable low disease activity target result ed in improved clinical , functional , and structural outcomes , with both adalimumab-continuation and methotrexate-monotherapy . However , a higher proportion of patients treated with initial adalimumab plus methotrexate achieved the low disease activity target compared with those initially treated with methotrexate alone . Outcomes were much the same whether adalimumab was continued or withdrawn in patients who initially responded to adalimumab plus methotrexate . FUNDING AbbVie [15996057] OBJECTIVE To evaluate safety , efficacy , and radiographic progression in patients with early rheumatoid arthritis ( RA ) undergoing longterm treatment with etanercept . METHODS Patients with early RA ( disease duration of 3 years or less ) who had completed a 2-year efficacy study comparing etanercept and methotrexate ( MTX ) were followed in an extension where they received 25 mg etanercept twice weekly . Safety was summarized descriptively and compared with data from the efficacy study . Efficacy and radiographic progression were assessed using American College of Rheumatology response criteria , disease activity scores , and Total Sharp Score ( TSS ) . RESULTS Rates of serious adverse events and serious infections did not increase with longterm exposure to etanercept , and were similar to rates reported for the blinded portion of the efficacy study . Efficacy was sustained in patients who completed 5 years of etanercept treatment at the time of this report ( N = 201 ) , even in those who decreased or discontinued use of MTX or corticosteroids . No radiographic progression ( change in TSS < or = 0 ) was seen in 55 % of patients with 5-year radiographs ; negative change ( TSS < 0 ) was seen in 11 % . CONCLUSION Etanercept treatment in patients with early RA was generally well tolerated for up to 5 years . The results indicate sustained efficacy and decreased rate of radiographic progression . The rate of radiographic progression was low compared with other studies , emphasizing the benefit gained in patients with early aggressive RA who undergo longterm treatment with etanercept [26324784] Objectives : It is well recognized that medication adherence of rheumatoid arthritis ( RA ) patients is often poor . As less attention has been paid to physicians ’ adherence to targeted treatment , we aim ed to investigate how it affects outcomes in aggressively treated early RA patients . Method : In the new Finnish RA Combination Therapy ( NEO-RACo ) trial , 99 patients with early active RA were treated , targeting remission , with a combination of methotrexate , sulfasalazine , hydroxychloroquine , and low-dose prednisolone for 2 years , and r and omized to receive infliximab or placebo for the initial 6 months . After 2 years , therapy was unrestricted while remission was still targeted . Patients were divided into tertiles by physicians ’ adherence to treat-to-target , which was evaluated with a scoring system during the initial 2 years . After 5 years of follow-up , the between-tertile differences in remission rates , 28-joint Disease Activity Score ( DAS28 ) levels , radiological changes , cumulative days off work , and the use of anti-rheumatic medication were assessed . Results : Follow-up data were available for 93 patients . Physicians ’ good adherence was associated with improved remission rates at 2–4 years and lower DAS28 levels throughout the follow-up . In a multivariable model , physicians ’ adherence was the most important predictor of remission at 3 months and 2 years ( p < 0.001 for both ) . Between 2 and 5 years , biologics were used more often in the tertile of low adherence compared with the other two groups ( p = 0.024 ) . No significant differences were observed in radiological progression and cumulative days off work . Conclusions : Physicians ’ good adherence is associated with improved remission rates and lesser use of biologics in early RA [27494516] OBJECTIVES To study the effects of neglecting intra-articular glucocorticoid injections ( IAGCIs ) into swollen joints in early rheumatoid arthritis ( RA ) . METHODS Ninety-nine patients with early , DMARD naive RA were treated , aim ing at remission , with methotrexate , sulfasalazine , hydroxychloroquine , low-dose oral prednisolone and , when needed , IAGCIs for 2 years , and r and omised to receive infliximab or placebo from weeks 4 to 26 . During each of the 15 study visits , patients were scored retrospectively 0.2 - 0.4 points ( depending on the number of non-injected joints ) if IAGCIs to all swollen joints were not given . Patients were divided into tertiles by their cumulative scores for neglected injections ( CSNI ) over 24 months . 28-joint disease activity score ( DAS28 ) area under the curve ( AUC ) between 0 - 24 months , remission rates , changes in quality of life , and radiological changes during the follow-up were assessed . Trends across tertiles of CSNI were tested with generalised linear models . RESULTS Higher CSNI was associated with lower strict remission rates ( p=0.005 ) , and lower quality of life ( p=0.004 ) at 24 months , and higher DAS28 AUC ( p<0.001 ) during the follow-up . At 24 months , DAS28 remission rates were 90 % , 93 % and 76 % ( p=0.081 ) , and strict remission rates were 74 % , 77 % and 39 % by tertiles of CSNI . No significant differences were observed in radiological progression ( p=0.089 ) . IAGCIs were well tolerated . CONCLUSIONS Neglecting IAGCIs into swollen joints is associated with lower remission rates , higher disease activity , and lower quality of life . Hence , IAGCIs should be used as an integral part of the targeted treatment of early RA [11096165] BACKGROUND Etanercept , which blocks the action of tumor necrosis factor , reduces disease activity in patients with long-st and ing rheumatoid arthritis . Its efficacy in reducing disease activity and preventing joint damage in patients with active early rheumatoid arthritis is unknown . METHODS We treated 632 patients with early rheumatoid arthritis with either twice-weekly subcutaneous etanercept ( 10 or 25 mg ) or weekly oral methotrexate ( mean , 19 mg per week ) for 12 months . Clinical response was defined as the percent improvement in disease activity according to the criteria of the American College of Rheumatology . Bone erosion and joint-space narrowing were measured radiographically and scored with use of the Sharp scale . On this scale , an increase of 1 point represents one new erosion or minimal narrowing . RESULTS As compared with patients who received methotrexate , patients who received the 25-mg dose of etanercept had a more rapid rate of improvement , with significantly more patients having 20 percent , 50 percent , and 70 percent improvement in disease activity during the first six months ( P<0.05 ) . The mean increase in the erosion score during the first 6 months was 0.30 in the group assigned to receive 25 mg of etanercept and 0.68 in the methotrexate group ( P= 0.001 ) , and the respective increases during the first 12 months were 0.47 and 1.03 ( P=0.002 ) . Among patients who received the 25-mg dose of etanercept , 72 percent had no increase in the erosion score , as compared with 60 percent of patients in the methotrexate group ( P=0.007 ) . This group of patients also had fewer adverse events ( P=0.02 ) and fewer infections ( P= 0.006 ) than the group that was treated with methotrexate . CONCLUSIONS As compared with oral methotrexate , subcutaneous [ corrected ] etanercept acted more rapidly to decrease symptoms and slow joint damage in patients with early active rheumatoid arthritis [26489704] Objectives To study clinical and radiographic outcomes after withdrawing 1 year 's adalimumab induction therapy for early rheumatoid arthritis ( eRA ) added to a methotrexate and intra-articular triamcinolone hexacetonide treat-to-target strategy ( NCT00660647 ) . Methods Disease-modifying antirheumatic drug (DMARD)-naive patients with eRA started methotrexate ( 20 mg/week ) and intra-articular triamcinolone ( 20 mg/ml ) for 2 years . In addition , they were r and omised to receive placebo adalimumab ( DMARD group , n=91 ) or adalimumab ( 40 mg/every other week ) ( DMARD+adalimumab group , n=89 ) during the first year . Sulfasalazine and hydroxychloroquine were added if disease activity persisted after 3 months . During year 2 , synthetic DMARDs continued . Adalimumab was (re)initiated if active disease reoccurred . Clinical response , remission , disability , quality of life and radiographic changes were assessed . Results One year after adalimumab withdrawal , treatment profiles and clinical responses did not differ between groups . In the DMARD/DMARD+adalimumab groups , the median 2-year methotrexate dose was 20/20 mg/week ( p=0.45 ) , triple DMARD therapy had been initiated in 33/27 patients ( p=0.49 ) , adalimumab was (re)initiated in 12/12 patients and cumulative triamcinolone dose was 160/120 mg ( p=0.15 ) . The treatment target ( disease activity score , 4 variables , C-reactive protein ( DAS28CRP ) ≤3.2 or DAS28>3.2 without swollen joints ) was achieved at all visits in ≥85 % of patients in year 2 ; remission rates were DAS28CRP<2.6:69%/66 % ; Clinical Disease Activity Index ≤2.8:55%/57 % ; Simplified Disease Activity Index < 3.3:54%/49 % ; American College of Rheumatology/European League against Rheumatism ( 28 joints):44%/45 % ( p=0.66–1.00 ) . Radiographic progression ( Δtotal Sharp score/year ) was similar 1.31/0.53 ( p=0.12 ) . Erosive progression ( Δerosion score (ES)/year ) was year 1:0.57/0.06 ( p=0.02 ) ; year 2:0.38/0.05 ( p=0.005 ) . Proportion of patients without erosive progression ( ΔES≤0 ) was year 1 : 59%/76 % ( p=0.03 ) ; year 2:64%/79 % ( p=0.04 ) . Conclusions An aggressive triamcinolone and synthetic DMARD treat-to-target strategy in eRA provided excellent 2-year clinical and radiographic disease control independent of adalimumab induction therapy . ES progression was slightly less during and following adalimumab induction therapy . Trial registration number NCT00660647 [22045836] Objective . Rheumatoid arthritis ( RA ) is associated with significant impairments in health-related quality of life ( HRQOL ) . We evaluated patient-reported outcomes including HRQOL outcomes following adalimumab plus methotrexate ( MTX ) therapy in patients with early RA . Methods . PREMIER was a phase III , multicenter , r and omized , double-blind , active-comparator clinical trial in early RA . Patients aged ≥ 18 years were r and omly assigned to receive adalimumab 40 mg every other week ( eow ) plus weekly MTX , weekly MTX , or adalimumab 40 mg eow for 104 weeks . American College of Rheumatology ( ACR ) criteria were used to evaluate clinical efficacy and response . Outcomes were assessed using the Health Assessment Question naire Disability Index ( HAQ-DI ) , Short-Form 36 Health Survey ( SF-36 ) , Short-Form 6 Dimension ( SF-6D ) , visual analog scale ( VAS ) assessment s of global disease activity ( patient ’s global assessment ; PtGA ) and pain , Functional Assessment of Chronic Illness Therapy-Fatigue ( FACIT-F ) , and Health Utility Index Mark 3 ( HUI-3 ) . Results . Of 799 patients enrolled , 268 received adalimumab plus MTX , 257 received MTX monotherapy , and 274 received adalimumab monotherapy . Patients treated with adalimumab plus MTX demonstrated significant baseline to Week 104 improvements in HAQ-DI ( p < 0.0001 ) , SF-36 Physical Component Summary ( p < 0.0001 ) , 4 SF-36 domains [ physical function ( p < 0.0001 ) , bodily pain ( p < 0.0001 ) , vitality ( p = 0.0139 ) , role limitations -physical ( p = 0.0005 ) ] , SF-6D ( p = 0.0152 ) , VAS-PtGA ( p < 0.0001 ) , VAS-pain ( p < 0.0001 ) , FACIT-F ( p < 0.0001 ) , and HUI-3 ( p = 0.0034 ) scores versus patients treated with MTX monotherapy . Both SF-6D and HUI-3 were found to be sensitive preference-based measures for assessing the effects of treatment on multidimensional function . No clinical ly meaningful differences between adalimumab and MTX monotherapy groups were observed for most measures . For each measure , there was significant association between HRQOL improvement and ACR clinical response . Conclusion . Adalimumab plus MTX significantly improved physical functioning and HRQOL in patients with early RA over 2 years of treatment . ( Clinical Trials.gov identifier NCT00195663 ) [26087654] Objectives : To investigate the levels of interleukin (IL)-23 in patients with early rheumatoid arthritis ( eRA ) and the effect of anti-tumour necrosis factor (anti-TNF)-α treatment on IL-23 levels . Method : Treatment-naïve eRA patients from the OPERA cohort were included ( n = 151 ) . Patients were r and omized to methotrexate ( MTX ) plus adalimumab ( ADA ; n = 75 ) or MTX plus placebo-ADA ( PLA ; n = 76 ) . Plasma sample s were obtained at baseline and at months 3 , 6 , and 12 together with values for C-reactive protein ( CRP ) , the 28-joint Disease Activity Score based on CRP ( DAS28CRP ) , scores on the Clinical Disease Activity Index ( CDAI ) and the Simplified Disease Activity Index ( SDAI ) , visual analogue scale ( VAS ) for pain/fatigue/physician global and total Sharp/van der Heijde score ( TSS ) . IL-23 was measured at each time point . Results : IL-23 levels decreased significantly in the ADA group from 20.6 pg/mL ( IQR 13.1–32.7 pg/mL ) at baseline to 18 pg/mL ( IQR 7.2–25.0 pg/mL ) at 12 months ( p < 0.01 ) . No significant decrease in IL-23 level was observed in the PLA group . No associations between baseline IL-23 levels and measures of disease activity ( DAS28CRP , CRP , CDAI , or SDAI ) at 12 or 24 months were present in the treatment groups . Baseline IL-23 correlated inversely with changes in TSS and symptom duration before diagnosis . Conclusions : Our data show increased baseline levels and a significant decrease in IL-23 levels in eRA patients treated with anti-TNF-α . The inverse correlation with duration of symptoms before diagnosis supports the importance of IL-23 in the pre clinical disease development of RA [27089068] Context A treat-to-target strategy , or treatment to achieve low disease activity , has been associated with improved outcomes among patients with early active rheumatoid arthritis ( RA ) . Long-term data on this approach are lacking . Contribution This r and omized , controlled trial compared 4 treat-to-target strategies for early active RA over 10 years . Most patients had persistently reduced disease activity scores , improved functional status , and limited joint damage during follow-up . They had survival similar to that of the general Dutch population . Caution The trial lacked a nontargeted treatment strategy . Implication Potential outcomes of a treat-to-target approach for early RA include sustained clinical improvement , drug-free remission , and normalized survival . Suppression of inflammation in patients with rheumatoid arthritis ( RA ) is associated with clinical improvement and prevention of radiographic joint damage . Rapid suppression can be achieved with initial combination therapy , including synthetic disease-modifying antirheumatic drugs and corticosteroids or a tumor necrosis factor- inhibitor ( 17 ) . In addition , tightly controlled targeted treatment ( that is , frequent measurements of disease activity with treatment adjustments aim ing to achieve a predefined target ) results in better outcomes than routine care ( 8 , 9 ) . The BeSt ( Beh and elStrategien in reumatode artritis ) study integrated a treat-to-target concept to achieve low disease activity ( defined as a disease activity score [ DAS ] 2.4 ) with a comparison of 4 dynamic treatment strategies . Patients with early active RA were r and omly assigned to sequential monotherapy , step-up combination therapy , or initial combination therapy with either prednisone or an antitumor necrosis factor- agent ( infliximab ) . Based on measurements of disease activity every 3 months , the medication dosage was increased when the DAS was higher than 2.4 and tapered if DAS was persistently 2.4 or less . The study compared the clinical , radiographic , and toxicity outcomes of these strategies over time . We report on these outcomes among participants during 10-year follow-up and compare their survival with that of the general population . Methods Design Overview The r and omized , multicenter , assessor-blinded BeSt study ( 2 ) was design ed by Dutch rheumatologists to determine in which order available antirheumatic medication could best be used to treat patients with newly diagnosed RA , aim ing at low disease activity over 10 years . The original study protocol and amendments for study extension after 2 and 5 years ( Supplements 1 through 3 ) were approved by the medical ethics committees of all participating hospitals . All patients gave written informed consent . Supplement . Data Supplement Setting and Participants The study enrolled 508 patients aged 18 years or older with early active RA according to the revised 1987 American College of Rheumatology criteria for RA ( 10 ) , with symptom duration of fewer than 2 years . They were recruited in 18 nonuniversity and 2 university hospitals in the Netherl and s between 2000 and 2002 . Exclusion criteria encompassed contraindications to the antirheumatic medications used in the study protocol ( Appendix 1 ) ( 2 , 11 ) . R and omization and Interventions Patients were allocated to 1 of 4 dynamic treatment strategies by variable block r and omization , stratified by center : strategy 1 , sequential monotherapy ; strategy 2 , step-up combination therapy ( both starting with methotrexate monotherapy ) ; strategy 3 ; initial combination therapy with methotrexate , sulfasalazine , and prednisone ; and strategy 4 , initial combination therapy with methotrexate and infliximab . For all strategies , subsequent treatment adjustments were specified in the study protocol for patients with an inadequate response ( Appendix Figure 1 ) . Over 10 years , treatment response was measured every 3 months using the DAS ( 12 ) based on a swollen joint count in 44 joints , a tender joint count in 53 joints ( Ritchie articular index ) ( 13 ) , erythrocyte sedimentation rate , and patient 's assessment of global health on a visual analogue scale ( 0 to 100 mm ) ( 12 ) . A DAS of 2.4 or less , indicating low disease activity ( 14 ) , was set as the treatment goal . Treatment was intensified ( medication changed or dosage increased , according to the treatment strategy ) at each study visit that the DAS was greater than 2.4 ( Appendix Figure 1 ) . In case of a continued good response ( DAS 2.4 for 6 months ) , dosage was tapered to a maintenance dose ( if DAS remained < 1.6 for 6 months ; defined as remission ) ( 15 ) and eventually discontinued ( defined as drug-free remission [ DFR ] ) ( Appendix 2 ) . Appendix Figure 1 . Flow diagram of treatment steps per strategy . The figure shows the required treatment intensification steps for each strategy as long as the DAS remained > 2.4 when measured every 3 mo . In all 4 strategies , patients may progress from one treatment step to the next at different times , depending on individual DAS results determined at observation every 3 mo . Patients receiving infliximab ( who receive their dose every 8 wk ) had additional DAS measurements 1 wk before each infusion . These measurements dictated if the next dose needed to be increased . Doses started at 3 mg/kg of body weight . If the DAS was greater than 2.4 , the dose was increased in a stepwise manner to 6 mg/kg , then 7.5 mg/kg , and finally 10 mg/kg ( always rounded to the nearest hundredth ) . The dosage could be tapered if DAS calculations determined every 3 mo were 2.4 or less for at least 6 mo consecutively . Medication dosages were as follows : azathioprine , 2 mg/kg to 3 mg/kg per day ; cyclosporine A , 2.5 mg/kg per day ; methylprednisolone , 3 doses of 120 mg in weeks 1 , 4 , and 8 ; gold , 50 mg/wk ; hydroxychloroquine , 200 mg/d ; infliximab , dose as indicated every 8 wk ; leflunomide , 20 mg/d ; methotrexate , dose as indicated every week ; prednisone , 7.5 mg/d unless indicated otherwise ; sulfasalazine , 2000 mg/d . DAS= disease activity score . Outcomes and Follow-up The patients were clinical ly assessed every 3 months at study visits during the 10-year follow-up . Functional status , laboratory tests , and adverse events ( AEs ) were assessed . Functional ability was measured using the Health Assessment Question naire ( HAQ ) ( range , 0 [ best ] to 3 [ worst ] ) ( 16 ) . Conventional radiography of h and s and feet were performed annually to assess joint damage progression . All radiographs from baseline to year 10 were scored by 2 independent blinded readers using the modified Sharpvan der Heijde score ( SHS ) ( range 0 [ best ] to 448 [ worst ] ) ( 17 ) in 1 session in r and om order . The intraclass correlation coefficient between the 2 readers was 0.96 ( 95 % CI , 0.95 to 0.97 ) . The mean score of the 2 readers was used for the analysis . The AEs , either reported during visits or apparent in continued laboratory assessment s every 3 months , and serious AEs ( SAEs ) , which also included death during follow-up , were recorded during the trial . For patients who dropped out of the study , life and death status from inclusion to year 10 was obtained from the hospital ( where they enrolled ) , general practitioner , or municipality of the patient 's residence . Those who emigrated and could not be traced thereafter were censored from the date of emigration ( n= 6 ) . One patient could not be located after loss to follow-up and was also censored from the last moment of contact . Survival data of the general Dutch population were acquired from Statistics Netherl and s. Statistical Analysis For each analysis , patients were analyzed in their allocated treatment strategy at baseline , regardless of the number of treatment steps during follow-up . Time to dropout was compared among the treatment strategies with the log-rank test . The HAQ score , low disease activity , remission rate , DFR , SHS , and initial treatment step at year 10 ( intention-to-treat and completer analyses ) were reported separately for each strategy . After multiple imputation of the DAS , the percentages of low disease activity ( DAS 2.4 ) and remission ( DAS < 1.6 ) at year 10 were estimated and compared among the strategies . The imputation model included terms for observed DAS , HAQ score , r and omization strategy , age , sex , anticitrullinated peptide antibody , rheumatoid factor , SHS , and treatment step ; 10 data sets were imputed ( Supplement 4 ) . The imputation method assumed the missing values to be missing at r and om . Sensitivity analyses using controlled imputation methods ( 18 ) tested the robustness of this assumption against violations ( Supplement 4 ) . The HAQ score was analyzed over time using a linear mixed model , taking into account repeated measurements , with a Toeplitz covariance type under the assumption of equally spaced visits ( scheduled every 3 months ) . This model included time as a continuous variable , treatment , and a time-by-treatment interaction term . Sensitivity analyses were also performed for this outcome ( Supplement 4 ) . Radiographic progression at 10 years ( defined as an increase in SHS from baseline to year 10 ) was observed in patients who completed the study using a cumulative probability plot . Radiographic progression over time was analyzed by using a weighted generalized estimating equation ( GEE ) with a negative binomial working distribution , AR1 ( that is , autoregressive ) working correlation , and robust estimation of SEs . This analysis is valid under the missing-at-r and om assumption and was chosen because of the skewed nature of the SHS ( 18 ) . Weights per patient per year were found by using a logistic regression that modeled the inverse probability of a patient having radiographic data available at that measurement time ( Supplement 5 ) . Survival in the study population was compared with the general population ( matched by sex , age , and calendar year ) using the st and ardized mortality ratio : ( observed deathsexpected deaths ) ( 19 ) . KaplanMeier curves and the log-rank test were used to compare survival among the treatment strategies . Cox regression analysis was used to identify [29142030] Objective . The aim was to identify plasma ( i.e. , cell-free ) microRNA ( miRNA ) predicting antitumor necrosis and /or methotrexate ( MTX ) treatment response in patients enrolled in an investigator-initiated , prospect i ve , double-blinded , placebo-controlled trial ( The OPERA study , NCT00660647 ) . Methods . We included 180 disease-modifying antirheumatic drug – naive patients with early rheumatoid arthritis ( RA ) r and omized to adalimumab ( ADA ; n = 89 ) or placebo ( n = 91 ) in combination with MTX . Plasma sample s before and 3 months after treatment initiation were analyzed for 91 specific miRNA by quantitative reverse transcriptase-polymerase chain reaction on microfluidic dynamic arrays . A linear mixed-effects model was used to test for associations between pretreatment miRNA and changes in miRNA expression and American College of Rheumatology/European League Against Rheumatism ( ACR/EULAR ) Boolean ( 28 joints ) remission at 3 and 12 months , applying false discovery rate correction for multiple testing . Using leave-one-out cross validation , we built predictive multivariate miRNA models and estimated classification performances using receiver-operating characteristics ( ROC ) curves . Results . In the ADA group , a higher pretreatment level of miR-27a-3p was significantly associated with remission at 12 months . The level decreased in remitting patients between pretreatment and 3 months , and increased in nonremitting patients . No associations were found in the placebo group receiving only MTX . Two multivariate miRNA models were able to predict response to ADA treatment after 3 and 12 months , with 63 % and 82 % area under the ROC curves , respectively . Conclusion . We identified miR-27a-3p as a potential predictive biomarker of ACR/EULAR remission in patients with early RA treated with ADA in combination with MTX . We conclude that pretreatment plasma-miRNA profiles may be of predictive value , but the results need confirmation in independent cohorts [29985080] Objectives : Measurement of serum biomarkers at disease onset may improve prediction of disease course in patients with early rheumatoid arthritis ( RA ) . We evaluated the multi-biomarker disease activity ( MBDA ) score and early changes in MBDA score for prediction of 28-joint Disease Activity Score based on C-reactive protein ( DAS28-CRP ) remission and radiographic progression in the double-blinded OPERA trial . Method : Treatment-naïve RA patients ( N = 180 ) with moderate or high DAS28 were r and omized to methotrexate ( MTX ) + adalimumab ( n = 89 ) or MTX + placebo ( n = 91 ) in combination with glucocorticoid injection into swollen joints . X-rays of h and s and feet were evaluated at months 0 and 12 ( n = 164 ) by the total Sharp van der Heijde score ( TSS ) . The smallest detectable change ( 1.8 TSS units ) defined radiographic progression ( ∆TSS ≥ 2 ) . Clinical remission ( DAS28-CRP < 2.6 ) was assessed at baseline and 6 months . MBDA score was determined at 0 and 3 months and tested in a multivariable logistic regression model for predicting DAS28 remission at 6 months and radiographic progression at 1 year . Results : Baseline MBDA score was independently associated with radiographic progression at 1 year [ odds ratio ( OR ) = 1.03/unit , 95 % confidence interval ( CI ) = 1.01–1.06 ] , and changes in MBDA score from baseline to 3 months with clinical remission at 6 months [ OR = 0.98/unit , 95 % CI 0.96–1.00 ) . In anti-cyclic citrullinated peptide antibody (anti-CCP)-positive patients , 35 of 89 with high MBDA score ( > 44 ) showed radiographic progression ( PPV = 39 % ) , compared with 0 of 15 patients ( NPV = 100 % ) with low/moderate MBDA score ( ≤ 44 ) ( p = 0.003 ) . Conclusion : Early changes in MBDA score were associated with clinical remission based on DAS28-CRP at 6 months . In anti-CCP-positive patients , a non-high baseline MBDA score ( ≤ 44 ) had a clinical value by predicting very low risk of radiographic progression at 12 months [6085639] Background In the present study , we explored the effects of immediate induction therapy with the anti-tumour necrosis factor (TNF)α antibody infliximab ( IFX ) plus methotrexate ( MTX ) compared with MTX alone and with placebo ( PL ) in patients with very early inflammatory arthritis . Methods In an investigator-initiated , double-blind , r and omised , placebo-controlled , multi-centre trial ( IS RCT N21272423 , http://www.is rct n.com/IS RCT N21272423 ) , patients with synovitis of 12 weeks duration in at least two joints underwent 1 year of treatment with IFX in combination with MTX , MTX monotherapy , or PL r and omised in a 2:2:1 ratio . The primary endpoint was clinical remission after 1 year ( sustained for at least two consecutive visits 8 weeks apart ) with remission defined as no swollen joints , 0–2 tender joints , and an acute-phase reactant within the normal range . Results Ninety patients participated in the present study . At week 54 ( primary endpoint ) , 32 % of the patients in the IFX + MTX group achieved sustained remission compared with 14 % on MTX alone and 0 % on PL . This difference ( p < 0.05 over all three groups ) was statistically significant for IFX + MTX vs PL ( p < 0.05 ) , but not for IFX + MTX vs MTX ( p = 0.10 ) , nor for MTX vs PL ( p = 0.31 ) . Remission was maintained during the second year on no therapy in 75 % of the IFX + MTX patients compared with 20 % of the MTX-only patients . Conclusions These results indicate that patients with early arthritis can benefit from induction therapy with anti-TNF plus MTX compared with MTX alone , suggesting that intensive treatment can alter the disease evolution . Trial registration The trial was registered at http://www.is rct n.com/IS RCT N21272423 on 4 October 2007 ( date applied)/12 December 2007 ( date assigned ) . The first patient was included on 24 October 2007 [27114561] OBJECTIVES To evaluate the effects of adalimumab plus MTX ( ADA + MTX ) vs MTX monotherapy on work-related outcomes in early RA patients with elevated risk of employment loss . METHODS A post hoc analysis at weeks 26 and 24 from the Optimal Protocol for Treatment Initiation with Methotrexate and Adalimumab ( OPTIMA ) and PRevention Of Work Disability ( PROWD ) trials , respectively , was conducted in MTX-naïve RA patients r and omized to ADA + MTX or placebo ( PBO ) + MTX . Work instability was assessed using the RA-Work Instability Scale ( RA-WIS ) and work productivity was measured with the Work Productivity and Activity Impairment Question naire . Employed patients with a baseline RA-WIS score ⩾10 , indicating medium to high risk for job loss , were included ( OPTIMA , n = 320 ; PROWD , n = 124 ) . RESULTS Patients receiving ADA + MTX in OPTIMA had significantly greater improvements in RA-WIS compared with PBO + MTX ( mean change -7.22 vs -5.23 , respectively ) . Significantly higher percentages of patients in the ADA + MTX group experienced improvements in one or more risk category ( 58 vs 47 % ) and ⩾5 ( 55 vs 43 % ) , ⩾7 ( 47 vs 35 % ) and ⩾9 ( 42 % vs 26 % ) points in their RA-WIS score . These trends were seen in PROWD but were not significant . In OPTIMA , patients receiving ADA + MTX showed significant changes in percentage points from baseline vs PBO + MTX in activity impairment , presenteeism and overall work impairment ( -32.0 vs -23.7 , -24.6 vs -17.1 , -27.3 vs -18.3 , respectively ) . CONCLUSIONS Among early RA patients with elevated risk of employment loss , ADA + MTX therapy was associated with a significant reduction in work instability vs PBO + MTX . Significantly greater percentages of patients receiving ADA + MTX therapy achieved clinical ly meaningful improvements in their RA-WIS scores [26091907] Objective To evaluate the construct validity of the rheumatoid arthritis MRI score ( RAMRIS ) erosion evaluation as structural damage end point and to assess the potential impact of incorporation in clinical trials . Methods In a r and omised trial of early methotrexate-naïve RA ( GO-BEFORE ) , RAMRIS scores were determined from MRIs and van der Heijde-Sharp ( vdHS ) scores from radiographs , at baseline , week 12 , week 24 and week 52 . Progression in damage scores was defined as change > 0.5 . Associations of X-ray and MRI outcomes with clinical features were evaluated for convergent validity . Iterative Wilcoxon rank sum tests and tests of proportion estimated the sample size required to detect differences between combination therapy ( methotrexate+golimumab ) and methotrexate-monotherapy arms in ( A ) change in damage score and ( B ) proportion of patients progressing . Results Patients with early MRI progression had higher DAS28 , C reactive protein ( CRP ) and vdHS at baseline , and higher 2-year HAQ . Associations were similar to those with 1-year vdHS progression . Differences in change in structural damage between treatment arms achieved significance with fewer subjects when 12-week or 24-week MRI erosion score was the outcome ( 150 patients ; 100 among an enriched sample with baseline-synovitis > 5 ) compared with the 52-week vdHS ( 275 patients ) . Differences in the proportion progressing could be detected in 234 total subjects with 12-week MRI in an enriched sample whereas 1-year X-ray required between 468 and 1160 subjects . Conclusions Early MRI erosion progression is a valid measure of structural damage that could substantially decrease sample size and study duration if used as structural damage end point in RA clinical trials Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: OBJECTIVES Rheumatoid arthritis ( RA ) is a chronic inflammatory disease associated with increasing disability , reduced quality of life and substantial costs ( as a result of both intervention acquisition and hospitalisation ) . The objective was to assess the clinical effectiveness and cost-effectiveness of seven biologic disease-modifying antirheumatic drugs ( bDMARDs ) compared with each other and conventional disease-modifying antirheumatic drugs ( cDMARDs ) . Sensitivity analyses were undertaken to explore the impact of including RCTs with a small proportion of bDMARD experienced patients and where MTX exposure was deemed insufficient . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

30755271

[3684530] Background Women with polycystic ovary syndrome ( PCOS ) have symptoms of depression and anxiety and impaired health related quality of life ( HRQoL ) . Here we test the post-hoc hypothesis that acupuncture and exercise improve depression and anxiety symptoms and HRQoL in PCOS women . Methods Seventy-two PCOS women were r and omly assigned to 16 weeks of 1 ) acupuncture ( n = 28 ) ; 2 ) exercise ( n = 29 ) ; or 3 ) no intervention ( control ) ( n = 15 ) . Outcome measures included : change in Montgomery Åsberg Depression Rating Scale ( MADRS-S ) , Brief Scale for Anxiety ( BSA-S ) , Swedish Short-Form 36 ( SF-36 ) , and PCOS Question naire ( PCOSQ ) scores from baseline to after 16-week intervention , and to 16-week post-intervention follow-up . Results A reduction in MADRS-S and BSA-S from baseline to 16-weeks post-intervention follow-up was observed for the acupuncture group . The SF-36 domains role physical , energy/vitality , general health perception and the mental component of summary scores improved in the acupuncture group after intervention and at follow-up . Within the exercise group the role physical decreased after treatment , while physical functioning and general health perception scores increased at follow-up . The emotion domain in the PCOSQ improved after 16-weeks of intervention within all three groups , and at follow-up in acupuncture and exercise groups . At follow-up , improvement in the infertility domain was observed within the exercise group . Conclusion There was a modest improvement in depression and anxiety scores in women treated with acupuncture , and improved HRQoL scores were noted in both intervention groups . While not a primary focus of the trial , these data suggest continued investigation of mental health outcomes in women treated for PCOS.Trial registration number Clinical Trials.gov Identifier : [23482444] Acupuncture has been demonstrated to improve menstrual frequency and to decrease circulating testosterone in women with polycystic ovary syndrome ( PCOS ) . Our aim was to investigate whether acupuncture affects ovulation frequency and to underst and the underlying mechanisms of any such effect by analyzing LH and sex steroid secretion in women with PCOS . This prospect i ve , r and omized , controlled clinical trial was conducted between June 2009 and September 2010 . Thirty-two women with PCOS were r and omized to receive either acupuncture with manual and low-frequency electrical stimulation or to meetings with a physical therapist twice a week for 10 - 13 wk . Main outcome measures were changes in LH secretion patterns from baseline to after 10 - 13 wk of treatment and ovulation frequency during the treatment period . Secondary outcomes were changes in the secretion of sex steroids , anti-Müllerian hormone , inhibin B , and serum cortisol . Ovulation frequency during treatment was higher in the acupuncture group than in the control group . After 10 - 13 wk of intervention , circulating levels of estrone , estrone sulfate , estradiol , dehydroepi and rosterone , dehydroepi and rosterone sulfate , and rostenedione , testosterone , free testosterone , dihydrotestosterone , and rosterone glucuronide , and rostane-3α,17β-diol-3-glucuronide , and and rostane-3α,17β-diol-17-glucuronide decreased within the acupuncture group and were significantly lower than in the control group for all of these except and rostenedione . We conclude that repeated acupuncture treatments result ed in higher ovulation frequency in lean/overweight women with PCOS and were more effective than just meeting with the therapist . Ovarian and adrenal sex steroid serum levels were reduced with no effect on LH secretion [22158730] BACKGROUND Some evidence has suggested that a diet with a higher ratio of protein to carbohydrates has metabolic advantages in the treatment of polycystic ovary syndrome ( PCOS ) . OBJECTIVE The objective of this study was to compare the effect of a high-protein ( HP ) diet to a st and ard-protein ( SP ) diet in women with PCOS . DESIGN A controlled , 6-mo trial was conducted in 57 PCOS women . The women were assigned through rank minimization to one of the following 2 diets without caloric restriction : an HP diet ( > 40 % of energy from protein and 30 % of energy from fat ) or an SP diet ( < 15 % of energy from protein and 30 % of energy from fat ) . The women received monthly dietary counseling . At baseline and 3 and 6 mo , anthropometric measurements were performed , and blood sample s were collected . RESULTS Seven women dropped out because of pregnancy , 23 women dropped out because of other reasons , and 27 women completed the study . The HP diet produced a greater weight loss ( mean : 4.4 kg ; 95 % CI : 0.3 , 8.6 kg ) and body fat loss ( mean : 4.3 kg ; 95 % CI : 0.9 , 7.6 kg ) than the SP diet after 6 mo . Waist circumference was reduced more by the HP diet than by the SP diet . The HP diet produced greater decreases in glucose than did the SP diet , which persisted after adjustment for weight changes . There were no differences in testosterone , sex hormone-binding globulin , and blood lipids between the groups after 6 mo . However , adjustment for weight changes led to significantly lower testosterone concentrations in the SP-diet group than in the HP-diet group . CONCLUSION Replacement of carbohydrates with protein in ad libitum diets improves weight loss and improves glucose metabolism by an effect that seems to be independent of the weight loss and , thus , seems to offer an improved dietary treatment of PCOS women [26862008] Background / Objectives : The aim of the study was to compare the effect of two-meal patterns ( three vs six meals per day ) on glucose and insulin levels in women with polycystic ovary syndrome (PCOS).Subjects/ Methods : In a r and omised , crossover , 24-week study , 40 women with PCOS , aged 27±6 years , body mass index 27±6 kg/m2 , followed a weight maintenance diet ( % carbohydrates : protein : fat , 40:25:35 ) , consumed either as a three- or a six-meal pattern , with each intervention lasting for 12 weeks . Anthropometric measurements , diet compliance and subjective hunger , satiety and desire to eat were assessed biweekly . All women underwent an oral glucose tolerance test ( OGTT ) with 75 g glucose for measurement of plasma glucose and insulin at the beginning and end of each intervention . HaemoglobinA1c ( HbA1c ) , blood lipids and hepatic enzymes were measured at the beginning and end of each intervention . Results : Body weight remained stable throughout the study . Six meals decreased significantly fasting insulin ( P=0.014 ) and post-OGTT insulin sensitivity ( Matsuda index , P=0.039 ) vs three meals . After incorporation of individual changes over time , with adjustment for potential confounders , the only variable that remained significant was the Matsuda index , which was then used in multivariate analysis and general linear models . Six meals improved post-OGTT insulin sensitivity independently of age and body weight vs three meals ( P=0.012 ) . No significant differences were found between six and three meals for glucose , HbA1c , blood lipids , hepatic enzymes , subjective desire to eat and satiety . Conclusions : Six meals had a more favourable effect on post-OGTT insulin sensitivity in women with PCOS compared with isocaloric three meals [22855917] Objective : The recommended composition of a hypocaloric diet for obese women with polycystic ovary syndrome ( PCOS ) is unclear . The aim of this study was to investigate the effects of a high-protein , low-glycemic-load diet compared with a conventional hypocaloric diet on reproductive hormones , inflammatory markers , lipids , glucose , and insulin levels in obese women with PCOS . Methods : A total of 60 overweight and obese women with PCOS who did not use insulin-sensitizing agents were recruited and r and omly assigned to 1 of the 2 hypocaloric diet groups for a single-blind clinical trial . The groups included a conventional hypocaloric diet ( CHCD ) ( 15 % of daily energy from protein ) and a modified hypocaloric diet ( MHCD ) with a high-protein , low-glycemic load ( 30 % of daily energy from protein plus low-glycemic-load foods selected from a list ) that was prescribed via counseling visits weekly during 12 weeks of study . Anthropometric assessment s and biochemical measurements including reproductive hormones , inflammatory factors , lipids , glucose , and insulin were performed on fasting blood sample s at baseline and after 12 weeks of dietary intervention . Results : Weight loss was significant and similar in the 2 groups . Mean of testosterone in the MHCD and CHCD groups decreased from 1.78 ± 0.32 to 1.31 ± 0.26 ng/ml and from 1.51 ± 0.12 to 1.15 ± 0.11 ng/ml , respectively ( p < 0.001 ) . Follicle sensitizing hormone ( FSH ) , luteinizing hormone ( LH ) , and blood lipids concentrations were not changed except low-density lipoprotein cholesterol ( LDL-C ) was reduced by 24.5 % ± 12.3 % ( p < 0.001 for both ) after 12 weeks of intervention . MHCD result ed in a significant reduction in insulin level , homeostatic model assessment for insulin resistance ( HOMA ) , and high-sensitivity C- reactive protein ( hsCRP ) concentration ( p < 0.001 ) . Conclusions : In this study both hypocaloric diets significantly led to reduced body weight and and rogen levels in these two groups of women with PCOS . The combination of high-protein and low-glycemic-load foods in a modified diet caused a significant increase in insulin sensitivity and a decrease in hsCRP level when compared with a conventional diet [22552687] BACKGROUND Women with polycystic ovary syndrome ( PCOS ) present with vascular abnormalities , including elevated markers of endothelial dysfunction . There is limited evidence for the effect of lifestyle modification and weight loss on these markers . The aim of this study was to determine if 20 weeks of a high-protein energy-restricted diet with or without exercise in women with PCOS could improve endothelial function . METHODS This is a secondary analysis of a subset of 50 overweight/obese women with PCOS ( age : 30.3 ± 6.3 years ; BMI : 36.5 ± 5.7 kg/m(2 ) ) from a previous study . Participants were r and omly assigned by computer generation to one of three 20-week interventions : diet only ( DO ; n = 14 , ≈ 6000 kJ/day ) , diet and aerobic exercise ( DA ; n = 16 , ≈ 6000 kJ/day and five walking sessions/week ) and diet and combined aerobic-resistance exercise ( DC ; n = 20 , ≈ 6000 kJ/day , three walking and two strength sessions/week ) . At Weeks 0 and 20 , weight , markers of endothelial function [ vascular cell adhesion molecule-1 ( sVCAM-1 ) , inter-cellular adhesion molecule-1 ( sICAM-1 ) , plasminogen activator inhibitor-1 ( PAI-1 ) and asymmetric dimethylarginine ( ADMA ) ] , insulin resistance and hormonal profile were assessed . RESULTS All three treatments result ed in significant weight loss ( DO 7.9 ± 1.2 % , DA 11.0 ± 1.6 % , DC 8.8 ± 1.1 ; P < 0.001 for time ; P = 0.6 time × treatment ) . sVCAM-1 , sICAM-1 and PAI-1 levels decreased with weight loss ( P≤ 0.01 ) , with no differences between treatments ( P ≥ 0.4 ) . ADMA levels did not change significantly ( P = 0.06 ) . Testosterone , sex hormone-binding globulin and the free and rogen index ( FAI ) and insulin resistance also improved ( P < 0.001 ) with no differences between treatments ( P ≥ 0.2 ) . Reductions in sVCAM-1 were correlated to reductions in testosterone ( r = 0.32 , P = 0.03 ) and FAI ( r = 0.33 , P = 0.02 ) as well as weight loss ( r= 0.44 , P = 0.002 ) . Weight loss was also associated with reductions in sICAM-1 ( r= 0.37 , P = 0.008 ) . CONCLUSIONS Exercise training provided no additional benefit to following a high-protein , hypocaloric diet on markers of endothelial function in overweight/obese women with PCOS [20943753] Polycystic ovary syndrome ( PCOS ) , the most common endocrine disorder in women of reproductive age , is characterized by hyper and rogenism , oligo/amenorrhea , and polycystic ovaries . We aim ed to determine whether low-frequency electro-acupuncture ( EA ) would decrease hyper and rogenism and improve oligo/amenorrhea more effectively than physical exercise or no intervention . We r and omized 84 women with PCOS , aged 18 - 37 yr , to 16 wk of low-frequency EA , physical exercise , or no intervention . The primary outcome measure changes in the concentration of total testosterone ( T ) at week 16 determined by gas and liquid chromatography-mass spectrometry was analyzed by intention to treat . Secondary outcome measures were changes in menstrual frequency ; concentrations of and rogens , estrogens , and rogen precursors , and glucuroni date d and rogen metabolites ; and acne and hirsutism . Outcomes were assessed at baseline , after 16 wk of intervention , and after a 16-wk follow-up . After 16 wk of intervention , circulating T decreased by -25 % , and rosterone glucuronide by -30 % , and and rostane-3α,17β-diol-3-glucuronide by -28 % in the EA group ( P = 0.038 , 0.030 , and 0.047 , respectively vs. exercise ) ; menstrual frequency increased to 0.69/month from 0.28 at baseline in the EA group ( P = 0.018 vs. exercise ) . After the 16-wk follow-up , the acne score decreased by -32 % in the EA group ( P = 0.006 vs. exercise ) . Both EA and exercise improved menstrual frequency and decreased the levels of several sex steroids at week 16 and at the 16-wk follow-up compared with no intervention . Low-frequency EA and physical exercise improved hyper and rogenism and menstrual frequency more effectively than no intervention in women with PCOS . Low-frequency EA was superior to physical exercise and may be useful for treating hyper and rogenism and oligo/amenorrhea [11527911] BACKGROUND Cross-sectional studies have shown a high frequency of impaired glucose tolerance ( IGT ) and non-insulin dependent diabetes mellitus ( NIDDM ) in women with polycystic ovarian syndrome ( PCOS ) . However , little is known about the change in glucose tolerance that occurs over a period of several years in women with PCOS . METHODS Sixty-seven women with PCOS received a 75 g glucose tolerance test and measurement of lipids at baseline and at follow-up after an average time of 6.2 years . All women followed prospect ively had normal glucose tolerance ( n = 54 ) or IGT ( n = 13 ) at the start of the study . RESULTS Change in glycaemic control from baseline was frequent , with 5/54 ( 9 % ) of normoglycaemic women at baseline developing IGT and a further 4/54 ( 8 % ) moving directly from normoglycaemic to NIDDM . For women with IGT at baseline , 7/13 ( 54 % ) had NIDDM at follow-up . Body mass index ( BMI ) at baseline was an independent significant predictor of adverse change in glycaemic control . CONCLUSIONS Women with PCOS , particularly those with a high BMI , should be review ed regularly with respect to IGT or NIDDM , as the frequency of impaired glycaemic control is high , and that the rate of conversion from normal glucose tolerance to IGT or NIDDM , or from IGT to NIDDM is substantial [18728175] CONTEXT Polycystic ovary syndrome ( PCOS ) presents in adolescence , and obesity is a common finding . The benefits and risks of alternate approaches to the management of PCOS in obese adolescent women are not clear . OBJECTIVE We investigated the effects of metformin , oral contraceptives ( OCs ) , and /or lifestyle modification in obese adolescent women with PCOS . DESIGN Two small , r and omized , placebo-controlled clinical trials were performed . PATIENTS AND PARTICIPANTS A total of 79 obese adolescent women with PCOS participated . INTERVENTIONS In the single treatment trial , subjects were r and omized to metformin , placebo , a lifestyle modification program , or OC . In the combined treatment trial , all subjects received lifestyle modification and OC and were r and omized to metformin or placebo . MAIN OUTCOME MEASURES Serum concentrations of and rogens and lipids were measured . RESULTS Lifestyle modification alone result ed in a 59 % reduction in free and rogen index with a 122 % increase in SHBG . OC result ed in a significant decrease in total testosterone ( 44 % ) and free and rogen index ( 86 % ) but also result ed in an increase in C-reactive protein ( 39.7 % ) and cholesterol ( 14 % ) . The combination of lifestyle modification , OC , and metformin result ed in a 55 % decrease in total testosterone , as compared to 33 % with combined treatment and placebo , a 4 % reduction in waist circumference , and a significant increase in HDL ( 46 % ) . CONCLUSIONS In these preliminary trials , both lifestyle modification and OCs significantly reduce and rogens and increase SHBG in obese adolescents with PCOS . Metformin , in combination with lifestyle modification and OC , reduces central adiposity , reduces total testosterone , and increases HDL , but does not enhance overall weight reduction [4865007] Background To evaluate the feasibility of executing a r and omized controlled trial of progressive resistance training ( PRT ) in women with polycystic ovary syndrome ( PCOS ) . Methods Women with PCOS were r and omized to an experimental ( PRT ) group or a no-exercise ( usual care ) control group . The PRT group was prescribed two supervised and two unsupervised ( home-based ) training sessions per week for 12 weeks . Feasibility outcomes included recruitment and attrition , adherence , adverse events , and completion of assessment s. Secondary outcomes , collected pre and post intervention , included a range of pertinent physiological , functional and psychological measures . Results Fifteen participants were r and omised into the PRT group ( n = 8) or control group ( n = 7 ) ; five women ( n = 2 in PRT group and n = 3 in control group ) withdrew from the study . The most successful recruitment sources were Facebook ( 40 % ) and online advertisement ( 27 % ) , while least successful methods were referrals by clinicians , colleagues and flyers . In the PRT group , attendance to supervised sessions was higher ( 95 % ; st and ard deviation ±6 % ) compared to unsupervised sessions ( 51 % ; st and ard deviation ±28 % ) . No adverse events were attributed to PRT . Change in menstrual cycle status was not significantly different between groups over time ( p = 0.503 ) . However , the PRT group significantly increased body weight ( p = 0.01 ) , BMI ( p = 0.04 ) , lean mass ( p = 0.01 ) , fat-free mass ( p = 0.005 ) and lower body strength ( p = 0.03 ) , while reducing waist circumference ( p = 0.03 ) and HbA1c ( p = 0.033 ) versus the control group . The PRT group also significantly improved across several domains of disease-specific and general health-related quality of life , depression , anxiety and exercise self-efficacy . Conclusion A r and omized controlled trial of PRT in PCOS would be feasible , and this mode of exercise may elicit a therapeutic effect on clinical ly important outcomes in this cohort . The success of a large-scale trial required to confirm these findings would be contingent on addressing the feasibility hurdles identified in this study with respect to recruitment , attrition , compliance , and collection of st and ardized clinical data .Trial registration Australia New Zeal and Clinical Trials Registry ; ACTRN12614000517673 Registered 15 May 2014 [10946879] Abdominal obesity and hyperinsulinemia play a key role in the development of the polycystic ovary syndrome ( PCOS ) . Dietary-induced weight loss and the administration of insulin-lowering drugs , such as metformin , are usually followed by improved hyper and rogenism and related clinical abnormalities . This study was carried out to evaluate the effects of combined hypocaloric diet and metformin on body weight , fat distribution , the glucose-insulin system , and hormones in a group of 20 obese PCOS women [ body mass index ( BMI ) > 28 kg/m2 ] with the abdominal phenotype ( waist to hip ratio > 0.80 ) , and an appropriate control group of 20 obese women who were comparable for age and pattern of body fat distribution but without PCOS . At baseline , we measured sex hormone , sex hormone-binding globulin ( SHBG ) , and leptin blood concentrations and performed an oral glucose tolerance test and computerized tomography ( CT ) at the L4-L5 level , to measure sc adipose tissue area ( SAT ) and visceral adipose tissue area . All women were then given a low-calorie diet ( 1,200 - 1,400 kcal/day ) alone for one month , after which anthropometric parameters and CT scan were newly measured . While continuing dietary treatment , PCOS women and obese controls were subsequently placed , in a r and om order , on metformin ( 850 mg/os , twice daily ) ( 12 and 8 , respectively ) or placebo ( 8 and 12 , respectively ) , according to a double-blind design , for the following 6 months . Blood tests and the CT scan were performed in each woman at the end of the study while they were still on treatment . During the treatment period , 3 women of the control group ( all treated with placebo ) were excluded because of noncompliance ; and 2 PCOS women , both treated with metformin , were also excluded because they became pregnant . Therefore , the women cohort available for final statistical analysis included 18 PCOS ( 10 treated with metformin and 8 with placebo ) and 17 control women ( 8 treated with metformin and 9 with placebo ) . The treatment was well tolerated . In the PCOS group , metformin therapy improved hirsutism and menstrual cycles significantly more than placebo . Baseline anthropometric and CT parameters were similar in all groups . Hypocaloric dieting for 1 month similarly reduced BMI values and the waist circumference in both PCOS and control groups , without any significant effect on CT scan parameters . In both PCOS and control women , however , metformin treatment reduced body weight and BMI significantly more than placebo . Changes in the waist-to-hip ratio values were similar in PCOS women and controls , regardless of pharmacological treatment . Metformin treatment significantly decreased SAT values in both PCOS and control groups , although only in the latter group were SAT changes significantly greater than those observed during the placebo treatment . On the contrary , visceral adipose tissue area values significantly decreased during metformin treatment in both PCOS and control groups , but only in the former was the effect of metformin treatment significantly higher than that of placebo . Fasting insulin significantly decreased in both PCOS women and controls , regardless of treatment , whereas glucose-stimulated insulin significantly decreased only in PCOS women and controls treated with metformin . Neither metformin or placebo significantly modified the levels of LH , FSH , dehydroepi and rosterone sulphate , and progesterone in any group , whereas testosterone concentrations decreased only in PCOS women treated with metformin . SHBG concentrations remained unchanged in all PCOS women ; whereas in the control group , they significantly increased after both metformin and placebo . Leptin levels decreased only during metformin treatment in both PCOS and control groups . ( ABSTRACT TRUNCATED [19012098] Objective . The objectives of the present pilot study were to : ( 1 ) examine the prevalence of body image distress in overweight and obese women with polycystic ovary syndrome ( PCOS ) ; ( 2 ) assess the effects of a low-cost intervention in the form of a self-directed brisk walking program on body image distress ; and ( 3 ) assess the level of participation , the feasibility of a larger study and the sample size required . Methods . This was an observational study whereby volunteers acted as their own control . Thirty-five women with PCOS ( mean age 29.26 ± 7.57 years ) with body mass index ( BMI ) > 25 kg/m2 volunteered for the study . Twenty-three returned six months later for re assessment . Of these , 12 completed the exercise program ( completers ) and 11 did not ( non-completers ) . Pre and post assessment s comprised the exercise tolerance test , the Body Dysmorphic Disorder Examination – Self-Report ( BDDE-SR ) , a question naire on self-perceived hirsutism and dietary and activity records . Results . Distress with body size was highly prevalent for the overall sample . However , completers had significantly higher BDDE-SR scores at baseline compared with non-completers ( p < 0.005 ) . Pre and post assessment s showed a significant reduction in body image distress only for completers ( p < 0.01 ) despite no significant change in BMI . Conclusions . A self-directed walking program is a low-cost intervention that can have psychological benefits for overweight women with PCOS . Specific recommendations for a r and omized study are put forward [23876536] OBJECTIVE To investigate whether r and omized diet and /or physical exercise influence serum levels of antimüllerian hormone ( AMH ) in obese women with polycystic ovary syndrome ( PCOS ) . DESIGN R and omized , 4-month trial with three interventions . SETTING Women 's health clinical research unit at a university hospital . PATIENT(S ) Fifty-seven overweight/obese women with PCOS . INTERVENTION(S ) Diet , physical exercise , or both , using programs individually adapted and supervised by a dietician and /or a physiotherapist . MAIN OUTCOME MEASURE(S ) Serum AMH levels before and after the interventions and correlations to reproductive function , body composition , and endocrine and metabolic variables . RESULT ( S ) After intervention , serum levels of AMH were significantly decreased only in the diet group , and the levels were significantly lower than in the exercise group . The strongest predictor of decreased AMH was a decrease in free T , whereas weight loss had no significant influence . Normalized levels of AMH were associated with improvements in menstrual cyclicity and hyper and rogenism but not in metabolic variables . CONCLUSION ( S ) This r and omized study supports that diet reduces serum AMH in association with decreased and rogen levels in obese women with PCOS . Increased serum AMH may be used as a marker of ovulatory dysfunction and hyper and rogenism but not as a marker of insulin resistance . CLINICAL TRIAL REGISTRY NUMBER IS RCT N48342048 [16900227] This pilot study assessed the effects of exercise and nutritional counseling on hormonal , menstrual , and reproductive function in women with polycystic ovary syndrome ( PCOS ) . Twelve females with a clinical , biochemical , and ultrasonographic diagnosis of PCOS were r and omly assigned to endurance and resistance exercise plus nutritional counseling ( EN ) or nutritional counseling only ( N ) for a period of 12 weeks . Anthropometry , resting metabolic rate ( RMR ) , selected hormones , and ovarian follicle population were measured pre and post-intervention . Following the 12 week intervention , greater decreases in sum of 2 skinfolds ( p = 0.002 ) and a greater increase in estimated VO2 max ( p = 0.017 ) occurred in the exercise group . Significant decreases in waist girth ( p = 0.001 ) and insulin levels ( p = 0.03 ) occurred in both groups . Hormonal changes were not statistically significant ; however , a trend towards an improved hormonal profile , specifically sex-hormone binding globulin ( EN , 39 % increase ; N , 8 % increase ) and lutenizing hormone : follicle-stimulating hormone ( LH : FSH ) ( EN , 9 % decrease ; N , 27 % decrease ) occurred in the absence of weight loss . These findings suggest exercise and nutritional counseling may benefit the metabolic and reproductive abnormalities associated with PCOS [22309675] Objective : To compare the efficacy of metformin with that of lifestyle changes in patients with polycystic ovary syndrome ( PCOS ) . Design : Prospect i ve , r and omized clinical trial of 40 women with PCOS to analyze the effects of metformin and lifestyle intervention treatments on menstrual pattern and hormone and metabolic profile . The duration of treatment was 6 months . Statistical analysis was done using Student ’s t-test . Results : Fifteen women in the metformin group and 12 in the lifestyle changes group completed the study . The menstrual pattern improved by ~67 % in both groups . There was a significant decrease in waist circumference in the lifestyle changes group ( 101.8 ± 3.9 and 95.1 ± 3.6 , at baseline and at 6 months of treatment , respectively ; p < 0.001 ) and in body mass index ( BMI ) in both groups . The predictor of menstrual pattern improvement was BMI . Conclusions : Both metformin and lifestyle changes may increase the number of menstrual cycles in PCOS . This effect was related to a decrease in BMI [17603048] OBJECTIVE To examine the efficacy of sibutramine together with brief lifestyle modification for weight reduction in obese women with polycystic ovary syndrome ( PCOS ) . DESIGN Investigator-initiated , multicenter , double-blind , r and omized , parallel-group clinical trial . SETTING Departments of Obstetrics and Gynecology in primary care , referral centers , and private practice . PATIENT(S ) Forty-two patients with confirmed PCOS were included in the study , and 34 patients completed the study . INTERVENTION Sibutramine 15 mg once daily together with brief lifestyle modification was compare with placebo together with brief lifestyle modification . MAIN OUTCOME MEASURE(S ) The primary endpoint was to assess weight loss . Secondary endpoints included the efficacy of sibutramine for treatment of menstrual pattern and cardiovascular risk factors . RESULT ( S ) After 6 months the sibutramine group had lost 7.8 + /- 5.1 kg compared with a weight loss of 2.8 + /- 6.2 kg in the placebo group . Sibutramine treatment result ed in significant decreases in apolipoprotein B , apolipoprotein B/apolipoprotein A ratio , triglycerides , and cystatin C levels . CONCLUSION ( S ) Sibutramine in combination with lifestyle intervention results in significant weight reduction in obese patients with PCOS . In addition to the weight loss , sibutramine seems to have beneficial effects on metabolic and cardiovascular risk factors [12923151] BACKGROUND This prospect i ve study evaluated the effect of weight reduction on anthropometric indices and ovarian morphology in anovulatory overweight patients with polycystic ovary syndrome ( PCOS ) . METHODS Thirty-three anovulatory overweight patients with PCOS were enrolled in the study . All had patent Fallopian tubes and chronic anovulation : 27 of them were oligo-amenorrhoeic . The partners were normospermic . Patients were prescribed a 1200 kcal/day diet , and physical exercise was recommended . Anthropometric indices and ovarian imaging parameters were assessed at baseline and after weight loss of 5 and 10 % . RESULTS Twenty-five patients ( 76 % ) lost at least 5 % of their body weight . Eleven of these patients ( 33 % ) reached a 10 % decrease in weight . Waist circumference at the umbilical level , hip circumference , four skin folds , body mass index and fatty mass ratio were significantly reduced after 5 and 10 % weight loss . Ovarian morphology changed during the diet : we observed a significant reduction in ovarian volume and in the number of microfollicles per ovary . Among the 27 patients with oligo-amenorrhoea , 18 had a resumption of regular cycles and 15 experienced spontaneous ovulation ; 10 spontaneous pregnancies occurred in patients who lost at least 5 % of their weight . CONCLUSIONS Weight loss through a controlled low-calorie diet improves anthropometric indices in obese PCOS patients , reduces ovarian volume and microfollicle number and can restore ovulatory cycles , allowing spontaneous pregnancy [19494176] We have recently shown that polycystic ovary syndrome ( PCOS ) is associated with high muscle sympathetic nerve activity ( MSNA ) . Animal studies support the concept that low-frequency electroacupuncture ( EA ) and physical exercise , via stimulation of ergoreceptors and somatic afferents in the muscles , may modulate the activity of the sympathetic nervous system . The aim of the present study was to investigate the effect of these interventions on sympathetic nerve activity in women with PCOS . In a r and omized controlled trial , 20 women with PCOS were r and omly allocated to one of three groups : low-frequency EA ( n = 9 ) , physical exercise ( n = 5 ) , or untreated control ( n = 6 ) during 16 wk . Direct recordings of multiunit efferent postganglionic MSNA in a muscle fascicle of the peroneal nerve before and following 16 wk of treatment . Biometric , hemodynamic , endocrine , and metabolic parameters were measured . Low-frequency EA ( P = 0.036 ) and physical exercise ( P = 0.030 ) decreased MSNA burst frequency compared with the untreated control group . The low-frequency EA group reduced sagittal diameter ( P = 0.001 ) , while the physical exercise group reduced body weight ( P = 0.004 ) and body mass index ( P = 0.004 ) compared with the untreated control group . Sagittal diameter was related to MSNA burst frequency ( Rs = 0.58 , P < 0.005 ) in the EA group . No correlation was found for body mass index and MSNA in the exercise group . There were no differences between the groups in hemodynamic , endocrine , and metabolic variables . For the first time we demonstrate that low-frequency EA and physical exercise lowers high sympathetic nerve activity in women with PCOS . Thus , treatment with low-frequency EA or physical exercise with the aim to reduce MSNA may be of importance for women with PCOS [16199429] BACKGROUND It has been reported that women with polycystic ovary syndrome ( PCOS ) benefit from metformin therapy . METHODS A r and omized , placebo-controlled , double-blind study of obese ( body mass index > 30 kg/m2 ) , oligo-/amenorrhoeic women with PCOS . Metformin ( 850 mg ) twice daily was compared with placebo over 6 months . All received the same advice from a dietitian . The primary outcome measures were : ( i ) change in menstrual cycle ; ( ii ) change in arthropometric measurements ; and ( iii ) changes in the endocrine parameters , insulin sensitivity and lipid profile . RESULTS A total of 143 subjects was r and omized [ metformin ( MET ) = 69 ; placebo ( PL ) = 74 ] . Both groups showed significant improvements in menstrual frequency [ median increase ( MET = 1 , P < 0.001 ; PL = 1 , P < 0.001 ) ] and weight loss [ mean ( kg ) ( MET = 2.84 ; P < 0.001 and PL = 1.46 ; P = 0.011 ) ] . However , there were no significant differences between the groups . Logistic regression analysis was used to analyse the independent variables ( metformin , percentage of weight loss , initial BMI and age ) in order to predict the improvement of menses . Only the percentage weight loss correlated with an improvement in menses ( regression coefficient = 0.199 , P = 0.047 , odds ratio = 1.126 , 95 % CI 1.001 , 1.266 ) . There were no significant changes in insulin sensitivity or lipid profiles in either of the groups . Those who received metformin achieved a significant reduction in waist circumference and free and rogen index . CONCLUSIONS Metformin does not improve weight loss or menstrual frequency in obese patients with PCOS . Weight loss alone through lifestyle changes improves menstrual frequency [4784413] Background This study assessed the perceived benefits and barriers to exercise participation in overweight and obese women with polycystic ovary syndrome ( PCOS ) and monitored changes in response to a lifestyle intervention . Methods Forty-three overweight/obese PCOS women ( Age , 30.3(6.2 ) yrs ; BMI , 36.4(5.6 ) kg/m2 ) were r and omised to one of three 20-week lifestyle programs : diet only ( DO , n = 13 ) , diet and aerobic exercise ( DA , n = 11 ) and diet and combined aerobic-resistance exercise ( DC , n = 19 ) . Exercise Benefits /Barriers Scale ( EBBS ) , weight , aerobic fitness , depression and PCOS specific health-related quality of life were measured . Results Barriers score was related to depression ( r = 0.45 , P = 0.002 ) and aerobic fitness ( r = −0.32 , P = 0.04 ) , while benefits score was related to aerobic fitness ( r = 0.41 , P = 0.007 ) . EBBS , benefits and barriers scores improved overtime ( P ≤ 0.001 ) . Benefits subscales psychological outlook and social interaction increased ( P ≤ 0.001 ) and life enhancement and preventative health did not change ( P ≥ 0.3 ) . Physical performance increased only in DA ( P = 0.009 ) . There were no differences between treatments for any of the other subscales ( P ≥ 0.2 ) . Barriers subscales exercise milieu , time expenditure and physical exertion reduced ( P ≤ 0.003 ) and family discouragement did not change ( P = 0.6 ) . Conclusions This study demonstrated that lifestyle modification consisting of an energy-restricted diet with or without exercise training improved the perceived benefits from and barriers to exercise . Trial registration Australian New Zeal and Clinical Trials Register ACTRN12606000198527 , registered 26 May [4540866] [ Purpose ] The short-term effects of structured exercise on the anthropometric , cardiovascular , and metabolic parameters of non-overweight women diagnosed with polycystic ovary syndrome were evaluated . [ Subjects and Methods ] Thirty women with a diagnosis of polycystic ovary syndrome were prospect ively r and omized to either a control group ( n=16 ) or a training group ( n=14 ) for a period of 8 weeks . Anthropometric , cardiovascular , and metabolic parameters and hormone levels were measured and compared before and after the intervention . [ Results ] Waist and hip measurements ( anthropometric parameters ) ; diastolic blood pressure ; respiratory rate ( cardiovascular parameters ) ; levels of low-density lipoprotein cholesterol , total cholesterol , fasting glucose , and fasting insulin ; and the homeostasis model assessment of insulin resistance index ( metabolic parameters ) were significantly lower in the training group after 8 weeks of exercise compared to the baseline values . After exercise , the training group had significantly higher oxygen consumption and high-density lipoprotein levels and significantly shorter menstrual cycle intervals . The corresponding values for controls did not significantly differ between the start and end of the 8-week experiment . [ Conclusion ] Short-term regular exercise programs can lead to improvements in anthropometric , cardiovascular , and metabolic parameters of non-overweight women with polycystic ovary syndrome [17673038] OBJECTIVE To compare the efficacy of weight loss , metformin and rosiglitazone in women with polycystic ovary syndrome ( PCOS ) . METHODS A r and omized controlled trial ( RCT ) was carried out in Peking Union Medical College Hospital ( PUMCH ) , one hundred and six women with PCOS were assigned to three intervention groups : weight loss , weight loss and metformin , weight loss and rosiglitazone group . Patients were treated with weight loss ( diet and exercise ) , weight loss and metformin ( 500 mg three times daily ) , weight loss and rosiglitazone ( 4 mg once daily ) for three months . Sixty patients completed treatments . Basal body temperature ( BBT ) , total testosterone as well as fasting serum insulin levels and lipid were measured and compared in all patients before and after weight loss . RESULTS No significant differences were found in the baseline characteristics among three groups . In weight loss group 51 % ( 22/43 ) patients completed treatment , and 23 % ( 5/22 ) patients resumed ovulation . In weight loss and metformin group 58 % ( 21/36 ) patients completed treatment , and 43 % ( 9/21 ) patients resumed ovulation . In weight loss and rosiglitazone group 63 % ( 17/27 ) patients completed treatment , and 59 % ( 10/17 ) patients resumed ovulation . Ovulation rate was significantly higher in weight loss and rosiglitazone group than in weight loss group . There was no significant difference among three groups in body mass index ( BMI ) , waist circumference , waist-hip ratio ( WHR ) , sex hormone , serum fasting insulin and lipid level after treatment . CONCLUSION Weight loss , metformin and rosiglitazone all can improve ovulation each [22154367] OBJECTIVE To investigate the possible effects of low-frequency electroacupuncture ( EA ) and physical exercise on markers of coagulation and fibrinolysis , insulin sensitivity , and adipose tissue characteristics in women with polycystic ovary syndrome ( PCOS ) . DESIGN Secondary analyses of a prospect i ve , r and omized controlled clinical trial . SETTING Department of Physiology and Department of Obstetrics and Gynecology , University of Gothenburg . PATIENT(S ) Eighty-four women with PCOS were r and omized . INTERVENTION(S ) Women with PCOS were r and omized to 16 weeks of low-frequency EA ( 14 treatments ) , physical exercise ( at least 3 times/wk ) , or no intervention . MAIN OUTCOME MEASURE(S ) Anthropometrics , circulating coagulation and fibrinolytic markers , insulin sensitivity ( euglycemic hyperinsulinemic clamp ) , hemodynamics , and adipose tissue morphology/function recorded at baseline , after 16 weeks of intervention , and after a 16-week follow-up . RESULT ( S ) In the low-frequency EA group , circulating plasminogen activator inhibitor 1 activity decreased by 21.8 % after 16 weeks of intervention and by 31.1 % at the 16-week follow-up and differed from the physical exercise and the no intervention groups . The EA group had decreases in circulating fibrinogen and tissue plasminogen activator ( t-PA ) , sagittal diameter , and diastolic blood pressure after treatment , and fibrinogen remained lower at the 16-week follow-up . In the physical exercise group , lipoprotein lipase activity increased and diastolic blood pressure decreased after treatment , and both diastolic and systolic blood pressure were lower at follow-up . No other variables were affected . CONCLUSION ( S ) Low-frequency EA counteracted a possible prothrombotic state in women with PCOS , as reflected by a decrease in plasminogen activator inhibitor 1 activity . Despite within-group improvements , there were no between-group differences in anthropometric , metabolic , or hemodynamic variables after 16 weeks of EA or physical exercise at the dose/intensity studied [25026923] The aim of this r and omized pilot was to assess the feasibility of a dietary intervention among women with polycystic ovary syndrome ( PCOS ) comparing a vegan to a low-calorie ( low-cal ) diet . Overweight ( body mass index , 39.9 ± 6.1 kg/m(2 ) ) women with PCOS ( n = 18 ; age , 27.8 ± 4.5 years ; 39 % black ) who were experiencing infertility were recruited to participate in a 6-month r and omized weight loss study delivered through nutrition counseling , e-mail , and Facebook . Body weight and dietary intake were assessed at 0 , 3 , and 6 months . We hypothesized that weight loss would be greater in the vegan group . Attrition was high at 3 ( 39 % ) and 6 months ( 67 % ) . All analyses were conducted as intention-to-treat and presented as median ( interquartile range ) . Vegan participants lost significantly more weight at 3 months ( -1.8 % [ -5.0 % , -0.9 % ] vegan , 0.0 [ -1.2 % , 0.3 % ] low-cal ; P = .04 ) , but there was no difference between groups at 6 months ( P = .39 ) . Use of Facebook groups was significantly related to percent weight loss at 3 ( P < .001 ) and 6 months ( P = .05 ) . Vegan participants had a greater decrease in energy ( -265 [ -439 , 0 ] kcal/d ) and fat intake ( -7.4 % [ -9.2 % , 0 ] energy ) at 6 months compared with low-cal participants ( 0 [ 0 , 112 ] kcal/d , P = .02 ; 0 [ 0 , 3.0 % ] energy , P = .02 ) . These preliminary results suggest that engagement with social media and adoption of a vegan diet may be effective for promoting short-term weight loss among women with PCOS ; however , a larger trial that addresses potential high attrition rates is needed to confirm these results [4296399] BACKGROUND : The effects of exercise , metformin , and orlistat on anthropometric parameters , lipid profile , endocrine parameters , and ovulation in polycystic ovarian syndrome ( PCOS ) women were compared . AIM : The aim was to study the efficacy of orlistat compared with metformin and exercise in PCOS . DESIGN : R and omized control trial . METHODS : A total of 90 eligible PCOS women were r and omly assigned to receive either of the two drugs ( orlistat or metformin ) in combination with lifestyle interventions or as controls where they received lifestyle interventions alone . Anthropometric parameters were assessed at baseline and 4 weekly intervals for 3 months . And rogen levels , insulin resistance , ovulation and conception rates and lipid profile were also assessed at the end of study . STATISTICAL ANALYSIS : Statistical analysis was performed using the SPSS version 17.0 . RESULTS : The levels of fasting blood sugar , fasting insulin and homeostatic model assessment insulin resistance were comparable in three treatment groups . Mean total testosterone , serum hormone binding globulin , free and rogen index , dehydroepi and rosterone sulfate in all arms were comparable and statistically nonsignificant . However , orlistat and metformin were more effective in reducing weight , body mass index , waist circumference and waist-hip ratio . However , side-effects were less with orlistat . Ovulation rate was 33.3 % , 23.35 % with orlistat and metformin group respectively , but were not statistically significant . In orlistat group , significant improvement was observed in lipid profile at the end of 3 months . Conception rates were 40 % and 16.7 % and 3.3 % in orlistat , metformin group and control group respectively ( P - 0.003 ) . Weight loss was found to be the best predictor of ovulation with sensitivity with good sensitivity . CONCLUSION : Orlistat is as effective as metformin in reducing weight and achieves similar ovulation rates in obese PCOS patients . However , orlistat has minimal side-effects and is better tolerated compared with metformin [26373822] OBJECTIVE The aim of this study was to examine the effects of acute exercise on insulin signaling in skeletal muscle of women with polycystic ovary syndrome ( PCOS ) and controls ( CTRL ) . METHODS Fifteen women with obesity and PCOS and 12 body mass index-matched CTRL participated in this study . Subjects performed a 40-min single bout of exercise . Muscle biopsies were performed before and 60 min after exercise . Selected proteins were assessed by Western blotting . RESULTS CTRL , but not PCOS , showed a significant increase in PI3-k p85 and AS160 Thr 642 after a single bout of exercise ( P = 0.018 and P = 0.018 , respectively ) . Only PCOS showed an increase in Akt Thr 308 and AMPK phosphorylation after exercise ( P = 0.018 and P = 0.018 , respectively ) . Total GLUT4 expression was comparable between groups ( P > 0.05 ) . GLUT4 translocation tended to be significantly higher in both groups after exercise ( PCOS : P = 0.093 ; CTRL : P = 0.091 ) , with no significant difference between them ( P > 0.05 ) . CONCLUSIONS A single bout of exercise elicited similar GLUT4 translocation in skeletal muscle of PCOS and CTRL , despite a slightly differential pattern of protein phosphorylation . The absence of impairment in GLUT4 translocation suggests that PCOS patients with obesity and insulin resistance may benefit from exercise training [26401593] CONTEXT Lifestyle modification is recommended in women with polycystic ovary syndrome ( PCOS ) prior to conception but there are few r and omized trials to support its implementation or benefit . OBJECTIVE This study aim ed to determine the relative efficacy of preconception intervention on reproductive and metabolic abnormalities in overweight/obese women with PCOS . DESIGN , SETTING , AND PARTICIPANTS This was a r and omized controlled trial of preconception and infertility treatment at Academic Health Centers in women with infertility due to PCOS , age 18 - 40 y and body mass index 27 - 42 kg/m(2 ) . INTERVENTION Women were r and omly assigned to receive either 16 weeks of 1 ) continuous oral contraceptive pills ( OCPs ) ( ethinyl estradiol 20 mcg/1 mg norethindrone acetate ) ( " OCP " ) ; 2 ) lifestyle modification consisting of caloric restriction with meal replacements , weight loss medication ( either sibutramine , or orlistat ) , and increased physical activity to promote a 7 % weight loss ( " Lifestyle " ) ; or 3 ) combined treatment with both OCP and lifestyle modification ( " Combined " ) . After preconception intervention , women underwent st and ardized ovulation induction with clomiphene citrate and timed intercourse for four cycles . Pregnancies were followed with trimester visits until delivery . MAIN OUTCOME MEASURES Weight , ovulation , and live birth were measured . RESULTS We consented 216 and r and omly assigned 149 women ( Lifestyle : n = 50 ; OCP : n = 49 ; Combined : n = 50 ) . We achieved significant weight loss with both Lifestyle ( mean weight loss , -6.2 % ; 95 % confidence interval ( CI ) , -7.4 - -5.0 ; and Combined ( mean weight loss , -6.4 % ; 95 % CI , -7.6 - -5.2 ) compared with baseline and OCP ( both P < .001 ) . There was a significant increase in the prevalence of metabolic syndrome at the end of preconception treatment compared with baseline within OCP ( odds ratio [ OR , 2.47 ; 95 % CI , 1.42 - 4.27 ) whereas no change in metabolic syndrome was detected in the Lifestyle ( OR , 1.18 ; 95 % CI , 0.63 - 2.19 ) or Combined ( OR , 0.72 ; 95 % CI , 0.44 - 1.17 ) groups . Cumulative ovulation rates were superior after weight loss : OCP , 46 % ; Lifestyle , 60 % ; and Combined , 67 % ( P < .05 ) . Live birth rates were OCP , 12 % ; Lifestyle , 26 % ; and Combined , 24 % ( P = .13 ) . CONCLUSIONS A preconception weight loss intervention eliminates the adverse metabolic oral contraceptive effects and , compared with oral contraceptive pretreatment , leads to higher ovulation rates [22334228] AIM The aim of this study was to evaluate the effects of diet alone , and in association with metformin in monotherapy or in cotreatment with myoinositol ( MYO ) on menstrual irregularities , hirsutism , body weight and composition in overweight/obese women with polycystic ovary syndrome ( PCOS ) . METHODS Twenty-seven PCOS overweight/obese patients were r and omly treated : nine with only diet ( D ) ; nine with diet and metformin 1000 mg/day continuously ( D+M ) ; nine with diet , metformin 500 mg/day and MYO 4 g/day plus 400 µg folic acid daily , continuously ( D+M+I ) . Menstrual cycle , Ferriman-Gallwey score , body mass index ( BMI ) , waist hip rate ( WHR ) , body composition by BIA 101 of AKERN SRL , were measured on basal condition and at 3 months . RESULTS Regularity of menstrual cycle was restored in a significantly number of patients of group D+M+I ( P<0.05 ) ; Ferriman score was significantly improved by weight loss ( P<0.05 ) . Body weight , BMI , waist and hip circumferences decreased significantly in all groups without WHR modification ; body weight loss significantly depended on adding metformin to diet . Fat mass ( FM ) kg and % was significantly reduced in groups D and D+M+I ; fat free mass ( FFM ) kg was slightly reduced by diet ( P<0.05 ) and correlated with Ferriman score . CONCLUSION Body weight loss in obese PCOS patients improves symptoms and body composition ; weight loss was dependent on adding metformin to diet ; MYO was more effective in restoring regularity of menstrual cycle . Further investigation occurs to confirm metformin and MYO rule on body composition improvement , specially regarding FFM that is likewise FM correlated to cardiovascular risk [16868063] CONTEXT The few controlled trials performed so far indicate that the addition of metformin and /or flutamide to a hypocaloric diet in obese women with polycystic ovary syndrome ( PCOS ) effectively influences different phenotypic aspects of the syndrome . All these studies are , however , characterized by a short to medium period of treatment . OBJECTIVE Our objective was to investigate the long-term effects of these therapies . DESIGN AND SETTING We conducted a prospect i ve , r and omized , placebo-controlled trial at a medical center . PATIENTS Of 80 overweight-obese women with PCOS , 76 completed the study . INTERVENTIONS Patients were placed on a hypocaloric diet for the first month and then on a hypocaloric diet plus placebo , metformin ( 850 mg , orally , twice a day ) , flutamide ( 250 mg , orally , twice a day ) , or metformin plus flutamide for the subsequent 12 months ( 20 subjects in each group ) . MAIN OUTCOME MEASURES We assessed clinical features , computerized tomography measurement of fat distribution , and rogens , lipids , and fasting and glucose-stimulated glucose and insulin levels at baseline and after 6 and 12 months of treatment . RESULTS After 6 months , compared with placebo , flutamide further decreased visceral/sc fat mass ( P = 0.044 ) , and rostenedione ( P < 0.001 ) , dehydroepi and rosterone sulfate ( P < 0.001 ) , and hirsutism score ( P < 0.001 ) , whereas metformin further increased frequency of menstruation ( P = 0.039 ) . After 12 months , flutamide maintained the effects observed after 6 months on visceral/sc fat mass ( P = 0.033 ) and and rostenedione ( P < 0.001 ) , whereas it produced an additional decrease in dehydroepi and rosterone sulfate ( P = 0.020 ) and hirsutism score ( P = 0.019 ) ; metformin further improved the menstrual pattern ( P = 0.013 ) . Moreover , after 12 months , flutamide improved more than placebo the menstrual pattern ( P = 0.008 ) , glucose-stimulated glucose levels ( P = 0.041 ) , insulin sensitivity ( P < 0.001 ) , and low-density lipoprotein cholesterol levels ( P = 0.003 ) , whereas metformin decreased glucose-stimulated insulin levels ( P = 0.014 ) . The combination of the two drugs maintained the specific effect of each of the compounds , without any additive or synergistic effect . CONCLUSIONS These findings add relevance to the usefulness of metformin and flutamide in the treatment of dieting overweight-obese PCOS women and provide a rationale for targeting different therapeutic options according to the required outcomes in the long term [25282112] INTRODUCTION Some pregnancy complications are characterized by increased levels of cell-free fetal ( cffDNA ) and maternal DNA ( cfmDNA ) , the latter may also be elevated during physical strain . This study aims at assessing the impact of exercise and metformin intervention in pregnancy , and to compare the levels of cell free DNA in pregnant women with or without PCOS diagnosis . METHODS Consecutive women from two previous r and omized controlled trials in pregnancy were included . Women came from a trial with organized exercise vs. st and ard antenatal care in pregnancy and a trial of metformin vs. placebo in PCOS women . Levels of cffDNA , cfmDNA and cell-free total DNA ( cftDNA ) were measured by qPCR . RESULTS Training in pregnancy did not affect the levels of cffDNA , cfmDNA or cftDNA . PCOS-women treated with metformin had lower levels of cfmDNA and cftDNA at week 32 ( mean ± SD : 301 ± 162 versus 570 ± 337 , p = 0.012 , 345 ± 173 versus 635 ± 370 , p = 0.019 ) ; otherwise the levels were comparable to PCOS-controls . Metformin-treated PCOS-women had higher cffDNA at inclusion , in the 1st trimester ; later on in pregnancy the levels in the metformin and placebo groups were equal . A comparison of pregnant women in the exercise study ( TRIP ) to placebo-treated pregnant PCOS-women , showed the levels of cffDNA , cfmDNA or cftDNA during mid-pregnancy ( weeks 18 - 36 ) to be equal . DISCUSSION Training during pregnancy was not associated with altered levels of cffDNA cfmDNA or cftDNA , but metformin treatment may reduce cfmDNA and cftDNA in pregnant PCOS women [18505468] Background Polycystic ovary syndrome ( PCOS ) is a common female reproductive‐age endocrine disease predominantly characterized by chronic anovulation , hyper and rogenism , insulin‐resistance and low‐ grade inflammatory status . Exercise training ( ET ) favourably modulates cardiopulmonary function and insulin‐sensitivity markers in PCOS women . The present study investigated the effects of ET on autonomic function and inflammatory pattern in PCOS women [8150098] OBJECTIVE To determine whether weight loss in obese , hyper and rogenic , anovulatory women is associated with resumption of ovulation and /or with changes in insulin , and rogen , and gonadotropin concentrations . DESIGN Prospect i ve , r and omized , controlled study . SETTING University research center . PATIENTS Twelve obese , hyper and rogenic , anovulatory women . INTERVENTIONS Twelve-week weight loss program in treatment ( n = 6 ) ; 12-week " waiting list " in control group ( n = 6 ) . MAIN OUTCOME MEASURES [ 1 ] Ovulation ; [ 2 ] fasting insulin and glucose measurements ; [ 3 ] sex hormone-binding globulin ( SHBG ) , total and non-SHBG T concentrations ; [ 4 ] LH pulse frequency , amplitude , and concentration ; and [ 5 ] FSH concentration . RESULTS In contrast with the control group who showed no change in weight , ovulation status , or hormone levels , women in the treatment group lost an average of 16.2 kg and showed a significant increase in SHBG , a significant decline in non-SHBG T , and a decline ( though nonsignificant ) in fasting insulin . Four of six subjects resumed ovulation . However , no changes were evident in LH pulse frequency or amplitude or in mean LH and FSH concentrations . CONCLUSIONS Weight loss in obese , hyper and rogenic , anovulatory women appears to reduce insulin and non-SHBG T concentrations despite the absence of a change in gonadotropin secretion and may lead to resumption of ovulation [7613427] Abstract Objective : To test the hypothesis that a single measurement , waist circumference , might be used to identify people at health risk both from being overweight and from having a central fat distribution . Design : A community derived r and om sample of men and women and a second , validation sample . Setting : North Glasgow . Subjects : 904 men and 1014 women ( first sample ) ; 86 men and 202 women ( validation sample ) . Main outcome measures : Waist circumference , body mass index , waist : hip ratio . Results : Waist circumference > /=94 cm for men and > /=80 cm for women identified subjects with high body mass index ( > /=25 kg/m2 ) and those with lower body mass index but high waist : hip ratio ( > /=0.95 for men , > /=0.80 women ) with a sensitivity of > 96 % and specificity > 97.5 % . Waist circumference > /=102 cm for men or > /=88 cm for women identified subjects with body mass index > /=30 and those with lower body mass index but high waist : hip ratio with a sensitivity of > 96 % and specificity > 98 % , with only about 2 % of the sample being misclassified . Conclusions : Waist circumference could be used in health promotion programmes to identify individuals who should seek and be offered weight management . Men with waist circumference > /=94 cm and women with waist circumference > /=80 cm should gain no further weight ; men with waist circumference > /=102 cm and women with waist circumference > /=88 cm should reduce their weight [15302293] OBJECTIVE To obtain data from a pilot r and omized trial on the effect of metformin therapy and lifestyle modification on ovulation and and rogen concentrations in women with polycystic ovary syndrome ( PCOS ) . DESIGN Prospect i ve , r and omized , placebo-controlled pilot trial . SETTING Academic medical center . PATIENT(S ) Thirty-eight overweight or obese women with PCOS . INTERVENTION(S ) All subjects were r and omized to one of four 48-week interventions : metformin 850 mg two times per day , lifestyle modification plus metformin 850 mg two times per day , lifestyle modification plus placebo , or placebo alone . MAIN OUTCOME MEASURE(S ) Recruitment , dropout , and compliance with a long-term lifestyle intervention in PCOS ; preliminary estimates of treatment effect on ovulation , as measured by weekly urinary pregnanediol glucuronide , and on total T and free and rogen index . RESULT ( S ) It was necessary to screen seven women to have one subject r and omized . The dropout rate was 39 % , with the majority of dropouts occurring within the first 24 weeks . Mean body mass index was > 39 mg/kg(2 ) . Modest weight reduction was found in all treatment groups , with the most significant reduction occurring with the combination of metformin and lifestyle intervention . Significant and rogen reduction occurred in the combination group only . Ovulation rates did not differ significantly between groups . However , when data were analyzed by presence or absence of weight reduction in subjects , independent of treatment group , the estimated odds ratio for weight loss was 9.0 ( 95 % confidence interval 1.2 - 64.7 ) with respect to regular ovulation . If weight loss occurred during metformin therapy , the odds ratio for regular ovulation was 16.2 ( 95 % confidence interval 4.4 - 60.2 ) . CONCLUSION ( S ) Key method ologic issues for a large-scale , r and omized trial of lifestyle intervention in PCOS include minimizing early dropout from the lifestyle intervention and including a range of body mass index that is not skewed toward severe obesity . Weight reduction might play the most significant role in restoration of ovulation in obese women with PCOS [26298524] STUDY OBJECTIVE To investigate the effect of dietary weight loss on menstrual regularity in obese adolescent women with polycystic ovary syndrome ( PCOS ) . DESIGN AND SETTING A r and omized controlled trial was held at the Faculty of Nursing , Mansoura University , and the Obesity Clinic of the Rheumatology Department at Mansoura University Hospitals between July 2011 and January 2013 . PARTICIPANTS Sixty adolescent women with PCOS , body mass index ( BMI ) greater than 30 , and complaints of menstrual irregularities were included in this study . Enrolled women were divided equally and r and omly into 2 groups : intervention and control groups . INTERVENTIONS Women in the intervention group ( n = 30 ) were subject to an intensive dietary educational program with instructions to follow a conventional energy restricted diet , whereas women in the control group were instructed to follow the same healthy diet of the first group without calorie restriction . MAIN OUTCOME MEASURES Menstrual regularity , weight loss , the effect on waist circumference , and hirsutism score . RESULTS The 2 groups were initially matched in average body weight , BMI , hirsutism score , and waist circumference . Six months later , there were significant decreases in all parameters in the weight reduction group . In addition , more menstrual episodes were recorded in the weight reduction compared with the control group ( 3.1 ± 1.2 vs. 2.3 ± 1.3 ; P = .010 ) . Also , BMI , waist circumference , and hirsutism score were all significantly decreased at the end of the study . CONCLUSION Dietary weight loss in adolescent women with PCOS result ed in significant improvement in menstrual regularity , BMI , waist circumference , and hirsutism score [16757529] CONTEXT Insulin resistance is a feature of polycystic ovary syndrome ( PCOS ) , and it is related to mitochondrial function , particularly with maximal oxygen consumption ( VO(2max ) ) . At the moment , no evaluation of cardiopulmonary functional capacity in young patients with PCOS has been performed . OBJECTIVE Our objective was to assess cardiopulmonary functional capacity in young PCOS overweight patients . DESIGN AND SETTING We conducted a prospect i ve baseline-controlled clinical study at University Federico II of Naples , School of Medicine ( Naples , Italy ) . PATIENTS Forty-five PCOS patients were matched with 45 healthy women for age ( mean + /- sd , 21.3 + /- 2.0 vs. 21.6 + /- 1.9 yr , respectively ) and body mass index ( 29.4 + /- 3.6 vs. 29.0 + /- 3.4 kg/m(2 ) , respectively ) . MEAN OUTCOME MEASURES We assessed hormonal and metabolic pattern and functional capacity by cardiopulmonary exercise testing to evaluate maximal oxygen consumption ( VO(2max ) ) , oxygen consumption at anaerobic threshold ( VO(2AT ) ) , and the maximal workload at peak exercise . RESULTS VO(2max ) ( 17.0 + /- 3.7 vs. 26.8 + /- 3.5 ml/kg.min ) , oxygen consumption at anaerobic threshold ( 13.9 + /- 3.0 vs. 21.2 + /- 3.8 ml/kg.min ) , and maximal workload at peak exercise ( 101.3 + /- 25.2 vs. 135 + /- 22.6 W ) were significantly ( P < 0.001 ) reduced in PCOS subjects compared with healthy women . The multiple linear regression analysis showed that only homeostasis model assessment appears to have a strong negative linear relation with VO(2max ) in PCOS . No relation was found in controls . CONCLUSIONS Our data demonstrate a reduced cardiopulmonary functional capacity in young PCOS patients [21324452] In a prospect i ve study , eight women with polycystic ovary syndrome completed 16 weeks of individualized aerobic exercise training . Independent of changes in body weight and adiposity there was a statistically significant increase in aerobic fitness and insulin sensitivity and a statistically significant decrease in the total number of follicles measured by magnetic resonance imaging [21193187] OBJECTIVE To determine if the combination of lifestyle ( caloric restriction and exercise ) and metformin ( MET ) would be superior to lifestyle and placebo ( PBO ) in improving the polycystic ovary syndrome ( PCOS ) phenotype . DESIGN Double-blind r and omized 6-month trial of MET versus PBO . SETTING Two academic medical centers . PATIENT(S ) One hundred fourteen subjects with PCOS were r and omized to MET ( N = 55 ) or PBO ( N = 59 ) . INTERVENTION(S ) Subjects collected urine daily for ovulation monitoring , had monthly monitoring of hormones and weight and determination of body composition by dual-energy x-ray absorptiometry , glucose tolerance , and were evaluated for quality of life at baseline and completion . MAIN OUTCOME MEASURE(S ) Ovulation rates and testosterone levels . RESULT ( S ) Dropout rates were high . There was no significant difference in ovulation rates . Testosterone levels were significantly lower compared with baseline in the MET group at 3 mos but not at 6 mos . There were no differences in weight loss between groups , but MET showed a significant decline at 6 months compared with baseline ( -3.4 kg , 95 % confidence interval -5.3 to -1.5 kg ) . We noted divergent effects of MET versus PBO on oral glucose tolerance test indices of insulin sensitivity ( increased ) and secretion ( worsened ) . Total bone mineral density increased significantly in MET . There were no differences in quality of life measures between the groups . The MET group had increased diarrhea and headache , but fewer bladder infections and musculoskeletal complaints . CONCLUSION ( S ) The addition of metformin to lifestyle therapy produced little reproductive or glycemic benefit in women with PCOS , although our study had limited power owing to a high dropout rate . It is not possible at baseline to identify women likely to drop out [19204602] PURPOSE Women with polycystic ovary syndrome ( PCOS ) commonly have insulin resistance . Insulin resistance is associated with marked abnormalities of lipoprotein size and subclass particle concentration . The purpose of this study was to examine the effects of a moderate-intensity exercise program without weight loss on lipoprotein profiles in women with PCOS . METHODS Thirty-seven sedentary PCOS women were r and omized to either an 8- to 12-wk ramp-up followed by a 12-wk moderate-intensity exercise program ( 16 - 24 wk total , approximately 228 min x wk at 40 - 60 % peak V x O2 , n = 21 ) or control ( no change in lifestyle , n = 16 ) . PCOS was defined as < or=8 menses per year and hyper and rogenism ( biochemical or clinical with Ferriman-Gallwey score > or=8 ) . Fasting lipoprotein profiles were obtained before and after the intervention . Nuclear magnetic resonance spectroscopy was used to quantify the following : average particle size , total and subclass concentrations of HDL , LDL , and VLDL particles , and calculated HDL cholesterol , triglycerides , and VLDL triglycerides . Wilcoxon exact rank sums tests were used to compare changes in these parameters in the exercise group relative to controls . RESULTS Twenty women ( 8 exercisers , 12 controls ) completed the study . Comparing exercisers to controls , significant changes were seen in concentrations of the following lipoprotein parameters that are associated with decreased insulin resistance : decreased large VLDL ( P = 0.007 ) , calculated triglycerides ( P = 0.003 ) , VLDL triglycerides ( P = 0.003 ) , and medium/small HDL ( P = 0.031 ) and increased large HDL ( P = 0.002 ) and average HDL size ( P = 0.001 ) . CONCLUSIONS In this trial , moderate-intensity exercise without significant weight loss improved several components of the lipoprotein profiles of women with PCOS . These findings support the beneficial role of moderate exercise in this high-risk population [23608322] BACKGROUND AND OBJECTIVES Polycystic ovary syndrome ( PCOS ) is a common problem in women at fertile age . A prospect i ve study was conducted to clarify the pathophysiological responses during an application of insulin sensitizer , metformin and weight reduction therapy at the Gynecology Center in Ohud hospital , in AL-Madinah AL-Munawarah , Kingdom of Saudi Arabia . METHODOLOGY Twenty healthy women served as controls and 180 PCOS women divided into three groups participated in the study . First group was treated with Clomid citrate 100mg/day from the 2nd day of menses to the 6th day plus gonadotrophin from day three to the 13th . Group II was treated as group I plus 850 mg metformin twice a day and group III was treated as group I plus weight reduction . Clinical symptoms , menstrual pattern , hirsutism , blood glucose , body mass index , waist-to-hip ratio , insulin , hormonal , and lipid profiles were assessed pre- and post treatment . Insulin resistance was calculated . RESULTS PCOS women had significantly higher values than the healthy women in most of the measurements . Metformin and weight reduction therapy result ed in a significant decrease in the fasting insulin , glucose/insulin ratio and HOMA-IR . Metformin and weight reduction therapy result ed in a significant decrease in the lipid parameters , testosterone , LH/FSH ratio , SHBG , and prolactin levels . HOMA-IR was significantly higher in women with PCOS . HOMA-IR was positively correlated with testosterone , estradiol , TG , total cholesterol and LDL-cholesterol parameters , and negatively correlated with HDL-cholesterol and FSH levels . CONCLUSION Metformin therapy and weight reduction had favorable influences on the basic metabolic and hormonal profiles in women with PCOS and that metformin and lifestyle modification ( weight reduction via diet restriction or exercise ) result ed in a significantly greater weight loss than hormonal therapy alone . Metformin and weight reduction therapy decreased also hyper and rogenism and insulin resistance [17264174] CONTEXT Polycystic ovary syndrome ( PCOS ) is an endocrine disease closely related to several risk factors for cardiovascular disease . An impaired cardiopulmonary functional capacity was previously demonstrated in PCOS women . No data regarding the effects of a structured exercise training ( ET ) program on cardiopulmonary functional capacity in PCOS women are available . OBJECTIVE Our objective was to evaluate the effects of a 3-month ET program on cardiopulmonary functional capacity in young PCOS women . DESIGN AND SETTING A prospect i ve baseline-r and omized clinical study was conducted at the University " Federico II " of Naples , School of Medicine ( Italy ) . PATIENTS Ninety young overweight PCOS women were enrolled . MEAN OUTCOME MEASURES Ninety young PCOS women were r and omly subdivided into two groups , each composed of 45 subjects . The PCOS-T ( trained ) group underwent a 3-month structured ET program , whereas the PCOS-UnT ( untrained ) group did not . Hormonal and metabolic profiles and cardiopulmonary and exercise parameters were evaluated . RESULTS After 3-month ET , PCOS-T showed a significant improvement in peak oxygen consumption ( + 35.4 % ; P<0.001 ) and in maximal workload ( + 37.2 % ; P<0.001 ) . In PCOS-T we also observed a significant reduction in body mass index ( -4.5 % ; P<0.001 ) and in C-reactive protein ( -10 % ; P<0.001 ) , and a significant ( P<0.001 ) improvement in insulin sensitivity indexes . After 3 months , no changes were observed in PCOS-UnT. CONCLUSIONS A 3-month structured ET program improves cardiopulmonary functional capacity in young PCOS women [9920077] Women with polycystic ovary syndrome ( PCOS ) are insulin resistant , have insulin secretory defects , and are at high risk for glucose intolerance . We performed this study to determine the prevalence of glucose intolerance and parameters associated with risk for this in PCOS women . Two-hundred and fifty-four PCOS women , aged 14 - 44 yr , were prospect ively evaluated at 2 centers , 1 urban and ethnically diverse ( n = 110 ) and 1 rural and ethnically homogeneous ( n = 144 ) . The rural PCOS women were compared to 80 control women of similar weight , ethnicity , and age . A 75-g oral glucose challenge was administered after a 3-day 300-g carbohydrate diet and an overnight fast with 0 and 2 h blood sample s for glucose levels . Diabetes was categorized according to WHO criteria . The prevalence of glucose intolerance was 31.1 % impaired glucose intolerance ( IGT ) and 7.5 % diabetes . In nonobese PCOS women ( body mass index , < 27 kg/m2 ) , 10.3 % IGT and 1.5 % diabetes were found . The prevalence of glucose intolerance was significantly higher in PCOS vs. control women ( chi2 = 7.0 ; P = 0.01 ; odds ratio = 2.76 ; 95 % confidence interval = 1.23 - 6.57 ) . Variables most associated with postchallenge glucose levels were fasting glucose levels ( P < 0.0001 ) , PCOS status ( P = 0.002 ) , waist/hip ratio ( P = 0.01 ) , and body mass index ( P = 0.021 ) . The American Diabetes Association criteria applied to fasting glucose significantly underdiagnosed diabetes compared to the WHO criteria ( 3.2 % vs. 7.5 % ; chi2 = 4.7 ; P = 0.046 ; odds ratio = 2.48 ; 95 % confidence interval = 1.01 - 6.69 ) . We conclude that 1 ) PCOS women are at significantly increased risk for IGT and type 2 diabetes mellitus at all weights and at a young age ; 2 ) these prevalence rates are similar in 2 different population s of PCOS women , suggesting that PCOS may be a more important risk factor than ethnicity or race for glucose intolerance in young women ; and 3 ) the American Diabetes Association diabetes diagnostic criteria failed to detect a significant number of PCOS women with diabetes by postchallenge glucose values [21419674] STUDY OBJECTIVE To compare the effects of a hypocaloric low-fat diet with those of a very low carbohydrate diet on body mass index ( BMI ) , waist circumference ( WC ) , and menstrual function in overweight adolescent females with polycystic ovary syndrome ( PCOS ) . DESIGN R and omized pilot trial of two diets in a prospect i ve , 12-week study . SETTING A hospital-based , academic adolescent medicine division . PARTICIPANTS 24 females , age 12 - 22 years ( mean 15.8 ± 2.2 ) , with PCOS and a BMI above the 85(th ) percentile for age ( mean 35.7 ± 6.0 kg/m(2 ) ) . INTERVENTIONS Nutrition counseling was given biweekly , and dietary compliance , menstrual history , and weight were recorded . WC was measured at the beginning and end of the study . MAIN OUTCOME MEASURES Changes in weight , BMI , WC , and improvement in menstrual function over the course of the study period . RESULTS 16 participants completed the study . 12 completers menstruated during the study period , 8 with regularity . The number of periods over 3 months increased from 0.6 ± 0.6 pre-treatment to 1.6 ± 1.3 post-treatment ( P = 0.003 ) . Overall , weight loss averaged 6.5 % ( P < 0.0001 ) and the WC decreased by an average of 5.7 ± 7.7 cm ( P = 0.01 ) . Those who lost weight were 3.4 times more likely to have improved menstrual function ( P = 0.001 ) . There were no statistically significant differences between the two groups . CONCLUSIONS Weight loss is feasible in adolescents with PCOS and results in significant improvements in BMI , WC , and menstrual function . Weight management may be preferable as first-line treatment in adolescents , because it targets both the menstrual dysfunction and risk factors for long-term morbidity associated with PCOS [25057845] Abstract Bressel , E , Wing , JE , Miller , AI , and Dolny , DG . High-intensity interval training on an aquatic treadmill in adults with osteoarthritis : effect on pain , balance , function , and mobility . J Strength Cond Res 28(8 ) : 2088–2096 , 2014—Although aquatic exercise is considered a potentially effective treatment intervention for people with osteoarthritis ( OA ) , previous research has focused primarily on calisthenics in a shallow pool with the inherent limitations on regulating exercise intensity . The purpose of this study was to quantify the efficacy of a 6-week aquatic treadmill exercise program on measures of pain , balance , function , and mobility . Eighteen participants ( age = 64.5 ± 10.2 years ) with knee OA completed a non-exercise control period followed by a 6-week exercise period . Outcome measures included visual analog scales for pain , posturography for balance , sit-to-st and test for function , and a 10-m walk test for mobility . The exercise protocol included balance training and high-intensity interval training ( HIT ) in an aquatic treadmill using water jets to destabilize while st and ing and achieve high ratings of perceived exertion ( 14–19 ) while walking . In comparison with pretests , participants displayed reduced joint pain ( pre = 50.3 ± 24.8 mm vs. post = 15.8 ± 10.6 mm ) , improved balance ( equilibrium pre = 66.6 ± 11.0 vs. post = 73.5 ± 7.1 ) , function ( rising index pre = 0.49 ± 0.19 % vs. post = 0.33 ± 0.11 % ) , and mobility ( walk pre = 8.6 ± 1.4 s vs. post = 7.8 ± 1.1 s ) after participating in the exercise protocol ( p = 0.03–0.001 ) . The same benefits were not observed after the non-exercise control period . Adherence to the exercise protocol was exceptional and no participants reported adverse effects , suggesting that aquatic treadmill exercise that incorporates balance and HIT training was well tolerated by patients with OA and may be effective at managing symptoms of OA [18158291] BACKGROUND Lifestyle modifications are successfully employed to treat obese and overweight women with polycystic ovary syndrome ( PCOS ) . The aims of the current pilot study were ( i ) to compare the efficacy on reproductive functions of a structured exercise training ( SET ) programme with a diet programme in obese PCOS patients and ( ii ) to study their clinical , hormonal and metabolic effects to eluci date potentially different mechanisms of action . METHODS Forty obese PCOS patients with anovulatory infertility underwent a SET programme ( SET group , n = 20 ) and a hypocaloric hyperproteic diet ( diet group , n = 20 ) . Clinical , hormonal and metabolic data were assessed at baseline , and at 12- and 24-week follow-ups . Primary endpoint was cumulative pregnancy rate . RESULTS The two groups had similar demographic , anthropometric and biochemical parameters . After intervention , a significant improvement in menstrual cycles and fertility was noted in both groups , with no differences between groups . The frequency of menses and the ovulation rate were significantly ( P < 0.05 ) higher in the SET group than in diet group but the increased cumulative pregnancy rate was not significant . Body weight , body mass index , waist circumference , insulin resistance indexes and serum levels of sex hormone-binding globulin , and rostenedione and dehydroepi and rosterone sulphate changed significantly ( P < 0.05 ) from baseline and were significantly different ( P < 0.05 ) between the two groups . CONCLUSIONS Both SET and diet interventions improve fertility in obese PCOS patients with anovulatory infertility . We hypothesize that in both interventions an improvement in insulin sensitivity is the pivotal factor involved in the restoration of ovarian function but potentially acting through different mechanisms [17509728] This study compared the psychological effects of a low-protein high-carbohydrate ( LPHC ) diet and a high-protein low-carbohydrate ( HPLC ) diet in women with polycystic ovary syndrome ( PCOS ) . Twenty-five overweight women with PCOS were matched for age , weight , and whether they were trying to conceive . They were r and omly allocated to the LPHC or HPLC diet for 16 weeks . All participants attended a weekly exercise , group support and educational program . The Hospital Anxiety and Depression Scale and the Rosenberg Self Esteem Scale were administered at the beginning and end of the study . The HPLC diet was associated with significant reduction in depression and improvement in self-esteem . There was no change in any psychological measures for the LPHC group . There was no difference in weight loss between the groups . Due to enhanced feelings of well-being , it is possible that HPLC diets may be associated with better compliance and hence be more successful in the long term treatment of obesity [19380385] BACKGROUND Anti-Müllerian hormone ( AMH ) has been proposed as a clinical predictor of improvements in reproductive function following weight loss in overweight and obese women with polycystic ovary syndrome ( PCOS ) . This study aim ed to assess whether baseline and /or change in AMH levels with weight loss predict improvements in reproductive function in overweight and obese women with PCOS . METHODS Fifty-two overweight and obese women with PCOS and reproductive impairment ( age 29.8 + /- 0.8 years , BMI 36.5 + /- 0.7 kg/m(2 ) ) followed a 20-week weight loss programme . AMH , weight , menstrual cyclicity and ovulatory function were assessed at baseline and post-intervention . RESULTS Participants who responded with improvements in reproductive function ( n = 26 ) had lower baseline AMH levels ( 23.5 + /- 3.7 versus 32.5 + /- 2.9 pmol/l ; P = 0.03 ) and experienced greater weight loss ( -11.7 + /- 1.2 versus -6.4 + /- 0.9 kg ; P = 0.001 ) compared with those who did not respond ( n = 26 ) . Logistic regression analysis showed that weight loss and baseline AMH were independently related to improvements in reproductive function ( P = 0.002 and P = 0.013 , respectively ) . AMH levels did not change with weight loss in both responders and non-responders . CONCLUSIONS In overweight and obese women with PCOS and reproductive dysfunction , a 20-week weight loss intervention result ed in improvements in reproductive function but no change in AMH levels . CLINICAL TRIALS REGISTRATION NUMBER ACTRN12606000198527 [19463994] OBJECTIVE To compare the effect of clomiphene citrate , metformin , and lifestyle modification on treatment of patients with polycystic ovary syndrome ( PCOS ) . DESIGN Prospect i ve r and omized double-blind study . SETTING University-based infertility clinic and research center . PATIENT(S ) Three hundred forty-three overweight infertile women with PCOS . INTERVENTION(S ) The participating women were assigned to four groups : clomiphene ( n = 90 ) , metformin ( n = 90 ) , clomiphene + metformin ( n = 88 ) , and lifestyle modification ( n = 75 ) . The patients in each group received st and ardized dietary and exercise advice from a dietitian . MAIN OUTCOME MEASURE(S ) The primary outcome variables were change in menstrual cycle , waist circumference measurements , endocrine parameters , and lipid profile . The main secondary outcome variable was clinical pregnancy rate . RESULT ( S ) The clinical pregnancy rate was 12.2 % in clomiphene group , 14.4 % in metformin group , 14.8 % in clomiphene + metformin group , and 20 % in lifestyle modification group . Lifestyle modification group achieved a significant reduction in waist circumference , total and rogen , and lipid profile . CONCLUSION ( S ) Lifestyle modification improves the lipid profile in PCOS patients . Therefore , lifestyle modification may be used as the first line of ovulation induction in PCOS patients [22808940] OBJECTIVES The objectives of this trial were to compare the effects of a holistic yoga program with the conventional exercise program in adolescent polycystic ovarian syndrome ( PCOS ) . DESIGN This was a prospect i ve , r and omized , active controlled trial . SETTING Ninety ( 90 ) adolescent ( 15 - 18 years ) girls from a residential college in And hra Pradesh who satisfied the Rotterdam criteria were r and omized into two groups . INTERVENTION The yoga group practice d a holistic yoga module , while the control group practice d a matching set of physical exercises ( 1 hour/day , for 12 weeks ) . OUTCOME MEASURES Anti-müllerian hormone ( AMH- primary outcome ) , luteinizing hormone ( LH ) , follicle-stimulating hormone ( FSH ) , testosterone , prolactin , body-mass index ( BMI ) , hirsutism , and menstrual frequency were measured at inclusion and after 12 weeks . RESULTS Mann-Whitney test on difference score shows that changes in AMH ( Y=-2.51 , C=-0.49 , p=0.006 ) , LH , and LH/FSH ratio ( LH : Y=-4.09 , C=3.00 , p=0.005 ; LH/FSH : Y=-1.17 , C=0.49 , p=0.015 ) were significantly different between the two intervention groups . Also , changes in testosterone ( Y=-6.01 , C=2.61 , p=0.014 ) and Modified Ferriman and Gallway ( mFG ) score ( Y=-1.14 , C=+0.06 , p=0.002 ) were significantly different between the two groups . On the other h and , changes in FSH and prolactin postintervention were nonsignificantly different between the two groups . Also , body weight and BMI showed nonsignificantly different changes between the two groups , while changes in menstrual frequency were significantly different between the two groups ( Y=0.89 , C=0.49 , p=0.049 ) . CONCLUSIONS A holistic yoga program for 12 weeks is significantly better than physical exercise in reducing AMH , LH , and testosterone , mFG score for hirsutism , and improving menstrual frequency with nonsignificant changes in body weight , FSH , and prolactin in adolescent PCOS [20004371] OBJECTIVE To assess the impact of adding exercise to dietary restriction on depressive symptoms and health-related quality of life ( HRQOL ) in women with polycystic ovary syndrome ( PCOS ) . DESIGN Analysis of depression and quality of life outcomes from a r and omized , controlled prospect i ve clinical intervention that evaluated the effects on a range of health outcomes in women with PCOS . SETTING Clinical research unit . PATIENT(S ) One hundred four overweight/obese PCOS women ( aged 29.3 ± 0.7 years ; body mass index [ BMI ] 36.1 ± 0.5 kg/m(2 ) ) . INTERVENTION(S ) R and omized to one of three 20-week lifestyle programs : diet only , diet and aerobic exercise , or diet and combined aerobic-resistance exercise . MAIN OUTCOME MEASURE(S ) Depression and PCOS-specific HRQOL . RESULT ( S ) Forty-nine women completed the intervention ( diet only = 14 , diet and aerobic exercise = 15 , diet and combined aerobic-resistance exercise = 20 ) . By week 20 all groups achieved weight loss and had improvements in depression and PCOS-specific HRQOL scores , except for body hair domain score . There was no difference between treatments for all outcomes . CONCLUSION ( S ) This study demonstrated that dietary restriction alone and combined with exercise had similar benefits for improving depression and HRQOL scores in overweight and obese women with PCOS

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### Context: [3684530] Background Women with polycystic ovary syndrome ( PCOS ) have symptoms of depression and anxiety and impaired health related quality of life ( HRQoL ) . Here we test the post-hoc hypothesis that acupuncture and exercise improve depression and anxiety symptoms and HRQoL in PCOS women . Methods Seventy-two PCOS women were r and omly assigned to 16 weeks of 1 ) acupuncture ( n = 28 ) ; 2 ) exercise ( n = 29 ) ; or 3 ) no intervention ( control ) ( n = 15 ) . Outcome measures included : change in Montgomery Åsberg Depression Rating Scale ( MADRS-S ) , Brief Scale for Anxiety ( BSA-S ) , Swedish Short-Form 36 ( SF-36 ) , and PCOS Question naire ( PCOSQ ) scores from baseline to after 16-week intervention , and to 16-week post-intervention follow-up . Results A reduction in MADRS-S and BSA-S from baseline to 16-weeks post-intervention follow-up was observed for the acupuncture group . The SF-36 domains role physical , energy/vitality , general health perception and the mental component of summary scores improved in the acupuncture group after intervention and at follow-up . Within the exercise group the role physical decreased after treatment , while physical functioning and general health perception scores increased at follow-up . The emotion domain in the PCOSQ improved after 16-weeks of intervention within all three groups , and at follow-up in acupuncture and exercise groups . At follow-up , improvement in the infertility domain was observed within the exercise group . Conclusion There was a modest improvement in depression and anxiety scores in women treated with acupuncture , and improved HRQoL scores were noted in both intervention groups . While not a primary focus of the trial , these data suggest continued investigation of mental health outcomes in women treated for PCOS.Trial registration number Clinical Trials.gov Identifier : [23482444] Acupuncture has been demonstrated to improve menstrual frequency and to decrease circulating testosterone in women with polycystic ovary syndrome ( PCOS ) . Our aim was to investigate whether acupuncture affects ovulation frequency and to underst and the underlying mechanisms of any such effect by analyzing LH and sex steroid secretion in women with PCOS . This prospect i ve , r and omized , controlled clinical trial was conducted between June 2009 and September 2010 . Thirty-two women with PCOS were r and omized to receive either acupuncture with manual and low-frequency electrical stimulation or to meetings with a physical therapist twice a week for 10 - 13 wk . Main outcome measures were changes in LH secretion patterns from baseline to after 10 - 13 wk of treatment and ovulation frequency during the treatment period . Secondary outcomes were changes in the secretion of sex steroids , anti-Müllerian hormone , inhibin B , and serum cortisol . Ovulation frequency during treatment was higher in the acupuncture group than in the control group . After 10 - 13 wk of intervention , circulating levels of estrone , estrone sulfate , estradiol , dehydroepi and rosterone , dehydroepi and rosterone sulfate , and rostenedione , testosterone , free testosterone , dihydrotestosterone , and rosterone glucuronide , and rostane-3α,17β-diol-3-glucuronide , and and rostane-3α,17β-diol-17-glucuronide decreased within the acupuncture group and were significantly lower than in the control group for all of these except and rostenedione . We conclude that repeated acupuncture treatments result ed in higher ovulation frequency in lean/overweight women with PCOS and were more effective than just meeting with the therapist . Ovarian and adrenal sex steroid serum levels were reduced with no effect on LH secretion [22158730] BACKGROUND Some evidence has suggested that a diet with a higher ratio of protein to carbohydrates has metabolic advantages in the treatment of polycystic ovary syndrome ( PCOS ) . OBJECTIVE The objective of this study was to compare the effect of a high-protein ( HP ) diet to a st and ard-protein ( SP ) diet in women with PCOS . DESIGN A controlled , 6-mo trial was conducted in 57 PCOS women . The women were assigned through rank minimization to one of the following 2 diets without caloric restriction : an HP diet ( > 40 % of energy from protein and 30 % of energy from fat ) or an SP diet ( < 15 % of energy from protein and 30 % of energy from fat ) . The women received monthly dietary counseling . At baseline and 3 and 6 mo , anthropometric measurements were performed , and blood sample s were collected . RESULTS Seven women dropped out because of pregnancy , 23 women dropped out because of other reasons , and 27 women completed the study . The HP diet produced a greater weight loss ( mean : 4.4 kg ; 95 % CI : 0.3 , 8.6 kg ) and body fat loss ( mean : 4.3 kg ; 95 % CI : 0.9 , 7.6 kg ) than the SP diet after 6 mo . Waist circumference was reduced more by the HP diet than by the SP diet . The HP diet produced greater decreases in glucose than did the SP diet , which persisted after adjustment for weight changes . There were no differences in testosterone , sex hormone-binding globulin , and blood lipids between the groups after 6 mo . However , adjustment for weight changes led to significantly lower testosterone concentrations in the SP-diet group than in the HP-diet group . CONCLUSION Replacement of carbohydrates with protein in ad libitum diets improves weight loss and improves glucose metabolism by an effect that seems to be independent of the weight loss and , thus , seems to offer an improved dietary treatment of PCOS women [26862008] Background / Objectives : The aim of the study was to compare the effect of two-meal patterns ( three vs six meals per day ) on glucose and insulin levels in women with polycystic ovary syndrome (PCOS).Subjects/ Methods : In a r and omised , crossover , 24-week study , 40 women with PCOS , aged 27±6 years , body mass index 27±6 kg/m2 , followed a weight maintenance diet ( % carbohydrates : protein : fat , 40:25:35 ) , consumed either as a three- or a six-meal pattern , with each intervention lasting for 12 weeks . Anthropometric measurements , diet compliance and subjective hunger , satiety and desire to eat were assessed biweekly . All women underwent an oral glucose tolerance test ( OGTT ) with 75 g glucose for measurement of plasma glucose and insulin at the beginning and end of each intervention . HaemoglobinA1c ( HbA1c ) , blood lipids and hepatic enzymes were measured at the beginning and end of each intervention . Results : Body weight remained stable throughout the study . Six meals decreased significantly fasting insulin ( P=0.014 ) and post-OGTT insulin sensitivity ( Matsuda index , P=0.039 ) vs three meals . After incorporation of individual changes over time , with adjustment for potential confounders , the only variable that remained significant was the Matsuda index , which was then used in multivariate analysis and general linear models . Six meals improved post-OGTT insulin sensitivity independently of age and body weight vs three meals ( P=0.012 ) . No significant differences were found between six and three meals for glucose , HbA1c , blood lipids , hepatic enzymes , subjective desire to eat and satiety . Conclusions : Six meals had a more favourable effect on post-OGTT insulin sensitivity in women with PCOS compared with isocaloric three meals [22855917] Objective : The recommended composition of a hypocaloric diet for obese women with polycystic ovary syndrome ( PCOS ) is unclear . The aim of this study was to investigate the effects of a high-protein , low-glycemic-load diet compared with a conventional hypocaloric diet on reproductive hormones , inflammatory markers , lipids , glucose , and insulin levels in obese women with PCOS . Methods : A total of 60 overweight and obese women with PCOS who did not use insulin-sensitizing agents were recruited and r and omly assigned to 1 of the 2 hypocaloric diet groups for a single-blind clinical trial . The groups included a conventional hypocaloric diet ( CHCD ) ( 15 % of daily energy from protein ) and a modified hypocaloric diet ( MHCD ) with a high-protein , low-glycemic load ( 30 % of daily energy from protein plus low-glycemic-load foods selected from a list ) that was prescribed via counseling visits weekly during 12 weeks of study . Anthropometric assessment s and biochemical measurements including reproductive hormones , inflammatory factors , lipids , glucose , and insulin were performed on fasting blood sample s at baseline and after 12 weeks of dietary intervention . Results : Weight loss was significant and similar in the 2 groups . Mean of testosterone in the MHCD and CHCD groups decreased from 1.78 ± 0.32 to 1.31 ± 0.26 ng/ml and from 1.51 ± 0.12 to 1.15 ± 0.11 ng/ml , respectively ( p < 0.001 ) . Follicle sensitizing hormone ( FSH ) , luteinizing hormone ( LH ) , and blood lipids concentrations were not changed except low-density lipoprotein cholesterol ( LDL-C ) was reduced by 24.5 % ± 12.3 % ( p < 0.001 for both ) after 12 weeks of intervention . MHCD result ed in a significant reduction in insulin level , homeostatic model assessment for insulin resistance ( HOMA ) , and high-sensitivity C- reactive protein ( hsCRP ) concentration ( p < 0.001 ) . Conclusions : In this study both hypocaloric diets significantly led to reduced body weight and and rogen levels in these two groups of women with PCOS . The combination of high-protein and low-glycemic-load foods in a modified diet caused a significant increase in insulin sensitivity and a decrease in hsCRP level when compared with a conventional diet [22552687] BACKGROUND Women with polycystic ovary syndrome ( PCOS ) present with vascular abnormalities , including elevated markers of endothelial dysfunction . There is limited evidence for the effect of lifestyle modification and weight loss on these markers . The aim of this study was to determine if 20 weeks of a high-protein energy-restricted diet with or without exercise in women with PCOS could improve endothelial function . METHODS This is a secondary analysis of a subset of 50 overweight/obese women with PCOS ( age : 30.3 ± 6.3 years ; BMI : 36.5 ± 5.7 kg/m(2 ) ) from a previous study . Participants were r and omly assigned by computer generation to one of three 20-week interventions : diet only ( DO ; n = 14 , ≈ 6000 kJ/day ) , diet and aerobic exercise ( DA ; n = 16 , ≈ 6000 kJ/day and five walking sessions/week ) and diet and combined aerobic-resistance exercise ( DC ; n = 20 , ≈ 6000 kJ/day , three walking and two strength sessions/week ) . At Weeks 0 and 20 , weight , markers of endothelial function [ vascular cell adhesion molecule-1 ( sVCAM-1 ) , inter-cellular adhesion molecule-1 ( sICAM-1 ) , plasminogen activator inhibitor-1 ( PAI-1 ) and asymmetric dimethylarginine ( ADMA ) ] , insulin resistance and hormonal profile were assessed . RESULTS All three treatments result ed in significant weight loss ( DO 7.9 ± 1.2 % , DA 11.0 ± 1.6 % , DC 8.8 ± 1.1 ; P < 0.001 for time ; P = 0.6 time × treatment ) . sVCAM-1 , sICAM-1 and PAI-1 levels decreased with weight loss ( P≤ 0.01 ) , with no differences between treatments ( P ≥ 0.4 ) . ADMA levels did not change significantly ( P = 0.06 ) . Testosterone , sex hormone-binding globulin and the free and rogen index ( FAI ) and insulin resistance also improved ( P < 0.001 ) with no differences between treatments ( P ≥ 0.2 ) . Reductions in sVCAM-1 were correlated to reductions in testosterone ( r = 0.32 , P = 0.03 ) and FAI ( r = 0.33 , P = 0.02 ) as well as weight loss ( r= 0.44 , P = 0.002 ) . Weight loss was also associated with reductions in sICAM-1 ( r= 0.37 , P = 0.008 ) . CONCLUSIONS Exercise training provided no additional benefit to following a high-protein , hypocaloric diet on markers of endothelial function in overweight/obese women with PCOS [20943753] Polycystic ovary syndrome ( PCOS ) , the most common endocrine disorder in women of reproductive age , is characterized by hyper and rogenism , oligo/amenorrhea , and polycystic ovaries . We aim ed to determine whether low-frequency electro-acupuncture ( EA ) would decrease hyper and rogenism and improve oligo/amenorrhea more effectively than physical exercise or no intervention . We r and omized 84 women with PCOS , aged 18 - 37 yr , to 16 wk of low-frequency EA , physical exercise , or no intervention . The primary outcome measure changes in the concentration of total testosterone ( T ) at week 16 determined by gas and liquid chromatography-mass spectrometry was analyzed by intention to treat . Secondary outcome measures were changes in menstrual frequency ; concentrations of and rogens , estrogens , and rogen precursors , and glucuroni date d and rogen metabolites ; and acne and hirsutism . Outcomes were assessed at baseline , after 16 wk of intervention , and after a 16-wk follow-up . After 16 wk of intervention , circulating T decreased by -25 % , and rosterone glucuronide by -30 % , and and rostane-3α,17β-diol-3-glucuronide by -28 % in the EA group ( P = 0.038 , 0.030 , and 0.047 , respectively vs. exercise ) ; menstrual frequency increased to 0.69/month from 0.28 at baseline in the EA group ( P = 0.018 vs. exercise ) . After the 16-wk follow-up , the acne score decreased by -32 % in the EA group ( P = 0.006 vs. exercise ) . Both EA and exercise improved menstrual frequency and decreased the levels of several sex steroids at week 16 and at the 16-wk follow-up compared with no intervention . Low-frequency EA and physical exercise improved hyper and rogenism and menstrual frequency more effectively than no intervention in women with PCOS . Low-frequency EA was superior to physical exercise and may be useful for treating hyper and rogenism and oligo/amenorrhea [11527911] BACKGROUND Cross-sectional studies have shown a high frequency of impaired glucose tolerance ( IGT ) and non-insulin dependent diabetes mellitus ( NIDDM ) in women with polycystic ovarian syndrome ( PCOS ) . However , little is known about the change in glucose tolerance that occurs over a period of several years in women with PCOS . METHODS Sixty-seven women with PCOS received a 75 g glucose tolerance test and measurement of lipids at baseline and at follow-up after an average time of 6.2 years . All women followed prospect ively had normal glucose tolerance ( n = 54 ) or IGT ( n = 13 ) at the start of the study . RESULTS Change in glycaemic control from baseline was frequent , with 5/54 ( 9 % ) of normoglycaemic women at baseline developing IGT and a further 4/54 ( 8 % ) moving directly from normoglycaemic to NIDDM . For women with IGT at baseline , 7/13 ( 54 % ) had NIDDM at follow-up . Body mass index ( BMI ) at baseline was an independent significant predictor of adverse change in glycaemic control . CONCLUSIONS Women with PCOS , particularly those with a high BMI , should be review ed regularly with respect to IGT or NIDDM , as the frequency of impaired glycaemic control is high , and that the rate of conversion from normal glucose tolerance to IGT or NIDDM , or from IGT to NIDDM is substantial [18728175] CONTEXT Polycystic ovary syndrome ( PCOS ) presents in adolescence , and obesity is a common finding . The benefits and risks of alternate approaches to the management of PCOS in obese adolescent women are not clear . OBJECTIVE We investigated the effects of metformin , oral contraceptives ( OCs ) , and /or lifestyle modification in obese adolescent women with PCOS . DESIGN Two small , r and omized , placebo-controlled clinical trials were performed . PATIENTS AND PARTICIPANTS A total of 79 obese adolescent women with PCOS participated . INTERVENTIONS In the single treatment trial , subjects were r and omized to metformin , placebo , a lifestyle modification program , or OC . In the combined treatment trial , all subjects received lifestyle modification and OC and were r and omized to metformin or placebo . MAIN OUTCOME MEASURES Serum concentrations of and rogens and lipids were measured . RESULTS Lifestyle modification alone result ed in a 59 % reduction in free and rogen index with a 122 % increase in SHBG . OC result ed in a significant decrease in total testosterone ( 44 % ) and free and rogen index ( 86 % ) but also result ed in an increase in C-reactive protein ( 39.7 % ) and cholesterol ( 14 % ) . The combination of lifestyle modification , OC , and metformin result ed in a 55 % decrease in total testosterone , as compared to 33 % with combined treatment and placebo , a 4 % reduction in waist circumference , and a significant increase in HDL ( 46 % ) . CONCLUSIONS In these preliminary trials , both lifestyle modification and OCs significantly reduce and rogens and increase SHBG in obese adolescents with PCOS . Metformin , in combination with lifestyle modification and OC , reduces central adiposity , reduces total testosterone , and increases HDL , but does not enhance overall weight reduction [4865007] Background To evaluate the feasibility of executing a r and omized controlled trial of progressive resistance training ( PRT ) in women with polycystic ovary syndrome ( PCOS ) . Methods Women with PCOS were r and omized to an experimental ( PRT ) group or a no-exercise ( usual care ) control group . The PRT group was prescribed two supervised and two unsupervised ( home-based ) training sessions per week for 12 weeks . Feasibility outcomes included recruitment and attrition , adherence , adverse events , and completion of assessment s. Secondary outcomes , collected pre and post intervention , included a range of pertinent physiological , functional and psychological measures . Results Fifteen participants were r and omised into the PRT group ( n = 8) or control group ( n = 7 ) ; five women ( n = 2 in PRT group and n = 3 in control group ) withdrew from the study . The most successful recruitment sources were Facebook ( 40 % ) and online advertisement ( 27 % ) , while least successful methods were referrals by clinicians , colleagues and flyers . In the PRT group , attendance to supervised sessions was higher ( 95 % ; st and ard deviation ±6 % ) compared to unsupervised sessions ( 51 % ; st and ard deviation ±28 % ) . No adverse events were attributed to PRT . Change in menstrual cycle status was not significantly different between groups over time ( p = 0.503 ) . However , the PRT group significantly increased body weight ( p = 0.01 ) , BMI ( p = 0.04 ) , lean mass ( p = 0.01 ) , fat-free mass ( p = 0.005 ) and lower body strength ( p = 0.03 ) , while reducing waist circumference ( p = 0.03 ) and HbA1c ( p = 0.033 ) versus the control group . The PRT group also significantly improved across several domains of disease-specific and general health-related quality of life , depression , anxiety and exercise self-efficacy . Conclusion A r and omized controlled trial of PRT in PCOS would be feasible , and this mode of exercise may elicit a therapeutic effect on clinical ly important outcomes in this cohort . The success of a large-scale trial required to confirm these findings would be contingent on addressing the feasibility hurdles identified in this study with respect to recruitment , attrition , compliance , and collection of st and ardized clinical data .Trial registration Australia New Zeal and Clinical Trials Registry ; ACTRN12614000517673 Registered 15 May 2014 [10946879] Abdominal obesity and hyperinsulinemia play a key role in the development of the polycystic ovary syndrome ( PCOS ) . Dietary-induced weight loss and the administration of insulin-lowering drugs , such as metformin , are usually followed by improved hyper and rogenism and related clinical abnormalities . This study was carried out to evaluate the effects of combined hypocaloric diet and metformin on body weight , fat distribution , the glucose-insulin system , and hormones in a group of 20 obese PCOS women [ body mass index ( BMI ) > 28 kg/m2 ] with the abdominal phenotype ( waist to hip ratio > 0.80 ) , and an appropriate control group of 20 obese women who were comparable for age and pattern of body fat distribution but without PCOS . At baseline , we measured sex hormone , sex hormone-binding globulin ( SHBG ) , and leptin blood concentrations and performed an oral glucose tolerance test and computerized tomography ( CT ) at the L4-L5 level , to measure sc adipose tissue area ( SAT ) and visceral adipose tissue area . All women were then given a low-calorie diet ( 1,200 - 1,400 kcal/day ) alone for one month , after which anthropometric parameters and CT scan were newly measured . While continuing dietary treatment , PCOS women and obese controls were subsequently placed , in a r and om order , on metformin ( 850 mg/os , twice daily ) ( 12 and 8 , respectively ) or placebo ( 8 and 12 , respectively ) , according to a double-blind design , for the following 6 months . Blood tests and the CT scan were performed in each woman at the end of the study while they were still on treatment . During the treatment period , 3 women of the control group ( all treated with placebo ) were excluded because of noncompliance ; and 2 PCOS women , both treated with metformin , were also excluded because they became pregnant . Therefore , the women cohort available for final statistical analysis included 18 PCOS ( 10 treated with metformin and 8 with placebo ) and 17 control women ( 8 treated with metformin and 9 with placebo ) . The treatment was well tolerated . In the PCOS group , metformin therapy improved hirsutism and menstrual cycles significantly more than placebo . Baseline anthropometric and CT parameters were similar in all groups . Hypocaloric dieting for 1 month similarly reduced BMI values and the waist circumference in both PCOS and control groups , without any significant effect on CT scan parameters . In both PCOS and control women , however , metformin treatment reduced body weight and BMI significantly more than placebo . Changes in the waist-to-hip ratio values were similar in PCOS women and controls , regardless of pharmacological treatment . Metformin treatment significantly decreased SAT values in both PCOS and control groups , although only in the latter group were SAT changes significantly greater than those observed during the placebo treatment . On the contrary , visceral adipose tissue area values significantly decreased during metformin treatment in both PCOS and control groups , but only in the former was the effect of metformin treatment significantly higher than that of placebo . Fasting insulin significantly decreased in both PCOS women and controls , regardless of treatment , whereas glucose-stimulated insulin significantly decreased only in PCOS women and controls treated with metformin . Neither metformin or placebo significantly modified the levels of LH , FSH , dehydroepi and rosterone sulphate , and progesterone in any group , whereas testosterone concentrations decreased only in PCOS women treated with metformin . SHBG concentrations remained unchanged in all PCOS women ; whereas in the control group , they significantly increased after both metformin and placebo . Leptin levels decreased only during metformin treatment in both PCOS and control groups . ( ABSTRACT TRUNCATED [19012098] Objective . The objectives of the present pilot study were to : ( 1 ) examine the prevalence of body image distress in overweight and obese women with polycystic ovary syndrome ( PCOS ) ; ( 2 ) assess the effects of a low-cost intervention in the form of a self-directed brisk walking program on body image distress ; and ( 3 ) assess the level of participation , the feasibility of a larger study and the sample size required . Methods . This was an observational study whereby volunteers acted as their own control . Thirty-five women with PCOS ( mean age 29.26 ± 7.57 years ) with body mass index ( BMI ) > 25 kg/m2 volunteered for the study . Twenty-three returned six months later for re assessment . Of these , 12 completed the exercise program ( completers ) and 11 did not ( non-completers ) . Pre and post assessment s comprised the exercise tolerance test , the Body Dysmorphic Disorder Examination – Self-Report ( BDDE-SR ) , a question naire on self-perceived hirsutism and dietary and activity records . Results . Distress with body size was highly prevalent for the overall sample . However , completers had significantly higher BDDE-SR scores at baseline compared with non-completers ( p < 0.005 ) . Pre and post assessment s showed a significant reduction in body image distress only for completers ( p < 0.01 ) despite no significant change in BMI . Conclusions . A self-directed walking program is a low-cost intervention that can have psychological benefits for overweight women with PCOS . Specific recommendations for a r and omized study are put forward [23876536] OBJECTIVE To investigate whether r and omized diet and /or physical exercise influence serum levels of antimüllerian hormone ( AMH ) in obese women with polycystic ovary syndrome ( PCOS ) . DESIGN R and omized , 4-month trial with three interventions . SETTING Women 's health clinical research unit at a university hospital . PATIENT(S ) Fifty-seven overweight/obese women with PCOS . INTERVENTION(S ) Diet , physical exercise , or both , using programs individually adapted and supervised by a dietician and /or a physiotherapist . MAIN OUTCOME MEASURE(S ) Serum AMH levels before and after the interventions and correlations to reproductive function , body composition , and endocrine and metabolic variables . RESULT ( S ) After intervention , serum levels of AMH were significantly decreased only in the diet group , and the levels were significantly lower than in the exercise group . The strongest predictor of decreased AMH was a decrease in free T , whereas weight loss had no significant influence . Normalized levels of AMH were associated with improvements in menstrual cyclicity and hyper and rogenism but not in metabolic variables . CONCLUSION ( S ) This r and omized study supports that diet reduces serum AMH in association with decreased and rogen levels in obese women with PCOS . Increased serum AMH may be used as a marker of ovulatory dysfunction and hyper and rogenism but not as a marker of insulin resistance . CLINICAL TRIAL REGISTRY NUMBER IS RCT N48342048 [16900227] This pilot study assessed the effects of exercise and nutritional counseling on hormonal , menstrual , and reproductive function in women with polycystic ovary syndrome ( PCOS ) . Twelve females with a clinical , biochemical , and ultrasonographic diagnosis of PCOS were r and omly assigned to endurance and resistance exercise plus nutritional counseling ( EN ) or nutritional counseling only ( N ) for a period of 12 weeks . Anthropometry , resting metabolic rate ( RMR ) , selected hormones , and ovarian follicle population were measured pre and post-intervention . Following the 12 week intervention , greater decreases in sum of 2 skinfolds ( p = 0.002 ) and a greater increase in estimated VO2 max ( p = 0.017 ) occurred in the exercise group . Significant decreases in waist girth ( p = 0.001 ) and insulin levels ( p = 0.03 ) occurred in both groups . Hormonal changes were not statistically significant ; however , a trend towards an improved hormonal profile , specifically sex-hormone binding globulin ( EN , 39 % increase ; N , 8 % increase ) and lutenizing hormone : follicle-stimulating hormone ( LH : FSH ) ( EN , 9 % decrease ; N , 27 % decrease ) occurred in the absence of weight loss . These findings suggest exercise and nutritional counseling may benefit the metabolic and reproductive abnormalities associated with PCOS [22309675] Objective : To compare the efficacy of metformin with that of lifestyle changes in patients with polycystic ovary syndrome ( PCOS ) . Design : Prospect i ve , r and omized clinical trial of 40 women with PCOS to analyze the effects of metformin and lifestyle intervention treatments on menstrual pattern and hormone and metabolic profile . The duration of treatment was 6 months . Statistical analysis was done using Student ’s t-test . Results : Fifteen women in the metformin group and 12 in the lifestyle changes group completed the study . The menstrual pattern improved by ~67 % in both groups . There was a significant decrease in waist circumference in the lifestyle changes group ( 101.8 ± 3.9 and 95.1 ± 3.6 , at baseline and at 6 months of treatment , respectively ; p < 0.001 ) and in body mass index ( BMI ) in both groups . The predictor of menstrual pattern improvement was BMI . Conclusions : Both metformin and lifestyle changes may increase the number of menstrual cycles in PCOS . This effect was related to a decrease in BMI [17603048] OBJECTIVE To examine the efficacy of sibutramine together with brief lifestyle modification for weight reduction in obese women with polycystic ovary syndrome ( PCOS ) . DESIGN Investigator-initiated , multicenter , double-blind , r and omized , parallel-group clinical trial . SETTING Departments of Obstetrics and Gynecology in primary care , referral centers , and private practice . PATIENT(S ) Forty-two patients with confirmed PCOS were included in the study , and 34 patients completed the study . INTERVENTION Sibutramine 15 mg once daily together with brief lifestyle modification was compare with placebo together with brief lifestyle modification . MAIN OUTCOME MEASURE(S ) The primary endpoint was to assess weight loss . Secondary endpoints included the efficacy of sibutramine for treatment of menstrual pattern and cardiovascular risk factors . RESULT ( S ) After 6 months the sibutramine group had lost 7.8 + /- 5.1 kg compared with a weight loss of 2.8 + /- 6.2 kg in the placebo group . Sibutramine treatment result ed in significant decreases in apolipoprotein B , apolipoprotein B/apolipoprotein A ratio , triglycerides , and cystatin C levels . CONCLUSION ( S ) Sibutramine in combination with lifestyle intervention results in significant weight reduction in obese patients with PCOS . In addition to the weight loss , sibutramine seems to have beneficial effects on metabolic and cardiovascular risk factors [12923151] BACKGROUND This prospect i ve study evaluated the effect of weight reduction on anthropometric indices and ovarian morphology in anovulatory overweight patients with polycystic ovary syndrome ( PCOS ) . METHODS Thirty-three anovulatory overweight patients with PCOS were enrolled in the study . All had patent Fallopian tubes and chronic anovulation : 27 of them were oligo-amenorrhoeic . The partners were normospermic . Patients were prescribed a 1200 kcal/day diet , and physical exercise was recommended . Anthropometric indices and ovarian imaging parameters were assessed at baseline and after weight loss of 5 and 10 % . RESULTS Twenty-five patients ( 76 % ) lost at least 5 % of their body weight . Eleven of these patients ( 33 % ) reached a 10 % decrease in weight . Waist circumference at the umbilical level , hip circumference , four skin folds , body mass index and fatty mass ratio were significantly reduced after 5 and 10 % weight loss . Ovarian morphology changed during the diet : we observed a significant reduction in ovarian volume and in the number of microfollicles per ovary . Among the 27 patients with oligo-amenorrhoea , 18 had a resumption of regular cycles and 15 experienced spontaneous ovulation ; 10 spontaneous pregnancies occurred in patients who lost at least 5 % of their weight . CONCLUSIONS Weight loss through a controlled low-calorie diet improves anthropometric indices in obese PCOS patients , reduces ovarian volume and microfollicle number and can restore ovulatory cycles , allowing spontaneous pregnancy [19494176] We have recently shown that polycystic ovary syndrome ( PCOS ) is associated with high muscle sympathetic nerve activity ( MSNA ) . Animal studies support the concept that low-frequency electroacupuncture ( EA ) and physical exercise , via stimulation of ergoreceptors and somatic afferents in the muscles , may modulate the activity of the sympathetic nervous system . The aim of the present study was to investigate the effect of these interventions on sympathetic nerve activity in women with PCOS . In a r and omized controlled trial , 20 women with PCOS were r and omly allocated to one of three groups : low-frequency EA ( n = 9 ) , physical exercise ( n = 5 ) , or untreated control ( n = 6 ) during 16 wk . Direct recordings of multiunit efferent postganglionic MSNA in a muscle fascicle of the peroneal nerve before and following 16 wk of treatment . Biometric , hemodynamic , endocrine , and metabolic parameters were measured . Low-frequency EA ( P = 0.036 ) and physical exercise ( P = 0.030 ) decreased MSNA burst frequency compared with the untreated control group . The low-frequency EA group reduced sagittal diameter ( P = 0.001 ) , while the physical exercise group reduced body weight ( P = 0.004 ) and body mass index ( P = 0.004 ) compared with the untreated control group . Sagittal diameter was related to MSNA burst frequency ( Rs = 0.58 , P < 0.005 ) in the EA group . No correlation was found for body mass index and MSNA in the exercise group . There were no differences between the groups in hemodynamic , endocrine , and metabolic variables . For the first time we demonstrate that low-frequency EA and physical exercise lowers high sympathetic nerve activity in women with PCOS . Thus , treatment with low-frequency EA or physical exercise with the aim to reduce MSNA may be of importance for women with PCOS [16199429] BACKGROUND It has been reported that women with polycystic ovary syndrome ( PCOS ) benefit from metformin therapy . METHODS A r and omized , placebo-controlled , double-blind study of obese ( body mass index > 30 kg/m2 ) , oligo-/amenorrhoeic women with PCOS . Metformin ( 850 mg ) twice daily was compared with placebo over 6 months . All received the same advice from a dietitian . The primary outcome measures were : ( i ) change in menstrual cycle ; ( ii ) change in arthropometric measurements ; and ( iii ) changes in the endocrine parameters , insulin sensitivity and lipid profile . RESULTS A total of 143 subjects was r and omized [ metformin ( MET ) = 69 ; placebo ( PL ) = 74 ] . Both groups showed significant improvements in menstrual frequency [ median increase ( MET = 1 , P < 0.001 ; PL = 1 , P < 0.001 ) ] and weight loss [ mean ( kg ) ( MET = 2.84 ; P < 0.001 and PL = 1.46 ; P = 0.011 ) ] . However , there were no significant differences between the groups . Logistic regression analysis was used to analyse the independent variables ( metformin , percentage of weight loss , initial BMI and age ) in order to predict the improvement of menses . Only the percentage weight loss correlated with an improvement in menses ( regression coefficient = 0.199 , P = 0.047 , odds ratio = 1.126 , 95 % CI 1.001 , 1.266 ) . There were no significant changes in insulin sensitivity or lipid profiles in either of the groups . Those who received metformin achieved a significant reduction in waist circumference and free and rogen index . CONCLUSIONS Metformin does not improve weight loss or menstrual frequency in obese patients with PCOS . Weight loss alone through lifestyle changes improves menstrual frequency [4784413] Background This study assessed the perceived benefits and barriers to exercise participation in overweight and obese women with polycystic ovary syndrome ( PCOS ) and monitored changes in response to a lifestyle intervention . Methods Forty-three overweight/obese PCOS women ( Age , 30.3(6.2 ) yrs ; BMI , 36.4(5.6 ) kg/m2 ) were r and omised to one of three 20-week lifestyle programs : diet only ( DO , n = 13 ) , diet and aerobic exercise ( DA , n = 11 ) and diet and combined aerobic-resistance exercise ( DC , n = 19 ) . Exercise Benefits /Barriers Scale ( EBBS ) , weight , aerobic fitness , depression and PCOS specific health-related quality of life were measured . Results Barriers score was related to depression ( r = 0.45 , P = 0.002 ) and aerobic fitness ( r = −0.32 , P = 0.04 ) , while benefits score was related to aerobic fitness ( r = 0.41 , P = 0.007 ) . EBBS , benefits and barriers scores improved overtime ( P ≤ 0.001 ) . Benefits subscales psychological outlook and social interaction increased ( P ≤ 0.001 ) and life enhancement and preventative health did not change ( P ≥ 0.3 ) . Physical performance increased only in DA ( P = 0.009 ) . There were no differences between treatments for any of the other subscales ( P ≥ 0.2 ) . Barriers subscales exercise milieu , time expenditure and physical exertion reduced ( P ≤ 0.003 ) and family discouragement did not change ( P = 0.6 ) . Conclusions This study demonstrated that lifestyle modification consisting of an energy-restricted diet with or without exercise training improved the perceived benefits from and barriers to exercise . Trial registration Australian New Zeal and Clinical Trials Register ACTRN12606000198527 , registered 26 May [4540866] [ Purpose ] The short-term effects of structured exercise on the anthropometric , cardiovascular , and metabolic parameters of non-overweight women diagnosed with polycystic ovary syndrome were evaluated . [ Subjects and Methods ] Thirty women with a diagnosis of polycystic ovary syndrome were prospect ively r and omized to either a control group ( n=16 ) or a training group ( n=14 ) for a period of 8 weeks . Anthropometric , cardiovascular , and metabolic parameters and hormone levels were measured and compared before and after the intervention . [ Results ] Waist and hip measurements ( anthropometric parameters ) ; diastolic blood pressure ; respiratory rate ( cardiovascular parameters ) ; levels of low-density lipoprotein cholesterol , total cholesterol , fasting glucose , and fasting insulin ; and the homeostasis model assessment of insulin resistance index ( metabolic parameters ) were significantly lower in the training group after 8 weeks of exercise compared to the baseline values . After exercise , the training group had significantly higher oxygen consumption and high-density lipoprotein levels and significantly shorter menstrual cycle intervals . The corresponding values for controls did not significantly differ between the start and end of the 8-week experiment . [ Conclusion ] Short-term regular exercise programs can lead to improvements in anthropometric , cardiovascular , and metabolic parameters of non-overweight women with polycystic ovary syndrome [17673038] OBJECTIVE To compare the efficacy of weight loss , metformin and rosiglitazone in women with polycystic ovary syndrome ( PCOS ) . METHODS A r and omized controlled trial ( RCT ) was carried out in Peking Union Medical College Hospital ( PUMCH ) , one hundred and six women with PCOS were assigned to three intervention groups : weight loss , weight loss and metformin , weight loss and rosiglitazone group . Patients were treated with weight loss ( diet and exercise ) , weight loss and metformin ( 500 mg three times daily ) , weight loss and rosiglitazone ( 4 mg once daily ) for three months . Sixty patients completed treatments . Basal body temperature ( BBT ) , total testosterone as well as fasting serum insulin levels and lipid were measured and compared in all patients before and after weight loss . RESULTS No significant differences were found in the baseline characteristics among three groups . In weight loss group 51 % ( 22/43 ) patients completed treatment , and 23 % ( 5/22 ) patients resumed ovulation . In weight loss and metformin group 58 % ( 21/36 ) patients completed treatment , and 43 % ( 9/21 ) patients resumed ovulation . In weight loss and rosiglitazone group 63 % ( 17/27 ) patients completed treatment , and 59 % ( 10/17 ) patients resumed ovulation . Ovulation rate was significantly higher in weight loss and rosiglitazone group than in weight loss group . There was no significant difference among three groups in body mass index ( BMI ) , waist circumference , waist-hip ratio ( WHR ) , sex hormone , serum fasting insulin and lipid level after treatment . CONCLUSION Weight loss , metformin and rosiglitazone all can improve ovulation each [22154367] OBJECTIVE To investigate the possible effects of low-frequency electroacupuncture ( EA ) and physical exercise on markers of coagulation and fibrinolysis , insulin sensitivity , and adipose tissue characteristics in women with polycystic ovary syndrome ( PCOS ) . DESIGN Secondary analyses of a prospect i ve , r and omized controlled clinical trial . SETTING Department of Physiology and Department of Obstetrics and Gynecology , University of Gothenburg . PATIENT(S ) Eighty-four women with PCOS were r and omized . INTERVENTION(S ) Women with PCOS were r and omized to 16 weeks of low-frequency EA ( 14 treatments ) , physical exercise ( at least 3 times/wk ) , or no intervention . MAIN OUTCOME MEASURE(S ) Anthropometrics , circulating coagulation and fibrinolytic markers , insulin sensitivity ( euglycemic hyperinsulinemic clamp ) , hemodynamics , and adipose tissue morphology/function recorded at baseline , after 16 weeks of intervention , and after a 16-week follow-up . RESULT ( S ) In the low-frequency EA group , circulating plasminogen activator inhibitor 1 activity decreased by 21.8 % after 16 weeks of intervention and by 31.1 % at the 16-week follow-up and differed from the physical exercise and the no intervention groups . The EA group had decreases in circulating fibrinogen and tissue plasminogen activator ( t-PA ) , sagittal diameter , and diastolic blood pressure after treatment , and fibrinogen remained lower at the 16-week follow-up . In the physical exercise group , lipoprotein lipase activity increased and diastolic blood pressure decreased after treatment , and both diastolic and systolic blood pressure were lower at follow-up . No other variables were affected . CONCLUSION ( S ) Low-frequency EA counteracted a possible prothrombotic state in women with PCOS , as reflected by a decrease in plasminogen activator inhibitor 1 activity . Despite within-group improvements , there were no between-group differences in anthropometric , metabolic , or hemodynamic variables after 16 weeks of EA or physical exercise at the dose/intensity studied [25026923] The aim of this r and omized pilot was to assess the feasibility of a dietary intervention among women with polycystic ovary syndrome ( PCOS ) comparing a vegan to a low-calorie ( low-cal ) diet . Overweight ( body mass index , 39.9 ± 6.1 kg/m(2 ) ) women with PCOS ( n = 18 ; age , 27.8 ± 4.5 years ; 39 % black ) who were experiencing infertility were recruited to participate in a 6-month r and omized weight loss study delivered through nutrition counseling , e-mail , and Facebook . Body weight and dietary intake were assessed at 0 , 3 , and 6 months . We hypothesized that weight loss would be greater in the vegan group . Attrition was high at 3 ( 39 % ) and 6 months ( 67 % ) . All analyses were conducted as intention-to-treat and presented as median ( interquartile range ) . Vegan participants lost significantly more weight at 3 months ( -1.8 % [ -5.0 % , -0.9 % ] vegan , 0.0 [ -1.2 % , 0.3 % ] low-cal ; P = .04 ) , but there was no difference between groups at 6 months ( P = .39 ) . Use of Facebook groups was significantly related to percent weight loss at 3 ( P < .001 ) and 6 months ( P = .05 ) . Vegan participants had a greater decrease in energy ( -265 [ -439 , 0 ] kcal/d ) and fat intake ( -7.4 % [ -9.2 % , 0 ] energy ) at 6 months compared with low-cal participants ( 0 [ 0 , 112 ] kcal/d , P = .02 ; 0 [ 0 , 3.0 % ] energy , P = .02 ) . These preliminary results suggest that engagement with social media and adoption of a vegan diet may be effective for promoting short-term weight loss among women with PCOS ; however , a larger trial that addresses potential high attrition rates is needed to confirm these results [4296399] BACKGROUND : The effects of exercise , metformin , and orlistat on anthropometric parameters , lipid profile , endocrine parameters , and ovulation in polycystic ovarian syndrome ( PCOS ) women were compared . AIM : The aim was to study the efficacy of orlistat compared with metformin and exercise in PCOS . DESIGN : R and omized control trial . METHODS : A total of 90 eligible PCOS women were r and omly assigned to receive either of the two drugs ( orlistat or metformin ) in combination with lifestyle interventions or as controls where they received lifestyle interventions alone . Anthropometric parameters were assessed at baseline and 4 weekly intervals for 3 months . And rogen levels , insulin resistance , ovulation and conception rates and lipid profile were also assessed at the end of study . STATISTICAL ANALYSIS : Statistical analysis was performed using the SPSS version 17.0 . RESULTS : The levels of fasting blood sugar , fasting insulin and homeostatic model assessment insulin resistance were comparable in three treatment groups . Mean total testosterone , serum hormone binding globulin , free and rogen index , dehydroepi and rosterone sulfate in all arms were comparable and statistically nonsignificant . However , orlistat and metformin were more effective in reducing weight , body mass index , waist circumference and waist-hip ratio . However , side-effects were less with orlistat . Ovulation rate was 33.3 % , 23.35 % with orlistat and metformin group respectively , but were not statistically significant . In orlistat group , significant improvement was observed in lipid profile at the end of 3 months . Conception rates were 40 % and 16.7 % and 3.3 % in orlistat , metformin group and control group respectively ( P - 0.003 ) . Weight loss was found to be the best predictor of ovulation with sensitivity with good sensitivity . CONCLUSION : Orlistat is as effective as metformin in reducing weight and achieves similar ovulation rates in obese PCOS patients . However , orlistat has minimal side-effects and is better tolerated compared with metformin [26373822] OBJECTIVE The aim of this study was to examine the effects of acute exercise on insulin signaling in skeletal muscle of women with polycystic ovary syndrome ( PCOS ) and controls ( CTRL ) . METHODS Fifteen women with obesity and PCOS and 12 body mass index-matched CTRL participated in this study . Subjects performed a 40-min single bout of exercise . Muscle biopsies were performed before and 60 min after exercise . Selected proteins were assessed by Western blotting . RESULTS CTRL , but not PCOS , showed a significant increase in PI3-k p85 and AS160 Thr 642 after a single bout of exercise ( P = 0.018 and P = 0.018 , respectively ) . Only PCOS showed an increase in Akt Thr 308 and AMPK phosphorylation after exercise ( P = 0.018 and P = 0.018 , respectively ) . Total GLUT4 expression was comparable between groups ( P > 0.05 ) . GLUT4 translocation tended to be significantly higher in both groups after exercise ( PCOS : P = 0.093 ; CTRL : P = 0.091 ) , with no significant difference between them ( P > 0.05 ) . CONCLUSIONS A single bout of exercise elicited similar GLUT4 translocation in skeletal muscle of PCOS and CTRL , despite a slightly differential pattern of protein phosphorylation . The absence of impairment in GLUT4 translocation suggests that PCOS patients with obesity and insulin resistance may benefit from exercise training [26401593] CONTEXT Lifestyle modification is recommended in women with polycystic ovary syndrome ( PCOS ) prior to conception but there are few r and omized trials to support its implementation or benefit . OBJECTIVE This study aim ed to determine the relative efficacy of preconception intervention on reproductive and metabolic abnormalities in overweight/obese women with PCOS . DESIGN , SETTING , AND PARTICIPANTS This was a r and omized controlled trial of preconception and infertility treatment at Academic Health Centers in women with infertility due to PCOS , age 18 - 40 y and body mass index 27 - 42 kg/m(2 ) . INTERVENTION Women were r and omly assigned to receive either 16 weeks of 1 ) continuous oral contraceptive pills ( OCPs ) ( ethinyl estradiol 20 mcg/1 mg norethindrone acetate ) ( " OCP " ) ; 2 ) lifestyle modification consisting of caloric restriction with meal replacements , weight loss medication ( either sibutramine , or orlistat ) , and increased physical activity to promote a 7 % weight loss ( " Lifestyle " ) ; or 3 ) combined treatment with both OCP and lifestyle modification ( " Combined " ) . After preconception intervention , women underwent st and ardized ovulation induction with clomiphene citrate and timed intercourse for four cycles . Pregnancies were followed with trimester visits until delivery . MAIN OUTCOME MEASURES Weight , ovulation , and live birth were measured . RESULTS We consented 216 and r and omly assigned 149 women ( Lifestyle : n = 50 ; OCP : n = 49 ; Combined : n = 50 ) . We achieved significant weight loss with both Lifestyle ( mean weight loss , -6.2 % ; 95 % confidence interval ( CI ) , -7.4 - -5.0 ; and Combined ( mean weight loss , -6.4 % ; 95 % CI , -7.6 - -5.2 ) compared with baseline and OCP ( both P < .001 ) . There was a significant increase in the prevalence of metabolic syndrome at the end of preconception treatment compared with baseline within OCP ( odds ratio [ OR , 2.47 ; 95 % CI , 1.42 - 4.27 ) whereas no change in metabolic syndrome was detected in the Lifestyle ( OR , 1.18 ; 95 % CI , 0.63 - 2.19 ) or Combined ( OR , 0.72 ; 95 % CI , 0.44 - 1.17 ) groups . Cumulative ovulation rates were superior after weight loss : OCP , 46 % ; Lifestyle , 60 % ; and Combined , 67 % ( P < .05 ) . Live birth rates were OCP , 12 % ; Lifestyle , 26 % ; and Combined , 24 % ( P = .13 ) . CONCLUSIONS A preconception weight loss intervention eliminates the adverse metabolic oral contraceptive effects and , compared with oral contraceptive pretreatment , leads to higher ovulation rates [22334228] AIM The aim of this study was to evaluate the effects of diet alone , and in association with metformin in monotherapy or in cotreatment with myoinositol ( MYO ) on menstrual irregularities , hirsutism , body weight and composition in overweight/obese women with polycystic ovary syndrome ( PCOS ) . METHODS Twenty-seven PCOS overweight/obese patients were r and omly treated : nine with only diet ( D ) ; nine with diet and metformin 1000 mg/day continuously ( D+M ) ; nine with diet , metformin 500 mg/day and MYO 4 g/day plus 400 µg folic acid daily , continuously ( D+M+I ) . Menstrual cycle , Ferriman-Gallwey score , body mass index ( BMI ) , waist hip rate ( WHR ) , body composition by BIA 101 of AKERN SRL , were measured on basal condition and at 3 months . RESULTS Regularity of menstrual cycle was restored in a significantly number of patients of group D+M+I ( P<0.05 ) ; Ferriman score was significantly improved by weight loss ( P<0.05 ) . Body weight , BMI , waist and hip circumferences decreased significantly in all groups without WHR modification ; body weight loss significantly depended on adding metformin to diet . Fat mass ( FM ) kg and % was significantly reduced in groups D and D+M+I ; fat free mass ( FFM ) kg was slightly reduced by diet ( P<0.05 ) and correlated with Ferriman score . CONCLUSION Body weight loss in obese PCOS patients improves symptoms and body composition ; weight loss was dependent on adding metformin to diet ; MYO was more effective in restoring regularity of menstrual cycle . Further investigation occurs to confirm metformin and MYO rule on body composition improvement , specially regarding FFM that is likewise FM correlated to cardiovascular risk [16868063] CONTEXT The few controlled trials performed so far indicate that the addition of metformin and /or flutamide to a hypocaloric diet in obese women with polycystic ovary syndrome ( PCOS ) effectively influences different phenotypic aspects of the syndrome . All these studies are , however , characterized by a short to medium period of treatment . OBJECTIVE Our objective was to investigate the long-term effects of these therapies . DESIGN AND SETTING We conducted a prospect i ve , r and omized , placebo-controlled trial at a medical center . PATIENTS Of 80 overweight-obese women with PCOS , 76 completed the study . INTERVENTIONS Patients were placed on a hypocaloric diet for the first month and then on a hypocaloric diet plus placebo , metformin ( 850 mg , orally , twice a day ) , flutamide ( 250 mg , orally , twice a day ) , or metformin plus flutamide for the subsequent 12 months ( 20 subjects in each group ) . MAIN OUTCOME MEASURES We assessed clinical features , computerized tomography measurement of fat distribution , and rogens , lipids , and fasting and glucose-stimulated glucose and insulin levels at baseline and after 6 and 12 months of treatment . RESULTS After 6 months , compared with placebo , flutamide further decreased visceral/sc fat mass ( P = 0.044 ) , and rostenedione ( P < 0.001 ) , dehydroepi and rosterone sulfate ( P < 0.001 ) , and hirsutism score ( P < 0.001 ) , whereas metformin further increased frequency of menstruation ( P = 0.039 ) . After 12 months , flutamide maintained the effects observed after 6 months on visceral/sc fat mass ( P = 0.033 ) and and rostenedione ( P < 0.001 ) , whereas it produced an additional decrease in dehydroepi and rosterone sulfate ( P = 0.020 ) and hirsutism score ( P = 0.019 ) ; metformin further improved the menstrual pattern ( P = 0.013 ) . Moreover , after 12 months , flutamide improved more than placebo the menstrual pattern ( P = 0.008 ) , glucose-stimulated glucose levels ( P = 0.041 ) , insulin sensitivity ( P < 0.001 ) , and low-density lipoprotein cholesterol levels ( P = 0.003 ) , whereas metformin decreased glucose-stimulated insulin levels ( P = 0.014 ) . The combination of the two drugs maintained the specific effect of each of the compounds , without any additive or synergistic effect . CONCLUSIONS These findings add relevance to the usefulness of metformin and flutamide in the treatment of dieting overweight-obese PCOS women and provide a rationale for targeting different therapeutic options according to the required outcomes in the long term [25282112] INTRODUCTION Some pregnancy complications are characterized by increased levels of cell-free fetal ( cffDNA ) and maternal DNA ( cfmDNA ) , the latter may also be elevated during physical strain . This study aims at assessing the impact of exercise and metformin intervention in pregnancy , and to compare the levels of cell free DNA in pregnant women with or without PCOS diagnosis . METHODS Consecutive women from two previous r and omized controlled trials in pregnancy were included . Women came from a trial with organized exercise vs. st and ard antenatal care in pregnancy and a trial of metformin vs. placebo in PCOS women . Levels of cffDNA , cfmDNA and cell-free total DNA ( cftDNA ) were measured by qPCR . RESULTS Training in pregnancy did not affect the levels of cffDNA , cfmDNA or cftDNA . PCOS-women treated with metformin had lower levels of cfmDNA and cftDNA at week 32 ( mean ± SD : 301 ± 162 versus 570 ± 337 , p = 0.012 , 345 ± 173 versus 635 ± 370 , p = 0.019 ) ; otherwise the levels were comparable to PCOS-controls . Metformin-treated PCOS-women had higher cffDNA at inclusion , in the 1st trimester ; later on in pregnancy the levels in the metformin and placebo groups were equal . A comparison of pregnant women in the exercise study ( TRIP ) to placebo-treated pregnant PCOS-women , showed the levels of cffDNA , cfmDNA or cftDNA during mid-pregnancy ( weeks 18 - 36 ) to be equal . DISCUSSION Training during pregnancy was not associated with altered levels of cffDNA cfmDNA or cftDNA , but metformin treatment may reduce cfmDNA and cftDNA in pregnant PCOS women [18505468] Background Polycystic ovary syndrome ( PCOS ) is a common female reproductive‐age endocrine disease predominantly characterized by chronic anovulation , hyper and rogenism , insulin‐resistance and low‐ grade inflammatory status . Exercise training ( ET ) favourably modulates cardiopulmonary function and insulin‐sensitivity markers in PCOS women . The present study investigated the effects of ET on autonomic function and inflammatory pattern in PCOS women [8150098] OBJECTIVE To determine whether weight loss in obese , hyper and rogenic , anovulatory women is associated with resumption of ovulation and /or with changes in insulin , and rogen , and gonadotropin concentrations . DESIGN Prospect i ve , r and omized , controlled study . SETTING University research center . PATIENTS Twelve obese , hyper and rogenic , anovulatory women . INTERVENTIONS Twelve-week weight loss program in treatment ( n = 6 ) ; 12-week " waiting list " in control group ( n = 6 ) . MAIN OUTCOME MEASURES [ 1 ] Ovulation ; [ 2 ] fasting insulin and glucose measurements ; [ 3 ] sex hormone-binding globulin ( SHBG ) , total and non-SHBG T concentrations ; [ 4 ] LH pulse frequency , amplitude , and concentration ; and [ 5 ] FSH concentration . RESULTS In contrast with the control group who showed no change in weight , ovulation status , or hormone levels , women in the treatment group lost an average of 16.2 kg and showed a significant increase in SHBG , a significant decline in non-SHBG T , and a decline ( though nonsignificant ) in fasting insulin . Four of six subjects resumed ovulation . However , no changes were evident in LH pulse frequency or amplitude or in mean LH and FSH concentrations . CONCLUSIONS Weight loss in obese , hyper and rogenic , anovulatory women appears to reduce insulin and non-SHBG T concentrations despite the absence of a change in gonadotropin secretion and may lead to resumption of ovulation [7613427] Abstract Objective : To test the hypothesis that a single measurement , waist circumference , might be used to identify people at health risk both from being overweight and from having a central fat distribution . Design : A community derived r and om sample of men and women and a second , validation sample . Setting : North Glasgow . Subjects : 904 men and 1014 women ( first sample ) ; 86 men and 202 women ( validation sample ) . Main outcome measures : Waist circumference , body mass index , waist : hip ratio . Results : Waist circumference > /=94 cm for men and > /=80 cm for women identified subjects with high body mass index ( > /=25 kg/m2 ) and those with lower body mass index but high waist : hip ratio ( > /=0.95 for men , > /=0.80 women ) with a sensitivity of > 96 % and specificity > 97.5 % . Waist circumference > /=102 cm for men or > /=88 cm for women identified subjects with body mass index > /=30 and those with lower body mass index but high waist : hip ratio with a sensitivity of > 96 % and specificity > 98 % , with only about 2 % of the sample being misclassified . Conclusions : Waist circumference could be used in health promotion programmes to identify individuals who should seek and be offered weight management . Men with waist circumference > /=94 cm and women with waist circumference > /=80 cm should gain no further weight ; men with waist circumference > /=102 cm and women with waist circumference > /=88 cm should reduce their weight [15302293] OBJECTIVE To obtain data from a pilot r and omized trial on the effect of metformin therapy and lifestyle modification on ovulation and and rogen concentrations in women with polycystic ovary syndrome ( PCOS ) . DESIGN Prospect i ve , r and omized , placebo-controlled pilot trial . SETTING Academic medical center . PATIENT(S ) Thirty-eight overweight or obese women with PCOS . INTERVENTION(S ) All subjects were r and omized to one of four 48-week interventions : metformin 850 mg two times per day , lifestyle modification plus metformin 850 mg two times per day , lifestyle modification plus placebo , or placebo alone . MAIN OUTCOME MEASURE(S ) Recruitment , dropout , and compliance with a long-term lifestyle intervention in PCOS ; preliminary estimates of treatment effect on ovulation , as measured by weekly urinary pregnanediol glucuronide , and on total T and free and rogen index . RESULT ( S ) It was necessary to screen seven women to have one subject r and omized . The dropout rate was 39 % , with the majority of dropouts occurring within the first 24 weeks . Mean body mass index was > 39 mg/kg(2 ) . Modest weight reduction was found in all treatment groups , with the most significant reduction occurring with the combination of metformin and lifestyle intervention . Significant and rogen reduction occurred in the combination group only . Ovulation rates did not differ significantly between groups . However , when data were analyzed by presence or absence of weight reduction in subjects , independent of treatment group , the estimated odds ratio for weight loss was 9.0 ( 95 % confidence interval 1.2 - 64.7 ) with respect to regular ovulation . If weight loss occurred during metformin therapy , the odds ratio for regular ovulation was 16.2 ( 95 % confidence interval 4.4 - 60.2 ) . CONCLUSION ( S ) Key method ologic issues for a large-scale , r and omized trial of lifestyle intervention in PCOS include minimizing early dropout from the lifestyle intervention and including a range of body mass index that is not skewed toward severe obesity . Weight reduction might play the most significant role in restoration of ovulation in obese women with PCOS [26298524] STUDY OBJECTIVE To investigate the effect of dietary weight loss on menstrual regularity in obese adolescent women with polycystic ovary syndrome ( PCOS ) . DESIGN AND SETTING A r and omized controlled trial was held at the Faculty of Nursing , Mansoura University , and the Obesity Clinic of the Rheumatology Department at Mansoura University Hospitals between July 2011 and January 2013 . PARTICIPANTS Sixty adolescent women with PCOS , body mass index ( BMI ) greater than 30 , and complaints of menstrual irregularities were included in this study . Enrolled women were divided equally and r and omly into 2 groups : intervention and control groups . INTERVENTIONS Women in the intervention group ( n = 30 ) were subject to an intensive dietary educational program with instructions to follow a conventional energy restricted diet , whereas women in the control group were instructed to follow the same healthy diet of the first group without calorie restriction . MAIN OUTCOME MEASURES Menstrual regularity , weight loss , the effect on waist circumference , and hirsutism score . RESULTS The 2 groups were initially matched in average body weight , BMI , hirsutism score , and waist circumference . Six months later , there were significant decreases in all parameters in the weight reduction group . In addition , more menstrual episodes were recorded in the weight reduction compared with the control group ( 3.1 ± 1.2 vs. 2.3 ± 1.3 ; P = .010 ) . Also , BMI , waist circumference , and hirsutism score were all significantly decreased at the end of the study . CONCLUSION Dietary weight loss in adolescent women with PCOS result ed in significant improvement in menstrual regularity , BMI , waist circumference , and hirsutism score [16757529] CONTEXT Insulin resistance is a feature of polycystic ovary syndrome ( PCOS ) , and it is related to mitochondrial function , particularly with maximal oxygen consumption ( VO(2max ) ) . At the moment , no evaluation of cardiopulmonary functional capacity in young patients with PCOS has been performed . OBJECTIVE Our objective was to assess cardiopulmonary functional capacity in young PCOS overweight patients . DESIGN AND SETTING We conducted a prospect i ve baseline-controlled clinical study at University Federico II of Naples , School of Medicine ( Naples , Italy ) . PATIENTS Forty-five PCOS patients were matched with 45 healthy women for age ( mean + /- sd , 21.3 + /- 2.0 vs. 21.6 + /- 1.9 yr , respectively ) and body mass index ( 29.4 + /- 3.6 vs. 29.0 + /- 3.4 kg/m(2 ) , respectively ) . MEAN OUTCOME MEASURES We assessed hormonal and metabolic pattern and functional capacity by cardiopulmonary exercise testing to evaluate maximal oxygen consumption ( VO(2max ) ) , oxygen consumption at anaerobic threshold ( VO(2AT ) ) , and the maximal workload at peak exercise . RESULTS VO(2max ) ( 17.0 + /- 3.7 vs. 26.8 + /- 3.5 ml/kg.min ) , oxygen consumption at anaerobic threshold ( 13.9 + /- 3.0 vs. 21.2 + /- 3.8 ml/kg.min ) , and maximal workload at peak exercise ( 101.3 + /- 25.2 vs. 135 + /- 22.6 W ) were significantly ( P < 0.001 ) reduced in PCOS subjects compared with healthy women . The multiple linear regression analysis showed that only homeostasis model assessment appears to have a strong negative linear relation with VO(2max ) in PCOS . No relation was found in controls . CONCLUSIONS Our data demonstrate a reduced cardiopulmonary functional capacity in young PCOS patients [21324452] In a prospect i ve study , eight women with polycystic ovary syndrome completed 16 weeks of individualized aerobic exercise training . Independent of changes in body weight and adiposity there was a statistically significant increase in aerobic fitness and insulin sensitivity and a statistically significant decrease in the total number of follicles measured by magnetic resonance imaging [21193187] OBJECTIVE To determine if the combination of lifestyle ( caloric restriction and exercise ) and metformin ( MET ) would be superior to lifestyle and placebo ( PBO ) in improving the polycystic ovary syndrome ( PCOS ) phenotype . DESIGN Double-blind r and omized 6-month trial of MET versus PBO . SETTING Two academic medical centers . PATIENT(S ) One hundred fourteen subjects with PCOS were r and omized to MET ( N = 55 ) or PBO ( N = 59 ) . INTERVENTION(S ) Subjects collected urine daily for ovulation monitoring , had monthly monitoring of hormones and weight and determination of body composition by dual-energy x-ray absorptiometry , glucose tolerance , and were evaluated for quality of life at baseline and completion . MAIN OUTCOME MEASURE(S ) Ovulation rates and testosterone levels . RESULT ( S ) Dropout rates were high . There was no significant difference in ovulation rates . Testosterone levels were significantly lower compared with baseline in the MET group at 3 mos but not at 6 mos . There were no differences in weight loss between groups , but MET showed a significant decline at 6 months compared with baseline ( -3.4 kg , 95 % confidence interval -5.3 to -1.5 kg ) . We noted divergent effects of MET versus PBO on oral glucose tolerance test indices of insulin sensitivity ( increased ) and secretion ( worsened ) . Total bone mineral density increased significantly in MET . There were no differences in quality of life measures between the groups . The MET group had increased diarrhea and headache , but fewer bladder infections and musculoskeletal complaints . CONCLUSION ( S ) The addition of metformin to lifestyle therapy produced little reproductive or glycemic benefit in women with PCOS , although our study had limited power owing to a high dropout rate . It is not possible at baseline to identify women likely to drop out [19204602] PURPOSE Women with polycystic ovary syndrome ( PCOS ) commonly have insulin resistance . Insulin resistance is associated with marked abnormalities of lipoprotein size and subclass particle concentration . The purpose of this study was to examine the effects of a moderate-intensity exercise program without weight loss on lipoprotein profiles in women with PCOS . METHODS Thirty-seven sedentary PCOS women were r and omized to either an 8- to 12-wk ramp-up followed by a 12-wk moderate-intensity exercise program ( 16 - 24 wk total , approximately 228 min x wk at 40 - 60 % peak V x O2 , n = 21 ) or control ( no change in lifestyle , n = 16 ) . PCOS was defined as < or=8 menses per year and hyper and rogenism ( biochemical or clinical with Ferriman-Gallwey score > or=8 ) . Fasting lipoprotein profiles were obtained before and after the intervention . Nuclear magnetic resonance spectroscopy was used to quantify the following : average particle size , total and subclass concentrations of HDL , LDL , and VLDL particles , and calculated HDL cholesterol , triglycerides , and VLDL triglycerides . Wilcoxon exact rank sums tests were used to compare changes in these parameters in the exercise group relative to controls . RESULTS Twenty women ( 8 exercisers , 12 controls ) completed the study . Comparing exercisers to controls , significant changes were seen in concentrations of the following lipoprotein parameters that are associated with decreased insulin resistance : decreased large VLDL ( P = 0.007 ) , calculated triglycerides ( P = 0.003 ) , VLDL triglycerides ( P = 0.003 ) , and medium/small HDL ( P = 0.031 ) and increased large HDL ( P = 0.002 ) and average HDL size ( P = 0.001 ) . CONCLUSIONS In this trial , moderate-intensity exercise without significant weight loss improved several components of the lipoprotein profiles of women with PCOS . These findings support the beneficial role of moderate exercise in this high-risk population [23608322] BACKGROUND AND OBJECTIVES Polycystic ovary syndrome ( PCOS ) is a common problem in women at fertile age . A prospect i ve study was conducted to clarify the pathophysiological responses during an application of insulin sensitizer , metformin and weight reduction therapy at the Gynecology Center in Ohud hospital , in AL-Madinah AL-Munawarah , Kingdom of Saudi Arabia . METHODOLOGY Twenty healthy women served as controls and 180 PCOS women divided into three groups participated in the study . First group was treated with Clomid citrate 100mg/day from the 2nd day of menses to the 6th day plus gonadotrophin from day three to the 13th . Group II was treated as group I plus 850 mg metformin twice a day and group III was treated as group I plus weight reduction . Clinical symptoms , menstrual pattern , hirsutism , blood glucose , body mass index , waist-to-hip ratio , insulin , hormonal , and lipid profiles were assessed pre- and post treatment . Insulin resistance was calculated . RESULTS PCOS women had significantly higher values than the healthy women in most of the measurements . Metformin and weight reduction therapy result ed in a significant decrease in the fasting insulin , glucose/insulin ratio and HOMA-IR . Metformin and weight reduction therapy result ed in a significant decrease in the lipid parameters , testosterone , LH/FSH ratio , SHBG , and prolactin levels . HOMA-IR was significantly higher in women with PCOS . HOMA-IR was positively correlated with testosterone , estradiol , TG , total cholesterol and LDL-cholesterol parameters , and negatively correlated with HDL-cholesterol and FSH levels . CONCLUSION Metformin therapy and weight reduction had favorable influences on the basic metabolic and hormonal profiles in women with PCOS and that metformin and lifestyle modification ( weight reduction via diet restriction or exercise ) result ed in a significantly greater weight loss than hormonal therapy alone . Metformin and weight reduction therapy decreased also hyper and rogenism and insulin resistance [17264174] CONTEXT Polycystic ovary syndrome ( PCOS ) is an endocrine disease closely related to several risk factors for cardiovascular disease . An impaired cardiopulmonary functional capacity was previously demonstrated in PCOS women . No data regarding the effects of a structured exercise training ( ET ) program on cardiopulmonary functional capacity in PCOS women are available . OBJECTIVE Our objective was to evaluate the effects of a 3-month ET program on cardiopulmonary functional capacity in young PCOS women . DESIGN AND SETTING A prospect i ve baseline-r and omized clinical study was conducted at the University " Federico II " of Naples , School of Medicine ( Italy ) . PATIENTS Ninety young overweight PCOS women were enrolled . MEAN OUTCOME MEASURES Ninety young PCOS women were r and omly subdivided into two groups , each composed of 45 subjects . The PCOS-T ( trained ) group underwent a 3-month structured ET program , whereas the PCOS-UnT ( untrained ) group did not . Hormonal and metabolic profiles and cardiopulmonary and exercise parameters were evaluated . RESULTS After 3-month ET , PCOS-T showed a significant improvement in peak oxygen consumption ( + 35.4 % ; P<0.001 ) and in maximal workload ( + 37.2 % ; P<0.001 ) . In PCOS-T we also observed a significant reduction in body mass index ( -4.5 % ; P<0.001 ) and in C-reactive protein ( -10 % ; P<0.001 ) , and a significant ( P<0.001 ) improvement in insulin sensitivity indexes . After 3 months , no changes were observed in PCOS-UnT. CONCLUSIONS A 3-month structured ET program improves cardiopulmonary functional capacity in young PCOS women [9920077] Women with polycystic ovary syndrome ( PCOS ) are insulin resistant , have insulin secretory defects , and are at high risk for glucose intolerance . We performed this study to determine the prevalence of glucose intolerance and parameters associated with risk for this in PCOS women . Two-hundred and fifty-four PCOS women , aged 14 - 44 yr , were prospect ively evaluated at 2 centers , 1 urban and ethnically diverse ( n = 110 ) and 1 rural and ethnically homogeneous ( n = 144 ) . The rural PCOS women were compared to 80 control women of similar weight , ethnicity , and age . A 75-g oral glucose challenge was administered after a 3-day 300-g carbohydrate diet and an overnight fast with 0 and 2 h blood sample s for glucose levels . Diabetes was categorized according to WHO criteria . The prevalence of glucose intolerance was 31.1 % impaired glucose intolerance ( IGT ) and 7.5 % diabetes . In nonobese PCOS women ( body mass index , < 27 kg/m2 ) , 10.3 % IGT and 1.5 % diabetes were found . The prevalence of glucose intolerance was significantly higher in PCOS vs. control women ( chi2 = 7.0 ; P = 0.01 ; odds ratio = 2.76 ; 95 % confidence interval = 1.23 - 6.57 ) . Variables most associated with postchallenge glucose levels were fasting glucose levels ( P < 0.0001 ) , PCOS status ( P = 0.002 ) , waist/hip ratio ( P = 0.01 ) , and body mass index ( P = 0.021 ) . The American Diabetes Association criteria applied to fasting glucose significantly underdiagnosed diabetes compared to the WHO criteria ( 3.2 % vs. 7.5 % ; chi2 = 4.7 ; P = 0.046 ; odds ratio = 2.48 ; 95 % confidence interval = 1.01 - 6.69 ) . We conclude that 1 ) PCOS women are at significantly increased risk for IGT and type 2 diabetes mellitus at all weights and at a young age ; 2 ) these prevalence rates are similar in 2 different population s of PCOS women , suggesting that PCOS may be a more important risk factor than ethnicity or race for glucose intolerance in young women ; and 3 ) the American Diabetes Association diabetes diagnostic criteria failed to detect a significant number of PCOS women with diabetes by postchallenge glucose values [21419674] STUDY OBJECTIVE To compare the effects of a hypocaloric low-fat diet with those of a very low carbohydrate diet on body mass index ( BMI ) , waist circumference ( WC ) , and menstrual function in overweight adolescent females with polycystic ovary syndrome ( PCOS ) . DESIGN R and omized pilot trial of two diets in a prospect i ve , 12-week study . SETTING A hospital-based , academic adolescent medicine division . PARTICIPANTS 24 females , age 12 - 22 years ( mean 15.8 ± 2.2 ) , with PCOS and a BMI above the 85(th ) percentile for age ( mean 35.7 ± 6.0 kg/m(2 ) ) . INTERVENTIONS Nutrition counseling was given biweekly , and dietary compliance , menstrual history , and weight were recorded . WC was measured at the beginning and end of the study . MAIN OUTCOME MEASURES Changes in weight , BMI , WC , and improvement in menstrual function over the course of the study period . RESULTS 16 participants completed the study . 12 completers menstruated during the study period , 8 with regularity . The number of periods over 3 months increased from 0.6 ± 0.6 pre-treatment to 1.6 ± 1.3 post-treatment ( P = 0.003 ) . Overall , weight loss averaged 6.5 % ( P < 0.0001 ) and the WC decreased by an average of 5.7 ± 7.7 cm ( P = 0.01 ) . Those who lost weight were 3.4 times more likely to have improved menstrual function ( P = 0.001 ) . There were no statistically significant differences between the two groups . CONCLUSIONS Weight loss is feasible in adolescents with PCOS and results in significant improvements in BMI , WC , and menstrual function . Weight management may be preferable as first-line treatment in adolescents , because it targets both the menstrual dysfunction and risk factors for long-term morbidity associated with PCOS [25057845] Abstract Bressel , E , Wing , JE , Miller , AI , and Dolny , DG . High-intensity interval training on an aquatic treadmill in adults with osteoarthritis : effect on pain , balance , function , and mobility . J Strength Cond Res 28(8 ) : 2088–2096 , 2014—Although aquatic exercise is considered a potentially effective treatment intervention for people with osteoarthritis ( OA ) , previous research has focused primarily on calisthenics in a shallow pool with the inherent limitations on regulating exercise intensity . The purpose of this study was to quantify the efficacy of a 6-week aquatic treadmill exercise program on measures of pain , balance , function , and mobility . Eighteen participants ( age = 64.5 ± 10.2 years ) with knee OA completed a non-exercise control period followed by a 6-week exercise period . Outcome measures included visual analog scales for pain , posturography for balance , sit-to-st and test for function , and a 10-m walk test for mobility . The exercise protocol included balance training and high-intensity interval training ( HIT ) in an aquatic treadmill using water jets to destabilize while st and ing and achieve high ratings of perceived exertion ( 14–19 ) while walking . In comparison with pretests , participants displayed reduced joint pain ( pre = 50.3 ± 24.8 mm vs. post = 15.8 ± 10.6 mm ) , improved balance ( equilibrium pre = 66.6 ± 11.0 vs. post = 73.5 ± 7.1 ) , function ( rising index pre = 0.49 ± 0.19 % vs. post = 0.33 ± 0.11 % ) , and mobility ( walk pre = 8.6 ± 1.4 s vs. post = 7.8 ± 1.1 s ) after participating in the exercise protocol ( p = 0.03–0.001 ) . The same benefits were not observed after the non-exercise control period . Adherence to the exercise protocol was exceptional and no participants reported adverse effects , suggesting that aquatic treadmill exercise that incorporates balance and HIT training was well tolerated by patients with OA and may be effective at managing symptoms of OA [18158291] BACKGROUND Lifestyle modifications are successfully employed to treat obese and overweight women with polycystic ovary syndrome ( PCOS ) . The aims of the current pilot study were ( i ) to compare the efficacy on reproductive functions of a structured exercise training ( SET ) programme with a diet programme in obese PCOS patients and ( ii ) to study their clinical , hormonal and metabolic effects to eluci date potentially different mechanisms of action . METHODS Forty obese PCOS patients with anovulatory infertility underwent a SET programme ( SET group , n = 20 ) and a hypocaloric hyperproteic diet ( diet group , n = 20 ) . Clinical , hormonal and metabolic data were assessed at baseline , and at 12- and 24-week follow-ups . Primary endpoint was cumulative pregnancy rate . RESULTS The two groups had similar demographic , anthropometric and biochemical parameters . After intervention , a significant improvement in menstrual cycles and fertility was noted in both groups , with no differences between groups . The frequency of menses and the ovulation rate were significantly ( P < 0.05 ) higher in the SET group than in diet group but the increased cumulative pregnancy rate was not significant . Body weight , body mass index , waist circumference , insulin resistance indexes and serum levels of sex hormone-binding globulin , and rostenedione and dehydroepi and rosterone sulphate changed significantly ( P < 0.05 ) from baseline and were significantly different ( P < 0.05 ) between the two groups . CONCLUSIONS Both SET and diet interventions improve fertility in obese PCOS patients with anovulatory infertility . We hypothesize that in both interventions an improvement in insulin sensitivity is the pivotal factor involved in the restoration of ovarian function but potentially acting through different mechanisms [17509728] This study compared the psychological effects of a low-protein high-carbohydrate ( LPHC ) diet and a high-protein low-carbohydrate ( HPLC ) diet in women with polycystic ovary syndrome ( PCOS ) . Twenty-five overweight women with PCOS were matched for age , weight , and whether they were trying to conceive . They were r and omly allocated to the LPHC or HPLC diet for 16 weeks . All participants attended a weekly exercise , group support and educational program . The Hospital Anxiety and Depression Scale and the Rosenberg Self Esteem Scale were administered at the beginning and end of the study . The HPLC diet was associated with significant reduction in depression and improvement in self-esteem . There was no change in any psychological measures for the LPHC group . There was no difference in weight loss between the groups . Due to enhanced feelings of well-being , it is possible that HPLC diets may be associated with better compliance and hence be more successful in the long term treatment of obesity [19380385] BACKGROUND Anti-Müllerian hormone ( AMH ) has been proposed as a clinical predictor of improvements in reproductive function following weight loss in overweight and obese women with polycystic ovary syndrome ( PCOS ) . This study aim ed to assess whether baseline and /or change in AMH levels with weight loss predict improvements in reproductive function in overweight and obese women with PCOS . METHODS Fifty-two overweight and obese women with PCOS and reproductive impairment ( age 29.8 + /- 0.8 years , BMI 36.5 + /- 0.7 kg/m(2 ) ) followed a 20-week weight loss programme . AMH , weight , menstrual cyclicity and ovulatory function were assessed at baseline and post-intervention . RESULTS Participants who responded with improvements in reproductive function ( n = 26 ) had lower baseline AMH levels ( 23.5 + /- 3.7 versus 32.5 + /- 2.9 pmol/l ; P = 0.03 ) and experienced greater weight loss ( -11.7 + /- 1.2 versus -6.4 + /- 0.9 kg ; P = 0.001 ) compared with those who did not respond ( n = 26 ) . Logistic regression analysis showed that weight loss and baseline AMH were independently related to improvements in reproductive function ( P = 0.002 and P = 0.013 , respectively ) . AMH levels did not change with weight loss in both responders and non-responders . CONCLUSIONS In overweight and obese women with PCOS and reproductive dysfunction , a 20-week weight loss intervention result ed in improvements in reproductive function but no change in AMH levels . CLINICAL TRIALS REGISTRATION NUMBER ACTRN12606000198527 [19463994] OBJECTIVE To compare the effect of clomiphene citrate , metformin , and lifestyle modification on treatment of patients with polycystic ovary syndrome ( PCOS ) . DESIGN Prospect i ve r and omized double-blind study . SETTING University-based infertility clinic and research center . PATIENT(S ) Three hundred forty-three overweight infertile women with PCOS . INTERVENTION(S ) The participating women were assigned to four groups : clomiphene ( n = 90 ) , metformin ( n = 90 ) , clomiphene + metformin ( n = 88 ) , and lifestyle modification ( n = 75 ) . The patients in each group received st and ardized dietary and exercise advice from a dietitian . MAIN OUTCOME MEASURE(S ) The primary outcome variables were change in menstrual cycle , waist circumference measurements , endocrine parameters , and lipid profile . The main secondary outcome variable was clinical pregnancy rate . RESULT ( S ) The clinical pregnancy rate was 12.2 % in clomiphene group , 14.4 % in metformin group , 14.8 % in clomiphene + metformin group , and 20 % in lifestyle modification group . Lifestyle modification group achieved a significant reduction in waist circumference , total and rogen , and lipid profile . CONCLUSION ( S ) Lifestyle modification improves the lipid profile in PCOS patients . Therefore , lifestyle modification may be used as the first line of ovulation induction in PCOS patients [22808940] OBJECTIVES The objectives of this trial were to compare the effects of a holistic yoga program with the conventional exercise program in adolescent polycystic ovarian syndrome ( PCOS ) . DESIGN This was a prospect i ve , r and omized , active controlled trial . SETTING Ninety ( 90 ) adolescent ( 15 - 18 years ) girls from a residential college in And hra Pradesh who satisfied the Rotterdam criteria were r and omized into two groups . INTERVENTION The yoga group practice d a holistic yoga module , while the control group practice d a matching set of physical exercises ( 1 hour/day , for 12 weeks ) . OUTCOME MEASURES Anti-müllerian hormone ( AMH- primary outcome ) , luteinizing hormone ( LH ) , follicle-stimulating hormone ( FSH ) , testosterone , prolactin , body-mass index ( BMI ) , hirsutism , and menstrual frequency were measured at inclusion and after 12 weeks . RESULTS Mann-Whitney test on difference score shows that changes in AMH ( Y=-2.51 , C=-0.49 , p=0.006 ) , LH , and LH/FSH ratio ( LH : Y=-4.09 , C=3.00 , p=0.005 ; LH/FSH : Y=-1.17 , C=0.49 , p=0.015 ) were significantly different between the two intervention groups . Also , changes in testosterone ( Y=-6.01 , C=2.61 , p=0.014 ) and Modified Ferriman and Gallway ( mFG ) score ( Y=-1.14 , C=+0.06 , p=0.002 ) were significantly different between the two groups . On the other h and , changes in FSH and prolactin postintervention were nonsignificantly different between the two groups . Also , body weight and BMI showed nonsignificantly different changes between the two groups , while changes in menstrual frequency were significantly different between the two groups ( Y=0.89 , C=0.49 , p=0.049 ) . CONCLUSIONS A holistic yoga program for 12 weeks is significantly better than physical exercise in reducing AMH , LH , and testosterone , mFG score for hirsutism , and improving menstrual frequency with nonsignificant changes in body weight , FSH , and prolactin in adolescent PCOS [20004371] OBJECTIVE To assess the impact of adding exercise to dietary restriction on depressive symptoms and health-related quality of life ( HRQOL ) in women with polycystic ovary syndrome ( PCOS ) . DESIGN Analysis of depression and quality of life outcomes from a r and omized , controlled prospect i ve clinical intervention that evaluated the effects on a range of health outcomes in women with PCOS . SETTING Clinical research unit . PATIENT(S ) One hundred four overweight/obese PCOS women ( aged 29.3 ± 0.7 years ; body mass index [ BMI ] 36.1 ± 0.5 kg/m(2 ) ) . INTERVENTION(S ) R and omized to one of three 20-week lifestyle programs : diet only , diet and aerobic exercise , or diet and combined aerobic-resistance exercise . MAIN OUTCOME MEASURE(S ) Depression and PCOS-specific HRQOL . RESULT ( S ) Forty-nine women completed the intervention ( diet only = 14 , diet and aerobic exercise = 15 , diet and combined aerobic-resistance exercise = 20 ) . By week 20 all groups achieved weight loss and had improvements in depression and PCOS-specific HRQOL scores , except for body hair domain score . There was no difference between treatments for all outcomes . CONCLUSION ( S ) This study demonstrated that dietary restriction alone and combined with exercise had similar benefits for improving depression and HRQOL scores in overweight and obese women with PCOS Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Oral cavity and oropharyngeal cancers are frequently described as part of a group of oral cancers or head and neck cancer . Treatment of oral cavity cancer is generally surgery followed by radiotherapy , whereas oropharyngeal cancers , which are more likely to be advanced at the time of diagnosis , are managed with radiotherapy or chemoradiation . Surgery for oral cancers can be disfiguring and both surgery and radiotherapy have significant functional side effects , notably impaired ability to eat , drink and talk . The development of new chemotherapy agents , new combinations of agents and changes in the relative timing of surgery , radiotherapy , and chemotherapy treatments may potentially bring about increases in both survival and quality of life for this group of patients . OBJECTIVES To determine whether chemotherapy , in addition to radiotherapy and /or surgery for oral cavity and oropharyngeal cancer results in improved survival , disease free survival , progression free survival , locoregional control and reduced recurrence of disease . To determine which regimen and time of administration ( induction , concomitant or adjuvant ) is associated with better outcomes . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

30350116

[15902172] OBJECTIVE This study was undertaken to compare outcomes after anterior colporrhaphy with and without a solvent dehydrated cadaveric fascia lata graft . STUDY DESIGN A total of 162 women were enrolled in a prospect i ve , r and omized trial that evaluated the impact of a solvent dehydrated cadaveric fascia lata patch on recurrent anterior vaginal prolapse . Subjects were r and omly assigned to st and ard colporrhaphy with or without a patch . Before and after surgery , subjects were evaluated by both the Baden-Walker and pelvic organ prolapse quantification systems . " Failure " was defined as stage II anterior wall prolapse or worse . RESULTS Of 154 women r and omly assigned ( 76 patch : 78 no patch ) , all underwent surgery and 153 ( 99 % ) returned for follow-up . Sixteen women ( 21 % ) in the patch group and 23 ( 29 % ) in the control group experienced recurrent anterior vaginal wall prolapse ( P = .229 ) . Only 26 % of all recurrences were symptomatic . Concomitant transvaginal Cooper 's ligament sling procedures were associated with a dramatic decrease in recurrent prolapse ( odds ratio [ OR ] 0.105 , P < .0001 ) . CONCLUSION Solvent dehydrated fascia lata as a barrier does not decrease recurrent prolapse after anterior colporrhaphy . Transvaginal bladder neck slings were associated with a significant reduction in the risk of recurrent anterior wall prolapse [20178542] AIMS Routine catheterization following vaginal prolapse surgery has advantages like prevention of postoperative retention of urine and prevention of any adverse effect on surgical outcome . However , it increases the risk of urinary tract infection ( UTI ) , prevent early ambulation and prolong hospital stay . This r and omized controlled trial was done on how best to minimize catheter related complication after prolapse surgery . METHODS 200 patients planned for vaginal prolapse surgery were recruited and r and omized into two groups . In group I and group II catheter was removed on 1(st ) and 4(th ) post operative day , respectively . After removal , if patient could not void or when residual urine volume exceeds 150 mL , recatheterisation was done for another three days . Sample of urine was sent for culture during catheter removal . RESULTS Age , parity , type of surgery and mean operation time did not differ significantly between the two groups . Mean duration of catheterization was significantly shorter ( 1.64 vs 4.09 ) and mean duration of hospital stay was shorter by 1.2 days , in first group . However a significantly higher number of retention of urine or residual urine more than 150 mL was found in the early removal group ( OR 3.10 ) but lesser chance of development of urinary tract infection ( OR 0.10 ) . CONCLUSIONS The early removal of catheter seems more advantageous , with lower incidence of urinary tract infection and a shorter hospital stay although associated with an increased risk of recatheterisation [28113069] OBJECTIVE It is unclear if any catheterisation is necessary after vaginal surgery for pelvic organ prolapse . The aim of this study was to determine if indwelling catheterisation is necessary after these procedures . STUDY DESIGN A r and omised controlled trial of immediate post-operative removal of catheter compared to a suprapubic catheter ( SPC ) after vaginal prolapse surgery . In the Suprapubic group the catheter was left on free drainage until a voiding trial was commenced at 48h . Women in the immediate removal group underwent in/out catheterisation only if they had not voided by 8h after surgery to ensure the bladder did not over-distend . RESULTS 55 % ( n=17 ) of patients in the immediate removal group did not require catheterisation postoperatively . A further 13 ( 42 % ) patients only required one in/out catheterisation 8h post operatively . In the immediate removal group duration of catheterisation was significantly shorter ( median 0h , IQR 0 - 8h , range 0 - 16h ) vs ( 6days ( IQR 2 - 8days , range 2 - 19h ) p=0.001 ) . The duration of hospital stay ( 7days ( range 3 - 16 ) vs. 9 ( range 3 - 27 ) p=0.014 ) , day of first mobilisation ( Day 1 , range 0 - 2 , vs. Day 2 , range 1 - 4 , p=0.001 ) , and rate of Symptomatic bacturia ( 16 % vs. 52 % , p<0.01 ) were all significantly better with immediate catheter removal . CONCLUSIONS After vaginal surgery for pelvic organ prolapse , the majority of patients do not require extended catheterisation . Early removal of a catheter reduces urinary tract infection and significantly decreases hospital stay . Such a policy should result in improved patient satisfaction and reduced hospital costs [28010989] BACKGROUND The use of transvaginal mesh and biological graft material in prolapse surgery is controversial and has led to a number of enquiries into their safety and efficacy . Existing trials of these augmentations are individually too small to be conclusive . We aim ed to compare the outcomes of prolapse repair involving either synthetic mesh inlays or biological grafts against st and ard repair in women . METHODS We did two pragmatic , parallel-group , multicentre , r and omised controlled trials for our study ( PROSPECT [ PROlapse Surgery : Pragmatic Evaluation and r and omised Controlled Trials ] ) in 35 centres ( a mix of secondary and tertiary referral hospitals ) in the UK . We recruited women undergoing primary transvaginal anterior or posterior compartment prolapse surgery by 65 gynaecological surgeons in these centres . We r and omly assigned participants by a remote web-based r and omisation system to one of the two trials : comparing st and ard ( native tissue ) repair alone with st and ard repair augmented with either synthetic mesh ( the mesh trial ) or biological graft ( the graft trial ) . We assigned women ( 1:1:1 or 1:1 ) within three strata : assigned to one of the three treatment options , comparison of st and ard repair with mesh , and comparison of st and ard repair with graft . Participants , ward staff , and outcome assessors were masked to r and omisation where possible ; masking was obviously not possible for the surgeon . Follow-up was for 2 years after the surgery ; the primary outcomes , measured at 1 year and 2 years , were participant-reported prolapse symptoms ( i.e. the Pelvic Organ Prolapse Symptom Score [ POP-SS ] ) and condition-specific ( ie , prolapse-related ) quality -of-life scores , analysed in the modified intention-to-treat population . This trial is registered as an International St and ard R and omised Controlled Trial , number IS RCT N60695184 . FINDINGS Between Jan 8 , 2010 , and Aug 30 , 2013 , we r and omly allocated 1352 women to treatment , of whom 1348 were included in the analysis . 865 women were included in the mesh trial ( 430 to st and ard repair alone , 435 to mesh augmentation ) and 735 were included in the graft trial ( 367 to st and ard repair alone , 368 to graft augmentation ) . Because the analyses were carried out separately for each trial ( mesh trial and graft trial ) some women in the st and ard repair arm assigned to all treatment options were included in the st and ard repair group of both trials . 23 of these women did not receive any surgery ( 15 in the mesh trial , 13 in the graft trial ; five were included in both trials ) and were included in the baseline analyses only . Mean POP-SS at 1 year did not differ substantially between comparisons ( st and ard 5·4 [ SD 5·5 ] vs mesh 5·5 [ 5·1 ] , mean difference 0·00 , 95 % CI -0·70 to 0·71 ; p=0·99 ; st and ard 5·5 [ SD 5·6 ] vs graft 5·6 [ 5·6 ] ; mean difference -0·15 , -0·93 to 0·63 ; p=0·71 ) . Mean prolapse-related quality -of-life scores also did not differ between groups at 1 year ( st and ard 2·0 [ SD 2·7 ] vs mesh 2·2 [ 2·7 ] , mean difference 0·13 , 95 % CI -0·25 to 0·51 ; p=0·50 ; st and ard 2·2 [ SD 2·8 ] vs graft 2·4 [ 2·9 ] ; mean difference 0·13 , -0·30 to 0·56 ; p=0·54 ) . Mean POP-SS at 2 years were : st and ard 4·9 ( SD 5·1 ) versus mesh 5·3 ( 5·1 ) , mean difference 0·32 , 95 % CI -0·39 to 1·03 ; p=0·37 ; st and ard 4·9 ( SD 5·1 ) versus graft 5·5 ( 5·7 ) ; mean difference 0·32 , -0·48 to 1·12 ; p=0·43 . Prolapse-related quality -of-life scores at 2 years were : st and ard 1·9 ( SD 2·5 ) versus mesh 2·2 ( 2·6 ) , mean difference 0·15 , 95 % CI -0·23 to 0·54 ; p=0·44 ; st and ard 2·0 ( 2·5 ) versus graft 2·2 ( 2·8 ) ; mean difference 0·10 , -0·33 to 0·52 ; p=0·66 . Serious adverse events such as infection , urinary retention , or dyspareunia or other pain , excluding mesh complications , occurred with similar frequency in the groups over 1 year ( mesh trial : 31/430 [ 7 % ] with st and ard repair vs 34/435 [ 8 % ] with mesh , risk ratio [ RR ] 1·08 , 95 % CI 0·68 to 1·72 ; p=0·73 ; graft trial : 23/367 [ 6 % ] with st and ard repair vs 36/368 [ 10 % ] with graft , RR 1·57 , 0·95 to 2·59 ; p=0·08 ) . The cumulative number of women with a mesh complication over 2 years in women actually exposed to synthetic mesh was 51 ( 12 % ) of 434 . INTERPRETATION Augmentation of a vaginal repair with mesh or graft material did not improve women 's outcomes in terms of effectiveness , quality of life , adverse effects , or any other outcome in the short term , but more than one in ten women had a mesh complication . Therefore , follow-up is vital to identify any longer-term potential benefits and serious adverse effects of mesh or graft reinforcement in vaginal prolapse surgery . FUNDING UK National Institute of Health Research [29607558] OBJECTIVE Twin-twin transfusion syndrome ( TTTS ) is associated with significant mortality and morbidity . Potential treatments for the condition require robust evaluation . The aim of this study was to evaluate outcome reporting across observational studies and r and omized controlled trials assessing treatments for TTTS . METHODS Cochrane Central Register of Controlled Trials , EMBASE and MEDLINE were search ed from inception to August 2016 . Observational studies and r and omized controlled trials reporting outcome following treatment for TTTS in monochorionic-diamniotic twin pregnancy and monochorionic-triamniotic or dichorionic-triamniotic triplet pregnancy were included . Outcome reporting was systematic ally extracted and categorized . RESULTS Six r and omized trials and 94 observational studies were included , reporting data from 20 071 maternal participants and 3199 children . Six different treatments were evaluated . Included studies reported 62 different outcomes , including six fetal , seven offspring mortality , 25 neonatal , six early childhood and 18 maternal/operative outcomes . Outcomes were reported inconsistently across trials . For example , when considering offspring mortality , 31 ( 31 % ) studies reported live birth , 31 ( 31 % ) reported intrauterine death , 49 ( 49 % ) reported neonatal mortality and 17 ( 17 % ) reported perinatal mortality . Four ( 4 % ) studies reported respiratory distress syndrome . Only 19 ( 19 % ) studies were design ed for long-term follow-up and 11 ( 11 % ) of these reported cerebral palsy . CONCLUSIONS Studies evaluating treatments for TTTS have often neglected to report clinical ly important outcomes , especially neonatal morbidity outcomes , and most are not design ed for long-term follow-up . The development of a core outcome set could help st and ardize outcome collection and reporting in TTTS studies . Copyright © 2018 ISUOG . Published by John Wiley & Sons [25305357] PURPOSE We compared the efficacy and safety of anterior colporrhaphy with transvaginal polypropylene mesh insertion for anterior vaginal wall prolapse at medium term followup . MATERIAL S AND METHODS In this prospect i ve , r and omized , controlled trial 100 women with stage II or greater anterior vaginal wall prolapse assessed by POP-Q were r and omized to anterior colporrhaphy ( controls ) or mesh insertion . Anatomical outcomes were assessed by POP-Q measurement and prolapse stage . Subjective outcomes and quality of life impact were evaluated by ICIQ question naires . We evaluated the procedure safety profile according to intraoperative complication rates throughout followup . RESULTS In the mesh and control groups 42 and 50 women completed the 24-month followup . Point Ba did not significantly differ between the groups at baseline but at 24-month followup it had significantly improved in the mesh group compared to controls . However , no difference was found between the groups when considering 2 cure criteria on prolapse stage and subjective parameters . Asymptomatic mesh exposure developed on the anterior vaginal wall prolapse in 7 patients ( 16.4 % ) in the mesh group . Minor mesh related complications consisted of mesh exposure , prepubic ecchymosis and groin pain , of which most were treated conservatively . Urinary retention was treated surgically . CONCLUSIONS Nazca TC ™ and anterior colporrhaphy provided good overall anatomical outcomes during a minimum 24-month followup . Vaginal and urinary symptoms , and quality of life improved postoperatively in each group . From the patient perspective Nazca TC did not show superior overall outcomes compared to anterior colporrhaphy performed with or without a retropubic sling [24402595] OBJECTIVE : To compare anatomical and patient-reported outcomes at 12 months postoperatively for women who had anterior compartment pelvic organ prolapse ( POP ) surgery using a repair augmented with porcine small intestine submucosa mesh ( Mesh Group ) compared with those who had a native tissue repair ( No Mesh Group ) . METHODS : This was a r and omized controlled trial with 12 months follow-up . The surgical procedure was identical in both groups except for the placement of intervening mesh . The primary outcome was anatomical “ cure ” ( Ba of −1 or less on Pelvic Organ Prolapse Quantification [ POP-Q ] ) . Secondary outcomes included POP-Q stage , patient-reported outcomes , and patient satisfaction . The study was powered to detect a 40 % difference at 80 % power ( & agr;=0.05 ) . RESULTS : Fifty-seven women were r and omized ( 28 to Mesh Group , 29 to No Mesh Group ) . Forty-five ( 79 % ) underwent concomitant surgery . At the 12-month follow-up , 56 % ( 15/27 ) in the Mesh Group and 61 % ( 17/28 ) in the No Mesh Group were considered cured ( relative risk 0.90 , 95 % confidence interval 0.52–1.54 ) . There were no significant differences between groups in recurrent or persistent prolapse ( 7 % in each group ) nor in patient-reported outcomes at 12 months . Pelvic girdle pain occurred in 4 of 27 in the Mesh Group and 3 of 28 in the No Mesh Group . CONCLUSION : No significant differences were observed in anatomical or patient-reported outcomes outcome parameters at 12 months after correction of symptomatic anterior POP by mesh or no mesh repair . In our study , porcine small intestine submucosa mesh did not confer additional benefit over a native tissue repair . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT0095544 . LEVEL OF EVEDIENCE : [15041988] OBJECTIVE The purpose of this study was to compare 2 anti-incontinence procedures in women who had severe genital prolapse and potential stress incontinence . STUDY DESIGN In addition to vaginal reconstructive surgery , 50 patients with stage II or higher anterior defect and a positive stress test result with prolapse reduction received either tension-free vaginal tape or plication of the endopelvic fascia . Preoperative evaluation included history , physical examination , stress test , and urodynamic assessment . Data were analyzed with the Student t test , the Fisher 's exact test , and the Wilcoxon signed-rank test . RESULTS The median follow-up time was similar for both groups , 26 and 24 months . Subjective ( 96 % vs 64 % ; P=.01 ) and objective ( 92 % vs 56 % ; P<.01 ) continence rates were higher after the tension-free vaginal tape procedure . Time for the resumption of spontaneous voiding , rates of urinary retention , or de novo urge incontinence were similar in the 2 groups . CONCLUSION Tension-free vaginal tape can be recommended for patients with prolapse and occult stress incontinence [23512113] Introduction and hypothesisTo compare the efficacy of a collagen-coated polypropylene mesh and anterior colporrhaphy in the treatment of stage 2 or more anterior vaginal wall prolapse . Methods Prospect i ve , r and omized , multicenter study conducted between April 2005 and December 2009 . The principal endpoint was the recurrence rate of stage 2 or more anterior vaginal wall prolapse 12 months after surgery . Secondary endpoints consisted of functional results and mesh-related morbidity . Results One hundred and forty-seven patients were included , r and omized and analyzed : 72 in the anterior colporrhaphy group and 75 in the mesh group . The anatomical success rate was significantly higher in the mesh group ( 89 % ) than in the colporrhaphy group ( 64 % ) ( p = 0.0006 ) . Anatomical and functional recurrence was also less frequent in the mesh group ( 31.3 % vs 52.2 % , p = 0.007 ) . Two patients ( 2.8 % ) were reoperated on in the colporrhaphy group for anterior vaginal wall prolapse recurrence . No significant difference was noted regarding minor complications . An erosion rate of 9.5 % was noted . De novo dyspareunia occurred in 1/14 patients in the colporrhaphy group and in 3/13 patients in the mesh group . An analysis of the quality of life question naires showed an overall improvement in both groups , with no statistical difference between them . Satisfaction rates were high in both groups ( 92 % in the colporrhaphy group and 96 % in the mesh group ) . Conclusion Trans-obturator Ugytex ® mesh used to treat anterior vaginal wall prolapse gives better 1-year anatomical results than traditional anterior colporrhaphy , but with small a increase in morbidity in the mesh group [25199496] Introduction and hypothesisThis trial aim ed to compare the outcomes of native vaginal tissue repair versus polypropylene mesh repair for the treatment of severe genital prolapse . Methods This multicenter r and omized trial included 184 women , with POP-Q stage 3 or 4 . They were r and omly assigned to undergo surgical treatment using native tissue repair ( n = 90 ) or synthetic mesh repair ( n = 94 ) . Native tissue repair surgery was performed according to site-specific defects , including sacrospinous ligament fixation for apical defects . Mesh repair ( Prolift ™ ) was performed in accordance with manufacturer recommendations . Hysterectomy was performed in all cases of uterine prolapse . Statistical tests were used to compare between-group and within-group differences before the surgery and at 1-year follow-up . We considered cure to have occurred when the POP-Q point evaluation was equal to or less than 0 and POP-Q point C better than or equal to half the total vaginal length ( TVL ) after 1 year . The patients answered the Prolapse Quality -of-Life Question naire ( PQoL ) and the Sexual Quotient Female Version ( QS-F ) question naire . Results Both groups were homogeneous preoperatively . There were no differences between the groups in operative time , complications or pain . At 1-year follow-up , anatomical cure rates were better in the mesh group in the anterior compartment ( p = 0.019 ) . Significant improvement in PQoL scores at 1-year follow up were observed in each group ; between-group comparisons of changes in PQoL scores revealed greater improvement in the mesh group . Conclusion Both techniques were effective . Anatomical efficacy was superior in the mesh group regarding the anterior compartment ; quality of life changes were also greater in the mesh group . Complications were significantly higher in the mesh group [3824218] Introduction and hypothesisThe aim of the study was to compare the efficacy and safety of transvaginal trocar-guided polypropylene mesh insertion with traditional colporrhaphy for treatment of anterior vaginal wall prolapse . Methods This is a r and omized controlled trial in which women with advanced anterior vaginal wall prolapse , at least stage II with Ba ≥ + 1 cm according to the Pelvic Organ Prolapse Quantification ( POP-Q ) classification , were r and omly assigned to have either anterior colporrhaphy ( n = 39 ) or repair using trocar-guided transvaginal mesh ( n = 40 ) . The primary outcome was objective cure rate of the anterior compartment ( point Ba ) assessed at the 12-month follow-up visit , with stages 0 and I defined as anatomical success . Secondary outcomes included quantification of other vaginal compartments ( POP-Q points ) , comparison of quality of life by the prolapse quality of life ( P-QOL ) question naire , and complication rate between the groups after 1 year . Study power was fixed as 80 % with 5 % cutoff point ( p < 0.05 ) for statistical significance . Results The groups were similar regarding demographic and clinical preoperative parameters . Anatomical success rates for colporrhaphy and repair with mesh placement groups were 56.4 vs 82.5 % ( 95 % confidence interval 0.068–0.54 ) , respectively , and the difference between the groups was statistically significant ( p = 0.018 ) . Similar total complication rates were observed in both groups , with tape exposure observed in 5 % of the patients . There was a significant improvement in all P-QOL domains as a result of both procedures ( p < 0.001 ) , but they were not distinct between groups ( p > 0.05 ) . Conclusions Trocar-guided transvaginal synthetic mesh for advanced anterior POP repair is associated with a higher anatomical success rate for the anterior compartment compared with traditional colporrhaphy . Quality of life equally improved after both techniques . However , the trial failed to detect differences in P-QOL scores and complication rates between the groups [25820682] AIMS To compare efficacy and safety of the traditional colporraphy and transvaginal polypropylene mesh for the treatment of advanced anterior vaginal prolapse according to different success criteria in two-year follow-up . METHODS In this r and omized controlled trial , women with anterior prolapse stage II or greater , with Ba point ≥ + 1 ( POP-Q quantification ) , were r and omly assigned to have either anterior colporraphy ( n = 43 ) or transvaginal mesh repair ( n = 43 ) . The primary outcome was to compare objective success rate under two success definitions : prolapse stage I ( Ba < -1 ) and stage II ( Ba < 0 ) . Secondary outcomes included complications and prolapse symptoms , satisfaction and quality of life ( QoL ) . Intention to treat was used for the primary endpoint and per protocol analysis for the secondary outcomes . RESULTS The groups presented similar preoperative data . Thirty three patients from the colporraphy and 37 from the mesh groups completed two-year follow-up . Under Ba < -1 definition , success rate was 39.53 % for both groups ( P = 1.00 ) . Considering success as Ba < 0 , analysis favored the mesh group by 23 % ( 51.16 % and 74.42 % ; 95 % CI for difference : 3 - 43 % ; P = 0.022 ) . Patients from the mesh group were more satisfied after two years ( 81.8 % and 97.3 % for colporraphy and mesh , respectively , 15.5 % difference ; 95 % CI for difference 1 - 29 % ; P = 0.032 ) . Both procedures similarly improved women 's symptoms and QoL. Some complications were observed , one being a 13.5 % mesh exposure rate . CONCLUSIONS Transvaginal synthetic mesh repair for advanced anterior vaginal prolapse provided higher anatomical success and satisfaction rates compared with traditional colporraphy . Both procedures equally improved quality of life . Neurourol . Urodynam . 35:509 - 514 , 2016 . © 2015 Wiley Periodicals , [21069291] Introduction and hypothesisThe optimal duration of urethral catheterization during and after pelvic reconstructive surgery is not established . This study investigated the optimal duration of urinary catheterization in patients undergoing anterior vaginal repair with or without other vaginal surgeries . Methods A total of 90 patients were included from April 2007 to March 2008 . They were r and omly divided into 2 , 3 , and 4 days urinary catheterization groups based on the color of the question naire papers they blindly chose . After catheter removal , the amount of post-void residual urine was used to measure the efficacy of bladder emptying . Differences between groups were determined using Chi-square test , Fisher 's exact test , or Kruskal – Wallis test , as appropriate . Results No significant differences were found in the amount of post-void residual urine between the three catheterization groups . Conclusions Our findings suggest that the duration of urethral catheterization after anterior colporrhaphy need not exceed 2 days [24054380] OBJECTIVE To compare the use of polypropylene mesh ( PM ) and the traditional anterior vaginal wall colporraphy in women with anterior vaginal wall prolapse ( AVWP ) using objective and subjective tests and evaluation of quality of life ( QoL ) . MATERIAL S AND METHODS One hundred women were r and omly distributed in two preoperatory groups . The first group ( mesh ) ( n = 45 ) received a PM implant and the control group ( n = 55 ) was su bmi tted to traditional colporraphy . Postoperatory follow-up was done after 12 months . The primary objective was the correction of the Ba point ≤ -2 POP-Q ( Pelvic Organ Prolapse Quantification System ) and the secondary objective was the improvement of vaginal symptoms and QoL through ICIQ-VS ( International Consultation on Incontinence Question naire - Vaginal Symptoms ) . Complications related to the use of PM or not were also described . RESULTS There was a significant difference between all POP-Q measures of pre- and postoperatory periods of each group in particular . There was a significant difference of the Ba point of the postoperatory period between the Mesh and Control group . The mean of Ba point in the Mesh group was statistically lower than of the Control group , depicting the better anatomical result of the first group . Both techniques improved vaginal symptoms and QoL. The most frequent complication of the Mesh group was prepubic hematoma in the perioperative period . In 9.3 % of the cases treated with mesh it was observed PM exposition at the anterior vaginal wall after 12 months , being most of them treated clinical ly . CONCLUSION The treatment of AVWP significantly improved the Ba point in the Mesh group in comparison to the Control group . There were no differences of the vaginal symptoms and QoL between the two groups after 12 months . There were few and low grade complications on both groups [17901910] The aim of this study was to compare the efficiency of polypropylene mesh surgery with the site-specific repair surgeries in the treatment of cystocoeles . We r and omized 90 patients into two groups according to a computer-based program . After a 12-month ( mean ) follow up , we noticed that the polypropylene mesh surgery yielded good anatomical results . Acceptable anatomical cure rates were 91 and 72 % in the mesh surgery group and site-specific surgery group , respectively . There were three cases ( 6.9 % ) of mesh erosion . One case of urinary retention and two cases of de novo dyspareunia were seen in the mesh surgery group . De novo stress urinary incontinence developed in three patients in the site-specific surgery group . We concluded that surgery with light polypropylene mesh ( Sofradim ® , Parietene ) is superior to the site-specific surgery in the treatment of cystocoeles [3072491] Introduction and hypothesisFor prolonged catheterization after vaginal prolapse surgery with anterior colporrhaphy , the optimal duration to prevent overdistention of the bladder remains unknown . We design ed this study to determine the optimal length of catheterization . Methods We conducted a prospect i ve r and omized trial in which 179 women were allocated to 1-day or 3-day suprapubic catheterization . The primary outcome was the duration of catheterization . Results Mean duration of catheterization and hospital stay was significantly shorter in the 1-day catheterization group . The number of successful voiding trials was higher in the 3-day catheterization group ( 90.9 % versus 79.3 % ) , but this did not reach statistical significance . The percentage of urinary tract infection did not differ significantly between the groups ( 4.5 % versus 2.4 % ) . ConclusionS tarting a voiding trial 1 day after vaginal prolapse surgery leads to shorter duration of catheterization and hospital stay [18923805] We compared safety and efficacy of Gynemesh PS ® and Pelvicol ® for recurrent cystocele repair . One hundred ninety patients were r and omly divided into Gynemesh PS ® and Pelvicol ® groups and underwent tension-free cystocele repair . The Chi-square test was used to compare categorical variables , the paired t test for continuous parametric variables , and the Mann – Whitney test for continuous nonparametric variables . Ninety-six Gynemesh PS ® patients and 94 Pelvicol ® patients were studied . Mesh erosions occurred in 6.3 % of Gynemesh PS ® patients . No erosions were observed in Pelvicol ® patients ( p = 0.02 ) . Objective cure was 71.9 % for Gynemesh PS ® and 56.4 % for Pelvicol ® ( p = 0.06 ) . Subjective cure was the same in both groups except for better sexuality in the Pelvicol ® group . At 24 months follow-up , only Gynemesh PS ® patients had mesh erosions . Anatomical outcome was similar in the two groups . Pelvicol ® gave a better impact on voiding and sexuality [20664388] OBJECTIVE : To present 3-month outcomes of a double-blind , multicenter r and omized controlled trial comparing traditional vaginal prolapse surgery without mesh with vaginal surgery with mesh . METHODS : Women with pelvic organ prolapse quantification prolapse stages 2–4 were r and omized to vaginal colpopexy repair with mesh or traditional vaginal colpopexy without mesh . The primary outcome measure was objective treatment success ( pelvic organ prolapse quantification stage 1 or lower ) at 3 months . Secondary outcome measures included quality -of-life variables and complication rates . RESULTS : Sixty-five women were recruited from January 2007 to August 2009 , when the study was halted due to predetermined stopping criteria for vaginal mesh erosion at a median follow-up of 9.7 months ( range , 2.4–26.7 months ) . Thirty-two women underwent mesh colpopexy ( 24 anterior mesh , eight total mesh ) , and 33 women had vaginal colpopexies without mesh ( primarily uterosacral ligament suspension ) and concurrent colporrhaphy . There were no statistically significant baseline differences between the mesh and no-mesh groups with respect to demographics , menopausal status , and race . Analysis of the mesh and no-mesh women found no difference with respect to overall recurrence ( mesh : 19 [ 59.4 % ] compared with no mesh : 24 [ 70.4 % ] , P=.28 ) . There were five ( 15.6 % ) vaginal mesh erosions . Two cystotomies and one blood transfusion occurred in the mesh group only . Subjective cure of bulge symptoms was noted in 93.3 % of mesh patients and 100 % of no-mesh patients . Furthermore , subjective quality -of-life measurements did not differ between the two groups at baseline or 3 months postoperatively . CONCLUSION : At 3 months , there is a high vaginal mesh erosion rate ( 15.6 % ) with no difference in overall objective and subjective cure rates . This study questions the value of additive synthetic polypropylene mesh for vaginal prolapse repairs . CLINICAL TRIAL REGISTRATION : Clinical trials.gov , www . clinical trials.gov , NCT00475540 . LEVEL OF EVIDENCE : [21797984] INTRODUCTION Surgical treatment of pelvic organ prolapse ( POP ) affects sexual function . Generally , this results in improved sexual function , but deterioration is reported also . AIM The purpose of this study was to evaluate and compare sexual function in patients with recurrent POP undergoing either a vaginal surgical repair with native tissue or a trocar-guided mesh insertion . METHODS Sexually active patients r and omly assigned to either native tissue repair or trocar-guided mesh insertion , which had completed the pelvic organ prolapse (POP)/urinary incontinence sexual question naire ( PISQ-12 ) both at baseline and at 12 months , were included . Total , subscale , and individual question analysis were performed . Logistic regression was used to identify factors that were independently associated with improvement/deterioration in total PISQ-12 scores . MAIN OUTCOME MEASURES Primary outcome was sexual function at 12 months following surgery , measured by the short form of the pelvic organ prolapse/urinary incontinence sexual question naire ( PISQ-12 ) . Secondary outcomes were the identification of factors independently associated with change in PISQ-12 scores and changes in individual PISQ-12 question scores . RESULTS Sixty patients were included ; 32 in the mesh arm and 28 in the native tissue arm . At 12 months , PISQ-12 scores were not different in both treatment arms ( 34.3 , st and ard deviation [ SD ] 6.7 vs. 34.7 , SD 5.7 ) , but improvement was detected in the native tissue arm , whereas PISQ-12 total score remained unchanged in the mesh arm . Deteriorations were observed in the behavioral/emotive subscale and partner-related items in the mesh arm . In the native tissue arm , significant improvements in the physical and partner-related subscales were observed . The presence of mesh exposure was independently associated with deterioration in total PISQ-12 score . CONCLUSION At 12 months , PISQ-12 scores were not different in either treatment arm , but were affected differently by trocar-guided mesh insertion or by native tissue repair . Mesh exposure was independently associated with deterioration in sexual function [20165833] Introduction and hypothesisThe effect of a Pelvicol ® graft compared with a conventional anterior vaginal repair was evaluated in this r and omised controlled study . Methods Only patients with a stage II or higher ( Ba ≥ −1 ) defect were included . Results Thirty-one patients were allocated to a conventional anterior repair ; 30 to Pelvicol ® graft . At 12 months follow-up , four patients among controls ( 15 % ) and two in the graft group ( 7 % ) had objective recurrence . Among controls , the difference at 3 months follow-up in Ba was 6.0 cm when compared with the position of Ba prior to surgery . In the graft group , the difference was 7.0 cm ( P < 0.05 ) . This difference was still present at 12 months follow-up ( 6.0 vs. 7.0 cm ; P < 0.05 ) . Conclusions The implantation of a Pelvicol ® graft does not improve the POP-Q stage [17120172] The purpose of this study is to compare the feasibility of local anesthesia with IV sedation versus general anesthesia for vaginal correction of pelvic organ prolapse . Patients with pelvic organ prolapse who were scheduled for an anterior or posterior colporrhaphy , or an obliterative procedure , and who did not have a contraindication or preference to type of anesthesia were r and omized to one of the two anesthesia groups . Nineteen patients were r and omized to the general group and 21 patients were r and omized to the local group . Mean operating room , anesthesia , and surgical time were similar in each group , and 10 patients in the local group bypassed the recovery room . Requests and doses of antiemetics , postoperative verbal numerical pain scores and length of hospital stay were similar between the two groups . Mean recovery room and total hospital costs were significantly lower in the local group . Local anesthesia with IV sedation is a feasible alternative for vaginal surgery to correct pelvic organ prolapse [2866119] To investigate the effect of prophylactic phenoxybenzamine on the bladder emptying after vaginal repair operations , 41 consecutive patients , who underwent the Manchester operation or an anterior + posterior repair because of genital descensus , were allocated at r and om to either prophylactic phenoxybenzamine ( PBZ-group ) or placebo treatment in the postoperative course . Prophylactic phenoxybenzamine was found to produce an improved emptying function of the bladder , leading to a statistically significant reduced number of acute urinary retentions ( P = 0.029 ) , decreased time until spontaneous voiding ( P = 0.026 ) and reduced volume of residual urine ( P = 0.018 ) . Furthermore , a reduced incidence of urinary tract infections was found in the PBZ-group . Prophylactic phenoxybenzamine treatment is recommended as an alternative to routine bladder drainage in preventing urinary retention following vaginal repair operations for genital descensus [22707003] Introduction and hypothesisThe optimal surgery for lateral defects is not well defined . Our objective was to assess the effects of anterior trocar-guided transvaginal mesh repair versus anterior colporrhaphy in women with lateral defects . Methods This sub analysis from a r and omized controlled trial of mesh kit versus anterior colporrhaphy assessed 99 patient diagnosed at baseline with lateral defects in the anterior vaginal wall . Thirty-nine patients underwent anterior colporrhaphy and 60 anterior trocar-guided transvaginal mesh surgery . Results One year after surgery , a persistent lateral defect was significantly more common after colporrhaphy compared with transvaginal mesh [ 11/32 ( 34.4 % ) vs 1/42 ( 2.4 % ) , risk ratio ( RR ) 14.4 , 95 % confidence interval ( CI ) 2.0–106.1 ; P < 0.001 ) ] However , there were no significant differences between treatment groups with regard to subjective symptoms as reflected by the overall Urogenital Distress Inventory scores , with mean difference from baseline 37.3 ± 50.6 in the colporrhaphy group vs 39.0 ± 45.8 in the mesh group ( p = 0.61 ) . Conclusions Use of a transvaginal mesh kit increases the odds for anatomical correction of lateral defects compared with anterior colporrhaphy but does not necessarily improve lower urinary tract symptoms [3051058] Introduction and hypothesisThe aim of this study was to compare the number of temporary catheter replacements and urinary tract infections after indwelling catheterization for 2 versus 5 days following an anterior colporrhaphy . Methods Two hundred forty-six patients were r and omly assigned to 2 or 5 days of indwelling catheterization . Outcome measures were temporary catheter replacements because of post-voiding residual > 200 mL after removal of the indwelling catheter , urinary tract infections , and hospital stay . All patients were analyzed according to the intention to treat principle . Results Compared to the 5-day protocol group , in the 2-day protocol group more patients needed temporary catheter replacement ( 9 % versus 28 % , odds ratio ( OR ) 4.0 , confidence interval ( CI ) 1.9–8.3 , p < 0.01 ) , whereas less patients had a urinary tract infection ( 37 % versus 22 % , OR 0.5 , CI 0.3–0.9 , p = 0.02 ) and median hospital stay was lower . Conclusions Removal of an indwelling catheter after 2 versus 5 days following anterior colporrhaphy is associated with more temporary catheter replacements , but less urinary tract infections and a shorter hospital stay [27939467] BACKGROUND Pre-eclampsia is a serious complication of pregnancy and contributes to maternal and offspring mortality and morbidity . R and omised controlled trials evaluating therapeutic interventions for pre-eclampsia have reported many different outcomes and outcome measures . Such variation contributes to an inability to compare , contrast , and combine individual studies , limiting the usefulness of research to inform clinical practice . The development and use of a core outcome set would help to address these issues ensuring outcomes important to all stakeholders , including patients , will be collected and reported in a st and ardised fashion . METHODS An international steering group including healthcare professionals , research ers , and patients , has been formed to guide the development of this core outcome set . Potential outcomes will be identified through a comprehensive literature review and semi-structured interviews with patients . Potential core outcomes will be entered into an international , multi-perspective online Delphi survey . All key stakeholders , including healthcare professionals , research ers , and patients will be invited to participate . The modified Delphi method encourages whole and stakeholder group convergence towards consensus ' core ' outcomes . Once core outcomes have been agreed upon it is important to determine how they should be measured . The truth , discrimination , and feasibility assessment framework will assess the quality of potential outcome measures . High quality outcome measures will be associated with core outcomes . Mechanisms exist to disseminate and implement the result ing core outcome set within an international context . DISCUSSION Embedding the core outcome set within future clinical trials , systematic review s , and clinical practice guidelines could make a profound contribution to advancing the usefulness of research to inform clinical practice , enhance patient care , and improve maternal and offspring outcomes . The infrastructure created by developing a core outcome set for pre-eclampsia could be leveraged in other setting s , for example selecting research priorities and clinical practice guideline development . PROSPECT IVE REGISTRATION : [ 1 ] Core Outcome Measures in Effectiveness Trials ( COMET ) registration number : 588 . [ 2 ] International Prospect i ve Register of Systematic Review s ( PROSPERO ) registration number : CRD42015015529 [3416890] OBJECTIVE : The aim of this study was to compare female sexual function after surgical treatment of anterior vaginal prolapse with either small intestine submucosa grafting or traditional colporrhaphy . METHODS : Subjects were r and omly assigned , preoperatively , to the small intestine submucosa graft ( n = 29 ) or traditional colporrhaphy ( n = 27 ) treatment group . Postoperative outcomes were analyzed at 12 months . The Female Sexual Function Index question naire was used to assess sexual function . Data were compared with independent sample s or a paired Student 's t-test . Clinical Trials.gov : NCT00827528 . RESULTS : In the small intestine submucosa group , the total mean Female Sexual Function Index score increased from 15.5±7.2 to 24.4±7.5 ( p<0.001 ) . In the traditional colporrhaphy group , the total mean Female Sexual Function Index score increased from 15.3±6.8 to 24.2±7.0 ( p<0.001 ) . Improvements were noted in the domains of desire , arousal , lubrication , orgasm , satisfaction , and pain . There were no differences between the two groups at the 12-month follow-up . CONCLUSIONS : Small intestine submucosa repair and traditional colporrhaphy both improved sexual function postoperatively . However , no differences were observed between the two techniques [5513392] Background Twin – Twin Transfusion Syndrome ( TTTS ) is associated with an increased risk of perinatal mortality and morbidity . Several treatment interventions have been described for TTTS , including fetoscopic laser surgery , amnioreduction , septostomy , expectant management , and pregnancy termination . Over the last decade , fetoscopic laser surgery has become the primary treatment . The literature to date reports on many different outcomes , making it difficult to compare results or combine data from individual studies , limiting the value of research to guide clinical practice . With the advent and ongoing development of new therapeutic techniques , this is more important than ever . The development and use of a core outcome set has been proposed to address these issues , prioritising outcomes important to the key stakeholders , including patients . We aim to produce , disseminate , and implement a core outcome set for TTTS . Methods An international steering group has been established to oversee the development of this core outcome set . This group includes healthcare professionals , research ers and patients . A systematic review is planned to identify previously reported outcomes following treatment for TTTS . Following completion , the identified outcomes will be evaluated by stakeholders using an international , multi-perspective online modified Delphi method to build consensus on core outcomes . This method encourages the participants towards consensus ‘ core ’ outcomes . All key stakeholders will be invited to participate . The steering group will then hold a consensus meeting to discuss results and form a core outcome set to be introduced and measured . Once core outcomes have been agreed , the next step will be to determine how they should be measured , disseminated , and implemented within an international context . Discussion The development , dissemination , and implementation of a core outcome set in TTTS will enable its use in future clinical trials , systematic review s and clinical practice guidelines . This is likely to advance the quality of research studies and their effective use in order to guide clinical practice and improve patient care , maternal , short-term perinatal outcomes and long-term neurodevelopmental outcomes .Trial registration Core Outcome Measures in Effectiveness Trials ( COMET ) , 921 Registered on July 2016.International Prospect i ve Register of Systematic Review s ( PROSPERO ) , CRD42016043999 . Registered on 2 August 2016 [20683580] Introduction and hypothesisDifferent forms of urinary drainage are applied after anterior colporrhaphy . Suprapubic urinary catheter ( SUC ) and indwelling urinary catheter ( IUC ) for 2 to 96 h are preferred . If there is no difference in symptomatic urinary tract infection ( SUTI ) or complications between IUCs for 96 and 24 h , the latter will be considered sufficient . If IUCs have no higher rate of infections or complications compared to SUC for 96 h , the former could be considered sufficient . Methods It was a three-arm prospect i ve , r and omized study including 257 patients . The three arms were : IUCs for 24 h , IUCs for 96 h , and SUCs for 96 h. Results We found no significant difference in SUTIs between all three groups . Although the SUC arm showed no SUTIs , a significant higher rate of complications was seen . Conclusion The optimal bladder catheter after anterior colporrhaphy was , in our trial , the IUC for 24 [17666627] OBJECTIVE : To compare anterior colporrhaphy with and without a tailored mesh . METHODS : Postmenopausal women with anterior vaginal prolapse to the hymen or beyond were r and omly assigned to undergo traditional anterior colporrhaphy alone or reinforced with mesh . The low-weight monofilament polypropylene mesh was self-tailored , having four arms and being placed over the plicated fascia . Before and 2 and 12 months after surgery , participants were evaluated by physical examination , postvoidal residual urine measurement and st and ard questions covering prolapse-related symptoms . The primary outcome was recurrence of anterior vaginal prolapse at 12 months . Secondary outcomes included operative complications , symptom resolution , and postvoidal urine residual volume . RESULTS : Of the 202 women r and omly assigned , 201 were operated on ( 97 without , 104 with mesh ) . Thirty-seven women ( 38.5 % ) in the no-mesh and seven ( 6.7 % ) in the mesh group experienced a recurrence of anterior wall prolapse ( P<.001 ) at 12 months ; as a result , the number needed to treat for benefit was four . The mean ( st and ard deviation ) postvoidal residual urine volume was lower in patients with mesh than in those undergoing the traditional operation : 25 ( 26 ) mL and 41 ( 57 ) mL ( P=.01 ) . Twenty-three women ( 23 % ) with mesh and 9 ( 10 % ) with no mesh reported stress urinary incontinence ( P=.02 ) . In 18 ( 17.3 % ) , exposure of the mesh was noted , mainly asymptomatic . CONCLUSION : Anterior colporrhaphy , reinforced with , tailored mesh significantly reduced the rate of recurrence of anterior vaginal wall prolapse compared with the traditional operation , but was associated more often with stress urinary incontinence . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00420225 LEVEL OF EVIDENCE : [8987919] OBJECTIVES Our purpose was to determine whether a vaginal or abdominal approach is more effective in correcting uterovaginal prolapse . STUDY DESIGN Eighty-eight women with cervical prolapse to or beyond the hymen or with vaginal vault inversion > 50 % of its length and anterior vaginal wall descent to or beyond the hymen were r and omized to a vaginal versus abdominal surgical approach . Forty-eight women underwent a vaginal approach with bilateral sacrospinous vault suspension and paravaginal repair , and 40 women underwent an abdominal approach with colposacral suspension and paravaginal repair . Ancillary procedures were performed as indicated . Detailed pelvic examination was performed postoperatively by the nonsurgeon coauthor yearly up to 5 years . The women were examined while st and ing during maximum strain . Surgery was classified as optimally effective if the woman remained asymptomatic , the vaginal apex was supported above the levator plate , and no protrusion of any vaginal tissue beyond the hymen occurred . Surgical effectiveness was considered unsatisfactory if the woman was symptomatic , the apex descended > 50 % of its length , or the vaginal wall protruded beyond the hymen . RESULTS Eighty women ( vaginal 42 , abdominal 38 ) were available for evaluation at 1 to 5.5 years ( mean 2.5 years ) . The groups were similar in age , weight , parity , and estrogen status , and 56 % had undergone prior pelvic surgery . There was no significant difference between the groups in morbidity , complications , hemoglobin change , dyspareunia , pain , or hospital stay . The vaginal group had longer catheter use , more urinary tract infections , more incontinence , decreased operative time , and lower hospital charge . Surgical effectiveness was optimal in 29 % of the vaginal group and 58 % of the abdominal group and was unsatisfactory leading to reoperation in 33 % of the vaginal group and 16 % of the abdominal group . The reoperations included procedures for recurrent incontinence in 12 % of the vaginal and 2 % of the abdominal groups . The relative risk of optimal effectiveness by the abdominal route is 2.03 ( 95 % confidence interval 1.22 to 9.83 ) , and the relative risk of unsatisfactory outcome using the vaginal route is 2.11 ( 95 % confidence interval 0.90 to 4.94 ) . CONCLUSIONS Reconstructive pelvic surgery for correction of significant pelvic support defects was more effective with an abdominal approach [24402594] OBJECTIVE : To compare surgeons ' intraoperative surgeon acceptability or assessment of the operative field regarding bowel contents and patients ' satisfaction with or without a mechanical bowel preparation before reconstructive vaginal prolapse surgery . METHODS : In this single-blind , r and omized trial , women scheduled to undergo vaginal prolapse surgery with a planned apical suspension and posterior colporrhaphy were allocated using block r and omization to an intervention or control group . Surgeons were blinded to patient allocation . One day before surgery , mechanical bowel preparation instructions consisted of a clear liquid diet and two self-administered saline enemas ; the participants in the control group sustained a regular diet and nothing by mouth after midnight . The primary outcome was surgeons ' intraoperative assessment of the surgical field regarding bowel content as measured on a 4-point Likert scale ( 1 , excellent ; 4 , poor ) . Secondary outcomes included participant satisfaction and bowel symptoms . The primary outcome was determined by intention-to-treat analysis and other analyses were per protocol . RESULTS : Of the 150 women r and omized ( 75 women to intervention and control group ) , 145 completed the study . No differences existed in the demographic , clinical , and intraoperative characteristics between groups ( P>.05 ) . Surgeons ' intraoperative assessment rating was 85 % “ excellent or good ” with bowel preparation compared with 90 % for participants in the control group ( odds ratio [ OR ] 0.59 , 95 % confidence interval [ CI ] 0.21–1.61 ; P=.30 ) . The bowel preparation group was less likely to report “ complete ” satisfaction compared with the participants in the control group ( OR 0.11 , 95 % CI 0.04–0.35 ; P<.001 ) . Abdominal fullness and cramping , fatigue , anal irritation , and hunger pains were greater in the bowel preparation group ( all P<.01 ) . CONCLUSION : Before reconstructive vaginal surgery , mechanical bowel preparation conferred no benefit regarding surgeons ' intraoperative assessment of the operative field , reflected decreased patient satisfaction , and had increased abdominal symptoms . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT01431040 . LEVEL OF EVIDENCE : [23812579] Introduction We set out to determine if insertion of a retropubic tension-free vaginal tape ( TVT ) sling at the time of pelvic organ prolapse surgery improves continence outcomes in women with pre-operative occult stress incontinence ( OSI ) or asymptomatic urodynamic stress incontinence ( USI ) . Methods We conducted a r and omised controlled study of prolapse surgery with or without a TVT midurethral sling . The pre- and post-operative assessment at 6 months included history , physical examination and urodynamic testing . Quality of life ( QOL ) and treatment success was assessed with the UDI-6 SF , IIQ-7 SF and a numerical success score . The primary outcome was symptomatic stress urinary incontinence ( SUI ) requiring continence surgery ( TVT ) at 6 months . Long-term follow-up continued to a minimum of 24 months . Secondary outcomes were quality of life parameters . Results Eighty women received prolapse surgery alone ( n = 43 ) or prolapse surgery with concurrent TVT ( n = 37 ) . Six months following prolapse surgery 3 out of 43 ( 7 % ) patients in the no TVT group requested sling surgery compared with 0 out of 37 ( 0 % ) in the TVT group ( ARR 7 % [ 95 % CI : 3 to 19 % ] , p = 0.11 ) . After 24 months there was one further participant in the no TVT group who received a TVT for treatment of SUI compared with none in the TVT group ( 4 out of 43 , 9.3 % versus 0 out of 37 ; ARR 9.3 % [ 95 % CI : −1 to 22 % ] , p = 0.06 ) . Both groups showed improvement in QOL difference scores for within-group analysis , without difference between groups . Conclusion These results support a policy that routine insertion of a sling in women with OSI at the time of prolapse repair is question able and should be subject to shared decision-making between clinician and patient [21864325] Please cite this paper as : Vollebregt A , Fischer K , Gietelink D , van der Vaart C. Primary surgical repair of anterior vaginal prolapse : a r and omised trial comparing anatomical and functional outcome between anterior colporrhaphy and trocar‐guided transobturator anterior mesh . BJOG 2011;118:1518–1527 [26294207] Introduction and hypothesisHydrodissection incorporating different types of vasoconstrictors is commonly used in vaginal prolapse surgery . There is little evidence as to whether it adds clinical value or whether it exposes the patient to unnecessary risk . The aim of this study was to compare the effect of a vasoconstrictor compared with saline alone on operative blood loss and cardiovascular parameters in a r and omised clinical trial setting . Methods Patients undergoing vaginal prolapse surgery were r and omised to an ornipressin ( Por-8 , Ferring ) solution or saline alone for hydrodissection . The surgeon and patient were blinded to the solution used . Operative blood loss was accurately quantified and blood pressure and pulse readings recorded Pre , intra- and postoperatively . Results Eighty women were r and omised . There was a statistically significant difference in the median blood loss : 35 ml ( 1 - 209 ml ) in the ornipressin group compared with 81 ml ( 2 - 328 ml ) in the saline group , p = 0.03 . There was no statistically significant difference in the median pre and postoperative blood pressure or pulse rate between groups . Conclusions The use of a vasoconstrictor ( ornipressin ) result ed in a statistically significant decrease in operative blood loss during vaginal prolapse surgery . This occurred without any significant changes in measured cardiovascular parameters [21561348] BACKGROUND The use of st and ardized mesh kits for repair of pelvic-organ prolapse has spread rapidly in recent years , but it is unclear whether this approach results in better outcomes than traditional colporrhaphy . METHODS In this multicenter , parallel-group , r and omized , controlled trial , we compared the use of a trocar-guided , transvaginal polypropylene-mesh repair kit with traditional colporrhaphy in women with prolapse of the anterior vaginal wall ( cystocele ) . The primary outcome was a composite of the objective anatomical design ation of stage 0 ( no prolapse ) or 1 ( position of the anterior vaginal wall more than 1 cm above the hymen ) , according to the Pelvic Organ Prolapse Quantification system , and the subjective absence of symptoms of vaginal bulging 12 months after the surgery . RESULTS Of 389 women who were r and omly assigned to a study treatment , 200 underwent prolapse repair with the transvaginal mesh kit and 189 underwent traditional colporrhaphy . At 1 year , the primary outcome was significantly more common in the women treated with transvaginal mesh repair ( 60.8 % ) than in those who underwent colporrhaphy ( 34.5 % ) ( absolute difference , 26.3 percentage points ; 95 % confidence interval , 15.6 to 37.0 ) . The surgery lasted longer and the rates of intraoperative hemorrhage were higher in the mesh-repair group than in the colporrhaphy group ( P<0.001 for both comparisons ) . Rates of bladder perforation were 3.5 % in the mesh-repair group and 0.5 % in the colporrhaphy group ( P=0.07 ) , and the respective rates of new stress urinary incontinence after surgery were 12.3 % and 6.3 % ( P=0.05 ) . Surgical reintervention to correct mesh exposure during follow-up occurred in 3.2 % of 186 patients in the mesh-repair group . CONCLUSIONS As compared with anterior colporrhaphy , use of a st and ardized , trocar-guided mesh kit for cystocele repair result ed in higher short-term rates of successful treatment but also in higher rates of surgical complications and postoperative adverse events . ( Funded by the Karolinska Institutet and Ethicon ; Clinical Trials.gov number , NCT00566917 . ) [22648445] Purpose To compare the clinical effectiveness of anterior colporrhaphy versus mesh repair as surgical management of anterior vaginal prolapse . Methods Of 50 patients with ≥stage II anterior vaginal prolapse on Pelvic Organ Prolapse Quantification ( POPQ ) system who were initially approached , 44 consented and underwent surgery . They were r and omly recruited into two groups . Group I ( 23 patients ) received anterior colporrhaphy , while group II ( 21 patients ) received soft polypropylene mesh ( GYNEMESH*PS , Gynecare , Ethicon , France ) . Clinical assessment took place preoperatively and postoperatively at definite intervals . Functional and anatomical comparisons were based on comparison between preoperative and 24 months postoperative assessment s of symptoms and POPQ stages , respectively . Four patients in total did not complete the follow-up assessment s and were excluded . Results Both groups showed clinical improvement in their symptoms and POPQ staging at the end of the postoperative follow-up period . Improvement , however , was more significant in the repair with mesh group , as patients in this group reported better improvement of their prolapse symptoms , mainly vaginal bulge/pressure sensation ( P < 0.05 ) , and showed better improvement in the anatomical staging , individual POP-Q points Aa and Ba ( P < 0.01 ) , than the anterior colporrhaphy group . Group II also showed more satisfactory outcome with the general POP-Q staging ( P < 0.05 ) than group I , reflecting a better quality of life of the patients in the repair with mesh group . Conclusion Our data shows that repair with mesh is superior to anterior colporrhaphy with more satisfactory outcome to the patients . Due to the small size of our study and uncertainty of the long-term safety and resilience of the mesh , we recommend larger studies to confirm our preliminary results [22321388] INTRODUCTION In pelvic organ prolapse ( POP ) repair , the use of synthetic mesh is not only increasing but also a subject of discussion . The focus shifts from anatomical toward functional outcome , with sexual function being an important parameter . One of the concerns with mesh usage in POP surgery is the possible negative effect on sexual function . AIM To compare and assess sexual function in women and men after primary cystocele repair with or without trocar-guided transobturator mesh . METHODS One hundred twenty-five women with a symptomatic cystocele stage ≥ II were included in this multicenter r and omized controlled trial and assessed at baseline and 6-month follow-up . MAIN OUTCOME MEASURES Female sexual function was measured by the Female Sexual Function Index ( FSFI ) and male sexual function by the Male Sexual Health Question naire . A subgroup analysis of women with a participating partner was performed . RESULTS In the mesh group , 54/59 women vs. 53/62 in the anterior colporrhaphy group participated . In men , 29 vs. 30 participated . After surgery , FSFI scores were comparable for both treatment groups . However , within group analysis showed significant improvement on the domains pain ( effect size = 0.5 ) , lubrication ( effect size = 0.4 ) , and overall satisfaction ( effect size = 0.5 ) in the colporrhaphy group . This improvement was not observed in the mesh group . A subgroup of women with a participating partner reported significantly higher baseline domain scores as compared with other women and did not report a significant improvement of sexual functioning irrespective of treatment allocation . Worsening of baseline sexual function was reported by 43 % of women in the mesh group compared with 18 % in anterior colporrhaphy group ( P = 0.05 ) . Male sexual functioning did not change in either group . CONCLUSIONS Women after an anterior colporrhaphy report a significant and clinical ly relevant improvement of their sexual functioning , whereas women after a mesh procedure did not [24310987] Introduction and hypothesisThe objective of this study was to evaluate the effect of vaginal packing following pelvic floor surgery with regard to post-operative pain , bleeding and infection . This was a double-blind r and omised study of women undergoing vaginal hysterectomy and /or pelvic floor repair at a tertiary urogynaecology unit . Methods The primary outcome of day 1 post-operative pain was assessed using the short-form McGill Pain score . Secondary outcomes were haematological and infective morbidity , evaluated using changes in full blood count , and cultures of midstream urine and high vaginal swabs . A transvaginal ultrasound scan to exclude pelvic haematoma was performed at 6 weeks in all women who underwent vaginal hysterectomy with or without a pelvic floor repair . Results In total , 190 women were recruited : mean age 58.3 years ( 27–91 years ) , mean body mass index 27.4 kg/m2 and median parity 3 . Women were r and omised into the ‘ pack ’ ( n = 86 ) and ‘ no pack ’ ( n = 87 ) arms with no demographic differences between the groups . No statistically significant differences in the post-operative pain scores or secondary outcome measures were demonstrated . Incidence of haematoma formation ( 14.8 % no pack , 7.3 % pack , p = 0.204 ) was not statistically significant . There were three clinical ly significant complications in the no pack group and none in the pack group . Conclusions This is the first study to examine pain in association with post-operative vaginal packing . There is no evidence to suggest that packing increases pain scores or post-operative morbidity . A trend towards increased haematoma and significant complications was seen in the no pack group . As vaginal packing does no harm and may be of some benefit it may be argued that packing should be recommended as routine clinical practice [26740197] Introduction and hypothesisWe compared pelvic organ prolapse ( POP ) repair with and without midurethral sling ( MUS ) in women with occult stress urinary incontinence ( SUI ) . Methods This was a r and omized trial conducted by a consortium of 13 teaching hospitals assessing a parallel cohort of continent women with symptomatic stage II or greater POP . Women with occult SUI were r and omly assigned to vaginal prolapse repair with or without MUS . Women without occult SUI received POP surgery . Main outcomes were the absence of SUI at the 12-month follow-up based on the Urogenital Distress Inventory and the need for additional treatment for SUI . Results We evaluated 231 women , of whom 91 r and omized as follows : 43 to POP surgery with and 47 without MUS . A greater number of women in the MUS group reported absence of SUI [ 86 % vs. 48 % ; relative risk ( RR ) 1.79 ; 95 % confidence interval ( CI ) 1.29–2.48 ] . No women in the MUS group received additional treatment for postoperative SUI ; six ( 13 % ) in the control group had a secondary MUS . Women with occult SUI reported more urinary symptoms after POP surgery and more often underwent treatment for postoperative SUI than women without occult SUI . Conclusions Women with occult SUI had a higher risk of reporting SUI after POP surgery compared with women without occult SUI . Adding a MUS to POP surgery reduced the risk of postoperative SUI and the need for its treatment in women with occult SUI . Of women with occult SUI undergoing POP-only surgery , 13 % needed additional MUS . We found no differences in global impression of improvement and quality of life [23084678] STUDY OBJECTIVE To compare the effectiveness and safety of 2 anterior transobturator mesh methods for treating anterior vaginal wall prolapse . DESIGN R and omized controlled study ( Canadian Task Force classification I ) . SETTING University hospital . PATIENTS Eighty-seven women with anterior vaginal wall prolapse stage ≥2 ( Pelvic Organ Prolapse Quantification [ POP-Q ] ) underwent an anterior transobturator mesh procedure using macropore polypropylene mesh . INTERVENTIONS Forty-five patients underwent the operation via the conventional 4-point , full-sized mesh method , and 42 patients underwent the operation via a novel 2-point , half-sized mesh method . MEASUREMENTS AND MAIN RESULTS Patient characteristics were comparable between the 2 groups . The anatomic cure rate was significantly lower in the 2-point group compared with the 4-point group at 12 months after surgery ( 87.2 % vs 100 % ; p = .03 ) . Healing abnormalities were significantly higher in the 2-point group than in the 4-point group ( 12.8 % vs 0 % ; p = .03 ) . Bladder perforation ( 2.6 % vs 0 % ) , stress urinary incontinence ( 23.1 % vs 22.5 % ) , urinary frequency ( 12.8 % vs 22.5 % ) , and voiding difficulty and dyspareunia ( 0 % vs 0 % ) were not statistically different between the 2 groups . At linear regression analysis , mean ( SD ) operation time did not differ between the 2 groups ( 74.9 [ 32.7 ] minutes vs 87.8 [ 36.7 ] minutes ; p = .11 ) . CONCLUSION Compared with the 4-point method , the 2-point anterior transobturator mesh method result ed in a lower rate of anatomic cure and a higher rate of healing abnormality [22239416] Please cite this paper as : Withagen M , Milani A , de Leeuw J , Vierhout M. Development of de novo prolapse in untreated vaginal compartments after prolapse repair with and without mesh : a secondary analysis of a r and omised controlled trial . BJOG 2012;119:354–360 [11744900] OBJECTIVE The purpose of this study was to compare outcomes after anterior colporrhaphy with the use of 3 different surgical techniques . STUDY DESIGN One hundred fourteen women with anterior vaginal prolapse were r and omly assigned to undergo anterior repair by one of 3 techniques : st and ard , st and ard plus polyglactin 910 mesh , or ultralateral anterior colporrhaphy . Before and after operation , patients underwent physical examination staging of prolapse ; the International Continence Society system was used . Symptoms were assessed by question naire and visual analog scales . We defined " cure " as satisfactory ( stage I ) or optimal ( stage 0 ) outcome at points Aa and Ba . RESULTS Of 114 patients who were originally enrolled , 109 patients underwent operation , and 83 patients ( 76 % ) returned for follow-up . Mean age ( + /- SD ) was 64.7 + /- 11.1 years . At entry , 7 patients ( 7 % ) had stage I anterior vaginal prolapse ; 35 patients ( 37 % ) had stage II anterior vaginal prolapse ; 51 patients ( 54 % ) had stage III anterior vaginal prolapse ; and 2 patients ( 2 % ) had stage IV anterior vaginal prolapse . At a median length of follow-up of 23.3 months , 10 of 33 patients ( 30 % ) who were r and omly assigned to the st and ard anterior colporrhaphy group experienced satisfactory or optimal anatomic results , compared with 11 of 26 patients ( 42 % ) with st and ard plus mesh and with 11 of 24 patients ( 46 % ) with ultralateral anterior colporrhaphy . The severity of symptoms that were related to prolapse improved markedly ( preoperative score , 6.9 + /- 2.7 ; postoperative score , 1.1 + /- 0.8 ) . Twenty-three of 24 patients ( 96 % ) no longer required manual pressure to void after operation . CONCLUSION These 3 techniques of anterior colporrhaphy provided similar anatomic cure rates and symptom resolution for anterior vaginal prolapse repair . The addition of polyglactin 910 mesh did not improve the cure rate compared with st and ard anterior colporrhaphy [17712655] Background . The aim of this prospect i ve , r and omised , study was to determine whether or not there was a higher incidence of bleeding , reoperation , urinary retention or bacterial count in the urine , depending on whether urinary catheter and vaginal pack was removed 3 h or 24 h after vaginal prolapse surgery . Methods . Some 136 women were r and omised into Group 1 ( removal of catheter and vaginal pack after 3 h ) , and Group 2 ( removal of catheter and vaginal pack after 24 h ) . Data on postoperative bleeding , reoperation , and urinary retention were collected . Preoperatively , day after operation , and 14 days after operation , a urine culture was performed . Results . There was no tendency towards more bleeding with early removal of vaginal pack and urinary catheter . No patients in either group were reoperated during the first 48 postoperative hours . Three patients in Group 1 required sterile intermittent catheterisation postoperatively , however , only once in 2 patients . There was a trend towards a higher postoperative bacterial count in patients in Group 2 ( p = 0.306 ) . Conclusion . We recommend removing the vaginal pack and urinary catheter after 3 h with careful monitoring of the patient 's voiding [22716974] BACKGROUND Women without stress urinary incontinence undergoing vaginal surgery for pelvic-organ prolapse are at risk for postoperative urinary incontinence . A midurethral sling may be placed at the time of prolapse repair to reduce this risk . METHODS We performed a multicenter trial involving women without symptoms of stress incontinence and with anterior prolapse ( of stage 2 or higher on a Pelvic Organ Prolapse Quantification system examination ) who were planning to undergo vaginal prolapse surgery . Women were r and omly assigned to receive either a midurethral sling or sham incisions during surgery . One primary end point was urinary incontinence or treatment for this condition at 3 months . The second primary end point was the presence of incontinence at 12 months , allowing for subsequent treatment for incontinence . RESULTS Of the 337 women who underwent r and omization , 327 ( 97 % ) completed follow-up at 1 year . At 3 months , the rate of urinary incontinence ( or treatment ) was 23.6 % in the sling group and 49.4 % in the sham group ( P<0.001 ) . At 12 months , urinary incontinence ( allowing for subsequent treatment of incontinence ) was present in 27.3 % and 43.0 % of patients in the sling and sham groups , respectively ( P=0.002 ) . The number needed to treat with a sling to prevent one case of urinary incontinence at 12 months was 6.3 . The rate of bladder perforation was higher in the sling group than in the sham group ( 6.7 % vs. 0 % ) , as were rates of urinary tract infection ( 31.0 % vs. 18.3 % ) , major bleeding complications ( 3.1 % vs. 0 % ) , and incomplete bladder emptying 6 weeks after surgery ( 3.7 % vs. 0 % ) ( P≤0.05 for all comparisons ) . CONCLUSIONS A prophylactic midurethral sling inserted during vaginal prolapse surgery result ed in a lower rate of urinary incontinence at 3 and 12 months but higher rates of adverse events . ( Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institutes of Health Office of Research on Women 's Health ; OPUS Clinical Trials.gov number , NCT00460434 . ) [22067717] OBJECTIVE : To report 2-year outcomes of a r and omized controlled trial comparing st and ard anterior colporrhaphy with reinforced vaginal paravaginal repair using xenograft or synthetic mesh in women with symptomatic anterior vaginal wall prolapse . METHODS : Women with stage II or greater anterior prolapse were r and omly assigned to three groups : anterior colporrhaphy , paravaginal repair with porcine dermis , or polypropylene mesh . Outcomes of prolapse stage , quality of life , degree of bother , and sexual symptoms were assessed by blinded examiners and vali date d measures at 2 years . Anatomic failure was defined as anterior prolapse at stage II or greater . Composite failure was defined as symptoms of “ bulge ” and anterior prolapse at stage II or greater . Power calculations determined 33 participants per arm would detect a 40 % difference in anatomic success between st and ard and grafted repair . & khgr;2 , Mann-Whitney U , and Student 's t tests were used for comparisons . RESULTS : Of the 99 participants enrolled , 78 ( 79 % ) completed a minimum of 2-year follow-up . Those with mesh had a significantly lower anatomic failure rate ( 18 % ) than both the porcine ( 46 % , P=.015 ) and colporrhaphy groups ( 58 % , P=.002 ) . All groups had statistically similar reductions in their prolapse and urinary symptom subscale scores . Composite failure was not statistically different between groups : 13 % colporrhaphy , 12 % porcine , and 4 % mesh . Two reoperations for anterior prolapse occurred in the porcine group . Mesh erosion rates were 14 % for the mesh group . CONCLUSION : Vaginal paravaginal repair with polypropylene mesh has the lowest anatomic failure rate when compared with that with xenograft and anterior colporrhaphy without differences in composite failures . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT0139171 . LEVEL OF EVIDENCE : [21895613] Objective . To determine the long‐term objective and subjective outcomes of use of a porcine skin graft ( Pelvicol ™ ) compared with conventional colporrhaphy in recurrent pelvic organ prolapse surgery and to analyze risk factors and safety . Design . Open r and omized controlled multicenter study . Setting . Eight Swedish hospitals . Population . 135 consecutive women with recurrent cystocele and /or rectocele admitted for vaginal prolapse surgery ; 132 completed the study , 64 were r and omly allocated to receive conventional colporrhaphy and 68 to Pelvicol . Methods . Conventional anterior and posterior colporrhaphy and colporrhaphy with use of Pelvicol ™ mesh reinforcement . Clinical evaluation by means of pelvic organ prolapse quantification ( POP‐Q ) and symptom question naire preoperatively , three months and three years postoperatively . Main outcome measures . Anatomical and subjective outcome . Recurrence was defined as POP‐Q≥stage 2 . Results . At three‐month follow‐up , early recurrence/surgical failures occurred significantly more often in the Pelvicol ™ group , but at the three‐year follow‐up the recurrence rates were similar . The recurrence rates in the anterior compartment were 57–62 % and 44–23 % in the posterior compartment for the colporrhaphy and Pelvicol ™ groups , respectively . Symptoms were substantially and equally reduced in the two groups after surgery . Sexual activity and function did not seem to be affected adversely in any group . The complication rate was low . Risk factors for anatomical recurrence were age , body mass index and preoperative stage of the prolapse . Conclusions . With the surgical technique used in this study , Pelvicol ™ did not provide advantages over conventional colporrhaphy in recurrent pelvic organ prolapse concerning anatomical and subjective outcomes [19546759] OBJECTIVE : To compare outcomes of anterior colporrhaphy alone to that reinforced with bovine pericardium graft . METHODS : Women with anterior vaginal wall prolapse were enrolled in a r and omized fashion in this grafted compared with nongrafted repair study . Outcome measures included pelvic organ prolapse quantification data , quality -of-life assessment , healing abnormalities , and complications . RESULTS : Ninety-four patients were enrolled . Seventy-two ( 77 % ) provided 1-year data , and 59 ( 63 % ) supplied 2-year data . Demographics and stage of prolapse were similar between groups at baseline . Postoperative complications consisted basically of low urinary tract infection and were low in both groups ( 10 in bovine pericardium graft and 16 in anterior colporrhaphy alone ) . One year after surgery , successful anterior vaginal wall support was obtained in 85.7 % of the bovine pericardium graft group and 78.4 % of anterior colporrhaphy – alone group ( P=.544 ) . For the cohort that comprised 2-year analyses , the success rate was 76.5 % for the bovine pericardium graft group and 63 % for anterior colporrhaphy – alone group ( P=.509 ) . Postoperative Urogenital Distress Inventory-6 and Pelvic Organ Prolapse – Urinary Incontinence Sexual Function Question naire-12 scores were uniformly improved over baseline in both groups . CONCLUSION : The use of bovine pericardium graft for anterior vaginal prolapse does not have higher complication rates or healing difficulties . At 1- and 2-year follow-up , anterior colporrhaphy with bovine pericardium reinforcement did not show a statistically significant improvement over colporrhaphy alone . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00860912 LEVEL OF EVIDENCE : [21335940] Aim : To compare the effect of suprapubic and transurethral catheterization on postvoid residual volumes ( PRVs ) after cystocele repair . Methods : 126 women who underwent pelvic organ prolapse surgery including cystocele repair were r and omized to suprapubic or transurethral catheterization . At the third postoperative day , PRVs were measured . The number of women with PRV > 150 ml , need for prolonged catheterization , recatheterization , length of hospital stay , frequency of urinary tract infections and complications were determined . Results : PRVs exceeded 150 ml in 13 out of 64 ( 20 % ) and 14 out of 62 ( 23 % ) women in the suprapubic and transurethral group , respectively ( p = 0.76 ) . In the suprapubic group a higher rate of urine leakage was noted ( 27 vs. 7 % , p = 0.003 ) . 10 women ( 16 % ) allocated to the suprapubic group switched to transurethral catheterization , because of problems with the suprapubic catheter . No protocol deviations were reported in the transurethral group . Of the women in both groups , 9 % developed urinary tract infections ( p = 0.93 ) . Conclusions : Suprapubic catheterization was comparable to transurethral catheterization in the prevention of postoperative voiding dysfunction after vaginal prolapse surgery , but it was associated with a higher rate of complications [15270931] Objective To determine whether prolonged urinary bladder catheterisation after vaginal prolapse surgery is advantageous [20428997] Introduction and hypothesisThis study seeks to compare the small intestine submucosa ( SIS ) graft with traditional colporrhaphy ( TC ) for surgical treatment of anterior vaginal prolapse . Methods Subjects were r and omly assigned to SIS ( n = 29 ) or to TC ( n = 27 ) preoperatively and outcomes analyzed at 12 months postoperatively . The primary outcome was the absence of POP-Q stage ≥ II prolapse , and secondary outcome was improvement in quality of life . Data were compared with independent sample s or paired Student ’s t test . Results SIS group had 86.2 % anatomic cure compared to 59.3 % in TC ( p = 0.03 ) . SIS improved point Ba measurement significantly ( −1.93 cm versus −1.37 cm , p = 0.02 ) . Both operations significantly improved quality of life , although there were no differences between the groups . We observed a greater number of complications in the SIS group , with no infections or erosion . Conclusions SIS repair improved point Ba significantly . However , there were no differences observed in quality of life between the techniques [24054381] OBJECTIVE To compare the effects of two surgical procedures for the correction of anterior vaginal wall prolapse ( AVWP ) on the lower urinary tract symptoms ( LUTS ) using symptom question naires and quality of life ( QoL ) . MATERIAL S AND METHODS One hundred women with Pelvic Organ Prolapse Quantification stage ( POP-Q ) ≥ 2 were r and omly distributed in two preoperatory groups . The first group ( mesh ) ( n = 45 ) received a polypropylene mesh ( PM ) implant and the control group ( n = 55 ) was su bmi tted to anterior colporraphy with or without synthetic sling . Postoperatory follow-up was done after 12 months . The primary objective was to compare the effect of the surgeries on LUTS using the final scores of the International Consultation on Incontinence Question naire Urinary Incontinence Short Form ( ICIQ-UI SF ) and Overactive Bladder Question naire ( OAB-V8 ) , as well as the analysis of the incapacitating urinary symptoms and ″de novo″ urinary symptoms after 12 months of surgery in both groups . RESULTS Although there was a different number of women in each group , r and omization was adequate , result ed in homogeneous groups that could be compared regarding socio demographic , clinical and gynecological ( POP-Q ) variables . Patients of both groups showed improvements regarding LUTS and QoL , whether using polypropylene mesh or not , based on the final scores of the ICIQ-UI SF and OAB-V8 question naires after 12-month follow-up . There were few incapacitating and ″de novo ″ urinary symptoms , without any significant statistical difference between both groups after 12 months of surgery . CONCLUSION There was a general improvement of LUTS and QoL in both groups after 12-month follow-up . However , there was no significant difference of LUTS , as well as the more incapacitating and ″de novo ″ urinary symptoms between both groups after 12 months of surgery [18716704] To evaluate whether symptom resolution and sexual function is better after reinforcement with polypropylene mesh than with traditional anterior repair . Ninety-seven patients were r and omized to anterior colporrhaphy and 105 to an operation with mesh . Participants were evaluated up to 24 months by physical examination , st and ard questions , and question naire . The overall symptom rate did not differ between the groups , but a sensation of vaginal bulge was reported less frequently in the mesh group , the figures being 17 versus 5 ( p = 0.003 ) . The recurrence rate for the no-mesh group was 41 % and for the mesh group 11 % ( p < 0.001 ) . The dyspareunia score was statistically significantly lower in the mesh group ( p = 0.015 ) . The mesh exposure rate was 8 % . Sensation of vaginal bulge was relieved more efficiently by the mesh technique without causing dyspareunia [22930216] Introduction and hypothesisIn surgery for pelvic organ prolapse ( POP ) the use of alloplastic meshes has become common . Among possible complications , mesh exposure is the most frequent problem . It is hypothesized that exposure rates are correlated to mesh weight and the amount of foreign material . Therefore , we conducted a prospect i ve open-label r and omized multicenter trial comparing a conventional polypropylene mesh ( PP ) with a partially absorbable polypropylene mesh ( PA ) for cystocele treatment . Methods A total of 200 patients with POP > stage I were r and omized either to a conventional or a partially absorbable mesh . Exposure rates were observed after 3 , 12 , and 36 months and correlated to mesh material , patient characteristics , intraoperative data , and treatment centers . Furthermore , management of mesh exposure , satisfaction with surgery , and postoperative pain were evaluated . Results At all follow-up intervals mesh exposure rate was smaller in the group of the partially absorbable mesh ( 3 months PP 11.3 % vs PA 3.2 % , p = 0.0492 ; 12 months 6.6 % vs 6.3 % ; 36 months 7.5 % vs 3.4 % ) . Over the course of time , mesh exposure was observed in 27 patients , with surgical intervention necessary in 11 patients . The rate of recurrent POP was higher ( p > 0.05 ) in patients with the partially absorbable mesh . The majority of patients were fully satisfied with the operation ( 52.8 % ) and had no pelvic floor pain ( 67.5 % ) . Conclusion In this prospect i ve , r and omized trial with a long-term follow-up there was a low exposure rate in both treatment groups with a trend toward fewer exposures in the group of the partially absorbable mesh [21860294] OBJECTIVE : To compare the diagnostic accuracy of two voiding trial methods to predict postoperative voiding dysfunction . METHODS : Women undergoing operations for urinary incontinence , prolapse , or both urinary incontinence and prolapse from November 2009 and March 2010 were r and omized into one of two groups : retro grade or spontaneous . All patients underwent both techniques of voiding trials with r and omization determining order . RESULTS : Fifty women were r and omized to 25 per group . Failure rates were 62 % for retro grade and 84 % for spontaneous . Women who failed both had 12.6±14.4 days of retention compared with 2.5±2.1 days for those who failed only one method ( P=.004 ) . The retro grade method had 94.4 % sensitivity and 58.1 % specificity to detect postoperative voiding dysfunction lasting at least 7 days compared with the spontaneous method with 100 % sensitivity and 25.8 % specificity . Positive and negative predictive values for the retro grade method were 56.7 % and 94.7 % , respectively , compared with the spontaneous method with 43.9 % and 100 % . Retro grade was preferred by patients ( 51.1 % compared with 44.4 % ) regardless of r and omization . CONCLUSION : The retro grade method is more accurate in evaluating postoperative voiding dysfunction , although both tests had a low positive predictive value . A longer period of retention was seen with failure of both methods . Retro grade was preferred by patients and provides an efficient alternative to the spontaneous method of voiding trial . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT01091844 . LEVEL OF EVIDENCE : [24573358] Introduction and hypothesisOur aim was to compare anatomical and functional outcome between vaginal colposuspension and transvaginal mesh . Methods This was a prospect i ve r and omized controlled trial in a teaching hospital . Sixty-eight women with stage ≥3 anterior vaginal wall prolapse according to the Pelvic Organ Prolapse Quantification ( POP-Q ) system were assessed , r and omized , and analyzed . Patients were r and omized to anterior colporrhaphy with vaginal colposuspension ( n = 35 ) or transvaginal mesh ( n = 33 ) . Primary outcome was objective cure rate of the anterior vaginal wall , defined as POP-Q ≤1 at 2 years . Secondary outcomes were functional results , quality -of-life ( QoL ) scores , mesh-related morbidity , and onset of urinary incontinence . Results The anatomical result for point Ba was significantly better at 2 years in the mesh group ( −2.8 cm ) than in the colposuspension group ( −2.4 cm ) ( p = 0.02 ) . Concerning POP-Q stages , the anatomical success rate at 2 years was 84.4 % for colposuspension and 100 % for mesh ( p = 0.05 ) . There were 5 anatomic recurrences ( 15.6 % ) in the colposuspension group . The erosion rate was 6 % ( n = 2 ) . No significant difference was noted regarding minor complications . Analysis of QoL question naires showed overall improvement in both groups , with no significant difference between them . Conclusions The vaginal colposuspension technique of anterior vaginal wall prolapse repair gave good anatomical and functional results at 2 years . Transobturator vaginal mesh gave better 2-year anatomical results than vaginal colposuspension , with overall improvement in QoL in both groups [21545996] OBJECTIVE The purpose of this study was to reanalyze the results of a previously published trial that compared 3 methods of anterior colporrhaphy according to the clinical ly relevant definitions of success . STUDY DESIGN A secondary analysis of a trial of 114 subjects who underwent surgery for anterior pelvic organ prolapse who were assigned r and omly to st and ard anterior colporrhaphy , ultralateral colporrhaphy , or anterior colporrhaphy plus polyglactin 910 mesh from 1996 - 1999 . For the current analysis , success was defined as ( 1 ) no prolapse beyond the hymen , ( 2 ) the absence of prolapse symptoms ( visual analog scale ≤ 2 ) , and ( 3 ) the absence of retreatment . RESULTS Eighty-eight percent of the women met our definition of success at 1 year . One subject ( 1 % ) underwent surgery for recurrence 29 months after surgery . No differences among the 3 groups were noted for any outcomes . CONCLUSION Re analysis of a trial of 3 methods of anterior colporrhaphy revealed considerably better success with the use of clinical ly relevant outcome criteria compared with strict anatomic criteria [24737300] Introduction The natural history of pelvic organ prolapse ( POP ) is poorly understood . We investigated the prevalence and risk factors of postnatal POP in premenopausal primiparous women and the associated effect of mode of delivery . Methods We conducted a prospect i ve cohort study in a tertiary teaching hospital attending 9,000 deliveries annually . Collagen-diseases history and clinical assessment was performed in 202 primiparae at ≥1 year postnatally . Assessment included Pelvic Organ Prolapse Quantification ( POP-Q ) system , Beighton mobility score , 2/3D-transperineal ultrasound ( US ) and quantification of collagen type III levels . Association with POP was assessed using various statistical tests , including logistic regression , where results with p < 0.1 in univariate analysis were included in multivariate analysis . Results POP had a high prevalence : uterine prolapse 89 % , cystocele 90 % , rectocele 70 % and up to 65 % having grade two on POP-Q staging . The majority had multicompartment involvement , and 80 % were asymptomatic . POP was significantly associated with joint hypermobility , vertebral hernia , varicose veins , asthma and high collagen type III levels ( p < 0.05 ) . In multivariate logistic regression , only levator ani muscle ( LAM ) avulsion was significant in selected cases ( p < 0.05 ) . Caesarean section ( CS ) was significantly protective against cystocele and rectocele but not for uterine prolapse . Conclusions Mild to moderate POP has a very high prevalence in premenopausal primiparous women . There is a significant association between POP , collagen levels , history of collagen disease and childbirth-related pelvic floor trauma . These findings support a congenital contribution to POP etiology , especially for uterine prolapse ; however , pelvic trauma seems to play paramount role . CS is significantly protective against some types of prolapse only [23124692] Introduction and hypothesisThe aim of this study was to compare the lower urinary tract symptom changes and surgical outcome between the tension-free vaginal tape ( TVT ) procedure with and without concomitant stage II pelvic organ prolapse ( cystocele ) repair in a r and omized clinical trial setting . Methods Patients with urodynamically proven stress urinary incontinence ( SUI ) and asymptomatic stage II cystocele were r and omly and equally allocated to either a TVT and concomitant cystocele repair group or TVT only group . SUI was corrected with TVT in all cases . The cystocele repair procedure was performed with Gynemesh ® . Lower urinary tract symptoms and surgical outcome were assessed at postoperative year 1 . Lower urinary tract symptoms were assessed with the American Urological Association Symptom Score ( AUASS ) question naire , uroflowmetry , and postvoid residual ( PVR ) . Results The cure rate of TVT only and the concomitant repair group was 87 and 91 % , respectively ( p > 0.05 ) . Cystocele was cured in all patients in the concomitant repair group . After the operation , the total AUASS were 6.4 and 8.4 in the TVT only group and concomitant repair group , respectively , with no statistical difference . There was no difference in the change in peak flow rate ( Qmax ) and PVR between the two groups . The prevalence of postoperative mixed incontinence was not different between the two groups . Conclusions In patients with stage II cystocele and SUI , there was no difference in the surgical outcome and lower urinary tract symptoms between the TVT sling only group and concomitant repair group . Cystocele repair can be safely omitted in patients with stage II cystocele [21252735] OBJECTIVE : To compare efficacy and safety of trocar-guided tension-free vaginal mesh insertion with conventional vaginal prolapse repair in patients with recurrent pelvic organ prolapse . METHODS : Patients with recurrent pelvic organ prolapse stage II or higher were r and omly assigned to either conventional vaginal prolapse surgery or polypropylene mesh insertion . Primary outcome was anatomic failure ( pelvic organ prolapse stage II or higher ) in the treated vaginal compartments . Secondary outcomes were subjective improvement , effects on bother , quality of life , and adverse events . Question naires such as the Incontinence Impact Question naire and Urogenital Distress Inventory were administered at baseline , 6 months , and 12 months . Anatomic outcomes were assessed by an unblinded surgeon . Power calculation with & agr;=0.05 and & bgr;=0.80 indicated that 194 patients were needed . RESULTS : Ninety-seven women underwent conventional repair and 93 mesh repair . The follow-up rate after 12 months was 186 of 190 patients ( 98 % ) . Twelve months postsurgery , anatomic failure in the treated compartment was observed in 38 of 84 patients ( 45.2 % ) in the conventional group and in eight of 83 patients ( 9.6 % ) in the mesh group ( P<.001 ; odds ratio , 7.7 ; 95 % confidence interval , 3.3–18 ) . Patients in either group reported less bulge and overactive bladder symptoms . Subjective improvement was reported by 64 of 80 patients ( 80 % ) in the conventional group compared with 63 of 78 patients ( 81 % ) in the mesh group . Mesh exposure was detected in 14 of 83 patients ( 16.9 % ) . CONCLUSION : At 12 months , the number of anatomic failures observed after tension-free vaginal mesh insertion was less than after conventional vaginal prolapse repair . Symptom decrease and improvement of quality of life were equal in both groups . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00372190 . LEVEL OF EVIDENCE : [23508540] OBJECTIVE To compare success rates between anterior colporrhaphy and abdominal paravaginal defect repair for treatment of anterior vaginal wall prolapse . METHODS This was a prospect i ve r and omized controlled trial comparing anterior colporrhaphy plus polyglactin 910 mesh ( vaginal ) to paravaginal defect repair ( abdominal ) in women with symptomatic anterior vaginal wall prolapse . Pelvic organ prolapse quantification staging ( POP-Q ) , pelvic floor distress inventory , pelvic floor impact question naire , and pelvic organ prolapse/urinary incontinence sexual question naires were administered pre and post-operatively . Women were followed up to 2 years . The primary outcome was anterior POP-Q stage , with failure defined as ≥stage II . RESULTS We enrolled 70 patients , 35 in each group . Demographic and most peri-operative characteristics were similar between the groups . Mean anterior vaginal wall prolapse repair time ( 39 min ) was shorter for vaginal versus abdominal repair ( 60 min ; P < 0.001 ) , with more concurrent hysterectomies in the vaginal ( 71 % ) versus abdominal group ( 42 % ) , P = 0.01 . At 2 years , objective failure rates for the vaginal and abdominal groups were 32 % and 40 % , respectively , P = 0.56 . Subjective failure rates were lower and similar for both groups . Patient satisfaction rates were 88 % for the vaginal and 73 % for the abdominal group , P = 0.11 . Quality of life question naires showed significant improvement from baseline but no difference between the groups ( P = 0.12 ) . CONCLUSIONS At 2 years follow-up , anterior colporrhaphy with polyglactin 910 mesh and abdominal paravaginal defect repair have similar success rates , with most objective failures being asymptomatic [22453316] Objectives The goals of this study were to assess the effect of a st and ardized postoperative bowel regimen of over-the-counter medications on ( 1 ) time to first bowel movement ( BM ) and ( 2 ) pain level associated with first BM in subjects undergoing minimally invasive urogynecologic surgery . Methods Eligible patients scheduled to undergo minimally invasive urogynecologic surgery were offered participation . Enrolled subjects were r and omized by computerized schedule . Demographic and perioperative data were collected . Subjects completed a vali date d question naire preoperatively and postoperatively assessing preexisting constipation , frequency and consistency of bowel movements , use of pain medications , mean daily pain level ( using visual analog scale ) , stool consistency , and pain associated with first postoperative bowel movement . The control group was instructed to take docusate sodium twice daily postoperatively . The treatment group took docusate sodium plus Miralax , fiber wafers , and bisacodyl suppositories as directed by protocol . Wilcoxon or t testing was used to compare continuous variables ; & khgr;2 testing was used for categorical relationships , and backward-elimination multiple regression was used to assess independent effects . Results Seventy-two subjects were enrolled and r and omized . Twelve subjects withdrew , leaving 60 ( 30 per group ) completing the study . There were no statistically significant differences between groups in baseline characteristics . Mean ( SD ) age was 63 ( 9 ) years for the control group and 58 ( 10 ) for the study group ( P = 0.06 ) . Mean pelvic organ prolapse stage was III in each group . The mean ( SD ) operating room time was 198 ( 65 ) minutes for the controls and 216 ( 74 ) for the study subjects . Sixty-five percent underwent robot-assisted surgery ( 50 % hysterectomy and 63 % sacrocolpopexy ) . Ninety-eight percent of surgeries were performed under general anesthesia . Before adjustment , the mean ( SD ) time to first BM was 77 ( 24 ) hours in controls versus 64 ( 21 ) in the study patients ( P = 0.03 ) . Using multiple regression , baseline frequency of defecation ( 1–2 BMs/wk ) was directly associated with the time to first BM ( added 25.2 hours ; P = 0.009 ) and being in the study group was inversely associated ( first BM , 11.7 hours sooner ; P = 0.04 ) . No other variables were retained . There was no difference in pain associated with first postoperative BM ( visual analog scale , 3.6 ( 3.2 ) vs 3.7 ( 2.8 ) ; P = 0.98 ) , but those with prior complaints of vaginal or rectal splinting had higher pain scores ( 1.9 and 2.8 points higher , respectively ; P = 0.04 for both ) . There was a trend toward higher pain scores with higher postoperative daily narcotic intake ( P = 0.06 ) . No other variables were retained . There was a significant difference in recorded compliance between control versus study regimens ( 94 % vs 81 % , respectively ; P = 0.002 ) . Conclusions Mean time to first postoperative BM after minimally invasive urogynecologic surgery is more than 3.5 days with use of docusate sodium alone and is only slightly shorter when combination therapy is used . First BM after surgery is considered to be painful despite the use of medications . Future studies targeting postoperative discomfort/pain with defecation could target preoperative bowel regimens or more aggressive postoperative interventions . Regimens should remain simple to increase compliance [18639302] PURPOSE We evaluated the impact of Burch colposuspension as an anti-incontinence measure in patients with urinary incontinence undergoing abdominal surgery for pelvic organ prolapse repair . MATERIAL S AND METHODS A total of 47 women with pelvic organ prolapse and urinary incontinence were r and omly assigned to abdominal pelvic organ prolapse repair and concomitant Burch colposuspension ( 24 patients , group A ) or pelvic organ prolapse repair alone without an anti-incontinence procedure ( 23 patients , group B ) . They were followed up at 3 , 6 and 9 months after surgery , and then annually . The primary outcome measures were anatomical outcome and changes in incontinence status as indicated by a bladder diary , the number of daily pads and the stress test . Secondary end points were changes in subjective symptoms and quality of life as measured by the Urogenital Distress Inventory and the Incontinence Impact Question naire . RESULTS In group A 13 of 24 patients ( 54.2 % ) were still incontinent after surgery compared with 9 of 23 ( 39.1 % ) in group B. The intragroup difference was significant ( group A p = 0.003 , group B p = 0.0001 ) , but there was no significant intergroup difference ( p = 0.459 for A vs B ) . No significant intergroup difference emerged in anatomical outcome . Urogenital Distress Inventory and Incontinence Impact Question naire scores improved in both groups ( p = 0.0001 ) but the intergroup difference was not significant in either question naire ( p = 0.769 and p = 0.327 , respectively ) . CONCLUSIONS Burch colposuspension does not provide any additional benefit in pelvic organ prolapse repair in patients with urinary incontinence [19940978] Introduction and hypothesisThis study aims to compare the result of an incontinence procedure performed at the time of prolapse repair or 3 months later in women with pelvic organ prolapse ( POP ) and stress urinary incontinence ( SUI ) . Methods In a multicenter prospect i ve r and omized trial , women with POP and SUI were r and omized to have a tension-free vaginal tape ( TVT ) at the time of prolapse repair ( n = 87 ; group I ) or 3 months later ( n = 94 ; group II ) . Women in group II were evaluated for SUI 3 months after the prolapse repair . Those with confirmed SUI had a TVT performed ( n = 53 ) . The main evaluation of all women was 1 year after the last surgery . Results On-treatment analysis result ed in 95 % cure of SUI in group I and 89 % in group II ( p = 0.12 ) . Twenty-seven percent were cured after prolapse surgery alone . Conclusions No differences were found between the two treatment strategies , but almost one third of women were cured of SUI by prolapse surgery alone [19731311] AIMS To investigate the urodynamic effects of anterior vaginal wall prolapse surgery using either trocar guided transvaginal mesh or colporraphy . METHODS A prospect i ve , r and omized multicenter trial enrolling 50 patients : 27 underwent anterior colporrhaphy and 23 anterior trocar guided transvaginal mesh . Urodynamic assessment was performed pre- and two months postoperatively . RESULTS De novo stress urinary incontinence was significantly more common after trocar guided transvaginal mesh surgery compared to colporraphy . In comparison to baseline urodynamics , transvaginal mesh surgery result ed in a significant decrease in maximal urethral closing pressures ( MUCP ) whereas conventional anterior colporraphy had no significant effect on urodynamic parameters . CONCLUSION Trocar guided transvaginal mesh of anterior vaginal wall prolapse results in a lowering of MUCPs and increases the risk for de novo stress urinary incontinence compared to colporraphy [10799192] PURPOSE We prospect ively compared transvaginal antimicrobial mesh ( MycroMesh * ) and anterior vaginal wall slings using an outcomes analysis . MATERIAL S AND METHODS Between August 1997 and November 1998 we implanted transvaginal slings in 40 consecutive women r and omized to a synthetic mesh ( 20 ) or vaginal wall ( 20 ) group . All patients had documented stress urinary incontinence on preoperative urodynamics . We prospect ively compared postoperative outcomes data obtained from pelvic examinations , cough stress test , cotton swab test and vali date d patient question naires using a visual analog scale . RESULTS Complete followup was available in all patients . Mean followup was 22 months ( range 12 to 27 ) . Stress incontinence was cured in 95 % of the mesh and 70 % of the vaginal wall group , and pelvic prolapse was cured in 100 % and 95 % , respectively . Transient de novo urge incontinence was noted in 12.5 % of the mesh and 14.3 % of the vaginal wall group . Mean postoperative cotton swab angle during Valsalva 's maneuver was 20 and 45 degrees for the mesh and vaginal wall groups , respectively . The incidence of urinary retention and tissue erosion was 0 % for both groups . The satisfaction rate was 100 % and 80 % for the mesh and vaginal wall groups , respectively . CONCLUSIONS The antimicrobial MycroMesh sling was superior to the vaginal wall sling for correction of stress incontinence and pelvic prolapse with comparatively low morbidity [11408853] OBJECTIVE Our aim was to evaluate the efficacy of polyglactin 910 mesh in preventing recurrent cystoceles and rectoceles . STUDY DESIGN In a prospect i ve , r and omized , controlled trial , patients undergoing vaginal reconstructive surgery with cystoceles to the hymenal ring and beyond were r and omly selected to undergo anterior and posterior colporrhaphy with or without polyglactin 910 mesh reinforcement . Results were evaluated preoperatively and at 2 , 6 , 12 , and 52 weeks postoperatively . RESULTS A total of 161 women were r and omly selected for this study . One woman was excluded at the time of surgery , and 17 women were lost to follow-up . Eighty women received mesh , and 80 did not . Both groups were found to be equivalent with respect to age , parity , concomitant surgery , and menopausal and hormone replacement status . Preoperatively 49 women had a central cystocele to the hymenal ring and 111 women had cystoceles beyond the introitus ; 91 women had a rectocele to the mid-vaginal plane , 31 to the hymenal ring , and 22 beyond the introitus . After 1 year , 30 ( 43 % ) of 70 subjects without mesh and 18 ( 25 % ) of 73 subjects with mesh had recurrent cystoceles beyond the mid-vaginal plane ( P = .02 ) . Eight women without mesh and 2 women with mesh had recurrent cystoceles to the hymenal ring ( P = .04 ) . No recurrent cystoceles beyond the hymenal ring occurred in either group . Multivariate logistic regression analysis showed concurrent slings to be associated with significantly fewer recurrent cystoceles ( odds ratio , 0.32 ; P = .005 ) , whereas the presence of mesh remained significantly predictive of fewer cystocele recurrences in this analysis . Thirteen recurrent rectoceles were noted 1 year postoperatively , with no differences between groups . CONCLUSION Polyglactin 910 mesh was found to be useful in the prevention of recurrent cystoceles [23916584] OBJECTIVE To compare the anatomical and functional results of traditional anterior colporrhaphy and polypropylene mesh surgery in cystocele treatment . STUDY DESIGN Prospect i ve study conducted in the Urogynecology Clinic of Etlik Zubeyde Hanim Maternity and Women 's Health Teaching and Research Hospital between June 2006 and February 2007 . Forty patients with stage II and III cystocele according to the Pelvic Organ Prolapse Quantification system were allocated by a computer programme to conventional or mesh surgery . Twenty patients each underwent anterior colporrhaphy ( group I ) or polypropylene mesh ( Sofradim ( ® ) , Parieten ) surgery ( group II ) . Both groups were followed for 12 months . RESULTS At the end of the 12th month , anatomical cure rates were 15/20 ( 75 % ) and 19/20 ( 95 % ) in groups I and II , respectively , and the difference between the two groups was statistically significant ( p<0.05 ) . De novo stress urinary incontinence developed in one patient in group I. Mesh erosion developed postoperatively in three cases ( 15 % ) . CONCLUSION In terms of anatomical cure rates , polypropylene mesh surgery was the more successful treatment option when compared with anterior colporrhaphy at the end of 1 year follow-up [28052810] BACKGROUND The use of mesh in prolapse surgery is controversial , leading to a number of enquiries into its safety and efficacy . OBJECTIVE To compare synthetic non-absorbable mesh inlay , biological graft and mesh kit with a st and ard repair in terms of clinical effectiveness , adverse effects , quality of life ( QoL ) , costs and cost-effectiveness . DESIGN Two r and omised controlled trials within a comprehensive cohort ( CC ) study . Allocation was by a remote web-based r and omisation system in a 1 :1 : 1 ratio ( Primary trial ) or 1 : 1 : 2 ratio ( Secondary trial ) , and was minimised on age , type of prolapse repair planned , need for a concomitant continence procedure , need for a concomitant upper vaginal prolapse procedure and surgeon . Participants and outcome assessors were blinded to r and omisation ; participants were unblinded if they requested the information . Surgeons were not blinded to allocated procedure . SETTING Thirty-five UK hospitals . PARTICIPANTS Primary study : 2474 women in the analysis ( including 1348 r and omised ) having primary anterior or posterior prolapse surgery . Secondary study : 398 in the analysis ( including 154 r and omised ) having repeat anterior or posterior prolapse surgery . CC3 : 215 women having either uterine or vault prolapse repair . INTERVENTIONS Anterior or posterior repair alone , or with mesh inlay , biological graft or mesh kit . MAIN OUTCOME MEASURES Prolapse symptoms [ Pelvic Organ Prolapse Symptom Score ( POP-SS ) ] ; prolapse-specific QoL ; cost-effectiveness [ incremental cost per quality -adjusted life-year ( QALY ) ] . RESULTS Primary trials : adjusting for baseline and minimisation covariates , mean POP-SS was similar for each comparison { st and ard 5.4 [ st and ard deviation ( SD ) 5.5 ] vs. mesh 5.5 ( SD 5.1 ) , mean difference ( MD ) 0.00 , 95 % confidence interval ( CI ) -0.70 to 0.71 ; st and ard 5.5 ( SD 5.6 ) vs. graft 5.6 ( SD 5.6 ) , MD -0.15 , 95 % CI -0.93 to 0.63}. Serious non-mesh adverse effects rates were similar between the groups in year 1 [ st and ard 7.2 % vs. mesh 7.8 % , risk ratio ( RR ) 1.08 , 95 % CI 0.68 to 1.72 ; st and ard 6.3 % vs. graft 9.8 % , RR 1.57 , 95 % CI 0.95 to 2.59 ] . There were no statistically significant differences between groups in any other outcome measure . The cumulative mesh complication rates over 2 years were 2 of 430 ( 0.5 % ) for st and ard repair ( trial 1 ) , 46 of 435 ( 10.6 % ) for mesh inlay and 2 of 368 ( 0.5 % ) for biological graft . The CC findings were comparable . Incremental costs were £ 363 ( 95 % CI -£32 to £ 758 ) and £ 565 ( 95 % CI £ 180 to £ 950 ) for mesh and graft vs. st and ard , respectively . Incremental QALYs were 0.071 ( 95 % CI -0.004 to 0.145 ) and 0.039 ( 95 % CI -0.041 to 0.120 ) for mesh and graft vs. st and ard , respectively . A Markov decision model extrapolating trial results over 5 years showed st and ard repair had the highest probability of cost-effectiveness , but results were surrounded by considerable uncertainty . Secondary trials : there were no statistically significant differences between the r and omised groups in any outcome measure , but the sample size was too small to be conclusive . The cumulative mesh complication rates over 2 years were 7 of 52 ( 13.5 % ) for mesh inlay and 4 of 46 ( 8.7 % ) for mesh kit , with no mesh exposures for st and ard repair . CONCLUSIONS In women who were having primary repairs , there was evidence of no benefit from the use of mesh inlay or biological graft compared with st and ard repair in terms of efficacy , QoL or adverse effects ( other than mesh complications ) in the short term . The Secondary trials were too small to provide conclusive results . LIMITATIONS Women in the Primary trials included some with a previous repair in another compartment . Follow-up is vital to identify any long-term potential benefits and serious adverse effects . FUTURE WORK Long-term follow-up to at least 6 years after surgery is ongoing to identify recurrence rates , need for further prolapse surgery , adverse effects and cost-effectiveness . TRIAI REGISTRATION Current Controlled Trials IS RCT N60695184 . FUNDING This project was funded by the National Institute for Health Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol . 20 , No. 95 . See the NIHR Journals Library website for further project information [22082789] OBJECTIVE We wished to determine the feasibility of a single-centre r and omized controlled trial to investigate whether avoiding cystocele plication in women undergoing transvaginal repair of cystocele decreases the need for catheterization beyond the second postoperative day . METHODS Patients undergoing transvaginal repair of cystocele were r and omly assigned to either have or not have plication sutures during their procedure . We assessed the success of recruitment , physician acceptability , and adherence to protocol , and we also assessed the need for catheterization beyond the second postoperative day . RESULTS Twenty-two women were r and omized ( a recruitment rate of 85 % ) , and participating surgeons did not feel that one surgical technique was superior to the other . There were no protocol violations after r and omization . No cases of postoperative voiding dysfunction were identified . CONCLUSION A multicentre r and omized controlled trial is required to determine the short-term and long-term risks and benefits of avoiding plication sutures in women undergoing transvaginal repair of cystocele . If patients and physicians support the study protocol , conducting such a trial is feasible [21627429] Summary The effects at 2 years of polyglactin ( Vicryl ) mesh inlay and polydioxanone ( PDS ) or polyglactin ( Vicryl ) suture material on prolapse symptoms , urinary , bowel , sexual function and prolapse related Quality -of-Life ( QoL ) in women undergoing pelvic organ prolapse surgery were evaluated in a r and omised controlled trial with a 2 × 2 factorial design of Vicryl mesh ( n = 32 ) or not ( n = 34 ) and PDS ( n = 33 ) or Vicryl suture ( n = 33 ) . The response rate at 2 years was 82 % . There were no differences in the prolapse symptom scores between the r and omised groups . Prolapse-related QoL score ( mean difference : 2.05 , 95 % CI 0.19–3.91 ) and urinary incontinence score ( mean difference : 2.56 , 95 % CI 0.02–5.11 ) were significantly lower ( better ) in women who had Vicryl compared with PDS sutures . The apparent superiority of the prolapse-related QoL and urinary incontinence scores in women using Vicryl suture material ( vs PDS ) needs to be confirmed in a larger trial [26825408] Objective Placement of vaginal packing after pelvic reconstructive surgery is common ; however , little evidence exists to support the practice . Furthermore , patients have reported discomfort from the packs . We describe pain and satisfaction in women treated with and without vaginal packing . Methods This institutional review board – approved r and omized-controlled trial enrolled patients undergoing vaginal hysterectomy with prolapse repairs . The primary outcome was visual analog scales ( VASs ) for pain on postoperative day 1 . Allocation to “ packing ” ( “ P ” ) or “ no-packing ” ( “ NP ” ) arms occurred intraoperatively at the end of surgery . Visual analog scales regarding pain and satisfaction were completed early on postoperative day 1 before packing removal . Visual analog scale scores for pain , satisfaction , and bother attributable to packing were recorded before discharge . All packing and perineal pads were weighed to calculate a “ postoperative vaginal blood loss . ” Perioperative data were collected from the hospital record . Our sample size estimation required 74 subjects . Results Ninety-three women were enrolled . After exclusions , 77 were r and omized ( P , 37 ; NP , 40 ) . No differences were found in surgical information , hemoglobin levels , or narcotic use between groups . However , “ postoperative vaginal blood loss ” was greater in packed subjects ( P < 0.001 ) . Visual analog scale scores for pain before removal of packing ( P , 41.6 vs NP , 46.3 ; P = 0.43 ] and before discharge ( P , 35.0 vs NP , 40.0 ; P = 0.43 ] were not significantly different between treatment arms . Likewise , VAS scores for satisfaction before removal of packing ( P , 81.0 vs NP , 90.0 ; P = 0.08 ] and before discharge ( P , 90.0 vs NP , 90.5 ; P = 0.60 ] were not significantly different . Packed patients noted lower nursing verbal pain scores ( P = 0.04 ) and used less ketorolac ( P = 0.01 ) . Bother from packing was low overall . Conclusions Although there was no difference based on VAS , women receiving vaginal packing had lower nursing documented pain and used less ketorolac than packed women . Vaginal packing may provide benefit and can remain part of the surgical practice [26032041] OBJECTIVE Dexamethasone is a corticosteroid with minimal side effects that may improve quality of recovery . We sought to evaluate st and ard use of this medication prior to vaginal reconstructive surgery . STUDY DESIGN This was a double-blind , r and omized , placebo-controlled trial of women undergoing vaginal reconstructive surgery for pelvic organ prolapse . Patients scheduled for an intraperitoneal vaginal vault suspension , with general anesthesia and an overnight stay , were enrolled . The intervention arm received dexamethasone 60 minutes prior to surgery , and controls received placebo . Postoperative pain medications , antiemetics , and voiding trials were st and ardized . Our primary outcome was the difference in Quality of Recovery ( QoR-40 ) scores on postoperative day 1 . Secondary measures included Postoperative Nausea and Vomiting Intensity scores , and visual analog scales for nausea/vomiting , and pain . Our power calculation demonstrated 31 subjects in each group would be necessary to document difference in QoR-40 scores ; to allow for attrition , a goal of 74 subjects was set . RESULTS Seventy-four women were enrolled and r and omized . Two withdrew , 9 were excluded , and 63 were analyzed ( 36 placebo , 27 dexamethasone ) . The mean age was 63 years . No significant differences were noted among demographics other than American Society for Anesthesiologists class ; there were greater numbers of dexamethasone subjects that were class 3 ( 5 vs 11 ; P = .030 ) . Postoperatively , more patients in the placebo group required promethazine as a rescue antiemetic for control of their nausea/vomiting ( 11 vs 2 ; P = .029 ) . Placebo subjects also failed their voiding trials more frequently , which remained following a logistic regression controlling for suburethral sling ( 30 vs 15 ; P = .037 ) . Regarding the QoR-40 following surgery , the emotional state domain declined less in dexamethasone patients ( -14.3 , interquartile range [ IQR ] , 16.8 vs -4.6 , IQR , 20.1 ; P = .042 ) , indicating better symptoms . Whereas pain scales were similar , the visual analog scales for nausea/vomiting was lower in dexamethasone subjects ( 0.7 ; IQR , 4.1 vs 0.4 ; IQR , 1.4 ; P = .042 ) . Postoperative Nausea and Vomiting Intensity scores were not significantly different ; nevertheless , twice as many placebo subjects had severe range symptoms ( 4 vs 2 ; P = .47 ) . No adverse effects from the dexamethasone were noted . CONCLUSION Use of dexamethasone prior to vaginal reconstructive surgery was associated with less nausea/vomiting and need for antiemetics as well as greater success with voiding trials . Furthermore , quality of recovery was enhanced , suggesting use of dexamethasone should be considered for these patients [23812462] OBJECTIVE : To compare rates of de novo dyspareunia in women with and without vaginal dilator use after posterior colporrhaphy . METHODS : This r and omized controlled trial included sexually active patients with prolapse and no bothersome baseline dyspareunia undergoing posterior colporrhaphy . Patients were r and omized to daily vaginal dilator use from postoperative weeks 4 through 8 or to no dilator use . Pelvic organ prolapse quantification examination and vaginal caliber were measured at baseline , 8 weeks , and 6 months postoperatively . Sexual function was evaluated at baseline , 3 months , and 6 months postoperatively using the Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Question naire-12 . Participants completed a Patient Global Impression of Improvement at 3 months and 6 months postoperatively . RESULTS : Sixty patients were r and omized : 30 in the dilator group and 30 in the control group . There were no differences in baseline characteristics and postoperative vaginal caliber between groups . At 3 months , 9.5 % of patients reported de novo dyspareunia in the dilator group compared with 19.2 % of control patients ( P=.44 ) . At 6 months , 12.5 % of patients in the dilator group reported de novo dyspareunia compared with 3.8 % of control patients ( P=.34 ) . There was a 13 % loss-to-follow-up rate , and therefore we did not meet appropriate power to detect a difference . There were no differences in overall sexual function or Patient Global Impression of Improvement scores between groups at 3 months and 6 months . CONCLUSION : There were no significant differences in de novo dyspareunia rates , overall postoperative sexual function scores , or global improvement scores between those using vaginal dilators compared with control patients . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT01299363 . LEVEL OF EVIDENCE : [19781044] In a multicentre r and omised , unblinded patient preference pilot trial to assess the feasibility of a definitive r and omised trial comparing colposuspension with tension‐free vaginal tape ( TVT ) plus anterior repair in women with incontinence and prolapse , we found that 31 of 56 eligible women agreed to participate ( 55 % ) . Recruitment was more successful face to face ( 87 % ) than by letter ( 16 % ) . Only four of our women agreed to be r and omised , 21 ( 68 % ) chose anterior repair + TVT and six ( 19 % ) chose colposuspension . This study demonstrates the importance of pilot work for complex trials to identify issues likely to adversely affect recruitment [27687468] STUDY OBJECTIVE Compare the effectiveness of nerve stimulator-guided pudendal nerve block ( PNB ) vs general anesthesia ( GA ) for anterior and posterior ( AP ) colporrhaphy in terms of pain relief and analgesic consumption within 24 and 48 hours postoperatively . DESIGN Prospect i ve r and omized trial . PATIENTS Fifty-seven patients whose ages ranged between 20 and 53 years scheduled to undergo AP colporrhaphy due to the presence of cystorectocele . INTERVENTIONS Patients were r and omly assigned into 2 groups receiving either nerve stimulator-guided PNB ( n = 28 ) or GA ( n = 29 ) . A total volume of 0.7 mL/kg of the local anesthetic mixture was injected at 4 sites . MAIN RESULTS Both groups were similar with respect to age , weight , height , and surgery duration . There was a significant difference in average pain scores within the first and second postoperative days ( P values = .005 and .004 , respectively ) . Total analgesic consumption ( ketoprofen and tramadol ) was significantly lower in the PNB within the first ( P values = .018 and .010 ) and second postoperative days ( P values = .041 and .011 ) , respectively . Return to normal daily activity was significantly ( P < .0001 ) shorter in the PNB group compared with the GA group ( 3.6 days vs 12.2 days ) . A total of 71.4 % of the patients in the PNB group were satisfied compared with 27.8 % in the GA group ( P < .0001 ) . Surgeon satisfaction was significantly higher in the PNB group ( 82.1 % vs 34.5 % , P < .0001 ) . CONCLUSION This r and omized controlled trial demonstrated that nerve stimulator-guided PNB could be used as an alternative to GA for AP repair of stages I and II prolapse because it is associated with less postoperative pain and analgesic consumption , in addition to shorter duration of recovery [29030992] R and omised trials and their syntheses in meta‐analyses offer a unique opportunity to assess the frequency and severity of adverse reactions

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### Context: [15902172] OBJECTIVE This study was undertaken to compare outcomes after anterior colporrhaphy with and without a solvent dehydrated cadaveric fascia lata graft . STUDY DESIGN A total of 162 women were enrolled in a prospect i ve , r and omized trial that evaluated the impact of a solvent dehydrated cadaveric fascia lata patch on recurrent anterior vaginal prolapse . Subjects were r and omly assigned to st and ard colporrhaphy with or without a patch . Before and after surgery , subjects were evaluated by both the Baden-Walker and pelvic organ prolapse quantification systems . " Failure " was defined as stage II anterior wall prolapse or worse . RESULTS Of 154 women r and omly assigned ( 76 patch : 78 no patch ) , all underwent surgery and 153 ( 99 % ) returned for follow-up . Sixteen women ( 21 % ) in the patch group and 23 ( 29 % ) in the control group experienced recurrent anterior vaginal wall prolapse ( P = .229 ) . Only 26 % of all recurrences were symptomatic . Concomitant transvaginal Cooper 's ligament sling procedures were associated with a dramatic decrease in recurrent prolapse ( odds ratio [ OR ] 0.105 , P < .0001 ) . CONCLUSION Solvent dehydrated fascia lata as a barrier does not decrease recurrent prolapse after anterior colporrhaphy . Transvaginal bladder neck slings were associated with a significant reduction in the risk of recurrent anterior wall prolapse [20178542] AIMS Routine catheterization following vaginal prolapse surgery has advantages like prevention of postoperative retention of urine and prevention of any adverse effect on surgical outcome . However , it increases the risk of urinary tract infection ( UTI ) , prevent early ambulation and prolong hospital stay . This r and omized controlled trial was done on how best to minimize catheter related complication after prolapse surgery . METHODS 200 patients planned for vaginal prolapse surgery were recruited and r and omized into two groups . In group I and group II catheter was removed on 1(st ) and 4(th ) post operative day , respectively . After removal , if patient could not void or when residual urine volume exceeds 150 mL , recatheterisation was done for another three days . Sample of urine was sent for culture during catheter removal . RESULTS Age , parity , type of surgery and mean operation time did not differ significantly between the two groups . Mean duration of catheterization was significantly shorter ( 1.64 vs 4.09 ) and mean duration of hospital stay was shorter by 1.2 days , in first group . However a significantly higher number of retention of urine or residual urine more than 150 mL was found in the early removal group ( OR 3.10 ) but lesser chance of development of urinary tract infection ( OR 0.10 ) . CONCLUSIONS The early removal of catheter seems more advantageous , with lower incidence of urinary tract infection and a shorter hospital stay although associated with an increased risk of recatheterisation [28113069] OBJECTIVE It is unclear if any catheterisation is necessary after vaginal surgery for pelvic organ prolapse . The aim of this study was to determine if indwelling catheterisation is necessary after these procedures . STUDY DESIGN A r and omised controlled trial of immediate post-operative removal of catheter compared to a suprapubic catheter ( SPC ) after vaginal prolapse surgery . In the Suprapubic group the catheter was left on free drainage until a voiding trial was commenced at 48h . Women in the immediate removal group underwent in/out catheterisation only if they had not voided by 8h after surgery to ensure the bladder did not over-distend . RESULTS 55 % ( n=17 ) of patients in the immediate removal group did not require catheterisation postoperatively . A further 13 ( 42 % ) patients only required one in/out catheterisation 8h post operatively . In the immediate removal group duration of catheterisation was significantly shorter ( median 0h , IQR 0 - 8h , range 0 - 16h ) vs ( 6days ( IQR 2 - 8days , range 2 - 19h ) p=0.001 ) . The duration of hospital stay ( 7days ( range 3 - 16 ) vs. 9 ( range 3 - 27 ) p=0.014 ) , day of first mobilisation ( Day 1 , range 0 - 2 , vs. Day 2 , range 1 - 4 , p=0.001 ) , and rate of Symptomatic bacturia ( 16 % vs. 52 % , p<0.01 ) were all significantly better with immediate catheter removal . CONCLUSIONS After vaginal surgery for pelvic organ prolapse , the majority of patients do not require extended catheterisation . Early removal of a catheter reduces urinary tract infection and significantly decreases hospital stay . Such a policy should result in improved patient satisfaction and reduced hospital costs [28010989] BACKGROUND The use of transvaginal mesh and biological graft material in prolapse surgery is controversial and has led to a number of enquiries into their safety and efficacy . Existing trials of these augmentations are individually too small to be conclusive . We aim ed to compare the outcomes of prolapse repair involving either synthetic mesh inlays or biological grafts against st and ard repair in women . METHODS We did two pragmatic , parallel-group , multicentre , r and omised controlled trials for our study ( PROSPECT [ PROlapse Surgery : Pragmatic Evaluation and r and omised Controlled Trials ] ) in 35 centres ( a mix of secondary and tertiary referral hospitals ) in the UK . We recruited women undergoing primary transvaginal anterior or posterior compartment prolapse surgery by 65 gynaecological surgeons in these centres . We r and omly assigned participants by a remote web-based r and omisation system to one of the two trials : comparing st and ard ( native tissue ) repair alone with st and ard repair augmented with either synthetic mesh ( the mesh trial ) or biological graft ( the graft trial ) . We assigned women ( 1:1:1 or 1:1 ) within three strata : assigned to one of the three treatment options , comparison of st and ard repair with mesh , and comparison of st and ard repair with graft . Participants , ward staff , and outcome assessors were masked to r and omisation where possible ; masking was obviously not possible for the surgeon . Follow-up was for 2 years after the surgery ; the primary outcomes , measured at 1 year and 2 years , were participant-reported prolapse symptoms ( i.e. the Pelvic Organ Prolapse Symptom Score [ POP-SS ] ) and condition-specific ( ie , prolapse-related ) quality -of-life scores , analysed in the modified intention-to-treat population . This trial is registered as an International St and ard R and omised Controlled Trial , number IS RCT N60695184 . FINDINGS Between Jan 8 , 2010 , and Aug 30 , 2013 , we r and omly allocated 1352 women to treatment , of whom 1348 were included in the analysis . 865 women were included in the mesh trial ( 430 to st and ard repair alone , 435 to mesh augmentation ) and 735 were included in the graft trial ( 367 to st and ard repair alone , 368 to graft augmentation ) . Because the analyses were carried out separately for each trial ( mesh trial and graft trial ) some women in the st and ard repair arm assigned to all treatment options were included in the st and ard repair group of both trials . 23 of these women did not receive any surgery ( 15 in the mesh trial , 13 in the graft trial ; five were included in both trials ) and were included in the baseline analyses only . Mean POP-SS at 1 year did not differ substantially between comparisons ( st and ard 5·4 [ SD 5·5 ] vs mesh 5·5 [ 5·1 ] , mean difference 0·00 , 95 % CI -0·70 to 0·71 ; p=0·99 ; st and ard 5·5 [ SD 5·6 ] vs graft 5·6 [ 5·6 ] ; mean difference -0·15 , -0·93 to 0·63 ; p=0·71 ) . Mean prolapse-related quality -of-life scores also did not differ between groups at 1 year ( st and ard 2·0 [ SD 2·7 ] vs mesh 2·2 [ 2·7 ] , mean difference 0·13 , 95 % CI -0·25 to 0·51 ; p=0·50 ; st and ard 2·2 [ SD 2·8 ] vs graft 2·4 [ 2·9 ] ; mean difference 0·13 , -0·30 to 0·56 ; p=0·54 ) . Mean POP-SS at 2 years were : st and ard 4·9 ( SD 5·1 ) versus mesh 5·3 ( 5·1 ) , mean difference 0·32 , 95 % CI -0·39 to 1·03 ; p=0·37 ; st and ard 4·9 ( SD 5·1 ) versus graft 5·5 ( 5·7 ) ; mean difference 0·32 , -0·48 to 1·12 ; p=0·43 . Prolapse-related quality -of-life scores at 2 years were : st and ard 1·9 ( SD 2·5 ) versus mesh 2·2 ( 2·6 ) , mean difference 0·15 , 95 % CI -0·23 to 0·54 ; p=0·44 ; st and ard 2·0 ( 2·5 ) versus graft 2·2 ( 2·8 ) ; mean difference 0·10 , -0·33 to 0·52 ; p=0·66 . Serious adverse events such as infection , urinary retention , or dyspareunia or other pain , excluding mesh complications , occurred with similar frequency in the groups over 1 year ( mesh trial : 31/430 [ 7 % ] with st and ard repair vs 34/435 [ 8 % ] with mesh , risk ratio [ RR ] 1·08 , 95 % CI 0·68 to 1·72 ; p=0·73 ; graft trial : 23/367 [ 6 % ] with st and ard repair vs 36/368 [ 10 % ] with graft , RR 1·57 , 0·95 to 2·59 ; p=0·08 ) . The cumulative number of women with a mesh complication over 2 years in women actually exposed to synthetic mesh was 51 ( 12 % ) of 434 . INTERPRETATION Augmentation of a vaginal repair with mesh or graft material did not improve women 's outcomes in terms of effectiveness , quality of life , adverse effects , or any other outcome in the short term , but more than one in ten women had a mesh complication . Therefore , follow-up is vital to identify any longer-term potential benefits and serious adverse effects of mesh or graft reinforcement in vaginal prolapse surgery . FUNDING UK National Institute of Health Research [29607558] OBJECTIVE Twin-twin transfusion syndrome ( TTTS ) is associated with significant mortality and morbidity . Potential treatments for the condition require robust evaluation . The aim of this study was to evaluate outcome reporting across observational studies and r and omized controlled trials assessing treatments for TTTS . METHODS Cochrane Central Register of Controlled Trials , EMBASE and MEDLINE were search ed from inception to August 2016 . Observational studies and r and omized controlled trials reporting outcome following treatment for TTTS in monochorionic-diamniotic twin pregnancy and monochorionic-triamniotic or dichorionic-triamniotic triplet pregnancy were included . Outcome reporting was systematic ally extracted and categorized . RESULTS Six r and omized trials and 94 observational studies were included , reporting data from 20 071 maternal participants and 3199 children . Six different treatments were evaluated . Included studies reported 62 different outcomes , including six fetal , seven offspring mortality , 25 neonatal , six early childhood and 18 maternal/operative outcomes . Outcomes were reported inconsistently across trials . For example , when considering offspring mortality , 31 ( 31 % ) studies reported live birth , 31 ( 31 % ) reported intrauterine death , 49 ( 49 % ) reported neonatal mortality and 17 ( 17 % ) reported perinatal mortality . Four ( 4 % ) studies reported respiratory distress syndrome . Only 19 ( 19 % ) studies were design ed for long-term follow-up and 11 ( 11 % ) of these reported cerebral palsy . CONCLUSIONS Studies evaluating treatments for TTTS have often neglected to report clinical ly important outcomes , especially neonatal morbidity outcomes , and most are not design ed for long-term follow-up . The development of a core outcome set could help st and ardize outcome collection and reporting in TTTS studies . Copyright © 2018 ISUOG . Published by John Wiley & Sons [25305357] PURPOSE We compared the efficacy and safety of anterior colporrhaphy with transvaginal polypropylene mesh insertion for anterior vaginal wall prolapse at medium term followup . MATERIAL S AND METHODS In this prospect i ve , r and omized , controlled trial 100 women with stage II or greater anterior vaginal wall prolapse assessed by POP-Q were r and omized to anterior colporrhaphy ( controls ) or mesh insertion . Anatomical outcomes were assessed by POP-Q measurement and prolapse stage . Subjective outcomes and quality of life impact were evaluated by ICIQ question naires . We evaluated the procedure safety profile according to intraoperative complication rates throughout followup . RESULTS In the mesh and control groups 42 and 50 women completed the 24-month followup . Point Ba did not significantly differ between the groups at baseline but at 24-month followup it had significantly improved in the mesh group compared to controls . However , no difference was found between the groups when considering 2 cure criteria on prolapse stage and subjective parameters . Asymptomatic mesh exposure developed on the anterior vaginal wall prolapse in 7 patients ( 16.4 % ) in the mesh group . Minor mesh related complications consisted of mesh exposure , prepubic ecchymosis and groin pain , of which most were treated conservatively . Urinary retention was treated surgically . CONCLUSIONS Nazca TC ™ and anterior colporrhaphy provided good overall anatomical outcomes during a minimum 24-month followup . Vaginal and urinary symptoms , and quality of life improved postoperatively in each group . From the patient perspective Nazca TC did not show superior overall outcomes compared to anterior colporrhaphy performed with or without a retropubic sling [24402595] OBJECTIVE : To compare anatomical and patient-reported outcomes at 12 months postoperatively for women who had anterior compartment pelvic organ prolapse ( POP ) surgery using a repair augmented with porcine small intestine submucosa mesh ( Mesh Group ) compared with those who had a native tissue repair ( No Mesh Group ) . METHODS : This was a r and omized controlled trial with 12 months follow-up . The surgical procedure was identical in both groups except for the placement of intervening mesh . The primary outcome was anatomical “ cure ” ( Ba of −1 or less on Pelvic Organ Prolapse Quantification [ POP-Q ] ) . Secondary outcomes included POP-Q stage , patient-reported outcomes , and patient satisfaction . The study was powered to detect a 40 % difference at 80 % power ( & agr;=0.05 ) . RESULTS : Fifty-seven women were r and omized ( 28 to Mesh Group , 29 to No Mesh Group ) . Forty-five ( 79 % ) underwent concomitant surgery . At the 12-month follow-up , 56 % ( 15/27 ) in the Mesh Group and 61 % ( 17/28 ) in the No Mesh Group were considered cured ( relative risk 0.90 , 95 % confidence interval 0.52–1.54 ) . There were no significant differences between groups in recurrent or persistent prolapse ( 7 % in each group ) nor in patient-reported outcomes at 12 months . Pelvic girdle pain occurred in 4 of 27 in the Mesh Group and 3 of 28 in the No Mesh Group . CONCLUSION : No significant differences were observed in anatomical or patient-reported outcomes outcome parameters at 12 months after correction of symptomatic anterior POP by mesh or no mesh repair . In our study , porcine small intestine submucosa mesh did not confer additional benefit over a native tissue repair . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT0095544 . LEVEL OF EVEDIENCE : [15041988] OBJECTIVE The purpose of this study was to compare 2 anti-incontinence procedures in women who had severe genital prolapse and potential stress incontinence . STUDY DESIGN In addition to vaginal reconstructive surgery , 50 patients with stage II or higher anterior defect and a positive stress test result with prolapse reduction received either tension-free vaginal tape or plication of the endopelvic fascia . Preoperative evaluation included history , physical examination , stress test , and urodynamic assessment . Data were analyzed with the Student t test , the Fisher 's exact test , and the Wilcoxon signed-rank test . RESULTS The median follow-up time was similar for both groups , 26 and 24 months . Subjective ( 96 % vs 64 % ; P=.01 ) and objective ( 92 % vs 56 % ; P<.01 ) continence rates were higher after the tension-free vaginal tape procedure . Time for the resumption of spontaneous voiding , rates of urinary retention , or de novo urge incontinence were similar in the 2 groups . CONCLUSION Tension-free vaginal tape can be recommended for patients with prolapse and occult stress incontinence [23512113] Introduction and hypothesisTo compare the efficacy of a collagen-coated polypropylene mesh and anterior colporrhaphy in the treatment of stage 2 or more anterior vaginal wall prolapse . Methods Prospect i ve , r and omized , multicenter study conducted between April 2005 and December 2009 . The principal endpoint was the recurrence rate of stage 2 or more anterior vaginal wall prolapse 12 months after surgery . Secondary endpoints consisted of functional results and mesh-related morbidity . Results One hundred and forty-seven patients were included , r and omized and analyzed : 72 in the anterior colporrhaphy group and 75 in the mesh group . The anatomical success rate was significantly higher in the mesh group ( 89 % ) than in the colporrhaphy group ( 64 % ) ( p = 0.0006 ) . Anatomical and functional recurrence was also less frequent in the mesh group ( 31.3 % vs 52.2 % , p = 0.007 ) . Two patients ( 2.8 % ) were reoperated on in the colporrhaphy group for anterior vaginal wall prolapse recurrence . No significant difference was noted regarding minor complications . An erosion rate of 9.5 % was noted . De novo dyspareunia occurred in 1/14 patients in the colporrhaphy group and in 3/13 patients in the mesh group . An analysis of the quality of life question naires showed an overall improvement in both groups , with no statistical difference between them . Satisfaction rates were high in both groups ( 92 % in the colporrhaphy group and 96 % in the mesh group ) . Conclusion Trans-obturator Ugytex ® mesh used to treat anterior vaginal wall prolapse gives better 1-year anatomical results than traditional anterior colporrhaphy , but with small a increase in morbidity in the mesh group [25199496] Introduction and hypothesisThis trial aim ed to compare the outcomes of native vaginal tissue repair versus polypropylene mesh repair for the treatment of severe genital prolapse . Methods This multicenter r and omized trial included 184 women , with POP-Q stage 3 or 4 . They were r and omly assigned to undergo surgical treatment using native tissue repair ( n = 90 ) or synthetic mesh repair ( n = 94 ) . Native tissue repair surgery was performed according to site-specific defects , including sacrospinous ligament fixation for apical defects . Mesh repair ( Prolift ™ ) was performed in accordance with manufacturer recommendations . Hysterectomy was performed in all cases of uterine prolapse . Statistical tests were used to compare between-group and within-group differences before the surgery and at 1-year follow-up . We considered cure to have occurred when the POP-Q point evaluation was equal to or less than 0 and POP-Q point C better than or equal to half the total vaginal length ( TVL ) after 1 year . The patients answered the Prolapse Quality -of-Life Question naire ( PQoL ) and the Sexual Quotient Female Version ( QS-F ) question naire . Results Both groups were homogeneous preoperatively . There were no differences between the groups in operative time , complications or pain . At 1-year follow-up , anatomical cure rates were better in the mesh group in the anterior compartment ( p = 0.019 ) . Significant improvement in PQoL scores at 1-year follow up were observed in each group ; between-group comparisons of changes in PQoL scores revealed greater improvement in the mesh group . Conclusion Both techniques were effective . Anatomical efficacy was superior in the mesh group regarding the anterior compartment ; quality of life changes were also greater in the mesh group . Complications were significantly higher in the mesh group [3824218] Introduction and hypothesisThe aim of the study was to compare the efficacy and safety of transvaginal trocar-guided polypropylene mesh insertion with traditional colporrhaphy for treatment of anterior vaginal wall prolapse . Methods This is a r and omized controlled trial in which women with advanced anterior vaginal wall prolapse , at least stage II with Ba ≥ + 1 cm according to the Pelvic Organ Prolapse Quantification ( POP-Q ) classification , were r and omly assigned to have either anterior colporrhaphy ( n = 39 ) or repair using trocar-guided transvaginal mesh ( n = 40 ) . The primary outcome was objective cure rate of the anterior compartment ( point Ba ) assessed at the 12-month follow-up visit , with stages 0 and I defined as anatomical success . Secondary outcomes included quantification of other vaginal compartments ( POP-Q points ) , comparison of quality of life by the prolapse quality of life ( P-QOL ) question naire , and complication rate between the groups after 1 year . Study power was fixed as 80 % with 5 % cutoff point ( p < 0.05 ) for statistical significance . Results The groups were similar regarding demographic and clinical preoperative parameters . Anatomical success rates for colporrhaphy and repair with mesh placement groups were 56.4 vs 82.5 % ( 95 % confidence interval 0.068–0.54 ) , respectively , and the difference between the groups was statistically significant ( p = 0.018 ) . Similar total complication rates were observed in both groups , with tape exposure observed in 5 % of the patients . There was a significant improvement in all P-QOL domains as a result of both procedures ( p < 0.001 ) , but they were not distinct between groups ( p > 0.05 ) . Conclusions Trocar-guided transvaginal synthetic mesh for advanced anterior POP repair is associated with a higher anatomical success rate for the anterior compartment compared with traditional colporrhaphy . Quality of life equally improved after both techniques . However , the trial failed to detect differences in P-QOL scores and complication rates between the groups [25820682] AIMS To compare efficacy and safety of the traditional colporraphy and transvaginal polypropylene mesh for the treatment of advanced anterior vaginal prolapse according to different success criteria in two-year follow-up . METHODS In this r and omized controlled trial , women with anterior prolapse stage II or greater , with Ba point ≥ + 1 ( POP-Q quantification ) , were r and omly assigned to have either anterior colporraphy ( n = 43 ) or transvaginal mesh repair ( n = 43 ) . The primary outcome was to compare objective success rate under two success definitions : prolapse stage I ( Ba < -1 ) and stage II ( Ba < 0 ) . Secondary outcomes included complications and prolapse symptoms , satisfaction and quality of life ( QoL ) . Intention to treat was used for the primary endpoint and per protocol analysis for the secondary outcomes . RESULTS The groups presented similar preoperative data . Thirty three patients from the colporraphy and 37 from the mesh groups completed two-year follow-up . Under Ba < -1 definition , success rate was 39.53 % for both groups ( P = 1.00 ) . Considering success as Ba < 0 , analysis favored the mesh group by 23 % ( 51.16 % and 74.42 % ; 95 % CI for difference : 3 - 43 % ; P = 0.022 ) . Patients from the mesh group were more satisfied after two years ( 81.8 % and 97.3 % for colporraphy and mesh , respectively , 15.5 % difference ; 95 % CI for difference 1 - 29 % ; P = 0.032 ) . Both procedures similarly improved women 's symptoms and QoL. Some complications were observed , one being a 13.5 % mesh exposure rate . CONCLUSIONS Transvaginal synthetic mesh repair for advanced anterior vaginal prolapse provided higher anatomical success and satisfaction rates compared with traditional colporraphy . Both procedures equally improved quality of life . Neurourol . Urodynam . 35:509 - 514 , 2016 . © 2015 Wiley Periodicals , [21069291] Introduction and hypothesisThe optimal duration of urethral catheterization during and after pelvic reconstructive surgery is not established . This study investigated the optimal duration of urinary catheterization in patients undergoing anterior vaginal repair with or without other vaginal surgeries . Methods A total of 90 patients were included from April 2007 to March 2008 . They were r and omly divided into 2 , 3 , and 4 days urinary catheterization groups based on the color of the question naire papers they blindly chose . After catheter removal , the amount of post-void residual urine was used to measure the efficacy of bladder emptying . Differences between groups were determined using Chi-square test , Fisher 's exact test , or Kruskal – Wallis test , as appropriate . Results No significant differences were found in the amount of post-void residual urine between the three catheterization groups . Conclusions Our findings suggest that the duration of urethral catheterization after anterior colporrhaphy need not exceed 2 days [24054380] OBJECTIVE To compare the use of polypropylene mesh ( PM ) and the traditional anterior vaginal wall colporraphy in women with anterior vaginal wall prolapse ( AVWP ) using objective and subjective tests and evaluation of quality of life ( QoL ) . MATERIAL S AND METHODS One hundred women were r and omly distributed in two preoperatory groups . The first group ( mesh ) ( n = 45 ) received a PM implant and the control group ( n = 55 ) was su bmi tted to traditional colporraphy . Postoperatory follow-up was done after 12 months . The primary objective was the correction of the Ba point ≤ -2 POP-Q ( Pelvic Organ Prolapse Quantification System ) and the secondary objective was the improvement of vaginal symptoms and QoL through ICIQ-VS ( International Consultation on Incontinence Question naire - Vaginal Symptoms ) . Complications related to the use of PM or not were also described . RESULTS There was a significant difference between all POP-Q measures of pre- and postoperatory periods of each group in particular . There was a significant difference of the Ba point of the postoperatory period between the Mesh and Control group . The mean of Ba point in the Mesh group was statistically lower than of the Control group , depicting the better anatomical result of the first group . Both techniques improved vaginal symptoms and QoL. The most frequent complication of the Mesh group was prepubic hematoma in the perioperative period . In 9.3 % of the cases treated with mesh it was observed PM exposition at the anterior vaginal wall after 12 months , being most of them treated clinical ly . CONCLUSION The treatment of AVWP significantly improved the Ba point in the Mesh group in comparison to the Control group . There were no differences of the vaginal symptoms and QoL between the two groups after 12 months . There were few and low grade complications on both groups [17901910] The aim of this study was to compare the efficiency of polypropylene mesh surgery with the site-specific repair surgeries in the treatment of cystocoeles . We r and omized 90 patients into two groups according to a computer-based program . After a 12-month ( mean ) follow up , we noticed that the polypropylene mesh surgery yielded good anatomical results . Acceptable anatomical cure rates were 91 and 72 % in the mesh surgery group and site-specific surgery group , respectively . There were three cases ( 6.9 % ) of mesh erosion . One case of urinary retention and two cases of de novo dyspareunia were seen in the mesh surgery group . De novo stress urinary incontinence developed in three patients in the site-specific surgery group . We concluded that surgery with light polypropylene mesh ( Sofradim ® , Parietene ) is superior to the site-specific surgery in the treatment of cystocoeles [3072491] Introduction and hypothesisFor prolonged catheterization after vaginal prolapse surgery with anterior colporrhaphy , the optimal duration to prevent overdistention of the bladder remains unknown . We design ed this study to determine the optimal length of catheterization . Methods We conducted a prospect i ve r and omized trial in which 179 women were allocated to 1-day or 3-day suprapubic catheterization . The primary outcome was the duration of catheterization . Results Mean duration of catheterization and hospital stay was significantly shorter in the 1-day catheterization group . The number of successful voiding trials was higher in the 3-day catheterization group ( 90.9 % versus 79.3 % ) , but this did not reach statistical significance . The percentage of urinary tract infection did not differ significantly between the groups ( 4.5 % versus 2.4 % ) . ConclusionS tarting a voiding trial 1 day after vaginal prolapse surgery leads to shorter duration of catheterization and hospital stay [18923805] We compared safety and efficacy of Gynemesh PS ® and Pelvicol ® for recurrent cystocele repair . One hundred ninety patients were r and omly divided into Gynemesh PS ® and Pelvicol ® groups and underwent tension-free cystocele repair . The Chi-square test was used to compare categorical variables , the paired t test for continuous parametric variables , and the Mann – Whitney test for continuous nonparametric variables . Ninety-six Gynemesh PS ® patients and 94 Pelvicol ® patients were studied . Mesh erosions occurred in 6.3 % of Gynemesh PS ® patients . No erosions were observed in Pelvicol ® patients ( p = 0.02 ) . Objective cure was 71.9 % for Gynemesh PS ® and 56.4 % for Pelvicol ® ( p = 0.06 ) . Subjective cure was the same in both groups except for better sexuality in the Pelvicol ® group . At 24 months follow-up , only Gynemesh PS ® patients had mesh erosions . Anatomical outcome was similar in the two groups . Pelvicol ® gave a better impact on voiding and sexuality [20664388] OBJECTIVE : To present 3-month outcomes of a double-blind , multicenter r and omized controlled trial comparing traditional vaginal prolapse surgery without mesh with vaginal surgery with mesh . METHODS : Women with pelvic organ prolapse quantification prolapse stages 2–4 were r and omized to vaginal colpopexy repair with mesh or traditional vaginal colpopexy without mesh . The primary outcome measure was objective treatment success ( pelvic organ prolapse quantification stage 1 or lower ) at 3 months . Secondary outcome measures included quality -of-life variables and complication rates . RESULTS : Sixty-five women were recruited from January 2007 to August 2009 , when the study was halted due to predetermined stopping criteria for vaginal mesh erosion at a median follow-up of 9.7 months ( range , 2.4–26.7 months ) . Thirty-two women underwent mesh colpopexy ( 24 anterior mesh , eight total mesh ) , and 33 women had vaginal colpopexies without mesh ( primarily uterosacral ligament suspension ) and concurrent colporrhaphy . There were no statistically significant baseline differences between the mesh and no-mesh groups with respect to demographics , menopausal status , and race . Analysis of the mesh and no-mesh women found no difference with respect to overall recurrence ( mesh : 19 [ 59.4 % ] compared with no mesh : 24 [ 70.4 % ] , P=.28 ) . There were five ( 15.6 % ) vaginal mesh erosions . Two cystotomies and one blood transfusion occurred in the mesh group only . Subjective cure of bulge symptoms was noted in 93.3 % of mesh patients and 100 % of no-mesh patients . Furthermore , subjective quality -of-life measurements did not differ between the two groups at baseline or 3 months postoperatively . CONCLUSION : At 3 months , there is a high vaginal mesh erosion rate ( 15.6 % ) with no difference in overall objective and subjective cure rates . This study questions the value of additive synthetic polypropylene mesh for vaginal prolapse repairs . CLINICAL TRIAL REGISTRATION : Clinical trials.gov , www . clinical trials.gov , NCT00475540 . LEVEL OF EVIDENCE : [21797984] INTRODUCTION Surgical treatment of pelvic organ prolapse ( POP ) affects sexual function . Generally , this results in improved sexual function , but deterioration is reported also . AIM The purpose of this study was to evaluate and compare sexual function in patients with recurrent POP undergoing either a vaginal surgical repair with native tissue or a trocar-guided mesh insertion . METHODS Sexually active patients r and omly assigned to either native tissue repair or trocar-guided mesh insertion , which had completed the pelvic organ prolapse (POP)/urinary incontinence sexual question naire ( PISQ-12 ) both at baseline and at 12 months , were included . Total , subscale , and individual question analysis were performed . Logistic regression was used to identify factors that were independently associated with improvement/deterioration in total PISQ-12 scores . MAIN OUTCOME MEASURES Primary outcome was sexual function at 12 months following surgery , measured by the short form of the pelvic organ prolapse/urinary incontinence sexual question naire ( PISQ-12 ) . Secondary outcomes were the identification of factors independently associated with change in PISQ-12 scores and changes in individual PISQ-12 question scores . RESULTS Sixty patients were included ; 32 in the mesh arm and 28 in the native tissue arm . At 12 months , PISQ-12 scores were not different in both treatment arms ( 34.3 , st and ard deviation [ SD ] 6.7 vs. 34.7 , SD 5.7 ) , but improvement was detected in the native tissue arm , whereas PISQ-12 total score remained unchanged in the mesh arm . Deteriorations were observed in the behavioral/emotive subscale and partner-related items in the mesh arm . In the native tissue arm , significant improvements in the physical and partner-related subscales were observed . The presence of mesh exposure was independently associated with deterioration in total PISQ-12 score . CONCLUSION At 12 months , PISQ-12 scores were not different in either treatment arm , but were affected differently by trocar-guided mesh insertion or by native tissue repair . Mesh exposure was independently associated with deterioration in sexual function [20165833] Introduction and hypothesisThe effect of a Pelvicol ® graft compared with a conventional anterior vaginal repair was evaluated in this r and omised controlled study . Methods Only patients with a stage II or higher ( Ba ≥ −1 ) defect were included . Results Thirty-one patients were allocated to a conventional anterior repair ; 30 to Pelvicol ® graft . At 12 months follow-up , four patients among controls ( 15 % ) and two in the graft group ( 7 % ) had objective recurrence . Among controls , the difference at 3 months follow-up in Ba was 6.0 cm when compared with the position of Ba prior to surgery . In the graft group , the difference was 7.0 cm ( P < 0.05 ) . This difference was still present at 12 months follow-up ( 6.0 vs. 7.0 cm ; P < 0.05 ) . Conclusions The implantation of a Pelvicol ® graft does not improve the POP-Q stage [17120172] The purpose of this study is to compare the feasibility of local anesthesia with IV sedation versus general anesthesia for vaginal correction of pelvic organ prolapse . Patients with pelvic organ prolapse who were scheduled for an anterior or posterior colporrhaphy , or an obliterative procedure , and who did not have a contraindication or preference to type of anesthesia were r and omized to one of the two anesthesia groups . Nineteen patients were r and omized to the general group and 21 patients were r and omized to the local group . Mean operating room , anesthesia , and surgical time were similar in each group , and 10 patients in the local group bypassed the recovery room . Requests and doses of antiemetics , postoperative verbal numerical pain scores and length of hospital stay were similar between the two groups . Mean recovery room and total hospital costs were significantly lower in the local group . Local anesthesia with IV sedation is a feasible alternative for vaginal surgery to correct pelvic organ prolapse [2866119] To investigate the effect of prophylactic phenoxybenzamine on the bladder emptying after vaginal repair operations , 41 consecutive patients , who underwent the Manchester operation or an anterior + posterior repair because of genital descensus , were allocated at r and om to either prophylactic phenoxybenzamine ( PBZ-group ) or placebo treatment in the postoperative course . Prophylactic phenoxybenzamine was found to produce an improved emptying function of the bladder , leading to a statistically significant reduced number of acute urinary retentions ( P = 0.029 ) , decreased time until spontaneous voiding ( P = 0.026 ) and reduced volume of residual urine ( P = 0.018 ) . Furthermore , a reduced incidence of urinary tract infections was found in the PBZ-group . Prophylactic phenoxybenzamine treatment is recommended as an alternative to routine bladder drainage in preventing urinary retention following vaginal repair operations for genital descensus [22707003] Introduction and hypothesisThe optimal surgery for lateral defects is not well defined . Our objective was to assess the effects of anterior trocar-guided transvaginal mesh repair versus anterior colporrhaphy in women with lateral defects . Methods This sub analysis from a r and omized controlled trial of mesh kit versus anterior colporrhaphy assessed 99 patient diagnosed at baseline with lateral defects in the anterior vaginal wall . Thirty-nine patients underwent anterior colporrhaphy and 60 anterior trocar-guided transvaginal mesh surgery . Results One year after surgery , a persistent lateral defect was significantly more common after colporrhaphy compared with transvaginal mesh [ 11/32 ( 34.4 % ) vs 1/42 ( 2.4 % ) , risk ratio ( RR ) 14.4 , 95 % confidence interval ( CI ) 2.0–106.1 ; P < 0.001 ) ] However , there were no significant differences between treatment groups with regard to subjective symptoms as reflected by the overall Urogenital Distress Inventory scores , with mean difference from baseline 37.3 ± 50.6 in the colporrhaphy group vs 39.0 ± 45.8 in the mesh group ( p = 0.61 ) . Conclusions Use of a transvaginal mesh kit increases the odds for anatomical correction of lateral defects compared with anterior colporrhaphy but does not necessarily improve lower urinary tract symptoms [3051058] Introduction and hypothesisThe aim of this study was to compare the number of temporary catheter replacements and urinary tract infections after indwelling catheterization for 2 versus 5 days following an anterior colporrhaphy . Methods Two hundred forty-six patients were r and omly assigned to 2 or 5 days of indwelling catheterization . Outcome measures were temporary catheter replacements because of post-voiding residual > 200 mL after removal of the indwelling catheter , urinary tract infections , and hospital stay . All patients were analyzed according to the intention to treat principle . Results Compared to the 5-day protocol group , in the 2-day protocol group more patients needed temporary catheter replacement ( 9 % versus 28 % , odds ratio ( OR ) 4.0 , confidence interval ( CI ) 1.9–8.3 , p < 0.01 ) , whereas less patients had a urinary tract infection ( 37 % versus 22 % , OR 0.5 , CI 0.3–0.9 , p = 0.02 ) and median hospital stay was lower . Conclusions Removal of an indwelling catheter after 2 versus 5 days following anterior colporrhaphy is associated with more temporary catheter replacements , but less urinary tract infections and a shorter hospital stay [27939467] BACKGROUND Pre-eclampsia is a serious complication of pregnancy and contributes to maternal and offspring mortality and morbidity . R and omised controlled trials evaluating therapeutic interventions for pre-eclampsia have reported many different outcomes and outcome measures . Such variation contributes to an inability to compare , contrast , and combine individual studies , limiting the usefulness of research to inform clinical practice . The development and use of a core outcome set would help to address these issues ensuring outcomes important to all stakeholders , including patients , will be collected and reported in a st and ardised fashion . METHODS An international steering group including healthcare professionals , research ers , and patients , has been formed to guide the development of this core outcome set . Potential outcomes will be identified through a comprehensive literature review and semi-structured interviews with patients . Potential core outcomes will be entered into an international , multi-perspective online Delphi survey . All key stakeholders , including healthcare professionals , research ers , and patients will be invited to participate . The modified Delphi method encourages whole and stakeholder group convergence towards consensus ' core ' outcomes . Once core outcomes have been agreed upon it is important to determine how they should be measured . The truth , discrimination , and feasibility assessment framework will assess the quality of potential outcome measures . High quality outcome measures will be associated with core outcomes . Mechanisms exist to disseminate and implement the result ing core outcome set within an international context . DISCUSSION Embedding the core outcome set within future clinical trials , systematic review s , and clinical practice guidelines could make a profound contribution to advancing the usefulness of research to inform clinical practice , enhance patient care , and improve maternal and offspring outcomes . The infrastructure created by developing a core outcome set for pre-eclampsia could be leveraged in other setting s , for example selecting research priorities and clinical practice guideline development . PROSPECT IVE REGISTRATION : [ 1 ] Core Outcome Measures in Effectiveness Trials ( COMET ) registration number : 588 . [ 2 ] International Prospect i ve Register of Systematic Review s ( PROSPERO ) registration number : CRD42015015529 [3416890] OBJECTIVE : The aim of this study was to compare female sexual function after surgical treatment of anterior vaginal prolapse with either small intestine submucosa grafting or traditional colporrhaphy . METHODS : Subjects were r and omly assigned , preoperatively , to the small intestine submucosa graft ( n = 29 ) or traditional colporrhaphy ( n = 27 ) treatment group . Postoperative outcomes were analyzed at 12 months . The Female Sexual Function Index question naire was used to assess sexual function . Data were compared with independent sample s or a paired Student 's t-test . Clinical Trials.gov : NCT00827528 . RESULTS : In the small intestine submucosa group , the total mean Female Sexual Function Index score increased from 15.5±7.2 to 24.4±7.5 ( p<0.001 ) . In the traditional colporrhaphy group , the total mean Female Sexual Function Index score increased from 15.3±6.8 to 24.2±7.0 ( p<0.001 ) . Improvements were noted in the domains of desire , arousal , lubrication , orgasm , satisfaction , and pain . There were no differences between the two groups at the 12-month follow-up . CONCLUSIONS : Small intestine submucosa repair and traditional colporrhaphy both improved sexual function postoperatively . However , no differences were observed between the two techniques [5513392] Background Twin – Twin Transfusion Syndrome ( TTTS ) is associated with an increased risk of perinatal mortality and morbidity . Several treatment interventions have been described for TTTS , including fetoscopic laser surgery , amnioreduction , septostomy , expectant management , and pregnancy termination . Over the last decade , fetoscopic laser surgery has become the primary treatment . The literature to date reports on many different outcomes , making it difficult to compare results or combine data from individual studies , limiting the value of research to guide clinical practice . With the advent and ongoing development of new therapeutic techniques , this is more important than ever . The development and use of a core outcome set has been proposed to address these issues , prioritising outcomes important to the key stakeholders , including patients . We aim to produce , disseminate , and implement a core outcome set for TTTS . Methods An international steering group has been established to oversee the development of this core outcome set . This group includes healthcare professionals , research ers and patients . A systematic review is planned to identify previously reported outcomes following treatment for TTTS . Following completion , the identified outcomes will be evaluated by stakeholders using an international , multi-perspective online modified Delphi method to build consensus on core outcomes . This method encourages the participants towards consensus ‘ core ’ outcomes . All key stakeholders will be invited to participate . The steering group will then hold a consensus meeting to discuss results and form a core outcome set to be introduced and measured . Once core outcomes have been agreed , the next step will be to determine how they should be measured , disseminated , and implemented within an international context . Discussion The development , dissemination , and implementation of a core outcome set in TTTS will enable its use in future clinical trials , systematic review s and clinical practice guidelines . This is likely to advance the quality of research studies and their effective use in order to guide clinical practice and improve patient care , maternal , short-term perinatal outcomes and long-term neurodevelopmental outcomes .Trial registration Core Outcome Measures in Effectiveness Trials ( COMET ) , 921 Registered on July 2016.International Prospect i ve Register of Systematic Review s ( PROSPERO ) , CRD42016043999 . Registered on 2 August 2016 [20683580] Introduction and hypothesisDifferent forms of urinary drainage are applied after anterior colporrhaphy . Suprapubic urinary catheter ( SUC ) and indwelling urinary catheter ( IUC ) for 2 to 96 h are preferred . If there is no difference in symptomatic urinary tract infection ( SUTI ) or complications between IUCs for 96 and 24 h , the latter will be considered sufficient . If IUCs have no higher rate of infections or complications compared to SUC for 96 h , the former could be considered sufficient . Methods It was a three-arm prospect i ve , r and omized study including 257 patients . The three arms were : IUCs for 24 h , IUCs for 96 h , and SUCs for 96 h. Results We found no significant difference in SUTIs between all three groups . Although the SUC arm showed no SUTIs , a significant higher rate of complications was seen . Conclusion The optimal bladder catheter after anterior colporrhaphy was , in our trial , the IUC for 24 [17666627] OBJECTIVE : To compare anterior colporrhaphy with and without a tailored mesh . METHODS : Postmenopausal women with anterior vaginal prolapse to the hymen or beyond were r and omly assigned to undergo traditional anterior colporrhaphy alone or reinforced with mesh . The low-weight monofilament polypropylene mesh was self-tailored , having four arms and being placed over the plicated fascia . Before and 2 and 12 months after surgery , participants were evaluated by physical examination , postvoidal residual urine measurement and st and ard questions covering prolapse-related symptoms . The primary outcome was recurrence of anterior vaginal prolapse at 12 months . Secondary outcomes included operative complications , symptom resolution , and postvoidal urine residual volume . RESULTS : Of the 202 women r and omly assigned , 201 were operated on ( 97 without , 104 with mesh ) . Thirty-seven women ( 38.5 % ) in the no-mesh and seven ( 6.7 % ) in the mesh group experienced a recurrence of anterior wall prolapse ( P<.001 ) at 12 months ; as a result , the number needed to treat for benefit was four . The mean ( st and ard deviation ) postvoidal residual urine volume was lower in patients with mesh than in those undergoing the traditional operation : 25 ( 26 ) mL and 41 ( 57 ) mL ( P=.01 ) . Twenty-three women ( 23 % ) with mesh and 9 ( 10 % ) with no mesh reported stress urinary incontinence ( P=.02 ) . In 18 ( 17.3 % ) , exposure of the mesh was noted , mainly asymptomatic . CONCLUSION : Anterior colporrhaphy , reinforced with , tailored mesh significantly reduced the rate of recurrence of anterior vaginal wall prolapse compared with the traditional operation , but was associated more often with stress urinary incontinence . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00420225 LEVEL OF EVIDENCE : [8987919] OBJECTIVES Our purpose was to determine whether a vaginal or abdominal approach is more effective in correcting uterovaginal prolapse . STUDY DESIGN Eighty-eight women with cervical prolapse to or beyond the hymen or with vaginal vault inversion > 50 % of its length and anterior vaginal wall descent to or beyond the hymen were r and omized to a vaginal versus abdominal surgical approach . Forty-eight women underwent a vaginal approach with bilateral sacrospinous vault suspension and paravaginal repair , and 40 women underwent an abdominal approach with colposacral suspension and paravaginal repair . Ancillary procedures were performed as indicated . Detailed pelvic examination was performed postoperatively by the nonsurgeon coauthor yearly up to 5 years . The women were examined while st and ing during maximum strain . Surgery was classified as optimally effective if the woman remained asymptomatic , the vaginal apex was supported above the levator plate , and no protrusion of any vaginal tissue beyond the hymen occurred . Surgical effectiveness was considered unsatisfactory if the woman was symptomatic , the apex descended > 50 % of its length , or the vaginal wall protruded beyond the hymen . RESULTS Eighty women ( vaginal 42 , abdominal 38 ) were available for evaluation at 1 to 5.5 years ( mean 2.5 years ) . The groups were similar in age , weight , parity , and estrogen status , and 56 % had undergone prior pelvic surgery . There was no significant difference between the groups in morbidity , complications , hemoglobin change , dyspareunia , pain , or hospital stay . The vaginal group had longer catheter use , more urinary tract infections , more incontinence , decreased operative time , and lower hospital charge . Surgical effectiveness was optimal in 29 % of the vaginal group and 58 % of the abdominal group and was unsatisfactory leading to reoperation in 33 % of the vaginal group and 16 % of the abdominal group . The reoperations included procedures for recurrent incontinence in 12 % of the vaginal and 2 % of the abdominal groups . The relative risk of optimal effectiveness by the abdominal route is 2.03 ( 95 % confidence interval 1.22 to 9.83 ) , and the relative risk of unsatisfactory outcome using the vaginal route is 2.11 ( 95 % confidence interval 0.90 to 4.94 ) . CONCLUSIONS Reconstructive pelvic surgery for correction of significant pelvic support defects was more effective with an abdominal approach [24402594] OBJECTIVE : To compare surgeons ' intraoperative surgeon acceptability or assessment of the operative field regarding bowel contents and patients ' satisfaction with or without a mechanical bowel preparation before reconstructive vaginal prolapse surgery . METHODS : In this single-blind , r and omized trial , women scheduled to undergo vaginal prolapse surgery with a planned apical suspension and posterior colporrhaphy were allocated using block r and omization to an intervention or control group . Surgeons were blinded to patient allocation . One day before surgery , mechanical bowel preparation instructions consisted of a clear liquid diet and two self-administered saline enemas ; the participants in the control group sustained a regular diet and nothing by mouth after midnight . The primary outcome was surgeons ' intraoperative assessment of the surgical field regarding bowel content as measured on a 4-point Likert scale ( 1 , excellent ; 4 , poor ) . Secondary outcomes included participant satisfaction and bowel symptoms . The primary outcome was determined by intention-to-treat analysis and other analyses were per protocol . RESULTS : Of the 150 women r and omized ( 75 women to intervention and control group ) , 145 completed the study . No differences existed in the demographic , clinical , and intraoperative characteristics between groups ( P>.05 ) . Surgeons ' intraoperative assessment rating was 85 % “ excellent or good ” with bowel preparation compared with 90 % for participants in the control group ( odds ratio [ OR ] 0.59 , 95 % confidence interval [ CI ] 0.21–1.61 ; P=.30 ) . The bowel preparation group was less likely to report “ complete ” satisfaction compared with the participants in the control group ( OR 0.11 , 95 % CI 0.04–0.35 ; P<.001 ) . Abdominal fullness and cramping , fatigue , anal irritation , and hunger pains were greater in the bowel preparation group ( all P<.01 ) . CONCLUSION : Before reconstructive vaginal surgery , mechanical bowel preparation conferred no benefit regarding surgeons ' intraoperative assessment of the operative field , reflected decreased patient satisfaction , and had increased abdominal symptoms . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT01431040 . LEVEL OF EVIDENCE : [23812579] Introduction We set out to determine if insertion of a retropubic tension-free vaginal tape ( TVT ) sling at the time of pelvic organ prolapse surgery improves continence outcomes in women with pre-operative occult stress incontinence ( OSI ) or asymptomatic urodynamic stress incontinence ( USI ) . Methods We conducted a r and omised controlled study of prolapse surgery with or without a TVT midurethral sling . The pre- and post-operative assessment at 6 months included history , physical examination and urodynamic testing . Quality of life ( QOL ) and treatment success was assessed with the UDI-6 SF , IIQ-7 SF and a numerical success score . The primary outcome was symptomatic stress urinary incontinence ( SUI ) requiring continence surgery ( TVT ) at 6 months . Long-term follow-up continued to a minimum of 24 months . Secondary outcomes were quality of life parameters . Results Eighty women received prolapse surgery alone ( n = 43 ) or prolapse surgery with concurrent TVT ( n = 37 ) . Six months following prolapse surgery 3 out of 43 ( 7 % ) patients in the no TVT group requested sling surgery compared with 0 out of 37 ( 0 % ) in the TVT group ( ARR 7 % [ 95 % CI : 3 to 19 % ] , p = 0.11 ) . After 24 months there was one further participant in the no TVT group who received a TVT for treatment of SUI compared with none in the TVT group ( 4 out of 43 , 9.3 % versus 0 out of 37 ; ARR 9.3 % [ 95 % CI : −1 to 22 % ] , p = 0.06 ) . Both groups showed improvement in QOL difference scores for within-group analysis , without difference between groups . Conclusion These results support a policy that routine insertion of a sling in women with OSI at the time of prolapse repair is question able and should be subject to shared decision-making between clinician and patient [21864325] Please cite this paper as : Vollebregt A , Fischer K , Gietelink D , van der Vaart C. Primary surgical repair of anterior vaginal prolapse : a r and omised trial comparing anatomical and functional outcome between anterior colporrhaphy and trocar‐guided transobturator anterior mesh . BJOG 2011;118:1518–1527 [26294207] Introduction and hypothesisHydrodissection incorporating different types of vasoconstrictors is commonly used in vaginal prolapse surgery . There is little evidence as to whether it adds clinical value or whether it exposes the patient to unnecessary risk . The aim of this study was to compare the effect of a vasoconstrictor compared with saline alone on operative blood loss and cardiovascular parameters in a r and omised clinical trial setting . Methods Patients undergoing vaginal prolapse surgery were r and omised to an ornipressin ( Por-8 , Ferring ) solution or saline alone for hydrodissection . The surgeon and patient were blinded to the solution used . Operative blood loss was accurately quantified and blood pressure and pulse readings recorded Pre , intra- and postoperatively . Results Eighty women were r and omised . There was a statistically significant difference in the median blood loss : 35 ml ( 1 - 209 ml ) in the ornipressin group compared with 81 ml ( 2 - 328 ml ) in the saline group , p = 0.03 . There was no statistically significant difference in the median pre and postoperative blood pressure or pulse rate between groups . Conclusions The use of a vasoconstrictor ( ornipressin ) result ed in a statistically significant decrease in operative blood loss during vaginal prolapse surgery . This occurred without any significant changes in measured cardiovascular parameters [21561348] BACKGROUND The use of st and ardized mesh kits for repair of pelvic-organ prolapse has spread rapidly in recent years , but it is unclear whether this approach results in better outcomes than traditional colporrhaphy . METHODS In this multicenter , parallel-group , r and omized , controlled trial , we compared the use of a trocar-guided , transvaginal polypropylene-mesh repair kit with traditional colporrhaphy in women with prolapse of the anterior vaginal wall ( cystocele ) . The primary outcome was a composite of the objective anatomical design ation of stage 0 ( no prolapse ) or 1 ( position of the anterior vaginal wall more than 1 cm above the hymen ) , according to the Pelvic Organ Prolapse Quantification system , and the subjective absence of symptoms of vaginal bulging 12 months after the surgery . RESULTS Of 389 women who were r and omly assigned to a study treatment , 200 underwent prolapse repair with the transvaginal mesh kit and 189 underwent traditional colporrhaphy . At 1 year , the primary outcome was significantly more common in the women treated with transvaginal mesh repair ( 60.8 % ) than in those who underwent colporrhaphy ( 34.5 % ) ( absolute difference , 26.3 percentage points ; 95 % confidence interval , 15.6 to 37.0 ) . The surgery lasted longer and the rates of intraoperative hemorrhage were higher in the mesh-repair group than in the colporrhaphy group ( P<0.001 for both comparisons ) . Rates of bladder perforation were 3.5 % in the mesh-repair group and 0.5 % in the colporrhaphy group ( P=0.07 ) , and the respective rates of new stress urinary incontinence after surgery were 12.3 % and 6.3 % ( P=0.05 ) . Surgical reintervention to correct mesh exposure during follow-up occurred in 3.2 % of 186 patients in the mesh-repair group . CONCLUSIONS As compared with anterior colporrhaphy , use of a st and ardized , trocar-guided mesh kit for cystocele repair result ed in higher short-term rates of successful treatment but also in higher rates of surgical complications and postoperative adverse events . ( Funded by the Karolinska Institutet and Ethicon ; Clinical Trials.gov number , NCT00566917 . ) [22648445] Purpose To compare the clinical effectiveness of anterior colporrhaphy versus mesh repair as surgical management of anterior vaginal prolapse . Methods Of 50 patients with ≥stage II anterior vaginal prolapse on Pelvic Organ Prolapse Quantification ( POPQ ) system who were initially approached , 44 consented and underwent surgery . They were r and omly recruited into two groups . Group I ( 23 patients ) received anterior colporrhaphy , while group II ( 21 patients ) received soft polypropylene mesh ( GYNEMESH*PS , Gynecare , Ethicon , France ) . Clinical assessment took place preoperatively and postoperatively at definite intervals . Functional and anatomical comparisons were based on comparison between preoperative and 24 months postoperative assessment s of symptoms and POPQ stages , respectively . Four patients in total did not complete the follow-up assessment s and were excluded . Results Both groups showed clinical improvement in their symptoms and POPQ staging at the end of the postoperative follow-up period . Improvement , however , was more significant in the repair with mesh group , as patients in this group reported better improvement of their prolapse symptoms , mainly vaginal bulge/pressure sensation ( P < 0.05 ) , and showed better improvement in the anatomical staging , individual POP-Q points Aa and Ba ( P < 0.01 ) , than the anterior colporrhaphy group . Group II also showed more satisfactory outcome with the general POP-Q staging ( P < 0.05 ) than group I , reflecting a better quality of life of the patients in the repair with mesh group . Conclusion Our data shows that repair with mesh is superior to anterior colporrhaphy with more satisfactory outcome to the patients . Due to the small size of our study and uncertainty of the long-term safety and resilience of the mesh , we recommend larger studies to confirm our preliminary results [22321388] INTRODUCTION In pelvic organ prolapse ( POP ) repair , the use of synthetic mesh is not only increasing but also a subject of discussion . The focus shifts from anatomical toward functional outcome , with sexual function being an important parameter . One of the concerns with mesh usage in POP surgery is the possible negative effect on sexual function . AIM To compare and assess sexual function in women and men after primary cystocele repair with or without trocar-guided transobturator mesh . METHODS One hundred twenty-five women with a symptomatic cystocele stage ≥ II were included in this multicenter r and omized controlled trial and assessed at baseline and 6-month follow-up . MAIN OUTCOME MEASURES Female sexual function was measured by the Female Sexual Function Index ( FSFI ) and male sexual function by the Male Sexual Health Question naire . A subgroup analysis of women with a participating partner was performed . RESULTS In the mesh group , 54/59 women vs. 53/62 in the anterior colporrhaphy group participated . In men , 29 vs. 30 participated . After surgery , FSFI scores were comparable for both treatment groups . However , within group analysis showed significant improvement on the domains pain ( effect size = 0.5 ) , lubrication ( effect size = 0.4 ) , and overall satisfaction ( effect size = 0.5 ) in the colporrhaphy group . This improvement was not observed in the mesh group . A subgroup of women with a participating partner reported significantly higher baseline domain scores as compared with other women and did not report a significant improvement of sexual functioning irrespective of treatment allocation . Worsening of baseline sexual function was reported by 43 % of women in the mesh group compared with 18 % in anterior colporrhaphy group ( P = 0.05 ) . Male sexual functioning did not change in either group . CONCLUSIONS Women after an anterior colporrhaphy report a significant and clinical ly relevant improvement of their sexual functioning , whereas women after a mesh procedure did not [24310987] Introduction and hypothesisThe objective of this study was to evaluate the effect of vaginal packing following pelvic floor surgery with regard to post-operative pain , bleeding and infection . This was a double-blind r and omised study of women undergoing vaginal hysterectomy and /or pelvic floor repair at a tertiary urogynaecology unit . Methods The primary outcome of day 1 post-operative pain was assessed using the short-form McGill Pain score . Secondary outcomes were haematological and infective morbidity , evaluated using changes in full blood count , and cultures of midstream urine and high vaginal swabs . A transvaginal ultrasound scan to exclude pelvic haematoma was performed at 6 weeks in all women who underwent vaginal hysterectomy with or without a pelvic floor repair . Results In total , 190 women were recruited : mean age 58.3 years ( 27–91 years ) , mean body mass index 27.4 kg/m2 and median parity 3 . Women were r and omised into the ‘ pack ’ ( n = 86 ) and ‘ no pack ’ ( n = 87 ) arms with no demographic differences between the groups . No statistically significant differences in the post-operative pain scores or secondary outcome measures were demonstrated . Incidence of haematoma formation ( 14.8 % no pack , 7.3 % pack , p = 0.204 ) was not statistically significant . There were three clinical ly significant complications in the no pack group and none in the pack group . Conclusions This is the first study to examine pain in association with post-operative vaginal packing . There is no evidence to suggest that packing increases pain scores or post-operative morbidity . A trend towards increased haematoma and significant complications was seen in the no pack group . As vaginal packing does no harm and may be of some benefit it may be argued that packing should be recommended as routine clinical practice [26740197] Introduction and hypothesisWe compared pelvic organ prolapse ( POP ) repair with and without midurethral sling ( MUS ) in women with occult stress urinary incontinence ( SUI ) . Methods This was a r and omized trial conducted by a consortium of 13 teaching hospitals assessing a parallel cohort of continent women with symptomatic stage II or greater POP . Women with occult SUI were r and omly assigned to vaginal prolapse repair with or without MUS . Women without occult SUI received POP surgery . Main outcomes were the absence of SUI at the 12-month follow-up based on the Urogenital Distress Inventory and the need for additional treatment for SUI . Results We evaluated 231 women , of whom 91 r and omized as follows : 43 to POP surgery with and 47 without MUS . A greater number of women in the MUS group reported absence of SUI [ 86 % vs. 48 % ; relative risk ( RR ) 1.79 ; 95 % confidence interval ( CI ) 1.29–2.48 ] . No women in the MUS group received additional treatment for postoperative SUI ; six ( 13 % ) in the control group had a secondary MUS . Women with occult SUI reported more urinary symptoms after POP surgery and more often underwent treatment for postoperative SUI than women without occult SUI . Conclusions Women with occult SUI had a higher risk of reporting SUI after POP surgery compared with women without occult SUI . Adding a MUS to POP surgery reduced the risk of postoperative SUI and the need for its treatment in women with occult SUI . Of women with occult SUI undergoing POP-only surgery , 13 % needed additional MUS . We found no differences in global impression of improvement and quality of life [23084678] STUDY OBJECTIVE To compare the effectiveness and safety of 2 anterior transobturator mesh methods for treating anterior vaginal wall prolapse . DESIGN R and omized controlled study ( Canadian Task Force classification I ) . SETTING University hospital . PATIENTS Eighty-seven women with anterior vaginal wall prolapse stage ≥2 ( Pelvic Organ Prolapse Quantification [ POP-Q ] ) underwent an anterior transobturator mesh procedure using macropore polypropylene mesh . INTERVENTIONS Forty-five patients underwent the operation via the conventional 4-point , full-sized mesh method , and 42 patients underwent the operation via a novel 2-point , half-sized mesh method . MEASUREMENTS AND MAIN RESULTS Patient characteristics were comparable between the 2 groups . The anatomic cure rate was significantly lower in the 2-point group compared with the 4-point group at 12 months after surgery ( 87.2 % vs 100 % ; p = .03 ) . Healing abnormalities were significantly higher in the 2-point group than in the 4-point group ( 12.8 % vs 0 % ; p = .03 ) . Bladder perforation ( 2.6 % vs 0 % ) , stress urinary incontinence ( 23.1 % vs 22.5 % ) , urinary frequency ( 12.8 % vs 22.5 % ) , and voiding difficulty and dyspareunia ( 0 % vs 0 % ) were not statistically different between the 2 groups . At linear regression analysis , mean ( SD ) operation time did not differ between the 2 groups ( 74.9 [ 32.7 ] minutes vs 87.8 [ 36.7 ] minutes ; p = .11 ) . CONCLUSION Compared with the 4-point method , the 2-point anterior transobturator mesh method result ed in a lower rate of anatomic cure and a higher rate of healing abnormality [22239416] Please cite this paper as : Withagen M , Milani A , de Leeuw J , Vierhout M. Development of de novo prolapse in untreated vaginal compartments after prolapse repair with and without mesh : a secondary analysis of a r and omised controlled trial . BJOG 2012;119:354–360 [11744900] OBJECTIVE The purpose of this study was to compare outcomes after anterior colporrhaphy with the use of 3 different surgical techniques . STUDY DESIGN One hundred fourteen women with anterior vaginal prolapse were r and omly assigned to undergo anterior repair by one of 3 techniques : st and ard , st and ard plus polyglactin 910 mesh , or ultralateral anterior colporrhaphy . Before and after operation , patients underwent physical examination staging of prolapse ; the International Continence Society system was used . Symptoms were assessed by question naire and visual analog scales . We defined " cure " as satisfactory ( stage I ) or optimal ( stage 0 ) outcome at points Aa and Ba . RESULTS Of 114 patients who were originally enrolled , 109 patients underwent operation , and 83 patients ( 76 % ) returned for follow-up . Mean age ( + /- SD ) was 64.7 + /- 11.1 years . At entry , 7 patients ( 7 % ) had stage I anterior vaginal prolapse ; 35 patients ( 37 % ) had stage II anterior vaginal prolapse ; 51 patients ( 54 % ) had stage III anterior vaginal prolapse ; and 2 patients ( 2 % ) had stage IV anterior vaginal prolapse . At a median length of follow-up of 23.3 months , 10 of 33 patients ( 30 % ) who were r and omly assigned to the st and ard anterior colporrhaphy group experienced satisfactory or optimal anatomic results , compared with 11 of 26 patients ( 42 % ) with st and ard plus mesh and with 11 of 24 patients ( 46 % ) with ultralateral anterior colporrhaphy . The severity of symptoms that were related to prolapse improved markedly ( preoperative score , 6.9 + /- 2.7 ; postoperative score , 1.1 + /- 0.8 ) . Twenty-three of 24 patients ( 96 % ) no longer required manual pressure to void after operation . CONCLUSION These 3 techniques of anterior colporrhaphy provided similar anatomic cure rates and symptom resolution for anterior vaginal prolapse repair . The addition of polyglactin 910 mesh did not improve the cure rate compared with st and ard anterior colporrhaphy [17712655] Background . The aim of this prospect i ve , r and omised , study was to determine whether or not there was a higher incidence of bleeding , reoperation , urinary retention or bacterial count in the urine , depending on whether urinary catheter and vaginal pack was removed 3 h or 24 h after vaginal prolapse surgery . Methods . Some 136 women were r and omised into Group 1 ( removal of catheter and vaginal pack after 3 h ) , and Group 2 ( removal of catheter and vaginal pack after 24 h ) . Data on postoperative bleeding , reoperation , and urinary retention were collected . Preoperatively , day after operation , and 14 days after operation , a urine culture was performed . Results . There was no tendency towards more bleeding with early removal of vaginal pack and urinary catheter . No patients in either group were reoperated during the first 48 postoperative hours . Three patients in Group 1 required sterile intermittent catheterisation postoperatively , however , only once in 2 patients . There was a trend towards a higher postoperative bacterial count in patients in Group 2 ( p = 0.306 ) . Conclusion . We recommend removing the vaginal pack and urinary catheter after 3 h with careful monitoring of the patient 's voiding [22716974] BACKGROUND Women without stress urinary incontinence undergoing vaginal surgery for pelvic-organ prolapse are at risk for postoperative urinary incontinence . A midurethral sling may be placed at the time of prolapse repair to reduce this risk . METHODS We performed a multicenter trial involving women without symptoms of stress incontinence and with anterior prolapse ( of stage 2 or higher on a Pelvic Organ Prolapse Quantification system examination ) who were planning to undergo vaginal prolapse surgery . Women were r and omly assigned to receive either a midurethral sling or sham incisions during surgery . One primary end point was urinary incontinence or treatment for this condition at 3 months . The second primary end point was the presence of incontinence at 12 months , allowing for subsequent treatment for incontinence . RESULTS Of the 337 women who underwent r and omization , 327 ( 97 % ) completed follow-up at 1 year . At 3 months , the rate of urinary incontinence ( or treatment ) was 23.6 % in the sling group and 49.4 % in the sham group ( P<0.001 ) . At 12 months , urinary incontinence ( allowing for subsequent treatment of incontinence ) was present in 27.3 % and 43.0 % of patients in the sling and sham groups , respectively ( P=0.002 ) . The number needed to treat with a sling to prevent one case of urinary incontinence at 12 months was 6.3 . The rate of bladder perforation was higher in the sling group than in the sham group ( 6.7 % vs. 0 % ) , as were rates of urinary tract infection ( 31.0 % vs. 18.3 % ) , major bleeding complications ( 3.1 % vs. 0 % ) , and incomplete bladder emptying 6 weeks after surgery ( 3.7 % vs. 0 % ) ( P≤0.05 for all comparisons ) . CONCLUSIONS A prophylactic midurethral sling inserted during vaginal prolapse surgery result ed in a lower rate of urinary incontinence at 3 and 12 months but higher rates of adverse events . ( Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institutes of Health Office of Research on Women 's Health ; OPUS Clinical Trials.gov number , NCT00460434 . ) [22067717] OBJECTIVE : To report 2-year outcomes of a r and omized controlled trial comparing st and ard anterior colporrhaphy with reinforced vaginal paravaginal repair using xenograft or synthetic mesh in women with symptomatic anterior vaginal wall prolapse . METHODS : Women with stage II or greater anterior prolapse were r and omly assigned to three groups : anterior colporrhaphy , paravaginal repair with porcine dermis , or polypropylene mesh . Outcomes of prolapse stage , quality of life , degree of bother , and sexual symptoms were assessed by blinded examiners and vali date d measures at 2 years . Anatomic failure was defined as anterior prolapse at stage II or greater . Composite failure was defined as symptoms of “ bulge ” and anterior prolapse at stage II or greater . Power calculations determined 33 participants per arm would detect a 40 % difference in anatomic success between st and ard and grafted repair . & khgr;2 , Mann-Whitney U , and Student 's t tests were used for comparisons . RESULTS : Of the 99 participants enrolled , 78 ( 79 % ) completed a minimum of 2-year follow-up . Those with mesh had a significantly lower anatomic failure rate ( 18 % ) than both the porcine ( 46 % , P=.015 ) and colporrhaphy groups ( 58 % , P=.002 ) . All groups had statistically similar reductions in their prolapse and urinary symptom subscale scores . Composite failure was not statistically different between groups : 13 % colporrhaphy , 12 % porcine , and 4 % mesh . Two reoperations for anterior prolapse occurred in the porcine group . Mesh erosion rates were 14 % for the mesh group . CONCLUSION : Vaginal paravaginal repair with polypropylene mesh has the lowest anatomic failure rate when compared with that with xenograft and anterior colporrhaphy without differences in composite failures . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT0139171 . LEVEL OF EVIDENCE : [21895613] Objective . To determine the long‐term objective and subjective outcomes of use of a porcine skin graft ( Pelvicol ™ ) compared with conventional colporrhaphy in recurrent pelvic organ prolapse surgery and to analyze risk factors and safety . Design . Open r and omized controlled multicenter study . Setting . Eight Swedish hospitals . Population . 135 consecutive women with recurrent cystocele and /or rectocele admitted for vaginal prolapse surgery ; 132 completed the study , 64 were r and omly allocated to receive conventional colporrhaphy and 68 to Pelvicol . Methods . Conventional anterior and posterior colporrhaphy and colporrhaphy with use of Pelvicol ™ mesh reinforcement . Clinical evaluation by means of pelvic organ prolapse quantification ( POP‐Q ) and symptom question naire preoperatively , three months and three years postoperatively . Main outcome measures . Anatomical and subjective outcome . Recurrence was defined as POP‐Q≥stage 2 . Results . At three‐month follow‐up , early recurrence/surgical failures occurred significantly more often in the Pelvicol ™ group , but at the three‐year follow‐up the recurrence rates were similar . The recurrence rates in the anterior compartment were 57–62 % and 44–23 % in the posterior compartment for the colporrhaphy and Pelvicol ™ groups , respectively . Symptoms were substantially and equally reduced in the two groups after surgery . Sexual activity and function did not seem to be affected adversely in any group . The complication rate was low . Risk factors for anatomical recurrence were age , body mass index and preoperative stage of the prolapse . Conclusions . With the surgical technique used in this study , Pelvicol ™ did not provide advantages over conventional colporrhaphy in recurrent pelvic organ prolapse concerning anatomical and subjective outcomes [19546759] OBJECTIVE : To compare outcomes of anterior colporrhaphy alone to that reinforced with bovine pericardium graft . METHODS : Women with anterior vaginal wall prolapse were enrolled in a r and omized fashion in this grafted compared with nongrafted repair study . Outcome measures included pelvic organ prolapse quantification data , quality -of-life assessment , healing abnormalities , and complications . RESULTS : Ninety-four patients were enrolled . Seventy-two ( 77 % ) provided 1-year data , and 59 ( 63 % ) supplied 2-year data . Demographics and stage of prolapse were similar between groups at baseline . Postoperative complications consisted basically of low urinary tract infection and were low in both groups ( 10 in bovine pericardium graft and 16 in anterior colporrhaphy alone ) . One year after surgery , successful anterior vaginal wall support was obtained in 85.7 % of the bovine pericardium graft group and 78.4 % of anterior colporrhaphy – alone group ( P=.544 ) . For the cohort that comprised 2-year analyses , the success rate was 76.5 % for the bovine pericardium graft group and 63 % for anterior colporrhaphy – alone group ( P=.509 ) . Postoperative Urogenital Distress Inventory-6 and Pelvic Organ Prolapse – Urinary Incontinence Sexual Function Question naire-12 scores were uniformly improved over baseline in both groups . CONCLUSION : The use of bovine pericardium graft for anterior vaginal prolapse does not have higher complication rates or healing difficulties . At 1- and 2-year follow-up , anterior colporrhaphy with bovine pericardium reinforcement did not show a statistically significant improvement over colporrhaphy alone . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00860912 LEVEL OF EVIDENCE : [21335940] Aim : To compare the effect of suprapubic and transurethral catheterization on postvoid residual volumes ( PRVs ) after cystocele repair . Methods : 126 women who underwent pelvic organ prolapse surgery including cystocele repair were r and omized to suprapubic or transurethral catheterization . At the third postoperative day , PRVs were measured . The number of women with PRV > 150 ml , need for prolonged catheterization , recatheterization , length of hospital stay , frequency of urinary tract infections and complications were determined . Results : PRVs exceeded 150 ml in 13 out of 64 ( 20 % ) and 14 out of 62 ( 23 % ) women in the suprapubic and transurethral group , respectively ( p = 0.76 ) . In the suprapubic group a higher rate of urine leakage was noted ( 27 vs. 7 % , p = 0.003 ) . 10 women ( 16 % ) allocated to the suprapubic group switched to transurethral catheterization , because of problems with the suprapubic catheter . No protocol deviations were reported in the transurethral group . Of the women in both groups , 9 % developed urinary tract infections ( p = 0.93 ) . Conclusions : Suprapubic catheterization was comparable to transurethral catheterization in the prevention of postoperative voiding dysfunction after vaginal prolapse surgery , but it was associated with a higher rate of complications [15270931] Objective To determine whether prolonged urinary bladder catheterisation after vaginal prolapse surgery is advantageous [20428997] Introduction and hypothesisThis study seeks to compare the small intestine submucosa ( SIS ) graft with traditional colporrhaphy ( TC ) for surgical treatment of anterior vaginal prolapse . Methods Subjects were r and omly assigned to SIS ( n = 29 ) or to TC ( n = 27 ) preoperatively and outcomes analyzed at 12 months postoperatively . The primary outcome was the absence of POP-Q stage ≥ II prolapse , and secondary outcome was improvement in quality of life . Data were compared with independent sample s or paired Student ’s t test . Results SIS group had 86.2 % anatomic cure compared to 59.3 % in TC ( p = 0.03 ) . SIS improved point Ba measurement significantly ( −1.93 cm versus −1.37 cm , p = 0.02 ) . Both operations significantly improved quality of life , although there were no differences between the groups . We observed a greater number of complications in the SIS group , with no infections or erosion . Conclusions SIS repair improved point Ba significantly . However , there were no differences observed in quality of life between the techniques [24054381] OBJECTIVE To compare the effects of two surgical procedures for the correction of anterior vaginal wall prolapse ( AVWP ) on the lower urinary tract symptoms ( LUTS ) using symptom question naires and quality of life ( QoL ) . MATERIAL S AND METHODS One hundred women with Pelvic Organ Prolapse Quantification stage ( POP-Q ) ≥ 2 were r and omly distributed in two preoperatory groups . The first group ( mesh ) ( n = 45 ) received a polypropylene mesh ( PM ) implant and the control group ( n = 55 ) was su bmi tted to anterior colporraphy with or without synthetic sling . Postoperatory follow-up was done after 12 months . The primary objective was to compare the effect of the surgeries on LUTS using the final scores of the International Consultation on Incontinence Question naire Urinary Incontinence Short Form ( ICIQ-UI SF ) and Overactive Bladder Question naire ( OAB-V8 ) , as well as the analysis of the incapacitating urinary symptoms and ″de novo″ urinary symptoms after 12 months of surgery in both groups . RESULTS Although there was a different number of women in each group , r and omization was adequate , result ed in homogeneous groups that could be compared regarding socio demographic , clinical and gynecological ( POP-Q ) variables . Patients of both groups showed improvements regarding LUTS and QoL , whether using polypropylene mesh or not , based on the final scores of the ICIQ-UI SF and OAB-V8 question naires after 12-month follow-up . There were few incapacitating and ″de novo ″ urinary symptoms , without any significant statistical difference between both groups after 12 months of surgery . CONCLUSION There was a general improvement of LUTS and QoL in both groups after 12-month follow-up . However , there was no significant difference of LUTS , as well as the more incapacitating and ″de novo ″ urinary symptoms between both groups after 12 months of surgery [18716704] To evaluate whether symptom resolution and sexual function is better after reinforcement with polypropylene mesh than with traditional anterior repair . Ninety-seven patients were r and omized to anterior colporrhaphy and 105 to an operation with mesh . Participants were evaluated up to 24 months by physical examination , st and ard questions , and question naire . The overall symptom rate did not differ between the groups , but a sensation of vaginal bulge was reported less frequently in the mesh group , the figures being 17 versus 5 ( p = 0.003 ) . The recurrence rate for the no-mesh group was 41 % and for the mesh group 11 % ( p < 0.001 ) . The dyspareunia score was statistically significantly lower in the mesh group ( p = 0.015 ) . The mesh exposure rate was 8 % . Sensation of vaginal bulge was relieved more efficiently by the mesh technique without causing dyspareunia [22930216] Introduction and hypothesisIn surgery for pelvic organ prolapse ( POP ) the use of alloplastic meshes has become common . Among possible complications , mesh exposure is the most frequent problem . It is hypothesized that exposure rates are correlated to mesh weight and the amount of foreign material . Therefore , we conducted a prospect i ve open-label r and omized multicenter trial comparing a conventional polypropylene mesh ( PP ) with a partially absorbable polypropylene mesh ( PA ) for cystocele treatment . Methods A total of 200 patients with POP > stage I were r and omized either to a conventional or a partially absorbable mesh . Exposure rates were observed after 3 , 12 , and 36 months and correlated to mesh material , patient characteristics , intraoperative data , and treatment centers . Furthermore , management of mesh exposure , satisfaction with surgery , and postoperative pain were evaluated . Results At all follow-up intervals mesh exposure rate was smaller in the group of the partially absorbable mesh ( 3 months PP 11.3 % vs PA 3.2 % , p = 0.0492 ; 12 months 6.6 % vs 6.3 % ; 36 months 7.5 % vs 3.4 % ) . Over the course of time , mesh exposure was observed in 27 patients , with surgical intervention necessary in 11 patients . The rate of recurrent POP was higher ( p > 0.05 ) in patients with the partially absorbable mesh . The majority of patients were fully satisfied with the operation ( 52.8 % ) and had no pelvic floor pain ( 67.5 % ) . Conclusion In this prospect i ve , r and omized trial with a long-term follow-up there was a low exposure rate in both treatment groups with a trend toward fewer exposures in the group of the partially absorbable mesh [21860294] OBJECTIVE : To compare the diagnostic accuracy of two voiding trial methods to predict postoperative voiding dysfunction . METHODS : Women undergoing operations for urinary incontinence , prolapse , or both urinary incontinence and prolapse from November 2009 and March 2010 were r and omized into one of two groups : retro grade or spontaneous . All patients underwent both techniques of voiding trials with r and omization determining order . RESULTS : Fifty women were r and omized to 25 per group . Failure rates were 62 % for retro grade and 84 % for spontaneous . Women who failed both had 12.6±14.4 days of retention compared with 2.5±2.1 days for those who failed only one method ( P=.004 ) . The retro grade method had 94.4 % sensitivity and 58.1 % specificity to detect postoperative voiding dysfunction lasting at least 7 days compared with the spontaneous method with 100 % sensitivity and 25.8 % specificity . Positive and negative predictive values for the retro grade method were 56.7 % and 94.7 % , respectively , compared with the spontaneous method with 43.9 % and 100 % . Retro grade was preferred by patients ( 51.1 % compared with 44.4 % ) regardless of r and omization . CONCLUSION : The retro grade method is more accurate in evaluating postoperative voiding dysfunction , although both tests had a low positive predictive value . A longer period of retention was seen with failure of both methods . Retro grade was preferred by patients and provides an efficient alternative to the spontaneous method of voiding trial . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT01091844 . LEVEL OF EVIDENCE : [24573358] Introduction and hypothesisOur aim was to compare anatomical and functional outcome between vaginal colposuspension and transvaginal mesh . Methods This was a prospect i ve r and omized controlled trial in a teaching hospital . Sixty-eight women with stage ≥3 anterior vaginal wall prolapse according to the Pelvic Organ Prolapse Quantification ( POP-Q ) system were assessed , r and omized , and analyzed . Patients were r and omized to anterior colporrhaphy with vaginal colposuspension ( n = 35 ) or transvaginal mesh ( n = 33 ) . Primary outcome was objective cure rate of the anterior vaginal wall , defined as POP-Q ≤1 at 2 years . Secondary outcomes were functional results , quality -of-life ( QoL ) scores , mesh-related morbidity , and onset of urinary incontinence . Results The anatomical result for point Ba was significantly better at 2 years in the mesh group ( −2.8 cm ) than in the colposuspension group ( −2.4 cm ) ( p = 0.02 ) . Concerning POP-Q stages , the anatomical success rate at 2 years was 84.4 % for colposuspension and 100 % for mesh ( p = 0.05 ) . There were 5 anatomic recurrences ( 15.6 % ) in the colposuspension group . The erosion rate was 6 % ( n = 2 ) . No significant difference was noted regarding minor complications . Analysis of QoL question naires showed overall improvement in both groups , with no significant difference between them . Conclusions The vaginal colposuspension technique of anterior vaginal wall prolapse repair gave good anatomical and functional results at 2 years . Transobturator vaginal mesh gave better 2-year anatomical results than vaginal colposuspension , with overall improvement in QoL in both groups [21545996] OBJECTIVE The purpose of this study was to reanalyze the results of a previously published trial that compared 3 methods of anterior colporrhaphy according to the clinical ly relevant definitions of success . STUDY DESIGN A secondary analysis of a trial of 114 subjects who underwent surgery for anterior pelvic organ prolapse who were assigned r and omly to st and ard anterior colporrhaphy , ultralateral colporrhaphy , or anterior colporrhaphy plus polyglactin 910 mesh from 1996 - 1999 . For the current analysis , success was defined as ( 1 ) no prolapse beyond the hymen , ( 2 ) the absence of prolapse symptoms ( visual analog scale ≤ 2 ) , and ( 3 ) the absence of retreatment . RESULTS Eighty-eight percent of the women met our definition of success at 1 year . One subject ( 1 % ) underwent surgery for recurrence 29 months after surgery . No differences among the 3 groups were noted for any outcomes . CONCLUSION Re analysis of a trial of 3 methods of anterior colporrhaphy revealed considerably better success with the use of clinical ly relevant outcome criteria compared with strict anatomic criteria [24737300] Introduction The natural history of pelvic organ prolapse ( POP ) is poorly understood . We investigated the prevalence and risk factors of postnatal POP in premenopausal primiparous women and the associated effect of mode of delivery . Methods We conducted a prospect i ve cohort study in a tertiary teaching hospital attending 9,000 deliveries annually . Collagen-diseases history and clinical assessment was performed in 202 primiparae at ≥1 year postnatally . Assessment included Pelvic Organ Prolapse Quantification ( POP-Q ) system , Beighton mobility score , 2/3D-transperineal ultrasound ( US ) and quantification of collagen type III levels . Association with POP was assessed using various statistical tests , including logistic regression , where results with p < 0.1 in univariate analysis were included in multivariate analysis . Results POP had a high prevalence : uterine prolapse 89 % , cystocele 90 % , rectocele 70 % and up to 65 % having grade two on POP-Q staging . The majority had multicompartment involvement , and 80 % were asymptomatic . POP was significantly associated with joint hypermobility , vertebral hernia , varicose veins , asthma and high collagen type III levels ( p < 0.05 ) . In multivariate logistic regression , only levator ani muscle ( LAM ) avulsion was significant in selected cases ( p < 0.05 ) . Caesarean section ( CS ) was significantly protective against cystocele and rectocele but not for uterine prolapse . Conclusions Mild to moderate POP has a very high prevalence in premenopausal primiparous women . There is a significant association between POP , collagen levels , history of collagen disease and childbirth-related pelvic floor trauma . These findings support a congenital contribution to POP etiology , especially for uterine prolapse ; however , pelvic trauma seems to play paramount role . CS is significantly protective against some types of prolapse only [23124692] Introduction and hypothesisThe aim of this study was to compare the lower urinary tract symptom changes and surgical outcome between the tension-free vaginal tape ( TVT ) procedure with and without concomitant stage II pelvic organ prolapse ( cystocele ) repair in a r and omized clinical trial setting . Methods Patients with urodynamically proven stress urinary incontinence ( SUI ) and asymptomatic stage II cystocele were r and omly and equally allocated to either a TVT and concomitant cystocele repair group or TVT only group . SUI was corrected with TVT in all cases . The cystocele repair procedure was performed with Gynemesh ® . Lower urinary tract symptoms and surgical outcome were assessed at postoperative year 1 . Lower urinary tract symptoms were assessed with the American Urological Association Symptom Score ( AUASS ) question naire , uroflowmetry , and postvoid residual ( PVR ) . Results The cure rate of TVT only and the concomitant repair group was 87 and 91 % , respectively ( p > 0.05 ) . Cystocele was cured in all patients in the concomitant repair group . After the operation , the total AUASS were 6.4 and 8.4 in the TVT only group and concomitant repair group , respectively , with no statistical difference . There was no difference in the change in peak flow rate ( Qmax ) and PVR between the two groups . The prevalence of postoperative mixed incontinence was not different between the two groups . Conclusions In patients with stage II cystocele and SUI , there was no difference in the surgical outcome and lower urinary tract symptoms between the TVT sling only group and concomitant repair group . Cystocele repair can be safely omitted in patients with stage II cystocele [21252735] OBJECTIVE : To compare efficacy and safety of trocar-guided tension-free vaginal mesh insertion with conventional vaginal prolapse repair in patients with recurrent pelvic organ prolapse . METHODS : Patients with recurrent pelvic organ prolapse stage II or higher were r and omly assigned to either conventional vaginal prolapse surgery or polypropylene mesh insertion . Primary outcome was anatomic failure ( pelvic organ prolapse stage II or higher ) in the treated vaginal compartments . Secondary outcomes were subjective improvement , effects on bother , quality of life , and adverse events . Question naires such as the Incontinence Impact Question naire and Urogenital Distress Inventory were administered at baseline , 6 months , and 12 months . Anatomic outcomes were assessed by an unblinded surgeon . Power calculation with & agr;=0.05 and & bgr;=0.80 indicated that 194 patients were needed . RESULTS : Ninety-seven women underwent conventional repair and 93 mesh repair . The follow-up rate after 12 months was 186 of 190 patients ( 98 % ) . Twelve months postsurgery , anatomic failure in the treated compartment was observed in 38 of 84 patients ( 45.2 % ) in the conventional group and in eight of 83 patients ( 9.6 % ) in the mesh group ( P<.001 ; odds ratio , 7.7 ; 95 % confidence interval , 3.3–18 ) . Patients in either group reported less bulge and overactive bladder symptoms . Subjective improvement was reported by 64 of 80 patients ( 80 % ) in the conventional group compared with 63 of 78 patients ( 81 % ) in the mesh group . Mesh exposure was detected in 14 of 83 patients ( 16.9 % ) . CONCLUSION : At 12 months , the number of anatomic failures observed after tension-free vaginal mesh insertion was less than after conventional vaginal prolapse repair . Symptom decrease and improvement of quality of life were equal in both groups . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00372190 . LEVEL OF EVIDENCE : [23508540] OBJECTIVE To compare success rates between anterior colporrhaphy and abdominal paravaginal defect repair for treatment of anterior vaginal wall prolapse . METHODS This was a prospect i ve r and omized controlled trial comparing anterior colporrhaphy plus polyglactin 910 mesh ( vaginal ) to paravaginal defect repair ( abdominal ) in women with symptomatic anterior vaginal wall prolapse . Pelvic organ prolapse quantification staging ( POP-Q ) , pelvic floor distress inventory , pelvic floor impact question naire , and pelvic organ prolapse/urinary incontinence sexual question naires were administered pre and post-operatively . Women were followed up to 2 years . The primary outcome was anterior POP-Q stage , with failure defined as ≥stage II . RESULTS We enrolled 70 patients , 35 in each group . Demographic and most peri-operative characteristics were similar between the groups . Mean anterior vaginal wall prolapse repair time ( 39 min ) was shorter for vaginal versus abdominal repair ( 60 min ; P < 0.001 ) , with more concurrent hysterectomies in the vaginal ( 71 % ) versus abdominal group ( 42 % ) , P = 0.01 . At 2 years , objective failure rates for the vaginal and abdominal groups were 32 % and 40 % , respectively , P = 0.56 . Subjective failure rates were lower and similar for both groups . Patient satisfaction rates were 88 % for the vaginal and 73 % for the abdominal group , P = 0.11 . Quality of life question naires showed significant improvement from baseline but no difference between the groups ( P = 0.12 ) . CONCLUSIONS At 2 years follow-up , anterior colporrhaphy with polyglactin 910 mesh and abdominal paravaginal defect repair have similar success rates , with most objective failures being asymptomatic [22453316] Objectives The goals of this study were to assess the effect of a st and ardized postoperative bowel regimen of over-the-counter medications on ( 1 ) time to first bowel movement ( BM ) and ( 2 ) pain level associated with first BM in subjects undergoing minimally invasive urogynecologic surgery . Methods Eligible patients scheduled to undergo minimally invasive urogynecologic surgery were offered participation . Enrolled subjects were r and omized by computerized schedule . Demographic and perioperative data were collected . Subjects completed a vali date d question naire preoperatively and postoperatively assessing preexisting constipation , frequency and consistency of bowel movements , use of pain medications , mean daily pain level ( using visual analog scale ) , stool consistency , and pain associated with first postoperative bowel movement . The control group was instructed to take docusate sodium twice daily postoperatively . The treatment group took docusate sodium plus Miralax , fiber wafers , and bisacodyl suppositories as directed by protocol . Wilcoxon or t testing was used to compare continuous variables ; & khgr;2 testing was used for categorical relationships , and backward-elimination multiple regression was used to assess independent effects . Results Seventy-two subjects were enrolled and r and omized . Twelve subjects withdrew , leaving 60 ( 30 per group ) completing the study . There were no statistically significant differences between groups in baseline characteristics . Mean ( SD ) age was 63 ( 9 ) years for the control group and 58 ( 10 ) for the study group ( P = 0.06 ) . Mean pelvic organ prolapse stage was III in each group . The mean ( SD ) operating room time was 198 ( 65 ) minutes for the controls and 216 ( 74 ) for the study subjects . Sixty-five percent underwent robot-assisted surgery ( 50 % hysterectomy and 63 % sacrocolpopexy ) . Ninety-eight percent of surgeries were performed under general anesthesia . Before adjustment , the mean ( SD ) time to first BM was 77 ( 24 ) hours in controls versus 64 ( 21 ) in the study patients ( P = 0.03 ) . Using multiple regression , baseline frequency of defecation ( 1–2 BMs/wk ) was directly associated with the time to first BM ( added 25.2 hours ; P = 0.009 ) and being in the study group was inversely associated ( first BM , 11.7 hours sooner ; P = 0.04 ) . No other variables were retained . There was no difference in pain associated with first postoperative BM ( visual analog scale , 3.6 ( 3.2 ) vs 3.7 ( 2.8 ) ; P = 0.98 ) , but those with prior complaints of vaginal or rectal splinting had higher pain scores ( 1.9 and 2.8 points higher , respectively ; P = 0.04 for both ) . There was a trend toward higher pain scores with higher postoperative daily narcotic intake ( P = 0.06 ) . No other variables were retained . There was a significant difference in recorded compliance between control versus study regimens ( 94 % vs 81 % , respectively ; P = 0.002 ) . Conclusions Mean time to first postoperative BM after minimally invasive urogynecologic surgery is more than 3.5 days with use of docusate sodium alone and is only slightly shorter when combination therapy is used . First BM after surgery is considered to be painful despite the use of medications . Future studies targeting postoperative discomfort/pain with defecation could target preoperative bowel regimens or more aggressive postoperative interventions . Regimens should remain simple to increase compliance [18639302] PURPOSE We evaluated the impact of Burch colposuspension as an anti-incontinence measure in patients with urinary incontinence undergoing abdominal surgery for pelvic organ prolapse repair . MATERIAL S AND METHODS A total of 47 women with pelvic organ prolapse and urinary incontinence were r and omly assigned to abdominal pelvic organ prolapse repair and concomitant Burch colposuspension ( 24 patients , group A ) or pelvic organ prolapse repair alone without an anti-incontinence procedure ( 23 patients , group B ) . They were followed up at 3 , 6 and 9 months after surgery , and then annually . The primary outcome measures were anatomical outcome and changes in incontinence status as indicated by a bladder diary , the number of daily pads and the stress test . Secondary end points were changes in subjective symptoms and quality of life as measured by the Urogenital Distress Inventory and the Incontinence Impact Question naire . RESULTS In group A 13 of 24 patients ( 54.2 % ) were still incontinent after surgery compared with 9 of 23 ( 39.1 % ) in group B. The intragroup difference was significant ( group A p = 0.003 , group B p = 0.0001 ) , but there was no significant intergroup difference ( p = 0.459 for A vs B ) . No significant intergroup difference emerged in anatomical outcome . Urogenital Distress Inventory and Incontinence Impact Question naire scores improved in both groups ( p = 0.0001 ) but the intergroup difference was not significant in either question naire ( p = 0.769 and p = 0.327 , respectively ) . CONCLUSIONS Burch colposuspension does not provide any additional benefit in pelvic organ prolapse repair in patients with urinary incontinence [19940978] Introduction and hypothesisThis study aims to compare the result of an incontinence procedure performed at the time of prolapse repair or 3 months later in women with pelvic organ prolapse ( POP ) and stress urinary incontinence ( SUI ) . Methods In a multicenter prospect i ve r and omized trial , women with POP and SUI were r and omized to have a tension-free vaginal tape ( TVT ) at the time of prolapse repair ( n = 87 ; group I ) or 3 months later ( n = 94 ; group II ) . Women in group II were evaluated for SUI 3 months after the prolapse repair . Those with confirmed SUI had a TVT performed ( n = 53 ) . The main evaluation of all women was 1 year after the last surgery . Results On-treatment analysis result ed in 95 % cure of SUI in group I and 89 % in group II ( p = 0.12 ) . Twenty-seven percent were cured after prolapse surgery alone . Conclusions No differences were found between the two treatment strategies , but almost one third of women were cured of SUI by prolapse surgery alone [19731311] AIMS To investigate the urodynamic effects of anterior vaginal wall prolapse surgery using either trocar guided transvaginal mesh or colporraphy . METHODS A prospect i ve , r and omized multicenter trial enrolling 50 patients : 27 underwent anterior colporrhaphy and 23 anterior trocar guided transvaginal mesh . Urodynamic assessment was performed pre- and two months postoperatively . RESULTS De novo stress urinary incontinence was significantly more common after trocar guided transvaginal mesh surgery compared to colporraphy . In comparison to baseline urodynamics , transvaginal mesh surgery result ed in a significant decrease in maximal urethral closing pressures ( MUCP ) whereas conventional anterior colporraphy had no significant effect on urodynamic parameters . CONCLUSION Trocar guided transvaginal mesh of anterior vaginal wall prolapse results in a lowering of MUCPs and increases the risk for de novo stress urinary incontinence compared to colporraphy [10799192] PURPOSE We prospect ively compared transvaginal antimicrobial mesh ( MycroMesh * ) and anterior vaginal wall slings using an outcomes analysis . MATERIAL S AND METHODS Between August 1997 and November 1998 we implanted transvaginal slings in 40 consecutive women r and omized to a synthetic mesh ( 20 ) or vaginal wall ( 20 ) group . All patients had documented stress urinary incontinence on preoperative urodynamics . We prospect ively compared postoperative outcomes data obtained from pelvic examinations , cough stress test , cotton swab test and vali date d patient question naires using a visual analog scale . RESULTS Complete followup was available in all patients . Mean followup was 22 months ( range 12 to 27 ) . Stress incontinence was cured in 95 % of the mesh and 70 % of the vaginal wall group , and pelvic prolapse was cured in 100 % and 95 % , respectively . Transient de novo urge incontinence was noted in 12.5 % of the mesh and 14.3 % of the vaginal wall group . Mean postoperative cotton swab angle during Valsalva 's maneuver was 20 and 45 degrees for the mesh and vaginal wall groups , respectively . The incidence of urinary retention and tissue erosion was 0 % for both groups . The satisfaction rate was 100 % and 80 % for the mesh and vaginal wall groups , respectively . CONCLUSIONS The antimicrobial MycroMesh sling was superior to the vaginal wall sling for correction of stress incontinence and pelvic prolapse with comparatively low morbidity [11408853] OBJECTIVE Our aim was to evaluate the efficacy of polyglactin 910 mesh in preventing recurrent cystoceles and rectoceles . STUDY DESIGN In a prospect i ve , r and omized , controlled trial , patients undergoing vaginal reconstructive surgery with cystoceles to the hymenal ring and beyond were r and omly selected to undergo anterior and posterior colporrhaphy with or without polyglactin 910 mesh reinforcement . Results were evaluated preoperatively and at 2 , 6 , 12 , and 52 weeks postoperatively . RESULTS A total of 161 women were r and omly selected for this study . One woman was excluded at the time of surgery , and 17 women were lost to follow-up . Eighty women received mesh , and 80 did not . Both groups were found to be equivalent with respect to age , parity , concomitant surgery , and menopausal and hormone replacement status . Preoperatively 49 women had a central cystocele to the hymenal ring and 111 women had cystoceles beyond the introitus ; 91 women had a rectocele to the mid-vaginal plane , 31 to the hymenal ring , and 22 beyond the introitus . After 1 year , 30 ( 43 % ) of 70 subjects without mesh and 18 ( 25 % ) of 73 subjects with mesh had recurrent cystoceles beyond the mid-vaginal plane ( P = .02 ) . Eight women without mesh and 2 women with mesh had recurrent cystoceles to the hymenal ring ( P = .04 ) . No recurrent cystoceles beyond the hymenal ring occurred in either group . Multivariate logistic regression analysis showed concurrent slings to be associated with significantly fewer recurrent cystoceles ( odds ratio , 0.32 ; P = .005 ) , whereas the presence of mesh remained significantly predictive of fewer cystocele recurrences in this analysis . Thirteen recurrent rectoceles were noted 1 year postoperatively , with no differences between groups . CONCLUSION Polyglactin 910 mesh was found to be useful in the prevention of recurrent cystoceles [23916584] OBJECTIVE To compare the anatomical and functional results of traditional anterior colporrhaphy and polypropylene mesh surgery in cystocele treatment . STUDY DESIGN Prospect i ve study conducted in the Urogynecology Clinic of Etlik Zubeyde Hanim Maternity and Women 's Health Teaching and Research Hospital between June 2006 and February 2007 . Forty patients with stage II and III cystocele according to the Pelvic Organ Prolapse Quantification system were allocated by a computer programme to conventional or mesh surgery . Twenty patients each underwent anterior colporrhaphy ( group I ) or polypropylene mesh ( Sofradim ( ® ) , Parieten ) surgery ( group II ) . Both groups were followed for 12 months . RESULTS At the end of the 12th month , anatomical cure rates were 15/20 ( 75 % ) and 19/20 ( 95 % ) in groups I and II , respectively , and the difference between the two groups was statistically significant ( p<0.05 ) . De novo stress urinary incontinence developed in one patient in group I. Mesh erosion developed postoperatively in three cases ( 15 % ) . CONCLUSION In terms of anatomical cure rates , polypropylene mesh surgery was the more successful treatment option when compared with anterior colporrhaphy at the end of 1 year follow-up [28052810] BACKGROUND The use of mesh in prolapse surgery is controversial , leading to a number of enquiries into its safety and efficacy . OBJECTIVE To compare synthetic non-absorbable mesh inlay , biological graft and mesh kit with a st and ard repair in terms of clinical effectiveness , adverse effects , quality of life ( QoL ) , costs and cost-effectiveness . DESIGN Two r and omised controlled trials within a comprehensive cohort ( CC ) study . Allocation was by a remote web-based r and omisation system in a 1 :1 : 1 ratio ( Primary trial ) or 1 : 1 : 2 ratio ( Secondary trial ) , and was minimised on age , type of prolapse repair planned , need for a concomitant continence procedure , need for a concomitant upper vaginal prolapse procedure and surgeon . Participants and outcome assessors were blinded to r and omisation ; participants were unblinded if they requested the information . Surgeons were not blinded to allocated procedure . SETTING Thirty-five UK hospitals . PARTICIPANTS Primary study : 2474 women in the analysis ( including 1348 r and omised ) having primary anterior or posterior prolapse surgery . Secondary study : 398 in the analysis ( including 154 r and omised ) having repeat anterior or posterior prolapse surgery . CC3 : 215 women having either uterine or vault prolapse repair . INTERVENTIONS Anterior or posterior repair alone , or with mesh inlay , biological graft or mesh kit . MAIN OUTCOME MEASURES Prolapse symptoms [ Pelvic Organ Prolapse Symptom Score ( POP-SS ) ] ; prolapse-specific QoL ; cost-effectiveness [ incremental cost per quality -adjusted life-year ( QALY ) ] . RESULTS Primary trials : adjusting for baseline and minimisation covariates , mean POP-SS was similar for each comparison { st and ard 5.4 [ st and ard deviation ( SD ) 5.5 ] vs. mesh 5.5 ( SD 5.1 ) , mean difference ( MD ) 0.00 , 95 % confidence interval ( CI ) -0.70 to 0.71 ; st and ard 5.5 ( SD 5.6 ) vs. graft 5.6 ( SD 5.6 ) , MD -0.15 , 95 % CI -0.93 to 0.63}. Serious non-mesh adverse effects rates were similar between the groups in year 1 [ st and ard 7.2 % vs. mesh 7.8 % , risk ratio ( RR ) 1.08 , 95 % CI 0.68 to 1.72 ; st and ard 6.3 % vs. graft 9.8 % , RR 1.57 , 95 % CI 0.95 to 2.59 ] . There were no statistically significant differences between groups in any other outcome measure . The cumulative mesh complication rates over 2 years were 2 of 430 ( 0.5 % ) for st and ard repair ( trial 1 ) , 46 of 435 ( 10.6 % ) for mesh inlay and 2 of 368 ( 0.5 % ) for biological graft . The CC findings were comparable . Incremental costs were £ 363 ( 95 % CI -£32 to £ 758 ) and £ 565 ( 95 % CI £ 180 to £ 950 ) for mesh and graft vs. st and ard , respectively . Incremental QALYs were 0.071 ( 95 % CI -0.004 to 0.145 ) and 0.039 ( 95 % CI -0.041 to 0.120 ) for mesh and graft vs. st and ard , respectively . A Markov decision model extrapolating trial results over 5 years showed st and ard repair had the highest probability of cost-effectiveness , but results were surrounded by considerable uncertainty . Secondary trials : there were no statistically significant differences between the r and omised groups in any outcome measure , but the sample size was too small to be conclusive . The cumulative mesh complication rates over 2 years were 7 of 52 ( 13.5 % ) for mesh inlay and 4 of 46 ( 8.7 % ) for mesh kit , with no mesh exposures for st and ard repair . CONCLUSIONS In women who were having primary repairs , there was evidence of no benefit from the use of mesh inlay or biological graft compared with st and ard repair in terms of efficacy , QoL or adverse effects ( other than mesh complications ) in the short term . The Secondary trials were too small to provide conclusive results . LIMITATIONS Women in the Primary trials included some with a previous repair in another compartment . Follow-up is vital to identify any long-term potential benefits and serious adverse effects . FUTURE WORK Long-term follow-up to at least 6 years after surgery is ongoing to identify recurrence rates , need for further prolapse surgery , adverse effects and cost-effectiveness . TRIAI REGISTRATION Current Controlled Trials IS RCT N60695184 . FUNDING This project was funded by the National Institute for Health Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol . 20 , No. 95 . See the NIHR Journals Library website for further project information [22082789] OBJECTIVE We wished to determine the feasibility of a single-centre r and omized controlled trial to investigate whether avoiding cystocele plication in women undergoing transvaginal repair of cystocele decreases the need for catheterization beyond the second postoperative day . METHODS Patients undergoing transvaginal repair of cystocele were r and omly assigned to either have or not have plication sutures during their procedure . We assessed the success of recruitment , physician acceptability , and adherence to protocol , and we also assessed the need for catheterization beyond the second postoperative day . RESULTS Twenty-two women were r and omized ( a recruitment rate of 85 % ) , and participating surgeons did not feel that one surgical technique was superior to the other . There were no protocol violations after r and omization . No cases of postoperative voiding dysfunction were identified . CONCLUSION A multicentre r and omized controlled trial is required to determine the short-term and long-term risks and benefits of avoiding plication sutures in women undergoing transvaginal repair of cystocele . If patients and physicians support the study protocol , conducting such a trial is feasible [21627429] Summary The effects at 2 years of polyglactin ( Vicryl ) mesh inlay and polydioxanone ( PDS ) or polyglactin ( Vicryl ) suture material on prolapse symptoms , urinary , bowel , sexual function and prolapse related Quality -of-Life ( QoL ) in women undergoing pelvic organ prolapse surgery were evaluated in a r and omised controlled trial with a 2 × 2 factorial design of Vicryl mesh ( n = 32 ) or not ( n = 34 ) and PDS ( n = 33 ) or Vicryl suture ( n = 33 ) . The response rate at 2 years was 82 % . There were no differences in the prolapse symptom scores between the r and omised groups . Prolapse-related QoL score ( mean difference : 2.05 , 95 % CI 0.19–3.91 ) and urinary incontinence score ( mean difference : 2.56 , 95 % CI 0.02–5.11 ) were significantly lower ( better ) in women who had Vicryl compared with PDS sutures . The apparent superiority of the prolapse-related QoL and urinary incontinence scores in women using Vicryl suture material ( vs PDS ) needs to be confirmed in a larger trial [26825408] Objective Placement of vaginal packing after pelvic reconstructive surgery is common ; however , little evidence exists to support the practice . Furthermore , patients have reported discomfort from the packs . We describe pain and satisfaction in women treated with and without vaginal packing . Methods This institutional review board – approved r and omized-controlled trial enrolled patients undergoing vaginal hysterectomy with prolapse repairs . The primary outcome was visual analog scales ( VASs ) for pain on postoperative day 1 . Allocation to “ packing ” ( “ P ” ) or “ no-packing ” ( “ NP ” ) arms occurred intraoperatively at the end of surgery . Visual analog scales regarding pain and satisfaction were completed early on postoperative day 1 before packing removal . Visual analog scale scores for pain , satisfaction , and bother attributable to packing were recorded before discharge . All packing and perineal pads were weighed to calculate a “ postoperative vaginal blood loss . ” Perioperative data were collected from the hospital record . Our sample size estimation required 74 subjects . Results Ninety-three women were enrolled . After exclusions , 77 were r and omized ( P , 37 ; NP , 40 ) . No differences were found in surgical information , hemoglobin levels , or narcotic use between groups . However , “ postoperative vaginal blood loss ” was greater in packed subjects ( P < 0.001 ) . Visual analog scale scores for pain before removal of packing ( P , 41.6 vs NP , 46.3 ; P = 0.43 ] and before discharge ( P , 35.0 vs NP , 40.0 ; P = 0.43 ] were not significantly different between treatment arms . Likewise , VAS scores for satisfaction before removal of packing ( P , 81.0 vs NP , 90.0 ; P = 0.08 ] and before discharge ( P , 90.0 vs NP , 90.5 ; P = 0.60 ] were not significantly different . Packed patients noted lower nursing verbal pain scores ( P = 0.04 ) and used less ketorolac ( P = 0.01 ) . Bother from packing was low overall . Conclusions Although there was no difference based on VAS , women receiving vaginal packing had lower nursing documented pain and used less ketorolac than packed women . Vaginal packing may provide benefit and can remain part of the surgical practice [26032041] OBJECTIVE Dexamethasone is a corticosteroid with minimal side effects that may improve quality of recovery . We sought to evaluate st and ard use of this medication prior to vaginal reconstructive surgery . STUDY DESIGN This was a double-blind , r and omized , placebo-controlled trial of women undergoing vaginal reconstructive surgery for pelvic organ prolapse . Patients scheduled for an intraperitoneal vaginal vault suspension , with general anesthesia and an overnight stay , were enrolled . The intervention arm received dexamethasone 60 minutes prior to surgery , and controls received placebo . Postoperative pain medications , antiemetics , and voiding trials were st and ardized . Our primary outcome was the difference in Quality of Recovery ( QoR-40 ) scores on postoperative day 1 . Secondary measures included Postoperative Nausea and Vomiting Intensity scores , and visual analog scales for nausea/vomiting , and pain . Our power calculation demonstrated 31 subjects in each group would be necessary to document difference in QoR-40 scores ; to allow for attrition , a goal of 74 subjects was set . RESULTS Seventy-four women were enrolled and r and omized . Two withdrew , 9 were excluded , and 63 were analyzed ( 36 placebo , 27 dexamethasone ) . The mean age was 63 years . No significant differences were noted among demographics other than American Society for Anesthesiologists class ; there were greater numbers of dexamethasone subjects that were class 3 ( 5 vs 11 ; P = .030 ) . Postoperatively , more patients in the placebo group required promethazine as a rescue antiemetic for control of their nausea/vomiting ( 11 vs 2 ; P = .029 ) . Placebo subjects also failed their voiding trials more frequently , which remained following a logistic regression controlling for suburethral sling ( 30 vs 15 ; P = .037 ) . Regarding the QoR-40 following surgery , the emotional state domain declined less in dexamethasone patients ( -14.3 , interquartile range [ IQR ] , 16.8 vs -4.6 , IQR , 20.1 ; P = .042 ) , indicating better symptoms . Whereas pain scales were similar , the visual analog scales for nausea/vomiting was lower in dexamethasone subjects ( 0.7 ; IQR , 4.1 vs 0.4 ; IQR , 1.4 ; P = .042 ) . Postoperative Nausea and Vomiting Intensity scores were not significantly different ; nevertheless , twice as many placebo subjects had severe range symptoms ( 4 vs 2 ; P = .47 ) . No adverse effects from the dexamethasone were noted . CONCLUSION Use of dexamethasone prior to vaginal reconstructive surgery was associated with less nausea/vomiting and need for antiemetics as well as greater success with voiding trials . Furthermore , quality of recovery was enhanced , suggesting use of dexamethasone should be considered for these patients [23812462] OBJECTIVE : To compare rates of de novo dyspareunia in women with and without vaginal dilator use after posterior colporrhaphy . METHODS : This r and omized controlled trial included sexually active patients with prolapse and no bothersome baseline dyspareunia undergoing posterior colporrhaphy . Patients were r and omized to daily vaginal dilator use from postoperative weeks 4 through 8 or to no dilator use . Pelvic organ prolapse quantification examination and vaginal caliber were measured at baseline , 8 weeks , and 6 months postoperatively . Sexual function was evaluated at baseline , 3 months , and 6 months postoperatively using the Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Question naire-12 . Participants completed a Patient Global Impression of Improvement at 3 months and 6 months postoperatively . RESULTS : Sixty patients were r and omized : 30 in the dilator group and 30 in the control group . There were no differences in baseline characteristics and postoperative vaginal caliber between groups . At 3 months , 9.5 % of patients reported de novo dyspareunia in the dilator group compared with 19.2 % of control patients ( P=.44 ) . At 6 months , 12.5 % of patients in the dilator group reported de novo dyspareunia compared with 3.8 % of control patients ( P=.34 ) . There was a 13 % loss-to-follow-up rate , and therefore we did not meet appropriate power to detect a difference . There were no differences in overall sexual function or Patient Global Impression of Improvement scores between groups at 3 months and 6 months . CONCLUSION : There were no significant differences in de novo dyspareunia rates , overall postoperative sexual function scores , or global improvement scores between those using vaginal dilators compared with control patients . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT01299363 . LEVEL OF EVIDENCE : [19781044] In a multicentre r and omised , unblinded patient preference pilot trial to assess the feasibility of a definitive r and omised trial comparing colposuspension with tension‐free vaginal tape ( TVT ) plus anterior repair in women with incontinence and prolapse , we found that 31 of 56 eligible women agreed to participate ( 55 % ) . Recruitment was more successful face to face ( 87 % ) than by letter ( 16 % ) . Only four of our women agreed to be r and omised , 21 ( 68 % ) chose anterior repair + TVT and six ( 19 % ) chose colposuspension . This study demonstrates the importance of pilot work for complex trials to identify issues likely to adversely affect recruitment [27687468] STUDY OBJECTIVE Compare the effectiveness of nerve stimulator-guided pudendal nerve block ( PNB ) vs general anesthesia ( GA ) for anterior and posterior ( AP ) colporrhaphy in terms of pain relief and analgesic consumption within 24 and 48 hours postoperatively . DESIGN Prospect i ve r and omized trial . PATIENTS Fifty-seven patients whose ages ranged between 20 and 53 years scheduled to undergo AP colporrhaphy due to the presence of cystorectocele . INTERVENTIONS Patients were r and omly assigned into 2 groups receiving either nerve stimulator-guided PNB ( n = 28 ) or GA ( n = 29 ) . A total volume of 0.7 mL/kg of the local anesthetic mixture was injected at 4 sites . MAIN RESULTS Both groups were similar with respect to age , weight , height , and surgery duration . There was a significant difference in average pain scores within the first and second postoperative days ( P values = .005 and .004 , respectively ) . Total analgesic consumption ( ketoprofen and tramadol ) was significantly lower in the PNB within the first ( P values = .018 and .010 ) and second postoperative days ( P values = .041 and .011 ) , respectively . Return to normal daily activity was significantly ( P < .0001 ) shorter in the PNB group compared with the GA group ( 3.6 days vs 12.2 days ) . A total of 71.4 % of the patients in the PNB group were satisfied compared with 27.8 % in the GA group ( P < .0001 ) . Surgeon satisfaction was significantly higher in the PNB group ( 82.1 % vs 34.5 % , P < .0001 ) . CONCLUSION This r and omized controlled trial demonstrated that nerve stimulator-guided PNB could be used as an alternative to GA for AP repair of stages I and II prolapse because it is associated with less postoperative pain and analgesic consumption , in addition to shorter duration of recovery [29030992] R and omised trials and their syntheses in meta‐analyses offer a unique opportunity to assess the frequency and severity of adverse reactions Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Obstructive sleep apnoea-hypopnoea is a syndrome characterised by recurrent episodes of partial or complete upper airway obstruction during sleep that are usually terminated by an arousal . Nasal continuous positive airway pressure is the primary treatment for obstructive sleep apnoea-hypopnoea , but many patients are unable or unwilling to comply with this treatment . Oral appliances are an alternative treatment for sleep apnoea . OBJECTIVES The objective was to review the effects of oral appliance in the treatment of sleep apnoea in adults . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

26186173

[6752873] One hundred and four patients with ankylosing spondylitis were involved in a comparative trial carried out in one single centre . They were given either pirprofene ( 1000 mg/day ) , indomethacin ( 125 mg/day ) or a placebo for 6 consecutive weeks . Response to treatment was assessed after 1 , 2 , 4 and 6 weeks on the basis of 4 subjective criteria and 6 st and ard measurements . The overall therapeutic results were judged by the investigator to be satisfactory in 87 % of patients in the pirprofene group , 77 % in the indomethacin group and 29 % in the placebo group ( p less than 0.01 ) . A large number of patients in each group ( including 34 % on placebo ) reported side effects . Treatment was discontinued on account of gastric pain in two patients ( one on pirprofen , the other on indomethacin ) . No abnormalities were detected in laboratory tests [16549855] Prognosis studies are investigations of future events or the evaluation of associations between risk factors and health outcomes in population s of patients ( 1 ) . The results of such studies improve our underst and ing of the clinical course of a disease and assist clinicians in making informed decisions about how best to manage patients . Prognostic research also informs the design of intervention studies by helping define subgroups of patients who may benefit from a new treatment and by providing necessary information about the natural history of a disorder ( 2 ) . There has recently been a rapid increase in the use of systematic review methods to synthesize the evidence on research questions related to prognosis . It is essential that investigators conducting systematic review s thoroughly appraise the method ologic quality of included studies to be confident that a study 's design , conduct , analysis , and interpretation have adequately reduced the opportunity for bias ( 3 , 4 ) . Caution is warranted , however , because inclusion of method ologically weak studies can threaten the internal validity of a systematic review ( 4 ) . This follows abundant empirical evidence that inadequate attention to biases can cause invalid results and inferences ( 5 - 9 ) . However , there is limited consensus on how to appraise the quality of prognosis studies ( 1 ) . A useful framework to assess bias in such studies follows the basic principles of epidemiologic research ( 10 , 11 ) . We focus on 6 areas of potential bias : study participation , study attrition , prognostic factor measurement , confounding measurement and account , outcome measurement , and analysis . The main objectives of our review of review s are to describe methods used to assess the quality of prognosis studies and to describe how well current practice s assess potential biases . Our secondary objective is to develop recommendations to guide future quality appraisal , both within single studies of prognostic factors and within systematic review s of the evidence . We hope this work facilitates future discussion and research on biases in prognosis studies and systematic review s. Methods Literature Search and Study Selection We identified systematic review s of prognosis studies by search ing MEDLINE ( 1966 to October 2005 ) using the search strategy recommended by McKibbon and colleagues ( 12 ) . This strategy combines broad search terms for systematic review s ( systematic review .mp ; meta- analysis .mp ) and a sensitive search strategy for prognosis studies ( cohort , incidence , mortality , follow-up studies , prognos * , predict * , or course ) . We also search ed the reference lists of included review s and method ologic papers to identify other relevant publications . We restricted our search to English- language publications . One review er conducted the search and selected the studies . Systematic review s , defined as review s of published studies with a comprehensive search and systematic selection , were included if they assessed the method ologic quality of the included studies by using 1 or more explicit criteria . We excluded studies if they were meta-analyses of independent patient data only , if their primary goal was to investigate the effectiveness of an intervention or specific diagnostic or screening tests , or if they included studies that were not done on humans . Data Extraction and Synthesis Individual items included in the quality assessment of the systematic review s were recorded as they were reported in the publication ( that is , the information that would be available to readers and future review ers ) . We review ed journal Web sites and contacted the authors of the systematic review s for additional information when authors made such an offer in their original papers . When review s assessed different study design s by using different sets of quality items , we extracted only those items used to assess cohort studies . We constructed a comprehensive list of distinct items that the review s used to assess the quality of their included studies . The full text of each review was screened . All items used by the review authors to assess the quality of studies were extracted into a computerized spreadsheet by 1 review er . Two experienced review ers , a clinical epidemiologist and an epidemiologist , independently synthesized the quality items extracted from the prognosis review s to determine how well the systematic review s assessed potential biases . We did this in 3 steps : 1 ) identified distinct concepts or domains addressed by the quality items ; 2 ) grouped each extracted quality item into the appropriate domain or domains ; and 3 ) identified the domains necessary to assess potential biases in prognosis studies . We then used this information to assess how well the review s ' quality assessment included items from the domains necessary to assess potential biases . After completing each of the first 3 steps , the review ers met to attempt to reach a consensus . The consensus process involved each review er presenting his or her observations and results , followed by discussion and debate . A third review er was available in cases of persistent disagreement or uncertainty . In the first step , all domains addressed by the quality items were identified . The first review er iteratively and progressively defined the domains as items were extracted from the included review s. The second review er defined domains from a r and om list of all extracted quality items . Limited guidance was provided to the review ers so that their assessment s and definitions of domains would be independent . The review ers agreed on a final set of domains that adequately and completely defined all of the extracted items . In the second step , review ers independently grouped each extracted item into the appropriate domains . Review ers considered each extracted item by asking , What is each particular quality item addressing ? or What are the review 's authors getting at with the particular quality assessment item ? . Items were grouped into the domain or domains that best represented the concepts being addressed . For example , the extracted items at least 80 % of the group originally identified was located for follow-up and follow-up was sufficiently complete or does n't jeopardize validity were each independently classified by both review ers as assessing the domain completeness of follow-up adequate , whereas the extracted item quantification and description of all subjects lost to follow-up was classified as assessing the domain completeness of follow-up described . In the third step , we identified the domains necessary to assess potential biases . Each review er considered the ability of the identified domains to adequately address , at least in part , 1 of the following 6 potential biases : 1 ) study participation , 2 ) study attrition , 3 ) prognostic factor measurement , 4 ) confounding measurement and account , 5 ) outcome measurement , and 6 ) analysis . Domains were considered to adequately address part of the framework if information garnered from that domain would inform the assessment of potential bias . For example , both review ers judged that the identified domain study population represents source population or population of interest assessed potential bias in a prognosis study , whereas the domain research question definition did not , although the latter is an important consideration in assessing the inclusion of studies in a systematic review . Finally , on the basis of our previous ratings , we looked at whether each review included items from the domains necessary to assess the 6 potential biases . We calculated the frequency of systematic review s by assessing each potential bias and the number of review s that adequately assessed bias overall . From this systematic synthesis , we developed recommendations for improving quality appraisal in future systematic review s of prognosis studies . We used Microsoft Access and Excel 2002 ( Microsoft Corp. , Redmond , Washington ) for data management and SAS for Windows , version 9.1 ( SAS Institute , Inc. , Cary , North Carolina ) for descriptive statistics . Role of the Funding Sources The funding sources , the Canadian Institutes of Health Research , the Canadian Chiropractic Research Foundation , the Ontario Chiropractic Association , and the Ontario Ministry of Health and Long Term Care , did not have a role in the collection , analysis , or interpretation of the data or in the decision to su bmi t the manuscript for publication . Results We identified 1384 potentially relevant articles . Figure 1 shows a flow chart of studies that were included and excluded . Figure 2 shows the number of review s identified by year of publication . We excluded 131 systematic review s of prognosis studies that did not seem to include any quality assessment of the included studies ; this represented 44 % of prognosis review s. We included 163 review s of prognosis studies in our analysis ( 13 - 175 ) . The most common topics were cancer ( 15 % ) , musculoskeletal disorders and rheumatology ( 13 % ) , cardiovascular ( 10 % ) , neurology ( 10 % ) , and obstetrics ( 10 % ) . Other review s included a wide range of health and health care topics . Sixty-three percent of the review s investigated the association between a specific prognostic factor and a particular outcome ; the remainder investigated multiple prognostic factors or models . The number of primary studies included in each systematic review ranged from 3 to 167 ( median , 18 [ interquartile range , 12 to 31 ] ) . A complete description of the included review s is available from the authors on request . Figure 1 . Flow diagram of inclusion and exclusion criteria of systematic review s. Figure 2 . Number of systematic review s of prognosis studies identified over time . Quality Items One hundred fifty-three review s provided adequate detail to allow extraction of quality items . Eight hundred eighty-two distinct quality items were extracted from the review s. Most review s developed their own set of quality items , with only a few applying criteria from previous review s. Most quality items [15731291] Objective : The combined efficacy of selective and non-selective cyclo-oxygenase-2 ( COX-2 ) inhibition on the axial manifestations of ankylosing spondylitis ( AS ) in the presence or absence of chronic peripheral arthritis was evaluated . Methods : In a post hoc subgroup analysis of a 6 week , r and omised , double blind , placebo controlled trial , 387 patients with active axial AS were r and omised to receive etoricoxib 90 mg or 120 mg once a day , naproxen 500 mg twice daily , or placebo . R and omisation was stratified by the presence or absence of chronic peripheral arthritis . The primary outcome measure was the time weighted average change from baseline of spine pain intensity . Efficacy data from the three groups receiving active treatment ( the NSAID/COX-2 inhibitor group ) were combined to improve precision . An analysis of covariance model was used to evaluate the effect of peripheral disease on treatment response . Results : 93 patients were allocated to receive placebo and 294 to active treatment ( naproxen or etoricoxib ) . The combined NSAID/COX-2 inhibitor group had a significant treatment response compared with the placebo group for all efficacy measures , both in patients with and without peripheral arthritis . A significantly greater difference in mean patient assessment of spine pain was found between active and placebo treatments in patients without compared with those with peripheral arthritis ( p = 0.005 ; −32.5 mm v −17.0 mm , respectively ) . Similar differences , although not statistically significant , were seen for other end points . Conclusion : NSAIDs and COX-2 inhibitors have a clinical ly relevant symptomatic effect on axial AS irrespective of the presence of peripheral arthritis . In this exploratory analysis spinal improvement appeared to be greater in patients without peripheral disease [18952641] Objective : To describe and assess the response to short-term etoricoxib as shown by MRI and clinical variables in patients with ankylosing spondylitis ( AS ) selected for eligibility for anti-tumour necrosis factor therapy . Methods : In a 6-week open-label study , 22 patients with AS and eligible for biological therapy were treated with 90 mg of etoricoxib daily . Clinical and laboratory parameters were obtained and MRI of the sacroiliac joints and the lower thoracic and lumbar spine performed at baseline and at week 6 . The primary end point was the proportion of patients fulfilling the SpondyloArthritis international Society ( ASAS ) response criteria for biological therapies ( ASASBIO ) while secondary end points included the change in MRI-determined bone lesions . Results : Eight of 20 completers improved enough to meet the ASASBIO response criteria and most clinical variables improved significantly . Fifteen patients had a total of 63 MRI-detectable lesions ; overall , 13/60 lesions with paired scans either resolved completely or improved , while five lesions worsened or appeared during treatment . Conclusion : Etoricoxib is an effective symptomatic treatment for patients with AS ; however , its effect on MRI-detected lesions is small . Further studies are needed to determine the effect of etoricoxib on MRI-determined bone oedema [16960941] OBJECTIVE To evaluate the efficacy and safety of celecoxib in patients with ankylosing spondylitis ( AS ) . METHODS This was a 12-week r and omized , double-blind , placebo-controlled study with 4 treatment arms : celecoxib 200 mg qd , celecoxib 400 mg qd , naproxen 500 mg bid , and placebo . Patients ( age 18 - 75 yrs ) requiring daily treatment with nonselective nonsteroidal antiinflammatory drugs , and with a pain intensity on visual analog scale ( VAS ) > or = 50 mm worsening by 30 % compared with a pre inclusion visit ( 14 days prior ) were studied . Primary endpoints were least-squares mean changes from baseline in pain intensity , disease activity ( patient global assessment VAS ) , and functional impairment [ Bath Ankylosing Spondylitis Functional Index ( BASFI ) ] . Adverse events were monitored throughout the study . RESULTS Of 611 r and omized patients , 137 were allocated to celecoxib 200 mg , 161 to celecoxib 400 mg , 157 to naproxen , and 156 to placebo . Improvements in least-squares mean pain intensity , disease activity , and BASFI scores were significantly greater in the celecoxib 200 mg , celecoxib 400 mg , and naproxen groups than in the placebo group ( p < or = 0.001 ) at Week 12 and the interim timepoints , Weeks 1 , 3 , and 6 . Celecoxib 400 mg was as effective as naproxen ; however , naproxen was more effective than celecoxib 200 mg . Celecoxib was well tolerated , with an adverse event profile similar to placebo . However , 3 naproxen-treated patients experienced serious treatment-related gastrointestinal ( GI ) adverse events ( one severe gastric ulcer , one moderate GI hemorrhage , one severe GI hemorrhage ) . CONCLUSION In this 12-week study , celecoxib 200 mg qd and 400 mg qd were efficacious and well tolerated in treating signs and symptoms of AS [22532639] Objectives The aim was to compare continuous and on-dem and NSAID treatment with respect to their ability to suppress radiographic progression in subgroups of patients with high/elevated CRP-levels , ESR , ASDAS-levels or BASDAI-levels in comparison to patients with normal levels . Methods Post-hoc analyses were performed in a r and omized trial comparing continuous and on-dem and NSAID treatment . Relevant high/elevated subgroups were created based on time-averaged ( ta ) CRP ( > 5mg/L ) , ta-ESR ( > 12mm/hr ) , ta-BASDAI ( > 4 ) , ta-ASDAS-CRP ( > 2.1 ) and ta-ASDAS-ESR ( > 2.1 ) . Subgroups were further split according to NSAID-use ( continuous vs. on-dem and ) . Radiological progression was presented in probability plots . Statistical interactions were tested using multiple and logistic regression analysis . Differences in radiological progression were analysed using the Chi-square and Mann-Whitney U test . Results 150 participants r and omized to either the continuous-treatment group ( n=76 ) , or the on-dem and group ( n=74 ) had complete radiographs and were included . The effect of slowing radiological progression with continuous NSAID therapy was more pronounced in patients with elevated ta-CRP-levels , elevated ta-ESR , high ta-ASDAS-CRP or high ta-ASDAS-ESR versus patients with low/normal values . No such effect was found for participants with high vs. low BASDAI . Also , in participants with elevated ta-ESR ( irrespective of treatment ) , there appeared to be a higher rate of structural progression than in participants with normal ta-ESR . Regression analyses showed that continuous NSAID treatment neutralizes the negative effect of inflammation ( high ta-ESR ) . Conclusions Patients with elevated acute phase reactants seem to benefit most from continuous treatment with NSAIDs . Continuous NSAID-therapy in patients with elevated acute phase reactants may lead to an improved benefit-risk-ratio of these drugs [2198157] A 12-week trial was carried out to compare the efficacy of pirazolac ( 300 - 600 mg b.i.d . ) with that of indomethacin ( 25 - 50 mg t.i.d . ) in patients with ankylosing spondylitis . A total of 119 patients completed the treatment period , with 32 drop-outs . Both therapies showed significant improvements in clinical symptoms [343727] In a double-blind double-placebo crossover study naproxen ( 500 - 750 mg daily ) was found to be equivalent to phenylbutazone ( 400 - 600 mg daily ) in the control of disease activity in 20 patients suffering from ankylosing spondylitis during a two times 5-week trial period . No serious side effects were observed during the trial period . Gastric complaints occurred twice as often under phenylbutazone as under naproxen [15713943] BACKGROUND Selective inhibition of cyclooxygenase-2 ( COX-2 ) may be associated with an increased risk of thrombotic events , but only limited long-term data have been available for analysis . We report on the cardiovascular outcomes associated with the use of the selective COX-2 inhibitor rofecoxib in a long-term , multicenter , r and omized , placebo-controlled , double-blind trial design ed to determine the effect of three years of treatment with rofecoxib on the risk of recurrent neoplastic polyps of the large bowel in patients with a history of colorectal adenomas . METHODS A total of 2586 patients with a history of colorectal adenomas underwent r and omization : 1287 were assigned to receive 25 mg of rofecoxib daily , and 1299 to receive placebo . All investigator-reported serious adverse events that represented potential thrombotic cardiovascular events were adjudicated in a blinded fashion by an external committee . RESULTS A total of 46 patients in the rofecoxib group had a confirmed thrombotic event during 3059 patient-years of follow-up ( 1.50 events per 100 patient-years ) , as compared with 26 patients in the placebo group during 3327 patient-years of follow-up ( 0.78 event per 100 patient-years ) ; the corresponding relative risk was 1.92 ( 95 percent confidence interval , 1.19 to 3.11 ; P=0.008 ) . The increased relative risk became apparent after 18 months of treatment ; during the first 18 months , the event rates were similar in the two groups . The results primarily reflect a greater number of myocardial infa rct ions and ischemic cerebrovascular events in the rofecoxib group . There was earlier separation ( at approximately five months ) between groups in the incidence of nonadjudicated investigator-reported congestive heart failure , pulmonary edema , or cardiac failure ( hazard ratio for the comparison of the rofecoxib group with the placebo group , 4.61 ; 95 percent confidence interval , 1.50 to 18.83 ) . Overall and cardiovascular mortality was similar in the two groups . CONCLUSIONS Among patients with a history of colorectal adenomas , the use of rofecoxib was associated with an increased cardiovascular risk [3553586] During almost 12 years of development and clinical trials , diclofenac sodium has been shown to be both effective and safe as a new nonsteroidal antiinflammatory drug ( NSAID ) for the treatment of rheumatic diseases including ankylosing spondylitis ( AS ) . We compared the safety and efficacy of 75 , 100 , or 125 mg/day of diclofenac with the same doses of indomethacin in a multicenter , r and omized , parallel group trial in patients with AS . A single blind placebo washout period of 2 days to 2 weeks preceded the 13-week double blind treatment period . Both diclofenac and indomethacin produced significant ( p less than 0.001 ) improvement from baseline for all 14 efficacy variables analyzed . There were no significant between treatment differences . Differences favored diclofenac in the frequency and the severity of adverse experiences reported and in the frequency of complaints affecting the central nervous system [3888608] Objective To investigate whether biologic-free remission can be achieved in patients with early , active axial spondyloarthritis ( SpA ) who were in partial remission after 28 weeks of infliximab (IFX)+naproxen ( NPX ) or placebo (PBO)+NPX treatment and whether treatment with NPX was superior to no treatment to maintain disease control . Method Infliximab as First-Line Therapy in Patients with Early Active Axial Spondyloarthritis Trial ( INFAST ) Part 1 was a double-blind , r and omised , controlled trial in biologic-naïve patients with early , active , moderate-to-severe axial SpA treated with either IFX 5 mg/kg+NPX 1000 mg/d or PBO+NPX 1000 mg/d for 28 weeks . Patients achieving Assessment of SpondyloArthritis international Society ( ASAS ) partial remission at week 28 continued to Part 2 and were r and omised ( 1:1 ) to NPX or no treatment until week 52 . Treatment group differences in ASAS partial remission and other efficacy variables were assessed through week 52 with Fisher exact tests . Results At week 52 , similar percentages of patients in the NPX group ( 47.5 % , 19/40 ) and the no-treatment group ( 40.0 % , 16/40 ) maintained partial remission , p=0.65 . Median duration of partial remission was 23 weeks in the NPX group and 12.6 weeks in the no-treatment group ( p=0.38 ) . Mean Bath Ankylosing Spondylitis Disease Activity Index scores were low at week 28 , the start of follow-up treatment ( NPX , 0.7 ; no treatment , 0.6 ) , and remained low at week 52 ( NPX , 1.2 ; no treatment , 1.7 ) . Conclusions In axial SpA patients who reached partial remission after treatment with either IFX+NPX or NPX alone , disease activity remained low , and about half of patients remained in remission during 6 months in which NPX was continued or all treatments were stopped [10979111] CONTEXT Conventional nonsteroidal anti-inflammatory drugs ( NSAIDs ) are associated with a spectrum of toxic effects , notably gastrointestinal ( GI ) effects , because of inhibition of cyclooxygenase (COX)-1 . Whether COX-2-specific inhibitors are associated with fewer clinical GI toxic effects is unknown . OBJECTIVE To determine whether celecoxib , a COX-2-specific inhibitor , is associated with a lower incidence of significant upper GI toxic effects and other adverse effects compared with conventional NSAIDs . DESIGN The Celecoxib Long-term Arthritis Safety Study ( CLASS ) , a double-blind , r and omized controlled trial conducted from September 1998 to March 2000 . SETTING Three hundred eighty-six clinical sites in the United States and Canada . PARTICIPANTS A total of 8059 patients ( > /=18 years old ) with osteoarthritis ( OA ) or rheumatoid arthritis ( RA ) were enrolled in the study , and 7968 received at least 1 dose of study drug . A total of 4573 patients ( 57 % ) received treatment for 6 months . INTERVENTIONS Patients were r and omly assigned to receive celecoxib , 400 mg twice per day ( 2 and 4 times the maximum RA and OA dosages , respectively ; n = 3987 ) ; ibuprofen , 800 mg 3 times per day ( n = 1985 ) ; or diclofenac , 75 mg twice per day ( n = 1996 ) . Aspirin use for cardiovascular prophylaxis ( < /=325 mg/d ) was permitted . MAIN OUTCOME MEASURES Incidence of prospect ively defined symptomatic upper GI ulcers and ulcer complications ( bleeding , perforation , and obstruction ) and other adverse effects during the 6-month treatment period . RESULTS For all patients , the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.76 % vs 1.45 % ( P = .09 ) and 2 . 08 % vs 3.54 % ( P = .02 ) , respectively . For patients not taking aspirin , the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.44 % vs 1.27 % ( P = .04 ) and 1.40 % vs 2.91 % ( P = .02 ) . For patients taking aspirin , the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 2.01 % vs 2.12 % ( P = .92 ) and 4.70 % vs 6.00 % ( P = .49 ) . Fewer celecoxib-treated patients than NSAID-treated patients experienced chronic GI blood loss , GI intolerance , hepatotoxicity , or renal toxicity . No difference was noted in the incidence of cardiovascular events between celecoxib and NSAIDs , irrespective of aspirin use . CONCLUSIONS In this study , celecoxib , at dosages greater than those indicated clinical ly , was associated with a lower incidence of symptomatic ulcers and ulcer complications combined , as well as other clinical ly important toxic effects , compared with NSAIDs at st and ard dosages . The decrease in upper GI toxicity was strongest among patients not taking aspirin concomitantly . JAMA . 2000;284:1247 - [10325662] OBJECTIVE To consider the relevance of the duration of a clinical trial in ankylosing spondylitis : long-term ( i.e. 1 yr ) vs short-term ( i.e. 6 weeks ) assessment of a non-steroidal anti-inflammatory drug (NSAID)-placebo controlled study . METHODS The design was a prospect i ve , multicentre , double-blind , placebo-controlled study of 6 weeks duration with a 12 months double-blind extension . Study drugs were placebo ( n = 121 ) or active NSAID ( n = 352 ) . A decrease of at least 50 % in pain and /or global assessment and /or functional impairment during the study defined the response to treatment . The percentage of patients discontinuing the study drug over time ( life table analysis ) permitted the evaluation of both the efficacy and toxicity . RESULTS Among the 473 recruited patients , the percentage of responders was similar at 1 yr and week 6 with a highly statistically significant difference in favour of the active NSAID groups when compared to placebo ( at 1 yr , 17 % in the placebo group vs 37 , 50 and 43 % in the piroxicam 20 mg , meloxicam 15 mg and meloxicam 22.5 mg , respectively , for the patient 's overall assessment ) without any statistically significant difference between the three active groups . However , evaluation of the patients discontinuing the study drug during the 1 yr of the study permitted the detection of a statistically significant difference between the active NSAID groups . A lower percentage of patients taking meloxicam 22.5 mg had to discontinue the study drug when compared to either meloxicam 15 mg or piroxicam 20 mg ( 37 % vs 53 % and 53 % , respectively , P < 0.05 ) . By 52 weeks , drug-related upper gastrointestinal adverse events occurred in 13 , 32 , 20 and 18 % in the placebo , piroxicam 20 mg , meloxicam 15 mg and meloxicam 22.5 mg groups , respectively . Some of the adverse events occurred only after week 6 . CONCLUSION This study suggests that a 1 yr trial might be of optimum value compared to a 6 week assessment in order to define better the efficacy and tolerability of NSAIDs in ankylosing spondylitis [356241] The effect and tolerance of proquazone and indomethacin in patients suffering from ankylosing spondylitis were compared in two separate 3-week clinical , double-blind , r and omized studies on total of 60 patients . In the first study 16 patients were treated with proquazone and 14 patients with indomethacin , and in the second study 15 patients were treated in each group . Both drugs were found to have an evident , equally strong effect on pain and functional capacity in daily doses of 900 mg and 75 mg respectively . Severe side effects were not noted with either one of the drugs . Patients with previously known intolerance to indomethacin were excluded from the studies . Gastronitestinal disturbances seem to be the most commonly appearing side effect in patients treated with proquazone [3159143] Background Clinical analgesic trials typically report response as group mean results . However , research has shown that few patients are average and most have responses at the extremes . Moreover , group mean results do not convey response levels and thus have limited value in representing the benefit-risk at an individual level . Responder analyses and numbers-needed-to-treat ( NNT ) are considered more relevant for evaluating treatment response . We evaluated levels of analgesic response and Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI ) score improvement and the associated NNTs . Methods This was a post-hoc analysis of a 6-week , r and omized , double-blind study ( N = 387 ) comparing etoricoxib 90 mg , etoricoxib 120 mg , naproxen 1000 mg , and placebo in AS . Spine pain and BASDAI were measured on a 100-mm visual analog scale . The number and percentage of patients achieving ≥30 % and ≥50 % improvement in both BASDAI and spine pain were calculated and used to determine the corresponding NNTs . Patients who discontinued from the study for any reason were assigned zero improvement beyond 7 days of the time of discontinuation . Results For etoricoxib 90 mg , etoricoxib 120 mg and naproxen 1000 mg , the NNTs at 6 weeks compared with placebo were 2.0 , 2.0 , and 2.7 respectively for BASDAI ≥30 % improvement , and 3.2 , 2.8 , and 4.1 for ≥50 % improvement . For spine pain , the NNTs were 1.9 , 2.0 , and 3.2 , respectively , for ≥30 % improvement , and 2.7 , 2.5 , and 3.7 for ≥50 % improvement . The differences between etoricoxib and naproxen exceeded the limit of ±0.5 units described as a clinical ly meaningful difference for pain . Response rates and NNTs were generally similar and stable over 2 , 4 , and 6 weeks . Conclusions For every 2 patients treated with etoricoxib , 1 achieved a clinical ly meaningful ( ≥30 % ) improvement in spine pain and BASDAI beyond that expected from placebo , whereas the corresponding values were approximately 1 in every 3 patients treated with naproxen . Use of NNTs and responder analyses provide additional , complementary information beyond population mean responses when assessing efficacy compared to placebo and amongst active therapies [3524970] Summary A 12-week double-blind r and omized drug trial followed by an open extension period of 36 weeks was carried out in 38 male patients with ankylosing spondylitis ( AS ) to compare the efficacy and safety of diflunisal ( 500 mg twice daily ) and phenylbutazone ( 200 mg twice daily ) . Both drugs proved to be effective in improving the severity of symptoms associated with AS , and this improvement was maintained throughout the open extension period . Initially diflunisal had a more pronounced and rapid analgesic action , whereas phenylbutazone was more effective in increasing axial mobility . During the study 9 patients dropped out : 3 in each treatment group due to side effects and 1 in each group due to lack of efficacy ; another patient was lost to follow-up . The two drugs were similarly safe as judged by the occurrence of adverse clinical effects , mainly gastrointestinal . This study again demonstrates the value of phenylbutazone in AS but , taking into account the possible haematological side effects , the use of other NSAIDs is stressed . Diflunisal is an alternative capable of improving the painful stiffness associated with AS [2181618] A system of classification criteria of spondyloarthropathies was experimented in three studies . They have permitted to measure its specificity which is 86.6 p. cent and its sensitivity which is 90 p. cent . This system permits to compare theory and clinical practice and also to classify disease not yet classified . The positive and negative predictive values of these tests remain to be vali date d and assessed , with a multicenter study including patients affected or not with spondyloarthropathy , in order to determine whether they can also be used as a diagnosis tool [1365469] Forty-two patients with ankylosing spondylitis were entered into a double-blind study to compare treatment with indomethacin and a new non-steroidal anti-inflammatory drug , nabumetone . Clinical , laboratory and side-effect profiles were measured over a three month period . Both drugs were effective in relieving pain and morning stiffness , indomethacin was better in alleviating general stiffness , nabumetone result ed in less side-effects . Objective measurements of spinal movements revealed no difference between the two drugs . Nabumetone , available as Relifex , appears as effective as indomethacin in relieving the symptoms of ankylosing spondylitis and is possibly better tolerated [6349653] 98 patients with reversible , definite , active ankylosing spondylitis were selected for this study . 49 patients were treated with N-(2,6-dichloro-m-tolyl)anthranilic acid , sodium salt ( meclofenamate sodium , Meclomen ) and 49 patients with indometacin . Following a single-blind baseline period on placebo , patients received either 200 mg meclofenamate sodium per day or 100 mg indometacin per day for one week , in the second week the doses were increased to 250 mg meclofenamate sodium and 125 mg indometacin and from the third through the eight week 300 mg meclofenamate sodium and 150 mg indometacin were given . The results of this double-blind study showed that similar improvement in mobility of the vertebral column and spondylitic pain could be achieved with meclofenamate sodium and indometacin in patients with ankylosing spondylitis . Although both treatments were well tolerated fewer meclofenamate sodium patients reported adverse reactions than did those who had received indometacin . It is concluded that meclofenamate sodium offers an effective and safe alternative to indometacin in the treatment of patients with ankylosing spondylitis [19297344] Objective : To vali date and refine two sets of c and i date criteria for the classification/diagnosis of axial spondyloarthritis ( SpA ) . Methods : All Assessment of SpondyloArthritis international Society ( ASAS ) members were invited to include consecutively new patients with chronic ( ⩾3 months ) back pain of unknown origin that began before 45 years of age . The c and i date criteria were first tested in the entire cohort of 649 patients from 25 centres , and then refined in a r and om selection of 40 % of cases and thereafter vali date d in the remaining 60 % . Results : Upon diagnostic work-up , axial SpA was diagnosed in 60.2 % of the cohort . Of these , 70 % did not fulfil modified New York criteria and , therefore , were classified as having “ non-radiographic ” axial SpA. Refinement of the c and i date criteria result ed in new ASAS classification criteria that are defined as : the presence of sacroiliitis by radiography or by magnetic resonance imaging ( MRI ) plus at least one SpA feature ( “ imaging arm ” ) or the presence of HLA-B27 plus at least two SpA features ( “ clinical arm ” ) . The sensitivity and specificity of the entire set of the new criteria were 82.9 % and 84.4 % , and for the imaging arm alone 66.2 % and 97.3 % , respectively . The specificity of the new criteria was much better than that of the European Spondylarthropathy Study Group criteria modified for MRI ( sensitivity 85.1 % , specificity 65.1 % ) and slightly better than that of the modified Amor criteria ( sensitivity 82.9 , specificity 77.5 % ) . Conclusion : The new ASAS classification criteria for axial SpA can reliably classify patients for clinical studies and may help rheumatologists in clinical practice in diagnosing axial SpA in those with chronic back pain . Trial registration number : NCT00328068 [11087881] BACKGROUND Each year , clinical upper gastrointestinal events occur in 2 to 4 percent of patients who are taking nonselective nonsteroidal antiinflammatory drugs ( NSAIDs ) . We assessed whether rofecoxib , a selective inhibitor of cyclooxygenase-2 , would be associated with a lower incidence of clinical ly important upper gastrointestinal events than is the nonselective NSAID naproxen among patients with rheumatoid arthritis . METHODS We r and omly assigned 8076 patients who were at least 50 years of age ( or at least 40 years of age and receiving long-term glucocorticoid therapy ) and who had rheumatoid arthritis to receive either 50 mg of rofecoxib daily or 500 mg of naproxen twice daily . The primary end point was confirmed clinical upper gastrointestinal events ( gastroduodenal perforation or obstruction , upper gastrointestinal bleeding , and symptomatic gastroduodenal ulcers ) . RESULTS Rofecoxib and naproxen had similar efficacy against rheumatoid arthritis . During a median follow-up of 9.0 months , 2.1 confirmed gastrointestinal events per 100 patient-years occurred with rofecoxib , as compared with 4.5 per 100 patient-years with naproxen ( relative risk , 0.5 ; 95 percent confidence interval , 0.3 to 0.6 ; P<0.001 ) . The respective rates of complicated confirmed events ( perforation , obstruction , and severe upper gastrointestinal bleeding ) were 0.6 per 100 patient-years and 1.4 per 100 patient-years ( relative risk , 0.4 ; 95 percent confidence interval , 0.2 to 0.8 ; P=0.005 ) . The incidence of myocardial infa rct ion was lower among patients in the naproxen group than among those in the rofecoxib group ( 0.1 percent vs. 0.4 percent ; relative risk , 0.2 ; 95 percent confidence interval , 0.1 to 0.7 ) ; the overall mortality rate and the rate of death from cardiovascular causes were similar in the two groups . CONCLUSIONS In patients with rheumatoid arthritis , treatment with rofecoxib , a selective inhibitor of cyclooxygenase-2 , is associated with significantly fewer clinical ly important upper gastrointestinal events than treatment with naproxen , a nonselective inhibitor [16646033] OBJECTIVE To determine whether the effects of anti-tumor necrosis factor alpha ( TNFalpha ) in reducing the signs and symptoms of ankylosing spondylitis ( AS ) coincide with a reduction in spinal inflammation as detected by magnetic resonance imaging ( MRI ) . METHODS Pre- and postgadolinium T1 and STIR MR images of the spine were acquired at baseline and at week 24 in patients with AS who participated in a multicenter , r and omized , double-blind , placebo-controlled study . Patients were r and omly assigned at an 8:3 ratio to receive infusions of infliximab ( 5 mg/kg ) or placebo at weeks 0 , 2 , and 6 and then every 6 weeks thereafter . MR images were obtained and evaluated independently by 2 readers who were blinded to the treatment allocation and time sequence of the images . RESULTS A total of 194 patients in the infliximab group and 72 patients in the placebo group had evaluable images at baseline and week 24 . About 80 % of the patients had at least 1 active spinal lesion at baseline , as assessed by MRI . The improvement in the MRI Activity Score after 6 months was significantly greater in the patients who received infliximab ( mean 5.02 , median 2.72 ) than in those who received placebo ( mean 0.60 , median 0.0 ) ( P < 0.001 ) . Almost complete resolution of spinal inflammation was seen in most patients who received infliximab , irrespective of baseline activity . CONCLUSION Patients with AS who received infliximab therapy showed a decrease in spinal inflammation as detected by MRI , whereas those who received placebo showed persistent inflammatory spondylitis [10609815] BACKGROUND Non-steroidal anti-inflammatory drugs ( NSAIDs ) inhibit cyclo-oxygenase ( COX ) , which leads to suppression of COX-1-mediated production of gastrointestinal-protective prostagl and ins . Gastrointestinal injury is a common outcome . We compared the efficacy , safety , and tolerability of long-term therapy with celecoxib , a COX-1 sparing inhibitor of COX-2 , with diclofenac , a non-specific COX inhibitor . METHODS 655 patients with adult-onset rheumatoid arthritis of at least 6 months ' duration were r and omly assigned oral celecoxib 200 mg twice daily or diclofenac SR 75 mg twice daily for 24 weeks . Anti-inflammatory and analgesic activity and tolerability were assessed at baseline , every 4 weeks , and at week 24 . We assessed gastrointestinal safety by upper-gastrointestinal endoscopy within 7 days of the last treatment dose at centres where the procedure was available . Analysis was by intention-to-treat . FINDINGS 430 patients underwent endoscopy ( celecoxib n=212 , diclofenac n=218 ) . The two drugs were similar in management of rheumatoid arthritis pain and inflammation . Gastroduodenal ulcers were detected endoscopically in 33 ( 15 % ) patients treated with diclofenac and in eight ( 4 % ) in the celecoxib group ( p<0.001 ) . The rate of withdrawal for any gastrointestinal-related adverse event , most commonly abdominal pain , diarrhoea , and dyspepsia , was nearly three times higher in the diclofenac-treated group than in the celecoxib group ( 16 vs 6 % ; p<0.001 ) . INTERPRETATION Celecoxib showed sustained anti-inflammatory and analgesic activity similar to diclofenac , with a lower frequency of upper gastrointestinal ulceration or gastrointestinal adverse events , and tolerability was better [21068095] Background The Ankylosing Spondylitis Disease Activity Score ( ASDAS ) is a new composite index to assess disease activity in ankylosing spondylitis ( AS ) . It fulfils important aspects of truth , feasibility and discrimination . Criteria for disease activity states and improvement scores are important for use in clinical practice , observational studies and clinical trials and so far have not been developed for the ASDAS . Objective To determine clinical ly relevant cut-off values for disease activity states and improvement scores using the ASDAS . Methods For the selection of cut-offs data from the Norwegian disease modifying antirheumatic drug ( NOR-DMARD ) registry , a cohort of patients with AS starting conventional or biological DMARDs , were used . Receiver operating characteristic analysis against several external criteria was performed and several approaches to determine the optimal cut-offs used . The final choice was made on clinical and statistical grounds , after debate and voting by Assessment of SpondyloArthritis international Society members . Crossvalidation was performed in NOR-DMARD and in Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy , a data base of patients with AS participating in a r and omised placebo-controlled trial with a tumour necrosis factor blocker . Results Four disease activity states were chosen by consensus : inactive disease , moderate , high and very high disease activity . The three cut-offs selected to separate these states were : 1.3 , 2.1 and 3.5 units . Selected cut-offs for improvement were : change ≥1.1 units for clinical ly important improvement and change ≥2.0 units for major improvement . Results of the crossvalidation strongly supported the cut-offs . Conclusions Cut-off values for disease activity states and improvement using the ASDAS have been developed . They proved to have external validity and a good performance compared to existing criteria [363071] A double-blind , cross-over comparison of Naprosyn ( naproxen ) 750 mg daily and Butacote ( enteric-coated phenylbutazone ) 300 mg daily was carried out in a multi-centre trial . Twenty-five patients , mostly male and under 40 years of age , were entered . After a 2-week period in which any existing anti-inflammatory drugs were tailed off , patients were entered into the trial and treated for 1 month with each drug . Patients were assessed at 4-weekly intervals . Both drugs significantly reduced morning stiffness . Morning pain and discomfort and wall-tragus distance were also significantly reduced by both drugs during the trial . Results of the Schober test showed improvement during both treatment periods . There were no overall statistically significant differences between the effects of the 2 drugs on objective parameters . However , overall subjective assessment of symptoms showed a greater improvement on Butacote . Treatment preferences by physician and subjective assessment by the patient both favoured Butacote but the difference between the 2 drugs was not statistically significant . Side effects were mostly of a minor nature . One patient had to discontinue the trial , due to indigestion while taking Butacote [4937661] Abstract Objective : Control of airway inflammation is the cornerstone of asthma management . The aim of the present pilot study was to assess the effects of a leukotriene receptor antagonist ( LTRA ) added to a basic treatment of inhaled corticosteroids ( ICS ) and long-acting beta-agonist ( LABA ) on airway hyperresponsiveness , inflammation , and quality of life in well-controlled patients with asthma . Research design and methods : Seventeen patients ( age 18–65 , 11 women ) with well-controlled asthma presenting airway hyperresponsiveness to mannitol and methacholine challenge were given add-on montelukast on a stable ICS + LABA for 4 weeks . Quality of life and selected parameters of airway inflammation were measured at baseline and at study end . ( Clinical Trials.gov ( NCT01725360 ) ) . Results : Adding montelukast to ICS + LABA result ed in an increase in mean FEV1 ( + 4.5 % , p = 0.057 ) , cumulated higher dose of mannitol ( + 32.5 % , p = 0.023 ) and methacholine ( + 17.2 % , 0.237 ) in the provocation test , lower airway reactivity with mannitol and methacholine ( response dose ratio ( RDR ) –50.0 % , p = 0.024 and –44.3 % , p = 0.006 , respectively ) , and improved airway sensitivity to mannitol and methacholine ( + 12.1 % , p = 0.590 and + 48.0 % , p = 0.129 for PD15 and PD20 FEV1 , respectively ) . Changes in inflammation parameters ( blood eosinophil count , serum eosinophil cationic protein , and exhaled nitric oxide ) were consistent with these findings . Asthma-related quality of life improved significantly in all domains and overall ( from 5.3 at baseline to 6.1 at the final visit , p < 0.001 ) . The main limitation was the absence of a control group . Conclusion : The consistency of the changes in airway hyperresponsiveness and inflammation as well as in quality of life observed with an add-on therapy with montelukast in well-controlled asthma patients during 4 weeks suggests that residual inflammation may represent an area for further improvement of asthma control to be explored in adequately powered r and omized controlled trials [7013054] The r and omized , double-blind trial was carried out with 50 patients suffering from ankylosing spondylarthritis and belonging all to type B27 in the HLA system . Tolfenamic acid ( 600 mg daily ) was effective as judged by subjective and numerous objective parameters and was preferable to indomethacin ( 75 mg daily ) . Indomethacin caused side effects more frequently than tolfenamic acid . In the indomethacin group 16 % of the patients interrupted the 6-month trial because of gastrointestinal complications . No discontinuation of treatment owing to adverse effects of tolfenamic acid occurred . Tolfenamic acid offers one new and good alternative for the medical treatment of ankylosing spondylarthritis [9402773] Abstract Objectives : To determine the profile of risk of upper gastrointestinal toxicity during continuous treatment with , and after cessation of , non-steroidal anti-inflammatory drugs . Design : Cohort study with a prospect ively constructed , population based , record linkage data base containing details of exposure to all community dispensed non-steroidal anti-inflammatory drugs and also all admissions to hospital for upper gastrointestinal diagnoses . Setting : The population of Tayside , Scotl and . Subjects : 52 293 subjects aged 50 and over who received one or more non-steroidal anti-inflammatory between 1 January 1989 and 31 December 1991 and 73 792 subjects who did not receive one during the same period ( controls ) . Main outcome measures : Admission to hospital for upper gastrointestinal bleeding and perforation , and admission for other upper gastrointestinal diagnoses . Results : About 2 % of the non-steroidal anti-inflammatory cohort were admitted with an upper gastrointestinal event during the study period compared with 1.4 % of controls . The risk of admission for upper gastrointestinal haemorrhage and perforation was constant during continuous non-steroidal anti-inflammatory exposure and carried over after the end of exposure . The results were similar for admissions for all upper gastrointestinal events . Conclusion : This study provides evidence that non-steroidal anti-inflammatory toxicity persists with continuous exposure . There seems to be carryover toxicity after the end of prescribing . These findings have implication s for the management of patients requiring non-steroidal anti-inflammatory drugs . Key messages The risk of upper gastrointestinal toxicity associated with non-steroidal anti-inflammatory drugs is constant with continuous exposure Gastrointestinal toxicity continues for some time after treatment stops Such toxicity is common in older patients and patients with a history of upper gastrointestinal disease Non-steroidal anti-inflammatory drugs should be avoided when possible ; when they are used the lowest effective dose of the least toxic drug should be used for the shortest period [3963017] Flurbiprofen ( Ansaid , Upjohn ) , a potent new analgesic and anti-inflammatory agent , was compared with phenylbutazone in 90 patients with ankylosing spondylitis . In this double-blind , r and omized , 26-week study , a total daily dose of 200 mg of flurbiprofen , administered three times daily , was as effective as 300 mg of phenylbutazone in controlling the pain and other symptoms of ankylosing spondylitis . In some patients , symptoms were adequately controlled by 150 mg of flurbiprofen per day , administered twice daily . There were no statistically significant differences between flurbiprofen and phenylbutazone in the investigators ' and patients ' assessment s of improvement at all key follow-up periods . In addition , there were no consistently significant differences between drugs in the efficacy pain scales and quantitative measurements studied . Flurbiprofen was well tolerated in doses of up to 300 mg per day , and no clinical ly significant laboratory abnormalities were detected . Flurbiprofen appears to be an excellent alternative to phenylbutazone in the management of patients with ankylosing spondylitis [1930310] Classification criteria for most of the disorders belonging to the spondylarthropathy group already exist . However , the spectrum of spondylarthropathy is wider than the sum of these disorders suggests . Seronegative oligoarthritis , dactylitis or polyarthritis of the lower extremities , heel pain due to enthesitis , and other undifferentiated cases of spondylarthropathy have been ignored in epidemiologic studies because of the inadequacy of existing criteria . In order to define classification criteria that also encompass patients with undifferentiated spondylarthropathy , we studied 403 patients with all forms of spondylarthropathy and 674 control patients with other rheumatic diseases . The diagnoses were based on the local clinical expert 's opinion . The 403 patients included 168 with ankylosing spondylitis , 68 with psoriatic arthritis , 41 with reactive arthritis , 17 with inflammatory bowel disease and arthritis , and 109 with unclassified spondylarthropathy . Based on statistical analysis and clinical reasoning , we propose the following classification criteria for spondylarthropathy : inflammatory spinal pain or synovitis ( asymmetric or predominantly in the lower limbs ) , together with at least 1 of the following : positive family history , psoriasis , inflammatory bowel disease , urethritis , or acute diarrhea , alternating buttock pain , enthesopathy , or sacroiliitis as determined from radiography of the pelvic region . These criteria result ed in a sensitivity of 87 % and a specificity of 87 % . The proposed classification criteria are easy to apply in clinical practice and performed well in all 7 participating centers . However , we regard them as preliminary until they have been further evaluated in other setting [7010512] Fenoprofen , 600 mg , three times daily , was compared with phenylbutazone , 100 mg , three times daily , in 30 patients suffering from ankylosing spondylitis in a double-blind cross-over study . Assessment s were made after an initial washout period and after each month-long treatment period . Phenylbutazone significantly improved morning stiffness , finger-to-floor distance , chest expansion , overall joint pain , spinal pain , the physician 's assessment of disease activity and ESR . Only chest expansion was significantly improved by fenoprofen , and phenylbutazone was significantly better than fenoprofen in its effects on finger-to-floor distance , morning stiffness , overall joint pain , spinal pain and the physician 's assessment of disease activity . Side-effects were of a minor nature apart from one patient who developed rectal bleeding on phenylbutazone which recurred on rechallenging [10580457] CONTEXT In vitro studies have shown that celecoxib inhibits cyclooxygenase 2 ( COX-2 ) but not COX-1 , suggesting that this drug may have anti-inflammatory and analgesic activity without adverse upper gastrointestinal ( GI ) tract effects that result from COX-1 inhibition . OBJECTIVE To test whether celecoxib has efficacy as an anti-inflammatory and analgesic with reduced GI tract mucosal damage compared with conventional nonsteroidal anti-inflammatory drugs in patients with rheumatoid arthritis . DESIGN R and omized , multicenter , placebo-controlled , double-blind trial lasting 12 weeks , with follow-up at weeks 2 , 6 , and 12 , from September 1996 thorugh February 1998 . SETTING Seventy-nine clinical sites in the United States and Canada . PATIENTS A total of 1149 patients aged 18 years or older with symptomatic rheumatoid arthritis who met inclusion criteria were r and omized ; 688 ( 60 % ) of these completed the study . INTERVENTIONS Patients were r and omized to receive celecoxib , 100 mg , 200 mg , or 400 mg twice per day ( n = 240 , 235 , and 218 , respectively ) ; naproxen , 500 mg twice per day ( n = 225 ) ; or placebo ( n = 231 ) . MAIN OUTCOME MEASURES Improvement in signs and symptoms of rheumatoid arthritis as assessed using st and ard measures of efficacy and GI tract safety as assessed by upper GI tract endoscopy before and after treatment , compared among treatment groups . RESULTS All dosages of celecoxib and naproxen significantly improved the signs and symptoms of arthritis compared with placebo . Maximal anti-inflammatory and analgesic activity was evident within 2 weeks of initiating treatment and was sustained throughout the 12 weeks . The incidence of endoscopically determined gastroduodenal ulcers in placebo-treated patients was 4 ( 4 % ) of 99 , and the incidences across all dosages of celecoxib were not significantly different ( P>.40 ) : 9 ( 6 % ) of 148 with 100 mg twice per day , 6 ( 4 % ) of 145 with 200 mg twice per day , and 8 ( 6 % ) of 130 with 400 mg twice per day . In contrast , the incidence with naproxen was 36 ( 26 % ) of 137 , significantly greater than either placebo or celecoxib ( P<.001 ) . The overall incidences of GI tract adverse effects were 19 % for placebo ; 28 % , 25 % , and 26 % for celecoxib 100 mg , 200 mg , and 400 mg twice per day , respectively ; and 31 % for naproxen . CONCLUSION In this study , all dosages of celecoxib were efficacious in the treatment of rheumatoid arthritis and did not affect COX-1 activity in the GI tract mucosa as evidence d by less frequent incidence of endoscopic ulcers compared with naproxen [4611579] A double-blind cross-over study in 35 patients with ankylosing spondylitis was carried out comparing flurbiprofen ( 150 mg daily)—a new non-steroidal anti-inflammatory agent — with phenylbutazone ( 300 mg daily ) over a four-week period . Flurbiprofen was well tolerated and shown to have therapeutic efficacy approaching that of phenylbutazone . The results suggest that flurbiprofen may prove a valuable alternative in the treatment of ankylosing spondylitis , and longterm efficacy and tolerance studies are clearly indicated [11434474] Abstract : The aim of the study was to analyse the 2-year follow-up of a series of patients with the diagnosis of undifferentiated spondyloarthropathy ( uSpA ) . A prospect i ve study was carried out analysing 68 patients with symptomatic uSpA who fulfilled the European Spondylarthropathy Study Group ( ESSG ) criteria for seronegative spondyloarthropathies ( SpA ) and were aged between 18 and 50 years . Inclusion criteria included inflammatory low back pain ( ILBP ) ( without radiographic sacroiliitis ) , asymmetric oligoarthritis ( predominantly affecting large joints in the lower limbs ) and heel enthesopathies ( Achilles tendinitis and /or plantar fasciitis ) . Imaging methods included pelvic radiography ( at study entry and after 2 years ) and calcaneal radiography ( at study entry ) . There was a predominance of male gender ( 78 % ) , caucasoid race ( 72 % ) and positive HLA-B27 ( 54 % ) , with a mean age of 31 years and mean disease duration of 5 years . The first disease manifestations were ILBP ( 49 % ) , asymmetric oligoarthritis ( 35 % ) and heel enthesopathies ( 16 % ) . A positive family history of a definite SpA was mentioned by 9 % of the patients . Seventeen patients ( 25 % ) scored 5 points in the Amor set of SpA criteria ; logistic regression analysis showed that HLA-B27 , heel enthesopathy and asymmetric oligoarthritis were significantly associated with Amor criteria ≥6 , whereas ILBP was associated with Amor criteria < 6 . Male sex was associated with heel enthesopathies ( p = 0.041 ) and ankle involvement ( p = 0.015 ) . Caucasoid race was associated with ILBP ( p = 0.015 ) and buttock pain ( p = 0.047 ) . Positive HLA-B27 was associated with wrist involvement ( p = 0.019 ) and Amor criteria ≥6 ( p = 0.001 ) . After a 2-year follow-up the following outcomes were observed : uSpA 75 % ; disease remission 13 % ; ankylosing spondylitis 10 % ; psoriatic arthritis 2 % . Logistic regression analysis showed that buttock pain and positive HLA-B27 ( trend ) were statistically associated with progression to a definite SpA. In conclusion , uSpA can represent a provisional diagnosis in the group of SpA and a systematic follow-up is necessary in order to better establish the different patterns of the disease [15934081] OBJECTIVE A 2-year r and omized controlled trial was performed to test the hypothesis that long-term , continuous treatment with nonsteroidal antiinflammatory drugs ( NSAIDs ) , in comparison with NSAID treatment on dem and only , influences radiographic progression in patients with ankylosing spondylitis ( AS ) . METHODS Patients with AS ( n = 215 ) , who had previously participated in a 6-week , r and omized , double-blind clinical trial that compared celecoxib , ketoprofen , and placebo , were r and omly allocated to receive either continuous treatment with NSAIDs or on-dem and treatment with NSAIDs for a period of 2 years . All patients began treatment with celecoxib , at a starting dosage of 100 mg twice daily ; patients could increase this dosage to 200 mg twice daily or could switch to another NSAID while maintaining the same treatment strategy . Structural changes were assessed by radiographs of the lumbar and cervical spine and scored according to the modified Stoke Ankylosing Spondylitis Spine Score by one observer who was blinded to the treatment strategy and temporal order of the radiographs . Statistical analyses included a between-group comparison of 1 ) radiographic progression scores ( by Mann-Whitney U test ) , 2 ) time-averaged values of variables reflecting signs and symptoms of AS ( by linear regression analysis ) , and 3 ) the frequency of reported site-specific adverse events ( by chi-square test or Fisher 's exact test , as appropriate ) . RESULTS Complete sets of radiographs were available for 76 of the 111 patients in the continuous-treatment group and for 74 of the 104 patients in the on-dem and group . The mean + /- SD scores for radiographic progression were 0.4 + /- 1.7 in the continuous-treatment group and 1.5 + /- 2.5 in the on-dem and treatment group ( P = 0.002 ) . Parameters reflecting signs and symptoms were not statistically significantly different between groups . The between-group difference in radiographic progression did not disappear after adjusting for baseline values of radiographic damage or disease activity variables and for time-averaged values of disease activity variables , nor after input of missing data . Relevant adverse events tended to occur more frequently in the continuous-treatment group than in the on-dem and group ( for hypertension , 9 % versus 3 % ; for abdominal pain , 11 % versus 6 % ; for dyspepsia , 41 % versus 38 % ) , but the differences were not statistically significant . CONCLUSION A strategy of continuous use of NSAIDs reduces radiographic progression in symptomatic patients with AS , without increasing toxicity substantially [2178870] A r and omized study was performed on 24 patients with ankylosing spondylitis to compare the efficacy and tolerability of 20 mg tenoxicam daily with 50 mg diclofenac twice daily . There were 6 withdrawals from the group taking tenoxicam and 4 from the diclofenac group . Depression in 1 patient taking tenoxicam was the only significant adverse event . Both drugs were otherwise well tolerated . Tenoxicam and diclofenac were rated as good or excellent by 27 % and 55 % of patients , respectively . Global assessment , pain and duration of morning stiffness were improved with both drugs but this improvement was not statistically significant and there was no statistically significant difference between the two groups . This study confirms that tenoxicam is effective and well tolerated but larger numbers would be required to detect a small difference between groups [3378661] The efficacy and tolerance of 1200 mg/day oxaprozin and 100 mg/day diclofenac sodium were compared in 40 patients with ankylosing spondylitis in a 6-week open study . Overall improvement was seen in the patients in both treatment groups . Oxaprozin-treated patients showed significant improvement in spontaneous pain of the vertebral spine and in morning stiffness after 6 weeks ' treatment . There were no statistically significant differences between the treatment groups . Therapy was discontinued in 10 patients ; five treated with oxaprozin ( three because of intolerance and two because of worsening of symptoms ) and five taking diclofenac sodium ( four because of intolerance and one because of worsening of symptoms ) . Five ( 25 % ) oxaprozin-treated patients and six ( 30 % ) diclofenac sodium-treated patients had side-effects , with gastro-intestinal disturbances and dizziness reported most frequently . There were no statistically significant differences between the groups in the frequency of side-effects . These results indicate that oxaprozin is a promising therapeutic agent for ankylosing spondylitis [6379678] A double-blind , crossover trial was carried out to compare the effectiveness and tolerance of indoprofen with indomethacin in the treatment of ankylosing spondylitis . Nineteen patients entered the study and 1 was withdrawn for reasons unrelated to therapy . Patients received 4-weeks ' treatment in r and om order , with 200 mg indoprofen 4-times daily and 25 mg indomethacin 4-times daily . Most subjective and objective clinical measurements of disease activity showed a comparable degree of improvement with either drug although few statistically significant changes were observed . There was no statistically significant difference between treatments and , although gastro-intestinal side-effects occurred more commonly with indoprofen , patients known to be intolerant of indomethacin had been excluded from this trial [334611] A double-blind crossover trial of fenclofenac was untertaken to compare the short-term effects of phenylbutazone ( Butacote ) therapy with fenclofenac therapy ( 1200 mg daily ) in 23 patients suffering from ankylosing spondylitis . The patients were r and omly allocated to each of the test drugs for a period of two weeks , following wash-out periods of paracetamol for four days . The results favoured Butacote therapy in a dosage of 300 mg daily in the expressed preferences of both the patients and the physicians conducting the trial . Butacote was also better tolerated , as no severe side-effects occurred during treatment , whereas five patients developed a widespread rash during the period of fenclofenac therapy . No significant differences were seen between the two drugs in terms of clinical measurements of pain , morning stiffness , spinal movements , chest expansion , and abduction of the hips . Butacote was shown to cause some significant depletion of haemoglobin level , probably due to water retention , and Butacote also reduced the serum urate level to a significant degree [7973477] Ximoprofen is a new propionic NSAID which has previously demonstrated its efficacy at a daily dose of 30 mg . The aim of the study was to evaluate the efficacy of different daily dosages of Ximoprofen in patients with active ankylosing spondylitis . For 2 weeks 5 parallel groups were studied : placebo and Ximoprofen at 5 , 10 , 20 and 30 mg daily . Response to treatment was defined as an improvement in pain ( VAS 100 mm ) of at least 50 % during the study . 285 out of the 332 screened patients were included . At the end of the study , the percentage of responders was higher in the Ximoprofen groups ( 54 % , 41 % , 53 % , 56 % in the 5 , 10 , 20 and 30 mg groups , respectively ) than in the placebo group ( 21 % ) . The clearest dose related effect of Ximoprofen observed occurred after one week of treatment . This study 1/confirms the efficacy of Ximoprofen at a 30 mg daily dosage , 2/shows the persistence of this efficacy at lower dosages , 3/suggests that ankylosing spondylitis is a sensitive and relevant human model to assess NSAIDs at an early stage of clinical evaluation [15818702] OBJECTIVE To assess the efficacy , safety , and tolerability of etoricoxib , a cyclooxygenase 2 ( COX-2 ) selective inhibitor , administered continuously over 52 weeks for the treatment of ankylosing spondylitis ( AS ) . METHODS This 2-part , multicenter , double-blind , parallel-group , 52-week study evaluated 2 doses of etoricoxib ( 90 and 120 mg ) compared with naproxen at 1,000 mg . A 6-week , active-comparator- and placebo-controlled period ( part I ) was followed by a 46-week active-comparator-controlled period ( part II ) . The primary outcome measures ( on 100-mm visual analog scales ) were patient 's assessment of spine pain , patient 's global assessment of disease activity , and the Bath Ankylosing Spondylitis Functional Index . RESULTS Of the 387 patients r and omized to receive treatment , 301 ( 77.8 % ) completed part I and 284 ( 75.9 % ) completed part II . Compared with placebo over 6 weeks , those receiving 90 mg etoricoxib , 120 mg etoricoxib , and naproxen demonstrated significantly ( P < 0.001 ) greater improvement in all primary end points ; treatment effects ( expressed as the difference in least squares mean change versus placebo ) were 21 - 29 mm for spine pain , 18 - 25 mm for disease activity , and 11 - 15 mm for function . Compared with patients receiving naproxen , significantly greater improvement in all primary end points was demonstrated in the combined group receiving either 90 mg etoricoxib or 120 mg etoricoxib over 6 weeks , in each individual etoricoxib treatment group over 6 weeks , and in the combined etoricoxib group over 1 year ( all P < 0.05 ) ; results for secondary and exploratory end points were generally consistent with those from the primary analysis . Among all groups , there were no significant differences in the incidence of overall clinical , drug-related , or serious adverse experiences ( AEs ) and discontinuations due to AEs . Safety observations during part II were generally consistent with those in part I. CONCLUSION Etoricoxib at doses of 90 mg and 120 mg demonstrated superior efficacy compared with placebo over 6 weeks , and compared with naproxen over 1 year . These study results demonstrate that etoricoxib is generally safe , well-tolerated , and efficacious for the treatment of AS [7282105] In a double lind test 60 patients with ankylosing spondylitis received either Azapropazone ( 30 patients ) or Indomethacin ( 30 patients ) during a period of three weeks . In the two well comparable groups the therapeutic effect was equally good . As the results show the Azapropazone group came out a little better concerning the finger-ground distance and the difference in circumference of thorax , and the Azapropazone group was favoured slightly by the general judgement of the patients . However , these differences are not relevant . The influence on the spontaneous pain in the daytime and during the night and the shifting of dorsal and lumbar vertebral column was equally good in both groups . The compatibility was good in 59 out of 60 patients . One patient had to stop the Azapropazone medication because of gastric trouble in the second week of treatment . This result shows that in most patients an adequate medication with Azapropazone or with Indomethacin leads to a distinct reduction of pain and even painlessness already after a 3 weeks ' treatment . This is particularly important regarding kinesiatrics . Indomethacin and Phenylbutazone are generally regarded as approved preparations in treatment of ankylosing spondylitis . If Azapropazone which , according to all previous reports has no hematotoxic effect like Phenylbutazone , had the same good effect in a double blind test as Indomethacin , this must be regarded as a very positive result . Concerning the good compatibility of Azapropazone , a change of drug is possible without a reduction of the effect [18438853] OBJECTIVE To investigate the effect of etanercept therapy on radiographic progression in patients with ankylosing spondylitis ( AS ) . METHODS Patients with AS who had previously participated in a 24-week r and omized , double-blind , placebo-controlled trial of etanercept therapy were enrolled in a 72-week open-label extension . Radiographs of the cervical and lumbar spine from patients who received etanercept ( 25 mg twice weekly ) for up to 96 weeks were compared with radiographs from patients in a large prevalence cohort ( Outcome Assessment s in Ankylosing Spondylitis International Study [ OASIS ] ) who had not been treated with anti-tumor necrosis factor alpha ( anti-TNFalpha ) agents . Radiographs obtained at 2 time points up to 96 weeks apart from patients in both study population s were digitized and read by 2 independent readers who were blinded with regard to patient group and sequence . The primary end point was the 96-week change in the modified Stoke AS Spine Score ( mSASSS ) . RESULTS A total of 257 patients treated with etanercept were compared with 175 unselected patients from the OASIS study . There was no significant difference in the change in the mSASSS from baseline among patients who received etanercept ( mean + /- SD 0.91 + /- 2.45 ) versus those from the OASIS group ( 0.95 + /- 3.18 ) . CONCLUSION Unlike other inflammatory rheumatic diseases such as rheumatoid arthritis and psoriatic arthritis , structural progression in AS seems to be independent of TNF , despite the fact that TNF is responsible for the signs and symptoms due to inflammation in this disease [480622] Ankylosing spondylitis affects about 1 % of the population . In the past , evaluation of therapy in the management of this disease has been hampered by the lack of availability of objective criteria for following the condition . By using recently developed measurements of spinal mobility and other variables we have compared sulindac , a recently introduced nonsteroidal antiinflammatory drug , and indomethacin in a double-blind six-month parallel study of 30 patients . Sulindac and indomethacin have comparable efficacy and tolerance . Advantages of sulindac include a twice-a-day dose regimen [11212158] OBJECTIVE To evaluate the short-term efficacy of celecoxib , a cyclooxygenase 2-specific inhibitor , in the treatment of ankylosing spondylitis ( AS ) . METHODS The study was a 6-week r and omized , double-blind , placebo-controlled trial with 3 treatment arms : placebo , ketoprofen 100 mg twice daily , and celecoxib 100 mg twice daily . Patients who had AS according to the modified New York criteria , without peripheral synovitis and with active disease ( pain > or = 40 mm on a 100-mm visual analog scale [ VAS ] and an increase in pain of at least 30 % after nonsteroidal antiinflammatory drug withdrawal ) were eligible for study . Primary outcome measures were change in pain intensity ( VAS ) and change in functional impairment ( Bath Ankylosing Spondylitis Functional Index [ BASFI ] ) . RESULTS Of the 246 r and omized patients , 76 were allocated to receive placebo , 90 ketoprofen , and 80 celecoxib . There were no statistically significant differences between treatment groups at study entry . During the 6 weeks of the study , the decrease in pain and functional impairment was greater in the active treatment groups than in the placebo group , with a trend in favor of celecoxib when the 2 active treatments were compared . The mean changes were -13 mm , -21 mm , and -27 mm ( P = 0.006 ) for pain and 1 , -6 , and -12 ( P = 0.0008 ) for BASFI score in the placebo , ketoprofen , and celecoxib groups , respectively . During treatment , the number of patients reporting epigastric pain was 6 ( 8 % ) , 13 ( 14 % ) , and 10 ( 13 % ) in the placebo , ketoprofen , and celecoxib groups , respectively . CONCLUSION The results of this study confirm the clinical ly relevant antiinflammatory effect of celecoxib at a 200-mg daily dosage , with significant improvement of both pain and function in patients with AS [20498215] Objective To study the relationship between spinal mobility , radiographic damage of the spine and spinal inflammation as assessed by MRI in patients with ankylosing spondylitis ( AS ) . Methods In this sub analysis of the Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy cohort , 214 patients , representing an 80 % r and om sample , were investigated . Only baseline data were used . MRI inflammation was assessed by the AS spinal MRI activity ( ASspiMRI-a ) score , structural damage by the modified Stoke AS Spine Score ( mSASSS ) and spinal mobility by the linear definition of the Bath Ankylosing Spondylitis Metrology Index ( BASMI ) . Univariate correlations were calculated on baseline values using Spearman rank correlation . Independent associations between the variables of interest were investigated by multivariate linear regression analysis . Associations with clinical disease activity , C-reactive protein , disease duration , age , gender , body mass index and HLA-B27 status were also investigated . Subanalyses were performed according to disease duration . Results BASMI correlated moderately well with mSASSS ( Spearman 's ρ=0.6 ) and weakly with ASspiMRI-a ( ρ=0.3 ) . A best-fit model for BASMI included both mSASSS ( regression coefficient (B)=0.865 , p<0.001 ) and ASspiMRI-a ( B=0.236 , p=0.018 ) . In patients with a disease duration ≤3 years , B was greater for ASspiMRI-a than for mSASSS ( 0.595 vs 0.380 ) , while in patients with a disease duration > 3 years B was greater for mSASSS than for ASspiMRI-a ( 0.924 vs 0.156 ) . Conclusion Spinal mobility impairment in AS is independently determined both by irreversible spinal damage and by reversible spinal inflammation . Spinal mobility impairment is more influenced by spinal inflammation in early disease , and by structural damage in later disease [4595274] Preliminary studies of flurbiprofen , a newly introduced anti-inflammatory agent , have shown that it exerts some anti-inflammatory and analgesic effects in man when compared with placebo and is relatively well tolerated ( Chalmers , Cathcart , Kumar , Dick and Buchanan , 1972 ) . The purpose of this paper is to compare the effects of flurbiprofen , indomethacin , and placebo under double-blind conditions in a group of patients with ankylosing spondylitis [19060001] Objectives : To evaluate various validity aspects of four disease activity scores ( ASDAS ) for ankylosing spondylitis ( AS ) in comparison with the Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI ) , its individual components and physician and patient global assessment of disease activity . Methods : The analyses were performed in two cohorts of patients with AS : ( 1 ) the NOR-DMARD data base which includes patients starting on a disease-modifying antirheumatic drug or tumour necrosis factor ( TNF ) blocker and ( 2 ) patients participating in double-blind placebo controlled r and omised clinical trials with TNF blockers in four centres . Discrimination between patients with low versus high disease activity according to various definitions and between various levels of change were analysed as the st and ardised mean difference ( difference in the group means divided by the pooled SD of the group means ) and t score . Results : The four ASDAS versions were highly discriminatory in differentiating patients with different levels of disease activity and patients with different levels of change . The ASDAS scores outperformed the BASDAI and its single components in all setting s : patient- or physician-based , reflecting status or change , with normal or raised C-reactive protein ( CRP ) , in the presence or absence of peripheral arthritis . There were no major differences between the four ASDAS scores . Based on feasibility , the ASAS membership selected the ASDAS version which included back pain , duration of morning stiffness , patient global assessment , peripheral joint complaints and CRP as the preferred version . Conclusions : The ASDAS is a vali date d , highly discriminatory instrument for assessing disease activity in AS , including patient-reported outcomes and CRP levels [71969] In a parallel , double-blind and r and omized trial of 6-weeks ' duration , flurbiprofen ( 150 mg to 200 mg daily ) was compared with indomethacin ( 75 mg to 100 mg daily ) in the management of 26 patients with active ankylosing spondylitis . None of the patients in either group withdrew from the study because of lack of efficacy of the drugs . Both drugs were equally effective in the relief of pain and tenderness of the affected joints . Overall subjective improvement , assessed by the patient and the investigator at the end of the trial , was present in 90 % of the patients in the flurbiprofen group and in 75 % of those in the indomethacin group . The mean values of all the spinal motion tests improved in the flurbiprofen group but not in the indomethacin group . Statistically significant improvement in the Schober test was achieved in the flurbiprofen group and in chest expansion in the indomethacin group . Characteristic untoward effects related to the central nervous system and gastro-intestinal tract were present in a few patients in both groups [1096904] 27 patients with ascertained ankylosing spondylitis experiencing constant after-midnight-pain received , following three medication-free days , in a double blind , r and omized , cross-over fashion indometacin ( 100 g/day ) and d-2-(6'-methoxy-2'-naphthyl)-propionic acid ( naproxen ) ( 500 mg/day ) , as suppositories , for a period of six days each . The intensity of the night-pain was recorded daily . Naproxen was shown to be equally effective as indometacin in alleviating the after-midnight backache of ankylosing spondylitis . Side effects occurred under indometacin in 5 cases , under naproxen in 3 cases [3620275] 1 Isoxicam , 200 mg once daily , was compared to ketoprofen , 100 mg three times daily , in 19 patients ( 16 males , three females ) with ankylosing spondylitis in a 30-day , double-blind study conducted in two centres . 2 Improvements from baseline to final assessment were noted after both isoxicam and ketoprofen in most clinical variables , with isoxicam , in general , being more effective than ketoprofen . 3 Isoxicam was significantly superior to ketoprofen in reducing pain and was judged by both patients and physicians to be superior overall to ketoprofen . 4 Of the 13 patients who expressed a preference , 10 preferred isoxicam . 5 Typical NSAID side effects were encountered with both drugs [17616556] OBJECTIVES To demonstrate the non-inferiority of celecoxib compared with diclofenac in subjects with ankylosing spondylitis ( AS ) . METHODS The basis of the present work was a 12-week r and omised , double-blind , controlled study in active AS subjects with three treatment arms : celecoxib 200 mg once a day , celecoxib 200 mg twice a day , and diclofenac SR 75 mg twice a day . The primary efficacy endpoint was the change from baseline in global pain intensity on a visual analogue scale ( VAS ) at week 12 . Secondary endpoints covered changes in disease activity , functional and mobility capacities , and adverse events . RESULTS A total of 458 subjects were r and omly assigned to either celecoxib 200 mg once a day ( n = 153 ) , celecoxib 200 mg twice a day ( n = 150 ) , or diclofenac ( n = 155 ) . Least square ( LS ) mean changes from baseline at week 12 on a pain VAS were clinical ly relevant in all treatment groups ( celecoxib 200 mg once a day : -29.1 mm ; celecoxib 200 mg twice a day:-31.7 mm ; diclofenac:-32.7 mm ) and non-inferior when compared to diclofenac . Ankylosing Spondylitis Assessment Study group 20 % ( ASAS 20 ) response and mean improvement in Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI ) scores at week 12 were numerically better on celecoxib 200 mg twice a day ( 59.7 % and -1.32 points ) and on diclofenac ( 60.2 % and -1.48 points ) than on celecoxib 200 mg once a day ( 46.0 % and -0.99 points ) . The incidence of gastrointestinal adverse events was significantly higher on diclofenac ( 28.4 % ) than on celecoxib 200 mg once a day ( 15.0 % ) or 200 mg twice a day ( 16.7 % ) . CONCLUSIONS The efficacy of celecoxib 200 mg once a day and 200 mg twice a day was comparable to that of diclofenac 75 mg twice a day with respect to pain reduction . Celecoxib 200 mg twice a day and diclofenac reduced some parameters associated with inflammation more effectively than celecoxib 200 mg once a day . Treatment was well tolerated , with celecoxib ( either dose ) exhibiting less frequent gastrointestinal adverse events than diclofenac [6993670] Benoxaprofen ( 600 mg once daily ) has been compared to indomethacin ( 25 mg 3 times daily ) in a double-blind crossover study of 20 patients with active ankylosing spondylitis ( AS ) . The clinical improvement was comparable with both drugs ; 6 patients preferred benoxaprofen and 7 patients indomethacin . Although 2 patients discontinued benoxaprofen because of lack of effect , no upper gastrointestinal side effects were reported with this drug . Benoxaprofen is an alternative to indomethacin in the treatment of AS [18821688] OBJECTIVE To evaluate the effect of infliximab on progression of structural damage over 2 years in patients with ankylosing spondylitis ( AS ) . METHODS In the Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy ( ASSERT ) , a r and omized , double-blind , placebo-controlled trial of the efficacy of infliximab compared with placebo , 279 patients with active AS received either placebo through week 24 and then infliximab 5 mg/kg from week 24 through week 96 ( n=78 ) or infliximab 5 mg/kg from baseline through week 96 , administered every 6 weeks after a loading dose ( n=201 ; these patients were the focus of the radiographic analyses ) . Radiographic findings in patients from the ASSERT trial were indistinguishable from those in a historical control cohort of patients who had no prior use of anti-tumor necrosis factor agents ( from the Outcome in Ankylosing Spondylitis International Study [ OASIS ] data base ; n=192 ) . Radiographic progression of structural damage from baseline to the 2-year followup was scored using the modified Stoke Ankylosing Spondylitis Spine Score ( mSASSS ) . All images were scored in one batch . RESULTS Median changes in the mSASSS from baseline to year 2 were 0.0 for both the OASIS and the ASSERT cohorts ( P=0.541 ) . Mean changes in the mSASSS were also similar between the OASIS and ASSERT cohorts ( mean+/-SD change over 2 years 1.0+/-3.2 and 0.9+/-2.6 , respectively ) . In addition , results from sensitivity analyses did not show a statistically significant difference in the mSASSS between the OASIS and ASSERT cohorts . CONCLUSION AS patients who received infliximab from baseline through week 96 did not show a statistically significant difference in inhibition of structural damage progression at year 2 , as assessed using the mSASSS scoring system , when compared with radiographic data from the historical control OASIS cohort . Improvements in clinical outcomes and spinal inflammation have been previously demonstrated with the use of infliximab therapy [324773] Summary Flurbiprofen ( 150–200 mg daily ) and phenylbutazone ( 300–400 mg daily ) were compared in the management of 27 patients with active ankylosing spondylitis . This was a parallel , double-blind , and r and omized trial of 6 weeks duration . Both drugs were equally effective in the relief of pain and tenderness of the affected joints . Overall subjective improvement , assessed by the patient and the investigator at the end of the trial , favored phenylbutazone , but it did not reach a statistically significant level . The mean values of the endpoint parameters of spinal motion showed statistically significant improvement in both groups , except in the Schober test in the flurbiprofen group and chest expansion in the phenylbutazone group . Untoward effects characteristic of these drugs were found in a few patients [15044211] OBJECTIVE To develop and compare c and i date improvement criteria for anti-TNFalpha treatment in ankylosing spondylitis with optimal discriminating capacity between treatment and placebo . METHODS Data from two r and omised controlled trials which included 99 patients treated with infliximab or etanercept were used to evaluate 50 c and i date improvement criteria . These were developed on the basis of pain , patient 's global assessment , function , morning stiffness , spinal mobility , and C reactive protein . Different levels of improvement in each domain ( 20 - 60 % ) were used to define Boolean type criteria . These criteria were compared with different percentages of improvement on the BASDAI and with modified ASAS improvement criteria . Bootstrap methods were applied to calculate 95 % confidence intervals ( CI ) of the chi(2 ) test values to select the best c and i date improvement criteria . RESULTS The best performing improvement criteria were " 20 % improvement in five of six domains " ( chi(2 ) = 31.9 ( 95 % CI , 18.0 to 46.9 ) ) with a low placebo response of 2.9 % and a high response to infliximab of 67.7 % ; and " ASAS 40 % improvement " ( chi(2 ) = 26.5 ( 13.3 to 41.1 ) ) , with response to placebo of 5.7 % and response to infliximab of 64.7 % . The good discriminating capacity of the two improvement criteria was confirmed by the combined data set of the infliximab and etanercept trial . CONCLUSIONS The " five of six " improvement criterion has the advantage of including the objective domains spinal mobility and acute phase reactants , but requires only 20 % improvement . The ASAS 40 % improvement criterion has the advantage of setting a high threshold , but only in patient reported outcomes . The choice between these improvement criteria needs to be based on further validation from upcoming trials [11508441] OBJECTIVE To develop criteria for symptomatic improvement in patients with ankylosing spondylitis ( AS ) , using outcome domain data from placebo-controlled clinical trials of nonsteroidal antiinflammatory drugs ( NSAIDs ) . METHODS Patient data from 5 short-term , r and omized , controlled trials were used to assess equivalence , reliability , and responsiveness of multiple items in the 5 outcome domains for AS treatment : physical function , pain , spinal mobility , patient global assessment , and inflammation . At least one measure per domain was responsive ( st and ardized response mean of > 0.5 ) , except for the spinal mobility domain , which was omitted from the criteria . We developed and tested c and i date improvement criteria in a r and om two-thirds subset from the 3 largest trials and used the remaining one-third for validation . These 3 largest trials included 923 patients ( 631 receiving NSAIDs , 292 in placebo groups ) . We selected the multiple domain definition that best distinguished NSAID treatment from placebo by chi-square test and that had a placebo response rate of < or = 25 % . RESULTS C and i date definitions were changes in single domains and in multiple measure indices , as well as combinations of improvements in multiple domains . Worsening in a domain was defined as a change for the worse of > or = 20 % and a net change for the worse of > or = 10 units on a scale of 0 - 100 . Partial remission ( for comparison purpose s ) was defined as an end-of-trial value of < 20/100 in each of the 4 domains . Among 20 c and i date criteria , change of > or = 20 % and > or = 10 units in each of 3 domains and absence of worsening in the fourth discriminated best in the development subset ( 51 % of patients improved with NSAIDs , 25 % with placebo ; chi2 = 36.4 , P < 0.001 ) . Results were confirmed in the validation subset . Almost all patients satisfying the definition of partial disease remission at the end of the trial had also improved by this criterion . Among all 923 patients , improvement rates using this criterion were 49 % for NSAID-treated patients and 24 % for placebo-treated patients . CONCLUSION Although further validation using data from new trials is still needed , we conclude that we have developed a clinical ly valid , easy-to-use measure of short-term improvement in AS [6752874] In this double blind , crossover trial , 40 patients with ankylosing spondylitis were treated during two successive periods of 4 weeks each with either pirprofen 800 mg/day or ketoprofen 300 mg/day administered orally in a r and omized order . The efficacy of pirprofen and ketoprofen was comparable , the results , as assessed by the clinician , were excellent or satisfactory in 53 % of both groups . Pirprofen was well tolerated by 71 % of the patients and ketoprofen by 59 % [1096903] In a multicenter double-blind cross-over trial the therapeutic effect and the tolerance of d-2-(6'-methoxy-2'-naphthyl)-propionic acid ( naproxen ) and indometacin were compared including 46 patients with rheumatoid arthritis , 35 patients with ankylosing spondylitis and 19 patients with osteoarthrosis . Duration of treatment with both drugs was two to four weeks each . The daily dose of naproxen was 750 mg , that of indometacin l50 mg . In rheumatoid arthritis the combined clinical effect of indometacin was stronger than that of naproxen while both drugs had the same clinical effectiveness in ankylosing spondylitis and osteoarthrosis . When differentiating the total clinical effect as to indices of pain , inflammation and function , indometacin was shown to be superior in all three diseases with regard to pain index . On the other h and , naproxen showed a better effect in ankylosing spondylitis and osteoarthrosis than indometacin as to inflammation , and as to function in osteoarthrosis [7003449] In a four week double-blind crossover study , flurbiprofen 200 mg daily was compared with naproxen 750 mg daily in the management of 30 patients with ankylosing spondylitis . Both treatments were found to be very effective in alleviating pain and stiffness . No significant difference in efficacy was discernible between the two drugs . Side-effects were more frequent with flurbiprofen . A small , but significant , increase in renal excretion of beta-n-acetyl glucosaminidase occurred during treatment with both naproxen and flurbiprofen . Although previous surveys have not shown evidence of renal damage , further surveillance of renal function in patients receiving long term treatment with these preparations to exclude possible renal impairment would be prudent [4164930] A clinical evaluation of indomethacin employing a controlled , cross-over technique with an inert placebo was undertaken in 30 patients with ankylosing spondylitis . Patients were studied for the frequency and dose relationship of side effects and for the subjective response of morning stiffness , chronic spinal pain , acute exacerbations of pain and peripheral arthralgia . Objective evaluation assessed measured change in movements of the cervical and lumbar spines , in chest expansion and in the range of movement of involved peripheral joints . Evaluation of the results indicated that a significant number of patients experienced side effects in the form of headache and dizziness while receiving indomethacin in doses above 150 mg . per day . Many other side effects reported by the patients were not found to occur at a statistically significant level . The significance of pulmonary infections encountered in three patients was review ed . Relief of chronic spinal pain and peripheral arthralgia occurred in 14 and 16 patients , respectively ( p < 0.05 ) . Relief of morning stiffness and acute exacerbations of pain , and increase in the range of movement of any of the segments of the spine or the involved peripheral joints were not significant ( p > 0.05 ) . Based on the results of this study , it is suggested that the role of indomethacin in the management of ankylosing spondylitis be re-evaluated and that the daily therapeutic dose of this drug which has been heretofore recommended be decreased [3515371] Tenoxicam ( 20 mg/day ) and piroxicam ( 20 mg/day ) were compared in a double-blind , parallel group study over 4 weeks in 30 patients with ankylosing spondylitis . Both tenoxicam and piroxicam reduced spinal pain , but the improvement was greater with piroxicam . Tenoxicam and piroxicam were equally effective at improving duration of morning stiffness . Slight improvement was seen with other symptoms with both treatments . Patients were slightly more tolerant of piroxicam than tenoxicam and most patients elected to continue on their particular therapy at the end of the study [1364937] Thirty-nine patients with ankylosing spondylitis participated in a r and omized , double-blind , double-dummy , multi-cross-over study with enteric-coated ( ECT ) and plain ( PT ) naproxen tablets . The duration of the study was 24 days with 6 treatment periods of 4 days . The majority of the patients were taking 750 mg naproxen daily . The mean plasma concentration of naproxen in the morning was 36 % higher with ECT ( p < 0.001 ) . No significant differences regarding duration of morning stiffness and night time pain were found in this patient category . The mean duration of morning stiffness was 116 minutes ( ECT ) and 125 minutes ( PT ) . We were not able to show correlation between plasma concentration of naproxen and duration of morning stiffness [3963018] In this r and omized , double-blind study , 57 patients with ankylosing spondylitis were evaluated after 26 weeks of treatment with either flurbiprofen ( Ansaid , Upjohn ) or indomethacin . Flurbiprofen administered four times a day in a total daily dose of 200 mg was effective in controlling the pain and associated symptoms of ankylosing spondylitis . Pain was adequately controlled in some patients following a total daily dose of 100 mg of flurbiprofen administered twice a day . Flurbiprofen was as effective as indomethacin in most key efficacy measurements analyzed . The drug was well tolerated in doses of up to 300 mg per day , and no clinical ly significant laboratory abnormalities were detected . Flurbiprofen is an excellent treatment for the control of pain and inflammation in patients with ankylosing spondylitis [6365231] The efficacy and tolerability of a new formulation of slow-release indomethacin tablet was compared in a double-blind cross-over manner with a conventional indomethacin capsule in 30 patients with ankylosing spondylitis . Gastrointestinal side-effects and dizziness were less frequent during the slow-release tablet period than during the capsule period [7026817] The relative effectiveness of six nonsteroidal anti-inflammatory agents was studied in 33 patients with rheumatoid arthritis and 32 patients with ankylosing spondylitis in a double-blind , r and omized , prospect i ve study employing a six-way multiple crossover design with six-week trials of each agent . In ankylosing spondylitis , naproxen , indomethacin , and fenoprofen calcium were the most effective agents . In rheumatoid arthritis , relatively little mean difference between drugs was found . Most of this difference could be attributed to compliance factors , which favored drugs that required only a small number of pills daily . Despite the small differences in effect , patients had strong preferences . More than 85 % of patients were still taking their preferred medication after a mean follow-up period of one year [8823693] OBJECTIVE To evaluate the efficacy and tolerability of aceclofenac , a new nonsteroidal antiinflammatory drug , in patients with active ankylosing spondylitis ( AS ) . METHODS 310 out patients with active AS were enrolled in a 3 month , multicenter , parallel , double blind trial and were r and omly assigned to receive aceclofenac ( 200 mg daily ) or indomethacin ( 100 mg daily ) . They were evaluated after a washout period of 7 days , at baseline , 15 , 30 , 60 , and 90 days . RESULTS No significant differences were found between aceclofenac and indomethacin in the number of withdrawals due to lack of efficacy or adverse events . A repeated measures analysis ( ANOVA ) of patients who completed the trial showed no significant differences between either treatment . Within-group comparisons in an intention-to-treat analysis showed improvement ( p < 0.05 ) in all the primary efficacy variables : pain visual analog scale ( VAS ) ( 37 vs 41 % ) , morning stiffness ( 51 vs 46 % ) , modified Schober 's test ( 21 vs 16 % ) , C7-iliac crest line distraction ( 11 vs 14 % ) , lateral spinal flexion ( 6 vs 10 % ) , in aceclofenac and indomethacin treated patients , respectively . Other variables including chest expansion , occiput-to-wall , Likert pain score , use of analgesic rescue , and patient and physician global assessment , also showed significant improvement from baseline values . No significant differences between treatments were noted for any efficacy variable . Good to excellent improvement in pain ( 52 vs 64 % ) and morning stiffness ( 70 vs 68 % ) was observed in aceclofenac and indomethacin treated patients , respectively . Patients taking aceclofenac had significantly fewer central nervous system related adverse events than patients treated with indomethacin ( p < 0.001 ) . CONCLUSION Aceclofenac and indomethacin did not differ with respect to efficacy in the treatment of active AS , although aceclofenac was slightly better tolerated [7044803] Benoxaprofen , 600 mg once daily , was compared with ketoprofen , 100 mg twice daily , in a double-blind parallel study of 23 patients with definite active ankylosing spondylitis . Results were assessed using the following measurements : day pain , night pain , and spinal stiffness . Spinal stiffness was determined by means of st and ard clinical tests . Patient 's evaluation and physician 's overall assessment at the end of therapy also were taken into account . Under these conditions , the therapeutic response for benoxaprofen was good/very good , 8 ; fair , 2 ; and no response , 2 . For ketoprofen , the response as good/very good , 5 ; fair 3 ; and no response 3 . This study shows that benoxaprofen provides very good therapeutic effectiveness in the treatment of ankylosing spondylitis . This is confirmed by the absence of any statistically significant difference between the results observed with benoxaprofen and with ketoprofen , a drug known to be of value in ankylosing spondylitis . The clinical and biologic tolerance of benoxaprofen in this study was quite satisfactory [796939] A series of 26 patients with ankylosing spondylitis have been included in a double-blind cross-over comparison of ketoprofen 200 mg daily and phenylbutazone 300 mg daily , each drug being given for 4 weeks , with paracetamol as a ' rescue drug ' . Six patients withdrew from the study : three on phenylbutazone and one on ketoprofen -- two defaulted treatment . Twenty patients ( 17 males and 3 females ) were eligible for assessment . Their ages ranged between 20 and 59 years ( mean 40.2 years ) . Patient characteristics were comparable in both groups . The results of this series indicate no suggestion of statistically significant differences in any of the nine movements measured . The only significant differences , both in favour of phenylbutazone , were in the paracetamol consumption in the second treatment period in the group receiving ketoprofen first ( 0.01 greater than P greater than 0.005 ) and in the patients ' preference for phenylbutazone ( 0.005 greater than P greater than 0.001 ) . Adverse reactions were comparable in both groups [333540] Feprazone , a non-steroidal anti-inflammatory drug , was compared with indomethacin in a double-blind cross-over trial in 24 patients with ankylosing spondylitis , over eight weeks . Both regimes caused significant reduction in pain . There were fewer side-effects and more patient preferences with feprazone but these differences did not reach statistical significance [10493676] OBJECTIVE To investigate the diagnostic value of magnetic resonance imaging ( MRI ) in the detection of early sacroiliitis . METHODS Twenty-five consecutive HLA-B27 positive patients with inflammatory low back pain and < or = grade 2 unilateral sacroiliitis on conventional radiography ( modified New York criteria ) were studied . Erythrocyte sedimentation rate , C-reactive protein , plain radiography ( PR ) , and MRI of the sacroiliac ( SI ) joints were obtained at study entry and PR of the SI joints after 3 years . Each radiograph and MR image set was interpreted independently . SI joints were scored according to the modified New York Criteria for radiological sacroiliitis . MRI scans were also scored for the presence of subchondral marrow edema . The relationship between > or = grade 2 sacroiliitis ( by modified New York criteria for radiological sacroiliitis ) shown on MRI and the subsequent development of > or = grade 2 sacroiliitis on PR after 3 years was investigated . RESULTS At study entry > or = grade 2 sacroiliitis was found on MRI in 36 of 50 SI joints . Edema was found in 20 of 50 SI joints . After 3 years > or = grade 2 sacroiliitis was found on PR in 21 of 44 SI joints . The positive predictive value of > or = grade 2 sacroiliitis on MRI for the development of > or = grade 2 sacroiliitis on PR after 3 years was 60 % ; sensitivity was 85 % and specificity 47 % . CONCLUSION Our data suggest that MRI of the SI joints can be used to identify sacroiliitis earlier than PR [3871329] We report 2 independently-conducted family studies of HLA-B27 positive prob and s with ankylosing spondylitis ( AS ) , both of which support the view that the clinical spectrum of AS is broader than ordinarily assumed , and should include individuals who have symptomatic disease but who do not show radiologic evidence of abnormalities of the sacroiliac joints or the spine . In the Clevel and study of 100 relatives of 30 B27 positive AS prob and s , 9 relatives did not show radiologic abnormalities of the sacroiliac joints or the spine but had symptoms of chronic inflammatory back pain previously reported to be characteristic of AS . These 9 relatives were all subsequently found to possess B27 , in contrast with only 27 of 60 asymptomatic relatives ( P less than 0.01 ) . In the Leiden study of 101 relatives of 20 r and omly chosen B27 positive AS prob and s , 13 of 86 relatives without radiographic evidence of sacroiliitis reported " thoracic pain and stiffness , " as defined in the Rome criteria for AS . Twelve of these 13 symptomatic relatives were B27 positive . In contrast , among the remaining 73 relatives , only 33 were B27 positive ( P less than 0.01 ) . The occurrence of these characteristic spondylitic symptoms in B27 positive , but not B27 negative , relatives of AS prob and s suggests that the spectrum of the clinical manifestations of AS may include individuals with symptomatic disease , but without radiographic evidence of abnormalities of the sacroiliac joints or the spine . The relatively large number of females we found in this group suggests that women are more likely to manifest this variety of disease than are men [20638563] BACKGROUND Cyclo-oxygenase (COX)-2-selective non-steroidal anti-inflammatory drugs ( NSAIDs ) and non-selective NSAIDs plus a proton-pump inhibitor ( PPI ) have similar upper gastrointestinal outcomes , but risk of clinical outcomes across the entire gastrointestinal tract might be lower with selective drugs than with non-selective drugs . We aim ed to compare risk of gastrointestinal events associated with celecoxib versus diclofenac slow release plus omeprazole . METHODS We undertook a 6-month , double-blind , r and omised trial in patients with osteoarthritis or rheumatoid arthritis at increased gastrointestinal risk at 196 centres in 32 countries or territories . Patients tested negative for Helicobacter pylori and were aged 60 years and older or 18 years and older with previous gastroduodenal ulceration . We used a computer-generated r and omisation schedule to assign patients in a 1:1 ratio to receive celecoxib 200 mg twice a day or diclofenac slow release 75 mg twice a day plus omeprazole 20 mg once a day . Patients and investigators were masked to treatment allocation . The primary endpoint was a composite of clinical ly significant upper or lower gastrointestinal events adjudicated by an independent committee . Analysis was by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00141102 . FINDINGS 4484 patients were r and omly allocated to treatment ( 2238 celecoxib ; 2246 diclofenac plus omeprazole ) and were included in intention-to-treat analyses . 20 ( 0.9 % ) patients receiving celecoxib and 81 ( 3.8 % ) receiving diclofenac plus omeprazole met criteria for the primary endpoint ( hazard ratio 4.3 , 95 % CI 2.6 - 7.0 ; p<0.0001 ) . 114 ( 6 % ) patients taking celecoxib versus 167 ( 8 % ) taking diclofenac plus omeprazole withdrew early because of gastrointestinal adverse events ( p=0.0006 ) . INTERPRETATION Risk of clinical outcomes throughout the gastrointestinal tract was lower in patients treated with a COX-2-selective NSAID than in those receiving a non-selective NSAID plus a PPI . These findings should encourage review of approaches to reduce risk of NSAID treatment . FUNDING Pfizer [22459541] Objective To investigate the influence of non-steroidal anti-inflammatory drugs ( NSAIDs ) intake on radiographic spinal progression over 2 years in patients with ankylosing spondylitis ( AS ) and non-radiographic axial spondyloarthritis ( SpA ) . Methods 164 patients with axial SpA ( 88 with AS and 76 with non-radiographic axial SpA ) were selected for this analysis based on availability of spinal radiographs at baseline and after 2 years of follow-up and the data on NSAIDs intake . Spinal radiographs were scored by two trained readers in a concealed r and omly selected order according to the modified Stoke Ankylosing Spondylitis Spine Score ( mSASSS ) system . An index of the NSAID intake counting both dose and duration of drug intake was calculated . Results High NSAIDs intake ( NSAID index≥50 ) in AS was associated with lower likelihood of significant radiographic progression defined as an mSASSS worsening by ≥2 units : OR=0.15 , 95 % CI 0.02 to 0.96 , p=0.045 ( adjusted for baseline structural damage , elevated C reactive protein ( CRP ) and smoking status ) in comparison with patients with low NSAIDs intake ( NSAID index<50 ) . This effect was most pronounced in patients with baseline syndesmophytes plus elevated CRP : mean mSASSS progression was 4.36±4.53 in patients with low NSAIDs intake versus 0.14±1.80 with high intake , p=0.02 . In non-radiographic axial SpA , no significant differences regarding radiographic progression between patients with high and low NSAIDs intake were found . Conclusion A high NSAIDs intake over 2 years is associated with retarded radiographic spinal progression in AS . In non-radiographic axial SpA this effect is less evident , probably due to a low grade of new bone formation in the spine at this stage

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### Context: [6752873] One hundred and four patients with ankylosing spondylitis were involved in a comparative trial carried out in one single centre . They were given either pirprofene ( 1000 mg/day ) , indomethacin ( 125 mg/day ) or a placebo for 6 consecutive weeks . Response to treatment was assessed after 1 , 2 , 4 and 6 weeks on the basis of 4 subjective criteria and 6 st and ard measurements . The overall therapeutic results were judged by the investigator to be satisfactory in 87 % of patients in the pirprofene group , 77 % in the indomethacin group and 29 % in the placebo group ( p less than 0.01 ) . A large number of patients in each group ( including 34 % on placebo ) reported side effects . Treatment was discontinued on account of gastric pain in two patients ( one on pirprofen , the other on indomethacin ) . No abnormalities were detected in laboratory tests [16549855] Prognosis studies are investigations of future events or the evaluation of associations between risk factors and health outcomes in population s of patients ( 1 ) . The results of such studies improve our underst and ing of the clinical course of a disease and assist clinicians in making informed decisions about how best to manage patients . Prognostic research also informs the design of intervention studies by helping define subgroups of patients who may benefit from a new treatment and by providing necessary information about the natural history of a disorder ( 2 ) . There has recently been a rapid increase in the use of systematic review methods to synthesize the evidence on research questions related to prognosis . It is essential that investigators conducting systematic review s thoroughly appraise the method ologic quality of included studies to be confident that a study 's design , conduct , analysis , and interpretation have adequately reduced the opportunity for bias ( 3 , 4 ) . Caution is warranted , however , because inclusion of method ologically weak studies can threaten the internal validity of a systematic review ( 4 ) . This follows abundant empirical evidence that inadequate attention to biases can cause invalid results and inferences ( 5 - 9 ) . However , there is limited consensus on how to appraise the quality of prognosis studies ( 1 ) . A useful framework to assess bias in such studies follows the basic principles of epidemiologic research ( 10 , 11 ) . We focus on 6 areas of potential bias : study participation , study attrition , prognostic factor measurement , confounding measurement and account , outcome measurement , and analysis . The main objectives of our review of review s are to describe methods used to assess the quality of prognosis studies and to describe how well current practice s assess potential biases . Our secondary objective is to develop recommendations to guide future quality appraisal , both within single studies of prognostic factors and within systematic review s of the evidence . We hope this work facilitates future discussion and research on biases in prognosis studies and systematic review s. Methods Literature Search and Study Selection We identified systematic review s of prognosis studies by search ing MEDLINE ( 1966 to October 2005 ) using the search strategy recommended by McKibbon and colleagues ( 12 ) . This strategy combines broad search terms for systematic review s ( systematic review .mp ; meta- analysis .mp ) and a sensitive search strategy for prognosis studies ( cohort , incidence , mortality , follow-up studies , prognos * , predict * , or course ) . We also search ed the reference lists of included review s and method ologic papers to identify other relevant publications . We restricted our search to English- language publications . One review er conducted the search and selected the studies . Systematic review s , defined as review s of published studies with a comprehensive search and systematic selection , were included if they assessed the method ologic quality of the included studies by using 1 or more explicit criteria . We excluded studies if they were meta-analyses of independent patient data only , if their primary goal was to investigate the effectiveness of an intervention or specific diagnostic or screening tests , or if they included studies that were not done on humans . Data Extraction and Synthesis Individual items included in the quality assessment of the systematic review s were recorded as they were reported in the publication ( that is , the information that would be available to readers and future review ers ) . We review ed journal Web sites and contacted the authors of the systematic review s for additional information when authors made such an offer in their original papers . When review s assessed different study design s by using different sets of quality items , we extracted only those items used to assess cohort studies . We constructed a comprehensive list of distinct items that the review s used to assess the quality of their included studies . The full text of each review was screened . All items used by the review authors to assess the quality of studies were extracted into a computerized spreadsheet by 1 review er . Two experienced review ers , a clinical epidemiologist and an epidemiologist , independently synthesized the quality items extracted from the prognosis review s to determine how well the systematic review s assessed potential biases . We did this in 3 steps : 1 ) identified distinct concepts or domains addressed by the quality items ; 2 ) grouped each extracted quality item into the appropriate domain or domains ; and 3 ) identified the domains necessary to assess potential biases in prognosis studies . We then used this information to assess how well the review s ' quality assessment included items from the domains necessary to assess potential biases . After completing each of the first 3 steps , the review ers met to attempt to reach a consensus . The consensus process involved each review er presenting his or her observations and results , followed by discussion and debate . A third review er was available in cases of persistent disagreement or uncertainty . In the first step , all domains addressed by the quality items were identified . The first review er iteratively and progressively defined the domains as items were extracted from the included review s. The second review er defined domains from a r and om list of all extracted quality items . Limited guidance was provided to the review ers so that their assessment s and definitions of domains would be independent . The review ers agreed on a final set of domains that adequately and completely defined all of the extracted items . In the second step , review ers independently grouped each extracted item into the appropriate domains . Review ers considered each extracted item by asking , What is each particular quality item addressing ? or What are the review 's authors getting at with the particular quality assessment item ? . Items were grouped into the domain or domains that best represented the concepts being addressed . For example , the extracted items at least 80 % of the group originally identified was located for follow-up and follow-up was sufficiently complete or does n't jeopardize validity were each independently classified by both review ers as assessing the domain completeness of follow-up adequate , whereas the extracted item quantification and description of all subjects lost to follow-up was classified as assessing the domain completeness of follow-up described . In the third step , we identified the domains necessary to assess potential biases . Each review er considered the ability of the identified domains to adequately address , at least in part , 1 of the following 6 potential biases : 1 ) study participation , 2 ) study attrition , 3 ) prognostic factor measurement , 4 ) confounding measurement and account , 5 ) outcome measurement , and 6 ) analysis . Domains were considered to adequately address part of the framework if information garnered from that domain would inform the assessment of potential bias . For example , both review ers judged that the identified domain study population represents source population or population of interest assessed potential bias in a prognosis study , whereas the domain research question definition did not , although the latter is an important consideration in assessing the inclusion of studies in a systematic review . Finally , on the basis of our previous ratings , we looked at whether each review included items from the domains necessary to assess the 6 potential biases . We calculated the frequency of systematic review s by assessing each potential bias and the number of review s that adequately assessed bias overall . From this systematic synthesis , we developed recommendations for improving quality appraisal in future systematic review s of prognosis studies . We used Microsoft Access and Excel 2002 ( Microsoft Corp. , Redmond , Washington ) for data management and SAS for Windows , version 9.1 ( SAS Institute , Inc. , Cary , North Carolina ) for descriptive statistics . Role of the Funding Sources The funding sources , the Canadian Institutes of Health Research , the Canadian Chiropractic Research Foundation , the Ontario Chiropractic Association , and the Ontario Ministry of Health and Long Term Care , did not have a role in the collection , analysis , or interpretation of the data or in the decision to su bmi t the manuscript for publication . Results We identified 1384 potentially relevant articles . Figure 1 shows a flow chart of studies that were included and excluded . Figure 2 shows the number of review s identified by year of publication . We excluded 131 systematic review s of prognosis studies that did not seem to include any quality assessment of the included studies ; this represented 44 % of prognosis review s. We included 163 review s of prognosis studies in our analysis ( 13 - 175 ) . The most common topics were cancer ( 15 % ) , musculoskeletal disorders and rheumatology ( 13 % ) , cardiovascular ( 10 % ) , neurology ( 10 % ) , and obstetrics ( 10 % ) . Other review s included a wide range of health and health care topics . Sixty-three percent of the review s investigated the association between a specific prognostic factor and a particular outcome ; the remainder investigated multiple prognostic factors or models . The number of primary studies included in each systematic review ranged from 3 to 167 ( median , 18 [ interquartile range , 12 to 31 ] ) . A complete description of the included review s is available from the authors on request . Figure 1 . Flow diagram of inclusion and exclusion criteria of systematic review s. Figure 2 . Number of systematic review s of prognosis studies identified over time . Quality Items One hundred fifty-three review s provided adequate detail to allow extraction of quality items . Eight hundred eighty-two distinct quality items were extracted from the review s. Most review s developed their own set of quality items , with only a few applying criteria from previous review s. Most quality items [15731291] Objective : The combined efficacy of selective and non-selective cyclo-oxygenase-2 ( COX-2 ) inhibition on the axial manifestations of ankylosing spondylitis ( AS ) in the presence or absence of chronic peripheral arthritis was evaluated . Methods : In a post hoc subgroup analysis of a 6 week , r and omised , double blind , placebo controlled trial , 387 patients with active axial AS were r and omised to receive etoricoxib 90 mg or 120 mg once a day , naproxen 500 mg twice daily , or placebo . R and omisation was stratified by the presence or absence of chronic peripheral arthritis . The primary outcome measure was the time weighted average change from baseline of spine pain intensity . Efficacy data from the three groups receiving active treatment ( the NSAID/COX-2 inhibitor group ) were combined to improve precision . An analysis of covariance model was used to evaluate the effect of peripheral disease on treatment response . Results : 93 patients were allocated to receive placebo and 294 to active treatment ( naproxen or etoricoxib ) . The combined NSAID/COX-2 inhibitor group had a significant treatment response compared with the placebo group for all efficacy measures , both in patients with and without peripheral arthritis . A significantly greater difference in mean patient assessment of spine pain was found between active and placebo treatments in patients without compared with those with peripheral arthritis ( p = 0.005 ; −32.5 mm v −17.0 mm , respectively ) . Similar differences , although not statistically significant , were seen for other end points . Conclusion : NSAIDs and COX-2 inhibitors have a clinical ly relevant symptomatic effect on axial AS irrespective of the presence of peripheral arthritis . In this exploratory analysis spinal improvement appeared to be greater in patients without peripheral disease [18952641] Objective : To describe and assess the response to short-term etoricoxib as shown by MRI and clinical variables in patients with ankylosing spondylitis ( AS ) selected for eligibility for anti-tumour necrosis factor therapy . Methods : In a 6-week open-label study , 22 patients with AS and eligible for biological therapy were treated with 90 mg of etoricoxib daily . Clinical and laboratory parameters were obtained and MRI of the sacroiliac joints and the lower thoracic and lumbar spine performed at baseline and at week 6 . The primary end point was the proportion of patients fulfilling the SpondyloArthritis international Society ( ASAS ) response criteria for biological therapies ( ASASBIO ) while secondary end points included the change in MRI-determined bone lesions . Results : Eight of 20 completers improved enough to meet the ASASBIO response criteria and most clinical variables improved significantly . Fifteen patients had a total of 63 MRI-detectable lesions ; overall , 13/60 lesions with paired scans either resolved completely or improved , while five lesions worsened or appeared during treatment . Conclusion : Etoricoxib is an effective symptomatic treatment for patients with AS ; however , its effect on MRI-detected lesions is small . Further studies are needed to determine the effect of etoricoxib on MRI-determined bone oedema [16960941] OBJECTIVE To evaluate the efficacy and safety of celecoxib in patients with ankylosing spondylitis ( AS ) . METHODS This was a 12-week r and omized , double-blind , placebo-controlled study with 4 treatment arms : celecoxib 200 mg qd , celecoxib 400 mg qd , naproxen 500 mg bid , and placebo . Patients ( age 18 - 75 yrs ) requiring daily treatment with nonselective nonsteroidal antiinflammatory drugs , and with a pain intensity on visual analog scale ( VAS ) > or = 50 mm worsening by 30 % compared with a pre inclusion visit ( 14 days prior ) were studied . Primary endpoints were least-squares mean changes from baseline in pain intensity , disease activity ( patient global assessment VAS ) , and functional impairment [ Bath Ankylosing Spondylitis Functional Index ( BASFI ) ] . Adverse events were monitored throughout the study . RESULTS Of 611 r and omized patients , 137 were allocated to celecoxib 200 mg , 161 to celecoxib 400 mg , 157 to naproxen , and 156 to placebo . Improvements in least-squares mean pain intensity , disease activity , and BASFI scores were significantly greater in the celecoxib 200 mg , celecoxib 400 mg , and naproxen groups than in the placebo group ( p < or = 0.001 ) at Week 12 and the interim timepoints , Weeks 1 , 3 , and 6 . Celecoxib 400 mg was as effective as naproxen ; however , naproxen was more effective than celecoxib 200 mg . Celecoxib was well tolerated , with an adverse event profile similar to placebo . However , 3 naproxen-treated patients experienced serious treatment-related gastrointestinal ( GI ) adverse events ( one severe gastric ulcer , one moderate GI hemorrhage , one severe GI hemorrhage ) . CONCLUSION In this 12-week study , celecoxib 200 mg qd and 400 mg qd were efficacious and well tolerated in treating signs and symptoms of AS [22532639] Objectives The aim was to compare continuous and on-dem and NSAID treatment with respect to their ability to suppress radiographic progression in subgroups of patients with high/elevated CRP-levels , ESR , ASDAS-levels or BASDAI-levels in comparison to patients with normal levels . Methods Post-hoc analyses were performed in a r and omized trial comparing continuous and on-dem and NSAID treatment . Relevant high/elevated subgroups were created based on time-averaged ( ta ) CRP ( > 5mg/L ) , ta-ESR ( > 12mm/hr ) , ta-BASDAI ( > 4 ) , ta-ASDAS-CRP ( > 2.1 ) and ta-ASDAS-ESR ( > 2.1 ) . Subgroups were further split according to NSAID-use ( continuous vs. on-dem and ) . Radiological progression was presented in probability plots . Statistical interactions were tested using multiple and logistic regression analysis . Differences in radiological progression were analysed using the Chi-square and Mann-Whitney U test . Results 150 participants r and omized to either the continuous-treatment group ( n=76 ) , or the on-dem and group ( n=74 ) had complete radiographs and were included . The effect of slowing radiological progression with continuous NSAID therapy was more pronounced in patients with elevated ta-CRP-levels , elevated ta-ESR , high ta-ASDAS-CRP or high ta-ASDAS-ESR versus patients with low/normal values . No such effect was found for participants with high vs. low BASDAI . Also , in participants with elevated ta-ESR ( irrespective of treatment ) , there appeared to be a higher rate of structural progression than in participants with normal ta-ESR . Regression analyses showed that continuous NSAID treatment neutralizes the negative effect of inflammation ( high ta-ESR ) . Conclusions Patients with elevated acute phase reactants seem to benefit most from continuous treatment with NSAIDs . Continuous NSAID-therapy in patients with elevated acute phase reactants may lead to an improved benefit-risk-ratio of these drugs [2198157] A 12-week trial was carried out to compare the efficacy of pirazolac ( 300 - 600 mg b.i.d . ) with that of indomethacin ( 25 - 50 mg t.i.d . ) in patients with ankylosing spondylitis . A total of 119 patients completed the treatment period , with 32 drop-outs . Both therapies showed significant improvements in clinical symptoms [343727] In a double-blind double-placebo crossover study naproxen ( 500 - 750 mg daily ) was found to be equivalent to phenylbutazone ( 400 - 600 mg daily ) in the control of disease activity in 20 patients suffering from ankylosing spondylitis during a two times 5-week trial period . No serious side effects were observed during the trial period . Gastric complaints occurred twice as often under phenylbutazone as under naproxen [15713943] BACKGROUND Selective inhibition of cyclooxygenase-2 ( COX-2 ) may be associated with an increased risk of thrombotic events , but only limited long-term data have been available for analysis . We report on the cardiovascular outcomes associated with the use of the selective COX-2 inhibitor rofecoxib in a long-term , multicenter , r and omized , placebo-controlled , double-blind trial design ed to determine the effect of three years of treatment with rofecoxib on the risk of recurrent neoplastic polyps of the large bowel in patients with a history of colorectal adenomas . METHODS A total of 2586 patients with a history of colorectal adenomas underwent r and omization : 1287 were assigned to receive 25 mg of rofecoxib daily , and 1299 to receive placebo . All investigator-reported serious adverse events that represented potential thrombotic cardiovascular events were adjudicated in a blinded fashion by an external committee . RESULTS A total of 46 patients in the rofecoxib group had a confirmed thrombotic event during 3059 patient-years of follow-up ( 1.50 events per 100 patient-years ) , as compared with 26 patients in the placebo group during 3327 patient-years of follow-up ( 0.78 event per 100 patient-years ) ; the corresponding relative risk was 1.92 ( 95 percent confidence interval , 1.19 to 3.11 ; P=0.008 ) . The increased relative risk became apparent after 18 months of treatment ; during the first 18 months , the event rates were similar in the two groups . The results primarily reflect a greater number of myocardial infa rct ions and ischemic cerebrovascular events in the rofecoxib group . There was earlier separation ( at approximately five months ) between groups in the incidence of nonadjudicated investigator-reported congestive heart failure , pulmonary edema , or cardiac failure ( hazard ratio for the comparison of the rofecoxib group with the placebo group , 4.61 ; 95 percent confidence interval , 1.50 to 18.83 ) . Overall and cardiovascular mortality was similar in the two groups . CONCLUSIONS Among patients with a history of colorectal adenomas , the use of rofecoxib was associated with an increased cardiovascular risk [3553586] During almost 12 years of development and clinical trials , diclofenac sodium has been shown to be both effective and safe as a new nonsteroidal antiinflammatory drug ( NSAID ) for the treatment of rheumatic diseases including ankylosing spondylitis ( AS ) . We compared the safety and efficacy of 75 , 100 , or 125 mg/day of diclofenac with the same doses of indomethacin in a multicenter , r and omized , parallel group trial in patients with AS . A single blind placebo washout period of 2 days to 2 weeks preceded the 13-week double blind treatment period . Both diclofenac and indomethacin produced significant ( p less than 0.001 ) improvement from baseline for all 14 efficacy variables analyzed . There were no significant between treatment differences . Differences favored diclofenac in the frequency and the severity of adverse experiences reported and in the frequency of complaints affecting the central nervous system [3888608] Objective To investigate whether biologic-free remission can be achieved in patients with early , active axial spondyloarthritis ( SpA ) who were in partial remission after 28 weeks of infliximab (IFX)+naproxen ( NPX ) or placebo (PBO)+NPX treatment and whether treatment with NPX was superior to no treatment to maintain disease control . Method Infliximab as First-Line Therapy in Patients with Early Active Axial Spondyloarthritis Trial ( INFAST ) Part 1 was a double-blind , r and omised , controlled trial in biologic-naïve patients with early , active , moderate-to-severe axial SpA treated with either IFX 5 mg/kg+NPX 1000 mg/d or PBO+NPX 1000 mg/d for 28 weeks . Patients achieving Assessment of SpondyloArthritis international Society ( ASAS ) partial remission at week 28 continued to Part 2 and were r and omised ( 1:1 ) to NPX or no treatment until week 52 . Treatment group differences in ASAS partial remission and other efficacy variables were assessed through week 52 with Fisher exact tests . Results At week 52 , similar percentages of patients in the NPX group ( 47.5 % , 19/40 ) and the no-treatment group ( 40.0 % , 16/40 ) maintained partial remission , p=0.65 . Median duration of partial remission was 23 weeks in the NPX group and 12.6 weeks in the no-treatment group ( p=0.38 ) . Mean Bath Ankylosing Spondylitis Disease Activity Index scores were low at week 28 , the start of follow-up treatment ( NPX , 0.7 ; no treatment , 0.6 ) , and remained low at week 52 ( NPX , 1.2 ; no treatment , 1.7 ) . Conclusions In axial SpA patients who reached partial remission after treatment with either IFX+NPX or NPX alone , disease activity remained low , and about half of patients remained in remission during 6 months in which NPX was continued or all treatments were stopped [10979111] CONTEXT Conventional nonsteroidal anti-inflammatory drugs ( NSAIDs ) are associated with a spectrum of toxic effects , notably gastrointestinal ( GI ) effects , because of inhibition of cyclooxygenase (COX)-1 . Whether COX-2-specific inhibitors are associated with fewer clinical GI toxic effects is unknown . OBJECTIVE To determine whether celecoxib , a COX-2-specific inhibitor , is associated with a lower incidence of significant upper GI toxic effects and other adverse effects compared with conventional NSAIDs . DESIGN The Celecoxib Long-term Arthritis Safety Study ( CLASS ) , a double-blind , r and omized controlled trial conducted from September 1998 to March 2000 . SETTING Three hundred eighty-six clinical sites in the United States and Canada . PARTICIPANTS A total of 8059 patients ( > /=18 years old ) with osteoarthritis ( OA ) or rheumatoid arthritis ( RA ) were enrolled in the study , and 7968 received at least 1 dose of study drug . A total of 4573 patients ( 57 % ) received treatment for 6 months . INTERVENTIONS Patients were r and omly assigned to receive celecoxib , 400 mg twice per day ( 2 and 4 times the maximum RA and OA dosages , respectively ; n = 3987 ) ; ibuprofen , 800 mg 3 times per day ( n = 1985 ) ; or diclofenac , 75 mg twice per day ( n = 1996 ) . Aspirin use for cardiovascular prophylaxis ( < /=325 mg/d ) was permitted . MAIN OUTCOME MEASURES Incidence of prospect ively defined symptomatic upper GI ulcers and ulcer complications ( bleeding , perforation , and obstruction ) and other adverse effects during the 6-month treatment period . RESULTS For all patients , the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.76 % vs 1.45 % ( P = .09 ) and 2 . 08 % vs 3.54 % ( P = .02 ) , respectively . For patients not taking aspirin , the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.44 % vs 1.27 % ( P = .04 ) and 1.40 % vs 2.91 % ( P = .02 ) . For patients taking aspirin , the annualized incidence rates of upper GI ulcer complications alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 2.01 % vs 2.12 % ( P = .92 ) and 4.70 % vs 6.00 % ( P = .49 ) . Fewer celecoxib-treated patients than NSAID-treated patients experienced chronic GI blood loss , GI intolerance , hepatotoxicity , or renal toxicity . No difference was noted in the incidence of cardiovascular events between celecoxib and NSAIDs , irrespective of aspirin use . CONCLUSIONS In this study , celecoxib , at dosages greater than those indicated clinical ly , was associated with a lower incidence of symptomatic ulcers and ulcer complications combined , as well as other clinical ly important toxic effects , compared with NSAIDs at st and ard dosages . The decrease in upper GI toxicity was strongest among patients not taking aspirin concomitantly . JAMA . 2000;284:1247 - [10325662] OBJECTIVE To consider the relevance of the duration of a clinical trial in ankylosing spondylitis : long-term ( i.e. 1 yr ) vs short-term ( i.e. 6 weeks ) assessment of a non-steroidal anti-inflammatory drug (NSAID)-placebo controlled study . METHODS The design was a prospect i ve , multicentre , double-blind , placebo-controlled study of 6 weeks duration with a 12 months double-blind extension . Study drugs were placebo ( n = 121 ) or active NSAID ( n = 352 ) . A decrease of at least 50 % in pain and /or global assessment and /or functional impairment during the study defined the response to treatment . The percentage of patients discontinuing the study drug over time ( life table analysis ) permitted the evaluation of both the efficacy and toxicity . RESULTS Among the 473 recruited patients , the percentage of responders was similar at 1 yr and week 6 with a highly statistically significant difference in favour of the active NSAID groups when compared to placebo ( at 1 yr , 17 % in the placebo group vs 37 , 50 and 43 % in the piroxicam 20 mg , meloxicam 15 mg and meloxicam 22.5 mg , respectively , for the patient 's overall assessment ) without any statistically significant difference between the three active groups . However , evaluation of the patients discontinuing the study drug during the 1 yr of the study permitted the detection of a statistically significant difference between the active NSAID groups . A lower percentage of patients taking meloxicam 22.5 mg had to discontinue the study drug when compared to either meloxicam 15 mg or piroxicam 20 mg ( 37 % vs 53 % and 53 % , respectively , P < 0.05 ) . By 52 weeks , drug-related upper gastrointestinal adverse events occurred in 13 , 32 , 20 and 18 % in the placebo , piroxicam 20 mg , meloxicam 15 mg and meloxicam 22.5 mg groups , respectively . Some of the adverse events occurred only after week 6 . CONCLUSION This study suggests that a 1 yr trial might be of optimum value compared to a 6 week assessment in order to define better the efficacy and tolerability of NSAIDs in ankylosing spondylitis [356241] The effect and tolerance of proquazone and indomethacin in patients suffering from ankylosing spondylitis were compared in two separate 3-week clinical , double-blind , r and omized studies on total of 60 patients . In the first study 16 patients were treated with proquazone and 14 patients with indomethacin , and in the second study 15 patients were treated in each group . Both drugs were found to have an evident , equally strong effect on pain and functional capacity in daily doses of 900 mg and 75 mg respectively . Severe side effects were not noted with either one of the drugs . Patients with previously known intolerance to indomethacin were excluded from the studies . Gastronitestinal disturbances seem to be the most commonly appearing side effect in patients treated with proquazone [3159143] Background Clinical analgesic trials typically report response as group mean results . However , research has shown that few patients are average and most have responses at the extremes . Moreover , group mean results do not convey response levels and thus have limited value in representing the benefit-risk at an individual level . Responder analyses and numbers-needed-to-treat ( NNT ) are considered more relevant for evaluating treatment response . We evaluated levels of analgesic response and Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI ) score improvement and the associated NNTs . Methods This was a post-hoc analysis of a 6-week , r and omized , double-blind study ( N = 387 ) comparing etoricoxib 90 mg , etoricoxib 120 mg , naproxen 1000 mg , and placebo in AS . Spine pain and BASDAI were measured on a 100-mm visual analog scale . The number and percentage of patients achieving ≥30 % and ≥50 % improvement in both BASDAI and spine pain were calculated and used to determine the corresponding NNTs . Patients who discontinued from the study for any reason were assigned zero improvement beyond 7 days of the time of discontinuation . Results For etoricoxib 90 mg , etoricoxib 120 mg and naproxen 1000 mg , the NNTs at 6 weeks compared with placebo were 2.0 , 2.0 , and 2.7 respectively for BASDAI ≥30 % improvement , and 3.2 , 2.8 , and 4.1 for ≥50 % improvement . For spine pain , the NNTs were 1.9 , 2.0 , and 3.2 , respectively , for ≥30 % improvement , and 2.7 , 2.5 , and 3.7 for ≥50 % improvement . The differences between etoricoxib and naproxen exceeded the limit of ±0.5 units described as a clinical ly meaningful difference for pain . Response rates and NNTs were generally similar and stable over 2 , 4 , and 6 weeks . Conclusions For every 2 patients treated with etoricoxib , 1 achieved a clinical ly meaningful ( ≥30 % ) improvement in spine pain and BASDAI beyond that expected from placebo , whereas the corresponding values were approximately 1 in every 3 patients treated with naproxen . Use of NNTs and responder analyses provide additional , complementary information beyond population mean responses when assessing efficacy compared to placebo and amongst active therapies [3524970] Summary A 12-week double-blind r and omized drug trial followed by an open extension period of 36 weeks was carried out in 38 male patients with ankylosing spondylitis ( AS ) to compare the efficacy and safety of diflunisal ( 500 mg twice daily ) and phenylbutazone ( 200 mg twice daily ) . Both drugs proved to be effective in improving the severity of symptoms associated with AS , and this improvement was maintained throughout the open extension period . Initially diflunisal had a more pronounced and rapid analgesic action , whereas phenylbutazone was more effective in increasing axial mobility . During the study 9 patients dropped out : 3 in each treatment group due to side effects and 1 in each group due to lack of efficacy ; another patient was lost to follow-up . The two drugs were similarly safe as judged by the occurrence of adverse clinical effects , mainly gastrointestinal . This study again demonstrates the value of phenylbutazone in AS but , taking into account the possible haematological side effects , the use of other NSAIDs is stressed . Diflunisal is an alternative capable of improving the painful stiffness associated with AS [2181618] A system of classification criteria of spondyloarthropathies was experimented in three studies . They have permitted to measure its specificity which is 86.6 p. cent and its sensitivity which is 90 p. cent . This system permits to compare theory and clinical practice and also to classify disease not yet classified . The positive and negative predictive values of these tests remain to be vali date d and assessed , with a multicenter study including patients affected or not with spondyloarthropathy , in order to determine whether they can also be used as a diagnosis tool [1365469] Forty-two patients with ankylosing spondylitis were entered into a double-blind study to compare treatment with indomethacin and a new non-steroidal anti-inflammatory drug , nabumetone . Clinical , laboratory and side-effect profiles were measured over a three month period . Both drugs were effective in relieving pain and morning stiffness , indomethacin was better in alleviating general stiffness , nabumetone result ed in less side-effects . Objective measurements of spinal movements revealed no difference between the two drugs . Nabumetone , available as Relifex , appears as effective as indomethacin in relieving the symptoms of ankylosing spondylitis and is possibly better tolerated [6349653] 98 patients with reversible , definite , active ankylosing spondylitis were selected for this study . 49 patients were treated with N-(2,6-dichloro-m-tolyl)anthranilic acid , sodium salt ( meclofenamate sodium , Meclomen ) and 49 patients with indometacin . Following a single-blind baseline period on placebo , patients received either 200 mg meclofenamate sodium per day or 100 mg indometacin per day for one week , in the second week the doses were increased to 250 mg meclofenamate sodium and 125 mg indometacin and from the third through the eight week 300 mg meclofenamate sodium and 150 mg indometacin were given . The results of this double-blind study showed that similar improvement in mobility of the vertebral column and spondylitic pain could be achieved with meclofenamate sodium and indometacin in patients with ankylosing spondylitis . Although both treatments were well tolerated fewer meclofenamate sodium patients reported adverse reactions than did those who had received indometacin . It is concluded that meclofenamate sodium offers an effective and safe alternative to indometacin in the treatment of patients with ankylosing spondylitis [19297344] Objective : To vali date and refine two sets of c and i date criteria for the classification/diagnosis of axial spondyloarthritis ( SpA ) . Methods : All Assessment of SpondyloArthritis international Society ( ASAS ) members were invited to include consecutively new patients with chronic ( ⩾3 months ) back pain of unknown origin that began before 45 years of age . The c and i date criteria were first tested in the entire cohort of 649 patients from 25 centres , and then refined in a r and om selection of 40 % of cases and thereafter vali date d in the remaining 60 % . Results : Upon diagnostic work-up , axial SpA was diagnosed in 60.2 % of the cohort . Of these , 70 % did not fulfil modified New York criteria and , therefore , were classified as having “ non-radiographic ” axial SpA. Refinement of the c and i date criteria result ed in new ASAS classification criteria that are defined as : the presence of sacroiliitis by radiography or by magnetic resonance imaging ( MRI ) plus at least one SpA feature ( “ imaging arm ” ) or the presence of HLA-B27 plus at least two SpA features ( “ clinical arm ” ) . The sensitivity and specificity of the entire set of the new criteria were 82.9 % and 84.4 % , and for the imaging arm alone 66.2 % and 97.3 % , respectively . The specificity of the new criteria was much better than that of the European Spondylarthropathy Study Group criteria modified for MRI ( sensitivity 85.1 % , specificity 65.1 % ) and slightly better than that of the modified Amor criteria ( sensitivity 82.9 , specificity 77.5 % ) . Conclusion : The new ASAS classification criteria for axial SpA can reliably classify patients for clinical studies and may help rheumatologists in clinical practice in diagnosing axial SpA in those with chronic back pain . Trial registration number : NCT00328068 [11087881] BACKGROUND Each year , clinical upper gastrointestinal events occur in 2 to 4 percent of patients who are taking nonselective nonsteroidal antiinflammatory drugs ( NSAIDs ) . We assessed whether rofecoxib , a selective inhibitor of cyclooxygenase-2 , would be associated with a lower incidence of clinical ly important upper gastrointestinal events than is the nonselective NSAID naproxen among patients with rheumatoid arthritis . METHODS We r and omly assigned 8076 patients who were at least 50 years of age ( or at least 40 years of age and receiving long-term glucocorticoid therapy ) and who had rheumatoid arthritis to receive either 50 mg of rofecoxib daily or 500 mg of naproxen twice daily . The primary end point was confirmed clinical upper gastrointestinal events ( gastroduodenal perforation or obstruction , upper gastrointestinal bleeding , and symptomatic gastroduodenal ulcers ) . RESULTS Rofecoxib and naproxen had similar efficacy against rheumatoid arthritis . During a median follow-up of 9.0 months , 2.1 confirmed gastrointestinal events per 100 patient-years occurred with rofecoxib , as compared with 4.5 per 100 patient-years with naproxen ( relative risk , 0.5 ; 95 percent confidence interval , 0.3 to 0.6 ; P<0.001 ) . The respective rates of complicated confirmed events ( perforation , obstruction , and severe upper gastrointestinal bleeding ) were 0.6 per 100 patient-years and 1.4 per 100 patient-years ( relative risk , 0.4 ; 95 percent confidence interval , 0.2 to 0.8 ; P=0.005 ) . The incidence of myocardial infa rct ion was lower among patients in the naproxen group than among those in the rofecoxib group ( 0.1 percent vs. 0.4 percent ; relative risk , 0.2 ; 95 percent confidence interval , 0.1 to 0.7 ) ; the overall mortality rate and the rate of death from cardiovascular causes were similar in the two groups . CONCLUSIONS In patients with rheumatoid arthritis , treatment with rofecoxib , a selective inhibitor of cyclooxygenase-2 , is associated with significantly fewer clinical ly important upper gastrointestinal events than treatment with naproxen , a nonselective inhibitor [16646033] OBJECTIVE To determine whether the effects of anti-tumor necrosis factor alpha ( TNFalpha ) in reducing the signs and symptoms of ankylosing spondylitis ( AS ) coincide with a reduction in spinal inflammation as detected by magnetic resonance imaging ( MRI ) . METHODS Pre- and postgadolinium T1 and STIR MR images of the spine were acquired at baseline and at week 24 in patients with AS who participated in a multicenter , r and omized , double-blind , placebo-controlled study . Patients were r and omly assigned at an 8:3 ratio to receive infusions of infliximab ( 5 mg/kg ) or placebo at weeks 0 , 2 , and 6 and then every 6 weeks thereafter . MR images were obtained and evaluated independently by 2 readers who were blinded to the treatment allocation and time sequence of the images . RESULTS A total of 194 patients in the infliximab group and 72 patients in the placebo group had evaluable images at baseline and week 24 . About 80 % of the patients had at least 1 active spinal lesion at baseline , as assessed by MRI . The improvement in the MRI Activity Score after 6 months was significantly greater in the patients who received infliximab ( mean 5.02 , median 2.72 ) than in those who received placebo ( mean 0.60 , median 0.0 ) ( P < 0.001 ) . Almost complete resolution of spinal inflammation was seen in most patients who received infliximab , irrespective of baseline activity . CONCLUSION Patients with AS who received infliximab therapy showed a decrease in spinal inflammation as detected by MRI , whereas those who received placebo showed persistent inflammatory spondylitis [10609815] BACKGROUND Non-steroidal anti-inflammatory drugs ( NSAIDs ) inhibit cyclo-oxygenase ( COX ) , which leads to suppression of COX-1-mediated production of gastrointestinal-protective prostagl and ins . Gastrointestinal injury is a common outcome . We compared the efficacy , safety , and tolerability of long-term therapy with celecoxib , a COX-1 sparing inhibitor of COX-2 , with diclofenac , a non-specific COX inhibitor . METHODS 655 patients with adult-onset rheumatoid arthritis of at least 6 months ' duration were r and omly assigned oral celecoxib 200 mg twice daily or diclofenac SR 75 mg twice daily for 24 weeks . Anti-inflammatory and analgesic activity and tolerability were assessed at baseline , every 4 weeks , and at week 24 . We assessed gastrointestinal safety by upper-gastrointestinal endoscopy within 7 days of the last treatment dose at centres where the procedure was available . Analysis was by intention-to-treat . FINDINGS 430 patients underwent endoscopy ( celecoxib n=212 , diclofenac n=218 ) . The two drugs were similar in management of rheumatoid arthritis pain and inflammation . Gastroduodenal ulcers were detected endoscopically in 33 ( 15 % ) patients treated with diclofenac and in eight ( 4 % ) in the celecoxib group ( p<0.001 ) . The rate of withdrawal for any gastrointestinal-related adverse event , most commonly abdominal pain , diarrhoea , and dyspepsia , was nearly three times higher in the diclofenac-treated group than in the celecoxib group ( 16 vs 6 % ; p<0.001 ) . INTERPRETATION Celecoxib showed sustained anti-inflammatory and analgesic activity similar to diclofenac , with a lower frequency of upper gastrointestinal ulceration or gastrointestinal adverse events , and tolerability was better [21068095] Background The Ankylosing Spondylitis Disease Activity Score ( ASDAS ) is a new composite index to assess disease activity in ankylosing spondylitis ( AS ) . It fulfils important aspects of truth , feasibility and discrimination . Criteria for disease activity states and improvement scores are important for use in clinical practice , observational studies and clinical trials and so far have not been developed for the ASDAS . Objective To determine clinical ly relevant cut-off values for disease activity states and improvement scores using the ASDAS . Methods For the selection of cut-offs data from the Norwegian disease modifying antirheumatic drug ( NOR-DMARD ) registry , a cohort of patients with AS starting conventional or biological DMARDs , were used . Receiver operating characteristic analysis against several external criteria was performed and several approaches to determine the optimal cut-offs used . The final choice was made on clinical and statistical grounds , after debate and voting by Assessment of SpondyloArthritis international Society members . Crossvalidation was performed in NOR-DMARD and in Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy , a data base of patients with AS participating in a r and omised placebo-controlled trial with a tumour necrosis factor blocker . Results Four disease activity states were chosen by consensus : inactive disease , moderate , high and very high disease activity . The three cut-offs selected to separate these states were : 1.3 , 2.1 and 3.5 units . Selected cut-offs for improvement were : change ≥1.1 units for clinical ly important improvement and change ≥2.0 units for major improvement . Results of the crossvalidation strongly supported the cut-offs . Conclusions Cut-off values for disease activity states and improvement using the ASDAS have been developed . They proved to have external validity and a good performance compared to existing criteria [363071] A double-blind , cross-over comparison of Naprosyn ( naproxen ) 750 mg daily and Butacote ( enteric-coated phenylbutazone ) 300 mg daily was carried out in a multi-centre trial . Twenty-five patients , mostly male and under 40 years of age , were entered . After a 2-week period in which any existing anti-inflammatory drugs were tailed off , patients were entered into the trial and treated for 1 month with each drug . Patients were assessed at 4-weekly intervals . Both drugs significantly reduced morning stiffness . Morning pain and discomfort and wall-tragus distance were also significantly reduced by both drugs during the trial . Results of the Schober test showed improvement during both treatment periods . There were no overall statistically significant differences between the effects of the 2 drugs on objective parameters . However , overall subjective assessment of symptoms showed a greater improvement on Butacote . Treatment preferences by physician and subjective assessment by the patient both favoured Butacote but the difference between the 2 drugs was not statistically significant . Side effects were mostly of a minor nature . One patient had to discontinue the trial , due to indigestion while taking Butacote [4937661] Abstract Objective : Control of airway inflammation is the cornerstone of asthma management . The aim of the present pilot study was to assess the effects of a leukotriene receptor antagonist ( LTRA ) added to a basic treatment of inhaled corticosteroids ( ICS ) and long-acting beta-agonist ( LABA ) on airway hyperresponsiveness , inflammation , and quality of life in well-controlled patients with asthma . Research design and methods : Seventeen patients ( age 18–65 , 11 women ) with well-controlled asthma presenting airway hyperresponsiveness to mannitol and methacholine challenge were given add-on montelukast on a stable ICS + LABA for 4 weeks . Quality of life and selected parameters of airway inflammation were measured at baseline and at study end . ( Clinical Trials.gov ( NCT01725360 ) ) . Results : Adding montelukast to ICS + LABA result ed in an increase in mean FEV1 ( + 4.5 % , p = 0.057 ) , cumulated higher dose of mannitol ( + 32.5 % , p = 0.023 ) and methacholine ( + 17.2 % , 0.237 ) in the provocation test , lower airway reactivity with mannitol and methacholine ( response dose ratio ( RDR ) –50.0 % , p = 0.024 and –44.3 % , p = 0.006 , respectively ) , and improved airway sensitivity to mannitol and methacholine ( + 12.1 % , p = 0.590 and + 48.0 % , p = 0.129 for PD15 and PD20 FEV1 , respectively ) . Changes in inflammation parameters ( blood eosinophil count , serum eosinophil cationic protein , and exhaled nitric oxide ) were consistent with these findings . Asthma-related quality of life improved significantly in all domains and overall ( from 5.3 at baseline to 6.1 at the final visit , p < 0.001 ) . The main limitation was the absence of a control group . Conclusion : The consistency of the changes in airway hyperresponsiveness and inflammation as well as in quality of life observed with an add-on therapy with montelukast in well-controlled asthma patients during 4 weeks suggests that residual inflammation may represent an area for further improvement of asthma control to be explored in adequately powered r and omized controlled trials [7013054] The r and omized , double-blind trial was carried out with 50 patients suffering from ankylosing spondylarthritis and belonging all to type B27 in the HLA system . Tolfenamic acid ( 600 mg daily ) was effective as judged by subjective and numerous objective parameters and was preferable to indomethacin ( 75 mg daily ) . Indomethacin caused side effects more frequently than tolfenamic acid . In the indomethacin group 16 % of the patients interrupted the 6-month trial because of gastrointestinal complications . No discontinuation of treatment owing to adverse effects of tolfenamic acid occurred . Tolfenamic acid offers one new and good alternative for the medical treatment of ankylosing spondylarthritis [9402773] Abstract Objectives : To determine the profile of risk of upper gastrointestinal toxicity during continuous treatment with , and after cessation of , non-steroidal anti-inflammatory drugs . Design : Cohort study with a prospect ively constructed , population based , record linkage data base containing details of exposure to all community dispensed non-steroidal anti-inflammatory drugs and also all admissions to hospital for upper gastrointestinal diagnoses . Setting : The population of Tayside , Scotl and . Subjects : 52 293 subjects aged 50 and over who received one or more non-steroidal anti-inflammatory between 1 January 1989 and 31 December 1991 and 73 792 subjects who did not receive one during the same period ( controls ) . Main outcome measures : Admission to hospital for upper gastrointestinal bleeding and perforation , and admission for other upper gastrointestinal diagnoses . Results : About 2 % of the non-steroidal anti-inflammatory cohort were admitted with an upper gastrointestinal event during the study period compared with 1.4 % of controls . The risk of admission for upper gastrointestinal haemorrhage and perforation was constant during continuous non-steroidal anti-inflammatory exposure and carried over after the end of exposure . The results were similar for admissions for all upper gastrointestinal events . Conclusion : This study provides evidence that non-steroidal anti-inflammatory toxicity persists with continuous exposure . There seems to be carryover toxicity after the end of prescribing . These findings have implication s for the management of patients requiring non-steroidal anti-inflammatory drugs . Key messages The risk of upper gastrointestinal toxicity associated with non-steroidal anti-inflammatory drugs is constant with continuous exposure Gastrointestinal toxicity continues for some time after treatment stops Such toxicity is common in older patients and patients with a history of upper gastrointestinal disease Non-steroidal anti-inflammatory drugs should be avoided when possible ; when they are used the lowest effective dose of the least toxic drug should be used for the shortest period [3963017] Flurbiprofen ( Ansaid , Upjohn ) , a potent new analgesic and anti-inflammatory agent , was compared with phenylbutazone in 90 patients with ankylosing spondylitis . In this double-blind , r and omized , 26-week study , a total daily dose of 200 mg of flurbiprofen , administered three times daily , was as effective as 300 mg of phenylbutazone in controlling the pain and other symptoms of ankylosing spondylitis . In some patients , symptoms were adequately controlled by 150 mg of flurbiprofen per day , administered twice daily . There were no statistically significant differences between flurbiprofen and phenylbutazone in the investigators ' and patients ' assessment s of improvement at all key follow-up periods . In addition , there were no consistently significant differences between drugs in the efficacy pain scales and quantitative measurements studied . Flurbiprofen was well tolerated in doses of up to 300 mg per day , and no clinical ly significant laboratory abnormalities were detected . Flurbiprofen appears to be an excellent alternative to phenylbutazone in the management of patients with ankylosing spondylitis [1930310] Classification criteria for most of the disorders belonging to the spondylarthropathy group already exist . However , the spectrum of spondylarthropathy is wider than the sum of these disorders suggests . Seronegative oligoarthritis , dactylitis or polyarthritis of the lower extremities , heel pain due to enthesitis , and other undifferentiated cases of spondylarthropathy have been ignored in epidemiologic studies because of the inadequacy of existing criteria . In order to define classification criteria that also encompass patients with undifferentiated spondylarthropathy , we studied 403 patients with all forms of spondylarthropathy and 674 control patients with other rheumatic diseases . The diagnoses were based on the local clinical expert 's opinion . The 403 patients included 168 with ankylosing spondylitis , 68 with psoriatic arthritis , 41 with reactive arthritis , 17 with inflammatory bowel disease and arthritis , and 109 with unclassified spondylarthropathy . Based on statistical analysis and clinical reasoning , we propose the following classification criteria for spondylarthropathy : inflammatory spinal pain or synovitis ( asymmetric or predominantly in the lower limbs ) , together with at least 1 of the following : positive family history , psoriasis , inflammatory bowel disease , urethritis , or acute diarrhea , alternating buttock pain , enthesopathy , or sacroiliitis as determined from radiography of the pelvic region . These criteria result ed in a sensitivity of 87 % and a specificity of 87 % . The proposed classification criteria are easy to apply in clinical practice and performed well in all 7 participating centers . However , we regard them as preliminary until they have been further evaluated in other setting [7010512] Fenoprofen , 600 mg , three times daily , was compared with phenylbutazone , 100 mg , three times daily , in 30 patients suffering from ankylosing spondylitis in a double-blind cross-over study . Assessment s were made after an initial washout period and after each month-long treatment period . Phenylbutazone significantly improved morning stiffness , finger-to-floor distance , chest expansion , overall joint pain , spinal pain , the physician 's assessment of disease activity and ESR . Only chest expansion was significantly improved by fenoprofen , and phenylbutazone was significantly better than fenoprofen in its effects on finger-to-floor distance , morning stiffness , overall joint pain , spinal pain and the physician 's assessment of disease activity . Side-effects were of a minor nature apart from one patient who developed rectal bleeding on phenylbutazone which recurred on rechallenging [10580457] CONTEXT In vitro studies have shown that celecoxib inhibits cyclooxygenase 2 ( COX-2 ) but not COX-1 , suggesting that this drug may have anti-inflammatory and analgesic activity without adverse upper gastrointestinal ( GI ) tract effects that result from COX-1 inhibition . OBJECTIVE To test whether celecoxib has efficacy as an anti-inflammatory and analgesic with reduced GI tract mucosal damage compared with conventional nonsteroidal anti-inflammatory drugs in patients with rheumatoid arthritis . DESIGN R and omized , multicenter , placebo-controlled , double-blind trial lasting 12 weeks , with follow-up at weeks 2 , 6 , and 12 , from September 1996 thorugh February 1998 . SETTING Seventy-nine clinical sites in the United States and Canada . PATIENTS A total of 1149 patients aged 18 years or older with symptomatic rheumatoid arthritis who met inclusion criteria were r and omized ; 688 ( 60 % ) of these completed the study . INTERVENTIONS Patients were r and omized to receive celecoxib , 100 mg , 200 mg , or 400 mg twice per day ( n = 240 , 235 , and 218 , respectively ) ; naproxen , 500 mg twice per day ( n = 225 ) ; or placebo ( n = 231 ) . MAIN OUTCOME MEASURES Improvement in signs and symptoms of rheumatoid arthritis as assessed using st and ard measures of efficacy and GI tract safety as assessed by upper GI tract endoscopy before and after treatment , compared among treatment groups . RESULTS All dosages of celecoxib and naproxen significantly improved the signs and symptoms of arthritis compared with placebo . Maximal anti-inflammatory and analgesic activity was evident within 2 weeks of initiating treatment and was sustained throughout the 12 weeks . The incidence of endoscopically determined gastroduodenal ulcers in placebo-treated patients was 4 ( 4 % ) of 99 , and the incidences across all dosages of celecoxib were not significantly different ( P>.40 ) : 9 ( 6 % ) of 148 with 100 mg twice per day , 6 ( 4 % ) of 145 with 200 mg twice per day , and 8 ( 6 % ) of 130 with 400 mg twice per day . In contrast , the incidence with naproxen was 36 ( 26 % ) of 137 , significantly greater than either placebo or celecoxib ( P<.001 ) . The overall incidences of GI tract adverse effects were 19 % for placebo ; 28 % , 25 % , and 26 % for celecoxib 100 mg , 200 mg , and 400 mg twice per day , respectively ; and 31 % for naproxen . CONCLUSION In this study , all dosages of celecoxib were efficacious in the treatment of rheumatoid arthritis and did not affect COX-1 activity in the GI tract mucosa as evidence d by less frequent incidence of endoscopic ulcers compared with naproxen [4611579] A double-blind cross-over study in 35 patients with ankylosing spondylitis was carried out comparing flurbiprofen ( 150 mg daily)—a new non-steroidal anti-inflammatory agent — with phenylbutazone ( 300 mg daily ) over a four-week period . Flurbiprofen was well tolerated and shown to have therapeutic efficacy approaching that of phenylbutazone . The results suggest that flurbiprofen may prove a valuable alternative in the treatment of ankylosing spondylitis , and longterm efficacy and tolerance studies are clearly indicated [11434474] Abstract : The aim of the study was to analyse the 2-year follow-up of a series of patients with the diagnosis of undifferentiated spondyloarthropathy ( uSpA ) . A prospect i ve study was carried out analysing 68 patients with symptomatic uSpA who fulfilled the European Spondylarthropathy Study Group ( ESSG ) criteria for seronegative spondyloarthropathies ( SpA ) and were aged between 18 and 50 years . Inclusion criteria included inflammatory low back pain ( ILBP ) ( without radiographic sacroiliitis ) , asymmetric oligoarthritis ( predominantly affecting large joints in the lower limbs ) and heel enthesopathies ( Achilles tendinitis and /or plantar fasciitis ) . Imaging methods included pelvic radiography ( at study entry and after 2 years ) and calcaneal radiography ( at study entry ) . There was a predominance of male gender ( 78 % ) , caucasoid race ( 72 % ) and positive HLA-B27 ( 54 % ) , with a mean age of 31 years and mean disease duration of 5 years . The first disease manifestations were ILBP ( 49 % ) , asymmetric oligoarthritis ( 35 % ) and heel enthesopathies ( 16 % ) . A positive family history of a definite SpA was mentioned by 9 % of the patients . Seventeen patients ( 25 % ) scored 5 points in the Amor set of SpA criteria ; logistic regression analysis showed that HLA-B27 , heel enthesopathy and asymmetric oligoarthritis were significantly associated with Amor criteria ≥6 , whereas ILBP was associated with Amor criteria < 6 . Male sex was associated with heel enthesopathies ( p = 0.041 ) and ankle involvement ( p = 0.015 ) . Caucasoid race was associated with ILBP ( p = 0.015 ) and buttock pain ( p = 0.047 ) . Positive HLA-B27 was associated with wrist involvement ( p = 0.019 ) and Amor criteria ≥6 ( p = 0.001 ) . After a 2-year follow-up the following outcomes were observed : uSpA 75 % ; disease remission 13 % ; ankylosing spondylitis 10 % ; psoriatic arthritis 2 % . Logistic regression analysis showed that buttock pain and positive HLA-B27 ( trend ) were statistically associated with progression to a definite SpA. In conclusion , uSpA can represent a provisional diagnosis in the group of SpA and a systematic follow-up is necessary in order to better establish the different patterns of the disease [15934081] OBJECTIVE A 2-year r and omized controlled trial was performed to test the hypothesis that long-term , continuous treatment with nonsteroidal antiinflammatory drugs ( NSAIDs ) , in comparison with NSAID treatment on dem and only , influences radiographic progression in patients with ankylosing spondylitis ( AS ) . METHODS Patients with AS ( n = 215 ) , who had previously participated in a 6-week , r and omized , double-blind clinical trial that compared celecoxib , ketoprofen , and placebo , were r and omly allocated to receive either continuous treatment with NSAIDs or on-dem and treatment with NSAIDs for a period of 2 years . All patients began treatment with celecoxib , at a starting dosage of 100 mg twice daily ; patients could increase this dosage to 200 mg twice daily or could switch to another NSAID while maintaining the same treatment strategy . Structural changes were assessed by radiographs of the lumbar and cervical spine and scored according to the modified Stoke Ankylosing Spondylitis Spine Score by one observer who was blinded to the treatment strategy and temporal order of the radiographs . Statistical analyses included a between-group comparison of 1 ) radiographic progression scores ( by Mann-Whitney U test ) , 2 ) time-averaged values of variables reflecting signs and symptoms of AS ( by linear regression analysis ) , and 3 ) the frequency of reported site-specific adverse events ( by chi-square test or Fisher 's exact test , as appropriate ) . RESULTS Complete sets of radiographs were available for 76 of the 111 patients in the continuous-treatment group and for 74 of the 104 patients in the on-dem and group . The mean + /- SD scores for radiographic progression were 0.4 + /- 1.7 in the continuous-treatment group and 1.5 + /- 2.5 in the on-dem and treatment group ( P = 0.002 ) . Parameters reflecting signs and symptoms were not statistically significantly different between groups . The between-group difference in radiographic progression did not disappear after adjusting for baseline values of radiographic damage or disease activity variables and for time-averaged values of disease activity variables , nor after input of missing data . Relevant adverse events tended to occur more frequently in the continuous-treatment group than in the on-dem and group ( for hypertension , 9 % versus 3 % ; for abdominal pain , 11 % versus 6 % ; for dyspepsia , 41 % versus 38 % ) , but the differences were not statistically significant . CONCLUSION A strategy of continuous use of NSAIDs reduces radiographic progression in symptomatic patients with AS , without increasing toxicity substantially [2178870] A r and omized study was performed on 24 patients with ankylosing spondylitis to compare the efficacy and tolerability of 20 mg tenoxicam daily with 50 mg diclofenac twice daily . There were 6 withdrawals from the group taking tenoxicam and 4 from the diclofenac group . Depression in 1 patient taking tenoxicam was the only significant adverse event . Both drugs were otherwise well tolerated . Tenoxicam and diclofenac were rated as good or excellent by 27 % and 55 % of patients , respectively . Global assessment , pain and duration of morning stiffness were improved with both drugs but this improvement was not statistically significant and there was no statistically significant difference between the two groups . This study confirms that tenoxicam is effective and well tolerated but larger numbers would be required to detect a small difference between groups [3378661] The efficacy and tolerance of 1200 mg/day oxaprozin and 100 mg/day diclofenac sodium were compared in 40 patients with ankylosing spondylitis in a 6-week open study . Overall improvement was seen in the patients in both treatment groups . Oxaprozin-treated patients showed significant improvement in spontaneous pain of the vertebral spine and in morning stiffness after 6 weeks ' treatment . There were no statistically significant differences between the treatment groups . Therapy was discontinued in 10 patients ; five treated with oxaprozin ( three because of intolerance and two because of worsening of symptoms ) and five taking diclofenac sodium ( four because of intolerance and one because of worsening of symptoms ) . Five ( 25 % ) oxaprozin-treated patients and six ( 30 % ) diclofenac sodium-treated patients had side-effects , with gastro-intestinal disturbances and dizziness reported most frequently . There were no statistically significant differences between the groups in the frequency of side-effects . These results indicate that oxaprozin is a promising therapeutic agent for ankylosing spondylitis [6379678] A double-blind , crossover trial was carried out to compare the effectiveness and tolerance of indoprofen with indomethacin in the treatment of ankylosing spondylitis . Nineteen patients entered the study and 1 was withdrawn for reasons unrelated to therapy . Patients received 4-weeks ' treatment in r and om order , with 200 mg indoprofen 4-times daily and 25 mg indomethacin 4-times daily . Most subjective and objective clinical measurements of disease activity showed a comparable degree of improvement with either drug although few statistically significant changes were observed . There was no statistically significant difference between treatments and , although gastro-intestinal side-effects occurred more commonly with indoprofen , patients known to be intolerant of indomethacin had been excluded from this trial [334611] A double-blind crossover trial of fenclofenac was untertaken to compare the short-term effects of phenylbutazone ( Butacote ) therapy with fenclofenac therapy ( 1200 mg daily ) in 23 patients suffering from ankylosing spondylitis . The patients were r and omly allocated to each of the test drugs for a period of two weeks , following wash-out periods of paracetamol for four days . The results favoured Butacote therapy in a dosage of 300 mg daily in the expressed preferences of both the patients and the physicians conducting the trial . Butacote was also better tolerated , as no severe side-effects occurred during treatment , whereas five patients developed a widespread rash during the period of fenclofenac therapy . No significant differences were seen between the two drugs in terms of clinical measurements of pain , morning stiffness , spinal movements , chest expansion , and abduction of the hips . Butacote was shown to cause some significant depletion of haemoglobin level , probably due to water retention , and Butacote also reduced the serum urate level to a significant degree [7973477] Ximoprofen is a new propionic NSAID which has previously demonstrated its efficacy at a daily dose of 30 mg . The aim of the study was to evaluate the efficacy of different daily dosages of Ximoprofen in patients with active ankylosing spondylitis . For 2 weeks 5 parallel groups were studied : placebo and Ximoprofen at 5 , 10 , 20 and 30 mg daily . Response to treatment was defined as an improvement in pain ( VAS 100 mm ) of at least 50 % during the study . 285 out of the 332 screened patients were included . At the end of the study , the percentage of responders was higher in the Ximoprofen groups ( 54 % , 41 % , 53 % , 56 % in the 5 , 10 , 20 and 30 mg groups , respectively ) than in the placebo group ( 21 % ) . The clearest dose related effect of Ximoprofen observed occurred after one week of treatment . This study 1/confirms the efficacy of Ximoprofen at a 30 mg daily dosage , 2/shows the persistence of this efficacy at lower dosages , 3/suggests that ankylosing spondylitis is a sensitive and relevant human model to assess NSAIDs at an early stage of clinical evaluation [15818702] OBJECTIVE To assess the efficacy , safety , and tolerability of etoricoxib , a cyclooxygenase 2 ( COX-2 ) selective inhibitor , administered continuously over 52 weeks for the treatment of ankylosing spondylitis ( AS ) . METHODS This 2-part , multicenter , double-blind , parallel-group , 52-week study evaluated 2 doses of etoricoxib ( 90 and 120 mg ) compared with naproxen at 1,000 mg . A 6-week , active-comparator- and placebo-controlled period ( part I ) was followed by a 46-week active-comparator-controlled period ( part II ) . The primary outcome measures ( on 100-mm visual analog scales ) were patient 's assessment of spine pain , patient 's global assessment of disease activity , and the Bath Ankylosing Spondylitis Functional Index . RESULTS Of the 387 patients r and omized to receive treatment , 301 ( 77.8 % ) completed part I and 284 ( 75.9 % ) completed part II . Compared with placebo over 6 weeks , those receiving 90 mg etoricoxib , 120 mg etoricoxib , and naproxen demonstrated significantly ( P < 0.001 ) greater improvement in all primary end points ; treatment effects ( expressed as the difference in least squares mean change versus placebo ) were 21 - 29 mm for spine pain , 18 - 25 mm for disease activity , and 11 - 15 mm for function . Compared with patients receiving naproxen , significantly greater improvement in all primary end points was demonstrated in the combined group receiving either 90 mg etoricoxib or 120 mg etoricoxib over 6 weeks , in each individual etoricoxib treatment group over 6 weeks , and in the combined etoricoxib group over 1 year ( all P < 0.05 ) ; results for secondary and exploratory end points were generally consistent with those from the primary analysis . Among all groups , there were no significant differences in the incidence of overall clinical , drug-related , or serious adverse experiences ( AEs ) and discontinuations due to AEs . Safety observations during part II were generally consistent with those in part I. CONCLUSION Etoricoxib at doses of 90 mg and 120 mg demonstrated superior efficacy compared with placebo over 6 weeks , and compared with naproxen over 1 year . These study results demonstrate that etoricoxib is generally safe , well-tolerated , and efficacious for the treatment of AS [7282105] In a double lind test 60 patients with ankylosing spondylitis received either Azapropazone ( 30 patients ) or Indomethacin ( 30 patients ) during a period of three weeks . In the two well comparable groups the therapeutic effect was equally good . As the results show the Azapropazone group came out a little better concerning the finger-ground distance and the difference in circumference of thorax , and the Azapropazone group was favoured slightly by the general judgement of the patients . However , these differences are not relevant . The influence on the spontaneous pain in the daytime and during the night and the shifting of dorsal and lumbar vertebral column was equally good in both groups . The compatibility was good in 59 out of 60 patients . One patient had to stop the Azapropazone medication because of gastric trouble in the second week of treatment . This result shows that in most patients an adequate medication with Azapropazone or with Indomethacin leads to a distinct reduction of pain and even painlessness already after a 3 weeks ' treatment . This is particularly important regarding kinesiatrics . Indomethacin and Phenylbutazone are generally regarded as approved preparations in treatment of ankylosing spondylitis . If Azapropazone which , according to all previous reports has no hematotoxic effect like Phenylbutazone , had the same good effect in a double blind test as Indomethacin , this must be regarded as a very positive result . Concerning the good compatibility of Azapropazone , a change of drug is possible without a reduction of the effect [18438853] OBJECTIVE To investigate the effect of etanercept therapy on radiographic progression in patients with ankylosing spondylitis ( AS ) . METHODS Patients with AS who had previously participated in a 24-week r and omized , double-blind , placebo-controlled trial of etanercept therapy were enrolled in a 72-week open-label extension . Radiographs of the cervical and lumbar spine from patients who received etanercept ( 25 mg twice weekly ) for up to 96 weeks were compared with radiographs from patients in a large prevalence cohort ( Outcome Assessment s in Ankylosing Spondylitis International Study [ OASIS ] ) who had not been treated with anti-tumor necrosis factor alpha ( anti-TNFalpha ) agents . Radiographs obtained at 2 time points up to 96 weeks apart from patients in both study population s were digitized and read by 2 independent readers who were blinded with regard to patient group and sequence . The primary end point was the 96-week change in the modified Stoke AS Spine Score ( mSASSS ) . RESULTS A total of 257 patients treated with etanercept were compared with 175 unselected patients from the OASIS study . There was no significant difference in the change in the mSASSS from baseline among patients who received etanercept ( mean + /- SD 0.91 + /- 2.45 ) versus those from the OASIS group ( 0.95 + /- 3.18 ) . CONCLUSION Unlike other inflammatory rheumatic diseases such as rheumatoid arthritis and psoriatic arthritis , structural progression in AS seems to be independent of TNF , despite the fact that TNF is responsible for the signs and symptoms due to inflammation in this disease [480622] Ankylosing spondylitis affects about 1 % of the population . In the past , evaluation of therapy in the management of this disease has been hampered by the lack of availability of objective criteria for following the condition . By using recently developed measurements of spinal mobility and other variables we have compared sulindac , a recently introduced nonsteroidal antiinflammatory drug , and indomethacin in a double-blind six-month parallel study of 30 patients . Sulindac and indomethacin have comparable efficacy and tolerance . Advantages of sulindac include a twice-a-day dose regimen [11212158] OBJECTIVE To evaluate the short-term efficacy of celecoxib , a cyclooxygenase 2-specific inhibitor , in the treatment of ankylosing spondylitis ( AS ) . METHODS The study was a 6-week r and omized , double-blind , placebo-controlled trial with 3 treatment arms : placebo , ketoprofen 100 mg twice daily , and celecoxib 100 mg twice daily . Patients who had AS according to the modified New York criteria , without peripheral synovitis and with active disease ( pain > or = 40 mm on a 100-mm visual analog scale [ VAS ] and an increase in pain of at least 30 % after nonsteroidal antiinflammatory drug withdrawal ) were eligible for study . Primary outcome measures were change in pain intensity ( VAS ) and change in functional impairment ( Bath Ankylosing Spondylitis Functional Index [ BASFI ] ) . RESULTS Of the 246 r and omized patients , 76 were allocated to receive placebo , 90 ketoprofen , and 80 celecoxib . There were no statistically significant differences between treatment groups at study entry . During the 6 weeks of the study , the decrease in pain and functional impairment was greater in the active treatment groups than in the placebo group , with a trend in favor of celecoxib when the 2 active treatments were compared . The mean changes were -13 mm , -21 mm , and -27 mm ( P = 0.006 ) for pain and 1 , -6 , and -12 ( P = 0.0008 ) for BASFI score in the placebo , ketoprofen , and celecoxib groups , respectively . During treatment , the number of patients reporting epigastric pain was 6 ( 8 % ) , 13 ( 14 % ) , and 10 ( 13 % ) in the placebo , ketoprofen , and celecoxib groups , respectively . CONCLUSION The results of this study confirm the clinical ly relevant antiinflammatory effect of celecoxib at a 200-mg daily dosage , with significant improvement of both pain and function in patients with AS [20498215] Objective To study the relationship between spinal mobility , radiographic damage of the spine and spinal inflammation as assessed by MRI in patients with ankylosing spondylitis ( AS ) . Methods In this sub analysis of the Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy cohort , 214 patients , representing an 80 % r and om sample , were investigated . Only baseline data were used . MRI inflammation was assessed by the AS spinal MRI activity ( ASspiMRI-a ) score , structural damage by the modified Stoke AS Spine Score ( mSASSS ) and spinal mobility by the linear definition of the Bath Ankylosing Spondylitis Metrology Index ( BASMI ) . Univariate correlations were calculated on baseline values using Spearman rank correlation . Independent associations between the variables of interest were investigated by multivariate linear regression analysis . Associations with clinical disease activity , C-reactive protein , disease duration , age , gender , body mass index and HLA-B27 status were also investigated . Subanalyses were performed according to disease duration . Results BASMI correlated moderately well with mSASSS ( Spearman 's ρ=0.6 ) and weakly with ASspiMRI-a ( ρ=0.3 ) . A best-fit model for BASMI included both mSASSS ( regression coefficient (B)=0.865 , p<0.001 ) and ASspiMRI-a ( B=0.236 , p=0.018 ) . In patients with a disease duration ≤3 years , B was greater for ASspiMRI-a than for mSASSS ( 0.595 vs 0.380 ) , while in patients with a disease duration > 3 years B was greater for mSASSS than for ASspiMRI-a ( 0.924 vs 0.156 ) . Conclusion Spinal mobility impairment in AS is independently determined both by irreversible spinal damage and by reversible spinal inflammation . Spinal mobility impairment is more influenced by spinal inflammation in early disease , and by structural damage in later disease [4595274] Preliminary studies of flurbiprofen , a newly introduced anti-inflammatory agent , have shown that it exerts some anti-inflammatory and analgesic effects in man when compared with placebo and is relatively well tolerated ( Chalmers , Cathcart , Kumar , Dick and Buchanan , 1972 ) . The purpose of this paper is to compare the effects of flurbiprofen , indomethacin , and placebo under double-blind conditions in a group of patients with ankylosing spondylitis [19060001] Objectives : To evaluate various validity aspects of four disease activity scores ( ASDAS ) for ankylosing spondylitis ( AS ) in comparison with the Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI ) , its individual components and physician and patient global assessment of disease activity . Methods : The analyses were performed in two cohorts of patients with AS : ( 1 ) the NOR-DMARD data base which includes patients starting on a disease-modifying antirheumatic drug or tumour necrosis factor ( TNF ) blocker and ( 2 ) patients participating in double-blind placebo controlled r and omised clinical trials with TNF blockers in four centres . Discrimination between patients with low versus high disease activity according to various definitions and between various levels of change were analysed as the st and ardised mean difference ( difference in the group means divided by the pooled SD of the group means ) and t score . Results : The four ASDAS versions were highly discriminatory in differentiating patients with different levels of disease activity and patients with different levels of change . The ASDAS scores outperformed the BASDAI and its single components in all setting s : patient- or physician-based , reflecting status or change , with normal or raised C-reactive protein ( CRP ) , in the presence or absence of peripheral arthritis . There were no major differences between the four ASDAS scores . Based on feasibility , the ASAS membership selected the ASDAS version which included back pain , duration of morning stiffness , patient global assessment , peripheral joint complaints and CRP as the preferred version . Conclusions : The ASDAS is a vali date d , highly discriminatory instrument for assessing disease activity in AS , including patient-reported outcomes and CRP levels [71969] In a parallel , double-blind and r and omized trial of 6-weeks ' duration , flurbiprofen ( 150 mg to 200 mg daily ) was compared with indomethacin ( 75 mg to 100 mg daily ) in the management of 26 patients with active ankylosing spondylitis . None of the patients in either group withdrew from the study because of lack of efficacy of the drugs . Both drugs were equally effective in the relief of pain and tenderness of the affected joints . Overall subjective improvement , assessed by the patient and the investigator at the end of the trial , was present in 90 % of the patients in the flurbiprofen group and in 75 % of those in the indomethacin group . The mean values of all the spinal motion tests improved in the flurbiprofen group but not in the indomethacin group . Statistically significant improvement in the Schober test was achieved in the flurbiprofen group and in chest expansion in the indomethacin group . Characteristic untoward effects related to the central nervous system and gastro-intestinal tract were present in a few patients in both groups [1096904] 27 patients with ascertained ankylosing spondylitis experiencing constant after-midnight-pain received , following three medication-free days , in a double blind , r and omized , cross-over fashion indometacin ( 100 g/day ) and d-2-(6'-methoxy-2'-naphthyl)-propionic acid ( naproxen ) ( 500 mg/day ) , as suppositories , for a period of six days each . The intensity of the night-pain was recorded daily . Naproxen was shown to be equally effective as indometacin in alleviating the after-midnight backache of ankylosing spondylitis . Side effects occurred under indometacin in 5 cases , under naproxen in 3 cases [3620275] 1 Isoxicam , 200 mg once daily , was compared to ketoprofen , 100 mg three times daily , in 19 patients ( 16 males , three females ) with ankylosing spondylitis in a 30-day , double-blind study conducted in two centres . 2 Improvements from baseline to final assessment were noted after both isoxicam and ketoprofen in most clinical variables , with isoxicam , in general , being more effective than ketoprofen . 3 Isoxicam was significantly superior to ketoprofen in reducing pain and was judged by both patients and physicians to be superior overall to ketoprofen . 4 Of the 13 patients who expressed a preference , 10 preferred isoxicam . 5 Typical NSAID side effects were encountered with both drugs [17616556] OBJECTIVES To demonstrate the non-inferiority of celecoxib compared with diclofenac in subjects with ankylosing spondylitis ( AS ) . METHODS The basis of the present work was a 12-week r and omised , double-blind , controlled study in active AS subjects with three treatment arms : celecoxib 200 mg once a day , celecoxib 200 mg twice a day , and diclofenac SR 75 mg twice a day . The primary efficacy endpoint was the change from baseline in global pain intensity on a visual analogue scale ( VAS ) at week 12 . Secondary endpoints covered changes in disease activity , functional and mobility capacities , and adverse events . RESULTS A total of 458 subjects were r and omly assigned to either celecoxib 200 mg once a day ( n = 153 ) , celecoxib 200 mg twice a day ( n = 150 ) , or diclofenac ( n = 155 ) . Least square ( LS ) mean changes from baseline at week 12 on a pain VAS were clinical ly relevant in all treatment groups ( celecoxib 200 mg once a day : -29.1 mm ; celecoxib 200 mg twice a day:-31.7 mm ; diclofenac:-32.7 mm ) and non-inferior when compared to diclofenac . Ankylosing Spondylitis Assessment Study group 20 % ( ASAS 20 ) response and mean improvement in Bath Ankylosing Spondylitis Disease Activity Index ( BASDAI ) scores at week 12 were numerically better on celecoxib 200 mg twice a day ( 59.7 % and -1.32 points ) and on diclofenac ( 60.2 % and -1.48 points ) than on celecoxib 200 mg once a day ( 46.0 % and -0.99 points ) . The incidence of gastrointestinal adverse events was significantly higher on diclofenac ( 28.4 % ) than on celecoxib 200 mg once a day ( 15.0 % ) or 200 mg twice a day ( 16.7 % ) . CONCLUSIONS The efficacy of celecoxib 200 mg once a day and 200 mg twice a day was comparable to that of diclofenac 75 mg twice a day with respect to pain reduction . Celecoxib 200 mg twice a day and diclofenac reduced some parameters associated with inflammation more effectively than celecoxib 200 mg once a day . Treatment was well tolerated , with celecoxib ( either dose ) exhibiting less frequent gastrointestinal adverse events than diclofenac [6993670] Benoxaprofen ( 600 mg once daily ) has been compared to indomethacin ( 25 mg 3 times daily ) in a double-blind crossover study of 20 patients with active ankylosing spondylitis ( AS ) . The clinical improvement was comparable with both drugs ; 6 patients preferred benoxaprofen and 7 patients indomethacin . Although 2 patients discontinued benoxaprofen because of lack of effect , no upper gastrointestinal side effects were reported with this drug . Benoxaprofen is an alternative to indomethacin in the treatment of AS [18821688] OBJECTIVE To evaluate the effect of infliximab on progression of structural damage over 2 years in patients with ankylosing spondylitis ( AS ) . METHODS In the Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy ( ASSERT ) , a r and omized , double-blind , placebo-controlled trial of the efficacy of infliximab compared with placebo , 279 patients with active AS received either placebo through week 24 and then infliximab 5 mg/kg from week 24 through week 96 ( n=78 ) or infliximab 5 mg/kg from baseline through week 96 , administered every 6 weeks after a loading dose ( n=201 ; these patients were the focus of the radiographic analyses ) . Radiographic findings in patients from the ASSERT trial were indistinguishable from those in a historical control cohort of patients who had no prior use of anti-tumor necrosis factor agents ( from the Outcome in Ankylosing Spondylitis International Study [ OASIS ] data base ; n=192 ) . Radiographic progression of structural damage from baseline to the 2-year followup was scored using the modified Stoke Ankylosing Spondylitis Spine Score ( mSASSS ) . All images were scored in one batch . RESULTS Median changes in the mSASSS from baseline to year 2 were 0.0 for both the OASIS and the ASSERT cohorts ( P=0.541 ) . Mean changes in the mSASSS were also similar between the OASIS and ASSERT cohorts ( mean+/-SD change over 2 years 1.0+/-3.2 and 0.9+/-2.6 , respectively ) . In addition , results from sensitivity analyses did not show a statistically significant difference in the mSASSS between the OASIS and ASSERT cohorts . CONCLUSION AS patients who received infliximab from baseline through week 96 did not show a statistically significant difference in inhibition of structural damage progression at year 2 , as assessed using the mSASSS scoring system , when compared with radiographic data from the historical control OASIS cohort . Improvements in clinical outcomes and spinal inflammation have been previously demonstrated with the use of infliximab therapy [324773] Summary Flurbiprofen ( 150–200 mg daily ) and phenylbutazone ( 300–400 mg daily ) were compared in the management of 27 patients with active ankylosing spondylitis . This was a parallel , double-blind , and r and omized trial of 6 weeks duration . Both drugs were equally effective in the relief of pain and tenderness of the affected joints . Overall subjective improvement , assessed by the patient and the investigator at the end of the trial , favored phenylbutazone , but it did not reach a statistically significant level . The mean values of the endpoint parameters of spinal motion showed statistically significant improvement in both groups , except in the Schober test in the flurbiprofen group and chest expansion in the phenylbutazone group . Untoward effects characteristic of these drugs were found in a few patients [15044211] OBJECTIVE To develop and compare c and i date improvement criteria for anti-TNFalpha treatment in ankylosing spondylitis with optimal discriminating capacity between treatment and placebo . METHODS Data from two r and omised controlled trials which included 99 patients treated with infliximab or etanercept were used to evaluate 50 c and i date improvement criteria . These were developed on the basis of pain , patient 's global assessment , function , morning stiffness , spinal mobility , and C reactive protein . Different levels of improvement in each domain ( 20 - 60 % ) were used to define Boolean type criteria . These criteria were compared with different percentages of improvement on the BASDAI and with modified ASAS improvement criteria . Bootstrap methods were applied to calculate 95 % confidence intervals ( CI ) of the chi(2 ) test values to select the best c and i date improvement criteria . RESULTS The best performing improvement criteria were " 20 % improvement in five of six domains " ( chi(2 ) = 31.9 ( 95 % CI , 18.0 to 46.9 ) ) with a low placebo response of 2.9 % and a high response to infliximab of 67.7 % ; and " ASAS 40 % improvement " ( chi(2 ) = 26.5 ( 13.3 to 41.1 ) ) , with response to placebo of 5.7 % and response to infliximab of 64.7 % . The good discriminating capacity of the two improvement criteria was confirmed by the combined data set of the infliximab and etanercept trial . CONCLUSIONS The " five of six " improvement criterion has the advantage of including the objective domains spinal mobility and acute phase reactants , but requires only 20 % improvement . The ASAS 40 % improvement criterion has the advantage of setting a high threshold , but only in patient reported outcomes . The choice between these improvement criteria needs to be based on further validation from upcoming trials [11508441] OBJECTIVE To develop criteria for symptomatic improvement in patients with ankylosing spondylitis ( AS ) , using outcome domain data from placebo-controlled clinical trials of nonsteroidal antiinflammatory drugs ( NSAIDs ) . METHODS Patient data from 5 short-term , r and omized , controlled trials were used to assess equivalence , reliability , and responsiveness of multiple items in the 5 outcome domains for AS treatment : physical function , pain , spinal mobility , patient global assessment , and inflammation . At least one measure per domain was responsive ( st and ardized response mean of > 0.5 ) , except for the spinal mobility domain , which was omitted from the criteria . We developed and tested c and i date improvement criteria in a r and om two-thirds subset from the 3 largest trials and used the remaining one-third for validation . These 3 largest trials included 923 patients ( 631 receiving NSAIDs , 292 in placebo groups ) . We selected the multiple domain definition that best distinguished NSAID treatment from placebo by chi-square test and that had a placebo response rate of < or = 25 % . RESULTS C and i date definitions were changes in single domains and in multiple measure indices , as well as combinations of improvements in multiple domains . Worsening in a domain was defined as a change for the worse of > or = 20 % and a net change for the worse of > or = 10 units on a scale of 0 - 100 . Partial remission ( for comparison purpose s ) was defined as an end-of-trial value of < 20/100 in each of the 4 domains . Among 20 c and i date criteria , change of > or = 20 % and > or = 10 units in each of 3 domains and absence of worsening in the fourth discriminated best in the development subset ( 51 % of patients improved with NSAIDs , 25 % with placebo ; chi2 = 36.4 , P < 0.001 ) . Results were confirmed in the validation subset . Almost all patients satisfying the definition of partial disease remission at the end of the trial had also improved by this criterion . Among all 923 patients , improvement rates using this criterion were 49 % for NSAID-treated patients and 24 % for placebo-treated patients . CONCLUSION Although further validation using data from new trials is still needed , we conclude that we have developed a clinical ly valid , easy-to-use measure of short-term improvement in AS [6752874] In this double blind , crossover trial , 40 patients with ankylosing spondylitis were treated during two successive periods of 4 weeks each with either pirprofen 800 mg/day or ketoprofen 300 mg/day administered orally in a r and omized order . The efficacy of pirprofen and ketoprofen was comparable , the results , as assessed by the clinician , were excellent or satisfactory in 53 % of both groups . Pirprofen was well tolerated by 71 % of the patients and ketoprofen by 59 % [1096903] In a multicenter double-blind cross-over trial the therapeutic effect and the tolerance of d-2-(6'-methoxy-2'-naphthyl)-propionic acid ( naproxen ) and indometacin were compared including 46 patients with rheumatoid arthritis , 35 patients with ankylosing spondylitis and 19 patients with osteoarthrosis . Duration of treatment with both drugs was two to four weeks each . The daily dose of naproxen was 750 mg , that of indometacin l50 mg . In rheumatoid arthritis the combined clinical effect of indometacin was stronger than that of naproxen while both drugs had the same clinical effectiveness in ankylosing spondylitis and osteoarthrosis . When differentiating the total clinical effect as to indices of pain , inflammation and function , indometacin was shown to be superior in all three diseases with regard to pain index . On the other h and , naproxen showed a better effect in ankylosing spondylitis and osteoarthrosis than indometacin as to inflammation , and as to function in osteoarthrosis [7003449] In a four week double-blind crossover study , flurbiprofen 200 mg daily was compared with naproxen 750 mg daily in the management of 30 patients with ankylosing spondylitis . Both treatments were found to be very effective in alleviating pain and stiffness . No significant difference in efficacy was discernible between the two drugs . Side-effects were more frequent with flurbiprofen . A small , but significant , increase in renal excretion of beta-n-acetyl glucosaminidase occurred during treatment with both naproxen and flurbiprofen . Although previous surveys have not shown evidence of renal damage , further surveillance of renal function in patients receiving long term treatment with these preparations to exclude possible renal impairment would be prudent [4164930] A clinical evaluation of indomethacin employing a controlled , cross-over technique with an inert placebo was undertaken in 30 patients with ankylosing spondylitis . Patients were studied for the frequency and dose relationship of side effects and for the subjective response of morning stiffness , chronic spinal pain , acute exacerbations of pain and peripheral arthralgia . Objective evaluation assessed measured change in movements of the cervical and lumbar spines , in chest expansion and in the range of movement of involved peripheral joints . Evaluation of the results indicated that a significant number of patients experienced side effects in the form of headache and dizziness while receiving indomethacin in doses above 150 mg . per day . Many other side effects reported by the patients were not found to occur at a statistically significant level . The significance of pulmonary infections encountered in three patients was review ed . Relief of chronic spinal pain and peripheral arthralgia occurred in 14 and 16 patients , respectively ( p < 0.05 ) . Relief of morning stiffness and acute exacerbations of pain , and increase in the range of movement of any of the segments of the spine or the involved peripheral joints were not significant ( p > 0.05 ) . Based on the results of this study , it is suggested that the role of indomethacin in the management of ankylosing spondylitis be re-evaluated and that the daily therapeutic dose of this drug which has been heretofore recommended be decreased [3515371] Tenoxicam ( 20 mg/day ) and piroxicam ( 20 mg/day ) were compared in a double-blind , parallel group study over 4 weeks in 30 patients with ankylosing spondylitis . Both tenoxicam and piroxicam reduced spinal pain , but the improvement was greater with piroxicam . Tenoxicam and piroxicam were equally effective at improving duration of morning stiffness . Slight improvement was seen with other symptoms with both treatments . Patients were slightly more tolerant of piroxicam than tenoxicam and most patients elected to continue on their particular therapy at the end of the study [1364937] Thirty-nine patients with ankylosing spondylitis participated in a r and omized , double-blind , double-dummy , multi-cross-over study with enteric-coated ( ECT ) and plain ( PT ) naproxen tablets . The duration of the study was 24 days with 6 treatment periods of 4 days . The majority of the patients were taking 750 mg naproxen daily . The mean plasma concentration of naproxen in the morning was 36 % higher with ECT ( p < 0.001 ) . No significant differences regarding duration of morning stiffness and night time pain were found in this patient category . The mean duration of morning stiffness was 116 minutes ( ECT ) and 125 minutes ( PT ) . We were not able to show correlation between plasma concentration of naproxen and duration of morning stiffness [3963018] In this r and omized , double-blind study , 57 patients with ankylosing spondylitis were evaluated after 26 weeks of treatment with either flurbiprofen ( Ansaid , Upjohn ) or indomethacin . Flurbiprofen administered four times a day in a total daily dose of 200 mg was effective in controlling the pain and associated symptoms of ankylosing spondylitis . Pain was adequately controlled in some patients following a total daily dose of 100 mg of flurbiprofen administered twice a day . Flurbiprofen was as effective as indomethacin in most key efficacy measurements analyzed . The drug was well tolerated in doses of up to 300 mg per day , and no clinical ly significant laboratory abnormalities were detected . Flurbiprofen is an excellent treatment for the control of pain and inflammation in patients with ankylosing spondylitis [6365231] The efficacy and tolerability of a new formulation of slow-release indomethacin tablet was compared in a double-blind cross-over manner with a conventional indomethacin capsule in 30 patients with ankylosing spondylitis . Gastrointestinal side-effects and dizziness were less frequent during the slow-release tablet period than during the capsule period [7026817] The relative effectiveness of six nonsteroidal anti-inflammatory agents was studied in 33 patients with rheumatoid arthritis and 32 patients with ankylosing spondylitis in a double-blind , r and omized , prospect i ve study employing a six-way multiple crossover design with six-week trials of each agent . In ankylosing spondylitis , naproxen , indomethacin , and fenoprofen calcium were the most effective agents . In rheumatoid arthritis , relatively little mean difference between drugs was found . Most of this difference could be attributed to compliance factors , which favored drugs that required only a small number of pills daily . Despite the small differences in effect , patients had strong preferences . More than 85 % of patients were still taking their preferred medication after a mean follow-up period of one year [8823693] OBJECTIVE To evaluate the efficacy and tolerability of aceclofenac , a new nonsteroidal antiinflammatory drug , in patients with active ankylosing spondylitis ( AS ) . METHODS 310 out patients with active AS were enrolled in a 3 month , multicenter , parallel , double blind trial and were r and omly assigned to receive aceclofenac ( 200 mg daily ) or indomethacin ( 100 mg daily ) . They were evaluated after a washout period of 7 days , at baseline , 15 , 30 , 60 , and 90 days . RESULTS No significant differences were found between aceclofenac and indomethacin in the number of withdrawals due to lack of efficacy or adverse events . A repeated measures analysis ( ANOVA ) of patients who completed the trial showed no significant differences between either treatment . Within-group comparisons in an intention-to-treat analysis showed improvement ( p < 0.05 ) in all the primary efficacy variables : pain visual analog scale ( VAS ) ( 37 vs 41 % ) , morning stiffness ( 51 vs 46 % ) , modified Schober 's test ( 21 vs 16 % ) , C7-iliac crest line distraction ( 11 vs 14 % ) , lateral spinal flexion ( 6 vs 10 % ) , in aceclofenac and indomethacin treated patients , respectively . Other variables including chest expansion , occiput-to-wall , Likert pain score , use of analgesic rescue , and patient and physician global assessment , also showed significant improvement from baseline values . No significant differences between treatments were noted for any efficacy variable . Good to excellent improvement in pain ( 52 vs 64 % ) and morning stiffness ( 70 vs 68 % ) was observed in aceclofenac and indomethacin treated patients , respectively . Patients taking aceclofenac had significantly fewer central nervous system related adverse events than patients treated with indomethacin ( p < 0.001 ) . CONCLUSION Aceclofenac and indomethacin did not differ with respect to efficacy in the treatment of active AS , although aceclofenac was slightly better tolerated [7044803] Benoxaprofen , 600 mg once daily , was compared with ketoprofen , 100 mg twice daily , in a double-blind parallel study of 23 patients with definite active ankylosing spondylitis . Results were assessed using the following measurements : day pain , night pain , and spinal stiffness . Spinal stiffness was determined by means of st and ard clinical tests . Patient 's evaluation and physician 's overall assessment at the end of therapy also were taken into account . Under these conditions , the therapeutic response for benoxaprofen was good/very good , 8 ; fair , 2 ; and no response , 2 . For ketoprofen , the response as good/very good , 5 ; fair 3 ; and no response 3 . This study shows that benoxaprofen provides very good therapeutic effectiveness in the treatment of ankylosing spondylitis . This is confirmed by the absence of any statistically significant difference between the results observed with benoxaprofen and with ketoprofen , a drug known to be of value in ankylosing spondylitis . The clinical and biologic tolerance of benoxaprofen in this study was quite satisfactory [796939] A series of 26 patients with ankylosing spondylitis have been included in a double-blind cross-over comparison of ketoprofen 200 mg daily and phenylbutazone 300 mg daily , each drug being given for 4 weeks , with paracetamol as a ' rescue drug ' . Six patients withdrew from the study : three on phenylbutazone and one on ketoprofen -- two defaulted treatment . Twenty patients ( 17 males and 3 females ) were eligible for assessment . Their ages ranged between 20 and 59 years ( mean 40.2 years ) . Patient characteristics were comparable in both groups . The results of this series indicate no suggestion of statistically significant differences in any of the nine movements measured . The only significant differences , both in favour of phenylbutazone , were in the paracetamol consumption in the second treatment period in the group receiving ketoprofen first ( 0.01 greater than P greater than 0.005 ) and in the patients ' preference for phenylbutazone ( 0.005 greater than P greater than 0.001 ) . Adverse reactions were comparable in both groups [333540] Feprazone , a non-steroidal anti-inflammatory drug , was compared with indomethacin in a double-blind cross-over trial in 24 patients with ankylosing spondylitis , over eight weeks . Both regimes caused significant reduction in pain . There were fewer side-effects and more patient preferences with feprazone but these differences did not reach statistical significance [10493676] OBJECTIVE To investigate the diagnostic value of magnetic resonance imaging ( MRI ) in the detection of early sacroiliitis . METHODS Twenty-five consecutive HLA-B27 positive patients with inflammatory low back pain and < or = grade 2 unilateral sacroiliitis on conventional radiography ( modified New York criteria ) were studied . Erythrocyte sedimentation rate , C-reactive protein , plain radiography ( PR ) , and MRI of the sacroiliac ( SI ) joints were obtained at study entry and PR of the SI joints after 3 years . Each radiograph and MR image set was interpreted independently . SI joints were scored according to the modified New York Criteria for radiological sacroiliitis . MRI scans were also scored for the presence of subchondral marrow edema . The relationship between > or = grade 2 sacroiliitis ( by modified New York criteria for radiological sacroiliitis ) shown on MRI and the subsequent development of > or = grade 2 sacroiliitis on PR after 3 years was investigated . RESULTS At study entry > or = grade 2 sacroiliitis was found on MRI in 36 of 50 SI joints . Edema was found in 20 of 50 SI joints . After 3 years > or = grade 2 sacroiliitis was found on PR in 21 of 44 SI joints . The positive predictive value of > or = grade 2 sacroiliitis on MRI for the development of > or = grade 2 sacroiliitis on PR after 3 years was 60 % ; sensitivity was 85 % and specificity 47 % . CONCLUSION Our data suggest that MRI of the SI joints can be used to identify sacroiliitis earlier than PR [3871329] We report 2 independently-conducted family studies of HLA-B27 positive prob and s with ankylosing spondylitis ( AS ) , both of which support the view that the clinical spectrum of AS is broader than ordinarily assumed , and should include individuals who have symptomatic disease but who do not show radiologic evidence of abnormalities of the sacroiliac joints or the spine . In the Clevel and study of 100 relatives of 30 B27 positive AS prob and s , 9 relatives did not show radiologic abnormalities of the sacroiliac joints or the spine but had symptoms of chronic inflammatory back pain previously reported to be characteristic of AS . These 9 relatives were all subsequently found to possess B27 , in contrast with only 27 of 60 asymptomatic relatives ( P less than 0.01 ) . In the Leiden study of 101 relatives of 20 r and omly chosen B27 positive AS prob and s , 13 of 86 relatives without radiographic evidence of sacroiliitis reported " thoracic pain and stiffness , " as defined in the Rome criteria for AS . Twelve of these 13 symptomatic relatives were B27 positive . In contrast , among the remaining 73 relatives , only 33 were B27 positive ( P less than 0.01 ) . The occurrence of these characteristic spondylitic symptoms in B27 positive , but not B27 negative , relatives of AS prob and s suggests that the spectrum of the clinical manifestations of AS may include individuals with symptomatic disease , but without radiographic evidence of abnormalities of the sacroiliac joints or the spine . The relatively large number of females we found in this group suggests that women are more likely to manifest this variety of disease than are men [20638563] BACKGROUND Cyclo-oxygenase (COX)-2-selective non-steroidal anti-inflammatory drugs ( NSAIDs ) and non-selective NSAIDs plus a proton-pump inhibitor ( PPI ) have similar upper gastrointestinal outcomes , but risk of clinical outcomes across the entire gastrointestinal tract might be lower with selective drugs than with non-selective drugs . We aim ed to compare risk of gastrointestinal events associated with celecoxib versus diclofenac slow release plus omeprazole . METHODS We undertook a 6-month , double-blind , r and omised trial in patients with osteoarthritis or rheumatoid arthritis at increased gastrointestinal risk at 196 centres in 32 countries or territories . Patients tested negative for Helicobacter pylori and were aged 60 years and older or 18 years and older with previous gastroduodenal ulceration . We used a computer-generated r and omisation schedule to assign patients in a 1:1 ratio to receive celecoxib 200 mg twice a day or diclofenac slow release 75 mg twice a day plus omeprazole 20 mg once a day . Patients and investigators were masked to treatment allocation . The primary endpoint was a composite of clinical ly significant upper or lower gastrointestinal events adjudicated by an independent committee . Analysis was by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00141102 . FINDINGS 4484 patients were r and omly allocated to treatment ( 2238 celecoxib ; 2246 diclofenac plus omeprazole ) and were included in intention-to-treat analyses . 20 ( 0.9 % ) patients receiving celecoxib and 81 ( 3.8 % ) receiving diclofenac plus omeprazole met criteria for the primary endpoint ( hazard ratio 4.3 , 95 % CI 2.6 - 7.0 ; p<0.0001 ) . 114 ( 6 % ) patients taking celecoxib versus 167 ( 8 % ) taking diclofenac plus omeprazole withdrew early because of gastrointestinal adverse events ( p=0.0006 ) . INTERPRETATION Risk of clinical outcomes throughout the gastrointestinal tract was lower in patients treated with a COX-2-selective NSAID than in those receiving a non-selective NSAID plus a PPI . These findings should encourage review of approaches to reduce risk of NSAID treatment . FUNDING Pfizer [22459541] Objective To investigate the influence of non-steroidal anti-inflammatory drugs ( NSAIDs ) intake on radiographic spinal progression over 2 years in patients with ankylosing spondylitis ( AS ) and non-radiographic axial spondyloarthritis ( SpA ) . Methods 164 patients with axial SpA ( 88 with AS and 76 with non-radiographic axial SpA ) were selected for this analysis based on availability of spinal radiographs at baseline and after 2 years of follow-up and the data on NSAIDs intake . Spinal radiographs were scored by two trained readers in a concealed r and omly selected order according to the modified Stoke Ankylosing Spondylitis Spine Score ( mSASSS ) system . An index of the NSAID intake counting both dose and duration of drug intake was calculated . Results High NSAIDs intake ( NSAID index≥50 ) in AS was associated with lower likelihood of significant radiographic progression defined as an mSASSS worsening by ≥2 units : OR=0.15 , 95 % CI 0.02 to 0.96 , p=0.045 ( adjusted for baseline structural damage , elevated C reactive protein ( CRP ) and smoking status ) in comparison with patients with low NSAIDs intake ( NSAID index<50 ) . This effect was most pronounced in patients with baseline syndesmophytes plus elevated CRP : mean mSASSS progression was 4.36±4.53 in patients with low NSAIDs intake versus 0.14±1.80 with high intake , p=0.02 . In non-radiographic axial SpA , no significant differences regarding radiographic progression between patients with high and low NSAIDs intake were found . Conclusion A high NSAIDs intake over 2 years is associated with retarded radiographic spinal progression in AS . In non-radiographic axial SpA this effect is less evident , probably due to a low grade of new bone formation in the spine at this stage Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Tumour necrosis factor (TNF)-α inhibitors ( anti-TNFs ) are typically used when the inflammatory rheumatologic diseases ankylosing spondylitis ( AS ) and non-radiographic axial spondyloarthritis ( nr-AxSpA ) have not responded adequately to conventional therapy . Current National Institute for Health and Care Excellence ( NICE ) guidance recommends treatment with adalimumab , etanercept and golimumab in adults with active ( severe ) AS only if certain criteria are fulfilled but it does not recommend infliximab for AS . Anti-TNFs for patients with nr-AxSpA have not previously been appraised by NICE . OBJECTIVE To determine the clinical effectiveness , safety and cost-effectiveness within the NHS of adalimumab , certolizumab pegol , etanercept , golimumab and infliximab , within their licensed indications , for the treatment of severe active AS or severe nr-AxSpA ( but with objective signs of inflammation ) . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

31074495

[24139824] BACKGROUND Provision of fortified juices may provide a convenient method to maintain and increase blood fat-soluble vitamins . OBJECTIVE To determine whether children consuming orange juice fortified with calcium and combinations of vitamins D , E , and A could increase serum 25-hydroxyvitamin D [ 25(OH)D ] , α-tocopherol , and retinol levels . DESIGN A 12-week r and omized , double-blind , controlled trial . PARTICIPANTS / SETTING One hundred eighty participants ( aged 8.04±1.42 years ) were recruited at Tufts ( n=70 ) and Boston University ( n=110 ) during 2005 - 2006 . Of those recruited , 176 children were r and omized into three groups : CaD ( 700 mg calcium+200 IU vitamin D ) , CaDEA ( 700 mg calcium+200 IU vitamin D+12 IU vitamin E+2,000 IU vitamin A as beta carotene ) , or Ca ( 700 mg calcium ) . Children consumed two 240-mL glasses of CaD , CaDEA , or Ca fortified orange juice daily for 12 weeks . MAIN OUTCOME MEASURES Serum 25(OH)D , α-tocopherol , and retinol concentrations . STATISTICAL ANALYSES Changes in 25(OH)D , α-tocopherol , retinol , and parathyroid hormone concentrations were examined . Covariates included sex , age , race/ethnicity , body mass index , and baseline 25(OH)D , α-tocopherol , retinol , or parathyroid hormone levels . Multivariate models and repeated measures analysis of variance tested for group differences with pre-post measures ( n=141 ) . RESULTS Baseline 25(OH)D was 68.4±27.7 nmol/L ( 27.4±11.10 ng/mL ) ) , with 21.7 % of participants having inadequate 25(OH)D ( < 50 nmol/L [ 20.03 ng/mL ] ) . The CaD group 's 25(OH)D increase was greater than that of the Ca group ( 12.7 nmol/L [ 5.09 ng/mL ] , 95 % CI 1.3 to 24.1 ; P=0.029 ) . The CaDEA group 's increase in α-tocopherol concentration was greater than that in the Ca or CaD groups ( 3.79 μmol/L [ 0.16 μg/mL ] , 95 % CI 2.5 to 5.1 and 3.09 μmol/L [ 0.13 μg/mL ] , 95 % CI -1.8 to 4.3 ) , respectively ( P<0.0001 ) . Retinol levels did not change , and body weight remained as expected for growth . CONCLUSIONS Daily consumption of orange juice providing 200 IU vitamin D and 12 IU vitamin E increased 25(OH)D and α-tocopherol concentrations in young children within 12 weeks [20529401] OBJECTIVE To assess the effect of an improved local ingredient-based gruel fortified or not with selected multiple micronutrients ( MM ) on Hb concentration of young children . DESIGN In a nutrition centre that we opened in their villages , children received either MM supplement ( containing iron , zinc , vitamin A , vitamin C and iodine ) with the improved gruel ( MMGG ) or the improved gruel only ( GG ) , twice daily , 6 d/week , for 6 months . We assessed baseline and endpoint Hb concentration and anthropometric indices . SETTING Kongoussi , a rural and poor district of Burkina Faso . SUBJECTS In a community-based trial , we r and omly assigned 131 children aged 6 - 23 months with Hb concentrations in the range of 80 - 109 g/l into two groups . RESULTS The groups did not differ significantly at baseline . Mean baseline Hb concentration was 89·2 ( sd 6·5 ) g/l and 90·3 ( sd 8·4 ) g/l in the GG and the MMGG , respectively ( P = 0·42 ) . It increased to 104·1 ( sd 11·4 ) g/l in the GG ( P < 0·001 ) and 107·6 ( sd 14·7 ) g/l in the MMGG ( P < 0·001 ) . The between-group difference of 3·5 ( 95 % CI -1·0 , 8·1 ) g/l in mean ( sd ) endpoint Hb concentration was not significant ( P = 0·13 ) . The endpoint anthropometric indices were not different between the groups . CONCLUSIONS This MM supplement had no additional effect on Hb concentration . Thorough studies are needed to evaluate the actual efficacy of the gruel before its introduction into household routine [19455176] Objective : ( 1 ) To determine whether nutritional supplementation ( energy and micronutrients ) in institutionalised elderly has a positive effect on dietary intake and nutritional status . ( 2 ) To investigate whether individuals tend to compensate for the energy content of the intervention product by decreasing their habitual food consumption . Methods : A 24-week , r and omised , double-blind , placebo-controlled , intervention trial in homes for the elderly ( n=3 ) , in nursing homes ( n=3 ) and ‘ mixed ’ homes ( n=3 ) in The Netherl and s. Institutionalised elderly people ( n=176 ) older than 60 years of age , with a body mass index ⩽30 kg/m2 and a Mini-Mental State Examination score of 10 points or higher , r and omly received a nutrient-enriched drink or a placebo drink twice a day during 24 weeks in addition to their usual diet . Allocation to treatment took into account of sex , the Mini-Mental State Examination score and the plasma homocysteine level . Body weight and several nutrition-related analyses in fasting blood sample s were measured in all participants . Data on dietary intake were collected in a sub sample ( n=66 ) . Results : A significantly favourable effect ( P<0.001 ) of the intervention drink was observed on vitamin intake , mineral intake and vitamin status in blood ( for example , homocysteine decreased from 14.7 to 9.5 μmol/l in the intervention group as compared with that in the placebo group ( 17.2–15.9 ) ) . The difference in change in total energy intake between the two treatment groups was 0.8 MJ/day ( P=0.166 ) . Energy intake from food decreased in both groups to the same extent ( −0.5 MJ/day ) . Therefore , this decrease can not be considered as compensation for the energy content of the product . Conclusions : This group of institutionalised elderly people does not compensate for the energy content of a concentrated nutritional supplement . Therefore , this supplement is effective for counteracting the development of malnutrition in this population [3217058] Objective To investigate the effects of delayed umbilical cord clamping , compared with early clamping , on infant iron status at 4 months of age in a European setting . Design R and omised controlled trial . Setting Swedish county hospital . Participants 400 full term infants born after a low risk pregnancy . Intervention Infants were r and omised to delayed umbilical cord clamping ( ≥180 seconds after delivery ) or early clamping ( ≤10 seconds after delivery ) . Main outcome measures Haemoglobin and iron status at 4 months of age with the power estimate based on serum ferritin levels . Secondary outcomes included neonatal anaemia , early respiratory symptoms , polycythaemia , and need for phototherapy . Results At 4 months of age , infants showed no significant differences in haemoglobin concentration between the groups , but infants subjected to delayed cord clamping had 45 % ( 95 % confidence interval 23 % to 71 % ) higher mean ferritin concentration ( 117 μg/L v 81 μg/L , P<0.001 ) and a lower prevalence of iron deficiency ( 1 ( 0.6 % ) v 10 ( 5.7 % ) , P=0.01 , relative risk reduction 0.90 ; number needed to treat=20 ( 17 to 67 ) ) . As for secondary outcomes , the delayed cord clamping group had lower prevalence of neonatal anaemia at 2 days of age ( 2 ( 1.2 % ) v 10 ( 6.3 % ) , P=0.02 , relative risk reduction 0.80 , number needed to treat 20 ( 15 to 111 ) ) . There were no significant differences between groups in postnatal respiratory symptoms , polycythaemia , or hyperbilirubinaemia requiring phototherapy . Conclusions Delayed cord clamping , compared with early clamping , result ed in improved iron status and reduced prevalence of iron deficiency at 4 months of age , and reduced prevalence of neonatal anaemia , without demonstrable adverse effects . As iron deficiency in infants even without anaemia has been associated with impaired development , delayed cord clamping seems to benefit full term infants even in regions with a relatively low prevalence of iron deficiency anaemia . Trial registration Clinical Trials NCT01245296 [12663288] BACKGROUND Dietary supplements providing physiologic amounts of several micronutrients simultaneously have not been thoroughly tested for combating micronutrient deficiencies . OBJECTIVE We determined whether a beverage fortified with 10 micronutrients at physiologic doses influenced the iron and vitamin A status and growth of rural children ( aged 6 - 11 y ) attending primary schools . DESIGN In this r and omized , double-blind , placebo-controlled efficacy trial , children were assigned to receive the fortified beverage or an unfortified beverage at school for 6 mo . RESULTS There were nonsignificant differences at baseline between children in the fortified and nonfortified groups in iron status , serum retinol , and anthropometry . At the 6-mo follow-up , among children with anemia ( hemoglobin < 110 g/L ) , there was a significantly larger increase in hemoglobin concentration in the fortified group than in the nonfortified group ( 9.2 and 0.2 g/L , respectively ) . Of those who were anemic at baseline , 69.4 % in the nonfortified group and 55.1 % in the fortified group remained anemic at follow-up ( RR : 0.79 ) , a cure rate of 21 % . The prevalence of children with low serum retinol concentrations ( < 200 microg/L ) dropped significantly from 21.4 % to 11.3 % in the fortified group compared with a nonsignificant change ( 20.6 % to 19.7 % ) in the nonfortified group . At follow-up , mean incremental changes in weight ( 1.79 compared with 1.24 kg ) , height ( 3.2 compared with 2.6 cm ) , and BMI ( 0.88 compared with 0.53 ) were significantly higher in the fortified group than in the nonfortified group . CONCLUSION The fortified beverage significantly improved hematologic and anthropometric measurements and significantly lowered the overall prevalence of anemia and vitamin A deficiency [11477464] Objective : To determine the effect of a biscuit with red palm oil as a source of β-carotene on the vitamin A status of primary school children and to compare this with the effect of a biscuit with β-carotene from a synthetic source . Design : R and omised controlled trial . Setting : A rural community in KwaZulu-Natal , South Africa . Subjects : A total of 437 primary school children , aged 5–11 y ; 400 completed the study .Intervention : Subjects were r and omly assigned to one of three groups , receiving , respectively : ( i ) a placebo biscuit ; ( ii ) a biscuit with synthetic β-carotene as a vitamin A fortificant ( SB ) ; ( iii ) a biscuit with red palm oil as a source of β-carotene ( PB ) ; SB and PB supplied 30 % of the RDA for vitamin A per serving of three biscuits . Biscuits were distributed daily during the school week ; vitamin A status was assessed at baseline and after 3 months . Results : There was a significant improvement in serum retinol compared to the control group in both the SB and PB groups ( P<0.005 ) ; the treatment effect for the two groups was equivalent ( difference in treatment effect 0.62 µg/dl , with a 90 % CI−0.33–1.57 ) . Conclusions : A biscuit with red palm oil as a source of β-carotene is as effective as a biscuit with synthetic β-carotene in improving the vitamin A status of primary school children . The additional qualities of red palm oil ( ie no trans fatty acids ; rich source of antioxidants ) make it an excellent alternative fortificant for addressing vitamin A deficiency . Sponsorship : Financial support from Palm Oil Research Institute of Malaysia (PORIM).European Journal of Clinical Nutrition ( 2001 ) 55 , [16702330] Anemia and co-existing deficiencies of zinc , iron , iodine , and vitamin A occur among children in many developing countries including NE Thail and , probably contributing to impairments in growth , immune competence , and cognition . Sustainable strategies are urgently required to combat these deficiencies . We assessed the efficacy of a micronutrient-fortified seasoning powder served with a school lunch on reducing anemia and improving the micronutrient status of rural NE Thai children . Children ( n = 569 ) aged 5.5 - 13.4y from 10 schools were r and omly assigned to receive a seasoning powder either unfortified or fortified with zinc ( 5 mg ) , iron ( 5 mg ) , vitamin A ( 270 microg ) , and iodine ( 50 microg ) ( per serving ) and incorporated into a school lunch prepared central ly and delivered 5 d/wk for 31 wk . Teachers monitored school lunch consumption . Baseline and final micronutrient status , hemoglobinopathies , and infection or inflammation were assessed from blood and urine sample s. For the primary outcome , anemia ( based on hemoglobin ) , no intervention effect was apparent ( odds ratio : 1.02 95 % CI : 0.69 , 1.51 ) after adjustment for design strata . The odds of zinc ( based on serum zinc ) and urinary iodine deficiency in the fortified group were 0.63 ( 0.42 , 0.94 ) and 0.52 ( 0.38 , 0.71 ) times those in the unfortified group , respectively . Fortification had no effect on serum retinol ( 0.61 : 0.25,1.51 ) , ferritin ( 1.12 : 0.43 , 2.96 ) , or mean red cell volume ( 1.16 : 0.82 , 1.64 ) . Therefore , a micronutrient-fortified seasoning powder is a promising vehicle for improving zinc , iodine , and hemoglobin status , and its potential for incorporation into lunch programs in day care centers and schools in NE Thail and warrants investigation [12771326] Due to their widespread acceptability , multinutrient-fortified foods and beverages may be useful in reducing micronutrient deficiencies , especially in developing countries . We studied the efficacy of a new fortified beverage in improving the nutritional status of children in Botswana . We screened 311 lower income urban school children , ages 6 - 11 y , in two primary schools near Gaborone . Children were given seven 240-mL servings weekly of either an experimental beverage ( EXP ) fortified with 12 micronutrients or an isoenergetic placebo drink ( CON ) for 8 wk . Weight , mid-upper arm circumference , hemoglobin , retinol , ferritin , vitamin B-12 , folate and riboflavin status were measured at baseline and at the end of the study . Plasma zinc and serum transferrin receptors also were measured at study end . A total of 145 children in the EXP group and 118 in the CON group completed the trial . Using multivariate analysis , the changes in mid-upper arm circumference , weight for age and total weight were significantly better in the EXP group than in the CON group ( P < 0.01 ) . Ferritin , riboflavin and folate status were significantly better in the EXP group than in the CON group at study end ( P < 0.01 ) , but serum vitamin B-12 was not . Zinc was significantly higher and transferrin receptors were significantly lower at the conclusion of the study in the EXP group than in the CON group ( P < 0.001 ) . Mean plasma retinol concentrations , which were low ( < 0.7 micro mol/L ) in both groups , did not change . We conclude that a micronutrient-fortified beverage may be beneficial as part of a comprehensive nutritional supplementation program in population s at risk for micronutrient deficiencies [17921387] BACKGROUND Little is known about the combined effect of micronutrients and essential fatty acids on cognitive function in school-aged children . OBJECTIVE We assessed the effect of micronutrients , long-chain n-3 fatty acids , or both on indicators of cognitive performance in well-nourished and marginally nourished school-aged children . DESIGN Two 2-by-2 factorial r and omized controlled double-blind trials were performed home-based in Adelaide , South Australia , and at 6 primary schools in Jakarta , Indonesia . A total of 396 children ( aged 6 - 10 y ) in Australia and 384 children in Indonesia were r and omly allocated to receive a drink with a micronutrient mix ( iron , zinc , folate , and vitamins A , B-6 , B-12 , and C ) , with docosahexanoic acid ( DHA , 88 mg/d ) and eicosapentaenoic acid ( EPA , 22 mg/d ) , or with both or placebo 6 d/wk for 12 mo . Biochemical indicators were determined at baseline and 12 mo . Cognitive performance was measured at baseline , 6 mo , and 12 mo . RESULTS The micronutrient treatment significantly improved plasma micronutrient concentrations in Australian and Indonesian children . DHA+EPA treatment increased plasma DHA and total plasma n-3 fatty acids in both countries . The micronutrient treatment result ed in significant increases in scores on tests representing verbal learning and memory in Australia ( estimated effect size : 0.23 ; 95 % CI : 0.01 , 0.46 ) . A similar effect was observed among Indonesian girls ( estimated effect size : 0.32 ; 95 % CI : -0.01 , 0.64 ) . No effects were found on tests measuring general intelligence or attention . No effects of DHA+EPA on the factors of cognitive tests were observed . CONCLUSION In well-nourished school-aged children , fortification with multiple micronutrients can result in improvements in verbal learning and memory [12730420] Maternal malnutrition continues to be a major contributor to adverse reproductive outcomes in developing countries , despite longst and ing efforts to fortify foods or to distribute medicinal supplements to pregnant women . The objective of this study was to test the effect of a micronutrient-fortified beverage containing 11 micronutrients ( iron , iodine , zinc , vitamin A , vitamin C , niacin , riboflavin , folate , vitamin B-12 , vitamin B-6 and vitamin E ) on the hemoglobin , iron and vitamin A status of pregnant women in Tanzania . A group of 259 pregnant women with gestational ages of 8 to 34 wk were enrolled in a r and omized double-blind controlled trial in which study women received 8 wk of supplementation . Hemoglobin , ferritin and dried blood spot retinol were measured at baseline and at the end of the supplementation period . The supplement result ed in a 4.16 g/L increase in hemoglobin concentration and a 3 micro g/L increase in ferritin and reduced the risk of anemia and iron deficiency anemia by 51 and 56 % , respectively . The risk of iron deficiency was reduced by 70 % among those who had iron deficiency at baseline and by 92 % among those who had adequate stores . The micronutrient-fortified beverage may be a useful and convenient preventative measure , one that could help improve the nutritional status of women both before and during pregnancy and thereby help avoid some of the potential maternal and fetal consequences of micronutrient deficiencies [17709456] Adolescent girls have high nutrient needs and are susceptible to micronutrient deficiencies . The objective of this study was to test the effect of a multiple-micronutrient-fortified beverage on hemoglobin ( Hb ) concentrations , micronutrient status , and growth among adolescent girls in rural Bangladesh . A total of 1125 girls ( Hb > or = 70 g/L ) enrolled in a r and omized , double-blind , placebo-controlled trial and were allocated to either a fortified or nonfortified beverage of similar taste and appearance . The beverage was provided at schools 6 d/wk for 12 mo . Concentrations of Hb and serum ferritin ( sFt ) , retinol , zinc , and C-reactive protein were measured in venous blood sample s at baseline , 6 mo , and 12 mo . In addition , weight , height , and mid-upper arm circumference ( MUAC ) measurements were taken . The fortified beverage increased the Hb and sFt and retinol concentrations at 6 mo ( P < 0.01 ) . Adolescent girls in the nonfortified beverage group were more likely to suffer from anemia ( Hb < 120 g/L ) , iron deficiency ( sFt < 12 microg/L ) , and low serum retinol concentrations ( serum retinol < 0.70 micromol/L ) ( OR = 2.04 , 5.38 , and 5.47 , respectively ; P < 0.01 ) . The fortified beverage group had greater increases in weight , MUAC , and BMI over 6 mo ( P < 0.01 ) . Consuming the beverage for an additional 6 mo did not further improve the Hb concentration , but the sFt level continued to increase ( P = 0.01 ) . The use of multiple-micronutrient-fortified beverage can contribute to the reduction of anemia and improvement of micronutrient status and growth in adolescent girls in rural Bangladesh [7733042] A 32-mo-long , double-blind field study involving one highl and control community receiving only vitamin A-fortified sugar and three vitamin A- and FeNaEDTA-sugar-fortified communities , two in the lowl and s and one in the highl and s of Guatemala , was undertaken to test the effectiveness of this approach in controlling iron deficiency . The communities ' population ranged between 1200 and 17000 . Sugar fortified with 1 g FeNaEDTA and 15 mg retinol as retinyl palmitate/kg was stable , did not segregate , and was well accepted by the communities . The impact of fortification on iron nutrition was estimated at 8 , 20 , and 32 mo of intervention . All pregnant women and subjects with severe anemia received supplements or treatment and were excluded from the analysis . Iron stores in the fortified communities increased significantly except for women 18 - 48 y of age in one lowl and community and > 49 y in the highl and community . Iron stores in the control community remained unchanged except for a rise among adult males [10075336] BACKGROUND Deficiencies of iron , iodine , and vitamin A are prevalent worldwide and can affect the mental development and learning ability of schoolchildren . OBJECTIVE The aim of this study was to determine the effect of micronutrient-fortified biscuits on the micronutrient status of primary school children . DESIGN Micronutrient status was assessed in 115 children aged 6 - 11 y before and after consumption of biscuits ( fortified with iron , iodine , and beta-carotene ) for 43 wk over a 12-mo period and was compared with that in a control group ( n = 113 ) who consumed nonfortified biscuits . Cognitive function , growth , and morbidity were assessed as secondary outcomes . RESULTS There was a significant between-group treatment effect on serum retinol , serum ferritin , serum iron , transferrin saturation , and urinary iodine ( P < 0.0001 ) and in hemoglobin and hematocrit ( P < 0.05 ) . The prevalence of low serum retinol concentrations ( < 0.70 micromol/L ) decreased from 39.1 % to 12.2 % , of low serum ferritin concentrations ( < 20 microg/L ) from 27.8 % to 13.9 % , of anemia ( hemoglobin < 120 g/L ) from 29.6 % to 15.6 % , and of low urinary iodine concentrations ( < 100 microg/L ) from 97.5 % to 5.4 % . There was a significant between-group treatment effect ( P < 0.05 ) in cognitive function with the digit span forward task ( short-term memory ) . Fewer school days were missed in the intervention than in the control group because of respiratory- ( P = 0.097 ) and diarrhea-related ( P = 0.013 ) illnesses . The intervention had no effect on anthropometric status [ corrected ] . CONCLUSIONS Fortified biscuits result ed in a significant improvement in the micronutrient status of primary school children from a poor rural community and also appeared to have a favorable effect on morbidity and cognitive function [ corrected ] [10966892] BACKGROUND Wheat flour is a possible food vehicle for vitamin A fortification . OBJECTIVE This study assessed the efficacy of consumption of a vitamin A-fortified wheat-flour bun ( p and esal ) on the vitamin A status of school-age children . DESIGN This was a double-masked clinical trial conducted in 396 and 439 children aged 6 - 13 y attending 4 rural schools in the Philippines . The children were r and omly assigned to a vitamin A-fortified ( experimental ) or nonfortified ( control ) group . A 60-g vitamin A-fortified p and esal ( containing approximately 133 microg retinol equivalents ) or a nonfortified p and esal was consumed by the children 5 d/wk for 30 wk . Vitamin A status , hemoglobin concentration , anthropometric status , morbidity , and dietary intake were assessed at baseline and 30 wk later . A modified relative dose response ( MRDR ) was assessed in a sub sample of 20 % of the children ( approximately 75/group ) with the lowest initial serum retinol concentration at the 30-wk follow-up . RESULTS Baseline serum retinol significantly modified the effect of the intervention . The fortified group , whose initial serum retinol concentrations were below the median , had a 0.07 + /- 0.03-micromol/L greater improvement in serum retinol at the 30-wk follow-up than did the control group ( P : = 0.02 ) . Improved vitamin A status was also evident in the MRDR sub sample . End-of- study differences in the MRDR showed that vitamin A- fortified p and esal intake decreased the percentage of children with inadequate liver vitamin A stores by 50 % ( 15.3 % compared with 28.6 % ; P : = 0.05 ) . CONCLUSIONS Daily consumption of vitamin A-fortified p and esal significantly improved the vitamin A status of Filipino school-age children with marginal-to-low initial serum retinol concentrations [15447908] BACKGROUND Multiple micronutrient deficiencies are often the basic causative factor in stunting and anemia , 2 conditions that affect entire generations of children in deprived population s. No generally accepted recommendations for micronutrient intakes for recovery from stunting are available . OBJECTIVE The objective was to assess the effect of a highly nutrient-dense spread fortified with vitamins and minerals , with or without antiparasitic metronidazole treatment , in correcting retarded linear growth and reducing anemia in stunted children . DESIGN Saharawi refugee children ( n = 374 ) aged 3 - 6 y with initial height-for-age z scores < -2 were assigned to 1 of 5 groups : fortified spread ( FS ) , fortified spread plus metronidazole ( FS+M ) , unfortified spread ( US ) , unfortified spread plus metronidazole ( US+M ) , or control . Supervised supplementation was given daily for 6 mo . Weight , height , knee-heel length , hematologic indexes , parasitic infections , and morbidity were assessed at 0 , 3 , and 6 mo . RESULTS Linear growth of children fed FS was 30 % faster at 3 mo than in US and control groups , after which height-for-age z scores increased only slightly in the FS group and remained unchanged in the other groups . No additional benefits from metronidazole were observed . Increase in hemoglobin concentrations in the FS group at 6 mo was twofold that in the US and control groups ( 37 + /- 40 , 19 + /- 15 , and 16 + /- 17 g/L , respectively ; P < 0.0001 ) , and anemia was reduced by nearly 90 % . CONCLUSIONS FS , and not US , induces catch-up growth in stunted children whose diets are poor in micronutrients . Our trial provides support for delivering multiple micronutrients to reverse stunting and reduce anemia in children up to age 6 [16280435] BACKGROUND Maize-meal porridge is used for infant feeding in many African countries , including South Africa . A low-cost , finely milled , maize-meal porridge was fortified with beta-carotene , iron , and zinc ( 100 % of recommended dietary allowance ) , as well as ascorbic acid , copper , selenium , riboflavin , vitamin B-6 , vitamin B-12 , and vitamin E. OBJECTIVE We assessed whether the fortified porridge could reduce anemia and improve the micronutrient status and motor development of infants . DESIGN Infants aged 6 - 12 mo ( n = 361 ) were r and omly assigned to receive either the fortified or unfortified porridge for 6 mo . Primary outcomes were hemoglobin and serum retinol , zinc , and ferritin concentrations and motor development . Growth was assessed as a secondary outcome . Primary and secondary outcomes were assessed at baseline and 6 mo . RESULTS Two hundred ninety-two infants completed the study . The fortified-porridge group had an intervention effect of 9.4 microg/L ( 95 % CI : 3.6 , 15.1 microg/L ) for serum ferritin and 9 g/L ( 95 % CI : 6 , 12 g/L ) for hemoglobin concentrations . The proportion of infants with anemia decreased from 45 % to 17 % in the fortified-porridge group , whereas it remained > 40 % in the control group . The fortified-porridge group achieved on average 15.5 of the 25 motor development score items , whereas the control group achieved 14.4 items ( P = 0.007 ) . Serum retinol concentration showed an inconsistent effect , and no intervention effect was observed for serum zinc concentrations . CONCLUSIONS This low-cost fortified porridge can potentially have a significant effect in reducing anemia and improving iron status and motor development of infants in poor setting s. The formulation needs some adjustment in terms of zinc fortification [26275329] BACKGROUND Vitamin A deficiency is a risk factor for blindness and for mortality from measles and diarrhoea in children aged 6 - 59 months . We aim ed to estimate trends in the prevalence of vitamin A deficiency between 1991 and 2013 and its mortality burden in low-income and middle-income countries . METHODS We collated 134 population -representative data sources from 83 countries with measured serum retinol concentration data . We used a Bayesian hierarchical model to estimate the prevalence of vitamin A deficiency , defined as a serum retinol concentration lower than 0·70 μmol/L. We estimated the relative risks ( RRs ) for the effects of vitamin A deficiency on mortality from measles and diarrhoea by pooling effect sizes from r and omised trials of vitamin A supplementation . We used information about prevalences of deficiency , RRs , and number of cause-specific child deaths to estimate deaths attributable to vitamin A deficiency . All analyses included a systematic quantification of uncertainty . FINDINGS In 1991 , 39 % ( 95 % credible interval 27 - 52 ) of children aged 6 - 59 months in low-income and middle-income countries were vitamin A deficient . In 2013 , the prevalence of deficiency was 29 % ( 17 - 42 ; posterior probability [ PP ] of being a true decline=0·81 ) . Vitamin A deficiency significantly declined in east and southeast Asia and Oceania from 42 % ( 19 - 70 ) to 6 % ( 1 - 16 ; PP>0·99 ) ; a decline in Latin America and the Caribbean from 21 % ( 11 - 33 ) to 11 % ( 4 - 23 ; PP=0·89 ) also occurred . In 2013 , the prevalence of deficiency was highest in sub-Saharan Africa ( 48 % ; 25 - 75 ) and south Asia ( 44 % ; 13 - 79 ) . 94 500 ( 54 200 - 146 800 ) deaths from diarrhoea and 11 200 ( 4300 - 20 500 ) deaths from measles were attributable to vitamin A deficiency in 2013 , which accounted for 1·7 % ( 1·0 - 2·6 ) of all deaths in children younger than 5 years in low-income and middle-income countries . More than 95 % of these deaths occurred in sub-Saharan Africa and south Asia . INTERPRETATION Vitamin A deficiency remains prevalent in south Asia and sub-Saharan Africa . Deaths attributable to this deficiency have decreased over time worldwide , and have been almost eliminated in regions other than south Asia and sub-Saharan Africa . This new evidence for both prevalence and absolute burden of vitamin A deficiency should be used to reconsider , and possibly revise , the list of priority countries for high-dose vitamin A supplementation such that a country 's priority status takes into account both the prevalence of deficiency and the expected mortality benefits of supplementation . FUNDIN Bill & Melinda Gates Foundation , Gr and Challenges Canada , UK Medical Research Council [25164452] BACKGROUND Multiple micronutrient deficiencies are prevalent in India . OBJECTIVE The study aims to establish the efficacy of multi-micronutrient fortified salt in addressing multiple micronutrient deficiencies among children compared to nutrition education and no intervention in Tamilnadu . METHODS The study employed a community based r and omized controlled trial design ed to study the impact of multiple micronutrient salt ( micronutrient group ) in comparison with nutrition education ( education group ) and no intervention ( control group ) on haemoglobin , serum ferritin , soluble transferrin receptor , body iron stores , serum retinol and urinary iodine outcomes over a period of 8 months . The fortified salt contained iron , iodine , vitamin A , vitamin B12 and folic acid . All the children were dewormed at baseline and at the end of the study just before the biochemical measurements . RESULTS There was a significant improvement in most biochemical parameters studied in the micronutrient group when compared with the control group whereas this was not seen between the education and control . Over 8 months , in the micronutrient group , hemoglobin increased by 0.52 g/dL , retinol by 8.56 μg/dL , ferritin by 10.8 μg/L , body iron stores by 1.27 mg and the decrease in the prevalence of retinol deficiency was from 51.6 % to 28.1 % , anaemia from 46.0 % to 32.6 % , iron deficiency from 66.9 % to 51.3 % and iron deficiency anaemia from 35.2 % to 31.0 % , while the prevalence of all these deficiencies increased or the changes were not significant in the other two groups . CONCLUSIONS Multiple micronutrient fortified salt was able to improve iron and vitamin A status , whereas this was not seen in the nutrition education group [20533221] OBJECTIVE This study was conducted to test the efficacy of a multiple micronutrient-fortified cooking salt . METHODS A r and omized controlled trial with a pre- and post-test design was used to study children 5 to 18 years of age , with an experimental ( n=213 ) and control group ( n=189 ) . The children were sample d from 3 residential schools and were studied for 9 months . The experimental group received a multiple micronutrient-fortified salt containing vitamins A , B(1 ) , B(2 ) , B(6 ) , B(12 ) , as well as folic acid , niacin , iron , iodine , and zinc . The control group received iodized salt . Biochemical measurements [ hemoglobin , serum ferritin ( SF ) , serum transferrin receptor ( sTfR ) , C-reactive protein ( CRP ) , alpha-1 acid glycoprotein ( AGP ) , serum retinol , serum vitamin B(12 ) , serum folic acid , serum zinc , and urinary iodine ( UI ) ] were measured at baseline and post-intervention . Hemoglobin was measured in all the children three times during the study period , while the remaining biochemical measurements were performed in a sub sample of children . Children between 11 and 18 years of age were given cognitive tests to assess memory and attention . RESULTS There was a significant improvement ( p<0.05 ) in all the biochemical measurements and memory tests in the experimental group when compared with the control group . Post-intervention in the experimental group , the increase in hemoglobin was 0.67 g/dL ( p<0.05 ) . Iron status and body iron stores increased significantly ( p<0.05 ) in the experimental group compared to the control group , while serum zinc increased by 50 mug/dL ( p<0.05 ) , and the prevalence of retinol deficiency decreased from 57.1 % at baseline to 16 % post-intervention ( p<0.05 ) . CONCLUSION The multiple micronutrients from the multiple micronutrient-fortified cooking salt were absorbed in the children and helped in combating micronutrient deficiencies [18057478] OBJECTIVE To assess the efficacy of micronutrient fortified sugar c and ies in improving the iron and vitamin A status in children aged 3 to 6 years . DESIGN Triple blind r and omized controlled trial . SETTING S Anganwadis and preparatory schools in rural Haryana . METHODS 410 children were r and omized in four groups . One group received full dose c and y ( vitamin A 1000 IU and 14 mg elemental iron ) daily , the second group received full dose c and y for 3 days a week , the third group received half dose c and y ( vitamin A 500 IU and 7 mg elemental iron ) daily and the fourth received placebo . The c and ies were provided to children under supervision of field workers . Hemoglobin , S. ferritin , S. retinol and S. retinol binding protein levels were estimated at baseline and after 13 weeks of intervention . RESULTS The increase in hemoglobin was least in the placebo group ( 0.3 g/dL ) as compared to the two full dose groups ( 1.15 - 1.18 g/dL , P < 0.001 ) . Among anemic children , the increase in hemoglobin was about 2 g/dL in the full dose group and 0.7 g/dL in the placebo group ( P < 0.001 ) . S. ferritin levels increased significantly only in the full dose daily group ( p < 0.05 ) . The prevalence of anemia decreased from around 50 % at baseline to 9.6 % in the full dose daily group ( p < 0.01 ) . Based on the S. retinol levels , the study area was not vitamin A deficient and the intervention did not result in a significant improvement in the vitamin A status of the children . CONCLUSION Micronutrient fortified c and ies were effective in improving the hemoglobin level and decreasing anemia prevalence . It could serve as a suitable vehicle for micronutrient supplementation in children and other target groups [12630494] OBJECTIVE To evaluate the efficacy of a multiple micronutrient fortified beverage containing eleven nutrients at physiological levels in prevention of anaemia and improving iron and vitamin A status during pregnancy . DESIGN A r and omised double blind placebo controlled study . SETTING Mpwapwa and Kongwa Districts in Dodoma Region of Tanzania . SUBJECTS Five hundred and seventy nine pregnant women were screened for entry into the study and 439 women who met the study criteria were enrolled . INTERVENTIONS Study participants received either a fortified ( F ) or non-fortified ( NF ) orange flavoured drinks identical in appearance , provided in two self administered servings per day for an eight week period . MAIN OUTCOME MEASURES Comparison of haemoglobin ( Hb ) , serum ferritin ( SF ) and serum retinol ( SR ) at baseline and follow up . RESULTS After eight weeks of supplementation , the F group ( n=129 ) had a significantly higher Hb increase of 0.86 g/dL compared to 0.45 g/dL in the NF group ( n=130 ) p<0.0001 . Gestational age at entry into the study , moderated the effect on Hb of the fortified drink . Women at earlier gestational age upon entry , had a higher rise in Hb than women of late gestational age ( 0.8 g/dL versus 0.04 g/dL rise respectively , p=0.038 , n=188 ) . The risk of being anaemic at the end of the study for those in the F group was reduced by 51 % ( RR=0.49 , CI=0.28 to 0.85 ) . Iron stores ( by serum ferritin levels ) increased by 3 microg/L in the F group ( p=0.012 ) and a decrease of 2 microg/L in the NF group ( p=0.115 ) . The follow up ferritin concentration depended on initial ferritin level . Regardless of treatment group , serum retinol concentrations were significantly higher in mothers who had delivered . Mothers who had adequate levels at entry benefited more from the supplement than those with low levels ( 0.26 micromol/L versus no significant difference ) . CONCLUSIONS The multiple micronutrient-fortified beverage given for eight weeks to pregnant women improved their haemoglobin , serum ferritin and retinol status . The risk for anaemia was also significantly reduced . The important predictors of Hb increase at follow up were the fortified beverage , baseline Hb , serum retinol , baseline ferritin and gestational age at entry into study . Anthropological research showed that the beverage was highly acceptable and well liked [11796083] OBJECTIVE To evaluate the long-term effect on micronutrient status of a beta-carotene- , iron- and iodine-fortified biscuit given to primary school children as school feeding . DESIGN Children receiving the fortified biscuit were followed in a longitudinal study for 2.5 years ( n = 108 ) ; in addition , cross-sectional data from three subsequent surveys conducted in the same school are reported . SETTING A rural community in KwaZulu-Natal , South Africa . SUBJECTS Children aged 6 - 11 years attending the primary school where the biscuit was distributed . RESULTS There was a significant improvement in serum retinol , serum ferritin , haemoglobin , transferrin saturation and urinary iodine during the first 12 months of the biscuit intervention . However , when the school reopened after the summer holidays , all variables , except urinary iodine , returned to pre-intervention levels . Serum retinol increased again during the next 9 months , but was significantly lower in a subsequent cross-sectional survey carried out directly after the summer holidays ; this pattern was repeated in two further cross-sectional surveys . Haemoglobin gradually deteriorated at each subsequent assessment , as did serum ferritin ( apart from a slight increase at the 42-month assessment at the end of the school year ) . CONCLUSIONS This study has shown that fortification of a biscuit with beta-carotene at a level of 50 % of the Recommended Dietary Allowance ( RDA ) was enough to maintain serum retinol concentrations from day to day , but not enough to sustain levels during the long school holiday break . Other long-term solutions , such as local food production programmes combined with nutrition education , should also be examined . The choice of the iron compound used as fortificant in the biscuit needs further investigation [23232585] Background / Objectives : A multiple micronutrient-fortified drink could be an effective strategy to combating micronutrient deficiencies in school going children . To assess the efficacy of a multiple micronutrient-fortified drink in reducing iron deficiency ( ID ) , ID anemia ( IDA ) , anemia and improving micronutrient status among schoolchildren with low iron stores . The study employed a school-based , r and omized , double-blind , placebo-controlled design .Subjects/ Methods : Schoolchildren with low serum ferritin ( SF < 20 μg/l ) ( n=246 ) , aged 6–12 years were r and omly assigned to receive either a multi-micronutrient fortified or an unfortified identical control drink . The drinks were provided 6 days/week for 8 weeks . Anthropometric and biochemical assessment s were taken at baseline and endline . Results : Study groups at baseline were comparable , and compliance to the intervention was similar . The overall prevalence of ID , IDA and anemia was 64 % , 19 % and 24 % , respectively . The prevalence of ID , IDA , vitamin C and vitamin B12 deficiencies significantly reduced by 42 % , 18 % , 21 % and 5 % , respectively , in the intervention arm ( P<0.01 ) as compared with the control arm at the end of the study . Similarly , the concentration of hemoglobin , SF , vitamin A , vitamin B12 , vitamin C and body iron stores were significantly higher in the intervention arm in comparison to the control arm ( P<0.001 ) . Red cell folate levels also improved significantly in the intervention arm ( P=0.04 ) , however , serum zinc status did not change in either of the study arms . Children who had received the fortified drink had significantly lower odds of being ID ( 0.15 ; 95 % confidence interval ( CI ) : 0.09–0.27 ) , IDA ( 0.14 ; 95 % CI : 0.04–0.52 ) , vitamin B12 deficient ( 0.36 ; 95 % CI : 0.18–0.73 ) and vitamin C deficient ( 0.24 ; 95 % CI : 0.13–0.46 ) , after adjusting for baseline age , gender and weight . Conclusions : The multi micronutrient-fortified drink was efficacious in reducing the prevalence of ID , IDA , vitamin C and vitamin B12 deficiency and improved micronutrient status in schoolchildren [27925426] Home fortification with multiple micronutrient powder ( MNP ) is effective in the prevention of anemia in young children . However , the impact on their vitamin A status remains controversial . This study aim ed to evaluate the effect of MNP on vitamin A status in young Brazilian children . A multicenter pragmatic , controlled trial was carried out in primary health centers in four Brazilian cities . In the beginning of the study , the control group ( CG ) consisted of children 11 - 14 months old ( n = 395 ) attending in routine pediatric health care . In parallel , the intervention group ( IG ) was composed of children 6 - 8 months old ( n = 399 ) , in the same health centers , who followed the intervention with MNP for 2 - 3 months . The analysis of the effect of MNP on vitamin A status was performed by comparing the IG with the CG after a 4- to 6-month follow-up when IG children had reached the age of the controls . The prevalence of vitamin A deficiency ( VAD ; serum retinol < 0.70 μmol/L ) in the CG was 16.2 % , while in the IG was 7.5%-a 55 % reduction in the VAD [ prevalence ratio ( 95 % confidence interval ) = 0.45 ( 0.28 ; 0.72 ) ] . This reduction was also significant when stratifying the study centers by coverage of the Brazilian Vitamin A Supplementation Program . The adjusted mean of vitamin A serum concentrations improved in the IG compared with CG children , with a shift to the right in the vitamin A distribution . Home fortification with MNP was effective in reducing VAD among young Brazilian children [19155581] Preschool children in developing countries are likely to have multiple , concurrent micronutrient deficiencies . This study was design ed to evaluate the effectiveness of different combinations of nutritional fortified diet to improve the blood levels of iron , vitamin A and other essential micronutrients in the preschool population of Banan District of Chongqing , China . From December 2005 to June 2006 , a total of 226 2 - 6 y old preschool children were recruited from three nurseries in the area , and they were r and omly assigned to three different fortified diet groups for 6 mo . Group I was fortified with vitamin A ; groups II and III were fortified with vitamin A plus iron and vitamin A plus iron , thiamine , riboflavin , folic acid , niacinamide , zinc and calcium , respectively . Subjects ' weight and height were measured for assessing the children 's growth and development . Blood sample s were taken at the beginning and the end of the 6-mo study period for measuring serum levels of micronutrients . Group III with the multiple micronutrient fortified diet was the most effective to improve the serum level of retinol from [ media ( P25 , P75 ) : 1.06 ( 0.89 , 1.32 ) ] micromol/L to 1.29 ( 1.04 , 1.39 ) micromol/L ( p<0.05 ) and retinol binding protein from 17.0 ( 12.6 , 25.6 ) mg/L to 31.6 ( 24.4 , 44.0 ) mg/L ( p<0.05 ) and to mobilize the stored iron in the liver ( p<0.05 ) . In addition , the three groups ' hemoglobin levels were elevated from 117.0 ( 109.0 , 124.1 ) g/L , 114.0 ( 109.2 , 119.7 ) g/L and 115.0 ( 109.5 , 122.7 ) g/L to 125.7 ( 119.2 , 133.1 ) g/L , 126.5 ( 122.2 , 135.9 ) g/L and 125.1 ( 119.8 , 131.6 ) g/L over the 6 mo of intervention period , but there were no difference among the three groups ( p>0.05 ) . Nevertheless , unexpected results were obtained when comparing the effects on growth status among the different supplement groups . Our study has demonstrated that a multiple micronutrient fortified diet for 6 mo is more effective to improve the levels of hemoglobin , serum retinol , and RBP as well as to facilitate the mobilization of iron storage in preschool children [5557358] Background Multiple micronutrients ( MMN ) are commonly prescribed in pediatric primary healthcare in sub-Saharan Africa to improve nutritional status and appetite without evidence for their effectiveness or international clinical guidelines . Community-wide MMN supplementation has shown limited and heterogeneous impact on growth and morbidity . Short-term ready-to-use therapeutic foods in acutely sick children in a hospital setting also had limited efficacy regarding subsequent growth . The effectiveness of MMN in improving morbidity or growth in sick children presenting for primary care has not been assessed . Methods and findings We undertook a double-blind r and omised controlled trial of small-quantity lipid-based nutrient supplements ( SQ-LNS ) fortified with 23 micronutrients in children aged 6 months ( mo ) to 5 years ( y ) presenting with an illness at a rural primary healthcare centre in The Gambia . Primary outcomes were repeat clinic presentations and growth over 24 wk . Participants were r and omly assigned to receive 1 of 3 interventions : ( 1 ) supplementation with micronutrient-fortified SQ-LNS for 12 wk ( MMN-12 ) , ( 2 ) supplementation with micronutrient-fortified SQ-LNS for 6 wk followed by unfortified SQ-LNS for 6 wk ( MMN-6 ) , or ( 3 ) supplementation with unfortified SQ-LNS for 12 wk ( MMN-0 ) to be consumed in daily portions . Treatment masking used 16 letters per 6-wk block in the r and omisation process . Blinded intention-to-treat analysis based on a prespecified statistical analysis plan included all participants eligible and correctly enrolled . Between December 2009 and June 2011 , 1,101 children ( age 6–60 mo , mean 25.5 mo ) were enrolled , and 1,085 were assessed ( MMN-0 = 361 , MMN-6 = 362 , MMN-12 = 362 ) . MMN supplementation was associated with a small increase in height-for-age z-scores 24 wk after recruitment ( effect size for MMN groups combined : 0.084 SD/24 wk , 95 % CI : 0.005 , 0.168 ; p = 0.037 ; equivalent to 2–5 mm depending on age ) . No significant difference in frequency of morbidity measured by the number of visits to the clinic within 24 wk follow-up was detected with 0.09 presentations per wk for all groups ( MMN-0 versus MMN-6 : adjusted incidence rate ratio [ IRR ] 1.03 , 95 % CI : 0.92 , 1.16 ; MMN-0 versus MMN-12 : 1.05 , 95 % CI : 0.93 , 1.18 ) . In post hoc analysis , clinic visits significantly increased by 43 % over the first 3 wk of fortified versus unfortified SQ-LNS ( adjusted IRR 1.43 ; 95 % CI : 1.07 , 1.92 ; p = 0.016 ) , with respiratory presentations increasing by 52 % with fortified SQ-LNS ( adjusted IRR 1.52 ; 95 % CI : 1.01 , 2.30 ; p = 0.046 ) . The number of severe adverse events during supplementation were similar between groups ( MMN-0 = 20 [ 1 death ] ; MMN-6 = 21 [ 1 death ] ; MMN-12 = 20 [ 0 death ] ) . No participant withdrew due to adverse effects . Study limitations included the lack of supervision of daily supplementation . Conclusion Prescribing micronutrient-fortified SQ-LNS to ill children presenting for primary care in rural Gambia had a very small effect on linear growth and did not reduce morbidity compared to unfortified SQ-LNS . An early increase in repeat visits indicates a need for the establishment of evidence -based guidelines and caution with systematic prescribing of MMN . Future research should be directed at underst and ing the mechanisms behind the lack of effect of MMN supplementation on morbidity measures and limited effect on growth . Trial registration IS RCT N 73571031 [23823584] Little is known about the effects of combined micronutrient and sugar consumption on growth and cognition . In the present study , we investigated the effects of micronutrients and sugar , alone and in combination , in a beverage on growth and cognition in schoolchildren . In a 2 × 2 factorial design , children ( n 414 , 6 - 11 years ) were r and omly allocated to consume beverages containing ( 1 ) micronutrients with sugar , ( 2 ) micronutrients with a non-nutritive sweetener , ( 3 ) no micronutrients with sugar or ( 4 ) no micronutrients with a non-nutritive sweetener for 8.5 months . Growth was assessed and cognition was tested using the Kaufman Assessment Battery for Children version II ( KABC-II ) subtests and the Hopkins Verbal Learning Test ( HVLT ) . Micronutrients decreased the OR for Fe deficiency at the endpoint ( OR 0.19 ; 95 % CI 0.07 , 0.53 ) . Micronutrients increased KABC Atlantis ( intervention effect : 0.76 ; 95 % CI 0.10 , 1.42 ) and HVLT Discrimination Index ( 1.00 ; 95 % CI 0.01 , 2.00 ) scores . Sugar increased KABC Atlantis ( 0.71 ; 95 % CI 0.05 , 1.37 ) and Rover ( 0.72 ; 95 % CI 0.08 , 1.35 ) scores and HVLT Recall 3 ( 0.94 ; 95 % CI 0.15 , 1.72 ) . Significant micronutrient × sugar interaction effects on the Atlantis , Number recall , Rover and Discrimination Index scores indicated that micronutrients and sugar in combination attenuated the beneficial effects of micronutrients or sugar alone . Micronutrients or sugar alone had a lowering effect on weight-for-age z-scores relative to controls ( micronutrients - 0.08 ; 95 % CI - 0.15 , - 0.01 ; sugar - 0.07 ; 95 % CI - 0.14 , - 0.002 ) , but in combination , this effect was attenuated . The beverages with micronutrients or added sugar alone had a beneficial effect on cognition , which was attenuated when provided in combination [18096105] OBJECTIVE To assess changes in the Fe and vitamin A status of the population of Nangweshi refugee camp associated with the introduction of maize meal fortification . DESIGN Pre- and post-intervention study using a longitudinal cohort . SETTING Nangweshi refugee camp , Zambia . SUBJECTS Two hundred and twelve adolescents ( 10 - 19 years ) , 157 children ( 6 - 59 months ) and 118 women ( 20 - 49 years ) were selected at r and om by household survey in July 2003 and followed up after 12 months . RESULTS Maize grain was milled and fortified in two custom- design ed mills installed at a central location in the camp and a daily ration of 400 g per person was distributed twice monthly to households as part of the routine food aid ration . During the intervention period mean Hb increased in children ( 0.87 g/dl ; P < 0.001 ) and adolescents ( 0.24 g/dl ; P = 0.043 ) but did not increase in women . Anaemia decreased in children by 23.4 % ( P < 0.001 ) but there was no significant change in adolescents or women . Serum transferrin receptor ( log10-transformed ) decreased by -0.082 microg/ml ( P = 0.036 ) indicating an improvement in the Fe status of adolescents but there was no significant decrease in the prevalence of deficiency ( -8.5 % ; P = 0.079 ) . In adolescents , serum retinol increased by 0.16 micromol/l ( P < 0.001 ) and vitamin A deficiency decreased by 26.1 % ( P < 0.001 ) . CONCLUSIONS The introduction of fortified maize meal led to a decrease in anaemia in children and a decrease in vitamin A deficiency in adolescents . Central ised , camp-level milling and fortification of maize meal is a feasible and pertinent intervention in food aid operations [28760007] Background : Iron deficiency is a global public health concern and has implication s on the health status of women in reproductive age . Objective : We hypothesized that improving iron intake with double fortified salt would improve food intake , result ing in higher energy , nutrient intakes , and weight indicators of female tea plantation workers . Methods : In this r and omized double-masked study , the participants ( n = 245 ) were assigned to receive salt double fortified with iron and iodine ( DFS ; treatment ) or salt fortified with iodine ( control ) and followed for 7.5 to 9 months . Dietary intakes were measured at three time points , baseline , midpoint , and end line using ( 1 ) food frequency question naire , ( 2 ) 24-hour recall , and ( 3 ) weighed lunch intake . Anthropometric measures of height ( cm ) , weight ( kg ) , and mid-upper arm circumference ( cm ) were also recorded at three time points . Mixed-model repeated- measures approach was used to detect group differences across time . Results : Double fortified salt improved dietary iron intake in the treatment group compared to the control group ( P < .001 ) . No other dietary or anthropometric differences could be attributed to treatment . Significant effect of time was observed in the intake frequency of major food groups and calcium , vitamin A and C ( P < .001 for all ) , suggesting an equal effect of seasonality in both the groups . Conclusion : Addition of DFS in the diet improved dietary iron intake but did not affect the intake of energy , other nutrients , or nutritional status indicators . The improvement observed in the dietary iron intake demonstrates that fortification is an effective strategy to address iron deficiency in at-risk population [27440679] BACKGROUND AND OBJECTIVES Mola ( Amblypharyngodon mola ) is a nutrient-rich , small fish found in ponds and rice fields in Bangladesh . The aim of the present intervention was to assess the effect of mola consumption on iron status in children with marginal vitamin A status . METHODS AND STUDY DESIGN Bangladeshi children ( n=196 ) , aged 3 - 7 years , with marginal vitamin A status were r and omly allocated to one of three intervention groups served different fish curries : mola curry ( experimental group ) ; rui ( Labeo rohita ) curry with added retinyl palmitate ( positive control group ) ; or rui curry ( negative control group ) . The intervention meals were served 6 days/week for 9 weeks . The experimental and positive control meals were design ed to contain similar amounts of retinol activity equivalents per portion . The mola curry contained four times more iron compared to the rui curries due to different iron content in the two fish species . Haemoglobin , ferritin , serum transferrin receptor and Creactive protein were measured at screening and endpoint . RESULTS In the experimental group receiving mola , serum transferrin receptor concentration declined 0.73 mg/L ( 95 % CI 0.17 , 1.28 , p=0.01 ) compared to the positive control group , while there were no differences between groups in ferritin or haemoglobin . CONCLUSIONS Consumption of mola instead of rui has potentially an effect on iron status in children with marginal vitamin A status , seen as a decrease in serum transferrin receptor concentration [17565762] OBJECTIVE To test the hypothesis that maternal food fortification with omega-3 fatty acids and multiple micronutrients increases birth weight and gestation duration , as primary outcomes . DESIGN Non-blinded , r and omised controlled study . SETTING Pregnant women received powdered milk during their health check-ups at 19 antenatal clinics and delivered at two maternity hospitals in Santiago , Chile . SUBJECT Pregnant women were assigned to receive regular powdered milk ( n = 477 ) or a milk product fortified with multiple micronutrients and omega-3 fatty acids ( n = 495 ) . RESULTS Intention-to-treat analysis showed that mean birth weight was higher in the intervention group than in controls ( 65.4 g difference , 95 % confidence interval ( CI ) 5 - 126 g ; P = 0.03 ) and the incidence of very preterm birth ( 0.80 just for mean birth weight and birth length in the on-treatment analysis ; birth length in that analysis had a difference of 0.57 cm ( 95 % CI 0.19 - 0.96 cm ; P = 0.003 ) . CONCLUSIONS The new intervention result ed in increased mean birth weight . Associations with gestation duration and most secondary outcomes need a larger sample size for confirmation [23537728] OBJECTIVE To examine the effects of three different school snacks on morbidity outcomes . DESIGN Twelve schools were r and omized to either one of three feeding groups or a Control group . There were three schools per group in this cluster r and omized trial . Children in feeding group schools received school snacks of a local plant-based dish , githeri , with meat , milk or extra oil added . The oil used was later found to be fortified with retinol . Physical status , food intake and morbidity outcomes were assessed longitudinally over two years . SETTING Rural Embu District , Kenya , an area with high prevalence of vitamin A deficiency . SUBJECTS St and ard 1 schoolchildren ( n 902 ; analytic sample ) enrolled in two cohorts from the same schools one year apart . RESULTS The Meat and Plain Githeri ( i.e. githeri+oil ) groups showed the greatest declines in the probability of a morbidity outcome ( PMO ) for total and severe illnesses , malaria , poor appetite , reduced activity , fever and chills . The Meat group showed significantly greater declines in PMO for gastroenteritis ( mainly diarrhoea ) and typhoid compared with the Control group , for jaundice compared with the Plain Githeri group , and for skin infection compared with the Milk group . The Milk group showed the greatest decline in PMO for upper respiratory infection . For nearly all morbidity outcomes the Control group had the highest PMO and the least decline over time . CONCLUSIONS The intervention study showed beneficial effects of both animal source foods and of vitamin A-fortified oil on morbidity status [17132678] Objective To evaluate the efficacy of milk fortified with specific multiple micronutrients on morbidity in children compared with the same milk without fortification . Design Community based , double masked , individually r and omised trial . Setting Peri-urban settlement in north India . Participants Children ( n=633 ) aged 1 - 3 r and omly allocated to receive fortified milk ( n=316 ) or control milk ( n=317 ) . Intervention One year of fortified milk providing additional 7.8 mg zinc , 9.6 mg iron , 4.2 � g selenium , 0.27 mg copper , 156 � g vitamin A , 40.2 mg vitamin C , 7.5 mg vitamin E per day ( three feeds ) . Main outcome measures Days with severe illnesses , incidence and prevalence of diarrhoea , and acute lower respiratory illness . Results Study groups were comparable at baseline ; compliance in the groups was similar . Mean number of episodes of diarrhoea per child was 4.46 ( SD 3.8 ) in the intervention ( fortified milk ) group and 5.36 ( SD 4.1 ) in the control group . Mean number of episodes of acute lower respiratory illness was 0.62 ( SD 1.1 ) and 0.83 ( SD 1.4 ) , respectively . The fortified milk reduced the odds for days with severe illnesses by 15 % ( 95 % confidence interval 5 % to 24 % ) , the incidence of diarrhoea by 18 % ( 7 % to 27 % ) , and the incidence of acute lower respiratory illness by 26 % ( 3 % to 43 % ) . Consistently greater beneficial effects were observed in children aged ≤24 months than in older children . Conclusion Milk is well accepted as a means of delivery of micronutrients . Consumption of milk fortified with specific micronutrients can significantly reduce the burden of common morbidities among preschool children , especially in the first two years of life . Trial registration NCT00255385 [16277798] OBJECTIVE To evaluate the efficacy of a community-based dietary intervention to reduce risk of micronutrient inadequacies in high-phytate maize-based Malawian diets . DESIGN Quasi-experimental post-test design with a non-equivalent control group . SETTING Four villages in Mangochi District , Southern Malawi . PARTICIPANTS Households with children aged 3 - 7 years in two intervention ( n = 200 ) and two control ( n = 81 ) villages participated in a 6-month intervention employing dietary diversification , changes in food selection patterns , and modifications to food processing to reduce the phytate content of maize-based diets . Baseline comparability between the groups was confirmed via assessment of sociodemographic characteristics , anthropometry , knowledge and practice s , morbidity , haemoglobin and hair zinc . After 12 months , knowledge and practice s and dietary intakes were assessed by interactive 24-hour recalls , one during the food plenty and a second during the food shortage season . Nutrient adequacy for the two groups was compared via dietary quality indicators and predicted prevalence of inadequate intakes using the probability approach . RESULTS Intervention children had diets that were significantly more diverse and of a higher quality than those of controls . Median daily intakes of protein , calcium , zinc ( total and available ) , haem iron , vitamin B12 and animal foods ( grams ; % of total energy ) were higher ( P < 0.05 ) whereas phytate intakes , phytate/zinc and phytate/iron molar ratios were lower ( P < 0.01 ) in the intervention group ; some spread of knowledge and practice s to controls occurred . CONCLUSIONS Our community-based dietary strategies reduced the predicted prevalence of inadequate intakes of protein , calcium , zinc and vitamin B12 , but not iron , in children from Malawian households with very limited re sources [5372889] Many children suffer from nutritional deficiencies that may negatively affect their academic performance . This cluster-r and omized controlled trial aim ed to test the effects of micronutrient-fortified milk in Chinese students . Participants received either micronutrient-fortified ( n = 177 ) or unfortified ( n = 183 ) milk for six months . Academic performance , motivation , and learning strategies were estimated by end-of-term tests and the Motivated Strategies for Learning Question naire . Blood sample s were analyzed for micronutrients . In total , 296 students ( 82.2 % ) completed this study . Compared with the control group , students in the intervention group reported higher scores in several academic subjects ( p < 0.05 ) , including language s , mathematics , ethics , and physical performance at the end of follow-up . Students in the intervention group showed greater self-efficacy and use of cognitive strategies in learning , and reported less test anxiety ( p < 0.001 ) . Moreover , vitamin B2 deficiency ( odds ratio ( OR ) = 0.18 , 95 % confidence interval ( CI ) : 0.11~0.30 ) and iron deficiency ( OR = 0.34 , 95 % CI : 0.14~0.81 ) were less likely in the students of the intervention group , whereas vitamin D , vitamin B12 , and selenium deficiencies were not significantly different . “ Cognitive strategy ” had a partial mediating effect on the test scores of English ( 95 % CI : 1.26~3.79 ) and Chinese ( 95 % CI : 0.53~2.21 ) . Our findings suggest that micronutrient-fortified milk may improve students ’ academic performance , motivation , and learning strategies [3671231] Background Interventions providing foods fortified with multiple micronutrients can be a cost-effective and sustainable strategy to improve micronutrient status and physical growth of school children . We evaluated the effect of micronutrient-fortified yoghurt on the biochemical status of important micronutrients ( iron , zinc , iodine , vitamin A ) as well as growth indicators among school children in Bogra district of Bangladesh . Methods In a double-masked r and omized controlled trial ( RCT ) conducted in 4 primary schools , 1010 children from classes 1–4 ( age 6–9 years ) were r and omly allocated to receive either micronutrient fortified yoghurt ( FY , n = 501 ) or non-fortified yoghurt ( NFY , n = 509 ) . For one year , children were fed with 60 g yoghurt everyday providing 30 % RDA for iron , zinc , iodine and vitamin A. Anthropometric measurements and blood/urine sample s were collected at base- , mid- and end-line . All children ( FY , n = 278 , NFY , n = 293 ) consenting for the end-line blood sample were included in the present analyses . Results Both groups were comparable at baseline for socio-economic status variables , micronutrient status markers and anthropometry measures . Compliance was similar in both the groups . At baseline 53.4 % of the population was anemic ; 2.1 % was iron deficient ( ferritin < 15.0 μg/L and TfR > 8.3 mg/L ) . Children in the FY group showed improvement in Hb ( mean difference : 1.5 ; 95 % CI : 0.4 - 2.5 ; p = 0.006 ) as compared to NFY group . Retinol binding protein ( mean diff : 0.05 ; 95 % CI : 0.002 - 0.09 ; p = 0.04 ) and iodine levels ( mean difference : 39.87 ; 95 % CI : 20.39 - 59.35 ; p < 0.001 ) decreased between base and end-line but the decrease was significantly less in the FY group . Compared to NFY , the FY group had better height gain velocity ( mean diff : 0.32 ; 95 % CI : 0.05 - 0.60 ; p = 0.02 ) and height-for-age z-scores ( mean diff : 0.18 ; 95 % CI : 0.02 - 0.33 ; p = 0.03 ) . There was no difference in weight gain velocity , weight-for-age z-scores or Body Mass Index z-scores . Conclusion In the absence of iron deficiency at baseline the impact on iron status would not be expected to be observed and hence can not be evaluated . Improved Hb concentrations in the absence of a change in iron status suggest improved utilization of iron possibly due to vitamin A and zinc availability . Fortification improved height gain without affecting weight gain . Trial registration Clinical Trial.gov : [4093981] Dietary lipids have been shown to increase bioavailability of provitamin A carotenoids from a single meal , but the effects of dietary lipids on conversion to vitamin A during absorption are essentially unknown . Based on previous animal studies , we hypothesized that the consumption of provitamin A carotenoids with dietary lipid would enhance conversion to vitamin A during absorption compared with the consumption of provitamin A carotenoids alone . Two separate sets of 12 healthy men and women were recruited for 2 r and omized , 2-way crossover studies . One meal was served with fresh avocado ( Persea americana Mill ) , cultivated variety Hass ( delivering 23 g of lipid ) , and a second meal was served without avocado . In study 1 , the source of provitamin A carotenoids was a tomato sauce made from a novel , high – β-carotene variety of tomatoes ( delivering 33.7 mg of β-carotene ) . In study 2 , the source of provitamin A carotenoids was raw carrots ( delivering 27.3 mg of β-carotene and 18.7 mg of α-carotene ) . Postpr and ial blood sample s were taken over 12 h , and provitamin A carotenoids and vitamin A were quantified in triglyceride-rich lipoprotein fractions to determine baseline-corrected area under the concentration-vs.-time curve . Consumption of lipid-rich avocado enhanced the absorption of β-carotene from study 1 by 2.4-fold ( P < 0.0001 ) . In study 2 , the absorption of β-carotene and α-carotene increased by 6.6- and 4.8-fold , respectively ( P < 0.0001 for both ) . Most notably , consumption of avocado enhanced the efficiency of conversion to vitamin A ( as measured by retinyl esters ) by 4.6-fold in study 1 ( P < 0.0001 ) and 12.6-fold in study 2 ( P = 0.0013 ) . These observations highlight the importance of provitamin A carotenoid consumption with a lipid-rich food such as avocado for maximum absorption and conversion to vitamin A , especially in population s in which vitamin A deficiency is prevalent . This trial was registered at clinical trials.gov as NCT01432210 [2921413] Background Multiple micronutrient deficiencies are highly prevalent among preschool children and often lead to anemia and growth faltering . Given the limited success of supplementation and health education programs , fortification of foods could be a viable and sustainable option . We report results from a community based double-masked , r and omized trial among children 1–4 years evaluating the effects of micronutrients ( especially of zinc and iron ) delivered through fortified milk on growth , anemia and iron status markers as part of a four group study design , running two studies simultaneously . Methods and Findings Enrolled children ( n = 633 ) were r and omly allocated to receive either micronutrients fortified milk ( MN = 316 ) or control milk ( Co = 317 ) . Intervention of MN milk provided additional 7.8 mg zinc , 9.6 mg iron , 4.2 µg selenium , 0.27 mg copper , 156 µg vitamin A , 40.2 mg vitamin C , and 7.5 mg vitamin E per day ( three serves ) for one year . Anthropometry was recorded at baseline , mid- and end- study . Hematological parameters were estimated at baseline and end- study . Both groups were comparable at baseline . Compliance was over 85 % and did not vary between groups . Compared to children consuming Co milk , children consuming MN milk showed significant improvement in weight gain ( difference of mean : 0.21 kg/year ; 95 % confidence interval [ CI ] 0.12 to 0.31 , p<0.001 ) and height gain ( difference of mean : 0.51 cm/year ; 95 % CI 0.27 to 0.75 , p<0.001 ) . Mean hemoglobin ( Hb ) ( difference of 13.6 g/L ; 95 % CI 11.1 to 16.0 , p<0.001 ) and serum ferritin levels ( difference of 7.9 µg/L ; 95 % CI 5.4 to 10.5 , p<0.001 ) also improved . Children in MN group had 88 % ( odds ratio = 0.12 , 95 % CI 0.08 to 0.20 , p<0.001 ) lower risk of iron deficiency anemia . Conclusions / Significance Milk provides an acceptable and effective vehicle for delivery of specific micronutrients , especially zinc and iron . Micronutrient bundle improved growth and iron status and reduced anemia in children 1–4 years old . Trial Registration Clinical Trials.gov [23999776] We studied the impact of a food supplementation program ( Plan Más Vida ( PMV ) ) on the micronutrient nutritional condition of pregnant women from low-income families 1 year after its implementation . The food program provided supplementary diet ( wheat and maize — fortified flour , rice or sugar , and fortified soup ) . We performed a prospect i ve , nonexperimental , cross-sectional study in the province of Buenos Aires , Argentina , evaluating pregnant women at baseline ( n = 164 ) and 1 year after PMV implementation ( n = 108 ) . Biochemical tests ( hemogram , ferritin , vitamin A , zinc , and folic acid ) , anthropometric assessment s ( weight and height ) , and dietary surveys ( 24 h recall ) were performed at the two study points . One year after PMV implementation , no significant changes in anthropometric values were observed . Folic acid deficiency and the risk of vitamin A deficiency ( retinol , 20–30 μg/dl ) decreased significantly ( 35.8 to 6.1 % and 64 to 41 % , respectively ; p < 0.000 ) . Anemia and prevalence of iron and zinc deficiency values did not change . Diet survey results showed that although nutrient intake increased significantly , it was still below recommendations . Implementation of the PMV and of the government nutritional strategies had a high impact on the prevalence of folic acid deficiency . We also observed a decrease in the risk of vitamin A deficiency , and no impact on iron and zinc nutritional status . Adherence to the specific fortified food ( soup ) was not good and intra-family dilution and distribution of food was high [1853789] Thirty elderly long-stay patients were r and omly allocated to receive either placebo or dietary supplementation with vitamins A , C and E for 28 days . Nutritional status and cell-mediated immune function were assessed before and after the period of supplementation . Following vitamin supplementation , cell-mediated immune function improved as indicated by a significant increase in the absolute number of T cells ( p less than 0.05 ) , T4 subsets ( p less than 0.05 ) , T4 to T8 ratio ( p less than 0.01 ) and the proliferation of lymphocytes in response to phytohaemagglutinin ( p less than 0.01 ) . In contrast , no significant changes were noted in the immune function of the placebo group . We conclude that supplementation with the dietary antioxidants vitamins A , C and E can improve aspects of cell-mediated immune function in elderly long-stay patients [8933117] OBJECTIVES This study assessed the effects of consuming a highly hydrogenated , vitamin A (VA)-fortified margarine not requiring refrigeration on VA status of preschool children . DESIGN A double-masked r and omized community trial . SETTING Six rural villages in Cavite , Southern Luzon , the Philippines . SUBJECTS 296 and 285 children 3 - 6 y of age in the VA-fortified ( experimental ) and non-fortified ( control ) margarine groups , respectively . INTERVENTION Each week for 6 months households were given 250 g of VA-fortified margarine [ providing 28.8 micrograms retinol equivalents ( RE ) per g ] or non-fortified ( 0 microgram RE ) margarine of identical appearance for each enrolled child . Children 's vitamin A status [ serum retinol , xerophthalmia , and conjunctival impression cytology ( CIC ) status ] and dietary intake were assessed at baseline and follow-up ; margarine intake was monitored throughout the study . RESULTS Daily margarine intake per child averaged 27 g in the experimental group ( providing 776 micrograms RE ) and 24 g ( 0 microgram RE ) in the control group . After 6 months , mean serum retinol increased from 26.4 to 28.8 micrograms/dl in the experimental group but decreased from 26.6 to 25.1 micrograms/dl in controls ( P < 0.001 at 6 months ) ; the multiple-adjusted increment over controls was 2.4 micrograms/dl ( P < 0.01 ) . More importantly , the prevalence of low serum retinol ( < 20 micrograms/dl ) decreased from 25.7 to 10.1 % in the experimental group but remained unchanged in controls ( 26.7 to 27.7 % ) ( P < 0.01 at 6 months ) . At follow-up no experimental children had developed xerophthalmia but 1.4 and 1.8 % of controls developed nightblindness and Bitot 's spots , respectively . There were no differences in CIC between groups . CONCLUSION Consumption of VA-fortified margarine significantly improved VA status of preschool Filipino children [11732150] Summary Single interventions for helminthic infections and micronutrient deficiencies are effective , but it is not clear whether combined interventions will provide equal , additive or synergistic effects to improve children 's health . The study objective was to determine the impact of single and combined interventions on nutritional status and scholastic and cognitive performance of school children . A double-blind , r and omized , placebo-controlled trial in 11 rural South African primary schools r and omly allocated 579 children aged between 8 and 10 years into six study groups , half of whom received antihelminthic treatment at baseline . The de-wormed and non-de-wormed arms were further divided into three groups and given biscuits , either unfortified or fortified with vitamin A and iron or with vitamin A only , given daily for 16 weeks . The outcome measures were anthropometric , micronutrient and parasite status , and scholastic and cognitive test scores . There was a significant treatment effect of vitamin A on serum retinol ( p < 0.01 ) , and the suggestion of an additive effect between vitamin A fortification and de-worming . Fortified biscuits improved micronutrient status in rural primary school children ; vitamin A with de-worming had a greater impact on micronutrient status than vitamin A fortification alone and antihelminthic treatment significantly reduced the overall prevalence of parasite infection . The burden of micronutrient deficiency ( anaemia , iron and vitamin A ) and stunting in this study population was low and , coupled with the restricted duration of the intervention ( 16 weeks ) , might have limited the impact of the interventions [19939650] BACKGROUND AND AIMS Several studies have suggested that polyunsaturated fatty acids , vitamins and minerals have beneficial effects on lipid profile and systemic inflammation in adults . METHODS AND RESULTS We examined the effects of a daily intake of milk enriched with longchain polyunsaturated fatty acids , oleic acid , carbohydrates , vitamins , minerals and low in saturated fatty acids ( SFAs ) for 5 months , on several cardiovascular ( CVD ) risk biomarkers in healthy children aged 8 - 14 years . In a r and omized double-blind placebo-controlled trial , a total of 107 children of both genders were assigned to two study groups : 1 ) a supplemented group ( SG , n=53 ) who consumed 0.6 L/day of an enriched dairy product , and 2 ) a control group ( CG , n=54 ) who consumed 0.6 L/day of st and ard whole milk . Both groups consumed the dairy drinks for 5 months , in addition to their usual diet . Serum levels of adhesion molecules as indices of vascular endothelial cell activation were assessed in both groups at 0 and 5 months as well as white blood cell counts , lipid profile , serum proteins , total serum calcium , 25-OH vitamin D , glucose , insulin and adiponectin . In the enriched dairy drink supplemented group , adhesion molecules E-selectin and ICAM-1 as well as lymphocyte levels decreased while plasma docosahexaenoic acid ( DHA ) and serum calcium concentrations increased . In the control group , serum total protein , transferrin , total cholesterol , HDL-cholesterol and adiponectin concentrations decreased . CONCLUSION The consumption of a milk enriched with fish oil , oleic acid , minerals and vitamins reduced indices of endothelial cell activation in the studied group of healthy children [16426962] OBJECTIVE We evaluated the effect of a micronutrient-fortified beverage on growth and morbidity in apparently healthy schoolchildren . METHODS This was a double-blind , placebo-controlled , matched-pair , cluster , r and omized study in semi-urban middle-income residential schoolchildren aged 6 to 16 y. Anthropometrics ( height and weight ) , clinical symptoms of deficiency , and morbidity data were collected at baseline in the supplemented group ( n = 446 in 10 grade s ) and the placebo group ( n = 423 in 10 grade s ) and after 14 mo of supplementation ( n = 355 in the supplement group and n = 340 in the placebo group from nine pairs ) . RESULTS After 14 mo of supplementation , there was a significant increase in mean increments of height and weight z scores of -0.04 and 0.02 , respectively , in the supplemented group compared with -0.14 and -0.09 in the placebo group . Velocity of weight ( 3.56 versus 3.00 ) was significantly ( P < 0.01 ) higher with supplementation . Although there were no differences in the incidence of common childhood diseases such as fever , cough and cold , diarrhea , and ear infections elicited for a reference period of 1 mo at every quarterly follow-up examination , the mean duration of illness ( calculated per person per year ) was significantly shorter ( 5.0 d ) in the supplemented group than in the placebo group ( 7.4 d ) . CONCLUSIONS The micronutrient-fortified beverage was beneficial in promoting growth and decreasing duration of common illnesses among middle-class residential schoolchildren who had adequate energy and protein intakes [20412603] OBJECTIVE To investigate the efficacy of biscuits fortified with different doses of vitamin A on improving vitamin A deficiency ( VAD ) , anaemia and physical growth of pre-school children . DESIGN A r and omised double-masked population -based field interventional trial with a positive control group . SETTING Banan district of Chongqing , China . SUBJECTS A total of 580 pre-school children aged 3 - 6 years were r and omly recruited into four groups . Children in groups I and II were given biscuits fortified with vitamin A at 30 % of the recommended daily intake ( RDA ) and 100 % of the RDA once a day for 9 and 3 months , respectively . Children in group III received biscuits containing 20,000 IU of vitamin A once a week for 3 months . Initially , the children in group IV received a 200,000 IU vitamin A capsule just once . At the beginning and end of the study , blood sample s were collected to measure Hb , serum retinol , retinol-binding protein and prealbumin , and weight and height were measured . RESULTS All the fortification types significantly decreased the prevalence of VAD and anaemia in each group ( P < 0.05 ) . The effect of 9-month intervention on group I was the most efficient ( P < 0.0045 ) . After intervention , the Z-scores of height-for-age , weight-for-age and weight-for-height in all groups increased markedly compared with baseline ( P < 0.05 ) , but no significant difference was observed among the groups . CONCLUSIONS Data indicated that consuming vitamin A-fortified biscuits with daily 100 % RDA for 3 months has the same effect on the improvement of VAD , anaemia and physical growth as did the weekly 20,000 IU and single 200,000 IU administration in pre-school children [18091768] Background / Objective : To develop a salt fortified with multiple micronutrients , to test its stability during storage and cooking , and to assess its efficacy in improving the micronutrient status and the health of schoolchildren . Subject/ Methods : A salt fortified with multiple micronutrients was developed containing chelated ferrous sulfate and microencapsulated vitamins A , B1 , B2 , B6 , B12 , folic acid , niacin , calcium pantothenate and iodine . Its stability during 20 min of cooking and 6 months of storage was determined . Thereafter , the efficacy of the salt was assessed in 5- to 15-year-old schoolchildren in Chennai , India . For the experimental group ( N=119 ) , the food in the school kitchen was cooked with fortified salt for a period of 1 year . The control group ( N=126 ) consisted of day scholars who did not eat at the school . Hemoglobin , red blood cell count , hematocrit , serum vitamin A and urinary iodine were measured at baseline and at the end of the study after 1 year . Results : All micronutrients were stable during cooking and storage . Over the study period , there was a significant improvement ( P<0.05 ) in hemoglobin , red cell count , urinary iodine and serum vitamin A in the experimental group , while there was a significant drop ( P<0.05 ) in hemoglobin , hematocrit , red cell count and urinary iodine in the control group . In the experimental group , there was a mean increase of 0.55 g/dl in hemoglobin , 0.001 l/l in hematocrit , 0.470 million/mm3 in red cell count , 212 μg/l in urinary iodine and 5.6 μg/dl in serum vitamin A. Conclusion : The study shows that the salt fortified with multiple micronutrients is stable during cooking and storage and effective in combating multiple micronutrient deficiencies [25591926] OBJECTIVE To assess oil consumption , vitamin A intake and retinol status before and a year after the fortification of unbr and ed palm oil with retinyl palmitate . DESIGN Pre-post evaluation between two surveys . SETTING Twenty-four villages in West Java . SUBJECTS Poor households were r and omly sample d. Serum retinol ( adjusted for sub clinical infection ) was analysed in cross-sectional sample s of lactating mothers ( baseline n 324/endline n 349 ) , their infants aged 6 - 11 months ( n 318/n 335 ) and children aged 12 - 59 months ( n 469/477 ) , and cohorts of children aged 5 - 9 years ( n 186 ) and women aged 15 - 29 years ( n 171 ) , alongside food and oil consumption from dietary recall . RESULTS Fortified oil improved vitamin A intakes , contributing on average 26 % , 40 % , 38 % , 29 % and 35 % of the daily Recommended Nutrient Intake for children aged 12 - 23 months , 24 - 59 months , 5 - 9 years , lactating and non-lactating women , respectively . Serum retinol was 2 - 19 % higher at endline than baseline ( P<0·001 in infants aged 6 - 11 months , children aged 5 - 9 years , lactating and non-lactating women ; non-significant in children aged 12 - 23 months ; P=0·057 in children aged 24 - 59 months ) . Retinol in breast milk averaged 20·5 μg/dl at baseline and 32·5 μg/dl at endline ( P<0·01 ) . Deficiency prevalence ( serum retinol < 20 μg/dl ) was 6·5 - 18 % across groups at baseline , and 0·6 - 6 % at endline ( P≤0·011 ) . In multivariate regressions adjusting for socio-economic differences , vitamin A intake from fortified oil predicted improved retinol status for children aged 6 - 59 months ( P=0·003 ) and 5 - 9 years ( P=0·03 ) . CONCLUSIONS Although this evaluation without a comparison group can not prove causality , retinyl contents in oil , Recommended Nutrient Intake contributions and relationships between vitamin intake and serum retinol provide strong plausibility of oil fortification impacting vitamin A status in Indonesian women and children [22244363] In Vietnam , nutrition interventions do not target school children despite a high prevalence of micronutrient deficiencies . The present r and omised , placebo-controlled study evaluated the impact of providing school children ( n 403 ) with daily multiple micronutrient-fortified biscuits ( FB ) or a weekly Fe supplement ( SUP ) on anaemia and Fe deficiency . Micronutrient status was assessed by concentrations of Hb , and plasma ferritin ( PF ) , transferrin receptor ( TfR ) , Zn and retinol . After 6 months of intervention , children receiving FB or SUP had a significantly better Fe status when compared with the control children ( C ) , indicated by higher PF ( FB : geometric mean 36·9 ( 95 % CI 28·0 , 55·4 ) μg/l ; SUP : geometric mean 46·0 ( 95 % CI 33·0 , 71·7 ) μg/l ; C : geometric mean 34·4 ( 95 % CI 15·2 , 51·2 ) μg/l ; P < 0·001 ) and lower TfR concentrations ( FB : geometric mean 5·7 ( 95 % CI 4·8 , 6·52 ) mg/l ; SUP : geometric mean 5·5 ( 95 % CI 4·9 , 6·2 ) mg/l ; C : geometric mean 5·9 ( 95 % CI 5·1 , 7·1 ) mg/l ; P = 0·007 ) . Consequently , body Fe was higher in children receiving FB ( mean 5·6 ( sd 2·2 ) mg/kg body weight ) and SUP ( mean 6·1 ( sd 2·5 ) mg/kg body weight ) compared with the C group ( mean 4·2 ( sd 3·3 ) mg/kg body weight , P < 0·001 ) . However , anaemia prevalence was significantly lower only in the FB group ( 1·0 % ) compared with the C group ( 10·4 % , P = 0·006 ) , with the SUP group being intermediate ( 7·4 % ) . Children receiving FB had better weight-for-height Z-scores after the intervention than children receiving the SUP ( P = 0·009 ) . Vitamin A deficiency at baseline modified the intervention effect , with higher Hb concentrations in vitamin A-deficient children receiving FB but not in those receiving the SUP . This indicates that vitamin A deficiency is implicated in the high prevalence of anaemia in Vietnamese school children , and that interventions should take other deficiencies besides Fe into account to improve Hb concentrations . Provision of biscuits fortified with multiple micronutrients is effective in reducing anaemia prevalence in school children [14760518] Excessive intake of vitamin A is postulated to have a detrimental effect on bone by inducing osteoporosis . This may lead to an increased risk of fracture , particularly in persons who are already at risk of osteoporosis . However , few studies have specifically examined the association of vitamin A intake through diet and supplement use , with fractures in a cohort of older , community-dwelling women . We prospect ively followed a cohort of 34,703 postmenopausal women from the Iowa Women ’s Health Study to determine if high levels of vitamin A and retinol intake through food and supplement use were associated with an increased risk of hip or all fractures . A semiquantitative food frequency question naire was used to obtain the participants ’ baseline vitamin A and retinol intake . Participants were followed for a mean duration of 9.5 years for incident self-reported hip and nonhip fractures . After multivariate adjustment , it was revealed that users of supplements containing vitamin A had a 1.18-fold increased risk of incident hip fracture ( n=525 ) compared with nonusers ( 95 % CI , 0.99 to 1.41 ) , but there was no evidence of an increased risk of all fractures ( n=6,502 ) among supplement users . There was also no evidence of a dose-response relationship in hip fracture risk with increasing amounts of vitamin A or retinol from supplements . Furthermore , our results showed no association between vitamin A or retinol intake from food and supplements , or food only , and the risk of hip or all fractures . In conclusion , we found little evidence of an increased risk of hip or all fractures with higher intakes of vitamin A or retinol among a cohort of older , postmenopausal women [28978232] Background : Industrial food fortification is a major strategy to improve dietary micronutrient intakes and prevent deficiencies . Zambia introduced m and atory sugar fortification with vitamin A , at a target of 10 mg/kg , in 1998 . Representative surveys conducted since that time do not support marked improvement in vitamin A status . Objective : To describe vitamin A concentrations in retail sugar , as well as vendor practice s , perceptions of fortified foods , and sugar use practice s. Methods : We conducted a census of sugar vendors in one Zambian community , capturing information on vendors , available br and s and packaging options , and storage conditions . We purchased all br and s and package types of sugar available at each vendor . In a 15 % sub sample , we conducted semi-structured interviews with vendor – consumer pairs . We tested 50 % of sugar sample s at r and om for vitamin A using an iCheck portable fluorimeter . Results : The distribution of vitamin A in sugar in market sample s was highly skewed , with a median of 3.1 mg/kg ( 25th-75th percentiles : 1.8 - 5.5 ) and a range from 0.2 to 29.9 mg/kg . Only 11.3 % of sample s met the 10 mg/kg statutory requirement . Sugar was primarily repackaged and sold in small quantities , with rapid turnover of stocks . Perceptions of fortification by vendors and consumers were generally positive . Conclusions : Vitamin A in fortified sugar fell well below statutory requirements . Our data point to challenges at regional depot and /or poor adherence to fortification st and ards at the factory level . A renewed commitment to monitoring and enforcement will be required for Zambia to benefit from a food fortification strategy [8914548] Malnutrition is an inclusive term that entails the lack , excess or imbalance of one or more nutrients required to maintain normal nutritional status and optimal health . Malnutrition affects a large segment of the world 's children . 1 It is estimated that the prevalence of childhood malnutrition in South Africa ranges from 5 % to 50 % of the current poputation.2 It is well documented that an inadequate intake of micronutrients causes deficiency disorders and that such deficiencies often accompany malnutrTtion . 3 The dietary intake of calcium , iron , zinc , folic acid , riboflavin , vitamin 86 and vitamin C has been reported to be low , in comparison with the recommended dietary allowances (RDA),4 in a significant proportion of children in the country ; it is often lower than 67 % of the RDA , indicating a population at risk of deficiency.s » In adults 15 - 64 years of age , the dietary intake of such micronutrients as vitamin 8 6 , iron , calcium , magnesium , zinc , copper and folic acid has also been reported to be significantly lower than the RDA.S , S Fortification of food staples has been successfully implemented in a number of countries to increase the dietary intake of micronutrients . [26001905] Objectives To study the impact of sorghum diet on growth , and micronutrient status of school going children for a period of 8 mo . Methods Children ( n = 160 boys and n = 160 girls ) aged between 9 to 12 y were r and omly allocated into two groups ( n = 80 in the control and n = 80 in the experimental group ) to receive 60 % sorghum diet and 40 % of rice diet ( Exp G ) and regular rice diet ( 100 % ; CG ) . Anthropometric indices and biochemical parameters were measured at baseline and at 8 mo using st and ardized methods . Results The growth rate was significantly higher ( p < 0.01 ) in the Exp G of girls , whereas in boys it was in the CG . Hemoglobin ( Hb ) , serum ferritin , albumin , retinol binding protein ( RBP ) and iron levels were significantly improved ( p < 0.05 ) in the Exp G of both the genders and in boys , serum folic acid and calcium levels were also improved with sorghum diet . Conclusions Serum micronutrient status , in terms of hemoglobin , serum folic acid , albumin , RBP , ferritin , calcium and iron can be improved with sorghum supplementation in school going children [23256139] Vitamin A ( VA ) deficiency ( VAD ) continues to be a major nutritional problem in developing countries , including Central America . In Mexico , milk is a well-accepted vehicle for the administration of micronutrients , including VA , to preschoolers . Thus , we conducted a r and omized , controlled , clinical trial to investigate the efficacy of daily consumption of 250 mL of VA-fortified milk ( which provided 196 retinol equivalents/d ) for 3 mo on VA stores in mildly to moderately VAD ( serum retinol concentration 0.35 - 0.7 μmol/L ) preschoolers who were not enrolled in a food assistance program . Twenty-seven mildly to moderately VAD children were r and omly assigned based on screening measurements to either the intervention ( n = 14 ) or control group ( n = 13 ) ( children in the control group did not receive placebo ) . All children in the control group and 79 % ( n = 11 ) of the children in the intervention group completed the study . The total body VA ( TBVA ) pool size was estimated using the deuterated retinol dilution technique before and after the intervention . After 3 mo , median changes in the serum retinol concentration for the intervention and control groups were 0.13 and -0.21 μmol/L , respectively ( P = 0.009 ) . Median changes in the TBVA stores were 0.06 and 0.01 mmol , respectively ( P = 0.006 ) and estimated median changes in the liver VA concentration were 0.09 and 0.01 μmol/g , respectively ( P = 0.002 ) . The VA-fortified milk was well accepted among preschoolers and significantly increased TBVA stores , liver VA stores , and serum retinol concentration , indicating that it may be an effective means to ameliorate VAD in young Mexican children [12462948] It was investigated the efficacy of a diet with caloric restriction ( 1350 kcal/day ) in correction of clinical and biochemical parameters in patients with type 2 diabetes mellitus with overweight and obesity . In study showed that the 3 week use of hypocaloric diet allows reduce significantly body overweight , hyperglycemia and hyperholesterolemia in this patients without side effects . Vitamin and mineral supplements in long use of hypocaloric diet are recommended [19321576] Concurrent micronutrient deficiencies are prevalent among Vietnamese school children . A school-based program providing food fortified with multiple micronutrients could be a cost-effective and sustainable strategy to improve health and cognitive function of school children . However , the efficacy of such an intervention may be compromised by the high prevalence of parasitic infestation . To evaluate the efficacy of school-based intervention using multi-micronutrient-fortified biscuits with or without deworming on anemia and micronutrient status in Vietnamese schoolchildren , a r and omized , double-blind , placebo-controlled trial was conducted among 510 primary schoolchildren , aged 6 - 8 y , in rural Vietnam . Albendazole ( Alb ) ( 400 mg ) or placebo was given at baseline . Nonfortified or multi-micronutrient-fortified biscuits including iron ( 6 mg ) , zinc ( 5.6 mg ) , iodine ( 35 microg ) , and vitamin A ( 300 microg retinol equivalents ) were given 5 d/wk for 4 mo . Multi-micronutrient fortification significantly improved the concentrations of hemoglobin ( + 1.87 g/L ; 95 % CI : 0.78 , 2.96 ) , plasma ferritin ( + 7.5 microg/L ; 95 % CI : 2.8 , 12.6 ) , body iron ( + 0.56 mg/kg body weight ; 95 % CI : 0.29 , 0.84 ) , plasma zinc ( + 0.61 micromol/L ; 95 % CI : 0.26 , 0.95 ) , plasma retinol ( + 0.041 micromol/L ; 95 % CI : 0.001 , 0.08 ) , and urinary iodine ( + 22.49 micromol/L ; 95 % CI : 7.68 , 37.31 ) . Fortification reduced the risk of anemia and deficiencies of zinc and iodine by > 40 % . Parasitic infestation did not affect fortification efficacy , whereas fortification significantly enhanced deworming efficacy , with the lowest reinfection rates in children receiving both micronutrients and Alb . Multi-micronutrient fortification of biscuits is an effective strategy to improve the micronutrient status of Vietnamese schoolchildren and enhances effectiveness of deworming [25441589] OBJECTIVE The aim of this study was to assess the vitamin A and anthropometric status of South African preschool children from four areas with known distinct eating patterns . METHODS Serum retinol , anthropometric indicators , and dietary intake were determined for r and omly selected preschool children from two rural areas , i.e. KwaZulu-Natal ( n = 140 ) and Limpopo ( n = 206 ) ; an urban area in the Northern Cape ( n = 194 ) ; and an urban metropolitan area in the Western Cape ( n = 207 ) . RESULTS Serum retinol < 20 μg/dL was prevalent in 8.2 % to 13.6 % children . Between 3 % ( urban-Northern Cape ) and 44.2 % ( rural-Limpopo ) children had received a high-dose vitamin A supplement during the preceding 6 mo . Vitamin A derived from fortified bread and /or maize meal ranged from 65 μg retinol activity equivalents ( 24%-31 % of the Estimated Average Requirement ) to 160 μg retinol activity equivalents ( 58%-76 % Estimated Average Requirement ) . Fortified bread and /or maize meal contributed 57 % to 59 % of total vitamin A intake in rural children , and 28 % to 38 % in urban children . Across the four areas , stunting in children ranged from 13.9 % to 40.9 % ; and overweight from 1.2 % to 15.1 % . CONCLUSION Prevalence of vitamin A deficiency was lower than national figures , and did not differ across areas despite differences in socioeconomics , dietary intake , and vitamin A supplementation coverage . Rural children benefited more from the national food fortification program in terms of vitamin A intake . Large variations in anthropometric status highlight the importance of targeting specific nutrition interventions , taking into account the double burden of overnutrition and undernutrition [22908698] Background Fortification of flour is one of the approaches for the control and prevention of vitamin and mineral deficiencies . Objective To assess the effect of fortification of flour with seven vitamins and minerals on a population of Chinese women . Methods Farmers who offered their l and for reforestation in 25 northwest provinces of China received compensation in the form of wheat flour ; the amount of flour given depended on the amount of l and that was given up for reforestation . This study observed the effects of providing families with fortified flour in the reforestation areas in Gansu Province . The study was conducted for 3 years . Families in the intervention village who offered l and for reforestation received flour fortified with seven vitamins and minerals , and those in the control village received unfortified flour . Seven surveys , spaced at least 6 months apart , were carried out in each village from 2004 to 2007 . At baseline and at each annual survey , measurements and blood sample s were taken from 300 adult female subjects aged 20 to 60 years to assess dietary intake , height , weight , body fat , hemoglobin , serum retinol , serum iron , free erythrocyte protoporphyrin , serum zinc . Serum folic acid was measured at baseline and 36-month only . At each 6-month survey , data were collected on anthropometric features , hemoglobin , and dietary intake . Results Consumption of fortified flour in the intervention village ranged from 158.7 to 232.7 g per person per day . Serum retinol status was significantly improved after 12-month intervention until the end of the trial compared with both the control group and the baseline level of the intervention group . Iron status expressed as FEP and SI levels showed higher than that of the control group and baseline levels only at 36-month . Hemoglobin levels of the intervention group were higher than that of the control group and baseline levels , but anemia prevalence of both the intervention and control groups remained unchanged in the intervention period . Levels of serum zinc showed increases compared with the control group and baseline data at 24-month and 36-month , and levels of serum folic acid of intervention group in 36-month was higher than that of both the control group and baseline level . Conclusions The evidence from this study confirms the positive bioeffectiveness of fortified flour in the rural female population in China , but a higher dosage of electrolytic elementary iron in flour fortification was suggested for anemia prevention and control [16153327] OBJECTIVE To evaluate the effectiveness of a vitamin-fortified maize meal to improve the nutritional status of 1 - 3-year-old malnourished African children . DESIGN A r and omised parallel intervention study was used in which 21 experimental children and their families received maize meal fortified with vitamin A , thiamine , riboflavin and pyridoxine , while 23 control children and their families received unfortified maize meal . The maize meal was provided for 12 months to replace the maize meal habitually consumed by these households . METHODS Sixty undernourished African children with height-for-age or weight-for-age below the 5th percentile of the National Center for Health Statistics ' criteria and aged 1 - 3 years were r and omly assigned to an experimental or control group . Baseline measurements included demographic , socio-economic and dietary data , as well as height , weight , haemoglobin , haematocrit , serum retinol and retinol-binding protein ( RBP ) . Anthropometric , blood and serum variables were measured again after 12 months of intervention . Complete baseline measurements were available for 44 children and end data for only 36 . Changes in these variables from baseline to end within and between groups were assessed for significance with paired t-tests , t-tests and analysis of variances using the SPSS program , controlling for expected weight gain in this age group over 12 months . Relationships between changes in variables were examined by calculating correlation coefficients . RESULTS The children in the experimental group had a significantly ( P < or = 0.05 ) higher increase in body weight than control children ( 4.6 kg vs. 2.0 kg ) and both groups had significant ( P < or = 0.05 ) but similar increases in height . The children in the experimental group showed non-significant increases in haemoglobin and serum retinol , while the control children had a significant ( P = 0.007 ) decrease in RBP . The change in serum retinol showed a significant correlation with baseline retinol ( P = 0.014 ) , RBP ( P = 0.007 ) and weight ( P = 0.029 ) , as well as with changes in haemoglobin ( P = 0.029 ) . CONCLUSION Despite a small sample size , this study showed positive effects of a vitamin-fortified maize meal on weight gain and some variables of vitamin A status in 1 - 3-year-old African children . The study confirmed the relationship between vitamin A and iron status . The results suggest that fortification of maize meal would be an effective strategy to address micronutrient deficiencies in small children in South Africa [20439555] Objective : To determine the efficacy of p and esal baked from wheat flour fortified with iron , with or without vitamin A ( VA ) , in improving anemic schoolchildren 's iron and anthropometric status . Methods : Anemic 6- to 12-year-old Filipino children ( n = 250 ) received two 60 g p and esal daily for 8 months . They were r and omized into 1 of 4 groups : ( 1 ) iron-fortified ( with hydrogen-reduced iron at 80 mg/kg , electrolytic iron at 80 mg/kg , or ferrous fumarate at 40 mg/kg ) , ( 2 ) iron and VA-fortified , ( 3 ) VA-fortified ( at 490 RE/100 g ) , and ( 4 ) nonfortified flour . Hemoglobin ( Hb ) and zinc protoporphyrin ( ZnPP ) concentrations and weight and height were determined before and after intervention . Analyses of variance and chi-square and multiple regression analyses were performed . Results : Mean Hb increased by 1.3 g/dL ( p < 0.001 ) and mean ZnPP decreased by 24.4 µmol/mol ( p < 0.001 ) after 8 months . Anemia decreased to 26 % and iron deficiency decreased from 58 % to 12 % . After controls were applied for baseline concentration , age , and gender , Hb concentration at post intervention was significantly higher in the Iron + VA group than in the nonfortified group ( coefficient = 0.37 ; p = 0.034 ) . The odds of being iron deficient at post intervention were significantly lower in the Iron group than in the nonfortified group after controls were applied for age , gender , and baseline prevalence ( coefficient = 0.12 ; p = 0.006 ) . None of the 3 fortified groups had significantly different weight-for-age z-score , body mass index-for-age z-score , or height-for-age z-score compared with the nonfortified group after controls were applied for baseline z-scores , age , and gender . Conclusions : Our study shows that in a non – malaria-endemic area , iron fortification of flour significantly reduced the prevalence of iron deficiency among anemic schoolchildren , and double fortification with iron and VA significantly improved Hb status [23800099] Food fortification is a cost-effective and sustainable strategy to prevent or correct micronutrient deficiencies . A double-blind cluster ( bari ) r and omised controlled trial was conducted in a rural community in Bangladesh to evaluate the impact of consumption of chapatti made of micronutrient-fortified wheat flour for 6 months by school-aged children on their vitamin A , haemoglobin and iron status . A total of 43 baris ( group of households ) were r and omly selected . The baris were r and omly assigned to either intervention or control group . The intervention group received wheat flour fortified with added micronutrients ( including 66 mg hydrogen-reduced elemental iron and 3030 μg retinol equivalent as retinyl palmitate per kilogram of flour ) , while the control group received wheat flour without added micronutrients . A total of 352 children were enrolled in the trial , 203 in the intervention group and 149 in the control group . Analyses were carried out on children who completed the study ( 191 in the intervention group and 143 in the control group ) . Micronutrient-fortified wheat flour chapatti significantly increased serum retinol concentration at 6 months by 0.12 μmol L(-1 ) [ 95 % confidence interval ( CI ) : 0.06 , 0.19 ; P < 0.01 ] . The odds of vitamin A deficiency was significantly lower for children in the intervention group at 3 months [ odds ratio ( OR ) = 0.26 ; 95 % confidence interval ( CI ) : 0.07 , 0.89 ; P < 0.05 ] and 6 months ( OR = 0.21 ; 95 % CI : 0.06 , 0.68 ; P < 0.01 ) . No demonstrable effect of fortified chapatti consumption on iron status , haemoglobin levels or anaemia was observed . Consumption of fortified chapattis demonstrated a significant improvement in the vitamin A status , but not in iron , haemoglobin or anaemia status [20605698] OBJECTIVE Improvement of hemoglobin and serum retinol and facilitation of the mobilization of iron storage were achieved with a multiple-micronutrient-fortified diet in preschoolers for 6 mo in a suburb of Chongqing , China . We investigated whether fortification with multiple micronutrients in a diet for preschool children results in changes in children 's infectious morbidity compared with diets fortified solely with vitamin A and with vitamin A plus iron . METHODS From December 2005 to June 2006 , 226 2- to 6-y-old preschool children were recruited from three nurseries r and omly assigned to three different fortified-diet groups for 6 mo . Group I was fortified with vitamin A ; groups II and III were fortified with vitamin A plus iron and vitamin A plus iron , thiamine , riboflavin , folic acid , niacinamide , zinc , and calcium , respectively . The secondary functional outcomes , morbidity of diarrhea and respiratory infection , were collected during supplementation . RESULTS The groups were comparable concerning compliance and loss to follow-up . There was evidence of a lower incidence rate of respiratory-related illnesses , diarrhea-related illness , fewer symptoms of runny nose , cough , and fever , and shorter duration of respiratory-related illnesses and cough for children in group III compared with children in groups I and II . However , there was no significantly or clinical ly important difference between children in groups I and II . CONCLUSION The beneficial effects on infectious morbidity over 6 mo , in addition to some biochemical improvements , highlight the potential of this micronutrient-fortified seasoning powder supplied in a diet for preschool children [20410083] Anemia and micronutrient deficiencies are common among Indian schoolchildren . We assessed the effectiveness of micronutrient fortification of meals cooked and fortified at school on anemia and micronutrient status of schoolchildren in Himalayan villages of India . In this placebo-controlled , cluster-r and omized study , 499 schoolchildren ( 6 - 10 y ) received either multiple micronutrients ( treatment group ) or placebo ( control group ) as part of school meals ( 6 d/wk ) for 8 mo . Both groups were dewormed at the beginning of the study . The micronutrient premix provided 10 mg iron , 375 microg vitamin A , 4.2 mg zinc , 225 microg folic acid , and 1.35 microg vitamin B-12 for each child per day ( approximately 75 % recommended dietary allowance ) . Blood sample s drawn before and after the intervention were analyzed for hemoglobin , ferritin , retinol , zinc , folate , and vitamin B-12 . Baseline prevalence of anemia ( 37 % ) , iron deficiency anemia ( 10 % ) , low serum ferritin ( 24 % ) , retinol ( 56 % ) , zinc ( 74 % ) , folate ( 68 % ) , and vitamin B-12 ( 17 % ) did not differ between groups . Postintervention , fewer in the treatment group had lower serum retinol [ odds ratio ( OR ) ( 95 % CI ) : 0.57 ( 0.33 - 0.97 ) ] and folate [ OR ( 95 % CI ) : 0.47 ( 0.26 - 0.84 ) ] than the control group . The serum vitamin B-12 concentration decreased in both groups , but the magnitude of change was less in the treatment than in the control group ( P < 0.05 ) . Total body iron ( TBI ) increased in both groups ; however , the change was greater in the treatment than in the control group ( P < 0.05 ) . Micronutrient fortification of school meals by trained school personnel was effective in improving vitamin A , folate , and TBI status while also reducing the magnitude of a decrease in vitamin B-12 status

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### Context: [24139824] BACKGROUND Provision of fortified juices may provide a convenient method to maintain and increase blood fat-soluble vitamins . OBJECTIVE To determine whether children consuming orange juice fortified with calcium and combinations of vitamins D , E , and A could increase serum 25-hydroxyvitamin D [ 25(OH)D ] , α-tocopherol , and retinol levels . DESIGN A 12-week r and omized , double-blind , controlled trial . PARTICIPANTS / SETTING One hundred eighty participants ( aged 8.04±1.42 years ) were recruited at Tufts ( n=70 ) and Boston University ( n=110 ) during 2005 - 2006 . Of those recruited , 176 children were r and omized into three groups : CaD ( 700 mg calcium+200 IU vitamin D ) , CaDEA ( 700 mg calcium+200 IU vitamin D+12 IU vitamin E+2,000 IU vitamin A as beta carotene ) , or Ca ( 700 mg calcium ) . Children consumed two 240-mL glasses of CaD , CaDEA , or Ca fortified orange juice daily for 12 weeks . MAIN OUTCOME MEASURES Serum 25(OH)D , α-tocopherol , and retinol concentrations . STATISTICAL ANALYSES Changes in 25(OH)D , α-tocopherol , retinol , and parathyroid hormone concentrations were examined . Covariates included sex , age , race/ethnicity , body mass index , and baseline 25(OH)D , α-tocopherol , retinol , or parathyroid hormone levels . Multivariate models and repeated measures analysis of variance tested for group differences with pre-post measures ( n=141 ) . RESULTS Baseline 25(OH)D was 68.4±27.7 nmol/L ( 27.4±11.10 ng/mL ) ) , with 21.7 % of participants having inadequate 25(OH)D ( < 50 nmol/L [ 20.03 ng/mL ] ) . The CaD group 's 25(OH)D increase was greater than that of the Ca group ( 12.7 nmol/L [ 5.09 ng/mL ] , 95 % CI 1.3 to 24.1 ; P=0.029 ) . The CaDEA group 's increase in α-tocopherol concentration was greater than that in the Ca or CaD groups ( 3.79 μmol/L [ 0.16 μg/mL ] , 95 % CI 2.5 to 5.1 and 3.09 μmol/L [ 0.13 μg/mL ] , 95 % CI -1.8 to 4.3 ) , respectively ( P<0.0001 ) . Retinol levels did not change , and body weight remained as expected for growth . CONCLUSIONS Daily consumption of orange juice providing 200 IU vitamin D and 12 IU vitamin E increased 25(OH)D and α-tocopherol concentrations in young children within 12 weeks [20529401] OBJECTIVE To assess the effect of an improved local ingredient-based gruel fortified or not with selected multiple micronutrients ( MM ) on Hb concentration of young children . DESIGN In a nutrition centre that we opened in their villages , children received either MM supplement ( containing iron , zinc , vitamin A , vitamin C and iodine ) with the improved gruel ( MMGG ) or the improved gruel only ( GG ) , twice daily , 6 d/week , for 6 months . We assessed baseline and endpoint Hb concentration and anthropometric indices . SETTING Kongoussi , a rural and poor district of Burkina Faso . SUBJECTS In a community-based trial , we r and omly assigned 131 children aged 6 - 23 months with Hb concentrations in the range of 80 - 109 g/l into two groups . RESULTS The groups did not differ significantly at baseline . Mean baseline Hb concentration was 89·2 ( sd 6·5 ) g/l and 90·3 ( sd 8·4 ) g/l in the GG and the MMGG , respectively ( P = 0·42 ) . It increased to 104·1 ( sd 11·4 ) g/l in the GG ( P < 0·001 ) and 107·6 ( sd 14·7 ) g/l in the MMGG ( P < 0·001 ) . The between-group difference of 3·5 ( 95 % CI -1·0 , 8·1 ) g/l in mean ( sd ) endpoint Hb concentration was not significant ( P = 0·13 ) . The endpoint anthropometric indices were not different between the groups . CONCLUSIONS This MM supplement had no additional effect on Hb concentration . Thorough studies are needed to evaluate the actual efficacy of the gruel before its introduction into household routine [19455176] Objective : ( 1 ) To determine whether nutritional supplementation ( energy and micronutrients ) in institutionalised elderly has a positive effect on dietary intake and nutritional status . ( 2 ) To investigate whether individuals tend to compensate for the energy content of the intervention product by decreasing their habitual food consumption . Methods : A 24-week , r and omised , double-blind , placebo-controlled , intervention trial in homes for the elderly ( n=3 ) , in nursing homes ( n=3 ) and ‘ mixed ’ homes ( n=3 ) in The Netherl and s. Institutionalised elderly people ( n=176 ) older than 60 years of age , with a body mass index ⩽30 kg/m2 and a Mini-Mental State Examination score of 10 points or higher , r and omly received a nutrient-enriched drink or a placebo drink twice a day during 24 weeks in addition to their usual diet . Allocation to treatment took into account of sex , the Mini-Mental State Examination score and the plasma homocysteine level . Body weight and several nutrition-related analyses in fasting blood sample s were measured in all participants . Data on dietary intake were collected in a sub sample ( n=66 ) . Results : A significantly favourable effect ( P<0.001 ) of the intervention drink was observed on vitamin intake , mineral intake and vitamin status in blood ( for example , homocysteine decreased from 14.7 to 9.5 μmol/l in the intervention group as compared with that in the placebo group ( 17.2–15.9 ) ) . The difference in change in total energy intake between the two treatment groups was 0.8 MJ/day ( P=0.166 ) . Energy intake from food decreased in both groups to the same extent ( −0.5 MJ/day ) . Therefore , this decrease can not be considered as compensation for the energy content of the product . Conclusions : This group of institutionalised elderly people does not compensate for the energy content of a concentrated nutritional supplement . Therefore , this supplement is effective for counteracting the development of malnutrition in this population [3217058] Objective To investigate the effects of delayed umbilical cord clamping , compared with early clamping , on infant iron status at 4 months of age in a European setting . Design R and omised controlled trial . Setting Swedish county hospital . Participants 400 full term infants born after a low risk pregnancy . Intervention Infants were r and omised to delayed umbilical cord clamping ( ≥180 seconds after delivery ) or early clamping ( ≤10 seconds after delivery ) . Main outcome measures Haemoglobin and iron status at 4 months of age with the power estimate based on serum ferritin levels . Secondary outcomes included neonatal anaemia , early respiratory symptoms , polycythaemia , and need for phototherapy . Results At 4 months of age , infants showed no significant differences in haemoglobin concentration between the groups , but infants subjected to delayed cord clamping had 45 % ( 95 % confidence interval 23 % to 71 % ) higher mean ferritin concentration ( 117 μg/L v 81 μg/L , P<0.001 ) and a lower prevalence of iron deficiency ( 1 ( 0.6 % ) v 10 ( 5.7 % ) , P=0.01 , relative risk reduction 0.90 ; number needed to treat=20 ( 17 to 67 ) ) . As for secondary outcomes , the delayed cord clamping group had lower prevalence of neonatal anaemia at 2 days of age ( 2 ( 1.2 % ) v 10 ( 6.3 % ) , P=0.02 , relative risk reduction 0.80 , number needed to treat 20 ( 15 to 111 ) ) . There were no significant differences between groups in postnatal respiratory symptoms , polycythaemia , or hyperbilirubinaemia requiring phototherapy . Conclusions Delayed cord clamping , compared with early clamping , result ed in improved iron status and reduced prevalence of iron deficiency at 4 months of age , and reduced prevalence of neonatal anaemia , without demonstrable adverse effects . As iron deficiency in infants even without anaemia has been associated with impaired development , delayed cord clamping seems to benefit full term infants even in regions with a relatively low prevalence of iron deficiency anaemia . Trial registration Clinical Trials NCT01245296 [12663288] BACKGROUND Dietary supplements providing physiologic amounts of several micronutrients simultaneously have not been thoroughly tested for combating micronutrient deficiencies . OBJECTIVE We determined whether a beverage fortified with 10 micronutrients at physiologic doses influenced the iron and vitamin A status and growth of rural children ( aged 6 - 11 y ) attending primary schools . DESIGN In this r and omized , double-blind , placebo-controlled efficacy trial , children were assigned to receive the fortified beverage or an unfortified beverage at school for 6 mo . RESULTS There were nonsignificant differences at baseline between children in the fortified and nonfortified groups in iron status , serum retinol , and anthropometry . At the 6-mo follow-up , among children with anemia ( hemoglobin < 110 g/L ) , there was a significantly larger increase in hemoglobin concentration in the fortified group than in the nonfortified group ( 9.2 and 0.2 g/L , respectively ) . Of those who were anemic at baseline , 69.4 % in the nonfortified group and 55.1 % in the fortified group remained anemic at follow-up ( RR : 0.79 ) , a cure rate of 21 % . The prevalence of children with low serum retinol concentrations ( < 200 microg/L ) dropped significantly from 21.4 % to 11.3 % in the fortified group compared with a nonsignificant change ( 20.6 % to 19.7 % ) in the nonfortified group . At follow-up , mean incremental changes in weight ( 1.79 compared with 1.24 kg ) , height ( 3.2 compared with 2.6 cm ) , and BMI ( 0.88 compared with 0.53 ) were significantly higher in the fortified group than in the nonfortified group . CONCLUSION The fortified beverage significantly improved hematologic and anthropometric measurements and significantly lowered the overall prevalence of anemia and vitamin A deficiency [11477464] Objective : To determine the effect of a biscuit with red palm oil as a source of β-carotene on the vitamin A status of primary school children and to compare this with the effect of a biscuit with β-carotene from a synthetic source . Design : R and omised controlled trial . Setting : A rural community in KwaZulu-Natal , South Africa . Subjects : A total of 437 primary school children , aged 5–11 y ; 400 completed the study .Intervention : Subjects were r and omly assigned to one of three groups , receiving , respectively : ( i ) a placebo biscuit ; ( ii ) a biscuit with synthetic β-carotene as a vitamin A fortificant ( SB ) ; ( iii ) a biscuit with red palm oil as a source of β-carotene ( PB ) ; SB and PB supplied 30 % of the RDA for vitamin A per serving of three biscuits . Biscuits were distributed daily during the school week ; vitamin A status was assessed at baseline and after 3 months . Results : There was a significant improvement in serum retinol compared to the control group in both the SB and PB groups ( P<0.005 ) ; the treatment effect for the two groups was equivalent ( difference in treatment effect 0.62 µg/dl , with a 90 % CI−0.33–1.57 ) . Conclusions : A biscuit with red palm oil as a source of β-carotene is as effective as a biscuit with synthetic β-carotene in improving the vitamin A status of primary school children . The additional qualities of red palm oil ( ie no trans fatty acids ; rich source of antioxidants ) make it an excellent alternative fortificant for addressing vitamin A deficiency . Sponsorship : Financial support from Palm Oil Research Institute of Malaysia (PORIM).European Journal of Clinical Nutrition ( 2001 ) 55 , [16702330] Anemia and co-existing deficiencies of zinc , iron , iodine , and vitamin A occur among children in many developing countries including NE Thail and , probably contributing to impairments in growth , immune competence , and cognition . Sustainable strategies are urgently required to combat these deficiencies . We assessed the efficacy of a micronutrient-fortified seasoning powder served with a school lunch on reducing anemia and improving the micronutrient status of rural NE Thai children . Children ( n = 569 ) aged 5.5 - 13.4y from 10 schools were r and omly assigned to receive a seasoning powder either unfortified or fortified with zinc ( 5 mg ) , iron ( 5 mg ) , vitamin A ( 270 microg ) , and iodine ( 50 microg ) ( per serving ) and incorporated into a school lunch prepared central ly and delivered 5 d/wk for 31 wk . Teachers monitored school lunch consumption . Baseline and final micronutrient status , hemoglobinopathies , and infection or inflammation were assessed from blood and urine sample s. For the primary outcome , anemia ( based on hemoglobin ) , no intervention effect was apparent ( odds ratio : 1.02 95 % CI : 0.69 , 1.51 ) after adjustment for design strata . The odds of zinc ( based on serum zinc ) and urinary iodine deficiency in the fortified group were 0.63 ( 0.42 , 0.94 ) and 0.52 ( 0.38 , 0.71 ) times those in the unfortified group , respectively . Fortification had no effect on serum retinol ( 0.61 : 0.25,1.51 ) , ferritin ( 1.12 : 0.43 , 2.96 ) , or mean red cell volume ( 1.16 : 0.82 , 1.64 ) . Therefore , a micronutrient-fortified seasoning powder is a promising vehicle for improving zinc , iodine , and hemoglobin status , and its potential for incorporation into lunch programs in day care centers and schools in NE Thail and warrants investigation [12771326] Due to their widespread acceptability , multinutrient-fortified foods and beverages may be useful in reducing micronutrient deficiencies , especially in developing countries . We studied the efficacy of a new fortified beverage in improving the nutritional status of children in Botswana . We screened 311 lower income urban school children , ages 6 - 11 y , in two primary schools near Gaborone . Children were given seven 240-mL servings weekly of either an experimental beverage ( EXP ) fortified with 12 micronutrients or an isoenergetic placebo drink ( CON ) for 8 wk . Weight , mid-upper arm circumference , hemoglobin , retinol , ferritin , vitamin B-12 , folate and riboflavin status were measured at baseline and at the end of the study . Plasma zinc and serum transferrin receptors also were measured at study end . A total of 145 children in the EXP group and 118 in the CON group completed the trial . Using multivariate analysis , the changes in mid-upper arm circumference , weight for age and total weight were significantly better in the EXP group than in the CON group ( P < 0.01 ) . Ferritin , riboflavin and folate status were significantly better in the EXP group than in the CON group at study end ( P < 0.01 ) , but serum vitamin B-12 was not . Zinc was significantly higher and transferrin receptors were significantly lower at the conclusion of the study in the EXP group than in the CON group ( P < 0.001 ) . Mean plasma retinol concentrations , which were low ( < 0.7 micro mol/L ) in both groups , did not change . We conclude that a micronutrient-fortified beverage may be beneficial as part of a comprehensive nutritional supplementation program in population s at risk for micronutrient deficiencies [17921387] BACKGROUND Little is known about the combined effect of micronutrients and essential fatty acids on cognitive function in school-aged children . OBJECTIVE We assessed the effect of micronutrients , long-chain n-3 fatty acids , or both on indicators of cognitive performance in well-nourished and marginally nourished school-aged children . DESIGN Two 2-by-2 factorial r and omized controlled double-blind trials were performed home-based in Adelaide , South Australia , and at 6 primary schools in Jakarta , Indonesia . A total of 396 children ( aged 6 - 10 y ) in Australia and 384 children in Indonesia were r and omly allocated to receive a drink with a micronutrient mix ( iron , zinc , folate , and vitamins A , B-6 , B-12 , and C ) , with docosahexanoic acid ( DHA , 88 mg/d ) and eicosapentaenoic acid ( EPA , 22 mg/d ) , or with both or placebo 6 d/wk for 12 mo . Biochemical indicators were determined at baseline and 12 mo . Cognitive performance was measured at baseline , 6 mo , and 12 mo . RESULTS The micronutrient treatment significantly improved plasma micronutrient concentrations in Australian and Indonesian children . DHA+EPA treatment increased plasma DHA and total plasma n-3 fatty acids in both countries . The micronutrient treatment result ed in significant increases in scores on tests representing verbal learning and memory in Australia ( estimated effect size : 0.23 ; 95 % CI : 0.01 , 0.46 ) . A similar effect was observed among Indonesian girls ( estimated effect size : 0.32 ; 95 % CI : -0.01 , 0.64 ) . No effects were found on tests measuring general intelligence or attention . No effects of DHA+EPA on the factors of cognitive tests were observed . CONCLUSION In well-nourished school-aged children , fortification with multiple micronutrients can result in improvements in verbal learning and memory [12730420] Maternal malnutrition continues to be a major contributor to adverse reproductive outcomes in developing countries , despite longst and ing efforts to fortify foods or to distribute medicinal supplements to pregnant women . The objective of this study was to test the effect of a micronutrient-fortified beverage containing 11 micronutrients ( iron , iodine , zinc , vitamin A , vitamin C , niacin , riboflavin , folate , vitamin B-12 , vitamin B-6 and vitamin E ) on the hemoglobin , iron and vitamin A status of pregnant women in Tanzania . A group of 259 pregnant women with gestational ages of 8 to 34 wk were enrolled in a r and omized double-blind controlled trial in which study women received 8 wk of supplementation . Hemoglobin , ferritin and dried blood spot retinol were measured at baseline and at the end of the supplementation period . The supplement result ed in a 4.16 g/L increase in hemoglobin concentration and a 3 micro g/L increase in ferritin and reduced the risk of anemia and iron deficiency anemia by 51 and 56 % , respectively . The risk of iron deficiency was reduced by 70 % among those who had iron deficiency at baseline and by 92 % among those who had adequate stores . The micronutrient-fortified beverage may be a useful and convenient preventative measure , one that could help improve the nutritional status of women both before and during pregnancy and thereby help avoid some of the potential maternal and fetal consequences of micronutrient deficiencies [17709456] Adolescent girls have high nutrient needs and are susceptible to micronutrient deficiencies . The objective of this study was to test the effect of a multiple-micronutrient-fortified beverage on hemoglobin ( Hb ) concentrations , micronutrient status , and growth among adolescent girls in rural Bangladesh . A total of 1125 girls ( Hb > or = 70 g/L ) enrolled in a r and omized , double-blind , placebo-controlled trial and were allocated to either a fortified or nonfortified beverage of similar taste and appearance . The beverage was provided at schools 6 d/wk for 12 mo . Concentrations of Hb and serum ferritin ( sFt ) , retinol , zinc , and C-reactive protein were measured in venous blood sample s at baseline , 6 mo , and 12 mo . In addition , weight , height , and mid-upper arm circumference ( MUAC ) measurements were taken . The fortified beverage increased the Hb and sFt and retinol concentrations at 6 mo ( P < 0.01 ) . Adolescent girls in the nonfortified beverage group were more likely to suffer from anemia ( Hb < 120 g/L ) , iron deficiency ( sFt < 12 microg/L ) , and low serum retinol concentrations ( serum retinol < 0.70 micromol/L ) ( OR = 2.04 , 5.38 , and 5.47 , respectively ; P < 0.01 ) . The fortified beverage group had greater increases in weight , MUAC , and BMI over 6 mo ( P < 0.01 ) . Consuming the beverage for an additional 6 mo did not further improve the Hb concentration , but the sFt level continued to increase ( P = 0.01 ) . The use of multiple-micronutrient-fortified beverage can contribute to the reduction of anemia and improvement of micronutrient status and growth in adolescent girls in rural Bangladesh [7733042] A 32-mo-long , double-blind field study involving one highl and control community receiving only vitamin A-fortified sugar and three vitamin A- and FeNaEDTA-sugar-fortified communities , two in the lowl and s and one in the highl and s of Guatemala , was undertaken to test the effectiveness of this approach in controlling iron deficiency . The communities ' population ranged between 1200 and 17000 . Sugar fortified with 1 g FeNaEDTA and 15 mg retinol as retinyl palmitate/kg was stable , did not segregate , and was well accepted by the communities . The impact of fortification on iron nutrition was estimated at 8 , 20 , and 32 mo of intervention . All pregnant women and subjects with severe anemia received supplements or treatment and were excluded from the analysis . Iron stores in the fortified communities increased significantly except for women 18 - 48 y of age in one lowl and community and > 49 y in the highl and community . Iron stores in the control community remained unchanged except for a rise among adult males [10075336] BACKGROUND Deficiencies of iron , iodine , and vitamin A are prevalent worldwide and can affect the mental development and learning ability of schoolchildren . OBJECTIVE The aim of this study was to determine the effect of micronutrient-fortified biscuits on the micronutrient status of primary school children . DESIGN Micronutrient status was assessed in 115 children aged 6 - 11 y before and after consumption of biscuits ( fortified with iron , iodine , and beta-carotene ) for 43 wk over a 12-mo period and was compared with that in a control group ( n = 113 ) who consumed nonfortified biscuits . Cognitive function , growth , and morbidity were assessed as secondary outcomes . RESULTS There was a significant between-group treatment effect on serum retinol , serum ferritin , serum iron , transferrin saturation , and urinary iodine ( P < 0.0001 ) and in hemoglobin and hematocrit ( P < 0.05 ) . The prevalence of low serum retinol concentrations ( < 0.70 micromol/L ) decreased from 39.1 % to 12.2 % , of low serum ferritin concentrations ( < 20 microg/L ) from 27.8 % to 13.9 % , of anemia ( hemoglobin < 120 g/L ) from 29.6 % to 15.6 % , and of low urinary iodine concentrations ( < 100 microg/L ) from 97.5 % to 5.4 % . There was a significant between-group treatment effect ( P < 0.05 ) in cognitive function with the digit span forward task ( short-term memory ) . Fewer school days were missed in the intervention than in the control group because of respiratory- ( P = 0.097 ) and diarrhea-related ( P = 0.013 ) illnesses . The intervention had no effect on anthropometric status [ corrected ] . CONCLUSIONS Fortified biscuits result ed in a significant improvement in the micronutrient status of primary school children from a poor rural community and also appeared to have a favorable effect on morbidity and cognitive function [ corrected ] [10966892] BACKGROUND Wheat flour is a possible food vehicle for vitamin A fortification . OBJECTIVE This study assessed the efficacy of consumption of a vitamin A-fortified wheat-flour bun ( p and esal ) on the vitamin A status of school-age children . DESIGN This was a double-masked clinical trial conducted in 396 and 439 children aged 6 - 13 y attending 4 rural schools in the Philippines . The children were r and omly assigned to a vitamin A-fortified ( experimental ) or nonfortified ( control ) group . A 60-g vitamin A-fortified p and esal ( containing approximately 133 microg retinol equivalents ) or a nonfortified p and esal was consumed by the children 5 d/wk for 30 wk . Vitamin A status , hemoglobin concentration , anthropometric status , morbidity , and dietary intake were assessed at baseline and 30 wk later . A modified relative dose response ( MRDR ) was assessed in a sub sample of 20 % of the children ( approximately 75/group ) with the lowest initial serum retinol concentration at the 30-wk follow-up . RESULTS Baseline serum retinol significantly modified the effect of the intervention . The fortified group , whose initial serum retinol concentrations were below the median , had a 0.07 + /- 0.03-micromol/L greater improvement in serum retinol at the 30-wk follow-up than did the control group ( P : = 0.02 ) . Improved vitamin A status was also evident in the MRDR sub sample . End-of- study differences in the MRDR showed that vitamin A- fortified p and esal intake decreased the percentage of children with inadequate liver vitamin A stores by 50 % ( 15.3 % compared with 28.6 % ; P : = 0.05 ) . CONCLUSIONS Daily consumption of vitamin A-fortified p and esal significantly improved the vitamin A status of Filipino school-age children with marginal-to-low initial serum retinol concentrations [15447908] BACKGROUND Multiple micronutrient deficiencies are often the basic causative factor in stunting and anemia , 2 conditions that affect entire generations of children in deprived population s. No generally accepted recommendations for micronutrient intakes for recovery from stunting are available . OBJECTIVE The objective was to assess the effect of a highly nutrient-dense spread fortified with vitamins and minerals , with or without antiparasitic metronidazole treatment , in correcting retarded linear growth and reducing anemia in stunted children . DESIGN Saharawi refugee children ( n = 374 ) aged 3 - 6 y with initial height-for-age z scores < -2 were assigned to 1 of 5 groups : fortified spread ( FS ) , fortified spread plus metronidazole ( FS+M ) , unfortified spread ( US ) , unfortified spread plus metronidazole ( US+M ) , or control . Supervised supplementation was given daily for 6 mo . Weight , height , knee-heel length , hematologic indexes , parasitic infections , and morbidity were assessed at 0 , 3 , and 6 mo . RESULTS Linear growth of children fed FS was 30 % faster at 3 mo than in US and control groups , after which height-for-age z scores increased only slightly in the FS group and remained unchanged in the other groups . No additional benefits from metronidazole were observed . Increase in hemoglobin concentrations in the FS group at 6 mo was twofold that in the US and control groups ( 37 + /- 40 , 19 + /- 15 , and 16 + /- 17 g/L , respectively ; P < 0.0001 ) , and anemia was reduced by nearly 90 % . CONCLUSIONS FS , and not US , induces catch-up growth in stunted children whose diets are poor in micronutrients . Our trial provides support for delivering multiple micronutrients to reverse stunting and reduce anemia in children up to age 6 [16280435] BACKGROUND Maize-meal porridge is used for infant feeding in many African countries , including South Africa . A low-cost , finely milled , maize-meal porridge was fortified with beta-carotene , iron , and zinc ( 100 % of recommended dietary allowance ) , as well as ascorbic acid , copper , selenium , riboflavin , vitamin B-6 , vitamin B-12 , and vitamin E. OBJECTIVE We assessed whether the fortified porridge could reduce anemia and improve the micronutrient status and motor development of infants . DESIGN Infants aged 6 - 12 mo ( n = 361 ) were r and omly assigned to receive either the fortified or unfortified porridge for 6 mo . Primary outcomes were hemoglobin and serum retinol , zinc , and ferritin concentrations and motor development . Growth was assessed as a secondary outcome . Primary and secondary outcomes were assessed at baseline and 6 mo . RESULTS Two hundred ninety-two infants completed the study . The fortified-porridge group had an intervention effect of 9.4 microg/L ( 95 % CI : 3.6 , 15.1 microg/L ) for serum ferritin and 9 g/L ( 95 % CI : 6 , 12 g/L ) for hemoglobin concentrations . The proportion of infants with anemia decreased from 45 % to 17 % in the fortified-porridge group , whereas it remained > 40 % in the control group . The fortified-porridge group achieved on average 15.5 of the 25 motor development score items , whereas the control group achieved 14.4 items ( P = 0.007 ) . Serum retinol concentration showed an inconsistent effect , and no intervention effect was observed for serum zinc concentrations . CONCLUSIONS This low-cost fortified porridge can potentially have a significant effect in reducing anemia and improving iron status and motor development of infants in poor setting s. The formulation needs some adjustment in terms of zinc fortification [26275329] BACKGROUND Vitamin A deficiency is a risk factor for blindness and for mortality from measles and diarrhoea in children aged 6 - 59 months . We aim ed to estimate trends in the prevalence of vitamin A deficiency between 1991 and 2013 and its mortality burden in low-income and middle-income countries . METHODS We collated 134 population -representative data sources from 83 countries with measured serum retinol concentration data . We used a Bayesian hierarchical model to estimate the prevalence of vitamin A deficiency , defined as a serum retinol concentration lower than 0·70 μmol/L. We estimated the relative risks ( RRs ) for the effects of vitamin A deficiency on mortality from measles and diarrhoea by pooling effect sizes from r and omised trials of vitamin A supplementation . We used information about prevalences of deficiency , RRs , and number of cause-specific child deaths to estimate deaths attributable to vitamin A deficiency . All analyses included a systematic quantification of uncertainty . FINDINGS In 1991 , 39 % ( 95 % credible interval 27 - 52 ) of children aged 6 - 59 months in low-income and middle-income countries were vitamin A deficient . In 2013 , the prevalence of deficiency was 29 % ( 17 - 42 ; posterior probability [ PP ] of being a true decline=0·81 ) . Vitamin A deficiency significantly declined in east and southeast Asia and Oceania from 42 % ( 19 - 70 ) to 6 % ( 1 - 16 ; PP>0·99 ) ; a decline in Latin America and the Caribbean from 21 % ( 11 - 33 ) to 11 % ( 4 - 23 ; PP=0·89 ) also occurred . In 2013 , the prevalence of deficiency was highest in sub-Saharan Africa ( 48 % ; 25 - 75 ) and south Asia ( 44 % ; 13 - 79 ) . 94 500 ( 54 200 - 146 800 ) deaths from diarrhoea and 11 200 ( 4300 - 20 500 ) deaths from measles were attributable to vitamin A deficiency in 2013 , which accounted for 1·7 % ( 1·0 - 2·6 ) of all deaths in children younger than 5 years in low-income and middle-income countries . More than 95 % of these deaths occurred in sub-Saharan Africa and south Asia . INTERPRETATION Vitamin A deficiency remains prevalent in south Asia and sub-Saharan Africa . Deaths attributable to this deficiency have decreased over time worldwide , and have been almost eliminated in regions other than south Asia and sub-Saharan Africa . This new evidence for both prevalence and absolute burden of vitamin A deficiency should be used to reconsider , and possibly revise , the list of priority countries for high-dose vitamin A supplementation such that a country 's priority status takes into account both the prevalence of deficiency and the expected mortality benefits of supplementation . FUNDIN Bill & Melinda Gates Foundation , Gr and Challenges Canada , UK Medical Research Council [25164452] BACKGROUND Multiple micronutrient deficiencies are prevalent in India . OBJECTIVE The study aims to establish the efficacy of multi-micronutrient fortified salt in addressing multiple micronutrient deficiencies among children compared to nutrition education and no intervention in Tamilnadu . METHODS The study employed a community based r and omized controlled trial design ed to study the impact of multiple micronutrient salt ( micronutrient group ) in comparison with nutrition education ( education group ) and no intervention ( control group ) on haemoglobin , serum ferritin , soluble transferrin receptor , body iron stores , serum retinol and urinary iodine outcomes over a period of 8 months . The fortified salt contained iron , iodine , vitamin A , vitamin B12 and folic acid . All the children were dewormed at baseline and at the end of the study just before the biochemical measurements . RESULTS There was a significant improvement in most biochemical parameters studied in the micronutrient group when compared with the control group whereas this was not seen between the education and control . Over 8 months , in the micronutrient group , hemoglobin increased by 0.52 g/dL , retinol by 8.56 μg/dL , ferritin by 10.8 μg/L , body iron stores by 1.27 mg and the decrease in the prevalence of retinol deficiency was from 51.6 % to 28.1 % , anaemia from 46.0 % to 32.6 % , iron deficiency from 66.9 % to 51.3 % and iron deficiency anaemia from 35.2 % to 31.0 % , while the prevalence of all these deficiencies increased or the changes were not significant in the other two groups . CONCLUSIONS Multiple micronutrient fortified salt was able to improve iron and vitamin A status , whereas this was not seen in the nutrition education group [20533221] OBJECTIVE This study was conducted to test the efficacy of a multiple micronutrient-fortified cooking salt . METHODS A r and omized controlled trial with a pre- and post-test design was used to study children 5 to 18 years of age , with an experimental ( n=213 ) and control group ( n=189 ) . The children were sample d from 3 residential schools and were studied for 9 months . The experimental group received a multiple micronutrient-fortified salt containing vitamins A , B(1 ) , B(2 ) , B(6 ) , B(12 ) , as well as folic acid , niacin , iron , iodine , and zinc . The control group received iodized salt . Biochemical measurements [ hemoglobin , serum ferritin ( SF ) , serum transferrin receptor ( sTfR ) , C-reactive protein ( CRP ) , alpha-1 acid glycoprotein ( AGP ) , serum retinol , serum vitamin B(12 ) , serum folic acid , serum zinc , and urinary iodine ( UI ) ] were measured at baseline and post-intervention . Hemoglobin was measured in all the children three times during the study period , while the remaining biochemical measurements were performed in a sub sample of children . Children between 11 and 18 years of age were given cognitive tests to assess memory and attention . RESULTS There was a significant improvement ( p<0.05 ) in all the biochemical measurements and memory tests in the experimental group when compared with the control group . Post-intervention in the experimental group , the increase in hemoglobin was 0.67 g/dL ( p<0.05 ) . Iron status and body iron stores increased significantly ( p<0.05 ) in the experimental group compared to the control group , while serum zinc increased by 50 mug/dL ( p<0.05 ) , and the prevalence of retinol deficiency decreased from 57.1 % at baseline to 16 % post-intervention ( p<0.05 ) . CONCLUSION The multiple micronutrients from the multiple micronutrient-fortified cooking salt were absorbed in the children and helped in combating micronutrient deficiencies [18057478] OBJECTIVE To assess the efficacy of micronutrient fortified sugar c and ies in improving the iron and vitamin A status in children aged 3 to 6 years . DESIGN Triple blind r and omized controlled trial . SETTING S Anganwadis and preparatory schools in rural Haryana . METHODS 410 children were r and omized in four groups . One group received full dose c and y ( vitamin A 1000 IU and 14 mg elemental iron ) daily , the second group received full dose c and y for 3 days a week , the third group received half dose c and y ( vitamin A 500 IU and 7 mg elemental iron ) daily and the fourth received placebo . The c and ies were provided to children under supervision of field workers . Hemoglobin , S. ferritin , S. retinol and S. retinol binding protein levels were estimated at baseline and after 13 weeks of intervention . RESULTS The increase in hemoglobin was least in the placebo group ( 0.3 g/dL ) as compared to the two full dose groups ( 1.15 - 1.18 g/dL , P < 0.001 ) . Among anemic children , the increase in hemoglobin was about 2 g/dL in the full dose group and 0.7 g/dL in the placebo group ( P < 0.001 ) . S. ferritin levels increased significantly only in the full dose daily group ( p < 0.05 ) . The prevalence of anemia decreased from around 50 % at baseline to 9.6 % in the full dose daily group ( p < 0.01 ) . Based on the S. retinol levels , the study area was not vitamin A deficient and the intervention did not result in a significant improvement in the vitamin A status of the children . CONCLUSION Micronutrient fortified c and ies were effective in improving the hemoglobin level and decreasing anemia prevalence . It could serve as a suitable vehicle for micronutrient supplementation in children and other target groups [12630494] OBJECTIVE To evaluate the efficacy of a multiple micronutrient fortified beverage containing eleven nutrients at physiological levels in prevention of anaemia and improving iron and vitamin A status during pregnancy . DESIGN A r and omised double blind placebo controlled study . SETTING Mpwapwa and Kongwa Districts in Dodoma Region of Tanzania . SUBJECTS Five hundred and seventy nine pregnant women were screened for entry into the study and 439 women who met the study criteria were enrolled . INTERVENTIONS Study participants received either a fortified ( F ) or non-fortified ( NF ) orange flavoured drinks identical in appearance , provided in two self administered servings per day for an eight week period . MAIN OUTCOME MEASURES Comparison of haemoglobin ( Hb ) , serum ferritin ( SF ) and serum retinol ( SR ) at baseline and follow up . RESULTS After eight weeks of supplementation , the F group ( n=129 ) had a significantly higher Hb increase of 0.86 g/dL compared to 0.45 g/dL in the NF group ( n=130 ) p<0.0001 . Gestational age at entry into the study , moderated the effect on Hb of the fortified drink . Women at earlier gestational age upon entry , had a higher rise in Hb than women of late gestational age ( 0.8 g/dL versus 0.04 g/dL rise respectively , p=0.038 , n=188 ) . The risk of being anaemic at the end of the study for those in the F group was reduced by 51 % ( RR=0.49 , CI=0.28 to 0.85 ) . Iron stores ( by serum ferritin levels ) increased by 3 microg/L in the F group ( p=0.012 ) and a decrease of 2 microg/L in the NF group ( p=0.115 ) . The follow up ferritin concentration depended on initial ferritin level . Regardless of treatment group , serum retinol concentrations were significantly higher in mothers who had delivered . Mothers who had adequate levels at entry benefited more from the supplement than those with low levels ( 0.26 micromol/L versus no significant difference ) . CONCLUSIONS The multiple micronutrient-fortified beverage given for eight weeks to pregnant women improved their haemoglobin , serum ferritin and retinol status . The risk for anaemia was also significantly reduced . The important predictors of Hb increase at follow up were the fortified beverage , baseline Hb , serum retinol , baseline ferritin and gestational age at entry into study . Anthropological research showed that the beverage was highly acceptable and well liked [11796083] OBJECTIVE To evaluate the long-term effect on micronutrient status of a beta-carotene- , iron- and iodine-fortified biscuit given to primary school children as school feeding . DESIGN Children receiving the fortified biscuit were followed in a longitudinal study for 2.5 years ( n = 108 ) ; in addition , cross-sectional data from three subsequent surveys conducted in the same school are reported . SETTING A rural community in KwaZulu-Natal , South Africa . SUBJECTS Children aged 6 - 11 years attending the primary school where the biscuit was distributed . RESULTS There was a significant improvement in serum retinol , serum ferritin , haemoglobin , transferrin saturation and urinary iodine during the first 12 months of the biscuit intervention . However , when the school reopened after the summer holidays , all variables , except urinary iodine , returned to pre-intervention levels . Serum retinol increased again during the next 9 months , but was significantly lower in a subsequent cross-sectional survey carried out directly after the summer holidays ; this pattern was repeated in two further cross-sectional surveys . Haemoglobin gradually deteriorated at each subsequent assessment , as did serum ferritin ( apart from a slight increase at the 42-month assessment at the end of the school year ) . CONCLUSIONS This study has shown that fortification of a biscuit with beta-carotene at a level of 50 % of the Recommended Dietary Allowance ( RDA ) was enough to maintain serum retinol concentrations from day to day , but not enough to sustain levels during the long school holiday break . Other long-term solutions , such as local food production programmes combined with nutrition education , should also be examined . The choice of the iron compound used as fortificant in the biscuit needs further investigation [23232585] Background / Objectives : A multiple micronutrient-fortified drink could be an effective strategy to combating micronutrient deficiencies in school going children . To assess the efficacy of a multiple micronutrient-fortified drink in reducing iron deficiency ( ID ) , ID anemia ( IDA ) , anemia and improving micronutrient status among schoolchildren with low iron stores . The study employed a school-based , r and omized , double-blind , placebo-controlled design .Subjects/ Methods : Schoolchildren with low serum ferritin ( SF < 20 μg/l ) ( n=246 ) , aged 6–12 years were r and omly assigned to receive either a multi-micronutrient fortified or an unfortified identical control drink . The drinks were provided 6 days/week for 8 weeks . Anthropometric and biochemical assessment s were taken at baseline and endline . Results : Study groups at baseline were comparable , and compliance to the intervention was similar . The overall prevalence of ID , IDA and anemia was 64 % , 19 % and 24 % , respectively . The prevalence of ID , IDA , vitamin C and vitamin B12 deficiencies significantly reduced by 42 % , 18 % , 21 % and 5 % , respectively , in the intervention arm ( P<0.01 ) as compared with the control arm at the end of the study . Similarly , the concentration of hemoglobin , SF , vitamin A , vitamin B12 , vitamin C and body iron stores were significantly higher in the intervention arm in comparison to the control arm ( P<0.001 ) . Red cell folate levels also improved significantly in the intervention arm ( P=0.04 ) , however , serum zinc status did not change in either of the study arms . Children who had received the fortified drink had significantly lower odds of being ID ( 0.15 ; 95 % confidence interval ( CI ) : 0.09–0.27 ) , IDA ( 0.14 ; 95 % CI : 0.04–0.52 ) , vitamin B12 deficient ( 0.36 ; 95 % CI : 0.18–0.73 ) and vitamin C deficient ( 0.24 ; 95 % CI : 0.13–0.46 ) , after adjusting for baseline age , gender and weight . Conclusions : The multi micronutrient-fortified drink was efficacious in reducing the prevalence of ID , IDA , vitamin C and vitamin B12 deficiency and improved micronutrient status in schoolchildren [27925426] Home fortification with multiple micronutrient powder ( MNP ) is effective in the prevention of anemia in young children . However , the impact on their vitamin A status remains controversial . This study aim ed to evaluate the effect of MNP on vitamin A status in young Brazilian children . A multicenter pragmatic , controlled trial was carried out in primary health centers in four Brazilian cities . In the beginning of the study , the control group ( CG ) consisted of children 11 - 14 months old ( n = 395 ) attending in routine pediatric health care . In parallel , the intervention group ( IG ) was composed of children 6 - 8 months old ( n = 399 ) , in the same health centers , who followed the intervention with MNP for 2 - 3 months . The analysis of the effect of MNP on vitamin A status was performed by comparing the IG with the CG after a 4- to 6-month follow-up when IG children had reached the age of the controls . The prevalence of vitamin A deficiency ( VAD ; serum retinol < 0.70 μmol/L ) in the CG was 16.2 % , while in the IG was 7.5%-a 55 % reduction in the VAD [ prevalence ratio ( 95 % confidence interval ) = 0.45 ( 0.28 ; 0.72 ) ] . This reduction was also significant when stratifying the study centers by coverage of the Brazilian Vitamin A Supplementation Program . The adjusted mean of vitamin A serum concentrations improved in the IG compared with CG children , with a shift to the right in the vitamin A distribution . Home fortification with MNP was effective in reducing VAD among young Brazilian children [19155581] Preschool children in developing countries are likely to have multiple , concurrent micronutrient deficiencies . This study was design ed to evaluate the effectiveness of different combinations of nutritional fortified diet to improve the blood levels of iron , vitamin A and other essential micronutrients in the preschool population of Banan District of Chongqing , China . From December 2005 to June 2006 , a total of 226 2 - 6 y old preschool children were recruited from three nurseries in the area , and they were r and omly assigned to three different fortified diet groups for 6 mo . Group I was fortified with vitamin A ; groups II and III were fortified with vitamin A plus iron and vitamin A plus iron , thiamine , riboflavin , folic acid , niacinamide , zinc and calcium , respectively . Subjects ' weight and height were measured for assessing the children 's growth and development . Blood sample s were taken at the beginning and the end of the 6-mo study period for measuring serum levels of micronutrients . Group III with the multiple micronutrient fortified diet was the most effective to improve the serum level of retinol from [ media ( P25 , P75 ) : 1.06 ( 0.89 , 1.32 ) ] micromol/L to 1.29 ( 1.04 , 1.39 ) micromol/L ( p<0.05 ) and retinol binding protein from 17.0 ( 12.6 , 25.6 ) mg/L to 31.6 ( 24.4 , 44.0 ) mg/L ( p<0.05 ) and to mobilize the stored iron in the liver ( p<0.05 ) . In addition , the three groups ' hemoglobin levels were elevated from 117.0 ( 109.0 , 124.1 ) g/L , 114.0 ( 109.2 , 119.7 ) g/L and 115.0 ( 109.5 , 122.7 ) g/L to 125.7 ( 119.2 , 133.1 ) g/L , 126.5 ( 122.2 , 135.9 ) g/L and 125.1 ( 119.8 , 131.6 ) g/L over the 6 mo of intervention period , but there were no difference among the three groups ( p>0.05 ) . Nevertheless , unexpected results were obtained when comparing the effects on growth status among the different supplement groups . Our study has demonstrated that a multiple micronutrient fortified diet for 6 mo is more effective to improve the levels of hemoglobin , serum retinol , and RBP as well as to facilitate the mobilization of iron storage in preschool children [5557358] Background Multiple micronutrients ( MMN ) are commonly prescribed in pediatric primary healthcare in sub-Saharan Africa to improve nutritional status and appetite without evidence for their effectiveness or international clinical guidelines . Community-wide MMN supplementation has shown limited and heterogeneous impact on growth and morbidity . Short-term ready-to-use therapeutic foods in acutely sick children in a hospital setting also had limited efficacy regarding subsequent growth . The effectiveness of MMN in improving morbidity or growth in sick children presenting for primary care has not been assessed . Methods and findings We undertook a double-blind r and omised controlled trial of small-quantity lipid-based nutrient supplements ( SQ-LNS ) fortified with 23 micronutrients in children aged 6 months ( mo ) to 5 years ( y ) presenting with an illness at a rural primary healthcare centre in The Gambia . Primary outcomes were repeat clinic presentations and growth over 24 wk . Participants were r and omly assigned to receive 1 of 3 interventions : ( 1 ) supplementation with micronutrient-fortified SQ-LNS for 12 wk ( MMN-12 ) , ( 2 ) supplementation with micronutrient-fortified SQ-LNS for 6 wk followed by unfortified SQ-LNS for 6 wk ( MMN-6 ) , or ( 3 ) supplementation with unfortified SQ-LNS for 12 wk ( MMN-0 ) to be consumed in daily portions . Treatment masking used 16 letters per 6-wk block in the r and omisation process . Blinded intention-to-treat analysis based on a prespecified statistical analysis plan included all participants eligible and correctly enrolled . Between December 2009 and June 2011 , 1,101 children ( age 6–60 mo , mean 25.5 mo ) were enrolled , and 1,085 were assessed ( MMN-0 = 361 , MMN-6 = 362 , MMN-12 = 362 ) . MMN supplementation was associated with a small increase in height-for-age z-scores 24 wk after recruitment ( effect size for MMN groups combined : 0.084 SD/24 wk , 95 % CI : 0.005 , 0.168 ; p = 0.037 ; equivalent to 2–5 mm depending on age ) . No significant difference in frequency of morbidity measured by the number of visits to the clinic within 24 wk follow-up was detected with 0.09 presentations per wk for all groups ( MMN-0 versus MMN-6 : adjusted incidence rate ratio [ IRR ] 1.03 , 95 % CI : 0.92 , 1.16 ; MMN-0 versus MMN-12 : 1.05 , 95 % CI : 0.93 , 1.18 ) . In post hoc analysis , clinic visits significantly increased by 43 % over the first 3 wk of fortified versus unfortified SQ-LNS ( adjusted IRR 1.43 ; 95 % CI : 1.07 , 1.92 ; p = 0.016 ) , with respiratory presentations increasing by 52 % with fortified SQ-LNS ( adjusted IRR 1.52 ; 95 % CI : 1.01 , 2.30 ; p = 0.046 ) . The number of severe adverse events during supplementation were similar between groups ( MMN-0 = 20 [ 1 death ] ; MMN-6 = 21 [ 1 death ] ; MMN-12 = 20 [ 0 death ] ) . No participant withdrew due to adverse effects . Study limitations included the lack of supervision of daily supplementation . Conclusion Prescribing micronutrient-fortified SQ-LNS to ill children presenting for primary care in rural Gambia had a very small effect on linear growth and did not reduce morbidity compared to unfortified SQ-LNS . An early increase in repeat visits indicates a need for the establishment of evidence -based guidelines and caution with systematic prescribing of MMN . Future research should be directed at underst and ing the mechanisms behind the lack of effect of MMN supplementation on morbidity measures and limited effect on growth . Trial registration IS RCT N 73571031 [23823584] Little is known about the effects of combined micronutrient and sugar consumption on growth and cognition . In the present study , we investigated the effects of micronutrients and sugar , alone and in combination , in a beverage on growth and cognition in schoolchildren . In a 2 × 2 factorial design , children ( n 414 , 6 - 11 years ) were r and omly allocated to consume beverages containing ( 1 ) micronutrients with sugar , ( 2 ) micronutrients with a non-nutritive sweetener , ( 3 ) no micronutrients with sugar or ( 4 ) no micronutrients with a non-nutritive sweetener for 8.5 months . Growth was assessed and cognition was tested using the Kaufman Assessment Battery for Children version II ( KABC-II ) subtests and the Hopkins Verbal Learning Test ( HVLT ) . Micronutrients decreased the OR for Fe deficiency at the endpoint ( OR 0.19 ; 95 % CI 0.07 , 0.53 ) . Micronutrients increased KABC Atlantis ( intervention effect : 0.76 ; 95 % CI 0.10 , 1.42 ) and HVLT Discrimination Index ( 1.00 ; 95 % CI 0.01 , 2.00 ) scores . Sugar increased KABC Atlantis ( 0.71 ; 95 % CI 0.05 , 1.37 ) and Rover ( 0.72 ; 95 % CI 0.08 , 1.35 ) scores and HVLT Recall 3 ( 0.94 ; 95 % CI 0.15 , 1.72 ) . Significant micronutrient × sugar interaction effects on the Atlantis , Number recall , Rover and Discrimination Index scores indicated that micronutrients and sugar in combination attenuated the beneficial effects of micronutrients or sugar alone . Micronutrients or sugar alone had a lowering effect on weight-for-age z-scores relative to controls ( micronutrients - 0.08 ; 95 % CI - 0.15 , - 0.01 ; sugar - 0.07 ; 95 % CI - 0.14 , - 0.002 ) , but in combination , this effect was attenuated . The beverages with micronutrients or added sugar alone had a beneficial effect on cognition , which was attenuated when provided in combination [18096105] OBJECTIVE To assess changes in the Fe and vitamin A status of the population of Nangweshi refugee camp associated with the introduction of maize meal fortification . DESIGN Pre- and post-intervention study using a longitudinal cohort . SETTING Nangweshi refugee camp , Zambia . SUBJECTS Two hundred and twelve adolescents ( 10 - 19 years ) , 157 children ( 6 - 59 months ) and 118 women ( 20 - 49 years ) were selected at r and om by household survey in July 2003 and followed up after 12 months . RESULTS Maize grain was milled and fortified in two custom- design ed mills installed at a central location in the camp and a daily ration of 400 g per person was distributed twice monthly to households as part of the routine food aid ration . During the intervention period mean Hb increased in children ( 0.87 g/dl ; P < 0.001 ) and adolescents ( 0.24 g/dl ; P = 0.043 ) but did not increase in women . Anaemia decreased in children by 23.4 % ( P < 0.001 ) but there was no significant change in adolescents or women . Serum transferrin receptor ( log10-transformed ) decreased by -0.082 microg/ml ( P = 0.036 ) indicating an improvement in the Fe status of adolescents but there was no significant decrease in the prevalence of deficiency ( -8.5 % ; P = 0.079 ) . In adolescents , serum retinol increased by 0.16 micromol/l ( P < 0.001 ) and vitamin A deficiency decreased by 26.1 % ( P < 0.001 ) . CONCLUSIONS The introduction of fortified maize meal led to a decrease in anaemia in children and a decrease in vitamin A deficiency in adolescents . Central ised , camp-level milling and fortification of maize meal is a feasible and pertinent intervention in food aid operations [28760007] Background : Iron deficiency is a global public health concern and has implication s on the health status of women in reproductive age . Objective : We hypothesized that improving iron intake with double fortified salt would improve food intake , result ing in higher energy , nutrient intakes , and weight indicators of female tea plantation workers . Methods : In this r and omized double-masked study , the participants ( n = 245 ) were assigned to receive salt double fortified with iron and iodine ( DFS ; treatment ) or salt fortified with iodine ( control ) and followed for 7.5 to 9 months . Dietary intakes were measured at three time points , baseline , midpoint , and end line using ( 1 ) food frequency question naire , ( 2 ) 24-hour recall , and ( 3 ) weighed lunch intake . Anthropometric measures of height ( cm ) , weight ( kg ) , and mid-upper arm circumference ( cm ) were also recorded at three time points . Mixed-model repeated- measures approach was used to detect group differences across time . Results : Double fortified salt improved dietary iron intake in the treatment group compared to the control group ( P < .001 ) . No other dietary or anthropometric differences could be attributed to treatment . Significant effect of time was observed in the intake frequency of major food groups and calcium , vitamin A and C ( P < .001 for all ) , suggesting an equal effect of seasonality in both the groups . Conclusion : Addition of DFS in the diet improved dietary iron intake but did not affect the intake of energy , other nutrients , or nutritional status indicators . The improvement observed in the dietary iron intake demonstrates that fortification is an effective strategy to address iron deficiency in at-risk population [27440679] BACKGROUND AND OBJECTIVES Mola ( Amblypharyngodon mola ) is a nutrient-rich , small fish found in ponds and rice fields in Bangladesh . The aim of the present intervention was to assess the effect of mola consumption on iron status in children with marginal vitamin A status . METHODS AND STUDY DESIGN Bangladeshi children ( n=196 ) , aged 3 - 7 years , with marginal vitamin A status were r and omly allocated to one of three intervention groups served different fish curries : mola curry ( experimental group ) ; rui ( Labeo rohita ) curry with added retinyl palmitate ( positive control group ) ; or rui curry ( negative control group ) . The intervention meals were served 6 days/week for 9 weeks . The experimental and positive control meals were design ed to contain similar amounts of retinol activity equivalents per portion . The mola curry contained four times more iron compared to the rui curries due to different iron content in the two fish species . Haemoglobin , ferritin , serum transferrin receptor and Creactive protein were measured at screening and endpoint . RESULTS In the experimental group receiving mola , serum transferrin receptor concentration declined 0.73 mg/L ( 95 % CI 0.17 , 1.28 , p=0.01 ) compared to the positive control group , while there were no differences between groups in ferritin or haemoglobin . CONCLUSIONS Consumption of mola instead of rui has potentially an effect on iron status in children with marginal vitamin A status , seen as a decrease in serum transferrin receptor concentration [17565762] OBJECTIVE To test the hypothesis that maternal food fortification with omega-3 fatty acids and multiple micronutrients increases birth weight and gestation duration , as primary outcomes . DESIGN Non-blinded , r and omised controlled study . SETTING Pregnant women received powdered milk during their health check-ups at 19 antenatal clinics and delivered at two maternity hospitals in Santiago , Chile . SUBJECT Pregnant women were assigned to receive regular powdered milk ( n = 477 ) or a milk product fortified with multiple micronutrients and omega-3 fatty acids ( n = 495 ) . RESULTS Intention-to-treat analysis showed that mean birth weight was higher in the intervention group than in controls ( 65.4 g difference , 95 % confidence interval ( CI ) 5 - 126 g ; P = 0.03 ) and the incidence of very preterm birth ( 0.80 just for mean birth weight and birth length in the on-treatment analysis ; birth length in that analysis had a difference of 0.57 cm ( 95 % CI 0.19 - 0.96 cm ; P = 0.003 ) . CONCLUSIONS The new intervention result ed in increased mean birth weight . Associations with gestation duration and most secondary outcomes need a larger sample size for confirmation [23537728] OBJECTIVE To examine the effects of three different school snacks on morbidity outcomes . DESIGN Twelve schools were r and omized to either one of three feeding groups or a Control group . There were three schools per group in this cluster r and omized trial . Children in feeding group schools received school snacks of a local plant-based dish , githeri , with meat , milk or extra oil added . The oil used was later found to be fortified with retinol . Physical status , food intake and morbidity outcomes were assessed longitudinally over two years . SETTING Rural Embu District , Kenya , an area with high prevalence of vitamin A deficiency . SUBJECTS St and ard 1 schoolchildren ( n 902 ; analytic sample ) enrolled in two cohorts from the same schools one year apart . RESULTS The Meat and Plain Githeri ( i.e. githeri+oil ) groups showed the greatest declines in the probability of a morbidity outcome ( PMO ) for total and severe illnesses , malaria , poor appetite , reduced activity , fever and chills . The Meat group showed significantly greater declines in PMO for gastroenteritis ( mainly diarrhoea ) and typhoid compared with the Control group , for jaundice compared with the Plain Githeri group , and for skin infection compared with the Milk group . The Milk group showed the greatest decline in PMO for upper respiratory infection . For nearly all morbidity outcomes the Control group had the highest PMO and the least decline over time . CONCLUSIONS The intervention study showed beneficial effects of both animal source foods and of vitamin A-fortified oil on morbidity status [17132678] Objective To evaluate the efficacy of milk fortified with specific multiple micronutrients on morbidity in children compared with the same milk without fortification . Design Community based , double masked , individually r and omised trial . Setting Peri-urban settlement in north India . Participants Children ( n=633 ) aged 1 - 3 r and omly allocated to receive fortified milk ( n=316 ) or control milk ( n=317 ) . Intervention One year of fortified milk providing additional 7.8 mg zinc , 9.6 mg iron , 4.2 � g selenium , 0.27 mg copper , 156 � g vitamin A , 40.2 mg vitamin C , 7.5 mg vitamin E per day ( three feeds ) . Main outcome measures Days with severe illnesses , incidence and prevalence of diarrhoea , and acute lower respiratory illness . Results Study groups were comparable at baseline ; compliance in the groups was similar . Mean number of episodes of diarrhoea per child was 4.46 ( SD 3.8 ) in the intervention ( fortified milk ) group and 5.36 ( SD 4.1 ) in the control group . Mean number of episodes of acute lower respiratory illness was 0.62 ( SD 1.1 ) and 0.83 ( SD 1.4 ) , respectively . The fortified milk reduced the odds for days with severe illnesses by 15 % ( 95 % confidence interval 5 % to 24 % ) , the incidence of diarrhoea by 18 % ( 7 % to 27 % ) , and the incidence of acute lower respiratory illness by 26 % ( 3 % to 43 % ) . Consistently greater beneficial effects were observed in children aged ≤24 months than in older children . Conclusion Milk is well accepted as a means of delivery of micronutrients . Consumption of milk fortified with specific micronutrients can significantly reduce the burden of common morbidities among preschool children , especially in the first two years of life . Trial registration NCT00255385 [16277798] OBJECTIVE To evaluate the efficacy of a community-based dietary intervention to reduce risk of micronutrient inadequacies in high-phytate maize-based Malawian diets . DESIGN Quasi-experimental post-test design with a non-equivalent control group . SETTING Four villages in Mangochi District , Southern Malawi . PARTICIPANTS Households with children aged 3 - 7 years in two intervention ( n = 200 ) and two control ( n = 81 ) villages participated in a 6-month intervention employing dietary diversification , changes in food selection patterns , and modifications to food processing to reduce the phytate content of maize-based diets . Baseline comparability between the groups was confirmed via assessment of sociodemographic characteristics , anthropometry , knowledge and practice s , morbidity , haemoglobin and hair zinc . After 12 months , knowledge and practice s and dietary intakes were assessed by interactive 24-hour recalls , one during the food plenty and a second during the food shortage season . Nutrient adequacy for the two groups was compared via dietary quality indicators and predicted prevalence of inadequate intakes using the probability approach . RESULTS Intervention children had diets that were significantly more diverse and of a higher quality than those of controls . Median daily intakes of protein , calcium , zinc ( total and available ) , haem iron , vitamin B12 and animal foods ( grams ; % of total energy ) were higher ( P < 0.05 ) whereas phytate intakes , phytate/zinc and phytate/iron molar ratios were lower ( P < 0.01 ) in the intervention group ; some spread of knowledge and practice s to controls occurred . CONCLUSIONS Our community-based dietary strategies reduced the predicted prevalence of inadequate intakes of protein , calcium , zinc and vitamin B12 , but not iron , in children from Malawian households with very limited re sources [5372889] Many children suffer from nutritional deficiencies that may negatively affect their academic performance . This cluster-r and omized controlled trial aim ed to test the effects of micronutrient-fortified milk in Chinese students . Participants received either micronutrient-fortified ( n = 177 ) or unfortified ( n = 183 ) milk for six months . Academic performance , motivation , and learning strategies were estimated by end-of-term tests and the Motivated Strategies for Learning Question naire . Blood sample s were analyzed for micronutrients . In total , 296 students ( 82.2 % ) completed this study . Compared with the control group , students in the intervention group reported higher scores in several academic subjects ( p < 0.05 ) , including language s , mathematics , ethics , and physical performance at the end of follow-up . Students in the intervention group showed greater self-efficacy and use of cognitive strategies in learning , and reported less test anxiety ( p < 0.001 ) . Moreover , vitamin B2 deficiency ( odds ratio ( OR ) = 0.18 , 95 % confidence interval ( CI ) : 0.11~0.30 ) and iron deficiency ( OR = 0.34 , 95 % CI : 0.14~0.81 ) were less likely in the students of the intervention group , whereas vitamin D , vitamin B12 , and selenium deficiencies were not significantly different . “ Cognitive strategy ” had a partial mediating effect on the test scores of English ( 95 % CI : 1.26~3.79 ) and Chinese ( 95 % CI : 0.53~2.21 ) . Our findings suggest that micronutrient-fortified milk may improve students ’ academic performance , motivation , and learning strategies [3671231] Background Interventions providing foods fortified with multiple micronutrients can be a cost-effective and sustainable strategy to improve micronutrient status and physical growth of school children . We evaluated the effect of micronutrient-fortified yoghurt on the biochemical status of important micronutrients ( iron , zinc , iodine , vitamin A ) as well as growth indicators among school children in Bogra district of Bangladesh . Methods In a double-masked r and omized controlled trial ( RCT ) conducted in 4 primary schools , 1010 children from classes 1–4 ( age 6–9 years ) were r and omly allocated to receive either micronutrient fortified yoghurt ( FY , n = 501 ) or non-fortified yoghurt ( NFY , n = 509 ) . For one year , children were fed with 60 g yoghurt everyday providing 30 % RDA for iron , zinc , iodine and vitamin A. Anthropometric measurements and blood/urine sample s were collected at base- , mid- and end-line . All children ( FY , n = 278 , NFY , n = 293 ) consenting for the end-line blood sample were included in the present analyses . Results Both groups were comparable at baseline for socio-economic status variables , micronutrient status markers and anthropometry measures . Compliance was similar in both the groups . At baseline 53.4 % of the population was anemic ; 2.1 % was iron deficient ( ferritin < 15.0 μg/L and TfR > 8.3 mg/L ) . Children in the FY group showed improvement in Hb ( mean difference : 1.5 ; 95 % CI : 0.4 - 2.5 ; p = 0.006 ) as compared to NFY group . Retinol binding protein ( mean diff : 0.05 ; 95 % CI : 0.002 - 0.09 ; p = 0.04 ) and iodine levels ( mean difference : 39.87 ; 95 % CI : 20.39 - 59.35 ; p < 0.001 ) decreased between base and end-line but the decrease was significantly less in the FY group . Compared to NFY , the FY group had better height gain velocity ( mean diff : 0.32 ; 95 % CI : 0.05 - 0.60 ; p = 0.02 ) and height-for-age z-scores ( mean diff : 0.18 ; 95 % CI : 0.02 - 0.33 ; p = 0.03 ) . There was no difference in weight gain velocity , weight-for-age z-scores or Body Mass Index z-scores . Conclusion In the absence of iron deficiency at baseline the impact on iron status would not be expected to be observed and hence can not be evaluated . Improved Hb concentrations in the absence of a change in iron status suggest improved utilization of iron possibly due to vitamin A and zinc availability . Fortification improved height gain without affecting weight gain . Trial registration Clinical Trial.gov : [4093981] Dietary lipids have been shown to increase bioavailability of provitamin A carotenoids from a single meal , but the effects of dietary lipids on conversion to vitamin A during absorption are essentially unknown . Based on previous animal studies , we hypothesized that the consumption of provitamin A carotenoids with dietary lipid would enhance conversion to vitamin A during absorption compared with the consumption of provitamin A carotenoids alone . Two separate sets of 12 healthy men and women were recruited for 2 r and omized , 2-way crossover studies . One meal was served with fresh avocado ( Persea americana Mill ) , cultivated variety Hass ( delivering 23 g of lipid ) , and a second meal was served without avocado . In study 1 , the source of provitamin A carotenoids was a tomato sauce made from a novel , high – β-carotene variety of tomatoes ( delivering 33.7 mg of β-carotene ) . In study 2 , the source of provitamin A carotenoids was raw carrots ( delivering 27.3 mg of β-carotene and 18.7 mg of α-carotene ) . Postpr and ial blood sample s were taken over 12 h , and provitamin A carotenoids and vitamin A were quantified in triglyceride-rich lipoprotein fractions to determine baseline-corrected area under the concentration-vs.-time curve . Consumption of lipid-rich avocado enhanced the absorption of β-carotene from study 1 by 2.4-fold ( P < 0.0001 ) . In study 2 , the absorption of β-carotene and α-carotene increased by 6.6- and 4.8-fold , respectively ( P < 0.0001 for both ) . Most notably , consumption of avocado enhanced the efficiency of conversion to vitamin A ( as measured by retinyl esters ) by 4.6-fold in study 1 ( P < 0.0001 ) and 12.6-fold in study 2 ( P = 0.0013 ) . These observations highlight the importance of provitamin A carotenoid consumption with a lipid-rich food such as avocado for maximum absorption and conversion to vitamin A , especially in population s in which vitamin A deficiency is prevalent . This trial was registered at clinical trials.gov as NCT01432210 [2921413] Background Multiple micronutrient deficiencies are highly prevalent among preschool children and often lead to anemia and growth faltering . Given the limited success of supplementation and health education programs , fortification of foods could be a viable and sustainable option . We report results from a community based double-masked , r and omized trial among children 1–4 years evaluating the effects of micronutrients ( especially of zinc and iron ) delivered through fortified milk on growth , anemia and iron status markers as part of a four group study design , running two studies simultaneously . Methods and Findings Enrolled children ( n = 633 ) were r and omly allocated to receive either micronutrients fortified milk ( MN = 316 ) or control milk ( Co = 317 ) . Intervention of MN milk provided additional 7.8 mg zinc , 9.6 mg iron , 4.2 µg selenium , 0.27 mg copper , 156 µg vitamin A , 40.2 mg vitamin C , and 7.5 mg vitamin E per day ( three serves ) for one year . Anthropometry was recorded at baseline , mid- and end- study . Hematological parameters were estimated at baseline and end- study . Both groups were comparable at baseline . Compliance was over 85 % and did not vary between groups . Compared to children consuming Co milk , children consuming MN milk showed significant improvement in weight gain ( difference of mean : 0.21 kg/year ; 95 % confidence interval [ CI ] 0.12 to 0.31 , p<0.001 ) and height gain ( difference of mean : 0.51 cm/year ; 95 % CI 0.27 to 0.75 , p<0.001 ) . Mean hemoglobin ( Hb ) ( difference of 13.6 g/L ; 95 % CI 11.1 to 16.0 , p<0.001 ) and serum ferritin levels ( difference of 7.9 µg/L ; 95 % CI 5.4 to 10.5 , p<0.001 ) also improved . Children in MN group had 88 % ( odds ratio = 0.12 , 95 % CI 0.08 to 0.20 , p<0.001 ) lower risk of iron deficiency anemia . Conclusions / Significance Milk provides an acceptable and effective vehicle for delivery of specific micronutrients , especially zinc and iron . Micronutrient bundle improved growth and iron status and reduced anemia in children 1–4 years old . Trial Registration Clinical Trials.gov [23999776] We studied the impact of a food supplementation program ( Plan Más Vida ( PMV ) ) on the micronutrient nutritional condition of pregnant women from low-income families 1 year after its implementation . The food program provided supplementary diet ( wheat and maize — fortified flour , rice or sugar , and fortified soup ) . We performed a prospect i ve , nonexperimental , cross-sectional study in the province of Buenos Aires , Argentina , evaluating pregnant women at baseline ( n = 164 ) and 1 year after PMV implementation ( n = 108 ) . Biochemical tests ( hemogram , ferritin , vitamin A , zinc , and folic acid ) , anthropometric assessment s ( weight and height ) , and dietary surveys ( 24 h recall ) were performed at the two study points . One year after PMV implementation , no significant changes in anthropometric values were observed . Folic acid deficiency and the risk of vitamin A deficiency ( retinol , 20–30 μg/dl ) decreased significantly ( 35.8 to 6.1 % and 64 to 41 % , respectively ; p < 0.000 ) . Anemia and prevalence of iron and zinc deficiency values did not change . Diet survey results showed that although nutrient intake increased significantly , it was still below recommendations . Implementation of the PMV and of the government nutritional strategies had a high impact on the prevalence of folic acid deficiency . We also observed a decrease in the risk of vitamin A deficiency , and no impact on iron and zinc nutritional status . Adherence to the specific fortified food ( soup ) was not good and intra-family dilution and distribution of food was high [1853789] Thirty elderly long-stay patients were r and omly allocated to receive either placebo or dietary supplementation with vitamins A , C and E for 28 days . Nutritional status and cell-mediated immune function were assessed before and after the period of supplementation . Following vitamin supplementation , cell-mediated immune function improved as indicated by a significant increase in the absolute number of T cells ( p less than 0.05 ) , T4 subsets ( p less than 0.05 ) , T4 to T8 ratio ( p less than 0.01 ) and the proliferation of lymphocytes in response to phytohaemagglutinin ( p less than 0.01 ) . In contrast , no significant changes were noted in the immune function of the placebo group . We conclude that supplementation with the dietary antioxidants vitamins A , C and E can improve aspects of cell-mediated immune function in elderly long-stay patients [8933117] OBJECTIVES This study assessed the effects of consuming a highly hydrogenated , vitamin A (VA)-fortified margarine not requiring refrigeration on VA status of preschool children . DESIGN A double-masked r and omized community trial . SETTING Six rural villages in Cavite , Southern Luzon , the Philippines . SUBJECTS 296 and 285 children 3 - 6 y of age in the VA-fortified ( experimental ) and non-fortified ( control ) margarine groups , respectively . INTERVENTION Each week for 6 months households were given 250 g of VA-fortified margarine [ providing 28.8 micrograms retinol equivalents ( RE ) per g ] or non-fortified ( 0 microgram RE ) margarine of identical appearance for each enrolled child . Children 's vitamin A status [ serum retinol , xerophthalmia , and conjunctival impression cytology ( CIC ) status ] and dietary intake were assessed at baseline and follow-up ; margarine intake was monitored throughout the study . RESULTS Daily margarine intake per child averaged 27 g in the experimental group ( providing 776 micrograms RE ) and 24 g ( 0 microgram RE ) in the control group . After 6 months , mean serum retinol increased from 26.4 to 28.8 micrograms/dl in the experimental group but decreased from 26.6 to 25.1 micrograms/dl in controls ( P < 0.001 at 6 months ) ; the multiple-adjusted increment over controls was 2.4 micrograms/dl ( P < 0.01 ) . More importantly , the prevalence of low serum retinol ( < 20 micrograms/dl ) decreased from 25.7 to 10.1 % in the experimental group but remained unchanged in controls ( 26.7 to 27.7 % ) ( P < 0.01 at 6 months ) . At follow-up no experimental children had developed xerophthalmia but 1.4 and 1.8 % of controls developed nightblindness and Bitot 's spots , respectively . There were no differences in CIC between groups . CONCLUSION Consumption of VA-fortified margarine significantly improved VA status of preschool Filipino children [11732150] Summary Single interventions for helminthic infections and micronutrient deficiencies are effective , but it is not clear whether combined interventions will provide equal , additive or synergistic effects to improve children 's health . The study objective was to determine the impact of single and combined interventions on nutritional status and scholastic and cognitive performance of school children . A double-blind , r and omized , placebo-controlled trial in 11 rural South African primary schools r and omly allocated 579 children aged between 8 and 10 years into six study groups , half of whom received antihelminthic treatment at baseline . The de-wormed and non-de-wormed arms were further divided into three groups and given biscuits , either unfortified or fortified with vitamin A and iron or with vitamin A only , given daily for 16 weeks . The outcome measures were anthropometric , micronutrient and parasite status , and scholastic and cognitive test scores . There was a significant treatment effect of vitamin A on serum retinol ( p < 0.01 ) , and the suggestion of an additive effect between vitamin A fortification and de-worming . Fortified biscuits improved micronutrient status in rural primary school children ; vitamin A with de-worming had a greater impact on micronutrient status than vitamin A fortification alone and antihelminthic treatment significantly reduced the overall prevalence of parasite infection . The burden of micronutrient deficiency ( anaemia , iron and vitamin A ) and stunting in this study population was low and , coupled with the restricted duration of the intervention ( 16 weeks ) , might have limited the impact of the interventions [19939650] BACKGROUND AND AIMS Several studies have suggested that polyunsaturated fatty acids , vitamins and minerals have beneficial effects on lipid profile and systemic inflammation in adults . METHODS AND RESULTS We examined the effects of a daily intake of milk enriched with longchain polyunsaturated fatty acids , oleic acid , carbohydrates , vitamins , minerals and low in saturated fatty acids ( SFAs ) for 5 months , on several cardiovascular ( CVD ) risk biomarkers in healthy children aged 8 - 14 years . In a r and omized double-blind placebo-controlled trial , a total of 107 children of both genders were assigned to two study groups : 1 ) a supplemented group ( SG , n=53 ) who consumed 0.6 L/day of an enriched dairy product , and 2 ) a control group ( CG , n=54 ) who consumed 0.6 L/day of st and ard whole milk . Both groups consumed the dairy drinks for 5 months , in addition to their usual diet . Serum levels of adhesion molecules as indices of vascular endothelial cell activation were assessed in both groups at 0 and 5 months as well as white blood cell counts , lipid profile , serum proteins , total serum calcium , 25-OH vitamin D , glucose , insulin and adiponectin . In the enriched dairy drink supplemented group , adhesion molecules E-selectin and ICAM-1 as well as lymphocyte levels decreased while plasma docosahexaenoic acid ( DHA ) and serum calcium concentrations increased . In the control group , serum total protein , transferrin , total cholesterol , HDL-cholesterol and adiponectin concentrations decreased . CONCLUSION The consumption of a milk enriched with fish oil , oleic acid , minerals and vitamins reduced indices of endothelial cell activation in the studied group of healthy children [16426962] OBJECTIVE We evaluated the effect of a micronutrient-fortified beverage on growth and morbidity in apparently healthy schoolchildren . METHODS This was a double-blind , placebo-controlled , matched-pair , cluster , r and omized study in semi-urban middle-income residential schoolchildren aged 6 to 16 y. Anthropometrics ( height and weight ) , clinical symptoms of deficiency , and morbidity data were collected at baseline in the supplemented group ( n = 446 in 10 grade s ) and the placebo group ( n = 423 in 10 grade s ) and after 14 mo of supplementation ( n = 355 in the supplement group and n = 340 in the placebo group from nine pairs ) . RESULTS After 14 mo of supplementation , there was a significant increase in mean increments of height and weight z scores of -0.04 and 0.02 , respectively , in the supplemented group compared with -0.14 and -0.09 in the placebo group . Velocity of weight ( 3.56 versus 3.00 ) was significantly ( P < 0.01 ) higher with supplementation . Although there were no differences in the incidence of common childhood diseases such as fever , cough and cold , diarrhea , and ear infections elicited for a reference period of 1 mo at every quarterly follow-up examination , the mean duration of illness ( calculated per person per year ) was significantly shorter ( 5.0 d ) in the supplemented group than in the placebo group ( 7.4 d ) . CONCLUSIONS The micronutrient-fortified beverage was beneficial in promoting growth and decreasing duration of common illnesses among middle-class residential schoolchildren who had adequate energy and protein intakes [20412603] OBJECTIVE To investigate the efficacy of biscuits fortified with different doses of vitamin A on improving vitamin A deficiency ( VAD ) , anaemia and physical growth of pre-school children . DESIGN A r and omised double-masked population -based field interventional trial with a positive control group . SETTING Banan district of Chongqing , China . SUBJECTS A total of 580 pre-school children aged 3 - 6 years were r and omly recruited into four groups . Children in groups I and II were given biscuits fortified with vitamin A at 30 % of the recommended daily intake ( RDA ) and 100 % of the RDA once a day for 9 and 3 months , respectively . Children in group III received biscuits containing 20,000 IU of vitamin A once a week for 3 months . Initially , the children in group IV received a 200,000 IU vitamin A capsule just once . At the beginning and end of the study , blood sample s were collected to measure Hb , serum retinol , retinol-binding protein and prealbumin , and weight and height were measured . RESULTS All the fortification types significantly decreased the prevalence of VAD and anaemia in each group ( P < 0.05 ) . The effect of 9-month intervention on group I was the most efficient ( P < 0.0045 ) . After intervention , the Z-scores of height-for-age , weight-for-age and weight-for-height in all groups increased markedly compared with baseline ( P < 0.05 ) , but no significant difference was observed among the groups . CONCLUSIONS Data indicated that consuming vitamin A-fortified biscuits with daily 100 % RDA for 3 months has the same effect on the improvement of VAD , anaemia and physical growth as did the weekly 20,000 IU and single 200,000 IU administration in pre-school children [18091768] Background / Objective : To develop a salt fortified with multiple micronutrients , to test its stability during storage and cooking , and to assess its efficacy in improving the micronutrient status and the health of schoolchildren . Subject/ Methods : A salt fortified with multiple micronutrients was developed containing chelated ferrous sulfate and microencapsulated vitamins A , B1 , B2 , B6 , B12 , folic acid , niacin , calcium pantothenate and iodine . Its stability during 20 min of cooking and 6 months of storage was determined . Thereafter , the efficacy of the salt was assessed in 5- to 15-year-old schoolchildren in Chennai , India . For the experimental group ( N=119 ) , the food in the school kitchen was cooked with fortified salt for a period of 1 year . The control group ( N=126 ) consisted of day scholars who did not eat at the school . Hemoglobin , red blood cell count , hematocrit , serum vitamin A and urinary iodine were measured at baseline and at the end of the study after 1 year . Results : All micronutrients were stable during cooking and storage . Over the study period , there was a significant improvement ( P<0.05 ) in hemoglobin , red cell count , urinary iodine and serum vitamin A in the experimental group , while there was a significant drop ( P<0.05 ) in hemoglobin , hematocrit , red cell count and urinary iodine in the control group . In the experimental group , there was a mean increase of 0.55 g/dl in hemoglobin , 0.001 l/l in hematocrit , 0.470 million/mm3 in red cell count , 212 μg/l in urinary iodine and 5.6 μg/dl in serum vitamin A. Conclusion : The study shows that the salt fortified with multiple micronutrients is stable during cooking and storage and effective in combating multiple micronutrient deficiencies [25591926] OBJECTIVE To assess oil consumption , vitamin A intake and retinol status before and a year after the fortification of unbr and ed palm oil with retinyl palmitate . DESIGN Pre-post evaluation between two surveys . SETTING Twenty-four villages in West Java . SUBJECTS Poor households were r and omly sample d. Serum retinol ( adjusted for sub clinical infection ) was analysed in cross-sectional sample s of lactating mothers ( baseline n 324/endline n 349 ) , their infants aged 6 - 11 months ( n 318/n 335 ) and children aged 12 - 59 months ( n 469/477 ) , and cohorts of children aged 5 - 9 years ( n 186 ) and women aged 15 - 29 years ( n 171 ) , alongside food and oil consumption from dietary recall . RESULTS Fortified oil improved vitamin A intakes , contributing on average 26 % , 40 % , 38 % , 29 % and 35 % of the daily Recommended Nutrient Intake for children aged 12 - 23 months , 24 - 59 months , 5 - 9 years , lactating and non-lactating women , respectively . Serum retinol was 2 - 19 % higher at endline than baseline ( P<0·001 in infants aged 6 - 11 months , children aged 5 - 9 years , lactating and non-lactating women ; non-significant in children aged 12 - 23 months ; P=0·057 in children aged 24 - 59 months ) . Retinol in breast milk averaged 20·5 μg/dl at baseline and 32·5 μg/dl at endline ( P<0·01 ) . Deficiency prevalence ( serum retinol < 20 μg/dl ) was 6·5 - 18 % across groups at baseline , and 0·6 - 6 % at endline ( P≤0·011 ) . In multivariate regressions adjusting for socio-economic differences , vitamin A intake from fortified oil predicted improved retinol status for children aged 6 - 59 months ( P=0·003 ) and 5 - 9 years ( P=0·03 ) . CONCLUSIONS Although this evaluation without a comparison group can not prove causality , retinyl contents in oil , Recommended Nutrient Intake contributions and relationships between vitamin intake and serum retinol provide strong plausibility of oil fortification impacting vitamin A status in Indonesian women and children [22244363] In Vietnam , nutrition interventions do not target school children despite a high prevalence of micronutrient deficiencies . The present r and omised , placebo-controlled study evaluated the impact of providing school children ( n 403 ) with daily multiple micronutrient-fortified biscuits ( FB ) or a weekly Fe supplement ( SUP ) on anaemia and Fe deficiency . Micronutrient status was assessed by concentrations of Hb , and plasma ferritin ( PF ) , transferrin receptor ( TfR ) , Zn and retinol . After 6 months of intervention , children receiving FB or SUP had a significantly better Fe status when compared with the control children ( C ) , indicated by higher PF ( FB : geometric mean 36·9 ( 95 % CI 28·0 , 55·4 ) μg/l ; SUP : geometric mean 46·0 ( 95 % CI 33·0 , 71·7 ) μg/l ; C : geometric mean 34·4 ( 95 % CI 15·2 , 51·2 ) μg/l ; P < 0·001 ) and lower TfR concentrations ( FB : geometric mean 5·7 ( 95 % CI 4·8 , 6·52 ) mg/l ; SUP : geometric mean 5·5 ( 95 % CI 4·9 , 6·2 ) mg/l ; C : geometric mean 5·9 ( 95 % CI 5·1 , 7·1 ) mg/l ; P = 0·007 ) . Consequently , body Fe was higher in children receiving FB ( mean 5·6 ( sd 2·2 ) mg/kg body weight ) and SUP ( mean 6·1 ( sd 2·5 ) mg/kg body weight ) compared with the C group ( mean 4·2 ( sd 3·3 ) mg/kg body weight , P < 0·001 ) . However , anaemia prevalence was significantly lower only in the FB group ( 1·0 % ) compared with the C group ( 10·4 % , P = 0·006 ) , with the SUP group being intermediate ( 7·4 % ) . Children receiving FB had better weight-for-height Z-scores after the intervention than children receiving the SUP ( P = 0·009 ) . Vitamin A deficiency at baseline modified the intervention effect , with higher Hb concentrations in vitamin A-deficient children receiving FB but not in those receiving the SUP . This indicates that vitamin A deficiency is implicated in the high prevalence of anaemia in Vietnamese school children , and that interventions should take other deficiencies besides Fe into account to improve Hb concentrations . Provision of biscuits fortified with multiple micronutrients is effective in reducing anaemia prevalence in school children [14760518] Excessive intake of vitamin A is postulated to have a detrimental effect on bone by inducing osteoporosis . This may lead to an increased risk of fracture , particularly in persons who are already at risk of osteoporosis . However , few studies have specifically examined the association of vitamin A intake through diet and supplement use , with fractures in a cohort of older , community-dwelling women . We prospect ively followed a cohort of 34,703 postmenopausal women from the Iowa Women ’s Health Study to determine if high levels of vitamin A and retinol intake through food and supplement use were associated with an increased risk of hip or all fractures . A semiquantitative food frequency question naire was used to obtain the participants ’ baseline vitamin A and retinol intake . Participants were followed for a mean duration of 9.5 years for incident self-reported hip and nonhip fractures . After multivariate adjustment , it was revealed that users of supplements containing vitamin A had a 1.18-fold increased risk of incident hip fracture ( n=525 ) compared with nonusers ( 95 % CI , 0.99 to 1.41 ) , but there was no evidence of an increased risk of all fractures ( n=6,502 ) among supplement users . There was also no evidence of a dose-response relationship in hip fracture risk with increasing amounts of vitamin A or retinol from supplements . Furthermore , our results showed no association between vitamin A or retinol intake from food and supplements , or food only , and the risk of hip or all fractures . In conclusion , we found little evidence of an increased risk of hip or all fractures with higher intakes of vitamin A or retinol among a cohort of older , postmenopausal women [28978232] Background : Industrial food fortification is a major strategy to improve dietary micronutrient intakes and prevent deficiencies . Zambia introduced m and atory sugar fortification with vitamin A , at a target of 10 mg/kg , in 1998 . Representative surveys conducted since that time do not support marked improvement in vitamin A status . Objective : To describe vitamin A concentrations in retail sugar , as well as vendor practice s , perceptions of fortified foods , and sugar use practice s. Methods : We conducted a census of sugar vendors in one Zambian community , capturing information on vendors , available br and s and packaging options , and storage conditions . We purchased all br and s and package types of sugar available at each vendor . In a 15 % sub sample , we conducted semi-structured interviews with vendor – consumer pairs . We tested 50 % of sugar sample s at r and om for vitamin A using an iCheck portable fluorimeter . Results : The distribution of vitamin A in sugar in market sample s was highly skewed , with a median of 3.1 mg/kg ( 25th-75th percentiles : 1.8 - 5.5 ) and a range from 0.2 to 29.9 mg/kg . Only 11.3 % of sample s met the 10 mg/kg statutory requirement . Sugar was primarily repackaged and sold in small quantities , with rapid turnover of stocks . Perceptions of fortification by vendors and consumers were generally positive . Conclusions : Vitamin A in fortified sugar fell well below statutory requirements . Our data point to challenges at regional depot and /or poor adherence to fortification st and ards at the factory level . A renewed commitment to monitoring and enforcement will be required for Zambia to benefit from a food fortification strategy [8914548] Malnutrition is an inclusive term that entails the lack , excess or imbalance of one or more nutrients required to maintain normal nutritional status and optimal health . Malnutrition affects a large segment of the world 's children . 1 It is estimated that the prevalence of childhood malnutrition in South Africa ranges from 5 % to 50 % of the current poputation.2 It is well documented that an inadequate intake of micronutrients causes deficiency disorders and that such deficiencies often accompany malnutrTtion . 3 The dietary intake of calcium , iron , zinc , folic acid , riboflavin , vitamin 86 and vitamin C has been reported to be low , in comparison with the recommended dietary allowances (RDA),4 in a significant proportion of children in the country ; it is often lower than 67 % of the RDA , indicating a population at risk of deficiency.s » In adults 15 - 64 years of age , the dietary intake of such micronutrients as vitamin 8 6 , iron , calcium , magnesium , zinc , copper and folic acid has also been reported to be significantly lower than the RDA.S , S Fortification of food staples has been successfully implemented in a number of countries to increase the dietary intake of micronutrients . [26001905] Objectives To study the impact of sorghum diet on growth , and micronutrient status of school going children for a period of 8 mo . Methods Children ( n = 160 boys and n = 160 girls ) aged between 9 to 12 y were r and omly allocated into two groups ( n = 80 in the control and n = 80 in the experimental group ) to receive 60 % sorghum diet and 40 % of rice diet ( Exp G ) and regular rice diet ( 100 % ; CG ) . Anthropometric indices and biochemical parameters were measured at baseline and at 8 mo using st and ardized methods . Results The growth rate was significantly higher ( p < 0.01 ) in the Exp G of girls , whereas in boys it was in the CG . Hemoglobin ( Hb ) , serum ferritin , albumin , retinol binding protein ( RBP ) and iron levels were significantly improved ( p < 0.05 ) in the Exp G of both the genders and in boys , serum folic acid and calcium levels were also improved with sorghum diet . Conclusions Serum micronutrient status , in terms of hemoglobin , serum folic acid , albumin , RBP , ferritin , calcium and iron can be improved with sorghum supplementation in school going children [23256139] Vitamin A ( VA ) deficiency ( VAD ) continues to be a major nutritional problem in developing countries , including Central America . In Mexico , milk is a well-accepted vehicle for the administration of micronutrients , including VA , to preschoolers . Thus , we conducted a r and omized , controlled , clinical trial to investigate the efficacy of daily consumption of 250 mL of VA-fortified milk ( which provided 196 retinol equivalents/d ) for 3 mo on VA stores in mildly to moderately VAD ( serum retinol concentration 0.35 - 0.7 μmol/L ) preschoolers who were not enrolled in a food assistance program . Twenty-seven mildly to moderately VAD children were r and omly assigned based on screening measurements to either the intervention ( n = 14 ) or control group ( n = 13 ) ( children in the control group did not receive placebo ) . All children in the control group and 79 % ( n = 11 ) of the children in the intervention group completed the study . The total body VA ( TBVA ) pool size was estimated using the deuterated retinol dilution technique before and after the intervention . After 3 mo , median changes in the serum retinol concentration for the intervention and control groups were 0.13 and -0.21 μmol/L , respectively ( P = 0.009 ) . Median changes in the TBVA stores were 0.06 and 0.01 mmol , respectively ( P = 0.006 ) and estimated median changes in the liver VA concentration were 0.09 and 0.01 μmol/g , respectively ( P = 0.002 ) . The VA-fortified milk was well accepted among preschoolers and significantly increased TBVA stores , liver VA stores , and serum retinol concentration , indicating that it may be an effective means to ameliorate VAD in young Mexican children [12462948] It was investigated the efficacy of a diet with caloric restriction ( 1350 kcal/day ) in correction of clinical and biochemical parameters in patients with type 2 diabetes mellitus with overweight and obesity . In study showed that the 3 week use of hypocaloric diet allows reduce significantly body overweight , hyperglycemia and hyperholesterolemia in this patients without side effects . Vitamin and mineral supplements in long use of hypocaloric diet are recommended [19321576] Concurrent micronutrient deficiencies are prevalent among Vietnamese school children . A school-based program providing food fortified with multiple micronutrients could be a cost-effective and sustainable strategy to improve health and cognitive function of school children . However , the efficacy of such an intervention may be compromised by the high prevalence of parasitic infestation . To evaluate the efficacy of school-based intervention using multi-micronutrient-fortified biscuits with or without deworming on anemia and micronutrient status in Vietnamese schoolchildren , a r and omized , double-blind , placebo-controlled trial was conducted among 510 primary schoolchildren , aged 6 - 8 y , in rural Vietnam . Albendazole ( Alb ) ( 400 mg ) or placebo was given at baseline . Nonfortified or multi-micronutrient-fortified biscuits including iron ( 6 mg ) , zinc ( 5.6 mg ) , iodine ( 35 microg ) , and vitamin A ( 300 microg retinol equivalents ) were given 5 d/wk for 4 mo . Multi-micronutrient fortification significantly improved the concentrations of hemoglobin ( + 1.87 g/L ; 95 % CI : 0.78 , 2.96 ) , plasma ferritin ( + 7.5 microg/L ; 95 % CI : 2.8 , 12.6 ) , body iron ( + 0.56 mg/kg body weight ; 95 % CI : 0.29 , 0.84 ) , plasma zinc ( + 0.61 micromol/L ; 95 % CI : 0.26 , 0.95 ) , plasma retinol ( + 0.041 micromol/L ; 95 % CI : 0.001 , 0.08 ) , and urinary iodine ( + 22.49 micromol/L ; 95 % CI : 7.68 , 37.31 ) . Fortification reduced the risk of anemia and deficiencies of zinc and iodine by > 40 % . Parasitic infestation did not affect fortification efficacy , whereas fortification significantly enhanced deworming efficacy , with the lowest reinfection rates in children receiving both micronutrients and Alb . Multi-micronutrient fortification of biscuits is an effective strategy to improve the micronutrient status of Vietnamese schoolchildren and enhances effectiveness of deworming [25441589] OBJECTIVE The aim of this study was to assess the vitamin A and anthropometric status of South African preschool children from four areas with known distinct eating patterns . METHODS Serum retinol , anthropometric indicators , and dietary intake were determined for r and omly selected preschool children from two rural areas , i.e. KwaZulu-Natal ( n = 140 ) and Limpopo ( n = 206 ) ; an urban area in the Northern Cape ( n = 194 ) ; and an urban metropolitan area in the Western Cape ( n = 207 ) . RESULTS Serum retinol < 20 μg/dL was prevalent in 8.2 % to 13.6 % children . Between 3 % ( urban-Northern Cape ) and 44.2 % ( rural-Limpopo ) children had received a high-dose vitamin A supplement during the preceding 6 mo . Vitamin A derived from fortified bread and /or maize meal ranged from 65 μg retinol activity equivalents ( 24%-31 % of the Estimated Average Requirement ) to 160 μg retinol activity equivalents ( 58%-76 % Estimated Average Requirement ) . Fortified bread and /or maize meal contributed 57 % to 59 % of total vitamin A intake in rural children , and 28 % to 38 % in urban children . Across the four areas , stunting in children ranged from 13.9 % to 40.9 % ; and overweight from 1.2 % to 15.1 % . CONCLUSION Prevalence of vitamin A deficiency was lower than national figures , and did not differ across areas despite differences in socioeconomics , dietary intake , and vitamin A supplementation coverage . Rural children benefited more from the national food fortification program in terms of vitamin A intake . Large variations in anthropometric status highlight the importance of targeting specific nutrition interventions , taking into account the double burden of overnutrition and undernutrition [22908698] Background Fortification of flour is one of the approaches for the control and prevention of vitamin and mineral deficiencies . Objective To assess the effect of fortification of flour with seven vitamins and minerals on a population of Chinese women . Methods Farmers who offered their l and for reforestation in 25 northwest provinces of China received compensation in the form of wheat flour ; the amount of flour given depended on the amount of l and that was given up for reforestation . This study observed the effects of providing families with fortified flour in the reforestation areas in Gansu Province . The study was conducted for 3 years . Families in the intervention village who offered l and for reforestation received flour fortified with seven vitamins and minerals , and those in the control village received unfortified flour . Seven surveys , spaced at least 6 months apart , were carried out in each village from 2004 to 2007 . At baseline and at each annual survey , measurements and blood sample s were taken from 300 adult female subjects aged 20 to 60 years to assess dietary intake , height , weight , body fat , hemoglobin , serum retinol , serum iron , free erythrocyte protoporphyrin , serum zinc . Serum folic acid was measured at baseline and 36-month only . At each 6-month survey , data were collected on anthropometric features , hemoglobin , and dietary intake . Results Consumption of fortified flour in the intervention village ranged from 158.7 to 232.7 g per person per day . Serum retinol status was significantly improved after 12-month intervention until the end of the trial compared with both the control group and the baseline level of the intervention group . Iron status expressed as FEP and SI levels showed higher than that of the control group and baseline levels only at 36-month . Hemoglobin levels of the intervention group were higher than that of the control group and baseline levels , but anemia prevalence of both the intervention and control groups remained unchanged in the intervention period . Levels of serum zinc showed increases compared with the control group and baseline data at 24-month and 36-month , and levels of serum folic acid of intervention group in 36-month was higher than that of both the control group and baseline level . Conclusions The evidence from this study confirms the positive bioeffectiveness of fortified flour in the rural female population in China , but a higher dosage of electrolytic elementary iron in flour fortification was suggested for anemia prevention and control [16153327] OBJECTIVE To evaluate the effectiveness of a vitamin-fortified maize meal to improve the nutritional status of 1 - 3-year-old malnourished African children . DESIGN A r and omised parallel intervention study was used in which 21 experimental children and their families received maize meal fortified with vitamin A , thiamine , riboflavin and pyridoxine , while 23 control children and their families received unfortified maize meal . The maize meal was provided for 12 months to replace the maize meal habitually consumed by these households . METHODS Sixty undernourished African children with height-for-age or weight-for-age below the 5th percentile of the National Center for Health Statistics ' criteria and aged 1 - 3 years were r and omly assigned to an experimental or control group . Baseline measurements included demographic , socio-economic and dietary data , as well as height , weight , haemoglobin , haematocrit , serum retinol and retinol-binding protein ( RBP ) . Anthropometric , blood and serum variables were measured again after 12 months of intervention . Complete baseline measurements were available for 44 children and end data for only 36 . Changes in these variables from baseline to end within and between groups were assessed for significance with paired t-tests , t-tests and analysis of variances using the SPSS program , controlling for expected weight gain in this age group over 12 months . Relationships between changes in variables were examined by calculating correlation coefficients . RESULTS The children in the experimental group had a significantly ( P < or = 0.05 ) higher increase in body weight than control children ( 4.6 kg vs. 2.0 kg ) and both groups had significant ( P < or = 0.05 ) but similar increases in height . The children in the experimental group showed non-significant increases in haemoglobin and serum retinol , while the control children had a significant ( P = 0.007 ) decrease in RBP . The change in serum retinol showed a significant correlation with baseline retinol ( P = 0.014 ) , RBP ( P = 0.007 ) and weight ( P = 0.029 ) , as well as with changes in haemoglobin ( P = 0.029 ) . CONCLUSION Despite a small sample size , this study showed positive effects of a vitamin-fortified maize meal on weight gain and some variables of vitamin A status in 1 - 3-year-old African children . The study confirmed the relationship between vitamin A and iron status . The results suggest that fortification of maize meal would be an effective strategy to address micronutrient deficiencies in small children in South Africa [20439555] Objective : To determine the efficacy of p and esal baked from wheat flour fortified with iron , with or without vitamin A ( VA ) , in improving anemic schoolchildren 's iron and anthropometric status . Methods : Anemic 6- to 12-year-old Filipino children ( n = 250 ) received two 60 g p and esal daily for 8 months . They were r and omized into 1 of 4 groups : ( 1 ) iron-fortified ( with hydrogen-reduced iron at 80 mg/kg , electrolytic iron at 80 mg/kg , or ferrous fumarate at 40 mg/kg ) , ( 2 ) iron and VA-fortified , ( 3 ) VA-fortified ( at 490 RE/100 g ) , and ( 4 ) nonfortified flour . Hemoglobin ( Hb ) and zinc protoporphyrin ( ZnPP ) concentrations and weight and height were determined before and after intervention . Analyses of variance and chi-square and multiple regression analyses were performed . Results : Mean Hb increased by 1.3 g/dL ( p < 0.001 ) and mean ZnPP decreased by 24.4 µmol/mol ( p < 0.001 ) after 8 months . Anemia decreased to 26 % and iron deficiency decreased from 58 % to 12 % . After controls were applied for baseline concentration , age , and gender , Hb concentration at post intervention was significantly higher in the Iron + VA group than in the nonfortified group ( coefficient = 0.37 ; p = 0.034 ) . The odds of being iron deficient at post intervention were significantly lower in the Iron group than in the nonfortified group after controls were applied for age , gender , and baseline prevalence ( coefficient = 0.12 ; p = 0.006 ) . None of the 3 fortified groups had significantly different weight-for-age z-score , body mass index-for-age z-score , or height-for-age z-score compared with the nonfortified group after controls were applied for baseline z-scores , age , and gender . Conclusions : Our study shows that in a non – malaria-endemic area , iron fortification of flour significantly reduced the prevalence of iron deficiency among anemic schoolchildren , and double fortification with iron and VA significantly improved Hb status [23800099] Food fortification is a cost-effective and sustainable strategy to prevent or correct micronutrient deficiencies . A double-blind cluster ( bari ) r and omised controlled trial was conducted in a rural community in Bangladesh to evaluate the impact of consumption of chapatti made of micronutrient-fortified wheat flour for 6 months by school-aged children on their vitamin A , haemoglobin and iron status . A total of 43 baris ( group of households ) were r and omly selected . The baris were r and omly assigned to either intervention or control group . The intervention group received wheat flour fortified with added micronutrients ( including 66 mg hydrogen-reduced elemental iron and 3030 μg retinol equivalent as retinyl palmitate per kilogram of flour ) , while the control group received wheat flour without added micronutrients . A total of 352 children were enrolled in the trial , 203 in the intervention group and 149 in the control group . Analyses were carried out on children who completed the study ( 191 in the intervention group and 143 in the control group ) . Micronutrient-fortified wheat flour chapatti significantly increased serum retinol concentration at 6 months by 0.12 μmol L(-1 ) [ 95 % confidence interval ( CI ) : 0.06 , 0.19 ; P < 0.01 ] . The odds of vitamin A deficiency was significantly lower for children in the intervention group at 3 months [ odds ratio ( OR ) = 0.26 ; 95 % confidence interval ( CI ) : 0.07 , 0.89 ; P < 0.05 ] and 6 months ( OR = 0.21 ; 95 % CI : 0.06 , 0.68 ; P < 0.01 ) . No demonstrable effect of fortified chapatti consumption on iron status , haemoglobin levels or anaemia was observed . Consumption of fortified chapattis demonstrated a significant improvement in the vitamin A status , but not in iron , haemoglobin or anaemia status [20605698] OBJECTIVE Improvement of hemoglobin and serum retinol and facilitation of the mobilization of iron storage were achieved with a multiple-micronutrient-fortified diet in preschoolers for 6 mo in a suburb of Chongqing , China . We investigated whether fortification with multiple micronutrients in a diet for preschool children results in changes in children 's infectious morbidity compared with diets fortified solely with vitamin A and with vitamin A plus iron . METHODS From December 2005 to June 2006 , 226 2- to 6-y-old preschool children were recruited from three nurseries r and omly assigned to three different fortified-diet groups for 6 mo . Group I was fortified with vitamin A ; groups II and III were fortified with vitamin A plus iron and vitamin A plus iron , thiamine , riboflavin , folic acid , niacinamide , zinc , and calcium , respectively . The secondary functional outcomes , morbidity of diarrhea and respiratory infection , were collected during supplementation . RESULTS The groups were comparable concerning compliance and loss to follow-up . There was evidence of a lower incidence rate of respiratory-related illnesses , diarrhea-related illness , fewer symptoms of runny nose , cough , and fever , and shorter duration of respiratory-related illnesses and cough for children in group III compared with children in groups I and II . However , there was no significantly or clinical ly important difference between children in groups I and II . CONCLUSION The beneficial effects on infectious morbidity over 6 mo , in addition to some biochemical improvements , highlight the potential of this micronutrient-fortified seasoning powder supplied in a diet for preschool children [20410083] Anemia and micronutrient deficiencies are common among Indian schoolchildren . We assessed the effectiveness of micronutrient fortification of meals cooked and fortified at school on anemia and micronutrient status of schoolchildren in Himalayan villages of India . In this placebo-controlled , cluster-r and omized study , 499 schoolchildren ( 6 - 10 y ) received either multiple micronutrients ( treatment group ) or placebo ( control group ) as part of school meals ( 6 d/wk ) for 8 mo . Both groups were dewormed at the beginning of the study . The micronutrient premix provided 10 mg iron , 375 microg vitamin A , 4.2 mg zinc , 225 microg folic acid , and 1.35 microg vitamin B-12 for each child per day ( approximately 75 % recommended dietary allowance ) . Blood sample s drawn before and after the intervention were analyzed for hemoglobin , ferritin , retinol , zinc , folate , and vitamin B-12 . Baseline prevalence of anemia ( 37 % ) , iron deficiency anemia ( 10 % ) , low serum ferritin ( 24 % ) , retinol ( 56 % ) , zinc ( 74 % ) , folate ( 68 % ) , and vitamin B-12 ( 17 % ) did not differ between groups . Postintervention , fewer in the treatment group had lower serum retinol [ odds ratio ( OR ) ( 95 % CI ) : 0.57 ( 0.33 - 0.97 ) ] and folate [ OR ( 95 % CI ) : 0.47 ( 0.26 - 0.84 ) ] than the control group . The serum vitamin B-12 concentration decreased in both groups , but the magnitude of change was less in the treatment than in the control group ( P < 0.05 ) . Total body iron ( TBI ) increased in both groups ; however , the change was greater in the treatment than in the control group ( P < 0.05 ) . Micronutrient fortification of school meals by trained school personnel was effective in improving vitamin A , folate , and TBI status while also reducing the magnitude of a decrease in vitamin B-12 status Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Vitamins and minerals are essential for growth and maintenance of a healthy body , and have a role in the functioning of almost every organ . Multiple interventions have been design ed to improve micronutrient deficiency , and food fortification is one of them . OBJECTIVES To assess the impact of food fortification with multiple micronutrients on health outcomes in the general population , including men , women and children . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

20614448

[18779540] BACKGROUND Anemia in patients with solid tumors is a common problem that is associated with impaired exercise capacity , increased fatigue , and lower quality of life ( QoL ) . Erythropoiesis-stimulating agents ( ESAs ) have been shown to improve these outcomes ; however , it is unknown if additional benefits can be achieved with aerobic exercise training . METHODS We conducted a single-center , prospect i ve , r and omized , controlled trial in 55 mild-to-moderately anemic patients with solid tumors . Patients were r and omized to either darbepoetin alfa alone ( DAL , n = 29 ) or darbepoetin alfa plus aerobic exercise training ( DEX ; n = 26 ) . The DEX group performed aerobic exercise training three times per week at 60%-100 % of baseline exercise capacity for 12 weeks . The primary endpoint was QoL assessed by the Functional Assessment of Cancer Therapy-Anemia scale . Secondary endpoints were fatigue , cardiorespiratory fitness ( VO(2peak ) ) , hemoglobin ( Hb ) response , and darbepoetin alfa dosing . RESULTS Intention-to-treat analyses indicated significant improvements in QoL and fatigue in both groups over time but there were no between-group differences . The DEX group had a significantly greater VO(2peak ) than the DAL group ( mean group difference , + 3.0 ml/kg per minute ; 95 % confidence interval , 1.2 - 4.7 ; p = .001 ) and there were borderline significant differences in favor of the DEX group for Hb response and darbepoetin alfa dosing . CONCLUSIONS Aerobic exercise training did not improve QoL or fatigue beyond the established benefits of DAL but it did result in favorable improvements in exercise capacity and a more rapid Hb response with lower dosing requirements . Our results may be useful to clinicians despite the more recent restrictions on the indications for ESAs [9893656] The aim of this study was to evaluate a low-dose regimen of megestrol acetate ( MA ; 320 mg/day ) on appetite in advanced cancer patients . Out- patients with far-advanced non-hormone responsive tumours and loss of appetite were r and omised in a phase III trial , with two consecutive phases : a 14-day double-blind placebo controlled phase ( phase A ) and a 76-day open phase ( phase B ) . During phase A , patients were treated with MA , two 160 mg tablets/day , or placebo . In phase B , the MA dose was titrated to clinical response in both groups . Appetite , food intake , body weight , performance status , mood and quality of life were evaluated with st and ardised measures ; patients ' global judgement about treatment efficacy was also requested . Of 42 patients entering the study , 33 ( 17 MA and 16 placebo ) were evaluable for efficacy . The appetite score improved significantly with MA after 7 days ( P = 0.0023 ) , and this effect was still significant at 14 days ( P = 0.0064 ) . Patients judged the treatment with MA effective in 88.2 % of cases ( 14th day ) , whilst placebo was considered effective by 25 % ( P = 0.0003 ) . None of the other measures showed significant changes during treatment . The remarkable effect on appetite evident after 7 days , without serious side-effects , shows that MA can produce significant subjective effects at a low-dose even in patients with far-advanced disease [2698804] The effectiveness of an 8-week , 125 mg/day intravenous course of methylprednisolone sodium succinate ( MPSS ) for improving quality of life in patients with preterminal cancer was investigated in a double-blind , placebo-controlled , multicenter study . Quality of life was assessed using the Nurses ' Observational Scale for Inpatient Evaluation ( NOSIE ) , the Linear Analog Self- Assessment Scale ( LASA ) , and the Physicians ' Global Evaluation . A total of 403 patients were enrolled : 207 were treated with MPSS and 196 were treated with placebo . MPSS was significantly more effective than placebo in improving quality of life as judged by the changes from baseline in the NOSIE and LASA total scores . ( P less than 0.05 ) and by the Physicians ' Global Evaluation ( P less than 0.001 ) . The mortality rate was similar between MPSS-treated males ( 40.2 % ) , placebo-treated males ( 35.5 % ) , and MPSS-treated females ( 40.0 % ) . However , the mortality rate of 27.7 % for female placebo-treated females was significantly lower than for their MPSS-treated counterparts . The reason for lower mortality among placebo-treated females is unknown and warrants further study [1968469] Patients with breast cancer treated with MPA often report an improvement in appetite . Similar appetite stimulation is seen in patients treated with some corticosteroids , but MPA has a potential advantage over these drugs in that it does not exert a catabolic effect . MPA ( 100 mg tds orally ) has therefore been compared with placebo in 60 patients with advanced malignant disease . Twenty-one patients in the MPA group and 20 in the placebo group were receiving chemotherapy . Patients were treated for 6 weeks and were assessed at weeks 0 , 3 and 6 for appetite , energy , mood and pain using visual analogue scales . Nutritional status was assessed by the measurement of serum proteins and anthropometrics . Karnofsky score was recorded as a measure of performance status . There was a significant improvement in appetite in the MPA group between weeks 0 ( pre- study ) and 3 ( P = 0.0002 ) and 0 and 6 ( P = 0.015 ) . There was no significant improvement in appetite in the placebo group . Supporting this finding was the significant increase in serum thyroid binding pre-albumin and retinol binding protein in the MPA group between weeks 0 and 3 and 0 and 6 ( P = 0.023 and P = 0.039 respectively ) . These two parameters showed no significant change in the placebo group . There was no change in anthropometric measurements , weight , performance status , energy , mood or pain in either group . These data indicate that there was a significant increase in appetite in anorexic patients with advanced cancer treated with MPA which was reflected in increases in rapid turnover proteins reported to reflect nutritional status . However , this apparent increase in appetite did not result in improved weight , performance status , energy levels , mood or relief of pain . Further studies to investigate the effect of higher doses of MPA are indicated [2483687] A total of 173 female terminal cancer patients were r and omized to treatment with daily 125 mg infusions of methylprednisolone sodium succinate or a matching placebo for a period of 8 consecutive weeks . Data were collected relative to quality of life , investigator assessment of efficacy and cause and time of death within the 8-week treatment period . Significant improvement in quality of life was reported across the 8-week follow-up period in the steroid group . Investigator global assessment of efficacy significantly favored the steroid-treatment patients . There were no significant differences between treatment groups with regard to overall mortality rates or time to death . The total number of reported adverse events did not differ significantly between treatment groups . However , significantly more steroid patients reported gastrointestinal and cardiovascular events . The severity and outcome of these events did not differ from the placebo patients . The results of this study confirm previous reports of steroid efficacy in improving quality of life in terminal cancer patients . The absence of any untoward effect on mortality and the favorable safety profile support the use of methylprednisolone as palliative therapy for terminal cancer patients [10675381] BACKGROUND Extracellular adenosine 5'-triphosphate ( ATP ) is involved in the regulation of a variety of biologic processes , including neurotransmission , muscle contraction , and liver glucose metabolism , via purinergic receptors . In nonr and omized studies involving patients with different tumor types including non-small-cell lung cancer ( NSCLC ) , ATP infusion appeared to inhibit loss of weight and deterioration of quality of life ( QOL ) and performance status . We conducted a r and omized clinical trial to evaluate the effects of ATP in patients with advanced NSCLC ( stage IIIB or IV ) . METHODS Fifty-eight patients were r and omly assigned to receive either 10 intravenous 30-hour ATP infusions , with the infusions given at 2- to 4-week intervals , or no ATP . Outcome parameters were assessed every 4 weeks until 28 weeks . Between-group differences were tested for statistical significance by use of repeated- measures analysis , and reported P values are two-sided . RESULTS Twenty-eight patients were allocated to receive ATP treatment and 30 received no ATP . Mean weight changes per 4-week period were -1.0 kg ( 95 % confidence interval [ CI ] = -1.5 to -0.5 ) in the control group and 0.2 kg ( 95 % CI = -0.2 to + 0.6 ) in the ATP group ( P = .002 ) . Serum albumin concentration declined by -1.2 g/L ( 95 % CI= -2.0 to -0.4 ) per 4 weeks in the control group but remained stable ( 0.0 g/L ; 95 % CI = -0.3 to + 0.3 ) in the ATP group ( P = .006 ) . Elbow flexor muscle strength declined by -5.5 % ( 95 % CI = -9.6 % to -1 . 4 % ) per 4 weeks in the control group but remained stable ( 0.0 % ; 95 % CI= -1.4 % to + 1.4 % ) in the ATP group ( P = .01 ) . A similar pattern was observed for knee extensor muscles ( P = .02 ) . The effects of ATP on body weight , muscle strength , and albumin concentration were especially marked in cachectic patients ( P = .0002 , P = .0001 , and P = . 0001 , respectively , for ATP versus no ATP ) . QOL score changes per 4-week period in the ATP group showed overall less deterioration than in the control group-physical scores ( -0.2 % versus -2.4 % ; P = . 0002 ) ; functional scores ( + 0.4 % versus -5.5 % ; P = .02 ) ; psychologic scores ( -0.7 % versus -2.4 % ; P = .11 ) ; overall QOL score ( + 0.1 % versus -3.5 % ; P = .0001 ) . CONCLUSIONS This r and omized trial demonstrates that ATP has beneficial effects on weight , muscle strength , and QOL in patients with advanced NSCLC [11176767] BACKGROUND Fatigue is a commonly encountered symptom of human immunodeficiency virus ( HIV ) disease , associated with significant psychological and functional morbidity and poor quality of life . Preliminary studies on the treatment of fatigue from the cancer and multiple sclerosis literature suggest that psychostimulants may be effective in reducing fatigue . OBJECTIVE To compare the efficacy of 2 psychostimulant medications , methylpheni date hydrochloride ( Ritalin ) and pemoline ( Cylert ) , with a placebo intervention for the treatment of fatigue in patients with HIV disease . METHODS In this double-blind trial , 144 ambulatory patients with HIV disease and persistent and severe fatigue were r and omized to treatment with methylpheni date , pemoline , or placebo . Medications were titrated up to a maximum dose of 60 mg of methlypheni date hydrochloride , 150 mg of pemoline , or 8 capsules of placebo daily . Fatigue was measured using 2 self-reported rating scales , the Piper Fatigue Scale ( PFS ) and the Visual Analogue Scale for Fatigue ( VAS-F ) . We also used the timed isometric unilateral straight leg-raising task , a measure of muscular endurance . Quality -of-life and psychological well-being measures included the Beck Depression Inventory , the Brief Symptom Inventory , and the 36-Item Short-Form Medical Outcomes Study Health Status Survey . Side effects were monitored using the Systematic Assessment for Treatment Emergent Events and the Extra-pyramidal Symptom Rating Scale . All measures were rated weekly . RESULTS One hundred nine subjects completed the 6-week trial ; 15 patients ( 41 % ) receiving methylpheni date and 12 patients ( 36 % ) receiving pemoline demonstrated clinical ly significant improvement compared with 6 patients ( 15 % ) receiving placebo . Patients receiving methylpheni date or pemoline demonstrated significantly more improvement in fatigue on several self-reported rating scales ( PFS total score , P=.04 ; affective subscale , P=.008 ; sensory subscale , P=.04 ; and VAS-F energy subscale , P=.02 ) . Analysis of the regression slopes by means of hierarchical linear modeling demonstrated a significantly greater rate of improvement in PFS total scores among patients receiving psychostimulants compared with the placebo group ( P=.02 ) . There were no significant differences in the efficacy between methlypheni date and pemoline on any outcome measure studied . Improvement in fatigue was also significantly correlated with improvement in measures of depression , psychological distress , and overall quality of life . Severe side effects were relatively uncommon among this sample , and only hyperactivity or jitteriness occurred significantly more often among subjects receiving active medication . CONCLUSIONS Many patients with HIV- and acquired immunodeficiency syndrome-unrelated fatigue respond favorably to treatment with methylpheni date or pemoline . Both psychostimulants appear to be equally effective and significantly superior to placebo in decreasing fatigue severity with minimal side effects . Moreover , improvement of fatigue was significantly associated with improved quality of life and decreased levels of depression and psychological distress [2362337] Summary Anaemia commonly occurs in cancer patients receiving chemotherapy , often necessitating blood transfusion . This multicentre study was design ed to evaluate the efficacy and safety of epoetin α in preventing the decline in haemoglobin ( Hb ) level , and to determine whether the transfusion requirement could be reduced , in patients receiving 4–6 cycles of primarily platinum-based combination cyclic chemotherapy for small cell lung cancer ( SCLC ) . A total of 130 non-anaemic SCLC patients were r and omized to receive no additional treatment ( n = 44 ) , epoetin α 150 IU kg–1 subcutaneously ( s.c . ) three times a week ( n = 42 ) or 300 IU kg–1 s.c . three times a week ( n = 44 ) . Reductions in epoetin α dosage were made during the study if Hb level increased to > 15 g dl–1 . The mean weekly dosage was 335 and 612 IU kg–1 , respectively , in the two active treatment groups . Significantly fewer ( P < 0.05 ) epoetin α-treated patients experienced anaemia ( Hb < 10 g dl–1 ) during the course of chemotherapy ( 300 IU kg–1 , 39 % ; 150 IU kg–1 , 48 % ; untreated , 66 % ) . This was reflected in the significantly lower number of treated patients transfused [ 300 IU kg–1 , 20 % ( P < 0.001 ) ; 150 IU kg–1 , 45 % ( P < 0.05 ) ; untreated , 59 % ] . Epoetin α was well-tolerated , and there was no evidence of sustained , clinical ly significant , hypertension . In summary , epoetin α is effective and well-tolerated in maintaining Hb level and reducing transfusion requirement in patients undergoing cyclic chemotherapy for SCLC [12011126] PURPOSE To investigate the effect of recombinant human erythropoietin ( epoetin beta ) on anemia , transfusion need , and quality of life ( QOL ) in severely anemic patients with low- grade non-Hodgkin 's lymphoma ( NHL ) , chronic lymphocytic leukemia ( CLL ) , or multiple myeloma ( MM ) . PATIENTS AND METHODS Transfusion-dependent patients with NHL ( n = 106 ) , CLL ( n = 126 ) , or MM ( n = 117 ) and a low serum erythropoietin concentration were r and omized to receive epoetin beta 150 IU/kg or placebo subcutaneously three times a week for 16 weeks . Primary efficacy criteria were transfusion-free and transfusion- and severe anemia-free survival ( hemoglobin [ Hb ] > 8.5 g/dL ) between weeks 5 to 16 . Response was defined as an increase in Hb > or = 2 g/dL with elimination of transfusion need . QOL was assessed by the Functional Assessment of Cancer Therapy scale . RESULTS Transfusion-free ( P = .0012 ) survival and transfusion- and severe anemia-free survival ( P = .0001 ) were significantly greater in the epoetin beta group versus placebo ( Wald chi(2 ) test ) , giving a relative risk reduction of 43 % and 51 % , respectively . The response rate was 67 % and 27 % in the epoetin beta versus the placebo group , respectively ( P < .0001 ) . After 12 and 16 weeks of treatment , QOL significantly improved in the epoetin beta group compared with placebo ( P < .05 ) ; this improvement correlated with an increase in Hb concentration ( > or = 2 g/dL ) . A target Hb that could be generally recommended could not be identified . CONCLUSION Many severely anemic and transfusion-dependent patients with advanced MM , NHL , and CLL and a low performance status benefited from epoetin therapy , with elimination of severe anemia and transfusion need , and improvement in QOL [19896571] Cancer and its treatment can induce subjective and objective evidence of diminished functional capacity encompassing physical fatigue and cognitive impairment . Dexmethylpheni date ( D-MPH ; the D-isomer of methylpheni date ) was evaluated for treatment of chemotherapy-related fatigue and cognitive impairment . A r and omized , double-blind , placebo-controlled , parallel-group study evaluated the potential therapeutic effect and safety of D-MPH in the treatment of patients with chemotherapy-related fatigue . Change from baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue Subscale ( FACIT-F ) total score at Week 8 was the primary outcome measure . One hundred fifty-four patients ( predominantly with breast and ovarian cancers ) were r and omized and treated . Compared with placebo , D-MPH-treated subjects demonstrated a significant improvement in fatigue symptoms at Week 8 in the FACIT-F ( P=0.02 ) and the Clinical Global Impression-Severity scores ( P=0.02 ) , without clinical ly relevant changes in hemoglobin levels . Cognitive function was not significantly improved . There was a higher rate of study drug-related adverse events ( AEs ) ( 48 of 76 [ 63 % ] vs. 22 of 78 [ 28 % ] ) and a higher discontinuation rate because of AEs ( 8 of 76 [ 11 % ] vs. 1 of 78 [ 1.3 % ] ) in D-MPH-treated subjects compared with placebo-treated subjects . The most commonly reported AEs independent of study drug relationship in D-MPH-treated subjects were headache , nausea , and dry mouth , and in placebo-treated subjects were headache , diarrhea , and insomnia . D-MPH produced significant improvement in fatigue in subjects previously treated with cytotoxic chemotherapy . Further studies with D-MPH or other agents to explore treatment response in chemotherapy-associated fatigue should be considered [2741110] A multicentre study evaluated the efficacy and safety of darbepoetin alpha administered weekly ( QW ) , every 3 weeks ( Q3W ) , and every 4 weeks ( Q4W ) to anaemic patients with cancer not concurrently receiving chemotherapy or radiotherapy . The QW portion ( n=102 ) was an open-label , sequential , dose-escalation design ; cohorts received darbepoetin alpha QW by subcutaneous ( s.c . ) injection at 0.5 , 1.0 , 2.25 , or 4.5 μg kg−1 week−1 for 12 weeks . The 12-week placebo-controlled , double – blind Q3W ( 6.75 μg kg−1 ) and Q4W ( 6.75 or 10.0 μg kg−1 ) schedules ( n=86 ) , which enrolled different patients , took place after the QW schedule and were followed by a 12-week , open-label phase . Patients were evaluated for change in haemoglobin end points and red blood cell transfusions , serum darbepoetin alpha concentration , and safety . Selected domains of health-related quality of life ( HRQOL ) were measured . With QW dosing , at least 70 % of each cohort had a haemoglobin increase from baseline of ⩾2 g dl−1 or a concentration ⩾12 g dl−1 ( haematopoietic response ) . In the 4.5 μg kg−1 QW cohort , all patients achieved a haematopoietic response ( 100 % ; 95 % confidence interval (CI)=100 , 100 ) . In the Q3W and Q4W schedules , all cohorts had at least 60 % of patients who achieved a haematopoietic response . Darbepoetin alpha effectively increases haemoglobin concentration when given QW , Q3W , or Q4W . Less-frequent administration may benefit patients with chronic anaemia of cancer and their caregivers alike [2361228] This multicentre , open-label , controlled clinical trial assessed the effects of epoetin alfa treatment on haematologic and quality of life ( QOL ) parameters in 182 anaemic ( Hb⩽12 g dl−1 ) ovarian cancer patients receiving platinum chemotherapy . Patients were r and omised 2 : 1 to receive epoetin alfa 10 000–20 000 IU three times weekly plus best st and ard treatment ( BST ) or BST only . Main study end points were changes from baseline in haemoglobin ( Hb ) level , transfusion requirements , and QOL . For the epoetin alfa group , mean Hb increased by 1.8 g dl−1 by weeks 4–6 and was significantly increased from baseline through study end ( P<0.001 ) . The mean change in Hb from baseline was significantly ( P<0.001 ) greater for epoetin alfa than BST patients at all postbaseline evaluations . Significantly fewer epoetin alfa than BST patients required transfusion(s ) after the first 4 weeks of treatment ( 7.9 vs 30.5 % ; P<0.001 ) . Also , significant ( P⩽0.04 ) differences favouring the epoetin alfa group over the BST group were found for all three median CLAS scores ( Energy Level , Ability to Do Daily Activities , Overall QOL ) and the median average CLAS score during chemotherapy . These findings support use of epoetin alfa to increase Hb levels , reduce transfusion use , and improve QOL in anaemic ovarian cancer patients receiving platinum chemotherapy [17762445] Background : Fatigue is a common symptom in cancer patients receiving radiation therapy . Patients and Methods : We conducted a double-blind r and omized crossover trial of multivitamins versus placebo in patients with breast cancer undergoing radiation therapy to evaluate fatigue and quality of life . Results : We r and omized 40 patients to either placebo or Centrum Silver . At the middle of the radiation treatments , patients were switched from placebo to multivitamins and vice versa . Patients answered the EORTC QLQ C-30 quality of life ( QOL ) and Chalder fatigue question naires at the beginning , middle , and end of radiation therapy . Both groups experienced decreases in general ( P = 0.009 ; P = 0.001 ) and physical fatigue scores ( P = 0.031 ; P = 0.029 ) at the end of the course of placebo compared with the assessment prior to this treatment . We also observed significant improvements in functional ( P = 0.026 ) and symptoms ( P = 0.016 ) score scales of the QOL question naire in the patients on placebo . No significant changes were elicited with the use of multivitamins . We also observed significantly lower rates of fatigue in the patients who had just finished a course of placebo as compared with patients finishing a course of multivitamins ( 0 vs. 25 % P = 0.035 ) . Conclusion : Multivitamins do not improve radiation-related fatigue in patients with breast cancer [15754122] Summary Background . Fatigue can significantly interfere with a cancer patient ’s ability to fulfill daily responsibilities and enjoy life . It commonly co-exists with depression in patients undergoing chemotherapy , suggesting that administration of an antidepressant that alleviates symptoms of depression could also reduce fatigue . Methods . We report on a double-blind clinical trial of 94 female breast cancer patients receiving at least four cycles of chemotherapy r and omly assigned to receive either 20 mg of the selective serotonin re-uptake inhibitor ( SSRI ) paroxetine ( Paxil ® , SmithKline Beecham Pharmaceuticals ) or an identical-appearing placebo . Patients began their study medication seven days following their first on- study treatment and continued until seven days following their fourth on- study treatment . Seven days after each treatment , participants completed question naires measuring fatigue ( Multidimensional Assessment of Fatigue , Profile of Mood States-Fatigue/Inertia subscale and Fatigue Symptom Checklist ) and depression ( Profile of Mood States-Depression subscale [ POMS-DD ] and Center for Epidemiologic Studies -Depression [ CES-D ] ) . Results . Repeated- measures ANOVAs , after controlling for baseline measures , showed that paroxetine was more effective than placebo in reducing depression during chemotherapy as measured by the CES-D ( p=0.006 ) and the POMS-DD ( p=0.07 ) but not in reducing fatigue ( all measures , ps > 0.27 ) . Conclusions . Although depression was significantly reduced in the 44 patients receiving paroxetine compared to the 50 patients receiving placebo , indicating that a biologically active dose was used , no significant differences between groups on any of the measures of fatigued were observed . Results suggest that modulation of serotonin may not be a primary mechanism of fatigue related to cancer treatment [15452187] PURPOSE To determine whether weekly epoetin alfa could improve hemoglobin ( HgB ) levels , reduce RBC transfusions , and improve quality of life ( QOL ) in patients with advanced cancer and with anemia after receiving myelosuppressive chemotherapy . PATIENTS AND METHODS This double-blind , placebo-controlled study r and omly assigned patients to placebo or epoetin alfa ( Ortho Biotech , Bridgewater , NJ ) 40,000 U subcutaneous weekly for 16 weeks . QOL , HgB , and RBC transfusions were measured pretreatment and monthly . RESULTS The study accrued 344 patients ; 330 were assessable for efficacy and 305 were assessable for QOL . Placebo-treated patients had a mean increase in HgB of 0.9 g/dL ( range , -3.8 to + 5.3 ) compared with 2.8 g/dL ( range , -2.2 to + 7.5 ) for epoetin-treated patients ( P < .0001 ) . During the study , 31.7 % of placebo-treated patients achieved a > or = 2 g/dL HgB increase compared with 72.7 % of epoetin-treated patients ( P < .0001 ) . The incidence of RBC transfusion for placebo and epoetin treatment arms was 39.6 % and 25.3 % ( P = .005 ) , respectively . The placebo group received 256 units of RBCs compared with 127 units in the epoetin group ( P < .0001 ) . The incidence of toxicity in the groups was similar . Changes in the average QOL scores from baseline to the end of the study were similar in the two groups ( P = not significant ) . The HgB responders ( irrespective of treatment arm ) had a mean change in Functional Assessment of Cancer Therapy ( FACT ) fatigue score from a baseline of + 5.1 compared with -2.1 for the nonresponders ( P = .006 ) . CONCLUSION Epoetin alfa significantly improved HgB and reduced transfusions in this patient population . These results support the use of weekly epoetin alfa as an ameliorative agent for cancer-related anemia [16622259] PURPOSE Maintaining dose-intensity with chemotherapeutic agents is hindered by a number of adverse effects including asthenia/fatigue . Tumor necrosis factor ( TNF ) is one of the cytokines responsible for the fatigue and cachexia associated with malignancies . We used etanercept ( TNF-decoy receptor ) to maintain dose-intensity of weekly docetaxel . PATIENTS AND METHODS Initially , 12 patients with advanced malignancies were r and omly assigned to either docetaxel 43 mg/m2 weekly alone ( cohort A ) or the same docetaxel dose plus etanercept 25 mg subcutaneously twice weekly ( cohort B ) . Subsequently , higher doses of docetaxel in combination with etanercept were evaluated . Pharmacokinetics ( PKs ) , nuclear factor-kappa B ( NF-kappaB ) activation , and intracellular cytokines levels were measured . Patients completed weekly question naires quantifying asthenia/fatigue . RESULTS Twenty-nine of 36 intended docetaxel doses during the first cycle were delivered in cohort A , and 35 of 36 doses were delivered in cohort B ( P = .055 ) . Three cohort B patients received additional cycles in the absence of disease progression or severe toxicity , whereas no patients from cohort A received additional cycles . Escalation to docetaxel 52 mg/m2 weekly with etanercept result ed in neutropenia , not fatigue , as the limiting adverse effect , and the addition of filgrastim permitted the maintenance of dose-intensity in additional patients . Patients r and omly selected to receive etanercept/docetaxel self-reported less fatigue ( P < .001 ) , and docetaxel PKs show no relevant influence of etanercept . NF-kappaB activation and increased expression of TNF-alpha were associated with increments in docetaxel dose . Antitumor activity was noticed exclusively in patients receiving etanercept . CONCLUSION The addition of etanercept is safe and had no impact on docetaxel concentrations . The significant improvement in tolerability and the trend toward preservation of dose-intensity suggests further exploration of TNF blockade as an adjunct to cancer therapies [12844250] The prevention of post-chemotherapy symptoms such as delayed emesis , anorexia , and fatigue induced by irinotecan has not been studied . We compared the effects of dexamethasone ( Dex ) with those of a placebo on these symptoms in a r and omized study . Seventy patients scheduled to receive irinotecan chemotherapy were enrolled in the study and r and omly divided into a treatment or a placebo group . In the treatment group , 8 mg of Dex were administered on days 2–4 after the start of chemotherapy . All patients in both groups received Dex and granisetron for prophylaxis against acute emesis on day 1 . We evaluated 68 patients ( 35 receiving Dex , 33 receiving the placebo ) . Although delayed emesis was completely prevented in most of patients in both groups ( Dex , 82.9 % ; placebo , 78.8 % ) , anorexia and fatigue were more completely prevented in those in the Dex group ( Dex , 62.9 % and 77.1 % , placebo , 39.4 % and 57.6 % , respectively ) . The effect of Dex on improving simultaneous prophylaxis against all three symptoms was almost significant ( Dex , 60.0 % ; placebo , 36.4 % ; P=0.058 ) . The safety profiles of the two groups were not discernibly different . These results suggest that treatment with Dex may be beneficial to reduce post-chemotherapy symptoms induced by irinotecan , specifically anorexia and fatigue , with acceptable toxicities [18262758] OBJECTIVE In April 2005 a phase III r and omized study was started to establish which was the most effective and safest treatment of cancer-related anorexia/cachexia syndrome and oxidative stress in improving identified primary endpoints : increase of lean body mass , decrease of resting energy expenditure ( REE ) , increase of total daily physical activity , decrease of interleukin-6 and tumor necrosis factor-alpha , and improvement of fatigue assessed by the Multidimensional Fatigue Symptom Inventory-Short Form ( MFSI-SF ) . METHODS All patients were given as basic treatment polyphenols plus antioxidant agents alpha-lipoic acid , carbocysteine , and vitamins A , C , and E , all orally . Patients were then r and omized to one of the following five arms : 1 ) medroxyprogesterone acetate/megestrol acetate ; 2 ) pharmacologic nutritional support containing eicosapentaenoic acid ; 3 ) L-carnitine ; 4 ) thalidomide ; or 5 ) medroxyprogesterone acetate/megestrol acetate plus pharmacologic nutritional support plus L-carnitine plus thalidomide . Treatment duration was 4 mo . The sample comprised 475 patients . RESULTS By January 2007 , 125 patients , well balanced for all clinical characteristics , were included . No severe side effects were observed . As for efficacy , an interim analysis on 125 patients showed an improvement of at least one primary endpoint in arms 3 , 4 , and 5 , whereas arm 2 showed a significant worsening of lean body mass , REE , and MFSI-SF . Analysis of variance comparing the change of primary endpoints between arms showed a significant improvement of REE in favor of arm 5 versus arm 2 and a significant improvement of MFSI-SF in favor of arms 1 , 3 , and 5 versus arm 2 . A significant inferiority of arm 2 versus arms 3 , 4 , and 5 for the primary endpoints lean body mass , REE , and MFSI-SF was observed on the basis of t test for changes . CONCLUSION The interim results obtained thus far seem to suggest that the most effective treatment for cancer-related anorexia/cachexia syndrome and oxidative stress should be a combination regimen . The study is still in progress and the final results should confirm these data [10387980] Advanced cancer is frequently associated with a significant anemia that may be due to the disease itself or the effect of concomitantly administered chemotherapeutic agents . In a series of double-blind , placebo-controlled trials , three population s of anemic cancer patients were r and omized to rHuEPO or placebo . The three population s were : A ) patients not receiving concomitant chemotherapy , B ) patients receiving chemotherapeutic regimens which did not contain cisplatin , and C ) patients receiving chemotherapeutic regimens which contained cisplatin . In the no-chemotherapy trials , patients were treated with rHuEPO ( 100 U/kg ) or placebo s.c . three times a week for up to eight weeks . In the two types of chemotherapy trials , patients were treated with rHuEPO ( 150 U/kg ) or placebo SC three times a week for 12 weeks . A total of 413 patients were enrolled in these trials ( 124 in the no-chemotherapy group , 157 in the no-cisplatin chemotherapy group and 132 in the cisplatin chemotherapy group ) . In each trial , patients r and omized to rHuEPO had a significantly greater ( p < .004 ) increase in hematocrit than placebo-treated patients . In the two types of chemotherapy trials combined , utilizing an rHuEPO dose of 150 U/kg , rHuEPO-treated patients had significantly lower ( p < /=.009 ) transfusion requirements ( percentage of patients transfused and mean units of blood transfused per patient ) than placebo-treated patients during months two and three , but not during month one . Quality -of-life parameters measured on a 100 mm visual analog scale significantly improved ( p<.05 ) in rHuEPO-treated patients whose hematocrit increased > /= 6 percentage points , compared to corresponding quality -of-life changes in placebo-treated patients . rHuEPO was well tolerated compared to placebo . The above results suggest that rHuEPO may be a useful agent to palliate the morbid consequences of the anemia that is often found in association with advanced cancer [19388866] CONTEXT AND OBJECTIVE Guaraná ( Paullinia cupana ) has been used medicinally for centuries . The aim of this study is evaluate the effectiveness of guaraná in the treatment of postradiation depression and fatigue . DESIGN AND SETTING This study had a double-blind r and omized design with crossover between experimental arms , at Faculdade de Medicina da Fundação do ABC . METHODS We conducted a r and omized double-blind crossover trial with 36 patients with breast cancer undergoing adjuvant radiation therapy . We r and omized patients to either guaraná 75 mg daily p.o . or to placebo . Patients were switched to the other experimental arm at the middle of the radiation treatment , which consisted of 28 daily fractions of 180 cGy . Evaluations were conducted at the beginning , at the middle , and at the end of radiation therapy . RESULTS We were unable to show any statistically significant differences between the guaraná and the placebo-treated group with any of the measured scores . Also , within the same group , we did not see any statistically significant associations during either the guaraná- or placebo-treated periods with any of the aforementioned measures . CONCLUSIONS We were unable to show that patients with breast cancer undergoing radiation therapy derive any advantage with guaraná over placebo for both fatigue and depressive symptoms [19164318] OBJECTIVE The efficacy and safety of weekly administration of epoetin beta ( EPO ) for chemotherapy-induced anemia ( CIA ) patients was evaluated . METHODS One hundred and twenty-two patients with lung cancer or malignant lymphoma undergoing chemotherapy were r and omized to the EPO 36 000 IU group or the placebo group . Hematological response and red blood cell ( RBC ) transfusion requirement were assessed . Quality of life ( QOL ) was assessed using the Functional Assessment of Cancer Therapy-Anemia ( FACT-An ) question naire . RESULTS Mean change in hemoglobin level with EPO increased significantly over placebo ( 1.4 + /- 1.9 g/dl versus -0.8 + /- 1.5 g/dl ; P < 0.001 ) . The proportion of patients with change in hemoglobin level > or = 2.0 g/dl was higher for EPO than those for placebo ( P < 0.001 ) . After 4 weeks of administration , the proportion of RBC transfusion or hemoglobin level < 8.0 g/dl was significantly lower for EPO than those for placebo ( P = 0.046 ) . The changes in the FACT-An total Fatigue Subscale Score ( FSS ) were less deteriorated with EPO than those with placebo . Progressive disease ( PD ) did not influence the change in hemoglobin level but there was less decrease in FSS in non-PD patients . No significant differences in adverse events were observed . Thrombovascular events and pure red cell aplasia related to EPO were not observed . Retrospective analysis of survival showing the hazard ratio of EPO to placebo was 0.94 . CONCLUSION Weekly administration of EPO 36 000 IU significantly increased hemoglobin level and ameliorated the decline of QOL in CIA patients over the 8-week administration period [9765767] PURPOSE To evaluate the effect of megestrol acetate at a lower dose than previously investigated on the symptoms of cachexia in patients with advanced cancer . METHODS A total of 84 patients with advanced , solid tumours not responsive to hormone therapy were enrolled in this double-blind , crossover study . During phase 1 , patients were r and omly assigned to receive megestrol acetate ( 160 mg 3 times daily ) for 10 days or placebo . During phase 2 , after a 2-day washout period , patients received the alternate treatment for 10 days . Patients underwent daily assessment s of activity , nausea , appetite and well-being by means of a visual analogue scale ( VAS ) . In addition , nutritional status ( weight , tricep skinfold measure , arm muscle circumference ) , energy intake , fatigue ( Piper Fatigue Scale ) and quality of life ( Functional Living Index-Cancer [ FLIC ] ) were assessed . RESULTS Among the 53 evaluable patients megestrol acetate result ed in a significant improvement in appetite ( p = 0.005 ) , activity ( p = 0.007 ) and well-being ( p = 0.03 ) . There was no significant change in the intensity of nausea , nutritional parameters , energy intake or FLIC scores . There was a significant improvement in 2 of the 3 factors measured by the Piper Fatigue Scale and in the overall fatigue score . Upon completion of the study , while still blind to the treatment condition , 30 patients indicated that they felt better overall after megestrol , 15 said they felt better after placebo , and 10 indicated no preference ( p = 0.001 ) . CONCLUSION Treatment with megestrol acetate results in rapid and significant improvement of symptoms in terminally ill patients at lower doses than previously reported . The effects are not secondary to nutritional changes . The FLIC quality -of-life question naire was unable to detect these changes [12877666] Summary . This phase 3 , r and omized , double‐blind , placebo‐controlled study was design ed to evaluate the efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies . Patients ( n = 344 ) with lymphoma or myeloma received darbepoetin alfa 2·25 μg/kg or placebo s.c . , once weekly for 12 weeks . The percentage of patients achieving a haemoglobin response was significantly higher in the darbepoetin alfa group ( 60 % ) than in the placebo group ( 18 % ) ( P < 0·001 ) , regardless of baseline endogenous erythropoietin level . However , increased responsiveness was observed in patients with lower baseline erythropoietin levels . Darbepoetin alfa also result ed in higher mean changes in haemoglobin than placebo from baseline to the last value during the treatment phase ( 1·80 g/dl vs 0·19 g/dl ) and after 12 weeks of treatment ( 2·66 g/dl vs 0·69 g/dl ) . A significantly lower percentage of patients in the darbepoetin alfa group received red blood cell transfusions than in the placebo group ( P < 0·001 ) . The efficacy of darbepoetin alfa was consistent for patients with lymphoma or myeloma . Improvements in quality of life were also observed with darbepoetin alfa . The overall safety profile of darbepoetin alfa was consistent with that expected for this patient population . Darbepoetin alfa significantly increased haemoglobin and reduced red blood cell transfusions in patients with lymphoproliferative malignancies receiving chemotherapy [2205358] This double‐blind , cross‐over trial was design ed to assess the effects of megestrol acetate ( MA ) on cancer‐induced cachexia . Forty consecutive malnourished patients with advanced non‐hormone‐responsive tumors receiving no antineoplastic treatment were r and omized to receive MA 480 mg/day versus placebo for 7 days . During day 8 , a cross‐over was made until day 15 . Appetite , pain , nausea , depression , energy , and well‐being were assessed with a visual analog scale ( 0 to 100 mm ) at 9:00 am and 4:00 pm during days 6 , 7 , 13 , and 14 . Weight ( W ; kg ) , tricep skinfold ( TS ; mm ) , arm circumference ( AC ; cm ) , and calf circumference ( CC ; cm ) were measured at days 1 , 8 , and 15 . Caloric intake ( CI ; Kcal/day ) was determined during days 6 , 7 , 13 , and 14 . In 31 evaluable patients , the percentual difference in appetite at 9:00 am , appetite at 4:00 pm , energy , and well‐being after MA was + 15.1 , + 14 , + 3.2 , and + 5.2 , versus −12 ( P = 0.03 ) , −5.1 ( P = 0.015 ) , −10 ( P = 0.024 ) , and −8.3 ( not significant ) after placebo . Percentual difference in W , TS , AC , and CC after MA was + 0.2 , + 1 , −0.1 , and + 0.4 versus −0.8 ( P = 0.03 ) , −0.8 ( P = 0.001 ) , −0.3 ( not significant ) , and −0.5 ( P = 0.04 ) after placebo . CI during MA was 3480 ± 1574 ( 48‐hour intake ) , versus 2793 ± 1542 ( P < 0.001 ) during placebo . Patients and investigators blindly chose MA in 20 ( 66 % , P = 0.023 ) and 28 cases ( 92 % , P < 0.001 ) , placebo in eight and two cases , and made no choice in three and one cases , respectively . Toxicity consisted of mild edema and nausea in three and two cases , respectively . After mean follow‐up of 27 ± 13 days , on an open basis , an average increase in W and AC of 4.8 ± 1.7 kg and 2.8 ± 1.7 cm was observed , respectively . The authors conclude that MA is a powerful appetite stimulant with subjective and objective effects on nutritional status [15748464] Impaired cognition , fatigue , and diminished quality of life ( QOL ) are commonly associated with breast cancer chemotherapy . This r and omized , double-blind , placebo-controlled pilot trial assessed the feasibility of quantifying the effects of epoetin alfa on cognitive function and mood , and evaluated its effects on fatigue and QOL in patients with breast cancer treated with anthracycline-based adjuvant or neoadjuvant chemotherapy . Patients were r and omized to receive epoetin alfa 40,000 U subcutaneously once weekly or placebo at the beginning of 4 cycles of chemotherapy administered over 12 weeks . Cognitive function was assessed by Executive Interview ( EXIT25 ) and Clock Drawing Tasks ; mood by Profile of Mood States ; anemia-related symptoms , including fatigue , by the Functional Assessment of Cancer Therapy-Anemia ( FACT-An ) subscale ; and QOL by Linear Analog Scale Assessment . Ninety-four patients were evaluable for efficacy and safety . Mean change in EXIT25 scores from baseline to cycle 4 in the epoetin alfa group was 1.3 + /- 3.3 ; the mean change was 0.3 + /- 2.4 in the placebo group ( a negative change indicates improved executive function ) . There was no difference between groups in mean change in EXIT25 score from baseline to 6-month follow-up assessment . Mean hemoglobin levels were higher in the epoetin alfa group compared with the placebo group after 4 cycles of chemotherapy . Epoetin alfa recipients had less of a decrease in FACT-An subscale scores from baseline to cycle 4 and improvement in FACT-An subscale scores at 6-month follow-up assessment compared with placebo . Epoetin alfa therapy was well tolerated . These data suggest that epoetin alfa may have attenuated the cognitive impairment and fatigue that occurred during adjuvant breast cancer chemotherapy [17972110] Background Women who receive adjuvant chemotherapy for breast cancer develop fatigue , and a subset reports cognitive impairment . Methylpheni date is reported to improve fatigue and to decrease cognitive impairment in other population s. Material s and methods Women were r and omised early during their chemotherapy to receive d-methylpheni date ( d-MPH ) , a form of methylpheni date , or an identical appearing placebo . All participants took placebo for one cycle to ensure compliance and then study medication until completion of chemotherapy . Subjects were assessed at baseline , end of chemotherapy and at ∼6 months follow-up with the High Sensitivity Cognitive Screen ( HSCS ) and the Hopkins Verbal Learning Test-Revised ( HVLT-R ) . They also completed the self-report Functional Assessment of Cancer Therapy-General ( FACT-G ) and FACT-F ( F = fatigue ) question naires , evaluating quality of life and fatigue . Results A total of 57 evaluable women were r and omised : 29 to d-MPH and 28 to placebo ; the study did not meet its accrual goal of 170 patients , mainly because women were reluctant to take additional medication in general and methylpheni date in particular . Groups were well matched for age ( median , 50 years ) and education . d-MPH and placebo were well tolerated . There were no significant differences between the r and omised groups in classification of cognitive function by HSCS or in summed FACT-F fatigue scores ( the primary endpoints of the study ) at any of the assessment s. There were also no differences in HLTV-R scores or quality of life . Conclusions This study is underpowered , but there are no trends to suggest that d-MPH , taken concurrently with adjuvant chemotherapy , improves quality of life or fatigue [9469326] PURPOSE The possibility that epoetin beta ( EPO ) could increase hemoglobin ( B-Hb ) levels and improve quality of life ( QoL ) in patients with advanced gastrointestinal cancers was investigated . PATIENTS AND METHODS One hundred patients with gastric , pancreatic , biliary , or colorectal cancers and subnormal B-Hb levels were included in a r and omized study to test low-dose EPO ( 2,000 U subcutaneously thrice weekly [ 2,000 group ] ) against a higher dose ( 10,000 U times three [ 10,000 group ] ) . Eighty-four patients were treated with chemotherapy . QoL was evaluated using the European Organization for Research and Treatment of Cancer ( EORTC ) QLQ-C30 instrument . RESULTS At baseline , mean B-Hb was 108 g/L with no difference between the groups . In the 10,000 group , an increase in B-Hb ( > 10 g/L ) was seen in 30 ( 73 % ) patients treated with chemotherapy , after a median of 4 weeks , whereas a corresponding increase in the 2,000 group was seen in 15 ( 30 % ) patients after a median of 10 weeks ( P < .001 ) . A difference in the proportion of responders ( five of eight v one of eight ) was also seen in the group of patients not treated with chemotherapy . The proportion of responders was independent of baseline endogenous serum EPO level or observed/predicted log10 serum (S)-EPO levels . Patients who demonstrated improved B-Hb levels also showed improvements in QoL parameters . Tumor response was usually also associated with QoL improvements . CONCLUSION Treatment with EPO at a dose of 10,000 U thrice weekly can rapidly and safely increase B-Hb levels in a high proportion of patients with advanced gastrointestinal cancers . QoL is influenced by the B-Hb increase , but also by the course of the underlying malignancy . It is therefore difficult to define clearly the clinical relevance of the B-Hb increase as such [18707619] Anaemia is common in patients receiving chemotherapy , causing symptoms that have a major impact on quality of life ( QoL ) . Epoetin beta rapidly increases haemoglobin ( Hb ) levels and improves QoL in anaemic patients with a variety of tumours . This was a r and omized , double-blind , parallel-group , dose-finding study assessing the efficacy and safety of once-weekly epoetin beta in patients with solid tumours receiving chemotherapy . Adult patients with anaemia ( Hb < 11 g/dL ) were r and omized to receive epoetin beta 30,000 IU or 20,000 IU once weekly for 12 weeks . All patients received oral iron supplementation . Haemoglobin levels , transfusion need and QoL [ Functional Assessment of Cancer Therapy-fatigue ( FACT-F ) subscale score ] were assessed at regular intervals . Fifty patients were r and omized ; 30 patients received epoetin beta 30,000 IU once weekly and 20 received 20,000 IU once weekly . Mean ( + /- SD ) increase in Hb from baseline to week 12 was 1.75 + /- 2.15 g/dL in the 30,000 IU group ( P = 0.008 vs. baseline ) and 1.04 + /- 1.75 g/dL in the 20,000 IU group ( non-significant ) . Haemoglobin response ( increase in Hb > or=2 g/dL from baseline ) was observed in 78.3 % of patients receiving epoetin beta 30,000 IU and 66.7 % receiving epoetin beta 20,000 IU . Improvements in FACT-F subscale score were significantly ( P < 0.001 ) correlated with increases in Hb level . Transfusion use was low during the study in both groups . Both epoetin beta regiments were well tolerated and there were no dose-dependent adverse events . Epoetin beta 30,000 IU once weekly is an effective and well-tolerated treatment of anaemia in patients with solid tumours [14673053] PURPOSE Fatigue and depression typically occur together in cancer patients , suggesting a common etiology , perhaps based on serotonin . This r and omized clinical trial tested whether paroxetine , a selective serotonin reuptake inhibitor antidepressant known to modulate brain serotonin , would reduce fatigue in cancer patients and whether any reduction was related to depression . PATIENTS AND METHODS Cancer patients undergoing chemotherapy for the first time were assessed for fatigue . Of 704 patients who reported fatigue at their second chemotherapy cycle , 549 patients were r and omly assigned to receive either 20 mg of oral paroxetine hydrochloride daily or placebo for 8 weeks . The assessment s of fatigue and depression were performed at cycles 3 and 4 of chemotherapy . RESULTS A total of 244 patients treated with paroxetine and 235 patients treated with placebo provided assessable data . No difference was detected in fatigue between patient groups . At the end of the study , there was a difference between groups in the mean level of depression ( Center for Epidemiologic Studies Depression scores , 12.0 v 14.8 , respectively ; P < .01 ) . CONCLUSION Paroxetine had no influence on fatigue in patients receiving chemotherapy . A possible explanation is that cancer-related fatigue does not involve a reduction in brain 5-HT levels [16619567] The objective of this r and omised , multicentre , double-blind clinical trial was to investigate the impact of PS76A2 , an aqueous mistletoe extract st and ardised to mistletoe lectins , on quality of life ( QoL ) in breast cancer patients . A total of 352 patients were r and omly allocated to 2 groups receiving PS76A2 ( 15 ng mistletoe lectin/0.5 ml ) or matching placebo twice weekly for 4 to 6 cycles of CMF ( cyclophosphamide , methotrexate , fluorouracil ) chemotherapy followed by 2 months follow-up . The primary efficacy end-point was the change from baseline of 3 FACT-G subscales ( physical , emotional and functional well-being ) during the fourth CMF cycle . Secondary measures included GLQ-8 ( 8 linear analogue self- assessment scales ) , Spitzer 's uniscale and haematological variables . The main variables of safety analysis were adverse events , including injection site reactions and clinical laboratory tests . The results showed that physical , emotional and functional well-being improved upon PS76A2 , but deteriorated following placebo . The treatment differences were statistically significant for the 3 subscales as well as for the summary score FACT-G , which was analysed as O'Brien 's rank sum of its 3 subscales : The total score increased by 4.40 + /- 11.28 , indicating a higher QoL after PS76A2 , but decreased by 5.11 + /- 11.77 with placebo ( p<0.0001 ) . The GLQ-8 sum of 8 LASA scales was analysed as a summary score of GLQ-5 ( sum of item nos. 1 , 5 , 6 , 7 , 8) and GLQ-3 ( sum of item nos. 2 , 3 , 4 ) . GLQ-5 characterises typical aspects of QoL , while GLQ-3 consists of 3 side-effects of CMF ( feeling sick , numbness or pins and needles , loss of hair ) . GLQ-5 decreased by 42.9 + /- 125.0 upon PS76A2 , indicating an improvement in QoL , but increased by 60.3 + /- 94.0 upon placebo ( p<0.0001 ) . GLQ-3 deteriorated in both groups ( PS76A2 : 13.9 + /- 52.4 ; placebo : 34.5 + /- 57.0 ) , but the differences in favour of PS76A2 were , nevertheless , statistically significant ( p=0.0007 ) . The total score GLQ-8 improved by 28.9 + /- 154.6 after PS76A2 and deteriorated by 94.8 + /- 141.1 after placebo ( p<0.0001 ) . Spitzer 's uniscale improved by 12.2 + /- 30.7 upon PS76A2 and deteriorated by 10.8 + /- 26.1 with placebo ( p<0.0001 ) . After follow-up without chemotherapy , a significant treatment difference in favour of PS76A2 was determined by means of FACT-G , GLQ-8 and Spitzer 's uniscale . PS76A2 was well tolerated in this trial , with the exception of slight local reactions in 17.6 % of the PS76A2 group . In conclusion , PS76A2 ( 15 ng mistletoe lectin/0.5 ml twice weekly ) was shown to be safe and effective in improving QoL in breast cancer patients during chemotherapy and follow-up [17602062] This r and omized , controlled trial evaluated the effect of darbepoetin alfa on hospitalization days , transfusion requirements , hemoglobin levels , and fatigue in patients with anemia of cancer ( AOC ) . Eligible patients were anemic ( hemoglobin < or=11 g/dl ) due to cancer , > or=18 years old , and had not received chemotherapy or radiotherapy within 4 weeks of study screening . Patients were r and omized 4:1 to receive darbepoetin alfa , 3.0 microg/kg every 2 weeks ( Q2W ) ( n = 226 ) , or observation only for 12 weeks ( n = 59 ) , followed by an optional 9 weeks of darbepoetin alfa , 3.0 microg/kg Q2W . Endpoints were compared between the two treatment arms at week 13 . A planned interim analysis indicated that assumptions regarding hospitalization in the study design were incorrect , so the study was terminated early . Therefore , results for the primary endpoint should be interpreted cautiously . The hospitalization rate was similar ( 0.5 days ) for both the darbepoetin alfa and observation groups ( p = .73 ) . Transfusion incidence ( weeks 5 - 12 ) was significantly lower for darbepoetin alfa patients ( 8 % ) than for observation patients ( 22 % ) ( p = .0092 ) . By week 13 , hemoglobin increased by 2.1 g/dl in patients receiving darbepoetin alfa , compared with 0.1 g/dl in the observation group p < .0001 . Hemoglobin improvements were paralleled by an increase in Functional Assessment of Cancer Therapy-Fatigue score ( mean change in score at week 13 : darbepoetin alfa , 6.0 ; observation , 2.2 ; p < .05 ) . Darbepoetin alfa Q2W can significantly improve hemoglobin levels and reduce transfusion requirements in patients with AOC , result ing in significant improvements in health-related quality of life [16505427] PURPOSE To compare maintenance epoetin alfa administered once every 3 weeks with continued weekly epoetin alfa for patients with cancer-associated anemia . PATIENTS AND METHODS Eligible patients were r and omly assigned at enrollment to receive three weekly doses of epoetin alfa 40,000 U subcutaneously ( SC ) , followed by either st and ard weekly epoetin alfa ( 40 K arm ) or 120,000 U of epoetin alfa ( 120 K arm ) SC every 3 weeks for 18 additional weeks . RESULTS Three hundred sixty-five patients were enrolled . One hundred eighty-three patients were assigned to the 40 K arm , and 182 were assigned to the 120 K arm . There was no difference in the proportion of patients requiring transfusions during the study ( 23 % in 40 K arm and 18 % in 120 K arm , P = .22 ) or specifically during the maintenance phase ( 13 % in 40 K arm v 15 % in 120 K arm , P = .58 ) . Patients r and omly assigned to the 40 K arm were more likely to have a > or = 2 or > or = 3 g/dL hemoglobin ( Hb ) increment , were more likely to have a drug dose held because of high Hb , and had higher mean end-of- study Hb levels . Toxicities , including thromboembolism , and overall survival were similar . Patients in the 40 K arm had a higher global quality of life ( QOL ) at baseline for unclear reasons , whereas patients in the 120 K arm had a greater global QOL improvement during the study , so end-of- study QOL was equivalent . CONCLUSION After three weekly doses of epoetin alfa 40,000 U , a dose of 120,000 U can be administered safely once every 3 weeks without increasing transfusion needs or sacrificing QOL . The Hb increment is somewhat greater with continued weekly epoetin alfa . Lack of blinding as a result of different treatment schedules may have confounded results [12189224] BACKGROUND Patients receiving chemotherapy often develop anemia . Darbepoetin alfa ( Aranesp(TM ) ) is an erythropoiesis-stimulating glycoprotein that has been shown , in dose-finding studies , to be safe and clinical ly active when administered to patients with cancer every 1 , 2 , or 3 weeks . This phase III study compared the safety and efficacy of darbepoetin alfa with placebo in patients with lung cancer receiving chemotherapy . METHODS In this multicenter , double-blind , placebo-controlled study , 320 anemic patients ( hemoglobin < or=11.0 g/dL ) were r and omly assigned to receive darbepoetin alfa or placebo injections weekly for 12 weeks . The 297 patients who completed at least the first 28 days of study were assessed for red blood cell transfusions , the primary endpoint . Patients were also assessed for hemoglobin concentration ( i.e. , hematopoietic response ) , adverse events , antibody formation to darbepoetin alfa , hospitalizations , Functional Assessment of Cancer Therapy (FACT)-Fatigue score , and disease outcome . Efficacy endpoints were assessed using Kaplan-Meier analyses , Cox proportional hazards analyses , and chi-square tests where appropriate . All statistical tests were two-sided . RESULTS Patients receiving darbepoetin alfa required fewer transfusions ( 27 % versus 52 % ; mean difference = 25 % ; 95 % confidence interval [ CI ] = 14 % to 36 % ; P<.001 ) , required fewer units of blood ( 0.67 versus 1.92 ; mean difference = 1.25 , 95 % CI = 0.65 to 1.84 ; P<.001 ) , had more hematopoietic responses ( 66 % versus 24 % ; mean difference = 42 % ; 95 % CI = 31 % to 53 % ; P<.001 ) , and had better improvement in FACT-Fatigue scores ( 56 % versus 44 % overall improvement ; 32 % versus 19 % with > or=25 % improvement ; mean difference = 13 % ; 95 % CI = 2 % to 23 % , P = .019 ) than patients receiving placebo . Patients receiving darbepoetin alfa did not appear to have any untoward effect in disease outcome and did not develop antibodies to the drug . Adverse events were similar between the groups . CONCLUSIONS Patients with chemotherapy-associated anemia can safely and effectively be treated with weekly darbepoetin alfa therapy . Darbepoetin alfa decreased blood transfusion requirements , increased hemoglobin concentration , and decreased fatigue . Although no conclusions can be drawn about survival from this study , the potential salutary effect on disease outcome warrants further investigation in a prospect ively design ed study [11927189] We have previously shown that the risk of major depression in patients with malignant melanoma undergoing interferon-α ( IFN-α ) therapy can be reduced by pretreatment with the antidepressant , paroxetine . Using dimensional analyses , the present study assessed the expression and treatment responsiveness of specific clusters of neuropsychiatric symptoms over the first three months of IFN-α therapy . Forty patients with malignant melanoma eligible for IFN-α treatment were r and omly assigned to receive either paroxetine or placebo in a double-blind design . Neuropsychiatric assessment s were conducted at regular intervals during the first twelve weeks of IFN-α therapy and included the 21-item Hamilton Depression Rating Scale , the 14-item Hamilton Anxiety Rating Scale and the Neurotoxicity Rating Scale . Neurovegetative and somatic symptoms including anorexia , fatigue and pain appeared within two weeks of IFN-α therapy in a large proportion of patients . In contrast , symptoms of depressed mood , anxiety and cognitive dysfunction appeared later during IFN-α treatment and more specifically in patients who met DSM-IV criteria for major depression . Symptoms of depression , anxiety , cognitive dysfunction and pain were more responsive , whereas symptoms of fatigue and anorexia were less responsive , to paroxetine treatment . These data demonstrate distinct phenomenology and treatment responsiveness of symptom dimensions induced by IFN-α , and suggest that different mechanisms mediate the various behavioral manifestations of cytokine-induced “ sickness behavior . [11387359] PURPOSE This r and omized , double-blind , placebo-controlled clinical trial assessed the effects of epoetin alfa on transfusion requirements , hematopoietic parameters , quality of life ( QOL ) , and safety in anemic cancer patients receiving nonplatinum chemotherapy . The study also explored a possible relationship between increased hemoglobin and survival . PATIENTS AND METHODS Three hundred seventy-five patients with solid or nonmyeloid hematologic malignancies and hemoglobin levels < or = 10.5 g/dL , or greater than 10.5 g/dL but < or = 12.0 g/dL after a hemoglobin decrease of > or = 1.5 g/dL per cycle since starting chemotherapy , were r and omized 2:1 to epoetin alfa 150 to 300 IU/kg ( n = 251 ) or placebo ( n = 124 ) three times per week subcutaneously for 12 to 24 weeks . The primary end point was proportion of patients transfused ; secondary end points were change in hemoglobin and QOL . The protocol was amended before unblinding to prospect ively collect and assess survival data 12 months after the last patient completed the study . RESULTS Epoetin alfa , compared with placebo , significantly decreased transfusion requirements ( P = .0057 ) and increased hemoglobin ( P < .001 ) . Improvement of all primary cancer- and anemia-specific QOL domains , including energy level , ability to do daily activities , and fatigue , was significantly ( P < .01 ) greater for epoetin alfa versus placebo patients . Although the study was not powered for survival as an end point , Kaplan-Meier estimates showed a trend in overall survival favoring epoetin alfa ( P = .13 , log-rank test ) , and Cox regression analysis showed an estimated hazards ratio of 1.309 ( P = .052 ) favoring epoetin alfa . Adverse events were comparable between groups . CONCLUSION Epoetin alfa safely and effectively ameliorates anemia and significantly improves QOL in cancer patients receiving nonplatinum chemotherapy . Encouraging results regarding increased survival warrant another trial design ed to confirm these findings [12506181] PURPOSE To determine whether high doses of fish oil , administered over 2 weeks , improve symptoms in patients with advanced cancer and decreased weight and appetite . PATIENTS AND METHODS Sixty patients were r and omly assigned to fish oil capsules or placebo . Appetite , tiredness , nausea , well-being , caloric intake , nutritional status , and function were prospect ively assessed at days 1 and 14 . RESULTS The baseline weight loss was 16 + /- 11 and 16 + /- 8 kg in the fish oil ( n = 30 ) and placebo ( n = 30 ) group respectively , whereas the baseline appetite ( 0 mm = best and 10 mm = worst ) was 58 + /- 24 mm and 67 + /- 19 mm , respectively ( P = not significant ) . The mean daily dose was 10 + /- 4 ( fish oil group ) and 9 + /- 3 ( placebo group ) capsules , which provided 1.8 g of eicosapentaenoic acid and 1.2 g of docosahexaenoic acid in the fish oil group . No significant differences in symptomatic or nutritional parameters were found ( P < .05 ) , and there was no correlation between changes in different variables between days 1 and 14 and the fish oil doses . Finally , the majority of the patients were not able to swallow more than 10 fish oil capsules per day , mainly because of burping and aftertaste . CONCLUSION Fish oil did not significantly influence appetite , tiredness , nausea , well-being , caloric intake , nutritional status , or function after 2 weeks compared with placebo in patients with advanced cancer and loss of both weight and appetite [19415341] Purpose This pilot trial sought to investigate whether any of three doses of American ginseng ( Panax quinquefolius ) might help cancer-related fatigue . A secondary aim was to evaluate toxicity . Methods Eligible adults with cancer were r and omized in a double-blind manner , to receive American ginseng in doses of 750 , 1,000 , or 2,000 mg/day or placebo given in twice daily dosing over 8 weeks . Outcome measures included the Brief Fatigue Inventory , vitality subscale of the Medical Outcome Scale Short Form-36 ( SF-36 ) , and the Global Impression of Benefit Scale at 4 and 8 weeks . Results Two hundred ninety patients were accrued to this trial . Nonsignificant trends for all outcomes were seen in favor of the 1,000- and 2,000-mg/day doses of American ginseng . Area under the curve analysis of activity interference from the Brief Fatigue Inventory was 460–467 in the placebo group and 750 mg/day group versus 480–551 in the 1,000- and 2,000-mg/day arms , respectively . Change from baseline in the vitality subscale of the SF-36 was 7.3–7.8 in the placebo and the 750-mg/day arm , versus 10.5–14.6 in the 1,000- and 2,000-mg/day arms . Over twice as many patients on ginseng perceived a benefit and were satisfied with treatment over those on placebo . There were no significant differences in any measured toxicities between any of the arms . Conclusion There appears to be some activity and tolerable toxicity at 1,000–2,000 mg/day doses of American ginseng with regard to cancer-related fatigue . Thus , further study of American ginseng is warranted [11676354] OBJECTIVE Erythropoietin is shown to be an effective treatment for anemia in various types of cancers , however only limited studies have evaluated its benefits in advanced hormone-refractory prostate cancer ( HRPC ) . This multi-center study investigated the influence of 2 different doses of epoetin beta on quality of life , hemoglobin level , need for blood transfusion , and safety , in the treatment of anemia in patients with metastatic HRPC . MATERIAL S AND METHODS This study r and omized 180 patients to receive either epoetin beta 1000 IU or 5000 IU subcutaneously 3 times per week for 12 weeks . Hemoglobin was evaluated at study start and 6 time-points during the study . Quality of life ( QoL ) was assessed by the European Organization for Research and Treatment of Cancer question naire , QLC-C30 , before treatment start and after 6 and 12 weeks of treatment . Best supportive care and blood transfusions were given , if clinical ly indicated . Additional laboratory values and adverse events were followed for safety . RESULTS Hemoglobin increased significantly ( > 20 g/l ) in 43 % in the high dose ( HD ) group and 25 % in the low dose ( LD ) group in response to treatment . Levels were significantly higher in the HD group than the LD group ( p < 0.001 ) after 8 and 12 weeks . QoL improved significantly if the increase in hemoglobin was > 20 g/l . Significantly more patients in the LD group received blood transfusions than the HD group ( p < 0.005 ) . There were no differences between the groups regarding overall quality of life and fatigue . The treatment was well tolerated in both groups . CONCLUSIONS Epoetin beta is shown to be safe and effective for the treatment of anemia in many patients with HRPC . It is found to improve QoL and physical functioning , and relieve fatigue symptoms , in many of these critically ill patients [17869448] PURPOSE The quality of life ( QOL ) and neurocognitive function of patients with brain tumors are negatively affected by the symptoms of their disease and brain radiation therapy ( RT ) . We assessed the effect of prophylactic d-threo-methylpheni date HCl ( d-MPH ) , a central nervous system ( CNS ) stimulant on QOL and cognitive function in patients undergoing RT . METHODS AND MATERIAL S Sixty-eight patients with primary or metastatic brain tumors were r and omly assigned to receive d-MPH or placebo . The starting dose of d-MPH was 5 mg twice daily ( b.i.d . ) and was escalated by 5 mg b.i.d . to a maximum of 15 mg b.i.d . The placebo was administered as one pill b.i.d . escalating three pills b.i.d . The primary outcome was fatigue . Patients were assessed at baseline , the end of radiation therapy , and 4 , 8 , and 12 weeks after brain RT using the Functional Assessment of Cancer Therapy with brain and fatigue ( FACIT-F ) subscales , as well as the Center for Epidemiologic Studies Scale and Mini-Mental Status Exam . RESULTS The Mean Fatigue Subscale Score at baseline was 34.7 for the d-MPH arm and 33.3 for the placebo arm ( p = 0.61 ) . At 8 weeks after the completion of brain RT , there was no difference in fatigue between patient groups . The adjusted least squares estimate of the Mean Fatigue Subscale Score was 33.7 for the d-MPH and 35.6 for the placebo arm ( p = 0.64 ) . Secondary outcomes were not different between the two treatment arms . CONCLUSIONS Prophylactic use of d-MPH in brain tumor patients undergoing RT did not result in an improvement in QOL [16710026] PURPOSE Chemotherapy-induced anemia is widely treated in the United States with darbepoetin alfa ( DA ) or epoetin alfa ( EA ) . This noninferiority study systematic ally compares efficacy and safety of DA and EA using common doses and schedules used in clinical practice . METHODS Patients had a diagnosis of nonmyeloid malignancy with > or = 8 weeks of planned chemotherapy , age > or = 18 years , and anemia ( hemoglobin < or = 11 g/dL ) . Patients were r and omly assigned 1:1 to DA 200 microg every two weeks ( Q2W ) or EA 40,000 units every week ( QW ) for up to 16 weeks with identical dose adjustment rules . Efficacy was assessed by the incidence of RBC transfusion ( Kaplan-Meier estimate ) . The definition of noninferiority was that the upper 95 % CI limit of the observed difference in RBC transfusions between groups was less than 11.5 % ; this noninferiority margin was based on the treatment effect observed in placebo-controlled EA studies . RESULTS Of 1,220 patients r and omly assigned , 1,209 received > or = one dose of the study drug . Common tumor types were lung ( 26 % ) , breast ( 21 % ) , and gastrointestinal ( 18 % ) . Transfusion incidence from week 5 to the end of the treatment phase ( the primary end point ) was 21 % in the DA group and 16 % in the EA group ; noninferiority was concluded because the upper 95 % CI limit of the difference between groups ( 10.8 % ) was below the prespecified noninferiority margin . Sensitivity analyses using alternate statistical methods and analysis sets yielded similar results . Hemoglobin , quality of life , and safety end points further support equivalency of the erythropoietic therapies . CONCLUSION This large , phase III study demonstrates comparable efficacy of DA Q2W and EA QW . Less frequent dosing offers potential benefits for patients , caregivers and health care providers [15953714] This work was conducted to evaluate the effect of early intervention with epoetin alfa ( EPO ) on transfusion requirements , hemoglobin level ( Hb ) , quality of life ( QOL ) and to explore a possible relationship between the use of EPO and survival , in patients with solid tumors receiving platinum-based chemotherapy . Three hundred and sixteen patients with Hb12.1g/dL were r and omised 2:1 to EPO 10000 IU thrice weekly subcutaneously ( n = 211 ) or best supportive care ( BSC ) ( n = 105 ) . The primary end point was proportion of patients transfused while secondary end points were changes in Hb and QOL . The protocol was amended before the first patient was recruited to also prospect ively collect survival data . EPO therapy significantly decreased transfusion requirements ( P < 0.001 ) and increased Hb ( P < 0.005 ) . EPO-treated patients had significantly improved QOL compared with BSC patients ( P < 0.05 ) . Kaplan-Meier estimates showed no differences in 12-month survival ( P = 0.39 ) , despite a significantly greater number of patients with metastatic disease in the EPO group ( 78 % vs. 61 % , P = 0.001 ) . EPO was well tolerated . This study has shown that early intervention with EPO can result in a significant reduction of transfusion requirements and increases in Hb and QOL in patients with mild anemia during platinum-based chemotherapy [12743146] PURPOSE To determine whether fluoxetine improves overall quality of life ( QOL ) in advanced cancer patients with symptoms of depression revealed by a simple survey . PATIENTS AND METHODS One hundred sixty-three patients with an advanced solid tumor and expected survival between 3 and 24 months were r and omly assigned in a double-blinded fashion to receive either fluoxetine ( 20 mg daily ) or placebo for 12 weeks . Patients were screened for at least minimal depressive symptoms and assessed every 3 to 6 weeks for QOL and depression . Patients with recent exposure to antidepressants were excluded . RESULTS The groups were comparable at baseline in terms of age , sex , disease distribution , performance status , and level of depressive symptoms . One hundred twenty-nine patients ( 79 % ) completed at least one follow-up assessment . Analysis using generalized estimating equation modeling revealed that patients treated with fluoxetine exhibited a significant improvement in QOL as shown by the Functional Assessment of Cancer Therapy-General , compared with patients given placebo ( P = .01 ) . Specifically , the level of depressive symptoms expressed was lower in patients treated with fluoxetine ( P = .0005 ) , and the subgroup of patients showing higher levels of depressive symptoms on the two- question screening survey were the most likely to benefit from treatment . CONCLUSION In this mix of patients with advanced cancer who had symptoms of depression as determined by a two- question bedside survey , use of fluoxetine was well tolerated , overall QOL was improved , and depressive symptoms were reduced [9779721] PURPOSE To evaluate prospect ively the effectiveness of epoetin alfa as an adjunct to chemotherapy in patients with cancer based on changes in quality -of-life parameters and hemoglobin levels , and to correlate these changes with antitumor response . PATIENTS AND METHODS Two thous and three hundred seventy patients with nonmyeloid malignancies who received chemotherapy were enrolled onto this study from 621 US community-based practice s. Patients received epoetin alfa 10,000 U three times weekly , which could be increased to 20,000 U three times weekly depending on the hemoglobin response at 4 weeks . Treatment continued for a maximum of 16 weeks in patients who showed evidence of hematologic response . RESULTS Two thous and two hundred eighty-nine patients ( 97 % ) were eligible for efficacy analyses . Epoetin alfa therapy was associated with improved quality -of-life parameters ; these improvements correlated significantly with hemoglobin levels and were independent of tumor response . Provider-reported Karnofsky performance scores did not correlate with the improved quality -of-life changes . Epoetin alfa therapy was also associated with a significant increase in hemoglobin levels and decrease in transfusion use . Tumor type , chemotherapy agent/regimen , prior chemotherapy , baseline hemoglobin level , and baseline erythropoietin level were not predictive of a positive response to treatment . Epoetin alfa was well tolerated . CONCLUSION Epoetin alfa appears to have a beneficial impact on patient-reported functional capacity and quality of life in patients with cancer who received chemotherapy independent of tumor response . Concordantly , epoetin alfa appeared to increase hemoglobin levels and decrease transfusion use . Patients responded across all tumor types . The results suggest that epoetin alfa effectively improves functional outcomes in patients with cancer who receive chemotherapy [12782431] The purpose of this study was to assess whether the administration of recombinant human erythropoietin ( rHuEPO ) would correct anemia and improve the quality of life ( QOL ) in cancer patients receiving chemotherapy . One hundred twenty-two patients with hemoglobin < /=11.0 g/dl were r and omized to receive rHuEPO 10,000 U three times weekly ( n = 61 ) or no additional treatment ( n = 61 ) . Response was assessed by measuring changes in hemoglobin level and QOL . QOL was evaluated before each cycle of chemotherapy at baseline , Week 4 , and Week 12 using two separate self-report question naires . The analyses indicated that the rHuEPO-treated patients experienced significantly less fatigue ( P < 0.05 ) than their control group counterparts , and reported significantly higher scores on energy level ( P < 0.05 ) , ability to perform daily activities ( P < 0.01 ) , and overall QOL ( P < 0.05 ) . The overall change in hemoglobin level was significantly greater in the rHuEPO group than in the control group ( 1.7 g/dl versus 0.3 g/dl , P < 0.001 ) . rHuEPO effectively corrects anemia and significantly improves QOL in patients with solid tumors receiving chemotherapy [16648508] PURPOSE To evaluate the effectiveness of patient-controlled methylpheni date as compared with placebo in cancer patients with fatigue , as measured by the Functional Assessment for Chronic Illness Therapy-Fatigue ( FACIT-F ) . PATIENTS AND METHODS Patients with a fatigue score of at least 4 on a scale of 0 to 10 ( 0 = no fatigue , 10 = worst possible fatigue ) and hemoglobin level of at least 10 g/dL were included . Patients were r and omly assigned to receive 5 mg methylpheni date or placebo every 2 hours as needed ( maximum of four capsules a day ) , for 7 days . Patients completed a daily diary including study drug record and fatigue intensity . A research nurse telephoned patients daily to assess toxicity and fatigue level . All patients were offered open-label methylpheni date for 4 weeks . FACIT-F and the Edmonton Symptom Assessment System ( ESAS ) were assessed at baseline , and days 8 , 15 , and 36 . The FACIT-F fatigue subscore on day 8 was considered the primary end point . RESULTS Of 112 patients r and omly assigned , 52 patients in the methylpheni date and 53 in the placebo group were assessable for analysis . Fatigue intensity improved significantly on day 8 in both the methylpheni date and placebo groups . However , there was no significant difference in fatigue improvement by FACIT-F ( P = .31 ) or ESAS ( P = .14 ) between groups . In open-label phase , fatigue intensity maintained low as compared with baseline . No significant toxicities were observed . CONCLUSION Both methylpheni date and placebo result ed in significant symptom improvement . Methylpheni date was not significantly superior to placebo after 1 week of treatment . Longer study duration is justified . The role of daily telephone calls from a research nurse should be explored as a palliative care intervention [17312332] PURPOSE Previous trials have suggested a quality -of-life ( QOL ) improvement for anemic cancer patients treated with erythropoietin , but few used QOL as the primary outcome . We design ed a trial to investigate the effects of epoetin alfa therapy on the QOL of anemic patients with advanced non-small-cell carcinoma of the lung ( NSCLC ) . PATIENTS AND METHODS A multicenter , r and omized , double-blind , placebo-controlled trial was conducted . The proposed sample size was 300 patients . Eligible patients were required to have NSCLC unsuitable for curative therapy and baseline hemoglobin ( Hgb ) levels less than 121 g/L. Patients were assigned to 12 weekly injections of subcutaneous epoetin alpha or placebo , targeting Hgb levels between 120 and 140 g/L. The primary outcome was the difference in the change in Functional Assessment of Cancer Therapy-Anemia scores between baseline and 12 weeks . RESULTS Reports of thrombotic events in other epoetin trials prompted an unplanned safety analysis after 70 patients had been r and omly assigned ( 33 to the active arm and 37 to the placebo arm ) . This revealed a significant difference in the median survival in favor of the patients on the placebo arm of the trial ( 63 v 129 days ; hazard ratio , 1.84 ; P = .04 ) . The Steering Committee closed the trial . Patient numbers compromised the interpretation of the QOL analysis , but a positive Hgb response was noted with epoetin alfa treatment . CONCLUSION An unplanned safety analysis suggested decreased overall survival in patients with advanced NSCLC treated with epoetin alfa . Although infrequent , other similar reports highlight the need for ongoing trials evaluating erythropoietin receptor agonists to ensure that overall survival is monitored closely [2410117] A 14-day , r and omized , double-blind crossover trial was carried out comparing an oral glucocorticoid , methylprednisolone ( MP ) , against placebo for the relief of pain and other symptoms in 40 terminally ill cancer patients . After the 14-day , double-blind phase was completed , all patients were given MP for 20 days . The daily dose of MP was 32 mg , and end points of the study were pain , psychiatric status , appetite , nutritional status , daily activity , and performance . Mean intensity of pain ( visual analogue , 0 - 100 + /- SD ) was 36.8 + /- 14 after MP treatment and 57.7 + /- 15 after placebo ( P less than 0.01 ) . Following the 14-day , double-blind phase , appetite and daily activity increased in 24 of 31 patients ( 77 % ) and in 21 of 31 patients ( 68 % ) with MP , respectively ; depression and analgesic consumption decreased in 22 of 31 patients ( 71 % ) and in 16 of 28 patients ( 57 % ) with MP , respectively . MP was preferred over placebo by 23 of the 31 patients ( 74 % ) , and , in 22 of the 31 cases ( 71 % ) , the investigator chose MP over placebo . No serious toxicity was found at the dose of MP used . It is concluded that MP increases the comfort of terminally ill cancer patients [12883695] Fixed dosing is potentially more convenient than weight-based dosing for both patients and physicians . Therefore , this open-label , r and omized ( 1:1 ) , multicenter study was conducted to compare the effectiveness , safety , and quality -of-life benefits of fixed vs. weight-based dosing of epoetin alpha in anemic cancer patients undergoing chemotherapy . Five hundred forty-six anemic patients undergoing platinum-based chemotherapy for solid malignancies were enrolled . Patients received epoetin alpha , either a fixed dose of 10,000 IU or a weight-based dose of 150 IU/kg , administered subcutaneously 3 times weekly for up to 12 weeks . Endpoints were transfusion requirements over days 29 - 84 , change in hemoglobin ( Hb ) level from baseline , and change in quality -of-life ( QOL ) scores from baseline as measured using the Cancer Linear Analog Scale ( CLAS ) . Five hundred and thirty-two patients received at least 1 dose of epoetin alpha , and 510 of these ( 255 in each treatment group ) were considered evaluable for efficacy . At day 84 , rates for freedom from transfusion were similar between the fixed-dose and the weight-based dose group ( 84 % vs. 87 % , respectively , p=0.32 ) , as calculated by the lifetable method . These rates were also similar between patients in the 45 - 63 kg weight group receiving the fixed 10,000 IU dose or 7,000 - 9,000 IU on a per-weight basis ( 83 % vs. 87 % , respectively ) , and those in the 70 - 100 kg weight group receiving the fixed 10,000 IU dose or 11,000 - 15,000 IU on a per-weight basis ( 85 % vs. 83 % , respectively ) . Mean Hb increases from baseline to last observation were 2.10 g/dl [ 95 % confidence intervals ( CI95 ) 1.85 - 2.35 ] in the 10,000 IU group ( from 9.64 - 11.74 g/dl ) and 2.06 g/dl ( CI95 1.82 - 2.30 ) in the 150 IU/kg group ( from 9.70 - 11.76 g/dl ) . QOL results were similar for both groups and cumulative data have been reported . For 275 patients ( in both groups combined ) with CLAS QOL scores both at baseline and 29 - 98 days thereafter , the QOL index ( average of scores for the 3 QOL parameters : energy level , ability to do daily activities and overall QOL ) increased by 10.4 mm ( CI95 7.5 - 13.2 ) , from 46.2 mm at baseline to 56.6 mm at the final observation . QOL improvements were directly associated with Hb increases ( p<0.001 , multiple linear regression analysis ) within all chemotherapy response classes . Epoetin alpha was well tolerated in both groups . Fixed ( 10,000 IU ) and weight-based ( 150 IU/kg ) dosing regimens of epoetin alpha demonstrated similar efficacy in maintaining freedom from transfusion , increasing Hb levels , and improving QOL in anemic cancer patients undergoing platinum-based chemotherapy . QOL improvements were directly associated with Hb increases . These findings support the use of a fixed-dose regimen of epoetin alpha , which may offer greater convenience for physicians and patients than weight-based dosing with this agent [17687152] PURPOSE To evaluate the effectiveness of donepezil compared with placebo in cancer patients with fatigue as measured by the Functional Assessment for Chronic Illness Therapy-Fatigue ( FACIT-F ) . PATIENTS AND METHODS Patients with fatigue score > or= 4 on a scale of 0 to 10 ( 0 = no fatigue , 10 = worst possible fatigue ) for more than 1 week were included . Patients were r and omly assigned to receive donepezil 5 mg or placebo orally every morning for 7 days . A research nurse contacted the patients by telephone daily to assess toxicity and fatigue level . All patients were offered open-label donepezil during the second week . FACIT-F and /or the Edmonton Symptom Assessment System ( ESAS ) were assessed at baseline , and days 8 , 11 , and 15 . The FACIT-F fatigue subscale score on day 8 was considered the primary end point . RESULTS Of 142 patients r and omly assigned to treatment , 47 patients in the donepezil group and 56 in the placebo group were assessable for final analysis . Fatigue intensity improved significantly on day 8 in both donepezil and placebo groups . However , there was no significant difference in fatigue improvement by FACIT-F ( P = .57 ) or ESAS ( P = .18 ) between groups . In the open-label phase , fatigue intensity continued to be low as compared with baseline . No significant toxicities were observed . CONCLUSION Donepezil was not significantly superior to placebo in the treatment of cancer-related fatigue [12957457] This dose-finding , placebo-controlled study evaluated the safety and efficacy of darbepoetin alfa administered every 3 weeks ( Q3W ) to anaemic patients receiving chemotherapy . In part A , patients ( haemoglobin < /=110 g/l ) were r and omised in a 1:4 ratio to receive 1 of 6 doses of darbepoetin alfa ( 4.5 , 6.75 , 9.0 , 12.0 , 13.5 and 15.0 microg/kg ) or placebo Q3W for 12 weeks . In part B , patients received open-label darbepoetin alfa . Patients ( n=249 ) were evaluated for safety , haemoglobin endpoints and red blood cell ( RBC ) transfusions . Darbepoetin alfa given at doses ranging from 4.5 to 15.0 microg/kg Q3W was well tolerated and comparable to placebo in terms of safety . No neutralising antibodies were detected . All doses ( from 4.5 to 15 microg/kg ) reduced transfusions compared with placebo , and result ed in > 50 % of patients achieving a haematopoietic response . Administration of darbepoetin alfa Q3W has a tolerable safety profile and effectively ameliorates anaemia due to chemotherapy [8487324] BACKGROUND Patients with advanced cancer frequently experience clinical ly significant anemia , which is often exacerbated by myelosuppressive chemotherapy . Consistent with the anemia of chronic disease , studies have documented serum erythropoietin levels that are inappropriately low for the degree of anemia in cancer patients . Myelosuppressive chemotherapy impairs erythropoiesis , which may not fully recover between treatment cycles . Recombinant human erythropoietin ( rHuEPO ) has been used safely and effectively to treat anemia in AIDS patients receiving zidovudine ( AZT ) and in patients with chronic renal failure . PURPOSE This study was design ed to evaluate the clinical role of rHuEPO in reducing symptomatic anemia in patients with advanced cancer who were receiving myelosuppressive chemotherapy ( excluding cisplatin ) . METHODS We studied 153 anemic cancer patients receiving cyclic combination chemotherapy in a prospect i ve multicenter , double-blind , placebo-controlled trial . The patients were r and omly assigned to receive either rHuEPO ( 150 U/kg ) or placebo subcutaneously three times a week for a maximum of 12 weeks or until the hematocrit level increased to 38%-40 % . If the hematocrit reached this target level before 12 weeks , the rHuEPO dose could be reduced to maintain the hematocrit at that level for the duration of the study . Response to rHuEPO therapy was assessed by measuring changes in hematocrit level , transfusion requirements , and quality of life . Quality -of-life assessment was based on patients ' responses to question naires before and after the courses of therapy . RESULTS The increase in hematocrit in the rHuEPO-treated group compared with hematocrit in the placebo-treated group was statistically significant ( P = .0001 ) as measured by percentage point of change from baseline to final evaluation , by an increase in hematocrit level of six percentage points or more unrelated to transfusion , and by a rise in hematocrit level to 38 % or more unrelated to transfusion . There was a trend toward the reduction in mean units of blood transfused per patient during months 2 and 3 of therapy combined in rHuEPO-treated patients compared with placebo-treated patients ( 0.91 U versus 1.65 U ; P = .056 ) . In addition , rHuEPO-treated patients experienced a statistically significant improvement in energy level and ability to perform daily activities ( P < or = .05 ) . The two treatment groups showed no statistically significant differences in toxic effects except for increased incidence of diaphoresis ( P < .05 ) and diarrhea ( P = .05 ) in the rHuEPO-treated group . CONCLUSIONS We conclude that rHuEPO is safe and effective for reversing anemia related to advanced cancer or to chemotherapy for cancer [12599240] Anemia in patients receiving chemotherapy can be ameliorated with recombinant human erythropoietin ( rHuEPO ) , which is administered one to three times per week . Darbepoetin α , a new erythropoietic agent , has longer serum residence time , allowing it to be administered less frequently [18790598] Fatigue is very common in patients with cancer . Current guidelines suggest that psychostimulants are " reasonable to consider for severe fatigue . " This r and omized , double-blind , placebo-controlled trial investigated the hypothesis that dexamphetamine in fatigued patients with advanced cancer would produce a clinical ly significant improvement with minimal side effects . Fifty patients with advanced cancer , who were receiving palliative care , were r and omized to dexamphetamine 10 mg twice daily or placebo for eight days . Effectiveness was assessed using the Brief Fatigue Inventory and the McGill Quality -of-Life Question naire . The side effects were recorded . The results were analyzed on an intention-to-treat basis . The baseline demographics , fatigue levels , and quality -of-life scores were similar between the two arms . Patients were elderly , had impaired performance status ( Eastern Cooperative Oncology Group score=3 ) , and were taking a range of neurologically active medications . Thirty-nine patients completed the trial . There was a transient improvement in the fatigue levels on day 2 , but no significant difference in fatigue ( P=0.267 ) or quality of life ( P=0.579 ) by the end of the study . Statistical modeling did not reveal any significant predictors of response to dexamphetamine . These results suggest that dexamphetamine 20 mg daily , although well tolerated , does not significantly improve fatigue or quality of life in patients with advanced cancer , as measured by the selected instruments [10492632] A r and omised double-blind placebo-controlled multicentre trial was performed to investigate the effects of megestrol acetate ( MA ) on the quality of life ( QoL ) , appetite , weight and survival of patients with advanced , incurable , hormone-insensitive cancer . QoL was assessed at the start of treatment and at 4 , 8 and 12 weeks , using the EORTC-QLQ-C30 instrument . 255 patients were r and omised to 320 mg of MA daily or placebo for 12 weeks . 244 patients were assessable at baseline , 190 at 4 weeks ( placebo 94 ; MA 96 ) , 150 at 8 weeks ( placebo 69 ; MA 81 ) and 112 at 12 weeks ( placebo 55 ; MA 57 ) . A beneficial effect of MA on appetite loss was observed at week 4 ( P < 0.0001 ) and possibly at week 8 ( P = 0.058 ) . Further weight loss during treatment was significant only in the placebo group . In the first 8 weeks , changes in mean global QoL were small and similar in both groups . By 12 weeks the decrease in mean global QoL was more pronounced in the MA group ( P = 0.028 ) , which was related to a deterioration in physical function , while psychosocial function was not affected . Survival was not affected by MA , and side-effects were mild . The results show that MA has a beneficial effect on appetite and that it may retard weight loss with no adverse impact on survival and with mild toxicity . However , MA does not appear to improve global QoL as measured by the EORTC QLQ-C30 [17548243] BACKGROUND Depression , anxiety , fatigue , and impaired wellbeing are common , important , and closely related in advanced cancer . We aim ed to identify the effects of an established antidepressant on these symptoms and survival in patients with advanced cancer who did not have major depression as assessed by clinicians . METHODS Between July , 2001 , and February , 2006 , 189 patients with advanced cancer were r and omly assigned sertraline 50 mg ( n=95 ) , or placebo ( n=94 ) , once per day . The primary outcome was depression as assessed by the Centre for Epidemiologic Studies Depression scale ( CES-D ) ; the main secondary outcomes were : anxiety as assessed by Hospital Anxiety and Depression Scales ( HADS-A ) ; overall quality of life and fatigue as assessed by Functional Assessment of Cancer Therapy General and Fatigue scales ( FACT-G and FACT-F , respectively ) ; and clinicians ' ratings of quality of life by use of Spizter 's Quality of Life Index ( SQLI ) . Multiple measures were used for corroboration of the most important outcomes . Primary analyses were done by intention to treat and were based on scale scores at 4 weeks and 8 weeks . The benefits of sertraline compared with placebo are expressed on a range from + 100 ( ie , maximum benefit ) to -100 ( ie , maximum harm ) ; a difference of 10 was deemed clinical ly significant . This clinical trial is registered at Current Controlled Trials website http://www.controlled-trials.com/IS RCT N72466475 . FINDINGS Sertraline had no significant effect ( scale , benefit over placebo [ 95 % CI ] ) on depression ( CES-D 0.4 [ -2.6 to 3.4 ] ) , anxiety ( HADS-A 2.0 [ -1.5 to 5.5 ] ) , fatigue ( FACT-F 0.3 [ -4.3 to 4.9 ] ) , overall quality of life ( FACT-G 1.7 [ -1.3 to 4.7 ] ) , or clinicians ' ratings ( SQLI 2.0 [ -2.5 to 6.5 ] ) , and the 95 % CI ruled out a clinical ly significant benefit for all main outcomes . Sertraline was discontinued more often and earlier than was placebo ( hazard ratio 1.46 [ 1.03 - 2.06 ] , p=0.03 ) . Recruitment was stopped after the first planned interim analysis in February 2006 ( n=150 ) showed that survival was longer in patients assigned placebo than in patients assigned sertraline ( unadjusted hazard ratio 1.60 [ 95 % CI 1.04 - 2.45 ] , log-rank p=0.04 ; adjusted hazard ratio 1.62 [ 1.06 - 2.41 ] , Cox model p=0.02 ) . However , at the final analysis in July 2006 of all patients ( n=189 ) and with longer follow-up , survival did not differ significantly between the treatment groups ( unadjusted hazard ratio 1.35 [ 0.95 - 1.91 ] , log-rank p=0.09 ; adjusted hazard ratio 1.27 [ 0.87 - 1.84 ] , Cox model p=0.20 ) . The trial was closed because it had ruled out a significant benefit of sertraline . INTERPRETATION Sertraline did not improve symptoms , wellbeing , or survival in patients with advanced cancer who do not have major depression , and should be reserved for those with a proven indication [12566906] Objectives : Platinum compounds are commonly associated with significant anemia . Erythropoietin administration has been found effective in correcting anemia in patients with solid tumors receiving chemotherapy . We conducted a r and omized , open label study to assess the efficacy of erythropoietin in preventing transfusions and significant anemia ( hemoglobin < 10 g/dl ) in patients with solid tumors receiving platinum-based chemotherapy . Methods : One hundred forty-four patients with hemoglobin < 13 g/dl were included in this study ( 72 in each arm ) . Patients in the treatment arm received 10,000 U of recombinant human erythropoietin ( rHuEPO ) thrice weekly s.c . during platinum-based chemotherapy , while patients in the control arm received no treatment . Results : All patients were evaluable for efficacy . Transfusions were reduced by the administration of rHuEPO ( 15.3 vs. 33.3 % , p = 0.019 ) , and fewer patients developed significant anemia ( 16.6 vs. 45.8 % , p < 0.0001 ) . Subgroup analysis showed that patients with observed to predicted ( O/P ) serum erythropoietin levels ≤0.9 and responders to chemotherapy benefited from erythropoietin administration in contrast to patients with O/P > 0.9 or non-responders . Conclusions : rHuEPO at a dose of 10,000 U thrice weekly prevents transfusions and development of significant anemia in patients with solid tumors receiving platinum-based chemotherapy [4135151] In a controlled double blind study involving 116 patients with far‐advanced gastrointestinal cancer , dexamethasone at dosages of 0.75 and 1.5 mg four times daily produced improved appetite and sense of well‐being in comparison to placebo treatment . This symptomatic palliation , however , was not accompanied by weight gain or improved performance status . Survival of the steroid treated patients was essentially identical to that of the placebo treated patients . Cancer 33:1607–1609 , 1974 [15452188] PURPOSE Epoetin alfa administered at 40,000 U once weekly ( qw ) to anemic cancer patients receiving chemotherapy increases hemoglobin levels , improves quality of life ( QOL ) , and reduces transfusions . The benefit of epoetin alfa in maintaining hemoglobin levels in cancer patients with hemoglobin less than 12 g/dL has not been evaluated . METHODS Breast cancer patients ( N = 354 ) receiving chemotherapy were r and omly assigned in 1:1 ratio to epoetin alfa ( 40,000 U qw ) or st and ard of care ( SOC ) . QOL was assessed at baseline and week 12 . Hemoglobin responses , transfusion requirements , and prognostic factors for responses were measured . RESULTS At week 12 , Functional Assessment of Cancer Therapy-Anemia ( FACT-An ; mean , 2.16 + /- 12.84 for epoetin alfa v -4.43 + /- 13.42 for SOC ) and FACT-An fatigue ( mean , 1.85 + /- 10.52 for epoetin alfa v -3.55 + /- 11.14 for SOC ) change scores were significantly higher in the epoetin alfa group ( P < .0001 ) . Hemoglobin responses defined as mean hemoglobin > or = 12 g/dL or a > or = 2 g/dL increase compared with baseline were significantly higher in the epoetin alfa group versus SOC : 52.0 % v 5.1 % and 65.7 % v 6.3 % , respectively ( P < .0001 for both comparisons ) . Percentage transfused was significantly lower in the epoetin alfa group compared with SOC ( 8.6 % v 22.9 % ) . More than 90 % of patients did not require a dose increase and 28.7 % had a dose reduction . CONCLUSION Epoetin alfa administered at 40,000 U qw is effective in improving QOL , maintaining hemoglobin level , and reducing transfusion requirements in breast cancer patients . The high effectiveness observed could be attributed in part to early treatment with epoetin alfa [11328297] Effects of epoetin alfa on transfusions , haemoglobin ( Hb ) and quality of life ( QOL ) were evaluated in a placebo‐controlled study of 145 patients with multiple myeloma and anaemia ( Hb < 11 g/dl ) . During the 12‐week , double‐blind phase , patients received 150 IU/kg epoetin alfa or a matching volume of placebo subcutaneously three times weekly ; the dose ( or volume ) was doubled at week 4 if Hb response was inadequate . Patients completing this phase could enter the subsequent optional 12‐week phase of open‐label epoetin alfa treatment . During double‐blind treatment , epoetin alfa significantly decreased the incidence of transfusion compared with placebo ( 28 % vs. 47 % , P = 0·017 ) , regardless of patients ' transfusion history , and increased mean Hb ( 1·8 g/dl vs. 0·0 g/dl , P < 0·001 ) . Univariate analysis showed significant ( P ≤ 0·05 ) improvement in more QOL measures with epoetin alfa than with placebo ; multivariate analysis discerned no between‐treatment differences . Significantly ( P = 0·038 ) more epoetin alfa vs. placebo patients had improved performance scores . At the end of the open‐label treatment phase , patients who had continued epoetin alfa maintained Hb status , and placebo patients who were switched to epoetin alfa had mean Hb increases of 2·4 g/dl . Adverse events were similar between treatment groups . Epoetin alfa proved effective and well tolerated for treating anaemia in patients with multiple myeloma [16177289] This is the first r and omized , open-label , multicenter trial design ed and powered to directly compare the hemoglobin ( Hb ) response to epoetin alfa ( EPO ) , 40,000 U once weekly ( QW ) , with that to darbepoetin alfa ( DARB ) , 200 microg every 2 weeks ( Q2W ) , in anemic patients with cancer receiving chemotherapy ( CT ) . Transfusion requirements , quality of life ( QOL ) , and safety also were evaluated . Adults with solid tumors scheduled to receive CT for > or = 12 weeks and with baseline Hb < or = 11 g/dl were r and omized to receive either EPO 40,000 U QW ( n = 178 ) or DARB 200 microg Q2W ( n = 180 ) s.c . for up to 16 weeks . Doses were increased for nonresponders ( Hb increase < 1 g/dl ) after 4 ( EPO ) or 6 ( DARB ) weeks , as per National Comprehensive Cancer Network guidelines , and were reduced for a rapid rise in Hb ( > 1.3 g/dl [ EPO ] or > 1.0 g/dl [ DARB ] within any 2-week period ) or for an Hb level > 13 g/dl . The proportion of patients achieving a > or = 1-g/dl Hb rise by week 5 , the primary end point , was significantly higher with EPO ( 47.0 % ) than with DARB ( 32.5 % ) , and EPO-treated patients achieved a > or = 1-g/dl Hb increase significantly earlier than those receiving DARB ( median , 35 days versus 46 days ) . The mean increase in Hb from baseline was significantly higher at weeks 5 , 9 , 13 , and the end of the study with EPO than with DARB . The number of units transfused per patient was significantly lower for the EPO group than for the DARB group . The proportions of patients requiring transfusions , mean QOL improvements , and tolerability profiles were similar in the two groups [8648360] PURPOSE To investigate the effects of medroxyprogesterone acetate ( MPA ) on appetite , weight , and quality of life ( QL ) in patients with advanced-stage , incurable , non-hormone-sensitive cancer . PATIENTS AND METHODS Two hundred six eligible patients were r and omized between double-blind MPA 500 mg twice daily or placebo . Appetite ( 0 to 10 numerical rating scale ) , weight , and QL ( European Organization for Research and Treatment of Cancer Quality of Life Question naire [ EORTC-QLQ-C30 ] ) were assessed before the start of treatment ( t = 0 ) , and 6 weeks ( t = 6 ) and 12 weeks ( t = 12 ) thereafter . RESULTS One hundred thirty-four patients ( 68 MPA and 66 placebo ) were assessable at t = 6 and 99 patients ( 53 MPA and 46 placebo ) at t = 12 . A beneficial effect of MPA on appetite was observed after both 6 weeks ( P = .008 ) and 12 weeks ( P = .01 ) of treatment . After 12 weeks , a mean weight gain of 0.6 + /- 4.4 kg was seen in the MPA , versus an ongoing mean weight loss of 1.4 + /- 4.6 kg in the placebo group . This difference of 2.0 kg was statistically significant ( P = .04 ) . During the study , several areas of QL deteriorated in the total group of patients . With the exception of an improvement in appetite and possible also a reduction in nausea and vomiting , no measurable beneficial effects of MPA on QL could be demonstrated . The side effects profile of MPA was favorable : only a trend toward an increase in ( usually mild ) peripheral edema was observed . CONCLUSION In weight-losing , advanced-stage non-hormone-sensitive cancer patients , MPA exhibits a mild side effects profile , has a beneficial effect on appetite , and may prevent further weight loss . However , general QL in the present study was not measurably influenced by MPA treatment [12910374] The aim of the study was to investigate the effects of erythropoietin ( epoetin beta ) on red blood cell ( RBC ) transfusions , hemoglobin ( Hb ) levels , and quality of life ( QOL ) in patients with relapsed lymphoma treated with an aggressive sequential salvage chemotherapy ( SSCT ) regimen . Sixty patients with early or late relapsed Hodgkin 's disease ( n=39 ) or first relapse of aggressive non-Hodgkin 's lymphoma ( n=21 ) were r and omized to receive epoetin beta 10,000 IE subcutaneously three times a week or no epoetin during salvage chemotherapy . Patients in both study arms received two cycles of DHAP ( dexamethasone , high-dose cytarabine , cisplatin ) ; patients in partial remission ( PR ) or complete remission ( CR ) then received cyclophosphamide , followed by peripheral blood stem cell ( PBSC ) harvest , methotrexate plus vincristine , and etoposide . The final myeloablative course was BEAM ( carmustine , etoposide , cytarabine , and melphalan ) followed by autologous stem cell support . The primary endpoint of the study was the number of RBC units needed during SSCT . In addition , Hb levels and QOL were measured . The mean number of RBC units given in the epoetin beta arm was 4.5 compared to 8.3 in the control arm ( P=0.0134 ) . The mean Hb levels during therapy were 10.4 g/dl in the epoetin beta arm and 9.7 g/dl in the control ( P=0.018 ) . From baseline until BEAM therapy QOL ( EORTC QLQ C30 ) and fatigue ( MFI ) assessment showed little QOL worsening or stable levels in both arms with a steeper increase of fatigue levels in the control group . Patients with relapsed lymphoma undergoing aggressive chemotherapy and stem cell support benefited from epoetin beta therapy , with a decrease of RBC transfusion requirements and lower rise of fatigue levels

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### Context: [18779540] BACKGROUND Anemia in patients with solid tumors is a common problem that is associated with impaired exercise capacity , increased fatigue , and lower quality of life ( QoL ) . Erythropoiesis-stimulating agents ( ESAs ) have been shown to improve these outcomes ; however , it is unknown if additional benefits can be achieved with aerobic exercise training . METHODS We conducted a single-center , prospect i ve , r and omized , controlled trial in 55 mild-to-moderately anemic patients with solid tumors . Patients were r and omized to either darbepoetin alfa alone ( DAL , n = 29 ) or darbepoetin alfa plus aerobic exercise training ( DEX ; n = 26 ) . The DEX group performed aerobic exercise training three times per week at 60%-100 % of baseline exercise capacity for 12 weeks . The primary endpoint was QoL assessed by the Functional Assessment of Cancer Therapy-Anemia scale . Secondary endpoints were fatigue , cardiorespiratory fitness ( VO(2peak ) ) , hemoglobin ( Hb ) response , and darbepoetin alfa dosing . RESULTS Intention-to-treat analyses indicated significant improvements in QoL and fatigue in both groups over time but there were no between-group differences . The DEX group had a significantly greater VO(2peak ) than the DAL group ( mean group difference , + 3.0 ml/kg per minute ; 95 % confidence interval , 1.2 - 4.7 ; p = .001 ) and there were borderline significant differences in favor of the DEX group for Hb response and darbepoetin alfa dosing . CONCLUSIONS Aerobic exercise training did not improve QoL or fatigue beyond the established benefits of DAL but it did result in favorable improvements in exercise capacity and a more rapid Hb response with lower dosing requirements . Our results may be useful to clinicians despite the more recent restrictions on the indications for ESAs [9893656] The aim of this study was to evaluate a low-dose regimen of megestrol acetate ( MA ; 320 mg/day ) on appetite in advanced cancer patients . Out- patients with far-advanced non-hormone responsive tumours and loss of appetite were r and omised in a phase III trial , with two consecutive phases : a 14-day double-blind placebo controlled phase ( phase A ) and a 76-day open phase ( phase B ) . During phase A , patients were treated with MA , two 160 mg tablets/day , or placebo . In phase B , the MA dose was titrated to clinical response in both groups . Appetite , food intake , body weight , performance status , mood and quality of life were evaluated with st and ardised measures ; patients ' global judgement about treatment efficacy was also requested . Of 42 patients entering the study , 33 ( 17 MA and 16 placebo ) were evaluable for efficacy . The appetite score improved significantly with MA after 7 days ( P = 0.0023 ) , and this effect was still significant at 14 days ( P = 0.0064 ) . Patients judged the treatment with MA effective in 88.2 % of cases ( 14th day ) , whilst placebo was considered effective by 25 % ( P = 0.0003 ) . None of the other measures showed significant changes during treatment . The remarkable effect on appetite evident after 7 days , without serious side-effects , shows that MA can produce significant subjective effects at a low-dose even in patients with far-advanced disease [2698804] The effectiveness of an 8-week , 125 mg/day intravenous course of methylprednisolone sodium succinate ( MPSS ) for improving quality of life in patients with preterminal cancer was investigated in a double-blind , placebo-controlled , multicenter study . Quality of life was assessed using the Nurses ' Observational Scale for Inpatient Evaluation ( NOSIE ) , the Linear Analog Self- Assessment Scale ( LASA ) , and the Physicians ' Global Evaluation . A total of 403 patients were enrolled : 207 were treated with MPSS and 196 were treated with placebo . MPSS was significantly more effective than placebo in improving quality of life as judged by the changes from baseline in the NOSIE and LASA total scores . ( P less than 0.05 ) and by the Physicians ' Global Evaluation ( P less than 0.001 ) . The mortality rate was similar between MPSS-treated males ( 40.2 % ) , placebo-treated males ( 35.5 % ) , and MPSS-treated females ( 40.0 % ) . However , the mortality rate of 27.7 % for female placebo-treated females was significantly lower than for their MPSS-treated counterparts . The reason for lower mortality among placebo-treated females is unknown and warrants further study [1968469] Patients with breast cancer treated with MPA often report an improvement in appetite . Similar appetite stimulation is seen in patients treated with some corticosteroids , but MPA has a potential advantage over these drugs in that it does not exert a catabolic effect . MPA ( 100 mg tds orally ) has therefore been compared with placebo in 60 patients with advanced malignant disease . Twenty-one patients in the MPA group and 20 in the placebo group were receiving chemotherapy . Patients were treated for 6 weeks and were assessed at weeks 0 , 3 and 6 for appetite , energy , mood and pain using visual analogue scales . Nutritional status was assessed by the measurement of serum proteins and anthropometrics . Karnofsky score was recorded as a measure of performance status . There was a significant improvement in appetite in the MPA group between weeks 0 ( pre- study ) and 3 ( P = 0.0002 ) and 0 and 6 ( P = 0.015 ) . There was no significant improvement in appetite in the placebo group . Supporting this finding was the significant increase in serum thyroid binding pre-albumin and retinol binding protein in the MPA group between weeks 0 and 3 and 0 and 6 ( P = 0.023 and P = 0.039 respectively ) . These two parameters showed no significant change in the placebo group . There was no change in anthropometric measurements , weight , performance status , energy , mood or pain in either group . These data indicate that there was a significant increase in appetite in anorexic patients with advanced cancer treated with MPA which was reflected in increases in rapid turnover proteins reported to reflect nutritional status . However , this apparent increase in appetite did not result in improved weight , performance status , energy levels , mood or relief of pain . Further studies to investigate the effect of higher doses of MPA are indicated [2483687] A total of 173 female terminal cancer patients were r and omized to treatment with daily 125 mg infusions of methylprednisolone sodium succinate or a matching placebo for a period of 8 consecutive weeks . Data were collected relative to quality of life , investigator assessment of efficacy and cause and time of death within the 8-week treatment period . Significant improvement in quality of life was reported across the 8-week follow-up period in the steroid group . Investigator global assessment of efficacy significantly favored the steroid-treatment patients . There were no significant differences between treatment groups with regard to overall mortality rates or time to death . The total number of reported adverse events did not differ significantly between treatment groups . However , significantly more steroid patients reported gastrointestinal and cardiovascular events . The severity and outcome of these events did not differ from the placebo patients . The results of this study confirm previous reports of steroid efficacy in improving quality of life in terminal cancer patients . The absence of any untoward effect on mortality and the favorable safety profile support the use of methylprednisolone as palliative therapy for terminal cancer patients [10675381] BACKGROUND Extracellular adenosine 5'-triphosphate ( ATP ) is involved in the regulation of a variety of biologic processes , including neurotransmission , muscle contraction , and liver glucose metabolism , via purinergic receptors . In nonr and omized studies involving patients with different tumor types including non-small-cell lung cancer ( NSCLC ) , ATP infusion appeared to inhibit loss of weight and deterioration of quality of life ( QOL ) and performance status . We conducted a r and omized clinical trial to evaluate the effects of ATP in patients with advanced NSCLC ( stage IIIB or IV ) . METHODS Fifty-eight patients were r and omly assigned to receive either 10 intravenous 30-hour ATP infusions , with the infusions given at 2- to 4-week intervals , or no ATP . Outcome parameters were assessed every 4 weeks until 28 weeks . Between-group differences were tested for statistical significance by use of repeated- measures analysis , and reported P values are two-sided . RESULTS Twenty-eight patients were allocated to receive ATP treatment and 30 received no ATP . Mean weight changes per 4-week period were -1.0 kg ( 95 % confidence interval [ CI ] = -1.5 to -0.5 ) in the control group and 0.2 kg ( 95 % CI = -0.2 to + 0.6 ) in the ATP group ( P = .002 ) . Serum albumin concentration declined by -1.2 g/L ( 95 % CI= -2.0 to -0.4 ) per 4 weeks in the control group but remained stable ( 0.0 g/L ; 95 % CI = -0.3 to + 0.3 ) in the ATP group ( P = .006 ) . Elbow flexor muscle strength declined by -5.5 % ( 95 % CI = -9.6 % to -1 . 4 % ) per 4 weeks in the control group but remained stable ( 0.0 % ; 95 % CI= -1.4 % to + 1.4 % ) in the ATP group ( P = .01 ) . A similar pattern was observed for knee extensor muscles ( P = .02 ) . The effects of ATP on body weight , muscle strength , and albumin concentration were especially marked in cachectic patients ( P = .0002 , P = .0001 , and P = . 0001 , respectively , for ATP versus no ATP ) . QOL score changes per 4-week period in the ATP group showed overall less deterioration than in the control group-physical scores ( -0.2 % versus -2.4 % ; P = . 0002 ) ; functional scores ( + 0.4 % versus -5.5 % ; P = .02 ) ; psychologic scores ( -0.7 % versus -2.4 % ; P = .11 ) ; overall QOL score ( + 0.1 % versus -3.5 % ; P = .0001 ) . CONCLUSIONS This r and omized trial demonstrates that ATP has beneficial effects on weight , muscle strength , and QOL in patients with advanced NSCLC [11176767] BACKGROUND Fatigue is a commonly encountered symptom of human immunodeficiency virus ( HIV ) disease , associated with significant psychological and functional morbidity and poor quality of life . Preliminary studies on the treatment of fatigue from the cancer and multiple sclerosis literature suggest that psychostimulants may be effective in reducing fatigue . OBJECTIVE To compare the efficacy of 2 psychostimulant medications , methylpheni date hydrochloride ( Ritalin ) and pemoline ( Cylert ) , with a placebo intervention for the treatment of fatigue in patients with HIV disease . METHODS In this double-blind trial , 144 ambulatory patients with HIV disease and persistent and severe fatigue were r and omized to treatment with methylpheni date , pemoline , or placebo . Medications were titrated up to a maximum dose of 60 mg of methlypheni date hydrochloride , 150 mg of pemoline , or 8 capsules of placebo daily . Fatigue was measured using 2 self-reported rating scales , the Piper Fatigue Scale ( PFS ) and the Visual Analogue Scale for Fatigue ( VAS-F ) . We also used the timed isometric unilateral straight leg-raising task , a measure of muscular endurance . Quality -of-life and psychological well-being measures included the Beck Depression Inventory , the Brief Symptom Inventory , and the 36-Item Short-Form Medical Outcomes Study Health Status Survey . Side effects were monitored using the Systematic Assessment for Treatment Emergent Events and the Extra-pyramidal Symptom Rating Scale . All measures were rated weekly . RESULTS One hundred nine subjects completed the 6-week trial ; 15 patients ( 41 % ) receiving methylpheni date and 12 patients ( 36 % ) receiving pemoline demonstrated clinical ly significant improvement compared with 6 patients ( 15 % ) receiving placebo . Patients receiving methylpheni date or pemoline demonstrated significantly more improvement in fatigue on several self-reported rating scales ( PFS total score , P=.04 ; affective subscale , P=.008 ; sensory subscale , P=.04 ; and VAS-F energy subscale , P=.02 ) . Analysis of the regression slopes by means of hierarchical linear modeling demonstrated a significantly greater rate of improvement in PFS total scores among patients receiving psychostimulants compared with the placebo group ( P=.02 ) . There were no significant differences in the efficacy between methlypheni date and pemoline on any outcome measure studied . Improvement in fatigue was also significantly correlated with improvement in measures of depression , psychological distress , and overall quality of life . Severe side effects were relatively uncommon among this sample , and only hyperactivity or jitteriness occurred significantly more often among subjects receiving active medication . CONCLUSIONS Many patients with HIV- and acquired immunodeficiency syndrome-unrelated fatigue respond favorably to treatment with methylpheni date or pemoline . Both psychostimulants appear to be equally effective and significantly superior to placebo in decreasing fatigue severity with minimal side effects . Moreover , improvement of fatigue was significantly associated with improved quality of life and decreased levels of depression and psychological distress [2362337] Summary Anaemia commonly occurs in cancer patients receiving chemotherapy , often necessitating blood transfusion . This multicentre study was design ed to evaluate the efficacy and safety of epoetin α in preventing the decline in haemoglobin ( Hb ) level , and to determine whether the transfusion requirement could be reduced , in patients receiving 4–6 cycles of primarily platinum-based combination cyclic chemotherapy for small cell lung cancer ( SCLC ) . A total of 130 non-anaemic SCLC patients were r and omized to receive no additional treatment ( n = 44 ) , epoetin α 150 IU kg–1 subcutaneously ( s.c . ) three times a week ( n = 42 ) or 300 IU kg–1 s.c . three times a week ( n = 44 ) . Reductions in epoetin α dosage were made during the study if Hb level increased to > 15 g dl–1 . The mean weekly dosage was 335 and 612 IU kg–1 , respectively , in the two active treatment groups . Significantly fewer ( P < 0.05 ) epoetin α-treated patients experienced anaemia ( Hb < 10 g dl–1 ) during the course of chemotherapy ( 300 IU kg–1 , 39 % ; 150 IU kg–1 , 48 % ; untreated , 66 % ) . This was reflected in the significantly lower number of treated patients transfused [ 300 IU kg–1 , 20 % ( P < 0.001 ) ; 150 IU kg–1 , 45 % ( P < 0.05 ) ; untreated , 59 % ] . Epoetin α was well-tolerated , and there was no evidence of sustained , clinical ly significant , hypertension . In summary , epoetin α is effective and well-tolerated in maintaining Hb level and reducing transfusion requirement in patients undergoing cyclic chemotherapy for SCLC [12011126] PURPOSE To investigate the effect of recombinant human erythropoietin ( epoetin beta ) on anemia , transfusion need , and quality of life ( QOL ) in severely anemic patients with low- grade non-Hodgkin 's lymphoma ( NHL ) , chronic lymphocytic leukemia ( CLL ) , or multiple myeloma ( MM ) . PATIENTS AND METHODS Transfusion-dependent patients with NHL ( n = 106 ) , CLL ( n = 126 ) , or MM ( n = 117 ) and a low serum erythropoietin concentration were r and omized to receive epoetin beta 150 IU/kg or placebo subcutaneously three times a week for 16 weeks . Primary efficacy criteria were transfusion-free and transfusion- and severe anemia-free survival ( hemoglobin [ Hb ] > 8.5 g/dL ) between weeks 5 to 16 . Response was defined as an increase in Hb > or = 2 g/dL with elimination of transfusion need . QOL was assessed by the Functional Assessment of Cancer Therapy scale . RESULTS Transfusion-free ( P = .0012 ) survival and transfusion- and severe anemia-free survival ( P = .0001 ) were significantly greater in the epoetin beta group versus placebo ( Wald chi(2 ) test ) , giving a relative risk reduction of 43 % and 51 % , respectively . The response rate was 67 % and 27 % in the epoetin beta versus the placebo group , respectively ( P < .0001 ) . After 12 and 16 weeks of treatment , QOL significantly improved in the epoetin beta group compared with placebo ( P < .05 ) ; this improvement correlated with an increase in Hb concentration ( > or = 2 g/dL ) . A target Hb that could be generally recommended could not be identified . CONCLUSION Many severely anemic and transfusion-dependent patients with advanced MM , NHL , and CLL and a low performance status benefited from epoetin therapy , with elimination of severe anemia and transfusion need , and improvement in QOL [19896571] Cancer and its treatment can induce subjective and objective evidence of diminished functional capacity encompassing physical fatigue and cognitive impairment . Dexmethylpheni date ( D-MPH ; the D-isomer of methylpheni date ) was evaluated for treatment of chemotherapy-related fatigue and cognitive impairment . A r and omized , double-blind , placebo-controlled , parallel-group study evaluated the potential therapeutic effect and safety of D-MPH in the treatment of patients with chemotherapy-related fatigue . Change from baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue Subscale ( FACIT-F ) total score at Week 8 was the primary outcome measure . One hundred fifty-four patients ( predominantly with breast and ovarian cancers ) were r and omized and treated . Compared with placebo , D-MPH-treated subjects demonstrated a significant improvement in fatigue symptoms at Week 8 in the FACIT-F ( P=0.02 ) and the Clinical Global Impression-Severity scores ( P=0.02 ) , without clinical ly relevant changes in hemoglobin levels . Cognitive function was not significantly improved . There was a higher rate of study drug-related adverse events ( AEs ) ( 48 of 76 [ 63 % ] vs. 22 of 78 [ 28 % ] ) and a higher discontinuation rate because of AEs ( 8 of 76 [ 11 % ] vs. 1 of 78 [ 1.3 % ] ) in D-MPH-treated subjects compared with placebo-treated subjects . The most commonly reported AEs independent of study drug relationship in D-MPH-treated subjects were headache , nausea , and dry mouth , and in placebo-treated subjects were headache , diarrhea , and insomnia . D-MPH produced significant improvement in fatigue in subjects previously treated with cytotoxic chemotherapy . Further studies with D-MPH or other agents to explore treatment response in chemotherapy-associated fatigue should be considered [2741110] A multicentre study evaluated the efficacy and safety of darbepoetin alpha administered weekly ( QW ) , every 3 weeks ( Q3W ) , and every 4 weeks ( Q4W ) to anaemic patients with cancer not concurrently receiving chemotherapy or radiotherapy . The QW portion ( n=102 ) was an open-label , sequential , dose-escalation design ; cohorts received darbepoetin alpha QW by subcutaneous ( s.c . ) injection at 0.5 , 1.0 , 2.25 , or 4.5 μg kg−1 week−1 for 12 weeks . The 12-week placebo-controlled , double – blind Q3W ( 6.75 μg kg−1 ) and Q4W ( 6.75 or 10.0 μg kg−1 ) schedules ( n=86 ) , which enrolled different patients , took place after the QW schedule and were followed by a 12-week , open-label phase . Patients were evaluated for change in haemoglobin end points and red blood cell transfusions , serum darbepoetin alpha concentration , and safety . Selected domains of health-related quality of life ( HRQOL ) were measured . With QW dosing , at least 70 % of each cohort had a haemoglobin increase from baseline of ⩾2 g dl−1 or a concentration ⩾12 g dl−1 ( haematopoietic response ) . In the 4.5 μg kg−1 QW cohort , all patients achieved a haematopoietic response ( 100 % ; 95 % confidence interval (CI)=100 , 100 ) . In the Q3W and Q4W schedules , all cohorts had at least 60 % of patients who achieved a haematopoietic response . Darbepoetin alpha effectively increases haemoglobin concentration when given QW , Q3W , or Q4W . Less-frequent administration may benefit patients with chronic anaemia of cancer and their caregivers alike [2361228] This multicentre , open-label , controlled clinical trial assessed the effects of epoetin alfa treatment on haematologic and quality of life ( QOL ) parameters in 182 anaemic ( Hb⩽12 g dl−1 ) ovarian cancer patients receiving platinum chemotherapy . Patients were r and omised 2 : 1 to receive epoetin alfa 10 000–20 000 IU three times weekly plus best st and ard treatment ( BST ) or BST only . Main study end points were changes from baseline in haemoglobin ( Hb ) level , transfusion requirements , and QOL . For the epoetin alfa group , mean Hb increased by 1.8 g dl−1 by weeks 4–6 and was significantly increased from baseline through study end ( P<0.001 ) . The mean change in Hb from baseline was significantly ( P<0.001 ) greater for epoetin alfa than BST patients at all postbaseline evaluations . Significantly fewer epoetin alfa than BST patients required transfusion(s ) after the first 4 weeks of treatment ( 7.9 vs 30.5 % ; P<0.001 ) . Also , significant ( P⩽0.04 ) differences favouring the epoetin alfa group over the BST group were found for all three median CLAS scores ( Energy Level , Ability to Do Daily Activities , Overall QOL ) and the median average CLAS score during chemotherapy . These findings support use of epoetin alfa to increase Hb levels , reduce transfusion use , and improve QOL in anaemic ovarian cancer patients receiving platinum chemotherapy [17762445] Background : Fatigue is a common symptom in cancer patients receiving radiation therapy . Patients and Methods : We conducted a double-blind r and omized crossover trial of multivitamins versus placebo in patients with breast cancer undergoing radiation therapy to evaluate fatigue and quality of life . Results : We r and omized 40 patients to either placebo or Centrum Silver . At the middle of the radiation treatments , patients were switched from placebo to multivitamins and vice versa . Patients answered the EORTC QLQ C-30 quality of life ( QOL ) and Chalder fatigue question naires at the beginning , middle , and end of radiation therapy . Both groups experienced decreases in general ( P = 0.009 ; P = 0.001 ) and physical fatigue scores ( P = 0.031 ; P = 0.029 ) at the end of the course of placebo compared with the assessment prior to this treatment . We also observed significant improvements in functional ( P = 0.026 ) and symptoms ( P = 0.016 ) score scales of the QOL question naire in the patients on placebo . No significant changes were elicited with the use of multivitamins . We also observed significantly lower rates of fatigue in the patients who had just finished a course of placebo as compared with patients finishing a course of multivitamins ( 0 vs. 25 % P = 0.035 ) . Conclusion : Multivitamins do not improve radiation-related fatigue in patients with breast cancer [15754122] Summary Background . Fatigue can significantly interfere with a cancer patient ’s ability to fulfill daily responsibilities and enjoy life . It commonly co-exists with depression in patients undergoing chemotherapy , suggesting that administration of an antidepressant that alleviates symptoms of depression could also reduce fatigue . Methods . We report on a double-blind clinical trial of 94 female breast cancer patients receiving at least four cycles of chemotherapy r and omly assigned to receive either 20 mg of the selective serotonin re-uptake inhibitor ( SSRI ) paroxetine ( Paxil ® , SmithKline Beecham Pharmaceuticals ) or an identical-appearing placebo . Patients began their study medication seven days following their first on- study treatment and continued until seven days following their fourth on- study treatment . Seven days after each treatment , participants completed question naires measuring fatigue ( Multidimensional Assessment of Fatigue , Profile of Mood States-Fatigue/Inertia subscale and Fatigue Symptom Checklist ) and depression ( Profile of Mood States-Depression subscale [ POMS-DD ] and Center for Epidemiologic Studies -Depression [ CES-D ] ) . Results . Repeated- measures ANOVAs , after controlling for baseline measures , showed that paroxetine was more effective than placebo in reducing depression during chemotherapy as measured by the CES-D ( p=0.006 ) and the POMS-DD ( p=0.07 ) but not in reducing fatigue ( all measures , ps > 0.27 ) . Conclusions . Although depression was significantly reduced in the 44 patients receiving paroxetine compared to the 50 patients receiving placebo , indicating that a biologically active dose was used , no significant differences between groups on any of the measures of fatigued were observed . Results suggest that modulation of serotonin may not be a primary mechanism of fatigue related to cancer treatment [15452187] PURPOSE To determine whether weekly epoetin alfa could improve hemoglobin ( HgB ) levels , reduce RBC transfusions , and improve quality of life ( QOL ) in patients with advanced cancer and with anemia after receiving myelosuppressive chemotherapy . PATIENTS AND METHODS This double-blind , placebo-controlled study r and omly assigned patients to placebo or epoetin alfa ( Ortho Biotech , Bridgewater , NJ ) 40,000 U subcutaneous weekly for 16 weeks . QOL , HgB , and RBC transfusions were measured pretreatment and monthly . RESULTS The study accrued 344 patients ; 330 were assessable for efficacy and 305 were assessable for QOL . Placebo-treated patients had a mean increase in HgB of 0.9 g/dL ( range , -3.8 to + 5.3 ) compared with 2.8 g/dL ( range , -2.2 to + 7.5 ) for epoetin-treated patients ( P < .0001 ) . During the study , 31.7 % of placebo-treated patients achieved a > or = 2 g/dL HgB increase compared with 72.7 % of epoetin-treated patients ( P < .0001 ) . The incidence of RBC transfusion for placebo and epoetin treatment arms was 39.6 % and 25.3 % ( P = .005 ) , respectively . The placebo group received 256 units of RBCs compared with 127 units in the epoetin group ( P < .0001 ) . The incidence of toxicity in the groups was similar . Changes in the average QOL scores from baseline to the end of the study were similar in the two groups ( P = not significant ) . The HgB responders ( irrespective of treatment arm ) had a mean change in Functional Assessment of Cancer Therapy ( FACT ) fatigue score from a baseline of + 5.1 compared with -2.1 for the nonresponders ( P = .006 ) . CONCLUSION Epoetin alfa significantly improved HgB and reduced transfusions in this patient population . These results support the use of weekly epoetin alfa as an ameliorative agent for cancer-related anemia [16622259] PURPOSE Maintaining dose-intensity with chemotherapeutic agents is hindered by a number of adverse effects including asthenia/fatigue . Tumor necrosis factor ( TNF ) is one of the cytokines responsible for the fatigue and cachexia associated with malignancies . We used etanercept ( TNF-decoy receptor ) to maintain dose-intensity of weekly docetaxel . PATIENTS AND METHODS Initially , 12 patients with advanced malignancies were r and omly assigned to either docetaxel 43 mg/m2 weekly alone ( cohort A ) or the same docetaxel dose plus etanercept 25 mg subcutaneously twice weekly ( cohort B ) . Subsequently , higher doses of docetaxel in combination with etanercept were evaluated . Pharmacokinetics ( PKs ) , nuclear factor-kappa B ( NF-kappaB ) activation , and intracellular cytokines levels were measured . Patients completed weekly question naires quantifying asthenia/fatigue . RESULTS Twenty-nine of 36 intended docetaxel doses during the first cycle were delivered in cohort A , and 35 of 36 doses were delivered in cohort B ( P = .055 ) . Three cohort B patients received additional cycles in the absence of disease progression or severe toxicity , whereas no patients from cohort A received additional cycles . Escalation to docetaxel 52 mg/m2 weekly with etanercept result ed in neutropenia , not fatigue , as the limiting adverse effect , and the addition of filgrastim permitted the maintenance of dose-intensity in additional patients . Patients r and omly selected to receive etanercept/docetaxel self-reported less fatigue ( P < .001 ) , and docetaxel PKs show no relevant influence of etanercept . NF-kappaB activation and increased expression of TNF-alpha were associated with increments in docetaxel dose . Antitumor activity was noticed exclusively in patients receiving etanercept . CONCLUSION The addition of etanercept is safe and had no impact on docetaxel concentrations . The significant improvement in tolerability and the trend toward preservation of dose-intensity suggests further exploration of TNF blockade as an adjunct to cancer therapies [12844250] The prevention of post-chemotherapy symptoms such as delayed emesis , anorexia , and fatigue induced by irinotecan has not been studied . We compared the effects of dexamethasone ( Dex ) with those of a placebo on these symptoms in a r and omized study . Seventy patients scheduled to receive irinotecan chemotherapy were enrolled in the study and r and omly divided into a treatment or a placebo group . In the treatment group , 8 mg of Dex were administered on days 2–4 after the start of chemotherapy . All patients in both groups received Dex and granisetron for prophylaxis against acute emesis on day 1 . We evaluated 68 patients ( 35 receiving Dex , 33 receiving the placebo ) . Although delayed emesis was completely prevented in most of patients in both groups ( Dex , 82.9 % ; placebo , 78.8 % ) , anorexia and fatigue were more completely prevented in those in the Dex group ( Dex , 62.9 % and 77.1 % , placebo , 39.4 % and 57.6 % , respectively ) . The effect of Dex on improving simultaneous prophylaxis against all three symptoms was almost significant ( Dex , 60.0 % ; placebo , 36.4 % ; P=0.058 ) . The safety profiles of the two groups were not discernibly different . These results suggest that treatment with Dex may be beneficial to reduce post-chemotherapy symptoms induced by irinotecan , specifically anorexia and fatigue , with acceptable toxicities [18262758] OBJECTIVE In April 2005 a phase III r and omized study was started to establish which was the most effective and safest treatment of cancer-related anorexia/cachexia syndrome and oxidative stress in improving identified primary endpoints : increase of lean body mass , decrease of resting energy expenditure ( REE ) , increase of total daily physical activity , decrease of interleukin-6 and tumor necrosis factor-alpha , and improvement of fatigue assessed by the Multidimensional Fatigue Symptom Inventory-Short Form ( MFSI-SF ) . METHODS All patients were given as basic treatment polyphenols plus antioxidant agents alpha-lipoic acid , carbocysteine , and vitamins A , C , and E , all orally . Patients were then r and omized to one of the following five arms : 1 ) medroxyprogesterone acetate/megestrol acetate ; 2 ) pharmacologic nutritional support containing eicosapentaenoic acid ; 3 ) L-carnitine ; 4 ) thalidomide ; or 5 ) medroxyprogesterone acetate/megestrol acetate plus pharmacologic nutritional support plus L-carnitine plus thalidomide . Treatment duration was 4 mo . The sample comprised 475 patients . RESULTS By January 2007 , 125 patients , well balanced for all clinical characteristics , were included . No severe side effects were observed . As for efficacy , an interim analysis on 125 patients showed an improvement of at least one primary endpoint in arms 3 , 4 , and 5 , whereas arm 2 showed a significant worsening of lean body mass , REE , and MFSI-SF . Analysis of variance comparing the change of primary endpoints between arms showed a significant improvement of REE in favor of arm 5 versus arm 2 and a significant improvement of MFSI-SF in favor of arms 1 , 3 , and 5 versus arm 2 . A significant inferiority of arm 2 versus arms 3 , 4 , and 5 for the primary endpoints lean body mass , REE , and MFSI-SF was observed on the basis of t test for changes . CONCLUSION The interim results obtained thus far seem to suggest that the most effective treatment for cancer-related anorexia/cachexia syndrome and oxidative stress should be a combination regimen . The study is still in progress and the final results should confirm these data [10387980] Advanced cancer is frequently associated with a significant anemia that may be due to the disease itself or the effect of concomitantly administered chemotherapeutic agents . In a series of double-blind , placebo-controlled trials , three population s of anemic cancer patients were r and omized to rHuEPO or placebo . The three population s were : A ) patients not receiving concomitant chemotherapy , B ) patients receiving chemotherapeutic regimens which did not contain cisplatin , and C ) patients receiving chemotherapeutic regimens which contained cisplatin . In the no-chemotherapy trials , patients were treated with rHuEPO ( 100 U/kg ) or placebo s.c . three times a week for up to eight weeks . In the two types of chemotherapy trials , patients were treated with rHuEPO ( 150 U/kg ) or placebo SC three times a week for 12 weeks . A total of 413 patients were enrolled in these trials ( 124 in the no-chemotherapy group , 157 in the no-cisplatin chemotherapy group and 132 in the cisplatin chemotherapy group ) . In each trial , patients r and omized to rHuEPO had a significantly greater ( p < .004 ) increase in hematocrit than placebo-treated patients . In the two types of chemotherapy trials combined , utilizing an rHuEPO dose of 150 U/kg , rHuEPO-treated patients had significantly lower ( p < /=.009 ) transfusion requirements ( percentage of patients transfused and mean units of blood transfused per patient ) than placebo-treated patients during months two and three , but not during month one . Quality -of-life parameters measured on a 100 mm visual analog scale significantly improved ( p<.05 ) in rHuEPO-treated patients whose hematocrit increased > /= 6 percentage points , compared to corresponding quality -of-life changes in placebo-treated patients . rHuEPO was well tolerated compared to placebo . The above results suggest that rHuEPO may be a useful agent to palliate the morbid consequences of the anemia that is often found in association with advanced cancer [19388866] CONTEXT AND OBJECTIVE Guaraná ( Paullinia cupana ) has been used medicinally for centuries . The aim of this study is evaluate the effectiveness of guaraná in the treatment of postradiation depression and fatigue . DESIGN AND SETTING This study had a double-blind r and omized design with crossover between experimental arms , at Faculdade de Medicina da Fundação do ABC . METHODS We conducted a r and omized double-blind crossover trial with 36 patients with breast cancer undergoing adjuvant radiation therapy . We r and omized patients to either guaraná 75 mg daily p.o . or to placebo . Patients were switched to the other experimental arm at the middle of the radiation treatment , which consisted of 28 daily fractions of 180 cGy . Evaluations were conducted at the beginning , at the middle , and at the end of radiation therapy . RESULTS We were unable to show any statistically significant differences between the guaraná and the placebo-treated group with any of the measured scores . Also , within the same group , we did not see any statistically significant associations during either the guaraná- or placebo-treated periods with any of the aforementioned measures . CONCLUSIONS We were unable to show that patients with breast cancer undergoing radiation therapy derive any advantage with guaraná over placebo for both fatigue and depressive symptoms [19164318] OBJECTIVE The efficacy and safety of weekly administration of epoetin beta ( EPO ) for chemotherapy-induced anemia ( CIA ) patients was evaluated . METHODS One hundred and twenty-two patients with lung cancer or malignant lymphoma undergoing chemotherapy were r and omized to the EPO 36 000 IU group or the placebo group . Hematological response and red blood cell ( RBC ) transfusion requirement were assessed . Quality of life ( QOL ) was assessed using the Functional Assessment of Cancer Therapy-Anemia ( FACT-An ) question naire . RESULTS Mean change in hemoglobin level with EPO increased significantly over placebo ( 1.4 + /- 1.9 g/dl versus -0.8 + /- 1.5 g/dl ; P < 0.001 ) . The proportion of patients with change in hemoglobin level > or = 2.0 g/dl was higher for EPO than those for placebo ( P < 0.001 ) . After 4 weeks of administration , the proportion of RBC transfusion or hemoglobin level < 8.0 g/dl was significantly lower for EPO than those for placebo ( P = 0.046 ) . The changes in the FACT-An total Fatigue Subscale Score ( FSS ) were less deteriorated with EPO than those with placebo . Progressive disease ( PD ) did not influence the change in hemoglobin level but there was less decrease in FSS in non-PD patients . No significant differences in adverse events were observed . Thrombovascular events and pure red cell aplasia related to EPO were not observed . Retrospective analysis of survival showing the hazard ratio of EPO to placebo was 0.94 . CONCLUSION Weekly administration of EPO 36 000 IU significantly increased hemoglobin level and ameliorated the decline of QOL in CIA patients over the 8-week administration period [9765767] PURPOSE To evaluate the effect of megestrol acetate at a lower dose than previously investigated on the symptoms of cachexia in patients with advanced cancer . METHODS A total of 84 patients with advanced , solid tumours not responsive to hormone therapy were enrolled in this double-blind , crossover study . During phase 1 , patients were r and omly assigned to receive megestrol acetate ( 160 mg 3 times daily ) for 10 days or placebo . During phase 2 , after a 2-day washout period , patients received the alternate treatment for 10 days . Patients underwent daily assessment s of activity , nausea , appetite and well-being by means of a visual analogue scale ( VAS ) . In addition , nutritional status ( weight , tricep skinfold measure , arm muscle circumference ) , energy intake , fatigue ( Piper Fatigue Scale ) and quality of life ( Functional Living Index-Cancer [ FLIC ] ) were assessed . RESULTS Among the 53 evaluable patients megestrol acetate result ed in a significant improvement in appetite ( p = 0.005 ) , activity ( p = 0.007 ) and well-being ( p = 0.03 ) . There was no significant change in the intensity of nausea , nutritional parameters , energy intake or FLIC scores . There was a significant improvement in 2 of the 3 factors measured by the Piper Fatigue Scale and in the overall fatigue score . Upon completion of the study , while still blind to the treatment condition , 30 patients indicated that they felt better overall after megestrol , 15 said they felt better after placebo , and 10 indicated no preference ( p = 0.001 ) . CONCLUSION Treatment with megestrol acetate results in rapid and significant improvement of symptoms in terminally ill patients at lower doses than previously reported . The effects are not secondary to nutritional changes . The FLIC quality -of-life question naire was unable to detect these changes [12877666] Summary . This phase 3 , r and omized , double‐blind , placebo‐controlled study was design ed to evaluate the efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies . Patients ( n = 344 ) with lymphoma or myeloma received darbepoetin alfa 2·25 μg/kg or placebo s.c . , once weekly for 12 weeks . The percentage of patients achieving a haemoglobin response was significantly higher in the darbepoetin alfa group ( 60 % ) than in the placebo group ( 18 % ) ( P < 0·001 ) , regardless of baseline endogenous erythropoietin level . However , increased responsiveness was observed in patients with lower baseline erythropoietin levels . Darbepoetin alfa also result ed in higher mean changes in haemoglobin than placebo from baseline to the last value during the treatment phase ( 1·80 g/dl vs 0·19 g/dl ) and after 12 weeks of treatment ( 2·66 g/dl vs 0·69 g/dl ) . A significantly lower percentage of patients in the darbepoetin alfa group received red blood cell transfusions than in the placebo group ( P < 0·001 ) . The efficacy of darbepoetin alfa was consistent for patients with lymphoma or myeloma . Improvements in quality of life were also observed with darbepoetin alfa . The overall safety profile of darbepoetin alfa was consistent with that expected for this patient population . Darbepoetin alfa significantly increased haemoglobin and reduced red blood cell transfusions in patients with lymphoproliferative malignancies receiving chemotherapy [2205358] This double‐blind , cross‐over trial was design ed to assess the effects of megestrol acetate ( MA ) on cancer‐induced cachexia . Forty consecutive malnourished patients with advanced non‐hormone‐responsive tumors receiving no antineoplastic treatment were r and omized to receive MA 480 mg/day versus placebo for 7 days . During day 8 , a cross‐over was made until day 15 . Appetite , pain , nausea , depression , energy , and well‐being were assessed with a visual analog scale ( 0 to 100 mm ) at 9:00 am and 4:00 pm during days 6 , 7 , 13 , and 14 . Weight ( W ; kg ) , tricep skinfold ( TS ; mm ) , arm circumference ( AC ; cm ) , and calf circumference ( CC ; cm ) were measured at days 1 , 8 , and 15 . Caloric intake ( CI ; Kcal/day ) was determined during days 6 , 7 , 13 , and 14 . In 31 evaluable patients , the percentual difference in appetite at 9:00 am , appetite at 4:00 pm , energy , and well‐being after MA was + 15.1 , + 14 , + 3.2 , and + 5.2 , versus −12 ( P = 0.03 ) , −5.1 ( P = 0.015 ) , −10 ( P = 0.024 ) , and −8.3 ( not significant ) after placebo . Percentual difference in W , TS , AC , and CC after MA was + 0.2 , + 1 , −0.1 , and + 0.4 versus −0.8 ( P = 0.03 ) , −0.8 ( P = 0.001 ) , −0.3 ( not significant ) , and −0.5 ( P = 0.04 ) after placebo . CI during MA was 3480 ± 1574 ( 48‐hour intake ) , versus 2793 ± 1542 ( P < 0.001 ) during placebo . Patients and investigators blindly chose MA in 20 ( 66 % , P = 0.023 ) and 28 cases ( 92 % , P < 0.001 ) , placebo in eight and two cases , and made no choice in three and one cases , respectively . Toxicity consisted of mild edema and nausea in three and two cases , respectively . After mean follow‐up of 27 ± 13 days , on an open basis , an average increase in W and AC of 4.8 ± 1.7 kg and 2.8 ± 1.7 cm was observed , respectively . The authors conclude that MA is a powerful appetite stimulant with subjective and objective effects on nutritional status [15748464] Impaired cognition , fatigue , and diminished quality of life ( QOL ) are commonly associated with breast cancer chemotherapy . This r and omized , double-blind , placebo-controlled pilot trial assessed the feasibility of quantifying the effects of epoetin alfa on cognitive function and mood , and evaluated its effects on fatigue and QOL in patients with breast cancer treated with anthracycline-based adjuvant or neoadjuvant chemotherapy . Patients were r and omized to receive epoetin alfa 40,000 U subcutaneously once weekly or placebo at the beginning of 4 cycles of chemotherapy administered over 12 weeks . Cognitive function was assessed by Executive Interview ( EXIT25 ) and Clock Drawing Tasks ; mood by Profile of Mood States ; anemia-related symptoms , including fatigue , by the Functional Assessment of Cancer Therapy-Anemia ( FACT-An ) subscale ; and QOL by Linear Analog Scale Assessment . Ninety-four patients were evaluable for efficacy and safety . Mean change in EXIT25 scores from baseline to cycle 4 in the epoetin alfa group was 1.3 + /- 3.3 ; the mean change was 0.3 + /- 2.4 in the placebo group ( a negative change indicates improved executive function ) . There was no difference between groups in mean change in EXIT25 score from baseline to 6-month follow-up assessment . Mean hemoglobin levels were higher in the epoetin alfa group compared with the placebo group after 4 cycles of chemotherapy . Epoetin alfa recipients had less of a decrease in FACT-An subscale scores from baseline to cycle 4 and improvement in FACT-An subscale scores at 6-month follow-up assessment compared with placebo . Epoetin alfa therapy was well tolerated . These data suggest that epoetin alfa may have attenuated the cognitive impairment and fatigue that occurred during adjuvant breast cancer chemotherapy [17972110] Background Women who receive adjuvant chemotherapy for breast cancer develop fatigue , and a subset reports cognitive impairment . Methylpheni date is reported to improve fatigue and to decrease cognitive impairment in other population s. Material s and methods Women were r and omised early during their chemotherapy to receive d-methylpheni date ( d-MPH ) , a form of methylpheni date , or an identical appearing placebo . All participants took placebo for one cycle to ensure compliance and then study medication until completion of chemotherapy . Subjects were assessed at baseline , end of chemotherapy and at ∼6 months follow-up with the High Sensitivity Cognitive Screen ( HSCS ) and the Hopkins Verbal Learning Test-Revised ( HVLT-R ) . They also completed the self-report Functional Assessment of Cancer Therapy-General ( FACT-G ) and FACT-F ( F = fatigue ) question naires , evaluating quality of life and fatigue . Results A total of 57 evaluable women were r and omised : 29 to d-MPH and 28 to placebo ; the study did not meet its accrual goal of 170 patients , mainly because women were reluctant to take additional medication in general and methylpheni date in particular . Groups were well matched for age ( median , 50 years ) and education . d-MPH and placebo were well tolerated . There were no significant differences between the r and omised groups in classification of cognitive function by HSCS or in summed FACT-F fatigue scores ( the primary endpoints of the study ) at any of the assessment s. There were also no differences in HLTV-R scores or quality of life . Conclusions This study is underpowered , but there are no trends to suggest that d-MPH , taken concurrently with adjuvant chemotherapy , improves quality of life or fatigue [9469326] PURPOSE The possibility that epoetin beta ( EPO ) could increase hemoglobin ( B-Hb ) levels and improve quality of life ( QoL ) in patients with advanced gastrointestinal cancers was investigated . PATIENTS AND METHODS One hundred patients with gastric , pancreatic , biliary , or colorectal cancers and subnormal B-Hb levels were included in a r and omized study to test low-dose EPO ( 2,000 U subcutaneously thrice weekly [ 2,000 group ] ) against a higher dose ( 10,000 U times three [ 10,000 group ] ) . Eighty-four patients were treated with chemotherapy . QoL was evaluated using the European Organization for Research and Treatment of Cancer ( EORTC ) QLQ-C30 instrument . RESULTS At baseline , mean B-Hb was 108 g/L with no difference between the groups . In the 10,000 group , an increase in B-Hb ( > 10 g/L ) was seen in 30 ( 73 % ) patients treated with chemotherapy , after a median of 4 weeks , whereas a corresponding increase in the 2,000 group was seen in 15 ( 30 % ) patients after a median of 10 weeks ( P < .001 ) . A difference in the proportion of responders ( five of eight v one of eight ) was also seen in the group of patients not treated with chemotherapy . The proportion of responders was independent of baseline endogenous serum EPO level or observed/predicted log10 serum (S)-EPO levels . Patients who demonstrated improved B-Hb levels also showed improvements in QoL parameters . Tumor response was usually also associated with QoL improvements . CONCLUSION Treatment with EPO at a dose of 10,000 U thrice weekly can rapidly and safely increase B-Hb levels in a high proportion of patients with advanced gastrointestinal cancers . QoL is influenced by the B-Hb increase , but also by the course of the underlying malignancy . It is therefore difficult to define clearly the clinical relevance of the B-Hb increase as such [18707619] Anaemia is common in patients receiving chemotherapy , causing symptoms that have a major impact on quality of life ( QoL ) . Epoetin beta rapidly increases haemoglobin ( Hb ) levels and improves QoL in anaemic patients with a variety of tumours . This was a r and omized , double-blind , parallel-group , dose-finding study assessing the efficacy and safety of once-weekly epoetin beta in patients with solid tumours receiving chemotherapy . Adult patients with anaemia ( Hb < 11 g/dL ) were r and omized to receive epoetin beta 30,000 IU or 20,000 IU once weekly for 12 weeks . All patients received oral iron supplementation . Haemoglobin levels , transfusion need and QoL [ Functional Assessment of Cancer Therapy-fatigue ( FACT-F ) subscale score ] were assessed at regular intervals . Fifty patients were r and omized ; 30 patients received epoetin beta 30,000 IU once weekly and 20 received 20,000 IU once weekly . Mean ( + /- SD ) increase in Hb from baseline to week 12 was 1.75 + /- 2.15 g/dL in the 30,000 IU group ( P = 0.008 vs. baseline ) and 1.04 + /- 1.75 g/dL in the 20,000 IU group ( non-significant ) . Haemoglobin response ( increase in Hb > or=2 g/dL from baseline ) was observed in 78.3 % of patients receiving epoetin beta 30,000 IU and 66.7 % receiving epoetin beta 20,000 IU . Improvements in FACT-F subscale score were significantly ( P < 0.001 ) correlated with increases in Hb level . Transfusion use was low during the study in both groups . Both epoetin beta regiments were well tolerated and there were no dose-dependent adverse events . Epoetin beta 30,000 IU once weekly is an effective and well-tolerated treatment of anaemia in patients with solid tumours [14673053] PURPOSE Fatigue and depression typically occur together in cancer patients , suggesting a common etiology , perhaps based on serotonin . This r and omized clinical trial tested whether paroxetine , a selective serotonin reuptake inhibitor antidepressant known to modulate brain serotonin , would reduce fatigue in cancer patients and whether any reduction was related to depression . PATIENTS AND METHODS Cancer patients undergoing chemotherapy for the first time were assessed for fatigue . Of 704 patients who reported fatigue at their second chemotherapy cycle , 549 patients were r and omly assigned to receive either 20 mg of oral paroxetine hydrochloride daily or placebo for 8 weeks . The assessment s of fatigue and depression were performed at cycles 3 and 4 of chemotherapy . RESULTS A total of 244 patients treated with paroxetine and 235 patients treated with placebo provided assessable data . No difference was detected in fatigue between patient groups . At the end of the study , there was a difference between groups in the mean level of depression ( Center for Epidemiologic Studies Depression scores , 12.0 v 14.8 , respectively ; P < .01 ) . CONCLUSION Paroxetine had no influence on fatigue in patients receiving chemotherapy . A possible explanation is that cancer-related fatigue does not involve a reduction in brain 5-HT levels [16619567] The objective of this r and omised , multicentre , double-blind clinical trial was to investigate the impact of PS76A2 , an aqueous mistletoe extract st and ardised to mistletoe lectins , on quality of life ( QoL ) in breast cancer patients . A total of 352 patients were r and omly allocated to 2 groups receiving PS76A2 ( 15 ng mistletoe lectin/0.5 ml ) or matching placebo twice weekly for 4 to 6 cycles of CMF ( cyclophosphamide , methotrexate , fluorouracil ) chemotherapy followed by 2 months follow-up . The primary efficacy end-point was the change from baseline of 3 FACT-G subscales ( physical , emotional and functional well-being ) during the fourth CMF cycle . Secondary measures included GLQ-8 ( 8 linear analogue self- assessment scales ) , Spitzer 's uniscale and haematological variables . The main variables of safety analysis were adverse events , including injection site reactions and clinical laboratory tests . The results showed that physical , emotional and functional well-being improved upon PS76A2 , but deteriorated following placebo . The treatment differences were statistically significant for the 3 subscales as well as for the summary score FACT-G , which was analysed as O'Brien 's rank sum of its 3 subscales : The total score increased by 4.40 + /- 11.28 , indicating a higher QoL after PS76A2 , but decreased by 5.11 + /- 11.77 with placebo ( p<0.0001 ) . The GLQ-8 sum of 8 LASA scales was analysed as a summary score of GLQ-5 ( sum of item nos. 1 , 5 , 6 , 7 , 8) and GLQ-3 ( sum of item nos. 2 , 3 , 4 ) . GLQ-5 characterises typical aspects of QoL , while GLQ-3 consists of 3 side-effects of CMF ( feeling sick , numbness or pins and needles , loss of hair ) . GLQ-5 decreased by 42.9 + /- 125.0 upon PS76A2 , indicating an improvement in QoL , but increased by 60.3 + /- 94.0 upon placebo ( p<0.0001 ) . GLQ-3 deteriorated in both groups ( PS76A2 : 13.9 + /- 52.4 ; placebo : 34.5 + /- 57.0 ) , but the differences in favour of PS76A2 were , nevertheless , statistically significant ( p=0.0007 ) . The total score GLQ-8 improved by 28.9 + /- 154.6 after PS76A2 and deteriorated by 94.8 + /- 141.1 after placebo ( p<0.0001 ) . Spitzer 's uniscale improved by 12.2 + /- 30.7 upon PS76A2 and deteriorated by 10.8 + /- 26.1 with placebo ( p<0.0001 ) . After follow-up without chemotherapy , a significant treatment difference in favour of PS76A2 was determined by means of FACT-G , GLQ-8 and Spitzer 's uniscale . PS76A2 was well tolerated in this trial , with the exception of slight local reactions in 17.6 % of the PS76A2 group . In conclusion , PS76A2 ( 15 ng mistletoe lectin/0.5 ml twice weekly ) was shown to be safe and effective in improving QoL in breast cancer patients during chemotherapy and follow-up [17602062] This r and omized , controlled trial evaluated the effect of darbepoetin alfa on hospitalization days , transfusion requirements , hemoglobin levels , and fatigue in patients with anemia of cancer ( AOC ) . Eligible patients were anemic ( hemoglobin < or=11 g/dl ) due to cancer , > or=18 years old , and had not received chemotherapy or radiotherapy within 4 weeks of study screening . Patients were r and omized 4:1 to receive darbepoetin alfa , 3.0 microg/kg every 2 weeks ( Q2W ) ( n = 226 ) , or observation only for 12 weeks ( n = 59 ) , followed by an optional 9 weeks of darbepoetin alfa , 3.0 microg/kg Q2W . Endpoints were compared between the two treatment arms at week 13 . A planned interim analysis indicated that assumptions regarding hospitalization in the study design were incorrect , so the study was terminated early . Therefore , results for the primary endpoint should be interpreted cautiously . The hospitalization rate was similar ( 0.5 days ) for both the darbepoetin alfa and observation groups ( p = .73 ) . Transfusion incidence ( weeks 5 - 12 ) was significantly lower for darbepoetin alfa patients ( 8 % ) than for observation patients ( 22 % ) ( p = .0092 ) . By week 13 , hemoglobin increased by 2.1 g/dl in patients receiving darbepoetin alfa , compared with 0.1 g/dl in the observation group p < .0001 . Hemoglobin improvements were paralleled by an increase in Functional Assessment of Cancer Therapy-Fatigue score ( mean change in score at week 13 : darbepoetin alfa , 6.0 ; observation , 2.2 ; p < .05 ) . Darbepoetin alfa Q2W can significantly improve hemoglobin levels and reduce transfusion requirements in patients with AOC , result ing in significant improvements in health-related quality of life [16505427] PURPOSE To compare maintenance epoetin alfa administered once every 3 weeks with continued weekly epoetin alfa for patients with cancer-associated anemia . PATIENTS AND METHODS Eligible patients were r and omly assigned at enrollment to receive three weekly doses of epoetin alfa 40,000 U subcutaneously ( SC ) , followed by either st and ard weekly epoetin alfa ( 40 K arm ) or 120,000 U of epoetin alfa ( 120 K arm ) SC every 3 weeks for 18 additional weeks . RESULTS Three hundred sixty-five patients were enrolled . One hundred eighty-three patients were assigned to the 40 K arm , and 182 were assigned to the 120 K arm . There was no difference in the proportion of patients requiring transfusions during the study ( 23 % in 40 K arm and 18 % in 120 K arm , P = .22 ) or specifically during the maintenance phase ( 13 % in 40 K arm v 15 % in 120 K arm , P = .58 ) . Patients r and omly assigned to the 40 K arm were more likely to have a > or = 2 or > or = 3 g/dL hemoglobin ( Hb ) increment , were more likely to have a drug dose held because of high Hb , and had higher mean end-of- study Hb levels . Toxicities , including thromboembolism , and overall survival were similar . Patients in the 40 K arm had a higher global quality of life ( QOL ) at baseline for unclear reasons , whereas patients in the 120 K arm had a greater global QOL improvement during the study , so end-of- study QOL was equivalent . CONCLUSION After three weekly doses of epoetin alfa 40,000 U , a dose of 120,000 U can be administered safely once every 3 weeks without increasing transfusion needs or sacrificing QOL . The Hb increment is somewhat greater with continued weekly epoetin alfa . Lack of blinding as a result of different treatment schedules may have confounded results [12189224] BACKGROUND Patients receiving chemotherapy often develop anemia . Darbepoetin alfa ( Aranesp(TM ) ) is an erythropoiesis-stimulating glycoprotein that has been shown , in dose-finding studies , to be safe and clinical ly active when administered to patients with cancer every 1 , 2 , or 3 weeks . This phase III study compared the safety and efficacy of darbepoetin alfa with placebo in patients with lung cancer receiving chemotherapy . METHODS In this multicenter , double-blind , placebo-controlled study , 320 anemic patients ( hemoglobin < or=11.0 g/dL ) were r and omly assigned to receive darbepoetin alfa or placebo injections weekly for 12 weeks . The 297 patients who completed at least the first 28 days of study were assessed for red blood cell transfusions , the primary endpoint . Patients were also assessed for hemoglobin concentration ( i.e. , hematopoietic response ) , adverse events , antibody formation to darbepoetin alfa , hospitalizations , Functional Assessment of Cancer Therapy (FACT)-Fatigue score , and disease outcome . Efficacy endpoints were assessed using Kaplan-Meier analyses , Cox proportional hazards analyses , and chi-square tests where appropriate . All statistical tests were two-sided . RESULTS Patients receiving darbepoetin alfa required fewer transfusions ( 27 % versus 52 % ; mean difference = 25 % ; 95 % confidence interval [ CI ] = 14 % to 36 % ; P<.001 ) , required fewer units of blood ( 0.67 versus 1.92 ; mean difference = 1.25 , 95 % CI = 0.65 to 1.84 ; P<.001 ) , had more hematopoietic responses ( 66 % versus 24 % ; mean difference = 42 % ; 95 % CI = 31 % to 53 % ; P<.001 ) , and had better improvement in FACT-Fatigue scores ( 56 % versus 44 % overall improvement ; 32 % versus 19 % with > or=25 % improvement ; mean difference = 13 % ; 95 % CI = 2 % to 23 % , P = .019 ) than patients receiving placebo . Patients receiving darbepoetin alfa did not appear to have any untoward effect in disease outcome and did not develop antibodies to the drug . Adverse events were similar between the groups . CONCLUSIONS Patients with chemotherapy-associated anemia can safely and effectively be treated with weekly darbepoetin alfa therapy . Darbepoetin alfa decreased blood transfusion requirements , increased hemoglobin concentration , and decreased fatigue . Although no conclusions can be drawn about survival from this study , the potential salutary effect on disease outcome warrants further investigation in a prospect ively design ed study [11927189] We have previously shown that the risk of major depression in patients with malignant melanoma undergoing interferon-α ( IFN-α ) therapy can be reduced by pretreatment with the antidepressant , paroxetine . Using dimensional analyses , the present study assessed the expression and treatment responsiveness of specific clusters of neuropsychiatric symptoms over the first three months of IFN-α therapy . Forty patients with malignant melanoma eligible for IFN-α treatment were r and omly assigned to receive either paroxetine or placebo in a double-blind design . Neuropsychiatric assessment s were conducted at regular intervals during the first twelve weeks of IFN-α therapy and included the 21-item Hamilton Depression Rating Scale , the 14-item Hamilton Anxiety Rating Scale and the Neurotoxicity Rating Scale . Neurovegetative and somatic symptoms including anorexia , fatigue and pain appeared within two weeks of IFN-α therapy in a large proportion of patients . In contrast , symptoms of depressed mood , anxiety and cognitive dysfunction appeared later during IFN-α treatment and more specifically in patients who met DSM-IV criteria for major depression . Symptoms of depression , anxiety , cognitive dysfunction and pain were more responsive , whereas symptoms of fatigue and anorexia were less responsive , to paroxetine treatment . These data demonstrate distinct phenomenology and treatment responsiveness of symptom dimensions induced by IFN-α , and suggest that different mechanisms mediate the various behavioral manifestations of cytokine-induced “ sickness behavior . [11387359] PURPOSE This r and omized , double-blind , placebo-controlled clinical trial assessed the effects of epoetin alfa on transfusion requirements , hematopoietic parameters , quality of life ( QOL ) , and safety in anemic cancer patients receiving nonplatinum chemotherapy . The study also explored a possible relationship between increased hemoglobin and survival . PATIENTS AND METHODS Three hundred seventy-five patients with solid or nonmyeloid hematologic malignancies and hemoglobin levels < or = 10.5 g/dL , or greater than 10.5 g/dL but < or = 12.0 g/dL after a hemoglobin decrease of > or = 1.5 g/dL per cycle since starting chemotherapy , were r and omized 2:1 to epoetin alfa 150 to 300 IU/kg ( n = 251 ) or placebo ( n = 124 ) three times per week subcutaneously for 12 to 24 weeks . The primary end point was proportion of patients transfused ; secondary end points were change in hemoglobin and QOL . The protocol was amended before unblinding to prospect ively collect and assess survival data 12 months after the last patient completed the study . RESULTS Epoetin alfa , compared with placebo , significantly decreased transfusion requirements ( P = .0057 ) and increased hemoglobin ( P < .001 ) . Improvement of all primary cancer- and anemia-specific QOL domains , including energy level , ability to do daily activities , and fatigue , was significantly ( P < .01 ) greater for epoetin alfa versus placebo patients . Although the study was not powered for survival as an end point , Kaplan-Meier estimates showed a trend in overall survival favoring epoetin alfa ( P = .13 , log-rank test ) , and Cox regression analysis showed an estimated hazards ratio of 1.309 ( P = .052 ) favoring epoetin alfa . Adverse events were comparable between groups . CONCLUSION Epoetin alfa safely and effectively ameliorates anemia and significantly improves QOL in cancer patients receiving nonplatinum chemotherapy . Encouraging results regarding increased survival warrant another trial design ed to confirm these findings [12506181] PURPOSE To determine whether high doses of fish oil , administered over 2 weeks , improve symptoms in patients with advanced cancer and decreased weight and appetite . PATIENTS AND METHODS Sixty patients were r and omly assigned to fish oil capsules or placebo . Appetite , tiredness , nausea , well-being , caloric intake , nutritional status , and function were prospect ively assessed at days 1 and 14 . RESULTS The baseline weight loss was 16 + /- 11 and 16 + /- 8 kg in the fish oil ( n = 30 ) and placebo ( n = 30 ) group respectively , whereas the baseline appetite ( 0 mm = best and 10 mm = worst ) was 58 + /- 24 mm and 67 + /- 19 mm , respectively ( P = not significant ) . The mean daily dose was 10 + /- 4 ( fish oil group ) and 9 + /- 3 ( placebo group ) capsules , which provided 1.8 g of eicosapentaenoic acid and 1.2 g of docosahexaenoic acid in the fish oil group . No significant differences in symptomatic or nutritional parameters were found ( P < .05 ) , and there was no correlation between changes in different variables between days 1 and 14 and the fish oil doses . Finally , the majority of the patients were not able to swallow more than 10 fish oil capsules per day , mainly because of burping and aftertaste . CONCLUSION Fish oil did not significantly influence appetite , tiredness , nausea , well-being , caloric intake , nutritional status , or function after 2 weeks compared with placebo in patients with advanced cancer and loss of both weight and appetite [19415341] Purpose This pilot trial sought to investigate whether any of three doses of American ginseng ( Panax quinquefolius ) might help cancer-related fatigue . A secondary aim was to evaluate toxicity . Methods Eligible adults with cancer were r and omized in a double-blind manner , to receive American ginseng in doses of 750 , 1,000 , or 2,000 mg/day or placebo given in twice daily dosing over 8 weeks . Outcome measures included the Brief Fatigue Inventory , vitality subscale of the Medical Outcome Scale Short Form-36 ( SF-36 ) , and the Global Impression of Benefit Scale at 4 and 8 weeks . Results Two hundred ninety patients were accrued to this trial . Nonsignificant trends for all outcomes were seen in favor of the 1,000- and 2,000-mg/day doses of American ginseng . Area under the curve analysis of activity interference from the Brief Fatigue Inventory was 460–467 in the placebo group and 750 mg/day group versus 480–551 in the 1,000- and 2,000-mg/day arms , respectively . Change from baseline in the vitality subscale of the SF-36 was 7.3–7.8 in the placebo and the 750-mg/day arm , versus 10.5–14.6 in the 1,000- and 2,000-mg/day arms . Over twice as many patients on ginseng perceived a benefit and were satisfied with treatment over those on placebo . There were no significant differences in any measured toxicities between any of the arms . Conclusion There appears to be some activity and tolerable toxicity at 1,000–2,000 mg/day doses of American ginseng with regard to cancer-related fatigue . Thus , further study of American ginseng is warranted [11676354] OBJECTIVE Erythropoietin is shown to be an effective treatment for anemia in various types of cancers , however only limited studies have evaluated its benefits in advanced hormone-refractory prostate cancer ( HRPC ) . This multi-center study investigated the influence of 2 different doses of epoetin beta on quality of life , hemoglobin level , need for blood transfusion , and safety , in the treatment of anemia in patients with metastatic HRPC . MATERIAL S AND METHODS This study r and omized 180 patients to receive either epoetin beta 1000 IU or 5000 IU subcutaneously 3 times per week for 12 weeks . Hemoglobin was evaluated at study start and 6 time-points during the study . Quality of life ( QoL ) was assessed by the European Organization for Research and Treatment of Cancer question naire , QLC-C30 , before treatment start and after 6 and 12 weeks of treatment . Best supportive care and blood transfusions were given , if clinical ly indicated . Additional laboratory values and adverse events were followed for safety . RESULTS Hemoglobin increased significantly ( > 20 g/l ) in 43 % in the high dose ( HD ) group and 25 % in the low dose ( LD ) group in response to treatment . Levels were significantly higher in the HD group than the LD group ( p < 0.001 ) after 8 and 12 weeks . QoL improved significantly if the increase in hemoglobin was > 20 g/l . Significantly more patients in the LD group received blood transfusions than the HD group ( p < 0.005 ) . There were no differences between the groups regarding overall quality of life and fatigue . The treatment was well tolerated in both groups . CONCLUSIONS Epoetin beta is shown to be safe and effective for the treatment of anemia in many patients with HRPC . It is found to improve QoL and physical functioning , and relieve fatigue symptoms , in many of these critically ill patients [17869448] PURPOSE The quality of life ( QOL ) and neurocognitive function of patients with brain tumors are negatively affected by the symptoms of their disease and brain radiation therapy ( RT ) . We assessed the effect of prophylactic d-threo-methylpheni date HCl ( d-MPH ) , a central nervous system ( CNS ) stimulant on QOL and cognitive function in patients undergoing RT . METHODS AND MATERIAL S Sixty-eight patients with primary or metastatic brain tumors were r and omly assigned to receive d-MPH or placebo . The starting dose of d-MPH was 5 mg twice daily ( b.i.d . ) and was escalated by 5 mg b.i.d . to a maximum of 15 mg b.i.d . The placebo was administered as one pill b.i.d . escalating three pills b.i.d . The primary outcome was fatigue . Patients were assessed at baseline , the end of radiation therapy , and 4 , 8 , and 12 weeks after brain RT using the Functional Assessment of Cancer Therapy with brain and fatigue ( FACIT-F ) subscales , as well as the Center for Epidemiologic Studies Scale and Mini-Mental Status Exam . RESULTS The Mean Fatigue Subscale Score at baseline was 34.7 for the d-MPH arm and 33.3 for the placebo arm ( p = 0.61 ) . At 8 weeks after the completion of brain RT , there was no difference in fatigue between patient groups . The adjusted least squares estimate of the Mean Fatigue Subscale Score was 33.7 for the d-MPH and 35.6 for the placebo arm ( p = 0.64 ) . Secondary outcomes were not different between the two treatment arms . CONCLUSIONS Prophylactic use of d-MPH in brain tumor patients undergoing RT did not result in an improvement in QOL [16710026] PURPOSE Chemotherapy-induced anemia is widely treated in the United States with darbepoetin alfa ( DA ) or epoetin alfa ( EA ) . This noninferiority study systematic ally compares efficacy and safety of DA and EA using common doses and schedules used in clinical practice . METHODS Patients had a diagnosis of nonmyeloid malignancy with > or = 8 weeks of planned chemotherapy , age > or = 18 years , and anemia ( hemoglobin < or = 11 g/dL ) . Patients were r and omly assigned 1:1 to DA 200 microg every two weeks ( Q2W ) or EA 40,000 units every week ( QW ) for up to 16 weeks with identical dose adjustment rules . Efficacy was assessed by the incidence of RBC transfusion ( Kaplan-Meier estimate ) . The definition of noninferiority was that the upper 95 % CI limit of the observed difference in RBC transfusions between groups was less than 11.5 % ; this noninferiority margin was based on the treatment effect observed in placebo-controlled EA studies . RESULTS Of 1,220 patients r and omly assigned , 1,209 received > or = one dose of the study drug . Common tumor types were lung ( 26 % ) , breast ( 21 % ) , and gastrointestinal ( 18 % ) . Transfusion incidence from week 5 to the end of the treatment phase ( the primary end point ) was 21 % in the DA group and 16 % in the EA group ; noninferiority was concluded because the upper 95 % CI limit of the difference between groups ( 10.8 % ) was below the prespecified noninferiority margin . Sensitivity analyses using alternate statistical methods and analysis sets yielded similar results . Hemoglobin , quality of life , and safety end points further support equivalency of the erythropoietic therapies . CONCLUSION This large , phase III study demonstrates comparable efficacy of DA Q2W and EA QW . Less frequent dosing offers potential benefits for patients , caregivers and health care providers [15953714] This work was conducted to evaluate the effect of early intervention with epoetin alfa ( EPO ) on transfusion requirements , hemoglobin level ( Hb ) , quality of life ( QOL ) and to explore a possible relationship between the use of EPO and survival , in patients with solid tumors receiving platinum-based chemotherapy . Three hundred and sixteen patients with Hb12.1g/dL were r and omised 2:1 to EPO 10000 IU thrice weekly subcutaneously ( n = 211 ) or best supportive care ( BSC ) ( n = 105 ) . The primary end point was proportion of patients transfused while secondary end points were changes in Hb and QOL . The protocol was amended before the first patient was recruited to also prospect ively collect survival data . EPO therapy significantly decreased transfusion requirements ( P < 0.001 ) and increased Hb ( P < 0.005 ) . EPO-treated patients had significantly improved QOL compared with BSC patients ( P < 0.05 ) . Kaplan-Meier estimates showed no differences in 12-month survival ( P = 0.39 ) , despite a significantly greater number of patients with metastatic disease in the EPO group ( 78 % vs. 61 % , P = 0.001 ) . EPO was well tolerated . This study has shown that early intervention with EPO can result in a significant reduction of transfusion requirements and increases in Hb and QOL in patients with mild anemia during platinum-based chemotherapy [12743146] PURPOSE To determine whether fluoxetine improves overall quality of life ( QOL ) in advanced cancer patients with symptoms of depression revealed by a simple survey . PATIENTS AND METHODS One hundred sixty-three patients with an advanced solid tumor and expected survival between 3 and 24 months were r and omly assigned in a double-blinded fashion to receive either fluoxetine ( 20 mg daily ) or placebo for 12 weeks . Patients were screened for at least minimal depressive symptoms and assessed every 3 to 6 weeks for QOL and depression . Patients with recent exposure to antidepressants were excluded . RESULTS The groups were comparable at baseline in terms of age , sex , disease distribution , performance status , and level of depressive symptoms . One hundred twenty-nine patients ( 79 % ) completed at least one follow-up assessment . Analysis using generalized estimating equation modeling revealed that patients treated with fluoxetine exhibited a significant improvement in QOL as shown by the Functional Assessment of Cancer Therapy-General , compared with patients given placebo ( P = .01 ) . Specifically , the level of depressive symptoms expressed was lower in patients treated with fluoxetine ( P = .0005 ) , and the subgroup of patients showing higher levels of depressive symptoms on the two- question screening survey were the most likely to benefit from treatment . CONCLUSION In this mix of patients with advanced cancer who had symptoms of depression as determined by a two- question bedside survey , use of fluoxetine was well tolerated , overall QOL was improved , and depressive symptoms were reduced [9779721] PURPOSE To evaluate prospect ively the effectiveness of epoetin alfa as an adjunct to chemotherapy in patients with cancer based on changes in quality -of-life parameters and hemoglobin levels , and to correlate these changes with antitumor response . PATIENTS AND METHODS Two thous and three hundred seventy patients with nonmyeloid malignancies who received chemotherapy were enrolled onto this study from 621 US community-based practice s. Patients received epoetin alfa 10,000 U three times weekly , which could be increased to 20,000 U three times weekly depending on the hemoglobin response at 4 weeks . Treatment continued for a maximum of 16 weeks in patients who showed evidence of hematologic response . RESULTS Two thous and two hundred eighty-nine patients ( 97 % ) were eligible for efficacy analyses . Epoetin alfa therapy was associated with improved quality -of-life parameters ; these improvements correlated significantly with hemoglobin levels and were independent of tumor response . Provider-reported Karnofsky performance scores did not correlate with the improved quality -of-life changes . Epoetin alfa therapy was also associated with a significant increase in hemoglobin levels and decrease in transfusion use . Tumor type , chemotherapy agent/regimen , prior chemotherapy , baseline hemoglobin level , and baseline erythropoietin level were not predictive of a positive response to treatment . Epoetin alfa was well tolerated . CONCLUSION Epoetin alfa appears to have a beneficial impact on patient-reported functional capacity and quality of life in patients with cancer who received chemotherapy independent of tumor response . Concordantly , epoetin alfa appeared to increase hemoglobin levels and decrease transfusion use . Patients responded across all tumor types . The results suggest that epoetin alfa effectively improves functional outcomes in patients with cancer who receive chemotherapy [12782431] The purpose of this study was to assess whether the administration of recombinant human erythropoietin ( rHuEPO ) would correct anemia and improve the quality of life ( QOL ) in cancer patients receiving chemotherapy . One hundred twenty-two patients with hemoglobin < /=11.0 g/dl were r and omized to receive rHuEPO 10,000 U three times weekly ( n = 61 ) or no additional treatment ( n = 61 ) . Response was assessed by measuring changes in hemoglobin level and QOL . QOL was evaluated before each cycle of chemotherapy at baseline , Week 4 , and Week 12 using two separate self-report question naires . The analyses indicated that the rHuEPO-treated patients experienced significantly less fatigue ( P < 0.05 ) than their control group counterparts , and reported significantly higher scores on energy level ( P < 0.05 ) , ability to perform daily activities ( P < 0.01 ) , and overall QOL ( P < 0.05 ) . The overall change in hemoglobin level was significantly greater in the rHuEPO group than in the control group ( 1.7 g/dl versus 0.3 g/dl , P < 0.001 ) . rHuEPO effectively corrects anemia and significantly improves QOL in patients with solid tumors receiving chemotherapy [16648508] PURPOSE To evaluate the effectiveness of patient-controlled methylpheni date as compared with placebo in cancer patients with fatigue , as measured by the Functional Assessment for Chronic Illness Therapy-Fatigue ( FACIT-F ) . PATIENTS AND METHODS Patients with a fatigue score of at least 4 on a scale of 0 to 10 ( 0 = no fatigue , 10 = worst possible fatigue ) and hemoglobin level of at least 10 g/dL were included . Patients were r and omly assigned to receive 5 mg methylpheni date or placebo every 2 hours as needed ( maximum of four capsules a day ) , for 7 days . Patients completed a daily diary including study drug record and fatigue intensity . A research nurse telephoned patients daily to assess toxicity and fatigue level . All patients were offered open-label methylpheni date for 4 weeks . FACIT-F and the Edmonton Symptom Assessment System ( ESAS ) were assessed at baseline , and days 8 , 15 , and 36 . The FACIT-F fatigue subscore on day 8 was considered the primary end point . RESULTS Of 112 patients r and omly assigned , 52 patients in the methylpheni date and 53 in the placebo group were assessable for analysis . Fatigue intensity improved significantly on day 8 in both the methylpheni date and placebo groups . However , there was no significant difference in fatigue improvement by FACIT-F ( P = .31 ) or ESAS ( P = .14 ) between groups . In open-label phase , fatigue intensity maintained low as compared with baseline . No significant toxicities were observed . CONCLUSION Both methylpheni date and placebo result ed in significant symptom improvement . Methylpheni date was not significantly superior to placebo after 1 week of treatment . Longer study duration is justified . The role of daily telephone calls from a research nurse should be explored as a palliative care intervention [17312332] PURPOSE Previous trials have suggested a quality -of-life ( QOL ) improvement for anemic cancer patients treated with erythropoietin , but few used QOL as the primary outcome . We design ed a trial to investigate the effects of epoetin alfa therapy on the QOL of anemic patients with advanced non-small-cell carcinoma of the lung ( NSCLC ) . PATIENTS AND METHODS A multicenter , r and omized , double-blind , placebo-controlled trial was conducted . The proposed sample size was 300 patients . Eligible patients were required to have NSCLC unsuitable for curative therapy and baseline hemoglobin ( Hgb ) levels less than 121 g/L. Patients were assigned to 12 weekly injections of subcutaneous epoetin alpha or placebo , targeting Hgb levels between 120 and 140 g/L. The primary outcome was the difference in the change in Functional Assessment of Cancer Therapy-Anemia scores between baseline and 12 weeks . RESULTS Reports of thrombotic events in other epoetin trials prompted an unplanned safety analysis after 70 patients had been r and omly assigned ( 33 to the active arm and 37 to the placebo arm ) . This revealed a significant difference in the median survival in favor of the patients on the placebo arm of the trial ( 63 v 129 days ; hazard ratio , 1.84 ; P = .04 ) . The Steering Committee closed the trial . Patient numbers compromised the interpretation of the QOL analysis , but a positive Hgb response was noted with epoetin alfa treatment . CONCLUSION An unplanned safety analysis suggested decreased overall survival in patients with advanced NSCLC treated with epoetin alfa . Although infrequent , other similar reports highlight the need for ongoing trials evaluating erythropoietin receptor agonists to ensure that overall survival is monitored closely [2410117] A 14-day , r and omized , double-blind crossover trial was carried out comparing an oral glucocorticoid , methylprednisolone ( MP ) , against placebo for the relief of pain and other symptoms in 40 terminally ill cancer patients . After the 14-day , double-blind phase was completed , all patients were given MP for 20 days . The daily dose of MP was 32 mg , and end points of the study were pain , psychiatric status , appetite , nutritional status , daily activity , and performance . Mean intensity of pain ( visual analogue , 0 - 100 + /- SD ) was 36.8 + /- 14 after MP treatment and 57.7 + /- 15 after placebo ( P less than 0.01 ) . Following the 14-day , double-blind phase , appetite and daily activity increased in 24 of 31 patients ( 77 % ) and in 21 of 31 patients ( 68 % ) with MP , respectively ; depression and analgesic consumption decreased in 22 of 31 patients ( 71 % ) and in 16 of 28 patients ( 57 % ) with MP , respectively . MP was preferred over placebo by 23 of the 31 patients ( 74 % ) , and , in 22 of the 31 cases ( 71 % ) , the investigator chose MP over placebo . No serious toxicity was found at the dose of MP used . It is concluded that MP increases the comfort of terminally ill cancer patients [12883695] Fixed dosing is potentially more convenient than weight-based dosing for both patients and physicians . Therefore , this open-label , r and omized ( 1:1 ) , multicenter study was conducted to compare the effectiveness , safety , and quality -of-life benefits of fixed vs. weight-based dosing of epoetin alpha in anemic cancer patients undergoing chemotherapy . Five hundred forty-six anemic patients undergoing platinum-based chemotherapy for solid malignancies were enrolled . Patients received epoetin alpha , either a fixed dose of 10,000 IU or a weight-based dose of 150 IU/kg , administered subcutaneously 3 times weekly for up to 12 weeks . Endpoints were transfusion requirements over days 29 - 84 , change in hemoglobin ( Hb ) level from baseline , and change in quality -of-life ( QOL ) scores from baseline as measured using the Cancer Linear Analog Scale ( CLAS ) . Five hundred and thirty-two patients received at least 1 dose of epoetin alpha , and 510 of these ( 255 in each treatment group ) were considered evaluable for efficacy . At day 84 , rates for freedom from transfusion were similar between the fixed-dose and the weight-based dose group ( 84 % vs. 87 % , respectively , p=0.32 ) , as calculated by the lifetable method . These rates were also similar between patients in the 45 - 63 kg weight group receiving the fixed 10,000 IU dose or 7,000 - 9,000 IU on a per-weight basis ( 83 % vs. 87 % , respectively ) , and those in the 70 - 100 kg weight group receiving the fixed 10,000 IU dose or 11,000 - 15,000 IU on a per-weight basis ( 85 % vs. 83 % , respectively ) . Mean Hb increases from baseline to last observation were 2.10 g/dl [ 95 % confidence intervals ( CI95 ) 1.85 - 2.35 ] in the 10,000 IU group ( from 9.64 - 11.74 g/dl ) and 2.06 g/dl ( CI95 1.82 - 2.30 ) in the 150 IU/kg group ( from 9.70 - 11.76 g/dl ) . QOL results were similar for both groups and cumulative data have been reported . For 275 patients ( in both groups combined ) with CLAS QOL scores both at baseline and 29 - 98 days thereafter , the QOL index ( average of scores for the 3 QOL parameters : energy level , ability to do daily activities and overall QOL ) increased by 10.4 mm ( CI95 7.5 - 13.2 ) , from 46.2 mm at baseline to 56.6 mm at the final observation . QOL improvements were directly associated with Hb increases ( p<0.001 , multiple linear regression analysis ) within all chemotherapy response classes . Epoetin alpha was well tolerated in both groups . Fixed ( 10,000 IU ) and weight-based ( 150 IU/kg ) dosing regimens of epoetin alpha demonstrated similar efficacy in maintaining freedom from transfusion , increasing Hb levels , and improving QOL in anemic cancer patients undergoing platinum-based chemotherapy . QOL improvements were directly associated with Hb increases . These findings support the use of a fixed-dose regimen of epoetin alpha , which may offer greater convenience for physicians and patients than weight-based dosing with this agent [17687152] PURPOSE To evaluate the effectiveness of donepezil compared with placebo in cancer patients with fatigue as measured by the Functional Assessment for Chronic Illness Therapy-Fatigue ( FACIT-F ) . PATIENTS AND METHODS Patients with fatigue score > or= 4 on a scale of 0 to 10 ( 0 = no fatigue , 10 = worst possible fatigue ) for more than 1 week were included . Patients were r and omly assigned to receive donepezil 5 mg or placebo orally every morning for 7 days . A research nurse contacted the patients by telephone daily to assess toxicity and fatigue level . All patients were offered open-label donepezil during the second week . FACIT-F and /or the Edmonton Symptom Assessment System ( ESAS ) were assessed at baseline , and days 8 , 11 , and 15 . The FACIT-F fatigue subscale score on day 8 was considered the primary end point . RESULTS Of 142 patients r and omly assigned to treatment , 47 patients in the donepezil group and 56 in the placebo group were assessable for final analysis . Fatigue intensity improved significantly on day 8 in both donepezil and placebo groups . However , there was no significant difference in fatigue improvement by FACIT-F ( P = .57 ) or ESAS ( P = .18 ) between groups . In the open-label phase , fatigue intensity continued to be low as compared with baseline . No significant toxicities were observed . CONCLUSION Donepezil was not significantly superior to placebo in the treatment of cancer-related fatigue [12957457] This dose-finding , placebo-controlled study evaluated the safety and efficacy of darbepoetin alfa administered every 3 weeks ( Q3W ) to anaemic patients receiving chemotherapy . In part A , patients ( haemoglobin < /=110 g/l ) were r and omised in a 1:4 ratio to receive 1 of 6 doses of darbepoetin alfa ( 4.5 , 6.75 , 9.0 , 12.0 , 13.5 and 15.0 microg/kg ) or placebo Q3W for 12 weeks . In part B , patients received open-label darbepoetin alfa . Patients ( n=249 ) were evaluated for safety , haemoglobin endpoints and red blood cell ( RBC ) transfusions . Darbepoetin alfa given at doses ranging from 4.5 to 15.0 microg/kg Q3W was well tolerated and comparable to placebo in terms of safety . No neutralising antibodies were detected . All doses ( from 4.5 to 15 microg/kg ) reduced transfusions compared with placebo , and result ed in > 50 % of patients achieving a haematopoietic response . Administration of darbepoetin alfa Q3W has a tolerable safety profile and effectively ameliorates anaemia due to chemotherapy [8487324] BACKGROUND Patients with advanced cancer frequently experience clinical ly significant anemia , which is often exacerbated by myelosuppressive chemotherapy . Consistent with the anemia of chronic disease , studies have documented serum erythropoietin levels that are inappropriately low for the degree of anemia in cancer patients . Myelosuppressive chemotherapy impairs erythropoiesis , which may not fully recover between treatment cycles . Recombinant human erythropoietin ( rHuEPO ) has been used safely and effectively to treat anemia in AIDS patients receiving zidovudine ( AZT ) and in patients with chronic renal failure . PURPOSE This study was design ed to evaluate the clinical role of rHuEPO in reducing symptomatic anemia in patients with advanced cancer who were receiving myelosuppressive chemotherapy ( excluding cisplatin ) . METHODS We studied 153 anemic cancer patients receiving cyclic combination chemotherapy in a prospect i ve multicenter , double-blind , placebo-controlled trial . The patients were r and omly assigned to receive either rHuEPO ( 150 U/kg ) or placebo subcutaneously three times a week for a maximum of 12 weeks or until the hematocrit level increased to 38%-40 % . If the hematocrit reached this target level before 12 weeks , the rHuEPO dose could be reduced to maintain the hematocrit at that level for the duration of the study . Response to rHuEPO therapy was assessed by measuring changes in hematocrit level , transfusion requirements , and quality of life . Quality -of-life assessment was based on patients ' responses to question naires before and after the courses of therapy . RESULTS The increase in hematocrit in the rHuEPO-treated group compared with hematocrit in the placebo-treated group was statistically significant ( P = .0001 ) as measured by percentage point of change from baseline to final evaluation , by an increase in hematocrit level of six percentage points or more unrelated to transfusion , and by a rise in hematocrit level to 38 % or more unrelated to transfusion . There was a trend toward the reduction in mean units of blood transfused per patient during months 2 and 3 of therapy combined in rHuEPO-treated patients compared with placebo-treated patients ( 0.91 U versus 1.65 U ; P = .056 ) . In addition , rHuEPO-treated patients experienced a statistically significant improvement in energy level and ability to perform daily activities ( P < or = .05 ) . The two treatment groups showed no statistically significant differences in toxic effects except for increased incidence of diaphoresis ( P < .05 ) and diarrhea ( P = .05 ) in the rHuEPO-treated group . CONCLUSIONS We conclude that rHuEPO is safe and effective for reversing anemia related to advanced cancer or to chemotherapy for cancer [12599240] Anemia in patients receiving chemotherapy can be ameliorated with recombinant human erythropoietin ( rHuEPO ) , which is administered one to three times per week . Darbepoetin α , a new erythropoietic agent , has longer serum residence time , allowing it to be administered less frequently [18790598] Fatigue is very common in patients with cancer . Current guidelines suggest that psychostimulants are " reasonable to consider for severe fatigue . " This r and omized , double-blind , placebo-controlled trial investigated the hypothesis that dexamphetamine in fatigued patients with advanced cancer would produce a clinical ly significant improvement with minimal side effects . Fifty patients with advanced cancer , who were receiving palliative care , were r and omized to dexamphetamine 10 mg twice daily or placebo for eight days . Effectiveness was assessed using the Brief Fatigue Inventory and the McGill Quality -of-Life Question naire . The side effects were recorded . The results were analyzed on an intention-to-treat basis . The baseline demographics , fatigue levels , and quality -of-life scores were similar between the two arms . Patients were elderly , had impaired performance status ( Eastern Cooperative Oncology Group score=3 ) , and were taking a range of neurologically active medications . Thirty-nine patients completed the trial . There was a transient improvement in the fatigue levels on day 2 , but no significant difference in fatigue ( P=0.267 ) or quality of life ( P=0.579 ) by the end of the study . Statistical modeling did not reveal any significant predictors of response to dexamphetamine . These results suggest that dexamphetamine 20 mg daily , although well tolerated , does not significantly improve fatigue or quality of life in patients with advanced cancer , as measured by the selected instruments [10492632] A r and omised double-blind placebo-controlled multicentre trial was performed to investigate the effects of megestrol acetate ( MA ) on the quality of life ( QoL ) , appetite , weight and survival of patients with advanced , incurable , hormone-insensitive cancer . QoL was assessed at the start of treatment and at 4 , 8 and 12 weeks , using the EORTC-QLQ-C30 instrument . 255 patients were r and omised to 320 mg of MA daily or placebo for 12 weeks . 244 patients were assessable at baseline , 190 at 4 weeks ( placebo 94 ; MA 96 ) , 150 at 8 weeks ( placebo 69 ; MA 81 ) and 112 at 12 weeks ( placebo 55 ; MA 57 ) . A beneficial effect of MA on appetite loss was observed at week 4 ( P < 0.0001 ) and possibly at week 8 ( P = 0.058 ) . Further weight loss during treatment was significant only in the placebo group . In the first 8 weeks , changes in mean global QoL were small and similar in both groups . By 12 weeks the decrease in mean global QoL was more pronounced in the MA group ( P = 0.028 ) , which was related to a deterioration in physical function , while psychosocial function was not affected . Survival was not affected by MA , and side-effects were mild . The results show that MA has a beneficial effect on appetite and that it may retard weight loss with no adverse impact on survival and with mild toxicity . However , MA does not appear to improve global QoL as measured by the EORTC QLQ-C30 [17548243] BACKGROUND Depression , anxiety , fatigue , and impaired wellbeing are common , important , and closely related in advanced cancer . We aim ed to identify the effects of an established antidepressant on these symptoms and survival in patients with advanced cancer who did not have major depression as assessed by clinicians . METHODS Between July , 2001 , and February , 2006 , 189 patients with advanced cancer were r and omly assigned sertraline 50 mg ( n=95 ) , or placebo ( n=94 ) , once per day . The primary outcome was depression as assessed by the Centre for Epidemiologic Studies Depression scale ( CES-D ) ; the main secondary outcomes were : anxiety as assessed by Hospital Anxiety and Depression Scales ( HADS-A ) ; overall quality of life and fatigue as assessed by Functional Assessment of Cancer Therapy General and Fatigue scales ( FACT-G and FACT-F , respectively ) ; and clinicians ' ratings of quality of life by use of Spizter 's Quality of Life Index ( SQLI ) . Multiple measures were used for corroboration of the most important outcomes . Primary analyses were done by intention to treat and were based on scale scores at 4 weeks and 8 weeks . The benefits of sertraline compared with placebo are expressed on a range from + 100 ( ie , maximum benefit ) to -100 ( ie , maximum harm ) ; a difference of 10 was deemed clinical ly significant . This clinical trial is registered at Current Controlled Trials website http://www.controlled-trials.com/IS RCT N72466475 . FINDINGS Sertraline had no significant effect ( scale , benefit over placebo [ 95 % CI ] ) on depression ( CES-D 0.4 [ -2.6 to 3.4 ] ) , anxiety ( HADS-A 2.0 [ -1.5 to 5.5 ] ) , fatigue ( FACT-F 0.3 [ -4.3 to 4.9 ] ) , overall quality of life ( FACT-G 1.7 [ -1.3 to 4.7 ] ) , or clinicians ' ratings ( SQLI 2.0 [ -2.5 to 6.5 ] ) , and the 95 % CI ruled out a clinical ly significant benefit for all main outcomes . Sertraline was discontinued more often and earlier than was placebo ( hazard ratio 1.46 [ 1.03 - 2.06 ] , p=0.03 ) . Recruitment was stopped after the first planned interim analysis in February 2006 ( n=150 ) showed that survival was longer in patients assigned placebo than in patients assigned sertraline ( unadjusted hazard ratio 1.60 [ 95 % CI 1.04 - 2.45 ] , log-rank p=0.04 ; adjusted hazard ratio 1.62 [ 1.06 - 2.41 ] , Cox model p=0.02 ) . However , at the final analysis in July 2006 of all patients ( n=189 ) and with longer follow-up , survival did not differ significantly between the treatment groups ( unadjusted hazard ratio 1.35 [ 0.95 - 1.91 ] , log-rank p=0.09 ; adjusted hazard ratio 1.27 [ 0.87 - 1.84 ] , Cox model p=0.20 ) . The trial was closed because it had ruled out a significant benefit of sertraline . INTERPRETATION Sertraline did not improve symptoms , wellbeing , or survival in patients with advanced cancer who do not have major depression , and should be reserved for those with a proven indication [12566906] Objectives : Platinum compounds are commonly associated with significant anemia . Erythropoietin administration has been found effective in correcting anemia in patients with solid tumors receiving chemotherapy . We conducted a r and omized , open label study to assess the efficacy of erythropoietin in preventing transfusions and significant anemia ( hemoglobin < 10 g/dl ) in patients with solid tumors receiving platinum-based chemotherapy . Methods : One hundred forty-four patients with hemoglobin < 13 g/dl were included in this study ( 72 in each arm ) . Patients in the treatment arm received 10,000 U of recombinant human erythropoietin ( rHuEPO ) thrice weekly s.c . during platinum-based chemotherapy , while patients in the control arm received no treatment . Results : All patients were evaluable for efficacy . Transfusions were reduced by the administration of rHuEPO ( 15.3 vs. 33.3 % , p = 0.019 ) , and fewer patients developed significant anemia ( 16.6 vs. 45.8 % , p < 0.0001 ) . Subgroup analysis showed that patients with observed to predicted ( O/P ) serum erythropoietin levels ≤0.9 and responders to chemotherapy benefited from erythropoietin administration in contrast to patients with O/P > 0.9 or non-responders . Conclusions : rHuEPO at a dose of 10,000 U thrice weekly prevents transfusions and development of significant anemia in patients with solid tumors receiving platinum-based chemotherapy [4135151] In a controlled double blind study involving 116 patients with far‐advanced gastrointestinal cancer , dexamethasone at dosages of 0.75 and 1.5 mg four times daily produced improved appetite and sense of well‐being in comparison to placebo treatment . This symptomatic palliation , however , was not accompanied by weight gain or improved performance status . Survival of the steroid treated patients was essentially identical to that of the placebo treated patients . Cancer 33:1607–1609 , 1974 [15452188] PURPOSE Epoetin alfa administered at 40,000 U once weekly ( qw ) to anemic cancer patients receiving chemotherapy increases hemoglobin levels , improves quality of life ( QOL ) , and reduces transfusions . The benefit of epoetin alfa in maintaining hemoglobin levels in cancer patients with hemoglobin less than 12 g/dL has not been evaluated . METHODS Breast cancer patients ( N = 354 ) receiving chemotherapy were r and omly assigned in 1:1 ratio to epoetin alfa ( 40,000 U qw ) or st and ard of care ( SOC ) . QOL was assessed at baseline and week 12 . Hemoglobin responses , transfusion requirements , and prognostic factors for responses were measured . RESULTS At week 12 , Functional Assessment of Cancer Therapy-Anemia ( FACT-An ; mean , 2.16 + /- 12.84 for epoetin alfa v -4.43 + /- 13.42 for SOC ) and FACT-An fatigue ( mean , 1.85 + /- 10.52 for epoetin alfa v -3.55 + /- 11.14 for SOC ) change scores were significantly higher in the epoetin alfa group ( P < .0001 ) . Hemoglobin responses defined as mean hemoglobin > or = 12 g/dL or a > or = 2 g/dL increase compared with baseline were significantly higher in the epoetin alfa group versus SOC : 52.0 % v 5.1 % and 65.7 % v 6.3 % , respectively ( P < .0001 for both comparisons ) . Percentage transfused was significantly lower in the epoetin alfa group compared with SOC ( 8.6 % v 22.9 % ) . More than 90 % of patients did not require a dose increase and 28.7 % had a dose reduction . CONCLUSION Epoetin alfa administered at 40,000 U qw is effective in improving QOL , maintaining hemoglobin level , and reducing transfusion requirements in breast cancer patients . The high effectiveness observed could be attributed in part to early treatment with epoetin alfa [11328297] Effects of epoetin alfa on transfusions , haemoglobin ( Hb ) and quality of life ( QOL ) were evaluated in a placebo‐controlled study of 145 patients with multiple myeloma and anaemia ( Hb < 11 g/dl ) . During the 12‐week , double‐blind phase , patients received 150 IU/kg epoetin alfa or a matching volume of placebo subcutaneously three times weekly ; the dose ( or volume ) was doubled at week 4 if Hb response was inadequate . Patients completing this phase could enter the subsequent optional 12‐week phase of open‐label epoetin alfa treatment . During double‐blind treatment , epoetin alfa significantly decreased the incidence of transfusion compared with placebo ( 28 % vs. 47 % , P = 0·017 ) , regardless of patients ' transfusion history , and increased mean Hb ( 1·8 g/dl vs. 0·0 g/dl , P < 0·001 ) . Univariate analysis showed significant ( P ≤ 0·05 ) improvement in more QOL measures with epoetin alfa than with placebo ; multivariate analysis discerned no between‐treatment differences . Significantly ( P = 0·038 ) more epoetin alfa vs. placebo patients had improved performance scores . At the end of the open‐label treatment phase , patients who had continued epoetin alfa maintained Hb status , and placebo patients who were switched to epoetin alfa had mean Hb increases of 2·4 g/dl . Adverse events were similar between treatment groups . Epoetin alfa proved effective and well tolerated for treating anaemia in patients with multiple myeloma [16177289] This is the first r and omized , open-label , multicenter trial design ed and powered to directly compare the hemoglobin ( Hb ) response to epoetin alfa ( EPO ) , 40,000 U once weekly ( QW ) , with that to darbepoetin alfa ( DARB ) , 200 microg every 2 weeks ( Q2W ) , in anemic patients with cancer receiving chemotherapy ( CT ) . Transfusion requirements , quality of life ( QOL ) , and safety also were evaluated . Adults with solid tumors scheduled to receive CT for > or = 12 weeks and with baseline Hb < or = 11 g/dl were r and omized to receive either EPO 40,000 U QW ( n = 178 ) or DARB 200 microg Q2W ( n = 180 ) s.c . for up to 16 weeks . Doses were increased for nonresponders ( Hb increase < 1 g/dl ) after 4 ( EPO ) or 6 ( DARB ) weeks , as per National Comprehensive Cancer Network guidelines , and were reduced for a rapid rise in Hb ( > 1.3 g/dl [ EPO ] or > 1.0 g/dl [ DARB ] within any 2-week period ) or for an Hb level > 13 g/dl . The proportion of patients achieving a > or = 1-g/dl Hb rise by week 5 , the primary end point , was significantly higher with EPO ( 47.0 % ) than with DARB ( 32.5 % ) , and EPO-treated patients achieved a > or = 1-g/dl Hb increase significantly earlier than those receiving DARB ( median , 35 days versus 46 days ) . The mean increase in Hb from baseline was significantly higher at weeks 5 , 9 , 13 , and the end of the study with EPO than with DARB . The number of units transfused per patient was significantly lower for the EPO group than for the DARB group . The proportions of patients requiring transfusions , mean QOL improvements , and tolerability profiles were similar in the two groups [8648360] PURPOSE To investigate the effects of medroxyprogesterone acetate ( MPA ) on appetite , weight , and quality of life ( QL ) in patients with advanced-stage , incurable , non-hormone-sensitive cancer . PATIENTS AND METHODS Two hundred six eligible patients were r and omized between double-blind MPA 500 mg twice daily or placebo . Appetite ( 0 to 10 numerical rating scale ) , weight , and QL ( European Organization for Research and Treatment of Cancer Quality of Life Question naire [ EORTC-QLQ-C30 ] ) were assessed before the start of treatment ( t = 0 ) , and 6 weeks ( t = 6 ) and 12 weeks ( t = 12 ) thereafter . RESULTS One hundred thirty-four patients ( 68 MPA and 66 placebo ) were assessable at t = 6 and 99 patients ( 53 MPA and 46 placebo ) at t = 12 . A beneficial effect of MPA on appetite was observed after both 6 weeks ( P = .008 ) and 12 weeks ( P = .01 ) of treatment . After 12 weeks , a mean weight gain of 0.6 + /- 4.4 kg was seen in the MPA , versus an ongoing mean weight loss of 1.4 + /- 4.6 kg in the placebo group . This difference of 2.0 kg was statistically significant ( P = .04 ) . During the study , several areas of QL deteriorated in the total group of patients . With the exception of an improvement in appetite and possible also a reduction in nausea and vomiting , no measurable beneficial effects of MPA on QL could be demonstrated . The side effects profile of MPA was favorable : only a trend toward an increase in ( usually mild ) peripheral edema was observed . CONCLUSION In weight-losing , advanced-stage non-hormone-sensitive cancer patients , MPA exhibits a mild side effects profile , has a beneficial effect on appetite , and may prevent further weight loss . However , general QL in the present study was not measurably influenced by MPA treatment [12910374] The aim of the study was to investigate the effects of erythropoietin ( epoetin beta ) on red blood cell ( RBC ) transfusions , hemoglobin ( Hb ) levels , and quality of life ( QOL ) in patients with relapsed lymphoma treated with an aggressive sequential salvage chemotherapy ( SSCT ) regimen . Sixty patients with early or late relapsed Hodgkin 's disease ( n=39 ) or first relapse of aggressive non-Hodgkin 's lymphoma ( n=21 ) were r and omized to receive epoetin beta 10,000 IE subcutaneously three times a week or no epoetin during salvage chemotherapy . Patients in both study arms received two cycles of DHAP ( dexamethasone , high-dose cytarabine , cisplatin ) ; patients in partial remission ( PR ) or complete remission ( CR ) then received cyclophosphamide , followed by peripheral blood stem cell ( PBSC ) harvest , methotrexate plus vincristine , and etoposide . The final myeloablative course was BEAM ( carmustine , etoposide , cytarabine , and melphalan ) followed by autologous stem cell support . The primary endpoint of the study was the number of RBC units needed during SSCT . In addition , Hb levels and QOL were measured . The mean number of RBC units given in the epoetin beta arm was 4.5 compared to 8.3 in the control arm ( P=0.0134 ) . The mean Hb levels during therapy were 10.4 g/dl in the epoetin beta arm and 9.7 g/dl in the control ( P=0.018 ) . From baseline until BEAM therapy QOL ( EORTC QLQ C30 ) and fatigue ( MFI ) assessment showed little QOL worsening or stable levels in both arms with a steeper increase of fatigue levels in the control group . Patients with relapsed lymphoma undergoing aggressive chemotherapy and stem cell support benefited from epoetin beta therapy , with a decrease of RBC transfusion requirements and lower rise of fatigue levels Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: Background Our objective was to determine whether , compared with control interventions , pharmacologic interventions reduce the severity of fatigue in patients with cancer or recipients of hematopoietic stem-cell transplantation ( hsct ) . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

31063090

[19586656] BACKGROUND The human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine was immunogenic , generally well tolerated , and effective against HPV-16 or HPV-18 infections , and associated precancerous lesions in an event-triggered interim analysis of the phase III r and omised , double-blind , controlled PApilloma TRIal against Cancer In young Adults ( PATRICIA ) . We now assess the vaccine efficacy in the final event-driven analysis . METHODS Women ( 15 - 25 years ) were vaccinated at months 0 , 1 , and 6 . Analyses were done in the according-to- protocol cohort for efficacy ( ATP-E ; vaccine , n=8093 ; control , n=8069 ) , total vaccinated cohort ( TVC , included all women receiving at least one vaccine dose , regardless of their baseline HPV status ; represents the general population , including those who are sexually active ; vaccine , n=9319 ; control , n=9325 ) , and TVC-naive ( no evidence of oncogenic HPV infection at baseline ; represents women before sexual debut ; vaccine , n=5822 ; control , n=5819 ) . The primary endpoint was to assess vaccine efficacy against cervical intraepithelial neoplasia 2 + ( CIN2 + ) that was associated with HPV-16 or HPV-18 in women who were seronegative at baseline , and DNA negative at baseline and month 6 for the corresponding type ( ATP-E ) . This trial is registered with Clinical Trials.gov , number NCT00122681 . FINDINGS Mean follow-up was 34.9 months ( SD 6.4 ) after the third dose . Vaccine efficacy against CIN2 + associated with HPV-16/18 was 92.9 % ( 96.1 % CI 79.9 - 98.3 ) in the primary analysis and 98.1 % ( 88.4 - 100 ) in an analysis in which probable causality to HPV type was assigned in lesions infected with multiple oncogenic types ( ATP-E cohort ) . Vaccine efficacy against CIN2 + irrespective of HPV DNA in lesions was 30.4 % ( 16.4 - 42.1 ) in the TVC and 70.2 % ( 54.7 - 80.9 ) in the TVC-naive . Corresponding values against CIN3 + were 33.4 % ( 9.1 - 51.5 ) in the TVC and 87.0 % ( 54.9 - 97.7 ) in the TVC-naive . Vaccine efficacy against CIN2 + associated with 12 non-vaccine oncogenic types was 54.0 % ( 34.0 - 68.4 ; ATP-E ) . Individual cross-protection against CIN2 + associated with HPV-31 , HPV-33 , and HPV-45 was seen in the TVC . INTERPRETATION The HPV-16/18 AS04-adjuvanted vaccine showed high efficacy against CIN2 + associated with HPV-16/18 and non-vaccine oncogenic HPV types and substantial overall effect in cohorts that are relevant to universal mass vaccination and catch-up programmes . FUNDING GlaxoSmithKline Biologicals [19493565] BACKGROUND Although the peak incidence of human papillomavirus ( HPV ) infection occurs in most population s within 5 - 10 years of first sexual experience , all women remain at risk for acquisition of HPV infections . We tested the safety , immunogenicity , and efficacy of the quadrivalent HPV ( types 6 , 11 , 16 , 18 ) L1 virus-like-particle vaccine in women aged 24 - 45 years . METHODS Women aged 24 - 45 years with no history of genital warts or cervical disease were enrolled from community health centres , academic health centres , and primary health-care providers into an ongoing multicentre , parallel , r and omised , placebo-controlled , double-blind study . Participants were allocated by computer-generated schedule to receive quadrivalent HPV vaccine ( n=1911 ) or placebo ( n=1908 ) at day 1 , and months 2 and 6 . All study site investigators and personnel , study participants , monitors , and central laboratory personnel were blinded to treatment allocation . Co primary efficacy endpoints were 6 months ' or more duration of infection and cervical and external genital disease due to HPV 6 , 11 , 16 , 18 ; and due to HPV 16 and 18 alone . Primary efficacy analyses were done in a per- protocol population , but intention-to-treat analyses were also undertaken . This study is registered with Clinical Trials.gov , number NCT00090220 . FINDINGS 1910 women received at least one dose of vaccine and 1907 at least one dose of placebo . In the per- protocol population , efficacy against the first co primary endpoint ( disease or infection related to HPV 6 , 11 , 16 , and 18 ) was 90.5 % ( 95 % CI 73.7 - 97.5 , four of 1615 cases in the vaccine group vs 41/1607 in the placebo group ) and 83.1 % ( 50.6 - 95.8 , four of 1601 cases vs 23/1579 cases ) against the second co primary endpoint ( disease or infection related to HPV 16 and 18 alone ) . In the intention-to-treat population , efficacy against the first co primary endpoint was 30.9 % ( 95 % CI 11.1 - 46.5 , 108/1886 cases vs 154/1883 cases ) and against the second co primary endpoint was 22.6 % ( -2.9 to 41.9 , 90/1886 cases vs 115/1883 cases ) , since infection and disease were present at baseline . We recorded no vaccine-related serious adverse events . INTERPRETATION The quadrivalent HPV vaccine is efficacious in women aged 24 - 45 years not infected with the relevant HPV types at enrolment . FUNDING Merck ( USA ) [3137403] Background : Previous analyses from a r and omised trial in women aged 24–45 years have shown the quadrivalent human papillomavirus ( qHPV ) vaccine to be efficacious in the prevention of infection , cervical intraepithelial neoplasia ( CIN ) , and external genital lesions ( EGLs ) related to HPV 6/11/16/18 . In this report , we present end-of- study efficacy , safety , and immunogenicity data with a median follow-up time of 4.0 years . Methods : We enrolled 3819 24–45-year-old women with no history of cervical disease or genital warts in the past 5 years . Women received quadrivalent vaccine or placebo at day 1 , and at months 2 and 6 . Ascertainment of CIN/EGL was accomplished through Pap testing , genital inspection , and cervicovaginal sampling ( every 6 months ) . The main analysis was conducted in a per- protocol efficacy population ( that received three doses , was naive to the relevant HPV types at day 1 , and remained free of infection through month 7 ) . Efficacy was also estimated in other naive and non-naive population s. Results : Vaccine efficacy against the combined incidence of persistent infection , CIN/EGL related to HPV6/11/16/18 in the per- protocol population was 88.7 % ( 95 % CI : 78.1 , 94.8 ) . Efficacy for women who were seropositive and DNA negative for the relevant vaccine HPV type at the time of enrolment who received at least 1 dose was 66.9 % ( 95 % CI : 4.3 , 90.6 ) . At month 48 , 91.5 , 92.0 , 97.4 , and 47.9 % of vaccinated women were seropositive to HPV 6/11/16/18 , respectively . No serious vaccine-related adverse experiences were reported . Conclusions : The qHPV vaccine demonstrated high efficacy , immunogenicity , and acceptable safety in women aged 24–45 years , regardless of previous exposure to HPV vaccine type [3636781] Background . Cervical cancer is a major public health problem for women in sub-Saharan Africa . Availability of a human papillomavirus ( HPV ) vaccine could have an important public health impact . Methods . In this phase IIIb , double-blind , r and omized , placebo-controlled , multicenter trial ( NCT00481767 ) , healthy African girls and young women seronegative for human immunodeficiency virus ( HIV ) were stratified by age ( 10–14 or 15–25 years ) and r and omized ( 2:1 ) to receive either HPV-16/18 AS04-adjuvanted vaccine ( n = 450 ) or placebo ( n = 226 ) at 0 , 1 , and 6 months . The primary objective was to evaluate HPV-16/18 antibody responses at month 7 . Seropositivity rates and corresponding geometric mean titers ( GMTs ) were measured by enzyme-linked immunosorbent assay . Results . In the according-to- protocol analysis at month 7 , 100 % of initially seronegative participants in the vaccine group were seropositive for both anti – HPV-16 and anti – HPV-18 antibodies ( n = 130 and n = 128 for 10–14-year-olds , respectively ; n = 190 and n = 212 for 15–25-year-olds ) . GMTs for HPV-16 and HPV-18 were higher in 10–14-year-olds ( 18 423 [ 95 % confidence interval , 16 185–20 970 ] and 6487 [ 5590–7529 ] enzyme-linked immunosorbent assay units (EU)/mL , respectively ) than in 15–25-year-olds ( 10 683 [ 9567–11 930 ] and 3743 [ 3400–4120 ] EU/mL , respectively ) . Seropositivity was maintained at month 12 . No participant withdrew owing to adverse events . No vaccine-related serious adverse events were reported . Conclusions . The HPV-16/18 AS04-adjuvanted vaccine was highly immunogenic and had a clinical ly acceptable safety profile when administered to healthy HIV-seronegative African girls and young women [22492244] Control of human papillomavirus (HPV)-related cancers by inclusion of HPV vaccination into national vaccination programmes is likely . One open question is replacement of the vaccine types with other high-risk ( hr ) HPV types in the vaccination era . We studied occurrence of HPV types in adolescent females participating in a population -based vaccination trial . A total of 4,808 16- to 17-year-old females from Finl and were enrolled in the 1:1 r and omized phase III ( PATRICIA ) trial of the efficacy of vaccination with the AS04-adjuvanted HPV-16/18 virus-like particle vaccine as compared to hepatitis A virus ( HAV ) vaccine . HPV infection was assessed from cervical sample s taken every 6 months for 4 years post-vaccination by polymerase chain reaction ( PCR ) for genital oncogenic HPV types 16 , 18 , 31 , 33 , 35 , 39 , 45 , 51 , 52 , 58 , 59 , 66 , 68 , and 73 as well as low-risk types HPV-6 and HPV-11 . The HPV-16/18 vaccine coverage ranged between 1 and 22 % by age-cohort and study community . Odds ratios ( ORs ) for infections with different HPV types in baseline PCR negative HPV-16/18 vs. HAV vaccinated women , and Poisson regression derived HPV incidence rate ratios ( IRRs ) in baseline positive vs. negative women were calculated . The OR and IRR estimates for acquisition of any genital HPV types showed no excess risk neither in baseline HPV DNA-negative HPV-16/18-vaccinated women compared to baseline HPV DNA-negative HAV vaccinated women nor in HPV-16/18-vaccinated baseline HPV-16/18-positive women compared to baseline HPV-16/18-negative women . In the HAV-vaccinated , baseline HPV-18-positive women showed an increased risk of acquiring other clade A7 HPV types ( 39 , 45 , 59 , 68 ) ( IRR 1.8 , 95 % confidence interval = 1.01.-3.1 ) . We found no increased occurrence of non-vaccine HPV types suggestive of type-replacement 1 - 4 years post-vaccination among HPV-16/18-vaccinated Finnish adolescents [3152758] Objective The study assessed the immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted cervical cancer vaccine in healthy Korean women aged 15 - 25 years . Methods Phase IIIB , double-blind , r and omised ( 2:1 ) , multi-centre trial was conducted in Korea from June 2007 to March 2008 . The study enrolled 225 women in the HPV ( N=149 ) and placebo ( N=76 ) groups who received three doses of HPV-16/18 AS04-adjuvanted vaccine or placebo ( aluminium hydroxide ) administered intramuscularly at 0 , 1 , and 6 months and were followed until one month post-dose 3 . Serum sample s were collected pre-vaccination and one month post-dose 3 . Safety and reactogenicity data were collected throughout . Results In this trial , 208 women completed the study ( 141 in HPV group ; 67 in placebo group ) . At month 7 , all initially seronegative women had seroconverted for HPV-16 and HPV-18 antibodies with anti-HPV-16 and anti-HPV-18 geometric mean titres of 9,351.4 El . U/mL ( 95 % CI , 8,145.5 to 10,735.8 ) and 4204.1 El . U/mL ( 95 % CI , 3,626.5 to 4,873.6 ) , respectively . Initially seropositive women showed similar increase in geometric mean titre levels . Compliance to the three dose vaccination course was 95.3 % in HPV and 89.5 % in placebo group . Solicited local ( pain ) and general ( fatigue , myalgia or headache ) symptoms were commonly reported in both groups . Three serious adverse events were reported ( two in HPV group ; one in placebo group ) , all unrelated to vaccination by the investigator ; all recovered . Conclusion The HPV-16/18 AS04-adjuvanted vaccine was highly immunogenic with a clinical ly acceptable safety profile in Korean women . This study was in line with previous global studies in Europe , North America , and Brazil . ( Clinical Trials.gov number , NCT 00485732 . [25693011] BACKGROUND The investigational 9-valent viruslike particle vaccine against human papillomavirus ( HPV ) includes the HPV types in the quadrivalent HPV ( qHPV ) vaccine ( 6 , 11 , 16 , and 18 ) and five additional oncogenic types ( 31 , 33 , 45 , 52 , and 58 ) . Here we present the results of a study of the efficacy and immunogenicity of the 9vHPV vaccine in women 16 to 26 years of age . METHODS We performed a r and omized , international , double-blind , phase 2b-3 study of the 9vHPV vaccine in 14,215 women . Participants received the 9vHPV vaccine or the qHPV vaccine in a series of three intramuscular injections on day 1 and at months 2 and 6 . Serum was collected for analysis of antibody responses . Swabs of labial , vulvar , perineal , perianal , endocervical , and ectocervical tissue were obtained and used for HPV DNA testing , and liquid-based cytologic testing ( Papanicolaou testing ) was performed regularly . Tissue obtained by means of biopsy or as part of definitive therapy ( including a loop electrosurgical excision procedure and conization ) was tested for HPV . RESULTS The rate of high- grade cervical , vulvar , or vaginal disease irrespective of HPV type ( i.e. , disease caused by HPV types included in the 9vHPV vaccine and those not included ) in the modified intention-to-treat population ( which included participants with and those without prevalent infection or disease ) was 14.0 per 1000 person-years in both vaccine groups . The rate of high- grade cervical , vulvar , or vaginal disease related to HPV-31 , 33 , 45 , 52 , and 58 in a prespecified per- protocol efficacy population ( susceptible population ) was 0.1 per 1000 person-years in the 9vHPV group and 1.6 per 1000 person-years in the qHPV group ( efficacy of the 9vHPV vaccine , 96.7 % ; 95 % confidence interval , 80.9 to 99.8 ) . Antibody responses to HPV-6 , 11 , 16 , and 18 were noninferior to those generated by the qHPV vaccine . Adverse events related to injection site were more common in the 9vHPV group than in the qHPV group . CONCLUSIONS The 9vHPV vaccine prevented infection and disease related to HPV-31 , 33 , 45 , 52 , and 58 in a susceptible population and generated an antibody response to HPV-6 , 11 , 16 , and 18 that was noninferior to that generated by the qHPV vaccine . The 9vHPV vaccine did not prevent infection and disease related to HPV types beyond the nine types covered by the vaccine . ( Funded by Merck ; Clinical Trials.gov number , NCT00543543 ) [3196245] Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more [21856349] BACKGROUND To evaluate co-administration of GlaxoSmithKline Biologicals ' human papillomavirus-16/18 AS04-adjuvanted vaccine ( HPV ) and hepatitis B vaccine ( HepB ) . METHODS This was a r and omized , controlled , open , multicenter study . Healthy girls , aged 9 - 15 years , were r and omized to receive HPV ( n=247 ) , HepB ( n=247 ) or HPV co-administered with HepB ( HPV+HepB ; n=247 ) at Months 0 , 1 and 6 . Antibodies against hepatitis B surface antigen ( HBs ) , HPV-16 and HPV-18 were measured , and reactogenicity and safety monitored . Co- primary objectives were to demonstrate non-inferiority of hepatitis B and HPV-16/18 immune responses at Month 7 for co-administered vaccines , compared with vaccines administered alone , in the according-to- protocol cohort . RESULTS The pre-defined criteria for non-inferiority were met for all co- primary immunogenicity endpoints at Month 7 . Anti-HBs seroprotection rates ≥10mIU/mL were achieved by 97.9 % and 100 % of girls , respectively , following co-administration or HepB alone . Anti-HBs geometric mean titers ( GMTs ) ( 95 % confidence interval ) were 1280.9 ( 973.3 - 1685.7 ) and 3107.7 ( 2473.1 - 3905.1 ) milli-international units/mL , respectively . Anti-HPV-16 and -18 seroconversion rates were achieved by ≥99 % of girls following co-administration or HPV alone . Anti-HPV-16 GMTs were 19819.8 ( 16856.9 - 23303.6 ) and 21712.6 ( 19460.2 - 24225.6 ) ELISA units (ELU)/mL , respectively . Anti-HPV-18 GMTs were 8835.1 ( 7636.3 - 10222.1 ) and 8838.6 ( 7948.5 - 9828.4 ) ELU/mL , respectively . Co-administration was generally well tolerated . CONCLUSIONS The study results support the co-administration of HPV-16/18 AS04-adjuvanted vaccine with hepatitis B vaccine in adolescent girls aged 9 - 15 years . CLINICAL TRIALS REGISTRATION Clinical Trials.gov registration number NCT00652938 [27373900] BACKGROUND Although the risk of human papillomavirus ( HPV ) infection is greatest in young women , women older than 25 years remain at risk . We present data from the VIVIANE study of the HPV 16/18 AS04-adjuvanted vaccine in adult women after 7 years of follow-up . METHODS In this phase 3 , double-blind , r and omised controlled trial , healthy women older than 25 years were enrolled ( age stratified : 26 - 35 years , 36 - 45 years , and ≥46 years ) . Up to 15 % in each age stratum had a history of HPV infection or disease . Women were r and omly assigned ( 1:1 ) to receive HPV 16/18 vaccine or aluminium hydroxide control , with an internet-based system . The primary endpoint was vaccine efficacy against 6-month persistent infection or cervical intraepithelial neoplasia grade 1 or greater ( CIN1 + ) associated with HPV 16/18 . We did analyses in the according-to- protocol cohort for efficacy and total vaccinated cohort . Data for the combined primary endpoint in the according-to- protocol cohort for efficacy were considered significant when the lower limit of the 96·2 % CI around the point estimate was greater than 30 % . For all other endpoints and cohorts , data were considered significant when the lower limit of the 96·2 % CI was greater than 0 % . This study is registered with Clinical Trials.gov , number NCT00294047 . FINDINGS The first participant was enrolled on Feb 16 , 2006 , and the last study visit took place on Jan 29 , 2014 . 4407 women were in the according-to- protocol cohort for efficacy ( n=2209 vaccine , n=2198 control ) and 5747 women in the total vaccinated cohort ( n=2877 vaccine , n=2870 control ) . At month 84 , in women seronegative for the corresponding HPV type in the according-to- protocol cohort for efficacy , vaccine efficacy against 6-month persistent infection or CIN1 + associated with HPV 16/18 was significant in all age groups combined ( 90·5 % , 96·2 % CI 78·6 - 96·5 ) . Vaccine efficacy against HPV 16/18-related cytological abnormalities ( atypical squamous cells of undetermined significance and low- grade squamous intraepithelial lesion ) and CIN1 + was also significant . We also noted significant cross-protective efficacy against 6-month persistent infection with HPV 31 ( 65·8 % , 96·2 % CI 24·9 - 85·8 ) and HPV 45 ( 70·7 % , 96·2 % CI 34·2 - 88·4 ) . In the total vaccinated cohort , vaccine efficacy against CIN1 + irrespective of HPV was significant ( 22·9 % , 96·2 % CI 4·8 - 37·7 ) . Serious adverse events related to vaccination occurred in five ( 0·2 % ) of 2877 women in the vaccine group and eight ( 0·3 % ) of 2870 women in the control group . INTERPRETATION In women older than 25 years , the HPV 16/18 vaccine continues to protect against infections , cytological abnormalities , and lesions associated with HPV 16/18 and CIN1 + irrespective of HPV type , and infection with non-vaccine types HPV 31 and HPV 45 over 7 years of follow-up . FUNDING GlaxoSmithKline Biologicals SA [25651922] ABSTRACT We report final event-driven analysis data on the immunogenicity and efficacy of the human papillomavirus 16 and 18 ( ( HPV-16/18 ) AS04-adjuvanted vaccine in young women aged 15 to 25 years from the PApilloma TRIal against Cancer In young Adults ( PATRICIA ) . The total vaccinated cohort ( TVC ) included all r and omized participants who received at least one vaccine dose ( vaccine , n = 9,319 ; control , n = 9,325 ) at months 0 , 1 , and /or 6 . The TVC-naive ( vaccine , n = 5,822 ; control , n = 5,819 ) had no evidence of high-risk HPV infection at baseline , approximating adolescent girls targeted by most HPV vaccination programs . Mean follow-up was approximately 39 months after the first vaccine dose in each cohort . At baseline , 26 % of women in the TVC had evidence of past and /or current HPV-16/18 infection . HPV-16 and HPV-18 antibody titers postvaccination tended to be higher among 15- to 17-year-olds than among 18- to 25-year-olds . In the TVC , vaccine efficacy ( VE ) against cervical intraepithelial neoplasia grade 1 or greater ( CIN1 + ) , CIN2 + , and CIN3 + associated with HPV-16/18 was 55.5 % ( 96.1 % confidence interval [ CI ] , 43.2 , 65.3 ) , 52.8 % ( 37.5 , 64.7 ) , and 33.6 % ( −1.1 , 56.9 ) . VE against CIN1 + , CIN2 + , and CIN3 + irrespective of HPV DNA was 21.7 % ( 10.7 , 31.4 ) , 30.4 % ( 16.4 , 42.1 ) , and 33.4 % ( 9.1 , 51.5 ) and was consistently significant only in 15- to 17-year-old women ( 27.4 % [ 10.8 , 40.9 ] , 41.8 % [ 22.3 , 56.7 ] , and 55.8 % [ 19.2 , 76.9 ] ) . In the TVC-naive , VE against CIN1 + , CIN2 + , and CIN3 + associated with HPV-16/18 was 96.5 % ( 89.0 , 99.4 ) , 98.4 % ( 90.4 , 100 ) , and 100 % ( 64.7 , 100 ) , and irrespective of HPV DNA it was 50.1 % ( 35.9 , 61.4 ) , 70.2 % ( 54.7 , 80.9 ) , and 87.0 % ( 54.9 , 97.7 ) . VE against 12-month persistent infection with HPV-16/18 was 89.9 % ( 84.0 , 94.0 ) , and that against HPV-31/33/45/51 was 49.0 % ( 34.7 , 60.3 ) . In conclusion , vaccinating adolescents before sexual debut has a substantial impact on the overall incidence of high- grade cervical abnormalities , and catch-up vaccination up to 18 years of age is most likely effective . ( This study has been registered at Clinical Trials.gov under registration no. NCT001226810 . [26467666] BACKGROUND Previous Costa Rica Vaccine Trial ( CVT ) reports separately demonstrated vaccine efficacy against HPV16 and HPV18 ( HPV16/18 ) infections at the cervical , anal , and oral regions ; however , the combined overall multisite efficacy ( protection at all three sites ) and vaccine efficacy among women infected with HPV16 or HPV18 prior to vaccination are less known . METHODS Women age 18 to 25 years from the CVT were r and omly assigned to the HPV16/18 vaccine ( Cervarix ) or a hepatitis A vaccine . Cervical , oral , and anal specimens were collected at the four-year follow-up visit from 4186 women . Multisite and single-site vaccine efficacies ( VEs ) and 95 % confidence intervals ( CIs ) were computed for one-time detection of point prevalent HPV16/18 in the cervical , anal , and oral regions four years after vaccination . All statistical tests were two-sided . RESULTS The multisite woman-level vaccine efficacy was highest among " naïve " women ( HPV16/18 seronegative and cervical HPV high-risk DNA negative at vaccination ) ( vaccine efficacy = 83.5 % , 95 % CI = 72.1 % to 90.8 % ) . Multisite woman-level vaccine efficacy was also demonstrated among women with evidence of a pre-enrollment HPV16 or HPV18 infection ( seropositive for HPV16 and /or HPV18 but cervical HPV16/18 DNA negative at vaccination ) ( vaccine efficacy = 57.8 % , 95 % CI = 34.4 % to 73.4 % ) , but not in those with cervical HPV16 and /or HPV18 DNA at vaccination ( anal/oral HPV16/18 VE = 25.3 % , 95 % CI = -40.4 % to 61.1 % ) . Concordant HPV16/18 infections at two or three sites were also less common in HPV16/18-infected women in the HPV vaccine vs control arm ( 7.4 % vs 30.4 % , P < .001 ) . CONCLUSIONS This study found high multisite vaccine efficacy among " naïve " women and also suggests the vaccine may provide protection against HPV16/18 infections at one or more anatomic sites among some women infected with these types prior to HPV16/18 vaccination [25912475] Due to sporadic and not easily accessible cervical cancer screening , human papillomavirus (HPV)-related cervical cancer is a leading cause of cancer death in Sub-Saharan African women . This study was design ed to assess the safety and immunogenicity of a quadrivalent human papillomavirus ( qHPV ) vaccine in sub-Saharan African women . This seven month , double-blind study enrolled 250 healthy , human immunodeficiency virus (HIV)-uninfected females ages 9–26 residing in Ghana , Kenya , and Senegal . Thirty females ages 13–15 and 120 females ages 16–26 received qHPV vaccine . In addition , 100 females ages 9–12 y were r and omized in a 4:1 ratio to receive either qHPV vaccine ( n = 80 ) or placebo ( n = 20 ) . The primary immunogenicity hypothesis was that an acceptable percentage of subjects who received the qHPV vaccine seroconvert to HPV6/11/16/18 at 4 weeks post-dose 3 , defined as the lower bound of the corresponding 95 % confidence interval ( CI ) exceeding 90 % . The primary safety objective was to demonstrate that qHPV vaccine was generally well tolerated when administered in a 3-dose regimen . The pre-specified statistical criterion for the primary immunogenicity hypothesis was met : the lower bound of the 95 % exact binomial CI on the seroconversion rate was at least 98 % for each vaccine HPV type and all subjects seroconverted by 4 weeks post-dose 3 . Across vaccination groups , the most common adverse events ( AE ) were at the injection site , including pain , swelling , and erythema . No subject discontinued study medication due to an AE and no serious AEs were reported . There were no deaths . This study demonstrated that qHPV vaccination of sub-Saharan African women was highly immunogenic and generally well tolerated [25018097] BACKGROUND A community-based r and omized trial was conducted in Costa Rica to evaluate the HPV-16/18 AS04-adjuvanted vaccine ( NCT00128661 ) . The primary objective was to evaluate efficacy of the vaccine to prevent cervical intraepithelial neoplasia 2 or more severe disease ( CIN2 + ) associated with incident HPV-16/18 cervical infections . Secondary objectives were to evaluate efficacy against CIN2 + associated with incident cervical infection by any oncogenic HPVs and to evaluate duration of protection against incident cervical infection with HPV-16/18 . Vaccine safety and immunogenicity over the 4-year follow-up were also evaluated . METHODS We r and omized ( 3727 HPV arm ; 3739 control arm ) , vaccinated ( HPV-16/18 or Hepatitis A ) and followed ( median 53.8 months ) 7466 healthy women aged 18 - 25 years . 5312 women ( 2635 HPV arm ; 2677 control arm ) were included in the according to protocol analysis for efficacy . The full cohort was evaluated for safety . Immunogenicity was considered on a subset of 354 ( HPV-16 ) and 379 ( HPV-18 ) women . HPV type was assessed by PCR on cervical specimens . Immunogenicity was assessed using ELISA and inhibition enzyme immunoassays . Disease outcomes were histologically confirmed . Vaccine efficacy and 95 % confidence intervals ( 95%CI ) were computed . RESULTS Vaccine efficacy was 89.8 % ( 95 % CI : 39.5 - 99.5 ; N=11 events total ) against HPV-16/18 associated CIN2 + , 59.9 % ( 95 % CI : 20.7 - 80.8 ; N=39 events total ) against CIN2 + associated with non-HPV-16/18 oncogenic HPVs and 61.4 % ( 95 % CI : 29.5 - 79.8 ; N=51 events total ) against CIN2 + irrespective of HPV type . The vaccine had an acceptable safety profile and induced robust and long-lasting antibody responses . CONCLUSIONS Our findings confirm the high efficacy and immunogenicity of the HPV-16/18 vaccine against incident HPV infections and cervical disease associated with HPV-16/18 and other oncogenic HPV types . These results will serve as a benchmark to which we can compare future findings from the ongoing extended follow-up of participants in the Costa Rica trial . TRIAL REGISTRATION Registered with clinical trials.gov : NCT00128661 [21288094] BACKGROUND Infection with human papillomavirus ( HPV ) and diseases caused by HPV are common in boys and men . We report on the safety of a quadrivalent vaccine ( active against HPV types 6 , 11 , 16 , and 18 ) and on its efficacy in preventing the development of external genital lesions and anogenital HPV infection in boys and men . METHODS We enrolled 4065 healthy boys and men 16 to 26 years of age , from 18 countries in a r and omized , placebo-controlled , double-blind trial . The primary efficacy objective was to show that the quadrivalent HPV vaccine reduced the incidence of external genital lesions related to HPV-6 , 11 , 16 , or 18 . Efficacy analyses were conducted in a per- protocol population , in which subjects received all three vaccinations and were negative for relevant HPV types at enrollment , and in an intention-to-treat population , in which subjects received vaccine or placebo , regardless of baseline HPV status . RESULTS In the intention-to-treat population , 36 external genital lesions were seen in the vaccine group as compared with 89 in the placebo group , for an observed efficacy of 60.2 % ( 95 % confidence interval [ CI ] , 40.8 to 73.8 ) ; the efficacy was 65.5 % ( 95 % CI , 45.8 to 78.6 ) for lesions related to HPV-6 , 11 , 16 , or 18 . In the per- protocol population , efficacy against lesions related to HPV-6 , 11 , 16 , or 18 was 90.4 % ( 95 % CI , 69.2 to 98.1 ) . Efficacy with respect to persistent infection with HPV-6 , 11 , 16 , or 18 and detection of related DNA at any time was 47.8 % ( 95 % CI , 36.0 to 57.6 ) and 27.1 % ( 95 % CI , 16.6 to 36.3 ) , respectively , in the intention-to-treat population and 85.6 % ( 97.5 % CI , 73.4 to 92.9 ) and 44.7 % ( 95 % CI , 31.5 to 55.6 ) in the per- protocol population . Injection-site pain was significantly more frequent among subjects receiving quadrivalent HPV vaccine than among those receiving placebo ( 57 % vs. 51 % , P<0.001 ) . CONCLUSIONS Quadrivalent HPV vaccine prevents infection with HPV-6 , 11 , 16 , and 18 and the development of related external genital lesions in males 16 to 26 years of age . ( Funded by Merck and others ; Clinical Trials.gov number , NCT00090285 . ) [2360730] Human papillomavirus ( HPV ) causes cervical , vulvar , and vaginal cancers , precancerous dysplasia , and genital warts . We report data for the longest efficacy evaluation to date of a prophylactic HPV vaccine . In total , 552 women ( 16–23 years ) were enrolled in a r and omised , placebo-controlled study of a quadrivalent HPV 6/11/16/18 L1 virus-like-particle vaccine with vaccination at months 0 , 2 , and 6 . At regular intervals through 3 years , subjects underwent gynaecologic examination , cervicovaginal sampling for HPV DNA , serum anti-HPV testing , and Pap testing , with follow-up biopsy as indicated . A subset of 241 subjects underwent two further years of follow-up . At 5 years post enrolment , the combined incidence of HPV 6/11/16/18-related persistent infection or disease was reduced in vaccine-recipients by 96 % ( two cases vaccine versus 46 placebo ) . There were no cases of HPV 6/11/16/18-related precancerous cervical dysplasia or genital warts in vaccine recipients , and six cases in placebo recipients ( efficacy=100 % ; 95 % CI:12–100 % ) . Through 5 years , vaccine-induced anti-HPV geometric mean titres remained at or above those following natural infection . In conclusion , a prophylactic quadrivalent HPV vaccine was effective through 5 years for prevention of persistent infection and disease caused by HPV 6/11/16/18 . This duration supports vaccination of adolescents and young adults , which is expected to greatly reduce the burden of cervical and genital cancers , precancerous dysplasia , and genital warts [2908791] The human papillomavirus (HPV)-16/18 AS04-adjuvanted cervical cancer vaccine has been demonstrated to be highly efficacious and immunogenic with a favorable safety profile . This study assessed the immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine in healthy Korean girls aged 10 - 14 yr . This multi-center , observer-blind trial r and omly assigned 321 healthy girls to receive three doses ( 0 , 1 , 6-month schedule ) of HPV-16/18 AS04-adjuvanted vaccine or hepatitis A vaccine . Immunogenicity against vaccine antigens was assessed one month post-Dose 3 . Solicited and unsolicited adverse events ( AEs ) and serious AEs ( SAEs ) were recorded . In the according-to- protocol analysis , all initially seronegative subjects vaccinated with the HPV-16/18 AS04-adjuvanted vaccine had seroconverted at Month 7 , with a peak geometric mean titer ( GMT ) that was 600-fold higher than the natural infection titer of 29.8 EU/mL for HPV-16 and a peak GMT that was 400-fold higher than the natural infection titer of 22.6 EU/mL for HPV-18 . The vaccine was well tolerated with no increase in reactogenicity with subsequent doses and no reports of vaccine-related SAEs . In conclusion , the HPV-16/18 AS04-adjuvanted vaccine is shown to be highly immunogenic and generally well-tolerated in Korean girls aged 10 - 14 yr [5215585] ABSTRACT This community-r and omized controlled trial was initiated to assess the overall and herd effects of 2 different human papillomavirus ( HPV ) immunization strategies in over 80,000 girls and boys aged 12–15 y in 33 communities in Finl and ( Clinical Trials.gov NCT00534638 ) . Overall , 14,838 adolescents received HPV-16/18 vaccine ( 2,440 boys and 12,398 girls ) and 17,338 received hepatitis-B virus ( HBV ) vaccine ( 9,221 boys and 8,117 girls ) . In an interim analysis , vaccine safety was assessed by active monitoring and surveillance via health registry linkage . Active monitoring showed that the HPV-16/18 vaccine has acceptable safety and reactogenicity in boys . In all study participants , the observed incidences ( per 100,000 person-years ) of serious adverse events ( SAEs ) possibly related to vaccination were 54.3 ( 95 % Confidence Interval [ CI ] : 34.0–82.1 ) in the HPV-16/18 group and 64.0 ( 95 % CI : 43.2–91.3 ) in the HBV group . During the follow-up period for this interim analysis , the most common new-onset autoimmune diseases ( NOADs ; with incidence rate ≥15 per 100,000 ) in any group based on hospital discharge registry ( HILMO ) download were ulcerative colitis , juvenile arthritis , celiac disease , insulin-dependent diabetes mellitus ( IDDM ) and Crohn 's disease . No increased NOAD incidences were observed in HPV-16/18 vaccine recipients compared to HBV vaccine recipients . In both the SAE possibly related- and HILMO-analyses , a lower incidence of IDDM was observed in HPV-16/18 vaccinees compared to HBV vaccinees ( relative risks , 0.26 [ 95 % CI : 0.03–1.24 ] and 0.16 [ 95 % CI : 0.03–0.55 ] , respectively ) [4896780] HPV-023 ( NCT00518336 ; Clinical Trial.gov ) is a long-term follow-up of an initial double-blind , r and omized ( 1:1 ) , placebo-controlled study ( HPV-001 , NCT00689741 ) evaluating the efficacy against human papillomavirus (HPV)-16/18 infection and associated cyto-histopathological abnormalities , persistence of immunogenicity , and safety of the HPV-16/18 AS04-adjuvanted vaccine . Among the women , aged 15–25 years , enrolled in HPV-001 and who participated in the follow-up study HPV-007 ( NCT00120848 ) , a subset of 437 women from five Brazilian centers participated in this 36-month long-term follow-up ( HPV-023 ) for a total of 113 months ( 9.4 years ) . During HPV-023 , anti-HPV-16/18 antibodies were measured annually by enzyme-linked immunosorbent assay ( ELISA ) and pseudovirion-based neutralisation assay ( PBNA ) . Cervical sample s were tested for HPV DNA every 6 months , and cyto-pathological examinations were performed annually . During HPV-023 , no new HPV-16/18-associated infections and cyto-histopathological abnormalities occurred in the vaccine group . Vaccine efficacy ( VE ) against HPV-16/18 incident infection was 100 % ( 95%CI : 66.1 , 100 ) . Over the 113 months ( 9.4 years ) , VE was 95.6 % ( 86.2 , 99.1 ; 3/50 cases in vaccine and placebo groups , respectively ) against incident infection , 100 % ( 84·1 , 100 ; 0/21 ) against 6-month persistent infection ( PI ) ; 100 % ( 61·4 , 100 ; 0/10 ) against 12-month PI ; 97·1 % ( 82.5 , 99.9 ; 1/30 ) against ≥ ASC-US ; 95·0 % ( 68.0 , 99.9 ; 1/18 ) against ≥ LSIL ; 100 % ( 45.2 , 100 ; 0/8 ) against CIN1 + ; and 100 % ( –128.1 , 100 ; 0/3 ) against CIN2 + associated with HPV-16/18 . All vaccinees remained seropositive to HPV-16/18 , with antibody titers remaining several folds above natural infection levels , as measured by ELISA and PBNA . There were no safety concerns . To date , these data represent the longest follow-up reported for a licensed HPV vaccine [17499406] BACKGROUND The duration of protection afforded by vaccines represents a critical test of their utility as public health interventions . Some vaccines induce long-term immunity , while others require booster doses . Vaccines that induce long-term protection are usually characterized by the generation of immune memory . Recent trials of a quadrivalent ( types 6 , 11 , 16 , 18 ) human papillomavirus ( HPV ) vaccine have demonstrated high efficacy through 5 years of follow-up . We evaluated the extent to which the vaccine is able to generate HPV type-specific immune memory . METHODS A total of 552 , 16 - 23-year-old women were enrolled in a double-blind , placebo-controlled study . At enrollment , subjects were r and omized in a 1:1 ratio to receive three-dose regimens of quadrivalent HPV vaccine or placebo with 3 years ' follow-up . A subset of 241 subjects ( n=114 in the quadrivalent HPV vaccine group and n=127 in the placebo group ) underwent 2 further years of follow-up . All extension subjects received quadrivalent HPV vaccine at month 60 to examine the extent of immune memory in response to the primary vaccination series . RESULTS Serum anti-HPV levels declined post-vaccination , but reached a plateau at month 24 that remained stable through month 60 . Administration of a challenge dose of vaccine induced a classic anamnestic response , with anti-HPV levels 1 week post-challenge reaching levels observed 1 month following the completion of the three-dose primary series . At 1 month post-challenge , anti-HPV responses were higher than those observed 1-month post-dose 3 . DISCUSSION A three-dose regimen of quadrivalent HPV vaccine induces high efficacy and stable anti-HPV levels for at least 5 years . Vaccination also induces robust immune memory . These findings suggest that the efficacy of this vaccine will be long lasting [4277330] This phase II/III , double-blind , r and omized trial assessed the efficacy , immunogenicity and safety of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in young Chinese women ( Clinical Trials.gov registration NCT00779766 ) . Women aged 18–25 years from Jiangsu province were r and omized ( 1:1 ) to receive HPV vaccine ( n = 3,026 ) or Al(OH)3 control ( n = 3,025 ) at months 0 , 1 and 6 . The primary objective was vaccine efficacy ( VE ) against HPV-16/18 associated 6-month persistent infection ( PI ) and /or cervical intraepithelial neoplasia ( CIN ) 1 + . Secondary objectives were VE against virological and clinical endpoints associated with HPV-16/18 and with high-risk HPV types , immunogenicity and safety . Mean follow-up for the according-to- protocol cohort for efficacy ( ATP-E ) was ∼15 months after the third dose . In the ATP-E ( vaccine = 2,889 ; control = 2,894 ) , for initially HPV DNA negative and seronegative subjects , HPV-16/18 related VE ( 95 % CI ) was 94.2 % ( 62.7 , 99.9 ) against 6-month PI and /or CIN1 + and 93.8 % ( 60.2 , 99.9 ) against cytological abnormalities . VE against HPV-16/18 associated CIN1 + and CIN2 + was 100 % ( −50.4 , 100 ) and 100 % ( −140.2 , 100 ) , respectively ( no cases in the vaccine group and 4 CIN1 + and 3 CIN2 + cases in the control group ) . At Month 7 , at least 99.7 % of initially seronegative vaccine recipients had seroconverted for HPV-16/18 ; geometric mean antibody titres ( 95 % CI ) were 6,996 ( 6,212 to 7,880 ) EU/mL for anti-HPV-16 and 3,309 ( 2,942 to 3,723 ) EU/mL for anti-HPV-18 . Safety outcomes between groups were generally similar . The HPV-16/18 AS04-adjuvanted vaccine is effective , immunogenic and has a clinical ly acceptable safety profile in young Chinese women . Prophylactic HPV vaccination has the potential to substantially reduce the burden of cervical cancer in China . What 's New ? With an estimated 75,000 new cases and 34,000 women dying from the disease annually , cervical cancer is a major public-health concern in China . This is the first large scale r and omised clinical trial of a human papillomavirus ( HPV ) vaccine in China . The vaccine was found to be effective , immunogenic , and to have a clinical ly acceptable safety profile in young Chinese women . Prophylactic HPV vaccination thus has the potential to substantially reduce the burden of cervical cancers and precancers in China [16631880] BACKGROUND Effective vaccination against HPV 16 and HPV 18 to prevent cervical cancer will require a high level of sustained protection against infection and precancerous lesions . Our aim was to assess the long-term efficacy , immunogenicity , and safety of a bivalent HPV-16/18 L1 virus-like particle AS04 vaccine against incident and persistent infection with HPV 16 and HPV 18 and their associated cytological and histological outcomes . METHODS We did a follow-up study of our multicentre , double-blind , r and omised , placebo-controlled trial reported in 2004 . We included women who originally received all three doses of bivalent HPV-16/18 virus-like particle AS04 vaccine ( 0.5 mL ; n=393 ) or placebo ( n=383 ) . We assessed HPV DNA , using cervical sample s , and did yearly cervical cytology assessment s. We also studied the long-term immunogenicity and safety of the vaccine . FINDINGS More than 98 % seropositivity was maintained for HPV-16/18 antibodies during the extended follow-up phase . We noted significant vaccine efficacy against HPV-16 and HPV-18 endpoints : incident infection , 96.9 % ( 95 % CI 81.3 - 99.9 ) ; persistent infection : 6 month definition , 94.3 ( 63.2 - 99.9 ) ; 12 month definition , 100 % ( 33.6 - 100 ) . In a combined analysis of the initial efficacy and extended follow-up studies , vaccine efficacy of 100 % ( 42.4 - 100 ) against cervical intraepithelial neoplasia ( CIN ) lesions associated with vaccine types . We noted broad protection against cytohistological outcomes beyond that anticipated for HPV 16/18 and protection against incident infection with HPV 45 and HPV 31 . The vaccine has a good long-term safety profile . INTERPRETATION Up to 4.5 years , the HPV-16/18 L1 virus-like particle AS04 vaccine is highly immunogenic and safe , and induces a high degree of protection against HPV-16/18 infection and associated cervical lesions . There is also evidence of cross protection [22586631] Target groups for human papillomavirus ( HPV ) vaccination are controversial . We evaluated vaccine efficacy ( VE ) against 1-year persistent infection , stratified by age and sexual behavior , among young women in Costa Rica . We r and omized 7,466 healthy women 18 to 25 years of age to HPV16/18 or hepatitis A vaccine ( follow-up , 50.4 months ) . According-to- protocol ( ATP ) cohorts included compliant HPV-negative women ; intention-to-treat ( ITT ) included all r and omized women . ATP VE was 90.9 % ( 95 % CI , 82.0 - 95.9 ) against HPV16/18 infections , 44.5 % against HPV31/33/45 ( 95 % CI , 17.5 - 63.1 ) , and 12.4 % ( 95 % CI , -3.2 to 25.6 ) against any oncogenic infection . Overall ITT VE against HPV16/18 infections was 49.0 % , but ATP and ITT VE almost reached 100 % in year 4 of follow-up . ATP efficacy against HPV16/18 was similar by age , but ITT VE was greatest among youngest women ( 68.9 % among those 18 - 19 years of age ; 21.8 % among those 24 - 25 years of age ) and 79.8 % among virgins . Among previously unexposed women , vaccination is highly efficacious against HPV16/18 and partially against HPV31/33/45 . Vaccination is most effective in women and girls before they initiate sexual activity , with programmatic and individual decision implication [21858807] In the Phase III PATRICIA study ( NCT00122681 ) , the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine ( Cervarix ( ® ) , GlaxoSmithKline Biologicals ) was highly efficacious against HPV-16/18 infections and precancerous lesions in women HPV-16/18 deoxyribose nucleic acid ( DNA ) negative and seronegative at baseline . We present further data on vaccine efficacy ( VE ) against HPV-16/18 in the total vaccinated cohort including women who may have been exposed to HPV-16/18 infection before vaccination . In women with no evidence of current or previous HPV-16/18 infection ( DNA negative and seronegative ) , VE was 90.3 % ( 96.1 % confidence interval : 87.3 - 92.6 ) against 6-month persistent infection ( PI ) , 91.9 % ( 84.6 - 96.2 ) against cervical intraepithelial neoplasia (CIN)1 + and 94.6 % ( 86.3 - 98.4 ) against CIN2 + [ 97.7 % ( 91.1 - 99.8 ) when using the HPV type assignment algorithm ( TAA ) ] . In women HPV-16/18 DNA negative but with serological evidence of previous HPV-16/18 infection ( seropositive ) , VE was 72.3 % ( 53.0 - 84.5 ) against 6-month PI , 67.2 % ( 10.9 - 89.9 ) against CIN1 + , and 68.8 % ( -28.3 - 95.0 ) against CIN2 + [ 88.5 % ( 10.8 - 99.8 ) when using TAA ] . In women with no evidence of current HPV-16/18 infection ( DNA negative ) , regardless of their baseline HPV-16/18 serological status , VE was 88.7 % ( 85.7 - 91.1 ) against 6-month PI , 89.1 % ( 81.6 - 94.0 ) against CIN1 + and 92.4 % ( 84.0 - 97.0 ) against CIN2 + [ 97.0 % ( 90.6 - 99.5 ) when using TAA ] . In women who were DNA positive for one vaccine type , the vaccine was efficacious against the other vaccine type . The vaccine did not impact the outcome of HPV-16/18 infections present at the time of vaccination . Vaccination was generally well tolerated regardless of the woman 's HPV-16/18 DNA or serological status at entry [19684472] This observer-blind study compared the prophylactic human papillomavirus ( HPV ) vaccines , Cervarix ™ ( GlaxoSmithKline ) and Gardasil ® ( Merck ) , by assessing immunogenicity and safety through one month after completion of the three-dose vaccination course . Women ( n=1106 ) were stratified by age ( 18–26 , 27–35 , 36–45 years ) and r and omized ( 1:1 ) to receive Cervarix ™ ( Months 0 , 1 , 6 ) or Gardasil ® ( Months 0 , 2 , 6 ) . At Month 7 after first vaccination , all women in the according-to- protocol cohort who were seronegative/DNA negative before vaccination for the HPV type analyzed had seroconverted for HPV-16 and HPV-18 serum neutralizing antibodies , as measured by pseudovirion-based neutralization assay ( PBNA ) , except for two women aged 27–35 years in the Gardasil ® group who did not seroconvert for HPV-18 ( 98 % ) . Geometric mean titers of serum neutralizing antibodies ranged from 2.3–4.8-fold higher for HPV-16 and 6.8–9.1-fold higher for HPV-18 after vaccination with Cervarix ™ compared with Gardasil ® , across all age strata . In the total vaccinated cohort ( all women who received at least one vaccine dose , regardless of their serological and DNA status prior to vaccination ) , Cervarix ™ induced significantly higher serum neutralizing antibody titers in all age strata ( [26090572] Background : A 9-valent human papillomavirus ( 9vHPV ) vaccine has been developed to prevent infections and diseases related to HPV 6/11/16/18 [ as per the licensed quadrivalent HPV ( qHPV ) vaccine ] , as well as 5 additional oncogenic HPV types ( HPV 31/33/45/52/58 ) . Compared with the qHPV vaccine , the 9vHPV vaccine potentially increases the coverage of protection from 70 % to 90 % of cervical cancers . We compared the immunogenicity and safety of the 9vHPV vaccine versus the qHPV vaccine in 9–15-year-old girls . Methods : Participants ( n = 600 ) were r and omized to receive 9vHPV or qHPV vaccines on day 1 , month 2 and month 6 . Serology testing was performed on day 1 and month 7 . HPV type-specific antibody titers ( anti-HPV 6/11/16/18/31/33/45/52/58 ) were determined by competitive Luminex immunoassay and expressed as geometric mean titers and seroconversion rates . Vaccine safety was also assessed . Results : The HPV 6/11/16/18 immune responses elicited by the 9vHPV vaccine were comparable with those elicited by the qHPV vaccine . All participants ( except 1 for HPV 45 ) receiving the 9vHPV vaccine seroconverted for HPV 31/33/45/52/58 . The 9vHPV and qHPV vaccines showed comparable safety profiles , although the incidence of injection-site swelling was higher in the 9vHPV vaccine group . Conclusions : In addition to immune responses to HPV 31/33/45/52/58 , a 3-dose regimen of the 9vHPV vaccine elicited a similar immune response to HPV 6/11/16/18 when compared with the qHPV vaccine in girls aged 9–15 years . The safety profile was also similar for the 2 vaccines [24273179] BACKGROUND We compared the immunogenicity and reactogenicity of Cervarix or Gardasil human papillomavirus ( HPV ) vaccines in adults infected with the human immunodeficiency virus ( HIV ) . METHODS This was a double-blind , controlled trial r and omizing HIV-positive adults to receive 3 doses of Cervarix or Gardasil at 0 , 1.5 , and 6 months . Immunogenicity was evaluated for up to 12 months . Neutralizing anti-HPV-16/18 antibodies were measured by pseudovirion-based neutralization assay . Laboratory tests and diary cards were used for safety assessment . The HPV-DNA status of the participants was determined before and after immunization . RESULTS Ninety-two participants were included in the study . Anti-HPV-18 antibody titers were higher in the Cervarix group compared with the Gardasil group at 7 and 12 months . No significant differences in anti-HPV-16 antibody titers were found among vaccine groups . Among Cervarix vaccinees , women had higher anti-HPV-16/18 antibody titers compared to men . No sex-specific differences in antibody titers were found in the Gardasil group . Mild injection site reactions were more common in the Cervarix group than in the Gardasil group ( 91.1 % vs 69.6 % ; P = .02 ) . No serious adverse events occurred . CONCLUSIONS Both vaccines were immunogenic and well tolerated . Compared with Gardasil , Cervarix induced superior vaccine responses among HIV-infected women , whereas in HIV-infected men the difference in immunogenicity was less pronounced [21712645] Prophylactic vaccination with a quadrivalent HPV ( types 6 , 11 , 16 , 18 ) vaccine ( qHPV ) has been shown to prevent infection with HPV 6/11/16/18 and associated disease in women and more recently , in men . Here we report on the safety and reactogenicity of the qHPV vaccine in males . A total of 4,065 healthy males aged 16 - 26 years were enrolled into a r and omized , placebo-controlled , double-blind trial . Subjects were r and omized 1:1 to receive qHPV vaccine or placebo at day 1 , month 2 , and month 6 . Safety and tolerability were assessed via the collection of reported adverse experiences ( AEs ) . All serious AEs ( vaccine- or procedure-related or not ) and all deaths occurring during the study were recorded . Safety analyses were conducted in all subjects who received at least one dose of vaccine or placebo . The proportion of subjects who reported at least one injection-site AE was higher in the qHPV vaccine group versus the placebo group ( 60.1 % vs 53.7 % , respectively ) , however most of these AEs were mild/moderate in intensity . The incidence of at least one systemic AE was comparable between the vaccine and placebo groups ( 31.7 % vs 31.4 % , respectively ) . There were no vaccine-related serious AEs or deaths . The occurrence of AEs did not increase with each successive injection , and among trial participants who were seropositive for at least one vaccine HPV type at enrollment , the profile of adverse events was similar to that of the entire study cohort . The qHPV vaccine was generally well tolerated in males aged 16 - 26 years and had a favorable safety profile [20413076] PURPOSE Immunization of girls against oncogenic human papillomavirus ( HPV ) types before sexual debut is important for cervical cancer prevention . This phase III blinded , r and omized , controlled trial in adolescent girls assessed safety of the HPV-16/18 AS04-adjuvanted vaccine . METHODS Girls ( mean age 12 years ) in 12 countries received the HPV-16/18 L1 virus-like particle AS04-adjuvanted vaccine ( N = 1,035 ) or hepatitis A virus vaccine as control ( N = 1,032 ) at 0 , 1 , and 6 months . The primary objective was to compare the occurrence of serious adverse events ( SAEs ) between groups . HPV-16 and HPV-18 antibody titers were assessed by enzyme-linked immunosorbent assay post-vaccination . RESULTS Up to study month 7 , 11 girls in the HPV-16/18 vaccine group reported 14 SAEs and 13 girls in the control group reported 15 SAEs . The difference in SAE incidence between groups was .20 % ( 95 % CI , -.78 , 1.20 ) . No SAE in the HPV-16/18 vaccine group was considered related to vaccination or led to withdrawal . The incidence of solicited local and general symptoms up to 7 days post-vaccination was moderately higher with the HPV-16/18 vaccine than with control . The incidence of unsolicited symptoms , new onset of chronic diseases , and medically significant conditions was similar between groups . All girls seroconverted for both antigens after three doses of the HPV-16/18 vaccine ; geometric mean titers were 19,882.0 and 8,262.0 EU/mL for anti-HPV-16 and -18 antibodies , respectively , in initially seronegative girls . CONCLUSIONS The HPV-16/18 AS04-adjuvanted vaccine was generally well tolerated and immunogenic when administered to young adolescent females , the primary target of organized vaccination programs [3714284] Background Human papillomavirus ( HPV ) infection , particularly with type 16 , causes a growing fraction of oropharyngeal cancers , whose incidence is increasing , mainly in developed countries . In a double-blind controlled trial conducted to investigate vaccine efficacy ( VE ) of the bivalent HPV 16/18 vaccine against cervical infections and lesions , we estimated VE against prevalent oral HPV infections 4 years after vaccination . Methods and Findings A total of 7,466 women 18–25 years old were r and omized ( 1∶1 ) to receive the HPV16/18 vaccine or hepatitis A vaccine as control . At the final blinded 4-year study visit , 5,840 participants provided oral specimens ( 91·9 % of eligible women ) to evaluate VE against oral infections . Our primary analysis evaluated prevalent oral HPV infection among all vaccinated women with oral and cervical HPV results . Corresponding VE against prevalent cervical HPV16/18 infection was calculated for comparison . Oral prevalence of identifiable mucosal HPV was relatively low ( 1·7 % ) . Approximately four years after vaccination , there were 15 prevalent HPV16/18 infections in the control group and one in the vaccine group , for an estimated VE of 93·3 % ( 95 % CI = 63 % to 100 % ) . Corresponding efficacy against prevalent cervical HPV16/18 infection for the same cohort at the same visit was 72·0 % ( 95 % CI = 63 % to 79 % ) ( p versus oral VE = 0·04 ) . There was no statistically significant protection against other oral HPV infections , though power was limited for these analyses . Conclusions HPV prevalence four years after vaccination with the ASO4-adjuvanted HPV16/18 vaccine was much lower among women in the vaccine arm compared to the control arm , suggesting that the vaccine affords strong protection against oral HPV16/18 infection , with potentially important implication s for prevention of increasingly common HPV-associated oropharyngeal cancer . Clinical Trials.gov , Registry number [20606533] Background : Human papillomavirus ( HPV ) type 16/18 AS04-adjuvanted vaccine was shown to be highly immunogenic and generally well tolerated in the interim analysis of a phase 2 double-blind , r and omized controlled multicenter study in Japanese healthy women aged 20 to 25 years . Vaccine efficacy , immunogenicity , and safety are assessed in this study through 24 months after the first vaccination . Methods : Japanese women aged 20 to 25 years were r and omly assigned to receive either HPV-16/18 AS04-adjuvanted vaccine ( n = 519 ) or hepatitis A vaccine ( n = 521 ) at 0 , 1 , and 6 months . Women were assessed for virological , cytological , and histological end points associated with HPV-16/18 and 12 other oncogenic HPV types ( types 31 , 33 , 35 , 39 , 45 , 51 , 52 , 56 , 58 , 59 , 66 , and 68 ) in cervical specimens and for the vaccine safety and immunogenicity . Antibody concentrations were measured by an enzyme-linked immunosorbent assay . Primary efficacy analysis was performed in the according-to- protocol cohort for efficacy , primary immunogenicity analysis was performed in the according-to- protocol cohort for immunogenicity , and primary safety analysis was done in the total vaccinated cohort . Results : Vaccine efficacy against persistent infections ( 6 month definition ) associated with HPV-16/18 was 100 % ( 95.5 % confidence interval , 71.3 - 100 ; P < 0.0001 ) . Vaccine efficacy against cervical intraepithelial neoplasia 1 + associated with 14 oncogenic HPV types was 64.9 % ( 95.5 % confidence interval , 4.9 - 89.0 ; P = 0.02 ) . At 24 months after the first dose of the vaccine , geometric mean antibody titers against HPV-16 and HPV-18 were 1521.5 enzyme-linked immunosorbent assay U/mL and 627.4 enzyme-linked immunosorbent assay U/mL , respectively . The HPV-16/18 AS04-adjuvanted vaccine had a clinical ly acceptable safety profile . Conclusions : The HPV-16/18 AS04-adjuvanted vaccine showed excellent prophylactic efficacy against 6-month persistent infection with HPV-16/18 . The HPV-16/18 AS04-adjuvanted vaccine was generally well tolerated and immunogenic in the study population of healthy Japanese women aged 20 to 25 years [18164106] Adolescents and young adults are at high risk for human papillomavirus ( HPV ) and hepatitis B virus ( HBV ) infections , which are preventable by currently available , safe and effective , prophylactic vaccines . However , development of a combined immunization strategy may lead to better compliance for these vaccines , thereby contributing to the overall goal of protection against these diseases . This study assessed the safety and immunogenicity of co-administered quadrivalent HPV-6/11/16/18 L1 VLP and HBV vaccines in women ( n=1877 ) aged 16 - 23 years . Co-administration of HPV and HBV vaccines induced robust anti-HPV-6 , HPV-11 , HPV-16 , HPV-18 geometric mean titers ( GMTs ) and > or = 99 % seroconversion rates ( Month 7 ) that were both non-inferior ( p<0.001 ) to those induced by HPV vaccine alone . High Month 7 anti-HBs GMTs were also observed following concomitant vaccination . These GMTs were lower compared to those induced by the HBV vaccine itself ; however , > 96 % of subjects achieved an anti-HBs seroprotection level of > or = 10 mIU/mL that was non-inferior ( p<0.001 ) to that of HBV vaccine alone . Overall , co-administered and individual vaccines were generally well-tolerated and did not interfere with the immune response of either vaccine ( Clinical Trials.gov number , NCT00092521 ) [17484215] Objective : Administration of a quadrivalent HPV-6/11/16/18 vaccine to 16- to 26-year-old women was highly effective in preventing HPV-6/11/16/18-related cervical/vulvar/vaginal precancerous lesions and genital warts . As the risk of acquiring HPV significantly rises after sexual debut , HPV vaccines should have the greatest benefit in sexually naive adolescents . We evaluated the tolerability and immunogenicity of quadrivalent vaccine in males and females 9 to 15 years of age through 18 months postenrollment . Methods : In this r and omized , double-blind trial , 1781 sexually naive children were assigned ( 2:1 ) to quadrivalent HPV-6/11/16/18 vaccine or saline placebo administered at day 1 and months 2 and 6 . Serum neutralizing anti-HPV-6/11/16/18 responses were summarized as geometric mean titers ( GMTs ) and seroconversion rates . Primary analyses were done per- protocol ( subjects received 3 doses , had no major protocol violations and were HPV type-specific seronegative at day 1 ) . Adverse experiences were collected by diary card . Results : At month 7 , seroconversion rates were ≥99.5 % for the 4 vaccine-HPV-types . GMTs and seroconversion rates in boys were noninferior to those in girls ( P < 0.001 ) . At month 18 , ≥91.5 % of vaccine recipients were seropositive , regardless of gender . A higher proportion of vaccine recipients ( 75.3 % ) than placebo recipients ( 50.0 % ) reported one or more injection-site adverse experiences following any vaccination . Rates of fever were similar between vaccination groups . No serious vaccine-related adverse experiences were reported . Conclusions : In 9- to 15-year-old adolescents , the quadrivalent vaccine was generally well tolerated and induced persistent anti-HPV serologic responses in the majority of subjects for at least 12 months following completion of a three-dose regimen . The vaccine durability supports universal HPV vaccination programs in adolescents to reduce the burden of clinical HPV disease , particularly cervical cancer and precancers [4186043] In this open , extended follow-up study ( NCT00929526 , Clinical trials.gov ) , we evaluated the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine efficacy , immunogenicity and safety up to 4 years after first vaccination in Japanese women aged 20–25 years . In the initial r and omized , double-blind study ( NCT00316693 ) , 1040 women received the study vaccine or hepatitis A control vaccine ; 752 women were included in the follow-up study . In women from the according-to- protocol efficacy cohort ( ATP-E ) , who were initially seronegative for the HPV type analyzed , no cervical intraepithelial neoplasia ( CIN ) grade 1 or greater ( CIN1 + ) cases associated with HPV-16/18 were reported in the HPV group , while in the control group , 5 cases were identified in extended follow-up analyses ( vaccine efficacy [ VE ] 100 % [ 95 % CI : −3.7–100 ] ) and 8 cases in combined initial and follow-up studies analyses ( VE 100 % [ 42.2–100 ] ) . In the ATP-E , VE against CIN1 + and CIN2 + associated with high-risk HPV types reached 66.4 % ( 21.6–87.1 ) and 83.0 % ( 22.1–98.2 ) in extended follow-up analyses , and 63.4 % ( 28.8–82.3 ) and 77.3 % ( 30.4–94.4 ) in analyses of combined studies , respectively . During the 4-year period , protection against CIN1 + and CIN2 + , irrespective of the HPV type , was 56.7 % ( 32.8–72.6 ) and 54.9 % ( 20.5–75.3 ) in women receiving ≥1 vaccine dose , regardless of baseline serostatus ( total vaccinated cohort [ TVC ] ) and 61.0 % ( 11.8–84.2 ) and 73.9 % ( 1.1–95.3 ) in women naïve to HPV infection at baseline ( TVC-naïve ) , respectively . The high VE observed in Japanese women , accompanied by a sustained immune response and a clinical ly acceptable safety profile , support findings of large , international trials [15863374] BACKGROUND A r and omised double-blind placebo-controlled phase II study was done to assess the efficacy of a prophylactic quadrivalent vaccine targeting the human papillomavirus ( HPV ) types associated with 70 % of cervical cancers ( types 16 and 18 ) and with 90 % of genital warts ( types 6 and 11 ) . METHODS 277 young women ( mean age 20.2 years [ SD 1.7 ] ) were r and omly assigned to quadrivalent HPV ( 20 microg type 6 , 40 microg type 11 , 40 microg type 16 , and 20 microg type 18 ) L1 virus-like-particle ( VLP ) vaccine and 275 ( mean age 20.0 years [ 1.7 ] ) to one of two placebo preparations at day 1 , month 2 , and month 6 . For 36 months , participants underwent regular gynaecological examinations , cervicovaginal sampling for HPV DNA , testing for serum antibodies to HPV , and Pap testing . The primary endpoint was the combined incidence of infection with HPV 6 , 11 , 16 , or 18 , or cervical or external genital disease ( ie , persistent HPV infection , HPV detection at the last recorded visit , cervical intraepithelial neoplasia , cervical cancer , or external genital lesions caused by the HPV types in the vaccine ) . Main analyses were done per protocol . FINDINGS Combined incidence of persistent infection or disease with HPV 6 , 11 , 16 , or 18 fell by 90 % ( 95 % CI 71 - 97 , p<0.0001 ) in those assigned vaccine compared with those assigned placebo . INTERPRETATION A vaccine targeting HPV types 6 , 11 , 16 , 18 could substantially reduce the acquisition of infection and clinical disease caused by common HPV types [17986242] Human papillomavirus ( HPV ) is a major causative agent of anogenital warts and a necessary cause of cervical cancer . This report will serve to assess the safety and immunogenicity of quadrivalent ( types 6 , 11 , 16 , and 18 ) HPV L1 virus-like particle ( VLP ) vaccine in the Korean population . We performed a r and omized , double-blind , placebo-controlled study in 176 volunteers aged 9–23 years . Using a 2:1 ratio for r and omization , 117 women were assigned to quadrivalent HPV ( 20 μg type 6 , 40 μg type 11 , 40 μg type 16 , and 20 μg type 18 ) vaccine and 59 women to placebo . Individuals received vaccine at day 1 , month 2 , and month 6 and provided blood sample s for analysis at enrollment at month 7 . Analyses were done as specified in the study protocol . Quadrivalent HPV vaccine was generally well tolerated , with no vaccine-related serious adverse experiences . Quadrivalent HPV vaccine induced seroconversion for each vaccine-related HPV type . At month 7 , vaccine-induced type-specific antibody titer was high . In conclusion , administration of quadrivalent HPV VLP vaccine to Korean women aged 9–23 years was generally well tolerated and highly [19853193] BACKGROUND AND AIMS Recognition of human papillomavirus ( HPV ) as a necessary cause of cervical cancer ( CC ) led to new perspectives for its control and the demonstration of an effective primary prevention strategy through vaccination . We undertook this study to evaluate the safety , efficacy and immunogenicity of a quadrivalent HPV6/11/16/18 vaccine in Mexican women . METHODS A total of 679 Mexican women between 18 and 23 years old participated in two Phase III double-blind , r and omized , placebo-controlled clinical trials of a quadrivalent HPV 6/11/16/18 vaccine . Women were enrolled who tested negative for pregnancy and reported having four or less sexual partners during their lifetime . Vaccine or placebo was administered at day 1 , month 2 and month 6 . RESULTS Among Mexican women who were naïve to the respective vaccine type at enrollment , the quadrivalent vaccine was highly efficacious , preventing 100 % of HPV6/11/16/18-related cervical intraepithelial neoplasia grade 2/3 , adenocarcinoma in situ , condyloma and vaginal intraepithelial neoplasia . Statistical significance was not reached for every endpoint due to the limited sample size . Vaccination was generally well tolerated and immunogenic . DISCUSSION To widely administer the vaccine , collaborative efforts should be coordinated among public , private and local community sectors . In light of the scarce knowledge of many health professionals with respect to the primary prevention of CC , it will be necessary to educate health providers on the advantages and specific recommendations of HPV vaccines and secondary prevention . Decision making should be based on scientific evidence , allowing health professionals to provide an organized social response that supports the universal right to health

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### Context: [19586656] BACKGROUND The human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine was immunogenic , generally well tolerated , and effective against HPV-16 or HPV-18 infections , and associated precancerous lesions in an event-triggered interim analysis of the phase III r and omised , double-blind , controlled PApilloma TRIal against Cancer In young Adults ( PATRICIA ) . We now assess the vaccine efficacy in the final event-driven analysis . METHODS Women ( 15 - 25 years ) were vaccinated at months 0 , 1 , and 6 . Analyses were done in the according-to- protocol cohort for efficacy ( ATP-E ; vaccine , n=8093 ; control , n=8069 ) , total vaccinated cohort ( TVC , included all women receiving at least one vaccine dose , regardless of their baseline HPV status ; represents the general population , including those who are sexually active ; vaccine , n=9319 ; control , n=9325 ) , and TVC-naive ( no evidence of oncogenic HPV infection at baseline ; represents women before sexual debut ; vaccine , n=5822 ; control , n=5819 ) . The primary endpoint was to assess vaccine efficacy against cervical intraepithelial neoplasia 2 + ( CIN2 + ) that was associated with HPV-16 or HPV-18 in women who were seronegative at baseline , and DNA negative at baseline and month 6 for the corresponding type ( ATP-E ) . This trial is registered with Clinical Trials.gov , number NCT00122681 . FINDINGS Mean follow-up was 34.9 months ( SD 6.4 ) after the third dose . Vaccine efficacy against CIN2 + associated with HPV-16/18 was 92.9 % ( 96.1 % CI 79.9 - 98.3 ) in the primary analysis and 98.1 % ( 88.4 - 100 ) in an analysis in which probable causality to HPV type was assigned in lesions infected with multiple oncogenic types ( ATP-E cohort ) . Vaccine efficacy against CIN2 + irrespective of HPV DNA in lesions was 30.4 % ( 16.4 - 42.1 ) in the TVC and 70.2 % ( 54.7 - 80.9 ) in the TVC-naive . Corresponding values against CIN3 + were 33.4 % ( 9.1 - 51.5 ) in the TVC and 87.0 % ( 54.9 - 97.7 ) in the TVC-naive . Vaccine efficacy against CIN2 + associated with 12 non-vaccine oncogenic types was 54.0 % ( 34.0 - 68.4 ; ATP-E ) . Individual cross-protection against CIN2 + associated with HPV-31 , HPV-33 , and HPV-45 was seen in the TVC . INTERPRETATION The HPV-16/18 AS04-adjuvanted vaccine showed high efficacy against CIN2 + associated with HPV-16/18 and non-vaccine oncogenic HPV types and substantial overall effect in cohorts that are relevant to universal mass vaccination and catch-up programmes . FUNDING GlaxoSmithKline Biologicals [19493565] BACKGROUND Although the peak incidence of human papillomavirus ( HPV ) infection occurs in most population s within 5 - 10 years of first sexual experience , all women remain at risk for acquisition of HPV infections . We tested the safety , immunogenicity , and efficacy of the quadrivalent HPV ( types 6 , 11 , 16 , 18 ) L1 virus-like-particle vaccine in women aged 24 - 45 years . METHODS Women aged 24 - 45 years with no history of genital warts or cervical disease were enrolled from community health centres , academic health centres , and primary health-care providers into an ongoing multicentre , parallel , r and omised , placebo-controlled , double-blind study . Participants were allocated by computer-generated schedule to receive quadrivalent HPV vaccine ( n=1911 ) or placebo ( n=1908 ) at day 1 , and months 2 and 6 . All study site investigators and personnel , study participants , monitors , and central laboratory personnel were blinded to treatment allocation . Co primary efficacy endpoints were 6 months ' or more duration of infection and cervical and external genital disease due to HPV 6 , 11 , 16 , 18 ; and due to HPV 16 and 18 alone . Primary efficacy analyses were done in a per- protocol population , but intention-to-treat analyses were also undertaken . This study is registered with Clinical Trials.gov , number NCT00090220 . FINDINGS 1910 women received at least one dose of vaccine and 1907 at least one dose of placebo . In the per- protocol population , efficacy against the first co primary endpoint ( disease or infection related to HPV 6 , 11 , 16 , and 18 ) was 90.5 % ( 95 % CI 73.7 - 97.5 , four of 1615 cases in the vaccine group vs 41/1607 in the placebo group ) and 83.1 % ( 50.6 - 95.8 , four of 1601 cases vs 23/1579 cases ) against the second co primary endpoint ( disease or infection related to HPV 16 and 18 alone ) . In the intention-to-treat population , efficacy against the first co primary endpoint was 30.9 % ( 95 % CI 11.1 - 46.5 , 108/1886 cases vs 154/1883 cases ) and against the second co primary endpoint was 22.6 % ( -2.9 to 41.9 , 90/1886 cases vs 115/1883 cases ) , since infection and disease were present at baseline . We recorded no vaccine-related serious adverse events . INTERPRETATION The quadrivalent HPV vaccine is efficacious in women aged 24 - 45 years not infected with the relevant HPV types at enrolment . FUNDING Merck ( USA ) [3137403] Background : Previous analyses from a r and omised trial in women aged 24–45 years have shown the quadrivalent human papillomavirus ( qHPV ) vaccine to be efficacious in the prevention of infection , cervical intraepithelial neoplasia ( CIN ) , and external genital lesions ( EGLs ) related to HPV 6/11/16/18 . In this report , we present end-of- study efficacy , safety , and immunogenicity data with a median follow-up time of 4.0 years . Methods : We enrolled 3819 24–45-year-old women with no history of cervical disease or genital warts in the past 5 years . Women received quadrivalent vaccine or placebo at day 1 , and at months 2 and 6 . Ascertainment of CIN/EGL was accomplished through Pap testing , genital inspection , and cervicovaginal sampling ( every 6 months ) . The main analysis was conducted in a per- protocol efficacy population ( that received three doses , was naive to the relevant HPV types at day 1 , and remained free of infection through month 7 ) . Efficacy was also estimated in other naive and non-naive population s. Results : Vaccine efficacy against the combined incidence of persistent infection , CIN/EGL related to HPV6/11/16/18 in the per- protocol population was 88.7 % ( 95 % CI : 78.1 , 94.8 ) . Efficacy for women who were seropositive and DNA negative for the relevant vaccine HPV type at the time of enrolment who received at least 1 dose was 66.9 % ( 95 % CI : 4.3 , 90.6 ) . At month 48 , 91.5 , 92.0 , 97.4 , and 47.9 % of vaccinated women were seropositive to HPV 6/11/16/18 , respectively . No serious vaccine-related adverse experiences were reported . Conclusions : The qHPV vaccine demonstrated high efficacy , immunogenicity , and acceptable safety in women aged 24–45 years , regardless of previous exposure to HPV vaccine type [3636781] Background . Cervical cancer is a major public health problem for women in sub-Saharan Africa . Availability of a human papillomavirus ( HPV ) vaccine could have an important public health impact . Methods . In this phase IIIb , double-blind , r and omized , placebo-controlled , multicenter trial ( NCT00481767 ) , healthy African girls and young women seronegative for human immunodeficiency virus ( HIV ) were stratified by age ( 10–14 or 15–25 years ) and r and omized ( 2:1 ) to receive either HPV-16/18 AS04-adjuvanted vaccine ( n = 450 ) or placebo ( n = 226 ) at 0 , 1 , and 6 months . The primary objective was to evaluate HPV-16/18 antibody responses at month 7 . Seropositivity rates and corresponding geometric mean titers ( GMTs ) were measured by enzyme-linked immunosorbent assay . Results . In the according-to- protocol analysis at month 7 , 100 % of initially seronegative participants in the vaccine group were seropositive for both anti – HPV-16 and anti – HPV-18 antibodies ( n = 130 and n = 128 for 10–14-year-olds , respectively ; n = 190 and n = 212 for 15–25-year-olds ) . GMTs for HPV-16 and HPV-18 were higher in 10–14-year-olds ( 18 423 [ 95 % confidence interval , 16 185–20 970 ] and 6487 [ 5590–7529 ] enzyme-linked immunosorbent assay units (EU)/mL , respectively ) than in 15–25-year-olds ( 10 683 [ 9567–11 930 ] and 3743 [ 3400–4120 ] EU/mL , respectively ) . Seropositivity was maintained at month 12 . No participant withdrew owing to adverse events . No vaccine-related serious adverse events were reported . Conclusions . The HPV-16/18 AS04-adjuvanted vaccine was highly immunogenic and had a clinical ly acceptable safety profile when administered to healthy HIV-seronegative African girls and young women [22492244] Control of human papillomavirus (HPV)-related cancers by inclusion of HPV vaccination into national vaccination programmes is likely . One open question is replacement of the vaccine types with other high-risk ( hr ) HPV types in the vaccination era . We studied occurrence of HPV types in adolescent females participating in a population -based vaccination trial . A total of 4,808 16- to 17-year-old females from Finl and were enrolled in the 1:1 r and omized phase III ( PATRICIA ) trial of the efficacy of vaccination with the AS04-adjuvanted HPV-16/18 virus-like particle vaccine as compared to hepatitis A virus ( HAV ) vaccine . HPV infection was assessed from cervical sample s taken every 6 months for 4 years post-vaccination by polymerase chain reaction ( PCR ) for genital oncogenic HPV types 16 , 18 , 31 , 33 , 35 , 39 , 45 , 51 , 52 , 58 , 59 , 66 , 68 , and 73 as well as low-risk types HPV-6 and HPV-11 . The HPV-16/18 vaccine coverage ranged between 1 and 22 % by age-cohort and study community . Odds ratios ( ORs ) for infections with different HPV types in baseline PCR negative HPV-16/18 vs. HAV vaccinated women , and Poisson regression derived HPV incidence rate ratios ( IRRs ) in baseline positive vs. negative women were calculated . The OR and IRR estimates for acquisition of any genital HPV types showed no excess risk neither in baseline HPV DNA-negative HPV-16/18-vaccinated women compared to baseline HPV DNA-negative HAV vaccinated women nor in HPV-16/18-vaccinated baseline HPV-16/18-positive women compared to baseline HPV-16/18-negative women . In the HAV-vaccinated , baseline HPV-18-positive women showed an increased risk of acquiring other clade A7 HPV types ( 39 , 45 , 59 , 68 ) ( IRR 1.8 , 95 % confidence interval = 1.01.-3.1 ) . We found no increased occurrence of non-vaccine HPV types suggestive of type-replacement 1 - 4 years post-vaccination among HPV-16/18-vaccinated Finnish adolescents [3152758] Objective The study assessed the immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted cervical cancer vaccine in healthy Korean women aged 15 - 25 years . Methods Phase IIIB , double-blind , r and omised ( 2:1 ) , multi-centre trial was conducted in Korea from June 2007 to March 2008 . The study enrolled 225 women in the HPV ( N=149 ) and placebo ( N=76 ) groups who received three doses of HPV-16/18 AS04-adjuvanted vaccine or placebo ( aluminium hydroxide ) administered intramuscularly at 0 , 1 , and 6 months and were followed until one month post-dose 3 . Serum sample s were collected pre-vaccination and one month post-dose 3 . Safety and reactogenicity data were collected throughout . Results In this trial , 208 women completed the study ( 141 in HPV group ; 67 in placebo group ) . At month 7 , all initially seronegative women had seroconverted for HPV-16 and HPV-18 antibodies with anti-HPV-16 and anti-HPV-18 geometric mean titres of 9,351.4 El . U/mL ( 95 % CI , 8,145.5 to 10,735.8 ) and 4204.1 El . U/mL ( 95 % CI , 3,626.5 to 4,873.6 ) , respectively . Initially seropositive women showed similar increase in geometric mean titre levels . Compliance to the three dose vaccination course was 95.3 % in HPV and 89.5 % in placebo group . Solicited local ( pain ) and general ( fatigue , myalgia or headache ) symptoms were commonly reported in both groups . Three serious adverse events were reported ( two in HPV group ; one in placebo group ) , all unrelated to vaccination by the investigator ; all recovered . Conclusion The HPV-16/18 AS04-adjuvanted vaccine was highly immunogenic with a clinical ly acceptable safety profile in Korean women . This study was in line with previous global studies in Europe , North America , and Brazil . ( Clinical Trials.gov number , NCT 00485732 . [25693011] BACKGROUND The investigational 9-valent viruslike particle vaccine against human papillomavirus ( HPV ) includes the HPV types in the quadrivalent HPV ( qHPV ) vaccine ( 6 , 11 , 16 , and 18 ) and five additional oncogenic types ( 31 , 33 , 45 , 52 , and 58 ) . Here we present the results of a study of the efficacy and immunogenicity of the 9vHPV vaccine in women 16 to 26 years of age . METHODS We performed a r and omized , international , double-blind , phase 2b-3 study of the 9vHPV vaccine in 14,215 women . Participants received the 9vHPV vaccine or the qHPV vaccine in a series of three intramuscular injections on day 1 and at months 2 and 6 . Serum was collected for analysis of antibody responses . Swabs of labial , vulvar , perineal , perianal , endocervical , and ectocervical tissue were obtained and used for HPV DNA testing , and liquid-based cytologic testing ( Papanicolaou testing ) was performed regularly . Tissue obtained by means of biopsy or as part of definitive therapy ( including a loop electrosurgical excision procedure and conization ) was tested for HPV . RESULTS The rate of high- grade cervical , vulvar , or vaginal disease irrespective of HPV type ( i.e. , disease caused by HPV types included in the 9vHPV vaccine and those not included ) in the modified intention-to-treat population ( which included participants with and those without prevalent infection or disease ) was 14.0 per 1000 person-years in both vaccine groups . The rate of high- grade cervical , vulvar , or vaginal disease related to HPV-31 , 33 , 45 , 52 , and 58 in a prespecified per- protocol efficacy population ( susceptible population ) was 0.1 per 1000 person-years in the 9vHPV group and 1.6 per 1000 person-years in the qHPV group ( efficacy of the 9vHPV vaccine , 96.7 % ; 95 % confidence interval , 80.9 to 99.8 ) . Antibody responses to HPV-6 , 11 , 16 , and 18 were noninferior to those generated by the qHPV vaccine . Adverse events related to injection site were more common in the 9vHPV group than in the qHPV group . CONCLUSIONS The 9vHPV vaccine prevented infection and disease related to HPV-31 , 33 , 45 , 52 , and 58 in a susceptible population and generated an antibody response to HPV-6 , 11 , 16 , and 18 that was noninferior to that generated by the qHPV vaccine . The 9vHPV vaccine did not prevent infection and disease related to HPV types beyond the nine types covered by the vaccine . ( Funded by Merck ; Clinical Trials.gov number , NCT00543543 ) [3196245] Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more [21856349] BACKGROUND To evaluate co-administration of GlaxoSmithKline Biologicals ' human papillomavirus-16/18 AS04-adjuvanted vaccine ( HPV ) and hepatitis B vaccine ( HepB ) . METHODS This was a r and omized , controlled , open , multicenter study . Healthy girls , aged 9 - 15 years , were r and omized to receive HPV ( n=247 ) , HepB ( n=247 ) or HPV co-administered with HepB ( HPV+HepB ; n=247 ) at Months 0 , 1 and 6 . Antibodies against hepatitis B surface antigen ( HBs ) , HPV-16 and HPV-18 were measured , and reactogenicity and safety monitored . Co- primary objectives were to demonstrate non-inferiority of hepatitis B and HPV-16/18 immune responses at Month 7 for co-administered vaccines , compared with vaccines administered alone , in the according-to- protocol cohort . RESULTS The pre-defined criteria for non-inferiority were met for all co- primary immunogenicity endpoints at Month 7 . Anti-HBs seroprotection rates ≥10mIU/mL were achieved by 97.9 % and 100 % of girls , respectively , following co-administration or HepB alone . Anti-HBs geometric mean titers ( GMTs ) ( 95 % confidence interval ) were 1280.9 ( 973.3 - 1685.7 ) and 3107.7 ( 2473.1 - 3905.1 ) milli-international units/mL , respectively . Anti-HPV-16 and -18 seroconversion rates were achieved by ≥99 % of girls following co-administration or HPV alone . Anti-HPV-16 GMTs were 19819.8 ( 16856.9 - 23303.6 ) and 21712.6 ( 19460.2 - 24225.6 ) ELISA units (ELU)/mL , respectively . Anti-HPV-18 GMTs were 8835.1 ( 7636.3 - 10222.1 ) and 8838.6 ( 7948.5 - 9828.4 ) ELU/mL , respectively . Co-administration was generally well tolerated . CONCLUSIONS The study results support the co-administration of HPV-16/18 AS04-adjuvanted vaccine with hepatitis B vaccine in adolescent girls aged 9 - 15 years . CLINICAL TRIALS REGISTRATION Clinical Trials.gov registration number NCT00652938 [27373900] BACKGROUND Although the risk of human papillomavirus ( HPV ) infection is greatest in young women , women older than 25 years remain at risk . We present data from the VIVIANE study of the HPV 16/18 AS04-adjuvanted vaccine in adult women after 7 years of follow-up . METHODS In this phase 3 , double-blind , r and omised controlled trial , healthy women older than 25 years were enrolled ( age stratified : 26 - 35 years , 36 - 45 years , and ≥46 years ) . Up to 15 % in each age stratum had a history of HPV infection or disease . Women were r and omly assigned ( 1:1 ) to receive HPV 16/18 vaccine or aluminium hydroxide control , with an internet-based system . The primary endpoint was vaccine efficacy against 6-month persistent infection or cervical intraepithelial neoplasia grade 1 or greater ( CIN1 + ) associated with HPV 16/18 . We did analyses in the according-to- protocol cohort for efficacy and total vaccinated cohort . Data for the combined primary endpoint in the according-to- protocol cohort for efficacy were considered significant when the lower limit of the 96·2 % CI around the point estimate was greater than 30 % . For all other endpoints and cohorts , data were considered significant when the lower limit of the 96·2 % CI was greater than 0 % . This study is registered with Clinical Trials.gov , number NCT00294047 . FINDINGS The first participant was enrolled on Feb 16 , 2006 , and the last study visit took place on Jan 29 , 2014 . 4407 women were in the according-to- protocol cohort for efficacy ( n=2209 vaccine , n=2198 control ) and 5747 women in the total vaccinated cohort ( n=2877 vaccine , n=2870 control ) . At month 84 , in women seronegative for the corresponding HPV type in the according-to- protocol cohort for efficacy , vaccine efficacy against 6-month persistent infection or CIN1 + associated with HPV 16/18 was significant in all age groups combined ( 90·5 % , 96·2 % CI 78·6 - 96·5 ) . Vaccine efficacy against HPV 16/18-related cytological abnormalities ( atypical squamous cells of undetermined significance and low- grade squamous intraepithelial lesion ) and CIN1 + was also significant . We also noted significant cross-protective efficacy against 6-month persistent infection with HPV 31 ( 65·8 % , 96·2 % CI 24·9 - 85·8 ) and HPV 45 ( 70·7 % , 96·2 % CI 34·2 - 88·4 ) . In the total vaccinated cohort , vaccine efficacy against CIN1 + irrespective of HPV was significant ( 22·9 % , 96·2 % CI 4·8 - 37·7 ) . Serious adverse events related to vaccination occurred in five ( 0·2 % ) of 2877 women in the vaccine group and eight ( 0·3 % ) of 2870 women in the control group . INTERPRETATION In women older than 25 years , the HPV 16/18 vaccine continues to protect against infections , cytological abnormalities , and lesions associated with HPV 16/18 and CIN1 + irrespective of HPV type , and infection with non-vaccine types HPV 31 and HPV 45 over 7 years of follow-up . FUNDING GlaxoSmithKline Biologicals SA [25651922] ABSTRACT We report final event-driven analysis data on the immunogenicity and efficacy of the human papillomavirus 16 and 18 ( ( HPV-16/18 ) AS04-adjuvanted vaccine in young women aged 15 to 25 years from the PApilloma TRIal against Cancer In young Adults ( PATRICIA ) . The total vaccinated cohort ( TVC ) included all r and omized participants who received at least one vaccine dose ( vaccine , n = 9,319 ; control , n = 9,325 ) at months 0 , 1 , and /or 6 . The TVC-naive ( vaccine , n = 5,822 ; control , n = 5,819 ) had no evidence of high-risk HPV infection at baseline , approximating adolescent girls targeted by most HPV vaccination programs . Mean follow-up was approximately 39 months after the first vaccine dose in each cohort . At baseline , 26 % of women in the TVC had evidence of past and /or current HPV-16/18 infection . HPV-16 and HPV-18 antibody titers postvaccination tended to be higher among 15- to 17-year-olds than among 18- to 25-year-olds . In the TVC , vaccine efficacy ( VE ) against cervical intraepithelial neoplasia grade 1 or greater ( CIN1 + ) , CIN2 + , and CIN3 + associated with HPV-16/18 was 55.5 % ( 96.1 % confidence interval [ CI ] , 43.2 , 65.3 ) , 52.8 % ( 37.5 , 64.7 ) , and 33.6 % ( −1.1 , 56.9 ) . VE against CIN1 + , CIN2 + , and CIN3 + irrespective of HPV DNA was 21.7 % ( 10.7 , 31.4 ) , 30.4 % ( 16.4 , 42.1 ) , and 33.4 % ( 9.1 , 51.5 ) and was consistently significant only in 15- to 17-year-old women ( 27.4 % [ 10.8 , 40.9 ] , 41.8 % [ 22.3 , 56.7 ] , and 55.8 % [ 19.2 , 76.9 ] ) . In the TVC-naive , VE against CIN1 + , CIN2 + , and CIN3 + associated with HPV-16/18 was 96.5 % ( 89.0 , 99.4 ) , 98.4 % ( 90.4 , 100 ) , and 100 % ( 64.7 , 100 ) , and irrespective of HPV DNA it was 50.1 % ( 35.9 , 61.4 ) , 70.2 % ( 54.7 , 80.9 ) , and 87.0 % ( 54.9 , 97.7 ) . VE against 12-month persistent infection with HPV-16/18 was 89.9 % ( 84.0 , 94.0 ) , and that against HPV-31/33/45/51 was 49.0 % ( 34.7 , 60.3 ) . In conclusion , vaccinating adolescents before sexual debut has a substantial impact on the overall incidence of high- grade cervical abnormalities , and catch-up vaccination up to 18 years of age is most likely effective . ( This study has been registered at Clinical Trials.gov under registration no. NCT001226810 . [26467666] BACKGROUND Previous Costa Rica Vaccine Trial ( CVT ) reports separately demonstrated vaccine efficacy against HPV16 and HPV18 ( HPV16/18 ) infections at the cervical , anal , and oral regions ; however , the combined overall multisite efficacy ( protection at all three sites ) and vaccine efficacy among women infected with HPV16 or HPV18 prior to vaccination are less known . METHODS Women age 18 to 25 years from the CVT were r and omly assigned to the HPV16/18 vaccine ( Cervarix ) or a hepatitis A vaccine . Cervical , oral , and anal specimens were collected at the four-year follow-up visit from 4186 women . Multisite and single-site vaccine efficacies ( VEs ) and 95 % confidence intervals ( CIs ) were computed for one-time detection of point prevalent HPV16/18 in the cervical , anal , and oral regions four years after vaccination . All statistical tests were two-sided . RESULTS The multisite woman-level vaccine efficacy was highest among " naïve " women ( HPV16/18 seronegative and cervical HPV high-risk DNA negative at vaccination ) ( vaccine efficacy = 83.5 % , 95 % CI = 72.1 % to 90.8 % ) . Multisite woman-level vaccine efficacy was also demonstrated among women with evidence of a pre-enrollment HPV16 or HPV18 infection ( seropositive for HPV16 and /or HPV18 but cervical HPV16/18 DNA negative at vaccination ) ( vaccine efficacy = 57.8 % , 95 % CI = 34.4 % to 73.4 % ) , but not in those with cervical HPV16 and /or HPV18 DNA at vaccination ( anal/oral HPV16/18 VE = 25.3 % , 95 % CI = -40.4 % to 61.1 % ) . Concordant HPV16/18 infections at two or three sites were also less common in HPV16/18-infected women in the HPV vaccine vs control arm ( 7.4 % vs 30.4 % , P < .001 ) . CONCLUSIONS This study found high multisite vaccine efficacy among " naïve " women and also suggests the vaccine may provide protection against HPV16/18 infections at one or more anatomic sites among some women infected with these types prior to HPV16/18 vaccination [25912475] Due to sporadic and not easily accessible cervical cancer screening , human papillomavirus (HPV)-related cervical cancer is a leading cause of cancer death in Sub-Saharan African women . This study was design ed to assess the safety and immunogenicity of a quadrivalent human papillomavirus ( qHPV ) vaccine in sub-Saharan African women . This seven month , double-blind study enrolled 250 healthy , human immunodeficiency virus (HIV)-uninfected females ages 9–26 residing in Ghana , Kenya , and Senegal . Thirty females ages 13–15 and 120 females ages 16–26 received qHPV vaccine . In addition , 100 females ages 9–12 y were r and omized in a 4:1 ratio to receive either qHPV vaccine ( n = 80 ) or placebo ( n = 20 ) . The primary immunogenicity hypothesis was that an acceptable percentage of subjects who received the qHPV vaccine seroconvert to HPV6/11/16/18 at 4 weeks post-dose 3 , defined as the lower bound of the corresponding 95 % confidence interval ( CI ) exceeding 90 % . The primary safety objective was to demonstrate that qHPV vaccine was generally well tolerated when administered in a 3-dose regimen . The pre-specified statistical criterion for the primary immunogenicity hypothesis was met : the lower bound of the 95 % exact binomial CI on the seroconversion rate was at least 98 % for each vaccine HPV type and all subjects seroconverted by 4 weeks post-dose 3 . Across vaccination groups , the most common adverse events ( AE ) were at the injection site , including pain , swelling , and erythema . No subject discontinued study medication due to an AE and no serious AEs were reported . There were no deaths . This study demonstrated that qHPV vaccination of sub-Saharan African women was highly immunogenic and generally well tolerated [25018097] BACKGROUND A community-based r and omized trial was conducted in Costa Rica to evaluate the HPV-16/18 AS04-adjuvanted vaccine ( NCT00128661 ) . The primary objective was to evaluate efficacy of the vaccine to prevent cervical intraepithelial neoplasia 2 or more severe disease ( CIN2 + ) associated with incident HPV-16/18 cervical infections . Secondary objectives were to evaluate efficacy against CIN2 + associated with incident cervical infection by any oncogenic HPVs and to evaluate duration of protection against incident cervical infection with HPV-16/18 . Vaccine safety and immunogenicity over the 4-year follow-up were also evaluated . METHODS We r and omized ( 3727 HPV arm ; 3739 control arm ) , vaccinated ( HPV-16/18 or Hepatitis A ) and followed ( median 53.8 months ) 7466 healthy women aged 18 - 25 years . 5312 women ( 2635 HPV arm ; 2677 control arm ) were included in the according to protocol analysis for efficacy . The full cohort was evaluated for safety . Immunogenicity was considered on a subset of 354 ( HPV-16 ) and 379 ( HPV-18 ) women . HPV type was assessed by PCR on cervical specimens . Immunogenicity was assessed using ELISA and inhibition enzyme immunoassays . Disease outcomes were histologically confirmed . Vaccine efficacy and 95 % confidence intervals ( 95%CI ) were computed . RESULTS Vaccine efficacy was 89.8 % ( 95 % CI : 39.5 - 99.5 ; N=11 events total ) against HPV-16/18 associated CIN2 + , 59.9 % ( 95 % CI : 20.7 - 80.8 ; N=39 events total ) against CIN2 + associated with non-HPV-16/18 oncogenic HPVs and 61.4 % ( 95 % CI : 29.5 - 79.8 ; N=51 events total ) against CIN2 + irrespective of HPV type . The vaccine had an acceptable safety profile and induced robust and long-lasting antibody responses . CONCLUSIONS Our findings confirm the high efficacy and immunogenicity of the HPV-16/18 vaccine against incident HPV infections and cervical disease associated with HPV-16/18 and other oncogenic HPV types . These results will serve as a benchmark to which we can compare future findings from the ongoing extended follow-up of participants in the Costa Rica trial . TRIAL REGISTRATION Registered with clinical trials.gov : NCT00128661 [21288094] BACKGROUND Infection with human papillomavirus ( HPV ) and diseases caused by HPV are common in boys and men . We report on the safety of a quadrivalent vaccine ( active against HPV types 6 , 11 , 16 , and 18 ) and on its efficacy in preventing the development of external genital lesions and anogenital HPV infection in boys and men . METHODS We enrolled 4065 healthy boys and men 16 to 26 years of age , from 18 countries in a r and omized , placebo-controlled , double-blind trial . The primary efficacy objective was to show that the quadrivalent HPV vaccine reduced the incidence of external genital lesions related to HPV-6 , 11 , 16 , or 18 . Efficacy analyses were conducted in a per- protocol population , in which subjects received all three vaccinations and were negative for relevant HPV types at enrollment , and in an intention-to-treat population , in which subjects received vaccine or placebo , regardless of baseline HPV status . RESULTS In the intention-to-treat population , 36 external genital lesions were seen in the vaccine group as compared with 89 in the placebo group , for an observed efficacy of 60.2 % ( 95 % confidence interval [ CI ] , 40.8 to 73.8 ) ; the efficacy was 65.5 % ( 95 % CI , 45.8 to 78.6 ) for lesions related to HPV-6 , 11 , 16 , or 18 . In the per- protocol population , efficacy against lesions related to HPV-6 , 11 , 16 , or 18 was 90.4 % ( 95 % CI , 69.2 to 98.1 ) . Efficacy with respect to persistent infection with HPV-6 , 11 , 16 , or 18 and detection of related DNA at any time was 47.8 % ( 95 % CI , 36.0 to 57.6 ) and 27.1 % ( 95 % CI , 16.6 to 36.3 ) , respectively , in the intention-to-treat population and 85.6 % ( 97.5 % CI , 73.4 to 92.9 ) and 44.7 % ( 95 % CI , 31.5 to 55.6 ) in the per- protocol population . Injection-site pain was significantly more frequent among subjects receiving quadrivalent HPV vaccine than among those receiving placebo ( 57 % vs. 51 % , P<0.001 ) . CONCLUSIONS Quadrivalent HPV vaccine prevents infection with HPV-6 , 11 , 16 , and 18 and the development of related external genital lesions in males 16 to 26 years of age . ( Funded by Merck and others ; Clinical Trials.gov number , NCT00090285 . ) [2360730] Human papillomavirus ( HPV ) causes cervical , vulvar , and vaginal cancers , precancerous dysplasia , and genital warts . We report data for the longest efficacy evaluation to date of a prophylactic HPV vaccine . In total , 552 women ( 16–23 years ) were enrolled in a r and omised , placebo-controlled study of a quadrivalent HPV 6/11/16/18 L1 virus-like-particle vaccine with vaccination at months 0 , 2 , and 6 . At regular intervals through 3 years , subjects underwent gynaecologic examination , cervicovaginal sampling for HPV DNA , serum anti-HPV testing , and Pap testing , with follow-up biopsy as indicated . A subset of 241 subjects underwent two further years of follow-up . At 5 years post enrolment , the combined incidence of HPV 6/11/16/18-related persistent infection or disease was reduced in vaccine-recipients by 96 % ( two cases vaccine versus 46 placebo ) . There were no cases of HPV 6/11/16/18-related precancerous cervical dysplasia or genital warts in vaccine recipients , and six cases in placebo recipients ( efficacy=100 % ; 95 % CI:12–100 % ) . Through 5 years , vaccine-induced anti-HPV geometric mean titres remained at or above those following natural infection . In conclusion , a prophylactic quadrivalent HPV vaccine was effective through 5 years for prevention of persistent infection and disease caused by HPV 6/11/16/18 . This duration supports vaccination of adolescents and young adults , which is expected to greatly reduce the burden of cervical and genital cancers , precancerous dysplasia , and genital warts [2908791] The human papillomavirus (HPV)-16/18 AS04-adjuvanted cervical cancer vaccine has been demonstrated to be highly efficacious and immunogenic with a favorable safety profile . This study assessed the immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine in healthy Korean girls aged 10 - 14 yr . This multi-center , observer-blind trial r and omly assigned 321 healthy girls to receive three doses ( 0 , 1 , 6-month schedule ) of HPV-16/18 AS04-adjuvanted vaccine or hepatitis A vaccine . Immunogenicity against vaccine antigens was assessed one month post-Dose 3 . Solicited and unsolicited adverse events ( AEs ) and serious AEs ( SAEs ) were recorded . In the according-to- protocol analysis , all initially seronegative subjects vaccinated with the HPV-16/18 AS04-adjuvanted vaccine had seroconverted at Month 7 , with a peak geometric mean titer ( GMT ) that was 600-fold higher than the natural infection titer of 29.8 EU/mL for HPV-16 and a peak GMT that was 400-fold higher than the natural infection titer of 22.6 EU/mL for HPV-18 . The vaccine was well tolerated with no increase in reactogenicity with subsequent doses and no reports of vaccine-related SAEs . In conclusion , the HPV-16/18 AS04-adjuvanted vaccine is shown to be highly immunogenic and generally well-tolerated in Korean girls aged 10 - 14 yr [5215585] ABSTRACT This community-r and omized controlled trial was initiated to assess the overall and herd effects of 2 different human papillomavirus ( HPV ) immunization strategies in over 80,000 girls and boys aged 12–15 y in 33 communities in Finl and ( Clinical Trials.gov NCT00534638 ) . Overall , 14,838 adolescents received HPV-16/18 vaccine ( 2,440 boys and 12,398 girls ) and 17,338 received hepatitis-B virus ( HBV ) vaccine ( 9,221 boys and 8,117 girls ) . In an interim analysis , vaccine safety was assessed by active monitoring and surveillance via health registry linkage . Active monitoring showed that the HPV-16/18 vaccine has acceptable safety and reactogenicity in boys . In all study participants , the observed incidences ( per 100,000 person-years ) of serious adverse events ( SAEs ) possibly related to vaccination were 54.3 ( 95 % Confidence Interval [ CI ] : 34.0–82.1 ) in the HPV-16/18 group and 64.0 ( 95 % CI : 43.2–91.3 ) in the HBV group . During the follow-up period for this interim analysis , the most common new-onset autoimmune diseases ( NOADs ; with incidence rate ≥15 per 100,000 ) in any group based on hospital discharge registry ( HILMO ) download were ulcerative colitis , juvenile arthritis , celiac disease , insulin-dependent diabetes mellitus ( IDDM ) and Crohn 's disease . No increased NOAD incidences were observed in HPV-16/18 vaccine recipients compared to HBV vaccine recipients . In both the SAE possibly related- and HILMO-analyses , a lower incidence of IDDM was observed in HPV-16/18 vaccinees compared to HBV vaccinees ( relative risks , 0.26 [ 95 % CI : 0.03–1.24 ] and 0.16 [ 95 % CI : 0.03–0.55 ] , respectively ) [4896780] HPV-023 ( NCT00518336 ; Clinical Trial.gov ) is a long-term follow-up of an initial double-blind , r and omized ( 1:1 ) , placebo-controlled study ( HPV-001 , NCT00689741 ) evaluating the efficacy against human papillomavirus (HPV)-16/18 infection and associated cyto-histopathological abnormalities , persistence of immunogenicity , and safety of the HPV-16/18 AS04-adjuvanted vaccine . Among the women , aged 15–25 years , enrolled in HPV-001 and who participated in the follow-up study HPV-007 ( NCT00120848 ) , a subset of 437 women from five Brazilian centers participated in this 36-month long-term follow-up ( HPV-023 ) for a total of 113 months ( 9.4 years ) . During HPV-023 , anti-HPV-16/18 antibodies were measured annually by enzyme-linked immunosorbent assay ( ELISA ) and pseudovirion-based neutralisation assay ( PBNA ) . Cervical sample s were tested for HPV DNA every 6 months , and cyto-pathological examinations were performed annually . During HPV-023 , no new HPV-16/18-associated infections and cyto-histopathological abnormalities occurred in the vaccine group . Vaccine efficacy ( VE ) against HPV-16/18 incident infection was 100 % ( 95%CI : 66.1 , 100 ) . Over the 113 months ( 9.4 years ) , VE was 95.6 % ( 86.2 , 99.1 ; 3/50 cases in vaccine and placebo groups , respectively ) against incident infection , 100 % ( 84·1 , 100 ; 0/21 ) against 6-month persistent infection ( PI ) ; 100 % ( 61·4 , 100 ; 0/10 ) against 12-month PI ; 97·1 % ( 82.5 , 99.9 ; 1/30 ) against ≥ ASC-US ; 95·0 % ( 68.0 , 99.9 ; 1/18 ) against ≥ LSIL ; 100 % ( 45.2 , 100 ; 0/8 ) against CIN1 + ; and 100 % ( –128.1 , 100 ; 0/3 ) against CIN2 + associated with HPV-16/18 . All vaccinees remained seropositive to HPV-16/18 , with antibody titers remaining several folds above natural infection levels , as measured by ELISA and PBNA . There were no safety concerns . To date , these data represent the longest follow-up reported for a licensed HPV vaccine [17499406] BACKGROUND The duration of protection afforded by vaccines represents a critical test of their utility as public health interventions . Some vaccines induce long-term immunity , while others require booster doses . Vaccines that induce long-term protection are usually characterized by the generation of immune memory . Recent trials of a quadrivalent ( types 6 , 11 , 16 , 18 ) human papillomavirus ( HPV ) vaccine have demonstrated high efficacy through 5 years of follow-up . We evaluated the extent to which the vaccine is able to generate HPV type-specific immune memory . METHODS A total of 552 , 16 - 23-year-old women were enrolled in a double-blind , placebo-controlled study . At enrollment , subjects were r and omized in a 1:1 ratio to receive three-dose regimens of quadrivalent HPV vaccine or placebo with 3 years ' follow-up . A subset of 241 subjects ( n=114 in the quadrivalent HPV vaccine group and n=127 in the placebo group ) underwent 2 further years of follow-up . All extension subjects received quadrivalent HPV vaccine at month 60 to examine the extent of immune memory in response to the primary vaccination series . RESULTS Serum anti-HPV levels declined post-vaccination , but reached a plateau at month 24 that remained stable through month 60 . Administration of a challenge dose of vaccine induced a classic anamnestic response , with anti-HPV levels 1 week post-challenge reaching levels observed 1 month following the completion of the three-dose primary series . At 1 month post-challenge , anti-HPV responses were higher than those observed 1-month post-dose 3 . DISCUSSION A three-dose regimen of quadrivalent HPV vaccine induces high efficacy and stable anti-HPV levels for at least 5 years . Vaccination also induces robust immune memory . These findings suggest that the efficacy of this vaccine will be long lasting [4277330] This phase II/III , double-blind , r and omized trial assessed the efficacy , immunogenicity and safety of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in young Chinese women ( Clinical Trials.gov registration NCT00779766 ) . Women aged 18–25 years from Jiangsu province were r and omized ( 1:1 ) to receive HPV vaccine ( n = 3,026 ) or Al(OH)3 control ( n = 3,025 ) at months 0 , 1 and 6 . The primary objective was vaccine efficacy ( VE ) against HPV-16/18 associated 6-month persistent infection ( PI ) and /or cervical intraepithelial neoplasia ( CIN ) 1 + . Secondary objectives were VE against virological and clinical endpoints associated with HPV-16/18 and with high-risk HPV types , immunogenicity and safety . Mean follow-up for the according-to- protocol cohort for efficacy ( ATP-E ) was ∼15 months after the third dose . In the ATP-E ( vaccine = 2,889 ; control = 2,894 ) , for initially HPV DNA negative and seronegative subjects , HPV-16/18 related VE ( 95 % CI ) was 94.2 % ( 62.7 , 99.9 ) against 6-month PI and /or CIN1 + and 93.8 % ( 60.2 , 99.9 ) against cytological abnormalities . VE against HPV-16/18 associated CIN1 + and CIN2 + was 100 % ( −50.4 , 100 ) and 100 % ( −140.2 , 100 ) , respectively ( no cases in the vaccine group and 4 CIN1 + and 3 CIN2 + cases in the control group ) . At Month 7 , at least 99.7 % of initially seronegative vaccine recipients had seroconverted for HPV-16/18 ; geometric mean antibody titres ( 95 % CI ) were 6,996 ( 6,212 to 7,880 ) EU/mL for anti-HPV-16 and 3,309 ( 2,942 to 3,723 ) EU/mL for anti-HPV-18 . Safety outcomes between groups were generally similar . The HPV-16/18 AS04-adjuvanted vaccine is effective , immunogenic and has a clinical ly acceptable safety profile in young Chinese women . Prophylactic HPV vaccination has the potential to substantially reduce the burden of cervical cancer in China . What 's New ? With an estimated 75,000 new cases and 34,000 women dying from the disease annually , cervical cancer is a major public-health concern in China . This is the first large scale r and omised clinical trial of a human papillomavirus ( HPV ) vaccine in China . The vaccine was found to be effective , immunogenic , and to have a clinical ly acceptable safety profile in young Chinese women . Prophylactic HPV vaccination thus has the potential to substantially reduce the burden of cervical cancers and precancers in China [16631880] BACKGROUND Effective vaccination against HPV 16 and HPV 18 to prevent cervical cancer will require a high level of sustained protection against infection and precancerous lesions . Our aim was to assess the long-term efficacy , immunogenicity , and safety of a bivalent HPV-16/18 L1 virus-like particle AS04 vaccine against incident and persistent infection with HPV 16 and HPV 18 and their associated cytological and histological outcomes . METHODS We did a follow-up study of our multicentre , double-blind , r and omised , placebo-controlled trial reported in 2004 . We included women who originally received all three doses of bivalent HPV-16/18 virus-like particle AS04 vaccine ( 0.5 mL ; n=393 ) or placebo ( n=383 ) . We assessed HPV DNA , using cervical sample s , and did yearly cervical cytology assessment s. We also studied the long-term immunogenicity and safety of the vaccine . FINDINGS More than 98 % seropositivity was maintained for HPV-16/18 antibodies during the extended follow-up phase . We noted significant vaccine efficacy against HPV-16 and HPV-18 endpoints : incident infection , 96.9 % ( 95 % CI 81.3 - 99.9 ) ; persistent infection : 6 month definition , 94.3 ( 63.2 - 99.9 ) ; 12 month definition , 100 % ( 33.6 - 100 ) . In a combined analysis of the initial efficacy and extended follow-up studies , vaccine efficacy of 100 % ( 42.4 - 100 ) against cervical intraepithelial neoplasia ( CIN ) lesions associated with vaccine types . We noted broad protection against cytohistological outcomes beyond that anticipated for HPV 16/18 and protection against incident infection with HPV 45 and HPV 31 . The vaccine has a good long-term safety profile . INTERPRETATION Up to 4.5 years , the HPV-16/18 L1 virus-like particle AS04 vaccine is highly immunogenic and safe , and induces a high degree of protection against HPV-16/18 infection and associated cervical lesions . There is also evidence of cross protection [22586631] Target groups for human papillomavirus ( HPV ) vaccination are controversial . We evaluated vaccine efficacy ( VE ) against 1-year persistent infection , stratified by age and sexual behavior , among young women in Costa Rica . We r and omized 7,466 healthy women 18 to 25 years of age to HPV16/18 or hepatitis A vaccine ( follow-up , 50.4 months ) . According-to- protocol ( ATP ) cohorts included compliant HPV-negative women ; intention-to-treat ( ITT ) included all r and omized women . ATP VE was 90.9 % ( 95 % CI , 82.0 - 95.9 ) against HPV16/18 infections , 44.5 % against HPV31/33/45 ( 95 % CI , 17.5 - 63.1 ) , and 12.4 % ( 95 % CI , -3.2 to 25.6 ) against any oncogenic infection . Overall ITT VE against HPV16/18 infections was 49.0 % , but ATP and ITT VE almost reached 100 % in year 4 of follow-up . ATP efficacy against HPV16/18 was similar by age , but ITT VE was greatest among youngest women ( 68.9 % among those 18 - 19 years of age ; 21.8 % among those 24 - 25 years of age ) and 79.8 % among virgins . Among previously unexposed women , vaccination is highly efficacious against HPV16/18 and partially against HPV31/33/45 . Vaccination is most effective in women and girls before they initiate sexual activity , with programmatic and individual decision implication [21858807] In the Phase III PATRICIA study ( NCT00122681 ) , the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine ( Cervarix ( ® ) , GlaxoSmithKline Biologicals ) was highly efficacious against HPV-16/18 infections and precancerous lesions in women HPV-16/18 deoxyribose nucleic acid ( DNA ) negative and seronegative at baseline . We present further data on vaccine efficacy ( VE ) against HPV-16/18 in the total vaccinated cohort including women who may have been exposed to HPV-16/18 infection before vaccination . In women with no evidence of current or previous HPV-16/18 infection ( DNA negative and seronegative ) , VE was 90.3 % ( 96.1 % confidence interval : 87.3 - 92.6 ) against 6-month persistent infection ( PI ) , 91.9 % ( 84.6 - 96.2 ) against cervical intraepithelial neoplasia (CIN)1 + and 94.6 % ( 86.3 - 98.4 ) against CIN2 + [ 97.7 % ( 91.1 - 99.8 ) when using the HPV type assignment algorithm ( TAA ) ] . In women HPV-16/18 DNA negative but with serological evidence of previous HPV-16/18 infection ( seropositive ) , VE was 72.3 % ( 53.0 - 84.5 ) against 6-month PI , 67.2 % ( 10.9 - 89.9 ) against CIN1 + , and 68.8 % ( -28.3 - 95.0 ) against CIN2 + [ 88.5 % ( 10.8 - 99.8 ) when using TAA ] . In women with no evidence of current HPV-16/18 infection ( DNA negative ) , regardless of their baseline HPV-16/18 serological status , VE was 88.7 % ( 85.7 - 91.1 ) against 6-month PI , 89.1 % ( 81.6 - 94.0 ) against CIN1 + and 92.4 % ( 84.0 - 97.0 ) against CIN2 + [ 97.0 % ( 90.6 - 99.5 ) when using TAA ] . In women who were DNA positive for one vaccine type , the vaccine was efficacious against the other vaccine type . The vaccine did not impact the outcome of HPV-16/18 infections present at the time of vaccination . Vaccination was generally well tolerated regardless of the woman 's HPV-16/18 DNA or serological status at entry [19684472] This observer-blind study compared the prophylactic human papillomavirus ( HPV ) vaccines , Cervarix ™ ( GlaxoSmithKline ) and Gardasil ® ( Merck ) , by assessing immunogenicity and safety through one month after completion of the three-dose vaccination course . Women ( n=1106 ) were stratified by age ( 18–26 , 27–35 , 36–45 years ) and r and omized ( 1:1 ) to receive Cervarix ™ ( Months 0 , 1 , 6 ) or Gardasil ® ( Months 0 , 2 , 6 ) . At Month 7 after first vaccination , all women in the according-to- protocol cohort who were seronegative/DNA negative before vaccination for the HPV type analyzed had seroconverted for HPV-16 and HPV-18 serum neutralizing antibodies , as measured by pseudovirion-based neutralization assay ( PBNA ) , except for two women aged 27–35 years in the Gardasil ® group who did not seroconvert for HPV-18 ( 98 % ) . Geometric mean titers of serum neutralizing antibodies ranged from 2.3–4.8-fold higher for HPV-16 and 6.8–9.1-fold higher for HPV-18 after vaccination with Cervarix ™ compared with Gardasil ® , across all age strata . In the total vaccinated cohort ( all women who received at least one vaccine dose , regardless of their serological and DNA status prior to vaccination ) , Cervarix ™ induced significantly higher serum neutralizing antibody titers in all age strata ( [26090572] Background : A 9-valent human papillomavirus ( 9vHPV ) vaccine has been developed to prevent infections and diseases related to HPV 6/11/16/18 [ as per the licensed quadrivalent HPV ( qHPV ) vaccine ] , as well as 5 additional oncogenic HPV types ( HPV 31/33/45/52/58 ) . Compared with the qHPV vaccine , the 9vHPV vaccine potentially increases the coverage of protection from 70 % to 90 % of cervical cancers . We compared the immunogenicity and safety of the 9vHPV vaccine versus the qHPV vaccine in 9–15-year-old girls . Methods : Participants ( n = 600 ) were r and omized to receive 9vHPV or qHPV vaccines on day 1 , month 2 and month 6 . Serology testing was performed on day 1 and month 7 . HPV type-specific antibody titers ( anti-HPV 6/11/16/18/31/33/45/52/58 ) were determined by competitive Luminex immunoassay and expressed as geometric mean titers and seroconversion rates . Vaccine safety was also assessed . Results : The HPV 6/11/16/18 immune responses elicited by the 9vHPV vaccine were comparable with those elicited by the qHPV vaccine . All participants ( except 1 for HPV 45 ) receiving the 9vHPV vaccine seroconverted for HPV 31/33/45/52/58 . The 9vHPV and qHPV vaccines showed comparable safety profiles , although the incidence of injection-site swelling was higher in the 9vHPV vaccine group . Conclusions : In addition to immune responses to HPV 31/33/45/52/58 , a 3-dose regimen of the 9vHPV vaccine elicited a similar immune response to HPV 6/11/16/18 when compared with the qHPV vaccine in girls aged 9–15 years . The safety profile was also similar for the 2 vaccines [24273179] BACKGROUND We compared the immunogenicity and reactogenicity of Cervarix or Gardasil human papillomavirus ( HPV ) vaccines in adults infected with the human immunodeficiency virus ( HIV ) . METHODS This was a double-blind , controlled trial r and omizing HIV-positive adults to receive 3 doses of Cervarix or Gardasil at 0 , 1.5 , and 6 months . Immunogenicity was evaluated for up to 12 months . Neutralizing anti-HPV-16/18 antibodies were measured by pseudovirion-based neutralization assay . Laboratory tests and diary cards were used for safety assessment . The HPV-DNA status of the participants was determined before and after immunization . RESULTS Ninety-two participants were included in the study . Anti-HPV-18 antibody titers were higher in the Cervarix group compared with the Gardasil group at 7 and 12 months . No significant differences in anti-HPV-16 antibody titers were found among vaccine groups . Among Cervarix vaccinees , women had higher anti-HPV-16/18 antibody titers compared to men . No sex-specific differences in antibody titers were found in the Gardasil group . Mild injection site reactions were more common in the Cervarix group than in the Gardasil group ( 91.1 % vs 69.6 % ; P = .02 ) . No serious adverse events occurred . CONCLUSIONS Both vaccines were immunogenic and well tolerated . Compared with Gardasil , Cervarix induced superior vaccine responses among HIV-infected women , whereas in HIV-infected men the difference in immunogenicity was less pronounced [21712645] Prophylactic vaccination with a quadrivalent HPV ( types 6 , 11 , 16 , 18 ) vaccine ( qHPV ) has been shown to prevent infection with HPV 6/11/16/18 and associated disease in women and more recently , in men . Here we report on the safety and reactogenicity of the qHPV vaccine in males . A total of 4,065 healthy males aged 16 - 26 years were enrolled into a r and omized , placebo-controlled , double-blind trial . Subjects were r and omized 1:1 to receive qHPV vaccine or placebo at day 1 , month 2 , and month 6 . Safety and tolerability were assessed via the collection of reported adverse experiences ( AEs ) . All serious AEs ( vaccine- or procedure-related or not ) and all deaths occurring during the study were recorded . Safety analyses were conducted in all subjects who received at least one dose of vaccine or placebo . The proportion of subjects who reported at least one injection-site AE was higher in the qHPV vaccine group versus the placebo group ( 60.1 % vs 53.7 % , respectively ) , however most of these AEs were mild/moderate in intensity . The incidence of at least one systemic AE was comparable between the vaccine and placebo groups ( 31.7 % vs 31.4 % , respectively ) . There were no vaccine-related serious AEs or deaths . The occurrence of AEs did not increase with each successive injection , and among trial participants who were seropositive for at least one vaccine HPV type at enrollment , the profile of adverse events was similar to that of the entire study cohort . The qHPV vaccine was generally well tolerated in males aged 16 - 26 years and had a favorable safety profile [20413076] PURPOSE Immunization of girls against oncogenic human papillomavirus ( HPV ) types before sexual debut is important for cervical cancer prevention . This phase III blinded , r and omized , controlled trial in adolescent girls assessed safety of the HPV-16/18 AS04-adjuvanted vaccine . METHODS Girls ( mean age 12 years ) in 12 countries received the HPV-16/18 L1 virus-like particle AS04-adjuvanted vaccine ( N = 1,035 ) or hepatitis A virus vaccine as control ( N = 1,032 ) at 0 , 1 , and 6 months . The primary objective was to compare the occurrence of serious adverse events ( SAEs ) between groups . HPV-16 and HPV-18 antibody titers were assessed by enzyme-linked immunosorbent assay post-vaccination . RESULTS Up to study month 7 , 11 girls in the HPV-16/18 vaccine group reported 14 SAEs and 13 girls in the control group reported 15 SAEs . The difference in SAE incidence between groups was .20 % ( 95 % CI , -.78 , 1.20 ) . No SAE in the HPV-16/18 vaccine group was considered related to vaccination or led to withdrawal . The incidence of solicited local and general symptoms up to 7 days post-vaccination was moderately higher with the HPV-16/18 vaccine than with control . The incidence of unsolicited symptoms , new onset of chronic diseases , and medically significant conditions was similar between groups . All girls seroconverted for both antigens after three doses of the HPV-16/18 vaccine ; geometric mean titers were 19,882.0 and 8,262.0 EU/mL for anti-HPV-16 and -18 antibodies , respectively , in initially seronegative girls . CONCLUSIONS The HPV-16/18 AS04-adjuvanted vaccine was generally well tolerated and immunogenic when administered to young adolescent females , the primary target of organized vaccination programs [3714284] Background Human papillomavirus ( HPV ) infection , particularly with type 16 , causes a growing fraction of oropharyngeal cancers , whose incidence is increasing , mainly in developed countries . In a double-blind controlled trial conducted to investigate vaccine efficacy ( VE ) of the bivalent HPV 16/18 vaccine against cervical infections and lesions , we estimated VE against prevalent oral HPV infections 4 years after vaccination . Methods and Findings A total of 7,466 women 18–25 years old were r and omized ( 1∶1 ) to receive the HPV16/18 vaccine or hepatitis A vaccine as control . At the final blinded 4-year study visit , 5,840 participants provided oral specimens ( 91·9 % of eligible women ) to evaluate VE against oral infections . Our primary analysis evaluated prevalent oral HPV infection among all vaccinated women with oral and cervical HPV results . Corresponding VE against prevalent cervical HPV16/18 infection was calculated for comparison . Oral prevalence of identifiable mucosal HPV was relatively low ( 1·7 % ) . Approximately four years after vaccination , there were 15 prevalent HPV16/18 infections in the control group and one in the vaccine group , for an estimated VE of 93·3 % ( 95 % CI = 63 % to 100 % ) . Corresponding efficacy against prevalent cervical HPV16/18 infection for the same cohort at the same visit was 72·0 % ( 95 % CI = 63 % to 79 % ) ( p versus oral VE = 0·04 ) . There was no statistically significant protection against other oral HPV infections , though power was limited for these analyses . Conclusions HPV prevalence four years after vaccination with the ASO4-adjuvanted HPV16/18 vaccine was much lower among women in the vaccine arm compared to the control arm , suggesting that the vaccine affords strong protection against oral HPV16/18 infection , with potentially important implication s for prevention of increasingly common HPV-associated oropharyngeal cancer . Clinical Trials.gov , Registry number [20606533] Background : Human papillomavirus ( HPV ) type 16/18 AS04-adjuvanted vaccine was shown to be highly immunogenic and generally well tolerated in the interim analysis of a phase 2 double-blind , r and omized controlled multicenter study in Japanese healthy women aged 20 to 25 years . Vaccine efficacy , immunogenicity , and safety are assessed in this study through 24 months after the first vaccination . Methods : Japanese women aged 20 to 25 years were r and omly assigned to receive either HPV-16/18 AS04-adjuvanted vaccine ( n = 519 ) or hepatitis A vaccine ( n = 521 ) at 0 , 1 , and 6 months . Women were assessed for virological , cytological , and histological end points associated with HPV-16/18 and 12 other oncogenic HPV types ( types 31 , 33 , 35 , 39 , 45 , 51 , 52 , 56 , 58 , 59 , 66 , and 68 ) in cervical specimens and for the vaccine safety and immunogenicity . Antibody concentrations were measured by an enzyme-linked immunosorbent assay . Primary efficacy analysis was performed in the according-to- protocol cohort for efficacy , primary immunogenicity analysis was performed in the according-to- protocol cohort for immunogenicity , and primary safety analysis was done in the total vaccinated cohort . Results : Vaccine efficacy against persistent infections ( 6 month definition ) associated with HPV-16/18 was 100 % ( 95.5 % confidence interval , 71.3 - 100 ; P < 0.0001 ) . Vaccine efficacy against cervical intraepithelial neoplasia 1 + associated with 14 oncogenic HPV types was 64.9 % ( 95.5 % confidence interval , 4.9 - 89.0 ; P = 0.02 ) . At 24 months after the first dose of the vaccine , geometric mean antibody titers against HPV-16 and HPV-18 were 1521.5 enzyme-linked immunosorbent assay U/mL and 627.4 enzyme-linked immunosorbent assay U/mL , respectively . The HPV-16/18 AS04-adjuvanted vaccine had a clinical ly acceptable safety profile . Conclusions : The HPV-16/18 AS04-adjuvanted vaccine showed excellent prophylactic efficacy against 6-month persistent infection with HPV-16/18 . The HPV-16/18 AS04-adjuvanted vaccine was generally well tolerated and immunogenic in the study population of healthy Japanese women aged 20 to 25 years [18164106] Adolescents and young adults are at high risk for human papillomavirus ( HPV ) and hepatitis B virus ( HBV ) infections , which are preventable by currently available , safe and effective , prophylactic vaccines . However , development of a combined immunization strategy may lead to better compliance for these vaccines , thereby contributing to the overall goal of protection against these diseases . This study assessed the safety and immunogenicity of co-administered quadrivalent HPV-6/11/16/18 L1 VLP and HBV vaccines in women ( n=1877 ) aged 16 - 23 years . Co-administration of HPV and HBV vaccines induced robust anti-HPV-6 , HPV-11 , HPV-16 , HPV-18 geometric mean titers ( GMTs ) and > or = 99 % seroconversion rates ( Month 7 ) that were both non-inferior ( p<0.001 ) to those induced by HPV vaccine alone . High Month 7 anti-HBs GMTs were also observed following concomitant vaccination . These GMTs were lower compared to those induced by the HBV vaccine itself ; however , > 96 % of subjects achieved an anti-HBs seroprotection level of > or = 10 mIU/mL that was non-inferior ( p<0.001 ) to that of HBV vaccine alone . Overall , co-administered and individual vaccines were generally well-tolerated and did not interfere with the immune response of either vaccine ( Clinical Trials.gov number , NCT00092521 ) [17484215] Objective : Administration of a quadrivalent HPV-6/11/16/18 vaccine to 16- to 26-year-old women was highly effective in preventing HPV-6/11/16/18-related cervical/vulvar/vaginal precancerous lesions and genital warts . As the risk of acquiring HPV significantly rises after sexual debut , HPV vaccines should have the greatest benefit in sexually naive adolescents . We evaluated the tolerability and immunogenicity of quadrivalent vaccine in males and females 9 to 15 years of age through 18 months postenrollment . Methods : In this r and omized , double-blind trial , 1781 sexually naive children were assigned ( 2:1 ) to quadrivalent HPV-6/11/16/18 vaccine or saline placebo administered at day 1 and months 2 and 6 . Serum neutralizing anti-HPV-6/11/16/18 responses were summarized as geometric mean titers ( GMTs ) and seroconversion rates . Primary analyses were done per- protocol ( subjects received 3 doses , had no major protocol violations and were HPV type-specific seronegative at day 1 ) . Adverse experiences were collected by diary card . Results : At month 7 , seroconversion rates were ≥99.5 % for the 4 vaccine-HPV-types . GMTs and seroconversion rates in boys were noninferior to those in girls ( P < 0.001 ) . At month 18 , ≥91.5 % of vaccine recipients were seropositive , regardless of gender . A higher proportion of vaccine recipients ( 75.3 % ) than placebo recipients ( 50.0 % ) reported one or more injection-site adverse experiences following any vaccination . Rates of fever were similar between vaccination groups . No serious vaccine-related adverse experiences were reported . Conclusions : In 9- to 15-year-old adolescents , the quadrivalent vaccine was generally well tolerated and induced persistent anti-HPV serologic responses in the majority of subjects for at least 12 months following completion of a three-dose regimen . The vaccine durability supports universal HPV vaccination programs in adolescents to reduce the burden of clinical HPV disease , particularly cervical cancer and precancers [4186043] In this open , extended follow-up study ( NCT00929526 , Clinical trials.gov ) , we evaluated the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine efficacy , immunogenicity and safety up to 4 years after first vaccination in Japanese women aged 20–25 years . In the initial r and omized , double-blind study ( NCT00316693 ) , 1040 women received the study vaccine or hepatitis A control vaccine ; 752 women were included in the follow-up study . In women from the according-to- protocol efficacy cohort ( ATP-E ) , who were initially seronegative for the HPV type analyzed , no cervical intraepithelial neoplasia ( CIN ) grade 1 or greater ( CIN1 + ) cases associated with HPV-16/18 were reported in the HPV group , while in the control group , 5 cases were identified in extended follow-up analyses ( vaccine efficacy [ VE ] 100 % [ 95 % CI : −3.7–100 ] ) and 8 cases in combined initial and follow-up studies analyses ( VE 100 % [ 42.2–100 ] ) . In the ATP-E , VE against CIN1 + and CIN2 + associated with high-risk HPV types reached 66.4 % ( 21.6–87.1 ) and 83.0 % ( 22.1–98.2 ) in extended follow-up analyses , and 63.4 % ( 28.8–82.3 ) and 77.3 % ( 30.4–94.4 ) in analyses of combined studies , respectively . During the 4-year period , protection against CIN1 + and CIN2 + , irrespective of the HPV type , was 56.7 % ( 32.8–72.6 ) and 54.9 % ( 20.5–75.3 ) in women receiving ≥1 vaccine dose , regardless of baseline serostatus ( total vaccinated cohort [ TVC ] ) and 61.0 % ( 11.8–84.2 ) and 73.9 % ( 1.1–95.3 ) in women naïve to HPV infection at baseline ( TVC-naïve ) , respectively . The high VE observed in Japanese women , accompanied by a sustained immune response and a clinical ly acceptable safety profile , support findings of large , international trials [15863374] BACKGROUND A r and omised double-blind placebo-controlled phase II study was done to assess the efficacy of a prophylactic quadrivalent vaccine targeting the human papillomavirus ( HPV ) types associated with 70 % of cervical cancers ( types 16 and 18 ) and with 90 % of genital warts ( types 6 and 11 ) . METHODS 277 young women ( mean age 20.2 years [ SD 1.7 ] ) were r and omly assigned to quadrivalent HPV ( 20 microg type 6 , 40 microg type 11 , 40 microg type 16 , and 20 microg type 18 ) L1 virus-like-particle ( VLP ) vaccine and 275 ( mean age 20.0 years [ 1.7 ] ) to one of two placebo preparations at day 1 , month 2 , and month 6 . For 36 months , participants underwent regular gynaecological examinations , cervicovaginal sampling for HPV DNA , testing for serum antibodies to HPV , and Pap testing . The primary endpoint was the combined incidence of infection with HPV 6 , 11 , 16 , or 18 , or cervical or external genital disease ( ie , persistent HPV infection , HPV detection at the last recorded visit , cervical intraepithelial neoplasia , cervical cancer , or external genital lesions caused by the HPV types in the vaccine ) . Main analyses were done per protocol . FINDINGS Combined incidence of persistent infection or disease with HPV 6 , 11 , 16 , or 18 fell by 90 % ( 95 % CI 71 - 97 , p<0.0001 ) in those assigned vaccine compared with those assigned placebo . INTERPRETATION A vaccine targeting HPV types 6 , 11 , 16 , 18 could substantially reduce the acquisition of infection and clinical disease caused by common HPV types [17986242] Human papillomavirus ( HPV ) is a major causative agent of anogenital warts and a necessary cause of cervical cancer . This report will serve to assess the safety and immunogenicity of quadrivalent ( types 6 , 11 , 16 , and 18 ) HPV L1 virus-like particle ( VLP ) vaccine in the Korean population . We performed a r and omized , double-blind , placebo-controlled study in 176 volunteers aged 9–23 years . Using a 2:1 ratio for r and omization , 117 women were assigned to quadrivalent HPV ( 20 μg type 6 , 40 μg type 11 , 40 μg type 16 , and 20 μg type 18 ) vaccine and 59 women to placebo . Individuals received vaccine at day 1 , month 2 , and month 6 and provided blood sample s for analysis at enrollment at month 7 . Analyses were done as specified in the study protocol . Quadrivalent HPV vaccine was generally well tolerated , with no vaccine-related serious adverse experiences . Quadrivalent HPV vaccine induced seroconversion for each vaccine-related HPV type . At month 7 , vaccine-induced type-specific antibody titer was high . In conclusion , administration of quadrivalent HPV VLP vaccine to Korean women aged 9–23 years was generally well tolerated and highly [19853193] BACKGROUND AND AIMS Recognition of human papillomavirus ( HPV ) as a necessary cause of cervical cancer ( CC ) led to new perspectives for its control and the demonstration of an effective primary prevention strategy through vaccination . We undertook this study to evaluate the safety , efficacy and immunogenicity of a quadrivalent HPV6/11/16/18 vaccine in Mexican women . METHODS A total of 679 Mexican women between 18 and 23 years old participated in two Phase III double-blind , r and omized , placebo-controlled clinical trials of a quadrivalent HPV 6/11/16/18 vaccine . Women were enrolled who tested negative for pregnancy and reported having four or less sexual partners during their lifetime . Vaccine or placebo was administered at day 1 , month 2 and month 6 . RESULTS Among Mexican women who were naïve to the respective vaccine type at enrollment , the quadrivalent vaccine was highly efficacious , preventing 100 % of HPV6/11/16/18-related cervical intraepithelial neoplasia grade 2/3 , adenocarcinoma in situ , condyloma and vaginal intraepithelial neoplasia . Statistical significance was not reached for every endpoint due to the limited sample size . Vaccination was generally well tolerated and immunogenic . DISCUSSION To widely administer the vaccine , collaborative efforts should be coordinated among public , private and local community sectors . In light of the scarce knowledge of many health professionals with respect to the primary prevention of CC , it will be necessary to educate health providers on the advantages and specific recommendations of HPV vaccines and secondary prevention . Decision making should be based on scientific evidence , allowing health professionals to provide an organized social response that supports the universal right to health Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: The combination of an increasing number of new cancer cases and improving survival rates has led to a large and rapidly growing population with unique health-care requirements . Exercise has been proposed as a strategy to help address the issues faced by cancer patients . Supported by a growing body of research , major health organizations commonly identify the importance of incorporating exercise in cancer care and advise patients to be physically active . This systematic review comprehensively summarizes the available epidemiologic and r and omized controlled trial evidence investigating the role of exercise in the management of cancer . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

24615270

[23018908] Chronic obstructive pulmonary disease ( COPD ) often coexists with other chronic diseases and comorbidities that can markedly influence patients ' health status and prognosis . This is particularly true for cardiovascular disease ( CVD ) . However , there have been no trials assessing the effect of COPD medications on CVD in patients with both diseases . The “ Study to Underst and Mortality and Morbidity in COPD ” ( SUMMIT ) aims at determining the impact of fluticasone furoate/vilanterol combination and the individual components on the survival of patients with moderate COPD and either a history of CVD or at increased risk for CVD . SUMMIT is a multicentre , r and omised , double-blind , parallel-group , placebo-controlled trial of 16 000 patients with moderate COPD r and omly assigned to once daily treatment with fluticasone furoate/vilanterol ( 100/25 & mgr;g ) , fluticasone furoate ( 100 & mgr;g ) , vilanterol ( 25 & mgr;g ) or matched placebo ; mortality is the primary end-point . The study is an event-driven trial powered by the comparison of furoate/vilanterol versus placebo . Secondary end-points are decline in forced expiratory volume in 1 s and effect on a composite cardiovascular end-point . This article describes the design of the SUMMIT study [17311843] Background : TORCH ( Towards a Revolution in COPD Health ) is an international multicentre , r and omised , placebo-controlled clinical trial of inhaled fluticasone propionate/salmeterol combination treatment and its monotherapy components for maintenance treatment of moderately to severely impaired patients with chronic obstructive pulmonary disease ( COPD ) . The primary outcome is all-cause mortality . Cause-specific mortality and deaths related to COPD are additional outcome measures , but systematic methods for ascertainment of these outcomes have not previously been described . Methods : A Clinical Endpoint Committee ( CEC ) was tasked with categorising the cause of death and the relationship of deaths to COPD in a systematic , unbiased and independent manner . The key elements of the operation of the committee were the use of predefined principles of operation and definitions of cause of death and COPD -relatedness ; the independent review of cases by all members with development of a consensus opinion ; and a substantial infrastructure to collect medical information . Results : 911 deaths were review ed and consensus was reached in all . Cause-specific mortality was : cardiovascular 27 % , respiratory 35 % , cancer 21 % , other 10 % and unknown 8 % . 40 % of deaths were definitely or probably related to COPD . Adjudications were identical in 83 % of blindly re-adjudicated cases ( κ = 0.80 ) . COPD -relatedness was reproduced 84 % of the time ( κ = 0.73 ) . The CEC adjudication was equivalent to the primary cause of death recorded by the site investigator in 52 % of cases . Conclusion : A CEC can provide st and ardised , reliable and informative adjudication of COPD mortality that provides information which frequently differs from data collected from assessment by site investigators [22383665] BACKGROUND Effects of β(2)-adrenergic receptor gene ( ADRB2 ) polymorphism on therapeutic responses to long-acting β(2)-adrenergic agonists have not been evaluated in long-term COPD trials . We aim ed to investigate the effects of the ADRB2 Gly16Arg polymorphism on response to formoterol alone or in combination with the inhaled corticosteroid budesonide in patients with COPD . METHODS Patients ≥ 40 years of age with moderate to very severe COPD from the 12-month trial I ( NCT00206167 ) or the 6-month trial II ( NCT00206154 ) were r and omly assigned to bid budesonide/formoterol pressurized metered-dose inhaler ( pMDI ) 320/9 μg or 160/9 μg , budesonide pMDI 320 μg + formoterol dry powder inhaler 9 μg ( trial II ) , budesonide pMDI 320 μg ( trial II ) , formoterol dry powder inhaler 9 μg , or placebo . The effect of Gly16Arg on predose FEV(1 ) and 1-h postdose FEV(1 ) , exacerbations , diary variables , and adverse events were analyzed . RESULTS No significant interaction between genotype and treatment response was observed for predose ( P ≥ .197 ) or postdose FEV(1 ) ( P ≥ .125 ) in either pharmacogenetic study ( n = 2,866 ) . The number of COPD exacerbations per patient-treatment year was low and similar across genotypes for the active treatment groups ( both studies ) . Percentages of patients with adverse events were similar across Gly16Arg genotype groups for each treatment . CONCLUSION Therapeutic response and tolerability to long-term treatment with formoterol alone or in combination with budesonide was not modified by ADRB2 Gly16Arg genotype in two large independent pharmacogenetic studies in patients with moderate to very severe COPD [17557771] Background : Airway inflammation in chronic obstructive pulmonary disease ( COPD ) is characterised by infiltration of CD8 + T cells and CD68 + macrophages and an increased number of neutrophils , whereas few studies have described the presence of eosinophils . Although the anti-inflammatory effects of corticosteroids in stable COPD are unclear , recent studies suggest that combination therapy could be beneficial . A study was therefore undertaken to evaluate combined salmeterol/fluticasone propionate ( SFC ) and fluticasone propionate ( FP ) alone on inflammatory cells in the airways of patients with COPD . Methods : Patients were treated in a r and omised , double blind , parallel group , placebo-controlled trial with either a combination of 50 µg salmeterol and 500 µg FP twice daily ( SFC , n = 19 , 19 men , mean age 62 years ) , 500 µg FP twice daily ( n = 20 , 15 men , mean age 64 years ) or placebo ( n = 21 , 17 men , mean age 66 years ) for 3 months . At the start and end of treatment bronchoscopy with bronchial biopsies was performed and the numbers of CD8 + T lymphocytes , CD68 + macrophages , neutrophils and eosinophils were measured . Results : CD8 + cells were significantly reduced by SFC compared with placebo ( difference −98.05 cells/mm2 ; 95 % CI −143.14 to −52.9 ; p<0.001 ) . Such a marked effect was not seen with FP alone ( −44.67 cells/mm2 ; 95 % CI −90.92 to 1.57 ; p = 0.06 ) . CD68 + macrophages were also reduced by SFC compared with placebo ( difference −31.68 cells/mm2 ; 95 % CI −61.07 to −2.29 ; p = 0.03 ) but not by FP . SFC did not significantly change neutrophils and eosinophils compared with placebo . Conclusions : SFC has airway anti-inflammatory effects not seen with inhaled corticosteroids alone [3812880] Background Inhaled corticosteroids ( ICS ) are known to increase the risk of pneumonia in patients with chronic obstructive pulmonary disease ( COPD ) . It is unclear whether the risk of pneumonia varies for different inhaled agents , particularly fluticasone and budesonide , and increases with the dose and long-term duration of use . Methods We formed a new-user cohort of patients with COPD treated during 1990–2005 . Subjects were identified using the Quebec health insurance data bases and followed through 2007 or until a serious pneumonia event , defined as a first hospitalisation for or death from pneumonia . A nested case – control analysis was used to estimate the rate ratio ( RR ) of serious pneumonia associated with current ICS use , adjusted for age , sex , respiratory disease severity and comorbidity . Results The cohort included 163 514 patients , of which 20 344 had a serious pneumonia event during the 5.4 years of follow-up ( incidence rate 2.4/100/year ) . Current use of ICS was associated with a 69 % increase in the rate of serious pneumonia ( RR 1.69 ; 95 % CI 1.63 to 1.75 ) . The risk was sustained with long-term use and declined gradually after stopping ICS use , disappearing after 6 months ( RR 1.08 ; 95 % CI 0.99 to 1.17 ) . The rate of serious pneumonia was higher with fluticasone ( RR 2.01 ; 95 % CI 1.93 to 2.10 ) , increasing with the daily dose , but was much lower with budesonide ( RR 1.17 ; 95 % CI 1.09 to 1.26 ) . Conclusions ICS use by patients with COPD increases the risk of serious pneumonia . The risk is particularly elevated and dose related with fluticasone . While residual confounding can not be ruled out , the results are consistent with those from recent r and omised trials [3646783] Rationale Smoking and inflammation contribute to the pathogenesis of chronic obstructive pulmonary disease ( COPD ) , which involves changes in extracellular matrix . This is thought to contribute to airway remodeling and airflow obstruction . We have previously observed that long-term treatment with inhaled corticosteroids can not only reduce bronchial inflammation , but can also attenuate lung function decline in moderate-severe COPD . We hypothesized that inhaled corticosteroids and current smoking modulate bronchial extracellular matrix components in COPD . Objective To compare major extracellular matrix components ( elastic fibers ; proteoglycans [ versican , decorin ] ; collagens type I and III ) in bronchial biopsies 1 ) after 30-months inhaled steroids treatment or placebo ; and 2 ) between current and ex-smokers with COPD . Methods We included 64 moderate-severe , steroid-naive COPD patients ( 24/40 (ex)-smokers , 62±7 years , 46 ( 31–54 ) packyears , post-bronchodilator forced expiratory volume in one second ( FEV1 ) 62±9 % predicted ) at baseline in this r and omized , controlled trial . 19 and 13 patients received 30-months treatment with fluticasone or placebo , respectively . Bronchial biopsies collected at baseline and after 30 months were studied using (immuno)histochemistry to evaluate extracellular matrix content . Percentage and density of stained area were calculated by digital image analysis . Results 30-Months inhaled steroids increased the percentage stained area of versican ( 9.6 % [ CI 0.9 to 18.3 % ] ; p = 0.03 ) and collagen III ( 20.6 % [ CI 3.8 to 37.4 % ] ; p = 0.02 ) compared to placebo . Increased collagen I staining density correlated with increased post-bronchodilator FEV1 after inhaled steroids treatment ( Rs = 0.45 , p = 0.04 ) . There were no differences between smokers and ex-smokers with COPD in percentages and densities for all extracellular matrix proteins . Conclusions These data show that long-term inhaled corticosteroids treatment partially changes the composition of extracellular matrix in moderate-severe COPD . This is associated with increased lung function , suggesting that long-term inhaled steroids modulate airway remodeling thereby potentially preventing airway collapse in COPD . Smoking status is not associated with bronchial extracellular matrix proteins . Trial Registration Clinical Trials.gov [24429127] BACKGROUND Whether the combination of a once-daily inhaled corticosteroid with a once-daily longacting β(2 ) agonist is more protective than a once-daily longacting β(2 ) agonist alone against exacerbations of chronic obstructive pulmonary disease ( COPD ) is unknown . We hypothesised that fluticasone furoate and vilanterol would prevent more exacerbations than would vilanterol alone . METHODS We did two replicate double-blind parallel-group 1 year trials . Both studies began on Sept 25 , 2009 . Study 1 ended on Oct 31 , 2011 , and study 2 on Oct 17 , 2011 . Eligible patients were aged 40 years or older , had a history of COPD , a smoking history of 10 or more pack-years , a ratio of forced expiratory volume in 1 s ( FEV(1 ) ) to forced vital capacity of 0·70 or less after bronchodilators ( and an FEV(1 ) of 70 % or less of predicted ) , and a documented history of one or more moderate or severe disease exacerbations in the year before screening . Patients were r and omly assigned ( 1:1:1:1 ) on the basis of the Registration and Medication Ordering System to 25 μg vilanterol alone or 25 μg vilanterol combined with either 50 μg , 100 μg , or 200 μg fluticasone furoate once daily . Our primary endpoint was the yearly rate of moderate and severe exacerbations . The trials were analysed separately and a pooled analysis was also done . These trials are registered with Clinical Trials.gov ( NCT01009463 and NCT01017952 ) . FINDINGS 1622 patients in study 1 and 1633 patients in study 2 were r and omly assigned . In study 1 , no significant difference in exacerbation rate was noted between the 200/25 μg fluticasone furoate/vilanterol group and the vilanterol only group ( mean 0·90 events vs 1·05 events per year ; ratio 0·9 [ 95 % CI 0·7 - 1·0 ] ) . Because of the statistical hierarchy used , we could not infer significance for the 50 μg and 100 μg groups . In study 2 , significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group ( p=0·0398 for the 50 μg group , 0·0244 for the 100 μg group , and 0·0004 for the 200 μg group ) . In the pooled analysis , significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group ( 0·0141 for the 50 μg group , < 0·0001 for the 100 μg group , and 0·0003 for the 200 μg group ) . Nasopharyngitis was the most frequently reported adverse event in both studies . Pneumonia and fractures were reported more frequently with fluticasone furoate and vilanterol than with vilanterol alone . Eight deaths from pneumonia were noted in the fluticasone furoate/vilanterol groups compared with none in the vilanterol only group . INTERPRETATION Addition of fluticasone furoate to vilanterol was associated with a decreased rate of moderate and severe exacerbations of COPD in patients with a history of exacerbation , but was also associated with an increased pneumonia risk . FUNDING GlaxoSmithKline [3580134] Background : Combination therapy with a long-acting bronchodilator and an inhaled corticosteroid ( ICS ) is recommended in patients with chronic obstructive pulmonary disease ( COPD ) who have frequent exacerbations . The efficacy and tolerability of the combination of budesonide/formoterol have been demonstrated in patients with COPD when administered via the dry powder inhaler ( DPI ) in a 1-year study and when administered via the hydrofluoroalkane ( HFA ) pressurized metered-dose inhaler ( pMDI ) in a 6-month study . Objective : This study assessed the long-term efficacy and tolerability of budesonide/formoterol HFA pMDI in patients with moderate to very severe COPD . Methods : This was a 12-month , r and omized , double-blind , double-dummy , parallel-group , active- and placebo-controlled , multicentre study ( NCT00206167 ) of 1964 patients aged ≥40 years with moderate to very severe COPD conducted from 2005 to 2007 at 237 sites in the US , Europe and Mexico . After 2 weeks of treatment based on previous therapy ( ICSs , short-acting bronchodilators allowed ) , patients received one of the following treatments twice daily : budesonide/formoterol pMDI 160/4.5 μg × two inhalations ( 320/9 μg ) ; budesonide/formoterol pMDI 80/4.5 μg × two inhalations ( 160/9 μg ) ; formoterol DPI 4.5 μg × two inhalations ( 9 μg ) ; or placebo . Main outcome measures : The co- primary efficacy variables were pre-dose forced expiratory volume in 1 second ( FEV1 ) and 1-hour post-dose FEV1 . Results : Budesonide/formoterol 320/9 μg demonstrated greater improvements in pre-dose FEV1 versus formoterol ( p = 0.008 ) , and both budesonide/formoterol doses demonstrated greater improvements in 1-hour post-dose FEV1 versus placebo ( p < 0.001 ) . The rate of COPD exacerbations was lower in both budesonide/formoterol groups compared with formoterol and placebo ( p ≤ 0.004 ) . Both budesonide/formoterol doses were more effective than placebo ( p ≤ 0.006 ) for controlling dyspnoea and improving health status ( St George ’s Respiratory Question naire ) . All treatments were generally well tolerated . The incidence of pneumonia was not different for active ( 3.4–4.0 % ) and placebo ( 5.0 % ) groups . Conclusions : Budesonide/formoterol pMDI ( 320/9 μg and 160/9 μg ) improved pulmonary function and reduced symptoms and exacerbations over 1 year in patients with moderate to very severe COPD . Only budesonide/formoterol pMDI 320/9 μg demonstrated greater efficacy for both co- primary variables compared with formoterol DPI 9 μg . Both budesonide/formoterol pMDI dosages were well tolerated relative to formoterol and placebo [19734176] Background : Patients with chronic obstructive pulmonary disease ( COPD ) often experience symptoms and problems with activities early in the morning . This is the first study to compare the effect of budesonide/formoterol and salmeterol/fluticasone on lung function , symptoms and activities early in the morning . Methods : Lung function ( peak expiratory flow [ PEF ] and forced expiratory volume in 1 second [ FEV 1 ] ) and symptoms were measured at bedside and activities were measured during the morning using a six-item question naire concerning basic morning routines . In a r and omised , double-blind , multicentre , cross-over study , 442 patients with COPD aged ≥40 years ( pre-bronchodilator FEV1 ≤50 % ; FEV1/vital capacity < 70 % ) received budesonide/formoterol ( 320/9 µg , one inhalation twice daily ) dry powder inhaler ( DPI ) or salmeterol/fluticasone ( 50/500 µg , one inhalation twice daily ) DPI daily , for 1 week each , separated by a 1- to 2-week washout . Lung function ( PEF and FEV1 ) shortly after rising from bed in the morning , symptoms and basic morning activities were assessed by electronic diary ( e-Diary ) recordings . Results : Budesonide/formoterol and salmeterol/fluticasone treatment increased morning PEF 5 minutes post-dose , measured as a mean improvement from baseline over the full study period ( primary endpoint ; adjusted mean change : 15.1 l/min and 14.2 l/min , respectively [ difference 1.0 l/min ; p = 0.603 ] ) . Mean morning FEV1 improved more following budesonide/ formoterol treatment versus salmeterol/fluticasone at 5 minutes ( 0.12 l versus 0.09 l ; p = 0.090 ) and 15 minutes ( 0.14 l versus 0.10 l ; p < 0.05 ) post-dose . Budesonide/formoterol demonstrated a more rapid onset of effect as reflected by increases in e-Diary-recorded PEF and FEV 1 from pre-dose to 5 and 15 minutes post-dose ( all p < 0.001 ) and spirometry at the clinic measured after the first dose ( FEV1 p < 0.001 ; 5 minutes post-dose ) . Improvements in symptom scores within 15 minutes after drug administration were similar for both drugs , but budesonide/formoterol treatment result ed in significantly greater improvements in total morning activities score ( getting washed , dried , dressed , eating breakfast and walking around the home ; 0.22 versus 0.12 respectively , p < 0.05 ) . Both treatments were well tolerated . Conclusions : Short-term treatment with budesonide/formoterol DPI or salmeterol/fluticasone DPI was effective in patients with COPD . Budesonide/formoterol had a more rapid onset of effect compared with salmeterol/fluticasone and result ed in greater improvements in ability to perform morning activities despite the lower inhaled corticosteroid dose [11208636] This study examined health status decline in patients with chronic obstructive pulmonary disease ( COPD ) . Data are from the Inhaled Steroids in Obstructive Lung Disease ( ISOLDE ) trial . After an 8-wk run-in , 751 patients ( 566 male ) , mean age 64 yr , were r and omized to receive fluticasone propionate ( FP ) 500 microg twice daily ( 376 patients ) or placebo ( 375 patients ) . Mean baseline postbronchodilator FEV1 was 50 + /- 15 % predicted . Patients completed the St George 's Respiratory Question naire ( SGRQ ) and the Short-Form 36 ( SF-36 ) at baseline and every 6 mo for 3 yr . FEV1 and smoking status were assessed at baseline and at 3-mo intervals . A total of 387 ( 212 FP ) patients completed the trial . All SGRQ components ( p = 0.03 to 0.004 ) and Physical Function , Mental Health , Energy/ Vitality , and Physical Role Limitation scales of the SF-36 ( p = 0.05 to 0.005 ) deteriorated faster in the placebo group . FEV1 and SGRQ scores correlated at baseline values ( r = -0.25 , p < 0.0001 ) , as did change in FEV1 and change in SGRQ ( Delta r = -0.24 , p < 0.0001 ) . At baseline values smokers had worse SGRQ Total , Symptoms , and Impacts scores than ex-smokers . This difference was maintained throughout the study . Smoking status did not influence the rate of decline in health status . The SGRQ Total scores of FP-treated patients took 59 % longer than placebo to deteriorate by a clinical ly significant amount . We conclude that health status decline in moderate to severe COPD can be reduced by high-dose fluticasone [3641457] Objective To identify subsets of chronic obstructive pulmonary disease ( COPD ) patients who are more protected from exacerbations with the use of an inhaled corticosteroid/long-acting β2 agonist ( ICS/LABA ) combination , compared with the use of LABA monotherapy . Design Post hoc cluster analysis of patients from two r and omised clinical trials of salmeterol/fluticasone propionate ( SFC ) and salmeterol ( SAL ) that had primary endpoints of moderate/severe exacerbation rates . Setting Centres in North America . Participants 1543 COPD patients were studied . Interventions SFC 50/250 µg or SAL 50 µg , twice daily . Primary and secondary outcome measures The analysis identified clusters of COPD patients more responsive to SFC versus SAL with respect to the annual rate of moderate/severe exacerbations and compared their baseline clinical characteristics . Results Overall , SFC significantly reduced the annual rate of moderate/severe exacerbations as compared with SAL alone ( rate ratio (RR)=0.701 , p<0.001 ) . Three-patient clusters were identified : COPD patients receiving diuretics ( RR=0.56 , p<0.001 ) ; patients not receiving diuretics but with forced expiratory volume in 1 s ( FEV1 ) reversibility ≥12 % ( RR=0.67 , p<0.001 ) exhibited a substantial reduction in the annual rate of moderate/severe exacerbations relative to SAL . A third cluster , consisting of patients not receiving diuretics and without FEV1 reversibility , demonstrated no difference for SFC versus SAL . Patients receiving diuretics had a significantly higher prevalence of comorbid cardiovascular disease . Conclusions COPD patients receiving diuretics and those not receiving diuretics but with FEV1 reversibility > 12 % at baseline were significantly more likely to experience a reduction in COPD -associated exacerbations with SFC versus SAL alone . Trial registration NCT00115492 , [18511702] RATIONALE Chronic obstructive pulmonary disease ( COPD ) is characterized by an accelerated decline in lung function . No drug has been shown conclusively to reduce this decline . OBJECTIVES In a post hoc analysis of the Toward a Revolution in COPD Health ( TORCH ) study , we investigated the effects of combined salmeterol 50 microg plus fluticasone propionate 500 microg , either component alone or placebo , on the rate of post-bronchodilator FEV(1 ) decline in patients with moderate or severe COPD . METHODS A r and omized , double-blind , placebo-controlled study was conducted from September 2000 to November 2005 in 42 countries . Of 6,112 patients from the efficacy population , 5,343 were included in this analysis . MEASUREMENTS AND MAIN RESULTS Spirometry was measured every 24 weeks for 3 years . There were 26,539 on-treatment observations . The adjusted rate of decline in FEV(1 ) was 55 ml/year for placebo , 42 ml/year for salmeterol , 42 ml/year for fluticasone propionate , and 39 ml/year for salmeterol plus fluticasone propionate . Salmeterol plus fluticasone propionate reduced the rate of FEV(1 ) decline by 16 ml/year compared with placebo ( 95 % confidence interval [ CI ] , 7 - 25 ; P < 0.001 ) . The difference was smaller for fluticasone propionate and salmeterol compared with placebo ( 13 ml/year ; 95 % CI , 5 - 22 ; P = 0.003 ) . Rates of decline were similar among the active treatment arms . FEV(1 ) declined faster in current smokers and patients with a lower body mass index , and varied between world regions . Patients who exacerbated more frequently had a faster FEV(1 ) decline . CONCLUSIONS Pharmacotherapy with salmeterol plus fluticasone propionate , or the components , reduces the rate of decline of FEV(1 ) in patients with moderate-to-severe COPD , thus slowing disease progression . Clinical trial ( GSK Study Code SCO30003 ) registered with www . clinical trials.gov ( NCT00268216 ) [15332386] Only long-term home oxygen therapy has been shown in r and omised controlled trials to increase survival in chronic obstructive pulmonary disease ( COPD ) . There have been no trials assessing the effect of inhaled corticosteroids and long-acting bronchodilators , alone or in combination , on mortality in patients with COPD , despite their known benefit in reducing symptoms and exacerbations . The “ TOwards a Revolution in COPD Health ” ( TORCH ) survival study is aim ing to determine the impact of salmeterol/fluticasone propionate ( SFC ) combination and the individual components on the survival of COPD patients . TORCH is a multicentre , r and omised , double-blind , parallel-group , placebo-controlled study . Approximately 6,200 patients with moderate-to-severe COPD were r and omly assigned to b.i.d . treatment with either SFC ( 50/500 µg ) , fluticasone propionate ( 500 µg ) , salmeterol ( 50 µg ) or placebo for 3 yrs . The primary end-point is all-cause mortality ; secondary end-points are COPD morbidity relating to rate of exacerbations and health status , using the St George 's Respiratory Question naire . Other end-points include other mortality and exacerbation end-points , requirement for long-term oxygen therapy , and clinic lung function . Safety end-points include adverse events , with additional information on bone fractures . The first patient was recruited in September 2000 and results should be available in 2006 . This paper describes the “ TOwards a Revolution in COPD Health ” study and explains the rationale behind it [12406823] The aim of this double-blind single center study ( the COPE study ) was to investigate the effect of discontinuation of the inhaled corticosteroid fluticasone propionate ( FP ) on exacerbations and health-related quality of life in patients with chronic obstructive pulmonary disease . After 4 months of treatment with FP ( 1,000 microg/day ) , 244 patients were r and omized to either continue FP or to receive placebo for 6 months : 123 patients continued FP ( FP group ) , and 121 received placebo ( placebo group ) . In the FP group , 58 ( 47 % ) patients developed at least one exacerbation compared with 69 ( 57 % ) in the placebo group . The hazard ratio of a first exacerbation in the placebo group compared with the FP group was 1.5 ( 95 % confidence interval [ CI ] 1.1 - 2.1 ) . In the placebo group 26 patients ( 21.5 % ) experienced rapid recurrent exacerbations and were subsequently unblinded and prescribed FP compared with 6 patients ( 4.9 % ) in the FP group ( relative risk = 4.4 ; 95 % CI 1.9 - 10.3 ) . Over a 6-month period , a significant difference in favor of the FP group was observed in the total score ( + 2.48 95 % CI 0.37 - 4.58 ) , activity domain ( + 4.64 95 % CI 1.60 - 7.68 ) , and symptom domain ( + 4.58 95 % CI 1.05 - 8.10 ) of the St. George 's Respiratory Question naire . This study indicates that discontinuation of FP in patients with chronic obstructive pulmonary disease is associated with a more rapid onset and higher recurrence-risk of exacerbations and a significant deterioration in aspects of Health-Related Quality of Life [9713447] BACKGROUND Inhaled corticosteroids are known to be beneficial for patients with asthma , but their role in treating patients with stable chronic obstructive pulmonary disease ( COPD ) remains controversial . A study was undertaken to determine whether inhaled corticosteroids are of functional benefit in patients who did not show improvement with a trial of oral corticosteroids . METHODS In phase I patients with stable COPD were given a two week course of oral placebo followed by two weeks of prednisone 40 mg per day in a single blind manner to distinguish between responders and non-responders to oral corticosteroids . In phase II a double blind , r and omised , parallel group trial of inhaled budesonide 1600 micrograms per day versus placebo was carried out in 79 nonresponders to oral corticosteroids . The primary outcome measure was forced expiratory volume in one second ( FEV1 ) , and secondary outcome measures were exercise capacity , dyspnoea with exertion , quality of life , peak expiration flow rate , and respiratory symptoms . RESULTS R and omisation allocated 39 subjects to inhaled corticosteroids and 40 to placebo . There was no difference in the change in FEV1 from baseline between the treatment and placebo groups ; mean difference -12 ml ( 95 % CI -88 to 63 ) at three months and -4 ml ( 95 % CI -95 to 87 ) at six months . The proportion of patients with a 15 % or greater improvement was no higher among those receiving inhaled corticosteroids than in the placebo group at any of the follow up visits . Changes in secondary outcomes were also no different . CONCLUSIONS Inhaled corticosteroids , even at high doses , were of no physiological or functional benefit in these patients with advanced COPD [12570111] Exacerbations of chronic obstructive pulmonary disease ( COPD ) are associated with worse health and increased healthcare utilisation . The Inhaled Steroids in Obstructive Lung Disease in Europe ( ISOLDE ) study in COPD showed a 26 % reduction in the yearly rate of exacerbations in patients treated with fluticasone propionate ( FP ) compared to placebo , but did not indicate which patients showed greatest benefit . In this study the patients were stratified into mild and moderate‐to‐severe COPD using the American Thoracic Society criterion of forced expiratory volume in one second ( FEV1 ) 50 % predicted , and the total number of exacerbations and those requiring treatment with oral corticosteroids were examined . There were 391 ( 195 FP ) patients with mild COPD and 359 ( 180 FP ) patients with moderate‐to‐severe disease . The exacerbation rate was highly skewed in mild disease , but more normally distributed in moderate‐to‐severe disease . FP reduced the overall exacerbation rate in moderate‐to‐severe disease ( FP median rate 1.47 yr−1 , placebo 1.75 yr−1 ) , but not in mild disease ( FP 0.67 yr−1 , placebo 0.92 yr−1 ) . FP use was associated with fewer patients with ≥1 exacerbation·yr−1 being treated with oral corticosteroids ( mild : FP 8 % , placebo 16 % ; moderate‐to‐severe : FP 17 % , placebo 30 % ) . Effects of fluticasone propionate on exacerbations were seen predominantly in patients with a postbronchodilator forced expiratory volume in one second < 50 % predicted . These data support recommendations in the Global Initiative for Chronic Obstructive Disease treatment guidelines that inhaled corticosteroids should be considered in patients with moderate‐to‐severe chronic obstructive pulmonary disease who experience recurrent exacerbations [19863361] Prevention and treatment of COPD exacerbations are recognized as key goals in disease management . This r and omized , double-blind , parallel-group , multicenter study evaluated the effect of fluticasone propionate/salmeterol 250 mcg/50 mcg ( FSC 250/50 ) and salmeterol 50 mcg ( SAL ) twice-daily on moderate/severe exacerbations . Subjects received treatment with FSC 250/50 during a one month run-in , followed by r and omization to FSC 250/50 or SAL for 52 weeks . Moderate/severe exacerbations were defined as worsening symptoms of COPD requiring antibiotics , oral corticosteroids and /or hospitalization . In 797 subjects with COPD ( mean FEV1 = 0.98L , 34 % predicted normal ) , treatment with FSC 250/50 significantly reduced the annual rate of moderate/severe exacerbations by 30.4 % compared with SAL ( 1.10 and 1.59 per subject per year , respectively , p < 0.001 ) , the annual rate of exacerbations requiring oral corticosteroids by 34 % ( p < 0.001 ) and the annual rate of moderate/severe exacerbations requiring hospitalization by 36 % ( p = 0.043 ) . Clinical improvements observed during run-in treatment with FSC 250/50 were better maintained over 52 weeks with FSC 250/50 compared to SAL . Statistically significant reductions in albuterol use , dyspnea scores , and nighttime awakenings and numerical benefits on quality of life were seen with FSC 250/50 compared with SAL . The incidence of adverse events was similar across groups . Pneumonia was reported more frequently with FSC 250/50 compared with SAL ( 7 % vs. 2 % ) . FSC 250/50 is more effective than SAL at reducing the rate of moderate/severe exacerbations . These data confirm the beneficial effect of FSC on the management of COPD exacerbations and support the use of FSC in patients with COPD [12885977] Background : A trial of corticosteroids has been recommended for all patients with chronic obstructive pulmonary disease ( COPD ) , with the subsequent “ response ” determining the treatment selected . This approach assumes that patients can be reliably divided into responder and non-responder groups . We have assessed whether such a separation is statistically valid , which factors influence the change in forced expiratory volume in 1 second ( FEV1 ) after prednisolone , and whether the prednisolone response predicts 3 year changes in FEV1 , health status , or number of exacerbations during placebo or fluticasone propionate treatment . Methods : Oral prednisolone 0.6 mg/kg was given for 14 days to 524 patients with COPD before r and omised treatment for 3 years with fluticasone propionate or placebo . Factors relating to change in FEV1 after prednisolone were investigated using multiple regression . The response to prednisolone was entered into separate mixed effects models of decline in FEV1 and health status during the 3 years of the study . Results : The post-bronchodilator FEV1 increased by a mean 60 ml ( CI 46 to 74 ) after prednisolone with a wide unimodal distribution . Current smoking was the factor most strongly associated with the change in FEV1 after prednisolone , with an increase of 35 ml in current smokers and 74 ml in confirmed ex-smokers ( p<0.001 ) . There was no relationship between the change in FEV1 after prednisolone and the response to inhaled bronchodilators , baseline FEV1 , atopic status , age , or sex . The response to prednisolone , however expressed , was unrelated to the subsequent change in FEV1 over the following 3 years on either placebo or fluticasone propionate . Regression to the mean effects explained much of the apparent prednisolone response . The significant effect of treatment on decline in health status was not predicted by the prednisolone response . Conclusion : Patients with COPD can not be separated into discrete groups of corticosteroid responders and non-responders . Current smoking reduces the FEV1 response to prednisolone . Prednisolone testing is an unreliable predictor of the benefit from inhaled fluticasone propionate in individual patients [12149529] Background : Treatment of chronic obstructive pulmonary disease ( COPD ) with inhaled corticosteroids does not appear to be as effective as similar treatment of asthma . It seems that only certain subgroups of patients with COPD benefit from steroid treatment . A study was undertaken to examine whether inhaled fluticasone propionate ( FP ) had an effect on lung function and on indices of inflammation in a subgroup of COPD patients with bronchial hyperresponsiveness ( BHR ) . Methods : Twenty three patients with COPD were studied . Patients had to be persistent current smokers between 40 and 70 years of age . Non-specific BHR was defined as a PC20 for histamine of ≤8 mg/ml . Patients received either 2 × 500 μg FP or placebo for 6 months . Expiratory volumes were measured at monthly visits , BHR was determined at the start of the study and after 3 and 6 months , and bronchial biopsy specimens were taken at the start and after 6 months of treatment . Biopsy specimens from asymptomatic smokers served as controls . Results : In contrast to asthma , indices of BHR were not significantly influenced by treatment with FP . Forced expiratory volume in 1 second ( FEV1 ) showed a steep decline in the placebo group but remained stable in patients treated with FP . FEV1/FVC , and maximal expiratory flows at 50 % and 25 % FVC ( MEF50 , MEF25 ) were significantly increased in the FP treated patients compared with the placebo group . Biopsy specimens were analysed for the presence of CD3 + , CD4 + , CD8 + , MBP+ , CD15 + , CD68 + , CD1a , and tryptase cells . FP treatment result ed in marginal reductions in these indices of inflammation . Conclusion : In patients with COPD and BHR , FP has a positive effect on indices of lung function compared with placebo . Bronchial inflammation analysed in bronchial biopsy specimens is only marginally reduced [23551359] BACKGROUND AND OBJECTIVE The efficacy and tolerability of budesonide/formoterol versus formoterol in patients with moderate to severe chronic obstructive pulmonary disease ( COPD ) was evaluated . METHODS In this r and omized , double-blind , parallel-group , phase III study ( NCT01069289 ) , patients with moderate to severe COPD for ≥2 years received either budesonide/formoterol 160/4.5 μg two inhalations twice daily via Turbuhaler ® or formoterol 4.5 μg two inhalations twice daily via Turbuhaler ® for 12 weeks . Salbutamol was available as reliever medication . Primary outcome variable : change from baseline to average during treatment in pre-dose forced expiratory volume in 1 s ( FEV1 ) . RESULTS One thous and two hundred ninety-three patients were r and omized ( budesonide/formoterol n = 636 ; formoterol n = 657 ) . Both budesonide/formoterol and formoterol increased pre-dose FEV1 versus baseline ( improvements of 4.6 % and 1.5 % over baseline , respectively ) , with the increase from baseline being significantly greater with budesonide/formoterol versus formoterol ( budesonide/formoterol : formoterol ratio 1.032 ; 95 % confidence interval : 1.013 - 1.052 ; P = 0.0011 ) . The budesonide/formoterol group had a significantly prolonged time to first exacerbation versus the formoterol group ( hazard ratio : 0.679 ; 95 % confidence interval : 0.507 - 0.909 ; P = 0.0094 ) and significantly greater improvements in many secondary outcome measures . Both treatments were well tolerated ; the incidence and type of adverse events were similar : most commonly reported ( budesonide/formoterol vs formoterol ) : COPD ( 8.0 % vs 9.4 % ) and nasopharyngitis ( 5.5 % vs 4.9 % ) . CONCLUSIONS Budesonide/formoterol 160/4.5 μg two inhalations twice daily was effective and well tolerated in patients with moderate to severe COPD , offering benefits over formoterol alone in terms of improved lung function and reduced risk of exacerbation [8625660] STUDY OBJECTIVE To determine the effectiveness of treatment with corticosteroids in patients with COPD . METHODS In this study , we investigated the effect of a 2-year treatment with corticosteroids on clinical symptoms and the decline of lung function in 58 nonallergic patients with COPD . Subjects were treated in a double-blind , r and omized , placebo-controlled , parallel way with inhaled budesonide ( bud ) , 1,600 micrograms/d ; inhaled budesonide , 1,600 micrograms/d , plus oral prednisolone , 5 micrograms/d ( bud + pred ) ; or placebo ( plac ) . Clinical assessment ( history , physical examination , and spirometry ) was carried out every 2 months . The rate of decline in FEV1 was assessed by calculating individual regression co-efficients from linear regression of FEV1 on time for each subject . RESULTS Eleven patients dropped out . The number of withdrawals due to pulmonary problems was significantly higher in the plac group ( n = 5 out of 18 ) than in the actively treated groups ( n = 2 out of 40 ) . Treatment with corticosteroids significantly reduced pulmonary symptoms . Median decline of FEV1 was 60 mL/yr in the plac group , 40 mL/yr in the bud + pred group , and 30 mL/yr in the bud group . Variation was large and differences were not statistically significant . No treatment effect was found on frequency or duration of exacerbations , possibly because of the high number of withdrawals due to pulmonary deterioration in the plac group . Treatment with a combination of inhaled plus oral corticosteroids was not more effective than inhaled corticosteroids alone . Morning plasma cortisol levels remained within the normal range in all three groups . CONCLUSIONS Our study shows beneficial effects of long-term daily treatment with inhaled corticosteroids in patients with COPD with regard to symptoms and drop out due to pulmonary problems . Lung function decline tends to decrease during treatment with inhaled corticosteroids . The observed effects are limited but warrant further studies on the effectiveness of corticosteroids in larger numbers of patients with COPD [12200525] Background : Inhaled corticosteroids ( ICS ) markedly reduce bronchial mucosal inflammation in asthma but whether they have an anti-inflammatory effect in airway tissue in chronic obstructive pulmonary disease ( COPD ) is unknown . Methods : A study of endobronchial biopsy sample s was conducted as part of a double blind , placebo controlled , r and omised trial of parallel design . Patients had mild to moderately severe COPD ( FEV1 25–80 % of predicted ) and were given 3 months treatment with ICS , fluticasone propionate ( FP ; 500 μg twice daily , n=14 ) or placebo ( n=10 ) . Biopsy tissue taken at baseline and after treatment was examined by transmission electron microscopy to count the numbers of all ultrastructurally distinct inflammatory cells . Results : Compared with their baseline values , FP result ed in a significant decrease ( on average 65 % ) in the numbers of mucosal mast cells ( median 7.8 ( range 1–33 ) v 2.8 ( 1–14 ) , p<0.05 ) . The reductive effect of FP held true when the post-treatment values of the placebo and FP groups were compared : 8.8 ( 1–24 ) v 2.8 ( 1–14 ) ( p<0.05 ) . Unexpectedly , there were significantly more neutrophils in the FP than in the placebo group : 4.0 ( 0–23 ) v 1.7 ( 0–8 ) , respectively ( p<0.05 ) . There were no alterations to other cell types including mononuclear cells . Symptoms markedly improved in the patients treated with FP for 3 months . Conclusion : Fluticasone propionate given for 3 months to patients with COPD has selective effects on the inflammatory cells in the bronchial mucosa : the reduction in mast cell numbers may account for the improvement in symptoms over this time [2245934] Background Guidelines recommend inhaled corticosteroids ( ICS ) for patients with severe chronic obstructive pulmonary disease ( COPD ) . Most COPD patients are managed in primary care and receive ICS long-term and irrespective of severity . The effect of withdrawing ICS from COPD patients in primary care is unknown . Methods In a pragmatic r and omised , double-blind , placebo-controlled trial in 31 practice s , 260 COPD patients stopped their usual ICS ( median duration of use 8 years ) and were allocated to 500 mcg fluticasone propionate twice daily ( n = 128 ) , or placebo ( n = 132 ) . Follow-up assessment s took place at three monthly intervals for a year at the patients ' practice . Our primary outcome was COPD exacerbation frequency . Secondary outcomes were time to first COPD exacerbation , reported symptoms , peak expiratory flow rate and reliever inhaler use , and lung function and health related quality of life . Results In patients r and omised to placebo , COPD exacerbation risk over one year was RR : 1.11 ( CI : 0.91–1.36 ) . Patients taking placebo were more likely to return to their usual ICS following exacerbation , placebo : 61/128 ( 48 % ) ; fluticasone : 34/132 ( 26 % ) , OR : 2.35 ( CI : 1.38–4.05 ) . Exacerbation risk whilst taking r and omised treatment was significantly raised in the placebo group 1.48 ( CI : 1.17–1.86 ) . Patients taking placebo exacerbated earlier ( median time to first exacerbation : placebo ( days ) : 44 ( CI : 29–59 ) ; fluticasone : 63 ( CI : 53–74 ) , log rank 3.81 , P = 0.05 ) and reported increased wheeze . In a post-hoc analysis , patients with mild COPD taking placebo had increased exacerbation risk RR : 1.94 ( CI : 1.20–3.14 ) . Conclusion Withdrawal of long-term ICS in COPD patients in primary care increases risk of exacerbation shortens time to exacerbation and causes symptom deterioration . Patients with mild COPD may be at increased risk of exacerbation after withdrawal . Trial Registration Clinical Trials.gov [22033040] BACKGROUND Treatment with an inhaled corticosteroid ( ICS ) and long-acting bronchodilator is recommended for severe/very severe chronic obstructive pulmonary disease ( COPD ) patients with repeated exacerbations . This r and omized , double-blind , double-dummy , parallel-group , 12-month multicenter study evaluated the effect of budesonide/formoterol pressurized metered-dose inhaler ( pMDI ) on COPD exacerbations . METHODS Following a 2-week run-in during which COPD patients aged ≥40 years with an exacerbation history discontinued medications except ICSs , 1219 patients were r and omized 1:1:1 to twice-daily budesonide/formoterol pMDI 320/9 μg , budesonide/formoterol pMDI 160/9 μg , or formoterol dry powder inhaler 9 μg . An exacerbation was defined as COPD worsening requiring oral corticosteroids and /or hospitalization . A post hoc analysis , with antibiotic treatment added to the exacerbation definition , was also performed . RESULTS Budesonide/formoterol 320/9 and 160/9 reduced exacerbation rates ( number per patient-treatment year ) by 34.6 % and 25.9 % , respectively , versus formoterol ( p ≤ 0.002 ) . Budesonide/formoterol 320/9 prolonged time to first exacerbation versus formoterol , corresponding to a 21.2 % reduction in hazard ratio ( 0.788 [ 95 % CI : 0.639 , 0.972 ] ; p = 0.026 ) . Exacerbation rates ( number per patient-treatment year ) including antibiotic treatment ( post hoc analysis ) were reduced by 25.9 % and 18.7 % with budesonide/formoterol 320/9 and 160/9 , respectively , versus formoterol ( p ≤ 0.023 ) . Both budesonide/formoterol doses were well tolerated with safety profiles similar to formoterol . Pneumonia adverse events occurred in 6.4 % , 4.7 % , and 2.7 % of patients in the budesonide/formoterol 320/9 , 160/9 , and formoterol groups . CONCLUSIONS Over 12 months , both budesonide/formoterol doses reduced the exacerbation rate ( defined with or without antibiotic treatment ) versus formoterol . Budesonide/formoterol pMDI is an appropriate treatment for reducing exacerbations in COPD patients with a history of exacerbations . ( NCT00419744 ) [1781748] Oxidative stress in the lung is important in the pathogenesis of COPD . Published data indicate that glucocorticoids inhibit blood cells in their capacity to produce reactive oxygen species ( ROS ) . We investigated the effect of Fluticasone propionate ( FP ) on the ROS production capabilities of pulmonary cells . Bronchoalveolar lavage ( BAL ) was performed in smoking COPD patients , before and after a six month , placebo-controlled treatment with FP . BAL cells were stimulated with phorbol myristrate acetate ( PMA ) alone , and together with superoxide dismutase ( SOD ) . From kinetic plots of ferricytochrome-c conversion we calculated the maximal rate of superoxide production : V(max ) . We also examined BAL cell subsets and performed correlation analyses on ROS production and relevant clinical determinants . Paired results were obtained from 6 FP- and 9 placebo-treated patients . No significant change of V(max ) was found in both patient groups . Also BAL cellularity was unchanged . Correlation analyses showed a significant ( inverse ) association of V(max ) with the number of cigarettes smoked per day . We concluded that a potent inhaled glucocorticoid had no effect on the ROS production capability of BAL cells from smoking COPD patients . Apparently , heavy smoking impaired the ability of alveolar macrophages to produce ROS , which was not further decreased by FP [23242950] It is by no means straightforward to analyse the change in the rate of chronic obstructive pulmonary disease ( COPD ) exacerbations in clinical trials . Exacerbation rates do not follow a normal distribution , nor do they occur at r and om . High exacerbation rates in a few patients can make average rates difficult to calculate and interpret . So , surely , transforming exacerbation rates into numbers needed to treat ( NNT ) should help . Not necessarily so — this is the message from Professor Suissa 's paper.1 He points out that the simplistic transformation from annual exacerbation rates to NNT in some published papers is misleading . He then goes on to present an alternative way of calculating NNT from survival curves showing time to first exacerbation , and a model to estimate such curves even if they are not presented . I have used the exponential model suggested by Suissa , with the data from two of the arms of the Towards a Revolution in Chronic obstructive pulmonary disease Health ( TORCH ) trial2 to show how this works in practice . I chose the arms in TORCH , that compared combination fluticasone/salmeterol therapy with salmeterol alone , as this seems to me to be a fair way to estimate the impact of additional inhaled corticosteroids . Figure 1 shows pairs of modelled survival curves for pneumonia ( in the upper part ) , and for COPD exacerbation ( in the lower part ) . [23352226] BACKGROUND Fluticasone furoate (FF)/vilanterol ( VI ) is a novel once-daily inhaled corticosteroid/long-acting β2-agonist combination therapy for COPD . We aim ed to assess the efficacy and safety of two strengths of FF/VI ( 100/25 μg ; 50/25 μg ) vs. individual components ( FF 100 μg , VI 25 μg ) and placebo over 24 weeks . METHODS Multicentre , r and omised , placebo-controlled , double-blind , parallel-group study of patients ( N = 1030 ) with moderate-to-severe COPD . All medication was administered once daily in the morning . Co- primary efficacy endpoints were : ( 1 ) weighted mean ( wm ) FEV1 ( 0 - 4 h post-dose on day 168 ) to assess acute lung function effects ; and ( 2 ) trough FEV1 ( 23 - 24 h post-dose on day 169 ) to assess long-lasting effects . Symptom-related outcomes were analysed and adverse events ( AEs ) assessed . RESULTS Main findings were : ( 1 ) the combination of FF/VI at a strength of 100/25 μg significantly ( p < 0.001 ) improved wm FEV1 ( 173 ml ) and trough FEV1 ( 115 ml ) vs. placebo . Similar effects were observed with FF/VI 50/25 μg ; ( 2 ) no significant difference was seen between FF/VI 100/25 μg and VI 25 μg for trough FEV1 ( 48 ml , p = 0.082 ) , while an effect was observed between FF/VI 100/25 μg and FF 100 μg for wm FEV1 ( 120 ml , p < 0.001 ) ; ( 3 ) VI 25 μg over 24 weeks improved lung function vs. placebo significantly for wm FEV1 ( 103 ml , p < 0.001 ) and trough FEV1 ( 67 ml , p = 0.017 ) ; and ( 4 ) no safety signal was observed . CONCLUSIONS In subjects with moderate-to-severe COPD , FF/VI 100/25 μg provides rapid and significant sustained bronchodilation at 24 weeks . Lung function is improved to a similar extent with FF/VI 50/25 μg and to a somewhat lesser extent with VI 25 μg . All treatments were well tolerated . GSK study number : HZC112206 . Clinical Trials.gov : NCT01053988 [2793071] Background The oral prednisolone test is widely used to distinguish chronic obstructive pulmonary disease ( COPD ) patients who might benefit from inhaled steroid treatment . Previous studies used selected patient groups that did not represent the large COPD population in primary care . Methods The study included smokers and exsmokers with chronic bronchitis or COPD from primary care , who underwent prednisolone testing ( 30 mg for 14 days ) before r and omization in a three-year follow-up r and omized controlled trial ( COOPT Study ) . Spirometry was performed before and after the test . Responders and nonresponders were classified according to international criteria . Effectiveness of inhaled fluticasone relative to placebo was compared in terms of health status ( Chronic Respiratory Disease Question naire ) , exacerbations , and postbronchodilator forced expiratory volume in one second ( FEV1 ) , using repeated measurement analysis . Results Two hundred eighty-six patients recruited from 44 primary care practice s were r and omized . Nine percent to 16 % of the COPD population was classified as responder , depending on the international guideline criteria used . On average , responders did not reach the minimum clinical ly important difference in health status ( 0.29 points/year , P = 0.05 ) , although a borderline significant effect of inhaled fluticasone was noted . Possible clinical ly relevant reductions in exacerbation rate ( rate ratio 0.67 ) and FEV1 decline ( 39 mL/year ) occurred in responders , but did not reach statistical significance . Conclusions Oral steroid testing identifies a limited proportion of COPD patients , but does not reveal any clinical ly relevant benefit from inhaled steroid treatment on health status . No significant effects on exacerbation rate and lung function decline occurred [3666306] Objective To investigate the occurrence of pneumonia and pneumonia related events in patients with chronic obstructive pulmonary disease ( COPD ) treated with two different fixed combinations of inhaled corticosteroid/long acting β2 agonist . Design Observational retrospective pairwise cohort study matched ( 1:1 ) for propensity score . Setting Primary care medical records data linked to Swedish hospital , drug , and cause of death registry data for years 1999 - 2009 . Participants Patients with COPD diagnosed by a physician and prescriptions of either budesonide/formoterol or fluticasone/salmeterol . Main outcome measures Yearly pneumonia event rates , admission to hospital related to pneumonia , and mortality . Results 9893 patients were eligible for matching ( 2738 in the fluticasone/salmeterol group ; 7155 in the budesonide/formoterol group ) , yielding two matched cohorts of 2734 patients each . In these patients , 2115 ( 39 % ) had at least one recorded episode of pneumonia during the study period , with 2746 episodes recorded during 19 170 patient years of follow up . Compared with budesonide/formoterol , rate of pneumonia and admission to hospital were higher in patients treated with fluticasone/salmeterol : rate ratio 1.73 ( 95 % confidence interval 1.57 to 1.90 ; P<0.001 ) and 1.74 ( 1.56 to 1.94 ; P<0.001 ) , respectively . The pneumonia event rate per 100 patient years for fluticasone/salmeterol versus budesonide/formoterol was 11.0 ( 10.4 to 11.8 ) versus 6.4 ( 6.0 to 6.9 ) and the rate of admission to hospital was 7.4 ( 6.9 to 8.0 ) versus 4.3 ( 3.9 to 4.6 ) . The mean duration of admissions related to pneumonia was similar for both groups , but mortality related to pneumonia was higher in the fluticasone/salmeterol group ( 97 deaths ) than in the budesonide/formoterol group ( 52 deaths ) ( hazard ratio 1.76 , 1.22 to 2.53 ; P=0.003 ) . All cause mortality did not differ between the treatments ( 1.08 , 0.93 to 1.14 ; P=0.59 ) . Conclusions There is an intra-class difference between fixed combinations of inhaled corticosteroid/long acting β2 agonist with regard to the risk of pneumonia and pneumonia related events in the treatment of patients with COPD . Trial registration Clinical Trials.gov NCT01146392 [15176682] Exacerbations of chronic obstuctive pulmonary disease ( COPD ) are associated with worse health status . The Inhaled Steroids in Obstructive Lung Disease in Europe ( ISOLDE ) study showed that treatment with fluticasone propionate ( FP ) reduced exacerbation frequency and the rate of deterioration in health status as compared with placebo . The present study analysed these data to test whether the effect of FP on health status was attributable to its effect on exacerbations . Rates of deterioration in St George 's Respiratory Question naire ( SGRQ ) total score were obtained for 613 patients with moderate to severe COPD followed for a maximum of 3 yrs . Exacerbation rates were skewed and could not be normalised , therefore , patients were stratified into three exacerbation groups : none , infrequent ( < 1.65 exacerbations·yr−1 ) and frequent ( > 1.65 exacerbations·yr−1 ) . There were 91 patients with no exacerbations , 285 with infrequent exacerbations and 235 with frequent exacerbations . Frequent exacerbations were independently associated with a worse baseline SGRQ score ( p<0.0001 ) and a more rapid rate of deterioration in health status ( p=0.0003 ) . Exacerbation frequency and rate of decline in forced expiratory volume in one second were independently related to the rate of deterioration in SGRQ score . Statistical modelling showed the beneficial effect of fluticasone propionate on deterioration in health status to be largely due to its effect on exacerbation frequency [12570112] The efficacy and safety of budesonide/formoterol in a single inhaler compared with placebo , budesonide and formoterol were evaluated in patients with moderate-to-severe chronic obstructive pulmonary disease ( COPD ) . In a 12-month , r and omised , double-blind , placebo-controlled , parallel-group study in 812 adults ( mean age 64 yrs , mean forced expiratory volume in one second ( FEV1 ) 36 % predicted normal ) , patients received two inhalations twice daily of either budesonide/formoterol ( Symbicort ® ) 160/4.5 µg ( delivered dose ) , budesonide 200 µg ( metered dose ) , formoterol 4.5 µg or placebo . Severe exacerbations and FEV1 ( primary variables ) , peak expiratory flow ( PEF ) , COPD symptoms , health-related quality of life ( HRQL ) , mild exacerbations , use of reliever β2‐agonist and safety variables were recorded . Budesonide/formoterol reduced the mean number of severe exacerbations per patient per year by 24 % versus placebo and 23 % versus formoterol . FEV1 increased by 15 % versus placebo and 9 % versus budesonide . Morning PEF improved significantly on day 1 versus placebo and budesonide ; after 1 week , morning PEF was improved versus placebo , budesonide and formoterol . Improvements in morning and evening PEF versus comparators were maintained over 12 months . Budesonide/formoterol decreased all symptom scores and use of reliever β2‐agonists significantly versus placebo and budesonide , and improved HRQL versus placebo . All treatments were well tolerated . These results suggest a role for budesonide/formoterol in the long-term management of moderate-to-severe chronic obstructive pulmonary disease [12583942] BACKGROUND Inhaled long-acting beta2 agonists improve lung function and health status in symptomatic chronic obstructive pulmonary disease ( COPD ) , whereas inhaled corticosteroids reduce the frequency of acute episodes of symptom exacerbation and delay deterioration in health status . We postulated that a combination of these treatments would be better than each component used alone . METHODS 1465 patients with COPD were recruited from outpatient departments in 25 countries . They were treated in a r and omised , double-blind , parallel-group , placebo-controlled study with either 50 microg salmeterol twice daily ( n=372 ) , 500 microg fluticasone twice daily ( n=374 ) , 50 microg salmeterol and 500 microg fluticasone twice daily ( n=358 ) , or placebo ( n=361 ) for 12 months . The primary outcome was the pretreatment forced expiratory volume in 1s ( FEV1 ) after 12 months treatment ' and after patients had abstained from all bronchodilators for at least 6h and from study medication for at least 12h . Secondary outcomes were other lung function measurements , symptoms and rescue treatment use , the number of exacerbations , patient withdrawals , and disease-specific health status . We assessed adverse events , serum cortisol concentrations , skin bruising , and electrocardiograms . Analysis was as predefined in the study protocol . FINDINGS All active treatments improved lung function , symptoms , and health status and reduced use of rescue medication and frequency of exacerbations . Combination therapy improved pretreatment FEV1 significantly more than did placebo ( treatment difference 133 mL , 95 % CI 105 - 161 , p<0.0001 ) , salmeterol ( 73 mL , 46 - 101 , p<0.0001 ) , or fluticasone alone ( 95 mL , 67 - 122 , p<0.0001 ) . Combination treatment produced a clinical ly significant improvement in health status and the greatest reduction in daily symptoms . All treatments were well tolerated with no difference in the frequency of adverse events , bruising , or clinical ly significant falls in serum cortisol concentration . INTERPRETATION Because inhaled long-acting beta2 agonists and corticosteroid combination treatment produces better control of symptoms and lung function , with no greater risk of side-effects than that with use of either component alone , this combination treatment should be considered for patients with COPD [14680078] Lung function in chronic obstructive pulmonary disease ( COPD ) can be improved acutely by oral corticosteroids and bronchodilators . Whether clinical improvement can be maintained by subsequent inhaled therapy is unknown . COPD patients ( n=1,022 , mean prebronchodilator forced expiratory volume in one second ( FEV1 ) 36 % predicted ) initially received formoterol ( 9 µg b.i.d . ) and oral prednisolone ( 30 mg o.d . ) for 2 weeks . After this time , patients were r and omised to b.i.d . inhaled budesonide/formoterol 320/9 µg , budesonide 400 µg , formoterol 9 µg or placebo for 12 months . Postmedication FEV1 improved by 0.21 L and health-related quality of life using the St George 's Respiratory Question naire ( SGRQ ) by 4.5 units after run-in . Fewer patients receiving budesonide/formoterol withdrew from the study than those receiving budesonide , formoterol or placebo . Budesonide/formoterol patients had a prolonged time to first exacerbation ( 254 versus 96 days ) and maintained higher FEV1 ( 99 % versus 87 % of baseline ) , both primary variables versus placebo . They had fewer exacerbations ( 1.38 versus 1.80 exacerbations per patient per year ) , had higher prebronchodilator peak expiratory flow , and showed clinical ly relevant improvements in SGRQ versus placebo ( −7.5 units ) . Budesonide/formoterol was more effective than either monocomponent in both primary variables . Budesonide/formoterol in a single inhaler ( Symbicort ® ) maintains the benefit of treatment optimisation , stabilising lung function and delaying exacerbations more effectively than either component drug alone or placebo [14555565] OBJECTIVES To investigate the determinants of patient withdrawal from our study , and the effect of these withdrawals on the outcome of treatment with inhaled corticosteroids in patients with COPD . DESIGN A double-blind , placebo-controlled , r and omized trial . SETTING Eighteen outpatient centers in the United Kingdom . PARTICIPANTS Seven hundred fifty-one patients with stable COPD defined clinical ly and as baseline postbronchodilator FEV(1 ) > or = 0.8 L and < 85 % predicted , FEV(1)/FVC ratio < 70 % , and FEV(1 ) change after albuterol < 10 % of predicted . INTERVENTION R and om assignment of either 500 microg bid of inhaled fluticasone propionate ( FP ) using a spacer device or an identical placebo inhaler . Treatment was continued for 3 years or until patients withdrew from follow-up . MEASUREMENTS AND RESULTS Postbronchodilator FEV(1 ) was measured on three occasions before r and omization and every 3 months thereafter . Health status was assessed by the disease-specific St. George Respiratory Question naire ( SGRQ ) and the modified short-form 36 question naire ( SF-36 ) at baseline and every 6 months . Three hundred thirty-nine patients withdrew , of whom 156 patients received FP . Prescription of frequent courses of oral prednisolone was the most common reason for withdrawing as specified in the protocol ( 69 patients in the FP group withdrew due to respiratory symptoms , compared with 93 patients in the placebo group ) . This explained the significantly greater dropout of placebo-treated patients that was most evident when FEV(1 ) was < 50 % predicted . Patients withdrawing had a significantly more rapid decline in health status , measured by both the SGRQ and the SF-36 ( p < 0.001 ) . Those withdrawing from the placebo group had a more rapid decline in FEV(1 ) and more exacerbations than the FP-treated groups . Baseline FEV(1 ) was lower in dropouts than in patients completing the study receiving placebo , but there was no difference between the respective groups receiving FP . CONCLUSIONS Patients who withdrew from follow-up were those with the most rapidly deteriorating health status and lung function . Losing these patients from the final analysis can reduce the power of a study to achieve its primary end point [19717476] The TOwards a Revolution in COPD Health ( TORCH ) study was a 3-yr multicentre trial of 6,112 patients r and omised to salmeterol ( Salm ) , fluticasone propionate ( FP ) , a Salm/FP combination ( SFC ) or placebo ( P ) . Here the cost-effectiveness of treatments evaluated in the TORCH study is assessed . For four regions , 3-yr all-cause hospitalisation , medication and outpatient care costs were calculated . The sample was restricted to the 21 countries ( n = 4,237 ) in which European quality of life five-dimension ( EQ-5D ) data were collected in order to estimate the number of quality -adjusted life years ( QALYs ) . Regression models were fitted to survival , study medication cost , other medication cost and EQ-5D data in order to estimate total cost , number of QALYs and cost per QALY , adjusted for missing data and region . SFC had a trial-wide estimate of cost per QALY of 43,600 US dollars ( USD ) compared with P ( 95 % confidence interval 21,400–123,500 USD ) . Estimates for Salm versus P ( 197,000 USD ) and FP versus P ( 78,000 USD ) were less favourable . The US estimates were greater than those from other regions ; for SFC versus P , the cost per QALY was 77,100 ( 46,200–241,700 ) USD compared to 24,200 ( 15,200–56,100 ) USD in Western Europe . Compared with P , SFC has a lower incremental cost-effectiveness ratio than either FP or Salm used alone , and is , therefore , preferred to these monotherapies on the grounds of cost-effectiveness [9519948] BACKGROUND The efficacy of inhaled corticosteroids in the treatment of chronic obstructive pulmonary disease ( COPD ) remains controversial because of a lack of placebo-controlled studies . We compared the effect of inhaled fluticasone propionate with placebo in the treatment of patients with COPD . METHODS We used a r and omised , double-blind , placebo-controlled design . We enrolled from 13 European countries , New Zeal and , and South Africa , 281 outpatient current or ex-smokers , aged between 50 and 75 years . They had a forced expiratory volume in 1 s ( FEV1 ) of between 35 % and 90 % of predicted normal values , a ratio of FEV1 to forced vital capacity of 70 % or less and bronchodilator reversibility of less than 15 % , as well as a history of chronic bronchitis . Patients were r and omly assigned fluticasone propionate 500 microg ( n=142 ) or placebo ( n=139 ) twice daily via a metered-dose inhaler for 6 months . The main outcome measures were the number of patients who had at least one exacerbation by the end of treatment , the number and severity of exacerbations , clinic lung function , diary card symptoms and peak expiratory flow and 6 min walking distance . FINDINGS 51 ( 37 % ) patients in the placebo group compared with 45 ( 32 % ) in the fluticasone propionate group had had at least one exacerbation by the end of treatment ( p=0.449 ) . Significantly more patients had moderate or severe exacerbations in the placebo group than in the fluticasone propionate group ( 86 % vs 60 % , p<0.001 ) . Diary-card and clinic morning peak expiratory flows improved significantly in the fluticasone propionate group ( p<0.001 , p=0.048 , respectively ) , as did clinic FEV1 ( p<0.001 ) , forced vital capacity ( p<0.001 ) , and mid-expiratory flow ( p=0.01 ) . Symptom scores for median daily cough and sputum volume were significantly lower with fluticasone propionate treatment than with placebo ( p=0.004 and p=0.016 , respectively ) . At the end of treatment , patients on fluticasone propionate had increased their 6 min walking distance significantly more than those on placebo ( p=0.032 ) . Fluticasone propionate was tolerated as well as placebo , with few adverse effects and without a clinical ly important effect on mean serum cortisol concentration . INTERPRETATION Fluticasone propionate may be of clinical benefit in patients with COPD over at least 6 months . Inhaled corticosteroids may have an important role in the long-term treatment of COPD [20685748] Background Previous studies have suggested that long-term use of β agonists to treat chronic obstructive pulmonary disease ( COPD ) may increase the risk of cardiovascular adverse events . In this post hoc analysis , data from the TOwards a Revolution in COPD Health ( TORCH ) study were used to investigate whether use of the long-acting β2 agonist salmeterol over 3 years increased the risk of cardiovascular adverse events in patients with moderate to severe COPD . Methods TORCH was a r and omised , double-blind , placebo controlled study conducted at 444 centres in 42 countries . Patients ( n=6184 ; safety population ) received twice daily combined salmeterol 50 μg plus fluticasone propionate 500 μg ( SFC ) , either component alone , or placebo . Adverse events were recorded every 12 weeks for 3 years . Results The probability of having a cardiovascular adverse event by 3 years was 24.2 % for placebo , 22.7 % for salmeterol , 24.3 % for fluticasone propionate and 20.8 % for SFC . Although a history of myocardial infa rct ion doubled the probability of cardiovascular adverse events , the event rates remained similar across treatment groups . Conclusion Post hoc analysis of the 3-year TORCH data set showed that salmeterol alone or in combination ( SFC ) did not increase the risk of cardiovascular events in patients with moderate to severe COPD [16514718] Background : Guidelines recommend inhaled corticosteroids ( ICS ) as maintenance treatment for patients with chronic obstructive pulmonary disease ( COPD ) with a post-bronchodilator forced expiratory volume in 1 second ( FEV1 ) < 50 % predicted and frequent exacerbations , although they have only a small preventive effect on the accelerated decline in lung function . Combined treatment with ICS and long acting β2 agonists ( LABA ) may provide benefit to the stability of COPD , but it is unknown if withdrawal of ICS will result in disease deterioration . Methods : The effects of 1 year withdrawal of the ICS fluticasone propionate ( FP ) after a 3 month run-in treatment period with FP combined with the LABA salmeterol ( S ) ( 500 μg FP + 50 μg S twice daily ; SFC ) were investigated in patients with COPD in a r and omised , double blind study . 497 patients were enrolled from 39 centres throughout the Netherl and s ; 373 were r and omised and 293 completed the study . Results : The drop out rate after r and omisation was similar in the two groups . Withdrawal of FP result ed in a sustained decrease in FEV1 : mean ( SE ) change from baseline −4.4 (0.9)% ( S ) v −0.1 (0.9)% ( SFC ) ; adjusted difference 4.1 ( 95 % CI 1.6 to 6.6 ) percentage points ( p<0.001 ) . Corresponding figures for the FEV1/FVC ratio were −3.7 (0.8)% ( S ) v 0.0 (0.8)% ( SFC ) ( p = 0.002 ) . The annual moderate to severe exacerbation rate was 1.6 and 1.3 in the S and SFC groups , respectively ( adjusted rate ratio 1.2 ; 95 % CI 0.9 to 1.5 ; p = 0.15 ) . The mean annual incidence rate of mild exacerbations was 1.3 ( S ) v 0.6 ( SFC ) , p = 0.020 . An immediate and sustained increase in dyspnoea score ( scale 0–4 ; mean difference between groups 0.17 ( 0.04 ) , p<0.001 ) and in the percentage of disturbed nights ( 6 ( 2 ) percentage points , p<0.001 ) occurred after withdrawal of fluticasone . Conclusions : Withdrawal of FP in COPD patients using SFC result ed in acute and persistent deterioration in lung function and dyspnoea and in an increase in mild exacerbations and percentage of disturbed nights . This study clearly indicates a key role for ICS in the management of COPD as their discontinuation leads to disease deterioration , even under treatment with a LABA [15790985] Background : Combined treatment with inhaled corticosteroids and long acting β2 agonists is approved for the treatment of chronic obstructive pulmonary disease ( COPD ) , but little is known about the onset of effect of the combination . Methods : Data were used from 1465 patients with COPD entered into a large 1 year double blind trial with daily measurements of peak expiratory flow ( PEF ) and symptom scores . Results : PEF was significantly higher after 1 day in patients treated with salmeterol 50 μg twice daily or the salmeterol/fluticasone propionate combination 50/500 μg twice daily than placebo . In patients treated with fluticasone propionate 500 μg twice daily alone , PEF differed from placebo after 2 days . The differences after 2 weeks compared with placebo were 16 l/min ( 95 % confidence interval ( CI ) 11 to 21 ) , 11 l/min ( 95 % CI 6 to 16 ) , and 27 l/min ( 95 % CI 22 to 33 ) for salmeterol , fluticasone propionate , and the salmeterol/fluticasone propionate combination , respectively . For all treatments the effect on PEF after 2 weeks was comparable to that seen at the end of the study . The difference between the salmeterol/fluticasone propionate combination and placebo after 2 weeks as a percentage of baseline was similar for PEF and clinic forced expiratory volume in 1 second ( FEV1 ) . Differences in breathlessness scores were statistically significant after 1 day for the group treated with salmeterol alone and after 2 days for the combination group . The 2 week change in FEV1 was only partly indicative of a long term response in individual patients . Conclusions : The effects of salmeterol and fluticasone propionate , alone or in combination , on PEF and breathlessness are seen within days and most of the obtainable effect on these parameters is reached within 2 weeks [15363007] OBJECTIVE Withdrawal of corticosteroid is associated with a deterioration of health status in COPD . In this study the aim was to determine whether high dose inhaled corticosteroid improves quality of life in patients with COPD . METHODOLOGY In total , 38 male patients with moderate COPD were included in the study . Baseline quality of life scores were determined using a Turkish version of the St George 's Respiratory Question naire ( SGRQ ) . Patients were r and omly divided into two groups . Group 1 consisted of 20 patients who received existing bronchodilator therapy plus inhaled corticosteroid ( 800 micro g budesonide ) for 12 weeks , while 18 patients in group 2 received bronchodilator and placebo . The SGRQ was repeated after the treatment period . RESULTS All patients were male and mean age was 67 + /- 8.2 years . Symptom , activity , impact , and total scores were assessed and a difference of four units with treatment was considered to be clinical ly significant . Total score and activity score were decreased by six units and eight units , respectively , in the placebo group while symptom and impact scores did not change significantly . Total scores and the three component scores improved significantly in the corticosteroid group compared to the placebo group ( Deltatotal score : -22 in corticosteroid group , -6 in placebo group , P < 0.01 ) . CONCLUSION Inhaled corticosteroid improved quality of life scores in patients with COPD , without significant improvement in airflow obstruction parameters . Since improvement of health status is one of the important aims in COPD treatment , use of inhaled corticosteroids should be considered from this perspective [19841453] BACKGROUND Inhaled corticosteroids ( ICSs ) and long-acting beta(2)-agonists ( LABAs ) are used to treat moderate to severe chronic obstructive pulmonary disease ( COPD ) . OBJECTIVE To determine whether long-term ICS therapy , with and without LABAs , reduces inflammation and improves pulmonary function in COPD . DESIGN R and omized , placebo-controlled trial . ( Clinical Trials.gov registration number : NCT00158847 ) SETTING 2 university medical centers in The Netherl and s. PATIENTS 114 steroid-naive current or former smokers with moderate to severe COPD . MEASUREMENTS Cell counts in bronchial biopsies and sputum ( primary outcome ) ; methacholine responsiveness at baseline , 6 , and 30 months ; and clinical outcomes every 3 months . INTERVENTION R and om assignment by minimization method to receive fluticasone propionate , 500 microg twice daily , for 6 months ( n = 31 ) or 30 months ( n = 26 ) ; fluticasone , 500 microg twice daily , and salmeterol , 50 microg twice daily , for 30 months ( single inhaler ; n = 28 ) ; or placebo twice daily ( n = 29 ) . RESULTS 101 patients were greater than 70 % adherent to therapy . Fluticasone therapy decreased counts of mucosal CD3(+ ) cells ( -55 % [ 95 % CI , -74 % to -22 % ] ; P = 0.004 ) , CD4(+ ) cells ( -78 % [ CI , -88 % to 60 % ] ; P < 0.001 ) , CD8(+ ) cells ( -57 % [ CI , -77 % to -18 % ] ; P = 0.010 ) , and mast cells ( -38 % [ CI , -60 % to -2 % ] ; P = 0.039 ) and reduced hyperresponsiveness ( P = 0.036 ) versus placebo at 6 months , with effects maintained after 30 months . Fluticasone therapy for 30 months reduced mast cell count and increased eosinophil count and percentage of intact epithelium , with accompanying reductions in sputum neutrophil , macrophage , and lymphocyte counts and improvements in FEV(1 ) decline , dyspnea , and quality of life . Reductions in inflammatory cells correlated with clinical improvements . Discontinuing fluticasone therapy at 6 months increased counts of CD3(+ ) cells ( 120 % [ CI , 24 % to 289 % ] ; P = 0.007 ) , mast cells ( 218 % [ CI , 99 % to 407 % ] ; P < 0.001 ) , and plasma cells ( 118 % [ CI , 9 % to 336 % ] ; P = 0.028 ) and worsened clinical outcome . Adding salmeterol improved FEV(1 ) level . LIMITATIONS The study was not design ed to evaluate clinical outcomes . Measurement of primary outcome was not available for 24 % of patients at 30 months . CONCLUSION ICS therapy decreases inflammation and can attenuate decline in lung function in steroid-naive patients with moderate to severe COPD . Adding LABAs does not enhance these effects . [12379552] This r and omized controlled trial examined the benefits of combining an inhaled corticosteroid , fluticasone propionate ( F ) , with an inhaled long-acting beta(2)-agonist , salmeterol ( S ) , to treat the inflammatory and bronchoconstrictive components of chronic obstructive pulmonary disease ( COPD ) . A total of 691 patients with COPD received the combination of F and S ( FSC ) , S ( 50 mcg ) , F ( 500 mcg ) , or placebo twice daily via the Diskus device for 24 weeks . A significantly greater increase in predose FEV(1 ) at the endpoint was observed after FSC ( 156 ml ) compared with S ( 107 ml , p = 0.012 ) and placebo ( -4 ml , p < 0.0001 ) . A significantly greater increase in 2-hour postdose FEV(1 ) at the endpoint was observed after treatment with FSC ( 261 ml ) compared with F ( 138 ml , p < 0.001 ) and placebo ( 28 ml , p < 0.001 ) . There were greater improvements in the Transition Dyspnea Index with FSC ( 2.1 ) compared with F ( 1.3 , p = 0.033 ) , S ( 0.9 , p < 0.001 ) , and placebo ( 0.4 , p < 0.0001 ) . The incidence of adverse effects ( except for an increase in oral c and idiasis with FSC and F ) was similar among the treatment groups . We conclude that FSC improved lung function and reduced the severity of dyspnea compared with individual components and placebo [18620853] The Inhaled Steroids in Obstructive Lung Disease ( ISOLDE ) study was a trial that r and omised 752 patients with moderate to severe COPD to fluticasone propionate 1000 mcg/day or placebo for three years . We aim ed to examine the causes of death of the ISOLDE participants after the original three up to 13 years post-r and omisation . Death certificates were obtained either from the NHS Strategic Tracing Service or from the Office of National statistics . Deaths were classified according to the trial protocol . In the sub sample of 375 participants from the seven ISOLDE original centers where complete extended follow-up was conducted , the factors associated with observed higher mortality ( p<0.05 ) were male gender , older age and more severe COPD . Causes of death were ; 107 ( 52 % ) respiratory , 38 ( 18 % ) cardiac , 29 ( 14 % ) lung cancer , 16 ( 8 % ) other cancer and 16 ( 8 % ) other causes . The percentage of respiratory-related deaths increased during the follow-up period ; from 46 % within the three-year trial , to 48 % after 3 - 6 years , 57 % after 6 - 9 years , and 60 % after 9 - 13 years of follow-up ( p for trend<0.05 ) . We conclude that participants ' survival is poor ( only 44 % in the 13 years after the ISOLDE trial ) , and that respiratory-related illnesses were the most frequent causes of death in patients with moderate to severe COPD [15946834] Chronic obstructive pulmonary disease ( COPD ) is characterised by a chronic inflammatory process in the large and small airways , as well as in the lung parenchyma . Although the role of oral corticosteroids in the management of acute exacerbations of COPD is well documented , its role in stable COPD is not clear . We examined the anti-inflammatory effect of inhaled budesonide on the percentage of neutrophils and on interleukin-8 ( IL-8 ) levels in bronchoalveolar lavage ( BAL ) and their correlation with spirometry and symptom scores . Twenty-six patients with stable COPD were r and omised , in a double-blinded , placebo-controlled trial with either 800 microg of inhaled budesonide or placebo for a 6-month period . The budesonide-treated subjects had significant reductions in IL-8 levels in the BAL after therapy ( mean+/-sem , 1.53+/-0.72 at baseline vs. 0.70+/-0.48 ng/ml at 6 months , P=0.004 ) and a reduction in the mean percentages of neutrophils ( 17.16+/-2.67 % vs. 13.25+/-2.28 % P=0.002 ) . The improvement in sputum production was of borderline ( P=0.058 ) significance but there was no improvement in lung function . In stable patients with COPD , treatment with inhaled budesonide for a period of 6 months has a positive effect on markers of lung inflammation , as assessed by reduction in percentage neutrophils and IL-8 concentration in BAL [21299472] Introduction : Whether smoking-induced lung inflammation subsides after smoking cessation is currently a matter of debate . We used computed tomography ( CT ) to evaluate the effect of smoking cessation on lung density in patients with COPD . Material and methods : Thirty-six patients quit smoking out of 254 current smokers with COPD who were followed with annual CT and lung function tests ( LFT ) for 2–4 years as part of a r and omised placebo-controlled trial of the effect of inhaled budesonide on CT-lung density . Lung density was expressed as the 15th percentile density ( PD15 ) and relative area of emphysema below -910 HU ( RA-910 ) . From the time-trends in the budesonide and placebo groups the expected CT-lung densities at the first visit after smoking cessation were calculated by linear regression and compared to the observed densities . Results : Following smoking cessation RA-910 increased by 2.6 % ( p = 0.003 ) and PD15 decreased by −4.9 HU ( p = 0.0002 ) . Furthermore , changes were larger in the budesonide group than the placebo group ( PD15 : −7.1 vs −2.8 HU . RA-910 3.7 % vs 1.7 % ) . These differences were , however , not statistically significant . The LFT parameters ( FEV1 and diffusion capacity ) were not significantly influenced by smoking cessation . Conclusion : Inflammation partly masks the presence of emphysema on CT and smoking cessation results in a paradoxical fall in lung density , which resembles rapid progression of emphysema . This fall in density is probably due to an anti-inflammatory effect of smoking cessation [15853436] Abstract Objective : To compare the healthcare costs and effects of budesonide/formoterol in a single inhaler with those of budesonide and formoterol monotherapies , and placebo , in a multinational study in patients with chronic obstructive pulmonary disease ( COPD ) , National Heart , Lung and Blood Institute (NHLBI)/WHO Global Initiative for Chronic Obstructive Lung Disease ( GOLD ) stages III or IV . Previous analysis of the clinical data from the study had shown that budesonide/formoterol was associated with better lung function and improved health-related QOL compared with the monocomponents or placebo and lower frequency of exacerbations compared with formoterol and placebo . Method : Patients ( n = 1022 ) were r and omised to twice-daily treatment with two inhalations of budesonide/formoterol ( 160μg/4.5μg ) in a single inhaler , budesonide 200μg , formoterol 4.5μg or placebo for 12 months . Data on medication and healthcare use were combined with Swedish unit cost data to estimate the total annual healthcare cost per patient from the Swedish healthcare payer perspective . Costs were valued in Swedish kronor ( SEK ) [ 2001 values ] and converted to euros ( SEK1 = € 0.11 , 25th April 2003 ) . Results : This evaluation estimated the total annual healthcare costs per patient to be numerically lower for budesonide/formoterol ( € 2518 ) than for budesonide ( € 3194 ) , formoterol ( € 3653 ) or placebo ( € 3213 ) . Cost-effectiveness acceptability curves suggest that budesonide/formoterol may be cost effective compared with formoterol , even if the decision maker is not willing to pay anything for the additional clinical effects , and that budesonide/formoterol is cost effective compared with placebo if a decision maker is willing to pay about € 2 per day , per avoided exacerbation . Conclusion : This economic analysis suggests that the clinical benefits of using budesonide/formoterol in a single inhaler are achieved at a numerically lower total healthcare cost than either monocomponent or placebo . Budesonide/formoterol in patients with severe COPD ( GOLD stages III or IV ) may be cost effective , from the healthcare provider perspective , compared with either monocomponent [17053207] RATIONALE Exacerbations of chronic obstructive pulmonary disease ( COPD ) greatly contribute to declining health status and the progression of the disease , thereby incurring significant direct and indirect health care costs . The prevention of exacerbations , therefore , is an important treatment goal . OBJECTIVES To assess the impact of combination therapy with salmeterol/fluticasone propionate compared with salmeterol alone on moderate and severe exacerbations in patients with severe COPD and a history of repeated exacerbations . METHODS R and omized , double-blind , parallel-group study . After a 4-wk run-in period , 994 clinical ly stable patients were r and omized to one of two treatment groups : 507 patients received the salmeterol/fluticasone combination 50/500 micro g twice daily and 487 received salmeterol 50 micro g twice daily for 44 wk . MAIN RESULTS The total number of exacerbations was 334 in the combination therapy and 464 in the salmeterol group ( p < 0.0001 ) . The annualized rate of moderate and severe exacerbations per patient was 0.92 in the combination therapy and 1.4 in the salmeterol group , corresponding to a 35 % decrease . In addition , the mean time to first exacerbation in the combination therapy group was significantly longer compared with that of the salmeterol group ( 128 vs. 93 d , p < 0.0001 ) . Other endpoints , including health-related quality of life , peak expiratory flow , and use of rescue medication , were significantly improved in the combination therapy group . Both treatments were well tolerated . CONCLUSIONS This study demonstrates that combination therapy with salmeterol/fluticasone compared with salmeterol monotherapy significantly reduces the frequency of moderate/severe exacerbations in patients with severe COPD [10359405] BACKGROUND Little is known about the long-term efficacy of inhaled corticosteroids in chronic obstructive pulmonary disease ( COPD ) . We investigated the efficacy of inhaled budesonide on decline in lung function and respiratory symptoms in a 3-year placebo-controlled study of patients with COPD . METHODS We used a parallel-group , r and omised , double-blind , placebo-controlled design in a singlecentre study , nested in a continuing epidemiological survey ( the Copenhagen City Heart Study ) . Inclusion criteria were as follows : no asthma ; a ratio of forced expiratory volume in 1 s ( FEV1 ) and vital capacity of 0.7 or less ; FEV1 which showed no response ( < 15 % change ) to 1 mg inhaled terbutaline or prednisolone 37.5 mg orally once daily for 10 days . 290 patients were r and omly assigned budesonide , 800 microg plus 400 microg daily for 6 months followed by 400 microg twice daily for 30 months , or placebo for 36 months . The mean age of the participants was 59 years and the mean FEV1 2.37 L or 86 % of predicted . The main outcome measure was rate of FEV1 decline . Analyses were by intention to treat . FINDINGS The crude rates of FEV1 decline were slightly smaller than expected ( placebo group 41.8 mL per year , budesonide group 45.1 mL per year ) . The estimated rates of decline from the regression model did not differ significantly ( 49.1 mL vs 46.0 mL per year ; difference 3.1 mL per year [ 95 % CI -12.8 to 19.0 ] ; p=0.7 ) . Before the study , the minimum relevant difference was defined as 20 mL per year ; this difference was outside the 95 % CI . No effect of inhaled budesonide was seen on respiratory symptoms . 316 exacerbations occurred during the study period , 155 in the budesonide group and 161 in the placebo group . Treatment was well tolerated . INTERPRETATION Inhaled budesonide was of no clinical benefit in COPD patients recruited from the general population by screening . We question the role of long-term inhaled corticosteroids in the treatment of mild to moderate COPD [19581353] BACKGROUND Osteoporosis is common in patients with COPD , but its prevalence and progression are not well characterized . Concerns have been raised over the possible deleterious effect of long-term therapy with inhaled corticosteroids ( ICSs ) on bone density in this population . Here , we investigated the long-term effects of therapy with fluticasone propionate ( FP ) alone , salmeterol ( SAL ) alone , and a SAL/FP combination ( SFC ) on bone mineral density ( BMD ) and bone fractures in patients with moderate-to-severe COPD in the TOwards a Revolution in COPD Health ( TORCH ) study . METHODS A r and omized , double-blind , parallel-group , placebo-controlled study conducted at 88 US centers involving 658 patients ( a subset of 6,184 international subjects in TORCH ) . Therapy with placebo , SAL ( 50 microg ) , FP ( 500 microg ) , or SFC ( SAL 50 microg/FP 500 microg ) twice daily was administered for 3 years . Baseline and yearly measurements of BMD at the hip and lumbar spine were performed . The incidence of traumatic and nontraumatic bone fractures was recorded . RESULTS At baseline , 18 % of men and 30 % of women had osteoporosis , and 42 % of men and 41 % of women had osteopenia based on BMD assessment s. Forty-three percent of subjects completed all testing . The changes in BMD at the hip and lumbar spine over 3 years were small . No significant differences were observed between treatment arms ( adjusted mean percent change from baseline at hip was -3.1 % for placebo , -1.7 % for SAL , -2.9 % for FP , and -3.2 % for SFC therapy , respectively ; while , the corresponding changes for the lumbar spine were 0 , 1.5 % , -0.3 % , and -0.3 % for placebo , respectively , SAL , FP , and SFC therapy ) . The incidence of fractures was low and was similar for all treatments ( 5.1 % to 6.3 % ) . CONCLUSIONS Osteoporosis is highly prevalent in patients with COPD , irrespective of gender . In the TORCH study , no significant effect on BMD was detected for ICS therapy compared with placebo . TRIAL REGISTRATION Clinical Trials.gov Identifier : NTC00268216 [10421835] Treatment of chronic obstructive pulmonary disease ( COPD ) with inhaled and oral corticosteroids is common , although their exact role is unclear . Previous studies suggest these drugs may reduce decline in lung function in this group of patients . We report a study investigating the effect of inhaled beclomethasone diproprionate ( BDP ) on lung function and symptoms in a group of patients with COPD . Treatment was given for 2 years , and the decline in FEV1 in individual patients calculated over this period . Ninety‐eight patients were r and omized for the study , 59 completing 2 years of treatment . Patients withdrawn had more severe airflow obstruction . Decline in FEV1 , measured both prior to and after bronchodilator , was less in patients receiving inhaled BDP , although the differences failed to reach statistical significance except in a subgroup of patients with more severe airflow obstruction . Exacerbation rates were also reduced by inhaled BDP , but again the differences failed to reach conventional levels of statistical significance . The results of this study are consistent with previous published work , but further insight into the long‐term role of corticosteroids in COPD await the publication of large studies which have recently been completed . Although the changes seen in this study and others are numerically small , the rate of decline in FEV1 returned to normal levels expected from age‐related decline , and hence such treatment combined with other strategies may well have a significant role in the long‐term treatment of this condition [10379018] BACKGROUND Although patients with chronic obstructive pulmonary disease ( COPD ) should stop smoking , some do not . In a double-blind , placebo-controlled study , we evaluated the effect of the inhaled glucocorticoid budesonide in patients with mild COPD who continued smoking . After a six-month run-in period , we r and omly assigned 1277 subjects ( mean age , 52 years ; mean forced expiratory volume in one second [ FEV1 ] , 77 percent of the predicted value ; 73 percent men ) to twice-daily treatment with 400 microg of budesonide or placebo , inhaled from a dry-powder inhaler , for three years . RESULTS Of the 1277 subjects , 912 ( 71 percent ) completed the study . Among these subjects , the median decline in the FEV1 after the use of a bronchodilator over the three-year period was 140 ml in the budesonide group and 180 ml in the placebo group ( P=0.05 ) , or 4.3 percent and 5.3 percent of the predicted value , respectively . During the first six months of the study , the FEV1 improved at the rate of 17 ml per year in the budesonide group , as compared with a decline of 81 ml per year in the placebo group ( P<0.001 ) . From nine months to the end of treatment , the FEV1 declined at similar rates in the two groups ( P=0.39 ) . Ten percent of the subjects in the budesonide group and 4 percent of those in the placebo group had skin bruising ( P<0.001 ) . Newly diagnosed hypertension , bone fractures , postcapsular cataracts , myopathy , and diabetes occurred in less than 5 percent of the subjects , and the diagnoses were equally distributed between the groups . CONCLUSIONS In patients with mild COPD who continue smoking , the use of inhaled budesonide is associated with a small one-time improvement in lung function but does not appreciably affect the long-term progressive decline [12070058] Inhaled corticosteroids ( ICS ) are effective in the treatment of asthma and markedly reduce the numbers of inflammatory cells in bronchial biopsies . However , the effect of ICS on the inflammatory profile of biopsies in smokers with chronic obstructive pulmonary disease ( COPD ) is unknown . We have performed a double-blind , placebo-controlled , r and omized study to compare fluticasone propionate ( FP ) 500 microg twice daily via a dry powder inhaler and placebo ( P ) over a 3-month period in subjects with COPD . Fiberoptic bronchoscopy and bronchial biopsy was carried out at baseline and after the 3 months of treatment . Thirty-one subjects completed the trial and 30 paired biopsies were available for analysis . Compared with P ( n = 14 ) , subjects on inhaled FP ( n = 16 ) had no significant reductions in the primary endpoints : CD8 + , CD68 + cells , or neutrophils , considered to be of importance in COPD . However , there was a reduction in the CD8:CD4 ratio in the epithelium and of the numbers of subepithelial mast cells in the FP group . CD4 + cells were significantly raised in the P group in both subepithelium and epithelium . Symptoms significantly improved , and there were significantly fewer exacerbations in subjects on FP , compared to subjects on P. The data indicate that inhaled fluticasone does affect selected aspects of airway inflammation in COPD , and this may explain , in part , the decrease in exacerbations seen in long-term studies with fluticasone propionate [18778120] BACKGROUND The combination of an inhaled corticosteroid ( ICS ) and a long-acting bronchodilator is recommended in the treatment of patients with chronic obstructive pulmonary disease ( COPD ) who have frequent exacerbations . Budesonide/formoterol dry powder inhaler ( DPI ) has demonstrated efficacy and tolerability in patients with COPD . OBJECTIVE To evaluate the efficacy and tolerability of budesonide/formoterol administered via one hydrofluoroalkane pressurized metered-dose inhaler ( pMDI ) in patients with COPD . METHODS This was a 6-month , r and omized , double-blind , double-dummy , placebo-controlled , parallel-group , multicentre study ( NCT00206154 ) of 1704 patients aged > or = 40 years with moderate to very severe COPD conducted in 194 centres in the US , Czech Republic , the Netherl and s , Pol and and South Africa . After 2 weeks of treatment based on previous therapy ( ICSs and short-acting bronchodilators allowed during the run-in period ) , patients received one of the following treatments administered twice daily : budesonide/formoterol pMDI 160/4.5 microg x two inhalations ( 320/9 microg ) ; budesonide/formoterol pMDI 80/4.5 microg x two inhalations ( 160/9 microg ) ; budesonide pMDI 160 microg x two inhalations ( 320 microg ) plus formoterol DPI 4.5 microg x two inhalations ( 9 microg ) ; budesonide pMDI 160 microg x two inhalations ( 320 microg ) ; formoterol DPI 4.5 microg x two inhalations ( 9 microg ) ; or placebo . MAIN OUTCOME MEASURES The co- primary efficacy variables were pre-dose forced expiratory volume in 1 second ( FEV(1 ) ) and 1-hour post-dose FEV(1 ) . RESULTS Budesonide/formoterol 320/9 microg demonstrated significantly greater improvements in pre-dose FEV(1 ) versus formoterol ( p = 0.026 ; pre-specified primary comparator ) and 1-hour post-dose FEV(1 ) versus budesonide ( p < 0.001 ; pre-specified primary comparator ) ; budesonide/formoterol 160/9 microg demonstrated significantly greater improvements versus budesonide ( p < 0.001 ) for 1-hour post-dose FEV(1 ) but not versus formoterol for pre-dose FEV(1 ) . Dyspnoea ( measured using the Breathlessness Diary ) and health-related quality -of-life ( HR-QOL ) scores ( based on the St George 's Respiratory Question naire total score ) were significantly improved with both dosage strengths of budesonide/formoterol compared with budesonide , formoterol and placebo ( p < or = 0.044 for all ) . Although not powered a priori for comparisons , the number of exacerbations per patient-treatment year requiring treatment with oral corticosteroids and /or hospitalization was numerically ( 20 - 25 % ) lower with the budesonide-containing treatments ( 0.710 - 0.884 ) versus formoterol ( 1.098 ) and placebo ( 1.110 ) . This result was driven by the exacerbations requiring treatment with oral corticosteroids ( 79 - 120 events ) . The number of exacerbations result ing in hospitalization was very low across treatment groups ( 11 - 22 ) ; the number per patient-treatment year was significantly different for budesonide/formoterol 320/9 microg ( 0.158 ) versus other treatment groups ( 0.081 - 0.108 ) except budesonide/formoterol 160/9 microg ( 0.139 ) , and for budesonide/formoterol 160/9 microg versus formoterol ( 0.081 ) [ p < or = 0.05 ] . All treatments were generally well tolerated . The incidence of individual non-fatal serious adverse events was similar across all treatment groups , except COPD , which was highest in the budesonide/formoterol 320/9 microg group ( 6.1 % ) and lowest in the budesonide ( 3.6 % ) and formoterol ( 3.9 % ) groups , with a range of 4.3 - 4.6 % in the budesonide/formoterol 160/9 microg , budesonide plus formoterol and placebo groups . Budesonide/formoterol had a safety profile comparable with that of the monocomponents and placebo . There was no increase in the incidence of pneumonia in the active treatment groups relative to placebo . CONCLUSIONS Budesonide/formoterol pMDI 320/9 microg demonstrated significantly greater efficacy for pulmonary function on both co- primary endpoints versus the pre-specified comparators ( formoterol DPI 9 microg for pre-dose FEV(1 ) and budesonide pMDI 320 microg for 1-hour post-dose FEV(1 ) ) . Budesonide/formoterol pMDI 160/9 microg demonstrated significantly greater efficacy for 1-hour post-dose FEV(1 ) versus budesonide pMDI 320 microg . Dyspnoea scores and HR-QOL were significantly improved with both budesonide/formoterol pMDI dosage strengths versus both monocomponents and placebo . Both budesonide/formoterol pMDI dosage strengths were well tolerated relative to the monocomponents and placebo [19138505] BACKGROUND Increased oxidative stress and bronchial inflammation are important mechanisms in the pathophysiology of COPD . AIM To investigate whether treatment with the inhaled corticosteroid fluticasone propionate ( FP ) or the anti-oxidative agent N-acetylcysteine ( NAC ) are effective in primary care patients . METHODS The study was a 3-year placebo-controlled r and omised controlled trial preceded by a 3-month washout and 2-week prednisolone pre-treatment . Patients were (ex-)smokers with chronic bronchitis or COPD . Interventions were inhaled FP 500microg b.i.d . , oral NAC 600 mg o.d . , or placebo . Exacerbation rate and quality of life measured with the Chronic Respiratory Question naire ( CRQ ) were the primary outcomes , FEV(1 ) decline and respiratory symptoms secondary outcomes . RESULTS 286 patients recruited from 44 general practice s were r and omised . Exacerbation rate was 1.35 times higher for NAC ( p=0.054 ) and 1.30 times higher for FP ( p=0.095 ) compared with placebo . CRQ total scores did not differ between NAC ( p=0.306 ) or FP ( p=0.581 ) treatment compared to placebo . Annual postbronchodilator FEV(1 ) decline was 64mL [ SD 5.4 ] for NAC [ p=0.569 versus placebo ] , 59mL [ SD 5.7 ] for FP [ p=0.935 ] , and 60mL [ SD 5.4 ] for placebo . CONCLUSION No beneficial treatment effects for either high-dosed inhaled fluticasone propionate or oral N-acetylcysteine were observed in our study population of patients with COPD or chronic bronchitis [18614347] OBJECTIVES COPD exacerbations are associated with significant morbidity and mortality . This r and omized , double-blind , parallel-group , multicenter study evaluated the effect of fluticasone propionate/salmeterol 250/50 and salmeterol 50 microg twice daily on moderate to severe exacerbations . METHODS Patients received st and ardized treatment with fluticasone propionate/salmeterol 250/50 during a 1-month run-in , followed by r and omization to fluticasone propionate/salmeterol 250/50 or salmeterol for 12 months . Moderate to severe exacerbations were defined as worsening symptoms of COPD requiring treatment with oral corticosteroids , antibiotics , or hospitalization . RESULTS In 782 patients with COPD ( mean FEV(1)=0.94+/-0.36 L , 33 % predicted normal ) , treatment with fluticasone propionate/salmeterol 250/50 significantly reduced ( 1 ) the annual rate of moderate to severe exacerbations by 30.5 % compared with salmeterol ( 1.06 and 1.53 per subject per year , respectively , p<0.001 ) , ( 2 ) the risk of time to first exacerbation by 25 % ( hazard ratio=0.750 , p=0.003 ) and ( 3 ) the annual rate of exacerbations requiring oral corticosteroids by 40 % ( p<0.001 ) . Clinical improvements observed during run-in treatment with fluticasone propionate/salmeterol 250/50 were better maintained over 12 months with fluticasone propionate/salmeterol 250/50 than salmeterol . Adverse events were reported for a similar percentage of subjects across groups . A higher reporting of pneumonia was observed with fluticasone propionate/salmeterol 250/50 than salmeterol ( 7 % vs. 4 % ) . CONCLUSIONS We conclude that fluticasone propionate/salmeterol 250/50 is more effective than salmeterol at reducing the rate of moderate to severe exacerbations over 1 year . The benefits of this reduction relative to the risk of a higher incidence of reported pneumonia should be considered . This study supports the use of fluticasone propionate/salmeterol 250/50 for the reduction of COPD exacerbations in patients with COPD [12108857] There is a need for study ing the effects of long-term inhaled corticosteroid therapy on bone mineral density ( BMD ) and vertebral fracture rates in patients with mild chronic obstructive pulmonary disease ( COPD ) . Patients ( n=912 , mean age 52 yrs ) with mild COPD ( mean forced expiratory volume in one second ( FEV1 ) 77 % of predicted ; mean FEV1/slow vital capacity ratio 62 % ) were r and omized to receive budesonide 400 µg , or placebo twice daily via Turbuhaler ® . BMD was measured at the L2–L4 vertebrae and the femoral neck , trochanter and Ward 's triangle by dual-energy X-ray absorptiometry at baseline and after 6 , 12 , 24 and 36 months ( n=161 ) . Radiographs of the thoracic and lumbar spine were obtained at the beginning and end of treatment ( n=653 ) . Previous fractures were present at baseline in 43 budesonide-treated patients ( 13.4 % ) and 38 placebo-treated patients ( 11.5 % ) . New fractures occurred in five budesonide-treated patients , compared with three in the placebo group ( p=0.50 ) . There were no significant changes in BMD at any site in budesonide-treated patients , compared with the placebo group , during the course of the study . Budesonide treatment was associated with a slight but statistically significant decrease in the area under the concentration-time curve for serum osteocalcin . In the present study , involving a large group of patients with chronic obstructive pulmonary disease , long-term treatment with budesonide 800 µg·day−1 via Turbuhaler ® had no clinical ly significant effects on bone mineral density or fracture rates [14682412] BACKGROUND Early treatment with inhaled corticosteroids may prevent progression of irreversible obstruction in COPD , especially in patients with bronchial hyperresponsiveness . We investigated the clinical effects of early introduction of inhaled steroids in subjects showing early signs and symptoms of COPD without a prior clinical diagnosis . METHODS Study subjects were detected in a general population screening and monitoring program . Those with a moderately accelerated annual FEV1 decline and persistent respiratory symptoms were invited to participate in a 2-year r and omized controlled trial comparing fluticasone propionate DPI 250 microg b.i.d . with placebo . Pre- and post-bronchodilator ( BD ) FEV1 , PC20 histamine , functional status ( COOP/WONCA charts ) and occurrence of exacerbations were periodically assessed . Subjects recorded respiratory symptoms . Post-BD FEV1 decline served as the main outcome . Multivariable repeated measurements analysis techniques were applied . RESULTS 48 subjects were r and omized ( 24 fluticasone , 24 placebo ) . After 3 months , the post-BD FEV1 had increased with 125 ml ( SE = 68 , P = 0.075 ) and the pre-BD FEV1 with 174 ml ( SE 90 , P = 0.059 ) in the fluticasone relative to the placebo group . The subsequent post-BD and pre-BD FEV1 decline were not beneficially modified by fluticasone treatment . There were no statistically significant differences in respiratory symptoms , functional status , or exacerbations favoring fluticasone . Subgroup analysis indicated that the presence of bronchial hyperresponsiveness modified the initial FEV1 response on fluticasone , but not the subsequent annual FEV1 decline . CONCLUSION Early initiation of inhaled steroid treatment does not seem to affect the progressive deterioration of lung function or other respiratory health outcomes in subjects with early signs and symptoms of COPD . In subjects at risk for , or in an early stage of COPD , long-term inhaled steroid treatment should not be based on a single spirometric evaluation after 3 months [15526804] The prevalence of chronic obstructive pulmonary disease ( COPD ) in women is increasing worldwide . Women may have greater susceptibility to COPD progression than men , and differences in efficacy and safety of respiratory medications by gender are largely unexplored . We aim ed to determine whether the response to treatment in women with COPD differed from men in a large , 1-year double-blind trial ( ' TRISTAN ' ) . In a sensitivity analysis , we compared 539 male and 180 female COPD patients , who were r and omized to the saLmeterol/fluticasone combination 50/500mcg bid or placebo for 12 months . Combination therapy improved pre-treatment FEV1 significantly more than placebo in women by 152 ml ( 95 % confidence interval 95 - 208 ) and in men by 127 ml ( 94 - 159 ) . Similarly , a reduction in COPD exacerbation rates of 31 % in women ( 9 - 48 % ) and of 23 % in men ( 8 - 35 % ) was observed . Combination therapy reduced COPD exacerbations requiring treatment with oral corticosteroids by 36 % in women and by 41 % in men . Finally , combination treatment produced a better improvement in health status than placebo with a decrease in the SGRQ scores in women by -2.3 ( -4.6 - 0.1 ) and in men by -2.1 ( -3.5 to -0.8 ) . No gender interaction was found for any outcome . Treatments were well tolerated with no difference in the frequency of adverse events in women and men . In this trial , therapy with the salmeterol/fluticasone combination produced significant improvements compared to placebo on all main endpoints and the magnitude of these improvements was similar for both men and women [23332861] BACKGROUND Once-daily combination treatment is an attractive maintenance therapy for COPD . However , the dose of inhaled corticosteroid to use in a once-daily combination is unknown . We compared two strengths of fluticasone furoate ( FF ) plus vilanterol ( VI ) , the same strengths of the individual components , and placebo . METHODS Multicentre , r and omised , 24-week , double-blind , placebo-controlled , parallel-group study in stable , moderate-to-severe COPD subjects ( N = 1224 ) . Subjects were r and omised to FF/VI ( 200/25 μg ; 100/25 μg ) , FF ( 200 μg ; 100 μg ) , VI 25 μg , or placebo , once daily in the morning . Co- primary efficacy endpoints ; 0 - 4 h weighted mean ( wm ) FEV(1 ) on day 168 , and change from baseline in trough ( 23 - 24 h post-dose ) FEV(1 ) on day 169 . The primary safety objective was adverse events ( AEs ) . RESULTS There was a statistically significant ( p < 0.001 ) increase in wm FEV(1 ) ( 209 ml ) and trough FEV(1 ) ( 131 ml ) for FF/VI 200/25 μg vs. placebo ; similar changes were seen for FF/VI 100/25 μg vs. placebo . Whereas the difference between FF/VI 200/25 μg and VI 25 μg in change from baseline trough FEV(1 ) ( 32 ml ) was not statistically significant ( p = 0.224 ) , the difference between FF/VI 200/25 μg and FF 200 μg for wm FEV(1 ) ( 168 ml ) was significantly different ( p < 0.001 ) . VI 25 μg significantly improved wm and trough FEV(1 ) vs. placebo ( 185 ml and 100 ml , [ corrected ] respectively ) . No increase was seen in on-treatment AEs or serious AEs ( SAEs ) , with active therapy vs. placebo . CONCLUSIONS FF/VI provides rapid and significant sustained improvement in FEV(1 ) in subjects with moderate-to-severe COPD , which was not influenced by the dose of FF . These data suggest that FF/VI may offer clinical efficacy in COPD and warrants additional study . GSK study number : HZC112207 . Clinical Trials.gov : NCT01054885 [16903992] OBJECTIVES To explore the cost-effectiveness of fluticasone propionate ( FP ) for the treatment of chronic obstructive pulmonary disease ( COPD ) , we estimated costs and quality -adjusted life-years ( QALYs ) over 3 years , based on an economic appraisal of a previously reported clinical trial ( Inhaled Steroids in Obstructive Lung Disease in Europe [ ISOLDE ] ) . METHODS Seven hundred forty-two patients enrolled in the ISOLDE trial who received either FP or placebo had data available on health-care costs and quality of life over the period of the study . The SF-36-based utility scores for quality of life were used to calculate QALYs . A combined imputation and bootstrapping procedure was employed to h and le missing data and to estimate statistical uncertainty in the estimated cumulative costs and QALYs over the study period . The imputation approach was based on propensity scoring and nesting this approach within the bootstrap ensured that multiple imputations were performed such that statistical estimates included imputation uncertainty . RESULTS Complete data were available on mortality within the follow-up period of the study and a nonsignificant trend toward improved survival of 0.06 ( 95 % confidence interval [CI]-0.01 to 0.15 ) life-years was observed . In an analysis based on a propensity scoring approach to missing data we estimated the incremental costs of FP versus placebo to be 1021 sterling pound(95 % CI 619 - 1338 sterling pound ) with an additional effect of 0.11 QALYs ( CI 0.04 - 0.20 ) . Cost-effectiveness estimates for the within-trial period of 17,700 sterling pound per life-year gained ( 6900 sterling pound to infinity ) and 9500 sterling pound per QALY gained ( CI 4300 - 26,500 sterling pound ) were generated that include uncertainty due to the imputation process . An alternative imputation approach did not material ly affect these estimates . CONCLUSIONS Previous analyses of the ISOLDE study showed significant improvement on disease-specific health status measures and a trend toward a survival advantage for treatment with FP . This analysis shows that joint considerations of quality of life and survival result in a substantial increase in QALYs favoring treatment with FP . Based on these data , the inhaled corticosteroid FP appears cost-effective for the treatment of COPD . Confirmation or refutation of this result may be achieved once the Towards a Revolution in COPD Health ( TORCH ) study reports , a large r and omized controlled trial powered to detect mortality changes associated with the use of FP alone , or in combination with salmeterol , which is also collecting re source use and utility data suitable for estimating cost-effectiveness [16014203] OBJECTIVES To survey the frequency of use of indirect comparisons in systematic review s and evaluate the methods used in their analysis and interpretation . Also to identify alternative statistical approaches for the analysis of indirect comparisons , to assess the properties of different statistical methods used for performing indirect comparisons and to compare direct and indirect estimates of the same effects within review s. DATA SOURCES Electronic data bases . REVIEW METHODS The Data base of Abstract s of Review s of Effects ( DARE ) was search ed for systematic review s involving meta- analysis of r and omised controlled trials ( RCTs ) that reported both direct and indirect comparisons , or indirect comparisons alone . A systematic review of MEDLINE and other data bases was carried out to identify published methods for analysing indirect comparisons . Study design s were created using data from the International Stroke Trial . R and om sample s of patients receiving aspirin , heparin or placebo in 16 centres were used to create meta-analyses , with half of the trials comparing aspirin and placebo and half heparin and placebo . Methods for indirect comparisons were used to estimate the contrast between aspirin and heparin . The whole process was repeated 1000 times and the results were compared with direct comparisons and also theoretical results . Further detailed case studies comparing the results from both direct and indirect comparisons of the same effects were undertaken . RESULTS Of the review s identified through DARE , 31/327 ( 9.5 % ) included indirect comparisons . A further five review s including indirect comparisons were identified through electronic search ing . Few review s carried out a formal analysis and some based analysis on the naive addition of data from the treatment arms of interest . Few method ological papers were identified . Some valid approaches for aggregate data that could be applied using st and ard software were found : the adjusted indirect comparison , meta-regression and , for binary data only , multiple logistic regression ( fixed effect models only ) . Simulation studies showed that the naive method is liable to bias and also produces over-precise answers . Several methods provide correct answers if strong but unverifiable assumptions are fulfilled . Four times as many similarly sized trials are needed for the indirect approach to have the same power as directly r and omised comparisons . Detailed case studies comparing direct and indirect comparisons of the same effect show considerable statistical discrepancies , but the direction of such discrepancy is unpredictable . CONCLUSIONS Direct evidence from good- quality RCTs should be used wherever possible . Without this evidence , it may be necessary to look for indirect comparisons from RCTs . However , the results may be susceptible to bias . When making indirect comparisons within a systematic review , an adjusted indirect comparison method should ideally be used employing the r and om effects model . If both direct and indirect comparisons are possible within a review , it is recommended that these be done separately before considering whether to pool data . There is a need to evaluate methods for the analysis of indirect comparisons for continuous data and for empirical research into how different methods of indirect comparison perform in cases where there is a large treatment effect . Further study is needed into when it is appropriate to look at indirect comparisons and when to combine both direct and indirect comparisons . Research into how evidence from indirect comparisons compares to that from non-r and omised studies may also be warranted . Investigations using individual patient data from a meta- analysis of several RCTs using different protocol s and an evaluation of the impact of choosing different binary effect measures for the inverse variance method would also be useful [9692107] The European Respiratory Society 's study on chronic obstructive pulmonary disease ( EUROSCOP ) is a multicentre study performed initially in 12 countries to assess the effect of 3 years ' treatment with inhaled corticosteroids on lung function decline in smokers with chronic obstructive pulmonary disease ( COPD ) . It aim ed at recruiting 50 subjects in 50 European centres . This study discusses the most successful , countrywise , recruitment strategies , an important issue since many multicentre European studies may follow in the future . The total number of recruited subjects was 2147 in 39 participating centres . In total , at least 25,000 screening spirometries were performed , and about 80,000 hospital records were checked . The most effective way of recruiting subjects was to screen subjects by spirometry after mass media campaigns ( eight out of nine countries ) . Others used workplace screenings and different types of population survey , and only a few centres successfully recruited participants by hospital records . Inclusion criteria were slightly changed upon low initial accrual rate . Initial surveys in one country , where 2405 subjects were screened by spirometry , gave an important indication for the change of the inclusion criteria . Extension of the upper age limit from 60 to 65 yr considerably improved recruitment , as did a change of the upper limit of FEV1 from below 80 % predicted normal to below 100 % predicted normal , while maintaining the FEV1/VC ratio below 70 % . A tremendous effort is needed to recruit individuals with pre clinical COPD , but this is certainly feasible with adequate strategies adjusted to each country [19880616] The TORCH ( Towards a Revolution in COPD Health ) trial has highlighted some important issues in the design and analysis of long term trials in chronic obstructive pulmonary disease . These include collection of off-treatment exacerbation data , analysis of exacerbation rates and the effect of inclusion of patients receiving inhaled corticosteroids ( ICS ) prior to r and omisation . When effective medications are available to patients who withdraw , inclusion of off-treatment data can mask important treatment effects on exacerbation rates . Analysis of on-treatment data avoids this bias but it needs to be combined with careful analysis of withdrawal patterns across treatments . The negative binomial model is currently the best approach to statistical analysis of exacerbation rates , while analysis of time to exacerbation can supplement this approach . In the TORCH trial , exacerbation rates were higher among patients with previous use of ICS compared to those with no prior use on all study treatments . Retrospective subgroup analysis suggests ICS reduced exacerbation rates compared with placebo , regardless of prior use of ICS before entry to the study . Factorial analysis provides an alternative analysis for trials with combinations of treatments , but assumes no interaction between treatments , an assumption which can not be verified by a significance test . No definitive conclusions can yet be drawn on whether ICS treatment has an effect on mortality [17314337] BACKGROUND Long-acting beta-agonists and inhaled corticosteroids are used to treat chronic obstructive pulmonary disease ( COPD ) , but their effect on survival is unknown . METHODS We conducted a r and omized , double-blind trial comparing salmeterol at a dose of 50 microg plus fluticasone propionate at a dose of 500 microg twice daily ( combination regimen ) , administered with a single inhaler , with placebo , salmeterol alone , or fluticasone propionate alone for a period of 3 years . The primary outcome was death from any cause for the comparison between the combination regimen and placebo ; the frequency of exacerbations , health status , and spirometric values were also assessed . RESULTS Of 6112 patients in the efficacy population , 875 died within 3 years after the start of the study treatment . All-cause mortality rates were 12.6 % in the combination-therapy group , 15.2 % in the placebo group , 13.5 % in the salmeterol group , and 16.0 % in the fluticasone group . The hazard ratio for death in the combination-therapy group , as compared with the placebo group , was 0.825 ( 95 % confidence interval [ CI ] , 0.681 to 1.002 ; P=0.052 , adjusted for the interim analyses ) , corresponding to a difference of 2.6 percentage points or a reduction in the risk of death of 17.5 % . The mortality rate for salmeterol alone or fluticasone propionate alone did not differ significantly from that for placebo . As compared with placebo , the combination regimen reduced the annual rate of exacerbations from 1.13 to 0.85 and improved health status and spirometric values ( P<0.001 for all comparisons with placebo ) . There was no difference in the incidence of ocular or bone side effects . The probability of having pneumonia reported as an adverse event was higher among patients receiving medications containing fluticasone propionate ( 19.6 % in the combination-therapy group and 18.3 % in the fluticasone group ) than in the placebo group ( 12.3 % , P<0.001 for comparisons between these treatments and placebo ) . CONCLUSIONS The reduction in death from all causes among patients with COPD in the combination-therapy group did not reach the predetermined level of statistical significance . There were significant benefits in all other outcomes among these patients . ( Clinical Trials.gov number , NCT00268216 [ Clinical Trials.gov ] . ) [1486974] Chronic obstructive pulmonary disease ( COPD ) is a common disease in industrialised countries and responsible for a considerable morbidity and mortality . Cigarette smoking is the most important aetiological factor . The EUROSCOP trial aims at investigating the hypothesis that airway inflammation plays an important pathogenic role in the development of chronic obstructive airway disease in smokers . In cigarette smokers with poorly reversible airflow obstruction , the effect over 3 yrs of an inhaled glucocorticosteroid , budesonide 400 micrograms b.i.d . , on the decline of lung function , measured as postbronchodilator forced expiratory volume in one second ( FEV1 ) , will be compared with that of placebo . The trial has been design ed to detect a difference in yearly decline of at least 30 ml.year-1 . The study is a parallel group , r and omised , double-blind , multicentre study . Patients will be recruited from 47 centres in 12 countries in Europe . It will start with a run-in consisting of two 3 month periods . During the first 3 months , the patients will be offered a smoking cessation programme . All patients who have not stopped smoking during this period will enter the second half of the run-in where compliance with the dosage regimen will be tested . After these two periods , patients will be r and omised to receive either inhaled budesonide , 400 micrograms b.i.d . , or placebo for a period of 3 yrs [20965712] OBJECTIVES To evaluate the effect of beclomethasone/formoterol versus budesonide/formoterol ( non-inferiority ) and versus formoterol ( superiority ) in patients with severe stable chronic obstructive pulmonary disease ( COPD ) . METHODS A double-blind , double-dummy , r and omised , active-controlled , parallel-group study . After 4 weeks run-in with ipratropium/salbutamol ( 40/200 μg , three times daily ) patients were r and omised to receive beclomethasone/formoterol ( 200/12 μg pressurised metered dose inhaler ) , budesonide/formoterol ( 400/12 μg dry powder inhaler ) or formoterol ( 12 μg dry powder inhaler ) twice daily for 48 weeks . Co- primary efficacy variables were change from baseline to 48 weeks in pre-dose morning forced expiratory volume in 1 s ( FEV(1 ) ) and mean rate of COPD exacerbations . RESULTS Of 718 patients r and omised , 703 ( 232 beclomethasone/formoterol , 238 budesonide/formoterol , 233 formoterol ) were in the ITT analysis . Improvement in pre-dose morning FEV(1 ) was 0.077 L , 0.080 L and 0.026 L for beclomethasone/formoterol , budesonide/formoterol and formoterol respectively ( LS mean from the ANCOVA model ) . Beclomethasone/formoterol was not inferior to budesonide/formoterol ( 95 % CI of the difference -0.052 , 0.048 ) and superior to formoterol ( p = 0.046 ) . The overall rate of COPD exacerbations/patient/year was similar and not statistically significantly different among treatments ( beclomethasone/formoterol 0.414 , budesonide/formoterol 0.423 and formoterol 0.431 ) . Quality of life and COPD symptoms improved in all groups and use of rescue medication decreased . Safety profiles were as expected and treatments well-tolerated . CONCLUSIONS Beclomethasone/formoterol ( 400/24 μg ) treatment for 48 weeks improved pulmonary function , reduced symptoms compared to formoterol , was safe and well-tolerated in patients with severe stable COPD . Neither of the long-acting β2-agonist/inhaled corticosteroid combinations affected the low exacerbation rate seen in this population [19378223] The objective was to evaluate the effect of inhaled corticosteroids on disease progression in smokers with moderate to severe chronic obstructive pulmonary disease ( COPD ) , as assessed by annual computed tomography ( CT ) using lung density ( LD ) measurements . Two hundred and fifty-four current smokers with COPD were r and omised to treatment with either an inhaled corticosteroids ( ICS ) , budesonide 400 μ g bid , or placebo . COPD was defined as FEV1 ≤ 70 % pred , FEV1/FVC ≤ 60 % and no reversibility to β2-agonists and oral corticosteroids . The patients were followed for 2–4 years with biannual spirometry and annual CT and comprehensive lung function tests ( LFT ) . CT images were analysed using Pulmo-CMS software . LD was derived from a pixel-density histogram of the whole lung as the 15thpercentile density ( PD15 ) and the relative area of emphysema at a threshold of −910 Hounsfield units ( RA-910 ) , and both were volume-adjusted to predicted total lung capacity . At baseline , mean age was 64 years and 64 years ; mean number of pack-years was 56 and 56 ; mean FEV1 was 1.53 L ( 51 % pred ) and 1.53 L ( 53 % pred ) ; mean PD15 was 103 g/L and 104 g/L ; and mean RA-910 was 14 % and 13 % , respectively , for the budesonide and placebo groups . The annual fall in PD15 was −1.12 g/L in the budesonide group and −1.81 g/L in the placebo group ( p = 0.09 ) ; the annual increase in RA–910 was 0.4 % in the budesonide group and 1.1 % in the placebo group ( p = 0.02 ) . There was no difference in annual decline in FEV1 between ICS ( −54 mL ) and placebo ( −56 mL ) ( p = 0.89 ) . Long-term budesonide inhalation shows a non-significant trend towards reducing the progression of emphysema as determined by the CT-derived 15th percentile lung density from annual CT scans in current smokers with moderate to severe COPD [11136260] BACKGROUND Chronic obstructive pulmonary disease ( COPD ) results from a progressive decline in lung function , which is thought to be the consequence of airway inflammation . We hypothesized that antiinflammatory therapy with inhaled corticosteroids would slow this decline . METHODS We enrolled 1116 persons with COPD whose forced expiratory volume in one second ( FEV1 ) was 30 to 90 percent of the predicted value in a 10-center , placebo-controlled , r and omized trial of inhaled triamcinolone acetonide administered at a dose of 600 microg twice daily . The primary outcome measure was the rate of decline in FEV1 after the administration of a bronchodilator . The secondary outcome measures included respiratory symptoms , use of health care services , and airway reactivity . In a sub study of 412 participants , we measured bone density in the lumbar spine and femur at base line and one and three years after the beginning of treatment . RESULTS The mean duration of follow-up was 40 months . The rate of decline in the FEV1 after bronchodilator use was similar in the 559 participants in the triamcinolone group and the 557 participants in the placebo group ( 44.2+/-2.9 vs. 47.0+/-3.0 ml per year , P= 0.50 ) . Members of the triamcinolone group had fewer respiratory symptoms during the course of the study ( 21.1 per 100 person-years vs. 28.2 per 100 person-years , P=0.005 ) and had fewer visits to a physician because of a respiratory illness ( 1.2 per 100 person-years vs. 2.1 per 100 person-years , P=0.03 ) . Those taking triamcinolone also had lower airway reactivity in response to methacholine challenge at 9 months and 33 months ( P=0.02 for both comparisons ) . After three years , the bone density of the lumbar spine and the femur was significantly lower in the triamcinolone group ( P < or = 0.007 ) . CONCLUSIONS Inhaled triamcinolone does not slow the rate of decline in lung function in people with COPD , but it improves airway reactivity and respiratory symptoms and decreases the use of health care services for respiratory problems . These benefits should be weighed against the potential long-term adverse effects of triamcinolone on bone mineral density [10581660] The aim of this study was evaluate the predictive value of a 2 week course of prednisolone on the effect of 6 months treatment with inhaled budesonide in patients with stable chronic obstructive pulmonary disease ( COPD ) . Forty patients with stable COPD entered the study , and received prednisolone ( 37.5 mg o.d . ) for 2 weeks . They were subsequently divided into steroid-irreversible and steroid-irreversible , using 15 % of baseline as a dividing point . In each group patients were r and omized to receive budesonide 400 micrograms b.i.d . or placebo for 6 months . During treatment with prednisolone , three patients dropped out because of side effects . Of the remaining 37 , only two patients ( 5 % ) were reversible with prednisolone forced expiratory volume in 1s [ ( FEV1 ) > 15 % of baseline ] , and among the steroid-irreversible , 26 patients were evaluated after 6 months treatment with either placebo or budesonide . No significant differences in spirometry values , symptoms , or number of exacerbations were found between these two groups . Reversibility with prednisolone is rarely seen in COPD . In out patients with stable COPD and no signs of asthma or atopy , 2 weeks treatment with prednisolone seems to be of no value in choosing subsequent long-term therapy [10464871] Withdrawal of inhaled corticosteroids is known to worsen disease control in bronchial asthma but similar data are lacking in chronic obstructive pulmonary disease ( COPD ) . We hypothesized that clinical exacerbations requiring treatment would occur more often in patients whose inhaled corticosteroids were stopped than in other patients not treated with these agents . We studied 272 patients in mean age 65 ( SD 0.8 ) years , mean FEV1 42.8 ( SD 12.6)% predicted , entering the run-in phase of the Inhaled Steroids in Obstructive Lung Disease ( ISOLDE ) trial . All had been clinical ly stable for at least 6 weeks and there were no differences in the degree of bronchodilator reversibility , baseline lung function or pack-years of smoking between the 160 patients receiving inhaled corticosteroids and those not so treated . Inhaled corticosteroids were withdrawn in the first week of the study and during the remaining 7 weeks of the study 38 % of those previously treated with these drugs had an exacerbation compared to 6 % of the chronically untreated group . Patients receiving inhaled corticosteroids reported a longer duration of symptoms but neither this or any other recorded variable predicted the risk of exacerbation . These data suggest that abrupt withdrawal of inhaled corticosteroids should be monitored carefully even in patients with apparently irreversible COPD [10807619] Abstract Objectives : To determine the effect of long term inhaled corticosteroids on lung function , exacerbations , and health status in patients with moderate to severe chronic obstructive pulmonary disease . Design : Double blind , placebo controlled study . Setting : Eighteen UK hospitals . Participants : 751 men and women aged between 40 and 75 years with mean forced expiratory volume in one second ( FEV1 ) 50 % of predicted normal . Interventions : Inhaled fluticasone propionate 500 μg twice daily from a metered dose inhaler or identical placebo . Main outcome measures : Efficacy measures : rate of decline in FEV1 after the bronchodilator and in health status , frequency of exacerbations , respiratory withdrawals . Safety measures : morning serum cortisol concentration , incidence of adverse events . Results : There was no significant difference in the annual rate of decline in FEV1 ( P=0.16 ) . Mean FEV1 after bronchodilator remained significantly higher throughout the study with fluticasone propionate compared with placebo ( P<0.001 ) . Median exacerbation rate was reduced by 25 % from 1.32 a year on placebo to 0.99 a year on with fluticasone propionate ( P=0.026 ) . Health status deteriorated by 3.2 units a year on placebo and 2.0 units a year on fluticasone propionate ( P=0.0043 ) . Withdrawals because of respiratory disease not related to malignancy were higher in the placebo group ( 25 % v 19 % , P=0.034 ) . Conclusions : Fluticasone propionate 500 μg twice daily did not affect the rate of decline in FEV1 but did produce a small increase in FEV1 . Patients on fluticasone propionate had fewer exacerbations and a slower decline in health status . These improvements in clinical outcomes support the use of this treatment in patients with moderate to severe chronic obstructive pulmonary disease [21159140] Introduction : R and omised controlled trials ( RCTs ) are considered the least biased method for evaluating drug efficacy and several large long‐term RCTs in chronic obstructive pulmonary disease have been published . These usually include drugs with symptomatic benefits and have significant withdrawal rates

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### Context: [23018908] Chronic obstructive pulmonary disease ( COPD ) often coexists with other chronic diseases and comorbidities that can markedly influence patients ' health status and prognosis . This is particularly true for cardiovascular disease ( CVD ) . However , there have been no trials assessing the effect of COPD medications on CVD in patients with both diseases . The “ Study to Underst and Mortality and Morbidity in COPD ” ( SUMMIT ) aims at determining the impact of fluticasone furoate/vilanterol combination and the individual components on the survival of patients with moderate COPD and either a history of CVD or at increased risk for CVD . SUMMIT is a multicentre , r and omised , double-blind , parallel-group , placebo-controlled trial of 16 000 patients with moderate COPD r and omly assigned to once daily treatment with fluticasone furoate/vilanterol ( 100/25 & mgr;g ) , fluticasone furoate ( 100 & mgr;g ) , vilanterol ( 25 & mgr;g ) or matched placebo ; mortality is the primary end-point . The study is an event-driven trial powered by the comparison of furoate/vilanterol versus placebo . Secondary end-points are decline in forced expiratory volume in 1 s and effect on a composite cardiovascular end-point . This article describes the design of the SUMMIT study [17311843] Background : TORCH ( Towards a Revolution in COPD Health ) is an international multicentre , r and omised , placebo-controlled clinical trial of inhaled fluticasone propionate/salmeterol combination treatment and its monotherapy components for maintenance treatment of moderately to severely impaired patients with chronic obstructive pulmonary disease ( COPD ) . The primary outcome is all-cause mortality . Cause-specific mortality and deaths related to COPD are additional outcome measures , but systematic methods for ascertainment of these outcomes have not previously been described . Methods : A Clinical Endpoint Committee ( CEC ) was tasked with categorising the cause of death and the relationship of deaths to COPD in a systematic , unbiased and independent manner . The key elements of the operation of the committee were the use of predefined principles of operation and definitions of cause of death and COPD -relatedness ; the independent review of cases by all members with development of a consensus opinion ; and a substantial infrastructure to collect medical information . Results : 911 deaths were review ed and consensus was reached in all . Cause-specific mortality was : cardiovascular 27 % , respiratory 35 % , cancer 21 % , other 10 % and unknown 8 % . 40 % of deaths were definitely or probably related to COPD . Adjudications were identical in 83 % of blindly re-adjudicated cases ( κ = 0.80 ) . COPD -relatedness was reproduced 84 % of the time ( κ = 0.73 ) . The CEC adjudication was equivalent to the primary cause of death recorded by the site investigator in 52 % of cases . Conclusion : A CEC can provide st and ardised , reliable and informative adjudication of COPD mortality that provides information which frequently differs from data collected from assessment by site investigators [22383665] BACKGROUND Effects of β(2)-adrenergic receptor gene ( ADRB2 ) polymorphism on therapeutic responses to long-acting β(2)-adrenergic agonists have not been evaluated in long-term COPD trials . We aim ed to investigate the effects of the ADRB2 Gly16Arg polymorphism on response to formoterol alone or in combination with the inhaled corticosteroid budesonide in patients with COPD . METHODS Patients ≥ 40 years of age with moderate to very severe COPD from the 12-month trial I ( NCT00206167 ) or the 6-month trial II ( NCT00206154 ) were r and omly assigned to bid budesonide/formoterol pressurized metered-dose inhaler ( pMDI ) 320/9 μg or 160/9 μg , budesonide pMDI 320 μg + formoterol dry powder inhaler 9 μg ( trial II ) , budesonide pMDI 320 μg ( trial II ) , formoterol dry powder inhaler 9 μg , or placebo . The effect of Gly16Arg on predose FEV(1 ) and 1-h postdose FEV(1 ) , exacerbations , diary variables , and adverse events were analyzed . RESULTS No significant interaction between genotype and treatment response was observed for predose ( P ≥ .197 ) or postdose FEV(1 ) ( P ≥ .125 ) in either pharmacogenetic study ( n = 2,866 ) . The number of COPD exacerbations per patient-treatment year was low and similar across genotypes for the active treatment groups ( both studies ) . Percentages of patients with adverse events were similar across Gly16Arg genotype groups for each treatment . CONCLUSION Therapeutic response and tolerability to long-term treatment with formoterol alone or in combination with budesonide was not modified by ADRB2 Gly16Arg genotype in two large independent pharmacogenetic studies in patients with moderate to very severe COPD [17557771] Background : Airway inflammation in chronic obstructive pulmonary disease ( COPD ) is characterised by infiltration of CD8 + T cells and CD68 + macrophages and an increased number of neutrophils , whereas few studies have described the presence of eosinophils . Although the anti-inflammatory effects of corticosteroids in stable COPD are unclear , recent studies suggest that combination therapy could be beneficial . A study was therefore undertaken to evaluate combined salmeterol/fluticasone propionate ( SFC ) and fluticasone propionate ( FP ) alone on inflammatory cells in the airways of patients with COPD . Methods : Patients were treated in a r and omised , double blind , parallel group , placebo-controlled trial with either a combination of 50 µg salmeterol and 500 µg FP twice daily ( SFC , n = 19 , 19 men , mean age 62 years ) , 500 µg FP twice daily ( n = 20 , 15 men , mean age 64 years ) or placebo ( n = 21 , 17 men , mean age 66 years ) for 3 months . At the start and end of treatment bronchoscopy with bronchial biopsies was performed and the numbers of CD8 + T lymphocytes , CD68 + macrophages , neutrophils and eosinophils were measured . Results : CD8 + cells were significantly reduced by SFC compared with placebo ( difference −98.05 cells/mm2 ; 95 % CI −143.14 to −52.9 ; p<0.001 ) . Such a marked effect was not seen with FP alone ( −44.67 cells/mm2 ; 95 % CI −90.92 to 1.57 ; p = 0.06 ) . CD68 + macrophages were also reduced by SFC compared with placebo ( difference −31.68 cells/mm2 ; 95 % CI −61.07 to −2.29 ; p = 0.03 ) but not by FP . SFC did not significantly change neutrophils and eosinophils compared with placebo . Conclusions : SFC has airway anti-inflammatory effects not seen with inhaled corticosteroids alone [3812880] Background Inhaled corticosteroids ( ICS ) are known to increase the risk of pneumonia in patients with chronic obstructive pulmonary disease ( COPD ) . It is unclear whether the risk of pneumonia varies for different inhaled agents , particularly fluticasone and budesonide , and increases with the dose and long-term duration of use . Methods We formed a new-user cohort of patients with COPD treated during 1990–2005 . Subjects were identified using the Quebec health insurance data bases and followed through 2007 or until a serious pneumonia event , defined as a first hospitalisation for or death from pneumonia . A nested case – control analysis was used to estimate the rate ratio ( RR ) of serious pneumonia associated with current ICS use , adjusted for age , sex , respiratory disease severity and comorbidity . Results The cohort included 163 514 patients , of which 20 344 had a serious pneumonia event during the 5.4 years of follow-up ( incidence rate 2.4/100/year ) . Current use of ICS was associated with a 69 % increase in the rate of serious pneumonia ( RR 1.69 ; 95 % CI 1.63 to 1.75 ) . The risk was sustained with long-term use and declined gradually after stopping ICS use , disappearing after 6 months ( RR 1.08 ; 95 % CI 0.99 to 1.17 ) . The rate of serious pneumonia was higher with fluticasone ( RR 2.01 ; 95 % CI 1.93 to 2.10 ) , increasing with the daily dose , but was much lower with budesonide ( RR 1.17 ; 95 % CI 1.09 to 1.26 ) . Conclusions ICS use by patients with COPD increases the risk of serious pneumonia . The risk is particularly elevated and dose related with fluticasone . While residual confounding can not be ruled out , the results are consistent with those from recent r and omised trials [3646783] Rationale Smoking and inflammation contribute to the pathogenesis of chronic obstructive pulmonary disease ( COPD ) , which involves changes in extracellular matrix . This is thought to contribute to airway remodeling and airflow obstruction . We have previously observed that long-term treatment with inhaled corticosteroids can not only reduce bronchial inflammation , but can also attenuate lung function decline in moderate-severe COPD . We hypothesized that inhaled corticosteroids and current smoking modulate bronchial extracellular matrix components in COPD . Objective To compare major extracellular matrix components ( elastic fibers ; proteoglycans [ versican , decorin ] ; collagens type I and III ) in bronchial biopsies 1 ) after 30-months inhaled steroids treatment or placebo ; and 2 ) between current and ex-smokers with COPD . Methods We included 64 moderate-severe , steroid-naive COPD patients ( 24/40 (ex)-smokers , 62±7 years , 46 ( 31–54 ) packyears , post-bronchodilator forced expiratory volume in one second ( FEV1 ) 62±9 % predicted ) at baseline in this r and omized , controlled trial . 19 and 13 patients received 30-months treatment with fluticasone or placebo , respectively . Bronchial biopsies collected at baseline and after 30 months were studied using (immuno)histochemistry to evaluate extracellular matrix content . Percentage and density of stained area were calculated by digital image analysis . Results 30-Months inhaled steroids increased the percentage stained area of versican ( 9.6 % [ CI 0.9 to 18.3 % ] ; p = 0.03 ) and collagen III ( 20.6 % [ CI 3.8 to 37.4 % ] ; p = 0.02 ) compared to placebo . Increased collagen I staining density correlated with increased post-bronchodilator FEV1 after inhaled steroids treatment ( Rs = 0.45 , p = 0.04 ) . There were no differences between smokers and ex-smokers with COPD in percentages and densities for all extracellular matrix proteins . Conclusions These data show that long-term inhaled corticosteroids treatment partially changes the composition of extracellular matrix in moderate-severe COPD . This is associated with increased lung function , suggesting that long-term inhaled steroids modulate airway remodeling thereby potentially preventing airway collapse in COPD . Smoking status is not associated with bronchial extracellular matrix proteins . Trial Registration Clinical Trials.gov [24429127] BACKGROUND Whether the combination of a once-daily inhaled corticosteroid with a once-daily longacting β(2 ) agonist is more protective than a once-daily longacting β(2 ) agonist alone against exacerbations of chronic obstructive pulmonary disease ( COPD ) is unknown . We hypothesised that fluticasone furoate and vilanterol would prevent more exacerbations than would vilanterol alone . METHODS We did two replicate double-blind parallel-group 1 year trials . Both studies began on Sept 25 , 2009 . Study 1 ended on Oct 31 , 2011 , and study 2 on Oct 17 , 2011 . Eligible patients were aged 40 years or older , had a history of COPD , a smoking history of 10 or more pack-years , a ratio of forced expiratory volume in 1 s ( FEV(1 ) ) to forced vital capacity of 0·70 or less after bronchodilators ( and an FEV(1 ) of 70 % or less of predicted ) , and a documented history of one or more moderate or severe disease exacerbations in the year before screening . Patients were r and omly assigned ( 1:1:1:1 ) on the basis of the Registration and Medication Ordering System to 25 μg vilanterol alone or 25 μg vilanterol combined with either 50 μg , 100 μg , or 200 μg fluticasone furoate once daily . Our primary endpoint was the yearly rate of moderate and severe exacerbations . The trials were analysed separately and a pooled analysis was also done . These trials are registered with Clinical Trials.gov ( NCT01009463 and NCT01017952 ) . FINDINGS 1622 patients in study 1 and 1633 patients in study 2 were r and omly assigned . In study 1 , no significant difference in exacerbation rate was noted between the 200/25 μg fluticasone furoate/vilanterol group and the vilanterol only group ( mean 0·90 events vs 1·05 events per year ; ratio 0·9 [ 95 % CI 0·7 - 1·0 ] ) . Because of the statistical hierarchy used , we could not infer significance for the 50 μg and 100 μg groups . In study 2 , significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group ( p=0·0398 for the 50 μg group , 0·0244 for the 100 μg group , and 0·0004 for the 200 μg group ) . In the pooled analysis , significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group ( 0·0141 for the 50 μg group , < 0·0001 for the 100 μg group , and 0·0003 for the 200 μg group ) . Nasopharyngitis was the most frequently reported adverse event in both studies . Pneumonia and fractures were reported more frequently with fluticasone furoate and vilanterol than with vilanterol alone . Eight deaths from pneumonia were noted in the fluticasone furoate/vilanterol groups compared with none in the vilanterol only group . INTERPRETATION Addition of fluticasone furoate to vilanterol was associated with a decreased rate of moderate and severe exacerbations of COPD in patients with a history of exacerbation , but was also associated with an increased pneumonia risk . FUNDING GlaxoSmithKline [3580134] Background : Combination therapy with a long-acting bronchodilator and an inhaled corticosteroid ( ICS ) is recommended in patients with chronic obstructive pulmonary disease ( COPD ) who have frequent exacerbations . The efficacy and tolerability of the combination of budesonide/formoterol have been demonstrated in patients with COPD when administered via the dry powder inhaler ( DPI ) in a 1-year study and when administered via the hydrofluoroalkane ( HFA ) pressurized metered-dose inhaler ( pMDI ) in a 6-month study . Objective : This study assessed the long-term efficacy and tolerability of budesonide/formoterol HFA pMDI in patients with moderate to very severe COPD . Methods : This was a 12-month , r and omized , double-blind , double-dummy , parallel-group , active- and placebo-controlled , multicentre study ( NCT00206167 ) of 1964 patients aged ≥40 years with moderate to very severe COPD conducted from 2005 to 2007 at 237 sites in the US , Europe and Mexico . After 2 weeks of treatment based on previous therapy ( ICSs , short-acting bronchodilators allowed ) , patients received one of the following treatments twice daily : budesonide/formoterol pMDI 160/4.5 μg × two inhalations ( 320/9 μg ) ; budesonide/formoterol pMDI 80/4.5 μg × two inhalations ( 160/9 μg ) ; formoterol DPI 4.5 μg × two inhalations ( 9 μg ) ; or placebo . Main outcome measures : The co- primary efficacy variables were pre-dose forced expiratory volume in 1 second ( FEV1 ) and 1-hour post-dose FEV1 . Results : Budesonide/formoterol 320/9 μg demonstrated greater improvements in pre-dose FEV1 versus formoterol ( p = 0.008 ) , and both budesonide/formoterol doses demonstrated greater improvements in 1-hour post-dose FEV1 versus placebo ( p < 0.001 ) . The rate of COPD exacerbations was lower in both budesonide/formoterol groups compared with formoterol and placebo ( p ≤ 0.004 ) . Both budesonide/formoterol doses were more effective than placebo ( p ≤ 0.006 ) for controlling dyspnoea and improving health status ( St George ’s Respiratory Question naire ) . All treatments were generally well tolerated . The incidence of pneumonia was not different for active ( 3.4–4.0 % ) and placebo ( 5.0 % ) groups . Conclusions : Budesonide/formoterol pMDI ( 320/9 μg and 160/9 μg ) improved pulmonary function and reduced symptoms and exacerbations over 1 year in patients with moderate to very severe COPD . Only budesonide/formoterol pMDI 320/9 μg demonstrated greater efficacy for both co- primary variables compared with formoterol DPI 9 μg . Both budesonide/formoterol pMDI dosages were well tolerated relative to formoterol and placebo [19734176] Background : Patients with chronic obstructive pulmonary disease ( COPD ) often experience symptoms and problems with activities early in the morning . This is the first study to compare the effect of budesonide/formoterol and salmeterol/fluticasone on lung function , symptoms and activities early in the morning . Methods : Lung function ( peak expiratory flow [ PEF ] and forced expiratory volume in 1 second [ FEV 1 ] ) and symptoms were measured at bedside and activities were measured during the morning using a six-item question naire concerning basic morning routines . In a r and omised , double-blind , multicentre , cross-over study , 442 patients with COPD aged ≥40 years ( pre-bronchodilator FEV1 ≤50 % ; FEV1/vital capacity < 70 % ) received budesonide/formoterol ( 320/9 µg , one inhalation twice daily ) dry powder inhaler ( DPI ) or salmeterol/fluticasone ( 50/500 µg , one inhalation twice daily ) DPI daily , for 1 week each , separated by a 1- to 2-week washout . Lung function ( PEF and FEV1 ) shortly after rising from bed in the morning , symptoms and basic morning activities were assessed by electronic diary ( e-Diary ) recordings . Results : Budesonide/formoterol and salmeterol/fluticasone treatment increased morning PEF 5 minutes post-dose , measured as a mean improvement from baseline over the full study period ( primary endpoint ; adjusted mean change : 15.1 l/min and 14.2 l/min , respectively [ difference 1.0 l/min ; p = 0.603 ] ) . Mean morning FEV1 improved more following budesonide/ formoterol treatment versus salmeterol/fluticasone at 5 minutes ( 0.12 l versus 0.09 l ; p = 0.090 ) and 15 minutes ( 0.14 l versus 0.10 l ; p < 0.05 ) post-dose . Budesonide/formoterol demonstrated a more rapid onset of effect as reflected by increases in e-Diary-recorded PEF and FEV 1 from pre-dose to 5 and 15 minutes post-dose ( all p < 0.001 ) and spirometry at the clinic measured after the first dose ( FEV1 p < 0.001 ; 5 minutes post-dose ) . Improvements in symptom scores within 15 minutes after drug administration were similar for both drugs , but budesonide/formoterol treatment result ed in significantly greater improvements in total morning activities score ( getting washed , dried , dressed , eating breakfast and walking around the home ; 0.22 versus 0.12 respectively , p < 0.05 ) . Both treatments were well tolerated . Conclusions : Short-term treatment with budesonide/formoterol DPI or salmeterol/fluticasone DPI was effective in patients with COPD . Budesonide/formoterol had a more rapid onset of effect compared with salmeterol/fluticasone and result ed in greater improvements in ability to perform morning activities despite the lower inhaled corticosteroid dose [11208636] This study examined health status decline in patients with chronic obstructive pulmonary disease ( COPD ) . Data are from the Inhaled Steroids in Obstructive Lung Disease ( ISOLDE ) trial . After an 8-wk run-in , 751 patients ( 566 male ) , mean age 64 yr , were r and omized to receive fluticasone propionate ( FP ) 500 microg twice daily ( 376 patients ) or placebo ( 375 patients ) . Mean baseline postbronchodilator FEV1 was 50 + /- 15 % predicted . Patients completed the St George 's Respiratory Question naire ( SGRQ ) and the Short-Form 36 ( SF-36 ) at baseline and every 6 mo for 3 yr . FEV1 and smoking status were assessed at baseline and at 3-mo intervals . A total of 387 ( 212 FP ) patients completed the trial . All SGRQ components ( p = 0.03 to 0.004 ) and Physical Function , Mental Health , Energy/ Vitality , and Physical Role Limitation scales of the SF-36 ( p = 0.05 to 0.005 ) deteriorated faster in the placebo group . FEV1 and SGRQ scores correlated at baseline values ( r = -0.25 , p < 0.0001 ) , as did change in FEV1 and change in SGRQ ( Delta r = -0.24 , p < 0.0001 ) . At baseline values smokers had worse SGRQ Total , Symptoms , and Impacts scores than ex-smokers . This difference was maintained throughout the study . Smoking status did not influence the rate of decline in health status . The SGRQ Total scores of FP-treated patients took 59 % longer than placebo to deteriorate by a clinical ly significant amount . We conclude that health status decline in moderate to severe COPD can be reduced by high-dose fluticasone [3641457] Objective To identify subsets of chronic obstructive pulmonary disease ( COPD ) patients who are more protected from exacerbations with the use of an inhaled corticosteroid/long-acting β2 agonist ( ICS/LABA ) combination , compared with the use of LABA monotherapy . Design Post hoc cluster analysis of patients from two r and omised clinical trials of salmeterol/fluticasone propionate ( SFC ) and salmeterol ( SAL ) that had primary endpoints of moderate/severe exacerbation rates . Setting Centres in North America . Participants 1543 COPD patients were studied . Interventions SFC 50/250 µg or SAL 50 µg , twice daily . Primary and secondary outcome measures The analysis identified clusters of COPD patients more responsive to SFC versus SAL with respect to the annual rate of moderate/severe exacerbations and compared their baseline clinical characteristics . Results Overall , SFC significantly reduced the annual rate of moderate/severe exacerbations as compared with SAL alone ( rate ratio (RR)=0.701 , p<0.001 ) . Three-patient clusters were identified : COPD patients receiving diuretics ( RR=0.56 , p<0.001 ) ; patients not receiving diuretics but with forced expiratory volume in 1 s ( FEV1 ) reversibility ≥12 % ( RR=0.67 , p<0.001 ) exhibited a substantial reduction in the annual rate of moderate/severe exacerbations relative to SAL . A third cluster , consisting of patients not receiving diuretics and without FEV1 reversibility , demonstrated no difference for SFC versus SAL . Patients receiving diuretics had a significantly higher prevalence of comorbid cardiovascular disease . Conclusions COPD patients receiving diuretics and those not receiving diuretics but with FEV1 reversibility > 12 % at baseline were significantly more likely to experience a reduction in COPD -associated exacerbations with SFC versus SAL alone . Trial registration NCT00115492 , [18511702] RATIONALE Chronic obstructive pulmonary disease ( COPD ) is characterized by an accelerated decline in lung function . No drug has been shown conclusively to reduce this decline . OBJECTIVES In a post hoc analysis of the Toward a Revolution in COPD Health ( TORCH ) study , we investigated the effects of combined salmeterol 50 microg plus fluticasone propionate 500 microg , either component alone or placebo , on the rate of post-bronchodilator FEV(1 ) decline in patients with moderate or severe COPD . METHODS A r and omized , double-blind , placebo-controlled study was conducted from September 2000 to November 2005 in 42 countries . Of 6,112 patients from the efficacy population , 5,343 were included in this analysis . MEASUREMENTS AND MAIN RESULTS Spirometry was measured every 24 weeks for 3 years . There were 26,539 on-treatment observations . The adjusted rate of decline in FEV(1 ) was 55 ml/year for placebo , 42 ml/year for salmeterol , 42 ml/year for fluticasone propionate , and 39 ml/year for salmeterol plus fluticasone propionate . Salmeterol plus fluticasone propionate reduced the rate of FEV(1 ) decline by 16 ml/year compared with placebo ( 95 % confidence interval [ CI ] , 7 - 25 ; P < 0.001 ) . The difference was smaller for fluticasone propionate and salmeterol compared with placebo ( 13 ml/year ; 95 % CI , 5 - 22 ; P = 0.003 ) . Rates of decline were similar among the active treatment arms . FEV(1 ) declined faster in current smokers and patients with a lower body mass index , and varied between world regions . Patients who exacerbated more frequently had a faster FEV(1 ) decline . CONCLUSIONS Pharmacotherapy with salmeterol plus fluticasone propionate , or the components , reduces the rate of decline of FEV(1 ) in patients with moderate-to-severe COPD , thus slowing disease progression . Clinical trial ( GSK Study Code SCO30003 ) registered with www . clinical trials.gov ( NCT00268216 ) [15332386] Only long-term home oxygen therapy has been shown in r and omised controlled trials to increase survival in chronic obstructive pulmonary disease ( COPD ) . There have been no trials assessing the effect of inhaled corticosteroids and long-acting bronchodilators , alone or in combination , on mortality in patients with COPD , despite their known benefit in reducing symptoms and exacerbations . The “ TOwards a Revolution in COPD Health ” ( TORCH ) survival study is aim ing to determine the impact of salmeterol/fluticasone propionate ( SFC ) combination and the individual components on the survival of COPD patients . TORCH is a multicentre , r and omised , double-blind , parallel-group , placebo-controlled study . Approximately 6,200 patients with moderate-to-severe COPD were r and omly assigned to b.i.d . treatment with either SFC ( 50/500 µg ) , fluticasone propionate ( 500 µg ) , salmeterol ( 50 µg ) or placebo for 3 yrs . The primary end-point is all-cause mortality ; secondary end-points are COPD morbidity relating to rate of exacerbations and health status , using the St George 's Respiratory Question naire . Other end-points include other mortality and exacerbation end-points , requirement for long-term oxygen therapy , and clinic lung function . Safety end-points include adverse events , with additional information on bone fractures . The first patient was recruited in September 2000 and results should be available in 2006 . This paper describes the “ TOwards a Revolution in COPD Health ” study and explains the rationale behind it [12406823] The aim of this double-blind single center study ( the COPE study ) was to investigate the effect of discontinuation of the inhaled corticosteroid fluticasone propionate ( FP ) on exacerbations and health-related quality of life in patients with chronic obstructive pulmonary disease . After 4 months of treatment with FP ( 1,000 microg/day ) , 244 patients were r and omized to either continue FP or to receive placebo for 6 months : 123 patients continued FP ( FP group ) , and 121 received placebo ( placebo group ) . In the FP group , 58 ( 47 % ) patients developed at least one exacerbation compared with 69 ( 57 % ) in the placebo group . The hazard ratio of a first exacerbation in the placebo group compared with the FP group was 1.5 ( 95 % confidence interval [ CI ] 1.1 - 2.1 ) . In the placebo group 26 patients ( 21.5 % ) experienced rapid recurrent exacerbations and were subsequently unblinded and prescribed FP compared with 6 patients ( 4.9 % ) in the FP group ( relative risk = 4.4 ; 95 % CI 1.9 - 10.3 ) . Over a 6-month period , a significant difference in favor of the FP group was observed in the total score ( + 2.48 95 % CI 0.37 - 4.58 ) , activity domain ( + 4.64 95 % CI 1.60 - 7.68 ) , and symptom domain ( + 4.58 95 % CI 1.05 - 8.10 ) of the St. George 's Respiratory Question naire . This study indicates that discontinuation of FP in patients with chronic obstructive pulmonary disease is associated with a more rapid onset and higher recurrence-risk of exacerbations and a significant deterioration in aspects of Health-Related Quality of Life [9713447] BACKGROUND Inhaled corticosteroids are known to be beneficial for patients with asthma , but their role in treating patients with stable chronic obstructive pulmonary disease ( COPD ) remains controversial . A study was undertaken to determine whether inhaled corticosteroids are of functional benefit in patients who did not show improvement with a trial of oral corticosteroids . METHODS In phase I patients with stable COPD were given a two week course of oral placebo followed by two weeks of prednisone 40 mg per day in a single blind manner to distinguish between responders and non-responders to oral corticosteroids . In phase II a double blind , r and omised , parallel group trial of inhaled budesonide 1600 micrograms per day versus placebo was carried out in 79 nonresponders to oral corticosteroids . The primary outcome measure was forced expiratory volume in one second ( FEV1 ) , and secondary outcome measures were exercise capacity , dyspnoea with exertion , quality of life , peak expiration flow rate , and respiratory symptoms . RESULTS R and omisation allocated 39 subjects to inhaled corticosteroids and 40 to placebo . There was no difference in the change in FEV1 from baseline between the treatment and placebo groups ; mean difference -12 ml ( 95 % CI -88 to 63 ) at three months and -4 ml ( 95 % CI -95 to 87 ) at six months . The proportion of patients with a 15 % or greater improvement was no higher among those receiving inhaled corticosteroids than in the placebo group at any of the follow up visits . Changes in secondary outcomes were also no different . CONCLUSIONS Inhaled corticosteroids , even at high doses , were of no physiological or functional benefit in these patients with advanced COPD [12570111] Exacerbations of chronic obstructive pulmonary disease ( COPD ) are associated with worse health and increased healthcare utilisation . The Inhaled Steroids in Obstructive Lung Disease in Europe ( ISOLDE ) study in COPD showed a 26 % reduction in the yearly rate of exacerbations in patients treated with fluticasone propionate ( FP ) compared to placebo , but did not indicate which patients showed greatest benefit . In this study the patients were stratified into mild and moderate‐to‐severe COPD using the American Thoracic Society criterion of forced expiratory volume in one second ( FEV1 ) 50 % predicted , and the total number of exacerbations and those requiring treatment with oral corticosteroids were examined . There were 391 ( 195 FP ) patients with mild COPD and 359 ( 180 FP ) patients with moderate‐to‐severe disease . The exacerbation rate was highly skewed in mild disease , but more normally distributed in moderate‐to‐severe disease . FP reduced the overall exacerbation rate in moderate‐to‐severe disease ( FP median rate 1.47 yr−1 , placebo 1.75 yr−1 ) , but not in mild disease ( FP 0.67 yr−1 , placebo 0.92 yr−1 ) . FP use was associated with fewer patients with ≥1 exacerbation·yr−1 being treated with oral corticosteroids ( mild : FP 8 % , placebo 16 % ; moderate‐to‐severe : FP 17 % , placebo 30 % ) . Effects of fluticasone propionate on exacerbations were seen predominantly in patients with a postbronchodilator forced expiratory volume in one second < 50 % predicted . These data support recommendations in the Global Initiative for Chronic Obstructive Disease treatment guidelines that inhaled corticosteroids should be considered in patients with moderate‐to‐severe chronic obstructive pulmonary disease who experience recurrent exacerbations [19863361] Prevention and treatment of COPD exacerbations are recognized as key goals in disease management . This r and omized , double-blind , parallel-group , multicenter study evaluated the effect of fluticasone propionate/salmeterol 250 mcg/50 mcg ( FSC 250/50 ) and salmeterol 50 mcg ( SAL ) twice-daily on moderate/severe exacerbations . Subjects received treatment with FSC 250/50 during a one month run-in , followed by r and omization to FSC 250/50 or SAL for 52 weeks . Moderate/severe exacerbations were defined as worsening symptoms of COPD requiring antibiotics , oral corticosteroids and /or hospitalization . In 797 subjects with COPD ( mean FEV1 = 0.98L , 34 % predicted normal ) , treatment with FSC 250/50 significantly reduced the annual rate of moderate/severe exacerbations by 30.4 % compared with SAL ( 1.10 and 1.59 per subject per year , respectively , p < 0.001 ) , the annual rate of exacerbations requiring oral corticosteroids by 34 % ( p < 0.001 ) and the annual rate of moderate/severe exacerbations requiring hospitalization by 36 % ( p = 0.043 ) . Clinical improvements observed during run-in treatment with FSC 250/50 were better maintained over 52 weeks with FSC 250/50 compared to SAL . Statistically significant reductions in albuterol use , dyspnea scores , and nighttime awakenings and numerical benefits on quality of life were seen with FSC 250/50 compared with SAL . The incidence of adverse events was similar across groups . Pneumonia was reported more frequently with FSC 250/50 compared with SAL ( 7 % vs. 2 % ) . FSC 250/50 is more effective than SAL at reducing the rate of moderate/severe exacerbations . These data confirm the beneficial effect of FSC on the management of COPD exacerbations and support the use of FSC in patients with COPD [12885977] Background : A trial of corticosteroids has been recommended for all patients with chronic obstructive pulmonary disease ( COPD ) , with the subsequent “ response ” determining the treatment selected . This approach assumes that patients can be reliably divided into responder and non-responder groups . We have assessed whether such a separation is statistically valid , which factors influence the change in forced expiratory volume in 1 second ( FEV1 ) after prednisolone , and whether the prednisolone response predicts 3 year changes in FEV1 , health status , or number of exacerbations during placebo or fluticasone propionate treatment . Methods : Oral prednisolone 0.6 mg/kg was given for 14 days to 524 patients with COPD before r and omised treatment for 3 years with fluticasone propionate or placebo . Factors relating to change in FEV1 after prednisolone were investigated using multiple regression . The response to prednisolone was entered into separate mixed effects models of decline in FEV1 and health status during the 3 years of the study . Results : The post-bronchodilator FEV1 increased by a mean 60 ml ( CI 46 to 74 ) after prednisolone with a wide unimodal distribution . Current smoking was the factor most strongly associated with the change in FEV1 after prednisolone , with an increase of 35 ml in current smokers and 74 ml in confirmed ex-smokers ( p<0.001 ) . There was no relationship between the change in FEV1 after prednisolone and the response to inhaled bronchodilators , baseline FEV1 , atopic status , age , or sex . The response to prednisolone , however expressed , was unrelated to the subsequent change in FEV1 over the following 3 years on either placebo or fluticasone propionate . Regression to the mean effects explained much of the apparent prednisolone response . The significant effect of treatment on decline in health status was not predicted by the prednisolone response . Conclusion : Patients with COPD can not be separated into discrete groups of corticosteroid responders and non-responders . Current smoking reduces the FEV1 response to prednisolone . Prednisolone testing is an unreliable predictor of the benefit from inhaled fluticasone propionate in individual patients [12149529] Background : Treatment of chronic obstructive pulmonary disease ( COPD ) with inhaled corticosteroids does not appear to be as effective as similar treatment of asthma . It seems that only certain subgroups of patients with COPD benefit from steroid treatment . A study was undertaken to examine whether inhaled fluticasone propionate ( FP ) had an effect on lung function and on indices of inflammation in a subgroup of COPD patients with bronchial hyperresponsiveness ( BHR ) . Methods : Twenty three patients with COPD were studied . Patients had to be persistent current smokers between 40 and 70 years of age . Non-specific BHR was defined as a PC20 for histamine of ≤8 mg/ml . Patients received either 2 × 500 μg FP or placebo for 6 months . Expiratory volumes were measured at monthly visits , BHR was determined at the start of the study and after 3 and 6 months , and bronchial biopsy specimens were taken at the start and after 6 months of treatment . Biopsy specimens from asymptomatic smokers served as controls . Results : In contrast to asthma , indices of BHR were not significantly influenced by treatment with FP . Forced expiratory volume in 1 second ( FEV1 ) showed a steep decline in the placebo group but remained stable in patients treated with FP . FEV1/FVC , and maximal expiratory flows at 50 % and 25 % FVC ( MEF50 , MEF25 ) were significantly increased in the FP treated patients compared with the placebo group . Biopsy specimens were analysed for the presence of CD3 + , CD4 + , CD8 + , MBP+ , CD15 + , CD68 + , CD1a , and tryptase cells . FP treatment result ed in marginal reductions in these indices of inflammation . Conclusion : In patients with COPD and BHR , FP has a positive effect on indices of lung function compared with placebo . Bronchial inflammation analysed in bronchial biopsy specimens is only marginally reduced [23551359] BACKGROUND AND OBJECTIVE The efficacy and tolerability of budesonide/formoterol versus formoterol in patients with moderate to severe chronic obstructive pulmonary disease ( COPD ) was evaluated . METHODS In this r and omized , double-blind , parallel-group , phase III study ( NCT01069289 ) , patients with moderate to severe COPD for ≥2 years received either budesonide/formoterol 160/4.5 μg two inhalations twice daily via Turbuhaler ® or formoterol 4.5 μg two inhalations twice daily via Turbuhaler ® for 12 weeks . Salbutamol was available as reliever medication . Primary outcome variable : change from baseline to average during treatment in pre-dose forced expiratory volume in 1 s ( FEV1 ) . RESULTS One thous and two hundred ninety-three patients were r and omized ( budesonide/formoterol n = 636 ; formoterol n = 657 ) . Both budesonide/formoterol and formoterol increased pre-dose FEV1 versus baseline ( improvements of 4.6 % and 1.5 % over baseline , respectively ) , with the increase from baseline being significantly greater with budesonide/formoterol versus formoterol ( budesonide/formoterol : formoterol ratio 1.032 ; 95 % confidence interval : 1.013 - 1.052 ; P = 0.0011 ) . The budesonide/formoterol group had a significantly prolonged time to first exacerbation versus the formoterol group ( hazard ratio : 0.679 ; 95 % confidence interval : 0.507 - 0.909 ; P = 0.0094 ) and significantly greater improvements in many secondary outcome measures . Both treatments were well tolerated ; the incidence and type of adverse events were similar : most commonly reported ( budesonide/formoterol vs formoterol ) : COPD ( 8.0 % vs 9.4 % ) and nasopharyngitis ( 5.5 % vs 4.9 % ) . CONCLUSIONS Budesonide/formoterol 160/4.5 μg two inhalations twice daily was effective and well tolerated in patients with moderate to severe COPD , offering benefits over formoterol alone in terms of improved lung function and reduced risk of exacerbation [8625660] STUDY OBJECTIVE To determine the effectiveness of treatment with corticosteroids in patients with COPD . METHODS In this study , we investigated the effect of a 2-year treatment with corticosteroids on clinical symptoms and the decline of lung function in 58 nonallergic patients with COPD . Subjects were treated in a double-blind , r and omized , placebo-controlled , parallel way with inhaled budesonide ( bud ) , 1,600 micrograms/d ; inhaled budesonide , 1,600 micrograms/d , plus oral prednisolone , 5 micrograms/d ( bud + pred ) ; or placebo ( plac ) . Clinical assessment ( history , physical examination , and spirometry ) was carried out every 2 months . The rate of decline in FEV1 was assessed by calculating individual regression co-efficients from linear regression of FEV1 on time for each subject . RESULTS Eleven patients dropped out . The number of withdrawals due to pulmonary problems was significantly higher in the plac group ( n = 5 out of 18 ) than in the actively treated groups ( n = 2 out of 40 ) . Treatment with corticosteroids significantly reduced pulmonary symptoms . Median decline of FEV1 was 60 mL/yr in the plac group , 40 mL/yr in the bud + pred group , and 30 mL/yr in the bud group . Variation was large and differences were not statistically significant . No treatment effect was found on frequency or duration of exacerbations , possibly because of the high number of withdrawals due to pulmonary deterioration in the plac group . Treatment with a combination of inhaled plus oral corticosteroids was not more effective than inhaled corticosteroids alone . Morning plasma cortisol levels remained within the normal range in all three groups . CONCLUSIONS Our study shows beneficial effects of long-term daily treatment with inhaled corticosteroids in patients with COPD with regard to symptoms and drop out due to pulmonary problems . Lung function decline tends to decrease during treatment with inhaled corticosteroids . The observed effects are limited but warrant further studies on the effectiveness of corticosteroids in larger numbers of patients with COPD [12200525] Background : Inhaled corticosteroids ( ICS ) markedly reduce bronchial mucosal inflammation in asthma but whether they have an anti-inflammatory effect in airway tissue in chronic obstructive pulmonary disease ( COPD ) is unknown . Methods : A study of endobronchial biopsy sample s was conducted as part of a double blind , placebo controlled , r and omised trial of parallel design . Patients had mild to moderately severe COPD ( FEV1 25–80 % of predicted ) and were given 3 months treatment with ICS , fluticasone propionate ( FP ; 500 μg twice daily , n=14 ) or placebo ( n=10 ) . Biopsy tissue taken at baseline and after treatment was examined by transmission electron microscopy to count the numbers of all ultrastructurally distinct inflammatory cells . Results : Compared with their baseline values , FP result ed in a significant decrease ( on average 65 % ) in the numbers of mucosal mast cells ( median 7.8 ( range 1–33 ) v 2.8 ( 1–14 ) , p<0.05 ) . The reductive effect of FP held true when the post-treatment values of the placebo and FP groups were compared : 8.8 ( 1–24 ) v 2.8 ( 1–14 ) ( p<0.05 ) . Unexpectedly , there were significantly more neutrophils in the FP than in the placebo group : 4.0 ( 0–23 ) v 1.7 ( 0–8 ) , respectively ( p<0.05 ) . There were no alterations to other cell types including mononuclear cells . Symptoms markedly improved in the patients treated with FP for 3 months . Conclusion : Fluticasone propionate given for 3 months to patients with COPD has selective effects on the inflammatory cells in the bronchial mucosa : the reduction in mast cell numbers may account for the improvement in symptoms over this time [2245934] Background Guidelines recommend inhaled corticosteroids ( ICS ) for patients with severe chronic obstructive pulmonary disease ( COPD ) . Most COPD patients are managed in primary care and receive ICS long-term and irrespective of severity . The effect of withdrawing ICS from COPD patients in primary care is unknown . Methods In a pragmatic r and omised , double-blind , placebo-controlled trial in 31 practice s , 260 COPD patients stopped their usual ICS ( median duration of use 8 years ) and were allocated to 500 mcg fluticasone propionate twice daily ( n = 128 ) , or placebo ( n = 132 ) . Follow-up assessment s took place at three monthly intervals for a year at the patients ' practice . Our primary outcome was COPD exacerbation frequency . Secondary outcomes were time to first COPD exacerbation , reported symptoms , peak expiratory flow rate and reliever inhaler use , and lung function and health related quality of life . Results In patients r and omised to placebo , COPD exacerbation risk over one year was RR : 1.11 ( CI : 0.91–1.36 ) . Patients taking placebo were more likely to return to their usual ICS following exacerbation , placebo : 61/128 ( 48 % ) ; fluticasone : 34/132 ( 26 % ) , OR : 2.35 ( CI : 1.38–4.05 ) . Exacerbation risk whilst taking r and omised treatment was significantly raised in the placebo group 1.48 ( CI : 1.17–1.86 ) . Patients taking placebo exacerbated earlier ( median time to first exacerbation : placebo ( days ) : 44 ( CI : 29–59 ) ; fluticasone : 63 ( CI : 53–74 ) , log rank 3.81 , P = 0.05 ) and reported increased wheeze . In a post-hoc analysis , patients with mild COPD taking placebo had increased exacerbation risk RR : 1.94 ( CI : 1.20–3.14 ) . Conclusion Withdrawal of long-term ICS in COPD patients in primary care increases risk of exacerbation shortens time to exacerbation and causes symptom deterioration . Patients with mild COPD may be at increased risk of exacerbation after withdrawal . Trial Registration Clinical Trials.gov [22033040] BACKGROUND Treatment with an inhaled corticosteroid ( ICS ) and long-acting bronchodilator is recommended for severe/very severe chronic obstructive pulmonary disease ( COPD ) patients with repeated exacerbations . This r and omized , double-blind , double-dummy , parallel-group , 12-month multicenter study evaluated the effect of budesonide/formoterol pressurized metered-dose inhaler ( pMDI ) on COPD exacerbations . METHODS Following a 2-week run-in during which COPD patients aged ≥40 years with an exacerbation history discontinued medications except ICSs , 1219 patients were r and omized 1:1:1 to twice-daily budesonide/formoterol pMDI 320/9 μg , budesonide/formoterol pMDI 160/9 μg , or formoterol dry powder inhaler 9 μg . An exacerbation was defined as COPD worsening requiring oral corticosteroids and /or hospitalization . A post hoc analysis , with antibiotic treatment added to the exacerbation definition , was also performed . RESULTS Budesonide/formoterol 320/9 and 160/9 reduced exacerbation rates ( number per patient-treatment year ) by 34.6 % and 25.9 % , respectively , versus formoterol ( p ≤ 0.002 ) . Budesonide/formoterol 320/9 prolonged time to first exacerbation versus formoterol , corresponding to a 21.2 % reduction in hazard ratio ( 0.788 [ 95 % CI : 0.639 , 0.972 ] ; p = 0.026 ) . Exacerbation rates ( number per patient-treatment year ) including antibiotic treatment ( post hoc analysis ) were reduced by 25.9 % and 18.7 % with budesonide/formoterol 320/9 and 160/9 , respectively , versus formoterol ( p ≤ 0.023 ) . Both budesonide/formoterol doses were well tolerated with safety profiles similar to formoterol . Pneumonia adverse events occurred in 6.4 % , 4.7 % , and 2.7 % of patients in the budesonide/formoterol 320/9 , 160/9 , and formoterol groups . CONCLUSIONS Over 12 months , both budesonide/formoterol doses reduced the exacerbation rate ( defined with or without antibiotic treatment ) versus formoterol . Budesonide/formoterol pMDI is an appropriate treatment for reducing exacerbations in COPD patients with a history of exacerbations . ( NCT00419744 ) [1781748] Oxidative stress in the lung is important in the pathogenesis of COPD . Published data indicate that glucocorticoids inhibit blood cells in their capacity to produce reactive oxygen species ( ROS ) . We investigated the effect of Fluticasone propionate ( FP ) on the ROS production capabilities of pulmonary cells . Bronchoalveolar lavage ( BAL ) was performed in smoking COPD patients , before and after a six month , placebo-controlled treatment with FP . BAL cells were stimulated with phorbol myristrate acetate ( PMA ) alone , and together with superoxide dismutase ( SOD ) . From kinetic plots of ferricytochrome-c conversion we calculated the maximal rate of superoxide production : V(max ) . We also examined BAL cell subsets and performed correlation analyses on ROS production and relevant clinical determinants . Paired results were obtained from 6 FP- and 9 placebo-treated patients . No significant change of V(max ) was found in both patient groups . Also BAL cellularity was unchanged . Correlation analyses showed a significant ( inverse ) association of V(max ) with the number of cigarettes smoked per day . We concluded that a potent inhaled glucocorticoid had no effect on the ROS production capability of BAL cells from smoking COPD patients . Apparently , heavy smoking impaired the ability of alveolar macrophages to produce ROS , which was not further decreased by FP [23242950] It is by no means straightforward to analyse the change in the rate of chronic obstructive pulmonary disease ( COPD ) exacerbations in clinical trials . Exacerbation rates do not follow a normal distribution , nor do they occur at r and om . High exacerbation rates in a few patients can make average rates difficult to calculate and interpret . So , surely , transforming exacerbation rates into numbers needed to treat ( NNT ) should help . Not necessarily so — this is the message from Professor Suissa 's paper.1 He points out that the simplistic transformation from annual exacerbation rates to NNT in some published papers is misleading . He then goes on to present an alternative way of calculating NNT from survival curves showing time to first exacerbation , and a model to estimate such curves even if they are not presented . I have used the exponential model suggested by Suissa , with the data from two of the arms of the Towards a Revolution in Chronic obstructive pulmonary disease Health ( TORCH ) trial2 to show how this works in practice . I chose the arms in TORCH , that compared combination fluticasone/salmeterol therapy with salmeterol alone , as this seems to me to be a fair way to estimate the impact of additional inhaled corticosteroids . Figure 1 shows pairs of modelled survival curves for pneumonia ( in the upper part ) , and for COPD exacerbation ( in the lower part ) . [23352226] BACKGROUND Fluticasone furoate (FF)/vilanterol ( VI ) is a novel once-daily inhaled corticosteroid/long-acting β2-agonist combination therapy for COPD . We aim ed to assess the efficacy and safety of two strengths of FF/VI ( 100/25 μg ; 50/25 μg ) vs. individual components ( FF 100 μg , VI 25 μg ) and placebo over 24 weeks . METHODS Multicentre , r and omised , placebo-controlled , double-blind , parallel-group study of patients ( N = 1030 ) with moderate-to-severe COPD . All medication was administered once daily in the morning . Co- primary efficacy endpoints were : ( 1 ) weighted mean ( wm ) FEV1 ( 0 - 4 h post-dose on day 168 ) to assess acute lung function effects ; and ( 2 ) trough FEV1 ( 23 - 24 h post-dose on day 169 ) to assess long-lasting effects . Symptom-related outcomes were analysed and adverse events ( AEs ) assessed . RESULTS Main findings were : ( 1 ) the combination of FF/VI at a strength of 100/25 μg significantly ( p < 0.001 ) improved wm FEV1 ( 173 ml ) and trough FEV1 ( 115 ml ) vs. placebo . Similar effects were observed with FF/VI 50/25 μg ; ( 2 ) no significant difference was seen between FF/VI 100/25 μg and VI 25 μg for trough FEV1 ( 48 ml , p = 0.082 ) , while an effect was observed between FF/VI 100/25 μg and FF 100 μg for wm FEV1 ( 120 ml , p < 0.001 ) ; ( 3 ) VI 25 μg over 24 weeks improved lung function vs. placebo significantly for wm FEV1 ( 103 ml , p < 0.001 ) and trough FEV1 ( 67 ml , p = 0.017 ) ; and ( 4 ) no safety signal was observed . CONCLUSIONS In subjects with moderate-to-severe COPD , FF/VI 100/25 μg provides rapid and significant sustained bronchodilation at 24 weeks . Lung function is improved to a similar extent with FF/VI 50/25 μg and to a somewhat lesser extent with VI 25 μg . All treatments were well tolerated . GSK study number : HZC112206 . Clinical Trials.gov : NCT01053988 [2793071] Background The oral prednisolone test is widely used to distinguish chronic obstructive pulmonary disease ( COPD ) patients who might benefit from inhaled steroid treatment . Previous studies used selected patient groups that did not represent the large COPD population in primary care . Methods The study included smokers and exsmokers with chronic bronchitis or COPD from primary care , who underwent prednisolone testing ( 30 mg for 14 days ) before r and omization in a three-year follow-up r and omized controlled trial ( COOPT Study ) . Spirometry was performed before and after the test . Responders and nonresponders were classified according to international criteria . Effectiveness of inhaled fluticasone relative to placebo was compared in terms of health status ( Chronic Respiratory Disease Question naire ) , exacerbations , and postbronchodilator forced expiratory volume in one second ( FEV1 ) , using repeated measurement analysis . Results Two hundred eighty-six patients recruited from 44 primary care practice s were r and omized . Nine percent to 16 % of the COPD population was classified as responder , depending on the international guideline criteria used . On average , responders did not reach the minimum clinical ly important difference in health status ( 0.29 points/year , P = 0.05 ) , although a borderline significant effect of inhaled fluticasone was noted . Possible clinical ly relevant reductions in exacerbation rate ( rate ratio 0.67 ) and FEV1 decline ( 39 mL/year ) occurred in responders , but did not reach statistical significance . Conclusions Oral steroid testing identifies a limited proportion of COPD patients , but does not reveal any clinical ly relevant benefit from inhaled steroid treatment on health status . No significant effects on exacerbation rate and lung function decline occurred [3666306] Objective To investigate the occurrence of pneumonia and pneumonia related events in patients with chronic obstructive pulmonary disease ( COPD ) treated with two different fixed combinations of inhaled corticosteroid/long acting β2 agonist . Design Observational retrospective pairwise cohort study matched ( 1:1 ) for propensity score . Setting Primary care medical records data linked to Swedish hospital , drug , and cause of death registry data for years 1999 - 2009 . Participants Patients with COPD diagnosed by a physician and prescriptions of either budesonide/formoterol or fluticasone/salmeterol . Main outcome measures Yearly pneumonia event rates , admission to hospital related to pneumonia , and mortality . Results 9893 patients were eligible for matching ( 2738 in the fluticasone/salmeterol group ; 7155 in the budesonide/formoterol group ) , yielding two matched cohorts of 2734 patients each . In these patients , 2115 ( 39 % ) had at least one recorded episode of pneumonia during the study period , with 2746 episodes recorded during 19 170 patient years of follow up . Compared with budesonide/formoterol , rate of pneumonia and admission to hospital were higher in patients treated with fluticasone/salmeterol : rate ratio 1.73 ( 95 % confidence interval 1.57 to 1.90 ; P<0.001 ) and 1.74 ( 1.56 to 1.94 ; P<0.001 ) , respectively . The pneumonia event rate per 100 patient years for fluticasone/salmeterol versus budesonide/formoterol was 11.0 ( 10.4 to 11.8 ) versus 6.4 ( 6.0 to 6.9 ) and the rate of admission to hospital was 7.4 ( 6.9 to 8.0 ) versus 4.3 ( 3.9 to 4.6 ) . The mean duration of admissions related to pneumonia was similar for both groups , but mortality related to pneumonia was higher in the fluticasone/salmeterol group ( 97 deaths ) than in the budesonide/formoterol group ( 52 deaths ) ( hazard ratio 1.76 , 1.22 to 2.53 ; P=0.003 ) . All cause mortality did not differ between the treatments ( 1.08 , 0.93 to 1.14 ; P=0.59 ) . Conclusions There is an intra-class difference between fixed combinations of inhaled corticosteroid/long acting β2 agonist with regard to the risk of pneumonia and pneumonia related events in the treatment of patients with COPD . Trial registration Clinical Trials.gov NCT01146392 [15176682] Exacerbations of chronic obstuctive pulmonary disease ( COPD ) are associated with worse health status . The Inhaled Steroids in Obstructive Lung Disease in Europe ( ISOLDE ) study showed that treatment with fluticasone propionate ( FP ) reduced exacerbation frequency and the rate of deterioration in health status as compared with placebo . The present study analysed these data to test whether the effect of FP on health status was attributable to its effect on exacerbations . Rates of deterioration in St George 's Respiratory Question naire ( SGRQ ) total score were obtained for 613 patients with moderate to severe COPD followed for a maximum of 3 yrs . Exacerbation rates were skewed and could not be normalised , therefore , patients were stratified into three exacerbation groups : none , infrequent ( < 1.65 exacerbations·yr−1 ) and frequent ( > 1.65 exacerbations·yr−1 ) . There were 91 patients with no exacerbations , 285 with infrequent exacerbations and 235 with frequent exacerbations . Frequent exacerbations were independently associated with a worse baseline SGRQ score ( p<0.0001 ) and a more rapid rate of deterioration in health status ( p=0.0003 ) . Exacerbation frequency and rate of decline in forced expiratory volume in one second were independently related to the rate of deterioration in SGRQ score . Statistical modelling showed the beneficial effect of fluticasone propionate on deterioration in health status to be largely due to its effect on exacerbation frequency [12570112] The efficacy and safety of budesonide/formoterol in a single inhaler compared with placebo , budesonide and formoterol were evaluated in patients with moderate-to-severe chronic obstructive pulmonary disease ( COPD ) . In a 12-month , r and omised , double-blind , placebo-controlled , parallel-group study in 812 adults ( mean age 64 yrs , mean forced expiratory volume in one second ( FEV1 ) 36 % predicted normal ) , patients received two inhalations twice daily of either budesonide/formoterol ( Symbicort ® ) 160/4.5 µg ( delivered dose ) , budesonide 200 µg ( metered dose ) , formoterol 4.5 µg or placebo . Severe exacerbations and FEV1 ( primary variables ) , peak expiratory flow ( PEF ) , COPD symptoms , health-related quality of life ( HRQL ) , mild exacerbations , use of reliever β2‐agonist and safety variables were recorded . Budesonide/formoterol reduced the mean number of severe exacerbations per patient per year by 24 % versus placebo and 23 % versus formoterol . FEV1 increased by 15 % versus placebo and 9 % versus budesonide . Morning PEF improved significantly on day 1 versus placebo and budesonide ; after 1 week , morning PEF was improved versus placebo , budesonide and formoterol . Improvements in morning and evening PEF versus comparators were maintained over 12 months . Budesonide/formoterol decreased all symptom scores and use of reliever β2‐agonists significantly versus placebo and budesonide , and improved HRQL versus placebo . All treatments were well tolerated . These results suggest a role for budesonide/formoterol in the long-term management of moderate-to-severe chronic obstructive pulmonary disease [12583942] BACKGROUND Inhaled long-acting beta2 agonists improve lung function and health status in symptomatic chronic obstructive pulmonary disease ( COPD ) , whereas inhaled corticosteroids reduce the frequency of acute episodes of symptom exacerbation and delay deterioration in health status . We postulated that a combination of these treatments would be better than each component used alone . METHODS 1465 patients with COPD were recruited from outpatient departments in 25 countries . They were treated in a r and omised , double-blind , parallel-group , placebo-controlled study with either 50 microg salmeterol twice daily ( n=372 ) , 500 microg fluticasone twice daily ( n=374 ) , 50 microg salmeterol and 500 microg fluticasone twice daily ( n=358 ) , or placebo ( n=361 ) for 12 months . The primary outcome was the pretreatment forced expiratory volume in 1s ( FEV1 ) after 12 months treatment ' and after patients had abstained from all bronchodilators for at least 6h and from study medication for at least 12h . Secondary outcomes were other lung function measurements , symptoms and rescue treatment use , the number of exacerbations , patient withdrawals , and disease-specific health status . We assessed adverse events , serum cortisol concentrations , skin bruising , and electrocardiograms . Analysis was as predefined in the study protocol . FINDINGS All active treatments improved lung function , symptoms , and health status and reduced use of rescue medication and frequency of exacerbations . Combination therapy improved pretreatment FEV1 significantly more than did placebo ( treatment difference 133 mL , 95 % CI 105 - 161 , p<0.0001 ) , salmeterol ( 73 mL , 46 - 101 , p<0.0001 ) , or fluticasone alone ( 95 mL , 67 - 122 , p<0.0001 ) . Combination treatment produced a clinical ly significant improvement in health status and the greatest reduction in daily symptoms . All treatments were well tolerated with no difference in the frequency of adverse events , bruising , or clinical ly significant falls in serum cortisol concentration . INTERPRETATION Because inhaled long-acting beta2 agonists and corticosteroid combination treatment produces better control of symptoms and lung function , with no greater risk of side-effects than that with use of either component alone , this combination treatment should be considered for patients with COPD [14680078] Lung function in chronic obstructive pulmonary disease ( COPD ) can be improved acutely by oral corticosteroids and bronchodilators . Whether clinical improvement can be maintained by subsequent inhaled therapy is unknown . COPD patients ( n=1,022 , mean prebronchodilator forced expiratory volume in one second ( FEV1 ) 36 % predicted ) initially received formoterol ( 9 µg b.i.d . ) and oral prednisolone ( 30 mg o.d . ) for 2 weeks . After this time , patients were r and omised to b.i.d . inhaled budesonide/formoterol 320/9 µg , budesonide 400 µg , formoterol 9 µg or placebo for 12 months . Postmedication FEV1 improved by 0.21 L and health-related quality of life using the St George 's Respiratory Question naire ( SGRQ ) by 4.5 units after run-in . Fewer patients receiving budesonide/formoterol withdrew from the study than those receiving budesonide , formoterol or placebo . Budesonide/formoterol patients had a prolonged time to first exacerbation ( 254 versus 96 days ) and maintained higher FEV1 ( 99 % versus 87 % of baseline ) , both primary variables versus placebo . They had fewer exacerbations ( 1.38 versus 1.80 exacerbations per patient per year ) , had higher prebronchodilator peak expiratory flow , and showed clinical ly relevant improvements in SGRQ versus placebo ( −7.5 units ) . Budesonide/formoterol was more effective than either monocomponent in both primary variables . Budesonide/formoterol in a single inhaler ( Symbicort ® ) maintains the benefit of treatment optimisation , stabilising lung function and delaying exacerbations more effectively than either component drug alone or placebo [14555565] OBJECTIVES To investigate the determinants of patient withdrawal from our study , and the effect of these withdrawals on the outcome of treatment with inhaled corticosteroids in patients with COPD . DESIGN A double-blind , placebo-controlled , r and omized trial . SETTING Eighteen outpatient centers in the United Kingdom . PARTICIPANTS Seven hundred fifty-one patients with stable COPD defined clinical ly and as baseline postbronchodilator FEV(1 ) > or = 0.8 L and < 85 % predicted , FEV(1)/FVC ratio < 70 % , and FEV(1 ) change after albuterol < 10 % of predicted . INTERVENTION R and om assignment of either 500 microg bid of inhaled fluticasone propionate ( FP ) using a spacer device or an identical placebo inhaler . Treatment was continued for 3 years or until patients withdrew from follow-up . MEASUREMENTS AND RESULTS Postbronchodilator FEV(1 ) was measured on three occasions before r and omization and every 3 months thereafter . Health status was assessed by the disease-specific St. George Respiratory Question naire ( SGRQ ) and the modified short-form 36 question naire ( SF-36 ) at baseline and every 6 months . Three hundred thirty-nine patients withdrew , of whom 156 patients received FP . Prescription of frequent courses of oral prednisolone was the most common reason for withdrawing as specified in the protocol ( 69 patients in the FP group withdrew due to respiratory symptoms , compared with 93 patients in the placebo group ) . This explained the significantly greater dropout of placebo-treated patients that was most evident when FEV(1 ) was < 50 % predicted . Patients withdrawing had a significantly more rapid decline in health status , measured by both the SGRQ and the SF-36 ( p < 0.001 ) . Those withdrawing from the placebo group had a more rapid decline in FEV(1 ) and more exacerbations than the FP-treated groups . Baseline FEV(1 ) was lower in dropouts than in patients completing the study receiving placebo , but there was no difference between the respective groups receiving FP . CONCLUSIONS Patients who withdrew from follow-up were those with the most rapidly deteriorating health status and lung function . Losing these patients from the final analysis can reduce the power of a study to achieve its primary end point [19717476] The TOwards a Revolution in COPD Health ( TORCH ) study was a 3-yr multicentre trial of 6,112 patients r and omised to salmeterol ( Salm ) , fluticasone propionate ( FP ) , a Salm/FP combination ( SFC ) or placebo ( P ) . Here the cost-effectiveness of treatments evaluated in the TORCH study is assessed . For four regions , 3-yr all-cause hospitalisation , medication and outpatient care costs were calculated . The sample was restricted to the 21 countries ( n = 4,237 ) in which European quality of life five-dimension ( EQ-5D ) data were collected in order to estimate the number of quality -adjusted life years ( QALYs ) . Regression models were fitted to survival , study medication cost , other medication cost and EQ-5D data in order to estimate total cost , number of QALYs and cost per QALY , adjusted for missing data and region . SFC had a trial-wide estimate of cost per QALY of 43,600 US dollars ( USD ) compared with P ( 95 % confidence interval 21,400–123,500 USD ) . Estimates for Salm versus P ( 197,000 USD ) and FP versus P ( 78,000 USD ) were less favourable . The US estimates were greater than those from other regions ; for SFC versus P , the cost per QALY was 77,100 ( 46,200–241,700 ) USD compared to 24,200 ( 15,200–56,100 ) USD in Western Europe . Compared with P , SFC has a lower incremental cost-effectiveness ratio than either FP or Salm used alone , and is , therefore , preferred to these monotherapies on the grounds of cost-effectiveness [9519948] BACKGROUND The efficacy of inhaled corticosteroids in the treatment of chronic obstructive pulmonary disease ( COPD ) remains controversial because of a lack of placebo-controlled studies . We compared the effect of inhaled fluticasone propionate with placebo in the treatment of patients with COPD . METHODS We used a r and omised , double-blind , placebo-controlled design . We enrolled from 13 European countries , New Zeal and , and South Africa , 281 outpatient current or ex-smokers , aged between 50 and 75 years . They had a forced expiratory volume in 1 s ( FEV1 ) of between 35 % and 90 % of predicted normal values , a ratio of FEV1 to forced vital capacity of 70 % or less and bronchodilator reversibility of less than 15 % , as well as a history of chronic bronchitis . Patients were r and omly assigned fluticasone propionate 500 microg ( n=142 ) or placebo ( n=139 ) twice daily via a metered-dose inhaler for 6 months . The main outcome measures were the number of patients who had at least one exacerbation by the end of treatment , the number and severity of exacerbations , clinic lung function , diary card symptoms and peak expiratory flow and 6 min walking distance . FINDINGS 51 ( 37 % ) patients in the placebo group compared with 45 ( 32 % ) in the fluticasone propionate group had had at least one exacerbation by the end of treatment ( p=0.449 ) . Significantly more patients had moderate or severe exacerbations in the placebo group than in the fluticasone propionate group ( 86 % vs 60 % , p<0.001 ) . Diary-card and clinic morning peak expiratory flows improved significantly in the fluticasone propionate group ( p<0.001 , p=0.048 , respectively ) , as did clinic FEV1 ( p<0.001 ) , forced vital capacity ( p<0.001 ) , and mid-expiratory flow ( p=0.01 ) . Symptom scores for median daily cough and sputum volume were significantly lower with fluticasone propionate treatment than with placebo ( p=0.004 and p=0.016 , respectively ) . At the end of treatment , patients on fluticasone propionate had increased their 6 min walking distance significantly more than those on placebo ( p=0.032 ) . Fluticasone propionate was tolerated as well as placebo , with few adverse effects and without a clinical ly important effect on mean serum cortisol concentration . INTERPRETATION Fluticasone propionate may be of clinical benefit in patients with COPD over at least 6 months . Inhaled corticosteroids may have an important role in the long-term treatment of COPD [20685748] Background Previous studies have suggested that long-term use of β agonists to treat chronic obstructive pulmonary disease ( COPD ) may increase the risk of cardiovascular adverse events . In this post hoc analysis , data from the TOwards a Revolution in COPD Health ( TORCH ) study were used to investigate whether use of the long-acting β2 agonist salmeterol over 3 years increased the risk of cardiovascular adverse events in patients with moderate to severe COPD . Methods TORCH was a r and omised , double-blind , placebo controlled study conducted at 444 centres in 42 countries . Patients ( n=6184 ; safety population ) received twice daily combined salmeterol 50 μg plus fluticasone propionate 500 μg ( SFC ) , either component alone , or placebo . Adverse events were recorded every 12 weeks for 3 years . Results The probability of having a cardiovascular adverse event by 3 years was 24.2 % for placebo , 22.7 % for salmeterol , 24.3 % for fluticasone propionate and 20.8 % for SFC . Although a history of myocardial infa rct ion doubled the probability of cardiovascular adverse events , the event rates remained similar across treatment groups . Conclusion Post hoc analysis of the 3-year TORCH data set showed that salmeterol alone or in combination ( SFC ) did not increase the risk of cardiovascular events in patients with moderate to severe COPD [16514718] Background : Guidelines recommend inhaled corticosteroids ( ICS ) as maintenance treatment for patients with chronic obstructive pulmonary disease ( COPD ) with a post-bronchodilator forced expiratory volume in 1 second ( FEV1 ) < 50 % predicted and frequent exacerbations , although they have only a small preventive effect on the accelerated decline in lung function . Combined treatment with ICS and long acting β2 agonists ( LABA ) may provide benefit to the stability of COPD , but it is unknown if withdrawal of ICS will result in disease deterioration . Methods : The effects of 1 year withdrawal of the ICS fluticasone propionate ( FP ) after a 3 month run-in treatment period with FP combined with the LABA salmeterol ( S ) ( 500 μg FP + 50 μg S twice daily ; SFC ) were investigated in patients with COPD in a r and omised , double blind study . 497 patients were enrolled from 39 centres throughout the Netherl and s ; 373 were r and omised and 293 completed the study . Results : The drop out rate after r and omisation was similar in the two groups . Withdrawal of FP result ed in a sustained decrease in FEV1 : mean ( SE ) change from baseline −4.4 (0.9)% ( S ) v −0.1 (0.9)% ( SFC ) ; adjusted difference 4.1 ( 95 % CI 1.6 to 6.6 ) percentage points ( p<0.001 ) . Corresponding figures for the FEV1/FVC ratio were −3.7 (0.8)% ( S ) v 0.0 (0.8)% ( SFC ) ( p = 0.002 ) . The annual moderate to severe exacerbation rate was 1.6 and 1.3 in the S and SFC groups , respectively ( adjusted rate ratio 1.2 ; 95 % CI 0.9 to 1.5 ; p = 0.15 ) . The mean annual incidence rate of mild exacerbations was 1.3 ( S ) v 0.6 ( SFC ) , p = 0.020 . An immediate and sustained increase in dyspnoea score ( scale 0–4 ; mean difference between groups 0.17 ( 0.04 ) , p<0.001 ) and in the percentage of disturbed nights ( 6 ( 2 ) percentage points , p<0.001 ) occurred after withdrawal of fluticasone . Conclusions : Withdrawal of FP in COPD patients using SFC result ed in acute and persistent deterioration in lung function and dyspnoea and in an increase in mild exacerbations and percentage of disturbed nights . This study clearly indicates a key role for ICS in the management of COPD as their discontinuation leads to disease deterioration , even under treatment with a LABA [15790985] Background : Combined treatment with inhaled corticosteroids and long acting β2 agonists is approved for the treatment of chronic obstructive pulmonary disease ( COPD ) , but little is known about the onset of effect of the combination . Methods : Data were used from 1465 patients with COPD entered into a large 1 year double blind trial with daily measurements of peak expiratory flow ( PEF ) and symptom scores . Results : PEF was significantly higher after 1 day in patients treated with salmeterol 50 μg twice daily or the salmeterol/fluticasone propionate combination 50/500 μg twice daily than placebo . In patients treated with fluticasone propionate 500 μg twice daily alone , PEF differed from placebo after 2 days . The differences after 2 weeks compared with placebo were 16 l/min ( 95 % confidence interval ( CI ) 11 to 21 ) , 11 l/min ( 95 % CI 6 to 16 ) , and 27 l/min ( 95 % CI 22 to 33 ) for salmeterol , fluticasone propionate , and the salmeterol/fluticasone propionate combination , respectively . For all treatments the effect on PEF after 2 weeks was comparable to that seen at the end of the study . The difference between the salmeterol/fluticasone propionate combination and placebo after 2 weeks as a percentage of baseline was similar for PEF and clinic forced expiratory volume in 1 second ( FEV1 ) . Differences in breathlessness scores were statistically significant after 1 day for the group treated with salmeterol alone and after 2 days for the combination group . The 2 week change in FEV1 was only partly indicative of a long term response in individual patients . Conclusions : The effects of salmeterol and fluticasone propionate , alone or in combination , on PEF and breathlessness are seen within days and most of the obtainable effect on these parameters is reached within 2 weeks [15363007] OBJECTIVE Withdrawal of corticosteroid is associated with a deterioration of health status in COPD . In this study the aim was to determine whether high dose inhaled corticosteroid improves quality of life in patients with COPD . METHODOLOGY In total , 38 male patients with moderate COPD were included in the study . Baseline quality of life scores were determined using a Turkish version of the St George 's Respiratory Question naire ( SGRQ ) . Patients were r and omly divided into two groups . Group 1 consisted of 20 patients who received existing bronchodilator therapy plus inhaled corticosteroid ( 800 micro g budesonide ) for 12 weeks , while 18 patients in group 2 received bronchodilator and placebo . The SGRQ was repeated after the treatment period . RESULTS All patients were male and mean age was 67 + /- 8.2 years . Symptom , activity , impact , and total scores were assessed and a difference of four units with treatment was considered to be clinical ly significant . Total score and activity score were decreased by six units and eight units , respectively , in the placebo group while symptom and impact scores did not change significantly . Total scores and the three component scores improved significantly in the corticosteroid group compared to the placebo group ( Deltatotal score : -22 in corticosteroid group , -6 in placebo group , P < 0.01 ) . CONCLUSION Inhaled corticosteroid improved quality of life scores in patients with COPD , without significant improvement in airflow obstruction parameters . Since improvement of health status is one of the important aims in COPD treatment , use of inhaled corticosteroids should be considered from this perspective [19841453] BACKGROUND Inhaled corticosteroids ( ICSs ) and long-acting beta(2)-agonists ( LABAs ) are used to treat moderate to severe chronic obstructive pulmonary disease ( COPD ) . OBJECTIVE To determine whether long-term ICS therapy , with and without LABAs , reduces inflammation and improves pulmonary function in COPD . DESIGN R and omized , placebo-controlled trial . ( Clinical Trials.gov registration number : NCT00158847 ) SETTING 2 university medical centers in The Netherl and s. PATIENTS 114 steroid-naive current or former smokers with moderate to severe COPD . MEASUREMENTS Cell counts in bronchial biopsies and sputum ( primary outcome ) ; methacholine responsiveness at baseline , 6 , and 30 months ; and clinical outcomes every 3 months . INTERVENTION R and om assignment by minimization method to receive fluticasone propionate , 500 microg twice daily , for 6 months ( n = 31 ) or 30 months ( n = 26 ) ; fluticasone , 500 microg twice daily , and salmeterol , 50 microg twice daily , for 30 months ( single inhaler ; n = 28 ) ; or placebo twice daily ( n = 29 ) . RESULTS 101 patients were greater than 70 % adherent to therapy . Fluticasone therapy decreased counts of mucosal CD3(+ ) cells ( -55 % [ 95 % CI , -74 % to -22 % ] ; P = 0.004 ) , CD4(+ ) cells ( -78 % [ CI , -88 % to 60 % ] ; P < 0.001 ) , CD8(+ ) cells ( -57 % [ CI , -77 % to -18 % ] ; P = 0.010 ) , and mast cells ( -38 % [ CI , -60 % to -2 % ] ; P = 0.039 ) and reduced hyperresponsiveness ( P = 0.036 ) versus placebo at 6 months , with effects maintained after 30 months . Fluticasone therapy for 30 months reduced mast cell count and increased eosinophil count and percentage of intact epithelium , with accompanying reductions in sputum neutrophil , macrophage , and lymphocyte counts and improvements in FEV(1 ) decline , dyspnea , and quality of life . Reductions in inflammatory cells correlated with clinical improvements . Discontinuing fluticasone therapy at 6 months increased counts of CD3(+ ) cells ( 120 % [ CI , 24 % to 289 % ] ; P = 0.007 ) , mast cells ( 218 % [ CI , 99 % to 407 % ] ; P < 0.001 ) , and plasma cells ( 118 % [ CI , 9 % to 336 % ] ; P = 0.028 ) and worsened clinical outcome . Adding salmeterol improved FEV(1 ) level . LIMITATIONS The study was not design ed to evaluate clinical outcomes . Measurement of primary outcome was not available for 24 % of patients at 30 months . CONCLUSION ICS therapy decreases inflammation and can attenuate decline in lung function in steroid-naive patients with moderate to severe COPD . Adding LABAs does not enhance these effects . [12379552] This r and omized controlled trial examined the benefits of combining an inhaled corticosteroid , fluticasone propionate ( F ) , with an inhaled long-acting beta(2)-agonist , salmeterol ( S ) , to treat the inflammatory and bronchoconstrictive components of chronic obstructive pulmonary disease ( COPD ) . A total of 691 patients with COPD received the combination of F and S ( FSC ) , S ( 50 mcg ) , F ( 500 mcg ) , or placebo twice daily via the Diskus device for 24 weeks . A significantly greater increase in predose FEV(1 ) at the endpoint was observed after FSC ( 156 ml ) compared with S ( 107 ml , p = 0.012 ) and placebo ( -4 ml , p < 0.0001 ) . A significantly greater increase in 2-hour postdose FEV(1 ) at the endpoint was observed after treatment with FSC ( 261 ml ) compared with F ( 138 ml , p < 0.001 ) and placebo ( 28 ml , p < 0.001 ) . There were greater improvements in the Transition Dyspnea Index with FSC ( 2.1 ) compared with F ( 1.3 , p = 0.033 ) , S ( 0.9 , p < 0.001 ) , and placebo ( 0.4 , p < 0.0001 ) . The incidence of adverse effects ( except for an increase in oral c and idiasis with FSC and F ) was similar among the treatment groups . We conclude that FSC improved lung function and reduced the severity of dyspnea compared with individual components and placebo [18620853] The Inhaled Steroids in Obstructive Lung Disease ( ISOLDE ) study was a trial that r and omised 752 patients with moderate to severe COPD to fluticasone propionate 1000 mcg/day or placebo for three years . We aim ed to examine the causes of death of the ISOLDE participants after the original three up to 13 years post-r and omisation . Death certificates were obtained either from the NHS Strategic Tracing Service or from the Office of National statistics . Deaths were classified according to the trial protocol . In the sub sample of 375 participants from the seven ISOLDE original centers where complete extended follow-up was conducted , the factors associated with observed higher mortality ( p<0.05 ) were male gender , older age and more severe COPD . Causes of death were ; 107 ( 52 % ) respiratory , 38 ( 18 % ) cardiac , 29 ( 14 % ) lung cancer , 16 ( 8 % ) other cancer and 16 ( 8 % ) other causes . The percentage of respiratory-related deaths increased during the follow-up period ; from 46 % within the three-year trial , to 48 % after 3 - 6 years , 57 % after 6 - 9 years , and 60 % after 9 - 13 years of follow-up ( p for trend<0.05 ) . We conclude that participants ' survival is poor ( only 44 % in the 13 years after the ISOLDE trial ) , and that respiratory-related illnesses were the most frequent causes of death in patients with moderate to severe COPD [15946834] Chronic obstructive pulmonary disease ( COPD ) is characterised by a chronic inflammatory process in the large and small airways , as well as in the lung parenchyma . Although the role of oral corticosteroids in the management of acute exacerbations of COPD is well documented , its role in stable COPD is not clear . We examined the anti-inflammatory effect of inhaled budesonide on the percentage of neutrophils and on interleukin-8 ( IL-8 ) levels in bronchoalveolar lavage ( BAL ) and their correlation with spirometry and symptom scores . Twenty-six patients with stable COPD were r and omised , in a double-blinded , placebo-controlled trial with either 800 microg of inhaled budesonide or placebo for a 6-month period . The budesonide-treated subjects had significant reductions in IL-8 levels in the BAL after therapy ( mean+/-sem , 1.53+/-0.72 at baseline vs. 0.70+/-0.48 ng/ml at 6 months , P=0.004 ) and a reduction in the mean percentages of neutrophils ( 17.16+/-2.67 % vs. 13.25+/-2.28 % P=0.002 ) . The improvement in sputum production was of borderline ( P=0.058 ) significance but there was no improvement in lung function . In stable patients with COPD , treatment with inhaled budesonide for a period of 6 months has a positive effect on markers of lung inflammation , as assessed by reduction in percentage neutrophils and IL-8 concentration in BAL [21299472] Introduction : Whether smoking-induced lung inflammation subsides after smoking cessation is currently a matter of debate . We used computed tomography ( CT ) to evaluate the effect of smoking cessation on lung density in patients with COPD . Material and methods : Thirty-six patients quit smoking out of 254 current smokers with COPD who were followed with annual CT and lung function tests ( LFT ) for 2–4 years as part of a r and omised placebo-controlled trial of the effect of inhaled budesonide on CT-lung density . Lung density was expressed as the 15th percentile density ( PD15 ) and relative area of emphysema below -910 HU ( RA-910 ) . From the time-trends in the budesonide and placebo groups the expected CT-lung densities at the first visit after smoking cessation were calculated by linear regression and compared to the observed densities . Results : Following smoking cessation RA-910 increased by 2.6 % ( p = 0.003 ) and PD15 decreased by −4.9 HU ( p = 0.0002 ) . Furthermore , changes were larger in the budesonide group than the placebo group ( PD15 : −7.1 vs −2.8 HU . RA-910 3.7 % vs 1.7 % ) . These differences were , however , not statistically significant . The LFT parameters ( FEV1 and diffusion capacity ) were not significantly influenced by smoking cessation . Conclusion : Inflammation partly masks the presence of emphysema on CT and smoking cessation results in a paradoxical fall in lung density , which resembles rapid progression of emphysema . This fall in density is probably due to an anti-inflammatory effect of smoking cessation [15853436] Abstract Objective : To compare the healthcare costs and effects of budesonide/formoterol in a single inhaler with those of budesonide and formoterol monotherapies , and placebo , in a multinational study in patients with chronic obstructive pulmonary disease ( COPD ) , National Heart , Lung and Blood Institute (NHLBI)/WHO Global Initiative for Chronic Obstructive Lung Disease ( GOLD ) stages III or IV . Previous analysis of the clinical data from the study had shown that budesonide/formoterol was associated with better lung function and improved health-related QOL compared with the monocomponents or placebo and lower frequency of exacerbations compared with formoterol and placebo . Method : Patients ( n = 1022 ) were r and omised to twice-daily treatment with two inhalations of budesonide/formoterol ( 160μg/4.5μg ) in a single inhaler , budesonide 200μg , formoterol 4.5μg or placebo for 12 months . Data on medication and healthcare use were combined with Swedish unit cost data to estimate the total annual healthcare cost per patient from the Swedish healthcare payer perspective . Costs were valued in Swedish kronor ( SEK ) [ 2001 values ] and converted to euros ( SEK1 = € 0.11 , 25th April 2003 ) . Results : This evaluation estimated the total annual healthcare costs per patient to be numerically lower for budesonide/formoterol ( € 2518 ) than for budesonide ( € 3194 ) , formoterol ( € 3653 ) or placebo ( € 3213 ) . Cost-effectiveness acceptability curves suggest that budesonide/formoterol may be cost effective compared with formoterol , even if the decision maker is not willing to pay anything for the additional clinical effects , and that budesonide/formoterol is cost effective compared with placebo if a decision maker is willing to pay about € 2 per day , per avoided exacerbation . Conclusion : This economic analysis suggests that the clinical benefits of using budesonide/formoterol in a single inhaler are achieved at a numerically lower total healthcare cost than either monocomponent or placebo . Budesonide/formoterol in patients with severe COPD ( GOLD stages III or IV ) may be cost effective , from the healthcare provider perspective , compared with either monocomponent [17053207] RATIONALE Exacerbations of chronic obstructive pulmonary disease ( COPD ) greatly contribute to declining health status and the progression of the disease , thereby incurring significant direct and indirect health care costs . The prevention of exacerbations , therefore , is an important treatment goal . OBJECTIVES To assess the impact of combination therapy with salmeterol/fluticasone propionate compared with salmeterol alone on moderate and severe exacerbations in patients with severe COPD and a history of repeated exacerbations . METHODS R and omized , double-blind , parallel-group study . After a 4-wk run-in period , 994 clinical ly stable patients were r and omized to one of two treatment groups : 507 patients received the salmeterol/fluticasone combination 50/500 micro g twice daily and 487 received salmeterol 50 micro g twice daily for 44 wk . MAIN RESULTS The total number of exacerbations was 334 in the combination therapy and 464 in the salmeterol group ( p < 0.0001 ) . The annualized rate of moderate and severe exacerbations per patient was 0.92 in the combination therapy and 1.4 in the salmeterol group , corresponding to a 35 % decrease . In addition , the mean time to first exacerbation in the combination therapy group was significantly longer compared with that of the salmeterol group ( 128 vs. 93 d , p < 0.0001 ) . Other endpoints , including health-related quality of life , peak expiratory flow , and use of rescue medication , were significantly improved in the combination therapy group . Both treatments were well tolerated . CONCLUSIONS This study demonstrates that combination therapy with salmeterol/fluticasone compared with salmeterol monotherapy significantly reduces the frequency of moderate/severe exacerbations in patients with severe COPD [10359405] BACKGROUND Little is known about the long-term efficacy of inhaled corticosteroids in chronic obstructive pulmonary disease ( COPD ) . We investigated the efficacy of inhaled budesonide on decline in lung function and respiratory symptoms in a 3-year placebo-controlled study of patients with COPD . METHODS We used a parallel-group , r and omised , double-blind , placebo-controlled design in a singlecentre study , nested in a continuing epidemiological survey ( the Copenhagen City Heart Study ) . Inclusion criteria were as follows : no asthma ; a ratio of forced expiratory volume in 1 s ( FEV1 ) and vital capacity of 0.7 or less ; FEV1 which showed no response ( < 15 % change ) to 1 mg inhaled terbutaline or prednisolone 37.5 mg orally once daily for 10 days . 290 patients were r and omly assigned budesonide , 800 microg plus 400 microg daily for 6 months followed by 400 microg twice daily for 30 months , or placebo for 36 months . The mean age of the participants was 59 years and the mean FEV1 2.37 L or 86 % of predicted . The main outcome measure was rate of FEV1 decline . Analyses were by intention to treat . FINDINGS The crude rates of FEV1 decline were slightly smaller than expected ( placebo group 41.8 mL per year , budesonide group 45.1 mL per year ) . The estimated rates of decline from the regression model did not differ significantly ( 49.1 mL vs 46.0 mL per year ; difference 3.1 mL per year [ 95 % CI -12.8 to 19.0 ] ; p=0.7 ) . Before the study , the minimum relevant difference was defined as 20 mL per year ; this difference was outside the 95 % CI . No effect of inhaled budesonide was seen on respiratory symptoms . 316 exacerbations occurred during the study period , 155 in the budesonide group and 161 in the placebo group . Treatment was well tolerated . INTERPRETATION Inhaled budesonide was of no clinical benefit in COPD patients recruited from the general population by screening . We question the role of long-term inhaled corticosteroids in the treatment of mild to moderate COPD [19581353] BACKGROUND Osteoporosis is common in patients with COPD , but its prevalence and progression are not well characterized . Concerns have been raised over the possible deleterious effect of long-term therapy with inhaled corticosteroids ( ICSs ) on bone density in this population . Here , we investigated the long-term effects of therapy with fluticasone propionate ( FP ) alone , salmeterol ( SAL ) alone , and a SAL/FP combination ( SFC ) on bone mineral density ( BMD ) and bone fractures in patients with moderate-to-severe COPD in the TOwards a Revolution in COPD Health ( TORCH ) study . METHODS A r and omized , double-blind , parallel-group , placebo-controlled study conducted at 88 US centers involving 658 patients ( a subset of 6,184 international subjects in TORCH ) . Therapy with placebo , SAL ( 50 microg ) , FP ( 500 microg ) , or SFC ( SAL 50 microg/FP 500 microg ) twice daily was administered for 3 years . Baseline and yearly measurements of BMD at the hip and lumbar spine were performed . The incidence of traumatic and nontraumatic bone fractures was recorded . RESULTS At baseline , 18 % of men and 30 % of women had osteoporosis , and 42 % of men and 41 % of women had osteopenia based on BMD assessment s. Forty-three percent of subjects completed all testing . The changes in BMD at the hip and lumbar spine over 3 years were small . No significant differences were observed between treatment arms ( adjusted mean percent change from baseline at hip was -3.1 % for placebo , -1.7 % for SAL , -2.9 % for FP , and -3.2 % for SFC therapy , respectively ; while , the corresponding changes for the lumbar spine were 0 , 1.5 % , -0.3 % , and -0.3 % for placebo , respectively , SAL , FP , and SFC therapy ) . The incidence of fractures was low and was similar for all treatments ( 5.1 % to 6.3 % ) . CONCLUSIONS Osteoporosis is highly prevalent in patients with COPD , irrespective of gender . In the TORCH study , no significant effect on BMD was detected for ICS therapy compared with placebo . TRIAL REGISTRATION Clinical Trials.gov Identifier : NTC00268216 [10421835] Treatment of chronic obstructive pulmonary disease ( COPD ) with inhaled and oral corticosteroids is common , although their exact role is unclear . Previous studies suggest these drugs may reduce decline in lung function in this group of patients . We report a study investigating the effect of inhaled beclomethasone diproprionate ( BDP ) on lung function and symptoms in a group of patients with COPD . Treatment was given for 2 years , and the decline in FEV1 in individual patients calculated over this period . Ninety‐eight patients were r and omized for the study , 59 completing 2 years of treatment . Patients withdrawn had more severe airflow obstruction . Decline in FEV1 , measured both prior to and after bronchodilator , was less in patients receiving inhaled BDP , although the differences failed to reach statistical significance except in a subgroup of patients with more severe airflow obstruction . Exacerbation rates were also reduced by inhaled BDP , but again the differences failed to reach conventional levels of statistical significance . The results of this study are consistent with previous published work , but further insight into the long‐term role of corticosteroids in COPD await the publication of large studies which have recently been completed . Although the changes seen in this study and others are numerically small , the rate of decline in FEV1 returned to normal levels expected from age‐related decline , and hence such treatment combined with other strategies may well have a significant role in the long‐term treatment of this condition [10379018] BACKGROUND Although patients with chronic obstructive pulmonary disease ( COPD ) should stop smoking , some do not . In a double-blind , placebo-controlled study , we evaluated the effect of the inhaled glucocorticoid budesonide in patients with mild COPD who continued smoking . After a six-month run-in period , we r and omly assigned 1277 subjects ( mean age , 52 years ; mean forced expiratory volume in one second [ FEV1 ] , 77 percent of the predicted value ; 73 percent men ) to twice-daily treatment with 400 microg of budesonide or placebo , inhaled from a dry-powder inhaler , for three years . RESULTS Of the 1277 subjects , 912 ( 71 percent ) completed the study . Among these subjects , the median decline in the FEV1 after the use of a bronchodilator over the three-year period was 140 ml in the budesonide group and 180 ml in the placebo group ( P=0.05 ) , or 4.3 percent and 5.3 percent of the predicted value , respectively . During the first six months of the study , the FEV1 improved at the rate of 17 ml per year in the budesonide group , as compared with a decline of 81 ml per year in the placebo group ( P<0.001 ) . From nine months to the end of treatment , the FEV1 declined at similar rates in the two groups ( P=0.39 ) . Ten percent of the subjects in the budesonide group and 4 percent of those in the placebo group had skin bruising ( P<0.001 ) . Newly diagnosed hypertension , bone fractures , postcapsular cataracts , myopathy , and diabetes occurred in less than 5 percent of the subjects , and the diagnoses were equally distributed between the groups . CONCLUSIONS In patients with mild COPD who continue smoking , the use of inhaled budesonide is associated with a small one-time improvement in lung function but does not appreciably affect the long-term progressive decline [12070058] Inhaled corticosteroids ( ICS ) are effective in the treatment of asthma and markedly reduce the numbers of inflammatory cells in bronchial biopsies . However , the effect of ICS on the inflammatory profile of biopsies in smokers with chronic obstructive pulmonary disease ( COPD ) is unknown . We have performed a double-blind , placebo-controlled , r and omized study to compare fluticasone propionate ( FP ) 500 microg twice daily via a dry powder inhaler and placebo ( P ) over a 3-month period in subjects with COPD . Fiberoptic bronchoscopy and bronchial biopsy was carried out at baseline and after the 3 months of treatment . Thirty-one subjects completed the trial and 30 paired biopsies were available for analysis . Compared with P ( n = 14 ) , subjects on inhaled FP ( n = 16 ) had no significant reductions in the primary endpoints : CD8 + , CD68 + cells , or neutrophils , considered to be of importance in COPD . However , there was a reduction in the CD8:CD4 ratio in the epithelium and of the numbers of subepithelial mast cells in the FP group . CD4 + cells were significantly raised in the P group in both subepithelium and epithelium . Symptoms significantly improved , and there were significantly fewer exacerbations in subjects on FP , compared to subjects on P. The data indicate that inhaled fluticasone does affect selected aspects of airway inflammation in COPD , and this may explain , in part , the decrease in exacerbations seen in long-term studies with fluticasone propionate [18778120] BACKGROUND The combination of an inhaled corticosteroid ( ICS ) and a long-acting bronchodilator is recommended in the treatment of patients with chronic obstructive pulmonary disease ( COPD ) who have frequent exacerbations . Budesonide/formoterol dry powder inhaler ( DPI ) has demonstrated efficacy and tolerability in patients with COPD . OBJECTIVE To evaluate the efficacy and tolerability of budesonide/formoterol administered via one hydrofluoroalkane pressurized metered-dose inhaler ( pMDI ) in patients with COPD . METHODS This was a 6-month , r and omized , double-blind , double-dummy , placebo-controlled , parallel-group , multicentre study ( NCT00206154 ) of 1704 patients aged > or = 40 years with moderate to very severe COPD conducted in 194 centres in the US , Czech Republic , the Netherl and s , Pol and and South Africa . After 2 weeks of treatment based on previous therapy ( ICSs and short-acting bronchodilators allowed during the run-in period ) , patients received one of the following treatments administered twice daily : budesonide/formoterol pMDI 160/4.5 microg x two inhalations ( 320/9 microg ) ; budesonide/formoterol pMDI 80/4.5 microg x two inhalations ( 160/9 microg ) ; budesonide pMDI 160 microg x two inhalations ( 320 microg ) plus formoterol DPI 4.5 microg x two inhalations ( 9 microg ) ; budesonide pMDI 160 microg x two inhalations ( 320 microg ) ; formoterol DPI 4.5 microg x two inhalations ( 9 microg ) ; or placebo . MAIN OUTCOME MEASURES The co- primary efficacy variables were pre-dose forced expiratory volume in 1 second ( FEV(1 ) ) and 1-hour post-dose FEV(1 ) . RESULTS Budesonide/formoterol 320/9 microg demonstrated significantly greater improvements in pre-dose FEV(1 ) versus formoterol ( p = 0.026 ; pre-specified primary comparator ) and 1-hour post-dose FEV(1 ) versus budesonide ( p < 0.001 ; pre-specified primary comparator ) ; budesonide/formoterol 160/9 microg demonstrated significantly greater improvements versus budesonide ( p < 0.001 ) for 1-hour post-dose FEV(1 ) but not versus formoterol for pre-dose FEV(1 ) . Dyspnoea ( measured using the Breathlessness Diary ) and health-related quality -of-life ( HR-QOL ) scores ( based on the St George 's Respiratory Question naire total score ) were significantly improved with both dosage strengths of budesonide/formoterol compared with budesonide , formoterol and placebo ( p < or = 0.044 for all ) . Although not powered a priori for comparisons , the number of exacerbations per patient-treatment year requiring treatment with oral corticosteroids and /or hospitalization was numerically ( 20 - 25 % ) lower with the budesonide-containing treatments ( 0.710 - 0.884 ) versus formoterol ( 1.098 ) and placebo ( 1.110 ) . This result was driven by the exacerbations requiring treatment with oral corticosteroids ( 79 - 120 events ) . The number of exacerbations result ing in hospitalization was very low across treatment groups ( 11 - 22 ) ; the number per patient-treatment year was significantly different for budesonide/formoterol 320/9 microg ( 0.158 ) versus other treatment groups ( 0.081 - 0.108 ) except budesonide/formoterol 160/9 microg ( 0.139 ) , and for budesonide/formoterol 160/9 microg versus formoterol ( 0.081 ) [ p < or = 0.05 ] . All treatments were generally well tolerated . The incidence of individual non-fatal serious adverse events was similar across all treatment groups , except COPD , which was highest in the budesonide/formoterol 320/9 microg group ( 6.1 % ) and lowest in the budesonide ( 3.6 % ) and formoterol ( 3.9 % ) groups , with a range of 4.3 - 4.6 % in the budesonide/formoterol 160/9 microg , budesonide plus formoterol and placebo groups . Budesonide/formoterol had a safety profile comparable with that of the monocomponents and placebo . There was no increase in the incidence of pneumonia in the active treatment groups relative to placebo . CONCLUSIONS Budesonide/formoterol pMDI 320/9 microg demonstrated significantly greater efficacy for pulmonary function on both co- primary endpoints versus the pre-specified comparators ( formoterol DPI 9 microg for pre-dose FEV(1 ) and budesonide pMDI 320 microg for 1-hour post-dose FEV(1 ) ) . Budesonide/formoterol pMDI 160/9 microg demonstrated significantly greater efficacy for 1-hour post-dose FEV(1 ) versus budesonide pMDI 320 microg . Dyspnoea scores and HR-QOL were significantly improved with both budesonide/formoterol pMDI dosage strengths versus both monocomponents and placebo . Both budesonide/formoterol pMDI dosage strengths were well tolerated relative to the monocomponents and placebo [19138505] BACKGROUND Increased oxidative stress and bronchial inflammation are important mechanisms in the pathophysiology of COPD . AIM To investigate whether treatment with the inhaled corticosteroid fluticasone propionate ( FP ) or the anti-oxidative agent N-acetylcysteine ( NAC ) are effective in primary care patients . METHODS The study was a 3-year placebo-controlled r and omised controlled trial preceded by a 3-month washout and 2-week prednisolone pre-treatment . Patients were (ex-)smokers with chronic bronchitis or COPD . Interventions were inhaled FP 500microg b.i.d . , oral NAC 600 mg o.d . , or placebo . Exacerbation rate and quality of life measured with the Chronic Respiratory Question naire ( CRQ ) were the primary outcomes , FEV(1 ) decline and respiratory symptoms secondary outcomes . RESULTS 286 patients recruited from 44 general practice s were r and omised . Exacerbation rate was 1.35 times higher for NAC ( p=0.054 ) and 1.30 times higher for FP ( p=0.095 ) compared with placebo . CRQ total scores did not differ between NAC ( p=0.306 ) or FP ( p=0.581 ) treatment compared to placebo . Annual postbronchodilator FEV(1 ) decline was 64mL [ SD 5.4 ] for NAC [ p=0.569 versus placebo ] , 59mL [ SD 5.7 ] for FP [ p=0.935 ] , and 60mL [ SD 5.4 ] for placebo . CONCLUSION No beneficial treatment effects for either high-dosed inhaled fluticasone propionate or oral N-acetylcysteine were observed in our study population of patients with COPD or chronic bronchitis [18614347] OBJECTIVES COPD exacerbations are associated with significant morbidity and mortality . This r and omized , double-blind , parallel-group , multicenter study evaluated the effect of fluticasone propionate/salmeterol 250/50 and salmeterol 50 microg twice daily on moderate to severe exacerbations . METHODS Patients received st and ardized treatment with fluticasone propionate/salmeterol 250/50 during a 1-month run-in , followed by r and omization to fluticasone propionate/salmeterol 250/50 or salmeterol for 12 months . Moderate to severe exacerbations were defined as worsening symptoms of COPD requiring treatment with oral corticosteroids , antibiotics , or hospitalization . RESULTS In 782 patients with COPD ( mean FEV(1)=0.94+/-0.36 L , 33 % predicted normal ) , treatment with fluticasone propionate/salmeterol 250/50 significantly reduced ( 1 ) the annual rate of moderate to severe exacerbations by 30.5 % compared with salmeterol ( 1.06 and 1.53 per subject per year , respectively , p<0.001 ) , ( 2 ) the risk of time to first exacerbation by 25 % ( hazard ratio=0.750 , p=0.003 ) and ( 3 ) the annual rate of exacerbations requiring oral corticosteroids by 40 % ( p<0.001 ) . Clinical improvements observed during run-in treatment with fluticasone propionate/salmeterol 250/50 were better maintained over 12 months with fluticasone propionate/salmeterol 250/50 than salmeterol . Adverse events were reported for a similar percentage of subjects across groups . A higher reporting of pneumonia was observed with fluticasone propionate/salmeterol 250/50 than salmeterol ( 7 % vs. 4 % ) . CONCLUSIONS We conclude that fluticasone propionate/salmeterol 250/50 is more effective than salmeterol at reducing the rate of moderate to severe exacerbations over 1 year . The benefits of this reduction relative to the risk of a higher incidence of reported pneumonia should be considered . This study supports the use of fluticasone propionate/salmeterol 250/50 for the reduction of COPD exacerbations in patients with COPD [12108857] There is a need for study ing the effects of long-term inhaled corticosteroid therapy on bone mineral density ( BMD ) and vertebral fracture rates in patients with mild chronic obstructive pulmonary disease ( COPD ) . Patients ( n=912 , mean age 52 yrs ) with mild COPD ( mean forced expiratory volume in one second ( FEV1 ) 77 % of predicted ; mean FEV1/slow vital capacity ratio 62 % ) were r and omized to receive budesonide 400 µg , or placebo twice daily via Turbuhaler ® . BMD was measured at the L2–L4 vertebrae and the femoral neck , trochanter and Ward 's triangle by dual-energy X-ray absorptiometry at baseline and after 6 , 12 , 24 and 36 months ( n=161 ) . Radiographs of the thoracic and lumbar spine were obtained at the beginning and end of treatment ( n=653 ) . Previous fractures were present at baseline in 43 budesonide-treated patients ( 13.4 % ) and 38 placebo-treated patients ( 11.5 % ) . New fractures occurred in five budesonide-treated patients , compared with three in the placebo group ( p=0.50 ) . There were no significant changes in BMD at any site in budesonide-treated patients , compared with the placebo group , during the course of the study . Budesonide treatment was associated with a slight but statistically significant decrease in the area under the concentration-time curve for serum osteocalcin . In the present study , involving a large group of patients with chronic obstructive pulmonary disease , long-term treatment with budesonide 800 µg·day−1 via Turbuhaler ® had no clinical ly significant effects on bone mineral density or fracture rates [14682412] BACKGROUND Early treatment with inhaled corticosteroids may prevent progression of irreversible obstruction in COPD , especially in patients with bronchial hyperresponsiveness . We investigated the clinical effects of early introduction of inhaled steroids in subjects showing early signs and symptoms of COPD without a prior clinical diagnosis . METHODS Study subjects were detected in a general population screening and monitoring program . Those with a moderately accelerated annual FEV1 decline and persistent respiratory symptoms were invited to participate in a 2-year r and omized controlled trial comparing fluticasone propionate DPI 250 microg b.i.d . with placebo . Pre- and post-bronchodilator ( BD ) FEV1 , PC20 histamine , functional status ( COOP/WONCA charts ) and occurrence of exacerbations were periodically assessed . Subjects recorded respiratory symptoms . Post-BD FEV1 decline served as the main outcome . Multivariable repeated measurements analysis techniques were applied . RESULTS 48 subjects were r and omized ( 24 fluticasone , 24 placebo ) . After 3 months , the post-BD FEV1 had increased with 125 ml ( SE = 68 , P = 0.075 ) and the pre-BD FEV1 with 174 ml ( SE 90 , P = 0.059 ) in the fluticasone relative to the placebo group . The subsequent post-BD and pre-BD FEV1 decline were not beneficially modified by fluticasone treatment . There were no statistically significant differences in respiratory symptoms , functional status , or exacerbations favoring fluticasone . Subgroup analysis indicated that the presence of bronchial hyperresponsiveness modified the initial FEV1 response on fluticasone , but not the subsequent annual FEV1 decline . CONCLUSION Early initiation of inhaled steroid treatment does not seem to affect the progressive deterioration of lung function or other respiratory health outcomes in subjects with early signs and symptoms of COPD . In subjects at risk for , or in an early stage of COPD , long-term inhaled steroid treatment should not be based on a single spirometric evaluation after 3 months [15526804] The prevalence of chronic obstructive pulmonary disease ( COPD ) in women is increasing worldwide . Women may have greater susceptibility to COPD progression than men , and differences in efficacy and safety of respiratory medications by gender are largely unexplored . We aim ed to determine whether the response to treatment in women with COPD differed from men in a large , 1-year double-blind trial ( ' TRISTAN ' ) . In a sensitivity analysis , we compared 539 male and 180 female COPD patients , who were r and omized to the saLmeterol/fluticasone combination 50/500mcg bid or placebo for 12 months . Combination therapy improved pre-treatment FEV1 significantly more than placebo in women by 152 ml ( 95 % confidence interval 95 - 208 ) and in men by 127 ml ( 94 - 159 ) . Similarly , a reduction in COPD exacerbation rates of 31 % in women ( 9 - 48 % ) and of 23 % in men ( 8 - 35 % ) was observed . Combination therapy reduced COPD exacerbations requiring treatment with oral corticosteroids by 36 % in women and by 41 % in men . Finally , combination treatment produced a better improvement in health status than placebo with a decrease in the SGRQ scores in women by -2.3 ( -4.6 - 0.1 ) and in men by -2.1 ( -3.5 to -0.8 ) . No gender interaction was found for any outcome . Treatments were well tolerated with no difference in the frequency of adverse events in women and men . In this trial , therapy with the salmeterol/fluticasone combination produced significant improvements compared to placebo on all main endpoints and the magnitude of these improvements was similar for both men and women [23332861] BACKGROUND Once-daily combination treatment is an attractive maintenance therapy for COPD . However , the dose of inhaled corticosteroid to use in a once-daily combination is unknown . We compared two strengths of fluticasone furoate ( FF ) plus vilanterol ( VI ) , the same strengths of the individual components , and placebo . METHODS Multicentre , r and omised , 24-week , double-blind , placebo-controlled , parallel-group study in stable , moderate-to-severe COPD subjects ( N = 1224 ) . Subjects were r and omised to FF/VI ( 200/25 μg ; 100/25 μg ) , FF ( 200 μg ; 100 μg ) , VI 25 μg , or placebo , once daily in the morning . Co- primary efficacy endpoints ; 0 - 4 h weighted mean ( wm ) FEV(1 ) on day 168 , and change from baseline in trough ( 23 - 24 h post-dose ) FEV(1 ) on day 169 . The primary safety objective was adverse events ( AEs ) . RESULTS There was a statistically significant ( p < 0.001 ) increase in wm FEV(1 ) ( 209 ml ) and trough FEV(1 ) ( 131 ml ) for FF/VI 200/25 μg vs. placebo ; similar changes were seen for FF/VI 100/25 μg vs. placebo . Whereas the difference between FF/VI 200/25 μg and VI 25 μg in change from baseline trough FEV(1 ) ( 32 ml ) was not statistically significant ( p = 0.224 ) , the difference between FF/VI 200/25 μg and FF 200 μg for wm FEV(1 ) ( 168 ml ) was significantly different ( p < 0.001 ) . VI 25 μg significantly improved wm and trough FEV(1 ) vs. placebo ( 185 ml and 100 ml , [ corrected ] respectively ) . No increase was seen in on-treatment AEs or serious AEs ( SAEs ) , with active therapy vs. placebo . CONCLUSIONS FF/VI provides rapid and significant sustained improvement in FEV(1 ) in subjects with moderate-to-severe COPD , which was not influenced by the dose of FF . These data suggest that FF/VI may offer clinical efficacy in COPD and warrants additional study . GSK study number : HZC112207 . Clinical Trials.gov : NCT01054885 [16903992] OBJECTIVES To explore the cost-effectiveness of fluticasone propionate ( FP ) for the treatment of chronic obstructive pulmonary disease ( COPD ) , we estimated costs and quality -adjusted life-years ( QALYs ) over 3 years , based on an economic appraisal of a previously reported clinical trial ( Inhaled Steroids in Obstructive Lung Disease in Europe [ ISOLDE ] ) . METHODS Seven hundred forty-two patients enrolled in the ISOLDE trial who received either FP or placebo had data available on health-care costs and quality of life over the period of the study . The SF-36-based utility scores for quality of life were used to calculate QALYs . A combined imputation and bootstrapping procedure was employed to h and le missing data and to estimate statistical uncertainty in the estimated cumulative costs and QALYs over the study period . The imputation approach was based on propensity scoring and nesting this approach within the bootstrap ensured that multiple imputations were performed such that statistical estimates included imputation uncertainty . RESULTS Complete data were available on mortality within the follow-up period of the study and a nonsignificant trend toward improved survival of 0.06 ( 95 % confidence interval [CI]-0.01 to 0.15 ) life-years was observed . In an analysis based on a propensity scoring approach to missing data we estimated the incremental costs of FP versus placebo to be 1021 sterling pound(95 % CI 619 - 1338 sterling pound ) with an additional effect of 0.11 QALYs ( CI 0.04 - 0.20 ) . Cost-effectiveness estimates for the within-trial period of 17,700 sterling pound per life-year gained ( 6900 sterling pound to infinity ) and 9500 sterling pound per QALY gained ( CI 4300 - 26,500 sterling pound ) were generated that include uncertainty due to the imputation process . An alternative imputation approach did not material ly affect these estimates . CONCLUSIONS Previous analyses of the ISOLDE study showed significant improvement on disease-specific health status measures and a trend toward a survival advantage for treatment with FP . This analysis shows that joint considerations of quality of life and survival result in a substantial increase in QALYs favoring treatment with FP . Based on these data , the inhaled corticosteroid FP appears cost-effective for the treatment of COPD . Confirmation or refutation of this result may be achieved once the Towards a Revolution in COPD Health ( TORCH ) study reports , a large r and omized controlled trial powered to detect mortality changes associated with the use of FP alone , or in combination with salmeterol , which is also collecting re source use and utility data suitable for estimating cost-effectiveness [16014203] OBJECTIVES To survey the frequency of use of indirect comparisons in systematic review s and evaluate the methods used in their analysis and interpretation . Also to identify alternative statistical approaches for the analysis of indirect comparisons , to assess the properties of different statistical methods used for performing indirect comparisons and to compare direct and indirect estimates of the same effects within review s. DATA SOURCES Electronic data bases . REVIEW METHODS The Data base of Abstract s of Review s of Effects ( DARE ) was search ed for systematic review s involving meta- analysis of r and omised controlled trials ( RCTs ) that reported both direct and indirect comparisons , or indirect comparisons alone . A systematic review of MEDLINE and other data bases was carried out to identify published methods for analysing indirect comparisons . Study design s were created using data from the International Stroke Trial . R and om sample s of patients receiving aspirin , heparin or placebo in 16 centres were used to create meta-analyses , with half of the trials comparing aspirin and placebo and half heparin and placebo . Methods for indirect comparisons were used to estimate the contrast between aspirin and heparin . The whole process was repeated 1000 times and the results were compared with direct comparisons and also theoretical results . Further detailed case studies comparing the results from both direct and indirect comparisons of the same effects were undertaken . RESULTS Of the review s identified through DARE , 31/327 ( 9.5 % ) included indirect comparisons . A further five review s including indirect comparisons were identified through electronic search ing . Few review s carried out a formal analysis and some based analysis on the naive addition of data from the treatment arms of interest . Few method ological papers were identified . Some valid approaches for aggregate data that could be applied using st and ard software were found : the adjusted indirect comparison , meta-regression and , for binary data only , multiple logistic regression ( fixed effect models only ) . Simulation studies showed that the naive method is liable to bias and also produces over-precise answers . Several methods provide correct answers if strong but unverifiable assumptions are fulfilled . Four times as many similarly sized trials are needed for the indirect approach to have the same power as directly r and omised comparisons . Detailed case studies comparing direct and indirect comparisons of the same effect show considerable statistical discrepancies , but the direction of such discrepancy is unpredictable . CONCLUSIONS Direct evidence from good- quality RCTs should be used wherever possible . Without this evidence , it may be necessary to look for indirect comparisons from RCTs . However , the results may be susceptible to bias . When making indirect comparisons within a systematic review , an adjusted indirect comparison method should ideally be used employing the r and om effects model . If both direct and indirect comparisons are possible within a review , it is recommended that these be done separately before considering whether to pool data . There is a need to evaluate methods for the analysis of indirect comparisons for continuous data and for empirical research into how different methods of indirect comparison perform in cases where there is a large treatment effect . Further study is needed into when it is appropriate to look at indirect comparisons and when to combine both direct and indirect comparisons . Research into how evidence from indirect comparisons compares to that from non-r and omised studies may also be warranted . Investigations using individual patient data from a meta- analysis of several RCTs using different protocol s and an evaluation of the impact of choosing different binary effect measures for the inverse variance method would also be useful [9692107] The European Respiratory Society 's study on chronic obstructive pulmonary disease ( EUROSCOP ) is a multicentre study performed initially in 12 countries to assess the effect of 3 years ' treatment with inhaled corticosteroids on lung function decline in smokers with chronic obstructive pulmonary disease ( COPD ) . It aim ed at recruiting 50 subjects in 50 European centres . This study discusses the most successful , countrywise , recruitment strategies , an important issue since many multicentre European studies may follow in the future . The total number of recruited subjects was 2147 in 39 participating centres . In total , at least 25,000 screening spirometries were performed , and about 80,000 hospital records were checked . The most effective way of recruiting subjects was to screen subjects by spirometry after mass media campaigns ( eight out of nine countries ) . Others used workplace screenings and different types of population survey , and only a few centres successfully recruited participants by hospital records . Inclusion criteria were slightly changed upon low initial accrual rate . Initial surveys in one country , where 2405 subjects were screened by spirometry , gave an important indication for the change of the inclusion criteria . Extension of the upper age limit from 60 to 65 yr considerably improved recruitment , as did a change of the upper limit of FEV1 from below 80 % predicted normal to below 100 % predicted normal , while maintaining the FEV1/VC ratio below 70 % . A tremendous effort is needed to recruit individuals with pre clinical COPD , but this is certainly feasible with adequate strategies adjusted to each country [19880616] The TORCH ( Towards a Revolution in COPD Health ) trial has highlighted some important issues in the design and analysis of long term trials in chronic obstructive pulmonary disease . These include collection of off-treatment exacerbation data , analysis of exacerbation rates and the effect of inclusion of patients receiving inhaled corticosteroids ( ICS ) prior to r and omisation . When effective medications are available to patients who withdraw , inclusion of off-treatment data can mask important treatment effects on exacerbation rates . Analysis of on-treatment data avoids this bias but it needs to be combined with careful analysis of withdrawal patterns across treatments . The negative binomial model is currently the best approach to statistical analysis of exacerbation rates , while analysis of time to exacerbation can supplement this approach . In the TORCH trial , exacerbation rates were higher among patients with previous use of ICS compared to those with no prior use on all study treatments . Retrospective subgroup analysis suggests ICS reduced exacerbation rates compared with placebo , regardless of prior use of ICS before entry to the study . Factorial analysis provides an alternative analysis for trials with combinations of treatments , but assumes no interaction between treatments , an assumption which can not be verified by a significance test . No definitive conclusions can yet be drawn on whether ICS treatment has an effect on mortality [17314337] BACKGROUND Long-acting beta-agonists and inhaled corticosteroids are used to treat chronic obstructive pulmonary disease ( COPD ) , but their effect on survival is unknown . METHODS We conducted a r and omized , double-blind trial comparing salmeterol at a dose of 50 microg plus fluticasone propionate at a dose of 500 microg twice daily ( combination regimen ) , administered with a single inhaler , with placebo , salmeterol alone , or fluticasone propionate alone for a period of 3 years . The primary outcome was death from any cause for the comparison between the combination regimen and placebo ; the frequency of exacerbations , health status , and spirometric values were also assessed . RESULTS Of 6112 patients in the efficacy population , 875 died within 3 years after the start of the study treatment . All-cause mortality rates were 12.6 % in the combination-therapy group , 15.2 % in the placebo group , 13.5 % in the salmeterol group , and 16.0 % in the fluticasone group . The hazard ratio for death in the combination-therapy group , as compared with the placebo group , was 0.825 ( 95 % confidence interval [ CI ] , 0.681 to 1.002 ; P=0.052 , adjusted for the interim analyses ) , corresponding to a difference of 2.6 percentage points or a reduction in the risk of death of 17.5 % . The mortality rate for salmeterol alone or fluticasone propionate alone did not differ significantly from that for placebo . As compared with placebo , the combination regimen reduced the annual rate of exacerbations from 1.13 to 0.85 and improved health status and spirometric values ( P<0.001 for all comparisons with placebo ) . There was no difference in the incidence of ocular or bone side effects . The probability of having pneumonia reported as an adverse event was higher among patients receiving medications containing fluticasone propionate ( 19.6 % in the combination-therapy group and 18.3 % in the fluticasone group ) than in the placebo group ( 12.3 % , P<0.001 for comparisons between these treatments and placebo ) . CONCLUSIONS The reduction in death from all causes among patients with COPD in the combination-therapy group did not reach the predetermined level of statistical significance . There were significant benefits in all other outcomes among these patients . ( Clinical Trials.gov number , NCT00268216 [ Clinical Trials.gov ] . ) [1486974] Chronic obstructive pulmonary disease ( COPD ) is a common disease in industrialised countries and responsible for a considerable morbidity and mortality . Cigarette smoking is the most important aetiological factor . The EUROSCOP trial aims at investigating the hypothesis that airway inflammation plays an important pathogenic role in the development of chronic obstructive airway disease in smokers . In cigarette smokers with poorly reversible airflow obstruction , the effect over 3 yrs of an inhaled glucocorticosteroid , budesonide 400 micrograms b.i.d . , on the decline of lung function , measured as postbronchodilator forced expiratory volume in one second ( FEV1 ) , will be compared with that of placebo . The trial has been design ed to detect a difference in yearly decline of at least 30 ml.year-1 . The study is a parallel group , r and omised , double-blind , multicentre study . Patients will be recruited from 47 centres in 12 countries in Europe . It will start with a run-in consisting of two 3 month periods . During the first 3 months , the patients will be offered a smoking cessation programme . All patients who have not stopped smoking during this period will enter the second half of the run-in where compliance with the dosage regimen will be tested . After these two periods , patients will be r and omised to receive either inhaled budesonide , 400 micrograms b.i.d . , or placebo for a period of 3 yrs [20965712] OBJECTIVES To evaluate the effect of beclomethasone/formoterol versus budesonide/formoterol ( non-inferiority ) and versus formoterol ( superiority ) in patients with severe stable chronic obstructive pulmonary disease ( COPD ) . METHODS A double-blind , double-dummy , r and omised , active-controlled , parallel-group study . After 4 weeks run-in with ipratropium/salbutamol ( 40/200 μg , three times daily ) patients were r and omised to receive beclomethasone/formoterol ( 200/12 μg pressurised metered dose inhaler ) , budesonide/formoterol ( 400/12 μg dry powder inhaler ) or formoterol ( 12 μg dry powder inhaler ) twice daily for 48 weeks . Co- primary efficacy variables were change from baseline to 48 weeks in pre-dose morning forced expiratory volume in 1 s ( FEV(1 ) ) and mean rate of COPD exacerbations . RESULTS Of 718 patients r and omised , 703 ( 232 beclomethasone/formoterol , 238 budesonide/formoterol , 233 formoterol ) were in the ITT analysis . Improvement in pre-dose morning FEV(1 ) was 0.077 L , 0.080 L and 0.026 L for beclomethasone/formoterol , budesonide/formoterol and formoterol respectively ( LS mean from the ANCOVA model ) . Beclomethasone/formoterol was not inferior to budesonide/formoterol ( 95 % CI of the difference -0.052 , 0.048 ) and superior to formoterol ( p = 0.046 ) . The overall rate of COPD exacerbations/patient/year was similar and not statistically significantly different among treatments ( beclomethasone/formoterol 0.414 , budesonide/formoterol 0.423 and formoterol 0.431 ) . Quality of life and COPD symptoms improved in all groups and use of rescue medication decreased . Safety profiles were as expected and treatments well-tolerated . CONCLUSIONS Beclomethasone/formoterol ( 400/24 μg ) treatment for 48 weeks improved pulmonary function , reduced symptoms compared to formoterol , was safe and well-tolerated in patients with severe stable COPD . Neither of the long-acting β2-agonist/inhaled corticosteroid combinations affected the low exacerbation rate seen in this population [19378223] The objective was to evaluate the effect of inhaled corticosteroids on disease progression in smokers with moderate to severe chronic obstructive pulmonary disease ( COPD ) , as assessed by annual computed tomography ( CT ) using lung density ( LD ) measurements . Two hundred and fifty-four current smokers with COPD were r and omised to treatment with either an inhaled corticosteroids ( ICS ) , budesonide 400 μ g bid , or placebo . COPD was defined as FEV1 ≤ 70 % pred , FEV1/FVC ≤ 60 % and no reversibility to β2-agonists and oral corticosteroids . The patients were followed for 2–4 years with biannual spirometry and annual CT and comprehensive lung function tests ( LFT ) . CT images were analysed using Pulmo-CMS software . LD was derived from a pixel-density histogram of the whole lung as the 15thpercentile density ( PD15 ) and the relative area of emphysema at a threshold of −910 Hounsfield units ( RA-910 ) , and both were volume-adjusted to predicted total lung capacity . At baseline , mean age was 64 years and 64 years ; mean number of pack-years was 56 and 56 ; mean FEV1 was 1.53 L ( 51 % pred ) and 1.53 L ( 53 % pred ) ; mean PD15 was 103 g/L and 104 g/L ; and mean RA-910 was 14 % and 13 % , respectively , for the budesonide and placebo groups . The annual fall in PD15 was −1.12 g/L in the budesonide group and −1.81 g/L in the placebo group ( p = 0.09 ) ; the annual increase in RA–910 was 0.4 % in the budesonide group and 1.1 % in the placebo group ( p = 0.02 ) . There was no difference in annual decline in FEV1 between ICS ( −54 mL ) and placebo ( −56 mL ) ( p = 0.89 ) . Long-term budesonide inhalation shows a non-significant trend towards reducing the progression of emphysema as determined by the CT-derived 15th percentile lung density from annual CT scans in current smokers with moderate to severe COPD [11136260] BACKGROUND Chronic obstructive pulmonary disease ( COPD ) results from a progressive decline in lung function , which is thought to be the consequence of airway inflammation . We hypothesized that antiinflammatory therapy with inhaled corticosteroids would slow this decline . METHODS We enrolled 1116 persons with COPD whose forced expiratory volume in one second ( FEV1 ) was 30 to 90 percent of the predicted value in a 10-center , placebo-controlled , r and omized trial of inhaled triamcinolone acetonide administered at a dose of 600 microg twice daily . The primary outcome measure was the rate of decline in FEV1 after the administration of a bronchodilator . The secondary outcome measures included respiratory symptoms , use of health care services , and airway reactivity . In a sub study of 412 participants , we measured bone density in the lumbar spine and femur at base line and one and three years after the beginning of treatment . RESULTS The mean duration of follow-up was 40 months . The rate of decline in the FEV1 after bronchodilator use was similar in the 559 participants in the triamcinolone group and the 557 participants in the placebo group ( 44.2+/-2.9 vs. 47.0+/-3.0 ml per year , P= 0.50 ) . Members of the triamcinolone group had fewer respiratory symptoms during the course of the study ( 21.1 per 100 person-years vs. 28.2 per 100 person-years , P=0.005 ) and had fewer visits to a physician because of a respiratory illness ( 1.2 per 100 person-years vs. 2.1 per 100 person-years , P=0.03 ) . Those taking triamcinolone also had lower airway reactivity in response to methacholine challenge at 9 months and 33 months ( P=0.02 for both comparisons ) . After three years , the bone density of the lumbar spine and the femur was significantly lower in the triamcinolone group ( P < or = 0.007 ) . CONCLUSIONS Inhaled triamcinolone does not slow the rate of decline in lung function in people with COPD , but it improves airway reactivity and respiratory symptoms and decreases the use of health care services for respiratory problems . These benefits should be weighed against the potential long-term adverse effects of triamcinolone on bone mineral density [10581660] The aim of this study was evaluate the predictive value of a 2 week course of prednisolone on the effect of 6 months treatment with inhaled budesonide in patients with stable chronic obstructive pulmonary disease ( COPD ) . Forty patients with stable COPD entered the study , and received prednisolone ( 37.5 mg o.d . ) for 2 weeks . They were subsequently divided into steroid-irreversible and steroid-irreversible , using 15 % of baseline as a dividing point . In each group patients were r and omized to receive budesonide 400 micrograms b.i.d . or placebo for 6 months . During treatment with prednisolone , three patients dropped out because of side effects . Of the remaining 37 , only two patients ( 5 % ) were reversible with prednisolone forced expiratory volume in 1s [ ( FEV1 ) > 15 % of baseline ] , and among the steroid-irreversible , 26 patients were evaluated after 6 months treatment with either placebo or budesonide . No significant differences in spirometry values , symptoms , or number of exacerbations were found between these two groups . Reversibility with prednisolone is rarely seen in COPD . In out patients with stable COPD and no signs of asthma or atopy , 2 weeks treatment with prednisolone seems to be of no value in choosing subsequent long-term therapy [10464871] Withdrawal of inhaled corticosteroids is known to worsen disease control in bronchial asthma but similar data are lacking in chronic obstructive pulmonary disease ( COPD ) . We hypothesized that clinical exacerbations requiring treatment would occur more often in patients whose inhaled corticosteroids were stopped than in other patients not treated with these agents . We studied 272 patients in mean age 65 ( SD 0.8 ) years , mean FEV1 42.8 ( SD 12.6)% predicted , entering the run-in phase of the Inhaled Steroids in Obstructive Lung Disease ( ISOLDE ) trial . All had been clinical ly stable for at least 6 weeks and there were no differences in the degree of bronchodilator reversibility , baseline lung function or pack-years of smoking between the 160 patients receiving inhaled corticosteroids and those not so treated . Inhaled corticosteroids were withdrawn in the first week of the study and during the remaining 7 weeks of the study 38 % of those previously treated with these drugs had an exacerbation compared to 6 % of the chronically untreated group . Patients receiving inhaled corticosteroids reported a longer duration of symptoms but neither this or any other recorded variable predicted the risk of exacerbation . These data suggest that abrupt withdrawal of inhaled corticosteroids should be monitored carefully even in patients with apparently irreversible COPD [10807619] Abstract Objectives : To determine the effect of long term inhaled corticosteroids on lung function , exacerbations , and health status in patients with moderate to severe chronic obstructive pulmonary disease . Design : Double blind , placebo controlled study . Setting : Eighteen UK hospitals . Participants : 751 men and women aged between 40 and 75 years with mean forced expiratory volume in one second ( FEV1 ) 50 % of predicted normal . Interventions : Inhaled fluticasone propionate 500 μg twice daily from a metered dose inhaler or identical placebo . Main outcome measures : Efficacy measures : rate of decline in FEV1 after the bronchodilator and in health status , frequency of exacerbations , respiratory withdrawals . Safety measures : morning serum cortisol concentration , incidence of adverse events . Results : There was no significant difference in the annual rate of decline in FEV1 ( P=0.16 ) . Mean FEV1 after bronchodilator remained significantly higher throughout the study with fluticasone propionate compared with placebo ( P<0.001 ) . Median exacerbation rate was reduced by 25 % from 1.32 a year on placebo to 0.99 a year on with fluticasone propionate ( P=0.026 ) . Health status deteriorated by 3.2 units a year on placebo and 2.0 units a year on fluticasone propionate ( P=0.0043 ) . Withdrawals because of respiratory disease not related to malignancy were higher in the placebo group ( 25 % v 19 % , P=0.034 ) . Conclusions : Fluticasone propionate 500 μg twice daily did not affect the rate of decline in FEV1 but did produce a small increase in FEV1 . Patients on fluticasone propionate had fewer exacerbations and a slower decline in health status . These improvements in clinical outcomes support the use of this treatment in patients with moderate to severe chronic obstructive pulmonary disease [21159140] Introduction : R and omised controlled trials ( RCTs ) are considered the least biased method for evaluating drug efficacy and several large long‐term RCTs in chronic obstructive pulmonary disease have been published . These usually include drugs with symptomatic benefits and have significant withdrawal rates Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Pharmacological therapy for chronic obstructive pulmonary disease ( COPD ) is aim ed at relieving symptoms , improving quality of life and preventing or treating exacerbations . Treatment tends to begin with one inhaler , and additional therapies are introduced as necessary . For persistent or worsening symptoms , long-acting inhaled therapies taken once or twice daily are preferred over short-acting inhalers . Several Cochrane review s have looked at the risks and benefits of specific long-acting inhaled therapies compared with placebo or other treatments . However for patients and clinicians , it is important to underst and the merits of these treatments relative to each other , and whether a particular class of inhaled therapies is more beneficial than the others . OBJECTIVES To assess the efficacy of treatment options for patients whose chronic obstructive pulmonary disease can not be controlled by short-acting therapies alone . The review will not look at combination therapies usually considered later in the course of the disease . How does long-term efficacy compare between different pharmacological treatments for COPD ? 2 . Are there limitations in the current evidence base that may compromise the conclusions drawn by this network meta- analysis ? If so , what are the implication s for future research ? AUTHORS ' CONCLUSIONS This network meta- analysis compares four different classes of long-acting inhalers for people with COPD who need more than short-acting bronchodilators . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

30284501

[4364646] Background Enhancing physical activity in overweight and obese individuals is an important means to promote health in this target population . The Health Action Process Approach ( HAPA ) , which was the theoretical framework of this study , focuses on individual self-regulation variables for successful health behavior change . One key self-regulation variable of this model is action control with its three subfacets awareness of intentions , self-monitoring and regulatory effort . The social context of individuals , however , is usually neglected in common health behavior change theories . In order to integrate social influences into the HAPA , this r and omized controlled trial investigated the effectiveness of a dyadic conceptualization of action control for promoting physical activity . Methods / Design This protocol describes the design of a single-blind r and omized controlled trial , which comprises four experimental groups : a dyadic action control group , an individual action control group and two control groups . Participants of this study are overweight or obese , heterosexual adult couples who intend to increase their physical activity . Blocking as means of a gender-balanced r and omization is used to allocate couples to conditions and partners to either being the target person of the intervention or to the partner condition . The ecological momentary intervention takes place in the first 14 days after baseline assessment and is followed by another 14 days diary phase without intervention . Follow-ups are one month and six months later . Subsequent to the six-months follow-up another 14 days diary phase takes place . The main outcome measures are self-reported and accelerometer-assessed physical activity . Secondary outcome measures are Body Mass Index ( BMI ) , aerobic fitness and habitual physical activity . Discussion This is the first study examining a dyadic action control intervention in comparison to an individual action control condition and two control groups applying a single-blind r and omized control trial . Challenges with running couples studies as well as advantages and disadvantages of certain design -related decisions are discussed . This RCT was funded by the Swiss National Science Foundation ( PP00P1_133632/1 ) and was registered on 27/04/2012 at http://www.is rct n.com/IS RCT N15705531 [22705016] OBJECTIVE The study presents the immediate post-intervention results of Kids and Adults Now - Defeat Obesity ! , a r and omized controlled trial to enhance healthy lifestyle behaviors in mother-preschooler ( 2 - 5 years old ) dyads in North Carolina ( 2007 - 2011 ) . The outcomes include change from baseline in the child 's diet , physical activity and weight , and in the mother 's parenting behaviors , diet , physical activity , and weight . METHOD The intervention targeted parenting through maternal emotion regulation , home environment , feeding practice s , and modeling of healthy behaviors . 400 mother-child dyads were r and omized . RESULTS Mothers in the intervention arm , compared to the control arm , reduced instrumental feeding ( -0.24 vs. 0.01 , p<0.001 ) and TV snacks ( -.069 vs. -0.24 , p=0.001 ) . There were also improvements in emotional feeding ( p=0.03 ) , mother 's sugary beverage ( p=0.03 ) and fruit/vegetable ( p=0.04 ) intake , and dinners eaten in front of TV ( p=0.01 ) ; these differences were not significant after adjustment for multiple comparisons . CONCLUSION KAN-DO , design ed to maximize the capacity of mothers as agents of change , improved several channels of maternal influence . There were no group differences in the primary outcomes , but differences were observed in the parenting and maternal outcomes and there were trends toward improvement in the preschoolers ' diets . Long-term follow-up will address whether these short-term trends ultimately improve weight status [25599511] IMPORTANCE Couples are highly concordant for unhealthy behaviors , and a change in one partner 's health behavior is often associated with a change in the other partner 's behavior . However , no studies have explicitly compared the influence of having a partner who takes up healthy behavior ( eg , quits smoking ) with one whose behavior is consistently healthy ( eg , never smokes ) . OBJECTIVE To examine the influence of partner 's behavior on making positive health behavior changes . DESIGN , SETTING , AND PARTICIPANTS We used prospect i ve data from married and cohabiting couples ( n , 3722 ) participating in the English Longitudinal Study of Ageing , a large population -based cohort of older adults ( ≥50 years ) . Study ing men and women who had unhealthy behaviors in 3 domains at baseline ( ie , smoking , physically inactive , or overweight/obese ) , we used logistic regression analysis to examine the influence of the partner 's behavior in the same domain on the odds of positive health behavior change over time . MAIN OUTCOMES AND MEASURES Smoking cessation , increased physical activity , and 5 % weight loss or greater . RESULTS Across all domains , we found that when one partner changed to a healthier behavior ( newly healthy ) , the other partner was more likely to make a positive health behavior change than if their partner remained unhealthy ( smoking : men 48 % vs 8 % , adjusted odds ratio [ OR ] , 11.82 [ 95 % CI , 4.84 - 28.90 ] ; women 50 % vs 8 % , OR , 11.23 [ 4.58 - 27.52 ] ) ( physical activity : men 67 % vs 26 % , OR , 5.28 [ 3.70 - 7.54 ] ; women 66 % vs 24 % , OR , 5.36 [ 3.74 - 7.68 ] ) ( weight loss : men 26 % vs 10 % , OR , 3.05 [ 1.96 - 4.74 ] ; women 36 % vs 15 % , OR , 3.08 [ 1.98 - 4.80 ] ) . For smoking and physical activity , having a consistently healthy partner also predicted positive change , but for each domain , the odds were significantly higher in individuals with a newly healthy partner than those with a consistently healthy partner ( smoking : men OR , 3.08 [ 1.43 - 6.62 ] ; women OR , 5.45 [ 2.44 - 12.16 ] ) ( physical activity : men OR , 1.92 [ 1.37 - 2.70 ] ; women OR , 1.84 [ 1.33 - 2.53 ] ) ( weight loss : men OR , 2.28 [ 1.36 - 3.84 ] ; women OR , 2.86 [ 1.55 - 5.26 ] ) . CONCLUSIONS AND RELEVANCE Men and women are more likely to make a positive health behavior change if their partner does too , and with a stronger effect than if the partner had been consistently healthy in that domain . Involving partners in behavior change interventions may therefore help improve outcomes [21108739] To assess the feasibility of conducting empirically supported family-based paediatric obesity group treatment via TeleMedicine . Seventeen families were r and omly assigned to one of two conditions ( physician visit , TeleMedicine ) . Measures included feasibility , satisfaction and intervention outcome measures such as BMI percentile , and nutrition and activity behaviours . Measures were completed at baseline , post-treatment and at 1-year follow-up . Analyses indicate that both feasibility and satisfaction data regarding the TeleMedicine intervention were positive . Intervention outcome indicates no change in BMI percentile or nutrition and activity behaviours for either treatment group . A behavioural family-based weight loss intervention delivered via TeleMedicine was well received by both parents and providers . Due to the small sample size , null findings regarding intervention outcome should be interpreted with caution . Future research should focus on methods to increase the impact of this intervention on key outcome variables [24495204] Morbidity and mortality are reliably lower for the married compared with the unmarried across a variety of illnesses . What is less well understood is how a couple uses their relationship for recommended lifestyle changes associated with decreased risk for illness . Partners for Life compared a patient and partner approach to behavior change with a patient only approach on such factors as exercise , nutrition , and medication adherence . Ninety-three patients and their spouses/partners consented to participate ( 26 % of those eligible ) and were r and omized into either the individual or couples condition . However , only 80 couples , distributed across conditions , contributed data to the analyses , due to missing data and missing data points . For exercise , there was a significant effect of couples treatment on the increase in activity and a significant effect of couples treatment on the acceleration of treatment over time . In addition , there was an interaction between marital satisfaction and treatment condition such that patients who reported higher levels of marital distress in the individuals condition did not maintain their physical activity gains by the end of treatment , while both distressed and nondistressed patients in the couples treatment exhibited accelerating gains throughout treatment . In terms of medication adherence , patients in the couples treatment exhibited virtually no change in medication adherence over time , while patients in the individuals treatment showed a 9 % relative decrease across time . There were no condition or time effects for nutritional outcomes . Finally , there was an interaction between baseline marital satisfaction and treatment condition such that patients in the individuals condition who reported lower levels of initial marital satisfaction showed deterioration in marital satisfaction , while non satisfied patients in the couples treatment showed improvement over time [22576339] Background A key barrier to achieving recommended intensity and duration of physical activity is motivation . Purpose We investigated whether a virtually present partner would influence participants ’ motivation ( duration ) during aerobic exercise . Method Fifty-eight females ( Mage = 20.54 ± 1.86 ) were r and omly assigned to either a coactive condition ( exercising alongside another person , independently ) , a conjunctive condition ( performance determined by whichever partner stops exercising first ) where they exercised with a superior partner , or to an individual condition . Participants exercised on a stationary bike at 65 % of heart rate reserve on six separate days . Results Across sessions , conjunctive condition participants exercised significantly longer ( M = 21.89 min , SD = ±10.08 min ) than those in coactive ( M = 19.77 min , SD = ± 9.00 min ) and individual ( M = 10.6 min , SD = ±5.84 min ) conditions ( p < 0.05 ) . Conclusion Exercising with a virtually present partner can improve performance on an aerobic exercise task across multiple sessions [5182111] Objective To develop and test a family-centered behavioral weight loss intervention for African American adults with type 2 diabetes . Methods In this r and omized trial , dyads consisting of African American adult with overweight or obesity and type 2 diabetes ( index participant ) paired with a family partner with overweight or obesity , but not diagnosed with diabetes , were assigned in a 2:1 ratio to a 20-week special intervention ( SI ) or delayed intervention ( DI ) control group . The primary outcome was weight loss among index participants at 20 weeks follow-up . Results One hundred-eight participants ( 54 dyads – 36 ( SI ) and 18 ( DI ) dyads ) were enrolled : 81 % females ; mean age , 51 years ; mean weight,103 kg ; and mean BMI , 37 kg/m2 . At post-intervention , 96 participants ( 89 % ) returned for follow-up measures . Among index participants , mean difference in weight loss between groups was −5.0 kg , p<.0001 ( −3.6 kg loss among SI ; 1.4 kg gain in DI ) . SI index participants showed significantly greater improvements in hemoglobin A1c , depressive symptoms , family interactions , and dietary , physical activity , and diabetes self-care behaviors . SI family partners also had significant weight loss ( −3.9 kg ( SI ) vs. −1.0 kg ( DI ) p=0.02 ) . Conclusions A family-centered , behavioral weight loss intervention led to clinical ly significant short-term weight loss among family dyads [4875491] Background Emerging technologies ( ie , mobile phones , Internet ) may be effective tools for promoting physical activity ( PA ) . However , few interventions have provided effective means to enhance social support through these platforms . Face-to-face programs that use group dynamics-based principles of behavior change have been shown to be highly effective in enhancing social support through promoting group cohesion and PA , but to date , no studies have examined their effects in Web-based programs . Objective The aim was to explore proof of concept and test the efficacy of a brief , online group dynamics-based intervention on PA in a controlled experiment . We expected that the impact of the intervention on PA would be moderated by perceptions of cohesion and the partner ’s degree of presence in the online media . Methods Participants ( n=135 ) were r and omized into same-sex dyads and r and omly assigned to one of four experimental conditions : st and ard social support ( st and ard ) , group dynamics-based – high presence , group dynamics-based – low presence , or individual control . Participants performed two sets of planking exercises ( pre-post ) . Between sets , participants in partnered conditions interacted with a virtual partner using either a st and ard social support app or a group dynamics-based app ( group dynamics-based – low presence and group dynamics-based – high presence ) , the latter of which they participated in a series of online team-building exercises . Individual participants were given an equivalent rest period between sets . To increase presence during the second set , participants in the group dynamics-based – high presence group saw a live video stream of their partner exercising . Perceptions of cohesion were measured using a modified PA Group Environment Question naire . Physical activity was calculated as the time persisted during set 2 after controlling for persistence in set 1 . Results Perceptions of cohesion were higher in the group dynamics-based – low presence ( overall mean 5.81 , SD 1.04 ) condition compared to the st and ard ( overall mean 5.04 , SD 0.81 ) conditions ( P=.006 ) , but did not differ between group dynamics-based – low presence and group dynamics-based – high presence ( overall mean 5.42 , SD 1.07 ) conditions ( P=.25 ) . Physical activity was higher in the high presence condition ( mean 64.48 , SD 20.19 , P=.01 ) than all other conditions ( mean 53.3 , SD 17.35 ) . Conclusions A brief , online group dynamics-based intervention may be an effective method of improving group cohesion in virtual PA groups . However , it may be insufficient on its own to improve PA [23515115] The effectiveness of methods to prevent stroke recurrence and of education focusing on learners ' needs has not been fully explored . The aims of this study were to assess the effects of such interventions among stroke patients and their primary caregivers and to evaluate the feasibility of a web-based stroke education program . The participants were 36 patients with a clinical diagnosis of ischemic stroke within 12 months post-stroke and their primary caregivers . The participants were r and omly assigned to either an experimental or a control group . The primary measures included blood chemistry , self-reported health behaviors , sense of control , and health motivation for stroke patients , and caregiver mastery for caregivers . To test the feasibility of the intervention program , the rates of participation and occurrence of technical problems were calculated . The experimental group tended to improve significantly more than the control group in terms of exercise , diet , sense of control and health motivation for the stroke patients and in terms of caregiver mastery for the primary caregivers . The rate of participation in the web-based program was 63.1 % . This program , which focuses on recurrence prevention in stroke patients and caregivers , has the potential to improve health behaviors for stroke patients [4174282] Background Screen-based activities , such as watching television ( TV ) , playing video games , and using computers , are common sedentary behaviors among young people and have been linked with increased energy intake and overweight . Previous home-based sedentary behaviour interventions have been limited by focusing primarily on the child , small sample sizes , and short follow-up periods . The SWITCH ( Screen-Time Weight-loss Intervention Targeting Children at Home ) study aim ed to determine the effect of a home-based , family-delivered intervention to reduce screen-based sedentary behaviour on body composition , sedentary behaviour , physical activity , and diet over 24 weeks in overweight and obese children . Methods A two-arm , parallel , r and omized controlled trial was conducted . Children and their primary caregiver living in Auckl and , New Zeal and were recruited via schools , community centres , and word of mouth . The intervention , delivered over 20 weeks , consisted of a face-to-face meeting with the parent/caregiver and the child to deliver intervention content , which focused on training and educating them to use a wide range of strategies design ed to reduce their child ’s screen time . Families were given Time Machine TV monitoring devices to assist with allocating screen time , activity packages to promote alternative activities , online support via a website , and monthly newsletters . Control participants were given the intervention material on completion of follow-up . The primary outcome was change in children ’s BMI z-score from baseline to 24 weeks . Results Children ( n = 251 ) aged 9 - 12 years and their primary caregiver were r and omized to receive the SWITCH intervention ( n = 127 ) or no intervention ( controls ; n = 124 ) . There was no significant difference in change of z BMI between the intervention and control groups , although a favorable trend was observed ( -0.016 ; 95 % CI : -0.084 , 0.051 ; p = 0.64 ) . There were also no significant differences on secondary outcomes , except for a trend towards increased children ’s moderate intensity physical activity in the intervention group ( 24.3 min/d ; 95 % CI : -0.94 , 49.51 ; p = 0.06 ) . Conclusions A home-based , family-delivered intervention to reduce all leisure-time screen use had no significant effect on screen-time or on BMI at 24 weeks in overweight and obese children aged 9 - 12 years . Trial registration Australian New Zeal and Clinical Trials RegistryWebsite : http://www.anzctr.org.auTrial registration number : [26367803] The study examined whether a behavior-change intervention focusing on self-regulatory strategies and emphasizing role model support increases physical activity ( PA ) among insufficiently active ( not meeting PA guidelines of 150 min/week ) cancer patients . Ambulatory cancer patients [ N = 72 ; 54 % female ; M = 56 years , SD = 12.34 ; most with breast or colon cancer ( 34 , 15 % ) ] were enrolled in the MOTIVACTION- study , a 4-week intervention ( 1-hr counseling , followed by weekly phone calls ) , with pretest ( T1 ) , posttest ( T2 ) and a 10-week follow-up ( T3 ) . Participants were r and omized to either an exercise or to a stress management intervention ( active control ) . The exercise intervention emphasized self-regulatory strategies ( e.g. action- and coping planning and self-monitoring ) ; patients were also encouraged to contact a physically active same-sex role model as a potential exercise partner . The active control condition consisted of coping and relaxation techniques . Sixty-seven patients remained in the study and completed the SQUASH assessment of PA and a measure of perceived stress . PA was vali date d by Actigraph accelerometry . At T2 , 46 % of the patients in the exercise group and 19 % of stress management patients increased their activity levels to meet PA guidelines ( > 150 min/week ; χ2(1 ) = 5.51 , p = .019 ) . At T3 , participants in the exercise intervention maintained their exercise level ( 46 % ) , but also 31 % of the stress management patients met the guidelines . All patients reported reductions in perceived stress . Additional analyses comparing patients in the exercise group by role model contact ( 63 % realized contact ) revealed that those who had contact with their role model were significantly more likely to adhere to the recommended guidelines ( T2:50 % ; T3:64 % ) compared to those who did not have contact with a role model ( T2:39 % ; T3:15 % ) , suggesting the potential of mobilizing role model support to facilitate PA . In sum , cancer patients may not only benefit from an exercise intervention emphasizing self-regulation , but also from stress management , regarding both reducing stress and increasing PA [23545372] BACKGROUND AND OBJECTIVE : Clinic-based programs for childhood obesity are not available to a large proportion of the population . The purpose of this study was to evaluate the efficacy of a guided self-help treatment of pediatric obesity ( GSH-PO ) compared with a delayed treatment control and to evaluate the impact of GSH-PO 6-months posttreatment . METHODS : Fifty overweight or obese 8- to 12-year-old children and their parents were r and omly assigned to immediate treatment or to delayed treatment . The GSH-PO includes 12 visits over 5 months and addresses key components included in more intensive clinic-based programs . Children and parents in the immediate treatment arm were assessed at time 1 ( T1 ) , participated in GSH-PO between T1 and T2 , and completed their 6-month posttreatment assessment at T3 . Children and parents in the delayed treatment arm were assessed at T1 , participated in GSH-PO between T2 and T3 , and completed their 6-month posttreatment assessment at T4 . The main outcome measures were BMI , BMI z score , and percentage overweight ( % OW ) . RESULTS : Children in the immediate treatment GSH-PO arm decreased their BMI significantly more than did the delayed treatment arm ( BMI group × time = −1.39 ; P < .001 ) . Similar results were found for BMI z score and % OW . At the 6-month posttreatment assessment , changes result ing from GSH-PO were maintained for BMI z score and % OW but not BMI ( BMI time effect = −0.06 , not significant ; BMI z score time effect = −0.10 , P < .001 ; % OW time effect = −4.86 , P < .05 ) . CONCLUSIONS : The GSH-PO showed initial efficacy in decreasing BMI for children in this study . Additional efficacy and translational studies are needed to additionally evaluate GSH-PO [26715587] Background Prostate cancer can negatively impact quality of life of the patient and his spouse caregiver , but interventions rarely target the health of both partners simultaneously . We tested the feasibility and preliminary efficacy of a partnered strength training program on the physical and mental health of prostate cancer survivors ( PCS ) and spouse caregivers . Methods Sixty-four couples were r and omly assigned to 6 months of partnered strength training ( Exercising Together , N = 32 ) or usual care ( UC , N = 32 ) . Objective measures included body composition ( lean , fat and trunk fat mass ( kg ) , and % body fat ) by DXA , upper and lower body muscle strength by 1-repetition maximum , and physical function by the physical performance battery ( PPB ) . Self-reported measures included the physical and mental health summary scales and physical function and fatigue subscales of the SF-36 and physical activity with the CHAMPS question naire . Results Couple retention rates were 100 % for Exercising Together and 84 % for UC . Median attendance of couples to Exercising Together sessions was 75 % . Men in Exercising Together became stronger in the upper body ( p < 0.01 ) and more physically active ( p < 0.01 ) than UC . Women in Exercising Together increased muscle mass ( p = 0.05 ) and improved upper ( p < 0.01 ) and lower body ( p < 0.01 ) strength and PPB scores ( p = 0.01 ) more than UC . Conclusions Exercising Together is a novel couples-based approach to exercise that was feasible and improved several health outcomes for both PCS and their spouses . Implication s for cancer survivorsA couples-based approach should be considered in cancer survivorship programs so that outcomes can mutually benefit both partners . Trial registration Clinical Trials.gov [23415190] BACKGROUND Few successful treatment modalities exist to address childhood obesity . Given Latinos ' strong identity with family , a family-focused intervention may be able to control Latino childhood obesity . PURPOSE To assess the feasibility and effectiveness of a family-centered , primary care-based approach to control childhood obesity through lifestyle choices . DESIGN R and omized waitlist controlled trial in which control participants received the intervention 6 months after the intervention group . SETTING / PARTICIPANTS Forty-one Latino children with BMI > 85 % , aged 9 - 12 years , and their caregivers were recruited from an urban community health center located in a predominantly low-income community . INTERVENTION Children and their caregivers received 6 weeks of interactive group classes followed by 6 months of culturally sensitive monthly in-person or phone coaching to empower families to incorporate learned lifestyles and to address both family and social barriers to making changes . MAIN OUTCOMES MEASURES Caregiver report on child and child self-reported health-related quality of life ( HRQoL ) ; metabolic markers of obesity ; BMI ; and accelerometer-based physical activity were measured July 2010-November 2011 and compared with post-intervention assessment s conducted at 6 months and as a function of condition assignment . Data were analyzed in 2012 . RESULTS Average attendance rate to each group class was 79 % . Socio-environmental and family factors , along with knowledge , were cited as barriers to changing lifestyles to control obesity . Caregiver proxy and child self-reported HRQoL improved for both groups with a larger but not nonsignificant difference among intervention vs control group children ( p=0.33 ) . No differences were found between intervention and control children for metabolic markers of obesity , BMI , or physical activity . CONCLUSIONS Latino families are willing to participate in group classes and health coaching to control childhood obesity . It may be necessary for primary care to partner with community initiatives to address childhood obesity in a more intense manner . TRIAL REGISTRATION This study is registered at Clinical trials.partners.org 2009P001721 [4222564] Background Levels of physical activity ( PA ) in UK children are much lower than recommended and novel approaches to its promotion are needed . The Children , Parents and Pets Exercising Together ( CPET ) study is the first exploratory r and omised controlled trial ( RCT ) to develop and evaluate an intervention aim ed at dog-based PA promotion in families . CPET aim ed to assess the feasibility , acceptability and potential efficacy of a theory-driven , family-based , dog walking intervention for 9–11 year olds . Methods Twenty-eight families were allocated r and omly to either receive a 10-week dog based PA intervention or to a control group . Families in the intervention group were motivated and supported to increase the frequency , intensity and duration of dog walking using a number of behaviour change techniques . Parents in the intervention group were asked to complete a short study exit question naire . In addition , focus groups with parents and children in the intervention group , and with key stakeholders were undertaken . The primary outcome measure was 10 week change in total volume of PA using the mean accelerometer count per minute ( cpm ) . Intervention and control groups were compared using analysis of covariance . Analysis was performed on an intention to treat basis . Results Twenty five families were retained at follow up ( 89 % ) and 97 % of all outcome data were collected at baseline and follow up . Thirteen of 14 ( 93 % ) intervention group parents available at follow up completed the study exit question naire and noted that study outcome measures were acceptable . There was a mean difference in child total volume of PA of 27 cpm ( 95 % CI -70 , 123 ) and -3 cpm ( 95 % CI -60 , 54 ) for intervention and control group children , respectively . This was not statistically significant . Approximately 21 % of dog walking time for parents and 39 % of dog walking time for children was moderate-vigorous PA . Conclusions The acceptability of the CPET intervention and outcome measures was high . Using pet dogs as the agent of lifestyle change in PA interventions in children and their parents is both feasible and acceptable , but did not result in a significant increase in child PA in this exploratory trial . Trial registration IS RCT [3999907] Background Mexico has the highest adult overweight and obesity prevalence in the Americas ; 23.8 % of children < 5 years old are at risk for overweight and 9.7 % are already overweight or obese . Creciendo Sanos was a pilot intervention to prevent obesity among preschoolers in Instituto Mexicano del Seguro Social ( IMSS ) clinics . Methods We r and omized 4 IMSS primary care clinics to either 6 weekly educational sessions promoting healthful nutrition and physical activity or usual care . We recruited 306 parent-child pairs : 168 intervention , 138 usual care . Children were 2 - 5 years old with WHO body mass index ( BMI ) z-score 0 - 3 . We measured children ’s height and weight and parents reported children ’s diet and physical activity at baseline and 3 and 6-month follow-up . We analyzed behavioral and BMI outcomes with generalized mixed models incorporating multiple imputation for missing values . Results 93 ( 55 % ) intervention and 96 ( 70 % ) usual care families completed 3 and 6-month follow-up . At 3 months , intervention v. usual care children increased vegetables by 6.3 servings/week ( 95 % CI , 1.8 , 10.8 ) . In stratified analyses , intervention participants with high program adherence ( 5 - 6 sessions ) decreased snacks and screen time and increased vegetables v. usual care . No further effects on behavioral outcomes or BMI were observed . Transportation time and expenses were barriers to adherence . 90 % of parents who completed the post-intervention survey were satisfied with the program . Conclusions Although satisfaction was high among participants , barriers to participation and retention included transportation cost and time . In intention to treat analyses , we found intervention effects on vegetable intake , but not other behaviors or BMI .Trial registration Clinical Trials.gov NCT01539070.Comisión Nacional de Investigación Científica del IMSS : 2009 - 785 - 120 [3196245] Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more [21808077] The present investigation examined the Köhler motivation gain effect in a health game using an absent partner , presented virtually . The Köhler effect occurs when an inferior team member performs a difficult task better in a team or coaction situation than one would expect from knowledge of his or her individual performance . The effect has been strongest in conjunctive task conditions in which the group 's potential productivity is equal to the productivity of its least capable member . Participants were r and omly assigned to one of four conditions ( individual control , coaction , additive , and conjunctive ) in a 4 ( conditions ) • 2 ( gender ) factorial design and performed a series of isometric plank exercises within an exercise game . They performed the first series of five exercises alone holding each position for as long as they could , and , after a rest period , those in the partner conditions were told they would do remaining trials with a same-sex virtual partner whom they could observe during their performance . The partner 's performance was manipulated to be always superior to the participant 's . Results showed that task persistence was significantly greater in all experimental conditions than in the individual control condition . The conjunctive condition was no more motivating than either the additive or coactive conditions . Results suggest that working out with virtually present , superior partners can improve persistence motivation on exercise game tasks [16336114] OBJECTIVE To evaluate an intervention aim ed at increasing family physical activity and parent education about diet and activity for kindergarten students and issues related to their children 's BMI . METHODS A r and omized , controlled trial design was used to assess intervention impact in parental report of child diet and physical activity , and step logs over a 4-week period . RESULTS Participants in the intervention group reported that their children obtained more steps by the end of the program period , were more active , and had consumed fewer sweets than the comparison group . CONCLUSION The proposed intervention for parents and their young children does produce awareness and behavior change [27642760] Objective : Action planning can help translate physical activity intentions into action by linking situational cues with behavioral responses . Dyadic planning extends action planning and refers to target persons forming plans for their own behavior change together with partners . This study investigated whether a dyadic planning intervention could increase physical activity in target persons and their partners , whether these effects were moderated by relationship quality and mediated by action control , activity-specific received partner support , and control . Method : Couples ( n = 338 ; target persons r and omized ) were r and omly assigned to ( a ) a dyadic planning condition ( DPC ) ; ( b ) an individual planning condition ( IPC ) , in which target persons planned and partners worked on a distractor task ; or ( c ) a control condition ( CC ) , in which couples worked on a distractor task . During 3 assessment s up to 6 weeks postintervention , moderate ( primary outcome ) and vigorous activity were objective ly measured ; other variables were self-reported . Multilevel and path models were fit . Results : There were no beneficial direct effects of the intervention for DPC target persons . Over time , DPC partners ’ vigorous activity increased , but decreased again . At lower relationship quality , DPC target persons ’ activity decreased , whereas IPC target persons ’ vigorous activity increased . Mediation hypotheses were not supported . Mutual influence models indicated positive effects of partners ’ on target persons ’ moderate activity in DPC and CC , whereas for IPC , negative effects of target persons ’ on partners ’ moderate activity emerged . Conclusions : Findings revealed the complexity of effects of dyadic planning on behavior change . Adding relationship quality to the equation clarified effects of DPC and IPC on physical activity [3533722] Background The diets , physical activity and sedentary behavior levels of both children and adults in Australia are suboptimal . The family environment , as the first ecological niche of children , exerts an important influence on the onset of children ’s habits . Parent modeling is one part of this environment and a logical focus for child obesity prevention initiatives . The focus on parent ’s own behaviors provides a potential opportunity to decrease obesity risk behaviors in parents as well . Objective To assess the effect of a parent-focused early childhood obesity prevention intervention on first-time mothers ’ diets , physical activity and TV viewing time . Methods The Melbourne InFANT Program is a cluster-r and omized controlled trial which involved 542 mothers over their newborn ’s first 18 months of life . The intervention focused on parenting skills and strategies , including parental modeling , and aim ed to promote development of healthy child and parent behaviors from birth , including healthy diet , increased physical activity and reduced TV viewing time . Data regarding mothers ’ diet ( food frequency question naire ) , physical activity and TV viewing times ( self-reported question naire ) were collected using vali date d tools at both baseline and post-intervention . Four dietary patterns were derived at baseline using principal components analyses including frequencies of 55 food groups . Analysis of covariance was used to measure the impact of the intervention . Results The scores of both the " High-energy snack and processed foods " and the " High-fat foods " dietary patterns decreased more in the intervention group : -0.22 ( −0.42;-0.02 ) and −0.25 ( −0.50;-0.01 ) , respectively . No other significant intervention vs. control effects were observed regarding total physical activity , TV viewing time , and the two other dietary patterns , i.e. “ Fruits and vegetables ” and “ Cereals and sweet foods ” . Conclusions These findings suggest that supporting first-time mothers to promote healthy lifestyle behaviors in their infants impacts maternal dietary intakes positively . Further research needs to assess ways in which we might further enhance those lifestyle behaviors not impacted by the InFANT intervention [12812815] Diet and physical activity habits may deteriorate after cohabitation , leading to weight gain and increased risk of lifestyle diseases . We carried out a 4-month , r and omized controlled trial of a diet and physical activity program for couples with a 1-year follow-up , comparing two methods of delivery . The program used six modules , which , after an initial group session , were mailed to the low-level intervention group . In the high-level intervention group , half of the modules were mailed , and the others were delivered at interactive group sessions . A control group received no intervention . Postintervention and at follow-up , physical fitness improved in the high-level group , saturated fat intake decreased in both intervention groups , and low-density lipoprotein cholesterol fell in the high-level group . Fewer participants in the high-level group became overweight or obese . Health promotion for couples can improve health behaviors and potentially lower the risk of lifestyle diseases in participants and their future families [20628481] ABSTRACT This study tested the efficacy of brief image-based print-mediated parent/caregiver and adolescent messages integrating physical activity with alcohol use avoidance . A total of 684 high school students were r and omly assigned to either the parent postcard or adolescent flyer arm , with baseline and four-month postintervention data collection s. A significant repeated measures interaction ( group × time ) was found ( F(4,344 ) = 2.48 , p = .04 ) , with univariate tests showing less alcohol use frequency and problems ( ps < .05 ) among adolescents exposed to parent material s. Repeated measures factorial MANOVAs for group × time × prior current drug use were significant , with drug using adolescents receiving parent print messages showing less alcohol initiation and frequency and marijuana initiation and frequency ( ps < .05 ) . Very brief print material s sent to parents/caregivers may hold some promise for influencing substance use among adolescents , particularly those already using drugs [26374480] Background and Purpose — The Stroke Health and Risk Education Project was a cluster-r and omized , faith-based , culturally sensitive , theory-based multicomponent behavioral intervention trial to reduce key stroke risk factor behaviors in Hispanics/Latinos and European Americans . Methods — Ten Catholic churches were r and omized to intervention or control group . The intervention group received a 1-year multicomponent intervention ( with poor adherence ) that included self-help material s , tailored newsletters , and motivational interviewing counseling calls . Multilevel modeling , accounting for clustering within subject pairs and parishes , was used to test treatment differences in the average change since baseline ( ascertained at 6 and 12 months ) in dietary sodium , fruit and vegetable intake , and physical activity , measured using st and ardized question naires . A priori , the trial was considered successful if any one of the 3 outcomes was significant at the 0.05/3 level . Results — Of 801 subjects who consented , 760 completed baseline data assessment s , and of these , 86 % completed at least one outcome assessment . The median age was 53 years ; 84 % subjects were Hispanic/Latino ; and 64 % subjects were women . The intervention group had a greater increase in fruit and vegetable intake than the control group ( 0.25 cups per day [ 95 % confidence interval : 0.08 , 0.42 ] , P=0.002 ) , a greater decrease in sodium intake ( −123.17 mg/d [ −194.76 , −51.59 ] , P=0.04 ) , but no difference in change in moderate- or greater-intensity physical activity ( −27 metabolic equivalent – minutes per week [ −526 , 471 ] , P=0.56 ) . Conclusions — This multicomponent behavioral intervention targeting stroke risk factors in predominantly Hispanics/Latinos was effective in increasing fruit and vegetable intake , reaching its primary end point . The intervention also seemed to lower sodium intake . Church-based health promotions can be successful in primary stroke prevention efforts . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT01378780 [25667250] BACKGROUND AND OBJECTIVE : Motivational interviewing ( MI ) has been shown to be an effective strategy for targeting obesity in adolescents , and parental involvement is associated with increased effectiveness . The aim of this study was to evaluate and compare the role of parental involvement in MI interventions for obese adolescents . METHODS : A total of 357 Iranian adolescents ( aged 14–18 years ) were r and omized to receive an MI intervention or an MI intervention with parental involvement ( MI + PI ) or assessment s only ( passive control ) . Data regarding anthropometric , biochemical , psychosocial , and behavioral measures were collected at baseline and 12 months later . A series of intention-to-treat , 2-way repeated- measures analysis of covariance were performed to examine group differences in change in outcomes measures over the 12-month follow-up period . RESULTS : Results revealed significant effects on most of the outcome parameters for MI + PI ( eg , mean ± SD BMI z score : 2.58 ± 0.61 ) compared with the passive control group ( 2.76 ± 0.70 ; post hoc test , P = .02 ) , as well as an additional superiority of MI + PI compared with MI only ( 2.81 ± 0.76 ; post hoc test , P = .05 ) . This pattern was also shown for most of the anthropometric , biochemical , psychometric , and behavioral outcome variables . CONCLUSIONS : MI with parental involvement is an effective strategy in changing obesity-related outcomes and has additional effects beyond MI with adolescents only . These findings might be important when administering MI interventions in school setting [4822262] Background School health promotion has been shown to improve the lifestyle of students , but it remains unclear whether school-based programs can influence family health . We developed an innovative program that enables school children to act as change agents in promoting healthy lifestyles of their mothers . The objective of this study was to examine the effect of the child-initiated intervention on weight , physical activity and dietary habit of their mothers . Methods A 12-month cluster r and omized trial was conducted , with school as a cluster . Participants were mothers with grade 8 students , aged around 13 years , of 20 schools in Homagama , Sri Lanka . Students of the intervention group were trained by facilitators to acquire the ability to assess noncommunicable disease risk factors in their homes and take action to address them , whereas those of the comparison group received no intervention . Body weight , step count and lifestyle of their mothers were assessed at baseline and post-intervention . Multi-level multivariable linear regression and logistic regression were used to assess the effects of intervention on continuous and binary outcomes , respectively . Results Of 308 study participants , 261 completed the final assessment at 12 month . There was a significantly greater decrease of weight and increase of physical activity in the intervention group . The mean ( 95 % confidence interval ) difference comparing the intervention group with the control group was −2.49 ( −3.38 to −1.60 ) kg for weight and −0.99 ( −1.40 to −0.58 ) kg/m2 for body mass index . The intervention group had a 3.25 ( 95 % confidence interval 1.87–5.62 ) times higher odds of engaging in adequate physical activity than the control group , and the former showed a greater number of steps than the latter after intervention . The intervention group showed a greater reduction of household purchase of biscuits and ice cream . Conclusions A program to motivate students to act as change agents of family ’s lifestyle was effective in decreasing weight and increasing physical activity of their mothers . Trial registration Sri Lanka Clinical Trials Registry SLCTR/2013/011 [4716156] Objective To assess the effectiveness of 2 interventions in improving the physical activity and well-being of secondary school children . Design A clustered r and omised controlled trial ; classes , 1 per school , were assigned to 1 of 3 intervention arms or a control group based on a 2 × 2 factorial design . The interventions were peer-mentoring and participative learning . Year 7 children ( aged 11–12 ) in the peer-mentoring intervention were paired with year 9 children for 6 weekly mentoring meetings . Year 7 children in the participative learning arm took part in 6 weekly geography lessons using personalised physical activity and Global Positioning System ( GPS ) data . Year 7 children in the combined intervention received both interventions , with the year 9 children only participating in the mentoring sessions . Participants 1494 year 7 students from 60 schools in the North of Engl and took part in the trial . Of these , 43 students opted out of taking part in the evaluation measurements , 2 moved teaching group and 58 changed school . Valid accelerometry outcome data were collected for 892 students from 53 schools ; and well-being outcome data were available for 927 students from 52 schools . Main outcome measures The primary outcomes were mean minutes of accelerometer-measured moderate-to-vigorous intensity physical activity per day , and well-being as evaluated by the KIDSCREEN-27 question naire . These data were collected 6 weeks after the intervention ; a 12-month follow-up is planned . Results No significant effects ( main or interaction ) were observed for the outcomes . However , small positive differences were found for both outcomes for the participative learning intervention . Conclusions These findings suggest that the 2 school-based interventions did not modify levels of physical activity or well-being within the period monitored . Change in physical activity may require more comprehensive individual behavioural intervention , and /or more system-based efforts to address wider environmental influences such as family , peers , physical environment , transport and educational policy . Trial registration number IS RCT N82956355 [3713945] Background Despite the physical and mental health benefits , few adults meet US Department of Health and Human Services physical activity guidelines for exercise frequency , intensity , and duration . One strategy that may increase physical activity duration is exercising with an Internet partner ( ie , someone who is virtually present , as in video chat ) . Internet partners help people overcome many barriers associated with face-to-face exercise groups ( eg , time , coordinating schedules , social physique anxiety ) . Past research examining individual performance in groups suggests that an increase in effort occurs when performing a task conjunctively , ie , when a participant is ( 1 ) less capable than fellow group members , and ( 2 ) participants efforts are particularly indispensable for group success ( ie , where the group ’s potential productivity is equal to the productivity of its least capable member ) . This boost in effort is more commonly known as the Köhler effect , named after the German psychologist who first observed the effect . While encouragement between group members is common practice in face-to-face group exercise , the effect of encouragement between partners exercising conjunctively across the Internet is unknown . Objective To examine the impact of exercising alone , compared to exercising conjunctively with an Internet partner , both with and without encouragement , on exercise persistence ( primary outcomes ) and secondary psychosocial outcomes ( self-efficacy , enjoyment , exercise intention ) . Methods Participants were recruited online and face-to-face from the campus of Michigan State University . With the assistance of the experimenter , participants ( n=115 ) played an exercise video game in a laboratory , performing a series of five abdominal plank exercises where they were asked to hold the plank for as long as possible ( Time 1 ) . They were then r and omized to a condition ( Individual , Partner-without-encouragement , or Partner-with-encouragement ) , where they performed the exercises again ( Time 2 ) . The impact of condition on the primary outcome measures and secondary outcome measures were evaluated using a 2 ( Gender ) x 3 ( Condition ) ANOVA on change scores ( Time 2-Time 1 ) . Results Those who exercised in online teams ( n=80 ) exercised significantly longer ( time=78.8s , P<.001 ) than those who worked individually ( n=35 ) . However , exercise duration was shorter when one ’s more capable partner gave verbal encouragement ( n=55 ) than when s/he did not ( n=25 ) ( a mean difference of 31.14s ) . These increases in effort were not accompanied by altered task self-efficacy , enjoyment of the task , or intention to exercise in the future . Conclusions Exercising conjunctively with an Internet partner can boost one ’s duration of exercise . However , encouragement from the stronger to the weaker member can mitigate these gains , especially if one perceives such comments being directed at someone other than themselves . To boost exercise duration , Internet-based physical activity interventions involving group interaction should make relative abilities of participants known and communication clear [4401690] Background There is evidence that physical activity ( PA ) is of cognitive benefit to the ageing brain , but little is known on the effect in patients with Alzheimer ’s disease ( AD ) . The present pilot study assessed the effect of a home-based PA training on clinical symptoms , functional abilities , and caregiver burden after 12 and 24 weeks . Methods In an RCT thirty patients ( aged 72.4±4.3 years ) with AD ( MMSE : 20.6±6.5 points ) and their family caregivers were allocated to a home-based 12-week PA intervention program or the usual care group . The program changed between passive , motor-assisted or active resistive leg training and changes in direction on a movement trainer in order to combine physical and cognitive stimuli . Results Analysis of activities of daily living in the patients ( ADCS ADL total score ) revealed a significant group × time interaction effect ( 95 % CI of the difference between both groups at T2 : 5.01–10.51 ) . The control group experienced decreases in ADL performance at week 12 and 24 whereas patients in the intervention group remained stable . Analyses of executive function and language ability revealed considerable effects for semantic word fluency with a group × time interaction ( 95 % CI of the difference between both groups at T2 : 0.18–4.02 ) . Patients in the intervention group improved during the intervention and returned to initial performance at week 12 whereas the controls revealed continuous worsening . Analyses of reaction time , h and -eye quickness and attention revealed improvement only in the intervention group . Caregiver burden remained stable in the intervention group but worsened in the control group . Conclusions This study suggests that PA in a home-based setting might be an effective and intrinsically attractive way to promote PA training in AD and modulate caregiver burden . The results demonstrate transfer benefits to ADL , cognitive and physical skill in patients with AD . Trial Registration Clinical Trials.gov [3766233] Background People with dementia have a disproportionately high rate of falls and fractures and poorer outcomes , yet there is currently no evidence to guide falls prevention in this population . Methods A r and omised trial design was used to test feasibility of study components and acceptability of a home hazard reduction and balance and strength exercise fall prevention program . The program was tailored to participant ’s individual cognitive levels and implemented as a carer-supported intervention . Feasibility of recruitment , retention and implementation of intervention were recorded through observation and documented in field notes . Adherence , carer burden and use of task simplification strategies were also monitored . Outcome measures , collected at 12 weeks included physiological , fear of falling , cognitive and functional measures . Results Recruitment was achievable but may be more challenging in a multisite trial . Twenty two dyads of persons with mild dementia and their carers were r and omised to intervention or usual care control group . Of 38 dyads referred to the study , there was a high rate of willingness to participate , with 6 ( 16 % ) declining and 10 ( 26 % ) not meeting inclusion criteria . The intervention was well received by participants and carers and adherence to both program components was very good . All participants implemented some home safety recommendations ( range 19 - 80 % ) with half implementing 50 % or more . At the end of 12 weeks , 72 % of the intervention group were exercising . Both the rate of falling and the risk of a fall were lower in the intervention group but these findings were not significant ( RR= 0.50 ( 95 % CI 0.11 - 2.19 ) . There were no differences in physiological outcome measures between the control and intervention groups . However results were influenced by the small study size and incomplete data primarily in the intervention group at follow up . Conclusions The pilot study was feasible and acceptable to people with mild dementia and their carers . The lessons learnt included : recruitment for a larger trial will require multiple approaches ; home safety recommendations should provide a greater emphasis on environmental use compared with behavioural change ; strategies to ensure an adequate dosage of exercise should be further explored . We recommend that intervention delivery incorporate an integrated occupational therapy and physiotherapy approach and that carers be provided with an individualised session to enhance dementia-specific skills in management and communication . A refined intervention should be tested in a r and omised trial with an adequately powered sample size . Trial registration Australia and New Zeal and Clinical Trials Registry [3598924] Background Many children spend too much time screen-viewing ( watching TV , surfing the internet and playing video games ) and do not meet physical activity ( PA ) guidelines . Parents are important influences on children ’s PA and screen-viewing ( SV ) . There is a shortage of parent-focused interventions to change children ’s PA and SV . Methods Teamplay was a two arm individualized r and omized controlled feasibility trial . Participants were parents of 6–8 year old children . Intervention participants were invited to attend an eight week parenting program with each session lasting 2 hours . Children and parents wore an accelerometer for seven days and minutes of moderate-to-vigorous intensity PA ( MVPA ) were derived . Parents were also asked to report the average number of hours per day that both they and the target child spent watching TV . Measures were assessed at baseline ( time 0 ) at the end of the intervention ( week 8) and 2 months after the intervention had ended ( week 16 ) . Results There were 75 participants who provided consent and were r and omized but 27 participants withdrew post-r and omization . Children in the intervention group engaged in 2.6 fewer minutes of weekday MVPA at Time 1 but engaged in 11 more minutes of weekend MVPA . At Time 1 the intervention parents engaged in 9 more minutes of weekday MVPA and 13 more minutes of weekend MVPA . The proportion of children in the intervention group watching ≥ 2 hours per day of TV on weekend days decreased after the intervention ( time 0 = 76 % , time 1 = 39 % , time 2 = 50 % ) , while the control group proportion increased slightly ( 79 % , 86 % and 87 % ) . Parental weekday TV watching decreased in both groups . In post- study interviews many mothers reported problems associated with wearing the accelerometers . In terms of a future full-scale trial , a sample of between 80 and 340 families would be needed to detect a mean difference of 10-minutes of weekend MVPA . Conclusions Teamplay is a promising parenting program in an under- research ed area . The intervention was acceptable to parents , and all elements of the study protocol were successfully completed . Simple changes to the trial protocol could result in more complete data collection and study engagement [10387506] In a pilot health promotion program for couples , we aim ed to build on re-evaluation of attitudes to health occurring early in marriage , and social support provided by partners , to address the weight gain and physical inactivity which may follow marriage . A r and omized controlled trial lasting 16 weeks used six modules focusing on nutrition and physical activity but including information about alcohol and smoking . Thirty-four of 39 couples enrolled completed the study . Self-efficacy for diet and physical activity increased significantly in the program group while ranking of barriers to healthy behaviours decreased and ranking of beliefs about the benefits of health behaviours increased relative to controls . Intake of fat , take-away foods and alcohol decreased , and consumption of fruit , vegetables and reduced-fat foods increased significantly in the program group . Physical activity in the program group increased by the equivalent of 50 min of brisk walking weekly but did not differ significantly from controls . Cholesterol fell significantly by 6 % more in the program group than controls . In focus groups , participants unanimously found the program valuable . Health promotion programs design ed for couples can achieve short-term changes in behaviour and risk factors . Larger trials with longer-term monitoring , incorporating feedback from focus groups and cost-benefit analysis , are in progress [23460688] OBJECTIVE : To assess the effectiveness of a parent-focused intervention on infants ’ obesity-risk behaviors and BMI . METHODS : This cluster r and omized controlled trial recruited 542 parents and their infants ( mean age 3.8 months at baseline ) from 62 first-time parent groups . Parents were offered six 2-hour dietitian-delivered sessions over 15 months focusing on parental knowledge , skills , and social support around infant feeding , diet , physical activity , and television viewing . Control group parents received 6 newsletters on nonobesity-focused themes ; all parents received usual care from child health nurses . The primary outcomes of interest were child diet ( 3 × 24-hour diet recalls ) , child physical activity ( accelerometry ) , and child TV viewing ( parent report ) . Secondary outcomes included BMI z-scores ( measured ) . Data were collected when children were 4 , 9 , and 20 months of age . RESULTS : Unadjusted analyses showed that , compared with controls , intervention group children consumed fewer grams of noncore drinks ( mean difference = –4.45 ; 95 % confidence interval [ CI ] : –7.92 to –0.99 ; P = .01 ) and were less likely to consume any noncore drinks ( odds ratio = 0.48 ; 95 % CI : 0.24 to 0.95 ; P = .034 ) midintervention ( mean age 9 months ) . At intervention conclusion ( mean age 19.8 months ) , intervention group children consumed fewer grams of sweet snacks ( mean difference = –3.69 ; 95 % CI : –6.41 to –0.96 ; P = .008 ) and viewed fewer daily minutes of television ( mean difference = –15.97 : 95 % CI : –25.97 to –5.96 ; P = .002 ) . There was little statistical evidence of differences in fruit , vegetable , savory snack , or water consumption or in BMI z-scores or physical activity . CONCLUSIONS : This intervention result ed in reductions in sweet snack consumption and television viewing in 20-month-old children [21473660] OBJECTIVE To evaluate the effectiveness of a psychological , family-based intervention to improve diabetes-related outcomes in patients with poorly controlled type 2 diabetes . METHODS This study was a r and omized controlled trial of a psychological family-based intervention targeted at individuals with poorly controlled type 2 diabetes . Recruitment and follow-up occurred at specialist diabetes clinics . Patients were r and omly allocated to an intervention group ( n=60 ) or a control group ( n=61 ) . Poor control was defined as at least 2 of the patient 's last 3 glycated hemoglobin ( A1C ) readings at > 8.0 % . The intervention consisted of 2 sessions delivered by a health psychologist to the patient and a family member in the patient 's home , with a third session involving a 15-minute follow-up telephone call . RESULTS At 6-month follow-up , the intervention group reported significantly lower mean A1C levels than the control group ( 8.4 % [ SD=0.99 % ] vs 8.8 % [ SD=1.36 % ] ; P=.04 ) . The intervention was most effective in those with the poorest control at baseline ( A1C>9.5 % ) ( intervention 8.7 % [ SD=1.16 % , n=15 ] vs control 9.9 % [ SD=1.31 % , n=15 ] ; P=.01 ) . The intervention group also reported statistically significant improvements in beliefs about diabetes , psychological well-being , diet , exercise , and family support . CONCLUSIONS After participating in a family-based intervention targeting negative and /or inaccurate illness perceptions , patients with poorly controlled type 2 diabetes showed improvements in A1C levels and other outcomes . Our results suggest that adding a psychological , family-based component to usual diabetes care may help improve diabetes management [20966907] Parent-only ( PO ) treatments for childhood obesity are feasible , more cost-effective and potentially easier to disseminate . The objective of this study was to determine whether a PO treatment is not inferior to a parent + child ( PC ) treatment for childhood obesity . Eighty parent-child dyads with an 8 - 12 year old overweight or obese child ( > 85th BMI -P ) were recruited and r and omized into PO or PC treatment for childhood obesity . Parents or parent-child dyads attended 5-month treatment groups . Child and parent body size , child caloric intake , and child physical activity were assessed at baseline , post-treatment , and 6-months follow-up . Noninferiority testing using mixed linear models was used to compare PO treatment with PC treatment . Results showed that the PO group was not inferior to the PC group in terms of child weight loss . Results also showed that the PO group was not inferior to the PC group in terms of parent weight loss and child physical activity , but not child caloric intake . This study suggests that a PO treatment could provide similar results to PC in child weight loss and other relevant outcomes , and potentially could be more cost-effective and easier to disseminate . Although further research is needed , this study suggests that PO groups are a viable method for providing childhood obesity treatment [5578653] Regular physical activity ( PA ) and the avoidance of prolonged sitting are essential for children ’s healthy growth , and for the physical and mental wellbeing of both children and adults . In the context of exercise , music may promote behavioral change through increased exercise adherence and participation . The purpose of this study was to determine whether a movement-to-music video program could reduce sedentary behavior ( SB ) and increase PA in mother-child pairs in the home environment . A r and omized controlled trial was conducted in the Pirkanmaa region , Finl and , in 2014–2016 . The participants consisted of 228 mother-child pairs ( child age 5–7 years ) . The primary outcomes of interest were tri-axial accelerometer-derived SB and PA , which were measured in weeks one ( baseline ) , two , and eight in both the intervention and control groups . Further , the mothers and children in the intervention group used a movement-to-music video program from the beginning of week two to the end of week eight . Secondary outcomes included self-reported screen time . The statistical methods employed comprised an intention-to-treat and linear mixed effects model design . No statistically significant differences between groups were found in primary or secondary outcomes . Among the children in the control group , light PA decreased significantly over time and screen time increased from 89 ( st and ard deviation , SD 37 ) to 99 ( SD 41 ) min/d . Among mothers and children in the intervention group , no statistical differences were found . In supplementary analysis , the children who stayed at home instead of attending daycare/preschool had on average 25 ( 95 % confidence interval , CI 19–30 ) min/d more sedentary time and 11 ( 95 % CI 8–14 ) min/d less moderate-to-vigorous PA than those who were at daycare/preschool . The higher body mass index of mothers was related with 5 ( 95 % CI 2–7 ) min/d more sedentary time and 1 ( 95 % CI 0–2 ) min/d less moderate-to-vigorous PA . The movement-to-music video program did not change the objective ly measured SB or PA of the mother-child pairs . However , mothers and children seemed to be more sedentary at home , and therefore interventions for decreasing SB and increasing PA should be targeted in the home environment [12740449] OBJECTIVE To determine whether maternal participation in an obesity prevention plus parenting support ( OPPS ) intervention would reduce the prevalence of obesity in high-risk Native-American children when compared with a parenting support (PS)-only intervention . RESEARCH METHODS AND PROCEDURES Forty-three mother/child pairs were recruited to participate . Mothers were 26.5 + /- 5 years old with a mean BMI of 29.9 + /- 3 kg/m(2 ) . Children ( 23 males ) were 22 + /- 8 months old with mean weight-for-height z ( WHZ ) scores of 0.73 + /- 1.4 . Mothers were r and omly assigned to a 16-week OPPS intervention or PS alone . The intervention was delivered one-on-one in homes by an indigenous peer educator . Baseline and week 16 assessment s included weight and height ( WHZ score and weight-for-height percentile for children ) , dietary intake ( 3-day food records ) , physical activity ( measured by accelerometers ) , parental feeding style ( Child Feeding Question naire ) , and maternal outcome expectations , self-efficacy , and intention to change diet and exercise behaviors . RESULTS Changes in WHZ scores showed a trend toward significance , with WHZ scores decreasing in the PS condition and increasing among the OPPS group ( -0.27 + /- 1.1 vs. 0.31 + /- 1.1 , p = 0.06 ) . Children in the OPPS condition also significantly decreased energy intake ( -316 + /- 835 kcal/d vs. 197 + /- 608 kcal/d , p < 0.05 ) . Scores on the restriction subscale of the Child Feeding Question naire decreased significantly in the OPPS condition ( -0.22+/- 0.42 vs. 0.08+/- 0.63 , p < 0.05 ) , indicating that mothers in the OPPS group were engaging in less restrictive child feeding practice s over time . DISCUSSION A home-visiting program focused on changing lifestyle behaviors and improving parenting skills showed promise for obesity prevention in high-risk Native-American children [22066521] BACKGROUND The primary care setting offers the opportunity to reach children and parents to encourage healthy lifestyle behaviours , and improve weight status among children . OBJECTIVE Test the feasibility of Helping H AND ( Healthy Activity and Nutrition Directions ) , an obesity intervention for 5- to 8-year-old children in primary care clinics . METHODS A r and omized controlled pilot study of Helping H AND , a 6-month intervention , targeted children with body mass index 85 - 99%tile and their parents . Intervention group attended monthly sessions and self-selected child behaviours and parenting practice s to change . Control group received regular paediatric care and was wait-listed for Helping H AND . Session completion , participant satisfaction , child anthropometrics , dietary intake , physical activity , TV viewing and behaviour-specific parenting practice s were measured pre and post intervention . RESULTS Forty parent-child dyads enrolled : 82.5 % were Hispanic , 80 % had a girl and 65 % reported income ≤ $ 30 , 000/year . There was 20 % attrition from Helping H AND ( attended < 4/6 sessions ) . Families self-selected 4.35 ( SD 1.75 ) behaviours to target during the 6-month programme and each of the seven behaviours was selected by 45 - 80 % of the families . There were no between group differences in the child 's body mass index z-score , dietary intake or physical activity post intervention . Intervention group viewed 14.9 ( SE 2.3 ) h/week of TV post intervention versus control group 23.3 ( SE 2.4 ) h/week ( P < 0.05 ) . CONCLUSION Helping H AND is feasible , due to low attrition , good programme attendance , and clinical ly relevant improvements in some child and parenting behaviours [24338799] OBJECTIVE The objective of this study is to evaluate the effectiveness of a simple dyadic ( person with dementia and their main carer ) exercise regimen as a therapy for the behavioural and psychological symptoms of dementia . METHOD A two arm , pragmatic , r and omised , controlled , single-blind , parallel-group trial of a dyadic exercise regimen ( individually tailored walking regimen design ed to become progressively intensive and last between 20 - 30 min , at least five times per week).Community-dwelling individuals with ICD-10 confirmed dementia with the following : clinical ly significant behavioural and psychological symptoms , a carer willing and able to co-participate in the exercise regimen , and no physical conditions or symptoms that would preclude exercise participation were invited by mental health or primary care services into the study . RESULTS One hundred and thirty-one dyads were recruited to this study . There was no significant difference in Behavioural and Psychological Symptoms as measured by the Neuropsychiatric Inventory at week 12 between the group receiving the dyadic exercise regimen and those that did not ( adjusted difference in means ( intervention minus control ) = -1.53 , p = 0.6 , 95 % CI [ -7.37 , 4.32 ] ) . There was a significant between-group difference in caregiver 's burden as measured by the Zarit Caregiver Burden Inventory at week 12 ( OR = 0.18 , p = 0.01 , CI [ 0.05 , 0.69 ] ) favouring the exercise group . CONCLUSIONS This study found that regular simple exercise does not appear to improve the behavioural and psychological symptoms of dementia , but did seem to attenuate caregiver burden . Further study to improve exercise uptake are needed [25110844] OBJECTIVE Although studies have shown that physical activity ( PA ) can reduce some treatment-related side effects of breast cancer , there is a need to offer PA programs outside of research setting s to reach more cancer survivors . We partnered with the American Cancer Society 's Reach to Recovery ( RTR ) program to train their volunteers ( breast cancer survivors ) to deliver a 12-week PA intervention to other breast cancer survivors . METHOD We conducted a r and omized controlled trial to compare the PA intervention delivered by RTR volunteers ( PA plus RTR ) with contact control ( RTR control ) . Eighteen RTR volunteers/coaches ( Mage = 54.9 years ; Mtime since diagnosis = 7.0 years ) delivered the contact control condition or the PA intervention . Seventy-six breast cancer survivors in New Engl and ( Mage = 55.6 years ; Mtime since diagnosis = 1.1 years ) were r and omized to 1 of the 2 groups . At baseline , 12 weeks ( postintervention ) , and at 24 weeks , participants wore an accelerometer for 7 days , were interviewed about their PA , and reported their motivational readiness for PA . RESULTS Adjusted , mixed-effects longitudinal regression models showed significant group differences favoring the PA plus RTR group in minutes of moderate to vigorous PA at 12 weeks ( Mdifference = 103 min/week , p < .001 ) and at 24 weeks ( Mdifference = 34.7 min/week , p = .03 ) . Results were corroborated with significant group differences in accelerometer data favoring the PA plus RTR group at both time points . CONCLUSION Peer volunteers were able to significantly increase PA among cancer survivors relative to contact control . Partnerships with existing volunteer programs can help to widen the reach of behavioral interventions among cancer survivors . ( PsycINFO Data base [22920808] Background : Physical inactivity is associated with obesity and type 2 diabetes . A key obstacle to physical activity is lack of motivation . Although some interactive exercise games ( i.e. , exergames — video games that require physical exertion in order to play ) motivate players to exercise more , few games take advantage of group dynamics to motivate players ' duration of exercise . In a test of the Kohler motivation gain effect , this study varied the ability level of a virtually presented partner in an interactive exergame that focused on abdominal strength to identify effects on a subject 's ( S ' ) persistence with the task . Method : Male ( n = 63 ) and female ( n = 72 ) undergraduate students were r and omly assigned to one of four conditions ( individual control or low- , moderate- , or high- partner discrepancy ) in a conditions x gender factorial design and tested on a series of isometric abdominal exercises using PlayStation 2 EyeToy : Kinetic software . They performed the first series of five exercises alone ( trial block 1 ) , and after a rest period , those in the partner conditions performed remaining trials ( trial block 2 ) with a same-sex virtually presented partner whom they could observe during their performance , while those in the individual control condition performed the remaining trials alone . In the partner conditions , the partner 's performance was manipulated to be always better than the S 's , the exact difference depending on the discrepancy condition . The partnered tasks were conjunctive ; that is , success in the game depended on the performance of the weaker team member . Persistence , the outcome measure for this study , consisted of the total number of seconds the S held the exercise position . Results : Using planned orthogonal contrasts on difference scores between blocks 1 and 2 , results showed that persistence was significantly ( p < .001 ) greater in all experimental conditions with a virtually presented partner ( M = 33.59 s ) than in the individual control condition ( M = −49.04 s ) . Subjects demonstrated more persistence in the moderate-discrepancy condition ( M = 51.36 s ) than in the low-discrepancy condition ( M = 22.52 s ) or the high-discrepancy condition ( M = 26.89 s ) . A significant quadratic trend confirmed the expected inverted-U function relating partner discrepancy and persistence ( p = .025 ) . Although Ss persisted longer and had higher heart rate in partnered conditions , they did not perceive their exertion to be any higher than those in the individual condition . Conclusions : Virtually presented partners who are moderately more capable than participants are the most effective at improving persistence in exergame tasks [21553972] OBJECTIVE Older adults have low rates of physical activity participation , but respond positively to telephone-mediated support programs . Programs are often limited by reliance on professional staff . This study tested telephone-based physical activity advice delivered by professional staff versus trained volunteer peer mentors . DESIGN A 12-month , r and omized , controlled clinical trial was executed from 2003 - 2008 . Twelve volunteer peer mentors and 181 initially inactive adults ages 50 years and older were recruited from the San Francisco Bay Area . Participants were r and omized to : ( 1 ) telephone-based physical activity advice delivered by professional staff , ( 2 ) telephone-based physical activity advice delivered by trained volunteer peers , or ( 3 ) an attention-control arm of staff-delivered telephone support for nutrition . MAIN OUTCOME MEASURES Moderate-intensity or more vigorous physical activity ( MVPA ) was assessed at baseline , 6 , and 12 months with the Community Healthy Activities Model Program for Seniors ( CHAMPS ) Question naire , with accelerometry validation ( Actigraph ) in a r and omly selected sub sample . Treatment fidelity was examined through analysis of quantity and quality of intervention delivery . RESULTS At 6 and 12 months , both physical activity arms significantly increased MVPA relative to the control arm . Both physical activity arms were comparable in quantity of intervention delivery , but peers demonstrated more versatility and comprehensiveness in quality of intervention content . CONCLUSIONS This study demonstrates that trained peer volunteers can effectively promote physical activity increases through telephone-based advice . The results support a program delivery model with good dissemination potential for a variety of community setting [15288394] & NA ; This study tested the separate and combined effects of spouse‐assisted pain coping skills training ( SA‐CST ) and exercise training ( ET ) in a sample of patients having persistent osteoarthritic knee pain . Seventy‐two married osteoarthritis ( OA ) patients with persistent knee pain and their spouses were r and omly assigned to : SA‐CST alone , SA‐CST plus ET , ET alone , or st and ard care ( SC ) . Patients in SA‐CST alone , together with their spouses , attended 12 weekly , 2‐h group sessions for training in pain coping and couples skills . Patients in SA‐CST+ET received spouse‐assisted coping skills training and attended 12‐weeks supervised ET . Patients in the ET alone condition received just an exercise program . Data analyses revealed : ( 1 ) physical fitness and strength : the SA‐CST+ET and ET alone groups had significant improvements in physical fitness compared to SA‐CST alone and patients in SA‐CST+ET and ET alone had significant improvements in leg flexion and extension compared to SA‐CST alone and SC , ( 2 ) pain coping : patients in SA‐CST+ET and SA‐CST alone groups had significant improvements in coping attempts compared to ET alone or SC and spouses in SA‐CST+ET rated their partners as showing significant improvements in coping attempts compared to ET alone or SC , and ( 3 ) self‐efficacy : patients in SA‐CST+ET reported significant improvements in self‐efficacy and their spouses rated them as showing significant improvements in self‐efficacy compared to ET alone or SC . Patients receiving SA‐CST+ET who showed increased self‐efficacy were more likely to have improvements in psychological disability . An intervention that combines spouse‐assisted coping skills training and exercise training can improve physical fitness , strength , pain coping , and self‐efficacy in patients suffering from pain due to osteoarthritis [22468716] OBJECTIVE The research tested the efficacy of planning and partner-based interventions to promote physical activity over six months . METHOD Local government ( council ) employees ( N = 257 ) were r and omly allocated to one of four conditions ( collaborative implementation intentions ; partner-only ; implementation intentions ; control group ) before completing measures at baseline and follow-ups at 1 , 3 and 6 months . Outcome measures comprised vali date d self-report measures of physical activity : the international physical activity question naire ( IPAQ ; Craig et al. , 2003 ) and self-report walking and exercise tables ( SWET ; Prestwich et al. , 2012 ) ; psychosocial mediators ( enjoyment , intention , self-efficacy , social influence ) ; weight and waist size ( baseline and 6 months only ) . RESULTS As well as losing the most weight , there was evidence that participants in the collaborative implementation-intention group were more physically active than each of the other three groups at 1- , 3- and 6-month follow-ups . Those in the implementation-intention and partner-only conditions did not outperform the control group on most measures . CONCLUSION Collaborative implementation intentions represent a potentially useful intervention to change important health behaviors that help reduce weight [24584818] This study evaluated spouse health behavior outcomes from a r and omized controlled trial of a spouse-assisted lifestyle intervention to reduce patient low-density lipoprotein cholesterol and improve patient health behaviors . Participants were 251 spouses of patients from the Durham Veterans Affairs Medical Center r and omized to intervention or usual care . The intervention comprised 9 monthly telephone calls to patients and spouses . Outcomes were assessed at baseline , 6 and 11 months . At 11 months , there were no differences in spouse outcomes between intervention and usual care groups for moderate intensity physical activity ( i.e. , frequency , duration ) or dietary intake ( i.e. , total calories , total fat , percentage of calories from total fat , saturated fat , percentage of calories from saturated fat , cholesterol , fiber ) . To improve spouse outcomes , couple interventions may need to include spouse behavior change goals and reciprocal support between patients and spouses and consider the need for improvement in spouse outcomes [16277142] Objective : This r and omized controlled trial tested the efficacy of an internetbased lifestyle behavior modification program for weight management in African-American girls . Design : African-American girls were r and omly assigned to an interactive behavioral internet program or an internet health education program , the control condition . The behavioral intervention included internet counseling and was highly interactive . The control intervention was a passive ( non-interactive ) educational program . Parents were also participants in the study . Participants in both treatment groups met in face-to-face sessions on four occasions over the first 12 weeks of a 6-month intervention . Subjects : The study enrolled 57 African-American adolescent girls ( ages 11 to 15 years ) who were overweight or obese and had at least one biological parent who was obese [ body mass index ( BMI ) > 30 kg/m2 ] . Of the 57 participants , 50 ( 88 % ) completed the 6-month trial . Measurements : Outcome data , including BMI , body weight , body composition , dietary intake , and weight loss behaviors were collected at baseline and 6-months later . A computer server tracked utilization of the websites . Participation in the program was measured by number of “ hits ” on the website . Results : Compared to the control condition , adolescents in the behavioral treatment lost more body fat ( group difference = 1.6 % body fat ) and parents lost significantly more body weight ( group difference = 2.1 kg ) . Utilization of the behavioral website by adolescents and parents was associated with positive outcome . Dietary fat intake was lowered for adolescents and parents in the behavioral treatment group . Conclusion : An internet-based behavioral intervention was superior to internet-based health education and yielded decreased body fat for adolescent girls and decreased body weight for parents [28070770] Purpose The purpose of this study was to assess the feasibility , acceptability , and impact of a ballroom dance intervention on improving quality of life ( QOL ) and relationship outcomes in cancer survivors and their partners . Methods We conducted a pilot r and omized controlled trial with two arms ( Restoring Health in You ( and Your Partner ) through Movement , RHYTHM ) : ( 1 ) immediate dance intervention and ( 2 ) delayed intervention ( wait-list control ) . The intervention consisted of 10 private weekly dance lessons and 2 practice parties over 12 weeks . Main outcomes were physical activity ( Godin Leisure-Time Exercise Question naire ) , functional capacity ( 6 Minute Walk Test ) , QOL ( SF-36 ) , Couples ’ trust ( Dyadic Trust Scale ) , and other dyadic outcomes . Exit interviews were completed by all participating couples . Results Thirty-one women survivors ( 68 % breast cancer ) and their partners participated . Survivors were 57.9 years old on average and 22.6 % African American . Partners had similar characteristics . RHYTHM had significant positive effects on physical activity ( p = 0.05 ) , on the mental component of QOL ( p = 0.04 ) , on vitality ( p = 0.03 ) , and on the dyadic trust scale ( p = 0.04 ) . Couples expressed satisfaction with the intervention including appreciating the opportunity to spend time and exercise together . Survivors saw this light-intensity physical activity as easing them into becoming more physically active . Conclusions Light intensity ballroom dancing has the potential to improve cancer survivors ’ QOL . Larger trials are needed to build strong support for this ubiquitous and acceptable activity . Implication s for cancer survivorsBallroom dance may be an important tool for cancer survivors to return to a physically active life and improve QOL and other aspects of their intimate life [19928484] Purpose . To test effects of parent/child training design ed to increase calcium intake , bone-loading physical activity ( PA ) , and bone density . Design . Two-group r and omized controlled trial . Setting . Family-based intervention delivered at research center . Subjects . 117 healthy children aged 10–13 years ( 58.1 % female , 42.7 % Hispanic , 40.2 % White ) . Ninety-seven percent of participants had at least one parent graduate from high school and 37.2 % had at least one parent graduate from a 4-year university . Intervention . Children and parents were r and omly assigned to diet and exercise ( experimental ) or injury prevention ( control ) interventions . Children were taught in eight weekly classes how to engage in bone-loading PA and eat calcium-rich foods or avoid injuries . Parents were taught behavior management techniques to modify children 's behaviors . Measures . Measures at baseline and at 3 , 9 , and 12 months included 24-hour diet and PA recalls , and bone mineral density ( BMD ) by dual-energy x-ray absorptiometry . Analysis . Analysis of variance and generalized estimating equations ( GEE ) assessed group by time differences . Comparisons were conducted separately for boys and girls . Results . For boys , cross-sectional differences between experimental and control groups were achieved for 3- and 9-month calcium intake ( 1352 vs. 1052 mg/day , 1298 vs. 970 mg/day , p < .05 ) . For girls , marginal cross-sectional differences were achieved for high-impact PA at 12 months ( p < .10 ) . For calcium intake , a significant group by time interaction was observed from pretest to posttest for the full sample ( p = .008 ) and for girls ( p = .006 ) but not for boys . No significant group by time differences in calcium were observed across the follow-up period . No group by time differences were observed for high-impact PA . Among boys , longitudinal group by time differences reached significance for total hip BMD ( p = .045 ) and femoral neck BMD ( p = .033 ) , even after adjusting for skeletal growth . Similar differential increases were observed among boys for bone mineral content ( BMC ) at the hip ( p = .068 ) and total body ( p = .054 ) regions . No significant group by time interaction effects were observed for girls at any bone site for BMD . For BMC , control girls showed a significant increase ( p = .03 ) in spine BMC compared to intervention girls . Conclusion . This study demonstrated that parent/preteen training can increase calcium intake and attenuate the decline in high-impact PA . Results suggest that more powerful interventions are needed to increase activity levels and maximize bone mineral accrual during preadolescent years [15264973] Obese children were r and omly assigned to a family-based behavioral treatment that included either stimulus control or reinforcement to reduce sedentary behaviors . Significant and equivalent decreases in sedentary behavior and high energy density foods , increases in physical activity and fruits and vegetables , and decreases in st and ardized body mass index ( z- BMI ) were observed . Children who substituted active for sedentary behaviors had significantly greater z- BMI changes at 6 ( -1.21 vs. -0.76 ) and 12 ( -1.05 vs. -0.51 ) months , respectively . Substitution of physically active for sedentary behaviors and changes in activity level predicted 6- and 12-month z- BMI changes . Results suggest stimulus control and reinforcing reduced sedentary behaviors are equivalent ways to decrease sedentary behaviors , and behavioral economic relationships in eating and activity may mediate the effects of treatment [23498969] Shaping network members into sources of support for healthy eating and exercise behaviors may be an effective strategy to enhance obesity treatment outcomes . This pilot study examined the feasibility and preliminary efficacy of a behavioral weight loss intervention adapted for Latinas with a social network component . Twenty-seven Latinas ( 43.0±10.2 years and body mass index 36.9±5.7 ) participated in a 24-week r and omized controlled intervention study . Participants attended group-based treatment either individually ( Individual Lifestyle Group [ ILG ] ) or with a weight loss partner selected from their existing network ( Partner Lifestyle Group [ PLG ] ) . Repeated measures analysis of variance was conducted to compare ILG and PLG participants on changes in weight or psychosocial variables . Participants in both intervention groups attended 70 % of treatment sessions ; 96 % and 100 % completed assessment at post-treatment ( 12 weeks ) and follow-up ( 24 weeks ) , respectively . Significant weight loss ( P<0.01 ) was achieved at post-treatment ( ILG -4.7±4.2 kg and PLG -4.3±4.4 kg ) and follow-up ( ILG -5.0±6.4 kg and PLG -4.7±5.0 kg ) , with nearly 50 % of participants losing at least 5 % of initial body weight . Both groups also experienced increased self-efficacy for weight loss ( P<0.01 ) , self-efficacy for exercise ( P=0.02 ) , and family social support for exercise habits ( P=0.01 ) . There were no significant differences between groups . Results from this study suggest a behavioral weight loss intervention for Latinas is feasible , but there is less support for the efficacy of weight loss partners [14559955] CONTEXT Exercise training for patients with Alzheimer disease combined with teaching caregivers how to manage behavioral problems may help decrease the frailty and behavioral impairment that are often prevalent in patients with Alzheimer disease . OBJECTIVE To determine whether a home-based exercise program combined with caregiver training in behavioral management techniques would reduce functional dependence and delay institutionalization among patients with Alzheimer disease . DESIGN , SETTING , AND PATIENTS R and omized controlled trial of 153 community-dwelling patients meeting National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer Disease and Related Disorders Association criteria for Alzheimer disease , conducted between June 1994 and April 1999 . INTERVENTIONS Patient-caregiver dyads were r and omly assigned to the combined exercise and caregiver training program , Reducing Disability in Alzheimer Disease ( RDAD ) , or to routine medical care ( RMC ) . The RDAD program was conducted in the patients ' home over 3 months . MAIN OUTCOME MEASURES Physical health and function ( 36-item Short-Form Health Survey 's [ SF-36 ] physical functioning and physical role functioning subscales and Sickness Impact Profile 's Mobility subscale ) , and affective status ( Hamilton Depression Rating Scale and Cornell Depression Scale for Depression in Dementia ) . RESULTS At 3 months , in comparison with the routine care patients , more patients in the RDAD group exercised at least 60 min/wk ( odds ratio [ OR ] , 2.82 ; 95 % confidence interval [ CI ] , 1.25 - 6.39 ; P = .01 ) and had fewer days of restricted activity ( OR , 3.10 ; 95 % CI , 1.08 - 8.95 ; P<.001 ) . Patients in the RDAD group also had improved scores for physical role functioning compared with worse scores for patients in the RMC group ( mean difference , 19.29 ; 95 % CI , 8.75 - 29.83 ; P<.001 ) . Patients in the RDAD group had improved Cornell Depression Scale for Depression in Dementia scores while the patients in the RMC group had worse scores ( mean difference , -1.03 ; 95 % CI , -0.17 to -1.91 ; P = .02 ) . At 2 years , the RDAD patients continued to have better physical role functioning scores than the RMC patients ( mean difference , 10.89 ; 95 % CI , 3.62 - 18.16 ; P = .003 ) and showed a trend ( 19 % vs 50 % ) for less institutionalization due to behavioral disturbance . For patients with higher depression scores at baseline , those in the RDAD group improved significantly more at 3 months on the Hamilton Depression Rating Scale ( mean difference , 2.21 ; 95 % CI , 0.22 - 4.20 ; P = .04 ) and maintained that improvement at 24 months ( mean difference , 2.14 ; 95 % CI , 0.14 - 4.17 ; P = .04 ) . CONCLUSION Exercise training combined with teaching caregivers behavioral management techniques improved physical health and depression in patients with Alzheimer disease [21838569] OBJECTIVE To describe the impact of a parent-led , family-focused child weight management program on the food intake and activity patterns of pre-pubertal children . METHODS An assessor-blinded , r and omized controlled trial involving 111 ( 64 % female ) overweight , pre-pubertal children 6 - 9 years of age r and omly assigned to parenting-skills training plus intensive diet and activity education ( P + DA ) , parenting-skills training alone ( P ) , or a 12-month wait-listed control ( WLC ) . Study outcomes were assessed at baseline , 6 months , and 12 months . This paper presents data on food intake assessed via a vali date d 54-item parent-completed dietary question naire and activity behaviours assessed via a parent-report 20-item activity question naire . RESULTS Intake of energy-dense nutrient-poor foods was lower in both intervention groups at 6 months ( mean difference , P + DA - 1.5 serves [ CI - 2.0 ; -1.0 ] ; P - 1.0 serves [ -2.0 ; -0.5 ] ) and 12 months ( mean difference P + DA - 1.0 serves [ CI - 2.0 ; -0.5 ] ; P - 1.0 serves [ - 1.5 ; 0.0 ] ) compared to baseline . Intake of vegetables , fruit , breads and cereals , meat and alternatives and dairy foods remained unchanged . Regardless of study group there were significant reductions over time in the reported time spent engaged in small screen activities and an increase in the time reported spent in active play . CONCLUSION A child weight management intervention that promotes food intake in line with national dietary guidelines achieves a reduction in children 's intake of energy-dense , nutrient-poor foods . This was achieved without compromising intake of nutrient-rich food and changes were maintained even once the intervention ceased [25161168] Background . The family and home environment is an influential antecedent of childhood obesity . The purpose of this study was to pilot test The Enabling Mothers to Prevent Pediatric Obesity through Web-Based Education and Reciprocal Determinism ( EMPOWER ) intervention ; a newly developed , theory-based , online program for prevention of childhood obesity . Method . The two-arm , parallel group , r and omized , participant-blinded trial targeted mothers with children between 4 and 6 years of age . Measures were collected at baseline , 4 weeks , and 8 weeks to evaluate programmatic effects on constructs of social cognitive theory ( SCT ) and obesity-related behaviors . Process evaluation transpired concurrently with each intervention session . Results . Fifty-seven participants were r and omly assigned to receive either experimental EMPOWER ( n = 29 ) or active control Healthy Lifestyles ( n = 28 ) intervention . Significant main effects were identified for child physical activity , sugar-free beverage consumption , and screen time , indicating that both groups improved in these behaviors . A significant group-by-time interaction was detected for child fruit and vegetable ( FV ) consumption as well as the SCT construct of environment in the EMPOWER cohort . An increase of 1.613 cups of FVs ( 95 % confidence interval = [ 0.698 , 2.529 ] ) was found in the experimental group , relative to the active control group . Change score analysis found changes in the home environment accounted for 31.4 % of the change in child FV intake for the experimental group . Conclusions . Child physical activity , sugar-free beverage consumption , and screen time improved in both groups over the course of the trial . Only the theory-based intervention was efficacious in increasing child FV consumption . The EMPOWER program was robust for inducing change in the home environment leading to an increase in child FV intake ( Cohen ’s f = 0.160 ) [23146744] OBJECTIVE This r and omized controlled trial evaluated the effectiveness of a telephone-delivered , spouse-assisted lifestyle intervention to reduce patient LDL-C. METHOD From 2007 to 2010 , 255 out patients with LDL-C>76 mg/dL and their spouses from the Durham Veterans Affairs Medical Center were r and omized to intervention or usual care . The intervention comprised nine monthly goal - setting telephone calls to patients and support planning calls to spouses . Outcomes were assessed at 11 months . RESULTS Patients were 95 % male and 65 % White . LDL-C did not differ between groups ( mean difference = 2.3 mg/dL , 95 % CI = -3.6 , 8.3 , p = 0.44 ) , nor did the odds of meeting goal LDL-C ( OR = 0.95 , 95 % CI = 0.6 , 1.7 ; p = 0.87 ) . Intakes of calories ( p = 0.03 ) , total fat ( p = 0.02 ) , and saturated fat ( p = 0.02 ) were lower for the intervention group . Cholesterol and fiber intake did not differ between groups ( p = 0.11 and 0.26 , respectively ) . The estimated rate of moderate intensity physical activity per week was 20 % higher in the intervention group ( IRR = 1.2 , 95 % CI = 1.0 , 1.5 , p = 0.06 ) . Most participants did not experience a change in cholesterol medication usage during the study period in the intervention ( 71.7 % ) and usual care ( 78.9 % ) groups . CONCLUSION This intervention might be an adjunct to usual primary care to improve adherence to lifestyle behaviors [21807446] In this study , we investigated the role of dyadic planning for health-behavior change . Dyadic planning refers to planning health-behavior change together with a partner . We assumed that dyadic planning would affect the implementation of regular pelvic-floor exercise ( PFE ) , with other indicators of social exchange and self-regulation strategies serving as mediators . In a r and omized-controlled trial at a German University Medical Center , 112 prostatectomy- patients with partners were r and omly assigned to a dyadic PFE-planning condition or one of three active control conditions . Question naire data were assessed at multiple time points within six months post-surgery , measuring self-reported dyadic PFE-planning and pelvic-floor exercise as primary outcomes and social exchange ( support , control ) and a self-regulation strategy ( action control ) as mediating mechanisms . There were no specific intervention effects with regard to dyadic PFE-planning or pelvic-floor exercise , as two active control groups also showed increases in either of these variables . However , results suggested that patients instructed to plan dyadically still benefited from self-reported dyadic PFE-planning regarding pelvic-floor exercise . Cross-sectionally , received negative control from partners was negatively related with PFE only in control groups and individual action control mediated between self-reported dyadic PFE-planning and PFE for participants instructed to plan PFE dyadically . Longitudinally , action control mediated between self-reported dyadic PFE-planning and pelvic-floor exercise for all groups . Findings provide support for further investigation of dyadic planning in health-behavior change with short-term mediating effects of behavior-specific social exchange and long-term mediating effects of better self-regulation [26652029] PURPOSE Studies have found disparities in psychological distress between lesbian and gay cancer survivors and their heterosexual counterparts . Exercise and partner support are shown to reduce distress . However , exercise interventions have n't been delivered to lesbian and gay survivors with support by caregivers included . METHODS In this pilot r and omized controlled trial ( RCT ) , ten lesbian and gay and twelve heterosexual survivors and their caregivers were r and omized as dyads to : Arm 1 , a survivor-only , 6-week , home-based , aerobic and resistance training program ( EXCAP © ® ) ; or Arm 2 , a dyadic version of the same exercise program involving both the survivor and caregiver . Psychological distress , partner support , and exercise adherence , were measured at baseline and post-intervention ( 6 weeks later ) . We used t-tests to examine group differences between lesbian/gay and heterosexual survivors and between those r and omized to survivor-only or dyadic exercise . RESULTS Twenty of the twenty-two recruited survivors were retained post-intervention . At baseline , lesbian and gay survivors reported significantly higher depressive symptoms ( P = .03 ) and fewer average steps walked ( P = .01 ) than heterosexual survivors . Post-intervention , these disparities were reduced and we detected no significant differences between lesbian/gay and heterosexual survivors . Participation in dyadic exercise result ed in a significantly greater reduction in depressive symptoms than participation in survivor-only exercise for all survivors ( P = .03 ) . No statistically significant differences emerged when looking across arm ( survivor-only vs. dyadic ) by subgroup ( lesbian/gay vs. heterosexual ) . CONCLUSION Exercise may be efficacious in ameliorating disparities in psychological distress among lesbian and gay cancer survivors , and dyadic exercise may be efficacious for survivors of diverse sexual orientations . Larger trials are needed to replicate these findings [27421075] RATIONALE Engaging in regular physical activity requires substantial self-regulatory effort such as action control ( e.g. , continuously monitoring and evaluating an ongoing behavior with regard to one 's st and ards ) . OBJECTIVE The present study examined the effectiveness of an ecological momentary action control intervention for promoting daily physical activity . Also , we tested whether a dyadic compared to an individual intervention displayed an additional benefit . METHODS 121 overweight and obese individuals and their partners were r and omly allocated to an intervention ( n = 60 ; information + action control text messages ) or a control group ( n = 61 ; information only ) . The intervention was delivered in a dyadic vs. individual version of action control . Allocation ratio was 1:1:2 for the dyadic , individual , and control groups , respectively . Daily physical activity was assessed with triaxial accelerometers during a 14-day intervention phase and a 14-day follow-up phase . RESULTS Participants in the intervention group showed a higher probability ( 36.5 % ) to achieve the recommended daily activity levels ( ≥30 min of moderate-to-vigorous physical activity per day performed in bouts of at least 10 min ) during the intervention and follow-up phase compared to those in the control group ( 23.0 % ) . The intervention and control group did not differ in terms of daily moderate-to-vigorous physical activity ( 40.7 vs. 38.6 min per day , p = 0.623 ) . CONCLUSION Interventions facilitating action control via text messages seem to be an effective tool for increasing adherence to physical activity guidelines in everyday life . The comparable effects for the dyadic and individual intervention suggest that automated text messages may be just as effective as personalized messages from the romantic partner . Further investigation is needed to examine the usefulness of a dyadic conceptualizing of action control . ( controlled-trials.com IS RCT N15705531 ) [28705312] BACKGROUND Among patients with coronary artery disease ( CAD ) , improvement of lifestyle-related risk factors ( LRFs ) reduces cardiovascular morbidity and mortality . However , modification of LRFs is highly challenging . OBJECTIVES This study sought to evaluate the impact of combining community-based lifestyle programs with regular hospital-based secondary prevention . METHODS The authors performed a r and omized controlled trial of nurse-coordinated referral of patients and their partners to 3 widely available community-based lifestyle programs , in 15 hospitals in the Netherl and s. Patients admitted for acute coronary syndrome and /or revascularization , with ≥1 LRF ( body mass index > 27 kg/m2 , self-reported physical inactivity , and /or smoking ) were included . All patients received guideline -based usual care . The intervention was based on 3 lifestyle programs for weight reduction , increasing physical activity , and smoking cessation . The primary outcome was the proportion of success at 12 months , defined as improvement in ≥1 qualifying LRF using weight ( ≥5 % reduction ) , 6-min-walking distance ( ≥10 % improvement ) , and urinary cotinine ( 200 ng/ml detection limit ) without deterioration in the other 2 . RESULTS The authors r and omized 824 patients . Complete data on the primary outcome were available in 711 patients . The proportion of successful patients in the intervention group was 37 % ( 133 of 360 ) compared with 26 % ( 91 of 351 ) in the control group ( p = 0.002 ; risk ratio : 1.43 ; 95 % confidence interval : 1.14 to 1.78 ) . In the intervention group , partner participation was associated with a significantly greater success rate ( 46 % vs. 34 % ; p = 0.03 ) . CONCLUSIONS Among patients with coronary artery disease , nurse-coordinated referral to a comprehensive set of community-based , widely available lifestyle interventions , with optional partner participation , leads to significant improvements in LRFs . ( RESPONSE-2 : R and omised Evaluation of Secondary Prevention by Outpatient Nurse SpEcialists 2 ; NTR3937 ) [22215470] Background Community-based interventions are needed to reduce the burden of childhood obesity . Purpose To evaluate the impact of a multi-level promotora-based ( Community Health Advisor ) intervention to promote healthy eating and physical activity and prevent excess weight gain among Latino children . Methods Thirteen elementary schools were r and omized to one of four intervention conditions : individual/family level ( Family-only ) , school/community level ( Community-only ) , combined ( Family + Community ) , or a measurement-only condition . Participants were 808 Latino parents and their children enrolled in kindergarten through 2nd grade . Measures included parent and child body mass index ( BMI ) and a self-administered parent survey that assessed several parent and child behaviors . Results There were no significant intervention effects on children ’s BMI z-score . The family intervention changed several obesity-related child behaviors ( e.g. , fruit/vegetable consumption ) and these were mediated by changes in parenting variables ( e.g. , parent monitoring ) . Conclusion A promotora-based behavioral intervention was efficacious at changing parental factors and child obesity-related health behaviors

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### Context: [4364646] Background Enhancing physical activity in overweight and obese individuals is an important means to promote health in this target population . The Health Action Process Approach ( HAPA ) , which was the theoretical framework of this study , focuses on individual self-regulation variables for successful health behavior change . One key self-regulation variable of this model is action control with its three subfacets awareness of intentions , self-monitoring and regulatory effort . The social context of individuals , however , is usually neglected in common health behavior change theories . In order to integrate social influences into the HAPA , this r and omized controlled trial investigated the effectiveness of a dyadic conceptualization of action control for promoting physical activity . Methods / Design This protocol describes the design of a single-blind r and omized controlled trial , which comprises four experimental groups : a dyadic action control group , an individual action control group and two control groups . Participants of this study are overweight or obese , heterosexual adult couples who intend to increase their physical activity . Blocking as means of a gender-balanced r and omization is used to allocate couples to conditions and partners to either being the target person of the intervention or to the partner condition . The ecological momentary intervention takes place in the first 14 days after baseline assessment and is followed by another 14 days diary phase without intervention . Follow-ups are one month and six months later . Subsequent to the six-months follow-up another 14 days diary phase takes place . The main outcome measures are self-reported and accelerometer-assessed physical activity . Secondary outcome measures are Body Mass Index ( BMI ) , aerobic fitness and habitual physical activity . Discussion This is the first study examining a dyadic action control intervention in comparison to an individual action control condition and two control groups applying a single-blind r and omized control trial . Challenges with running couples studies as well as advantages and disadvantages of certain design -related decisions are discussed . This RCT was funded by the Swiss National Science Foundation ( PP00P1_133632/1 ) and was registered on 27/04/2012 at http://www.is rct n.com/IS RCT N15705531 [22705016] OBJECTIVE The study presents the immediate post-intervention results of Kids and Adults Now - Defeat Obesity ! , a r and omized controlled trial to enhance healthy lifestyle behaviors in mother-preschooler ( 2 - 5 years old ) dyads in North Carolina ( 2007 - 2011 ) . The outcomes include change from baseline in the child 's diet , physical activity and weight , and in the mother 's parenting behaviors , diet , physical activity , and weight . METHOD The intervention targeted parenting through maternal emotion regulation , home environment , feeding practice s , and modeling of healthy behaviors . 400 mother-child dyads were r and omized . RESULTS Mothers in the intervention arm , compared to the control arm , reduced instrumental feeding ( -0.24 vs. 0.01 , p<0.001 ) and TV snacks ( -.069 vs. -0.24 , p=0.001 ) . There were also improvements in emotional feeding ( p=0.03 ) , mother 's sugary beverage ( p=0.03 ) and fruit/vegetable ( p=0.04 ) intake , and dinners eaten in front of TV ( p=0.01 ) ; these differences were not significant after adjustment for multiple comparisons . CONCLUSION KAN-DO , design ed to maximize the capacity of mothers as agents of change , improved several channels of maternal influence . There were no group differences in the primary outcomes , but differences were observed in the parenting and maternal outcomes and there were trends toward improvement in the preschoolers ' diets . Long-term follow-up will address whether these short-term trends ultimately improve weight status [25599511] IMPORTANCE Couples are highly concordant for unhealthy behaviors , and a change in one partner 's health behavior is often associated with a change in the other partner 's behavior . However , no studies have explicitly compared the influence of having a partner who takes up healthy behavior ( eg , quits smoking ) with one whose behavior is consistently healthy ( eg , never smokes ) . OBJECTIVE To examine the influence of partner 's behavior on making positive health behavior changes . DESIGN , SETTING , AND PARTICIPANTS We used prospect i ve data from married and cohabiting couples ( n , 3722 ) participating in the English Longitudinal Study of Ageing , a large population -based cohort of older adults ( ≥50 years ) . Study ing men and women who had unhealthy behaviors in 3 domains at baseline ( ie , smoking , physically inactive , or overweight/obese ) , we used logistic regression analysis to examine the influence of the partner 's behavior in the same domain on the odds of positive health behavior change over time . MAIN OUTCOMES AND MEASURES Smoking cessation , increased physical activity , and 5 % weight loss or greater . RESULTS Across all domains , we found that when one partner changed to a healthier behavior ( newly healthy ) , the other partner was more likely to make a positive health behavior change than if their partner remained unhealthy ( smoking : men 48 % vs 8 % , adjusted odds ratio [ OR ] , 11.82 [ 95 % CI , 4.84 - 28.90 ] ; women 50 % vs 8 % , OR , 11.23 [ 4.58 - 27.52 ] ) ( physical activity : men 67 % vs 26 % , OR , 5.28 [ 3.70 - 7.54 ] ; women 66 % vs 24 % , OR , 5.36 [ 3.74 - 7.68 ] ) ( weight loss : men 26 % vs 10 % , OR , 3.05 [ 1.96 - 4.74 ] ; women 36 % vs 15 % , OR , 3.08 [ 1.98 - 4.80 ] ) . For smoking and physical activity , having a consistently healthy partner also predicted positive change , but for each domain , the odds were significantly higher in individuals with a newly healthy partner than those with a consistently healthy partner ( smoking : men OR , 3.08 [ 1.43 - 6.62 ] ; women OR , 5.45 [ 2.44 - 12.16 ] ) ( physical activity : men OR , 1.92 [ 1.37 - 2.70 ] ; women OR , 1.84 [ 1.33 - 2.53 ] ) ( weight loss : men OR , 2.28 [ 1.36 - 3.84 ] ; women OR , 2.86 [ 1.55 - 5.26 ] ) . CONCLUSIONS AND RELEVANCE Men and women are more likely to make a positive health behavior change if their partner does too , and with a stronger effect than if the partner had been consistently healthy in that domain . Involving partners in behavior change interventions may therefore help improve outcomes [21108739] To assess the feasibility of conducting empirically supported family-based paediatric obesity group treatment via TeleMedicine . Seventeen families were r and omly assigned to one of two conditions ( physician visit , TeleMedicine ) . Measures included feasibility , satisfaction and intervention outcome measures such as BMI percentile , and nutrition and activity behaviours . Measures were completed at baseline , post-treatment and at 1-year follow-up . Analyses indicate that both feasibility and satisfaction data regarding the TeleMedicine intervention were positive . Intervention outcome indicates no change in BMI percentile or nutrition and activity behaviours for either treatment group . A behavioural family-based weight loss intervention delivered via TeleMedicine was well received by both parents and providers . Due to the small sample size , null findings regarding intervention outcome should be interpreted with caution . Future research should focus on methods to increase the impact of this intervention on key outcome variables [24495204] Morbidity and mortality are reliably lower for the married compared with the unmarried across a variety of illnesses . What is less well understood is how a couple uses their relationship for recommended lifestyle changes associated with decreased risk for illness . Partners for Life compared a patient and partner approach to behavior change with a patient only approach on such factors as exercise , nutrition , and medication adherence . Ninety-three patients and their spouses/partners consented to participate ( 26 % of those eligible ) and were r and omized into either the individual or couples condition . However , only 80 couples , distributed across conditions , contributed data to the analyses , due to missing data and missing data points . For exercise , there was a significant effect of couples treatment on the increase in activity and a significant effect of couples treatment on the acceleration of treatment over time . In addition , there was an interaction between marital satisfaction and treatment condition such that patients who reported higher levels of marital distress in the individuals condition did not maintain their physical activity gains by the end of treatment , while both distressed and nondistressed patients in the couples treatment exhibited accelerating gains throughout treatment . In terms of medication adherence , patients in the couples treatment exhibited virtually no change in medication adherence over time , while patients in the individuals treatment showed a 9 % relative decrease across time . There were no condition or time effects for nutritional outcomes . Finally , there was an interaction between baseline marital satisfaction and treatment condition such that patients in the individuals condition who reported lower levels of initial marital satisfaction showed deterioration in marital satisfaction , while non satisfied patients in the couples treatment showed improvement over time [22576339] Background A key barrier to achieving recommended intensity and duration of physical activity is motivation . Purpose We investigated whether a virtually present partner would influence participants ’ motivation ( duration ) during aerobic exercise . Method Fifty-eight females ( Mage = 20.54 ± 1.86 ) were r and omly assigned to either a coactive condition ( exercising alongside another person , independently ) , a conjunctive condition ( performance determined by whichever partner stops exercising first ) where they exercised with a superior partner , or to an individual condition . Participants exercised on a stationary bike at 65 % of heart rate reserve on six separate days . Results Across sessions , conjunctive condition participants exercised significantly longer ( M = 21.89 min , SD = ±10.08 min ) than those in coactive ( M = 19.77 min , SD = ± 9.00 min ) and individual ( M = 10.6 min , SD = ±5.84 min ) conditions ( p < 0.05 ) . Conclusion Exercising with a virtually present partner can improve performance on an aerobic exercise task across multiple sessions [5182111] Objective To develop and test a family-centered behavioral weight loss intervention for African American adults with type 2 diabetes . Methods In this r and omized trial , dyads consisting of African American adult with overweight or obesity and type 2 diabetes ( index participant ) paired with a family partner with overweight or obesity , but not diagnosed with diabetes , were assigned in a 2:1 ratio to a 20-week special intervention ( SI ) or delayed intervention ( DI ) control group . The primary outcome was weight loss among index participants at 20 weeks follow-up . Results One hundred-eight participants ( 54 dyads – 36 ( SI ) and 18 ( DI ) dyads ) were enrolled : 81 % females ; mean age , 51 years ; mean weight,103 kg ; and mean BMI , 37 kg/m2 . At post-intervention , 96 participants ( 89 % ) returned for follow-up measures . Among index participants , mean difference in weight loss between groups was −5.0 kg , p<.0001 ( −3.6 kg loss among SI ; 1.4 kg gain in DI ) . SI index participants showed significantly greater improvements in hemoglobin A1c , depressive symptoms , family interactions , and dietary , physical activity , and diabetes self-care behaviors . SI family partners also had significant weight loss ( −3.9 kg ( SI ) vs. −1.0 kg ( DI ) p=0.02 ) . Conclusions A family-centered , behavioral weight loss intervention led to clinical ly significant short-term weight loss among family dyads [4875491] Background Emerging technologies ( ie , mobile phones , Internet ) may be effective tools for promoting physical activity ( PA ) . However , few interventions have provided effective means to enhance social support through these platforms . Face-to-face programs that use group dynamics-based principles of behavior change have been shown to be highly effective in enhancing social support through promoting group cohesion and PA , but to date , no studies have examined their effects in Web-based programs . Objective The aim was to explore proof of concept and test the efficacy of a brief , online group dynamics-based intervention on PA in a controlled experiment . We expected that the impact of the intervention on PA would be moderated by perceptions of cohesion and the partner ’s degree of presence in the online media . Methods Participants ( n=135 ) were r and omized into same-sex dyads and r and omly assigned to one of four experimental conditions : st and ard social support ( st and ard ) , group dynamics-based – high presence , group dynamics-based – low presence , or individual control . Participants performed two sets of planking exercises ( pre-post ) . Between sets , participants in partnered conditions interacted with a virtual partner using either a st and ard social support app or a group dynamics-based app ( group dynamics-based – low presence and group dynamics-based – high presence ) , the latter of which they participated in a series of online team-building exercises . Individual participants were given an equivalent rest period between sets . To increase presence during the second set , participants in the group dynamics-based – high presence group saw a live video stream of their partner exercising . Perceptions of cohesion were measured using a modified PA Group Environment Question naire . Physical activity was calculated as the time persisted during set 2 after controlling for persistence in set 1 . Results Perceptions of cohesion were higher in the group dynamics-based – low presence ( overall mean 5.81 , SD 1.04 ) condition compared to the st and ard ( overall mean 5.04 , SD 0.81 ) conditions ( P=.006 ) , but did not differ between group dynamics-based – low presence and group dynamics-based – high presence ( overall mean 5.42 , SD 1.07 ) conditions ( P=.25 ) . Physical activity was higher in the high presence condition ( mean 64.48 , SD 20.19 , P=.01 ) than all other conditions ( mean 53.3 , SD 17.35 ) . Conclusions A brief , online group dynamics-based intervention may be an effective method of improving group cohesion in virtual PA groups . However , it may be insufficient on its own to improve PA [23515115] The effectiveness of methods to prevent stroke recurrence and of education focusing on learners ' needs has not been fully explored . The aims of this study were to assess the effects of such interventions among stroke patients and their primary caregivers and to evaluate the feasibility of a web-based stroke education program . The participants were 36 patients with a clinical diagnosis of ischemic stroke within 12 months post-stroke and their primary caregivers . The participants were r and omly assigned to either an experimental or a control group . The primary measures included blood chemistry , self-reported health behaviors , sense of control , and health motivation for stroke patients , and caregiver mastery for caregivers . To test the feasibility of the intervention program , the rates of participation and occurrence of technical problems were calculated . The experimental group tended to improve significantly more than the control group in terms of exercise , diet , sense of control and health motivation for the stroke patients and in terms of caregiver mastery for the primary caregivers . The rate of participation in the web-based program was 63.1 % . This program , which focuses on recurrence prevention in stroke patients and caregivers , has the potential to improve health behaviors for stroke patients [4174282] Background Screen-based activities , such as watching television ( TV ) , playing video games , and using computers , are common sedentary behaviors among young people and have been linked with increased energy intake and overweight . Previous home-based sedentary behaviour interventions have been limited by focusing primarily on the child , small sample sizes , and short follow-up periods . The SWITCH ( Screen-Time Weight-loss Intervention Targeting Children at Home ) study aim ed to determine the effect of a home-based , family-delivered intervention to reduce screen-based sedentary behaviour on body composition , sedentary behaviour , physical activity , and diet over 24 weeks in overweight and obese children . Methods A two-arm , parallel , r and omized controlled trial was conducted . Children and their primary caregiver living in Auckl and , New Zeal and were recruited via schools , community centres , and word of mouth . The intervention , delivered over 20 weeks , consisted of a face-to-face meeting with the parent/caregiver and the child to deliver intervention content , which focused on training and educating them to use a wide range of strategies design ed to reduce their child ’s screen time . Families were given Time Machine TV monitoring devices to assist with allocating screen time , activity packages to promote alternative activities , online support via a website , and monthly newsletters . Control participants were given the intervention material on completion of follow-up . The primary outcome was change in children ’s BMI z-score from baseline to 24 weeks . Results Children ( n = 251 ) aged 9 - 12 years and their primary caregiver were r and omized to receive the SWITCH intervention ( n = 127 ) or no intervention ( controls ; n = 124 ) . There was no significant difference in change of z BMI between the intervention and control groups , although a favorable trend was observed ( -0.016 ; 95 % CI : -0.084 , 0.051 ; p = 0.64 ) . There were also no significant differences on secondary outcomes , except for a trend towards increased children ’s moderate intensity physical activity in the intervention group ( 24.3 min/d ; 95 % CI : -0.94 , 49.51 ; p = 0.06 ) . Conclusions A home-based , family-delivered intervention to reduce all leisure-time screen use had no significant effect on screen-time or on BMI at 24 weeks in overweight and obese children aged 9 - 12 years . Trial registration Australian New Zeal and Clinical Trials RegistryWebsite : http://www.anzctr.org.auTrial registration number : [26367803] The study examined whether a behavior-change intervention focusing on self-regulatory strategies and emphasizing role model support increases physical activity ( PA ) among insufficiently active ( not meeting PA guidelines of 150 min/week ) cancer patients . Ambulatory cancer patients [ N = 72 ; 54 % female ; M = 56 years , SD = 12.34 ; most with breast or colon cancer ( 34 , 15 % ) ] were enrolled in the MOTIVACTION- study , a 4-week intervention ( 1-hr counseling , followed by weekly phone calls ) , with pretest ( T1 ) , posttest ( T2 ) and a 10-week follow-up ( T3 ) . Participants were r and omized to either an exercise or to a stress management intervention ( active control ) . The exercise intervention emphasized self-regulatory strategies ( e.g. action- and coping planning and self-monitoring ) ; patients were also encouraged to contact a physically active same-sex role model as a potential exercise partner . The active control condition consisted of coping and relaxation techniques . Sixty-seven patients remained in the study and completed the SQUASH assessment of PA and a measure of perceived stress . PA was vali date d by Actigraph accelerometry . At T2 , 46 % of the patients in the exercise group and 19 % of stress management patients increased their activity levels to meet PA guidelines ( > 150 min/week ; χ2(1 ) = 5.51 , p = .019 ) . At T3 , participants in the exercise intervention maintained their exercise level ( 46 % ) , but also 31 % of the stress management patients met the guidelines . All patients reported reductions in perceived stress . Additional analyses comparing patients in the exercise group by role model contact ( 63 % realized contact ) revealed that those who had contact with their role model were significantly more likely to adhere to the recommended guidelines ( T2:50 % ; T3:64 % ) compared to those who did not have contact with a role model ( T2:39 % ; T3:15 % ) , suggesting the potential of mobilizing role model support to facilitate PA . In sum , cancer patients may not only benefit from an exercise intervention emphasizing self-regulation , but also from stress management , regarding both reducing stress and increasing PA [23545372] BACKGROUND AND OBJECTIVE : Clinic-based programs for childhood obesity are not available to a large proportion of the population . The purpose of this study was to evaluate the efficacy of a guided self-help treatment of pediatric obesity ( GSH-PO ) compared with a delayed treatment control and to evaluate the impact of GSH-PO 6-months posttreatment . METHODS : Fifty overweight or obese 8- to 12-year-old children and their parents were r and omly assigned to immediate treatment or to delayed treatment . The GSH-PO includes 12 visits over 5 months and addresses key components included in more intensive clinic-based programs . Children and parents in the immediate treatment arm were assessed at time 1 ( T1 ) , participated in GSH-PO between T1 and T2 , and completed their 6-month posttreatment assessment at T3 . Children and parents in the delayed treatment arm were assessed at T1 , participated in GSH-PO between T2 and T3 , and completed their 6-month posttreatment assessment at T4 . The main outcome measures were BMI , BMI z score , and percentage overweight ( % OW ) . RESULTS : Children in the immediate treatment GSH-PO arm decreased their BMI significantly more than did the delayed treatment arm ( BMI group × time = −1.39 ; P < .001 ) . Similar results were found for BMI z score and % OW . At the 6-month posttreatment assessment , changes result ing from GSH-PO were maintained for BMI z score and % OW but not BMI ( BMI time effect = −0.06 , not significant ; BMI z score time effect = −0.10 , P < .001 ; % OW time effect = −4.86 , P < .05 ) . CONCLUSIONS : The GSH-PO showed initial efficacy in decreasing BMI for children in this study . Additional efficacy and translational studies are needed to additionally evaluate GSH-PO [26715587] Background Prostate cancer can negatively impact quality of life of the patient and his spouse caregiver , but interventions rarely target the health of both partners simultaneously . We tested the feasibility and preliminary efficacy of a partnered strength training program on the physical and mental health of prostate cancer survivors ( PCS ) and spouse caregivers . Methods Sixty-four couples were r and omly assigned to 6 months of partnered strength training ( Exercising Together , N = 32 ) or usual care ( UC , N = 32 ) . Objective measures included body composition ( lean , fat and trunk fat mass ( kg ) , and % body fat ) by DXA , upper and lower body muscle strength by 1-repetition maximum , and physical function by the physical performance battery ( PPB ) . Self-reported measures included the physical and mental health summary scales and physical function and fatigue subscales of the SF-36 and physical activity with the CHAMPS question naire . Results Couple retention rates were 100 % for Exercising Together and 84 % for UC . Median attendance of couples to Exercising Together sessions was 75 % . Men in Exercising Together became stronger in the upper body ( p < 0.01 ) and more physically active ( p < 0.01 ) than UC . Women in Exercising Together increased muscle mass ( p = 0.05 ) and improved upper ( p < 0.01 ) and lower body ( p < 0.01 ) strength and PPB scores ( p = 0.01 ) more than UC . Conclusions Exercising Together is a novel couples-based approach to exercise that was feasible and improved several health outcomes for both PCS and their spouses . Implication s for cancer survivorsA couples-based approach should be considered in cancer survivorship programs so that outcomes can mutually benefit both partners . Trial registration Clinical Trials.gov [23415190] BACKGROUND Few successful treatment modalities exist to address childhood obesity . Given Latinos ' strong identity with family , a family-focused intervention may be able to control Latino childhood obesity . PURPOSE To assess the feasibility and effectiveness of a family-centered , primary care-based approach to control childhood obesity through lifestyle choices . DESIGN R and omized waitlist controlled trial in which control participants received the intervention 6 months after the intervention group . SETTING / PARTICIPANTS Forty-one Latino children with BMI > 85 % , aged 9 - 12 years , and their caregivers were recruited from an urban community health center located in a predominantly low-income community . INTERVENTION Children and their caregivers received 6 weeks of interactive group classes followed by 6 months of culturally sensitive monthly in-person or phone coaching to empower families to incorporate learned lifestyles and to address both family and social barriers to making changes . MAIN OUTCOMES MEASURES Caregiver report on child and child self-reported health-related quality of life ( HRQoL ) ; metabolic markers of obesity ; BMI ; and accelerometer-based physical activity were measured July 2010-November 2011 and compared with post-intervention assessment s conducted at 6 months and as a function of condition assignment . Data were analyzed in 2012 . RESULTS Average attendance rate to each group class was 79 % . Socio-environmental and family factors , along with knowledge , were cited as barriers to changing lifestyles to control obesity . Caregiver proxy and child self-reported HRQoL improved for both groups with a larger but not nonsignificant difference among intervention vs control group children ( p=0.33 ) . No differences were found between intervention and control children for metabolic markers of obesity , BMI , or physical activity . CONCLUSIONS Latino families are willing to participate in group classes and health coaching to control childhood obesity . It may be necessary for primary care to partner with community initiatives to address childhood obesity in a more intense manner . TRIAL REGISTRATION This study is registered at Clinical trials.partners.org 2009P001721 [4222564] Background Levels of physical activity ( PA ) in UK children are much lower than recommended and novel approaches to its promotion are needed . The Children , Parents and Pets Exercising Together ( CPET ) study is the first exploratory r and omised controlled trial ( RCT ) to develop and evaluate an intervention aim ed at dog-based PA promotion in families . CPET aim ed to assess the feasibility , acceptability and potential efficacy of a theory-driven , family-based , dog walking intervention for 9–11 year olds . Methods Twenty-eight families were allocated r and omly to either receive a 10-week dog based PA intervention or to a control group . Families in the intervention group were motivated and supported to increase the frequency , intensity and duration of dog walking using a number of behaviour change techniques . Parents in the intervention group were asked to complete a short study exit question naire . In addition , focus groups with parents and children in the intervention group , and with key stakeholders were undertaken . The primary outcome measure was 10 week change in total volume of PA using the mean accelerometer count per minute ( cpm ) . Intervention and control groups were compared using analysis of covariance . Analysis was performed on an intention to treat basis . Results Twenty five families were retained at follow up ( 89 % ) and 97 % of all outcome data were collected at baseline and follow up . Thirteen of 14 ( 93 % ) intervention group parents available at follow up completed the study exit question naire and noted that study outcome measures were acceptable . There was a mean difference in child total volume of PA of 27 cpm ( 95 % CI -70 , 123 ) and -3 cpm ( 95 % CI -60 , 54 ) for intervention and control group children , respectively . This was not statistically significant . Approximately 21 % of dog walking time for parents and 39 % of dog walking time for children was moderate-vigorous PA . Conclusions The acceptability of the CPET intervention and outcome measures was high . Using pet dogs as the agent of lifestyle change in PA interventions in children and their parents is both feasible and acceptable , but did not result in a significant increase in child PA in this exploratory trial . Trial registration IS RCT [3999907] Background Mexico has the highest adult overweight and obesity prevalence in the Americas ; 23.8 % of children < 5 years old are at risk for overweight and 9.7 % are already overweight or obese . Creciendo Sanos was a pilot intervention to prevent obesity among preschoolers in Instituto Mexicano del Seguro Social ( IMSS ) clinics . Methods We r and omized 4 IMSS primary care clinics to either 6 weekly educational sessions promoting healthful nutrition and physical activity or usual care . We recruited 306 parent-child pairs : 168 intervention , 138 usual care . Children were 2 - 5 years old with WHO body mass index ( BMI ) z-score 0 - 3 . We measured children ’s height and weight and parents reported children ’s diet and physical activity at baseline and 3 and 6-month follow-up . We analyzed behavioral and BMI outcomes with generalized mixed models incorporating multiple imputation for missing values . Results 93 ( 55 % ) intervention and 96 ( 70 % ) usual care families completed 3 and 6-month follow-up . At 3 months , intervention v. usual care children increased vegetables by 6.3 servings/week ( 95 % CI , 1.8 , 10.8 ) . In stratified analyses , intervention participants with high program adherence ( 5 - 6 sessions ) decreased snacks and screen time and increased vegetables v. usual care . No further effects on behavioral outcomes or BMI were observed . Transportation time and expenses were barriers to adherence . 90 % of parents who completed the post-intervention survey were satisfied with the program . Conclusions Although satisfaction was high among participants , barriers to participation and retention included transportation cost and time . In intention to treat analyses , we found intervention effects on vegetable intake , but not other behaviors or BMI .Trial registration Clinical Trials.gov NCT01539070.Comisión Nacional de Investigación Científica del IMSS : 2009 - 785 - 120 [3196245] Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more [21808077] The present investigation examined the Köhler motivation gain effect in a health game using an absent partner , presented virtually . The Köhler effect occurs when an inferior team member performs a difficult task better in a team or coaction situation than one would expect from knowledge of his or her individual performance . The effect has been strongest in conjunctive task conditions in which the group 's potential productivity is equal to the productivity of its least capable member . Participants were r and omly assigned to one of four conditions ( individual control , coaction , additive , and conjunctive ) in a 4 ( conditions ) • 2 ( gender ) factorial design and performed a series of isometric plank exercises within an exercise game . They performed the first series of five exercises alone holding each position for as long as they could , and , after a rest period , those in the partner conditions were told they would do remaining trials with a same-sex virtual partner whom they could observe during their performance . The partner 's performance was manipulated to be always superior to the participant 's . Results showed that task persistence was significantly greater in all experimental conditions than in the individual control condition . The conjunctive condition was no more motivating than either the additive or coactive conditions . Results suggest that working out with virtually present , superior partners can improve persistence motivation on exercise game tasks [16336114] OBJECTIVE To evaluate an intervention aim ed at increasing family physical activity and parent education about diet and activity for kindergarten students and issues related to their children 's BMI . METHODS A r and omized , controlled trial design was used to assess intervention impact in parental report of child diet and physical activity , and step logs over a 4-week period . RESULTS Participants in the intervention group reported that their children obtained more steps by the end of the program period , were more active , and had consumed fewer sweets than the comparison group . CONCLUSION The proposed intervention for parents and their young children does produce awareness and behavior change [27642760] Objective : Action planning can help translate physical activity intentions into action by linking situational cues with behavioral responses . Dyadic planning extends action planning and refers to target persons forming plans for their own behavior change together with partners . This study investigated whether a dyadic planning intervention could increase physical activity in target persons and their partners , whether these effects were moderated by relationship quality and mediated by action control , activity-specific received partner support , and control . Method : Couples ( n = 338 ; target persons r and omized ) were r and omly assigned to ( a ) a dyadic planning condition ( DPC ) ; ( b ) an individual planning condition ( IPC ) , in which target persons planned and partners worked on a distractor task ; or ( c ) a control condition ( CC ) , in which couples worked on a distractor task . During 3 assessment s up to 6 weeks postintervention , moderate ( primary outcome ) and vigorous activity were objective ly measured ; other variables were self-reported . Multilevel and path models were fit . Results : There were no beneficial direct effects of the intervention for DPC target persons . Over time , DPC partners ’ vigorous activity increased , but decreased again . At lower relationship quality , DPC target persons ’ activity decreased , whereas IPC target persons ’ vigorous activity increased . Mediation hypotheses were not supported . Mutual influence models indicated positive effects of partners ’ on target persons ’ moderate activity in DPC and CC , whereas for IPC , negative effects of target persons ’ on partners ’ moderate activity emerged . Conclusions : Findings revealed the complexity of effects of dyadic planning on behavior change . Adding relationship quality to the equation clarified effects of DPC and IPC on physical activity [3533722] Background The diets , physical activity and sedentary behavior levels of both children and adults in Australia are suboptimal . The family environment , as the first ecological niche of children , exerts an important influence on the onset of children ’s habits . Parent modeling is one part of this environment and a logical focus for child obesity prevention initiatives . The focus on parent ’s own behaviors provides a potential opportunity to decrease obesity risk behaviors in parents as well . Objective To assess the effect of a parent-focused early childhood obesity prevention intervention on first-time mothers ’ diets , physical activity and TV viewing time . Methods The Melbourne InFANT Program is a cluster-r and omized controlled trial which involved 542 mothers over their newborn ’s first 18 months of life . The intervention focused on parenting skills and strategies , including parental modeling , and aim ed to promote development of healthy child and parent behaviors from birth , including healthy diet , increased physical activity and reduced TV viewing time . Data regarding mothers ’ diet ( food frequency question naire ) , physical activity and TV viewing times ( self-reported question naire ) were collected using vali date d tools at both baseline and post-intervention . Four dietary patterns were derived at baseline using principal components analyses including frequencies of 55 food groups . Analysis of covariance was used to measure the impact of the intervention . Results The scores of both the " High-energy snack and processed foods " and the " High-fat foods " dietary patterns decreased more in the intervention group : -0.22 ( −0.42;-0.02 ) and −0.25 ( −0.50;-0.01 ) , respectively . No other significant intervention vs. control effects were observed regarding total physical activity , TV viewing time , and the two other dietary patterns , i.e. “ Fruits and vegetables ” and “ Cereals and sweet foods ” . Conclusions These findings suggest that supporting first-time mothers to promote healthy lifestyle behaviors in their infants impacts maternal dietary intakes positively . Further research needs to assess ways in which we might further enhance those lifestyle behaviors not impacted by the InFANT intervention [12812815] Diet and physical activity habits may deteriorate after cohabitation , leading to weight gain and increased risk of lifestyle diseases . We carried out a 4-month , r and omized controlled trial of a diet and physical activity program for couples with a 1-year follow-up , comparing two methods of delivery . The program used six modules , which , after an initial group session , were mailed to the low-level intervention group . In the high-level intervention group , half of the modules were mailed , and the others were delivered at interactive group sessions . A control group received no intervention . Postintervention and at follow-up , physical fitness improved in the high-level group , saturated fat intake decreased in both intervention groups , and low-density lipoprotein cholesterol fell in the high-level group . Fewer participants in the high-level group became overweight or obese . Health promotion for couples can improve health behaviors and potentially lower the risk of lifestyle diseases in participants and their future families [20628481] ABSTRACT This study tested the efficacy of brief image-based print-mediated parent/caregiver and adolescent messages integrating physical activity with alcohol use avoidance . A total of 684 high school students were r and omly assigned to either the parent postcard or adolescent flyer arm , with baseline and four-month postintervention data collection s. A significant repeated measures interaction ( group × time ) was found ( F(4,344 ) = 2.48 , p = .04 ) , with univariate tests showing less alcohol use frequency and problems ( ps < .05 ) among adolescents exposed to parent material s. Repeated measures factorial MANOVAs for group × time × prior current drug use were significant , with drug using adolescents receiving parent print messages showing less alcohol initiation and frequency and marijuana initiation and frequency ( ps < .05 ) . Very brief print material s sent to parents/caregivers may hold some promise for influencing substance use among adolescents , particularly those already using drugs [26374480] Background and Purpose — The Stroke Health and Risk Education Project was a cluster-r and omized , faith-based , culturally sensitive , theory-based multicomponent behavioral intervention trial to reduce key stroke risk factor behaviors in Hispanics/Latinos and European Americans . Methods — Ten Catholic churches were r and omized to intervention or control group . The intervention group received a 1-year multicomponent intervention ( with poor adherence ) that included self-help material s , tailored newsletters , and motivational interviewing counseling calls . Multilevel modeling , accounting for clustering within subject pairs and parishes , was used to test treatment differences in the average change since baseline ( ascertained at 6 and 12 months ) in dietary sodium , fruit and vegetable intake , and physical activity , measured using st and ardized question naires . A priori , the trial was considered successful if any one of the 3 outcomes was significant at the 0.05/3 level . Results — Of 801 subjects who consented , 760 completed baseline data assessment s , and of these , 86 % completed at least one outcome assessment . The median age was 53 years ; 84 % subjects were Hispanic/Latino ; and 64 % subjects were women . The intervention group had a greater increase in fruit and vegetable intake than the control group ( 0.25 cups per day [ 95 % confidence interval : 0.08 , 0.42 ] , P=0.002 ) , a greater decrease in sodium intake ( −123.17 mg/d [ −194.76 , −51.59 ] , P=0.04 ) , but no difference in change in moderate- or greater-intensity physical activity ( −27 metabolic equivalent – minutes per week [ −526 , 471 ] , P=0.56 ) . Conclusions — This multicomponent behavioral intervention targeting stroke risk factors in predominantly Hispanics/Latinos was effective in increasing fruit and vegetable intake , reaching its primary end point . The intervention also seemed to lower sodium intake . Church-based health promotions can be successful in primary stroke prevention efforts . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT01378780 [25667250] BACKGROUND AND OBJECTIVE : Motivational interviewing ( MI ) has been shown to be an effective strategy for targeting obesity in adolescents , and parental involvement is associated with increased effectiveness . The aim of this study was to evaluate and compare the role of parental involvement in MI interventions for obese adolescents . METHODS : A total of 357 Iranian adolescents ( aged 14–18 years ) were r and omized to receive an MI intervention or an MI intervention with parental involvement ( MI + PI ) or assessment s only ( passive control ) . Data regarding anthropometric , biochemical , psychosocial , and behavioral measures were collected at baseline and 12 months later . A series of intention-to-treat , 2-way repeated- measures analysis of covariance were performed to examine group differences in change in outcomes measures over the 12-month follow-up period . RESULTS : Results revealed significant effects on most of the outcome parameters for MI + PI ( eg , mean ± SD BMI z score : 2.58 ± 0.61 ) compared with the passive control group ( 2.76 ± 0.70 ; post hoc test , P = .02 ) , as well as an additional superiority of MI + PI compared with MI only ( 2.81 ± 0.76 ; post hoc test , P = .05 ) . This pattern was also shown for most of the anthropometric , biochemical , psychometric , and behavioral outcome variables . CONCLUSIONS : MI with parental involvement is an effective strategy in changing obesity-related outcomes and has additional effects beyond MI with adolescents only . These findings might be important when administering MI interventions in school setting [4822262] Background School health promotion has been shown to improve the lifestyle of students , but it remains unclear whether school-based programs can influence family health . We developed an innovative program that enables school children to act as change agents in promoting healthy lifestyles of their mothers . The objective of this study was to examine the effect of the child-initiated intervention on weight , physical activity and dietary habit of their mothers . Methods A 12-month cluster r and omized trial was conducted , with school as a cluster . Participants were mothers with grade 8 students , aged around 13 years , of 20 schools in Homagama , Sri Lanka . Students of the intervention group were trained by facilitators to acquire the ability to assess noncommunicable disease risk factors in their homes and take action to address them , whereas those of the comparison group received no intervention . Body weight , step count and lifestyle of their mothers were assessed at baseline and post-intervention . Multi-level multivariable linear regression and logistic regression were used to assess the effects of intervention on continuous and binary outcomes , respectively . Results Of 308 study participants , 261 completed the final assessment at 12 month . There was a significantly greater decrease of weight and increase of physical activity in the intervention group . The mean ( 95 % confidence interval ) difference comparing the intervention group with the control group was −2.49 ( −3.38 to −1.60 ) kg for weight and −0.99 ( −1.40 to −0.58 ) kg/m2 for body mass index . The intervention group had a 3.25 ( 95 % confidence interval 1.87–5.62 ) times higher odds of engaging in adequate physical activity than the control group , and the former showed a greater number of steps than the latter after intervention . The intervention group showed a greater reduction of household purchase of biscuits and ice cream . Conclusions A program to motivate students to act as change agents of family ’s lifestyle was effective in decreasing weight and increasing physical activity of their mothers . Trial registration Sri Lanka Clinical Trials Registry SLCTR/2013/011 [4716156] Objective To assess the effectiveness of 2 interventions in improving the physical activity and well-being of secondary school children . Design A clustered r and omised controlled trial ; classes , 1 per school , were assigned to 1 of 3 intervention arms or a control group based on a 2 × 2 factorial design . The interventions were peer-mentoring and participative learning . Year 7 children ( aged 11–12 ) in the peer-mentoring intervention were paired with year 9 children for 6 weekly mentoring meetings . Year 7 children in the participative learning arm took part in 6 weekly geography lessons using personalised physical activity and Global Positioning System ( GPS ) data . Year 7 children in the combined intervention received both interventions , with the year 9 children only participating in the mentoring sessions . Participants 1494 year 7 students from 60 schools in the North of Engl and took part in the trial . Of these , 43 students opted out of taking part in the evaluation measurements , 2 moved teaching group and 58 changed school . Valid accelerometry outcome data were collected for 892 students from 53 schools ; and well-being outcome data were available for 927 students from 52 schools . Main outcome measures The primary outcomes were mean minutes of accelerometer-measured moderate-to-vigorous intensity physical activity per day , and well-being as evaluated by the KIDSCREEN-27 question naire . These data were collected 6 weeks after the intervention ; a 12-month follow-up is planned . Results No significant effects ( main or interaction ) were observed for the outcomes . However , small positive differences were found for both outcomes for the participative learning intervention . Conclusions These findings suggest that the 2 school-based interventions did not modify levels of physical activity or well-being within the period monitored . Change in physical activity may require more comprehensive individual behavioural intervention , and /or more system-based efforts to address wider environmental influences such as family , peers , physical environment , transport and educational policy . Trial registration number IS RCT N82956355 [3713945] Background Despite the physical and mental health benefits , few adults meet US Department of Health and Human Services physical activity guidelines for exercise frequency , intensity , and duration . One strategy that may increase physical activity duration is exercising with an Internet partner ( ie , someone who is virtually present , as in video chat ) . Internet partners help people overcome many barriers associated with face-to-face exercise groups ( eg , time , coordinating schedules , social physique anxiety ) . Past research examining individual performance in groups suggests that an increase in effort occurs when performing a task conjunctively , ie , when a participant is ( 1 ) less capable than fellow group members , and ( 2 ) participants efforts are particularly indispensable for group success ( ie , where the group ’s potential productivity is equal to the productivity of its least capable member ) . This boost in effort is more commonly known as the Köhler effect , named after the German psychologist who first observed the effect . While encouragement between group members is common practice in face-to-face group exercise , the effect of encouragement between partners exercising conjunctively across the Internet is unknown . Objective To examine the impact of exercising alone , compared to exercising conjunctively with an Internet partner , both with and without encouragement , on exercise persistence ( primary outcomes ) and secondary psychosocial outcomes ( self-efficacy , enjoyment , exercise intention ) . Methods Participants were recruited online and face-to-face from the campus of Michigan State University . With the assistance of the experimenter , participants ( n=115 ) played an exercise video game in a laboratory , performing a series of five abdominal plank exercises where they were asked to hold the plank for as long as possible ( Time 1 ) . They were then r and omized to a condition ( Individual , Partner-without-encouragement , or Partner-with-encouragement ) , where they performed the exercises again ( Time 2 ) . The impact of condition on the primary outcome measures and secondary outcome measures were evaluated using a 2 ( Gender ) x 3 ( Condition ) ANOVA on change scores ( Time 2-Time 1 ) . Results Those who exercised in online teams ( n=80 ) exercised significantly longer ( time=78.8s , P<.001 ) than those who worked individually ( n=35 ) . However , exercise duration was shorter when one ’s more capable partner gave verbal encouragement ( n=55 ) than when s/he did not ( n=25 ) ( a mean difference of 31.14s ) . These increases in effort were not accompanied by altered task self-efficacy , enjoyment of the task , or intention to exercise in the future . Conclusions Exercising conjunctively with an Internet partner can boost one ’s duration of exercise . However , encouragement from the stronger to the weaker member can mitigate these gains , especially if one perceives such comments being directed at someone other than themselves . To boost exercise duration , Internet-based physical activity interventions involving group interaction should make relative abilities of participants known and communication clear [4401690] Background There is evidence that physical activity ( PA ) is of cognitive benefit to the ageing brain , but little is known on the effect in patients with Alzheimer ’s disease ( AD ) . The present pilot study assessed the effect of a home-based PA training on clinical symptoms , functional abilities , and caregiver burden after 12 and 24 weeks . Methods In an RCT thirty patients ( aged 72.4±4.3 years ) with AD ( MMSE : 20.6±6.5 points ) and their family caregivers were allocated to a home-based 12-week PA intervention program or the usual care group . The program changed between passive , motor-assisted or active resistive leg training and changes in direction on a movement trainer in order to combine physical and cognitive stimuli . Results Analysis of activities of daily living in the patients ( ADCS ADL total score ) revealed a significant group × time interaction effect ( 95 % CI of the difference between both groups at T2 : 5.01–10.51 ) . The control group experienced decreases in ADL performance at week 12 and 24 whereas patients in the intervention group remained stable . Analyses of executive function and language ability revealed considerable effects for semantic word fluency with a group × time interaction ( 95 % CI of the difference between both groups at T2 : 0.18–4.02 ) . Patients in the intervention group improved during the intervention and returned to initial performance at week 12 whereas the controls revealed continuous worsening . Analyses of reaction time , h and -eye quickness and attention revealed improvement only in the intervention group . Caregiver burden remained stable in the intervention group but worsened in the control group . Conclusions This study suggests that PA in a home-based setting might be an effective and intrinsically attractive way to promote PA training in AD and modulate caregiver burden . The results demonstrate transfer benefits to ADL , cognitive and physical skill in patients with AD . Trial Registration Clinical Trials.gov [3766233] Background People with dementia have a disproportionately high rate of falls and fractures and poorer outcomes , yet there is currently no evidence to guide falls prevention in this population . Methods A r and omised trial design was used to test feasibility of study components and acceptability of a home hazard reduction and balance and strength exercise fall prevention program . The program was tailored to participant ’s individual cognitive levels and implemented as a carer-supported intervention . Feasibility of recruitment , retention and implementation of intervention were recorded through observation and documented in field notes . Adherence , carer burden and use of task simplification strategies were also monitored . Outcome measures , collected at 12 weeks included physiological , fear of falling , cognitive and functional measures . Results Recruitment was achievable but may be more challenging in a multisite trial . Twenty two dyads of persons with mild dementia and their carers were r and omised to intervention or usual care control group . Of 38 dyads referred to the study , there was a high rate of willingness to participate , with 6 ( 16 % ) declining and 10 ( 26 % ) not meeting inclusion criteria . The intervention was well received by participants and carers and adherence to both program components was very good . All participants implemented some home safety recommendations ( range 19 - 80 % ) with half implementing 50 % or more . At the end of 12 weeks , 72 % of the intervention group were exercising . Both the rate of falling and the risk of a fall were lower in the intervention group but these findings were not significant ( RR= 0.50 ( 95 % CI 0.11 - 2.19 ) . There were no differences in physiological outcome measures between the control and intervention groups . However results were influenced by the small study size and incomplete data primarily in the intervention group at follow up . Conclusions The pilot study was feasible and acceptable to people with mild dementia and their carers . The lessons learnt included : recruitment for a larger trial will require multiple approaches ; home safety recommendations should provide a greater emphasis on environmental use compared with behavioural change ; strategies to ensure an adequate dosage of exercise should be further explored . We recommend that intervention delivery incorporate an integrated occupational therapy and physiotherapy approach and that carers be provided with an individualised session to enhance dementia-specific skills in management and communication . A refined intervention should be tested in a r and omised trial with an adequately powered sample size . Trial registration Australia and New Zeal and Clinical Trials Registry [3598924] Background Many children spend too much time screen-viewing ( watching TV , surfing the internet and playing video games ) and do not meet physical activity ( PA ) guidelines . Parents are important influences on children ’s PA and screen-viewing ( SV ) . There is a shortage of parent-focused interventions to change children ’s PA and SV . Methods Teamplay was a two arm individualized r and omized controlled feasibility trial . Participants were parents of 6–8 year old children . Intervention participants were invited to attend an eight week parenting program with each session lasting 2 hours . Children and parents wore an accelerometer for seven days and minutes of moderate-to-vigorous intensity PA ( MVPA ) were derived . Parents were also asked to report the average number of hours per day that both they and the target child spent watching TV . Measures were assessed at baseline ( time 0 ) at the end of the intervention ( week 8) and 2 months after the intervention had ended ( week 16 ) . Results There were 75 participants who provided consent and were r and omized but 27 participants withdrew post-r and omization . Children in the intervention group engaged in 2.6 fewer minutes of weekday MVPA at Time 1 but engaged in 11 more minutes of weekend MVPA . At Time 1 the intervention parents engaged in 9 more minutes of weekday MVPA and 13 more minutes of weekend MVPA . The proportion of children in the intervention group watching ≥ 2 hours per day of TV on weekend days decreased after the intervention ( time 0 = 76 % , time 1 = 39 % , time 2 = 50 % ) , while the control group proportion increased slightly ( 79 % , 86 % and 87 % ) . Parental weekday TV watching decreased in both groups . In post- study interviews many mothers reported problems associated with wearing the accelerometers . In terms of a future full-scale trial , a sample of between 80 and 340 families would be needed to detect a mean difference of 10-minutes of weekend MVPA . Conclusions Teamplay is a promising parenting program in an under- research ed area . The intervention was acceptable to parents , and all elements of the study protocol were successfully completed . Simple changes to the trial protocol could result in more complete data collection and study engagement [10387506] In a pilot health promotion program for couples , we aim ed to build on re-evaluation of attitudes to health occurring early in marriage , and social support provided by partners , to address the weight gain and physical inactivity which may follow marriage . A r and omized controlled trial lasting 16 weeks used six modules focusing on nutrition and physical activity but including information about alcohol and smoking . Thirty-four of 39 couples enrolled completed the study . Self-efficacy for diet and physical activity increased significantly in the program group while ranking of barriers to healthy behaviours decreased and ranking of beliefs about the benefits of health behaviours increased relative to controls . Intake of fat , take-away foods and alcohol decreased , and consumption of fruit , vegetables and reduced-fat foods increased significantly in the program group . Physical activity in the program group increased by the equivalent of 50 min of brisk walking weekly but did not differ significantly from controls . Cholesterol fell significantly by 6 % more in the program group than controls . In focus groups , participants unanimously found the program valuable . Health promotion programs design ed for couples can achieve short-term changes in behaviour and risk factors . Larger trials with longer-term monitoring , incorporating feedback from focus groups and cost-benefit analysis , are in progress [23460688] OBJECTIVE : To assess the effectiveness of a parent-focused intervention on infants ’ obesity-risk behaviors and BMI . METHODS : This cluster r and omized controlled trial recruited 542 parents and their infants ( mean age 3.8 months at baseline ) from 62 first-time parent groups . Parents were offered six 2-hour dietitian-delivered sessions over 15 months focusing on parental knowledge , skills , and social support around infant feeding , diet , physical activity , and television viewing . Control group parents received 6 newsletters on nonobesity-focused themes ; all parents received usual care from child health nurses . The primary outcomes of interest were child diet ( 3 × 24-hour diet recalls ) , child physical activity ( accelerometry ) , and child TV viewing ( parent report ) . Secondary outcomes included BMI z-scores ( measured ) . Data were collected when children were 4 , 9 , and 20 months of age . RESULTS : Unadjusted analyses showed that , compared with controls , intervention group children consumed fewer grams of noncore drinks ( mean difference = –4.45 ; 95 % confidence interval [ CI ] : –7.92 to –0.99 ; P = .01 ) and were less likely to consume any noncore drinks ( odds ratio = 0.48 ; 95 % CI : 0.24 to 0.95 ; P = .034 ) midintervention ( mean age 9 months ) . At intervention conclusion ( mean age 19.8 months ) , intervention group children consumed fewer grams of sweet snacks ( mean difference = –3.69 ; 95 % CI : –6.41 to –0.96 ; P = .008 ) and viewed fewer daily minutes of television ( mean difference = –15.97 : 95 % CI : –25.97 to –5.96 ; P = .002 ) . There was little statistical evidence of differences in fruit , vegetable , savory snack , or water consumption or in BMI z-scores or physical activity . CONCLUSIONS : This intervention result ed in reductions in sweet snack consumption and television viewing in 20-month-old children [21473660] OBJECTIVE To evaluate the effectiveness of a psychological , family-based intervention to improve diabetes-related outcomes in patients with poorly controlled type 2 diabetes . METHODS This study was a r and omized controlled trial of a psychological family-based intervention targeted at individuals with poorly controlled type 2 diabetes . Recruitment and follow-up occurred at specialist diabetes clinics . Patients were r and omly allocated to an intervention group ( n=60 ) or a control group ( n=61 ) . Poor control was defined as at least 2 of the patient 's last 3 glycated hemoglobin ( A1C ) readings at > 8.0 % . The intervention consisted of 2 sessions delivered by a health psychologist to the patient and a family member in the patient 's home , with a third session involving a 15-minute follow-up telephone call . RESULTS At 6-month follow-up , the intervention group reported significantly lower mean A1C levels than the control group ( 8.4 % [ SD=0.99 % ] vs 8.8 % [ SD=1.36 % ] ; P=.04 ) . The intervention was most effective in those with the poorest control at baseline ( A1C>9.5 % ) ( intervention 8.7 % [ SD=1.16 % , n=15 ] vs control 9.9 % [ SD=1.31 % , n=15 ] ; P=.01 ) . The intervention group also reported statistically significant improvements in beliefs about diabetes , psychological well-being , diet , exercise , and family support . CONCLUSIONS After participating in a family-based intervention targeting negative and /or inaccurate illness perceptions , patients with poorly controlled type 2 diabetes showed improvements in A1C levels and other outcomes . Our results suggest that adding a psychological , family-based component to usual diabetes care may help improve diabetes management [20966907] Parent-only ( PO ) treatments for childhood obesity are feasible , more cost-effective and potentially easier to disseminate . The objective of this study was to determine whether a PO treatment is not inferior to a parent + child ( PC ) treatment for childhood obesity . Eighty parent-child dyads with an 8 - 12 year old overweight or obese child ( > 85th BMI -P ) were recruited and r and omized into PO or PC treatment for childhood obesity . Parents or parent-child dyads attended 5-month treatment groups . Child and parent body size , child caloric intake , and child physical activity were assessed at baseline , post-treatment , and 6-months follow-up . Noninferiority testing using mixed linear models was used to compare PO treatment with PC treatment . Results showed that the PO group was not inferior to the PC group in terms of child weight loss . Results also showed that the PO group was not inferior to the PC group in terms of parent weight loss and child physical activity , but not child caloric intake . This study suggests that a PO treatment could provide similar results to PC in child weight loss and other relevant outcomes , and potentially could be more cost-effective and easier to disseminate . Although further research is needed , this study suggests that PO groups are a viable method for providing childhood obesity treatment [5578653] Regular physical activity ( PA ) and the avoidance of prolonged sitting are essential for children ’s healthy growth , and for the physical and mental wellbeing of both children and adults . In the context of exercise , music may promote behavioral change through increased exercise adherence and participation . The purpose of this study was to determine whether a movement-to-music video program could reduce sedentary behavior ( SB ) and increase PA in mother-child pairs in the home environment . A r and omized controlled trial was conducted in the Pirkanmaa region , Finl and , in 2014–2016 . The participants consisted of 228 mother-child pairs ( child age 5–7 years ) . The primary outcomes of interest were tri-axial accelerometer-derived SB and PA , which were measured in weeks one ( baseline ) , two , and eight in both the intervention and control groups . Further , the mothers and children in the intervention group used a movement-to-music video program from the beginning of week two to the end of week eight . Secondary outcomes included self-reported screen time . The statistical methods employed comprised an intention-to-treat and linear mixed effects model design . No statistically significant differences between groups were found in primary or secondary outcomes . Among the children in the control group , light PA decreased significantly over time and screen time increased from 89 ( st and ard deviation , SD 37 ) to 99 ( SD 41 ) min/d . Among mothers and children in the intervention group , no statistical differences were found . In supplementary analysis , the children who stayed at home instead of attending daycare/preschool had on average 25 ( 95 % confidence interval , CI 19–30 ) min/d more sedentary time and 11 ( 95 % CI 8–14 ) min/d less moderate-to-vigorous PA than those who were at daycare/preschool . The higher body mass index of mothers was related with 5 ( 95 % CI 2–7 ) min/d more sedentary time and 1 ( 95 % CI 0–2 ) min/d less moderate-to-vigorous PA . The movement-to-music video program did not change the objective ly measured SB or PA of the mother-child pairs . However , mothers and children seemed to be more sedentary at home , and therefore interventions for decreasing SB and increasing PA should be targeted in the home environment [12740449] OBJECTIVE To determine whether maternal participation in an obesity prevention plus parenting support ( OPPS ) intervention would reduce the prevalence of obesity in high-risk Native-American children when compared with a parenting support (PS)-only intervention . RESEARCH METHODS AND PROCEDURES Forty-three mother/child pairs were recruited to participate . Mothers were 26.5 + /- 5 years old with a mean BMI of 29.9 + /- 3 kg/m(2 ) . Children ( 23 males ) were 22 + /- 8 months old with mean weight-for-height z ( WHZ ) scores of 0.73 + /- 1.4 . Mothers were r and omly assigned to a 16-week OPPS intervention or PS alone . The intervention was delivered one-on-one in homes by an indigenous peer educator . Baseline and week 16 assessment s included weight and height ( WHZ score and weight-for-height percentile for children ) , dietary intake ( 3-day food records ) , physical activity ( measured by accelerometers ) , parental feeding style ( Child Feeding Question naire ) , and maternal outcome expectations , self-efficacy , and intention to change diet and exercise behaviors . RESULTS Changes in WHZ scores showed a trend toward significance , with WHZ scores decreasing in the PS condition and increasing among the OPPS group ( -0.27 + /- 1.1 vs. 0.31 + /- 1.1 , p = 0.06 ) . Children in the OPPS condition also significantly decreased energy intake ( -316 + /- 835 kcal/d vs. 197 + /- 608 kcal/d , p < 0.05 ) . Scores on the restriction subscale of the Child Feeding Question naire decreased significantly in the OPPS condition ( -0.22+/- 0.42 vs. 0.08+/- 0.63 , p < 0.05 ) , indicating that mothers in the OPPS group were engaging in less restrictive child feeding practice s over time . DISCUSSION A home-visiting program focused on changing lifestyle behaviors and improving parenting skills showed promise for obesity prevention in high-risk Native-American children [22066521] BACKGROUND The primary care setting offers the opportunity to reach children and parents to encourage healthy lifestyle behaviours , and improve weight status among children . OBJECTIVE Test the feasibility of Helping H AND ( Healthy Activity and Nutrition Directions ) , an obesity intervention for 5- to 8-year-old children in primary care clinics . METHODS A r and omized controlled pilot study of Helping H AND , a 6-month intervention , targeted children with body mass index 85 - 99%tile and their parents . Intervention group attended monthly sessions and self-selected child behaviours and parenting practice s to change . Control group received regular paediatric care and was wait-listed for Helping H AND . Session completion , participant satisfaction , child anthropometrics , dietary intake , physical activity , TV viewing and behaviour-specific parenting practice s were measured pre and post intervention . RESULTS Forty parent-child dyads enrolled : 82.5 % were Hispanic , 80 % had a girl and 65 % reported income ≤ $ 30 , 000/year . There was 20 % attrition from Helping H AND ( attended < 4/6 sessions ) . Families self-selected 4.35 ( SD 1.75 ) behaviours to target during the 6-month programme and each of the seven behaviours was selected by 45 - 80 % of the families . There were no between group differences in the child 's body mass index z-score , dietary intake or physical activity post intervention . Intervention group viewed 14.9 ( SE 2.3 ) h/week of TV post intervention versus control group 23.3 ( SE 2.4 ) h/week ( P < 0.05 ) . CONCLUSION Helping H AND is feasible , due to low attrition , good programme attendance , and clinical ly relevant improvements in some child and parenting behaviours [24338799] OBJECTIVE The objective of this study is to evaluate the effectiveness of a simple dyadic ( person with dementia and their main carer ) exercise regimen as a therapy for the behavioural and psychological symptoms of dementia . METHOD A two arm , pragmatic , r and omised , controlled , single-blind , parallel-group trial of a dyadic exercise regimen ( individually tailored walking regimen design ed to become progressively intensive and last between 20 - 30 min , at least five times per week).Community-dwelling individuals with ICD-10 confirmed dementia with the following : clinical ly significant behavioural and psychological symptoms , a carer willing and able to co-participate in the exercise regimen , and no physical conditions or symptoms that would preclude exercise participation were invited by mental health or primary care services into the study . RESULTS One hundred and thirty-one dyads were recruited to this study . There was no significant difference in Behavioural and Psychological Symptoms as measured by the Neuropsychiatric Inventory at week 12 between the group receiving the dyadic exercise regimen and those that did not ( adjusted difference in means ( intervention minus control ) = -1.53 , p = 0.6 , 95 % CI [ -7.37 , 4.32 ] ) . There was a significant between-group difference in caregiver 's burden as measured by the Zarit Caregiver Burden Inventory at week 12 ( OR = 0.18 , p = 0.01 , CI [ 0.05 , 0.69 ] ) favouring the exercise group . CONCLUSIONS This study found that regular simple exercise does not appear to improve the behavioural and psychological symptoms of dementia , but did seem to attenuate caregiver burden . Further study to improve exercise uptake are needed [25110844] OBJECTIVE Although studies have shown that physical activity ( PA ) can reduce some treatment-related side effects of breast cancer , there is a need to offer PA programs outside of research setting s to reach more cancer survivors . We partnered with the American Cancer Society 's Reach to Recovery ( RTR ) program to train their volunteers ( breast cancer survivors ) to deliver a 12-week PA intervention to other breast cancer survivors . METHOD We conducted a r and omized controlled trial to compare the PA intervention delivered by RTR volunteers ( PA plus RTR ) with contact control ( RTR control ) . Eighteen RTR volunteers/coaches ( Mage = 54.9 years ; Mtime since diagnosis = 7.0 years ) delivered the contact control condition or the PA intervention . Seventy-six breast cancer survivors in New Engl and ( Mage = 55.6 years ; Mtime since diagnosis = 1.1 years ) were r and omized to 1 of the 2 groups . At baseline , 12 weeks ( postintervention ) , and at 24 weeks , participants wore an accelerometer for 7 days , were interviewed about their PA , and reported their motivational readiness for PA . RESULTS Adjusted , mixed-effects longitudinal regression models showed significant group differences favoring the PA plus RTR group in minutes of moderate to vigorous PA at 12 weeks ( Mdifference = 103 min/week , p < .001 ) and at 24 weeks ( Mdifference = 34.7 min/week , p = .03 ) . Results were corroborated with significant group differences in accelerometer data favoring the PA plus RTR group at both time points . CONCLUSION Peer volunteers were able to significantly increase PA among cancer survivors relative to contact control . Partnerships with existing volunteer programs can help to widen the reach of behavioral interventions among cancer survivors . ( PsycINFO Data base [22920808] Background : Physical inactivity is associated with obesity and type 2 diabetes . A key obstacle to physical activity is lack of motivation . Although some interactive exercise games ( i.e. , exergames — video games that require physical exertion in order to play ) motivate players to exercise more , few games take advantage of group dynamics to motivate players ' duration of exercise . In a test of the Kohler motivation gain effect , this study varied the ability level of a virtually presented partner in an interactive exergame that focused on abdominal strength to identify effects on a subject 's ( S ' ) persistence with the task . Method : Male ( n = 63 ) and female ( n = 72 ) undergraduate students were r and omly assigned to one of four conditions ( individual control or low- , moderate- , or high- partner discrepancy ) in a conditions x gender factorial design and tested on a series of isometric abdominal exercises using PlayStation 2 EyeToy : Kinetic software . They performed the first series of five exercises alone ( trial block 1 ) , and after a rest period , those in the partner conditions performed remaining trials ( trial block 2 ) with a same-sex virtually presented partner whom they could observe during their performance , while those in the individual control condition performed the remaining trials alone . In the partner conditions , the partner 's performance was manipulated to be always better than the S 's , the exact difference depending on the discrepancy condition . The partnered tasks were conjunctive ; that is , success in the game depended on the performance of the weaker team member . Persistence , the outcome measure for this study , consisted of the total number of seconds the S held the exercise position . Results : Using planned orthogonal contrasts on difference scores between blocks 1 and 2 , results showed that persistence was significantly ( p < .001 ) greater in all experimental conditions with a virtually presented partner ( M = 33.59 s ) than in the individual control condition ( M = −49.04 s ) . Subjects demonstrated more persistence in the moderate-discrepancy condition ( M = 51.36 s ) than in the low-discrepancy condition ( M = 22.52 s ) or the high-discrepancy condition ( M = 26.89 s ) . A significant quadratic trend confirmed the expected inverted-U function relating partner discrepancy and persistence ( p = .025 ) . Although Ss persisted longer and had higher heart rate in partnered conditions , they did not perceive their exertion to be any higher than those in the individual condition . Conclusions : Virtually presented partners who are moderately more capable than participants are the most effective at improving persistence in exergame tasks [21553972] OBJECTIVE Older adults have low rates of physical activity participation , but respond positively to telephone-mediated support programs . Programs are often limited by reliance on professional staff . This study tested telephone-based physical activity advice delivered by professional staff versus trained volunteer peer mentors . DESIGN A 12-month , r and omized , controlled clinical trial was executed from 2003 - 2008 . Twelve volunteer peer mentors and 181 initially inactive adults ages 50 years and older were recruited from the San Francisco Bay Area . Participants were r and omized to : ( 1 ) telephone-based physical activity advice delivered by professional staff , ( 2 ) telephone-based physical activity advice delivered by trained volunteer peers , or ( 3 ) an attention-control arm of staff-delivered telephone support for nutrition . MAIN OUTCOME MEASURES Moderate-intensity or more vigorous physical activity ( MVPA ) was assessed at baseline , 6 , and 12 months with the Community Healthy Activities Model Program for Seniors ( CHAMPS ) Question naire , with accelerometry validation ( Actigraph ) in a r and omly selected sub sample . Treatment fidelity was examined through analysis of quantity and quality of intervention delivery . RESULTS At 6 and 12 months , both physical activity arms significantly increased MVPA relative to the control arm . Both physical activity arms were comparable in quantity of intervention delivery , but peers demonstrated more versatility and comprehensiveness in quality of intervention content . CONCLUSIONS This study demonstrates that trained peer volunteers can effectively promote physical activity increases through telephone-based advice . The results support a program delivery model with good dissemination potential for a variety of community setting [15288394] & NA ; This study tested the separate and combined effects of spouse‐assisted pain coping skills training ( SA‐CST ) and exercise training ( ET ) in a sample of patients having persistent osteoarthritic knee pain . Seventy‐two married osteoarthritis ( OA ) patients with persistent knee pain and their spouses were r and omly assigned to : SA‐CST alone , SA‐CST plus ET , ET alone , or st and ard care ( SC ) . Patients in SA‐CST alone , together with their spouses , attended 12 weekly , 2‐h group sessions for training in pain coping and couples skills . Patients in SA‐CST+ET received spouse‐assisted coping skills training and attended 12‐weeks supervised ET . Patients in the ET alone condition received just an exercise program . Data analyses revealed : ( 1 ) physical fitness and strength : the SA‐CST+ET and ET alone groups had significant improvements in physical fitness compared to SA‐CST alone and patients in SA‐CST+ET and ET alone had significant improvements in leg flexion and extension compared to SA‐CST alone and SC , ( 2 ) pain coping : patients in SA‐CST+ET and SA‐CST alone groups had significant improvements in coping attempts compared to ET alone or SC and spouses in SA‐CST+ET rated their partners as showing significant improvements in coping attempts compared to ET alone or SC , and ( 3 ) self‐efficacy : patients in SA‐CST+ET reported significant improvements in self‐efficacy and their spouses rated them as showing significant improvements in self‐efficacy compared to ET alone or SC . Patients receiving SA‐CST+ET who showed increased self‐efficacy were more likely to have improvements in psychological disability . An intervention that combines spouse‐assisted coping skills training and exercise training can improve physical fitness , strength , pain coping , and self‐efficacy in patients suffering from pain due to osteoarthritis [22468716] OBJECTIVE The research tested the efficacy of planning and partner-based interventions to promote physical activity over six months . METHOD Local government ( council ) employees ( N = 257 ) were r and omly allocated to one of four conditions ( collaborative implementation intentions ; partner-only ; implementation intentions ; control group ) before completing measures at baseline and follow-ups at 1 , 3 and 6 months . Outcome measures comprised vali date d self-report measures of physical activity : the international physical activity question naire ( IPAQ ; Craig et al. , 2003 ) and self-report walking and exercise tables ( SWET ; Prestwich et al. , 2012 ) ; psychosocial mediators ( enjoyment , intention , self-efficacy , social influence ) ; weight and waist size ( baseline and 6 months only ) . RESULTS As well as losing the most weight , there was evidence that participants in the collaborative implementation-intention group were more physically active than each of the other three groups at 1- , 3- and 6-month follow-ups . Those in the implementation-intention and partner-only conditions did not outperform the control group on most measures . CONCLUSION Collaborative implementation intentions represent a potentially useful intervention to change important health behaviors that help reduce weight [24584818] This study evaluated spouse health behavior outcomes from a r and omized controlled trial of a spouse-assisted lifestyle intervention to reduce patient low-density lipoprotein cholesterol and improve patient health behaviors . Participants were 251 spouses of patients from the Durham Veterans Affairs Medical Center r and omized to intervention or usual care . The intervention comprised 9 monthly telephone calls to patients and spouses . Outcomes were assessed at baseline , 6 and 11 months . At 11 months , there were no differences in spouse outcomes between intervention and usual care groups for moderate intensity physical activity ( i.e. , frequency , duration ) or dietary intake ( i.e. , total calories , total fat , percentage of calories from total fat , saturated fat , percentage of calories from saturated fat , cholesterol , fiber ) . To improve spouse outcomes , couple interventions may need to include spouse behavior change goals and reciprocal support between patients and spouses and consider the need for improvement in spouse outcomes [16277142] Objective : This r and omized controlled trial tested the efficacy of an internetbased lifestyle behavior modification program for weight management in African-American girls . Design : African-American girls were r and omly assigned to an interactive behavioral internet program or an internet health education program , the control condition . The behavioral intervention included internet counseling and was highly interactive . The control intervention was a passive ( non-interactive ) educational program . Parents were also participants in the study . Participants in both treatment groups met in face-to-face sessions on four occasions over the first 12 weeks of a 6-month intervention . Subjects : The study enrolled 57 African-American adolescent girls ( ages 11 to 15 years ) who were overweight or obese and had at least one biological parent who was obese [ body mass index ( BMI ) > 30 kg/m2 ] . Of the 57 participants , 50 ( 88 % ) completed the 6-month trial . Measurements : Outcome data , including BMI , body weight , body composition , dietary intake , and weight loss behaviors were collected at baseline and 6-months later . A computer server tracked utilization of the websites . Participation in the program was measured by number of “ hits ” on the website . Results : Compared to the control condition , adolescents in the behavioral treatment lost more body fat ( group difference = 1.6 % body fat ) and parents lost significantly more body weight ( group difference = 2.1 kg ) . Utilization of the behavioral website by adolescents and parents was associated with positive outcome . Dietary fat intake was lowered for adolescents and parents in the behavioral treatment group . Conclusion : An internet-based behavioral intervention was superior to internet-based health education and yielded decreased body fat for adolescent girls and decreased body weight for parents [28070770] Purpose The purpose of this study was to assess the feasibility , acceptability , and impact of a ballroom dance intervention on improving quality of life ( QOL ) and relationship outcomes in cancer survivors and their partners . Methods We conducted a pilot r and omized controlled trial with two arms ( Restoring Health in You ( and Your Partner ) through Movement , RHYTHM ) : ( 1 ) immediate dance intervention and ( 2 ) delayed intervention ( wait-list control ) . The intervention consisted of 10 private weekly dance lessons and 2 practice parties over 12 weeks . Main outcomes were physical activity ( Godin Leisure-Time Exercise Question naire ) , functional capacity ( 6 Minute Walk Test ) , QOL ( SF-36 ) , Couples ’ trust ( Dyadic Trust Scale ) , and other dyadic outcomes . Exit interviews were completed by all participating couples . Results Thirty-one women survivors ( 68 % breast cancer ) and their partners participated . Survivors were 57.9 years old on average and 22.6 % African American . Partners had similar characteristics . RHYTHM had significant positive effects on physical activity ( p = 0.05 ) , on the mental component of QOL ( p = 0.04 ) , on vitality ( p = 0.03 ) , and on the dyadic trust scale ( p = 0.04 ) . Couples expressed satisfaction with the intervention including appreciating the opportunity to spend time and exercise together . Survivors saw this light-intensity physical activity as easing them into becoming more physically active . Conclusions Light intensity ballroom dancing has the potential to improve cancer survivors ’ QOL . Larger trials are needed to build strong support for this ubiquitous and acceptable activity . Implication s for cancer survivorsBallroom dance may be an important tool for cancer survivors to return to a physically active life and improve QOL and other aspects of their intimate life [19928484] Purpose . To test effects of parent/child training design ed to increase calcium intake , bone-loading physical activity ( PA ) , and bone density . Design . Two-group r and omized controlled trial . Setting . Family-based intervention delivered at research center . Subjects . 117 healthy children aged 10–13 years ( 58.1 % female , 42.7 % Hispanic , 40.2 % White ) . Ninety-seven percent of participants had at least one parent graduate from high school and 37.2 % had at least one parent graduate from a 4-year university . Intervention . Children and parents were r and omly assigned to diet and exercise ( experimental ) or injury prevention ( control ) interventions . Children were taught in eight weekly classes how to engage in bone-loading PA and eat calcium-rich foods or avoid injuries . Parents were taught behavior management techniques to modify children 's behaviors . Measures . Measures at baseline and at 3 , 9 , and 12 months included 24-hour diet and PA recalls , and bone mineral density ( BMD ) by dual-energy x-ray absorptiometry . Analysis . Analysis of variance and generalized estimating equations ( GEE ) assessed group by time differences . Comparisons were conducted separately for boys and girls . Results . For boys , cross-sectional differences between experimental and control groups were achieved for 3- and 9-month calcium intake ( 1352 vs. 1052 mg/day , 1298 vs. 970 mg/day , p < .05 ) . For girls , marginal cross-sectional differences were achieved for high-impact PA at 12 months ( p < .10 ) . For calcium intake , a significant group by time interaction was observed from pretest to posttest for the full sample ( p = .008 ) and for girls ( p = .006 ) but not for boys . No significant group by time differences in calcium were observed across the follow-up period . No group by time differences were observed for high-impact PA . Among boys , longitudinal group by time differences reached significance for total hip BMD ( p = .045 ) and femoral neck BMD ( p = .033 ) , even after adjusting for skeletal growth . Similar differential increases were observed among boys for bone mineral content ( BMC ) at the hip ( p = .068 ) and total body ( p = .054 ) regions . No significant group by time interaction effects were observed for girls at any bone site for BMD . For BMC , control girls showed a significant increase ( p = .03 ) in spine BMC compared to intervention girls . Conclusion . This study demonstrated that parent/preteen training can increase calcium intake and attenuate the decline in high-impact PA . Results suggest that more powerful interventions are needed to increase activity levels and maximize bone mineral accrual during preadolescent years [15264973] Obese children were r and omly assigned to a family-based behavioral treatment that included either stimulus control or reinforcement to reduce sedentary behaviors . Significant and equivalent decreases in sedentary behavior and high energy density foods , increases in physical activity and fruits and vegetables , and decreases in st and ardized body mass index ( z- BMI ) were observed . Children who substituted active for sedentary behaviors had significantly greater z- BMI changes at 6 ( -1.21 vs. -0.76 ) and 12 ( -1.05 vs. -0.51 ) months , respectively . Substitution of physically active for sedentary behaviors and changes in activity level predicted 6- and 12-month z- BMI changes . Results suggest stimulus control and reinforcing reduced sedentary behaviors are equivalent ways to decrease sedentary behaviors , and behavioral economic relationships in eating and activity may mediate the effects of treatment [23498969] Shaping network members into sources of support for healthy eating and exercise behaviors may be an effective strategy to enhance obesity treatment outcomes . This pilot study examined the feasibility and preliminary efficacy of a behavioral weight loss intervention adapted for Latinas with a social network component . Twenty-seven Latinas ( 43.0±10.2 years and body mass index 36.9±5.7 ) participated in a 24-week r and omized controlled intervention study . Participants attended group-based treatment either individually ( Individual Lifestyle Group [ ILG ] ) or with a weight loss partner selected from their existing network ( Partner Lifestyle Group [ PLG ] ) . Repeated measures analysis of variance was conducted to compare ILG and PLG participants on changes in weight or psychosocial variables . Participants in both intervention groups attended 70 % of treatment sessions ; 96 % and 100 % completed assessment at post-treatment ( 12 weeks ) and follow-up ( 24 weeks ) , respectively . Significant weight loss ( P<0.01 ) was achieved at post-treatment ( ILG -4.7±4.2 kg and PLG -4.3±4.4 kg ) and follow-up ( ILG -5.0±6.4 kg and PLG -4.7±5.0 kg ) , with nearly 50 % of participants losing at least 5 % of initial body weight . Both groups also experienced increased self-efficacy for weight loss ( P<0.01 ) , self-efficacy for exercise ( P=0.02 ) , and family social support for exercise habits ( P=0.01 ) . There were no significant differences between groups . Results from this study suggest a behavioral weight loss intervention for Latinas is feasible , but there is less support for the efficacy of weight loss partners [14559955] CONTEXT Exercise training for patients with Alzheimer disease combined with teaching caregivers how to manage behavioral problems may help decrease the frailty and behavioral impairment that are often prevalent in patients with Alzheimer disease . OBJECTIVE To determine whether a home-based exercise program combined with caregiver training in behavioral management techniques would reduce functional dependence and delay institutionalization among patients with Alzheimer disease . DESIGN , SETTING , AND PATIENTS R and omized controlled trial of 153 community-dwelling patients meeting National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer Disease and Related Disorders Association criteria for Alzheimer disease , conducted between June 1994 and April 1999 . INTERVENTIONS Patient-caregiver dyads were r and omly assigned to the combined exercise and caregiver training program , Reducing Disability in Alzheimer Disease ( RDAD ) , or to routine medical care ( RMC ) . The RDAD program was conducted in the patients ' home over 3 months . MAIN OUTCOME MEASURES Physical health and function ( 36-item Short-Form Health Survey 's [ SF-36 ] physical functioning and physical role functioning subscales and Sickness Impact Profile 's Mobility subscale ) , and affective status ( Hamilton Depression Rating Scale and Cornell Depression Scale for Depression in Dementia ) . RESULTS At 3 months , in comparison with the routine care patients , more patients in the RDAD group exercised at least 60 min/wk ( odds ratio [ OR ] , 2.82 ; 95 % confidence interval [ CI ] , 1.25 - 6.39 ; P = .01 ) and had fewer days of restricted activity ( OR , 3.10 ; 95 % CI , 1.08 - 8.95 ; P<.001 ) . Patients in the RDAD group also had improved scores for physical role functioning compared with worse scores for patients in the RMC group ( mean difference , 19.29 ; 95 % CI , 8.75 - 29.83 ; P<.001 ) . Patients in the RDAD group had improved Cornell Depression Scale for Depression in Dementia scores while the patients in the RMC group had worse scores ( mean difference , -1.03 ; 95 % CI , -0.17 to -1.91 ; P = .02 ) . At 2 years , the RDAD patients continued to have better physical role functioning scores than the RMC patients ( mean difference , 10.89 ; 95 % CI , 3.62 - 18.16 ; P = .003 ) and showed a trend ( 19 % vs 50 % ) for less institutionalization due to behavioral disturbance . For patients with higher depression scores at baseline , those in the RDAD group improved significantly more at 3 months on the Hamilton Depression Rating Scale ( mean difference , 2.21 ; 95 % CI , 0.22 - 4.20 ; P = .04 ) and maintained that improvement at 24 months ( mean difference , 2.14 ; 95 % CI , 0.14 - 4.17 ; P = .04 ) . CONCLUSION Exercise training combined with teaching caregivers behavioral management techniques improved physical health and depression in patients with Alzheimer disease [21838569] OBJECTIVE To describe the impact of a parent-led , family-focused child weight management program on the food intake and activity patterns of pre-pubertal children . METHODS An assessor-blinded , r and omized controlled trial involving 111 ( 64 % female ) overweight , pre-pubertal children 6 - 9 years of age r and omly assigned to parenting-skills training plus intensive diet and activity education ( P + DA ) , parenting-skills training alone ( P ) , or a 12-month wait-listed control ( WLC ) . Study outcomes were assessed at baseline , 6 months , and 12 months . This paper presents data on food intake assessed via a vali date d 54-item parent-completed dietary question naire and activity behaviours assessed via a parent-report 20-item activity question naire . RESULTS Intake of energy-dense nutrient-poor foods was lower in both intervention groups at 6 months ( mean difference , P + DA - 1.5 serves [ CI - 2.0 ; -1.0 ] ; P - 1.0 serves [ -2.0 ; -0.5 ] ) and 12 months ( mean difference P + DA - 1.0 serves [ CI - 2.0 ; -0.5 ] ; P - 1.0 serves [ - 1.5 ; 0.0 ] ) compared to baseline . Intake of vegetables , fruit , breads and cereals , meat and alternatives and dairy foods remained unchanged . Regardless of study group there were significant reductions over time in the reported time spent engaged in small screen activities and an increase in the time reported spent in active play . CONCLUSION A child weight management intervention that promotes food intake in line with national dietary guidelines achieves a reduction in children 's intake of energy-dense , nutrient-poor foods . This was achieved without compromising intake of nutrient-rich food and changes were maintained even once the intervention ceased [25161168] Background . The family and home environment is an influential antecedent of childhood obesity . The purpose of this study was to pilot test The Enabling Mothers to Prevent Pediatric Obesity through Web-Based Education and Reciprocal Determinism ( EMPOWER ) intervention ; a newly developed , theory-based , online program for prevention of childhood obesity . Method . The two-arm , parallel group , r and omized , participant-blinded trial targeted mothers with children between 4 and 6 years of age . Measures were collected at baseline , 4 weeks , and 8 weeks to evaluate programmatic effects on constructs of social cognitive theory ( SCT ) and obesity-related behaviors . Process evaluation transpired concurrently with each intervention session . Results . Fifty-seven participants were r and omly assigned to receive either experimental EMPOWER ( n = 29 ) or active control Healthy Lifestyles ( n = 28 ) intervention . Significant main effects were identified for child physical activity , sugar-free beverage consumption , and screen time , indicating that both groups improved in these behaviors . A significant group-by-time interaction was detected for child fruit and vegetable ( FV ) consumption as well as the SCT construct of environment in the EMPOWER cohort . An increase of 1.613 cups of FVs ( 95 % confidence interval = [ 0.698 , 2.529 ] ) was found in the experimental group , relative to the active control group . Change score analysis found changes in the home environment accounted for 31.4 % of the change in child FV intake for the experimental group . Conclusions . Child physical activity , sugar-free beverage consumption , and screen time improved in both groups over the course of the trial . Only the theory-based intervention was efficacious in increasing child FV consumption . The EMPOWER program was robust for inducing change in the home environment leading to an increase in child FV intake ( Cohen ’s f = 0.160 ) [23146744] OBJECTIVE This r and omized controlled trial evaluated the effectiveness of a telephone-delivered , spouse-assisted lifestyle intervention to reduce patient LDL-C. METHOD From 2007 to 2010 , 255 out patients with LDL-C>76 mg/dL and their spouses from the Durham Veterans Affairs Medical Center were r and omized to intervention or usual care . The intervention comprised nine monthly goal - setting telephone calls to patients and support planning calls to spouses . Outcomes were assessed at 11 months . RESULTS Patients were 95 % male and 65 % White . LDL-C did not differ between groups ( mean difference = 2.3 mg/dL , 95 % CI = -3.6 , 8.3 , p = 0.44 ) , nor did the odds of meeting goal LDL-C ( OR = 0.95 , 95 % CI = 0.6 , 1.7 ; p = 0.87 ) . Intakes of calories ( p = 0.03 ) , total fat ( p = 0.02 ) , and saturated fat ( p = 0.02 ) were lower for the intervention group . Cholesterol and fiber intake did not differ between groups ( p = 0.11 and 0.26 , respectively ) . The estimated rate of moderate intensity physical activity per week was 20 % higher in the intervention group ( IRR = 1.2 , 95 % CI = 1.0 , 1.5 , p = 0.06 ) . Most participants did not experience a change in cholesterol medication usage during the study period in the intervention ( 71.7 % ) and usual care ( 78.9 % ) groups . CONCLUSION This intervention might be an adjunct to usual primary care to improve adherence to lifestyle behaviors [21807446] In this study , we investigated the role of dyadic planning for health-behavior change . Dyadic planning refers to planning health-behavior change together with a partner . We assumed that dyadic planning would affect the implementation of regular pelvic-floor exercise ( PFE ) , with other indicators of social exchange and self-regulation strategies serving as mediators . In a r and omized-controlled trial at a German University Medical Center , 112 prostatectomy- patients with partners were r and omly assigned to a dyadic PFE-planning condition or one of three active control conditions . Question naire data were assessed at multiple time points within six months post-surgery , measuring self-reported dyadic PFE-planning and pelvic-floor exercise as primary outcomes and social exchange ( support , control ) and a self-regulation strategy ( action control ) as mediating mechanisms . There were no specific intervention effects with regard to dyadic PFE-planning or pelvic-floor exercise , as two active control groups also showed increases in either of these variables . However , results suggested that patients instructed to plan dyadically still benefited from self-reported dyadic PFE-planning regarding pelvic-floor exercise . Cross-sectionally , received negative control from partners was negatively related with PFE only in control groups and individual action control mediated between self-reported dyadic PFE-planning and PFE for participants instructed to plan PFE dyadically . Longitudinally , action control mediated between self-reported dyadic PFE-planning and pelvic-floor exercise for all groups . Findings provide support for further investigation of dyadic planning in health-behavior change with short-term mediating effects of behavior-specific social exchange and long-term mediating effects of better self-regulation [26652029] PURPOSE Studies have found disparities in psychological distress between lesbian and gay cancer survivors and their heterosexual counterparts . Exercise and partner support are shown to reduce distress . However , exercise interventions have n't been delivered to lesbian and gay survivors with support by caregivers included . METHODS In this pilot r and omized controlled trial ( RCT ) , ten lesbian and gay and twelve heterosexual survivors and their caregivers were r and omized as dyads to : Arm 1 , a survivor-only , 6-week , home-based , aerobic and resistance training program ( EXCAP © ® ) ; or Arm 2 , a dyadic version of the same exercise program involving both the survivor and caregiver . Psychological distress , partner support , and exercise adherence , were measured at baseline and post-intervention ( 6 weeks later ) . We used t-tests to examine group differences between lesbian/gay and heterosexual survivors and between those r and omized to survivor-only or dyadic exercise . RESULTS Twenty of the twenty-two recruited survivors were retained post-intervention . At baseline , lesbian and gay survivors reported significantly higher depressive symptoms ( P = .03 ) and fewer average steps walked ( P = .01 ) than heterosexual survivors . Post-intervention , these disparities were reduced and we detected no significant differences between lesbian/gay and heterosexual survivors . Participation in dyadic exercise result ed in a significantly greater reduction in depressive symptoms than participation in survivor-only exercise for all survivors ( P = .03 ) . No statistically significant differences emerged when looking across arm ( survivor-only vs. dyadic ) by subgroup ( lesbian/gay vs. heterosexual ) . CONCLUSION Exercise may be efficacious in ameliorating disparities in psychological distress among lesbian and gay cancer survivors , and dyadic exercise may be efficacious for survivors of diverse sexual orientations . Larger trials are needed to replicate these findings [27421075] RATIONALE Engaging in regular physical activity requires substantial self-regulatory effort such as action control ( e.g. , continuously monitoring and evaluating an ongoing behavior with regard to one 's st and ards ) . OBJECTIVE The present study examined the effectiveness of an ecological momentary action control intervention for promoting daily physical activity . Also , we tested whether a dyadic compared to an individual intervention displayed an additional benefit . METHODS 121 overweight and obese individuals and their partners were r and omly allocated to an intervention ( n = 60 ; information + action control text messages ) or a control group ( n = 61 ; information only ) . The intervention was delivered in a dyadic vs. individual version of action control . Allocation ratio was 1:1:2 for the dyadic , individual , and control groups , respectively . Daily physical activity was assessed with triaxial accelerometers during a 14-day intervention phase and a 14-day follow-up phase . RESULTS Participants in the intervention group showed a higher probability ( 36.5 % ) to achieve the recommended daily activity levels ( ≥30 min of moderate-to-vigorous physical activity per day performed in bouts of at least 10 min ) during the intervention and follow-up phase compared to those in the control group ( 23.0 % ) . The intervention and control group did not differ in terms of daily moderate-to-vigorous physical activity ( 40.7 vs. 38.6 min per day , p = 0.623 ) . CONCLUSION Interventions facilitating action control via text messages seem to be an effective tool for increasing adherence to physical activity guidelines in everyday life . The comparable effects for the dyadic and individual intervention suggest that automated text messages may be just as effective as personalized messages from the romantic partner . Further investigation is needed to examine the usefulness of a dyadic conceptualizing of action control . ( controlled-trials.com IS RCT N15705531 ) [28705312] BACKGROUND Among patients with coronary artery disease ( CAD ) , improvement of lifestyle-related risk factors ( LRFs ) reduces cardiovascular morbidity and mortality . However , modification of LRFs is highly challenging . OBJECTIVES This study sought to evaluate the impact of combining community-based lifestyle programs with regular hospital-based secondary prevention . METHODS The authors performed a r and omized controlled trial of nurse-coordinated referral of patients and their partners to 3 widely available community-based lifestyle programs , in 15 hospitals in the Netherl and s. Patients admitted for acute coronary syndrome and /or revascularization , with ≥1 LRF ( body mass index > 27 kg/m2 , self-reported physical inactivity , and /or smoking ) were included . All patients received guideline -based usual care . The intervention was based on 3 lifestyle programs for weight reduction , increasing physical activity , and smoking cessation . The primary outcome was the proportion of success at 12 months , defined as improvement in ≥1 qualifying LRF using weight ( ≥5 % reduction ) , 6-min-walking distance ( ≥10 % improvement ) , and urinary cotinine ( 200 ng/ml detection limit ) without deterioration in the other 2 . RESULTS The authors r and omized 824 patients . Complete data on the primary outcome were available in 711 patients . The proportion of successful patients in the intervention group was 37 % ( 133 of 360 ) compared with 26 % ( 91 of 351 ) in the control group ( p = 0.002 ; risk ratio : 1.43 ; 95 % confidence interval : 1.14 to 1.78 ) . In the intervention group , partner participation was associated with a significantly greater success rate ( 46 % vs. 34 % ; p = 0.03 ) . CONCLUSIONS Among patients with coronary artery disease , nurse-coordinated referral to a comprehensive set of community-based , widely available lifestyle interventions , with optional partner participation , leads to significant improvements in LRFs . ( RESPONSE-2 : R and omised Evaluation of Secondary Prevention by Outpatient Nurse SpEcialists 2 ; NTR3937 ) [22215470] Background Community-based interventions are needed to reduce the burden of childhood obesity . Purpose To evaluate the impact of a multi-level promotora-based ( Community Health Advisor ) intervention to promote healthy eating and physical activity and prevent excess weight gain among Latino children . Methods Thirteen elementary schools were r and omized to one of four intervention conditions : individual/family level ( Family-only ) , school/community level ( Community-only ) , combined ( Family + Community ) , or a measurement-only condition . Participants were 808 Latino parents and their children enrolled in kindergarten through 2nd grade . Measures included parent and child body mass index ( BMI ) and a self-administered parent survey that assessed several parent and child behaviors . Results There were no significant intervention effects on children ’s BMI z-score . The family intervention changed several obesity-related child behaviors ( e.g. , fruit/vegetable consumption ) and these were mediated by changes in parenting variables ( e.g. , parent monitoring ) . Conclusion A promotora-based behavioral intervention was efficacious at changing parental factors and child obesity-related health behaviors Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: Background Two-thirds of people living with dementia live at home in the UK and many experience distressing behavioural and psychological symptoms . This systematic review evaluates the effectiveness of non-pharmacological interventions for behavioural and psychological symptoms among community-dwelling people living with dementia . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

28573757

[11823669] Background and Purpose — A new gait training strategy for patients with stroke seeks to increase walking speed through treadmill training . This study compares the effects of structured speed-dependent treadmill training ( STT ) ( with the use of an interval paradigm to increase the treadmill speed stepwise according to principles of sport physiology ) with limited progressive treadmill training ( LTT ) and conventional gait training ( CGT ) on clinical outcome measures for patients with hemiparesis . Methods — Sixty ambulatory poststroke patients were each r and omly selected to receive 1 of the 3 different gait therapies : 20 subjects were treated with STT , 20 subjects were trained to walk on a treadmill with a 20 % increase of belt speed over the treatment period ( LTT ) , and 20 subjects were treated with CGT . Treatment outcomes were assessed on the basis of overground walking speed , cadence , stride length , and Functional Ambulation Category scores . Results — After a 4-week training period , the STT group scored significantly higher than the LTT and CGT groups for overground walking speed ( STT versus LTT , P < 0.001 ; STT versus CGT , P < 0.001 ) , cadence ( STT versus LTT , P = 0.007 ; STT versus CGT , P < 0.001 ) , stride length ( STT versus LTT , P < 0.001 ; STT versus CGT , P < 0.001 ) , and Functional Ambulation Category scores ( STT versus LTT , P = 0.007 ; STT versus CGT , P < 0.001 ) . Conclusions — Structured STT in poststroke patients result ed in better walking abilities than LTT or CGT . This gait training strategy provides a dynamic and integrative approach for the treatment of gait dysfunction after stroke [11935055] Background and Purpose — This study compared the psychometric properties of 3 clinical balance measures , the Berg Balance Scale ( BBS ) , the Balance subscale of the Fugl-Meyer test ( FM-B ) , and the Postural Assessment Scale for Stroke Patients ( PASS ) , in stroke patients with a broad range of neurological and functional impairment from the acute stage up to 180 days after onset . Methods — One hundred twenty-three stroke patients were followed up prospect ively with the 3 balance measures 14 , 30 , 90 , and 180 days after stroke onset ( DAS ) . Reliability ( interrater reliability and internal consistency ) and validity ( concurrent validity , convergent validity , and predictive validity ) of each measure were examined . A comparison of the responsiveness of each of the 3 measures was made on the basis of the entire group of patients and 3 separate groups classified by degree of neurological severity . Results — The FM-B and BBS showed a significant floor or ceiling effect at some DAS points , whereas the PASS did not show these effects . The BBS , FM-B , and PASS all had good reliability and validity for patients at different recovery stages after stroke . The results of effect size demonstrated fair to good responsiveness of all 3 measures within the first 90 DAS but , as expected , only a low level of responsiveness at 90 to 180 DAS . The PASS was more responsive to changes in severe stroke patients at the earliest period after stroke onset , 14 to 30 DAS . Conclusions — All 3 measures tested showed very acceptable levels of reliability , validity , and responsiveness for both clinicians and research ers . The PASS showed slightly better psychometric characteristics than the other 2 measures [25790018] Background Increased therapy has been linked to improvements in functional ability of people with stroke . Aim To determine the effectiveness of two alternative models of increased physiotherapy service delivery ( seven-day week therapy or group circuit class therapy five days a week ) to usual care . Method Three-armed r and omized controlled trial with blinded assessment of outcome . People admitted with a diagnosis of stroke , previously independently ambulant and with a moderate level of disability were recruited . ‘ Usual care ’ was individual physiotherapy provided five-days a week . Seven-day week therapy was usual care physiotherapy provided seven-days a week . Participants in the circuit class therapy arm of the trial received physiotherapy in group circuit classes in two 90-min sessions , five-days a week . Primary outcome was distance walked on the six-minute walk test at four-weeks post-r and omization . Results Two hundred eighty-three participants were r and omized ; primary outcome data were available for 259 ( 92 % ) . In the seven-day arm participants received an additional three hours of physiotherapy and thosein the circuit class armanadditional 22 h. There were no significant between-group differences at four-weeks in walking distance ( P = 0·72 ) . Length of stay was shorter for seven-day ( mean difference −2·9 days , 95 % confidence interval −17·9 to 12·0 ) and circuit class participants ( mean difference −9·2 days , 95 % confidence interval −24·2 to 5·8 ) compared to usual care , but this was not significant . Conclusions Both seven-day therapy and group circuit class therapy increased physiotherapy time , but walking outcomes were equivalent to usual care [11552192] OBJECTIVES To identify the most responsive method of measuring gait speed , to estimate the responsiveness of other outcome measures , and to determine whether gait speed predicts discharge destination in acute stroke . DESIGN A prospect i ve cohort study . SETTING Five acute-care hospitals . PATIENTS Fifty subjects with residual gait deficits after a first-time stroke . INTERVENTIONS Five- ( 5mWT ) and 10-meter walk tests ( 10mWT ) at comfortable and maximum speeds , with 2 evaluations conducted an average + /- st and ard deviation ( SD ) of 8 + /- 3 and 38 + /- 5 days poststroke . MAIN OUTCOME MEASURE St and ardized response mean ( SRM = mean change/SD of change ) was used to estimate responsiveness for each walk test , the Berg Balance Scale , the Barthel Index , the Stroke Rehabilitation Assessment of Movement ( STREAM ) , and the Timed Up and Go ( TUG ) . RESULTS The SRMs were 1.22 and 1.00 for the 5mWT , and .92 and .83 for the 10mWT performed at a comfortable and maximum pace , respectively . The SRMs for the Berg Balance Scale , the Barthel Index , the STREAM , and the TUG were 1.04,.99,.89 , and .73 , respectively . The probability of discharge to a rehabilitation center for persons walking at < or = 0.3 m/s or > 0.6 m/s at the first evaluation was.95 and .22 , respectively . CONCLUSIONS The 5mWT at a comfortable pace is recommended as the measure of choice for clinicians and research ers who need to detect longitudinal change in walking disability in the first 5 weeks poststroke [14988574] Background and Purpose — One way that stroke units may improve outcome is by reducing complications of immobility through early mobilization ; however , this intervention needs testing . The purpose of this study was to determine the physical activity patterns of stroke patients managed within acute stroke units as a first step in developing an early mobilization protocol . Methods — We recruited 64 patients within 14 days after stroke from 5 metropolitan stroke units and observed them for 2 consecutive days at 10-minute intervals between the hours of 8 am and 5 pm . At each observation , we ascertained physical activity , location , and other person(s ) present . Therapists recorded therapy details . Results — The 58 patients who completed the study had a mean age of 71.3 years . Stroke severity ranged from mild ( National Institutes of Health Stroke Scale score , 1 ) to severe ( score , 27 ) , and mean time after stroke at observation was 5.6 days ( range , 0 to 13 days ) . Only 9 patients were restricted to bed . During the therapeutic day , patients spent > 50 % resting in bed , 28 % sitting out of bed , and only 13 % engaged in activities with the potential to prevent complications and improve recovery of mobility . Patients were alone > 60 % of the time . Conclusions — This is the first multicenter study of physical activity early after stroke . We believe the next step is to conduct a r and omized controlled trial to evaluate the effect of increased levels of physical activity early after stroke compared with current st and ards of care [24856940] QUESTION Do people with stroke spend more time in active task practice during circuit class therapy sessions versus individual physiotherapy sessions ? Do people with stroke practise different tasks during circuit class therapy sessions versus individual physiotherapy sessions ? DESIGN Prospect i ve , observational study . PARTICIPANTS Twenty-nine people with stroke in inpatient rehabilitation setting s. INTERVENTIONS Individual therapy sessions and circuit class therapy sessions provided within a larger r and omised controlled trial . OUTCOME MEASURES Seventy-nine therapy sessions were video-recorded and the footage was analysed for time spent engaged in various categories of activity . In a sub sample of 28 videos , the number of steps taken by people with stroke per therapy session was counted . RESULTS Circuit class therapy sessions were of a longer duration ( mean difference 38.0minutes , 95 % CI 29.9 to 46.1 ) , and participants spent more time engaged in active task practice ( mean difference 23.8minutes , 95 % CI 16.1 to 31.4 ) compared with individual sessions . A greater percentage of time in circuit class therapy sessions was spent practising tasks in sitting ( mean difference 5.3 % , 95 % CI 2.4 to 8.2 ) and in sit-to-st and practice ( mean difference 2.7 % , 95 % CI 1.4 to 4.1 ) , and a lower percentage of time in walking practice ( mean difference 19.1 % , 95 % CI 10.0 to 28.1 ) compared with individual sessions . PARTICIPANTS took an average of 371 steps ( SD 418 ) during therapy sessions and this did not differ significantly between group and individual sessions . CONCLUSION People with stroke spent more time in active task practice , but a similar amount of time in walking practice when physiotherapy was offered in circuit class therapy sessions versus individual therapy sessions . There is a need for effective strategies to increase the amount of walking practice during physiotherapy sessions for people after stroke [20719820] Objective : To investigate the feasibility and the effects on gait of a high intensity task-oriented training , incorporating a high cardiovascular workload and large number of repetitions , in patients with subacute stroke , when compared to a low intensity physiotherapy-programme . Design and subjects : R and omized controlled clinical trial : Forty-four patients with stroke were recruited at 2 to 8 weeks after stroke onset . Measures : Maximal gait speed assessed with the 10-metre timed walking test ( 10MTWT ) , walking capacity assessed with the six-minute walk test ( 6MWT ) . Control of st and ing balance assessed with the Berg Balance Scale and the Functional Reach test . Group differences were analysed using a Mann — Whitney U-test . Results : Between-group analysis showed a statistically significant difference in favour of the high intensity task-oriented training in performance on the 10MTWT ( Z = -2.13 , P = 0.03 ) and the 6MWT ( Z = -2.26 , P = 0.02 ) . No between-group difference were found for the Berg Balance Scale ( Z = —0.07 , P = 0.45 ) and the Functional Reach test ( Z = —0.21 , P = 0.84 ) . Conclusion : A high-intensity task-oriented training programme design ed to improve hemiplegic gait and physical fitness was feasible in the present study and the effectiveness exceeds a low intensity physiotherapy-programme in terms of gait speed and walking capacity in patients with subacute stroke . In a future study , it seems appropriate to additionally use measures to evaluate physical fitness and energy expenditure while walking [15179638] OBJECTIVE To evaluate the effect of an 8-week , water-based exercise program ( experimental group ) with that of an upper-extremity function program ( control group ) to increase cardiovascular fitness within a community setting for people with stroke . DESIGN Single-blind r and omized controlled trial . SETTING Public community center . PARTICIPANTS A volunteer sample of 12 community-dwelling people with stroke with mild to moderate residual motor deficits . INTERVENTION Study subjects participated in group exercise programs for 1 hour , 3 times a week for 8 weeks . The experimental group exercised in chest-deep water at targeted heart rates . The control group performed arm and h and exercises while sitting . Main outcome measures The primary outcome measure was cardiovascular fitness ( V(O2)max ) . Secondary measures were maximal workload , muscle strength , gait speed , and the Berg Balance Scale score . RESULTS The experimental group attained significant improvements over the control group in cardiovascular fitness , maximal workload , gait speed , and paretic lower-extremity muscle strength . The relatively short program ( 8 wk ) of water-based exercise result ed in a 22 % improvement in cardiovascular fitness in a small group of people with stroke who had relatively high function . CONCLUSIONS A water-based exercise program undertaken as a group program may be an effective way to promote fitness in people with stroke [22544817] Background . Exercise interventions can enhance mobility after stroke as well as prevent falls in elderly persons . Objective . Investigate whether an exercise intervention can enhance mobility , prevent falls , and increase physical activity among community-dwelling people after stroke . Method . A r and omized trial with blinding of physical outcome assessment was conducted through local stroke clubs . Both groups , on average 5.9 years poststroke , received exercise classes , advice , and a home program for 12 months . The experimental group ( EG ) program ( n = 76 ) aim ed to improve walking , prevent falls and increase physical activity . The control group ( CG ) program ( n = 75 ) aim ed to improve upper-limb and cognitive functions . The primary outcomes were walking capacity , walking speed measured before and after the intervention , and fall rates monitored monthly . Results . At 12 months , the EG walked 34 m further in 6 minutes ( 95 % confidence interval [ CI ] = 19 - 50 ; P < .001 ) and 0.07 m/s faster over 10 m ( 95 % CI = 0.01 - 0.14 ; P = .03 ) than the CG . The EG had 129 falls , and the CG had 133 . There were no differences in proportion of fallers ( relative risk = 1.22 ; 95 % CI = 0.91 - 1.62 ; P = .19 ) or the rate of falls between groups ( incidence rate ratio = 0.96 ; 95 % CI = 0.59 - 1.51 ; P = .88 ) . Conclusion . The experimental intervention delivered through stroke clubs enhanced aspects of mobility but had no effect on falls [12473421] BACKGROUND In an 18-month exercise intervention in previously sedentary older women ( 40 - 65 years ) , we examined whether an initial 6 months of supervised exercise leads to greater long-term retention and adherence to regular physical activity than an unsupervised home-based program and whether these outcomes are influenced by the exercise intensity . METHODS Women ( N = 126 ) were recruited from the community and r and omly assigned to either center-based or home-based exercise three times/week . The center-based group attended supervised sessions for 6 months , while after 10 initial sessions the home-based group exercised at home . After 6 months both groups were home-based for a further 12 months . Within each arm , subjects were further r and omized to exercise at either moderate or vigorous intensity . RESULTS The center-based group had higher retention than the home-based ( 97 , 94 , 81 versus 87 , 76 , and 61 % ) at 6 , 12 , and 18 months , respectively ( P < 0.05 ) . At 6 months , adherence was higher in the center-based group ( 84 versus 63 % , P < 0.001 ) and energy expenditure was higher at 6 ( P < 0.05 ) and 12 ( P < 0.01 ) months . At 18 months , retention was higher with moderate exercise ( P < 0.05 ) , while adherence was similar with both intensities . CONCLUSION An initial 6 months of center-based exercise enhanced retention in both the short and the long term and promoted short-term adherence and energy expenditure . Long-term , moderate exercise retained more subjects , but had little influence on adherence [3349299] Objective To analyse the effect of task oriented circuit training compared with usual physiotherapy in terms of self reported walking competency for patients with stroke discharged from a rehabilitation centre to their own home . Design R and omised controlled trial with follow-up to 24 weeks . Setting Multicentre trial in nine outpatient rehabilitation centres in the Netherl and s Participants Patients with stroke who were able to walk a minimum of 10 m without physical assistance and were discharged from inpatient rehabilitation to an outpatient rehabilitation clinic . Patients were r and omly allocated to circuit training or usual physiotherapy , after stratification by rehabilitation centre , with an online r and omisation procedure . Intervention Patients in the intervention group received circuit training in 90 minute sessions twice a week for 12 weeks . The training included eight different workstations in a gym and was intended to improve performance in tasks relating to walking competency . The control group received usual outpatient physiotherapy . Main outcome measures The primary outcome was the mobility domain of the stroke impact scale ( SIS , version 3.0 ) . Secondary outcomes were st and ing balance , self reported abilities , gait speed , walking distance , stair climbing , instrumental activities of daily living , fatigue , anxiety , and depression . Differences between groups were analysed according to the intention to treat principle . All outcomes were assessed by blinded observers in a repeated measurement design lasting 24 weeks . Results 126 patients were included in the circuit training group and 124 in the usual care group ( control ) , with data from 125 and 117 , respectively , available for analysis . One patient from the circuit training group and seven from the control group dropped out . Circuit training was a safe intervention , and no serious adverse events were reported . There were no significant differences between groups for the stroke impact scale mobility domain ( β=0.05 ( SE 0.68 ) , P=0.943 ) at 12 weeks . Circuit training was associated with significantly higher scores in terms of gait speed ( 0.09 m/s ( SE 0.02 ) , P<0.001 ) , walking distance ( 20.0 m ( SE 7.4 ) , P=0.007 ) , and modified stairs test ( −1.6 s ( SE 0.7 ) , P=0.015 ) . There were no significant differences between groups for the other secondary outcomes , except for the leisure domain of the Nottingham extended activities of daily living and the memory and thinking domain of the stroke impact scale . With the exception of gait speed ( −0.04 m/s ( SE 0.02 ) , P=0.040 ) , there were no significant differences between groups at follow-up . Conclusion Task oriented circuit training can safely replace usual physiotherapy for patients with stroke who are discharged from inpatient rehabilitation to the community and need further training in gait and gait related activities as an outpatient . Trial registration Dutch Trial Register ( NTR1534 ) [15293485] Objective : To evaluate the efficacy of a task-orientated intervention in enhancing competence in walking in people with stroke . Design : Two-centre observer-blinded stratified block-r and omized controlled trial . Setting : General community . Subjects : Between May 2000 and February 2003 , 91 individuals with a residual walking deficit within one year of a first or recurrent stroke consented to participate . Interventions : The experimental intervention comprised 10 functional tasks design ed to strengthen the lower extremities and enhance walking balance , speed and distance . The control intervention involved the practice of upper extremity activities . Subjects in both groups attended sessions three times a week for six weeks . Main measures : Six-minute walk test ( SMWT ) , 5-m walk ( comfortable and maximum pace ) , Berg Balance Scale , timed ‘ up and go ’ . Results : At baseline , subjects in the experimental ( n = 44 ) and control ( n = 47 ) groups walked an average distance of 209 m ( SD = 126 ) and 204 m ( SD = 131 ) , respectively , on the SMWT . Mean improvements of 40 m ( SD = 72 ) , and 5 m ( SD = 66 ) were observed following the experimental and control interventions , respectively . The between-group difference was 35 m ( 95 % confidence interval ( CI ) 7 , 64 ) . Significant between-group effects of 0.21 m/s ( 95 % CI 0.12 , 0.30 ) and of 0.11 m/s ( 95 % CI 0.03 , 0.19 ) in maximum and comfortable walking speed , respectively , were observed . People with a mild , moderate or severe walking deficit at baseline improved an average of 36 ( SD = 96 ) , 55 ( SD = 56 ) and 18 m ( SD = 23 ) , respectively , in SMWT performance following the experimental intervention . Conclusions : Study findings support the efficacy of a task-orientated intervention in enhancing walking distance and speed in the first year post stroke , particularly in people with moderate walking deficits [10527076] OBJECTIVE To evaluate the impact of a program of muscle strengthening and physical conditioning on impairment and disability in chronic stroke subjects . DESIGN A r and omized pretest and posttest control group , followed by a single-group pretest and posttest design . SUBJECTS Thirteen community-dwelling stroke survivors of at least 9 months . INTERVENTION A 10-week ( 3 days/week ) program consisting of a warm-up , aerobic exercises , lower extremity muscle strengthening , and a cool-down . MAIN OUTCOME MEASURES Peak isokinetic torque of the major muscle groups of the affected lower limb , quadriceps and ankle plantarflexor spasticity , gait speed , rate of stair climbing , the Human Activity Profile ( HAP ) , and the Nottingham Health Profile ( NHP ) were recorded twice for the treatment group and three times for the control group . RESULTS Significant improvements were found for all the selected outcome measures ( HAP , NHP , and gait speed ) for the treatment group ( p < .001 ) . In terms of overall training effects , the 13 subjects demonstrated increases in strength of the affected major muscle groups , in HAP and NHP profiles , and in gait speed and rate of stair climbing without concomitant increases in either quadriceps or ankle plantarflexor spasticity . CONCLUSIONS The 10-week combined program of muscle strengthening and physical conditioning result ed in gains in all measures of impairment and disability . These gains were not associated with measurable changes of spasticity in either quadriceps or ankle plantarflexors [5025604] Background Stroke rehabilitation in low- and middle-income countries , such as Mexico , is often hampered by lack of clinical re sources and funding . To provide a cost-effective solution for comprehensive post-stroke rehabilitation that can alleviate the need for one-on-one physical or occupational therapy , in lower and upper extremities , we proposed and implemented a technology-assisted rehabilitation gymnasium in Chihuahua , Mexico . The Gymnasium for Robotic Rehabilitation ( Robot Gym ) consisted of low- and high-tech systems for upper and lower limb rehabilitation . Our hypothesis is that the Robot Gym can provide a cost- and labor-efficient alternative for post-stroke rehabilitation , while being more or as effective as traditional physical and occupational therapy approaches . Methods A typical group of stroke patients was r and omly allocated to an intervention ( n = 10 ) or a control group ( n = 10 ) . The intervention group received rehabilitation using the devices in the Robot Gym , whereas the control group ( n = 10 ) received time-matched st and ard care . All of the study subjects were subjected to 24 two-hour therapy sessions over a period of 6 to 8 weeks . Several clinical assessment s tests for upper and lower extremities were used to evaluate motor function pre- and post-intervention . A cost analysis was done to compare the cost effectiveness for both therapies . Results No significant differences were observed when comparing the results of the pre-intervention Mini-mental , Brunnstrom Test , and Geriatric Depression Scale Test , showing that both groups were functionally similar prior to the intervention . Although , both training groups were functionally equivalent , they had a significant age difference . The results of all of the upper extremity tests showed an improvement in function in both groups with no statistically significant differences between the groups . The Fugl-Meyer and the 10 Meters Walk lower extremity tests showed greater improvement in the intervention group compared to the control group . On the Time Up and Go Test , no statistically significant differences were observed pre- and post-intervention when comparing the control and the intervention groups . For the 6 Minute Walk Test , both groups presented a statistically significant difference pre- and post-intervention , showing progress in their performance . The robot gym therapy was more cost-effective than the traditional one-to-one therapy used during this study in that it enabled therapist to train up to 1.5 to 6 times more patients for the approximately same cost in the long term . Conclusions The results of this study showed that the patients that received therapy using the Robot Gym had enhanced functionality in the upper extremity tests similar to patients in the control group . In the lower extremity tests , the intervention patients showed more improvement than those subjected to traditional therapy . These results support that the Robot Gym can be as effective as traditional therapy for stroke patients , presenting a more cost- and labor-efficient option for countries with scarce clinical re sources and funding .Trial registration IS RCT N98578807 [24148695] Background and aims Cardiovascular co-morbidities are prevalent after stroke , with heart disease , hypertension and impaired glucose tolerance present in the majority of cases . Exercise has the potential to mediate cardiovascular risk factors commonly present in people with stroke . This single-blinded r and omized controlled trial compared the effects of high versus low intensity exercise on fitness , cardiovascular risk factors , and cardiac function after stroke . Methods Fifty participants ( age 50–80 y , > 1 y post-stroke ) were r and omized to a high-intensity Aerobic Exercise ( AE ) or low-intensity non-aerobic Balance/Flexibility ( BF ) program ( 6 months , 3 60-min sessions/week ) . Outcomes assessed by VO2peak ( primary outcome ) , arterial stiffness , ambulatory capacity , hemodynamics and cardiac function using echocardiography , and lipid , glucose and homocysteine levels . Assessors were blinded to group allocation . Results Twenty-three ( 92 % ) of 25 AE group participants ( withdrawals unrelated to the intervention ) and all BF group participants completed the program . One BF group participant experienced 2 non-injurious falls during class . No other adverse events occurred . There were no changes in VO2peak in either group ( AE 16·9 ±7 to 17·4 ± 7 ml•kg−1•min−1 vs. BF 16·9 ±6 to 16·6 ± 5 ml•kg−1•min−1 , P = 0·45 ) , but AE group demonstrated greater improvement in right atrial emptying fraction ( AE 30 ± 22 to 37 ± 22 % vs. BF 35 ± 20 to 31 ± 20 % , P = 0·04 ) . Both groups demonstrated improvements in lipid profiles , glucose and homocysteine levels , and ambulatory capacity ( P < 0·04 ) . Conclusions This was the first study to examine the effects of aerobic exercise after stroke on cardiovascular hemodynamics . High-intensity exercise improved right-sided function and early myocardial relaxation . Low-intensity exercise may also benefit plasma lipid , glucose and inflammatory markers , and ambulatory capacity . This study is an important step towards underst and ing mechanisms by which exercise may reduce cardiovascular risk and function [16696738] OBJECTIVES To estimate the magnitude of small meaningful and substantial individual change in physical performance measures and evaluate their responsiveness . DESIGN Secondary data analyses using distribution- and anchor-based methods to determine meaningful change . SETTING Secondary analysis of data from an observational study and clinical trials of community-dwelling older people and subacute stroke survivors . PARTICIPANTS Older adults with mobility disabilities in a strength training trial ( n=100 ) , subacute stroke survivors in an intervention trial ( n=100 ) , and a prospect i ve cohort of community-dwelling older people ( n=492 ) . MEASUREMENTS Gait speed , Short Physical Performance Battery ( SPPB ) , 6-minute-walk distance ( 6MWD ) , and self-reported mobility . RESULTS Most small meaningful change estimates ranged from 0.04 to 0.06 m/s for gait speed , 0.27 to 0.55 points for SPPB , and 19 to 22 m for 6MWD . Most substantial change estimates ranged from 0.08 to 0.14 m/s for gait speed , 0.99 to 1.34 points for SPPB , and 47 to 49 m for 6MWD . Based on responsiveness indices , per-group sample sizes for clinical trials ranged from 13 to 42 for substantial change and 71 to 161 for small meaningful change . CONCLUSION Best initial estimates of small meaningful change are near 0.05 m/s for gait speed , 0.5 points for SPPB , and 20 m for 6MWD and of substantial change are near 0.10 m/s for gait speed , 1.0 point for SPPB , and 50 m for 6MWD . For clinical use , substantial change in these measures and small change in gait speed and 6MWD , but not SPPB , are detectable . For research use , these measures yield feasible sample sizes for detecting meaningful change [16649886] BACKGROUND AND PURPOSE To facilitate optimal stroke rehabilitation , valid interpretation of observed functional recovery is required . The purpose of this study was to examine the longitudinal relationship between comfortable walking speed and Functional Ambulation Categories ( FAC ) scores for physically independent gait . SUBJECTS This study was a prospect i ve cohort study with 73 subjects who were severely affected by acute stroke . METHODS Functional Ambulation Categories classification and walking speed were measured between weeks 4 and 26 after stroke . The responsiveness of walking speed measurements for detecting clinical ly important speed changes was determined , and the longitudinal association between walking speed and FAC scores and its time dependency were established . This relationship subsequently was scrutinized for possible speed changes occurring within specific FAC scores . Responsiveness ratios , r and om coefficient analysis , paired Student t tests , and the Cohen kappa statistic were used for statistical analyses . RESULTS Responsiveness ratios exceeded the smallest detectable differences . R and om coefficient analysis demonstrated a significant between- and within-subject coefficient and a significant negative interaction between timing of measurements and FAC scores . Paired Student t tests revealed mostly significant pretest-posttest differences in walking speeds , and all kappa values for pretest-posttest FAC scores were significant . DISCUSSION AND CONCLUSION Walking speed measurements are sensitive for detecting clinical ly important changes . Functional Ambulation Categories scores are dependent on the timing of comfortable walking speed measurements after stroke . Moreover , there are indications that , in this relationship , repeated FAC appraisal s are not only based on steady walking speeds , but that the walking speeds related to a specific FAC appraisal also change and , over time , may shift gradually from higher to lower speeds [2736157] Background Most patients who suffer a stroke experience reduced walking competency and health-related quality of life ( HRQoL ) . A key factor in effective stroke rehabilitation is intensive , task-specific training . Recent studies suggest that intensive , patient-tailored training can be organized as a circuit with a series of task-oriented workstations . Primary aim of the FIT-Stroke trial is to evaluate the effects and cost-effectiveness of a structured , progressive task-oriented circuit class training ( CCT ) programme , compared to usual physiotherapeutic care during outpatient rehabilitation in a rehabilitation centre . The task-oriented CCT will be applied in groups of 4 to 6 patients . Outcome will be defined in terms of gait and gait-related ADLs after stroke . The trial will also investigate the generalizability of treatment effects of task-oriented CCT in terms of perceived fatigue , anxiety , depression and perceived HRQoL. Methods / design The multicentre single-blinded r and omized trial will include 220 stroke patients discharged to the community from inpatient rehabilitation , who are able to communicate and walk at least 10 m without physical , h and s-on assistance . After discharge from inpatient rehabilitation , patients in the experimental group will receive task-oriented CCT two times a week for 12 weeks at the physiotherapy department of the rehabilitation centre . Control group patients will receive usual individual , face-to-face , physiotherapy . Costs will be evaluated by having each patient keep a cost diary for the first 24 weeks after r and omisation . Primary outcomes are the mobility part of the Stroke Impact Scale ( SIS-3.0 ) and the EuroQol . Secondary outcomes are the other domains of SIS-3.0 , lower limb muscle strength , walking endurance , gait speed , balance , confidence not to fall , instrumental ADL , fatigue , anxiety , depression and HRQoL. Discussion Based on assumptions about the effect of intensity of practice and specificity of treatment effects , FIT-Stroke will address two key aims . The first aim is to investigate the effects of task-oriented CCT on walking competency and HRQoL compared to usual face-to-face physiotherapy . The second aim is to reveal the cost-effectiveness of task-oriented CCT in the first 6 months post stroke . Both aims were recently recommended as priorities by the American Hearth Association and Stroke Council . Trial registration This study is registered in the Dutch Trial Register as NTR1534 [16410482] BACKGROUND AND PURPOSE Little is known about the relative efficacy of supervised versus unsupervised community exercise programs for stroke survivors . This study compared the effectiveness of a 10-week supervised strengthening and conditioning program ( supervised ) with a 1-week supervised instruction program followed by a 9-week unsupervised home program ( unsupervised ) and evaluated retention of changes at 6 months and 1 year after program completion . METHODS Seventy-two subjects retained at baseline ( 27 women , 45 men ; mean+/-SD age , 64.6+/-11.8 years ) were r and omly allocated to receive the supervised or unsupervised program . The primary outcome was walking speed over 6 minutes , and secondary outcome measures were Human Activity Profile , Medical Outcome Study 36-Item Short-Form survey ( SF-36 ) , Physiological Cost Index , and lower extremity muscle strength . RESULTS The 6-minute walking speed increased significantly in both groups and remained significantly improved by 1 year . The Human Activity Profile demonstrated an increasing trend only in the supervised group that was significant by 1 year . The SF-36 Physical Component summary score increased significantly in the supervised group and remained improved by 1 year ; the unsupervised group showed significant improvement at 1 year . Women made greater gains in supervised programs , but men made greater gains in unsupervised programs . CONCLUSIONS Supervised exercise programs and unsupervised programs after initial supervised instruction were both associated with physical benefits that were retained for 1 year , although supervised programs showed trends to greater improvements in self-reported gains . Gender differences require further research [4755997] [ Purpose ] To investigate how task-oriented circuit training for the recovery motor control of the lower-extremity , balance and walking endurance could be clinical ly applied to subacute stroke inpatient group therapy . [ Subjects and Methods ] Twenty subacute stroke patients were r and omly assigned to the intervention group ( n=10 ) or the control group ( n=10 ) . The intervention consisted of a structured , progressive , inpatient circuit training program focused on mobility and gait training as well as physical fitness training that was performed for 90 minutes , 5 days a week for 4 weeks . The control group received individual physiotherapy of neurodevelopmental treatment for 60 minutes , 5 days a week for 4 weeks . Outcome measures were lower-extremity motor control , balance , gait endurance and activities of daily living before and after 4 weeks . [ Results ] There were no significant differences at baseline between the two groups . After 4 weeks , both groups showed significant improvements in all outcome measures , but there were no significant differences between the two groups during the invention period . [ Conclusion ] In spite of the small sample size , these findings suggest that task-oriented circuit training might be used as a cost-effective and alternative method of individual physiotherapy for the motor recovery of lower-extremity , balance and walking endurance of subacute stroke patients [2719587] Background Stroke is the most common disabling neurological condition in adults . Falls and poor mobility are major contributors to stroke-related disability . Falls are more frequent and more likely to result in injury among stroke survivors than among the general older population . Currently there is good evidence that exercise can enhance mobility after stroke , yet ongoing exercise programs for general community-based stroke survivors are not routinely available . This r and omised controlled trial will investigate whether exercise can reduce fall rates and increase mobility and physical activity levels in stroke survivors . Methods and design Three hundred and fifty community dwelling stroke survivors will be recruited . Participants will have no medical contradictions to exercise and be cognitively and physically able to complete the assessment s and exercise program . After the completion of the pre-test assessment , participants will be r and omly allocated to one of two intervention groups . Both intervention groups will participate in weekly group-based exercises and a home program for twelve months . In the lower limb intervention group , individualised programs of weight-bearing balance and strengthening exercises will be prescribed . The upper limb/cognition group will receive exercises aim ed at management and improvement of function of the affected upper limb and cognition carried out in the seated position . The primary outcome measures will be falls ( measured with 12 month calendars ) and mobility . Secondary outcome measures will be risk of falling , physical activity levels , community participation , quality of life , health service utilisation , upper limb function and cognition . Discussion This study aims to establish and evaluate community-based sustainable exercise programs for stroke survivors . We will determine the effects of the exercise programs in preventing falls and enhancing mobility among people following stroke . This program , if found to be effective , has the potential to be implemented within existing community services . Trial registration The protocol for this study is registered with the Australian New Zeal and Clinical Trials Registry ( ACTRN12606000479505 ) [4932078] [ Purpose ] The purpose of this study was to analyze the effects of task-oriented circuit training on the balance ability and gait endurance of chronic stroke in patients . [ Subjects and Methods ] The participants were 30 patients who had stroke > 6 months previously , result ing in a disability such as hemiparesis . The participants were r and omly divided into the group task-oriented circuit training group and the individual task-oriented circuit-training group . They performed eight types of modified task-oriented training . Balance ability and gait endurance were measured by using the Berg balance scale question naire and the 6-min walk test , respectively , before and after the experiment . [ Results ] Significant differences were observed between before and after the intervention in all variables . There was a significant difference between groups in Berg balance scale scores ; however , no significant differences were seen in the timed up and go test and the 6-min walk test . [ Conclusion ] The results of this study indicated that group exercise can better improve the balance ability of chronic stroke in patients after stroke than can individualized exercise intervention [2956448] Abstract The aim of the study was to evaluate the impact of a high-intensive exercise program containing high-intensive functional exercises implemented to real-life situations together with group discussion s on falls and security aspects in stroke subjects with risk of falls . This was a pre-specified secondary outcome for this study . For evaluation , Short Form-36 ( SF-36 ) health-related quality of life ( HRQoL ) and the Geriatric Depression Scale-15 ( GDS-15 ) were used . This was a single-center , single-blinded , r and omized , controlled trial . Consecutive ≥55 years old stroke patients with risk of falls at 3–6 months after first or recurrent stroke were r and omized to the intervention group ( IG , n=15 ) or to the control group ( CG , n=19 ) who received group discussion with focus on hidden dysfunctions but no physical fitness training . The 5-week high-intensive exercise program was related to an improvement in the CG in the SF-36 Mental Component Scale and the Mental Health subscale at 3 months follow-up compared with baseline values while no improvement was seen in the IG at this time . For the SF-36 Physical Component Scale , there was an improvement in the whole study group at 3 and 6 months follow-up compared with baseline values without any significant changes between the IG and CG . The GDS-15 was unchanged throughout the follow-up period for both groups . Based on these data , it is concluded that high-intensive functional exercises implemented in real-life situations should also include education on hidden dysfunctions after stroke instead of solely focus on falls and safety aspects to have a favorable impact on [15743283] OBJECTIVES To determine the effect of two different community-based group exercise programs on functional balance , mobility , postural reflexes , and falls in older adults with chronic stroke . DESIGN A r and omized , clinical trial . SETTING Community center . PARTICIPANTS Sixty-one community-dwelling older adults with chronic stroke . INTERVENTION Participants were r and omly assigned to an agility ( n=30 ) or stretching/weight-shifting ( n=31 ) exercise group . Both groups exercised three times a week for 10 weeks . MEASUREMENTS Participants were assessed before , immediately after , and 1 month after the intervention for Berg Balance , Timed Up and Go , step reaction time , Activities-specific Balance Confidence , and Nottingham Health Profile . Testing of st and ing postural reflexes and induced falls evoked by a translating platform was also performed . In addition , falls in the community were tracked for 1 year from the start of the interventions . RESULTS Although exercise led to improvements in all clinical outcome measures for both groups , the agility group demonstrated greater improvement in step reaction time and paretic rectus femoris postural reflex onset latency than the stretching/weight-shifting group . In addition , the agility group experienced fewer induced falls on the platform . CONCLUSION Group exercise programs that include agility or stretching/weight shifting exercises improve postural reflexes , functional balance , and mobility and may lead to a reduction of falls in older adults with stroke [3922602] Background Given the rising number of strokes worldwide , and the large number of individuals left with disabilities after stroke , novel strategies to reduce disability , increase functions in the motor and the cognitive domains , and improve quality of life are of major importance . Physical activity is a promising intervention to address these challenges but , as yet , there is no study demonstrating definite outcomes . Our objective is to assess whether additional treatment in the form of physical fitness-based training for patients early after stroke will provide benefits in terms of functional outcomes , in particular gait speed and the Barthel Index ( co- primary outcome measures ) reflecting activities of daily living ( ADL ) . We will gather secondary functional outcomes as well as mechanistic parameters in an exploratory approach . Methods / Design Our phase III r and omised controlled trial will recruit 215 adults with moderate to severe limitations of walking and ADL 5 to 45 days after stroke onset . Participants will be stratified for the prognostic variables of “ centre ” , “ age ” , and “ stroke severity ” , and r and omly assigned to one of two groups . The interventional group receives physical fitness training delivered as supported or unsupported treadmill training ( cardiovascular active aerobic training ; five times per week , over 4 weeks ; each session 50 minutes ; total of 20 additional physical fitness training sessions ) in addition to st and ard rehabilitation treatment . The control intervention consists of relaxation sessions ( non-cardiovascular active ; five times per week week , over 4 weeks ; each session 50 minutes ) in addition to st and ard rehabilitation treatment . Co- primary efficacy endpoints will be gait speed ( in m/s , 10 m walk ) and the Barthel Index ( 100 points total ) at 3 months post-stroke , compared to baseline measurements . Secondary outcomes include st and ard measures of quality of life , sleep and mood , cognition , arm function , maximal oxygen uptake , and cardiovascular risk factors including blood pressure , pulse , waist-to-hip ratio , markers of inflammation , immunity and the insulin-glucose pathway , lipid profile , and others . Discussion The goal of this endpoint-blinded , phase III r and omised controlled trial is to provide evidence to guide post-stroke physical fitness-based rehabilitation programmes , and to eluci date the mechanisms underlying this intervention . Trial registration Registered in Clinical Trials.gov with the Identifier NCT01953549 [4460628] Background Currently , the key advocacy in neuroscientific studies for stroke rehabilitation is that therapy should be directed towards task specificity performed with multiple repetitions . Circuit Class Therapy ( CCT ) is well suited to accomplish multiple task-specific activities . However , while repetitive task practice is achievable with circuit class therapy , in stroke survivors repetitive activities may be affected by poor neurologic inputs to motor units , result ing in decreases in discharging rates which consequently may reduce the efficiency of muscular contraction . To accomplish multiple repetitions , stroke survivors may require augmented duration of practice . To date , no study has examined the effect of augmented duration of CCT in stroke rehabilitation , and specifically what duration of CCT is more effective in influencing functional capacity among stroke survivors . Methods / design Using a r and omised controlled trial with blinded outcome assessment , this study is aim ed at determining the effectiveness of structured augmented CCT in stroke rehabilitation . Sixty-eight stroke survivors ( to be recruited from a tertiary health institution in Kano , Northwest , Nigeria ) will be r and omised into one of four groups : three intervention groups of differing CCT duration s namely : 60 min , 90 min , and 120minuntes respectively , and a control group . Participants will take part in an 8-week structured intensive CCT intervention . Participants will be assessed at baseline , post-intervention , and six-month follow-up for the effectiveness of the varied duration s of therapy , using st and ardised tools . Based on the WHO-ICF model , the outcomes are body structure/function , activity limitation , and participation restriction measures . Discussion It is expected that the outcome of this study will clarify whether increasing CCT duration leads to better recovery of motor function in stroke survivors . Trial registration Pan African Clinical Trial Registry ( PACTR ) : [15574110] The purpose of this study was to investigate whether additional practice of either upper limb or mobility tasks improved functional outcome during inpatient stroke rehabilitation . This prospect i ve , r and omised , single blind clinical trial recruited 30 stroke subjects into either an Upper Limb or a Mobility Group . All subjects received their usual rehabilitation and an additional session of task-related practice using a circuit class format . Independent assessors , blinded to group allocation , tested all subjects . Outcome measures used were three items of the Jebsen Taylor H and Function Test ( JTHFT ) , two arm items of the Motor Assessment Scale ( MAS ) , and three mobility measures , the Timed Up and Go Test ( TUGT ) , Step Test , and Six Minute Walk Test ( 6MWT ) . Both groups improved significantly between pre- and post-tests on all of the mobility measures , however only the Upper Limb Group made a significant improvement on the JTHFT and MAS upper arm items . Following four weeks training , the Mobility Group had better locomotor ability than the Upper Limb Group ( between-group differences in the 6MWT of 116.4 m , 95 % CI 31.4 to 201.3 m , Step Test 2.6 repetitions , 95 % CI -1.0 to 6.2 repetitions , and TUGT -7.6 sec , 95 % CI -15.5 to 0.2 sec ) . The JTHFT dexterity scores in the Upper Limb Group were 6.5 sec ( 95 % CI -7.4 to 20.4 sec ) faster than the Mobility Group . Our findings support the use of additional task-related practice during inpatient stroke rehabilitation . The circuit class format was a practical and effective means to provide supervised additional practice that led to significant and meaningful functional gains [17141639] OBJECTIVE To evaluate the internal and absolute reliability and construct validity of the Activities-Specific Balance Confidence ( ABC ) scale and a new Canadian French version ( ABC-CF ) of it among people with stroke . DESIGN Cross-sectional data from a r and omized controlled trial . SETTING Community . PARTICIPANTS Ninety-one people with a residual walking deficit between 57 and 386 days poststroke . INTERVENTIONS Not applicable . MAIN OUTCOME MEASURES The ABC and ABC-CF scales , Berg Balance Scale ( BBS ) , comfortable and maximum gait speeds , Timed Up & Go ( TUG ) test , 6-minute walk test ( 6MWT ) , Barthel Index , physical function scale of the Medical Outcomes Study 36-Item Short-Form Health Survey , Geriatric Depression Scale ( GDS ) , and the EQ-5D visual analog scale ( EQ VAS ) . RESULTS Internal consistency ( Cronbach alpha ) was .94 and .93 and the st and ard error of measurement was 5.05 and 5.13 for the ABC ( n=51 ) and the ABC-CF ( n=35 ) scales , respectively . Spearman rho values ranged from .30 to .60 for the ABC scale and from .45 to .68 on the ABC-CF scale for associations with scores on the BBS , comfortable and maximum gait speeds , TUG , 6MWT , Barthel Index , physical function scale , GDS , and EQ VAS . CONCLUSIONS Evidence of internal and absolute reliability and of construct validity of the ABC and the ABC-CF scales supports their use for cross-sectional measurements of balance self-efficacy among community-dwelling people in the first year poststroke [4868212] [ Purpose ] The aim of this study was to investigate the impact of a circuit training program on the walking and balance abilities of stroke patients using an up-to- date walking analysis device . [ Subjects and Methods ] The subjects of this study were 12 adults who were diagnosed with stroke . Evaluation was conducted using the Smart Step test for walking ability ; ( BBS ) for balance ability ; and the Timed Up and Go test ( TUG ) for functional mobility and movement ability . The 12 stroke patients were r and omly recruited and divided into two groups ; an experimental group which performed circuit training with obstacles , and a control group which performed flat gait training ) . [ Results ] Between-group comparison of the change in the 10-m walking speed found a statistically significant difference between the two groups . Between-group comparison of the changes in BBS and TUG found statistically significant differences between the two groups . [ Conclusion ] The circuit training program using obstacles had a positive effect on the gait and balance abilities of the stroke patients [17678655] OBJECTIVE To compare the effectiveness of circuit class therapy and individual physiotherapy ( PT ) sessions in improving walking ability and functional balance for people recovering from stroke . DESIGN Nonr and omized , single-blind controlled trial . SETTING Medical rehabilitation ward of a rehabilitation hospital . PARTICIPANTS Sixty-eight persons receiving inpatient rehabilitation after a stroke . INTERVENTIONS Subjects received group circuit class therapy or individual treatment sessions as the sole method of PT service delivery for the duration of their inpatient stay . MAIN OUTCOME MEASURES Five-meter walk test ( 5MWT ) , two-minute walk test ( 2MWT ) , and the Berg Balance Scale ( BBS ) measured 4 weeks after admission . Secondary outcome measures included the Iowa Level of Assistance Scale , Motor Assessment Scale upper-limb items , and patient satisfaction . Measures were taken on admission and 4 weeks later . RESULTS Subjects in both groups showed significant improvements between admission and week 4 in all primary outcome measures . There were no significant between group differences in the primary outcome measures at week 4 ( 5MWT mean difference , .07 m/s ; 2MWT mean difference , 1.8 m ; BBS mean difference , 3.9 points ) . A significantly higher proportion of subjects in the circuit class therapy group were able to walk independently at discharge ( P=.01 ) and were satisfied with the amount of therapy received ( P=.007 ) . CONCLUSIONS Circuit class therapy appeared as effective as individual PT sessions for this sample of subjects receiving inpatient rehabilitation poststroke . Favorable results for circuit classes in terms of increased walking independence and patient satisfaction suggest this model of service delivery warrants further investigation [24982002] OBJECTIVE To compare the effect of a balance and stability-focused outpatient community-based rehabilitation and a regular physiotherapy program on balance , stability , and perceptions of improvement after acute stroke . DESIGN A r and omized controlled trial in a community-based therapy center . PARTICIPANTS Fifty consecutive patients with a first stroke , who reported to a community-based therapy center over a 7-month period were allocated to the control group ( regular physiotherapy ) or the experimental group ( balance and stability-focused rehabilitation ) . INTERVENTION A program of physiotherapy focused on balance and stability exercises . The control group received the regular physiotherapy program . MAIN OUTCOME MEASUREMENTS The Postural Assessment Scale for Stroke Patients ( PASS ) and the Berg Balance Scale ( BBS ) monitored stability and balance . The normalized data ( PASS and BBS ) were analyzed by using analysis of covariance . Qualitative data were thematically described . RESULTS Internal consistency of baseline PASS and BBS scores was high ( Cronbach α , .964 and .974 , respectively ) . PASS overall pretest scores increased from 21.96 ± 21.41 ( mean ± st and ard deviation ) and 21.52 ± 8.43 to 67.67 ± 28.42 and 80.16 ± 22.60 posttest in the control and experimental groups , respectively . Posttest scores were significantly different ( P = .004 ) . The effect size was medium ( .490 ) . The overall BBS scores showed overall mean ( st and ard deviation ) increases from 44.71 ± 22.24 and 43.43 ± 17.11 pretest to 48.71 ± 23.18 and 59.71 ± 18.20 posttest for the control and experimental groups , respectively . The effect size was considered medium ( .532 ) . CONCLUSION The balance and stability-focused community-based rehabilitation program was more effective in improving stability and balance in patients with stroke compared with the regular physiotherapy program in re source -poor setting [10768528] OBJECTIVE To evaluate the immediate and retention effects of a 4-week training program on the performance of locomotor-related tasks in chronic stroke . DESIGN R and omized , controlled pilot study with 2-month follow-up . SETTING Rehabilitation center . SUBJECTS A convenience sample consisting of 12 chronic stroke subjects was used . Subjects were r and omly assigned to the experimental or the control group . Three subjects withdrew from the study . INTERVENTION Both experimental and control groups participated in exercise classes three times a week for 4 weeks . The exercise class for the experimental group focused on strengthening the affected lower limb and practicing functional tasks involving the lower limbs , while the control group practice d upper-limb tasks . MAIN OUTCOME MEASURES Lower-limb function was evaluated by measuring walking speed and endurance , peak vertical ground reaction force through the affected foot during sit-to-st and , and the step test . RESULTS The experimental group demonstrated significant immediate and retained ( 2-month follow-up ) improvement ( p < or = .05 ) compared with the control group in walking speed and endurance , force production through the affected leg during sit-to-st and , and the number of repetitions of the step test . CONCLUSION The pilot study provides evidence for the efficacy of a task-related circuit class at improving locomotor function in chronic stroke [25357149] Objective The effects of combined aerobic and resistance exercise training on central arterial stiffness and gait velocity in patients with chronic poststroke hemiparesis were investigated . Design Twenty-six patients with chronic poststroke hemiparesis were r and omly assigned to either the combined aerobic and resistance exercise group ( n = 14 ) or the control group ( n = 12 ) . The exercise intervention group received a combined aerobic and resistance exercise training ( 1 hr/day , three times/week for 16 wks ) , whereas the control group received usual care . Central arterial stiffness was determined by pulse wave velocity and augmentation index . Gait velocity was assessed using the 6-min walk test , 10-m walk test , and the Timed Up- and -Go test . Results Patients in the exercise intervention group had greater improvement of mean pulse wave velocity ( P < 0.001 ) , augmentation index ( P = 0.048 ) , and gait velocity ( 6-min walk test , P < 0.001 ; 10-m walk test , P < 0.001 ) than did patients in the control group . Patients in the exercise intervention group also had greater improvements in physical fitness component ( grip strength , P < 0.001 ; muscular strength of upper and lower limbs , P < 0.027 ; flexibility , P < 0.001 ) when compared with control patients . Conclusions The combined aerobic and resistance exercise program significantly reduced central arterial stiffness and increased gait velocity in patients with chronic poststroke hemiparesis [16500170] OBJECTIVES To estimate the level of balance self-efficacy among community-dwelling subjects with stroke and to determine the relative importance of balance self-efficacy compared with functional walking capacity in predicting physical function and perceived health status . DESIGN Secondary analysis of baseline , postintervention , and 6-month follow-up data from a r and omized trial . SETTING General community . PARTICIPANTS Ninety-one subjects with a first or recurrent stroke , discharged from rehabilitation therapy with a residual walking deficit . INTERVENTIONS Not applicable . MAIN OUTCOME MEASURES The Activities-Specific Balance Confidence ( ABC ) Scale , Medical Outcomes Study 36-Item Short-Form Health Survey physical function scale , and the EQ-5D visual analog scale of perceived health status . RESULTS Average balance self-efficacy was 59 out of 100 points on the ABC scale ( 95 % confidence interval , 55 - 64 ; n=89 ) . After adjusting for age and sex , functional walking capacity explained 32 % and 0 % of the respective variability in physical function and perceived health status scores obtained 6 months later . After adjustment for age , sex , and functional walking capacity , balance self-efficacy explained 3 % and 19 % of variation in 6-month physical function and perceived health status scores , respectively . CONCLUSIONS Subjects living in the community after stroke experience impaired balance self-efficacy . Enhancing balance self-efficacy in addition to functional walking capacity may lead to greater improvement , primarily in perceived health status , but also in physical function , than the enhancement of functional walking capacity alone [20176772] Objectives : To explore whether a group programme for community-dwelling chronic stroke survivors and their carers is feasible in rural setting s ; to measure the impact of the programme on health-related quality of life and functional performance ; and to determine if any benefits gained are maintained . Design : R and omized , assessor blind , cross-over , controlled trial . Setting : Rural outpatient . Subjects : Twenty-five community-dwelling , chronic stroke survivors and 17 carers of participant stroke survivors . Intervention : The intervention group undertook a once-a-week , seven-week group programme combining physical activity , education , self-management principles and a ‘ healthy options ’ morning tea . At completion , the control group crossed over to receive the intervention . Main measures : Stroke Impact Scale ( stroke survivors ) , Health Impact Scale ( carers ) , Six Minute Walk Test , Timed Up and Go , Caregiver Strain Index . Results : There were insufficient participants for results to reach statistical significance . However between-group trends favoured the intervention group in the majority of outcome measures for stroke survivors and carers . The majority of measures remained above baseline at 12 weeks post programme for stroke survivor participants . The programme was well attended . Of the seven sessions all participants attended four or more and 88 % attended six or seven sessions . Conclusions : This novel programme incorporating physical activity , education and social interaction proved feasible to undertake by a stroke-specific multidisciplinary team in three rural Australian setting s. This programme may improve and maintain health-related quality of life and physical functioning for chronic stroke survivors and their carers and warrants further investigation [22111802] Rationale There is strong evidence for a dose – response relationship between physical therapy early after stroke and recovery of function . The optimal method of maximizing physical therapy within finite health care re sources is unknown . Aims To determine the effectiveness and cost-effectiveness of two alternative models of physical therapy service delivery ( seven-days per week therapy services or group circuit class therapy over five-days a week ) to usual care for people receiving inpatient rehabilitation after stroke . Design Multicenter , three-armed r and omized controlled trial with blinded assessment of outcomes . Study A total of 282 people admitted to inpatient rehabilitation facilities after stroke with an admission functional independence measure ( FIM ) score within the moderate range ( total 40–80 points or motor 38–62 points ) will be r and omized to receive one of three interventions : • usual care therapy over five-days a week • st and ard care therapy over seven-days a week , or • group circuit class therapy over five-days a week . Participants will receive the allocated intervention for the length of their hospital stay . Analysis will be by intention-to-treat . Outcomes The primary outcome measure is walking ability ( six-minute walk test ) at four-week postintervention with three- and six-month follow-up . Economic analysis will include a costing analysis based on length of hospital stay and staffing/re source costs and a cost-utility analysis ( incremental quality of life per incremental cost , relative to usual care ) . Secondary outcomes include walking speed and independence , ability to perform activities of daily living , arm function , quality of life and participant satisfaction [18240042] Purpose : To evaluate the impact of two different physiotherapy exercise regimes in patients after acute stroke on health-related quality of life ( HRQoL ) and to investigate how the degree of motor and balance function , gait capacity , activities of daily living and instrumental activities of daily living influenced HRQoL. Methods : A longitudinal r and omized controlled stratified trial of two interventions : the intensive exercise groups with scheduled intensive training during four periods of the first year after stroke and the regular exercise group with self-initiated training . Results : There was a tendency of better HRQoL in the regular exercise group on NHP total score ( p= 0.05 ) . Patients with low scores in activities of daily living , balance and motor function and inability to perform 6-minute walk test on admission , scored lower on self-perceived health than patients with high scores and ability to perform the walking test . At 1 year post-stroke , total scores on NHP were moderately associated with motor function ( r= −0.63 ) , balance ( r= −0.56 ) , gait ( r= −0.57 ) , activities of daily living ( r= −0.57 ) and instrumental activities of daily living ( r= −0.49–0.58 ) . The physical mobility sub-scale of NHP had the strongest association ranging from r= −0.47–0.82 . Conclusion : The regular exercise group with self-initiated training seemed to enhance HRQoL more than the intensive exercise group with scheduled intensive training . The degree of motor function , balance , walking capacity and independence in activities of daily living is of importance for perceived [27378733] BACKGROUND The cardiorespiratory fitness of stroke survivors is low . Center-based exercise programs that include an aerobic component have been shown to improve poststroke cardiorespiratory fitness . This pilot study aims to determine the feasibility , safety , and preliminary efficacy of an individually tailored home- and community-based exercise program to improve cardiorespiratory fitness and walking capacity in stroke survivors . METHODS Independently ambulant , community-dwelling stroke survivors were recruited . The control ( n = 10 ) and intervention ( n = 10 ) groups both received usual care . In addition the intervention group undertook a 12-week , individually tailored , home- and community-based exercise program , including once-weekly telephone or e-mail support . Assessment s were conducted at baseline and at 12 weeks . Feasibility was determined by retention and program participation , and safety by adverse events . Efficacy measures included change in cardiorespiratory fitness ( peak oxygen consumption [ VO2peak ] ) and distance walked during the Six-Minute Walk Test ( 6MWT ) . Analysis of covariance was used for data analysis . RESULTS All participants completed the study with no adverse events . All intervention participants reported undertaking their prescribed program . VO2peak improved more in the intervention group ( 1.17 ± .29 L/min to 1.35 ± .33 L/min ) than the control group ( 1.24 ± .23 L/min to 1.24 ± .33 L/min , between-group difference = .18 L/min , 95 % confidence interval [ CI ] : .01-.36 ) . Distance walked improved more in the intervention group ( 427 ± 123 m to 494 ± 67 m ) compared to the control group ( 456 ± 101 m to 470 ± 106 m , between-group difference = 45 m , 95 % CI : .3 - 90 ) . CONCLUSIONS Our individually tailored approach with once-weekly telephone or e-mail support was feasible and effective in selected stroke survivors . The 16 % greater improvement in VO2peak during the 6MWT achieved in the intervention versus control group is comparable to improvements attained in supervised , center-based programs [23093165] CONTEXT Most medical interventions have modest effects , but occasionally some clinical trials may find very large effects for benefits or harms . OBJECTIVE To evaluate the frequency and features of very large effects in medicine . DATA SOURCES Cochrane Data base of Systematic Review s ( CDSR , 2010 , issue 7 ) . STUDY SELECTION We separated all binary- outcome CDSR forest plots with comparisons of interventions according to whether the first published trial , a subsequent trial ( not the first ) , or no trial had a nominally statistically significant ( P < .05 ) very large effect ( odds ratio [ OR ] , ≥5 ) . We also sample d r and omly 250 topics from each group for further in-depth evaluation . DATA EXTRACTION We assessed the types of treatments and outcomes in trials with very large effects , examined how often large-effect trials were followed up by other trials on the same topic , and how these effects compared against the effects of the respective meta-analyses . RESULTS Among 85,002 forest plots ( from 3082 review s ) , 8239 ( 9.7 % ) had a significant very large effect in the first published trial , 5158 ( 6.1 % ) only after the first published trial , and 71,605 ( 84.2 % ) had no trials with significant very large effects . Nominally significant very large effects typically appeared in small trials with median number of events : 18 in first trials and 15 in subsequent trials . Topics with very large effects were less likely than other topics to address mortality ( 3.6 % in first trials , 3.2 % in subsequent trials , and 11.6 % in no trials with significant very large effects ) and were more likely to address laboratory-defined efficacy ( 10 % in first trials,10.8 % in subsequent , and 3.2 % in no trials with significant very large effects ) . First trials with very large effects were as likely as trials with no very large effects to have subsequent published trials . Ninety percent and 98 % of the very large effects observed in first and subsequently published trials , respectively , became smaller in meta-analyses that included other trials ; the median odds ratio decreased from 11.88 to 4.20 for first trials , and from 10.02 to 2.60 for subsequent trials . For 46 of the 500 selected topics ( 9.2 % ; first and subsequent trials ) with a very large-effect trial , the meta- analysis maintained very large effects with P < .001 when additional trials were included , but none pertained to mortality-related outcomes . Across the whole CDSR , there was only 1 intervention with large beneficial effects on mortality , P < .001 , and no major concerns about the quality of the evidence ( for a trial on extracorporeal oxygenation for severe respiratory failure in newborns ) . CONCLUSIONS Most large treatment effects emerge from small studies , and when additional trials are performed , the effect sizes become typically much smaller . Well-vali date d large effects are uncommon and pertain to nonfatal outcomes [20636719] Rationale Gait deficits contribute considerably to functional disability after stroke , and the regaining of walking ability is a major goal in most stroke rehabilitation programmes . Evidence suggests that muscular strengthening exercises after stroke can improve strength and activity . Additionally , task-related practice performed at high intensities may enhance walking competency in people with stroke . However , there is insufficient evidence to conclude which approach is most effective . Aim This study will test the hypothesis that task-specific walking training plus targeted strength training is superior to task-specific walking training alone in improving strength , motor co-ordination , quality of independent walking , and participation in acute stroke patients . Design This trial is a prospect i ve , r and omised clinical trial . People after stroke who are living at home and attending outpatient clinics will be r and omly allocated into either an experimental or a control group . The experimental group will undertake task-specific walking training , plus targeted strength training three times per week over 10 weeks , while the control group will only undertake task-specific walking training . At baseline , after 10 weeks of intervention and 4 weeks after the cessation of the interventions , allocation-blinded research ers will collect outcome measures . Study outcomes Primary outcomes will be measured for levels of impairment ( strength and co-ordination ) , activity ( quality of walking ) , and participation ( quality of life ) . Secondary outcomes will be the minimal clinical ly important differences of lower limb strength , motor co-ordination , and gait speed [25023152] Objective : Exercise has beneficial effects on vascular risk factors in transient ischaemic attack ( TIA ) patients within the sub-acute phase . This study examined whether TIA patients r and omized to an early exercise and education programme within 2 weeks of TIA diagnosis would demonstrate improvements in cardiovascular risk factors and aerobic fitness 12 months post-diagnosis compared with control patients . Methods : A single-centre , r and omized , parallel-group clinical trial . Sixty TIA patients ( 69 ± 11 years ) completed a vascular risk stratification baseline assessment and a physical fitness examination . Individuals were r and omized to either an 8-week early exercise and education group or control group . Fifty-one patients attended post-intervention assessment s that were completed immediately ( post-intervention ) and 12 months after ( 12PI ) . Results : A significantly greater improvement in resting SBP was observed between baseline and post-intervention for EX than for CON ( –11 mmHg cf . –1 mmHg , respectively ; P < 0.05 ) . The improvement in SBP was maintained between post-intervention and 12PI ( P > 0.05 ) . Similar findings were demonstrated for BMI , bodyweight and peak oxygen uptake ( P < 0.05 ) . Exercise blood pressure , pulse pressure and double product ( SBP x heart rate ; an indication of myocardial workload ) were significantly lower at post-intervention and 12PI for EX than for CON ( all P < 0.05 ) . Conclusion : An 8-week exercise programme soon after TIA result ed in beneficial changes in resting and exercise blood pressure that were maintained for 12 months . Clinical trial registration : http://www.anzctr.org.au/ Trial Registration Number : [16181164] OBJECTIVES To examine the effects of a community-based group exercise program for older individuals with chronic stroke . DESIGN Prospect i ve , single-blind , r and omized , controlled intervention trial . SETTING Intervention was community-based . Data collection was performed in a research laboratory located in a rehabilitation hospital . PARTICIPANTS Sixty-three older individuals ( aged > or = 50 ) with chronic stroke ( poststroke duration > or = 1 year ) who were living in the community . INTERVENTION Participants were r and omized into intervention group ( n=32 ) or control group ( n=31 ) . The intervention group underwent a fitness and mobility exercise ( FAME ) program design ed to improve cardiorespiratory fitness , mobility , leg muscle strength , balance , and hip bone mineral density ( BMD ) ( 1-hour sessions , three sessions/week , for 19 weeks ) . The control group underwent a seated upper extremity program . MEASUREMENTS Cardiorespiratory fitness ( maximal oxygen consumption ) , mobility ( 6-minute walk test ) , leg muscle strength ( isometric knee extension ) , balance ( Berg Balance Scale ) , activity and participation ( Physical Activity Scale for Individuals with Physical Disabilities ) , and femoral neck BMD ( using dual-energy x-ray absorptiometry ) . RESULTS The intervention group had significantly more gains in cardiorespiratory fitness , mobility , and paretic leg muscle strength than controls . Femoral neck BMD of the paretic leg was maintained in the intervention group , whereas a significant decline of the same occurred in controls . There was no significant time-by-group interaction for balance , activity and participation , nonparetic leg muscle strength , or nonparetic femoral neck BMD . CONCLUSION The FAME program is feasible and beneficial for improving some of the secondary complications result ing from physical inactivity in older adults living with stroke . It may serve as a good model of a community-based fitness program for preventing secondary diseases in older adults living with chronic conditions [14970978] OBJECTIVE To establish the test-retest reliability and concurrent validity with maximum oxygen consumption ( VO2max ) for 3 submaximal exercise tests in persons with chronic stroke : ( 1 ) submaximal treadmill test , ( 2 ) submaximal cycle ergometer test , and ( 3 ) 6-minute walk test ( 6MWT ) . DESIGN Prospect i ve study using a convenience sample . SETTING Free-st and ing tertiary rehabilitation center . PARTICIPANTS A volunteer sample of 12 community-dwelling individuals who had a stroke with moderate motor deficits . INTERVENTIONS Not applicable . MAIN OUTCOME MEASURES Heart rate , blood pressure , and oxygen consumption ( VO2 ) were assessed during the exercise tests . RESULTS Test-retest reliability was good to excellent for the exercise tests ( maximal and submaximal tests ) . VO2 for all submaximal measures related to VO2max ( r range , .66-.80 ) . Neither the 6MWT distance , self-selected gait speed , nor hemodynamic measures related to VO2max . CONCLUSION The VO2 measures of the submaximal exercise tests had excellent reliability and good concurrent validity with VO2max . Submaximal exercise tests may be a method by which to monitor the effects of interventions after a screening test ( eg , symptom-limited grade d exercise test , dobutamine stress echocardiograph ) [25483170] Stroke patients live with balance and walking dysfunction . Walking is the most important factor for independent community activities . The purpose of this study was to investigate the effect of a community walking training program ( CWTP ) within the real environment on walking function and social participation in chronic stroke patients . Twenty-two stroke patients ( 13 male , 50.45 years old , post stroke duration 231.64 days ) were r and omly assigned to either the CWTP group or the control group . All subjects participated in the same st and ard rehabilitation program consisting of physical and occupational therapy for 60 min per day , five times a week , for four weeks . In addition , the CWTP group participated in CWTP for 30 min per day , five times a week , for four weeks . Walking function was assessed using the 10-m walk test ( measurement for 10-meter walking speed ) , 6-min walk assessment ( measurement of gait length for 6-minutes ) , and community gait assessment . Social participation was assessed using a social participation domain of stroke impact scale . In walking function , greater improvement was observed in the CWTP group compared with the control group ( P < 0.05 ) . In addition , social participation improved more in the CWTP group compared with the control group ( P < 0.05 ) . These findings demonstrate the efficacy of CWTP on walking function and social participation in chronic stroke patients . Therefore , we suggest that CWTP within the real environment may be an effective method for improving walking function and social participation of chronic stroke patients when added to st and ard rehabilitation [11552860] The Berg Balance Scale ( BBS ) was design ed to help determine change in functional st and ing balance over time . The purpose of this paper was to estimate the minimum detectable change score ( MDC ) using the st and ard error of measure ( SEM ) , thereby providing a means to decide if genuine change had occurred . Calculation of the agreement regarding the presence of change as determined by the MDC and clinicians ' perceptions was performed to give an indication of the validity of this criterion value . Forty-eight subjects who were receiving inpatient rehabilitation after stroke were assessed on consecutive days by two raters using the BBS . The MDC analysis suggests that a change of + /- 6 BBS points is necessary to be 90 % confident of genuine change . Only 25/45 subjects showed agreement between the statistically derived presence of change and clinicians ' perceptions of change . The lack of agreement may relate to the validity of the SEM/MDC methodology to determine the criterion BBS value , the heterogeneity of the subjects , or the use of clinician gestalt impressions of change [18511529] Objective : To establish the effects of group exercise on mobility and strength . Design : R and omized controlled trial . Setting : Two public hospital outpatient rehabilitation services . Participants : One hundred and seventy-three people ( mean age 74.9 years , SD 10.8 ) with impaired mobility were r and omized and 159 people ( 92 % ) completed the trial . Interventions : Five-week , twice-weekly ` circuit-style ' group exercise programme run by a physiotherapist ( n = 85 ) and a no-intervention waiting list control group ( n = 88 ) . Main outcome measures : Three aspects of mobility : balance while st and ing and stepping ( Step Test , semi-t and em and t and em stance times ) ; sit-to-st and ability ( rate and minimum height ) and gait ( 6-metre and 6-minute walk tests ) . Lower limb muscle strength ( knee flexion and extension ) . Results : At retest , exercise participants had improved significantly more than their control counterparts on measures of balance while stepping , sit to st and and gait . Exercise participants averaged 1.6 more steps on the 15-second Step Test ( 95 % confidence interval ( CI ) 0.5 to 2.8 , P=0.005 ) , walked an average of 0.12 m/s faster ( 95 % CI 0.05 to 0.2 , P=0.002 ) and took 2.5 fewer steps in 6 metres ( 95 % CI —4.2 to —0.8 , P=0.004 ) . Exercise participants also averaged 0.04 more sit-to-st and s/second , ( 95 % CI 0.003 to 0.08 , P=0.037 ) and walked an average of 30.9 metres further in 6 minutes ( 95 % CI 9.4 to 52.4 , P=0.005 ) . There were no clinical ly important or statistically significant between-group differences at retest for the measures of strength ( knee extension and flexion ) , balance while st and ing or minimal sit-to-st and height . Conclusion : This short- duration circuit class programme improved mobility , but not strength [19969159] UNLABELLED Mudge S , Barber PA , Stott NS . Circuit-based rehabilitation improves gait endurance but not usual walking activity in chronic stroke : a r and omized controlled trial . OBJECTIVE To determine whether circuit-based rehabilitation would increase the amount and rate that individuals with stroke walk in their usual environments . DESIGN Single-blind r and omized controlled trial . SETTING Rehabilitation clinic . PARTICIPANTS Sixty participants with a residual gait deficit at least 6 months after stroke originally enrolled in the study . Two withdrew in the initial phase , leaving 58 participants ( median age , 71.5y ; range , 39.0 - 89.0y ) who were r and omized to the 2 intervention groups . INTERVENTIONS The exercise group had 12 sessions of clinic-based rehabilitation delivered in a circuit class design ed to improve walking . The control group received a comparable duration of group social and educational classes . MAIN OUTCOME MEASURES Usual walking performance was assessed using the StepWatch Activity Monitor . Clinical tests were gait speed ( timed 10-meter walk ) and endurance ( six-minute walk test [ 6MWT ] ) , confidence ( Activities-Based Confidence Scale ) , self-reported mobility ( Rivermead Mobility Index [ RMI ] ) , and self-reported physical activity ( Physical Activity and Disability Scale ) . RESULTS Intention-to-treat analysis revealed that the exercise group showed a significantly greater distance for the 6MWT than the control group immediately after the intervention ( P=.030 ) but that this effect was not retained 3 months later . There were no changes in the StepWatch measures of usual walking performance for either group . The exercise and control groups had significantly different gait speed ( P=.038 ) and scores on the RMI ( P=.025 ) at the 3-month follow-up . These differences represented a greater decline in the control group compared with the exercise group for both outcome measures . CONCLUSIONS Circuit-based rehabilitation leads to improvements in gait endurance but does not change the amount or rate of walking performance in usual environments . Clinical gains made by the exercise group were lost 3 months later . Future studies should consider whether rehabilitation needs to occur in usual environments to improve walking performance [17601461] OBJECTIVE To test the efficacy of functional electric stimulation (FES)-assisted exercise therapy ( FES-ET ) on a workstation in the subacute phase of recovery from a stroke . DESIGN Single-blind , r and omly controlled comparison of high- and low-intensity treatment . SETTING Laboratory in a rehabilitation hospital . PARTICIPANTS Nineteen stroke survivors ( 10 men , 9 women ; mean age + /- st and ard deviation , 60.6+/-5.8y ) , with upper-extremity hemiplegia ( mean poststroke time , 48+/-17d ) . The main inclusion criteria were : stroke occurred within 3 months of onset of trial and result ed in severe upper-limb dysfunction , and FES produced adequate h and opening . INTERVENTION An FES stimulator and an exercise workstation with instrumented objects were used by 2 groups to perform specific motor tasks with their affected upper extremity . Ten subjects in the high-intensity FES-ET group received FES-ET for 1 hour a day on 15 to 20 consecutive workdays . Nine subjects in the low-intensity FES-ET group received 15 minutes of sensory electric stimulation 4 days a week and on the fifth day they received 1 hour of FES-ET . MAIN OUTCOME MEASURES Primary outcome measure included the Wolf Motor Function Test ( WMFT ) . Secondary outcome measures included the Motor Activity Log ( MAL ) , the upper-extremity portion of the Fugl-Meyer Assessment ( FMA ) , and the combined kinematic score ( CKS ) derived from workstation measurements . The WMFT , MAL , and FMA were used to assess function in the absence of FES whereas CKS was used to evaluate function assisted by FES . RESULTS Improvements in the WMFT and CKS were significantly greater in the high-intensity group ( post-treatment effect size , .95 ) than the low-intensity group ( post-treatment effect size , 1.3 ) . The differences in MAL and FMA were not statistically significant . CONCLUSIONS Subjects performing high-intensity FES-ET showed significantly greater improvements on the WMFT than those performing low-intensity FES-ET . However , this was not reflected in subjects ' self- assessment s ( MAL ) or in their FMA scores , so the clinical significance of the result is open to debate . The CKS data suggest that high-intensity FES-ET may be advantageous in neuroprosthetic applications [16401430] OBJECTIVE To assess the effects of a community-based exercise program on motor recovery and functional abilities of the paretic upper extremity in persons with chronic stroke . DESIGN R and omized controlled trial . SETTING Rehabilitation research laboratory and a community hall . PARTICIPANTS A sample of 63 people ( > or = 50y ) with chronic deficits result ing from stroke ( onset > or = 1y ) . INTERVENTIONS The arm group underwent an exercise program design ed to improve upper-extremity function ( 1h/session , 3 sessions/wk for 19wk ) . The leg group underwent a lower-extremity exercise program . MAIN OUTCOME MEASURES The Wolf Motor Function Test ( WMFT ) , Fugl-Meyer Assessment ( FMA ) , h and -held dynamometry ( grip strength ) , and the Motor Activity Log . RESULTS Multivariate analysis showed a significant group by time interaction ( Wilks lambda=.726 , P=.017 ) , indicating that overall , the arm group had significantly more improvement than the leg group . Post hoc analysis demonstrated that gains in WMFT ( functional ability ) ( P=.001 ) and FMA ( P=.001 ) scores were significantly higher in the arm group . The amount of improvement was comparable to other novel treatment approaches such as constraint-induced movement therapy or robot-aided exercise training previously reported in chronic stroke . Participants with moderate arm impairment benefited more from the program . CONCLUSIONS The pilot study showed that a community-based exercise program can improve upper-extremity function in persons with chronic stroke . This outcome justifies a larger clinical trial to further assess efficacy and cost effectiveness [19541916] Background . Cognitive deficits impede stroke recovery . Aerobic exercise ( AEX ) improves cognitive executive function ( EF ) processes in healthy individuals , although the learning benefits after stroke are unknown . Objective . To underst and AEX-induced improvements in EF , motor learning , and mobility poststroke . Methods . Following cardiorespiratory testing , 38 chronic stroke survivors were r and omized to 2 different groups that exercised 3 times a week ( 45-minute sessions ) for 8 weeks . The AEX group ( n = 19 ; 9 women ; 10 men ; 64.10 ± 12.30 years ) performed progressive resistive stationary bicycle training at 70 % maximal heart rate , whereas the Stretching Exercise ( SE ) group ( n = 19 ; 12 women ; 7 men ; 58.96 ± 14.68 years ) performed stretches at home . Between-group comparisons were performed on the change in performance at “ Post ” and “ Retention ” ( 8 weeks later ) for neuropsychological and motor function measures . Results . VO2max significantly improved at Post with AEX ( P = .04 ) . AEX also improved motor learning in the less-affected h and , with large effect sizes ( Cohen ’s d calculation ) . Specifically , AEX significantly improved information processing speed on the serial reaction time task ( SRTT ; ie , “ procedural motor learning ” ) compared with the SE group at Post ( P = .024 ) , but not at Retention . Also , at Post ( P = .038 ) , AEX significantly improved predictive force accuracy for a precision grip task requiring attention and conditional motor learning of visual cues . Ambulation and sit-to-st and transfers were significantly faster in the AEX group at Post ( P = .038 ) , with balance control significantly improved at Retention ( P = .041 ) . EF measurements were not significantly different for the AEX group . Conclusion . AEX improved mobility and selected cognitive domains related to motor learning , which enhances sensorimotor control after stroke [17537090] OBJECTIVES To determine the feasibility and effect of exercise training after stroke . DESIGN R and omized exploratory trial comparing exercise training ( including progressive endurance and resistance training ) with relaxation ( attention control ) . SETTING Interventions were performed in a rehabilitation hospital . PARTICIPANTS Sixty-six independently ambulatory patients ( mean age 72 , 36 men ) without significant dysphasia , confusion , or medical contraindications to exercise training who had completed their usual rehabilitation and had been discharged from hospital . INTERVENTION Both interventions were held three times a week for 12 weeks . Up to seven patients attended each session . MEASUREMENTS The Functional Independence Measure ; Nottingham Extended Activities of Daily Living ; Rivermead Mobility Index ; functional reach ; sit-to-st and ; elderly mobility score ; timed up- and -go ; Medical Outcomes Study 36-Item Short Form Question naire , version 2 ( SF-36 ) ; Hospital Anxiety and Depression Score ; aspects of physical fitness ( comfortable walking speed , walking economy , and explosive leg extensor power ) were measured at baseline , immediately after interventions ( 3 months ) , and 7 months after baseline . RESULTS The median number of intervention sessions attended was 36 ( interquartile range ( IQR ) 30.00 - 36.75 ) for exercise and 36 ( IQR 30.50 - 37.00 ) for relaxation . Adherence to the individual exercises ranged from 94 % to 99 % . At 3 months , role-physical ( an item in SF-36 ) , timed up- and -go , and walking economy were significantly better in the exercise group ( analysis of covariance ) . At 7 months , role-physical was the only significant difference between groups . CONCLUSION Exercise training for ambulatory stroke patients was feasible and led to significantly greater benefits in aspects of physical function and perceived effect of physical health on daily life [17895349] Background and Purpose : A phase II , single-blinded , r and omized clinical trial was conducted to determine the effects of combined task-specific and lower-extremity ( LE ) strength training to improve walking ability after stroke . Subjects : The participants were 80 adults who were ambulatory 4 months to 5 years after a unilateral stroke . Method : The exercise interventions consisted of body-weight – supported treadmill training ( BWSTT ) , limb-loaded resistive leg cycling ( CYCLE ) , LE muscle-specific progressive-resistive exercise ( LE-EX ) , and upper-extremity ergometry ( UE-EX ) . After baseline assessment s , participants were r and omly assigned to a combined exercise program that included an exercise pair . The exercise pairs were : BWSTT/UE-EX , CYCLE/UE-EX , BWSTT/CYCLE , and BWSTT/LE-EX . Exercise sessions were 4 times per week for 6 weeks ( total of 24 sessions ) , with exercise type completed on alternate days . Outcomes were self-selected walking speed , fast walking speed , and 6-minute walk distance measured before and after intervention and at a 6-month follow-up . Results : The BWSTT/UE-EX group had significantly greater walking speed increases compared with the CYCLE/UE-EX group ; both groups improved in distance walked . All BWSTT groups increased walking speed and distance whether BWSTT was combined with LE strength training or not . Discussion and Conclusion : After chronic stroke , task-specific training during treadmill walking with body-weight support is more effective in improving walking speed and maintaining these gains at 6 months than resisted leg cycling alone . Consistent with the overtraining literature , LE strength training alternated daily with BWSTT walking did not provide an added benefit to walking outcomes [17008338] Objective : To examine the effectiveness of task-oriented progressive resistance strength training on lower extremity strength and functional performance in chronic stroke subjects . Design : Single-blind , r and omized controlled trial . Setting : Medical centre and district hospital . Subjects : Forty-eight subjects at least one year post stroke . Interventions : Participants r and omly allocated to two groups , control ( n-/24 ) and experimental ( n-/24 ) . Subjects in the control group did not receive any rehabilitation training . Subjects in the experimental group were put on a four-week task-oriented progressive resistance strength training . Main measures : Lower extremity muscle strength , gait velocity , cadence , stride length , six-minute walk test , step test , and timed up and go test . Results : Muscle strength significantly improved in the experimental group for strong side muscle groups ( ranged from 23.9 % to 36.5 % ) and paretic side muscle groups ( ranged from 10.1 % to 77.9 % ) . In the control group muscle strength changes ranged from 6.7 % gain to 11.2 % decline . The experimental group showed significant improvement in all selected measures of functional performance except for the step test . In the control group , the number of repetitions of the step test significantly decreased ( -20.3 % ) with no change in other functional tests . There was a significant difference between groups for muscle strength and all functional measures . The strength gain was significantly associated with gain in the functional tests . Conclusions : The task-oriented progressive resistance strength training programme could improve lower extremity muscle strength in individuals with chronic stroke and could carry over into improvement in functional abilities [21844283] Background . Sitting balance and the ability to perform selective truncal movements are important predictors of functional outcome after stroke . However , few clinical trials have evaluated the effect of truncal exercises . Objective . The authors assessed the effect of additional truncal exercises on truncal function , st and ing balance , and mobility . Methods . An assessor-blinded r and omized controlled trial was carried out at a stroke rehabilitation hospital . A total of 33 participants ( mean 35 days post onset ) were r and omly assigned to an experimental group ( n = 18 ) or a control group ( n = 15 ) . In addition to conventional therapy , the experimental group received 16 hours of truncal exercises . The control group received 16 hours of sham treatment . Truncal function was evaluated by the Trunk Impairment Scale ( TIS ) and st and ing balance and mobility by the Tinetti Test . The Romberg with eyes open and eyes closed , Four Test Balance Scale ( FTBS ) , Berg Balance Scale ( BBS ) , Rivermead Motor Assessment Battery ( RMAB ) , Functional Ambulation Categories , and Dynamic Gait Index ( DGI ) were performed to eluci date the findings of the primary outcome measures . Results . A treatment effect was found for the experimental group on the TIS ( P < .001 ) , Tinetti Test ( P < .001 ) , FTBS ( P = .014 ) , BBS ( P = .007 ) , RMAB ( P < .001 ) , and DGI ( P = .006 ) . Conclusions . In addition to conventional therapy , truncal exercises have a beneficial effect on truncal function , st and ing balance , and mobility in people after stroke [22120031] Abstract Background and Objective : The ability to walk is impaired in more than 80 % of poststroke patients . The objective of the present study was to evaluate the effectiveness of the task-oriented circuit class training ( TOCCT ) with motor imagery ( MI ) on the gait during the subacute phase after a stroke . Method : This was a r and omized , controlled , assessor-blinded trial in a neurology department of a university hospital . A convenience sample of 30 people , 4 to 12 weeks ( mean , 6.3 weeks ) after the stroke was r and omized into 2 groups ( the TOCCT with MI and st and ard training group ) of 15 people each . Twenty-nine participants completed the 6-week follow-up . Participants were assigned to receive either the TOCCT with MI or dose-matched st and ard training program based on the Bobath ’s neurodevelopmental technique , 7 days a week for 2 weeks , as out patients or in patients . Outcome measures were the Functional Ambulation Classification ( FAC ) , the Rivermead Visual Gait Assessment ( RVGA ) , step length asymmetry , walking speed , and 6-minute walk test ( 6MWT ) . Results : The TOCCT with MI group showed a positive improvement in the mean/median scores on most of the outcome measures at post and follow-up assessment s in comparison to the control group . However , statistically significant differences were observed in changes between the groups at post and follow-up assessment for FAC , RVGA , walking speed , and 6MWT ( ANOVA , P = .001 to .049 ; Mann-Whitney U test , P = .001 ) . Conclusion : Among the patients who had a stroke within the previous 4 to 12 weeks , the TOCCT with MI produced statistically significant and clinical ly relevant improvements in the gait and the gait-related activities [22668675] Abstract Background / Objective : The upper extremity motor deficit is one of the functional challenges in post stroke patients . The objective of the present study was to evaluate the effectiveness of the meaningful task-specific training ( MTST ) on the upper extremity motor recovery during the subacute phase after a stroke . Method : This was a r and omized , controlled , double-blinded trial in the neurology department of a university hospital and occupational therapy unit of a rehabilitation institute . A convenience sample of 103 people , 4 to 24 weeks ( mean , 12.15 weeks ) after the stroke , was r and omized into 2 groups ( MTST , 51 ; st and ard training group , 52 ) . Subjects in the Brunnstrom stage of arm recovery of 2 to 5 were included in the study . Ninety-five participants completed the 8-week follow-up . Interventions : Participants were assigned to receive either the MTST or dose-matched st and ard training program based on the Brunnstrom stage and Bobath neurodevelopmental technique , 4 to 5 days a week for 4 weeks . Fugl-Meyer assessment ( FMA ) , Action Research Arm Test ( ARAT ) , Grade d Wolf Motor Function Test ( GWMFT ) , and Motor Activity Log ( MAL ) were outcome measures Results : The MTST group showed a positive improvement in the mean scores on the outcome measures at post and follow-up assessment s in comparison to the control group . Further , statistically significant differences were observed in changes between the groups at post and follow-up assessment for FMA , ARAT , GWMFT , and MAL . Conclusion : The MTST produced statistically significant and clinical ly relevant improvements in the upper extremity motor recovery of the patients who had a subacute stroke [24473242] BACKGROUND Despite the beneficial effect of cardiac rehabilitation after myocardial infa rct ion , a rehabilitation program to improve cardiorespiratory fitness and influence secondary prevention has not been implemented for ischemic stroke and transient ischemic attack ( TIA ) . OBJECTIVE To investigate the safety and feasibility of a post-stroke care including an exercise program after minor ischemic stroke or TIA . METHODS In a r and omised controlled trial , 20 patients with a recent minor stroke or TIA without cardiac contraindications were r and omly assigned to one of the two interventions ; post-stroke care without exercise or post-stroke care with exercise . Patients were evaluated at baseline , 6 and 12 months . RESULTS Eighteen patients completed the intervention . In none of the patients cardiopulmonary contraindications for the maximal exercise test and exercise program were found . No cardiovascular events occurred during the maximal exercise tests and exercise program . After one year , significantly more patients in the post-stroke care with exercise group achieved the composite endpoint of optimal medical therapy . CONCLUSIONS Post-stroke care including an exercise program is safe and feasible in the acute phase after minor stroke or TIA and might be a way to increase effectiveness of secondary stroke prevention . We are currently conducting a larger trial to vali date these results

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### Context: [11823669] Background and Purpose — A new gait training strategy for patients with stroke seeks to increase walking speed through treadmill training . This study compares the effects of structured speed-dependent treadmill training ( STT ) ( with the use of an interval paradigm to increase the treadmill speed stepwise according to principles of sport physiology ) with limited progressive treadmill training ( LTT ) and conventional gait training ( CGT ) on clinical outcome measures for patients with hemiparesis . Methods — Sixty ambulatory poststroke patients were each r and omly selected to receive 1 of the 3 different gait therapies : 20 subjects were treated with STT , 20 subjects were trained to walk on a treadmill with a 20 % increase of belt speed over the treatment period ( LTT ) , and 20 subjects were treated with CGT . Treatment outcomes were assessed on the basis of overground walking speed , cadence , stride length , and Functional Ambulation Category scores . Results — After a 4-week training period , the STT group scored significantly higher than the LTT and CGT groups for overground walking speed ( STT versus LTT , P < 0.001 ; STT versus CGT , P < 0.001 ) , cadence ( STT versus LTT , P = 0.007 ; STT versus CGT , P < 0.001 ) , stride length ( STT versus LTT , P < 0.001 ; STT versus CGT , P < 0.001 ) , and Functional Ambulation Category scores ( STT versus LTT , P = 0.007 ; STT versus CGT , P < 0.001 ) . Conclusions — Structured STT in poststroke patients result ed in better walking abilities than LTT or CGT . This gait training strategy provides a dynamic and integrative approach for the treatment of gait dysfunction after stroke [11935055] Background and Purpose — This study compared the psychometric properties of 3 clinical balance measures , the Berg Balance Scale ( BBS ) , the Balance subscale of the Fugl-Meyer test ( FM-B ) , and the Postural Assessment Scale for Stroke Patients ( PASS ) , in stroke patients with a broad range of neurological and functional impairment from the acute stage up to 180 days after onset . Methods — One hundred twenty-three stroke patients were followed up prospect ively with the 3 balance measures 14 , 30 , 90 , and 180 days after stroke onset ( DAS ) . Reliability ( interrater reliability and internal consistency ) and validity ( concurrent validity , convergent validity , and predictive validity ) of each measure were examined . A comparison of the responsiveness of each of the 3 measures was made on the basis of the entire group of patients and 3 separate groups classified by degree of neurological severity . Results — The FM-B and BBS showed a significant floor or ceiling effect at some DAS points , whereas the PASS did not show these effects . The BBS , FM-B , and PASS all had good reliability and validity for patients at different recovery stages after stroke . The results of effect size demonstrated fair to good responsiveness of all 3 measures within the first 90 DAS but , as expected , only a low level of responsiveness at 90 to 180 DAS . The PASS was more responsive to changes in severe stroke patients at the earliest period after stroke onset , 14 to 30 DAS . Conclusions — All 3 measures tested showed very acceptable levels of reliability , validity , and responsiveness for both clinicians and research ers . The PASS showed slightly better psychometric characteristics than the other 2 measures [25790018] Background Increased therapy has been linked to improvements in functional ability of people with stroke . Aim To determine the effectiveness of two alternative models of increased physiotherapy service delivery ( seven-day week therapy or group circuit class therapy five days a week ) to usual care . Method Three-armed r and omized controlled trial with blinded assessment of outcome . People admitted with a diagnosis of stroke , previously independently ambulant and with a moderate level of disability were recruited . ‘ Usual care ’ was individual physiotherapy provided five-days a week . Seven-day week therapy was usual care physiotherapy provided seven-days a week . Participants in the circuit class therapy arm of the trial received physiotherapy in group circuit classes in two 90-min sessions , five-days a week . Primary outcome was distance walked on the six-minute walk test at four-weeks post-r and omization . Results Two hundred eighty-three participants were r and omized ; primary outcome data were available for 259 ( 92 % ) . In the seven-day arm participants received an additional three hours of physiotherapy and thosein the circuit class armanadditional 22 h. There were no significant between-group differences at four-weeks in walking distance ( P = 0·72 ) . Length of stay was shorter for seven-day ( mean difference −2·9 days , 95 % confidence interval −17·9 to 12·0 ) and circuit class participants ( mean difference −9·2 days , 95 % confidence interval −24·2 to 5·8 ) compared to usual care , but this was not significant . Conclusions Both seven-day therapy and group circuit class therapy increased physiotherapy time , but walking outcomes were equivalent to usual care [11552192] OBJECTIVES To identify the most responsive method of measuring gait speed , to estimate the responsiveness of other outcome measures , and to determine whether gait speed predicts discharge destination in acute stroke . DESIGN A prospect i ve cohort study . SETTING Five acute-care hospitals . PATIENTS Fifty subjects with residual gait deficits after a first-time stroke . INTERVENTIONS Five- ( 5mWT ) and 10-meter walk tests ( 10mWT ) at comfortable and maximum speeds , with 2 evaluations conducted an average + /- st and ard deviation ( SD ) of 8 + /- 3 and 38 + /- 5 days poststroke . MAIN OUTCOME MEASURE St and ardized response mean ( SRM = mean change/SD of change ) was used to estimate responsiveness for each walk test , the Berg Balance Scale , the Barthel Index , the Stroke Rehabilitation Assessment of Movement ( STREAM ) , and the Timed Up and Go ( TUG ) . RESULTS The SRMs were 1.22 and 1.00 for the 5mWT , and .92 and .83 for the 10mWT performed at a comfortable and maximum pace , respectively . The SRMs for the Berg Balance Scale , the Barthel Index , the STREAM , and the TUG were 1.04,.99,.89 , and .73 , respectively . The probability of discharge to a rehabilitation center for persons walking at < or = 0.3 m/s or > 0.6 m/s at the first evaluation was.95 and .22 , respectively . CONCLUSIONS The 5mWT at a comfortable pace is recommended as the measure of choice for clinicians and research ers who need to detect longitudinal change in walking disability in the first 5 weeks poststroke [14988574] Background and Purpose — One way that stroke units may improve outcome is by reducing complications of immobility through early mobilization ; however , this intervention needs testing . The purpose of this study was to determine the physical activity patterns of stroke patients managed within acute stroke units as a first step in developing an early mobilization protocol . Methods — We recruited 64 patients within 14 days after stroke from 5 metropolitan stroke units and observed them for 2 consecutive days at 10-minute intervals between the hours of 8 am and 5 pm . At each observation , we ascertained physical activity , location , and other person(s ) present . Therapists recorded therapy details . Results — The 58 patients who completed the study had a mean age of 71.3 years . Stroke severity ranged from mild ( National Institutes of Health Stroke Scale score , 1 ) to severe ( score , 27 ) , and mean time after stroke at observation was 5.6 days ( range , 0 to 13 days ) . Only 9 patients were restricted to bed . During the therapeutic day , patients spent > 50 % resting in bed , 28 % sitting out of bed , and only 13 % engaged in activities with the potential to prevent complications and improve recovery of mobility . Patients were alone > 60 % of the time . Conclusions — This is the first multicenter study of physical activity early after stroke . We believe the next step is to conduct a r and omized controlled trial to evaluate the effect of increased levels of physical activity early after stroke compared with current st and ards of care [24856940] QUESTION Do people with stroke spend more time in active task practice during circuit class therapy sessions versus individual physiotherapy sessions ? Do people with stroke practise different tasks during circuit class therapy sessions versus individual physiotherapy sessions ? DESIGN Prospect i ve , observational study . PARTICIPANTS Twenty-nine people with stroke in inpatient rehabilitation setting s. INTERVENTIONS Individual therapy sessions and circuit class therapy sessions provided within a larger r and omised controlled trial . OUTCOME MEASURES Seventy-nine therapy sessions were video-recorded and the footage was analysed for time spent engaged in various categories of activity . In a sub sample of 28 videos , the number of steps taken by people with stroke per therapy session was counted . RESULTS Circuit class therapy sessions were of a longer duration ( mean difference 38.0minutes , 95 % CI 29.9 to 46.1 ) , and participants spent more time engaged in active task practice ( mean difference 23.8minutes , 95 % CI 16.1 to 31.4 ) compared with individual sessions . A greater percentage of time in circuit class therapy sessions was spent practising tasks in sitting ( mean difference 5.3 % , 95 % CI 2.4 to 8.2 ) and in sit-to-st and practice ( mean difference 2.7 % , 95 % CI 1.4 to 4.1 ) , and a lower percentage of time in walking practice ( mean difference 19.1 % , 95 % CI 10.0 to 28.1 ) compared with individual sessions . PARTICIPANTS took an average of 371 steps ( SD 418 ) during therapy sessions and this did not differ significantly between group and individual sessions . CONCLUSION People with stroke spent more time in active task practice , but a similar amount of time in walking practice when physiotherapy was offered in circuit class therapy sessions versus individual therapy sessions . There is a need for effective strategies to increase the amount of walking practice during physiotherapy sessions for people after stroke [20719820] Objective : To investigate the feasibility and the effects on gait of a high intensity task-oriented training , incorporating a high cardiovascular workload and large number of repetitions , in patients with subacute stroke , when compared to a low intensity physiotherapy-programme . Design and subjects : R and omized controlled clinical trial : Forty-four patients with stroke were recruited at 2 to 8 weeks after stroke onset . Measures : Maximal gait speed assessed with the 10-metre timed walking test ( 10MTWT ) , walking capacity assessed with the six-minute walk test ( 6MWT ) . Control of st and ing balance assessed with the Berg Balance Scale and the Functional Reach test . Group differences were analysed using a Mann — Whitney U-test . Results : Between-group analysis showed a statistically significant difference in favour of the high intensity task-oriented training in performance on the 10MTWT ( Z = -2.13 , P = 0.03 ) and the 6MWT ( Z = -2.26 , P = 0.02 ) . No between-group difference were found for the Berg Balance Scale ( Z = —0.07 , P = 0.45 ) and the Functional Reach test ( Z = —0.21 , P = 0.84 ) . Conclusion : A high-intensity task-oriented training programme design ed to improve hemiplegic gait and physical fitness was feasible in the present study and the effectiveness exceeds a low intensity physiotherapy-programme in terms of gait speed and walking capacity in patients with subacute stroke . In a future study , it seems appropriate to additionally use measures to evaluate physical fitness and energy expenditure while walking [15179638] OBJECTIVE To evaluate the effect of an 8-week , water-based exercise program ( experimental group ) with that of an upper-extremity function program ( control group ) to increase cardiovascular fitness within a community setting for people with stroke . DESIGN Single-blind r and omized controlled trial . SETTING Public community center . PARTICIPANTS A volunteer sample of 12 community-dwelling people with stroke with mild to moderate residual motor deficits . INTERVENTION Study subjects participated in group exercise programs for 1 hour , 3 times a week for 8 weeks . The experimental group exercised in chest-deep water at targeted heart rates . The control group performed arm and h and exercises while sitting . Main outcome measures The primary outcome measure was cardiovascular fitness ( V(O2)max ) . Secondary measures were maximal workload , muscle strength , gait speed , and the Berg Balance Scale score . RESULTS The experimental group attained significant improvements over the control group in cardiovascular fitness , maximal workload , gait speed , and paretic lower-extremity muscle strength . The relatively short program ( 8 wk ) of water-based exercise result ed in a 22 % improvement in cardiovascular fitness in a small group of people with stroke who had relatively high function . CONCLUSIONS A water-based exercise program undertaken as a group program may be an effective way to promote fitness in people with stroke [22544817] Background . Exercise interventions can enhance mobility after stroke as well as prevent falls in elderly persons . Objective . Investigate whether an exercise intervention can enhance mobility , prevent falls , and increase physical activity among community-dwelling people after stroke . Method . A r and omized trial with blinding of physical outcome assessment was conducted through local stroke clubs . Both groups , on average 5.9 years poststroke , received exercise classes , advice , and a home program for 12 months . The experimental group ( EG ) program ( n = 76 ) aim ed to improve walking , prevent falls and increase physical activity . The control group ( CG ) program ( n = 75 ) aim ed to improve upper-limb and cognitive functions . The primary outcomes were walking capacity , walking speed measured before and after the intervention , and fall rates monitored monthly . Results . At 12 months , the EG walked 34 m further in 6 minutes ( 95 % confidence interval [ CI ] = 19 - 50 ; P < .001 ) and 0.07 m/s faster over 10 m ( 95 % CI = 0.01 - 0.14 ; P = .03 ) than the CG . The EG had 129 falls , and the CG had 133 . There were no differences in proportion of fallers ( relative risk = 1.22 ; 95 % CI = 0.91 - 1.62 ; P = .19 ) or the rate of falls between groups ( incidence rate ratio = 0.96 ; 95 % CI = 0.59 - 1.51 ; P = .88 ) . Conclusion . The experimental intervention delivered through stroke clubs enhanced aspects of mobility but had no effect on falls [12473421] BACKGROUND In an 18-month exercise intervention in previously sedentary older women ( 40 - 65 years ) , we examined whether an initial 6 months of supervised exercise leads to greater long-term retention and adherence to regular physical activity than an unsupervised home-based program and whether these outcomes are influenced by the exercise intensity . METHODS Women ( N = 126 ) were recruited from the community and r and omly assigned to either center-based or home-based exercise three times/week . The center-based group attended supervised sessions for 6 months , while after 10 initial sessions the home-based group exercised at home . After 6 months both groups were home-based for a further 12 months . Within each arm , subjects were further r and omized to exercise at either moderate or vigorous intensity . RESULTS The center-based group had higher retention than the home-based ( 97 , 94 , 81 versus 87 , 76 , and 61 % ) at 6 , 12 , and 18 months , respectively ( P < 0.05 ) . At 6 months , adherence was higher in the center-based group ( 84 versus 63 % , P < 0.001 ) and energy expenditure was higher at 6 ( P < 0.05 ) and 12 ( P < 0.01 ) months . At 18 months , retention was higher with moderate exercise ( P < 0.05 ) , while adherence was similar with both intensities . CONCLUSION An initial 6 months of center-based exercise enhanced retention in both the short and the long term and promoted short-term adherence and energy expenditure . Long-term , moderate exercise retained more subjects , but had little influence on adherence [3349299] Objective To analyse the effect of task oriented circuit training compared with usual physiotherapy in terms of self reported walking competency for patients with stroke discharged from a rehabilitation centre to their own home . Design R and omised controlled trial with follow-up to 24 weeks . Setting Multicentre trial in nine outpatient rehabilitation centres in the Netherl and s Participants Patients with stroke who were able to walk a minimum of 10 m without physical assistance and were discharged from inpatient rehabilitation to an outpatient rehabilitation clinic . Patients were r and omly allocated to circuit training or usual physiotherapy , after stratification by rehabilitation centre , with an online r and omisation procedure . Intervention Patients in the intervention group received circuit training in 90 minute sessions twice a week for 12 weeks . The training included eight different workstations in a gym and was intended to improve performance in tasks relating to walking competency . The control group received usual outpatient physiotherapy . Main outcome measures The primary outcome was the mobility domain of the stroke impact scale ( SIS , version 3.0 ) . Secondary outcomes were st and ing balance , self reported abilities , gait speed , walking distance , stair climbing , instrumental activities of daily living , fatigue , anxiety , and depression . Differences between groups were analysed according to the intention to treat principle . All outcomes were assessed by blinded observers in a repeated measurement design lasting 24 weeks . Results 126 patients were included in the circuit training group and 124 in the usual care group ( control ) , with data from 125 and 117 , respectively , available for analysis . One patient from the circuit training group and seven from the control group dropped out . Circuit training was a safe intervention , and no serious adverse events were reported . There were no significant differences between groups for the stroke impact scale mobility domain ( β=0.05 ( SE 0.68 ) , P=0.943 ) at 12 weeks . Circuit training was associated with significantly higher scores in terms of gait speed ( 0.09 m/s ( SE 0.02 ) , P<0.001 ) , walking distance ( 20.0 m ( SE 7.4 ) , P=0.007 ) , and modified stairs test ( −1.6 s ( SE 0.7 ) , P=0.015 ) . There were no significant differences between groups for the other secondary outcomes , except for the leisure domain of the Nottingham extended activities of daily living and the memory and thinking domain of the stroke impact scale . With the exception of gait speed ( −0.04 m/s ( SE 0.02 ) , P=0.040 ) , there were no significant differences between groups at follow-up . Conclusion Task oriented circuit training can safely replace usual physiotherapy for patients with stroke who are discharged from inpatient rehabilitation to the community and need further training in gait and gait related activities as an outpatient . Trial registration Dutch Trial Register ( NTR1534 ) [15293485] Objective : To evaluate the efficacy of a task-orientated intervention in enhancing competence in walking in people with stroke . Design : Two-centre observer-blinded stratified block-r and omized controlled trial . Setting : General community . Subjects : Between May 2000 and February 2003 , 91 individuals with a residual walking deficit within one year of a first or recurrent stroke consented to participate . Interventions : The experimental intervention comprised 10 functional tasks design ed to strengthen the lower extremities and enhance walking balance , speed and distance . The control intervention involved the practice of upper extremity activities . Subjects in both groups attended sessions three times a week for six weeks . Main measures : Six-minute walk test ( SMWT ) , 5-m walk ( comfortable and maximum pace ) , Berg Balance Scale , timed ‘ up and go ’ . Results : At baseline , subjects in the experimental ( n = 44 ) and control ( n = 47 ) groups walked an average distance of 209 m ( SD = 126 ) and 204 m ( SD = 131 ) , respectively , on the SMWT . Mean improvements of 40 m ( SD = 72 ) , and 5 m ( SD = 66 ) were observed following the experimental and control interventions , respectively . The between-group difference was 35 m ( 95 % confidence interval ( CI ) 7 , 64 ) . Significant between-group effects of 0.21 m/s ( 95 % CI 0.12 , 0.30 ) and of 0.11 m/s ( 95 % CI 0.03 , 0.19 ) in maximum and comfortable walking speed , respectively , were observed . People with a mild , moderate or severe walking deficit at baseline improved an average of 36 ( SD = 96 ) , 55 ( SD = 56 ) and 18 m ( SD = 23 ) , respectively , in SMWT performance following the experimental intervention . Conclusions : Study findings support the efficacy of a task-orientated intervention in enhancing walking distance and speed in the first year post stroke , particularly in people with moderate walking deficits [10527076] OBJECTIVE To evaluate the impact of a program of muscle strengthening and physical conditioning on impairment and disability in chronic stroke subjects . DESIGN A r and omized pretest and posttest control group , followed by a single-group pretest and posttest design . SUBJECTS Thirteen community-dwelling stroke survivors of at least 9 months . INTERVENTION A 10-week ( 3 days/week ) program consisting of a warm-up , aerobic exercises , lower extremity muscle strengthening , and a cool-down . MAIN OUTCOME MEASURES Peak isokinetic torque of the major muscle groups of the affected lower limb , quadriceps and ankle plantarflexor spasticity , gait speed , rate of stair climbing , the Human Activity Profile ( HAP ) , and the Nottingham Health Profile ( NHP ) were recorded twice for the treatment group and three times for the control group . RESULTS Significant improvements were found for all the selected outcome measures ( HAP , NHP , and gait speed ) for the treatment group ( p < .001 ) . In terms of overall training effects , the 13 subjects demonstrated increases in strength of the affected major muscle groups , in HAP and NHP profiles , and in gait speed and rate of stair climbing without concomitant increases in either quadriceps or ankle plantarflexor spasticity . CONCLUSIONS The 10-week combined program of muscle strengthening and physical conditioning result ed in gains in all measures of impairment and disability . These gains were not associated with measurable changes of spasticity in either quadriceps or ankle plantarflexors [5025604] Background Stroke rehabilitation in low- and middle-income countries , such as Mexico , is often hampered by lack of clinical re sources and funding . To provide a cost-effective solution for comprehensive post-stroke rehabilitation that can alleviate the need for one-on-one physical or occupational therapy , in lower and upper extremities , we proposed and implemented a technology-assisted rehabilitation gymnasium in Chihuahua , Mexico . The Gymnasium for Robotic Rehabilitation ( Robot Gym ) consisted of low- and high-tech systems for upper and lower limb rehabilitation . Our hypothesis is that the Robot Gym can provide a cost- and labor-efficient alternative for post-stroke rehabilitation , while being more or as effective as traditional physical and occupational therapy approaches . Methods A typical group of stroke patients was r and omly allocated to an intervention ( n = 10 ) or a control group ( n = 10 ) . The intervention group received rehabilitation using the devices in the Robot Gym , whereas the control group ( n = 10 ) received time-matched st and ard care . All of the study subjects were subjected to 24 two-hour therapy sessions over a period of 6 to 8 weeks . Several clinical assessment s tests for upper and lower extremities were used to evaluate motor function pre- and post-intervention . A cost analysis was done to compare the cost effectiveness for both therapies . Results No significant differences were observed when comparing the results of the pre-intervention Mini-mental , Brunnstrom Test , and Geriatric Depression Scale Test , showing that both groups were functionally similar prior to the intervention . Although , both training groups were functionally equivalent , they had a significant age difference . The results of all of the upper extremity tests showed an improvement in function in both groups with no statistically significant differences between the groups . The Fugl-Meyer and the 10 Meters Walk lower extremity tests showed greater improvement in the intervention group compared to the control group . On the Time Up and Go Test , no statistically significant differences were observed pre- and post-intervention when comparing the control and the intervention groups . For the 6 Minute Walk Test , both groups presented a statistically significant difference pre- and post-intervention , showing progress in their performance . The robot gym therapy was more cost-effective than the traditional one-to-one therapy used during this study in that it enabled therapist to train up to 1.5 to 6 times more patients for the approximately same cost in the long term . Conclusions The results of this study showed that the patients that received therapy using the Robot Gym had enhanced functionality in the upper extremity tests similar to patients in the control group . In the lower extremity tests , the intervention patients showed more improvement than those subjected to traditional therapy . These results support that the Robot Gym can be as effective as traditional therapy for stroke patients , presenting a more cost- and labor-efficient option for countries with scarce clinical re sources and funding .Trial registration IS RCT N98578807 [24148695] Background and aims Cardiovascular co-morbidities are prevalent after stroke , with heart disease , hypertension and impaired glucose tolerance present in the majority of cases . Exercise has the potential to mediate cardiovascular risk factors commonly present in people with stroke . This single-blinded r and omized controlled trial compared the effects of high versus low intensity exercise on fitness , cardiovascular risk factors , and cardiac function after stroke . Methods Fifty participants ( age 50–80 y , > 1 y post-stroke ) were r and omized to a high-intensity Aerobic Exercise ( AE ) or low-intensity non-aerobic Balance/Flexibility ( BF ) program ( 6 months , 3 60-min sessions/week ) . Outcomes assessed by VO2peak ( primary outcome ) , arterial stiffness , ambulatory capacity , hemodynamics and cardiac function using echocardiography , and lipid , glucose and homocysteine levels . Assessors were blinded to group allocation . Results Twenty-three ( 92 % ) of 25 AE group participants ( withdrawals unrelated to the intervention ) and all BF group participants completed the program . One BF group participant experienced 2 non-injurious falls during class . No other adverse events occurred . There were no changes in VO2peak in either group ( AE 16·9 ±7 to 17·4 ± 7 ml•kg−1•min−1 vs. BF 16·9 ±6 to 16·6 ± 5 ml•kg−1•min−1 , P = 0·45 ) , but AE group demonstrated greater improvement in right atrial emptying fraction ( AE 30 ± 22 to 37 ± 22 % vs. BF 35 ± 20 to 31 ± 20 % , P = 0·04 ) . Both groups demonstrated improvements in lipid profiles , glucose and homocysteine levels , and ambulatory capacity ( P < 0·04 ) . Conclusions This was the first study to examine the effects of aerobic exercise after stroke on cardiovascular hemodynamics . High-intensity exercise improved right-sided function and early myocardial relaxation . Low-intensity exercise may also benefit plasma lipid , glucose and inflammatory markers , and ambulatory capacity . This study is an important step towards underst and ing mechanisms by which exercise may reduce cardiovascular risk and function [16696738] OBJECTIVES To estimate the magnitude of small meaningful and substantial individual change in physical performance measures and evaluate their responsiveness . DESIGN Secondary data analyses using distribution- and anchor-based methods to determine meaningful change . SETTING Secondary analysis of data from an observational study and clinical trials of community-dwelling older people and subacute stroke survivors . PARTICIPANTS Older adults with mobility disabilities in a strength training trial ( n=100 ) , subacute stroke survivors in an intervention trial ( n=100 ) , and a prospect i ve cohort of community-dwelling older people ( n=492 ) . MEASUREMENTS Gait speed , Short Physical Performance Battery ( SPPB ) , 6-minute-walk distance ( 6MWD ) , and self-reported mobility . RESULTS Most small meaningful change estimates ranged from 0.04 to 0.06 m/s for gait speed , 0.27 to 0.55 points for SPPB , and 19 to 22 m for 6MWD . Most substantial change estimates ranged from 0.08 to 0.14 m/s for gait speed , 0.99 to 1.34 points for SPPB , and 47 to 49 m for 6MWD . Based on responsiveness indices , per-group sample sizes for clinical trials ranged from 13 to 42 for substantial change and 71 to 161 for small meaningful change . CONCLUSION Best initial estimates of small meaningful change are near 0.05 m/s for gait speed , 0.5 points for SPPB , and 20 m for 6MWD and of substantial change are near 0.10 m/s for gait speed , 1.0 point for SPPB , and 50 m for 6MWD . For clinical use , substantial change in these measures and small change in gait speed and 6MWD , but not SPPB , are detectable . For research use , these measures yield feasible sample sizes for detecting meaningful change [16649886] BACKGROUND AND PURPOSE To facilitate optimal stroke rehabilitation , valid interpretation of observed functional recovery is required . The purpose of this study was to examine the longitudinal relationship between comfortable walking speed and Functional Ambulation Categories ( FAC ) scores for physically independent gait . SUBJECTS This study was a prospect i ve cohort study with 73 subjects who were severely affected by acute stroke . METHODS Functional Ambulation Categories classification and walking speed were measured between weeks 4 and 26 after stroke . The responsiveness of walking speed measurements for detecting clinical ly important speed changes was determined , and the longitudinal association between walking speed and FAC scores and its time dependency were established . This relationship subsequently was scrutinized for possible speed changes occurring within specific FAC scores . Responsiveness ratios , r and om coefficient analysis , paired Student t tests , and the Cohen kappa statistic were used for statistical analyses . RESULTS Responsiveness ratios exceeded the smallest detectable differences . R and om coefficient analysis demonstrated a significant between- and within-subject coefficient and a significant negative interaction between timing of measurements and FAC scores . Paired Student t tests revealed mostly significant pretest-posttest differences in walking speeds , and all kappa values for pretest-posttest FAC scores were significant . DISCUSSION AND CONCLUSION Walking speed measurements are sensitive for detecting clinical ly important changes . Functional Ambulation Categories scores are dependent on the timing of comfortable walking speed measurements after stroke . Moreover , there are indications that , in this relationship , repeated FAC appraisal s are not only based on steady walking speeds , but that the walking speeds related to a specific FAC appraisal also change and , over time , may shift gradually from higher to lower speeds [2736157] Background Most patients who suffer a stroke experience reduced walking competency and health-related quality of life ( HRQoL ) . A key factor in effective stroke rehabilitation is intensive , task-specific training . Recent studies suggest that intensive , patient-tailored training can be organized as a circuit with a series of task-oriented workstations . Primary aim of the FIT-Stroke trial is to evaluate the effects and cost-effectiveness of a structured , progressive task-oriented circuit class training ( CCT ) programme , compared to usual physiotherapeutic care during outpatient rehabilitation in a rehabilitation centre . The task-oriented CCT will be applied in groups of 4 to 6 patients . Outcome will be defined in terms of gait and gait-related ADLs after stroke . The trial will also investigate the generalizability of treatment effects of task-oriented CCT in terms of perceived fatigue , anxiety , depression and perceived HRQoL. Methods / design The multicentre single-blinded r and omized trial will include 220 stroke patients discharged to the community from inpatient rehabilitation , who are able to communicate and walk at least 10 m without physical , h and s-on assistance . After discharge from inpatient rehabilitation , patients in the experimental group will receive task-oriented CCT two times a week for 12 weeks at the physiotherapy department of the rehabilitation centre . Control group patients will receive usual individual , face-to-face , physiotherapy . Costs will be evaluated by having each patient keep a cost diary for the first 24 weeks after r and omisation . Primary outcomes are the mobility part of the Stroke Impact Scale ( SIS-3.0 ) and the EuroQol . Secondary outcomes are the other domains of SIS-3.0 , lower limb muscle strength , walking endurance , gait speed , balance , confidence not to fall , instrumental ADL , fatigue , anxiety , depression and HRQoL. Discussion Based on assumptions about the effect of intensity of practice and specificity of treatment effects , FIT-Stroke will address two key aims . The first aim is to investigate the effects of task-oriented CCT on walking competency and HRQoL compared to usual face-to-face physiotherapy . The second aim is to reveal the cost-effectiveness of task-oriented CCT in the first 6 months post stroke . Both aims were recently recommended as priorities by the American Hearth Association and Stroke Council . Trial registration This study is registered in the Dutch Trial Register as NTR1534 [16410482] BACKGROUND AND PURPOSE Little is known about the relative efficacy of supervised versus unsupervised community exercise programs for stroke survivors . This study compared the effectiveness of a 10-week supervised strengthening and conditioning program ( supervised ) with a 1-week supervised instruction program followed by a 9-week unsupervised home program ( unsupervised ) and evaluated retention of changes at 6 months and 1 year after program completion . METHODS Seventy-two subjects retained at baseline ( 27 women , 45 men ; mean+/-SD age , 64.6+/-11.8 years ) were r and omly allocated to receive the supervised or unsupervised program . The primary outcome was walking speed over 6 minutes , and secondary outcome measures were Human Activity Profile , Medical Outcome Study 36-Item Short-Form survey ( SF-36 ) , Physiological Cost Index , and lower extremity muscle strength . RESULTS The 6-minute walking speed increased significantly in both groups and remained significantly improved by 1 year . The Human Activity Profile demonstrated an increasing trend only in the supervised group that was significant by 1 year . The SF-36 Physical Component summary score increased significantly in the supervised group and remained improved by 1 year ; the unsupervised group showed significant improvement at 1 year . Women made greater gains in supervised programs , but men made greater gains in unsupervised programs . CONCLUSIONS Supervised exercise programs and unsupervised programs after initial supervised instruction were both associated with physical benefits that were retained for 1 year , although supervised programs showed trends to greater improvements in self-reported gains . Gender differences require further research [4755997] [ Purpose ] To investigate how task-oriented circuit training for the recovery motor control of the lower-extremity , balance and walking endurance could be clinical ly applied to subacute stroke inpatient group therapy . [ Subjects and Methods ] Twenty subacute stroke patients were r and omly assigned to the intervention group ( n=10 ) or the control group ( n=10 ) . The intervention consisted of a structured , progressive , inpatient circuit training program focused on mobility and gait training as well as physical fitness training that was performed for 90 minutes , 5 days a week for 4 weeks . The control group received individual physiotherapy of neurodevelopmental treatment for 60 minutes , 5 days a week for 4 weeks . Outcome measures were lower-extremity motor control , balance , gait endurance and activities of daily living before and after 4 weeks . [ Results ] There were no significant differences at baseline between the two groups . After 4 weeks , both groups showed significant improvements in all outcome measures , but there were no significant differences between the two groups during the invention period . [ Conclusion ] In spite of the small sample size , these findings suggest that task-oriented circuit training might be used as a cost-effective and alternative method of individual physiotherapy for the motor recovery of lower-extremity , balance and walking endurance of subacute stroke patients [2719587] Background Stroke is the most common disabling neurological condition in adults . Falls and poor mobility are major contributors to stroke-related disability . Falls are more frequent and more likely to result in injury among stroke survivors than among the general older population . Currently there is good evidence that exercise can enhance mobility after stroke , yet ongoing exercise programs for general community-based stroke survivors are not routinely available . This r and omised controlled trial will investigate whether exercise can reduce fall rates and increase mobility and physical activity levels in stroke survivors . Methods and design Three hundred and fifty community dwelling stroke survivors will be recruited . Participants will have no medical contradictions to exercise and be cognitively and physically able to complete the assessment s and exercise program . After the completion of the pre-test assessment , participants will be r and omly allocated to one of two intervention groups . Both intervention groups will participate in weekly group-based exercises and a home program for twelve months . In the lower limb intervention group , individualised programs of weight-bearing balance and strengthening exercises will be prescribed . The upper limb/cognition group will receive exercises aim ed at management and improvement of function of the affected upper limb and cognition carried out in the seated position . The primary outcome measures will be falls ( measured with 12 month calendars ) and mobility . Secondary outcome measures will be risk of falling , physical activity levels , community participation , quality of life , health service utilisation , upper limb function and cognition . Discussion This study aims to establish and evaluate community-based sustainable exercise programs for stroke survivors . We will determine the effects of the exercise programs in preventing falls and enhancing mobility among people following stroke . This program , if found to be effective , has the potential to be implemented within existing community services . Trial registration The protocol for this study is registered with the Australian New Zeal and Clinical Trials Registry ( ACTRN12606000479505 ) [4932078] [ Purpose ] The purpose of this study was to analyze the effects of task-oriented circuit training on the balance ability and gait endurance of chronic stroke in patients . [ Subjects and Methods ] The participants were 30 patients who had stroke > 6 months previously , result ing in a disability such as hemiparesis . The participants were r and omly divided into the group task-oriented circuit training group and the individual task-oriented circuit-training group . They performed eight types of modified task-oriented training . Balance ability and gait endurance were measured by using the Berg balance scale question naire and the 6-min walk test , respectively , before and after the experiment . [ Results ] Significant differences were observed between before and after the intervention in all variables . There was a significant difference between groups in Berg balance scale scores ; however , no significant differences were seen in the timed up and go test and the 6-min walk test . [ Conclusion ] The results of this study indicated that group exercise can better improve the balance ability of chronic stroke in patients after stroke than can individualized exercise intervention [2956448] Abstract The aim of the study was to evaluate the impact of a high-intensive exercise program containing high-intensive functional exercises implemented to real-life situations together with group discussion s on falls and security aspects in stroke subjects with risk of falls . This was a pre-specified secondary outcome for this study . For evaluation , Short Form-36 ( SF-36 ) health-related quality of life ( HRQoL ) and the Geriatric Depression Scale-15 ( GDS-15 ) were used . This was a single-center , single-blinded , r and omized , controlled trial . Consecutive ≥55 years old stroke patients with risk of falls at 3–6 months after first or recurrent stroke were r and omized to the intervention group ( IG , n=15 ) or to the control group ( CG , n=19 ) who received group discussion with focus on hidden dysfunctions but no physical fitness training . The 5-week high-intensive exercise program was related to an improvement in the CG in the SF-36 Mental Component Scale and the Mental Health subscale at 3 months follow-up compared with baseline values while no improvement was seen in the IG at this time . For the SF-36 Physical Component Scale , there was an improvement in the whole study group at 3 and 6 months follow-up compared with baseline values without any significant changes between the IG and CG . The GDS-15 was unchanged throughout the follow-up period for both groups . Based on these data , it is concluded that high-intensive functional exercises implemented in real-life situations should also include education on hidden dysfunctions after stroke instead of solely focus on falls and safety aspects to have a favorable impact on [15743283] OBJECTIVES To determine the effect of two different community-based group exercise programs on functional balance , mobility , postural reflexes , and falls in older adults with chronic stroke . DESIGN A r and omized , clinical trial . SETTING Community center . PARTICIPANTS Sixty-one community-dwelling older adults with chronic stroke . INTERVENTION Participants were r and omly assigned to an agility ( n=30 ) or stretching/weight-shifting ( n=31 ) exercise group . Both groups exercised three times a week for 10 weeks . MEASUREMENTS Participants were assessed before , immediately after , and 1 month after the intervention for Berg Balance , Timed Up and Go , step reaction time , Activities-specific Balance Confidence , and Nottingham Health Profile . Testing of st and ing postural reflexes and induced falls evoked by a translating platform was also performed . In addition , falls in the community were tracked for 1 year from the start of the interventions . RESULTS Although exercise led to improvements in all clinical outcome measures for both groups , the agility group demonstrated greater improvement in step reaction time and paretic rectus femoris postural reflex onset latency than the stretching/weight-shifting group . In addition , the agility group experienced fewer induced falls on the platform . CONCLUSION Group exercise programs that include agility or stretching/weight shifting exercises improve postural reflexes , functional balance , and mobility and may lead to a reduction of falls in older adults with stroke [3922602] Background Given the rising number of strokes worldwide , and the large number of individuals left with disabilities after stroke , novel strategies to reduce disability , increase functions in the motor and the cognitive domains , and improve quality of life are of major importance . Physical activity is a promising intervention to address these challenges but , as yet , there is no study demonstrating definite outcomes . Our objective is to assess whether additional treatment in the form of physical fitness-based training for patients early after stroke will provide benefits in terms of functional outcomes , in particular gait speed and the Barthel Index ( co- primary outcome measures ) reflecting activities of daily living ( ADL ) . We will gather secondary functional outcomes as well as mechanistic parameters in an exploratory approach . Methods / Design Our phase III r and omised controlled trial will recruit 215 adults with moderate to severe limitations of walking and ADL 5 to 45 days after stroke onset . Participants will be stratified for the prognostic variables of “ centre ” , “ age ” , and “ stroke severity ” , and r and omly assigned to one of two groups . The interventional group receives physical fitness training delivered as supported or unsupported treadmill training ( cardiovascular active aerobic training ; five times per week , over 4 weeks ; each session 50 minutes ; total of 20 additional physical fitness training sessions ) in addition to st and ard rehabilitation treatment . The control intervention consists of relaxation sessions ( non-cardiovascular active ; five times per week week , over 4 weeks ; each session 50 minutes ) in addition to st and ard rehabilitation treatment . Co- primary efficacy endpoints will be gait speed ( in m/s , 10 m walk ) and the Barthel Index ( 100 points total ) at 3 months post-stroke , compared to baseline measurements . Secondary outcomes include st and ard measures of quality of life , sleep and mood , cognition , arm function , maximal oxygen uptake , and cardiovascular risk factors including blood pressure , pulse , waist-to-hip ratio , markers of inflammation , immunity and the insulin-glucose pathway , lipid profile , and others . Discussion The goal of this endpoint-blinded , phase III r and omised controlled trial is to provide evidence to guide post-stroke physical fitness-based rehabilitation programmes , and to eluci date the mechanisms underlying this intervention . Trial registration Registered in Clinical Trials.gov with the Identifier NCT01953549 [4460628] Background Currently , the key advocacy in neuroscientific studies for stroke rehabilitation is that therapy should be directed towards task specificity performed with multiple repetitions . Circuit Class Therapy ( CCT ) is well suited to accomplish multiple task-specific activities . However , while repetitive task practice is achievable with circuit class therapy , in stroke survivors repetitive activities may be affected by poor neurologic inputs to motor units , result ing in decreases in discharging rates which consequently may reduce the efficiency of muscular contraction . To accomplish multiple repetitions , stroke survivors may require augmented duration of practice . To date , no study has examined the effect of augmented duration of CCT in stroke rehabilitation , and specifically what duration of CCT is more effective in influencing functional capacity among stroke survivors . Methods / design Using a r and omised controlled trial with blinded outcome assessment , this study is aim ed at determining the effectiveness of structured augmented CCT in stroke rehabilitation . Sixty-eight stroke survivors ( to be recruited from a tertiary health institution in Kano , Northwest , Nigeria ) will be r and omised into one of four groups : three intervention groups of differing CCT duration s namely : 60 min , 90 min , and 120minuntes respectively , and a control group . Participants will take part in an 8-week structured intensive CCT intervention . Participants will be assessed at baseline , post-intervention , and six-month follow-up for the effectiveness of the varied duration s of therapy , using st and ardised tools . Based on the WHO-ICF model , the outcomes are body structure/function , activity limitation , and participation restriction measures . Discussion It is expected that the outcome of this study will clarify whether increasing CCT duration leads to better recovery of motor function in stroke survivors . Trial registration Pan African Clinical Trial Registry ( PACTR ) : [15574110] The purpose of this study was to investigate whether additional practice of either upper limb or mobility tasks improved functional outcome during inpatient stroke rehabilitation . This prospect i ve , r and omised , single blind clinical trial recruited 30 stroke subjects into either an Upper Limb or a Mobility Group . All subjects received their usual rehabilitation and an additional session of task-related practice using a circuit class format . Independent assessors , blinded to group allocation , tested all subjects . Outcome measures used were three items of the Jebsen Taylor H and Function Test ( JTHFT ) , two arm items of the Motor Assessment Scale ( MAS ) , and three mobility measures , the Timed Up and Go Test ( TUGT ) , Step Test , and Six Minute Walk Test ( 6MWT ) . Both groups improved significantly between pre- and post-tests on all of the mobility measures , however only the Upper Limb Group made a significant improvement on the JTHFT and MAS upper arm items . Following four weeks training , the Mobility Group had better locomotor ability than the Upper Limb Group ( between-group differences in the 6MWT of 116.4 m , 95 % CI 31.4 to 201.3 m , Step Test 2.6 repetitions , 95 % CI -1.0 to 6.2 repetitions , and TUGT -7.6 sec , 95 % CI -15.5 to 0.2 sec ) . The JTHFT dexterity scores in the Upper Limb Group were 6.5 sec ( 95 % CI -7.4 to 20.4 sec ) faster than the Mobility Group . Our findings support the use of additional task-related practice during inpatient stroke rehabilitation . The circuit class format was a practical and effective means to provide supervised additional practice that led to significant and meaningful functional gains [17141639] OBJECTIVE To evaluate the internal and absolute reliability and construct validity of the Activities-Specific Balance Confidence ( ABC ) scale and a new Canadian French version ( ABC-CF ) of it among people with stroke . DESIGN Cross-sectional data from a r and omized controlled trial . SETTING Community . PARTICIPANTS Ninety-one people with a residual walking deficit between 57 and 386 days poststroke . INTERVENTIONS Not applicable . MAIN OUTCOME MEASURES The ABC and ABC-CF scales , Berg Balance Scale ( BBS ) , comfortable and maximum gait speeds , Timed Up & Go ( TUG ) test , 6-minute walk test ( 6MWT ) , Barthel Index , physical function scale of the Medical Outcomes Study 36-Item Short-Form Health Survey , Geriatric Depression Scale ( GDS ) , and the EQ-5D visual analog scale ( EQ VAS ) . RESULTS Internal consistency ( Cronbach alpha ) was .94 and .93 and the st and ard error of measurement was 5.05 and 5.13 for the ABC ( n=51 ) and the ABC-CF ( n=35 ) scales , respectively . Spearman rho values ranged from .30 to .60 for the ABC scale and from .45 to .68 on the ABC-CF scale for associations with scores on the BBS , comfortable and maximum gait speeds , TUG , 6MWT , Barthel Index , physical function scale , GDS , and EQ VAS . CONCLUSIONS Evidence of internal and absolute reliability and of construct validity of the ABC and the ABC-CF scales supports their use for cross-sectional measurements of balance self-efficacy among community-dwelling people in the first year poststroke [4868212] [ Purpose ] The aim of this study was to investigate the impact of a circuit training program on the walking and balance abilities of stroke patients using an up-to- date walking analysis device . [ Subjects and Methods ] The subjects of this study were 12 adults who were diagnosed with stroke . Evaluation was conducted using the Smart Step test for walking ability ; ( BBS ) for balance ability ; and the Timed Up and Go test ( TUG ) for functional mobility and movement ability . The 12 stroke patients were r and omly recruited and divided into two groups ; an experimental group which performed circuit training with obstacles , and a control group which performed flat gait training ) . [ Results ] Between-group comparison of the change in the 10-m walking speed found a statistically significant difference between the two groups . Between-group comparison of the changes in BBS and TUG found statistically significant differences between the two groups . [ Conclusion ] The circuit training program using obstacles had a positive effect on the gait and balance abilities of the stroke patients [17678655] OBJECTIVE To compare the effectiveness of circuit class therapy and individual physiotherapy ( PT ) sessions in improving walking ability and functional balance for people recovering from stroke . DESIGN Nonr and omized , single-blind controlled trial . SETTING Medical rehabilitation ward of a rehabilitation hospital . PARTICIPANTS Sixty-eight persons receiving inpatient rehabilitation after a stroke . INTERVENTIONS Subjects received group circuit class therapy or individual treatment sessions as the sole method of PT service delivery for the duration of their inpatient stay . MAIN OUTCOME MEASURES Five-meter walk test ( 5MWT ) , two-minute walk test ( 2MWT ) , and the Berg Balance Scale ( BBS ) measured 4 weeks after admission . Secondary outcome measures included the Iowa Level of Assistance Scale , Motor Assessment Scale upper-limb items , and patient satisfaction . Measures were taken on admission and 4 weeks later . RESULTS Subjects in both groups showed significant improvements between admission and week 4 in all primary outcome measures . There were no significant between group differences in the primary outcome measures at week 4 ( 5MWT mean difference , .07 m/s ; 2MWT mean difference , 1.8 m ; BBS mean difference , 3.9 points ) . A significantly higher proportion of subjects in the circuit class therapy group were able to walk independently at discharge ( P=.01 ) and were satisfied with the amount of therapy received ( P=.007 ) . CONCLUSIONS Circuit class therapy appeared as effective as individual PT sessions for this sample of subjects receiving inpatient rehabilitation poststroke . Favorable results for circuit classes in terms of increased walking independence and patient satisfaction suggest this model of service delivery warrants further investigation [24982002] OBJECTIVE To compare the effect of a balance and stability-focused outpatient community-based rehabilitation and a regular physiotherapy program on balance , stability , and perceptions of improvement after acute stroke . DESIGN A r and omized controlled trial in a community-based therapy center . PARTICIPANTS Fifty consecutive patients with a first stroke , who reported to a community-based therapy center over a 7-month period were allocated to the control group ( regular physiotherapy ) or the experimental group ( balance and stability-focused rehabilitation ) . INTERVENTION A program of physiotherapy focused on balance and stability exercises . The control group received the regular physiotherapy program . MAIN OUTCOME MEASUREMENTS The Postural Assessment Scale for Stroke Patients ( PASS ) and the Berg Balance Scale ( BBS ) monitored stability and balance . The normalized data ( PASS and BBS ) were analyzed by using analysis of covariance . Qualitative data were thematically described . RESULTS Internal consistency of baseline PASS and BBS scores was high ( Cronbach α , .964 and .974 , respectively ) . PASS overall pretest scores increased from 21.96 ± 21.41 ( mean ± st and ard deviation ) and 21.52 ± 8.43 to 67.67 ± 28.42 and 80.16 ± 22.60 posttest in the control and experimental groups , respectively . Posttest scores were significantly different ( P = .004 ) . The effect size was medium ( .490 ) . The overall BBS scores showed overall mean ( st and ard deviation ) increases from 44.71 ± 22.24 and 43.43 ± 17.11 pretest to 48.71 ± 23.18 and 59.71 ± 18.20 posttest for the control and experimental groups , respectively . The effect size was considered medium ( .532 ) . CONCLUSION The balance and stability-focused community-based rehabilitation program was more effective in improving stability and balance in patients with stroke compared with the regular physiotherapy program in re source -poor setting [10768528] OBJECTIVE To evaluate the immediate and retention effects of a 4-week training program on the performance of locomotor-related tasks in chronic stroke . DESIGN R and omized , controlled pilot study with 2-month follow-up . SETTING Rehabilitation center . SUBJECTS A convenience sample consisting of 12 chronic stroke subjects was used . Subjects were r and omly assigned to the experimental or the control group . Three subjects withdrew from the study . INTERVENTION Both experimental and control groups participated in exercise classes three times a week for 4 weeks . The exercise class for the experimental group focused on strengthening the affected lower limb and practicing functional tasks involving the lower limbs , while the control group practice d upper-limb tasks . MAIN OUTCOME MEASURES Lower-limb function was evaluated by measuring walking speed and endurance , peak vertical ground reaction force through the affected foot during sit-to-st and , and the step test . RESULTS The experimental group demonstrated significant immediate and retained ( 2-month follow-up ) improvement ( p < or = .05 ) compared with the control group in walking speed and endurance , force production through the affected leg during sit-to-st and , and the number of repetitions of the step test . CONCLUSION The pilot study provides evidence for the efficacy of a task-related circuit class at improving locomotor function in chronic stroke [25357149] Objective The effects of combined aerobic and resistance exercise training on central arterial stiffness and gait velocity in patients with chronic poststroke hemiparesis were investigated . Design Twenty-six patients with chronic poststroke hemiparesis were r and omly assigned to either the combined aerobic and resistance exercise group ( n = 14 ) or the control group ( n = 12 ) . The exercise intervention group received a combined aerobic and resistance exercise training ( 1 hr/day , three times/week for 16 wks ) , whereas the control group received usual care . Central arterial stiffness was determined by pulse wave velocity and augmentation index . Gait velocity was assessed using the 6-min walk test , 10-m walk test , and the Timed Up- and -Go test . Results Patients in the exercise intervention group had greater improvement of mean pulse wave velocity ( P < 0.001 ) , augmentation index ( P = 0.048 ) , and gait velocity ( 6-min walk test , P < 0.001 ; 10-m walk test , P < 0.001 ) than did patients in the control group . Patients in the exercise intervention group also had greater improvements in physical fitness component ( grip strength , P < 0.001 ; muscular strength of upper and lower limbs , P < 0.027 ; flexibility , P < 0.001 ) when compared with control patients . Conclusions The combined aerobic and resistance exercise program significantly reduced central arterial stiffness and increased gait velocity in patients with chronic poststroke hemiparesis [16500170] OBJECTIVES To estimate the level of balance self-efficacy among community-dwelling subjects with stroke and to determine the relative importance of balance self-efficacy compared with functional walking capacity in predicting physical function and perceived health status . DESIGN Secondary analysis of baseline , postintervention , and 6-month follow-up data from a r and omized trial . SETTING General community . PARTICIPANTS Ninety-one subjects with a first or recurrent stroke , discharged from rehabilitation therapy with a residual walking deficit . INTERVENTIONS Not applicable . MAIN OUTCOME MEASURES The Activities-Specific Balance Confidence ( ABC ) Scale , Medical Outcomes Study 36-Item Short-Form Health Survey physical function scale , and the EQ-5D visual analog scale of perceived health status . RESULTS Average balance self-efficacy was 59 out of 100 points on the ABC scale ( 95 % confidence interval , 55 - 64 ; n=89 ) . After adjusting for age and sex , functional walking capacity explained 32 % and 0 % of the respective variability in physical function and perceived health status scores obtained 6 months later . After adjustment for age , sex , and functional walking capacity , balance self-efficacy explained 3 % and 19 % of variation in 6-month physical function and perceived health status scores , respectively . CONCLUSIONS Subjects living in the community after stroke experience impaired balance self-efficacy . Enhancing balance self-efficacy in addition to functional walking capacity may lead to greater improvement , primarily in perceived health status , but also in physical function , than the enhancement of functional walking capacity alone [20176772] Objectives : To explore whether a group programme for community-dwelling chronic stroke survivors and their carers is feasible in rural setting s ; to measure the impact of the programme on health-related quality of life and functional performance ; and to determine if any benefits gained are maintained . Design : R and omized , assessor blind , cross-over , controlled trial . Setting : Rural outpatient . Subjects : Twenty-five community-dwelling , chronic stroke survivors and 17 carers of participant stroke survivors . Intervention : The intervention group undertook a once-a-week , seven-week group programme combining physical activity , education , self-management principles and a ‘ healthy options ’ morning tea . At completion , the control group crossed over to receive the intervention . Main measures : Stroke Impact Scale ( stroke survivors ) , Health Impact Scale ( carers ) , Six Minute Walk Test , Timed Up and Go , Caregiver Strain Index . Results : There were insufficient participants for results to reach statistical significance . However between-group trends favoured the intervention group in the majority of outcome measures for stroke survivors and carers . The majority of measures remained above baseline at 12 weeks post programme for stroke survivor participants . The programme was well attended . Of the seven sessions all participants attended four or more and 88 % attended six or seven sessions . Conclusions : This novel programme incorporating physical activity , education and social interaction proved feasible to undertake by a stroke-specific multidisciplinary team in three rural Australian setting s. This programme may improve and maintain health-related quality of life and physical functioning for chronic stroke survivors and their carers and warrants further investigation [22111802] Rationale There is strong evidence for a dose – response relationship between physical therapy early after stroke and recovery of function . The optimal method of maximizing physical therapy within finite health care re sources is unknown . Aims To determine the effectiveness and cost-effectiveness of two alternative models of physical therapy service delivery ( seven-days per week therapy services or group circuit class therapy over five-days a week ) to usual care for people receiving inpatient rehabilitation after stroke . Design Multicenter , three-armed r and omized controlled trial with blinded assessment of outcomes . Study A total of 282 people admitted to inpatient rehabilitation facilities after stroke with an admission functional independence measure ( FIM ) score within the moderate range ( total 40–80 points or motor 38–62 points ) will be r and omized to receive one of three interventions : • usual care therapy over five-days a week • st and ard care therapy over seven-days a week , or • group circuit class therapy over five-days a week . Participants will receive the allocated intervention for the length of their hospital stay . Analysis will be by intention-to-treat . Outcomes The primary outcome measure is walking ability ( six-minute walk test ) at four-week postintervention with three- and six-month follow-up . Economic analysis will include a costing analysis based on length of hospital stay and staffing/re source costs and a cost-utility analysis ( incremental quality of life per incremental cost , relative to usual care ) . Secondary outcomes include walking speed and independence , ability to perform activities of daily living , arm function , quality of life and participant satisfaction [18240042] Purpose : To evaluate the impact of two different physiotherapy exercise regimes in patients after acute stroke on health-related quality of life ( HRQoL ) and to investigate how the degree of motor and balance function , gait capacity , activities of daily living and instrumental activities of daily living influenced HRQoL. Methods : A longitudinal r and omized controlled stratified trial of two interventions : the intensive exercise groups with scheduled intensive training during four periods of the first year after stroke and the regular exercise group with self-initiated training . Results : There was a tendency of better HRQoL in the regular exercise group on NHP total score ( p= 0.05 ) . Patients with low scores in activities of daily living , balance and motor function and inability to perform 6-minute walk test on admission , scored lower on self-perceived health than patients with high scores and ability to perform the walking test . At 1 year post-stroke , total scores on NHP were moderately associated with motor function ( r= −0.63 ) , balance ( r= −0.56 ) , gait ( r= −0.57 ) , activities of daily living ( r= −0.57 ) and instrumental activities of daily living ( r= −0.49–0.58 ) . The physical mobility sub-scale of NHP had the strongest association ranging from r= −0.47–0.82 . Conclusion : The regular exercise group with self-initiated training seemed to enhance HRQoL more than the intensive exercise group with scheduled intensive training . The degree of motor function , balance , walking capacity and independence in activities of daily living is of importance for perceived [27378733] BACKGROUND The cardiorespiratory fitness of stroke survivors is low . Center-based exercise programs that include an aerobic component have been shown to improve poststroke cardiorespiratory fitness . This pilot study aims to determine the feasibility , safety , and preliminary efficacy of an individually tailored home- and community-based exercise program to improve cardiorespiratory fitness and walking capacity in stroke survivors . METHODS Independently ambulant , community-dwelling stroke survivors were recruited . The control ( n = 10 ) and intervention ( n = 10 ) groups both received usual care . In addition the intervention group undertook a 12-week , individually tailored , home- and community-based exercise program , including once-weekly telephone or e-mail support . Assessment s were conducted at baseline and at 12 weeks . Feasibility was determined by retention and program participation , and safety by adverse events . Efficacy measures included change in cardiorespiratory fitness ( peak oxygen consumption [ VO2peak ] ) and distance walked during the Six-Minute Walk Test ( 6MWT ) . Analysis of covariance was used for data analysis . RESULTS All participants completed the study with no adverse events . All intervention participants reported undertaking their prescribed program . VO2peak improved more in the intervention group ( 1.17 ± .29 L/min to 1.35 ± .33 L/min ) than the control group ( 1.24 ± .23 L/min to 1.24 ± .33 L/min , between-group difference = .18 L/min , 95 % confidence interval [ CI ] : .01-.36 ) . Distance walked improved more in the intervention group ( 427 ± 123 m to 494 ± 67 m ) compared to the control group ( 456 ± 101 m to 470 ± 106 m , between-group difference = 45 m , 95 % CI : .3 - 90 ) . CONCLUSIONS Our individually tailored approach with once-weekly telephone or e-mail support was feasible and effective in selected stroke survivors . The 16 % greater improvement in VO2peak during the 6MWT achieved in the intervention versus control group is comparable to improvements attained in supervised , center-based programs [23093165] CONTEXT Most medical interventions have modest effects , but occasionally some clinical trials may find very large effects for benefits or harms . OBJECTIVE To evaluate the frequency and features of very large effects in medicine . DATA SOURCES Cochrane Data base of Systematic Review s ( CDSR , 2010 , issue 7 ) . STUDY SELECTION We separated all binary- outcome CDSR forest plots with comparisons of interventions according to whether the first published trial , a subsequent trial ( not the first ) , or no trial had a nominally statistically significant ( P < .05 ) very large effect ( odds ratio [ OR ] , ≥5 ) . We also sample d r and omly 250 topics from each group for further in-depth evaluation . DATA EXTRACTION We assessed the types of treatments and outcomes in trials with very large effects , examined how often large-effect trials were followed up by other trials on the same topic , and how these effects compared against the effects of the respective meta-analyses . RESULTS Among 85,002 forest plots ( from 3082 review s ) , 8239 ( 9.7 % ) had a significant very large effect in the first published trial , 5158 ( 6.1 % ) only after the first published trial , and 71,605 ( 84.2 % ) had no trials with significant very large effects . Nominally significant very large effects typically appeared in small trials with median number of events : 18 in first trials and 15 in subsequent trials . Topics with very large effects were less likely than other topics to address mortality ( 3.6 % in first trials , 3.2 % in subsequent trials , and 11.6 % in no trials with significant very large effects ) and were more likely to address laboratory-defined efficacy ( 10 % in first trials,10.8 % in subsequent , and 3.2 % in no trials with significant very large effects ) . First trials with very large effects were as likely as trials with no very large effects to have subsequent published trials . Ninety percent and 98 % of the very large effects observed in first and subsequently published trials , respectively , became smaller in meta-analyses that included other trials ; the median odds ratio decreased from 11.88 to 4.20 for first trials , and from 10.02 to 2.60 for subsequent trials . For 46 of the 500 selected topics ( 9.2 % ; first and subsequent trials ) with a very large-effect trial , the meta- analysis maintained very large effects with P < .001 when additional trials were included , but none pertained to mortality-related outcomes . Across the whole CDSR , there was only 1 intervention with large beneficial effects on mortality , P < .001 , and no major concerns about the quality of the evidence ( for a trial on extracorporeal oxygenation for severe respiratory failure in newborns ) . CONCLUSIONS Most large treatment effects emerge from small studies , and when additional trials are performed , the effect sizes become typically much smaller . Well-vali date d large effects are uncommon and pertain to nonfatal outcomes [20636719] Rationale Gait deficits contribute considerably to functional disability after stroke , and the regaining of walking ability is a major goal in most stroke rehabilitation programmes . Evidence suggests that muscular strengthening exercises after stroke can improve strength and activity . Additionally , task-related practice performed at high intensities may enhance walking competency in people with stroke . However , there is insufficient evidence to conclude which approach is most effective . Aim This study will test the hypothesis that task-specific walking training plus targeted strength training is superior to task-specific walking training alone in improving strength , motor co-ordination , quality of independent walking , and participation in acute stroke patients . Design This trial is a prospect i ve , r and omised clinical trial . People after stroke who are living at home and attending outpatient clinics will be r and omly allocated into either an experimental or a control group . The experimental group will undertake task-specific walking training , plus targeted strength training three times per week over 10 weeks , while the control group will only undertake task-specific walking training . At baseline , after 10 weeks of intervention and 4 weeks after the cessation of the interventions , allocation-blinded research ers will collect outcome measures . Study outcomes Primary outcomes will be measured for levels of impairment ( strength and co-ordination ) , activity ( quality of walking ) , and participation ( quality of life ) . Secondary outcomes will be the minimal clinical ly important differences of lower limb strength , motor co-ordination , and gait speed [25023152] Objective : Exercise has beneficial effects on vascular risk factors in transient ischaemic attack ( TIA ) patients within the sub-acute phase . This study examined whether TIA patients r and omized to an early exercise and education programme within 2 weeks of TIA diagnosis would demonstrate improvements in cardiovascular risk factors and aerobic fitness 12 months post-diagnosis compared with control patients . Methods : A single-centre , r and omized , parallel-group clinical trial . Sixty TIA patients ( 69 ± 11 years ) completed a vascular risk stratification baseline assessment and a physical fitness examination . Individuals were r and omized to either an 8-week early exercise and education group or control group . Fifty-one patients attended post-intervention assessment s that were completed immediately ( post-intervention ) and 12 months after ( 12PI ) . Results : A significantly greater improvement in resting SBP was observed between baseline and post-intervention for EX than for CON ( –11 mmHg cf . –1 mmHg , respectively ; P < 0.05 ) . The improvement in SBP was maintained between post-intervention and 12PI ( P > 0.05 ) . Similar findings were demonstrated for BMI , bodyweight and peak oxygen uptake ( P < 0.05 ) . Exercise blood pressure , pulse pressure and double product ( SBP x heart rate ; an indication of myocardial workload ) were significantly lower at post-intervention and 12PI for EX than for CON ( all P < 0.05 ) . Conclusion : An 8-week exercise programme soon after TIA result ed in beneficial changes in resting and exercise blood pressure that were maintained for 12 months . Clinical trial registration : http://www.anzctr.org.au/ Trial Registration Number : [16181164] OBJECTIVES To examine the effects of a community-based group exercise program for older individuals with chronic stroke . DESIGN Prospect i ve , single-blind , r and omized , controlled intervention trial . SETTING Intervention was community-based . Data collection was performed in a research laboratory located in a rehabilitation hospital . PARTICIPANTS Sixty-three older individuals ( aged > or = 50 ) with chronic stroke ( poststroke duration > or = 1 year ) who were living in the community . INTERVENTION Participants were r and omized into intervention group ( n=32 ) or control group ( n=31 ) . The intervention group underwent a fitness and mobility exercise ( FAME ) program design ed to improve cardiorespiratory fitness , mobility , leg muscle strength , balance , and hip bone mineral density ( BMD ) ( 1-hour sessions , three sessions/week , for 19 weeks ) . The control group underwent a seated upper extremity program . MEASUREMENTS Cardiorespiratory fitness ( maximal oxygen consumption ) , mobility ( 6-minute walk test ) , leg muscle strength ( isometric knee extension ) , balance ( Berg Balance Scale ) , activity and participation ( Physical Activity Scale for Individuals with Physical Disabilities ) , and femoral neck BMD ( using dual-energy x-ray absorptiometry ) . RESULTS The intervention group had significantly more gains in cardiorespiratory fitness , mobility , and paretic leg muscle strength than controls . Femoral neck BMD of the paretic leg was maintained in the intervention group , whereas a significant decline of the same occurred in controls . There was no significant time-by-group interaction for balance , activity and participation , nonparetic leg muscle strength , or nonparetic femoral neck BMD . CONCLUSION The FAME program is feasible and beneficial for improving some of the secondary complications result ing from physical inactivity in older adults living with stroke . It may serve as a good model of a community-based fitness program for preventing secondary diseases in older adults living with chronic conditions [14970978] OBJECTIVE To establish the test-retest reliability and concurrent validity with maximum oxygen consumption ( VO2max ) for 3 submaximal exercise tests in persons with chronic stroke : ( 1 ) submaximal treadmill test , ( 2 ) submaximal cycle ergometer test , and ( 3 ) 6-minute walk test ( 6MWT ) . DESIGN Prospect i ve study using a convenience sample . SETTING Free-st and ing tertiary rehabilitation center . PARTICIPANTS A volunteer sample of 12 community-dwelling individuals who had a stroke with moderate motor deficits . INTERVENTIONS Not applicable . MAIN OUTCOME MEASURES Heart rate , blood pressure , and oxygen consumption ( VO2 ) were assessed during the exercise tests . RESULTS Test-retest reliability was good to excellent for the exercise tests ( maximal and submaximal tests ) . VO2 for all submaximal measures related to VO2max ( r range , .66-.80 ) . Neither the 6MWT distance , self-selected gait speed , nor hemodynamic measures related to VO2max . CONCLUSION The VO2 measures of the submaximal exercise tests had excellent reliability and good concurrent validity with VO2max . Submaximal exercise tests may be a method by which to monitor the effects of interventions after a screening test ( eg , symptom-limited grade d exercise test , dobutamine stress echocardiograph ) [25483170] Stroke patients live with balance and walking dysfunction . Walking is the most important factor for independent community activities . The purpose of this study was to investigate the effect of a community walking training program ( CWTP ) within the real environment on walking function and social participation in chronic stroke patients . Twenty-two stroke patients ( 13 male , 50.45 years old , post stroke duration 231.64 days ) were r and omly assigned to either the CWTP group or the control group . All subjects participated in the same st and ard rehabilitation program consisting of physical and occupational therapy for 60 min per day , five times a week , for four weeks . In addition , the CWTP group participated in CWTP for 30 min per day , five times a week , for four weeks . Walking function was assessed using the 10-m walk test ( measurement for 10-meter walking speed ) , 6-min walk assessment ( measurement of gait length for 6-minutes ) , and community gait assessment . Social participation was assessed using a social participation domain of stroke impact scale . In walking function , greater improvement was observed in the CWTP group compared with the control group ( P < 0.05 ) . In addition , social participation improved more in the CWTP group compared with the control group ( P < 0.05 ) . These findings demonstrate the efficacy of CWTP on walking function and social participation in chronic stroke patients . Therefore , we suggest that CWTP within the real environment may be an effective method for improving walking function and social participation of chronic stroke patients when added to st and ard rehabilitation [11552860] The Berg Balance Scale ( BBS ) was design ed to help determine change in functional st and ing balance over time . The purpose of this paper was to estimate the minimum detectable change score ( MDC ) using the st and ard error of measure ( SEM ) , thereby providing a means to decide if genuine change had occurred . Calculation of the agreement regarding the presence of change as determined by the MDC and clinicians ' perceptions was performed to give an indication of the validity of this criterion value . Forty-eight subjects who were receiving inpatient rehabilitation after stroke were assessed on consecutive days by two raters using the BBS . The MDC analysis suggests that a change of + /- 6 BBS points is necessary to be 90 % confident of genuine change . Only 25/45 subjects showed agreement between the statistically derived presence of change and clinicians ' perceptions of change . The lack of agreement may relate to the validity of the SEM/MDC methodology to determine the criterion BBS value , the heterogeneity of the subjects , or the use of clinician gestalt impressions of change [18511529] Objective : To establish the effects of group exercise on mobility and strength . Design : R and omized controlled trial . Setting : Two public hospital outpatient rehabilitation services . Participants : One hundred and seventy-three people ( mean age 74.9 years , SD 10.8 ) with impaired mobility were r and omized and 159 people ( 92 % ) completed the trial . Interventions : Five-week , twice-weekly ` circuit-style ' group exercise programme run by a physiotherapist ( n = 85 ) and a no-intervention waiting list control group ( n = 88 ) . Main outcome measures : Three aspects of mobility : balance while st and ing and stepping ( Step Test , semi-t and em and t and em stance times ) ; sit-to-st and ability ( rate and minimum height ) and gait ( 6-metre and 6-minute walk tests ) . Lower limb muscle strength ( knee flexion and extension ) . Results : At retest , exercise participants had improved significantly more than their control counterparts on measures of balance while stepping , sit to st and and gait . Exercise participants averaged 1.6 more steps on the 15-second Step Test ( 95 % confidence interval ( CI ) 0.5 to 2.8 , P=0.005 ) , walked an average of 0.12 m/s faster ( 95 % CI 0.05 to 0.2 , P=0.002 ) and took 2.5 fewer steps in 6 metres ( 95 % CI —4.2 to —0.8 , P=0.004 ) . Exercise participants also averaged 0.04 more sit-to-st and s/second , ( 95 % CI 0.003 to 0.08 , P=0.037 ) and walked an average of 30.9 metres further in 6 minutes ( 95 % CI 9.4 to 52.4 , P=0.005 ) . There were no clinical ly important or statistically significant between-group differences at retest for the measures of strength ( knee extension and flexion ) , balance while st and ing or minimal sit-to-st and height . Conclusion : This short- duration circuit class programme improved mobility , but not strength [19969159] UNLABELLED Mudge S , Barber PA , Stott NS . Circuit-based rehabilitation improves gait endurance but not usual walking activity in chronic stroke : a r and omized controlled trial . OBJECTIVE To determine whether circuit-based rehabilitation would increase the amount and rate that individuals with stroke walk in their usual environments . DESIGN Single-blind r and omized controlled trial . SETTING Rehabilitation clinic . PARTICIPANTS Sixty participants with a residual gait deficit at least 6 months after stroke originally enrolled in the study . Two withdrew in the initial phase , leaving 58 participants ( median age , 71.5y ; range , 39.0 - 89.0y ) who were r and omized to the 2 intervention groups . INTERVENTIONS The exercise group had 12 sessions of clinic-based rehabilitation delivered in a circuit class design ed to improve walking . The control group received a comparable duration of group social and educational classes . MAIN OUTCOME MEASURES Usual walking performance was assessed using the StepWatch Activity Monitor . Clinical tests were gait speed ( timed 10-meter walk ) and endurance ( six-minute walk test [ 6MWT ] ) , confidence ( Activities-Based Confidence Scale ) , self-reported mobility ( Rivermead Mobility Index [ RMI ] ) , and self-reported physical activity ( Physical Activity and Disability Scale ) . RESULTS Intention-to-treat analysis revealed that the exercise group showed a significantly greater distance for the 6MWT than the control group immediately after the intervention ( P=.030 ) but that this effect was not retained 3 months later . There were no changes in the StepWatch measures of usual walking performance for either group . The exercise and control groups had significantly different gait speed ( P=.038 ) and scores on the RMI ( P=.025 ) at the 3-month follow-up . These differences represented a greater decline in the control group compared with the exercise group for both outcome measures . CONCLUSIONS Circuit-based rehabilitation leads to improvements in gait endurance but does not change the amount or rate of walking performance in usual environments . Clinical gains made by the exercise group were lost 3 months later . Future studies should consider whether rehabilitation needs to occur in usual environments to improve walking performance [17601461] OBJECTIVE To test the efficacy of functional electric stimulation (FES)-assisted exercise therapy ( FES-ET ) on a workstation in the subacute phase of recovery from a stroke . DESIGN Single-blind , r and omly controlled comparison of high- and low-intensity treatment . SETTING Laboratory in a rehabilitation hospital . PARTICIPANTS Nineteen stroke survivors ( 10 men , 9 women ; mean age + /- st and ard deviation , 60.6+/-5.8y ) , with upper-extremity hemiplegia ( mean poststroke time , 48+/-17d ) . The main inclusion criteria were : stroke occurred within 3 months of onset of trial and result ed in severe upper-limb dysfunction , and FES produced adequate h and opening . INTERVENTION An FES stimulator and an exercise workstation with instrumented objects were used by 2 groups to perform specific motor tasks with their affected upper extremity . Ten subjects in the high-intensity FES-ET group received FES-ET for 1 hour a day on 15 to 20 consecutive workdays . Nine subjects in the low-intensity FES-ET group received 15 minutes of sensory electric stimulation 4 days a week and on the fifth day they received 1 hour of FES-ET . MAIN OUTCOME MEASURES Primary outcome measure included the Wolf Motor Function Test ( WMFT ) . Secondary outcome measures included the Motor Activity Log ( MAL ) , the upper-extremity portion of the Fugl-Meyer Assessment ( FMA ) , and the combined kinematic score ( CKS ) derived from workstation measurements . The WMFT , MAL , and FMA were used to assess function in the absence of FES whereas CKS was used to evaluate function assisted by FES . RESULTS Improvements in the WMFT and CKS were significantly greater in the high-intensity group ( post-treatment effect size , .95 ) than the low-intensity group ( post-treatment effect size , 1.3 ) . The differences in MAL and FMA were not statistically significant . CONCLUSIONS Subjects performing high-intensity FES-ET showed significantly greater improvements on the WMFT than those performing low-intensity FES-ET . However , this was not reflected in subjects ' self- assessment s ( MAL ) or in their FMA scores , so the clinical significance of the result is open to debate . The CKS data suggest that high-intensity FES-ET may be advantageous in neuroprosthetic applications [16401430] OBJECTIVE To assess the effects of a community-based exercise program on motor recovery and functional abilities of the paretic upper extremity in persons with chronic stroke . DESIGN R and omized controlled trial . SETTING Rehabilitation research laboratory and a community hall . PARTICIPANTS A sample of 63 people ( > or = 50y ) with chronic deficits result ing from stroke ( onset > or = 1y ) . INTERVENTIONS The arm group underwent an exercise program design ed to improve upper-extremity function ( 1h/session , 3 sessions/wk for 19wk ) . The leg group underwent a lower-extremity exercise program . MAIN OUTCOME MEASURES The Wolf Motor Function Test ( WMFT ) , Fugl-Meyer Assessment ( FMA ) , h and -held dynamometry ( grip strength ) , and the Motor Activity Log . RESULTS Multivariate analysis showed a significant group by time interaction ( Wilks lambda=.726 , P=.017 ) , indicating that overall , the arm group had significantly more improvement than the leg group . Post hoc analysis demonstrated that gains in WMFT ( functional ability ) ( P=.001 ) and FMA ( P=.001 ) scores were significantly higher in the arm group . The amount of improvement was comparable to other novel treatment approaches such as constraint-induced movement therapy or robot-aided exercise training previously reported in chronic stroke . Participants with moderate arm impairment benefited more from the program . CONCLUSIONS The pilot study showed that a community-based exercise program can improve upper-extremity function in persons with chronic stroke . This outcome justifies a larger clinical trial to further assess efficacy and cost effectiveness [19541916] Background . Cognitive deficits impede stroke recovery . Aerobic exercise ( AEX ) improves cognitive executive function ( EF ) processes in healthy individuals , although the learning benefits after stroke are unknown . Objective . To underst and AEX-induced improvements in EF , motor learning , and mobility poststroke . Methods . Following cardiorespiratory testing , 38 chronic stroke survivors were r and omized to 2 different groups that exercised 3 times a week ( 45-minute sessions ) for 8 weeks . The AEX group ( n = 19 ; 9 women ; 10 men ; 64.10 ± 12.30 years ) performed progressive resistive stationary bicycle training at 70 % maximal heart rate , whereas the Stretching Exercise ( SE ) group ( n = 19 ; 12 women ; 7 men ; 58.96 ± 14.68 years ) performed stretches at home . Between-group comparisons were performed on the change in performance at “ Post ” and “ Retention ” ( 8 weeks later ) for neuropsychological and motor function measures . Results . VO2max significantly improved at Post with AEX ( P = .04 ) . AEX also improved motor learning in the less-affected h and , with large effect sizes ( Cohen ’s d calculation ) . Specifically , AEX significantly improved information processing speed on the serial reaction time task ( SRTT ; ie , “ procedural motor learning ” ) compared with the SE group at Post ( P = .024 ) , but not at Retention . Also , at Post ( P = .038 ) , AEX significantly improved predictive force accuracy for a precision grip task requiring attention and conditional motor learning of visual cues . Ambulation and sit-to-st and transfers were significantly faster in the AEX group at Post ( P = .038 ) , with balance control significantly improved at Retention ( P = .041 ) . EF measurements were not significantly different for the AEX group . Conclusion . AEX improved mobility and selected cognitive domains related to motor learning , which enhances sensorimotor control after stroke [17537090] OBJECTIVES To determine the feasibility and effect of exercise training after stroke . DESIGN R and omized exploratory trial comparing exercise training ( including progressive endurance and resistance training ) with relaxation ( attention control ) . SETTING Interventions were performed in a rehabilitation hospital . PARTICIPANTS Sixty-six independently ambulatory patients ( mean age 72 , 36 men ) without significant dysphasia , confusion , or medical contraindications to exercise training who had completed their usual rehabilitation and had been discharged from hospital . INTERVENTION Both interventions were held three times a week for 12 weeks . Up to seven patients attended each session . MEASUREMENTS The Functional Independence Measure ; Nottingham Extended Activities of Daily Living ; Rivermead Mobility Index ; functional reach ; sit-to-st and ; elderly mobility score ; timed up- and -go ; Medical Outcomes Study 36-Item Short Form Question naire , version 2 ( SF-36 ) ; Hospital Anxiety and Depression Score ; aspects of physical fitness ( comfortable walking speed , walking economy , and explosive leg extensor power ) were measured at baseline , immediately after interventions ( 3 months ) , and 7 months after baseline . RESULTS The median number of intervention sessions attended was 36 ( interquartile range ( IQR ) 30.00 - 36.75 ) for exercise and 36 ( IQR 30.50 - 37.00 ) for relaxation . Adherence to the individual exercises ranged from 94 % to 99 % . At 3 months , role-physical ( an item in SF-36 ) , timed up- and -go , and walking economy were significantly better in the exercise group ( analysis of covariance ) . At 7 months , role-physical was the only significant difference between groups . CONCLUSION Exercise training for ambulatory stroke patients was feasible and led to significantly greater benefits in aspects of physical function and perceived effect of physical health on daily life [17895349] Background and Purpose : A phase II , single-blinded , r and omized clinical trial was conducted to determine the effects of combined task-specific and lower-extremity ( LE ) strength training to improve walking ability after stroke . Subjects : The participants were 80 adults who were ambulatory 4 months to 5 years after a unilateral stroke . Method : The exercise interventions consisted of body-weight – supported treadmill training ( BWSTT ) , limb-loaded resistive leg cycling ( CYCLE ) , LE muscle-specific progressive-resistive exercise ( LE-EX ) , and upper-extremity ergometry ( UE-EX ) . After baseline assessment s , participants were r and omly assigned to a combined exercise program that included an exercise pair . The exercise pairs were : BWSTT/UE-EX , CYCLE/UE-EX , BWSTT/CYCLE , and BWSTT/LE-EX . Exercise sessions were 4 times per week for 6 weeks ( total of 24 sessions ) , with exercise type completed on alternate days . Outcomes were self-selected walking speed , fast walking speed , and 6-minute walk distance measured before and after intervention and at a 6-month follow-up . Results : The BWSTT/UE-EX group had significantly greater walking speed increases compared with the CYCLE/UE-EX group ; both groups improved in distance walked . All BWSTT groups increased walking speed and distance whether BWSTT was combined with LE strength training or not . Discussion and Conclusion : After chronic stroke , task-specific training during treadmill walking with body-weight support is more effective in improving walking speed and maintaining these gains at 6 months than resisted leg cycling alone . Consistent with the overtraining literature , LE strength training alternated daily with BWSTT walking did not provide an added benefit to walking outcomes [17008338] Objective : To examine the effectiveness of task-oriented progressive resistance strength training on lower extremity strength and functional performance in chronic stroke subjects . Design : Single-blind , r and omized controlled trial . Setting : Medical centre and district hospital . Subjects : Forty-eight subjects at least one year post stroke . Interventions : Participants r and omly allocated to two groups , control ( n-/24 ) and experimental ( n-/24 ) . Subjects in the control group did not receive any rehabilitation training . Subjects in the experimental group were put on a four-week task-oriented progressive resistance strength training . Main measures : Lower extremity muscle strength , gait velocity , cadence , stride length , six-minute walk test , step test , and timed up and go test . Results : Muscle strength significantly improved in the experimental group for strong side muscle groups ( ranged from 23.9 % to 36.5 % ) and paretic side muscle groups ( ranged from 10.1 % to 77.9 % ) . In the control group muscle strength changes ranged from 6.7 % gain to 11.2 % decline . The experimental group showed significant improvement in all selected measures of functional performance except for the step test . In the control group , the number of repetitions of the step test significantly decreased ( -20.3 % ) with no change in other functional tests . There was a significant difference between groups for muscle strength and all functional measures . The strength gain was significantly associated with gain in the functional tests . Conclusions : The task-oriented progressive resistance strength training programme could improve lower extremity muscle strength in individuals with chronic stroke and could carry over into improvement in functional abilities [21844283] Background . Sitting balance and the ability to perform selective truncal movements are important predictors of functional outcome after stroke . However , few clinical trials have evaluated the effect of truncal exercises . Objective . The authors assessed the effect of additional truncal exercises on truncal function , st and ing balance , and mobility . Methods . An assessor-blinded r and omized controlled trial was carried out at a stroke rehabilitation hospital . A total of 33 participants ( mean 35 days post onset ) were r and omly assigned to an experimental group ( n = 18 ) or a control group ( n = 15 ) . In addition to conventional therapy , the experimental group received 16 hours of truncal exercises . The control group received 16 hours of sham treatment . Truncal function was evaluated by the Trunk Impairment Scale ( TIS ) and st and ing balance and mobility by the Tinetti Test . The Romberg with eyes open and eyes closed , Four Test Balance Scale ( FTBS ) , Berg Balance Scale ( BBS ) , Rivermead Motor Assessment Battery ( RMAB ) , Functional Ambulation Categories , and Dynamic Gait Index ( DGI ) were performed to eluci date the findings of the primary outcome measures . Results . A treatment effect was found for the experimental group on the TIS ( P < .001 ) , Tinetti Test ( P < .001 ) , FTBS ( P = .014 ) , BBS ( P = .007 ) , RMAB ( P < .001 ) , and DGI ( P = .006 ) . Conclusions . In addition to conventional therapy , truncal exercises have a beneficial effect on truncal function , st and ing balance , and mobility in people after stroke [22120031] Abstract Background and Objective : The ability to walk is impaired in more than 80 % of poststroke patients . The objective of the present study was to evaluate the effectiveness of the task-oriented circuit class training ( TOCCT ) with motor imagery ( MI ) on the gait during the subacute phase after a stroke . Method : This was a r and omized , controlled , assessor-blinded trial in a neurology department of a university hospital . A convenience sample of 30 people , 4 to 12 weeks ( mean , 6.3 weeks ) after the stroke was r and omized into 2 groups ( the TOCCT with MI and st and ard training group ) of 15 people each . Twenty-nine participants completed the 6-week follow-up . Participants were assigned to receive either the TOCCT with MI or dose-matched st and ard training program based on the Bobath ’s neurodevelopmental technique , 7 days a week for 2 weeks , as out patients or in patients . Outcome measures were the Functional Ambulation Classification ( FAC ) , the Rivermead Visual Gait Assessment ( RVGA ) , step length asymmetry , walking speed , and 6-minute walk test ( 6MWT ) . Results : The TOCCT with MI group showed a positive improvement in the mean/median scores on most of the outcome measures at post and follow-up assessment s in comparison to the control group . However , statistically significant differences were observed in changes between the groups at post and follow-up assessment for FAC , RVGA , walking speed , and 6MWT ( ANOVA , P = .001 to .049 ; Mann-Whitney U test , P = .001 ) . Conclusion : Among the patients who had a stroke within the previous 4 to 12 weeks , the TOCCT with MI produced statistically significant and clinical ly relevant improvements in the gait and the gait-related activities [22668675] Abstract Background / Objective : The upper extremity motor deficit is one of the functional challenges in post stroke patients . The objective of the present study was to evaluate the effectiveness of the meaningful task-specific training ( MTST ) on the upper extremity motor recovery during the subacute phase after a stroke . Method : This was a r and omized , controlled , double-blinded trial in the neurology department of a university hospital and occupational therapy unit of a rehabilitation institute . A convenience sample of 103 people , 4 to 24 weeks ( mean , 12.15 weeks ) after the stroke , was r and omized into 2 groups ( MTST , 51 ; st and ard training group , 52 ) . Subjects in the Brunnstrom stage of arm recovery of 2 to 5 were included in the study . Ninety-five participants completed the 8-week follow-up . Interventions : Participants were assigned to receive either the MTST or dose-matched st and ard training program based on the Brunnstrom stage and Bobath neurodevelopmental technique , 4 to 5 days a week for 4 weeks . Fugl-Meyer assessment ( FMA ) , Action Research Arm Test ( ARAT ) , Grade d Wolf Motor Function Test ( GWMFT ) , and Motor Activity Log ( MAL ) were outcome measures Results : The MTST group showed a positive improvement in the mean scores on the outcome measures at post and follow-up assessment s in comparison to the control group . Further , statistically significant differences were observed in changes between the groups at post and follow-up assessment for FMA , ARAT , GWMFT , and MAL . Conclusion : The MTST produced statistically significant and clinical ly relevant improvements in the upper extremity motor recovery of the patients who had a subacute stroke [24473242] BACKGROUND Despite the beneficial effect of cardiac rehabilitation after myocardial infa rct ion , a rehabilitation program to improve cardiorespiratory fitness and influence secondary prevention has not been implemented for ischemic stroke and transient ischemic attack ( TIA ) . OBJECTIVE To investigate the safety and feasibility of a post-stroke care including an exercise program after minor ischemic stroke or TIA . METHODS In a r and omised controlled trial , 20 patients with a recent minor stroke or TIA without cardiac contraindications were r and omly assigned to one of the two interventions ; post-stroke care without exercise or post-stroke care with exercise . Patients were evaluated at baseline , 6 and 12 months . RESULTS Eighteen patients completed the intervention . In none of the patients cardiopulmonary contraindications for the maximal exercise test and exercise program were found . No cardiovascular events occurred during the maximal exercise tests and exercise program . After one year , significantly more patients in the post-stroke care with exercise group achieved the composite endpoint of optimal medical therapy . CONCLUSIONS Post-stroke care including an exercise program is safe and feasible in the acute phase after minor stroke or TIA and might be a way to increase effectiveness of secondary stroke prevention . We are currently conducting a larger trial to vali date these results Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Repetitive task training ( RTT ) involves the active practice of task-specific motor activities and is a component of current therapy approaches in stroke rehabilitation . OBJECTIVES Primary objective : To determine if RTT improves upper limb function/reach and lower limb function/balance in adults after stroke . Secondary objectives : 1 ) To determine the effect of RTT on secondary outcome measures including activities of daily living , global motor function , quality of life/health status and adverse events . 2 ) To determine the factors that could influence primary and secondary outcome measures , including the effect of ' dose ' of task practice ; type of task ( whole therapy , mixed or single task ) ; timing of the intervention and type of intervention . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

19487615

[14586050] Background : Until now , care provided by asthma nurses has been additional to care provided by paediatricians . A study was undertaken to compare nurse led outpatient management of childhood asthma with follow up by a paediatrician . Methods : Seventy four children referred because of insufficient control of persistent asthma were r and omly allocated to 1 year follow up by a paediatrician or asthma nurse . The main outcome measure was the percentage of symptom-free days . Additional outcome measures were airway hyperresponsiveness , lung function , daily dose of inhaled corticosteroids ( ICS ) , number of exacerbations , number of additional visits to the general practitioner , absence from school , functional health status , and disease specific quality of life . Results : There were no significant differences at the end of the 1 year study period between the two treatment groups in percentage of symptom-free days ( mean difference 2.5 % ; 95 % CI −8.8 to 13.8 ) , airway hyperresponsiveness ( log10 PD20 0.06 ; −0.19 to 0.32 ) , functional health status ( 10.1 ; −0.3 to 19.8 ) , disease specific quality of life of patients ( 0.08 ; −0.9 to 0.7 ) , and disease specific quality of life of caregivers ( 0.09 ; −0.2 to 0.3 ) , nor in any other outcome parameters . Most outcome parameters improved considerably over the 1 year study period . These improvements were achieved although the daily dose of ICS was reduced by a mean of 26 % compared with the dose received by children at referral . All parents were satisfied with the asthma care received . Conclusions : After initial assessment in a multidisciplinary clinic , childhood asthma can be successfully managed by an asthma nurse in close cooperation with a paediatrician . During close follow up by paediatrician or asthma nurse , asthma control improved despite a reduction in ICS dose [15356304] BACKGROUND Children with asthma who live in the inner city are exposed to multiple indoor allergens and environmental tobacco smoke in their homes . Reductions in these triggers of asthma have been difficult to achieve and have seldom been associated with decreased morbidity from asthma . The objective of this study was to determine whether an environmental intervention tailored to each child 's allergic sensitization and environmental risk factors could improve asthma-related outcomes . METHODS We enrolled 937 children with atopic asthma ( age , 5 to 11 years ) in seven major U.S. cities in a r and omized , controlled trial of an environmental intervention that lasted one year ( intervention year ) and included education and remediation for exposure to both allergens and environmental tobacco smoke . Home environmental exposures were assessed every six months , and asthma-related complications were assessed every two months during the intervention and for one year after the intervention . RESULTS For every 2-week period , the intervention group had fewer days with symptoms than did the control group both during the intervention year ( 3.39 vs. 4.20 days , P<0.001 ) and the year afterward ( 2.62 vs. 3.21 days , P<0.001 ) , as well as greater declines in the levels of allergens at home , such as Dermatophagoides farinae ( Der f1 ) allergen in the bed ( P<0.001 ) and on the bedroom floor ( P=0.004 ) , D. pteronyssinus in the bed ( P=0.007 ) , and cockroach allergen on the bedroom floor ( P<0.001 ) . Reductions in the levels of cockroach allergen and dust-mite allergen ( Der f1 ) on the bedroom floor were significantly correlated with reduced complications of asthma ( P<0.001 ) . CONCLUSIONS Among inner-city children with atopic asthma , an individualized , home-based , comprehensive environmental intervention decreases exposure to indoor allergens , including cockroach and dust-mite allergens , result ing in reduced asthma-associated morbidity [8428857] The parents of asthmatic children treated in the pediatric respiratory service of Wolfson Hospital were r and omly divided into two groups . One group compromised 26 parents who voluntarily attended a teaching session . After completion of the course , a question naire was completed by parents who had attended the course and parents who had not . The first group showed greater knowledge of all aspects of the disease and , after a year 's follow up , it was noted that there was a statistically significant lower hospitalization rate of their asthmatic child [11809988] Background : The effects on morbidity were examined of providing an educational intervention and a written guided self-management plan to the parents of pre-school children following a recent attendance at hospital for asthma or wheeze . Methods : A prospect i ve , r and omised , partially blinded , controlled trial was design ed at two secondary care centres . Over a 13 month period 200 children aged 18 months to 5 years at the time of admission to a children 's ward or attendance at an accident and emergency department or children 's ( emergency ) assessment unit ( A&E/CAU ) with a primary diagnosis of acute severe asthma or wheezing were recruited . 101 children were r and omised into the control group and received usual care and 99 were assigned to the intervention group and received : ( 1 ) a pre-school asthma booklet ; ( 2 ) a written guided self-management plan ; and ( 3 ) two 20 minute structured educational sessions between a specialist respiratory nurse and the parent(s ) and child . Subjects were assessed at 3 , 6 , and 12 months . The main outcomes were GP consultation rates , hospital re-admissions , and attendances at A&E/CAU . Secondary outcomes included disability score , caregivers ' quality of life , and parental knowledge of asthma . Results : There were no statistically significant differences between the two groups during the 12 month follow up period for any of the main or secondary outcome measures . Conclusions : These results do not support the hypothesis that the introduction of an educational package and a written guided self-management plan to the parents of pre-school children with asthma who had recently attended hospital for troublesome asthma or wheeze reduces morbidity over the subsequent 12 months [9565410] OBJECTIVES This study was conducted to assess the impact of an interactive seminar based on self-regulation theory on 1 ) the treatment practice s and communications and education behavior of physicians , 2 ) the health status and medical care utilization of their pediatric patients with asthma , and 3 ) the satisfaction with care of the subjects ' parents . METHODS A total of 74 general practice pediatricians were assigned to either a program or a control group in a r and omized controlled study . Data were collected from physicians at baseline , and 69 ( 93 % ) provided follow-up data 5 months after the program . Data were also collected from 637 of their patients at baseline , and in a 22-month window after the intervention , 472 ( 74 % ) of this number provided follow-up data . RESULTS After the seminar , physicians in the program group were more likely than were control group physicians to address patients ' fears about medicines , review written instructions , provide a sequence of educational messages , write down how to adjust the medicines at home when symptoms change , and report that they spent less time with their patients . Parents of the children treated by program physicians were significantly more likely than were control group parents to report that the physician had been reassuring , described as a goal that the child be fully active , and gave information to relieve specific worries . After a visit with the physician , these parents were also more likely to report that they knew how to make management decisions at home . After the intervention compared to controls , patients of physicians in the program group were more likely to have received a prescription for inhaled antiinflammatory medicine and to have been asked by the physician to demonstrate how to use a metered-dose inhaler . After the intervention , children seen by program physicians made significantly fewer nonemergency office visits and visits for follow-up of an episode of symptoms ; however , there were no differences in emergency department visits and hospitalizations . Among children who were placed on inhaled corticosteroids during this study , however , children treated by physicians who had received education had significantly fewer symptoms and fewer follow-up office visits , nonemergency physician office visits , emergency department visits , and hospitalizations . CONCLUSIONS The interactive seminar based on theories of self-regulation led to patient-physician encounters that were of shorter duration , had significant impact on the prescribing and communications behavior of physicians , led to more favorable patient responses to physicians ' actions , and led to reductions in health care utilization [15867121] OBJECTIVE To test a quality improvement intervention , a learning collaborative based on the Institute for Healthcare Improvement 's Breakthrough Series methodology , specifically intended to improve care and outcomes for patients with childhood asthma . DESIGN R and omized trial in primary care practice s. SETTING Practice s in greater Boston , Mass , and greater Detroit , Mich. PARTICIPANTS Forty-three practice s , with 13 878 pediatric patients with asthma , r and omized to intervention and control groups . Intervention Participation in a learning collaborative project based on the Breakthrough Series methodology of continuous quality improvement . MAIN OUTCOME MEASURES Change from baseline in the proportion of children with persistent asthma who received appropriate medication therapy for asthma , and in the proportion of children whose parent received a written management plan for their child 's asthma , as determined by telephone interviews with parents of 631 children . RESULTS After adjusting for state , practice size , child age , sex , and within- practice clustering , no overall effect of the intervention was found . CONCLUSIONS This method ologically rigorous assessment of a widely used quality improvement technique did not demonstrate a significant effect on processes or outcomes of care for children with asthma . Potential deficiencies in program implementation , project duration , sample selection , and data sources preclude making the general inference that this type of improvement program is ineffective . Additional rigorous studies should be undertaken under more optimal setting s to assess the efficacy of this method for improving care [11040726] An interactive multimedia computer game to enhance self-management skills and thereby improve asthma outcomes in inner city children with asthma was evaluated . Subjects aged 6 - 17 were recruited from four pediatric practice s and r and omly assigned to the computer intervention condition or to the usual-care comparison . The main character in the game could match the subject on gender and ethnicity . Characteristics of the protagonist 's asthma were tailored to be like those of the subject . Subjects played the computer game as part of regular asthma visits . Time between pre- and post-test varied from 4 to 15.6 months ( mean , 7.6 months ) . Analysis of covariance , with pre-test scores , age , and asthma severity as covariates , found that the intervention was associated with fewer hospitalizations , better symptom scores , increased functional status , greater knowledge of asthma management , and better child self-management behavior for those in the intervention condition . Interactions with covariates were found and discussed in terms of variable efficacy of the intervention [15582348] This study describes a self-treatment program for parents of children with asthma . The aim was to prevent asthma exacerbations by learning to recognise prodromal signs and acting upon them by increasing inhaled corticosteroids ( ICS ) . The study questions were : ( 1 ) can we teach parents and children to recognise prodromal signs ? ( 2 ) are instructions to increase inhalation medication followed ? ( 3 ) will frequency and severity of asthma attacks diminish subsequently ? Due to physicians ' changed attitude towards prescription of ICS , fewer children could be recruited who were " ICS-naive " than expected . Twenty-nine children of the age of 4 - 11 years with moderate asthma , participated in a one year prospect i ve r and omised study . Structured information was given to all patients on asthma , symptoms and medication . The experimental group received additional information on recognising prodromal signs and doubling ICS during one week . Only in 25 % of the patients who recognised prodromal signs the dose of ICS was doubled ( as prescribed ) , in 75 % inadequately or not at all . Recognition of prodromal signs was poor as well as compliance to increase as-needed medication . No significant decrease of asthma symptoms occurred in the experimental group . Clinical implication s are important for self-treatment instructions : an individually tailored and multi-component program should be offered by health care providers in order to help the patient to recognise early alarm symptoms , comply to self-treatment instructions and to make adaptations for continuous self-regulation [1984619] Care of asthmatic children is often episodic and more therapeutic than preventive . A 2-year r and omized , controlled trial involving 95 children measured the impact of a comprehensive home and ambulatory program for pediatric asthma management using objective outcome measures . Interventions for the study group during the first year included 3-month clinic visits , education , and home visits by a specially trained research nurse . Control subjects continued to receive regular care from a family physician or pediatrician . Eight-nine subjects ( 93 % ) completed the study . Study subjects had less school absenteeism than control subjects ( 10.7 vs. 16.0 days , P = .04 ) and showed significantly better small airway function after 1 year . Asthma severity improved in 13 study subjects and worsened in 5 . The reverse was true for control subjects . Study subjects exhibited better metered aerosol technique than control subjects ( P = .0005 ) . Fewer days were spent in hospital by the study subjects admitted compared with control subjects ( 3.67 vs 11.2 days , P = .02 ) . After 1 year , more study than control families ( 72.1 % vs 33.1 % , P = .006 ) reported that their asthmatic child took responsibility for the asthma management . The intervention failed to reduce exposure to secondh and smoke or to household pets . There were no significant differences in medical visits , theophylline levels , or records of asthma symptoms . One year after discontinuing the intervention , a marked " washout " effect was observed . Comprehensive ambulatory programs of childhood asthma management can improve objective measures of illness severity but must be sustained [16336546] OBJECTIVE To assess the practice -level effects of ( 1 ) a physician peer leader intervention and ( 2 ) peer leaders in combination with the introduction of asthma education nurses to facilitate care improvement . And , to compare findings with previously reported patient-level outcomes of trial enrollees . STUDY SETTING Data were included on children 5 - 17 years old with asthma in 40 primary care practice s , affiliated with managed health care plans enrolled in the Pediatric Asthma Care Patient Outcomes Research Team ( PORT ) r and omized trial . STUDY DESIGN Primary care practice s were r and omly assigned to one of two care improvement arms or to usual care . Automated cl aims data were analyzed for 12-month periods using a repeated cross-sectional design . The primary outcome was evidence of at least one controller medication dispensed among patients with persistent asthma . Secondary outcomes included controller dispensing among all identified asthmatics , evidence of chronic controller use , and the dispensing of oral steroids . Health service utilization outcomes included numbers of ambulatory visits and hospital-based events . PRINCIPAL FINDINGS The proportion of children with persistent asthma prescribed controllers increased in all study arms . No effect of the interventions on the proportion receiving controllers was detected ( peer leader intervention effect 0.01 , 95 percent confidence interval [ CI ] : -0.07 , 0.08 ; planned care intervention effect -0.03 , 95 percent CI : -0.09 , 0.02 ) . A statistical trend was seen toward an increased number of oral corticosteroid bursts dispensed in intervention practice s. Significant adjusted increases in ambulatory visits of 0.08 - 0.10 visits per child per year were seen in the first intervention year , but only a statistical trend in these outcomes persisted into the second year of follow-up . No differences in hospital-based events were detected . CONCLUSIONS This analysis showed a slight increase in ambulatory asthma visits as a result of asthma care improvement interventions , using automated data . The absence of detectable impact on medication use at the practice level differs from the positive intervention effect observed in patient self-reported data from trial enrollees . Analysis of automated data on nonenrollees adds information about practice -level impact of care improvement strategies . Benefits of practice -level interventions may accrue disproportionately to the subgroup of trial enrollees . The effect of such interventions may be less apparent at the level of practice s or health plans [6384911] A r and omized control trial of a curriculum , A.C.T. ( Asthma Care Training ) for Kids , was conducted . Seventy-six children between the ages of 8 and 12 years , whose asthma required treatment with medications at least 25 % of the days per month , were r and omly assigned to control and experimental groups . The control group received 4 1/2 hours of lecture presentations on asthma and its management . The experimental groups ( consisting of four to seven children and their parents ) received five 1-hour sessions comprising " the treatment . " Children and their parents were interviewed before the sessions and 3 , 6 , and 12 months after the completion of the experimental treatment . Use of emergency rooms and hospitals was determined by review ing the records of these patients ( all members of the Los Angeles Kaiser Permanente health care system ) for the period of 1 year before and 1 year after the treatment . Results include ( 1 ) equivalent increases in knowledge and changes in beliefs in both groups , ( 2 ) significant changes in the self-reported compliance behaviors of the experimental group only , and ( 3 ) significant reductions in emergency room visits and days of hospitalization among those receiving the experimental treatment , compared with the control group . These changes represent an estimated savings of approximately $ 180 per child per year for those in the experimental group [15982192] Optimal home self-management in young children with asthma includes accurate symptom identification followed by timely and appropriate treatment . The objective of this study was to evaluate a home-based asthma educational intervention targeting symptom identification for parents of children with asthma . Two hundred twenty-one children with asthma were enrolled into an ongoing home-based clinical trial and r and omized into either a st and ard asthma education ( SAE ) or a symptom/nebulizer education intervention ( SNEI ) . Data included home visit records and parent 's self-report on question naires . Symptom identification and self-management skills significantly improved from preintervention to postintervention for parents in both groups with the exception of checking medications for expiration date s and the frequency of cleaning nebulizer device and equipment . However , significantly more parents of children in the SNEI group reported treating cough symptoms as compared with the SAE group ( p = 0.05 ) . Of concern is that only 38 % of all parents reported having an asthma action plan in the home . A targeted home-based asthma education intervention can be effective for improving symptom identification and appropriate use of medications in children with asthma . Home asthma educational programs should address accurate symptom identification and a demonstration of asthma medication delivery devices [10933079] This r and omized clinical trial evaluated the long-term impact of an interactive seminar for physicians based on principles of self-regulation on clinician behaviour , children 's use of health services for asthma , and parent 's views of physician performance . Seventy-four general practice paediatricians , and 637 of their asthma patients aged 1 - 12 yrs , were r and omized to treatment or control . Children and parents were blind to physicians ' participation . Data were collected at baseline and follow-up through self-administered surveys ( paediatricians ) , telephone interviews ( parents ) and medical records . The seminar focused on development of communication and teaching skills and use of therapeutic medical regimens for asthma as outlined in the National Asthma Education and Prevention Program guidelines . Approximately 2 yrs postintervention , treatment group physicians were more likely than control physicians to : use protocol s for delivering asthma education ( odds ratio ( OR ) 4.9 , p=0.2 ) , write down for patients how to adjust medicines when symptoms change ( OR 5.7 , p=0.05 ) , and provide more guidelines for modifying therapy ( OR 3.8 , p=0.06 ) . Parents scored treatment group physicians higher than control physicians on five specific positive communication behaviours . Children seen by treatment group physicians had fewer hospitalizations ( p=0.03 ) and those with higher levels of emergency department ( ED ) use at baseline had fewer subsequent ED visits ( p=0.03 ) . No differences regarding the number of office visits were noted . There were no significant differences found between treatment and control group physicians in the amount of time spent with patients during office visits ( 26 versus 29 min ) or in the number of patients treated with anti-inflammatory medicine . It is concluded that interactive asthma seminars for paediatricians had significant long-term benefits for their asthma care [12528584] AIM To compare a nurse-led clinic in schools versus care in general practice for adolescents with asthma . DESIGN OF STUDY R and omised controlled trial in four schools ; parallel observational study in two schools . SETTING Six comprehensive schools . METHOD In the r and omised trial , pupils were invited to attend asthma review at a nurse-led clinic either in school , or in general practice . The parallel observational study compared pupils invited to practice care within and outside the r and omised trial . Primary outcome measures were attendance for asthma review , symptom control , and quality of life . Secondary outcomes were knowledge , attitudes , inhaler technique , use of steroids , school absence , peak flow rate , preference for future care , health service utilisation , and costs . RESULTS School clinic pupils were more likely to attend an asthma review than those r and omised to practice care ( 90.8 % versus 51.0 % overall [ P < 0.001 , not consistent across schools ] ) . No differences were observed in symptom control ( P = 0.42 ) or quality of life ( P = 0.63 ) . Pupils attending school clinics had greater knowledge of asthma ( difference = + 0.38 , 95 % CI = 0.19 to 0.56 ) , more positive attitudes ( difference = + 0.21 , 95 % CI = 0.05 to 0.36 ) , and better inhaler technique ( P < 0.001 , not consistent across all schools ) . No differences were observed in school absence or peak flow rate . A majority ( 63 % ) of those who had received care at school preferred this model in future . Median costs of providing care at school and at the practice were 32.10 Pounds and 19.80 Pounds , respectively . No differences were observed between the groups in the observational comparison on any outcome . CONCLUSIONS The schools asthma clinic increased uptake of asthma review s. There were improvements in various process measures , but not in clinical outcomes [1506461] Children with asthma are at special risk for problems in psychological functioning , as are children with other chronic illnesses . We conducted a controlled trial of a combined education and stress management program among children ages 6 to 14 years with asthma . Eighty-one children were r and omly assigned to an intervention or a control group ; 56 children completed data collection , 29 intervention and 27 control . Psychological status was assessed by the Child Behavior Checklist ( CBCL ) before and after the intervention , as were children 's knowledge of asthma , stress ( as measured by children 's life events ) , and functional status ( as indicated by such activities as school attendance , time playing with friends , and daily chore performance ) . Children in the intervention group had a significant improvement in the total Behavior Problems score ( p < .04 ) and Internalizing scale ( p < .01 ) on the CBCL and a significant increase in daily chores ( p < .04 ) compared with the control group . Before intervention , the two groups had statistically significant positive relationships between negative life events and behavior problem scores . After intervention , children in the control group still demonstrated a significant relationship between negative life events and total and Internalizing Behavior Problem scores , although participation in the intervention group negated that relationship . Children in the intervention group whose knowledge of asthma increased were more likely to report an increase in daily chores ( p < .02 ) . We conclude that the intervention had a beneficial effect on psychological status and on children 's daily activities . The effect may have occurred in part by decreasing the likelihood that perceived stress from negative life events led to poorer adjustment [14500440] Abstract Objectives To assess the feasibility and effectiveness of a general practice based , proactive system of asthma care in children . Design R and omised controlled trial with cluster sampling by general practice . Setting General practice s in the northern region of the Australian Capital Territory . Participants 174 children with moderate to severe asthma who attended 24 general practitioners . Intervention System of structured asthma care ( the 3 + visit plan ) , with participating families reminded to attend the general practitioner . Main outcome measures Process measures : rates for asthma consultations with general practitioner , written asthma plans , completion of the 3 + visit plan ; clinical measures : rates for emergency department visits for asthma , days absent from school , symptom-free days , symptoms over the past year , activity limitation over the past year , and asthma drug use over the past year ; spirometric lung function measures before and after cold air challenge . Results Intervention group children had significantly more asthma related consultations ( odds ratio for three or more asthma related consultations 3.8 ( 95 % confidence interval 1.9 to 7.6 ; P = 0.0001 ) , written asthma plans ( 2.2 ( 1.2 to 4.1 ) ; P = 0.01 ) , and completed 3 + visit plans ( 24.2 ( 5.7 to 103.2 ) ; P = 0.0001 ) than control children and a mean reduction in measurements of forced expiratory volume in one second after cold air challenge of 2.6 % ( 1.7 to 3.5 ) ; P = 0.0001 ) less than control children . The number needed to treat ( benefit ) for one additional written asthma action plan was 5 ( 3 to 41 ) children . Intervention group children had lower emergency department attendance rates for asthma ( odds ratio 0.4 ( 0.2 to 1.04 ) ; P = 0.06 ) and less speech limiting wheeze ( 0.2 ( 0.1 to 0.4 ) ; P = 0.0001 ) than control children and were more likely to use a spacer ( 2.8 ( 1.6 to 4.7 ) ; P = 0.0001 ) . No differences occurred in number of days absent from school or symptom-free day scores . Conclusions Proactive care with active recall for children with moderate to severe asthma is feasible in general practice and seems to be beneficial [10276475] To evaluate a health education program to improve family management of asthma , 310 children with asthma and their 290 parents were r and omly assigned to a program or control group . Program families participated in health education design ed to resolve specific management problems and build self-confidence in the ability to manage asthma . Following education , program parents scored better on an asthma self-management index than parents in the control group ( + 1.57 versus -0.83 , P less than 0.0001 ) . Program parents also scored better on two subindices of the self-management index : attack management ( + 0.87 vs. + 0.42 , P less than 0.05 ) and preventive measures ( + 0.42 vs. -0.35 , P less than 0.05 ) . Also , program parents reported significantly more use of guidelines to determine appropriate levels of physical activity for children . Following education , program children reported more use of three management steps than control children : productive cough or postural drainage ( 59 % vs. 35 % , P less than 0.004 ) , breathing and relaxation exercises ( 80 % vs. 65 % , P less than 0.05 ) , and attempts to stay calm ( 12 % vs. 2 % , P less than 0.05 ) . Program children reported significantly less worry than control children about the limitations asthma imposes and about making mistakes at school [12403858] OBJECTIVE To conduct a controlled trial of a home-based education program for low-income caregivers of young children with asthma . METHODS Participants were r and omized to treatment-eight weekly asthma education sessions adapted from the Wee Wheezers program ( n = 49)-or usual care ( n = 46 ) . Baseline and 3- and 12-month follow-up data were gathered from caregivers and from children 's medical records . RESULTS Treatment was associated with less bother from asthma symptoms , more symptom-free days , and better caregiver quality of life at follow-up for children 1 - 3 , but not those 4 - 6 , years of age . Treatment and control groups did not differ in caregiver asthma management behavior or children 's acute care utilization . CONCLUSIONS This home-based asthma education program was most effective with younger children ; perhaps their caregivers were more motivated to learn about asthma management . Targeting psychosocial factors associated with asthma morbidity might also enhance the efficacy of asthma education for these families [10790458] OBJECTIVES To evaluate health care and financial outcomes in a population of Medicaid-insured asthmatic children after a comprehensive asthma intervention program . DESIGN Controlled clinical trial . SETTING Pediatric allergy clinic in an urban , tertiary care children 's hospital . SUBJECTS Eighty children , 2 to 16 years old , with a history of frequent use of emergent health care services for asthma . Intervention . Children in the intervention group received asthma education and medical treatment in the setting of a tertiary care pediatric allergy clinic . An asthma outreach nurse maintained monthly contact with the families enrolled in the intervention group . OUTCOME MEASURES Emergency department ( ED ) visits , hospitalizations , and health care charges per patient in the year after enrollment . RESULTS Baseline demographics did not differ significantly between the 2 groups . In the year before the study , there were no significant differences between intervention and control children in ED visits ( mean , 3.5 per patient ) , hospitalizations ( mean,.6 per patient ) or health care charges ( $ 2969 per patient ) . During the study year , ED visits decreased to a mean of 1.7 per patient in the intervention group and 2.4 in controls , while hospitalizations decreased to a mean of.2 per patient in the intervention group and .5 in the controls . Average asthma health care charges decreased by $ 721/child/year in the intervention group and by $ 178/patient/year in the control group . CONCLUSIONS A comprehensive asthma intervention program for Medicaid-insured asthmatic children can significantly improve health outcomes while reducing health care costs.asthma education , health care outcomes , Medicaid , asthma outreach , utilization [8621369] A r and omized trial of an instructional method was conducted in which school nurses taught children asthma self-management principles and skills , including peak flow monitoring , in 20-min , individual sessions over an 8-week period . Thirty-six children participated . An intervention group of 18 children received the teaching sessions . A control group of 18 children received regular care by the nurses , but no teaching sessions . The sample included 64 % boys , 69 % African-Americans , and 69 % Medicaid recipients . The average age of subjects was 10.2 years . The two groups were demographically similar , but despite r and om assignment , the control group had a significantly earlier age of onset of asthma and tended to have had more asthma attacks in the preceding year . These factors were statistically controlled in outcome analyses . Results of group comparisons showed no significant differences in the number of postintervention emergency room visits and days absent from school . However , nurses reported that children who practice d breathing exercises had less anxiety during exacerbations , and the nurses ' knowledge of the children 's baseline peak expiratory flow rates facilitated care of the children . Nurses expressed the opinion that the individual sessions with students might be useful in motivating them to participate effectively in later group sessions . The intervention was well accepted by students , parents , and nurses . We believe that this intervention is promising as a practical , low-cost approach to enhancing children 's asthma self-management skills and warrants further testing in a larger sample , with the intervention conducted over a longer period [16440537] BACKGROUND Despite significant medical advances , many ethnic and racial minority children who live in inner cities continue to experience disproportionately high levels of asthma morbidity and mortality compared with white children . As a result , a growing number of psychosocial asthma management interventions are being developed to address their needs ; however , only a few of these interventions have incorporated cultural variables into their treatments and have had their efficacy evaluated . OBJECTIVE To examine the efficacy of the Multifamily Asthma Group Treatment ( MFAGT ) , design ed to enhance asthma management and reduce emergency department ( ED ) visits among African American and Hispanic families . METHODS Twenty-four African American and Hispanic families who have children with asthma were r and omly assigned to either the MFAGT or the St and ard Psychoeducational Asthma Intervention . Differences in the number of ED visits and the level of asthma management in both groups were compared 1 year before and 1 year after the intervention . In addition , these groups were contrasted to a control group that did not receive any psychoeducational intervention . RESULTS The MFAGT was significantly ( P = .04 ) more effective than the St and ard Psychoeducational Asthma Intervention and the control in decreasing ED visits and increasing parental asthma knowledge . CONCLUSIONS These preliminary results suggest that the MFAGT is efficacious in enhancing asthma management and in reducing ED visits in inner-city African American and Hispanic children from a lower socioeconomic background [14979508] The high burden of asthma on healthcare utilisation and costs warrants economic appraisal of management approaches . The authors previously demonstrated that the efficacy of nurse-led outpatient management of childhood asthma was comparable to management by a paediatrician and now report on the healthcare utilisation and costs of both management approaches . A total of 74 newly referred children with asthma were r and omly assigned to a 1‐yr follow-up by paediatricians or asthma nurse . Healthcare utilisation was recorded and associated costs calculated for both management approaches . There were no significant differences in healthcare utilisation except for the total time spent on patient contact ( 136(n=14 ) versus 187(n=41 ) min , for patients followed-up by paediatrician and an asthma nurse repectively ) . Costs within the healthcare sector were reduced by 7.2 % in favour of nurse-led care . The reduction in costs was solely attributable to a 17.5 % reduction in the costs of outpatient visits . Nurse-led care appeared to be cost-saving even if the duration of follow-up visits would be twice that of doctor 's visits . Overall healthcare costs ( within and outside the healthcare sector ) were 4.1 % lower for nurse-led outpatient management compared to traditional medical care . Nurse-led outpatient management of childhood asthma can be provided at a lower cost than medical care by paediatricians [11238152] Abstract Objective : To determine the effect of a peer led programme for asthma education on quality of life and related morbidity in adolescents with asthma . Design : Cluster r and omised controlled trial . Setting : Six high schools in rural Australia . Participants : 272 students with recent wheeze , recruited from a cohort of 1515 students from two school years ( mean age 12.5 and 15.5 years ) ; 251 ( 92.3 % ) completed the study . Intervention : A structured education programme for peers comprising three steps ( the “ Triple A Program ” ) . Main outcome measures : Quality of life , school absenteeism , asthma attacks , and lung function . Results : When adjusted for year and sex , mean total quality of life scores showed significant improvement in the intervention than control group . Clinical ly important improvement in quality of life ( > 0.5 units ) occurred in 25 % of students with asthma in the intervention group compared with 12 % in the control group ( P=0.01 ) . The number needed to treat was 8 ( 95 % confidence interval 4.5 to 35.7 ) . The effect of the intervention was greatest in students in year 10 and in females . Significant improvements occurred in the activities domain ( 41 % v 28 % ) and in the emotions domain ( 39 % v 19 % ) in males in the intervention group . School absenteeism significantly decreased in the intervention group only . Asthma attacks at school increased in the control group only . Conclusion : The triple A programme leads to a clinical ly relevant improvement in quality of life and related morbidity in students with asthma . Wider dissemination of this programme in schools could play an important part in reducing the burden of asthma in [16537855] BACKGROUND Asthma is the most common chronic disease among children in Germany . Approaches to reduce the burden of asthma include patient education to improve self-management skills . STUDY OBJECTIVES We determined whether a continuous Internet-based education program ( IEP ) as an add-on to a st and ardized patient management program ( SPMP ) improves health outcomes of asthma patients at a favorable benefit-cost ratio . PATIENTS AND METHODS A total of 438 asthmatic patients aged 8 to 16 years in 36 study centers were enrolled during a 6-month period . We performed a prospect i ve cost-benefit analysis alongside a nonr and omized trial . At baseline and at 6 months and 12 months , health service utilization data were collected . INTERVENTIONS Study participants were assigned to a control group and two intervention groups . Patients in both intervention groups participated in an SPMP . Additionally , patients in one intervention group received the IEP . RESULTS Utilization of various health-care services decreased significantly in both intervention groups . From a payer perspective , the benefit-cost ratio of the traditional education program was 0.55 . Adding the IEP improved the ratio ( 0.79 ) . For patients with moderate or severe asthma , the benefit-cost ratios were 1.07 and 1.42 ( with IEP ) , respectively . CONCLUSIONS The IEP offers the potential to decrease the burden of disease and to realize incremental morbidity cost savings . Subgroup analysis demonstrated that within 1 year , the savings exceed the intervention costs in patients with moderate or severe asthma [15351753] BACKGROUND Traditional primary care practice change approaches have not led to full implementation of national asthma guidelines . OBJECTIVE To evaluate the effectiveness of 2 asthma care improvement strategies in primary care . DESIGN Two-year r and omized controlled clinical trial . SETTING Forty-two primary care pediatric practice s affiliated with 4 managed care organizations . PARTICIPANTS Children aged 3 to 17 years with mild to moderate persistent asthma enrolled in primary care practice s affiliated with managed care organizations . INTERVENTIONS Peer leader education consisted of training 1 physician per practice in asthma guidelines and peer teaching methods . Planned care combined the peer leader program with nurse-mediated organizational change through planned visits with assessment s , care planning , and self-management support , in collaboration with physicians . Analyses compared each intervention with usual care . MAIN OUTCOME MEASURES Annualized asthma symptom days , asthma-specific functional health status ( Children 's Health Survey for Asthma ) , and frequency of brief oral steroid courses ( bursts ) . RESULTS Six hundred thirty-eight children completed baseline evaluations , representing 64 % of those screened and eligible . Mean + /- SD age was 9.4 + /- 3.5 years ; 60 % were boys . Three hundred fifty ( 55 % ) were taking controller medication . Mean + /- SD annualized asthma symptom days was 107.4 + /- 122 days . Children in the peer leader arm had 6.5 fewer symptom days per year ( 95 % confidence interval [ CI ] , - 16.9 to 3.6 ) , a nonsignificant difference , but had a 36 % ( 95 % CI , 11 % to 54 % ) lower oral steroid burst rate per year compared with children receiving usual care . Children in the planned care arm had 13.3 ( 95 % CI , - 24.7 to -2.1 ) fewer symptom days annually ( -12 % from baseline ; P = .02 ) and a 39 % ( 95 % CI , 11 % to 58 % ) lower oral steroid burst rate per year relative to usual care . Both interventions showed small , statistically significant effects for 2 of 5 Children 's Health Survey for Asthma scales . Planned care subjects had greater controller adherence ( parent report ) compared with usual care subjects ( rate ratio , 1.05 [ 95 % CI , 1.00 to 1.09 ] ) . CONCLUSIONS Planned care ( nurse-mediated organizational change plus peer leader education ) is an effective model for improving asthma care in the primary care setting . Peer leader education on its own may also serve as a useful model for improving asthma care , although it is less comprehensive and the treatment effect less pronounced [11814370] BACKGROUND Asthma is an important cause of morbidity , absence from school , and use of health services among children . Computer-based educational programs can be design ed to enhance children 's self-management skills and to reduce adverse outcomes . OBJECTIVE To assess the effectiveness of an interactive device programmed for the management of pediatric asthma . DESIGN A r and omized controlled trial ( 66 participants were in the intervention group and 68 were in the control group ) . SETTING Interventions conducted at home and in an outpatient hospital clinic . PARTICIPANTS Inner-city children aged 8 to 16 years diagnosed as having asthma by a physician . INTERVENTION An asthma self-management and education program , the Health Buddy , design ed to enable children to assess and monitor their asthma symptoms and quality of life and to transmit this information to health care providers ( physicians , nurses , or other case managers ) through a secure Web site . Control group participants used an asthma diary . MAIN OUTCOME MEASURES Any limitation in activity was the primary outcome . Secondary outcomes included perceived asthma symptoms , absence from school , any peak flow reading in the yellow or red zone , and use of health services . RESULTS After adjusting for covariates , the odds of having any limitation in activity during the 90-day trial were significantly ( P = .03 ) lower for children r and omized to the Health Buddy . The intervention group also was significantly ( P = .01 ) less likely to report peak flow readings in the yellow or red zone or to make urgent calls to the hospital ( P = .05 ) . Self-care behaviors , which were important correlates of asthma outcomes , also improved far more for the intervention group . CONCLUSION Compared with the asthma diary , monitoring asthma symptoms and functional status with the Health Buddy increases self-management skills and improves asthma outcomes [11926622] BACKGROUND Accurate symptom evaluation is a critical component of asthma management . Limited data are available about the accuracy of symptom evaluation by children with asthma and their parents , or the impact of various symptom-monitoring strategies on asthma morbidity outcomes . OBJECTIVE The purpose of this r and omized clinical trial was to evaluate the effect of three different intensities of symptom monitoring on asthma morbidity outcomes . METHODS One hundred sixty-eight children ( ages 6 to 19 ) of diverse racial , geographic , and socioeconomic background s were r and omized to 1 of 3 treatment groups ( subjective symptom evaluation , symptom-time peak expiratory flow rate ( PEFR ) monitoring , daily PEFR monitoring ) in this longitudinal , clinical trial . Outcome measures included a summary asthma severity score , forced expiratory volume in 1 second , symptom days , and health care utilization . RESULTS Children who used PEFR meters ( PFMs ) when symptomatic had a lower asthma severity score , fewer symptom days , and less health care utilization than children in the other two treatment groups . Minority and poor children had the greatest amount of improvement using PFMs when symptomatic . Results were much less striking in white families . Thirty percent of families in the PFM treatment groups discontinued use entirely by 1 year postexit , whereas the majority of families who continued use ( 94 % ) used them only when symptomatic to inform symptom interpretation and management decisions . CONCLUSIONS Not every child with asthma needs a PFM . Children and families facing extra challenges as a result of illness severity , sociodemographic , or health care system characteristics clearly benefited most from PFM use [15302719] STUDY OBJECTIVES To determine whether an interactive physician seminar that has been shown to improve patient/parent satisfaction and to decrease emergency department visits for children with asthma was also effective for those children from low-income families . DESIGN Seventy-four pediatricians and 637 of their patients were r and omized to receive two asthma seminars or no educational programs and were observed for 2 years . SETTING Physicians in the New York , NY , and Ann Arbor , MI , areas were enrolled , and , on average , 10 patients with asthma per provider were surveyed and observed for 2 years . PATIENTS OR PARTICIPANTS A total of 637 subjects were enrolled , and 369 subjects remained in the study after 2 years . Of these , 279 had complete medical and survey information . INTERVENTIONS Physicians were r and omized , and then a r and om sample of their patients was enrolled and surveyed regarding the physician 's communication style , the child 's asthma symptoms , medical needs , and asthma care . Low income was defined as annual income of < 20,000 dollars . MEASUREMENTS AND RESULTS The families of 36 children ( 13 % ) had an income of < 20,000 dollars , and they were treated by 23 physicians . Low-income children in the treatment group tended to have higher levels of use of controller medications , to receive a written asthma action plan , and to miss fewer days of school , although these differences were not statistically significant compared to low-income children in the control group . However , low-income treatment group children were significantly less likely to be admitted to an emergency department ( annual rate , 0.208 vs 1.441 , respectively ) or to a hospital ( annual rate , 0 vs 0.029 , respectively ) for asthma care compared to children in the control group . CONCLUSIONS The educational program for physicians improved asthma outcomes for their low-income patients . Provider interventions targeted to these high-risk patients may diminish hospital and emergency department asthma care [12195271] BACKGROUND Asthma is common and is often poorly controlled in adolescent subjects . OBJECTIVE To determine the impact of an age-specific asthma program on asthma control , particularly on exacerbations of asthma requiring emergency department treatment , and on the quality of life of adolescents with asthma . METHODS The present r and omized , controlled trial included patients who were 15 to 20 years of age and had visited emergency departments for management of their asthma . The interventional group attended an age-specific asthma program that included assessment , education and management by a team of asthma educators , respiratory therapists and respiratory physicians . In the control group , spirometry was performed , and the patients continued to receive usual care from their regular physicians . The outcomes were assessed by a question naire six months after entry into the study . RESULTS Ninety-three subjects entered the study and were r and omly assigned to the intervention or control group . Of these , only 62 patients were available for review after six months . Subjects in both the control and the intervention groups showed a marked improvement in their level of asthma control , reflected primarily by a 73 % reduction in the rate of emergency department attendance for asthma . Other indexes of disease control , including disease-specific quality of life , as assessed by question naires , were improved . There was , however , no discernible difference between the subjects in the two groups , with the exception of an improvement in favour of the intervention group in the symptom ( actual difference 0.7 , P=0.048 ) and emotional ( actual difference 0.8 , P=0.028 ) domains of the asthma quality of life question naire . The overall quality of life score favoured the intervention group by a clinical ly relevant difference of 0.6 , but this difference did not reach statistical significance ( P=0.06 ) . CONCLUSIONS Although all subjects demonstrated a significant improvement in asthma control and quality of life , the improvement attributable to this intervention was limited to two domains in disease-specific quality of life [3902784] A small , controlled trial of joint treatment of childhood asthma by a doctor , a physiotherapist , a psychologist , and a social worker , working together in the family setting , demonstrated an improvement in ventilatory capacity . The limited scope of this trial does not permit more general conclusions as to the effect of such treatment on the severity and frequency of attacks , but the observation that some measurable physiological improvement occurred suggests that the place of multidisciplinary nonpharmaceutical management of childhood asthma should be investigated in more detail [16236837] OBJECTIVE To evaluate an asthma education program for children with asthma that is delivered in their school by certified asthma educators from a local hospital-based asthma center . STUDY DESIGN R and omized controlled trial . SETTING Twenty-six elementary schools located in a suburb of Toronto . PARTICIPANTS A total of 256 children in grade s 2 to 5 with asthma and their parents were r and omized to control and experimental groups . INTERVENTION Children in the experimental group received the " Roaring Adventures of Puff " asthma education program over the course of six weekly 1-h sessions . Those in the control group continued receiving usual care . MEASUREMENTS AND RESULTS Data collection involved measuring asthma quality of life , self-efficacy for managing asthma , school absenteeism , days of interrupted activity , health services use , and parental loss of time from work . Quality of life and self-efficacy data were collected from the children at baseline and 2 months . Telephone parental interviews conducted over 1 year were used to collect data on the remaining variables . Unpaired t test , analysis of variance , and chi2 test were used to determine whether differences existed between the groups . The results are reported as the mean + /- SD . The experimental group demonstrated higher scores than the control group for self-efficacy ( 3.6 + /- 0.7 vs 3.8 + /- 0.9 , respectively ; p < 0.05 ) and quality of life ( 5.0 + /- 1.4 vs 5.5 + /- 1.4 , respectively ; p < 0.05 ) . At 1 year , the experimental group demonstrated fewer mean urgent health-care visits ( 2.5 + /- 2.5 vs 1.7 + /- 1.9 visits per year , respectively ; p < 0.01 ) , days of missed school ( 4.3 + /- 5.7 vs 3.0 + /- 4.4 days per year , respectively ; p > 0.05 ) , and days of interrupted activity ( 9.1 + /- 10.5 vs 6.2 + /- 7.3 days per year ; p < 0.01 ) related to asthma than the control group . There were no differences between the groups for parental work absenteeism or scheduled asthma visits . CONCLUSION Providing an asthma education program to children in their school can significantly improve quality of life and reduce the burden of childhood asthma [7659625] Asthma is a very common chronic disease among preschool children in primary health care . Research has shown that planned and systematic patient education positively affects the management of asthma by parents . This study focuses on the question of whether an asthma patient education protocol that is used by general practitioners ( GPs ) has an effect on medical care consumption . The treatment group consisted of 28 GPs , representing 47 asthmatic infants . The control group contained 18 GPs , representing 38 patients . Data were collected from medical records ( with a written instrument ) for a 12-month period preceding and after the intervention period in which the education protocol was tested . Results indicated that sociodemographic variables and pretest data on asthma severity and medical care utilization were largely comparable for patients in both study groups . Furthermore , the treatment group showed a significantly greater decrease than the control group from pre- to post-test measurement in the number of contacts with the GP and the number of emergency visits to the physician 's office [15690558] Our objective was to determine whether an asthma education program in schools would have 1 ) a direct impact on student knowledge and attitudes to asthma and quality of life of the students with asthma , 2 ) an indirect impact on teacher knowledge and attitudes to asthma and on school policies about asthma , and 3 ) a sustainable program after the re sources to implement the research were withdrawn . Seventeen intervention and 15 control schools participated in a controlled trial . Baseline knowledge and attitudes were measured in year 8 students ( ages 13 - 14 years ) and their teachers together with quality of life in the students with asthma . A three-lesson package about asthma was delivered by teachers as part of the Personal Development/Health/Physical Education ( PD/H/PE ) curriculum . Follow-up question naires were administered to students and staff . Efforts to change school policies were documented . Five years after the intervention , PD/H/PE teachers were contacted to determine whether the program was still operating . Main outcome measures included asthma knowledge , attitudes , and quality of life . Question naires were returned by 4,161/4,475 of the year 8 students at baseline and by 3,443 at follow-up . In intervention schools , compared with control schools , students showed improved asthma knowledge ( P < 0.0001 ) , improvement in tolerance to asthma ( P = 0.02 ) , internal control ( P = 0.03 ) , and less tendency to believe in the role of chance in asthma control ( P = 0.04 ) . Students from intervention but not control schools showed significant improvements in overall quality of life ( P = 0.003 vs. P = 0.82 , respectively ) . Teachers from intervention schools showed significant increases in knowledge compared to control schools ( P < 0.0001 ) . Intervention schools were more likely to seek further health education about asthma ( P < 0.01 ) . Five years after the 35 schools involved in the development of the material s or the trial had been offered the Living With Asthma package , 25 ( 71 % ) were still teaching the program to most or all of their students . Fifty-nine of the 61 ( 97 % ) high schools in the Hunter Region now have the program . Management and distribution of the Living With Asthma program have been taken over by the Asthma Foundation of New South Wales . The package has been up date d and is being offered to all high schools throughout New South Wales as part of the National Asthma-Friendly Schools Project . In conclusion , a teacher-led asthma education program in secondary school had direct and indirect beneficial outcomes and was sustained at a high level for 5 years in most schools in the Hunter Region , despite minimal ongoing maintenance and support from health workers [16478844] STUDY OBJECTIVES To examine the effectiveness of an interdisciplinary intervention for pediatric asthma . DESIGN R and omized , controlled study . SETTING Urban tertiary-referral pediatric hospital . PARTICIPANTS One hundred seventy-five patients with asthma lacking written treatment plans and presenting with asthma-related emergency department visits ( two or more ) and /or hospitalizations ( one or more ) in the past year were r and omized to a comparison group receiving medical care alone ( n = 86 ) or to an interdisciplinary intervention group receiving medical care , asthma education , and problem-solving therapy ( n = 89 ) INTERVENTION All participants received written asthma management plans , peak flow meters , and spacer devices . The intervention group also received asthma education , an asthma risk profile assessment , brief problem-solving therapy , and access to a 24-h nurse advice line . The primary outcome measure was change in asthma symptoms , and secondary outcomes included health-care utilization and asthma-related quality of life . RESULTS Both groups demonstrated significant reductions in asthma symptoms and improvements in quality of life without any between-group differences identified over the course of follow-up . In contrast , the intervention group demonstrated less frequent health-care utilization than the comparison group , with 28 % of the intervention group requiring emergency department or inpatient services for asthma compared to 41 % of the comparison group ( adjusted odds ratio , 1.92 ; 95 % confidence interval , 1.00 to 3.69 ) over the 12-month follow-up period . CONCLUSIONS This study examined the effectiveness of an interdisciplinary intervention for undertreated asthma . The intervention did not result in improvements in asthma symptoms , but accomplished modest reductions in the utilization of acute medical care [7928930] This paper describes the results of an asthma self-management protocol delivered to parents of children aged 0 - 4 years . The protocol was delivered by general practitioners ( GPs ) , community nurses , asthma nurses , and doctors to child health centers . It consisted of 16 educational modules developed after an initial needs assessment of parents and a task analysis of primary care practitioners . The program was evaluated by means of an experimental design . Parents participating in the program had significantly more knowledge , a more favorable attitude toward asthma , and a higher self-efficacy score with respect to performing asthma self-management behaviors . Also , they reported performing self-management behaviors more frequently than parents in the control group . One-year follow-up results , which were collected for parents in the treatment group only , showed that the described changes were sustained . Further , the treatment group was found to have decreased its emergency and nonemergency use of the physician 's office and to have a reduction in ( reported ) asthma severity . Process evaluation indicated that most modules were provided by the GPs to nearly all parents . After parents had read the modules at home , almost all the information was discussed in the next contact . GPs seldom referred patients to the community nurses , although this was suggested in the protocol [8185365] A clinic supervised by a nurse , using principles originally developed in general practice , was established in the paediatric department of a district general hospital . A r and omised controlled study was conducted comparing children admitted with asthma or attending out patients who were given a patient education programme and self management plan ( intervention group ) with a control group . The study comprised 91 patients aged 3 - 14 years admitted for asthma or attending a hospital outpatient department from November 1989 to November 1990 . Seventy seven patients completed the study and kept diaries for a median of 283 days . Patients in the intervention group had significantly less restriction of activity ( 95 % confidence interval ( CI ) -0.27 to -0.01 ) and fewer episodes of peak flow below 30 % of best ( 95 % CI 0.03 to 1.17 ) . Patients in the intervention group were more likely to make the correct response to an acute exacerbation of their asthma than the control group ( 71 % v 47 % , 95 % CI 9.51 to 39.1 ) . The intervention group had fewer school absences and fewer home visits by a general practitioner . There was an increase in the readmission rate for the intervention group . A subgroup of patients who self managed by doubling their use of inhaled steroids during an exacerbation performed better than those patients who only increased their bronchodilator or were managed on salbutamol or sodium cromoglycate alone . Improvements in patient follow up and the structure of the self management plans used , particularly changing the peak flow level at which inhaled steroids are doubled , may further improve the outcome of patients attending the asthma clinic [4077545] The Self-Care Rehabilitation in Pediatric Asthma ( SCRPA ) project was design ed to ascertain ( 1 ) the level to which children with asthma are able to acquire the asthma knowledge and skills presented in a self-management training program conducted by the American Lung Association of Utah and ( 2 ) the effect of such training on the asthma experience . The preschool SCRPA Curriculum ( ages 2 - 5 ) consisted of six 1-hour classes scheduled twice a week for 3 weeks . The first and last classes were for one or both parents only , and the middle four sessions were for the child and parent(s ) . The school-age SCRPA curriculum ( ages 6 - 14 ) consisted of eight 90-minute classes for both child and parent(s ) scheduled twice a week for 4 weeks . Private physicians referred 21 preschool children and 38 school-age children into the program . The school-age children were r and omly assigned to a study or control group , and the preschool children served as their own controls . A comparison of asthma episodes during the 3 months before and after training showed a statistically significant decrease in the number of episodes but no change in severity in the preschool , school study , and school control groups . The decrease in episodes for the control groups suggest that the family record keeping required of all subjects may have a beneficial effect , a phenomenon worth further investigation . Also , the school-age group , in pre- and posttesting , demonstrated that the SCRPA curriculum increased knowledge and skills in the study group , changes not found in the control group [16393717] The goal of this study was to determine the effectiveness of an asthma educational intervention in improving asthma knowledge , self-efficacy , and quality of life in rural families . Children 6 to 12 years of age ( 62 % male , 56 % white , and 22 % Medicaid ) with persistent asthma ( 61 % ) were recruited from rural elementary schools and r and omized into the control st and ard asthma education ( CON ) group or an interactive educational intervention ( INT ) group geared toward rural families . Parent/caregiver and child asthma knowledge , self-efficacy , and quality of life were assessed at baseline and at 10 months post enrollment . Despite high frequency of symptom reports , only 18 % children reported an emergency department visit in the prior 6 months . Significant improvement in asthma knowledge was noted for INT parents and young INT children at follow-up ( Parent : CON = 16.3 ; INT = 17.5 , p < 0.001 ; Young children : CON = 10.8 , INT = 12.45 , p < 0.001 ) . Child self-efficacy significantly increased in the INT group at follow-up ; however , there was no significant difference in parent self-efficacy or parent and child quality of life at follow-up . Asthma symptom reports were significantly lower for the INT group at follow-up . For young rural children , an interactive asthma education intervention was associated with increased asthma knowledge and self-efficacy , decreased symptom reports , but not increased quality of life [15237762] BACKGROUND Improving asthma knowledge and self-management is a common focus of asthma educational programs , but most programs have had little influence on morbidity outcomes . We developed a novel multiple-component intervention that included the use of an asthma education video game intended to promote adoption of asthma self-management behaviors and appropriate asthma care . OBJECTIVE To determine the effectiveness of an asthma education video game in reducing morbidity among high-risk , school-aged children with asthma . METHODS We enrolled 119 children aged 5 to 12 years from low-income , urban areas in and around San Francisco , CA , and San Jose , CA . Children with moderate-to-severe asthma and parental reports of significant asthma health care utilization were r and omized to participate in the disease management intervention or to receive their usual care ( control group ) . Patients were evaluated for clinical and quality -of-life outcomes at weeks 8 , 32 , and 52 of the study . RESULTS Compared with controls , the intervention group had significant improvements in the physical domain ( P = .04 and P = .01 at 32 and 52 weeks , respectively ) and social activity domain ( P = .02 and P = .05 at 32 and 52 weeks , respectively ) of asthma quality of life on the Child Health Survey for Asthma and child ( P = .02 at 8 weeks ) and parent ( P = .04 and .004 at 32 and 52 weeks , respectively ) asthma self-management knowledge . There were no significant differences between groups on clinical outcome variables . CONCLUSIONS A multicomponent educational , behavioral , and medical intervention targeted at high-risk , inner-city children with asthma can improve asthma knowledge and quality of life [9732652] To address the recent rise in asthma morbidity and mortality in Russia , an intervention study was conducted to improve asthma diagnosis , treatment and prevention . US recommendations for asthma management were adapted for use in educating Moscow families with children with asthma . Two hundred and fifty-two children with asthma aged 4 - 14 years receiving health care in eight Moscow public health clinics together with their parents were enrolled in the study to see whether US teaching manuals for asthma management would be acceptable and effective in Russia . Children at four of the clinics with recent asthma attacks were r and omly assigned to either the education or control group to test if patient education and guided asthma care would improve outcomes for patients . Modern medications were made available to both groups to see if training in the US guidelines was necessary to get physicians to use the medications . Children with recent asthma attacks at the other four clinics were defined as comparison group 1 to control for the possible effect of medication availability . All children at the eight clinics who had no asthma attacks composed comparison group 2 to see if the outcomes for these children would change over time . One-year follow-up results showed significant improvement in asthma self-management skills of children and parents , in terms of asthma treatment , only among those in the education group . Significant increases were observed in the subgroup of children in the education group using anti-inflammatory drugs for asthma control . Children in the education group had markedly increased peak flow rates and reduced daily peak flow variability as compared to control and comparison groups . There was a significantly greater reduction in doctor visits by the education group of children compared to control . Presumably , changes in parents ' and children 's behaviour in terms of asthma treatment and prevention skills , proper treatment of the disease and access to medications could be responsible for reducing asthma morbidity in children [9389290] BACKGROUND We have previously reported a high prevalence of current asthma-related symptoms affecting predominantly Hispanic , socioeconomically disadvantaged schoolchildren in Southeast San Diego . OBJECTIVE We sought to assess the impact of a school-based education program on asthma outcomes . METHODS In cooperation with the San Diego Unified Schools , we developed and implemented a school-based asthma education program . Based on the National Heart , Lung , and Blood Institute consensus guidelines for asthma , the five-session bilingual , interactive curriculum was conducted in 20-minute segments . Asthma knowledge was tested before and after the education program , and asthma severity was prospect ively assessed at monthly intervals . Outcome parameters were compared in educated and control ( noneducated ) fourth grade students with asthma by using nonparametric techniques . RESULTS After asthma education , students demonstrated improvement with increases in mean scores for : asthma knowledge quiz from 9.9 ( SEM = 0.44 , n = 34 ) to 13.7 ( SEM = 0.30 ) ; peak flowmeter technique from 3.9 ( SEM = 0.33 , n = 32 ) to 6.4 ( SEM = 0.29 ) ; and inhaler technique from 2.3 ( SEM = 0.26 , n = 32 ) to 4.3 ( SEM = 0.26 ) . All changes were highly significant ( p < or = 0.00001 as determined by Wilcoxon matched-pairs signed-rank test ) . Mean score comparisons for asthmatic control students given paired examinations after a time interval matched with the educated students , did not reach statistical significance : quiz score of 11.3 ( SEM = 0.80 , n = 11 ) versus 10.9 ( SEM = 0.68 ) , peak flowmeter technique score of 2.6 ( SEM = 0.50 , n = 18 ) versus 3.1 ( SEM = 0.37 ) , and inhaler technique score of 2.5 ( SEM = 0.37 , n = 18 ) versus 2.2 ( SEM = 0.31 ) . Prospect i ve monthly data were collected on 27 educated and 15 control asthmatic subjects . Severity of asthma was not significantly different between groups at entry to the study . Symptom question naires , vali date d for functional asthma severity , revealed a significant reduction in mean symptom scores at 180 days for the educated ( 2.87 , SEM = 0.447 ) versus the control ( 4.36 , SEM = 0.573 ) groups ( p = 0.0188 as determined by the Mann-Whitney U test ) . CONCLUSION Child-centered asthma education can be successfully conducted in the school setting , result ing in increased asthma knowledge , improved skills for peak flowmeter and inhaler use , and a reduction in the severity of asthma symptoms [15184205] We asked whether the addition of PEF recordings to a symptom-based self-management plan improved outcome in school children with asthma . In an open-r and omized , parallel-group , controlled trial , we studied children aged 7 - 14 years with moderate asthma . After a 4-week run-in , 90 children were r and omized to receive either PEF plus symptom-based management or symptom-based management alone for 12 weeks . Thresholds for action based on PEF were 70 % of best ( for increasing inhaled steroids ) and 50 % of best ( for commencing prednisolone ) . Children were asked to perform twice-daily spirometry at home ( using an electronic recording spirometer that revealed only PEF to the study group alone ) and to record a symptom diary . The mean daily symptom score was the main outcome . There were no differences between groups in mean symptom score or in spirometric lung function , PEF , quality of life score , or reported use of health services over 12 weeks . During acute episodes , children responded to changes in symptoms by increasing their inhaled steroids at a mean value of PEF of greater than 70 % of best so that overall PEF did not contribute to this important self-management decision . Knowledge of PEF did not enhance self-management even during acute exacerbations [16532761] OBJECTIVES This report presents both age-adjusted and unadjusted statistics from the 2004 National Health Interview Survey ( NHIS ) on selected health measures for children under 18 years of age , classified by sex , age , race , Hispanic origin , family structure , parent 's education , family income , poverty status , health insurance coverage , place of residence , region , and current health status . The topics covered are asthma , allergies , learning disability and Attention Deficit Hyperactivity Disorder ( ADHD ) , prescription medication use , respondent-assessed health status , school-loss days , usual place of health care , time since last contact with a health care professional , selected measures of health care access and utilization , and dental care . SOURCE OF DATA The NHIS is a multistage probability sample survey conducted annually by interviewers of the U. S. Census Bureau for the Centers for Disease Control and Prevention 's National Center for Health Statistics and is representative of the civilian noninstitutionalized population of the United States . Data are collected for all family members during face-to-face interviews with adults present at the time of interview . Additional information about children is collected for one r and omly selected child per family in face-to-face interviews with an adult proxy respondent familiar with the child 's health . SELECTED HIGHLIGHTS In 2004 , most U.S. children under 18 years of age had excellent or very good health ( 82 % ) . However , 9 % of children had no health insurance coverage , and 5 % of children had no usual place of health care . Twelve percent of children had ever been diagnosed with asthma . An estimated 8 % of children 3 - 17 years of age had a learning disability , and an estimated 7 % of children had ADHD [12269709] OBJECTIVE To assess the effect of a structured program of pharmaceutical care on changes in disease control , functional status , and health services utilization for pediatric and adolescent patients with moderate-to-severe asthma . DESIGN R and omized , controlled trial . SETTING Community and clinic pharmacies ( 14 intervention and 18 usual care pharmacies ) in western Washington State . PATIENTS Three hundred thirty children , aged 6 to 17 years , with asthma . INTERVENTION Structured training for the intervention group pharmacists to provide individualized asthma management services during patient-pharmacist encounters for up to 1 year following the patient 's enrollment into the study . MAIN OUTCOME MEASURES The primary outcome measure was change in pulmonary function as measured by peak expiratory flow rate and spirometry . Secondary outcome measures included changes in functional status and use of asthma-related health care services . RESULTS The intervention had no significant effect on the health or health services use outcomes of study subjects . When compared with the usual care group , there was no evidence that patients from the intervention group experienced improvements in pulmonary function , functional status , quality of life , asthma management , or satisfaction with care . In addition , there were no differences between groups in use of anti-inflammatory medications , total or asthma-related medical care utilization , or total or asthma-related school days lost . CONCLUSION This pharmaceutical care intervention had no significant effect on the health or health services use outcomes of pediatric patients with asthma . The intervention may not have been powerful enough to significantly affect pharmacists ' behaviors and asthma patients ' outcomes in community pharmacy setting s , and there is evidence that the pharmacists ' compliance with the study protocol was low due , in part , to patient- and practice -related obstacles [12612228] OBJECTIVE To determine whether health outcomes of children who have asthma can be improved through the use of an Internet-enabled interactive multimedia asthma education program . METHODS Two hundred twenty-eight children with asthma visiting a pediatric pulmonary clinic were r and omly assigned to control and intervention groups . Children and caregivers in both groups received traditional patient education based on the National Asthma Education and Prevention Program . Intervention group participants received additional self-management education through the Interactive Multimedia Program for Asthma Control and Tracking . Pediatric Asthma Care Knowledge Survey , Pediatric Asthma Caregiver 's Quality of Life Question naire , asthma symptom history , spirometry , and health services utilization data were collected at the initial visit and at 3 and 12 months . RESULTS Interactive Multimedia Program for Asthma Control and Tracking significantly increased asthma knowledge of children and caregivers , decreased asthma symptom days ( 81 vs 51 per year ) , and decreased number of emergency department visits ( 1.93 vs 0.62 per year ) among the intervention group participants . The intervention group children were also using a significantly lower average daily dose of inhaled corticosteroids ( 434 vs 754 micro g [ beclomethasone equivalents ] ) at visit 3 . Asthma knowledge of all 7- to 17-year-old children correlated with fewer urgent physician visits ( r = 0.37 ) and less frequent use of quick-relief medicines ( r = 0.30 ) . CONCLUSIONS Supplementing conventional asthma care with interactive multimedia education can significantly improve asthma knowledge and reduce the burden of childhood asthma [11564356] The increased prevalence , morbidity , mortality , and health costs associated with asthma among children suggest the need for accessible asthma education . This study examined the effect of telepharmacy counseling , using interactive compressed video , on metered-dose inhaler ( MDI ) technique and patient satisfaction among adolescents with asthma in rural Arkansas . The telepharmacy counseling provided accessible education regarding MDI technique for adolescents in this study . Twenty percent of the adolescents who participated had never been shown the appropriate use of an MDI . The study used an experimental design with r and om assignment of participants to a telepharmacy counseling group ( n = 15 ) or a control group ( n = 21 ) . Both groups participated in pre-test , post-test , and 2- to 4-week follow-up assessment s for MDI technique and patients satisfaction ( follow-up assessment only ) via interactive compressed video . Results indicated that from pre-test to follow-up the telepharmacy counseling group showed more improvement in MDI technique than participants in the control group ( p < 0.001 ) . There was no significant difference between the telepharmacy counseling group and control group in satisfaction with the instructional sessions ( p = 0.132 ) . Both groups had high levels of satisfaction with the telepharmacy sessions . The study findings demonstrated that patient education provided by pharmacists via interactive compressed video was superior to education provided via written instructions on an inhaler package insert . Interactive compressed video is an effective medium for teaching and improving MDI technique in this rural , adolescent , predominantly African-American population [15791897] OBJECTIVES This report presents both age-adjusted and unadjusted statistics from the 2002 National Health Interview Survey on selected health measures for children under 18 years of age , classified by sex , age , race , Hispanic origin , family structure , parent 's education , family income , poverty status , health insurance coverage , place of residence , region , and current health status . The topics covered are asthma , allergies , learning disability , Attention Deficit Hyperactivity Disorder ( ADHD ) , use of prescription medication , respondent-assessed health status , school-loss days , usual place of health care , time since last contact with a health care professional , unmet dental needs , time since last dental contact , and selected measures of health care access . SOURCE OF DATA The NHIS is a multistage probability sample survey conducted annually by interviewers of the U.S. Census Bureau for the Centers for Disease Control and Prevention 's National Center for Health Statistics and is representative of the civilian noninstitutionalized population of the United States . Data are collected during face-to-face interviews with adults present at the time of interview . Information about children is collected for one r and omly selected child per family in face-to-face interviews with an adult proxy respondent familiar with the child 's health . SELECTED HIGHLIGHTS In 2002 , most U.S. children under 18 years of age had excellent or very good health ( 84 % ) . However , 10 % of children had no health insurance coverage , and 5 % of children had no usual place of health care . Twelve percent of children had ever been diagnosed with asthma . An estimated 8 % of children 3 - 17 years of age had a learning disability , and an estimated 7 % of children had ADHD [12132605] OBJECTIVE To highlight the unique challenges of evaluative research on practice behavior change in the " real world " setting s of contemporary managed-care organizations , using the experience of the Pediatric Asthma Care PORT ( Patient Outcomes Research Team ) . STUDY SETTING The Pediatric Asthma Care PORT is a five-year initiative funded by the Agency for Healthcare Research and Quality to study strategies for asthma care improvement in three managed-care plans in Chicago , Seattle , and Boston . At its core is a r and omized trial of two care improvement strategies compared with usual care : ( 1 ) a targeted physician education program using practice based Peer Leaders ( PL ) as change agents , ( 2 ) adding to the PL intervention a " Planned Asthma Care Intervention " incorporating joint " asthma check-tips " by nurse-physician teams . During the trial , each of the participating organizations viewed asthma care improvement as an immediate priority and had their own corporate improvement programs underway . DATA COLLECTION Investigators at each health plan described the organizational and implementation challenges in conducting the PAC PORT r and omized trial . These experiences were review ed for common themes and " lessons " that might be useful to investigators planning interventional research in similar care-delivery setting s. CONCLUSIONS R and omized trials in " real world " setting s represent the most robust design available to test care improvement strategies . In complex , rapidly changing managed-care organizations , blinding is not feasible , corporate initiatives may complicate implementation , and the assumption that a " usual care " arm will be static is highly likely to be mistaken . Investigators must be prepared to use innovative strategies to maintain the integrity of the study design , including : continuous improvement within the intervention arms , comanagement by research ers and health plan managers of condition-related quality improvement initiatives , procedures for avoiding respondent burden in health plan enrollees , and anticipation and minimization of risks from experimental arm contamination and major organizational change . With attention to these delivery system issues , as well as the usual design features of r and omized trials , we believe managed-care organizations can serve as important laboratories to test care improvement strategies [10069877] BACKGROUND Previous studies have shown that asthma education and case management may reduce asthma emergency care , hospitalizations , and expenditures . OBJECTIVE We sought to study the effect of an asthma outreach program ( AOP ) , a team-based , case-management intervention , on emergency ward ( EW ) and hospital use . METHODS Fifty-seven patients aged 1 to 15 years with the diagnosis of asthma based on the usual clinical practice criteria who were continuously enrolled in a staff-model health maintenance organization for a period of at least 2 consecutive years were r and omized into 2 intervention groups . The control group received a single intensive asthma education intervention , and the AOP group received the same initial education but then was followed-up by an asthma case management nurse throughout the intervention period . RESULTS EW visits , hospitalizations , and total outside-of-health-plan expenditures ( consisting of EW and hospital expenses , as well as miscellaneous costs , such as ambulance , durable medical equipment , tertiary referrals , and home care ) were assessed from cl aims filed for a year before and after enrollment . Control group patients experienced significant reductions in EW visits ( 39 % ) , hospitalizations ( 43 % ) , and outside-of-health-plan costs ( 28 % ) , possibly as a result of the baseline educational intervention received by all enrolled patients , in conjunction with regression to the mean . AOP group patients experienced significant reductions in EW visits , ( 73 % , P = .0002 ) , hospitalizations ( 84 % , P = .0012 ) , and outside-of-health-plan use ( 82 % , P < .0001 ) . When compared with the control group , AOP group patients demonstrated additional significant reductions in EW visits ( 57 % , P < .05 ) , hospitalizations ( 75 % , P < .05 ) , and outside-of-health-plan use ( 71 % , P < .001 ) . Estimates of direct savings to the health plan ranged from $ 7.69 to $ 11.67 for every dollar spent on the AOP nurse 's salary , depending on assumptions . CONCLUSIONS Asthma patients in a staff-model health maintenance organization decreased their re source use between 57 % to 75 % by participation in an AOP as compared with a r and omized control group receiving only an educational intervention . Substantial savings were achieved compared with the cost of the AOP nurse [8450129] A research project , which looks at the value of health education in the prevention of childhood asthma , is described . The project was a controlled trial by a health visitor focused within the community . This exploratory research looked at three groups of children over a 2-year period , and compared the effect of : ( a ) individual health education , and ( b ) group health education . During the first year , two groups were active , one receiving individual health education , the other collecting data of the same type . During the second year , a third group was involved in health education sessions . The findings have been similar in both cases , in that both groups have demonstrated a good improvement in knowledge of asthma and its treatment . Through the active involvement of using a peakflow meter and diary records in the health education programme , both groups receiving health education have shown a significant improvement in the morbidity indicators related to night symptoms and restricted activities . The qualitative analysis of the research also highlighted the value parents of asthmatic children place on counselling [15867115] BACKGROUND A decision to implement innovative disease management interventions in health plans often requires evidence of clinical benefit and financial impact . The Pediatric Asthma Care Patient Outcomes Research Team II trial evaluated 2 asthma care strategies : a peer leader-based physician behavior change intervention ( PLE ) and a practice -based re design called the planned asthma care intervention ( PACI ) . OBJECTIVE To estimate the cost-effectiveness of the interventions . METHODS This was a 3-arm , cluster r and omized trial conducted in 42 primary care practice s. A total of 638 children ( age range , 3 - 17 years ) with mild to moderate persistent asthma were followed up for 2 years . Practice s were r and omized to PLE ( n = 226 ) , PACI ( n = 213 ) , or usual care ( n = 199 ) . The primary outcome was symptom-free days ( SFDs ) . Costs included asthma-related health care utilization and intervention costs . RESULTS Annual costs per patient were as follows : PACI , USD 1292 ; PLE , USD 504 ; and usual care , USD 385 . The difference in annual SFDs was 6.5 days ( 95 % confidence interval [ CI ] , -3.6 to 16.9 days ) for PLE vs usual care and 13.3 days ( 95 % CI , 2.1 - 24.7 days ) for PACI vs usual care . Compared with usual care , the incremental cost-effectiveness ratio was USD 18 per SFD gained for PLE ( 95 % CI , USD 5.21-dominated ) and USD 68 per SFD gained for PACI ( 95 % CI , USD 37.36 - 361.16 ) . CONCLUSIONS Results of this study show that it is possible to increase SFDs in children and move organizations toward guideline recommendations on asthma control in setting s where most children are receiving controller medications at baseline . However , the improvements were realized with an increase in the costs associated with asthma care [3088085] A sample of 310 low income urban children with asthma from 290 families was r and omized into a control group and an experimental group that received health education to improve asthma management at home . No significant decreases in subsequent health care use were observed when the experimental group was compared to the control group without regard to previous hospitalization . When the comparison was restricted to children who had been hospitalized during the preceding year , however , the experimental group was found to have decreased its use of the emergency room significantly more than the control group ( p less than 0.05 ) and to have experienced a significantly greater reduction in the mean number of hospitalizations ( p less than 0.05 ) during the year of follow-up . The program reduced health care costs for children with one or more hospitalizations , saving $ 11.22 for every $ 1.00 spent to deliver health education [11553420] A r and omised controlled trial , involving 112 adolescents with asthma , and a 2-year follow-up was conducted to assess the impact of an intervention programme aim ed at enhancing adherence to asthma medication . This programme had a duration of 1 year and consisted of an experimental group which received usual care from a paediatrician , but additionally attended individual and group sessions with an asthma nurse , and a control group which received usual care only . The programme aim ed at enhancing adherence by stimulating a positive attitude , increasing feelings of social support , and enhancing self-efficacy . At baseline , and after 12-month ( T1 ) and 24-month ( T2 ) follow-up , the participants filled in question naires which were based on the concepts of the ASE-model . Adherence was assessed by self-report ( range : 1 - 10 ) at the same points in time . After 12 months , 97 adolescents ( 87 % ) were available for follow-up , decreasing to 86 adolescents ( 77 % ) after 24 months . No statistically significant differences were found between the control and the experimental group , except for one . At T2 , self-reported adherence appeared to be statistically significantly higher in the experimental group . In conclusion , there seems to have been no substantial effect of the intervention programme [1747614] OBJECTIVE --To determine whether an intervention programme based on existing school and community re sources can reduce school absence and improve participation in games lessons and sport in children with unrecognised or undertreated asthma . DESIGN --Parallel group controlled intervention study . SETTING --102 primary schools in Nottingham : 49 were r and omised to receive the intervention and 53 to be control schools . SUBJECTS -- All children aged 5 to 10 years with parent reported absence from school because of wheezing in the previous year and taking no treatment or beta agonists only . INTERVENTIONS --Children with asthma were referred to their general practitioner for assessment of symptoms and treatment . Teachers were given education on asthma by the school nurse in 44 of the 49 intervention schools . MAIN OUTCOME MEASURES --Changes in school absence and missed games and swimming lessons because of wheezing , and schools ' policy towards management of asthma in school . RESULTS --Of 17,432 children screened , 451 met the entry criteria --228 in intervention schools and 223 in control schools . 152 ( 67 % ) children in intervention schools visited their general practitioner , of whom 39 ( 26 % ) were given a new diagnosis of asthma and 58 ( 38 % ) had treatment for asthma increased or changed . Over the next academic year mean ( SE ) parent reported school absence due to wheezing fell significantly , but to a similar extent , in both intervention and control schools ( 0.82 ( 0.11 ) and 1.09 ( 0.21 ) weeks respectively ) . There was little change in school recorded absence or participation in games lessons and swimming lessons in either group . At the end of the study intervention schools were more likely to have improved aspects of management of asthma in school . CONCLUSION --The intervention result ed in a majority of children being assessed by their general practitioner and improved teachers ' underst and ing and management of asthma , but it did not result in any appreciable reduction in morbidity [15867114] BACKGROUND Guidelines recommend preventive medications for all children with persistent asthma , yet young urban children often receive inadequate therapy . This may occur in part because primary care providers are unaware of the severity of their patients ' symptoms . OBJECTIVE To determine whether systematic school-based asthma screening , coupled with primary care provider notification of asthma severity , will prompt providers to take preventive medication action ( prescribe a new preventive medication or change a current dose ) . DESIGN Children aged 3 to 7 years with mild persistent to severe persistent asthma were identified at the start of the 2002 - 2003 school year in Rochester . Children were assigned r and omly to a provider notification group ( child 's primary care provider notified of asthma severity ) or a control group ( provider not notified of severity ) . Primary care providers of children in the provider notification group were sent a facsimile indicating the child 's symptoms and recommending medication action based on national criteria . Interviewers blinded to the child 's group assignment called parents 3 to 6 months later to determine if preventive actions were taken . RESULTS Of 164 eligible children with mild persistent or more severe asthma , 151 ( 92.1 % ) were enrolled . Children in the provider notification group were not more likely to receive a preventive medication action than were children in the control group ( 21.9 % vs 26.0 % ; P = .57 ) . Additional preventive measures , including encouraging compliance with medications ( 33.3 % vs 31.3 % ; P = .85 ) , recommending environmental modifications ( 39.3 % vs 42.4 % ; P = .86 ) , and referrals for specialty care ( 6.6 % vs 6.0 % ; P > .99 ) , also did not differ between the provider notification and control groups . At the end of the study , 52.4 % of children in both groups with no medication changes were still experiencing persistent symptoms . CONCLUSIONS School-based asthma screening identified many symptomatic children in need of medication modification . Provider notification , however , did not improve preventive care . Findings suggest that more powerful interventions are needed to make systematic asthma screening effective [8707779] A r and omized control trial of the Wee Wheezers asthma education program was conducted with 76 children < 7 years of age , 31 % of whom were on a medication regimen consistent with mild , 51 % with moderate , and 18 % with moderately severe/severe asthma . Treatment children showed improved morbidity at 3-month follow-up relative to the changes in the controls : increased symptom-free days in the preceding 2 weeks ( mean change of + 2.2 vs. -2.6 in the controls ; p = .004 ) and month ( + 2.0 vs. -3.8 ; p < .02 ) , fewer nights of parental sleep interruption in a typical week ( + 0.7 vs. + 1.8 ; p < or = .05 ) , and a trend toward fewer asthma sick days ( -0.2 vs + 0.7 ; p = ns ) . These improvements were accompanied by significantly better parental asthma management compared with controls ( more consistent use of preventive medications , p < or = .01 ; early symptom intervention , [ corrected ] p < or = .05 ) and trends toward more restrictions on smoking in the home ( p < .07 ) and decreased parental confusion about asthma treatment ( p < .11 ) . This study provides evidence that a multisession program of asthma education for parents can improve parental asthma management and clinical outcomes in very young children and provides information on the validity and sensitivity of various asthma outcome measures in this age group [14531243] The adherence and disease-control outcomes associated with the use of an Internet-based store- and -forward video home telehealth system to manage asthma in children were studied . Pediatric patients with persistent asthma were provided with home computers and Internet access and monitored biweekly over the Internet . All patients were seen in the pediatric clinic at 0 , 2 , 6 , 12 , and 24 weeks . Half of the patients received asthma education in person and half via an interactive Web site . Adherence measures were assessed by therapeutic and diagnostic monitoring . Therapeutic monitoring included digital videos of patients using their controller medication inhaler . Diagnostic monitoring included an asthma symptom diary and a video of peak flow meter use . Videos were su bmi tted electronically twice a week by using in-home telemonitoring with store- and -forward technology . Feedback was provided electronically to each patient . Disease control was assessed by examining quality of life , utilization of services , rescue-therapy use , symptom control , satisfaction with home telemonitoring , and retention of asthma knowledge . Patients were r and omly assigned to an asthma education group ( Internet versus office ) , and the data were analyzed by comparing results for study days 0 - 90 and 91 - 180 . Ten children participated . A total of 321 videos of inhaler use and 309 videos of peak flow meter use were su bmi tted . Inhaler technique scores improved significantly in the second study period . Su bmi ssion of diagnostic monitoring videos and asthma diary entries decreased significantly . Peak flow values as a percentage of personal best values increased significantly . Overall , there was no change in quality of life reported by patients . However , the caregivers in the virtual-education group reported an increase in the patients ' quality -of-life survey scores . Emergency department visits and hospital admissions for asthma were avoided . Rescue therapy was infrequent . A high rate of satisfaction with home telemonitoring was reported . Internet-based , store- and -forward video assessment of children 's use of asthma medications and monitoring tools in their homes appeared effective and well accepted [9024439] OBJECTIVE Recent studies have shown that lack of continuing primary care for asthma is associated with increased levels of morbidity in low-income minority children . Although effective preventive therapy is available , many African-American and Latino children receive episodic treatment for asthma that does not follow current guidelines for care . To see if access , continuity , and quality of care could be improved in pediatric clinics serving low-income children in New York City , we trained staff in New York City Bureau of Child Health clinics to provide continuing , preventive care for asthma . METHODS We evaluated the impact of the intervention over a 2-year period in a controlled study of 22 clinics . Training for intervention clinic staff was based on National Asthma Education and Prevention Program guidelines for the diagnosis and management of asthma , and included screening to identify new cases and health education to improve family management . The intervention included strong administrative support by the Bureau of Child Health to promote staff behavior change . We hypothesized that after the intervention , clinics that received the intervention would , compared with control clinics , have increased numbers of children with asthma receiving continuing care in the clinics and increased staff use of new pharmacologic and educational treatment methods . RESULTS In both the first and second follow-up years , the intervention clinics had greater positive changes than control clinics on measures of access , continuity , and quality of care . For second year follow-up data these include : for access , greater rate of new asthma patients ( 40/1000 vs 16/1000 ; P < .01 ) ; for continuity , greater percentage of asthma patients returning for treatment 2 years in a row ( 42 % vs 12 % ; P < .001 ) and greater annual frequency of scheduled visits for asthma per patient ( 1.85 vs .88 ; P < .001 ) ; and for quality , greater percentage of patients receiving inhaled beta agonists ( 52 % vs 15 % ; P < .001 ) and inhaled antiinflammatory drugs ( 25 % vs 2 % ; P < .001 ) , and greater percentages of parents who reported receiving patient education on 12 topics from Bureau of Child Health physicians ( 71 % vs 58 % ; P < .01 ) and nurses ( 61 % vs 44 % ; P < .05 ) . CONCLUSION We conclude that the intervention substantially increased the Bureau of Child Health staff 's ability to identify children with asthma , involve them in continuing care , and provide them with state-of-the-art care for asthma

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### Context: [14586050] Background : Until now , care provided by asthma nurses has been additional to care provided by paediatricians . A study was undertaken to compare nurse led outpatient management of childhood asthma with follow up by a paediatrician . Methods : Seventy four children referred because of insufficient control of persistent asthma were r and omly allocated to 1 year follow up by a paediatrician or asthma nurse . The main outcome measure was the percentage of symptom-free days . Additional outcome measures were airway hyperresponsiveness , lung function , daily dose of inhaled corticosteroids ( ICS ) , number of exacerbations , number of additional visits to the general practitioner , absence from school , functional health status , and disease specific quality of life . Results : There were no significant differences at the end of the 1 year study period between the two treatment groups in percentage of symptom-free days ( mean difference 2.5 % ; 95 % CI −8.8 to 13.8 ) , airway hyperresponsiveness ( log10 PD20 0.06 ; −0.19 to 0.32 ) , functional health status ( 10.1 ; −0.3 to 19.8 ) , disease specific quality of life of patients ( 0.08 ; −0.9 to 0.7 ) , and disease specific quality of life of caregivers ( 0.09 ; −0.2 to 0.3 ) , nor in any other outcome parameters . Most outcome parameters improved considerably over the 1 year study period . These improvements were achieved although the daily dose of ICS was reduced by a mean of 26 % compared with the dose received by children at referral . All parents were satisfied with the asthma care received . Conclusions : After initial assessment in a multidisciplinary clinic , childhood asthma can be successfully managed by an asthma nurse in close cooperation with a paediatrician . During close follow up by paediatrician or asthma nurse , asthma control improved despite a reduction in ICS dose [15356304] BACKGROUND Children with asthma who live in the inner city are exposed to multiple indoor allergens and environmental tobacco smoke in their homes . Reductions in these triggers of asthma have been difficult to achieve and have seldom been associated with decreased morbidity from asthma . The objective of this study was to determine whether an environmental intervention tailored to each child 's allergic sensitization and environmental risk factors could improve asthma-related outcomes . METHODS We enrolled 937 children with atopic asthma ( age , 5 to 11 years ) in seven major U.S. cities in a r and omized , controlled trial of an environmental intervention that lasted one year ( intervention year ) and included education and remediation for exposure to both allergens and environmental tobacco smoke . Home environmental exposures were assessed every six months , and asthma-related complications were assessed every two months during the intervention and for one year after the intervention . RESULTS For every 2-week period , the intervention group had fewer days with symptoms than did the control group both during the intervention year ( 3.39 vs. 4.20 days , P<0.001 ) and the year afterward ( 2.62 vs. 3.21 days , P<0.001 ) , as well as greater declines in the levels of allergens at home , such as Dermatophagoides farinae ( Der f1 ) allergen in the bed ( P<0.001 ) and on the bedroom floor ( P=0.004 ) , D. pteronyssinus in the bed ( P=0.007 ) , and cockroach allergen on the bedroom floor ( P<0.001 ) . Reductions in the levels of cockroach allergen and dust-mite allergen ( Der f1 ) on the bedroom floor were significantly correlated with reduced complications of asthma ( P<0.001 ) . CONCLUSIONS Among inner-city children with atopic asthma , an individualized , home-based , comprehensive environmental intervention decreases exposure to indoor allergens , including cockroach and dust-mite allergens , result ing in reduced asthma-associated morbidity [8428857] The parents of asthmatic children treated in the pediatric respiratory service of Wolfson Hospital were r and omly divided into two groups . One group compromised 26 parents who voluntarily attended a teaching session . After completion of the course , a question naire was completed by parents who had attended the course and parents who had not . The first group showed greater knowledge of all aspects of the disease and , after a year 's follow up , it was noted that there was a statistically significant lower hospitalization rate of their asthmatic child [11809988] Background : The effects on morbidity were examined of providing an educational intervention and a written guided self-management plan to the parents of pre-school children following a recent attendance at hospital for asthma or wheeze . Methods : A prospect i ve , r and omised , partially blinded , controlled trial was design ed at two secondary care centres . Over a 13 month period 200 children aged 18 months to 5 years at the time of admission to a children 's ward or attendance at an accident and emergency department or children 's ( emergency ) assessment unit ( A&E/CAU ) with a primary diagnosis of acute severe asthma or wheezing were recruited . 101 children were r and omised into the control group and received usual care and 99 were assigned to the intervention group and received : ( 1 ) a pre-school asthma booklet ; ( 2 ) a written guided self-management plan ; and ( 3 ) two 20 minute structured educational sessions between a specialist respiratory nurse and the parent(s ) and child . Subjects were assessed at 3 , 6 , and 12 months . The main outcomes were GP consultation rates , hospital re-admissions , and attendances at A&E/CAU . Secondary outcomes included disability score , caregivers ' quality of life , and parental knowledge of asthma . Results : There were no statistically significant differences between the two groups during the 12 month follow up period for any of the main or secondary outcome measures . Conclusions : These results do not support the hypothesis that the introduction of an educational package and a written guided self-management plan to the parents of pre-school children with asthma who had recently attended hospital for troublesome asthma or wheeze reduces morbidity over the subsequent 12 months [9565410] OBJECTIVES This study was conducted to assess the impact of an interactive seminar based on self-regulation theory on 1 ) the treatment practice s and communications and education behavior of physicians , 2 ) the health status and medical care utilization of their pediatric patients with asthma , and 3 ) the satisfaction with care of the subjects ' parents . METHODS A total of 74 general practice pediatricians were assigned to either a program or a control group in a r and omized controlled study . Data were collected from physicians at baseline , and 69 ( 93 % ) provided follow-up data 5 months after the program . Data were also collected from 637 of their patients at baseline , and in a 22-month window after the intervention , 472 ( 74 % ) of this number provided follow-up data . RESULTS After the seminar , physicians in the program group were more likely than were control group physicians to address patients ' fears about medicines , review written instructions , provide a sequence of educational messages , write down how to adjust the medicines at home when symptoms change , and report that they spent less time with their patients . Parents of the children treated by program physicians were significantly more likely than were control group parents to report that the physician had been reassuring , described as a goal that the child be fully active , and gave information to relieve specific worries . After a visit with the physician , these parents were also more likely to report that they knew how to make management decisions at home . After the intervention compared to controls , patients of physicians in the program group were more likely to have received a prescription for inhaled antiinflammatory medicine and to have been asked by the physician to demonstrate how to use a metered-dose inhaler . After the intervention , children seen by program physicians made significantly fewer nonemergency office visits and visits for follow-up of an episode of symptoms ; however , there were no differences in emergency department visits and hospitalizations . Among children who were placed on inhaled corticosteroids during this study , however , children treated by physicians who had received education had significantly fewer symptoms and fewer follow-up office visits , nonemergency physician office visits , emergency department visits , and hospitalizations . CONCLUSIONS The interactive seminar based on theories of self-regulation led to patient-physician encounters that were of shorter duration , had significant impact on the prescribing and communications behavior of physicians , led to more favorable patient responses to physicians ' actions , and led to reductions in health care utilization [15867121] OBJECTIVE To test a quality improvement intervention , a learning collaborative based on the Institute for Healthcare Improvement 's Breakthrough Series methodology , specifically intended to improve care and outcomes for patients with childhood asthma . DESIGN R and omized trial in primary care practice s. SETTING Practice s in greater Boston , Mass , and greater Detroit , Mich. PARTICIPANTS Forty-three practice s , with 13 878 pediatric patients with asthma , r and omized to intervention and control groups . Intervention Participation in a learning collaborative project based on the Breakthrough Series methodology of continuous quality improvement . MAIN OUTCOME MEASURES Change from baseline in the proportion of children with persistent asthma who received appropriate medication therapy for asthma , and in the proportion of children whose parent received a written management plan for their child 's asthma , as determined by telephone interviews with parents of 631 children . RESULTS After adjusting for state , practice size , child age , sex , and within- practice clustering , no overall effect of the intervention was found . CONCLUSIONS This method ologically rigorous assessment of a widely used quality improvement technique did not demonstrate a significant effect on processes or outcomes of care for children with asthma . Potential deficiencies in program implementation , project duration , sample selection , and data sources preclude making the general inference that this type of improvement program is ineffective . Additional rigorous studies should be undertaken under more optimal setting s to assess the efficacy of this method for improving care [11040726] An interactive multimedia computer game to enhance self-management skills and thereby improve asthma outcomes in inner city children with asthma was evaluated . Subjects aged 6 - 17 were recruited from four pediatric practice s and r and omly assigned to the computer intervention condition or to the usual-care comparison . The main character in the game could match the subject on gender and ethnicity . Characteristics of the protagonist 's asthma were tailored to be like those of the subject . Subjects played the computer game as part of regular asthma visits . Time between pre- and post-test varied from 4 to 15.6 months ( mean , 7.6 months ) . Analysis of covariance , with pre-test scores , age , and asthma severity as covariates , found that the intervention was associated with fewer hospitalizations , better symptom scores , increased functional status , greater knowledge of asthma management , and better child self-management behavior for those in the intervention condition . Interactions with covariates were found and discussed in terms of variable efficacy of the intervention [15582348] This study describes a self-treatment program for parents of children with asthma . The aim was to prevent asthma exacerbations by learning to recognise prodromal signs and acting upon them by increasing inhaled corticosteroids ( ICS ) . The study questions were : ( 1 ) can we teach parents and children to recognise prodromal signs ? ( 2 ) are instructions to increase inhalation medication followed ? ( 3 ) will frequency and severity of asthma attacks diminish subsequently ? Due to physicians ' changed attitude towards prescription of ICS , fewer children could be recruited who were " ICS-naive " than expected . Twenty-nine children of the age of 4 - 11 years with moderate asthma , participated in a one year prospect i ve r and omised study . Structured information was given to all patients on asthma , symptoms and medication . The experimental group received additional information on recognising prodromal signs and doubling ICS during one week . Only in 25 % of the patients who recognised prodromal signs the dose of ICS was doubled ( as prescribed ) , in 75 % inadequately or not at all . Recognition of prodromal signs was poor as well as compliance to increase as-needed medication . No significant decrease of asthma symptoms occurred in the experimental group . Clinical implication s are important for self-treatment instructions : an individually tailored and multi-component program should be offered by health care providers in order to help the patient to recognise early alarm symptoms , comply to self-treatment instructions and to make adaptations for continuous self-regulation [1984619] Care of asthmatic children is often episodic and more therapeutic than preventive . A 2-year r and omized , controlled trial involving 95 children measured the impact of a comprehensive home and ambulatory program for pediatric asthma management using objective outcome measures . Interventions for the study group during the first year included 3-month clinic visits , education , and home visits by a specially trained research nurse . Control subjects continued to receive regular care from a family physician or pediatrician . Eight-nine subjects ( 93 % ) completed the study . Study subjects had less school absenteeism than control subjects ( 10.7 vs. 16.0 days , P = .04 ) and showed significantly better small airway function after 1 year . Asthma severity improved in 13 study subjects and worsened in 5 . The reverse was true for control subjects . Study subjects exhibited better metered aerosol technique than control subjects ( P = .0005 ) . Fewer days were spent in hospital by the study subjects admitted compared with control subjects ( 3.67 vs 11.2 days , P = .02 ) . After 1 year , more study than control families ( 72.1 % vs 33.1 % , P = .006 ) reported that their asthmatic child took responsibility for the asthma management . The intervention failed to reduce exposure to secondh and smoke or to household pets . There were no significant differences in medical visits , theophylline levels , or records of asthma symptoms . One year after discontinuing the intervention , a marked " washout " effect was observed . Comprehensive ambulatory programs of childhood asthma management can improve objective measures of illness severity but must be sustained [16336546] OBJECTIVE To assess the practice -level effects of ( 1 ) a physician peer leader intervention and ( 2 ) peer leaders in combination with the introduction of asthma education nurses to facilitate care improvement . And , to compare findings with previously reported patient-level outcomes of trial enrollees . STUDY SETTING Data were included on children 5 - 17 years old with asthma in 40 primary care practice s , affiliated with managed health care plans enrolled in the Pediatric Asthma Care Patient Outcomes Research Team ( PORT ) r and omized trial . STUDY DESIGN Primary care practice s were r and omly assigned to one of two care improvement arms or to usual care . Automated cl aims data were analyzed for 12-month periods using a repeated cross-sectional design . The primary outcome was evidence of at least one controller medication dispensed among patients with persistent asthma . Secondary outcomes included controller dispensing among all identified asthmatics , evidence of chronic controller use , and the dispensing of oral steroids . Health service utilization outcomes included numbers of ambulatory visits and hospital-based events . PRINCIPAL FINDINGS The proportion of children with persistent asthma prescribed controllers increased in all study arms . No effect of the interventions on the proportion receiving controllers was detected ( peer leader intervention effect 0.01 , 95 percent confidence interval [ CI ] : -0.07 , 0.08 ; planned care intervention effect -0.03 , 95 percent CI : -0.09 , 0.02 ) . A statistical trend was seen toward an increased number of oral corticosteroid bursts dispensed in intervention practice s. Significant adjusted increases in ambulatory visits of 0.08 - 0.10 visits per child per year were seen in the first intervention year , but only a statistical trend in these outcomes persisted into the second year of follow-up . No differences in hospital-based events were detected . CONCLUSIONS This analysis showed a slight increase in ambulatory asthma visits as a result of asthma care improvement interventions , using automated data . The absence of detectable impact on medication use at the practice level differs from the positive intervention effect observed in patient self-reported data from trial enrollees . Analysis of automated data on nonenrollees adds information about practice -level impact of care improvement strategies . Benefits of practice -level interventions may accrue disproportionately to the subgroup of trial enrollees . The effect of such interventions may be less apparent at the level of practice s or health plans [6384911] A r and omized control trial of a curriculum , A.C.T. ( Asthma Care Training ) for Kids , was conducted . Seventy-six children between the ages of 8 and 12 years , whose asthma required treatment with medications at least 25 % of the days per month , were r and omly assigned to control and experimental groups . The control group received 4 1/2 hours of lecture presentations on asthma and its management . The experimental groups ( consisting of four to seven children and their parents ) received five 1-hour sessions comprising " the treatment . " Children and their parents were interviewed before the sessions and 3 , 6 , and 12 months after the completion of the experimental treatment . Use of emergency rooms and hospitals was determined by review ing the records of these patients ( all members of the Los Angeles Kaiser Permanente health care system ) for the period of 1 year before and 1 year after the treatment . Results include ( 1 ) equivalent increases in knowledge and changes in beliefs in both groups , ( 2 ) significant changes in the self-reported compliance behaviors of the experimental group only , and ( 3 ) significant reductions in emergency room visits and days of hospitalization among those receiving the experimental treatment , compared with the control group . These changes represent an estimated savings of approximately $ 180 per child per year for those in the experimental group [15982192] Optimal home self-management in young children with asthma includes accurate symptom identification followed by timely and appropriate treatment . The objective of this study was to evaluate a home-based asthma educational intervention targeting symptom identification for parents of children with asthma . Two hundred twenty-one children with asthma were enrolled into an ongoing home-based clinical trial and r and omized into either a st and ard asthma education ( SAE ) or a symptom/nebulizer education intervention ( SNEI ) . Data included home visit records and parent 's self-report on question naires . Symptom identification and self-management skills significantly improved from preintervention to postintervention for parents in both groups with the exception of checking medications for expiration date s and the frequency of cleaning nebulizer device and equipment . However , significantly more parents of children in the SNEI group reported treating cough symptoms as compared with the SAE group ( p = 0.05 ) . Of concern is that only 38 % of all parents reported having an asthma action plan in the home . A targeted home-based asthma education intervention can be effective for improving symptom identification and appropriate use of medications in children with asthma . Home asthma educational programs should address accurate symptom identification and a demonstration of asthma medication delivery devices [10933079] This r and omized clinical trial evaluated the long-term impact of an interactive seminar for physicians based on principles of self-regulation on clinician behaviour , children 's use of health services for asthma , and parent 's views of physician performance . Seventy-four general practice paediatricians , and 637 of their asthma patients aged 1 - 12 yrs , were r and omized to treatment or control . Children and parents were blind to physicians ' participation . Data were collected at baseline and follow-up through self-administered surveys ( paediatricians ) , telephone interviews ( parents ) and medical records . The seminar focused on development of communication and teaching skills and use of therapeutic medical regimens for asthma as outlined in the National Asthma Education and Prevention Program guidelines . Approximately 2 yrs postintervention , treatment group physicians were more likely than control physicians to : use protocol s for delivering asthma education ( odds ratio ( OR ) 4.9 , p=0.2 ) , write down for patients how to adjust medicines when symptoms change ( OR 5.7 , p=0.05 ) , and provide more guidelines for modifying therapy ( OR 3.8 , p=0.06 ) . Parents scored treatment group physicians higher than control physicians on five specific positive communication behaviours . Children seen by treatment group physicians had fewer hospitalizations ( p=0.03 ) and those with higher levels of emergency department ( ED ) use at baseline had fewer subsequent ED visits ( p=0.03 ) . No differences regarding the number of office visits were noted . There were no significant differences found between treatment and control group physicians in the amount of time spent with patients during office visits ( 26 versus 29 min ) or in the number of patients treated with anti-inflammatory medicine . It is concluded that interactive asthma seminars for paediatricians had significant long-term benefits for their asthma care [12528584] AIM To compare a nurse-led clinic in schools versus care in general practice for adolescents with asthma . DESIGN OF STUDY R and omised controlled trial in four schools ; parallel observational study in two schools . SETTING Six comprehensive schools . METHOD In the r and omised trial , pupils were invited to attend asthma review at a nurse-led clinic either in school , or in general practice . The parallel observational study compared pupils invited to practice care within and outside the r and omised trial . Primary outcome measures were attendance for asthma review , symptom control , and quality of life . Secondary outcomes were knowledge , attitudes , inhaler technique , use of steroids , school absence , peak flow rate , preference for future care , health service utilisation , and costs . RESULTS School clinic pupils were more likely to attend an asthma review than those r and omised to practice care ( 90.8 % versus 51.0 % overall [ P < 0.001 , not consistent across schools ] ) . No differences were observed in symptom control ( P = 0.42 ) or quality of life ( P = 0.63 ) . Pupils attending school clinics had greater knowledge of asthma ( difference = + 0.38 , 95 % CI = 0.19 to 0.56 ) , more positive attitudes ( difference = + 0.21 , 95 % CI = 0.05 to 0.36 ) , and better inhaler technique ( P < 0.001 , not consistent across all schools ) . No differences were observed in school absence or peak flow rate . A majority ( 63 % ) of those who had received care at school preferred this model in future . Median costs of providing care at school and at the practice were 32.10 Pounds and 19.80 Pounds , respectively . No differences were observed between the groups in the observational comparison on any outcome . CONCLUSIONS The schools asthma clinic increased uptake of asthma review s. There were improvements in various process measures , but not in clinical outcomes [1506461] Children with asthma are at special risk for problems in psychological functioning , as are children with other chronic illnesses . We conducted a controlled trial of a combined education and stress management program among children ages 6 to 14 years with asthma . Eighty-one children were r and omly assigned to an intervention or a control group ; 56 children completed data collection , 29 intervention and 27 control . Psychological status was assessed by the Child Behavior Checklist ( CBCL ) before and after the intervention , as were children 's knowledge of asthma , stress ( as measured by children 's life events ) , and functional status ( as indicated by such activities as school attendance , time playing with friends , and daily chore performance ) . Children in the intervention group had a significant improvement in the total Behavior Problems score ( p < .04 ) and Internalizing scale ( p < .01 ) on the CBCL and a significant increase in daily chores ( p < .04 ) compared with the control group . Before intervention , the two groups had statistically significant positive relationships between negative life events and behavior problem scores . After intervention , children in the control group still demonstrated a significant relationship between negative life events and total and Internalizing Behavior Problem scores , although participation in the intervention group negated that relationship . Children in the intervention group whose knowledge of asthma increased were more likely to report an increase in daily chores ( p < .02 ) . We conclude that the intervention had a beneficial effect on psychological status and on children 's daily activities . The effect may have occurred in part by decreasing the likelihood that perceived stress from negative life events led to poorer adjustment [14500440] Abstract Objectives To assess the feasibility and effectiveness of a general practice based , proactive system of asthma care in children . Design R and omised controlled trial with cluster sampling by general practice . Setting General practice s in the northern region of the Australian Capital Territory . Participants 174 children with moderate to severe asthma who attended 24 general practitioners . Intervention System of structured asthma care ( the 3 + visit plan ) , with participating families reminded to attend the general practitioner . Main outcome measures Process measures : rates for asthma consultations with general practitioner , written asthma plans , completion of the 3 + visit plan ; clinical measures : rates for emergency department visits for asthma , days absent from school , symptom-free days , symptoms over the past year , activity limitation over the past year , and asthma drug use over the past year ; spirometric lung function measures before and after cold air challenge . Results Intervention group children had significantly more asthma related consultations ( odds ratio for three or more asthma related consultations 3.8 ( 95 % confidence interval 1.9 to 7.6 ; P = 0.0001 ) , written asthma plans ( 2.2 ( 1.2 to 4.1 ) ; P = 0.01 ) , and completed 3 + visit plans ( 24.2 ( 5.7 to 103.2 ) ; P = 0.0001 ) than control children and a mean reduction in measurements of forced expiratory volume in one second after cold air challenge of 2.6 % ( 1.7 to 3.5 ) ; P = 0.0001 ) less than control children . The number needed to treat ( benefit ) for one additional written asthma action plan was 5 ( 3 to 41 ) children . Intervention group children had lower emergency department attendance rates for asthma ( odds ratio 0.4 ( 0.2 to 1.04 ) ; P = 0.06 ) and less speech limiting wheeze ( 0.2 ( 0.1 to 0.4 ) ; P = 0.0001 ) than control children and were more likely to use a spacer ( 2.8 ( 1.6 to 4.7 ) ; P = 0.0001 ) . No differences occurred in number of days absent from school or symptom-free day scores . Conclusions Proactive care with active recall for children with moderate to severe asthma is feasible in general practice and seems to be beneficial [10276475] To evaluate a health education program to improve family management of asthma , 310 children with asthma and their 290 parents were r and omly assigned to a program or control group . Program families participated in health education design ed to resolve specific management problems and build self-confidence in the ability to manage asthma . Following education , program parents scored better on an asthma self-management index than parents in the control group ( + 1.57 versus -0.83 , P less than 0.0001 ) . Program parents also scored better on two subindices of the self-management index : attack management ( + 0.87 vs. + 0.42 , P less than 0.05 ) and preventive measures ( + 0.42 vs. -0.35 , P less than 0.05 ) . Also , program parents reported significantly more use of guidelines to determine appropriate levels of physical activity for children . Following education , program children reported more use of three management steps than control children : productive cough or postural drainage ( 59 % vs. 35 % , P less than 0.004 ) , breathing and relaxation exercises ( 80 % vs. 65 % , P less than 0.05 ) , and attempts to stay calm ( 12 % vs. 2 % , P less than 0.05 ) . Program children reported significantly less worry than control children about the limitations asthma imposes and about making mistakes at school [12403858] OBJECTIVE To conduct a controlled trial of a home-based education program for low-income caregivers of young children with asthma . METHODS Participants were r and omized to treatment-eight weekly asthma education sessions adapted from the Wee Wheezers program ( n = 49)-or usual care ( n = 46 ) . Baseline and 3- and 12-month follow-up data were gathered from caregivers and from children 's medical records . RESULTS Treatment was associated with less bother from asthma symptoms , more symptom-free days , and better caregiver quality of life at follow-up for children 1 - 3 , but not those 4 - 6 , years of age . Treatment and control groups did not differ in caregiver asthma management behavior or children 's acute care utilization . CONCLUSIONS This home-based asthma education program was most effective with younger children ; perhaps their caregivers were more motivated to learn about asthma management . Targeting psychosocial factors associated with asthma morbidity might also enhance the efficacy of asthma education for these families [10790458] OBJECTIVES To evaluate health care and financial outcomes in a population of Medicaid-insured asthmatic children after a comprehensive asthma intervention program . DESIGN Controlled clinical trial . SETTING Pediatric allergy clinic in an urban , tertiary care children 's hospital . SUBJECTS Eighty children , 2 to 16 years old , with a history of frequent use of emergent health care services for asthma . Intervention . Children in the intervention group received asthma education and medical treatment in the setting of a tertiary care pediatric allergy clinic . An asthma outreach nurse maintained monthly contact with the families enrolled in the intervention group . OUTCOME MEASURES Emergency department ( ED ) visits , hospitalizations , and health care charges per patient in the year after enrollment . RESULTS Baseline demographics did not differ significantly between the 2 groups . In the year before the study , there were no significant differences between intervention and control children in ED visits ( mean , 3.5 per patient ) , hospitalizations ( mean,.6 per patient ) or health care charges ( $ 2969 per patient ) . During the study year , ED visits decreased to a mean of 1.7 per patient in the intervention group and 2.4 in controls , while hospitalizations decreased to a mean of.2 per patient in the intervention group and .5 in the controls . Average asthma health care charges decreased by $ 721/child/year in the intervention group and by $ 178/patient/year in the control group . CONCLUSIONS A comprehensive asthma intervention program for Medicaid-insured asthmatic children can significantly improve health outcomes while reducing health care costs.asthma education , health care outcomes , Medicaid , asthma outreach , utilization [8621369] A r and omized trial of an instructional method was conducted in which school nurses taught children asthma self-management principles and skills , including peak flow monitoring , in 20-min , individual sessions over an 8-week period . Thirty-six children participated . An intervention group of 18 children received the teaching sessions . A control group of 18 children received regular care by the nurses , but no teaching sessions . The sample included 64 % boys , 69 % African-Americans , and 69 % Medicaid recipients . The average age of subjects was 10.2 years . The two groups were demographically similar , but despite r and om assignment , the control group had a significantly earlier age of onset of asthma and tended to have had more asthma attacks in the preceding year . These factors were statistically controlled in outcome analyses . Results of group comparisons showed no significant differences in the number of postintervention emergency room visits and days absent from school . However , nurses reported that children who practice d breathing exercises had less anxiety during exacerbations , and the nurses ' knowledge of the children 's baseline peak expiratory flow rates facilitated care of the children . Nurses expressed the opinion that the individual sessions with students might be useful in motivating them to participate effectively in later group sessions . The intervention was well accepted by students , parents , and nurses . We believe that this intervention is promising as a practical , low-cost approach to enhancing children 's asthma self-management skills and warrants further testing in a larger sample , with the intervention conducted over a longer period [16440537] BACKGROUND Despite significant medical advances , many ethnic and racial minority children who live in inner cities continue to experience disproportionately high levels of asthma morbidity and mortality compared with white children . As a result , a growing number of psychosocial asthma management interventions are being developed to address their needs ; however , only a few of these interventions have incorporated cultural variables into their treatments and have had their efficacy evaluated . OBJECTIVE To examine the efficacy of the Multifamily Asthma Group Treatment ( MFAGT ) , design ed to enhance asthma management and reduce emergency department ( ED ) visits among African American and Hispanic families . METHODS Twenty-four African American and Hispanic families who have children with asthma were r and omly assigned to either the MFAGT or the St and ard Psychoeducational Asthma Intervention . Differences in the number of ED visits and the level of asthma management in both groups were compared 1 year before and 1 year after the intervention . In addition , these groups were contrasted to a control group that did not receive any psychoeducational intervention . RESULTS The MFAGT was significantly ( P = .04 ) more effective than the St and ard Psychoeducational Asthma Intervention and the control in decreasing ED visits and increasing parental asthma knowledge . CONCLUSIONS These preliminary results suggest that the MFAGT is efficacious in enhancing asthma management and in reducing ED visits in inner-city African American and Hispanic children from a lower socioeconomic background [14979508] The high burden of asthma on healthcare utilisation and costs warrants economic appraisal of management approaches . The authors previously demonstrated that the efficacy of nurse-led outpatient management of childhood asthma was comparable to management by a paediatrician and now report on the healthcare utilisation and costs of both management approaches . A total of 74 newly referred children with asthma were r and omly assigned to a 1‐yr follow-up by paediatricians or asthma nurse . Healthcare utilisation was recorded and associated costs calculated for both management approaches . There were no significant differences in healthcare utilisation except for the total time spent on patient contact ( 136(n=14 ) versus 187(n=41 ) min , for patients followed-up by paediatrician and an asthma nurse repectively ) . Costs within the healthcare sector were reduced by 7.2 % in favour of nurse-led care . The reduction in costs was solely attributable to a 17.5 % reduction in the costs of outpatient visits . Nurse-led care appeared to be cost-saving even if the duration of follow-up visits would be twice that of doctor 's visits . Overall healthcare costs ( within and outside the healthcare sector ) were 4.1 % lower for nurse-led outpatient management compared to traditional medical care . Nurse-led outpatient management of childhood asthma can be provided at a lower cost than medical care by paediatricians [11238152] Abstract Objective : To determine the effect of a peer led programme for asthma education on quality of life and related morbidity in adolescents with asthma . Design : Cluster r and omised controlled trial . Setting : Six high schools in rural Australia . Participants : 272 students with recent wheeze , recruited from a cohort of 1515 students from two school years ( mean age 12.5 and 15.5 years ) ; 251 ( 92.3 % ) completed the study . Intervention : A structured education programme for peers comprising three steps ( the “ Triple A Program ” ) . Main outcome measures : Quality of life , school absenteeism , asthma attacks , and lung function . Results : When adjusted for year and sex , mean total quality of life scores showed significant improvement in the intervention than control group . Clinical ly important improvement in quality of life ( > 0.5 units ) occurred in 25 % of students with asthma in the intervention group compared with 12 % in the control group ( P=0.01 ) . The number needed to treat was 8 ( 95 % confidence interval 4.5 to 35.7 ) . The effect of the intervention was greatest in students in year 10 and in females . Significant improvements occurred in the activities domain ( 41 % v 28 % ) and in the emotions domain ( 39 % v 19 % ) in males in the intervention group . School absenteeism significantly decreased in the intervention group only . Asthma attacks at school increased in the control group only . Conclusion : The triple A programme leads to a clinical ly relevant improvement in quality of life and related morbidity in students with asthma . Wider dissemination of this programme in schools could play an important part in reducing the burden of asthma in [16537855] BACKGROUND Asthma is the most common chronic disease among children in Germany . Approaches to reduce the burden of asthma include patient education to improve self-management skills . STUDY OBJECTIVES We determined whether a continuous Internet-based education program ( IEP ) as an add-on to a st and ardized patient management program ( SPMP ) improves health outcomes of asthma patients at a favorable benefit-cost ratio . PATIENTS AND METHODS A total of 438 asthmatic patients aged 8 to 16 years in 36 study centers were enrolled during a 6-month period . We performed a prospect i ve cost-benefit analysis alongside a nonr and omized trial . At baseline and at 6 months and 12 months , health service utilization data were collected . INTERVENTIONS Study participants were assigned to a control group and two intervention groups . Patients in both intervention groups participated in an SPMP . Additionally , patients in one intervention group received the IEP . RESULTS Utilization of various health-care services decreased significantly in both intervention groups . From a payer perspective , the benefit-cost ratio of the traditional education program was 0.55 . Adding the IEP improved the ratio ( 0.79 ) . For patients with moderate or severe asthma , the benefit-cost ratios were 1.07 and 1.42 ( with IEP ) , respectively . CONCLUSIONS The IEP offers the potential to decrease the burden of disease and to realize incremental morbidity cost savings . Subgroup analysis demonstrated that within 1 year , the savings exceed the intervention costs in patients with moderate or severe asthma [15351753] BACKGROUND Traditional primary care practice change approaches have not led to full implementation of national asthma guidelines . OBJECTIVE To evaluate the effectiveness of 2 asthma care improvement strategies in primary care . DESIGN Two-year r and omized controlled clinical trial . SETTING Forty-two primary care pediatric practice s affiliated with 4 managed care organizations . PARTICIPANTS Children aged 3 to 17 years with mild to moderate persistent asthma enrolled in primary care practice s affiliated with managed care organizations . INTERVENTIONS Peer leader education consisted of training 1 physician per practice in asthma guidelines and peer teaching methods . Planned care combined the peer leader program with nurse-mediated organizational change through planned visits with assessment s , care planning , and self-management support , in collaboration with physicians . Analyses compared each intervention with usual care . MAIN OUTCOME MEASURES Annualized asthma symptom days , asthma-specific functional health status ( Children 's Health Survey for Asthma ) , and frequency of brief oral steroid courses ( bursts ) . RESULTS Six hundred thirty-eight children completed baseline evaluations , representing 64 % of those screened and eligible . Mean + /- SD age was 9.4 + /- 3.5 years ; 60 % were boys . Three hundred fifty ( 55 % ) were taking controller medication . Mean + /- SD annualized asthma symptom days was 107.4 + /- 122 days . Children in the peer leader arm had 6.5 fewer symptom days per year ( 95 % confidence interval [ CI ] , - 16.9 to 3.6 ) , a nonsignificant difference , but had a 36 % ( 95 % CI , 11 % to 54 % ) lower oral steroid burst rate per year compared with children receiving usual care . Children in the planned care arm had 13.3 ( 95 % CI , - 24.7 to -2.1 ) fewer symptom days annually ( -12 % from baseline ; P = .02 ) and a 39 % ( 95 % CI , 11 % to 58 % ) lower oral steroid burst rate per year relative to usual care . Both interventions showed small , statistically significant effects for 2 of 5 Children 's Health Survey for Asthma scales . Planned care subjects had greater controller adherence ( parent report ) compared with usual care subjects ( rate ratio , 1.05 [ 95 % CI , 1.00 to 1.09 ] ) . CONCLUSIONS Planned care ( nurse-mediated organizational change plus peer leader education ) is an effective model for improving asthma care in the primary care setting . Peer leader education on its own may also serve as a useful model for improving asthma care , although it is less comprehensive and the treatment effect less pronounced [11814370] BACKGROUND Asthma is an important cause of morbidity , absence from school , and use of health services among children . Computer-based educational programs can be design ed to enhance children 's self-management skills and to reduce adverse outcomes . OBJECTIVE To assess the effectiveness of an interactive device programmed for the management of pediatric asthma . DESIGN A r and omized controlled trial ( 66 participants were in the intervention group and 68 were in the control group ) . SETTING Interventions conducted at home and in an outpatient hospital clinic . PARTICIPANTS Inner-city children aged 8 to 16 years diagnosed as having asthma by a physician . INTERVENTION An asthma self-management and education program , the Health Buddy , design ed to enable children to assess and monitor their asthma symptoms and quality of life and to transmit this information to health care providers ( physicians , nurses , or other case managers ) through a secure Web site . Control group participants used an asthma diary . MAIN OUTCOME MEASURES Any limitation in activity was the primary outcome . Secondary outcomes included perceived asthma symptoms , absence from school , any peak flow reading in the yellow or red zone , and use of health services . RESULTS After adjusting for covariates , the odds of having any limitation in activity during the 90-day trial were significantly ( P = .03 ) lower for children r and omized to the Health Buddy . The intervention group also was significantly ( P = .01 ) less likely to report peak flow readings in the yellow or red zone or to make urgent calls to the hospital ( P = .05 ) . Self-care behaviors , which were important correlates of asthma outcomes , also improved far more for the intervention group . CONCLUSION Compared with the asthma diary , monitoring asthma symptoms and functional status with the Health Buddy increases self-management skills and improves asthma outcomes [11926622] BACKGROUND Accurate symptom evaluation is a critical component of asthma management . Limited data are available about the accuracy of symptom evaluation by children with asthma and their parents , or the impact of various symptom-monitoring strategies on asthma morbidity outcomes . OBJECTIVE The purpose of this r and omized clinical trial was to evaluate the effect of three different intensities of symptom monitoring on asthma morbidity outcomes . METHODS One hundred sixty-eight children ( ages 6 to 19 ) of diverse racial , geographic , and socioeconomic background s were r and omized to 1 of 3 treatment groups ( subjective symptom evaluation , symptom-time peak expiratory flow rate ( PEFR ) monitoring , daily PEFR monitoring ) in this longitudinal , clinical trial . Outcome measures included a summary asthma severity score , forced expiratory volume in 1 second , symptom days , and health care utilization . RESULTS Children who used PEFR meters ( PFMs ) when symptomatic had a lower asthma severity score , fewer symptom days , and less health care utilization than children in the other two treatment groups . Minority and poor children had the greatest amount of improvement using PFMs when symptomatic . Results were much less striking in white families . Thirty percent of families in the PFM treatment groups discontinued use entirely by 1 year postexit , whereas the majority of families who continued use ( 94 % ) used them only when symptomatic to inform symptom interpretation and management decisions . CONCLUSIONS Not every child with asthma needs a PFM . Children and families facing extra challenges as a result of illness severity , sociodemographic , or health care system characteristics clearly benefited most from PFM use [15302719] STUDY OBJECTIVES To determine whether an interactive physician seminar that has been shown to improve patient/parent satisfaction and to decrease emergency department visits for children with asthma was also effective for those children from low-income families . DESIGN Seventy-four pediatricians and 637 of their patients were r and omized to receive two asthma seminars or no educational programs and were observed for 2 years . SETTING Physicians in the New York , NY , and Ann Arbor , MI , areas were enrolled , and , on average , 10 patients with asthma per provider were surveyed and observed for 2 years . PATIENTS OR PARTICIPANTS A total of 637 subjects were enrolled , and 369 subjects remained in the study after 2 years . Of these , 279 had complete medical and survey information . INTERVENTIONS Physicians were r and omized , and then a r and om sample of their patients was enrolled and surveyed regarding the physician 's communication style , the child 's asthma symptoms , medical needs , and asthma care . Low income was defined as annual income of < 20,000 dollars . MEASUREMENTS AND RESULTS The families of 36 children ( 13 % ) had an income of < 20,000 dollars , and they were treated by 23 physicians . Low-income children in the treatment group tended to have higher levels of use of controller medications , to receive a written asthma action plan , and to miss fewer days of school , although these differences were not statistically significant compared to low-income children in the control group . However , low-income treatment group children were significantly less likely to be admitted to an emergency department ( annual rate , 0.208 vs 1.441 , respectively ) or to a hospital ( annual rate , 0 vs 0.029 , respectively ) for asthma care compared to children in the control group . CONCLUSIONS The educational program for physicians improved asthma outcomes for their low-income patients . Provider interventions targeted to these high-risk patients may diminish hospital and emergency department asthma care [12195271] BACKGROUND Asthma is common and is often poorly controlled in adolescent subjects . OBJECTIVE To determine the impact of an age-specific asthma program on asthma control , particularly on exacerbations of asthma requiring emergency department treatment , and on the quality of life of adolescents with asthma . METHODS The present r and omized , controlled trial included patients who were 15 to 20 years of age and had visited emergency departments for management of their asthma . The interventional group attended an age-specific asthma program that included assessment , education and management by a team of asthma educators , respiratory therapists and respiratory physicians . In the control group , spirometry was performed , and the patients continued to receive usual care from their regular physicians . The outcomes were assessed by a question naire six months after entry into the study . RESULTS Ninety-three subjects entered the study and were r and omly assigned to the intervention or control group . Of these , only 62 patients were available for review after six months . Subjects in both the control and the intervention groups showed a marked improvement in their level of asthma control , reflected primarily by a 73 % reduction in the rate of emergency department attendance for asthma . Other indexes of disease control , including disease-specific quality of life , as assessed by question naires , were improved . There was , however , no discernible difference between the subjects in the two groups , with the exception of an improvement in favour of the intervention group in the symptom ( actual difference 0.7 , P=0.048 ) and emotional ( actual difference 0.8 , P=0.028 ) domains of the asthma quality of life question naire . The overall quality of life score favoured the intervention group by a clinical ly relevant difference of 0.6 , but this difference did not reach statistical significance ( P=0.06 ) . CONCLUSIONS Although all subjects demonstrated a significant improvement in asthma control and quality of life , the improvement attributable to this intervention was limited to two domains in disease-specific quality of life [3902784] A small , controlled trial of joint treatment of childhood asthma by a doctor , a physiotherapist , a psychologist , and a social worker , working together in the family setting , demonstrated an improvement in ventilatory capacity . The limited scope of this trial does not permit more general conclusions as to the effect of such treatment on the severity and frequency of attacks , but the observation that some measurable physiological improvement occurred suggests that the place of multidisciplinary nonpharmaceutical management of childhood asthma should be investigated in more detail [16236837] OBJECTIVE To evaluate an asthma education program for children with asthma that is delivered in their school by certified asthma educators from a local hospital-based asthma center . STUDY DESIGN R and omized controlled trial . SETTING Twenty-six elementary schools located in a suburb of Toronto . PARTICIPANTS A total of 256 children in grade s 2 to 5 with asthma and their parents were r and omized to control and experimental groups . INTERVENTION Children in the experimental group received the " Roaring Adventures of Puff " asthma education program over the course of six weekly 1-h sessions . Those in the control group continued receiving usual care . MEASUREMENTS AND RESULTS Data collection involved measuring asthma quality of life , self-efficacy for managing asthma , school absenteeism , days of interrupted activity , health services use , and parental loss of time from work . Quality of life and self-efficacy data were collected from the children at baseline and 2 months . Telephone parental interviews conducted over 1 year were used to collect data on the remaining variables . Unpaired t test , analysis of variance , and chi2 test were used to determine whether differences existed between the groups . The results are reported as the mean + /- SD . The experimental group demonstrated higher scores than the control group for self-efficacy ( 3.6 + /- 0.7 vs 3.8 + /- 0.9 , respectively ; p < 0.05 ) and quality of life ( 5.0 + /- 1.4 vs 5.5 + /- 1.4 , respectively ; p < 0.05 ) . At 1 year , the experimental group demonstrated fewer mean urgent health-care visits ( 2.5 + /- 2.5 vs 1.7 + /- 1.9 visits per year , respectively ; p < 0.01 ) , days of missed school ( 4.3 + /- 5.7 vs 3.0 + /- 4.4 days per year , respectively ; p > 0.05 ) , and days of interrupted activity ( 9.1 + /- 10.5 vs 6.2 + /- 7.3 days per year ; p < 0.01 ) related to asthma than the control group . There were no differences between the groups for parental work absenteeism or scheduled asthma visits . CONCLUSION Providing an asthma education program to children in their school can significantly improve quality of life and reduce the burden of childhood asthma [7659625] Asthma is a very common chronic disease among preschool children in primary health care . Research has shown that planned and systematic patient education positively affects the management of asthma by parents . This study focuses on the question of whether an asthma patient education protocol that is used by general practitioners ( GPs ) has an effect on medical care consumption . The treatment group consisted of 28 GPs , representing 47 asthmatic infants . The control group contained 18 GPs , representing 38 patients . Data were collected from medical records ( with a written instrument ) for a 12-month period preceding and after the intervention period in which the education protocol was tested . Results indicated that sociodemographic variables and pretest data on asthma severity and medical care utilization were largely comparable for patients in both study groups . Furthermore , the treatment group showed a significantly greater decrease than the control group from pre- to post-test measurement in the number of contacts with the GP and the number of emergency visits to the physician 's office [15690558] Our objective was to determine whether an asthma education program in schools would have 1 ) a direct impact on student knowledge and attitudes to asthma and quality of life of the students with asthma , 2 ) an indirect impact on teacher knowledge and attitudes to asthma and on school policies about asthma , and 3 ) a sustainable program after the re sources to implement the research were withdrawn . Seventeen intervention and 15 control schools participated in a controlled trial . Baseline knowledge and attitudes were measured in year 8 students ( ages 13 - 14 years ) and their teachers together with quality of life in the students with asthma . A three-lesson package about asthma was delivered by teachers as part of the Personal Development/Health/Physical Education ( PD/H/PE ) curriculum . Follow-up question naires were administered to students and staff . Efforts to change school policies were documented . Five years after the intervention , PD/H/PE teachers were contacted to determine whether the program was still operating . Main outcome measures included asthma knowledge , attitudes , and quality of life . Question naires were returned by 4,161/4,475 of the year 8 students at baseline and by 3,443 at follow-up . In intervention schools , compared with control schools , students showed improved asthma knowledge ( P < 0.0001 ) , improvement in tolerance to asthma ( P = 0.02 ) , internal control ( P = 0.03 ) , and less tendency to believe in the role of chance in asthma control ( P = 0.04 ) . Students from intervention but not control schools showed significant improvements in overall quality of life ( P = 0.003 vs. P = 0.82 , respectively ) . Teachers from intervention schools showed significant increases in knowledge compared to control schools ( P < 0.0001 ) . Intervention schools were more likely to seek further health education about asthma ( P < 0.01 ) . Five years after the 35 schools involved in the development of the material s or the trial had been offered the Living With Asthma package , 25 ( 71 % ) were still teaching the program to most or all of their students . Fifty-nine of the 61 ( 97 % ) high schools in the Hunter Region now have the program . Management and distribution of the Living With Asthma program have been taken over by the Asthma Foundation of New South Wales . The package has been up date d and is being offered to all high schools throughout New South Wales as part of the National Asthma-Friendly Schools Project . In conclusion , a teacher-led asthma education program in secondary school had direct and indirect beneficial outcomes and was sustained at a high level for 5 years in most schools in the Hunter Region , despite minimal ongoing maintenance and support from health workers [16478844] STUDY OBJECTIVES To examine the effectiveness of an interdisciplinary intervention for pediatric asthma . DESIGN R and omized , controlled study . SETTING Urban tertiary-referral pediatric hospital . PARTICIPANTS One hundred seventy-five patients with asthma lacking written treatment plans and presenting with asthma-related emergency department visits ( two or more ) and /or hospitalizations ( one or more ) in the past year were r and omized to a comparison group receiving medical care alone ( n = 86 ) or to an interdisciplinary intervention group receiving medical care , asthma education , and problem-solving therapy ( n = 89 ) INTERVENTION All participants received written asthma management plans , peak flow meters , and spacer devices . The intervention group also received asthma education , an asthma risk profile assessment , brief problem-solving therapy , and access to a 24-h nurse advice line . The primary outcome measure was change in asthma symptoms , and secondary outcomes included health-care utilization and asthma-related quality of life . RESULTS Both groups demonstrated significant reductions in asthma symptoms and improvements in quality of life without any between-group differences identified over the course of follow-up . In contrast , the intervention group demonstrated less frequent health-care utilization than the comparison group , with 28 % of the intervention group requiring emergency department or inpatient services for asthma compared to 41 % of the comparison group ( adjusted odds ratio , 1.92 ; 95 % confidence interval , 1.00 to 3.69 ) over the 12-month follow-up period . CONCLUSIONS This study examined the effectiveness of an interdisciplinary intervention for undertreated asthma . The intervention did not result in improvements in asthma symptoms , but accomplished modest reductions in the utilization of acute medical care [7928930] This paper describes the results of an asthma self-management protocol delivered to parents of children aged 0 - 4 years . The protocol was delivered by general practitioners ( GPs ) , community nurses , asthma nurses , and doctors to child health centers . It consisted of 16 educational modules developed after an initial needs assessment of parents and a task analysis of primary care practitioners . The program was evaluated by means of an experimental design . Parents participating in the program had significantly more knowledge , a more favorable attitude toward asthma , and a higher self-efficacy score with respect to performing asthma self-management behaviors . Also , they reported performing self-management behaviors more frequently than parents in the control group . One-year follow-up results , which were collected for parents in the treatment group only , showed that the described changes were sustained . Further , the treatment group was found to have decreased its emergency and nonemergency use of the physician 's office and to have a reduction in ( reported ) asthma severity . Process evaluation indicated that most modules were provided by the GPs to nearly all parents . After parents had read the modules at home , almost all the information was discussed in the next contact . GPs seldom referred patients to the community nurses , although this was suggested in the protocol [8185365] A clinic supervised by a nurse , using principles originally developed in general practice , was established in the paediatric department of a district general hospital . A r and omised controlled study was conducted comparing children admitted with asthma or attending out patients who were given a patient education programme and self management plan ( intervention group ) with a control group . The study comprised 91 patients aged 3 - 14 years admitted for asthma or attending a hospital outpatient department from November 1989 to November 1990 . Seventy seven patients completed the study and kept diaries for a median of 283 days . Patients in the intervention group had significantly less restriction of activity ( 95 % confidence interval ( CI ) -0.27 to -0.01 ) and fewer episodes of peak flow below 30 % of best ( 95 % CI 0.03 to 1.17 ) . Patients in the intervention group were more likely to make the correct response to an acute exacerbation of their asthma than the control group ( 71 % v 47 % , 95 % CI 9.51 to 39.1 ) . The intervention group had fewer school absences and fewer home visits by a general practitioner . There was an increase in the readmission rate for the intervention group . A subgroup of patients who self managed by doubling their use of inhaled steroids during an exacerbation performed better than those patients who only increased their bronchodilator or were managed on salbutamol or sodium cromoglycate alone . Improvements in patient follow up and the structure of the self management plans used , particularly changing the peak flow level at which inhaled steroids are doubled , may further improve the outcome of patients attending the asthma clinic [4077545] The Self-Care Rehabilitation in Pediatric Asthma ( SCRPA ) project was design ed to ascertain ( 1 ) the level to which children with asthma are able to acquire the asthma knowledge and skills presented in a self-management training program conducted by the American Lung Association of Utah and ( 2 ) the effect of such training on the asthma experience . The preschool SCRPA Curriculum ( ages 2 - 5 ) consisted of six 1-hour classes scheduled twice a week for 3 weeks . The first and last classes were for one or both parents only , and the middle four sessions were for the child and parent(s ) . The school-age SCRPA curriculum ( ages 6 - 14 ) consisted of eight 90-minute classes for both child and parent(s ) scheduled twice a week for 4 weeks . Private physicians referred 21 preschool children and 38 school-age children into the program . The school-age children were r and omly assigned to a study or control group , and the preschool children served as their own controls . A comparison of asthma episodes during the 3 months before and after training showed a statistically significant decrease in the number of episodes but no change in severity in the preschool , school study , and school control groups . The decrease in episodes for the control groups suggest that the family record keeping required of all subjects may have a beneficial effect , a phenomenon worth further investigation . Also , the school-age group , in pre- and posttesting , demonstrated that the SCRPA curriculum increased knowledge and skills in the study group , changes not found in the control group [16393717] The goal of this study was to determine the effectiveness of an asthma educational intervention in improving asthma knowledge , self-efficacy , and quality of life in rural families . Children 6 to 12 years of age ( 62 % male , 56 % white , and 22 % Medicaid ) with persistent asthma ( 61 % ) were recruited from rural elementary schools and r and omized into the control st and ard asthma education ( CON ) group or an interactive educational intervention ( INT ) group geared toward rural families . Parent/caregiver and child asthma knowledge , self-efficacy , and quality of life were assessed at baseline and at 10 months post enrollment . Despite high frequency of symptom reports , only 18 % children reported an emergency department visit in the prior 6 months . Significant improvement in asthma knowledge was noted for INT parents and young INT children at follow-up ( Parent : CON = 16.3 ; INT = 17.5 , p < 0.001 ; Young children : CON = 10.8 , INT = 12.45 , p < 0.001 ) . Child self-efficacy significantly increased in the INT group at follow-up ; however , there was no significant difference in parent self-efficacy or parent and child quality of life at follow-up . Asthma symptom reports were significantly lower for the INT group at follow-up . For young rural children , an interactive asthma education intervention was associated with increased asthma knowledge and self-efficacy , decreased symptom reports , but not increased quality of life [15237762] BACKGROUND Improving asthma knowledge and self-management is a common focus of asthma educational programs , but most programs have had little influence on morbidity outcomes . We developed a novel multiple-component intervention that included the use of an asthma education video game intended to promote adoption of asthma self-management behaviors and appropriate asthma care . OBJECTIVE To determine the effectiveness of an asthma education video game in reducing morbidity among high-risk , school-aged children with asthma . METHODS We enrolled 119 children aged 5 to 12 years from low-income , urban areas in and around San Francisco , CA , and San Jose , CA . Children with moderate-to-severe asthma and parental reports of significant asthma health care utilization were r and omized to participate in the disease management intervention or to receive their usual care ( control group ) . Patients were evaluated for clinical and quality -of-life outcomes at weeks 8 , 32 , and 52 of the study . RESULTS Compared with controls , the intervention group had significant improvements in the physical domain ( P = .04 and P = .01 at 32 and 52 weeks , respectively ) and social activity domain ( P = .02 and P = .05 at 32 and 52 weeks , respectively ) of asthma quality of life on the Child Health Survey for Asthma and child ( P = .02 at 8 weeks ) and parent ( P = .04 and .004 at 32 and 52 weeks , respectively ) asthma self-management knowledge . There were no significant differences between groups on clinical outcome variables . CONCLUSIONS A multicomponent educational , behavioral , and medical intervention targeted at high-risk , inner-city children with asthma can improve asthma knowledge and quality of life [9732652] To address the recent rise in asthma morbidity and mortality in Russia , an intervention study was conducted to improve asthma diagnosis , treatment and prevention . US recommendations for asthma management were adapted for use in educating Moscow families with children with asthma . Two hundred and fifty-two children with asthma aged 4 - 14 years receiving health care in eight Moscow public health clinics together with their parents were enrolled in the study to see whether US teaching manuals for asthma management would be acceptable and effective in Russia . Children at four of the clinics with recent asthma attacks were r and omly assigned to either the education or control group to test if patient education and guided asthma care would improve outcomes for patients . Modern medications were made available to both groups to see if training in the US guidelines was necessary to get physicians to use the medications . Children with recent asthma attacks at the other four clinics were defined as comparison group 1 to control for the possible effect of medication availability . All children at the eight clinics who had no asthma attacks composed comparison group 2 to see if the outcomes for these children would change over time . One-year follow-up results showed significant improvement in asthma self-management skills of children and parents , in terms of asthma treatment , only among those in the education group . Significant increases were observed in the subgroup of children in the education group using anti-inflammatory drugs for asthma control . Children in the education group had markedly increased peak flow rates and reduced daily peak flow variability as compared to control and comparison groups . There was a significantly greater reduction in doctor visits by the education group of children compared to control . Presumably , changes in parents ' and children 's behaviour in terms of asthma treatment and prevention skills , proper treatment of the disease and access to medications could be responsible for reducing asthma morbidity in children [9389290] BACKGROUND We have previously reported a high prevalence of current asthma-related symptoms affecting predominantly Hispanic , socioeconomically disadvantaged schoolchildren in Southeast San Diego . OBJECTIVE We sought to assess the impact of a school-based education program on asthma outcomes . METHODS In cooperation with the San Diego Unified Schools , we developed and implemented a school-based asthma education program . Based on the National Heart , Lung , and Blood Institute consensus guidelines for asthma , the five-session bilingual , interactive curriculum was conducted in 20-minute segments . Asthma knowledge was tested before and after the education program , and asthma severity was prospect ively assessed at monthly intervals . Outcome parameters were compared in educated and control ( noneducated ) fourth grade students with asthma by using nonparametric techniques . RESULTS After asthma education , students demonstrated improvement with increases in mean scores for : asthma knowledge quiz from 9.9 ( SEM = 0.44 , n = 34 ) to 13.7 ( SEM = 0.30 ) ; peak flowmeter technique from 3.9 ( SEM = 0.33 , n = 32 ) to 6.4 ( SEM = 0.29 ) ; and inhaler technique from 2.3 ( SEM = 0.26 , n = 32 ) to 4.3 ( SEM = 0.26 ) . All changes were highly significant ( p < or = 0.00001 as determined by Wilcoxon matched-pairs signed-rank test ) . Mean score comparisons for asthmatic control students given paired examinations after a time interval matched with the educated students , did not reach statistical significance : quiz score of 11.3 ( SEM = 0.80 , n = 11 ) versus 10.9 ( SEM = 0.68 ) , peak flowmeter technique score of 2.6 ( SEM = 0.50 , n = 18 ) versus 3.1 ( SEM = 0.37 ) , and inhaler technique score of 2.5 ( SEM = 0.37 , n = 18 ) versus 2.2 ( SEM = 0.31 ) . Prospect i ve monthly data were collected on 27 educated and 15 control asthmatic subjects . Severity of asthma was not significantly different between groups at entry to the study . Symptom question naires , vali date d for functional asthma severity , revealed a significant reduction in mean symptom scores at 180 days for the educated ( 2.87 , SEM = 0.447 ) versus the control ( 4.36 , SEM = 0.573 ) groups ( p = 0.0188 as determined by the Mann-Whitney U test ) . CONCLUSION Child-centered asthma education can be successfully conducted in the school setting , result ing in increased asthma knowledge , improved skills for peak flowmeter and inhaler use , and a reduction in the severity of asthma symptoms [15184205] We asked whether the addition of PEF recordings to a symptom-based self-management plan improved outcome in school children with asthma . In an open-r and omized , parallel-group , controlled trial , we studied children aged 7 - 14 years with moderate asthma . After a 4-week run-in , 90 children were r and omized to receive either PEF plus symptom-based management or symptom-based management alone for 12 weeks . Thresholds for action based on PEF were 70 % of best ( for increasing inhaled steroids ) and 50 % of best ( for commencing prednisolone ) . Children were asked to perform twice-daily spirometry at home ( using an electronic recording spirometer that revealed only PEF to the study group alone ) and to record a symptom diary . The mean daily symptom score was the main outcome . There were no differences between groups in mean symptom score or in spirometric lung function , PEF , quality of life score , or reported use of health services over 12 weeks . During acute episodes , children responded to changes in symptoms by increasing their inhaled steroids at a mean value of PEF of greater than 70 % of best so that overall PEF did not contribute to this important self-management decision . Knowledge of PEF did not enhance self-management even during acute exacerbations [16532761] OBJECTIVES This report presents both age-adjusted and unadjusted statistics from the 2004 National Health Interview Survey ( NHIS ) on selected health measures for children under 18 years of age , classified by sex , age , race , Hispanic origin , family structure , parent 's education , family income , poverty status , health insurance coverage , place of residence , region , and current health status . The topics covered are asthma , allergies , learning disability and Attention Deficit Hyperactivity Disorder ( ADHD ) , prescription medication use , respondent-assessed health status , school-loss days , usual place of health care , time since last contact with a health care professional , selected measures of health care access and utilization , and dental care . SOURCE OF DATA The NHIS is a multistage probability sample survey conducted annually by interviewers of the U. S. Census Bureau for the Centers for Disease Control and Prevention 's National Center for Health Statistics and is representative of the civilian noninstitutionalized population of the United States . Data are collected for all family members during face-to-face interviews with adults present at the time of interview . Additional information about children is collected for one r and omly selected child per family in face-to-face interviews with an adult proxy respondent familiar with the child 's health . SELECTED HIGHLIGHTS In 2004 , most U.S. children under 18 years of age had excellent or very good health ( 82 % ) . However , 9 % of children had no health insurance coverage , and 5 % of children had no usual place of health care . Twelve percent of children had ever been diagnosed with asthma . An estimated 8 % of children 3 - 17 years of age had a learning disability , and an estimated 7 % of children had ADHD [12269709] OBJECTIVE To assess the effect of a structured program of pharmaceutical care on changes in disease control , functional status , and health services utilization for pediatric and adolescent patients with moderate-to-severe asthma . DESIGN R and omized , controlled trial . SETTING Community and clinic pharmacies ( 14 intervention and 18 usual care pharmacies ) in western Washington State . PATIENTS Three hundred thirty children , aged 6 to 17 years , with asthma . INTERVENTION Structured training for the intervention group pharmacists to provide individualized asthma management services during patient-pharmacist encounters for up to 1 year following the patient 's enrollment into the study . MAIN OUTCOME MEASURES The primary outcome measure was change in pulmonary function as measured by peak expiratory flow rate and spirometry . Secondary outcome measures included changes in functional status and use of asthma-related health care services . RESULTS The intervention had no significant effect on the health or health services use outcomes of study subjects . When compared with the usual care group , there was no evidence that patients from the intervention group experienced improvements in pulmonary function , functional status , quality of life , asthma management , or satisfaction with care . In addition , there were no differences between groups in use of anti-inflammatory medications , total or asthma-related medical care utilization , or total or asthma-related school days lost . CONCLUSION This pharmaceutical care intervention had no significant effect on the health or health services use outcomes of pediatric patients with asthma . The intervention may not have been powerful enough to significantly affect pharmacists ' behaviors and asthma patients ' outcomes in community pharmacy setting s , and there is evidence that the pharmacists ' compliance with the study protocol was low due , in part , to patient- and practice -related obstacles [12612228] OBJECTIVE To determine whether health outcomes of children who have asthma can be improved through the use of an Internet-enabled interactive multimedia asthma education program . METHODS Two hundred twenty-eight children with asthma visiting a pediatric pulmonary clinic were r and omly assigned to control and intervention groups . Children and caregivers in both groups received traditional patient education based on the National Asthma Education and Prevention Program . Intervention group participants received additional self-management education through the Interactive Multimedia Program for Asthma Control and Tracking . Pediatric Asthma Care Knowledge Survey , Pediatric Asthma Caregiver 's Quality of Life Question naire , asthma symptom history , spirometry , and health services utilization data were collected at the initial visit and at 3 and 12 months . RESULTS Interactive Multimedia Program for Asthma Control and Tracking significantly increased asthma knowledge of children and caregivers , decreased asthma symptom days ( 81 vs 51 per year ) , and decreased number of emergency department visits ( 1.93 vs 0.62 per year ) among the intervention group participants . The intervention group children were also using a significantly lower average daily dose of inhaled corticosteroids ( 434 vs 754 micro g [ beclomethasone equivalents ] ) at visit 3 . Asthma knowledge of all 7- to 17-year-old children correlated with fewer urgent physician visits ( r = 0.37 ) and less frequent use of quick-relief medicines ( r = 0.30 ) . CONCLUSIONS Supplementing conventional asthma care with interactive multimedia education can significantly improve asthma knowledge and reduce the burden of childhood asthma [11564356] The increased prevalence , morbidity , mortality , and health costs associated with asthma among children suggest the need for accessible asthma education . This study examined the effect of telepharmacy counseling , using interactive compressed video , on metered-dose inhaler ( MDI ) technique and patient satisfaction among adolescents with asthma in rural Arkansas . The telepharmacy counseling provided accessible education regarding MDI technique for adolescents in this study . Twenty percent of the adolescents who participated had never been shown the appropriate use of an MDI . The study used an experimental design with r and om assignment of participants to a telepharmacy counseling group ( n = 15 ) or a control group ( n = 21 ) . Both groups participated in pre-test , post-test , and 2- to 4-week follow-up assessment s for MDI technique and patients satisfaction ( follow-up assessment only ) via interactive compressed video . Results indicated that from pre-test to follow-up the telepharmacy counseling group showed more improvement in MDI technique than participants in the control group ( p < 0.001 ) . There was no significant difference between the telepharmacy counseling group and control group in satisfaction with the instructional sessions ( p = 0.132 ) . Both groups had high levels of satisfaction with the telepharmacy sessions . The study findings demonstrated that patient education provided by pharmacists via interactive compressed video was superior to education provided via written instructions on an inhaler package insert . Interactive compressed video is an effective medium for teaching and improving MDI technique in this rural , adolescent , predominantly African-American population [15791897] OBJECTIVES This report presents both age-adjusted and unadjusted statistics from the 2002 National Health Interview Survey on selected health measures for children under 18 years of age , classified by sex , age , race , Hispanic origin , family structure , parent 's education , family income , poverty status , health insurance coverage , place of residence , region , and current health status . The topics covered are asthma , allergies , learning disability , Attention Deficit Hyperactivity Disorder ( ADHD ) , use of prescription medication , respondent-assessed health status , school-loss days , usual place of health care , time since last contact with a health care professional , unmet dental needs , time since last dental contact , and selected measures of health care access . SOURCE OF DATA The NHIS is a multistage probability sample survey conducted annually by interviewers of the U.S. Census Bureau for the Centers for Disease Control and Prevention 's National Center for Health Statistics and is representative of the civilian noninstitutionalized population of the United States . Data are collected during face-to-face interviews with adults present at the time of interview . Information about children is collected for one r and omly selected child per family in face-to-face interviews with an adult proxy respondent familiar with the child 's health . SELECTED HIGHLIGHTS In 2002 , most U.S. children under 18 years of age had excellent or very good health ( 84 % ) . However , 10 % of children had no health insurance coverage , and 5 % of children had no usual place of health care . Twelve percent of children had ever been diagnosed with asthma . An estimated 8 % of children 3 - 17 years of age had a learning disability , and an estimated 7 % of children had ADHD [12132605] OBJECTIVE To highlight the unique challenges of evaluative research on practice behavior change in the " real world " setting s of contemporary managed-care organizations , using the experience of the Pediatric Asthma Care PORT ( Patient Outcomes Research Team ) . STUDY SETTING The Pediatric Asthma Care PORT is a five-year initiative funded by the Agency for Healthcare Research and Quality to study strategies for asthma care improvement in three managed-care plans in Chicago , Seattle , and Boston . At its core is a r and omized trial of two care improvement strategies compared with usual care : ( 1 ) a targeted physician education program using practice based Peer Leaders ( PL ) as change agents , ( 2 ) adding to the PL intervention a " Planned Asthma Care Intervention " incorporating joint " asthma check-tips " by nurse-physician teams . During the trial , each of the participating organizations viewed asthma care improvement as an immediate priority and had their own corporate improvement programs underway . DATA COLLECTION Investigators at each health plan described the organizational and implementation challenges in conducting the PAC PORT r and omized trial . These experiences were review ed for common themes and " lessons " that might be useful to investigators planning interventional research in similar care-delivery setting s. CONCLUSIONS R and omized trials in " real world " setting s represent the most robust design available to test care improvement strategies . In complex , rapidly changing managed-care organizations , blinding is not feasible , corporate initiatives may complicate implementation , and the assumption that a " usual care " arm will be static is highly likely to be mistaken . Investigators must be prepared to use innovative strategies to maintain the integrity of the study design , including : continuous improvement within the intervention arms , comanagement by research ers and health plan managers of condition-related quality improvement initiatives , procedures for avoiding respondent burden in health plan enrollees , and anticipation and minimization of risks from experimental arm contamination and major organizational change . With attention to these delivery system issues , as well as the usual design features of r and omized trials , we believe managed-care organizations can serve as important laboratories to test care improvement strategies [10069877] BACKGROUND Previous studies have shown that asthma education and case management may reduce asthma emergency care , hospitalizations , and expenditures . OBJECTIVE We sought to study the effect of an asthma outreach program ( AOP ) , a team-based , case-management intervention , on emergency ward ( EW ) and hospital use . METHODS Fifty-seven patients aged 1 to 15 years with the diagnosis of asthma based on the usual clinical practice criteria who were continuously enrolled in a staff-model health maintenance organization for a period of at least 2 consecutive years were r and omized into 2 intervention groups . The control group received a single intensive asthma education intervention , and the AOP group received the same initial education but then was followed-up by an asthma case management nurse throughout the intervention period . RESULTS EW visits , hospitalizations , and total outside-of-health-plan expenditures ( consisting of EW and hospital expenses , as well as miscellaneous costs , such as ambulance , durable medical equipment , tertiary referrals , and home care ) were assessed from cl aims filed for a year before and after enrollment . Control group patients experienced significant reductions in EW visits ( 39 % ) , hospitalizations ( 43 % ) , and outside-of-health-plan costs ( 28 % ) , possibly as a result of the baseline educational intervention received by all enrolled patients , in conjunction with regression to the mean . AOP group patients experienced significant reductions in EW visits , ( 73 % , P = .0002 ) , hospitalizations ( 84 % , P = .0012 ) , and outside-of-health-plan use ( 82 % , P < .0001 ) . When compared with the control group , AOP group patients demonstrated additional significant reductions in EW visits ( 57 % , P < .05 ) , hospitalizations ( 75 % , P < .05 ) , and outside-of-health-plan use ( 71 % , P < .001 ) . Estimates of direct savings to the health plan ranged from $ 7.69 to $ 11.67 for every dollar spent on the AOP nurse 's salary , depending on assumptions . CONCLUSIONS Asthma patients in a staff-model health maintenance organization decreased their re source use between 57 % to 75 % by participation in an AOP as compared with a r and omized control group receiving only an educational intervention . Substantial savings were achieved compared with the cost of the AOP nurse [8450129] A research project , which looks at the value of health education in the prevention of childhood asthma , is described . The project was a controlled trial by a health visitor focused within the community . This exploratory research looked at three groups of children over a 2-year period , and compared the effect of : ( a ) individual health education , and ( b ) group health education . During the first year , two groups were active , one receiving individual health education , the other collecting data of the same type . During the second year , a third group was involved in health education sessions . The findings have been similar in both cases , in that both groups have demonstrated a good improvement in knowledge of asthma and its treatment . Through the active involvement of using a peakflow meter and diary records in the health education programme , both groups receiving health education have shown a significant improvement in the morbidity indicators related to night symptoms and restricted activities . The qualitative analysis of the research also highlighted the value parents of asthmatic children place on counselling [15867115] BACKGROUND A decision to implement innovative disease management interventions in health plans often requires evidence of clinical benefit and financial impact . The Pediatric Asthma Care Patient Outcomes Research Team II trial evaluated 2 asthma care strategies : a peer leader-based physician behavior change intervention ( PLE ) and a practice -based re design called the planned asthma care intervention ( PACI ) . OBJECTIVE To estimate the cost-effectiveness of the interventions . METHODS This was a 3-arm , cluster r and omized trial conducted in 42 primary care practice s. A total of 638 children ( age range , 3 - 17 years ) with mild to moderate persistent asthma were followed up for 2 years . Practice s were r and omized to PLE ( n = 226 ) , PACI ( n = 213 ) , or usual care ( n = 199 ) . The primary outcome was symptom-free days ( SFDs ) . Costs included asthma-related health care utilization and intervention costs . RESULTS Annual costs per patient were as follows : PACI , USD 1292 ; PLE , USD 504 ; and usual care , USD 385 . The difference in annual SFDs was 6.5 days ( 95 % confidence interval [ CI ] , -3.6 to 16.9 days ) for PLE vs usual care and 13.3 days ( 95 % CI , 2.1 - 24.7 days ) for PACI vs usual care . Compared with usual care , the incremental cost-effectiveness ratio was USD 18 per SFD gained for PLE ( 95 % CI , USD 5.21-dominated ) and USD 68 per SFD gained for PACI ( 95 % CI , USD 37.36 - 361.16 ) . CONCLUSIONS Results of this study show that it is possible to increase SFDs in children and move organizations toward guideline recommendations on asthma control in setting s where most children are receiving controller medications at baseline . However , the improvements were realized with an increase in the costs associated with asthma care [3088085] A sample of 310 low income urban children with asthma from 290 families was r and omized into a control group and an experimental group that received health education to improve asthma management at home . No significant decreases in subsequent health care use were observed when the experimental group was compared to the control group without regard to previous hospitalization . When the comparison was restricted to children who had been hospitalized during the preceding year , however , the experimental group was found to have decreased its use of the emergency room significantly more than the control group ( p less than 0.05 ) and to have experienced a significantly greater reduction in the mean number of hospitalizations ( p less than 0.05 ) during the year of follow-up . The program reduced health care costs for children with one or more hospitalizations , saving $ 11.22 for every $ 1.00 spent to deliver health education [11553420] A r and omised controlled trial , involving 112 adolescents with asthma , and a 2-year follow-up was conducted to assess the impact of an intervention programme aim ed at enhancing adherence to asthma medication . This programme had a duration of 1 year and consisted of an experimental group which received usual care from a paediatrician , but additionally attended individual and group sessions with an asthma nurse , and a control group which received usual care only . The programme aim ed at enhancing adherence by stimulating a positive attitude , increasing feelings of social support , and enhancing self-efficacy . At baseline , and after 12-month ( T1 ) and 24-month ( T2 ) follow-up , the participants filled in question naires which were based on the concepts of the ASE-model . Adherence was assessed by self-report ( range : 1 - 10 ) at the same points in time . After 12 months , 97 adolescents ( 87 % ) were available for follow-up , decreasing to 86 adolescents ( 77 % ) after 24 months . No statistically significant differences were found between the control and the experimental group , except for one . At T2 , self-reported adherence appeared to be statistically significantly higher in the experimental group . In conclusion , there seems to have been no substantial effect of the intervention programme [1747614] OBJECTIVE --To determine whether an intervention programme based on existing school and community re sources can reduce school absence and improve participation in games lessons and sport in children with unrecognised or undertreated asthma . DESIGN --Parallel group controlled intervention study . SETTING --102 primary schools in Nottingham : 49 were r and omised to receive the intervention and 53 to be control schools . SUBJECTS -- All children aged 5 to 10 years with parent reported absence from school because of wheezing in the previous year and taking no treatment or beta agonists only . INTERVENTIONS --Children with asthma were referred to their general practitioner for assessment of symptoms and treatment . Teachers were given education on asthma by the school nurse in 44 of the 49 intervention schools . MAIN OUTCOME MEASURES --Changes in school absence and missed games and swimming lessons because of wheezing , and schools ' policy towards management of asthma in school . RESULTS --Of 17,432 children screened , 451 met the entry criteria --228 in intervention schools and 223 in control schools . 152 ( 67 % ) children in intervention schools visited their general practitioner , of whom 39 ( 26 % ) were given a new diagnosis of asthma and 58 ( 38 % ) had treatment for asthma increased or changed . Over the next academic year mean ( SE ) parent reported school absence due to wheezing fell significantly , but to a similar extent , in both intervention and control schools ( 0.82 ( 0.11 ) and 1.09 ( 0.21 ) weeks respectively ) . There was little change in school recorded absence or participation in games lessons and swimming lessons in either group . At the end of the study intervention schools were more likely to have improved aspects of management of asthma in school . CONCLUSION --The intervention result ed in a majority of children being assessed by their general practitioner and improved teachers ' underst and ing and management of asthma , but it did not result in any appreciable reduction in morbidity [15867114] BACKGROUND Guidelines recommend preventive medications for all children with persistent asthma , yet young urban children often receive inadequate therapy . This may occur in part because primary care providers are unaware of the severity of their patients ' symptoms . OBJECTIVE To determine whether systematic school-based asthma screening , coupled with primary care provider notification of asthma severity , will prompt providers to take preventive medication action ( prescribe a new preventive medication or change a current dose ) . DESIGN Children aged 3 to 7 years with mild persistent to severe persistent asthma were identified at the start of the 2002 - 2003 school year in Rochester . Children were assigned r and omly to a provider notification group ( child 's primary care provider notified of asthma severity ) or a control group ( provider not notified of severity ) . Primary care providers of children in the provider notification group were sent a facsimile indicating the child 's symptoms and recommending medication action based on national criteria . Interviewers blinded to the child 's group assignment called parents 3 to 6 months later to determine if preventive actions were taken . RESULTS Of 164 eligible children with mild persistent or more severe asthma , 151 ( 92.1 % ) were enrolled . Children in the provider notification group were not more likely to receive a preventive medication action than were children in the control group ( 21.9 % vs 26.0 % ; P = .57 ) . Additional preventive measures , including encouraging compliance with medications ( 33.3 % vs 31.3 % ; P = .85 ) , recommending environmental modifications ( 39.3 % vs 42.4 % ; P = .86 ) , and referrals for specialty care ( 6.6 % vs 6.0 % ; P > .99 ) , also did not differ between the provider notification and control groups . At the end of the study , 52.4 % of children in both groups with no medication changes were still experiencing persistent symptoms . CONCLUSIONS School-based asthma screening identified many symptomatic children in need of medication modification . Provider notification , however , did not improve preventive care . Findings suggest that more powerful interventions are needed to make systematic asthma screening effective [8707779] A r and omized control trial of the Wee Wheezers asthma education program was conducted with 76 children < 7 years of age , 31 % of whom were on a medication regimen consistent with mild , 51 % with moderate , and 18 % with moderately severe/severe asthma . Treatment children showed improved morbidity at 3-month follow-up relative to the changes in the controls : increased symptom-free days in the preceding 2 weeks ( mean change of + 2.2 vs. -2.6 in the controls ; p = .004 ) and month ( + 2.0 vs. -3.8 ; p < .02 ) , fewer nights of parental sleep interruption in a typical week ( + 0.7 vs. + 1.8 ; p < or = .05 ) , and a trend toward fewer asthma sick days ( -0.2 vs + 0.7 ; p = ns ) . These improvements were accompanied by significantly better parental asthma management compared with controls ( more consistent use of preventive medications , p < or = .01 ; early symptom intervention , [ corrected ] p < or = .05 ) and trends toward more restrictions on smoking in the home ( p < .07 ) and decreased parental confusion about asthma treatment ( p < .11 ) . This study provides evidence that a multisession program of asthma education for parents can improve parental asthma management and clinical outcomes in very young children and provides information on the validity and sensitivity of various asthma outcome measures in this age group [14531243] The adherence and disease-control outcomes associated with the use of an Internet-based store- and -forward video home telehealth system to manage asthma in children were studied . Pediatric patients with persistent asthma were provided with home computers and Internet access and monitored biweekly over the Internet . All patients were seen in the pediatric clinic at 0 , 2 , 6 , 12 , and 24 weeks . Half of the patients received asthma education in person and half via an interactive Web site . Adherence measures were assessed by therapeutic and diagnostic monitoring . Therapeutic monitoring included digital videos of patients using their controller medication inhaler . Diagnostic monitoring included an asthma symptom diary and a video of peak flow meter use . Videos were su bmi tted electronically twice a week by using in-home telemonitoring with store- and -forward technology . Feedback was provided electronically to each patient . Disease control was assessed by examining quality of life , utilization of services , rescue-therapy use , symptom control , satisfaction with home telemonitoring , and retention of asthma knowledge . Patients were r and omly assigned to an asthma education group ( Internet versus office ) , and the data were analyzed by comparing results for study days 0 - 90 and 91 - 180 . Ten children participated . A total of 321 videos of inhaler use and 309 videos of peak flow meter use were su bmi tted . Inhaler technique scores improved significantly in the second study period . Su bmi ssion of diagnostic monitoring videos and asthma diary entries decreased significantly . Peak flow values as a percentage of personal best values increased significantly . Overall , there was no change in quality of life reported by patients . However , the caregivers in the virtual-education group reported an increase in the patients ' quality -of-life survey scores . Emergency department visits and hospital admissions for asthma were avoided . Rescue therapy was infrequent . A high rate of satisfaction with home telemonitoring was reported . Internet-based , store- and -forward video assessment of children 's use of asthma medications and monitoring tools in their homes appeared effective and well accepted [9024439] OBJECTIVE Recent studies have shown that lack of continuing primary care for asthma is associated with increased levels of morbidity in low-income minority children . Although effective preventive therapy is available , many African-American and Latino children receive episodic treatment for asthma that does not follow current guidelines for care . To see if access , continuity , and quality of care could be improved in pediatric clinics serving low-income children in New York City , we trained staff in New York City Bureau of Child Health clinics to provide continuing , preventive care for asthma . METHODS We evaluated the impact of the intervention over a 2-year period in a controlled study of 22 clinics . Training for intervention clinic staff was based on National Asthma Education and Prevention Program guidelines for the diagnosis and management of asthma , and included screening to identify new cases and health education to improve family management . The intervention included strong administrative support by the Bureau of Child Health to promote staff behavior change . We hypothesized that after the intervention , clinics that received the intervention would , compared with control clinics , have increased numbers of children with asthma receiving continuing care in the clinics and increased staff use of new pharmacologic and educational treatment methods . RESULTS In both the first and second follow-up years , the intervention clinics had greater positive changes than control clinics on measures of access , continuity , and quality of care . For second year follow-up data these include : for access , greater rate of new asthma patients ( 40/1000 vs 16/1000 ; P < .01 ) ; for continuity , greater percentage of asthma patients returning for treatment 2 years in a row ( 42 % vs 12 % ; P < .001 ) and greater annual frequency of scheduled visits for asthma per patient ( 1.85 vs .88 ; P < .001 ) ; and for quality , greater percentage of patients receiving inhaled beta agonists ( 52 % vs 15 % ; P < .001 ) and inhaled antiinflammatory drugs ( 25 % vs 2 % ; P < .001 ) , and greater percentages of parents who reported receiving patient education on 12 topics from Bureau of Child Health physicians ( 71 % vs 58 % ; P < .01 ) and nurses ( 61 % vs 44 % ; P < .05 ) . CONCLUSION We conclude that the intervention substantially increased the Bureau of Child Health staff 's ability to identify children with asthma , involve them in continuing care , and provide them with state-of-the-art care for asthma Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Self-management programs have been widely reported to help patients manage symptoms and contain utilization of health care re sources for several chronic conditions , but to date no systematic review across multiple chronic diseases has been reported . We evaluated the efficacy of patient self-management educational programs for chronic diseases and critically review ed their methodology . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

24425500

[17559610] AIM This paper is a report of a study to assess the effect of an adapted arthritis self-management programme with an added focus on exercise practice among osteoarthritic knee sufferers . BACKGROUND Osteoarthritis of the knee is a major source of loss of function in older people . Previous studies have found self-management programmes to be effective in increasing arthritis self-efficacy and in mastery of self-management practice . METHOD A r and omized control trial was carried out from December 2002 to May 2003 and 120 participants ( 65.9 % , including 67 in intervention group and 53 in control group ) completed the 16-week postintervention assessment s. Outcome measures included arthritis self-efficacy , use of self-management techniques , pain intensity and daily activity . FINDINGS At 16 weeks , there was a ' statistically ' significant improvement in the arthritis self-efficacy level ( P < or= 0.001 ) , in most of the self-management skills , i.e. use of cold and hot compresses , in two of three joint protective practice s ( P < or= 0.001 ; P = 0.01 ) , an increase in the duration of light exercise practice ( P < or= 0.001 ) , reduction of current arthritis pain ( P < or= 0.001 ) and in the ability to perform daily activities ( P < or= 0.001 ) among the intervention group but not for the control group ( P-range from 0.04 to 0.95 ) . One joint protective practice showed a statistically significant increase in both groups ( P < or= 0.001 ) . CONCLUSION Our findings add to evidence showing short-term beneficial effects of self-efficacy theory in education programmes . Self-efficacy theory has great potential for empowering sufferers of chronic conditions to live with their illness [2235871] Background Supporting self-management intends to improve life-style , which is beneficial for patients with mild osteoarthritis ( OA ) . We evaluated a nurse-based intervention on older OA patients ' self-management with the aim to assess its effects on mobility and functioning . Methods R and omized controlled trial of patients ( ≥ 65 years ) with mild hip or knee OA from nine family practice s in the Netherl and s. Intervention consisted of supporting patients ' self-management of OA symptoms using a practice -based nurse . Outcome measures were patients ' mobility , using the Timed Up and Go test ( TUG ) , and patient reported functioning , using an arthritis specific scale ( Dutch AIMS 2 SF ) . Results Fifty-one patients were r and omized to the intervention group and 53 to the control group . Patient-reported functioning improved on four scales in the intervention group compared to one scale in the control group . However , this result was not significant . Mobility improved in both groups , without a significant difference between the two groups . There were no differences between the groups regarding consultations with family physicians or physiotherapists , or medication use . Conclusion A nurse-based intervention on older OA patients ' self-management did not improve self-reported functioning , mobility or patients ' use of health care re sources [20156912] Objective To examine the prevalence of outcome reporting bias — the selection for publication of a subset of the original recorded outcome variables on the basis of the results — and its impact on Cochrane review s. Design A nine point classification system for missing outcome data in r and omised trials was developed and applied to the trials assessed in a large , unselected cohort of Cochrane systematic review s. Research ers who conducted the trials were contacted and the reason sought for the non-reporting of data . A sensitivity analysis was undertaken to assess the impact of outcome reporting bias on review s that included a single meta- analysis of the review primary outcome . Results More than half ( 157/283 ( 55 % ) ) the review s did not include full data for the review primary outcome of interest from all eligible trials . The median amount of review outcome data missing for any reason was 10 % , whereas 50 % or more of the potential data were missing in 70 ( 25 % ) review s. It was clear from the publications for 155 ( 6 % ) of the 2486 assessable trials that the research ers had measured and analysed the review primary outcome but did not report or only partially reported the results . For reports that did not mention the review primary outcome , our classification regarding the presence of outcome reporting bias was shown to have a sensitivity of 88 % ( 95 % CI 65 % to 100 % ) and specificity of 80 % ( 95 % CI 69 % to 90 % ) on the basis of responses from 62 trialists . A third of Cochrane review s ( 96/283 ( 34 % ) ) contained at least one trial with high suspicion of outcome reporting bias for the review primary outcome . In a sensitivity analysis undertaken for 81 review s with a single meta- analysis of the primary outcome of interest , the treatment effect estimate was reduced by 20 % or more in 19 ( 23 % ) . Of the 42 meta-analyses with a statistically significant result only , eight ( 19 % ) became non-significant after adjustment for outcome reporting bias and 11 ( 26 % ) would have overestimated the treatment effect by 20 % or more . Conclusions Outcome reporting bias is an under-recognised problem that affects the conclusions in a substantial proportion of Cochrane review s. Individuals conducting systematic review s need to address explicitly the issue of missing outcome data for their review to be considered a reliable source of evidence . Extra care is required during data extraction , review ers should identify when a trial reports that an outcome was measured but no results were reported or events observed , and contact with trialists should be encouraged [19486959] INTRODUCTION To evaluate the efficacy of a self-management support program including a 6 week self-management course , individualised phone support and goal setting in osteoarthritis patients on a waiting list for arthroplasty surgery . METHOD R and omised controlled trial of 152 public hospital out patients awaiting hip or knee replacement surgery who were not classified as requiring urgent surgery . Participants were r and omised to a self-management program or to usual care . The primary outcome was change in the Health Education Intervention Question naire ( HeiQ ) from r and omisation to 6 month follow-up . Quality of life and depressive symptoms were also measured . Changes in pain and function were assessed using the Western Ontario and McMaster Universities ( WOMAC ) Arthritis Index . RESULTS At 6 month follow-up , health-directed behaviour was significantly greater in the intervention [ mean 4.29 , 95 % confidence interval ( CI ) 3.99 - 4.58 ] than the control ( mean 3.81 , 95 % CI 3.52 - 4.09 ; P=0.017 ) . There was also a significant effect on skill and technique acquisition for the intervention ( mean 4.37 , 95 % CI 4.19 - 4.55 ) in comparison to control ( mean 4.11 , 95 % CI 3.93 - 4.29 ; P=0.036 ) . There was no significant effect of the intervention on the remaining HeiQ subscales , WOMAC pain or disability , quality of life or depressive symptoms . DISCUSSION The arthritis self-management program improved health-directed behaviours , skill acquisition and stiffness in patients on a joint replacement waiting list , although the observed effects were of modest size ( Cohen 's d between 0.36 and 0.42 ) . There was no significant effect on pain , function or quality of life in the short term . Self-management programs can assist in maintaining health behaviours ( particularly walking ) in this patient group . Further research is needed to assess their impact on quality of life and over longer periods [1525193] Background This study examined the impact of a home-based self-management intervention for housebound older adults with arthritis on the adoption of health behaviors . The moderating role of socio-demographic , psychological , and physical characteristics in the process of behavior change was also investigated . Methods Participants were 113 older adult women ( n = 102 ) and men ( n = 11 ) with osteoarthritis ( OA ) or rheumatoid arthritis ( RA ) who were r and omly assigned to experimental ( n = 68 ) or wait list control ( n = 45 ) groups . Participants were interviewed using st and ardized question naires at baseline , pre-intervention , and post-intervention . Results Adjusted multilevel modeling analyses indicated that from pre to post intervention , experimental participants significantly increased their weekly frequency of exercise and relaxation activities . Socioeconomic status and depression played a moderating role in this change for exercise with larger effects occurring among more privileged , non-depressed participants . Conclusion We conclude that a self-management intervention can successfully improve involvement in exercise and relaxation among housebound older adults with arthritis [14731152] Osteoarthritis ( OA ) is a common and often disabling condition that predominately affects older adults . It is the commonest cause of locomotor disability and forms a major element of the workload in primary care . Previous studies suggest that there are both deficits in the knowledge patients have about their disease and extensive ' unmet ' information needs . This paper explores the patients ' perspective on the meaning and significance of living with arthritis , identified through quantitative and qualitative approaches undertaken during a trial that evaluated the effectiveness of a primary care-based patient education programme . This paper draws on qualitative and quantitative data from : the baseline interview ( knowledge of arthritis , satisfaction with services and support received in primary care ) ; patient diaries ( individual goals and reflections on treatment ) ; and group teaching sessions ( themes describing the patient 's experience ) . The different data sources were interrogated for common and divergent themes . One hundred and ninety-four participants were identified and 170 completed baseline interviews . Participants were predominantly female ( 73 % ) , with a mean age of 63 and arthritis of long-st and ing ; 55 % reported that they had had it for 5 years or more . Use of primary care services was high , with 41 % consulting their GP in the 2 weeks before interview . Levels of information were low , with less than 25 % receiving support/advice about the disease , pain management or its impact upon daily life . Set against negative perceptions of the quality of services , patients ' personal priorities were for improved pain management and enhanced mobility/functional ability . The combined quantitative and qualitative data provide insight into the patients ' perspective on the causes and impact of knee OA , individual goals desired from treatment and the quality of care . There is consistent evidence of unmet needs for information and support and the priority placed by patients on finding strategies to cope with OA and maintaining independence . Even within a tightly defined study sample participating in the intervention , a diversity of experience and goals were revealed , which highlights the importance of taking account of context ual factors and individual differences when evaluating complex interventions [2907317] Background Non-pharmacological treatment ( NPT ) is a useful treatment option in the management of hip or knee osteoarthritis . To our knowledge however , no studies have investigated the effect of NPT in patients with generalized osteoarthritis ( GOA ) . The primary aim of this study is to compare the effectiveness of two currently existing health care programs with different intensity and mode of delivery on daily functioning in patients with GOA . The secondary objective is to compare the cost-effectiveness of both interventions . Methods / Design In this r and omized , single blind , clinical trial with active controls , we aim to include 170 patients with GOA . The experimental intervention consist of six self-management group sessions provided by a multi-disciplinary team ( occupational therapist , physiotherapist , dietician and specialized nurse ) . The active control group consists of two group sessions and four sessions by telephone , provided by a specialized nurse and physiotherapist . Both therapies last six weeks . Main study outcome is daily functioning during the first year after the treatment , assessed on the Health Assessment Question naire . Secondary outcomes are health related quality of life , specific complaints , fatigue , and costs . Illness cognitions , global perceived effect and self-efficacy , will also be assessed for a responder analysis . Outcome assessment s are performed directly after the intervention , after 26 weeks and after 52 weeks . Discussion This article describes the design of a r and omized , single blind , clinical trial with a one year follow up to compare the costs and effectiveness of two non-pharmacological interventions with different modes of delivery for patients with GOA.Trial registration Dutch Trial Register [2987970] Background Osteoarthritis ( OA ) is a degenerative disease , considered to be one of the major public health problems . Research suggests that patient education is feasible and valuable for achieving improvements in quality of life , in function , well-being and improved coping . Since 1994 , Primary Health Care in Malmö has used a patient education programme directed towards OA . The aim of this study was to evaluate the effects of this education programme for patients with OA in primary health care in terms of self-efficacy , function and self-perceived health . Method The study was a single-blind , r and omized controlled trial ( RCT ) in which the EuroQol-5D and Arthritis self-efficacy scale were used to measure self-perceived health and self-efficacy and function was measured with Grip Ability Test for the upper extremity and five different functional tests for the lower extremity . Results We found differences between the intervention group and the control group , comparing the results at baseline and after 6 months in EuroQol-5D ( p < 0.001 ) and in st and ing one leg eyes closed ( p = 0.02 ) in favour of the intervention group . No other differences between the groups were found . Conclusion This study has shown that patient education for patients with osteoarthritis is feasible in a primary health care setting and can improve self-perceived health as well as function in some degree , but not self-efficacy . Further research to investigate the effect of exercise performance on function , as well as self-efficacy is warranted . Trial registration The trial is registered with Clinical Trials.gov . Registration number : [18821646] OBJECTIVE To examine effects of activity strategy training ( AST ) , a structured rehabilitation program taught by occupational therapists and design ed to teach adaptive strategies for symptom control and engagement in physical activity ( PA ) . METHODS A r and omized controlled pilot trial was conducted at 4 sites ( 3 senior housing facilities and 1 senior center ) in southeastern , lower Michigan . Fifty-four older adults with hip or knee osteoarthritis ( mean + /- SD age 75.3+/-7.1 years ) participated . At each site , older adults were r and omly assigned to 1 of 2 programs : exercise plus AST ( Ex + AST ) or exercise plus health education ( Ex + Ed ) . The programs involved 8 sessions over 4 weeks with 2 followup sessions over a 6-month period , and were conducted concurrently within each site . Pain , total PA and PA intensity ( measured objective ly by actigraphy and subjectively by the Community Healthy Activities Model Program for Seniors question naire ) , arthritis self-efficacy , and physical function were assessed at baseline and posttest . RESULTS At posttest , participants who received Ex + AST had significantly higher levels of objective peak PA ( P=0.02 ) compared with participants who received Ex + Ed . Although not statistically significant , participants in Ex + AST tended to have larger pain decreases , increased total objective and subjective PA , and increased physical function . No effects were found for arthritis self-efficacy . CONCLUSION Although participants were involved in identical exercise programs , participants who received AST tended to have larger increases in PA at posttest compared with participants who received health education . Future studies will be needed to examine larger sample s and long-term effects of AST [11838857] OBJECTIVE Studies have suggested that the Arthritis Self-Management Program ( ASMP ) course is effective at reducing arthritis pain and health care costs in volunteer participants . There have been no reports of trials of the ASMP in the context of primary care physicians ' practice s , where the potential for spreading the program may be greatest . We conducted a r and omized controlled trial of the ASMP course in a large primary care physician network . METHODS Patients with osteoarthritis , rheumatoid arthritis , or fibromyalgia were recruited for the study . Subjects in the intervention practice s received the 6 week course and those in the control practice s received only the ASMP book , without course . Disability , pain , self-efficacy , mental health , and satisfaction were measured using vali date d instruments at baseline and at 4 months . RESULTS One hundred thirteen patients were recruited for the ASMP course ( intervention ) and completed baseline and 4 month followup question naires . Eighty-four percent completed at least 4 of 6 classes . Seventy-four patients received the ASMP manual ( controls ) and completed both question naires . Patients in the intervention and control groups had similar baseline pain ( p = 0.94 ) , self-efficacy to control pain ( p = 0.90 ) , mental health ( p = 0.10 ) , and vitality scores ( p = 0.21 ) , but those in the intervention arm had slightly less disability ( p = 0.04 ) . At 4 months , there was no significant improvement from baseline in any endpoint and no difference between patients in the intervention and control groups ( all p > 0.2 ) . Patient satisfaction with arthritis care and outcomes was no different for intervention and control patients ( all p > 0.3 ) . All types of health care re source use were similar at baseline and followup for both intervention and control groups ( all p > 0.2 ) . CONCLUSION While the ASMP course has been found to be effective in other patient groups , there were no significant clinical benefits noted at 4 months in patients recruited from primary care practice [1693560] Background Patient education and self-management programs are offered in many countries to people with chronic conditions such as osteoarthritis ( OA ) . The most well-known is the disease-specific Stanford Arthritis Self-Management Program ( ASMP ) . While Australian and international clinical guidelines promote the concept of self-management for OA , there is currently little evidence to support the use of the ASMP . Several meta-analyses have reported that arthritis self-management programs had minimal or no effect on reducing pain and disability . However , previous studies have had method ological shortcomings including the use of outcome measures which do not accurately reflect program goals . Additionally , limited cost-effectiveness analyses have been undertaken and the cost-utility of the program has not been explored . Methods / design This study is a r and omised controlled trial to determine the efficacy ( in terms of Health-Related Quality of Life and self-management skills ) and cost-utility of a 6-week group-based Stanford ASMP for people with hip or knee OA.Six hundred participants referred to an orthopaedic surgeon or rheumatologist for hip or knee OA will be recruited from outpatient clinics at 2 public hospitals and community-based private practice s within 2 private hospital setting s in Victoria , Australia . Participants must be 18 years or over , fluent in English and able to attend ASMP sessions . Exclusion criteria include cognitive dysfunction , previous participation in self-management programs and placement on a waiting list for joint replacement surgery or scheduled joint replacement . Eligible , consenting participants will be r and omised to an intervention group ( who receive the ASMP and an arthritis self-management book ) or a control group ( who receive the book only ) . Follow-up will be at 6 weeks , 3 months and 12 months using st and ardised self-report measures . The primary outcome is Health-Related Quality of Life at 12 months , measured using the Assessment of Quality of Life instrument . Secondary outcome measures include the Health Education Impact Question naire , Western Ontario and McMaster Universities Osteoarthritis Index ( pain subscale and total scores ) , Kessler Psychological Distress Scale and the Hip and Knee Multi-Attribute Priority Tool . Cost-utility analyses will be undertaken using administrative records and self-report data . A subgroup of 100 participants will undergo qualitative interviews to explore the broader potential impacts of the ASMP . Discussion Using an innovative design combining both quantitative and qualitative components , this project will provide high quality data to facilitate evidence -based recommendations regarding the ASMP [10413387] OBJECTIVES This study evaluated the effectiveness ( changes in health behaviors , health status , and health service utilization ) of a self-management program for chronic disease design ed for use with a heterogeneous group of chronic disease patients . It also explored the differential effectiveness of the intervention for subjects with specific diseases and comorbidities . METHODS The study was a six-month r and omized , controlled trial at community-based sites comparing treatment subjects with wait-list control subjects . Participants were 952 patients 40 years of age or older with a physician-confirmed diagnosis of heart disease , lung disease , stroke , or arthritis . Health behaviors , health status , and health service utilization , as determined by mailed , self-administered question naires , were measured . RESULTS Treatment subjects , when compared with control subjects , demonstrated improvements at 6 months in weekly minutes of exercise , frequency of cognitive symptom management , communication with physicians , self-reported health , health distress , fatigue , disability , and social/role activities limitations . They also had fewer hospitalizations and days in the hospital . No differences were found in pain/physical discomfort , shortness of breath , or psychological well-being . CONCLUSIONS An intervention design ed specifically to meet the needs of a heterogeneous group of chronic disease patients , including those with comorbid conditions , was feasible and beneficial beyond usual care in terms of improved health behaviors and health status . It also result ed in fewer hospitalizations and days of hospitalization [21218677] OBJECTIVE We examined whether tailored activity pacing intervention was more effective at reducing pain and fatigue than general activity pacing intervention . METHOD Adults with knee or hip osteoarthritis ( N = 32 ) stratified by age and gender were r and omized to receive either tailored or general pacing intervention . Participants wore an accelerometer for 5 days that measured physical activity and allowed for repeated symptom assessment . Physical activity and symptom data were used to tailor activity pacing instruction . Outcomes at 10-week follow-up were pain ( Western Ontario and McMaster Universities Osteoarthritis Index ) and fatigue ( Brief Fatigue Inventory ) . RESULTS Compared with general intervention , the tailored group had less fatigue interference ( p = .02 ) and trended toward decreased fatigue severity ( p = .09 ) at 10-wk follow-up . No group differences were found in pain reduction . CONCLUSION Tailoring instruction on the basis of recent symptoms and physical activity may be a more effective symptom management approach than general instruction given the positive effects on fatigue [10527090] OBJECTIVE To evaluate the effects of isokinetic exercise versus a program of patient education on pain and function in older persons with knee osteoarthritis . DESIGN A r and omized , comparative clinical trial , with interventions lasting 8 weeks and evaluations of 12 weeks . SETTING An outpatient Veterans Affairs Medical Center clinic and an affiliated university hospital . PATIENTS One hundred thirteen men and women between 50 and 80 years old with diagnosed osteoarthritis of the knee ; 98 completed the entire assigned treatment . INTERVENTION Patients received either a regimen of isokinetic exercise of the quadriceps muscle three times weekly over 8 weeks or a series of 4 discussion s and lectures led by health care professionals . MAIN OUTCOME MEASURES Variables studied for change were isokinetic and isometric quadriceps strength , pain and function determined by categorical and visual analog scales , and overall status using physician and patient global evaluations by the Arthritis Impact Scale , version 2 , Western Ontario McMaster 's Arthritis Index , and Medical Outcome Study Short Form 36 . RESULTS Both treatment groups showed significant strength gains ( p < .05 ) , which occurred over a wider velocity spectrum for the exercise group . Exercised patients also had improved pain scores for more of the variables measured than those receiving education . Both groups had positive functional outcomes and slightly improved measures of overall status . CONCLUSIONS Isokinetic exercise is an effective and well-tolerated treatment for knee osteoarthritis , but a much less costly education program also showed some benefits [15075418] PURPOSE This study assessed the impact of a low cost , multicomponent physical activity intervention for older adults with lower extremity osteoarthritis . DESIGN AND METHODS A r and omized controlled trial compared the effects of a facility-based multiple-component training program followed by home-based adherence ( n = 80 ) to a wait list control group ( n = 70 ) . Assessment s were conducted at baseline and at 2 and 6 months following r and omization . The training program consisted of range of motion , resistance training , aerobic walking , and education-group problem solving regarding self-efficacy for exercise and exercise adherence . All training group participants developed individualized plans for posttraining adherence . RESULTS Relative to the persons in the control group , individuals who participated in the exercise program experienced a statistically significant improvement in exercise efficacy , a 48.5 % increase in exercise adherence , and a 13.3 % increase in 6-min distance walk that were accompanied by significant decreases in lower extremity stiffness at 2 and 6 months . Program participants also experienced a significant decrease in lower extremity pain and a borderline significant improvement in efficacy to adhere to exercise over time at 6 months ( p = .052 ) . In contrast , persons in the control group deteriorated over time on the efficacy and adherence measures and showed no change on the other measures . No adverse health effects were encountered . IMPLICATION S These benefits indicate that this low-cost intervention may hold great promise as one of a growing number of public health intervention strategies for older adults in the United States with osteoarthritis [15611487] Context Previous studies of acupuncture for osteoarthritis have had conflicting results . This may have occurred because most studies have included small sample s , a limited number of treatment sessions , or other limitations . Contribution This r and omized , controlled trial compared 24 acupuncture sessions over 26 weeks with sham acupuncture or arthritis education in 570 patients with osteoarthritis of the knee . Acupuncture led to greater improvements in function but not pain after 8 weeks and in both pain and function after 26 weeks . No adverse effects were associated with acupuncture . Caution s Many participants dropped out of the study , so readers should interpret the findings at 26 weeks with caution . The Editors Osteoarthritis is the most common form of arthritis and is a major cause of morbidity , limitation of activity , and health care utilization , especially in elderly patients ( 1 , 2 ) . Pain and functional limitation are the primary clinical manifestations of osteoarthritis of the knee . Current recommendations for managing osteoarthritis , including guidelines published by the American College of Rheumatology ( 3 ) and European League of Associations of Rheumatology ( 4 ) , focus on relieving pain and stiffness and maintaining or improving physical function as important goals of therapy . No curative therapies exist for osteoarthritis ; thus , both pharmacologic and nonpharmacologic management focus on controlling pain and reducing functional limitation ( 5 ) . Nonpharmacologic therapy , which includes patient education , social support , physical and occupational therapy , aerobic and resistive exercises , and weight loss , is the cornerstone of a multidisciplinary approach to osteoarthritis patient management ( 3 ) . Pharmacologic therapies include nonopioid analgesics ( such as acetaminophen ) , nonsteroidal anti-inflammatory drugs ( NSAIDs ) ( including cyclooxygenase-2 [ COX-2 ] enzyme selective inhibitors ) , topical analgesics ( capsaicin cream ) , opioid analgesics , and intra-articular steroid and hyaluronate injections . Often , these agents are used in combination for additive analgesic efficacy ( 6 ) . Pharmacologic management of osteoarthritis is often ineffective , and agents such as NSAIDs may cause unwanted and dangerous side effects ( 7 , 8) . Complementary and alternative medicine is another approach to treating osteoarthritis ( 9 - 12 ) , particularly in Asian societies ( 13 ) . Many U.S. patients with osteoarthritis also use complementary and alternative medical therapies ( 14 ) . A systematic review of acupuncture and knee osteoarthritis ( 15 ) identified 7 small r and omized , controlled trials published in English . Within the method ologic limitations of the studies , the evidence suggested that acupuncture seemed to alleviate knee pain and function compared with sham acupuncture controls , although 2 trials comparing acupuncture with an active , nonpharmacologic treatment ( physical therapy ) did not indicate such an effect ( 16 , 17 ) . Before conducting our large-scale trial , we completed both a pilot study ( 18 ) and a r and omized , single-blind trial ( 19 ) of the effect of acupuncture on osteoarthritis of the knee . Participants in the uncontrolled pilot study ( n= 12 ) showed statistically significant improvement in both self-reported pain and physical function , as well as performance measures of physical function after 8 weeks of acupuncture treatment and at 12-week follow-up as compared with their baseline ( 18 ) . In our larger r and omized , single-blind trial ( n= 73 ) , which examined the benefit of acupuncture added to st and ard management with NSAIDs , the acupuncture treatment group experienced statistically significant improvements in self-reported pain and disability scores compared with a st and ard-care control group as late as 4 weeks after the end of treatment ( 19 ) . However , this effect diminished within 18 weeks ( 26 weeks after the beginning of the trial ) after the final acupuncture treatment . Together , however , the previously conducted trials ( both our preliminary studies [ 18 , 19 ] and those referenced in the systematic review [ 15 ] ) have 3 method ologic limitations : lack of credible controls for the placebo effect , inadequate assessment of long-term treatment benefits , and insufficient sample sizes . We tested the hypothesis that an 8-week intensive acupuncture treatment regimen , followed by an 18-week tapering regimen , reduces pain and improves function among patients with knee osteoarthritis as compared with both sham acupuncture and education control groups . Methods Patient Recruitment We recruited patients for this multisite , placebo-controlled trial from March 2000 through December 2003 , primarily through print and radio advertisements . The 3 sites were the Integrative Medicine Clinic of the University of Maryl and School of Medicine , Baltimore , Maryl and ; the Innovative Medical Research Center ( a private research firm ) , Towson , Maryl and ; and the Hospital for Special Surgery , New York City , New York . The institutional review boards of the 3 sites approved the study . We determined the sample size ( n= 570 ) by a power analysis based on our r and omized pilot study ( 19 ) , adjusted by the estimated decrease in effect size result ing from the inclusion of a sham acupuncture group design ed to control for placebo effects . Patients met the following inclusion criteria : age 50 years or older , a diagnosis of osteoarthritis of the knee , radiographic evidence of at least 1 osteophyte at the tibiofemoral joint ( KellgrenLawrence grade 2 ) , moderate or greater clinical ly significant knee pain on most days during the past month , and willingness to be r and omly assigned . Exclusion criteria were the presence of serious medical conditions that precluded participation in study , bleeding disorders that might contraindicate acupuncture , intra-articular corticosteroid or hyaluronate injections ( as well as any knee surgeries or concomitant use of topical capsaicin cream ) during the past 6 months , previous experience with acupuncture , or any planned events ( including total knee replacement ) that would interfere with participation in the study during the following 26 weeks . After a brief telephone screening , patients were scheduled to visit 1 of the 3 participating sites to sign an informed consent statement and undergo a brief rheumatologic examination ( including radiographic examination of affected knees ) by a physician or a nurse practitioner . Because the education course was a group activity , patients were recruited until a cohort of 12 to 21 patients was formed , at which point each cohort at each site was r and omly assigned to 1 of 3 groups by a computer-generated process using r and omly selected blocks of 3 , 6 , and 9 . We assured allocation concealment by using disguised letter codes that were generated and sent to the site coordinators by a central statistical core . We used this procedure to ensure that approximately equal numbers of participants were in each treatment group across the course of the study , to ensure that each cohort would have participants assigned to all 3 treatment groups , and to make the breaking of the group assignment process more difficult . The research assistants who collected assessment s from participants , the participants themselves ( in the true acupuncture and sham acupuncture groups ) , and the statistician were blinded to group assignment . Assessment s were conducted at baseline and 4 , 8 , 14 , and 26 weeks after r and omization . Study Interventions We developed and modified the acupuncture treatment and sham control protocol s from previously reported and vali date d procedures ( 18 - 21 ) . During the trial , 7 acupuncturists were used : 3 at the Integrative Medicine Clinic , 3 at the Innovative Medical Research Center , and 1 at the Hospital for Special Surgery . In general , acupuncturists were assigned to the same participants throughout the 26-week treatment schedule , except for vacation conflicts and staff turnover , and provided approximately the same proportions of true versus sham procedures . All acupuncturists were state-licensed and had at least 2 years of clinical experience . The study 's principal acupuncturist trained and supervised the acupuncturists in performing true or sham procedures and avoiding interactions that could inadvertently communicate group assignment . True Acupuncture The true acupuncture ( experimental ) group underwent 26 weeks of gradually tapering treatment according to the following schedule : 8 weeks of 2 treatments per week followed by 2 weeks of 1 treatment per week , 4 weeks of 1 treatment every other week , and 12 weeks of 1 treatment per month . We based the acupuncture point selection s on Traditional Chinese Medicine meridian theory to treat knee joint pain , known as the Bi syndrome . These points consisted of 5 local points ( Yanglinquan [ gall bladder meridian point 34 ] , Yinlinquan [ spleen meridian point 9 ] , Zhusanli [ stomach meridian point 36 ] , Dubi [ stomach meridian point 35 ] , and extra point Xiyan ) and 4 distal points ( Kunlun [ urinarybladder , meridian point 60 ] , Xuanzhong [ gall bladder meridian point 39 ] , Sanyinjiao [ spleen meridian point 6 ] , and Taixi [ kidney meridian point 3 ] ) on meridians that traverse the area of pain ( 22 , 23 ) . The same points were treated for each affected leg . If both knees were affected , 9 needles were inserted in each leg . ( The outcome measures were not specifically targeted to whether the patient had osteoarthritis in 1 or both knees , and we observed no differential effects on the basis of the number of knees treated . ) The acupuncturists inserted 1.5-inch ( for local points ) and 1-inch ( for distal points ) 32-gauge ( 0.25-mm diameter ) acupuncture needles to a conventional depth of approximately 0.3 to 1.0 inch , depending on point location . All participants in the treatment group achieved the De-Qi sensation , a local sensation of heaviness , numbness , soreness , or paresthesia that accompanies the insertion and manipulation of needles during acupuncture , at these 9 points . Acupuncturists applied electrical [20177766] The purpose of this study was to assess the relative effects of coping self-efficacy and catastrophizing on physical functioning . Over a 9-month period , study ing changes in self-efficacy as possible mediator between catastrophizing changes and physical functioning changes might provide evidence for the most promising treatment target . Data came from a r and omized , longitudinal controlled trial comparing exercise , self-management and the two combined to treat 254 individuals with early knee osteoarthritis . A secondary analysis using a bootstrapped linear mixed-effects mediational model produced estimates of both the direct and indirect effects . Results indicated that self-efficacy partially mediated the effect between catastrophizing and physical functioning suggesting that self-efficacy was the more direct treatment target compared to catastrophizing . Treatments targeting both self-efficacy and catastrophizing may have greater impact on physical functioning compared to treatments that focus on only one [8702449] OBJECTIVE The effects of treatment counseling or symptom monitoring telephone intervention strategies on the health outcomes of patients with rheumatoid arthritis ( RA ) or osteoarthritis ( OA ) , compared with usual care , were assessed . METHODS A 3-group , r and omized , controlled 9-month trial was conducted incorporating 405 patients with RA or OA and using the Arthritis Impact Measurement Scales ( AIMS 2 ) as the outcome measure . RESULTS Analyses of covariance showed that the AIMS 2 total health status of the treatment counseling group ( effect size = 33 , P < 0.01 ) , but not the symptom monitoring group ( effect size = 0.21 , P = 0.10 ) , was significantly improved , compared with usual care , for both RA and OA patients . The specific types of benefits differed significantly between RA and OA patients . The mean number of medical visits by OA patients in the treatment counseling group was also significantly reduced ( P < 0.01 ) . CONCLUSION Telephone contact using the treatment counseling strategy produced significant , but different , health status benefits for RA and OA patients . The symptom monitoring strategy produced modest benefits [2749163] Objective To assess the cost effectiveness of a self management programme plus education booklet for arthritis in primary care . Design Cost effectiveness and cost utility analysis from health and social care and societal perspectives alongside a r and omised controlled trial . Setting 74 general practice s in the United Kingdom . Participants 812 patients aged 50 or more with osteoarthritis of the hips or knees , or both , and pain or disability , or both . Interventions R and omisation to either six sessions of an arthritis self management programme plus an education booklet ( intervention group ) or the education booklet alone ( st and ard care control group ) . Main outcome measures Total health and social care costs and total societal costs at 12 months ; cost effectiveness ( incremental cost effectiveness ratios and cost effectiveness acceptability curves ) on basis of quality of life ( SF-36 , primary outcome measure ) , EuroQol visual analogue scale , and quality adjusted life years ( QALYs ) . Results At 12 months health and social care costs in the intervention group were £ 101 higher ( 95 % confidence interval £ 3 to £ 176 ) than those in the control group because the additional costs of the arthritis self management programme did not seem to be fully offset by savings elsewhere . There were no significant differences in societal costs ( which were up to 13 times the size of health and social care costs ) or any of the outcomes . From the health and social care perspective the intervention was dominated by the control on the basis of QALYs ( which were non-significantly lower in the intervention group ) and had incremental cost effectiveness ratios between £ 279 and £ 13 473 for the other outcomes . From the societal perspective the intervention seemed superior to the control owing to non-significantly lower costs and non-significantly better outcomes on all measures except QALYs . Probabilities of the arthritis self management programme ’s cost effectiveness ranged between 12 % and 97 % ( for thresholds ranging £ 0 to £ 1000 ) based on one point improvements in SF-36 outcomes , but the clinical significance of this is debatable . Probabilities of cost effectiveness on the basis of the visual analogue scale and QALYs were low . Conclusions Cost effectiveness of an arthritis self management programme is not suggested on the basis of current National Institute for Health and Clinical Excellence cost perspectives and QALY thresholds . The probability of cost effectiveness is greater when broader costs and other quality of life outcomes are considered . These results suggest that the cost effectiveness of the Department of Health ’s expert patients programme can not be assumed across all clinical conditions and that further rigorous evaluations for other conditions may be needed . Trial registration Current Controlled Trials IS RCT N79115352 [15006216] We conducted a pilot study of a nurse-run telephone self-management programme for elderly people with osteoarthritis ( OA ) . Thirty-two subjects , aged 60 years or more , with a diagnosis of OA were recruited from two hospital rheumatology clinics and were r and omized to a control or intervention group . The intervention group received six weekly mailings of OA health education modules , a relaxation audio-tape and six weekly 45 min follow-up telephone self-management sessions . There was a 100 % compliance rate in the intervention group , and all subjects completed baseline and three-month interviews ; one subject in each group was lost to six-month follow-up . There were no significant differences in self-management between the control and intervention groups . However , at three months there were improvements in the intervention group ( relative to baseline ) on some outcome measures . The results suggest that the telephone may be a useful tool for reinforcing health-promoting activities for patients [21493910] Background and Purpose — The benefits of chronic disease self-management programs for stroke survivors are uncertain because individuals with severe impairments have been excluded from previous research . We undertook a phase II r and omized controlled trial to determine whether a self-management program design ed for survivors ( SSMP ; 8 weeks ) was safe and feasible compared to st and ard care ( control ) or a generic self-management program ( generic ; 6 weeks ) . Methods — Stroke survivors were recruited from 7 South Australian hospitals via a letter or indirectly ( eg , newspapers ) . Eligible participants were r and omized at a 1:1:1 ratio of 50 per group . Primary outcomes were recruitment , participation , and participant safety . Secondary outcomes were positive and active engagement in life using the Health Education Impact Question naire and characteristics of quality of life and mood at 6 months from program completion . Results — Of 315 people screened , 149 were eligible and 143 were r and omized ( 48 SSMP , 47 generic , 48 control ) ; mean age was 69 years ( SD , 11 ) and 59 % were female . Demographic features were similar between groups and 41 % had severe cognitive impairment ; 57 % accessed the interventions , with 52 % SSMP and 38 % generic completing > 50 % of sessions ( P=0.18 ) . Thirty-two participants reported adverse events ( 7 control , 12 generic , 13 SSMP ; P=0.3 ; 34 % severe ) ; however , none was attributable to the interventions . Potential benefits for improved mood were found . Conclusions — SSMP was safe and feasible . Benefits of the stroke-specific program over the generic program included greater participation and completion rates . An efficacy trial is warranted given the forecast growth in the stroke population and improved survival trends [3433311] Background Osteoarthritis ( OA ) of the hip and knee are among the most common chronic conditions , result ing in substantial pain and functional limitations . Adequate management of OA requires a combination of medical and behavioral strategies . However , some recommended therapies are under-utilized in clinical setting s , and the majority of patients with hip and knee OA are overweight and physically inactive . Consequently , interventions at the provider-level and patient-level both have potential for improving outcomes . This manuscript describes two ongoing r and omized clinical trials being conducted in two different health care systems , examining patient-based and provider-based interventions for managing hip and knee OA in primary care . Methods / Design One study is being conducted within the Department of Veterans Affairs ( VA ) health care system and will compare a Combined Patient and Provider intervention relative to usual care among n = 300 patients ( 10 from each of 30 primary care providers ) . Another study is being conducted within the Duke Primary Care Research Consortium and will compare Patient Only , Provider Only , and Combined ( Patient + Provider ) interventions relative to usual care among n = 560 patients across 10 clinics . Participants in these studies have clinical and / or radiographic evidence of hip or knee osteoarthritis , are overweight , and do not meet current physical activity guidelines . The 12-month , telephone-based patient intervention focuses on physical activity , weight management , and cognitive behavioral pain management . The provider intervention involves provision of patient-specific recommendations for care ( e.g. , referral to physical therapy , knee brace , joint injection ) , based on evidence -based guidelines . Outcomes are collected at baseline , 6-months , and 12-months . The primary outcome is the Western Ontario and McMasters Universities Osteoarthritis Index ( self-reported pain , stiffness , and function ) , and secondary outcomes are the Short Physical Performance Test Protocol ( objective physical function ) and the Patient Health Question naire-8 ( depressive symptoms ) . Cost effectiveness of the interventions will also be assessed . Discussion Results of these two studies will further our underst and ing of the most effective strategies for improving hip and knee OA outcomes in primary care setting s . Trial registration NCT01130740 ( VA ) ; NCT 01435109 ( NIH [3392814] Introduction Our aim in the present study was to determine whether a disease-specific self-management program for primary care patients with osteoarthritis ( OA ) of the knee ( the Osteoarthritis of the Knee Self-Management Program ( OAK ) ) implemented by health care professionals would achieve and maintain clinical ly meaningful improvements in health-related outcomes compared with a control group . Methods Medical practitioners referred 146 primary care patients with OA of the knee . Volunteers with coexistent inflammatory joint disease or serious comorbidities were excluded . R and omisation was to either a control group or the OAK group . The OAK group completed a 6-week self-management program . The control group had a 6-month waiting period before entering the OAK program . Assessment s were taken at baseline , 8 weeks and 6 months . The primary outcomes were the results measured using the Western Ontario and McMaster Universities Arthritis Index ( WOMAC ) Pain and Function subscales on the Short Form 36 version 1 question naire ( SF-36 ) Secondary outcomes were Visual Analogue Scale ( VAS ) pain , Timed Up & Go Test ( TUG ) , knee range of motion and quadriceps and hamstring strength-isometric contraction . Responses to treatment ( responders ) and minimal clinical ly important improvements ( MCIIs ) were determined . Results In the OAK group , VAS pain improved from baseline to week 8 from mean ( SEM ) 5.21 ( 0.30 ) to 3.65 ( 0.29 ) ( P ≤ 0.001 ) . During this period , improvements in the OAK group compared with the control group and responses to treatment were demonstrated according to the following outcomes : WOMAC Pain , Physical Function and Total dimensions , as well as SF-36 Physical Function , Role Physical , Body Pain , Vitality and Social Functioning domains . In addition , from baseline to week 8 , the proportion of MCIIs was greater among the OAK group than the control group for all outcomes . For the period between baseline and month 6 , WOMAC Pain , Physical Function and Total dimensions significantly improved in the OAK group compared to the control group , as did the SF-36 Physical Function , Role Physical , Body Pain , Vitality and Social Functioning domains , as well as hamstring strength in both legs . During the same period , the TUG Test , range of motion extension and left-knee flexion improved compared with the control group , although these improvements had little clinical relevance . Conclusions We recorded statistically significant improvements compared with a control group with regard to pain , quality of life and function for participants in the OAK program on the basis of WOMAC and SF-36 measures taken 8 weeks and 6 months from baseline [2850876] Abstract Background Self-management has become increasingly popular in the management of chronic diseases . There are many different self-management models . Meta analyses of arthritis self-management have concluded that it is difficult to recommend any one program in preference to another due to inconsistencies in the study design s used to evaluate different programs . The Stanford Arthritis Self-Management Program ( ASMP ) , most commonly delivered by trained lay leaders , is a generic program widely used for people with rheumatological disorders . We have developed a more specific program expressly for people with osteoarthritis of the knee ( OAKP ) . It includes information design ed to be delivered by health professionals and results in improvements in pain , function and quality of life . Aim : To determine whether , for people with osteoarthritis ( OA ) of the knee , the OAKP implemented in a primary health care setting can achieve and maintain clinical ly meaningful improvements in more participants than ASMP delivered in the same environment . Methods / Design The effectiveness of the programs will be compared in a single-blind r and omized study . Participants : 146 participants with established OA knee will be recruited . Volunteers with coexistent inflammatory joint disease or serious co-morbidities will be excluded . Interventions : Participants will be r and omised into either OAKP or ASMP groups and followed for 6 months . Measurements : Assessment s will be immediately before and after the intervention and at 6 months . Primary outcome measures will be WOMAC and SF-36 question naires and a VAS for pain . Secondary outcomes will include balance , tested using a timed single leg balance test and a timed step test and self-efficacy . Data will be analysed using repeated measures ANOVA . Discussion With an aging population the health care costs for people with arthritis are ever increasing . Although cost analysis is beyond the scope of this study , it is reasonable to expect that costs will be greater when health professionals deliver self-management programs as opposed to lay leaders . Consequently it is critical to examine the relative effectiveness of the primary care management strategies available for OA.Trial Registration This study is registered with the Australian New Zeal and Clinical Trials Registry : [11142075] The objective of this study was to determine whether the Arthritis Self-Management Programme ( ASMP ) improves perceptions of control , health behaviours and health status , and changes use of health care re sources . The design was a pragmatic r and omized controlled study ; participants were allocated to ASMP ( Intervention Group ) or a 4-month waiting-list Control Group . The Intervention Group completed a 12-month follow-up . In total , 544 people with arthritis were recruited from the community--311 in the Intervention Group and 233 in the Control Group . Main outcome measures included : arthritis self-efficacy , health behaviours ( exercise , cognitive symptom management , diet and relaxation ) and health status ( pain , fatigue , anxiety , depression and positive affect ) . At 4 months follow-up , the ASMP had a significant effect on arthritis self-efficacy for other symptoms and pain subscales . Performance of a range of health behaviours ( cognitive symptom management , communication with physicians , dietary habit , exercise and relaxation ) was significantly greater among the Intervention Group . The Intervention Group were significantly less depressed and had greater positive mood . In addition , trends towards decreases on fatigue and anxiety were noted . Physical functioning , pain and GP visits remained stable at 4 months . A similar pattern of findings was found at 12 months follow-up for the Intervention Group . Furthermore , a significant improvement was found on pain and visits to GPs had decreased . Apart from a small improvement on physical functioning among the Intervention Group participants with osteoarthritis 12 months , all effects were independent of the type of arthritis . The findings suggest that the ASMP is effective in promoting improvements in perception of control , health behaviours and health status , when delivered in UK setting [2673355] Objective Chronic knee pain is a major cause of disability and health care expenditure , but there are concerns about efficacy , cost , and side effects associated with usual primary care . Conservative rehabilitation may offer a safe , effective , affordable alternative . We compared the effectiveness of a rehabilitation program integrating exercise , self-management , and active coping strategies ( Enabling Self-management and Coping with Arthritic Knee Pain through Exercise [ ESCAPE-knee pain ] ) with usual primary care in improving functioning in persons with chronic knee pain . Methods We conducted a single-blind , pragmatic , cluster r and omized controlled trial . Participants age ≥50 years , reporting knee pain for > 6 months , were recruited from 54 inner-city primary care practice s. Primary care practice s were r and omized to continued usual primary care ( i.e. , whatever intervention a participant 's primary care physician deemed appropriate ) , usual primary care plus the rehabilitation program delivered to individual participants , or usual primary care plus the rehabilitation program delivered to groups of 8 participants . The primary outcome was self-reported functioning ( Western Ontario and McMaster Universities Osteoarthritis Index physical functioning [ WOMAC-func ] ) 6 months after completing rehabilitation . Results A total of 418 participants were recruited ; 76 ( 18 % ) withdrew , only 5 ( 1 % ) due to adverse events . Rehabilitated participants had better functioning than participants continuing usual primary care ( −3.33 difference in WOMAC-func score ; 95 % confidence interval [ 95 % CI ] −5.88 , −0.78 ; P = 0.01 ) . Improvements were similar whether participants received individual rehabilitation ( −3.53 ; 95 % CI −6.52 , −0.55 ) or group rehabilitation ( −3.16 ; 95 % CI −6.55 , −0.12 ) . Conclusion ESCAPE-knee pain provides a safe , relatively brief intervention for chronic knee pain that is equally effective whether delivered to individuals or groups of participants [3524463] Background Knee osteoarthritis ( OA ) is a prevalent chronic musculoskeletal condition with no cure . Pain is the primary symptom and results from a complex interaction between structural changes , physical impairments and psychological factors . Much evidence supports the use of strengthening exercises to improve pain and physical function in this patient population . There is also a growing body of research examining the effects of psychologist-delivered pain coping skills training ( PCST ) particularly in other chronic pain conditions . Though typically provided separately , there are symptom , re source and personnel advantages of exercise and PCST being delivered together by a single healthcare professional . Physiotherapists are a logical choice to be trained to deliver a PCST intervention as they already have expertise in administering exercise for knee OA and are cognisant of the need for a biopsychosocial approach to management . No studies to date have examined the effects of an integrated exercise and PCST program delivered solely by physiotherapists in this population . The primary aim of this multisite r and omised controlled trial is to investigate whether an integrated 12-week PCST and exercise treatment program delivered by physiotherapists is more efficacious than either program alone in treating pain and physical function in individuals with knee OA . Methods / design This will be an assessor-blinded , 3-arm r and omised controlled trial of a 12-week intervention involving 10 physiotherapy visits together with home practice . Participants with symptomatic and radiographic knee OA will be recruited from the community in two cities in Australia and r and omized into one of three groups : exercise alone , PCST alone , or integrated PCST and exercise . R and omisation will be stratified by city ( Melbourne or Brisbane ) and gender . Primary outcomes are overall average pain in the past week measured by a Visual Analogue Scale and physical function measured by the Western Ontario and McMaster Universities Osteoarthritis Index subscale . Secondary outcomes include global rating of change , muscle strength , functional performance , physical activity levels , health related quality of life and psychological factors . Measurements will be taken at baseline and immediately following the intervention ( 12 weeks ) as well as at 32 weeks and 52 weeks to examine maintenance of any intervention effects . Specific assessment of adherence to the treatment program will also be made at weeks 22 and 42 . Relative cost-effectiveness will be determined from health service usage and outcome data . Discussion The findings from this r and omised controlled trial will provide evidence for the efficacy of an integrated PCST and exercise program delivered by physiotherapists in the management of painful and functionally limiting knee OA compared to either program alone . Trial registration Australian New Zeal and Clinical Trials Registry reference number : [19194641] Summary Osteoporosis is an increasing burden on individuals and health re sources . The Osteoporosis Prevention and Self-Management Course ( OPSMC ) was design ed to assist individuals to prevent and manage osteoporosis ; however , it had not been evaluated in an Australian setting . This r and omised controlled trial showed that the course increased osteoporosis knowledge . Introduction and hypothesisOsteoporosis is a major and growing public health concern . An OPSMC was design ed to provide individuals with information and skills to prevent or manage osteoporosis , but its effectiveness has not previously been evaluated . This study aim ed to determine whether OPSMC attendance improved osteoporosis knowledge , self-efficacy , self-management skills or behaviour . Material s and methods Using a wait list r and omised controlled trial design , 198 people ( 92 % female ) recruited from the community and aged over 40 ( mean age = 63 ) were r and omised into control ( n = 95 ) and intervention ( n = 103 ) groups . The OPSMC consists of four weekly sessions which run for 2 h and are led by two facilitators . The primary outcome were osteoporosis knowledge , health-directed behaviour , self-monitoring and insight and self-efficacy . Results The groups were comparable at baseline . At 6-week follow-up , the intervention group showed a significant increase in osteoporosis knowledge compared with the control group ; mean change 3.5 ( p < 0.001 ) on a measure of 0–20 . The intervention group also demonstrated a larger increase in health-directed behaviour , mean change 0.16 ( p < 0.05 ) , on a measure of 0–6 . Conclusion The results indicate that the OPSMC is an effective intervention for improving underst and ing of osteoporosis and some aspects of behaviour in the short term [4004977] Behavioral and health status outcomes of an unreinforced , self-help education program for arthritis patients taught by lay persons were examined in 2 ways : a 4-month r and omized experiment and a 20-month longitudinal study . At 4 months , experimental subjects significantly exceeded control subjects in knowledge , recommended behaviors , and in lessened pain . These changes remained significant at 20 months . The course was inexpensive and well-accepted by patients , physicians , and other health professionals [12554315] This study evaluated a novel intervention for older osteoarthritis ( OA ) patients and their spousal caregivers that consisted of st and ard patient education supplemented by information related to effectively managing arthritis as a couple . Twenty-four female OA patients and their husb and s were r and omly assigned to either an educational intervention that was targeted at both patient and spouse or to a patient education intervention that was targeted at only the patient . Findings revealed that both interventions were evaluated favorably but the couple intervention was better attended than the patient intervention . In addition , patients in the couple intervention experienced greater increased efficacy in managing arthritis pain and other symptoms . The findings of this pilot study point to the utility of a dyadic intervention approach to management of OA in late life [22484341] Six weekly sessions of group cognitive-behavioral therapy for insomnia and osteoarthritis pain ( CBT-PI ) , and for osteoarthritis pain alone ( CBT-P ) were compared to an education only control ( EOC ) . Basic education about pain and sleep was comparable , so EOC controlled for information and group participation . Active interventions differed from EOC in training pain coping skills ( CBT-P and CBT-PI ) and sleep enhancement techniques ( CBT-PI ) . Persons with osteoarthritis age 60 or older were screened for osteoarthritis pain and insomnia severity via mailed survey . Primary outcomes were pain severity ( pain intensity and interference ratings from the Grade d Chronic Pain Scale ) and insomnia severity ( Insomnia Severity Index ) . Secondary outcomes were arthritis pain ( AIMS -2 symptom scale ) and sleep efficiency assessed by wrist actigraphy . Ancillary outcomes included : cognitive function , depression , and health care use . A clustered r and omized design provided adequate power to identify moderate effects on primary outcomes ( effect size>0.35 ) . Modified intent to treat analyses , including all participants who attended the first session , assessed effects across CBT-PI , CBT-P , and EOC groups . Treatment effects were assessed post-intervention ( 2 months ) and at 9 months , with durability of intervention effects evaluated at 18 months . The trial was executed in 6 primary clinics , r and omizing 367 participants , with 93.2 % of r and omized patients attending at least 4 group sessions . Response rates for post-intervention and 9 month assessment s were 96.7 % and 92.9 % respectively . This hybrid efficacy-effectiveness trial design evaluates whether interventions yield specific benefits for clinical and behavioral outcomes relative to an education only control when implemented in a primary care setting [17043539] Objective : The objective of this study was to evaluate a nurse-directed self-management intervention for managed care patients with knee osteoarthritis ( OA ) , emphasizing nonpharmacologic ( NonPharm ) management of pain and functional impairments and minimization of exposure to the risks and costs of nonsteroidal antiinflammatory drugs ( NSAIDs ) . Methods : Subjects were 186 patients from a large health maintenance organization ( HMO ) who satisfied American College of Rheumatology clinical criteria for knee OA . Two of 4 HMO sites ( and their patient cohorts ) were r and omly assigned to the education group ; the other 2 served as a delayed-intervention control group . At each location of care for the education group , an arthritis nurse educator , in consultation with the patient 's primary care physician ( PCP ) , followed a detailed algorithm for implementing and monitoring the response to NonPharm treatment modalities ( eg , quadriceps strengthening exercises , counseling in principles of joint protection , use of thermal modalities ) . The nurses apprised the PCP of the patient 's progress and made algorithm-based recommendations , as appropriate , for reduction of dose , and eventual discontinuation , of NSAIDs in favor of acetaminophen . Outcomes ( measured at baseline , 3 , 6 , and 12 months ) included pain and function scales from the Western Ontario and McMaster Universities ( WOMAC ) OA Index . Results : The treatment groups were similar at baseline with respect to sociodemographic and clinical characteristics . Medical record audits revealed that NonPharm treatments ( most often exercise ) were implemented by 75 % of patients in the education group but by only 18 % of patients receiving routine care ( P < 0.00001 ) . Over the subsequent 12 months , 20 patients ( 26 % ) in the education group , but only 3 ( 5 % ) in the control group ( P = 0.002 ) , underwent changes in drug treatment of OA pain consistent with the NSAID-sparing goals of the intervention , ie , acetaminophen as initial drug of choice ; reduction in dose , or discontinuation , of NSAID ; switch from an NSAID to an analgesic . Only one patient in the education group required reinstitution of NSAIDs because of an increase in knee pain . Mean WOMAC scores indicated no deterioration of pain control or function over 12 months in the group treated according to the algorithm . Conclusion : Incorporation into the primary care setting of self-care education for patients with knee OA , with collaboration between a proactive arthritis nurse and the patient 's PCP , can reduce reliance on NSAIDs without a result ant increase in OA pain and disability [2735963] We examined the effectiveness of 2 models of arthritis self-care intervention , the home study model and the small group model . The effects of disease diagnosis and duration , self-care behavior , perceived helplessness , social support , treatment choice , and formal education level on outcomes among persons with arthritis who participated in these programs were evaluated . A pretest-posttest control group design was utilized in the initial experimental study ; comparison group design s were used in the longitudinal studies . Three hundred seventy-four subjects completed the interventions and 12 months of research followup . We found that the intervention models had a statistically significant positive impact on arthritis knowledge , self-care behavior , perceived helplessness , and pain . These findings did not vary when the effects of education level , disease diagnosis and duration , informal social support , and treatment choice were controlled . The small group intervention was more effective in bringing about initial improvements in pain and depression , whereas the home study intervention was more effective in maintaining improvements in perceived helplessness . Changes in perceived helplessness and self-care behavior appear to explain in part the observed improvement in pain [8980206] OBJECTIVE To determine the effects of structured exercise programs on self-reported disability in older adults with knee osteoarthritis . SETTING AND DESIGN A r and omized , single-blind clinical trial lasting 18 months conducted at 2 academic medical centers . PARTICIPANTS A total of 439 community-dwelling adults , aged 60 years or older , with radiographically evident knee osteoarthritis , pain , and self-reported physical disability . INTERVENTIONS An aerobic exercise program , a resistance exercise program , and a health education program . MAIN OUTCOME MEASURES The primary outcome was self-reported disability score ( range , 1 - 5 ) . The secondary outcomes were knee pain score ( range , 1 - 6 ) , performance measures of physical function , x-ray score , aerobic capacity , and knee muscle strength . RESULTS A total of 365 ( 83 % ) participants completed the trial . Overall compliance with the exercise prescription was 68 % in the aerobic training group and 70 % in the resistance training group . Postr and omization , participants in the aerobic exercise group had a 10 % lower adjusted mean ( + /- SE ) score on the physical disability question naire ( 1.71 + /- 0.03 vs 1.90 + /- 0.04 units ; P<.001 ) , a 12 % lower score on the knee pain question naire ( 2.1 + /- 0.05 vs 2.4 + /- 0.05 units ; P=.001 ) , and performed better ( mean [ + /- SE ] ) on the 6-minute walk test ( 1507 + /- 16 vs 1349 + /- 16 ft ; P<.001 ) , mean ( + /-SE ) time to climb and descend stairs ( 12.7 + /- 0.4 vs 13.9 + /- 0.4 seconds ; P=.05 ) , time to lift and carry 10 pounds ( 9.1 + /- 0.2 vs 10.0 + /- 0.1 seconds ; P<.001 ) , and mean ( + /-SE ) time to get in and out of a car ( 8.7 + /- 0.3 vs 10.6 + /- 0.3 seconds ; P<.001 ) than the health education group . The resistance exercise group had an 8 % lower score on the physical disability question naire ( 1.74 + /- 0.04 vs 1.90 + /- 0.03 units ; P=.003 ) , 8 % lower pain score ( 2.2 + /- 0.06 vs 2.4 + /- 0.05 units ; P=.02 ) , greater distance on the 6-minute walk ( 1406 + /- 17 vs 1349 + /- 16 ft ; P=.02 ) , faster times on the lifting and carrying task ( 9.3 + /- 0.1 vs 10.0 + /- 0.16 seconds ; P=.001 ) , and the car task ( 9.0 + /- 0.3 vs 10.6 + /- 0.3 seconds ; P=.003 ) than the health education group . There were no differences in x-ray scores between either exercise group and the health education group . CONCLUSIONS Older disabled persons with osteoarthritis of the knee had modest improvements in measures of disability , physical performance , and pain from participating in either an aerobic or a resistance exercise program . These data suggest that exercise should be prescribed as part of the treatment for knee osteoarthritis [8997917] OBJECTIVE To evaluate the effects of a spouse-assisted pain-coping skills training intervention on pain , psychological disability , physical disability , pain-coping , and pain behavior in patients with osteoarthritis ( OA ) of the knees . METHODS Eighty-eight OA patients with persistent knee pain were r and omly assigned to 1 of 3 conditions : 1 ) spouse-assisted pain-coping skills training , ( spouse-assisted CST ) , 2 ) a conventional CST intervention with no spouse involvement ( CST ) , or 3 ) an arthritis education-spousal support ( AE-SS ) control condition . All treatment was carried out in 10 weekly , 2-hour group sessions . RESULTS Data analysis revealed that at the completion of treatment , patients in the spouse-assisted CST condition had significantly lower levels of pain , psychological disability , and pain behavior , and higher scores on measures of coping attempts , marital adjustment , and self-efficacy than patients in the AE-SS control condition . Compared to patients in the AE-SS control condition , patients who received CST without spouse involvement had significantly higher post-treatment levels of self-efficacy and marital adjustment and showed a tendency toward lower levels of pain and psychological disability and higher scores on measures of coping attempts and ratings of the perceived effectiveness of pain-coping strategies . CONCLUSION These findings suggest that spouse-assisted CST has potential as a method for reducing pain and disability in OA patients [22382340] Objective . To evaluate the influence of a 6-week Arthritis Self-Management Program ( ASMP ) on health-related quality of life ( HRQOL ) and self-management skills in clinical setting s. Methods . Individuals with hip or knee osteoarthritis referred to orthopedic surgeons or rheumatologists at 6 hospitals in Victoria , Australia , were recruited . In a r and omized controlled trial , participants received the Stanford ASMP and self-help book ( intervention ) or book only ( control ) . Assessment s included the Assessment of Quality of Life instrument ( AQoL ; range −0.04 to 1.00 ) and Health Education Impact Question naire ( heiQ ; range 1–6 ) at baseline and up to 12 months . The primary outcome was HRQOL at 12 months ( assessed using the AQoL ) . Results . Recruitment was concluded early due to persistent challenges including infrequent referrals and patient inability or disinterest in participating . Of 1125 individuals screened , only 120 were r and omized ( control , n = 62 ; intervention , n = 58 ) . Seven ASMP were conducted while 18 scheduled ASMP were cancelled . Forty-four of 58 intervention group participants received the intervention as allocated ( 76 % ) ; all control group participants were sent the book ( 100 % ) . Ninety-four participants ( 78 % ) completed 12-month assessment s ( control , 90 % ; intervention , 66 % ) . There was no difference in HRQOL at 12 months ( adjusted mean difference −0.02 , 95 % CI −0.09 to 0.05 ) . At 6 weeks , the intervention group reported higher heiQ skill and technique acquisition scores ( adjusted mean difference 0.29 , 95 % CI 0.04 to 0.55 ) ; however , this dissipated by 3 months . Conclusion . Significant challenges hampered this evaluation of the ASMP . The observed lack of enthusiasm from potential referrers and patients raises doubts about the practicality of this intervention in real-world setting s. ( ANZCTR Clinical Trials Registry no. ACTRN12606000174583 [10513498] OBJECTIVE To evaluate the long-term effects of a spouse-assisted coping skills intervention in patients with osteoarthritis ( OA ) of the knees , and to evaluate how pre- to posttreatment changes in marital adjustment and self-efficacy relate to long-term improvements in pain , psychological disability , physical disability , pain coping , and pain behavior . METHODS A followup study was conducted with 88 OA patients who had been r and omly assigned to 1 of 3 treatment conditions : 1 ) spouse-assisted coping skills training ( spouse-assisted CST ) , 2 ) a conventional CST intervention with no spouse involvement , and 3 ) an arthritis education-spousal support ( AE-SS ) control condition . To evaluate long-term outcome , comprehensive measures of self-efficacy , marital adjustment , pain , psychological disability , physical disability , pain coping , and pain behavior were collected from these individuals at 6 and 12 months posttreatment . RESULTS Data analysis revealed that , at 6-month followup , patients in the spouse-assisted CST condition scored higher on measures of coping and self-efficacy than those in the AE-SS control group . At 6-month followup , patients who received CST without spouse involvement showed a significantly higher frequency of coping attempts and reported higher levels of marital adjustment than those in the AE-SS control group . At 12-month followup , patients in the spouse-assisted CST condition had significantly higher overall self-efficacy than those in the AE-SS control condition . In addition , patients in both the spouse-assisted CST and CST only conditions tended to show improvements in physical disability at the 12-month followup . Individual differences in outcome were noted at the 12-month followup . Patients in the spouse-assisted CST condition who reported initial ( pre- to posttreatment ) increases in marital adjustment had lower levels of psychological disability , physical disability , and pain behavior at 12-month followup . However , for patients in the conventional CST and AE-SS control conditions , increases in marital adjustment occurring over the initial phase of treatment were related to increases in pain and decreases in scores on the Pain Control in Rational Thinking factor of the Coping Strategies Question naire . Finally , patients in the spouse-assisted CST condition who showed pre- to posttreatment increases in self-efficacy were more likely to show decreases in pain , psychological disability , and physical disability at 12-month followup . CONCLUSIONS These findings suggest that spouse-assisted CST can enhance self-efficacy and improve the coping abilities of OA patients in the long term . Individual differences in the long-term outcome of spouse-assisted CST were noted , with some patients ( those showing increases in marital satisfaction and self-efficacy ) showing much better outcomes than others [16208674] OBJECTIVE To examine changes in mobility-related self efficacy following exercise and dietary weight loss interventions in overweight and obese older adults with knee osteoarthritis ( OA ) , and to determine if self efficacy and pain mediate the effects of the interventions on mobility task performance . METHODS The Arthritis , Diet , and Activity Promotion Trial was an 18-month , single-blind , r and omized , controlled trial comparing the effects of exercise alone , dietary weight loss alone , a combination of exercise plus dietary weight loss , and a healthy lifestyle control intervention in the treatment of 316 overweight or obese older adults with symptomatic knee OA . Participants completed measures of stair-climb time and 6-minute walk distance , self efficacy for completing each mobility task , and self-reported pain at baseline , 6 months , and 18 months during the trial . RESULTS Mixed model analyses of covariance of baseline adjusted change in the outcomes demonstrated that the exercise + dietary weight loss intervention produced greater improvements in mobility-related self efficacy ( P = 0.0035 ) , stair climb ( P = 0.0249 ) and 6-minute walk performance ( P = 0.00031 ) , and pain ( P = 0.09 ) when compared with the healthy lifestyle control intervention . Mediation analyses revealed that self efficacy and pain served as partial mediators of the beneficial effect of exercise + dietary weight loss on stair-climb time . CONCLUSION Exercise + dietary weight loss results in improved mobility-related self efficacy ; changes in these task-specific control beliefs and self-reported pain serve as independent partial mediators of the beneficial effect of exercise + dietary weight loss on stair-climb performance [18576310] OBJECTIVE To determine the efficacy of an Internet-based Arthritis Self-Management Program ( ASMP ) as a re source for arthritis patients unable or unwilling to attend small-group ASMPs , which have proven effective in changing health-related behaviors and improving health status measures . METHODS R and omized intervention participants were compared with usual care controls at 6 months and 1 year using repeated- measures analyses of variance . Patients with rheumatoid arthritis , osteoarthritis , or fibromyalgia and Internet and e-mail access ( n = 855 ) were r and omized to an intervention ( n = 433 ) or usual care control ( n = 422 ) group . Measures included 6 health status variables ( pain , fatigue , activity limitation , health distress , disability , and self-reported global health ) , 4 health behaviors ( aerobic exercise , stretching and strengthening exercise , practice of stress management , and communication with physicians ) , 5 utilization variables ( physician visits , emergency room visits , chiropractic visits , physical therapist visits , and nights in hospital ) , and self-efficacy . RESULTS At 1 year , the intervention group significantly improved in 4 of 6 health status measures and self-efficacy . No significant differences in health behaviors or health care utilization were found . CONCLUSION The Internet-based ASMP proved effective in improving health status measures at 1 year and is a viable alternative to the small-group ASMP [10366121] OBJECTIVE To determine the extent to which the cost of an effective self-care intervention for primary care patients with knee osteoarthritis ( OA ) was offset by savings result ing from reduced utilization of ambulatory medical services . METHODS In an attention-controlled clinical trial , 211 patients with knee OA from the general medicine clinic of a municipal hospital were assigned arbitrarily to conditions of self-care education ( group E ) or attention control ( group AC ) . Group E ( n = 105 ) received individualized instruction and followup emphasizing nonpharmacologic management of joint pain . Group AC ( n = 106 ) received a st and ard public education presentation and attention-controlling followup . A comprehensive clinical data base provided data concerning utilization and cost of health services during the following year . RESULTS Only 25 subjects ( 12 % ) were lost to followup . The 94 subjects remaining in group E made 528 primary care visits during the year following intervention , compared with 616 visits by the 92 patients remaining in group AC ( median visits 5 versus 6 , respectively ; P < 0.05 ) . Fewer visits translated directly into reduced clinic costs in group E , relative to controls ( median costs [ 1996 dollars ] $ 229 versus $ 305 , respectively ; P < 0.05 ) . However , self-care education had no significant effects on utilization and costs of outpatient pharmacy , laboratory , or radiology services over the ensuing year . The cost per patient to deliver the self-care intervention was estimated to be $ 58.70 . CONCLUSION Eighty percent of the cost of delivering effective self-care education to the knee OA patients in this study was offset within 1 year by the reduced frequency and costs of primary care visits . For > 50 % of patients receiving the intervention , the savings associated with fewer primary care visits exceeded the cost of self-care education [15937632] Osteoarthritis ( OA ) is the commonest cause of locomotor disability and forms a major element of the workload of the primary care team . There is evidence that patient education may improve quality of life , physical functioning , mental health and coping as well as reducing health service use . The aim of this study was to evaluate the effectiveness of a primary care-based patient education programme ( PEP ) using a r and omised controlled trial . A cluster r and omised controlled trial , involving 22 practice s , was used to determine the efficacy of a nurse-led education programme . The programme consisted of a home visit and four 1-h teaching sessions . Patients were assessed at baseline and then 1 , 3 , 6 and 12 months post intervention using 36-item Short Form ( SF-36 ) , Western Ontario and McMaster Universities Arthritis Index ( WOMAC ) , arthritis helplessness index and a patient knowledge question naire . Direct interviews were used at baseline and at the 12-month follow-up . There were no differences in depression , OA knowledge , pain or physical ability at either 1 month or 1 year between the two groups . Control practice s ( 65 patients from 12 practice s ) recruited significantly fewer patients than intervention practice s ( 105 patients from ten practice s , p=0.02 ) . Control practice s had more doctors ( p=0.02 ) , more non-white patients ( p=0.007 ) , fewer patients living alone ( p=0.005 ) and lower levels of disability ( p=0.008 ) . We detected a lack of benefit of PEP for people with OA of the knee . This was thought to be due in part to the short intervention time employed and the heterogeneous nature of the disease and the population studied [9259427] OBJECTIVE To evaluate a concise program of self-care education delivered by an arthritis nurse specialist as an adjunct to primary care for inner-city patients with knee osteoarthritis ( OA ) . METHODS An attention-controlled clinical trial ; 211 inner-city patients with knee OA were assigned arbitrarily to education ( E ) or attention-control ( AC ) conditions . Group E received an individualized 30 - 60-minute educational intervention that emphasized nonpharmacologic management of joint pain , preservation of function by problem-solving , and practice of principles of joint protection . Brief telephone contacts 1 week and 4 weeks later monitored and reinforced new self-care activities . Group AC viewed a 20-minute st and ardized public education presentation on arthritis and received followup telephone calls ( only to encourage continued participation in the study ) . Outcomes included the Health Assessment Question naire ( HAQ ) Disability and Discomfort Scales , 10-cm visual analog scales measuring knee pain at rest and while walking , and the Quality of Well-Being ( QWB ) scale . Assessment s were made at baseline and at 4-month intervals for 1 year . RESULTS A total of 165 subjects ( 78 % ) completed all assessment s. After control for baseline status , group E had significantly lower scores for disability and resting knee pain throughout the year of postintervention followup ( P < 0.05 for both ) . Effects were somewhat discordant . By 12 months , functional benefits had begun to wane , while the effect on resting knee pain had grown . The overall effects of education on walking knee pain , overall joint pain ( by HAQ ) , and general health status ( by QWB ) were not significant . CONCLUSION Self-care education for inner-city patients with knee OA , delivered as an adjunct to primary care , was found to result in notable preservation of function and control of resting knee pain . The magnitude of the observed effects compares well with those of more labor-intensive and time-consuming intervention models . However , more sustained preservation of function and consistent effects on pain may require prolonged , more proactive followup , either by the patient educator or by a trained clinical assistant dedicated to the task of supporting self-care by patients with knee OA [21343219] Thail and has a history of implementing innovative and proactive policies to address the health needs of its population . Since 1962 Thail and has implemented initiatives that led to it having a health system characterized by a primary care focus , de central ization and mechanisms to maximize equity and universal access to basic care at the local level . Thai health structures initially evolved to meet challenges including infectious and developmental diseases and later HIV . Early in the 21st century chronic illness rapidly became the greatest cause of morbidity and mortality and the question has arisen how Thail and can adapt its strong health system to deal with the new epidemics . This article describes an effort to reorient provincial health services to meet the needs of the increasing number of people with diabetes and heart disease . It describes measures taken to build on the equity-promoting elements of the Thai health system . The project included ; a situational analysis , development and implementation of a chronic disease self-management intervention implemented by nurses and alignment of provincial health services . The self-management intervention is currently being evaluated within a clustered r and omized control trial . The evaluation has been developed to fit with the focus on equity in relation to both selection criteria and the outcomes that are being assessed [15288394] & NA ; This study tested the separate and combined effects of spouse‐assisted pain coping skills training ( SA‐CST ) and exercise training ( ET ) in a sample of patients having persistent osteoarthritic knee pain . Seventy‐two married osteoarthritis ( OA ) patients with persistent knee pain and their spouses were r and omly assigned to : SA‐CST alone , SA‐CST plus ET , ET alone , or st and ard care ( SC ) . Patients in SA‐CST alone , together with their spouses , attended 12 weekly , 2‐h group sessions for training in pain coping and couples skills . Patients in SA‐CST+ET received spouse‐assisted coping skills training and attended 12‐weeks supervised ET . Patients in the ET alone condition received just an exercise program . Data analyses revealed : ( 1 ) physical fitness and strength : the SA‐CST+ET and ET alone groups had significant improvements in physical fitness compared to SA‐CST alone and patients in SA‐CST+ET and ET alone had significant improvements in leg flexion and extension compared to SA‐CST alone and SC , ( 2 ) pain coping : patients in SA‐CST+ET and SA‐CST alone groups had significant improvements in coping attempts compared to ET alone or SC and spouses in SA‐CST+ET rated their partners as showing significant improvements in coping attempts compared to ET alone or SC , and ( 3 ) self‐efficacy : patients in SA‐CST+ET reported significant improvements in self‐efficacy and their spouses rated them as showing significant improvements in self‐efficacy compared to ET alone or SC . Patients receiving SA‐CST+ET who showed increased self‐efficacy were more likely to have improvements in psychological disability . An intervention that combines spouse‐assisted coping skills training and exercise training can improve physical fitness , strength , pain coping , and self‐efficacy in patients suffering from pain due to osteoarthritis [15742451] OBJECTIVE To assess in a primary healthcare setting the efficacy of a self-management program in middle-aged patients with osteoarthritis ( OA ) . METHODS This was a 2-group r and omized controlled trial , with 273 patients aged 40 to 60 years with OA of the hip(s ) and /or knee(s ) . The experimental intervention was compared with care-as-usual . Treatments and followup measurements were performed in a general healthcare setting by general practitioners . Duration of followup was 21 months after start of the intervention . Instruction in self-management techniques was given by physiotherapists . The main outcome measures were pain severity in hips and knees , other significant complaints , and functional limitations . RESULTS To begin , 297 patients were r and omized : 149 as self-management and 148 controls ; before the intervention 24 withdrew for practical reasons ( 17 self-management , 7 controls ) . At 3-month followup the intervention group was significantly improved on a visual analog scale ( VAS ) for knee pain ( score 0.67 ; SD 2.10 ) and the WOMAC ( score 2.46 ; SD 9.49 ) , while the control group showed stable VAS knee pain ( 0.01 ; SD 2.00 ) and deterioration on WOMAC ( -0.53 ; SD 9.47 ) . At 21-month followup the differences between the groups increased in favor of the intervention group ( VAS pain knee : p values from 0.023 at 3 mo to 0.004 at 21 mo ; WOMAC : p values from 0.030 to 0.022 ) . CONCLUSION The self-management program positively influenced knee pain and self-reported functional level in this sample of patients with OA . Differences between the study groups increased during followup in favor of the intervention group [9084954] OBJECTIVE Past research has shown response biases to influence the accuracy of results from self-report measures . In pain assessment , where a percentage of patients have financial and other reasons to minimize or exaggerate psychological disturbance , it becomes especially important to identify the influence of response bias in self-report of adjustment . This study investigated the susceptibility of three commonly used self-report pain assessment measures to response bias . DESIGN This study used a within-subjects ( asymptomatic subjects ) design with two experimental conditions and nonequivalent control group ( chronic pain patients ) . SUBJECTS Experimental group : 40 students enrolled in an occupational therapy program at a major southeastern United States university . CONTROL GROUP 200 subjects referred to a multidisciplinary pain clinic at a major teaching hospital . MEASURES Coping Strategies Question naire , Multidimensional Pain Inventory , and Pain Beliefs and Perceptions Inventory . RESULTS With few exceptions , asymptomatic subjects scored significantly differently on these measures while portraying themselves as either coping well or coping poorly . In addition , when using the " coping poorly " response set , asymptomatic subjects reproduced scores similar to those of symptomatic chronic pain patients . CONCLUSION The susceptibility to manipulation appeared constant across the three measures , a finding that highlighted the difficulties clinicians and research ers encounter in accurate interpretation of results from these measures in the absence of validity indicators . This study also emphasizes the ease with which subjects with sufficient motivation can present themselves in an untruthful and manipulative manner and can generate scores that are , on their own , difficult to distinguish from those of a group of typical chronic pain patients [17040926] Abstract Objective To evaluate clinical effectiveness of a self management programme for arthritis in patients in primary care with osteoarthritis . Design R and omised controlled trial . Setting 74 general practice s in the United Kingdom . Participants 812 patients aged 50 and over with osteoarthritis of hips or knees ( or both ) and pain or disability ( or both ) . Intervention Participants were r and omised to six sessions of self management of arthritis and an education booklet ( intervention group ) or the education booklet alone ( control group ) . Main outcome measures Primary outcome was quality of life , as assessed by the short form health survey ( SF-36 ) . Several other physical and psychosocial secondary outcomes were assessed . Data were collected at baseline , four months , and 12 months . Results Response rates were 80 % and 76 % at four and 12 months . The two groups showed significant differences at 12 months on the anxiety subscore of the hospital anxiety and depression scale ( mean difference −0.62 , 95 % confidence interval −1.08 to −0.16 ) , arthritis self efficacy scale for pain ( 0.98 , 0.07 to 1.89 ) , and self efficacy for other aspects of management ( 1.58 , 0.25 to 2.90 ) . Results were similar for intention to treat and per protocol analyses . No significant difference was seen in number of visits to the general practitioner at 12 months . Conclusions The self management of arthritis programme reduced anxiety and improved participants ' perceived self efficacy to manage symptoms , but it had no significant effect on pain , physical functioning , or contact with primary care . Trial registration Current Controlled Trials IS RCT N79115352 [ controlled-trials.com ] [9273984] Women increasingly outnumber men in the US population ( Arber & Ginn , 1993 ) , but most research has been conducted with men ( Stacey & Olesen , 1988 ) . The purpose of this study was to determine whether older men and women differ in their participation rates and in their responsiveness to a health intervention . Three hundred sixty-three health maintenance organization members with osteoarthritis , 60 years of age or older , were r and omly assigned to a control group or to receive social support , education , or a combination of education and social support , education , or a combination of education and social support . Of the 363 r and omly assigned members , 245 completed all of the follow-up assessment s. Men and women volunteered in proportion to their representation in the osteoarthritis population . Although the genders differed in several ways , the interventions were equally effective for men and women , and the study results applied to both genders [17169935] PURPOSE We present final outcomes from the multiple-component Fit and Strong ! intervention for older adults with lower extremity osteoarthritis . DESIGN AND METHODS A r and omized controlled trial compared the effects of this exercise and behavior-change program followed by home-based reinforcement ( n=115 ) with a wait list control ( n=100 ) at 2 , 6 , and 12 months . Fit and Strong ! combined flexibility , aerobic walking , and resistance training with education and group problem solving to enhance self-efficacy for exercise and maintenance of physical activity . All participants developed individualized plans for long-term maintenance . RESULTS Relative to controls , treatment participants experienced statistically significant improvements in self-efficacy for exercise ( p=.001 ) , minutes of exercise per week ( p=.000 ) , and lower extremity stiffness ( p=.018 ) at 2 months . These benefits were maintained at 6 months and were accompanied by increased self-efficacy for adherence to exercise over time ( p=.001 ) , reduced pain ( p=.040 ) , and a marginally significant increase in self-efficacy for arthritis pain management ( p=.052 ) . Despite a substantially smaller sample size at 12 months , significant treatment-group effects were maintained on self-efficacy for exercise ( p=.006 ) and minutes of exercise per week ( p=.001 ) , accompanied by marginally significant reductions in lower extremity stiffness ( p=.056 ) and pain ( p=.066 ) . No adverse health effects were seen . Effect sizes for self-efficacy for exercise and for maintenance of physical activity were 0.798 and 0.713 , and 0.905 and 0.669 , respectively , in the treatment group at 6 and 12 months . IMPLICATION S This consistent pattern of benefits indicates that this low-cost intervention is efficacious for older adults with lower extremity osteoarthritis [18206425] BACKGROUND Osteoarthritis ( OA ) is a leading cause of disability among adults . Although self-management behaviors such as exercise and weight management can improve pain and function , these behaviors are vastly underutilized . There is a need to implement effective self-management programs among the growing number of adults with OA . OBJECTIVES The Self-Management of OsteoArthritis ( SeMOA ) in Veterans Study examines a 12-month telephone-based OA self-management program in the primary care setting . This manuscript details the design , methodology , and advances of the SeMOA trial . METHODS Participants ( N=519 ) with hip or knee OA are r and omly assigned to one of three groups : OA self-management , health education ( attention control ) , or usual care . The OA self-management group receives written and audio material s regarding OA care ( including health behaviors , medical care , and interacting with health care providers ) . A health educator calls participants monthly to review these material s and provide support for developing individualized goals and action plans related to OA management . The health education group receives written and audio material s and monthly calls from a health educator discussing health issues unrelated to OA . Usual care involves no additional material s or phone calls . The primary outcome is change in the Arthritis Impact Measurement Scales-2 pain subscale from baseline to 12 months . Analysis of covariance models will compare changes in pain across study groups . The cost-effectiveness of the OA self-management program will also be assessed . CONCLUSION SeMOA is one of the first to examine telephone-based delivery of OA self-management and one of few trials to target the primary care setting . This program has the potential for broad dissemination because it reduces both the costs and barriers that accompany in-person programs . This study will provide important information about its feasibility and effectiveness in a real-world clinical setting [9830877] OBJECTIVE To determine whether experimentally developed social support , education about appropriate use of the health care system , and their combination are effective in reducing health care costs for people with osteoarthritis at a 3-year followup assessment . METHOD Three hundred sixty-three health maintenance organization members with osteoarthritis were r and omly assigned to 1 of 3 intervention groups or to a control group . Two hundred fifty-six participants completed the 3-year assessment . Health status and health care use were assessed upon entering the study , and after 1 , 2 , and 3 years . RESULTS Health care costs in the combined experimental groups were lower than those in the control group by $ 1,279/participant/year in year 3 . There were no significant changes in health status between participants ' entry into the study and the year 3 assessment . The 3 interventions had nearly equal effects on health status and health care costs . Implementation costs were least for the social support intervention , but the group that combined education and social support had less attrition and greater persistence . CONCLUSION Interventions that target appropriate use of the health care system can be highly cost-effective without adversely affecting health status [9313398] OBJECTIVE To determine whether experimentally developed social support and education about appropriate use of the health care system decrease health care costs without negatively affecting health status . METHOD Three hundred sixty-three health maintenance organization members with osteoarthritis were r and omly assigned to 1 of 3 intervention groups or to a control group . Health status and health care use were assessed upon entering the study , and after 1 year and 2 years . RESULTS A savings of $ 1,156/participant/year was obtained when health care costs of the experimental groups were compared with those of the control group . Production or implementation costs were least for the social support intervention . The nearly equal effects of the 3 interventions on health care costs make implementation costs the primary focus when deciding which intervention to use . CONCLUSION We believe that the social support treatment is the most cost-effective intervention [20633669] OBJECTIVE To compare the efficacy of patient education and supervised exercise with that of patient education alone for the management of pain in patients with hip osteoarthritis ( OA ) . DESIGN Single blind r and omized clinical trial . SETTING Recruitment of patients from hospitals , primary health care and advertisement , Oslo , Norway . PARTICIPANTS 109 patients with radiographic and symptomatic hip OA with mild to moderate symptoms . INTERVENTIONS Patient education ( PE ) . Patient education and supervised exercise ( PE+SE ) . PRIMARY OUTCOME MEASURE The pain subscale of the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC pain ) . RESULTS No significant between group differences were found for WOMAC pain over the 16-month follow-up . Significant improvements were found for the secondary outcome WOMAC physical function ( P=0.011 ) in the group receiving PE+SE compared to the group receiving PE only . No significant differences were found for WOMAC stiffness , the SF-36 subscales or the activity scale . The effect sizes ( 95 % confidence interval ) for WOMAC pain were -0.26 ( 0.11 , -0.64 ) , -0.35 ( 0.07 , -0.77 ) , and -0.30 ( 0.15 , -0.75 ) , and for WOMAC physical function -0.29 ( 0.09 , -0.67 ) , -0.48 ( -0.06 , -0.91 ) , and -0.47 ( -0.02 , -0.93 ) at 4 , 10 and 16 months , respectively , in favor of the group receiving both PE and SE . All patients attended the three-session PE program , and 75 % performed ≥16 sessions of the 12-week SE program . CONCLUSION The study could not demonstrate a significant difference in pain reduction over time between PE+SE vs PE alone . Adding SE to PE may improve physical function , but the magnitude of possible benefit is unknown as the 95 % confidence intervals around the mean difference were wide . TRIAL REGISTRATION Clinical Trials NCT00319423 [27820499] Background Osteoarthritis ( OA ) is a common cause of pain and disability , and is the most common form of arthritis in the Western world . The most common joint to be affected is the knee . Pain and functional disability are common symptoms , which can lead to reduced quality of life and increase the risk of further morbidity . Current treatment aims to educate patients about the management of OA , reduce pain , improve function , decrease disability and reduce the progression of the disease . Education with clients has been described as a set of planned educational activities design ed to improve patients ' health behaviours and /or health status . The purpose of self‐education is to maintain or improve health , or , in some cases , to slow deterioration by increasing participant 's perception of self efficacy defined as an ability to control or manage various aspects of OA . To date , there is no systematic review of the literature undertaken to identify the effectiveness of self‐management educational activities for osteoarthritis of the knee . Objective The objective of this systematic review is to evaluate the effectiveness of self‐management educational interventions on function and quality of life for adult subjects with OA of the knee . Search strategy A comprehensive search strategy was undertaken on data bases available from University of South Australia from their inception to January 2007 . Selection criteria R and omised controlled trials or clinical controlled trials were sought which evaluated any self management interventions for osteoarthritis knee . Critical appraisal of study quality was undertaken using Joanna Briggs Institute critical appraisal instruments . Data extraction was via the Joanna Briggs Institute st and ard data extraction form for evidence of effectiveness , and Review Manager Software was used to calculate comparative statistics . Results Thirteen trials were included in the review . Trials were clinical ly and method ologically heterogeneous . Pooled results indicate evidence of a beneficial effect from self management strategies with reducing pain ( SMD ‐0.25 , 95%CI ‐0.36 to ‐0.13 , 11 trials 1379 participants ) . There was no effect on physical function ( SMD 0.13 , 95%CI ‐0.33 to ‐0.08 , eight trials , 1156 subjects ) . No beneficial effects were found from self management interventions with improving quality of life . We also found the exercise component of self management ( four trials ) demonstrated a benefit with reducing pain , improving function and quality of life . Exercise also offered a benefit over no exercise . Overall method ological quality was moderate . Discussion Pooled results indicate evidence of a beneficial effect from self management strategies with reducing pain and improving function . Significant heterogeneity was found between trials . This was controlled for in the analysis but may be explained by heterogeneity in both the intervention and control group . The exercise component of self management programmes appears to contribute a significant benefit . Conclusion There is encouraging evidence of a small benefit from exercise in self management programs . Clear guidelines can not be provided for practice regarding the exercise content due to heterogeneity but overall benefit suggests this component should be emphasized and implemented in primary care self management programmes [18825579] The aim was to assess the self-efficacy and health outcomes of an adopted Arthritis Self-Management Programme ( ASMP ) among osteoarthritic knee sufferers in Hong Kong at 1 year . An experimental study with 95 participants assigned r and omly to the intervention ( n=45 ) or control group ( n=50 ) . Seventy-seven ( 81.1 % ) participants joined at least one out of three follow-ups in the 12 month period . Participants in the intervention group received a 6-week ASMP with an added exercise component in two general clinics . Outcome measures included arthritis self-efficacy ( ASE ) and health outcomes including pain and fatigue rating , self-rated health , daily activities limitation and number of unplanned arthritis-related medical consultations . Mean change ( 12 months minus baseline ) and the effect size of the outcome measures were calculated by Mann – Whitney U test and nQuery Advisor 4.0 . At 12 months , there were significant reductions of current pain ( p=0.0001 ) , pain at night ( p=0.001 ) , pain during walking ( p=0.01 ) and number of unplanned arthritis-related medical consultations ( p=0.03 ) and a significant increase in ASE for pain ( p=0.01 ) and other symptoms ( p=0.02 ) and self-rated health ( p=0.04 ) among the intervention group but not for the control group . However , there were similarities in outcome measures of pain while switching from a sitting to a st and ing position , fatigue rating and physical functional limitation ( p=0.15 ; p=0.22 and p=0.91 , respectively ) for both groups . Our findings add to the evidence that the modified arthritis empowering programme improved perception of control of osteoarthritis and three health outcomes after 12 months of treatment [16342084] OBJECTIVE Both the Arthritis Self-Management Program ( ASMP ) and the generic Chronic Disease Self-Management Program ( CDSMP ) have been shown to be successful in improving conditions in patients with arthritis . This study compared the relative effectiveness of the 2 programs for individuals with arthritis . METHODS Patients whose primary disease was arthritis were r and omized to the ASMP ( n = 239 ) or to the CDSMP ( n = 116 ) . Analyses of covariance were used to compare the outcome measures for the 2 programs at 4 months and 1 year . Measures included quality of life outcomes ( self reported , health distress , disability , activity limitation , global health , pain , and fatigue ) , health behaviors ( practice of mental stress management , stretching and strength exercise , aerobic exercise ) , self efficacy , and health care utilization ( physician visits and hospitalizations ) . RESULTS Both programs showed positive results . The disease-specific ASMP appeared to have advantages over the more generic CDSMP for patients with arthritis at 4 months . These advantages had lessened slightly by 1 year . CONCLUSION The disease-specific ASMP should be considered first where there are sufficient re sources and participants . However , both programs had positive effects , and the CDSMP should be considered a viable alternative [21290963] & NA ; Osteoarthritis of the knee , a prevalent condition in older adults , can impact physical function and ability to perform physical activity . This r and omized controlled trial examined the effects of a 6‐month self‐efficacy‐based , individually delivered , lower‐extremity exercise and fitness walking intervention with 6‐month follow‐up on physical activity and function . The 26 subjects were mostly older ( M = 63.2 years , SD = 9.8 ) , White ( 83 % ) , obese ( BMI M = 33.3 , SD = 6.0 ) women ( 96 % ) . Physical activity was measured by diaries . Physical function was measured by the 6‐minute walk , Short Physical Performance Battery ( SPPB ) , and WOMAC Physical Function subscale . Exercise self‐efficacy was assessed by a question naire . Results showed significant increases in self‐reported performance of lower‐extremity exercise and participation in fitness walking , distance in the 6‐minute walk , and SPPB scores from baseline to 6‐month follow‐up with a trend for improvement in self‐efficacy . Results suggest that the intervention was feasible , acceptable , and improved physical activity and function [10965386] The soaring cost of health care is a national problem that needs response at multiple levels , including that of the community . Reducing or limiting health care costs through interventions that emphasize the self-management of health may promote broader health care coverage , better quality of health care , and a sense of control over one 's health . Therefore , it behooves community psychologists to perform cost analyses when testing interventions for people in a community . The present study investigated the effects of social support and education interventions on psychosocial variables , health status , and health care costs in older people with osteoarthritis . Participants were 363 members of a health maintenance organization ( HMO ) , 60 years of age and older , with osteoarthritis . Participants were r and omly assigned to one of three intervention groups ( social support , education , or a combination of both ) or to a control group . The results indicated that feelings of helplessness decreased in the intervention groups but not in the control group . All groups showed increases in self-efficacy and overall health status . In addition , health care costs increased less in the intervention groups than in the control group . Cost analysis was used to demonstrate that the monetary savings of the intervention greatly outweighed the cost of conducting the intervention . It appears that interventions can limit health care costs while improving health and increasing feelings of control for older people with osteoarthritis . Further , this paper demonstrates how a cost-benefit focus can benefit community studies [10493473] OBJECTIVES To determine 4-month and 1-year health-related outcomes of a 6-week , lay-led , and community-based arthritis self-management program for Spanish-speaking participants and to determine the role of self-efficacy in predicting health status for this population . METHODS Three hundred and thirty one subjects were r and omized to the program or to a 4-month wait list control group . One hundred ninety eight subjects continued in a 1-year longitudinal study . Data were collected via mailed question naires with telephone follow up . RESULTS At 4 months , treatment subjects , compared with controls , demonstrated positive changes in exercise , disability , pain , and self-efficacy ( P < 0.05 ) . At 1 year , compared with baseline , treatment subjects demonstrated improvements in exercise , general health , disability , pain , self-efficacy , and depression ( P < 0.05 ) . Baseline and 4-month changes in self-efficacy predicted health status at 1 year . CONCLUSIONS Spanish-speaking participants of an arthritis self-management program demonstrate short- and long-term benefits ( improved health behaviors , health status , and self-efficacy ) [10955337] OBJECTIVE Evaluation of a self-management program for patients with osteoarthritis ( OA ) of the hip or knee . The program , which consisted of 6 weekly sessions of 2 hours , included health education by a peer and physical exercises taught by a physical therapist . METHODS R and omized controlled trial . Inclusion criteria were diagnosis of OA of the hip or knee according to ACR clinical and radiographic criteria and age 55 to 75 years . EXCLUSION CRITERIA on waiting list for joint replacement . There were pretest , posttest , and followup ( 6 months ) assessment s. The experimental group consisted of 56 patients , the control group 49 . Outcome variables were pain , quality of life , activity restrictions , knowledge about OA , self-efficacy , body mass index ( BMI ) , and mobility measures . Attention was also paid to effects on health care utilization and lifestyle behavior . RESULTS Significant MANOVA group x time effects ( p < 0.05 , one-sided ) were found for pain , quality of life , strength of the left M. quadriceps , knowledge , self-efficacy , BMI , physically active lifestyle , and visits to the physical therapist . Most effects were moderate at posttest assessment and smaller at followup . No effects were found for range of motion and functional tasks . CONCLUSION The program was reasonably effective , but more attention should be paid to proactive followup interventions and to the selection of participants [2917233] The benefits of patient education for those with chronic arthritis are well documented . Informed patients should practice self care more often , and may show reduced disability from their disease . An important question relates to maintenance of the knowledge and skills acquired in educational programmes . This prospect i ve study evaluated an education programme for people with rheumatoid arthritis ( RA ) and osteoarthritis ( OA ) . The intervention group participated in a comprehensively planned six session behaviourally based programme . A question naire was given to 100 patients and 95 matched but non-r and om controls before the programme , 1 month later , and at 3 and 12 months . The intervention group demonstrated improvements in knowledge , self-reported health behaviour and disability scores at 12 months , compared to the controls . No differences were reported in symptoms , compliance with therapy , pain perception , and locus of control [19627690] BACKGROUND Chronic knee pain is a major cause of disability in the elderly . Management guidelines recommend exercise and self-management interventions as effective treatments . The authors previously described a rehabilitation programme integrating exercise and self-management [ Enabling Self-management and Coping with Arthritic knee Pain through Exercise ( ESCAPE-knee pain ) ] that produced short-term improvements in pain and physical function , but sustaining these improvements is difficult . Moreover , the programme is untried in clinical environments , where it would ultimately be delivered . OBJECTIVES To establish the feasibility of ESCAPE-knee pain and compare its clinical effectiveness and costs with outpatient physiotherapy . DESIGN Pragmatic , r and omised controlled trial . SETTING Outpatient physiotherapy department and community centre . PARTICIPANTS Sixty-four people with chronic knee pain . INTERVENTIONS Outpatient physiotherapy compared with ESCAPE-knee pain . OUTCOMES The primary outcome was physical function assessed using the Western Ontario and McMaster Universities Osteoarthritis Index . Secondary outcomes included pain , objective functional performance , anxiety , depression , exercise-related health beliefs and healthcare utilisation . All outcomes were assessed at baseline and 12 months after completing the interventions ( primary endpoint ) . ANCOVA investigated between-group differences . RESULTS Both groups demonstrated similar improvements in clinical outcomes . Outpatient physiotherapy cost pound 130 per person and the healthcare utilisation costs of participants over 1 year were pound 583 . The ESCAPE-knee pain programme cost pound 64 per person and the healthcare utilisation costs of participants over 1 year were pound 320 . CONCLUSIONS ESCAPE-knee pain can be delivered as a community-based integrated rehabilitation programme for people with chronic knee pain . Both ESCAPE-knee pain and outpatient physiotherapy produced sustained physical and psychosocial benefits , but ESCAPE-knee pain cost less and was more cost-effective [16309929] OBJECTIVE To evaluate the effect of therapeutic education and functional readaptation ( TEFR ) on health-related quality of life ( HRQL ) in patients diagnosed with osteoarthritis on a waiting list for total knee replacement ( TKR ) . METHODS R and omized controlled trial of 9 months duration was conducted . One hundred consecutive out patients ( 71 females , mean age 71 years ( range 50 - 86 ) , mean disease duration 11.84+/-10.52 months ) were included . Patients were r and omized in two groups . The intervention group received TEFR added to conventional ( pharmacological ) treatment ( n=51 ) . The control group received conventional ( pharmacological ) treatment only ( n=49 ) . The main outcome variable was self-reported HRQL measured by the Spanish version of Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) . Secondary outcomes were general HRQL measured by Short Form Health Survey general question naire ( SF-36 ) , number of visits to general physicians and their cost . Assessment s were done at baseline and at 9 months . MAIN RESULTS Eighty patients completed the study . Significant improvement in the WOMAC function was found at 9 months in the TERF group with respect to the control group ( P=0.035 ) . Consumption of analgesics increased significantly in the TERF group compared with controls ( P=0.036 ) . Significant improvements in pain ( P=0.027 ) measured by WOMAC and in bodily pain ( P=0.043 ) and physical function ( P=0.031 ) , measured by SF-36 , were observed in the intervention group with respect to baseline . CONCLUSIONS The function dimension measured by WOMAC of patients who received both pharmacological treatment and TERF improved with respect to the control group receiving only pharmacological treatment . This suggests that a program of TEFR during the period on the waiting list for TKR may reduce the negative impact of this situation [20420960] OBJECTIVES To assess the effect of a group education programme on pain and function through knowledge acquisition and a home-based exercise programme . DESIGN A parallel r and omised single-blind clinical trial . PARTICIPANTS Fifty patients aged 65 years or over with knee osteoarthritis . INTERVENTIONS The study group ( n=25 ) was given a group education programme once a week for 4 weeks , followed by a self-executed home-based exercise programme . The controls ( n=25 ) were given a brief course in short-wave diathermy treatment . MAIN OUTCOME MEASURES Patients were assessed before the intervention , after the intervention ( 4 weeks ) and again 8 weeks later ( follow-up ) using the Western Ontario McMaster Osteoarthritis Index ( WOMAC ) , the repeated sit-to-st and test and the get-up- and -go test . RESULTS At 4 weeks , there was a significant improvement in both groups in all outcome variables except the WOMAC stiffness score ; for example , the WOMAC total score was reduced by a mean of 9.5 points [ 95 % confidence interval ( CI ) -12.3 to -6.7 ] . However , at follow-up , patients in the study group demonstrated continued improvement in the get-up- and -go test and the WOMAC total , pain and disability scores , but no such improvement was noted among the controls . This difference was significant ; for example , the difference in mean WOMAC total score between the groups was -9.0 points ( 95%CI -14.5 to -3.4 ) . CONCLUSION A simple group education programme for patients with knee osteoarthritis is associated with improved functional abilities and pain reduction . Further study is required to determine if this positive effect can be maintained over a longer period [1489766] We compared a cognitive-behavior modification and a traditional education intervention for adults with osteoarthritis ( OA ) . Forty OA patients were r and omly assigned to one of two groups : cognitive-behavior modification or didactic lectures . During ten weekly sessions , the cognitive-behavior group learned methods for coping with pain and the disabilities associated with OA . The traditional education group experienced a series of lectures from health care professionals . Prior to the interventions and following 2 , 6 , and 12 months , patients in both groups were evaluated with a general Quality of Well-being ( QWB ) scale , the Arthritis Impact Measurement Scales ( AIMS ) , the Beck Depression Inventory ( BDI ) , and other measures . Although there were some differences between the two groups at 2-month follow-up , by the end of 1 year , physical and psychological functioning did not differ significantly between the two groups . In comparison to baseline , both groups demonstrated initial changes on QWB , depression , and the pain component of the AIMS . Improvements in depression remained through the 1-year follow-up . Multiple regression analysis demonstrated that the mobility and physical activity aspects of the AIMS were significant long-term predictors of outcome ( 1 year ) for general quality -of-life measures . One-year outcomes for depression were significantly predicted from scores on social support and mobility measures from the AIMS . We conclude that cognitive-behavior modification and education produce similar effects on long-term physical and psychological functioning in OA patients [21041576] BACKGROUND Osteoarthritis is a leading cause of pain and disability , and self-management behaviors for osteoarthritis are underutilized . OBJECTIVE To examine the effectiveness of a telephone-based self-management intervention for hip or knee osteoarthritis in a primary care setting . DESIGN R and omized clinical trial with equal assignment to osteoarthritis self-management , health education ( attention control ) , and usual care control groups . ( Clinical Trials.gov registration number : NCT00288912 ) SETTING Primary care clinics in a Veterans Affairs Medical Center . PATIENTS 515 patients with symptomatic hip or knee osteoarthritis . INTERVENTION The osteoarthritis self-management intervention involved educational material s and 12 monthly telephone calls to support individualized goals and action plans . The health education intervention involved nonosteoarthritis educational material s and 12 monthly telephone calls related to general health screening topics . MEASUREMENTS The primary outcome was score on the Arthritis Impact Measurement Scales-2 pain subscale ( range , 0 to 10 ) . Pain was also assessed with a 10-cm visual analog scale . Measurements were collected at baseline and 12 months . RESULTS 461 participants ( 90 % ) completed the 12-month assessment . The mean Arthritis Impact Measurement Scales-2 pain score in the osteoarthritis self-management group was 0.4 point lower ( 95 % CI , -0.8 to 0.1 point ; P = 0.105 ) than in the usual care group and 0.6 point lower ( CI , -1.0 to -0.2 point ; P = 0.007 ) than in the health education group at 12 months . The mean visual analog scale pain score in the osteoarthritis self-management group was 1.1 points lower ( CI , -1.6 to -0.6 point ; P < 0.001 ) than in the usual care group and 1.0 point lower ( CI , -1.5 to -0.5 point ; P < 0.001 ) than in the health education group . Health care use did not differ across the groups . LIMITATION The study was conducted at 1 Veterans Affairs Medical Center , and the sample consisted primarily of men . CONCLUSION A telephone-based osteoarthritis self-management program produced moderate improvements in pain , particularly compared with a health education control group . PRIMARY FUNDING SOURCE U.S. Department of Veterans Affairs Health Services Research and Development Service [21726907] PURPOSE To evaluate the effectiveness of the Taipei Osteoarthritis Program ( TOAP ) for community elderly persons who suffer from knee OA . METHODS A quasi-experimental study was conducted between January 2008 and December 2008 . Two hundred and five community-dwelling individuals aged 67±10 years with knee OA were recruited from four districts in Taipei City and r and omized . By a clustered r and omization according to the districts , 114 participants were in the intervention group ( IG ) with a 4-week TOAP program and 91 participants were in the control group ( CG ) with routine care . The main outcome measures included health-related quality of life ( HRQOL ) and disability level , which were assessed by the Short Form-36 Taiwan Version ( T-SF36 ) and the Western Ontario McMaster Universities Arthritis Index Taiwan Version ( T-WOMAC ) , respectively , and were repeatedly measured at the baseline , post invention ( 4 weeks after baseline ) , and follow-up ( 8 weeks after baseline ) . RESULTS Subjects in the IG increased their changes of GH scores from baseline to post-intervention and follow-up , which were significantly more than those of subjects in the CG ( p=0.011 and 0.005 , respectively ) . Significant difference of changes was also found at follow-up for the mental component scale between the groups ( p=0.013 ) . There was no change in disability level . CONCLUSIONS The arthritis self-management program improved the psychological outcomes among the participants , but it had no significant effect on a self-reported disability level [22503223] Summary Combined training in pain and weight management in overweight and obese OA patients result ed in improved pain and other outcomes compared to either training alone . ABSTRACT Overweight and obese patients with osteoarthritis ( OA ) experience more OA pain and disability than patients who are not overweight . This study examined the long‐term efficacy of a combined pain coping skills training ( PCST ) and lifestyle behavioral weight management ( BWM ) intervention in overweight and obese OA patients . Patients ( n = 232 ) were r and omized to a 6‐month program of : 1 ) PCST + BWM ; 2 ) PCST‐only ; 3 ) BWM‐only ; or 4 ) st and ard care control . Assessment s of pain , physical disability ( Arthritis Impact Measurement Scales [ AIMS ] physical disability , stiffness , activity , and gait ) , psychological disability ( AIMS psychological disability , pain catastrophizing , arthritis self‐efficacy , weight self‐efficacy ) , and body weight were collected at 4 time points ( pretreatment , posttreatment , and 6 months and 12 months after the completion of treatment ) . Patients r and omized to PCST + BWM demonstrated significantly better treatment outcomes ( average of all 3 posttreatment values ) in terms of pain , physical disability , stiffness , activity , weight self‐efficacy , and weight when compared to the other 3 conditions ( Ps < 0.05 ) . PCST + BWM also did significantly better than at least one of the other conditions ( ie , PCST‐only , BWM‐only , or st and ard care ) in terms of psychological disability , pain catastrophizing , and arthritis self‐efficacy . Interventions teaching overweight and obese OA patients pain coping skills and weight management simultaneously may provide the more comprehensive long‐term benefits

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### Context: [17559610] AIM This paper is a report of a study to assess the effect of an adapted arthritis self-management programme with an added focus on exercise practice among osteoarthritic knee sufferers . BACKGROUND Osteoarthritis of the knee is a major source of loss of function in older people . Previous studies have found self-management programmes to be effective in increasing arthritis self-efficacy and in mastery of self-management practice . METHOD A r and omized control trial was carried out from December 2002 to May 2003 and 120 participants ( 65.9 % , including 67 in intervention group and 53 in control group ) completed the 16-week postintervention assessment s. Outcome measures included arthritis self-efficacy , use of self-management techniques , pain intensity and daily activity . FINDINGS At 16 weeks , there was a ' statistically ' significant improvement in the arthritis self-efficacy level ( P < or= 0.001 ) , in most of the self-management skills , i.e. use of cold and hot compresses , in two of three joint protective practice s ( P < or= 0.001 ; P = 0.01 ) , an increase in the duration of light exercise practice ( P < or= 0.001 ) , reduction of current arthritis pain ( P < or= 0.001 ) and in the ability to perform daily activities ( P < or= 0.001 ) among the intervention group but not for the control group ( P-range from 0.04 to 0.95 ) . One joint protective practice showed a statistically significant increase in both groups ( P < or= 0.001 ) . CONCLUSION Our findings add to evidence showing short-term beneficial effects of self-efficacy theory in education programmes . Self-efficacy theory has great potential for empowering sufferers of chronic conditions to live with their illness [2235871] Background Supporting self-management intends to improve life-style , which is beneficial for patients with mild osteoarthritis ( OA ) . We evaluated a nurse-based intervention on older OA patients ' self-management with the aim to assess its effects on mobility and functioning . Methods R and omized controlled trial of patients ( ≥ 65 years ) with mild hip or knee OA from nine family practice s in the Netherl and s. Intervention consisted of supporting patients ' self-management of OA symptoms using a practice -based nurse . Outcome measures were patients ' mobility , using the Timed Up and Go test ( TUG ) , and patient reported functioning , using an arthritis specific scale ( Dutch AIMS 2 SF ) . Results Fifty-one patients were r and omized to the intervention group and 53 to the control group . Patient-reported functioning improved on four scales in the intervention group compared to one scale in the control group . However , this result was not significant . Mobility improved in both groups , without a significant difference between the two groups . There were no differences between the groups regarding consultations with family physicians or physiotherapists , or medication use . Conclusion A nurse-based intervention on older OA patients ' self-management did not improve self-reported functioning , mobility or patients ' use of health care re sources [20156912] Objective To examine the prevalence of outcome reporting bias — the selection for publication of a subset of the original recorded outcome variables on the basis of the results — and its impact on Cochrane review s. Design A nine point classification system for missing outcome data in r and omised trials was developed and applied to the trials assessed in a large , unselected cohort of Cochrane systematic review s. Research ers who conducted the trials were contacted and the reason sought for the non-reporting of data . A sensitivity analysis was undertaken to assess the impact of outcome reporting bias on review s that included a single meta- analysis of the review primary outcome . Results More than half ( 157/283 ( 55 % ) ) the review s did not include full data for the review primary outcome of interest from all eligible trials . The median amount of review outcome data missing for any reason was 10 % , whereas 50 % or more of the potential data were missing in 70 ( 25 % ) review s. It was clear from the publications for 155 ( 6 % ) of the 2486 assessable trials that the research ers had measured and analysed the review primary outcome but did not report or only partially reported the results . For reports that did not mention the review primary outcome , our classification regarding the presence of outcome reporting bias was shown to have a sensitivity of 88 % ( 95 % CI 65 % to 100 % ) and specificity of 80 % ( 95 % CI 69 % to 90 % ) on the basis of responses from 62 trialists . A third of Cochrane review s ( 96/283 ( 34 % ) ) contained at least one trial with high suspicion of outcome reporting bias for the review primary outcome . In a sensitivity analysis undertaken for 81 review s with a single meta- analysis of the primary outcome of interest , the treatment effect estimate was reduced by 20 % or more in 19 ( 23 % ) . Of the 42 meta-analyses with a statistically significant result only , eight ( 19 % ) became non-significant after adjustment for outcome reporting bias and 11 ( 26 % ) would have overestimated the treatment effect by 20 % or more . Conclusions Outcome reporting bias is an under-recognised problem that affects the conclusions in a substantial proportion of Cochrane review s. Individuals conducting systematic review s need to address explicitly the issue of missing outcome data for their review to be considered a reliable source of evidence . Extra care is required during data extraction , review ers should identify when a trial reports that an outcome was measured but no results were reported or events observed , and contact with trialists should be encouraged [19486959] INTRODUCTION To evaluate the efficacy of a self-management support program including a 6 week self-management course , individualised phone support and goal setting in osteoarthritis patients on a waiting list for arthroplasty surgery . METHOD R and omised controlled trial of 152 public hospital out patients awaiting hip or knee replacement surgery who were not classified as requiring urgent surgery . Participants were r and omised to a self-management program or to usual care . The primary outcome was change in the Health Education Intervention Question naire ( HeiQ ) from r and omisation to 6 month follow-up . Quality of life and depressive symptoms were also measured . Changes in pain and function were assessed using the Western Ontario and McMaster Universities ( WOMAC ) Arthritis Index . RESULTS At 6 month follow-up , health-directed behaviour was significantly greater in the intervention [ mean 4.29 , 95 % confidence interval ( CI ) 3.99 - 4.58 ] than the control ( mean 3.81 , 95 % CI 3.52 - 4.09 ; P=0.017 ) . There was also a significant effect on skill and technique acquisition for the intervention ( mean 4.37 , 95 % CI 4.19 - 4.55 ) in comparison to control ( mean 4.11 , 95 % CI 3.93 - 4.29 ; P=0.036 ) . There was no significant effect of the intervention on the remaining HeiQ subscales , WOMAC pain or disability , quality of life or depressive symptoms . DISCUSSION The arthritis self-management program improved health-directed behaviours , skill acquisition and stiffness in patients on a joint replacement waiting list , although the observed effects were of modest size ( Cohen 's d between 0.36 and 0.42 ) . There was no significant effect on pain , function or quality of life in the short term . Self-management programs can assist in maintaining health behaviours ( particularly walking ) in this patient group . Further research is needed to assess their impact on quality of life and over longer periods [1525193] Background This study examined the impact of a home-based self-management intervention for housebound older adults with arthritis on the adoption of health behaviors . The moderating role of socio-demographic , psychological , and physical characteristics in the process of behavior change was also investigated . Methods Participants were 113 older adult women ( n = 102 ) and men ( n = 11 ) with osteoarthritis ( OA ) or rheumatoid arthritis ( RA ) who were r and omly assigned to experimental ( n = 68 ) or wait list control ( n = 45 ) groups . Participants were interviewed using st and ardized question naires at baseline , pre-intervention , and post-intervention . Results Adjusted multilevel modeling analyses indicated that from pre to post intervention , experimental participants significantly increased their weekly frequency of exercise and relaxation activities . Socioeconomic status and depression played a moderating role in this change for exercise with larger effects occurring among more privileged , non-depressed participants . Conclusion We conclude that a self-management intervention can successfully improve involvement in exercise and relaxation among housebound older adults with arthritis [14731152] Osteoarthritis ( OA ) is a common and often disabling condition that predominately affects older adults . It is the commonest cause of locomotor disability and forms a major element of the workload in primary care . Previous studies suggest that there are both deficits in the knowledge patients have about their disease and extensive ' unmet ' information needs . This paper explores the patients ' perspective on the meaning and significance of living with arthritis , identified through quantitative and qualitative approaches undertaken during a trial that evaluated the effectiveness of a primary care-based patient education programme . This paper draws on qualitative and quantitative data from : the baseline interview ( knowledge of arthritis , satisfaction with services and support received in primary care ) ; patient diaries ( individual goals and reflections on treatment ) ; and group teaching sessions ( themes describing the patient 's experience ) . The different data sources were interrogated for common and divergent themes . One hundred and ninety-four participants were identified and 170 completed baseline interviews . Participants were predominantly female ( 73 % ) , with a mean age of 63 and arthritis of long-st and ing ; 55 % reported that they had had it for 5 years or more . Use of primary care services was high , with 41 % consulting their GP in the 2 weeks before interview . Levels of information were low , with less than 25 % receiving support/advice about the disease , pain management or its impact upon daily life . Set against negative perceptions of the quality of services , patients ' personal priorities were for improved pain management and enhanced mobility/functional ability . The combined quantitative and qualitative data provide insight into the patients ' perspective on the causes and impact of knee OA , individual goals desired from treatment and the quality of care . There is consistent evidence of unmet needs for information and support and the priority placed by patients on finding strategies to cope with OA and maintaining independence . Even within a tightly defined study sample participating in the intervention , a diversity of experience and goals were revealed , which highlights the importance of taking account of context ual factors and individual differences when evaluating complex interventions [2907317] Background Non-pharmacological treatment ( NPT ) is a useful treatment option in the management of hip or knee osteoarthritis . To our knowledge however , no studies have investigated the effect of NPT in patients with generalized osteoarthritis ( GOA ) . The primary aim of this study is to compare the effectiveness of two currently existing health care programs with different intensity and mode of delivery on daily functioning in patients with GOA . The secondary objective is to compare the cost-effectiveness of both interventions . Methods / Design In this r and omized , single blind , clinical trial with active controls , we aim to include 170 patients with GOA . The experimental intervention consist of six self-management group sessions provided by a multi-disciplinary team ( occupational therapist , physiotherapist , dietician and specialized nurse ) . The active control group consists of two group sessions and four sessions by telephone , provided by a specialized nurse and physiotherapist . Both therapies last six weeks . Main study outcome is daily functioning during the first year after the treatment , assessed on the Health Assessment Question naire . Secondary outcomes are health related quality of life , specific complaints , fatigue , and costs . Illness cognitions , global perceived effect and self-efficacy , will also be assessed for a responder analysis . Outcome assessment s are performed directly after the intervention , after 26 weeks and after 52 weeks . Discussion This article describes the design of a r and omized , single blind , clinical trial with a one year follow up to compare the costs and effectiveness of two non-pharmacological interventions with different modes of delivery for patients with GOA.Trial registration Dutch Trial Register [2987970] Background Osteoarthritis ( OA ) is a degenerative disease , considered to be one of the major public health problems . Research suggests that patient education is feasible and valuable for achieving improvements in quality of life , in function , well-being and improved coping . Since 1994 , Primary Health Care in Malmö has used a patient education programme directed towards OA . The aim of this study was to evaluate the effects of this education programme for patients with OA in primary health care in terms of self-efficacy , function and self-perceived health . Method The study was a single-blind , r and omized controlled trial ( RCT ) in which the EuroQol-5D and Arthritis self-efficacy scale were used to measure self-perceived health and self-efficacy and function was measured with Grip Ability Test for the upper extremity and five different functional tests for the lower extremity . Results We found differences between the intervention group and the control group , comparing the results at baseline and after 6 months in EuroQol-5D ( p < 0.001 ) and in st and ing one leg eyes closed ( p = 0.02 ) in favour of the intervention group . No other differences between the groups were found . Conclusion This study has shown that patient education for patients with osteoarthritis is feasible in a primary health care setting and can improve self-perceived health as well as function in some degree , but not self-efficacy . Further research to investigate the effect of exercise performance on function , as well as self-efficacy is warranted . Trial registration The trial is registered with Clinical Trials.gov . Registration number : [18821646] OBJECTIVE To examine effects of activity strategy training ( AST ) , a structured rehabilitation program taught by occupational therapists and design ed to teach adaptive strategies for symptom control and engagement in physical activity ( PA ) . METHODS A r and omized controlled pilot trial was conducted at 4 sites ( 3 senior housing facilities and 1 senior center ) in southeastern , lower Michigan . Fifty-four older adults with hip or knee osteoarthritis ( mean + /- SD age 75.3+/-7.1 years ) participated . At each site , older adults were r and omly assigned to 1 of 2 programs : exercise plus AST ( Ex + AST ) or exercise plus health education ( Ex + Ed ) . The programs involved 8 sessions over 4 weeks with 2 followup sessions over a 6-month period , and were conducted concurrently within each site . Pain , total PA and PA intensity ( measured objective ly by actigraphy and subjectively by the Community Healthy Activities Model Program for Seniors question naire ) , arthritis self-efficacy , and physical function were assessed at baseline and posttest . RESULTS At posttest , participants who received Ex + AST had significantly higher levels of objective peak PA ( P=0.02 ) compared with participants who received Ex + Ed . Although not statistically significant , participants in Ex + AST tended to have larger pain decreases , increased total objective and subjective PA , and increased physical function . No effects were found for arthritis self-efficacy . CONCLUSION Although participants were involved in identical exercise programs , participants who received AST tended to have larger increases in PA at posttest compared with participants who received health education . Future studies will be needed to examine larger sample s and long-term effects of AST [11838857] OBJECTIVE Studies have suggested that the Arthritis Self-Management Program ( ASMP ) course is effective at reducing arthritis pain and health care costs in volunteer participants . There have been no reports of trials of the ASMP in the context of primary care physicians ' practice s , where the potential for spreading the program may be greatest . We conducted a r and omized controlled trial of the ASMP course in a large primary care physician network . METHODS Patients with osteoarthritis , rheumatoid arthritis , or fibromyalgia were recruited for the study . Subjects in the intervention practice s received the 6 week course and those in the control practice s received only the ASMP book , without course . Disability , pain , self-efficacy , mental health , and satisfaction were measured using vali date d instruments at baseline and at 4 months . RESULTS One hundred thirteen patients were recruited for the ASMP course ( intervention ) and completed baseline and 4 month followup question naires . Eighty-four percent completed at least 4 of 6 classes . Seventy-four patients received the ASMP manual ( controls ) and completed both question naires . Patients in the intervention and control groups had similar baseline pain ( p = 0.94 ) , self-efficacy to control pain ( p = 0.90 ) , mental health ( p = 0.10 ) , and vitality scores ( p = 0.21 ) , but those in the intervention arm had slightly less disability ( p = 0.04 ) . At 4 months , there was no significant improvement from baseline in any endpoint and no difference between patients in the intervention and control groups ( all p > 0.2 ) . Patient satisfaction with arthritis care and outcomes was no different for intervention and control patients ( all p > 0.3 ) . All types of health care re source use were similar at baseline and followup for both intervention and control groups ( all p > 0.2 ) . CONCLUSION While the ASMP course has been found to be effective in other patient groups , there were no significant clinical benefits noted at 4 months in patients recruited from primary care practice [1693560] Background Patient education and self-management programs are offered in many countries to people with chronic conditions such as osteoarthritis ( OA ) . The most well-known is the disease-specific Stanford Arthritis Self-Management Program ( ASMP ) . While Australian and international clinical guidelines promote the concept of self-management for OA , there is currently little evidence to support the use of the ASMP . Several meta-analyses have reported that arthritis self-management programs had minimal or no effect on reducing pain and disability . However , previous studies have had method ological shortcomings including the use of outcome measures which do not accurately reflect program goals . Additionally , limited cost-effectiveness analyses have been undertaken and the cost-utility of the program has not been explored . Methods / design This study is a r and omised controlled trial to determine the efficacy ( in terms of Health-Related Quality of Life and self-management skills ) and cost-utility of a 6-week group-based Stanford ASMP for people with hip or knee OA.Six hundred participants referred to an orthopaedic surgeon or rheumatologist for hip or knee OA will be recruited from outpatient clinics at 2 public hospitals and community-based private practice s within 2 private hospital setting s in Victoria , Australia . Participants must be 18 years or over , fluent in English and able to attend ASMP sessions . Exclusion criteria include cognitive dysfunction , previous participation in self-management programs and placement on a waiting list for joint replacement surgery or scheduled joint replacement . Eligible , consenting participants will be r and omised to an intervention group ( who receive the ASMP and an arthritis self-management book ) or a control group ( who receive the book only ) . Follow-up will be at 6 weeks , 3 months and 12 months using st and ardised self-report measures . The primary outcome is Health-Related Quality of Life at 12 months , measured using the Assessment of Quality of Life instrument . Secondary outcome measures include the Health Education Impact Question naire , Western Ontario and McMaster Universities Osteoarthritis Index ( pain subscale and total scores ) , Kessler Psychological Distress Scale and the Hip and Knee Multi-Attribute Priority Tool . Cost-utility analyses will be undertaken using administrative records and self-report data . A subgroup of 100 participants will undergo qualitative interviews to explore the broader potential impacts of the ASMP . Discussion Using an innovative design combining both quantitative and qualitative components , this project will provide high quality data to facilitate evidence -based recommendations regarding the ASMP [10413387] OBJECTIVES This study evaluated the effectiveness ( changes in health behaviors , health status , and health service utilization ) of a self-management program for chronic disease design ed for use with a heterogeneous group of chronic disease patients . It also explored the differential effectiveness of the intervention for subjects with specific diseases and comorbidities . METHODS The study was a six-month r and omized , controlled trial at community-based sites comparing treatment subjects with wait-list control subjects . Participants were 952 patients 40 years of age or older with a physician-confirmed diagnosis of heart disease , lung disease , stroke , or arthritis . Health behaviors , health status , and health service utilization , as determined by mailed , self-administered question naires , were measured . RESULTS Treatment subjects , when compared with control subjects , demonstrated improvements at 6 months in weekly minutes of exercise , frequency of cognitive symptom management , communication with physicians , self-reported health , health distress , fatigue , disability , and social/role activities limitations . They also had fewer hospitalizations and days in the hospital . No differences were found in pain/physical discomfort , shortness of breath , or psychological well-being . CONCLUSIONS An intervention design ed specifically to meet the needs of a heterogeneous group of chronic disease patients , including those with comorbid conditions , was feasible and beneficial beyond usual care in terms of improved health behaviors and health status . It also result ed in fewer hospitalizations and days of hospitalization [21218677] OBJECTIVE We examined whether tailored activity pacing intervention was more effective at reducing pain and fatigue than general activity pacing intervention . METHOD Adults with knee or hip osteoarthritis ( N = 32 ) stratified by age and gender were r and omized to receive either tailored or general pacing intervention . Participants wore an accelerometer for 5 days that measured physical activity and allowed for repeated symptom assessment . Physical activity and symptom data were used to tailor activity pacing instruction . Outcomes at 10-week follow-up were pain ( Western Ontario and McMaster Universities Osteoarthritis Index ) and fatigue ( Brief Fatigue Inventory ) . RESULTS Compared with general intervention , the tailored group had less fatigue interference ( p = .02 ) and trended toward decreased fatigue severity ( p = .09 ) at 10-wk follow-up . No group differences were found in pain reduction . CONCLUSION Tailoring instruction on the basis of recent symptoms and physical activity may be a more effective symptom management approach than general instruction given the positive effects on fatigue [10527090] OBJECTIVE To evaluate the effects of isokinetic exercise versus a program of patient education on pain and function in older persons with knee osteoarthritis . DESIGN A r and omized , comparative clinical trial , with interventions lasting 8 weeks and evaluations of 12 weeks . SETTING An outpatient Veterans Affairs Medical Center clinic and an affiliated university hospital . PATIENTS One hundred thirteen men and women between 50 and 80 years old with diagnosed osteoarthritis of the knee ; 98 completed the entire assigned treatment . INTERVENTION Patients received either a regimen of isokinetic exercise of the quadriceps muscle three times weekly over 8 weeks or a series of 4 discussion s and lectures led by health care professionals . MAIN OUTCOME MEASURES Variables studied for change were isokinetic and isometric quadriceps strength , pain and function determined by categorical and visual analog scales , and overall status using physician and patient global evaluations by the Arthritis Impact Scale , version 2 , Western Ontario McMaster 's Arthritis Index , and Medical Outcome Study Short Form 36 . RESULTS Both treatment groups showed significant strength gains ( p < .05 ) , which occurred over a wider velocity spectrum for the exercise group . Exercised patients also had improved pain scores for more of the variables measured than those receiving education . Both groups had positive functional outcomes and slightly improved measures of overall status . CONCLUSIONS Isokinetic exercise is an effective and well-tolerated treatment for knee osteoarthritis , but a much less costly education program also showed some benefits [15075418] PURPOSE This study assessed the impact of a low cost , multicomponent physical activity intervention for older adults with lower extremity osteoarthritis . DESIGN AND METHODS A r and omized controlled trial compared the effects of a facility-based multiple-component training program followed by home-based adherence ( n = 80 ) to a wait list control group ( n = 70 ) . Assessment s were conducted at baseline and at 2 and 6 months following r and omization . The training program consisted of range of motion , resistance training , aerobic walking , and education-group problem solving regarding self-efficacy for exercise and exercise adherence . All training group participants developed individualized plans for posttraining adherence . RESULTS Relative to the persons in the control group , individuals who participated in the exercise program experienced a statistically significant improvement in exercise efficacy , a 48.5 % increase in exercise adherence , and a 13.3 % increase in 6-min distance walk that were accompanied by significant decreases in lower extremity stiffness at 2 and 6 months . Program participants also experienced a significant decrease in lower extremity pain and a borderline significant improvement in efficacy to adhere to exercise over time at 6 months ( p = .052 ) . In contrast , persons in the control group deteriorated over time on the efficacy and adherence measures and showed no change on the other measures . No adverse health effects were encountered . IMPLICATION S These benefits indicate that this low-cost intervention may hold great promise as one of a growing number of public health intervention strategies for older adults in the United States with osteoarthritis [15611487] Context Previous studies of acupuncture for osteoarthritis have had conflicting results . This may have occurred because most studies have included small sample s , a limited number of treatment sessions , or other limitations . Contribution This r and omized , controlled trial compared 24 acupuncture sessions over 26 weeks with sham acupuncture or arthritis education in 570 patients with osteoarthritis of the knee . Acupuncture led to greater improvements in function but not pain after 8 weeks and in both pain and function after 26 weeks . No adverse effects were associated with acupuncture . Caution s Many participants dropped out of the study , so readers should interpret the findings at 26 weeks with caution . The Editors Osteoarthritis is the most common form of arthritis and is a major cause of morbidity , limitation of activity , and health care utilization , especially in elderly patients ( 1 , 2 ) . Pain and functional limitation are the primary clinical manifestations of osteoarthritis of the knee . Current recommendations for managing osteoarthritis , including guidelines published by the American College of Rheumatology ( 3 ) and European League of Associations of Rheumatology ( 4 ) , focus on relieving pain and stiffness and maintaining or improving physical function as important goals of therapy . No curative therapies exist for osteoarthritis ; thus , both pharmacologic and nonpharmacologic management focus on controlling pain and reducing functional limitation ( 5 ) . Nonpharmacologic therapy , which includes patient education , social support , physical and occupational therapy , aerobic and resistive exercises , and weight loss , is the cornerstone of a multidisciplinary approach to osteoarthritis patient management ( 3 ) . Pharmacologic therapies include nonopioid analgesics ( such as acetaminophen ) , nonsteroidal anti-inflammatory drugs ( NSAIDs ) ( including cyclooxygenase-2 [ COX-2 ] enzyme selective inhibitors ) , topical analgesics ( capsaicin cream ) , opioid analgesics , and intra-articular steroid and hyaluronate injections . Often , these agents are used in combination for additive analgesic efficacy ( 6 ) . Pharmacologic management of osteoarthritis is often ineffective , and agents such as NSAIDs may cause unwanted and dangerous side effects ( 7 , 8) . Complementary and alternative medicine is another approach to treating osteoarthritis ( 9 - 12 ) , particularly in Asian societies ( 13 ) . Many U.S. patients with osteoarthritis also use complementary and alternative medical therapies ( 14 ) . A systematic review of acupuncture and knee osteoarthritis ( 15 ) identified 7 small r and omized , controlled trials published in English . Within the method ologic limitations of the studies , the evidence suggested that acupuncture seemed to alleviate knee pain and function compared with sham acupuncture controls , although 2 trials comparing acupuncture with an active , nonpharmacologic treatment ( physical therapy ) did not indicate such an effect ( 16 , 17 ) . Before conducting our large-scale trial , we completed both a pilot study ( 18 ) and a r and omized , single-blind trial ( 19 ) of the effect of acupuncture on osteoarthritis of the knee . Participants in the uncontrolled pilot study ( n= 12 ) showed statistically significant improvement in both self-reported pain and physical function , as well as performance measures of physical function after 8 weeks of acupuncture treatment and at 12-week follow-up as compared with their baseline ( 18 ) . In our larger r and omized , single-blind trial ( n= 73 ) , which examined the benefit of acupuncture added to st and ard management with NSAIDs , the acupuncture treatment group experienced statistically significant improvements in self-reported pain and disability scores compared with a st and ard-care control group as late as 4 weeks after the end of treatment ( 19 ) . However , this effect diminished within 18 weeks ( 26 weeks after the beginning of the trial ) after the final acupuncture treatment . Together , however , the previously conducted trials ( both our preliminary studies [ 18 , 19 ] and those referenced in the systematic review [ 15 ] ) have 3 method ologic limitations : lack of credible controls for the placebo effect , inadequate assessment of long-term treatment benefits , and insufficient sample sizes . We tested the hypothesis that an 8-week intensive acupuncture treatment regimen , followed by an 18-week tapering regimen , reduces pain and improves function among patients with knee osteoarthritis as compared with both sham acupuncture and education control groups . Methods Patient Recruitment We recruited patients for this multisite , placebo-controlled trial from March 2000 through December 2003 , primarily through print and radio advertisements . The 3 sites were the Integrative Medicine Clinic of the University of Maryl and School of Medicine , Baltimore , Maryl and ; the Innovative Medical Research Center ( a private research firm ) , Towson , Maryl and ; and the Hospital for Special Surgery , New York City , New York . The institutional review boards of the 3 sites approved the study . We determined the sample size ( n= 570 ) by a power analysis based on our r and omized pilot study ( 19 ) , adjusted by the estimated decrease in effect size result ing from the inclusion of a sham acupuncture group design ed to control for placebo effects . Patients met the following inclusion criteria : age 50 years or older , a diagnosis of osteoarthritis of the knee , radiographic evidence of at least 1 osteophyte at the tibiofemoral joint ( KellgrenLawrence grade 2 ) , moderate or greater clinical ly significant knee pain on most days during the past month , and willingness to be r and omly assigned . Exclusion criteria were the presence of serious medical conditions that precluded participation in study , bleeding disorders that might contraindicate acupuncture , intra-articular corticosteroid or hyaluronate injections ( as well as any knee surgeries or concomitant use of topical capsaicin cream ) during the past 6 months , previous experience with acupuncture , or any planned events ( including total knee replacement ) that would interfere with participation in the study during the following 26 weeks . After a brief telephone screening , patients were scheduled to visit 1 of the 3 participating sites to sign an informed consent statement and undergo a brief rheumatologic examination ( including radiographic examination of affected knees ) by a physician or a nurse practitioner . Because the education course was a group activity , patients were recruited until a cohort of 12 to 21 patients was formed , at which point each cohort at each site was r and omly assigned to 1 of 3 groups by a computer-generated process using r and omly selected blocks of 3 , 6 , and 9 . We assured allocation concealment by using disguised letter codes that were generated and sent to the site coordinators by a central statistical core . We used this procedure to ensure that approximately equal numbers of participants were in each treatment group across the course of the study , to ensure that each cohort would have participants assigned to all 3 treatment groups , and to make the breaking of the group assignment process more difficult . The research assistants who collected assessment s from participants , the participants themselves ( in the true acupuncture and sham acupuncture groups ) , and the statistician were blinded to group assignment . Assessment s were conducted at baseline and 4 , 8 , 14 , and 26 weeks after r and omization . Study Interventions We developed and modified the acupuncture treatment and sham control protocol s from previously reported and vali date d procedures ( 18 - 21 ) . During the trial , 7 acupuncturists were used : 3 at the Integrative Medicine Clinic , 3 at the Innovative Medical Research Center , and 1 at the Hospital for Special Surgery . In general , acupuncturists were assigned to the same participants throughout the 26-week treatment schedule , except for vacation conflicts and staff turnover , and provided approximately the same proportions of true versus sham procedures . All acupuncturists were state-licensed and had at least 2 years of clinical experience . The study 's principal acupuncturist trained and supervised the acupuncturists in performing true or sham procedures and avoiding interactions that could inadvertently communicate group assignment . True Acupuncture The true acupuncture ( experimental ) group underwent 26 weeks of gradually tapering treatment according to the following schedule : 8 weeks of 2 treatments per week followed by 2 weeks of 1 treatment per week , 4 weeks of 1 treatment every other week , and 12 weeks of 1 treatment per month . We based the acupuncture point selection s on Traditional Chinese Medicine meridian theory to treat knee joint pain , known as the Bi syndrome . These points consisted of 5 local points ( Yanglinquan [ gall bladder meridian point 34 ] , Yinlinquan [ spleen meridian point 9 ] , Zhusanli [ stomach meridian point 36 ] , Dubi [ stomach meridian point 35 ] , and extra point Xiyan ) and 4 distal points ( Kunlun [ urinarybladder , meridian point 60 ] , Xuanzhong [ gall bladder meridian point 39 ] , Sanyinjiao [ spleen meridian point 6 ] , and Taixi [ kidney meridian point 3 ] ) on meridians that traverse the area of pain ( 22 , 23 ) . The same points were treated for each affected leg . If both knees were affected , 9 needles were inserted in each leg . ( The outcome measures were not specifically targeted to whether the patient had osteoarthritis in 1 or both knees , and we observed no differential effects on the basis of the number of knees treated . ) The acupuncturists inserted 1.5-inch ( for local points ) and 1-inch ( for distal points ) 32-gauge ( 0.25-mm diameter ) acupuncture needles to a conventional depth of approximately 0.3 to 1.0 inch , depending on point location . All participants in the treatment group achieved the De-Qi sensation , a local sensation of heaviness , numbness , soreness , or paresthesia that accompanies the insertion and manipulation of needles during acupuncture , at these 9 points . Acupuncturists applied electrical [20177766] The purpose of this study was to assess the relative effects of coping self-efficacy and catastrophizing on physical functioning . Over a 9-month period , study ing changes in self-efficacy as possible mediator between catastrophizing changes and physical functioning changes might provide evidence for the most promising treatment target . Data came from a r and omized , longitudinal controlled trial comparing exercise , self-management and the two combined to treat 254 individuals with early knee osteoarthritis . A secondary analysis using a bootstrapped linear mixed-effects mediational model produced estimates of both the direct and indirect effects . Results indicated that self-efficacy partially mediated the effect between catastrophizing and physical functioning suggesting that self-efficacy was the more direct treatment target compared to catastrophizing . Treatments targeting both self-efficacy and catastrophizing may have greater impact on physical functioning compared to treatments that focus on only one [8702449] OBJECTIVE The effects of treatment counseling or symptom monitoring telephone intervention strategies on the health outcomes of patients with rheumatoid arthritis ( RA ) or osteoarthritis ( OA ) , compared with usual care , were assessed . METHODS A 3-group , r and omized , controlled 9-month trial was conducted incorporating 405 patients with RA or OA and using the Arthritis Impact Measurement Scales ( AIMS 2 ) as the outcome measure . RESULTS Analyses of covariance showed that the AIMS 2 total health status of the treatment counseling group ( effect size = 33 , P < 0.01 ) , but not the symptom monitoring group ( effect size = 0.21 , P = 0.10 ) , was significantly improved , compared with usual care , for both RA and OA patients . The specific types of benefits differed significantly between RA and OA patients . The mean number of medical visits by OA patients in the treatment counseling group was also significantly reduced ( P < 0.01 ) . CONCLUSION Telephone contact using the treatment counseling strategy produced significant , but different , health status benefits for RA and OA patients . The symptom monitoring strategy produced modest benefits [2749163] Objective To assess the cost effectiveness of a self management programme plus education booklet for arthritis in primary care . Design Cost effectiveness and cost utility analysis from health and social care and societal perspectives alongside a r and omised controlled trial . Setting 74 general practice s in the United Kingdom . Participants 812 patients aged 50 or more with osteoarthritis of the hips or knees , or both , and pain or disability , or both . Interventions R and omisation to either six sessions of an arthritis self management programme plus an education booklet ( intervention group ) or the education booklet alone ( st and ard care control group ) . Main outcome measures Total health and social care costs and total societal costs at 12 months ; cost effectiveness ( incremental cost effectiveness ratios and cost effectiveness acceptability curves ) on basis of quality of life ( SF-36 , primary outcome measure ) , EuroQol visual analogue scale , and quality adjusted life years ( QALYs ) . Results At 12 months health and social care costs in the intervention group were £ 101 higher ( 95 % confidence interval £ 3 to £ 176 ) than those in the control group because the additional costs of the arthritis self management programme did not seem to be fully offset by savings elsewhere . There were no significant differences in societal costs ( which were up to 13 times the size of health and social care costs ) or any of the outcomes . From the health and social care perspective the intervention was dominated by the control on the basis of QALYs ( which were non-significantly lower in the intervention group ) and had incremental cost effectiveness ratios between £ 279 and £ 13 473 for the other outcomes . From the societal perspective the intervention seemed superior to the control owing to non-significantly lower costs and non-significantly better outcomes on all measures except QALYs . Probabilities of the arthritis self management programme ’s cost effectiveness ranged between 12 % and 97 % ( for thresholds ranging £ 0 to £ 1000 ) based on one point improvements in SF-36 outcomes , but the clinical significance of this is debatable . Probabilities of cost effectiveness on the basis of the visual analogue scale and QALYs were low . Conclusions Cost effectiveness of an arthritis self management programme is not suggested on the basis of current National Institute for Health and Clinical Excellence cost perspectives and QALY thresholds . The probability of cost effectiveness is greater when broader costs and other quality of life outcomes are considered . These results suggest that the cost effectiveness of the Department of Health ’s expert patients programme can not be assumed across all clinical conditions and that further rigorous evaluations for other conditions may be needed . Trial registration Current Controlled Trials IS RCT N79115352 [15006216] We conducted a pilot study of a nurse-run telephone self-management programme for elderly people with osteoarthritis ( OA ) . Thirty-two subjects , aged 60 years or more , with a diagnosis of OA were recruited from two hospital rheumatology clinics and were r and omized to a control or intervention group . The intervention group received six weekly mailings of OA health education modules , a relaxation audio-tape and six weekly 45 min follow-up telephone self-management sessions . There was a 100 % compliance rate in the intervention group , and all subjects completed baseline and three-month interviews ; one subject in each group was lost to six-month follow-up . There were no significant differences in self-management between the control and intervention groups . However , at three months there were improvements in the intervention group ( relative to baseline ) on some outcome measures . The results suggest that the telephone may be a useful tool for reinforcing health-promoting activities for patients [21493910] Background and Purpose — The benefits of chronic disease self-management programs for stroke survivors are uncertain because individuals with severe impairments have been excluded from previous research . We undertook a phase II r and omized controlled trial to determine whether a self-management program design ed for survivors ( SSMP ; 8 weeks ) was safe and feasible compared to st and ard care ( control ) or a generic self-management program ( generic ; 6 weeks ) . Methods — Stroke survivors were recruited from 7 South Australian hospitals via a letter or indirectly ( eg , newspapers ) . Eligible participants were r and omized at a 1:1:1 ratio of 50 per group . Primary outcomes were recruitment , participation , and participant safety . Secondary outcomes were positive and active engagement in life using the Health Education Impact Question naire and characteristics of quality of life and mood at 6 months from program completion . Results — Of 315 people screened , 149 were eligible and 143 were r and omized ( 48 SSMP , 47 generic , 48 control ) ; mean age was 69 years ( SD , 11 ) and 59 % were female . Demographic features were similar between groups and 41 % had severe cognitive impairment ; 57 % accessed the interventions , with 52 % SSMP and 38 % generic completing > 50 % of sessions ( P=0.18 ) . Thirty-two participants reported adverse events ( 7 control , 12 generic , 13 SSMP ; P=0.3 ; 34 % severe ) ; however , none was attributable to the interventions . Potential benefits for improved mood were found . Conclusions — SSMP was safe and feasible . Benefits of the stroke-specific program over the generic program included greater participation and completion rates . An efficacy trial is warranted given the forecast growth in the stroke population and improved survival trends [3433311] Background Osteoarthritis ( OA ) of the hip and knee are among the most common chronic conditions , result ing in substantial pain and functional limitations . Adequate management of OA requires a combination of medical and behavioral strategies . However , some recommended therapies are under-utilized in clinical setting s , and the majority of patients with hip and knee OA are overweight and physically inactive . Consequently , interventions at the provider-level and patient-level both have potential for improving outcomes . This manuscript describes two ongoing r and omized clinical trials being conducted in two different health care systems , examining patient-based and provider-based interventions for managing hip and knee OA in primary care . Methods / Design One study is being conducted within the Department of Veterans Affairs ( VA ) health care system and will compare a Combined Patient and Provider intervention relative to usual care among n = 300 patients ( 10 from each of 30 primary care providers ) . Another study is being conducted within the Duke Primary Care Research Consortium and will compare Patient Only , Provider Only , and Combined ( Patient + Provider ) interventions relative to usual care among n = 560 patients across 10 clinics . Participants in these studies have clinical and / or radiographic evidence of hip or knee osteoarthritis , are overweight , and do not meet current physical activity guidelines . The 12-month , telephone-based patient intervention focuses on physical activity , weight management , and cognitive behavioral pain management . The provider intervention involves provision of patient-specific recommendations for care ( e.g. , referral to physical therapy , knee brace , joint injection ) , based on evidence -based guidelines . Outcomes are collected at baseline , 6-months , and 12-months . The primary outcome is the Western Ontario and McMasters Universities Osteoarthritis Index ( self-reported pain , stiffness , and function ) , and secondary outcomes are the Short Physical Performance Test Protocol ( objective physical function ) and the Patient Health Question naire-8 ( depressive symptoms ) . Cost effectiveness of the interventions will also be assessed . Discussion Results of these two studies will further our underst and ing of the most effective strategies for improving hip and knee OA outcomes in primary care setting s . Trial registration NCT01130740 ( VA ) ; NCT 01435109 ( NIH [3392814] Introduction Our aim in the present study was to determine whether a disease-specific self-management program for primary care patients with osteoarthritis ( OA ) of the knee ( the Osteoarthritis of the Knee Self-Management Program ( OAK ) ) implemented by health care professionals would achieve and maintain clinical ly meaningful improvements in health-related outcomes compared with a control group . Methods Medical practitioners referred 146 primary care patients with OA of the knee . Volunteers with coexistent inflammatory joint disease or serious comorbidities were excluded . R and omisation was to either a control group or the OAK group . The OAK group completed a 6-week self-management program . The control group had a 6-month waiting period before entering the OAK program . Assessment s were taken at baseline , 8 weeks and 6 months . The primary outcomes were the results measured using the Western Ontario and McMaster Universities Arthritis Index ( WOMAC ) Pain and Function subscales on the Short Form 36 version 1 question naire ( SF-36 ) Secondary outcomes were Visual Analogue Scale ( VAS ) pain , Timed Up & Go Test ( TUG ) , knee range of motion and quadriceps and hamstring strength-isometric contraction . Responses to treatment ( responders ) and minimal clinical ly important improvements ( MCIIs ) were determined . Results In the OAK group , VAS pain improved from baseline to week 8 from mean ( SEM ) 5.21 ( 0.30 ) to 3.65 ( 0.29 ) ( P ≤ 0.001 ) . During this period , improvements in the OAK group compared with the control group and responses to treatment were demonstrated according to the following outcomes : WOMAC Pain , Physical Function and Total dimensions , as well as SF-36 Physical Function , Role Physical , Body Pain , Vitality and Social Functioning domains . In addition , from baseline to week 8 , the proportion of MCIIs was greater among the OAK group than the control group for all outcomes . For the period between baseline and month 6 , WOMAC Pain , Physical Function and Total dimensions significantly improved in the OAK group compared to the control group , as did the SF-36 Physical Function , Role Physical , Body Pain , Vitality and Social Functioning domains , as well as hamstring strength in both legs . During the same period , the TUG Test , range of motion extension and left-knee flexion improved compared with the control group , although these improvements had little clinical relevance . Conclusions We recorded statistically significant improvements compared with a control group with regard to pain , quality of life and function for participants in the OAK program on the basis of WOMAC and SF-36 measures taken 8 weeks and 6 months from baseline [2850876] Abstract Background Self-management has become increasingly popular in the management of chronic diseases . There are many different self-management models . Meta analyses of arthritis self-management have concluded that it is difficult to recommend any one program in preference to another due to inconsistencies in the study design s used to evaluate different programs . The Stanford Arthritis Self-Management Program ( ASMP ) , most commonly delivered by trained lay leaders , is a generic program widely used for people with rheumatological disorders . We have developed a more specific program expressly for people with osteoarthritis of the knee ( OAKP ) . It includes information design ed to be delivered by health professionals and results in improvements in pain , function and quality of life . Aim : To determine whether , for people with osteoarthritis ( OA ) of the knee , the OAKP implemented in a primary health care setting can achieve and maintain clinical ly meaningful improvements in more participants than ASMP delivered in the same environment . Methods / Design The effectiveness of the programs will be compared in a single-blind r and omized study . Participants : 146 participants with established OA knee will be recruited . Volunteers with coexistent inflammatory joint disease or serious co-morbidities will be excluded . Interventions : Participants will be r and omised into either OAKP or ASMP groups and followed for 6 months . Measurements : Assessment s will be immediately before and after the intervention and at 6 months . Primary outcome measures will be WOMAC and SF-36 question naires and a VAS for pain . Secondary outcomes will include balance , tested using a timed single leg balance test and a timed step test and self-efficacy . Data will be analysed using repeated measures ANOVA . Discussion With an aging population the health care costs for people with arthritis are ever increasing . Although cost analysis is beyond the scope of this study , it is reasonable to expect that costs will be greater when health professionals deliver self-management programs as opposed to lay leaders . Consequently it is critical to examine the relative effectiveness of the primary care management strategies available for OA.Trial Registration This study is registered with the Australian New Zeal and Clinical Trials Registry : [11142075] The objective of this study was to determine whether the Arthritis Self-Management Programme ( ASMP ) improves perceptions of control , health behaviours and health status , and changes use of health care re sources . The design was a pragmatic r and omized controlled study ; participants were allocated to ASMP ( Intervention Group ) or a 4-month waiting-list Control Group . The Intervention Group completed a 12-month follow-up . In total , 544 people with arthritis were recruited from the community--311 in the Intervention Group and 233 in the Control Group . Main outcome measures included : arthritis self-efficacy , health behaviours ( exercise , cognitive symptom management , diet and relaxation ) and health status ( pain , fatigue , anxiety , depression and positive affect ) . At 4 months follow-up , the ASMP had a significant effect on arthritis self-efficacy for other symptoms and pain subscales . Performance of a range of health behaviours ( cognitive symptom management , communication with physicians , dietary habit , exercise and relaxation ) was significantly greater among the Intervention Group . The Intervention Group were significantly less depressed and had greater positive mood . In addition , trends towards decreases on fatigue and anxiety were noted . Physical functioning , pain and GP visits remained stable at 4 months . A similar pattern of findings was found at 12 months follow-up for the Intervention Group . Furthermore , a significant improvement was found on pain and visits to GPs had decreased . Apart from a small improvement on physical functioning among the Intervention Group participants with osteoarthritis 12 months , all effects were independent of the type of arthritis . The findings suggest that the ASMP is effective in promoting improvements in perception of control , health behaviours and health status , when delivered in UK setting [2673355] Objective Chronic knee pain is a major cause of disability and health care expenditure , but there are concerns about efficacy , cost , and side effects associated with usual primary care . Conservative rehabilitation may offer a safe , effective , affordable alternative . We compared the effectiveness of a rehabilitation program integrating exercise , self-management , and active coping strategies ( Enabling Self-management and Coping with Arthritic Knee Pain through Exercise [ ESCAPE-knee pain ] ) with usual primary care in improving functioning in persons with chronic knee pain . Methods We conducted a single-blind , pragmatic , cluster r and omized controlled trial . Participants age ≥50 years , reporting knee pain for > 6 months , were recruited from 54 inner-city primary care practice s. Primary care practice s were r and omized to continued usual primary care ( i.e. , whatever intervention a participant 's primary care physician deemed appropriate ) , usual primary care plus the rehabilitation program delivered to individual participants , or usual primary care plus the rehabilitation program delivered to groups of 8 participants . The primary outcome was self-reported functioning ( Western Ontario and McMaster Universities Osteoarthritis Index physical functioning [ WOMAC-func ] ) 6 months after completing rehabilitation . Results A total of 418 participants were recruited ; 76 ( 18 % ) withdrew , only 5 ( 1 % ) due to adverse events . Rehabilitated participants had better functioning than participants continuing usual primary care ( −3.33 difference in WOMAC-func score ; 95 % confidence interval [ 95 % CI ] −5.88 , −0.78 ; P = 0.01 ) . Improvements were similar whether participants received individual rehabilitation ( −3.53 ; 95 % CI −6.52 , −0.55 ) or group rehabilitation ( −3.16 ; 95 % CI −6.55 , −0.12 ) . Conclusion ESCAPE-knee pain provides a safe , relatively brief intervention for chronic knee pain that is equally effective whether delivered to individuals or groups of participants [3524463] Background Knee osteoarthritis ( OA ) is a prevalent chronic musculoskeletal condition with no cure . Pain is the primary symptom and results from a complex interaction between structural changes , physical impairments and psychological factors . Much evidence supports the use of strengthening exercises to improve pain and physical function in this patient population . There is also a growing body of research examining the effects of psychologist-delivered pain coping skills training ( PCST ) particularly in other chronic pain conditions . Though typically provided separately , there are symptom , re source and personnel advantages of exercise and PCST being delivered together by a single healthcare professional . Physiotherapists are a logical choice to be trained to deliver a PCST intervention as they already have expertise in administering exercise for knee OA and are cognisant of the need for a biopsychosocial approach to management . No studies to date have examined the effects of an integrated exercise and PCST program delivered solely by physiotherapists in this population . The primary aim of this multisite r and omised controlled trial is to investigate whether an integrated 12-week PCST and exercise treatment program delivered by physiotherapists is more efficacious than either program alone in treating pain and physical function in individuals with knee OA . Methods / design This will be an assessor-blinded , 3-arm r and omised controlled trial of a 12-week intervention involving 10 physiotherapy visits together with home practice . Participants with symptomatic and radiographic knee OA will be recruited from the community in two cities in Australia and r and omized into one of three groups : exercise alone , PCST alone , or integrated PCST and exercise . R and omisation will be stratified by city ( Melbourne or Brisbane ) and gender . Primary outcomes are overall average pain in the past week measured by a Visual Analogue Scale and physical function measured by the Western Ontario and McMaster Universities Osteoarthritis Index subscale . Secondary outcomes include global rating of change , muscle strength , functional performance , physical activity levels , health related quality of life and psychological factors . Measurements will be taken at baseline and immediately following the intervention ( 12 weeks ) as well as at 32 weeks and 52 weeks to examine maintenance of any intervention effects . Specific assessment of adherence to the treatment program will also be made at weeks 22 and 42 . Relative cost-effectiveness will be determined from health service usage and outcome data . Discussion The findings from this r and omised controlled trial will provide evidence for the efficacy of an integrated PCST and exercise program delivered by physiotherapists in the management of painful and functionally limiting knee OA compared to either program alone . Trial registration Australian New Zeal and Clinical Trials Registry reference number : [19194641] Summary Osteoporosis is an increasing burden on individuals and health re sources . The Osteoporosis Prevention and Self-Management Course ( OPSMC ) was design ed to assist individuals to prevent and manage osteoporosis ; however , it had not been evaluated in an Australian setting . This r and omised controlled trial showed that the course increased osteoporosis knowledge . Introduction and hypothesisOsteoporosis is a major and growing public health concern . An OPSMC was design ed to provide individuals with information and skills to prevent or manage osteoporosis , but its effectiveness has not previously been evaluated . This study aim ed to determine whether OPSMC attendance improved osteoporosis knowledge , self-efficacy , self-management skills or behaviour . Material s and methods Using a wait list r and omised controlled trial design , 198 people ( 92 % female ) recruited from the community and aged over 40 ( mean age = 63 ) were r and omised into control ( n = 95 ) and intervention ( n = 103 ) groups . The OPSMC consists of four weekly sessions which run for 2 h and are led by two facilitators . The primary outcome were osteoporosis knowledge , health-directed behaviour , self-monitoring and insight and self-efficacy . Results The groups were comparable at baseline . At 6-week follow-up , the intervention group showed a significant increase in osteoporosis knowledge compared with the control group ; mean change 3.5 ( p < 0.001 ) on a measure of 0–20 . The intervention group also demonstrated a larger increase in health-directed behaviour , mean change 0.16 ( p < 0.05 ) , on a measure of 0–6 . Conclusion The results indicate that the OPSMC is an effective intervention for improving underst and ing of osteoporosis and some aspects of behaviour in the short term [4004977] Behavioral and health status outcomes of an unreinforced , self-help education program for arthritis patients taught by lay persons were examined in 2 ways : a 4-month r and omized experiment and a 20-month longitudinal study . At 4 months , experimental subjects significantly exceeded control subjects in knowledge , recommended behaviors , and in lessened pain . These changes remained significant at 20 months . The course was inexpensive and well-accepted by patients , physicians , and other health professionals [12554315] This study evaluated a novel intervention for older osteoarthritis ( OA ) patients and their spousal caregivers that consisted of st and ard patient education supplemented by information related to effectively managing arthritis as a couple . Twenty-four female OA patients and their husb and s were r and omly assigned to either an educational intervention that was targeted at both patient and spouse or to a patient education intervention that was targeted at only the patient . Findings revealed that both interventions were evaluated favorably but the couple intervention was better attended than the patient intervention . In addition , patients in the couple intervention experienced greater increased efficacy in managing arthritis pain and other symptoms . The findings of this pilot study point to the utility of a dyadic intervention approach to management of OA in late life [22484341] Six weekly sessions of group cognitive-behavioral therapy for insomnia and osteoarthritis pain ( CBT-PI ) , and for osteoarthritis pain alone ( CBT-P ) were compared to an education only control ( EOC ) . Basic education about pain and sleep was comparable , so EOC controlled for information and group participation . Active interventions differed from EOC in training pain coping skills ( CBT-P and CBT-PI ) and sleep enhancement techniques ( CBT-PI ) . Persons with osteoarthritis age 60 or older were screened for osteoarthritis pain and insomnia severity via mailed survey . Primary outcomes were pain severity ( pain intensity and interference ratings from the Grade d Chronic Pain Scale ) and insomnia severity ( Insomnia Severity Index ) . Secondary outcomes were arthritis pain ( AIMS -2 symptom scale ) and sleep efficiency assessed by wrist actigraphy . Ancillary outcomes included : cognitive function , depression , and health care use . A clustered r and omized design provided adequate power to identify moderate effects on primary outcomes ( effect size>0.35 ) . Modified intent to treat analyses , including all participants who attended the first session , assessed effects across CBT-PI , CBT-P , and EOC groups . Treatment effects were assessed post-intervention ( 2 months ) and at 9 months , with durability of intervention effects evaluated at 18 months . The trial was executed in 6 primary clinics , r and omizing 367 participants , with 93.2 % of r and omized patients attending at least 4 group sessions . Response rates for post-intervention and 9 month assessment s were 96.7 % and 92.9 % respectively . This hybrid efficacy-effectiveness trial design evaluates whether interventions yield specific benefits for clinical and behavioral outcomes relative to an education only control when implemented in a primary care setting [17043539] Objective : The objective of this study was to evaluate a nurse-directed self-management intervention for managed care patients with knee osteoarthritis ( OA ) , emphasizing nonpharmacologic ( NonPharm ) management of pain and functional impairments and minimization of exposure to the risks and costs of nonsteroidal antiinflammatory drugs ( NSAIDs ) . Methods : Subjects were 186 patients from a large health maintenance organization ( HMO ) who satisfied American College of Rheumatology clinical criteria for knee OA . Two of 4 HMO sites ( and their patient cohorts ) were r and omly assigned to the education group ; the other 2 served as a delayed-intervention control group . At each location of care for the education group , an arthritis nurse educator , in consultation with the patient 's primary care physician ( PCP ) , followed a detailed algorithm for implementing and monitoring the response to NonPharm treatment modalities ( eg , quadriceps strengthening exercises , counseling in principles of joint protection , use of thermal modalities ) . The nurses apprised the PCP of the patient 's progress and made algorithm-based recommendations , as appropriate , for reduction of dose , and eventual discontinuation , of NSAIDs in favor of acetaminophen . Outcomes ( measured at baseline , 3 , 6 , and 12 months ) included pain and function scales from the Western Ontario and McMaster Universities ( WOMAC ) OA Index . Results : The treatment groups were similar at baseline with respect to sociodemographic and clinical characteristics . Medical record audits revealed that NonPharm treatments ( most often exercise ) were implemented by 75 % of patients in the education group but by only 18 % of patients receiving routine care ( P < 0.00001 ) . Over the subsequent 12 months , 20 patients ( 26 % ) in the education group , but only 3 ( 5 % ) in the control group ( P = 0.002 ) , underwent changes in drug treatment of OA pain consistent with the NSAID-sparing goals of the intervention , ie , acetaminophen as initial drug of choice ; reduction in dose , or discontinuation , of NSAID ; switch from an NSAID to an analgesic . Only one patient in the education group required reinstitution of NSAIDs because of an increase in knee pain . Mean WOMAC scores indicated no deterioration of pain control or function over 12 months in the group treated according to the algorithm . Conclusion : Incorporation into the primary care setting of self-care education for patients with knee OA , with collaboration between a proactive arthritis nurse and the patient 's PCP , can reduce reliance on NSAIDs without a result ant increase in OA pain and disability [2735963] We examined the effectiveness of 2 models of arthritis self-care intervention , the home study model and the small group model . The effects of disease diagnosis and duration , self-care behavior , perceived helplessness , social support , treatment choice , and formal education level on outcomes among persons with arthritis who participated in these programs were evaluated . A pretest-posttest control group design was utilized in the initial experimental study ; comparison group design s were used in the longitudinal studies . Three hundred seventy-four subjects completed the interventions and 12 months of research followup . We found that the intervention models had a statistically significant positive impact on arthritis knowledge , self-care behavior , perceived helplessness , and pain . These findings did not vary when the effects of education level , disease diagnosis and duration , informal social support , and treatment choice were controlled . The small group intervention was more effective in bringing about initial improvements in pain and depression , whereas the home study intervention was more effective in maintaining improvements in perceived helplessness . Changes in perceived helplessness and self-care behavior appear to explain in part the observed improvement in pain [8980206] OBJECTIVE To determine the effects of structured exercise programs on self-reported disability in older adults with knee osteoarthritis . SETTING AND DESIGN A r and omized , single-blind clinical trial lasting 18 months conducted at 2 academic medical centers . PARTICIPANTS A total of 439 community-dwelling adults , aged 60 years or older , with radiographically evident knee osteoarthritis , pain , and self-reported physical disability . INTERVENTIONS An aerobic exercise program , a resistance exercise program , and a health education program . MAIN OUTCOME MEASURES The primary outcome was self-reported disability score ( range , 1 - 5 ) . The secondary outcomes were knee pain score ( range , 1 - 6 ) , performance measures of physical function , x-ray score , aerobic capacity , and knee muscle strength . RESULTS A total of 365 ( 83 % ) participants completed the trial . Overall compliance with the exercise prescription was 68 % in the aerobic training group and 70 % in the resistance training group . Postr and omization , participants in the aerobic exercise group had a 10 % lower adjusted mean ( + /- SE ) score on the physical disability question naire ( 1.71 + /- 0.03 vs 1.90 + /- 0.04 units ; P<.001 ) , a 12 % lower score on the knee pain question naire ( 2.1 + /- 0.05 vs 2.4 + /- 0.05 units ; P=.001 ) , and performed better ( mean [ + /- SE ] ) on the 6-minute walk test ( 1507 + /- 16 vs 1349 + /- 16 ft ; P<.001 ) , mean ( + /-SE ) time to climb and descend stairs ( 12.7 + /- 0.4 vs 13.9 + /- 0.4 seconds ; P=.05 ) , time to lift and carry 10 pounds ( 9.1 + /- 0.2 vs 10.0 + /- 0.1 seconds ; P<.001 ) , and mean ( + /-SE ) time to get in and out of a car ( 8.7 + /- 0.3 vs 10.6 + /- 0.3 seconds ; P<.001 ) than the health education group . The resistance exercise group had an 8 % lower score on the physical disability question naire ( 1.74 + /- 0.04 vs 1.90 + /- 0.03 units ; P=.003 ) , 8 % lower pain score ( 2.2 + /- 0.06 vs 2.4 + /- 0.05 units ; P=.02 ) , greater distance on the 6-minute walk ( 1406 + /- 17 vs 1349 + /- 16 ft ; P=.02 ) , faster times on the lifting and carrying task ( 9.3 + /- 0.1 vs 10.0 + /- 0.16 seconds ; P=.001 ) , and the car task ( 9.0 + /- 0.3 vs 10.6 + /- 0.3 seconds ; P=.003 ) than the health education group . There were no differences in x-ray scores between either exercise group and the health education group . CONCLUSIONS Older disabled persons with osteoarthritis of the knee had modest improvements in measures of disability , physical performance , and pain from participating in either an aerobic or a resistance exercise program . These data suggest that exercise should be prescribed as part of the treatment for knee osteoarthritis [8997917] OBJECTIVE To evaluate the effects of a spouse-assisted pain-coping skills training intervention on pain , psychological disability , physical disability , pain-coping , and pain behavior in patients with osteoarthritis ( OA ) of the knees . METHODS Eighty-eight OA patients with persistent knee pain were r and omly assigned to 1 of 3 conditions : 1 ) spouse-assisted pain-coping skills training , ( spouse-assisted CST ) , 2 ) a conventional CST intervention with no spouse involvement ( CST ) , or 3 ) an arthritis education-spousal support ( AE-SS ) control condition . All treatment was carried out in 10 weekly , 2-hour group sessions . RESULTS Data analysis revealed that at the completion of treatment , patients in the spouse-assisted CST condition had significantly lower levels of pain , psychological disability , and pain behavior , and higher scores on measures of coping attempts , marital adjustment , and self-efficacy than patients in the AE-SS control condition . Compared to patients in the AE-SS control condition , patients who received CST without spouse involvement had significantly higher post-treatment levels of self-efficacy and marital adjustment and showed a tendency toward lower levels of pain and psychological disability and higher scores on measures of coping attempts and ratings of the perceived effectiveness of pain-coping strategies . CONCLUSION These findings suggest that spouse-assisted CST has potential as a method for reducing pain and disability in OA patients [22382340] Objective . To evaluate the influence of a 6-week Arthritis Self-Management Program ( ASMP ) on health-related quality of life ( HRQOL ) and self-management skills in clinical setting s. Methods . Individuals with hip or knee osteoarthritis referred to orthopedic surgeons or rheumatologists at 6 hospitals in Victoria , Australia , were recruited . In a r and omized controlled trial , participants received the Stanford ASMP and self-help book ( intervention ) or book only ( control ) . Assessment s included the Assessment of Quality of Life instrument ( AQoL ; range −0.04 to 1.00 ) and Health Education Impact Question naire ( heiQ ; range 1–6 ) at baseline and up to 12 months . The primary outcome was HRQOL at 12 months ( assessed using the AQoL ) . Results . Recruitment was concluded early due to persistent challenges including infrequent referrals and patient inability or disinterest in participating . Of 1125 individuals screened , only 120 were r and omized ( control , n = 62 ; intervention , n = 58 ) . Seven ASMP were conducted while 18 scheduled ASMP were cancelled . Forty-four of 58 intervention group participants received the intervention as allocated ( 76 % ) ; all control group participants were sent the book ( 100 % ) . Ninety-four participants ( 78 % ) completed 12-month assessment s ( control , 90 % ; intervention , 66 % ) . There was no difference in HRQOL at 12 months ( adjusted mean difference −0.02 , 95 % CI −0.09 to 0.05 ) . At 6 weeks , the intervention group reported higher heiQ skill and technique acquisition scores ( adjusted mean difference 0.29 , 95 % CI 0.04 to 0.55 ) ; however , this dissipated by 3 months . Conclusion . Significant challenges hampered this evaluation of the ASMP . The observed lack of enthusiasm from potential referrers and patients raises doubts about the practicality of this intervention in real-world setting s. ( ANZCTR Clinical Trials Registry no. ACTRN12606000174583 [10513498] OBJECTIVE To evaluate the long-term effects of a spouse-assisted coping skills intervention in patients with osteoarthritis ( OA ) of the knees , and to evaluate how pre- to posttreatment changes in marital adjustment and self-efficacy relate to long-term improvements in pain , psychological disability , physical disability , pain coping , and pain behavior . METHODS A followup study was conducted with 88 OA patients who had been r and omly assigned to 1 of 3 treatment conditions : 1 ) spouse-assisted coping skills training ( spouse-assisted CST ) , 2 ) a conventional CST intervention with no spouse involvement , and 3 ) an arthritis education-spousal support ( AE-SS ) control condition . To evaluate long-term outcome , comprehensive measures of self-efficacy , marital adjustment , pain , psychological disability , physical disability , pain coping , and pain behavior were collected from these individuals at 6 and 12 months posttreatment . RESULTS Data analysis revealed that , at 6-month followup , patients in the spouse-assisted CST condition scored higher on measures of coping and self-efficacy than those in the AE-SS control group . At 6-month followup , patients who received CST without spouse involvement showed a significantly higher frequency of coping attempts and reported higher levels of marital adjustment than those in the AE-SS control group . At 12-month followup , patients in the spouse-assisted CST condition had significantly higher overall self-efficacy than those in the AE-SS control condition . In addition , patients in both the spouse-assisted CST and CST only conditions tended to show improvements in physical disability at the 12-month followup . Individual differences in outcome were noted at the 12-month followup . Patients in the spouse-assisted CST condition who reported initial ( pre- to posttreatment ) increases in marital adjustment had lower levels of psychological disability , physical disability , and pain behavior at 12-month followup . However , for patients in the conventional CST and AE-SS control conditions , increases in marital adjustment occurring over the initial phase of treatment were related to increases in pain and decreases in scores on the Pain Control in Rational Thinking factor of the Coping Strategies Question naire . Finally , patients in the spouse-assisted CST condition who showed pre- to posttreatment increases in self-efficacy were more likely to show decreases in pain , psychological disability , and physical disability at 12-month followup . CONCLUSIONS These findings suggest that spouse-assisted CST can enhance self-efficacy and improve the coping abilities of OA patients in the long term . Individual differences in the long-term outcome of spouse-assisted CST were noted , with some patients ( those showing increases in marital satisfaction and self-efficacy ) showing much better outcomes than others [16208674] OBJECTIVE To examine changes in mobility-related self efficacy following exercise and dietary weight loss interventions in overweight and obese older adults with knee osteoarthritis ( OA ) , and to determine if self efficacy and pain mediate the effects of the interventions on mobility task performance . METHODS The Arthritis , Diet , and Activity Promotion Trial was an 18-month , single-blind , r and omized , controlled trial comparing the effects of exercise alone , dietary weight loss alone , a combination of exercise plus dietary weight loss , and a healthy lifestyle control intervention in the treatment of 316 overweight or obese older adults with symptomatic knee OA . Participants completed measures of stair-climb time and 6-minute walk distance , self efficacy for completing each mobility task , and self-reported pain at baseline , 6 months , and 18 months during the trial . RESULTS Mixed model analyses of covariance of baseline adjusted change in the outcomes demonstrated that the exercise + dietary weight loss intervention produced greater improvements in mobility-related self efficacy ( P = 0.0035 ) , stair climb ( P = 0.0249 ) and 6-minute walk performance ( P = 0.00031 ) , and pain ( P = 0.09 ) when compared with the healthy lifestyle control intervention . Mediation analyses revealed that self efficacy and pain served as partial mediators of the beneficial effect of exercise + dietary weight loss on stair-climb time . CONCLUSION Exercise + dietary weight loss results in improved mobility-related self efficacy ; changes in these task-specific control beliefs and self-reported pain serve as independent partial mediators of the beneficial effect of exercise + dietary weight loss on stair-climb performance [18576310] OBJECTIVE To determine the efficacy of an Internet-based Arthritis Self-Management Program ( ASMP ) as a re source for arthritis patients unable or unwilling to attend small-group ASMPs , which have proven effective in changing health-related behaviors and improving health status measures . METHODS R and omized intervention participants were compared with usual care controls at 6 months and 1 year using repeated- measures analyses of variance . Patients with rheumatoid arthritis , osteoarthritis , or fibromyalgia and Internet and e-mail access ( n = 855 ) were r and omized to an intervention ( n = 433 ) or usual care control ( n = 422 ) group . Measures included 6 health status variables ( pain , fatigue , activity limitation , health distress , disability , and self-reported global health ) , 4 health behaviors ( aerobic exercise , stretching and strengthening exercise , practice of stress management , and communication with physicians ) , 5 utilization variables ( physician visits , emergency room visits , chiropractic visits , physical therapist visits , and nights in hospital ) , and self-efficacy . RESULTS At 1 year , the intervention group significantly improved in 4 of 6 health status measures and self-efficacy . No significant differences in health behaviors or health care utilization were found . CONCLUSION The Internet-based ASMP proved effective in improving health status measures at 1 year and is a viable alternative to the small-group ASMP [10366121] OBJECTIVE To determine the extent to which the cost of an effective self-care intervention for primary care patients with knee osteoarthritis ( OA ) was offset by savings result ing from reduced utilization of ambulatory medical services . METHODS In an attention-controlled clinical trial , 211 patients with knee OA from the general medicine clinic of a municipal hospital were assigned arbitrarily to conditions of self-care education ( group E ) or attention control ( group AC ) . Group E ( n = 105 ) received individualized instruction and followup emphasizing nonpharmacologic management of joint pain . Group AC ( n = 106 ) received a st and ard public education presentation and attention-controlling followup . A comprehensive clinical data base provided data concerning utilization and cost of health services during the following year . RESULTS Only 25 subjects ( 12 % ) were lost to followup . The 94 subjects remaining in group E made 528 primary care visits during the year following intervention , compared with 616 visits by the 92 patients remaining in group AC ( median visits 5 versus 6 , respectively ; P < 0.05 ) . Fewer visits translated directly into reduced clinic costs in group E , relative to controls ( median costs [ 1996 dollars ] $ 229 versus $ 305 , respectively ; P < 0.05 ) . However , self-care education had no significant effects on utilization and costs of outpatient pharmacy , laboratory , or radiology services over the ensuing year . The cost per patient to deliver the self-care intervention was estimated to be $ 58.70 . CONCLUSION Eighty percent of the cost of delivering effective self-care education to the knee OA patients in this study was offset within 1 year by the reduced frequency and costs of primary care visits . For > 50 % of patients receiving the intervention , the savings associated with fewer primary care visits exceeded the cost of self-care education [15937632] Osteoarthritis ( OA ) is the commonest cause of locomotor disability and forms a major element of the workload of the primary care team . There is evidence that patient education may improve quality of life , physical functioning , mental health and coping as well as reducing health service use . The aim of this study was to evaluate the effectiveness of a primary care-based patient education programme ( PEP ) using a r and omised controlled trial . A cluster r and omised controlled trial , involving 22 practice s , was used to determine the efficacy of a nurse-led education programme . The programme consisted of a home visit and four 1-h teaching sessions . Patients were assessed at baseline and then 1 , 3 , 6 and 12 months post intervention using 36-item Short Form ( SF-36 ) , Western Ontario and McMaster Universities Arthritis Index ( WOMAC ) , arthritis helplessness index and a patient knowledge question naire . Direct interviews were used at baseline and at the 12-month follow-up . There were no differences in depression , OA knowledge , pain or physical ability at either 1 month or 1 year between the two groups . Control practice s ( 65 patients from 12 practice s ) recruited significantly fewer patients than intervention practice s ( 105 patients from ten practice s , p=0.02 ) . Control practice s had more doctors ( p=0.02 ) , more non-white patients ( p=0.007 ) , fewer patients living alone ( p=0.005 ) and lower levels of disability ( p=0.008 ) . We detected a lack of benefit of PEP for people with OA of the knee . This was thought to be due in part to the short intervention time employed and the heterogeneous nature of the disease and the population studied [9259427] OBJECTIVE To evaluate a concise program of self-care education delivered by an arthritis nurse specialist as an adjunct to primary care for inner-city patients with knee osteoarthritis ( OA ) . METHODS An attention-controlled clinical trial ; 211 inner-city patients with knee OA were assigned arbitrarily to education ( E ) or attention-control ( AC ) conditions . Group E received an individualized 30 - 60-minute educational intervention that emphasized nonpharmacologic management of joint pain , preservation of function by problem-solving , and practice of principles of joint protection . Brief telephone contacts 1 week and 4 weeks later monitored and reinforced new self-care activities . Group AC viewed a 20-minute st and ardized public education presentation on arthritis and received followup telephone calls ( only to encourage continued participation in the study ) . Outcomes included the Health Assessment Question naire ( HAQ ) Disability and Discomfort Scales , 10-cm visual analog scales measuring knee pain at rest and while walking , and the Quality of Well-Being ( QWB ) scale . Assessment s were made at baseline and at 4-month intervals for 1 year . RESULTS A total of 165 subjects ( 78 % ) completed all assessment s. After control for baseline status , group E had significantly lower scores for disability and resting knee pain throughout the year of postintervention followup ( P < 0.05 for both ) . Effects were somewhat discordant . By 12 months , functional benefits had begun to wane , while the effect on resting knee pain had grown . The overall effects of education on walking knee pain , overall joint pain ( by HAQ ) , and general health status ( by QWB ) were not significant . CONCLUSION Self-care education for inner-city patients with knee OA , delivered as an adjunct to primary care , was found to result in notable preservation of function and control of resting knee pain . The magnitude of the observed effects compares well with those of more labor-intensive and time-consuming intervention models . However , more sustained preservation of function and consistent effects on pain may require prolonged , more proactive followup , either by the patient educator or by a trained clinical assistant dedicated to the task of supporting self-care by patients with knee OA [21343219] Thail and has a history of implementing innovative and proactive policies to address the health needs of its population . Since 1962 Thail and has implemented initiatives that led to it having a health system characterized by a primary care focus , de central ization and mechanisms to maximize equity and universal access to basic care at the local level . Thai health structures initially evolved to meet challenges including infectious and developmental diseases and later HIV . Early in the 21st century chronic illness rapidly became the greatest cause of morbidity and mortality and the question has arisen how Thail and can adapt its strong health system to deal with the new epidemics . This article describes an effort to reorient provincial health services to meet the needs of the increasing number of people with diabetes and heart disease . It describes measures taken to build on the equity-promoting elements of the Thai health system . The project included ; a situational analysis , development and implementation of a chronic disease self-management intervention implemented by nurses and alignment of provincial health services . The self-management intervention is currently being evaluated within a clustered r and omized control trial . The evaluation has been developed to fit with the focus on equity in relation to both selection criteria and the outcomes that are being assessed [15288394] & NA ; This study tested the separate and combined effects of spouse‐assisted pain coping skills training ( SA‐CST ) and exercise training ( ET ) in a sample of patients having persistent osteoarthritic knee pain . Seventy‐two married osteoarthritis ( OA ) patients with persistent knee pain and their spouses were r and omly assigned to : SA‐CST alone , SA‐CST plus ET , ET alone , or st and ard care ( SC ) . Patients in SA‐CST alone , together with their spouses , attended 12 weekly , 2‐h group sessions for training in pain coping and couples skills . Patients in SA‐CST+ET received spouse‐assisted coping skills training and attended 12‐weeks supervised ET . Patients in the ET alone condition received just an exercise program . Data analyses revealed : ( 1 ) physical fitness and strength : the SA‐CST+ET and ET alone groups had significant improvements in physical fitness compared to SA‐CST alone and patients in SA‐CST+ET and ET alone had significant improvements in leg flexion and extension compared to SA‐CST alone and SC , ( 2 ) pain coping : patients in SA‐CST+ET and SA‐CST alone groups had significant improvements in coping attempts compared to ET alone or SC and spouses in SA‐CST+ET rated their partners as showing significant improvements in coping attempts compared to ET alone or SC , and ( 3 ) self‐efficacy : patients in SA‐CST+ET reported significant improvements in self‐efficacy and their spouses rated them as showing significant improvements in self‐efficacy compared to ET alone or SC . Patients receiving SA‐CST+ET who showed increased self‐efficacy were more likely to have improvements in psychological disability . An intervention that combines spouse‐assisted coping skills training and exercise training can improve physical fitness , strength , pain coping , and self‐efficacy in patients suffering from pain due to osteoarthritis [15742451] OBJECTIVE To assess in a primary healthcare setting the efficacy of a self-management program in middle-aged patients with osteoarthritis ( OA ) . METHODS This was a 2-group r and omized controlled trial , with 273 patients aged 40 to 60 years with OA of the hip(s ) and /or knee(s ) . The experimental intervention was compared with care-as-usual . Treatments and followup measurements were performed in a general healthcare setting by general practitioners . Duration of followup was 21 months after start of the intervention . Instruction in self-management techniques was given by physiotherapists . The main outcome measures were pain severity in hips and knees , other significant complaints , and functional limitations . RESULTS To begin , 297 patients were r and omized : 149 as self-management and 148 controls ; before the intervention 24 withdrew for practical reasons ( 17 self-management , 7 controls ) . At 3-month followup the intervention group was significantly improved on a visual analog scale ( VAS ) for knee pain ( score 0.67 ; SD 2.10 ) and the WOMAC ( score 2.46 ; SD 9.49 ) , while the control group showed stable VAS knee pain ( 0.01 ; SD 2.00 ) and deterioration on WOMAC ( -0.53 ; SD 9.47 ) . At 21-month followup the differences between the groups increased in favor of the intervention group ( VAS pain knee : p values from 0.023 at 3 mo to 0.004 at 21 mo ; WOMAC : p values from 0.030 to 0.022 ) . CONCLUSION The self-management program positively influenced knee pain and self-reported functional level in this sample of patients with OA . Differences between the study groups increased during followup in favor of the intervention group [9084954] OBJECTIVE Past research has shown response biases to influence the accuracy of results from self-report measures . In pain assessment , where a percentage of patients have financial and other reasons to minimize or exaggerate psychological disturbance , it becomes especially important to identify the influence of response bias in self-report of adjustment . This study investigated the susceptibility of three commonly used self-report pain assessment measures to response bias . DESIGN This study used a within-subjects ( asymptomatic subjects ) design with two experimental conditions and nonequivalent control group ( chronic pain patients ) . SUBJECTS Experimental group : 40 students enrolled in an occupational therapy program at a major southeastern United States university . CONTROL GROUP 200 subjects referred to a multidisciplinary pain clinic at a major teaching hospital . MEASURES Coping Strategies Question naire , Multidimensional Pain Inventory , and Pain Beliefs and Perceptions Inventory . RESULTS With few exceptions , asymptomatic subjects scored significantly differently on these measures while portraying themselves as either coping well or coping poorly . In addition , when using the " coping poorly " response set , asymptomatic subjects reproduced scores similar to those of symptomatic chronic pain patients . CONCLUSION The susceptibility to manipulation appeared constant across the three measures , a finding that highlighted the difficulties clinicians and research ers encounter in accurate interpretation of results from these measures in the absence of validity indicators . This study also emphasizes the ease with which subjects with sufficient motivation can present themselves in an untruthful and manipulative manner and can generate scores that are , on their own , difficult to distinguish from those of a group of typical chronic pain patients [17040926] Abstract Objective To evaluate clinical effectiveness of a self management programme for arthritis in patients in primary care with osteoarthritis . Design R and omised controlled trial . Setting 74 general practice s in the United Kingdom . Participants 812 patients aged 50 and over with osteoarthritis of hips or knees ( or both ) and pain or disability ( or both ) . Intervention Participants were r and omised to six sessions of self management of arthritis and an education booklet ( intervention group ) or the education booklet alone ( control group ) . Main outcome measures Primary outcome was quality of life , as assessed by the short form health survey ( SF-36 ) . Several other physical and psychosocial secondary outcomes were assessed . Data were collected at baseline , four months , and 12 months . Results Response rates were 80 % and 76 % at four and 12 months . The two groups showed significant differences at 12 months on the anxiety subscore of the hospital anxiety and depression scale ( mean difference −0.62 , 95 % confidence interval −1.08 to −0.16 ) , arthritis self efficacy scale for pain ( 0.98 , 0.07 to 1.89 ) , and self efficacy for other aspects of management ( 1.58 , 0.25 to 2.90 ) . Results were similar for intention to treat and per protocol analyses . No significant difference was seen in number of visits to the general practitioner at 12 months . Conclusions The self management of arthritis programme reduced anxiety and improved participants ' perceived self efficacy to manage symptoms , but it had no significant effect on pain , physical functioning , or contact with primary care . Trial registration Current Controlled Trials IS RCT N79115352 [ controlled-trials.com ] [9273984] Women increasingly outnumber men in the US population ( Arber & Ginn , 1993 ) , but most research has been conducted with men ( Stacey & Olesen , 1988 ) . The purpose of this study was to determine whether older men and women differ in their participation rates and in their responsiveness to a health intervention . Three hundred sixty-three health maintenance organization members with osteoarthritis , 60 years of age or older , were r and omly assigned to a control group or to receive social support , education , or a combination of education and social support , education , or a combination of education and social support . Of the 363 r and omly assigned members , 245 completed all of the follow-up assessment s. Men and women volunteered in proportion to their representation in the osteoarthritis population . Although the genders differed in several ways , the interventions were equally effective for men and women , and the study results applied to both genders [17169935] PURPOSE We present final outcomes from the multiple-component Fit and Strong ! intervention for older adults with lower extremity osteoarthritis . DESIGN AND METHODS A r and omized controlled trial compared the effects of this exercise and behavior-change program followed by home-based reinforcement ( n=115 ) with a wait list control ( n=100 ) at 2 , 6 , and 12 months . Fit and Strong ! combined flexibility , aerobic walking , and resistance training with education and group problem solving to enhance self-efficacy for exercise and maintenance of physical activity . All participants developed individualized plans for long-term maintenance . RESULTS Relative to controls , treatment participants experienced statistically significant improvements in self-efficacy for exercise ( p=.001 ) , minutes of exercise per week ( p=.000 ) , and lower extremity stiffness ( p=.018 ) at 2 months . These benefits were maintained at 6 months and were accompanied by increased self-efficacy for adherence to exercise over time ( p=.001 ) , reduced pain ( p=.040 ) , and a marginally significant increase in self-efficacy for arthritis pain management ( p=.052 ) . Despite a substantially smaller sample size at 12 months , significant treatment-group effects were maintained on self-efficacy for exercise ( p=.006 ) and minutes of exercise per week ( p=.001 ) , accompanied by marginally significant reductions in lower extremity stiffness ( p=.056 ) and pain ( p=.066 ) . No adverse health effects were seen . Effect sizes for self-efficacy for exercise and for maintenance of physical activity were 0.798 and 0.713 , and 0.905 and 0.669 , respectively , in the treatment group at 6 and 12 months . IMPLICATION S This consistent pattern of benefits indicates that this low-cost intervention is efficacious for older adults with lower extremity osteoarthritis [18206425] BACKGROUND Osteoarthritis ( OA ) is a leading cause of disability among adults . Although self-management behaviors such as exercise and weight management can improve pain and function , these behaviors are vastly underutilized . There is a need to implement effective self-management programs among the growing number of adults with OA . OBJECTIVES The Self-Management of OsteoArthritis ( SeMOA ) in Veterans Study examines a 12-month telephone-based OA self-management program in the primary care setting . This manuscript details the design , methodology , and advances of the SeMOA trial . METHODS Participants ( N=519 ) with hip or knee OA are r and omly assigned to one of three groups : OA self-management , health education ( attention control ) , or usual care . The OA self-management group receives written and audio material s regarding OA care ( including health behaviors , medical care , and interacting with health care providers ) . A health educator calls participants monthly to review these material s and provide support for developing individualized goals and action plans related to OA management . The health education group receives written and audio material s and monthly calls from a health educator discussing health issues unrelated to OA . Usual care involves no additional material s or phone calls . The primary outcome is change in the Arthritis Impact Measurement Scales-2 pain subscale from baseline to 12 months . Analysis of covariance models will compare changes in pain across study groups . The cost-effectiveness of the OA self-management program will also be assessed . CONCLUSION SeMOA is one of the first to examine telephone-based delivery of OA self-management and one of few trials to target the primary care setting . This program has the potential for broad dissemination because it reduces both the costs and barriers that accompany in-person programs . This study will provide important information about its feasibility and effectiveness in a real-world clinical setting [9830877] OBJECTIVE To determine whether experimentally developed social support , education about appropriate use of the health care system , and their combination are effective in reducing health care costs for people with osteoarthritis at a 3-year followup assessment . METHOD Three hundred sixty-three health maintenance organization members with osteoarthritis were r and omly assigned to 1 of 3 intervention groups or to a control group . Two hundred fifty-six participants completed the 3-year assessment . Health status and health care use were assessed upon entering the study , and after 1 , 2 , and 3 years . RESULTS Health care costs in the combined experimental groups were lower than those in the control group by $ 1,279/participant/year in year 3 . There were no significant changes in health status between participants ' entry into the study and the year 3 assessment . The 3 interventions had nearly equal effects on health status and health care costs . Implementation costs were least for the social support intervention , but the group that combined education and social support had less attrition and greater persistence . CONCLUSION Interventions that target appropriate use of the health care system can be highly cost-effective without adversely affecting health status [9313398] OBJECTIVE To determine whether experimentally developed social support and education about appropriate use of the health care system decrease health care costs without negatively affecting health status . METHOD Three hundred sixty-three health maintenance organization members with osteoarthritis were r and omly assigned to 1 of 3 intervention groups or to a control group . Health status and health care use were assessed upon entering the study , and after 1 year and 2 years . RESULTS A savings of $ 1,156/participant/year was obtained when health care costs of the experimental groups were compared with those of the control group . Production or implementation costs were least for the social support intervention . The nearly equal effects of the 3 interventions on health care costs make implementation costs the primary focus when deciding which intervention to use . CONCLUSION We believe that the social support treatment is the most cost-effective intervention [20633669] OBJECTIVE To compare the efficacy of patient education and supervised exercise with that of patient education alone for the management of pain in patients with hip osteoarthritis ( OA ) . DESIGN Single blind r and omized clinical trial . SETTING Recruitment of patients from hospitals , primary health care and advertisement , Oslo , Norway . PARTICIPANTS 109 patients with radiographic and symptomatic hip OA with mild to moderate symptoms . INTERVENTIONS Patient education ( PE ) . Patient education and supervised exercise ( PE+SE ) . PRIMARY OUTCOME MEASURE The pain subscale of the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC pain ) . RESULTS No significant between group differences were found for WOMAC pain over the 16-month follow-up . Significant improvements were found for the secondary outcome WOMAC physical function ( P=0.011 ) in the group receiving PE+SE compared to the group receiving PE only . No significant differences were found for WOMAC stiffness , the SF-36 subscales or the activity scale . The effect sizes ( 95 % confidence interval ) for WOMAC pain were -0.26 ( 0.11 , -0.64 ) , -0.35 ( 0.07 , -0.77 ) , and -0.30 ( 0.15 , -0.75 ) , and for WOMAC physical function -0.29 ( 0.09 , -0.67 ) , -0.48 ( -0.06 , -0.91 ) , and -0.47 ( -0.02 , -0.93 ) at 4 , 10 and 16 months , respectively , in favor of the group receiving both PE and SE . All patients attended the three-session PE program , and 75 % performed ≥16 sessions of the 12-week SE program . CONCLUSION The study could not demonstrate a significant difference in pain reduction over time between PE+SE vs PE alone . Adding SE to PE may improve physical function , but the magnitude of possible benefit is unknown as the 95 % confidence intervals around the mean difference were wide . TRIAL REGISTRATION Clinical Trials NCT00319423 [27820499] Background Osteoarthritis ( OA ) is a common cause of pain and disability , and is the most common form of arthritis in the Western world . The most common joint to be affected is the knee . Pain and functional disability are common symptoms , which can lead to reduced quality of life and increase the risk of further morbidity . Current treatment aims to educate patients about the management of OA , reduce pain , improve function , decrease disability and reduce the progression of the disease . Education with clients has been described as a set of planned educational activities design ed to improve patients ' health behaviours and /or health status . The purpose of self‐education is to maintain or improve health , or , in some cases , to slow deterioration by increasing participant 's perception of self efficacy defined as an ability to control or manage various aspects of OA . To date , there is no systematic review of the literature undertaken to identify the effectiveness of self‐management educational activities for osteoarthritis of the knee . Objective The objective of this systematic review is to evaluate the effectiveness of self‐management educational interventions on function and quality of life for adult subjects with OA of the knee . Search strategy A comprehensive search strategy was undertaken on data bases available from University of South Australia from their inception to January 2007 . Selection criteria R and omised controlled trials or clinical controlled trials were sought which evaluated any self management interventions for osteoarthritis knee . Critical appraisal of study quality was undertaken using Joanna Briggs Institute critical appraisal instruments . Data extraction was via the Joanna Briggs Institute st and ard data extraction form for evidence of effectiveness , and Review Manager Software was used to calculate comparative statistics . Results Thirteen trials were included in the review . Trials were clinical ly and method ologically heterogeneous . Pooled results indicate evidence of a beneficial effect from self management strategies with reducing pain ( SMD ‐0.25 , 95%CI ‐0.36 to ‐0.13 , 11 trials 1379 participants ) . There was no effect on physical function ( SMD 0.13 , 95%CI ‐0.33 to ‐0.08 , eight trials , 1156 subjects ) . No beneficial effects were found from self management interventions with improving quality of life . We also found the exercise component of self management ( four trials ) demonstrated a benefit with reducing pain , improving function and quality of life . Exercise also offered a benefit over no exercise . Overall method ological quality was moderate . Discussion Pooled results indicate evidence of a beneficial effect from self management strategies with reducing pain and improving function . Significant heterogeneity was found between trials . This was controlled for in the analysis but may be explained by heterogeneity in both the intervention and control group . The exercise component of self management programmes appears to contribute a significant benefit . Conclusion There is encouraging evidence of a small benefit from exercise in self management programs . Clear guidelines can not be provided for practice regarding the exercise content due to heterogeneity but overall benefit suggests this component should be emphasized and implemented in primary care self management programmes [18825579] The aim was to assess the self-efficacy and health outcomes of an adopted Arthritis Self-Management Programme ( ASMP ) among osteoarthritic knee sufferers in Hong Kong at 1 year . An experimental study with 95 participants assigned r and omly to the intervention ( n=45 ) or control group ( n=50 ) . Seventy-seven ( 81.1 % ) participants joined at least one out of three follow-ups in the 12 month period . Participants in the intervention group received a 6-week ASMP with an added exercise component in two general clinics . Outcome measures included arthritis self-efficacy ( ASE ) and health outcomes including pain and fatigue rating , self-rated health , daily activities limitation and number of unplanned arthritis-related medical consultations . Mean change ( 12 months minus baseline ) and the effect size of the outcome measures were calculated by Mann – Whitney U test and nQuery Advisor 4.0 . At 12 months , there were significant reductions of current pain ( p=0.0001 ) , pain at night ( p=0.001 ) , pain during walking ( p=0.01 ) and number of unplanned arthritis-related medical consultations ( p=0.03 ) and a significant increase in ASE for pain ( p=0.01 ) and other symptoms ( p=0.02 ) and self-rated health ( p=0.04 ) among the intervention group but not for the control group . However , there were similarities in outcome measures of pain while switching from a sitting to a st and ing position , fatigue rating and physical functional limitation ( p=0.15 ; p=0.22 and p=0.91 , respectively ) for both groups . Our findings add to the evidence that the modified arthritis empowering programme improved perception of control of osteoarthritis and three health outcomes after 12 months of treatment [16342084] OBJECTIVE Both the Arthritis Self-Management Program ( ASMP ) and the generic Chronic Disease Self-Management Program ( CDSMP ) have been shown to be successful in improving conditions in patients with arthritis . This study compared the relative effectiveness of the 2 programs for individuals with arthritis . METHODS Patients whose primary disease was arthritis were r and omized to the ASMP ( n = 239 ) or to the CDSMP ( n = 116 ) . Analyses of covariance were used to compare the outcome measures for the 2 programs at 4 months and 1 year . Measures included quality of life outcomes ( self reported , health distress , disability , activity limitation , global health , pain , and fatigue ) , health behaviors ( practice of mental stress management , stretching and strength exercise , aerobic exercise ) , self efficacy , and health care utilization ( physician visits and hospitalizations ) . RESULTS Both programs showed positive results . The disease-specific ASMP appeared to have advantages over the more generic CDSMP for patients with arthritis at 4 months . These advantages had lessened slightly by 1 year . CONCLUSION The disease-specific ASMP should be considered first where there are sufficient re sources and participants . However , both programs had positive effects , and the CDSMP should be considered a viable alternative [21290963] & NA ; Osteoarthritis of the knee , a prevalent condition in older adults , can impact physical function and ability to perform physical activity . This r and omized controlled trial examined the effects of a 6‐month self‐efficacy‐based , individually delivered , lower‐extremity exercise and fitness walking intervention with 6‐month follow‐up on physical activity and function . The 26 subjects were mostly older ( M = 63.2 years , SD = 9.8 ) , White ( 83 % ) , obese ( BMI M = 33.3 , SD = 6.0 ) women ( 96 % ) . Physical activity was measured by diaries . Physical function was measured by the 6‐minute walk , Short Physical Performance Battery ( SPPB ) , and WOMAC Physical Function subscale . Exercise self‐efficacy was assessed by a question naire . Results showed significant increases in self‐reported performance of lower‐extremity exercise and participation in fitness walking , distance in the 6‐minute walk , and SPPB scores from baseline to 6‐month follow‐up with a trend for improvement in self‐efficacy . Results suggest that the intervention was feasible , acceptable , and improved physical activity and function [10965386] The soaring cost of health care is a national problem that needs response at multiple levels , including that of the community . Reducing or limiting health care costs through interventions that emphasize the self-management of health may promote broader health care coverage , better quality of health care , and a sense of control over one 's health . Therefore , it behooves community psychologists to perform cost analyses when testing interventions for people in a community . The present study investigated the effects of social support and education interventions on psychosocial variables , health status , and health care costs in older people with osteoarthritis . Participants were 363 members of a health maintenance organization ( HMO ) , 60 years of age and older , with osteoarthritis . Participants were r and omly assigned to one of three intervention groups ( social support , education , or a combination of both ) or to a control group . The results indicated that feelings of helplessness decreased in the intervention groups but not in the control group . All groups showed increases in self-efficacy and overall health status . In addition , health care costs increased less in the intervention groups than in the control group . Cost analysis was used to demonstrate that the monetary savings of the intervention greatly outweighed the cost of conducting the intervention . It appears that interventions can limit health care costs while improving health and increasing feelings of control for older people with osteoarthritis . Further , this paper demonstrates how a cost-benefit focus can benefit community studies [10493473] OBJECTIVES To determine 4-month and 1-year health-related outcomes of a 6-week , lay-led , and community-based arthritis self-management program for Spanish-speaking participants and to determine the role of self-efficacy in predicting health status for this population . METHODS Three hundred and thirty one subjects were r and omized to the program or to a 4-month wait list control group . One hundred ninety eight subjects continued in a 1-year longitudinal study . Data were collected via mailed question naires with telephone follow up . RESULTS At 4 months , treatment subjects , compared with controls , demonstrated positive changes in exercise , disability , pain , and self-efficacy ( P < 0.05 ) . At 1 year , compared with baseline , treatment subjects demonstrated improvements in exercise , general health , disability , pain , self-efficacy , and depression ( P < 0.05 ) . Baseline and 4-month changes in self-efficacy predicted health status at 1 year . CONCLUSIONS Spanish-speaking participants of an arthritis self-management program demonstrate short- and long-term benefits ( improved health behaviors , health status , and self-efficacy ) [10955337] OBJECTIVE Evaluation of a self-management program for patients with osteoarthritis ( OA ) of the hip or knee . The program , which consisted of 6 weekly sessions of 2 hours , included health education by a peer and physical exercises taught by a physical therapist . METHODS R and omized controlled trial . Inclusion criteria were diagnosis of OA of the hip or knee according to ACR clinical and radiographic criteria and age 55 to 75 years . EXCLUSION CRITERIA on waiting list for joint replacement . There were pretest , posttest , and followup ( 6 months ) assessment s. The experimental group consisted of 56 patients , the control group 49 . Outcome variables were pain , quality of life , activity restrictions , knowledge about OA , self-efficacy , body mass index ( BMI ) , and mobility measures . Attention was also paid to effects on health care utilization and lifestyle behavior . RESULTS Significant MANOVA group x time effects ( p < 0.05 , one-sided ) were found for pain , quality of life , strength of the left M. quadriceps , knowledge , self-efficacy , BMI , physically active lifestyle , and visits to the physical therapist . Most effects were moderate at posttest assessment and smaller at followup . No effects were found for range of motion and functional tasks . CONCLUSION The program was reasonably effective , but more attention should be paid to proactive followup interventions and to the selection of participants [2917233] The benefits of patient education for those with chronic arthritis are well documented . Informed patients should practice self care more often , and may show reduced disability from their disease . An important question relates to maintenance of the knowledge and skills acquired in educational programmes . This prospect i ve study evaluated an education programme for people with rheumatoid arthritis ( RA ) and osteoarthritis ( OA ) . The intervention group participated in a comprehensively planned six session behaviourally based programme . A question naire was given to 100 patients and 95 matched but non-r and om controls before the programme , 1 month later , and at 3 and 12 months . The intervention group demonstrated improvements in knowledge , self-reported health behaviour and disability scores at 12 months , compared to the controls . No differences were reported in symptoms , compliance with therapy , pain perception , and locus of control [19627690] BACKGROUND Chronic knee pain is a major cause of disability in the elderly . Management guidelines recommend exercise and self-management interventions as effective treatments . The authors previously described a rehabilitation programme integrating exercise and self-management [ Enabling Self-management and Coping with Arthritic knee Pain through Exercise ( ESCAPE-knee pain ) ] that produced short-term improvements in pain and physical function , but sustaining these improvements is difficult . Moreover , the programme is untried in clinical environments , where it would ultimately be delivered . OBJECTIVES To establish the feasibility of ESCAPE-knee pain and compare its clinical effectiveness and costs with outpatient physiotherapy . DESIGN Pragmatic , r and omised controlled trial . SETTING Outpatient physiotherapy department and community centre . PARTICIPANTS Sixty-four people with chronic knee pain . INTERVENTIONS Outpatient physiotherapy compared with ESCAPE-knee pain . OUTCOMES The primary outcome was physical function assessed using the Western Ontario and McMaster Universities Osteoarthritis Index . Secondary outcomes included pain , objective functional performance , anxiety , depression , exercise-related health beliefs and healthcare utilisation . All outcomes were assessed at baseline and 12 months after completing the interventions ( primary endpoint ) . ANCOVA investigated between-group differences . RESULTS Both groups demonstrated similar improvements in clinical outcomes . Outpatient physiotherapy cost pound 130 per person and the healthcare utilisation costs of participants over 1 year were pound 583 . The ESCAPE-knee pain programme cost pound 64 per person and the healthcare utilisation costs of participants over 1 year were pound 320 . CONCLUSIONS ESCAPE-knee pain can be delivered as a community-based integrated rehabilitation programme for people with chronic knee pain . Both ESCAPE-knee pain and outpatient physiotherapy produced sustained physical and psychosocial benefits , but ESCAPE-knee pain cost less and was more cost-effective [16309929] OBJECTIVE To evaluate the effect of therapeutic education and functional readaptation ( TEFR ) on health-related quality of life ( HRQL ) in patients diagnosed with osteoarthritis on a waiting list for total knee replacement ( TKR ) . METHODS R and omized controlled trial of 9 months duration was conducted . One hundred consecutive out patients ( 71 females , mean age 71 years ( range 50 - 86 ) , mean disease duration 11.84+/-10.52 months ) were included . Patients were r and omized in two groups . The intervention group received TEFR added to conventional ( pharmacological ) treatment ( n=51 ) . The control group received conventional ( pharmacological ) treatment only ( n=49 ) . The main outcome variable was self-reported HRQL measured by the Spanish version of Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) . Secondary outcomes were general HRQL measured by Short Form Health Survey general question naire ( SF-36 ) , number of visits to general physicians and their cost . Assessment s were done at baseline and at 9 months . MAIN RESULTS Eighty patients completed the study . Significant improvement in the WOMAC function was found at 9 months in the TERF group with respect to the control group ( P=0.035 ) . Consumption of analgesics increased significantly in the TERF group compared with controls ( P=0.036 ) . Significant improvements in pain ( P=0.027 ) measured by WOMAC and in bodily pain ( P=0.043 ) and physical function ( P=0.031 ) , measured by SF-36 , were observed in the intervention group with respect to baseline . CONCLUSIONS The function dimension measured by WOMAC of patients who received both pharmacological treatment and TERF improved with respect to the control group receiving only pharmacological treatment . This suggests that a program of TEFR during the period on the waiting list for TKR may reduce the negative impact of this situation [20420960] OBJECTIVES To assess the effect of a group education programme on pain and function through knowledge acquisition and a home-based exercise programme . DESIGN A parallel r and omised single-blind clinical trial . PARTICIPANTS Fifty patients aged 65 years or over with knee osteoarthritis . INTERVENTIONS The study group ( n=25 ) was given a group education programme once a week for 4 weeks , followed by a self-executed home-based exercise programme . The controls ( n=25 ) were given a brief course in short-wave diathermy treatment . MAIN OUTCOME MEASURES Patients were assessed before the intervention , after the intervention ( 4 weeks ) and again 8 weeks later ( follow-up ) using the Western Ontario McMaster Osteoarthritis Index ( WOMAC ) , the repeated sit-to-st and test and the get-up- and -go test . RESULTS At 4 weeks , there was a significant improvement in both groups in all outcome variables except the WOMAC stiffness score ; for example , the WOMAC total score was reduced by a mean of 9.5 points [ 95 % confidence interval ( CI ) -12.3 to -6.7 ] . However , at follow-up , patients in the study group demonstrated continued improvement in the get-up- and -go test and the WOMAC total , pain and disability scores , but no such improvement was noted among the controls . This difference was significant ; for example , the difference in mean WOMAC total score between the groups was -9.0 points ( 95%CI -14.5 to -3.4 ) . CONCLUSION A simple group education programme for patients with knee osteoarthritis is associated with improved functional abilities and pain reduction . Further study is required to determine if this positive effect can be maintained over a longer period [1489766] We compared a cognitive-behavior modification and a traditional education intervention for adults with osteoarthritis ( OA ) . Forty OA patients were r and omly assigned to one of two groups : cognitive-behavior modification or didactic lectures . During ten weekly sessions , the cognitive-behavior group learned methods for coping with pain and the disabilities associated with OA . The traditional education group experienced a series of lectures from health care professionals . Prior to the interventions and following 2 , 6 , and 12 months , patients in both groups were evaluated with a general Quality of Well-being ( QWB ) scale , the Arthritis Impact Measurement Scales ( AIMS ) , the Beck Depression Inventory ( BDI ) , and other measures . Although there were some differences between the two groups at 2-month follow-up , by the end of 1 year , physical and psychological functioning did not differ significantly between the two groups . In comparison to baseline , both groups demonstrated initial changes on QWB , depression , and the pain component of the AIMS . Improvements in depression remained through the 1-year follow-up . Multiple regression analysis demonstrated that the mobility and physical activity aspects of the AIMS were significant long-term predictors of outcome ( 1 year ) for general quality -of-life measures . One-year outcomes for depression were significantly predicted from scores on social support and mobility measures from the AIMS . We conclude that cognitive-behavior modification and education produce similar effects on long-term physical and psychological functioning in OA patients [21041576] BACKGROUND Osteoarthritis is a leading cause of pain and disability , and self-management behaviors for osteoarthritis are underutilized . OBJECTIVE To examine the effectiveness of a telephone-based self-management intervention for hip or knee osteoarthritis in a primary care setting . DESIGN R and omized clinical trial with equal assignment to osteoarthritis self-management , health education ( attention control ) , and usual care control groups . ( Clinical Trials.gov registration number : NCT00288912 ) SETTING Primary care clinics in a Veterans Affairs Medical Center . PATIENTS 515 patients with symptomatic hip or knee osteoarthritis . INTERVENTION The osteoarthritis self-management intervention involved educational material s and 12 monthly telephone calls to support individualized goals and action plans . The health education intervention involved nonosteoarthritis educational material s and 12 monthly telephone calls related to general health screening topics . MEASUREMENTS The primary outcome was score on the Arthritis Impact Measurement Scales-2 pain subscale ( range , 0 to 10 ) . Pain was also assessed with a 10-cm visual analog scale . Measurements were collected at baseline and 12 months . RESULTS 461 participants ( 90 % ) completed the 12-month assessment . The mean Arthritis Impact Measurement Scales-2 pain score in the osteoarthritis self-management group was 0.4 point lower ( 95 % CI , -0.8 to 0.1 point ; P = 0.105 ) than in the usual care group and 0.6 point lower ( CI , -1.0 to -0.2 point ; P = 0.007 ) than in the health education group at 12 months . The mean visual analog scale pain score in the osteoarthritis self-management group was 1.1 points lower ( CI , -1.6 to -0.6 point ; P < 0.001 ) than in the usual care group and 1.0 point lower ( CI , -1.5 to -0.5 point ; P < 0.001 ) than in the health education group . Health care use did not differ across the groups . LIMITATION The study was conducted at 1 Veterans Affairs Medical Center , and the sample consisted primarily of men . CONCLUSION A telephone-based osteoarthritis self-management program produced moderate improvements in pain , particularly compared with a health education control group . PRIMARY FUNDING SOURCE U.S. Department of Veterans Affairs Health Services Research and Development Service [21726907] PURPOSE To evaluate the effectiveness of the Taipei Osteoarthritis Program ( TOAP ) for community elderly persons who suffer from knee OA . METHODS A quasi-experimental study was conducted between January 2008 and December 2008 . Two hundred and five community-dwelling individuals aged 67±10 years with knee OA were recruited from four districts in Taipei City and r and omized . By a clustered r and omization according to the districts , 114 participants were in the intervention group ( IG ) with a 4-week TOAP program and 91 participants were in the control group ( CG ) with routine care . The main outcome measures included health-related quality of life ( HRQOL ) and disability level , which were assessed by the Short Form-36 Taiwan Version ( T-SF36 ) and the Western Ontario McMaster Universities Arthritis Index Taiwan Version ( T-WOMAC ) , respectively , and were repeatedly measured at the baseline , post invention ( 4 weeks after baseline ) , and follow-up ( 8 weeks after baseline ) . RESULTS Subjects in the IG increased their changes of GH scores from baseline to post-intervention and follow-up , which were significantly more than those of subjects in the CG ( p=0.011 and 0.005 , respectively ) . Significant difference of changes was also found at follow-up for the mental component scale between the groups ( p=0.013 ) . There was no change in disability level . CONCLUSIONS The arthritis self-management program improved the psychological outcomes among the participants , but it had no significant effect on a self-reported disability level [22503223] Summary Combined training in pain and weight management in overweight and obese OA patients result ed in improved pain and other outcomes compared to either training alone . ABSTRACT Overweight and obese patients with osteoarthritis ( OA ) experience more OA pain and disability than patients who are not overweight . This study examined the long‐term efficacy of a combined pain coping skills training ( PCST ) and lifestyle behavioral weight management ( BWM ) intervention in overweight and obese OA patients . Patients ( n = 232 ) were r and omized to a 6‐month program of : 1 ) PCST + BWM ; 2 ) PCST‐only ; 3 ) BWM‐only ; or 4 ) st and ard care control . Assessment s of pain , physical disability ( Arthritis Impact Measurement Scales [ AIMS ] physical disability , stiffness , activity , and gait ) , psychological disability ( AIMS psychological disability , pain catastrophizing , arthritis self‐efficacy , weight self‐efficacy ) , and body weight were collected at 4 time points ( pretreatment , posttreatment , and 6 months and 12 months after the completion of treatment ) . Patients r and omized to PCST + BWM demonstrated significantly better treatment outcomes ( average of all 3 posttreatment values ) in terms of pain , physical disability , stiffness , activity , weight self‐efficacy , and weight when compared to the other 3 conditions ( Ps < 0.05 ) . PCST + BWM also did significantly better than at least one of the other conditions ( ie , PCST‐only , BWM‐only , or st and ard care ) in terms of psychological disability , pain catastrophizing , and arthritis self‐efficacy . Interventions teaching overweight and obese OA patients pain coping skills and weight management simultaneously may provide the more comprehensive long‐term benefits Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Self-management programs have been widely reported to help patients manage symptoms and contain utilization of health care re sources for several chronic conditions , but to date no systematic review across multiple chronic diseases has been reported . We evaluated the efficacy of patient self-management educational programs for chronic diseases and critically review ed their methodology . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

30168868

[28374648] Background : There is no consensus over best approaches to reliably prevent malnutrition in rural communities in low-income countries . Objective : We compared the effectiveness of 2 lipid-based ready-to-use supplementary foods ( RUSFs ) differing in dairy protein content to improve the nutritional status of mothers and at-risk infants and young children in rural Guinea-Bissau . Methods : A 3-month cluster-r and omized controlled pilot trial of 2 RUSFs was conducted with 692 mothers and 580 mildly or moderately malnourished infants ( 6 - 23 months ) and children ( 24 - 59 months ) from 13 villages . The RUSFs contained either 478 ( mothers , children ) or 239 kcal/d ( infants ) with 15 % or 33 % of protein from dairy and were distributed at community health centers 5 d/wk . Controls were wait-listed to receive RUSF . Primary outcomes were mid-upper arm circumference ( MUAC ) in mothers , and weight-for-age and height-for-age z-scores ( WAZ and HAZ ) in infants and children . Results : There was a significant effect of the RUSF-33 % on MUAC in mothers ( P = .03 ) . The WAZ and HAZ increased substantially , by ≈1 z-score , in infants and children ( P < .01 ) independent of group r and omization . In children , but not infants , baseline WAZ and change in maternal MUAC were associated with change in WAZ ( β = .07 , P = .02 ) . Conclusion : Ready-to-use supplementary foods with higher dairy protein content had a significant benefit in village mothers , supporting a comparable recent finding in preschool children . In addition , supplementation of children < 2 years result ed in improved growth independent of family nutritional status , whereas success in older children was associated with change in maternal nutrition , suggesting the need for community-level education about preventing malnutrition in older , as well as younger , children [24225356] BACKGROUND Haiti has experienced rapid urbanization that has exacerbated poverty and undernutrition in large slum areas . Stunting affects 1 in 5 young children . OBJECTIVE We aim ed to test the efficacy of a daily lipid-based nutrient supplement ( LNS ) for increased linear growth in young children . DESIGN Healthy , singleton infants aged 6 - 11 mo ( n = 589 ) were recruited from an urban slum of Cap Haitien and r and omly assigned to receive : 1 ) a control ; 2 ) a 3-mo LNS ; or 3 ) a 6-mo LNS . The LNS provided 108 kcal and other nutrients including vitamin A , vitamin B-12 , iron , and zinc at ≥80 % of the recommended amounts . Infants were followed monthly on growth , morbidity , and developmental outcomes over a 6-mo intervention period and at one additional time point 6 mo postintervention to assess sustained effects . The Bonferroni multiple comparisons test was applied , and generalized least-squares ( GLS ) regressions with mixed effects was used to examine impacts longitudinally . RESULTS Baseline characteristics did not differ by trial arm except for a higher mean age in the 6-mo LNS group . GLS modeling showed LNS supplementation for 6 mo significantly increased the length-for-age z score ( ±SE ) by 0.13 ± 0.05 and the weight-for-age z score by 0.12 ± 0.02 compared with in the control group after adjustment for child age ( P < 0.001 ) . The effects were sustained 6 mo postintervention . Morbidity and developmental outcomes did not differ by trial arm . CONCLUSION A low-energy , fortified product improved the linear growth of young children in this urban setting . The trial was registered at clinical trials.gov as NCT01552512 [23535609] In developing countries , prenatal lipid-based nutrient supplements ( LNSs ) were shown to increase birth size ; however , the mechanism of this effect remains unknown . Cord blood hormone concentrations are strongly associated with birth size . Therefore , we hypothesize that LNSs increase birth size through a change in the endocrine regulation of fetal development . We compared the effect of daily prenatal LNSs with multiple micronutrient tablets on cord blood hormone concentrations using a r and omized , controlled design including 197 pregnant women from rural Burkina Faso . Insulin-like growth factors ( IGF ) I and II , their binding proteins IGFBP-1 and IGFBP-3 , leptin , cortisol , and insulin were quantified in cord sera using immunoassays . LNS was associated with higher cord blood leptin mainly in primigravidae ( + 57 % ; P = 0.02 ) and women from the highest tertile of BMI at study inclusion ( + 41 % ; P = 0.02 ) . We did not find any significant LNS effects on other measured cord hormones . The observed increase in cord leptin was associated with a significantly higher birth weight . Cord sera from small-for-gestational age newborns had lower median IGF-I ( -9 μg/L ; P = 0.003 ) , IGF-II ( -79 μg/L ; P = 0.003 ) , IGFBP-3 ( -0.7 μg/L ; P = 0.007 ) , and leptin ( -1.0 μg/L ; P = 0.016 ) concentrations but higher median cortisol ( + 18 μg/L ; P = 0.037 ) concentrations compared with normally grown newborns . Prenatal LNS result ed in increased cord leptin concentrations in primigravidae and mothers with higher BMI at study inclusion . The elevated leptin concentrations could point toward a higher neonatal fat mass [5697619] Background Previous review s have identified 44 risk factors for poor early child development ( ECD ) in low‐ and middle‐income countries . Further underst and ing of their relative influence and pathways is needed to inform the design of interventions targeting ECD . Methods We conducted path analyses of factors associated with 18‐month language and motor development in four prospect i ve cohorts of children who participated in trials conducted as part of the International Lipid‐Based Nutrient Supplements ( iLiNS ) Project in Ghana ( n = 1,023 ) , Malawi ( n = 675 and 1,385 ) , and Burkina Faso ( n = 1,122 ) . In two cohorts , women were enrolled during pregnancy . In two cohorts , infants were enrolled at 6 or 9 months . In multiple linear regression and structural equation models ( SEM ) , we examined 22 out of 44 factors identified in previous review s , plus 12 additional factors expected to be associated with ECD . Results Out of 42 indicators of the 34 factors examined , 6 were associated with 18‐month language and /or motor development in 3 or 4 cohorts : child linear and ponderal growth , variety of play material s , activities with caregivers , dietary diversity , and child hemoglobin/iron status . Factors that were not associated with child development were indicators of maternal Hb/iron status , maternal illness and inflammation during pregnancy , maternal perceived stress and depression , exclusive breastfeeding during 6 months postpartum , and child diarrhea , fever , malaria , and acute respiratory infections . Associations between socioeconomic status and language development were consistently mediated to a greater extent by caregiving practice s than by maternal or child biomedical conditions , while this pattern for motor development was not consistent across cohorts . Conclusions Key elements of interventions to ensure quality ECD are likely to be promotion of caregiver activities with children , a variety of play material s , and a diverse diet , and prevention of faltering in linear and ponderal growth and improvement in child hemoglobin/iron status [6088232] Abstract Small‐quantity lipid‐based nutrient supplements ( SQ‐LNS ) are design ed to enrich maternal and child diets with the objective of preventing undernutrition during the first 1,000 days . Scaling up the delivery of supplements such as SQ‐LNS hinges on underst and ing private dem and and creatively leveraging policy‐relevant factors that might influence dem and . We used longitudinal stated willingness‐to‐pay ( WTP ) data from contingent valuation studies that were integrated into r and omized controlled nutrition trials in Ghana and Malawi to estimate private valuation of SQ‐LNS during pregnancy , postpartum , and early childhood . We found that average stated WTP for a day 's supply of SQ‐LNS was more than twice as high in Ghana than Malawi , indicating that dem and for SQ‐LNS ( and by extension , the options for effective delivery of SQ‐LNS ) may be very context specific . We also examined factors associated with WTP , including intervention group , household socioeconomic status , birth outcomes , child growth , and maternal and child morbidity . In both sites , WTP was consistently negatively associated with household food insecurity , indicating that subsidization might be needed to permit food insecure households to acquire SQ‐LNS if it is made available for purchase . In Ghana , WTP was higher among heads of household than among mothers , which may be related to control over household re sources . Personal experience using SQ‐LNS was not associated with WTP in either site [5901033] Abstract Pregnant and post‐partum women require increased nutrient intake and optimal cognition , which depends on adequate nutrition , to enable reasoning and learning for caregiving . We aim ed to assess ( a ) differences in maternal cognition and caregiving between women in Malawi who received different nutritional supplements , ( b ) 14 effect modifiers , and ( c ) associations of cognition and caregiving with biomarkers of iron , Vitamin A , B‐vitamin , and fatty acid status . In a r and omized controlled trial ( n = 869 ) , pregnant women daily received either multiple micronutrients ( MMN ) , 20 g/day lipid‐based nutrient supplements ( LNS ) , or a control iron/folic acid ( IFA ) tablet . After delivery , supplementation continued in the MMN and LNS arms , and the IFA control group received placebo until 6 months post‐partum , when cognition ( n = 712 ) , caregiving behaviour ( n = 669 ) , and biomarkers of nutritional status ( n = 283 ) were assessed . In the full group , only one difference was significant : the IFA arm scored 0.22 SD ( 95 % CI [ 0.01 , 0.39 ] , p = .03 ) higher than the LNS arm in mental rotation . Among subgroups of women with baseline low hemoglobin , poor iron status , or malaria , those who received LNS scored 0.4 to 0.7 SD higher than the IFA arm in verbal fluency . Breastmilk docosahexaenoic acid and Vitamin B12 concentrations were positively associated with verbal fluency and digit span forward ( adjusting for covariates ps < .05 ) . In this population in Malawi , maternal supplementation with MMN or LNS did not positively affect maternal cognition or caregiving . Maternal docosahexaenoic acid and B12 status may be important for post‐partum attention and executive function [5004276] Background Supplementing pregnant and lactating mothers with small quantity lipid-based nutrient supplements ( SQ-LNS ) has result ed in improvements in birth outcomes in some low-income setting s. In order to be effective , SQ-LNS must be consumed regularly over sustained periods . Methods The objective was to assess and compare acceptability of and adherence to SQ-LNS consumption among pregnant and lactating women in Ghana and Malawi throughout 12 months of supplementation . We enrolled women before 20 gestation weeks into r and omized trials in Ghana ( n = 1320 ) and Malawi ( n = 869 ) . In the SQ-LNS group participants received a 20 g sachet of supplement per day during pregnancy and the first 6 months of lactation . In the control groups participants received multiple micronutrients ( MMN ) during pregnancy and lactation or iron and folic acid ( IFA ) during pregnancy and calcium during lactation . We used question naires to collect data on self-reported adherence to daily use of supplements and conducted in-depth interviews with women in the SQ-LNS group to examine acceptability . Results The mean self-reported adherence during the supplementation period was lower in Ghana ( 79.9 % ) than in Malawi ( 91.7 % ) for all supplements ( difference 11.8 % , P < 0.001 ) . Over time , adherence increased in Malawi but decreased in Ghana . In both countries , adherence in the SQ-LNS group was non-inferior to that in the control groups . Participants typically reported consuming SQ-LNS as instructed but when interviewers queried about experiences , most of the women described incidents of non-adherence . A usual reason for not consuming SQ-LNS was nausea and vomiting during pregnancy . Especially in Malawi , women reported sharing SQ-LNS with families and friends . Sustained use of SQ-LNS was attributed to expected health benefits and favorable sensory attributes . Often women compared their pregnancy to previous ones , and were of the view that SQ-LNS made a positive difference . ConclusionS elf-reported sustained adherence to consume SQ-LNS daily was high in both sites but lower in Ghana than in Malawi . In Ghana , adherence decreased over time whereas in Malawi adherence increased . Acceptability and adherence appeared interlinked , complex and context -related . Sustained consumption of SQ-LNS may require tailoring interventions by context .Trial registration The Ghana trial was registered at clinical trials.gov as NCT00970866 , and the Malawi trial as NCT01239693 [12885713] BACKGROUND The World Health Organization recommends a liquid , milk-based diet ( F100 ) during the rehabilitation phase of the treatment of severe malnutrition . A dry , solid , ready-to-use food ( RTUF ) that can be eaten without adding water has been proposed to eliminate the risk of bacterial contamination from added water . The efficacies of RTUF and F100 have not been compared . OBJECTIVE The objective was to compare the efficacy of RTUF and F100 in promoting weight gain in malnourished children . DESIGN In an open-labeled , r and omized trial , 70 severely malnourished Senegalese children aged 6 - 36 mo were r and omly allocated to receive 3 meals containing either F100 ( n = 35 ) or RTUF ( n = 35 ) in addition to the local diet . The data from 30 children in each group were analyzed . RESULTS The mean ( + /- SD ) daily energy intake in the RTUF group was 808 + /- 280 ( 95 % CI : 703.8 , 912.9 ) kJ x kg body wt(-1 ) x d(-1 ) , and that in the F100 group was 573 + /- 201 ( 95 % CI : 497.9 , 648.7 ) kJ. kg body wt(-1 ) x d(-1 ) ( P < 0.001 ) . The average weight gains in the RTUF and F100 groups were 15.6 ( 95 % CI : 13.4 , 17.8 ) and 10.1 ( 95 % CI : 8.7 , 11.4 ) g x kg body wt(-1 ) x d(-1 ) , respectively ( P < 0.001 ) . The difference in weight gain was greater in the most wasted children ( P < 0.05 ) . The average duration of rehabilitation was 17.3 ( 95 % CI : 15.6 , 19.0 ) d in the F100 group and was 13.4 ( 95 % CI : 12.1 , 14.7 ) d in the RTUF group ( P < 0.001 ) . CONCLUSIONS This study indicated that RTUF can be used efficiently for the rehabilitation of severely malnourished children [5762799] We examined the impact on depression at 6 months postpartum of maternal supplementation with small-quantity lipid-based nutrient supplement ( SQ-LNS ) compared to supplementation with iron and folic acid ( IFA ) or multiple micronutrients ( MMN ) . In this partially double-blinded r and omized controlled trial , pregnant women ≤20 weeks gestation ( n = 1320 ) were recruited from antenatal clinics and r and omly assigned to receive either ( 1 ) SQ-LNS during pregnancy and for 6 months postpartum , or ( 2 ) IFA during pregnancy only , or ( 3 ) MMN during pregnancy and for 6 months postpartum . Maternal depressive symptoms were measured at 6 months postpartum using the Edinburgh Postnatal Depression Scale ( EPDS ) . Women who scored 12 or more on the EPDS were considered to show symptoms of depression . One thous and one hundred fifty-one women were included in this analysis ( LNS = 382 , IFA = 387 and MMN = 382 ) . Characteristics of the three groups were similar at baseline , and there were no significant differences between women who were included in the analysis ( n = 1151 ) and those who were not ( n = 169 ) . At 6 months postpartum , 13 % of the women overall showed symptoms of depression , and this did not differ by group ( LNS = 13.1 % , IFA = 11.2 % and MMN = 14.7 % . P = 0.36 ) . The median ( 25 , 75 percentile ) EPDS score did not differ by group ( LNS 4.0 ( 1.0 , 8.0 ) , IFA 4.0 ( 1.0 , 8.0 ) , MMN 5.0 ( 2.0 , 9.0 ) , Ptransformed = 0.13 ) . Adjustment for covariates did not alter these findings . Maternal supplementation with SQ-LNS compared to MMN or IFA did not affect postnatal depressive symptoms in this sample of Ghanaian women [6866179] Abstract Small‐quantity lipid‐based nutrient supplements ( SQ‐LNS ) have been studied in efficacy and effectiveness trials , but little is known about how parents perceive the products and their effects . In a r and omised trial in Ghana , efficacy of SQ‐LNS provided to women during pregnancy and the first 6 months postpartum and to their children from 6 to 18 months of age was assessed by comparison with iron‐folic acid ( IFA ) capsules and multiple micronutrient ( MMN ) capsules provided to women . In a follow‐up study conducted when the index children from the original trial were between 4 and 6 years of age , we used survey‐based methods to assess retrospective and current parental perceptions of nutrient supplements generally and of SQ‐LNS and their effects compared with perceptions IFA and MMN capsules . Most parents perceived that the assigned supplements ( SQ‐LNS , IFA , or MMN ) positively impacted the mother during pregnancy ( approximately 89 % of both mothers and fathers ) and during lactation ( 84 % of mothers and 86 % of fathers ) . Almost all ( ≥90 % ) of mothers and fathers perceived that the assigned supplement positively impacted the index child and expected continued positive impacts on the child 's health and human capital into the future . A smaller percentage of parents perceived negative impacts of the supplements ( 7%–17 % of mothers and 4%–12 % of fathers ) . Perceptions of positive impacts and of negative impacts did not differ by intervention group . The results suggest that similar population s would likely be receptive to programs to deliver SQ‐LNS or micronutrient capsules [26898720] Limited knowledge exists on sustained adherence to small-quantity lipid-based nutrient supplements for pregnant and lactating women ( LNS-PL ) and how this compares with that of other prenatal supplements . To address these gaps , a r and om sub sample of women ( n = 360 ) during pregnancy , early ( 6- to 12-week post-partum ) and late ( 12- to 24-week post-partum ) lactation , from an ongoing effectiveness trial in Bangladesh , was selected for in-home interviews about LNS-PL or iron/folic acid ( IFA ) use and preferences . Prevalence of high adherence ( ≥70 % of the recommendation ) based on self-reported supplement consumption was 67 % , 68 % and 81 % among LNS-PL recipients during pregnancy , early and late lactation , and was 87 % and 71 % among IFA recipients during pregnancy and early lactation , respectively ( P = 0.044 ) . Programmatic factors ( e.g. distribution and visits by programme staff ) were consistently statistically significantly associated with reported high adherence . Among LNS-PL recipients , high overall supplement acceptability score [ odds ratio ( OR ) : 8.62 ; 95 % confidence interval ( CI ) 3.53 , 20.83 ] and use of reminder techniques ( OR : 4.41 ; 95%CI 1.65 , 11.76 ) were positively associated , and reported vomiting at enrollment was negatively associated ( OR : 0.34 ; 95%CI 0.14 , 0.80 ) , with reported high adherence . Selected women ( n = 16 ) and key informants ( n = 18 ) participated in in-depth interviews about perceptions and acceptability of LNS-PL . Women perceived benefits of taking LNS-PL , but some faced barriers to consumption including aversion to odour and taste during pregnancy , forgetfulness and disruptions in supply . To achieve high adherence , results from this study suggest that maternal supplementation programmes should focus on programmatic barriers and consider incorporating reminder techniques . Organoleptic acceptability of LNS-PL , particularly during pregnancy , may also need to be addressed [27060705] Abstract Perinatal depression is highly prevalent in low‐ and ‐middle‐income countries and has been linked to poor child health . Suboptimal maternal nutrition may be a risk factor for perinatal depression . In this r and omised‐controlled trial conducted in rural Malawi , we set out to test the hypothesis that women taking a fatty acid‐rich lipid‐based nutrient supplement ( LNS ) would have fewer depressive symptoms postpartum than those taking iron‐folate ( IFA ) or multiple‐micronutrient ( MMN ) capsules . Women were recruited from antenatal clinics and r and omised to receive LNS or MMN during pregnancy and for 6 months postpartum , or IFA during pregnancy only . Maternal depressive symptoms were measured using vali date d translations of the Self Reporting Question naire ( SRQ ) and Edinburgh Postnatal Depression Scale ( EPDS ) , antenatally ( SRQ only ) and at 6 months postpartum ( SRQ and EPDS ) . Analysis was by modified intention to treat . One thous and three hundred and ninety one women were r and omised ( LNS = 462 , MMN = 466 , IFA = 463 ) . The groups were similar across a range of baseline variables . At 6 months postpartum , 1078 ( 77.5 % ) had SRQ completed ; mean ( SD ) scores were LNS 1.76(2.73 ) , MMN 1.92(2.75 ) , IFA 1.71(2.66 ) , P = 0.541 . One thous and and fifty seven ( 76.0 % ) had EPDS completed ; mean ( SD ) scores were LNS 5.77(5.53 ) , MMN 5.43(4.97 ) , IFA 5.52(5.18 ) , P = 0.676 . There were no statistically significant differences between the groups on SRQ or EPDS scores ( continuous or dichotomised ) in unadjusted or adjusted models . In conclusion , fortification of maternal diet with LNS compared with MMN or IFA did not reduce postnatal depressive symptoms in this study [27440259] BACKGROUND Maternal undernutrition and low macro- and micronutrient intake and weight gain during pregnancy have been reported in Bangladesh . OBJECTIVE We aim ed to determine the effects of lipid-based nutrient supplements for pregnant and lactating women ( LNS-PL ) on weight gain and midupper arm circumference ( MUAC ) during pregnancy . METHODS The Rang-Din Nutrition Study , a cluster-r and omized effectiveness trial conducted in Bangladesh , enrolled 4011 pregnant women at ≤20 wk gestation who received either 60 mg Fe + 400 μg folic acid/d or 20 g LNS-PL/d ( 118 kcal ) containing essential fatty acids and vitamins and minerals until delivery . At 36 wk gestation , women were interviewed at home and then attended a follow-up examination at local clinics ( n = 2877 ) , where anthropometric measurements were taken . RESULTS No significant differences between intervention groups in maternal weight gain per week , low weight gain per week , or MUAC at 36 wk gestation were observed in the full sample . However , among multiparous women aged ≥25 y , those in the LNS-PL group gained 34 g/wk more than their counterparts in the iron and folic acid ( IFA ) group ( P = 0.001 ) , whereas no differences were seen in the other parity/age subgroups . Women aged ≥25 y in the LNS-PL group had a 0.4-cm greater MUAC than their counterparts in the IFA group ( P = 0.003 ) ; no significant differences were observed in the other age groups . Among women whose height at baseline was in the lowest quartile of the distribution , those in the LNS-PL group had a 0.1 - 0.3-cm greater MUAC at 36 wk gestation than those in the IFA group ( P = 0.004 - 0.014 ) . CONCLUSIONS Lipid-based nutrient supplements provided during pregnancy did not affect maternal anthropometric indicators in the overall sample but increased MUAC among women aged ≥25 y and those with lower stature and weight gain among multiparous women aged ≥25 y. This trial was registered at clinical trials.gov as NCT01715038 [4438573] Background Malaria and undernutrition frequently coexist , especially in pregnant women and young children . Nutrient supplementation of these vulnerable groups might reduce their susceptibility to malaria by improving immunity . Methods Antibody immunity to antigens expressed by a placental-binding parasite isolate , a non-placental binding parasite isolate , merozoites and schizonts at enrolment ( before 20 gestation weeks ) and at 36 gestation weeks were measured in 1,009 Malawian pregnant women receiving a daily lipid-based nutrient supplement , multiple micronutrients or iron and folic acid , who were participants in a r and omized clinical trial assessing the effects of nutrient supplementation on pregnancy outcomes and child development ( registration ID : NCT01239693 ) . Results Antibodies to placental-binding isolates significantly increased while antibodies to most merozoite antigens declined over pregnancy . Overall , after adjustment for covariates , the type of supplementation did not influence antibody levels at 36 gestation weeks or the rate of change in antibody levels from enrolment to 36 weeks . A negative association between maternal body mass index and opsonizing antibodies to placental-binding antigens ( coefficient ( 95 % CI ) -1.04 ( −1.84 , −0.24 ) , was observed . Similarly , women with higher socioeconomic status had significantly lower IgG and opsonizing antibodies to placental-binding antigens . Neither of these associations was significantly influenced by the supplementation type . Conclusions In the current cohort nutrient supplementation did not affect anti-malarial antibody responses , but poor and undernourished mothers should be a priority group in future trials [26764321] BACKGROUND High circulating cortisol is associated with miscarriage , preterm birth , and low birth weight . Research in nonpregnant individuals suggests that improved nutrition may lower cortisol concentrations . It is unknown whether nutritional supplementation during pregnancy lowers cortisol . OBJECTIVE Our objective was to determine whether women receiving a lipid-based nutrient supplement ( LNS ) throughout pregnancy would have lower salivary cortisol at 36 wk gestation compared with women receiving other nutrient supplements . METHODS We conducted a r and omized controlled trial in 1320 pregnant Ghanaian women at ≤20 wk gestation who were assigned to receive daily throughout pregnancy : 1 ) 60 mg iron + 400 μg folic acid ( IFA ) , 2 ) multiple micronutrients ( MMNs ) , or 3 ) 20 g LNS ( containing 118 kcal , 22 micronutrients , and protein ) . Morning salivary cortisol was collected from a sub sample at baseline and at 28 and 36 wk gestation . RESULTS A total of 758 women had cortisol measurements at 28 or 36 wk gestation . Salivary cortisol at 36 wk gestation did not differ between groups and was ( mean ± SE ) 7.97 ± 0.199 in the IFA group , 7.84 ± 0.191 in the MMN group , and 7.77 ± 0.199 nmol/L in the LNS group , when adjusted for baseline cortisol , time of waking , and time between waking and saliva collection ( P = 0.67 ) . There was an interaction between supplementation group and women 's age ( continuous variable , P-interaction = 0.03 ) ; and when age was dichotomized by the median , significant differences in salivary cortisol concentrations between groups were seen in women ≤26 y of age ( IFA = 8.23 ± 0.284 nmol/L , MMN = 8.20 ± 0.274 nmol/L , and LNS = 7.44 ± 0.284 nmol/L ; P = 0.03 ) but not in women > 26 y old ( IFA = 7.71 ± 0.281 nmol/L , MMN = 7.50 ± 0.274 nmol/L , and LNS = 8.08 ± 0.281 nmol/L ; P = 0.13 ) . CONCLUSIONS We conclude that supplementation with LNSs or MMNs during pregnancy did not affect the cortisol concentration in the study population as a whole , in comparison with IFA , but that LNS consumption among younger women may lead to lower cortisol at 36 wk gestation . This trial was registered at clinical trials.gov as NCT00970866 [25646337] BACKGROUND Small birth size , often associated with insufficient maternal nutrition , contributes to a large share of global child undernutrition , morbidity , and mortality . We developed a small-quantity lipid-based nutrient supplement ( SQ-LNS ) to enrich the diets of pregnant women . OBJECTIVE The objective was to test a hypothesis that home fortification of pregnant women 's diets with SQ-LNS would increase birth size in an African community . DESIGN We enrolled 1391 women with uncomplicated pregnancies ( < 20 gestational weeks ) in a r and omized controlled trial in Malawi . The women were provided with one daily iron-folic acid ( IFA ) capsule , one capsule containing multiple micronutrients ( MMNs ) , or one 20-g sachet of SQ-LNS ( LNS , containing 118 kcal , protein , carbohydrates , essential fatty acids , and 21 micronutrients ) . Primary outcomes were birth weight and newborn length . Secondary outcomes included newborn weight , head and arm circumference , and pregnancy duration . Analysis was by intention to treat . RESULTS The mean ± SD birth weight and newborn length were 2948 ± 432 , 2964 ± 460 , and 3000 ± 447 g ( P = 0.258 ) and 49.5 ± 2.4 , 49.7 ± 2.2 , and 49.9 ± 2.1 cm ( P = 0.104 ) in the IFA , MMN , and LNS groups , respectively . For newborn weight-for-age , head circumference , and arm circumference , the point estimate for the mean was also highest in the LNS group , intermediate in the MMN group , and lowest in the IFA group , but except for midupper arm circumference ( P = 0.024 ) , the differences were not statistically significant . The prevalence of low birth weight ( < 2500 g ) was 12.7 % , 13.5 % , and 12.1 % ( P = 0.856 ) , respectively ; newborn stunting ( length-for-age z score < -2 ) was 19.2 % , 14.0 % , and 14.9 % ( P = 0.130 ) , respectively ; and newborn small head circumference ( head circumference-for-age z score < -2 ) was 5.8 % , 3.0 % , and 3.1 % ( P = 0.099 ) , respectively . The associations between the intervention and the outcomes were not modified by maternal parity , age , or nutritional status ( P > 0.100 ) . CONCLUSION The study findings do not support a hypothesis that provision of SQ-LNS to all pregnant women would increase the mean birth size in rural Malawi . The trial was registered at clinical trials.gov as NCT01239693 [19812173] BACKGROUND Prenatal multiple micronutrient ( MMN ) or balanced energy and protein supplementation has a limited effect on birth size of the offspring . OBJECTIVE The objective was to determine whether a prenatal MMN-fortified food supplement ( FFS ) improves anthropometric measures at birth compared with supplementation with an MMN pill alone . DESIGN We conducted a nonblinded , individually r and omized controlled trial in 1296 pregnant women in 2 villages in rural Burkina Faso . Supplements were provided on a daily basis , and compliance was closely verified by using a community-based network of home visitors . RESULTS Anthropometric measures at birth were available for analysis for 87 % of the 1175 live singleton deliveries enrolled . After adjustment for gestational age at birth , the FFS group had a significantly higher birth length ( + 4.6 mm ; P = 0.001 ) . FFS supplementation result ed in a modestly higher birth weight ( + 31 g ; P = 0.197 ) . Subgroup analyses showed clinical ly important treatment effects on birth length ( + 12.0 mm ; P = 0.005 ) and on birth weight ( + 111 g ; P = 0.133 ) for underweight [ body mass index ( in kg/m(2 ) ) < 18.5 ] pregnant women . Women with early pregnancy anemia who received FFS gave birth to longer newborns ( + 7.3 mm ; P = 0.002 ) than did those who received MMN supplementation . CONCLUSIONS The provision of FFS to pregnant women result ed in higher birth length than did MMN supplementation . For women with a suboptimal prepregnancy nutritional status , MMN supplementation should be complemented with a balanced energy and protein supplement to produce a clinical effect on birth size . The trial was registered at clinical trials.gov as NCT00909974 [28275128] Background : Nutrition during the first 1000 d is critical for brain development . Objective : We evaluated the effects on child development of home fortification with lipid-based nutrient supplements ( LNSs ) for mothers and /or children or micronutrient powder ( MNP ) for children . Design : We conducted a cluster-r and omized effectiveness trial with 4 arms : 1 ) LNSs during pregnancy and the first 6 mo postpartum and LNSs for the offspring from 6 to 24 mo ( LNS-LNS ) , 2 ) iron and folic acid ( IFA ) during pregnancy and the first 3 mo postpartum and LNSs for the children from 6 to 24 mo ( IFA-LNS ) , 3 ) IFA ( as above ) and MNP for the offspring from 6 to 24 mo ( IFA-MNP ) , and 4 ) IFA ( as above ) and no child supplement ( IFA-Control ) . Women were enrolled at ≤20 wk of gestation ; children were assessed at 12 ( n = 3331 ) , 18 ( n = 3364 ) , and 24 ( n = 3379 ) mo . Results : Compared with the IFA-Control group , motor development scores were higher in the LNS-LNS ( P = 0.016 ) and IFA-LNS groups ( P = 0.006 ) at 18 mo and in the IFA-MNP group ( P = 0.048 ) at 24 mo . Receptive language scores were higher for the LNS-LNS group ( P = 0.028 ) at 18 mo and for all 3 groups at 24 mo ( P = 0.008 for LNS-LNS , P = 0.022 for IFA-LNS , and P = 0.009 for IFA-MNP compared with IFA-Control ) . Expressive language scores did not differ at 18 mo ( P = 0.236 ) but were higher in the LNS-LNS ( P = 0.035 ) and IFA-MNP ( P = 0.002 ) groups than in the IFA-Control group at 24 mo . Groups did not differ in personal-social scores at 18 ( P = 0.233 ) or 24 ( P = 0.146 ) mo or in executive function score at 24 mo ( P = 0.467 ) . Conclusion : Prenatal LNSs , postnatal LNSs , or both , or postnatal MNP had a positive effect on motor and language development in Bangladeshi children . This trial was registered at clinical trials.gov as NCT01715038 [5610548] Background : Human milk oligosaccharides ( HMOs ) and bioactive proteins are beneficial to infant health . Recent evidence suggests that maternal nutrition may affect the amount of HMOs and proteins in breast milk ; however , the effect of nutrient supplementation on HMOs and bioactive proteins has not yet been well studied . Objective : We aim ed to determine whether lipid-based nutrient supplements ( LNSs ) affect milk bioactive protein and HMO concentrations at 6 mo postpartum in women in rural Malawi . These are secondary outcomes of a previously published r and omized controlled trial . Methods : Women were r and omly assigned to consume either an iron and folic acid capsule ( IFA ) daily from ≤20 wk gestation until delivery , followed by placebo daily from delivery to 6 mo postpartum , or a multiple micronutrient ( MMN ) capsule or LNS daily from ≤20 wk gestation to 6 mo postpartum . Breast milk concentrations of total HMOs , sialylated HMOs , fucosylated HMOs , lactoferrin , lactalbumin , lysozymes , antitrypsin , immunoglobulin A , and osteopontin were analyzed at 6 mo postpartum ( n = 647 ) . Between-group differences in concentrations and in proportions of women classified as having low concentrations were tested . Results : HMO and bioactive protein concentrations did not differ between groups ( P > 0.10 for all comparisons ) . At 6 mo postpartum , the proportions of women with low HMOs or bioactive proteins were not different between groups except for osteopontin . A lower proportion of women in the IFA group had low osteopontin compared with the LNS group after adjusting for covariates ( OR : 0.5 ; 95 % CI : 0.3 , 0.9 ; P = 0.016 ) . Conclusion : The study findings do not support the hypothesis that supplementation with an LNS or MMN capsule during pregnancy and postpartum would increase HMO or bioactive milk proteins at 6 mo postpartum among Malawian women . This trial was registered at clinical trials.gov as NCT01239693 [22649265] The Breastfeeding , Antiretrovirals , and Nutrition Study evaluated the effect of daily consumption of lipid-based nutrient supplements ( LNS ) by 2121 lactating , HIV-infected mothers on the growth of their exclusively breast-fed , HIV-uninfected infants from 0 to 24 wk . The study had a 2 × 3 factorial design . Malawian mothers with CD4(+ ) ≥250 cells/mm(3 ) , hemoglobin ≥70 g/L , and BMI ≥17 kg/m(2 ) were r and omized within 36 h of delivery to receive either no LNS or 140 g/d of LNS to meet lactation energy and protein needs , and mother-infant pairs were assigned to maternal antiretroviral drugs ( ARV ) , infant ARV , or no ARV . Sex-stratified , longitudinal , r and om effects models were used to estimate the effect of the 6 study arms on infant weight , length , and BMI . Logistic regression models were used to calculate the odds of growth faltering [ decline in weight-for-age Z-score ( WAZ ) or length-for-age Z-score ( LAZ ) > 0.67 ] using the control arm as the reference . Although some differences between study arms emerged with increasing infant age in boys , there were no consistent effects of the maternal supplement across the 3 growth outcomes in longitudinal models . At the ages where differences were observed , the effects on weight and BMI were quite small ( ≤200 g and ≤0.4 kg/m(2 ) ) and unlikely to be of clinical importance . Overall , 21 and 34 % of infants faltered in WAZ and LAZ , respectively . Maternal supplementation did not reduce the odds of infant weight or length faltering from 0 to 24 wk in any arm . These results indicate that blanket supplementation of HIV-infected lactating women may have little impact on infant growth [5338685] It is unknown whether a novel small-quantity lipid-based nutrient supplement ( SQ-LNS ) containing alpha-linolenic ( ALA ) and linoleic acids impacts maternal plasma lipids and fatty acid status . We measured plasma fatty acids ( wt% ) and lipid concentrations at 36 wk gestation and breast milk fatty acids ( wt% ) at 6 months postpartum in a sub sample of women enrolled in a r and omized controlled trial study ing the effects of SQ-LNS on birth outcomes and child growth . Women≤20 wk gestation in Ghana ( n=1,320 ) and Malawi ( n=1,391 ) were assigned to receive daily either : 1 ) iron-folic acid ( pregnancy ) ; 2 ) multiple micronutrients ( pregnancy and lactation ) ; or 3 ) SQ-LNS ( pregnancy and lactation ) . At 36 wk , plasma ALA levels were higher in those receiving SQ-LNS . SQ-LNS increased breast milk ALA in Ghana but not Malawi . There was no effect on plasma lipids or other selected fatty acids . SQ-LNS may impact plasma and breast milk ALA levels depending on the population [4997301] Background : Childhood stunting usually begins in utero and continues after birth ; therefore , its reduction must involve actions across different stages of early life . Objective : We evaluated the efficacy of small-quantity , lipid-based nutrient supplements ( SQ-LNSs ) provided during pregnancy , lactation , and infancy on attained size by 18 mo of age . Design : In this partially double-blind , individually r and omized trial , 1320 women at ≤20 wk of gestation received st and ard iron and folic acid ( IFA group ) , multiple micronutrients ( MMN group ) , or SQ-LNS ( LNS group ) daily until delivery , and then placebo , MMNs , or SQ-LNS , respectively , for 6 mo postpartum ; infants in the LNS group received SQ-LNS formulated for infants from 6 to 18 mo of age ( endline ) . The primary outcome was child length by 18 mo of age . Results : At endline , data were available for 85 % of 1228 infants enrolled ; overall mean length and length-for-age z score ( LAZ ) were 79.3 cm and −0.83 , respectively , and 12 % of the children were stunted ( LAZ < −2 ) . In analysis based on the intended treatment , mean ± SD length and LAZ for the LNS group ( 79.7 ± 2.9 cm and −0.69 ± 1.01 , respectively ) were significantly greater than for the IFA ( 79.1 ± 2.9 cm and −0.87 ± 0.99 ) and MMN ( 79.1 ± 2.9 cm and −0.91 ± 1.01 ) groups ( P = 0.006 and P = 0.009 , respectively ) . Differences were also significant for weight and weight-for-age z score but not head or midupper arm circumference , and the prevalence of stunting in the LNS group was 8.9 % , compared with 13.7 % in the IFA group and 12.9 % in the MMN group ( P = 0.12 ) . In analysis based on actual supplement provided at enrollment , stunting prevalences were 8.9 % compared with 15.1 % and 11.5 % , respectively ( P = 0.045 ) . Conclusion : Provision of SQ-LNSs to women from pregnancy to 6 mo postpartum and to their infants from 6 to 18 mo of age may increase the child ’s attained length by age 18 mo in similar setting s. This trial was registered at clinical trials.gov as NCT00970866 [4891833] Background Over half of the world ’s children suffer from poor nutrition , and as a consequence they experience delays in physical and mental health , and cognitive development . There is little data evaluating the effects of delivery of lipid-based , nutrition supplementation on growth and development during pregnancy and early childhood within the context of a scaled-up program . Furthermore , there is limited evidence on effects of scaled-up , home-visiting programs that focus on the promotion of child development within the context of an existing , national nutrition program . Methods / Design The MAHAY ( " smart " in Malagasy ) study uses a multi-arm r and omized-controlled trial ( RCT ) to test the effects and cost-effectiveness of combined interventions to address chronic malnutrition and poor child development . The arms of the trial are : ( T0 ) existing program with monthly growth monitoring and nutritional/hygiene education ; ( T1 ) is T0 + home visits for intensive nutrition counseling within a behavior change framework ; ( T2 ) is T1 + lipid-based supplementation ( LNS ) for children 6–18 months old ; ( T3 ) is T2 + LNS supplementation of pregnant/lactating women ; and ( T4 ) is T1 + intensive home visiting program to support child development . There are anticipated to be n = 25 communities in each arm ( n = 1250 pregnant women , n = 1250 children 0–6 months old , and n = 1250 children 6–18 months old ) . Primary outcomes include growth ( length/height-for-age z-scores ) and child development ( mental , motor and social development ) . Secondary outcomes include care-giver reported child morbidity , household food security and diet diversity , micro-nutrient status , maternal knowledge of child care and feeding practice s , and home stimulation practice s. We will estimate unadjusted and adjusted intention-to-treat effects . Study protocol s have been review ed and approved by the Malagasy Ethics Committee at the Ministry of Health in Madagascar and by the institutional review board at the University of California , Davis . This study is funded by the Strategic Impact Evaluation Fund ( SIEF ) , the World Bank Innovation Grant , the Early Learning Partnership Grant , the Japan Scaling-up for Nutrition Trustfund , and Gr and Challenges Canada . The implementation of the study is financed by Madagascar 's National Nutrition Office . Trial registration Current Controlled Trials IS RCT N14393738 . Registered June 23 , 2015 [26607935] BACKGROUND Maternal undernutrition and newborn stunting [ birth length-for-age z score ( LAZ ) < -2 ] are common in Bangladesh . OBJECTIVE The objective was to evaluate the effect of lipid-based nutrient supplements for pregnant and lactating women ( LNS-PLs ) on birth outcomes . DESIGN We conducted a cluster-r and omized effectiveness trial ( the Rang-Din Nutrition Study ) within a community health program in rural Bangladesh . We enrolled 4011 pregnant women at ≤20 gestational weeks ; 48 clusters received iron and folic acid ( IFA ; 60 mg Fe + 400 μg folic acid ) and 16 clusters received LNS-PLs ( 20 g/d , 118 kcal ) containing essential fatty acids and 22 vitamins and minerals . Both of the supplements were intended for daily consumption until delivery . Primary outcomes were birth weight and length . RESULTS Infants in the LNS-PL group had higher birth weights ( 2629 ± 408 compared with 2588 ± 413 g ; P = 0.007 ) , weight-for-age z scores ( -1.48 ± 1.01 compared with -1.59 ± 1.02 ; P = 0.006 ) , head-circumference-for-age z scores ( HCZs ; -1.26 ± 1.08 compared with -1.34 ± 1.12 ; P = 0.028 ) , and body mass index z scores ( -1.57 ± 1.05 compared with -1.66 ± 1.03 ; P = 0.005 ) than those in the IFA group ; in adjusted models , the differences in length ( 47.6 ± 0.07 compared with 47.4 ± 0.04 cm ; P = 0.043 ) and LAZ ( -1.15 ± 0.04 compared with -1.24 ± 0.02 ; P = 0.035 ) were also significant . LNS-PLs reduced the risk of newborn stunting ( 18.7 % compared with 22.6 % ; RR : 0.83 ; 95 % CI : 0.71 , 0.97 ) and small head size ( HCZ < -2 ) ( 20.7 % compared with 24.9 % ; RR : 0.85 ; 95 % CI : 0.73 , 0.98 ) . The effects of LNS-PL on newborn stunting were greatest in infants born before a 10-wk interruption in LNS-PL distribution ( n = 1301 ; 15.7 % compared with 23.6 % ; adjusted RR : 0.69 ; 95 % CI : 0.53 , 0.89 ) and in infants born to women ≤24 y of age or with household food insecurity . CONCLUSION Prenatal lipid-based nutrient supplements can improve birth outcomes in Bangladeshi women , especially those at higher risk of fetal growth restriction . This trial was registered at clinical trials.gov as NCT01715038 [18606932] OBJECTIVE To compare growth and incidence of malnutrition in infants receiving long-term dietary supplementation with ready-to-use fortified spread ( FS ) or micronutrient-fortified maize-soy flour ( likuni phala [ LP ] ) . DESIGN R and omized , controlled , single-blind trial . SETTING Rural Malawi . PARTICIPANTS A total of 182 six-month-old infants . INTERVENTION Participants were r and omized to receive 1 year of daily supplementation with 71 g of LP ( 282 kcal ) , 50 g of FS ( FS50 ) ( 256 kcal ) , or 25 g of FS ( FS25 ) ( 130 [ corrected ] kcal ) . OUTCOME MEASURES Weight and length gains and the incidences of severe stunting , underweight , and wasting . RESULTS Mean weight and length gains in the LP , FS50 , and FS25 groups were 2.37 , 2.47 , and 2.37 kg ( P = .66 ) and 12.7 , 13.5 , and 13.2 cm ( P = .23 ) , respectively . In the same groups , the cumulative 12-month incidence of severe stunting was 13.3 % , 0.0 % , and 3.5 % ( P = .01 ) , of severe underweight was 15.0 % , 22.5 % , and 16.9 % ( P = .71 ) , and of severe wasting was 1.8 % , 1.9 % , and 1.8 % ( P > .99 ) . Compared with LP-supplemented infants , those given FS50 gained a mean of 100 g more weight and 0.8 cm more length . There was a significant interaction between baseline length and intervention ( P = .04 ) ; in children with below-median length at enrollment , those given FS50 gained a mean of 1.9 cm more than individuals receiving LP . CONCLUSION One-year-long complementary feeding with FS does not have a significantly larger effect than LP on mean weight gain in all infants , but it is likely to boost linear growth in the most disadvantaged individuals and , hence , decrease the incidence of severe stunting [21496207] Inadequate micronutrient intake during pregnancy , lactation and infancy is a major problem in many developing countries . Lipid-based nutrient supplements ( LNS ) can improve micronutrient status , growth and development of infants , and also have potential to improve nutritional status of pregnant and lactating women . The objective of the study was to test the acceptability of LNS design ed for infants ( LNS-20gM ) and pregnant or lactating women ( LNS-P&L ) . Participants were infants ( n = 22 , mean age = 8 months ) and pregnant or lactating women ( n = 24 ) attending routine services at a hospital in Ghana . Infants consumed 45 g of a test meal consisting of one part LNS-20gM and three parts fermented maize porridge , while women consumed 50 g of a similar test meal containing LNS-P&L instead . Participants also used their respective LNS at home for 14 days . Primary outcome was the proportion of the test meal consumed . On average , infants consumed 76.2 % of the test meal [ 95 % ( confidence interval ) CI : 65.7 , 86.7 ] , while women consumed 87.1 % ( 95 % CI : 82.6 , 91.6 ) . During the 14-day period , median daily consumption of LNS-20gM was 19.3 g , very close to the recommended 20 g d(-1 ) , while that of LNS-P&L was one sachet , as recommended . We conclude that LNS-20gM and LNS-P&L were well accepted [20861218] Although widely used , there is little information concerning the efficacy of corn-soy blend ( CSB ) supplementation in the treatment of moderate underweight in African children . Lipid-based nutrient supplements ( LNS ) , which have proven to be beneficial treatment for severely wasted children , could offer benefits to less severely affected individuals . We conducted a clinical r and omized trial to determine whether LNS or CSB supplementation improves weight gain of moderately underweight children . A total of 182 underweight [ weight-for-age Z-score ( WAZ ) < -2 ] 6- to 15-mo-old children were r and omized to receive for 12 wk a ration of 43 g/d LNS or 71 g/d CSB , providing 1189 and 921 kJ , respectively , or no supplementation ( control ) . The primary outcome was weight change ; secondary outcomes included changes in anthropometric indices , hemoglobin levels , and morbidity . The body weight increases ( mean ± SD ) did not differ and were 620 ± 470 , 510 ± 350 , and 470 ± 350 g in the LNS , CSB , and control groups , respectively ( P = 0.11 ) . Compared with controls , infants and children in the LNS group gained more weight [ mean ( 95 % CI ) = 150 g ( 0 - 300 g ) ; P = 0.05 ] and had a greater increase in WAZ [ 0.33 ( -0.02 - 0.65 ) ; P = 0.04 ] . Weight and WAZ changes did not differ between the control and CSB groups . In exploratory stratified analysis , the weight increase was higher in the LNS group compared with the control group among those with lower initial WAZ [ 250 g ( 60 - 430 g ; P = 0.01 ] . Supplementation with LNS but not CSB modestly increases weight gain among moderately underweight children and the effect appears most pronounced among those with a lower initial WAZ [28724657] Background : Pregnancy and childbirth complications and cesarean delivery are common in Bangladesh . Objective : We evaluated the effect of lipid-based nutrient supplements for pregnant and lactating women ( LNS-PL ) on pregnancy and childbirth complications and cesarean delivery . Methods : We conducted the Rang-Din Nutrition Study , a cluster-r and omized controlled effectiveness trial within a community health program in rural Bangladesh . We enrolled 4011 pregnant women in early pregnancy . Women in 48 clusters received iron and folic acid ( IFA ; 60 mg Fe + 400 μg folic acid/d ) and women in 16 clusters received LNS-PL ( 20 g/d , 118 kcal ) containing essential fatty acids and 22 vitamins and minerals . Pregnancy and childbirth complications and the cesarean delivery rate were secondary outcomes of the study . Results : Women in the LNS-PL group did not differ significantly from the IFA group with respect to mean systolic blood pressure at 36 wk gestation ( 113 and 112 mm Hg ; P = 0.17 ) , diastolic blood pressure at 36 wk gestation ( 68.9 and 68.7 mmHg ; P = 0.88 ) , or mean total number of pregnancy and childbirth complications ( 0.32 and 0.31 ; P = 0.86 ) . They also did not differ significantly with respect to the prevalence of high blood pressure at 36 wk ( 1.74 % and 2.03 % ; P = 0.62 ) , antepartum hemorrhage ( 0.83 % and 1.39 % ; P = 0.21 ) , prolonged labor ( 8.34 % and 8.79 % ; P = 0.68 ) , early rupture of membranes ( 9.30 % and 8.45 % ; P = 0.43 ) , convulsions ( 1.57 % and 1.08 % ; P = 0.24 ) , high blood pressure in labor ( 1.54 % and 1.19 % ; P = 0.46 ) , obstructed labor ( 2.83 % and 2.91 % ; P = 0.90 ) , any complications during pregnancy or childbirth ( 35.9 % and 37.1 % ; P = 0.64 ) , episiotomy ( 6.31 % and 6.44 % ; P = 0.90 ) , or cesarean delivery ( 15.6 % and 14.2 % ; P = 0.48 ) . Conclusion : Compared with IFA , antenatal LNS-PL did not increase or decrease pregnancy and childbirth complications or cesarean delivery among women in rural Bangladesh . This trial was registered at clinical trials.gov as NCT01715038 [5396370] Abstract Prenatal supplementation with protein‐energy ( PE ) and /or multiple‐micronutrients ( MMNs ) may improve fetal growth , but trials of lipid‐based nutritional supplements ( LNSs ) have reported inconsistent results . We conducted a post‐hoc analysis of non‐ primary outcomes in a trial in Gambia , with the aim to test the associations of LNS with fetal growth and explore how efficacy varies depending on nutritional status . The sample comprised 620 pregnant women in an individually r and omized , partially blinded trial with four arms : ( a ) iron and folic acid ( FeFol ) tablet ( usual care , referent group ) , ( b ) MMN tablet , ( c ) PE LNS , and ( d ) PE + MMN LNS . Analysis of variance examined unadjusted differences in fetal biometry z‐scores at 20 and 30 weeks and neonatal anthropometry z‐scores , while regression tested for modification of intervention‐ outcome associations by season and maternal height , body mass index , and weight gain . Despite evidence of between‐arm differences in some fetal biometry , z‐scores at birth were not greater in the intervention arms than the FeFol arm ( e.g. , birth weight z‐scores : FeFol −0.71 , MMN −0.63 , PE −0.64 , PE + MMN −0.62 ; group‐wise p = .796 ) . In regression analyses , intervention associations with birth weight and head circumference were modified by maternal weight gain between booking and 30 weeks gestation ( e.g. , PE + MMN associations with birth weight were + 0.462 z‐scores ( 95 % CI [ 0.097 , 0.826 ] ) in the highest quartile of weight gain but –0.099 z‐scores ( −0.459 , 0.260 ) in the lowest ) . In conclusion , we found no strong evidence that a prenatal LNS intervention was associated with better fetal growth in the whole sample [26843155] BACKGROUND Maternal and infant undernutrition is associated with poor infant development ; however , few studies have examined the impact of combined pre- and postnatal dietary supplementation on infant development . OBJECTIVE Our objective was to determine whether provision of small-quantity lipid-based nutrient supplements ( SQ-LNSs ) to mothers during pregnancy and the first 6 mo postpartum , and to children aged 6 - 18 mo , improves infant development in Malawi . DESIGN We r and omly assigned 869 pregnant women to receive one of the following daily : an iron and folic acid ( IFA ) capsule , a multiple micronutrient ( MMN ) capsule containing 18 micronutrients , or a 20-g sachet of SQ-LNSs containing 22 vitamins and minerals , protein , carbohydrates , essential fatty acids , and 118 kcal . Children in the lipid-based nutrient supplement ( LNS ) group only received SQ-LNSs from 6 to 18 mo of age . We monitored the acquisition of 11 developmental milestones monthly by maternal report ; observed the attainment of 7 motor milestones at 6 , 12 , and 18 mo of age ; and conducted a comprehensive assessment of motor , language , and socioemotional development and executive function at 18 mo of age . The primary analysis was by intention-to-treat . RESULTS By maternal report , children in the LNS group achieved walking alone ( B = 0.53 ; 95 % CI : 0.11 , 0.94 ; P = 0.034 ) and waving goodbye ( B = 0.60 ; 95 % CI : 0.12 , 1.08 ; P = 0.040 ) earlier than the IFA group and st and ing with assistance earlier than the MMN group ( B = 0.51 ; 95 % CI : 0.12 , 0.89 ; P = 0.029 ) . By research er observation , there was a trend ( P = 0.052 ) for a greater percentage of children in the LNS group ( 58 % ) to walk alone at age 12 mo than in the IFA ( 49 % ) and MMN ( 49 % ) groups . At age 18 mo , there were no significant differences between groups in any scores . CONCLUSION Although provision of SQ-LNSs to pregnant women and infants in Malawi may affect the age of acquisition of certain developmental milestones , it did not affect our assessment s of motor , language , socioemotional , or executive function skills at 18 mo of age . This trial was registered at clinical trials.gov as NCT01239693 [24500152] BACKGROUND Selenium is found in soils and is essential for human antioxidant defense and immune function . In Malawi , low soil selenium and dietary intakes coupled with low plasma selenium concentrations in HIV infection could have negative consequences for the health of HIV-infected mothers and their exclusively breastfed infants . OBJECTIVE We tested the effects of lipid-based nutrient supplements ( LNS ) that contained 1.3 times the Recommended Dietary Allowance of sodium selenite and antiretroviral drugs ( ARV ) on maternal plasma and breast-milk selenium concentrations . DESIGN HIV-infected Malawian mothers in the Breastfeeding , Antiretrovirals , and Nutrition study were r and omly assigned at delivery to receive : LNS , ARV , LNS and ARV , or a control . In a sub sample of 526 mothers and their uninfected infants , we measured plasma and breast-milk selenium concentrations at 2 or 6 ( depending on the availability of infant sample s ) and 24 wk postpartum . RESULTS Overall , mean ( ± SD ) maternal ( range : 81.2 ± 20.4 to 86.2 ± 19.9 μg/L ) and infant ( 55.6 ± 16.3 to 61.0 ± 15.4 μg/L ) plasma selenium concentrations increased , whereas breast-milk selenium concentrations declined ( 14.3 ± 11.5 to 9.8 ± 7.3 μg/L ) from 2 or 6 to 24 wk postpartum ( all P < 0.001 ) . Compared with the highest baseline selenium tertile , low and middle tertiles were positively associated with a change in maternal plasma or breast-milk selenium from 2 or 6 to 24 wk postpartum ( both P < 0.001 ) . With the use of linear regression , we showed that LNS that contained selenium and ARV were not associated with changes in maternal plasma and breast-milk selenium , but maternal selenium concentrations were positively associated with infant plasma selenium at 2 or 6 and 24 wk postpartum ( P < 0.001 ) regardless of the study arm . CONCLUSIONS Selenite supplementation of HIV-infected Malawian women was not associated with a change in their plasma or breast-milk selenium concentrations . Future research should examine effects of more readily incorporated forms of selenium ( ie , selenomethionine ) in HIV-infected breastfeeding women [22258269] BACKGROUND Breastfeeding increases metabolic dem and s on the mother , and excessive postnatal weight loss increases maternal mortality . OBJECTIVE We evaluated the efficacy of a lipid-based nutrient supplement ( LNS ) for prevention of excess weight loss in breastfeeding , HIV-infected women . DESIGN The BAN ( Breastfeeding , Antiretrovirals , and Nutrition ) Study was a r and omized controlled trial in Lilongwe , Malawi . At delivery , HIV-infected mothers and their infants were r and omly assigned according to a 2-arm ( with and without LNS ) by 3-arm ( maternal triple-antiretroviral prophylaxis , infant-nevirapine prophylaxis , or neither ) factorial design . The 28-wk LNS intervention provided daily energy ( 700 kcal ) , protein ( 20 g ) , and micronutrients ( except for vitamin A ) to meet lactation needs . Women were counseled to breastfeed exclusively for 24 wk and to wean by 28 wk . Weight change ( 0 - 28 wk ) was tested in an intent-to-treat analysis by using 2-factor ANOVA and with longitudinal mixed-effects models . RESULTS At delivery , the LNS ( n = 1184 ) and control ( n = 1185 ) groups had similar mean weights and BMI s. Women receiving the LNS had less 0 - 28-wk weight loss ( -1.97 compared with -2.56 kg , P = 0.003 ) . This difference remained significant after adjustment for maternal antiretroviral drug therapy and baseline BMI . Women receiving antiretroviral drugs had more weight loss than did those not receiving antiretroviral drugs ( -2.93 compared with -1.90 kg , P < 0.001 ) . The benefit of the LNS for reducing weight loss was observed both in those receiving antiretroviral drugs ( -2.56 compared with -3.32 kg , P = 0.019 ) and in those not receiving antiretroviral drugs ( -1.63 compared with -2.16 kg , P = 0.034 ) . CONCLUSIONS The LNS reduced weight loss among HIV-infected , breastfeeding women , both in those taking maternal antiretroviral prophylaxis to prevent postnatal HIV transmission and in those not receiving antiretroviral prophylaxis . Provision of an LNS may benefit HIV-infected , breastfeeding women in re source -limited setting s. This trial was registered at clinical trials.gov as NCT00164762 [28275125] Background : Stunting in linear growth occurs mainly during the first 1000 d , from conception through 24 mo of age . Despite the recognition of this critical period , there have been few evaluations of the growth impact of interventions that cover most of this window . Objective : We evaluated home fortification approaches for preventing maternal and child undernutrition within a community-based health program . We hypothesized that small-quantity lipid-based nutrient supplements ( LNSs ) provided to women during pregnancy and the first 6 mo postpartum , LNSs provided to their offspring from 6 to 24 mo of age , or both would result in greater child length-for-age z score ( LAZ ) at 24 mo than iron and folic acid ( IFA ) provided to women during pregnancy and postpartum plus micronutrient powder ( MNP ) or no supplementation for their offspring from 6 to 24 mo . Design : We conducted a cluster-r and omized effectiveness trial with 4 arms : 1 ) women and children both received LNSs ( LNS-LNS group ) , 2 ) women received IFA and children received LNSs ( IFA-LNS group ) , 3 ) women received IFA and children received MNP ( IFA-MNP group ) , and 4 ) women received IFA and children received no supplements ( IFA-Control group ) . We enrolled 4011 women at ≤20 wk of gestation within 64 clusters , each comprising the supervision area of a community health worker . Analyses were primarily performed by using ANCOVA F tests and Tukey-Kramer-corrected pairwise comparisons . Results : At 24 mo , the LNS-LNS group had significantly higher LAZ ( + 0.13 compared with the IFA-MNP group ) and head circumference ( + 0.15 z score compared with the IFA-Control group ) ; these outcomes did not differ between the other groups . Stunting prevalence ( LAZ < -2 ) was lower in the LNS-LNS group at 18 mo than in the IFA-MNP group ( OR : 0.70 ; 95 % CI : 0.53 , 0.92 ) , but the difference diminished by 24 mo ( OR : 0.81 ; 95 % CI : 0.63 , 1.04 ) . Conclusion : Home fortification with small-quantity LNSs , but not MNP , during the first 1000 d improved child linear growth and head size in rural Bangladesh . This trial was registered at clinical trials.gov as NCT01715038 [25833980] BACKGROUND The International Lipid-Based Nutrient Supplements Project developed a small-quantity ( 20 g/d ) lipid-based nutrient supplement ( LNS ) for pregnant and lactating women . OBJECTIVE We evaluated the effects of prenatal LNS supplementation on fetal growth . DESIGN In a community-based , partially double-blind , individually r and omized controlled trial , 1320 women ≤20 wk pregnant received 60 mg Fe/400 μg folic acid ( IFA ) , or 1 - 2 Recommended Dietary Allowances of 18 micronutrients , including 20 mg Fe ( MMN ) , or LNS with the same micronutrients as the MMN group , plus 4 minerals and macronutrients contributing 118 kcal ( LNS ) daily until delivery . Fetal growth was compared across groups by using intention-to-treat analysis . The primary outcome was birth length . RESULTS This analysis included 1057 women ( IFA = 349 , MMN = 354 , LNS = 354 ) . Groups did not differ significantly in mean birth length , length-for-age z score ( LAZ ) , head circumference , or percentage low birth length but differed in mean birth weight ( P = 0.044 ) , weight-for-age z score ( WAZ ; P = 0.046 ) , and BMI -for-age z score ( BMI Z ; P = 0.040 ) , with a trend toward differences in low birth weight ( P = 0.069 ) . In pairwise comparisons , the LNS group had greater mean birth weight ( + 85 g ; P = 0.040 ) , WAZ ( + 0.19 ; P = 0.045 ) , and BMI Z ( + 0.21 ; P = 0.035 ) and a lower risk of low birth weight ( RR : 0.61 , 95 % CI : 0.39 , 0.96 ; P = 0.032 ) than did the IFA group . The other group differences were not significant . The effect of intervention was modified by mother 's parity , age , height , baseline hemoglobin , household food insecurity , and child sex , with parity being the most consistent modifier . Among primiparous women ( IFA = 131 ; MMN = 110 ; LNS = 128 ) , the LNS group had greater mean birth length ( + 0.91 cm ; P = 0.001 ) , LAZ ( + 0.47 ; P = 0.001 ) , weight ( + 237 g ; P < 0.001 ) , WAZ ( + 0.56 ; P < 0.001 ) , BMI Z ( + 0.52 ; P < 0.001 ) , head circumference ( 0.50 cm ; P = 0.017 ) , and head circumference-for-age z score ( + 0.40 ; P = 0.022 ) than did the IFA group ; similar differences were found when comparing the LNS and MMN groups among primiparous women , and no group differences were found among multiparous women . CONCLUSION Prenatal LNS supplementation can improve fetal growth among vulnerable women in Ghana , particularly primiparous women . This trial was registered at clinical trials.gov as NCT00970866 [25926413] BACKGROUND Intrauterine growth restriction may be reduced by supplementing maternal diets during pregnancy , but few studies have assessed the impact of combined prenatal and postnatal interventions on child growth . OBJECTIVE We tested a hypothesis that provision of small-quantity lipid-based nutrient supplements ( SQ-LNSs ) to mothers in pregnancy and 6 mo postpartum and to their infants from 6 to 18 mo of age would promote infant and child growth in the study area in rural Malawi . METHODS We enrolled 869 pregnant women in a r and omized trial in Malawi . During pregnancy and 6 mo thereafter , the women received daily 1 capsule of iron-folic acid ( IFA ) , 1 capsule containing 18 micronutrients ( MMN ) , or one 20-g sachet of SQ-LNS [ lipid-based nutrient supplements ( LNS ) , containing 21 MMN , protein , carbohydrates , essential fatty acids , and 118 kcal ] . Children in the IFA and MMN groups received no supplementation ; children in the LNS group received SQ-LNSs from 6 to 18 mo . Primary outcome was child length at 18 mo . RESULTS At 18 mo , the mean length in the IFA , MMN , and LNS groups was 77.0 , 76.9 , and 76.8 cm ( P = 0.90 ) , respectively , and the prevalence of stunting was 32.7 % , 35.6 % , and 37.9 % ( P = 0.54 ) , respectively . No intergroup differences were found in the mean weight , head circumference , or midupper arm circumference or the proportions with low z scores for these variables ( P > 0.05 ) . Covariate adjustment did not change the analysis results , and the associations between the intervention and child length were not modified by maternal parity , age , or nutritional status ( P > 0.10 ) . CONCLUSIONS The findings do not support a hypothesis that provision of SQ-LNSs to women in pregnancy and postpartum and to children from 6 to 18 mo of age would promote child growth in this Malawian study area . This trial was registered at clinical trials.gov as NCT01239693 [28615379] Background : Maternal iodine deficiency during pregnancy and lactation is common in Bangladesh . Objective : We evaluated the effect of lipid-based nutrient supplements for pregnant and lactating women ( LNS-PL ) on urinary iodine concentration ( UIC ) . Methods : We conducted a cluster-r and omized controlled effectiveness trial in which we enrolled 4011 pregnant women at ≤20 gestational weeks . Women in 48 clusters received iron and folic acid ( IFA ; 60 mg Fe/d + 400 μg folic acid/d ) and women in 16 clusters received LNS-PL ( 20 g/d , 118 kcal ) containing 22 vitamins and minerals ( including 250 μg I ) . We r and omly selected a sub sample of 1159 women for repeated urine sample collection , i.e. , at enrollment , at 36 wk of gestation , and at 6 mo postpartum , for UIC analysis , a secondary outcome of the trial . Results : The geometric mean UIC at 36 wk of gestation and at 6 mo postpartum did not differ significantly between the IFA and LNS-PL groups . The median ( quartile 1 , quartile 3 ) UIC at 36 wk was 27.4 μg/L ( 16.9 , 52.7 μg/L ) in the IFA group and 30.2 μg/L ( 17.7 , 56.6 μg/L ) in the LNS-PL group ; at 6 mo , these were 23.0 μg/L ( 10.0 , 45.9 μg/L ) in the IFA group and 22.2 μg/L ( 9.1 , 50.4 μg/L ) in the LNS-PL group . Conclusion : Daily consumption of LNS-PL containing 250 μg I did not increase the UICs of pregnant and lactating women in Bangladesh . Iodine from lipid-based nutrient supplements may have been stored in the thyroid gl and or secreted in breast milk instead of being excreted in urine . Additional research that uses other biomarkers of iodine status is needed to determine how to meet the iodine requirements of pregnant and lactating women in Bangladesh and similar setting s. This trial was registered at clinical trials.gov as NCT01715038 [26924599] Abstract We examined hemoglobin ( Hb , g/L ) , iron status ( zinc protoporphyrin , ZPP , & mgr;mol/mol heme , and transferrin receptor , TfR , mg/L ) and inflammation ( C‐reactive protein , CRP and alpha‐1 glycoprotein , AGP ) in pregnant Ghanaian women who participated in a r and omized controlled trial . Women ( n = 1320 ) received either 60 mg Fe + 400‐&mgr;g folic acid ( IFA ) ; 18 micronutrients including 20‐mg Fe ( MMN ) or small‐quantity lipid‐based nutrient supplements ( SQ‐LNS , 118 kcal/d ) with the same micronutrient levels as in MMN , plus four additional minerals ( LNS ) daily during pregnancy . Intention‐to‐treat analysis included 349 , 354 and 354 women in the IFA , MMN and LNS groups , respectively , with overall baseline mean Hb and anemia ( Hb < 100 ) prevalence of 112 and 13.3 % , respectively . At 36 gestational weeks , overall Hb was 117 , and anemia prevalence was 5.3 % . Compared with the IFA group , the LNS and MMN groups had lower mean Hb ( 120 ± 11 vs. 115 ± 12 and 117 ± 12 , respectively ; P < 0.001 ) , higher mean ZPP ( 42 ± 30 vs. 50 ± 29 and 49 ± 30 ; P = 0.010 ) and TfR ( 4.0 ± 1.3 vs. 4.9 ± 1.8 and 4.6 ± 1.7 ; P < 0.001 ) , and greater prevalence of anemia ( 2.2 % vs. 7.9 % and 5.8 % ; P = 0.019 ) , elevated ZPP ( > 60 ) [ 9.4 % vs. 18.6 % and 19.2 % ; P = 0.003 ] and elevated TfR ( > 6.0 ) [ 9.0 % vs. 19.2 % and 15.1 % ; P = 0.004 ] . CRP and AGP concentrations did not differ among groups . We conclude that among pregnant women in a semi‐urban setting in Ghana , supplementation with SQ‐LNS or MMN containing 20 mg iron result ed in lower Hb and iron status but had no impact on inflammation , when compared with iron ( 60 mg ) plus folic acid ( 400 & mgr;g ) . The amount of iron in such supplements that is most effective for improving both maternal Hb/iron status and birth outcomes requires further evaluation . This trial was registered at Clinical Trials.gov as : NCT00970866 [5697970] Background : It is unknown whether self-reported measures of household food insecurity change in response to food-based nutrient supplementation . Objective : We assessed the impacts of providing lipid-based nutrient supplements ( LNSs ) to women during pregnancy and postpartum and /or to their children on self-reported household food insecurity in Malawi [ DOSE and DYAD trial in Malawi ( DYAD-M ) ] , Ghana [ DYAD trial in Ghana ( DYAD-G ) ] , and Bangladesh [ Rang-Din Nutrition Study ( RDNS ) trial ] . Methods : Longitudinal household food-insecurity data were collected during 3 individually r and omized trials and 1 cluster-r and omized trial testing the efficacy or effectiveness of LNSs ( generally 118 kcal/d ) . Seasonally adjusted Household Food Insecurity Access Scale ( HFIAS ) scores were constructed for 1127 DOSE households , 732 DYAD-M households , 1109 DYAD-G households , and 3671 RDNS households . The impact of providing LNSs to women during pregnancy and the first 6 mo postpartum and /or to their children from 6 to 18–24 mo on seasonally adjusted HFIAS scores was assessed by using negative binomial models ( DOSE , DYAD-M , and DYAD-G trials ) and mixed-effect negative binomial models ( RDNS trial ) . Results : In the DOSE and DYAD-G trials , seasonally adjusted HFIAS scores were not different between the LNS and non-LNS groups . In the DYAD-M trial , the average household food-insecurity scores were 14 % lower ( P = 0.01 ) in LNS households than in non-LNS households . In the RDNS trial , compared with non-LNS households , food-insecurity scores were 17 % lower ( P = 0.02 ) during pregnancy and the first 6 mo postpartum and 15 % lower ( P = 0.02 ) at 6–24 mo postpartum in LNS households . Conclusions : The daily provision of LNSs to mothers and their children throughout much of the “ first 1000 d ” may improve household food security in some setting s , which could be viewed as an additional benefit that may accrue in households should policy makers choose to invest in LNSs to promote child growth and development . These trials were registered at clinical trials.gov as NCT00945698 ( DOSE ) NCT01239693 ( DYAD-M ) , NCT00970866 ( DYAD-G ) and NCT01715038 ( RDNS ) [27391572] BACKGROUND Maternal and infant undernutrition is negatively associated with infant development . AIMS We tested the hypothesis that provision of small-quantity lipid-based nutrient supplements ( SQ-LNS ) to pregnant women and infants positively affects infant development . STUDY DESIGN In a partially double-blind r and omized controlled trial , we compared the following daily maternal supplements during pregnancy and until 6months post-partum : iron/folic acid capsule ( IFA ) , capsule containing 18 micronutrients ( MMN ) , or 20 g SQ-LNS . Children in the SQ-LNS group also received SQ-LNS from age 6 to 18months . The study is registered as NCT00970866 . SUBJECTS 1320 pregnant women in Ghana enrolled in the trial ; 1173 of their children participated in developmental assessment . OUTCOME MEASURES We monitored the acquisition of 10 developmental milestones monthly by parental report , observed the attainment of 6 motor milestones at 6 , 12 , and 18months , and conducted detailed assessment of motor , language , socio-emotional , and executive function at 18months . RESULTS By research er observation , a greater percentage of children in the SQ-LNS group ( 53 % ) was able to walk alone at 12months than in the IFA group ( 43 % ; RR=1.23 , 95 % CI=1.02 - 1.49 ; p=0.025 ) . We found no significant differences between groups in milestone acquisition by parent report or in any scores at 18months . The difference in mean z-scores between groups ranged from 0.03 - 0.13 for motor ( p=0.84 ) , 0.01 - 0.08 for language ( p=0.46 ) , 0.01 - 0.02 for socio-emotional ( p=0.75 ) , and 0.00 - 0.02 for executive function ( p=0.95 ) . CONCLUSION While provision of maternal and child SQ-LNS in Ghana may affect walking at 12months , it did not affect infant development at 18months [4688934] Background Prenatal micronutrient supplements have been found to increase birth weight , but mechanisms for increased growth are poorly understood . Our hypotheses were that 1 ) women who receive lipid-based nutrient supplements ( LNS ) during pregnancy would have lower mean salivary cortisol concentration at 28 wk and 36 wk gestation compared to the multiple micronutrient ( MMN ) and iron-folic acid ( IFA ) supplement groups and 2 ) both salivary cortisol and perceived stress during pregnancy would be associated with shorter duration of gestation and smaller size at birth . Methods Women were enrolled in the trial in early pregnancy and r and omized to receive LNS , MMN , or iron-folic acid ( IFA ) supplements daily throughout pregnancy . At enrollment , 28 wk and 36 wk gestation , saliva sample s were collected and their cortisol concentration was measured . Self-report of perceived stress was measured using question naires . Gestation duration was indicated by ultrasound dating and newborn anthropometric measurements ( weight , length , head circumference ) provided indicators of intrauterine growth . Results Of the 1391 women enrolled in the trial , 1372 , 906 and 1049 saliva sample s were collected from women at baseline , 28 wk and 36 wk , respectively . There were no significant differences in mean cortisol concentrations by intervention group at 28 wk or 36 wk gestation . Cortisol concentrations were negatively associated with duration of gestation ( Baseline : β = −0.05 , p = 0.039 ; 36 wk : β = −0.04 , p = 0.037 ) and birth weight ( 28 wk : β = −0.08 , p = 0.035 ; 36 wk : β = −0.11 , p = 0.003 ) but not associated with length-for-age or head circumference-for-age z-scores . Perceived stress at 36 wk was significantly associated with shorter newborn LAZ ( p = 0.001 ) . There were no significant associations with the risk of small for gestational age , preterm birth , or low birth weight . Conclusions Maternal salivary cortisol concentration was strongly associated with birth weight and duration of gestation in rural Malawi , but these data do not support the hypothesis that LNS provision to pregnant women would influence their salivary cortisol concentrations . Trial registration Clinical trials.gov identifier [25733482] BACKGROUND Maternal nutritional status is a major determinant of low birth weight and fluctuates across seasons . Seasonality may influence the outcome of prenatal nutrition interventions that aim to enhance fetal growth . OBJECTIVE This study investigated seasonal modifications of the efficacy of a r and omized controlled prenatal nutrition intervention trial in pregnant women to improve fetal growth in rural Burkina Faso . METHODS The second Micronutriments et Santé de la Mère et de l'Enfant study compared a lipid-based nutrient supplement ( LNS ) fortified with multiple micronutrients ( MMNs ) to an MMN supplement . Truncated Fourier series were used to characterize seasonality in birth outcomes . Models that included the Fourier series and newborn and maternal characteristics were used to assess seasonal effect modifications of prenatal supplementation on birth outcomes . RESULTS Birth weight , birth length , small for gestational age as a proxy for intrauterine growth retardation , and preterm birth were significantly related to date of birth and showed important seasonal variations . LNSs , which supply energy in addition to MMNs , result ed in a significant increase in birth length ( + 13.5 mm , 95 % CI : 6.5 , 20.5 mm ) at the transition from rain to dry season ( September to November ) compared to MMNs alone . CONCLUSIONS The climatologic and agricultural seasonal patterns in Burkina Faso affect the efficacy of prenatal LNSs on birth length . In this context , prenatal MMN supplementation programs should be complemented by energy supplementation during the annual rain season to promote fetal growth . This trial was registered at clinical trials.gov as NCT00909974 [26740682] BACKGROUND Vitamin A deficiency remains a global public health problem . Daily supplementation with a lipid-based nutrient supplement ( LNS ) has potential for increasing milk vitamin A concentrations . OBJECTIVE The objective of this study was to determine whether daily supplementation with approximately the recommended daily intake of vitamin A in an LNS or a multiple-micronutrient supplement ( MMN ) during pregnancy and the first 6 mo postpartum has an effect on breast milk retinol concentration at 6 mo postpartum . METHODS Women ≤20 wk pregnant ( n = 1320 ) were r and omly assigned to receive either the MMN providing 18 micronutrients , including 800 μg retinol equivalents of vitamin A , or the LNS with the same nutrients as the MMN group , plus 4 minerals and macronutrients , until 6 mo postpartum ; a control group received iron and folic acid during pregnancy and a placebo ( calcium tablet ) during the first 6 mo postpartum . Breast milk sample s collected at 6 mo postpartum were analyzed for retinol and fat concentrations by HPLC and creamatocrit , respectively , in a sub sample of 756 women . RESULTS The breast milk retinol concentration was ( mean ± SD ) 56.3 ± 2.1 nmol/g fat , with no significant differences between groups [ iron and folic acid ( n = 243 ) : 59.1 ± 2.8 ; MMN ( n = 260 ) : 55.4 ± 2.5 ; LNS ( n = 253 ) : 54.7 ± 2.5 nmol/g fat ; P = 0.45 ] , regardless of whether the woman had or had not received a high-dose vitamin A supplement ( 200,000 IU ) soon after childbirth . Around 17 % of participants had low milk retinol ( ≤28 nmol/g fat ) . We estimated that 41 % of infants were potentially receiving vitamin A at amounts above the Tolerable Upper Intake Level ( 600 μg retinol activity equivalents/d ) , with no group differences in percentages with low or high milk retinol concentration . CONCLUSION Daily consumption of approximately the recommended intake of vitamin A did not increase breast milk retinol concentrations in this sample of Ghanaian women . This trial was registered at clinical trials.gov as NCT00970866 [5368579] Background : It is unclear whether maternal supplementation with small-quantity lipid-based nutrient supplements ( SQ-LNSs ; 118 kcal/d ) affects maternal weight . Objective : We compared several secondary anthropometric measures between 3 groups of women in the iLiNS ( International Lipid-based Nutrient Supplements)-DYAD trial in Ghana . Methods : Women ( n = 1320 ; < 20 wk of gestation ) were r and omly assigned to receive 60 mg Fe + 400 μg folic acid/d ( IFA ) , 18 vitamins and minerals/d [ multiple micronutrients ( MMNs ) ] , or 20 g SQ-LNSs with 22 micronutrients/d ( LNS ) during pregnancy and a placebo ( 200 mg Ca/d ) , MMNs , or SQ-LNSs , respectively , for 6 mo postpartum . Weight , midupper arm circumference ( MUAC ) , and triceps skinfold ( TSF ) thickness at 36 wk of gestation and 6 mo postpartum were analyzed , as were changes from estimated prepregnancy values . We assessed the adequacy of estimated gestational weight gain ( GWG ) by using Institute of Medicine ( IOM ) and International Fetal and Newborn Growth St and ards for the 21st Century ( INTERGROWTH-21st ) guidelines . Results : The estimated prepregnancy prevalence of overweight or obesity was 38.5 % . By 36 wk of gestation , women ( n = 1015 ) had a mean ± SD weight gain of 7.4 ± 3.7 kg and changes of −1.0 ± 1.7 cm in MUAC and −2.8 ± 4.1 mm in TSF thickness . The LNS group had a lower prevalence of inadequate GWG on the basis of IOM guidelines ( 57.4 % ) than the MMN ( 67.2 % ) but not the IFA ( 63.1 % ) groups ( P = 0.030 ) , whereas the prevalence of adequate ( 26.9 % overall ) and excessive ( 10.4 % overall ) GWG did not differ by group . The percentages of normal-weight women ( in kg/m2 : 18.5 < body mass index < 25.0 ; n = 754 ) whose GWG was less than the third centile of the INTERGROWTH-21st st and ards were 23.0 % , 28.7 % , and 28.5 % for the LNS , MMN , and IFA groups , respectively ( P = 0.36 ) . At 6 mo postpartum , the prevalence of overweight or obesity was 45.3 % , and the risk of becoming overweight or obese did not differ by group . Conclusion : SQ-LNS supplementation is one potential strategy to address the high prevalence of inadequate GWG in women in setting s similar to Ghana , without increasing the risk of excessive GWG . This trial was registered at clinical trials.gov as NCT00970866

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### Context: [28374648] Background : There is no consensus over best approaches to reliably prevent malnutrition in rural communities in low-income countries . Objective : We compared the effectiveness of 2 lipid-based ready-to-use supplementary foods ( RUSFs ) differing in dairy protein content to improve the nutritional status of mothers and at-risk infants and young children in rural Guinea-Bissau . Methods : A 3-month cluster-r and omized controlled pilot trial of 2 RUSFs was conducted with 692 mothers and 580 mildly or moderately malnourished infants ( 6 - 23 months ) and children ( 24 - 59 months ) from 13 villages . The RUSFs contained either 478 ( mothers , children ) or 239 kcal/d ( infants ) with 15 % or 33 % of protein from dairy and were distributed at community health centers 5 d/wk . Controls were wait-listed to receive RUSF . Primary outcomes were mid-upper arm circumference ( MUAC ) in mothers , and weight-for-age and height-for-age z-scores ( WAZ and HAZ ) in infants and children . Results : There was a significant effect of the RUSF-33 % on MUAC in mothers ( P = .03 ) . The WAZ and HAZ increased substantially , by ≈1 z-score , in infants and children ( P < .01 ) independent of group r and omization . In children , but not infants , baseline WAZ and change in maternal MUAC were associated with change in WAZ ( β = .07 , P = .02 ) . Conclusion : Ready-to-use supplementary foods with higher dairy protein content had a significant benefit in village mothers , supporting a comparable recent finding in preschool children . In addition , supplementation of children < 2 years result ed in improved growth independent of family nutritional status , whereas success in older children was associated with change in maternal nutrition , suggesting the need for community-level education about preventing malnutrition in older , as well as younger , children [24225356] BACKGROUND Haiti has experienced rapid urbanization that has exacerbated poverty and undernutrition in large slum areas . Stunting affects 1 in 5 young children . OBJECTIVE We aim ed to test the efficacy of a daily lipid-based nutrient supplement ( LNS ) for increased linear growth in young children . DESIGN Healthy , singleton infants aged 6 - 11 mo ( n = 589 ) were recruited from an urban slum of Cap Haitien and r and omly assigned to receive : 1 ) a control ; 2 ) a 3-mo LNS ; or 3 ) a 6-mo LNS . The LNS provided 108 kcal and other nutrients including vitamin A , vitamin B-12 , iron , and zinc at ≥80 % of the recommended amounts . Infants were followed monthly on growth , morbidity , and developmental outcomes over a 6-mo intervention period and at one additional time point 6 mo postintervention to assess sustained effects . The Bonferroni multiple comparisons test was applied , and generalized least-squares ( GLS ) regressions with mixed effects was used to examine impacts longitudinally . RESULTS Baseline characteristics did not differ by trial arm except for a higher mean age in the 6-mo LNS group . GLS modeling showed LNS supplementation for 6 mo significantly increased the length-for-age z score ( ±SE ) by 0.13 ± 0.05 and the weight-for-age z score by 0.12 ± 0.02 compared with in the control group after adjustment for child age ( P < 0.001 ) . The effects were sustained 6 mo postintervention . Morbidity and developmental outcomes did not differ by trial arm . CONCLUSION A low-energy , fortified product improved the linear growth of young children in this urban setting . The trial was registered at clinical trials.gov as NCT01552512 [23535609] In developing countries , prenatal lipid-based nutrient supplements ( LNSs ) were shown to increase birth size ; however , the mechanism of this effect remains unknown . Cord blood hormone concentrations are strongly associated with birth size . Therefore , we hypothesize that LNSs increase birth size through a change in the endocrine regulation of fetal development . We compared the effect of daily prenatal LNSs with multiple micronutrient tablets on cord blood hormone concentrations using a r and omized , controlled design including 197 pregnant women from rural Burkina Faso . Insulin-like growth factors ( IGF ) I and II , their binding proteins IGFBP-1 and IGFBP-3 , leptin , cortisol , and insulin were quantified in cord sera using immunoassays . LNS was associated with higher cord blood leptin mainly in primigravidae ( + 57 % ; P = 0.02 ) and women from the highest tertile of BMI at study inclusion ( + 41 % ; P = 0.02 ) . We did not find any significant LNS effects on other measured cord hormones . The observed increase in cord leptin was associated with a significantly higher birth weight . Cord sera from small-for-gestational age newborns had lower median IGF-I ( -9 μg/L ; P = 0.003 ) , IGF-II ( -79 μg/L ; P = 0.003 ) , IGFBP-3 ( -0.7 μg/L ; P = 0.007 ) , and leptin ( -1.0 μg/L ; P = 0.016 ) concentrations but higher median cortisol ( + 18 μg/L ; P = 0.037 ) concentrations compared with normally grown newborns . Prenatal LNS result ed in increased cord leptin concentrations in primigravidae and mothers with higher BMI at study inclusion . The elevated leptin concentrations could point toward a higher neonatal fat mass [5697619] Background Previous review s have identified 44 risk factors for poor early child development ( ECD ) in low‐ and middle‐income countries . Further underst and ing of their relative influence and pathways is needed to inform the design of interventions targeting ECD . Methods We conducted path analyses of factors associated with 18‐month language and motor development in four prospect i ve cohorts of children who participated in trials conducted as part of the International Lipid‐Based Nutrient Supplements ( iLiNS ) Project in Ghana ( n = 1,023 ) , Malawi ( n = 675 and 1,385 ) , and Burkina Faso ( n = 1,122 ) . In two cohorts , women were enrolled during pregnancy . In two cohorts , infants were enrolled at 6 or 9 months . In multiple linear regression and structural equation models ( SEM ) , we examined 22 out of 44 factors identified in previous review s , plus 12 additional factors expected to be associated with ECD . Results Out of 42 indicators of the 34 factors examined , 6 were associated with 18‐month language and /or motor development in 3 or 4 cohorts : child linear and ponderal growth , variety of play material s , activities with caregivers , dietary diversity , and child hemoglobin/iron status . Factors that were not associated with child development were indicators of maternal Hb/iron status , maternal illness and inflammation during pregnancy , maternal perceived stress and depression , exclusive breastfeeding during 6 months postpartum , and child diarrhea , fever , malaria , and acute respiratory infections . Associations between socioeconomic status and language development were consistently mediated to a greater extent by caregiving practice s than by maternal or child biomedical conditions , while this pattern for motor development was not consistent across cohorts . Conclusions Key elements of interventions to ensure quality ECD are likely to be promotion of caregiver activities with children , a variety of play material s , and a diverse diet , and prevention of faltering in linear and ponderal growth and improvement in child hemoglobin/iron status [6088232] Abstract Small‐quantity lipid‐based nutrient supplements ( SQ‐LNS ) are design ed to enrich maternal and child diets with the objective of preventing undernutrition during the first 1,000 days . Scaling up the delivery of supplements such as SQ‐LNS hinges on underst and ing private dem and and creatively leveraging policy‐relevant factors that might influence dem and . We used longitudinal stated willingness‐to‐pay ( WTP ) data from contingent valuation studies that were integrated into r and omized controlled nutrition trials in Ghana and Malawi to estimate private valuation of SQ‐LNS during pregnancy , postpartum , and early childhood . We found that average stated WTP for a day 's supply of SQ‐LNS was more than twice as high in Ghana than Malawi , indicating that dem and for SQ‐LNS ( and by extension , the options for effective delivery of SQ‐LNS ) may be very context specific . We also examined factors associated with WTP , including intervention group , household socioeconomic status , birth outcomes , child growth , and maternal and child morbidity . In both sites , WTP was consistently negatively associated with household food insecurity , indicating that subsidization might be needed to permit food insecure households to acquire SQ‐LNS if it is made available for purchase . In Ghana , WTP was higher among heads of household than among mothers , which may be related to control over household re sources . Personal experience using SQ‐LNS was not associated with WTP in either site [5901033] Abstract Pregnant and post‐partum women require increased nutrient intake and optimal cognition , which depends on adequate nutrition , to enable reasoning and learning for caregiving . We aim ed to assess ( a ) differences in maternal cognition and caregiving between women in Malawi who received different nutritional supplements , ( b ) 14 effect modifiers , and ( c ) associations of cognition and caregiving with biomarkers of iron , Vitamin A , B‐vitamin , and fatty acid status . In a r and omized controlled trial ( n = 869 ) , pregnant women daily received either multiple micronutrients ( MMN ) , 20 g/day lipid‐based nutrient supplements ( LNS ) , or a control iron/folic acid ( IFA ) tablet . After delivery , supplementation continued in the MMN and LNS arms , and the IFA control group received placebo until 6 months post‐partum , when cognition ( n = 712 ) , caregiving behaviour ( n = 669 ) , and biomarkers of nutritional status ( n = 283 ) were assessed . In the full group , only one difference was significant : the IFA arm scored 0.22 SD ( 95 % CI [ 0.01 , 0.39 ] , p = .03 ) higher than the LNS arm in mental rotation . Among subgroups of women with baseline low hemoglobin , poor iron status , or malaria , those who received LNS scored 0.4 to 0.7 SD higher than the IFA arm in verbal fluency . Breastmilk docosahexaenoic acid and Vitamin B12 concentrations were positively associated with verbal fluency and digit span forward ( adjusting for covariates ps < .05 ) . In this population in Malawi , maternal supplementation with MMN or LNS did not positively affect maternal cognition or caregiving . Maternal docosahexaenoic acid and B12 status may be important for post‐partum attention and executive function [5004276] Background Supplementing pregnant and lactating mothers with small quantity lipid-based nutrient supplements ( SQ-LNS ) has result ed in improvements in birth outcomes in some low-income setting s. In order to be effective , SQ-LNS must be consumed regularly over sustained periods . Methods The objective was to assess and compare acceptability of and adherence to SQ-LNS consumption among pregnant and lactating women in Ghana and Malawi throughout 12 months of supplementation . We enrolled women before 20 gestation weeks into r and omized trials in Ghana ( n = 1320 ) and Malawi ( n = 869 ) . In the SQ-LNS group participants received a 20 g sachet of supplement per day during pregnancy and the first 6 months of lactation . In the control groups participants received multiple micronutrients ( MMN ) during pregnancy and lactation or iron and folic acid ( IFA ) during pregnancy and calcium during lactation . We used question naires to collect data on self-reported adherence to daily use of supplements and conducted in-depth interviews with women in the SQ-LNS group to examine acceptability . Results The mean self-reported adherence during the supplementation period was lower in Ghana ( 79.9 % ) than in Malawi ( 91.7 % ) for all supplements ( difference 11.8 % , P < 0.001 ) . Over time , adherence increased in Malawi but decreased in Ghana . In both countries , adherence in the SQ-LNS group was non-inferior to that in the control groups . Participants typically reported consuming SQ-LNS as instructed but when interviewers queried about experiences , most of the women described incidents of non-adherence . A usual reason for not consuming SQ-LNS was nausea and vomiting during pregnancy . Especially in Malawi , women reported sharing SQ-LNS with families and friends . Sustained use of SQ-LNS was attributed to expected health benefits and favorable sensory attributes . Often women compared their pregnancy to previous ones , and were of the view that SQ-LNS made a positive difference . ConclusionS elf-reported sustained adherence to consume SQ-LNS daily was high in both sites but lower in Ghana than in Malawi . In Ghana , adherence decreased over time whereas in Malawi adherence increased . Acceptability and adherence appeared interlinked , complex and context -related . Sustained consumption of SQ-LNS may require tailoring interventions by context .Trial registration The Ghana trial was registered at clinical trials.gov as NCT00970866 , and the Malawi trial as NCT01239693 [12885713] BACKGROUND The World Health Organization recommends a liquid , milk-based diet ( F100 ) during the rehabilitation phase of the treatment of severe malnutrition . A dry , solid , ready-to-use food ( RTUF ) that can be eaten without adding water has been proposed to eliminate the risk of bacterial contamination from added water . The efficacies of RTUF and F100 have not been compared . OBJECTIVE The objective was to compare the efficacy of RTUF and F100 in promoting weight gain in malnourished children . DESIGN In an open-labeled , r and omized trial , 70 severely malnourished Senegalese children aged 6 - 36 mo were r and omly allocated to receive 3 meals containing either F100 ( n = 35 ) or RTUF ( n = 35 ) in addition to the local diet . The data from 30 children in each group were analyzed . RESULTS The mean ( + /- SD ) daily energy intake in the RTUF group was 808 + /- 280 ( 95 % CI : 703.8 , 912.9 ) kJ x kg body wt(-1 ) x d(-1 ) , and that in the F100 group was 573 + /- 201 ( 95 % CI : 497.9 , 648.7 ) kJ. kg body wt(-1 ) x d(-1 ) ( P < 0.001 ) . The average weight gains in the RTUF and F100 groups were 15.6 ( 95 % CI : 13.4 , 17.8 ) and 10.1 ( 95 % CI : 8.7 , 11.4 ) g x kg body wt(-1 ) x d(-1 ) , respectively ( P < 0.001 ) . The difference in weight gain was greater in the most wasted children ( P < 0.05 ) . The average duration of rehabilitation was 17.3 ( 95 % CI : 15.6 , 19.0 ) d in the F100 group and was 13.4 ( 95 % CI : 12.1 , 14.7 ) d in the RTUF group ( P < 0.001 ) . CONCLUSIONS This study indicated that RTUF can be used efficiently for the rehabilitation of severely malnourished children [5762799] We examined the impact on depression at 6 months postpartum of maternal supplementation with small-quantity lipid-based nutrient supplement ( SQ-LNS ) compared to supplementation with iron and folic acid ( IFA ) or multiple micronutrients ( MMN ) . In this partially double-blinded r and omized controlled trial , pregnant women ≤20 weeks gestation ( n = 1320 ) were recruited from antenatal clinics and r and omly assigned to receive either ( 1 ) SQ-LNS during pregnancy and for 6 months postpartum , or ( 2 ) IFA during pregnancy only , or ( 3 ) MMN during pregnancy and for 6 months postpartum . Maternal depressive symptoms were measured at 6 months postpartum using the Edinburgh Postnatal Depression Scale ( EPDS ) . Women who scored 12 or more on the EPDS were considered to show symptoms of depression . One thous and one hundred fifty-one women were included in this analysis ( LNS = 382 , IFA = 387 and MMN = 382 ) . Characteristics of the three groups were similar at baseline , and there were no significant differences between women who were included in the analysis ( n = 1151 ) and those who were not ( n = 169 ) . At 6 months postpartum , 13 % of the women overall showed symptoms of depression , and this did not differ by group ( LNS = 13.1 % , IFA = 11.2 % and MMN = 14.7 % . P = 0.36 ) . The median ( 25 , 75 percentile ) EPDS score did not differ by group ( LNS 4.0 ( 1.0 , 8.0 ) , IFA 4.0 ( 1.0 , 8.0 ) , MMN 5.0 ( 2.0 , 9.0 ) , Ptransformed = 0.13 ) . Adjustment for covariates did not alter these findings . Maternal supplementation with SQ-LNS compared to MMN or IFA did not affect postnatal depressive symptoms in this sample of Ghanaian women [6866179] Abstract Small‐quantity lipid‐based nutrient supplements ( SQ‐LNS ) have been studied in efficacy and effectiveness trials , but little is known about how parents perceive the products and their effects . In a r and omised trial in Ghana , efficacy of SQ‐LNS provided to women during pregnancy and the first 6 months postpartum and to their children from 6 to 18 months of age was assessed by comparison with iron‐folic acid ( IFA ) capsules and multiple micronutrient ( MMN ) capsules provided to women . In a follow‐up study conducted when the index children from the original trial were between 4 and 6 years of age , we used survey‐based methods to assess retrospective and current parental perceptions of nutrient supplements generally and of SQ‐LNS and their effects compared with perceptions IFA and MMN capsules . Most parents perceived that the assigned supplements ( SQ‐LNS , IFA , or MMN ) positively impacted the mother during pregnancy ( approximately 89 % of both mothers and fathers ) and during lactation ( 84 % of mothers and 86 % of fathers ) . Almost all ( ≥90 % ) of mothers and fathers perceived that the assigned supplement positively impacted the index child and expected continued positive impacts on the child 's health and human capital into the future . A smaller percentage of parents perceived negative impacts of the supplements ( 7%–17 % of mothers and 4%–12 % of fathers ) . Perceptions of positive impacts and of negative impacts did not differ by intervention group . The results suggest that similar population s would likely be receptive to programs to deliver SQ‐LNS or micronutrient capsules [26898720] Limited knowledge exists on sustained adherence to small-quantity lipid-based nutrient supplements for pregnant and lactating women ( LNS-PL ) and how this compares with that of other prenatal supplements . To address these gaps , a r and om sub sample of women ( n = 360 ) during pregnancy , early ( 6- to 12-week post-partum ) and late ( 12- to 24-week post-partum ) lactation , from an ongoing effectiveness trial in Bangladesh , was selected for in-home interviews about LNS-PL or iron/folic acid ( IFA ) use and preferences . Prevalence of high adherence ( ≥70 % of the recommendation ) based on self-reported supplement consumption was 67 % , 68 % and 81 % among LNS-PL recipients during pregnancy , early and late lactation , and was 87 % and 71 % among IFA recipients during pregnancy and early lactation , respectively ( P = 0.044 ) . Programmatic factors ( e.g. distribution and visits by programme staff ) were consistently statistically significantly associated with reported high adherence . Among LNS-PL recipients , high overall supplement acceptability score [ odds ratio ( OR ) : 8.62 ; 95 % confidence interval ( CI ) 3.53 , 20.83 ] and use of reminder techniques ( OR : 4.41 ; 95%CI 1.65 , 11.76 ) were positively associated , and reported vomiting at enrollment was negatively associated ( OR : 0.34 ; 95%CI 0.14 , 0.80 ) , with reported high adherence . Selected women ( n = 16 ) and key informants ( n = 18 ) participated in in-depth interviews about perceptions and acceptability of LNS-PL . Women perceived benefits of taking LNS-PL , but some faced barriers to consumption including aversion to odour and taste during pregnancy , forgetfulness and disruptions in supply . To achieve high adherence , results from this study suggest that maternal supplementation programmes should focus on programmatic barriers and consider incorporating reminder techniques . Organoleptic acceptability of LNS-PL , particularly during pregnancy , may also need to be addressed [27060705] Abstract Perinatal depression is highly prevalent in low‐ and ‐middle‐income countries and has been linked to poor child health . Suboptimal maternal nutrition may be a risk factor for perinatal depression . In this r and omised‐controlled trial conducted in rural Malawi , we set out to test the hypothesis that women taking a fatty acid‐rich lipid‐based nutrient supplement ( LNS ) would have fewer depressive symptoms postpartum than those taking iron‐folate ( IFA ) or multiple‐micronutrient ( MMN ) capsules . Women were recruited from antenatal clinics and r and omised to receive LNS or MMN during pregnancy and for 6 months postpartum , or IFA during pregnancy only . Maternal depressive symptoms were measured using vali date d translations of the Self Reporting Question naire ( SRQ ) and Edinburgh Postnatal Depression Scale ( EPDS ) , antenatally ( SRQ only ) and at 6 months postpartum ( SRQ and EPDS ) . Analysis was by modified intention to treat . One thous and three hundred and ninety one women were r and omised ( LNS = 462 , MMN = 466 , IFA = 463 ) . The groups were similar across a range of baseline variables . At 6 months postpartum , 1078 ( 77.5 % ) had SRQ completed ; mean ( SD ) scores were LNS 1.76(2.73 ) , MMN 1.92(2.75 ) , IFA 1.71(2.66 ) , P = 0.541 . One thous and and fifty seven ( 76.0 % ) had EPDS completed ; mean ( SD ) scores were LNS 5.77(5.53 ) , MMN 5.43(4.97 ) , IFA 5.52(5.18 ) , P = 0.676 . There were no statistically significant differences between the groups on SRQ or EPDS scores ( continuous or dichotomised ) in unadjusted or adjusted models . In conclusion , fortification of maternal diet with LNS compared with MMN or IFA did not reduce postnatal depressive symptoms in this study [27440259] BACKGROUND Maternal undernutrition and low macro- and micronutrient intake and weight gain during pregnancy have been reported in Bangladesh . OBJECTIVE We aim ed to determine the effects of lipid-based nutrient supplements for pregnant and lactating women ( LNS-PL ) on weight gain and midupper arm circumference ( MUAC ) during pregnancy . METHODS The Rang-Din Nutrition Study , a cluster-r and omized effectiveness trial conducted in Bangladesh , enrolled 4011 pregnant women at ≤20 wk gestation who received either 60 mg Fe + 400 μg folic acid/d or 20 g LNS-PL/d ( 118 kcal ) containing essential fatty acids and vitamins and minerals until delivery . At 36 wk gestation , women were interviewed at home and then attended a follow-up examination at local clinics ( n = 2877 ) , where anthropometric measurements were taken . RESULTS No significant differences between intervention groups in maternal weight gain per week , low weight gain per week , or MUAC at 36 wk gestation were observed in the full sample . However , among multiparous women aged ≥25 y , those in the LNS-PL group gained 34 g/wk more than their counterparts in the iron and folic acid ( IFA ) group ( P = 0.001 ) , whereas no differences were seen in the other parity/age subgroups . Women aged ≥25 y in the LNS-PL group had a 0.4-cm greater MUAC than their counterparts in the IFA group ( P = 0.003 ) ; no significant differences were observed in the other age groups . Among women whose height at baseline was in the lowest quartile of the distribution , those in the LNS-PL group had a 0.1 - 0.3-cm greater MUAC at 36 wk gestation than those in the IFA group ( P = 0.004 - 0.014 ) . CONCLUSIONS Lipid-based nutrient supplements provided during pregnancy did not affect maternal anthropometric indicators in the overall sample but increased MUAC among women aged ≥25 y and those with lower stature and weight gain among multiparous women aged ≥25 y. This trial was registered at clinical trials.gov as NCT01715038 [4438573] Background Malaria and undernutrition frequently coexist , especially in pregnant women and young children . Nutrient supplementation of these vulnerable groups might reduce their susceptibility to malaria by improving immunity . Methods Antibody immunity to antigens expressed by a placental-binding parasite isolate , a non-placental binding parasite isolate , merozoites and schizonts at enrolment ( before 20 gestation weeks ) and at 36 gestation weeks were measured in 1,009 Malawian pregnant women receiving a daily lipid-based nutrient supplement , multiple micronutrients or iron and folic acid , who were participants in a r and omized clinical trial assessing the effects of nutrient supplementation on pregnancy outcomes and child development ( registration ID : NCT01239693 ) . Results Antibodies to placental-binding isolates significantly increased while antibodies to most merozoite antigens declined over pregnancy . Overall , after adjustment for covariates , the type of supplementation did not influence antibody levels at 36 gestation weeks or the rate of change in antibody levels from enrolment to 36 weeks . A negative association between maternal body mass index and opsonizing antibodies to placental-binding antigens ( coefficient ( 95 % CI ) -1.04 ( −1.84 , −0.24 ) , was observed . Similarly , women with higher socioeconomic status had significantly lower IgG and opsonizing antibodies to placental-binding antigens . Neither of these associations was significantly influenced by the supplementation type . Conclusions In the current cohort nutrient supplementation did not affect anti-malarial antibody responses , but poor and undernourished mothers should be a priority group in future trials [26764321] BACKGROUND High circulating cortisol is associated with miscarriage , preterm birth , and low birth weight . Research in nonpregnant individuals suggests that improved nutrition may lower cortisol concentrations . It is unknown whether nutritional supplementation during pregnancy lowers cortisol . OBJECTIVE Our objective was to determine whether women receiving a lipid-based nutrient supplement ( LNS ) throughout pregnancy would have lower salivary cortisol at 36 wk gestation compared with women receiving other nutrient supplements . METHODS We conducted a r and omized controlled trial in 1320 pregnant Ghanaian women at ≤20 wk gestation who were assigned to receive daily throughout pregnancy : 1 ) 60 mg iron + 400 μg folic acid ( IFA ) , 2 ) multiple micronutrients ( MMNs ) , or 3 ) 20 g LNS ( containing 118 kcal , 22 micronutrients , and protein ) . Morning salivary cortisol was collected from a sub sample at baseline and at 28 and 36 wk gestation . RESULTS A total of 758 women had cortisol measurements at 28 or 36 wk gestation . Salivary cortisol at 36 wk gestation did not differ between groups and was ( mean ± SE ) 7.97 ± 0.199 in the IFA group , 7.84 ± 0.191 in the MMN group , and 7.77 ± 0.199 nmol/L in the LNS group , when adjusted for baseline cortisol , time of waking , and time between waking and saliva collection ( P = 0.67 ) . There was an interaction between supplementation group and women 's age ( continuous variable , P-interaction = 0.03 ) ; and when age was dichotomized by the median , significant differences in salivary cortisol concentrations between groups were seen in women ≤26 y of age ( IFA = 8.23 ± 0.284 nmol/L , MMN = 8.20 ± 0.274 nmol/L , and LNS = 7.44 ± 0.284 nmol/L ; P = 0.03 ) but not in women > 26 y old ( IFA = 7.71 ± 0.281 nmol/L , MMN = 7.50 ± 0.274 nmol/L , and LNS = 8.08 ± 0.281 nmol/L ; P = 0.13 ) . CONCLUSIONS We conclude that supplementation with LNSs or MMNs during pregnancy did not affect the cortisol concentration in the study population as a whole , in comparison with IFA , but that LNS consumption among younger women may lead to lower cortisol at 36 wk gestation . This trial was registered at clinical trials.gov as NCT00970866 [25646337] BACKGROUND Small birth size , often associated with insufficient maternal nutrition , contributes to a large share of global child undernutrition , morbidity , and mortality . We developed a small-quantity lipid-based nutrient supplement ( SQ-LNS ) to enrich the diets of pregnant women . OBJECTIVE The objective was to test a hypothesis that home fortification of pregnant women 's diets with SQ-LNS would increase birth size in an African community . DESIGN We enrolled 1391 women with uncomplicated pregnancies ( < 20 gestational weeks ) in a r and omized controlled trial in Malawi . The women were provided with one daily iron-folic acid ( IFA ) capsule , one capsule containing multiple micronutrients ( MMNs ) , or one 20-g sachet of SQ-LNS ( LNS , containing 118 kcal , protein , carbohydrates , essential fatty acids , and 21 micronutrients ) . Primary outcomes were birth weight and newborn length . Secondary outcomes included newborn weight , head and arm circumference , and pregnancy duration . Analysis was by intention to treat . RESULTS The mean ± SD birth weight and newborn length were 2948 ± 432 , 2964 ± 460 , and 3000 ± 447 g ( P = 0.258 ) and 49.5 ± 2.4 , 49.7 ± 2.2 , and 49.9 ± 2.1 cm ( P = 0.104 ) in the IFA , MMN , and LNS groups , respectively . For newborn weight-for-age , head circumference , and arm circumference , the point estimate for the mean was also highest in the LNS group , intermediate in the MMN group , and lowest in the IFA group , but except for midupper arm circumference ( P = 0.024 ) , the differences were not statistically significant . The prevalence of low birth weight ( < 2500 g ) was 12.7 % , 13.5 % , and 12.1 % ( P = 0.856 ) , respectively ; newborn stunting ( length-for-age z score < -2 ) was 19.2 % , 14.0 % , and 14.9 % ( P = 0.130 ) , respectively ; and newborn small head circumference ( head circumference-for-age z score < -2 ) was 5.8 % , 3.0 % , and 3.1 % ( P = 0.099 ) , respectively . The associations between the intervention and the outcomes were not modified by maternal parity , age , or nutritional status ( P > 0.100 ) . CONCLUSION The study findings do not support a hypothesis that provision of SQ-LNS to all pregnant women would increase the mean birth size in rural Malawi . The trial was registered at clinical trials.gov as NCT01239693 [19812173] BACKGROUND Prenatal multiple micronutrient ( MMN ) or balanced energy and protein supplementation has a limited effect on birth size of the offspring . OBJECTIVE The objective was to determine whether a prenatal MMN-fortified food supplement ( FFS ) improves anthropometric measures at birth compared with supplementation with an MMN pill alone . DESIGN We conducted a nonblinded , individually r and omized controlled trial in 1296 pregnant women in 2 villages in rural Burkina Faso . Supplements were provided on a daily basis , and compliance was closely verified by using a community-based network of home visitors . RESULTS Anthropometric measures at birth were available for analysis for 87 % of the 1175 live singleton deliveries enrolled . After adjustment for gestational age at birth , the FFS group had a significantly higher birth length ( + 4.6 mm ; P = 0.001 ) . FFS supplementation result ed in a modestly higher birth weight ( + 31 g ; P = 0.197 ) . Subgroup analyses showed clinical ly important treatment effects on birth length ( + 12.0 mm ; P = 0.005 ) and on birth weight ( + 111 g ; P = 0.133 ) for underweight [ body mass index ( in kg/m(2 ) ) < 18.5 ] pregnant women . Women with early pregnancy anemia who received FFS gave birth to longer newborns ( + 7.3 mm ; P = 0.002 ) than did those who received MMN supplementation . CONCLUSIONS The provision of FFS to pregnant women result ed in higher birth length than did MMN supplementation . For women with a suboptimal prepregnancy nutritional status , MMN supplementation should be complemented with a balanced energy and protein supplement to produce a clinical effect on birth size . The trial was registered at clinical trials.gov as NCT00909974 [28275128] Background : Nutrition during the first 1000 d is critical for brain development . Objective : We evaluated the effects on child development of home fortification with lipid-based nutrient supplements ( LNSs ) for mothers and /or children or micronutrient powder ( MNP ) for children . Design : We conducted a cluster-r and omized effectiveness trial with 4 arms : 1 ) LNSs during pregnancy and the first 6 mo postpartum and LNSs for the offspring from 6 to 24 mo ( LNS-LNS ) , 2 ) iron and folic acid ( IFA ) during pregnancy and the first 3 mo postpartum and LNSs for the children from 6 to 24 mo ( IFA-LNS ) , 3 ) IFA ( as above ) and MNP for the offspring from 6 to 24 mo ( IFA-MNP ) , and 4 ) IFA ( as above ) and no child supplement ( IFA-Control ) . Women were enrolled at ≤20 wk of gestation ; children were assessed at 12 ( n = 3331 ) , 18 ( n = 3364 ) , and 24 ( n = 3379 ) mo . Results : Compared with the IFA-Control group , motor development scores were higher in the LNS-LNS ( P = 0.016 ) and IFA-LNS groups ( P = 0.006 ) at 18 mo and in the IFA-MNP group ( P = 0.048 ) at 24 mo . Receptive language scores were higher for the LNS-LNS group ( P = 0.028 ) at 18 mo and for all 3 groups at 24 mo ( P = 0.008 for LNS-LNS , P = 0.022 for IFA-LNS , and P = 0.009 for IFA-MNP compared with IFA-Control ) . Expressive language scores did not differ at 18 mo ( P = 0.236 ) but were higher in the LNS-LNS ( P = 0.035 ) and IFA-MNP ( P = 0.002 ) groups than in the IFA-Control group at 24 mo . Groups did not differ in personal-social scores at 18 ( P = 0.233 ) or 24 ( P = 0.146 ) mo or in executive function score at 24 mo ( P = 0.467 ) . Conclusion : Prenatal LNSs , postnatal LNSs , or both , or postnatal MNP had a positive effect on motor and language development in Bangladeshi children . This trial was registered at clinical trials.gov as NCT01715038 [5610548] Background : Human milk oligosaccharides ( HMOs ) and bioactive proteins are beneficial to infant health . Recent evidence suggests that maternal nutrition may affect the amount of HMOs and proteins in breast milk ; however , the effect of nutrient supplementation on HMOs and bioactive proteins has not yet been well studied . Objective : We aim ed to determine whether lipid-based nutrient supplements ( LNSs ) affect milk bioactive protein and HMO concentrations at 6 mo postpartum in women in rural Malawi . These are secondary outcomes of a previously published r and omized controlled trial . Methods : Women were r and omly assigned to consume either an iron and folic acid capsule ( IFA ) daily from ≤20 wk gestation until delivery , followed by placebo daily from delivery to 6 mo postpartum , or a multiple micronutrient ( MMN ) capsule or LNS daily from ≤20 wk gestation to 6 mo postpartum . Breast milk concentrations of total HMOs , sialylated HMOs , fucosylated HMOs , lactoferrin , lactalbumin , lysozymes , antitrypsin , immunoglobulin A , and osteopontin were analyzed at 6 mo postpartum ( n = 647 ) . Between-group differences in concentrations and in proportions of women classified as having low concentrations were tested . Results : HMO and bioactive protein concentrations did not differ between groups ( P > 0.10 for all comparisons ) . At 6 mo postpartum , the proportions of women with low HMOs or bioactive proteins were not different between groups except for osteopontin . A lower proportion of women in the IFA group had low osteopontin compared with the LNS group after adjusting for covariates ( OR : 0.5 ; 95 % CI : 0.3 , 0.9 ; P = 0.016 ) . Conclusion : The study findings do not support the hypothesis that supplementation with an LNS or MMN capsule during pregnancy and postpartum would increase HMO or bioactive milk proteins at 6 mo postpartum among Malawian women . This trial was registered at clinical trials.gov as NCT01239693 [22649265] The Breastfeeding , Antiretrovirals , and Nutrition Study evaluated the effect of daily consumption of lipid-based nutrient supplements ( LNS ) by 2121 lactating , HIV-infected mothers on the growth of their exclusively breast-fed , HIV-uninfected infants from 0 to 24 wk . The study had a 2 × 3 factorial design . Malawian mothers with CD4(+ ) ≥250 cells/mm(3 ) , hemoglobin ≥70 g/L , and BMI ≥17 kg/m(2 ) were r and omized within 36 h of delivery to receive either no LNS or 140 g/d of LNS to meet lactation energy and protein needs , and mother-infant pairs were assigned to maternal antiretroviral drugs ( ARV ) , infant ARV , or no ARV . Sex-stratified , longitudinal , r and om effects models were used to estimate the effect of the 6 study arms on infant weight , length , and BMI . Logistic regression models were used to calculate the odds of growth faltering [ decline in weight-for-age Z-score ( WAZ ) or length-for-age Z-score ( LAZ ) > 0.67 ] using the control arm as the reference . Although some differences between study arms emerged with increasing infant age in boys , there were no consistent effects of the maternal supplement across the 3 growth outcomes in longitudinal models . At the ages where differences were observed , the effects on weight and BMI were quite small ( ≤200 g and ≤0.4 kg/m(2 ) ) and unlikely to be of clinical importance . Overall , 21 and 34 % of infants faltered in WAZ and LAZ , respectively . Maternal supplementation did not reduce the odds of infant weight or length faltering from 0 to 24 wk in any arm . These results indicate that blanket supplementation of HIV-infected lactating women may have little impact on infant growth [5338685] It is unknown whether a novel small-quantity lipid-based nutrient supplement ( SQ-LNS ) containing alpha-linolenic ( ALA ) and linoleic acids impacts maternal plasma lipids and fatty acid status . We measured plasma fatty acids ( wt% ) and lipid concentrations at 36 wk gestation and breast milk fatty acids ( wt% ) at 6 months postpartum in a sub sample of women enrolled in a r and omized controlled trial study ing the effects of SQ-LNS on birth outcomes and child growth . Women≤20 wk gestation in Ghana ( n=1,320 ) and Malawi ( n=1,391 ) were assigned to receive daily either : 1 ) iron-folic acid ( pregnancy ) ; 2 ) multiple micronutrients ( pregnancy and lactation ) ; or 3 ) SQ-LNS ( pregnancy and lactation ) . At 36 wk , plasma ALA levels were higher in those receiving SQ-LNS . SQ-LNS increased breast milk ALA in Ghana but not Malawi . There was no effect on plasma lipids or other selected fatty acids . SQ-LNS may impact plasma and breast milk ALA levels depending on the population [4997301] Background : Childhood stunting usually begins in utero and continues after birth ; therefore , its reduction must involve actions across different stages of early life . Objective : We evaluated the efficacy of small-quantity , lipid-based nutrient supplements ( SQ-LNSs ) provided during pregnancy , lactation , and infancy on attained size by 18 mo of age . Design : In this partially double-blind , individually r and omized trial , 1320 women at ≤20 wk of gestation received st and ard iron and folic acid ( IFA group ) , multiple micronutrients ( MMN group ) , or SQ-LNS ( LNS group ) daily until delivery , and then placebo , MMNs , or SQ-LNS , respectively , for 6 mo postpartum ; infants in the LNS group received SQ-LNS formulated for infants from 6 to 18 mo of age ( endline ) . The primary outcome was child length by 18 mo of age . Results : At endline , data were available for 85 % of 1228 infants enrolled ; overall mean length and length-for-age z score ( LAZ ) were 79.3 cm and −0.83 , respectively , and 12 % of the children were stunted ( LAZ < −2 ) . In analysis based on the intended treatment , mean ± SD length and LAZ for the LNS group ( 79.7 ± 2.9 cm and −0.69 ± 1.01 , respectively ) were significantly greater than for the IFA ( 79.1 ± 2.9 cm and −0.87 ± 0.99 ) and MMN ( 79.1 ± 2.9 cm and −0.91 ± 1.01 ) groups ( P = 0.006 and P = 0.009 , respectively ) . Differences were also significant for weight and weight-for-age z score but not head or midupper arm circumference , and the prevalence of stunting in the LNS group was 8.9 % , compared with 13.7 % in the IFA group and 12.9 % in the MMN group ( P = 0.12 ) . In analysis based on actual supplement provided at enrollment , stunting prevalences were 8.9 % compared with 15.1 % and 11.5 % , respectively ( P = 0.045 ) . Conclusion : Provision of SQ-LNSs to women from pregnancy to 6 mo postpartum and to their infants from 6 to 18 mo of age may increase the child ’s attained length by age 18 mo in similar setting s. This trial was registered at clinical trials.gov as NCT00970866 [4891833] Background Over half of the world ’s children suffer from poor nutrition , and as a consequence they experience delays in physical and mental health , and cognitive development . There is little data evaluating the effects of delivery of lipid-based , nutrition supplementation on growth and development during pregnancy and early childhood within the context of a scaled-up program . Furthermore , there is limited evidence on effects of scaled-up , home-visiting programs that focus on the promotion of child development within the context of an existing , national nutrition program . Methods / Design The MAHAY ( " smart " in Malagasy ) study uses a multi-arm r and omized-controlled trial ( RCT ) to test the effects and cost-effectiveness of combined interventions to address chronic malnutrition and poor child development . The arms of the trial are : ( T0 ) existing program with monthly growth monitoring and nutritional/hygiene education ; ( T1 ) is T0 + home visits for intensive nutrition counseling within a behavior change framework ; ( T2 ) is T1 + lipid-based supplementation ( LNS ) for children 6–18 months old ; ( T3 ) is T2 + LNS supplementation of pregnant/lactating women ; and ( T4 ) is T1 + intensive home visiting program to support child development . There are anticipated to be n = 25 communities in each arm ( n = 1250 pregnant women , n = 1250 children 0–6 months old , and n = 1250 children 6–18 months old ) . Primary outcomes include growth ( length/height-for-age z-scores ) and child development ( mental , motor and social development ) . Secondary outcomes include care-giver reported child morbidity , household food security and diet diversity , micro-nutrient status , maternal knowledge of child care and feeding practice s , and home stimulation practice s. We will estimate unadjusted and adjusted intention-to-treat effects . Study protocol s have been review ed and approved by the Malagasy Ethics Committee at the Ministry of Health in Madagascar and by the institutional review board at the University of California , Davis . This study is funded by the Strategic Impact Evaluation Fund ( SIEF ) , the World Bank Innovation Grant , the Early Learning Partnership Grant , the Japan Scaling-up for Nutrition Trustfund , and Gr and Challenges Canada . The implementation of the study is financed by Madagascar 's National Nutrition Office . Trial registration Current Controlled Trials IS RCT N14393738 . Registered June 23 , 2015 [26607935] BACKGROUND Maternal undernutrition and newborn stunting [ birth length-for-age z score ( LAZ ) < -2 ] are common in Bangladesh . OBJECTIVE The objective was to evaluate the effect of lipid-based nutrient supplements for pregnant and lactating women ( LNS-PLs ) on birth outcomes . DESIGN We conducted a cluster-r and omized effectiveness trial ( the Rang-Din Nutrition Study ) within a community health program in rural Bangladesh . We enrolled 4011 pregnant women at ≤20 gestational weeks ; 48 clusters received iron and folic acid ( IFA ; 60 mg Fe + 400 μg folic acid ) and 16 clusters received LNS-PLs ( 20 g/d , 118 kcal ) containing essential fatty acids and 22 vitamins and minerals . Both of the supplements were intended for daily consumption until delivery . Primary outcomes were birth weight and length . RESULTS Infants in the LNS-PL group had higher birth weights ( 2629 ± 408 compared with 2588 ± 413 g ; P = 0.007 ) , weight-for-age z scores ( -1.48 ± 1.01 compared with -1.59 ± 1.02 ; P = 0.006 ) , head-circumference-for-age z scores ( HCZs ; -1.26 ± 1.08 compared with -1.34 ± 1.12 ; P = 0.028 ) , and body mass index z scores ( -1.57 ± 1.05 compared with -1.66 ± 1.03 ; P = 0.005 ) than those in the IFA group ; in adjusted models , the differences in length ( 47.6 ± 0.07 compared with 47.4 ± 0.04 cm ; P = 0.043 ) and LAZ ( -1.15 ± 0.04 compared with -1.24 ± 0.02 ; P = 0.035 ) were also significant . LNS-PLs reduced the risk of newborn stunting ( 18.7 % compared with 22.6 % ; RR : 0.83 ; 95 % CI : 0.71 , 0.97 ) and small head size ( HCZ < -2 ) ( 20.7 % compared with 24.9 % ; RR : 0.85 ; 95 % CI : 0.73 , 0.98 ) . The effects of LNS-PL on newborn stunting were greatest in infants born before a 10-wk interruption in LNS-PL distribution ( n = 1301 ; 15.7 % compared with 23.6 % ; adjusted RR : 0.69 ; 95 % CI : 0.53 , 0.89 ) and in infants born to women ≤24 y of age or with household food insecurity . CONCLUSION Prenatal lipid-based nutrient supplements can improve birth outcomes in Bangladeshi women , especially those at higher risk of fetal growth restriction . This trial was registered at clinical trials.gov as NCT01715038 [18606932] OBJECTIVE To compare growth and incidence of malnutrition in infants receiving long-term dietary supplementation with ready-to-use fortified spread ( FS ) or micronutrient-fortified maize-soy flour ( likuni phala [ LP ] ) . DESIGN R and omized , controlled , single-blind trial . SETTING Rural Malawi . PARTICIPANTS A total of 182 six-month-old infants . INTERVENTION Participants were r and omized to receive 1 year of daily supplementation with 71 g of LP ( 282 kcal ) , 50 g of FS ( FS50 ) ( 256 kcal ) , or 25 g of FS ( FS25 ) ( 130 [ corrected ] kcal ) . OUTCOME MEASURES Weight and length gains and the incidences of severe stunting , underweight , and wasting . RESULTS Mean weight and length gains in the LP , FS50 , and FS25 groups were 2.37 , 2.47 , and 2.37 kg ( P = .66 ) and 12.7 , 13.5 , and 13.2 cm ( P = .23 ) , respectively . In the same groups , the cumulative 12-month incidence of severe stunting was 13.3 % , 0.0 % , and 3.5 % ( P = .01 ) , of severe underweight was 15.0 % , 22.5 % , and 16.9 % ( P = .71 ) , and of severe wasting was 1.8 % , 1.9 % , and 1.8 % ( P > .99 ) . Compared with LP-supplemented infants , those given FS50 gained a mean of 100 g more weight and 0.8 cm more length . There was a significant interaction between baseline length and intervention ( P = .04 ) ; in children with below-median length at enrollment , those given FS50 gained a mean of 1.9 cm more than individuals receiving LP . CONCLUSION One-year-long complementary feeding with FS does not have a significantly larger effect than LP on mean weight gain in all infants , but it is likely to boost linear growth in the most disadvantaged individuals and , hence , decrease the incidence of severe stunting [21496207] Inadequate micronutrient intake during pregnancy , lactation and infancy is a major problem in many developing countries . Lipid-based nutrient supplements ( LNS ) can improve micronutrient status , growth and development of infants , and also have potential to improve nutritional status of pregnant and lactating women . The objective of the study was to test the acceptability of LNS design ed for infants ( LNS-20gM ) and pregnant or lactating women ( LNS-P&L ) . Participants were infants ( n = 22 , mean age = 8 months ) and pregnant or lactating women ( n = 24 ) attending routine services at a hospital in Ghana . Infants consumed 45 g of a test meal consisting of one part LNS-20gM and three parts fermented maize porridge , while women consumed 50 g of a similar test meal containing LNS-P&L instead . Participants also used their respective LNS at home for 14 days . Primary outcome was the proportion of the test meal consumed . On average , infants consumed 76.2 % of the test meal [ 95 % ( confidence interval ) CI : 65.7 , 86.7 ] , while women consumed 87.1 % ( 95 % CI : 82.6 , 91.6 ) . During the 14-day period , median daily consumption of LNS-20gM was 19.3 g , very close to the recommended 20 g d(-1 ) , while that of LNS-P&L was one sachet , as recommended . We conclude that LNS-20gM and LNS-P&L were well accepted [20861218] Although widely used , there is little information concerning the efficacy of corn-soy blend ( CSB ) supplementation in the treatment of moderate underweight in African children . Lipid-based nutrient supplements ( LNS ) , which have proven to be beneficial treatment for severely wasted children , could offer benefits to less severely affected individuals . We conducted a clinical r and omized trial to determine whether LNS or CSB supplementation improves weight gain of moderately underweight children . A total of 182 underweight [ weight-for-age Z-score ( WAZ ) < -2 ] 6- to 15-mo-old children were r and omized to receive for 12 wk a ration of 43 g/d LNS or 71 g/d CSB , providing 1189 and 921 kJ , respectively , or no supplementation ( control ) . The primary outcome was weight change ; secondary outcomes included changes in anthropometric indices , hemoglobin levels , and morbidity . The body weight increases ( mean ± SD ) did not differ and were 620 ± 470 , 510 ± 350 , and 470 ± 350 g in the LNS , CSB , and control groups , respectively ( P = 0.11 ) . Compared with controls , infants and children in the LNS group gained more weight [ mean ( 95 % CI ) = 150 g ( 0 - 300 g ) ; P = 0.05 ] and had a greater increase in WAZ [ 0.33 ( -0.02 - 0.65 ) ; P = 0.04 ] . Weight and WAZ changes did not differ between the control and CSB groups . In exploratory stratified analysis , the weight increase was higher in the LNS group compared with the control group among those with lower initial WAZ [ 250 g ( 60 - 430 g ; P = 0.01 ] . Supplementation with LNS but not CSB modestly increases weight gain among moderately underweight children and the effect appears most pronounced among those with a lower initial WAZ [28724657] Background : Pregnancy and childbirth complications and cesarean delivery are common in Bangladesh . Objective : We evaluated the effect of lipid-based nutrient supplements for pregnant and lactating women ( LNS-PL ) on pregnancy and childbirth complications and cesarean delivery . Methods : We conducted the Rang-Din Nutrition Study , a cluster-r and omized controlled effectiveness trial within a community health program in rural Bangladesh . We enrolled 4011 pregnant women in early pregnancy . Women in 48 clusters received iron and folic acid ( IFA ; 60 mg Fe + 400 μg folic acid/d ) and women in 16 clusters received LNS-PL ( 20 g/d , 118 kcal ) containing essential fatty acids and 22 vitamins and minerals . Pregnancy and childbirth complications and the cesarean delivery rate were secondary outcomes of the study . Results : Women in the LNS-PL group did not differ significantly from the IFA group with respect to mean systolic blood pressure at 36 wk gestation ( 113 and 112 mm Hg ; P = 0.17 ) , diastolic blood pressure at 36 wk gestation ( 68.9 and 68.7 mmHg ; P = 0.88 ) , or mean total number of pregnancy and childbirth complications ( 0.32 and 0.31 ; P = 0.86 ) . They also did not differ significantly with respect to the prevalence of high blood pressure at 36 wk ( 1.74 % and 2.03 % ; P = 0.62 ) , antepartum hemorrhage ( 0.83 % and 1.39 % ; P = 0.21 ) , prolonged labor ( 8.34 % and 8.79 % ; P = 0.68 ) , early rupture of membranes ( 9.30 % and 8.45 % ; P = 0.43 ) , convulsions ( 1.57 % and 1.08 % ; P = 0.24 ) , high blood pressure in labor ( 1.54 % and 1.19 % ; P = 0.46 ) , obstructed labor ( 2.83 % and 2.91 % ; P = 0.90 ) , any complications during pregnancy or childbirth ( 35.9 % and 37.1 % ; P = 0.64 ) , episiotomy ( 6.31 % and 6.44 % ; P = 0.90 ) , or cesarean delivery ( 15.6 % and 14.2 % ; P = 0.48 ) . Conclusion : Compared with IFA , antenatal LNS-PL did not increase or decrease pregnancy and childbirth complications or cesarean delivery among women in rural Bangladesh . This trial was registered at clinical trials.gov as NCT01715038 [5396370] Abstract Prenatal supplementation with protein‐energy ( PE ) and /or multiple‐micronutrients ( MMNs ) may improve fetal growth , but trials of lipid‐based nutritional supplements ( LNSs ) have reported inconsistent results . We conducted a post‐hoc analysis of non‐ primary outcomes in a trial in Gambia , with the aim to test the associations of LNS with fetal growth and explore how efficacy varies depending on nutritional status . The sample comprised 620 pregnant women in an individually r and omized , partially blinded trial with four arms : ( a ) iron and folic acid ( FeFol ) tablet ( usual care , referent group ) , ( b ) MMN tablet , ( c ) PE LNS , and ( d ) PE + MMN LNS . Analysis of variance examined unadjusted differences in fetal biometry z‐scores at 20 and 30 weeks and neonatal anthropometry z‐scores , while regression tested for modification of intervention‐ outcome associations by season and maternal height , body mass index , and weight gain . Despite evidence of between‐arm differences in some fetal biometry , z‐scores at birth were not greater in the intervention arms than the FeFol arm ( e.g. , birth weight z‐scores : FeFol −0.71 , MMN −0.63 , PE −0.64 , PE + MMN −0.62 ; group‐wise p = .796 ) . In regression analyses , intervention associations with birth weight and head circumference were modified by maternal weight gain between booking and 30 weeks gestation ( e.g. , PE + MMN associations with birth weight were + 0.462 z‐scores ( 95 % CI [ 0.097 , 0.826 ] ) in the highest quartile of weight gain but –0.099 z‐scores ( −0.459 , 0.260 ) in the lowest ) . In conclusion , we found no strong evidence that a prenatal LNS intervention was associated with better fetal growth in the whole sample [26843155] BACKGROUND Maternal and infant undernutrition is associated with poor infant development ; however , few studies have examined the impact of combined pre- and postnatal dietary supplementation on infant development . OBJECTIVE Our objective was to determine whether provision of small-quantity lipid-based nutrient supplements ( SQ-LNSs ) to mothers during pregnancy and the first 6 mo postpartum , and to children aged 6 - 18 mo , improves infant development in Malawi . DESIGN We r and omly assigned 869 pregnant women to receive one of the following daily : an iron and folic acid ( IFA ) capsule , a multiple micronutrient ( MMN ) capsule containing 18 micronutrients , or a 20-g sachet of SQ-LNSs containing 22 vitamins and minerals , protein , carbohydrates , essential fatty acids , and 118 kcal . Children in the lipid-based nutrient supplement ( LNS ) group only received SQ-LNSs from 6 to 18 mo of age . We monitored the acquisition of 11 developmental milestones monthly by maternal report ; observed the attainment of 7 motor milestones at 6 , 12 , and 18 mo of age ; and conducted a comprehensive assessment of motor , language , and socioemotional development and executive function at 18 mo of age . The primary analysis was by intention-to-treat . RESULTS By maternal report , children in the LNS group achieved walking alone ( B = 0.53 ; 95 % CI : 0.11 , 0.94 ; P = 0.034 ) and waving goodbye ( B = 0.60 ; 95 % CI : 0.12 , 1.08 ; P = 0.040 ) earlier than the IFA group and st and ing with assistance earlier than the MMN group ( B = 0.51 ; 95 % CI : 0.12 , 0.89 ; P = 0.029 ) . By research er observation , there was a trend ( P = 0.052 ) for a greater percentage of children in the LNS group ( 58 % ) to walk alone at age 12 mo than in the IFA ( 49 % ) and MMN ( 49 % ) groups . At age 18 mo , there were no significant differences between groups in any scores . CONCLUSION Although provision of SQ-LNSs to pregnant women and infants in Malawi may affect the age of acquisition of certain developmental milestones , it did not affect our assessment s of motor , language , socioemotional , or executive function skills at 18 mo of age . This trial was registered at clinical trials.gov as NCT01239693 [24500152] BACKGROUND Selenium is found in soils and is essential for human antioxidant defense and immune function . In Malawi , low soil selenium and dietary intakes coupled with low plasma selenium concentrations in HIV infection could have negative consequences for the health of HIV-infected mothers and their exclusively breastfed infants . OBJECTIVE We tested the effects of lipid-based nutrient supplements ( LNS ) that contained 1.3 times the Recommended Dietary Allowance of sodium selenite and antiretroviral drugs ( ARV ) on maternal plasma and breast-milk selenium concentrations . DESIGN HIV-infected Malawian mothers in the Breastfeeding , Antiretrovirals , and Nutrition study were r and omly assigned at delivery to receive : LNS , ARV , LNS and ARV , or a control . In a sub sample of 526 mothers and their uninfected infants , we measured plasma and breast-milk selenium concentrations at 2 or 6 ( depending on the availability of infant sample s ) and 24 wk postpartum . RESULTS Overall , mean ( ± SD ) maternal ( range : 81.2 ± 20.4 to 86.2 ± 19.9 μg/L ) and infant ( 55.6 ± 16.3 to 61.0 ± 15.4 μg/L ) plasma selenium concentrations increased , whereas breast-milk selenium concentrations declined ( 14.3 ± 11.5 to 9.8 ± 7.3 μg/L ) from 2 or 6 to 24 wk postpartum ( all P < 0.001 ) . Compared with the highest baseline selenium tertile , low and middle tertiles were positively associated with a change in maternal plasma or breast-milk selenium from 2 or 6 to 24 wk postpartum ( both P < 0.001 ) . With the use of linear regression , we showed that LNS that contained selenium and ARV were not associated with changes in maternal plasma and breast-milk selenium , but maternal selenium concentrations were positively associated with infant plasma selenium at 2 or 6 and 24 wk postpartum ( P < 0.001 ) regardless of the study arm . CONCLUSIONS Selenite supplementation of HIV-infected Malawian women was not associated with a change in their plasma or breast-milk selenium concentrations . Future research should examine effects of more readily incorporated forms of selenium ( ie , selenomethionine ) in HIV-infected breastfeeding women [22258269] BACKGROUND Breastfeeding increases metabolic dem and s on the mother , and excessive postnatal weight loss increases maternal mortality . OBJECTIVE We evaluated the efficacy of a lipid-based nutrient supplement ( LNS ) for prevention of excess weight loss in breastfeeding , HIV-infected women . DESIGN The BAN ( Breastfeeding , Antiretrovirals , and Nutrition ) Study was a r and omized controlled trial in Lilongwe , Malawi . At delivery , HIV-infected mothers and their infants were r and omly assigned according to a 2-arm ( with and without LNS ) by 3-arm ( maternal triple-antiretroviral prophylaxis , infant-nevirapine prophylaxis , or neither ) factorial design . The 28-wk LNS intervention provided daily energy ( 700 kcal ) , protein ( 20 g ) , and micronutrients ( except for vitamin A ) to meet lactation needs . Women were counseled to breastfeed exclusively for 24 wk and to wean by 28 wk . Weight change ( 0 - 28 wk ) was tested in an intent-to-treat analysis by using 2-factor ANOVA and with longitudinal mixed-effects models . RESULTS At delivery , the LNS ( n = 1184 ) and control ( n = 1185 ) groups had similar mean weights and BMI s. Women receiving the LNS had less 0 - 28-wk weight loss ( -1.97 compared with -2.56 kg , P = 0.003 ) . This difference remained significant after adjustment for maternal antiretroviral drug therapy and baseline BMI . Women receiving antiretroviral drugs had more weight loss than did those not receiving antiretroviral drugs ( -2.93 compared with -1.90 kg , P < 0.001 ) . The benefit of the LNS for reducing weight loss was observed both in those receiving antiretroviral drugs ( -2.56 compared with -3.32 kg , P = 0.019 ) and in those not receiving antiretroviral drugs ( -1.63 compared with -2.16 kg , P = 0.034 ) . CONCLUSIONS The LNS reduced weight loss among HIV-infected , breastfeeding women , both in those taking maternal antiretroviral prophylaxis to prevent postnatal HIV transmission and in those not receiving antiretroviral prophylaxis . Provision of an LNS may benefit HIV-infected , breastfeeding women in re source -limited setting s. This trial was registered at clinical trials.gov as NCT00164762 [28275125] Background : Stunting in linear growth occurs mainly during the first 1000 d , from conception through 24 mo of age . Despite the recognition of this critical period , there have been few evaluations of the growth impact of interventions that cover most of this window . Objective : We evaluated home fortification approaches for preventing maternal and child undernutrition within a community-based health program . We hypothesized that small-quantity lipid-based nutrient supplements ( LNSs ) provided to women during pregnancy and the first 6 mo postpartum , LNSs provided to their offspring from 6 to 24 mo of age , or both would result in greater child length-for-age z score ( LAZ ) at 24 mo than iron and folic acid ( IFA ) provided to women during pregnancy and postpartum plus micronutrient powder ( MNP ) or no supplementation for their offspring from 6 to 24 mo . Design : We conducted a cluster-r and omized effectiveness trial with 4 arms : 1 ) women and children both received LNSs ( LNS-LNS group ) , 2 ) women received IFA and children received LNSs ( IFA-LNS group ) , 3 ) women received IFA and children received MNP ( IFA-MNP group ) , and 4 ) women received IFA and children received no supplements ( IFA-Control group ) . We enrolled 4011 women at ≤20 wk of gestation within 64 clusters , each comprising the supervision area of a community health worker . Analyses were primarily performed by using ANCOVA F tests and Tukey-Kramer-corrected pairwise comparisons . Results : At 24 mo , the LNS-LNS group had significantly higher LAZ ( + 0.13 compared with the IFA-MNP group ) and head circumference ( + 0.15 z score compared with the IFA-Control group ) ; these outcomes did not differ between the other groups . Stunting prevalence ( LAZ < -2 ) was lower in the LNS-LNS group at 18 mo than in the IFA-MNP group ( OR : 0.70 ; 95 % CI : 0.53 , 0.92 ) , but the difference diminished by 24 mo ( OR : 0.81 ; 95 % CI : 0.63 , 1.04 ) . Conclusion : Home fortification with small-quantity LNSs , but not MNP , during the first 1000 d improved child linear growth and head size in rural Bangladesh . This trial was registered at clinical trials.gov as NCT01715038 [25833980] BACKGROUND The International Lipid-Based Nutrient Supplements Project developed a small-quantity ( 20 g/d ) lipid-based nutrient supplement ( LNS ) for pregnant and lactating women . OBJECTIVE We evaluated the effects of prenatal LNS supplementation on fetal growth . DESIGN In a community-based , partially double-blind , individually r and omized controlled trial , 1320 women ≤20 wk pregnant received 60 mg Fe/400 μg folic acid ( IFA ) , or 1 - 2 Recommended Dietary Allowances of 18 micronutrients , including 20 mg Fe ( MMN ) , or LNS with the same micronutrients as the MMN group , plus 4 minerals and macronutrients contributing 118 kcal ( LNS ) daily until delivery . Fetal growth was compared across groups by using intention-to-treat analysis . The primary outcome was birth length . RESULTS This analysis included 1057 women ( IFA = 349 , MMN = 354 , LNS = 354 ) . Groups did not differ significantly in mean birth length , length-for-age z score ( LAZ ) , head circumference , or percentage low birth length but differed in mean birth weight ( P = 0.044 ) , weight-for-age z score ( WAZ ; P = 0.046 ) , and BMI -for-age z score ( BMI Z ; P = 0.040 ) , with a trend toward differences in low birth weight ( P = 0.069 ) . In pairwise comparisons , the LNS group had greater mean birth weight ( + 85 g ; P = 0.040 ) , WAZ ( + 0.19 ; P = 0.045 ) , and BMI Z ( + 0.21 ; P = 0.035 ) and a lower risk of low birth weight ( RR : 0.61 , 95 % CI : 0.39 , 0.96 ; P = 0.032 ) than did the IFA group . The other group differences were not significant . The effect of intervention was modified by mother 's parity , age , height , baseline hemoglobin , household food insecurity , and child sex , with parity being the most consistent modifier . Among primiparous women ( IFA = 131 ; MMN = 110 ; LNS = 128 ) , the LNS group had greater mean birth length ( + 0.91 cm ; P = 0.001 ) , LAZ ( + 0.47 ; P = 0.001 ) , weight ( + 237 g ; P < 0.001 ) , WAZ ( + 0.56 ; P < 0.001 ) , BMI Z ( + 0.52 ; P < 0.001 ) , head circumference ( 0.50 cm ; P = 0.017 ) , and head circumference-for-age z score ( + 0.40 ; P = 0.022 ) than did the IFA group ; similar differences were found when comparing the LNS and MMN groups among primiparous women , and no group differences were found among multiparous women . CONCLUSION Prenatal LNS supplementation can improve fetal growth among vulnerable women in Ghana , particularly primiparous women . This trial was registered at clinical trials.gov as NCT00970866 [25926413] BACKGROUND Intrauterine growth restriction may be reduced by supplementing maternal diets during pregnancy , but few studies have assessed the impact of combined prenatal and postnatal interventions on child growth . OBJECTIVE We tested a hypothesis that provision of small-quantity lipid-based nutrient supplements ( SQ-LNSs ) to mothers in pregnancy and 6 mo postpartum and to their infants from 6 to 18 mo of age would promote infant and child growth in the study area in rural Malawi . METHODS We enrolled 869 pregnant women in a r and omized trial in Malawi . During pregnancy and 6 mo thereafter , the women received daily 1 capsule of iron-folic acid ( IFA ) , 1 capsule containing 18 micronutrients ( MMN ) , or one 20-g sachet of SQ-LNS [ lipid-based nutrient supplements ( LNS ) , containing 21 MMN , protein , carbohydrates , essential fatty acids , and 118 kcal ] . Children in the IFA and MMN groups received no supplementation ; children in the LNS group received SQ-LNSs from 6 to 18 mo . Primary outcome was child length at 18 mo . RESULTS At 18 mo , the mean length in the IFA , MMN , and LNS groups was 77.0 , 76.9 , and 76.8 cm ( P = 0.90 ) , respectively , and the prevalence of stunting was 32.7 % , 35.6 % , and 37.9 % ( P = 0.54 ) , respectively . No intergroup differences were found in the mean weight , head circumference , or midupper arm circumference or the proportions with low z scores for these variables ( P > 0.05 ) . Covariate adjustment did not change the analysis results , and the associations between the intervention and child length were not modified by maternal parity , age , or nutritional status ( P > 0.10 ) . CONCLUSIONS The findings do not support a hypothesis that provision of SQ-LNSs to women in pregnancy and postpartum and to children from 6 to 18 mo of age would promote child growth in this Malawian study area . This trial was registered at clinical trials.gov as NCT01239693 [28615379] Background : Maternal iodine deficiency during pregnancy and lactation is common in Bangladesh . Objective : We evaluated the effect of lipid-based nutrient supplements for pregnant and lactating women ( LNS-PL ) on urinary iodine concentration ( UIC ) . Methods : We conducted a cluster-r and omized controlled effectiveness trial in which we enrolled 4011 pregnant women at ≤20 gestational weeks . Women in 48 clusters received iron and folic acid ( IFA ; 60 mg Fe/d + 400 μg folic acid/d ) and women in 16 clusters received LNS-PL ( 20 g/d , 118 kcal ) containing 22 vitamins and minerals ( including 250 μg I ) . We r and omly selected a sub sample of 1159 women for repeated urine sample collection , i.e. , at enrollment , at 36 wk of gestation , and at 6 mo postpartum , for UIC analysis , a secondary outcome of the trial . Results : The geometric mean UIC at 36 wk of gestation and at 6 mo postpartum did not differ significantly between the IFA and LNS-PL groups . The median ( quartile 1 , quartile 3 ) UIC at 36 wk was 27.4 μg/L ( 16.9 , 52.7 μg/L ) in the IFA group and 30.2 μg/L ( 17.7 , 56.6 μg/L ) in the LNS-PL group ; at 6 mo , these were 23.0 μg/L ( 10.0 , 45.9 μg/L ) in the IFA group and 22.2 μg/L ( 9.1 , 50.4 μg/L ) in the LNS-PL group . Conclusion : Daily consumption of LNS-PL containing 250 μg I did not increase the UICs of pregnant and lactating women in Bangladesh . Iodine from lipid-based nutrient supplements may have been stored in the thyroid gl and or secreted in breast milk instead of being excreted in urine . Additional research that uses other biomarkers of iodine status is needed to determine how to meet the iodine requirements of pregnant and lactating women in Bangladesh and similar setting s. This trial was registered at clinical trials.gov as NCT01715038 [26924599] Abstract We examined hemoglobin ( Hb , g/L ) , iron status ( zinc protoporphyrin , ZPP , & mgr;mol/mol heme , and transferrin receptor , TfR , mg/L ) and inflammation ( C‐reactive protein , CRP and alpha‐1 glycoprotein , AGP ) in pregnant Ghanaian women who participated in a r and omized controlled trial . Women ( n = 1320 ) received either 60 mg Fe + 400‐&mgr;g folic acid ( IFA ) ; 18 micronutrients including 20‐mg Fe ( MMN ) or small‐quantity lipid‐based nutrient supplements ( SQ‐LNS , 118 kcal/d ) with the same micronutrient levels as in MMN , plus four additional minerals ( LNS ) daily during pregnancy . Intention‐to‐treat analysis included 349 , 354 and 354 women in the IFA , MMN and LNS groups , respectively , with overall baseline mean Hb and anemia ( Hb < 100 ) prevalence of 112 and 13.3 % , respectively . At 36 gestational weeks , overall Hb was 117 , and anemia prevalence was 5.3 % . Compared with the IFA group , the LNS and MMN groups had lower mean Hb ( 120 ± 11 vs. 115 ± 12 and 117 ± 12 , respectively ; P < 0.001 ) , higher mean ZPP ( 42 ± 30 vs. 50 ± 29 and 49 ± 30 ; P = 0.010 ) and TfR ( 4.0 ± 1.3 vs. 4.9 ± 1.8 and 4.6 ± 1.7 ; P < 0.001 ) , and greater prevalence of anemia ( 2.2 % vs. 7.9 % and 5.8 % ; P = 0.019 ) , elevated ZPP ( > 60 ) [ 9.4 % vs. 18.6 % and 19.2 % ; P = 0.003 ] and elevated TfR ( > 6.0 ) [ 9.0 % vs. 19.2 % and 15.1 % ; P = 0.004 ] . CRP and AGP concentrations did not differ among groups . We conclude that among pregnant women in a semi‐urban setting in Ghana , supplementation with SQ‐LNS or MMN containing 20 mg iron result ed in lower Hb and iron status but had no impact on inflammation , when compared with iron ( 60 mg ) plus folic acid ( 400 & mgr;g ) . The amount of iron in such supplements that is most effective for improving both maternal Hb/iron status and birth outcomes requires further evaluation . This trial was registered at Clinical Trials.gov as : NCT00970866 [5697970] Background : It is unknown whether self-reported measures of household food insecurity change in response to food-based nutrient supplementation . Objective : We assessed the impacts of providing lipid-based nutrient supplements ( LNSs ) to women during pregnancy and postpartum and /or to their children on self-reported household food insecurity in Malawi [ DOSE and DYAD trial in Malawi ( DYAD-M ) ] , Ghana [ DYAD trial in Ghana ( DYAD-G ) ] , and Bangladesh [ Rang-Din Nutrition Study ( RDNS ) trial ] . Methods : Longitudinal household food-insecurity data were collected during 3 individually r and omized trials and 1 cluster-r and omized trial testing the efficacy or effectiveness of LNSs ( generally 118 kcal/d ) . Seasonally adjusted Household Food Insecurity Access Scale ( HFIAS ) scores were constructed for 1127 DOSE households , 732 DYAD-M households , 1109 DYAD-G households , and 3671 RDNS households . The impact of providing LNSs to women during pregnancy and the first 6 mo postpartum and /or to their children from 6 to 18–24 mo on seasonally adjusted HFIAS scores was assessed by using negative binomial models ( DOSE , DYAD-M , and DYAD-G trials ) and mixed-effect negative binomial models ( RDNS trial ) . Results : In the DOSE and DYAD-G trials , seasonally adjusted HFIAS scores were not different between the LNS and non-LNS groups . In the DYAD-M trial , the average household food-insecurity scores were 14 % lower ( P = 0.01 ) in LNS households than in non-LNS households . In the RDNS trial , compared with non-LNS households , food-insecurity scores were 17 % lower ( P = 0.02 ) during pregnancy and the first 6 mo postpartum and 15 % lower ( P = 0.02 ) at 6–24 mo postpartum in LNS households . Conclusions : The daily provision of LNSs to mothers and their children throughout much of the “ first 1000 d ” may improve household food security in some setting s , which could be viewed as an additional benefit that may accrue in households should policy makers choose to invest in LNSs to promote child growth and development . These trials were registered at clinical trials.gov as NCT00945698 ( DOSE ) NCT01239693 ( DYAD-M ) , NCT00970866 ( DYAD-G ) and NCT01715038 ( RDNS ) [27391572] BACKGROUND Maternal and infant undernutrition is negatively associated with infant development . AIMS We tested the hypothesis that provision of small-quantity lipid-based nutrient supplements ( SQ-LNS ) to pregnant women and infants positively affects infant development . STUDY DESIGN In a partially double-blind r and omized controlled trial , we compared the following daily maternal supplements during pregnancy and until 6months post-partum : iron/folic acid capsule ( IFA ) , capsule containing 18 micronutrients ( MMN ) , or 20 g SQ-LNS . Children in the SQ-LNS group also received SQ-LNS from age 6 to 18months . The study is registered as NCT00970866 . SUBJECTS 1320 pregnant women in Ghana enrolled in the trial ; 1173 of their children participated in developmental assessment . OUTCOME MEASURES We monitored the acquisition of 10 developmental milestones monthly by parental report , observed the attainment of 6 motor milestones at 6 , 12 , and 18months , and conducted detailed assessment of motor , language , socio-emotional , and executive function at 18months . RESULTS By research er observation , a greater percentage of children in the SQ-LNS group ( 53 % ) was able to walk alone at 12months than in the IFA group ( 43 % ; RR=1.23 , 95 % CI=1.02 - 1.49 ; p=0.025 ) . We found no significant differences between groups in milestone acquisition by parent report or in any scores at 18months . The difference in mean z-scores between groups ranged from 0.03 - 0.13 for motor ( p=0.84 ) , 0.01 - 0.08 for language ( p=0.46 ) , 0.01 - 0.02 for socio-emotional ( p=0.75 ) , and 0.00 - 0.02 for executive function ( p=0.95 ) . CONCLUSION While provision of maternal and child SQ-LNS in Ghana may affect walking at 12months , it did not affect infant development at 18months [4688934] Background Prenatal micronutrient supplements have been found to increase birth weight , but mechanisms for increased growth are poorly understood . Our hypotheses were that 1 ) women who receive lipid-based nutrient supplements ( LNS ) during pregnancy would have lower mean salivary cortisol concentration at 28 wk and 36 wk gestation compared to the multiple micronutrient ( MMN ) and iron-folic acid ( IFA ) supplement groups and 2 ) both salivary cortisol and perceived stress during pregnancy would be associated with shorter duration of gestation and smaller size at birth . Methods Women were enrolled in the trial in early pregnancy and r and omized to receive LNS , MMN , or iron-folic acid ( IFA ) supplements daily throughout pregnancy . At enrollment , 28 wk and 36 wk gestation , saliva sample s were collected and their cortisol concentration was measured . Self-report of perceived stress was measured using question naires . Gestation duration was indicated by ultrasound dating and newborn anthropometric measurements ( weight , length , head circumference ) provided indicators of intrauterine growth . Results Of the 1391 women enrolled in the trial , 1372 , 906 and 1049 saliva sample s were collected from women at baseline , 28 wk and 36 wk , respectively . There were no significant differences in mean cortisol concentrations by intervention group at 28 wk or 36 wk gestation . Cortisol concentrations were negatively associated with duration of gestation ( Baseline : β = −0.05 , p = 0.039 ; 36 wk : β = −0.04 , p = 0.037 ) and birth weight ( 28 wk : β = −0.08 , p = 0.035 ; 36 wk : β = −0.11 , p = 0.003 ) but not associated with length-for-age or head circumference-for-age z-scores . Perceived stress at 36 wk was significantly associated with shorter newborn LAZ ( p = 0.001 ) . There were no significant associations with the risk of small for gestational age , preterm birth , or low birth weight . Conclusions Maternal salivary cortisol concentration was strongly associated with birth weight and duration of gestation in rural Malawi , but these data do not support the hypothesis that LNS provision to pregnant women would influence their salivary cortisol concentrations . Trial registration Clinical trials.gov identifier [25733482] BACKGROUND Maternal nutritional status is a major determinant of low birth weight and fluctuates across seasons . Seasonality may influence the outcome of prenatal nutrition interventions that aim to enhance fetal growth . OBJECTIVE This study investigated seasonal modifications of the efficacy of a r and omized controlled prenatal nutrition intervention trial in pregnant women to improve fetal growth in rural Burkina Faso . METHODS The second Micronutriments et Santé de la Mère et de l'Enfant study compared a lipid-based nutrient supplement ( LNS ) fortified with multiple micronutrients ( MMNs ) to an MMN supplement . Truncated Fourier series were used to characterize seasonality in birth outcomes . Models that included the Fourier series and newborn and maternal characteristics were used to assess seasonal effect modifications of prenatal supplementation on birth outcomes . RESULTS Birth weight , birth length , small for gestational age as a proxy for intrauterine growth retardation , and preterm birth were significantly related to date of birth and showed important seasonal variations . LNSs , which supply energy in addition to MMNs , result ed in a significant increase in birth length ( + 13.5 mm , 95 % CI : 6.5 , 20.5 mm ) at the transition from rain to dry season ( September to November ) compared to MMNs alone . CONCLUSIONS The climatologic and agricultural seasonal patterns in Burkina Faso affect the efficacy of prenatal LNSs on birth length . In this context , prenatal MMN supplementation programs should be complemented by energy supplementation during the annual rain season to promote fetal growth . This trial was registered at clinical trials.gov as NCT00909974 [26740682] BACKGROUND Vitamin A deficiency remains a global public health problem . Daily supplementation with a lipid-based nutrient supplement ( LNS ) has potential for increasing milk vitamin A concentrations . OBJECTIVE The objective of this study was to determine whether daily supplementation with approximately the recommended daily intake of vitamin A in an LNS or a multiple-micronutrient supplement ( MMN ) during pregnancy and the first 6 mo postpartum has an effect on breast milk retinol concentration at 6 mo postpartum . METHODS Women ≤20 wk pregnant ( n = 1320 ) were r and omly assigned to receive either the MMN providing 18 micronutrients , including 800 μg retinol equivalents of vitamin A , or the LNS with the same nutrients as the MMN group , plus 4 minerals and macronutrients , until 6 mo postpartum ; a control group received iron and folic acid during pregnancy and a placebo ( calcium tablet ) during the first 6 mo postpartum . Breast milk sample s collected at 6 mo postpartum were analyzed for retinol and fat concentrations by HPLC and creamatocrit , respectively , in a sub sample of 756 women . RESULTS The breast milk retinol concentration was ( mean ± SD ) 56.3 ± 2.1 nmol/g fat , with no significant differences between groups [ iron and folic acid ( n = 243 ) : 59.1 ± 2.8 ; MMN ( n = 260 ) : 55.4 ± 2.5 ; LNS ( n = 253 ) : 54.7 ± 2.5 nmol/g fat ; P = 0.45 ] , regardless of whether the woman had or had not received a high-dose vitamin A supplement ( 200,000 IU ) soon after childbirth . Around 17 % of participants had low milk retinol ( ≤28 nmol/g fat ) . We estimated that 41 % of infants were potentially receiving vitamin A at amounts above the Tolerable Upper Intake Level ( 600 μg retinol activity equivalents/d ) , with no group differences in percentages with low or high milk retinol concentration . CONCLUSION Daily consumption of approximately the recommended intake of vitamin A did not increase breast milk retinol concentrations in this sample of Ghanaian women . This trial was registered at clinical trials.gov as NCT00970866 [5368579] Background : It is unclear whether maternal supplementation with small-quantity lipid-based nutrient supplements ( SQ-LNSs ; 118 kcal/d ) affects maternal weight . Objective : We compared several secondary anthropometric measures between 3 groups of women in the iLiNS ( International Lipid-based Nutrient Supplements)-DYAD trial in Ghana . Methods : Women ( n = 1320 ; < 20 wk of gestation ) were r and omly assigned to receive 60 mg Fe + 400 μg folic acid/d ( IFA ) , 18 vitamins and minerals/d [ multiple micronutrients ( MMNs ) ] , or 20 g SQ-LNSs with 22 micronutrients/d ( LNS ) during pregnancy and a placebo ( 200 mg Ca/d ) , MMNs , or SQ-LNSs , respectively , for 6 mo postpartum . Weight , midupper arm circumference ( MUAC ) , and triceps skinfold ( TSF ) thickness at 36 wk of gestation and 6 mo postpartum were analyzed , as were changes from estimated prepregnancy values . We assessed the adequacy of estimated gestational weight gain ( GWG ) by using Institute of Medicine ( IOM ) and International Fetal and Newborn Growth St and ards for the 21st Century ( INTERGROWTH-21st ) guidelines . Results : The estimated prepregnancy prevalence of overweight or obesity was 38.5 % . By 36 wk of gestation , women ( n = 1015 ) had a mean ± SD weight gain of 7.4 ± 3.7 kg and changes of −1.0 ± 1.7 cm in MUAC and −2.8 ± 4.1 mm in TSF thickness . The LNS group had a lower prevalence of inadequate GWG on the basis of IOM guidelines ( 57.4 % ) than the MMN ( 67.2 % ) but not the IFA ( 63.1 % ) groups ( P = 0.030 ) , whereas the prevalence of adequate ( 26.9 % overall ) and excessive ( 10.4 % overall ) GWG did not differ by group . The percentages of normal-weight women ( in kg/m2 : 18.5 < body mass index < 25.0 ; n = 754 ) whose GWG was less than the third centile of the INTERGROWTH-21st st and ards were 23.0 % , 28.7 % , and 28.5 % for the LNS , MMN , and IFA groups , respectively ( P = 0.36 ) . At 6 mo postpartum , the prevalence of overweight or obesity was 45.3 % , and the risk of becoming overweight or obese did not differ by group . Conclusion : SQ-LNS supplementation is one potential strategy to address the high prevalence of inadequate GWG in women in setting s similar to Ghana , without increasing the risk of excessive GWG . This trial was registered at clinical trials.gov as NCT00970866 Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Child stunting is a major public health problem , afflicting 155 million people worldwide . Lack of animal- source protein has been identified as a risk , but effects of animal protein supplementation are not well established . OBJECTIVE The aim of this study was to investigate effects of animal protein supplementation in mothers , preterm infants , and term infants/children on birth and growth outcomes . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

28472859

[17596471] It is recognized that women with gestational diabetes mellitus ( GDM ) who have significantly elevated fasting blood glucose levels are at increased risk for fetal macrosomia and perinatal morbidity if treatment is not provided ( 1,2 ) . The association of milder forms of GDM with perinatal morbidity and mortality remains unclear , primarily because the condition is often confounded with other risk factors such as maternal obesity , age , and parity . Screening for GDM is recommended for most pregnant women , yet it is unknown whether there is a benefit to the identification and treatment of mild carbohydrate intolerance during pregnancy ( 3,4 ) . The present report is an up date of our previous description of a current ongoing r and omized treatment trial for mild GDM ( 5 ) . A r and omized clinical trial of women with mild GDM ( fasting glucose < 95 mg/dl ) is being undertaken that compares perinatal outcomes in those receiving diet therapy and insulin as required versus those r and omized to no specific treatment . This study aims to clarify whether there is utility in identifying and treating women with a normal fasting glucose level who meet st and ard criteria for GDM . We plan to compare perinatal outcomes in women who have been r and omized to diet and /or insulin therapy with women who have been r and omized to no specific treatment . A r and omized treatment trial of mild GDM will clarify whether identification and treatment of mild GDM reduce perinatal morbidity . This information will assist in determining appropriate thresholds for the treatment of GDM . Overall , with broader identification and aggressive treatment , perinatal mortality rates associated with GDM appear to be similar to the nondiabetic population ( 1 ) . Several analyses of 20 years ago did document an increased stillbirth rate for GDM pregnancies that would qualify as preexisting diabetes according to World Health Organization criteria ( 6–9 ) . Below this threshold , the extent to [3120183] OBJECTIVE To pilot , among women with gestational diabetes mellitus ( GDM ) , the feasibility of a prenatal/postpartum intervention to modify diet and physical activity similar to the Diabetes Prevention Program . The intervention was delivered by telephone , and support for breastfeeding was addressed . RESEARCH DESIGN AND METHODS The goal was to help women return to their prepregnancy weight , if it was normal , or achieve a 5 % reduction from prepregnancy weight if overweight . Eligible participants were identified shortly after a GDM diagnosis ; 83.8 % consented to be r and omly assigned to intervention or usual medical care ( 96 and 101 women , respectively ) . The retention was 85.2 % at 12 months postpartum . RESULTS The proportion of women who reached the postpartum weight goal was higher , although not statistically significant , in the intervention condition than among usual care ( 37.5 vs. 21.4 % , absolute difference 16.1 % , P = 0.07 ) . The intervention was more effective among women who did not exceed the recommended gestational weight gain ( difference in the proportion of women meeting the weight goals : 22.5 % , P = 0.04 ) . The intervention condition decreased dietary fat intake more than the usual care ( condition difference in the mean change in percent of calories from fat : −3.6 % , P = 0.002 ) and increased breastfeeding , although not significantly ( condition difference in proportion : 15.0 % , P = 0.09 ) . No differences in postpartum physical activity were observed between conditions . CONCLUSIONS This study suggests that a lifestyle intervention that starts during pregnancy and continues postpartum is feasible and may prevent pregnancy weight retention and help overweight women lose weight . Strategies to help postpartum women overcome barriers to increasing physical activity are needed [19696205] Diabetes in pregnancy is a major public health problem in Mexico . Nutrition therapy is an important component of treatment . Intensive nutrition intervention has not been implemented for Mexican pregnant women with diabetes . Its effect on different types of diabetes mellitus has not been studied . Purpose The authors assessed the effect of a medical nutrition therapy ( MNT ) program on perinatal complications in Mexico City . Methods Quasi-experimental design with a historical control . Women were assigned to a MNT program ( n = 88 ) and were followed up with every 2 weeks until delivery ( 2004 - 2007 ) . The control group ( n = 86 ) was selected from medical charts ( 2001 - 2003 ) and the same inclusion criteria were used . In each group , 55 % of women had type 2 diabetes mellitus and 45 % had gestational diabetes . The MNT program included a moderate intake of carbohydrate ( 40%-45 % of total energy ) and reduction in energy intake , capillary glucose self-monitoring , and education . The control group received usual hospital routine care . Statistical analysis included descriptive statistics , chi-square , and multivariate logistic regression ( OR , 95 % CI ) as indicated . Results Women in the MNT program had a lower risk of preeclampsia , fewer maternal hospitalization , and neonatal deaths in both types of diabetes . Low birth weight was less frequent only in women with gestational diabetes receiving MNT , while neonatal intensive care unit admissions were lower only in women with type 2 diabetes . Conclusions An intensive MNT program , including counseling , education , and capillary glucose self-monitoring , has a positive effect over preeclampsia , maternal hospitalization , and neonatal death in women with diabetes in pregnancy . MNT guidelines should be implemented in Mexican health care facilities treating diabetes in pregnancy [12073958] PURPOSE The purpose of this study was to examine the effects of self-monitoring of blood glucose ( SMBG ) on feelings of self-efficacy , dietary compliance , and pregnancy outcomes in women with diet-controlled gestational diabetes mellitus ( GDM ) . METHODS Fifty-eight women with GDM and a fasting blood glucose level < 95 mg/dL were r and omly assigned to 2 groups . The experimental group measured their blood glucose levels 4 times daily using a reflectance meter with memory . Metabolic status was assessed in the control group by periodic monitoring at prenatal visits . Otherwise the management protocol was identical for both groups . The Diabetes Empowerment Scale was completed at study entry and at 37 weeks gestation to assess feelings of self-efficacy . Dietary compliance was assessed at each visit . RESULTS Both groups of women achieved excellent glucose control ; only 1 woman in each group required insulin therapy . There were no significant differences with regard to feelings of self-efficacy , dietary compliance , birth weight , gestational age at delivery , Apgar scores , and neonatal complications . Rates of macrosomia , delivery by cesarean section , and occurrence of birth trauma were similar . CONCLUSIONS SMBG appears to have little effect on maternal feelings of self-efficacy , dietary compliance , or pregnancy outcomes in women with diet-controlled GDM [6259925] The determine the effect of different foods on the blood glucose , 62 commonly eaten foods and sugars were fed individually to groups of 5 to 10 healthy fasting volunteers . Blood glucose levels were measured over 2 h , and expressed as a percentage of the area under the glucose response curve when the same amount of carbohydrate was taken as glucose . The largest rises were seen with vegetables ( 70 + /- 5 % ) , followed by breakfast cereals ( 65 + /- 5 % ) , cereals and biscuits ( 60 + /- 3 % ) , fruit ( 50 + /- 5 % ) , dairy products ( 35 + /- 1 % ) , and dried legumes ( 31 + /- 3 % ) . A significant negative relationship was seen between fat ( p less than 0.01 ) and protein ( p less than 0.001 ) and postpr and ial glucose rise but not with fiber or sugar content [18582171] OBJECTIVE Studies in predominantly non-Hispanic white population s have suggested that physical activity during pregnancy is associated with a reduced risk of gestational diabetes mellitus ( GDM ) . There are few such studies in Hispanic women , a group at increased risk for GDM . METHODS We conducted a prospect i ve cohort study of household/caregiving , occupational , sports/exercise , and active living habits and the risk of GDM among 1006 Hispanic ( predominantly Puerto Rican ) prenatal care patients in western Massachusetts from 2000 to 2004 . Prepregnancy , early pregnancy , and midpregnancy physical activity was assessed using the Kaiser Physical Activity Survey . RESULTS A total of 33 women ( 3.3 % ) were diagnosed with GDM , and 119 women ( 11.8 % ) were diagnosed with abnormal glucose tolerance . There were no significant associations between GDM risk and occupational and active living activities in prepregnancy , early pregnancy , and midpregnancy or with a change in levels of household/caregiving , occupational , and active living activities from prepregnancy to during pregnancy . However , after controlling for age and prepregnancy body mass index ( BMI ) , women in the highest quartile of prepregnancy ( OR = 0.2 , 95 % CI 0.1 - 0.8 , p(trend ) = 0.03 ) and midpregnancy ( OR = 0.2 , 95 % CI 0.1 - 0.8 , p(trend ) = 0.004 ) household/caregiving activities as well as midpregnancy sports/exercise ( 0.1 , 95 % CI 0.0 - 0.7 , p(trend ) = 0.12 ) had a reduced risk of GDM compared with women in the lowest quartile . CONCLUSIONS Findings in this Hispanic population , although based on small numbers of cases , are consistent with prior research among predominantly non-Hispanic white population [7565999] BACKGROUND The fetuses of women with gestational diabetes mellitus are at risk for macrosomia and its attendant complications . The best method of achieving euglycemia in these women and reducing morbidity in their infants is not known . We compared the efficacy of postpr and ial and prepr and ial monitoring in achieving glycemic control in women with gestational diabetes . METHODS We studied 66 women with gestational diabetes mellitus who required insulin therapy at 30 weeks of gestation or earlier . The women were r and omly assigned to have their diabetes managed according to the results of prepr and ial monitoring or postpr and ial monitoring ( one hour after meals ) of blood glucose concentrations . Both groups were also monitored with fasting blood glucose measurements . The goal of insulin therapy was a prepr and ial value of 60 to 105 mg per deciliter ( 3.3 to 5.9 mmol per liter ) or a postpr and ial value of less than 140 mg per deciliter ( 7.8 mmol per liter ) . Obstetrical data and information on neonatal outcomes were collected . RESULTS The prepregnancy weight , weight gain during pregnancy , gestational age at the diagnosis of diabetes and at delivery , degree of compliance with therapy , and degree of achievement of target blood glucose concentrations were similar in the two groups . The mean ( + /- SD ) change in the glycosylated hemoglobin value was greater in the group in which postpr and ial measurements were used ( -3.0 + /- 2.2 percent vs. 0.6 + /- 1.6 percent , P < 0.001 ) and the infants ' birth weight was lower ( 3469 + /- 668 vs. 3848 + /- 434 g , P = 0.01 ) . Similarly , the infants born to the women in the postpr and ial-monitoring group had a lower rate of neonatal hypoglycemia ( 3 percent vs. 21 percent , P = 0.05 ) , were less often large for gestational age ( 12 percent vs. 42 percent , P = 0.01 ) and were less often delivered by cesarean section because of cephalopelvic disproportion ( 12 percent vs. 36 percent , P = 0.04 ) than those in the prepr and ial-monitoring group . CONCLUSIONS Adjustment of insulin therapy in women with gestational diabetes according to the results of postpr and ial , rather than prepr and ial , blood glucose values improves glycemic control and decreases the risk of neonatal hypoglycemia , macrosomia , and cesarean delivery [3311138] The study was design ed to identify those pregnant women who are diagnosed as having gestational diabetes by National Diabetes Data Group ( NDDG ) criteria , but normal glucose tolerance ( NGT ) or impaired glucose tolerance ( IGT ) by the World Health Organization ( WHO ) criteria , and to test whether treatment changed the perinatal outcome in those with NGT and IGT . The 216 women with an abnormal 100 g oral glucose tolerance test ( OGTT ) using NDDG criteria were subjected to a 75 g OGTT . Using the WHO criteria , 111 women ( 51 % ) had NGT , 98 ( 45 % ) had IGT and 7 ( 3 % ) had frank diabetes mellitus . Those with NGT and IGT were r and omized into control and treatment groups . The perinatal outcome in these two groups was comparable whether the NGT and IGT groups were analysed together or separately except , that in those who were treated for IGT , smaller babies were born one week earlier than in the control group ( 3407 g vs 3110 g , P less than 0.01 ) . This suggests that the WHO criteria can safely replace the 100 g OGTT with substantial savings in manpower , money and patients ' time [1865537] Background Mild gestational diabetes is a common complication of pregnancy , affecting up to 9 % of pregnant women . Treatment of mild GDM is known to reduce adverse perinatal outcomes such as macrosomia and associated birth injuries , such as shoulder dystocia , bone fractures and nerve palsies . This study aim ed to compare the plasma glucose concentrations and serum insulin , leptin and adiponectin in cord blood of babies of women ( a ) without gestational diabetes mellitus ( GDM ) , ( b ) with mild GDM under routine care , or ( c ) mild GDM with treatment . Methods 95 women with mild GDM on oral glucose tolerance testing ( OGTT ) at one tertiary level maternity hospital who had been recruited to the ACHOIS trial at one of the collaborating hospitals and r and omised to either Treatment ( n = 46 ) or Routine Care ( n = 49 ) and Control women with a normal OGTT ( n = 133 ) were included in the study . Women with mild GDM ( treatment or routine care group ) and OGTT normal women received routine pregnancy care . In addition , women with treated mild GDM received dietary advice , blood glucose monitoring and insulin if necessary . The primary outcome measures were cord blood concentrations of glucose , insulin , adiponectin and leptin . Results Cord plasma glucose was higher in women receiving routine care compared with control , but was normalized by treatment for mild GDM ( p = 0.01 ) . Cord serum insulin and insulin to glucose ratio were similar between the three groups . Leptin concentration in cord serum was lower in GDM treated women compared with routine care ( p = 0.02 ) and not different to control ( p = 0.11 ) . Adiponectin was lower in both mild GDM groups compared with control ( Treatment p = 0.02 and Routine Care p = 0.07 ) , while the adiponectin to leptin ratio was lower for women receiving routine care compared with treatment ( p = 0.08 ) and control ( p = 0.05 ) . Conclusion Treatment of women with mild GDM using diet , blood glucose monitoring and insulin if necessary , influences the altered fetal adipoinsular axis characteristic of mild GDM in pregnancy [9240606] OBJECTIVES The purpose of this study was to determine whether strict maternal glycemic control for the treatment of gestational diabetes lessened the risk of fetal macrosomia , birth trauma , neonatal hypoglycemia , and operative delivery . The aim of the pilot study was to prepare for a multicenter trial by assessing patient acceptance of the study , by determining realistic accrual rates , and by detecting any major adverse outcomes in the control group that received routine obstetric care . STUDY DESIGN The study was a prospect i ve r and omized controlled trial comparing fetal-neonatal and maternal outcomes in 300 women with gestational diabetes . Women r and omized to the treatment arm were managed by strict glycemic control and tertiary level obstetric care , and women in the control arm received routine obstetric care . RESULTS Three hundred women with gestational diabetes mellitus were studied . There was no difference in maternal age , weight , or length of gestation between groups . The treatment mean birth weight was 3437 + /- 575 gm compared with 3544 + /- 601 gm in the control group , a difference of 107 gm ( not significant ) . Macrosomia rates were similar . There was no birth trauma in either group . The frequency of neonatal hypoglycemia and other metabolic complications was the same . The mode of delivery also showed similar patterns . The treatment group had significantly lower prepr and ial and postpr and ial glucose levels by 32 weeks ' gestation , which continued to term . CONCLUSION This pilot study suggests that intensive treatment of gestational diabetes mellitus may have little effect on birth weight , birth trauma , operative delivery , or neonatal metabolic disorders . It has demonstrated the safety of proceeding to a multicenter trial of sufficient sample size to confirm these findings [15951574] BACKGROUND We conducted a r and omized clinical trial to determine whether treatment of women with gestational diabetes mellitus reduced the risk of perinatal complications . METHODS We r and omly assigned women between 24 and 34 weeks ' gestation who had gestational diabetes to receive dietary advice , blood glucose monitoring , and insulin therapy as needed ( the intervention group ) or routine care . Primary outcomes included serious perinatal complications ( defined as death , shoulder dystocia , bone fracture , and nerve palsy ) , admission to the neonatal nursery , jaundice requiring phototherapy , induction of labor , cesarean birth , and maternal anxiety , depression , and health status . RESULTS The rate of serious perinatal complications was significantly lower among the infants of the 490 women in the intervention group than among the infants of the 510 women in the routine-care group ( 1 percent vs. 4 percent ; relative risk adjusted for maternal age , race or ethnic group , and parity , 0.33 ; 95 percent confidence interval , 0.14 to 0.75 ; P=0.01 ) . However , more infants of women in the intervention group were admitted to the neonatal nursery ( 71 percent vs. 61 percent ; adjusted relative risk , 1.13 ; 95 percent confidence interval , 1.03 to 1.23 ; P=0.01 ) . Women in the intervention group had a higher rate of induction of labor than the women in the routine-care group ( 39 percent vs. 29 percent ; adjusted relative risk , 1.36 ; 95 percent confidence interval , 1.15 to 1.62 ; P<0.001 ) , although the rates of cesarean delivery were similar ( 31 percent and 32 percent , respectively ; adjusted relative risk , 0.97 ; 95 percent confidence interval , 0.81 to 1.16 ; P=0.73 ) . At three months post partum , data on the women 's mood and quality of life , available for 573 women , revealed lower rates of depression and higher scores , consistent with improved health status , in the intervention group . CONCLUSIONS Treatment of gestational diabetes reduces serious perinatal morbidity and may also improve the woman 's health-related quality of life [2681032] OBJECTIVE A low – glycemic index diet is effective as a treatment for individuals with diabetes and has been shown to improve pregnancy outcomes when used from the first trimester . A low – glycemic index diet is commonly advised as treatment for women with gestational diabetes mellitus ( GDM ) . However , the efficacy of this advice and associated pregnancy outcomes have not been systematic ally examined . The purpose of this study was to determine whether prescribing a low – glycemic index diet for women with GDM could reduce the number of women requiring insulin without compromise of pregnancy outcomes . RESEARCH DESIGN AND METHODS All women with GDM seen over a 12-month period were considered for inclusion in the study . Women ( n = 63 ) were r and omly assigned to receive either a low – glycemic index diet or a conventional high-fiber ( and higher glycemic index ) diet . RESULTS Of the 31 women r and omly assigned to a low – glycemic index diet , 9 ( 29 % ) required insulin . Of the women r and omly assigned to a higher – glycemic index diet , a significantly higher proportion , 19 of 32 ( 59 % ) , met the criteria to commence insulin treatment ( P = 0.023 ) . However , 9 of these 19 women were able to avoid insulin use by changing to a low – glycemic index diet . Key obstetric and fetal outcomes were not significantly different . CONCLUSIONS Using a low – glycemic index diet for women with GDM effectively halved the number needing to use insulin , with no compromise of obstetric or fetal outcomes [24947793] OBJECTIVE The use of the new International Association of the Diabetes and Pregnancy Study Groups criteria ( IADPSGC ) for the diagnosis of gestational diabetes mellitus ( GDM ) results in an increased prevalence of GDM . Whether their introduction improves pregnancy outcomes has yet to be established . We sought to evaluate the cost-effectiveness of one-step IADPSGC for screening and diagnosis of GDM compared with traditional two-step Carpenter-Coustan ( CC ) criteria . RESEARCH DESIGN AND METHODS GDM risk factors and pregnancy and newborn outcomes were prospect ively assessed in 1,750 pregnant women from April 2011 to March 2012 using CC and in 1,526 pregnant women from April 2012 to March 2013 using IADPSGC between 24 and 28 weeks of gestation . Both groups received the same treatment and follow-up regimes . RESULTS The use of IADPSGC result ed in an important increase in GDM rate ( 35.5 % vs. 10.6 % ) and an improvement in pregnancy outcomes , with a decrease in the rate of gestational hypertension ( 4.1 to 3.5 % : −14.6 % , P < 0.021 ) , prematurity ( 6.4 to 5.7 % : −10.9 % , P < 0.039 ) , cesarean section ( 25.4 to 19.7 % : −23.9 % , P < 0.002 ) , small for gestational age ( 7.7 to 7.1 % : −6.5 % , P < 0.042 ) , large for gestational age ( 4.6 to 3.7 % : −20 % , P < 0.004 ) , Apgar 1-min score < 7 ( 3.8 to 3.5 % : −9 % , P < 0.015 ) , and admission to neonatal intensive care unit ( 8.2 to 6.2 % : −24.4 % , P < 0.001 ) . Estimated cost savings was of € 14,358.06 per 100 women evaluated using IADPSGC versus the group diagnosed using CC . CONCLUSIONS The application of the new IADPSGC was associated with a 3.5-fold increase in GDM prevalence in our study population , as well as significant improvements in pregnancy outcomes , and was cost-effective . Our results support their adoption [2241640] Background Recommended best practice is that economic evaluation of health care interventions should be integral with r and omised clinical trials . We performed a cost-consequence analysis of treating women with mild gestational diabetes mellitus by dietary advice , blood glucose monitoring and insulin therapy as needed compared with routine pregnancy care , using patient-level data from a multi-centre r and omised clinical trial . Methods Women with a singleton pregnancy who had mild gestational diabetes diagnosed by an oral glucose-tolerance test between 24 and 34 weeks ' gestation and their infants were included . Clinical outcomes and outpatient costs derived from all women and infants in the trial . Inpatient costs derived from women and infants attending the hospital contributing the largest number of enrolments ( 26.1 % ) , and charges to women and their families derived from a sub sample of participants from that hospital ( in 2002 Australian dollars ) . Occasions of service and health outcomes were adjusted for maternal age , ethnicity and parity . Analysis of variance was used with bootstrapping to confirm results . Primary clinical outcomes were serious perinatal complications ; admission to neonatal nursery ; jaundice requiring phototherapy ; induction of labour and caesarean delivery . Economic outcome measures were outpatient and inpatient costs , and charges to women and their families . Results For every 100 women with a singleton pregnancy and positive oral glucose tolerance test who were offered treatment for mild gestational diabetes mellitus in addition to routine obstetric care , $ 53,985 additional direct costs were incurred at the obstetric hospital , $ 6,521 additional charges were incurred by women and their families , 9.7 additional women experienced induction of labour , and 8.6 more babies were admitted to a neonatal nursery . However , 2.2 fewer babies experienced serious perinatal complication and 1.0 fewer babies experienced perinatal death . The incremental cost per additional serious perinatal complication prevented was $ 27,503 , per perinatal death prevented was $ 60,506 and per discounted life-year gained was $ 2,988 . Conclusion It is likely that the general public in high-income countries such as Australia would find reductions in perinatal mortality and in serious perinatal complications sufficient to justify additional health service and personal monetary charges . Over the whole lifespan , the incremental cost per extra life-year gained is highly favourable . Trial Registration Australian Clinical Trials Registry [3177748] OBJECTIVE In women with gestational diabetes mellitus , who were r and omized to metformin or insulin treatment , pregnancy outcomes were similar ( Metformin in Gestational diabetes [ MiG ] trial ) . Metformin crosses the placenta , so it is important to assess potential effects on growth of the children . RESEARCH DESIGN AND METHODS In Auckl and , New Zeal and , and Adelaide , Australia , women who had participated in the MiG trial were review ed when their children were 2 years old . Body composition was measured in 154 and 164 children whose mothers had been r and omized to metformin and insulin , respectively . Children were assessed with anthropometry , bioimpedance , and dual energy X-ray absorptiometry ( DEXA ) , using st and ard methods . RESULTS The children were similar for baseline maternal characteristics and pregnancy outcomes . In the metformin group , compared with the insulin group , children had larger mid-upper arm circumferences ( 17.2 ± 1.5 vs. 16.7 ± 1.5 cm ; P = 0.002 ) and subscapular ( 6.3 ± 1.9 vs. 6.0 ± 1.7 mm ; P = 0.02 ) and biceps skinfolds ( 6.03 ± 1.9 vs. 5.6 ± 1.7 mm ; P = 0.04 ) . Total fat mass and percentage body fat assessed by bioimpedance ( n = 221 ) and DEXA ( n = 114 ) were not different . CONCLUSIONS Children exposed to metformin had larger measures of subcutaneous fat , but overall body fat was the same as in children whose mothers were treated with insulin alone . Further follow-up is required to examine whether these findings persist into later life and whether children exposed to metformin will develop less visceral fat and be more insulin sensitive . If so , this would have significant implication s for the current p and emic of diabetes [2533645] Background The impact of borderline gestational diabetes mellitus ( BGDM ) , defined as a positive oral glucose challenge test ( OGCT ) and normal oral glucose tolerance test ( OGTT ) , on maternal and infant health is unclear . We assessed maternal and infant health outcomes in women with BGDM and compared these to women who had a normal OGCT screen for gestational diabetes . Methods We compared demographic , obstetric and neonatal outcomes between women participating in the Australian Collaborative Trial of Supplements with antioxidants Vitamin C and Vitamin E to pregnant women for the prevention of pre-eclampsia ( ACTS ) who had BGDM and who screened negative on OGCT . Results Women who had BGDM were older ( mean difference 1.3 years , [ 95 % confidence interval ( CI ) 0.3 , 2.2 ] , p = 0.01 ) and more likely to be obese ( 27.1 % vs 14.1 % , relative risk ( RR ) 1.92 , [ 95 % CI 1.41 , 2.62 ] , p < 0.0001 ) than women who screened negative on OGCT . The risk of adverse maternal outcome overall was higher ( 12.9 % vs 8.1 % , RR 1.59 , [ 95 % CI 1.00 , 2.52 ] , p = 0.05 ) in women with BGDM compared with women with a normal OGCT . Women with BGDM were more likely to develop pregnancy induced hypertension ( 17.9 % vs 11.8 % , RR 1.51 , [ 95 % CI 1.03 , 2.20 ] , p = 0.03 ) , have a caesarean for fetal distress ( 17.1 % vs 10.5 % , RR 1.63 , [ 95 % CI 1.10 , 2.41 ] , p = 0.01 ) , and require a longer postnatal hospital stay ( mean difference 0.4 day , [ 95 % CI 0.1 , 0.7 ] , p = 0.01 ) than those with a normal glucose tolerance . Infants born to BGDM mothers were more likely to be born preterm ( 10.7 % vs 6.4 % , RR 1.68 , [ 95 % CI 1.00 , 2.80 ] , p = 0.05 ) , have macrosomia ( birthweight ≥4.5 kg ) ( 4.3 % vs 1.7 % , RR 2.53 , [ 95 % CI 1.06 , 6.03 ] , p = 0.04 ) , be admitted to the neonatal intensive care unit ( NICU ) ( 6.5 % vs 3.0 % , RR 2.18 , [ 95 % CI 1.09 , 4.36 ] , p = 0.03 ) or the neonatal nursery ( 40.3 % vs 28.4 % , RR 1.42 , [ 95 % CI 1.14 , 1.76 ] , p = 0.002 ) , and have a longer hospital stay ( p = 0.001 ) . More infants in the BGDM group had Sarnat stage 2 or 3 neonatal encephalopathy ( 12.9 % vs 7.8 % , RR 1.65 , [ 95 % CI 1.04 , 2.63 ] , p = 0.03 ) . Conclusion Women with BGDM and their infants had an increased risk of adverse health outcomes compared with women with a negative OGCT . Intervention strategies to reduce the risks for these women and their infants need evaluation . Trial registration Current Controlled Trials IS RCT [3907028] Background Women who are diagnosed with gestational diabetes mellitus ( GDM ) are at increased risk for developing prediabetes and type 2 diabetes mellitus ( T2DM ) . To date , there have been few interdisciplinary interventions that target predominantly ethnic minority low-income women diagnosed with GDM . This paper describes the rationale , design and methodology of a 2-year , r and omized , controlled study being conducted in North Carolina . Methods / Design Using a two-group , repeated measures , experimental design , we will test a 14- week intensive intervention on the benefits of breastfeeding , underst and ing gestational diabetes and risk of progression to prediabetes and T2DM , nutrition and exercise education , coping skills training , physical activity ( Phase I ) , educational and motivational text messaging and 3 months of continued monthly contact ( Phase II ) . A total of 100 African American , non-Hispanic white , and bilingual Hispanic women between 22–36 weeks of pregnancy who are diagnosed with GDM and their infants will be r and omized to either the experimental group or the wait-listed control group . The first aim of the study is to determine the feasibility of the intervention . The second aim of study is to test the effects of the intervention on maternal outcomes from baseline ( 22–36 weeks pregnant ) to 10 months postpartum . Primary maternal outcomes will include fasting blood glucose and weight ( BMI ) from baseline to 10 months postpartum . Secondary maternal outcomes will include clinical , adiposity , health behaviors and self-efficacy outcomes from baseline to 10 months postpartum . The third aim of the study is to quantify the effects of the intervention on infant feeding and growth . Infant outcomes will include weight status and breastfeeding from birth through 10 months of age . Data analysis will include general linear mixed-effects models . Safety endpoints include adverse event reporting . Discussion Findings from this trial may lead to an effective intervention to assist women diagnosed with GDM to improve maternal glucose homeostasis and weight as well as stabilize infant growth trajectory , reducing the burden of metabolic disease across two generations . Trial registration [2858199] OBJECTIVE Gestational diabetes mellitus ( GDM ) may cause obesity in the offspring . The objective was to assess the effect of treatment for mild GDM on the BMI of 4- to 5-year-old children . RESEARCH DESIGN AND METHODS Participants were 199 mothers who participated in a r and omized controlled trial of the treatment of mild GDM during pregnancy and their children . Trained nurses measured the height and weight of the children at preschool visits in a state-wide surveillance program in the state of South Australia . The main outcome measure was age- and sex-specific BMI Z score based on st and ards of the International Obesity Task Force . RESULTS At birth , prevalence of macrosomia ( birth weight ≥4,000 g ) was 5.3 % among the 94 children whose mothers were in the intervention group , and 21.9 % among the 105 children in the routine care control group . At 4- to 5-years-old , mean ( SD ) BMI Z score was 0.49 ( 1.20 ) in intervention children and 0.41 ( 1.40 ) among controls . The difference between treatment groups was 0.08 ( 95 % CI −0.29 to 0.44 ) , an estimate minimally changed by adjustment for maternal race , parity , age , and socio-economic index ( 0.08 [ −0.29 to 0.45 ] ) . Evaluating BMI ≥85th percentile rather than continuous BMI Z score gave similarly null results . CONCLUSIONS Although treatment of GDM substantially reduced macrosomia at birth , it did not result in a change in BMI at age 4- to 5-years-old [2764059] We studied the impact of a training program on glucose tolerance in gestational diabetes mellitus . Women with gestational diabetes mellitus ( N = 19 ) were r and omized into either group I , a 6-week diet alone group ( 24 to 30 kcal/kg/24 hours ; 20 % protein , 40 % carbohydrate , 40 % fat ) , or group II , which followed the same diet plus exercise ( 20 minutes three times a week for 6 weeks ) . An arm ergometer was used to maintain heart rate in the training range . Glycemic response was monitored by glycosylated hemoglobin , a 50 gm oral glucose challenge with a fasting and 1-hour plasma glucose , and blood glucose self-monitoring , fasting and 1 hour after meals . Week 1 glycemic parameters were the same for both groups . Week 6 data ( mean + /- SD ) were as follows : group I glycosylated hemoglobin , 4.7 % + 0.2 % versus group II , 4.2 % + /- 0.2 % ; p less than 0.001 . The group I glucose challenge fasting value was 87.6 + /- 6.2 versus 70.1 + /- 6.6 mg/dl , p less than 0.001 for group II . The group I 1-hour plasma glucose challenge result was 187.5 + /- 12.9 mg/dl versus 105.9 + /- 18.9 mg/dl for group II , p less than 0.001 . The glycemic levels diverged between the groups at week 4 . We conclude that arm ergometer training is feasible in women with gestational diabetes mellitus and results in lower glycosylated hemoglobin , fasting , and 1-hour plasma glucose concentrations than diet alone . Arm ergometer training may provide a useful treatment option for women with gestational diabetes mellitus and may obviate insulin treatment [25848127] Women with diabetes often experience a higher level of anxiety . The aim of the study was to evaluate the effect of acupressure on relieving anxiety of women with gestational diabetes mellitus ( GDM ) . A r and omized clinical trial was conducted on 60 women with GDM at a university hospital . The participants were allocated to an experimental and a placebo group ( 30 women per group ) . The experimental group received a nurse-provided acupressure at the true point , and the placebo group received pressure ( touching ) at a sham ( false ) point . Anxiety was measured immediately in the groups prior to and after a 2-day intervention by a question naire and the Visual Analogue Scale . The data were analyzed using descriptive and inferential statistics . Results indicated that the acupressure group had significantly lower anxiety than the placebo group ( p ≤ .0001 ) . In conclusion , the effects of acupressure appeared to be effective in reducing anxiety in diabetic pregnant women [20542272] OBJECTIVE To assess blood glucose control and neonatal outcomes when women with gestational diabetes mellitus ( GDM ) were treated with metformin or glyburide . METHODS When an appropriate diet was insufficient to control their blood glucose levels , women with GDM were r and omized to a glyburide or a metformin treatment group . If the maximum dose was reached , the assessed drug was replaced by insulin . The primary outcome measures analyzed were maternal glucose levels during pregnancy , birth weight , and neonatal glucose levels . RESULTS The only significant difference in outcome between the 2 treatment drugs was that maternal weight gain during pregnancy was less in the metformin ( n=40 ) than in the glyburide group ( n=32 ) ( 10.3 kg vs 7.6 kg ; P=0.02 ) . No differences were found in treatment failure , mean level of fasting or postpr and ial plasma glucose , rate of participants with glycated hemoglobin , birth weight , rate of large-for-gestational-age newborns , or newborns with hypoglycemia . CONCLUSION The treatment of GDM with metformin or glyburide was found to be equivalent for both women and newborns [11333990] BACKGROUND Type 2 diabetes mellitus is increasingly common , primarily because of increases in the prevalence of a sedentary lifestyle and obesity . Whether type 2 diabetes can be prevented by interventions that affect the lifestyles of subjects at high risk for the disease is not known . METHODS We r and omly assigned 522 middle-aged , overweight subjects ( 172 men and 350 women ; mean age , 55 years ; mean body-mass index [ weight in kilograms divided by the square of the height in meters ] , 31 ) with impaired glucose tolerance to either the intervention group or the control group . Each subject in the intervention group received individualized counseling aim ed at reducing weight , total intake of fat , and intake of saturated fat and increasing intake of fiber and physical activity . An oral glucose-tolerance test was performed annually ; the diagnosis of diabetes was confirmed by a second test . The mean duration of follow-up was 3.2 years . RESULTS The mean ( + /-SD ) amount of weight lost between base line and the end of year 1 was 4.2+/-5.1 kg in the intervention group and 0.8+/-3.7 kg in the control group ; the net loss by the end of year 2 was 3.5+/-5.5 kg in the intervention group and 0.8+/-4.4 kg in the control group ( P<0.001 for both comparisons between the groups ) . The cumulative incidence of diabetes after four years was 11 percent ( 95 percent confidence interval , 6 to 15 percent ) in the intervention group and 23 percent ( 95 percent confidence interval , 17 to 29 percent ) in the control group . During the trial , the risk of diabetes was reduced by 58 percent ( P<0.001 ) in the intervention group . The reduction in the incidence of diabetes was directly associated with changes in lifestyle . CONCLUSIONS Type 2 diabetes can be prevented by changes in the lifestyles of high-risk subjects [10774766] The goal of this study was to determine whether the type of fat plays a role in the glucose response to a meal , independent of the carbohydrate content . Ten gestational diabetic women ( gestational weeks 29 - 34 ) who were well controlled on diet alone were r and omized as to the order in which they would eat a meal , after overnight fast , containing saturated fat ( SF ) or monounsaturated fat ( MUFA ) . Blood was drawn at 0 , 60 , 120 , and 180 min for plasma glucose , insulin , lipid profile ( triglycerides , total cholesterol , HDL-cholesterol , LDL-cholesterol , VLDL-cholesterol ) and free fatty acids . After 2 weeks , each patient received the other type of meal . The test meal was composed of 20 % of the total daily caloric needs based on ideal body weight . The area under the curve showed a significantly lower glucose concentration for SF meal ( p = 0.001 ) . Serum insulin concentrations followed the glucose response with the peak at the 60-min time point and a significantly lower concentration at the 180-min time point in the SF than in the MUFA group . The present study demonstrated that the addition of SF to the meal result ed in lower postpr and ial glucose and insulin than when the meal contained MUFA . Thus , SF may be useful in controlling postpr and ial glucose [2675597] In this study we sought to test the hypothesis that treatment of women with one abnormal oral glucose tolerance test value will result in reduction of adverse outcome . One hundred twenty-six women with one abnormal oral glucose tolerance test value and 146 women in the control group ( normal oral glucose tolerance test values ) participated in a prospect i ve study during the third trimester of pregnancy . The subjects with one abnormal test result were r and omized into treated ( group 1 ) and untreated groups ( group II ) . Group 1 subjects were treated with a strict diabetic protocol to maintain tight glycemic control by means of diet and insulin therapy . Group 2 subjects tested their capillary blood glucose for a baseline period . The study revealed that the level of glycemic control was similar before initiation of therapy ( mean capillary blood glucose 118 + /- 14 vs. 119 + /- 15 mg/dl , p = NS ) for groups 1 and 2 , respectively . There was a significant difference in mean capillary blood glucose ( 95 + /- 10 vs. 119 + /- 15 mg/dl , p less than 0.0001 ) , prepr and ial , and postpr and ial determinations between the treated and untreated groups . The overall incidence of neonatal metabolic complications ( 4 % vs. 14 % , p less than 0.05 ) and large infants ( 6 % vs. 24 % , p less than 0.03 ) was significantly lower in the treated group . Comparison between the control ( normal oral glucose tolerance test ) and the untreated groups showed a significantly higher incidence of large infants and metabolic complications . No difference was found between the normal and treated groups . Thus we conclude that treatment of individuals with one abnormal oral glucose tolerance test value will result in significant reduction in adverse outcome in pregnancy [22542118] OBJECTIVE We evaluated whether improvements in pregnancy outcomes after treatment of mild gestational diabetes mellitus differed in magnitude on the basis of fetal gender . STUDY DESIGN This is a secondary analysis of a masked r and omized controlled trial of treatment for mild gestational diabetes mellitus . The results included preeclampsia or gestational hypertension , birthweight , neonatal fat mass , and composite adverse outcomes for both neonate ( preterm birth , small for gestational age , or neonatal intensive care unit admission ) and mother ( labor induction , cesarean delivery , preeclampsia , or gestational hypertension ) . After stratification according to fetal gender , the interaction of gender with treatment status was estimated for these outcomes . RESULTS Of the 469 pregnancies with male fetuses , 244 pregnancies were assigned r and omly to treatment , and 225 pregnancies were assigned r and omly to routine care . Of the 463 pregnancies with female fetuses , 233 pregnancies were assigned r and omly to treatment , and 230 pregnancies were assigned r and omly to routine care . The interaction of gender with treatment status was significant for fat mass ( P = .04 ) and birthweight percentile ( P = .02 ) . Among women who were assigned to the treatment group , male offspring were significantly more likely to have both a lower birthweight percentile ( 50.7 ± 29.2 vs 62.5 ± 30.2 percentile ; P < .0001 ) and less neonatal fat mass ( 487 ± 229.6 g vs 416.6 ± 172.8 g ; P = .0005 , ) whereas these differences were not significant among female offspring . There was no interaction between fetal gender and treatment group with regard to other outcomes . CONCLUSION The magnitude of the reduction of a newborn 's birthweight percentile and neonatal fat mass that were related to the treatment of mild gestational diabetes mellitus appears greater for male neonates [9170478] Objective To assess the usefulness of a breakfast test in determining which women with gestational diabetes do not need self-monitoring of blood glucose levels ( home monitoring ) . Methods a 1-hour post-st and ardized breakfast blood glucose below 7.8 mmol/L ( 140 mg/dL ) was measured in 227 women and at or above 7.8 mmol/L in 115 . Within each group , women were r and omized to home monitoring with a meter or to clinic follow-up . Target glucose values were 5.3 mmol/L ( 95 mg/dL ) fasting , 5.6 mmol/L ( 101 mg/dL ) before meals , and 7.8 mmol/L ( 140 mg/dL ) 1 hour postpr and ial . Up to these thresholds women on clinic follow-up were transferred to home monitoring . Insulin therapy was started on the same thresholds in women r and omized or transferred to home monitoring . Large ofr gestational age ( LGA ) newborns represented the main outcome , with the transfer rate to home monitoring and need of insulin therapy the secondary ones . Results The LGA delivery rate was not significantly different in the two follow-up groups in women with a breakfast result below 7.8 mmol/L ( 9.8 versus 4.3 % ) but was higher in the clinic follow-up among women with a breakfast result at or above 7.8 mmol/L ( 13.3 % versus 30.9 % ; P < .05 ) . Fewer women with a breakfast result below 7.8 mmol/L were transferred to home monitoring ( 2.6 versus 52.7 % ; P < .001 ) or started on insulin therapy ( 3.6 versus 25.2 % ; P < .001 ) . The breakfast test cutoff of 7.8 mmol/L predicted insulin need with a sensitivity of 91.0 % and a specificity of 72.0 % . Conclusion A breakfast test is useful in identifying a low-risk population in which clinic follow-up may be used safely [6993163] A 16-yr prospect i ve study of 615 gestational diabetic subjects , half of whom were r and omly assigned to insulin therapy during pregnancy , is evaluated to report on the potential reduction in subsequent diabetes due to insulin therapy . No such difference in incidence rates was observed between the two groups . In the subsets of women managed with insulin who bore a baby of large birthweight or who had a family history of diabetes , subsequent decompensated diabetes was found to be significantly reduced . Both life table and multivariate analyses to adjust for the effects of age , weight , level of blood glucose at selection , duration of follow-up , and other potentially confounding covariables confirmed this conclusion . The finding suggests the possibility of long-term preventive benefits from insulin treatment in high risk subsets of women with gestational diabetes [18211656] RATIONALE , AIMS AND OBJECTIVE To investigate whether the introduction of a programme of optimising drug treatment , intensive education and self-monitoring of patients diagnosed with gestational diabetes mellitus ( GDM ) at an early stage ( < 20 gestational weeks ) , will improve management outcomes as determined by objective measures of patient knowledge about diabetes , glycaemia control , maternal/neonatal complications , and health-related quality of life . METHODS The study was a r and omized , controlled , longitudinal , prospect i ve clinical trial performed at Al-Ain Hospital , Al-Ain , United Arab Emirates . Over an 18-month period , patients diagnosed with GDM were recruited and were r and omly assigned to either an intervention or a control group , in a ratio of 3:2 . Intervention patients received a structured pharmaceutical care service ( including education and introduction of intensive self-monitoring ) while control patients received traditional services . Patients were followed up from time of recruitment until 6 months postnatally at scheduled outpatient clinics . A range of clinical and humanistic outcome measures , including maternal and neonatal complications , were used to assess the impact of the intervention . RESULTS A total of 165 patients ( 99 intervention , 66 control ) completed the study . The intervention patients exhibited a range of benefits from the provision of the programme when compared with control group patients . Statistically significant ( P < 0.05 ) improvements were shown in the intervention group for knowledge of diabetes , health-related quality of life ( as determined by the SF36 ) , control of plasma glucose and HbA(1c ) , maternal complications [ e.g. decreased incidence of pre-eclampsia ( 5.1 % vs. 16.7 % ) , eclampsia ( 1.0 % vs. 7.6 % ) , episodes of severe hyperglycaemia ( 3.0 % vs. 19.7 % ) and need for Caesarean section ( 7.1 % vs. 18.2 % ) ] , and neonatal complications [ e.g. decreased incidence of neonatal hypoglycaemia ( 2.0 % vs. 10.6 % ) , respiratory distress at birth ( 4.0 % vs. 15.2 % ) , hyperbilirubinaemia ( 1.0 % vs. 12.1 % ) and large for gestational age ( 9.0 % vs. 22.7 % ) ] . CONCLUSION The research provides clear evidence that provision of pharmaceutical care adds value to the management of GDM as exemplified by improved maternal and neonatal outcomes [10955425] Objective To determine whether a study of a less intensive form of management for impaired glucose tolerance in pregnancy is feasible and whether women would accept r and omisation [15565082] Abstract Women with gestational diabetes mellitus ( GDM ) have a greater risk of developing type 2 diabetes mellitus ( DM ) and heart disease than pregnant women without GDM . Advice given during the GDM pregnancy provides an opportunity to develop protective dietary patterns for the long-term management of this risk . Dietary guidelines for the prevention and management of type 2 DM support the inclusion of unsaturated fats , but food advice needs to target this outcome . The aim of this study was to compare the dietary intakes of women with GDM given general low-fat advice ( control group ) to women with GDM given the same advice with additional targets for food sources of unsaturated fats ( intervention group ) . After approximately 6 weeks , the intervention group reported more ideal dietary fatty acid intakes than the control group , with polyunsaturated : saturated fat ratios of 1:1 and 0.4:1 , respectively ( P < .001 ) , assessed using repeated measures analysis of variance . These results confirm the need to include food sources of unsaturated fats in advice strategies to assure optimal protective eating habits in this at-risk group [21094553] AIM The objectives of this pilot study were to determine the feasibility and effect on glycaemic control of a low-glycaemic-index ( GI ) diet in women with gestational diabetes or impaired glucose tolerance of pregnancy . METHODS participants , recruited from the Diabetes-in-Pregnancy Clinic of an inner-city teaching hospital serving a predominantly non-Caucasian population , were r and omized to a low-GI ( n=23 ) or control ( n=24 ) diet and followed from 28 weeks gestation until delivery . Self-monitored-blood-glucose ( SMBG ) , maternal and infant weight were collected from medical charts . Dietary intakes were assessed using diet records and question naires . RESULTS diet GI on control ( 58 , 95 % CI : 56,60 ) was significantly higher than on low-GI ( 49 , 95 % CI : 47,51 ; p=0.001 ) . Glycaemic control improved on both diets , but more postpr and ial glucose values were within target on low-GI ( 58.4 % of n=1891 ) than control ( 48.7 % of n=1834 ; p<0.001 ) . SMBG post-breakfast was directly related to pre-pregnancy BMI in the control , but not the low-GI group ( BMI * diet interaction ; p=0.021 ) . Participants accepted the study foods and were willing to consume them post-intervention . CONCLUSIONS a low-GI diet was feasible and acceptable in this sample and facilitated control of postpr and ial glucose . A larger study is needed to determine the effect of a low-GI diet on maternal and infant outcomes [16963348] Nutrition practice guidelines were developed for gestational diabetes mellitus by registered dietitians from the Diabetes Care and Education and the Women 's Health and Reproductive Nutrition dietetic practice groups . To vali date the guidelines , a clinical trial was design ed with clinic sites r and omly assigned to either nutrition practice guidelines care ( 12 sites ) or usual nutrition care ( 13 sites ) , with diabetes , obstetric , and other clinic types represented in both groups . Volunteer dietitians served as study coordinators and recruited women diagnosed with gestational diabetes mellitus . The nutrition practice guidelines define medical nutrition therapy ( MNT ) for gestational diabetes and emphasize three areas -definition of MNT clinical goals with indexes to modify or advance MNT and criteria to start insulin ; use of self-monitoring tools ; and provision of three nutrition visits . Usual care sites provided prenatal nutrition care according to usual practice . The effect of nutrition care ( sites following the nutrition care guidelines ) and type of clinic site on changes in glycated hemoglobin and infant birth weight , adjusted for other covariates , were evaluated using linear regression . Differences in insulin use and other infant outcomes between treatment groups were evaluated using logistic regression . Generalized estimating equations were used to accommo date nonindependence within r and omized clusters of patients within clinic sites . Data from 215 women indicated less insulin use at diabetes clinic sites in the nutrition practice guidelines groups and improved glycated hemoglobin control during the treatment period in diabetes clinics compared with obstetric or other clinics . A higher proportion of women in the usual care group had glycated hemoglobin levels that exceeded 6 % at follow-up compared with women in the nutrition practice guidelines group ( 13.6 % vs 8.1 % ) , although not statistically significant ( P=0.26 ) . A significant clinic type and treatment group effect was found for birth weight . Nutrition practice guidelines for gestational diabetes mellitus reflected nutrition care already being provided by registered dietitians in diabetes clinics prior to this study because outcomes at these clinics were not impacted . Use of the guidelines by dietitians at obstetric and other clinics tended to improve outcomes at these sites [25753159] Purpose To create a positive step toward achieving an efficient method for gestational diabetes treatment , the present study was carried out to compare the treatment outcomes based on single impaired blood glucose versus regular method in health care centers in Iran . Methods This r and omized clinical trial was carried out in Tehran/Iran between March 2012 and August 2013 . Study sample consisted of mothers whose fasting blood sugar was disturbed or a disturbed blood sugar was seen in OGTT with 75 g glucose load , according to ADA st and ards . For each outcome , multiple logistic regressions were used to control for the effects of potential confounders . When a confounder was measured on a continuous scale ( e.g. , age ) , LOWESS ( locally weighted scatter plot smoothing ) algorithm was used to determine whether the effect of that variable was linear . We also used the fractional polynomial regression to determine the optimal transformation of continuous covariates . Results The information of 189 pregnant women was used in this study ; 87 in the interventional group ( 46 % ) and 102 in the control group ( 54 % ) . Treatment based on the new protocol has very high protective effect ( OR 0.25 , 95 % CI 0.68–0.88 ) in terms of neonatal hyperbilirubinemia . This difference was not seen in other outcomes including stillbirth , macrosomic newborn delivery , hypoglycemia , and hypocalcemia . The risk of neonatal hypoglycemia reduced after the 25th week of gestation ( OR 0.39 , 95 % CI 0.15–0.98 ) . Conclusions Although the treatment of mild gestational diabetes could not significantly decrease severe neonatal outcomes , it did significantly reduce the risk of hyperbilirubinemia and its subsequent complications [26222270] A r and omized multicenter study was conducted in the Stockholm‐Örebro areas in Sweden to evaluate how treatment aim ing at normoglycemia affects fetal growth , pregnancy and neonatal outcome in pregnant women with severe hyperglycemia [24607755] OBJECTIVE The purpose of this study was to evaluate the relationship between gestational age ( GA ) and induction of labor ( IOL ) and the rate of cesarean delivery in women with mild gestational diabetes mellitus . STUDY DESIGN We conducted a secondary analysis of data from a multicenter r and omized controlled trial of mild gestational diabetes mellitus treatment . Cesarean delivery rate of women delivering at term ( ≥37 weeks ' gestation ) was evaluated by 2 complementary approaches : ( 1 ) IOL vs spontaneous labor : women who were induced at each GA compared with those who spontaneously labored at the same GA and ( 2 ) IOL vs expectant management : women who delivered after IOL at each GA compared with those who delivered after spontaneous labor at the same GA or subsequently after spontaneous or induced labor ( outcome at each week compared with expectant management at that week ) . Logistic regression adjusted for potential confounders . RESULTS The overall cesarean delivery rate was 13 % . When compared with 39 weeks ' gestation ( either IOL or spontaneous labor ) as the referent , there was no significant difference in the cesarean delivery rate in women who delivered at 37 , 38 , or 40 weeks ' gestation . However , IOL was associated with a 3-fold increase in cesarean delivery rate at 41 weeks ' gestation and beyond , as compared with IOL at 39 weeks ' gestation . Similarly , there was a 3-fold increase in the cesarean delivery rate in women who were induced when compared with those who were treated expectantly at 40 completed weeks ' gestation . CONCLUSION Induction of labor in women with mild gestational diabetes mellitus does not increase the rate of cesarean delivery at < 40 weeks ' gestation [5936737] The purpose of this study was to examine pregnancy outcome in women with abnormal oral glucose tolerance tests , in relation to treatment with diet and insulin . Glucose tolerance tests , done because of well-known historical risk factors , were considered abnormal if two or more readings exceeded the following : fasting , 110 ; 1 hour , 170 ; 2 hours , 120 ; and 3 hours , 110 ( all in mg/100 mL , measured as total reducing substances in whole venous blood ) . Those with positive tests were divided r and omly into a “ positive-control ” group ( n 308 ) that received st and ard prenatal care or a “ positive-treated ” group ( n 307 ) that received dietary instructions ( 30 kcal/kg ideal body weight , 40 % as carbohydrate , and 1.5–2 g protein/kg body weight ) and insulin ( initial dose 10 U per day of intermediate-acting insulin , adjusted subsequently as directed by blood and urine studies ) , beginning at usually about 32 weeks . A third group ( n 328 ) , termed “ negative controls , ” had exhibited normal glucose tolerance testing . The three groups were similar , except that those with abnormal glucose tolerance tended to be older and heavier , as expected . With respect to outcome , infants with birth weights exceeding 9 lb were three times as frequent in positive-control subjects as in either positive-treated subjects or negative controls ( 13.1 % , 4.3 % , and 3.7 % , respectively ) . Perinatal deaths ( 28 weeks ’ gestation through 14 days after birth ) were similar in the two positive groups ( 4.9 % in control and 4.3 % in treated ) and significantly higher than in negative controls ( 1.9 % ) , with the increase involving both fetal and neonatal components . The conclusions were 1 ) abnormal glucose tolerance during pregnancy leads to larger infants and higher perinatal mortality and 2 ) treatment with diet and insulin ameliorates the former but not the latter . This study concerned what O’Sullivan called potential diabetes and others at the time termed latent or chemical diabetes or prediabetes , but what today we refer to as gestational diabetes . Acceptance of it as a pathologic entity was far from unanimous in 1966 . O’Sullivan resolved the controversy with this large , well- design ed , and well-analyzed clinical trial . The immediate influence was two-fold . In the first place , it settled the existing disagreement as to whether or not impaired glucose tolerance adversely influences pregnancy outcome ; large infants occurred three times as frequently and perinatal deaths were more than doubled in women with abnormal carbohydrate metabolism . Second , the findings of the intervention trial indicated clearly that treatment of gestational diabetes with diet and insulin in late gestation normalizes birth weight ( although it did not seem to influence perinatal mortality ) , a finding confirmed a number of times by subsequent investigators . Incidentally , the frequencies of both fetal and neonatal deaths may seem high , but it needs to be remembered that this experience ante date d the advent of modern fetal surveillance and neonatal intensive care . John B. O’Sullivan , a pioneer in clinical research in gestational diabetes , was an internist . He defined st and ards for the oral glucose tolerance test in pregnancy that , though modified slightly by subsequent investigators , are basically those in use today . Born in 1926 , he received his medical education in his native Irel and before immigrating to the United States in 1955 . After further training in internal medicine at the Lahey Clinic , he took a faculty position at the Boston University School of Medicine , where he did his original work on early diabetes as medical director of the Prenatal Metabolism Clinic at Boston City Hospital and chief of medicine at St. Margaret ’s Hospital . In addition to his position as Associate Professor at Boston University , he also served on the faculties of the Harvard and Yale medical schools . Later he was director of employee health for the Liberty Mutual Insurance Company . He died of cancer in August 2001 [9315766] CONTEXT Gestational diabetes mellitus ( GDM ) affects 3 % to 5 % of pregnancies . Knowledge of risk factors for GDM is needed to identify possible preventive strategies . OBJECTIVE To assess whether recognized determinants of noninsulin-dependent diabetes mellitus also may be markers for increased risk of GDM . DESIGN Prospect i ve cohort study . SETTING The Nurses ' Health Study II , which involves female US nurses aged 25 to 42 years at entry . PARTICIPANTS The analyses included 14613 women without previous GDM or other known diabetes who reported a singleton pregnancy between 1990 and 1994 . Of these women , 722 ( 4.9 % ) reported a new diagnosis of GDM . MAIN OUTCOME MEASURE Self-report of GDM , vali date d by medical record review in a subset . RESULTS In multivariate analyses including age , pregravid body mass index ( BMI ) , and other GDM risk factors , the risk for GDM increased significantly with increasing maternal age ( P for trend , < .01 ) and family history of diabetes mellitus ( relative risk , 1.68 ; 95 % confidence interval [ CI ] , 1.39 - 2.04 ) . Relative risks for GDM were 2.13 ( 95 % CI , 1.65 - 2.74 ) for pregravid BMI of 25 to 29.9 kg/m2 and 2.90 ( 95 % CI , 2.15 - 3.91 ) for BMI of 30 kg/m2 or more ( vs BMI of < 20 kg/m2 ) . Risk for GDM increased with greater weight gain in early adulthood , and it also increased among nonwhite women . Pregravid current smokers had a relative risk for GDM of 1.43 ( 95 % CI , 1.14 - 1.80 ) , and pregravid vigorous exercise was associated with a nonsignificant reduction in GDM risk . CONCLUSIONS Advanced maternal age , family history of diabetes mellitus , nonwhite ethnicity , higher BMI , weight gain in early adulthood , and cigarette smoking predict increased GDM risk . These observations may facilitate the identification of women at particular risk for GDM and suggest potential strategies for reducing this risk even before a woman becomes pregnant , such as avoiding substantial weight gain and smoking [4829275] The outcome of pregnancy in control and treated gestational diabetics was not significantly different . The decreased loss rate among the insulin- and diet-treated gestational diabetics , however , did become significant when the data were reanalyzed with consideration of two important influencing variables . The high-risk group of gestational diabetics aged 25 years and older who received insulin therapy before the 32nd week of gestation had fewer fetal losses . Documentation of the critical role played by both maternal age and the gestational age at which insulin therapy is commenced now makes the institution of a conclusive prospect i ve study feasible . The adequately established hypothesis that insulin management of gestational diabetics favorably affects the outcome of their pregnancies can then be finally resolved [10586979] Infant macrosomia is a serious medical concern . Pregnant women who do not meet the specific diagnosis for gestational diabetes may still have glucose-mediated macrosomia . In Santa Barbara County all pregnant women are screened for gestational diabetes at 24 - 28 weeks with a 50-g , 1-hr glucose challenge test ( GCT ) . All patients who fail this test are placed on a st and ard euglycemic diet ( 40 % carbohydrate , 20 % protein , 40 % fat ) and perform home glucose monitoring of fasting and postpr and ial glucose levels . The objective of this study was to examine the effectiveness of this treatment program in decreasing infant macrosomia , maternal and infant morbidity , maternal complications , and operative delivery . We studied 103 women who had a positive GCT , but a negative 100-g , 3-hr oral glucose tolerance test ( OGTT ) . The women were r and omly assigned to either experimental or control groups with experimental women receiving dietary counseling and home glucose monitoring instruction ( HBGM ) . HBGM diaries were review ed weekly by clinic nurses . All women had hemoglobin A1c ( HbA1c ) tests at 28 and 32 weeks . Maternal and fetal charts were review ed to determine delivery type and complications , indications for cesarean section ( C-section ) , and infant gestational age , gender , Apgar scores , birth weight , morbidities , and congenital anomalies . Of the 103 women , 5 women required insulin treatment , 1 woman had an abortion , and 14 women were indeterminate regarding compliance or were control women who received diet counseling and HBGM . The results are based on 83 women--48 control and 35 experimental . There were no significant differences between the groups for age , parity , or weight at 28 - 30 weeks or 37 weeks to delivery , or HbA1c at 28 weeks . HbA1c was significantly higher in control women at 32 weeks . Birth weight expressed in grams or as a percentile specific for gender , ethnicity , and gestational age was significantly higher in control infants . Birth weight was significantly correlated with maternal intake weight , weight at 28 - 30 weeks , and weight at delivery and with HbA1c at 32 weeks ' gestation . There were no significant differences between groups for maternal complications . Groups were significantly different for mode of delivery with experimental women having more induced vaginal deliveries but fewer repeat C-sections than control women . Groups were not different for primary C-sections . Women who fail the GCT , but not the OGTT and thus do not receive the diagnosis of GDM are still at risk for delivering a macrosomic infant and operative delivery . Our program of treatment for all women who fail the GCT improves outcome by reducing infant birth weight and the number of cesarean sections [25014091] This practice guideline on gestational diabetes is a treatment oriented short version of the evidence based guideline that can be viewed in the internet . It replaces the DDG and DGGG recommendations of 2001 for diagnostic and therapy of gestational diabetes . A complete rework had become necessary in view of epidemiologically based diagnostic criteria , which had been derived from the Hyperglycaemia and Adverse Pregnancy Outcome study ( HAPO ) by international consensus , and in view of r and omised therapy and observation studies published after 2001 . With this , Germany has adopted the international st and ard . Screening and diagnosing gestational diabetes by means of blood glucose are part of the legally binding maternity guidelines in Germany since March 3 , 2012 [4336499] Background : There are no r and omised controlled trials to demonstrate whether lifestyle modifications can improve pregnancy outcomes of gestational diabetes mellitus ( GDM ) diagnosed by the International Association of Diabetes and Pregnancy Study Group ’s ( IADPSG ) criteria . We tested the effectiveness of lifestyle modifications implemented in a 3-tier ’s shared care ( SC ) on pregnancy outcomes of GDM . Methods : Between December 2010 and October 2012 , we r and omly assigned 700 women with IADPSG-defined GDM but without diabetes at 26.3 ( interquartile range : 25.4 - 27.3 ) gestational weeks in Tianjin , China , to receive SC or usual care ( UC ) . The SC group received individual consultations and group sessions and performed regular self-monitoring of blood glucose compared to one hospital-based education session in the UC group . The outcomes were macrosomia defined as birth weight ≥ 4.0 kg and the pregnancy-induced hypertension ( PIH ) . Results : Women in the SC ( n = 339 ) and UC ( n = 361 ) groups delivered their infants at similar gestational weeks . Birth weight of infants in the SC group was lower than that in the UC group ( 3469 vs. 3371 grams , P = 0.021 ) . The rate of macrosomia was 11.2 % ( 38/339 ) in the SC group compared to 17.5 % ( 63/361 ) in the UC group with relative risk ( RR ) of 0.64 ( 95 % CI : 0.44 - 0.93 ) . The rate of PIH was 8.0 % ( 27/339 ) in the SC compared to 4.4 % ( 16/361 ) in the UC with RR of 1.80 ( 0.99 - 3.28 ) . Apgar score at 1 min < 7 was lower but preeclampsia was higher in the SC than in the UC [21422852] OBJECTIVE : To estimate the association between fasting and 2-hour postpr and ial blood glucose levels and neonatal outcomes in women treated for mild gestational diabetes . METHODS : In this secondary analysis of a multicenter r and omized treatment trial of mild gestational diabetes , the median fasting and 2-hour postpr and ial glucose levels were analyzed in 2-week intervals and change over time ( slope ) was calculated for women with gestational diabetes ( abnormal oral glucose tolerance test ) and a fasting glucose less than 95 mg/dL who received nutritional management with self blood glucose monitoring and insulin as needed . Regression analyses were performed to estimate the relationship between median fasting and postpr and ial glucose and neonatal fat mass , cord blood C-peptide , birth weight , large-for-gestational-age neonates , macrosomia ( greater than 4,000 g ) , and neonatal hypoglycemia . RESULTS : Among 460 women with gestational diabetes , median fasting ( P<.001 ) , postpr and ial breakfast ( P<.001 ) , and postpr and ial lunch ( P<.001 ) glucose values declined over the treatment period , whereas postpr and ial dinner values remained stable ( P=.83 ) . Higher median fasting glucose during the first 2 weeks of treatment was significantly associated with increased odds ratios for neonatal fat mass ( 1.35 ; 95 % CI 1.09–1.66 ; P=.006 ) and elevated C-peptide ( 1.29 ; CI 1.09–1.52 ; P=.003 ) . Higher median fasting glucose during the last 2 weeks before delivery was associated with higher rates of large-for-gestational-age neonates ( 1.27 ; CI 1.05–1.53 ; P=.01 ) , macrosomia ( 1.32 ; CI 1.04–1.65 ; P = .02 ) , and elevated C-peptide ( 1.19 ; CI 1.03–1.38 ; P=.02 ) . CONCLUSION : In women treated for mild gestational diabetes , higher fasting glucose during initiation of diet therapy was associated with increased neonatal fat mass and elevated C-peptide and during the last 2 weeks before delivery with macrosomia , large-for-gestational age , and elevated C-peptide . LEVEL OF EVIDENCE : [24629718] AIM This r and omized controlled trial was carried out to investigate the effect of mindfulness eating and yoga exercise on blood sugar levels among pregnant Thai women with GDM . BACKGROUND Interventions promoting achievement of good glycemic control result in desired pregnancy outcomes . Little is known about the health benefits of mindfulness eating and yoga exercise on blood sugar levels among pregnant with GDM . METHODS A r and omized controlled trial was carried out . Main outcome measures were capillary fasting plasma glucose , 2-h postpr and ial blood glucose , and hemoglobin A1c . RESULTS The intervention group showed significantly reduced fasting plasma glucose , 2-h postpr and ial blood glucose , and glycosylated hemoglobin ( HbA1c ) in the intervention group ( p<0.05 ) . CONCLUSIONS Mindfulness eating and yoga exercise had health benefits on glycemic control in pregnant women with GDM . It should be recommended in clinical and community health services [18754979] OBJECTIVE To examine the effects of a Parish Nurse Intervention Program ( PNIP ) on maternal health behaviors , glycemic control , and neonatal outcomes among Mexican American women with gestational diabetes . DESIGN A r and omized controlled trial comparing care as usual ( CAU ) with a supplementary 1-hour education session for diabetes education reinforcement by a Parish Nurse . SETTING An outpatient treatment clinic for gestational diabetes within a 250-bed tertiary care , non-profit hospital with a Parish Nurse partnership . PARTICIPANTS One hundred Mexican American women were included in the study with r and omization into Parish Nurse Intervention Program ( n=49 ) and care as usual ( n=51 ) groups . MAIN OUTCOME MEASURES The Health Promoting Lifestyle Profile II ( HPLP II ) and two measures of glycemic control pre- and post-intervention , as well as newborn size , and days of maternal and neonatal hospitalization . RESULTS Outcomes indicate significantly improved Health Promoting Lifestyle Profile II scores in the Parish Nurse Intervention Program group post-intervention compared with the Care As Usual group . No significant differences between groups regarding glycemic control , macrosomia , or days of maternal or neonatal hospitalization were found . CONCLUSIONS A Parish Nurse Intervention Program for pregnant women of Mexican descent with gestational diabetes is effective in leading to improved self-reported health promoting behaviors [26071920] OBJECTIVE The purpose of this study was to examine the association between gestational age ( GA ) at the time of treatment initiation for gestational diabetes mellitus ( GDM ) and maternal and perinatal outcomes . STUDY DESIGN We conducted a secondary analysis of a multicenter r and omized treatment trial of mild GDM in which women with mild GDM were assigned r and omly to treatment vs usual care . The primary outcome of the original trial , as well as this analysis , was a composite perinatal adverse outcome that included neonatal hypoglycemia , hyperbilirubinemia , hyperinsulinemia , and perinatal death . Other outcomes that were examined included the frequency of large for GA , birthweight , neonatal intensive care unit admission , gestational hypertension/preeclampsia , and cesarean delivery . The interaction between GA at treatment initiation ( stratified as 24 - 26 , 27 , 28 , 29 , and ≥30 weeks of gestation ) and treatment group ( treated vs routine care ) , with the outcomes of interest , was used to determine whether GA at treatment initiation was associated with outcome differences . RESULTS Of 958 women whose cases were analyzed , those who initiated treatment at an earlier GA did not gain an additional treatment benefit compared with those who initiated treatment at a later GA ( probability value for interaction with the primary outcome , .44 ) . Similarly , there was no evidence that other outcomes were improved significantly by earlier initiation of GDM treatment ( large for GA , P = .76 ; neonatal intensive care unit admission , P = .8 ; cesarean delivery , P = .82 ) . The only outcome that had a significant interaction between GA and treatment was gestational hypertension/preeclampsia ( P = .04 ) , although there was not a clear cut GA trend where this outcome improved with treatment . CONCLUSION Earlier initiation of treatment of mild GDM was not associated with stronger effect of treatment on perinatal outcomes [12375675] Objective : A planned study is described which will determine whether a benefit exists for the treatment of mild carbohydrate intolerance during pregnancy . Methods : A r and omized clinical trial of women with mild gestational diabetes will compare perinatal outcomes in those receiving diet therapy and insulin as required versus those r and omized to no specific treatment . Results : The primary outcome of this study will be a composite of neonatal morbidity in the treatment and control groups . Conclusions : A r and omized treatment trial of mild gestational diabetes mellitus will clarify whether identification and treatment of mild gestational diabetes mellitus reduces perinatal morbidity . This information will aid in selecting appropriate thresholds for the treatment of gestational diabetes mellitus [24839145] OBJECTIVE The aim of the article is to determine whether maternal body mass index ( BMI ) influences the beneficial effects of diabetes treatment in women with gestational diabetes mellitus ( GDM ) . STUDY DESIGN Secondary analysis of a multicenter r and omized treatment trial of women with GDM . Outcomes of interest were elevated umbilical cord c-peptide levels ( > 90th percentile 1.77 ng/mL ) , large for gestational age ( LGA ) birth weight ( > 90th percentile ) , and neonatal fat mass ( g ) . Women were grouped into five BMI categories adapted from the World Health Organization International Classification of normal , overweight , and obese adults . Outcomes were analyzed according to treatment group assignment . RESULTS A total of 958 women were enrolled ( 485 treated and 473 controls ) . Maternal BMI at enrollment was not related to umbilical cord c-peptide levels . However , treatment of women in the overweight , Class I , and Class II obese categories was associated with a reduction in both LGA birth weight and neonatal fat mass . Neither measure of excess fetal growth was reduced with treatment in normal weight ( BMI < 25 kg/m(2 ) ) or Class III ( BMI ≥ 40 kg/m(2 ) ) obese women . CONCLUSION There was a beneficial effect of treatment on fetal growth in women with mild GDM who were overweight or Class I and Class II obese . These effects were not apparent for normal weight and very obese women [30866027] OBJECTIVE The main purpose of this article is to evaluate whether identification and treatment of women with mild gestational diabetes mellitus ( GDM ) during pregnancy affects subsequent maternal body mass index ( BMI ) , anthropometry , metabolic syndrome , and risk of diabetes . STUDY DESIGN This is a follow-up study of women who participated in a r and omized controlled treatment trial for mild GDM . Women were enrolled between 5 and 10 years after their index pregnancy . Participants underwent blood pressure , height , weight , and anthropometric measurements by trained nursing personnel using a st and ardized approach . A nurse-assisted question naire regarding screening and treatment of diabetes or hypercholesterolemia , diet , and physical activity was completed . Laboratory evaluation included fasting serum glucose , fasting insulin , oral glucose tolerance test , and a lipid panel . Subsequent diabetes , metabolic syndrome , obesity , and adiposity in those diagnosed with mild GDM and r and omized to nutritional counseling and medical therapy ( treated ) were compared with those who underwent routine pregnancy management ( untreated ) . Multivariable analyses were performed adjusting for race/ethnicity and years between r and omization and follow-up visit . RESULTS Four-hundred fifty-seven women with mild GDM during the index pregnancy were included in this analysis ( 243 treated ; 214 untreated ) and evaluated at a median 7 years after their index pregnancy . Baseline and follow-up characteristics were similar between treatment groups . Frequency of diabetes ( 9.2 vs. 8.5 % , p = 0.80 ) , metabolic syndrome ( 32.2 vs. 34.3 % , p = 0.63 ) , as well as adjusted mean values of homeostasis model assessment for insulin resistance ( 2.5 vs. 2.3 , p = 0.11 ) and BMI ( 29.4 vs. 29.1 kg/m2 , p = 0.67 ) were also not different . CONCLUSION Identification and treatment of women with mild GDM during pregnancy had no discernible impact on subsequent diabetes , metabolic syndrome , or obesity 7 years after delivery [24646172] The benefits of exercise and behavioural recommendations in gestational diabetes mellitus ( GDM ) are controversial . In a r and omized trial with a 2 × 2 factorial design , we examined the effect of exercise and behavioural recommendations on metabolic variables , and maternal/neonatal outcomes in 200 GDM patients . All women were given the same diet : group D received dietary recommendations only ; group E was advised to briskly walk 20‐min/day ; group B received behavioural dietary recommendations ; group BE was prescribed the same as B + E. Dietary habits improved in all groups . In a multivariable regression model , fasting glucose did not change . Exercise , but not behavioural recommendations , was associated with the reduction of postpr and ial glucose ( p < 0001 ) , glycated haemoglobin ( HbA1c ; p < 0.001 ) , triglycerides ( p = 0.02 ) and C‐reactive protein ( CRP ; p < 0.001 ) and reduced any maternal/neonatal complications ( OR = 0.50 ; 95%CI=0.28–0.89;p = 0.02 ) . In GDM patients a simple exercise programme reduced maternal postpr and ial glucose , HbA1c , CRP , triglycerides and any maternal/neonatal complications , but not fasting glucose values [19797280] BACKGROUND It is uncertain whether treatment of mild gestational diabetes mellitus improves pregnancy outcomes . METHODS Women who were in the 24th to 31st week of gestation and who met the criteria for mild gestational diabetes mellitus ( i.e. , an abnormal result on an oral glucose-tolerance test but a fasting glucose level below 95 mg per deciliter [ 5.3 mmol per liter ] ) were r and omly assigned to usual prenatal care ( control group ) or dietary intervention , self-monitoring of blood glucose , and insulin therapy , if necessary ( treatment group ) . The primary outcome was a composite of stillbirth or perinatal death and neonatal complications , including hyperbilirubinemia , hypoglycemia , hyperinsulinemia , and birth trauma . RESULTS A total of 958 women were r and omly assigned to a study group--485 to the treatment group and 473 to the control group . We observed no significant difference between groups in the frequency of the composite outcome ( 32.4 % and 37.0 % in the treatment and control groups , respectively ; P=0.14 ) . There were no perinatal deaths . However , there were significant reductions with treatment as compared with usual care in several prespecified secondary outcomes , including mean birth weight ( 3302 vs. 3408 g ) , neonatal fat mass ( 427 vs. 464 g ) , the frequency of large-for-gestational-age infants ( 7.1 % vs. 14.5 % ) , birth weight greater than 4000 g ( 5.9 % vs. 14.3 % ) , shoulder dystocia ( 1.5 % vs. 4.0 % ) , and cesarean delivery ( 26.9 % vs. 33.8 % ) . Treatment of gestational diabetes mellitus , as compared with usual care , was also associated with reduced rates of preeclampsia and gestational hypertension ( combined rates for the two conditions , 8.6 % vs. 13.6 % ; P=0.01 ) . CONCLUSIONS Although treatment of mild gestational diabetes mellitus did not significantly reduce the frequency of a composite outcome that included stillbirth or perinatal death and several neonatal complications , it did reduce the risks of fetal overgrowth , shoulder dystocia , cesarean delivery , and hypertensive disorders . ( Clinical Trials.gov number , NCT00069576 . [23046401] OBJECTIVE This study identified the impact of intensive therapy on neonatal outcomes in women with gestational diabetes mellitus ( GDM ) and determined the effects on the postpartum metabolic status of the mothers . RESEARCH DESIGN AND METHODS In total , 127 pregnant women with GDM were r and omly selected to receive an intensive treatment regimen , which included one-to-one education , lifestyle intervention , scheduled clinic visits , strict glucose control , and frequent glucose self-monitoring . Meanwhile , 148 age-matched pregnant women with GDM were selected as controls and given the st and ard treatment regimen . Pregnancy outcomes including parameters related to the GDM mothers and to their neonates were comparatively analyzed between the two treatment groups . GDM patient follow-up ( range , 1 - 3 years after delivery ) included an oral glucose tolerance test and measurements of lipid concentration and insulin secretion . The insulinogenic index ( ΔInsulin(30 min)/ΔBlood glucose(30 min ) ) and homeostasis model assessment index of β-cell function and insulin resistance were calculated . The patients ' demographic and anthropometric data were also recorded for comparative analysis . RESULTS Compared with GDM patients receiving st and ard treatment , GDM patients receiving intensive treatment had lower instances of premature delivery ( 2.4 % vs. 8.3 % , P<0.05 ) and neonatal care unit admission ( 21.3 % vs. 33.3 % , P<0.05 ) and lower neonatal birth weight ( 3.26±0.53 vs. 3.45±0.55 kg , P<0.0001 ) . At follow-up , GDM patients from the intensive treatment group had a smaller waist circumference ( 75.83±3.11 vs. 78.34±4.20 cm , P<0.01 ) , lower 30-min glucose levels after a 75-g glucose load ( 8.26±1.85 vs. 9.46±2.74 mmol/L , P<0.05 ) , and higher high-density lipoprotein levels ( 1.30±0.24 vs. 1.18±0.23 mmol/L , P<0.05 ) . CONCLUSIONS The intensive GDM treatment regimen led to healthier outcomes for the women , the neonates , and the birth event and was associated with better maternal metabolic situations in the months and years after delivery [21050147] Objective . To examine pregnancy outcomes in relation to different categories of glucose tolerance during pregnancy . Design . Prospect i ve observational cohort study . Setting . Patient recruitment and data collection were performed in four delivery departments in southern Sweden . Population . Women delivering during 2003–2005 ; 306 with gestational diabetes mellitus , 744 with gestational impaired glucose tolerance and 329 r and omly selected controls . Methods . All women were offered a 75 g oral glucose tolerance test during pregnancy . On the basis of their capillary 2‐hour plasma glucose concentrations , three groups were identified : gestational diabetes mellitus ( > 10.0 mmol/l ) , gestational impaired glucose tolerance ( 8.6–9.9 mmol/l ) and controls ( < 8.6 mmol/l ) . Data for the groups were compared using a population ‐based data base . Main outcome measures . Maternal and fetal outcomes . Results . For the gestational diabetes mellitus group , adjusted odds ratios ( 95 % confidence intervals ) for hypertensive disorders during pregnancy and induction of labor and emergency cesarean section were 2.7 ( 1.3–5.8 ) , 3.1 ( 1.8–5.2 ) and 2.5 ( 1.5–4.4 ) , respectively ; and for Apgar score < 7 at 5 minutes , need for neonatal intensive care > 1 day and large‐for‐gestational age infant were 9.6 ( 1.2–78.0 ) , 5.2 ( 2.8–9.6 ) and 2.5 ( 1.3–5.1 ) , respectively . The increases in odds ratios for the gestational impaired glucose tolerance group were less pronounced but still significant for hypertension during pregnancy , induction of labor , large‐for‐gestational age infant and use of neonatal intensive care > 1 day , with odds ratios ( 95 % confidence interval ) 2.0 ( 1.0–4.1 ) , 1.8 ( 1.1–3.0 ) , 2.1 ( 1.1–3.9 ) and 2.1 ( 1.1–3.8 ) , respectively . Conclusions . These data indicate that even limited degrees of maternal hyperglycemia may affect the outcome of pregnancy

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### Context: [17596471] It is recognized that women with gestational diabetes mellitus ( GDM ) who have significantly elevated fasting blood glucose levels are at increased risk for fetal macrosomia and perinatal morbidity if treatment is not provided ( 1,2 ) . The association of milder forms of GDM with perinatal morbidity and mortality remains unclear , primarily because the condition is often confounded with other risk factors such as maternal obesity , age , and parity . Screening for GDM is recommended for most pregnant women , yet it is unknown whether there is a benefit to the identification and treatment of mild carbohydrate intolerance during pregnancy ( 3,4 ) . The present report is an up date of our previous description of a current ongoing r and omized treatment trial for mild GDM ( 5 ) . A r and omized clinical trial of women with mild GDM ( fasting glucose < 95 mg/dl ) is being undertaken that compares perinatal outcomes in those receiving diet therapy and insulin as required versus those r and omized to no specific treatment . This study aims to clarify whether there is utility in identifying and treating women with a normal fasting glucose level who meet st and ard criteria for GDM . We plan to compare perinatal outcomes in women who have been r and omized to diet and /or insulin therapy with women who have been r and omized to no specific treatment . A r and omized treatment trial of mild GDM will clarify whether identification and treatment of mild GDM reduce perinatal morbidity . This information will assist in determining appropriate thresholds for the treatment of GDM . Overall , with broader identification and aggressive treatment , perinatal mortality rates associated with GDM appear to be similar to the nondiabetic population ( 1 ) . Several analyses of 20 years ago did document an increased stillbirth rate for GDM pregnancies that would qualify as preexisting diabetes according to World Health Organization criteria ( 6–9 ) . Below this threshold , the extent to [3120183] OBJECTIVE To pilot , among women with gestational diabetes mellitus ( GDM ) , the feasibility of a prenatal/postpartum intervention to modify diet and physical activity similar to the Diabetes Prevention Program . The intervention was delivered by telephone , and support for breastfeeding was addressed . RESEARCH DESIGN AND METHODS The goal was to help women return to their prepregnancy weight , if it was normal , or achieve a 5 % reduction from prepregnancy weight if overweight . Eligible participants were identified shortly after a GDM diagnosis ; 83.8 % consented to be r and omly assigned to intervention or usual medical care ( 96 and 101 women , respectively ) . The retention was 85.2 % at 12 months postpartum . RESULTS The proportion of women who reached the postpartum weight goal was higher , although not statistically significant , in the intervention condition than among usual care ( 37.5 vs. 21.4 % , absolute difference 16.1 % , P = 0.07 ) . The intervention was more effective among women who did not exceed the recommended gestational weight gain ( difference in the proportion of women meeting the weight goals : 22.5 % , P = 0.04 ) . The intervention condition decreased dietary fat intake more than the usual care ( condition difference in the mean change in percent of calories from fat : −3.6 % , P = 0.002 ) and increased breastfeeding , although not significantly ( condition difference in proportion : 15.0 % , P = 0.09 ) . No differences in postpartum physical activity were observed between conditions . CONCLUSIONS This study suggests that a lifestyle intervention that starts during pregnancy and continues postpartum is feasible and may prevent pregnancy weight retention and help overweight women lose weight . Strategies to help postpartum women overcome barriers to increasing physical activity are needed [19696205] Diabetes in pregnancy is a major public health problem in Mexico . Nutrition therapy is an important component of treatment . Intensive nutrition intervention has not been implemented for Mexican pregnant women with diabetes . Its effect on different types of diabetes mellitus has not been studied . Purpose The authors assessed the effect of a medical nutrition therapy ( MNT ) program on perinatal complications in Mexico City . Methods Quasi-experimental design with a historical control . Women were assigned to a MNT program ( n = 88 ) and were followed up with every 2 weeks until delivery ( 2004 - 2007 ) . The control group ( n = 86 ) was selected from medical charts ( 2001 - 2003 ) and the same inclusion criteria were used . In each group , 55 % of women had type 2 diabetes mellitus and 45 % had gestational diabetes . The MNT program included a moderate intake of carbohydrate ( 40%-45 % of total energy ) and reduction in energy intake , capillary glucose self-monitoring , and education . The control group received usual hospital routine care . Statistical analysis included descriptive statistics , chi-square , and multivariate logistic regression ( OR , 95 % CI ) as indicated . Results Women in the MNT program had a lower risk of preeclampsia , fewer maternal hospitalization , and neonatal deaths in both types of diabetes . Low birth weight was less frequent only in women with gestational diabetes receiving MNT , while neonatal intensive care unit admissions were lower only in women with type 2 diabetes . Conclusions An intensive MNT program , including counseling , education , and capillary glucose self-monitoring , has a positive effect over preeclampsia , maternal hospitalization , and neonatal death in women with diabetes in pregnancy . MNT guidelines should be implemented in Mexican health care facilities treating diabetes in pregnancy [12073958] PURPOSE The purpose of this study was to examine the effects of self-monitoring of blood glucose ( SMBG ) on feelings of self-efficacy , dietary compliance , and pregnancy outcomes in women with diet-controlled gestational diabetes mellitus ( GDM ) . METHODS Fifty-eight women with GDM and a fasting blood glucose level < 95 mg/dL were r and omly assigned to 2 groups . The experimental group measured their blood glucose levels 4 times daily using a reflectance meter with memory . Metabolic status was assessed in the control group by periodic monitoring at prenatal visits . Otherwise the management protocol was identical for both groups . The Diabetes Empowerment Scale was completed at study entry and at 37 weeks gestation to assess feelings of self-efficacy . Dietary compliance was assessed at each visit . RESULTS Both groups of women achieved excellent glucose control ; only 1 woman in each group required insulin therapy . There were no significant differences with regard to feelings of self-efficacy , dietary compliance , birth weight , gestational age at delivery , Apgar scores , and neonatal complications . Rates of macrosomia , delivery by cesarean section , and occurrence of birth trauma were similar . CONCLUSIONS SMBG appears to have little effect on maternal feelings of self-efficacy , dietary compliance , or pregnancy outcomes in women with diet-controlled GDM [6259925] The determine the effect of different foods on the blood glucose , 62 commonly eaten foods and sugars were fed individually to groups of 5 to 10 healthy fasting volunteers . Blood glucose levels were measured over 2 h , and expressed as a percentage of the area under the glucose response curve when the same amount of carbohydrate was taken as glucose . The largest rises were seen with vegetables ( 70 + /- 5 % ) , followed by breakfast cereals ( 65 + /- 5 % ) , cereals and biscuits ( 60 + /- 3 % ) , fruit ( 50 + /- 5 % ) , dairy products ( 35 + /- 1 % ) , and dried legumes ( 31 + /- 3 % ) . A significant negative relationship was seen between fat ( p less than 0.01 ) and protein ( p less than 0.001 ) and postpr and ial glucose rise but not with fiber or sugar content [18582171] OBJECTIVE Studies in predominantly non-Hispanic white population s have suggested that physical activity during pregnancy is associated with a reduced risk of gestational diabetes mellitus ( GDM ) . There are few such studies in Hispanic women , a group at increased risk for GDM . METHODS We conducted a prospect i ve cohort study of household/caregiving , occupational , sports/exercise , and active living habits and the risk of GDM among 1006 Hispanic ( predominantly Puerto Rican ) prenatal care patients in western Massachusetts from 2000 to 2004 . Prepregnancy , early pregnancy , and midpregnancy physical activity was assessed using the Kaiser Physical Activity Survey . RESULTS A total of 33 women ( 3.3 % ) were diagnosed with GDM , and 119 women ( 11.8 % ) were diagnosed with abnormal glucose tolerance . There were no significant associations between GDM risk and occupational and active living activities in prepregnancy , early pregnancy , and midpregnancy or with a change in levels of household/caregiving , occupational , and active living activities from prepregnancy to during pregnancy . However , after controlling for age and prepregnancy body mass index ( BMI ) , women in the highest quartile of prepregnancy ( OR = 0.2 , 95 % CI 0.1 - 0.8 , p(trend ) = 0.03 ) and midpregnancy ( OR = 0.2 , 95 % CI 0.1 - 0.8 , p(trend ) = 0.004 ) household/caregiving activities as well as midpregnancy sports/exercise ( 0.1 , 95 % CI 0.0 - 0.7 , p(trend ) = 0.12 ) had a reduced risk of GDM compared with women in the lowest quartile . CONCLUSIONS Findings in this Hispanic population , although based on small numbers of cases , are consistent with prior research among predominantly non-Hispanic white population [7565999] BACKGROUND The fetuses of women with gestational diabetes mellitus are at risk for macrosomia and its attendant complications . The best method of achieving euglycemia in these women and reducing morbidity in their infants is not known . We compared the efficacy of postpr and ial and prepr and ial monitoring in achieving glycemic control in women with gestational diabetes . METHODS We studied 66 women with gestational diabetes mellitus who required insulin therapy at 30 weeks of gestation or earlier . The women were r and omly assigned to have their diabetes managed according to the results of prepr and ial monitoring or postpr and ial monitoring ( one hour after meals ) of blood glucose concentrations . Both groups were also monitored with fasting blood glucose measurements . The goal of insulin therapy was a prepr and ial value of 60 to 105 mg per deciliter ( 3.3 to 5.9 mmol per liter ) or a postpr and ial value of less than 140 mg per deciliter ( 7.8 mmol per liter ) . Obstetrical data and information on neonatal outcomes were collected . RESULTS The prepregnancy weight , weight gain during pregnancy , gestational age at the diagnosis of diabetes and at delivery , degree of compliance with therapy , and degree of achievement of target blood glucose concentrations were similar in the two groups . The mean ( + /- SD ) change in the glycosylated hemoglobin value was greater in the group in which postpr and ial measurements were used ( -3.0 + /- 2.2 percent vs. 0.6 + /- 1.6 percent , P < 0.001 ) and the infants ' birth weight was lower ( 3469 + /- 668 vs. 3848 + /- 434 g , P = 0.01 ) . Similarly , the infants born to the women in the postpr and ial-monitoring group had a lower rate of neonatal hypoglycemia ( 3 percent vs. 21 percent , P = 0.05 ) , were less often large for gestational age ( 12 percent vs. 42 percent , P = 0.01 ) and were less often delivered by cesarean section because of cephalopelvic disproportion ( 12 percent vs. 36 percent , P = 0.04 ) than those in the prepr and ial-monitoring group . CONCLUSIONS Adjustment of insulin therapy in women with gestational diabetes according to the results of postpr and ial , rather than prepr and ial , blood glucose values improves glycemic control and decreases the risk of neonatal hypoglycemia , macrosomia , and cesarean delivery [3311138] The study was design ed to identify those pregnant women who are diagnosed as having gestational diabetes by National Diabetes Data Group ( NDDG ) criteria , but normal glucose tolerance ( NGT ) or impaired glucose tolerance ( IGT ) by the World Health Organization ( WHO ) criteria , and to test whether treatment changed the perinatal outcome in those with NGT and IGT . The 216 women with an abnormal 100 g oral glucose tolerance test ( OGTT ) using NDDG criteria were subjected to a 75 g OGTT . Using the WHO criteria , 111 women ( 51 % ) had NGT , 98 ( 45 % ) had IGT and 7 ( 3 % ) had frank diabetes mellitus . Those with NGT and IGT were r and omized into control and treatment groups . The perinatal outcome in these two groups was comparable whether the NGT and IGT groups were analysed together or separately except , that in those who were treated for IGT , smaller babies were born one week earlier than in the control group ( 3407 g vs 3110 g , P less than 0.01 ) . This suggests that the WHO criteria can safely replace the 100 g OGTT with substantial savings in manpower , money and patients ' time [1865537] Background Mild gestational diabetes is a common complication of pregnancy , affecting up to 9 % of pregnant women . Treatment of mild GDM is known to reduce adverse perinatal outcomes such as macrosomia and associated birth injuries , such as shoulder dystocia , bone fractures and nerve palsies . This study aim ed to compare the plasma glucose concentrations and serum insulin , leptin and adiponectin in cord blood of babies of women ( a ) without gestational diabetes mellitus ( GDM ) , ( b ) with mild GDM under routine care , or ( c ) mild GDM with treatment . Methods 95 women with mild GDM on oral glucose tolerance testing ( OGTT ) at one tertiary level maternity hospital who had been recruited to the ACHOIS trial at one of the collaborating hospitals and r and omised to either Treatment ( n = 46 ) or Routine Care ( n = 49 ) and Control women with a normal OGTT ( n = 133 ) were included in the study . Women with mild GDM ( treatment or routine care group ) and OGTT normal women received routine pregnancy care . In addition , women with treated mild GDM received dietary advice , blood glucose monitoring and insulin if necessary . The primary outcome measures were cord blood concentrations of glucose , insulin , adiponectin and leptin . Results Cord plasma glucose was higher in women receiving routine care compared with control , but was normalized by treatment for mild GDM ( p = 0.01 ) . Cord serum insulin and insulin to glucose ratio were similar between the three groups . Leptin concentration in cord serum was lower in GDM treated women compared with routine care ( p = 0.02 ) and not different to control ( p = 0.11 ) . Adiponectin was lower in both mild GDM groups compared with control ( Treatment p = 0.02 and Routine Care p = 0.07 ) , while the adiponectin to leptin ratio was lower for women receiving routine care compared with treatment ( p = 0.08 ) and control ( p = 0.05 ) . Conclusion Treatment of women with mild GDM using diet , blood glucose monitoring and insulin if necessary , influences the altered fetal adipoinsular axis characteristic of mild GDM in pregnancy [9240606] OBJECTIVES The purpose of this study was to determine whether strict maternal glycemic control for the treatment of gestational diabetes lessened the risk of fetal macrosomia , birth trauma , neonatal hypoglycemia , and operative delivery . The aim of the pilot study was to prepare for a multicenter trial by assessing patient acceptance of the study , by determining realistic accrual rates , and by detecting any major adverse outcomes in the control group that received routine obstetric care . STUDY DESIGN The study was a prospect i ve r and omized controlled trial comparing fetal-neonatal and maternal outcomes in 300 women with gestational diabetes . Women r and omized to the treatment arm were managed by strict glycemic control and tertiary level obstetric care , and women in the control arm received routine obstetric care . RESULTS Three hundred women with gestational diabetes mellitus were studied . There was no difference in maternal age , weight , or length of gestation between groups . The treatment mean birth weight was 3437 + /- 575 gm compared with 3544 + /- 601 gm in the control group , a difference of 107 gm ( not significant ) . Macrosomia rates were similar . There was no birth trauma in either group . The frequency of neonatal hypoglycemia and other metabolic complications was the same . The mode of delivery also showed similar patterns . The treatment group had significantly lower prepr and ial and postpr and ial glucose levels by 32 weeks ' gestation , which continued to term . CONCLUSION This pilot study suggests that intensive treatment of gestational diabetes mellitus may have little effect on birth weight , birth trauma , operative delivery , or neonatal metabolic disorders . It has demonstrated the safety of proceeding to a multicenter trial of sufficient sample size to confirm these findings [15951574] BACKGROUND We conducted a r and omized clinical trial to determine whether treatment of women with gestational diabetes mellitus reduced the risk of perinatal complications . METHODS We r and omly assigned women between 24 and 34 weeks ' gestation who had gestational diabetes to receive dietary advice , blood glucose monitoring , and insulin therapy as needed ( the intervention group ) or routine care . Primary outcomes included serious perinatal complications ( defined as death , shoulder dystocia , bone fracture , and nerve palsy ) , admission to the neonatal nursery , jaundice requiring phototherapy , induction of labor , cesarean birth , and maternal anxiety , depression , and health status . RESULTS The rate of serious perinatal complications was significantly lower among the infants of the 490 women in the intervention group than among the infants of the 510 women in the routine-care group ( 1 percent vs. 4 percent ; relative risk adjusted for maternal age , race or ethnic group , and parity , 0.33 ; 95 percent confidence interval , 0.14 to 0.75 ; P=0.01 ) . However , more infants of women in the intervention group were admitted to the neonatal nursery ( 71 percent vs. 61 percent ; adjusted relative risk , 1.13 ; 95 percent confidence interval , 1.03 to 1.23 ; P=0.01 ) . Women in the intervention group had a higher rate of induction of labor than the women in the routine-care group ( 39 percent vs. 29 percent ; adjusted relative risk , 1.36 ; 95 percent confidence interval , 1.15 to 1.62 ; P<0.001 ) , although the rates of cesarean delivery were similar ( 31 percent and 32 percent , respectively ; adjusted relative risk , 0.97 ; 95 percent confidence interval , 0.81 to 1.16 ; P=0.73 ) . At three months post partum , data on the women 's mood and quality of life , available for 573 women , revealed lower rates of depression and higher scores , consistent with improved health status , in the intervention group . CONCLUSIONS Treatment of gestational diabetes reduces serious perinatal morbidity and may also improve the woman 's health-related quality of life [2681032] OBJECTIVE A low – glycemic index diet is effective as a treatment for individuals with diabetes and has been shown to improve pregnancy outcomes when used from the first trimester . A low – glycemic index diet is commonly advised as treatment for women with gestational diabetes mellitus ( GDM ) . However , the efficacy of this advice and associated pregnancy outcomes have not been systematic ally examined . The purpose of this study was to determine whether prescribing a low – glycemic index diet for women with GDM could reduce the number of women requiring insulin without compromise of pregnancy outcomes . RESEARCH DESIGN AND METHODS All women with GDM seen over a 12-month period were considered for inclusion in the study . Women ( n = 63 ) were r and omly assigned to receive either a low – glycemic index diet or a conventional high-fiber ( and higher glycemic index ) diet . RESULTS Of the 31 women r and omly assigned to a low – glycemic index diet , 9 ( 29 % ) required insulin . Of the women r and omly assigned to a higher – glycemic index diet , a significantly higher proportion , 19 of 32 ( 59 % ) , met the criteria to commence insulin treatment ( P = 0.023 ) . However , 9 of these 19 women were able to avoid insulin use by changing to a low – glycemic index diet . Key obstetric and fetal outcomes were not significantly different . CONCLUSIONS Using a low – glycemic index diet for women with GDM effectively halved the number needing to use insulin , with no compromise of obstetric or fetal outcomes [24947793] OBJECTIVE The use of the new International Association of the Diabetes and Pregnancy Study Groups criteria ( IADPSGC ) for the diagnosis of gestational diabetes mellitus ( GDM ) results in an increased prevalence of GDM . Whether their introduction improves pregnancy outcomes has yet to be established . We sought to evaluate the cost-effectiveness of one-step IADPSGC for screening and diagnosis of GDM compared with traditional two-step Carpenter-Coustan ( CC ) criteria . RESEARCH DESIGN AND METHODS GDM risk factors and pregnancy and newborn outcomes were prospect ively assessed in 1,750 pregnant women from April 2011 to March 2012 using CC and in 1,526 pregnant women from April 2012 to March 2013 using IADPSGC between 24 and 28 weeks of gestation . Both groups received the same treatment and follow-up regimes . RESULTS The use of IADPSGC result ed in an important increase in GDM rate ( 35.5 % vs. 10.6 % ) and an improvement in pregnancy outcomes , with a decrease in the rate of gestational hypertension ( 4.1 to 3.5 % : −14.6 % , P < 0.021 ) , prematurity ( 6.4 to 5.7 % : −10.9 % , P < 0.039 ) , cesarean section ( 25.4 to 19.7 % : −23.9 % , P < 0.002 ) , small for gestational age ( 7.7 to 7.1 % : −6.5 % , P < 0.042 ) , large for gestational age ( 4.6 to 3.7 % : −20 % , P < 0.004 ) , Apgar 1-min score < 7 ( 3.8 to 3.5 % : −9 % , P < 0.015 ) , and admission to neonatal intensive care unit ( 8.2 to 6.2 % : −24.4 % , P < 0.001 ) . Estimated cost savings was of € 14,358.06 per 100 women evaluated using IADPSGC versus the group diagnosed using CC . CONCLUSIONS The application of the new IADPSGC was associated with a 3.5-fold increase in GDM prevalence in our study population , as well as significant improvements in pregnancy outcomes , and was cost-effective . Our results support their adoption [2241640] Background Recommended best practice is that economic evaluation of health care interventions should be integral with r and omised clinical trials . We performed a cost-consequence analysis of treating women with mild gestational diabetes mellitus by dietary advice , blood glucose monitoring and insulin therapy as needed compared with routine pregnancy care , using patient-level data from a multi-centre r and omised clinical trial . Methods Women with a singleton pregnancy who had mild gestational diabetes diagnosed by an oral glucose-tolerance test between 24 and 34 weeks ' gestation and their infants were included . Clinical outcomes and outpatient costs derived from all women and infants in the trial . Inpatient costs derived from women and infants attending the hospital contributing the largest number of enrolments ( 26.1 % ) , and charges to women and their families derived from a sub sample of participants from that hospital ( in 2002 Australian dollars ) . Occasions of service and health outcomes were adjusted for maternal age , ethnicity and parity . Analysis of variance was used with bootstrapping to confirm results . Primary clinical outcomes were serious perinatal complications ; admission to neonatal nursery ; jaundice requiring phototherapy ; induction of labour and caesarean delivery . Economic outcome measures were outpatient and inpatient costs , and charges to women and their families . Results For every 100 women with a singleton pregnancy and positive oral glucose tolerance test who were offered treatment for mild gestational diabetes mellitus in addition to routine obstetric care , $ 53,985 additional direct costs were incurred at the obstetric hospital , $ 6,521 additional charges were incurred by women and their families , 9.7 additional women experienced induction of labour , and 8.6 more babies were admitted to a neonatal nursery . However , 2.2 fewer babies experienced serious perinatal complication and 1.0 fewer babies experienced perinatal death . The incremental cost per additional serious perinatal complication prevented was $ 27,503 , per perinatal death prevented was $ 60,506 and per discounted life-year gained was $ 2,988 . Conclusion It is likely that the general public in high-income countries such as Australia would find reductions in perinatal mortality and in serious perinatal complications sufficient to justify additional health service and personal monetary charges . Over the whole lifespan , the incremental cost per extra life-year gained is highly favourable . Trial Registration Australian Clinical Trials Registry [3177748] OBJECTIVE In women with gestational diabetes mellitus , who were r and omized to metformin or insulin treatment , pregnancy outcomes were similar ( Metformin in Gestational diabetes [ MiG ] trial ) . Metformin crosses the placenta , so it is important to assess potential effects on growth of the children . RESEARCH DESIGN AND METHODS In Auckl and , New Zeal and , and Adelaide , Australia , women who had participated in the MiG trial were review ed when their children were 2 years old . Body composition was measured in 154 and 164 children whose mothers had been r and omized to metformin and insulin , respectively . Children were assessed with anthropometry , bioimpedance , and dual energy X-ray absorptiometry ( DEXA ) , using st and ard methods . RESULTS The children were similar for baseline maternal characteristics and pregnancy outcomes . In the metformin group , compared with the insulin group , children had larger mid-upper arm circumferences ( 17.2 ± 1.5 vs. 16.7 ± 1.5 cm ; P = 0.002 ) and subscapular ( 6.3 ± 1.9 vs. 6.0 ± 1.7 mm ; P = 0.02 ) and biceps skinfolds ( 6.03 ± 1.9 vs. 5.6 ± 1.7 mm ; P = 0.04 ) . Total fat mass and percentage body fat assessed by bioimpedance ( n = 221 ) and DEXA ( n = 114 ) were not different . CONCLUSIONS Children exposed to metformin had larger measures of subcutaneous fat , but overall body fat was the same as in children whose mothers were treated with insulin alone . Further follow-up is required to examine whether these findings persist into later life and whether children exposed to metformin will develop less visceral fat and be more insulin sensitive . If so , this would have significant implication s for the current p and emic of diabetes [2533645] Background The impact of borderline gestational diabetes mellitus ( BGDM ) , defined as a positive oral glucose challenge test ( OGCT ) and normal oral glucose tolerance test ( OGTT ) , on maternal and infant health is unclear . We assessed maternal and infant health outcomes in women with BGDM and compared these to women who had a normal OGCT screen for gestational diabetes . Methods We compared demographic , obstetric and neonatal outcomes between women participating in the Australian Collaborative Trial of Supplements with antioxidants Vitamin C and Vitamin E to pregnant women for the prevention of pre-eclampsia ( ACTS ) who had BGDM and who screened negative on OGCT . Results Women who had BGDM were older ( mean difference 1.3 years , [ 95 % confidence interval ( CI ) 0.3 , 2.2 ] , p = 0.01 ) and more likely to be obese ( 27.1 % vs 14.1 % , relative risk ( RR ) 1.92 , [ 95 % CI 1.41 , 2.62 ] , p < 0.0001 ) than women who screened negative on OGCT . The risk of adverse maternal outcome overall was higher ( 12.9 % vs 8.1 % , RR 1.59 , [ 95 % CI 1.00 , 2.52 ] , p = 0.05 ) in women with BGDM compared with women with a normal OGCT . Women with BGDM were more likely to develop pregnancy induced hypertension ( 17.9 % vs 11.8 % , RR 1.51 , [ 95 % CI 1.03 , 2.20 ] , p = 0.03 ) , have a caesarean for fetal distress ( 17.1 % vs 10.5 % , RR 1.63 , [ 95 % CI 1.10 , 2.41 ] , p = 0.01 ) , and require a longer postnatal hospital stay ( mean difference 0.4 day , [ 95 % CI 0.1 , 0.7 ] , p = 0.01 ) than those with a normal glucose tolerance . Infants born to BGDM mothers were more likely to be born preterm ( 10.7 % vs 6.4 % , RR 1.68 , [ 95 % CI 1.00 , 2.80 ] , p = 0.05 ) , have macrosomia ( birthweight ≥4.5 kg ) ( 4.3 % vs 1.7 % , RR 2.53 , [ 95 % CI 1.06 , 6.03 ] , p = 0.04 ) , be admitted to the neonatal intensive care unit ( NICU ) ( 6.5 % vs 3.0 % , RR 2.18 , [ 95 % CI 1.09 , 4.36 ] , p = 0.03 ) or the neonatal nursery ( 40.3 % vs 28.4 % , RR 1.42 , [ 95 % CI 1.14 , 1.76 ] , p = 0.002 ) , and have a longer hospital stay ( p = 0.001 ) . More infants in the BGDM group had Sarnat stage 2 or 3 neonatal encephalopathy ( 12.9 % vs 7.8 % , RR 1.65 , [ 95 % CI 1.04 , 2.63 ] , p = 0.03 ) . Conclusion Women with BGDM and their infants had an increased risk of adverse health outcomes compared with women with a negative OGCT . Intervention strategies to reduce the risks for these women and their infants need evaluation . Trial registration Current Controlled Trials IS RCT [3907028] Background Women who are diagnosed with gestational diabetes mellitus ( GDM ) are at increased risk for developing prediabetes and type 2 diabetes mellitus ( T2DM ) . To date , there have been few interdisciplinary interventions that target predominantly ethnic minority low-income women diagnosed with GDM . This paper describes the rationale , design and methodology of a 2-year , r and omized , controlled study being conducted in North Carolina . Methods / Design Using a two-group , repeated measures , experimental design , we will test a 14- week intensive intervention on the benefits of breastfeeding , underst and ing gestational diabetes and risk of progression to prediabetes and T2DM , nutrition and exercise education , coping skills training , physical activity ( Phase I ) , educational and motivational text messaging and 3 months of continued monthly contact ( Phase II ) . A total of 100 African American , non-Hispanic white , and bilingual Hispanic women between 22–36 weeks of pregnancy who are diagnosed with GDM and their infants will be r and omized to either the experimental group or the wait-listed control group . The first aim of the study is to determine the feasibility of the intervention . The second aim of study is to test the effects of the intervention on maternal outcomes from baseline ( 22–36 weeks pregnant ) to 10 months postpartum . Primary maternal outcomes will include fasting blood glucose and weight ( BMI ) from baseline to 10 months postpartum . Secondary maternal outcomes will include clinical , adiposity , health behaviors and self-efficacy outcomes from baseline to 10 months postpartum . The third aim of the study is to quantify the effects of the intervention on infant feeding and growth . Infant outcomes will include weight status and breastfeeding from birth through 10 months of age . Data analysis will include general linear mixed-effects models . Safety endpoints include adverse event reporting . Discussion Findings from this trial may lead to an effective intervention to assist women diagnosed with GDM to improve maternal glucose homeostasis and weight as well as stabilize infant growth trajectory , reducing the burden of metabolic disease across two generations . Trial registration [2858199] OBJECTIVE Gestational diabetes mellitus ( GDM ) may cause obesity in the offspring . The objective was to assess the effect of treatment for mild GDM on the BMI of 4- to 5-year-old children . RESEARCH DESIGN AND METHODS Participants were 199 mothers who participated in a r and omized controlled trial of the treatment of mild GDM during pregnancy and their children . Trained nurses measured the height and weight of the children at preschool visits in a state-wide surveillance program in the state of South Australia . The main outcome measure was age- and sex-specific BMI Z score based on st and ards of the International Obesity Task Force . RESULTS At birth , prevalence of macrosomia ( birth weight ≥4,000 g ) was 5.3 % among the 94 children whose mothers were in the intervention group , and 21.9 % among the 105 children in the routine care control group . At 4- to 5-years-old , mean ( SD ) BMI Z score was 0.49 ( 1.20 ) in intervention children and 0.41 ( 1.40 ) among controls . The difference between treatment groups was 0.08 ( 95 % CI −0.29 to 0.44 ) , an estimate minimally changed by adjustment for maternal race , parity , age , and socio-economic index ( 0.08 [ −0.29 to 0.45 ] ) . Evaluating BMI ≥85th percentile rather than continuous BMI Z score gave similarly null results . CONCLUSIONS Although treatment of GDM substantially reduced macrosomia at birth , it did not result in a change in BMI at age 4- to 5-years-old [2764059] We studied the impact of a training program on glucose tolerance in gestational diabetes mellitus . Women with gestational diabetes mellitus ( N = 19 ) were r and omized into either group I , a 6-week diet alone group ( 24 to 30 kcal/kg/24 hours ; 20 % protein , 40 % carbohydrate , 40 % fat ) , or group II , which followed the same diet plus exercise ( 20 minutes three times a week for 6 weeks ) . An arm ergometer was used to maintain heart rate in the training range . Glycemic response was monitored by glycosylated hemoglobin , a 50 gm oral glucose challenge with a fasting and 1-hour plasma glucose , and blood glucose self-monitoring , fasting and 1 hour after meals . Week 1 glycemic parameters were the same for both groups . Week 6 data ( mean + /- SD ) were as follows : group I glycosylated hemoglobin , 4.7 % + 0.2 % versus group II , 4.2 % + /- 0.2 % ; p less than 0.001 . The group I glucose challenge fasting value was 87.6 + /- 6.2 versus 70.1 + /- 6.6 mg/dl , p less than 0.001 for group II . The group I 1-hour plasma glucose challenge result was 187.5 + /- 12.9 mg/dl versus 105.9 + /- 18.9 mg/dl for group II , p less than 0.001 . The glycemic levels diverged between the groups at week 4 . We conclude that arm ergometer training is feasible in women with gestational diabetes mellitus and results in lower glycosylated hemoglobin , fasting , and 1-hour plasma glucose concentrations than diet alone . Arm ergometer training may provide a useful treatment option for women with gestational diabetes mellitus and may obviate insulin treatment [25848127] Women with diabetes often experience a higher level of anxiety . The aim of the study was to evaluate the effect of acupressure on relieving anxiety of women with gestational diabetes mellitus ( GDM ) . A r and omized clinical trial was conducted on 60 women with GDM at a university hospital . The participants were allocated to an experimental and a placebo group ( 30 women per group ) . The experimental group received a nurse-provided acupressure at the true point , and the placebo group received pressure ( touching ) at a sham ( false ) point . Anxiety was measured immediately in the groups prior to and after a 2-day intervention by a question naire and the Visual Analogue Scale . The data were analyzed using descriptive and inferential statistics . Results indicated that the acupressure group had significantly lower anxiety than the placebo group ( p ≤ .0001 ) . In conclusion , the effects of acupressure appeared to be effective in reducing anxiety in diabetic pregnant women [20542272] OBJECTIVE To assess blood glucose control and neonatal outcomes when women with gestational diabetes mellitus ( GDM ) were treated with metformin or glyburide . METHODS When an appropriate diet was insufficient to control their blood glucose levels , women with GDM were r and omized to a glyburide or a metformin treatment group . If the maximum dose was reached , the assessed drug was replaced by insulin . The primary outcome measures analyzed were maternal glucose levels during pregnancy , birth weight , and neonatal glucose levels . RESULTS The only significant difference in outcome between the 2 treatment drugs was that maternal weight gain during pregnancy was less in the metformin ( n=40 ) than in the glyburide group ( n=32 ) ( 10.3 kg vs 7.6 kg ; P=0.02 ) . No differences were found in treatment failure , mean level of fasting or postpr and ial plasma glucose , rate of participants with glycated hemoglobin , birth weight , rate of large-for-gestational-age newborns , or newborns with hypoglycemia . CONCLUSION The treatment of GDM with metformin or glyburide was found to be equivalent for both women and newborns [11333990] BACKGROUND Type 2 diabetes mellitus is increasingly common , primarily because of increases in the prevalence of a sedentary lifestyle and obesity . Whether type 2 diabetes can be prevented by interventions that affect the lifestyles of subjects at high risk for the disease is not known . METHODS We r and omly assigned 522 middle-aged , overweight subjects ( 172 men and 350 women ; mean age , 55 years ; mean body-mass index [ weight in kilograms divided by the square of the height in meters ] , 31 ) with impaired glucose tolerance to either the intervention group or the control group . Each subject in the intervention group received individualized counseling aim ed at reducing weight , total intake of fat , and intake of saturated fat and increasing intake of fiber and physical activity . An oral glucose-tolerance test was performed annually ; the diagnosis of diabetes was confirmed by a second test . The mean duration of follow-up was 3.2 years . RESULTS The mean ( + /-SD ) amount of weight lost between base line and the end of year 1 was 4.2+/-5.1 kg in the intervention group and 0.8+/-3.7 kg in the control group ; the net loss by the end of year 2 was 3.5+/-5.5 kg in the intervention group and 0.8+/-4.4 kg in the control group ( P<0.001 for both comparisons between the groups ) . The cumulative incidence of diabetes after four years was 11 percent ( 95 percent confidence interval , 6 to 15 percent ) in the intervention group and 23 percent ( 95 percent confidence interval , 17 to 29 percent ) in the control group . During the trial , the risk of diabetes was reduced by 58 percent ( P<0.001 ) in the intervention group . The reduction in the incidence of diabetes was directly associated with changes in lifestyle . CONCLUSIONS Type 2 diabetes can be prevented by changes in the lifestyles of high-risk subjects [10774766] The goal of this study was to determine whether the type of fat plays a role in the glucose response to a meal , independent of the carbohydrate content . Ten gestational diabetic women ( gestational weeks 29 - 34 ) who were well controlled on diet alone were r and omized as to the order in which they would eat a meal , after overnight fast , containing saturated fat ( SF ) or monounsaturated fat ( MUFA ) . Blood was drawn at 0 , 60 , 120 , and 180 min for plasma glucose , insulin , lipid profile ( triglycerides , total cholesterol , HDL-cholesterol , LDL-cholesterol , VLDL-cholesterol ) and free fatty acids . After 2 weeks , each patient received the other type of meal . The test meal was composed of 20 % of the total daily caloric needs based on ideal body weight . The area under the curve showed a significantly lower glucose concentration for SF meal ( p = 0.001 ) . Serum insulin concentrations followed the glucose response with the peak at the 60-min time point and a significantly lower concentration at the 180-min time point in the SF than in the MUFA group . The present study demonstrated that the addition of SF to the meal result ed in lower postpr and ial glucose and insulin than when the meal contained MUFA . Thus , SF may be useful in controlling postpr and ial glucose [2675597] In this study we sought to test the hypothesis that treatment of women with one abnormal oral glucose tolerance test value will result in reduction of adverse outcome . One hundred twenty-six women with one abnormal oral glucose tolerance test value and 146 women in the control group ( normal oral glucose tolerance test values ) participated in a prospect i ve study during the third trimester of pregnancy . The subjects with one abnormal test result were r and omized into treated ( group 1 ) and untreated groups ( group II ) . Group 1 subjects were treated with a strict diabetic protocol to maintain tight glycemic control by means of diet and insulin therapy . Group 2 subjects tested their capillary blood glucose for a baseline period . The study revealed that the level of glycemic control was similar before initiation of therapy ( mean capillary blood glucose 118 + /- 14 vs. 119 + /- 15 mg/dl , p = NS ) for groups 1 and 2 , respectively . There was a significant difference in mean capillary blood glucose ( 95 + /- 10 vs. 119 + /- 15 mg/dl , p less than 0.0001 ) , prepr and ial , and postpr and ial determinations between the treated and untreated groups . The overall incidence of neonatal metabolic complications ( 4 % vs. 14 % , p less than 0.05 ) and large infants ( 6 % vs. 24 % , p less than 0.03 ) was significantly lower in the treated group . Comparison between the control ( normal oral glucose tolerance test ) and the untreated groups showed a significantly higher incidence of large infants and metabolic complications . No difference was found between the normal and treated groups . Thus we conclude that treatment of individuals with one abnormal oral glucose tolerance test value will result in significant reduction in adverse outcome in pregnancy [22542118] OBJECTIVE We evaluated whether improvements in pregnancy outcomes after treatment of mild gestational diabetes mellitus differed in magnitude on the basis of fetal gender . STUDY DESIGN This is a secondary analysis of a masked r and omized controlled trial of treatment for mild gestational diabetes mellitus . The results included preeclampsia or gestational hypertension , birthweight , neonatal fat mass , and composite adverse outcomes for both neonate ( preterm birth , small for gestational age , or neonatal intensive care unit admission ) and mother ( labor induction , cesarean delivery , preeclampsia , or gestational hypertension ) . After stratification according to fetal gender , the interaction of gender with treatment status was estimated for these outcomes . RESULTS Of the 469 pregnancies with male fetuses , 244 pregnancies were assigned r and omly to treatment , and 225 pregnancies were assigned r and omly to routine care . Of the 463 pregnancies with female fetuses , 233 pregnancies were assigned r and omly to treatment , and 230 pregnancies were assigned r and omly to routine care . The interaction of gender with treatment status was significant for fat mass ( P = .04 ) and birthweight percentile ( P = .02 ) . Among women who were assigned to the treatment group , male offspring were significantly more likely to have both a lower birthweight percentile ( 50.7 ± 29.2 vs 62.5 ± 30.2 percentile ; P < .0001 ) and less neonatal fat mass ( 487 ± 229.6 g vs 416.6 ± 172.8 g ; P = .0005 , ) whereas these differences were not significant among female offspring . There was no interaction between fetal gender and treatment group with regard to other outcomes . CONCLUSION The magnitude of the reduction of a newborn 's birthweight percentile and neonatal fat mass that were related to the treatment of mild gestational diabetes mellitus appears greater for male neonates [9170478] Objective To assess the usefulness of a breakfast test in determining which women with gestational diabetes do not need self-monitoring of blood glucose levels ( home monitoring ) . Methods a 1-hour post-st and ardized breakfast blood glucose below 7.8 mmol/L ( 140 mg/dL ) was measured in 227 women and at or above 7.8 mmol/L in 115 . Within each group , women were r and omized to home monitoring with a meter or to clinic follow-up . Target glucose values were 5.3 mmol/L ( 95 mg/dL ) fasting , 5.6 mmol/L ( 101 mg/dL ) before meals , and 7.8 mmol/L ( 140 mg/dL ) 1 hour postpr and ial . Up to these thresholds women on clinic follow-up were transferred to home monitoring . Insulin therapy was started on the same thresholds in women r and omized or transferred to home monitoring . Large ofr gestational age ( LGA ) newborns represented the main outcome , with the transfer rate to home monitoring and need of insulin therapy the secondary ones . Results The LGA delivery rate was not significantly different in the two follow-up groups in women with a breakfast result below 7.8 mmol/L ( 9.8 versus 4.3 % ) but was higher in the clinic follow-up among women with a breakfast result at or above 7.8 mmol/L ( 13.3 % versus 30.9 % ; P < .05 ) . Fewer women with a breakfast result below 7.8 mmol/L were transferred to home monitoring ( 2.6 versus 52.7 % ; P < .001 ) or started on insulin therapy ( 3.6 versus 25.2 % ; P < .001 ) . The breakfast test cutoff of 7.8 mmol/L predicted insulin need with a sensitivity of 91.0 % and a specificity of 72.0 % . Conclusion A breakfast test is useful in identifying a low-risk population in which clinic follow-up may be used safely [6993163] A 16-yr prospect i ve study of 615 gestational diabetic subjects , half of whom were r and omly assigned to insulin therapy during pregnancy , is evaluated to report on the potential reduction in subsequent diabetes due to insulin therapy . No such difference in incidence rates was observed between the two groups . In the subsets of women managed with insulin who bore a baby of large birthweight or who had a family history of diabetes , subsequent decompensated diabetes was found to be significantly reduced . Both life table and multivariate analyses to adjust for the effects of age , weight , level of blood glucose at selection , duration of follow-up , and other potentially confounding covariables confirmed this conclusion . The finding suggests the possibility of long-term preventive benefits from insulin treatment in high risk subsets of women with gestational diabetes [18211656] RATIONALE , AIMS AND OBJECTIVE To investigate whether the introduction of a programme of optimising drug treatment , intensive education and self-monitoring of patients diagnosed with gestational diabetes mellitus ( GDM ) at an early stage ( < 20 gestational weeks ) , will improve management outcomes as determined by objective measures of patient knowledge about diabetes , glycaemia control , maternal/neonatal complications , and health-related quality of life . METHODS The study was a r and omized , controlled , longitudinal , prospect i ve clinical trial performed at Al-Ain Hospital , Al-Ain , United Arab Emirates . Over an 18-month period , patients diagnosed with GDM were recruited and were r and omly assigned to either an intervention or a control group , in a ratio of 3:2 . Intervention patients received a structured pharmaceutical care service ( including education and introduction of intensive self-monitoring ) while control patients received traditional services . Patients were followed up from time of recruitment until 6 months postnatally at scheduled outpatient clinics . A range of clinical and humanistic outcome measures , including maternal and neonatal complications , were used to assess the impact of the intervention . RESULTS A total of 165 patients ( 99 intervention , 66 control ) completed the study . The intervention patients exhibited a range of benefits from the provision of the programme when compared with control group patients . Statistically significant ( P < 0.05 ) improvements were shown in the intervention group for knowledge of diabetes , health-related quality of life ( as determined by the SF36 ) , control of plasma glucose and HbA(1c ) , maternal complications [ e.g. decreased incidence of pre-eclampsia ( 5.1 % vs. 16.7 % ) , eclampsia ( 1.0 % vs. 7.6 % ) , episodes of severe hyperglycaemia ( 3.0 % vs. 19.7 % ) and need for Caesarean section ( 7.1 % vs. 18.2 % ) ] , and neonatal complications [ e.g. decreased incidence of neonatal hypoglycaemia ( 2.0 % vs. 10.6 % ) , respiratory distress at birth ( 4.0 % vs. 15.2 % ) , hyperbilirubinaemia ( 1.0 % vs. 12.1 % ) and large for gestational age ( 9.0 % vs. 22.7 % ) ] . CONCLUSION The research provides clear evidence that provision of pharmaceutical care adds value to the management of GDM as exemplified by improved maternal and neonatal outcomes [10955425] Objective To determine whether a study of a less intensive form of management for impaired glucose tolerance in pregnancy is feasible and whether women would accept r and omisation [15565082] Abstract Women with gestational diabetes mellitus ( GDM ) have a greater risk of developing type 2 diabetes mellitus ( DM ) and heart disease than pregnant women without GDM . Advice given during the GDM pregnancy provides an opportunity to develop protective dietary patterns for the long-term management of this risk . Dietary guidelines for the prevention and management of type 2 DM support the inclusion of unsaturated fats , but food advice needs to target this outcome . The aim of this study was to compare the dietary intakes of women with GDM given general low-fat advice ( control group ) to women with GDM given the same advice with additional targets for food sources of unsaturated fats ( intervention group ) . After approximately 6 weeks , the intervention group reported more ideal dietary fatty acid intakes than the control group , with polyunsaturated : saturated fat ratios of 1:1 and 0.4:1 , respectively ( P < .001 ) , assessed using repeated measures analysis of variance . These results confirm the need to include food sources of unsaturated fats in advice strategies to assure optimal protective eating habits in this at-risk group [21094553] AIM The objectives of this pilot study were to determine the feasibility and effect on glycaemic control of a low-glycaemic-index ( GI ) diet in women with gestational diabetes or impaired glucose tolerance of pregnancy . METHODS participants , recruited from the Diabetes-in-Pregnancy Clinic of an inner-city teaching hospital serving a predominantly non-Caucasian population , were r and omized to a low-GI ( n=23 ) or control ( n=24 ) diet and followed from 28 weeks gestation until delivery . Self-monitored-blood-glucose ( SMBG ) , maternal and infant weight were collected from medical charts . Dietary intakes were assessed using diet records and question naires . RESULTS diet GI on control ( 58 , 95 % CI : 56,60 ) was significantly higher than on low-GI ( 49 , 95 % CI : 47,51 ; p=0.001 ) . Glycaemic control improved on both diets , but more postpr and ial glucose values were within target on low-GI ( 58.4 % of n=1891 ) than control ( 48.7 % of n=1834 ; p<0.001 ) . SMBG post-breakfast was directly related to pre-pregnancy BMI in the control , but not the low-GI group ( BMI * diet interaction ; p=0.021 ) . Participants accepted the study foods and were willing to consume them post-intervention . CONCLUSIONS a low-GI diet was feasible and acceptable in this sample and facilitated control of postpr and ial glucose . A larger study is needed to determine the effect of a low-GI diet on maternal and infant outcomes [16963348] Nutrition practice guidelines were developed for gestational diabetes mellitus by registered dietitians from the Diabetes Care and Education and the Women 's Health and Reproductive Nutrition dietetic practice groups . To vali date the guidelines , a clinical trial was design ed with clinic sites r and omly assigned to either nutrition practice guidelines care ( 12 sites ) or usual nutrition care ( 13 sites ) , with diabetes , obstetric , and other clinic types represented in both groups . Volunteer dietitians served as study coordinators and recruited women diagnosed with gestational diabetes mellitus . The nutrition practice guidelines define medical nutrition therapy ( MNT ) for gestational diabetes and emphasize three areas -definition of MNT clinical goals with indexes to modify or advance MNT and criteria to start insulin ; use of self-monitoring tools ; and provision of three nutrition visits . Usual care sites provided prenatal nutrition care according to usual practice . The effect of nutrition care ( sites following the nutrition care guidelines ) and type of clinic site on changes in glycated hemoglobin and infant birth weight , adjusted for other covariates , were evaluated using linear regression . Differences in insulin use and other infant outcomes between treatment groups were evaluated using logistic regression . Generalized estimating equations were used to accommo date nonindependence within r and omized clusters of patients within clinic sites . Data from 215 women indicated less insulin use at diabetes clinic sites in the nutrition practice guidelines groups and improved glycated hemoglobin control during the treatment period in diabetes clinics compared with obstetric or other clinics . A higher proportion of women in the usual care group had glycated hemoglobin levels that exceeded 6 % at follow-up compared with women in the nutrition practice guidelines group ( 13.6 % vs 8.1 % ) , although not statistically significant ( P=0.26 ) . A significant clinic type and treatment group effect was found for birth weight . Nutrition practice guidelines for gestational diabetes mellitus reflected nutrition care already being provided by registered dietitians in diabetes clinics prior to this study because outcomes at these clinics were not impacted . Use of the guidelines by dietitians at obstetric and other clinics tended to improve outcomes at these sites [25753159] Purpose To create a positive step toward achieving an efficient method for gestational diabetes treatment , the present study was carried out to compare the treatment outcomes based on single impaired blood glucose versus regular method in health care centers in Iran . Methods This r and omized clinical trial was carried out in Tehran/Iran between March 2012 and August 2013 . Study sample consisted of mothers whose fasting blood sugar was disturbed or a disturbed blood sugar was seen in OGTT with 75 g glucose load , according to ADA st and ards . For each outcome , multiple logistic regressions were used to control for the effects of potential confounders . When a confounder was measured on a continuous scale ( e.g. , age ) , LOWESS ( locally weighted scatter plot smoothing ) algorithm was used to determine whether the effect of that variable was linear . We also used the fractional polynomial regression to determine the optimal transformation of continuous covariates . Results The information of 189 pregnant women was used in this study ; 87 in the interventional group ( 46 % ) and 102 in the control group ( 54 % ) . Treatment based on the new protocol has very high protective effect ( OR 0.25 , 95 % CI 0.68–0.88 ) in terms of neonatal hyperbilirubinemia . This difference was not seen in other outcomes including stillbirth , macrosomic newborn delivery , hypoglycemia , and hypocalcemia . The risk of neonatal hypoglycemia reduced after the 25th week of gestation ( OR 0.39 , 95 % CI 0.15–0.98 ) . Conclusions Although the treatment of mild gestational diabetes could not significantly decrease severe neonatal outcomes , it did significantly reduce the risk of hyperbilirubinemia and its subsequent complications [26222270] A r and omized multicenter study was conducted in the Stockholm‐Örebro areas in Sweden to evaluate how treatment aim ing at normoglycemia affects fetal growth , pregnancy and neonatal outcome in pregnant women with severe hyperglycemia [24607755] OBJECTIVE The purpose of this study was to evaluate the relationship between gestational age ( GA ) and induction of labor ( IOL ) and the rate of cesarean delivery in women with mild gestational diabetes mellitus . STUDY DESIGN We conducted a secondary analysis of data from a multicenter r and omized controlled trial of mild gestational diabetes mellitus treatment . Cesarean delivery rate of women delivering at term ( ≥37 weeks ' gestation ) was evaluated by 2 complementary approaches : ( 1 ) IOL vs spontaneous labor : women who were induced at each GA compared with those who spontaneously labored at the same GA and ( 2 ) IOL vs expectant management : women who delivered after IOL at each GA compared with those who delivered after spontaneous labor at the same GA or subsequently after spontaneous or induced labor ( outcome at each week compared with expectant management at that week ) . Logistic regression adjusted for potential confounders . RESULTS The overall cesarean delivery rate was 13 % . When compared with 39 weeks ' gestation ( either IOL or spontaneous labor ) as the referent , there was no significant difference in the cesarean delivery rate in women who delivered at 37 , 38 , or 40 weeks ' gestation . However , IOL was associated with a 3-fold increase in cesarean delivery rate at 41 weeks ' gestation and beyond , as compared with IOL at 39 weeks ' gestation . Similarly , there was a 3-fold increase in the cesarean delivery rate in women who were induced when compared with those who were treated expectantly at 40 completed weeks ' gestation . CONCLUSION Induction of labor in women with mild gestational diabetes mellitus does not increase the rate of cesarean delivery at < 40 weeks ' gestation [5936737] The purpose of this study was to examine pregnancy outcome in women with abnormal oral glucose tolerance tests , in relation to treatment with diet and insulin . Glucose tolerance tests , done because of well-known historical risk factors , were considered abnormal if two or more readings exceeded the following : fasting , 110 ; 1 hour , 170 ; 2 hours , 120 ; and 3 hours , 110 ( all in mg/100 mL , measured as total reducing substances in whole venous blood ) . Those with positive tests were divided r and omly into a “ positive-control ” group ( n 308 ) that received st and ard prenatal care or a “ positive-treated ” group ( n 307 ) that received dietary instructions ( 30 kcal/kg ideal body weight , 40 % as carbohydrate , and 1.5–2 g protein/kg body weight ) and insulin ( initial dose 10 U per day of intermediate-acting insulin , adjusted subsequently as directed by blood and urine studies ) , beginning at usually about 32 weeks . A third group ( n 328 ) , termed “ negative controls , ” had exhibited normal glucose tolerance testing . The three groups were similar , except that those with abnormal glucose tolerance tended to be older and heavier , as expected . With respect to outcome , infants with birth weights exceeding 9 lb were three times as frequent in positive-control subjects as in either positive-treated subjects or negative controls ( 13.1 % , 4.3 % , and 3.7 % , respectively ) . Perinatal deaths ( 28 weeks ’ gestation through 14 days after birth ) were similar in the two positive groups ( 4.9 % in control and 4.3 % in treated ) and significantly higher than in negative controls ( 1.9 % ) , with the increase involving both fetal and neonatal components . The conclusions were 1 ) abnormal glucose tolerance during pregnancy leads to larger infants and higher perinatal mortality and 2 ) treatment with diet and insulin ameliorates the former but not the latter . This study concerned what O’Sullivan called potential diabetes and others at the time termed latent or chemical diabetes or prediabetes , but what today we refer to as gestational diabetes . Acceptance of it as a pathologic entity was far from unanimous in 1966 . O’Sullivan resolved the controversy with this large , well- design ed , and well-analyzed clinical trial . The immediate influence was two-fold . In the first place , it settled the existing disagreement as to whether or not impaired glucose tolerance adversely influences pregnancy outcome ; large infants occurred three times as frequently and perinatal deaths were more than doubled in women with abnormal carbohydrate metabolism . Second , the findings of the intervention trial indicated clearly that treatment of gestational diabetes with diet and insulin in late gestation normalizes birth weight ( although it did not seem to influence perinatal mortality ) , a finding confirmed a number of times by subsequent investigators . Incidentally , the frequencies of both fetal and neonatal deaths may seem high , but it needs to be remembered that this experience ante date d the advent of modern fetal surveillance and neonatal intensive care . John B. O’Sullivan , a pioneer in clinical research in gestational diabetes , was an internist . He defined st and ards for the oral glucose tolerance test in pregnancy that , though modified slightly by subsequent investigators , are basically those in use today . Born in 1926 , he received his medical education in his native Irel and before immigrating to the United States in 1955 . After further training in internal medicine at the Lahey Clinic , he took a faculty position at the Boston University School of Medicine , where he did his original work on early diabetes as medical director of the Prenatal Metabolism Clinic at Boston City Hospital and chief of medicine at St. Margaret ’s Hospital . In addition to his position as Associate Professor at Boston University , he also served on the faculties of the Harvard and Yale medical schools . Later he was director of employee health for the Liberty Mutual Insurance Company . He died of cancer in August 2001 [9315766] CONTEXT Gestational diabetes mellitus ( GDM ) affects 3 % to 5 % of pregnancies . Knowledge of risk factors for GDM is needed to identify possible preventive strategies . OBJECTIVE To assess whether recognized determinants of noninsulin-dependent diabetes mellitus also may be markers for increased risk of GDM . DESIGN Prospect i ve cohort study . SETTING The Nurses ' Health Study II , which involves female US nurses aged 25 to 42 years at entry . PARTICIPANTS The analyses included 14613 women without previous GDM or other known diabetes who reported a singleton pregnancy between 1990 and 1994 . Of these women , 722 ( 4.9 % ) reported a new diagnosis of GDM . MAIN OUTCOME MEASURE Self-report of GDM , vali date d by medical record review in a subset . RESULTS In multivariate analyses including age , pregravid body mass index ( BMI ) , and other GDM risk factors , the risk for GDM increased significantly with increasing maternal age ( P for trend , < .01 ) and family history of diabetes mellitus ( relative risk , 1.68 ; 95 % confidence interval [ CI ] , 1.39 - 2.04 ) . Relative risks for GDM were 2.13 ( 95 % CI , 1.65 - 2.74 ) for pregravid BMI of 25 to 29.9 kg/m2 and 2.90 ( 95 % CI , 2.15 - 3.91 ) for BMI of 30 kg/m2 or more ( vs BMI of < 20 kg/m2 ) . Risk for GDM increased with greater weight gain in early adulthood , and it also increased among nonwhite women . Pregravid current smokers had a relative risk for GDM of 1.43 ( 95 % CI , 1.14 - 1.80 ) , and pregravid vigorous exercise was associated with a nonsignificant reduction in GDM risk . CONCLUSIONS Advanced maternal age , family history of diabetes mellitus , nonwhite ethnicity , higher BMI , weight gain in early adulthood , and cigarette smoking predict increased GDM risk . These observations may facilitate the identification of women at particular risk for GDM and suggest potential strategies for reducing this risk even before a woman becomes pregnant , such as avoiding substantial weight gain and smoking [4829275] The outcome of pregnancy in control and treated gestational diabetics was not significantly different . The decreased loss rate among the insulin- and diet-treated gestational diabetics , however , did become significant when the data were reanalyzed with consideration of two important influencing variables . The high-risk group of gestational diabetics aged 25 years and older who received insulin therapy before the 32nd week of gestation had fewer fetal losses . Documentation of the critical role played by both maternal age and the gestational age at which insulin therapy is commenced now makes the institution of a conclusive prospect i ve study feasible . The adequately established hypothesis that insulin management of gestational diabetics favorably affects the outcome of their pregnancies can then be finally resolved [10586979] Infant macrosomia is a serious medical concern . Pregnant women who do not meet the specific diagnosis for gestational diabetes may still have glucose-mediated macrosomia . In Santa Barbara County all pregnant women are screened for gestational diabetes at 24 - 28 weeks with a 50-g , 1-hr glucose challenge test ( GCT ) . All patients who fail this test are placed on a st and ard euglycemic diet ( 40 % carbohydrate , 20 % protein , 40 % fat ) and perform home glucose monitoring of fasting and postpr and ial glucose levels . The objective of this study was to examine the effectiveness of this treatment program in decreasing infant macrosomia , maternal and infant morbidity , maternal complications , and operative delivery . We studied 103 women who had a positive GCT , but a negative 100-g , 3-hr oral glucose tolerance test ( OGTT ) . The women were r and omly assigned to either experimental or control groups with experimental women receiving dietary counseling and home glucose monitoring instruction ( HBGM ) . HBGM diaries were review ed weekly by clinic nurses . All women had hemoglobin A1c ( HbA1c ) tests at 28 and 32 weeks . Maternal and fetal charts were review ed to determine delivery type and complications , indications for cesarean section ( C-section ) , and infant gestational age , gender , Apgar scores , birth weight , morbidities , and congenital anomalies . Of the 103 women , 5 women required insulin treatment , 1 woman had an abortion , and 14 women were indeterminate regarding compliance or were control women who received diet counseling and HBGM . The results are based on 83 women--48 control and 35 experimental . There were no significant differences between the groups for age , parity , or weight at 28 - 30 weeks or 37 weeks to delivery , or HbA1c at 28 weeks . HbA1c was significantly higher in control women at 32 weeks . Birth weight expressed in grams or as a percentile specific for gender , ethnicity , and gestational age was significantly higher in control infants . Birth weight was significantly correlated with maternal intake weight , weight at 28 - 30 weeks , and weight at delivery and with HbA1c at 32 weeks ' gestation . There were no significant differences between groups for maternal complications . Groups were significantly different for mode of delivery with experimental women having more induced vaginal deliveries but fewer repeat C-sections than control women . Groups were not different for primary C-sections . Women who fail the GCT , but not the OGTT and thus do not receive the diagnosis of GDM are still at risk for delivering a macrosomic infant and operative delivery . Our program of treatment for all women who fail the GCT improves outcome by reducing infant birth weight and the number of cesarean sections [25014091] This practice guideline on gestational diabetes is a treatment oriented short version of the evidence based guideline that can be viewed in the internet . It replaces the DDG and DGGG recommendations of 2001 for diagnostic and therapy of gestational diabetes . A complete rework had become necessary in view of epidemiologically based diagnostic criteria , which had been derived from the Hyperglycaemia and Adverse Pregnancy Outcome study ( HAPO ) by international consensus , and in view of r and omised therapy and observation studies published after 2001 . With this , Germany has adopted the international st and ard . Screening and diagnosing gestational diabetes by means of blood glucose are part of the legally binding maternity guidelines in Germany since March 3 , 2012 [4336499] Background : There are no r and omised controlled trials to demonstrate whether lifestyle modifications can improve pregnancy outcomes of gestational diabetes mellitus ( GDM ) diagnosed by the International Association of Diabetes and Pregnancy Study Group ’s ( IADPSG ) criteria . We tested the effectiveness of lifestyle modifications implemented in a 3-tier ’s shared care ( SC ) on pregnancy outcomes of GDM . Methods : Between December 2010 and October 2012 , we r and omly assigned 700 women with IADPSG-defined GDM but without diabetes at 26.3 ( interquartile range : 25.4 - 27.3 ) gestational weeks in Tianjin , China , to receive SC or usual care ( UC ) . The SC group received individual consultations and group sessions and performed regular self-monitoring of blood glucose compared to one hospital-based education session in the UC group . The outcomes were macrosomia defined as birth weight ≥ 4.0 kg and the pregnancy-induced hypertension ( PIH ) . Results : Women in the SC ( n = 339 ) and UC ( n = 361 ) groups delivered their infants at similar gestational weeks . Birth weight of infants in the SC group was lower than that in the UC group ( 3469 vs. 3371 grams , P = 0.021 ) . The rate of macrosomia was 11.2 % ( 38/339 ) in the SC group compared to 17.5 % ( 63/361 ) in the UC group with relative risk ( RR ) of 0.64 ( 95 % CI : 0.44 - 0.93 ) . The rate of PIH was 8.0 % ( 27/339 ) in the SC compared to 4.4 % ( 16/361 ) in the UC with RR of 1.80 ( 0.99 - 3.28 ) . Apgar score at 1 min < 7 was lower but preeclampsia was higher in the SC than in the UC [21422852] OBJECTIVE : To estimate the association between fasting and 2-hour postpr and ial blood glucose levels and neonatal outcomes in women treated for mild gestational diabetes . METHODS : In this secondary analysis of a multicenter r and omized treatment trial of mild gestational diabetes , the median fasting and 2-hour postpr and ial glucose levels were analyzed in 2-week intervals and change over time ( slope ) was calculated for women with gestational diabetes ( abnormal oral glucose tolerance test ) and a fasting glucose less than 95 mg/dL who received nutritional management with self blood glucose monitoring and insulin as needed . Regression analyses were performed to estimate the relationship between median fasting and postpr and ial glucose and neonatal fat mass , cord blood C-peptide , birth weight , large-for-gestational-age neonates , macrosomia ( greater than 4,000 g ) , and neonatal hypoglycemia . RESULTS : Among 460 women with gestational diabetes , median fasting ( P<.001 ) , postpr and ial breakfast ( P<.001 ) , and postpr and ial lunch ( P<.001 ) glucose values declined over the treatment period , whereas postpr and ial dinner values remained stable ( P=.83 ) . Higher median fasting glucose during the first 2 weeks of treatment was significantly associated with increased odds ratios for neonatal fat mass ( 1.35 ; 95 % CI 1.09–1.66 ; P=.006 ) and elevated C-peptide ( 1.29 ; CI 1.09–1.52 ; P=.003 ) . Higher median fasting glucose during the last 2 weeks before delivery was associated with higher rates of large-for-gestational-age neonates ( 1.27 ; CI 1.05–1.53 ; P=.01 ) , macrosomia ( 1.32 ; CI 1.04–1.65 ; P = .02 ) , and elevated C-peptide ( 1.19 ; CI 1.03–1.38 ; P=.02 ) . CONCLUSION : In women treated for mild gestational diabetes , higher fasting glucose during initiation of diet therapy was associated with increased neonatal fat mass and elevated C-peptide and during the last 2 weeks before delivery with macrosomia , large-for-gestational age , and elevated C-peptide . LEVEL OF EVIDENCE : [24629718] AIM This r and omized controlled trial was carried out to investigate the effect of mindfulness eating and yoga exercise on blood sugar levels among pregnant Thai women with GDM . BACKGROUND Interventions promoting achievement of good glycemic control result in desired pregnancy outcomes . Little is known about the health benefits of mindfulness eating and yoga exercise on blood sugar levels among pregnant with GDM . METHODS A r and omized controlled trial was carried out . Main outcome measures were capillary fasting plasma glucose , 2-h postpr and ial blood glucose , and hemoglobin A1c . RESULTS The intervention group showed significantly reduced fasting plasma glucose , 2-h postpr and ial blood glucose , and glycosylated hemoglobin ( HbA1c ) in the intervention group ( p<0.05 ) . CONCLUSIONS Mindfulness eating and yoga exercise had health benefits on glycemic control in pregnant women with GDM . It should be recommended in clinical and community health services [18754979] OBJECTIVE To examine the effects of a Parish Nurse Intervention Program ( PNIP ) on maternal health behaviors , glycemic control , and neonatal outcomes among Mexican American women with gestational diabetes . DESIGN A r and omized controlled trial comparing care as usual ( CAU ) with a supplementary 1-hour education session for diabetes education reinforcement by a Parish Nurse . SETTING An outpatient treatment clinic for gestational diabetes within a 250-bed tertiary care , non-profit hospital with a Parish Nurse partnership . PARTICIPANTS One hundred Mexican American women were included in the study with r and omization into Parish Nurse Intervention Program ( n=49 ) and care as usual ( n=51 ) groups . MAIN OUTCOME MEASURES The Health Promoting Lifestyle Profile II ( HPLP II ) and two measures of glycemic control pre- and post-intervention , as well as newborn size , and days of maternal and neonatal hospitalization . RESULTS Outcomes indicate significantly improved Health Promoting Lifestyle Profile II scores in the Parish Nurse Intervention Program group post-intervention compared with the Care As Usual group . No significant differences between groups regarding glycemic control , macrosomia , or days of maternal or neonatal hospitalization were found . CONCLUSIONS A Parish Nurse Intervention Program for pregnant women of Mexican descent with gestational diabetes is effective in leading to improved self-reported health promoting behaviors [26071920] OBJECTIVE The purpose of this study was to examine the association between gestational age ( GA ) at the time of treatment initiation for gestational diabetes mellitus ( GDM ) and maternal and perinatal outcomes . STUDY DESIGN We conducted a secondary analysis of a multicenter r and omized treatment trial of mild GDM in which women with mild GDM were assigned r and omly to treatment vs usual care . The primary outcome of the original trial , as well as this analysis , was a composite perinatal adverse outcome that included neonatal hypoglycemia , hyperbilirubinemia , hyperinsulinemia , and perinatal death . Other outcomes that were examined included the frequency of large for GA , birthweight , neonatal intensive care unit admission , gestational hypertension/preeclampsia , and cesarean delivery . The interaction between GA at treatment initiation ( stratified as 24 - 26 , 27 , 28 , 29 , and ≥30 weeks of gestation ) and treatment group ( treated vs routine care ) , with the outcomes of interest , was used to determine whether GA at treatment initiation was associated with outcome differences . RESULTS Of 958 women whose cases were analyzed , those who initiated treatment at an earlier GA did not gain an additional treatment benefit compared with those who initiated treatment at a later GA ( probability value for interaction with the primary outcome , .44 ) . Similarly , there was no evidence that other outcomes were improved significantly by earlier initiation of GDM treatment ( large for GA , P = .76 ; neonatal intensive care unit admission , P = .8 ; cesarean delivery , P = .82 ) . The only outcome that had a significant interaction between GA and treatment was gestational hypertension/preeclampsia ( P = .04 ) , although there was not a clear cut GA trend where this outcome improved with treatment . CONCLUSION Earlier initiation of treatment of mild GDM was not associated with stronger effect of treatment on perinatal outcomes [12375675] Objective : A planned study is described which will determine whether a benefit exists for the treatment of mild carbohydrate intolerance during pregnancy . Methods : A r and omized clinical trial of women with mild gestational diabetes will compare perinatal outcomes in those receiving diet therapy and insulin as required versus those r and omized to no specific treatment . Results : The primary outcome of this study will be a composite of neonatal morbidity in the treatment and control groups . Conclusions : A r and omized treatment trial of mild gestational diabetes mellitus will clarify whether identification and treatment of mild gestational diabetes mellitus reduces perinatal morbidity . This information will aid in selecting appropriate thresholds for the treatment of gestational diabetes mellitus [24839145] OBJECTIVE The aim of the article is to determine whether maternal body mass index ( BMI ) influences the beneficial effects of diabetes treatment in women with gestational diabetes mellitus ( GDM ) . STUDY DESIGN Secondary analysis of a multicenter r and omized treatment trial of women with GDM . Outcomes of interest were elevated umbilical cord c-peptide levels ( > 90th percentile 1.77 ng/mL ) , large for gestational age ( LGA ) birth weight ( > 90th percentile ) , and neonatal fat mass ( g ) . Women were grouped into five BMI categories adapted from the World Health Organization International Classification of normal , overweight , and obese adults . Outcomes were analyzed according to treatment group assignment . RESULTS A total of 958 women were enrolled ( 485 treated and 473 controls ) . Maternal BMI at enrollment was not related to umbilical cord c-peptide levels . However , treatment of women in the overweight , Class I , and Class II obese categories was associated with a reduction in both LGA birth weight and neonatal fat mass . Neither measure of excess fetal growth was reduced with treatment in normal weight ( BMI < 25 kg/m(2 ) ) or Class III ( BMI ≥ 40 kg/m(2 ) ) obese women . CONCLUSION There was a beneficial effect of treatment on fetal growth in women with mild GDM who were overweight or Class I and Class II obese . These effects were not apparent for normal weight and very obese women [30866027] OBJECTIVE The main purpose of this article is to evaluate whether identification and treatment of women with mild gestational diabetes mellitus ( GDM ) during pregnancy affects subsequent maternal body mass index ( BMI ) , anthropometry , metabolic syndrome , and risk of diabetes . STUDY DESIGN This is a follow-up study of women who participated in a r and omized controlled treatment trial for mild GDM . Women were enrolled between 5 and 10 years after their index pregnancy . Participants underwent blood pressure , height , weight , and anthropometric measurements by trained nursing personnel using a st and ardized approach . A nurse-assisted question naire regarding screening and treatment of diabetes or hypercholesterolemia , diet , and physical activity was completed . Laboratory evaluation included fasting serum glucose , fasting insulin , oral glucose tolerance test , and a lipid panel . Subsequent diabetes , metabolic syndrome , obesity , and adiposity in those diagnosed with mild GDM and r and omized to nutritional counseling and medical therapy ( treated ) were compared with those who underwent routine pregnancy management ( untreated ) . Multivariable analyses were performed adjusting for race/ethnicity and years between r and omization and follow-up visit . RESULTS Four-hundred fifty-seven women with mild GDM during the index pregnancy were included in this analysis ( 243 treated ; 214 untreated ) and evaluated at a median 7 years after their index pregnancy . Baseline and follow-up characteristics were similar between treatment groups . Frequency of diabetes ( 9.2 vs. 8.5 % , p = 0.80 ) , metabolic syndrome ( 32.2 vs. 34.3 % , p = 0.63 ) , as well as adjusted mean values of homeostasis model assessment for insulin resistance ( 2.5 vs. 2.3 , p = 0.11 ) and BMI ( 29.4 vs. 29.1 kg/m2 , p = 0.67 ) were also not different . CONCLUSION Identification and treatment of women with mild GDM during pregnancy had no discernible impact on subsequent diabetes , metabolic syndrome , or obesity 7 years after delivery [24646172] The benefits of exercise and behavioural recommendations in gestational diabetes mellitus ( GDM ) are controversial . In a r and omized trial with a 2 × 2 factorial design , we examined the effect of exercise and behavioural recommendations on metabolic variables , and maternal/neonatal outcomes in 200 GDM patients . All women were given the same diet : group D received dietary recommendations only ; group E was advised to briskly walk 20‐min/day ; group B received behavioural dietary recommendations ; group BE was prescribed the same as B + E. Dietary habits improved in all groups . In a multivariable regression model , fasting glucose did not change . Exercise , but not behavioural recommendations , was associated with the reduction of postpr and ial glucose ( p < 0001 ) , glycated haemoglobin ( HbA1c ; p < 0.001 ) , triglycerides ( p = 0.02 ) and C‐reactive protein ( CRP ; p < 0.001 ) and reduced any maternal/neonatal complications ( OR = 0.50 ; 95%CI=0.28–0.89;p = 0.02 ) . In GDM patients a simple exercise programme reduced maternal postpr and ial glucose , HbA1c , CRP , triglycerides and any maternal/neonatal complications , but not fasting glucose values [19797280] BACKGROUND It is uncertain whether treatment of mild gestational diabetes mellitus improves pregnancy outcomes . METHODS Women who were in the 24th to 31st week of gestation and who met the criteria for mild gestational diabetes mellitus ( i.e. , an abnormal result on an oral glucose-tolerance test but a fasting glucose level below 95 mg per deciliter [ 5.3 mmol per liter ] ) were r and omly assigned to usual prenatal care ( control group ) or dietary intervention , self-monitoring of blood glucose , and insulin therapy , if necessary ( treatment group ) . The primary outcome was a composite of stillbirth or perinatal death and neonatal complications , including hyperbilirubinemia , hypoglycemia , hyperinsulinemia , and birth trauma . RESULTS A total of 958 women were r and omly assigned to a study group--485 to the treatment group and 473 to the control group . We observed no significant difference between groups in the frequency of the composite outcome ( 32.4 % and 37.0 % in the treatment and control groups , respectively ; P=0.14 ) . There were no perinatal deaths . However , there were significant reductions with treatment as compared with usual care in several prespecified secondary outcomes , including mean birth weight ( 3302 vs. 3408 g ) , neonatal fat mass ( 427 vs. 464 g ) , the frequency of large-for-gestational-age infants ( 7.1 % vs. 14.5 % ) , birth weight greater than 4000 g ( 5.9 % vs. 14.3 % ) , shoulder dystocia ( 1.5 % vs. 4.0 % ) , and cesarean delivery ( 26.9 % vs. 33.8 % ) . Treatment of gestational diabetes mellitus , as compared with usual care , was also associated with reduced rates of preeclampsia and gestational hypertension ( combined rates for the two conditions , 8.6 % vs. 13.6 % ; P=0.01 ) . CONCLUSIONS Although treatment of mild gestational diabetes mellitus did not significantly reduce the frequency of a composite outcome that included stillbirth or perinatal death and several neonatal complications , it did reduce the risks of fetal overgrowth , shoulder dystocia , cesarean delivery , and hypertensive disorders . ( Clinical Trials.gov number , NCT00069576 . [23046401] OBJECTIVE This study identified the impact of intensive therapy on neonatal outcomes in women with gestational diabetes mellitus ( GDM ) and determined the effects on the postpartum metabolic status of the mothers . RESEARCH DESIGN AND METHODS In total , 127 pregnant women with GDM were r and omly selected to receive an intensive treatment regimen , which included one-to-one education , lifestyle intervention , scheduled clinic visits , strict glucose control , and frequent glucose self-monitoring . Meanwhile , 148 age-matched pregnant women with GDM were selected as controls and given the st and ard treatment regimen . Pregnancy outcomes including parameters related to the GDM mothers and to their neonates were comparatively analyzed between the two treatment groups . GDM patient follow-up ( range , 1 - 3 years after delivery ) included an oral glucose tolerance test and measurements of lipid concentration and insulin secretion . The insulinogenic index ( ΔInsulin(30 min)/ΔBlood glucose(30 min ) ) and homeostasis model assessment index of β-cell function and insulin resistance were calculated . The patients ' demographic and anthropometric data were also recorded for comparative analysis . RESULTS Compared with GDM patients receiving st and ard treatment , GDM patients receiving intensive treatment had lower instances of premature delivery ( 2.4 % vs. 8.3 % , P<0.05 ) and neonatal care unit admission ( 21.3 % vs. 33.3 % , P<0.05 ) and lower neonatal birth weight ( 3.26±0.53 vs. 3.45±0.55 kg , P<0.0001 ) . At follow-up , GDM patients from the intensive treatment group had a smaller waist circumference ( 75.83±3.11 vs. 78.34±4.20 cm , P<0.01 ) , lower 30-min glucose levels after a 75-g glucose load ( 8.26±1.85 vs. 9.46±2.74 mmol/L , P<0.05 ) , and higher high-density lipoprotein levels ( 1.30±0.24 vs. 1.18±0.23 mmol/L , P<0.05 ) . CONCLUSIONS The intensive GDM treatment regimen led to healthier outcomes for the women , the neonates , and the birth event and was associated with better maternal metabolic situations in the months and years after delivery [21050147] Objective . To examine pregnancy outcomes in relation to different categories of glucose tolerance during pregnancy . Design . Prospect i ve observational cohort study . Setting . Patient recruitment and data collection were performed in four delivery departments in southern Sweden . Population . Women delivering during 2003–2005 ; 306 with gestational diabetes mellitus , 744 with gestational impaired glucose tolerance and 329 r and omly selected controls . Methods . All women were offered a 75 g oral glucose tolerance test during pregnancy . On the basis of their capillary 2‐hour plasma glucose concentrations , three groups were identified : gestational diabetes mellitus ( > 10.0 mmol/l ) , gestational impaired glucose tolerance ( 8.6–9.9 mmol/l ) and controls ( < 8.6 mmol/l ) . Data for the groups were compared using a population ‐based data base . Main outcome measures . Maternal and fetal outcomes . Results . For the gestational diabetes mellitus group , adjusted odds ratios ( 95 % confidence intervals ) for hypertensive disorders during pregnancy and induction of labor and emergency cesarean section were 2.7 ( 1.3–5.8 ) , 3.1 ( 1.8–5.2 ) and 2.5 ( 1.5–4.4 ) , respectively ; and for Apgar score < 7 at 5 minutes , need for neonatal intensive care > 1 day and large‐for‐gestational age infant were 9.6 ( 1.2–78.0 ) , 5.2 ( 2.8–9.6 ) and 2.5 ( 1.3–5.1 ) , respectively . The increases in odds ratios for the gestational impaired glucose tolerance group were less pronounced but still significant for hypertension during pregnancy , induction of labor , large‐for‐gestational age infant and use of neonatal intensive care > 1 day , with odds ratios ( 95 % confidence interval ) 2.0 ( 1.0–4.1 ) , 1.8 ( 1.1–3.0 ) , 2.1 ( 1.1–3.9 ) and 2.1 ( 1.1–3.8 ) , respectively . Conclusions . These data indicate that even limited degrees of maternal hyperglycemia may affect the outcome of pregnancy Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Gestational diabetes ( GDM ) affects 3 % to 6 % of all pregnancies . Women are often intensively managed with increased obstetric monitoring , dietary regulation , and insulin . However , there has been no sound evidence base to support intensive treatment . The key issue for clinicians and consumers is whether treatment of GDM improves perinatal outcome . OBJECTIVES To compare the effect of alternative treatment policies for GDM on both maternal and infant outcomes . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

27515753

[17784901] AIMS ( i ) To evaluate the effect of receiving one of two brief interventions in reducing alcohol consumption among general hospital patients compared with usual care . ( ii ) To assess whether a brief intervention of self-efficacy enhancement was superior to a self-help booklet in reducing alcohol consumption . DESIGN A three-arm cluster r and omized controlled trial . SETTING Seven general medical , six general surgical , one dermatology and two otolaryngology wards of a large teaching hospital covering a large urban and rural area . PARTICIPANTS A total of 215 of 789 in- patients aged 18 - 75 years , who screened positive for alcohol consumption in excess of national recommended limits according to a 7-day retrospective drinking diary . INTERVENTIONS Participants were allocated to receive one of three interventions : ( i ) face-to-face self-efficacy enhancement ; ( ii ) a self-help booklet ; or ( iii ) usual care . MEASUREMENTS The primary outcome measure was change in reported alcohol consumption at 6-month follow-up as measured by a 7-day retrospective drinking diary . Secondary outcomes were change in : number of alcohol drinking days in last week ; the maximum units of alcohol consumed on any one day in last week ; and Drinking Refusal Self-efficacy Expectancy Question naire score . FINDINGS Compared to the usual care group the self-efficacy enhancement group ( -10.1 units 95 % CI -16.1 to -4.1 ) and the self-help booklet group ( -10.0 units 95 % CI -16.0 to -3.9 ) had greater reductions in self-reported weekly alcohol consumption . There was no evidence that self-efficacy enhancement was superior to the self-help booklet ( P = 0.96 ) . CONCLUSIONS Brief interventions delivered in hospital offer simple means of helping heavy drinkers to reduce their alcohol consumption [2858246] Seven hundred and thirty one men admitted to medical wards were interviewed to identify problem drinkers who had not received previous treatment for alcoholism and who had some social support . One hundred and sixty one met the diagnostic criteria ; 156 agreed to a follow up interview and were allocated to one of two groups . One group received a session of counselling about their drinking habits from a nurse while the other received only routine medical care . Both groups reported a reduction in alcohol consumption when interviewed 12 months later , but the counselled group had a significantly better outcome than the control group . It is concluded that systematic screening for alcohol consumption and related problems should become a routine part of medical assessment and that advice on drinking habits is effective if given before irreversible physical or psychosocial problems have developed [24961378] BACKGROUND Brief motivational intervention ( BMI ) has shown promising results to reduce alcohol use in young adults . Knowledge on mechanisms that predict BMI efficacy could potentially improve treatment effect sizes through data that optimize clinical training and implementation . Particularly , little attention has been given to counselor influence on treatment mechanisms . METHODS We investigated the influence of counselors on BMI efficacy in reducing alcohol use among non-treatment-seeking young men ( age 20 ) screened as hazardous drinkers . Participants were r and omly allocated to ( i ) a group receiving a single BMI from 1 of 18 counselors selected to maximize differences in several of their characteristics ( gender , professional status , clinical experience , and motivational interviewing [ MI ] experience ) or ( ii ) a control group receiving assessment only . Drinking at 3-month follow-up was first compared between the BMI and control groups to assess efficacy . Then , the influence of counselors ' characteristics ( i.e. , gender , professional status , clinical experience , MI experience , BMI attitudes , and expectancies ) and within-session behaviors ( i.e. , measured by the Motivational Interviewing Skill Code ) on outcome was tested in regression analyses . RESULTS There was a significant ( p = 0.02 ) decrease in alcohol use among the BMI group compared to the control group . Counselors that were male , more experienced , that had more favorable BMI attitudes and expectancies , higher MI skills , but surprisingly less MI-consistent behaviors , had significantly better outcomes than the control group while their counterparts did not . CONCLUSIONS The current study demonstrated BMI efficacy on alcohol use reduction within a sample of non-treatment-seeking young adult males . Moreover , BMI effect was related to interindividual differences among counselors , and results therefore provide recommendations for BMI training and implementation with similar population [20670329] OBJECTIVES Adolescents in their late teens and early 20s have the highest alcohol consumption in the United States ; binge drinking peaks at age 21 - 25 years . Underage drinking is associated with many negative consequences , including academic problems and risk of intentional and unintentional injuries . This study tested the effectiveness of pediatric emergency department ( PED ) screening and brief intervention to reduce alcohol consumption and associated risks . METHODS A three-group r and omized assignment trial was structured to test differences between intervention ( I ) and st and ard assessed control ( AC ) groups in alcohol consumption and alcohol-related behaviors from baseline to 12 months and to compare the AC group with a minimally assessed control ( MAC ) group to adjust for the effect of assessment reactivity on control group behavior . Patients aged 14 - 21 years were eligible if they screened positive on the Alcohol Use Disorders Identification Test ( AUDIT ) or for binge drinking or high-risk behaviors . The MAC group received a re source h and out , written advice about alcohol-related risks , and a 12-month follow-up appointment . Patients in the AC group were assessed using st and ardized instruments in addition to the MAC protocol . The I group received a peer-conducted motivational intervention , referral to community re sources and treatment if indicated , and a 10-day booster in addition to assessment . Measurements included 30-day self-report of alcohol consumption and alcohol-related behaviors , screens for depression and posttraumatic stress disorder , and self-report of attempts to quit , cut back , or change conditions of use , all repeated at follow-up . Motor vehicle records and medical records were also analyzed for changes from baseline to 1-year follow-up . RESULTS Among 7,807 PED patients screened , 1,202 were eligible ; 853 enrolled ( I , n = 283 ; AC , n = 284 ; MAC , n = 286 ) , with a 12-month follow-up rate of 72 % . At 12 months , more than half of enrollees in Reaching Adolescents for Prevention ( RAP ) attempted to cut back on drinking , and over a third tried to quit . A significantly larger proportion of the I group made efforts to quit drinking and to be careful about situations when drinking compared to AC enrollees , and there was a numerically but not significantly greater likelihood ( p = 0.065 ) among the I group for efforts to cut back on drinking . At 3 months , the likelihood of the I group making attempts to cut back was almost triple that of ACs . For efforts to quit , it was double , and for trying to be careful about situations when drinking , there was a 72 % increase in the odds ratio ( OR ) for the I group . Three-month results for attempts were sustained at 12 months for quit attempts and efforts to be careful . Consumption declined in both groups from baseline to 3 months to 12 months , but there were no significant between-group differences in alcohol-related consequences at 12 months or in alcohol-related risk behaviors . We found a pattern suggestive of assessment reactivity in only one variable at 12 months : the attempt to cut back ( 73.3 % for the I group vs. 64.9 % among the AC group and 54.8 % among the MAC group ) . CONCLUSIONS Brief motivational intervention result ed in significant efforts to change behavior ( quit drinking and be careful about situations while drinking ) but did not alter between-group consumption or consequences [3409578] Background Internet-based interventions for heavy drinkers show promising results , but existing research is characterized by few studies in nonstudent adult population s and few comparisons with appropriate control groups . Objective To test whether a fully automated Internet-based brief personalized feedback intervention and a fully automated Internet-based personalized brief advice intervention in a non-treatment-seeking population of heavy drinkers would result in a reduced alcohol intake . Methods We conducted a 3-arm parallel r and omized controlled trial in a general population -based sample of heavy drinkers . The 54,157 participants ( median age of 58 years ) were screened for heavy drinking . Of the 3418 participants who had a weekly alcohol consumption above 14 drinks for women and 21 drinks for men , 1380 ( 619 women ) consented to take part in the trial and were r and omly assigned to an Internet-based brief personalized feedback intervention group ( normative feedback , n = 476 ) , an Internet-based personalized brief advice intervention group ( n = 450 ) , or a nonintervention control group ( n = 454 ) . Follow-up after 6 and 12 months included 871 and 1064 participants , respectively , of all groups combined . The outcome measure was self-reported weekly alcohol consumption . We analyzed the data according to the intention-to-treat principle . To examine changes over time and to account for the multiple time measurements , we used a multilevel linear mixed model . To take attrition into account , we used multiple imputation to address missing data . Results The intervention effect of the Internet-based brief personalized feedback intervention , determined as the mean additional difference in changes in alcohol consumption in the Internet-based brief personalized feedback intervention compared with the control group , was –1.8 drinks/week after 6 months and –1.4 drinks/week after 12 months ; these effects were nonsignificant ( 95 % confidence interval –4.0 to 0.3 at 6 months , –3.4 to 0.6 at 12 months ) . The intervention effect of the Internet-based personalized brief advice intervention was –0.5 drinks/week after 6 months and –1.2 drinks/week after 12 months ; these effects were nonsignificant ( 95 % confidence interval –2.7 to 1.6 at 6 months , –3.3 to 0.9 at 12 months ) . Conclusions In this r and omized controlled trial we found no evidence that an Internet-based brief personalized feedback intervention was effective in reducing drinking in an adult population of heavy drinkers . Trial registration Clinical Trials.gov NCT00751985 ; http:// clinical trials.gov/ct2/show/NCT00751985 ( Archived by WebCite at http://www.webcitation.org/68WCRLyaP [25063992] AIM To evaluate the effectiveness of different brief intervention strategies at reducing hazardous or harmful drinking in the probation setting . Offender managers were r and omized to three interventions , each of which built on the previous one : feedback on screening outcome and a client information leaflet control group , 5 min of structured brief advice and 20 min of brief lifestyle counselling . METHODS A pragmatic multicentre factorial cluster r and omized controlled trial . The primary outcome was self-reported hazardous or harmful drinking status measured by Alcohol Use Disorders Identification Test ( AUDIT ) at 6 months ( negative status was a score of < 8) . Secondary outcomes were AUDIT status at 12 months , experience of alcohol-related problems , health utility , service utilization , readiness to change and reduction in conviction rates . RESULTS Follow-up rates were 68 % at 6 months and 60 % at 12 months . At both time points , there was no significant advantage of more intensive interventions compared with the control group in terms of AUDIT status . Those in the brief advice and brief lifestyle counselling intervention groups were statistically significantly less likely to reoffend ( 36 and 38 % , respectively ) than those in the client information leaflet group ( 50 % ) in the year following intervention . CONCLUSION Brief advice or brief lifestyle counselling provided no additional benefit in reducing hazardous or harmful drinking compared with feedback on screening outcome and a client information leaflet . The impact of more intensive brief intervention on reoffending warrants further research [17345916] Motivational interviewing ( MI ) is a brief intervention that has been shown to reduce heavy drinking among college students . Because all college studies of MI to date have included a personalized feedback report , it remains unclear which of the components is necessary to produce behavior change . This study evaluated the separate and collective effects of MI and feedback among 122 “ binge ” drinking college students . Participants were r and omized to : 1 ) MI with feedback , 2 ) MI without feedback , 3 ) Mailed feedback only , 4 ) MI with mailed feedback , or 5 ) Assessment only control . At an eight-week follow-up , all groups reduced their consumption , peak BAC , consequences , and dependence symptoms . For females , there were reductions in consequences and dependence symptoms in groups that received feedback , as compared to groups that did not receive feedback . For females , there was an effect of the feedback on consequences and dependence symptoms , but was no overall effect of MI on any outcome measure [22197301] This study evaluated the efficacy of two brief personalized feedback interventions ( PFIs ) using identical feedback and motivational interviewing strategies aim ed at reducing alcohol consumption and alcohol-related problems to two control conditions among a sample of high-risk drinking college students . Students ( N = 152 ) were r and omly assigned to a computer-delivered PFI with a video interviewer , a face-to-face PFI with a live interviewer , a comprehensive assessment condition , or a minimal assessment -only condition . At 10 weeks posttreatment , the face-to-face PFI significantly reduced weekly drinking quantity and peak and typical blood alcohol concentration compared with the comprehensive assessment and minimal assessment -only conditions ( d values ranged from 0.32 to 0.61 ) . No significant between-group differences were evidence d for the computer-delivered PFI condition , although effect sizes were comparable to other college drinking studies using computer-delivered interventions ( d values ranged from 0.20 to 0.27 ) . Results provide further support for the use of a face-to-face PFI to help reduce college students ' alcohol consumption and suggest that a video interviewer in the context of a computer-delivered PFI is likely a helpful but not necessarily a complete substitute for a live interviewer [4070907] Background Alcohol misuse is common in people attending emergency departments ( EDs ) and there is some evidence of efficacy of alcohol screening and brief interventions ( SBI ) . This study investigated the effectiveness of SBI approaches of different intensities delivered by ED staff in nine typical EDs in Engl and : the SIPS ED trial . Methods and Findings Pragmatic multicentre cluster r and omized controlled trial of SBI for hazardous and harmful drinkers presenting to ED . Nine EDs were r and omized to three conditions : a patient information leaflet ( PIL ) , 5 minutes of brief advice ( BA ) , and referral to an alcohol health worker who provided 20 minutes of brief lifestyle counseling ( BLC ) . The primary outcome measure was the Alcohol Use Disorders Identification Test ( AUDIT ) status at 6 months . Of 5899 patients aged 18 or more presenting to EDs , 3737 ( 63·3 % ) were eligible to participate and 1497 ( 40·1 % ) screened positive for hazardous or harmful drinking , of whom 1204 ( 80·4 % ) gave consent to participate in the trial . Follow up rates were 72 % ( n = 863 ) at six , and 67 % ( n = 810 ) at 12 months . There was no evidence of any differences between intervention conditions for AUDIT status or any other outcome measures at months 6 or 12 in an intention to treat analysis . At month 6 , compared to the PIL group , the odds ratio of being AUDIT negative for brief advice was 1·103 ( 95 % CI 0·328 to 3·715 ) . The odds ratio comparing BLC to PIL was 1·247 ( 95 % CI 0·315 to 4·939 ) . A per protocol analysis confirmed these findings . Conclusions SBI is difficult to implement in typical EDs . The results do not support widespread implementation of alcohol SBI in ED beyond screening followed by simple clinical feedback and alcohol information , which is likely to be easier and less expensive to implement than more complex interventions . Trial Registration Current Controlled Trials IS RCT N [7888970] In a controlled evaluation of general practitioner (GP)-based brief intervention , 378 excessive drinkers identified opportunistically by screening in 40 group practice s in metropolitan Sydney were assigned to groups receiving : ( i ) a five-session intervention by the GP ( the Alcoholscreen Program ) ; ( ii ) a single session of 5 minutes ' advice by the GP plus a self-help manual ( minimal intervention ) ; ( iii ) an alcohol-related assessment but no intervention ; ( iv ) neither intervention nor assessment . Among all patients allocated to receive it , the Alcoholscreen Program did not result in a significantly greater reduction in consumption at follow-up than control conditions but patients offered Alcoholscreen reported a significantly greater reduction in alcohol-related problems in the period to 6 months follow-up . A greater proportion of patients who returned for the second Alcoholscreen visit were drinking below recommended levels at follow-up than in the remainder of the sample . There was no evidence that minimal intervention or alcohol-related assessment were effective in reducing alcohol consumption or problems . Implication s for further research into GP-based brief interventions are discussed [4016505] Background The evidence suggests that brief alcohol-focused interventions , directed at hazardous and harmful drinkers in non-specialist setting s such as primary care are effective in reducing alcohol consumption . However , there is a need for further research in the hospital setting . This is a r and omised controlled trial to investigate the effectiveness of a 10-minute brief intervention amongst ' at risk ’ drinkers admitted to general hospital wards . Unlike some previous trials , this trial is r and omised , used blinded assessors , includes an intention-to-treat analysis , included female subjects and excluded people with alcohol dependence . Methods A total of 250 ' at risk ’ drinkers admitted to King ’s College Hospital were identified using the Alcohol Use Disorders Identification Test ( AUDIT ) . Some 154 subjects entered the study and were r and omly allocated to the control and intervention groups . Subjects in the control group received no advice about their drinking whilst subjects in the intervention group received 10 minutes of simple advice on reducing alcohol consumption . Recruitment took place between 1995 and 1997 . The primary outcome was the AUDIT question naire at 12 months . Secondary outcomes were a previous week ’s Drinks Diary , question naires ( General Health Question naire , Alcohol Problems Question naire and the Severity of Alcohol Dependence Question naire ) and laboratory blood tests ( gamma glutamyl transferase , mean cell volume and haemoglobin ) . Results At 3-month and 12-month follow-up , all participants were included in the intention-to-treat analysis . At both time points there was no evidence of an intervention effect that could be attributed to the brief intervention . Both the intervention and control groups had an improved AUDIT score and reduced levels of alcohol consumption as measured by a subjective Drinks Diary at 3 months which was maintained at 12 months . Conclusions This study has added further evidence on brief interventions in the hospital setting . In contrast to the recent Cochrane review by McQueen et al. , the results of this study do not support the effectiveness of a brief alcohol intervention in general hospital wards . However our study was underpowered and there were flaws in the statistical analyses , and these limitations temper the strength of our conclusions [21777259] BACKGROUND Heavy drinking is one of the leading causes of morbidity and mortality in young men . Brief motivational intervention ( BMI ) has shown promising results for young people , but has never been tested in young men in the community who volunteered to receive an intervention . METHODS We evaluated the effectiveness of BMI in reducing alcohol use among heavy episodic users and in maintaining low-risk drinking among nonheavy episodic users . Participants were French-speaking young men attending the m and atory Swiss army conscription process . They were offered the opportunity to receive a 20-minute BMI , and those interested were r and omized into an intervention group ( BMI immediately ) or into a control group ( BMI after the 6-month follow-up assessment , in a waiting list design ) . Analyses were conducted separately for heavy and nonheavy episodic users ( separated using baseline heavy episodic use frequency ) as the hypotheses tested were different between both groups ( primary vs. secondary prevention intervention ) . RESULTS From a pool of 6,085 young men invited to receive BMI , 727 ( 11.9 % ) showed up and 572 were included in the study ( after exclusions related to organizational aspects of the conscription process ) . Among nonheavy episodic users , there was a protective effect of BMI on weekly alcohol use ( p < 0.05 ) . Among heavy episodic users , there were no significant effects of BMI . CONCLUSIONS About 12 % of young men were interested in addressing their drinking within the BMI framework , suggesting that there is some need for easily accessible alcohol intervention . The present intervention did have a preventive effect among low-risk young drinkers in helping them maintain their patterns of alcohol use . An explanation for the lack of effectiveness among heavy episodic users might be that those individuals interested in BMI had patterns of more severe alcohol use , thereby making change more difficult [3448228] Sixteen general practitioners participated in a controlled trial of the Scottish Health Education Group 's DRAMS ( drinking reasonably and moderately with self-control ) scheme . The scheme was evaluated by r and omly assigning 104 heavy or problem drinkers to three groups - a group participating in the DRAMS scheme ( n = 34 ) , a group given simple advice only ( n = 32 ) and a non-intervention control group ( n = 38 ) . Six month follow-up information was obtained for 91 subjects ( 87.5 % of initial sample ) . There were no significant differences between the groups in reduction in alcohol consumption , but patients in the DRAMS group showed a significantly greater reduction in a logarithmic measure of serum gamma-glutamyl-transpeptidase than patients in the group receiving advice only . Only 14 patients in the DRAMS group completed the full DRAMS procedure . For the sample as a whole , there was a significant reduction in alcohol consumption , a significant improvement on a measure of physical health and well-being , and significant reductions in the logarithmic measure of serum gamma-glutamyl transpeptidase and in mean corpuscular volume . The implication s of these findings for future research into controlled drinking minimal interventions in general practice are discussed [23410849] Brief interventions for college heavy drinkers have shown promise in reducing drinking and alcohol-related negative consequences . However , intervention duration , content , method of delivery , and follow-up length vary across studies . It therefore remains unclear whether intervention length significantly influences the interventions ' efficacy . The present study is a r and omized clinical trial systematic ally evaluating the efficacy of two brief interventions aim ed at reducing alcohol use and alcohol-related negative consequences among college student drinkers . Treatment mediators were also evaluated . Participants ( N=278 ) were , on average , 20.1 years old ( SD=2.4 ) , mostly Caucasian ( 87 % ) and female ( 71 % ) . They were r and omly assigned to a 10-minute brief intervention , a 50-minute brief intervention , or an attention-control group . Both active interventions were provided by clinical graduate students trained in Brief Alcohol Screening and Intervention for College Students ( BASICS ) . As hypothesized , participants in both active conditions significantly reduced their alcohol consumption , as compared to the control group participants F(2,264)=9.84 , p=.00 , η(2)=.07 . There were no significant differences in alcohol-related negative consequences F(2,264)=3.08 , p=.06 , η(2)=.02 . The hypothesized mediators , alcohol drinking norms and coping behavioral strategies , explained significant variance in intervention efficacy , but neither self-efficacy nor alcohol expectancies were significant mediators . Given the preliminary nature of our investigation , more research is warranted to determine parameters of the critical mechanisms of change within brief alcohol interventions with college student drinkers [11373259] The aim of this research was to evaluate the effectiveness of long-term brief intervention in routine general practice . In five primary care out-patient clinics in a Finnish town , 296 male early-phase heavy drinkers consulting a general practitioner ( GP ) for various reasons were identified . Control group C ( n = 88 ) was informed of the risks of drinking after the screening and were advised at the subsequent feedback about 2 weeks later to reduce their drinking . Groups A ( n = 109 ) and B ( n = 99 ) were offered in addition seven and three brief intervention sessions , respectively . All GPs took part , whether or not they indicated a special interest . The main outcome measures were differences between beginning and end-point at 3 years in self-reported alcohol consumption , mean corpuscular volume ( MCV ) , and serum carbohydrate-deficient transferrin , aspartate aminotransferase , alanine aminotransferase and gamma-glutamyltransferase . There were no statistically significant differences between study groups A , B and C in mean changes in outcome measures . Within all the groups , MCV decreased . Depending on the outcome measure used and the study group analysed , clinical ly significant reduction of drinking was found in 25 - 53 % of the subjects . In routine general practice , giving additional sessions of brief intervention may not be as effective as in special research conditions . Factors reducing the effectiveness of brief intervention programmes should be investigated , so that primary health care staff can be better supported in their efforts [3541471] Objective To evaluate the effectiveness of different brief intervention strategies at reducing hazardous or harmful drinking in primary care . The hypothesis was that more intensive intervention would result in a greater reduction in hazardous or harmful drinking . Design Pragmatic cluster r and omised controlled trial . Setting Primary care practice s in the north east and south east of Engl and and in London . Participants 3562 patients aged 18 or more routinely presenting in primary care , of whom 2991 ( 84.0 % ) were eligible to enter the trial : 900 ( 30.1 % ) screened positive for hazardous or harmful drinking and 756 ( 84.0 % ) received a brief intervention . The sample was predominantly male ( 62 % ) and white ( 92 % ) , and 34 % were current smokers . Interventions Practice s were r and omised to three interventions , each of which built on the previous one : a patient information leaflet control group , five minutes of structured brief advice , and 20 minutes of brief lifestyle counselling . Delivery of the patient leaflet and brief advice occurred directly after screening and brief lifestyle counselling in a subsequent consultation . Main outcome measures The primary outcome was patients ’ self reported hazardous or harmful drinking status as measured by the alcohol use disorders identification test ( AUDIT ) at six months . A negative AUDIT result ( score < 8) indicated non-hazardous or non-harmful drinking . Secondary outcomes were a negative AUDIT result at 12 months , experience of alcohol related problems ( alcohol problems question naire ) , health utility ( EQ-5D ) , service utilisation , and patients ’ motivation to change drinking behaviour ( readiness to change ) as measured by a modified readiness ruler . Results Patient follow-up rates were 83 % at six months ( n=644 ) and 79 % at 12 months ( n=617 ) . At both time points an intention to treat analysis found no significant differences in AUDIT negative status between the three interventions . Compared with the patient information leaflet group , the odds ratio of having a negative AUDIT result for brief advice was 0.85 ( 95 % confidence interval 0.52 to 1.39 ) and for brief lifestyle counselling was 0.78 ( 0.48 to 1.25 ) . A per protocol analysis confirmed these findings . Conclusions All patients received simple feedback on their screening outcome . Beyond this input , however , evidence that brief advice or brief lifestyle counselling provided important additional benefit in reducing hazardous or harmful drinking compared with the patient information leaflet was lacking . Trial registration Current Controlled Trials IS RCT N06145674 [19538921] OBJECTIVE This study tested the effectiveness of brief primary care provider interventions delivered in a college student health center to a sample of college students who screened positive for high-risk drinking . METHOD Between November 2005 and August 2006 , 8,753 students who presented as new patients to the health service at a large public university were screened for high-risk drinking , and 2,484 students ( 28 % ) screened positive on the 5/4 gender-specific high-risk drinking question ( i.e. , five or more drinks per occasion for men and four or more for women ) . Students who screened positive for high-risk drinking and consented to participate ( N= 363 ; 52 % female ) were r and omly assigned either to a control group ( n = 182 ) or to an experimental group ( n = 181 ) . Participants in the experimental group received two brief intervention sessions that were founded in motivational interviewing techniques and delivered by four specially trained providers within the student health center . Data on alcohol use and related harms were obtained from a Web-based Healthy Lifestyle Question naire , 30-day Timeline Followback alcohol-use diaries , the Rutgers Alcohol Problem Index ( RAPI ) , and eight items from the Drinker Inventory of Consequences-2L . RESULTS Repeated measures analysis showed that , compared with the control group ( C ) , the intervention group ( I ) had significant reductions in typical estimated blood alcohol concentration ( BAC ) ( C = .071 vs I = .057 at 3 months ; C = .073 vs I = .057 at 6 months ) , peak BAC ( C = . 142 vs I = .112 at 3 months ; C = .145 vs I = .108 at 6 months ) , peak number of drinks per sitting ( C = 8.03 vs I = 6.87 at 3 months ; C = 7.98 vs I = 6.52 at 6 months ) , average number of drinks per week ( C = 9.47 vs I = 7.33 at 3 months ; C = 8.90 vs I = 6.16 at 6 months ) , number of drunk episodes in a typical week ( C = 1.24 vs I = 0.85 at 3 months ; C = 1.10 vs I = 0.71 at 6 months ) , number of times taken foolish risks ( C = 2.24 vs I = 1.12 at 3 months ) , and RAPI sum scores ( C = 6.55 vs I = 4.96 at 6 months ; C = 6.17 vs I = 4.58 at 9 months ) . CONCLUSIONS Brief interventions delivered by primary care providers in a student health center to high-risk-drinking students may result in significantly decreased alcohol consumption , high-risk drinking , and alcohol-related harms [11767271] The authors evaluated the efficacy of Brief Alcohol Screening and Intervention for College Students ( BASICS - L. A. Dimeff , J. S. Baer , D. R. Kivlahan , & G. A. Marlatt , 1999 ) , a single session of drinking-related feedback intended to reduce heavy drinking and related harm . College student drinkers ( N = 99 ) were assigned to BASICS , an educational intervention , or an assessment -only control group . At 3 months postintervention . there were no overall significant group differences , but heavier drinking BASICS participants showed greater reductions in weekly alcohol consumption and binge drinking than did heavier drinking control and education participants . At 9 months , heavier drinking BASICS participants again showed the largest effect sizes . BASICS participants evaluated the intervention more favorably than did education participants . This study suggests that BASICS may be more efficacious than educational interventions for heavier drinking college students [17565563] AIMS To evaluate the effectiveness of brief alcohol intervention ( BAI ) in reducing alcohol use among hazardous drinkers treated in the emergency department ( ED ) after an injury ; in addition it tests whether assessment of alcohol use without BAI is sufficient to reduce hazardous drinking . DESIGN R and omized controlled clinical trial with 12-month follow-up conducted between January 2003 and June 2005 . SETTING Urban academic emergency department ( ED ) of the Lausanne University Hospital , Lausanne , Switzerl and . PARTICIPANTS A total of 5136 consecutive patients attending ED after an injury completed a seven-item general and a three-item alcohol screen and 1472 ( 28.7 % ) were positive for hazardous drinking according to the National Institute on Alcohol Abuse and Addiction definition ; of these 987 ( 67.1 % ) were r and omized into a BAI group ( n = 310 ) or a control group with screening and assessment ( n = 342 ) or a control group with screening only ( n = 335 ) and then a total of 770 patients ( 78.0 % ) completed the 12-month follow-up procedures . INTERVENTION A single 10 - 15-minute session of st and ardized BAI conducted by a trained research assistant . MEASUREMENTS Percentage of participants who have changed to low-risk drinking at follow-up . FINDINGS Data obtained at 12 months indicated that similar proportions were low-risk drinkers in BAI versus control groups with and without assessment ( 35.6 % , 34.0 % , 37.0 % , respectively , P = 0.71 ) . Data also indicated similar reductions in drinking frequency , quantity , binge drinking frequency and Alcohol Use Disorders Identification Test ( AUDIT ) scores across groups . All groups reported similar numbers of days hospitalized and numbers of medical consults in the last 12 months . A model including age groups , gender , AUDIT and injury severity scores indicated that BAI had no influence on the main alcohol use outcome . CONCLUSIONS This study provides the evidence that a 10 - 15-minute BAI does not decrease alcohol use and health re source utilization in hazardous drinkers treated in the ED , and demonstrates that commonly found decreases in hazardous alcohol use in control groups can not be attributed to the baseline alcohol assessment [11045860] BACKGROUND Studies suggest that 14 % of women age 18 to 40 drink alcohol above recommended limits . Of special concern is the increasing use of alcohol by women during pregnancy . This article reports 48 month follow-up data from a sub analysis of a trial for early alcohol treatment ( Project TrEAT ) focused on women of childbearing age . METHODS Project TrEAT was conducted in the offices of 64 primary care , community-based physicians from 10 Wisconsin counties . Of 5979 female patients ages 18 to 40 who were screened for problem drinking , 205 were r and omized into an experimental group ( n = 103 ) or control group ( n = 102 ) . The intervention consisted of two 15 min , physician-delivered counseling visits that included advice , education , and contracting by using a scripted workbook . A total of 174 subjects ( 85 % ) completed the 48 month follow-up procedures . RESULTS No significant differences were found between the experimental and control groups at baseline for alcohol use , age , socioeconomic status , smoking , depression or anxiety , conduct disorder , lifetime drug use , or health care utilization . The trial found a significant treatment effect in reducing both 7 day alcohol use ( p = 0.0039 ) and binge drinking episodes ( p = 0.0021 ) over the 48 month follow-up period . Women in the experimental group who became pregnant during the follow-up period had the most dramatic decreases in alcohol use . A logistic regression model based on a 20 % or greater reduction in drinking found an odds ratio of 1.93 ( confidence interval 1.07 - 3.46 ) in the sample exposed to physician intervention . Age , smoking , depression , conduct disorder , antisocial personality disorder , and illicit drug use did not reduce drinking significantly . No significant differences were found in health care utilization and health status between groups . CONCLUSIONS This trial provides the first direct evidence that brief intervention is associated with sustained reductions in alcohol consumption by women of childbearing age . The results have enormous implication s for the U.S. health care system [24315218] AIMS The aim of this study is to assess the effect of brief motivational enhancement intervention postpartum alcohol use . DESIGN This study is a single-blinded , r and omized controlled effectiveness trial in which pregnant women were assigned to receive usual care or up to 5 face-to-face brief motivational enhancement sessions lasting 10 - 30 minutes each and occurring at study enrollment , 4 and 8 weeks after enrollment , 32 weeks of gestation , and 6 weeks postpartum . SETTING The setting is in a large , urban , obstetrics clinic . PARTICIPANTS Participants were women who were ≥ 18 years old , < 20 weeks of gestation , and consumed alcohol during pregnancy . Of 3438 women screened , 330 eligible women were assigned to usual care ( n = 165 ) or intervention ( n=165 ) . Due to missing data , we analyzed 125 in the intervention group and 126 in the usual care group . MEASUREMENTS The measurements were the proportion of women with any alcohol use and the number of drinks per day , reported via follow-up telephone interviews at 4 and 8 weeks after enrollment , 32 weeks of gestation , and 6 weeks , 6 months , and 12 months postpartum . FINDINGS In r and om effects models adjusted for confounders , the intervention group was less likely to use any alcohol ( odds ratio 0.50 ; 95 % confidence interval [ CI ] , 0.23 - 1.09 ; P=0.08 ) and consumed fewer drinks per day ( coefficient -0.11 ; 95 % CI -0.23 - 0.01 ; P=0.07 ) than , the usual care group in the postpartum period but these differences were non-significant . Missing data during the prenatal period prevented us from modeling prenatal alcohol use . CONCLUSIONS Brief motivational enhancement intervention delivered in an obstetrical outpatient setting did not conclusively decrease alcohol use during the postpartum period [19170454] Motivational interviewing ( MI ) is a counseling style that has been shown to reduce heavy drinking among college students . To date , all studies of MI among college students have used a format that includes a feedback profile delivered in an MI style . This study was a dismantling trial of MI and feedback among heavy-drinking college students . After an initial screen , 279 heavy-drinking students were r and omized to ( a ) Web feedback only , ( b ) a single MI session without feedback , ( c ) a single MI session with feedback , or ( d ) assessment only . At 6 months , MI with feedback significantly reduced drinking , as compared with assessment only ( effect size = .54 ) , MI without feedback ( effect size = .63 ) , and feedback alone ( effect size = .48 ) . Neither MI alone nor feedback alone differed from assessment only . Neither sex , race or ethnicity , nor baseline severity of drinking moderated the effect of the intervention . Norm perceptions mediated the effect of the intervention on drinking . MI with feedback appears to be a robust intervention for reducing drinking and may be mediated by changes in normative perceptions [9735576] This r and omized controlled trial evaluated the efficacy of a brief intervention design ed to reduce the harmful consequences of heavy drinking among high-risk college students . Students screened for risk while in their senior year of high school ( 188 women and 160 men ) were r and omly assigned to receive an individualized motivational brief intervention in their freshman year of college or to a no-treatment control condition . A normative group selected from the entire screening pool provided a natural history comparison . Follow-up assessment s over a 2-year period showed significant reductions in both drinking rates and harmful consequences , favoring students receiving the intervention . Although high-risk students continued to experience more alcohol problems than the natural history comparison group over the 2-year period , most showed a decline in problems over time , suggesting a developmental maturational effect [19919597] BACKGROUND Evidence suggests that brief interventions in the trauma care setting reduce drinking , subsequent injury and driving under the influence ( DUI ) arrest . However , evidence on the effectiveness of these interventions in ethnic minority groups is lacking . The current study evaluates the efficacy of brief intervention among whites , blacks and Hispanics in the United States . METHODS We conducted a two-group parallel r and omized trial comparing brief motivational intervention ( BMI ) and treatment as usual with assessment ( TAU+ ) to evaluate treatment differences in drinking patterns by ethnicity . Patients were recruited from a level 1 urban trauma center over a 2-year period . The study included 1493 trauma patients , including 668 whites , 288 blacks and 537 Hispanics . Hierarchical linear modeling was used to evaluate ethnic differences in drinking outcomes including volume per week , maximum amount consumed in 1 day , percentage days abstinent and percentage days heavy drinking at 6- and 12-month follow-up . Analyses controlled for age , gender , employment status , marital status , prior alcohol treatment , type of injury and injury severity . Special emphasis was given to potential ethnic differences by testing the interaction between ethnicity and BMI . RESULTS At 6- and 12-month follow-up , BMI significantly reduced maximum amount consumed in 1 day ( P < 0.001 ; P < 0.001 , respectively ) and percentage days heavy drinking ( P < 0.05 ; P < 0.05 , respectively ) among Hispanics . Hispanics in the BMI group also reduced average volume per week at 12-month follow-up ( chi(2 ) = 6.8 , df = 1 , P < 0.01 ) . In addition , Hispanics in TAU+ reduced maximum amount consumed at 6- and 12-month follow-up ( P < 0.001 ; P < 0.001 ) and volume per week at 12-month follow-up ( P < 0.001 ) . Whites and blacks in both BMI and TAU+ reduced volume per week and percentage days heavy drinking at 12-month follow-up ( P < 0.001 ; P < 0.01 , respectively ) and decreased maximum amount at 6- ( P < 0.001 ) and 12-month follow-up ( P < 0.001 ) . All three ethnic groups In both BMI and TAU+ reduced volume per week at 6-month follow-up ( P < 0.001 ) and percentage days abstinent at 6- ( P < 0.001 ) and 12-month follow-up ( P < 0.001 ) . CONCLUSIONS All three ethnic groups evidence d reductions in drinking at 6- and 12-month follow-up independent of treatment assignment . Among Hispanics , BMI reduced alcohol intake significantly as measured by average volume per week , percentage days heavy drinking and maximum amount consumed in 1 day [20236990] AIMS To determine the effectiveness of Motivational Enhancement Therapy ( MET ) for hazardous drinkers in Primary Care Unit ( PCU ) setting s in rural Thail and . METHODS A r and omized controlled trial was conducted in eight PCUs in Ubonratchatanee and Chachoengsao provinces in Thail and . Hazardous drinkers were identified using the World Health Organization-recommended Alcohol Use Disorder Identification Test . Of 117 eligible participants ( 91 % male ) , 59 were r and omized to the intervention group to receive MET in three individual appointments with a trained nurse and 58 to an assessment -only control group . Outcome evaluations were carried out after 6 weeks , 3 months and 6 months . RESULTS Follow-up data were available on 84 , 94 and 91 % of subjects , respectively , at the three intervals . Self-reported drinks per drinking day , frequency of hazardous drinking assessed either on a daily or weekly basis , and of binge drinking sessions were reduced in the intervention group more than in the control group ( P < 0.05 ) after both 3 and 6 months . The groups did not generally differ at 6 weeks . However , although self-reported consumption in both groups fell from baseline to 6-month follow-up , serum gamma-glutamyl transferase increased in both groups , which raises doubts about the validity of this marker in this sample and /or the validity of the self-reported data in this study . CONCLUSION MET delivered by nurses in PCUs in Thail and appears to be an effective intervention for male hazardous drinkers . Uncertainties about the validity of self-reported data jeopardize the safety of this conclusion [15506584] BACKGROUND High-risk alcohol use in persons 18 to 30 years of age is a critical public health problem . It is the number 1 cause of death in this population . This article reports the results of a sub analysis of young adults ( aged 18 to 30 years ) who participated in Project TrEAT ( Trial of Early Alcohol Treatment ) conducted in the offices of 64 primary care physicians located in 10 counties in southern Wisconsin . METHODS Project TrEAT was a r and omized clinical trial design ed to test the efficacy of a brief intervention protocol to reduce alcohol use , improve health status , and decrease health care utilization . A total of 226 young adults were r and omly assigned to either a usual care or brief intervention group . RESULTS There were no significant differences between the 2 groups at baseline on a number of potential confounders . During the 4-year follow-up period , there were significant reductions in number of persons drinking more than 3 drinks per day , average 7-day alcohol use , number of persons drinking 6 or more drinks per occasion , and number of binge drinking episodes in the previous 30 days ( P < .01 to P < .001 ) . There were also significant differences ( P < .05 ) in emergency department visits ( 103 vs 177 ) , motor vehicle crashes ( 9 vs 20 ) , total motor vehicle events ( 114 vs 149 ) , and arrests for controlled substance or liquor violation ( 0 vs 8) . CONCLUSION In this 4-year sub analysis of young adults who participated in Project TrEAT , we found long-term reductions in high-risk drinking behaviors and consequences . The findings of this study support more widespread implementation of brief interventions in primary care setting [12608685] This study examined the 1-year follow-up effects of the STARS ( Start Taking Alcohol Risks Seriously ) for Families program , a 2-year preventive intervention based on a stage of acquisition model , and consisting of nurse consultations and parent material s. A r and omized controlled trial was conducted , with participants receiving either the intervention or a minimal intervention control . Participants included a cohort of 650 sixth- grade students from two urban middle schools-one magnet ( bused ) and one neighborhood . Trained project staff administered question naires to students following a st and ardized protocol in the schools . For the magnet school sample , significantly fewer intervention students ( 5 % ) were planning to drink in the next 6 months than control students ( 18 % ) , chi2 = 11.53 , 1 d.f . , P = 0.001 . Magnet school intervention students also had less intentions to drink in the future , greater motivation to avoid drinking and less total alcohol risk than control students , Ps < 0.05 . For the neighborhood school , intervention students ( m = 7.90 , SD = 1.87 ) had less total alcohol risk than control students ( m = 8.42 , SD = 1.83 ) , F(1,205 ) = 4.09 , P = 0.04 . These findings suggest that a brief , stage and risk/protective factor tailored program holds promise for reducing risk for alcohol use among urban school youth 1 year after intervention , and has the unique advantage of greater ' transportability ' over classroom-based prevention programs [10522717] OBJECTIVE Alcoholism is the leading risk factor for injury . The authors hypothesized that providing brief alcohol interventions as a routine component of trauma care would significantly reduce alcohol consumption and would decrease the rate of trauma recidivism . METHODS This study was a r and omized , prospect i ve controlled trial in a level 1 trauma center . Patients were screened using a blood alcohol concentration , gamma glutamyl transpeptidase level , and short Michigan Alcoholism Screening Test ( SMAST ) . Those with positive results were r and omized to a brief intervention or control group . Reinjury was detected by a computerized search of emergency department and statewide hospital discharge records , and 6- and 12-month interviews were conducted to assess alcohol use . RESULTS A total of 2524 patients were screened ; 1153 screened positive ( 46 % ) . Three hundred sixty-six were r and omized to the intervention group , and 396 to controls . At 12 months , the intervention group decreased alcohol consumption by 21.8+/-3.7 drinks per week ; in the control group , the decrease was 6.7+/-5.8 ( p = 0.03 ) . The reduction was most apparent in patients with mild to moderate alcohol problems ( SMAST score 3 to 8) ; they had 21.6+/-4.2 fewer drinks per week , compared to an increase of 2.3+/-8.3 drinks per week in controls ( p < 0.01 ) . There was a 47 % reduction in injuries requiring either emergency department or trauma center admission ( hazard ratio 0.53 , 95 % confidence interval 0.26 to 1.07 , p = 0.07 ) and a 48 % reduction in injuries requiring hospital admission ( 3 years follow-up ) . CONCLUSION Alcohol interventions are associated with a reduction in alcohol intake and a reduced risk of trauma recidivism . Given the prevalence of alcohol problems in trauma centers , screening , intervention , and counseling for alcohol problems should be routine [20659072] BACKGROUND A r and omized controlled trial of screening , brief intervention , and referral to treatment ( SBIRT ) among at-risk ( based on average number of drinks per week and drinks per drinking day ) and dependent drinkers was conducted in an emergency department ( ED ) among 446 patients 18 and older in Sosnowiec , Pol and . METHODS Patients were recruited over a 23-week period ( 4:00 pm to 12:00 midnight ) and r and omized to 1 of 3 conditions : screened-only ( n = 147 ) , assessed ( n = 152 ) , and intervention ( n = 147 ) . Patients in the assessed and intervention conditions were blindly reassessed via a telephone interview at 3 months , and all 3 groups were assessed at 12 months ( screened-only = 92 , assessed = 99 , and intervention = 87 ) . RESULTS No difference was found across the 3 conditions in at-risk drinking at 12 months , as the primary outcome variable , or in decrease in the number of drinks per drinking day , with all 3 groups showing a significant reduction in both . Significant declines between baseline and 12 months in secondary outcomes of the RAPS4 , number of drinking days per week , and the maximum number of drinks on an occasion were seen only for the intervention condition , and in negative consequences for both the assessment and intervention conditions . CONCLUSIONS Data suggest that improvements in drinking outcomes found in the assessment condition were not because of assessment reactivity , with both the screened and intervention conditions demonstrating greater ( although nonsignificant ) improvement than the assessed condition . Only those in the intervention condition showed significant improvement in all outcome variables from baseline to 12-month follow-up . Although group by time interaction effects were not found to be significant , these findings suggest that declines in drinking measures for those receiving a brief intervention can be maintained at long-term follow-up [18054445] AIM To test the effectiveness of a brief alcohol intervention among non-dependent general hospital in patients with alcohol problems , delivered by either a specialized liaison service or hospital physicians . METHOD All in patients of 29 wards from four general hospitals of one region in Germany were screened for alcohol problems ( n=14,332 ) . Of those screening positive , 595 patients were included in a r and omized controlled group design using a time-frame . Patients with alcohol dependence were not considered in this study . Patients received Motivational Interviewing based counselling either by a specialized liaison service , by hospital physicians trained under routine conditions or received hospital treatment as usual without additional counselling . One year later , alcohol consumption , motivation and well-being were assessed . Sample survey analyses and generalized estimating equations were conducted . RESULTS At baseline , the three groups differed regarding motivation , with higher motivation among the controls . At follow-up , the groups did not differ regarding alcohol consumption , alcohol-related problems and well-being . All groups decreased their alcohol consumption significantly . Regarding motivation , longitudinal analyses revealed significant interaction effects of time and intervention ( p<0.05 ) , indicating a stronger increase of readiness to change drinking and a less profound drop of readiness to seek help among those who received intervention compared to the controls . CONCLUSION The intervention was not effective in reducing alcohol consumption or in increasing well-being 12 months after hospitalization . It had a positive effect on readiness to change drinking and on readiness to seek formal help for alcohol problems . The intervention groups compensated their lag of motivation [9415794] INTRODUCTION The study was design ed to test a brief intervention for reducing alcohol consumption among moderate to heavy ( hazardous ) drinkers in a busy HMO primary care setting . METHODS In a r and omized controlled trial , hazardous drinkers ( n = 516 ) were identified by the AUDIT screening question naire . Intervention included brief clinician advice ( 30 seconds ) , a 15-minute motivational session by counselors , and printed material s. RESULTS At six-month follow-up , intervention subjects reported fewer total st and ard drinks in the past three months ( 176 versus 216 , P = .04 , one-tailed ) and fewer drinking days per week ( 2.8 versus 3.3 , P = .02 ) than controls , but similar drinks per drinking day ( 3.3 versus 3.5 ; P = .13 ) . At 12 months , intervention subjects again reported fewer drinking days per week ( 2.7 versus 3.1 ; P = .04 ) than controls , but similar numbers of st and ard drinks ( 157 versus 179 ; P = .13 ) and drinks per drinking day ( 3.6 versus 3.3 ; P = .20 ) . Intervention subjects were somewhat more likely than controls to report drinking within daily recommended limits ( < or = 3 for men , < or = 2 for women ) at both six months ( 79 % versus 71 % ; P = .06 ) and 12 months ( 80 % versus 73 % ; P = .07 ) , but did not differ significantly from controls on other drinking outcomes ( percent abstinent , frequency of drinking > or = 6 drinks per drinking occasion , estimated peak blood alcohol concentration ) , or use of medical care in the year following intervention . CONCLUSIONS A one-time , brief motivational intervention using minimal clinician time supplemented by trained counselors result ed in a modest reduction in frequency of alcohol consumption in a busy primary care population . Future research should focus on strengthening and maintaining intervention effects [20381972] OBJECTIVE Brief interventions for college student drinkers have been shown to be effective in reducing the amount of alcohol consumed as well as the number of alcohol-related problems . However , the duration of brief interventions varies substantially across studies . METHOD In the present study 114 undergraduate students who drank alcohol heavily were r and omly assigned to a 10-minute brief intervention , a 50-minute brief intervention , or assessment -only control . The content of the active interventions was based on the same concept , and both interventions incorporated motivational interviewing components . Participants were assessed at baseline and 4-week post intervention on quantity of alcohol use , alcohol-related problems , and protective behavioral strategies . RESULTS As hypothesized , there was a significant difference between participants in the 10-minute intervention and control condition regarding their alcohol consumption at 4-week follow up . However , there was no significant difference between the 50-minute intervention and the control condition on alcohol consumption . There were also no significant differences between active intervention conditions , and neither intervention showed advantages for reducing problems or increasing protective behaviors relative to the control condition . CONCLUSIONS Results suggest a very brief intervention can impact short-term alcohol use outcomes , with potentially no advantage of longer interventions for this population [9091691] OBJECTIVE Project TrEAT ( Trial for Early Alcohol Treatment ) was design ed to test the efficacy of brief physician advice in reducing alcohol use and health care utilization in problem drinkers . DESIGN R and omized controlled clinical trial with 12-month follow-up . SETTING A total of 17 community-based primary care practice s ( 64 physicians ) located in 10 Wisconsin counties . PARTICIPANTS Of the 17695 patients screened for problem drinking , 482 men and 292 women met inclusion criteria and were r and omized into a control ( n=382 ) or an experimental ( n=392 ) group . A total of 723 subjects ( 93 % ) participated in the 12-month follow-up procedures . INTERVENTION The intervention consisted of two 10- to 15-minute counseling visits delivered by physicians using a scripted workbook that included advice , education , and contracting information . MAIN OUTCOME MEASURES Alcohol use measures , emergency department visits , and hospital days . RESULTS There were no significant differences between groups at baseline on alcohol use , age , socioeconomic status , smoking status , rates of depression or anxiety , frequency of conduct disorders , lifetime drug use , or health care utilization . At the time of the 12-month follow-up , there were significant reductions in 7-day alcohol use ( mean number of drinks in previous 7 days decreased from 19.1 at baseline to 11.5 at 12 months for the experimental group vs 18.9 at baseline to 15.5 at 12 months for controls ; t=4.33 ; P<.001 ) , episodes of binge drinking ( mean number of binge drinking episodes during previous 30 days decreased from 5.7 at baseline to 3.1 at 12 months for the experimental group vs 5.3 at baseline to 4.2 at 12 months for controls ; t=2.81 ; P<.001 ) , and frequency of excessive drinking ( percentage drinking excessively in previous 7 days decreased from 47.5 % at baseline to 17.8 % at 12 months for the experimental group vs 48.1 % at baseline to 32.5 % at 12 months for controls ; t=4.53 ; P<.001 ) . The chi2 test of independence revealed a significant relationship between group status and length of hospitalization over the study period for men ( P<.01 ) . CONCLUSIONS This study provides the first direct evidence that physician intervention with problem drinkers decreases alcohol use and health re source utilization in the US health care system [11414347] OBJECTIVE The current study tested the efficacy of a brief intervention design ed to reduce drinking and drinking-related consequences among first-year fraternity members . METHOD Twelve fraternities were r and omly assigned to receive either a motivational enhancement intervention with individual and housewide feedback components ( n = 6 houses ) or a treatment-as-usual control condition ( n = 6 houses ) . Individual feedback was delivered either by peer interviewers or professional research staff . Participants were assessed during their pledge ( first ) year of house membership and during a follow-up period 1 year later . RESULTS Of the participants who completed follow-up ( N = 120 ) , fraternity members who received the brief intervention reported significant reductions in alcohol use ( total average consumption ) and typical peak blood alcohol concentrations when compared with fraternity members in the control condition . No differences in drinking-related consequences were observed . Fraternity members who received their individualized feedback from peer interviewers and professional members of the research staff reported similar outcomes . CONCLUSIONS Results provide support for the efficacy of a brief motivational enhancement intervention in reducing drinking within this high-risk population . The cost-effective use of peer interviewers appears to be a promising strategy for delivering individualized prevention programming in college population [17855332] AIMS Recommendations for routine alcohol screening and brief counselling intervention in primary health care rest on results from intervention efficacy studies . By conducting a pragmatic controlled trial ( PCT ) , we aim ed at evaluating the effectiveness of the WHO recommendations for screening and brief intervention ( SBI ) in general practice . METHODS A r and omized PCT ( brief counselling intervention vs no intervention ) involving 39 Danish general practitioners ( GPs ) . Systematic screening of 6897 adults led to inclusion of 906 risky drinkers , and research follow-up on 537 of these after 12 - 14 months . Outcome measures focused on patients ' acceptance of screening and intervention and their self-reported alcohol consumption . RESULTS Patient acceptance of screening and intervention -10.3 % ( N = 794 ) of the target population ( N = 7 , 691 ) explicitly refused screening . All intervention group subjects ( N = 442 ) were exposed to an instant brief counselling session while only 17.9 % of them ( 79/442 ) attended a follow-up consultation that was offered by their GP . Consumption Changes At one-year follow-up , average weekly consumption had increased by 0.7 drinks in both comparison groups . As secondary findings , we observed an indiscriminate absolute risk reduction ( ARR = 0.08 ( 95 % CI : -0.02 ; 0.18 ) ) in male binge drinking , but adverse intervention effects for women on the secondary outcomes ( binge drinking ARR = -0.30 ( 95 % CI : -0.47 ; -0.09 ) ) . CONCLUSIONS The results of brief interventions in everyday general practice performed on the basis of systematic question naire screening may fall short of theoretical expectations . When applied to non-selected groups in everyday general practice SBI may have little effect and engender diverse outcome . Women may be more susceptible to defensive reactions than men [3390235] We studied 120 injured male patients of working age who were heavy drinkers or alcoholics , obtaining seven points or more in the Michigan Alcoholism Screening Test ( MAST ) . They were r and omly allocated either to an intervention group ( IG ) or to a control group ( CG ) . In addition to the MAST interview , the consumption of alcohol during the previous week prior to hospital admission was calculated and laboratory measures ( serum GGT , ASAT and ALAT ) were obtained . Counselling of the patients in the IG was carried out by a trained assistant nurse and a physician . Forty-nine patients in IG and 40 patients in CG were re-examined after 6 months . In the IG 45 % and in the CG 20 % of the patients were improved ( Chi square test , P less than 0.05 ) . Improvement criteria were a decrease in alcohol consumption by at least one-third and decrease of S-GGT by at least 20 % during the follow-up period . In respect to the laboratory measures the groups were identical at the beginning of the study and after 6 months ' follow-up . Our results are encouraging and suggest that the assessment of heavy drinking should be a routine in the treatment of alcohol-related injuries and that education and counselling must be intensive to be effective [1410953] The study examined the effectiveness of routine intervention in alcohol abuse by a general practitioner , with help of a laboratory test . Patients diagnosed as abusers because of high erythrocyte mean cell volume value ( MCV ) and having no other cause for it were r and omly allocated to two groups : 1 ) an intervention group , comprising 92 patients ( 69 men and 23 women ) , who were invited for follow-up at three-monthly intervals for a year ; 2 ) a control ( mini-intervention ) group , 86 patients ( 71 men and 15 women ) , who were followed-up only after 12 months . Follow-up attendance was poor , particularly in the intervention group . In general , MCV-values were unchanged in the groups at the end of the study , though there was a clear trend for the female controls to have lower values ( 101.9 fl at the start , 98.5 fl at the end , p = 0.06 ) . Altogether 11 % ( 4/38 ) of the women and 7 % ( 10/140 ) of the men had clearly reduced their alcohol consumption after one year , and this was also seen in their MCV-values . Mini-intervention , especially in women with an abnormal laboratory value , seems to be , with the help of MCV , at least as effective a way of counselling nonalcoholic abusers as a more systematic intervention [16441282] This article summarizes the proceedings of a symposium at the 2005 Research Society on Alcoholism , Santa Barbara , California . The purpose of the symposium was to address challenges that arise in translating evidence for efficacy of alcohol brief intervention ( BI ) into diverse clinical setting s and population s by review ing the literature and describing 4 research studies . Dr. Saitz review ed the limitations in evidence for efficacy of BIs and then described results of a r and omized clinical trial of brief motivational intervention for medical in patients drinking risky amounts . Dr. Svikis presented alternative methods for identifying pregnant women in prenatal care at risk for alcohol and drug problems ( including nicotine and caffeine ) and BIs to reduce or eliminate use . Dr. D'Onofrio discussed results of a r and omized trial of the brief negotiated interview in emergency department patients . Dr. Kraemer presented results of a decision analytic and computer-simulation model regarding the cost-effectiveness of alcohol screening and intervention in primary care setting s. Finally , Dr. Perl discussed the salient issues and suggested future directions for work in the area of alcohol BI [24813652] BACKGROUND Excessive use of alcohol is associated with poor sexual health , but the clinical effectiveness and cost-effectiveness of brief alcohol intervention in this setting has not been investigated . OBJECTIVE To examine the effects and cost-effectiveness of brief intervention for excessive alcohol consumption among people who attend sexual health clinics . DESIGN A two-arm , parallel-group , single-blind , pragmatic , r and omised controlled trial . Participants were r and omised via an independent and remote telephone r and omisation service using permuted blocks , stratified by clinic . SETTING Study participants were recruited from three sexual health clinics in central and west London . PARTICIPANTS For inclusion , potential participants had to be aged ≥ 19 years , drink excessive alcohol according to the Modified-Single Alcohol Screening Question , and be willing to provide written informed consent . We excluded those who were unable to communicate in English sufficiently well to complete the baseline assessment and those who could not provide contact details for the follow-up assessment . INTERVENTIONS Brief advice was delivered by the treating clinician and comprised feedback on the possible health consequences of excessive drinking , a discussion of whether the participant 's clinic attendance was linked to current alcohol use , written information on alcohol and health and an offer of an appointment with an alcohol health worker ( AHW ) . Appointments with AHWs took place either in person or by telephone , lasted up to 30 minutes , and used the ' FRAMES ' ( Feedback about the adverse effects of alcohol , an emphasis on personal Responsibility for changing drinking behaviour , Advice about alcohol consumption , a Menu of options for further help and advice , an Empathic stance towards the patient and an emphasis on Self-efficacy ) approach . Those in the control arm of the trial were offered a copy of a leaflet providing general information on health and lifestyle . MAIN OUTCOME MEASURES Outcomes were assessed 6 months after r and omisation . The primary outcome was mean weekly alcohol consumption during the previous 90 days . The main secondary outcome was unprotected sex during this period . RESULTS Eight hundred and two people were recruited to the study of whom 592 ( 74 % ) were followed up 6 months later . Among 402 participants who were r and omised to brief intervention , 397 ( 99 % ) received brief advice from the treating clinician and 81 ( 20 % ) also received input from an AHW . The adjusted mean difference in alcohol consumption after 6 months was -2.33 units per week [ 95 % confidence interval ( CI ) -4.69 to 0.03 units per week , p = 0.053 ] for those in the active arm compared with the control arm . Unprotected sex was reported by 154 ( 53 % ) of those who received brief intervention and by 178 ( 59 % ) of controls ( adjusted odds ratio 0.89 , 95 % CI 0.63 to 1.25 , p = 0.496 ) . Participants r and omised to brief intervention reported drinking a mean of 10.4 units of alcohol per drinking day compared with 9.3 units among control participants ( difference 1.10 , 95 % CI 0.29 to 1.96 , p = 0.009 ) . We found no statistically significant differences in other outcomes . Brief intervention ( brief advice and input from an AHW ) cost on average £ 12.60 per person to deliver and did not appear to provide a cost-effective use of re sources . CONCLUSIONS Introduction of universal screening and brief intervention for excessive alcohol use among people who attend sexual health clinics does not result in clinical ly important reductions in alcohol consumption or provide a cost-effective use of re sources . While people attending sexual health clinics may want to achieve better sexual health , attempts to reduce alcohol consumption may not be seen by them as a necessary means of trying to achieve this aim . TRIAL REGISTRATION This trial is registered as IS RCT N 99963322 . FUNDING This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol . 18 , No. 30 . See the NIHR Journals Library website for further project information [11499124] OBJECTIVES This study examined long-term response to an individual preventive intervention for high-risk college drinkers relative to the natural history of college drinking . METHODS A single-session , individualized preventive intervention was evaluated within a r and omized controlled trial with college freshmen who reported drinking heavily while in high school . An additional group r and omly selected from the entire screening pool provided a normative comparison . Participant self-report was assessed annually for 4 years . RESULTS High-risk controls showed secular trends for reduced drinking quantity and negative consequences without changes in drinking frequency . Those receiving the brief preventive intervention reported significant additional reductions , particularly with respect to negative consequences . Categorical individual change analyses show that remission is normative , and they suggest that participants receiving the brief intervention are more likely to improve and less likely to worsen regarding negative drinking consequences . CONCLUSIONS Brief individual preventive interventions for high-risk college drinkers can achieve long-term benefits even in the context of maturational trends [11702799] OBJECTIVE Brief interventions for hazardous and low-dependent drinkers in the primary care setting have considerable empirical support . The purpose of this study was to ( 1 ) evaluate the effects of brief advice ( BA ) and motivational enhancement ( ME ) interventions on alcohol consumption . In addition , a hindsight matching design was used to ( 2 ) study the moderator effects of patient readiness to change ( alcohol use ) on alcohol consumption . METHOD The subjects ( N = 301 , 70 % men ) were patients 21 years of age or older who presented for treatment at one of 12 primary care clinics . After screening for eligibility and providing consent to participate in the study , the patients completed a baseline assessment and were r and omly assigned to the BA , ME or st and ard care ( SC ) interventions condition . Follow-up assessment s were completed at 1- , 3- , 6- , 9- and 12-months postbaseline assessment . RESULTS Evaluation of the first hypothesis ( n = 232 for these analyses ) showed that all participants tended to reduce their alcohol use considerably between the baseline and 12-month assessment s. In addition , evaluation of the second hypothesis showed a moderator effect of readiness to change in predicting the number of drinks at 12 months , such that the BA intervention seemed more effective for patients relatively low in readiness to change compared to those higher in readiness . Readiness to change did not seem to be related to changes in drinking of participants in the SC or ME conditions . CONCLUSIONS The results confirm that , among primary care patients , substantial changes in alcohol consumption are possible . They further suggest that matching studies of patient readiness to change their alcohol use , as well as other variables , are warranted [1525531] The objective of the study was to determine the effectiveness of advice from general practitioners to heavy drinking men ( consuming 350 - 1050 grams of alcohol per week ) to reduce their alcohol consumption . One hundred and fifty-four men recruited from eight general practice s were allocated r and omly to treatment and control groups . Men in the treatment group received advice from their own general practitioner . At one year follow-up , when analyzed according to intention to treat , the treatment group had reduced their consumption by an excess of 65 grams of alcohol per week when compared with the control group ( p less than 0.05 ) . General practitioners should be recommended to screen for alcohol consumption amongst their patients and to give advice to those found to be at risk because of their drinking [18237661] INTRODUCTION Alcohol is the single greatest contributor to injury in the United States . Numerous studies have reported that a st and ardized screening , brief intervention , and referral to treatment ( SBIRT ) intervention can effectively minimize future alcohol consumption , reduce injury recurrence , and decrease the number of repeat ED visits . To date , SBIRT studies have been conducted in setting s in which physicians or research assistants carried out SBIRT . Little is known about ED nurses carrying out SBIRT . The purpose of this study was to examine ED nurse training needs and identify both barriers to , and enablers of , SBIRT implementation in the emergency department . METHODS Two coordinators from each of the 5 ED sites selected for the study attended a 1-day SBIRT educational session . Site coordinators then trained their staff nurses to conduct SBIRT . Site coordinators were surveyed at the midpoint and end of the 6-month implementation study period . Patient data from each facility was collected . RESULTS Ten site coordinators were trained and held subsequent training sessions with nursing staff in their respective emergency departments . All sites encountered barriers to implementation , but 2 of 5 sites were able to implement the SBIRT process fully by the end of the evaluation period . A total of 3265 patients were screened for alcohol use problems . Of those screened , 678 ( 21 % ) were classified as hazardous drinkers . Overall , 56 % of the positive-screened patients received 3 to 5 minutes of a brief intervention . After the brief intervention , between 9 % and 82 % of patients were referred for further care . DISCUSSION The SBIRT process can be conducted successfully by emergency nurses . However , substantial operational barriers to widespread routine implementation exist . These barriers need to be addressed before emergency nurses incorporate SBIRT as routine part of ED care [20105410] OBJECTIVE The aim of this study was to test the efficacy of brief physician advice in reducing alcohol use and related harm in college students . METHOD The College Health Intervention Projects ( CHIPs ) is a r and omized , controlled clinical trial with 12-month follow-up conducted in five college health clinics in Wisconsin ; Washington state ; and Vancouver , Canada . Of the 12,900 students screened for high-risk drinking , 484 men and 502 women met inclusion criteria and were r and omized into a control ( n = 493 ) or intervention ( n = 493 ) group . Ninety-six percent of students participated in the follow-up procedures . The intervention consisted of two 15-minute counseling visits and two follow-up phone calls , and used motivational interviewing , contracting , diary cards , and take-home exercises . RESULTS No significant differences were found between groups at baseline on alcohol use , age , socioeconomic or smoking status , rates of depression , or measures of alcohol-related harm . At 12 months , the experimental subjects reduced their 28-day drinking totals by 27.2 % , and the control group reduced their totals by 21 % . A mixed effects repeated measures model found a statistical difference in favor of the brief-intervention group ( beta = 4.7 , SE = 2.0 , p = .018 ) in 28-day drinking totals . The total Rutgers Alcohol Problem Index score was also significantly different during the 12-month follow-up period ( beta = 0.8 , SE = 0.4 , p = .033 ) . There was no difference on the other outcome measures of interest , such as frequency of excessive heavy drinking , health care utilization , injuries , drunk driving , depression , or tobacco use . CONCLUSIONS The study supports re source allocation and implementation of alcohol screening and brief physician advice in primary care-based college health clinics [12492754] AIM To evaluate the effectiveness of a brief motivational intervention on alcohol consumption and misuse in young males with alcohol-related face injury . DESIGN R and omized controlled trial . SETTING Oral and maxillofacial surgery out-patient clinic in an urban teaching hospital . PARTICIPANTS One hundred and fifty-one participants were r and omized to motivational intervention and control conditions . INTERVENTIONS Control was treatment as usual . The intervention was treatment as usual plus a one-session brief motivational intervention administered by a nurse . MEASUREMENTS Three sets of measurements were taken at baseline , 3-month and 1-year follow-up . Collateral measurements were also taken at 1-year follow-up . Primary outcome measures were total alcohol consumption , typical weeks consumption and days abstinent in preceding 3 months . Other outcome measures included the Alcohol Use Disorders Identification Test , a short form of the Alcohol Problems Question naire , and a measure of satisfaction with social relationships . RESULTS There was a significant decrease in 84-day total alcohol consumption across the year ( P < 0.006 ) and further , a significant effect for the motivational intervention was demonstrated ( P < 0.029 ) . This pattern was repeated for days abstinent and alcohol consumption in a typical week as well as alcohol-related problems . There was a significantly greater reduction in the percentage of hazardous drinkers in the motivational intervention group ( from 60 % to 27 % , P < 0.009 ) compared to the control group ( from 54 % to 51 % , NS ) . CONCLUSION A proportion of young men change their alcohol consumption following alcohol-related injury . A nurse-led psychological intervention adds significantly to the proportion and magnitude of response [17032098] In this r and omized controlled trial , the authors evaluated brief motivational interventions ( BMI s ) for at-risk college drinkers . Heavy drinking students ( N = 509 ; 65 % women , 35 % men ) were r and omized into 1 of 6 intervention conditions formed by crossing the baseline Timeline Followback ( TLFB ) interview ( present versus absent ) and intervention type ( basic BMI , BMI enhanced with a decisional balance module , or none ) . Assessment s completed at baseline , 1 , 6 , and 12 months measured typical and risky drinking as well as drinking-related problems . Relative to controls , the TLFB interview reduced consumption but not problems at 1 month . The basic BMI improved all drinking outcomes beyond the effects of the TLFB interview at 1 month , whereas the enhanced BMI did not . Risk reduction achieved by brief interventions maintained throughout the follow-up year [11104115] BACKGROUND Today , heavy drinking is a common health hazard among women . The evidence in favor of providing some kind of brief intervention to reduce drinking is quite convincing . However , we do not know if intervention works in a natural environment of routine health care . The purpose of this study was to evaluate the effectiveness of long-lasting , brief alcohol intervention counseling for women in a routine general practice setting . METHODS In five primary care outpatient clinics in a Finnish town , 118 female early-phase heavy drinkers who consulted their general practitioners for various reasons were given brief alcohol intervention counseling . Intervention groups A ( n = 40 ) and B ( n = 38 ) were offered seven and three brief intervention sessions , respectively , over a 3-yr period . The control group C ( n = 40 ) was advised to reduce drinking at baseline . Main outcome measures were self-reported weekly alcohol consumption , carbohydrate-deficient transferrin , mean corpuscular volume ( MCV ) , aspartate aminotransferase , alanine aminotransferase , and gamma-glutamyltransferase . RESULTS Depending on the outcome measure and the study group , clinical ly meaningful reduction of drinking was found in 27 % to 75 % of the heavy drinkers . Within all the groups , MCV significantly decreased . However , there were no statistically significant differences between study groups A , B , and C in the mean changes between the beginning and endpoint in the main outcome measures . CONCLUSIONS The present study indicated that minimal advice , as offered to group C , was associated with reduced drinking as much as the brief intervention , as offered to groups A and B , given over a 3-yr period . Furthermore , in the routine setting of the general practice office , the effectiveness of the brief intervention may not be as good as in special research conditions . The factors possibly reducing the effectiveness in a routine setting are unknown . Thus , different methods of implementing brief intervention need to be evaluated to find better ways to support general practice personnel in their efforts to help heavy-drinking female patients to reduce their drinking [10078798] OBJECTIVE The project was design ed to compare the effectiveness of brief intervention ( BI ) versus simple advice ( SA ) in the secondary prevention of hazardous alcohol consumption . METHODS A r and omized controlled trial with a 12-month follow-up was conducted . A total of 74 community-based primary care practice s ( 328 physicians ) located in 13 Spanish autonomous regions were recruited initially . Out of 546 men screened , only 229 were r and omized into BI ( n = 104 ) and SA ( n = 125 ) ; 44.6 % of practice s finalized the study . The interventions on the BI group consisted of a 15-minute counselling visit carried out by physicians which included : ( i ) alcohol quantification , ( ii ) information on safe limits , ( iii ) advice , ( iv ) drinking limits agreement , ( v ) self-informative booklet with drinking diary record and ( vi ) unscheduled reinforcement visits . The SA group spent 5 minutes which included ( i ) , ( ii ) and ( iii ) . RESULTS There were no significant differences between both groups at baseline on alcohol use , age , socioeconomic status and CAGE score . After the 12-month follow-up there was a significant decrease in frequency of excessive drinkers ( 67 % of BI group reached targeted consumption , versus 44 % of SA ; P < 0.001 ) as well as weekly alcohol intake reduction ( BI reached 52 versus 32 % in SA ; P < 0.001 ) . A trend to improve outcome with the number of reinforcement visits was found with BI . The only predictor of success was the initial alcohol consumption level . CONCLUSIONS Brief intervention is more effective than simple advice to reduce alcohol intake on adult men who attend primary care services in Spain [12683736] This r and omized trial evaluated an intervention for reducing at-risk drinking practice s in a sample of 307 patients . Eligible drinking patterns included chronic drinking ( > or = 2 drinks per day in the past month ) , binge drinking ( > or = 5 drinks per occasion at least twice in the past month ) , and drinking and driving ( driving after > 2 drinks in the past month ) . Members of the intervention group received a message from their physician during their regularly scheduled visit , a self-help manual , written personalized feedback , and up to 3 telephone counseling calls . Dropout was significantly higher in the intervention than control group [21205050] AIMS To evaluate the effectiveness of a brief intervention in hospitalized Taiwanese men to reduce unhealthy alcohol consumption . DESIGN R and omized controlled trial . SETTING Medical/surgical wards of a medical centre in Taipei , Taiwan . PARTICIPANTS Of 3669 consecutive adult male in- patients , 616 were identified as unhealthy alcohol users ( > 14 drinks/week ) and assigned r and omly to either usual care ( n = 308 ) or a brief intervention ( n = 308 ) . MEASUREMENTS Primary outcomes were changes in alcohol consumption at 4 , 9 and 12 months , including self-reported weekly alcohol consumption , drinking days and heavy drinking episodes assessed by 7-day time-line follow-back . Secondary outcomes were ( i ) self-reported alcohol problems , ( ii ) health-care utilization ( hospital days and emergency department visits ) , ( iii ) self-reported seeking of speciality treatment for alcohol problems and ( iv ) 3-month Quick Drinking Screen . FINDINGS Based on intention-to-treat analyses , the intervention group consumed significantly less alcohol than the control group among both unhealthy drinkers and the subgroup of alcohol-dependent participants over 12 months , on both 7-day and 3-month assessment s. Adjunctive analyses of only those who completed all assessment s found that total drinks consumed did not remain significant . Significantly more participants with alcohol use disorders in the intervention than in the control group ( 8.3 % , 19 of 230 versus 2.1 % , four of 189 ) consulted specialists by 12 months ( P = 0.01 ) . However , alcohol-related problems and health-care utilization did not differ significantly in the two groups during follow-up . CONCLUSIONS Data from Taiwan confirm that brief in-hospital intervention can result in a reduction in alcohol intake by men who drink heavily or are diagnosed with an alcohol use disorder [20102995] BACKGROUND Binge drinking is a common pattern of alcohol use in the US . However , no studies have evaluated the effectiveness of brief interventions targeting only binge drinkers . METHODS R and omized controlled clinical trial with a 12-month follow-up period conducted from March 1 , 2003 to March 1 , 2006 in Spain . Of a screened population of 15,325 patients seeking routine medical care from their primary care providers , patients who met inclusion criteria were r and omized into an experimental group ( n=371 ) or a control group ( n=381 ) . The primary outcome measures were the frequency of binge drinking episodes and weekly alcohol intake . RESULTS There were no significant differences at baseline between groups in alcohol use and demographic variables . At the end of the 12-month follow-up period , there were significant reductions in binge-drinking status ( 52.2 % vs 67.2 % , P < .001 ) , number of episodes of binge drinking ( 1.14 vs 1.56 , P < .001 ) , number of drinks weekly ( 19.2 vs 22.4 , P < .001 ) , and frequency of excessive alcohol intake in 7 days ( 47.9 % vs 66.6 % , P > .001 ) . CONCLUSIONS This study provided evidence that screening and brief counseling delivered by a primary care physician as part of regular health care significantly reduced binge drinking episodes in binge drinkers [23192220] Alcohol exposed pregnancy ( AEP ) is a leading cause of preventable birth defects . While r and omized controlled trials ( RCTs ) have shown that multi-session motivational interviewing-based interventions reduce AEP risk , a one-session intervention could facilitate broader implementation . The purpose s of this study were to : ( 1 ) test a one-session motivational AEP prevention intervention for community women and ( 2 ) compare outcomes to previous RCTs . Participants at risk for AEP ( N=217 ) were r and omized to motivational interviewing+ assessment feedback ( EARLY ) , informational video , or informational brochure conditions . Outcomes were drinks per drinking day ( DDD ) , ineffective contraception rate , and AEP risk at 3 and 6 months . All interventions were associated with decreased DDD , ineffective contraception rate , and AEP risk . Participants who received EARLY had larger absolute risk reductions in ineffective contraception and AEP risk , but not DDD . Effect sizes were compared to previous RCTs . The one-session EARLY intervention had less powerful effects than multi-session AEP prevention interventions among community women , but may provide a new option in a continuum of preventive care [20729010] BACKGROUND Brief motivational intervention ( BMI ) is one of the few effective strategies targeting alcohol consumption , but has not been tested in young men in the community . We evaluated the efficacy of BMI in reducing alcohol use and related problems among binge drinkers and in maintaining low-risk drinking among non-bingers . METHODS A r and om sample of a census of men included during army conscription ( which is m and atory for 20-year-old males in Switzerl and ) was r and omized to receive a single face-to-face BMI session ( N=199 ) or no intervention ( N=219 ) . A six-month follow-up rate was obtained for 88.7 % of the subjects . RESULTS Among binge drinkers , there was 20 % less drinking in the BMI group versus the control group ( incidence rate ratio=0.80 , confidence interval 0.66 - 0.98 , p=0.03 ) ; the BMI group showed a weekly reduction of 1.5 drinks compared to an increase of 0.8 drinks weekly in the control group . Among subjects who experienced one or more alcohol-related consequences over the last 12 months , there was 19 % less drinking in the BMI group compared to the control group ( incidence rate ratio=0.81 , confidence interval 0.67 - 0.97 , p=0.04 ) . Among non-bingers , BMI did not contribute to the maintenance of low-risk drinking . CONCLUSION BMI reduced the alcohol use of binge drinkers , particularly among those who experienced certain alcohol-related adverse consequences . No preventive effect of BMI was observed among non-bingers . BMI is a plausible secondary preventive option for young binge drinkers

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### Context: [17784901] AIMS ( i ) To evaluate the effect of receiving one of two brief interventions in reducing alcohol consumption among general hospital patients compared with usual care . ( ii ) To assess whether a brief intervention of self-efficacy enhancement was superior to a self-help booklet in reducing alcohol consumption . DESIGN A three-arm cluster r and omized controlled trial . SETTING Seven general medical , six general surgical , one dermatology and two otolaryngology wards of a large teaching hospital covering a large urban and rural area . PARTICIPANTS A total of 215 of 789 in- patients aged 18 - 75 years , who screened positive for alcohol consumption in excess of national recommended limits according to a 7-day retrospective drinking diary . INTERVENTIONS Participants were allocated to receive one of three interventions : ( i ) face-to-face self-efficacy enhancement ; ( ii ) a self-help booklet ; or ( iii ) usual care . MEASUREMENTS The primary outcome measure was change in reported alcohol consumption at 6-month follow-up as measured by a 7-day retrospective drinking diary . Secondary outcomes were change in : number of alcohol drinking days in last week ; the maximum units of alcohol consumed on any one day in last week ; and Drinking Refusal Self-efficacy Expectancy Question naire score . FINDINGS Compared to the usual care group the self-efficacy enhancement group ( -10.1 units 95 % CI -16.1 to -4.1 ) and the self-help booklet group ( -10.0 units 95 % CI -16.0 to -3.9 ) had greater reductions in self-reported weekly alcohol consumption . There was no evidence that self-efficacy enhancement was superior to the self-help booklet ( P = 0.96 ) . CONCLUSIONS Brief interventions delivered in hospital offer simple means of helping heavy drinkers to reduce their alcohol consumption [2858246] Seven hundred and thirty one men admitted to medical wards were interviewed to identify problem drinkers who had not received previous treatment for alcoholism and who had some social support . One hundred and sixty one met the diagnostic criteria ; 156 agreed to a follow up interview and were allocated to one of two groups . One group received a session of counselling about their drinking habits from a nurse while the other received only routine medical care . Both groups reported a reduction in alcohol consumption when interviewed 12 months later , but the counselled group had a significantly better outcome than the control group . It is concluded that systematic screening for alcohol consumption and related problems should become a routine part of medical assessment and that advice on drinking habits is effective if given before irreversible physical or psychosocial problems have developed [24961378] BACKGROUND Brief motivational intervention ( BMI ) has shown promising results to reduce alcohol use in young adults . Knowledge on mechanisms that predict BMI efficacy could potentially improve treatment effect sizes through data that optimize clinical training and implementation . Particularly , little attention has been given to counselor influence on treatment mechanisms . METHODS We investigated the influence of counselors on BMI efficacy in reducing alcohol use among non-treatment-seeking young men ( age 20 ) screened as hazardous drinkers . Participants were r and omly allocated to ( i ) a group receiving a single BMI from 1 of 18 counselors selected to maximize differences in several of their characteristics ( gender , professional status , clinical experience , and motivational interviewing [ MI ] experience ) or ( ii ) a control group receiving assessment only . Drinking at 3-month follow-up was first compared between the BMI and control groups to assess efficacy . Then , the influence of counselors ' characteristics ( i.e. , gender , professional status , clinical experience , MI experience , BMI attitudes , and expectancies ) and within-session behaviors ( i.e. , measured by the Motivational Interviewing Skill Code ) on outcome was tested in regression analyses . RESULTS There was a significant ( p = 0.02 ) decrease in alcohol use among the BMI group compared to the control group . Counselors that were male , more experienced , that had more favorable BMI attitudes and expectancies , higher MI skills , but surprisingly less MI-consistent behaviors , had significantly better outcomes than the control group while their counterparts did not . CONCLUSIONS The current study demonstrated BMI efficacy on alcohol use reduction within a sample of non-treatment-seeking young adult males . Moreover , BMI effect was related to interindividual differences among counselors , and results therefore provide recommendations for BMI training and implementation with similar population [20670329] OBJECTIVES Adolescents in their late teens and early 20s have the highest alcohol consumption in the United States ; binge drinking peaks at age 21 - 25 years . Underage drinking is associated with many negative consequences , including academic problems and risk of intentional and unintentional injuries . This study tested the effectiveness of pediatric emergency department ( PED ) screening and brief intervention to reduce alcohol consumption and associated risks . METHODS A three-group r and omized assignment trial was structured to test differences between intervention ( I ) and st and ard assessed control ( AC ) groups in alcohol consumption and alcohol-related behaviors from baseline to 12 months and to compare the AC group with a minimally assessed control ( MAC ) group to adjust for the effect of assessment reactivity on control group behavior . Patients aged 14 - 21 years were eligible if they screened positive on the Alcohol Use Disorders Identification Test ( AUDIT ) or for binge drinking or high-risk behaviors . The MAC group received a re source h and out , written advice about alcohol-related risks , and a 12-month follow-up appointment . Patients in the AC group were assessed using st and ardized instruments in addition to the MAC protocol . The I group received a peer-conducted motivational intervention , referral to community re sources and treatment if indicated , and a 10-day booster in addition to assessment . Measurements included 30-day self-report of alcohol consumption and alcohol-related behaviors , screens for depression and posttraumatic stress disorder , and self-report of attempts to quit , cut back , or change conditions of use , all repeated at follow-up . Motor vehicle records and medical records were also analyzed for changes from baseline to 1-year follow-up . RESULTS Among 7,807 PED patients screened , 1,202 were eligible ; 853 enrolled ( I , n = 283 ; AC , n = 284 ; MAC , n = 286 ) , with a 12-month follow-up rate of 72 % . At 12 months , more than half of enrollees in Reaching Adolescents for Prevention ( RAP ) attempted to cut back on drinking , and over a third tried to quit . A significantly larger proportion of the I group made efforts to quit drinking and to be careful about situations when drinking compared to AC enrollees , and there was a numerically but not significantly greater likelihood ( p = 0.065 ) among the I group for efforts to cut back on drinking . At 3 months , the likelihood of the I group making attempts to cut back was almost triple that of ACs . For efforts to quit , it was double , and for trying to be careful about situations when drinking , there was a 72 % increase in the odds ratio ( OR ) for the I group . Three-month results for attempts were sustained at 12 months for quit attempts and efforts to be careful . Consumption declined in both groups from baseline to 3 months to 12 months , but there were no significant between-group differences in alcohol-related consequences at 12 months or in alcohol-related risk behaviors . We found a pattern suggestive of assessment reactivity in only one variable at 12 months : the attempt to cut back ( 73.3 % for the I group vs. 64.9 % among the AC group and 54.8 % among the MAC group ) . CONCLUSIONS Brief motivational intervention result ed in significant efforts to change behavior ( quit drinking and be careful about situations while drinking ) but did not alter between-group consumption or consequences [3409578] Background Internet-based interventions for heavy drinkers show promising results , but existing research is characterized by few studies in nonstudent adult population s and few comparisons with appropriate control groups . Objective To test whether a fully automated Internet-based brief personalized feedback intervention and a fully automated Internet-based personalized brief advice intervention in a non-treatment-seeking population of heavy drinkers would result in a reduced alcohol intake . Methods We conducted a 3-arm parallel r and omized controlled trial in a general population -based sample of heavy drinkers . The 54,157 participants ( median age of 58 years ) were screened for heavy drinking . Of the 3418 participants who had a weekly alcohol consumption above 14 drinks for women and 21 drinks for men , 1380 ( 619 women ) consented to take part in the trial and were r and omly assigned to an Internet-based brief personalized feedback intervention group ( normative feedback , n = 476 ) , an Internet-based personalized brief advice intervention group ( n = 450 ) , or a nonintervention control group ( n = 454 ) . Follow-up after 6 and 12 months included 871 and 1064 participants , respectively , of all groups combined . The outcome measure was self-reported weekly alcohol consumption . We analyzed the data according to the intention-to-treat principle . To examine changes over time and to account for the multiple time measurements , we used a multilevel linear mixed model . To take attrition into account , we used multiple imputation to address missing data . Results The intervention effect of the Internet-based brief personalized feedback intervention , determined as the mean additional difference in changes in alcohol consumption in the Internet-based brief personalized feedback intervention compared with the control group , was –1.8 drinks/week after 6 months and –1.4 drinks/week after 12 months ; these effects were nonsignificant ( 95 % confidence interval –4.0 to 0.3 at 6 months , –3.4 to 0.6 at 12 months ) . The intervention effect of the Internet-based personalized brief advice intervention was –0.5 drinks/week after 6 months and –1.2 drinks/week after 12 months ; these effects were nonsignificant ( 95 % confidence interval –2.7 to 1.6 at 6 months , –3.3 to 0.9 at 12 months ) . Conclusions In this r and omized controlled trial we found no evidence that an Internet-based brief personalized feedback intervention was effective in reducing drinking in an adult population of heavy drinkers . Trial registration Clinical Trials.gov NCT00751985 ; http:// clinical trials.gov/ct2/show/NCT00751985 ( Archived by WebCite at http://www.webcitation.org/68WCRLyaP [25063992] AIM To evaluate the effectiveness of different brief intervention strategies at reducing hazardous or harmful drinking in the probation setting . Offender managers were r and omized to three interventions , each of which built on the previous one : feedback on screening outcome and a client information leaflet control group , 5 min of structured brief advice and 20 min of brief lifestyle counselling . METHODS A pragmatic multicentre factorial cluster r and omized controlled trial . The primary outcome was self-reported hazardous or harmful drinking status measured by Alcohol Use Disorders Identification Test ( AUDIT ) at 6 months ( negative status was a score of < 8) . Secondary outcomes were AUDIT status at 12 months , experience of alcohol-related problems , health utility , service utilization , readiness to change and reduction in conviction rates . RESULTS Follow-up rates were 68 % at 6 months and 60 % at 12 months . At both time points , there was no significant advantage of more intensive interventions compared with the control group in terms of AUDIT status . Those in the brief advice and brief lifestyle counselling intervention groups were statistically significantly less likely to reoffend ( 36 and 38 % , respectively ) than those in the client information leaflet group ( 50 % ) in the year following intervention . CONCLUSION Brief advice or brief lifestyle counselling provided no additional benefit in reducing hazardous or harmful drinking compared with feedback on screening outcome and a client information leaflet . The impact of more intensive brief intervention on reoffending warrants further research [17345916] Motivational interviewing ( MI ) is a brief intervention that has been shown to reduce heavy drinking among college students . Because all college studies of MI to date have included a personalized feedback report , it remains unclear which of the components is necessary to produce behavior change . This study evaluated the separate and collective effects of MI and feedback among 122 “ binge ” drinking college students . Participants were r and omized to : 1 ) MI with feedback , 2 ) MI without feedback , 3 ) Mailed feedback only , 4 ) MI with mailed feedback , or 5 ) Assessment only control . At an eight-week follow-up , all groups reduced their consumption , peak BAC , consequences , and dependence symptoms . For females , there were reductions in consequences and dependence symptoms in groups that received feedback , as compared to groups that did not receive feedback . For females , there was an effect of the feedback on consequences and dependence symptoms , but was no overall effect of MI on any outcome measure [22197301] This study evaluated the efficacy of two brief personalized feedback interventions ( PFIs ) using identical feedback and motivational interviewing strategies aim ed at reducing alcohol consumption and alcohol-related problems to two control conditions among a sample of high-risk drinking college students . Students ( N = 152 ) were r and omly assigned to a computer-delivered PFI with a video interviewer , a face-to-face PFI with a live interviewer , a comprehensive assessment condition , or a minimal assessment -only condition . At 10 weeks posttreatment , the face-to-face PFI significantly reduced weekly drinking quantity and peak and typical blood alcohol concentration compared with the comprehensive assessment and minimal assessment -only conditions ( d values ranged from 0.32 to 0.61 ) . No significant between-group differences were evidence d for the computer-delivered PFI condition , although effect sizes were comparable to other college drinking studies using computer-delivered interventions ( d values ranged from 0.20 to 0.27 ) . Results provide further support for the use of a face-to-face PFI to help reduce college students ' alcohol consumption and suggest that a video interviewer in the context of a computer-delivered PFI is likely a helpful but not necessarily a complete substitute for a live interviewer [4070907] Background Alcohol misuse is common in people attending emergency departments ( EDs ) and there is some evidence of efficacy of alcohol screening and brief interventions ( SBI ) . This study investigated the effectiveness of SBI approaches of different intensities delivered by ED staff in nine typical EDs in Engl and : the SIPS ED trial . Methods and Findings Pragmatic multicentre cluster r and omized controlled trial of SBI for hazardous and harmful drinkers presenting to ED . Nine EDs were r and omized to three conditions : a patient information leaflet ( PIL ) , 5 minutes of brief advice ( BA ) , and referral to an alcohol health worker who provided 20 minutes of brief lifestyle counseling ( BLC ) . The primary outcome measure was the Alcohol Use Disorders Identification Test ( AUDIT ) status at 6 months . Of 5899 patients aged 18 or more presenting to EDs , 3737 ( 63·3 % ) were eligible to participate and 1497 ( 40·1 % ) screened positive for hazardous or harmful drinking , of whom 1204 ( 80·4 % ) gave consent to participate in the trial . Follow up rates were 72 % ( n = 863 ) at six , and 67 % ( n = 810 ) at 12 months . There was no evidence of any differences between intervention conditions for AUDIT status or any other outcome measures at months 6 or 12 in an intention to treat analysis . At month 6 , compared to the PIL group , the odds ratio of being AUDIT negative for brief advice was 1·103 ( 95 % CI 0·328 to 3·715 ) . The odds ratio comparing BLC to PIL was 1·247 ( 95 % CI 0·315 to 4·939 ) . A per protocol analysis confirmed these findings . Conclusions SBI is difficult to implement in typical EDs . The results do not support widespread implementation of alcohol SBI in ED beyond screening followed by simple clinical feedback and alcohol information , which is likely to be easier and less expensive to implement than more complex interventions . Trial Registration Current Controlled Trials IS RCT N [7888970] In a controlled evaluation of general practitioner (GP)-based brief intervention , 378 excessive drinkers identified opportunistically by screening in 40 group practice s in metropolitan Sydney were assigned to groups receiving : ( i ) a five-session intervention by the GP ( the Alcoholscreen Program ) ; ( ii ) a single session of 5 minutes ' advice by the GP plus a self-help manual ( minimal intervention ) ; ( iii ) an alcohol-related assessment but no intervention ; ( iv ) neither intervention nor assessment . Among all patients allocated to receive it , the Alcoholscreen Program did not result in a significantly greater reduction in consumption at follow-up than control conditions but patients offered Alcoholscreen reported a significantly greater reduction in alcohol-related problems in the period to 6 months follow-up . A greater proportion of patients who returned for the second Alcoholscreen visit were drinking below recommended levels at follow-up than in the remainder of the sample . There was no evidence that minimal intervention or alcohol-related assessment were effective in reducing alcohol consumption or problems . Implication s for further research into GP-based brief interventions are discussed [4016505] Background The evidence suggests that brief alcohol-focused interventions , directed at hazardous and harmful drinkers in non-specialist setting s such as primary care are effective in reducing alcohol consumption . However , there is a need for further research in the hospital setting . This is a r and omised controlled trial to investigate the effectiveness of a 10-minute brief intervention amongst ' at risk ’ drinkers admitted to general hospital wards . Unlike some previous trials , this trial is r and omised , used blinded assessors , includes an intention-to-treat analysis , included female subjects and excluded people with alcohol dependence . Methods A total of 250 ' at risk ’ drinkers admitted to King ’s College Hospital were identified using the Alcohol Use Disorders Identification Test ( AUDIT ) . Some 154 subjects entered the study and were r and omly allocated to the control and intervention groups . Subjects in the control group received no advice about their drinking whilst subjects in the intervention group received 10 minutes of simple advice on reducing alcohol consumption . Recruitment took place between 1995 and 1997 . The primary outcome was the AUDIT question naire at 12 months . Secondary outcomes were a previous week ’s Drinks Diary , question naires ( General Health Question naire , Alcohol Problems Question naire and the Severity of Alcohol Dependence Question naire ) and laboratory blood tests ( gamma glutamyl transferase , mean cell volume and haemoglobin ) . Results At 3-month and 12-month follow-up , all participants were included in the intention-to-treat analysis . At both time points there was no evidence of an intervention effect that could be attributed to the brief intervention . Both the intervention and control groups had an improved AUDIT score and reduced levels of alcohol consumption as measured by a subjective Drinks Diary at 3 months which was maintained at 12 months . Conclusions This study has added further evidence on brief interventions in the hospital setting . In contrast to the recent Cochrane review by McQueen et al. , the results of this study do not support the effectiveness of a brief alcohol intervention in general hospital wards . However our study was underpowered and there were flaws in the statistical analyses , and these limitations temper the strength of our conclusions [21777259] BACKGROUND Heavy drinking is one of the leading causes of morbidity and mortality in young men . Brief motivational intervention ( BMI ) has shown promising results for young people , but has never been tested in young men in the community who volunteered to receive an intervention . METHODS We evaluated the effectiveness of BMI in reducing alcohol use among heavy episodic users and in maintaining low-risk drinking among nonheavy episodic users . Participants were French-speaking young men attending the m and atory Swiss army conscription process . They were offered the opportunity to receive a 20-minute BMI , and those interested were r and omized into an intervention group ( BMI immediately ) or into a control group ( BMI after the 6-month follow-up assessment , in a waiting list design ) . Analyses were conducted separately for heavy and nonheavy episodic users ( separated using baseline heavy episodic use frequency ) as the hypotheses tested were different between both groups ( primary vs. secondary prevention intervention ) . RESULTS From a pool of 6,085 young men invited to receive BMI , 727 ( 11.9 % ) showed up and 572 were included in the study ( after exclusions related to organizational aspects of the conscription process ) . Among nonheavy episodic users , there was a protective effect of BMI on weekly alcohol use ( p < 0.05 ) . Among heavy episodic users , there were no significant effects of BMI . CONCLUSIONS About 12 % of young men were interested in addressing their drinking within the BMI framework , suggesting that there is some need for easily accessible alcohol intervention . The present intervention did have a preventive effect among low-risk young drinkers in helping them maintain their patterns of alcohol use . An explanation for the lack of effectiveness among heavy episodic users might be that those individuals interested in BMI had patterns of more severe alcohol use , thereby making change more difficult [3448228] Sixteen general practitioners participated in a controlled trial of the Scottish Health Education Group 's DRAMS ( drinking reasonably and moderately with self-control ) scheme . The scheme was evaluated by r and omly assigning 104 heavy or problem drinkers to three groups - a group participating in the DRAMS scheme ( n = 34 ) , a group given simple advice only ( n = 32 ) and a non-intervention control group ( n = 38 ) . Six month follow-up information was obtained for 91 subjects ( 87.5 % of initial sample ) . There were no significant differences between the groups in reduction in alcohol consumption , but patients in the DRAMS group showed a significantly greater reduction in a logarithmic measure of serum gamma-glutamyl-transpeptidase than patients in the group receiving advice only . Only 14 patients in the DRAMS group completed the full DRAMS procedure . For the sample as a whole , there was a significant reduction in alcohol consumption , a significant improvement on a measure of physical health and well-being , and significant reductions in the logarithmic measure of serum gamma-glutamyl transpeptidase and in mean corpuscular volume . The implication s of these findings for future research into controlled drinking minimal interventions in general practice are discussed [23410849] Brief interventions for college heavy drinkers have shown promise in reducing drinking and alcohol-related negative consequences . However , intervention duration , content , method of delivery , and follow-up length vary across studies . It therefore remains unclear whether intervention length significantly influences the interventions ' efficacy . The present study is a r and omized clinical trial systematic ally evaluating the efficacy of two brief interventions aim ed at reducing alcohol use and alcohol-related negative consequences among college student drinkers . Treatment mediators were also evaluated . Participants ( N=278 ) were , on average , 20.1 years old ( SD=2.4 ) , mostly Caucasian ( 87 % ) and female ( 71 % ) . They were r and omly assigned to a 10-minute brief intervention , a 50-minute brief intervention , or an attention-control group . Both active interventions were provided by clinical graduate students trained in Brief Alcohol Screening and Intervention for College Students ( BASICS ) . As hypothesized , participants in both active conditions significantly reduced their alcohol consumption , as compared to the control group participants F(2,264)=9.84 , p=.00 , η(2)=.07 . There were no significant differences in alcohol-related negative consequences F(2,264)=3.08 , p=.06 , η(2)=.02 . The hypothesized mediators , alcohol drinking norms and coping behavioral strategies , explained significant variance in intervention efficacy , but neither self-efficacy nor alcohol expectancies were significant mediators . Given the preliminary nature of our investigation , more research is warranted to determine parameters of the critical mechanisms of change within brief alcohol interventions with college student drinkers [11373259] The aim of this research was to evaluate the effectiveness of long-term brief intervention in routine general practice . In five primary care out-patient clinics in a Finnish town , 296 male early-phase heavy drinkers consulting a general practitioner ( GP ) for various reasons were identified . Control group C ( n = 88 ) was informed of the risks of drinking after the screening and were advised at the subsequent feedback about 2 weeks later to reduce their drinking . Groups A ( n = 109 ) and B ( n = 99 ) were offered in addition seven and three brief intervention sessions , respectively . All GPs took part , whether or not they indicated a special interest . The main outcome measures were differences between beginning and end-point at 3 years in self-reported alcohol consumption , mean corpuscular volume ( MCV ) , and serum carbohydrate-deficient transferrin , aspartate aminotransferase , alanine aminotransferase and gamma-glutamyltransferase . There were no statistically significant differences between study groups A , B and C in mean changes in outcome measures . Within all the groups , MCV decreased . Depending on the outcome measure used and the study group analysed , clinical ly significant reduction of drinking was found in 25 - 53 % of the subjects . In routine general practice , giving additional sessions of brief intervention may not be as effective as in special research conditions . Factors reducing the effectiveness of brief intervention programmes should be investigated , so that primary health care staff can be better supported in their efforts [3541471] Objective To evaluate the effectiveness of different brief intervention strategies at reducing hazardous or harmful drinking in primary care . The hypothesis was that more intensive intervention would result in a greater reduction in hazardous or harmful drinking . Design Pragmatic cluster r and omised controlled trial . Setting Primary care practice s in the north east and south east of Engl and and in London . Participants 3562 patients aged 18 or more routinely presenting in primary care , of whom 2991 ( 84.0 % ) were eligible to enter the trial : 900 ( 30.1 % ) screened positive for hazardous or harmful drinking and 756 ( 84.0 % ) received a brief intervention . The sample was predominantly male ( 62 % ) and white ( 92 % ) , and 34 % were current smokers . Interventions Practice s were r and omised to three interventions , each of which built on the previous one : a patient information leaflet control group , five minutes of structured brief advice , and 20 minutes of brief lifestyle counselling . Delivery of the patient leaflet and brief advice occurred directly after screening and brief lifestyle counselling in a subsequent consultation . Main outcome measures The primary outcome was patients ’ self reported hazardous or harmful drinking status as measured by the alcohol use disorders identification test ( AUDIT ) at six months . A negative AUDIT result ( score < 8) indicated non-hazardous or non-harmful drinking . Secondary outcomes were a negative AUDIT result at 12 months , experience of alcohol related problems ( alcohol problems question naire ) , health utility ( EQ-5D ) , service utilisation , and patients ’ motivation to change drinking behaviour ( readiness to change ) as measured by a modified readiness ruler . Results Patient follow-up rates were 83 % at six months ( n=644 ) and 79 % at 12 months ( n=617 ) . At both time points an intention to treat analysis found no significant differences in AUDIT negative status between the three interventions . Compared with the patient information leaflet group , the odds ratio of having a negative AUDIT result for brief advice was 0.85 ( 95 % confidence interval 0.52 to 1.39 ) and for brief lifestyle counselling was 0.78 ( 0.48 to 1.25 ) . A per protocol analysis confirmed these findings . Conclusions All patients received simple feedback on their screening outcome . Beyond this input , however , evidence that brief advice or brief lifestyle counselling provided important additional benefit in reducing hazardous or harmful drinking compared with the patient information leaflet was lacking . Trial registration Current Controlled Trials IS RCT N06145674 [19538921] OBJECTIVE This study tested the effectiveness of brief primary care provider interventions delivered in a college student health center to a sample of college students who screened positive for high-risk drinking . METHOD Between November 2005 and August 2006 , 8,753 students who presented as new patients to the health service at a large public university were screened for high-risk drinking , and 2,484 students ( 28 % ) screened positive on the 5/4 gender-specific high-risk drinking question ( i.e. , five or more drinks per occasion for men and four or more for women ) . Students who screened positive for high-risk drinking and consented to participate ( N= 363 ; 52 % female ) were r and omly assigned either to a control group ( n = 182 ) or to an experimental group ( n = 181 ) . Participants in the experimental group received two brief intervention sessions that were founded in motivational interviewing techniques and delivered by four specially trained providers within the student health center . Data on alcohol use and related harms were obtained from a Web-based Healthy Lifestyle Question naire , 30-day Timeline Followback alcohol-use diaries , the Rutgers Alcohol Problem Index ( RAPI ) , and eight items from the Drinker Inventory of Consequences-2L . RESULTS Repeated measures analysis showed that , compared with the control group ( C ) , the intervention group ( I ) had significant reductions in typical estimated blood alcohol concentration ( BAC ) ( C = .071 vs I = .057 at 3 months ; C = .073 vs I = .057 at 6 months ) , peak BAC ( C = . 142 vs I = .112 at 3 months ; C = .145 vs I = .108 at 6 months ) , peak number of drinks per sitting ( C = 8.03 vs I = 6.87 at 3 months ; C = 7.98 vs I = 6.52 at 6 months ) , average number of drinks per week ( C = 9.47 vs I = 7.33 at 3 months ; C = 8.90 vs I = 6.16 at 6 months ) , number of drunk episodes in a typical week ( C = 1.24 vs I = 0.85 at 3 months ; C = 1.10 vs I = 0.71 at 6 months ) , number of times taken foolish risks ( C = 2.24 vs I = 1.12 at 3 months ) , and RAPI sum scores ( C = 6.55 vs I = 4.96 at 6 months ; C = 6.17 vs I = 4.58 at 9 months ) . CONCLUSIONS Brief interventions delivered by primary care providers in a student health center to high-risk-drinking students may result in significantly decreased alcohol consumption , high-risk drinking , and alcohol-related harms [11767271] The authors evaluated the efficacy of Brief Alcohol Screening and Intervention for College Students ( BASICS - L. A. Dimeff , J. S. Baer , D. R. Kivlahan , & G. A. Marlatt , 1999 ) , a single session of drinking-related feedback intended to reduce heavy drinking and related harm . College student drinkers ( N = 99 ) were assigned to BASICS , an educational intervention , or an assessment -only control group . At 3 months postintervention . there were no overall significant group differences , but heavier drinking BASICS participants showed greater reductions in weekly alcohol consumption and binge drinking than did heavier drinking control and education participants . At 9 months , heavier drinking BASICS participants again showed the largest effect sizes . BASICS participants evaluated the intervention more favorably than did education participants . This study suggests that BASICS may be more efficacious than educational interventions for heavier drinking college students [17565563] AIMS To evaluate the effectiveness of brief alcohol intervention ( BAI ) in reducing alcohol use among hazardous drinkers treated in the emergency department ( ED ) after an injury ; in addition it tests whether assessment of alcohol use without BAI is sufficient to reduce hazardous drinking . DESIGN R and omized controlled clinical trial with 12-month follow-up conducted between January 2003 and June 2005 . SETTING Urban academic emergency department ( ED ) of the Lausanne University Hospital , Lausanne , Switzerl and . PARTICIPANTS A total of 5136 consecutive patients attending ED after an injury completed a seven-item general and a three-item alcohol screen and 1472 ( 28.7 % ) were positive for hazardous drinking according to the National Institute on Alcohol Abuse and Addiction definition ; of these 987 ( 67.1 % ) were r and omized into a BAI group ( n = 310 ) or a control group with screening and assessment ( n = 342 ) or a control group with screening only ( n = 335 ) and then a total of 770 patients ( 78.0 % ) completed the 12-month follow-up procedures . INTERVENTION A single 10 - 15-minute session of st and ardized BAI conducted by a trained research assistant . MEASUREMENTS Percentage of participants who have changed to low-risk drinking at follow-up . FINDINGS Data obtained at 12 months indicated that similar proportions were low-risk drinkers in BAI versus control groups with and without assessment ( 35.6 % , 34.0 % , 37.0 % , respectively , P = 0.71 ) . Data also indicated similar reductions in drinking frequency , quantity , binge drinking frequency and Alcohol Use Disorders Identification Test ( AUDIT ) scores across groups . All groups reported similar numbers of days hospitalized and numbers of medical consults in the last 12 months . A model including age groups , gender , AUDIT and injury severity scores indicated that BAI had no influence on the main alcohol use outcome . CONCLUSIONS This study provides the evidence that a 10 - 15-minute BAI does not decrease alcohol use and health re source utilization in hazardous drinkers treated in the ED , and demonstrates that commonly found decreases in hazardous alcohol use in control groups can not be attributed to the baseline alcohol assessment [11045860] BACKGROUND Studies suggest that 14 % of women age 18 to 40 drink alcohol above recommended limits . Of special concern is the increasing use of alcohol by women during pregnancy . This article reports 48 month follow-up data from a sub analysis of a trial for early alcohol treatment ( Project TrEAT ) focused on women of childbearing age . METHODS Project TrEAT was conducted in the offices of 64 primary care , community-based physicians from 10 Wisconsin counties . Of 5979 female patients ages 18 to 40 who were screened for problem drinking , 205 were r and omized into an experimental group ( n = 103 ) or control group ( n = 102 ) . The intervention consisted of two 15 min , physician-delivered counseling visits that included advice , education , and contracting by using a scripted workbook . A total of 174 subjects ( 85 % ) completed the 48 month follow-up procedures . RESULTS No significant differences were found between the experimental and control groups at baseline for alcohol use , age , socioeconomic status , smoking , depression or anxiety , conduct disorder , lifetime drug use , or health care utilization . The trial found a significant treatment effect in reducing both 7 day alcohol use ( p = 0.0039 ) and binge drinking episodes ( p = 0.0021 ) over the 48 month follow-up period . Women in the experimental group who became pregnant during the follow-up period had the most dramatic decreases in alcohol use . A logistic regression model based on a 20 % or greater reduction in drinking found an odds ratio of 1.93 ( confidence interval 1.07 - 3.46 ) in the sample exposed to physician intervention . Age , smoking , depression , conduct disorder , antisocial personality disorder , and illicit drug use did not reduce drinking significantly . No significant differences were found in health care utilization and health status between groups . CONCLUSIONS This trial provides the first direct evidence that brief intervention is associated with sustained reductions in alcohol consumption by women of childbearing age . The results have enormous implication s for the U.S. health care system [24315218] AIMS The aim of this study is to assess the effect of brief motivational enhancement intervention postpartum alcohol use . DESIGN This study is a single-blinded , r and omized controlled effectiveness trial in which pregnant women were assigned to receive usual care or up to 5 face-to-face brief motivational enhancement sessions lasting 10 - 30 minutes each and occurring at study enrollment , 4 and 8 weeks after enrollment , 32 weeks of gestation , and 6 weeks postpartum . SETTING The setting is in a large , urban , obstetrics clinic . PARTICIPANTS Participants were women who were ≥ 18 years old , < 20 weeks of gestation , and consumed alcohol during pregnancy . Of 3438 women screened , 330 eligible women were assigned to usual care ( n = 165 ) or intervention ( n=165 ) . Due to missing data , we analyzed 125 in the intervention group and 126 in the usual care group . MEASUREMENTS The measurements were the proportion of women with any alcohol use and the number of drinks per day , reported via follow-up telephone interviews at 4 and 8 weeks after enrollment , 32 weeks of gestation , and 6 weeks , 6 months , and 12 months postpartum . FINDINGS In r and om effects models adjusted for confounders , the intervention group was less likely to use any alcohol ( odds ratio 0.50 ; 95 % confidence interval [ CI ] , 0.23 - 1.09 ; P=0.08 ) and consumed fewer drinks per day ( coefficient -0.11 ; 95 % CI -0.23 - 0.01 ; P=0.07 ) than , the usual care group in the postpartum period but these differences were non-significant . Missing data during the prenatal period prevented us from modeling prenatal alcohol use . CONCLUSIONS Brief motivational enhancement intervention delivered in an obstetrical outpatient setting did not conclusively decrease alcohol use during the postpartum period [19170454] Motivational interviewing ( MI ) is a counseling style that has been shown to reduce heavy drinking among college students . To date , all studies of MI among college students have used a format that includes a feedback profile delivered in an MI style . This study was a dismantling trial of MI and feedback among heavy-drinking college students . After an initial screen , 279 heavy-drinking students were r and omized to ( a ) Web feedback only , ( b ) a single MI session without feedback , ( c ) a single MI session with feedback , or ( d ) assessment only . At 6 months , MI with feedback significantly reduced drinking , as compared with assessment only ( effect size = .54 ) , MI without feedback ( effect size = .63 ) , and feedback alone ( effect size = .48 ) . Neither MI alone nor feedback alone differed from assessment only . Neither sex , race or ethnicity , nor baseline severity of drinking moderated the effect of the intervention . Norm perceptions mediated the effect of the intervention on drinking . MI with feedback appears to be a robust intervention for reducing drinking and may be mediated by changes in normative perceptions [9735576] This r and omized controlled trial evaluated the efficacy of a brief intervention design ed to reduce the harmful consequences of heavy drinking among high-risk college students . Students screened for risk while in their senior year of high school ( 188 women and 160 men ) were r and omly assigned to receive an individualized motivational brief intervention in their freshman year of college or to a no-treatment control condition . A normative group selected from the entire screening pool provided a natural history comparison . Follow-up assessment s over a 2-year period showed significant reductions in both drinking rates and harmful consequences , favoring students receiving the intervention . Although high-risk students continued to experience more alcohol problems than the natural history comparison group over the 2-year period , most showed a decline in problems over time , suggesting a developmental maturational effect [19919597] BACKGROUND Evidence suggests that brief interventions in the trauma care setting reduce drinking , subsequent injury and driving under the influence ( DUI ) arrest . However , evidence on the effectiveness of these interventions in ethnic minority groups is lacking . The current study evaluates the efficacy of brief intervention among whites , blacks and Hispanics in the United States . METHODS We conducted a two-group parallel r and omized trial comparing brief motivational intervention ( BMI ) and treatment as usual with assessment ( TAU+ ) to evaluate treatment differences in drinking patterns by ethnicity . Patients were recruited from a level 1 urban trauma center over a 2-year period . The study included 1493 trauma patients , including 668 whites , 288 blacks and 537 Hispanics . Hierarchical linear modeling was used to evaluate ethnic differences in drinking outcomes including volume per week , maximum amount consumed in 1 day , percentage days abstinent and percentage days heavy drinking at 6- and 12-month follow-up . Analyses controlled for age , gender , employment status , marital status , prior alcohol treatment , type of injury and injury severity . Special emphasis was given to potential ethnic differences by testing the interaction between ethnicity and BMI . RESULTS At 6- and 12-month follow-up , BMI significantly reduced maximum amount consumed in 1 day ( P < 0.001 ; P < 0.001 , respectively ) and percentage days heavy drinking ( P < 0.05 ; P < 0.05 , respectively ) among Hispanics . Hispanics in the BMI group also reduced average volume per week at 12-month follow-up ( chi(2 ) = 6.8 , df = 1 , P < 0.01 ) . In addition , Hispanics in TAU+ reduced maximum amount consumed at 6- and 12-month follow-up ( P < 0.001 ; P < 0.001 ) and volume per week at 12-month follow-up ( P < 0.001 ) . Whites and blacks in both BMI and TAU+ reduced volume per week and percentage days heavy drinking at 12-month follow-up ( P < 0.001 ; P < 0.01 , respectively ) and decreased maximum amount at 6- ( P < 0.001 ) and 12-month follow-up ( P < 0.001 ) . All three ethnic groups In both BMI and TAU+ reduced volume per week at 6-month follow-up ( P < 0.001 ) and percentage days abstinent at 6- ( P < 0.001 ) and 12-month follow-up ( P < 0.001 ) . CONCLUSIONS All three ethnic groups evidence d reductions in drinking at 6- and 12-month follow-up independent of treatment assignment . Among Hispanics , BMI reduced alcohol intake significantly as measured by average volume per week , percentage days heavy drinking and maximum amount consumed in 1 day [20236990] AIMS To determine the effectiveness of Motivational Enhancement Therapy ( MET ) for hazardous drinkers in Primary Care Unit ( PCU ) setting s in rural Thail and . METHODS A r and omized controlled trial was conducted in eight PCUs in Ubonratchatanee and Chachoengsao provinces in Thail and . Hazardous drinkers were identified using the World Health Organization-recommended Alcohol Use Disorder Identification Test . Of 117 eligible participants ( 91 % male ) , 59 were r and omized to the intervention group to receive MET in three individual appointments with a trained nurse and 58 to an assessment -only control group . Outcome evaluations were carried out after 6 weeks , 3 months and 6 months . RESULTS Follow-up data were available on 84 , 94 and 91 % of subjects , respectively , at the three intervals . Self-reported drinks per drinking day , frequency of hazardous drinking assessed either on a daily or weekly basis , and of binge drinking sessions were reduced in the intervention group more than in the control group ( P < 0.05 ) after both 3 and 6 months . The groups did not generally differ at 6 weeks . However , although self-reported consumption in both groups fell from baseline to 6-month follow-up , serum gamma-glutamyl transferase increased in both groups , which raises doubts about the validity of this marker in this sample and /or the validity of the self-reported data in this study . CONCLUSION MET delivered by nurses in PCUs in Thail and appears to be an effective intervention for male hazardous drinkers . Uncertainties about the validity of self-reported data jeopardize the safety of this conclusion [15506584] BACKGROUND High-risk alcohol use in persons 18 to 30 years of age is a critical public health problem . It is the number 1 cause of death in this population . This article reports the results of a sub analysis of young adults ( aged 18 to 30 years ) who participated in Project TrEAT ( Trial of Early Alcohol Treatment ) conducted in the offices of 64 primary care physicians located in 10 counties in southern Wisconsin . METHODS Project TrEAT was a r and omized clinical trial design ed to test the efficacy of a brief intervention protocol to reduce alcohol use , improve health status , and decrease health care utilization . A total of 226 young adults were r and omly assigned to either a usual care or brief intervention group . RESULTS There were no significant differences between the 2 groups at baseline on a number of potential confounders . During the 4-year follow-up period , there were significant reductions in number of persons drinking more than 3 drinks per day , average 7-day alcohol use , number of persons drinking 6 or more drinks per occasion , and number of binge drinking episodes in the previous 30 days ( P < .01 to P < .001 ) . There were also significant differences ( P < .05 ) in emergency department visits ( 103 vs 177 ) , motor vehicle crashes ( 9 vs 20 ) , total motor vehicle events ( 114 vs 149 ) , and arrests for controlled substance or liquor violation ( 0 vs 8) . CONCLUSION In this 4-year sub analysis of young adults who participated in Project TrEAT , we found long-term reductions in high-risk drinking behaviors and consequences . The findings of this study support more widespread implementation of brief interventions in primary care setting [12608685] This study examined the 1-year follow-up effects of the STARS ( Start Taking Alcohol Risks Seriously ) for Families program , a 2-year preventive intervention based on a stage of acquisition model , and consisting of nurse consultations and parent material s. A r and omized controlled trial was conducted , with participants receiving either the intervention or a minimal intervention control . Participants included a cohort of 650 sixth- grade students from two urban middle schools-one magnet ( bused ) and one neighborhood . Trained project staff administered question naires to students following a st and ardized protocol in the schools . For the magnet school sample , significantly fewer intervention students ( 5 % ) were planning to drink in the next 6 months than control students ( 18 % ) , chi2 = 11.53 , 1 d.f . , P = 0.001 . Magnet school intervention students also had less intentions to drink in the future , greater motivation to avoid drinking and less total alcohol risk than control students , Ps < 0.05 . For the neighborhood school , intervention students ( m = 7.90 , SD = 1.87 ) had less total alcohol risk than control students ( m = 8.42 , SD = 1.83 ) , F(1,205 ) = 4.09 , P = 0.04 . These findings suggest that a brief , stage and risk/protective factor tailored program holds promise for reducing risk for alcohol use among urban school youth 1 year after intervention , and has the unique advantage of greater ' transportability ' over classroom-based prevention programs [10522717] OBJECTIVE Alcoholism is the leading risk factor for injury . The authors hypothesized that providing brief alcohol interventions as a routine component of trauma care would significantly reduce alcohol consumption and would decrease the rate of trauma recidivism . METHODS This study was a r and omized , prospect i ve controlled trial in a level 1 trauma center . Patients were screened using a blood alcohol concentration , gamma glutamyl transpeptidase level , and short Michigan Alcoholism Screening Test ( SMAST ) . Those with positive results were r and omized to a brief intervention or control group . Reinjury was detected by a computerized search of emergency department and statewide hospital discharge records , and 6- and 12-month interviews were conducted to assess alcohol use . RESULTS A total of 2524 patients were screened ; 1153 screened positive ( 46 % ) . Three hundred sixty-six were r and omized to the intervention group , and 396 to controls . At 12 months , the intervention group decreased alcohol consumption by 21.8+/-3.7 drinks per week ; in the control group , the decrease was 6.7+/-5.8 ( p = 0.03 ) . The reduction was most apparent in patients with mild to moderate alcohol problems ( SMAST score 3 to 8) ; they had 21.6+/-4.2 fewer drinks per week , compared to an increase of 2.3+/-8.3 drinks per week in controls ( p < 0.01 ) . There was a 47 % reduction in injuries requiring either emergency department or trauma center admission ( hazard ratio 0.53 , 95 % confidence interval 0.26 to 1.07 , p = 0.07 ) and a 48 % reduction in injuries requiring hospital admission ( 3 years follow-up ) . CONCLUSION Alcohol interventions are associated with a reduction in alcohol intake and a reduced risk of trauma recidivism . Given the prevalence of alcohol problems in trauma centers , screening , intervention , and counseling for alcohol problems should be routine [20659072] BACKGROUND A r and omized controlled trial of screening , brief intervention , and referral to treatment ( SBIRT ) among at-risk ( based on average number of drinks per week and drinks per drinking day ) and dependent drinkers was conducted in an emergency department ( ED ) among 446 patients 18 and older in Sosnowiec , Pol and . METHODS Patients were recruited over a 23-week period ( 4:00 pm to 12:00 midnight ) and r and omized to 1 of 3 conditions : screened-only ( n = 147 ) , assessed ( n = 152 ) , and intervention ( n = 147 ) . Patients in the assessed and intervention conditions were blindly reassessed via a telephone interview at 3 months , and all 3 groups were assessed at 12 months ( screened-only = 92 , assessed = 99 , and intervention = 87 ) . RESULTS No difference was found across the 3 conditions in at-risk drinking at 12 months , as the primary outcome variable , or in decrease in the number of drinks per drinking day , with all 3 groups showing a significant reduction in both . Significant declines between baseline and 12 months in secondary outcomes of the RAPS4 , number of drinking days per week , and the maximum number of drinks on an occasion were seen only for the intervention condition , and in negative consequences for both the assessment and intervention conditions . CONCLUSIONS Data suggest that improvements in drinking outcomes found in the assessment condition were not because of assessment reactivity , with both the screened and intervention conditions demonstrating greater ( although nonsignificant ) improvement than the assessed condition . Only those in the intervention condition showed significant improvement in all outcome variables from baseline to 12-month follow-up . Although group by time interaction effects were not found to be significant , these findings suggest that declines in drinking measures for those receiving a brief intervention can be maintained at long-term follow-up [18054445] AIM To test the effectiveness of a brief alcohol intervention among non-dependent general hospital in patients with alcohol problems , delivered by either a specialized liaison service or hospital physicians . METHOD All in patients of 29 wards from four general hospitals of one region in Germany were screened for alcohol problems ( n=14,332 ) . Of those screening positive , 595 patients were included in a r and omized controlled group design using a time-frame . Patients with alcohol dependence were not considered in this study . Patients received Motivational Interviewing based counselling either by a specialized liaison service , by hospital physicians trained under routine conditions or received hospital treatment as usual without additional counselling . One year later , alcohol consumption , motivation and well-being were assessed . Sample survey analyses and generalized estimating equations were conducted . RESULTS At baseline , the three groups differed regarding motivation , with higher motivation among the controls . At follow-up , the groups did not differ regarding alcohol consumption , alcohol-related problems and well-being . All groups decreased their alcohol consumption significantly . Regarding motivation , longitudinal analyses revealed significant interaction effects of time and intervention ( p<0.05 ) , indicating a stronger increase of readiness to change drinking and a less profound drop of readiness to seek help among those who received intervention compared to the controls . CONCLUSION The intervention was not effective in reducing alcohol consumption or in increasing well-being 12 months after hospitalization . It had a positive effect on readiness to change drinking and on readiness to seek formal help for alcohol problems . The intervention groups compensated their lag of motivation [9415794] INTRODUCTION The study was design ed to test a brief intervention for reducing alcohol consumption among moderate to heavy ( hazardous ) drinkers in a busy HMO primary care setting . METHODS In a r and omized controlled trial , hazardous drinkers ( n = 516 ) were identified by the AUDIT screening question naire . Intervention included brief clinician advice ( 30 seconds ) , a 15-minute motivational session by counselors , and printed material s. RESULTS At six-month follow-up , intervention subjects reported fewer total st and ard drinks in the past three months ( 176 versus 216 , P = .04 , one-tailed ) and fewer drinking days per week ( 2.8 versus 3.3 , P = .02 ) than controls , but similar drinks per drinking day ( 3.3 versus 3.5 ; P = .13 ) . At 12 months , intervention subjects again reported fewer drinking days per week ( 2.7 versus 3.1 ; P = .04 ) than controls , but similar numbers of st and ard drinks ( 157 versus 179 ; P = .13 ) and drinks per drinking day ( 3.6 versus 3.3 ; P = .20 ) . Intervention subjects were somewhat more likely than controls to report drinking within daily recommended limits ( < or = 3 for men , < or = 2 for women ) at both six months ( 79 % versus 71 % ; P = .06 ) and 12 months ( 80 % versus 73 % ; P = .07 ) , but did not differ significantly from controls on other drinking outcomes ( percent abstinent , frequency of drinking > or = 6 drinks per drinking occasion , estimated peak blood alcohol concentration ) , or use of medical care in the year following intervention . CONCLUSIONS A one-time , brief motivational intervention using minimal clinician time supplemented by trained counselors result ed in a modest reduction in frequency of alcohol consumption in a busy primary care population . Future research should focus on strengthening and maintaining intervention effects [20381972] OBJECTIVE Brief interventions for college student drinkers have been shown to be effective in reducing the amount of alcohol consumed as well as the number of alcohol-related problems . However , the duration of brief interventions varies substantially across studies . METHOD In the present study 114 undergraduate students who drank alcohol heavily were r and omly assigned to a 10-minute brief intervention , a 50-minute brief intervention , or assessment -only control . The content of the active interventions was based on the same concept , and both interventions incorporated motivational interviewing components . Participants were assessed at baseline and 4-week post intervention on quantity of alcohol use , alcohol-related problems , and protective behavioral strategies . RESULTS As hypothesized , there was a significant difference between participants in the 10-minute intervention and control condition regarding their alcohol consumption at 4-week follow up . However , there was no significant difference between the 50-minute intervention and the control condition on alcohol consumption . There were also no significant differences between active intervention conditions , and neither intervention showed advantages for reducing problems or increasing protective behaviors relative to the control condition . CONCLUSIONS Results suggest a very brief intervention can impact short-term alcohol use outcomes , with potentially no advantage of longer interventions for this population [9091691] OBJECTIVE Project TrEAT ( Trial for Early Alcohol Treatment ) was design ed to test the efficacy of brief physician advice in reducing alcohol use and health care utilization in problem drinkers . DESIGN R and omized controlled clinical trial with 12-month follow-up . SETTING A total of 17 community-based primary care practice s ( 64 physicians ) located in 10 Wisconsin counties . PARTICIPANTS Of the 17695 patients screened for problem drinking , 482 men and 292 women met inclusion criteria and were r and omized into a control ( n=382 ) or an experimental ( n=392 ) group . A total of 723 subjects ( 93 % ) participated in the 12-month follow-up procedures . INTERVENTION The intervention consisted of two 10- to 15-minute counseling visits delivered by physicians using a scripted workbook that included advice , education , and contracting information . MAIN OUTCOME MEASURES Alcohol use measures , emergency department visits , and hospital days . RESULTS There were no significant differences between groups at baseline on alcohol use , age , socioeconomic status , smoking status , rates of depression or anxiety , frequency of conduct disorders , lifetime drug use , or health care utilization . At the time of the 12-month follow-up , there were significant reductions in 7-day alcohol use ( mean number of drinks in previous 7 days decreased from 19.1 at baseline to 11.5 at 12 months for the experimental group vs 18.9 at baseline to 15.5 at 12 months for controls ; t=4.33 ; P<.001 ) , episodes of binge drinking ( mean number of binge drinking episodes during previous 30 days decreased from 5.7 at baseline to 3.1 at 12 months for the experimental group vs 5.3 at baseline to 4.2 at 12 months for controls ; t=2.81 ; P<.001 ) , and frequency of excessive drinking ( percentage drinking excessively in previous 7 days decreased from 47.5 % at baseline to 17.8 % at 12 months for the experimental group vs 48.1 % at baseline to 32.5 % at 12 months for controls ; t=4.53 ; P<.001 ) . The chi2 test of independence revealed a significant relationship between group status and length of hospitalization over the study period for men ( P<.01 ) . CONCLUSIONS This study provides the first direct evidence that physician intervention with problem drinkers decreases alcohol use and health re source utilization in the US health care system [11414347] OBJECTIVE The current study tested the efficacy of a brief intervention design ed to reduce drinking and drinking-related consequences among first-year fraternity members . METHOD Twelve fraternities were r and omly assigned to receive either a motivational enhancement intervention with individual and housewide feedback components ( n = 6 houses ) or a treatment-as-usual control condition ( n = 6 houses ) . Individual feedback was delivered either by peer interviewers or professional research staff . Participants were assessed during their pledge ( first ) year of house membership and during a follow-up period 1 year later . RESULTS Of the participants who completed follow-up ( N = 120 ) , fraternity members who received the brief intervention reported significant reductions in alcohol use ( total average consumption ) and typical peak blood alcohol concentrations when compared with fraternity members in the control condition . No differences in drinking-related consequences were observed . Fraternity members who received their individualized feedback from peer interviewers and professional members of the research staff reported similar outcomes . CONCLUSIONS Results provide support for the efficacy of a brief motivational enhancement intervention in reducing drinking within this high-risk population . The cost-effective use of peer interviewers appears to be a promising strategy for delivering individualized prevention programming in college population [17855332] AIMS Recommendations for routine alcohol screening and brief counselling intervention in primary health care rest on results from intervention efficacy studies . By conducting a pragmatic controlled trial ( PCT ) , we aim ed at evaluating the effectiveness of the WHO recommendations for screening and brief intervention ( SBI ) in general practice . METHODS A r and omized PCT ( brief counselling intervention vs no intervention ) involving 39 Danish general practitioners ( GPs ) . Systematic screening of 6897 adults led to inclusion of 906 risky drinkers , and research follow-up on 537 of these after 12 - 14 months . Outcome measures focused on patients ' acceptance of screening and intervention and their self-reported alcohol consumption . RESULTS Patient acceptance of screening and intervention -10.3 % ( N = 794 ) of the target population ( N = 7 , 691 ) explicitly refused screening . All intervention group subjects ( N = 442 ) were exposed to an instant brief counselling session while only 17.9 % of them ( 79/442 ) attended a follow-up consultation that was offered by their GP . Consumption Changes At one-year follow-up , average weekly consumption had increased by 0.7 drinks in both comparison groups . As secondary findings , we observed an indiscriminate absolute risk reduction ( ARR = 0.08 ( 95 % CI : -0.02 ; 0.18 ) ) in male binge drinking , but adverse intervention effects for women on the secondary outcomes ( binge drinking ARR = -0.30 ( 95 % CI : -0.47 ; -0.09 ) ) . CONCLUSIONS The results of brief interventions in everyday general practice performed on the basis of systematic question naire screening may fall short of theoretical expectations . When applied to non-selected groups in everyday general practice SBI may have little effect and engender diverse outcome . Women may be more susceptible to defensive reactions than men [3390235] We studied 120 injured male patients of working age who were heavy drinkers or alcoholics , obtaining seven points or more in the Michigan Alcoholism Screening Test ( MAST ) . They were r and omly allocated either to an intervention group ( IG ) or to a control group ( CG ) . In addition to the MAST interview , the consumption of alcohol during the previous week prior to hospital admission was calculated and laboratory measures ( serum GGT , ASAT and ALAT ) were obtained . Counselling of the patients in the IG was carried out by a trained assistant nurse and a physician . Forty-nine patients in IG and 40 patients in CG were re-examined after 6 months . In the IG 45 % and in the CG 20 % of the patients were improved ( Chi square test , P less than 0.05 ) . Improvement criteria were a decrease in alcohol consumption by at least one-third and decrease of S-GGT by at least 20 % during the follow-up period . In respect to the laboratory measures the groups were identical at the beginning of the study and after 6 months ' follow-up . Our results are encouraging and suggest that the assessment of heavy drinking should be a routine in the treatment of alcohol-related injuries and that education and counselling must be intensive to be effective [1410953] The study examined the effectiveness of routine intervention in alcohol abuse by a general practitioner , with help of a laboratory test . Patients diagnosed as abusers because of high erythrocyte mean cell volume value ( MCV ) and having no other cause for it were r and omly allocated to two groups : 1 ) an intervention group , comprising 92 patients ( 69 men and 23 women ) , who were invited for follow-up at three-monthly intervals for a year ; 2 ) a control ( mini-intervention ) group , 86 patients ( 71 men and 15 women ) , who were followed-up only after 12 months . Follow-up attendance was poor , particularly in the intervention group . In general , MCV-values were unchanged in the groups at the end of the study , though there was a clear trend for the female controls to have lower values ( 101.9 fl at the start , 98.5 fl at the end , p = 0.06 ) . Altogether 11 % ( 4/38 ) of the women and 7 % ( 10/140 ) of the men had clearly reduced their alcohol consumption after one year , and this was also seen in their MCV-values . Mini-intervention , especially in women with an abnormal laboratory value , seems to be , with the help of MCV , at least as effective a way of counselling nonalcoholic abusers as a more systematic intervention [16441282] This article summarizes the proceedings of a symposium at the 2005 Research Society on Alcoholism , Santa Barbara , California . The purpose of the symposium was to address challenges that arise in translating evidence for efficacy of alcohol brief intervention ( BI ) into diverse clinical setting s and population s by review ing the literature and describing 4 research studies . Dr. Saitz review ed the limitations in evidence for efficacy of BIs and then described results of a r and omized clinical trial of brief motivational intervention for medical in patients drinking risky amounts . Dr. Svikis presented alternative methods for identifying pregnant women in prenatal care at risk for alcohol and drug problems ( including nicotine and caffeine ) and BIs to reduce or eliminate use . Dr. D'Onofrio discussed results of a r and omized trial of the brief negotiated interview in emergency department patients . Dr. Kraemer presented results of a decision analytic and computer-simulation model regarding the cost-effectiveness of alcohol screening and intervention in primary care setting s. Finally , Dr. Perl discussed the salient issues and suggested future directions for work in the area of alcohol BI [24813652] BACKGROUND Excessive use of alcohol is associated with poor sexual health , but the clinical effectiveness and cost-effectiveness of brief alcohol intervention in this setting has not been investigated . OBJECTIVE To examine the effects and cost-effectiveness of brief intervention for excessive alcohol consumption among people who attend sexual health clinics . DESIGN A two-arm , parallel-group , single-blind , pragmatic , r and omised controlled trial . Participants were r and omised via an independent and remote telephone r and omisation service using permuted blocks , stratified by clinic . SETTING Study participants were recruited from three sexual health clinics in central and west London . PARTICIPANTS For inclusion , potential participants had to be aged ≥ 19 years , drink excessive alcohol according to the Modified-Single Alcohol Screening Question , and be willing to provide written informed consent . We excluded those who were unable to communicate in English sufficiently well to complete the baseline assessment and those who could not provide contact details for the follow-up assessment . INTERVENTIONS Brief advice was delivered by the treating clinician and comprised feedback on the possible health consequences of excessive drinking , a discussion of whether the participant 's clinic attendance was linked to current alcohol use , written information on alcohol and health and an offer of an appointment with an alcohol health worker ( AHW ) . Appointments with AHWs took place either in person or by telephone , lasted up to 30 minutes , and used the ' FRAMES ' ( Feedback about the adverse effects of alcohol , an emphasis on personal Responsibility for changing drinking behaviour , Advice about alcohol consumption , a Menu of options for further help and advice , an Empathic stance towards the patient and an emphasis on Self-efficacy ) approach . Those in the control arm of the trial were offered a copy of a leaflet providing general information on health and lifestyle . MAIN OUTCOME MEASURES Outcomes were assessed 6 months after r and omisation . The primary outcome was mean weekly alcohol consumption during the previous 90 days . The main secondary outcome was unprotected sex during this period . RESULTS Eight hundred and two people were recruited to the study of whom 592 ( 74 % ) were followed up 6 months later . Among 402 participants who were r and omised to brief intervention , 397 ( 99 % ) received brief advice from the treating clinician and 81 ( 20 % ) also received input from an AHW . The adjusted mean difference in alcohol consumption after 6 months was -2.33 units per week [ 95 % confidence interval ( CI ) -4.69 to 0.03 units per week , p = 0.053 ] for those in the active arm compared with the control arm . Unprotected sex was reported by 154 ( 53 % ) of those who received brief intervention and by 178 ( 59 % ) of controls ( adjusted odds ratio 0.89 , 95 % CI 0.63 to 1.25 , p = 0.496 ) . Participants r and omised to brief intervention reported drinking a mean of 10.4 units of alcohol per drinking day compared with 9.3 units among control participants ( difference 1.10 , 95 % CI 0.29 to 1.96 , p = 0.009 ) . We found no statistically significant differences in other outcomes . Brief intervention ( brief advice and input from an AHW ) cost on average £ 12.60 per person to deliver and did not appear to provide a cost-effective use of re sources . CONCLUSIONS Introduction of universal screening and brief intervention for excessive alcohol use among people who attend sexual health clinics does not result in clinical ly important reductions in alcohol consumption or provide a cost-effective use of re sources . While people attending sexual health clinics may want to achieve better sexual health , attempts to reduce alcohol consumption may not be seen by them as a necessary means of trying to achieve this aim . TRIAL REGISTRATION This trial is registered as IS RCT N 99963322 . FUNDING This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol . 18 , No. 30 . See the NIHR Journals Library website for further project information [11499124] OBJECTIVES This study examined long-term response to an individual preventive intervention for high-risk college drinkers relative to the natural history of college drinking . METHODS A single-session , individualized preventive intervention was evaluated within a r and omized controlled trial with college freshmen who reported drinking heavily while in high school . An additional group r and omly selected from the entire screening pool provided a normative comparison . Participant self-report was assessed annually for 4 years . RESULTS High-risk controls showed secular trends for reduced drinking quantity and negative consequences without changes in drinking frequency . Those receiving the brief preventive intervention reported significant additional reductions , particularly with respect to negative consequences . Categorical individual change analyses show that remission is normative , and they suggest that participants receiving the brief intervention are more likely to improve and less likely to worsen regarding negative drinking consequences . CONCLUSIONS Brief individual preventive interventions for high-risk college drinkers can achieve long-term benefits even in the context of maturational trends [11702799] OBJECTIVE Brief interventions for hazardous and low-dependent drinkers in the primary care setting have considerable empirical support . The purpose of this study was to ( 1 ) evaluate the effects of brief advice ( BA ) and motivational enhancement ( ME ) interventions on alcohol consumption . In addition , a hindsight matching design was used to ( 2 ) study the moderator effects of patient readiness to change ( alcohol use ) on alcohol consumption . METHOD The subjects ( N = 301 , 70 % men ) were patients 21 years of age or older who presented for treatment at one of 12 primary care clinics . After screening for eligibility and providing consent to participate in the study , the patients completed a baseline assessment and were r and omly assigned to the BA , ME or st and ard care ( SC ) interventions condition . Follow-up assessment s were completed at 1- , 3- , 6- , 9- and 12-months postbaseline assessment . RESULTS Evaluation of the first hypothesis ( n = 232 for these analyses ) showed that all participants tended to reduce their alcohol use considerably between the baseline and 12-month assessment s. In addition , evaluation of the second hypothesis showed a moderator effect of readiness to change in predicting the number of drinks at 12 months , such that the BA intervention seemed more effective for patients relatively low in readiness to change compared to those higher in readiness . Readiness to change did not seem to be related to changes in drinking of participants in the SC or ME conditions . CONCLUSIONS The results confirm that , among primary care patients , substantial changes in alcohol consumption are possible . They further suggest that matching studies of patient readiness to change their alcohol use , as well as other variables , are warranted [1525531] The objective of the study was to determine the effectiveness of advice from general practitioners to heavy drinking men ( consuming 350 - 1050 grams of alcohol per week ) to reduce their alcohol consumption . One hundred and fifty-four men recruited from eight general practice s were allocated r and omly to treatment and control groups . Men in the treatment group received advice from their own general practitioner . At one year follow-up , when analyzed according to intention to treat , the treatment group had reduced their consumption by an excess of 65 grams of alcohol per week when compared with the control group ( p less than 0.05 ) . General practitioners should be recommended to screen for alcohol consumption amongst their patients and to give advice to those found to be at risk because of their drinking [18237661] INTRODUCTION Alcohol is the single greatest contributor to injury in the United States . Numerous studies have reported that a st and ardized screening , brief intervention , and referral to treatment ( SBIRT ) intervention can effectively minimize future alcohol consumption , reduce injury recurrence , and decrease the number of repeat ED visits . To date , SBIRT studies have been conducted in setting s in which physicians or research assistants carried out SBIRT . Little is known about ED nurses carrying out SBIRT . The purpose of this study was to examine ED nurse training needs and identify both barriers to , and enablers of , SBIRT implementation in the emergency department . METHODS Two coordinators from each of the 5 ED sites selected for the study attended a 1-day SBIRT educational session . Site coordinators then trained their staff nurses to conduct SBIRT . Site coordinators were surveyed at the midpoint and end of the 6-month implementation study period . Patient data from each facility was collected . RESULTS Ten site coordinators were trained and held subsequent training sessions with nursing staff in their respective emergency departments . All sites encountered barriers to implementation , but 2 of 5 sites were able to implement the SBIRT process fully by the end of the evaluation period . A total of 3265 patients were screened for alcohol use problems . Of those screened , 678 ( 21 % ) were classified as hazardous drinkers . Overall , 56 % of the positive-screened patients received 3 to 5 minutes of a brief intervention . After the brief intervention , between 9 % and 82 % of patients were referred for further care . DISCUSSION The SBIRT process can be conducted successfully by emergency nurses . However , substantial operational barriers to widespread routine implementation exist . These barriers need to be addressed before emergency nurses incorporate SBIRT as routine part of ED care [20105410] OBJECTIVE The aim of this study was to test the efficacy of brief physician advice in reducing alcohol use and related harm in college students . METHOD The College Health Intervention Projects ( CHIPs ) is a r and omized , controlled clinical trial with 12-month follow-up conducted in five college health clinics in Wisconsin ; Washington state ; and Vancouver , Canada . Of the 12,900 students screened for high-risk drinking , 484 men and 502 women met inclusion criteria and were r and omized into a control ( n = 493 ) or intervention ( n = 493 ) group . Ninety-six percent of students participated in the follow-up procedures . The intervention consisted of two 15-minute counseling visits and two follow-up phone calls , and used motivational interviewing , contracting , diary cards , and take-home exercises . RESULTS No significant differences were found between groups at baseline on alcohol use , age , socioeconomic or smoking status , rates of depression , or measures of alcohol-related harm . At 12 months , the experimental subjects reduced their 28-day drinking totals by 27.2 % , and the control group reduced their totals by 21 % . A mixed effects repeated measures model found a statistical difference in favor of the brief-intervention group ( beta = 4.7 , SE = 2.0 , p = .018 ) in 28-day drinking totals . The total Rutgers Alcohol Problem Index score was also significantly different during the 12-month follow-up period ( beta = 0.8 , SE = 0.4 , p = .033 ) . There was no difference on the other outcome measures of interest , such as frequency of excessive heavy drinking , health care utilization , injuries , drunk driving , depression , or tobacco use . CONCLUSIONS The study supports re source allocation and implementation of alcohol screening and brief physician advice in primary care-based college health clinics [12492754] AIM To evaluate the effectiveness of a brief motivational intervention on alcohol consumption and misuse in young males with alcohol-related face injury . DESIGN R and omized controlled trial . SETTING Oral and maxillofacial surgery out-patient clinic in an urban teaching hospital . PARTICIPANTS One hundred and fifty-one participants were r and omized to motivational intervention and control conditions . INTERVENTIONS Control was treatment as usual . The intervention was treatment as usual plus a one-session brief motivational intervention administered by a nurse . MEASUREMENTS Three sets of measurements were taken at baseline , 3-month and 1-year follow-up . Collateral measurements were also taken at 1-year follow-up . Primary outcome measures were total alcohol consumption , typical weeks consumption and days abstinent in preceding 3 months . Other outcome measures included the Alcohol Use Disorders Identification Test , a short form of the Alcohol Problems Question naire , and a measure of satisfaction with social relationships . RESULTS There was a significant decrease in 84-day total alcohol consumption across the year ( P < 0.006 ) and further , a significant effect for the motivational intervention was demonstrated ( P < 0.029 ) . This pattern was repeated for days abstinent and alcohol consumption in a typical week as well as alcohol-related problems . There was a significantly greater reduction in the percentage of hazardous drinkers in the motivational intervention group ( from 60 % to 27 % , P < 0.009 ) compared to the control group ( from 54 % to 51 % , NS ) . CONCLUSION A proportion of young men change their alcohol consumption following alcohol-related injury . A nurse-led psychological intervention adds significantly to the proportion and magnitude of response [17032098] In this r and omized controlled trial , the authors evaluated brief motivational interventions ( BMI s ) for at-risk college drinkers . Heavy drinking students ( N = 509 ; 65 % women , 35 % men ) were r and omized into 1 of 6 intervention conditions formed by crossing the baseline Timeline Followback ( TLFB ) interview ( present versus absent ) and intervention type ( basic BMI , BMI enhanced with a decisional balance module , or none ) . Assessment s completed at baseline , 1 , 6 , and 12 months measured typical and risky drinking as well as drinking-related problems . Relative to controls , the TLFB interview reduced consumption but not problems at 1 month . The basic BMI improved all drinking outcomes beyond the effects of the TLFB interview at 1 month , whereas the enhanced BMI did not . Risk reduction achieved by brief interventions maintained throughout the follow-up year [11104115] BACKGROUND Today , heavy drinking is a common health hazard among women . The evidence in favor of providing some kind of brief intervention to reduce drinking is quite convincing . However , we do not know if intervention works in a natural environment of routine health care . The purpose of this study was to evaluate the effectiveness of long-lasting , brief alcohol intervention counseling for women in a routine general practice setting . METHODS In five primary care outpatient clinics in a Finnish town , 118 female early-phase heavy drinkers who consulted their general practitioners for various reasons were given brief alcohol intervention counseling . Intervention groups A ( n = 40 ) and B ( n = 38 ) were offered seven and three brief intervention sessions , respectively , over a 3-yr period . The control group C ( n = 40 ) was advised to reduce drinking at baseline . Main outcome measures were self-reported weekly alcohol consumption , carbohydrate-deficient transferrin , mean corpuscular volume ( MCV ) , aspartate aminotransferase , alanine aminotransferase , and gamma-glutamyltransferase . RESULTS Depending on the outcome measure and the study group , clinical ly meaningful reduction of drinking was found in 27 % to 75 % of the heavy drinkers . Within all the groups , MCV significantly decreased . However , there were no statistically significant differences between study groups A , B , and C in the mean changes between the beginning and endpoint in the main outcome measures . CONCLUSIONS The present study indicated that minimal advice , as offered to group C , was associated with reduced drinking as much as the brief intervention , as offered to groups A and B , given over a 3-yr period . Furthermore , in the routine setting of the general practice office , the effectiveness of the brief intervention may not be as good as in special research conditions . The factors possibly reducing the effectiveness in a routine setting are unknown . Thus , different methods of implementing brief intervention need to be evaluated to find better ways to support general practice personnel in their efforts to help heavy-drinking female patients to reduce their drinking [10078798] OBJECTIVE The project was design ed to compare the effectiveness of brief intervention ( BI ) versus simple advice ( SA ) in the secondary prevention of hazardous alcohol consumption . METHODS A r and omized controlled trial with a 12-month follow-up was conducted . A total of 74 community-based primary care practice s ( 328 physicians ) located in 13 Spanish autonomous regions were recruited initially . Out of 546 men screened , only 229 were r and omized into BI ( n = 104 ) and SA ( n = 125 ) ; 44.6 % of practice s finalized the study . The interventions on the BI group consisted of a 15-minute counselling visit carried out by physicians which included : ( i ) alcohol quantification , ( ii ) information on safe limits , ( iii ) advice , ( iv ) drinking limits agreement , ( v ) self-informative booklet with drinking diary record and ( vi ) unscheduled reinforcement visits . The SA group spent 5 minutes which included ( i ) , ( ii ) and ( iii ) . RESULTS There were no significant differences between both groups at baseline on alcohol use , age , socioeconomic status and CAGE score . After the 12-month follow-up there was a significant decrease in frequency of excessive drinkers ( 67 % of BI group reached targeted consumption , versus 44 % of SA ; P < 0.001 ) as well as weekly alcohol intake reduction ( BI reached 52 versus 32 % in SA ; P < 0.001 ) . A trend to improve outcome with the number of reinforcement visits was found with BI . The only predictor of success was the initial alcohol consumption level . CONCLUSIONS Brief intervention is more effective than simple advice to reduce alcohol intake on adult men who attend primary care services in Spain [12683736] This r and omized trial evaluated an intervention for reducing at-risk drinking practice s in a sample of 307 patients . Eligible drinking patterns included chronic drinking ( > or = 2 drinks per day in the past month ) , binge drinking ( > or = 5 drinks per occasion at least twice in the past month ) , and drinking and driving ( driving after > 2 drinks in the past month ) . Members of the intervention group received a message from their physician during their regularly scheduled visit , a self-help manual , written personalized feedback , and up to 3 telephone counseling calls . Dropout was significantly higher in the intervention than control group [21205050] AIMS To evaluate the effectiveness of a brief intervention in hospitalized Taiwanese men to reduce unhealthy alcohol consumption . DESIGN R and omized controlled trial . SETTING Medical/surgical wards of a medical centre in Taipei , Taiwan . PARTICIPANTS Of 3669 consecutive adult male in- patients , 616 were identified as unhealthy alcohol users ( > 14 drinks/week ) and assigned r and omly to either usual care ( n = 308 ) or a brief intervention ( n = 308 ) . MEASUREMENTS Primary outcomes were changes in alcohol consumption at 4 , 9 and 12 months , including self-reported weekly alcohol consumption , drinking days and heavy drinking episodes assessed by 7-day time-line follow-back . Secondary outcomes were ( i ) self-reported alcohol problems , ( ii ) health-care utilization ( hospital days and emergency department visits ) , ( iii ) self-reported seeking of speciality treatment for alcohol problems and ( iv ) 3-month Quick Drinking Screen . FINDINGS Based on intention-to-treat analyses , the intervention group consumed significantly less alcohol than the control group among both unhealthy drinkers and the subgroup of alcohol-dependent participants over 12 months , on both 7-day and 3-month assessment s. Adjunctive analyses of only those who completed all assessment s found that total drinks consumed did not remain significant . Significantly more participants with alcohol use disorders in the intervention than in the control group ( 8.3 % , 19 of 230 versus 2.1 % , four of 189 ) consulted specialists by 12 months ( P = 0.01 ) . However , alcohol-related problems and health-care utilization did not differ significantly in the two groups during follow-up . CONCLUSIONS Data from Taiwan confirm that brief in-hospital intervention can result in a reduction in alcohol intake by men who drink heavily or are diagnosed with an alcohol use disorder [20102995] BACKGROUND Binge drinking is a common pattern of alcohol use in the US . However , no studies have evaluated the effectiveness of brief interventions targeting only binge drinkers . METHODS R and omized controlled clinical trial with a 12-month follow-up period conducted from March 1 , 2003 to March 1 , 2006 in Spain . Of a screened population of 15,325 patients seeking routine medical care from their primary care providers , patients who met inclusion criteria were r and omized into an experimental group ( n=371 ) or a control group ( n=381 ) . The primary outcome measures were the frequency of binge drinking episodes and weekly alcohol intake . RESULTS There were no significant differences at baseline between groups in alcohol use and demographic variables . At the end of the 12-month follow-up period , there were significant reductions in binge-drinking status ( 52.2 % vs 67.2 % , P < .001 ) , number of episodes of binge drinking ( 1.14 vs 1.56 , P < .001 ) , number of drinks weekly ( 19.2 vs 22.4 , P < .001 ) , and frequency of excessive alcohol intake in 7 days ( 47.9 % vs 66.6 % , P > .001 ) . CONCLUSIONS This study provided evidence that screening and brief counseling delivered by a primary care physician as part of regular health care significantly reduced binge drinking episodes in binge drinkers [23192220] Alcohol exposed pregnancy ( AEP ) is a leading cause of preventable birth defects . While r and omized controlled trials ( RCTs ) have shown that multi-session motivational interviewing-based interventions reduce AEP risk , a one-session intervention could facilitate broader implementation . The purpose s of this study were to : ( 1 ) test a one-session motivational AEP prevention intervention for community women and ( 2 ) compare outcomes to previous RCTs . Participants at risk for AEP ( N=217 ) were r and omized to motivational interviewing+ assessment feedback ( EARLY ) , informational video , or informational brochure conditions . Outcomes were drinks per drinking day ( DDD ) , ineffective contraception rate , and AEP risk at 3 and 6 months . All interventions were associated with decreased DDD , ineffective contraception rate , and AEP risk . Participants who received EARLY had larger absolute risk reductions in ineffective contraception and AEP risk , but not DDD . Effect sizes were compared to previous RCTs . The one-session EARLY intervention had less powerful effects than multi-session AEP prevention interventions among community women , but may provide a new option in a continuum of preventive care [20729010] BACKGROUND Brief motivational intervention ( BMI ) is one of the few effective strategies targeting alcohol consumption , but has not been tested in young men in the community . We evaluated the efficacy of BMI in reducing alcohol use and related problems among binge drinkers and in maintaining low-risk drinking among non-bingers . METHODS A r and om sample of a census of men included during army conscription ( which is m and atory for 20-year-old males in Switzerl and ) was r and omized to receive a single face-to-face BMI session ( N=199 ) or no intervention ( N=219 ) . A six-month follow-up rate was obtained for 88.7 % of the subjects . RESULTS Among binge drinkers , there was 20 % less drinking in the BMI group versus the control group ( incidence rate ratio=0.80 , confidence interval 0.66 - 0.98 , p=0.03 ) ; the BMI group showed a weekly reduction of 1.5 drinks compared to an increase of 0.8 drinks weekly in the control group . Among subjects who experienced one or more alcohol-related consequences over the last 12 months , there was 19 % less drinking in the BMI group compared to the control group ( incidence rate ratio=0.81 , confidence interval 0.67 - 0.97 , p=0.04 ) . Among non-bingers , BMI did not contribute to the maintenance of low-risk drinking . CONCLUSION BMI reduced the alcohol use of binge drinkers , particularly among those who experienced certain alcohol-related adverse consequences . No preventive effect of BMI was observed among non-bingers . BMI is a plausible secondary preventive option for young binge drinkers Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND Drinking is influenced by youth perceptions of how their peers drink . These perceptions are often incorrect , overestimating peer drinking norms . If inaccurate perceptions can be corrected , young people may drink less . OBJECTIVES To determine whether social norms interventions reduce alcohol-related negative consequences , alcohol misuse or alcohol consumption when compared with a control ( ranging from assessment only/no intervention to other educational or psychosocial interventions ) among university and college students . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs:

Medicine

11289485

[7851264] Forty patients were r and omly assigned to receive either the individualized learning activity packages or classroom instruction . Effectiveness was evaluated on the basis of fasting plasma glucose , glycosylated hemoglobin , percent of ideal body weight , and knowledge and behavior scores . No significant differences were found between the groups at entry or at the 2-month follow-up . At the 5-month follow-up , the group that received the learning activity packages scored significantly higher on knowledge assessment , significantly increased their behavior score , and decreased their percent of ideal body weight . Patients who received classroom instruction increased their behavior score and exhibited significantly decreased glycosylated hemoglobin levels . Behavior and blood glucose levels were significantly correlated . Although the learning activity packages proved effective in increasing knowledge , no significant improvement was observed in blood glucose levels [8314427] Newly diagnosed mild Type 2 diabetic patients , aged 30 - 55 years , were included in the prospect i ve , multi-centre Diabetes Intervention Study . They were r and omly allotted to either an intervention group receiving intensified health education or to a control group on usual care . This paper reports the incidence , duration of and causes for absence from work due to any disease in the patients who were working during the first 5-year follow-up . Data from 817 patients could be taken into account . 14.5 % of the intervention patients and 17.3 % of the control patients had never been on the sick list . Those patients who had undergone intensified health education were listed sick less often . Women showed a higher work absenteeism in either group ; they had higher blood pressure and higher body mass index at entry . Cardiovascular diseases and musculo-skeletal disorders were major reasons for absence from work . However , when compared to the general population , these Type 2-diabetic patients were approximately four times more often on the sick list . Thus , the health education programme of the Diabetes Intervention Study was shown to be effective with respect to work absenteeism . Teaching patients is recommended as an important part of the therapeutic regimen [9219407] BACKGROUND Type 2 diabetes is up to four times more common in British Asians , but they know little about its management and complications . AIM To design and evaluate a structured pictorial teaching programme for Pakistani Moslem patients in Manchester with type 2 diabetes . METHOD A r and omized controlled trial of pictorial flashcard one-to-one education in 201 patients attending a hospital outpatient clinic or diabetic clinics in ten general practice s in Manchester . Patients ' knowledge , self-caring skills and attitudes to diabetes were measured on four topics before the structured teaching , and compared with results six months later . RESULTS All parameters of knowledge were increased in the study group ; for example , percentage scores for correctly identifying different food values increased from 57 % to 71 % ( Analysis of Variance ( ANOVA ) adjusted difference + 11.8 % ) and knowledge of one diabetic complication from 18 % to 78 % . Self-caring behaviour improved , with 92 % of patients doing regular glucose tests at six months compared with 63 % at the start . Attitudinal views were more resistant to change , with patients still finding it hard to choose suitable foods at social occasions . Haemoglobin A1c control improved by 0.34 % over six months ( ANOVA adjusted difference , 95 % CI -0.8 % to + 0.1 % ) . CONCLUSION It is concluded that this health education programme can empower Asian diabetics to take control of their diets , learn to monitor and interpret glucose results , and underst and the implication s of poor glycaemic control for diabetic complications [3612778] The treatment of choice for Type II or non-insulin-dependent diabetes mellitus is a behavioral program for the management of weight . However , compliance with this lifelong dietary regimen is often poor . In the current investigation male and female adults with diagnosed Type II diabetes were r and omly assigned to either a behavior modification , a cognitive modification , a cognitive-behavior modification , or a control group . Patients were evaluated in terms of weight , percentage of body fat , and glycosylated hemoglobin measures . Men lost signficantly more weight than women and subjects in the behavior modification group lost more weight and demonstrated greater decreases in diabetes control than subjects in the cognitive-behavior modification , cognitive , and control groups . A significant interaction indicated that diabetic men may benefit more from behavioral weight reduction programs than diabetic women . Several explanations for these findings are considered [10531848] PURPOSE Few culturally competent health programs have been design ed for Mexican Americans , a group that bears a disproportionate burden of Type 2 diabetes . In Starr County , a Texas-Mexico border community , investigators design ed and tested a culturally competent intervention aim ed at improving the health of this target population . The purpose of this article is to describe the development process of this diabetes education and support group intervention . METHODS The development stages were ( 1 ) community assessment , ( 2 ) intervention design , ( 3 ) selection or development of outcomes , ( 4 ) pilot testing , and ( 5 ) a r and omized clinical investigation . RESULTS Focus group participants identified knowledge deficits regarding diabetes and self-management strategies , and suggested characteristics of an effective intervention for Mexican Americans . Outcome measures included metabolic control indicators , a newly developed knowledge instrument , and an existing health belief instrument . Preliminary analyses indicated that the intervention was successful in significantly improving metabolic control in the target population . CONCLUSIONS Developing successful diabetes interventions for minority groups requires a number of stages , careful planning , assessment of cultural characteristics of the target population , and a systematic approach to implementation [1298950] A 10-session , self-management training program was design ed specifically for persons over 60 years of age having Type II diabetes . It targeted social learning variables , especially problem-solving skills and self-efficacy , found to be related to diabetes self-care in earlier correlational research . One hundred two adults were r and omized to immediate or delayed intervention conditions . At posttest , subjects in the immediate intervention condition showed significantly greater reductions in caloric intake and percent of calories from fat than control subjects . The intervention also produced greater weight reductions and increases in the frequency of glucose testing than did the control condition . Improvements among immediate intervention subjects were generally maintained at a 6-month follow-up . Intervention results from subjects receiving delayed intervention closely replicated those for immediate intervention subjects . We conclude that a relatively short-term program can improve self-management skills of older diabetic adults , and that there is an important need for such interventions [8900703] This paper describes the development and evaluation of a computer-aided learning ( CAL ) program . The program was tested in a trial that involved 36 people with diabetes ; 20 received CAL lessons in diabetes management and 16 attended conventional diabetes classes conducted by diabetes educators . When measurements taken before and three months after the education were compared , both groups showed significant improvement in their knowledge ; the blood glucose levels of the CAL group were significantly lower but those of the conventional education group were higher . This means that the CAL program was as effective as conventional education in imparting knowledge but it was more likely to motivate people to control their glucose levels . The CAL program allows diabetes educators to spend less time on education in basic knowledge and to concentrate more on motivational and social factors that are important determinants of patient compliance . It can also benefit people with diabetes whose access to health professionals and /or conventional diabetes education is restricted [9368810] Objective : To investigate the impact of intensive lifestyle education on dietary practice s , exercise and metabolic measurements in people with insulin-dependent diabetes mellitus ( IDDM ) . Design : Sixty-one volunteer subjects with IDDM were r and omised to intensive ( Group 1 ) or st and ard ( Group 2 ) education programmes for six months . During a second six month period of observation Group 1 subjects received routine surveillance for their condition and those in Group 2 were given intensive advice ( phase 2 ) . Current insulin regimens were modified to optimise glycaemic control before the start of the intervention phase . Nutrient intakes , weight , blood pressure , glycated haemoglobin ( HbA ) , plasma lipids , lipoproteins and maximal oxygen consumption ( VO max ) were measured at the time of recruitment and at three monthly intervals during the trial and phase 2 . Setting : Department of Human Nutrition at the University of Otago . Results : Glycated haemoglobin decreased significantly in both groups between recruitment and r and omisation , the improvement being sustained during the six months of the r and omised trial and for group 1 during the six months of post trial observation . A further decrease was seen in Group 2 during the second six month period when they were given intensive advice . Comparable changes were seen with total and low density lipoprotein ( LDL ) cholesterol in Group 1 during the trial , but significant decreases were only seen in Group 2 in association with intensive intervention ( phase 2 ) . These changes occurred in parallel with increases in intakes of carbohydrate and monounsaturated fatty acids , a reduction in intakes of total and saturated fat , and an improvement in maximum oxygen consumption . Conclusions : A lifestyle programme for people with IDDM results in modest changes in diet and exercise habits sufficient to improve measures of glycaemic control and lipoprotein mediated risk of coronary heart disease independent of changes in insulin regime . More innovative approaches to achieve lifestyle changes are required to meet current recommendations which in turn are likely to produce even greater beneficial changes than those observed here . Sponsorship : This study was supported by the Eli Lilly Research Grant ( Eli Lilly and Company ( New Zeal and ) Ltd ) , The Deans Research Grant ( Otago Medical School , New Zeal and ) and The New Zeal and Dietetic Association ( Abbott Award ) [8842601] OBJECTIVE There is a pressing need for brief practical interventions that address diabetes management . Using a r and omized design , we evaluated a medical office-based intervention focused on behavioral issues relevant to dietary self-management . RESEARCH DESIGN AND METHODS There were 206 adult diabetes patients r and omized to usual care or brief intervention , which consisted of touchscreen computer-assisted assessment to provide immediate feedback on key barriers to dietary self-management , and goal setting and problem-solving counseling for patients . Follow-up components to the single session intervention included phone calls and interactive video or videotape instruction as needed . RESULTS Multivariate analyses of covariance revealed that the brief intervention produced greater improvements than usual care on a number of measures of dietary behavior ( e.g. , fewer calories from saturated fat , fewer high-fat eating habits and behaviors ) at the 3-month follow-up . There were also significant differences favoring intervention on changes in serum cholesterol levels and patient satisfaction but not on glycosylated hemoglobin . The intervention effects were relatively robust across a variety of patient characteristics , the two participating physicians , and intervention staff members . CONCLUSIONS If the long-term results are equally positive and generalize to other setting , this intervention could provide a prototype for a feasible cost-effective way to integrate patient views and behavioral management into office-based care for diabetes [2589581] This prospect i ve r and omized study evaluated the influence of a simple education program on the incidence of lower extremity amputation in diabetic patients . Two hundred three patients were r and omized into two groups : Group 1 , education ( 103 patients , 203 limbs ) and Group 2 , no education ( 100 patients , 193 limbs ) . There were no significant differences in medical management or clinical risk factors between the two groups . The amputation rate was three times higher in Group 2 ( 21 of 177 limbs versus 7 of 177 limbs ; p less than or equal to 0.025 ) , the ulceration rate was three times higher in Group 2 ( 26 of 177 limbs versus 8 of 177 limbs ; p less than or equal to 0.005 ) , and there was no difference in the overall incidence of infection ( 2 of 177 limbs ) . Overall success in Group 1 was highly significantly different from Group 2 ( 160 of 177 limbs versus 128 of 177 limbs ; p less than or equal to 0.0005 ) . This study demonstrated that a simple education program significantly reduced the incidence of ulcer or foot and limb amputation in diabetic patients [1547677] Objective — To evaluate Diabeto , a computer-assisted diet education system . Research Design And Methods — One hundred five patients with insulin-dependent diabetes mellitus ( IDDM ) or non-insulin-dependent diabetes mellitus ( NIDDM ) were divided into two r and omized groups to participate in the evaluation of Diabeto . With free access through Minitel , the French public videotex network , Diabeto helps diabetic patients self-monitor their diets and balance their meals with personalized counseling . Results — During the first 6-mo study , group A ( 54 patients ) used Diabeto , whereas group B ( 51 patients ) were control subjects . For the second 6-mo study , group B used the system . Evaluation was based on patients ' dietetic knowledge , dietary habits , and metabolic balance . Conclusions –Diabeto led to a significant improvement of dietetic , knowledge in group A ( P < 0.0005 ) and also to improved dietary habits ; decreased caloric intake in patients initially overeating ( P < 0.05 ) , increase of dietary carbohydrate from 39.7 ± 0.7 to 42.9 ± 0.9 % in patients with an initial intake < 45 % carbohydrate , and decrease of fat intake from 41.9 ± 0.9 to 37.4 ± 1.1 % in patients with an initial intake of > 35 % fat ( P < 0.0005 ) . In the second study , in addition to similar improvements to those observed in the first study , HbA1 decreased from 11.0 ± 0.4 to 9.9 ± 0.4 % ( P < 0.005 ) and fructosamine from 5.00 ± 0.17 to 4.57 ± 0.17 % ( P < 0.001 ) . Diabeto appears to be an effective therapeutic tool in the control of metabolic diseases [3338379] In patients with non-insulin-dependent diabetes mellitus ( NIDDM ) , the influence of knowledge about their disease on the treatment and control of the disease is not clear . We evaluated the efficacy of educational group meetings with NIDDM patients on improving their knowledge of the disease and on disease management . Fifty-one NIDDM patients were r and omly assigned to either intervention or control groups . The intervention group participated in courses of three weekly lessons presented by a physician , nurse , and dietitian once every 4 mo . The intervention and control groups were also followed once every 2 mo in the clinic by the same staff . Medical treatment remained unchanged during the study . After a 12-mo follow-up of the intervention group , no significant improvement in their knowledge of diabetes could be demonstrated . However , mean fasting and postpr and ial blood glucose levels and HbA1c improved significantly in comparison with the control goup . The same tendency was evident with the weight and lipoprotein profile . We conclude that educational group therapy can improve diabetes control in patients with NIDDM [9423499] This study evaluated the 12-month follow-up results and costs of a personalized , medical office-based intervention focused on behavioral issues related to dietary self-management . Two hundred and six adults having diabetes attending an internal medicine outpatient clinic visit were r and omized to either Usual Care or to Brief Intervention . The single session intervention involved touchscreen computer-assisted assessment that provided immediate feedback on key barriers to dietary self-management , goal setting and problem-solving counselling . Follow-up components included phone calls and videotape intervention relevant to each participant . Brief Intervention produced significantly greater improvement than Usual Care on multiple measures of change in dietary behaviour ( e.g. , covariate adjusted difference of 2.2 % of calories from fat ; p = 0.023 ) and on serum cholesterol levels ( covariate adjusted difference of 15 mg/dl ; p = 0.002 ) at 12-month follow-up . There were also significant differences favouring intervention on patient satisfaction ( p < 0.02 ) but not on HbA1c levels . The costs of intervention ( $ 137 per patient ) were modest relative to many commonly used practice [4042800] High-density lipoprotein ( HDL ) cholesterol is known to be low in patients with diabetes mellitus . Low HDL levels are correlated with premature cardiovascular mortality in several major epidemiologic studies and many investigators believe increases in HDL cholesterol may reduce the risk of coronary heart disease . We evaluated dietary and exercise interventions in relation to HDL cholesterol in patients with type II diabetes mellitus . Sixty-five volunteers were r and omly assigned to one of four experimental conditions : diet , exercise , diet plus exercise , or education control . Three months after entering the program , those exposed to the dietary intervention had significant increases in HDL cholesterol . HDL increases for the other two treatment groups did not differ significantly from the education control [2060433] Objective In a r and omized 5-yr multi-intervention trial , we tested the efficacy of intensified health education ( IHE ) in improving metabolic control and reducing the level of coronary risk factors and incidence of ischemic heart disease ( IHD ) . Research Design and Methods Within the intervention group , the benefit of clofibric acid was evaluated in a double-blind study . One thous and one hundred thirty-nine newly diagnosed middle-aged ( 30- to 55-yr-old ) patients with non-insulindependent diabetes mellitus ( NIDDM ) entered the study . They were classified as diet controlled after a 6- wk screening phase with conventional dietary treatment . During the follow-up , the control group ( n = 378 ) was cared for at different diabetes outpatient clinics with a st and ardized surveillance . The intervention group ( n = 761 ) had a structured IHE that included dietary advice , antismoking and antialcohol education , and ways to enhance physical activity . Results R and omly , 379 of the IHE patients received 1.6 g clofibric acid/day , and the others received placebo . IHE result ed in improved glucose control ( adjusted fasting blood glucose ) levels after 5 yr ( control subjects 9.27 mM , IHE group 8.71 mM , and IHE plus clofibric acid group 8.60 mM , P < 0.01 ) . The better glycemic control was achieved with fewer antidiabetic drugs . After 5 yr , antidiabetic drugs were prescribed to 47 % of the control subjects , 28 % of the IHE group , and 34 % of the IHE plus clofibric acid group ( cutoff limit for drug application was postpr and ial blood glucose of ≥13.87 mM ) . The ratio of polyunsaturated to saturated fatty acids ( 0.26 vs. 0.40 , P < 0.01 ) and physical activity ( 174 vs. 327 scores , P < 0.01 ) were increased , and blood pressure , tobacco , and alcohol consumption were significantly reduced by IHE . However , IHE had no effect on calorie intake , percentage of fat in the diet ( 45 % ) , and body weight . The most important finding was the significant increase of blood cholesterol in all three groups ( + 0.47 , + 0.36 , and + 0.34 mM , respectively ) . Clofibric acid only prevented the increase of triglyceride levels ( + 0.56 , + 0.24 , and + 0.05 mM , respectively ) . The incidence rate per 1000 for myocardial infa rct ion was 30.3 for control subjects , 53.6 for the IHE group , and 55.6 for the IHE plus clofibric acid group . The corresponding rates for IHD incidence were 90.9 , 97.8 , and 98.8 , respectively . Men suffered more frequently from myocardial infa rct ion , whereas women developed ECG criteria for IHD more frequently . Among the 35 cases of death , besides cardiovascular diseases , liver cirrhosis and neoplasia were the predominant causes . The death rate per 1000 in control subjects was 46.2 , 30.6 in the IHE group , and 27 among patients with IHE plus clofibric acid . Conclusions IHE was of substantial benefit for the control of glycemia , significantly diminished the need for antidiabetic drugs , and reduced a cluster of risk factors but had no effect on the control of blood lipids . This could be one major reason for the failure of IHE , effective lowering of blood pressure , and clofibric acid to prevent cardiovascular complications . Clofibric acid was only effective in reducing triglycerides [2209318] The aim of this study was to compare the effects of an intensive educational approach incorporating longer time , greater simplicity , repetition , and cognitive motivational techniques with a conventional one in subjects with established non-insulin-dependent diabetes mellitus ( NIDDM ) whose weight , glycemic control , and diet were not optimal . Subjects were r and omly allocated to intensive or conventional education . Of 350 subjects , 70 met the study criteria , which included established NIDDM ( ≥3 mo ) , suboptimal recent glycemic control , dietary fat intake ≥35 % of total energy intake , and body massindex ≥25 kg/m2 . The intensive approach was associated with significantly greater improvements in dietary compliance , dietary intake ( complex carbohydrate , [ P = 0.013 ] , legumes [ P < 0.0001 ] , fiber [ P < 0.0001 ] , total fat [ P < 0.004 ] , saturated fat [ P < 0.004 ] ) , and total cholesterol level ( P = 0.007 ) . The transient improvement in glycemic control was similar in both groups . An intensive education program can improve dietary compliance in established NIDDM subjects more than a conventional one . These recommended dietary improvements achieve better improvement in total cholesterol but do not necessarily improve glycemic control [6347578] The effect of patient education on diabetic control in insulin-treated diabetic adults was studied in 77 subjects r and omized into two groups : intensive patient education ( group A ) and control ( group B ) . The subjects in group A received intensive patient instruction , both individually and in small groups , from a team of physicians , teaching nurses , and a dietitian . The patients in group B received a short instruction course consisting mainly of printed material . A highly significant improvement in diabetic control was observed in both groups immediately after the education programs , with gradual return to the original level during the following 3–6 mo . No difference was observed between the two groups in any of the measured parameters during the 18-mo investigation . Factors related to good control during the study included the length of school education , the quality of the control at the beginning of the study , and the high degree of self-confidence and lack of signs of anxiety in the psychological tests . The results demonstrate that the effects of educational programs are of limited value if they do not lead to permanent changes in attitudes and motivation , which are critical factors affecting long-term diabetic control [9314625] OBJECTIVE To evaluate a weight loss and exercise program design ed to improve diabetes management in older African-Americans . RESEARCH DESIGN AND METHODS Overweight African-Americans ( n = 64 ) ages 55–79 years with NIDDM were r and omized to either an intervention ( 12 weekly group sessions , 1 individual session , and 6 biweekly group sessions ) or usual care ( 1 class and 2 informational mailings ) . Clinical and behavioral variables were assessed at 0 , 3 , and 6 months of treatment . RESULTS Significant net differences in the intervention versus usual care were observed for weight ( −2.0 kg , P = 0.006 ) , physical activity , and dietary intake of fat , saturated fat , cholesterol , and nutrition knowledge at 3 months ( all P < 0.05 ) and for weight at 6 months ( −2.4 kg ; P = 0.006 ) and mean HbA1c values at 3 and 6 months ( respectively , −1.6 and −2.4 % , both P < 0.01 ) . After the adjustment for changes in weight and activity , the intervention participants were ∼ twice as likely to have a one unit decrease in HbA1c value as those in usual care . Blood pressure increase sin usual care participants result ed in net differences ( intervention minus control ) at 3 and 6 months of −3.3 ( P = 0.09 ) and −4.0 ( P = 0.05 ) mmHg diastolic , respectively , and −8.4 ( P = 0.06 ) and −5.9 ( P > 0.10 ) mmHg systolic , respectively . Blood lipid profiles improved more in intervention than usual care participants , but not significantly . CONCLUSIONS The intervention program was effective in improving glycemic and blood pressure control . The decrease in HbA1c values was generally independent of the relatively modest changes in dietary intake , weight , and activity and may reflect indirect program effects on other aspects of self-care [8846745] In this r and omized trial patients with non-insulin-dependent diabetes were allocated to one of four programs : a minimal instruction program ( n=59 ) . an education program of individual visits ( n=57 ) , an education program incorporating a group education course ( n=66 ) , and a behavioral program ( n=59 ) . Individual and group education programs had higher attrition rates than the behavioral and minimal programs . The four programs , which involved different amounts of patient contact time , delivery format , and instructional strategies . all produced reductions in HbA atid BMI , with no significant differences between the programs . There were no differences between groups over three time periods in total cholesterol , HDL cholesterol , systolic blood pressure , or proportion of patients consulting an ophthalmologist . The behavioral program ploduced a greater reduction in diastolic blood pressure over 12 months that the education programs and a greater reduction in the cholesterol risk ratio over 3 months than the other programs . The behavioral program patients were more likely to have visited a podiatrist after 6 months and reported higher satisfaction [3535493] Self-monitoring of blood glucose levels is currently being recommended for obese patients with type II diabetes to improve weight loss and glycemic control . To determine whether self-monitoring of blood glucose levels improves dietary compliance in these patients , 50 obese patients with type II diabetes were r and omly assigned either to a st and ard behavioral weight control program or to a weight control program that included self-monitoring of blood glucose levels and focused on the weight-blood glucose relationship . Both groups lost significant amounts of weight and maintained their losses for at least one year ; reductions in medication could be made for 70 percent of patients . These data suggest that the behavioral weight control used in this study may be of benefit to patients with type II diabetes . However , there was no evidence that the addition of self-monitoring of blood glucose levels to the treatment program improved the outcome in terms of weight loss , reduction in medication , dietary compliance , or mood state [2974778] It has been suggested that much effort expended in teaching diabetic diets is ineffective and wasteful . We have tested a different system by r and omly allocating 75 newly diagnosed obese Type 2 diabetic patients to usual ‘ unstructured ’ clinic care or to group education by diabetes specialist nurses and a dietitian . Patients allocated to group education attended five 90‐min group sessions during the first 6 months . Six months after diagnosis they had lost more weight ( median ( 95 % CI ) , 7 ( 5.5–9 ) vs 2 ( 1–5 ) kg , p<0.002 ) and were better controlled ( HbA1 : 7.5 ( 7.0–8.1 ) vs 9.5 ( 8.7–10.4 ) % , p<0.001 ) than those r and omized to the usual clinic system . At 1 year ( after no further visits ) the difference in weight loss was less ( 5.5 ( 4–6.5 ) vs 3 ( 2–4 ) kg , p<0.05 ) and diabetic control was similar ( HbA1:9.0 ( 8.2–9.8 ) vs 9.9 ( 8.9–10.9 ) % . At 1 year only 14 ( 39 % ) of the education group and 9 ( 23 % ) of those attending the clinic had a fasting blood glucose less than 7.0 mmol l−1 [2702897] Two diabetes education programs were compared to a control condition . Seventy-eight type II ( non-insulindependent ) diabetic out patients were r and omly assigned to nutrition education , nutrition education plus social learning intervention , or wait-list control conditions . Both interventions involved five weekly meetings that focused on reducing calorie intake , increasing dietary fiber , and decreasing fat consumption . The social learning condition also included individualized goal setting and feedback and training in problem-solving and relapse prevention . Within-group analyses and between-group comparisons generally revealed greater improvement in targeted goals ( e.g. , calorie intake , fat reduction ) among intervention conditions than the control condition . There were few differences in more distal measures of outcome such as weight or glycosylated hemoglobin . The social learning component did not improve outcome more than the nutrition education program . Possible reasons for the observed findings and the advantages and limitations of focused time-limited diabetes education efforts are discussed [2137754] Forty-eight families with children less than 13 years old attending a paediatric diabetic clinic volunteered for a 2-year r and omized crossover trial to determine whether an informal education programme ( diabetic club ) could improve diabetic control . Group A attended the diabetic club for 10 afternoons of informal education in the first year , while Group B continued at the routine clinic ( 5 visits per year ) . For the second year Group A returned to the clinic , Group B attended the club . Glycosylated haemoglobin ( HbA1 ) remained stable while attending the club but rose significantly ( p less than 0.01 ) while attending the clinic in both groups ( HbA1 at baseline , 1 year , and 2 years : Group A , 9.6 ( SD 1.2 ) , 9.6(1.4 ) , 10.7(2.1)% ; Group B 8.9(1.3 ) , 10.4(1.4 ) , 10.5(1.4)% ( normal reference range 4.7 - 7.9 % ) ) . Other indices of control were unchanged . Diabetic problem-solving scores of parents improved ( p less than 0.01 ) but their knowledge of diabetes did not correlate with their child 's HbA1 . Dietary intake showed a reduction in percentage of energy taken as fat ( 40 % vs 37.7 % , p less than 0.05 ) during club attendance . The percentage of parents reporting helpful social contact between families increased during their club year ( Group A 50 to 78 % , Group B 32 to 57 % , p less than 0.001 ) . Psychological measurements remained unchanged . An education programme for diabetic children may stabilize diabetic control in the short term but this effect is not sustained . The main benefit was the support provided by increased social contact with families of other diabetic children within the informal framework of the diabetic club [3425385] Eighty consecutive newly diagnosed non-insulin-dependent diabetic patients were r and omly allocated into two groups to compare two different patient education regimens . One group received individual dietary instructions by a nurse and the other a short , written leaflet given by a doctor . The principal aim of the dietary instructions was weight reduction . A significant weight loss and improvement in the control of diabetes occurred in both groups , and these changes were similar in the two groups . At the end of one year 's follow-up , however , only 25 % of the patients were satisfactorily controlled ( fasting blood glucose less than or equal to 6.0 mmol/l ) . The degree of weight loss correlated only weakly with the improvement in the metabolic control . The degree of obesity and insulin secretion capacity as measured at the beginning of the study did not predict the improvement of glycaemic control during the study . At the end of the study a significant improvement was observed in serum lipids of patients with good control ( fasting blood glucose less than or equal to 6.0 mmol/l ) or weight loss ( greater than 5 kg ) . In conclusion , both brief , written and individual dietary instructions induced a significant weight loss as well as improved glucose and lipid metabolism in newly diagnosed non-insulin-dependent diabetic patients , but satisfactory metabolic control was achieved only in a minority of the patients [3219992] Insulin/sulphonylurea-treated diabetics attending a busy university diabetic clinic were studied to determine whether issuing drug information sheets and /or age influenced underst and ing and behaviour regarding their disease and its treatment , especially with respect to avoiding hypoglycaemia . Patients were each asked 10 basic questions ( each correct answer scoring 1 ) , stratified by age ( 20 were less than or equal to 45 years and 91 greater than 45 years ) . According to a single-blind r and omised protocol , they were issued or not issued with drug information sheets ( providing information to correctly answer all 10 questions ) . After 2 - 3 months , 107 ( 88 aged greater than 45 years ) were retested and asked whether they recalled an information sheet , read it themselves or had it read to them . Whether or not patients received sheets , corresponding mean aggregate scores were very similar in both age groups and there was no correlation with age . Second test scores yielded clinical ly and statistically significant increments in both the sheet and no sheet groups , respective mean aggregate scores increasing from 4.48 to 5.80 and 5.14 to 6.27 ( P less than 0.001 ) . Among patients issued with sheets , 32 who recalled reading them achieved the greatest improvement in mean scores ( 4.53 to 6.16 , P less than 0.001 ) . Active interaction/communication ( participation in first test , recall and reading of information sheet ) had a favourable educational impact irrespective of age , but merely issuing drug information sheets had no benefit [1827394] Despite the established role of foot care education in diabetes management , reports evaluating such interventions are rare . The effectiveness of an intensive foot care intervention programme and a conventional one were therefore compared in Type 2 diabetes . The intensive group showed significantly greater improvements than the conventional group in foot care knowledge ( p less than 0.001 ) , compliance with the recommended foot care routine ( p = 0.012 ) , and compliance with the initial advice to consult a podiatrist ( other than the project podiatrist ) for further treatment ( p = 0.008 ) . At the first follow-up visit the intensive group also showed a significantly greater reduction in the number of foot problems requiring treatment than the conventional group [1740599] OBJECTIVE To assess whether knowledge or psychosocial and glycemic benefits of a diabetes education program are enhanced by a support group for older patients . DESIGN A partially r and omized controlled trial involving two groups of patients : Group A , subjects who received an education program followed by 18 months of support group sessions ; Group B , only the diabetes education program . A third convenience sample , Group C , received neither intervention . Groups A and B were assessed before and immediately after the education program , and all groups were assessed 2 years after the education program . SETTING Diabetes clinic at a Veterans Affairs Medical Center . PATIENTS All subjects were male ( mean age = 68 + /- 1.3 years , range = 57 - 82 years ; duration of diabetes = 10 + /- 2 years , range 3 - 16 ) . Sample sizes were 11 in Group A , 13 in Group B , and 8 in Group C. INTERVENTION The education program consisted of six weekly sessions covering aspects of diabetes self-care . The support group consisted of 18 monthly sessions for continuing education , discussion , and structured social activities . OUTCOME MEASURES Diabetes knowledge , psychosocial factors ( self-care-related quality of life , stress , family involvement in care , and social involvement ) , depression , and glycemic control . RESULTS Group A scored better ( at least P less than 0.05 ) on knowledge , quality of life , and depression than the other groups . Groups A and B showed less stress , greater family involvement , better glycemic control , but less involvement in social activities than Group C. CONCLUSION Diabetes education programs can have long term benefits on knowledge , psychosocial functioning , and glycemic control for older diabetic patients . The addition of support groups enhances diabetes knowledge and psychosocial functioning [10414474] BACKGROUND This study was done to determine the efficacy and ease of administration of education/behavior modification classes , provided by a nurse and a dietitian in a primary care clinic for improving control of type 2 diabetes mellitus . METHODS Patients were divided r and omly into two groups . Eighteen patients completed 6 months of structured , office-based classes , and 20 similar patients served as control subjects . All were patients of the same group practice and had their usual office visits . Glycemic control , lipid levels , body weight , knowledge about diabetes , medication requirements , and symptoms were monitored during the 6 months , with follow-up at 12 months . RESULTS At the end of 6 months , the intervention group had significant reductions in mean fasting blood glucose , glycosylated hemoglobin , total cholesterol , and low-density lipoprotein cholesterol ( LDL-C ) values . Their mean body weight was significantly reduced at 12 months , and their knowledge of diabetes was improved . Control patients had significant improvement only in glycosylated hemoglobin and body weight at 6 months . Minimal physician time was required . CONCLUSION The education/behavior modification program was clinical ly worthwhile , and it was easy to administer [7698064] This study evaluated pharmaceutical care as an adjunct to an existing , coordinated-care program at a Regional Diabetes Center . The progress of a control group receiving the st and ard pharmacist instruction was compared with two treatment groups receiving additional small group or individual supplementary education for a 2-month period . Outcome evaluation included assessment of individual diabetes management through blood glucose monitoring and responses on a pretest and posttest question naire . Patients in the treatment groups demonstrated significantly lower average weekly blood glucose levels and a decreased incidence of hyperglycemic episodes compared with the control group . Question naire data for both treatment groups demonstrated a significant increase in patient underst and ing of diabetes medications and medications for associated illnesses , an increase in knowledge about blood glucose monitoring , and a positive difference in perceptions/attitudes toward diabetes and communication with the pharmacist . This approach is consistent with the concept of pharmaceutical care in which the pharmacist helps patients avoid long-term complications and thus improve their quality of life [2630378] To study if self-monitoring of glucose , urinary or capillary , could help them to improve their metabolic control through better compliance to diet and /or hypoglycaemic agents , 208 non-insulin-treated poorly controlled diabetic patients were r and omized to : group A -- regular HbA1c determinations but no self-monitoring , group B -- self-urine glucose monitoring , twice every other day , group C -- self blood glucose monitoring , twice every other day , and followed six months . At the end of the study period , the decrease of HbA1c over six months -- main endpoint -- was not significantly different between the three groups ( mean + /- SEM ; group A : -0.5 + /- 0.2 % ; group B : -0.1 + /- 0.3 % ; group C : -0.4 + /- 0.3 % ) . However , the degree of compliance to blood glucose self-monitoring in group C appeared to relate to the outcome : a significant correlation was found between the number of blood glucose strips used and the decrease of HbA1c ( r = .36 , p less than .02 ) . We conclude that regular self-monitoring has no definite advantage over the usual management for improving metabolic control in non-insulin-treated diabetic patients , though it may possibly help patients ready to comply with its use [3698783] Home health nurses provided individualized instruction in diabetes self-care within the home environment of 393 diabetic individuals . Each subject was r and omly assigned to either the intervention ( those receiving home teaching ) or control ( those not receiving home teaching ) group . At 6 mo postenrollment , intervention subjects showed significantly greater self-care knowledge and skills than control subjects , although the actual differences between the two groups in terms of self-care skills were probably too small to have any practical meaning . The primary objective of the study , which was the reduction of the number of preventable diabetes-related hospitalizations ( ketoacidosis , ketotic coma , nonketotic coma , insulin reaction , and diabetes out of control ) , was not achieved ; no differences between the groups were noted after 12 mo of follow-up . Similarly , length of hospital stay , foot problems , emergency room and physician visits , and sick days were roughly equivalent in both groups during the follow-up year . These results suggest that , in the absence of concurrent changes in the health-care delivery system and strategies for influencing attitudes toward self-care , education alone is ineffective [7657902] OBJECTIVE To assess the effect of medical nutrition therapy ( MNT ) provided by dietitians on medical and clinical outcomes for adults with non-insulin-dependent diabetes mellitus ( NIDDM ) , and to compare MNT administered according to practice guidelines nutrition care ( PGC ) to MNT administered with basic nutrition care ( BC ) . DESIGN A prospect i ve , r and omized , controlled clinical trial of two levels of MNT on metabolic control in persons newly diagnosed with or currently under treatment for NIDDM was conducted at diabetes centers in three states ( Minnesota , Florida , and Colorado ) . BC consisted of a single visit with a dietitian ; PGC involved an initial visit with a dietitian followed by two visits during the first 6 weeks of the study period . Data were collected at entry to the study and at 3 and 6 months . SUBJECTS Results are reported for 179 men and women aged 38 to 76 years : 85 assigned r and omly to BC and 94 to PGC . This represents 72 % of the 247 subjects enrolled . An additional 62 adults with NIDDM at one site who had no contact with a dietitian were identified as a nonr and om comparison group . OUTCOMES Medical outcome measures included fasting plasma glucose ( FPG ) , glycated hemoglobin ( HbA1c ) , and serum lipid levels . Clinical outcomes included weight , body mass index , waist-to-hip ratio , and changes in medical therapy . STATISTICAL ANALYSES Initial analysis of the discrete variables was done using the chi 2 statistic with Yates ' correction . Initial analysis of continuous variables was done by analysis of variance . The changes in variables between time periods were analyzed by paired t test , and comparisons between groups were analyzed using a t test for independent groups . RESULTS At 6 months , PGC result ed in significant improvements in blood glucose control as indicated by FPG and HbA1c levels and BC result ed in significant improvements in HbA1c level . Participants assigned to the PGC group had a mean FPG level at 6 months that was 10.5 % lower than the level at entry , and those in the BC group had a 5.3 % lower value . Among subjects who had diabetes for longer than 6 months , those who received PGC had a significantly better HbA1c level at 3 months compared with those receiving BC . The comparison group showed no improvement in glycemic control over a comparable 6 months . PGC subjects had significant improvements in cholesterol values at 6 months , and subjects in both the PGC and the BC groups had significant weight loss . CONCLUSIONS MNT provided by dietitians result ed in significant improvements in medical and clinical outcomes in both the BC and PGC groups and is beneficial to persons with NIDDM . Persons with a duration of diabetes longer than 6 months tended to do better with PGC than with BC . Because of the upward trend in glucose levels after 3 months , ongoing MNT by dietitians is important for long-term metabolic control [4006661] It is not clear whether diabetic patients can learn accurate self-monitoring of blood glucose ( SMBG ) by use of written package instructions . In addition , it is unclear whether the improvement in accuracy of monitoring that results from professional training is due to the professional intervention or to a personal practice effect . For these reasons , improvement in accuracy of SMBG ( using Chemstrip bG , Biodynamics Division , Boehringer-Mannheim , Indianapolis , Indiana ) after a 30-min session of professional instruction in one group of diabetic patients was compared with improvement after 30 min of practice and study of package instructions in another group . After initial reading of package instructions in both groups , and after the practice session in the control group , mean percent error was 22–37 % . In contrast , mean percent error declined to 9 % after a professional training session . We conclude that learning SMBG solely by reading package instructions leads to unacceptable inaccuracy . However , by use of short , intensive instruction sessions , a diabetes educator can reduce such errors and teach highly accurate monitoring to most diabetic patients [1296898] This study investigated the effectiveness of a " h and s-on " foot care teaching/learning approach for adults with diabetes . By r and om assignment , the control group received a lecture presentation on foot care , while the experimental group participated in a h and s-on session on foot care in addition to the lecture presentation . Data concerning the subjects ' foot care knowledge and skills , the condition of their feet , and their level of HbA1c were gathered prior to and six months after the foot care educational sessions . No significant increases in knowledge about foot care were observed in the experimental group . The experimental group reported improvements in inspecting and washing their feet on a daily basis , and in care of the toenails . No significant differences were observed in the status of the subjects ' feet . The HbAlc readings were significantly improved for both the experimental ( t=4.10 , df=10 , p=0.002 ) and control ( t=2.25 , df=9 , p=0.051 ) groups . A h and s-on educational session may improve foot care practice s temporarily . However , long term effects need to be studied to discern overall improvement of foot care practice s and physical status of the feet [3549757] To examine the effects of intensive patient and /or physician diabetes education on patient health outcomes , a controlled trial was conducted in which internal medicine residents and their 532 diabetic patients were r and omly assigned to : routine care ; patient education ; physician education ; or both patient and physician education . Patient outcome data were analyzed either by analysis of covariance on post intervention values ( 2-hour post-pr and ial plasma glucose [ PPG ] ; body weight [ BW ] ; blood pressure [ BP ] ; or analysis of variance conducted on change values ( fasting plasma glucose [ FPG ] and glycosylated hemoglobin [ A1Hgb ] ) . After patient education , significant improvements were observed in FPG , A1Hgb , BW , and systolic and diastolic BP . Physician education result ed in significant decreases in FPG , A1Hgb and BW . The combination of patient plus physician education result ed in the greatest improvements in patients ' health outcomes including FPG , A1Hgb , PPG , BW and diastolic BP . Adjusted systolic BPs were not significantly different in the two groups . While these physiologic improvements were statistically and probably clinical ly significant , hyperglycemia and obesity still persisted . Thus , achieving optimal patient outcomes for a chronic disease like diabetes mellitus may require a greater or more effective use of re sources than currently estimated [2357919] This study tested the hypothesis that follow-up intervention ( by telephone calls and home visit ) affects compliance in patients with non-insulin-dependent diabetes mellitus ( NIDDM ) . Sixty NIDDM patients were r and omly assigned to two groups — a control group , which received the st and ard protocol ( 3-day educational program and a review session 1 month after the program ) ; and an intervention group , which received the st and ard protocol as well as a series offour telephone calls and one home visit by a registered nurse over a 3-month period . Compliance to prescribed regimens was determined by analyzing three sets of data : changes in pre- to post study glycosylated hemoglobin ( HbA1c ) values ; changes in pre- to post study weight ; and frequency with which self-monitoring of blood glucose ( SMBG ) was practice d. Results showed that SMBG practice was significantly better for the intervention group . No significant differences were seen in post study HbA 1c values and weight changes between the two groups . Follow-up inter vention by telephone calls and home visit can enhance patient compliance to certain aspects of the prescribed diabetes management plan [8498761] Given that 14 million Americans have diabetes [ 1 ] , the common complications of this disorder , such as foot ulcers and lower extremity amputations , are of major concern to the medical community . Approximately 20 % of all diabetic patients hospitalized in the United States are admitted because of foot complications [ 2 , 3 ] . Furthermore , about 50 % of all nontraumatic amputations in the United States are done in patients with diabetes [ 1 , 4 ] . This proportion equates to about 55 000 amputations a year [ 1 ] or 59.7 amputations for every 10 000 persons with diabetes [ 5 ] . Patients who undergo an amputation are at greater risk for a second similar procedure on either the same or the other leg [ 6 , 7 ] . Yet , it has been estimated that about one half of the amputations in patients with diabetes , or about one fourth of the total amputations done in the United States , are preventable [ 1 , 4 ] . Recently , the focus has been on preventive strategies that minimize foot damage in diabetic patients and thereby reduce the rates of ulcers and amputations . These preventive strategies are based on two observations : first , that simple efforts on the part of the health care provider or patient can reduce the likelihood of subsequent amputation due to diabetes-associated foot disease [ 8 ] ; and second , that many of these simple procedures are not being systematic ally applied by health care providers or patients [ 9 ] . For example , studies indicate that physicians infrequently examine the feet of patients with diabetes [ 9 , 10 ] . Also , most patients with diabetes do not engage in simple foot-care assessment s to identify lesions requiring early treatment [ 11 ] . Preventive strategies are not systematic ally applied for several reasons : First , patients may not be aware of foot-care procedures or how to do them , or they may not believe that such procedures can make a difference ; second , podiatry and orthopedics services that could assist in foot salvage in diabetic patients may not be available ; and , finally , the health care system may make it difficult for patients or health care providers to examine the feet of patients with diabetes [ 10 ] . Several uncontrolled studies found that implementation of improved foot-care programs can significantly reduce lower extremity complications in patients with diabetes ; these studies showed a 44 % to 85 % reduction in the rate of lower extremity amputations [ 4 , 12 - 14 ] . A recent casecontrol study also supports the implementation of preventive strategies , such as foot care , use of protective footwear , and aggressive treatment of foot infection by patients or health care providers , to decrease the risk for lower extremity amputation [ 15 ] . The intervention in our study was design ed to reduce the prevalence of risk factors for lower extremity amputations in patients with noninsulin-dependent diabetes and involved the three major elements of a prevention program : the patient , health care providers , and the health care system . Specifically , we did a r and omized , controlled trial to determine whether a comprehensive foot-care intervention could improve patients ' knowledge and performance of appropriate foot care ; increase the number of referrals to specialty clinics such as the podiatry clinic ; increase the frequency of foot examinations by health care providers and the documentation of risk factors in the medical record ; and improve short-term patient outcomes such as skin and nail conditions known to be risk factors for ulcers and amputations . Methods Setting Our study , the design of which is summarized in Figure 1 , was done from April 1989 to March 1991 in the academic general medicine practice of the Regenstrief Health Center in Indianapolis , Indiana [ 16 ] . The practice is subdivided into four primary care teams ( labeled A , B , C , and D ) , each with its own nursing and clerical staff . Each team sees patients for eight half-day sessions per week , with each session staffed by one or two faculty internists and two to four housestaff . Teams A and C were r and omly assigned to the intervention group ; teams B and D were assigned to the control group . Previous studies in which this method of r and omization was used have shown no baseline interteam differences in patient characteristics and physician practice behavior and no effect of the team on the study outcome [ 16 - 19 ] . Figure 1 . Summary of the study design . Patient Identification and Recruitment The computerized Regenstrief Medical Record System [ 20 ] was used to identify approximately 3000 patients with noninsulin-dependent diabetes , as well as the date and time of their next appointment . Only patients with noninsulin-dependent diabetes who were seen at least two times in the preceding year by the same provider were included in the study . Additional criteria for inclusion were as follows : an age greater than 40 years ; a diagnosis of diabetes after 30 years of age ; a diagnosis of diabetes based on National Diabetes Data Group criteria [ 21 ] or the presence of disease requiring medication for the control of hyperglycemia ; an intention to obtain care at the general medicine practice for the next 2 years ; and a body weight that was either ideal or heavier than ideal . Exclusion criteria included pregnancy ; major psychiatric illness , including dementia ; terminal illness likely to cause death within 1 year ; renal failure ( serum creatinine > 440 mol/L ) ; previous bilateral amputations above or below the knee ; or an inability to provide any self-care . Patients of investigators involved in the protocol were also excluded from the study . Of the 728 eligible patients , 244 refused to participate , 89 enrolled in the study but failed to keep their appointments for assessment , and 395 were assessed by trained nurse-clinicians . Of the 395 patients assessed , 352 ( 89 % ) completed the study ; 43 patients ( 11 % ) did not complete the study for the following reasons : death ( 11 patients ) ; change of residence ( 15 patients ) ; illness ( 6 patients ) ; transportation problems ( 3 patients ) ; and miscellaneous reasons ( 8 patients ) . Patient Assessment Sample s for determining fasting plasma glucose , cholesterol , triglyceride , high-density lipoprotein , hemoglobin A1C , and C-peptide levels were obtained from enrolled patients and immediately transported to a certified laboratory for analysis . Patients gave a history and had a physical examination at study entry and approximately 1 year later ( mean , 11.8 1.5 months ) . These examinations focused on risk factors for amputation and were administered by two trained nurse-clinicians who were blinded to the patients ' experimental conditions . Foot-related data derived from the history and physical examination included the patient 's self-reported foot-care behaviors ; the quality of the patient 's examination of his or her feet ; the severity of any foot lesions ; and the presence of musculoskeletal abnormalities , dermatologic conditions , peripheral vascular disease , and peripheral neuropathy ( the neuropathy assessment included quantitative measures of pressure and temperature sensation ) . Patients were question ed about their regular foot-care routine and were asked to show how they examined their feet . During this self-examination , nurse-clinicians observed whether patients ' scrutinized the toenails , the soles of the feet , and the area between toes . Musculoskeletal and dermatologic abnormalities were assessed using st and ard definitions of findings such as callus , hammer toe , and Charcot foot [ 3 , 22 ] . The nurse-clinicians palpated the dorsalis pedis , posterior tibial , and femoral pulses bilaterally in their assessment for peripheral vascular disease . If a pulse was absent at any one of the six sites palpated , the assessment was considered abnormal . Foot lesions were rated for severity using the Seattle Wound Classification System [ 23 ] , which ranges from a grade of 1.1 ( absence of lesions ) to a grade of 10 ( entire foot or leg is gangrenous ) . In our study , a foot lesion was defined as any wound , with or without functional interruption of the protective cutaneous barrier , ranging from a superficial scratch to an ulcer involving the epidermis . A serious foot lesion was defined by a severity grade of at least 1.3 , which indicates a minor , nonulcerated lesion with clinical evidence of healing sufficient to close previous interruption of the cutaneous barrier [ 23 ] or a blister . Pressure and temperature sensations were measured using the 5.07-log ( 0.1 mg)-force Semmes-Weinstein monofilament and the thermal sensitivity testing apparatus , according to st and ard techniques [ 24 - 26 ] . Thermal sensitivity was considered abnormal if the patient had a value greater than 2 st and ard deviations from the mean value for a group of healthy persons without diabetes ( warm > 2.04 C ; cool > 1.58 C ) . Practice Patterns of Health Care Providers Immediately after each scheduled visit , study patients had a structured interview [ 10 ] with a research assistant , who asked about foot self-examination and foot-care education given by health care providers ( the primary care physician or nursing personnel ) . In addition , a chart audit was conducted by a nurse-clinician who was blinded to the patients ' experimental condition . Information abstract ed from the medical record included the physician 's documentation of the findings from the history and physical examination ; any referral to podiatry , orthopedics , or vascular surgery clinics ; and diagnostic-test ordering related to the evaluation and treatment of diabetes-associated foot problems . Intervention The intervention cohort was exposed to several risk-reduction strategies . The nurse-clinicians conducted the patient education session with one to four patients , covering appropriate foot-care behaviors and footwear , using a commercially available slide and audiotape presentation [ 27 ] and pamphlets [ 28 ] . Behavioral contracts regarding desired foot-care behaviors were negotiated with each patient . Follow-up was done by telephone 2 weeks after the education sessions to remind patients [8401245] The implication s of behavioral analysis for practice and research have significant potential for nursing . This present study was conducted to determine the effectiveness of nurses and patients actively participating in behavioral analysis and the implementation of behavioral strategies in order to improve the patients ' self-management of their Type H diabetes . Patients ( N = 156 ) were r and omly assigned to one of four groups . The attention control group ( n = 41 ) received routine care . The compliance group ( n = 32 ) agreed to practice compliance behaviors related to the prescribed medical regimen . The behavioral strategies group ( n = 42 ) participated in behavioral analysis and agreed to practice behavioral strategies . The behavioral strategies with instruction group ( n = 41 ) participated in behavioral analysis , agreed to practice behavioral strategies , and received classes and programmed instruction about behavioral analysis and behavioral strategies . There were no outcome differences between groups relative to glycosylated hemoglobin ( GHb ) and weight loss . There were differences in the outcome measures in subgroups by age , gender , and employment , which have practice and research implication s for the individualization of interventions using behavioral strategies [10159676] There is a pressing need for brief , practical interventions that address diabetes management . We have developed an office-based intervention to prompt both patients and providers to focus on behavioral issues relevant to dietary self-management that is being evaluated in a r and omized trial . The intervention is design ed to be broadly applicable to the majority of adult diabetes out patients during medical visits ; uses touchscreen computer assessment to provide immediate feedback on key issues to patients and providers just prior to their interaction ; and provides goal setting and problem-solving assistance to patients following their meeting with the physician . Follow-up components include phone calls and videotape or interactive video instruction as needed . The program is described , and demographic and behavioral characteristics of participants are presented for the first 95 patients r and omized . Initial process results suggest success in producing modest , targeted behavior changes among a broad cross-section of patients . If the long-term results are equally positive , this intervention could provide a prototype for a feasible , cost-effective way to integrate patient views and behavioral management into office-based care for diabetes [7851238] Two objectives were established for this study : 1 ) to assess the impact of a culturally specific , intensive diabetes education program on dietary patterns , and 2 ) to assess nutrient consumption relative to the Recommended Dietary Allowances . The study population consisted of elderly Mexican Americans with diabetes living in Harlingen and Brownsville , Texas . The experimental group ( n=78 ) participated in an intense , 2-hour nutrition education session , while the control group ( n=74 ) did not . The education session was conducted for groups of eight subjects via videotapes and interactive discussion . All groups experienced significant weight loss except the women in the experimental group . After the education program , however , the experimental women had increased the percentage of calories consumed daily from carbohydrate . Mean calcium consumption was substantially less than the RDA in all groups , and inadequate amounts of ascorbic acid and vitamin A often were consumed . Intensive , frequent , long-term follow-up appears essential for more sustained results [3769719] The purpose of our study was to compare the effect on diabetes control of group management with the advice-educational technique traditionally used in managing obese out patients with poorly controlled non-insulin-dependent diabetes mellitus ( NIDDM ) . Forty-one patients were r and omly assigned to these two treatment programs , and 32 patients completed the 6-mo study . Initially , patients were seen for 1-h sessions at 1- and 2-wk intervals and later at 1-mo intervals . Patients were asked to do home blood glucose monitoring , decrease caloric intake , increase exercise , and if they were taking insulin , to adjust the dose to attain approximate euglycemia and to stabilize food and exercise patterns . The combined groups reduced mean ± SD glycohemoglobin from 10.9 ± 3.1 to 9.4 ± 2.4 % ( P < .05 ) . Internal Health Locus of Control Scale was negatively and significantly correlated with initial and subsequent glycohemoglobin values ( the more internal , the lower the glycohemoglobin ) . At the end of the study the patients in the group management program had significantly lower blood glucose levels than those given advice and education , but no significant differences in glycohemoglobin values or percentage overweight were observed . One patient had a normal initial glycohemoglobin , and only 4 patients had values in the normal range of 4–6.8 % at the end of the study . Better management programs need to be developed for treating obese out patients with NIDDM [9614604] OBJECTIVE To examine the effects of patient choice between two education curriculums that emphasized either the st and ard or nutritional management of type 2 diabetes on class attendance and other outcomes among a mostly Hispanic patient population . RESEARCH DESIGN AND METHODS A total of 596 patients with type 2 diabetes were r and omly assigned to either a choice or no choice condition . Patients in the choice condition were allowed to choose their curriculum , while patients in the no choice condition were r and omly assigned to one of the two curriculums . Outcomes were assessed at baseline and at a 6-month follow-up . RESULTS When given a choice , patients chose the nutrition curriculum almost four times more frequently than the st and ard curriculum . Contrary to our hypothesis , however , patients who had a choice did not significantly increase their attendance rates or demonstrate improvements in other diabetes outcomes compared with patients who were r and omly assigned to the two curriculums . Patients in the nutrition curriculum had significantly lower serum cholesterol at a 6-month follow-up , whereas patients in the st and ard curriculum had significant improvements in glycemic control . Of the r and omized patients , 30 % never attended any classes ; the most frequently cited reasons for nonattendance were socioeconomic . Hispanic patients , however , were just as likely as non-Hispanic patients to attend classes and participate at the follow-up . Patients who attended all five classes of either curriculum significantly increased their diabetes knowledge , gained less weight , and reported improved physical functioning compared with patients who did not attend any classes . CONCLUSIONS Although providing patients with a choice in curriculums at the introductory level did not improve outcomes , differential improvements were noted between patients who attended curriculums with different content emphasis . We suggest that diabetes education programs should provide the opportunity for long-term , repetitive contacts to exp and on the modest gains achieved at the introductory level , as well as provide more options to match individual needs and interests and to address socioeconomic barriers to participation [8949977] Non-insulin-dependent diabetes mellitus ( NIDDM ) is preceded by impaired glucose tolerance ( IGT ) lasting for years before manifesting as overt hyperglycaemia . Both genetic and environmental factors contribute to the development of IGT and NIDDM . Obesity , physical inactivity and high-fat diet have been found to predict IGT and NIDDM . Therefore , a diet and exercise intervention from diagnosis of NIDDM could improve the treatment outcome and prognosis of patients with NIDDM . Furthermore , because subjects with IGT are at increased risk for diabetes and atherosclerotic vascular disease , it is reasonable to assume that in terms of reducing the incidence and longterm consequences of NIDDM an intervention at this phase is more effective than in overt diabetes . Although the nonpharmacological approach is generally accepted as the first-line treatment of NIDDM its efficacy has often been question ed . Therefore , it is important to carry out long-term controlled studies to find out to what extent lifestyle modification could improve the metabolic control and level of major cardiovascular risk factors known to be associated with poor outcome in NIDDM . This kind of study also gave relevant experience in planning studies aim ing at primary prevention of NIDDM . One-year dietary and exercise intervention on newly diagnosed NIDDM patients in Kuopio , Finl and result ed in a better metabolic control and a moderate reduction in cardiovascular risk factors as compared to the conventional treatment group . After the second year of follow-up only 12.5 % in the intervention group were receiving oral antidiabetic drugs vs. 34.8 % in the conventional treatment group . Weight reduction and a reduced use of saturated fats appeared to be the main determinants of successful treatment results . Good aerobic capacity was associated with an increase in HDL cholesterol . A multicentre primary prevention study on IGT patients is continuing in Finl and applying the same principles of intervention as used in the study on newly diagnosed NIDDM patients . Pilot results show that glucose tolerance can be improved by lifestyle changes [9434649] OBJECTIVE Evaluations of trials of the effectiveness of dietary intervention programs may be compromised by response set biases , such as those attributable to social desirability . Participants who receive a behavioral intervention may bias their reports of diet to appear in compliance with intervention goals . This study examined whether responses to st and ard dietary assessment instruments could be affected by a brief dietary intervention . DESIGN We assigned 192 undergraduate students r and omly to ( a ) see a 17-minute videotape on the consequences of eating a high-fat diet or a placebo videotape on workplace management and ( b ) receive preintervention and post-intervention assessment s or only postintervention assessment . Dietary assessment s included 4 independent measures of fat intake . RESULTS Among women , bias ( intervention minus control ) was -9.7 g fat ( from a short food frequency question naire ) and -0.6 high-fat foods ( from a question naire about use of 23 foods in the previous day ) ( P < .05 for both ) . No results were significant among men or for 2 instruments that measured more qualitative aspects of fat-related dietary habits . APPLICATIONS Even a modest dietary intervention can affect responses to dietary assessment instruments . Nutritionists should recognize that assessment of adherence to dietary change recommendations , when based on dietary self-report , can be overestimated as a result of response set biases [3565666] We assessed diabetes education and peer support interventions as facilitators of weight loss and glycemic control in a community sample of 79 elderly persons with noninsulin-dependent diabetes mellitus ( NIDDM ) . Different groups received : education only , education and peer support , and no treatment . Peer support was higher in groups where it was actively facilitated . Weight loss and reduction in level of glycemic control occurred within groups receiving both diabetes education and peer support [2305110] The quality of reported research representing a number of disciplines involved in diabetes patient education was investigated in this study . A rigorous literature search identified 47 studies reported between 1954 and 1986 that met inclusion criteria ; 29 were published studies , 18 were unpublished . Quality of the research was measured by Duffy 's Research Appraisal Checklist ( RAC ) and also by coding each study as to the number of threats to internal and external validity present . Overall quality as measured by the RAC ranged from 34 to 95 on a 100-point scale . A statistically significant relationship was found between publication date of the research report and quality , indicating improvement in quality during recent years . Quality of published versus unpublished research reports was not found to differ significantly . Recommendations for improving method ological rigor of future studies include : ( a ) the use of more rigorous design s , particularly those involving control groups such as r and omized clinical trials ; ( b ) reporting of more complete data in research reports ; and ( c ) monitoring of the quality of future studies [6522737] The design of the study was " 2-period changeover " ; each period lasted 6 months and 6 counseling sessions were offered during each period . Group 1 ( n = 81 ) , counseled in the first period , was controlled by a noncounseled group 2 ( n = 82 ) . R and omization of patients into the 2 groups took place at each office . The primary variable for consideration was the postpr and ial ( pp ) blood sugar level ( mg/dl ) . Weight reduction of overweight patients was also considered . A highly significant ( p less than 0,01 ) difference of mean pp-blood sugar reduction between the groups was found during both periods . In view of the large estimated difference in the residual effects of both treatments ( counseling , no counseling ) a crossover analysis was excluded . The best pp-blood sugar effect was obtained for patients with high pp-blood sugar level ( greater than or equal to 250 ) at the beginning of the counseling period [3775139] A population -based study on the therapeutic effects of a diabetes teaching programme ( DTP ) based on problem oriented participatory education (POPE)--a method based on learner activity in group meetings -- was undertaken at the Primary Health Care Centre , Kisa , Sweden , in collaboration with educationalists . A control group was given conventional classroom teaching . To be included a patient had to be aged 55 - 73 years , to live in his own home , and to have non-insulin-treated type II diabetes mellitus . The therapeutic effects of the DTP were studied before , during , and after POPE with regard to three factors , diabetes related knowledge , behaviour assessed by dietary and exercise habits , and the quality of the anti-diabetic therapy as assessed by metabolic profile including Hb-A1 . Significant improvement in knowledge and transient improvement in Hb-A1 concentration were recorded among patients taking part in a DTP adjusted to their individual problems and needs . When improvement in metabolic control does not last , group meetings should be continued for more than the three months used in the present study . We believe that such improvement is intimately bound up with the psycho-social process that is involved in the group meetings and that helps the patient to cope with the disease in particular and life in general [8382712] Compliance with dietary recommendations and the effect of intensified dietary therapy on energy and nutrient intakes and fatty acid composition of serum lipids were studied in 86 obese subjects ( aged 40 to 64 years ) with recently diagnosed non-insulin-dependent diabetes mellitus ( NIDDM ) . After three months of basic education , the subjects were r and omly separated into an intervention group ( n = 40 ) and a conventional treatment group ( n = 46 ) . Members of the intervention group participated in 12 months of intensified education ; those in the conventional group visited local health centers . Compliance with dietary instructions was monitored through food records . Intensified dietary therapy result ed in greater weight loss , better metabolic control , and a less atherogenic lipid profile than conventional treatment . Intake of energy and saturated fatty acids tended to decline in the intervention group . A higher percentage of patients in the intervention group had a total fat intake of 30 % of energy or less after 15 months ( 32.5 % [ 12 of 38 ] vs 17.4 % [ 8 of 46 ] ) . Similarly , more patients in the intervention group had a saturated fatty acid intake of 10 % or less of total energy intake at the end of the study ( 35.0 % [ 13 of 38 ] vs 8.7 % [ 4 of 46 ] ) . The mean dietary cholesterol intake was within recommendations in both groups at the end of the study . The relative percentage of linoleic acid of serum lipids increased significantly and the relative percentage of palmitic acid of serum triglycerides , phospholipids , and cholesterol esters decreased in the intervention group . These changes indicate that intensified dietary therapy improved the quality of fat in the diet of patients with NIDDM [3948638] The Diabetes Education Study ( DIABEDS ) was a r and omized , controlled trial of the effects of patient and physician education . This article describes a systematic education program for diabetes patients and its effects on patient knowledge , skills , self-care behaviors , and relevant physiologic outcomes . The original sample consisted of 532 diabetes patients from the general medicine clinic at an urban medical center . Patients were predominantly elderly , black women with non-insulin-dependent diabetes mellitus of long duration . Patients r and omly assigned to experimental groups ( N = 263 ) were offered up to seven modules of patient education . Each content area module contained didactic instruction ( lecture , discussion , audio-visual presentation ) , skill exercises ( demonstration , practice , feedback ) , and behavioral modification techniques ( goal setting , contracting , regular follow-up ) . Two hundred seventy-five patients remained in the study throughout baseline , intervention , and postintervention periods ( August 1978 to July 1982 ) . Despite the requirement that patients demonstrate mastery of educational objectives for each module , postintervention assessment 11–14 mo after instruction showed only rare differences between experimental and control patients in diabetes knowledge . However , statistically significant group differences in self-care skills and compliance behaviors were relatively more numerous . Experimental group patients experienced significantly greater reductions in fasting blood glucose ( −27.5 mg/dl versus −2.8 mg/dl , P < 0.05 ) and glycosylated hemoglobin ( −0.43 % versus + 0.35 % , P < 0.05 ) as compared with control subjects . Patient education also had similar effects on body weight , blood pressure , and serum creatinine . Continued follow-up is planned for DIABEDS patients to determine the longevity of effects and subsequent impact on emergency room visits and hospitalization [3739801] Patients with diabetes are usually placed on exchange system diets to ensure a nutritionally adequate intake . However , there have been few studies which have actually compared the nutritional adequacy of diets selected by patients on exchange system diets , with that selected by patients on the calorie-counting diets typically used in behavioral weight control programs . This study compared the nutritional adequacy of the diets selected by overweight patients with Type II diabetes who had been r and omly assigned to either an exchange system diet or a calorie-counting diet . Three-day food diaries were completed by all patients at the start and end of a 16-week weight control program . No significant differences were observed between patients on the calorie-counting diet compared to those on the exchange system diet with respect to nutrient intake , macronutrient distribution , or percent of the RDA obtained . Patients on both types of diet reported decreases in the proportion of calories from fat . The average intake exceeded 100 % of the RDA for all nutrients except calcium . This study suggests that patients are able to improve the nutritional adequacy of their intake while following either a calorie-counting or an exchange system diet [8833634] This study aim ed to determine if patients can set their own educational priorities accurately and if the impact of diabetes education on knowledge differed between patients who did and did not set their own priorities . Forty patients referred for individual education were r and omly assigned to one of two groups . Prior to education with a diabetes specialist nurse ( DSN ) patients ranked 10 diabetes care topics in order of perceived importance and relevance to their needs and completed a knowledge question naire . Group 1 set their own priorities and the DSN directed education according to the patients stated priorities . In Group 2 the DSN set the educational priorities without seeing the patients priority list . The priority ranking by the two groups of the 10 topics and their pre-education knowledge score were not significantly different . Post-education knowledge scores improved equally and significantly in both groups ( Group 1 from 23 to 87 % ; Group 2 from 21 to 79 % ) ; P < 0.0001 ) . In both groups , knowledge scores for the top three priorities were significantly higher than for the three lowest ranked topics . Knowledge is neither dependent on , nor a good discriminator of , patient-selected priorities . There may be reasons why it is important for patients to set their own priorities , but education directed solely at those priorities may leave knowledge deficits which could compromise diabetes care [6562009] Individuals with noninsulin depend ent diabetes mellitus referred to a dia betes education programme were al located at r and om to treatment ( n = 32 ) or non-treatment ( n = 28 ) groups to assess the effectiveness of this pro gramme . The education course lasted four weeks , at the end of which the participants showed reductions of HbA1c and post-pr and ial glucose levels , improvement in knowledge and less anxiety . On the other h and , the control group experienced more anxiety and did not show significant changes in measured indices of glu cose control . Nevertheless , these i m provements in glucose control were not sustained . Within four weeks of cessation of the intervention pro gramme , HbA1c and glucose levels were not significantly different from those measured at entry to the pro gramme . In addition , a delay of four weeks from the time of referral until initiation of education was associated with lack of significant reduction of HbA1c and glucose levels [7555554] OBJECTIVE The purpose of this study was to determine if participation in a patient empowerment program would result in improved psychosocial self-efficacy and attitudes toward diabetes , as well as a reduction in blood glucose levels . RESEARCH DESIGN AND METHODS This study was conducted as a r and omized , wait-listed control group trial . The intervention group received a six-session ( one session per week ) patient empowerment education program ; the control group was assigned to a wait-list . At the end of 6 weeks , the control group completed the six-session empowerment program . Six weeks after the program , both groups provided follow-up data . RESULTS The intervention group showed gains over the control group on four of the eight self-efficacy subscales and two of the five diabetes attitude subscales . Also , the intervention group showed a significant reduction in glycated hemoglobin levels . Within groups , analysis of data from all program participants showed sustained improvements in all of the self-efficacy areas and two of the five diabetes attitude subscales and a modest improvement in blood glucose levels . CONCLUSIONS This study indicated that patient empowerment is an effective approach to developing educational interventions for addressing the psychosocial aspects of living with diabetes . Furthermore , patient empowerment is conducive to improving blood glucose control . In an ideal setting , patient education would address equally blood glucose management and the psychosocial challenges of living with diabetes [6341015] To determine whether a group behavior modification approach might be preferable to individual counseling in the nutritional therapy of non-insulin-dependent diabetes mellitus , 40 adults younger than 65 yr of age with diabetes mellitus who were not receiving insulin were r and omized to either a program of individualized dietary review and recommendations or a program of group meetings aim ed at controlling the signals leading to overeating and noncompliance with a diabetic dietary regimen . Statistically significant ( P < 0.05 ) decreases in body weight , sum skin-fold thickness , fasting serum glucose , and serum triglycerides but not LDL-C or HDL-C were observed . The individual counseling group had a greater amount of weight loss than the behavior modification group . There were no significant ( P < 0.05 ) differences between the two groups with respect to the biochemical outcome variables . Patient characteristics assessed at entry — namely anxiety , internal versus external locus of control and perceived disease severity , and compliance with advice — were significantly associated with weight loss in the behavior modification group while only the latter index was of value in the individual counseling group . Thus , our use of these programs does not identify a clear advantage of either approach in the nutritional therapy of non-insulin-dependent diabetic patients [10589324] OBJECTIVES This study evaluated a multicomponent educational intervention to increase ophthalmic examination rates among African Americans with diabetes . METHODS A r and omized trial was conducted with 280 African Americans with diabetes , enrolled from outpatient departments of 5 medical centers in the New York City metropolitan area , who had not had a dilated retinal examination within 14 months of r and omization ( 65.7 % female , mean age = 54.7 years [ SD = 12.8 years ] ) . RESULTS After site differences were controlled , the odds ratio for receiving a retinal examination associated with the intervention was 4.3 ( 95 % confidence interval = 2.4 , 7.8 ) . The examination rate pooled across sites was 54.7 % in the intervention group and 27.3 % in the control group . CONCLUSIONS The intervention was associated with a rate of ophthalmic examination double the rate achieved with routine medical care

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### Context: [7851264] Forty patients were r and omly assigned to receive either the individualized learning activity packages or classroom instruction . Effectiveness was evaluated on the basis of fasting plasma glucose , glycosylated hemoglobin , percent of ideal body weight , and knowledge and behavior scores . No significant differences were found between the groups at entry or at the 2-month follow-up . At the 5-month follow-up , the group that received the learning activity packages scored significantly higher on knowledge assessment , significantly increased their behavior score , and decreased their percent of ideal body weight . Patients who received classroom instruction increased their behavior score and exhibited significantly decreased glycosylated hemoglobin levels . Behavior and blood glucose levels were significantly correlated . Although the learning activity packages proved effective in increasing knowledge , no significant improvement was observed in blood glucose levels [8314427] Newly diagnosed mild Type 2 diabetic patients , aged 30 - 55 years , were included in the prospect i ve , multi-centre Diabetes Intervention Study . They were r and omly allotted to either an intervention group receiving intensified health education or to a control group on usual care . This paper reports the incidence , duration of and causes for absence from work due to any disease in the patients who were working during the first 5-year follow-up . Data from 817 patients could be taken into account . 14.5 % of the intervention patients and 17.3 % of the control patients had never been on the sick list . Those patients who had undergone intensified health education were listed sick less often . Women showed a higher work absenteeism in either group ; they had higher blood pressure and higher body mass index at entry . Cardiovascular diseases and musculo-skeletal disorders were major reasons for absence from work . However , when compared to the general population , these Type 2-diabetic patients were approximately four times more often on the sick list . Thus , the health education programme of the Diabetes Intervention Study was shown to be effective with respect to work absenteeism . Teaching patients is recommended as an important part of the therapeutic regimen [9219407] BACKGROUND Type 2 diabetes is up to four times more common in British Asians , but they know little about its management and complications . AIM To design and evaluate a structured pictorial teaching programme for Pakistani Moslem patients in Manchester with type 2 diabetes . METHOD A r and omized controlled trial of pictorial flashcard one-to-one education in 201 patients attending a hospital outpatient clinic or diabetic clinics in ten general practice s in Manchester . Patients ' knowledge , self-caring skills and attitudes to diabetes were measured on four topics before the structured teaching , and compared with results six months later . RESULTS All parameters of knowledge were increased in the study group ; for example , percentage scores for correctly identifying different food values increased from 57 % to 71 % ( Analysis of Variance ( ANOVA ) adjusted difference + 11.8 % ) and knowledge of one diabetic complication from 18 % to 78 % . Self-caring behaviour improved , with 92 % of patients doing regular glucose tests at six months compared with 63 % at the start . Attitudinal views were more resistant to change , with patients still finding it hard to choose suitable foods at social occasions . Haemoglobin A1c control improved by 0.34 % over six months ( ANOVA adjusted difference , 95 % CI -0.8 % to + 0.1 % ) . CONCLUSION It is concluded that this health education programme can empower Asian diabetics to take control of their diets , learn to monitor and interpret glucose results , and underst and the implication s of poor glycaemic control for diabetic complications [3612778] The treatment of choice for Type II or non-insulin-dependent diabetes mellitus is a behavioral program for the management of weight . However , compliance with this lifelong dietary regimen is often poor . In the current investigation male and female adults with diagnosed Type II diabetes were r and omly assigned to either a behavior modification , a cognitive modification , a cognitive-behavior modification , or a control group . Patients were evaluated in terms of weight , percentage of body fat , and glycosylated hemoglobin measures . Men lost signficantly more weight than women and subjects in the behavior modification group lost more weight and demonstrated greater decreases in diabetes control than subjects in the cognitive-behavior modification , cognitive , and control groups . A significant interaction indicated that diabetic men may benefit more from behavioral weight reduction programs than diabetic women . Several explanations for these findings are considered [10531848] PURPOSE Few culturally competent health programs have been design ed for Mexican Americans , a group that bears a disproportionate burden of Type 2 diabetes . In Starr County , a Texas-Mexico border community , investigators design ed and tested a culturally competent intervention aim ed at improving the health of this target population . The purpose of this article is to describe the development process of this diabetes education and support group intervention . METHODS The development stages were ( 1 ) community assessment , ( 2 ) intervention design , ( 3 ) selection or development of outcomes , ( 4 ) pilot testing , and ( 5 ) a r and omized clinical investigation . RESULTS Focus group participants identified knowledge deficits regarding diabetes and self-management strategies , and suggested characteristics of an effective intervention for Mexican Americans . Outcome measures included metabolic control indicators , a newly developed knowledge instrument , and an existing health belief instrument . Preliminary analyses indicated that the intervention was successful in significantly improving metabolic control in the target population . CONCLUSIONS Developing successful diabetes interventions for minority groups requires a number of stages , careful planning , assessment of cultural characteristics of the target population , and a systematic approach to implementation [1298950] A 10-session , self-management training program was design ed specifically for persons over 60 years of age having Type II diabetes . It targeted social learning variables , especially problem-solving skills and self-efficacy , found to be related to diabetes self-care in earlier correlational research . One hundred two adults were r and omized to immediate or delayed intervention conditions . At posttest , subjects in the immediate intervention condition showed significantly greater reductions in caloric intake and percent of calories from fat than control subjects . The intervention also produced greater weight reductions and increases in the frequency of glucose testing than did the control condition . Improvements among immediate intervention subjects were generally maintained at a 6-month follow-up . Intervention results from subjects receiving delayed intervention closely replicated those for immediate intervention subjects . We conclude that a relatively short-term program can improve self-management skills of older diabetic adults , and that there is an important need for such interventions [8900703] This paper describes the development and evaluation of a computer-aided learning ( CAL ) program . The program was tested in a trial that involved 36 people with diabetes ; 20 received CAL lessons in diabetes management and 16 attended conventional diabetes classes conducted by diabetes educators . When measurements taken before and three months after the education were compared , both groups showed significant improvement in their knowledge ; the blood glucose levels of the CAL group were significantly lower but those of the conventional education group were higher . This means that the CAL program was as effective as conventional education in imparting knowledge but it was more likely to motivate people to control their glucose levels . The CAL program allows diabetes educators to spend less time on education in basic knowledge and to concentrate more on motivational and social factors that are important determinants of patient compliance . It can also benefit people with diabetes whose access to health professionals and /or conventional diabetes education is restricted [9368810] Objective : To investigate the impact of intensive lifestyle education on dietary practice s , exercise and metabolic measurements in people with insulin-dependent diabetes mellitus ( IDDM ) . Design : Sixty-one volunteer subjects with IDDM were r and omised to intensive ( Group 1 ) or st and ard ( Group 2 ) education programmes for six months . During a second six month period of observation Group 1 subjects received routine surveillance for their condition and those in Group 2 were given intensive advice ( phase 2 ) . Current insulin regimens were modified to optimise glycaemic control before the start of the intervention phase . Nutrient intakes , weight , blood pressure , glycated haemoglobin ( HbA ) , plasma lipids , lipoproteins and maximal oxygen consumption ( VO max ) were measured at the time of recruitment and at three monthly intervals during the trial and phase 2 . Setting : Department of Human Nutrition at the University of Otago . Results : Glycated haemoglobin decreased significantly in both groups between recruitment and r and omisation , the improvement being sustained during the six months of the r and omised trial and for group 1 during the six months of post trial observation . A further decrease was seen in Group 2 during the second six month period when they were given intensive advice . Comparable changes were seen with total and low density lipoprotein ( LDL ) cholesterol in Group 1 during the trial , but significant decreases were only seen in Group 2 in association with intensive intervention ( phase 2 ) . These changes occurred in parallel with increases in intakes of carbohydrate and monounsaturated fatty acids , a reduction in intakes of total and saturated fat , and an improvement in maximum oxygen consumption . Conclusions : A lifestyle programme for people with IDDM results in modest changes in diet and exercise habits sufficient to improve measures of glycaemic control and lipoprotein mediated risk of coronary heart disease independent of changes in insulin regime . More innovative approaches to achieve lifestyle changes are required to meet current recommendations which in turn are likely to produce even greater beneficial changes than those observed here . Sponsorship : This study was supported by the Eli Lilly Research Grant ( Eli Lilly and Company ( New Zeal and ) Ltd ) , The Deans Research Grant ( Otago Medical School , New Zeal and ) and The New Zeal and Dietetic Association ( Abbott Award ) [8842601] OBJECTIVE There is a pressing need for brief practical interventions that address diabetes management . Using a r and omized design , we evaluated a medical office-based intervention focused on behavioral issues relevant to dietary self-management . RESEARCH DESIGN AND METHODS There were 206 adult diabetes patients r and omized to usual care or brief intervention , which consisted of touchscreen computer-assisted assessment to provide immediate feedback on key barriers to dietary self-management , and goal setting and problem-solving counseling for patients . Follow-up components to the single session intervention included phone calls and interactive video or videotape instruction as needed . RESULTS Multivariate analyses of covariance revealed that the brief intervention produced greater improvements than usual care on a number of measures of dietary behavior ( e.g. , fewer calories from saturated fat , fewer high-fat eating habits and behaviors ) at the 3-month follow-up . There were also significant differences favoring intervention on changes in serum cholesterol levels and patient satisfaction but not on glycosylated hemoglobin . The intervention effects were relatively robust across a variety of patient characteristics , the two participating physicians , and intervention staff members . CONCLUSIONS If the long-term results are equally positive and generalize to other setting , this intervention could provide a prototype for a feasible cost-effective way to integrate patient views and behavioral management into office-based care for diabetes [2589581] This prospect i ve r and omized study evaluated the influence of a simple education program on the incidence of lower extremity amputation in diabetic patients . Two hundred three patients were r and omized into two groups : Group 1 , education ( 103 patients , 203 limbs ) and Group 2 , no education ( 100 patients , 193 limbs ) . There were no significant differences in medical management or clinical risk factors between the two groups . The amputation rate was three times higher in Group 2 ( 21 of 177 limbs versus 7 of 177 limbs ; p less than or equal to 0.025 ) , the ulceration rate was three times higher in Group 2 ( 26 of 177 limbs versus 8 of 177 limbs ; p less than or equal to 0.005 ) , and there was no difference in the overall incidence of infection ( 2 of 177 limbs ) . Overall success in Group 1 was highly significantly different from Group 2 ( 160 of 177 limbs versus 128 of 177 limbs ; p less than or equal to 0.0005 ) . This study demonstrated that a simple education program significantly reduced the incidence of ulcer or foot and limb amputation in diabetic patients [1547677] Objective — To evaluate Diabeto , a computer-assisted diet education system . Research Design And Methods — One hundred five patients with insulin-dependent diabetes mellitus ( IDDM ) or non-insulin-dependent diabetes mellitus ( NIDDM ) were divided into two r and omized groups to participate in the evaluation of Diabeto . With free access through Minitel , the French public videotex network , Diabeto helps diabetic patients self-monitor their diets and balance their meals with personalized counseling . Results — During the first 6-mo study , group A ( 54 patients ) used Diabeto , whereas group B ( 51 patients ) were control subjects . For the second 6-mo study , group B used the system . Evaluation was based on patients ' dietetic knowledge , dietary habits , and metabolic balance . Conclusions –Diabeto led to a significant improvement of dietetic , knowledge in group A ( P < 0.0005 ) and also to improved dietary habits ; decreased caloric intake in patients initially overeating ( P < 0.05 ) , increase of dietary carbohydrate from 39.7 ± 0.7 to 42.9 ± 0.9 % in patients with an initial intake < 45 % carbohydrate , and decrease of fat intake from 41.9 ± 0.9 to 37.4 ± 1.1 % in patients with an initial intake of > 35 % fat ( P < 0.0005 ) . In the second study , in addition to similar improvements to those observed in the first study , HbA1 decreased from 11.0 ± 0.4 to 9.9 ± 0.4 % ( P < 0.005 ) and fructosamine from 5.00 ± 0.17 to 4.57 ± 0.17 % ( P < 0.001 ) . Diabeto appears to be an effective therapeutic tool in the control of metabolic diseases [3338379] In patients with non-insulin-dependent diabetes mellitus ( NIDDM ) , the influence of knowledge about their disease on the treatment and control of the disease is not clear . We evaluated the efficacy of educational group meetings with NIDDM patients on improving their knowledge of the disease and on disease management . Fifty-one NIDDM patients were r and omly assigned to either intervention or control groups . The intervention group participated in courses of three weekly lessons presented by a physician , nurse , and dietitian once every 4 mo . The intervention and control groups were also followed once every 2 mo in the clinic by the same staff . Medical treatment remained unchanged during the study . After a 12-mo follow-up of the intervention group , no significant improvement in their knowledge of diabetes could be demonstrated . However , mean fasting and postpr and ial blood glucose levels and HbA1c improved significantly in comparison with the control goup . The same tendency was evident with the weight and lipoprotein profile . We conclude that educational group therapy can improve diabetes control in patients with NIDDM [9423499] This study evaluated the 12-month follow-up results and costs of a personalized , medical office-based intervention focused on behavioral issues related to dietary self-management . Two hundred and six adults having diabetes attending an internal medicine outpatient clinic visit were r and omized to either Usual Care or to Brief Intervention . The single session intervention involved touchscreen computer-assisted assessment that provided immediate feedback on key barriers to dietary self-management , goal setting and problem-solving counselling . Follow-up components included phone calls and videotape intervention relevant to each participant . Brief Intervention produced significantly greater improvement than Usual Care on multiple measures of change in dietary behaviour ( e.g. , covariate adjusted difference of 2.2 % of calories from fat ; p = 0.023 ) and on serum cholesterol levels ( covariate adjusted difference of 15 mg/dl ; p = 0.002 ) at 12-month follow-up . There were also significant differences favouring intervention on patient satisfaction ( p < 0.02 ) but not on HbA1c levels . The costs of intervention ( $ 137 per patient ) were modest relative to many commonly used practice [4042800] High-density lipoprotein ( HDL ) cholesterol is known to be low in patients with diabetes mellitus . Low HDL levels are correlated with premature cardiovascular mortality in several major epidemiologic studies and many investigators believe increases in HDL cholesterol may reduce the risk of coronary heart disease . We evaluated dietary and exercise interventions in relation to HDL cholesterol in patients with type II diabetes mellitus . Sixty-five volunteers were r and omly assigned to one of four experimental conditions : diet , exercise , diet plus exercise , or education control . Three months after entering the program , those exposed to the dietary intervention had significant increases in HDL cholesterol . HDL increases for the other two treatment groups did not differ significantly from the education control [2060433] Objective In a r and omized 5-yr multi-intervention trial , we tested the efficacy of intensified health education ( IHE ) in improving metabolic control and reducing the level of coronary risk factors and incidence of ischemic heart disease ( IHD ) . Research Design and Methods Within the intervention group , the benefit of clofibric acid was evaluated in a double-blind study . One thous and one hundred thirty-nine newly diagnosed middle-aged ( 30- to 55-yr-old ) patients with non-insulindependent diabetes mellitus ( NIDDM ) entered the study . They were classified as diet controlled after a 6- wk screening phase with conventional dietary treatment . During the follow-up , the control group ( n = 378 ) was cared for at different diabetes outpatient clinics with a st and ardized surveillance . The intervention group ( n = 761 ) had a structured IHE that included dietary advice , antismoking and antialcohol education , and ways to enhance physical activity . Results R and omly , 379 of the IHE patients received 1.6 g clofibric acid/day , and the others received placebo . IHE result ed in improved glucose control ( adjusted fasting blood glucose ) levels after 5 yr ( control subjects 9.27 mM , IHE group 8.71 mM , and IHE plus clofibric acid group 8.60 mM , P < 0.01 ) . The better glycemic control was achieved with fewer antidiabetic drugs . After 5 yr , antidiabetic drugs were prescribed to 47 % of the control subjects , 28 % of the IHE group , and 34 % of the IHE plus clofibric acid group ( cutoff limit for drug application was postpr and ial blood glucose of ≥13.87 mM ) . The ratio of polyunsaturated to saturated fatty acids ( 0.26 vs. 0.40 , P < 0.01 ) and physical activity ( 174 vs. 327 scores , P < 0.01 ) were increased , and blood pressure , tobacco , and alcohol consumption were significantly reduced by IHE . However , IHE had no effect on calorie intake , percentage of fat in the diet ( 45 % ) , and body weight . The most important finding was the significant increase of blood cholesterol in all three groups ( + 0.47 , + 0.36 , and + 0.34 mM , respectively ) . Clofibric acid only prevented the increase of triglyceride levels ( + 0.56 , + 0.24 , and + 0.05 mM , respectively ) . The incidence rate per 1000 for myocardial infa rct ion was 30.3 for control subjects , 53.6 for the IHE group , and 55.6 for the IHE plus clofibric acid group . The corresponding rates for IHD incidence were 90.9 , 97.8 , and 98.8 , respectively . Men suffered more frequently from myocardial infa rct ion , whereas women developed ECG criteria for IHD more frequently . Among the 35 cases of death , besides cardiovascular diseases , liver cirrhosis and neoplasia were the predominant causes . The death rate per 1000 in control subjects was 46.2 , 30.6 in the IHE group , and 27 among patients with IHE plus clofibric acid . Conclusions IHE was of substantial benefit for the control of glycemia , significantly diminished the need for antidiabetic drugs , and reduced a cluster of risk factors but had no effect on the control of blood lipids . This could be one major reason for the failure of IHE , effective lowering of blood pressure , and clofibric acid to prevent cardiovascular complications . Clofibric acid was only effective in reducing triglycerides [2209318] The aim of this study was to compare the effects of an intensive educational approach incorporating longer time , greater simplicity , repetition , and cognitive motivational techniques with a conventional one in subjects with established non-insulin-dependent diabetes mellitus ( NIDDM ) whose weight , glycemic control , and diet were not optimal . Subjects were r and omly allocated to intensive or conventional education . Of 350 subjects , 70 met the study criteria , which included established NIDDM ( ≥3 mo ) , suboptimal recent glycemic control , dietary fat intake ≥35 % of total energy intake , and body massindex ≥25 kg/m2 . The intensive approach was associated with significantly greater improvements in dietary compliance , dietary intake ( complex carbohydrate , [ P = 0.013 ] , legumes [ P < 0.0001 ] , fiber [ P < 0.0001 ] , total fat [ P < 0.004 ] , saturated fat [ P < 0.004 ] ) , and total cholesterol level ( P = 0.007 ) . The transient improvement in glycemic control was similar in both groups . An intensive education program can improve dietary compliance in established NIDDM subjects more than a conventional one . These recommended dietary improvements achieve better improvement in total cholesterol but do not necessarily improve glycemic control [6347578] The effect of patient education on diabetic control in insulin-treated diabetic adults was studied in 77 subjects r and omized into two groups : intensive patient education ( group A ) and control ( group B ) . The subjects in group A received intensive patient instruction , both individually and in small groups , from a team of physicians , teaching nurses , and a dietitian . The patients in group B received a short instruction course consisting mainly of printed material . A highly significant improvement in diabetic control was observed in both groups immediately after the education programs , with gradual return to the original level during the following 3–6 mo . No difference was observed between the two groups in any of the measured parameters during the 18-mo investigation . Factors related to good control during the study included the length of school education , the quality of the control at the beginning of the study , and the high degree of self-confidence and lack of signs of anxiety in the psychological tests . The results demonstrate that the effects of educational programs are of limited value if they do not lead to permanent changes in attitudes and motivation , which are critical factors affecting long-term diabetic control [9314625] OBJECTIVE To evaluate a weight loss and exercise program design ed to improve diabetes management in older African-Americans . RESEARCH DESIGN AND METHODS Overweight African-Americans ( n = 64 ) ages 55–79 years with NIDDM were r and omized to either an intervention ( 12 weekly group sessions , 1 individual session , and 6 biweekly group sessions ) or usual care ( 1 class and 2 informational mailings ) . Clinical and behavioral variables were assessed at 0 , 3 , and 6 months of treatment . RESULTS Significant net differences in the intervention versus usual care were observed for weight ( −2.0 kg , P = 0.006 ) , physical activity , and dietary intake of fat , saturated fat , cholesterol , and nutrition knowledge at 3 months ( all P < 0.05 ) and for weight at 6 months ( −2.4 kg ; P = 0.006 ) and mean HbA1c values at 3 and 6 months ( respectively , −1.6 and −2.4 % , both P < 0.01 ) . After the adjustment for changes in weight and activity , the intervention participants were ∼ twice as likely to have a one unit decrease in HbA1c value as those in usual care . Blood pressure increase sin usual care participants result ed in net differences ( intervention minus control ) at 3 and 6 months of −3.3 ( P = 0.09 ) and −4.0 ( P = 0.05 ) mmHg diastolic , respectively , and −8.4 ( P = 0.06 ) and −5.9 ( P > 0.10 ) mmHg systolic , respectively . Blood lipid profiles improved more in intervention than usual care participants , but not significantly . CONCLUSIONS The intervention program was effective in improving glycemic and blood pressure control . The decrease in HbA1c values was generally independent of the relatively modest changes in dietary intake , weight , and activity and may reflect indirect program effects on other aspects of self-care [8846745] In this r and omized trial patients with non-insulin-dependent diabetes were allocated to one of four programs : a minimal instruction program ( n=59 ) . an education program of individual visits ( n=57 ) , an education program incorporating a group education course ( n=66 ) , and a behavioral program ( n=59 ) . Individual and group education programs had higher attrition rates than the behavioral and minimal programs . The four programs , which involved different amounts of patient contact time , delivery format , and instructional strategies . all produced reductions in HbA atid BMI , with no significant differences between the programs . There were no differences between groups over three time periods in total cholesterol , HDL cholesterol , systolic blood pressure , or proportion of patients consulting an ophthalmologist . The behavioral program ploduced a greater reduction in diastolic blood pressure over 12 months that the education programs and a greater reduction in the cholesterol risk ratio over 3 months than the other programs . The behavioral program patients were more likely to have visited a podiatrist after 6 months and reported higher satisfaction [3535493] Self-monitoring of blood glucose levels is currently being recommended for obese patients with type II diabetes to improve weight loss and glycemic control . To determine whether self-monitoring of blood glucose levels improves dietary compliance in these patients , 50 obese patients with type II diabetes were r and omly assigned either to a st and ard behavioral weight control program or to a weight control program that included self-monitoring of blood glucose levels and focused on the weight-blood glucose relationship . Both groups lost significant amounts of weight and maintained their losses for at least one year ; reductions in medication could be made for 70 percent of patients . These data suggest that the behavioral weight control used in this study may be of benefit to patients with type II diabetes . However , there was no evidence that the addition of self-monitoring of blood glucose levels to the treatment program improved the outcome in terms of weight loss , reduction in medication , dietary compliance , or mood state [2974778] It has been suggested that much effort expended in teaching diabetic diets is ineffective and wasteful . We have tested a different system by r and omly allocating 75 newly diagnosed obese Type 2 diabetic patients to usual ‘ unstructured ’ clinic care or to group education by diabetes specialist nurses and a dietitian . Patients allocated to group education attended five 90‐min group sessions during the first 6 months . Six months after diagnosis they had lost more weight ( median ( 95 % CI ) , 7 ( 5.5–9 ) vs 2 ( 1–5 ) kg , p<0.002 ) and were better controlled ( HbA1 : 7.5 ( 7.0–8.1 ) vs 9.5 ( 8.7–10.4 ) % , p<0.001 ) than those r and omized to the usual clinic system . At 1 year ( after no further visits ) the difference in weight loss was less ( 5.5 ( 4–6.5 ) vs 3 ( 2–4 ) kg , p<0.05 ) and diabetic control was similar ( HbA1:9.0 ( 8.2–9.8 ) vs 9.9 ( 8.9–10.9 ) % . At 1 year only 14 ( 39 % ) of the education group and 9 ( 23 % ) of those attending the clinic had a fasting blood glucose less than 7.0 mmol l−1 [2702897] Two diabetes education programs were compared to a control condition . Seventy-eight type II ( non-insulindependent ) diabetic out patients were r and omly assigned to nutrition education , nutrition education plus social learning intervention , or wait-list control conditions . Both interventions involved five weekly meetings that focused on reducing calorie intake , increasing dietary fiber , and decreasing fat consumption . The social learning condition also included individualized goal setting and feedback and training in problem-solving and relapse prevention . Within-group analyses and between-group comparisons generally revealed greater improvement in targeted goals ( e.g. , calorie intake , fat reduction ) among intervention conditions than the control condition . There were few differences in more distal measures of outcome such as weight or glycosylated hemoglobin . The social learning component did not improve outcome more than the nutrition education program . Possible reasons for the observed findings and the advantages and limitations of focused time-limited diabetes education efforts are discussed [2137754] Forty-eight families with children less than 13 years old attending a paediatric diabetic clinic volunteered for a 2-year r and omized crossover trial to determine whether an informal education programme ( diabetic club ) could improve diabetic control . Group A attended the diabetic club for 10 afternoons of informal education in the first year , while Group B continued at the routine clinic ( 5 visits per year ) . For the second year Group A returned to the clinic , Group B attended the club . Glycosylated haemoglobin ( HbA1 ) remained stable while attending the club but rose significantly ( p less than 0.01 ) while attending the clinic in both groups ( HbA1 at baseline , 1 year , and 2 years : Group A , 9.6 ( SD 1.2 ) , 9.6(1.4 ) , 10.7(2.1)% ; Group B 8.9(1.3 ) , 10.4(1.4 ) , 10.5(1.4)% ( normal reference range 4.7 - 7.9 % ) ) . Other indices of control were unchanged . Diabetic problem-solving scores of parents improved ( p less than 0.01 ) but their knowledge of diabetes did not correlate with their child 's HbA1 . Dietary intake showed a reduction in percentage of energy taken as fat ( 40 % vs 37.7 % , p less than 0.05 ) during club attendance . The percentage of parents reporting helpful social contact between families increased during their club year ( Group A 50 to 78 % , Group B 32 to 57 % , p less than 0.001 ) . Psychological measurements remained unchanged . An education programme for diabetic children may stabilize diabetic control in the short term but this effect is not sustained . The main benefit was the support provided by increased social contact with families of other diabetic children within the informal framework of the diabetic club [3425385] Eighty consecutive newly diagnosed non-insulin-dependent diabetic patients were r and omly allocated into two groups to compare two different patient education regimens . One group received individual dietary instructions by a nurse and the other a short , written leaflet given by a doctor . The principal aim of the dietary instructions was weight reduction . A significant weight loss and improvement in the control of diabetes occurred in both groups , and these changes were similar in the two groups . At the end of one year 's follow-up , however , only 25 % of the patients were satisfactorily controlled ( fasting blood glucose less than or equal to 6.0 mmol/l ) . The degree of weight loss correlated only weakly with the improvement in the metabolic control . The degree of obesity and insulin secretion capacity as measured at the beginning of the study did not predict the improvement of glycaemic control during the study . At the end of the study a significant improvement was observed in serum lipids of patients with good control ( fasting blood glucose less than or equal to 6.0 mmol/l ) or weight loss ( greater than 5 kg ) . In conclusion , both brief , written and individual dietary instructions induced a significant weight loss as well as improved glucose and lipid metabolism in newly diagnosed non-insulin-dependent diabetic patients , but satisfactory metabolic control was achieved only in a minority of the patients [3219992] Insulin/sulphonylurea-treated diabetics attending a busy university diabetic clinic were studied to determine whether issuing drug information sheets and /or age influenced underst and ing and behaviour regarding their disease and its treatment , especially with respect to avoiding hypoglycaemia . Patients were each asked 10 basic questions ( each correct answer scoring 1 ) , stratified by age ( 20 were less than or equal to 45 years and 91 greater than 45 years ) . According to a single-blind r and omised protocol , they were issued or not issued with drug information sheets ( providing information to correctly answer all 10 questions ) . After 2 - 3 months , 107 ( 88 aged greater than 45 years ) were retested and asked whether they recalled an information sheet , read it themselves or had it read to them . Whether or not patients received sheets , corresponding mean aggregate scores were very similar in both age groups and there was no correlation with age . Second test scores yielded clinical ly and statistically significant increments in both the sheet and no sheet groups , respective mean aggregate scores increasing from 4.48 to 5.80 and 5.14 to 6.27 ( P less than 0.001 ) . Among patients issued with sheets , 32 who recalled reading them achieved the greatest improvement in mean scores ( 4.53 to 6.16 , P less than 0.001 ) . Active interaction/communication ( participation in first test , recall and reading of information sheet ) had a favourable educational impact irrespective of age , but merely issuing drug information sheets had no benefit [1827394] Despite the established role of foot care education in diabetes management , reports evaluating such interventions are rare . The effectiveness of an intensive foot care intervention programme and a conventional one were therefore compared in Type 2 diabetes . The intensive group showed significantly greater improvements than the conventional group in foot care knowledge ( p less than 0.001 ) , compliance with the recommended foot care routine ( p = 0.012 ) , and compliance with the initial advice to consult a podiatrist ( other than the project podiatrist ) for further treatment ( p = 0.008 ) . At the first follow-up visit the intensive group also showed a significantly greater reduction in the number of foot problems requiring treatment than the conventional group [1740599] OBJECTIVE To assess whether knowledge or psychosocial and glycemic benefits of a diabetes education program are enhanced by a support group for older patients . DESIGN A partially r and omized controlled trial involving two groups of patients : Group A , subjects who received an education program followed by 18 months of support group sessions ; Group B , only the diabetes education program . A third convenience sample , Group C , received neither intervention . Groups A and B were assessed before and immediately after the education program , and all groups were assessed 2 years after the education program . SETTING Diabetes clinic at a Veterans Affairs Medical Center . PATIENTS All subjects were male ( mean age = 68 + /- 1.3 years , range = 57 - 82 years ; duration of diabetes = 10 + /- 2 years , range 3 - 16 ) . Sample sizes were 11 in Group A , 13 in Group B , and 8 in Group C. INTERVENTION The education program consisted of six weekly sessions covering aspects of diabetes self-care . The support group consisted of 18 monthly sessions for continuing education , discussion , and structured social activities . OUTCOME MEASURES Diabetes knowledge , psychosocial factors ( self-care-related quality of life , stress , family involvement in care , and social involvement ) , depression , and glycemic control . RESULTS Group A scored better ( at least P less than 0.05 ) on knowledge , quality of life , and depression than the other groups . Groups A and B showed less stress , greater family involvement , better glycemic control , but less involvement in social activities than Group C. CONCLUSION Diabetes education programs can have long term benefits on knowledge , psychosocial functioning , and glycemic control for older diabetic patients . The addition of support groups enhances diabetes knowledge and psychosocial functioning [10414474] BACKGROUND This study was done to determine the efficacy and ease of administration of education/behavior modification classes , provided by a nurse and a dietitian in a primary care clinic for improving control of type 2 diabetes mellitus . METHODS Patients were divided r and omly into two groups . Eighteen patients completed 6 months of structured , office-based classes , and 20 similar patients served as control subjects . All were patients of the same group practice and had their usual office visits . Glycemic control , lipid levels , body weight , knowledge about diabetes , medication requirements , and symptoms were monitored during the 6 months , with follow-up at 12 months . RESULTS At the end of 6 months , the intervention group had significant reductions in mean fasting blood glucose , glycosylated hemoglobin , total cholesterol , and low-density lipoprotein cholesterol ( LDL-C ) values . Their mean body weight was significantly reduced at 12 months , and their knowledge of diabetes was improved . Control patients had significant improvement only in glycosylated hemoglobin and body weight at 6 months . Minimal physician time was required . CONCLUSION The education/behavior modification program was clinical ly worthwhile , and it was easy to administer [7698064] This study evaluated pharmaceutical care as an adjunct to an existing , coordinated-care program at a Regional Diabetes Center . The progress of a control group receiving the st and ard pharmacist instruction was compared with two treatment groups receiving additional small group or individual supplementary education for a 2-month period . Outcome evaluation included assessment of individual diabetes management through blood glucose monitoring and responses on a pretest and posttest question naire . Patients in the treatment groups demonstrated significantly lower average weekly blood glucose levels and a decreased incidence of hyperglycemic episodes compared with the control group . Question naire data for both treatment groups demonstrated a significant increase in patient underst and ing of diabetes medications and medications for associated illnesses , an increase in knowledge about blood glucose monitoring , and a positive difference in perceptions/attitudes toward diabetes and communication with the pharmacist . This approach is consistent with the concept of pharmaceutical care in which the pharmacist helps patients avoid long-term complications and thus improve their quality of life [2630378] To study if self-monitoring of glucose , urinary or capillary , could help them to improve their metabolic control through better compliance to diet and /or hypoglycaemic agents , 208 non-insulin-treated poorly controlled diabetic patients were r and omized to : group A -- regular HbA1c determinations but no self-monitoring , group B -- self-urine glucose monitoring , twice every other day , group C -- self blood glucose monitoring , twice every other day , and followed six months . At the end of the study period , the decrease of HbA1c over six months -- main endpoint -- was not significantly different between the three groups ( mean + /- SEM ; group A : -0.5 + /- 0.2 % ; group B : -0.1 + /- 0.3 % ; group C : -0.4 + /- 0.3 % ) . However , the degree of compliance to blood glucose self-monitoring in group C appeared to relate to the outcome : a significant correlation was found between the number of blood glucose strips used and the decrease of HbA1c ( r = .36 , p less than .02 ) . We conclude that regular self-monitoring has no definite advantage over the usual management for improving metabolic control in non-insulin-treated diabetic patients , though it may possibly help patients ready to comply with its use [3698783] Home health nurses provided individualized instruction in diabetes self-care within the home environment of 393 diabetic individuals . Each subject was r and omly assigned to either the intervention ( those receiving home teaching ) or control ( those not receiving home teaching ) group . At 6 mo postenrollment , intervention subjects showed significantly greater self-care knowledge and skills than control subjects , although the actual differences between the two groups in terms of self-care skills were probably too small to have any practical meaning . The primary objective of the study , which was the reduction of the number of preventable diabetes-related hospitalizations ( ketoacidosis , ketotic coma , nonketotic coma , insulin reaction , and diabetes out of control ) , was not achieved ; no differences between the groups were noted after 12 mo of follow-up . Similarly , length of hospital stay , foot problems , emergency room and physician visits , and sick days were roughly equivalent in both groups during the follow-up year . These results suggest that , in the absence of concurrent changes in the health-care delivery system and strategies for influencing attitudes toward self-care , education alone is ineffective [7657902] OBJECTIVE To assess the effect of medical nutrition therapy ( MNT ) provided by dietitians on medical and clinical outcomes for adults with non-insulin-dependent diabetes mellitus ( NIDDM ) , and to compare MNT administered according to practice guidelines nutrition care ( PGC ) to MNT administered with basic nutrition care ( BC ) . DESIGN A prospect i ve , r and omized , controlled clinical trial of two levels of MNT on metabolic control in persons newly diagnosed with or currently under treatment for NIDDM was conducted at diabetes centers in three states ( Minnesota , Florida , and Colorado ) . BC consisted of a single visit with a dietitian ; PGC involved an initial visit with a dietitian followed by two visits during the first 6 weeks of the study period . Data were collected at entry to the study and at 3 and 6 months . SUBJECTS Results are reported for 179 men and women aged 38 to 76 years : 85 assigned r and omly to BC and 94 to PGC . This represents 72 % of the 247 subjects enrolled . An additional 62 adults with NIDDM at one site who had no contact with a dietitian were identified as a nonr and om comparison group . OUTCOMES Medical outcome measures included fasting plasma glucose ( FPG ) , glycated hemoglobin ( HbA1c ) , and serum lipid levels . Clinical outcomes included weight , body mass index , waist-to-hip ratio , and changes in medical therapy . STATISTICAL ANALYSES Initial analysis of the discrete variables was done using the chi 2 statistic with Yates ' correction . Initial analysis of continuous variables was done by analysis of variance . The changes in variables between time periods were analyzed by paired t test , and comparisons between groups were analyzed using a t test for independent groups . RESULTS At 6 months , PGC result ed in significant improvements in blood glucose control as indicated by FPG and HbA1c levels and BC result ed in significant improvements in HbA1c level . Participants assigned to the PGC group had a mean FPG level at 6 months that was 10.5 % lower than the level at entry , and those in the BC group had a 5.3 % lower value . Among subjects who had diabetes for longer than 6 months , those who received PGC had a significantly better HbA1c level at 3 months compared with those receiving BC . The comparison group showed no improvement in glycemic control over a comparable 6 months . PGC subjects had significant improvements in cholesterol values at 6 months , and subjects in both the PGC and the BC groups had significant weight loss . CONCLUSIONS MNT provided by dietitians result ed in significant improvements in medical and clinical outcomes in both the BC and PGC groups and is beneficial to persons with NIDDM . Persons with a duration of diabetes longer than 6 months tended to do better with PGC than with BC . Because of the upward trend in glucose levels after 3 months , ongoing MNT by dietitians is important for long-term metabolic control [4006661] It is not clear whether diabetic patients can learn accurate self-monitoring of blood glucose ( SMBG ) by use of written package instructions . In addition , it is unclear whether the improvement in accuracy of monitoring that results from professional training is due to the professional intervention or to a personal practice effect . For these reasons , improvement in accuracy of SMBG ( using Chemstrip bG , Biodynamics Division , Boehringer-Mannheim , Indianapolis , Indiana ) after a 30-min session of professional instruction in one group of diabetic patients was compared with improvement after 30 min of practice and study of package instructions in another group . After initial reading of package instructions in both groups , and after the practice session in the control group , mean percent error was 22–37 % . In contrast , mean percent error declined to 9 % after a professional training session . We conclude that learning SMBG solely by reading package instructions leads to unacceptable inaccuracy . However , by use of short , intensive instruction sessions , a diabetes educator can reduce such errors and teach highly accurate monitoring to most diabetic patients [1296898] This study investigated the effectiveness of a " h and s-on " foot care teaching/learning approach for adults with diabetes . By r and om assignment , the control group received a lecture presentation on foot care , while the experimental group participated in a h and s-on session on foot care in addition to the lecture presentation . Data concerning the subjects ' foot care knowledge and skills , the condition of their feet , and their level of HbA1c were gathered prior to and six months after the foot care educational sessions . No significant increases in knowledge about foot care were observed in the experimental group . The experimental group reported improvements in inspecting and washing their feet on a daily basis , and in care of the toenails . No significant differences were observed in the status of the subjects ' feet . The HbAlc readings were significantly improved for both the experimental ( t=4.10 , df=10 , p=0.002 ) and control ( t=2.25 , df=9 , p=0.051 ) groups . A h and s-on educational session may improve foot care practice s temporarily . However , long term effects need to be studied to discern overall improvement of foot care practice s and physical status of the feet [3549757] To examine the effects of intensive patient and /or physician diabetes education on patient health outcomes , a controlled trial was conducted in which internal medicine residents and their 532 diabetic patients were r and omly assigned to : routine care ; patient education ; physician education ; or both patient and physician education . Patient outcome data were analyzed either by analysis of covariance on post intervention values ( 2-hour post-pr and ial plasma glucose [ PPG ] ; body weight [ BW ] ; blood pressure [ BP ] ; or analysis of variance conducted on change values ( fasting plasma glucose [ FPG ] and glycosylated hemoglobin [ A1Hgb ] ) . After patient education , significant improvements were observed in FPG , A1Hgb , BW , and systolic and diastolic BP . Physician education result ed in significant decreases in FPG , A1Hgb and BW . The combination of patient plus physician education result ed in the greatest improvements in patients ' health outcomes including FPG , A1Hgb , PPG , BW and diastolic BP . Adjusted systolic BPs were not significantly different in the two groups . While these physiologic improvements were statistically and probably clinical ly significant , hyperglycemia and obesity still persisted . Thus , achieving optimal patient outcomes for a chronic disease like diabetes mellitus may require a greater or more effective use of re sources than currently estimated [2357919] This study tested the hypothesis that follow-up intervention ( by telephone calls and home visit ) affects compliance in patients with non-insulin-dependent diabetes mellitus ( NIDDM ) . Sixty NIDDM patients were r and omly assigned to two groups — a control group , which received the st and ard protocol ( 3-day educational program and a review session 1 month after the program ) ; and an intervention group , which received the st and ard protocol as well as a series offour telephone calls and one home visit by a registered nurse over a 3-month period . Compliance to prescribed regimens was determined by analyzing three sets of data : changes in pre- to post study glycosylated hemoglobin ( HbA1c ) values ; changes in pre- to post study weight ; and frequency with which self-monitoring of blood glucose ( SMBG ) was practice d. Results showed that SMBG practice was significantly better for the intervention group . No significant differences were seen in post study HbA 1c values and weight changes between the two groups . Follow-up inter vention by telephone calls and home visit can enhance patient compliance to certain aspects of the prescribed diabetes management plan [8498761] Given that 14 million Americans have diabetes [ 1 ] , the common complications of this disorder , such as foot ulcers and lower extremity amputations , are of major concern to the medical community . Approximately 20 % of all diabetic patients hospitalized in the United States are admitted because of foot complications [ 2 , 3 ] . Furthermore , about 50 % of all nontraumatic amputations in the United States are done in patients with diabetes [ 1 , 4 ] . This proportion equates to about 55 000 amputations a year [ 1 ] or 59.7 amputations for every 10 000 persons with diabetes [ 5 ] . Patients who undergo an amputation are at greater risk for a second similar procedure on either the same or the other leg [ 6 , 7 ] . Yet , it has been estimated that about one half of the amputations in patients with diabetes , or about one fourth of the total amputations done in the United States , are preventable [ 1 , 4 ] . Recently , the focus has been on preventive strategies that minimize foot damage in diabetic patients and thereby reduce the rates of ulcers and amputations . These preventive strategies are based on two observations : first , that simple efforts on the part of the health care provider or patient can reduce the likelihood of subsequent amputation due to diabetes-associated foot disease [ 8 ] ; and second , that many of these simple procedures are not being systematic ally applied by health care providers or patients [ 9 ] . For example , studies indicate that physicians infrequently examine the feet of patients with diabetes [ 9 , 10 ] . Also , most patients with diabetes do not engage in simple foot-care assessment s to identify lesions requiring early treatment [ 11 ] . Preventive strategies are not systematic ally applied for several reasons : First , patients may not be aware of foot-care procedures or how to do them , or they may not believe that such procedures can make a difference ; second , podiatry and orthopedics services that could assist in foot salvage in diabetic patients may not be available ; and , finally , the health care system may make it difficult for patients or health care providers to examine the feet of patients with diabetes [ 10 ] . Several uncontrolled studies found that implementation of improved foot-care programs can significantly reduce lower extremity complications in patients with diabetes ; these studies showed a 44 % to 85 % reduction in the rate of lower extremity amputations [ 4 , 12 - 14 ] . A recent casecontrol study also supports the implementation of preventive strategies , such as foot care , use of protective footwear , and aggressive treatment of foot infection by patients or health care providers , to decrease the risk for lower extremity amputation [ 15 ] . The intervention in our study was design ed to reduce the prevalence of risk factors for lower extremity amputations in patients with noninsulin-dependent diabetes and involved the three major elements of a prevention program : the patient , health care providers , and the health care system . Specifically , we did a r and omized , controlled trial to determine whether a comprehensive foot-care intervention could improve patients ' knowledge and performance of appropriate foot care ; increase the number of referrals to specialty clinics such as the podiatry clinic ; increase the frequency of foot examinations by health care providers and the documentation of risk factors in the medical record ; and improve short-term patient outcomes such as skin and nail conditions known to be risk factors for ulcers and amputations . Methods Setting Our study , the design of which is summarized in Figure 1 , was done from April 1989 to March 1991 in the academic general medicine practice of the Regenstrief Health Center in Indianapolis , Indiana [ 16 ] . The practice is subdivided into four primary care teams ( labeled A , B , C , and D ) , each with its own nursing and clerical staff . Each team sees patients for eight half-day sessions per week , with each session staffed by one or two faculty internists and two to four housestaff . Teams A and C were r and omly assigned to the intervention group ; teams B and D were assigned to the control group . Previous studies in which this method of r and omization was used have shown no baseline interteam differences in patient characteristics and physician practice behavior and no effect of the team on the study outcome [ 16 - 19 ] . Figure 1 . Summary of the study design . Patient Identification and Recruitment The computerized Regenstrief Medical Record System [ 20 ] was used to identify approximately 3000 patients with noninsulin-dependent diabetes , as well as the date and time of their next appointment . Only patients with noninsulin-dependent diabetes who were seen at least two times in the preceding year by the same provider were included in the study . Additional criteria for inclusion were as follows : an age greater than 40 years ; a diagnosis of diabetes after 30 years of age ; a diagnosis of diabetes based on National Diabetes Data Group criteria [ 21 ] or the presence of disease requiring medication for the control of hyperglycemia ; an intention to obtain care at the general medicine practice for the next 2 years ; and a body weight that was either ideal or heavier than ideal . Exclusion criteria included pregnancy ; major psychiatric illness , including dementia ; terminal illness likely to cause death within 1 year ; renal failure ( serum creatinine > 440 mol/L ) ; previous bilateral amputations above or below the knee ; or an inability to provide any self-care . Patients of investigators involved in the protocol were also excluded from the study . Of the 728 eligible patients , 244 refused to participate , 89 enrolled in the study but failed to keep their appointments for assessment , and 395 were assessed by trained nurse-clinicians . Of the 395 patients assessed , 352 ( 89 % ) completed the study ; 43 patients ( 11 % ) did not complete the study for the following reasons : death ( 11 patients ) ; change of residence ( 15 patients ) ; illness ( 6 patients ) ; transportation problems ( 3 patients ) ; and miscellaneous reasons ( 8 patients ) . Patient Assessment Sample s for determining fasting plasma glucose , cholesterol , triglyceride , high-density lipoprotein , hemoglobin A1C , and C-peptide levels were obtained from enrolled patients and immediately transported to a certified laboratory for analysis . Patients gave a history and had a physical examination at study entry and approximately 1 year later ( mean , 11.8 1.5 months ) . These examinations focused on risk factors for amputation and were administered by two trained nurse-clinicians who were blinded to the patients ' experimental conditions . Foot-related data derived from the history and physical examination included the patient 's self-reported foot-care behaviors ; the quality of the patient 's examination of his or her feet ; the severity of any foot lesions ; and the presence of musculoskeletal abnormalities , dermatologic conditions , peripheral vascular disease , and peripheral neuropathy ( the neuropathy assessment included quantitative measures of pressure and temperature sensation ) . Patients were question ed about their regular foot-care routine and were asked to show how they examined their feet . During this self-examination , nurse-clinicians observed whether patients ' scrutinized the toenails , the soles of the feet , and the area between toes . Musculoskeletal and dermatologic abnormalities were assessed using st and ard definitions of findings such as callus , hammer toe , and Charcot foot [ 3 , 22 ] . The nurse-clinicians palpated the dorsalis pedis , posterior tibial , and femoral pulses bilaterally in their assessment for peripheral vascular disease . If a pulse was absent at any one of the six sites palpated , the assessment was considered abnormal . Foot lesions were rated for severity using the Seattle Wound Classification System [ 23 ] , which ranges from a grade of 1.1 ( absence of lesions ) to a grade of 10 ( entire foot or leg is gangrenous ) . In our study , a foot lesion was defined as any wound , with or without functional interruption of the protective cutaneous barrier , ranging from a superficial scratch to an ulcer involving the epidermis . A serious foot lesion was defined by a severity grade of at least 1.3 , which indicates a minor , nonulcerated lesion with clinical evidence of healing sufficient to close previous interruption of the cutaneous barrier [ 23 ] or a blister . Pressure and temperature sensations were measured using the 5.07-log ( 0.1 mg)-force Semmes-Weinstein monofilament and the thermal sensitivity testing apparatus , according to st and ard techniques [ 24 - 26 ] . Thermal sensitivity was considered abnormal if the patient had a value greater than 2 st and ard deviations from the mean value for a group of healthy persons without diabetes ( warm > 2.04 C ; cool > 1.58 C ) . Practice Patterns of Health Care Providers Immediately after each scheduled visit , study patients had a structured interview [ 10 ] with a research assistant , who asked about foot self-examination and foot-care education given by health care providers ( the primary care physician or nursing personnel ) . In addition , a chart audit was conducted by a nurse-clinician who was blinded to the patients ' experimental condition . Information abstract ed from the medical record included the physician 's documentation of the findings from the history and physical examination ; any referral to podiatry , orthopedics , or vascular surgery clinics ; and diagnostic-test ordering related to the evaluation and treatment of diabetes-associated foot problems . Intervention The intervention cohort was exposed to several risk-reduction strategies . The nurse-clinicians conducted the patient education session with one to four patients , covering appropriate foot-care behaviors and footwear , using a commercially available slide and audiotape presentation [ 27 ] and pamphlets [ 28 ] . Behavioral contracts regarding desired foot-care behaviors were negotiated with each patient . Follow-up was done by telephone 2 weeks after the education sessions to remind patients [8401245] The implication s of behavioral analysis for practice and research have significant potential for nursing . This present study was conducted to determine the effectiveness of nurses and patients actively participating in behavioral analysis and the implementation of behavioral strategies in order to improve the patients ' self-management of their Type H diabetes . Patients ( N = 156 ) were r and omly assigned to one of four groups . The attention control group ( n = 41 ) received routine care . The compliance group ( n = 32 ) agreed to practice compliance behaviors related to the prescribed medical regimen . The behavioral strategies group ( n = 42 ) participated in behavioral analysis and agreed to practice behavioral strategies . The behavioral strategies with instruction group ( n = 41 ) participated in behavioral analysis , agreed to practice behavioral strategies , and received classes and programmed instruction about behavioral analysis and behavioral strategies . There were no outcome differences between groups relative to glycosylated hemoglobin ( GHb ) and weight loss . There were differences in the outcome measures in subgroups by age , gender , and employment , which have practice and research implication s for the individualization of interventions using behavioral strategies [10159676] There is a pressing need for brief , practical interventions that address diabetes management . We have developed an office-based intervention to prompt both patients and providers to focus on behavioral issues relevant to dietary self-management that is being evaluated in a r and omized trial . The intervention is design ed to be broadly applicable to the majority of adult diabetes out patients during medical visits ; uses touchscreen computer assessment to provide immediate feedback on key issues to patients and providers just prior to their interaction ; and provides goal setting and problem-solving assistance to patients following their meeting with the physician . Follow-up components include phone calls and videotape or interactive video instruction as needed . The program is described , and demographic and behavioral characteristics of participants are presented for the first 95 patients r and omized . Initial process results suggest success in producing modest , targeted behavior changes among a broad cross-section of patients . If the long-term results are equally positive , this intervention could provide a prototype for a feasible , cost-effective way to integrate patient views and behavioral management into office-based care for diabetes [7851238] Two objectives were established for this study : 1 ) to assess the impact of a culturally specific , intensive diabetes education program on dietary patterns , and 2 ) to assess nutrient consumption relative to the Recommended Dietary Allowances . The study population consisted of elderly Mexican Americans with diabetes living in Harlingen and Brownsville , Texas . The experimental group ( n=78 ) participated in an intense , 2-hour nutrition education session , while the control group ( n=74 ) did not . The education session was conducted for groups of eight subjects via videotapes and interactive discussion . All groups experienced significant weight loss except the women in the experimental group . After the education program , however , the experimental women had increased the percentage of calories consumed daily from carbohydrate . Mean calcium consumption was substantially less than the RDA in all groups , and inadequate amounts of ascorbic acid and vitamin A often were consumed . Intensive , frequent , long-term follow-up appears essential for more sustained results [3769719] The purpose of our study was to compare the effect on diabetes control of group management with the advice-educational technique traditionally used in managing obese out patients with poorly controlled non-insulin-dependent diabetes mellitus ( NIDDM ) . Forty-one patients were r and omly assigned to these two treatment programs , and 32 patients completed the 6-mo study . Initially , patients were seen for 1-h sessions at 1- and 2-wk intervals and later at 1-mo intervals . Patients were asked to do home blood glucose monitoring , decrease caloric intake , increase exercise , and if they were taking insulin , to adjust the dose to attain approximate euglycemia and to stabilize food and exercise patterns . The combined groups reduced mean ± SD glycohemoglobin from 10.9 ± 3.1 to 9.4 ± 2.4 % ( P < .05 ) . Internal Health Locus of Control Scale was negatively and significantly correlated with initial and subsequent glycohemoglobin values ( the more internal , the lower the glycohemoglobin ) . At the end of the study the patients in the group management program had significantly lower blood glucose levels than those given advice and education , but no significant differences in glycohemoglobin values or percentage overweight were observed . One patient had a normal initial glycohemoglobin , and only 4 patients had values in the normal range of 4–6.8 % at the end of the study . Better management programs need to be developed for treating obese out patients with NIDDM [9614604] OBJECTIVE To examine the effects of patient choice between two education curriculums that emphasized either the st and ard or nutritional management of type 2 diabetes on class attendance and other outcomes among a mostly Hispanic patient population . RESEARCH DESIGN AND METHODS A total of 596 patients with type 2 diabetes were r and omly assigned to either a choice or no choice condition . Patients in the choice condition were allowed to choose their curriculum , while patients in the no choice condition were r and omly assigned to one of the two curriculums . Outcomes were assessed at baseline and at a 6-month follow-up . RESULTS When given a choice , patients chose the nutrition curriculum almost four times more frequently than the st and ard curriculum . Contrary to our hypothesis , however , patients who had a choice did not significantly increase their attendance rates or demonstrate improvements in other diabetes outcomes compared with patients who were r and omly assigned to the two curriculums . Patients in the nutrition curriculum had significantly lower serum cholesterol at a 6-month follow-up , whereas patients in the st and ard curriculum had significant improvements in glycemic control . Of the r and omized patients , 30 % never attended any classes ; the most frequently cited reasons for nonattendance were socioeconomic . Hispanic patients , however , were just as likely as non-Hispanic patients to attend classes and participate at the follow-up . Patients who attended all five classes of either curriculum significantly increased their diabetes knowledge , gained less weight , and reported improved physical functioning compared with patients who did not attend any classes . CONCLUSIONS Although providing patients with a choice in curriculums at the introductory level did not improve outcomes , differential improvements were noted between patients who attended curriculums with different content emphasis . We suggest that diabetes education programs should provide the opportunity for long-term , repetitive contacts to exp and on the modest gains achieved at the introductory level , as well as provide more options to match individual needs and interests and to address socioeconomic barriers to participation [8949977] Non-insulin-dependent diabetes mellitus ( NIDDM ) is preceded by impaired glucose tolerance ( IGT ) lasting for years before manifesting as overt hyperglycaemia . Both genetic and environmental factors contribute to the development of IGT and NIDDM . Obesity , physical inactivity and high-fat diet have been found to predict IGT and NIDDM . Therefore , a diet and exercise intervention from diagnosis of NIDDM could improve the treatment outcome and prognosis of patients with NIDDM . Furthermore , because subjects with IGT are at increased risk for diabetes and atherosclerotic vascular disease , it is reasonable to assume that in terms of reducing the incidence and longterm consequences of NIDDM an intervention at this phase is more effective than in overt diabetes . Although the nonpharmacological approach is generally accepted as the first-line treatment of NIDDM its efficacy has often been question ed . Therefore , it is important to carry out long-term controlled studies to find out to what extent lifestyle modification could improve the metabolic control and level of major cardiovascular risk factors known to be associated with poor outcome in NIDDM . This kind of study also gave relevant experience in planning studies aim ing at primary prevention of NIDDM . One-year dietary and exercise intervention on newly diagnosed NIDDM patients in Kuopio , Finl and result ed in a better metabolic control and a moderate reduction in cardiovascular risk factors as compared to the conventional treatment group . After the second year of follow-up only 12.5 % in the intervention group were receiving oral antidiabetic drugs vs. 34.8 % in the conventional treatment group . Weight reduction and a reduced use of saturated fats appeared to be the main determinants of successful treatment results . Good aerobic capacity was associated with an increase in HDL cholesterol . A multicentre primary prevention study on IGT patients is continuing in Finl and applying the same principles of intervention as used in the study on newly diagnosed NIDDM patients . Pilot results show that glucose tolerance can be improved by lifestyle changes [9434649] OBJECTIVE Evaluations of trials of the effectiveness of dietary intervention programs may be compromised by response set biases , such as those attributable to social desirability . Participants who receive a behavioral intervention may bias their reports of diet to appear in compliance with intervention goals . This study examined whether responses to st and ard dietary assessment instruments could be affected by a brief dietary intervention . DESIGN We assigned 192 undergraduate students r and omly to ( a ) see a 17-minute videotape on the consequences of eating a high-fat diet or a placebo videotape on workplace management and ( b ) receive preintervention and post-intervention assessment s or only postintervention assessment . Dietary assessment s included 4 independent measures of fat intake . RESULTS Among women , bias ( intervention minus control ) was -9.7 g fat ( from a short food frequency question naire ) and -0.6 high-fat foods ( from a question naire about use of 23 foods in the previous day ) ( P < .05 for both ) . No results were significant among men or for 2 instruments that measured more qualitative aspects of fat-related dietary habits . APPLICATIONS Even a modest dietary intervention can affect responses to dietary assessment instruments . Nutritionists should recognize that assessment of adherence to dietary change recommendations , when based on dietary self-report , can be overestimated as a result of response set biases [3565666] We assessed diabetes education and peer support interventions as facilitators of weight loss and glycemic control in a community sample of 79 elderly persons with noninsulin-dependent diabetes mellitus ( NIDDM ) . Different groups received : education only , education and peer support , and no treatment . Peer support was higher in groups where it was actively facilitated . Weight loss and reduction in level of glycemic control occurred within groups receiving both diabetes education and peer support [2305110] The quality of reported research representing a number of disciplines involved in diabetes patient education was investigated in this study . A rigorous literature search identified 47 studies reported between 1954 and 1986 that met inclusion criteria ; 29 were published studies , 18 were unpublished . Quality of the research was measured by Duffy 's Research Appraisal Checklist ( RAC ) and also by coding each study as to the number of threats to internal and external validity present . Overall quality as measured by the RAC ranged from 34 to 95 on a 100-point scale . A statistically significant relationship was found between publication date of the research report and quality , indicating improvement in quality during recent years . Quality of published versus unpublished research reports was not found to differ significantly . Recommendations for improving method ological rigor of future studies include : ( a ) the use of more rigorous design s , particularly those involving control groups such as r and omized clinical trials ; ( b ) reporting of more complete data in research reports ; and ( c ) monitoring of the quality of future studies [6522737] The design of the study was " 2-period changeover " ; each period lasted 6 months and 6 counseling sessions were offered during each period . Group 1 ( n = 81 ) , counseled in the first period , was controlled by a noncounseled group 2 ( n = 82 ) . R and omization of patients into the 2 groups took place at each office . The primary variable for consideration was the postpr and ial ( pp ) blood sugar level ( mg/dl ) . Weight reduction of overweight patients was also considered . A highly significant ( p less than 0,01 ) difference of mean pp-blood sugar reduction between the groups was found during both periods . In view of the large estimated difference in the residual effects of both treatments ( counseling , no counseling ) a crossover analysis was excluded . The best pp-blood sugar effect was obtained for patients with high pp-blood sugar level ( greater than or equal to 250 ) at the beginning of the counseling period [3775139] A population -based study on the therapeutic effects of a diabetes teaching programme ( DTP ) based on problem oriented participatory education (POPE)--a method based on learner activity in group meetings -- was undertaken at the Primary Health Care Centre , Kisa , Sweden , in collaboration with educationalists . A control group was given conventional classroom teaching . To be included a patient had to be aged 55 - 73 years , to live in his own home , and to have non-insulin-treated type II diabetes mellitus . The therapeutic effects of the DTP were studied before , during , and after POPE with regard to three factors , diabetes related knowledge , behaviour assessed by dietary and exercise habits , and the quality of the anti-diabetic therapy as assessed by metabolic profile including Hb-A1 . Significant improvement in knowledge and transient improvement in Hb-A1 concentration were recorded among patients taking part in a DTP adjusted to their individual problems and needs . When improvement in metabolic control does not last , group meetings should be continued for more than the three months used in the present study . We believe that such improvement is intimately bound up with the psycho-social process that is involved in the group meetings and that helps the patient to cope with the disease in particular and life in general [8382712] Compliance with dietary recommendations and the effect of intensified dietary therapy on energy and nutrient intakes and fatty acid composition of serum lipids were studied in 86 obese subjects ( aged 40 to 64 years ) with recently diagnosed non-insulin-dependent diabetes mellitus ( NIDDM ) . After three months of basic education , the subjects were r and omly separated into an intervention group ( n = 40 ) and a conventional treatment group ( n = 46 ) . Members of the intervention group participated in 12 months of intensified education ; those in the conventional group visited local health centers . Compliance with dietary instructions was monitored through food records . Intensified dietary therapy result ed in greater weight loss , better metabolic control , and a less atherogenic lipid profile than conventional treatment . Intake of energy and saturated fatty acids tended to decline in the intervention group . A higher percentage of patients in the intervention group had a total fat intake of 30 % of energy or less after 15 months ( 32.5 % [ 12 of 38 ] vs 17.4 % [ 8 of 46 ] ) . Similarly , more patients in the intervention group had a saturated fatty acid intake of 10 % or less of total energy intake at the end of the study ( 35.0 % [ 13 of 38 ] vs 8.7 % [ 4 of 46 ] ) . The mean dietary cholesterol intake was within recommendations in both groups at the end of the study . The relative percentage of linoleic acid of serum lipids increased significantly and the relative percentage of palmitic acid of serum triglycerides , phospholipids , and cholesterol esters decreased in the intervention group . These changes indicate that intensified dietary therapy improved the quality of fat in the diet of patients with NIDDM [3948638] The Diabetes Education Study ( DIABEDS ) was a r and omized , controlled trial of the effects of patient and physician education . This article describes a systematic education program for diabetes patients and its effects on patient knowledge , skills , self-care behaviors , and relevant physiologic outcomes . The original sample consisted of 532 diabetes patients from the general medicine clinic at an urban medical center . Patients were predominantly elderly , black women with non-insulin-dependent diabetes mellitus of long duration . Patients r and omly assigned to experimental groups ( N = 263 ) were offered up to seven modules of patient education . Each content area module contained didactic instruction ( lecture , discussion , audio-visual presentation ) , skill exercises ( demonstration , practice , feedback ) , and behavioral modification techniques ( goal setting , contracting , regular follow-up ) . Two hundred seventy-five patients remained in the study throughout baseline , intervention , and postintervention periods ( August 1978 to July 1982 ) . Despite the requirement that patients demonstrate mastery of educational objectives for each module , postintervention assessment 11–14 mo after instruction showed only rare differences between experimental and control patients in diabetes knowledge . However , statistically significant group differences in self-care skills and compliance behaviors were relatively more numerous . Experimental group patients experienced significantly greater reductions in fasting blood glucose ( −27.5 mg/dl versus −2.8 mg/dl , P < 0.05 ) and glycosylated hemoglobin ( −0.43 % versus + 0.35 % , P < 0.05 ) as compared with control subjects . Patient education also had similar effects on body weight , blood pressure , and serum creatinine . Continued follow-up is planned for DIABEDS patients to determine the longevity of effects and subsequent impact on emergency room visits and hospitalization [3739801] Patients with diabetes are usually placed on exchange system diets to ensure a nutritionally adequate intake . However , there have been few studies which have actually compared the nutritional adequacy of diets selected by patients on exchange system diets , with that selected by patients on the calorie-counting diets typically used in behavioral weight control programs . This study compared the nutritional adequacy of the diets selected by overweight patients with Type II diabetes who had been r and omly assigned to either an exchange system diet or a calorie-counting diet . Three-day food diaries were completed by all patients at the start and end of a 16-week weight control program . No significant differences were observed between patients on the calorie-counting diet compared to those on the exchange system diet with respect to nutrient intake , macronutrient distribution , or percent of the RDA obtained . Patients on both types of diet reported decreases in the proportion of calories from fat . The average intake exceeded 100 % of the RDA for all nutrients except calcium . This study suggests that patients are able to improve the nutritional adequacy of their intake while following either a calorie-counting or an exchange system diet [8833634] This study aim ed to determine if patients can set their own educational priorities accurately and if the impact of diabetes education on knowledge differed between patients who did and did not set their own priorities . Forty patients referred for individual education were r and omly assigned to one of two groups . Prior to education with a diabetes specialist nurse ( DSN ) patients ranked 10 diabetes care topics in order of perceived importance and relevance to their needs and completed a knowledge question naire . Group 1 set their own priorities and the DSN directed education according to the patients stated priorities . In Group 2 the DSN set the educational priorities without seeing the patients priority list . The priority ranking by the two groups of the 10 topics and their pre-education knowledge score were not significantly different . Post-education knowledge scores improved equally and significantly in both groups ( Group 1 from 23 to 87 % ; Group 2 from 21 to 79 % ) ; P < 0.0001 ) . In both groups , knowledge scores for the top three priorities were significantly higher than for the three lowest ranked topics . Knowledge is neither dependent on , nor a good discriminator of , patient-selected priorities . There may be reasons why it is important for patients to set their own priorities , but education directed solely at those priorities may leave knowledge deficits which could compromise diabetes care [6562009] Individuals with noninsulin depend ent diabetes mellitus referred to a dia betes education programme were al located at r and om to treatment ( n = 32 ) or non-treatment ( n = 28 ) groups to assess the effectiveness of this pro gramme . The education course lasted four weeks , at the end of which the participants showed reductions of HbA1c and post-pr and ial glucose levels , improvement in knowledge and less anxiety . On the other h and , the control group experienced more anxiety and did not show significant changes in measured indices of glu cose control . Nevertheless , these i m provements in glucose control were not sustained . Within four weeks of cessation of the intervention pro gramme , HbA1c and glucose levels were not significantly different from those measured at entry to the pro gramme . In addition , a delay of four weeks from the time of referral until initiation of education was associated with lack of significant reduction of HbA1c and glucose levels [7555554] OBJECTIVE The purpose of this study was to determine if participation in a patient empowerment program would result in improved psychosocial self-efficacy and attitudes toward diabetes , as well as a reduction in blood glucose levels . RESEARCH DESIGN AND METHODS This study was conducted as a r and omized , wait-listed control group trial . The intervention group received a six-session ( one session per week ) patient empowerment education program ; the control group was assigned to a wait-list . At the end of 6 weeks , the control group completed the six-session empowerment program . Six weeks after the program , both groups provided follow-up data . RESULTS The intervention group showed gains over the control group on four of the eight self-efficacy subscales and two of the five diabetes attitude subscales . Also , the intervention group showed a significant reduction in glycated hemoglobin levels . Within groups , analysis of data from all program participants showed sustained improvements in all of the self-efficacy areas and two of the five diabetes attitude subscales and a modest improvement in blood glucose levels . CONCLUSIONS This study indicated that patient empowerment is an effective approach to developing educational interventions for addressing the psychosocial aspects of living with diabetes . Furthermore , patient empowerment is conducive to improving blood glucose control . In an ideal setting , patient education would address equally blood glucose management and the psychosocial challenges of living with diabetes [6341015] To determine whether a group behavior modification approach might be preferable to individual counseling in the nutritional therapy of non-insulin-dependent diabetes mellitus , 40 adults younger than 65 yr of age with diabetes mellitus who were not receiving insulin were r and omized to either a program of individualized dietary review and recommendations or a program of group meetings aim ed at controlling the signals leading to overeating and noncompliance with a diabetic dietary regimen . Statistically significant ( P < 0.05 ) decreases in body weight , sum skin-fold thickness , fasting serum glucose , and serum triglycerides but not LDL-C or HDL-C were observed . The individual counseling group had a greater amount of weight loss than the behavior modification group . There were no significant ( P < 0.05 ) differences between the two groups with respect to the biochemical outcome variables . Patient characteristics assessed at entry — namely anxiety , internal versus external locus of control and perceived disease severity , and compliance with advice — were significantly associated with weight loss in the behavior modification group while only the latter index was of value in the individual counseling group . Thus , our use of these programs does not identify a clear advantage of either approach in the nutritional therapy of non-insulin-dependent diabetic patients [10589324] OBJECTIVES This study evaluated a multicomponent educational intervention to increase ophthalmic examination rates among African Americans with diabetes . METHODS A r and omized trial was conducted with 280 African Americans with diabetes , enrolled from outpatient departments of 5 medical centers in the New York City metropolitan area , who had not had a dilated retinal examination within 14 months of r and omization ( 65.7 % female , mean age = 54.7 years [ SD = 12.8 years ] ) . RESULTS After site differences were controlled , the odds ratio for receiving a retinal examination associated with the intervention was 4.3 ( 95 % confidence interval = 2.4 , 7.8 ) . The examination rate pooled across sites was 54.7 % in the intervention group and 27.3 % in the control group . CONCLUSIONS The intervention was associated with a rate of ophthalmic examination double the rate achieved with routine medical care Now, respond to the instruction. ### Instruction: For each study, assess how the information presented aligns with the selection criteria for systematic reviews focused on clinical outcomes, treatments, or healthcare interventions. Consider whether the study's methodology, findings, or broader implications contribute to the robustness of a systematic review. Label its ID accordingly under one of the following categories: - "Core IDs": Studies that meet the necessary criteria for inclusion in systematic reviews due to their direct contribution to clinical evidence or intervention outcomes. - "Supplementary IDs": Studies that provide additional insights, but may not meet the primary inclusion criteria for systematic reviews. ### Background: BACKGROUND The average level of blood cholesterol is an important determinant of the risk of coronary heart disease . Blood cholesterol can be reduced by dietary means . Although dietitians are trained to provide dietary advice , for practical reasons it is also given by other health professionals and occasionally through the use of self-help re sources . OBJECTIVES To assess the effects of dietary advice given by a dietitian compared with another health professional , or the use of self-help re sources , in reducing blood cholesterol in adults . Now, label each study under the correct category. Ensure that EVERY study is labeled under at least one category. Use square brackets to surround each ID, without explanations, and separate them by commas. Follow the following format. - Core IDs: - Supplementary IDs: